UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Divinylcyclopropane rearrangements : preparation of tricyclic ring systems and a formal total synthesis… Moss, Neil 1985

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
831-UBC_1985_A1 M67_7.pdf [ 11.58MB ]
Metadata
JSON: 831-1.0060519.json
JSON-LD: 831-1.0060519-ld.json
RDF/XML (Pretty): 831-1.0060519-rdf.xml
RDF/JSON: 831-1.0060519-rdf.json
Turtle: 831-1.0060519-turtle.txt
N-Triples: 831-1.0060519-rdf-ntriples.txt
Original Record: 831-1.0060519-source.json
Full Text
831-1.0060519-fulltext.txt
Citation
831-1.0060519.ris

Full Text

DIVINYLCYCLOPROPANE REARRANGEMENTS: PREPARATION OF TRICYCLIC RING SYSTEMS AND A FORMAL TOTAL SYNTHESIS OF (±)-QUADRONE by NEIL MOSS B . S c , U n i v e r s i t y of A l b e r t a , 1981 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n THE FACULTY OF GRADUATE STUDIES (DEPARTMENT OF CHEMISTRY) We accept th is thes is as conforming to the rectuired standard/' THE UNIVERSITY OF BRITISH COLUMBIA September 1985 © N e i l Moss In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department The University of British Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date QcV. °l \ DE-6(3/81) i i ABSTRACT The f i r s t sect ion of th i s thes is describes three model s tudies invo lv ing the synthesis of the d iv inylcyc lopropanes (135), (136), and (137) and the subsequent thermal rearrangement of these compounds to provide the i n t e r e s t i n g t r i c y c l i c compounds (139), (140), and (141). The second sect ion of th i s thes is describes a formal t o t a l synthesis of the antitumor sesquiterpenoid ( ± ) - q u a d r o n e (34). The synthesis i s based on the chemistry developed i n the model studies and involves the thermal rearrangement of the d iv inylcyc lopropane (304) as the key s tep . The r e s u l t i n g product , compound (305), is- subsequently elaborated into the keto aldehyde (230), and since compound (230) has i i i previously been converted into (t)-quadrone (34) by Burke and coworkers,101 the isolation of (230) comprises a formal total synthesis of the sesquiterpenoid. 298 t t O H O 34 230 The third section of this thesis describes a study involving the facile vinylmethylenecyclopropane rearrangement of enolates derived from various 7-exo-vinylbicyclo[4.1.0]heptan-2-ones. ^ i v TABLE OF CONTENTS Page TITLE PAGE i ABSTRACT i i TABLE OF CONTENTS i v LIST OF FIGURES v i i ACKNOWLEDGEMENTS i x ABBREVIATIONS x INTRODUCTION 1 A. General 1 B. The Thermal Rearrangement of 1 , 2 - D i v i n y l c y c l o -propanes: Preparat ion of Seven-Membered Ring Containing Compounds 4 C. The Thermal Rearrangement of 1 , 2 - D i v i n y l c y c l o -propanes: Preparat ion of Compounds Containing B icyc lo [3 .2 .1 ]oc tane and Bicyclo[3 .2 .2]nonane Ring Skeletons 7 D. General Strategies for the Preparat ion of Funct iona l i zed Versions of the B i c y c l i c D i v i n y l cyclopropanes (27), (28), (30), and (31) 10 E . The Thermal Rearrangement of Divinylcyclopropanes Derived from Various E x o - 6 - ( l - A l k e n y l ) b i c y c l o [3.1.0]hexan-2-ones 21 F . The Thermal Rearrangement of Div iny lcyc lopropanes: Exo-7 - (1 -Alkeny l )b icyc lo [4 .1 .0 ]hept -2 -ene Systems 30 G. Conclusion 33 DISCUSSION 34 A. General 34 B. Model Study 1 40 C. Model Study 2 65 D. Model Study 3 73 V Page Synthesis of ( ± ) - Q u a d r o n e INTRODUCTION 95 A. I s o l a t i o n , S t r u c t u r a l E l u c i d a t i o n , and B i o l o g i c a l Propert ies of Quadrone 95 B. Biogenetic O r i g i n of Quadrone 97 C. Previous Synthetic Approaches to Quadrone 100 DISCUSSION I l l A. Synthetic Plan I l l B. Synthetic Studies Directed Towards the Preparat ion of the Div inylcyc lopropane (252) 118 C. Model Study 4 142 D. Modif ied Synthetic Approach to ( i)-Quadrone . . . . 149 The F a c i l e Vinylmethylenecyclopropane Rearrangement of Enolates Derived from Various 7 - E x o - V i n y l b i c y c l o -[4.1.0]heptan-2-ones DISCUSSION 168 EXPERIMENTAL 189 General 189 Model Study 1 191 General Procedure 1 196 General Procedure 2 199 General Procedure 3 200 General Procedure 4 202 General Procedure 5 203 General Procedure 6 206 General Procedure 7 207 vi Page Model Study 2 210 Model Study 3 221 Synthesis of ( ± ) - Q u a d r o n e (34) 240 Model Study 4 265 Synthesis of ( ± ) - Q u a d r o n e cont . 274 Compounds Associated with the Vinylmethylenecyc lo-propane Rearrangement Study 300 REFERENCES 317 v i i LIST OF FIGURES Page Figure 1. The 400 MHz X H nmr spectrum of (148) 51 Figure 2. The 400 MHz X H nmr spectrum of (149) 51 Figure 3. The 400 MHz lE nmr spectrum of (151a) 55 Figure 4. The 400 MHz lE nmr spectrum of (151b) 55 Figure 5. The 400 MHz *H nmr spectrum of a t y p i c a l e x o - v i n y l moiety 60 Figure 6. The 400 MHz *H nmr spectrum of (135) 64 Figure 7. The 400 MHz X H nmr spectrum of (139) 64 Figure 8. The 400 MHz lE nmr spectrum of (152a) 67 Figure 9. The 400 MHz X H nmr spectrum of (152b) 67 Figure 10. The 400 MHz *H nmr spectrum of (136) 71 Figure 11. The 400 MHz X H nmr spectrum of (140) . . 71 Figure 12. The 400 MHz X H nmr spectrum of (150) 79 Figure 13. The 400 MHz X H nmr spectrum of (195) 79 Figure 14. The 400 MHz X H nmr spectrum of (200) 84 Figure 15. The 400 MHz lE nmr spectrum of (201) 84 Figure 16. The 400 MHz X H nmr spectrum of (137) 89 Figure 17. The 400 MHz *H nmr spectrum of (141) 89 Figure 18. The 400 MHz X H nmr spectrum of (261) 126 Figure 19. The 400 MHz *H nmr spectrum of (249) 126 Figure 20. The 400 MHz L H nmr spectrum of (271) 132 Figure 21. The 400 MHz lE nmr spectrum of (304) 153 Figure 22. The 400 MHz lK nmr spectrum of (306) 153 Figure 23. The 400 MHz X H nmr spectrum of (299) 165 v i i i Page Figure 24. The 400 MHz lR nmr spectrum of (300) 165 Figure 25. The 400 MHz X H nmr spectrum of (230) 167 I i x ACKNOWLEDGEMENTS The four or more years of labor that are associated with obtaining a graduate degree do not pass without one developing meaning-f u l f r i endships and r e l a t i o n s h i p s , and i t i s to these people that I take the p r i v i l e g e of dedicat ing th i s page. I am foremost indebted to my research supervisor Professor Edward Piers who taught me how to think properly about chemistry and i n a d d i t i o n , made me r e a l i z e how much more th inking I s t i l l need to do. I am also indebted to Drs . Ian Suckl ing and Michael Chong for passing on t h e i r years of acquired wisdom and for making me r e a l i z e that the ego has no place i n the l earn ing of proper laboratory technique. I am a lso g r a t e f u l for the i n t e l l e c t u a l d iscuss ions and the companionship that I have had with Peter Marrs , Ashwin Gaval , Grace Jung, Brian Keay, and the other members of Dr . P i e r s ' group. Together we slowly learned the virtuousness of patience and perseverance. I would l i k e to extend s p e c i a l thanks to Peter Marrs and Rick Fr ie sen for t h e i r d i l i g e n t proof reading, and to the t echn ica l s t a f f at UBC for t h e i r cheerfu l recording of a l l my s p e c t r a l data . I thank these people for t h e i r time and e f f o r t and for enduring my "learned patience". 5 X ABBREVIATIONS The fo l lowing abbreviat ions have been used throughout th i s t h e s i s : Ac = a c e t y l br = broad Bu = buty l d = doublet DMF = dimethylformamide DMSO = dimethyl su l fox ide equiv = equivalent(s ) Et = e thy l g l c = gas l i q u i d chromatography HMPA = hexamethylphosphoramide i r = i n f r a r e d LAH = l i t h i u m aluminum hydride LDA = l i t h i u m di isopropylamide m = m u l t i p l e t MCPBA = m-chloroperoxybenzoic ac id Me = methyl mp = melting point 2N or 3N = two neck or three neck NBS = N-bromosuccinimide NIS = N-iodosuccinimide nmr = nuclear magnetic resonance x i PCC = pyr id in ium chlorochromate Py = pyr id ine RB = round bottomed q = quartet s = s ing l e t t = t r i p l e t TBAF = tetra-n-butylammonium f l u o r i d e THF = tetrahydrofuran THP = tetrahydropyran t i c = th in layer chromatography TMEDA = tetramethylethylenediamine TMS = t r i m e t h y l s i l y l Ts = p - to luenesu l fony l w = weak X = times (2X = two times) x i i To the i n s t r u c t o r s at RDC with respect and gratitude 1 INTRODUCTION A. General Upon surveying the large number of organic syntheses that have appeared over the years, one cannot help but marvel at some of the amazing displays of synthetic inventiveness shown. Considering the immense s t r u c t u r a l complexity of some of the molecules synthesized, i t becomes a challenge to understand how synthetic organic chemists devise th e i r s t r a t e g i e s . While learning organic synthesis, a student i s taught to examine a target molecule i n terms of a suitable retrosynthetic a n a l y s i s . 1 This analysis involves the " l o g i c a l " disconnection of the target molecule into progressively simpler molecules u n t i l a disconnection produces a compound that i s either widely known or commercially a v a i l a b l e . The synthesis then involves the systematic construction of the planned intermediates through the a p p l i c a t i o n of established chemical reactions. Upon reapplying t h i s form of analysis to published syntheses, one immediately begins to gain insight into the planning process used by many organic chemists. However i t also becomes apparent that some retrosynthetic disconnections do not appear to be quite so " l o g i c a l " as others. With retrosynthetic plans involving bond cleavages at unexpected s i t e s and others a c t u a l l y involving the production of precursors more complex than their targets, one begins to wonder how such plans could ever have arisen. 2 Quite o f ten , these syntheses invo lv ing unexpected synthet ic plans ar i se from a chemist applying a new chemical reac t ion or synthet ic strategy that he or she has dev i sed . Wanting to demonstrate the general a p p l i c a b i l i t y of his or her new method, a synthesis i s designed around a key step invo lv ing the newly developed chemistry. L i k e l y , as th i s new method becomes more widely used, i t s appearance i n other synthet ic plans w i l l not seem so unusual . New synthet ic s trateg ies which are perhaps the most d i f f i c u l t to envisage as obvious choices of d isconnect ion i n re trosynthe t i c planning are the mul t ip l e bond forming processes associated with thermal and photochemical r e a c t i o n s . New ingenious methods such as Oppolzer and coworkers' thermal magnesium-ene r e a c t i o n 2 (Scheme 1) and Wender and coworkers' photochemical a r e n e - o l e f i n c y c l o a d d i t i o n 3 (Scheme 2) have each been appl ied to the synthesis of complex natura l products . However, the novelty and complexity of the transformations involved i n each of these s trateg ies c e r t a i n l y does not make them obvious choices i n re trosynthe t i c p lanning . In f a c t , just fo l lowing what i s happening i n the reac t ion alone becomes a task i n i t s e l f . Scheme 1 3 Oppolzer and coworkers' method (Scheme 1) involved the treatment of the a l l y l i c ch lor ide (1) with magnesium and heating the r e s u l t i n g Grignard compound to effect a h igh ly novel intramolecular magnesium-ene r e a c t i o n . The c y c l i z e d product was then reacted i n s i t u with Mo05*HMPA to a f ford (2). This compound was subsequently elaborated to 12-acetoxysinularene (3). Scheme 2 Wender and coworkers' strategy involved the remarkable i n t r a -molecular arene-o le f in c y c l o a d d i t i o n of (4) to y i e l d the h ighly func t iona l i zed adduct (_5), which was in turn further elaborated to provide the complex tr iquinane natura l product c o r i o l i n (6). Another not so obvious, but nevertheless useful synthet ic s trategy is the use of the thermal rearrangement of 1,2 - d i v i n y l -cyclopropanes. Like the two s trateg ies just shown, the appl i ca t ions of th i s rearrangement may also be d i f f i c u l t to fol low at f i r s t , but hope-f u l l y as the reader becomes more f a m i l i a r with i t s use, the syntheses and thermal rearrangement of 1,2-divinylcyclopropanes w i l l become c l e a r , and the rearrangement's u t i l i t y as a v iab le synthet ic strategy w i l l become apparent. 4 B . The Thermal Rearrangement of 1 ,2 -Div inylcyc lopropanes: Preparat ion  of Seven-Membered Ring Containing Compounds. The thermal rearrangement of 1 ,2 -d iv inylcyc lopropanes to cycloheptadienes , a f a c i l e process due to r e l i e f of r ing s t r a i n , i s a reac t ion that has been known for more than 25 y e a r s . 4 - 6 The simplest system, c i s - 1 , 2 - d i v i n y l c y c l o p r o p a n e (7) , rearranges so e a s i l y i t s i s o l a t i o n i s d i f f i c u l t even at temperatures below - 2 0 ° C ( h a l f - l i f e 7.5 min at 2 0 . 4 ° C ) . 5 » 7 ~ 1 0 Mechanist ic studies ind ica te that th i s rearrangement, along with other c i s - 1 , 2 - d i v i n y l c y c l o p r o p a n e rearrangements , occur i n a concerted manner invo lv ing a b o a t - l i k e t r a n s i t i o n state (A) in which the two v i n y l groups are pos i t ioned over the cyclopropane r i n g (Scheme 3) . Scheme 3 5 Trans -1 ,2 -d iv iny lcyc lopropane (8) , on the other hand, being p h y s i c a l l y unable to a t t a i n the geometry required for rearrangement, i s far more stable than the corresponding c i s - i somer (7_). At temperatures around 1 9 0 ° C , though, the trans-isomer also rearranges to 1 , 4 - c y c l o -h e p t a d i e n e . 1 * » 6 Mechanist ic studies suggest that t h i s r eac t ion occurs v i a a rate determining i somer izat ion of (8) to the corresponding c i s - i somer (7_) followed by the usual concerted rearrangement. Though the mechanism of i somer izat ion i s not thoroughly understood, the * intermediacy of a s t a b i l i z e d d i r a d i c a l (B) i s postulated . The d iv iny lcyc lopropane rearrangement has not gone unnoticed by synthet ic organic chemists as a method of synthes iz ing compounds containing seven-membered r i n g s . Developmental w o r k 2 5 - 3 3 s tarted to appear i n the middle 1970s, and shor t ly afterwards, syntheses of seven membered r ing containing natura l products fo l lowed. The rearrangement of the d iv iny lcyc lopropanes (9)-(14) to the cycloheptadienes (15)-(20) were the key steps i n the syntheses shown i n Scheme 4. F i r s t appl ied to the synthesis of the monocyclic cycloheptane na tura l p r o d u c t s 3 1 * - 3 7 (eg. dictyopterene D' ( 1 5 ) 3 7 ) , more h ighly developed methodology was l a t e r appl ied to the syntheses of R-himachalene ( 2 1 ) , 3 8 damsinic ac id (22) , 3 1 * c o n f e r t i n (23) , 3 9 and karahanaenone ( 2 4 ) . 1 1 0 The d iv iny lcyc lopropane rearrangement was also appl ied in synthet ic studies d irec ted towards the synthesis of phorbol ( 2 5 ) 4 1 and p o r t u l a l ( 2 6 ) . 1 + 2 For examples of the rearrangement of various c i s - and trans -1 ,2-d iv inylcyc lopropanes and the ir mechanistic impl icat ions see r e f s . 11-24. Refs . 13 and 14 are reviews. 7 Scheme 4 cont. 14 20 26 C. The Thermal Rearrangement of 1 ,2 -Div iny lcyc lopropanes: Preparat ion  of Compounds Containing Bicyc lo [3 .2 .1 ]oc tane and B i c y c l o [ 3 . 2 . 2 ] - nonane Ring Skeletons. Extensions of c i s - 1 , 2 - d i v i n y l c y c l o p r o p a n e (7_) are the b i c y c l i c analogues 6-endo-v inylbicyc lo[3 .1 .0]hex-2-ene (28)**3> and 7-endo-v iny lb icyc lo [4 .1 .0 ]hept -2 -ene ( 3 1 ) 2 0 . Like (7) , (28) and (31) are a lso only i s o l a b l e at lower temperatures ( h a l f - l i f e of (28) i s ~ 1 day at 25°C 1 *'*) . However, in these two cases the f a c i l e rearrangement of (28) and (31) produces the s t r u c t u r a l l y more complex b i c y c l i c dienes b i c y c l o -[3 .2 .1]octa-2 ,6-diene (29) and b icyc lo [3 .2 .2 ]nona-2 ,6 -d iene (32) (Scheme 5 ) . 8 Scheme 5 3 0 31 32 The corresponding exo-isomers ( 2 7 ) 1 8 and ( 3 0 ) 2 0 a lso behave l i k e t h e i r counterpart t rans -1 ,2 -d iv iny l cyc lopropane (8) . They are both stable at ambient temperatures, but rearrange smoothly to the correspon-ding b i c y c l i c dienes at elevated temperatures ( 1 9 5 ° C for ( 2 7 ) 1 8 and 160°C for ( 3 0 ) 2 0 ) » For the d iv iny lcyc lopropane (27), th i s process was shown to occur v i a a one-center epimerizat ion to the endo-isomer (28) followed by a rapid rearrangement to the b i c y c l i c diene ( 2 9 ) . 1 8 Considering the large array of na tura l products that contain a b icyc lo [3 .2 .1 ]oc tane ske leton, i l l u s t r a t e d by the sesquiterpenoids , s inularene (33) 1 4 5 , quadrone (34) 1* 6 , zizaene ( 3 5 ) 4 7 , 9- isocyano-pupukeanane (36) ** 8, and cedrene (37_) 4 9 , the a p p l i c a t i o n of a d iv inylcyc lopropane rearrangement of th i s type seems very a t t r a c t i v e . For reports on the i s o l a t i o n and synthet ic work done on the l i s t e d sesquiterpenes see r e f s . 45-49 and the r e f s . quoted t h e r e i n . 9 3 7 3 8 Natural products containing a bicyclo[3.2.2]nonane skeleton, on the other hand, are quite rare. The rotundene analogue (38) 5 0» 5 1 is one of the few documented examples. However, functionalized versions of (32) could provide valuable intermediates that might prove suitable for further elaboration to other classes of natural products (e.g. see ref. 52). Despite the attractiveness of this strategy for the preparation of bicyclo[3.2.1]octane and bicyclo[3.2.2]nonane ring systems, l i t t l e 10 i n v e s t i g a t i o n had been done i n th i s area p r i o r to work s tar ted in our l abora tory . Perhaps one major contr ibut ing reason for th i s was the somewhat formidable challenge associated with the synthesis of s u i t a b l y funct iona l i zed versions of the divinycyclopropanes ( 2 7 ) , (28), (30), or (31). D. General Strateg ies for the Preparat ion of Funct iona l i zed Versions  of the B i c y c l i c Divinylcyclopropanes (27) , (28) , (30), and (31) . The synthesis of the endo-divinylcyclopropane ( 2 8 ) 4 L f > 1 8 was accomplished by a Wi t t i g methylenation of the aldehyde (39) which was i n turn unexpectedly produced in a peracid ox idat ion of norbornadiene (40) (Scheme 6 ) . The corresponding exo-div inylcyclopropane ( 2 7 ) 1 8 was made Scheme 6 D 28 39 40 27 41 11 v i a an epimerizat ion of the aldehyde (39) with sodium methoxide, followed by a W i t t i g methylenation of the r e s u l t i n g exo-eplmer (41) . Subsequent i n v e s t i g a t i o n s 5 3 - 5 6 involved the synthesis and r e a r -rangement of analogues of the compound (28) that were subst i tuted at the D and/or H pos i t ions (Scheme 7 ) . The syntheses of the compounds (42a- i ) a l l r e l i e d on the reac t ion sequence depicted i n Scheme 6; the only exten-sions being the use of d i f f e r e n t condensation react ions on the aldehyde (39) and the use of 7-tert-butoxynorbornadiene as the s t a r t i n g m a t e r i a l . Scheme 7 42 43 a ) 5 3 R l , 2 H, R 3 = OMe b) R l , 3 = H, R 2 - OMe C) 5" R l , 2 = H, = COOH d) R l , 3 = H, R 2 = COOH R l = O - t - B u , R 2 = H, R 3 = COOH f) R l O - t - B u , R 2 = COOH, R 3 - H R l , 2 = H, R^ = COOEt h R l , 3 = H, R 2 - COOEt i ) 5 6 R l = H > R 2 , 3 = CH 3 12 The exo- and endo-divinylcyclopropanes (30) and (31) were synthesised in a reac t ion that involved the thermal decomposition of the b i c y c l i c d i v i n y l - A ^ - p y r a z o l i n e (44)• The compound (44) i n turn was made by a 1 ,3 -d ipo lar cyc loadd i t i on of 3-diazo- l -propene to 1 ,3 - cyc lo -hexadiene (Scheme 8 ) 2 0 . Scheme 8 3 0 Both of the methods just discussed are f a i r l y l i m i t e d i n t h e i r p o t e n t i a l to provide the more d i v e r s e l y f u n c t i o n a l i z e d b i c y c l i c compounds that would be necessary for e laborat ion to any of the na tura l products depicted e a r l i e r . A d d i t i o n a l methods for the preparat ion of b i c y c l i c d iv inylcyc lopropanes would have to be developed i n order for the d iv inylcyc lopropane rearrangement to become a v iab l e s trategy in natura l product synthes i s . The r e a l i z a t i o n , introduced with the compounds (42a) and (42b), that one of the v i n y l groups of the d iv iny lcyc lopropane can be i n the form of an enol ether i s a valuable extension. By applying th i s strategy to the i n t e r n a l double bond of (27) and (30) i n such a manner 13 shown in Scheme 9, the enol ethers (45) and (49) should thermally rearrange to the enol ethers (46) and (5Q)t r e s p e c t i v e l y . Hydrolysis of these r e s u l t i n g enol ethers should i n turn provide the ketones (47) and (51). Containing two d i f f e r e n t functional groups, the b i c y c l i c compounds (47) and (51) become p o t e n t i a l l y useful intermediates for 29 30 1-32 52 0 51 14 further e l a b o r a t i o n . The preparat ion of the ketones (48) ( 6 - e x o - v i n y l -bicyclo[3.1 .0]hexan-2-one) and (52) ( 7 - exo -v iny lb i cyc lo [4 .1 .0 ]heptan-2-one), the most obvious precursors to the enol ethers (45) and (49), opens up several new avenues of synthet ic approach. Due to extensive work d irec ted towards the synthesis of prostaglandins , two approaches towards v i n y l c y c l o p r o p y l ketones l i k e (48) and (52) had already been reported . Corey and W o l l e n b e r g 5 7 synthesized the compound (48) as a s t a r t i n g mater ia l in a prostaglandin synthes i s . Their approach involved the add i t ion of the cuprate (53) to 2-cyclopenten- l -one followed by conversion of the r e s u l t i n g te trahydro-pyranyl ether (54) in to the mesylate (55). Base promoted c losure of compound (55) afforded the v i n y l c y c l o p r o p y l ketone (48) (Scheme 10). The preparat ion of the v i n y l c y c l o p r o p y l ketone (52) should be f eas ib l e by applying the same sequence of react ions to 2-cyclohexen- l -one . Scheme 10 15 This strategy appears a t t r a c t i v e because i t o f f e r s f l e x i b i l i t y i n the choice of the s t a r t i n g enone. This f l e x i b i l i t y should allow for the preparation of a range of vinylcyclopropyl ketone skeletons not necessarily r e s t r i c t e d to the two examples shown. Scheme 11 16 In work also connected with prostaglandin synthes i s , Kondo and coworkers 5 8 and T a b e r 5 9 independently reported the preparat ion of the v i n y l c y c l o p r o p y l ketone (59)• Later an extension of th i s work by Kondo and coworkers led to the synthesis of the v i n y l c y c l o p r o p y l ketone (63) (Scheme 11). Their s trateg ies involved the reac t ion of the d ian ion of methyl acetoacetate with e i ther the a l l y l i c bromide (56) or the conjugated aldehyde (60), followed by conversion of the r e s u l t i n g p-keto esters (57) and (61) into the corresponding diazo compounds (58) and (62). Copper catalyzed intramolecular carbenoid a d d i t i o n 6 1 provided the v i n y l c y c l o p r o p y l ketones (59) and (63). This intramolecular carbenoid add i t ion strategy was a lso appl ied to the synthesis of the v i n y l c y c l o p r o p y l ketone (48) which was prepared by the copper cata lyzed r i n g c losure of the diazoketone (64) (Scheme 12). Scheme 12 This approach appears a t t r a c t i v e because i t o f fers f l e x i b i l i t y i n in troduc ing f u n c t i o n a l i t y at several s i t e s on the b icyc lo[3 .1 .0]hexane r i n g ske le ton. This i s most not iceable with respect to the 6 -exo-v iny l moiety ( p o s i t i o n H) . Corey and Wollenberg's approach, i n c o n t r a s t , i s 17 p r i m a r i l y l i m i t e d to the parent 6 -exo-v iny l group. However, the intramolecular carbenoid addi t ion strategy seems l i m i t e d to the preparat ion of the b icyc lo [3 . l .OJhexane r ing systems, since r e a c t i o n of the diazoketone (65) (Scheme 13) indicates that attempts to extend th i s strategy to the b icyc lo[4 .1 .0]heptane r ing systems w i l l l i k e l y produce an i n s e r t i o n adduct l i k e the compound ( 6 6 ) . 6 2 Scheme 13 Another approach to v i n y l c y c l o p r o p y l ketones l i k e (27) and (30) which has not been d i r e c t l y a p p l i e d , but nevertheless appears v i a b l e , involves the e laborat ion of products derived from the add i t i on of dibromocarbene to various c y c l i c a l l y l i c e t h e r s . 6 6 P iers and coworkers, inves t iga t ing the homo-[ l ,5] -s igmatropic hydrogen m i g r a t i o n , 6 3 * 6 4 synthesized several test substrates using dibromocarbene a d d i t i o n s , two of which happened to be the compounds (72) and (76) . The synthesis of the compound (72) i s de ta i l ed in Scheme 14. 18 Scheme 14 6 8 6 9 7 0 7 3 7 2 71 i i i 7 5 4 8 74 7 6 The addition of dibromocarbene to the a l l y l i c ether (68) produced the dibromocyclopropane (69). Selective removal of the exo-bromine atom with t r i - n - b u t y l t i n hydride provided the endo-bromide intermediate (70). Treatment of (70) with t e r t - b u t y l l i t h i u m and trapping of the r e s u l t i n g anion with dimethylformaraide yielded the aldehyde (71). Compound (71) 19 was subsequently converted into the alkene (72) by a W i t t i g methylena-t i o n . A s i m i l a r set of react ions was used for the preparat ion of the compound (76) . The conversion of the compound (72) into the e n d o - v i n y l -cyc lopropy l ketone (73) by an extension of th i s sequence seems reasonable. With l i t e r a t u r e precedent for the epimerizat ion of the endo-aldehyde (71) into the exo-aldehyde ( 7 4 ) , 1 8 the synthesis of the exo -v iny l cyc lopropy l ketone (48) also seems reasonable v i a th i s s trategy . In a d d i t i o n , a method has been reported that ind ica tes the p o s s i b i l i t y of the predominant formation of the exo-bromide (75) from the dibromocyclopropane ( 6 9 ) 6 5 . This would al low the d i r e c t synthesis of the e x o - v i n y l c y c l o p r o p y l ketone (48) v i a an a p p l i c a t i o n of the same reac t ion sequence. A l l i n a l l , th i s s trategy appears quite a t t r a c t i v e . A wide choice of c y c l i c a l l y l i c ethers are r e a d i l y a v a i l a b l e as s t a r t i n g m a t e r i a l s , and the reac t ion sequence o f fers the opportunity to introduce a d d i t i o n a l f u n c t i o n a l i t y that may be required i n a t o t a l synthes i s . An a d d i t i o n a l approach to v i n y l c y c l o p r o p y l ketones l i k e (48) and (52), which complements the dibromocarbene strategy jus t described but l ikewise has not yet been d i r e c t l y a p p l i e d , involves the e laborat ion of products derived from the carbenoid a d d i t i o n of e thy l diazoacetate to various c y c l i c a l l y l i c e thers . The carbenoid add i t ion of e thy l diazoacetate to alkenes i s a reac t ion that has been known for many y e a r s , 6 6 and with the advent of new h igh ly e f f i c i e n t c a t a l y s t s , 6 7 th i s react ion i s becoming i n c r e a s i n g l y usefu l s y n t h e t i c a l l y . A l o g i c a l r eac t ion sequence (Scheme 15) could involve the 20 reaction of ethyl diazoacetate with a c y c l i c a l l y l i c ether such as (77) , followed by the elaboration of the r e s u l t i n g cyclopropyl ester product (78) to the corresponding v i n y l compound (79). Conversion of (79) to the v i n y l c y c l o p r o p y l ketone (52) should be straightforward. This approach appears just as a t t r a c t i v e as the dibromocarbene approach described e a r l i e r . It of f e r s the same choice of s t a r t i n g c y c l i c a l l y l i c ethers, and i t o f f e r s plenty of opportunity for the introduction of additional f u n c t i o n a l i t y . Scheme 15 52 79 21 E . The Thermal Rearrangement of Divinylcyclopropanes Derived From  Various Exo-6 - ( l -Alkeny l )b icyc lo [3 .1 .0 ]hexan-2-ones I n i t i a l work in our l a b o r a t o r y 6 8 revolved around the thermal rearrangement of d iv inylcyc lopropanes that were derived from e x o - 6 - v i n y l b i c y c l o [ 3 . 1 « 0 ] h e x a n - 2 - o n e s l i k e compound (48). The synthet ic approach used for the preparat ion of these compounds u t i l i z e d the intramolecular carbenoid add i t ion methodology shown previous ly i n Scheme 11. Reaction of the a l l y l i c hal ides (80) - (82) with the d ianion of methyl acetoacetate , followed by d i a z o t i z a t i o n of the r e s u l t i n g B-keto esters and subsequent copper catalyzed carbenoid a d d i t i o n , e f f i c i e n t l y provided the v i n y l c y c l o p r o p y l ketones (83) - (85) (Scheme 16). This sequence success fu l ly introduced f u n c t i o n a l i t y at the A, E and H pos i t ions on the v i n y l c y c l o p r o p y l ske le ton. The v i n y l c y c l o p r o p y l ketone (85) was a d d i t i o n a l l y func t iona l i zed at the C p o s i t i o n by react ion with l i t h i u m di isopropylamide (LDA) and trapping of the r e s u l t i n g enolate with methyl i o d i d e . 22 Scheme 16 8 3 8 4 8 5 8 6 23 The second required v i n y l group was then introduced in the form of a t e r t - b u t y l d i m e t h y l s i l y l enol ether. This type of enol ether was chosen because of i t s ease of preparation and because of i t s r e l a t i v e l y high s t a b i l i t y during routine handling. Thus, treatment of the ketones (83)-(86) with LDA in THF at -78°C, followed by trapping of the re s u l t i n g enolates with t e r t - b u t y l d i m e t h y l s i l y l chloride, produced the divinylcyclopropanes (87)-(90), respectively, i n e s s e n t i a l l y quantitative y i e l d s . Thermal rearrangement of these enol ethers i n re f l u x i n g xylene (bp 138°C) or mesitylene (bp 165°C) proceeded smoothly and cleanly i n each case to give the rearranged enol s i l y l ethers (91)-(94), each i n greater than 90% y i e l d . Regeneration of the ketone group to afford the compounds (95)-(98) was accomplished by treatment of the corresponding enol s i l y l ethers with anhydrous potassium f l u o r i d e . This i n i t i a l study c l e a r l y demonstrated the ease of preparation of bicyclo[3.2.ljoctane ring systems functionalized at the A, C, E and H p o s i t i o n s . An important aspect of this thermal rearrangement centered around i t s s t e r e o s p e c i f i c i t y . The previously shown rearrangement of the endo-6-vinylbicyclo[3.1.0]hex-2-enes (42g) and (42h) (Scheme 7) to give the bicyclo[3.2.1]octadiene products (43g) and (43h), respectively, demonstrated that this rearrangement was s t e r e o s p e c i f i c . That i s , the stereochemistry about carbon H in (42g) and (42h) was translated into the stereochemistry about carbon H i n (43g) and (43h). This stereo-s p e c i f i c i t y , though implied by investigations done on simple divinylcyclopropane systems, 2 2 had not been demonstrated for the corresponding exo-6-vinylbicyclo[3.1.0]hex-2-enes. 24 The rearrangement of the exo-div inylcyclopropane (87) as a s ing le compound containing a t rans -or iented methyl subst i tuent on carbon H, did proceed c leanly to give only one b icyc lo [3 .2 .1 ]oc tad iene isomer. In isomers about carbon H, did produce the corresponding b i c y c l o [ 3 . 2 . 1 ] -octadiene product (91) also as a 1:1 mixture of isomers about carbon H. Though t h i s reac t ion d id provide evidence for the s t e r e o s p e c i f i c i t y of the rearrangement, i t was not the most r igorous of examples. A more in-depth i n v e s t i g a t i o n was undertaken to further test the s t e r e o s p e c i f i c i t y of the rearrangement and also to test what e f fect a large c i s - o r i e n t e d subst i tuent on carbon H might have on the s tereo-s p e c i f i c i t y of the reac t ion and indeed on the v i a b i l i t y of the rearrangement i t s e l f . The s tructure (99) shows the geometry a d i v i n y l -cyclopropane molecule must adopt before rearrangement can occur . It can be seen that s i g n i f i c a n t s t e r i c i n t e r a c t i o n i s involved between the c i s -oriented subst i tuent on carbon H and the hydrogen atom on carbon D, e s p e c i a l l y when the c i s - s u b s t i t u e n t i s bu lky . This i n t e r a c t i o n would indeed be expected to impede the rearrangement i f not prevent i t a l l together. a d d i t i o n , the exo-div inylcyc lopropane (87) as a 1:1 mixture of methyl H 99 25 To examine th i s quest ion, the d iv iny lcyc lopropanes (103) and (108), each containing a bulky i sopropy l group on carbon H, were synthesized as shown in Scheme 1 7 . 6 9 The d ianion of methyl acetoacetate was a lky la ted with the a l l y l i c bromide (100). The' B-keto ester (101) was treated with tosy laz ide and t r i e thy lamine , and the r e s u l t i n g diazo compound was converted into the v i n y l c y c l o p r o p y l ketone (102) by a copper(II) acetoacetate catalyzed intramolecular carbenoid a d d i t i o n . Enol s i l y l ether formation of (102) provided the d iv iny lcyc lopropane (103), a test substrate with a t rans -or i ented subst i tuent on carbon H. The synthesis of the d iv iny lcyc lopropane (108) containing a c i s -or iented i sopropy l group was c a r r i e d out in a d i f f e r e n t manner. The a l l y l i c a l coho l (104) was heated with t r i e thy lor thoace ta te and a c a t a l y t i c amount of propanoic acid to form the ester (105). Compound (105) was then converted into the diazo ketone (106) by a standard sequence of react ions invo lv ing hydro lys i s of the ester moiety with potassium hydroxide, conversion of the r e s u l t i n g carboxy l i c ac id to an acid c h l o r i d e , and subsequent reac t ion of the ac id c h l o r i d e with d i a z o -methane. Copper(II) acetoacetate catalyzed intramolecular carbenoid addi t ion provided the keto acetylene (107) . The d iv iny lcyc lopropane (108) was then formed by c a t a l y t i c hydrogenation of (107) followed by enol s i l y l ether formation of the r e s u l t i n g keto alkene. With both test substrates synthesized, t h e i r thermal rearrange-ments were examined. Heating of the d iv iny lcyc lopropane (103) i n benzene for 2 h at 200°C c leanly provided the rearranged product (109) i n greater than 95% y i e l d (Scheme 18). The geometr ica l ly isomeric d iv inylcyc lopropane (108) also rearranged c l e a n l y , though not unexpec-26 Scheme 17 108 27 t e d l y , more f o r c i n g condit ions were required to ef fect i t s rearrangement (benzene, 2 4 0 ° C , 4.5 h ) . The rearranged product (110) was obtained in a 93% y i e l d . These two examples supply very good evidence to support that the thermal rearrangement of exo -6 - ( l -a lkeny l )b icyc lo [3 .1 .0 ]hex -2 -enes occurs s t e r e o s p e c i f i c a l l y . The conversion of (108) into (110) also shows that the rearrangement i s v iab l e even with substrates possessing a bulky c i s - o r i e n t e d subst i tutent on carbon H of the d iv iny lcyc lopropane system. Scheme 18 The pre l iminary inves t iga t ions just discussed provided the foundation for a planned synthesis of the novel sesquiterpenoid s inularene (33). **5 This work was the f i r s t reported a p p l i c a t i o n of a d iv inylcyc lopropane rearrangement to the synthesis of a b i c y c l o [ 3 . 2 . 1 ] -octane containing natura l product . 29 As shown in Scheme 19, the a l l y l i c a lcohol (111) was heated with t r i e thy lor thoace ta te in the presence of a c a t a l y t i c amount of propanoic ac id to form the ester compound (112). The ester group i n (112) was modified to the diazo ketone group i n (113) by a standard sequence of react ions described i n Scheme 17. Copper(II) acetoacetate catalyzed intramolecular carbenoid addi t ion produced the keto acetylene (114), which when subjected to c a t a l y t i c hydrogenation provided the v i n y l c y c l o -propyl ketone (115). The enone (116) was then synthesized by treatment of (115) with t r i m e t h y l s i l y l iodide and tr ie thylamine followed by reac t ion of the r e s u l t i n g enol s i l y l ether with pal ladium(II) acetate . Conjugate add i t ion of l i t h i u m d iv iny l cupra te to the enone (116) gave the ketone (117) as the major product, and th i s mater ia l was subsequently converted into the d iv iny lcyc lopropane (118) by treatment of (117) with LDA and trapping of the r e s u l t i n g enolate with t e r t - b u t y l d i m e t h y l s i l y l c h l o r i d e . Heating the d iv iny lcyc lopropane (118) for 4.5 h at 220°C i n benzene c leanly produced the b icyc lo [3 .2 .1 ]oc tad iene product (119) . With the success ful completion of the key step of the synthes i s , the e x i s t i n g f u n c t i o n a l i t y was then modified to complete the t o t a l synthes i s . Thus, reac t ion of (119) with dis iamylborane, followed by oxidat ive workup of the r e s u l t i n g borane, s e l e c t i v e l y gave the a lcoho l (120). To construct the las t r i n g , the a lcohol (120) was treated with to sy l ch lor ide and 4-dimethylaminopyridine to provide d i r e c t l y the ketone (121) . The synthesis was completed by c a t a l y t i c hydrogenation of the double bond i n (121), followed by a W i t t i g methylenation of the r e s u l t i n g ketone. A couple of points to note in th i s synthesis include the success-30 f u l in t roduc t ion of f u n c t i o n a l i t y at carbon D of the b i c y c l o [ 3 . 1 . 0 ] -hexan-2-one skeleton and the absence of any homo-[ l .5] -s igmatropic hydrogen migrat ion of the d iv iny lcyc lopropane (118) to the h i g h l y subst i tuted cyclopentene (122) (Scheme 20). This type of side r e a c t i o n had been observed i n other s y s t e m s . 7 0 C l e a r l y th i s synthesis e legant ly i l l u s t r a t e d the p o t e n t i a l of d iv iny lcyc lopropane rearrangements as a valuable strategy for synthes iz ing n a t u r a l products conta in ing a b icyc lo [3 .2 .1 ]oc tane ske le ton. Scheme 20 118 122 F . The Thermal Rearrangement of Div iny lcyc lopropanes; Exo- 7 - ( l - A l k e n y l ) b i c y c l o [ 4 . 1 . 0 ] h e p t - 2 - e n e Systems. Another b r i e f i n v e s t i g a t i o n from our l a b o r a t o r y 7 1 centered around the thermal d iv inylcyc lopropane rearrangement of the e x o - 7 - ( l - a l k e n y l ) b icyc lo[4 .1 .0]hept-2-enes of general s tructure represented by (123). Though these systems are not l i k e the s tructure (49) discussed e a r l i e r (Scheme 9) , that i s , a s tructure with the i n t e r n a l double bond of the 31 The d iv inylcyc lopropanes (123), having an external enol ether as one of the v i n y l moie t ies , were derived from the corresponding ketones (124). The method used to synthesize the ketones (124) i s out l ined i n Scheme 21, and i s based on a dibromocarbene approach s i m i l a r to that discussed previous ly in Scheme 14. Thus, add i t i on of dibromocarbene to 1,3-cyclohexadiene produced the dibromocyclopropane (125) . Predominant removal of the exo-bromide was accomplished by treatment of (125) with z inc and ace t i c a c i d . Reaction of the product (126) with t e r t -b u t y l l i t h i u m , trapping of the r e s u l t i n g anion with the carboxy l i c ac id sa l t s (127a-g), and subsequent epimerizat ion of the r e s u l t i n g ketones, afforded the v i n y l c y c l o p r o p y l ketones (128a-g), r e s p e c t i v e l y . The ketones (128a-g) were then converted into the ir corresponding enol s i l y l ethers (d iv inylcyc lopropanes) (129a-g) by reac t ion with LDA and trapping of the r e s u l t i n g enolates with t r i m e t h y l s i l y l c h l o r i d e . Heating of the d iv inylcyc lopropanes (129a-g) (benzene, 2 4 0 ° C , 6-12 h) and acid hydro-l y s i s of the r e s u l t i n g rearranged products provided the b i c y c l o[3 . 2 . 2 ] -non-6-en-3-ones (130a-g) in y i e l d s ranging from 50-80%. 32 Scheme 21 T M S O A 3 Br « 2 or 130 125 o r T M S O \J 129 >V3 126 ') IBuLi RCOOLi 127 2) KO-f-128 a) R = b) R = cyclo-C 3H 5 c) R s cyclo-Cj^Hy d) R z= cyclo-C 5H 9 e) R CS c y c l o - C 6 H n f ) R GE c y c l o - C 7 H 1 3 b) n c) n d) n e) n f ) n 3 4 5 6 7 a-E) R : = H, R 2 = CH 3 a-Z) R1 - CH 3, R 2 = H 33 The successful rearrangement of (129a-E) and (129a-Z) provided a d d i t i o n a l evidence for the general s t e r e o s p e c i f i c i t y of the d i v i n y l -cyclopropane rearrangement, while the success ful rearrangement of the d iv inylcyc lopropanes (129b-f) further demonstrated the success of the reac t ion even with substrates containing bulky c i s - o r i e n t e d s u b s t i t u -ents on the exo -v iny l moiety. As w e l l , th i s study extended the general a p p l i c a b i l i t y of the method to the synthesis of f u n c t i o n a l i z e d b i c y c l o -[3.2.2]nonane systems. G. Conclusion Aside from the work about to be described in the next sect ion of th i s t h e s i s , the previous d i scuss ion has b r i e f l y covered most of the synthet ic work published to date on the a p p l i c a t i o n of d i v i n y l c y c l o -propane rearrangements. Because of the p o t e n t i a l th i s rearrangement has shown as a key strategy i n natura l products synthes i s , i t was decided to explore a d d i t i o n a l methods for the preparat ion of func t iona l i zed d iv inylcyc lopropanes and to extend the a p p l i c a t i o n of the rearrangement to the synthesis of use fu l t r i c y c l i c r ing systems. 34 DISCUSSION A . General Because of the p o t e n t i a l the d iv iny lcyc lopropane rearrangement showed i n providing func t iona l i zed b icyc lo [3 .2 .1 ]oc tane and b i c y c l o -[3.2.2]nonane r ing systems, i t was envisioned that an extension of t h i s method to the d i r e c t cons truct ion of t r i c y c l i c r ing systems containing a b icyc lo [3 .2 .1 ]oc tane or bicyclo[3 .2 .2]nonane substructure would be s y n t h e t i c a l l y v a l u a b l e . This idea was f i r s t implemented with the rearrangement of the d iv inylcyc lopropanes ( 1 2 9 b - f ) . 7 1 Compounds (130b-f) , formed af ter hydro lys i s of the rearranged enol s i l y l ethers (Scheme 21), each contained a b icyc lo[3 .2 .2]non-6-en-3-one r ing skeleton with an at tached, v a r i a b l y - s i z e d spiro r i n g . Further ing th i s i d e a , i t was envisioned that the thermal rearrangement of d iv iny lcyc lopropanes such as (135)-(138), which should be der ivable from the corresponding v i n y l c y c l o p r o p y l ketones (131)-(134) by previous ly discussed methods, should provide the i n t e r e s t i n g and complex r ing systems contained in the products (139)-(142), r e s p e c t i v e l y (Scheme 22). The major question that arose regarding th i s a p p l i c a t i o n centered around how to synthesize the parent v i n y l c y c l o p r o p y l ketones (131)-(134). It was i n i t i a l l y hoped that the a p p l i c a t i o n of Corey and Wollenberg's method, shown prev ious ly in Scheme 10, to the enones (143)-(145) would provide quick access to the des ired v i n y l c y c l o p r o p y l ketones (Scheme 23). 35 Scheme 22 132 136 140 However, attempts in our laboratory to prepare the precursor to the cuprate reagent (53) lead to the i s o l a t i o n of isomers that were r e l a t i v e l y d i f f i c u l t to separate. In addition, the cuprate reaction i t s e l f appeared to be quite capricious in nature. For these reasons this approach was not pursued any further. 36 Scheme 23 134 An a p p l i c a t i o n of the intramolecular carbenoid add i t ion r e a c t i o n , shown prev ious ly in Schemes 11 and 12, would only have been appl icable to the synthesis of the 5-membered r ing v i n y l c y c l o p r o p y l ketones (131) and (132) (see Scheme 13), and even in these two cases, the i n t e r -mediates (146) and (147) required for the intramolecular carbenoid addi t ion posed a d i f f i c u l t synthet ic challenge (Scheme 24). 37 Scheme 24 O 0 H H 146 131 o J/ 147 132 H The dibromocarbene and ethyl diazoacetate methods, shown previously in Schemes 14 and 15, respectively, appeared to be the most attractive approaches to the synthesis of the vinylcyclopropyl ketones (131)-(134). Since the use of ethyl diazoacetate as a reagent for cyclopropanation had been used sparingly in our laboratory, it was decided to explore its potential by applying it to the synthesis of these compounds. Successful application of this reagent would complement the existing methods available for the preparation of vinyl-cyclopropyl ketones. Logical substrates that were envisioned to react with ethyl diazoacetate to provide intermediates that might be suitable for elabo-ration to the vinylcyclopropyl ketones (131)-(134) were the allylic s i l y l ethers (148)-(150) (Scheme 25). The cyclopropyl esters (151)-(154) were expected to be convertible into the ketones (131)-(134) by simple functional group manipulation. 38 Scheme 25 The use of an allylic ether functionality as the receptor for the addition of ethyl diazoacetate was deemed necessary for the following reasons (Scheme 26). Firstly, the double bond of an enone functionality * would be too electron deficient to allow for facile carbenoid addition . For an example of the preparation of cyclopropyl esters from enones using sulfur ylide methodology, see ref. 107. 39 Secondly, the stereochemical o r i e n t a t i o n of the a l l y l i c ether moiety was ant ic ipated to s t e r i c a l l y and poss ib ly e l e c t r o n i c a l l y inf luence the d i r e c t i o n of attack of the carbenoid spec ies . T h i r d l y , the use of an a l l y l i c ether group as opposed to an a l l y l i c a lcohol group was required since e thyl diazoacetate had been reported to react with a l l y l i c a lcohols such as (155) by p r e f e r e n t i a l i n s e r t i o n into the 0-H bond to produce ethers l i k e ( 1 5 6 ) . 7 2 L a s t l y , the use of unsaturated aceta ls such as (158) was ant i c ipated to pose synthet ic problems because the double bond f u n c t i o n a l i t y in enones l i k e (157) had been reported to migrate during a c e t a l i z a t i o n to provide unsaturated aceta ls l i k e (159) . 7 3 Also unsaturated aceta ls such as (158) were expected to provide minimal s t e r i c inf luence on the d i r e c t i o n of carbenoid a t tack . Scheme 26 0 157 1 5 5 E t O O C C H N 2 158 RO or ^ 5 159 Interest in the development of th i s strategy for the preparat ion of the v i n y l c y c l o p r o p y l ketones (131)-(134) was p r e c i p i t a t e d by the r e a l i z a t i o n that the rearranged enol s i l y l ether products (139) and 40 (140) each contained the same basic carbon ring framework, as the novel antitumor lactone quadrone (34) (Scheme 27). It was hoped that if a l l went well in the preparation and rearrangement of the divinylcyclo-propanes (135) and (136), a more highly functionalized form of (135) or (136) might later be synthesized that, after rearrangement, would provide a compound that could be further elaborated to quadrone (34). Scheme 27 B. Model Study 1 The first study that was undertaken was the synthesis of the divinylcyclopropane (135). Analysis of this molecule retrosynthe-tically (Scheme 28), using the rationale just discussed, indicated that the vinylcyclopropyl ketone (131), the immediate precursor to (135), could be derived by functional group manipulation of the cyclopropyl ester mixture (151). The mixture (151) could in turn be prepared by an intermolecular carbenoid addition of ethyl diazoacetate to the allylic s i l y l ether (148), and it was hoped that (148) could be synthesized in turn by functional group manipulation of readily available cis-bicyclo[3.3.0]oct-2-ene (160)• 41 Scheme 28 H 160 H 148 In planning this synthesis, the stereochemistry of the allylic * sily l ether moiety in (148) was chosen to be a so that the subsequent carbenoid addition of ethyl diazoacetate would be favored to occur on the (3-face of (148), away from the sterically large tert-butyldimethyl-si l y l ether group. In addition, the folded nature of the bicyclo[3.3.0]octene ring skeleton was expected to encourage reagent attack on the less hindered convex (R) face. These two steric considerations were predicted to facilitate stereoselective carbenoid addition. The synthesis of the allylic s i l y l ether (148) was accomplished by the series of reactions shown in Scheme 29. The starting material, cis-bicyclo[3.3.0]oct-2-ene (160), was readily made by refluxing Using steroidal nomenclature, an a-substituent or face is located below the plane of the carbon ring skeleton as drawn while a R-substituent or face is located above the plane of the carbon ring skeleton. 42 commercially a v a i l a b l e 1 ,3-cyclooctadiene with potassium metal according to the procedure of Brown and Hammer.71* Subject ion of a s o l u t i o n of the alkene (160) i n dimethyl sul foxide (DMSO)-water (100:1) to N-bromo-succinimide ( N B S ) , 7 5 followed by immediate treatment of the r e s u l t i n g crude bromohydrin mixture with aqueous sodium hydroxide, provided, by g lc a n a l y s i s , an 80:18:2 mixture of the a-epoxide (161), the B-epoxide (162), and an unknown minor component, r e s p e c t i v e l y , i n 80% y i e l d . The des ired a-epoxide (161) was conveniently separated from the B-epoxide isomer (162) and the unknown minor component by preparat ive l i q u i d chromatography. Scheme 29 Reaction of the a-epoxide (161) with sodium phenylselenide i n ethanol-THF, followed by aqueous hydrogen peroxide ox idat ion of the 43 selenides and heating of the r e s u l t i n g se lenoxides , a f forded , by g lc a n a l y s i s , an 8:1:1 mixture of the a l l y l i c a l coho l (163), the a l l y l i c a l coho l (164), and two ketonic products , r e s p e c t i v e l y , i n 66% y i e l d . I t proved d i f f i c u l t to separate the components of th i s mixture, so the d i s t i l l e d reac t ion product was used d i r e c t l y i n the next r e a c t i o n . Treatment of a DMF s o l u t i o n of th i s mixture with t e r t - b u t y l d i m e t h y l s i l y l c h l o r i d e and imidazole gave, a f ter chromatography, the a l l y l i c s i l y l ethers (148) and (149) i n 77% and 10% y i e l d s , r e s p e c t i v e l y . Several aspects of th i s scheme require further e l a b o r a t i o n . The a-stereochemistry of the epoxide moiety i n (161) was i n f e r r e d by chemical reasoning and by spec tra l comparison to the B-epoxide (162), a compound prev ious ly synthesized by Whi te se l l and Matthews 7 8 by r e a c t i o n of c i s - b i c y c l o [ 3 . 3 . 0 ] o c t - 2 - e n e (160) with m-chloroperoxybenzoic a c i d . A repeat of Whi te se l l and Matthews' preparat ion produced, by g l c a n a l y s i s , a 14:83:3 mixture of the a-epoxide (161), the B-epoxide (162), and the same unknown minor component, r e s p e c t i v e l y . Considering that e l e c t r o p h i l e s were expected to at tack the less hindered convex (8) face of the c i s - b i c y c l o [ 3 . 3 . 0 ] o c t e n e r ing ske le ton , Whi te se l l and Matthews assumed that the m-chloroperoxybenzoic ac id had reacted with (160) to form predominantly the B-epoxide (162) (Scheme 30). Epoxide formation v i a the bromohydrin route , on the other hand, presumably involved i n i t i a l formation of the bromonium ion (165), opening of the bromonium ion with DMSO, and hydro lys i s of the r e s u l t i n g intermediates (166a-b) to provide the mixture of bromohydrins (167a,b) (Scheme 3 0 ) . 7 9 Since i n i t i a l bromonium ion formation was expected to occur on the less hindered convex (8) face of b icyc lo [3 .3 .0 ]oc tene r i n g 44 ske leton, bromonium ion opening should have occcurred from the ot-face of the molecule. Subsequent treatment of the r e s u l t i n g bromohydrins (167a-b) with hydroxide should have produced predominantly the oc-epoxide (161). Scheme 30 H 161 A5 The lR nmr spectra of (161) and (162) each c l e a r l y showed the presence of two epoxide protons in the region of 6 3.50 to 6 3.30. The coupl ing patterns exhibi ted by these protons, however, did not i n d i c a t e with any degree of c e r t a i n t y the r e l a t i v e stereochemistry of the two epoxide moiet ies . These coupling patterns were nevertheless d i s t i n c t l y d i f f e r e n t from each other , and since the *H nmr spectrum of the minor isomer produced i n the m-chloroperoxybenzoic acid reac t ion coincided with the nmr spectrum of the major isomer produced v i a the bromo-hydrin route , the stereochemical assignment of the epoxide (161) was beyond doubt. The reac t ion that was f i r s t attempted to ef fect the i somer izat ion of the a-epoxide (161) to the a l l y l i c a l coho l (163) was not the selenium mediated reac t ion shown in Scheme 29, but rather the c l a s s i c a l reac t ion invo lv ing treatment of (161) with l i t h i u m d i e t h y l a m i d e 8 0 (Scheme 31). Scheme 31 HO H H 162 168 0-. H >> MOSTLY KETONES H 161 46 This well-known base-promoted i somerizat ion had been used success fu l ly by Whi te se l l and Matthews in e f f ec t ing the conversion of the R-epoxide (162) in to the R - a l l y l i c a lcohol ( 1 6 8 ) . 7 8 However, when th i s reac t ion was c a r r i e d out on oc-epoxide (161), the i r spectrum of the r e s u l t i n g crude react ion product showed a very prominent ketone absorp-t ion at 1720 c m - 1 with only a weak a lcohol absorption at 3400 c m - 1 . Scheme 32 171 172 In re trospec t , the predominance of ketone products in the l i t h i u m diethylamide treatment of the cr-epoxide (161) was not so unusual when the mechanism of epoxide to a l l y l i c a lcohol conversion was cons idered . 47 Evidence had been p u b l i s h e d 8 u to suggest that th i s type of epoxide to a l l y l i c a l coho l i somerizat ion occurred , as shown i n Scheme 32, by base abs trac t ion of an adjacent proton that was s i tuated syn to the epoxide oxygen. A coordinat ion argument was invoked. In order for t h i s abs trac t ion to have occurred with the a-epoxide (161), the l i t h i u m diethylamide base would have had to attack from the s t e r i c a l l y hindered a-face of the c i s - b i c y c l o [ 3 . 3 . 0 ] o c t a n e r i n g ske le ton. Instead, the base probably p r e f e r e n t i a l l y abstracted the s t e r i c a l l y access ib le epoxide protons and H ^ , and the r e s u l t i n g intermediates rearranged to the enolates (169) and (170) which on workup provided the ketones (171) and (172). The problem of convert ing the epoxide (161) into the a l l y l i c a l coho l (163) was solved by the a p p l i c a t i o n of Sharpless and Lauers' selenium method (Scheme 3 3 ) . 7 6 The i n i t i a l step i n th i s sequence involved the opening of the epoxide (161) by n u c l e o p h i l i c at tack of a phenylselenide anion that had been prev ious ly generated by the reac t ion of sodium borohydride with diphenyl d i s e l e n i d e . This epoxide opening process was deemed to be favorable s ince , as was previous ly d i scussed , reagent attack from the less hindered 8-face of the c i s - b i c y c l o [ 3 . 3 . 0 ] o c t a n e r i n g skeleton was expected to be qui te f a c i l e . In p r a c t i c e , the phenylselenide anion attacked both of the epoxide centers , and thus, upon peroxide ox idat ion of the selenides (173) and (174) and heating of the r e s u l t i n g selenoxides , a mixture of the a l l y l i c a lcochols (163) and (164) was obtained ( r a t i o ~ 8:1, r e s p e c t i v e l y ) . The predominance of the major a l l y l i c a l coho l (163) was a t t r i b u t e d to anion attack at the less hindered 3 p o s i t i o n of the b icyc lo [3 .3 .OJoctane 48 ring skeleton. The ketone products (171) and (172) were also produced in this reaction, though only as minor products comprising, by glc analysis, 10% of the total reaction product. Scheme 33 H 163 I : 8 |64 As a point of interest, Whitesell and Matthews tried this same selenium approach on the (3-epoxide (162) and found that the yields of the allylic alcohol (168) were unsatisfactory. This result, together with the results just discussed, provide an interesting example of the effect steric environment has on functional group reactivity. The protection of the alcohol functions in (163) and (164) as their tert-butyldimethylsilyl ethers was chosen for the following reasons.81 Tert-Butyldimethylsilyl ethers are easily formed, they are stable to a wide range of reagents, and most importantly, they are readily cleaved by fluoride ion. This cleavage reaction poses minimal 49 threat to any other functional group which might be present i n the molecule. Evidence for the structures of the separated a l l y l i c s i l y l ethers (148) and (149) came primarily from their respective *H nmr spectra. Two d i s t i n c t , symmetrical patterns at 6 5.65 and 6 5.56 (J = 5.7, 2.2, 1.6 Hz) were observed for the two o l e f i n i c protons i n the major a l l y l i c s i l y l ether (148) (Figure 1). Evidence for the stereochemical assign-ment of the s i l y l ether moiety i n (148) was provided by the s p l i t t i n g pattern of (6 2.69, J_ = 8.5, 8.5, 8.5, 4.8 Hz). The occurrence of three equivalent coupling constants indicated that three protons must have been positioned with approximately the same dihedral angle to H„. This was only possible i f the s i l y l ether moiety had the stereochemistry shown. Decoupling of H^ (6 4.58, J_ = 8.5, 2.2, 1.6 Hz) simplified YL^ to a d of d of d (J = 8.5, 8.5, 4.8 Hz), thereby confirming the assignment of 6 2.69. The !H nmr spectrum of the minor a l l y l i c ether (149) (Figure 2) exhibited a broad singlet for the o l e f i n i c hydrogen H^  (6 5.25) and a complex multiplet for the a l l y l i c ether proton H (6 5.17 - 6 5.09). 148 149 50 The coupling patterns of H c (6 2 .49, J_ = 12, 8, 8 Hz) and Hp (6 1.29, J_ = 12, 6, 6 Hz) provided evidence for the stereochemistry of the s i l y l ether moiety. The equal coupl ing of H^ to both Hg and H^,, (6 2.65 - 6 2.84) , and the equal coupl ing of H^ to both Hg and Hg, suggested a symmetrical d ihedra l angle r e l a t i o n s h i p between H„, H„ , and the two geminal protons H and H . This r e l a t i o n s h i p was most probable when the s i l y l ether group had the stereochemistry shown i n (149). The a s s i g n -ments of the protons H ^ , Hp, and Hg were supported by a decoupling study. I r r a d i a t i o n at 6 1-29 ( H Q ) , s i m p l i f i e d the m u l t i p l e t s at 6 5.17 - 6 5.09 (H_) and 6 2.65 - 6 2.54 (H c ) and s i m p l i f i e d 6 2.49 (H„) to a d i i ti O of d (J = 8, 8 Hz) . With an ample amount of the s i l y l ether (148) i n hand, the carbenoid add i t i on r e a c t i o n of e thy l diazoacetate was i n v e s t i g a t e d . A survey of the l i t e r a t u r e indicated that rhodium(II) acetate was probably the reagent of choice to cata lyze the carbenoid a d d i t i o n . 6 7 However, ** t h i s survey a l so turned up a s i g n i f i c a n t synthet ic problem. Most of the studies r e l a t e d to the a d d i t i o n of e thy l diazoacetate to alkenes r e l i e d on the use of a large excess of alkene and on the use of e t h y l d iazo -acetate as the l i m i t i n g reagent. C l e a r l y , i n our work, th i s was not a s y n t h e t i c a l l y usefu l approach, s ince any alkene substrate that was to be used would be the more valuable reagent, and e f f i c i e n t conversion of * The assignments of the protons and Hp were t e n t a t i v e l y based on chemical s h i f t d i f ferences that were observed between a- and p-oriented protons i n other c i s - b i c y c l o [ 3 . 3 . 0 ] o c t a n e compounds synthesized l a t e r i n th i s t h e s i s . This problem was addressed i n reference 82. 51 52 of th i s alkene substrate to the corresponding cyclopropane would be required i n order to make th i s strategy useful for the preparat ion of v i n y l c y c l o p r o p y l ketones l i k e (131)-(134). Another synthet ic problem associated with the carbenoid a d d i t i o n of e thyl diazoacetate centered around a side reac t ion that consumed the carbenoid reagent. This s ide reac t ion involved the coupl ing of two carbenoid units to form e i ther d i e t h y l maleate or d i e t h y l fumarate. This undesirable process was more l i k e l y to occur when the concentrat ion of carbenoid in the reac t ion mixture was high and when the concentrat ion of alkene substrate i n the reac t ion mixture was low. After some experimentation, the procedure found most e f f i c i e n t for the carbenoid add i t ion r e a c t i o n involved the very slow add i t i on of 1-3 equivalents of neat e thy l diazoacetate to a r a p i d l y s t i r r i n g neat alkene substrate containing approximately 0.2 mole % rhodium(II) acetate . The slow add i t i on of e thy l diazoacetate presented some e x p e r i -mental d i f f i c u l t i e s . The add i t i on of th i s reagent from a common dropping funnel introduced too large a quanti ty with each drop, consequently producing a concentrat ion of carbenoid in the r e a c t i o n mixture that was p e r i o d i c a l l y too h igh . E t h y l diazoacetate also had a propensity to give off small quant i t i e s of n i trogen gas upon prolonged standing in the l i g h t at room temperature. This prevented the slow add i t ion of th i s reagent from a syringe and syringe pump apparatus, s ince any ni trogen that was given of f c o l l e c t e d as a bubble i n the syringe which ended up pushing the e thy l diazoacetate into the reac t ion mixture . These two problems were circumvented by adding the e thy l 53 diazoacetate by slow siphon ac t ion through a very f i n e l y drawn glass c a p i l l a r y (see general procedure 1 i n the experimental sect ion of t h i s t h e s i s ) . The a p p l i c a t i o n of th i s technique allowed the constant in troduct ion of small drops of e thy l diazoacetate every 15-45 sec . It was found that as the concentrat ion of the cyc lopropyl ester product increased i n the reac t ion mixture , the e f f i c i e n c y of the carbenoid add i t ion to the remaining alkene substrate dropped markedly. Usual ly af ter 1-3 equivalents of e thy l diazoacetate had been added, further addi t ion l a r g e l y resu l ted i n production of d i e t h y l maleate and d i e t h y l fumarate. At th i s p o i n t , the add i t i on was stopped, and the cyc lopropy l ester product was separated from the remaining alkene substrate and any d i e t h y l maleate and d i e t h y l fumarate by chromatography. Scheme 34 EtOOC 54 The add i t ion of 2 equiv of e thy l diazoacetate over a period of 12.5 h to the a l l y l i c s i l y l ether (148) (Rh 2 (OAc) l + c a t a l y s t ) provided a f ter chromatography, a mixture of carbenoid add i t i on and i n s e r t i o n products i n 78% y i e l d based on unrecovered s t a r t i n g m a t e r i a l . Glc ana lys i s of th i s mixture showed i t to cons i s t of three components i n a 11:7:1 r a t i o . These components were l a t e r i d e n t i f i e d as the exo-cyc lopropyl ester (151a), the endo-cyclopropyl ester (151b), and the i n s e r t i o n adduct (175), r e s p e c t i v e l y (Scheme 34). The separat ion of these three components was achieved by column chromatography. The i r spectra of (151a) and (151b) showed the expected ester carbonyl absorptions at 1725 c m - 1 , and the mass spectrum of each compound showed the expected parent mass of 324. The stereochemistry i n (151a) and (151b) was assigned by *H nmr a n a l y s i s . Evidence that the attack of e thy l diazoacetate had occurred on the less hindered B-face of s i l y l ether (148), as p r e d i c t e d , was provided by the absence of coupl ing between the protons H^ and H^ i n the *H nmr spectra of both (151a) and (151b) (Figures 3 and 4) . Examination of molecular models ind icated that when (151a) and (151b) had the s t e -reochemistry shown, the protons and H^ were oriented at 90° to each other . A 90° d ihedra l angle between two protons usua l ly r e s u l t s i n n e g l i g i b l e coupl ing i n the l\i n m r . 8 6 The protons Rg, 6 4.09 for (151a) and 6 4.38 for (151b), were observed i n each case as a doublet with coupl ing (J = 6.5 Hz) only to the proton H . On the basis of s t e r i c cons iderat ions , i t was also expected that add i t i on of e thy l diazoacetate to the a l l y l i c s i l y l ether (148) would produce predominantly the major exo-cyc lopropyl ester (151a). Proton H^ (6 1.23) was observed as a d of d with a coupl ing constant of 3 Hz to 55 Jill I • o onm 1 1 i 0 Figure 3. The 400 MHz X H nmr Spectrum of the Cyclopropyl Ester (151a) ' ~4 ' ~ 3 2 PP"1 1 0 Figure 4. The 400 MHz *H nmr Spectrum of the Cyclopropyl Ester (151b) 56 both and Yi^. The protons H^ and Hg (6 1.99 and 6 1.91) were each observed as a d of d with a coupl ing constant of 6 Hz to each other and a coupling constant of 3 Hz to H . Since i t i s commonly known that the coupl ing between two c i s - c y c l o p r o p y l protons i s normally stronger than the coupling between two t r a n s - c y c l o p r o p y l p r o t o n s , 8 9 the observed coupl ing patterns were consis tent with the s tructure of the major c y c l o -propyl ester isomer (151a). Unfortunately the cyc lopropy l protons of the minor cyc lopropyl ester isomer (151b) could not be d i r e c t l y observed. The i d e n t i t y of the minor i n s e r t i o n adduct (175) formed i n the carbenoid add i t i on reac t ion was i n f e r r e d from a *H nmr spectrum of a sample containing a mixture of (175) and (151a). The s ignals that provided the best evidence included those due to the o l e f i n i c protons H^ and H (6 5.65 and 6 5.56, J = 6.2 Hz for each s i g n a l ) , and that corresponding to the s i l y l ether proton H^ (6 4.93, J_ = 8, 2, 2 Hz) . The presence of only two couplings for each of the alkene protons i n (175), as opposed to the three couplings observed for each of the alkene protons i n the a l l y l i c s i l y l ether (148), suggested that carbenoid C-H i n s e r t i o n had occurred at the a l l y l i c bridgehead p o s i t i o n of (148). The i n s e r t i o n of carbenoids into a l l y l i c C-H bonds had been prev ious ly reported • 6 2 In connection with another study conducted i n our l a b o r a t o r y , e thy l diazoacetate was added to c i s - b i c y c l o [ 3 . 3 . 0 ] o c t - 2 - e n e (160) (Scheme 35) . In r e l a t i o n to the carbenoid add i t ion react ion just d iscussed , th i s study of fered an i n t e r e s t i n g est imat ion of the e f fec t of the s i l y l ether moiety on the s t e r e o s e l e c t i v i t y of the carbenoid a d d i t i o n . Indeed the e f fec t was quite marked. The a d d i t i o n of e t h y l 57 diazoacetate to the alkene (160), via a procedure identical with that just described, provided, after chromatographic isolation, a 78% yield of a mixture of the exo-cyclopropyl ester (176a), the endo-cyclopropyl ester (176b), and a mixture of four other minor compounds in a ratio of 4:2:1, respectively (glc analysis). Clearly the presence of the si l y l ether moiety in (148) greatly favored the production of the desired cyclopropyl ester isomers (151a) and (151b). Scheme 35 E t O O C 160 176a 176b -+- 4 OTHERS With the successful synthesis of the cyclopropyl ester isomers (151a) and (151b), the existing functionality in these compounds had to be elaborated to the functionality present in the vinylcyclopropyl ketone (131). This was accomplished by the sequence of reactions outlined in Scheme 36. * The cyclopropyl ester mixture (151) was reduced with lithium aluminum hydride in ether to provide, after workup, predominantly the alcohol mixture (177) in 95% yield. The ir spectrum of this material showed a characteristic broad 0-H absorption at 3300 cm"1. This mixture did contain the insertion addduct (175). 58 The a lcohol mixture (177) was oxidized to the aldehyde mixture (178) with pyridinium chlorochromate (PCC) i n d i c h l o r o m e t h a n e . 8 3 This o x i d a t i o n , as wel l as the ox idat ion of a l l subsequent oc-hydroxycyclo-propanes, was done in the presence of sodium acetate . Since previous r e p o r t s 8 4 had indicated that a-hydroxycyclopropanes are ac id s e n s i t i v e , and since PCC i s an a c i d i c o x i d i z i n g agent, the presence of sodium acetate as a buffer was deemed necessary. Scheme 36 EtOOC 151 177 178 59 Based on the l i t e r a t u r e precedent discussed e a r l i e r , i a the aldehyde mixture (178) was e q u i l i b r a t e d e x c l u s i v e l y to the exo-aldehyde isomer (179) by treatment of a THF so lu t ion of (178) with a t e r t - b u t y l a l coho l so lu t ion of potassium t e r t - b u t o x i d e . The aldehyde (179) was character ized by i r absorptions at 2700 and 1700 c m - 1 and by an *H nmr s igna l at 6 9.01 (aldehyde proton, = 6 Hz) . I t was found necessary to e q u i l i b r a t e the aldehyde mixture (178) as opposed to the cyc lopropy l ester mixture (151), s ince treatment of (151) with sodium ethoxide i n ethanol resu l ted i n minimal e q u i l i b r a t i o n and eventual substrate decomposition. The crude exo-aldehyde product (179) was used d i r e c t l y i n a W i t t i g methylenation reac t ion with a THF so lu t ion of methylenetr iphenyl -phosphorane. Workup afforded the alkene product (180) i n 78% o v e r a l l y i e l d from the a l coho l mixture (177). A small quant i ty of c l e a r viscous residue was l e f t i n the s t i l l pot a f ter d i s t i l l a t i o n of the alkene (180), and i t was speculated that t h i s mater ia l might have been produced by a condensation reac t ion between two aldehyde molecules during the previous base-catalyzed e q u i l i b r a t i o n r e a c t i o n . C h a r a c t e r i z a t i o n of t h i s mater ia l was not attempted. The exo -v iny l moiety in the alkene (180) exhibi ted c h a r a c t e r i s t i c i r bands at 3060 and 1630 c m - 1 and a very diagnost ic s p l i t t i n g pattern i n the *H nmr spectrum. Shown i n Figure 5 i s a reproduct ion of the s p l i t t i n g pattern observed for the protons H . , H D and H„ of a t y p i c a l A D CI exo-cyclopropyl v i n y l moiety. This pattern was present i n e s s e n t i a l l y * For another method of epimeriz ing endo-cyclopropyl aldehydes to exo-cyc lopropyl aldehydes, see r e f . 85. 60 a l l subsequently prepared compounds containing th i s funct iona l group. Figure 5 With the ester group of the cyc lopropy l esters (151a) and (151b) success fu l ly modified to the v i n y l group i n (180), the s i l y l ether funct ion had to be modified to the ketone funct ion present i n the v i n y l -cyc lopropyl ketone (131). This was accomplished by treatment of a THF so lu t ion of (180) with tetra-n-butylammonium f l u o r i d e 7 7 to provide the a lcohol (181) in 91% y i e l d ( i r , 0-H absorpt ion , 3350 c m - 1 ) , followed by ox idat ion of (181) with PCC i n dichloromethane to give the v i n y l c y c l o -propyl ketone (131) in 85% y i e l d ( i r , carbonyl absorpt ion , 1710 c m - 1 ) . With the synthesis of the v i n y l c y c l o p r o p y l ketone (131) completed, the next task was to introduce the second required v i n y l 61 group i n the form of an enol s i l y l e ther . This was accomplished i n a manner s i m i l a r to that done in previous inves t iga t ions i n our laboratory (Scheme 37). S p e c i f i c a l l y , reac t ion of the v i n y l c y c l o p r o p y l ketone (131) with LDA in THF, followed by treatment of the r e s u l t i n g so lu t ion of enolate anion with t e r t - b u t y l d i m e t h y l s i l y l ch lor ide and hexamethylphosphoramide (HMPA) gave the d iv iny lcyc lopropane (135) in 77% y i e l d . The i r spectrum of th i s mater ia l exhibi ted a strong enol ether alkene s tre tch at 1675 c m - 1 and the *H nmr spectrum exhibi ted c h a r a c t e r i s t i c t e r t - b u t y l and methyl s ing l e t s at 6 0.95 and 6 0.15, r e s p e c t i v e l y (see Figure 6 ) . Scheme 37 The d iv inylcyc lopropane (135) was not as stable as the d i v i n y l -cyclopropanes prev ious ly prepared in our l abora tory . Even when stored at temperatures around - 1 0 ° C , th i s mater ia l slowly turned yel low. This lack of s t a b i l i t y may be a t t r ibuted to the s i g n i f i c a n t s t r a i n associated with the r ing system present i n (135). This r i g i d system does not have the conformational f l e x i b i l i t y that i s inherent in the prev ious ly prepared div inylcyc lopropanes which contained only a s ing le 5-membered r i n g . 62 In view of the i n s t a b i l i t y of the d iv iny lcyc lopropane (135), t h i s substance, immediately a f ter i t s preparat ion , was d i l u t e d with benzene, and the r e s u l t i n g so lut ion , was sealed in a th ick walled glass p y r o l y s i s tube and heated at 155°C for 5 h r . Glc analys is of the r e s u l t i n g product showed i t to cons is t of a 90:5:5 mixture of the des ired rearranged enol s i l y l ether (139), a s ing le unknown compound, and a number of minor unknown compounds (Scheme 38). The major product (139) was i so la ted in 90% y i e l d , in reasonably pure form, by chromatography of the mixture through tr ie thylamine washed, grade 1, basic alumina. This chromatography technique proved useful for the separat ion of ac id s ens i t i ve enol s i l y l e thers . Heating of the d iv iny lcyc lopropane (135) at higher temperatures resu l ted in a s u b s t a n t i a l increase in the r e l a t i v e proport ion of the minor compounds In the reac t ion product . For example, heating of (135) for 2 h at 200°C produced, by g lc a n a l y s i s , a 75:25 mixture of the desired enol s i l y l ether (139) to minor products . Scheme 38 A 135 139 63 The *H nmr spectrum of (139) (Figure 7) was consistent with the proposed s t r u c t u r e . The o l e f i n i c proton H r (6 6.27) showed v i c i n a l coupl ing (J = 9.5 , 5.7 Hz) to the protons H^ (6 5.37) and H_. (6 2 .50) , r e s p e c t i v e l y , and a l l y l i c coupl ing (J_ = 2 .5 , 1.8 Hz) to the protons H ,^ and H p (6 2.24 and 6 1.94). The o l e f i n i c proton showed coupl ing (J_ = 9.5 , 3 .5 , 3.5 Hz) to the protons H „ , H_ and H„, r e s p e c t i v e l y , and the enol ether proton H (6 4.86) showed coupl ing (J_ = 2.8 Hz) to the proton Hg. The assignments of the protons H ^ , H^ and H ,^ were v e r i f i e d by decoupling of the proton H . A l l coupled protons s i m p l i f i e d as expected. To complete the o v e r a l l sequence, a THF s o l u t i o n of the rearranged enol s i l y l ether (139) was treated at - 7 8 ° C with t e t r a - n -butylammonium f l u o r i d e to provide the ketone (182) i n 93% y i e l d (Scheme 39). The i r spectrum of th i s mater ia l exhibi ted the required ketone absorption of 1730 c m - 1 , and the *H nmr spectrum showed o l e f i n i c s ignals s i m i l a r to those observed for H ,^ and H^ i n the enol s i l y l ether (139). Scheme 39 —f- S i O / 139 182 64 — g — 3 2 PP"1 1 0 Figure 6. The 400 MHz XH nmr Spectrum of the Divinylcyclopropane (135) 6 5 2 PP"1 1 0 Figure 7. The 400 MHz :H nmr Spectrum of the Enol S i l y l Ether (139) 65 This f i r s t model study success fu l ly demonstrated the p o t e n t i a l of the d iv inylcyc lopropane rearrangement as a key strategy for the prepara-t i o n of i n t e r e s t i n g . t r i c y c l i c r ing compounds, and i t also demonstrated the u t i l i t y of the carbenoid add i t i on reac t ion of e thy l diazoacetate to a l l y l i c ethers as a v iab l e approach to the synthesis of v i n y l c y c l o p r o p y l ketones. C. Model Study 2 The a l l y l i c s i l y l ether (149), the protected form of the minor a l l y l i c a lcohol isomer (164) produced in the i somerizat ion of a-epoxide (161) (Scheme 29) was chosen as another test substrate for the prepara-t i o n of cyc lopropy l esters v i a the carbenoid add i t ion reac t ion of e thy l d iazoacetate . This study was perceived as a more chal lenging test of the method due to the ant i c ipated r ing s t r a i n i n the r e s u l t i n g c y c l o -propyl esters (152a) and (152b) (Scheme 40). The add i t ion of 1.7 equiv of e thy l diazoacetate over a 7 h period to the a l l y l i c s i l y l ether (149) (Rh 2 (0Ac) 1 + c a t a l y s t ) produced, a f ter chromatographic separat ion of unreacted s t a r t i n g m a t e r i a l , d i e t h y l maleate, and d i e t h y l fumarate, a mixture of the cyc lopropyl esters (152a) and (152b) in 56% y i e l d based on unrecovered s t a r t i n g m a t e r i a l , and a 5% y i e l d of several minor ester containing compounds. Glc analys i s of the cyc lopropyl ester mixture showed i t to cons is t of (152a) and (152b) i n nearly equal amounts. For c h a r a c t e r i z a t i o n purposes these two isomers were separated by c a r e f u l chromatography. 66 Scheme 40 152a 152b The i r spectra of both isomers exhibi ted the expected carbonyl absorption at 1720 c m - 1 , and the mass spectra exhibi ted the required parent mass of 324. Evidence that carbenoid add i t ion had occurred predominantly on the less hindered B-face of the b icyc lo [3 .3 .0 ]oc tene r ing skeleton of the a l l y l i c s i l y l ether (149) was provided, once again, by the absence of coupling between the protons and i n the *H nmr spectra of both the cyc lopropy l esters (152a) and (152b) (Figures 8 and 9 ) . The examination of molecular models of (152a) and (152b) confirmed that the d ihedra l angle between and H ,^ was approximately 9 0 ° . The stereochemistry of the cyc lopropy l ester moiety was assigned by the fol lowing c r i t e r i a . The *H nmr spectra of the exo-isomer (152a) and the endo-isomer (152b) showed the chemical sh i f t of H 4 to be 6 4.26 A and 6 4.45, r e s p e c t i v e l y . This s h i f t d i f ference was i n d i r e c t compari-67 68 son to the corresponding d i f ference in the exo-cyc lopropyl ester (151a) (H = 6 4 .38) . In a d d i t i o n , the coupl ing constant for one of the c y c l o -B propyl protons (6 1.40) in the exo-isomer (152a) was 4 Hz, while the coupling constant for one of the cyc lopropy l protons (6 1.51) in the endo-isomer (152b) was 8.7 Hz. The smaller coupl ing constant was consistent with the a n t i - r e l a t i o n s h i p between the two cyc lopropy l protons i n (152a), while the larger coupling constant was consistent with the s y n - r e l a t i o n s h i p between the two cyc lopropyl protons i n ( 1 5 2 b ) » 8 6 The mixture of the cyc lopropy l esters (152a) and (152b) was success fu l ly converted into the v i n y l c y c l o p r o p y l ketone (132) (Scheme 41) by a ser ies of react ions s i m i l a r to that used in the previous model study. A mixture of the cyc lopropy l esters (152a) and (152b) was reduced with l i t h i u m aluminum hydride in ether to provide , a f ter workup, the a lcohol mixture (183) i n 94% y i e l d . Oxidat ion of (183) with PCC i n dichloromethane and e q u i l i b r a t i o n of the r e s u l t i n g aldehyde mixture (184) with potassium ter t -butox ide in a t e r t - b u t y l a lcohol - THF solvent mixture produced the exo-aldehyde (185). Treatment of (185) with methylenetriphenylphosphorane i n THF afforded the alkene (186) in an i s o l a t e d y i e l d of 77% from the a lcoho l mixture (183). Removal of the s i l y l protect ing group i n (186) with tetra-n-butylammonium f l u o r i d e i n THF gave the c r y s t a l l i n e a lcohol (187) i n 90% y i e l d . Subsequent reac t ion of (187) with PCC i n dichloromethane provided the v i n y l c y c l o -propyl ketone (132) i n 85% y i e l d . A l l of the synthet ic intermediates shown in Scheme 41 showed spec tra l data that was consistent with the proposed s t r u c t u r e s . 69 Scheme 41 Introduct ion of the second v i n y l group of the required d i v i n y l -cyclopropane as a t e r t - b u t y l d i m e t h y l s i l y l enol ether was accomplished by the standard procedure. Treatment of the v i n y l c y c l o p r o p y l ketone (132) with IDA i n THF, followed by add i t ion of t e r t - b u t y l d i m e t h y l s i l y l ch lor ide and HMPA af forded, af ter chromatography of the i so la ted product through tr ie thylamine washed, grade 1, basic alumina, the d i v i n y l c y c l o -propane (136) in 75% y i e l d (Scheme 42). 70 Scheme 42 The i r spectrum of (136) showed the required strong enol ether alkene absorpt ion at 1620 c m - 1 and the *H nmr spectrum (Figure 10) showed the standard s ing l e t s at 6 0.95 and 6 0.17 for the t e r t - b u t y l and methyl groups, r e s p e c t i v e l y . Compared to the d iv iny lcyc lopropane (135), the compound (136) was s i g n i f i c a n t l y more s t a b l e . This was probably because the presence of the enol s i l y l ether moiety did not impart much a d d i t i o n a l s t r a i n in to the r ing system of (136). The thermal rearrangement of the d iv iny lcyc lopropane (136) ( 1 7 0 ° C , 5 h) proceded c l ean ly and smoothly to provide the rearranged enol s i l y l ether (140) i n e s s e n t i a l l y quant i ta t ive y i e l d (Scheme 43). The *H nmr spectrum of (140) (Figure 11) supported the proposed s t r u c t u r e . The proton (6 6.27) showed v i c i n a l coupl ing (J = 9.5 Hz) to the proton 1L_ (6 5.25) and a l l y l i c coupl ing (J = 2 .1 , 2.1 Hz) to the protons H c and Hp (6 2.20 - 6 2 .15) . The proton H f i showed coupl ing ( £ = 9.5 , 3.2, 3.2 Hz) to the protons H ^ , H ,^ and Hp, r e s p e c t i v e l y , and a long range coupling (J_ = 1.3 Hz) to the proton H ,^ (6 2 .50) . The assignments of the protons H c , Hp and Hg were v e r i f i e d by decoupling of the proton Hg. Each s igna l s i m p l i f i e d as expected. The enol ether proton H^ was observed as a s ing le t at 6 4.68. 71 72 Scheme 43 It i s i n t e r e s t i n g to compare the s tructure of the t r i c y c l i c enol s i l y l ether (140) from this model study to that of the t r i c y c l i c enol s i l y l ether (139) from the f i r s t model study. Not ice , as shown i n Scheme 43, that both products can be represented as having the same carbon r ing skeleton but with d i f f e r e n t arrangements of f u n c t i o n a l i t y about the b icyc lo [3 .2 .1 ]oc tad iene port ion of the molecule. This choice of f u n c t i o n a l i z a t i o n pattern of fers two poss ib le synthet ic routes to e s tab l i sh in g a func t iona l i zed t r i c y c l i c r ing skeleton that might be elaborated into quadrone (34) i n a l a t e r synthes i s . Treatment of a cold ( - 7 8 ° C ) THF s o l u t i o n of the enol s i l y l ether (140) with tetra-n-butylammonium f l u o r i d e af forded, af ter workup and chromatography, the t r i c y c l i c ketone (188) i n near quant i ta t ive y i e l d (Scheme 44). The i r spectrum of th i s mater ia l showed the presence of a ketone absorption at 1740 c m - 1 and the *H nmr spectrum was consistent with the proposed s t r u c t u r e , showing o l e f i n i c proton s ignals that were s i m i l a r to those observed for the o l e f i n i c protons H^ and H^ of the enol s i l y l ether (140). 73 Scheme 44 This model study further extended the a p p l i c a b i l i t y of the d iv iny lcyc lopropane rearrangement as a method for the preparat ion of t r i c y c l i c r ing systems and further i l l u s t r a t e d the use of the carbenoid add i t i on reac t ion of e thy l diazoacetate to a l l y l i c s i l y l ethers as a convenient way of construct ing v i n y l c y c l o p r o p y l ketones. However, i n order for th i s o v e r a l l synthet ic plan to become more a t t r a c t i v e , a more e f f i c i e n t preparat ion of the a l l y l i c s i l y l ether (149) would have to be developed. D. Model Study 3 The f i r s t two model studies demonstrated the a p p l i c a b i l i t y of reac t ing e thyl diazoacetate with a l l y l i c s i l y l ethers for the prepara-t i o n of the five-membered r i n g v i n y l c y c l o p r o p y l ketones (131) and (132)• As a further test of the general usefulness of th i s s trategy , i t was decided to apply i t to the synthesis of the six-membered r i n g v i n y l -cyc lopropy l ketones (133) and (134). Compounds (133) and (134) were ant i c ipated to be su i tab le precursors to the d iv inylcyc lopropanes (137) and (138) which should in turn provide two more substrates to test the 74 applicability of the divinylcyclopropane rearrangement as a key strategy for the preparation of tricyclic ring skeletons. Scheme 45 189 ft 150 H A retrosynthetic analysis of the vinylcyclopropyl ketones (133) and (134), using the same type of rationale that was used in the previous model studies, suggested that each compound could be available by functional group manipulation of the cyclopropyl ester mixtures (153) and (154), respectively (Scheme 45). The cyclopropyl ester mixtures (153) and (154) could in turn both be produced in the carbenoid addition reaction of ethyl diazoacetate to the allylic s i l y l ether (150), and the 75 preparation of (150) was envisioned to be possible from commercially available 1-decalone (189). Scheme 46 194 195 The synthesis of the allylic s i l y l ether (150) was accomplished by the reaction sequence shown in Scheme 46. An 80:20 mixture of cis-76 and trans - l -deca lone (189), which was e i ther commercially a v a i l a b l e or r e a d i l y preparable by a two step sequence from a - n a p h t h o l , 8 7 was e q u i l i b r a t e d to a 4:96 mixture of c i s - and trans - l -deca lone (190) (g lc a n a l y s i s ) , in near quant i ta t ive y i e l d , by treatment of (189) with potassium ter t -butox ide i n a t e r t - b u t y l a lcohol - THF solvent mixture . This e q u i l i b r a t i o n reac t ion had prev ious ly been reported by Cope and c o w o r k e r s . 8 8 They reported that re f lux ing c i s - l - d e c a l o n e with sodium methoxide i n methanol provided, a f ter workup, pure t r a n s - l -decalone. A repeat of th i s procedure i n fact produced, by g lc a n a l y s i s , a 7:93 mixture of c i s - and t r a n s - l - d e c a l o n e . The use of the procedure using potassium ter t -butox ide did provide a s l i g h t l y better trans to c i s r a t i o . Treatment of the decalone mixture (190) with LDA i n THF, followed by trapping of the r e s u l t i n g enolate at - 7 8 ° C with bromine i n d i c h l o r o -methane 8 9 a f forded , by g lc a n a l y s i s , a 12:6:1:1 mixture of the bromo ketone (191a), the bromo ketone (191b), the s t a r t i n g decalone mixture (190), and three other unknown minor compounds, r e s p e c t i v e l y , i n 80% y i e l d . This mater ia l was used without further p u r i f i c a t i o n for the next r e a c t i o n , but for c h a r a c t e r i z a t i o n purposes, the bromo ketones (191a) and (191b) could be separated by chromatography. The stereochemistry of the bromine atom i n both (191a) and (191b) was r e a d i l y assignable based on the coupl ing constants observed for protons H^ and H ^ ' . The *H nmr spectrum of the major isomer (191a) showed proton H^ (6 4.35) to be weakly coupled (J = 3.3 Hz) to the two adjacent protons . It was thus c l ear that H^ was e q u a t o r i a l l y o r i e n t e d . The *H nmr spectrum of the minor isomer (191b) showed proton H ' (6 4.66) to have coupl ing constants 77 of 13, 6, and 1.5 Hz. The presence of the large coupling constant ( a x i a l - a x i a l coupling) showed that H^' was a x i a l l y o r i e n t e d . A DMF so lu t ion of the bromo ketone mixture from the previous reac t ion was heated i n the presence of anhydrous l i t h i u m bromide and l i t h i u m carbonate to e f fect dehydroha logenat ion . 9 0 The enone (192) was i s o l a t e d , a f ter chromatography of the crude reac t ion mixture, i n 75% y i e l d as a h ighly c r y s t a l l i n e white s o l i d which exhibi ted a melt ing point that was s i m i l a r to that prev ious ly reported for ( 1 9 2 ) . 9 1 In f a c t , th i s mater ia l c r y s t a l l i z e d so r e a d i l y from heptane that mixtures only 50% pure i n the enone (192) could e a s i l y be p u r i f i e d . The i r spectrum of th is mater ia l exhibi ted a strong carbonyl absorption at 1665 c m - 1 . Reaction of the enone (192) with l i t h i u m aluminum hydride i n ether furn i shed , a f ter workup, a 9:1 mixture of the a l l y l i c a lcohols (193) and (194), r e s p e c t i v e l y , (glc ana lys i s ) i n near quant i ta t ive y i e l d . The i r spectrum of th i s mater ia l showed the required broad 0-H absorption at 3300 c m - 1 and the required C=C absorpt ion at 1650 c m - 1 . This spectrum ind ica ted that reduct ion of carbonyl group had occurred c l e a n l y , and that conjugate reduct ion of the enone double bond had not occurred as a side r e a c t i o n . Separation of the a l l y l i c a l coho l isomers (193) and (194) proved very d i f f i c u l t by conventional chromatography, so a DMF s o l u t i o n of the a l coho l mixture was treated with imidazole and t e r t - b u t y l d i m e t h y l s i l y l ch lor ide to produce, a f ter workup, a 9:1 mixture of the a l l y l i c s i l y l ethers (150) and (195) (glc ana lys i s ) i n e s s e n t i a l l y quant i ta t ive y i e l d . These two isomers were r e a d i l y separable by chromatography. 78 Evidence for the stereochemical assignment of the s i l y l ether moiety in (150) and (195) was provided by nmr analys i s (Scheme 47) . In the *H nmr spectrum of the major isomer (150) (Figure 12), H (6 3.85) showed coupling to Hp (J_ = 8.7 Hz) . This value was consistent with a pseudo d i a x i a l r e l a t i o n s h i p between H ,^ and Hp. In the ^H nmr spectrum of the minor isomer (195) (Figure 13), H^ ( 6 3.85) showed coupl ing to Hp (J_ = 3.7 Hz, determined by a decoupling s tudy) . The smaller value of the coupl ing constant was consistent with the pseudo e q u a t o r i a l - a x i a l r e l a t i o n s h i p between H p and H . Scheme 47 J C D=8.7 Hz J C D = 3.7Hz With ample quant i t i e s of the a l l y l i c s i l y l ether (150) i n hand, i t s react ion with e thy l diazoacetate was i n v e s t i g a t e d . A d d i t i o n of 2.9 equiv of e thy l diazoacetate over a 12 h period to the a l l y l i c s i l y l ether (150) (Rh 2 (0Ac)^ c a t a l y s t ) provided, af ter chromatographic removal of unreacted s t a r t i n g m a t e r i a l , d i e t h y l maleate, and d i e t h y l fumarate, a mixture of cyc lopropyl esters i n 92% y i e l d based on unrecovered s t a r t i n g m a t e r i a l . Glc analys i s of th i s mixture showed i t to consis t of four 79 80 components in a ratio of 41:31:20:8. The ir spectrum of this mixture showed the required ester carbonyl absorption at 1720 cm-1, and the mass spectrum showed the required parent mass of 352. The exact structure of each of the four cyclopropyl ester isomers was not rigorously established since separation of each component from the mixture proved difficult. The carbenoid addition of ethyl diazoacetate to the allylic s i l y l ether (150) was not expected to occur with much face selectivity since the equatorial orientation of the si l y l ether moiety was not anticipated to provide much steric influence. On this basis, the four cyclopropyl ester products were speculated to have, in order of decreasing percentage content in the mixture, the structures (153a), (154a), (153b), and (154b), respectively. EtOOC EtOOC H H 153a 154a COOEt 153b 154b 81 The conversion of the cyc lopropy l esters (153a), (153b) in to the v i n y l c y c l o p r o p y l ketone (133) and the conversion of the cyc lopropy l esters (154a) and (154b) into the v i n y l c y c l o p r o p y l ketone (134) were ant i c ipa ted to be v iab l e v i a the same sequence of react ions that was used i n the f i r s t two model s tud ies . Since the aldehyde e q u i l i b r a t i o n react ion used i n th i s sequence should convert the mixture of four isomers into a mixture of two isomers, i t was hoped that the r e s u l t i n g mixture a f ter th i s step would be eas ier to separate . On t h i s b a s i s , the sequence of react ions i n Scheme 48 was c a r r i e d out . Scheme 48 EtOOC 82 The mixture of the cyc lopropyl esters (153a), (153b), (154a), and (154b) was reduced with l i t h i u m aluminum hydride i n ether to g ive , a f ter workup, a 92% y i e l d of the cyc lopropyl a lcohol mixture (196) ( i r , 0-H absorpt ion, 3300 c m - 1 ) . The a lcohol mixture (196) was oxidized with PCC i n dichloromethane, and a THF so lu t ion of the r e s u l t i n g aldehyde mixture (197) was treated with a t e r t - b u t y l a lcohol so lu t ion of potassium t e r t -butoxide . Glc analys i s of the crude product from th i s reac t ion showed i t to cons is t of approximately a 2:1 mixture of the aldehydes (198) and (199), r e s p e c t i v e l y . The i r spectrum of th i s mixture showed the expected aldehydic C-H and C=0 absorptions at 2680 and 1700 c m - 1 , r e s p e c t i v e l y . Separation of the aldehydes (198) and (199) was not e f f i c i e n t by conventional chromatography so the mixture was subjected to W i t t i g methylenation condit ions (methylenetriphenylphosphorane, THF) to f u r n i s h , a f ter workup, a 2:1 mixture of the cyc lopropy l alkenes (200) and (201), r e s p e c t i v e l y , (g lc ana lys i s ) in an o v e r a l l y i e l d from the cyc lopropyl a lcohol mixture (196) of 76%. The alkene isomers (200) and (201) were fortunate ly r e a d i l y separable from each other , and each isomer showed s p e c t r a l c h a r a c t e r i s t i c s consistent with the proposed s t r u c t u r e s . The stereochemical o r i e n t a t i o n of the cyclopropane r ing i n the alkenes (200) and (201) was supported by % nmr spectroscopy. Examination of molecular models indicated that the d ihedra l angle between the protons H„ and H in the major alkene isomer (200) was 90° (Scheme 49). This should have precluded s i g n i f i c a n t coupl ing between H^ and H _ , and indeed the *H nmr spectrum of (200) (Figure 14) showed H G ti 83 ( 6 3.26) as a simple doublet with coupl ing only to (J = 9 Hz) . Molecular models also showed that the d ihedra l angle between H and H in minor alkene isomer (201) was approximately 3 0 ° . Therefore , not unexpectedly, the *H nmr spectrum of (201) (Figure 15) showed the proton H G ( 6 3 .73) , as a doublet of doublets with coupling to (J_ = 8.8 Hz and H_ (J = 5 Hz) , r — Scheme 49 The 2:1 mixture of (200) to (201) ind icated that the carbenoid add i t i on of e thy l diazoacetate to the a l l y l i c s i l y l ether (150) had favored attack on the a-face of the t rans -b icyc lo [4 .4 .Ojdecene r i n g ske leton, away from the R -or iented s i l y l ether moiety. This seemed reasonable based on s t e r i c cons idera t ions . However, one important observation regarding th i s r eac t ion sequence was not made u n t i l a f ter the completion of th is model s tudy. It was l a t e r noticed that the 41:31:20:8 mixture of the cyc lopropy l ester isomers (153a), (153b), (154a), and (154b) produced in the carbenoid addi t ion reac t ion did not agree with the 2:1 mixture of the alkenes (200) and (201) i s o l a t e d further along in the reac t ion scheme. 84 85 I f the four cyc lopropyl ester isomers were indeed produced in the indicated r a t i o and had the s tructure that were assigned to them, then the alkenes (200) and (201) should have been i s o l a t e d in a r a t i o of 1.5:1, r e s p e c t i v e l y , not 2:1. This ambiguity was invest igated more c l o s e l y . A more i n depth examination of the g lc traces of the cyc lopropy l a l coho l mixture (196) and the cyc lopropy l aldehyde mixture (197) turned up a s u r p r i s i n g r e s u l t . In each case, a mixture of only three compounds was observed in a r a t i o of approximately 4:3:2. Comparison of these r a t i o s with the r a t i o of components present i n the s t a r t i n g cyc lopropy l ester mixture seemed to ind ica te that the minor ester isomer (154b) had somehow "disappeared" during the reac t ion sequence. * To examine th i s p e c u l i a r i t y more c l o s e l y , a 3:1 mixture of the cyc lopropy l esters (153b) and (154b), the two minor isomers i s o l a t e d by care fu l chromatography of the i n i t i a l cyc lopropy l ester mixture, was reduced with l i t h i u m aluminum hydride i n e ther . A c l e a r , c o l o r l e s s , viscous l i q u i d was i s o l a t e d i n 84% y i e l d , and g lc analys i s of th is mater ia l showed i t to cons i s t of only one component. However t i c analys is of t h i s mater ia l ( s i l i c a gel p l a t e , e l u t i o n with petroleum ether:e ther , 1:1) showed the presence of two spots, the minor spot having an value close to zero and the major spot having an expected R^ value close to 0 .5 . The lower R^ component was i s o l a t e d by chromatography and mass spectrometric analys i s showed i t to have a parent mass of 196. The •^H nmr analys i s of t h i s mixture was consistent with the proposed s tructures of the compounds (153b) and (154b). 86 molecular mass and the high p o l a r i t y shown by th i s minor component lead to the pred ic t ion that i t s s tructure was that of the d i o l (202) (Scheme 50). The formation of th i s unexpected product was probably f a c i l i t a t e d by the s t e r i c crowding present in the endo-ester isomer (154b). The c lose proximity of the s i l y l ether moiety to the ester funct ion l i k e l y promoted some form of intramolecular s i l y l ether cleavage, during the reduct ion r e a c t i o n . Scheme 50 154b 2 0 2 134 The d i o l (202) escaped detect ion previous ly because the a l c o h o l mixture (196) and the aldehyde mixture (198) were character ized only by i r spectroscopy and mass s p e c t r a l a n a l y s i s . F u l l c h a r a c t e r i z a t i o n was not conducted u n t i l the alkene stage, at which po in t , any surv iv ing intermediates derived from (202) would already have been chromato-g r a p h i c a l l y removed, poss ib ly as the v i n y l c y c l o p r o p y l ketone (134). The f a i l u r e of th i s minor component to show up by g lc analys i s was a l i t t l e s u r p r i s i n g . Despite th i s f i n d i n g , no other reduct ion procedures were examined since the o v e r a l l reac t ion sequence was s t i l l r e l a t i v e l y e f f i c i e n t . 87 With pure samples of the alkenes (200) and (201) in hand, a t tent ion was turned to the preparat ion and rearrangement of the d iv inylcyc lopropanes (137) and (138). The f i r s t d iv iny lcyc lopropane invest igated was the compound (137), and i t s s traightforward preparat ion i s out l ined in Scheme 51. Scheme 51 137 133 Treatment of a THF so lu t ion of the s i l y l ether (200) with t e t r a -n-butylammoniura f luor ide provided, af ter workup, the c r y s t a l l i n e a lcohol (203) in near quant i ta t ive y i e l d . PCC oxidat ion of the a l coho l (203) afforded the low melt ing ketone (133) in 94% y i e l d , and r e a c t i o n of th i s mater ia l with LDA i n THF, followed by addi t ion of t e r t - b u t y l d l m e t h y l -s i l y l ch lor ide and HMPA to the r e s u l t i n g so lu t ion of enolate anion gave, 88 after workup, a 93% yie l d of the divinylcyclopropane (137). A l l the intermediates shown i n Scheme 51 exhibited spectral characteristics that were consistent with the proposed structures. Figure 16 shows the *H nmr spectrum of (137) . With the synthesis of the divinylcyclopropane (137) completed, i t s behavior on thermal rearrangement was examined. Heating of (137) for 5 h at 165-170°C i n benzene cleanly produced the enol s i l y l ether (141) in essentially quantitative yi e l d (Scheme 52). The i r spectrum of this material showed the required strong enol ether alkene absorption at 1635 cm - 1 and the *H nmr spectrum (Figure 17) showed signals that supported the proposed structure. The o l e f i n i c proton H^ , (6 6.05) showed v i c i n a l coupling to the protons H^ (6 5.25) and H D (6 2.51 - 6 D o 2.43) (J_ = 10.5, 8.2 Hz, respectively) plus a l l y l i c coupling to the protons Hj, and ^ (6 2.12 and 6 1.81, J = 2.7, 2 Hz). Scheme 52 The stereochemistry about center * was supported by the coupling constant between the protons H^ and H^. The proton H^ (6 2.28, J_ = 13, 9.3, 1.2 Hz) was assigned by decoupling the proton HL which removed the 89 90 weak coupl ing (J = 1.2 Hz, d ihedra l angle close to 9 0 ° ) between H^ and H^j. The 13 Hz coupl ing constant was assigned to the geminal coupl ing between H^ and H^, and the remaining coupling constant (Jjj-r = 9.3 Hz) was consistent with the 0° d ihedra l angle between the protons H^ and , an angle observed upon examination of molecular models of (141). This stereochemical point was of s i g n i f i c a n c e s ince the rearrangement of the isomeric d iv iny lcyc lopropane (138) (Scheme 53) was expected to produce the enol s i l y l ether (142), a compound that i s epimeric to (141) at center * . Coupling between H^ and H^ (142) was expected to be s i g n i f i c a n t l y weaker than the coupl ing observed i n (141), s ince molecular models showed that the d i h e d r a l angle between H^ and H^ i n (142) was approximately 1 2 0 ° . Scheme 53 Treatment of a co ld ( - 7 8 ° C ) THF s o l u t i o n of the enol s i l y l ether (141) with tetra-n-butylammonium f l u o r i d e regenerated the ketone f u n c t i o n a l i t y and provided the compound (204) i n 93% y i e l d (Scheme 54). The i r spectrum of th i s mater ia l showed a t y p i c a l carbonyl absorpt ion at Compound (142) i s drawn as i t s enantiomer i n order to make the r e l a t i o n s h i p between (142) and (141) eas ier to see. 91 1700 c m - 1 , and the X H nmr spectrum showed two o l e f i n i c s ignals that had e s s e n t i a l l y the same coupling patterns as the protons H ,^ and of the enol s i l y l ether (141). Scheme 54 With the successful synthesis and rearrangement of the d i v i n y l -cyclopropane (137), the synthesis of the isomeric d iv iny lcyc lopropane (138) was undertaken (Scheme 55). Treatment of a THF s o l u t i o n of the s i l y l ether (201) with tetra-n-butylammonlura f l u o r i d e a f forded , af ter workup, the c r y s t a l l i n e a l coho l (205) i n 97% y i e l d . As a point of i n t e r e s t , the s t e r i c a l l y hindered environment around the s i l y l ether moiety i n (201) was exemplif ied by a required reac t ion time that was over double that required i n any previous d e s i l y l a t i o n r e a c t i o n . Nevertheless , ox idat ion of the a l coho l (205) with PCC i n dichloromethane proceeded as usual to give the v i n y l c y c l o p r o p y l ketone (134) i n greater than 94% y i e l d . Spectra l ana lys i s of (205) and (134) supported the proposed s t r u c t u r e s . 92 Scheme 55 Treatment of the ketone (134) i n the usual manner with LDA in THF followed by add i t i on of t e r t - b u t y l d i m e t h y l s i l y l ch lor ide and HMPA s u r p r i s i n g l y produced, by g lc a n a l y s i s , a complex mixture of products , the major component having a g lc re tent ion time c lose to that of the s t a r t i n g ketone (134). The des ired d iv iny lcyc lopropane (138), i f produced at a l l , was present i n only miniscule amounts. This d i sconcer t ing re su l t was examined more c l o s e l y . Reaction of the ketone (134) with LDA i n THF ( - 7 8 ° C ) , followed by b r i e f warming of the so lu t ion of enolate anion with a 0°C bath and treatment of the r e s u l t i n g reac t ion mixture with water, a f forded , by g lc a n a l y s i s , a mixture of two compounds, the s t a r t i n g ketone (134) and the same compound observed as the major product in the previous experiment. 93 This new product was iso l a t e d by chromatography, and spectros-copic analysis of t h i s material showed the following c h a r a c t e r i s t i c s . The i r spectrum exhibited a broad alcohol absorption at 3450 cm - 1 but no ketone absorption. The mass spectrum showed a parent mass equal to that of the st a r t i n g ketone (134), while the *H nmr spectrum showed the presence of three o l e f i n i c protons and the absence of a proton a to a hydroxy group. This spectroscopic data lead to the postulation that the structure of the new product was that shown for the alcohol (206) (Scheme 56). Scheme 56 Further attempts to make an enol ether from the v i n y l c y c l o p r o p y l ketone (134) f a i l e d , though an exhaustive study of this conversion was not undertaken. Instead, attention was turned to the unusual isomerization of the ketone (134) to the alcohol (206). Work done i n this regard Is described i n a l a t e r section of t h i s t h e s i s , and i n the meantime, the mechanism for the conversion of (134) to (206) i s l e f t as an i n t e l l e c t u a l exercise for the reader. 94 Despite f a i l i n g to prepare the divinylcyclopropane (138), the preparation and rearrangement of the divinylcyclopropane (137) further demonstrated the a p p l i c a b i l i t y of the divinylcyclopropane rearrangement as a key strategy for the preparation of novel t r i c y c l i c ring systems. This study also further exemplified the general a p p l i c a b i l i t y of the carbenoid addition reaction of ethyl diazoacetate to a l l y l i c s i l y l ethers as a viable approach to the preparation of v i n y l c y c l o p r o p y l ketones. As a further test of the general a p p l i c a b i l i t y of t h i s o v e r a l l strategy, a synthesis of the i n t e r e s t i n g natural product quadrone (34) was undertaken based on this strategy. 95 Synthesis of ( ± ) - Q u a d r o n e (34) INTRODUCTION A. I s o l a t i o n S t r u c t u r a l E l u c i d a t i o n , and B i o l o g i c a l Propert ies of  Quadrone (34) Work that was being conducted i n the middle 1970s by R a n i e r i and Calton of the W.R. Grace and Co. centered around the i s o l a t i o n of p o t e n t i a l l y usefu l antitumor compounds from various fermentation sources . In th is regard, the tox igenic fungus A s p e r g i l l u s terreus was i n v e s t i g a t e d , 9 2 > 9 3 and i t was found that the crude broth from t h i s fungus exhibi ted marked I n h i b i t o r y a c t i v i t y i n v i t r o against KB human epidermoid carcinoma of the nasopharynx and i n v ivo against P388 lymphocytic leukemia i n mice. Because of th i s a c t i v i t y , these workers used b i o l o g i c a l assays to guide them i n the i s o l a t i o n of the ac t ive component of th i s b r o t h . Their e f f o r t s led to the i s o l a t i o n of a c r y s t a l l i n e compound whose s p e c t r a l propert ies suggested the presence of geminal d imethyl , cyclopentanone, and 6-lactone funct ions . Single c r y s t a l X-ray analys i s of th i s substance showed i t to have the s tructure (34), and because of i t s inherent t e t r a c y c l i c r i n g system and ketone f u n c t i o n , (34) was given the t r i v i a l name quadrone . This i n i t i a l i n v e s t i g a t i o n f a i l e d , however, to ass ign the absolute stereochemistry of quadrone (34) . The systematic name for quadrone (34) i s octahydro-10,10-dimethyl -6,8b-ethano-8bH-cyclopenta[dej [2]benzopyran-1,4-dione (chemical abstracts numbering system). 96 It i s i n t e r e s t i n g to speculate on the o r i g i n of the antitumor a c t i v i t y shown by quadrone (34) . On f i r s t i n s p e c t i o n , th i s a c t i v i t y seems quite s u r p r i s i n g since quadrone (34) i s e s s e n t i a l l y devoid of any e l e c t r o p h i l i c f u n c t i o n a l i t y that i s commonly associated with other antitumor agents. 9 1 * However, Danishefsky and c o w o r k e r s , 9 9 i n designing a synthesis of ( ± ) - q u a d r o n e (34), made an important deduct ion. They recognized that the a-methylene keto ac id (207) was re la ted to quadrone (34) by a simple Michael reac t ion (Scheme 57). Compound (207) was reasoned to be a much more p l a u s i b l e cytotox ic agent s ince the presence of an a-methylene ketone funct ion had already been associated with the b i o l o g i c a l a c t i v i t y of other natura l products . 9 1 * Scheme 57 34 207 97 Evidence i n support of th i s reasoning was shown l a t e r by Sakai and coworkers 9 5 who reported the i s o l a t i o n of (207) from a d i f f e r e n t s t r a i n of A s p e r g i l l u s t e r r e u s . As might be expected, compound (207), named t e r r e c y c l i c ac id A, showed greater acute t o x i c i t y than quadrone * i t s e l f . In 1984, Isoe and coworkers reported a c h i r a l synthesis of t e r r e c y c l i c ac id A (207) which s tar ted from o p t i c a l l y pure (+)-fenchone. Synthetic (207), i s o l a t e d at the completion of th i s study, showed an o p t i c a l r o t a t i o n that was opposite to that reported for natura l t e r r e c y c l i c ac id A. This ind icated that natura l t e r r e c y c l i c ac id A (207) and quadrone (34) each had the absolute conf igurat ion shown i n Scheme 57. B. Biogenetic O r i g i n of Quadrone Quadrone (34) and t e r r e c y c l i c ac id A (207) represent a unique s t r u c t u r a l c lass of sesqui terpenoids . To date, they are the only two compounds known to possess th i s p a r t i c u l a r type of t r i c y c l i c carbon r i n g ske le ton . With th i s f a c t , i t i s i n t e r e s t i n g to speculate on the biogenet ic o r i g i n of (34) and (207) and see how th i s c lass of compounds might r e l a t e to the other c lasses of sesquiterpene n a t u r a l products . In a biogenic study conducted by Cane and cowo r k e r s , 9 6 [ 1 - 1 3 C ] and [ 1 , 2 - 1 3 C 2 ] acetate were fed separately to A s p e r g i l l u s t erreus , and the r e s u l t i n g 1 3 C enriched samples of quadrone (34) and t e r r e c y c l i c a c i d T e r r e c y c l i c ac id A (207) had a i n t r a p e r i t o n e a l LD^ Q value i n mice of 125-63 mg/kg while quadrone (34) had a value of greater than 340 mg/kg. 98 (207) were analyzed by 1 3C nmr. The resulting patterns of LiC enrichments and couplings demonstrated the mevalonoid origin of these metabolites, and i n addition indicated the likel i h o o d of farnesyl pyrophosphate as a biogenetic precursor. A biogenetic pathway consistent with the observed data i s shown in Scheme 58. Scheme 58 2 0 8 I 99 Cane and coworkers postulated that farnesyl pyrophosphate (208) first cyclizes to the humulyl cation (209). Then via a sequence involving two transannular cyclizations, two hydride shifts, and a final deprotonation, (209) is transformed into the intermediate (210), a compound that possesses the basic carbon framework of quadrone (34) and terrecyclic acid A (207). Oxidation and reduction of the intermediate (210) at the necessary centers provides terrecyclic acid (207) and subsequent cyclization of (207) produces quadrone (34). The intermediacy of a humulyl cation links the biogenesis of quadrone (34) to the biogeneses of a wide range of other structurally interesting natural products. A few examples of compounds that are also believed to arise biogenetically from the humulyl cation (209) include coriolin (211), fomannosin (212), illudin M (213), and pentalenene (214). 9 7» 9 8 The actual sequence of transformations that convert the humulyl cation (210) into each of these compounds will not be discussed in this thesis. Nevertheless, evidence for their biogenetic origins, in the form of labeling studies similar to that done for quadrone (34), can be found in references 97 and 98. 100 The biological properties and unusual chemical structure of quadrone (34), have tempted a large number of organic chemists Into pursuing a synthesis of this novel substance. To this date, a total of nine syntheses 9 9" 1 0 7 and four s t u d i e s 1 0 8 " 1 1 1 related to the synthesis of quadrone (34) have appeared. The range of synthetic ingenuity contained in a l l this work is quite amazing, but unfortunately it is beyond the range of this thesis to fully discuss each synthesis. However, notable aspects of each synthesis will be discussed as background material for the synthetic work to be discussed later in this thesis and simply for the general enlightenment of the reader. The first synthesis of (i)-quadrone (34) was reported by Danishefsky and coworkers99 in 1981. Their approach involved the systematic construction of the quadracyclic ring system via a stepwise annulation sequence of B + A + C + D (Scheme 59). This strategy appears to have been devised from a "logical" retrosynthetic analysis of the target molecule, (±)-quadrone (34), by such a manner as was described on page one of this thesis. 101 221 Scheme 59 2 0 7 3 4 102 As was mentioned e a r l i e r , Daneshefsky and coworkers reasoned that ( i ) - t e r r e c y c l i c ac id A (207) would cons t i tu te a reasonable target molecule in the synthesis of ( i ) -quadrone (34). The synthesis of (207) was accomplished, as shown in Scheme 59, from the enone (215). The f u n c t i o n a l i t y i n the enone (215) was used to introduce the appendages observed i n the compound (216), and an intramolecular condensation react ion of an intermediate derived from the compound (216) provided the b i c y c l i c enone (217). Compound (217), containing the A and B r ings of the quadrone r i n g system, was modified to the iodo ester (218). I n t r a -molecular a l k y l a t i o n of the ester enolate of (218) constructed the C r ing of ( i )-quadrone (34) and introduced an ester group at Cg on the C r ing with the correct s tereochemistry. Further e laborat ion of th i s intermediate afforded the keto ac id (219). Attempts to introduce f u n c t i o n a l i t y at the C 5 p o s i t i o n of (219) were thwarted due to the propensity of the C^ ketone to enol ize e x c l u s i -ve ly toward the C 3 p o s i t i o n . This problem was circumvented by b locking the C 3 p o s i t i o n with a double bond as shown by the compound (220). F u n c t l o n a l i z a t i o n of the C 5 p o s i t i o n was now poss ib le and the i n t e r -mediate (221) was r e a d i l y elaborated into ( i ) - t e r r e c y c l i c ac id A (207). As pred ic ted , ( ± ) - t e r r e c y c l i c acid A (207) could be converted d i r e c t l y into ( i )-quadrone (34). Heating of (207) (neat) at 1 9 0 - 1 9 5 ° C for approximately 6 min proved to be the best cond i t ions , providing an e q u i l i b r i u m 1:4 mixture of ( i ) - t e r r e c y c l i c acid A (207) and ( ± ) - q u a d r o n e (34), r e s p e c t i v e l y . This general s trategy , of f i r s t construct ing r ings A and B of the quadrone r ing system, then construct ing r ing C v i a an intramolecular 103 al leviat ion of an ester enolate derived from an iodo ester l i k e (218) , was also used by Helquist and c o w o r k e r s 1 0 0 i n a synthesis of ( ± ) - q u a d r o n e (34) . The report of th is work appeared shor t ly a f ter the synthesis reported by Danishefsky and coworkers. This same approach was used l a t e r by Isoe and c o w o r k e r s 1 0 6 who, as mentioned e a r l i e r , synthesized t e r r e c y c l i c ac id A (207) i n an o p t i c a l l y act ive form from (+)-fenchone. As further demonstration of the appeal of th i s general s trategy , Iwata and c o w o r k e r s 1 0 7 published yet another synthesis based on t h i s approach. However, Helquis t and coworkers, who used the iodo ester (222) as an intermediate , and Isoe and Iwata and t h e i r respect ive coworkers, who used the iodo ester (223) as an intermediate , a l l avoided the regiochemical problems encountered by Danishefsky and coworkers i n t h e i r attempt to f u n c t i o n a l i z e the keto ac id (219) at the C 5 p o s i t i o n . Nevertheless , the enone (220), synthesized by Danishefsky and coworkers i n an attempt to solve th i s regiochemical problem, proved to be a popular target molecule i n subsequent syntheses of (t)-quadrone (34) . 222 223 The t h i r d synthesis of ( i ) -quadrone (34) to appear was published by Burke and c o w o r k e r s . 1 0 1 3 They approached the cons truct ion of the 104 carbon ring skeleton of (±)-quadrone (34) in a manner entirely different from that just described. Their synthesis, as outlined in Scheme 60, relied on an oxidative cleavage/Michael addition/aldol cyclization sequence in converting the spiro[4.5]decadienone (224) into the tricyclic intermediate (227). Scheme 60 105 The spiro compound (224), a mater ia l synthesized by Burke and coworkers in a previous i n v e s t i g a t i o n , was o x i d a t i v e l y cleaved to the keto aldehyde (225). In a key two step reac t ion sequence, the various n u c l e o p h i l i c and e l e c t r o p h i l i c s i t e s i n (225) were made to react as des ired to form the t r i c y c l i c intermediate (227). F i r s t l y , r e f l u x i n g a benzene so lu t ion of (225) with morpholine and p- to luenesul fonic ac id ef fected a Michael add i t i on react ion to the b i c y c l i c compound (226). Secondly treatment of a benzene s o l u t i o n of (226) with potassium hydro-xide and a phase transfer ca ta ly s t promoted an a l d o l c y c l i z a t i o n to the t r i c y c l i c intermediate (227). This sequence success fu l ly constructed the t r i c y c l i c carbon framework of ( ± ) - q u a d r o n e (34). The f u n c t i o n a l i t y i n (227) was then modified to the a l l y l i c a lcohol and ace ta l moieties found i n the compound (228). Treatment of (228) with e thy l v i n y l ether and mercury(II) acetate , followed by Cla i sen rearrangement of the r e s u l -t ing v i n y l ether provided the unsaturated aldehyde (229). This interme-diate could be converted into the keto ac id (219) v i a a three step se-quence of react ions that involved hydrogenation of the carbon-carbon double bond, ox idat ive decarbonylat ion of the aldehyde moiety, and removal of the ke ta l protect ing group. Since compound (219) had been converted into (t)-quadrone by Danishefsky and c o w o r k e r s , " the a c q u i s i t i o n of the former substance const i tuted a formal t o t a l synthesis of (t)-quadrone (34) . In a l a t e r p u b l i c a t i o n , 1 0 6 * * Burke and coworkers modified the C la i sen rearrangement product (229) into the keto aldehyde (230), and then used (230) (Scheme 61) to f i n i s h the synthesis of ( ± ) - q u a d r o n e (34) v i a a sequence of react ions d i f f e r e n t from that employed prev ious ly by Danishefsky and c o w o r k e r s . " 106 Scheme 61 The keto aldehyde (230) was treated with a mixture of acetic acid and sulfuric acid to effect an aldol reaction, and the resulting acetoxy ketone was pyrolyzed to provide the unsaturated ketone (231). Reduction of the carbonyl group in (231) (LAH) followed by protection of the resulting alcohol, afforded the s i l y l ether compound (232). Ozonolysis of (232) followed by reductive workup with sodium borohydride furnished the diol (233). This material was converted into (±)-quadrone (34) by a two step oxidation sequence involving Fetizon's reagent (Ag 2C0 3-celite) and Jones' reagent. The modest yield in this two step procedure reflected a lack of site-selectivity in the diol to 6-lactone conversion. The regioisomeric lactone (234) was also isolated in 47% yield after the i n i t i a l oxidation. 107 The fourth synthesis of ( i)-quadrone (34) to appear was published by Kende and c o w o r k e r s . 1 0 2 The ir synthet ic plan centered around the a p p l i c a t i o n of a novel pal ladium(II) mediated c y c l o a l k e n y l a t i o n r e a c t i o n , a new method that they had just developed for the cons truc t ion of bridged p o l y c y c l i c r i n g systems. The key step i n the reac t ion sequence i s shown i n Scheme 62. Scheme 62 235 236 220 Reaction of the f u n c t i o n a l i z e d enol s i l y l ether (235) under standard c y c l o a l k e n y l a t i o n condit ions (1 equiv of pal ladium(II) acetate , a c e t o n i t r i l e , room temperature, 8 h) a f forded , a f ter workup and chroma-tography, the b i c y c l i c ketone (236) i n greater than 55% y i e l d . This key reac t ion es tabl i shed the b icyc lo [3 .2 .1Joctane por t ion of the quadrone r ing skeleton and provided useful f u n c t i o n a l i t y that could be used to elaborate (236) into the t r i c y c l i c enone (220), an intermediate prev ious ly c a r r i e d onto ( ± ) - q u a d r o n e (34) by Danishefsky and coworkers . 9 Another approach to ( i ) -quadrone (34) was reported by Y o s h i i and c o w o r k e r s , 1 0 3 and i t centered around the a p p l i c a t i o n of an i n t e r e s t i n g 108 solvolylic rearrangement reaction. The key step of their synthesis is shown in Scheme 63. Scheme 63 237 238 220 The tt-hydroxycylobutane (237) was converted into the bicyclic ketone (238) in 31% yield via a three step sequence involving formolysis of (237) at 25°C for 40 h, hydrolysis of the resulting formates with aqueous sodium hydroxide, and oxidation of the resulting alcohols with PCC. This key sequence, like that of Kende and coworkers, established a functionalized bicyclo[3.2.1]octane product that was suitable for elaboration into the intermediate (220), previously prepared by Danishefsky and coworkers. Perhaps one of the most widely used synthetic strategies in organic synthesis is the intramolecular Diels-Alder r e a c t i o n . 1 1 2 In both the past and the present, this reaction has been used as the key step in an incredible number of diverse syntheses. Unfailingly, this strategy has also been applied to the synthesis of (±)-quadrone (34). In two separate but nevertheless highly similar approaches, Schlessinger 109 and coworkers 1 0 and Vandewalle and coworkers 1 0 b both reported a synthesis of (t)-quadrone (34) based on this reaction. The essence of their approach is outlined in Scheme 64. Scheme 64 239 240 220 In both syntheses, heating the enone (239) at approximately 120°C effected an intramolecular Diels-Alder reaction to provide the t r i c y c l i c ketone (240). This reaction set up the required bicyclo[3.2.1]octane portion of the quadrone ring system. The cyclohexene ring was then modified and later oxidatively cleaved to provide a suitable compound that could once again be elaborated to the Danishefsky intermediate (220). The discussion given above briefly summarizes a l l the total syntheses of quadrone (34) published to date. In addition to this work, references 108-111 describe studies directed towards the synthesis of (34), which though not culminating in total syntheses, do involve ingenious approaches that deserve closer examination by the reader. Despite a l l the synthetic efforts devoted towards quadrone (34), 110 the divinylcyclopropane rearrangement strategy about to be described involves a totally different approach to the construction of the tricyclic carbon ring skeleton of this interesting natural product. This approach, we feel, compliments the existing array of ingenious synthetic strategies. I l l Synthesis of ( ± ) - Q u a d r o n e (34) DISCUSSION A. Synthetic Plan The f i r s t two model s tud ies , discussed e a r l i e r i n th i s t h e s i s , i l l u s t r a t e d the preparat ion of the two enol s i l y l ethers (139) and (140), and as was shown previous ly in Scheme 27, (139) and (140) each have the same carbon r ing skeleton as the na tura l quadracycl ic lactone quadrone (34) . It was envisaged that the general strategy used for the preparat ion of the enol s i l y l ethers (139) and (140) might also be appl i cab le to the synthesis of a su i tab le d e r i v a t i v e of (139) or (140) which could i n turn be elaborated into ( ± ) - q u a d r o n e (34). The f i r s t question that had to be asked regarding th i s idea was what a d d i t i o n a l features would have to be incorporated into e i ther (139) or (140) i n order to make a usefu l d e r i v a t i v e that might be su i tab le for e laborat ion into quadrone (34) . The analys i s of th i s question i s shown in Scheme 65. The analys i s was i n i t i a l l y s i m p l i f i e d by the recogni t ion that the keto ac id (219) and the keto aldehyde (230), compounds synthesised by Danishefsky and coworkers and by Burke and coworkers in t h e i r respect ive synthesis of ( ± ) - q u a d r o n e (34) would each make su i tab le synthet ic targets that could be constructed v i a our d iv iny lcyc lopropane rearrange-ment s trategy . It was apparent that the enol s i l y l ethers (139) and (140) would have to be modified to incorporate an oxygen funct ion at 112 carbon J and a su i tab le a l k y l or acy l subst i tuent at carbon H of the t r i c y c l i c r i n g ske le ton . The inherent enol s i l y l ether funct ion In both (139) and (140) could be used to introduce the required geminal dimethyl group at carbon A. Scheme 65 Trans la t ing th i s ana lys i s into the d iv iny lcyc lopropane p r e c u r -sors , der iva t ives of (135) and (136) would have to be prepared that 113 contained an oxygen function at carbon J and a suitably oriented substituent at carbon H. A choice had to be made between pursuing the synthesis of quadrone (34) via a functionalized form of the divinylcyclopropane (135) or (136). For the following reasons, i t was decided that a functiona-lized form of the divinylcyclopropane (135) would be a better choice. Fi r s t l y , the divinylcyclopropane (135) was prepared from the readily available a l l y l i c s i l y l ether (148) (Scheme 66). The precursor to the divinylcyclopropane (136), the a l l y l i c s i l y l ether (149), was isolated as a minor product in a reaction sequence designed primarily to construct the a l l y l i c s i l y l ether (148). This would thereby necessitate a different and more efficient synthesis of the a l l y l i c s i l y l ether functionality in (148) i f a derivative of (148) were to be used in the synthesis of (i)-quadrone (34). 114 Secondly, the y i e l d of the carbenoid addi t ion of e thy l d i a z o -acetate to the a l l y l i c s i l y l ether (148) (preparat ion of (151)) was s i g n i f i c a n t l y higher than that of the corresponding addi t ion invo lv ing (149) as substrate (preparat ion of (152)) . T h i r d l y , i t was envisaged that the in t roduc t ion of a s tereo-chemical ly correct a l k y l or acy l group at carbon H on the t r i c y c l i c carbon skeleton af ter rearrangement would be eas ier i f the synthesis were pursued v i a a func t iona l i zed form of the d iv iny lcyc lopropane (135). As can be seen in Scheme 65, the appendages at carbon H for both the keto ac id (219) and the keto aldehyde (230) must have the s tereo-chemistry shown in order that further e laborat ion to ( ± ) - q u a d r o n e (34) be p o s s i b l e . The in troduc t ion of th i s appropriate appendage was predicted to be d i f f i c u l t v i a a func t iona l i zed form of the d iv iny lcyc lopropane (136). To allow for appendage i n t r o d u c t i o n v i a a compound l i k e (136), a molecule l i k e the endo-div inylcyclopropane (241) would have to be prepared (Scheme 67). The synthesis of (241), though not imposs ib le , could cause s i g n i f i c a n t problems. In a d d i t i o n , the r e s u l t i n g product (242) formed on rearrangement of (241) would not yet have the required stereochemistry at carbon H because of the carbon-carbon double bond. On examination of molecular models, i t was predicted that any reduct ion of th i s double bond would l i k e l y occur from the more open top face of the molecule, as drawn, to produce the adduct (243), a compound with the wrong stereochemistry at carbon H. It was also predicted that any attempts to epimerize the subst i tuent at carbon H would l i k e l y favor the isomer (243) with the incorrec t s tereochemistry. 115 Scheme 67 242 243 On the other hand, the use of a functionalized version of the divinylcyclopropane (135) appeared to be well suited for the introduc-tion of an appropriate alkyl or acyl substituent at carbon H. As shown earlier in Scheme 18, the rearrangement of the divinylcyclopropanes (103) and (108) occurred stereospecifically to produce the bicyclic enol si l y l ether products (109) and (110), respectively. COOMe 103 109 108 110 116 These r e s u l t s ind icated that a d iv iny lcyc lopropane such as (244) (Scheme 67), containing a c i s - o r i e n t e d a l k y l or acy l subst i tuent at carbon H, should prov ide , on rearrangement, a t r i c y c l i c enol s i l y l ether intermediate such as (245) with a stereochemical ly correct a l k y l or acy l moiety at the required p o s i t i o n on the t r i c y c l i c carbon r ing ske le ton . Since e i ther the keto ac id (219), prepared by Danishefsky and coworkers, or the keto aldehyde (230), prepared by Burke and coworkers, were considered v iab l e synthet ic targets on route to ( i ) -quadrone (34), the re trosynthe t i c ana lys i s shown in Scheme 68 was devised . The keto ac id (219), prepared by Danishefsky and coworkers, was perceived as being der ivable by func t iona l group manipulat ion of the enol s i l y l ether compound (246), which i n turn was expected to be produ-ced from the thermal rearrangement of the d iv iny lcyc lopropane (247). The required ketone funct ion i n (219) at carbon J was planned on being c a r r i e d through the synthesis as an ace ta l group, while the ac id group at carbon H was thought to be a v a i l a b l e from a protected a lcohol f u n c t i o n . Analogously, the keto aldehyde (230), prepared by Burke and coworkers, was perceived as being der ivable by func t iona l group manipu-l a t i o n of the enol s i l y l ether compound (253), which i n turn was expected to be a v a i l a b l e by thermal rearrangement of the d i v i n y l c y c l o -propane (252). The protected aldehyde side chain at carbon H i n (252) was chosen because the required aldehyde and ketone functions i n (230) could be l i b e r a t e d simultaneously i n a s ing le deprotect ion r e a c t i o n , and because the W i t t i g reac t ion between the known phosphorane (250) and the aldehyde (251) was expected to introduce the required side chain i n 117 Scheme 68 only one synthetic step. For these two reasons, it was decided to attempt the synthesis of (±)-quadrone (34) via the intermediate (230)• The preparation of the aldehyde (251) was anticipated to be viable via a sequence of reactions similar to that used in the first model study. Explicitly, carbenoid addition of ethyl diazoacetate to 118 the a l l y l i c s i l y l ether (249), followed by func t iona l group manipulat ion of the r e s u l t i n g cyc lopropy l ester mixture, would be expected to provide a convenient route to (251). The a l l y l i c s i l y l ether (249) was thought to be preparable from the r e a d i l y a v a i l a b l e c i s - b i c y c l o [ 3 . 3 . 0 ] o c t a n e -3,7-dione (248). B. Synthetic Studies Directed Towards the Preparat ion of the  Div inylcyclopropane (252) The s t a r t i n g mater ia l chosen for the synthes i s , c i s - b i c y c l o -[3 .3 .0]octane-3 ,7-dione (248), was commercially a v a i l a b l e and also r e a d i l y synthesized i n large quant i t i e s v i a a procedure reported by Kubiak, Cook, and Weiss (Scheme 6 9 ) . 1 1 3 This procedure involved the condensation reac t ion between two molecules of dimethyl 3-ketoglutarate and one molecule of g l y o x a l , followed by ac id catalyzed h y d r o l y s i s -decarboxylat ion of the r e s u l t i n g b i c y c l i c t e traes ter intermediate (254). Scheme 69 H 248 MeOOC COOMe MeOOC 254 119 The s t a r t i n g dione (248) already contained the required b i c y c l o -[3.3.0]octane ske le ton. The plan was to protect one of the ketone groups in (248) as an a c e t a l , and to convert the other ketone group into the a l l y l i c s i l y l ether funct ion found i n (249). The a c e t a l protected ketone was u l t imate ly intended to become the ketone moiety present i n ( ± ) - q u a d r o n e (34) . The preparat ion of the a l l y l i c s i l y l ether (249) i s out l ined i n Scheme 70. Reaction of the dione (248) with 1 equiv of 2 , 2 - d i m e t h y l - l , 3 -propanediol and a c a t a l y t i c amount of p - to luenesu l fon ic a c i d i n r e f l u x i n g benzene provided a s t a t i s t i c a l 1:2:1 mixture of the s t a r t i n g dione (248), the keto a c e t a l (256), and the d i a c e t a l (255), r e s p e c t i v e -l y . The three components of th i s mixture could e a s i l y be separated by column chromatography, and the recovered dione (248) and d i a c e t a l (255) were e q u i l i b r a t e d to the same s t a t i s t i c a l 1:2:1 mixture of (248), (256), and (255) by t r e a t i n g an equimolar mixture of (248) and (255) with p- to luenesul fonic ac id i n benzene. This s e p a r a t i o n - e q u i l i b r a t i o n procedure was repeated once more to provide the keto ace ta l (256) i n a t o t a l y i e l d of 79%. The i r spectrum of (256) showed the required carbonyl absorpt ion at 1730 c m - 1 , and the *H nmr spectrum was consis tent with the symmetrical nature of the molecule. Heating an ethanol s o l u t i o n of the keto a c e t a l (256) and p-toluene sulfonhydrazide effected the formation of the hydrazone (257) (96% y i e l d ) . Treatment of a co ld ( - 7 8 ° C ) ether-HMPA so lu t ion of (257) with a so lu t ion of n - b u t y l l i t h i u r a , followed by warming of the r e a c t i o n mixture to room temperature, resu l ted i n c lean decomposition of the t o s y l h y d r a -zone moiety i n (257) to the alkene funct ion i n (258) (Shapiro r e a c t i o n ) . 1 120 Scheme 70 121 C r y s t a l l i n e (258) was i s o l a t e d af ter workup i n 96% y i e l d . The i r spectrum of th is mater ia l showed an expected C=C absorption at 1610 c m - 1 , and the *H nmr showed the presence of two o l e f i n i c protons (6 5.59 and 6 5.55, = 5.5, 2.2, 2 .2 , 2.2 Hz in each case) . The alkene (258) was converted into the a l l y l i c s i l y l ether (249) by a ser ies of react ions s i m i l a r to that used i n the f i r s t model s tudy. S p e c i f i c a l l y , treatment of a DMS0-H20 so lu t ion of (258) with N B S , 7 5 followed by immediate treatment of the r e s u l t i n g crude bromohydrin product with potassium carbonate i n methanol furn i shed , by *H nmr a n a l y s i s , a 3:1 mixture of the a-epoxide (259) and the B-epoxide (260), r e s p e c t i v e l y , in a combined y i e l d of 93%. Reaction of the epoxide mixture with sodium phenylselenide i n ethanol-THF, followed by aqueous hydrogen peroxide ox idat ion of the selenides and heating of the r e s u l t i n g se lenoxides , gave a complex mixture of a l l y l i c a lcohols and some ketonic products . The des ired a l l y l i c a l coho l (261) was conveniently separated from the mixture by columnm chromatography (43% i s o l a t e d y i e l d ) . The i r spectrum of t h i s mater ia l showed the required broad 0-H absorption at 3320 c m - 1 and the *H nmr spectrum (Figure 18) showed the presence of two o l e f i n i c protons (6 5.79 and 6 5.70) and an a l l y l i c proton a to the hydroxyl group (6 4 .66) . Protec t ion of the a l coho l funct ion i n (261) as a t e r t - b u t y l d i m e t h y l s i l y l ether was accomplished i n near q u a n t i t a t i v e y i e l d by treatment of a DMF s o l u t i o n of (261) with imidazole and t e r t - b u t y l d i m e t h y l s i l y l c h l o r i d e . Several aspects of the work summarized i n Scheme 70 require further e l a b o r a t i o n . The dimethylpropylene ace ta l pro tec t ing group, found i n the keto a c e t a l (256), was chosen over the more commonly used 122 ethylene aceta l for three reasons. F i r s t l y , experience in our laboratory had shown that compounds containing a dimethylpropylene ace ta l as a protect ing group had a higher propensity to be c r y s t a l l i n e i n nature than the corresponding compounds containing an ethylene a c e t a l . Secondly and t h i r d l y the presence of the two methyl groups provided good ind ica tor s ignals in the nmr spectra for compound p u r i t y , and prevented the p o s s i b i l i t y of fragmentation of the ace ta l group under s trongly bas ic condit ions . This fragmentation process was a d e f i n i t e p o s s i b i l i t y i n the Shapiro reac t ion and i n other react ions that were to be used l a t e r i n the synthes i s . For the conversion of the hydrazone (257) into the alkene (258), the use of HMPA was found to be c r u c i a l . In the absence of HMPA, the alkene (258) was produced in an impure form (90% by g lc ana lys i s ) and i n y i e l d s ranging between 50 and 70%. In no way was the presence of HMPA found to be detr imental to the r e a c t i o n , s ince after simple aqueous workup, the alkene (258) could be i s o l a t e d pure and i n high y i e l d s . Other p r o c e d u r e s 1 1 4 have prescr ibed the use of TMEDA as opposed to HMPA. However e f f i c i e n t removal of the TMEDA during workup can be d i f f i c u l t , and i n some cases repeated ac id washing i s r e q u i r e d . This was not des ired i n l i g h t of the ac id s ens i t ive nature of the ace ta l group present i n (258). Epoxide formation v i a the bromohydrin route produced a rather d isappoint ing 3:1 mixture of the epoxides (259) and (260), r e s p e c t i v e l y . The fragmentation of c y c l i c acetals that contain hydrogens pos i t ioned 8 to e i ther of the ace ta l oxygens i s a side reac t ion that i s common when aceta ls are subjected to s trongly bas ic condit ions at higher reac t ion temperatures. 123 This r a t i o was worse than the 4:1 r a t i o obtained in the f i r s t model study. The increase i n the r e l a t i v e proport ion of the 8-epoxide (260) was thought to be p r i m a r i l y due to coord inat ion of the incoming B r + species to the a-oriented oxygen of the ace ta l group. Attempts to use other reagents (eg. NIS, D M S 0 - H 2 0 1 1 5 ; A g 2 0 , I 2 , d i o x a n e - H 2 0 1 1 6 ) for the preparat ion of the a-epoxide (259) d id not produce a better r a t i o of (259) to (260), and in most cases, the o v e r a l l y i e l d s were not as good. Glc ana lys i s of the epoxide mixture containing (259) and (260) unexpectedly showed only one peak and t i c ana lys i s showed only one spot . The r a t i o of (259) to (260) therefore had to be es tabl i shed by lR nmr a n a l y s i s . Two pa ir of methyl s ing le t s could c l e a r l y be seen. Integra-t ion of these s ignals ind icated the presence of two isomers i n a r a t i o of approximately 3:1. This was a s u r p r i s i n g contrast to the two epoxides (161) and (162) synthesized i n the f i r s t model study, which c l e a r l y showed two peaks by g lc ana lys i s and two spots by t i c a n a l y s i s . The lack of chromatographic separat ion between the epoxides (259) and (260) necess i tated using the 3:1 mixture i n the subsequent i s o m e r i -zat ion r e a c t i o n . This was c e r t a i n l y not d e s i r a b l e , s ince the a p p l i c a -t i o n of the Sharpless and Lauer i somer izat ion procedure to (259) alone was ant ic ipated to produce a mixture of isomers. Indeed, subject ion of the mixture of epoxides to the Sharpless and Lauer procedure did produce a complex mixture of isomers, but , again i n complete contrast to the f i r s t model study, the des ired a l l y l i c a l coho l isomer (261) could i n th i s case be separated r e a d i l y by column chromatography. The conversion of the alkene (258) into the a l l y l i c a l coho l (261) was accomplished i n a rather mediocre y i e l d of 40%. Unfortunate ly , 124 attempts to increase the efficiency of this conversion via the application of different reaction sequences were unsuccessful. The allylic oxida-tion of the alkene (258) with the chromic anhydride-3,5-dimethylpyrazole complex117 (Scheme 71) did produce the enone (262) in a yield of 41% after purification. However, even if the subsequent reduction of (262) to (261) would have occurred in quantitative yield, the overall conver-sion of the alkene (258) to the allylic alcohol (261) would not have been any more efficient than the sequence used. For this reason the established conversion was accepted, and in its favor, it did provide convenient access to multigram quantities of the allylic alcohol (261). Scheme 71 2 5 8 2 6 2 2 6 1 Evidence for the a-stereochemistry of the allylic s i l y l ether moiety in (249) was provided by a *H nmr analysis similar to that u6ed for the allylic s i l y l ether (148) in the ini t i a l model study. The presence of three equal couplings to the proton in (249) (6 2.44, J_ • 10, 8, 8, 8 Hz) suggested that three of the adjacent protons must be situated with approximately the same dihedral angle to H . This would 125 only be possible if the sil y l ether moiety in (249) had the stereo-chemistry shown. 2 4 9 Figures 18 and 19 show the 1H nmr spectra of the allylic alcohol (261) and the allylic s i l y l ether (249), respectively. It is interest-ing to observe the significant chemical shift and coupling differences between similar protons in the two compounds. These two spectra clearly show the marked effect that a single substituent change can have on the *H nmr spectrum. With ample quantities of the allylic s i l y l ether (249) in hand, its reaction with ethyl diazoacetate was investigated. It is interest-ing to note that a l l of the synthetic intermediates prior to the allylic si l y l ether (249) were white crystalline solids. This had caused some concern with regard to the carbenoid addition reaction, since the reaction of ethyl diazoacetate with alkenes was found to be most efficient when neat liquid alkene substrate was used. Fortunately and somewhat surprisingly, the allylic s i l y l ether (249) did in fact turn out to be a free flowing liquid. Scheme 72 summarizes the results of the carbenoid addition reaction and the subsequent reactions that were used to prepare the aldehyde (251). 126 5 3 2 PPm i 0 Figure 19. The 400 MHz XH nmr Spectrum of the A l l y l i c S i l y l Ether ( 2 4 9 ) 127 128 Addi t ion of 3 equiv of e t h y l diazoacetate over a period of 16 h to the a l l y l i c s i l y l ether (249) (Rh 2 (OAc) H c a t a l y s t ) provided, a f t er chromatographic removal of unreacted s t a r t i n g m a t e r i a l , d i e t h y l maleate, and d i e t h y l fumarate, a mixture of addi t ion and i n s e r t i o n products i n 90% y i e l d , based on unrecovered s t a r t i n g m a t e r i a l . Glc ana lys i s of th i s mixture showed i t to cons is t of a 10:6:1 mixture of three compounds that were presumed to be the exo-cyc lopropyl ester (263a), the endo-cyc lopropy l ester (263b), and the i n s e r t i o n adduct (264), r e s p e c t i v e l y , based on analogy with the f i r s t model study. The separat ion of these three compounds proved to be d i f f i c u l t , so f u l l c h a r a c t e r i z a t i o n was not attempted. The mixture of (263a), (263b), and (264) was reduced with l i t h i u m aluminum hydride i n ether to a f f o r d , af ter workup, the a lcohol mixture (265) together with the reduced i n s e r t i o n adduct (266) in a combined y i e l d of 91%. Oxidat ion of th i s a l coho l mixture with PCC i n d i c h l o r o -methane gave the aldehyde mixture (267) and the aldehyde (268). Treatment of a THF s o l u t i o n of the crude aldehyde mixture conta in ing both (267) and (268) with potassium tert -butoxlde in t e r t - b u t y l a lcohol furnished , af ter workup and chromatography, pure exo-aldehyde (251) (65% y i e l d from the a lcohol mixture of (265) and (266)) and a small quanti ty of the aldehyde (268) . The mixtures shown i n Scheme 72 gave s a t i s f a c t o r y i r and mass s p e c t r a l data that was consistent with the proposed s t r u c t u r e s . The ^H nmr spectrum of the aldehyde (251) showed the presence of an aldehydic proton (6 9.06, J_ = 5 Hz) and a proton a to the s i l y l ether moiety (6 4.13, J = 6 Hz) . The fact that the proton a to the s i l y l 129 ether moiety was observed only as a doublet provided evidence, once again, that the carbenoid addi t ion of e thy l diazoacetate had occurred e x c l u s i v e l y from the B-face of the b icyc lo [3 .3 .0 ]oc tene skeleton of the a l l y l i c s i l y l ether (249). With the stereochemistry of the cyclopropane r ing as shown for the aldehyde (251), the angle between the proton a to the s i l y l ether group and the adjacent cyc lopropy l proton i s approxima-t e l y 9 0 ° . Evidence for the s tructure of the aldehyde (268) was provided by *H nmr analys i s which showed the presence of an aldehydic proton ( 6 9 .68, J = 2.5, 2.5 Hz) , two o l e f i n i c protons (6 5.80 and 6 5.53, J_ = 6.2 Hz i n each case) and an a l l y l i c proton a to the s i l y l ether moiety (6 4.93, J_ = 8, 2, 2 Hz) . With s u f f i c i e n t quant i t i e s of the pure exo-aldehyde (251) i n hand, the next task was to transform the aldehyde group into an appropriate side chain with a c i s carbon-carbon double bond. This operation was accomplished, as shown i n Scheme 73, by a W i t t i g reac t ion done according to the procedure reported by Stowell and K e i t h . 1 1 8 Thus, reac t ion of the aldehyde (251) with a DMSO-THF so lu t ion of the phosphorane (250), prev ious ly prepared by reac t ion of the corresponding phosphonium bromide with potassium t e r t - b u t o x i d e , provided, by g lc a n a l y s i s , the alkene (269) as a 9:1 mixture of c i s - and trans- i somers , r e spec t ive ly (combined y i e l d of 87%). The i r spectrum of th i s m a t e r i a l showed a weak C=C absorption at 1640 c m - 1 , and the mass spectrum showed the required parent mass of 478. The two isomers were not r e a d i l y separable by conventional chromatography, so (269) was c a r r i e d on to the next reac t ion as a mixture . 130 Reaction of the alkene mixture (269) with tetra-n-butylammonium fluoride in THF afforded, after workup, a 96% yield of the alcohol 131 mixture (270). This mixture was allowed to react with PCC i n d i c h l o r o -methane to g ive , by g lc a n a l y s i s , a 9:1 mixture of the v i n y l c y c l o p r o p y l ketones (271) and (272), r e s p e c t i v e l y , in 93% y i e l d . These two com-pounds were also d i f f i c u l t to separate by conventional chromatography. However, i t was found that the major c i s - i somer (271) could e a s i l y be p u r i f i e d by f r a c t i o n a l c r y s t a l l i z a t i o n of the mixture from heptane (66% y i e l d of i s o m e r i c a l l y pure (271)) . It was also found that the mother l i q u o r s from the f i r s t r e c r y s t a l l i z a t i o n provided a reasonably pure sample of the trans-isomer (272) which could i n turn be p u r i f i e d further by f r a c t i o n a l c r y s t a l l i z a t i o n from heptane. The separation of the c i s -and trans-isomers v i a f r a c t i o n a l c r y s t a l l i z a t i o n was found to be far more e f f i c i e n t at the ketone stage rather than at the s i l y l ether or the a lcohol stages. Evidence for the stereochemistry about the a lkenyl moiety i n com-pounds (271) and (272) was provided, i n each case, by the coupl ing con-stant between the two o l e f i n i c protons. In the *H nmr spectrum of the v i n y l c y c l o p r o p y l ketone (271) (Figure 20), the two o l e f i n i c protons (6 5.45 and 6 4.90) exhibi ted a coupling constant of 11 Hz, while the c o r -responding coupling constant between the two o l e f i n i c protons (6 5.56 and 6 5.07) i n the *H nmr spectrum of the v i n y l c y c l o p r o p y l ketone (272) was 15.5 Hz. C l e a r l y on the basis of es tabl i shed coupl ing values between c i s - and trans -or iented protons on a carbon-carbon double b o n d , 8 6 the stereochemistry of the side chain i n both (271) and (272) was beyond doubt. With the successful synthesis of the v i n y l c y c l o p r o p y l ketone (271), the second required v i n y l group had to be introduced i n the form of a t e r t - b u t y l d i m e t h y l s i l y l enol e ther . This transformation proved to 132 133 r be far more d i f f i c u l t than was expected based on analogy with the f i r s t model study. Subjection of the vinylcyclopropyl ketone (271) to the usual reaction conditions, that i s , reaction with 1.2 equiv of LDA in THF at -78°C, followed by treatment of the resulting solution with HMPA and tert-butyldimethylsilyl chloride, provided, in addition to recovered starting material, primarily a new compound that, by glc analysis, had a glc retention time shorter than that of the starting vinylcyclopropyl ketone. Essentially none of the desired divinylcyclopropane (252) was detected. Chromatographic isolation of this new compound and subsequent characterization showed i t to have the structure (273) (Scheme 74). Scheme 74 134 The i r spectrum of (273) showed the presence of a conjugated aldehyde funct ion (C-H absorpt ion , 2700 c m - 1 ; C=0 absorpt ion , 1680 c m - 1 ) and an enol s i l y l ether funct ion (strong C=C absorpt ion , 1650 c m - 1 ) and the mass spectrum showed a parent mass of 418. The *H nmr spectrum of (273) showed the presence of an aldehyde proton ( 6 9.53, J[ = 8 Hz) , four o l e f i n i c protons each with one large coupl ing constant ( 6 7.06, J_ = 16, 9.5 Hz; 6 6-26, J = 15.5, 9.5 Hz; 6 6.19, J = 15.5, 6.5 Hz; 6 6.07, J = 16, 8 Hz) , and an enol s i l y l ether proton ( 6 4.37, wj = 4 Hz) . The s u r p r i s i n g formation of the conjugated aldehyde (273) instead of the d iv iny lcyc lopropane (252) was i n i t i a l l y r a t i o n a l i z e d according to the mechanism shown i n Scheme 75- It was postulated that before the enolate anion (274) could react with the t e r t - b u t y l d i m e t h y l s i l y l c h l o r i d e , a process that requires a temperature around room temperature, another enolate anion or any excess LDA could abstract a proton 8 to the oxygen funct ion of the c y c l i c a c e t a l group to form, a f ter fragmentation of the ace ta l moiety, the aldehyde species (275) . E q u i l i b r a t i o n of (275) to the more stable enolate (276), followed by opening of the cyclopropane r i n g , would provide the intermediate enolate (277), which upon trapping with t e r t - b u t y l d i m e t h y l s i l y l c h l o r i d e , would give the observed conjugated aldehyde (273) • The formation of the enolate (274) was v e r i f i e d by t r e a t i n g the ketone (271) with LDA i n THF at - 7 8 ° C and then adding D 2 0 to the r e s u l t -ing reac t ion mixture . The *H nmr spectrum of the r e s u l t i n g deuterated ketone showed e s s e n t i a l l y the complete absence of the proton s i tuated a to the ketone funct ion at the bridgehead p o s i t i o n on the 5-5 r i n g system. 135 Scheme 75 -B If the process shown in Scheme 75 was indeed occurring, then replacement of the two protons situated p to the oxygen functions of the cyclic acetal moiety with two methyl groups should prevent the acetal fragmentation. In this regard, the vinylcyclopropyl ketone (281) was synthesized (Scheme 76). 136 Using a procedure identical with that used for the previous Wittig reaction, the aldehyde (251) was allowed to react with the phosphorane (278) , a reagent which contained a dimethylpropylene The phosphorane (278) was synthesized by a procedure identical with that described by Stowell and Keith for the preparation of the phosphorane (250). 137 ace ta l protect ing group as opposed to a propylene ace ta l protect ing group. The alkene (279), also i s o l a t e d as a 9:1 mixture of c i s - and trans--isomers (g lc a n a l y s i s ) , was produced i n 73% y i e l d . Reaction of (279) with tetra-n-butylammonium f l u o r i d e in THF provided the a l coho l mixture (280) (97% y i e l d ) , and subsequent ox idat ion with PCC i n dichloromethane produced, by g lc a n a l y s i s , a 9:1 mixture of the v i n y l -cyc lopropy l ketones (281) and (282), r e sp e c t ive ly (combined y i e l d 94%). The major v i n y l c y c l o p r o p y l ketone (281) could be e f f i c i e n t l y p u r i f i e d by f r a c t i o n a l c r y s t a l l i z a t i o n of the mixture from heptane. The compounds shown i n Scheme 76 showed s p e c t r a l data that was consis tent with the proposed s t r u c t u r e s . Reaction of the v i n y l c y c l o p r o p y l ketone (281) with 1.2 equiv of LDA i n THF at - 8 9 ° C , followed by treatment of the r e s u l t i n g s o l u t i o n with HMPA and t e r t - b u t y l d i m e t h y l s i l y l c h l o r i d e , produced a r e s u l t essen-t i a l l y i d e n t i c a l with that observed for the v i n y l c y c l o p r o p y l ketone (271). That i s the r e a c t i o n gave predominant formation of the conjugated aldehyde (273). It i s postulated that fragmentation of the ace ta l group i n both (271) and (281) i s most l i k e l y occurr ing v i a an abs trac t ion of the a l l y l i c proton on the exo-alkenyl s ide chain (Scheme 77). A b s t r a c t i o n of th is proton, also s i tuated B to the oxygen atoms of the c y c l i c a c e t a l , by e i ther another enolate anion or by any excess LDA, would l i k e l y produce the intermediate (284a). This species does not appear to have a d i r e c t means of opening up to an intermediate that might provide the conjugated aldehyde (273) upon reac t ion with t e r t - b u t y l d i m e t h y l s i l y l c h l o r i d e . However, the formation of the intermediate (284b) could 138 R Scheme 77 R 2 7 3 result if the enolate function in (284a) acts as a base and abstracts an available acidic proton . Intermediate (284b) could undergo a Undoubtedly, the overall sequence of acid-base reactions is more complex than stated. 139 fragmentation to the s t a b i l i z e d enolate (276) which i n turn could undergo r i n g opening to the enolate (277). Trapping of (277) with t e r t - b u t y l d i -m e t h y l s i l y l ch lor ide would provide the observed conjugated aldehyde (273). It was reasoned that th is undesired fragmentation process might l a r g e l y be avoided If a more react ive trapping reagent was employed. I t was hoped that such a reagent would react with the i n i t i a l l y formed enolate anion (283) before the l a t e r species had a chance to undergo the ace ta l fragmentation. The reagent that eventual ly proved successful i n th i s regard was the h ighly react ive s i l y l a t i n g agent t e r t - b u t y l d i m e t h y l s i l y l t r i f l a t e . This compound had been reported by Corey and coworkers to be useful for the pro tec t ion of hindered a l c o h o l s . 1 1 9 Reaction of the v i n y l c y c l o p r o p y l ketone (271) with IDA i n THF at - 7 8 ° C , followed by treatment of the r e s u l t i n g so lu t ion with HMPA and t e r t - b u t y l d i m e t h y l s i l y l t r i f l a t e , provided, by g lc a n a l y s i s , approxima-te ly a 30:10:1:3 mixture of the des ired d iv iny lcyc lopropane (252), an unknown compound with a r e l a t i v e l y high g lc re tent ion time, the conju-gated aldehyde (273), and recovered s t a r t i n g m a t e r i a l , r e sp e c t ive ly (Scheme 78). The components of th i s mixture were separated by chromato-graphy and the des ired d iv iny lcyc lopropane (252) was i s o l a t e d i n 47% y i e l d . The i r spectrum of t h i s mater ia l showed the required strong enol ether C=C absorption at 1680 c m - 1 , and the mass spectrum showed the required parent mass of 476. The *H nmr spectrum was consis tent with the proposed s t r u c t u r e . & The exact mechanism of fragmentation i s not known. Oxetane formation or carbon dioxide and isobutylene formation might be i n v o l v e d . 140 Scheme 78 The mass spectrum of the unknown compound exhibited a parent mass of 590, and the *H nmr showed the presence of 4 olefinic protons (6 6.56, J = 12 Hz; 6 5.88, J = 12, 11 Hz; 6 5.79, J = 11, 11 Hz; 6 4.56, J = 11, 9 Hz) and two tert-butyldimethylsilyl groups. This data lead to the postulation that the unknown compound had the structure (285). Though the use of the reactive silylating agent, tert-butyl-dimethylsilyl t r i f l a t e , largely eliminated the problem of the formation of the conjugated aldehyde (273), i t introduced a new problem by f a c i l i -tating the direct opening of the cyclic acetal. In fact, reactions that were done in the presence of a large excess of the s i l y l t r i f l a t e provided significantly higher proportions of the adduct (285). The isolation of (285), however, did provide some evidence for the mechanism 141 postulated in Scheme 77. Clearly, the production of the divinylcyclo-propane (252) from the vinylcyclopropyl ketone (271) is an exceedingly problematical conversion. Nevertheless, at this point, i t was grati-fying to have a quantity of the desired divinylcyclopropane (252) in hand. Attention was turned to the thermal rearrangement of the divinylcyclopropane (252). Heating a benzene solution of (252) for 5 h a 170°C produced, by t i c analysis, a mixture of three products. *H nmr analysis of this mixture showed no olefinic signals that would have been characteristic of the enol s i l y l ether (253) (Scheme 79). This result was indeed very disconcerting. It was i n i t i a l l y believed that the large "floppy" acetal side chain was in some manner sterically impeding the transition state required for rearrangement of the divinylcyclopropane (252) to the enol s i l y l ether (253). For this reason, an investigation was undertaken to examine what effect a relatively small cis-oriented substituent on the exo-alkenyl group would have on the product composition on thermal rearrangement. Scheme 79 252 253 142 C. Model Study 4 The model compound that was chosen to examine the v i a b i l i t y of the thermal rearrangement in the presence of a "small" cis-oriented substituent was the divinylcyclopropane (286). The relatively small cis-oriented methyl group in (286) was anticipated to pose a minimal steric threat to the transition state required for divinylcyclopropane rearrangement. 286 The synthesis of the divinylcyclopropane (286) was initiated from the aldehyde (179), an intermediate that was used in the f i r s t model study. It was i n i t i a l l y planned to introduce the cis-oriented methyl substituent by a simple Wittig reaction (Scheme 80). However, treatment of the aldehyde (179) with a THF-DMSO solution of ethylidenetriphenyl-phosphorane, previously generated by the reaction of ethyltriphenyl-phosphonium bromide with potassium tert-butoxide, provided at best an 87:13 mixture of the cis-alkene (287) and the trans-alkene (288), respectively (glc analysis). Unfortunately these two isomers proved very d i f f i c u l t to separate, at this stage and at the subsequent alcohol and ketone stages. 143 Scheme 80 Since the purpose of this model study was to investigate the product composition after thermal rearrangement, the presence of a mixture of cis- and trans-isomers was anticipated to complicate matters considerably. For this reason, a more stereoselective approach to the cis-alkene (287) was undertaken as shown in Scheme 81. Treatment of the aldehyde (179) with a dichloromethane solution of dibromomethylenetriphenylphosphorane, previously generated by the reaction of triphenylphosphine and carbon tetrabromide with z i n c , 1 2 0 provided the crystalline dibromoalkene (289) in greater than 95% yield. Reaction of a THF solution of (289) with a solution of n-butyllithium (2 equiv) and trapping the resulting lithium acetylide with methyl iodide, afforded, after chromatography of the crude reaction product, the acetylene (290) in 78% yield. The cis-alkene (287) was prepared by catalytic hydrogenation of (290) in pentane using Lindlar's catalyst poisoned with quinoline. Glc analysis of the chromatographed product showed a 96:4 mixture of the cis-alkene (287) and the trans-alkene (288), respectively (92% yield). Nevertheless, this mixture was deemed more suitable than the mixture obtained from the Wittig reaction involving the aldehyde (179) 144 and ethylidenetriphenylphosphorane. The XH nmr spectrum of (287) provided strong evidence for the cis-stereochemistry about the double bond. The coupling constant between the two olefinic protons ( 6 5.31 and 6 4.78) was observed to be 10.5 Hz, a value that was consistent with a cis-arrangement of substituents about a carbon-carbon double bond. 8 6 Scheme 81 Removal of the s i l y l protecting group was accomplished in the usual manner by treating a THF solution of (287) with tetra-n-butyl-145 ammonium f l u o r i d e . The a lcoho l (291) was i s o l a t e d i n 94% y i e l d . Oxidation of (291) with PCC i n dichloromethane produced the v i n y l c y c l o -propyl ketone (292) i n 89% y i e l d . The intermediates from Scheme 81 just discussed a l l showed s p e c t r a l data that was consistent with the proposed s t r u c t u r e s . The in t roduc t ion of the second required v i n y l group i n the form of a t e r t - b u t y l d i m e t h y l s i l y l enol ether proceeded without i n c i d e n t . Reaction of the v i n y l c y c l o p r o p y l ketone (292) with LDA i n THF at - 7 8 ° C , followed by treatment of the r e s u l t i n g so lu t ion with HMPA and t e r t -b u t y l d i m e t h y l s i l y l t r i f l a t e furnished the d iv iny lcyc lopropane (286) i n 76% y i e l d . A so lu t ion of the d iv iny lcyc lopropane (286) i n benzene was sealed i n a p y r o l y s i s tube and the tube was heated at 1 7 0 - 1 7 5 ° C for 4 h . A s t o n i s h i n g l y , g l c ana lys i s of the r e s u l t i n g product showed i t to cons is t of a mixture of 3 major compounds together with approximately 5 minor products i n a r a t i o of 40:32:15:13, r e s p e c t i v e l y . C l e a r l y , t h i s ominous r e s u l t cast considerable doubt on the v i a b i l i t y of the d iv iny lcyc lopropane rearrangement of compounds such as (286). Nevertheless , an i n v e s t i g a t i o n into the i d e n t i t y of the three major components of the mixture was undertaken to see i f any of them had the s tructure of the des ired product (293). P a r t i a l separat ion of the three major products was accomplished by chromatography of the reac t ion product mixture through tr ie thy lamine washed, grade 1, basic alumina. The major component of the mixture , i so la ted i n e s s e n t i a l l y pure form, was shown to have the s tructure (294) (Scheme 82). 146 Scheme 82 / 293 294 The i r spectrum of (294) showed C=C absorptions at 1650 and 1590 c m - 1 and the mass spectrum showed a predominant M+-2 peak which presuma-b ly resu l ted from the loss of two hydrogen atoms from the six-membered r i n g to form an aromatic system. The *H nmr spectrum of (294) showed o l e f i n i c s ignals at 6 6.73 - 6 6.65 (H^ and Hp), 6 5.41 (d of q, H , J = 11, 7 Hz) , and 6 5.25 (d of d of q, H. , , J = 11, 9.5, 2 Hz) , the l a t t e r D * — two s ignals confirming the presence of the c i s - l - p r o p e n y l moiety. Decoupling of the proton H c (6 3 .07, J_= 9.5, 8, 5.5 Hz) s i m p l i f i e d Hg and Hp each into a d (J_ = 9.5 Hz) and s i m p l i f i e d H^ in to a d of q ( J = 11, 2 Hz) . This decoupling experiment provided a d d i t i o n a l conf irmation of the s tructure (294), though the stereochemistry of H^ could not be assigned with any degree of confidence. The chromatography of the reac t ion product r e s u l t i n g from the 147 heating of divinylcyclopropane (286) also provided a sample 80% pure in the second most abundant product and a sample 50% pure in the third most abundant product. Each of these samples was contaminated with various amounts of the other reaction products. The *H nmr data for both of these samples is detailed in the experimental section of this thesis; however, the identity of each of the products can not be elucidated with any degree of certainty. Clearly though, neither of the olefinic patterns observed for these two products is consistent with the structure of (293). Considering a l l the divinylcyclopropanes in our laboratory that had previously undergone successful rearrangement, why did the desired rearrangement of the divinylcyclopropanes (252) and (286) fail? Upon examination of molecular models of the presumed transition state for rearrangement of the divinylcyclopropane (286) to the desired enol s i l y l ether (293), it became apparent that a severe interaction existed between the cis-methyl substituent at carbon H and the hydrogen atom at carbon D (see structure (297)). This interaction appeared to be more severe than the corresponding interactions in the transition states for rearrangement of other substrates studied in our laboratory. In the previously studied substrates, the divinylcyclopropane moiety was part of a system that could adopt a conformation which minimized this interaction. This conformational flexibility was not 148 available in the rigid 5-5 ring system of (252) and (286), so the interaction between the cis-oriented substituent at carbon H and the hydrogen atom at carbon D was sufficiently severe that the geometry required for divinylcyclopropane rearrangement could not be attained. It was clear that the heating of any divinylcyclopropane which contained a t r i c y c l i c ring skeleton like (286) and a cis-oriented alkyl substituent at carbon H would not produce any desired product(s) containing the bicyclo[3.2.1]octadiene ring system. With this unfortu-nate fact, the synthesis of (±)-quadrone (34) had to be reevaluated. A mechanism that provides a rationale for the formation of (294) is shown in Scheme 83. The stabilized diradical (295) is thought to undergo a further carbon-carbon bond homolysis to produce the stabilized diradical (296). Simple coupling of the two radicals in (296) would provide the observed product (294). Scheme 83 149 D. Modified Synthetic Approach to (±)-Quadrone (34) The model study just discussed indicated that the synthesis of (i)-quadrone (34) would most l i k e l y have to proceed via the enol s i l y l ether (298) (Scheme 84). In order to introduce the necessary substi-tuent at carbon H with the correct stereochemistry, i t was envisaged that the alkene function i n (298) could be modified to the a l l y l i c v i n y l ether function i n (299) which upon heating should undergo a Claisen rearrangement to the unsaturated aldehyde (300). This Claisen rearrangement strategy had previously been exploited by Burke and coworkers i n their synthesis of (±)-quadrone ( 3 4 ) . 1 0 1 Scheme 84 Before this approach could be explored, the synthesis and the rearrangement of the divinylcyclopropane (305) had to be accomplished. The preparation of (305) i s outlined i n Scheme 85. The crude exo-aldehyde (251), which s t i l l contained a small amount of the adduct (268), was allowed to react with methylene-150 triphenylphosphorane i n THF to produce predominantly the alkene (301) i n a y i e l d of 78%. It was found to be more e f f i c i e n t to use the crude aldehyde mixture of (251) and (268) d i r e c t l y i n the W i t t i g r e a c t i o n rather than chromatographical ly pur i fy the aldehyde (251) f i r s t . Scheme 85 305 Treatment of the alkene (301) (containing a small amount of an isomer derived from (268)) with tetra-n-butylammonium f l u o r i d e i n THF 151 provided, after workup and chromatography, pure crystalline alcohol (302) (91% yield) and the alcohol (303) (4% yield). Oxidation of (302) with PCC in dichloromethane furnished the divinylcyclopropyl ketone (304) in 91% yield. The compounds from Scheme 85 just discussed a l l showed spectral data that was consistent with the proposed structures. Figure 21 shows the *H nmr of the vinylcyclopropyl ketone (304). Introduction of the second required vinyl group as a tert-butyl-dimethylsilyl enol ether proceeded without incident, using the usual reaction conditions and tert-butyldimethylsilyl t r i f l a t e as the trapping agent. The divinylcyclopropane (305) isolated from this reaction was unstable towards d i s t i l l a t i o n and was hydrolyzed readily on attempted chromatography. For these reasons, the crude (305) was used directly in the subsequent thermal reaction. Heating a benzene solution of (305) for 5 h at 170-175°C, provided, by 1H nmr analysis, predominantly the desired enol s i l y l ether (298) (Scheme 86). *H nmr analysis, in addition to glc analysis, showed that some minor contaminants were also present. Scheme 86 152 Chromatographic p u r i f i c a t i o n of (298) was not very e f f i c i e n t , so a THF solution of the crude enol s i l y l ether product was treated at -78°C with tetra-n-butylammoniura f l u o r i d e . Workup and chromatography afforded pure c r y s t a l l i n e ketone (306) in a very reasonable 77% y i e l d from the vinyl c y c l o p r o p y l ketone (304). The i d e n t i t y of the minor contaminants detected a f t e r the thermal rearrangement was not established. The *H nmr spectrum of (306) (Figure 22) showed the presence of two o l e f i n i c protons that exhibited chemical s h i f t s and coupling constants e s s e n t i a l l y i d e n t i c a l with that of the two o l e f i n i c protons i n the corresponding ketone (182), obtained from the f i r s t model study. With ample quantities of the ketone (306) i n hand, the next task was to use the existi n g f u n c t i o n a l i t y to introduce the geminal dimethyl and a l l y l i c v i n y l ether moieties needed for the compound (299). The f i r s t conversion that was investigated was the introduction of the geminal dimethyl group. The procedure that was found most e f f i c i e n t for this conversion involved a two step methylation sequence (Scheme 87). Reaction of the ketone (306) with LDA i n THF, followed by treatment of the r e s u l t i n g solution with methyl iodide gave predominant-l y the isomerically pure monomethylated compound (307). Subjection of (307) to the same reaction conditions provided l a r g e l y the dimethylated ketone (308). This two step methylation sequence proved to be somewhat capricious in nature, since varying quantities of unmethylated material were frequently i s o l a t e d after each methylation reaction. In addition, the second methylation reaction produced variable quantities (up to 7% 153 6 3 2 PPm 1 0 Figure 22. The 400 MHz lH nmr Spectrum of the Ketone (306) 154 Scheme 87 308 309 of the t o t a l product) of the methyl enol ether (309). Nevertheless, pure ketone (308) could be iso l a t e d , after chromatography of the crude reaction product, i n yields up to 71%. The i r spectrum of the ketone (308) showed the required carbonyl absorption at 1730 cm - 1 and the *H nmr spectrum showed the presence of four d i s t i n c t methyl singlets i n the region between 6 1.25 and 6 0.80. The stereochemistry of the methyl group i n the monomethylated ketone 155 (307) was supported by X H nmr a n a l y s i s , which showed a coupl ing of 5.7 Hz between (6 2.72) and H £ (6 2 .62) . I f the methyl group i n (307) had possessed the opposite stereochemistry, the d i h e d r a l angle between H^ and H^ would have been approximately 90° and minimal coupl ing should have been observed. The i r spectrum of the methyl enol ether (309) showed a strong absorption at 1660 c m - 1 and the *H nmr spectrum showed methyl s ing l e t s at 6 3.70 and 6 1.76 which were i n d i c a t i v e of the enol methyl and the v i n y l methyl groups, r e s p e c t i v e l y . The ketone group i n (308), having wel l served i t s purpose by previous ly providing the second required v i n y l group of the d i v i n y l -cyclopropane (305) and by f a c i l i t a t i n g the d i r e c t in troduct ion of the geminal dimethyl group, had to be removed. This transformation was not expected to be easy cons ider ing the s t e r i c a l l y hindered environment of the keto group. Indeed, the modified Wolff -Kishner procedure of Paquette and c o w o r k e r s 1 2 1 f a i l e d to remove the doubly neopentyl s i tuated ketone. Therefore , a more c i r c u i t o u s approach was undertaken. This approach r e l i e d on the phosphorodiamidate reduct ion procedure described by Ireland and c o w o r k e r s . 1 2 2 The i n v e s t i g a t i o n of th i s approach i s out l ined i n Scheme 88. Reaction of the ketone (308) with l i t h i u m aluminum hydride i n ether provided, a f ter workup, a 3:1 mixture (g lc ana lys i s ) of the a lcohol epimers (310) and (311), r e s p e c t i v e l y , i n 95% y i e l d . The stereochemistry of the a lcohol center i n compounds (310) and (311) was i n i t i a l l y predicted on the bas is of s t e r i c approach of the hydride reducing agent. Treatment of a so lu t ion of the a lcohol mixture i n THF-HMPA with a so lu t ion of n - b u t y l l i t h i u m and trapping of the r e s u l t i n g Scheme 88 157 alkoxldes with bis(dimethylamiho)phosphorochloridate, afforded a near quantitative yield of the phosphorodiamidates (312) and (313). Subjection of the mixture of (312) and (313) to reduction with 10 equiv of lithium and 2 equiv of tert-butyl alcohol in ethylamine at 0°C for ~ 1 h, as presribed by Ireland and coworkers, 1 2 2 gave a single compound in good yield. However, 1H nmr analysis of this material showed that i t contained no olefinic protons. Apparently the reduction reaction had not only removed the phosporodiamidate groups, but had also reduced the double bond to produce the saturated compound (315). Since the presence of the double bond was v i t a l to the continuation of the synthesis, different conditions for the reduction of the phosphorodiamidate had to be found. Quenching the lithium and ethylamine reduction reaction with water after 2 min provided, by glc analysis, an equal mixture of the alkene (314) and the saturated compound (315) together with substantial quantities of the starting phosphorodiamidate mixture. This experiment indicated that double bond reduction was indeed competing with phosphorodiamidate reduction. Reaction of the mixture of phosphorodiamidates (312) and (313) with lithium in ammonium, however, provided predominantly the alkene (314). Unfortunately, this reduction was extremely slow and only small quantities of product were isolated even after a reaction time of several hours. Since lithium in ethylamine was too reactive a reducing medium and lithium in ammonia was not reactive enough, the reduction of (312) and (313) was attempted in methylamine. Treatment of the phosphoro-diamidate mixture with lithium in methylamine at -20°C for 16 min 158 produced, by g lc a n a l y s i s , an approximately 7:1 mixture of the alkene (314) to the saturated compound (315), r e s p e c t i v e l y . However only moderate conversion had taken place and the alkene-saturated compound mixture could only be i s o l a t e d i n 50-60% y i e l d . Prolonged reac t ion times did increase the degree of conversion but , unfortunate ly , they also increased the r e l a t i v e percentage of the saturated compound (315). However, g l c ana lys i s of the mater ia l i s o l a t e d from the l a s t reduct ion showed that the recovered phosphorodiamidates (312) and (313) were present i n a r a t i o cons iderably d i f f e r e n t from that of the s t a r t i n g mater ia l ((312): (313) = 3:1, r e s p e c t i v e l y ) . In f a c t , i n the recovered m a t e r i a l , the phosphorodiamidate (313) was by far the major isomer present . This important observat ion indicated that carbon-carbon double bond reduct ion might be l a r g e l y avoided i f the reduct ion were to be c a r r i e d out on the e p i m e r i c a l l y pure phosphorodiamidate (312). A study was undertaken to prepare the e p i m e r i c a l l y pure a lcohol (310) and the re su l t s of th i s i n v e s t i g a t i o n are summarized i n Scheme 89. It was predicted that the reduct ion of the ketone moiety In (308) could be made more s t ereose lec t ive by simply employing the use of a reducing agent b u l k i e r than l i t h i u m aluminum hydr ide . With th is premise i n mind, the ketone (308) was treated with di isobutylaluminum hydride (DIBAL), and much to our s u r p r i s e , the g lc ana lys i s of the r e s u l t i n g product showed i t to consis t of a 1:3 mixture of the a lcohols (310) and (311), r e s p e c t i v e l y . This unexpected resu l t was r a t i o n a l i z e d on the bas is of p r i o r coordinat ion of the neutra l DIBAL reducing agent to the oxygen of the c y c l i c ace ta l moiety. This coord inat ion would favor hydride in troduct ion from the s t e r i c a l l y more hindered side of the ketone. 159 Scheme 89 This result led to the testing of bulky anionic hydride reducing agents. The use of lithium triethylborohydride 1 2 3 did provide epimeri-cally pure alcohol (310), but, unfortunately, the yield of this reaction could not be improved above 76%. Sodium bis(2-methoxyethoxy)alumino-hydride (Red-Al or V i t r i d e ) 1 2 4 surprisingly afforded a mixture of (310) and (311) in no better a ratio than did lithium aluminum hydride, and both L-selectride 1 2 3 and lithium tri-tert-butoxyaluminohydride125 failed to reduce the ketone moiety (308) at a l l . 160 As a last effort, lithium diisobutyl-n-butylaluminum hydride, a bulky anionic hydride reducing agent made by the reaction of equimolar quantities of DIBAL and n-butyllithium, was t r i e d . 1 2 6 Gratifyingly, the desired alcohol epimer (310) was obtained exclusively in virtually quantitative yield. Conversion of the epimerically pure alcohol (310) into the corresponding phosphorodiamidate (312) proceeded in near quantitative yield by a procedure identical with that described earlier. After some experimentation, the best conditions found for the phosphorodiamidate reduction involved treatment of (312) with 5 equiv of lithium in methylamine at -20° for approximately 10 min. A mixture of the alkene (314) and the saturated compound (315) were thus obtained in a 9:1 ratio, respectively, (glc analysis) in a combined yield of 88%. The i r spectrum of this mixture showed a weak C=C absorption at 1630 cm - 1, and the -^H nmr spectrum showed the two expected olefinic signals. Additional evidence for the stereochemical assignment of the alcohol group in (310) was provided when a sample of (310) was dissolved in deuterochloroform for ^-H nmr analysis. Apparently the alcohol (310) was extremely sensitive to trace amounts of acid, and in deutero-chlorof orm, i t underwent internal acetalization to the alcohol (316) (Scheme 90). On prolonged standing in deuterochloroform the keto alcohol (317) was also formed. Compounds (310), (316) and (317) could be chromatographically separated and spectral analysis including 1H nmr, this time in deuterobenzene, provided confirmation of the proposed structures. With the successful introduction of the geminal dimethyl group 161 Scheme 90 0 310 316 317 and the removal of the oxygen function, the alkene group in (314) had to be modified to the a l l y l i c vinyl ether moiety in (299). This was accomplished by the series of reactions shown in Scheme 91. The 9:1 mixture of the alkene (314) and the saturated compound (315) proved d i f f i c u l t to separate by conventional chromatography, so the mixture was used in the next reaction. Treatment of a dichloro-methane solution of the mixture with m-chloroperoxybenzoic acid, using aqueous sodium bicarbonate as a b u f f e r , 1 2 7 afforded, by glc analysis, a 9:1 mixture of the epimerically pure epoxide (318) and the saturated compound (315), respectively. These two compounds were readily separable by chromatography. The epoxide moiety in (318) was assumed to have the stereochemistry shown, based on steric approach of the m-chloroperoxybenzoic acid from the less hindered top face of the alkene (314). The *H nmr spectrum of (318) showed the presence of two protons a to the epoxide moiety (6 3.24, J_ = 4, 4 Hz; 6 3.03, £ = 4, 4 Hz). However, this data did not provide a conclusive means of assigning the stereochemistry of the epoxide function. 162 Scheme 91 It was actually found to be more efficient to chromatographically remove the saturated compound (315) after the next reaction. Thus, a 9:1 mixture of the epoxide (318) and the saturated compound (315) was gently refluxed in a benzene solution of lithium diethylamide for approximately 2 h to effect isomerization of the epoxide moiety in (318) to the allylic alcohol moiety in (319). 8 0 Chromatography of the crude reaction product furnished pure allylic alcohol (319) in 74% yield from the alkene (314). The ir spectrum of this material exhibited the required broad 0-H stretch at 3350 cm-1 and the *H nmr spectrum showed 163 the presence of two o l e f i n i c protons (6 6.15, J = 9 Hz; 6 5.54, J = 9, 4.2, 1.5 Hz) and an a l l y l i c hydrogen a to an a l coho l group (6 4.24 -6 4 .17) . Unl ike the i somer izat ion reac t ion of the a-epoxide isomer (259) which had to be done in the ear ly part of th i s synthesis v i a the selenium procedure of Sharpless and L a u e r , 7 6 the conversion of the epoxide (318) into the a l l y l i c a l coho l (319) was i d e a l l y set up for a base promoted i s o m e r i z a t i o n . The epoxide moiety and the syn-or iented 6-hydrogen atom i n (318) were both s t e r i c a l l y access ib le to the amide base while the hydrogens a to the epoxide were s t e r i c a l l y h indered, thereby reducing the p o s s i b i l i t y of ketone product ion . This base promoted i somerizat ion was i n i t i a l l y attempted using the t r a d i t i o n a l so lvent , e t h e r . 8 0 However, complete conversion of the epoxide (318) into the a l l y l i c a l coho l (319) required several days of r e f l u x . For th i s reason the ether solvent was replaced by the higher b o i l i n g , non-coordinat ing solvent benzene. The a l l y l i c a l coho l (319) d i f f e r s only i n the nature of the ace ta l protec t ing group from the intermediate (228) used by Burke and coworkers i n t h e i r synthesis of ( i ) -quadrone (34). Thus, the four step sequence which was employed to convert (319) into the ul t imate target molecule (230) e s s e n t i a l l y p a r a l l e l s the work of Burke and coworkers. Reaction of the a l l y l i c a l coho l (319) with e t h y l v i n y l ether and mercury(II) acetate provided the a l l y l i c v i n y l ether (299) i n 86%. The *H nmr spectrum of th i s mater ia l i s shown i n Figure 23. Heating of (299) i n benzene and di isopropylamine at 2 3 5 - 2 4 0 ° C for 4.5 h ef fected a C la i sen rearrangement to g ive , a f ter chromatography, the unsaturated 164 aldehyde (300) in 91% yield (Scheme 92). The use of the amine base was found vital for the success of the Claisen rearrangement. Presumably, the base suppressed any acid catalyzed decomposition of the vinyl enol ether and resulting aldehyde moieties. Scheme 92 The ir spectrum of (300) showed the expected absorptions at 2700 and 1725 cm"1 that were characteristic of the aldehyde function. The nmr spectrum (Figure 24) showed signals characteristic of the structure of (300), but the stereochemistry of the aldehyde containing appendage, 165 166 though predicted to be as shown, could not be unambiguously ass igned. C a t a l y t i c hydrogenation of the carbon-carbon double bond i n (300) proved to be somewhat prob lemat i ca l . Burke and coworkers reported the successful hydrogenation of the unsaturated aldehyde (229) using' 5% Pd/C as the ca ta lys t and ethanol as the so lvent . In our hands, th i s r eac t ion f a i l e d to provide any of the des ired saturated aldehyde (320), and i n fact produced an uncharacter izable mixture of unknown m a t e r i a l . Since c e r t a i n hydrogenation ca ta ly s t s are reported to be more act ive i n solvents of high d i e l e c t r i c c o n s t a n t , 1 2 5 i t was decided to t ry the hydrogenation i n a solvent less polar than e thanol . When the hydrogenation was done i n THF a mixture of compounds was produced that ind icated that competit ive hydrogenation of the aldehyde moiety was o c c u r r i n g . Hydrogenation of the unsaturated aldehyde (300) i n the non-polar solvent hexane, however, proceeded c l ean ly and smoothly to provide the saturated aldehyde (320) i n e s s e n t i a l l y quant i ta t ive y i e l d . To complete the synthes i s , the saturated aldehyde (320) was treated with aqueous HC1 i n acetone to g ive , a f ter chromatography, the pure c r y s t a l l i n e keto aldehyde (230) i n greater than 90% y i e l d . This mater ia l exhibi ted melt ing point and spectra that were i d e n t i c a l with * i those of (230) synthesized by Burke and coworkers . The 400 MHz i H nmr spectrum of (230) i s shown i n Figure 25. Since the keto aldehyde (230) had been c a r r i e d on to ( ± ) - q u a d r o n e (34) by Burke and c o w o r k e r s , 1 0 l C the success ful synthesis of (230) cons t i tu ted a formal t o t a l synthesis of ( ± ) - q u a d r o n e (34)• We are very g r e a t f u l to Professor Burke for sending us copies of spectra of the keto aldehyde (230). 167 Despite the failure of the divinylcyclopropane (252) to rearrange as desired, an unfortunate circumstance which increased the length of the synthesis, the successful rearrangement of the divinylcyclopropane (305) and the further elaboration of the resulting t r i c y c l i c product (298) into the keto aldehyde (230) did further illustrate the u t i l i t y of the divinylcyclopropane rearrangement as a viable strategy in natural product synthesis. 168 The Facile Vinylmethylenecyclopropane Rearrangement of Enolates Derived from Various 7-Exo-Vinylbicyclo[4.1.0]heptan-2-ones Work that was discussed in earlier sections of this thesis centered around the preparation and rearrangement of various divinyl-cyclopropanes. In this regard, the synthesis of the divinylcyclo-propane (138) was attempted (see p. 92-93), and i t was found that upon applying the standard procedure, that i s , reaction of the vinylcyclo-propyl ketone (134) with LDA in THF, followed by treatment of the resulting solution of enolate anion with HMPA and tert-butyldimethyl-s i l y l chloride, the only product that could be isolated was not the desired divinylcyclopropane (138) but rather the diene alcohol (206) (Scheme 93). DISCUSSION Scheme 93 H H 134 138 206 169 Additional experimentation showed that treatment of (134) with a cold (-78°C) solution of LDA, followed by a brief warming of the reac-tion mixture with a 0°C bath afforded, after workup and chromatography, the pure alcohol (206) in yields between 15 and 25%. The majority of the remaining material balance was made up of uncharacterized high molecular weight compounds (polymers). A mechanism that accounts for the production of the alcohol (206) is shown in Scheme 94. It is postulated that reaction of the vinylcyclo-propyl ketone (134) with LDA does not produce the expected and desired enolate species (321), but instead produces the isomeric enolate species (322) (shown as the two rotomeric forms (322a) and (322b)). This species would arise from deprotonation of (134) at the cyclopropyl center a to the ketone. In retrospect, this result is not so surprising when the hindered nature of the other proton a to the ketone is considered. As can be appreciated, the strain associated with a species like (322) would be expected to be quite severe. Consequently, i t is believed that on warming a solution of the enolate (322), (322) under-goes a cyclopropane bond homolysis to the two diradical intermediates (324) and (323). The relative ratio of the two diradical intermediates is tentatively predicted to be dependent on the activation energy required for each of the two rotomeric forms (322a) and (322b) to attain the transition state required for cyclopropane bond homolysis. Since the intermediate (324) has a favorable geometry for intra-molecular coupling of its two radical centers, i t is believed that (324) undergoes a ring closure to the alkoxide (325), and subsequent aqueous workup provides the observed alcohol (206). 170 Scheme 94 The dlradical Intermediate (323), on the other hand, cannot directly undergo ring closure to the alkoxide (325). Since it has been reported 1 2 9 that allylic radicals have a high barrier to interconversion 171 (the cis-l-methallyl radical and the trans-l-methallyl radical do not interconvert even at 0°), it is suggested that a significant proportion of the isolated polymeric material arises from various intermolecular radical addition and coupling reactions involving the intermediate (323). The enolate species (322) formally contains a 2-vinylmethylene-cyclopropane function, and compounds containing this type of function have previously been reported to undergo thermal rearrangement to the corresponding methylene-cyclopentene adduct. 2-Vinylmethylenecyclo-propane itself, compound (326), upon heating for 13 h at 80°C in pentane rearranges to 3-methylenecyclopentene (327) (Scheme 95). Scheme 95 326 327 For studies related to the thermal rearrangement of vinylmethylene-cyclopropane systems see refs. 129 and 130 and refs. cited therein. 172 Various other 2-vinylmethylenecyclopropane systems have been investigated, and in most cases, temperatures over 100°C were employed to effect rearrangement. The major emphasis of this past work was on whether the vinylraethylenecyclopropane rearrangement occurred via diradical intermediates like those shown in Scheme 94 or via some form of concerted process. The exact mechanism of rearrangement has not been rigorously established; however, i t does appear that the intermediacy of a diradical species is favored. The most interesting aspect about the conversion of the divinyl-cyclopropyl ketone (134) into the alcohol (206) is the fact that the transformation occurs under very mild conditions. While the rearrange-ment of most of the previously reported 2-vinylmethylenecyclopropanes requires temperatures over 100°C, the rearrangement of the enolate (321) occurs at temperatures well below 0°C. One feature that undoubtedly facilitates the rearrangement of the enolate (322) to the alkoxide (325) is the significant ring strain asso-ciated with (322). This strain should substantially lower the activa-tion energy required for homolysis of required cyclopropane bond. Another feature that might help f a c i l i t a t e the rearrangement of (322) to (325) is the presence of the alkoxide moiety (enolate) in (322). Alkoxy-accelerated rearrangements of 1,5 dienes (Cope rearrange-ments), 1 3 2 a l l y l i c alkyl compounds ([l,3]-sigmatropic rearrangements), 1 3 and vinylcyclopropanes 1 3 4 are well documented processes, and rate enhan-cements of 10 1 0-10 1 7 over the corresponding alcohol compounds have Cyclopropane bond homolysis has been postulated as being the rate determining step in the rearrangement of 2-vinylmethylenecyclopropanes. 173 been reported (Scheme 96). Scheme 96 * O. -O^R *• o~°-Evans and Ba i l l argeon 1 ^ reported that the presence of an alkoxide function as opposed to an alcohol function weakens an adjacent carbon-carbon bond to homolysis by a margin of 13-17 kcal/mole (Scheme 97). A similar type of bond weakening effect might be occurring in the enolate (322), though in this case the effect would have to be manifested through resonance. Scheme 97 I I -0—C—R fc. - O - O • R I I 174 Experiments that might have quantified the respective influence of the ring strain and the alkoxide (enolate) moiety in facilitating the rearrangement of (322) were not conducted. At this point, it was decided to explore the generality of this rearrangement and establish more favorable reaction conditions that would Increase the overall yield of this process. As a consequence of this investigation, it was hoped that more insight would be gained into the mechanism of the rearrangement. In this regard, the vinylcyclo-propyl ketone (328) was synthesized in which the acidic protons a to the ketone and away from the cyclopropane moiety were replaced by methyl groups. The synthesis of (328), outlined in Scheme 98, involved chemistry that was very similar to that employed earlier in the model studies and in the synthesis of (±)-quadrone (34). The allylic s i l y l ether (329), readily prepared by reaction of commercially available 2-cyclohexene-l-ol with tert-butyldimethylsilyl chloride under standard reaction conditions, was allowed to react with 1.5 equiv of ethyl diazoacetate (Rh2(OAc)lt catalyst) to afford, after chromatographic separation of the starting material (329), diethyl maleate, and diethyl fumarate, the cyclopropyl ester (330) as a 3 2 8 175 Scheme 98 335 336 328 41:38:16:5 mixture of isomers (glc analysis) in 86% yield based on unrecovered starting material. This mixture was reduced with LAH to afford, after workup, the alcohol mixture (331) in 86% yield. Reaction of (331) with PCC in dichloromethane, followed by treat-ment of the resulting mixture of aldehydes with potassium tert-butoxide in THF-tert-butyl alcohol provided the aldehyde mixture (332) as a 176 57:43 mixture of isomers (glc analysis). Wittig methylenation of (332) -I (methylenetriphenylphosphprane, THF) furnished the alkene mixture (333) in 80% yield from the alcohol mixture (331) • Removal of the s i l y l ether moiety in (333) (TBAF, THF) gave the alcohol (334) in 85% yield, and subsequent treatment of (334) with PCC in dichloromethane provided the vinylcylopropyl ketone (335) (89% yield). The geminal dimethyl group in (328) was introduced via a two step methylation sequence. Treatment of (335) with LDA in THF followed by trapping of the resulting enolate with methyl iodide afforded the mono-methylated vinylcyclopropyl ketone (336) as a 93:7 mixture (glc analysis) of isomers (92% yield). Subjection of (336) to an identical methylation procedure provided, after chromatography of the crude reaction product, the dimethylated vinylcyclopropyl ketone (328) in 78% yield. A l l the intermediates shown in Scheme 98 showed spectral data that was consistent with the proposed structures. With quantities of (328) in hand, i t s rearrangement on treatment with LDA was investigated. Subjection of (328) to reaction conditions similar to those previously used for rearrangement of the vinylcyclo-propyl ketone (134) (LDA, -78°C; brief warming to 0°C) provided, by glc analysis, a mixture of two compounds in a ratio of 7.5:1. Chromato-graphy of the crude reaction product provided the two compounds in a combined yield no greater than 10%, and subsequent spectral analysis showed them to have the structures (337) and (338), respectively (Scheme 99). The remainder of the material balance was made up of various polymers, and in fact, mass spectral analysis of the crude reaction product showed peaks corresponding to compounds containing up 177 to 8 monomer units (i.e. m/e = 1312). Scheme 99 328 o 337 OH + -|- POLYMERS The i r spectrum of the alcohol (337) showed the expected 0-H absorption, and the *H nmr spectrum showed the presence of 3 olefinic protons with splitting patterns almost identical with those observed for the alcohol (206). The i r spectrum of the ketone (338) showed a typical C=0 absorp-tion at 1700 cm - 1 and two absorptions characteristic of a carbon-carbon double bond (3050 and 1650 cm - 1). The *H nmr spectrum of (338) showed the presence of two symmetrical olefinic signals at 6 5.83 and 6 5.71 (J_ = 5.6, 2.4, 2.4, 2.4 Hz in each case). The cis-stereochemistry about the ring junction was Inferred from the coupling constants between H p and H^ and between H^, and H^  (J_ = 9 and 8.4 Hz, respectively). If a trans-ring junction were present, stronger couplings between the above protons would have been expected. A mechanism that accounts for the formation of both the alcohol (337) and the ketone (338) is shown in Scheme 100. The i n i t i a l l y formed 178 Scheme 100 179 enolate (339) on warming is believe to undergo cyclopropane bond homolysis to the diradical intermediate (340) , which is represented in Scheme 100 by the two rotomeric forms (340a) and (340b). Coupling of the two radical centers in (340a) is believed to provide the alkoxide (341), while coupling of the two radical centers in (340b) is predicted to produce the extended enolate (342). Subsequent aqueous workup would then provide the observed alcohol (337) and the ketone (338). Since the alcohol (337) was present in the reaction product mixture in a significantly larger amount than the ketone (338), i t appears that the production of the alkoxide (341) is kinetically preferred over the production of the extended enolate (342)• The reason for this preference is not at a l l clear. With the establishment that the enolate (339) does indeed undergo the 2-vinylmethylenecyclopropane rearrangement, a systematic study was undertaken to determine more favorable conditions that would increase the overall yield of the rearrangement process. It was found that the enolate (339) was stable in THF at -78°C, since a solution of (339) could be stirred at -78°C for over 2 h, and subsequent water quench and workup provided an almost quantitative reco-very of the vinylcyclopropyl ketone (328). Evidence for the existence of the enolate (339) at -78°C was provided by quenching a THF solution of (339) at -78°C with D20. The mass spectrum of the recovered vinyl-cyclopropyl ketone showed >90% incorporation of deuterium (Scheme 101). * The diradical intermediate (340c) is also likely produced in this reaction, but the extent to which this species is involved in the production of the observed products (337) and (338) is not known. 180 Additional evidence for the formation of the enolate (339) was provided when a THF solution of (339) was treated at -78°C with methyl iodide. Workup and chromatography afforded the methylated species (343) in 68% yield (Sceme 101). Spectral data for (343) was consistent with the proposed structure. Scheme 101 3 4 3 Upon warming a cold (-78°C) THF solution of the enolate (339) to -35°C, the reaction mixture turned a deep blue color. This color persisted for approximately 1.5 h, after which time, the color of the reaction mixture faded to near colorless. After workup, glc analysis of the resulting product showed essentially the same 7.5:1 mixture of the alcohol (337) and the ketone (338), respectively, as was previously observed. However, after chromatography, (337) and (338) were isolated in a combined yield of less than 5%. The remainder of the material balance was, as before, made up of polymeric mixtures. More favorable conditions for rearrangement were found when a 181 solution of the enolate (339) in THF at -78°C was warmed to -20°C. As in the previously described experiment, the reaction mixture turned a deep blue color; however, this color persisted for no longer than 20 min. After i t had been stirred for an additional 15 min at -20°C, the reaction mixture was worked up, and glc analysis once again showed the crude product to contain the alcohol (337) and the ketone (338) in a ratio of 7.5:1, respectively. The crude product was directly chromato-graphed to afford, after concentration of the appropriate fractions and d i s t i l l a t i o n , the alcohol (337) and the ketone (338) in yields of 25.5% and 3.7%, respectively. The use of reaction temperatures higher than -20°C (e.g. 0°C) resulted in lower isolated yields of the products (337) and (338) in comparison to yields obtained when the reaction was done at -20°C. The blue reaction mixture color was observed when the reaction was done at 0°C, but the color lasted for only a brief 30 second period. The occurrence of the deeply blue colored reaction mixture is indeed a curiosity. It was i n i t i a l l y postulated that the diradical species (340) were responsible for the observed color, since conjugated ketyl species (e.g. sodium benzophenone ketyl) are known to be blue in color. However, when the reaction mixture, at -20°C, was treated with water immediately after the blue color had disappeared (~20 min), a significant amount of the starting vinylcyclopropyl ketone (328) was isolated along with the products (337) and (338). This seems to it This reaction was done using a f a i r l y dilute THF solution of the ketone (328) (~0.02 M), since the use of higher substrate concen-trations did seem to lower the yield. 182 suggest that the blue color is not associated with the production of either the alkoxide (341) or the extended enolate (342) • The process which is responsible for the blue color is unknown at the present time. It appears that at temperatures around -35°C, the enolate species (339) slowly undergoes cyclopropane bond homolysis to the diradical intermediates (340). However, at this temperature, i t seems that (340a) and (340b) barely have enough energy to attain the transition state required for closure to either the alkoxide (341) or the extended enolate (342) before they react via some form of intermolecular radical coupling or addition process. At temperatures around -20°C, however, the formation of the alkoxide (341) and the extended enolate (342) appears to compete more favorably with the various polymer forming processes. At higher reaction temperatures, i t seems that additional polymer forming processes also become favorable and the overall conversion to (341) and (342) drops once again. For interest, i t was decided to see what effect solvating of the lithium counterion had on the rate of the rearrangement reaction. In this regard, the reaction was carried out in the presence of HMPA. Treatment of a cold (-78°C) THF solution of the ketone (328) with LDA, in the presence of 2 equiv of HMPA, and warming the resulting solution to -20°C for 35 min, surprisingly provided, after workup, essentially none of the desired products (337) or (338). The presence of HMPA is obviously deleterious to the rearrangement reaction; however, the reason for this is not at a l l clear. The reaction described above was repeated using TMEDA in place of 183 HMPA, and i t was found that the TMEDA had essentially no effect on the rearrangement reaction, since both the alcohol (337) and (338) could be isolated in essentially the same yield as when the reaction was done in the absence of TMEDA. To further demonstrate the generality of this rearrangement reaction, the methylated vinylcyclopropyl ketone (344) was prepared (Scheme 102). Its preparation was accomplished by reaction of the vinylcyclopropyl ketone (133) with LDA in THF, followed by treatment of the resulting solution with methyl iodide. Compound (344) was isolated, after workup and chromatography, in a 65% yield. The stereochemistry of the methyl group in (344) was predicted to be as shown based on attack of the methyl iodide on the less hindered B-face of the enolate of (133). Scheme 102 133 3 4 4 • 3 4 5 3 4 6 184 Subjection of the methylated vinylcyclopropyl ketone (344) to conditions identical with those found best for the rearrangement reaction of the vinylcyclopropyl ketone (328), that i s , reaction of (344) with LDA in THF at -78°C, followed by warming of the resulting solution of enolate anion to -20°C, induced the reaction mixture to turn a very intense deep blue color. This color faded after approximately 5 min, and after an additional 30 min at -20°C, the reaction mixture was worked up. Glc analysis of the crude product showed the presence of two compounds in a ratio of 3:1, and these two compounds were later shown to have the structures (345) and (346), respectively. The alcohol (345) and the ketone (346) were isolated, after chromatography of the crude reaction product, in yields of 19% and 6%, respectively. The spectral characteristics of the alcohol (345) were very similar to those observed for the previous two alcohols (206) and (337). An additional spectral characteristic that appeared to be diagnostic for compounds like (206), (337) and (345) could be found in the mass spectra of each of these compounds. In each case, the base peak in the spectrum was found at m/e = 108. This fragment ion likely arose from a retro-Diels-Alder process as shown in Scheme 103. 185 The stereochemistry of the a l coho l center i n (345), and l ikewise i n (206), was assigned to be as shown by chemical reasoning. Examina-t i o n of molecular models c l e a r l y showed that i f the a l coho l center had the opposite stereochemistry, the cyclohexene moiety would have been be forced to ex i s t i n a b o a t - l i k e conformation. Unfortunate ly , no s p e c t r a l data was obtained that supported th i s assignment. The r e l a t i v e stereochemistry between the protons H ,^ and H .^ i n the ketone (346) was assigned based on a *H nmr decoupling experiment. I r r a d i a t i o n of the proton ^ ( 6 2.84 - 2.79) s i m p l i f i e d the proton (6 1.86, J_ = 14, 14, 7 Hz) to a d of d (J_ = 14, 14 Hz) . The r e l a t i v e l y weak coupl ing between H^ and H^ (7 Hz) ind icated that a pseudo a x i a l -equator ia l r e l a t i o n s h i p ex is ted between the two protons. Examination of molecular models of (346) c l e a r l y showed that i f the stereochemistry of Hp was opposite to that shown, the d i h e d r a l angle between R^ , and H^ would have been c lose to 1 8 0 ° , and therefore a much higher coupl ing constant should have been observed. The stereochemistry of H^ was chosen to be c i s to H ,^ based on analogy with the ketone (338), and because i f H^ was or iented trans to H^,, the cyclohexanone r i n g would have been forced to ex i s t i n a b o a t - l i k e conformation. The lower y i e l d and r e g i o s e l e c t i v i t y observed for the conversion of the methylated v i n y l c y c l o p r o p y l ketone (344) into the a l c o h o l (345) and (346), as compared to the conversion of the dimethylated v i n y l c y c l o -propyl ketone (328) into the a l coho l (337) and the ketone (338), can be r a t i o n a l i z e d on the basis of s t e r i c hindrance . Because of the r i g i d trans-fused 6-6 r i n g system i n the methylated v i n y l c y c l o p r o p y l ketone (344), the a x i a l l y oriented methyl group In the subsequent d i r a d i c a l 186 intermediate (347) significantly impedes the radical containing side chain from attacking the 8-face of the molecule. This interaction is not so severe in the analogous diradical intermediate (340) derived from the dimethylated vinylcyclopropyl ketone (328), since the single six-membered ring in (340) is far more flexible than the 6-6 ring system in (347). Consequently (340) can adopt a conformation that minimizes the interaction between the attacking radical side chain and the pseudo-axial oriented methyl group. With more favorable conditions for the rearrangement reaction established, the rearrangement reaction of the vinylcyclopropyl ketone (134) was reinvestigated. It was found that treatment of (134) with LDA in THF at -78°C, followed by warming the resulting solution to -20°C for 20 min provided, after workup, a 90:6:4 mixture of the alcohol (206), the starting vinylcyclopropyl ketone (134), and the ketone (348) (glc analysis) (Scheme 104). After chromatography of the crude reaction mixture and d i s t i l l a t i o n , the alcohol (206) was isolated pure in a yield of 39%. The ketone (348) could not be isolated pure in sufficient quantities necessary for characterization, but its identity was postulated by analogy with the previous two ketones (338) and (346). 187 Increasing the length of the reaction time did not diminish the amount of the recovered starting (134), thus suggesting that a small amount of the enolate (321) was being formed during the initial LDA treatment. Scheme 104 There are four important comparisons that are apparent between the rearrangement reaction of the vinylcyclopropyl ketone (134) and the rearrangement reactions of the compounds (328) and (344). Firstly, the deep blue color that was characteristic of the rearrangement reactions of (328) and (344) was barely noticeable during the rearrangement reaction of (134). Secondly, the time required for maximum conversion of the enolate of (134) into the alkoxide of (206) was approximately half that required for the conversions involved in the other two cases. 188 Thirdly, the yield of the overall process was significantly higher for the production of (206), and fourthly the regioselectivity was much greater. The ratio of (206) to (348) was greater than 20:1. The latter three comparisons support the argument previously postulated that the rearrangement reaction is sensitive to steric factors. Since the vinylcyclopropyl ketone (134) contains no axially oriented methyl group a to the ketone as do the ketones (328) and (344), the steric interaction involved in the transition state leading to the alkoxide precursor to the alcohol (206) is proportionally less than the steric interaction involved in the transition states leading to the alkoxide precursors to the alcohols (337) and (338). This reduced steric interaction is reflected by a faster rate, a higher yield, and a greater regioselectivity in the rearrangement reaction of the vinylcyclopropyl ketone (134) as compared to the rearrangement reactions of (328) and (344). This discussion covers most of the work that has been done to date on the remarkably facile vinylmethylenecyclopropane rearrangement of enolates derived from various 7-exo-vinylbicyclo[4.1.0]heptan-2-ones• Clearly this interesting rearrangement reaction requires further inves-tigation. 189 EXPERIMENTAL General Proton nuclear magnetic resonance (*H nmr) spectra were run on e i ther a Bruker model WP-80 or WH-400 spectrometer, using deuterochloro-form or deuterobenzene as solvent with te tramethyls i lane (TMS) as the Interna l re ference . S igna l pos i t ions are given i n parts per m i l l i o n (5) from TMS with an accuracy no greater than ± 0.01 ppm. Coupling constants (J -va lues) are measured with an accuracy no greater than ± 0.2 Hz. Signal m u l t i p l i c i t i e s are recorded according to the number of chemical ly s h i f t d i f f e r e n t protons that couple to the s i g n a l . The m u l t i p l i c i t y , number of protons, assignments (where p o s s i b l e ) , and coupl ing constants are ind ica ted i n parentheses. Abbreviat ions used are: s, s i n g l e t ; d , doublet; t , t r i p l e t ; q, quartet ; b r , broad; w -^, peak width at ha l f height; m, m u l t i p l e t . Infrared ( i r ) spectra were run on a Perkin-Elmer model 710B spectrometer as f i lms between NaCl p lates for l i q u i d compounds or as chloroform so lut ions i n a NaCl c e l l for s o l i d compounds. Recorded values were c a l i b r a t e d with the 1601 c m - 1 band of po lys tyrene . A l l s i g -n i f i c a n t bands i n the d iagnost ic region (4000-1600 c m - 1 ) were recorded, while only the most prominent bands i n the f i n g e r p r i n t region (1600-600 c m - 1 ) were recorded. Abbreviat ions used are: b r , broad; w, weak. Low r e s o l u t i o n mass spectra were run on a Varian/MAT CH4B spectrometer and are reported only for molecules whose s tructure was unexpected and whose spectrum was d i a g n o s t i c . 190 High resolution mass spectra were run on a Kratos/AEl MS 50 or MS 902 spectrometer. Gas-liquid chromatography (glc) analyses were performed on a Hewlett-Packard model 5880 capillary gas chromatograph using a flame ionization detector and a 25 m x 0.21 mm fused s i l i c a column coated with cross-linked SE-54. Thin layer chromatography (tic) analyses were done on commercial aluminum-backed s i l i c a gel plates (E. Merck, Type 5554). Visualization was accomplished with ultraviolet light, iodine, and/or 5% ammonium molybdate - 10% aqueous sulfuric acid. Microanalyses were performed by Mr. P. Borda, Microanalytical Laboratory, University of British Columbia. Melting points were determined using a Fisher-Johns melting point apparatus except for the compound (230) where a Bdchi melting point apparatus was used. A l l values are uncorrected. Boiling points were recorded as air-bath temperatures required for bulb-to-bulb (Kugelrohr) d i s t i l l a t i o n . Flash chromatography was carried out using 230-400 mesh s i l i c a gel (E. Merck) according to the procedure reported by S t i l l and coworkers. Cold temperatures used for various reactions were obtained as follows: -78°C, acetone/C02; -35°C, 40 g CaCl2/100 mL H20/C02; -20°C, 27 g CaCl2/100 mL H20/C02; -10°C, ice/acetone. Concentration refers to solvent removal via a BUchi rotary evaporater at 15 Torr. Reagents added to a reaction mixture by syringe were i n i t i a l l y stored in an oven dried, argon flushed pear shaped flask or v i a l 191 equipped with a septum. Solvent quantities indicated by (x + y mL) refer to the solvent amount used for i n i t i a l reagent addition followed by the solvent amount used for storage flask and syringe rinse. A l l solvents were d i s t i l l e d before use. The word "dry" before a specific solvent means the following treatment was conducted prior to use. Ether and THF were d i s t i l l e d from sodium benzophenone ketyl. Benzene, HMPA, DMSO, DMF and tert-butyl alcohol were d i s t i l l e d from calcium hydride. Methylene chloride (CH2C12) was d i s t i l l e d from P2°5' 1 3 7 Petroleum ether refers to the fraction boiling between 30-60°C. Solutions of n-butyllithium were obtained from Aldrich Chemical Company, Inc. and were standardized using the procedure published by Kafron and Baclawski. 1 3 8 A l l amine bases, diisopropylamine, diethylamine, and N,N-diiso-propylethylamine, were d i s t i l l e d from CaH2 and stored over 3A molecular sieves. Model Study 1 Preparation of the Epoxides (161) and (162) 161 1 6 2 192 To a 2 L-RB flask, equipped with a magnetic stirring bar, was added DMSO (1.1 L), water (38 mL), and cis-bicyclo[3.3.0]oct-2-ene (160) (20 g, 0.18 mol). To this stirring solution at room temperature was added N-bromosuccinimide (NBS) (34 g, 0.19 mol) in one portion. After 45 min, the reaction mixture was treated with saturated aqueous sodium bicarbonate (100 mL) and diluted with water (1.5 L). The resulting mixture was extracted with ether (4X),and the combined ether extracts were washed (water (3X), brine), dried (MgSO^), fi l t e r e d , and concentrated to afford a clear pale yellow liquid which was used directly in the next reaction. The above product, a mixture of bromohydrins, was added neat to an aqueous (70 mL) solution of sodium hydroxide (7.5 g, 0.19 mol) in a 250 mL-RB flask. The reaction mixture was stirred vigorously for 1 h, after which time i t was extracted with ether. The ether extract was washed (water, brine), dried (MgSO^), fi l t e r e d , and carefully concentrated to give a clear pale yellow liquid. Glc analysis of this material showed i t to consist of a 80:18:2 mixture of the a-epoxide (161), the R-epoxide (162), and an unknown minor component, respectively. Tic analysis ( s i l i c a gel plate, petroleum ether-ether, 2:1) showed only two spots. D i s t i l l a t i o n (air-bath temperature 70-80°C/15 Torr) afforded a clear colorless liquid (18.4 g, 80%). Separation of the components of this mixture was achieved by preparative * liquid chromatography (elution with petroleum ether-ether, 20:1). Concentration of the appropriate fractions and d i s t i l l a t i o n provided the a-epoxide (161) as a clear colorless liquid (12.6 g, 55%), and the Preparative liquid chromatography was done on a Waters Associates PrepLC/System 500. 193 B-epoxide (162) together with the minor component (5.0 g). Compound (161). Ir (film): 1440, 850 cm-1; *H nmr (400 MHz, CDC13) 6: 3.49 (br s, 1H, wj = 5.2 Hz), 3.37 (d of d, 1H, J = 2.2 Hz), 2.57-2.38 (m, 2H), 1.95-1.65 (m, 6H), 1.45-1.32 (m, 1H), 1.24-1.12 (m, 1H). Exact Mass calcd. for C 8H 1 20: 124.0888; found: 124.0890. Preparation of the A l l y l i c Alcohols (163) and (164) HO H 163 164 To an oven dried, argon flushed 2 L-RB-3N flask, equipped with a condenser, dropping funnel, magnetic stirring bar, and solid addition tube containing sodium borohydride (3.9 g, 0.10 mol), was added diphenyl diselenide (16 g, 0.051 mol) and absolute ethanol (300 mL). To this stirring suspension at room temperature was slowly added the sodium borohydride in small portions. To the resulting cloudy colorless solution was added, over a period of 15 min from the dropping funnel, a dry THF (400 mL) solution of the epoxide (161) (10 g, 0.081 mmol). After being refluxed for 1 h, the reaction mixture was cooled to 0°C, and hydrogen peroxide (110 mL, 40% aqueous solution) was added over 20 min from the dropping funnel. Upon warming to room temperature, the reaction mixture started to bubble profusely, and after cessation, reflux was commenced for 1 h. After this time, the reaction mixture was 194 cooled and diluted with water. The resulting mixture was extracted with ether (2X) and the combined ether extracts were washed (aqueous 10% Na2C03 (3X)), dried (MgSO^), filte r e d , and concentrated to afford a yellow liquid. D i s t i l l a t i o n (air-bath temperature 70-80°C/15 Torr) gave a clear colorless liquid (6.6 g, 66%). Glc analysis of this material showed i t to consist of a mixture of the a l l y l i c alcohols (163) and (164) together with two ketonic products in a ratio of 8:1:1, respectively. This material was used without further purification for the next reaction. Preparation of the A l l y l i c S i l y l Ethers (148) and (149) To an oven dried, argon flushed 500 mL-RB-3N flask, equipped with an argon inlet and magnetic stirring bar, was added the product mixture from the previous reaction (6.0 g, ~ 48 mmol) and dry DMF (120 mL). Imidazole (8.2 g, 120 mmol) and tert-butyldimethylsilyl chloride (8.7 g, 58 mmol) were added in one portion successively, and the reaction mixture was stirred at room temperature for 6 h. After this time, the reaction mixture was treated with saturated aqueous sodium bicarbonate (~ 20 mL) and diluted with water (~ 300 mL). The resulting mixture was extracted with ether (2X) and the combined ether extracts were washed 195 (water (2X), b r i n e ) , dr ied (MgSO^), f i l t e r e d , and concentrated to a f ford a c l ear c o l o r l e s s l i q u i d . This l i q u i d was f la sh chromatographed (5 x 20 cm column of s i l i c a g e l , e l u t i n g with petroleum e ther -e ther , 200:1) to a f f o r d , a f ter concentrat ion of the appropriate f rac t ions and d i s t i l l a t i o n ( a i r - b a t h temperature 1 0 0 - 1 1 0 ° C / 1 5 T o r r ) , the a l l y l i c s i l y l ethers (148) and (149) as c l ear c o l o r l e s s l i q u i d s (8.9 g, 77% and 1.1 g, 10%, r e s p e c t i v e l y ) . Compound (148). Ir ( f i l m ) : 3020(w), 1720, 1060 c m - 1 ; *H nmr (400 MHz, CDC1,) 6: 5.65 and 5.56 (each d of d of d, 1H, H,, and H _ , J D „ = 5.7 Hz, J = J _ _ = 2.2 Hz, J D . = J _ . = 1.6 Hz) , 4,85 (d of d of d, 1H, —au —L.JJ —UA —L.A H A « 4 E = 8 , 5 H Z > 4 B = 4 c = 4 D = 1 , 6 H z ) » 3 - 0 8 - 2 - 9 9 (m» 1 H » V > 2 - 6 9 (d of d of d of d, 1H, H^,, J = J = J _ _ = 8.5 Hz, J = 4.8 Hz) , 1.98-1.88 (m, 1H), 1.70-1.60 (m, 1H), 1.51-1.22 (m, 4H), 0.92 (s , 9H, - S i - t - B u ) , 0.08 (s , 6H, - S i - M e ' s ) . I r r a d i a t i o n at 6 4 .85: 6 5.65 and 6 5.56 s i m p l i f i e d to a d of d (J = 5.7, 2.2 Hz) , 6 3.08-2.99 changed, 6 2.69 s i m p l i f i e d to a d of d of d (J = 8.5, 8 .5 , 4.8 Hz) . Exact Mass c a l c d . for C 1 1 + H 2 g 0 S i : 238.1753; found: 238.1755. A n a l , c a l c d . for C 1 1 + H 2 6 0 S i : C 70.52, H 10.99; found: C 70.60, H 10.91. Compound (149). Ir ( f i l m ) : 3030(w), 1660, 1260 c m - 1 ; *H nmr (400 MHz, CDC1 3) 6: 5.25 (br s, 1H, H , w| = 6 Hz, 5.17-5.09 (m, 1H, H g ) , 2.65-2.54 (m, 1H, Hg), 2.49 (d of d of d , 1H, H c , = 12 Hz, = = 8 Hz) , 2.30-1.80 (m, 5H), 1.29 (d of d of d , 1H, H _ , J n _ = 12 Hz, J n D = J _ _ = 6 Hz) , 1.18-1.06 (m, 1H), 0.91 ( s , 9H, - S i - t - B u ) , 6 0.08 (s , 3H, —DE — - S i - M e ) , 6 0.07 (s , 3H, - S i - M e ) . I r r a d i a t i o n at 6 1.29: mul t ip l e t at 6 5.17-5.09 and 6 2.65-2.54 each s i m p l i f i e d , 6 2.49 s i m p l i f i e d to a d of d (J = 8, 8 Hz) . Exact Mass c a l c d . for C l l + H 2 6 0 S i : 238.1753; found: 238.17 196 General Procedure 1: Rhodlum(II) Acetate Catalyzed Addition of Ethyl Diazoacetate to Alkenes 6-8cm FINELY DRAWN CAPILLARY A To the reaction flask A was added neat liquid alkene substrate and rhodium(II) acetate (Rh 2(OAc) H)(~ 0.2 mol % ) . To the flask B was added neat ethyl diazoacetate. A siphon between the flask B and the reaction flask A was started, and the rate of addition of the ethyl diazoacetate to the rapidly stirring alkene was adjusted to one drop per 15-45 seconds by adjusting the height difference between the two flasks. Periodically, the height difference between A and B was readjusted to allow further reagent addition. After complete addition, the yellow-green reaction mixture was directly flash chromatographed to afford, after concentration of the appropriate fractions and d i s t i l l a t i o n , cyclopropyl ester mixtures and recovered starting alkene. 197 Preparation of the Cyclopropyl Esters (151a) and (151b) EtOOC General procedure 1 was followed. Ethyl diazoacetate (7.0 mL, 67 mmol) was added over a period of 12.5 h to the a l l y l i c s i l y l ether (148) (8.8 g, 37 mmol) containing rhodium(II) acetate (35 mg, 0.08 mmol). The crude reaction product was flash chromatographed (5x20 cm column of s i l i c a gel eluting with petroleum ether-ether, 25:1) to afford, after concentration of the appropriate fractions and d i s t i l l a t i o n , the recovered a l l y l i c s i l y l ether (148) (4.95 g) and a mixture of ester containing compounds (4.09 g, 78% based on unrecovered starting material) as a clear colorless liquid ( d i s t i l l a t i o n air-bath temperature 100-110°C/0.1 Torr). Glc analysis of this mixture showed i t to consist of the cyclopropyl esters (151a) and (151b) together with the Insertion product (175) in a ratio of 11:7:1, respectively. This material was used without further purification for the next reaction. The cyclo-propyl esters (151a) and (151b) were separated for characterization by flash chromatography (elution with petroleum ether-ether, 50:1). Concentration of the appropriate fractions and d i s t i l l a t i o n provided the pure cyclopropyl esters (151a) and (151b) as clear colorless liquids 198 Compound (151a). Ir (film): 1725, 1260, 1180 cm-1; lH nmr (400 MHz, CDC13) 6: 4.11 (q, 2H, -OCH^CHg, J = 7 Hz), 4.09 (d, 1H, Hg, J [ B A = 6.5 Hz), 2.35 (d of d of d, 1H, H,,, J = 9.9 Hz, J = J = 7.8 Hz), r — — r A — 2.11-2.03 (m, 1H, H^), 1.99 and 1.91 (each d of d, 1H, Hp and H^ , = 6 Hz, = = 3 Hz), 1.88-1.69 (m, 3H), 1.55-1.35 (m, 3H), 1.26 (t, 3H, -OCH0CH3) , 6 1.23 (d of d, 1H, H , J^p = = 3 Hz), 6 0.91 (s, 9H, -Si-t-Bu), 6 0.10 (s, 3H, -Si-Me), 6 0.05 (s, 3H, -Si-Me). Irradiation at 6 4.09: multiplet at 6 2.11-2.03 simplified. Exact Mass calcd. for C 1 8H 3 20 3Si: 324.2122; found: 324.2113. Anal, calcd. for C 1 8 H 3 2 0 3 S i : C 66.62, H 9.94; found: C 66.72, H 9.80. Compound (151b). Ir (film): 1725, 1250, 1270 cm"1; XH nmr (400 MHz, CDC13) 6: 4.38 (d, 1H, Hfi, = 6.5 Hz), 4.14 (q, 3H, -OCH_2CH3, J_ = 7 Hz), 2.52-2.39 (m, 2H), 1.97-1.60 (m, 6H), 1.49-1.38 (m, 3H), 1.27 (t, 3H, -OCH^Hg, J_ = 7 Hz), 0.92 (s, 9H, -Si-t-Bu), 0.08 (s, 3H, -Si-Me), 0.06 (s, 3H, -Si-Me). Exact Mass calcd. for C 1 8 H 3 2 0 3 S i : 324.2122; found: 324.2120. Preparation of the Alcohol Mixture (177) HOCH 177 To an oven dried, argon flushed, 1 L-RB-3N flask, equipped with a magnetic stirring bar and dropping funnel, was added lithium aluminum 199 hydride (2.1 g, 55 mmol) and anhydrous ether (400 mL). To this stirring suspension at room temperature was added, over a period of 30 min from the dropping funnel, an ether (200 mL) solution of the cyclopropyl ester mixture from the previous reaction (8.9 g, 27.5 mmol). After complete addition, the reaction mixture was stirred for an additional 1 h. The reaction mixture was cautiously treated with sodium sulfate decahydrate (Na 2SO l t»10H 2O), and after complete precipitation of the aluminum salts, the resulting slurry was filtered through F l o r i s i l (6x6 cm column, eluting with ether). Concentration and d i s t i l l a t i o n (air-bath temperature 100-110°C/0.1 Torr) afforded largely the alcohol mixture (177) (7.8 g, 95%) as a clear, colorless, viscous liquid. Ir (film): 3300(br), 1255, 1070 cm - 1. Exact Mass calcd. for C 1 6H 3 0O 2Si: 282.2016; found: 282.2013. General Procedure 2: Pyridinium Chlorochromate Oxidation of oc-Hydroxy  Cyclopropane Derivatives To an oven-dried, argon flushed, RB-3N-flask, equipped with an argon inlet, magnetic stirring bar, and septum, was added pyridinium chlorochromate (PCC) (1.5 equiv), sodium acetate (~ 1.5 equiv), and dry CH2C12. To this stirring suspension at room temperature was added a dry CH2C12 solution of the alcohol via a syringe. The reaction mixture, which quickly turned black, was stirred for approximately 1 h, and then was diluted with two volumes of anhydrous ether. After any black tarry 200 lumps had been broken up with a spatula, the mixture was filtered through a short column of F l o r i s i l (~ 6 cm) containing a 2 cm plug of Celite on top. The column was flushed with ether, and the combined f i l t r a t e was concentrated to afford a clear pale yellow liquid. This liquid was pumped on with agitation (room temperature/0.1 Torr) for ~ 15 min before being used directly in the next reaction. Preparation of the Aldehyde Mixture (178) 178 General procedure 2 was followed. To a stirring suspension of pyridinium chlorochromate (4.6 g, 21 mmol), sodium acetate (2 g), and CH2C12 (30 mL) in a 250 mL-RB-3N flask was added a solution of the alcohol mixture (177) (4.0 g, 14 mmol) in CH2C12 ( 5 + 4 mL). General conditions and reaction workup produced a clear pale yellow liquid (3.90) which was used without further purification for the next reaction. General procedure 3: Aldehyde Equilibrations To an oven dried, argon flushed RB-3N flask, equipped with an argon inlet, magnetic stirring bar, and septum, was added a dry THF solution of the aldehyde mixture (1 equiv) from the previous reaction. 201 This solution was cooled to -10°C, and a solution of potassium tert-butoxide (~ 0.1 equiv) in dry tert-butyl alcohol was added via a syringe. The reaction mixture turned yellow, and after having been stirred at -10°C for 15 min, i t was treated with saturated aqueous ammonium chloride. The resulting mixture was diluted with water and extracted with ether (2X). The combined ether extracts were washed (water (2X), brine), dried (MgSO^), fil t e r e d , and concentrated to afford a single aldehyde epimer as a clear yellow liquid. Preparation of the Aldehyde (179) 179 General procedure 3 was followed. To a THF (80 mL) solution of the aldehyde mixture (178) (3.8 g, 13.5 mmol) in a 250 mL-RB-3N flask was added a tert-butyl alcohol (20 mL) solution of potassium tert-butoxide (0.16 g, 1.4 mmol). General conditions and reaction workup afforded the aldehyde (179) as a clear yellow liquid (3.83 g). This material was used for the next reaction without further purification. For character-ization purposes, the crude aldehyde could be d i s t i l l e d (air-bath temperature 100-110°C/0.1 Torr) with some resultant decomposition in the s t i l l pot to provide (179) as a clear colorless liquid. Ir (film): 2700, 1700, 1080, 840 cm-1; XH nmr (400 MHz, CDC13) 202 6: 9.01 (d, 1H, -CHO, J = 6 Hz), 4.13 (d, 1H, HA, J = 7 Hz), 2.40 (d of d of d, 1H, J_ = 10, 8, 8 Hz), 2.17-2.00 (m, 2H), 2.05 (d of d, 1H, J = 6.5, 3.5 Hz), 1.90-1.74 (m, 3H), 1.60-1.35 (m, 4H), 0.92 (s, 9H, -Si-t-Bu), 0.10 (s, 3H, -Si-Me), 0.06 (s, 3H, -Si-Me). Exact Mass calcd. for C 1 6H 2 80 2Si: 280.1859; found: 280.1860. General Procedure 4: Wittig Methylenation of Aldehydes To an oven dried, argon flushed RB-3N flask, equipped with an argon inlet, magnetic stirring bar, and septum, was added methyltri-phenylphosphonium bromide (1.5 equiv) and dry THF. This stirring sus-pension was cooled to -78°C, and a solution of n-butyllithium (1.5 equiv) in hexanes was added via a syringe. The reaction mixture was warmed to room temperature over 30 min and a solution of crude aldehyde (1 equiv) in dry THF was added over 10 min via a syringe. After being stirred for 30 min, the reaction mixture was diluted with petroleum ether (1-2 volumes) and the resulting mixture was filtered through a short column of F l o r i s i l (8 cm), flushing the column with additional petroleum ether. Concentration and d i s t i l l a t i o n afforded the desired alkene. Preparation of the Alkene (180) 203 General procedure 4 was followed. To a THF (250 mL) solution of methylenetriphenylphosphorane (21.4 mmol) in a 1 L-RB-3N flask was added a THF (10 + 5 mL) solution of the aldehyde (179). General conditions, reaction workup, and d i s t i l l a t i o n (air-bath temperature 90-100°C/0.1 Torr) afforded the alkene (180) as a clear colorless liquid (3.0 g, 78% from the alcohol mixture (177)) along with a yellow viscous residue (0.7 g) remaining in the s t i l l pot. Ir (film): 3060(w), 1630, 1255, 1075 cm"1, lH nmr (400 MHz, CDC13) 6: 5.35 (d of d of d, 1H, H c > = 17 Hz, J^ , = 10 Hz, = 9 Hz), 4.96 (d of d, 1 H, H , J = 17 Hz, J _ = 2 Hz), 4.80 (d of d, 1H, HB, JL^, = 10 Hz, - 2 Hz), 6 4.07 (d, 1H, Hg, = 6 Hz), 2.31 (d of d of d, 1H, H , J = 10, 7.5, 7.5 Hz), 2.15-2.05 (m, 1H, H_), 1.88-1.74 (m, 3H), 1.56-1.30 (m, 5H), 1.04 (d of d of d, 1H, H, 1 = 9 Hz, J = u —DC —Dr. J_ = 3 Hz), 0.91 (s, 9H, -Si-t-Bu), 0.09 (s, 3H, -Si-Me), 0.05 (s, 3H, — D r — -Si-Me). Exact Mass calcd. for C 1 7H 3 ( )0Si: 278.2067; found: 278.2065. Anal, calcd. for C 1 7H 3 0OSi: C 73.32, H 10.86; found: C 73.42, H 10.80. General Procedure 5: Removal of the S i l y l Ether Protecting Group To an oven dried, argon flushed RB-3N flask, equipped with an argon inlet, magnetic stirring bar, and septum, was added the s i l y l ether (1 equiv) in dry THF. This solution was cooled to -78°C, and a solution of tetra-n-butylammonium fluoride (TBAF) (2 equiv) in dry THF was added via a syringe. The reaction mixture was warmed to room temperature, and after i t was stirred for 6-8 h, i t was poured into water, 204 and the resulting mixture was extracted with ether. The ether extract was washed (water, brine), dried (MgSO^), filte r e d , and concentrated to afford the crude alcohol product. Preparation of the Alcohol (181) 181 General procedure 5 was followed. To a cold (-78°C) THF (40 mL) solution of the s i l y l ether (180) (1.5 g, 5.4 mmol) in a 100 mL-RB-3N flask was added a THF (10 mL) solution of TBAF (3.0 g, 11.5 mmol). General conditions and reaction workup produced a clear colorless liquid. This liquid was pumped on with agitation (room temperature/0.1 Torr, 20 min) to remove the volatile silicon containing byproducts before being d i s t i l l e d (air-bath temperature 60-70°C/0.1 Torr) to yield the alcohol (181) as a clear colorless liquid (807 mg, 91%). Ir (film): 3250(br), 3050(w), 1630, 895 cm"1; *H nmr (400 MHz, CDCL3) 6: 5.35 (d of d of d, 1H, Hc, = 17 Hz, = 10 Hz, = 8.5 Hz), 4.96 (d of d, 1H, H^ , = 17 Hz, = 2 Hz), 4.81 (d of d, 1H, V -BC =10 HZ' -BA =2 Bz)t 4*09 (d °f d' 1H' V ^GH = ^ GI =6 HZ)' 2.37 (d of d of d, 1H, rljy J - 10, 8, 8 Hz), 2.24-2.14 (m, 1H, H^), 1.90-1.47 (m, 7H), 1.30-1.15 (m, 2H), 1.08 (d of d of d, 1H, Hp, = 8.5 Hz, J = 3 Hz). D90 added: 6 4.09 simplified to a d (J = 6 Hz). 205 Irradiation at 6 2.37: multiplet at 6 2.24-2.14 simplified. Exact Mass calcd. for C nH 1 60: 164.1202; found: 164.1200. Preparation of the Ketone (131) General procedure 2 was followed. To a stirring suspension of pyridinium chlorochromate (1.5 g, 7.1 mmol), sodium acetate (1.2 g), and CH2C12 (15 mL) in a 100 mL-RB-3N flask was added a solution of the alcohol (181) (773 mg, 4.7 mmol) in CH2C12 (10 + 5 mL). General conditions and reaction workup produced a pale yellow liquid. D i s t i l l a t i o n (air-bath temperature 60-70°C/0.1 Torr) afforded the ketone (131) as a clear colorless liquid (650 mg, 85%). Ir (film): 1710, 1630, 890 cm-1; XH nmr (400 MHz, CDC13) 6: 5.36 (d of d of d, 1H, Hc, = 17 Hz, = 10.2 H, = 8.5 Hz), 5.12 (br d, 1H, H., J , . = 17 Hz), 4.98 (d of d, 1H, Hn, - 10.2 Hz, J_. = 1.2 Hz), 2.78-2.68 (m, 1H), 2.47-2.37 (m, 1H), 2.00-1.70 (m, 6H), 1.64-1.37 (m, 3H). Exact Mass calcd. for C 1 1H l i |0: 162.1045; found: 162.1041. Anal, calcd. for CnH,.0: C 81.44, H 8.70; found: C 81.27, H 8.78. 131 206 General Procedure 6: Preparation of Lithium Dllsopropylamlde (LDA) To a flame dried, argon flushed, RB-3N flask, equipped with an argon inlet, magnetic stirring bar and septum, was added dry THF. Upon cooling the flask to -78°C, diisopropylamine (1 equiv) and a solution of n-butyllithium in hexanes (1 equiv) were added successively via syringes. The reaction flask was warmed to 0°C for 10 min; then cooled back down to -78°C, now ready for use. Preparation of the Divinylcyclopropane (135) To a cold (-78°C) THF (5.5 mL) solution of LDA (1.1 mmol) in a 25 mL-RB-3N flask was added a solution of the ketone (131) (120 mg, 0.74 mmol) in THF (0.9 + 0.9 mL) via a syringe. The reaction mixture was stirred at -78°C for 30 min, after which time, a THF (1.5 mL) solution of HMPA (265 uL, 1.5 mmol) and freshly sublimed tert-butyldimethylsilyl chloride (300 mg, 2.0 mmol) was added via a syringe. The reaction mixture was stirred at -78°C for 15 min, after which time, It was allowed to warm to room temperature with additional stirring for 2 h. The reaction mixture was treated with saturated aqueous sodium bicarbonate and diluted with water. The resulting mixture was extracted with ether, and the ether extract was washed (water (2X), brine), dried (MgSO^), H B 135 207 filte r e d , and concentrated to afford a pale yellow liquid. This liquid was pumped on with agitation (30°C/0.1 Torr, 30 rain) to remove the vola-t i l e silicon byproducts before being d i s t i l l e d (air-bath temperature 85-95°C/0.1 Torr) to provide the enol s i l y l ether (135) as a clear colorless liquid (157 mg, 77%). This material was used quickly for the next reaction since slow decomposition resulted, even with storage at -10 Ir (film): 1675, 1630, 860 cm-1; *H nmr (400 MHz, CDC13) 6: 5.41 (d of d of d, 1H, Hc, = 17 Hz, - 10.5 Hz, = 8.5 Hz), 4.98 (br d, 1H, HA, J^, = 17 Hz), 4.83 (br d, 1H, H , = 10.5 Hz), 2.53-2.45 (m, 1H), 2.27-2.16 (m, 1H), 1.92-1.64 (m, 7H), 1.47 (d of d of d, 1H, Hp, J^, = 8.5 Hz, Jp E = Jp F = 3 Hz), 0.95 (s, 9H, -Si-t-Bu), 0.15 (s, 6H, -Si-Me's). Exact Mass calcd. for C 1 7H 2 80Si: 276.1910, found: 276.1909. General Procedure 7: Thermal Rearrangements A solution of substrate in dry benzene was added to a base washed, silylated pyrolysis tube (0.4 x 8 cm or 0.4 x 20 cm, 1 mm thick). This tube was connected to a vacuum line, cooled with liquid nitrogen, pumped on (0.1 Torr) for 5 min, and then warmed back to room temperature. This freeze-pump-thaw cycle was repeated twice more. The cold pyrolysis tube from the last cycle was sealed under vacuum, warmed to room temperature, and then lowered into a preheated aluminum pyrolysis chamber. After the required time of heating, the pyrolysis tube was cooled to room temperature and broken, and the benzene solution was concentrated to yield the resulting product. 208 Preparation of the Enol S i l y l Ether (139) 139 General procedure 7 was followed. A solution of the divinylcyclopropane (135) (82 mg, 0.30 mmol) in benzene (2 mL) was heated for 5 h at 155°C. Concentration afforded a yellow liquid. Glc analysis of this material showed i t to consist largely of a mixture of two compounds, 90% and 5% respectively, along with a number of minor compounds comprising the remaining 5%. This material was chromatographed through triethylamine washed, grade 1, basic alumina (0.4 x 5 cm column, eluting with pentane). Concentration of the early fractions and d i s t i l l a t i o n (air-bath temperature 80-90°C/0.1 Torr) afforded, by glc analysis, 94% pure enol s i l y l ether (139) as a clear colorless liquid (74 mg, 90%). Purer material for characterization was obtained by repeating the chromatography. Ir (film): 3010, 1650, 1250, 870 cm-1; lR nmr (400 MHz, CDC13) 6: 6.27 (d of d of d of d, 1H, H„, J _ = 9.5 Hz, J _ D = 5.7 Hz, J = 2.5 and 1.8 Hz - a l l y l i c coupling to H^. and H^ ,), 5.37 (d of d of d, 1H, Hp, = 9.5 Hz, J = J__ = 3.2 Hz), 4.86 (d, 1H, H , J = 2.8 Hz), 2.50 (d —UL —Dr A —AD of d, 1H, Hfi, J f i C = 5.7 Hz, - 2.8 Hz), 2.24 (d of d of d, 1H, or H_, J__ = 18 Hz, J = 3.2 Hz, J_ = 1.8 Hz), 2.11-2.01 (m, 2H), 1.94 F —EF ~~D (d of d of d, 1H, or H^ ,, = 18 Hz, Jp = 3.2 Hz, = 2.5 Hz), 209 1.73-1.62 (m, 3H), 1.58-1.48 (m, 1H), 1.28-1.17 (m, 1H), 0.91 (s, 9H, -Si-t-Bu), 0.14 (s, 3H, -Si-Me), 0.12 (s, 3H, -Si-Me). Irradiation at 6 6.27: 6 5.37 simplified to a d of d (J = 3.2, 3.2 Hz), 6 2.50 simplified to a d (J = 2.8 Hz), 6 2.24 simplified to a d of d (J = 18, 3.2 Hz), 6 1.94 simplified to a d of d (£ = 18, 3.2 Hz). Exact Mass calcd. for C 1 7H 2 80Si: 276.1910; found: 276.1913. Preparation of the Ketone (182) To an oven dried, argon flushed 25 mL-RB-3N flask, equipped with an argon inlet, magnetic stirring bar, and septum, was added a solution of the enol s i l y l ether (139) (42 mg, 0.15 mmol) in dry THF (3 mL). This solution was cooled to -78°C, and a solution of tetra-n-butyl-ammonium fluoride (100 mg, 0.38 mmol) in THF (1.5 mL) was added via a syringe. The reaction mixture turned dark yellow, and after i t was stirred for 5 min at -78°C, the reaction mixture was treated with saturated aqueous ammonium chloride and diluted with water. The resulting mixture was extracted with ether, and the ether extract was washed (water, brine), dried (MgSO^), filte r e d , and concentrated to afford a clear colorless liquid. This liquid was flash chromatographed (1.5 x 16 cm column of s i l i c a gel, eluting with petroleum ether-ether, 'B 182 210 5:1) to provide, after concentration of the appropriate fractions and di s t i l l a t i o n (air-bath temperature 40-50°C/0.1 Torr), the ketone (182) as a clear colorless liquid (23 mg, 93%). Ir (film): 3010, 1730, 1640(w), 740 cm"1; *H nmr (400 MHz, CDC13) 6: 6.14 (d of d of d of d, 1H, Hp, J^, = 9.5 Hz, = 6.5 Hz, J = J = 2 Hz), 5.55 (d of d of d, 1H, H^ , = 9.5 Hz, J = 3.8 Hz, J = 2.5 Hz) 2.71 (d of d, 1H, H_, = 6.5 Hz, J =6 Hz), 2.47 (d of d, 1H, H , J„. = 18 Hz, J_„ = 6 Hz), 2.38-2.11 (m, 5H), 1.92-1.80 (m, 1H), 1.71-1.59 (m, 2H), 1.54-1.45 (m, 1H), 1.28-1.16 (m, 1H). Irradiation at 6 2.71: 6 6.14 simplified to a d of d of d (J = 9.5, 2, 2 Hz), 6 2.47 simplified to a d (J = 18 Hz). Exact Mass calcd. for C nH l l +0: 162.1045; found: 162.1040. Model Study 2 Preparation of the Cyclopropyl Esters (152a) and (152b) •••COOEt EtOOC 152a General procedure 1 was followed. Ethyl diazoacetate (0.4 mL, 3.8 mmol) was added over a period of 7 h to the a l l y l i c s i l y l ether (149) (546 mg, 2.29 mmol) containing rhodium(II) acetate (~ 2 mg). The 211 crude react ion product was f la sh chromatographed (3 x 18 cm column of s i l i c a g e l , e l u t i n g with petroleum ether-e ther , 30:1) to a f f o r d , a f t er concentrat ion of the appropriate f rac t ions and d i s t i l l a t i o n , the recovered alkene (182) (160 mg) as a c l ear c o l o r l e s s l i q u i d , the c y c l o -propyl esters (152a) and (152b) (293 mg, 56% based on unrecovered s t a r t i n g mater ia l ) as a c l ear c o l o r l e s s l i q u i d ( d i s t i l l a t i o n a i r - b a t h temperature 1 0 0 - 1 1 0 ° C / 0 . 1 T o r r ) , and various minor ester containing products (25 mg, 5%). Glc ana lys i s of the cyc lopropy l ester mixture showed i t to cons i s t of (152a) and (152b) i n near ly equal amounts. This mater ia l was used without further p u r i f i c a t i o n for the next r e a c t i o n . For c h a r a c t e r i z a t i o n purposes, the cyc lopropy l esters (152a) and (152b) were separated by f l a s h chromatography ( e lu t ing with petroleum e ther -e ther , 40:1) to a f f o r d , a f ter concentrat ion of the appropriate f rac t ions and d i s t i l l a t i o n ( a i r - b a t h temperature 1 0 0 - 1 1 0 ° C / 0 . 1 T o r r ) , each epimer as a c l ear c o l o r l e s s l i q u i d . Compound (152a). Ir ( f i l m ) : 1720 c m - 1 , X H nmr (400 MHz, CDC1 3) 6: 4.26 (d, 1H. H , J A C = 5.3 Hz) , 4.19-4.05 (m, 2 H , - O C H 2 C H 3 ) , 2.21-2.11 (m, 1H), 2.05-1.48 (m, 9H), 1.40 (d , 1H, cyc lcopropy l proton, J_ = 4 Hz) , 1.26 ( t , 1H, - O C H T C H J , £ = 7 Hz) , 0.88 (s , 9H, - S i - t - B u ) , 0.06 (s , 3H, - S i - M e ) , 0.03 (s , 3H, - S i - M e ) . Exact Mass c a l c d . for C 1 8 H 3 2 0 3 S i : 324.2122; found: 324.2120. Compound (152b). Ir ( f i l m ) : 1720 c m - 1 ; X H nmr (400 MHz, CDC1 3) 6: 4.45 (d of d, 1H, H^, = 6.2 Hz, = 3.2 Hz) , 4.11 (m, 2H, - O C H ^ C H ^ , 2.40-2.31 (m, 1H), 2.19 (d of d of d, 1H, H c > = 13.5 Hz, JL,n = 7.8 Hz, = 6.2 Hz) , 1.97-1.56 (m, 7H), 1.51 (d, 1H, cyc lopropy l proton, J_ = 8.7 Hz) , 1.27 ( t , 3H, - O C H ^ H j ) , 0.89 (s , 9H, - S i - t - B u ) , 212 0.05 (s, 3H, -Si-Me), 0.04 (s, 3H, -Si-Me). Irradiation at 6 4.45: 6 2.19 simplified to a d of d (J_ = 13.5, 7.8 Hz). Exact Mass calcd. for C 1 8 H 3 2 0 3 S i : 324.2122; found: 324.2102. Preparation of the Alcohol Mixture (183) To an oven dried, argon flushed 50 mL-RB-3N flask, equipped with an argon i n l e t , magnetic s t i r r i n g bar, and septum, was added lithium aluminum hydride (60 mg, 1.58 mmol) and anhydrous ether (10 mL). To this s t i r r i n g suspension at room temperature was added, via a syringe, a solution of the cyclopropyl ester mixture from the previous reaction (341 mg, 1.05 mmol) i n ether (2.5 + 2 mL). After 30 min, the reaction mixture was treated with Na2S04»10H20, and the resulting slurry was f i l t e r e d through F l o r i s i l (4x3 cm column, flushing with ether). Concentration and d i s t i l l a t i o n (air-bath temperature 95-105°C/0.1 Torr) afforded the alcohol mixture (183) as a clear, colorless viscous l i q u i d (280 mg, 94%). Ir ( f i l m ) : 3300(br), 1255, 840 cm - 1. Exact Mass calcd. for C 1 6H 3 0O 2Si: 282.2016; found: 282.2003. H 183 213 Preparation of the Aldehyde Mixture (184) —|- S i O " H 184 General procedure 2 was followed. To a s t i r r i n g suspension of pyridinium chlorochromate (310 mg, 1.44 mmol), sodium acetate (150 mg), and CH 2C1 2 (5 mL) i n a 50 mL-RB-3N f l a s k was added a so l u t i o n of the alcohol mixture (183) (270 mg, 0.96 mmol) i n CH 2C1 2 (1.5 + 1 mL). General conditions and reaction workup produced a clear pale yellow l i q u i d (256 mg, 96%) which was used without further p u r i f i c a t i o n i n the next reaction. Preparation of the Aldehyde (185) General procedure 3 was followed. To a THF (6 mL) solu t i o n of the aldehyde mixture (185) (256 mg, 0.913 mmol) i n a 50 mL-RB-3N f l a s k was added a t e r t - b u t y l alcohol (1 mL) solution of potassium t e r t -butoxide (~ 10 mg). General conditions and reaction workup afforded the • •CHO H 185 214 aldehyde (185) as a clear yellow liquid (250 mg, 98%). This liquid was used in the next reaction without further purification. For characteri-zation purposes, the crude aldehyde could be d i s t i l l e d (air-bath temperature 100-110°C/0.1 Torr), with some resultant decomposition in the s t i l l pot, to yield (185) as a clear colorless liquid. Ir (film): 2780, 1705, 1260, 1060, 845 cm-1; lK nmr (400 MHz, CDC13) 6: 9.10 (d, 1H, -CHO, J_ = 6.5 Hz), 4.29 (d, 1H, H^, J_ = 4.7 Hz), 2.26-2.18 (m, 1H), 2.02-1.92 (m, 3H), 1.88-1.54 (m, 7H), 0.89 (s, 9H, -Si-_t-Bu), 0.07 (s, 3H, -Si-Me), 0.05 (s, 3H, -Si-Me). Exact Mass calcd. for C 1 6 H 2 8 0 2 S i : 280.1859; found: 280.1839. Preparation of the Alkene (186) 186 General procedure 4 was followed. To a THF (20 mL) solution of methylenetriphenylphosphorane (1.34 mmol) in a 50 mL-RB-3N flask was added a THF (1.5 + 1 mL) solution of the crude aldehyde (185) (238 mg, 0.891 mmol). General conditions, reaction workup, and d i s t i l l a t i o n (air-bath temperature 85-95°C/0.1 Torr) afforded the alkene (186) as a clear colorless liquid (194 mg, 82%). Some yellow viscous residue was left in the s t i l l pot. Ir (film): 3050(w), 1615, 1260, 1060, 840 cm-1; *H nmr (400 MHz, 215 C D C l o ) 6: 5.41 (d of d of d, 1H, H„, J „ A = 17 Hz, J _ D = = 9.5 Hz) , J C — C A —CD — C D 5.03 (d of d, 1H, H A , = 17 Hz, = 2 Hz) , 4.88 (d of d, 1H, H , J D _ - 9.5 Hz, J = 2 Hz) , 4.24 (br d, 1H, I L , J = 5 Hz) , 2.11-2.04 (m, —BL. —DA r — 1H), 1.96-1.51 (m, 8H), 1.25 (d of d, 1H, H„, J n „ = 9.5 Hz, J _ _ - 3.5 D —UL. —Un Hz), 1.04 (d , 1H, H _ , J _ _ = 3.5 Hz), 0.88 (s , 9H, - S i - t - B u ) , 0.05 (s , fc. —CJU — 3H, - S i - M e ) , 0.03 (s , 3H, - S i - M e ) . I r r a d i a t i o n at 6 1.25: 6 5.41 s i m p l i f i e d to a d of d (J_ = 17, 9.5 Hz) , 6 1.04 s i m p l i f i e d to a s. Exact Mass c a l c d . for C 1 7 H 3 Q O S i : 278.2067; found: 278.2065. Preparat ion of the Alcoho l (187) 187 General procedure 5 was followed. To a -78°C (5 mL) solution of the s i l y l ether (186) (185 mg, 0.664 mmol) was added a THF (2.3 mL) solution of TBAF (430 mg, 1.66 mmol). General conditions and reaction workup produced a clear colorless liquid. Because of the v o l a t i l i t y of the resulting alcohol, the silicon containing byproducts were removed by flash chromatography (3 x 18 cm column of s i l i c a gel eluting with petroleum ether-ether, 2:1). Concentration of the appropriate fractions and d i s t i l l a t i o n (air-bath temperature 50-60°C/0.1 Torr) provided the alcohol (187) as a white solid (98 mg, 90%) (mp 44-46°C). Ir (CHC13): 3600, 3300(br), 3050(w), 1630, 910 cm-1; *H nmr (400 216 MHz, CDCI3) 6: 5.41 (d of d of d, 1H, H c > = 17 Hz, = 10.5 Hz, = 9.5 Hz), 5.04 (d of d, 1H, H^ , = 17 Hz, = 2 Hz), 4.91 (d of d, 1H, H , T = 10.5 Hz, J D A = 2 Hz), 4.31 (d of d, 1H, H_, J - 3.2, ti — D C —oA r — 3.2 Hz), 2.20-2.10 (m, 1H), 2.00-1.40 (m, 9H), 1.30 (d of d, 1H, Hp, J p C = 9.5 Hz, = 3.5 Hz), 1.14 (d, 1H, H„, JT = 3.5 Hz). Exact Mass — t i —tiL) — — — calcd. for C uH 1 60: 164.1202; found: 164.1206. Preparation of the Ketone (132) H 132 General procedure 2 was followed. To a stirring suspension of PCC (200 mg, 0.928 mmol), sodium acetate (150 mg), and CH 2C1 2 (3 mL) in a 50 mL-RB-3N flask was added a solution of the alcohol (132) (94 mg; 0.572 mmol) in CH 2C1 2 ( 2 + 1 mL). General conditions and reaction work-up produced a pale yellow li q u i d . D i s t i l l a t i o n (air-bath temperature 50-60°C/0.1 Torr) afforded the ketone (132) as a white solid (79 mg, 85%) (mp 29-30°C). Ir (CHCI3): 3070(w), 1700, 1630, 1220, 915 cm-1; XH nmr (400 MHz, CDCI3) 6: 5.38 (d of d of d, 1H, Hc, = 17 Hz, = 10 Hz, = 9.2 Hz), 6 5.20 (d of d, 1H, H , = 17 Hz, = 1.5 Hz), 6 5.06 (d of d, 1H, H , J D„ = 10 Hz, J_. = 1.5 Hz), 2.45-2.36 (m, 1H), 2.29 (d of d, 1H, B — D C — D A J = 19 Hz, J = 7.5 Hz), 2.18 (d of d, 1H, Hp, - 9.2 Hz, Jp £ = 2.5 217 Hz), 2.12-1.87 (m, 4H), 1.82-1.68 (m, 2H), 1.60 (br s, 1H, Hg, = 5 Hz), 1.40-1.26 (m, 1H). Exact Mass calcd. for C^H^O: 162.1045; found: 162.1039. Anal, calcd. for CJ^ HJ^ O: C 81.44; H 8.70; found: C 81.28; H 8.67. Preparation of the Divinylcyclopropane (136) HA Hp H G 1 3 6 To a cold (-78°C) THF (4 mL) solution of LDA (0.398 mmol) in a 25 mL-RB-3N flask was added a THF (1 + 0.5 mL) solution of the ketone (132) (43 mg, 0.265 mmol) via a syringe. The reaction mixture was stirred at -78°C for 25 min, after which time, a THF (1 mL) solution of HMPA (95 uL, 0.53 mmol) and freshly sublimed tert-butyldimethylsilyl chloride (70 mg, 0.464 mmol) was added via a syringe. The reaction mixture was stirred at -78°C for 10 min, after which time, i t was allowed to warm to room temperature with additional stirring for 1.5 h. The reaction mixture was treated with saturated aqueous sodium bicarbonate and diluted with water. The resulting mixture was extracted with ether, and the ether extract was washed (water (2X), brine), dried (MgSO^), fil t e r e d , and concentrated to afford a pale yellow liquid. Glc analysis of this material showed i t to consist of the starting ketone (~10%) together with the enol s i l y l ether (136). The crude reaction product 218 was chromatographed through triethylamine washed, grade 1, basic alumina (0.4 x 6 cm column, eluting with petroleum ether). Concentration of the early eluent, pumping with agitation (30°C/0.1 Torr, 20 min), and d i s t i l l a t i o n (air-bath temperature 85-95°C/0.1 Torr) afforded the pure enol s i l y l ether (136) as a clear colorless liquid (55.5 mg, 75%). Ir (film): 3070(w), 1620, 850 cm-1; lE nmr (400 MHz, CDC13) 6: 5.44 (d of d of d, 1H, H , J„ A = 17 Hz, = 10.5 Hz, J _ = 9.5 Hz), L — L A —OB —LU 5.08 (d of d, 1H, H , J A„ = 17 Hz, J A T J = 2 Hz), 4.95 (d of d, 1H, HD, A —AC —AB o J D O = 10.5 Hz, J O A = 2 Hz), 4.53 (d, 1H, H_, J__ = 2.5 Hz), 2.60-2.53 —DC — B A F —r(j (m, 1H, H_), 2.04-1.94 (m, 2H), 1.80-1.53 (m, 3H), 1.41-1.35 (m, 2H, G Hp), 1.26-1.15 (m, 1H), 0.95 (s, 9H, -Si-t-Bu), 0.17 (s, 6H, -Si-Me's). Irradiation at 6 5.44: 6 5.08 and 6 4.95 each simplified to a d (J = 2 Hz), multiplet at 6 1.41-1.35 simplified. Irradiation at 2.60-2.53: 6 4.53 simplified to a s, multiplets at 6 2.04-1.94 and 6 1.26-1.15 simplified. Exact Mass calcd. for C 1 7H 2 8OSi: 276.1910; found: 276.1916. Preparation of the Enol S i l y l Ether (140) 1 4 0 General procedure 7 was followed. A solution of the divinylcyclopropane (136) (34 mg, 0.123 mmol) in benzene (2.5 mL) was 219 heated for 5 h at 170°C. Concentration afforded a clear colorless liquid. D i s t i l l a t i o n (air-bath temperature 85-95°C/0.1 Torr) gave the enol s i l y l ether (140) as a clear colorless liquid (34 mg, 100%). Ir (film): 3000, 1620, 1240, 860 cm-1; *H nmr (400 MH, CDC13) 6: 6.27 (d of d of d, 1H, H , = 9.5 Hz, J_kQ = = 2.1 Hz), 5.26 (d of d of d of d, 1H, Hg, = 9.5 Hz, = J f i D = 3.2 Hz, = 1.3 Hz), 4.68 (s, 1H, Hp), 2.50 (br s, 1H, Hg) 2.20-2.15 (m, 2H, H c and Hp), 2.03-1.97 (m, 1H), 1.78-1.47 (m, 5H), 1.40-1.31 (m, 1H), 0.91 (s, 9H, -Si-t-Bu), 0.14 (s, 3H, -Si-Me), 0.13 (s, 3H, -Si-Me). Irradiation at 6 5.26: 6 6.27 simplified to a d of d (J = 2.2, 2.2 Hz), multiplet at 6 2.20 - 2.15 simplified, br s at 6 2.50 simplified to a d of d (J = 3.1, 3.1 Hz). Irradiation at 6 2.50: 6 5.26 simplified to a d of d of d (J = 9.5, 3.2, 3.2 Hz), multiplet at 6 2.20-2.15 simplified. Exact Mass calcd. for C 1 7H 2 80Si: 276.1910; found: 276.1908. Preparation of the Ketone (188) To an oven dried, argon flushed 25 mL-RB-3N flask equipped with an argon inlet, magnetic stirring bar, and septum was added a solution of the enol s i l y l ether (140) (34 mg, 0.123 mmol) in dry THF (4 mL). This solution was cooled to -78°C, and a solution of TBAF (~ 65 mg, 0.25 220 mmol) in THF (0.3 mL) was added via a syringe. The resulting yellow reaction mixture was stirred at -78°C for 15 min, after which time, i t was treated with saturated aqueous ammonium chloride and diluted with water. The resulting mixture was extracted with ether, and the ether extract was washed (water, brine), dried (MgSO^), filtered, and concen-trated to afford a clear colorless liquid. This liquid was chromato-graphed through a short column of s i l i c a gel (0.4 x 7 cm, eluting f i r s t with petroleum ether, eluting second with petroleum ether-ether, 2:1). Concentration of the latter eluent, pumping with agitation (35°C/15 Torr), and d i s t i l l a t i o n (air-bath temperature 50-60°C/0.1 Torr) provided the pure ketone (188) as a clear colorless liquid (19.5 mg, 97%). Ir (film): 3010, 1740, 1625, 1140 cm-1; XH nmr (400 MHz, CDC13) 6: 6.17 (d of d of d, IH, H^ , JT^ = 9.5 Hz, £ = 2.5, 1.9 Hz = couplings to H c and Hp), 5.44 (br d of d of d, IH, Hg, £ f i A = 9.5 Hz, £ = 3.8, 2.7 Hz = couplings to H c and Hp), 2.67 (br d, IH, H£,, J = 5.4 Hz), 2.44 (d of d of d of d, IH, H or H. J__ = 18.2 Hz, J = 5.4 Hz, J = 2.7 Hz, C D -CD — i i —B r J A = 2.5 Hz), 2.27 (d of d, IH, L, OR H , J__ = 18 Hz, J = 2 Hz), 2.24 —A r G —r G — (d of d of d of d, IH, H c or Hp, = 18.2 Hz, £g = 3.8 Hz, = Jg = 1.9 Hz), 2.22-2.17 (m, IH), 2.03 (d, IH, or H , J p G = 18 Hz), 1.98-1.78 (m, 4H), 1.67-1.53 (m, 2H), 1.32-1.18 (m, IH). Irradiation at 6 5.44: 6 6.17 simplified to a d of d (J = 2.5, 1.9 Hz), 6 2.44 simplified to a d of d of d (£ = 18.2, 5.4, 2.5 Hz), 6 2.24 simplified to a d of d of d (J = 18.2, 1.9, 1.9 Hz). Irradiation at 6 2.67: 6 5.44 sharpened, 6 2.44 simplified to a d of d of d (J = 18.2, 2.7, 2.5 Hz), 6 2.24 simplified to a d of d of d (J = 18.2, 3.8, 1.9 Hz). Exact Mass calcd. for C nH 1 1 +0: 162.1045; found: 162.1047. 221 Model Study 3 Preparation of Trans-l-Decalone (190) 1 9 0 To an oven dried, argon flushed 1 L-RB-3N flask, equipped with an argon inlet, magnetic stirring bar, and septum, was added 1-decalone (189) (80:20 mixture of c i s - and trans-isomers) (35 g, 230 mmol) and dry THF (350 mL). This solution was cooled to 0°C, and a solution of potassium tert-butoxide (1.0 g, 8.9 mmol) in dry tert-butyl alcohol (25 mL) was added rapidly via a syringe. The resulting yellow colored reac-tion mixture was stirred at 0°C for 30 min, after which time, i t was treated with saturated aqueous ammonium chloride and diluted with water. The resulting mixture was extracted with ether (2X), and the combined ether extracts were washed (water (2X), brine), dried (MgSO^), fil t e r e d , and concentrated to afford a clear pale yellow liquid. This liquid was di s t i l l e d (air-bath temperature 60-65°C/0.1 Torr) to give, by glc analysis, 1-decalone (190) as a 4:96 mixture of c i s - and trans-isomers (34 g, 97%). Preparation of the q-Bromo Ketones (191a) and (191b) 191a I9lb 222 To a cold (-78°C) THF (80 mL) solution of LDA (27.6 mmol) in a 250 mL-RB-3N flask was added, over 15 min via a syringe, a THF ( 8 + 4 mL) solution of 96% pure trans-l-decalone (190) (2.98 g, 19.6 mmol). The reaction mixture was stirred at -78°C for 30 min, after which time, a dry CHjClg (15 mL) solution of freshly d i s t i l l e d bromine (1.4 mL, 27.6 mmol) was added rapidly via a syringe. The bromine color quickly disappeared, and after the reaction mixture had been stirred for 1 min at -78°C, i t was treated with saturated aqueous sodium bicarbonate and diluted with water. The resulting mixture was extracted with ether, and the ether extract was washed (water, cold aqueous 3% H2S01+, water), dried (MgSO^), fil t e r e d , and concentrated to afford a clear yellow liquid. This liquid was passed through a short column of F l o r i s i l (6 x 3 cm), eluting with petroleum ether. Concentration and d i s t i l l a t i o n in two portions (preheated air-bath temperature of ~ 90°C) afforded a clear colorless liquid which solidified on storage at -10°C (3.62 g, 80%). Glc analysis of this material showed i t to consist of the bromo ketones (191a) and (191b) together with the starting decalone mixture (190) and three other minor compounds in a ratio of 12:6:1:1, respectively. This material was used without further purification for the next reaction. The bromo ketones (191a) and (191b) could be separated by flash chromatography (eluting with petroleum ether-ether, 20:1). The bromo ketone (191a), eluting f i r s t , was characterized by *H nmr (80 MHz, CDC13). Proton H A (6 4.35) was observed as a d of d (J = 3.3 Hz). The bromo ketone (191b), eluting second, showed H A / ( 6 4*66) as a d of d of d (J = 13, 6, 1.5 Hz). 223 Preparation of the Enone (192) 0 To an oven dried, argon flushed 500 mL-RB-3N flask, equipped with an argon inlet, condenser, and magnetic stirring bar, was added anhydrous lithium bromide (3.6 g, 41 mmol), anhydrous lithium * carbonate (4.1 g, 55 mmol), and dry DMF (120 mL). To this stirring suspension at room temperature was added a DMF (20 mL) solutionm of the bromo ketone mixture from the previous reaction (3.5 g, 15 mmol). The reaction mixture was refluxed for 45 min, after which time, i t was cooled to room temperature and was carefully diluted with aqueous 10% acetic acid (100 mL) and water (150 mL). The resulting mixture was extracted with ether (3X), and the combined ether extracts were washed (water, saturated aqueous sodium bicarbonate, brine), dried (MgS0i4), fil t e r e d , and concentrated to afford a pale yellow solid. Glc analysis of this material showed i t to consist of the enone (192) (85% pure), together with a number of minor compounds. This material was dissolved in petroleum ether-CH 2Cl 2, L:^- a n t* w a s flash chromatographed (5 x 16 cm column of s i l i c a gel, eluting with petroleum ether-ether, 10:1). Concentration of the appropriate fractions and d i s t i l l a t i o n (air-bath temperature 65-75°C/0.1 Torr) gave the enone (192) as a white solid (1.7 g, LiBr and L i 2 C 0 3 were dried at 100°C/0.1 Torr, 18 h. 224 75%). Crude samples of the enone were effectively recrystallized from heptane to afford pure (192) as colorless rectangular prisms (mp 70-71°C). Literature 9 1 mp 71.5-72.5°C. Ir (CHC13): 1665 cm - 1, *H nmr (400 MHz, CDC13) 6: 6.90 (d of d of d, IH, Hg, J B A = 10.2 Hz, J B D = 6 Hz, = 2 Hz), 5.97 (d of d, IH, H^ , = 10.2 Hz, = 3 Hz), 2.34 (d of d of d, IH, Hp, = 18.8 Hz, JpB= 6 Hz, = 4.5 Hz), 2.30 - 2.22 (m, IH), 2.12 (d of d of d of d, IH, Hc, ^ = 18.8 Hz, - 11 Hz, - 3 Hz, Jgj - 2 Hz), 1.98 (d of d of d, IH, J = 11.5, 11.5, 4 Hz), 1.92 - 1.68 (m, 4H), 1.34 - 1,05 (m, 4H). Exact Mass calcd. for C10HlltO: 150.1045; found: 150.1046. Preparation of the A l l y l i c Alcohols (193) and (194) HO HO 193 134 To an oven dried, argon flushed 1 L-RB-3N flask, equipped with an argon inlet, dropping funnel, and magnetic stirring bar, was added LAH (1.5 g, 40 mmol) and anhydrous ether (350 mL). To this stirring suspension at room temperature was added, over 20 min from the dropping funnel, an ether (100 mL) solution of the enone (192) (5.9 g, 39 mmol). After complete addition, the reaction mixture was stirred for 15 min, and was then cautiously treated with NajSO^'lOHjO. The resulting white-gray slurry was filtered through F l o r i s i l (6 x 8 cm column, flushing 225 with ether). Concentration and d i s t i l l a t i o n (air-bath temperature 65-75°C/0.1 Torr) afforded the a l l y l i c alcohol mixture as a white solid (5.91 g, 99%) (mp 74-76°C). Glc analysis of this material showed i t to consist of (193) and (194) in a ratio of 9:1, respectively, while t i c analysis ( s i l i c a gel plate, petroleum ether-ether, 1:1) showed only one spot. This mixture was used without further purification for the next reaction. Ir (CHC13): 3580, 3300(br), 1650, 1000 cm - 1. Exact Mass calcd. for C 1 0H 1 60: 152.1202; found: 152.1199. Preparation of the A l l y l i c S i l y l Ethers (150) and (195) To an oven dried, argon flushed 250 mL-RB-3N flask equipped with an argon inlet and magnetic stirring bar, was added the a l l y l i c alcohol mixture from the previous reaction (5.23 g, 34.4 mmol) and dry DMF (70 mL). Imidazole (6.3 g, 92.5 mmol) and tert-butyldimethylsilyl chloride (6.7 g, 44.4 mmol) were added in one portion successively, and the reaction mixture was stirred at room temperature for 3 h. After this time, the reaction mixture was treated with aqueous sodium bicarbonate (~ 15 mL) and was diluted with water (200 mL). The resulting mixture 226 was extracted with ether (2X), and the combined ether extracts were washed (water (2X), brine), dried (MgS04), fi l t e r e d , concentrated, and pumped on with agitation (35°C/0.1 Torr, 25 min), to afford a clear colorless liquid (9.15 g, 100%). Glc analysis of this material showed i t to consist of a mixture of (150) and (195) in a ratio of 9:1, respectively. The two isomers were separated by two flash chromatographies (5 x 20 cm column of s i l i c a gel, eluting with petroleum ether). Concentration of the appropriate fractions and d i s t i l l a t i o n (air-bath temperature 75-85°C/0.1 Torr) yielded the pure a l l y l i c s i l y l ether (150) (7.9 g, 86%) and the pure a l l y l i c s i l y l ether (195) (0.9 g, 10%) as clear colorless liquids. Compound (150). Ir (film): 3010(w), 1080, 840 cm-1; LE nmr (400 MHz, CDC13) 6: 5.63 (d of d of d of d, 1H, H^, = 10.5 Hz, = 5 Hz, J A„ = J._ - 2.3 Hz), 5.52 (d of d of d of d, 1H, H , J_. = 10.5 Hz, —AC —AG B —BA JQG = 2.7 Hz, = J g F = 1.3 Hz), 3.85 (d of d of d of d, 1H, H c > = 8.7 Hz, J„ A = 2.3 Hz, J__ = J__ = 1.3 Hz), 2.16 - 2.09 (m, 1H), 1.98 (d —CA —Co —Or of d of d of d of d, 1H, Hp, J F G = 18 Hz, Jp A = J F E = 5 Hz, J p B = J_ F C = 1.3 Hz), 1.80 - 1.62 (m, 4H), 1.40 - 0.72 (m, 6H), 0.90 (s, 9H, -Si-t-Bu), 0.06 (s, 3H, -Si-Me), 0.05 (s, 3H, -Si-Me). Irradiation at 6 5.63: 6 3.85 simplified to a d of d of d (J = 8.7, 1.3, 1.3 Hz), 6 1.98 simplified to a d of d of d of d (J = 18, 5, 1.3, 1.3 Hz). Irradiation at 6 3.85: 6 5.63 simplified to a d of d of d (J = 10.5, 5, 2.3 Hz), 6 5.52 simplified to a d of d of d (J = 10.5, 2.7, 1.3 Hz), 6 1.98 simplified to a d of d of d of d (J_ = 18, 5, 5, 1.3 Hz). Exact Mass calcd. for C 1 6H 3 0OSi: 266.2067; found: 266.2072. Anal, calcd. for C 1 6H 3 0OSi: C 72.11, H 11.35; found: C 72.30, H 11.38. 227 Compound (195). Ir (film): 3000, 1250 cm-1; XH nmr (400 MHz, CDC13) 6: 5.74-5.70 (m, 2H, H^ and Hfi), 3.87-3.83 (m, IH, H c), 2.10-2.03 (m, IH), 1.80-1.42 (m, 7H), 1.30-1.15 (m, 3H), 0.88'(s, 9H, -Si-t-Bu), 0.04 (s, 6H, -Si-Me's). Irradiation at 6 5.74-5.70: multiplet at 6 3.87-3.83 simplified to a br d (J = 3.7 Hz), multiplet at 6 2.10-2.03 simplified. Exact Mass calcd. for C 1 6H 3 0OSi: 266.2067; found: 266.2060. Preparation of the Cyclopropyl Ester Mixtures (153) and (154) EtOOC 153 154 General procedure 1 was followed. Ethyl diazoacetate (5.0 mL, 47.5 mmol) was added over a period of 12 h to the a l l y l i c s i l y l ether (150) (4.4 g, 16.5 mmol) containing rhodium(II) acetate (~ 15 mg). The crude reaction product was flash chromatographed (5 x 18 cm column of s i l i c a gel, eluting f i r s t with petroleum ether-ether, 100:1 and eluting second with petroleum ether-ether, 20:1) to afford the recovered a l l y l i c s i l y l ether (150) (1.0 g, after concentration and d i s t i l l a t i o n of the i n i t i a l eluent) and the crude cyclopropyl ester mixture. The crude ester product was pumped on with agitation (50-60°C/0.1 Torr, 20 min) to remove the diethyl maleate and diethyl fumarate that eluted during the 228 t a i l end of the chromatography. D i s t i l l a t i o n (air-bath temperature 110-120°C/0.1 Torr) afforded a clear, colorless, viscous liquid (4.13 g, 92% based on unrecovered starting material). Glc analysis of this material showed i t consist of four cyclopropyl ester isomers in a ratio of 41:31:20:8. Tic analysis ( s i l i c a gel plate, petroleum ether-ether, 10:1) showed the presence of two pairs of overlapping spots. The top pair (R^ ~ 0.5) contained the two minor isomers and the bottom pair (R^ ~ 0.33) contained the two major isomers (determined by glc analysis of the chromatography fractions). Ir (film): 1720, 1170, 1080 cm - 1. Exact Mass calcd. for C 2 0H 3 6O 3Si: 352.2435; found: 352.2439. Preparation of the Alcohol Mixture (196) —f-SiO To an oven dried, argon flushed 1 L-RB-3N flask, equipped with an argon inlet, magnetic stirring bar, and dropping funnel, was added LAH (1.6 g, 42 mmol) and anhydrous ether (320 mL). To this stirring suspension at room temperature was added, over 20 min from the dropping funnel, an ether (150 mL) solution of the cyclopropyl ester mixture from the previous reaction (7.5 g, 21.3 mmol). After being stirred for an additional 15 min, the reaction mixture was treated with Na 2S0,«10H 20, 229 and the resulting slurry was filtered through F l o r i s i l (8 x 6 cm column, flushing with ether). Concentration, and d i s t i l l a t i o n (air-bath temperature 110-120°C/0.1 Torr) afforded the alcohol mixture (196) as a clear, colorless, highly viscous liquid (6.1 g, 92%). Glc analysis of this mixture showed i t to consist of a 4:3:2 mixture of components. Ir (film): 3300(br), 1260, 1080, 840 cm"1. Exact mass calcd. for C 1 8H 3 1 +0 2Si: 310.2329; found: 310.2307. Preparation of the Aldehyde Mixture (197) —{- SiO H 197 General procedure 2 was followed. To a stirring suspension of PCC (6.4 g, 30 mmol), sodium acetate (~ 3 g), and CH2C12 (50 mL) in a 500 mL-RB-3N flask was added a solution of the alcohol mixture (196) (5.95 g, 19.2 mmol) in CH2C12 (15+5 mL). General conditions and reaction workup produced a clear pale yellow liquid (~ 5.80 g) which was used without further purification for the next reaction. The minor component of the cyclopropyl ester mixture lost i t s s i l y l ether group during the LAH reduction. This resulting component appeared to be removed during the subsequent reaction sequence leading to the alkenes (200) and (201). 230 Preparation of the Aldehydes (198) and (199) General procedure 3 was followed. To a THF (250 mL) solution of the aldehyde mixture (197) (5.80 g, 18.8 mmol) in a 500 mL-RB-3N flask was added a tert-butyl alcohol (19 mL) solution of potassium tert-butoxide (~ 200 mg). General conditions and reaction workup afforded the aldehydes (198) and (199) as a clear yellow liquid (5.75 g). This liquid was used for the next reaction without further purification. For characterization purposes, the crude aldehyde mixture could be d i s t i l l e d (air-bath temperature 105-115°C/0.1 Torr), with substantial loss in the s t i l l pot, to afford, by glc analysis, a 2:1 mixture of (198) and (199), respectively, as a clear colorless viscous liquid. Ir (film): 2680, 1700, 1080, 840 cm"1. Exact Mass calcd. for C 1 8H 3 20 2Si: 308.2173; found: 308.2167. Preparation of the Alkenes (200) and (201) 231 General procedure 4 was followed. To a THF (280 mL) solution of methylenetriphenylphosphorane (28.2 mmol) in a 1 L-RB-3N flask was added a THF (35 + 8 mL) solution of the aldehydes (198) and (199) (5.75 g, 18.6 mmol). General conditions, reaction workup, and d i s t i l l a t i o n (air-bath temperature 95-105°C/0.1 Torr) afforded a clear colorless liquid (4.74 g). Glc analysis of this material showed i t to consist of the alkenes (200) and (201) in a ratio of 2:1, respectively. This mixture was subjected to two flash chromatographies (5 x 20 cm column of s i l i c a gel, eluting with petroleum ether) to provide, after concentration of the appropriate fractions and d i s t i l l a t i o n , (200) (2.97 g) and (201) (1.48 g) each as clear colorless liquids (combined yield, 76% from the alcohol mixture (196)). Compound (200). Ir (film): 3060(w), 1625, 1080 cm-1; lE nmr (400 MHz, CDC1,) 6: 5.48 (d of d of d, 1H, H„, J „ K = 17 Hz, J O T J = 10.5 Hz, ° C —OA —OB = 8.3 Hz), 4.96 (d of d, 1H, H^ , ^ = 17 Hz, = 1.7 Hz), 4.79 (d of d, 1H, HB, = 10.5 Hz, J B A = 1.7 Hz), 3.26 (d, 1H, Hg, = 9 Hz), 2.11 - 2.03 (m, 1H), 1.85 (d of d, 1H, H„, J__T = 13.5 Hz, J_,T = 4.4 Hz), 1.75 - 1.59 (m, 3H), 1.38 (d of d of d, 1H, H = J = 13.5 Hz, J T = 12 * J J K. — J A. Hz, J T T 7 = 5.2 Hz), 1.22 - 0.59 (m, 9H), 0.90 (s, 9H, -Si-t-Bu), 0.07 (s, 3H, -Si-Me), 0.05 (s, 3H, -Si-Me). Irradiation at 6 5.48: region around 6 1.02 changed. Irradiation at 6 3.26: region around 6 0.86 changed. Exact Mass calcd. for C 1 9H 3 1 +OSi: 306.2380; found: 306.2366. Anal. calcd. for C 1 9H 3 1 +OSi: C 74.44, H 11.18; found: C 74.44, H 11.17. Compound (201). Ir (film): 3060(w), 1625, 1250, 1070 cm-1; *H nmr (400 MHz, CDCU) 6 5.35 (d of d of d, H„, 1H, J_ A = 17 Hz, J _ D = J C — C A — C D 10.2 Hz, = 8.6 Hz), 4.98 (d of d, 1H, H , J. = 17 Hz, J. = 1.7 —'XJ'D A • AL* AJ5 232 Hz), 4.79 (d of d, IH, H , J = 10.2 Hz, J_. = 1.7 Hz), 3.73 (d of d, B —BC —BA IH, H , J = 8.8 Hz, -J = 5 Hz), 2.18 - 2.09 (m, IH,), 1.95 (d of d of G ~-\JH. — \ j r d, IH, H , J = 13 Hz, J__ = 8 Hz, J T T = 5 Hz), 1.75 - 1.56 (m, 3H), 1.35 (d of d of d, IH, Hp, = 8.6 Hz, J Q E = = 4.3 Hz), 1.18 -0.64 (m, 9H), 0.89 (s, 9H, -Si-_t-Bu), 0.06 (s, 6H, -Si-Me's). Irradiation at 6 5.35: 6 1.35 simplified to a d of d (J_ = 4.3, 4.3 Hz). Irradiation at 6 1.18 - 1.09: 6 3.73 simplified to a d (J = 5 Hz), 6 1.95 simplified to a d of d (J = 13, 5 Hz), 6 1.35 simplified to a d (J = 8.6 Hz). Exact Mass calcd. for C 1 9H 3 1 +OSi: 306.2380; found: 306.2397. Preparation of the Alcohol (203) 203 General procedure 5 was followed. To a cold (-78°C) THF (30 mL) solution of the s i l y l ether (200) (1.017 g, 3.318 mmol) in a 100 mL-RB-3N flask was added a THF (10 mL) solution of TBAF (2.5 g, 9.6 mmol). General conditions and reaction workup afforded a clear colorless liquid. Pumping with agitation (30-40°C/0.1 Torr) for 20 min, and d i s t i l l a t i o n (air-bath temperature 80-90°C/0.1 Torr) gave the alcohol (203) as a white solid (0.623 g, 97%) (mp 77-78°C). Recrystallization could be accomplished from heptane. Ir (CHC13): 3580, 3300(br), 3050(w), 1625, 1030 cm-1; XH nmr (400 233 MHz, CDCI3) 6: 5.38 (d of d of d, IH, H c > = 17 Hz, = 10.2 Hz, = 8.3 Hz), 4.98 (d of d, IH, H^ , = 17 Hz, = 1.7 Hz), 4.81 (d of d, IH, HB, J B D = 10.2 Hz, J^k = 1.7 Hz), 3.38 (d, IH, Hg, = 7.3 Hz), 2.17 - 2.04 (m, IH), 1.87 (d of d, IH, H^ , = 13.5 Hz, = 3.5 Hz), 1.80 - 1.60 (m, 4H), 1.38 (d of d of d, IH, H , JL^ = 13.5 Hz, = 11 Hz, = 4.8 Hz), 1.28 - 1.07 (m, 4H), 1.02 (d of d, IH, Hp, J F £ = 8 Hz, J „ = 4.8 Hz), 0.95 - 0.69 (m, 4H). D,0 added: multiplet at —FD ^ 6 1.80 - 1.60 simplified. Irradiation at 6 5.38: multiplet at 6 1.28 -1.07 changed. Irradiation at 6 1.38: 6 1.87 simplified to a d (J = 3.5 Hz), multiplets at 6 1.28 - 1.07 and 6 0.95 - 0.69 each changed. Exact  Mass calcd. for C 1 3H 2 ( )0: 192.1515; found: 192.1508. Preparation of the Ketone (133) General procedure 2 was followed. To a stirring suspension of PCC (500 mg, 2.32 mmol), sodium acetate (150 mg), and CH2C12 (6 mL) in a 50 mL-RB-3N flask was added a solution of the alcohol (203) (300 mg, 1.56 mmol) in CH2C12 ( 4 + 2 mL). General conditions and reaction workup produced a pale yellow liquid. D i s t i l l a t i o n (air-bath temperature 70-80°C/0.1 Torr) afforded the ketone (133) as a white semi-solid (278 mg, 94%) (mp ~ 25°C). 234 Ir (film): 3060(w), 1685, 1630, 900 cm - 1; XH nmr (400 MHz, CDC13) 6 5.35 (d of d of d, IH, H , J„ 4 = 17 Hz, J . D = 10.2 Hz, J m = 8.4 Hz), L — L A — L D — L U 6 5.11 (d of d, IH, H , = 17 Hz, = 1.3 Hz), 6 4.95 (d of d, IH, V ^BC = 1 0 * 2 H z * = 1 , 3 H z ) ' 2 , 3 7 " 2 , 2 8 ( m ' 1 H ) > 2 , 1 2 " 2 , 0 2 ( m ' 2H, Hp), 1.98 - 1.56 (m, 7H), 1.49 (d of d of d, IH, J = 12, 12, 2.5 Hz), 1.38 - 1.25 (m, IH), 1.24 - 1.11 (m, 2H), 1.06 - 0.90 (m, 2H). Irradiation at 2.37 - 2.28: changes observed near 6 1.82 and 1.70, 6 1.49 simplified to a d of d (J = 12, 12 Hz), multiplets at 6 1.24 -1.11 and 6 1.06 - 0.90 each changed. Irradiation at 6 2.12 - 2.02: 6 5.35 simplified to a d of d (J = 17, 10.2 Hz), several changes observed in multiplet at 6 1.98 - 1.56, multiplet at 6 1.38 - 1.25 simplified. Exact Mass calcd. for C 1 3H 1 80: 190.1358; found: 190.1356. Anal, calcd. for C 1 3H 1 80: C 82.06, H 9.53; found: C 82.14, H 9.63. Preparation of the Divinylcyclopropane (137) 0Si + H, To a cold (-78°C) THF (8 mL) solution of LDA (1.57 mmol) in a 50 mL-RB-3N flask was added a THF (1.5 + 1 mL) solution of the ketone (133) (196 mg, 1.03 mmol). The reaction mixture was stirred at -78°C for 30 min, after which time a THF (2 mL) solution of freshly sublimed tert-butyldimethylsilyl chloride (270 mg, 1.79 mmol) and HMPA (0.38 mL, 2.1 235 mmol) was added via a syringe. After 10 min at -78°C, the reaction mixture was warmed to room temperature with addition stirring for 1.5 h. The reaction mixture was treated with saturated aqueous sodium bicarbonate and diluted with water. The resulting mixture was extracted with ether, and the ether extract was washed (water (2X), brine), dried (MgSO^), fil t e r e d , and concentrated to afford a yellow liquid. Chromatography through triethylamine washed, grade 1, basic alumina (1.5 x 8 cm column, eluting with petroleum ether), concentration of the early eluent, pumping with agitation (30°C/0.1 Torr, 20 min), and d i s t i l l a t i o n (air-bath temperature 95-105°C/0.1 Torr) provided the divinylcyclopropane (137) as a clear colorless liquid (196 mg, 93%). Ir (film): 3050(w), 1650, 1630, 1290, 840 cm-1; XH nmr (400 MHz, CDC1,) 6: 5.37 (d of d of d, 1H, H„, J O A = 17 Hz, J , D = 10.4 Hz, J _ = 9 3 L —LA —OB —CL) Hz), 5.00 (d of d, 1H, H , J = . 1 7 Hz, J 4 T J - 1.7 Hz), 4.85 (d of d, 1H, A —AC —AB Ht>> J u o = 1 0 ' 4 J n » ° 1« 7 Hz). 2«88 - 2.80 (m, 1H), 2.10 - 2.03 (m, 1H), 1.89 - 1.74 (m, 2H), 1.72 - 1.62 (m, 2H), 1.61 - 1.52 (m, 2H), 1.43 - 1.32 (m, 2H), 1.28 - 1.07 (m, 4H), 0.97 (s, 9H, -Si-t-Bu), 0.14 (s, 3H, -Si-Me), 0.11 (s, 3H, -Si-Me). Exact Mass calcd. for C 1 9H 3 20Si: 304.2224; found: 304.2213. Preparation of the Enol S i l y l Ether (141) 141 236 General procedure 7 was followed. A solution of the divinylcyclopropane (137) (88 mg, 0.29 mmol) in benzene (2 mL) was heated for 5 h at 165-170°C. Concentration afforded a clear colorless liquid. D i s t i l l a t i o n (air-bath temperature 95-105°C/0.1 Torr) gave the enol s i l y l ether (141) as a clear colorless liquid (88 mg, 100%). Ir (film): 3020(w), 1635, 1180, 860 cm-1; ^E nmr (400 MHz, CDC13) 6: 6.05 (d of d of d of d, IH, H„, J = 10.5 Hz, J _ D = 8.2 Hz, J _ and C —CD — C D — C E J__ = 2.7, 2 Hz), 5.26 (d, IH, H , J._ = 7.8 Hz), 5.25 (d of d of d of —•v>r A —AB d, IH, Hp, J^, = 10.5 Hz, ^  and J^, = 4, 3.7 Hz, = 0.8 Hz), 2.51 -2.43 (m, IH, Hg), 2.28 (d of d of d, IH, HR, = 13 Hz, JL^  = 9.3 Hz, = 1.2 Hz), 2.12 (d of d of d, IH, HLg or H^ , = 18.8 Hz, = 4 Hz, ^ = 2 Hz), 2.08 - 2.03 (m, IH), 1.81 (d of d of d, IH, E^ or Hp, J__ = 18.8 Hz, J_ = 3.7 Hz, J_ = 2.7 Hz), 1.82 - 1.75 (m, IH), 1.62 -1.42 (m, 4H), 1.21 - 1.07 (m, 3H), 0.94 (s, 9H, -Si-t-Bu), 0.91 - 0.79 (m, IH), 0.19 (s, 3H, -Si-Me), 0.14 (s, 3H, -Si-Me). Irradiation at 6 6.05: 6 5.25 simplified, multiplet at 6 2.51 - 2.43 simplified, 6 2.12 simplified to a d of d (J = 18.8, 4 Hz), 6 1.81 simplified to a d of d (J_ = 18.8, 3.7 Hz). Irradiation at 2.51 - 2.43: 6 6.05 simplified to a br d (J = 10.5 Hz), 6 5.26 simplified to a s, 6 5.24 sharpened to a d of d of d (J = 10.5, 4, 3.7 Hz), 6 2.28 simplified to a d of d (J = 13, 9.3 Hz), multiplet at 1.21 - 1.07 changed. Exact Mass calcd. for C 1 9H 3 2OSI: 304.2224; found: 304.2226. 237 Preparation of the Ketone (204) 204 To an oven dried, argon flushed 25 mL-RB-3N flask, equipped with an argon inlet, magnetic stirring bar, and septum, was added the enol s i l y l ether (141) (59 mg, 0.194 mmol) and dry THF (6 ml). This solution was cooled to -78°C, and a solution of TBAF (120 mg, 0.459 mmol) in dry THF (1.5 mL) was added via a syringe. The resulting yellow reaction mixture was stirred at -78°C for 10 min, after which time, i t was treated with saturated aqueous ammonium chloride and diluted with water. The resulting mixture was extracted with ether, and the ether extract was washed (water, brine), dried (MgSO^), filtered and concentrated to afford a clear colorless liquid. Pumping with agitation (30°C/0.1 Torr) for 25 min and d i s t i l l a t i o n (air-bath temperature 80-90°C/0.1 Torr) gave the ketone (204) as a clear colorless liquid (34.5 mg, 93%). Ir (film): 1700 cm-1; lR nmr (400 MHz, CDC13) 6: 5.97 (d of d of d of d, 1H, Hg, J B C = 10.5 Hz, J f i A = 8.5 Hz, J B D = J f i E = 2.2 Hz), 5.42 (d of d of d, 1H, H_, J _ D = 10.5 Hz, J . n = Jf = 3.8 Hz), 2.53 - 2.32 L —Co —•CD —oL (m, 4H), 2.31 - 2.22 (m, 1H), 2.18 - 2.05 (m, 2H, Hp and Hg), 1.96 -1.84 (m, 1H), 1.73 - 1.40 (m, 4H), 1.19 - 1.00 (m, 3H), 0.89 - 0.76 (m, 1H). Irradiation at 6 5.24: multiplet at 6 2.18 - 2.05 simplified. Exact Mass calcd. for C 1 3H 1 80: 190.1358; found: 190.1364. Anal, calcd. for C 1 3H 1 80: C 82.06, H 9.53; found: C 81.88, H 9.63. 238 Preparation of the Alcohol (205) 205 General procedure 5 was followed. To a cold (-78°C) THF (25 mL) solution of the s i l y l ether (201) (993 mg, 3.24 mmol) in a 100 mL-RB-3N flask was added a THF (10 mL) solution of TBAF (2.2 g, 8.4 mmol). General conditions, with 14 h of reaction time, and reaction workup afforded a clear colorless liquid. Pumping with agitation (30°C/0.1 Torr) provided the alcohol (205) as a white solid (605 mg, 97%) (mp 90-91°C). Recrystallization from heptane produced long needle shaped crystals. Ir (CHC13): 3580, 3300(br,w), 3050(w), 1625, 990 cm-1; XH nmr (400 MHz, CDC13) 6: 5.38 (d of d of d, 1H, H_, J.. = 17 Hz, J__ - 10.2 Hz, = 8.2 Hz), 5.02 (d of d, 1H, H^ , = 17 Hz, = 1.7 Hz), 4.83 (d of d, 1H, H , J__ = 10.2 Hz, J_. = 1.7 Hz), 3.72 (d of d of d, 1H, HG, Jgj. = 10 Hz, ^  = ^  * 4.2 Hz), 2.23 - 2.15 (m, 1H, Hj), 1.99 (d of d of d, 1H, J - 15, 9, 6 Hz), 1.77 - 1.59 (m, 3H), 1.38 - 0.74 (m, 10H), 0.66 (d of d of d of d, 1H, H , J T = J T = J = 10 Hz, J T _ - 4 1 — i ( j -IK — — I J Hz). Irradiation at 6 3.72: region around 6 1.32 changed, 6 0.66 simplified to a d of d of d (J_ = 10, 10, 4 Hz). Irradiation at 6 2.23 -2.15: 6 0.66 simplified to a d of d of d (J = 10, 10, 10 Hz). Exact  Mass calcd. for C 1 3H 2 00: 192.1515; found: 192.1527. 239 Preparation of the Ketone (134) 1 3 4 General procedure 2 was followed. To a stirring suspension of PCC (600 mg, 2.78 mmol), sodium acetate (250 mg), and CH 2C1 2 (6 mL) in a 50 mL-RB-3N flask was added a solution of the alcohol (205) (348 mg, 1.81 mmol) in CH2C12 ( 3 + 2 mL). General conditions and reaction workup produced a pale yellow liquid. D i s t i l l a t i o n (air-bath temperature 70-80°C/0.1 Torr) afforded the ketone (134) as a white solid (325 mg, 94.5%) (mp 36-37°C). Ir (CHC13): 3050(w), 1675, 1625, 910 cm"1; XH nmr (400 MHz, CDCI3) 6: 5.34 (d of d of d, 1H, Hg, = 17 Hz, ^ = 10 Hz, = 8.5 Hz), 5.11 (d of d, 1H, HA, = 17 Hz, - 1.2 Hz), 4.96 (d of d, 1H, HT>> J»n " 1 0 H zt i » " l ' 2 H z)» 2.19 (d of d of d, 1H, J = 14, 8.5, 5.5 B "~BL» • — D A — Hz) 2.00 - 1.92 (m, 1H), 1.90 (d of d of d, 1H, H^ , = 8.5, = J = 4.2 Hz), 1.83 - 1.50 (m, 7H), 1.46 - 1.35 (m, 1H), 1.28 - 0.94 (m, 4H). Irradiation at 6 5.34: 6 1.90 simplified to a d of d (J = 4.2, 4.2 Hz. Exact Mass calcd. for C 1 3H 1 80: 190.1358; found: 190.1353. Anal, calcd. for C 1 3H 1 80: C 82.06, H 90.53; found: C 81.95, H 9.70. 240 Synthesis of (±) Quadrone (34) Preparation of the Keto Acetal (256) and the Diacetal (255); Equilibration of the Dione (248) and the Diacetal (255) To a 1 L-RB-3N flask, equipped with a magnetic stirring bar, Dean-Stark apparatus, and condenser, was added cis-bicyclo[3.3.0]octane-3,7-dione (248) (70 g, 0.51 mol), 2,2-dimethyl-l,3-propanediol (53 g, 0.51 mol), benzene (500 mL), and p-toluenesulfonic acid (0.5 g). This mixture was refluxed for 2 h, cooled to room temperature, and diluted with ether (500 mL). The resulting mixture was washed (aqueous 10% NaOH, water, brine), dried (MgS04), fi l t e r e d , and concentrated to provide a white semi-solid. Glc analysis of this material showed i t to consist of a 1:2:1 mixture of (248), (256), and (255), respectively. This material was dissolved in petroleum ether-ethyl acetate-CH2CH2, 3:2:1 (140 mL), and the resulting solution was chromatographed through a column of s i l i c a gel (300 g), eluting f i r s t with petroleum ether-ethyl 241 acetate, 2:1 to remove the keto acetal (256) and the diacetal (255), and eluting second with neat ethyl acetate to remove the dione (248) (16.4 g after concentration). The concentrated keto acetal and diacetal mixture was dissolved in the same solvent mixture as the previous chromatography and the resulting solution was rechromatographed through a column of s i l i c a gel (1500 g), eluting with petroleum ether-ether, 3:1. This column was reused for chromatography of the subsequent equilibration reaction product. Concentration of the appropriate fractions afforded the keto acetal (256) (53.4 g) and the diacetal (255) (36.9 g), both as white solids. The keto acetal (256) could be recrystallized from heptane (mp 48°C), while the diacetal (255) could be recrystallized from ethanol or methanol to provide colorless plates (mp 140-142°C). To a 500 mL-RB-3N flask, equipped with a magnetic stirring bar and condenser, was added the recovered dione and diacetal from the previous reaction, _p_-toluenesulfonic acid (250 mg) and benzene (250 mL, di s t i l l e d discarding the i n i t i a l d i s t i l l a t e ) . The reaction mixture was refluxed for 1 h, cooled to room temperature, diluted with ether (250 mL), and worked up as before. Glc analysis of the reaction product again showed i t to consist of the equilibrium 1:2:1 ratio of (248), (256) and (255). Separation was achieved by chromatography as before (1st column, 150 g s i l i c a gel), and concentration of the appropriate fractions yielded the dione (248) (7.6 g), the keto acetal (256) (24.7 g) and the diacetal (255) (17.1 g). The recovered (248) and (255) were equilibrated again by the same procedure (half scale) to yield the dione (248) (3.5 g), the keto acetal (256) (11.3 g) and the diacetal (255) (7.8 g). The total yield of (256) was 89.4 g, 79%. 242 Compound (256). Ir (CHC13): 1730, 1110 cm - 1; XH nmr (400 MHz, CDC13) 6: 3.47 (s, 2H, acetal methylenes), 3.44 (s, 2H, acetal methylenes), 2.82 (m, 2H, H c), 2.46 (d of d, 2H, H^ , = 19 Hz, _J_AC = 9.7 Hz), 2.29 (d of d, 2H, , = 13.7 Hz, J E C = 8.8 Hz), 2.17 (d of d, 2H, Hg, J B A = 19 Hz, Jg C = 4.5 Hz), 1.82 (d of d, 2H, Hp, Jp E = 13.7 Hz, = 5 Hz) 0.97 (s, 6H, acetal methyls). Exact Mass calcd. for C 1 3 H 2 0 ° 3 : 2 24«1413; found: 224.1416. Anal, calcd. for C 1 3H 2 0O 3: C 69.61; H 8.99; found: C 69.55, H 8.85. Compound (255). Ir (CHC13): 1210 cm-1; XH nmr (400 MHz, CDCI3): 3.46 (s, 4H, acetal methylenes), 3.45 (s, 4H, acetal methylenes), 2.55 (m, 2H, H c), 2.21 (d of d, 4H, HA, = 13 Hz, = 8.8 Hz), 1.72 ( d of d, 4H, H„, J D A = 13 Hz, J,,. = 6.2 Hz), 0.95 (s, 12H, acetal methyls). B —BA —BL Exact Mass calcd. for C 1 8H 3 0O 1 +: 310.2145; found: 310.2146. Anal, calcd. for C 1 8H 3 0O 4: C 69.64, H 9.74; found: C 69.94, H 9.70. Preparation of the Hydrazone (257) . H 257 To a 500 mL-RB-3N flask, equipped with a mechanical stirrer and condenser, was added the keto acetal (256) (32.7 g, 0.146 mmol) and absolute ethanol (200 mL). To this stirring solution was added pure r e c r y s t a l l i z e d 1 3 7 p-toluenesulfonhydrazide (28.5 g, 0.153 mol) in one portion. The mixture was heated to ~ 50°C at which point the hydrazide 2 4 3 dissolved. Shortly afterwards, a heavy white precipitate formed. After having been stirred for an additional 2 0 min at 5 0 ° C , the reaction mixture was suction f i l t e r e d . The resulting white solid was shaken with ethanol (~ 4 0 0 mL) and refiltered. Pumping for 1 day (room temperature/ 0 . 1 Torr) afforded the hydrazone ( 2 5 7 ) ( 5 4 . 9 g, 9 6 % ) (mp 1 9 3 - 1 9 4 ° C dec). Ir ( C H C 1 3 ) : 3 2 5 0 ( b r ) , 3 1 8 0 ( b r ) , 3 0 0 0(w), 1 5 9 0 , 1 1 7 0 cm - 1. Exact  Mass calcd. for C J Q H J Q N J O ^ S : 3 9 2 . 1 7 7 0 ; found: 3 9 2 . 1 7 7 1 . Preparation of the Alkene ( 2 5 8 ) To an oven dried, argon flushed 1 L-RB-3N flask, equipped with an argon in l e t , magnetic stirring bar, and septum, was added dry ether ( 3 2 0 mL), HMPA ( 3 0 mL), and the hydrazone ( 2 5 7 ) ( 2 0 g, 5 1 mmol). This stirring suspension was cooled to - 7 8 ° C and a solution of ti-butyllithium ( 4 2 mL, 2 . 6 9 M hexanes solution, 1 1 3 mmol) was added via a syringe. The reaction mixture turned yellow, and upon warming to room temperature, the white suspension was replaced by a clear dark orange solution. After having been stirred for 2 h at room temperature, the reaction mixture, now containing a white-yellow precipitate, was treated with water. The ether layer was washed (water ( 2 X ) , brine), dried (MgSO^) filter e d , and concentrated to give a pale yellow liquid. D i s t i l l a t i o n (air-bath temperature 6 0 - 7 0 ° C / 0 . 1 Torr) afforded the alkene ( 2 5 8 ) as a H H,Hj 2 5 8 244 white solid (9.7 g, 91%) (mp 34-36°C). Ir (CHC13): 3010, 1610(w), 1110 cm-1; lE nmr (400 MHz, CDCI3) 6: 5.59 and 5.55 (each d of d of d of d, 1H, Hp and Hg, = 5.5 Hz, = J_Q-p = J_QQ = = = _JgQ - 2.2 Hz), 3.49 (s, 2H, acetal methylenes), 3.43 (s, 2H, acetal methylenes), 3.19-3.10 (m, 1H, H ), 2.71 (d of d of d of d of d, 1H, H J J , JJJJ, - Jgp - Jgj - 0 ^ » 9 Hz, J^G = 2.5 Hz), 2.55 (d of d of d of d of d, 1H, Hp, = 16.8 Hz, J p H = 9 Hz, = J_ F D -= 2.2 Hz), 2.36-2.28 (m, 2H, H. and H T), 2.10 (d of d of d of d of — r h A J d, 1H, HG, = 16.8 Hz, = 2.5 Hz, = = = 2.2 Hz), 1.58 (d of d, 1H, H , J . D = 12.8 Hz, J.„ = 6 Hz), 1.50 (d of d, 1H, HT, J T T = D —AH — A L 1 — I J 13 Hz, J_„ = 9 Hz), 0.96 (s, 3H, acetal methyl), 0.95 (s, 3H, acetal methyl). Irradiation at 6 3.19-3.10: 6 5.59 and 6 5.55 each simplified to a d of d of d (J_ = 5.5, 2.2, 2.2 Hz), 6 2.7l simplified to a d of d of d of d (J = 9, 9, 9, 2.5 Hz), 6 2.55 and 6 2.10 each simplified by removal of a 2.2 Hz coupling, multiplet at 5 2.36-2.28 simplified, 6 1.58 simplified to a d (J_ = 12.8 Hz). Exact Mass calcd. for C 1 3H 2 00 2: 208.1464; found: 208.1459. Anal, calcd. for C 1 3H 2 0O 2: C 74.96, H 9.68; found: C 74.77, H 9.77. Preparation of the Epoxides (259) and (260) 0 ^ H 259 260 245 To a 2 L-RB flask, equipped with a magnetic stirring bar, was added DMSO (750 mL), water (20 mL), and the alkene (258) (20 g, 96 mmol). Upon dissolution, NBS (17 g, 96 mmol) was added in one portion, and the reaction mixture turned bright yellow. After 15 min, the color had faded, and excess NBS (1-2 g) was added in small portions until the reaction mixture remained yellow for 10 min. The reaction mixture was treated with saturated aqueous sodium bicarbonate (~ 50 mL) and diluted with water (1.5 L). The resulting mixture was extracted with ether (4X), and the combined ether extracts were washed (water (3X), brine), dried (MgSO^), fil t e r e d , and concentrated to afford a clear yellow liquid which was used directly in the next reaction. To a 500 mL-RB flask, equipped with a magnetic stirring bar, was added potassium carbonate (16 g, 116 mmol), methanol (160 mL), and the previous reaction product. After having been vigorously stirred for 1.5 h at room temperature, the reaction mixture was diluted with water (500 mL), and the resulting mixture was extracted wth ether (2X). The combined ether extracts were washed (water (2X), brine), dried (MgSO^), filter e d , and concentrated to afford a pale yellow liquid. D i s t i l l a t i o n of this material (air-bath temperature 80-90°C/0.1 Torr) provided a mixture of the epoxides (259) and (260) as a white solid (20.1 g, 93%). Glc analysis of this mixture showed only one peak and tic analysis ( s i l i c a gel plate, petroleum ether-ether, 2:1) showed only one spot. However, the *H nmr spectrum (400 MHz, CDC13) of this mixture showed i t to consist of (259) and (260) in a ratio of 3:1, respectively. This material was used without further purification for the next reaction. The epoxide (259) could be obtained pure by 3 recrystallizations from 246 heptane (mp 51-52°C). Compound (259). Ir (CHC1 3): 1110, 850 cm"1; 2H nmr (400 MHz, CDCI3) 6: 3.58 (br s, IH, epoxide H, Wj = 5.2 Hz), 3.45 (s, 2H, acetal methylenes), 3.42 (br s, 3H, epoxide H and acetal methylenes), 2.61-2.47 (m, 2H), 2.38-2.22 (m, 2H), 1.94-1.82 (m, 3H), 1.41 (d of d, IH, J_ = 11.7, 11.7 Hz), 0.97 (s, 3H, acetal methyl), 0.92 (s, 3H, acetal methyl). Exact Mass calcd. for C 1 3H 2 0O 3: 224.1413; found: 224.1411. Anal, calcd. for C 1 3H 2 0O 3: C 69.61, H 8.99; found: C 69.91, H 9.16. Preparation of the A l l y l i c Alcohol (261) 261 To an oven dried, argon flushed 500 mL-RB-3N flask, equipped with a condenser, dropping funnel, magnetic stirring bar, and solid addition tube containing sodium borohydride (2.2 g, 58 mmol), was added diphenyl diselenide (7.1 g, 23 mmol) and absolute ethanol (130 mL). To this stirring suspension at room temperature was slowly added the sodium borohydride in small portions. To the resulting cloudy colorless solution was added, over a period of 15 min from the dropping funnel, a dry THF (130 mL) solution of the epoxide mixture from the previous reaction (8.0 g, 36 mmol). After having been refluxed for 1 h, the reaction mixture was cooled to 0°C, and hydrogen peroxide (60 mL, 40% 247 aqueous solution) was added over 15 min from the dropping funnel. Upon warming to room temperature, the reaction mixture started to bubble profusely, and after cessation, reflux was commenced for 1 h. After this time, the reaction mixture was cooled and diluted with water. The resulting mixture was extracted with ether (2X) and the combined ether extracts were washed (aqueous saturated sodium carbonate (3X), water, brine), dried (MgSO^), filte r e d , and concentrated to afford a yellow liquid. This material was flash chromatographed (5 x 25 cm column of s i l i c a gel, eluting with petroleum ether-ether, 3:1) to provide, after concentration of the appropriate fractions and d i s t i l l a t i o n (air-bath temperature 80-90°C, 0.1 Torr), the recovered epoxide mixture (1 g) and the a l l y l i c alcohol (261) (3 g, 43% based on unrecovered starting material). Further elution of the column, using petroleum ether-ether, 1:1, gave a mixture of other a l l y l i c alcohol isomers (2.6 g). Compound (261) could be recrystallized from heptane (mp 57-58°C). Ir (CHC13): 3320(br), 3030, 1610(w), 1120, 1020 cm"1; lR nmr (400 MHz, CDC1,) 6: 5.79 (d of d, 1H, H , J._, = 5.5 Hz, J _ u = 2.5 Hz), 5.70 (d of d of d, 1H, H_, J = 5.5 Hz, J__ = J _ = 2 Hz), 4.66 (br d of d, F — i G — r D --FH 1H, Hp, - J_DE = 10 Hz), 3.53-3.35 (m, 4H, acetal methylenes), 3.23-3.14 (m, 1H, R^), 2.95-2.83 (m, 2H, H c and R^ ,), 2.35 (d of d of d, 1H, R^, J f i A = 13.5 Hz, J_ B C = J f i I = 2 Hz), 2.19 (d of d of d, 1H, Hj, J T T = 13.5 Hz, J T U = 2.8 Hz, J T_ = 2 Hz), 1.96 (d of d, 1H, H., J\ = — I J — I n —IB A —AB 13.5 Hz, J._ = 10 Hz), 1.79 (d of d, 1H, H , J T T = 13.5 Hz, J-, = 11 —AC J — J J. — J H Hz), 1.07 (s, 3H, acetal methyl), 0.82 (s, 3H, acetal methyl)). D20 added: 6 4.66 simplified to a br d (J_ = 10 Hz), multiplet of 6 3.53-3.35 simplified. Irradiation at 6 4.66: 6 5.70 simplified to a d of d (J = 248 5.5, 2 Hz), multiplet at 6 2.95-2.83 simplified. Irradiation at 6 3.23-3.14: 6 5.79 simplified to a d (J = 5.5 Hz), 6 5.70 simplified to a d of d (J_ = 5.5, 2 Hz), multiplet at 6 2.95-2.83 simplified, 6 2.19 simplified to a d of d (J = 13.5, 2 Hz), 6 1.79 simplified to a d (J = 11 Hz). Exact Mass calcd. for C 1 3H 2 0O 3: 224.1413; found 224.1403. Anal, calcd. for C 1 3H 2 0O 3: C 69.91, H 8.99; found: C 69.54, H 8.87. Preparation of the A l l y l i c S i l y l Ether (249) To an oven dried, argon flushed 250 mL-RB-3N flask, equipped with an argon inlet and magnetic stirring bar, was added the a l l y l i c alcohol (261) (9.1 g, 40.6 mmol) and dry DMF (100 mL). Imidazole (7.5 g, 110 mmol) and tert-butyldimethylsilyl chloride (7.95 g, 52.7 mmol) were added in one portion successively, and the reaction mixture was stirred at room temperature for 2 h. After this time, the reaction mixture was treated with saturated aqueous sodium bicarbonate and diluted with water (250 mL). The resulting mixture was extrated with ether (3X), and the combined ether extracts were washed (water (3X), brine), dried (MgSO^), filter e d , and concentrated to afford a clear colorless liquid. Pumping with agitation (30°C/0.1 Torr) for 45 min, and d i s t i l l a t i o n (air-bath temperature 110-120°C/0.1 Torr) provided the s i l y l ether (249) as a clear colorless liquid (13.5 g, 98%). H E 249 Ir (film): 3020, 1110 cm-1; XH nmr (400 MHz, CDC13) 6: 5.73 and 5.53 (each d of d of d, Hg and Hp, = 5.5 Hz, ^ D ' ' ^ ' I F G = 2Hz), 4.88 (d of d of d of d, IH, Hp, = 8 Hz, J ^ . = J ^ , = J ^ , = 2 Hz), 3.54-3.40 (m, 4H, acetal methylenes), 3.03-2.95 (m, IH, H^), 2.86 (d of d of d of d, IH, Hc, J^g = 10 Hz, = = J ^ , = 8 Hz), 2.44 (d of d of d, IH, Hj, J_ I H = 13 Hz, J_ I G - 9 Hz, = 2 Hz), 2.03 (d of d, IH, HB, J f i A = 13 Hz, J f i C = 10 Hz), 1.96 (d of d of d, IH, H^ , = 13 Hz, = 8 Hz, = 2 Hz), 1.50 (d of d, IH, H^ , = 13 Hz, J^, = 7 Hz), 0.99 (s, 3H, acetal methyl), 0.94 (s, 3H, acetal methyl), 0.90 (s, 9H, -Si-t-Bu), 0.07 (s, 6H, -Si-Me's). Irradiation at 6 4.88: 6 5.73 and 6 5.53 each simplified to a d of d (J = 5.5, 2Hz), 6 2.86 simplified to a d of d of d (J = 10, 8, 8 Hz). Irradiation at 6 2.44: multiplet at 6 3.03-2.95 simplified, 6 1.96 simplified to a d of d (J_ = 13, 8 Hz), 6 1.50 simplified to a d (J = 13 Hz). Exact Mass calcd. for C 1 9H 3 1 t0 3Si: 338.2278; found: 338.2279. Anal, calcd. for C 1 9H 3 1 +0 3Si: C 67.41, H 10.12; found: C 67.44, H 9.99. Preparation of the Cyclopropyl Esters (263a) and (264b) and the Adduct (264) EfOOC 263a EtOOC 2 6 4 250 General procedure 1 was followed. Ethyl diazoacetate (9 mL, 86 mmol) was added over a period of 16 h to the a l l y l i c s i l y l ether (249) (9.23 g, 27.3 mmol) containing rhodium(II) acetate (~ 30 mg). The crude yellow reaction product was flash chromatographed (5 x 20 cm column of s i l i c a gel, eluting f i r s t with petroleum ether-ether, 10:1, and eluting second with petroleum ether-ether, 5:1) to afford the recovered a l l y l i c s i l y l ether (249) (6.99 g, after d i s t i l l a t i o n ) and the crude ester mixture. The latter material was pumped on with agitation (70°C/0.1 Torr, 2 min) to remove any diethyl maleate and diethyl fumarate. Glc analysis of the resulting colorless viscous liquid (2.53 g, 90% based on unrecovered starting material) showed i t to consist of a 10:6:1 mixture of the exo-cyclopropyl ester (263a), the endo-cyclopropyl ester (263b), and the adduct (264), respectively. Ir (film): 1720, 1110, 840 cm - 1. Exact Mass calcd. for C 2 3H 4 0O 5Si: 424.2646; found: 424.2636. Anal, calcd. for C 2 3H 1 + 0O 5Si: C 65.05, H 9.49; found: C 65.14, H 9.39. 251 To an oven dried, argon flushed 500 mL-RB-3N flask, equipped with an argon inlet, magnetic stirring bar, and septum, was added LAH (0.8 g, 21 mmol) and anhydrous ether (200 mL). To this stirring suspension at room temperature was added, over a period of 10 min from a syringe, an ether (30 + 20 mL) solution of the ester mixture from the previous reaction (4.53 g, 10.7 mmol). After having been stirred for an addi-tional 1 h, the reaction mixture was treated with Na2SO^•10H20 and the resulting slurry was filtered through F l o r i s i l (8 x 6 cm column, rinsing with ether). Concentration, and d i s t i l l a t i o n (air-bath temperature 130-140°C/0.1 Torr) afforded the alcohol mixture (265) together with the alcohol (266) as a clear colorless "glass" (3.71 g, 91%). Ir (film): 3350(br), 1110 cm - 1. Exact Mass calcd. for C 2 1H 3 80 4Si: 382.2540; found: 382.2554. Anal, calcd. for C^B^gO^Si: C 65.92, H 10.01; found: C 65.82, H 10.00. Preparation of the Aldehyde Mixture (267) and the Aldehyde (268) General procedure 2 was followed. To a stirring suspension of PCC (3.2 g, 14.8 mmol), sodium acetate (1.5 g) and CH2C12 (40 mL) in a 250 mL-RB-3N flask was added a solution of the alcohol mixture from the previous reaction (3.71 g, 9.7 mmol) in CH2C12 (15 + 5 mL). General 252 conditions and reaction workup produced a clear pale yellow viscous liquid (3.47 g) which was used without further purification for the next reaction. Preparation of the Aldehyde (251) General procedure 3 was followed. To a THF (60 mL) solution of the aldehyde mixture from the previous reaction (3.47 g, 9.1 mmol) in a 250 mL-RB-3N flask was added a tert-butyl alcohol (8 mL) solution of potassium tert-butoxide (100 mg). General conditions and reaction workup afforded the crude aldehyde epimer (251) together with the aldehyde (268) as a yellow viscous liquid (3.40 g). This crude material was used without further purification for the Wittig methylenation reaction, but was purified as follows for the other described Wittig reactions. The crude aldehyde mixture was flash chromatographed (4 x 24 cm column of s i l i c a gel, eluting f i r s t with petroleum ether-ether, 4:1, and eluting second with petroleum ether-ether, 2:1) to provide, after concentration and pumping (room temperature/0.1 Torr, 3 h), pure aldehyde (251) as a white solid (2.39 g, 65% from the alcohol mixture of (265) and (266)) (mp 80-81°C). The earlier fractions from this 251 H HH ( 253 chromatography contained the aldehyde (268). Compound (251). Ir (CHC13): 1695, 1110 cm-1; :H nmr (400 MHz, CDC13) 6: 9.06 (d, IH, H A > = 5 Hz), 4.13 (d, IH, Hg, = 6 Hz), 3.53-3.39 (m, 4H, acetal methylenes), 2.53 (d of d of d, IH, H„, J _ u = G —GH 12.5 Hz, = Jgj « 7 Hz), 2.25 (d of d, IH, H^ J _ I H = 12.5 Hz, J _ I G = 7 Hz), 2.20-2.00 (m, 5H), 1.59 (d of d, IH, H„, J U T = J u„ = 12.5 Hz), 1.52 rl — r i l —HG (d of d of d, IH, H , J_. = 5 Hz, J D„ = J = 3 Hz), 0.99 (s, 3H, acetal Jo —BA —BL. —BL) methyl), 0.92 (s, 12H, acetal methyl and -Si-t-Bu), 0.11 (s, 3H, -Si-Me), 0.07 (s, 3H, -Si-Me). Irradiation at 6 2.53: 6 2.25 and 6 1.59 each simplified to a d (J_ = 12.5 Hz). Exact Mass calcd. for CjjHjgO^Si: 380.2384; found: 380.2381. Anal, calcd. for C^HggO^Si: C- 66.27, H 9.53; found: C 66.08, H 9.50. Preparation of the Alkene Mixture (269) To an oven dried, argon flushed 50 mL-RB-3N flask, equipped with an argon inlet, magnetic stirring bar, and septum, was added potassium tert-butoxide (650 mg, 5.8 mmol) and dry THF (10 mL). To this stirring solution at room temperature was added, via a syringe, a solution of the phosphonium bromide (250a) 1 1 8 (2.7 g, 5.9 mmol) in dry DMS0 (5.5 mL). 254 The resulting red reaction mixture was stirred for 30 min at room temperature after which time, a solution of the pure aldehyde (251) (745 mg, 1.96 mmol) in dry THF (2 + 0.5 mL) was added via a syringe. After 1.5 h, the reaction mixture was poured into water (50 mL), and the resulting mixture was extracted with ether (2X). The combined ether extracts were washed (water (2X), brine), dried (MgSO^), filte r e d , and concentrated to afford a yellow liquid-solid mixture. This material was flash chromatographed (3 x 18 cm column of s i l i c a gel, eluting with petroleum ether-ether, 2:1) to give, after concentration of the appropriate fractions and pumping with agitation (60°C/0.1 Torr, 20 min), the alkene mixture (269) as a clear, colorless, viscous gum (815 mg, 87%). Glc analysis of this material showed i t to consist of a mixture of c i s - and trans-isomers in a ratio of 9:1, respectively. Tic analysis of this mixture ( s i l i c a gel plate, petroleum ether-ether, 2:1) showed only one spot. The mixture was used in the next reaction without further purification. Ir (CHC13): 3010(w), 1640(w), 1250, 1110, 1080 cm - 1. Exact Mass calcd. for C 2 7H 1 | 60 5Si: 478.3116; found: 478.3122. Preparation of the Alcohol Mixture (270) 255 General procedure 5 was followed. To a cold (-78°C) THF (17 mL) solution of the s i l y l ether mixture (269) (815 mg, 1.7 mmol) in a 50 mL-RB-3N flask was added a THF (5 mL) solution of TBAF (1.3 g, 5 mmol). General conditions, reaction workup, and pumping with agitation (60°C/0.1 Torr, 30 min) afforded the alcohol mixture (270) as clear, colorless, viscous gum which slowly solidified on storage (596 mg, 96%). This mixture was used in the next reaction without further purification. Ir (CHC13): 3400(br), 1650(w), 1110, 1010 cm - 1. Exact Mass calcd. for C 2 1H 3 20 5: 364.2251; found: 364.2268. Preparation of the Vinylcyclopropyl ketones (271) and (272) General procedure 2 was followed. To a stirring suspension of PCC (500 mg, 2.3 mmol), sodium acetate (300 mg), and CH2C12 (7 mL) in a 50 mL-RB-3N flask was added a solution of the alcohol mixture (270) (500 mg, 1.37 mmol) in CH2C12 ( 4 + 2 mL). General conditions and reaction workup provided a clear colorless gum which solidified upon cooling (-10°C) with heptane (few drops). Pumping of the resulting product (room temperature/0.1 Torr, 6 h) afforded a mixture of the vinylcyclo-propyl ketones (271) and (272) as a white solid (462 mg, 93%). Glc 271 272 256 analysis of this mixture showed i t to consist of (271) and (272) in a ratio of 9:1, respectively. This mixture was recrystallized (3X) from heptane to provide the vinylcyclopropyl ketone (271) (326 mg, 66%) (mp 102-104°C). The material isolated from the f i r s t mother liquors was recrystallized (3X) from heptane to provide the vinylcyclopropyl ketone (272) (~ 25 mg) (mp 109-111°C). Compound (271). Ir ( C H C 1 3 ) : 3020, 1710, 1 1 1 0 cm-1; XH nmr (400 MHz, C D C 1 3 ) 6: 5 . 4 5 (d of t, 1 H , Hp, = 11 Hz, = = 7.4 Hz), 4.95-4.86 (m, 1 H , Hg), 4.56 (t, 1 H , H , = = 5.1 Hz), 4.14-4.06 and 3.81-3.71 (each m, 2 H , -OCj^-CH^CH^O-), 3.53-3.26 (m, 4 H , acetal methylenes), 2.84 (d of d of d, 1 H , ^ or EJt J_ = 1 0 , 7.8, 4.3 Hz), 2.63 (br d, J = 13.5 Hz), 2.49-2.40 (m, 3H, H_, H„, and H_ or H T), 2.18 (d of — a L> 1 J d, 1 H , J_ = 13.5, 1 0 Hz), 2.14-2.01 (m, 1 H , -OGT^-CI^-CHjO-), 1.94-1.86 (m, 3H, Hj,, HG, and H R), 1.83 (d of d of d, 1 H , J = 13.5, 4.3, 2 Hz), 1.80 (d of d, 1 H , J = 13.5, 9 Hz), 1.37-1.30 (m, 1 H , -0CH 2-CH 2-CH 20-), 1.08 (s, 3H, acetal methyl), 0.80 (s, 3H, acetal methyl). Irradiation at 6 5 . 4 5 : multiplet at 6 2.49-2.40 simplified. Irradiation at 6 2.84: multiplet at 6 2.49-2.40 simplified, 6 2.18 simplified to a d (J_ = 13.5 Hz) 1.83 simplified to a d of d (J = 13.5, 2 Hz). Irradiation at 6 2.63: 6 1.83 simplified to a d of d (J = 13.5, 4.3 Hz), 6 1.80 simplified to a d (J = 9 Hz). Irradiation at 6 1.37-1.30: multiplets at 4.14-4.06, 3.81-3.71, and 2.14-2.01 a l l simplfied. Exact Mass calcd. for C 2 1H 3 Q0 5: 362.2094; found: 362.2087. Anal, calcd. for C 2 1H 2 0O 5: C 69 . 5 9 , H 8.34; found: C 69 . 5 7 , H 8.28. Compound (272). Ir ( C H C I 3 ) : 1710, 1 1 1 0 cm-1; *H nmr (400 MHz, C D C I 3 ) 6 5.56 (d of t, 1 H , Hp, = 15.5 Hz, - Jp C = 7.5 Hz), 5.07 257 (d of d of t, IH, Hg, ^  - 15.5 Hz, ^  = 8.5, = = 1.2 Hz), 4.50 (t, IH, H., J. - J. - 5.1 Hz), 4.13-4.06 and 3.79-3.70 (each m, A ~^AD —AC 2H, -OO^-CHj-CH^O-), 3.52-3.28 (m, 4H, acetal methylenes), 2.83 (d of d of d, IH, Hj. or H J f J = 10, 8, 4 Hz), 2.64 (br d, J - 13.5 Hz), 2.41 (br d of d, IH, Hj or H , J = 8, 8 Hz), 2.30 (d of d of d, 2H, Hg and H c > = 7.5 Hz, J. = 5.1, J_ = 1.2 Hz), 2.18 (d of d, IH, J = 13.5, 10 Hz), 2.13-2.01 (m, IH, -0CH2-CH2-CH20-), 1.96-1.71 (m, 5H), 1.37-1.30 (m, IH, - O C H J - C H ^ - C H J O - ) , 1.08 (s, 3H, acetal methyl), 0.79 (s, 3H, acetal methyl). Exact Mass calcd. for C 2 1H 3 Q0 5: 362.2094; found: 362.2098. Preparation of the Bromo Acetal (278b) 278b To an oven dried 250 mL-RB-3N flask, equipped with a drying tube (Drierite), magnetic stirring bar, and adapter fitted with a Pasteur pipette, was added freshly d i s t i l l e d acrolein (22.5 mL, 0.337 mol) and dry CH2C12 (100 mL). To this stirring solution at room temperature was bubbled, through the pipette, anhydrous hydrogen bromide gas for ~ 1 h. After this time, the reaction mixture was degassed by a stream of argon for ~ 30 min, and 2,2-dimethyl-l,3-propanediol (35 g, 0.336 mol) and £-toluenesulfonic acid (300 mg) were added. The reaction mixture was stirred.at room temperature for 4 h, after which time, i t was treated 258 with saturated aqueous sodium bicarbonate (50 mL). The C H 2 C 1 2 layer was washed (water (2X), dried (MgSO^), f i l t e r e d , and concentrated to a f ford a brownish l i q u i d . Pumping with a g i t a t i o n (room temperature/0.1 Torr) provided the bromo ace ta l (278b) as a white semi-so l id (52.5 g, 70%). This mater ia l darkened on standing, so i t was stored at - 1 0 ° C , protected from l i g h t . Ir ( f i l m ) : 1480, 1130, 1040 c m - 1 ; *H nmr (80 MHz, CDC1 3) 6: 4.60 ( t , 1H, J = 5.5 Hz) , 3.83-3.30 (m, 6H), 2.32-2.04 (m, 2H), 1.18 (s, 3H), 0.75 (s , 3H). Exact Mass c a l c d . for C 8 H l 4 0 8 1 B r (M+-1): 223.0159; found 223.0159. Preparat ion of the Phosphonium Bromide (278a) To a 100 mL-RB-2N f l a s k , equipped with a mechanical s t i r r e r , condenser, and drying tube ( D r i e r i t e ) , was added the bromo a c e t a l (278b) (4.5 g, 20.2 mmol), cyclohexane (15 mL), and triphenylphosphine (8.36 g, 32 mmo 1) . The s t i r r i n g mixture was immersed i n a 90°C o i l bath and heated for 24 h. After th i s time, the remaining solvent was decanted of f , and the re s idua l co lor l e s s glassy mater ia l was scrapped out and ground into a f ine powder. This powder was washed with ether and pe tro -leum ether , (2X) r e s p e c t i v e l y . Pumping overnight (room temperature/0.1 Torr) afforded the phosphonium sa l t (278a) as a white powder (4.9 g, 51%). 278a 259 Ir (CHCI3): 3050, 1590, 1440, 1130, 1120 cm - 1; XH nmr (80 MHz, CDCI3) 6: 8.00-7.60 (m, 15H), 5.00 (t, 1H, J = 5 Hz), 4.10-3.66 (m, 2H), 3.51 (s, 4H, acetal methylenes), 2.15-1.70 (m, 2H), 1.10 (s, 3H, acetal methyl), 0.72 (s, 3H, acetal methyl); ms m/e: 405 (M-Br). Preparation of the Alkene Mixture (279) 2 7 9 To an oven dried, argon flushed 50 mL-RB-3N flask, equipped with an argon inlet, magnetic stirring bar, and septum, was added potassium tert-butoxide (500 mg, 4.42 mmol) and dry THF (8 mL). To this stirring suspension at room temperature was added, via a syringe, a solution of the phosphonium bromide (278a) (2.2 g, 4.6 mmol) in dry DMS0 (4.5 mL). The resulting red reaction mixture was stirred for 30 min at room temperature, after which time, a solution of the pure aldehyde (251) (700 mg, 1.84 mmol) in dry THF ( 2 + 1 mL) was added via a syringe. After 1 h, the reaction mixture was poured into water (50 mL), and the resulting mixture was extracted with ether (2X). The combined ether extracts were washed (water (2X), brine), dried (MgSO^), filte r e d , and concentrated to afford a yellow liquid-solid mixture. This material was 260 flash chromatographed (3 x 18 cm column of s i l i c a gel, eluting with petroleum ether-ether, 5:1) to give, after concentration of the appro-priate fractions and pumping with agitation (60°C/0.1 Torr, 15 min), the alkene mixture (279) as a clear colorless viscous gum (681 mg, 73%). Glc analysis of this material showed i t to consist of a mixture of c i s -and trans-isomers in a ratio of 9:1, respectively. This material was used without further purification for the next reaction. Ir (CHC13): 3020(w), 1640(w), 1110, 840 cm - 1. Exact Mass calcd. for C 2 gH 5 Q0 5Si: 506.3427; found: 506.3423. Preparation of the Alcohol Mixture (280) General procedure 5 was followed. To a cold (-78°C) THF (15 mL) solution of the s i l y l ether mixture (279) (680 mg, 1.34 mmol) in a 50 mL-RB-3N flask was added a THF (4 mL) solution of TBAF (1.2 g, 4.9 mmol). General conditions, reaction workup, and pumping with agitation (60°C/0.1 Torr, 30 min) afforded the alcohol mixture (280) as a white solid (509 mg, 97%). Ir (CHC13): 3400(br), 1640(w), 1110 cm - 1. Exact Mass calcd. for C23 H36°5 : 3 9 2 « 2 5 6 4 ; found: 392.2561. 2 8 0 261 Preparation of Vinylcyclopropyl Ketones (281) and (282) 281 282 General procedure 2 was followed. To a stirring suspension of PCC (500 mg, 2.3 mmol), sodium acetate (~ 300 mg), and CH 2C1 2 (6 mL) in a 50 mL-RB-3N flask was added a solution of the alcohol mixture (280) (509 mg, 1.30 mmol) in CH 2C1 2 ( 3 + 1 mL). General conditions, reaction workup, and pumping with agitation (50°C/0.1 Torr, 25 min) afforded a white solid (475 mg, 94%). Glc analysis of this material showed i t to consist of a 9:1 mixture of the c i s - and trans-isomers, respectively. This material was recrystallized (3X) from heptane to give the pure vinylcyclopropyl ketone (281) as a white solid (312 mg, 62%) (mp 97-98°C). The material isolated from the f i r s t mother liquors was recrystallized (4X) from heptane to provide the vinylcyclopropyl ketone (282) (~ 20 mg) (mp 100-102°C). Compound (281). Ir (CHCI3): 1710, 1110 cm-1; lH nmr (400 MHz, CDCI3) 6 5.48 (d of t, IH, H , JL^ = 10.5 Hz, = J^ , = 7.5 Hz), 4.91 (m, IH, Hz), 4.47 (t, IH, H^ , = = 5.1 Hz), 3.64-3.27 (m, 8H, acetal methylenes), 2.85 (d of d of d, IH, H or EJt J = 10.5, 8, 4.5 Hz), 2.66 (br d, IH, J = 13 Hz), 2.50 (d of d of d, 2H, Hg and Hc, = 7.5 Hz, J A = 5.1 Hz, J,, = 1.6 Hz), 2.45 (br d of d, IH, H_ or HT, J = 8, 262 8 Hz), 2.18 (d of d, 1H, J = 13.5, 10.5 Hz), 1.94-1.88 (m, 3H, Hp, H^ and H u ) , 1.85 (d of d of d, 1H, J = 13.5, 4 .5 , 2 Hz) , 1.80 (d of d, 1H, H — J = 13, 8 Hz) , 1.20, 1.09, 0.80, 0.72 (each s, 3H, a c e t a l methyls ) . Exact Mass c a l c d . for C 2 3 H 3 l 4 0 5 : 390.2407; found: 390.2408. A n a l , c a l c d . for C 2 3 H 3 1 + 0 5 : C 70.74, H 8.77; found: C 70.73, H 8.71. Compound (282). Ir (CHC1 3 ) : 1710, 1110 c m - 1 ; X H nmr (400 MHz, CDC1 3) 6: 5.57 (d of t , 1H, Hp, = 15.5 Hz, = J _ D C = 7.5 Hz) , 5.08 (d of d of t , 1H, Hg, J £ D = 15.5 Hz, Jgp = 8.5 Hz, = = 1.2 Hz) , 4.39 ( t , 1H, H A , = = 5 Hz) , 3.64-3.27 (m, 8H, ace ta l methylenes), 2.82 (d of d of d, 1H, H or H , J = 10, 8, 4.2 Hz) , 2.64 (br d, 1H, J = 13.5 Hz) , 2.41 (br d of d, 1H, H or H J } J = 8, 8 Hz) , 2.34 (d of d of d, 2H, H and H„, Jn = 7.5 Hz, J . = 5.1 Hz, J _ = 1.2 D L. —D —A —fc. Hz), 2.18 (d of d, 1H, J = 13.5, 10 Hz) , 1.96-1.89 (m, 2H, H^ and H u ) , 1.84 (d of d of d, 1H, J = 13.5, 4 .2, 1.8 Hz) , 1.78 (d of d , 1H, J = 13.5, 8 Hz) , 1.74 (d of d of d , 1H, Hp, J _ F E = 8.5 Hz, J _ F G = J ^ R = 3.2 Hz) , 1.19, 1.09, 0.80, 0.72 (each s, 3H, ace ta l methyls ) . Exact Mass c a l c d . for C 2 3 H 3 1 + 0 5 : 390.2407; found: 390.2407. Preparat ion of the compounds (252), (273) and (285) 0Si + 263 285 To a cold (-78°C) THF (3 mL) solution of LDA (0.292 mmol), in a 25 mL-RB-3N flask, was added a THF (1 + 0.5 mL) solution of the vinyl -cyclopropyl ketone (271) (88 mg, 0.243 mmol). The reaction mixture was stirred at -78°C for 30 min, after which time, HMPA (74 uL, 0.413 mmol) was added via a syringe. After an additional 5 min of sti r r i n g , tert-butyldimethylsilyl t r i f l a t e (112 uL, 0.486 mmol) was added via a syringe. After 20 min at -78°C, the reaction mixture was warmed to room temperature and was stirred for an additional 1.5 h. The reaction mixture was treated with saturated aqueous sodium bicarbonate and diluted with water. The resulting mixture was extracted with ether, and the ether extract was washed (water (2X), brine), dried (MgSO^), filt e r e d , and concentrated to afford a yellow liquid. Glc analysis of this material showed i t to consist of a mixture of (252), (285), (273) and the starting vinylcyclopropyl ketone (271) in a 30:10:1:3 ratio, respectively. This material was chromatographed through triethylamine washed, grade 1, basic alumina (1 x 15 cm column, eluting with petroleum ether-ether, 3:1) to afford, after concentration of the appropriate fractions and pumping with agitation (35°C/0.1 Torr), in order of elution, (285) as a clear, colorless, viscous liquid (~ 20 mg), and 264 (252) as a clear colorless liquid (54 mg, 47%). Flushing the column with ether eluted (273) and the starting vinylcyclopropyl ketone (271) (~ 13 mg). Compound (252). Ir (film): 1680, 1650, 1220, 1110 cm - 1; *H nmr (400 MHz, CDC13) 6: 5.38 (d of t, IH, Hp, = 11 Hz, = J^, = 7 Hz), 4.87 (m, IH, Hg), 4.55 (t, H p = = 5.2 Hz), 4.13-4.06 and 3.80-3.71 (each m, 2H, -OCH2-CH2-CH20-), 3.53-3.40 (m, 4H, acetal methylenes), 2.76-2.68 (m, IH), 2.58 (d, IH, J = 15 Hz), 2.52-2.41 (m, 2H), 2.28-2.20 (m, 2H), 2.16-2.02 (m, IH), 1.73-1.58 (m, 3H), 1.37-1.31 (m, 2H), 1.02 (s, 3H, acetal methyl), 0.94 (s, 9H, -Si-t-Bu), 0.90 (s, 3H, acetal methyl), 0.14 (s, 6H, -Si-Me's). Exact Mass calcd. for C27 H44°5 S i : 476.2959; found: 476.2957. Compound (285). Ir (film): 3010(w), 1690, 1650, 1610, 1260, 1110, 850 cm-1; *H nmr (400 MHz, CDC13) 6: 6.56 (d, IH, H , J. = 12 Hz), 5.88 (d of d, IH, H , = 12 Hz, JL^ = 11 Hz), 5.79 (d of d, IH, Hc, J^g = 11 Hz, J^p = 11 Hz), 4.56 (d dof d, IH, Hp, Jp C = 11 Hz, ^  = 9 Hz), 3.83 and 3.72 (each d of d, 2H, -O-CH^ -CHg-CH^ O-, J = 6.2 Hz), 3.53-3.43 (m, 4H, acetal methylenes), 2.79-2.72 (m, IH), 2.61 (d, IH, J_ = 15 Hz), 2.29-2.21 (m, 2H), 1.90-1.82 (m, 2H), 1.73-1.63 (m, 3H), 1.35 (d of d, IH, J_ = 12, 12 Hz), 1.03 (s, 3H, acetal methyl), 0.95 (s, 9H, -Si-t-Bu), 0.91 (s, 3H, acetal methyl), 0.90 (s, 9H, -Si-t-Bu), 0.16 (s, 6H, -Si-Me's), 0.06 (s, 6H, -Si-Me's). Irradiation at 6 6.56: 6 5.88 simplified to a d (J = 11 Hz). Irradiation at 6 4.56: 6 5.79 simplified to a d (J = 11 Hz), multiplet at 6 1.73-1.63 simplified; ms m/e: 590 (M+) . Compound (273). Ir (film): 2700(w), 1680, 1650, 1110, 850 cm-1; lH nmr (400 MHz; CDCI3) 6: 9.53 (d, IH, H^, J _ A B = 8 Hz), 7.06 (d of d, 265 IH, Hc, = 16 Hz, = 9.5 Hz), 6.26 (d of d, IH, Hp, = 15.5 Hz, J_„ = 9.5 Hz), 6.19 (d of d, IH, H_, J = 15.5 Hz, J „ = 6.5 Hz), 6.07 IA, E —ED fcif (d of d, IH, Hfi, Jg C = 16 Hz, J g A = 8 Hz), 4.37 (br s, IH, Hg, w| = 4 Hz), 3.51-3.42 (m, 4H, acetal methylenes), 3.09-3.00 (m, 2H), 2.44-2.35 (m, 2H), 2.04 (d of d, IH, J = 13.5, 9 Hz), 1.88 (d of d, IH, J = 13.5, 5 Hz), 1.66 (d of d, IH, J - 11, 4.5 Hz), 0.97 and 0.94 (each s, 3H, acetal methyls), 0.93 (s, 9H, -Si-t-Bu), 0.18 and 0.17 (each s, 3H, -Si-Me's); ms m/e: 418 (M+). Model Study 4 Preparation of the Dibromoalkene (289) 289 To an oven dried argon flushed 100 mL-RB-3N flask, equipped with an argon inlet, magnetic stirring bar, and septum, was added successive-ly, dry recrystallized triphenylphosphine (1.46 g, 5.57 mmol), dry CH2C12 (20 mL), sublimed carbon tetrabromide (air-bath temperature 40-50°C/0.1 Torr) (1.85 g, 5.57 mmol), and activated zinc dust (364 mg, 5.57 mmol). The reaction mixture, slowly appearing as a white suspen-sion in a purple solution, was stirred at room temperature for 16 h, * Zinc washed successively with 1M HC1, water, ethanol, and ether. 266 after which time, a solution of the pure aldehyde (179) (520 mg, 1.85 mmol) in dry CH2C12 ( 2 + 1 mL) was added via a syringe. After having been stirred at room temperature for 30 min, the reaction mixture was diluted with petroleum ether (50 mL), and the resulting mixture was filtered through F l o r i s i l (4 x 8 cm column). The dark red-brown residue left in the reaction flask was redissolved in CH2C12, and after diluting with petroleum ether, the resulting mixture was filtered through the F l o r i s i l column. The column was rinsed with addition petro-leum ether, and the combined eluents were concentrated and d i s t i l l e d (air-bath temperature 125-135°C/0.1 Torr) to provide the dibromoalkene (289) as a white solid (774 mg, 96%) (mp 73-74°C). Ir (CHC13): 3010(w), 1080, 780, 670 cm"1; *H nmr (400 MHz, CDC13) 6: 5.78 (d, 1H, H , = 9.3 Hz), 4.09 (d, 1H, H^ , = 7 Hz), 2.36 (d of d of d, 1H, H , J = 10, 7.5, 7.5 Hz) 2.20-2.11 (m, 1H, E^), 1.87-1.27 (m, 8H), 1.23 (d of d of d, 1H, Hg, J_M= 9.3 Hz, £ B C = J B D = 3.1 Hz), 0.91 (s, 9H, -Si-£-Bu) 0.10 (s, 3H, -Si-Me), 0.06 (s, 3H, -Si-Me). Exact Mass calcd. for C 1 7H 2 80 7 9BrSi: 434.0276; found: 434.0276. Preparation of the Alkyne (290) 290 The crude aldehyde (179) was purified by flash chromatography (eluting with petroleum ether-ether, 7:1) prior to use. 267 To an oven dried, argon flushed 100 mL-RB-3N f l a s k , equipped with an argon i n l e t , magnetic s t i r r i n g bar, and septum, was added the dibromoalkene (289) (750 mg, 1.72 mmol) and dry THF (20 mL). Upon cooling this solution to -78°C, a solution of n-butyllithium (2.8 mL, 1.55 M hexanes solu t i o n , 4.34 mmol) was added, and the reaction mixture was s t i r r e d for 1.5 h. After this time, methyl iodide (2 mL, previously run through grade 1 basic alumina) was added v i a a syringe. The mixture was allowed to warm to room temperature, and a f t e r 15 min, i t was poured into water and extracted with ether. The ether extract was washed (water (2X), b r i n e ) , dried (MgSO^), f i l t e r e d , and concentrated to a f f o r d a yellow l i q u i d . This l i q u i d was f l a s h chromatographed (3 x 18 cm column of s i l i c a g e l , el u t i n g with petroleum ether) to a f f o r d , a f t e r concentration of the appropriate fractions and d i s t i l l a t i o n (air-bath temperature 70-80°C/0.1 Torr), the alkyne (290) as a clear c o l o r l e s s l i q u i d (392 mg, 78%). This l i q u i d s o l i d i f i e d at temperatures below 0°C. Ir ( f i l m ) : 2240(w), 1260, 1080, 850, 780 cm"1; XH nmr (400 MHz, CDC13) 6 4.03 (d, 1H, H , = 6.1 Hz), 2.29 (d of d of d, 1H, H p, J = 10, 7.6, 7.6 Hz), 2.03-1.95 (m, 1H, H_), 1.84-1.67 (m, 2H), 1.76 (d, 3H, alkyne methyl, J = 2.1 Hz), 1.65 and 1.58 (each d of d, H_ and H_, J „ n = 6 Hz, *J_. = J = 3.2 Hz), 1.54-1.25 (m, 4H), 0.90 (s, 9H, -Si-t-Bu), —BA —OA — 0.81-0.77 (m, 1H, H ), 0.11 (s, 3H, -Si-Me), 0.05 (s, 3H, -Si-Me). A Exact Mass calcd. for C 1 8H 3 ( )OSi: 290.2067; found: 290.2068. 268 Preparation of the Alkene (287) 2 8 7 To a 20 mL-RB-2N flask, equipped with a septum and magnetic stirring bar, was added Lindlar's catalyst (30 mg), pentane (7 mL), and quinoline (200 uL). This flask was attached to a hydrogen line, and the mixture was stirred under 1 atm of H 2 for 5 min, after which time, a solution of the alkyne (290) (332 mg, 1:14 mmol) in pentane ( 2 + 1 mL) was added via a syringe. The reaction was monitored by glc, and after ~ 1 h, a l l the alkyne substrate had been consumed. The reaction mixture was filtered and concentrated to afford a clear colorless liquid. Glc analysis of this material showed i t to consist of a mixture of the cis--alkene (287), the trans-alkene (288), and the corresponding alkane in a ratio of 96:3.4:0.6, respectively. This material was flash chromato-graphed (3 x 17 cm column of s i l i c a gel, eluting with petroleum ether) to provide, after concentration of the appropriate fractions and d i s t i l -lation (air bath temperature 70-80°C/O.l Torr), a mixture the cis-alkene (287) and the corresponding trans-isomer (288) in a ratio (glc analysis) of ~ 96:4, respectively (306 mg, 92%). Ir (film): 3005, 1650, 1080, 850 cm-1; XH nmr (400 MHz, CDC13) 6: 5.31 (d of q, IH, H , J = 10.5 Hz, J „ =7 Hz), 4.78 (d of d of q, A —AJJ —A—L/Hj IH, H , J = 10.5 Hz, J f i C = 10 Hz, J_ B_ C H = 2 Hz), 4.08 (d, IH, H p ) 269 J_ F G = 6.5 Hz), 2.33 (d of d of d, 1H, H^ , J_ = 10, 7, 7 Hz), 2.19-2.11 (m, 1H, H„), 1.89-1.69 (m, 3H), 1.69 (d of d, 3H, vinyl methyl, J = 7 G —A Hz, J D = 2 Hz), 1.58-1.30 (m, 5H), 1.17 (d of d of d, 1H, H„, J___ = 10 — D C —CB Hz, = J.^ = 3.2 Hz), 0.91 (s, 9H, -Si-t-Bu), 0.09 (s, 3H, -Si-Me), 0.06 (s, 3H, -Si-Me). Exact Mass calcd. for C 1 8H 3 20Si: 292.2222; found 202.2222. Preparation of the Alcohol (291) General procedure 5 was followed. To a cold (-78°C) THF (5 mL) solution of the s i l y l ether (287) (295 mg, 1.01 mmol) in a 25 mL-RB-3N flask was added a THF (1 mL) solution of TBAF (500 mg, 1.91 mmol). General conditions, reaction workup, pumping with agitation (30°C/0.1 Torr, 10 min), and d i s t i l l a t i o n (air-bath temperature 60-70°C/0.1 Torr) gave the alcohol (291) as a clear colorless liquid (168 mg, 94%). Ir (film): 3350(br), 3000, 1650, 1020, 710 cm"1; H nmr (400 MHz, CDC13) 6: 5.34 (d of q, 1H, H^ , = 10.7 Hz, J ^ . ^ = 7 Hz), 4.79 (d of d of q, 1H, HB, J f i A = 10.7 Hz, J_B(, = 10 Hz, J B _ C H = 1-7 Hz), 4.14-4.08 (m, 1H, H^), 2.39 (d of d of d, 1H, Hp, J = 10.3, 8, 8 Hz), 2.27-2.17 (m, 1H, H^), 1.91-1.73 (m, 3H), 1.69 (d of d, 3H, vinyl methyl, J = 7 Hz, J = 1.7 Hz), 1.65-1.50 (m, 2H), 1.48-1.42 (m, 2H), —A —B 270 1.30-1.17 (m, 3H). D20 added: multiplet at 4.14-4.08 simplified to a d (Jpg = 6.3 Hz). Exact Mass calcd. for C 1 2H 1 80: 178.1358; found: 178.1359. Preparation of the Vinylcyclopropyl Ketone (292) General procedure 2 was followed. To a stirring suspension of PCC (300 mg, 1.39 mmol), sodium acetate (150 mg), and CH2C12 (3 mL) in a 25 mL-RB-3N flask was added a solution of the alcohol (291) (160 mg, 0.90 mmol) in CH2C12 (1 + 0.5 mL). General conditions, reaction workup, and d i s t i l l a t i o n (air-bath temperature 60-70°C/0.1 Torr) afforded the vinylcyclopropyl ketone (292) as a clear colorless liquid (141 mg, 89%). Ir (film): 1710, 1650(w), 1190, 880 cm-1; XH nmr (400 MHz, CDC13) 6: 5.46 (d of q, IH, H., J._ = 10.7 Hz, J. _ u = 7.3 Hz) 4.79 (d of d of A • " A D — " A - L< rl ^  q, IH, Hfi, = 10.7, = 9.5 Hz, JB_CH = 1 - 7 Hz), 2.77-2.69 (m, IH), 2.51-2.43 (m, IH), 1.99 (d of d of d, IH, Hc, = 9.5 Hz, = = 3 Hz), 1.96-1.73 (m, 5H), 1.72 (d of d, 3H, vinyl methyl, = 7 Hz, Jg = 1.7 Hz), 1.56-1.38 (m, 3H). Exact Mass calcd. for C 1 2H 1 60: 176.1202; found: 176.1206. 271 Preparation of the Divinylcyclopropane (286) 286 To a cold (-78°C) THF (2 mL) solution of LDA (0.25 mmol) in a 25 mL-RB-3N flask was added a THF (0.3 + 0.2 mL) solution of the vinyl-cyclopropyl ketone (292) (27 mg, 0.153 mmol). After the reaction mixture had been stirred at -78°C for 30 min, HMPA (50 uL, 0.29 mmol) was added via a syringe. The reaction mixture was stirred for an addi-tional 5 min, and tert-butyldimethylsilyl t r i f l a t e (70 uL, 0.305 mmol) was added via a syringe. After 20 min at -78°C, the reaction mixture was warmed to room temperature and was stirred for an additional 1 h. The reaction mixture was treated with saturated aqueous sodium bicarbo-nate and diluted with water. The resulting mixture was extracted with ether, and the ether extract was washed (water (2X), brine), dried (MgSO^), filte r e d , and concentrated to afford a yellow liquid. Pumping with agitation (35°C/0/l Torr, 30 min) and d i s t i l l a t i o n (air-bath tempe-rature 70-80°C/0.1 Torr) provided a clear colorless liquid (37 mg, 88%). Glc analysis of this material showed i t to consist of a mixture of the divinylcyclopropane (286) together with the starting vinylcyclopropyl ketone (292) and two compounds with lower glc retention times in a ratio of 93.6:2.6:3.8, respectively. This material was chromatographed through triethylamine washed, grade 1, basic alumina (0.4 x 5 cm column, 272 eluting with petroleum ether) to afford, after concentration of the appropriate fractions and d i s t i l l a t i o n , the reasonably pure divinylcyclopropane (286) (32 mg, 76%). Ir (film): 1680, 1650, 1210, 850 cm-1; *H nmr (400 MHz, CDC13) 6: 5.38 (d of q, IH, H , J A T 3 = 11 Hz, J A m = 7 Hz), 4.78 (d of d of q, A —AH — A - o n ^  IH, Eg, J M = 11 Hz, J f i C = 9.5 Hz, J^_m = 1-9 Hz), 2.57-2.50 (m, IH), 2.29-2.20 (m, IH), 1.93-1.80 (m, 2H), 1.74 (d of d, 3H, vinyl methyl, = 7 Hz. J D = 1.9 Hz), 1.76-1.63 (m, 6H), 0.95 (s, 9H, -Si-t-Bu), 0.15 (s, 6H, -Si-Me's). Exact Mass calcd. for C 1 8H 3 0OSi: 290.2067; found: 260.2060. Thermolysis of (286) and the Products Produced General procedure 7 was followed. A solution of the divinyl-cyclopropane (286) (17 mg, 0.058 mmol) in benzene (2 mL) was heated for 4 h at 170-175°C. Concentration afforded a pale yellow liquid (17 mg). Glc analysis of this material showed i t to consist of a mixture of 3 major compounds and 5 minor compounds in a ratio of 40:32:15:13, respectively. This material was chromatographed through triethylamine washed, grade 1, basic alumina (0.4 x 7 cm column, eluting with petroleum ether). Concentration of the appropriate fractions provided, 273 i n order of e l u t i o n , a sample 80% pure i n the 2nd most abundant product , a sample 50% pure i n the 3rd most abundant product , and a sample 94% pure i n the most abundant product (glc a n a l y s i s ) . Each of these samples was contaminated with various proport ions of the other products . Each sample was d i s t i l l e d ( a i r - b a t h temperature 7 0 - 8 0 ° C / 0 . 1 Torr) to a f ford a c l ear c o l o r l e s s l i q u i d . Major product (294). Ir ( f i l m ) : 1650(br), 1590, 1250, 840 c m - 1 ; X H nmr (400 MHz, CDC1 3) 6: 6.73-6.65 (m, 2H, and H £ ) , 5.41 (d of q, 1H» V 4 B = 1 1 H Z ' ^ A - C H 3 = 7 H z ) > 5 , 2 5 ( d 0 f d ° f q ' 1 H « H B ' ^BA = 1 1 Hz, ^ = 9.5 Hz, J f i _ C H 3 - 2 Hz) , 3.07 (d of d of d, 1H, EQ, = 9.5 Hz, J , , _ = 8 Hz, J _ _ = 5.5 Hz) , 2.88-2.76 (m, 1H, H„) 2.49-2.40 (m, 1H), —-Or — -01) r 2.17-2.06 (m, 1H), 1.83-1.70 (m, 2H), 1.60 (d of d, 3H, v i n y l methyl , £ A = 7 Hz, J = 2 Hz) , 1.53-1.47 (m, 2H), 0.94 (s , 9H, - S i - t - B u ) , 1.01 (s , 3H, - S i - M e ) , 1.00 (s , 3H, - S i - M e ) . I r r a d i a t i o n at 6 3.07: m u l t i p l e t at 6 6.73-6.65 s i m p l i f i e d to two d's ( J „ _ = 9.5 Hz) , 6 5.25 s i m p l i f i e d to a d of q (J = 11, 2 Hz) , m u l t i p l e t at 2.88-2.76 s i m p l i f i e d , ms m/e: 290 (M+), 288 (M+-2). Exact Mass c a l c d . for C 1 8 H 3 0 O S i : 290.2067; found 290.2066. Second most abundant product . nmr (400 MHz, CDC1 3) 6: 5.55 (br d , 1H, J = 6 Hz) , 3.05 (br d of d of d , 1H, J = 9.5, 9.5, 5 Hz) , 2.71-2.52 (m, 3H), 2.52-2.43 (m, 1H), 2.38 (d of d of d, 1H, J = 10.5, 10.5, 10.5 Hz) , 1.98 (symmetrical 5 l i n e pa t t ern , 2H, J = 7.5 Hz) , 1.95 (d of d of d of d , 1H, J = 10.5, 10.5, 9 .5 , 2.2 Hz) , 1.89 (br s, 3H), 1.44-1.34 (m, 2H), 0.95 (s , 9H), 0.10 (s , 6H). I r r a d i a t i o n at 6 5.55: 6 3.05 s i m p l i f i e d to a d of d (J = 9.5 , 9.5 Hz) , mul t ip l e t at 6 2.52-2.43 s i m p l i f i e d with removal of a small coupl ing , 6 1.89 sharpened. 274 Irradiation at 6 3.05: 6 5.55 simplified to a br s, multiplet at 6 2.52-2.43 simplified with removal of a small coupling, 6 1.95 simplified to a d of d of d (J = 10.5, 10.5, 2.2 Hz), multiplet at 6 1.44-1.34 simplified with removal of a large coupling (10 Hz). Third most abundant product. *H nmr (400 MHz, CDC13) i d e n t i f i -able signals 6: 5.54 (d of d, 1H, J = 10, 6 Hz), 5.19 (d of d, 1H, J_ = 10, 6 Hz), 4.88 (d, 1H, J = 6 Hz). Synthesis of (±)-Quadrone Cont. Preparation of the Alkene (301) General procedure 4 was followed: To a THF (100 mL) solution of methylenetriphenylphosphorane (14.5 mmol) in a 500 mL-RB-3N flask was added a THF (15 + 10 mL) solution of the crude aldehyde mixture containing both (251) and (268) (3.68 g, 9.7 mmol). General conditions, reaction workup, and d i s t i l l a t i o n (air-bath temperature 115-125°C/0.1 Torr) afforded, by glc analysis, a 95:5 mixture of the alkene (301) and the product resulting from reduction of (268), respectively, as a white solid (3.1 g, 78% from the alcohol mixture of (265) and (266)) (mp 275 64-66°C). Tic analysis ( s i l i c a gel plate, petroleum ether-ether, 10:1) showed only one spot. This material was used without further purifica-tion for the next reaction. Ir (CHCI3): 3060(w), 1630, 1080, 850 cm-1; *H nmr (400 MHz, CDCI3) 6: 5.34 (d of d of d, IH, H c > = 17 Hz, = 10.3 Hz, = 8.8 Hz), 4.96 (d of d, IH, H , = 17 Hz, - 1.9 Hz), 4.81 (d of d, IH, Hg, J f i C = 10.3 Hz, J M - 1.9 Hz), 4.08 (d, IH, Hg, = 5.9 Hz), 4.53-4.38 (m, 4H, acetal methylenes), 2.47 (d of d of d, IH, J_ = 12.6, 7, 7 Hz), 2.22-1.99 (m, 6H), 1.58 (d, IH, J = 12.5 Hz), 1.49-1.43 (m, 2H, Hg and Hp), 1.04 (d of d of d, IH, Hp, JL^ = 8.8 Hz, = = 3.2 Hz), 0.99 (s, 3H, acetal methyl), 0.92 (s, 12H, -Si-tHJu and acetal methyl), 0.11 (s, 3H, -Si-Me), 0.07 (s, 3H, -Si-Me). Irradiation at 6 1.04: 6 5.34 simplified to a d of d (J = 17, 10.3 Hz), multiplet at 1.49-1.43 simplified to an AB pattern ( J ^ = 5 Hz). Exact Mass calcd. for C 2 2H 3 80 3Si: 378.2591; found: 378.2602. Anal, calcd, for C 2 2 H 3 8 0 3 S i : C 69.79, H 10.12; found: C 69.44, H 10.08. Preparation of the Alcohols (302) and (303) 276 General procedure 5 was followed. To a cold (-78°C) THF (60 mL) solution of the s i l y l ether mixture from the previous reaction (3.1 g, 8.2 mmol) in a 250 mL-RB-3N flask was added a THF (20 mL) solution of TBAF (4.0 g, 15.3 mmol). General conditions and reaction workup afforded an oily white solid. This material was flash chromatographed (5 x 20 cm column of s i l i c a gel, eluting with petroleum ether-ether, 1:1) to provide, after concentration and d i s t i l l a t i o n (air-bath tempera-ture 100-110°C/0.1 Torr), the alcohol (302) as a white solid (1.97 g, 91%) (mp 93-94°C) and the alcohol (303) as a clear colorless liquid (86 mg). Compound (302). Ir (CHC13): 3400(br), 3060(w), 1630, 1110 cm-1; XH nmr (400 MHz, CDC1,) 6 : 5.34 (d of d of d, IH, H„, J_. = 17 Hz, J„ 0 C — C A —CD = 10 Hz, =8.8 Hz), 4.96 (d of d, IH, H^ , = 17 Hz, =1.5 Hz), 4.82 (d of d, IH, H , J D„ = 10 Hz, J_. = 1.5 Hz), 4.09 (d of d, IH, 0 —iJC —DA H„, J _ u = 8 Hz, = 7 Hz), 3.52 (s, 2H, acetal methylenes), 3.46 (s, G ~~GH. — G l 2H, acetal methylenes), 2.95 (d, IH, H^ , = 8 Hz), 2.66 (d of d of d, IH, H , J = 9.5, 9, 8 Hz), 2.44-2.36 (m, 2H, Hj and or H^), 2.20 (d of d, IH, Hj, or HL, = 14 Hz, Jj = 9.5 Hz), 1.97 (d of d, IH, or HN, J M N= 14.5, J j = 10 Hz), 1.84 (d of d, IH, R^ or H^ = 14 Hz, J j = 8 Hz), 1.60 and 1.44 (each d of d, IH, Hg and Hp, = 5.8 Hz, = J„ n = 3.2 Hz), 1.01 (s, 3H, acetal methyl), 0.99 (d of d of d, IH, H , —FD D J„„ = 8.8 Hz, J„_ = J__ = 3.2 Hz), 0.92 (s, 3H, acetal methyl). D,0 —DC —Dh —Ur *• added: 6 4.09 simplified to a d ( £ = 7 Hz), 6 2.95 disappeared. Irradiation at 6 2.66: multiplet at 6 2.44-2.36 simplified, 6 2.20 and 6 1.84 each simplified to a d (J = 14 Hz). Exact Mass calcd. for C 1 6H 2i +0 3: 264.1726; found: 264.1721. Anal, calcd. for C 1 6H 2 1 +0 3: C 72.69, 277 H 9.15; found: C 72.91, H 9.10. Compound (303). Ir (film): 3400(br), 3040(w), 3020(w), 1630(w), 1110 cm"1; ln nmr (400 MHz, CDC13) 6: 5.78-5.65 (m, IH, Hg), 5.67 (s, 2H, H^ and H„), 5.07-5.02 (m, 2H, H and H D), 4.67 (d of d, IH, Hu, J U T F t» A o ti —t i l = 11.5, J„ T = 8.5 Hz), 3.53-3.36 (m, 4H, acetal methylenes), 3.05 (d, —HJ IH, Hj, J = 11.5 Hz), 2.51-2.43 (m, IH, H p , 2.41-2.31 (m, 2H, ti^ and ^ or IL^), 2.28 (d of d of d of d, IH, Hp or Hg, = 13.5 Hz, = 6.7 Hz, = Jg = 1.1 Hz), 2.18 (d of d of d of d, IH, Hp or Hg, J^E = 13.5 Hz, J„ = 7.7 Hz, J = J = 1 Hz), 1.96 (d of d, IH, H, , J T = 13.8 Hz, —L —A —D 1) —LK. J^j = 10 Hz), 1.61 (d, IH, ti^ or H^ , = 13.6 Hz), 1.09 (s, 3H, acetal methyl), 0.78 (s, 3H, acetal methyl). Irradiation at 6 5.07-5.02: multiplet at 6 5.78-5.65 simplified to a d of d (J = 7.7, 6.7 Hz), 6 2.28 sharpened to a d of d (J = 13.5, 6.7 Hz), 6 2.18 sharpened to a d of d (J = 13.5, 7.7 Hz). Irradiation at 6 4.67: 6 3.05 simplified to a s, multiplet at 6 2.51-2.43 simplified to a br d (J = 10 Hz). Exact  Mass calcd. for C 1 6H 3 1 +0 3: 264.1726; found: 264.1730. Preparation of the Vinylcyclopropyl Ketone (304) 304 278 General procedure 2 was followed. To a stirring suspension of PCC (2 g, 9.3 mmol), sodium acetate (1 g), and CH2C12 (25 mL) in a 250 mL-RB-3N flask was added a solution of the alcohol (302) (1.5 g, 5.7 mmol) in CH2C12 ( 5 + 3 mL). General conditions, reaction workup, and d i s t i l l a t i o n (air-bath temperature 100-110°C/0.1 Torr) provided the vinylcyclopropyl ketone (304) as a white solid (1.37 g, 92%) (mp 61-62°C) . Ir (CHC13): 3070(w), 1710, 1635, 1110 cm-1; *H nmr (400 MHz, CDC1,) 6: 5.36 (d of d of d, IH, H0, J_. = 17 Hz, J__ = 10.2 Hz, J__ = 0 L —UA —LD —LD 8.5 Hz), 5.12 (d of d, IH, H , J A C = 17 Hz, = 1.3 Hz), 4.97 (d of d, IH, Hg, _J = 10.2 Hz, J M = 1.3 Hz), 3.55-3.28 (m, 4H, acetal methylenes), 2.86 (d of d of d, IH, EQ or E^, J = 10, 7.5, 4 Hz), 2.67 (br d, IH, J_ = 13.2 Hz), 2.44 (br d of d, IH, H Q or H^, J = 10, 7.5 Hz), 2.20 (d of d, IH, J = 13.2, 10 Hz), 1.98-1.94 (m, 2H, Hg and H p), 1.86 (d of d of d, IH, J_ = 13.2, 4, 2 Hz), 1.80 (d of d, IH, J = 13.2, 10 Hz), 1.77 (d of d of d, IH, Hp, = 8.5 Hz, = = 3.2 Hz), 1.10 (s, 3H, acetal methyl), 0.81 (s, 3H, acetal methyl). Irradiation at 6 2.86: 6 2.44 simplified to a br d (J = 10 Hz), 6 2.20 simplified to a d (J = 13.2 Hz), 6 1.86 simplified to a d of d (J = 13.2, 2 Hz). Irradia-tion at 6 2.67: 6 2.44 sharpened to a d of d (J = 10, 7.5 Hz), 6 1.86 simplified to a d of d (J = 13.2, 4 Hz), 6 1.80 simplified to a d (J_ = 10 Hz). Exact Mass calcd. for C 1 6H 2 20 3: 262.1570; found: 262.1571. Anal, calcd. for C 1 6H 2 20 3: C 73.25, H 8.45; found: C 73.20, H 8.43. 279 Preparation of the Divinylcyclopropane (305) - J -S iO 305 To a -78°C THF (10 mL) solution of LDA (3.4 mmol) in a 50 mL-RB-3N flask was added, via a syringe, a THF ( 2 + 1 mL) solution of the vinylcyclopropyl ketone (304) (595 mg, 2.27 mmol). After the reaction mixture had been stirred at -78°C for 25 min, HMPA (690 uL, 3.86 mmol) was added via syringe, and the resulting mixture was stirred for an additional 5 min. Tert-butyldimethylsilyl t r i f l a t e (1.04 mL, 4.54 mmol) was added via a syringe, and after 20 min at -78°C, the reaction mixture was warmed to 0°C for 45 min and then to room temperature for an addi-tional 30 min. The reaction mixture was treated with saturated aqueous sodium bicarbonate and diluted with water. The resulting mixture was extracted with ether, and the ether extract was washed (water (2X), brine), dried (MgSO^), filtered, concentrated, and pumped on with agita-tion (30°C/0.1 Torr, 45 min) to afford the crude divinylcyclopropane (305) as a yellow liquid (845 mg). Since d i s t i l l a t i o n of this material led to significant decomposition and chromatography resulted in substantial hydrolysis, this material was used in the next reaction without further purification. 280 Preparation of the Enol S i l y l Ether (298) General procedure 7 was followed. A solution of the crude divinylcyclopropane (305) (845 mg) in benzene (9 mL) was divided between three pyrolysis tubes, and the tubes were heated for 5 h at 170-175°C. Concentration afforded a dark yellow liquid (845 mg). Glc analysis of this material showed i t to consist of a mixture of (298), 4 minor products, and the vinylcyclopropyl ketone (304) in a ratio of 91:6.3:2.7, respectively. This material was used in the next reaction without further purification. Preparation of the Ketone (306) H, HG 306 To an oven dried, argon flushed 50 mL-RB-3N flask, equipped with 281 an argon inlet, magnetic stirring bar, and septum, was added a solution of the crude enol s i l y l ether (298) from the previous reaction (845 mg) in dry THF (20 mL). This solution was cooled to -78°C, and a solution of TBAF (1 g, 3.8 mmol) in dry THF (2 mL) was added via a syringe. The resulting red reaction mixture was stirred at -78°C for 15 min, after which time, i t was treated with saturated aqueous ammonium chloride and diluted with water. The resulting mixture was extracted with ether, and the ether extract was washed (water, brine), dried (MgSO^), fil t e r e d , and concentrated to afford a yellow liquid. This material was directly flash chromatographed (4 x 18 cm column of s i l i c a gel, eluting with petroleum ether-ether, 6:1) to furnish, after concentration of the appropriate fractions and d i s t i l l a t i o n in two portions (air-bath tempe-rature 90-100°C/0.1 Torr), the pure ketone (306) as a white solid (458 mg, 77% from the vinylcyclopropyl ketone (304)) (mp 85-86°C). Further elution of the column provided some unknown viscous material (~ 50 mg) followed by the starting vinylcyclopropyl ketone (304). Ir (CHC13): 1730, 1620, 1110 cm-1; *H nmr (400 MHz, CDCI3) 6: 6.12 (d of d of d of d, IH, HD, = 9.4 Hz, = 6.5 Hz, = i o B " 2 Hz), 5.50 (d of d of d, IH, EQ, = 9.4 Hz, = = 3.2 Hz), 3.52-3.31 (m, 4H, acetal methylenes), 2.70 (d, IH, or H^ , = 13.7 Hz), 2.68 (br d of d, IH, H , = 6.5 Hz), ^ = 5.8 Hz, = 1.3 Hz), 2.60 (br d of d, IH, H^, J - 10, 9 Hz), 2.55 (d of d, IH, H^ , 3^ = 17.4 Hz, J__ = 5.8 Hz), 2.30 (d of d, IH, HT or H , J T T = 14 Hz, T. = 9 Hz), 2.28 (d of d, IH, H_, J__ = 17.4 Hz, J = 1.3 Hz), 2.28-2.25 (m, 2H, V J - O r —OH HAand H g), 1.77 (d, IH, or HR, = 13.7 Hz) 1.63 (d of d, IH, Hj or H , J = 14 Hz, J = 10 Hz), 1.03 (s, 3H, acetal methyl), 0.86 (s, 3H, 282 acetal methyl). Irradiation at 6 6.12: 6 2.68 simplified to a br d (J = 5.8 Hz), multiplet at 6 2.28-2.25 simplified. Irradiation at the region between 6 2.35-2.25: 6 6.12 simplified to a d of d (J = 9.4, 6.5 Hz), 6 5.50 simplified to a d (J = 9.4 Hz), 6 2.60 simplified to a br d (J_ = 10 Hz), 6 2.55 simplified to a d (J = 5.8 Hz), 6 1.63 simplified to a d (J = 14 Hz). Exact Mass calcd. for C 1 6H 2 20 3: 262.1570; found: 262.1564. Anal, calcd. for C 1 6H 2 20 3: C 73.25, H 8.45; found: C 73.17, H 8.35. Methylation of the Ketone (306). Production of (307), (308) and (309) To a -78°C THF (8 mL) solution of LDA (2.46 mmol) in a 50 mL-RB-3N flask, was added, via a syringe, a THF ( 2 + 1 mL) solution of the ketone (306) (430 mg, 1.64 mmol). The reaction mixture was stirred at -78°C for 15 min and was then warmed to 0°C for an additional 15 min. After this time, methyl iodide (~ 0.4 mL) was introduced through grade 1 basic alumina contained in a Pasteur pipette pushed through the septum of the reaction flask. The reaction mixture was stirred at 0°C for 1 h and at room temperature for 30 min, after which time, i t was poured into water, and the resulting mixture was extracted with ether. 307 308 309 283 The ether layer was washed (water (3X), brine), dried, filtered and concentrated to afford a pale yellow liquid. This material was run through a 2 x 4 cm plug of F l o r i s i l (flushing with petroleum ether-ether, 2:1) to provide, after concentration and pumping with agitation (30°C/0.1 Torr, 15 min), a clear colorless liquid which was used without further purification for the next methylation. Glc analysis of this material showed i t to consist of a mixture of the monomethylated ketone (307) and the starting ketone (306) in a ratio of 95:5, respectively. A procedure identical to that just described was applied to the above mixture to afford, by glc analysis, the dimethylated ketone (308), the monomethylated ketone (307) and the methyl enol ether (309) in a ratio of 80:16:4, respectively. The crude yellow product was flash chromato-graphed (4 x 19 cm column of s i l i c a gel, eluting with petroleum ether-ether, 10:1) to produce, after concentration of the appropriate fractions and d i s t i l l a t i o n (air-bath temperature 95-105°C/0.1 Torr), (308) as a white solid (338 mg, 71%) (mp 47-49°C), (307) as a white solid (63 mg) (mp 49-51°C), and (309) as a clear, colorless, viscous liquid (14 mg). Compound (308). Ir (CHC1 3): 1730, 1620(w), 1120 cm - 1; XH nmr (400 MHz, CDCI3) 6: 6.08 (d of d of d of d, IH, Hp, = 9.4 Hz, J^, = 7 Hz, JJJA » JOB " 2 Hz), 5.52 (d of d of d, IH, RQ, = 9.4 Hz, = J„ D = 3.2 Hz), 3.52-3.32 (m, 4H, acetal methylenes), 2.65 (d, IH, H or H , Jj. = 13.8 Hz), 2.60 (d of d, IH, H^,, J = 11, 9 Hz), 2.48 (d, IH, H £ = 7 Hz), 2.28 (d of d, IH, H^ or H^ , = 14 Hz, J^, = 9 Hz), 2.25-2.21 (m, 2H, H A and Hg), 1.91 (d of d, IH, EQ or H^ , = 14 Hz, J p= 11 Hz), 1.82 (d, IH, H or H t J = 13.8 Hz), 1.24, 1.10, 1.00, 0.89 (each 284 s, 3H, methyl). Exact Mass calcd. for C 1 8H 2 60 3: 290.1883; found: 290.1877. Anal, calcd. for C 1 8H 2 60 3: C 74.45, H 9.02; found: C 74.35, H 9.10. Compound (307). Ir (CHC13): 1730, 1620(w), 1110 cm - 1; lU nmr (400 MHz, CDC13) 6: 6.00 (d of d of d of d, IH, Hp, = 10.4, J ^ = 6.3 Hz, = = 2.1 Hz), 5.54 (d of d of d, IH, Hc, = 10.4 Hz, JQk = J f i A = 3.2 Hz), 3.51-3.28 (m, 4H, acetal methylenes), 2.75 (d, IH, Hj. or H J ( JJJ = 13.7 Hz), 2.72 (d of q, IH, 1^, = 5.7 Hz, = 7 Hz), 2.62 (br d of d, IH, HLg, 'J^ = 6.3 Hz, £ E R = 5.7 Hz), 2.58 (br d of d, IH, Hp, J = 10, 8.8 Hz), 2.26 (d of d, IH, H Q or H^, J ^ = 14.5 Hz, Jp = 10 Hz), 2.23-2.20 (m, 2H, H^ and Hg), 1.83 (d of d, IH, H Q or HH» icH = 1 4 , 5 H z» i f = 8 , 8 1 , 7 0 ( d» 1 H ' H I o r H J ' - I J = 1 3 , 7 1.06 (d, 3H, methyl, J__ = 7 Hz), 1.03 (s, 3H, acetal methyl), 0.83 (s, 3H, acetal methyl. Irradiation at 6 6.00: 6 2.62 simplified to a d (J = 5.7 Hz), multiplet at 6 2.23-2.20 simplified. Exact Mass calcd. for C 1 7 H 2 H ° 3 : 276.1726; found: 276.1726. Anal, calcd. for C 1 ?H 2 40 3: C 73.88, H 8.75; found: C 73.90, H 8.75. Compound (309). Ir (film): 1660, 1120 cm-1; *H nmr (400 MHz, CDC13) 6: 6.38 (d of d of d of d, IH, Hp, Jp C = 9.5 Hz, Jp E - 6.2 Hz, J ^ = J^g = 2.2 Hz), 5.41 (d of d of d, IH, H c > J^p = 9.5 Hz, = J ^ = 3.3 Hz), 3.70 (s, 3H, -OCH3), 3.55-3.41 (m, 4H, acetal methylenes), 2.55 (d, IH, Hj or Hj, J = 14 Hz), 2.34-2.16 (m, 4H), 2.01 (d of d of d, H^ or Hg, J ^ = 17.8 Hz, 3^ = 3.3 Hz, Jp = 2.2 Hz), 1.80 (d of d, IH, J = 15.5, 13 Hz), 1.76 (s, 3H, vinyl methyl), 1.61 (d, IH, ^  or RJt J_TJ = 14 Hz), 0.98 (s, 3H, acetal methyl), 0.93 (s, 3H, acetal methyl). Exact  Mass calcd. for C 1 8H 2 60 3: 290.1883; found: 290.1881. 285 Preparation of the Alcohols (310) and (311), and the Compounds (316) and (317) .0 OH 311 316 317 Reaction 1; To an oven dried argon flushed 25 mL-RB-3N flask, equipped with an argon inlet, magnetic stirring bar, and septum, was added LAH (10 mg, 0.263 mmol) and dry ether (6 mL). To this stirring suspension at room temperature was added, via a syringe, a solution of the ketone (308) (75 mg, 0.258 mmol) in dry ether (1.5 + 1 mL). After 30 min, the reaction mixture was treated cautiously with NajSO^'lOHjO, and the resulting slurry was filtered through F l o r i s i l (3 x 4 cm column, flushing with ether). Concentration and d i s t i l l a t i o n (air-bath tempera-ture 110-120°C/0.1 Torr) afforded a clear, colorless, highly viscous, 286 liquid (72 mg, 95%). Glc analysis of this material showed i t to consist of a mixture of the alcohols (310) and (311) in a ratio of 3:1, respec-tively. The two epimers were separated by flash chromatography (3 x 15 cm column of s i l i c a gel, eluting with petroleum ether-ether, 1.5:1) to provide, after concentration of the appropriate fractions and d i s t i l l a -tion, the alcohol (310) as a white solid (46 mg) (mp 86-87°C) and the alcohol (310) as a white solid (23 mg) (mp 109-110°C). Preparation of Lithium Diisobutyl-n-butylaluminum Hydride: To a dry, cold (-78°C), 10 mL-RB flask, equipped with a magnetic stirring bar, septum, and argon needle, was added, via a syringe, a solution of diisobutylaluminum hydride (2 mL, 1 M solution in hexanes, 2 mmol), and slowly afterwards, via a syringe, a solution of n-butyllithium (1.35 mL, 1.48 M solution in hexanes). After 15 min at -78°C, the reaction mixture was warmed to 0°C, and dry ether (2 mL) was added. This solution was stored at 0°C until use. Reaction 2: To an oven dried, argon flushed 50 mL-RB-3N flask, equipped with an argon inlet, magnetic stirring bar, and septum, was added the ketone (308) (136 mg, 0.468 mmol) and dry ether (8 mL). This solution was cooled to -78°C, and a solution of lithium diisobutyl-n-butylaluminum hydride prepared previously (2.3 mL, 0.344 M, 0.791 mmol) was added via a syringe. The reaction mixture was warmed to 0°C and was stirred for 2 h before being treated with Na 2SO 1 +»10H 2O. Aqueous 10% sodium hydroxide (0.7 mL) was added, and the white sluirry was stirred for 15 min. Anhydrous magnesium sulfate was added and the resulting mixture was filtered through Florosil (3 x 5 cm column, rinsing with ether). Concentration and d i s t i l l a t i o n (air-bath temperature 110-287 120°C/0.1 Torr) afforded, by glc analysis, the epimerically pure alcohol (310) (135 mg, 99%). This material was unstable in CDC13, and, by glc analysis, decomposed to varying mixtures of (316), (317), (310) and 2,2-dimethyl-l,3-propanediol. These compounds could be separated by flash chromatography, using f i r s t , petroleum ether-ether, 2:1 to elute the alcohol (316) (clear, colorless, viscous liquid) and the alcohol (310), and using second, petroleum ether-ether, 1:1 to elute the keto alcohol (317) (white solid, mp 123-124°C). Compound (311). Ir (CHC1 3): 3600, 3450(br), 1630(w), 1120 cm-1; XH nmr (400 MHz, CDCI3) 6: 5.92 (d of d of d of d, IH, Hp, Jp E = 9.4 Hz, Jp E = 7 Hz, Jp A = * 2 Hz), 5.47 (d of d of d, IH, Hg, = 9.4 Hz, j * j = 3.2 Hz), 3.97 (s, IH, H_), 3.52-3.43 (m, 4H, acetal —CA —CB r methylenes), 2.63 (d of d of d, IH, H^ or Hg, = 18 Hz, = 3.2 Hz, Jg - 2 Hz), 2.40 (d, IH, R^ or H]., = 14 Hz), 2.36-2.29 (m, 2H), 2.13-2.07 (m, 2H), 1.97 (br d, IH, H. or H , J = 18 Hz), 1.79 (d, IH, A 0 —Ac H^ or H , JJJ = 14 Hz), 1.53-1.39 (br s, IH, RQ), 1.25, 0.99, 0.96, 0.94 (each s, 3H, methyl). D20 added: 6 1.53-1.39 disappeared. Exact Mass calcd. for C 1 8H 2 80 3: 292.2039; found: 292.2039. Compound (310). Ir (CHCI3): 3400(br), 1630(w), 1120 cm-1; lR nmr (400 MHz, C 6D 6) 6: 5.90 (d of d of d of d, IH, Hp, Jp C = 9.7 Hz, Jp E - 7 H Z > ^ D A = 4 B = 2 , 1 H Z ) ' 5 , 3 3 ( D ° F D ° F D ' 1 H * H C ^CD = 9 , 7 H Z » ^CA = = 3.3 Hz), 3.57 (d, IH, H p or RQ, = 12 Hz), 3.26 (d, 2H, acetal methylenes, J = 11.5 Hz), 3.24 (d, IH, Hp or H , J_pG = 12 Hz), 3.17 (d, 2H, acetal methylenes, J_ = 11.5 Hz), 2.85 (d, IH, H^ or H^., = 14 Hz), 2.35 (d of d, IH, RJ} J = 11, 9 Hz), 2.23 (d of d, IH, H^ or H^ , J = 14.7 Hz, J = 9 Hz)), 2.12-2.09 (m, 2H, H and H ), 2.09 (d of d, 288 IH, tL^  or t^, = 14.7 Hz, J j = 11 Hz), 1.98 (d, IH, Hg, = 7 Hz), 1.73 (d, IH, ^  or H]., = 14 Hz), 1.25, 1.20, 0.76, 0.69 (each s, 3H, methyl). Exact Mass calcd. for C 1 8H 2 80 3: 292.2039; found: 292.2039. Anal, calcd. for C 1 8H 2 80 3: C 73.93, H 9.65; found: C 74.10, H 9.70. Compound (316). Ir (film): 3450(br), 1630(w), 1310, 1020 cm-1; XH nmr (400 MHz, CgD6) 6: 5.76 (m, IH, Hp), 5.28 (d of d of d, IH, Hg, JgP = 9.4 Hz, = Jgg = 3.3 Hz), 3.64 (d, IH, -OCH^ -, J = 9.7 Hz), 3.62 (br d of d, IH, HOCH^ -, J = 12 Hz, Jg = 6.5 Hz), 3.49 (d of d, IH, HOCH^ -, J = 12 Hz, Jg = 8 Hz), 3.40 (d, IH, -OCH^ -, J = 9.7 Hz), 3.28 (br s, IH, Hg, W^- = 4.5 Hz) 3.10 (br d of d, IH, HQ, J = 8, 6.5 Hz), 2.23 (br d, IH, H^ or Hg, = 18.5 Hz), 1.97 (d of d of d, IH, J_ = 12.5, 2.5, 2.5 Hz), 1.94-1.88 (m, 2H), 1.80 (br d, IH, H^ or Hg, = 18.5 Hz), 1.76-1.69 (m, 2H), 1.24 (d, IH, J_ = 9.5 Hz), 1.20, 0.94, 0.91, 0.81 (each s, 3H, methyl). Exact Mass calcd. for C 1 8H 2 80 3: 292.2039; found: 292.2033. Compound (317). Ir (CHC13): 3620, 3450(br), 1730, 1635(w), 1055 cm-1; lR nmr (400 MHz, CDC13) 6: 6.00 (d of d of d of d, IH, Hp, J^g = 9.4 Hz, Jgg = 7.4 Hz, = = 2.4 Hz), 5.49 (d of d of d, IH, Hg, Jg D = 9.4 Hz, = Jgg = 3.4 Hz), 3.57 (s, IH, H p), 3.73 (d, IH, J = 17 Hz), 2.60 (d of d, IH, J = 17.5, 11.5 Hz), 2.51-2.42 (m, 2H), 2.38-2.26 (m, 3H), 1.99 (d, IH, _J = 17 Hz), 1.20 (s, 3H, methyl) 1.16 (s, 3H, methyl). Exact Mass calcd. for C 1 3H 1 80 2: 206.1307; found: 206.1314. 289 Preparation of the Phosphorodiamidate (312) 312 To an oven dried, argon flushed 25 mL-RB-3N flask, equipped with an argon inlet, magnetic stirring bar and septum, was added the alcohol (310) (72 mg, 0.246 mmol) and dry THF (5 mL). This solution was cooled to 0°C, and a solution of n-butyllithium (250 uL, 1.48 M solution in hexanes, 0.369 mmol) was added via a syringe. After 30 min at 0°C, HMPA (300 uL) and 90% bis(dimethylamino)phosphorochloridate (83 uL, 0.504 mmol), were added, successively, via syringes. After 1 h at 0°C, the reaction mixture was poured into water, and the resulting mixture was extracted with ether. The ether extract was washed (water (2X), brine), dried (MgSO^), filtered, concentrated, and pumped on with agitation (room temperature/0.1 Torr, 30 min) to provide the phosphorodiamidate (312) as a clear, colorless, viscous liquid (105 mg). Ir (film): 1300, 1120, 1000 cm - 1. Exact Mass calcd. for C 2 2H 3 9N 20 4P: 426.2647; found: 426.2643. 290 Preparation of the Alkene (314) and the Saturated Compound (315) 314 315 To an argon flushed 25 mL-RB-3N flask, equipped with a gas inlet, dry ice condenser with argon inlet, glass coated stirring bar, and septum, was added lithium metal (9 mg, 1.3 mmol). This apparatus was flame dried under a flow of argon, and upon cooling, a l l the joints were well wrapped with Parafilm. The apparatus (condenser and flask) was cooled to -78°C, and anhydrous methylamine (3-4 mL) was introduced through the gas inlet from a lecture bottle. The -78°C cooling bath on the flask was removed, and after the reaction mixture had turned dark blue (3-7 min), the cooling bath was replaced, and a solution of the phosphorodiamidate (312) (103 mg) in dry THF (0.3 + 0.2 mL) was added via a syringe. The reaction mixture was warmed to -20°C for 10 min, after which time, i t was carefully treated with saturated aqueous ammonium chloride and diluted with ether. The resulting mixture was poured into water, and the ether layer was washed (water (2X), brine), dried (MgS04), filte r e d , concentrated, and d i s t i l l e d (air-bath tempera-ture 80-90°C/0.1 Torr) to afford a clear colorless liquid (60 mg, 88%). Glc analysis of this material showed i t to consist of a mixture of the 291 alkene (314) and saturated compound (315) in a 9:1 ratio, respectively. Tic analysis or this material ( s i l i c a gel plate, petroleum ether-ether, 10:1) showed only one spot. This material was used for the next reaction without further purification. Compound (314) (90% pure). Ir (film): 1630(w), 1120 cm-1; AH nmr (400 MHz, CDC13) 6: 5.92 (d of d of d of d, IH, Hp, = 9.4 Hz, J_ D E = 7.2 Hz, .T = j = 2.1 Hz), 5.46 (d of d of d, IH, H„, J__ = 9.4 Hz, — U A —UD —\JU J/^* = JrM> = 3 « 2 H z)» 3.51-3.42 (m, 4H, acetal methylenes), 2.32-2.07 (m, —CA —Co 7H), 1.85 (d of d, IH, J = 13.5, 2 Hz), 1.77 (d, IH, J = 13.5 Hz), 1.48 (d, IH, J = 13.5 Hz), 1.22, 1.04 (each s, 3H, methyl), 0.96 (s, 6H, 2 methyls). Exact Mass calcd. for C 1 8H 2 80 2: 276.2090; found: 276.2090. Compound (315) (isolated in pure form after the next reaction). Ir (film): 1120 cm-1; *H nmr (400 MHz, CDCI3) 6: 3.51-3.42 (m, 4H, acetal methylenes), 2.26-2.14 (m, 2H), 2.06 (d, IH, J = 13.5 Hz), 1.85-1.64 (m, 6H), 1.58-1.34 (m, 5H), 1.21 (s, 3H, methyl), 1.10 (s, 3H, methyl), 0.96 (s, 6H, 2 methyls). Exact Mass calcd. for C l gH 3 0O 2: 278.2247; found: 278.2248. Preparation of the Epoxide (318) 318 292 To a 50 mL-RB flask, equipped with a magnetic stirring bar, was added a 9:1 mixture of the alkene (314) and the saturated compound (315) (210 mg, 0.684 mmol in alkene), CH2C12 (15 mL), and aqueous 0.5 M sodium bicarbonate (4.4 mL). This rapidly stirring mixture was cooled to 0°C, and m-chloroperoxybenzoic acid (650 mg, ~ 3 mmol) was added. After having been stirred at 0°C for 2 h, the reaction mixture was poured into water and the resulting mixture was extracted with ether. The ether extract was washed (aqueous 1 M sodium bi s u l f i t e , saturated aqueous sodium bicarbonate, water, brine), dried (MgS01+), fi l t e r e d , concen-trated, and pumped on to afford a clear colorless liquid which would slowly partially solidify (209 mg). Glc analysis of this material showed i t to consist of a mixture of the isomerically pure epoxide (318) and the saturated compound (315) in a 9:1 ratio, respectively. This material was used for the next reaction without further purification. For characterization purposes, the crude product was flash chromato-graphed (elution with petroleum ether-ether, 3:1 to provide, after concentration of the appropriate fractions, the saturated compound (315) as a clear colorless liquid and the epoxide (318) as a white solid (mp 85-86°C). Some epoxide loss on chromatography was observed. Compound (318). Ir (CHC13): 1120, 1110 cm-1; XH nmr (400 MHz, CDC13) 6: 3.48-3.38 (m, 4H, acetal methylenes), 3.24 (d of d, IH, Hp, 4 c = ^DE = 4 H Z ) ' 3 , 0 3 ( d ° f d ' 1 H ' H C icD = ^CB = 4 H Z ) » 2 , 5 2 ( d ° f d, IH, J = 12.5, 8.5 Hz), 2.20 (d of d, IH, J_ = 13.5, 8.5 Hz), 2.15 (d, IH, Hg, J^p = 4 Hz), 2.09 (d, IH, J_ = 14 Hz), 2.07 (d, IH, J_ = 13 Hz), 2.01-1.89 (m, 3H, H^ and Hg) 1.64 (d, IH, J = 14 Hz), 1.47 (d, IH, J = 13 Hz), 1.27, 1.19, 0.96, 0.93 (each s, 3H, methyl). Irradiation at 6 293 3.03: 6 3.43 simplified to a d (J = 4 Hz), multiplet at 6 2.01-1.89 simplified. Exact Mass calcd. for C 1 8H 2 80 3: 292.2039; found: 292.2049. Anal, calcd. for C 1 8H 2 80 3: C 73.93, H 9.65; found: C 73.73, H 9.51. Preparation of the A l l y l i c Alcohol (319) An oven dried, argon flushed 25 mL-RB flask-condenser apparatus, equipped with a magnetic stirring bar, septum, and argon needle, was cooled to -78°C, and diethyl amine (300 uL, 2.90 mmol) and dry benzene (6 mL) were added via syringes. Upon warming to 0°C, a solution of n-butyllithium (1.87 mL, 1.55 M solution in hexanes, 2.90 mmol) was added via a syringe, and the reaction mixture was stirred at 0°C for 20 min. The epoxide-saturated compound mixture from the previous reaction (209 mg) was added, via a syringe, as a solution in benzene ( 2 + 1 mL), and the resulting reaction mixture was gently refluxed for 2 h. After cooling, the yellow reaction mixture was treated with water, and the resulting mixture was extracted with ether. The ether extract was washed (water, brine), dried (MgS04), fi l t e r e d , and concentrated to afford a yellow liquid. This material was flash chromatographed (3 x 19 cm column of s i l i c a gel, eluting with petroleum ether-ether, 1:1) to 319 294 produce, after concentration of the appropriate fractions and d i s t i l l a t i o n , the saturated compound (315) (19 mg) and the a l l y l i c alcohol (319) as a clear colorless gum (148 mg, 74% from alkene (314)) (air-bath d i s t i l l a t i o n temperature 115-125°C/0.1 Torr). Compound (319). Ir (film): 3350(br), 1630(w), 1120, 1105, 1050 cm-1; XH nmr (400 MHz, CDC1,) 6: 6.15 (d, IH, H. , J t T, = 9 Hz), 5.54 (d 0 A —AB of d of d, IH, Hn, J_. = 9 Hz, J D„ = 4.2 Hz, J D r i = 1.5 Hz), 4.24-4.17 B —BA —BL. —BJJ (m, IH, H ), 4.52-4.42 (m, 4H, acetal methylenes), 2.33 (d of d, IH, J = 12, 7 Hz), 2.28 (d of d, IH, J_ = 12, 7 Hz), 2.14 (d, IH, J_ = 13.5 Hz), 2.08 (br s, IH, Hp), 2.00 (d of d, IH, J_ = 12, 12 Hz), 1.87 (d, IH, J = 13.5 Hz), 1.75 (d, IH, J = 13 Hz), 1.51 (d, IH, J = 13 Hz), 1.24, 1.03, 0.99, 0.96 (each s, 3H, methyl). Irradiation at 6 5.54: 6 6.15 siomplified to a s, multiplet at 6 4.24-4.17 simplified, 6 2.08 simplified to a d (J^Q = 2.8 Hz). Exact Mass calcd. for C 1 8H 2 80 3: 292.2039; found: 292.2037. Anal, calcd. for C 1 8H 2 80 3: C 73.93, H 9.65; found: C 72.96, H 9.75. Preparation of the A l l y l i c Vinyl Ether (299) 295 To a 25 mL-RB flask-condenser apparatus, equipped with a magnetic stirring bar, was added the a l l y l i c alcohol (319) (31 mg, 0.106 mmol) in dry ether. The ether was evaporated under a stream of argon, mercury(II) acetate (60 mg, 0.19 mmol) was added, a septum was attached, and the apparatus was evacuated and flushed with argon (2X). Sodium dried ethyl vinyl ether (4 mL) was added via a syringe, and the reaction mixture was refluxed for a total of 24 h. After 2, 4, 7 and 13.5 h of reflux, respectively, an additional portion of mercury(II) acetate (60 mg) in ethyl vinyl ether (0.7 mL) was added. After 24 h, the yellow reaction mixture was poured into aqueous 5% sodium hydroxide (50 mL), resulting in precipitation of yellow mercury(II) oxide. This mixture was extracted with ether (2X), and the combined ether extracts were washed (water, brine), dried, fil t e r e d , and concentrated to afford a yellow liquid. Chromatography through triethylamine washed, grade 1, basic alumina (0.4 x 6 cm column, eluting with petroleum ether-ether, 10:1) provided, after concentration of the eluent and d i s t i l l a t i o n (air-bath temperature, 120-130°C/0.1 Torr), the pure a l l y l i c vinyl ether (299) as a clear, colorless, viscous liquid (29 mg, 86%). Ir (film): 3020(w), 1630, 1610, 1190, 1120, 1105 cm"1; XH nmr (400 MHz, CDC13) 6: 6.34 (d of d, IH, , = 14 Hz, ^ = 6.6 Hz), 6.22 (d, IH, HA, = 9.2 Hz), 5.54 (d of d of d, IH, Hg, J R A = 9.2 Hz, J_ B C = 4 Hz, J D n = 1.4 Hz), 4.31-4.24 (m, 2H, H_ and H u), 3.99 (d of d, IH, — DU 0 tl H„, J__ = 6.6 Hz, J _ = 1.6 Hz), 3.49-3.41 (m, 4H, acetal methylenes), G —•GE —•GF it Mercury(II) acetate was recrystallized from ethanol. A hot f i l t r a -tion was required. The resulting white flakes were pumped on (0.1 Torr) for 1 day. 296 2.44 (d of d, IH, J = 13, 7.5 Hz), 2.31 (d of d, IH, J = 13, 7.5 Hz), 2.19 (br s, IH, H^ , w|- = 5.7 Hz), 2.14 (d, IH, J = 13.5 Hz), 1.97 (d of d, IH, J = 13, 13 Hz), 1.87 (d, IH, J = 13.5 Hz) 1.78 (d, IH, J = 13 Hz), 1.52 (d, IH, J = 13 Hz), 1.24, 1.04, 0.98, 0.93 (each s, 3H, methyl). Exact Mass calcd. for C 2 0H 3 0O 3: 318.2196; found: 318.2196. Anal, calcd. for C 2 0H 3 0O 3: C 75.43, H 9.49; found: C 75.53, H 9.60. Preparation of the Unsaturated Aldehyde (300) 300 General procedure 7 was followed. A solution of the a l l y l i c vinyl ether (299) (28 mg, 0.088 mmol) and N,N-diisopropylethylamine (15 uL) in benzene (2 mL) was heated for 4.5 h at 235-240°C. Concentration afforded a clear colorless liquid liquid. Chromatography (0.4 x 5 cm column of s i l i c a gel, eluting f i r s t with petroleum ether-ether, 10:1, and eluting second with petroleum ether-ether, 5:1) afforded, after con-centration of the appropriate fractions and pumping (room temperature/ 0.1 Torr, lh), the unsaturated aldehyde (300) as a white solid (25.5 mg, 91%) (mp 47-48°C). This material could be d i s t i l l e d without significant loss using a grease sealed d i s t i l l a t i o n apparatus and a preheated 297 oven (air-bath temperature 140°C/0.1 Torr). Ir (CHCI3): 2700, 1725, 1120 cm-1; JH nmr (400 MHz, CDCI3) 6: 9.81 (d of d, IH, HA, J = 1.8, 1.5 Hz), 5.96 (d of d of d, IH, Hp, = 9.5 Hz, Jp G - 7.1 Hz, J p D = 1.8 Hz), 5.34 (d of d, IH, Rg, = 9.5 Hz, J„^ = 3.3 Hz), 3.51-3.39 (m, 4H, acetal methylenes), 2.78-2.71 (m, IH, Hp), 2.67 (d of d of d, IH, Hg or Hc, £ B C = 17 Hz, = 7.2 Hz, ^ = 1.5 Hz), 2.33 (d of d of d, IH, 1L or H„, J = 17 Hz, J_ = 5.7 Hz, J. = 1.8 B C —*BC — 0 -A Hz), 2.22-2.13 (m, 3H), 2.10 (d, IH, H_, J_, = 7.1 Hz), 1.98 (d, IH, J = 13.8 Hz), 1.91 (d, IH, J = 14 Hz), 1.81 (d, IH, J = 14 Hz), 1.62 (d, IH, J_ = 13.8 Hz), 1.24, 1.04, 0.96, 0.95 (each s, IH, methyl). Irradiation at 6 9.81: 6 2.67 simplified to a d of d (J = 17, 7.2 Hz), 6 2.33 simplified to a d of d (J = 17, 5.7 Hz). Irradiation at 6 5.96: multi-plet at 6 2.78-2.71 simplified, 6 2.10 simplified to a s. Exact Mass calcd. for C 2 0H 3 0O 3: 318.2196; found: 318.2192. Anal, calcd. for C 2 0H 3 0O 3: C 75.43, H 9,49; found: C 75.16, H 9.29. Preparation of the Saturated Aldehyde (320) 320 To a 20 mL-RB-2N flask, equipped with a septum and magnetic stirring bar, was added 10% Pd on C (~ 1.5 mg) and hexane (0.5 mL). 298 This flask was attached to a hydrogen line, and the mixture was stirred under 1 atm of H 2 for 10 min, after which time, a solution of the unsaturated aldehyde (300) (18 mg, 0.056 mmol) in hexane (0.5 + 0.5 mL) was added via a syringe. After being vigorously stirred for 7 h at room temperature, the reaction mixture was filtered and concentrated. The crude product was run through a 0.4 x 1 cm plug of s i l i c a gel, flushing with petroleum ether-ether, 1:1. Concentration and pumping with agita-tion (30°C/0.1 Torr, 45 min) afforded the saturated aldehyde (320) as a clear, colorless, viscous liquid (18 mg, > 99%). Ir (film): 2700, 1725, 1120 cm-1; *H nmr (400 MHz, CDC13) 6: 9.77 (d of d, IH, H , _J = 2.7, 1 Hz), 3.50-3.49 (m, 4H, acetal methylenes), 2.58 (br d, IH, Hg or Hg, J^Q = 17 Hz), 2.41 (d of d of d, IH, Hg or Hg, J = 17 Hz, :L = 9.5 Hz, J. 2.7 Hz) 2.27-2.18 (m, 2H), 2.12 (d of d, —BC —D —A IH, J - 12.5, 12.5 Hz), 2.02-1.73 (m, 6H), 1.68-1.59 (m, IH), 1.46-1.35 (m, IH), 1.23, 1.10, 0.98, 0.94 (each s, 3H, methyl). Irradiation at 6 9.77: 6 2.58 simplified, 6 2.41 simplified to a d of d (J = 17, 9.5 Hz). Exact Mass calcd. for C 2 0H 3 2O 3: 320.2353; found: 320.2352. Preparation of the Keto Aldehyde (230) 299 To a 10 mL-RB flask, equipped with a magnetic stirring bar, was added the saturated aldehyde (320) (18 mg, 0.56 mmol) and acetone (2 mL). To this stirring solution at room temperature was added 1 drop of aqueous 1 M HC1. After 2 h, the reaction mixture was poured into water and the resulting mixture was extracted with ether (2X). The combined ether extracts were washed (water, brine), dried (MgSO^), fil t e r e d , and concentrated to afford a white solid. This material was chromatographed (0.4 x 6 cm column of s i l i c a gel, eluting f i r s t with petroleum ether-ether, 2:1, and eluting second with petroleum ether-ether, 1:1) to provide, after concentration of the appropriate fractions, the keto aldehyde (230) as a white solid (12 mg, 91%). An analytical sample was obtained by recrystallization from heptane (evacuated sealed tube mp 78°C) ( l i t . 1 0 1 mp 78°C). Ir (CHC13): 2710, 1720, 1450, 1410 cm-1; 2H nmr (400 MHz, CDCI3) 6: 9.77 (d of d, IH, -CHO, J = 2.4, 1.3 Hz), 2.61-2.37 (m, 4H), 2.32-2.14 (m, 4H), 1.90-1.82 (m, 2H), 1.78-1.70 (m, IH), 1.66-1.49 (m, 3H), 1.36 (d of d, IH, J = 15, 6 Hz), 1.19 (s, 3H, methyl), 1.17 (s, 3H, methyl). Exact Mass calcd. for C 1 5H 2 20 2: 234.1621; found: 234.1625. Anal, calcd. for C 1 5H 2 20 2: 76.88, H 9.46; found: C 76.88, H 9.60. 300 Compounds Associated with the Vinylmethylenecyclopropane Rearrangement Study Preparation of the A l l y l i c S i l y l Ether (329) 329 To an oven dried, argon flushed 500 mL-RB-3N flask, equipped with an argon inlet and magnetic stirring bar, was added 2-cyclohexen-l-ol (8.7 g, 88.6 mmol) and dry DMF (100 mL). Imidazole (13.2 g, 194 mmol) and tert-butyldimethylsilyl chloride (16 g, 106 mmol) were added in one portion successively, and the reaction mixture was stirred at room temperature for 3.5 h. After this time, the reaction mixture was treated with saturated aqueous sodium bicarbonate (20 mL) and poured into water (700 mL). The resulting mixture was extracted with ether (3X), and the combined ether extracts were washed (water (3X), brine), dried (MgSO^), filte r e d , and concentrated to afford a clear colorless liquid. This material was divided into 2 portions, and each portion was pumped on with agitation (30°C/15 Torr, 30 min) and d i s t i l l e d (air-bath temperature 80-90°C/15 Torr) disgarding approximately the f i r s t 0.8 g of d i s t i l l a t e . The a l l y l i c s i l y l ether (329) was isolated as a clear colorless liquid (16.4 g, 88% yield). Ir (film): 3020, 1255, 1090 cm - 1; lU nmr (400 MHz, CDC13) 6: 5.78 - 5.72 (m, IH), 5.66 - 5.60 (m, IH), 4.26 - 4.20 (m, IH), 2.10 - 1.72 (m, 4H), 1.62 - 1.50 (m, 2H), 0.91 (s, 9H, -Si-t-Bu), 0.08 (s, 3H, -Si-Me), 0.07 (s, 3H, 301 -Si-Me). Exact Mass calcd. for C 1 2H 2 1 +0Si: 212.1597; found: 212.1591. Preparation of the Cyclopropyl Ester Mixture (330) General procedure 1 was followed. Ethyl diazoacetate (11 mL, 105 mmol) was added over a period of 15 h to the a l l y l i c s i l y l ether (329) (14.35 g, 67.5 mmol) containing rhodium(II) acetate (~ 30 mg). The crude yellow reaction product was flash chromatographed in 2 portions (5 x 18 cm column of s i l i c a gel, eluting f i r s t with petroleum ether, and eluting second with petroleum ether-ether, 20:1) to afford the recovered a l l y l i c s i l y l ether (329) (10.6 g, after d i s t i l l a t i o n ) and after d i s t i l l a t i o n (air-bath temperature 95-105°C/0.1 Torr), the cyclopropyl ester mixture (330) as a clear colorless liquid (4.55 g, 86% based on unrecovered starting material). Glc analysis of this material showed i t to consist of a mixture of 4 isomers in a ratio of 41:38:16:5. Ir (film): 1725, 1180, 1090, 840 cm - 1. Exact Mass calcd. for C 1 6H 3 0O 3Si: 298.1965; found: 298.1960. Preparation of the Alcohol Mixture (331) -j-SiO 330 —|- SiO HOCH 331 302 To an oven dried, argon flushed 500 mL-RB-3N flask, equipped with an argon inlet, magnetic stirring bar, and septum, was added LAH (0.7 g, 18.4 mmol) and anhydrous ether (150 mL). To this stirring suspension at room temperature was added, over a period of 30 min via a syringe, an ether (30 + 20 mL) solution of the cyclopropyl ester mixture (330) (4.16 g, 15.4 mmol). After having been stirred for an additional 45 min, the reaction mixture was cautiously treated with Na 2S0 4»10H 20, and the resulting slurry was filtered through F l o r i s i l (8 x 6 cm column, eluting with ether). Concentration and d i s t i l l a t i o n (air-bath temperature 95-105°C/0.1 Torr) afforded the alcohol mixture (331) as a clear, colorless, viscous liquid (3.4 g, 86%). Ir (film): 3350(br), 1260, 1090, 850 cm - 1. Exact Mass calcd. for C 1 4 H 2 8 ° 2 S i : 2 5 6' 1859; found: 256.1856. Preparation of the Aldehyde Mixture (332a) 332a General procedure 2 was followed. To a stirring suspension of PCC (4.8 g, 22.2 mmol), sodium acetate (2.5 g), and CH2C12 (60 mL) in a 500 mL-3N flask was added a solution of the alcohol mixture (331) (3.385 g, 14.8 mmol) in CH2C12 (20 + 15 mL). General conditions and reaction work-up provided the aldehyde mixture (332) as a pale yellow liquid (~3.3 g), which was used without further purification for the next reaction. 303 Preparation of the Aldehyde Mixture (332) 332 General procedure 3 was followed. To a THF (120 mL) solution of the crude aldehyde mixture (332a) from the previous reaction (3.3 g) in a 250 mL-RB-3N flask was added a tert-butyl alcohol (15 mL) solution of potassium tert-butoxide (120 mg). General conditions and reaction workup afforded the crude aldehyde mixture (333) as a yellow liquid (3.2 g). This material was used in the next reaction without further purification. For characterization purposes, this material could be d i s t i l l e d with some resulting loss (air-bath temperature 90-100°C/0.1 Torr) to provide (332) as a clear colorless liquid. Glc analysis of this material showed i t to consist of a 57:43 mixture of epimers. Ir (film): 2700, 1705, 1255, 1090, 840 cm - 1. Exact Mass calcd. for C 1 4 H 2 6 0 2 S i : 254.1703; found: 254.1695. Preparation of the Alkene Mixture (333) 333 304 General procedure 4 was followed. To a THF (150 mL) solution of methylenetriphenylphosphorane (22.2 mmol) in a 500 mL-RB-3N flask was added a THF (20 + 15 mL) solution of the aldehyde mixture (332) (3.2 g). General conditions, reaction workup, and d i s t i l l a t i o n (air-bath tempera-ture 75-85°C/0.1 Torr) afforded the alkene mixture (333) as a clear colorless liquid (2.65 g, 80% from the alcohol mixture (331)). Glc analysis of this material showed i t to consist of a 57:43 mixture of epimers. Ir (film): 3070(w), 1635, 1255, 1090, 840 cm - 1. Exact Mass calcd. for C 1 5H 2 8OSi: 252.1910; found: 252.1905. Preparation of the Alcohol Mixture (334) General procedure 5 was followed. To a cold (-78°C) THF (150 mL) solution of the s i l y l ether mixture (333) (2.62 g, 11.7 mmol) in a 250 mL-RB-3N flask was added a THF (20 mL) solution of TBAF (4.0 g, 15.3 mmol). General conditions and reaction workup afforded a clear color-less liquid. Flash chromatography (3 x 17 cm column of s i l i c a gel, eluting with petroleum ether-ether, 2:1) provided, after concentration of the appropriate fractions and d i s t i l l a t i o n (air-bath temperature 80-90°C/15 Torr), the alcohol mixture (334) as a clear colorless liquid HO 334 305 (1.38 g, 85%). Glc analysis of this material showed i t to consist of a 57:43 mixture of alcohol epimers. Ir (film): 3350(br), 3070(w), 1635, 1070, 1050, 895 cm - 1. Exact  Mass calcd. for C9Hll+0: 138.1045; found: 138.1047. Preparation of the Vinylcyclopropyl Ketone (335) General procedure 2 was followed. To a stirring suspension of PCC (3.2 g, 14.7 mmol), sodium acetate (1.5 g) and CHjClj (35 mL) in a 250 mL-RB-3N flask was added a solution of the alcohol (334) (1.35 g, 9.80 mmol) in CH2C12 (13 + 10 mL). General conditions, reaction workup and d i s t i l l a t i o n (air-bath temperature 75-85°C/15 Torr) provided the vinylcyclopropyl ketone (335) as a clear colorless liquid (1.19 g, 89%). Ir (film): 3080, 1680, 1640, 1240, 900 cm-1; XH nmr (400 MHz, CDC13) 6: 5.29 (d of d of d, IH, nQ, - 17 Hz, ^ - 10.2 Hz, = 8.3 Hz), 5.04 (d of d of d, IH, H^ , = 17 Hz, = 1.3 Hz, = 0.4 Hz), 4.89 (d of d, IH, Hfi, JL^ » 10.2 Hz, = 1.3 Hz), 2.20 (d of d of d, IH, J = 18, 4.3, 4.3 Hz), 2.10 (br d of d of d, IH, H^ , = 8.3 Hz, Jn- - J__ - 4 Hz), 2.04-1.88 (ra, 2H), 1.87-1.75 (m, IH), 1.74-1.50 (m, —DE —DF 4H). Exact Mass calcd. for C 9H 1 20: 136.0889; found: 136.0886. 3 3 5 306 Preparation of the Monomethylated Vinylcyclopropyl Ketone Mixture (336) To a cold (-78°C) THF (16 mL) solution of LDA (4.04 mmol) in a 50 mL-RB-3N flask was added a THF (2.5 + 2 mL) solution of the vinyl-cyclopropyl ketone (335) (0.50 g, 3.67 mmol) via a syringe. After 20 min at -78°C, the reaction mixture was warmed to 0°C, and methyl iodide (~2 mL) was introduced through grade 1 basic alumina contained in a Pasteur pipette pushed through the septum of the reaction flask. After 1 h at 0°C and 30 min at room temperature, the reaction mixture was poured into water, and the resulting mixture was extracted with ether. The ether extract was washed (water (2X), brine), dried (MgSO^), filt e r e d , and concentrated to afford a pale yellow liquid. This material was passed through F l o r i s i l (3 x 4 cm column, eluting with petroleum ether-ether, 2:1), and concentration and d i s t i l l a t i o n (air-bath temperature 85-95°C/15 Torr) afforded the monomethylated vinyl-cyclopropyl ketone mixture (336) as a clear colorless liquid (508 mg, 92%). Glc analysis of this material showed i t to consist of a 92.5: 6.5:1 mixture of the major methyl epimer, the minor methyl epimer and the starting vinylcyclopropyl ketone (335), respectively. Ir (film): 3080, 1690, 1640, 910 cm - 1. Exact Mass calcd. for C10H11+O: 150.1045; found: 150.1049. 336 307 Preparation of the Dimethylated Vinylcyclopropyl Ketone (328) 328 Using 3.72 mmol of LDA, the previous procedure was applied to the monomethylated vinylcyclopropyl ketone (336) (508 mg, 3.38 mmol). Upon warming to 0°C, the reaction mixture turned a faint blue color. Glc analysis of the crude reaction mixture showed i t to consist of 92% pure (328) and 5 other minor compounds. The crude product was flash chroma-tographed (4 x 17 cm column of s i l i c a gel, eluting with petroleum ether-ether, 8:1) to give, after concentration of the appropriate fractions and d i s t i l l a t i o n (air-bath temperature 85-95°C/15 Torr) pure (328) as a clear colorless liquid (430 mg, 78%). Ir (film): 3080(w), 1690, 1640, 1385, 1335, 1120, 910 cm - 1; XH nmr (400 MHZ, CDC13) 6: 5.38 (d of d of d, IH, Hg, = 17 Hz, J^g = 10.1 Hz, J^p = 8.3 Hz), 5.13 (d of d of d, IH, H^, - 17 Hz, = 1.2 Hz, J A T , = 0.4 Hz), 4.97 (d of d, IH, H , J_._ - 10.1 Hz, J_. = 1.2 —AU D —JJL. — o A Hz), 2.09 (br d of d of d, IH, Hp, JL^ = 8.3 Hz, = = 4 Hz), 2.05-1.93 (m, 2H), 1.75 (d of d, IH, H_, J__ = 7.5 Hz, J__ - 4 Hz), ti —-£jf — L U 1.69-1.63 (m, IH), 1.56 (d of d of d, IH, J = 14, 14, 5 Hz) 1.45 (d of d of d, IH, £ = 14, 5, 3 Hz), 1.08 (s, 3H, methyl), 1.05 (s, 3H, methyl). Irradiation at 6 5.38: 6 2.09 simplified to a d of d (J = 4, 4 Hz). Exact Mass calcd. for C nH l f i0: 164.1202; found: 164.1195. Anal, calcd. 308 for C nH 1 60: C 80.44, H 9.82; found: C 80.18, H 10.00. Preparation of the Alcohol (337) and the Ketone (338) H B H A H H "6 H IJ 337 338 To a cold (-78°C) THF (30 mL) solution of LDA (0.86 mmol) in a 100 mL-RB-3N flask was added a THF (0.3 + 0.3 mL) solution of the dimethylated vinylcyclopropyl ketone (328) (94 mg, 0.572 mmol) via a syringe. After 15 min at -78°C, the reaction mixture was warmed to -20°C, and i t turned a dark blue color. The color disappeared after 20 min, and the reaction mixture, after having been stirred for an addi-tional 10 min, was treated with water. The resulting mixture was extracted with ether, and the ether extract was washed (water, brine), dried (MgS01+), f i l t e r e d , and concentrated to afford a clear colorless liquid (~ 90 mg). Glc analysis of this material showed i t to consist of approximately a 7.5:1 mixture of the alcohol (337) and ketone (338), respectively. Upon contact with petroleum ether-ether solvent mixtures, part of the reaction product precipitated as a white solid. The crude product was dissolved in CH2C12 and flash chromatographed (3 x 15 cm column of s i l i c a gel eluting with petroleum ether-ether, 5:1) to 309 provide, after concentration of the appropriate fractions and flash d i s t i l l a t i o n (preheated air-bath temperature 80°C/0.1 Torr), the ketone (338) as a clear colorless liquid (3.5 mg, 3.7%) and the alcohol (337) as a clear colorless liquid (24 mg, 25.5%). The sti l l - p o t s and the other chromatography fractions contained various amounts of non-volatile, viscous material. Compound (337). Ir (film): 3450(br), 3050(w), 1640(w) 1040, 900 cm"1; 1H nmr (400 MHz, CDC13) 6: 6.14 (d of d of d, IH, H c or HD, Jgp = 6 Hz, = J_B = 2 Hz), 5.95-5.91 (m, IH, Hg or Hp), 5.60 (d of d, IH, Hg = J_,„ = 3.8 Hz) 2.68 (br d, IH, H. or H_, J A 1 3 = 17.5 Hz), 2.32 (d of — t r —fciC A o — A D d of d, IH, H or H_, J._ 17.5 Hz, J_ = = 2 Hz), 2.24-2.17 (m, 2H, H_ A D — -AD —0 — U r and H„), 1.97 (d of d of d, IH, H u or HT, J U T = 14 Hz, J = 5 Hz, J = 3.4 C rl 1 —HI — — Hz), 1.08 (s, 3H, methyl), 0.81 (s, 3H, methyl). Irradiation at 6 5.60: multiplet at 6 2.24 - 2.17 simplified. Irradiation at 6 2.68: 6 6.14 simplified to a d of d (J = 6, 2 Hz), multiplet at 6 5.95 - 5.91 simplified to a br d (J = 6 Hz), 6 2.32 changed. Irradiation at 6 1.27: multiplet at 6 2.24 - 2.17 simplified, 6 1.97 simplified to a d of d of d (J = 9, 9 Hz). Ms m/e: 164 (M+), 149 (M+-CH3), 146 (M+-H20), 108 (M+-CkH8, base). Exact Mass calcd. for C nH 1 60: 164.1202; found: 164.1202. Anal, calcd. for C HH 1 60: C 80.44, H 9.82; found: C 80.17, H 9.92. Compound (338). Ir (film): 3050, 1700, 1650(w), 1460, 1140 cm-1; *H nmr (400 MHz, CDCl.) 6: 5.83 (d of d of d of d, IH, H or H , J D„ = •J D C —DO 5.6 Hz, J. = J_, = J„ = 2.4 Hz), 5.71 (d of d of d of d, IH, H or H_, — A — D — G D C J D _ = 5.6 Hz, J = J = Jj, = 2.4 Hz), 3.45 (d of d of d of d of d, IH, V 1^ - 0 Hz, = J A C = = = 2.4 Hz), 2.83-2.73 (m, IH, Hg), 310 2.57 (d of d of d of d of d, IH, Hp, - 16.5 Hz, Jp p = 8.4 Hz, = i c B = i c e = 2* A H z ) ' 2 , 1 1 ( d ° f d ° f d ° f d ° f d' 1 H* \ r —ED = 1 6 ' 5 H z* 4A = ifiB = ^EC = ^EF = 2 , 4 ^ 1 ' 8 6 - 1 - 7 7 (m» 1H> "E °r V» 1 , 1 3 ( S > 3H, methyl), 1.07 (s, 3H, methyl). Irradiation at 6 3.45: 6 5.83 and 6 5.71 each simplified to d of d of d ( J_ = 5.6, 2.4, 2.4 Hz), multiplet at 6 2.83-2.73 simplified, 6 2.57 simplified to a d of d of d of d (J = 16.5, 8.4, 2.4, 2.4 Hz), 6 2.11 simplified to a d of d of d of d (J = 16.5, 2.4, 2.4, 2.4 Hz). Irradiation at 6 2.83-2.73: 6 3.45 simplified to a d of d of d of d (J_ = 2.4, 2.4, 2.4, 2.4 Hz), 6 2.57 simplified to a d of d of d of d (_J - 16.5, 2.4, 2.4, 2.4 Hz), 6 2.11 simplified to a d of d of d of d (J = 16.5, 2.4, 2.4, 2.4 Hz), multiplets at 6 1.87-1.77 and 6 1.54-1.44 each simplified. Exact Mass calcd. for C^H^gO: 164.1202; found: 164.1200. Preparation of the Methylated Compound (343) To a cold (-78°C) THF (2 mL) solution of LDA (0.068 mmol) in a 10 mL-RB-3N flask was added a THF (0.25 + 0.2 mL) solution of the dime-thylated vinylcyclopropyl ketone (328) (7.5 mg, 0.046 mmol) via a syringe. After 1 h at -78°C, methyl iodide (200 uL, previously run through grade 1 basic alumina), was added via a syringe. The reaction 311 mixture was stirred at -78°C for 1 h, after which time, i t was poured into water, and the resulting mixture was extracted with ether. The ether extract was washed (water, brine), dried (MgSO^), fil t e r e d , and concentrated to afford a pale yellow liquid. Glc analysis of this material showed i t to consist of a 87:13 mixture of the compound (343) and the starting material (328), respectively. Chromatography (0.4 x 7 cm column of s i l i c a gel, eluting with petroleum ether-ether, 10:1) provided, after concentration of the appropriate fractions and d i s t i l l a t i o n (air-bath temperature 85-95°C/15 Torr), the starting material (328) (0.7 mg) and the methylated species (343) as a clear colorless liquid (5 mg, 68% based on unrecovered starting material). Ir (film): 3080(w), 1680, 1635, 1390, 1060 cm-1; :H nmr (400 MHz, CDC13) 6: 5.54 (d of d of d, IH, Hg, = 17 Hz, = 10.2 Hz, = 8.2 Hz), 5.16 (d of d of d, IH, H^, = 17 Hz, = 1.7 Hz, = 0.6 Hz), 5.10 (d of d of d, IH, Hg, Jg C = 10.2 Hz, J g A = 1.7 Hz, J Q D = 0.4 Hz), 2.06 (d of d of d of d, IH, J = 13.8, 13.8, 5, 3.5 Hz), 2.01 (br d of d, IH, H„, J__ = 8.2 Hz, J__ = 5 Hz), 1.90 (d of d of d of d, IH, J -L) —1K1 —Dt. — 13.8, 5, 2.4, 2.4 Hz), 1.63 (d of d of d, IH, 13.8, 13.8, 5 Hz), 1.49-1.41 (m, 2H), 1.20, 1.10, 1.03 (each s, 3H, methyl). Exact Mass calcd. for C 1 2H 1 80: 178.1358; found: 178.1360. 312 Preparation of the Methylated Vinylcyclopropyl Ketone (344) 9 C H 3 H B ^ H D 344 To a -78°C THF (15 mL) solution of LDA (2.7 mmol) in a 50 mL-RB-3N flask was added a THF (1.5 + 1.5 mL) solution of the vinylcyclopropyl ketone (133) (465 mg, 2.44 mmol) via a syringe. After 20 min at -78°C, the reaction mixture was warmed to 0°C, and methyl iodide (~ 2 mL) was introduced through grade 1, basic alumina contained in a Pasteur pipette pushed through the septum of the reaction flask. After 1 h at 0°C and 20 min at room temperature, the reaction mixture was poured into water and the resulting mixture was extracted with ether. The ether extract was washed (water (2X), brine), dried (MgSO^), fi l t e r e d , and concen-trated to afford a pale yellow liquid. Glc analysis of this material showed i t to consist of the product (344) and the starting material (133) in a 97.5:2.5 ratio, respectively, while t i c analysis ( s i l i c a gel plate, petroleum ether-ether, 2:1) showed two major spots neither of which corresponded to the starting material. This material was flash chromatographed (3 x 15 cm column of s i l i c a gel, eluting with petroleum ether-ether, 8:1) to afford, in order of elution, an uncharacterized clear, viscous, non-volatile liquid (150 mg), and, after d i s t i l l a t i o n (air-bath temperature 70-80°C/0.1 Torr) the methylated vinylcyclopropyl ketone (344) as a white solid (325 mg, .65%) (mp 27-28°C). 313 Compound (344). Ir (film): 3070(w), 1690, 1635, 1245, 900 cm - 1; XH nmr (400 MHz, CDC1„) 6: 5.35 (d of d of d, IH, H„, JnA = 17 Hz, J„ D = 0 C — O A —CD 10.2 Hz, J = 8.5 Hz), 5.10 (d of d, IH, H,, J A O = 17 Hz, J . D = 1.2 — C D A — A C — A U Hz), 4.93 (d of d, IH, H , JL„ = 10.2 Hz, J,,, = 1.2 Hz), 1.99-1.86 (m, D —BO —DA 2H), 1.84-1.55 (m, 5H), 1.53-1.46 (m, IH), 1.44-1.09 (m, 6H), 0.99 (s, 3H, methyl). Exact Mass calcd. for C^H^O: 204.1515; found: 204.1506. Anal, calcd. for C 1 1 +H 2 Q0: C 82.30; H 9.87; found: C 82.08, H 9.99. Preparation of the Alcohol (345) and the Ketone (346) To a cold (-78°C) THF (35 mL) solution of LDA (0.75 mmol) in a 100 mL-RB-3N flask was added a THF (0.3 + 0.3 mL) solution of the methylated vinylcyclopropyl ketone (344) (102 mg, 0.50 mmol) via a syringe. The faintly blue reaction mixture was immediately warmed to -20°C, and the intensity of the blue color increased markedly. After approximately 5 min, the blue color faded, and after an additional 25 rain at -20°C, the reaction mixture was treated with water. The resulting mixture was extracted with ether, and the ether extract was washed (water, brine), dried (MgS04), filte r e d , and concentrated to 314 afford a clear colorless liquid (~ 100 mg). Glc analysis of this material showed i t to consist of a 3:1 mixture of the alcohol (345) and the ketone (346), respectively. Upon contact with petroleum ether-ether solvent mixtures, part of the reaction product precipitated as a white solid. The reaction product was dissolved in CH2C12 and flash chromato-graphed (3 x 16 cm column of s i l i c a gel, eluting with petroleum ether-ether, 5:1) to provide, after concentration of the appropriate fractions and flash d i s t i l l a t i o n (preheated air-bath temperature, 120°C/0.1 Torr), the alcohol (345) as a clear colorless liquid (19.5 mg, 19%) and the ketone (346) as a white solid (6 mg, 6%) (mp 55-57°C). The s t i l l - p o t s and the other chromatography fractions contained substantial quantities of viscous, non-volatile material. Compound (345). Ir (film): 3470(br), 3050(w), 1450, 1035, 900 cm-1; lE nmr (400 MHz, CDC13) 6: 6.17-6.12 (m, IH, H Q or Hp), 5.98-5.93 (m, IH, H c and Hp), 5.56 (d of d, IH, Hg, J_ = 3.6, 3.6 Hz), 2.66 and 2.26 (each br d, IH, H^ and Hg, J^g = 17.5 Hz), 2.17-2.00 (m, 2H), 1.85 (d of d of d, IH, J = 13.5, 13.5, 4 Hz), 1.77-1.16 (m, 8 H), 0.73 (s, 3H, methyl). Irradiation at 6 2.66: multiplets at 6 6.17-6.12 and 6 5.98-5.93 each simplified to a br d (Jgp = 5.5 Hz), 6 2.26 simplified to a br s. Ms m/e: 204 (M+), 186 (M+-H20), 108 (m +-C 7H 1 2, base). Exact  Mass calcd. for C l t tH 2 Q0: 204.1515; found: 204.1517. Anal, calcd. for Cll+H20O: C 82.30, H 9.87; found: C 82.13, H 9.68. Compound (346). Ir (CHC1 3): 1700, 1460 cm-1; lU nmr (400 MHz, CDCI3) 6: 5.96-5.91 (m, IH, Hg or Hg), 5.88-5.83 (IH, Hfi or Hg), 3.44 (br d, IH, HA, J^, = 9.5 Hz), 2.84-2.73 (m, IH, H p), 2.38 (d of d of d of d, IH, Hg, Jgp = 16 Hz, Jg F = 8.5 Hz, Jgg = 2.5 Hz, = 1.3 Hz), 315 2.13 (d of d of d of d of d, IH, H_, J n t 7 = 16 Hz, J._ = 10.3 Hz, J ^ A = D —Ub — u r . —UA iDB * iDC * 2 H Z ) ' ^ ( d ° f d ° f d ' 1 H ' HH 1*G " 4 l = 1 4 H Z» = 7 Hz), 1.74-1.54 (m, 4H), 1.50-1.04 (m, 6H), 1.11 (s, 3H, methyl). Irradiation at region between 6 5.96-5.83: 6 3.44 simplified to a d of d (J = 9.5, 2 Hz), 6 2.38 simplified to a d of d, J = 16, 8.5 Hz), 6 2.13 simplified to a d of d of d (J = 16, 10.3 2 Hz). Irradiation at 6 2.84-2.73: 6 3.44 simplified to a br s, 6 2.38 simplified to a d of d of d (J = 16, 2.5, 1.3 Hz), 6 2.13 simplified to a d of d of d of d (J = 16, 2, 2, 2 Hz), 6 1.86 simplified to a d of d (J = 14, 14 Hz). Exact Mass calcd. for C 1 4H 2 Q0: 204.1515; found: 204.1519. Preparation of the Alcohol (206) To a cold (-78°C) THF (25 mL) solution of LDA (0.426 mmol) in a 100 mL-RB-3N flask was added a THF (0.3 + 0.3 mL) solution of the vinyl-cyclopropyl ketone (134) (54 mg, 0.284 mmol) via a syringe. After 5 min at -78°C, the reaction mixture was warmed to -20°C and a very faint blue color formed. After having been stirred at -20°C for 20 min, the reaction mixture was treated with water, and the resulting mixture was extracted with ether. The ether extract was washed (water, brine), 316 dried (MgSO^), filte r e d , and concentrated to afford a clear colorless liquid. Glc analysis of ths material showed i t to consist of a 90:6:4 mixture of the alcohol (206), the starting material (134), and a compound that was presumed to be the ketone (348), respectively. The crude product was dissolved in CH2C12 and flash chromatographed (3 x 15 cm column of s i l i c a gel, eluting with petroleum ether-ether, 5:1). Concentration of the appropriate fractions and flash d i s t i l l a t i o n (preheated air-bath temperature, 120°C/0.1 Torr) yielded the alcohol (206) as a clear colorless liquid (21 mg, 39%). The earlier chromato-graphy fractions contained substantial quantities of viscous, non-volatile material. Compound (206). Ir (film): 3450(br), 3030, 1650(w), 1030, 900 cm-1; lK nmr (400 MHz, CDC13) 6: 6.16 (d of d of d, IH, Hg or H^, J^, = 5.8 Hz, J_ = 2.8 Hz, J = 1.4 Hz), 5.99-5.94 (m, IH, Hg or Hp), 5.56 (d of d, IH, Hg, Jg F * J^g * 3.4 Hz), 2.48 (d of d of d, IH, H^ or Hg, = 17.5 Hz, J = 2.6, J_ = 1.4 Hz), 2.42-2.26 (m, 2H, H^ or Hg and H^  or Hg), 1.88-1.66 (m, 6H), 1.52-1.43 (m, 2H), 1.38-1.18 (m, 3H), 1.10-0.98 (m, IH). D20 added: multiplet at 6 1.52-1.43 simplified. Irradiation at 6 6.16: 6 2.48 simplified to a d of d (J = 17.5, 2.6 Hz), multiplet at 6 2.42-2.26 simplified. Irradiation at 6 5.56: multiplet at 6 2.42-2.26 simplified, region around 6 2.78 changed. Ms m/e: 190 (M+), 172 (M+-H20), 108 (M+-C6H1Q). Exact Mass calcd. for C 1 3H 1 80: 190.1358; found: 190.1352. 317 REFERENCES 1. Perhaps one of the most formal documentations on retrosynthetic analysis is found in S. Warren, "Organic Synthesis: The Disconnection Approach", Wiley, New York (1982). 2. W. Oppolzer, T. Begley, and A. Ashcroft, Tetrahderon Lett. 25_, 825 (1984) and refs. therein. 3. P.A. Wender and J.J. Howbert, Tetrahedron Lett. 24, 5325 (1983) and refs. therein. 4. E. Vogel, Angew. Chem. 72_, 4 (1960). 5. E. Vogel, K-H., Ott, and K. Gajek, Justus Liebigs Ann. Chem. 644 (1961). 6. E. Vogel, Angew. Chem. Int. Ed. Engl. 2^, 1 (1963). 7. W. von E. Doering and W.R. Roth, Tetrahedron, 19_, 715 (1963). 8. J.M. Brown, B.T. Golding, and J.J. Stofko Jr., J. Chem. Soc. Chem. Commun. 319 (1973); J. Chem. Soc. Perkin Trans. II, 436 (1978). 9. M.P. Schneider and J. Rebell, J. Chem. Soc. Chem. Commun, 283 (1975). 10. M. Schneider, Angew. Chem. Int. Ed. Engl. _14, 707 (1975). 11. G. Ohloff and W. Pickenhagen, Helv. Chim. Acta, 52, 880 (1969). 12. T. Sasaki, S. Equchi, and M. Ohno, J. Org. Chem. 37, 466 (1972). 13. S.J. Rhoads and N.R. Raulins, Org. React. 22, 1 (1975). 14. E.M. Mil'vitskaya, A.V. Tarakanova, and A.F. Plate, Russ. Chem. Rev. 45, 469 (1976). 15. J.E. Baldwin and C. Ullenius, J. Am. Chem. Soc. 96, 1542 (1974). 16. J.A. Berson, T. Miyashi, and G. Jones II, J. Am. Chem. Soc. 96, 3468 (1974). 17. J.A. Berson, P.B. Dervan, R. Malherbe, and J.A. Jenkins, J. Am. Chem. Soc. 98, 5937 (1976). 18. J.E. Baldwin and K.E. Gilbert, J. Am. Chem. Soc. 98, 8283 (1976). 19. E. Vedejs, W.R. Wilber, and R. Twieg, J. Org. Chem. 42, 402 (1977). 318 20. M.P. Schneider and B. Csacsko, J. Chem. Soc. Chem. Commun. 330 (1977). 21. D.L. Garin, Tetrahedron Lett. 3035 (1977). 22. M.P. Schneider and A. Rau, J. Am. Chem. Soc. 101, 4426 (1979). 23. 0. BrulS, J.-C. Chalchat, R.-P. Garry, B. Lacroix, A. Michet, and R. Vessiere, Bull. Soc. Chim. Fr. II, 57 (1981). 24. S. Sarel, A. Schlossman, and M. Langbeheim, Tetrahedron Lett. 22, 691 (1981). 25. J.P. Marino and T. Kaneko, Tetrahedron Lett. 3971 (1973). 26. J.P. Marino and T. Kaneko, J. Org. Chem. 39, 3175 (1974). 28. E. Piers and I. Nagakura, Tetrahedron Lett. 3237 (1976). 29. J.P. Marino and L.J. Browne, Tetrahedron Lett. 3245 (1976). 30. P.A. Wender and M.P. Filosa, J. Org. Chem. 4^ , 3490 (1976). 31. E. Piers, I. Nagakura, and H.E. Morton, J. Org. Chem. 43, 3630 (1978) . 32. E. Piers and H.-U. Reissig, Angew. Chem. Int. Ed. Engl. 18, 791 (1979) . 33. E. Piers, H.E. Morton, I. Nagakura, and R.W. Thies, Can. J. Chem. 61^ , 1226 (1983). 34. M. Schneider and A. Erben, Angew. Chem. Int. Ed. Engl. 16, 192 (1977). 35. M. Schneider and A. Rau, Angew. Chem. Int. Ed. Engl. 18, 231 (1979) . 36. T. Akintobi, L. Jaenicke, F.-J. Marner, and S. Waffenschmidt, Justus Liebigs Ann. Chem. 986 (1979). 37. M.P. Schneider and M. Goldbach, J. Am. Chem. Soc. 102, 6114 (1980) . 38. E. Piers and E.H. Ruediger, J. Chem. Soc. Chem. Comm. 166 (1979); Can. J. Chem. 61, 1239 (1983). 39. P.A. Wender, M.A. Eissenstat and M.P. Filosa, J. Am. Chem. Soc. 101, 2196 (1979). 319 AO. P.M. Cairns, L. Crombie, and G. Pattenden, Tetrahedron Lett. 23, 1405 (1982). 41. P.A. Wender, C L . Hillemann, and J. Szymonifka, Tetrahedron Lett. 2205 (1980). 42. J.P. Marino and M.P. Ferro, J. Org. Chem. 46, 1912 (1981). 43. C. Cupas, W.E. Watts and P. von R. Schleyer, Tetrahedron Lett. 2503 (1964) . 44. J.M. Brown, J. Chem. Soc. Chem. Comm. 226 (1965). 45. E. Piers and G.L. Jung, Can. J. Chem. 63_, 996 (1985). 46. See refs. 92, 93, and 99-107. 47. A.J. Barker and G. Pattenden, J. Chem. Soc. Perkin Trans. I, 1901 (1983). 48. G. Fra"ter and J. Wenger, Helv. Chim. Acta, 67_, 1702 (1984). 49. M. Horton and G. Pattenden, Tetrahedron Lett. 24, 2125 (1983). 50. F. Bohlmann, A. Suwita, J. Jakupovic, R.W. King, and H. Robinson, Phytochemistry, 20, 1649 (1981). 51. S.K. Paknikar, 0. Motl, and K.K. Chakravarti, Tetrahedron Lett. 2121 (1977). 52. T. Uychara, K. Ogata, J. Yamada and T. Kato, J. Chem. Soc. Chem. Comm. 17 (1983). 53. J.M. Brown, J. Chem. Soc. Chem. Comm. 638 (1967). 54. G.W. Klump, J.W.F.K. Barnick, A.H. Veefkind, and F. Bickelhaupt, Reel. Trav. Chim. Pays-Bas, 88, 766 (1969). 55. B.C.C. Cantello, J.M. Mellor, and G. Scholes, J. Chem. Soc. (C), 2915 (1971). 56. W. Adam, 0. De Lucchi, and D. Scheutzow, J. Org. Chem. 46_, 4130 (1981). 57. E.J. Corey and R.H. Wollenberg, J. Org. Chem. 4£, 2265 (1975). 58. K. Kondo, T. Umemoto, Y. Takahatake, and D. Tunemato, Tetrahedron Lett. 113 (1977). 59. D.F. Taber, J. Am. Chem. Soc. 99, 3513 (1977). 320 60. K. Kondo, T. Umemato, K. Yako, and D. Tunemato, Tetrahedron Lett. 3927 (1978). 61. S.D. Burke and P.A. Grieco, Org. React. 26, 361 (1979). 62. D. Taber and E.H. Petty, J. Org. Chem. 47_, 4808 (1982). 63. E. Piers and A.R. Maxwell, Can. J. Chem. 62^ , 2392 (1984). 64. E. Piers, I. Nagakura, and J.E. Shaw, J. Org. Chem. 43, 3431 (1978). 65. K. Kitatani, T. Hiyama, and H. Nozaki, J. Am. Chem. Soc. 97_, 949 (1975). 66. For more information on the addition of carbenes to olefins, see W. Kirmse, "Carbene Chemistry", 2nd Ed., Academic Press, New York (1971) . 67. For a detailed survey on the efficiency of various catalysts used in the carbenoid addition of ethyl diazoacetate to olefins, see A.J. Anciaux, A.J. Hubert, A.F. Noels, N. Petiniot, and P. Teyssie*, J. Org. Chem. 45_, 695 (1980). 68. E. Piers and E.H. Ruediger, J. Org. Chem. 45_, 1725 (1980). 69. E. Piers, G.L. Jung, and N. Moss, Tetrahedron Lett. 25^ , 3959 (1984). 70. See ref. 38 for further references. 71. J.R. Grierson, Ph.D. Thesis, University of British Columbia, 1980. 72. A.F. Noels, A. Demonceau, N, Petiniot, A.J. Hubert, and P. Teyssie", Tetrahedron, 38, 2733 (1982). 73. For a solution to this problem see T. Tsunoda, M. Suzuki, and R. Noyori, Tetrahedron Lett. 21, 1357 (1980). 74. H.C. Brown and W.J. Hammer, Tetrahedron, 34, 3405 (1978). 75. M. Yamazaki, M. Shibasaki, and I. Ikegami, Chemistry Lett. 1245 (1981). 76. K.B. Sharpless and R.F. Lauer, J. Am. Chem. Soc. 95_, 2697 (1973). 77. E.J. Corey and A. Venkateswarlu, J. Am. Chem. Soc. 94, 6190 (1972) . 78. J.K. Whitesell and R.S. Matthews, J. Org. Chem. 42, 3878 (1977). 321 79. D.R. Dalton, V.P. Dutta, and D.C. Jones, J. Am. Chem. Soc. jK), 5498 (1968). 80. J.K. Crandall and M. Apparu, Org. React. 29, 345 (1983). 81. T.W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York (1981). 82. M.P. Doyle, D. Van Leusen, and W.H. Tamblyn, Synthesis, 787 (1981). 83. E.J. Corey and J.W. Suggs, Tetrahedron Lett. 2647 (1975). For a review on the applications of PCC see G. Piancatelli, A. Scettri, and M. D'Auria, Synthesis, 245 (1982). 84. B. Young and W.S. Trahanovsky, J. Org. Chem. 32, 2349 (1967). 85. D.L. Garin, J. Org. Chem. 3_6, 1697 (1971). 86. D.L. Pavia, G.M. Lampman, and G.S. Kriz, "Introduction to Spectroscopy", W.B. Saunders Company, Philadelphia (1979). 87. W.G. Dauben, R.C. Twrit, and C. Mannerskrantz, J. Am. Chem. Soc. 76, 4240 (1954). 88. A.C. Cope, R.J. Cotter, and G.G. Roller, J. Am. Chem. Soc. _77, 3594 (1955). 89. P.L. Stotter and K.A. H i l l , J. Org. Chem. 38, 2577 (1973). 90. L.H. Briggs, J.P. Bartley, and P.S. Rutledge, J. Chem. Soc. Perkin I, 806 (1973). 91. W.S. Johnson, J. Dolf Bass, and K.L. Williamson, Tetrahedron, 19, 861 (1963). 92. R.L. Ranieri and G.J. Calton, Tetrahedron Lett. 499 (1978). 93. G.L. Calton, R.L. Ranieri, and M.A. Espenshade, J. Antibiot. 3_1, 38 (1978). 94. S.M. Kupchan, M.A. Eakin, and A.M. Thomas, J. Med. Chem. 14, 1147 (1971); S.M. Kupcan, Fed. Proc. 33, 2288 (1974). 95. M. Nakagawa, A. Hirota, H. Sakai, and A. Isogai, J. Antibiot. 35, 778 (1982); J. Antibiot. 785 (1982). 96. D.E. Cane, Y.G. Whittle, and T.-C. Liang, Tetrahedron Lett. 25_, 1119 (1984). 97. D.E. Cane and T. Rossi, Tetrahedron Lett. 2973 (1979). 322 98. D.E. Cane and R.B. Nachbar, J. Am. Chem. Soc. 100, 3208 (1978). 99. S. Danishefsky, K. Vaughan, R. Gadwood, and K. Tsuzuki, J. Am. Chem. Soc. 102, 4262 (1980); J. Am. Chem. Soc. 103, 4136 (1981). 100. W.K. Bornack, S.S. Bhagwat, J. Ponton, and P. Helquist, J. Am. Chem. Soc. 103, 4647 (1981). 101. a) S.D. Burke, CW. Murtiashaw, J.O. Saunders, and M.S. Dike, J. Am. Chem. Soc. 104, 872 (1982); b) S.D. Burke, CW. Murtiashaw, and J.A. Oplinger, Tetrahedron Lett. 24, 2949 (1983); c) S.D. Burke, D.W. Murtiashaw, J.O. Saunders, J.A. Oplinger, and M.S. Dike, J. Am. Chem. Soc. 106, 4558 (1984). 102. A.S. Kende, B. Roth, P.J. Sanfilippo, and T.J. Blacklock, J. Am. Chem. Soc. 104, 5808 (1982). 103. K. Takeda, Y. Shimona, and E. Yoshii, J. Am. Chem. Soc. 105, 563 (1983). 104. R.H. Schlessinger, J.L. Wood, A.J. Poss, R.A. Nugent, and W.H. Parsons, J. Org. Chem. 48, 1146 (1983). 105. J.M. Dewanokele, F. Zutterman, and M. Vanderwalle, Tetrahedron, 39, 3235 (1983). 106. K. Kon, K. Ito, and S. Isoe, Tetrahedron Lett. 25_, 3739 (1984). 107. C. Iwata, M. Yamashita, S.-I. Aoki, K. Suzuki, I. Takahashi, H. Arakawa, T. Imanishi, and T. Tanaka, Chem. Pharm. Bull. Jap. 33, 436 (1985). 108. A.B. Smith III, B.A. Wexler, and J. Slade, Tetrahedron Lett. 23_, 1631 (1982). 109. S.A. Monti and T.R. Dean, J. Org. Chem. 47, 2679 (1982). 110. L.A. Paquette, CD. Annis, and H. Schostarez. J. Am. Chem Soc. 104, 6646 (1982). 111. K. Kakiuchi, T. Nakao, M. Takeda, Y. Tobe, amd Y. Odaira, Tetrahedron Lett. 25, 557 (1984). 112. For a recent review on the intramolecular Diels-Alder reaction see A.G. F a l l i s , Can. J. Chem. 62, 183 (1984). 113. G. Kubiac, J.M. Cook, and U. Weiss, J. Org. Chem. 49, 561 (1984). 114. R.H. Shapiro, Org. React. 23, 405 (1976). 323 115. The procedure used for this reaction was identical to the NBS procedure, except that NIS was used in place of NBS. See refs. 75 and 79. 116. M. P a r r i l l i , G. Barone, M. Adinolfi, and L. Mangoni, Tetrahedron Lett. 207 (1976). 117. W.G. Salmond, M.A. Barta, and J.L. Havens, J. Org. Chem. 43, 2057 (1978). P. Kok, P.J. De Clercq, and M.E. Vandewalle, J. Org. Chem. 44, 4553 (1979). 118. J.C. Stowell, and D.R. Keith, Synthesis, 132 (1979). 119. E.J. Corey, H. Cho, C. Rucker, and D. Hua, Tetrahedron Lett. 2_2, 3455 (1981). 120. E.J. Corey and P.L. Fuchs, Tetrahedron Lett. 3769 (1972). 121. L.A. Paquette and G.D. Annis, J. Am. Chem. Soc. 105, 7358 (1983). 122. R.E. Ireland, D.C. Muchmore, and U. Hengartner, J. Am. Chem. Soc 94, 5098 (1972); R.E. Ireland, T.H. 0'Neil, and G.L. Tolman, Org. Synth. 61, 116 (1983). 123. S. Krishnamurthy, Aldrichimica Acta, ]_, 32 (1974). 124. J. M51ek and M. Cerny, Synthesis, 217 (1972). 125. H. Haubenstock and P. Quezada, J. Org. Chem. 37, 4067 (1972). 126. G. Kovacs, G. Galambos, and Z. Junanez, Synthesis, 171 (1977). 127. W.K. Anderson and T. Veysoglu, J. Org. Chem. 38, 2267 (1978). 128. P.N. Rylander, "Catalytic Hydrogenation in Organic Synthesis", Academic Press, New York (1979). 129. P.J. Krusic and J.K. Kochi, J. Am. Chem. Soc. 90, 7157 (1968). 130. E. Piers and H.-U. Reissig, Angew. Chem. Int. Ed. Engl. 18, 791 (1979). 131. W.E. Billups, B.A. Baker, W.Y. Chow, K.H. Leavell, and E.S. Lewis, J. Org. Chem. 40, 1702 (1975). 132. T.C. Shields, W.E. Billups, and A.R. Lepley, J. Am. Chem. Soc. 90, 4749 (1968). 133. D.A. Evans and J.V. Nelson, J. Am. Chem. Soc. 102, 774 (1980). See refs. therein. 324 134. D.A. Evans and D.J. Baillargeon, Tetrahedron Lett. 3319 (1978). See refs. therein. 135. R.L. Danheiser, C. Martinez-Davila, R.J. Auchus, and J.T. Kadonaga, J. Am. Chem. Soc. 103, 2443 (1981). 136. W.C. S t i l l , M. Kahn, and A. Mitra, J. Org. Chem. 43, 2923 (1978). 137. D.D. Perrin, W.L.F. Armarego, and D.R. Perrin, "Purification of Laboratory Chemicals", 2nd Ed., Pergamon Press, Oxford (1980). 138. W.G. Kofron and L.M. Baclawski, J. Org. Chem. 41, 1879 (1976). 

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
https://iiif.library.ubc.ca/presentation/dsp.831.1-0060519/manifest

Comment

Related Items