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Total synthesis of stemodane-type diterpenoids : (±)-maritimol, (±)-stemodin, (±)-stemodinone and (±)-2-desoxystemodinone Suckling, Ian Douglas 1983

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TOTAL SYNTHESIS OF STEMODANE-TYPE DITERPENOIDS: (±)-MARITIMOL, (±)-STEMODIN, (±)-STEMODINONE AND (±)-2-DESOXYSTEMODINONE By IAN DOUGLAS SUCKLING B . S c , V i c t o r i a U n i v e r s i t y of We l l i n g t o n , 1977 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 t h i s t h e s i s as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA September 1983 © Ian Douglas S u c k l i n g , 1983 In presenting t h i s thesis i n p a r t i a l f u l f i l m e n t of the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Library s h a l l make i t f r e e l y a v a i l a b l e for reference and study. I further agree that permission for extensive copying of t h i s thesis for s c h o l a r l y purposes may be granted by the head of my department or by his or her representatives. It i s understood that copying or pu b l i c a t i o n of t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of C/)g/7)/$ hjj The University of B r i t i s h Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 Date 1% Och ber t m A B S T R A C T This t h e s i s describes work le a d i n g to the completion of a t o t a l synthe-s i s of (±)-stemodin 3^  and (±)-maritimol _5, as w e l l as a formal t o t a l synthesis of (±)-stemodinone 4_ and (±)-2-desoxystemodinone 6. The t r i c y c l i c enone 66_ was prepared, i n a s e r i e s of steps, from the Weiland-Miescher ketone 68. Photoaddition of a l l e n e to t h i s enone provided equal amounts of two photoadducts, 79_ and 80. Ozon o l y s i s , followed by t r e a t -ment of the r e s u l t i n g 1,3-dione w i t h sodium methoxide i n methanol, generated the same keto e s t e r b5_ from both photoadducts. Two p o s s i b l e mechanisms f o r the unexpected conversion of the oc-photoadduct 80_ i n t o the keto e s t e r 65_ are presented. The keto e s t e r 65^ was elab o r a t e d , l n a s e r i e s of steps, i n t o the t e t r a -c y c l i c dlone 63. The key step i n t h i s r e a c t i o n sequence was a Thorpe-Ziegler condensation of the d i n i t r i l e s 77. The gemlnal methyl groups r e q u i r e d at C-4 i n the target n a t u r a l products 3_ - 6_ were introduced using a 5-step sequence. Treatment of the r e s u l t i n g a l k y l a t e d dione 62_ w i t h m e t h y l t r i i s o p r o p o x y t i t a n i u r a afforded the keto a l c o h o l 61, admixed w i t h i t s C-13 epimer, i n the r a t i o of 5:1. This keto a l c o h o l 61_ was subsequently converted i n t o (±)-maritimol _5, and a l s o i n t o (±)-stemodin _3, v i a compound 55. Since the keto a l c o h o l 61_ has p r e v i o u s l y been converted i n t o (±)-2-desoxystemodinone 6^, and 55_ has been converted i n t o (±)-stemodinone 4_, the work described here a l s o c o n s t i t u t e s a formal t o t a l s y n t h e s i s of compounds 4 and 6. - i i i -4 R'.R^ O - i v -TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS i v LIST OF TABLES v i LIST OF FIGURES v i i ACKNOWLEDGEMENTS v i i i ABBREVIATIONS i x INTRODUCTION 1 1. A p h i d i c o l i n and Stemodane-type Diterpenoids 1 2. Previous T o t a l Syntheses of (±)-Aphidicolin and the Stemodane-type Diterpenoids 5 DISCUSSION 24 1. A B r i e f Summary of the Syn t h e t i c Route 24 2. P r e p a r a t i o n of the B i c y c l i c Keto K e t a l 67_ 34 3. Synthesis of the T r i c y c l i c Enone 66^ 35 4. Photoaddition Studies 44 4.1 Photoaddition of A l l e n e to the Enone 66^ 44 4.2 Photoaddition of A l l e n e to the Enone 88_ 54 4.3 Hydrogenation and L1-NH3 Reduction of 66 and 88 57 4.4 A Dis c u s s i o n of the Stereochemistry of Pho t o c y c l o a d d i t i o n of Alkenes to a,p-Unsaturated Ketones 63 5. P r e p a r a t i o n of the Keto E s t e r 65_ 73 6. Formation of the T e t r a c y c l i c Dione 63_ 82 - v -Page 7. Attempted Synthesis of the T e t r a c y c l i c Keto Ketal 160 v i a a Dieckmann Condensation 91 8. Synthesis of the Bis Enone 7_5 94 9. Preparation of the Alkylated Dione 62^  107 9.1 Dimethylation of the A 1 » 2 ; 1 1 » 1 2 - B i s Enone 75 107 9.2 The lR nmr Spectra of Compounds 75_, 177, 7 6 and 175 113 9.3 Preparation of 62^  117 10. Synthesis of the Keto Alcohol 61_ 117 11. Synthesis of (±)-Maritimol 5_ and (i)-Stemodin 3_ 129 EXPERIMENTAL 140 BIBLIOGRAPHY 186 - v i -LIST OF TABLES Page Table I Coupling Constants Between the Protons on and Around the Cyclobutane Ring i n Compound 7_9_ 51 Table I I The P r e p a r a t i o n of "Thermodynamic Mixtures" of S i l y l Enol Ethers from 2-Methylcyclohexanone 172.... 102 Table I I I The P r e p a r a t i o n of the B i s T r i m e t h y l s i l y l Enol Ethers _170 and _m from 63 104 Table IV The Chemical S h i f t s of Selected Protons i n Compounds 75, 177, 76 and 175 •... 114 - v i i -LIST OF FIGURES Page Figure I : The P a r t i a l XH nmr Spectrum of 7_9: The Sig n a l s Assigned to the Protons on and Around the Cyclobutane Ring 52 - v i i i -A C K N O W L E D G E M E N T S Many people have helped to make this work possible. In particular my thanks goes out to: Dr. Edward Piers, for his advice, interest and encouragement during the course of this work. The members of Dr. Pier's research group, both past and present, for sharing in the agonies and, a l l too Infrequent, ecstacy. Particular mention must be made here of Messrs Brian Abeysekera and Michael Chong. The New Zealand National Research Advisory Council, for financial support in the form of a Fellowship, and members of the staff at the Forest Research Institute, Rotorua, New Zealand, for their advice and encouragement. Jeeva Jonahs and J i l l Vedamani for the prompt and efficient typing of this manuscript. Ms. Margot Alderdice and others from my laboratory for proof reading this thesis. - i x -ABBREVIATIONS The folowing abbreviations are used i n t h i s t h e s i s : Ac A c e t y l _t-Am tert-Amyl Bu B u t y l 9-BBN 9-Borabicyclo[3.3.1]nonane DBU 1,8-Diazabicyclo[5.4 .0]undec-7-ene DDQ 2,3-Dichloro-5,6-dicyano-l,4-benzoquinone DHP Dihydropyran DMAP 4-Dimethylaminopyridine DME Dimethoxyethane DMSO Dimethyl S u l f o x i d e E t E t h y l g l c g a s - l i q u i d chromatography *H nmr proton nuclear magnetic resonance HMPA Hexamethylphosphoramide HPLC High Performance L i q u i d Chromatography HRMS High R e s o l u t i o n Mass Spectrometry i r i n f r a r e d LDA L i t h i u m Diisopropylamide Me Methyl mp me l t i n g point Ms Methanesulfonyl - x -NOE Nuclear Overhauser Effect PCC Pyridinium Chlorochromate Ph Phenyl PPTS Pyridinium para-Toluenesulfonate py pyridine TBDMS tert-Butyldimethylsilyl THF Tetrahydrofuran THP Tetrahydropyranyl t i c thin layer chromatography TMS Trimethylsilyl Ts para-Toluenesulfonyl - 1 -INTRODUCTION 1. Aphidlcolin and Stemodane-type Dlterpenoids In 1972 Hesp and co-workers (1,2) reported the I s o l a t i o n of a p h i d i c o l i n J_, a novel diterpene metabolite of the fungus Cephalosporium a p h i d i c o l a Petch.* The s t r u c t u r e of t h i s t e t r a o l was determined using both degradative and spectroscopic techniques, along w i t h an X-ray a n a l y s i s of i t s b i s acetonide 2. A p h i d i c o l i n _1_ was the f i r s t reported member of a new c l a s s of t e t r a c y c l i c d i t e r p e n o i d s . A p o s s i b l e b i o s y n t h e t i c pathway to t h i s compound has been proposed (2) , and subsequent l a b e l l i n g s t u d i e s (4,5) are con s i s t e n t w i t h t h i s proposal. Rather s u r p r i s i n g l y , i n view of the simple f u n c t i o n a l groups present i n the molecule, a p h i d i c o l i n has been found to possess i n t e r e s t i n g b i o l o g i c a l A p h i d i c o l i n has since been i s o l a t e d as a metabolite produced by Nigrosporum sphaerica ( 3 ) . - 2 -properties. It exhibits a n t i v i r a l (6) and antitumor a c t i v i t y (7), while showing no mutagenic a c t i v i t y (8). This b i o l o g i c a l a c t i v i t y Is presumably due to the a b i l i t y of a p h i d i c o l i n to act as a re v e r s i b l e enzyme i n h i b i t o r of DNA polymerase a (9), although the mechanism of t h i s action i s not known i n d e t a i l . More recently, examination of the above-ground portion of Stemodia  maritima L.(Schrophulariaceae), a plant used i n the Caribbean for the t r e a t -ment of venereal disease, has resulted i n the i s o l a t i o n of stemodin 3_ (10), H O H O O. H H 3 4 H O H Q H O H H 5 6 - 3 -stemodinone 4^  (10), maritimol _5 (11) and 2-desoxystemodinone _6 (12). 2 I t can be seen that the carbon skeletons of a p h i d i c o l i n 1_ and the stemodane-type diterpenoids 3> - 6^ d i f f e r only i n the stereochemistry at C - 9 , 13 and 14 (stemodane numbering). The proposed numbering systems for the parent hydrocarbons of these diterpenoids, aphidicolane _9 (1,2) and stemodane 10 (10), d i f f e r s l i g h t l y and are shown below. The structure of stemodinone 4_ was determined by X-ray analysis (10). Stemodin 3_ was oxidized to stemodinone _4, suggesting structure 3 or i t s C-2 epimer for the former substance. On the basis of XH nmr data, the C-2 Hufford and co-workers (11) also reported the i s o l a t i o n of a compound which they named stemodinol and to which they assigned structure 7. However subsequent work showed that t h i s substance was i n fact a s t r u c t u r a l isomer which proved to be i d e n t i c a l with stemarin The l a t t e r natural product 8^  was independently i s o l a t e d from ][. maritima, and i t s structure was determined by X-ray analysis (13). ~~ HO - 4 -hydroxyl group of stemodin was shown to be equatorial (10). This then led to structure 3_ for stemodin. Maritimol _5 was oxidized (Jones' reagent) to the corresponding ketone, which, upon reduction under Huang-Minion conditions (14), gave 2-desoxystemo-dinone (11). Since steraodinone 4_ had previously been reduced under si m i l a r conditions to the same desoxy compound 6_ (10), t h i s oxidation-reduction sequence showed that maritimol _5 possessed the stemodane ring skeleton. The p o s i t i o n and stereochemistry of the secondary alcohol function in maritimol 5^  was assigned on the basis of spectral data and degradative studies (11). Within the family of diterpenoid natural products, a p h i d i c o l i n 1_ and the f u n c t i o n a l i z e d stemodanes _3 - _6 possess unique carbon skeletons. In addition, as previously mentioned, these substances ( p a r t i c u l a r l y a p h i d i c o l i n ) exhibit i n t e r e s t i n g p h y s i o l o g i c a l a c t i v i t i e s . Therefore t h i s group of compounds constitutes a very a t t r a c t i v e target to the synthetic organic chemist, and i t i s not at a l l s u r p r i s i n g to f i n d that over the past few years reports have appeared i n the l i t e r a t u r e describing the t o t a l synthesis of (±)-aphidicolin 1_ (15-21), (l)-stemodin _3 and (±)-stemodinone 4_ (22,23), (±)-maritimol 5_ (23,24), (±)-2-desoxystemodinone 6^  (12,23,25) and (+)-2-desoxystemodinone 6_ (12). In addition, a number of publications describing synthetic approaches to (±)-aphidicolin 1_ (26-29), and the stemodane-type diterpenoids (30) have appeared. Several years ago, a project aimed at the t o t a l synthesis of (±)-aphidi-c o l i n _1. a n < i (±) -stemodin 3^ was started i n our laboratory. The work reported i n t h i s thesis i s a continuation of t h i s project ( f o r e a r l i e r reports see - 5 -r e f s . 31-33), and describes the t o t a l synthesis of (±)-stemodin _3 and (±)-maritimol _5, as well as the formal t o t a l synthesis of (±)-stemodinone 4 and (+)-2-desoxystemodinone 6_. 2. Previous T o t a l Syntheses of (±)-Aphidicolin and the Stemodane-type  Di t e r p e n o i d s Examination of the structures of a p h i d i c o l i n 1_ and the stemodane-type diterpenoids 3_ ~ 6_ shows that the primary problem they present to the synthetic organic chemist i s the construction of the novel BCD r i n g system. A c r u c i a l part of t h i s challenge involves s e t t i n g up the quaternary centre at C-9 with the desired stereochemistry, thus leading to either the aphidicolane 9_ or stemodane JL0_ ring system. It i s appropriate here to look b r i e f l y at the published syntheses of these molecules 1_ and 3_ - 6_, to see how others have overcome the problems t h e i r syntheses present. This discussion w i l l be very b r i e f , and w i l l focus on how the BCD r i n g system i s assembled, and how the stereochemistry at the C-9 quaternary centre i s established. Although a number of other very i n t e r e s t i n g approaches to the synthesis of these two ring systems have also been published (26-30), for the sake of compactness they w i l l not be discussed here. In the synthesis of (±)-aphidicolin 1_ by Trost and co-workers (15) (see Scheme I ) , the two c r i t i c a l disconnections are shown i n p a r t i a l structure 11. Thus, the ketone at C - l l was used as a handle to form the D-ring by i n t r o -ducing a 3-carbon unit between C-9 and C-12. 3 The numbering scheme used throughout the rest of the Introduction a n t i c i p a t e s the f i n a l product. Thus the carbons are numbered as they w i l l appear i n the t e t r a c y c l i c skeletons. See structures _9 (aphidicolane) and _10_ (stemodane) for the numbering schemes used i n the two skeletons. - 6 -[a] ( i ) £-C 3H 5S +Ph 2 BFi+~, KOH ( i i ) PhSeSePh, NaBH4 ( i i i ) CH3-C(OTMS)=NTMS, E t 3 N ( i v ) f l a s h p y r o l y s i s , 610°C (54%) [b] ( i ) Pd(OAc) 2 ( i i ) L i , NH 3, t-BuOH, then TMSC1 (60%) tc] ( i ) n-BuLl, HMPA, a l l y l i o d i d e ( i i ) (CH3)2CHC(CH3) 2BH2, then NaOH, H 2 0 2 (20%) [d] ( i ) PCC, NaOAc ( i i ) 2% KOH i n Me OH (54%) [e] ( i ) DHP, TsOH ( i i ) H2N-NH2, KOH ( i i i ) TsOH, acetone ( i v ) PCC, NaOAc (62%). - 7 -The key t r i c y c l i c s i l y l enol ether ]A_ was generated from the b i c y c l i c ketone 1_2 using a procedure developed e a r l i e r i n t h e i r laboratory (34). Unfortunately, the cyclopentanone annulation did not proceed quite as they had an t i c i p a t e d , generating a 2:1 mixture of the eplmeric (at C-8) s i l y l enol ethers _13_ and 14. A d d i t i o n a l steps were required to convert t h i s mixture into the desired s i l y l enol ether 14. A l k y l a t i o n of the enolate anion derived from the s i l y l enol ether _14_ with a l l y l iodide occurred mainly from the s t e r i c a l l y less hindered a-face of the molecule to a f f o r d , a f t e r hydroboration of the double bond i n the newly-introduced side chain, the keto alcohol 15. The primary alcohol function i n 15. was oxidized to the corresponding aldehyde, and the f i n a l r i n g was then closed by a base-catalyzed a l d o l condensation. Subsequent functional group manipulation afforded the t e t r a c y c l i c keto acetonide 17. The a c q u i s i t i o n of the l a t t e r substance constituted a formal t o t a l synthesis of (±)-aphidicolin, since previous workers had obtained 1_7_ i n o p t i c a l l y active form from, and reconverted i t back into, (-)-aphidicolin _1 In the most i n t e r e s t i n g step i n McMurry's synthesis of ( i ) - a p h i d i c o l i n _1 (16,17) (see Scheme I I ) , disodium tetracarbonylferrate (35) was used to (2). [1] 18 17 - 8 -22 17 Scheme II [a] ( i ) LiAlHij ( i i ) ether v i n y l ether, Hg(OAc) 2 (86%) [b] heat, 220°C, cat. j t-C 5HiiONa (60%) [c] ( i ) LiAlHjj ( i i ) TsCl, py (90%) [d] Na 2Fe(C0 ) i + , N-methylpiperidone (30% y i e l d of 17 ) . - 9 -introduce the elements of "C=0" between what was to become C-12 and C-15 of the aphidicolane skeleton (eq. [ 1 ] ) . This transformation served, i n a s i n g l e step, to introduce the ex t r a carbon required to form C-16, and to close the D-ring. The key intermediate _18_ was obtained from the enone 19 as f o l l o w s . Reduction of compound 1_9_ (see Section 3 of the Di s c u s s i o n f o r the synthesis of t h i s enone from compound 12) occurred s t e r e o s e l e c t i v e l y from the more open fB-face to generate the oc-alcohol. E t h e r i f i c a t i o n of the r e s u l t a n t a l c o h o l a f f o r d e d _20_, which, upon heating, underwent a C l a i s e n rearrangement to give compound 21. This conversion e s t a b l i s h e d the desired C-9 stereochemistry. Reduction of the aldehyde 21_, followed by t o s y l a t i o n of the r e s u l t i n g primary a l c o h o l , y i e l d e d compound 18. Treatment of t h i s alkene t o s y l a t e j_8_ w i t h disodium t e t r a c a r b o n y l f e r r a t e (35) afforded the d e s i r e d t e t r a c y c l i c ketone 17, along w i t h an equal amount of the undesired compound 22. In t h e i r syntheses of ( t ) - a p h i d i c o l i n _1, (±)-steraodin 3^  and (±)-stemo-dinone 4_, Corey at a l . (18,22) took a somewhat d i f f e r e n t approach to those discussed p r e v i o u s l y , f u s i n g the D-ring onto a preformed AB r i n g system and then f i n a l l y generating the C r i n g . Considering the h y p o t h e t i c a l p a r t -s t r u c t u r e 23_y they r e a l i z e d that i f i n t r a m o l e c u l a r a l k y l a t i o n was to occur between C-a and the CH2OTS group, one would generate an aphidicolane-type skeleton (eq. [2]) whereas s u c c e s s f u l i n t e r n a l a l k y l a t i o n i n v o l v i n g C-b and the CH2OTS f u n c t i o n would produce in s t e a d a stemodane-type sk e l e t o n . - 10 -0 Thus, i n t h e i r synthesis of (±)-aphidicolin 1_ (18) (see Scheme I I I ) , Robinson a n n u l a t i o n of the keto aldehyde 2A_ w i t h methyl v i n y l ketone y i e l d e d the s p i r o c y c l i c keto enone 25. ** The next o p e r a t i o n , replacement of the C-8 ketone oxygen by -H and -CH20H, proved troublesome. This d i f f i c u l t y was due to the preference of a v a r i e t y of n u c l e o p h i l e s to deprotonate, r a t h e r than add t o , the s t e r i c a l l y hindered C-8 ketone. E v e n t u a l l y a new m u l t i s t e p route was developed to overcome t h i s problem (see eq. [ 3 ] ) . Thus, compound 25_ was converted, i n a s e r i e s of steps, i n t o the keto t o s y l a t e 26. K i n e t i c a l l y c o n t r o l l e d deprotonation of 26 occurred r e g i o s e l e c t i v e l y at C-12, and A d i f f e r e n t approach towards the c o n s t r u c t i o n of such s p i r o c y c l i c compounds has been reported (36). - 11 -o o 27 Scheme I I I [a] ( i ) methyl v i n y l ketone, K 2C0 3, DBU ( i i ) p y r r o l i d i n i u m acetate (?%) [b] ( i ) CH 2(CH 2STMS) 2, Z n l 2 ( i i ) TMSCN, Z n l 2 ( i i i ) ( i - B u ) 2 A l H ( i v ) TMSLi (v) LDA ( v i ) H 3 0 + ( v i i ) NaBH^ ( v i i i ) TBDMSC1, DMAP, E t 3 N ( i x ) 1,3-diiodo-5,5-dimethylhydantoin (x) H 2, Pd/C ( x i ) n-Bu^NF ( x i i ) T s C l , DMAP, E t 3 N (29%) [c] LiN(_t-Bu) 2, -120° - 0°C (90%). - 12 -TMS TMSCN Znl , OTMS .CN (i-Bu).AIH OTMS CHO TMSLi OTMS LDA [3] 47// overall CHO OTMS subsequent Intramolecular a l k y l a t i o n of the r e s u l t a n t enolate anion a f f o r d e d the t e t r a c y c l i c ketone 27. The l a t t e r substance was converted, v i a a s e r i e s of steps, i n t o (±)-aphidicolin l_. Corey's synthesis of (±)-stemodin 3_ and (±)-steraodinone h_ (22) proceeded along s i m i l a r l i n e s as i s shown i n Scheme IV. Michael a d d i t i o n of the enolate anion of J28_ to methyl v i n y l ketone proceeded s t e r e o s e l e c t i v e l y from the l e s s -hindered ct-face of 28_ to a f f o r d , a f t e r c y c l i z a t i o n , the keto enone 29. In the key step, deprotonation of 3_0 occurred at the only e n o l i z a b l e s i t e (C -14 ) , and subsequent i n t r a m o l e c u l a r a l k y l a t i o n of the r e s u l t a n t enolate anion afforded the t e t r a c y c l i c enone 31. Many of the steps used to complete the synth e s i s of (±)-stemodin 3_ and (±)-stemodinone 4_ from compound 3J_ w i l l be discussed subsequently (see Sections 10 and 11 of the D i s c u s s i o n ) . I r e l a n d and co-workers' synthesis of (±)-aphidicolln 1_ (19,20) was planned to proceed v i a s o l v o l y s i s of the alkene sulfonate 33 ( c f . r e f . 37). However, - 13 -31 Scheme IV [a] ( i ) methyl v i n y l ketone, K 2C0 3, DBU ( i i ) p y r r o l i d i n i u m acetate (70%) [b] ( i ) CH 2(CH 2STMS)2, Z n l 2 ( i i ) TMSCN ( i i i ) (i_-Bu) 2AIH ( i v ) TMSLi (v) LDA ( v i ) H 3 0 + ( v i i ) NaBHi+ ( v i i i ) T s C l , DMAP* py ( i x ) l,3-diiodo-5,5-dimethylhydantoin [c] _t-BuOK (= 22% f o r [b] and [ c ] ) . they ran i n t o problems when they t r i e d to add a f u n c t i o n a l i z e d one carbon u n i t ( i . e . C-13) to the ketone at C-8 of a compound very s i m i l a r to 32_ (-CH2TMS - 14 -replaced by -CH3) ( c f . 25 •*• 26 (18)). Successful model studies Indicated that they should be able to introduce the desired C-13 carbon v i a Meinwald-Cava (38) photochemical ring contraction of a 7-raembered c y c l i c diazo ketone i . e . 40_ -* 42_ (see Scheme V). This was not to be. Diels-Alder cycloaddition of methyl a-(trimethylsilyl)methacrylate to the enone 3_5 (see Scheme V) produced compound 3_6_ admixed with i t s C-16 epimer i n the r a t i o of 7:3. Compound 36_ was converted into the v i n y l dihydropyran 37, which smoothly underwent a Claisen rearrangement to generate the required spiro ketone 38. Compound 38^  was converted into the a-diazo ketone 40, v i a the a-oximino ketone 39. A l l attempts to form the desired ester hl_ from the diazo ketone 40_ f a i l e d (even when the photolysis was carried out i n methanol containing an excess of sodium methoxide), r e s u l t i n g instead i n the almost exclusive formation of the unstable cyclobutanone 4_3_. This product was formed as a r e s u l t of a thermally-allowed [2-rca + 2^] cycloaddition between the [a] = < ^ ^ e , 125°C (89% of mixture) [b] ( i ) (i-Bu) 2AlH, -78°C ( i i ) Ph 3P=CH 2 (95%) [c] heat, 150°C [d] n-BuLi, i_-AmONO (85%) [e] NH2C1 [f] hv, E t 2 0 [g] s i l i c a gel chromatography (60% from 39). - 16 -ketene and the alkene i n intermediate 41. F o r t u i t o u s l y however, attempted p u r i f i c a t i o n of t h i s cyclobutanone 43_ by s i l i c a gel chromatography resulted i n i t s acid-catalyzed rearrangement to the t e t r a c y c l i c ketone ^4_! This ketone was then converted, v i a a series of steps, into ( t ) - a p h i d i c o l i n ±. The most popular approach to the synthesis of the BCD ring system of compounds 1_ and 3_ - 6^  i s based upon a method developed by Wiesner and his co-workers (39) i n t h e i r syntheses of the delphinine- and napelline-type diterpene a l k a l o i d s . This method involves the synthesis of an appropriately substituted bicyclo[2.2.2]octane and i t s subsequent s o l v o l y t i c rearrangement to the desired bicyclo[3.2.1 ] octane systems of compounds 1_ and 3_ - 6. The o v e r a l l approach, ignoring most of the fun c t i o n a l groups, i s shown i n equation [4]. - 17 -This approach has been applied by van Tamelen to the synthesis of (±)-maritimol 5_ (24) and ( i ) - a p h i d i c o l i n j_ (21), by K e l l y to the synthesis of (±)- and (+)-2-desoxystemodinone ji (12, 25) and, very recently, by Marini Bettolo i n a synthesis of a l l four stemodane-type diterpenoids 3_ - 6_ (23). Although the o v e r a l l approach used by the three groups i s the same, they chose to carry out the c r i t i c a l s o l v o l y s i s reaction on d i f f e r e n t substrates, and i n a somewhat d i f f e r e n t manner. The d i f f e r e n t approaches are shown i n equations [5] (12,25), [6] (24) and [7] (23), and, as one can see, lead to d i f f e r e n t l y f u n c t i o n a l i z e d D ri n g s . The elaboration of these D-rings to that of the natural products 3_ - 6_ w i l l be considered i n Section 10 of the Discussion. H H N a + CH,SOCH, D M S O H [5] 4 7 4 8 H HO TsCl -py Ts [6] H H H 5 8 5 9 - 18 -OH One feature of t h i s s o l v o l y s i s reaction, as can be seen from these examples, i s that the bond which migrates i s that which i s antiperiplanar to the leaving group. Furthermore, as suggested by K e l l y (40), and l a t e r demon-strated by Marini Bettolo (29), t h i s approach r e a d i l y lends i t s e l f to the 48 - 19 -synthesis of both the aphidicolane and stemodane skeletons. From a common keto alcohol like 4_5_ (40) i t should be possible, by choosing an appropriate sequence of reactions, to generate selectively either of the two tosylates or 47. Solvolytic rearrangement of 46, in the presence of a base, would lead to an aphidicolane-type skeleton, whereas rearrangement of WT_ would afford a stemodane-type skeleton. Kelly (12,25), in the f i r s t synthesis of (±)-2-desoxystemodinone 6_, used this approach (i.e. ^5_ •*• 47_ -> 48) to construct the required carbon skeleton. The method they employed to make the tetracyclic keto alcohol 45 parallels very closely that used by Marini Bettolo and co-workers (23) to synthesize their keto alcohol 52. The latter work w i l l be discussed in more detail below. In their synthesis of a l l four stemodane-type diterpenoids 3_ - b_ (see Scheme VI), Marini Bettolo and Lupi (23) constructed the required bicyclo-[2.2.2]octane system by f i r s t adding allene photocheraically to the t r i c y c l i c enone 49_ (for a discussion of the stereochemistry of allene photoadditions to enones see Section 4.4 of the Discussion). The a-photoadduct 50_ was converted into the ketal alcohol j51_, which underwent, after removal of the ketal protecting group, a base-catalyzed^ isomerization to the more stable keto alcohol 52. The hydroxyl group of 52_ was formed mainly (4.5:1) with the desired p-configuration at C-14, presumably due to stabilization of this configuration by H-bonding (cf. 45). This keto alcohol _52_ was then converted, in a series of steps, into the mesylate 53_, which, as shown in equation [7], underwent the desired solvolytic rearrangement on warming in acetone-water to generate the a l l y l i c alcohol 54. These workers found that this rearrangement proceeds best with a double bond syn to the leaving group (cf. ref. 41). The - 20 -Scheme VI [a] =•=, hv (87%) [b] ( i ) TsOH ( i i ) 0 3, EtOH-CH 2Cl 2 ( i i i ) NaBH^ [c] ( i ) H 30 +, THF ( i i ) NaOH, H20-THF-MeOH (64% from 50) [d] ( i ) DHP, TsOH ( i i ) NaBH^ ( i i i ) NaH ( i v ) CS 2 (v) Mel ( v i ) heat, 145°C ( v i i ) H 30+ ( v i i i ) MsCl, E t 3 N (41%) [e] H 20, acetone, 70°C (82%). - 21 -a l l y l i c a l c o h o l _54_ was subsequently converted i n t o (± )-maritimol 5^, (±)-2-desoxystemodinone 6_ and the alkene 55, an intermediate i n Corey's synthesis of (±)-stemodin 3_ and (±)-stemodinone k_ (22). Van Tamelen (24), i n h i s synthesis of (±)-maritimol _5, chose to construct the required bicyclo[2.2.2]octane system i n a somewhat d i f f e r e n t manner, as shown i n Scheme V I I . A D i e l s - A l d e r r e a c t i o n between maleic anhydride and the diene 56_ occurred s t e r e o s e l e c t i v e l y from the l e s s hindered p-face to form o 5 9 Scheme VII [a] maleic anhydride, 90°C [b] ( i ) KOH ( i i ) Pb(OAc)i+, 0 2 - s a t u r a t e d py ( i i i ) NaBHi+ (<11% from 56) [c] T s C l , py (77%). - 22 -compound 57. The l a t t e r adduct was converted, v i a a ser i e s of steps, into the alcohol _58_, which, on warming with £-toluenesulfonyl chloride i n pyridine, rearranged, as shown i n equation [6], to the diene 59. This diene was used to complete the f i r s t synthesis of (±)-maritimol _5. In t h e i r recent t o t a l synthesis of (±)-aphidicolin 1, van Tamelen and O o" a O H H b OH c 17 60 Scheme VIII [a] maleic anhydride, 80°C (86%) [b] ( i ) anhydride hydrolysis ( i i ) H 2, Pt ( i i i ) Pb(0Ac ) i t , 0 2-saturated pyridine ( i v ) m-ClC 6H t tC0 3H (v) Na, PhH(= 5%) [c] ( i ) mesylation ( i i ) H 20, acetone, CaC0 3 ( i i i ) Cr0 3, py (54%). - 23 -co-workers (21) constructed the required bicyclo[2.2.2]octane system (see Scheme VIII) via an approach similar to that which they employed in their synthesis of (±)-maritimol (24). The solvolytic rearrangement of the mesylate corresponding to alcohol 60_ was however carried out along lines similar to that shown in equation [7] (no double bond present). Oxidation of the rearranged alcohol afforded the tetracyclic keto acetonide 17. The acquisition of the keto acetonide J7_ completes a formal total synthesis of (±)-aphidicolin since this compound has previously (17) been converted into (±)-l. - 24 -DISCUSSION 1. A Brief Summary of the Synthetic Route The synthetic route we employed i n our synthesis of the raceraic stemodane-type diterpenoids 3_ - b_ i s presented i n compressed form, i n terms of a retrosynthetic a n a l y s i s , i n Scheme IX. It i s proposed to discuss this analysis only b r i e f l y here, and to leave a more detailed discussion of the various steps, or sequences of steps, to the appropriate section i n the Discussion. Previous work on t h i s project i n our laboratory (31,32) had res u l t e d i n the development of a route to the t e t r a c y c l i c dione 63. Looking at the structures of stemodin 3_, stemodinone 4_, maritimol 5^  and 2-desoxystemodinone 6^, which d i f f e r only i n t h e i r f u n c t i o n a l i t y , or lack of i t , i n the A-ring, we reasoned that i t should be possible to synthesize a l l four of these products from the common intermediate 6l_, having a carbonyl group at C-2.^ Some of the work ca r r i e d out i n previous published syntheses of these molecules 3_ - j> i s of relevance here. Corey et a l . (22), i n t h e i r A l l the t e t r a c y c l i c products such as 61_ are numbered following the numbering system proposed for the stemodane skeleton (10), which i s shown i n structure 10. The other carbon skeletons 69_ - 73_ found in t h i s thesis are numbered following the schemes used i n Chemical Abstracts. The side chains are then numbered as required (non-systematically) with l ' , 2 ' . . . or 1",2".... 17 H H 5 H 4 8 6 H 5 18 10 6 9 70 Scheme IX - 26 -synthesis of stemodin 3_ and stemodinone 4^  made the alkene _55_ and converted i t , v i a a 3-step sequence, into (±)-stemodinone 4_. Reduction of the C-2 carbonyl group of (±)-4_ then generated (±)-stemodin J 3 . Marini Bettolo and co-workers (23) have recently reported the oxidation of racemic maritiraol 5^  i n t o our proposed key intermediate, the ketone 61. This ketone was then transformed into (±)-2-desoxystemodinone 6_ and also into Corey's alkene 55. The work of both these groups w i l l be discussed i n more d e t a i l l a t e r . In our work (Section 11) the ketone (>1_ was converted into (±)-maritimol 5_, and in t o (±)-steraodin ^, v i a the alkene 55. Thus, i n addition to completing the synthesis of stemodin and maritimol, we have also completed a formal t o t a l synthesis of (±)-2-desoxystemodinone 6_ (via synthesis of 61) and (±)-stemodinone 4_ (by synthesis of 55). Elaboration of the t e t r a c y c l i c dione 63_ into the desired keto alcohol 61 posed three major problems: ( i ) As we need to introduce geminal methyl groups at C-4, how are we going to d i f f e r e n t i a t e between the three d i f f e r e n t e nolizable s i t e s at C-2, C-4, and C-12 i n compound 63? The C-14 carbon i s already e f f e c t i v e l y "blocked" to proton abstraction by the nature of the rin g system, since the enolate 74_ which would be generated as a r e s u l t of proton abstraction at C-14 would be highly strained (an anti-Bredt (42, 43) compound) and thus would not be expected to form to any s i g n i f i c a n t extent. 71 72 73 7 4 ( i i ) How are we going to d i f f e r e n t i a t e between the two carbonyl groups i n the A- and D-rings of compound 63? Both are i n 6-membered rings and both are situated i n s i m i l a r s t e r i c environments. ( i i i ) How are we going to add the methyl group to the ketone carbonyl at C-13 with the correct stereochemistry? The desired configuration i s that i n which the hydroxyl group i s a x i a l and the methyl group equatorial to the D-ring. The solution to this problem i s not obvious since no one side of the C-13 carbonyl group i n compound 63_ i s much less hindered than the other, and the addition of organometallic reagents (e.g. MeLi or MeMgBr) to - 28 -r i g i d cyclohexanones i s frequently non-stereoselective (44). We reasoned, a f t e r examination of molecular models of the t e t r a c y c l i c dione _63_ and the alkylated dione 62_, that, i f we wanted to d i f f e r e n t i a t e between the two carbonyl groups at C-3 and C-13 on s t e r i c grounds, we were better off t r y i n g to do th i s at the stage of the alkylated dione 62. In t h i s compound, 62, the C-13 carbonyl moiety i s more "open" ( i . e . s t e r i c a l l y more accessible) than that at C-3, since the l a t t e r p o s i t i o n i s now adjacent to a quaternary centre. 62 76 Our immediate target, then, became the alkyla t e d dione 62^ . The approach we employed to make th i s compound (see eq. [8]) involved f i r s t - 29 -b l o c k i n g both C-2 and C-12 to proton a b s t r a c t i o n by generating the 1 2*11 12 A • ' ' - b i s enone 75. This proved to be unexpectedly d i f f i c u l t , and our work i n t h i s area w i l l be discussed i n Section 8. I t i s r e a d i l y apparent that the only protons i n the b i s enone 7_5_ which are a v a i l a b l e f o r enolate anion formation are those at C-4. Thus, d i m e t h y l a t i o n of t h i s b i s enone, followed by removal of the b l o c k i n g double bonds i n compound 76, afforded the des i r e d a l k y l a t e d dione 62_ ( S e c t i o n 9 ). With compound 62_ i n hand, i t proved p o s s i b l e , using the l e s s r e a c t i v e organometallic reagent MeTi(Oi-Pr)3 (45), to add a methyl group both r e g i o s e l e c t i v e l y and s t e r e o s e l e c t i v e l y to the carbonyl group at C-13. This work, as w e l l as the s o l u t i o n s others have developed to generate the C-13 stere o c e n t r e , i s discussed i n Section 10. The o v e r a l l s t r a t e g y we used to synthesize the key t e t r a c y c l i c dione 6>3_ (31,32) i s e s s e n t i a l l y the same as that employed by McMurry (16,17) i n h i s synthe s i s of (±)-aphidicolin _1. The f i n a l skeleton and the way the various transformations were accomplished are, however, qu i t e d i f f e r e n t . The D-ring of compound 63_ was closed by what i s f o r m a l l y analogous to a d d i t i o n of a carbonyl dianion (" 2^=0") to the dimesylate 64. This t r a n s f o r m a t i o n was c a r r i e d out i n our case (32) v i a the sequence shown i n equation [ 9 ] , The key step i n t h i s sequence was a base-promoted Thorpe-Ziegler condensation of the d i n i t r i l e s 7_7_ (a mixture of epimers at C-2) to form the t e t r a c y c l i c e n a m i n o n i t r i l e 78. This r e a c t i o n sequence, as w e l l as the formation of the dimesylates 64_ from the keto e s t e r 65_, w i l l be discussed i n S e c t i o n 6. One rather unfortunate consequence of t h i s s e r i e s of r e a c t i o n s - 30 -was that the k e t a l function at C-3 was hydrolyzed i n the l a s t step. An a l t e r n a t i v e (unsuccessful) method for e f f e c t i n g t h i s D-ring closure without concomitant loss of the ketal group i n the A-ring was investigated b r i e f l y , and i s discussed i n Section 7. The introduction of the 2-carbon side chain present i n the keto ester 65, with the required stereochemistry at C-9b, was accomplished i n 3 steps from the enone 66. Nonstereoselective photocycloaddition of allene to the enone J56_ provided a 1:1 mixture of the two photoadducts 79_ and 80. Both these compounds were then transformed, as shown i n equation [10], into the same keto ester 65. The conversion of the a-photoadduct 80_ into compound 65, rather - 31 -than the isomeric e s t e r 81 , was t o t a l l y unexpected since what we had appar-e n t l y e f f e c t e d was e p i m e r i z a t i o n at the i s o l a t e d C-9b quaternary centre. P o s s i b l e mechanisms by which t h i s novel transformation occurs are presented i n S e c t i o n 5, while the p h o t o c y c l o a d d i t i o n of a l l e n e to the enone 66_ and some r e l a t e d work are discussed i n Secti o n 4 . The key t r i c y c l i c enone 66_ had been prepared p r e v i o u s l y i n our l a b o r a -tory from the keto k e t a l 6J_ v i a a number of d i f f e r e n t routes ( 3 1 , 3 2 ) . In Se c t i o n 3 of t h i s t h e s i s a f u r t h e r method f o r e f f e c t i n g the required c y c l o -pentenone annulation i s discussed. The sequence of r e a c t i o n s employed i s shown i n equation [11] . - 32 -[11] 66 The required keto k e t a l 67_ was made, i n a s t r a i g h t f o r w a r d s e r i e s of steps, from the w e l l known Wieland-Miescher ketone 68^  (46) f o l l o w i n g the procedures reported e a r l i e r (31,32)(Section 2 ) . The reader may w e l l have wondered why the geminal methyl groups r e q u i r e d at C-4 i n the target n a t u r a l products _3 - j> were not introduced at the s t a r t of the s y n t h e t i c sequence (e.g. using compound Sk_, rather than the keto k e t a l 67). In l i g h t of the d i f f i c u l t i e s we experienced i n o - 33 -Scheme X - 34 -However th i s project was o r i g i n a l l y planned to lead to the synthesis of both the aphidicolane- and stemodane-type diterpenoids, 1_ and 3_ - 6. As previously mentioned, the photoaddition of allene to the enone 66_ provided a separable mixture (=1:1) of the two photoadducts 7_9_ and 80. Since i t was found that the photoadduct 79_ could be e f f i c i e n t l y converted into the keto ester 65_ (31), i t was expected that, i n an analogous manner, the ct-photoadduct 80 would be converted into the ester 81. In t h i s manner, then, we would have made two intermediates p o t e n t i a l l y suitable for elaboration into both the stemodane and aphidicolane skeletons (see Scheme X). Since the f u n c t i o n a l i t y present at C-4 i n a p h i d i c o l i n 1_ d i f f e r s from that found i n compounds 3_ - 6_, the substituents at C-4 must obviously be introduced a f t e r the photoaddition step. Because we had already made substantial amounts of the t r i c y c l i c enone 65 before we knew that both photoadducts 79 and 80 were converted into the same keto ester 65_ (suitable only for synthesis of the stemodane skeleton), i t was decided to use the material we had already made and to bring i n the geminal methyl groups at C-4 l a t e r i n the sequence. 2. P r e p a r a t i o n of the B i c y c l i c Keto K e t a l 67 The synthesis of the keto k e t a l 67_ from the Wieland-Miescher ketone 68_ (46) i s straightforward, and was ca r r i e d out as shown in Scheme XI, following methods developed e a r l i e r i n our laboratory (31,32). Greater d e t a i l regarding these steps may be found i n these e a r l i e r theses (31,32). - 35 -67 Scheme XI 3. Synthesis of the T r i c y c l i c Enone 66_ A number of methods have been developed to carry out the o v e r a l l a n n ulation r e a c t i o n represented i n general terms by 85_ •+ 86. A summary of some of these methods i s provided i n r e f . (47). The required transforma-A • 4 85 86 t i o n , i n our work, i s shown below. Thus, a l k y l a t i o n of the enolate anion of the ketone 67_ w i t h the s y n t h e t i c equivalent of an "acetonyl c a t i o n " _87_ a f f o r d s , a f t e r appropriate unmasking, the 1,4-dione 83. Base-promoted - 36 -n i base O B 4 83 66 87 67 o 88 i n t r a m o l e c u l a r a l d o l condensation of t h i s 1,4-diketone j$3_ should then generate the desired cyclopentenone 66. A number of reagents have been developed to serve as eq u i v a l e n t s of the c a t i o n 87_ i n t h i s a l k y l a t i o n r e a c t i o n . However, the c o n d i t i o n s which have been required to unmask the hidden acetonyl side chain have f r e q u e n t l y been rather vigorous, and have thus l i m i t e d the choice of f u n c t i o n a l groups which may be present i n the k e t o n i c s u b s t r a t e . For example, i n our case (compound 67) i t i s necessary to avoid s t r o n g l y a c i d i c c o n d i t i o n s since a k e t a l f u n c t i o n i s present i n the A - r i n g . This problem, and the s o l u t i o n s which have been developed to overcome i t , have been discussed i n greater d e t a i l elsewhere (32,47). A second more serious problem i s that the i n i t i a l l y - f o r m e d enone 66_ may, under the co n d i t i o n s of the a l d o l condensation, undergo a base-catalyzed i s o m e r i z a t i o n to the isomeric and, i n the present case, thermodynamically more st a b l e enone 88. In i n v e s t i g a t i n g t h i s r e a c t i o n w i t h a s t r u c t u r a l l y s i m i l a r s u b s t r a t e , J39_, Brown and Ragault (48,49) found that t h i s problem of double - 37 -89 90 91 bond isomerization could be avoided by carrying out the a l d o l condensation 2 under ap r o t i c conditions. Thus, i n our case, treatment of the dione 83 with sodium tert-butoxide (2 equivalents) i n re f l u x i n g benzene was reported (31) to a f f o r d a 79% y i e l d of the desired enone 66, along with 18% of i t s isomer 88. More recently McMurry (16,17) found, i n connection with his synthesis of a p h i d i c o l i n _1_, that, i f the a l d o l condensation of the s i m i l a r 1,4-diketone Under p r o t i c conditions (_t-BuOK, t_-BuOH) mixtures of the two isomers are formed (48,49). - 38 -93 was c a r r i e d out with sodium hydride i n benzene containing a small amount of tert-amyl a l c o h o l , a 95% y i e l d of the desired enone 19_ was obtained. The cyclopentenone annulation sequence they employed i s shown i n equation [12]. Further work in our laboratory (32,47) led to the development of a new cyclopentenone annulation method. This method i s shown i n equation [13], and proceeds i n an o v e r a l l y i e l d of 63%. Thus, a l k y l a t i o n of the enolate anion of [13] 66 96 the ketone 67_ with dimethyl 3-bromo-2-ethoxypropenylphosphonate 94_ gave compound 9_5, which was hydrolyzed under controlled conditions to generate the diketo phosphonate 96. Intramolecular Horner-Emmons reaction of 96_ then afforded the enone 66, free of any of the undesired isomer 88. We also became interested i n determining whether or not we could suc c e s s f u l l y apply McMurry's a l d o l condensation procedure (16,17) to the formation of the enone 66_ from compound 67. Somewhat to our surprise then, we - 39 -found that a l k y l a t i o n of the li t h i u m enolate anion of 67_ with methallyl iodide (50) i n tetrahydrofuran at 0°C proceeded to give a mixture of the two epimeric a l k y l a t e d k e t a l ketones 82_ and 97_, along with 5% of the di a l k y l a t e d material 98 and a trace of s t a r t i n g material. This r e s u l t i s in contrast with previous work i n our laboratory (31) i n which a l k y l a t i o n of 67_ with methallyl iodide was reported to give r i s e to a single epimer. The formation of both epimers 82_ and 97_ Is not, however, a serious problem. I f , a f t e r quenching, the reaction mixture was concentrated and 8 3 6 6 treated for a short while with a small amount of sodium methoxide i n methanol, a single epimer was produced. This epimer i s presumably the desired a-isomer 82, having the methallyl side chain i n the thermodynamically more stable - 40 e q u a t o r i a l o r i e n t a t i o n . This step serves to set up the stereochemistry at C-8 in the target molecules 3_ - _6. A sample of the alkylated keto k e t a l 82_ was i s o l a t e d by chromatography as a white s o l i d , mp 87°C ( l i t . (31) mp 74-76°C), which exhibited s p e c t r a l properties i n accord with the assigned structure. Evidence which confirms the incorporation of the methallyl side chain includes, i n the *H nmr spectrum, the presence of two o l e f i n i c signals (6 4.63 and 4.75) and a broad 3-proton si n g l e t at 6 1.69 attributed to the v i n y l methyl group, as well as a weak band i n the i r spectrum at 1630 cm-^ consistent with the presence of a double bond in the molecule. At t h i s point i t i s perhaps worthwhile considering one further feature of the 1H nmr spectrum of th i s compound 82: the multiplet i n the region 6 3.35-3.63 assigned to the methylene protons on the k e t a l function. Closer examination indicates that this multiplet i s made up of four 1-proton signals, two of which, 6 3.51 and 3.59, are doublets, J_ = 11 Hz. The other two sign a l s , at 6 3.39 and 3.44, are doublet of doublets, J_ = 11, 1 Hz. The higher f i e l d s i gnals, assigned to the two non-equivalent equatorial protons e 99 - 41 -(H e and H ' i n 99) co n t a i n , i n a d d i t i o n to an 11 Hz geminal coupling to H a or H a', a 1 Hz long range mutual coupling (51). Although, w i t h the exception of compound 109, t h i s s i g n a l p a t t e r n i s common to the *H nmr spectra of a l l the compounds prepared i n t h i s study which contain the 2,2-dimethyl-propylene k e t a l f u n c t i o n , we w i l l normally report these s i g n a l s as a "4-proton m u l t i p l e t " . The coupling p a t t e r n of the 2,2-dimethylpropylene k e t a l moiety has been discussed elsewhere i n greater d e t a i l (52). Also i s o l a t e d from chromatography of the a l k y l a t i o n mixture was a small amount of the d i a l k y l a t e d keto k e t a l 98. The *H nmr spectrum of t h i s compound i s c o n s i s t e n t w i t h t h i s s t r u c t u r a l assignment, showing two broad 3-proton s i g n a l s at 6 1.61 and 1.71 a t t r i b u t e d to the two v i n y l methyl groups, and a t o t a l of four o l e f i n i c protons. Double bond cleavage of the a l k y l a t e d product ( i . e . 82_ •*• 83) was, i n our hands, best c a r r i e d out using a m o d i f i c a t i o n of a procedure reported by Evans .et a l . (53). Thus, the crude mixture of products, obtained a f t e r a l k y -l a t i o n of the keto k e t a l 67_ w i t h m e t h a l l y l i o d i d e and subsequent e p i m e r i z a t i o n of the i n i t i a l l y formed product mixture, was t r e a t e d w i t h 6 equi v a l e n t s of sodium periodate and a c a t a l y t i c amount of osmium t e t r o x i d e i n a mixture of water and t e r t - b u t a n o l . An equivalent of sodium acetate was al s o added to suppress a small amount of k e t a l cleavage which occurred i n i t s absence. A f t e r appropriate workup an 88% y i e l d (based on the keto k e t a l 67) of the desi r e d 1,4-dione 83_ was obtained. This 1,4-diketone 83, mp 90-91 °C ( l i t . (31) mp 77-78°C), e x h i b i t e d s p e c t r a l data i n accord w i t h the assigned s t r u c t u r e . In p a r t i c u l a r , the *H nmr spectrum e x h i b i t e d no s i g n a l s due to o l e f i n i c protons, but did show a 3-proton s i n g l e t at 6 2.20 which may be a t t r i b u t e d to the C-3' methyl group. - 42 -Our attempts at e f f e c t i n g the c r u c i a l i n t r a m o l e c u l a r a l d o l condensation of the 1,4-diketone 83_ using the sodium hyd r i d e - b e n z e n e - c a t a l y t i c t e r t - a m y l a l c o h o l procedure described e a r l i e r (16,17)(see eq. [12]) were somewhat l e s s s u c c e s s f u l than that reported by McMurry. In our i n i t i a l s m a l l - s c a l e reac-t i o n s , i t was found t h a t , i f t h i s r e a c t i o n was allowed to proceed u n t i l only a l i t t l e s t a r t i n g m a t e r i a l remained, s i g n i f i c a n t amounts of double bond i s o m e r i -z a t i o n ( i . e . 66_ •*• 88) occurred. Separation of these two enones, 66_ and 88, was d i f f i c u l t . For t h i s reason, and also because the isomerized enone 88_ was of l i t t l e use to us, subsequent r e a c t i o n s were not allowed to proceed to completion. Heating a mixture of the dione 83_ w i t h 1.25 e q u i v a l e n t s of sodium hydride and 0.3 equivalents of tert-amyl a l c o h o l i n benzene under r e f l u x f o r 1 hour a f f o r d e d , a f t e r workup and chromatographic s e p a r a t i o n , 11% of the s t a r t -in g dione 83_, 73% of the d e s i r e d enone 66, plus 5% of a mixture of the two isomeric enones, (&_ and 88. The y i e l d of the enone 66_, based on unrecovered s t a r t i n g m a t e r i a l , was thus 83%. We observed that i n t h i s r e a c t i o n the extent to which double bond i s o m e r i z a t i o n occurred depended very s i g n i f i c a n t l y on the p a r t i c u l a r batch of sodium hydride that was used. Although the reasons underlying t h i s observa-t i o n are not c l e a r , i t i s q u i t e p o s s i b l e that b e t t e r samples of sodium hydride may give r e s u l t s s u p e r i o r to those which we obtained. Both the enone 6£, mp 115-116°C ( l i t . (32) mp 116-117°C) and the isomerized enone 88, mp 139-140°C ( l i t . (31) mp 136.5-137°C), e x h i b i t e d s p e c t r a l data i d e n t i c a l w i t h that reported e a r l i e r (31,32). I t i s perhaps p e r t i n e n t at t h i s point to look b r i e f l y at the evidence used to assign the s t r u c t u r e s of the enones 66_ and 88. Both compounds show bands i n the i r spectrum at 1690, 1670 and 1600 (66) or 1610 ( 88 ) cm , consistent with the presence of an a,^-unsaturated ketone i n a 5-membered r i n g . The structure of the major product 66_ was subsequently v e r i f i e d by determination of the structure of compound 7_9_, an allene photoadduct of 66^ , by X-ray crystallography. Three other isomeric structures, 88_, 100 and 101 are, at least i n theory, possible for the unwanted enone formed during the a l d o l condensation. However, isomerization of the desired enone into compounds 100 100 88 101 or 101 can be ruled out since examination of molecular models of these two enones 100 and 101, indicates that, i n these compounds, the B-ring i s required to adopt an unstable boat-like conformation. Consequently, structure 88 was assigned to the isomeric enone. Examination of a molecular model of compound j88_ shows that, in t h i s enone, the protons of the angular methyl group are situated within the " s h i e l d i n g cone" (51) of the enone double bond. This would lead one to 66 88 - 44 -predict that the angular methyl group protons in compound 88_ should resonate at unusually high f i e l d . This Is indeed the case, since the *H nmr spectrum of 88_ shows a 3-proton s i n g l e t at 6 0.64. In contrast to t h i s value, the bridgehead methyl group protons in the isomer 66_ resonate at 6 1.13. Furthermore ( c f . ref. 31), the o l e f i n i c proton at C-l i n compound 66_ resonates as a doublet, J_ = 1.5 Hz, e x h i b i t i n g an a l l y l i c coupling to the C-3a proton ( 6 2.98). On the other hand, the o l e f i n i c proton of the isomer 88 resonates at 6 5.90 as a doublet of doublets, J_ = 2, 2 Hz. One of these a l l y l i c couplings i s to the C-9b proton ( 6 2.54), and the other i s presumably to the C-4oc proton. As compound 66_ possesses only one a l l y l i c proton, t h i s provides further evidence to support the assigned structures j>6_ and 88. Thus the cyclopentenone annulation procedure described above, which proceeds i n an o v e r a l l y i e l d of 73%, compares favourably with annulation v i a the bromophosphonate route (see eq. [13]). 4. Ph o t o a d d l t i o n Studies 4.1 Ph o t o a d d i t i o n of A l l e n e to the Enone 66_ The next task we faced was addition of an appropriate side chain at C-9b of the enone 66, i n order to incorporate some, or a l l , of the extra carbons required to complete the D-ring. Furthermore t h i s side chain had to be introduced s t e r e o s e l e c t i v e l y from the p-face of the molecule to allow for synthesis of the desired stemodane skeleton. - 45 -I n i t i a l attempts (31) to introduce t h i s side chain by conjugate addi-t i o n of a vinylcuprate reagent to the enone 66_ f a i l e d , presumably due mainly to the extremely hindered nature of the C-9b centre. McMurry (17), i n his synthesis of a p h i d i c o l i n \_, reported a s i m i l a r observation. The approach we eventually chose i s shown i n equation [15](ignoring stereochemistry), and involves photoaddition of allene to the enone 66, oxida-t i v e cleavage of the double bond i n the photoproduct 102, and f i n a l l y opening 66 102 103 [15] of the cyclobutanone r i n g by treatment of the 1,3-dione 103 with sodium methoxide (31,32). One can see that what this procedure accomplishes, i n an o v e r a l l sense, i s the formal addition of a methyl acetate anion, in a conjugate fashion, to the enone 66. A number of workers have u t i l i z e d variants of t h i s procedure as a way of adding a f u n c t i o n a l i z e d two-carbon side chain to the B - p o s i t i o n of an enone (12,23,25,29,39,40,54). Looking at equation [15] one can see that the new c h i r a l centre at C-9b w i l l be introduced i n the photoaddition step. It was not clear at the outset of this project what the stereochemistry of this photoaddition would be. Wiesner (55) has proposed two rules which may be used to predict the stereo-chemistry of such photoadditions. These rules w i l l be discussed l a t e r (Section 4.4) i n l i g h t of our r e s u l t s . - 46 -In p r a c t i c e , i t turned out (31) that photoaddition of allene to the enone 66 i n THF at -78°C, gave a chromatographically separable 1:1 mixture of two photoadducts 79_ and 80. The structure of 79_ was established by X-ray analysis (56) and the other adduct was assigned structure 80. The lack of s t e r e o s e l e c t i v i t y i n the photoaddition was, i n f a c t , a bonus, since i t then appeared that, as discussed i n Section 1, we would be able to synthesize both the stemodane- and aphidicolane-type diterpenoids. Cleavage of the exocyclic double bond of the (3-photoadduct 79_ by ozono-l y s i s , followed by treatment of the crude 1,3-dione 104 with sodium methoxide i n methanol, gave the keto ester 65_ (31,32). However, treatment of the other photoadduct, which had been assigned structure 80, under i d e n t i c a l conditions, gave r i s e , i n good y i e l d , to the same keto ester 65_ (32). It was thus clear that, either the structure 80_ assigned to the second photoadduct was i n -cor r e c t , or an i n t e r e s t i n g rearrangement had occurred. One p o s s i b i l i t y (32) was that the second photoadduct possessed the trans-fused bicyclo[3.2.0 ]-heptanone structure 106. While such a proposal could r e a d i l y account for the transformation of t h i s photoadduct Into the keto ester 65, t h i s highly strained structure appeared u n l i k e l y . - 48 -alkenes and cyclopentenones (55,57,60). Furthermore, a l l reported allene photoadditions occur l n a c i s - f a s h l o n (see for example r e f s . 55,57,60). Further evidence for the structure of the second photoadduct was obviously d e s i r a b l e . Because of our i n a b i l i t y to obtain c r y s t a l s of t h i s substance of suitable q u a l i t y for X-ray analysis, the photoadduct was reduced with sodium borohydride to y i e l d a single alcohol ( i r : 3540 and 3450 cm - 1). This alcohol was obtained as a viscous o i l which could not be c r y s t a l l i z e d . However both t i c and the *H nmr spectrum of t h i s o i l (only 3 t e r t i a r y methyl group signals) indicated the presence of only one compound. The p-bromo-benzoate of this alcohol c r y s t a l l i z e d as cubes (mp 184-185°C) which were of suitable q u a l i t y for X-ray a n a l y s i s . This a n a l y s i s , c a r r i e d out i n our department (61), showed the structure of the p_-bromobenzoate to be 107. Hence the structure of the second photoadduct must be 80_, as was o r i g i n a l l y assigned. The mechanism(s) by which this material i s converted into the keto ester j>5_ w i l l be discussed i n Section 5. A more c a r e f u l reexamination of the photocycloaddition of allene to the enone 6b_ revealed that, i n addition to the two major head-to-head photoadducts , C 6 H « B r 80 107 - 49 -79 (40%) and 80_ (51%) i s o l a t e d previously, two further minor products were formed. These isomeric products were assigned structures 108 and 109, and represented 6 and 3% respectively of the photoadduct mixture. 108 109 The two major photoadducts 79_ and 80_ were i s o l a t e d , as previously described (31,32), by a combination of chromatography and r e c r y s t a l l i z a t i o n , and were i d e n t i c a l (mp, t i c , *H nmr) with samples prepared previously. One feature common to the *H nmr spectra of both 79_ and 80_ (also 110 and 111, Section 4.2) are the signals attributed to the protons on and around the cyclobutane r i n g . The |3-photoadduct 79 serves as an example. The protons on C-9, and C-lOa, along with the two o l e f i n i c protons, form an almost i s o l a t e d system. In this system, with the exception of a very small or non-existent mutual coupling between the two o l e f i n i c protons, each proton i s - 50 -coupled to a l l four other protons (long range couplings across a cyclobutane ring are well documented (51)). The signals at 6 4.95 ( s i g n a l 1) and 4.80 ( s i g n a l 2) were assigned to the two o l e f i n i c protons while the broad s i n g l e t at 6 3.26 ( s i g n a l 3) was a t t r i b u t e d to the proton at C-lOa, which i s both a l l y l i c and a- to the carbonyl group. The two C-9 protons resonate at 6 2.83 ( s i g n a l 4) and 6 2.66 ( s i g n a l 5) as doublets which also show further coupling. By a series of decoupling and spectrum simulation experiments, the coupling constants shown i n Table 1 were determined ( a l l coupling constants were assumed to be of the same sign). Figure 1 shows that the simulated p a r t i a l spectrum and the appropriate parts of the actual spectrum (400 MHz) are i n good agreement. Since a decoupling experiment indicated the presence of a small (1 Hz) coupling between the C-lOa proton ( s i g n a l 3) and a proton giving r i s e to a signal at 6 1.89 (assigned to the C-2a proton), this coupling constant was also included i n the simulation. Neither the coupling constants determined above nor the chemical s h i f t s allow one to assign signal 1 s p e c i f i c a l l y to one of the two o l e f i n i c protons i n compound 79. S i m i l a r l y , i t was not possible to assign signals 4 and 5 to one of the two C-10 protons. 79 - 51 -Table 1. Coupling Constants Between the Protons On and Around the Cyclobutane Ring i n Compound 79 Coupling Constant Value/Hz J l , 2 a 0 J l , 3 1.5 J l , 4 " J2,4 2 J l , 5 = J2,5 2.5 J2,3 2 J3,4 2.5 J3,5 3.0 J4,5 17.0 ° J j 2 means the coupling between the two protons giving r i s e to signals 1 and 2. By virt u e of the fact that the head-to-tail photoadducts 108 and 109 are apparently less susceptible to ozonolysis (perhaps due to s t e r i c f a c t o r s ) , i t proved possible to i s o l a t e small samples of these two products. Thus a mixture of a l l four photoadducts 79, 80, 108 and 109 was subjected to ozono-l y s i s and the resultant crude product was treated with sodium methoxide i n methanol (see Section 5). Chromatography of the mixture of products thus obtained provided, i n addition to the keto ester j)5_, a small amount (=3% Figure 1. The P a r t i a l XH nmr spectrum of J_9_: The s i g n a l s assigned to the protons on and around the cyclobutane r i n g . a) The a c t u a l spectrum (400 MHz) b) I t s computer s i m u l a t i o n y i e l d ) of a r e l a t i v e l y nonpolar mixture of products, c o n t a i n i n g mainly compounds 108 and 109. Rechromatography of t h i s mixture provided pure samples of H)8, mp 132-133.5°C, and 109_, mp 146-148°C. In a d d i t i o n to t h e i r chemical o r i g i n and s i m i l a r chromatographic behaviour ( t i c , g l c ) , the f o l l o w i n g evidence suggested that the two minor products 108 and 109 were isomeric w i t h the known photoadducts 79_ and 80. Both compounds (C22H32°3» HRMS) e x h i b i t e d a band i n the I r spectrum at 1720 - 53 -,0 108 109 - l cm~J' and a l s o a weak band at 1660 (109) or 1650 (108) cm - 1. These two bands were a t t r i b u t e d to the 5-membered r i n g ketone and the e x o c y c l i c methylene group, r e s p e c t i v e l y . Furthermore, the *H nmr spectra of both compounds e x h i b i t e d s i g n a l s due to two o l e f i n i c protons and showed three 3-proton s i n g l e t s , which may be assigned to the t e r t i a r y methyl groups. The assignment of the stereochemistry to these two products r e s t s on three pieces of 1H nmr data: ( i ) The spectrum of 109 shows an unusually h i g h - f i e l d (6 0.89) 1-proton m u l t i p l e t . Examination of molecular models shows t h a t , i n compound 109, the C-8a proton i s s i t u a t e d d i r e c t l y i n the s i m i l a r l y - s h i e l d e d proton e x i s t s i n the p-isomer 108. ( i i ) Examination of a molecular model shows t h a t , i n the 6-isoraer 108, one of the o l e f i n i c protons i s i n cl o s e p r o x i m i t y to the angular methyl group. That t h i s i s indeed the case was shown by a nuclear Overhauser e f f e c t (N0E) d i f f e r e n c e experiment (62). Thus, on i r r a d i a t i o n of a l l three t e r t i a r y methyl groups of 108 ( i t was not c l e a r which s i g n a l was due to the bridgehead methyl s h i e l d i n g cone produced by the o l e f i n i c double bond. No - 54 -group) a small NOE enhancement of the o l e f i n i c s i g n a l at 6 5.26 was observed. No such enhancement of the o l e f i n i c signals was observed on i r r a d i a t i o n of the three t e r t i a r y methyl groups of the a-isomer 109. ( i i i ) In the p-isomer 108, one of the o l e f i n i c protons resonates s i g n i -f i c a n t l y downfield (6 5.26) of the o l e f i n i c protons i n compounds 79, 80 and 109 (6 4.8-5.02). Since s t e r i c compression i s known to deshield protons, t h i s evidence i s also consistent with one of the o l e f i n i c protons being i n close proximity to the angular methyl group. As discussed above, i t i s this downfield o l e f i n i c s i g n a l which shows a NOE enhancement on i r r a d i a t i o n of the angular methyl group. 4.2 P h o t o a d d i t i o n o f A l l e n e t o t h e E n o n e 88 As we had a sample of the enone J38_ on hand, i t was also of i n t e r e s t to look at the stereochemistry of allene photoaddition to t h i s enone. I r r a d i a -t i o n of a -78°C solution of the enone J$8_ i n tetrahydrofuran containing an excess of allene gave, af t e r workup and chromatography, a 96% y i e l d of a mixture of the four possible photoadducts 110, 111, 112 and 113, i n the approximate r a t i o of 48:37:3:12. This product r a t i o was determined by i n t e g r a t i o n over the o l e f i n i c region of the 400 MHz *H nmr spectrum of the photoadduct mixture. The chemical s h i f t s assigned to the two o l e f i n i c protons 3 This e f f e c t i s a t t r i b u t e d to intramolecular van der Waals forces operating between two non-bonded atoms which are in close proximity to each other. These forces cause the electron clouds of the two atoms to undergo assymetrical d i s t o r t i o n leading to mutual deshielding of the n u c l e i ! (51). - 55 -i n each of the four isomers are given above, along with, i f possible, the chemical s h i f t of the bridgehead methyl group. Samples of the two major photoadducts, 110 and 111, could be i s o l a t e d , with d i f f i c u l t y , by a combination of chromatography and r e c r y s t a l l i z a t i o n . Both photoadducts, 110 (mp 151-152°C) and 1_11_ (mp 163-165°C), exhibited s p e c t r a l data consistent with the presence of a 5-membered ring ketone ( i r : 1720 cm - 1), a double bond ( i r : 1665 (110), or 1660 (111) cm"1) and two d i f f e r -ent o l e f i n i c protons ( XH nmr, chemical s h i f t s as above). The assignment of the stereochemistry of these two products was made on the basis of the chemical s h i f t s of the angular methyl groups (see above). Examination of molecular models of 110 and 111 shows that, i n the a-adduct 111 the protons on the angular methyl group are situated i n the shielding cone of - 56 -o 110 111 the carbonyl group. Hence, as i s observed, the angular methyl group protons of 111 would be expected to resonate u p f i e l d of those i n the 8-isomer 110. Some corroborating evidence may be found i n the 1H nmr spectrum of the 8-isomer 110. One of the a l l y l i c C-4 protons i n 110 resonates at 6 3.11, s i g n i f i c a n t l y downfield of the signals a t t r i b u t e d to s i m i l a r protons i n compounds 79, 80 and 111 (6 = 2.4-2.9). Molecular models show that in the B-isomer 110 the C-4p proton Is i n close proximity to the angular methyl group and, as discussed e a r l i e r , might therefore be expected to be deshielded r e l a t i v e to other s i m i l a r protons. The two minor photoadducts 112 and 113 were not obtained in pure form and the s t r u c t u r a l assignments must therefore be regarded as tentative. By analogy with the photoaddition of allene to the isomeric enone 66_, the minor products were assumed to be head-to-tail photoadducts. During attempted p u r i -f i c a t i o n of 111, the *H nmr spectrum of a p a r t i a l l y p u r i f i e d sample showed, i n addi t i o n to the signals due to 111, minor signals at 6 0.63, 4.84 and 4.94. These three signals may be assigned to the 12% component in the photoadduct mixture. Using a l i n e of reasoning s i m i l a r to that described above, based / - 57 -upon the chemical s h i f t of the angular methyl group, we suggest s t r u c t u r e 113 f o r t h i s 12% component. The s t r u c t u r e of the 3% component i n the photoadduct mixture was assigned as 112 mainly because i t represents the only other isomer p o s s i b l e . Examination of a model of 112 i n d i c a t e s t h a t , l i k e compound 108, one of the o l e f i n i c protons i s i n close proximity to the angular methyl group. One might t h e r e f o r e expect, as found i n the spectrum of 108, an unusually l o w - f i e l d o l e f i n i c proton. As the p o s i t i o n of one of the o l e f i n i c s i g n a l s (6 5.31) a t t r i b u t e d to t h i s 3% photoadduct i s s i g n i f i c a n t l y downfield of those i n the adducts 110, 111, and 113, t h i s provides some support f o r the s t r u c t u r e 112 assigned to the minor photoadduct. 4.3 Hydrogenation and Li-NH 3 Reduction of 66_ and 88 Since an analogy has been drawn between the stereochemical outcomes of the a l k a l i metal-ammonia reduction of, and the c i s - p h o t o a d d i t i o n of an alkene to an enone system (60,63), i t was of i n t e r e s t to i n v e s t i g a t e the Li-NH 3 reduction of the two enones 66_ and 88. I n s p e c t i o n of the chemical l i t e r a t u r e revealed that the Li-NH 3 reduc-t i o n of two c l o s e l y r e l a t e d hydrindenones 90_ and 9_1_ has been examined by Brown and Ragault (48,49). The p e r t i n e n t r e s u l t s from t h i s study are presented below. Thus, from t h i s study they concluded that Li-NH 3 reduction of both enones _90_ and _91_ gave r i s e to the same trans-fused product 115. C a t a l y t i c hydrogenation of 90_ did not proceed as a n t i c i p a t e d . The authors expected that hydrogenation of 90_ would occur from what they considered to be the s t e r i c a l l y - 58 -more accessible a-face, to give the trans-fused product 115. Instead, they i s o l a t e d the cis-product 114. However, pre d i c t i n g the stereochemical outcome of c a t a l y t i c hydrogenation of a,p-unsaturated ketones i s frequently rather d i f f i c u l t , since a number of factors are involved i n determining the outcome of such a reaction (64). H Ph.CO H», P d - C 90 57?. 217. i Li.NH, ii Ph.CCI.py4 15% H„, P d - C Ph.CO Ph.CO 114 115 Ph .co-i n view of the poor y i e l d s reported i n most of these reactions i t i s rather d i f f i c u l t to conclude that other components are not i n fact present i n During the reduction, the t r i t y l (triphenylmethyl) group was cleaved so r e t r i t y l a t i o n was required. - 59 -the reaction products. Consequently, we decided to investigate the Li-NH 3 reduction and the hydrogenation of both of the enones 66 and 88. Addition of lithium metal (= 2.5 equivalents) to a so l u t i o n of the enone 66_ i n ammonia and ether, containing an equivalent of t e r t - b u t y l alcohol, at -33°C, followed by s t i r r i n g of the reaction mixture for 1 h at the same temperature gave, a f t e r workup and chromatography of the crude product, a 76% y i e l d of a white s o l i d . *H nmr analysis of t h i s s o l i d indicated the presence 3 7 of two compounds having angular methyl groups which resonate at 6 0.85 and 1.03, i n the r a t i o of =7:3. F r a c t i o n a l r e c r y s t a l l i z a t i o n of the mixture from pentane provided a small amount of the minor component, which was i d e n t i c a l ( t i c , *H nmr, mp) with a sample of 118 prepared by c a t a l y t i c hydrogenation of the enone 66_ (vide i n f r a ) . The major product was assigned structure 117, p r i m a r i l y by comparison of the *H nmr spectrum of pure 117 (vide i n f r a ) with that of the mixture of 117 and 118 obtained from the Li-NH 3 reduction of 66. The two reduced products 117 and 118 were inseparable by t i c in a number of solvent systems. C a t a l y t i c hydrogenation of the enone 66_ at atmospheric pressure i n methanol with 5% palladium-on-carbon as c a t a l y s t , proceeded cleanly and - 60 -afforded almost excl u s i v e l y the cis-fused product 118. The XH nmr spectrum of the crude product from hydrogenatlon of 66_ also Indicated the presence of a 4 + 4 [22] 118 117 96% trace trace of the trans product 117. R e c r y s t a l l i z a t i o n of this crude product from pentane afforded a 96% y i e l d of J_18_, mp 152-153°C. The spectral data exhi-bited by t h i s compound, and the reasons for assigning i t structure 118 w i l l be discussed l a t e r , i n conjunction with a more detai l e d discussion of the spec-t r a l data exhibited by compounds 117 and 119. LI-NH3 reduction of the isomeric enone 88_, under conditions very s i m i l a r to those used i n the reduction of 66_, proceeded to give almost exclu-s i v e l y the trans-fused product 117. As overreduction of the saturated ketone was a problem i n th i s case, the crude L1-NH3 reduction products were oxidized with pyridinium chlorochromate (PCC) (65) to give, a f t e r chromatography of the crude product thus obtained, a 66% y i e l d of compounds 117 and 119 i n the r a t i o of 99:1 ( g l c ) . R e c r y s t a l l i z a t i o n of t h i s s o l i d provided a pure sample of the trans-fused product 117, mp 91.5-92°C. A small amount ( = 8%) of s t a r t i n g material 88_ was also recovered from t h i s reaction. C a t a l y t i c hydrogenatlon of the enone 88_ did not proceed as cleanly as that of the isomer 66. Thus, hydrogenatlon of 88_ at atmospheric pressure i n H,,Pd-C 6 6 - 61 -dry dioxane with 5% palladium-on-carbon as catalyst afforded, a f t e r chromato-graphy, an 88% y i e l d of a 95:5 mixture (glc) of 119 and 117. 8 8 117 119 5 95 R e c r y s t a l l i z a t i o n of t h i s s o l i d provided a pure sample of 119, rap 126-128°C. Some s t a r t i n g material remained, and a number of other minor products were also formed. A l l three isomers 117, 118, and U9_ (C 19H 3 0O 3, HRMS), showed, i n t h e i r i r spectrum, a band at 1730 (117 and 119) or 1725 (118) cm - 1, which, although somewhat lower than the more normal range for a cyclopentanone (1750 - 1740 cm - 1), may be at t r i b u t e d to the saturated 5-membered rin g ketone. The assignment of the stereochemistry at C-3a and C-9b of compounds 117 - 119 follows the reasoning of Brown and Ragault (49). The structure of the - 62 -major product obtained from Li-NH 3 r e d u c t i o n of both isomeric enones must be 117, as i t i s formed from the compounds 66_ and 88, i n which the stereochemis-t r i e s at the C-3a and C-9b centres, r e s p e c t i v e l y , are already e s t a b l i s h e d . Since the other two products 118 and 119 are isomeric w i t h the trans-fused product 117, and i n each case the stereochemistry at one of the centres i s already set up i n the precursor (66 and 88_ r e s p e c t i v e l y ) , the s t r u c t u r e s must be 118 and 119. 6(C-9a CH,) 1-04 118 0-85 117 o 0-73 H 119 - 63 -The chemical shifts of the angular methyl groups in the three ketones 117, 118 and 119 are shown above. These chemical shifts are consistent with the assigned structures. Examination of a molecular model of compound 119 shows that, in this compound, the angular methyl group protons are situated in the "shielding cone" of the carbonyl group. These protons would thus be expected to resonate significantly upfield of those in compound 118, in which this effect is not present. This is indeed the case. 4.4 A Discussion of the Stereochemistry of the Photocycloaddition of Aikenes to a,B-Unsaturated Ketones The photoaddition of alkenes to a,8-unsaturated ketones is frequently highly ste reoselective• This stereoselectivity is d i f f i c u l t to rationalize adequately on the basis of either product stability or steric hindrance during approach of the alkene to the enone (55). This has led Wiesner (55) to propose two empirical rules for predicting the stereochemistry of this type of photoaddition. These rules are based upon the geometry of the enone in i t s excited state. In the f i r s t , Rule A, the enone, in Its excited state, is assumed to be trigonal at the a-carbon and pyramidal at the B-carbon (eq. [22]). The 8-carbon is assumed to select the more stable of the two possible epimeric - 64 -configurations, 120 or 121, and reaction with the ground state alkene mole-cule occurs out of the excited state possessing the more stable configura-t i o n . This rule assumes that bonding of the alkene occurs f i r s t to the 8-carbon of the enone ( i t has yet to be established whether or not this i s true (66)). This rule has been found to be very useful, since quite a number of a d d i t i o n a l examples have been reported i n which the stereochemistry of the photoaddition of alkenes to enones can be predicted using this rule (12,23, 25,28,29,40,60,67). The s i m i l a r i t y between the excited states 120 and 121 of the enone, as proposed i n rule A, and the postulated tetrahedral dianion, or r a d i c a l anion (68,69), i n the di s s o l v i n g metal reduction of the same enone, was soon r e a l i z e d . Z i e g l e r (63), i n f a c t , has suggested that i t may be possible to predict the stereochemistry of the cis-photocycloaddition of an alkene to an enone from the re s u l t of an a l k a l i metal-ammonia reduction of the same a, p-unsaturated ketone. A number of examples have shown this to be the case (60,63). Wiesner (60), however, points out that "while the equilibrium constants between the two diastereomeric photo-excited states and anionic intermediates respectively should be s i m i l a r , there i s no reason to expect that they would be numerically i d e n t i c a l " . In his i n i t i a l paper concerning t h i s matter Wiesner (55) also proposed an a l t e r n a t i v e r u l e , Rule B. " I t i s conceivable that the excited state i s planar and the p-carbon i s pyramidalized i n the process of the reaction with the o l e f i n . In such an event the energy of pyramidalization could be related to the s t a b i l i t y of the corresponding pyramidal isomer and the process of con-- 65 -f i g u r a t i o n - s e l e c t i o n would be k i n e t i c a l l y c o n t r o l l e d " . Such a rule i s more d i f f i c u l t to use as a p r e d i c t i v e t o o l than i s rule A. Since i t seems to be accepted that the photoaddition of alkenes to enones proceeds v i a an intermediate b i r a d i c a l (70), presumably what t h i s rule means, i s that the t r a n s i t i o n state i n the photoaddition reaction can " f e e l " the r e l a t i v e s t a b i l i t y of the two possible b i r a d i c a l intermediates 122 and 122 123 123. Once again bonding i s assumed to occur at the p-carbon f i r s t . The extent to which the t r a n s i t i o n state w i l l " f e e l " the s t a b i l i t y of the two possible b i r a d i c a l intermediates could, of course, vary from case to case. The two extremes possible are a r e a c t a n t - l i k e and a product-like t r a n s i t i o n s t a t e . In the former case s t e r i c hindrance during approach of the alkene to the planar excited state of the enone would control the stereochemistry of the photoaddition. If the t r a n s i t i o n state i s product-like, then the stereo-chemistry of the major photoadduct would be that r e s u l t i n g from closure of the most stable b i r a d i c a l intermediate. This rule i s obviously much more d i f f i c u l t to use as a p r e d i c t i v e t o o l , e s p e c i a l l y i n cases where s t e r i c hind-rance i n approach of the alkene to the enone and reaction v i a the most stable b i r a d i c a l intermediate predict opposite r e s u l t s . - 66 -At t h i s point three further pieces of work should be mentioned. In an attempt to d i s t i n g u i s h between rules A and B, C a r g i l l (59) has reported that the photoaddition of ethylene to the cyclohexenone 124 gives a 15:85 mixture of 128 and 129. Analogously, Wiesner found that cycloaddition of allene to 0 1 2 8 1 2 9 4-isopropylcyclohexenone gave a 1:1 mixture of the syn and a n t i cycloadducts (71). C a r g i l l claims that these r e s u l t s are inconsistent with rule A, as t h i s rule would predict 128 to be the major product. Considering only the two possible excited states 125 and 126, i t i s c l e a r that configuration 126 (leading to 129), with an a x i a l t e r t - b u t y l group, i s less stable than the a l t e r n a t i v e excited state 125. However, an important assumption i s made here. - 67 -This i s that, by analogy with Stork's a l k a l i metal-ammonia reduction proposals (68), the o r b i t a l on the 8-carbon of the excited state must overlap with that on the a-carbon and the it-system of the carbonyl group. If such an assumption i s not made, then reaction out of the excited state 127 could e a s i l y account for the formation of 129 as the major product. C a r g i l l ' s r e s u l t (59) i s consistent with rule B. Examination of mole-cular models indicates that the observed product 129 i s that which would be predicted both on the basis of s t e r i c hindrance during approach of the alkene to the enone, and as the product r e s u l t i n g from closure of the most stable b i r a d i c a l intermediate. Valenta and Grien (72) have ca r r i e d out t h e o r e t i c a l c a l c u l a t i o n s on a c r o l e i n , which suggest that none of the excited states of i n t e r e s t in the photocycloaddition of enones to alkenes are pyramidal at the B-carbon. However, the energy b a r r i e r to pyramidalization i s much smaller i n these excited states than i t i s in the ground state. De Mayo (66) has reported the r e s u l t s of his i n v e s t i g a t i o n s into the photoaddition of alkenes to a number of enones. Based on these r e s u l t s and e a r l i e r work from both his and other.groups, he concluded that, i n this photo-add i t i o n , the f i r s t step i s the i r r e v e r s i b l e formation of a t r i p l e t exciplex (73). This intermediate i s s h o r t - l i v e d , and collapses to a 1,4-biradical, which can then either c y c l i z e to the product(s), or revert to s t a r t i n g material. This reversion represents the main source of the i n e f f i c i e n c y i n these cycloaddition reactions. Measured quantum y i e l d s for t h i s photoaddition reaction varied from 0.72 to 0.052. This means that the rate of b i r a d i c a l reversion to closure can be as high as 18:1. - 68 -We are unaware of any quantum y i e l d measurements on the cycloaddition of allene to enones. Such information i s c l e a r l y desirable. If the quantum y i e l d i s high then i t i s v a l i d to suggest, as do Wiesner's ru l e s , that the product d i s t r i b u t i o n i s controlled during the addition of the alkene to the enone. On the other hand, i f the quantum y i e l d i s low, then the product r a t i o s found in these photoaddition reactions must also r e f l e c t the r e l a t i v e rates at which the intermediate b i r a d i c a l s c y c l i z e to product or revert to s t a r t i n g material. What do Wiesner's rules predict for the photochemical cycloadditions c a r r i e d out in our work? Considering f i r s t rule A, for enone 66_, we must consider the two possible excited states 130 and 131. P r e d i c t i n g the r e l a t i v e s t a b i l i t i e s of 130 and 131 i s not as easy as i t i s i n the case of fused 6-membered ring systems. If the assumption i s made that the f i l l e d o r b i t a l i n 130 and 131 has a size comparable to that of a proton (74), then the nonbonded s t e r i c i n t e r a c t i o n s present i n 131 w i l l be less than those present in 130. However, 131 possesses more rin g s t r a i n . We know (Section 5) that 81 rearranges cleanly (at least 95% 5), under thermodynamically controlled condi-tio n s , into the epimeric keto ester 65. This would suggest an energy d i f f e r -ence between 81_ and 65_ of at least 1.7 k c a l m o l - 1 . Since the s t e r i c i n t e r a c -tions present i n both 81_ and 65_ are s i m i l a r , the d r i v i n g force for t h i s rearrangement must be the r e l i e f of ring s t r a i n . A comparable amount of ring s t r a i n should also be present in the excited state 131. Since t h i s extra r i n g This rearrangement was complete as judged by t i c and H nmr. Therefore, the equilibrium i n t h i s reaction may well l i e much more than 95:5 in favour of the keto ester 65. - 69 -81 65 s t r a i n i n 131 would be expected to s i g n i f i c a n t l y exceed the d e s t a b i l i z i n g influence introduced by the a d d i t i o n a l s t e r i c i n t e r a c t i o n s present i n 130, then we would predict, using rule A, that 130 would be the more stable excited state, and hence 79_ the major photoadduct. This r u l e thus appears to f a i l i n the case of our enone 66. In the case of the isomeric enone 88_ the two excited states to be considered are 132 and 133. The p r i n c i p a l d e s t a b i l i z i n g influence present i n 132 i s the r i n g s t r a i n , while the two 1,3-diaxial i n t e r a c t i o n s present i n structure 133 w i l l tend to d e s t a b i l i z e this excited state. It i s thus d i f f i -- 70 -cult to predict which one of these excited states i s the most stable, and hence which photoadduct would be expected to predominate. Perhaps the d e s t a b i l i z i n g influences present i n 132 and 133 almost balance out so that reaction occurs out of both excited states leading to the observed mixture of photoadducts. In a related system, Z i e g l e r (75) has reported that photoaddition of allene to the a,6-unsaturated aldehyde 134 gives almost e x c l u s i v e l y the a-product 136. In t h i s case the excited state 135 i s claimed to be more stable than 137. While rule B can explain the mixture of products formed i n the photo-addition of allene to the enone 66, i t i s unable to r a t i o n a l i z e the mixture of products formed i n photoaddition of allene to the isomeric enone 88. For the - 71 -137 enone 66_ the two possible intermediate b i r a d i c a l s which must be considered are 138 and 139. Since these intermediates should be analogous to the two corres-ponding keto esters 65_ and 8_1_ (see e a r l i e r ) , then reaction v i a the more stable b i r a d i c a l intermediate would predict that the photoaddition should occur predominantly or excl u s i v e l y through the b i r a d i c a l 138, leading to the B-photoadduct 79. In contrast to t h i s , s t e r i c hindrance during approach of the allene to the planar excited state of the enone 66_ would be expected to favour the reaction leading to the a-adduct 80. Thus, to explain the r e s u l t s of the photoaddition in the case of enone 66^ , one must assume a t r a n s i t i o n state i n which s t e r i c hindrance during approach of the allene to the enone, and reaction leading to the more stable b i r a d i c a l intermediate, are of essen-t i a l l y equal importance. For photoaddition to the isomeric enone 88, the two possible b i r a d i c a l intermediates are 140 and 141. A product- ( i . e . b i r a d i c a l - ) l i k e t r a n s i t i o n 79 80 s t a t e would p r e d i c t that photoaddition should occur predominantly v i a the b i r a d i c a l 141 l e a d i n g to the a-adduct 111, as the major product. I t would be a n t i c i p a t e d that the i n s t a b i l i t y due to the 1 , 3 - d i a x i a l i n t e r a c t i o n and the a d d i t i o n a l r i n g s t r a i n present i n the b i r a d i c a l 140, would more than o f f s e t 88 140 141 - 73 -the i n s t a b i l i t y introduced into the b i r a d i c a l 141 by the two 1,3-diaxial 2 i n t e r a c t i o n s of the angular methyl group with the sp centres on the 5-merabered ri n g . S t e r i c hindrance during approach of the allene to the planar excited state of the enone 88_ would also be expected to favour the a-photo-adduct 111. Thus rule B i s unable to r a t i o n a l i z e the observed mixture of products formed i n the photoaddition of allene to 88. Although there i s a good c o r r e l a t i o n between the stereochemistry obtained from Li/NH3 reduction of ( c i s : t r a n s 3:7, equation [18]) and from the allene photoaddition to (79:80 4:5, equation [16]) the enone 66^ , t h i s i s not the case for the isomeric enone 88. While allene photoaddition to 88_ yielded a 5:4 mixture of 110 and 111 (equation [17]), Li/NH3 reduction provided products 117 and 119 i n the r a t i o of 99:1 (equation [20]). This i s the f i r s t case we are aware of i n which these two reactions give a s i g n i f i c a n t l y d i f f e r e n t stereochemical r e s u l t . 5. Preparation of the Keto Ester 65 As has been already mentioned, previous work (31,32) had shown that the 8-photoadduct _79_ could be converted into the keto ester 65_ i n good y i e l d . O 88 - 74 -Thus, ozonolysis of t h i s photoadduct 79_ i n methanol, followed by reduction of the intermediate formed with dimethyl s u l f i d e (76), gave the unstable [23] 79 104 65 1,3-diketone 104, which, on treatment with sodium methoxide i n methanol (room temperature, 1 hour), afforded the keto ester 65_ (eq. [23]). It was a n t i c i p a -ted that the a-photoadduct 80_, v i a an analogous series of transformations, would give r i s e to the keto ester 81_ (eq. [24]). However, treatment of t h i s o [24] 80 105 81 photoadduct 80_ under conditions i d e n t i c a l with those used on the 8-isomer J9. produced instead, i n good y i e l d , the keto ester 65_ (32). A number of possible mechanisms may be proposed by which the conversion of 80_ into the keto ester 65_ occurs under the reaction conditions mentioned above. In a l l cases, the ozonolysis step i s assumed to afford the 1,3-dione - 75 -105, v i a oxidative cleavage of the double bond of 80. Two of the most reason-able mechanisms by which the 1,3-diketone 105 could be converted into the keto ester 65_ on treatment with sodium methoxide i n methanol are presented i n Schemes XII and XIII. Since the conditions under which t h i s rearrangement occurs (NaOMe, MeOH) are r e v e r s i b l e conditions, we would expect that treatment of the dione 105 with sodium methoxide in methanol would lead eventually to the thermodynamically most stable product possible under these reaction conditions. o Scheme XII In the f i r s t proposal (Scheme XII), methoxide attack i s assumed to occur at the cyclobutanone carbonyl of 105 to afford the keto ester 81. If t h i s keto ester 81 was then to undergo a base-promoted intramolecular Claisen - 76 -condensation v i a the enolate anion 142, the 1,3-dione 143 would be generated. Attack by methoxide at carbonyl B of this 1,3-dione 143 would generate, a f t e r r i n g opening and protonation of the resultant enolate anion, the keto ester 65. A l t e r n a t i v e l y attack at carbonyl A of 143 would reform the keto ester 81_. In the second proposal (Scheme XIII), attack on the dione 105 by methoxide i s assumed to occur at the carbonyl group i n the 5-membered ring (carbonyl B). This would then lead, v i a a reverse Claisen condensation, to the cyclobutanone ester 144. If t h i s ester was to undergo deprotonation at C-4, followed by an intramolecular Claisen condensation, the 1,3-dione 104 would be formed. Attack of methoxide at the cyclobutanone carbonyl of 104 - 77 -would then generate the keto ester 65_ ( c f . eq. [23]). Examination of these two proposed mechanisms would suggest that, i f we were to run t h i s NaOMe/MeOH reaction for a short period of time, we might be able to i s o l a t e some of the more stable Intermediates i n these reaction sequences. For example, i f the f i r s t mechanism (Scheme XII) was involved i n t h i s rearrangement, i t might prove possible to i s o l a t e either the ester 81_ or the dione 143. I f , however, the second mechanism (Scheme XIII) was respon-s i b l e for t h i s transformation, we might expect to i s o l a t e the cyclobutanone ester 144. Such intermediates would only be i s o l a b l e i f the rate at which they form exceeds the rate at which they undergo further reaction. Consequently, a sample of the a-photoadduct j$0_ was ozonolyzed i n dichloromethane containing 1.5 equivalents of methanol, and reductively worked up with dimethyl s u l f i d e (76,77). The crude dione 105, obtained a f t e r workup of the above reaction, was dissolved in methanol and the resultant solution was treated for 5 min at 0°C with a small amount of sodium methoxide. After workup of the reaction mixture and chromatography of the material thus 80 144 81 6 5 33% 39% trace obtained, two new products, assigned structures 144 and 81_, were i s o l a t e d i n y i e l d s of 33 and 39% r e s p e c t i v e l y . A mixed f r a c t i o n (13%), containing 144, 81 and 65 i n a r a t i o of approximately 4:6:1, was also obtained. - 78 -By way of comparison, treatment of the 8-photoadduct 79_, under condi-tions i d e n t i c a l with those described above, afforded only (94% i s o l a t e d y i e l d ) the keto ester 65. This keto ester 65_ exhibited s p e c t r a l and physical proper-t i e s i d e n t i c a l with those reported previously (31,32). Previous work i n our laboratory (31) had shown that, i f ozonolysis of the a-photoadduct 80_ was carried out i n methanol, and an excess of dimethyl s u l f i d e was then added to the resultant s o l u t i o n (to reduce the intermediate a-methoxy hydroperoxy compound), then, a f t e r s t i r r i n g for 18 hours at room temperature, a 55% y i e l d of the keto ester j$l_ was obtained (eq. [25]). [25] 80 81 145 Compound 145 was also i s o l a t e d i n a y i e l d of 20%. This experiment indicated that methanol i t s e l f i s a s u f f i c i e n t l y strong nucleophile to e f f e c t the r e t r o - C l a i s e n condensation required to generate the keto ester 6\_ ( c f . r e f . 63). The spectral properties of the keto ester 81_, mp 156-157°C ( l i t . (31) mp 154-155°C), were very s i m i l a r to those reported e a r l i e r (31). Thus, the i r spectrum of t h i s compound 81_ exhibited a broad band centered at 1725 cm - 1, consistent with the presence of an ester and a 5-membered r i n g ketone, while the *H nmr spectrum showed a 3-proton si n g l e t at 6 3.59 a t t r i b u t e d to the ester methoxy group. - 79 -The cyclobutanone ester 144 ( C 2 2 H 3 i t 0 5 » HRMS), mp 157-158°C, was also isomeric with the keto ester 65. This compound exhibited bands i n the i r spectrum at 1760 and 1720 cm - 1 which were at t r i b u t e d to the cyclobutanone and ester carbonyl groups, r e s p e c t i v e l y . The *H nmr spectrum of 144 exhibited, i n addition to a 3-proton s i n g l e t at 6 3.70, assigned to the methoxy group of the ester, a 4-proton ABMN system i n the regions of 6 2.57-2.78 and 6 2.91-3.08, which was at t r i b u t e d to the protons on the cyclobutanone r i n g . It i s known that protons on a cyclobutanone r i n g , such as those i n compound 144, ex h i b i t , i n addition to the expected geminal couplings, long range couplings (both c i s and trans) across the cyclobutane ring (78). While complete analysis of the coupling constants and chemical s h i f t s i n th i s i s o l a t e d system was not car r i e d out, i r r a d i a t i o n of the higher f i e l d ( 6 2.57-2.78) 2-proton multiplet almost removed the large (J_ = 18 Hz) geminal couplings from the 6 2.91-3.08 MN part of the ABMN system. This decoupling experiment indicated that the AB or MN parts of t h i s system were not due to protons on the same carbon of the four-raembered r i n g . Both the keto ester 81_ and the ester 144, i f treated with a small amount of sodium methoxide i n methanol at room temperature for 2.5 hours, rearranged cleanly i n t o the keto ester 65_ in y i e l d s of 91 and 81% respec-t i v e l y . The clean conversion of 81_ and 144 into the isomeric keto ester 65_ must be r a t i o n a l i z e d on the basis that 65 i s thermodynamically more stable than the isomeric esters 8_1_ and 144. In p a r t i c u l a r , examination of molecular models indicates that 65_ possesses the smallest amount of rin g s t r a i n . The experiments discussed above suggest that both of the postulated mechanisms shown i n Schemes XII and XIII, f o r the rearrangement of the - 80 -144 diketone 105 i n t o the keto e s t e r 65_, are important i n t h i s transformation. The p a r t i c i p a t i o n of the mechanism i n v o l v i n g the cyclobutanone e s t e r 144 (Scheme X I I I ) was not i n i t i a l l y a n t i c i p a t e d . However, examination of a molecular model of the dione 105 i n d i c a t e s t h a t , r e l a t i v e to the dione 104, the 5-membered r i n g possesses s i g n i f i c a n t l y more r i n g s t r a i n . Consequently, compared to compound 104, the e l e c t r o p h i l i c i t y of the cyclopentanone carbonyl group of 105 w i l l be increased r e l a t i v e to that of the cyclobutanone carbonyl. Thus, attack by methoxide at the cyclopentanone carbonyl group of 105 could then become competitive w i t h attack at the s t i l l more s t r a i n e d , but qu i t e hindered, cyclobutanone carbonyl. In p r e p a r a t i v e - s c a l e experiments, a mixture of the four photoadducts - 81 -79, 80, 108 and 109 (40:51:6:3) was ozonolyzed as described e a r l i e r i n dichloromethane-methanol and the resultant material was treated for 16 h at room temperature with sodium methoxide i n methanol. Chromatography of the s o l i d r e s u l t i n g from workup of th i s reaction mixture afforded a 70% y i e l d of the keto ester 65. Small amounts of a number of la r g e l y u n i d e n t i f i e d products were also produced. The only minor products which were i s o l a t e d and i d e n t i f i e d were the two photoadducts 108 and 109 (see Section 4.1), present to the extent of about 3%. In l i n e with previous work (32), a small amount of the acids corres-ponding to the esters 65, 81 and 144 was also formed. Treatment of these acids with an excess of ethereal diazomethane afforded a mixture of the esters 65, 81 and 144, which could be isomerized (NaOMe/MeOH) and chromatographed to y i e l d a further 3% of the keto ester 65. As these acids presumably ar i s e o [26] 65 or 81 - 82 -e i t h e r by attack of water on the diones 104 or 105 (e.g. eq. [26]), or by basic hydrolysis of the esters 65_, 81_ and 144 during the methanolysis step, by taking a l l possible precautions to exclude moisture from the ozonolysis-methanolysis reaction sequence, the quantity of these side products could be greatly reduced. 6. Formation of the T e t r a c y c l i c Dione 63_ With the keto ester 65_ i n hand, two a d d i t i o n a l synthetic operations had to be c a r r i e d out to complete the t e t r a c y c l i c skeleton of the stemodane-type diterpenoids. F i r s t l y , a one-carbon unit (C-13) had to be added, and secondly, i t was necessary to close the D-ring. The manner in which i t was o r i g i n a l l y intended to accomplish these transformations i s shown i n equation [27], This involved addition of a carbonyl dianion (_C=0) equivalent to the diraesylate q-64. While the required dimesylate oc-64 could be obtained e a s i l y from the keto ester 65_ (vide i n f r a ) , addition of the carbonyl dianion equiva-l e n t , methyl thiomethyl sulfoxide (79), to the dimesylate q-64, f a i l e d to provide any of the desired t e t r a c y c l i c product (32). The approach that was eventually u t i l i z e d to generate a compound 63, containing the stemodane carbon skeleton, i s shown i n Scheme XIV (32). Thus-, Scheme XIV - 84 -treatment of e i t h e r of the two epimeric (at C-2) d i n i t r i l e s 77_ with potassium tert-butoxide i n tert-butanol effected a Thorpe-Ziegler condensation ( f o r reviews of t h i s condensation see r e f s . 80,81), generating the t e t r a c y c l i c enaminonitrile 78_ i n high y i e l d . Regarding t h i s condensation, two points should perhaps be mentioned. F i r s t l y , since, under the basic conditions used i n t h i s reaction (_t-Bu0K, _t-Bu0H), the C-2 centre i s epimerizable, both epimers of 77_ r e a d i l y underwent the desired c y c l i z a t i o n . This means that the stereochemical outcome of the reduction of the ketone carbonyl group of 65_ i s unimportant, since both alcohol epimers are equally u s e f u l . Secondly, t h i s condensation was carried out under r e v e r s i b l e conditions and therefore r i n g closure was expected to lead to compound 78_, since the anion 147, correspond-ing to the desired enaminonitrile 78, would be predicted to be considerably more stable than the anion 148, corresponding to the a l t e r n a t i v e c y c l i z e d product 149. The d i n i t r i l e s 77_> required for t h i s condensation, were obtained from the keto ester 65_ by reduction to the d i o l s 146, formation of the dimesylates 64^ , and displacement of the mesylate groups i n compound _64_ with the cyanide ion. In t h i s e a r l i e r work (32), the keto ester 65_ was reduced to a mixture of the alcohol ester 150 and the lactone 151. These two products were separated and independently reduced to the two possible epimeric d i o l s , a- and 6-146. Each epimeric d i o l was then independently converted into the corresponding d i n i t r i l e . The hydrolysis and subsequent decarboxylation of enaminonitriles such as 7_8_ have been found to be best c a r r i e d out under a c i d i c conditions (82). While the hydrolysis of 78_ proceeded well under a c i d i c conditions, the k e t a l - 85 -151 P - 146 protecting group at C-3 was also hydrolyzed. This was rather unfortunate, since we were then faced with the problem of having to somehow d i f f e r e n t i a t e between the two carbonyl groups i n the diketone 63. Nevertheless, since the condensation sequence Tl_ •*• 78_ •> 63_ was shown (32) to work e f f i c i e n t l y , i t was decided to proceed v i a t h i s route and to try to d i f f e r e n t i a t e between the two carbonyl groups at C-3 and C-13 i n 63_ l a t e r i n the synthetic sequence. In t h i s t h e s i s , a number of minor modifications to the sequence shown i n Scheme XIV are reported. Reduction of the keto ester 65_ with lithium aluminium hydride i n ether at 0°C provided a mixture of the epimeric alcohols 146 ( i r : 3590, 3370 (br) cm" 1). This material, as well as the mixtures of dimesylates j>4_ and d i n i t r i l e s 7_7_, prepared as described below, exhibited s p e c t r a l data ( i r , *H nmr) and t i c behaviour consistent with these materials being mixtures of the two epimers at C-2. Both epimers of these three - 86 -mixtures have been i s o l a t e d and characterized previously (32). Formation of the mixed dimesylates jj4_ was carried out by t r e a t i n g a solution of the crude mixture of alcohols 146, prepared as described above, i n HO MsO dichloromethane with 3 equivalents of triethylamine and 2.1 equivalents of methanesuifonyl chloride at 0°C for 1 hour (83). This procedure was experi-mentally easier to carry out and provided a cleaner product than did the a l t e r n a t i v e methanesulfonyl chloride-pyridine procedure (32). The mixture of epimeric dimesylates 64_ was obtained as a colourless foam, which exhibited bands i n the i r spectrum at 1360, 1340 and 1180 cm - 1, a t t r i b u t e d to the sulfonate ester group. The nmr spectrum of t h i s foam showed three s i n g l e t s at 6 2.98, 3.00 and 3.02 which integrated for a t o t a l of 6 protons and were assigned to the methyl groups of the methanesulfonyl moieties. - 87 -This mixture of dimesylates 64_ was dissolved i n dry hexamethylphosphor-amide and enough sodium cyanide was added to saturate the so l u t i o n . The r e s u l t i n g mixture was s t i r r e d at 62°C overnight, worked up, and the crude product thus obtained was chromatographed to provide a 63% y i e l d (from 65) of 64 77 152 153 a mixture of the epimeric d i n i t r i l e s J]_ (a:B-CN =2:1, g l c ) , as a white s o l i d ( i r 2220, 2210 cm - 1, v(C=N)). The major side products i n t h i s reaction sequence were the o l e f i n i c n i t r i l e s 152 and 153, is o l a t e d as an inseparable mixture (=1:1) i n a y i e l d of 6%. The two structures 152 and 153 were assigned on the basis of the spectral data exhibited by the mixture. This mixture of 152 and 153 (C22H33NO2, HRMS) exhibited a band i n the i r spectrum at 2230 cm - 1 which was attr i b u t e d to the n i t r i l e groups of the two compounds, while the *H nmr spectrum of this o i l showed the presence of two o l e f i n i c protons (m, 6 5.43-5.93). A broad 1-proton multiplet at 6 2.98, which was attr i b u t e d to the epimeric C-2 protons of the d i n i t r i l e s 77_, was absent i n the *H nmr spectrum of 152 and 153. The i s o l a t i o n of the o l e f i n i c n i t r i l e s 152 and 153 was not unexpected, as el i m i n a t i o n frequently competes with S N2 su b s t i t u t i o n at secondary centres (84). V a r i a t i o n of the solvent (use of DMSO rather than HMPA) and reaction temperature (45°C, 1 week; or 110°, 24 h) did not improve s i g n i f i -cantly the r a t i o of su b s t i t u t i o n to elimination. - 88 -The Thorpe-Ziegler condensation of the d i n i t r i l e s 77 a n d t n e subsequent hydrolysis of the r e s u l t i n g enaminonitrile _78_ were found to be best c a r r i e d out i n the same pot. Thus, a f t e r the d i n i t r i l e s 7_7_ h a d b e e n c y c l i z e d using potassium tert-butoxide i n t e r t - b u t y l alcohol as described previously (32), the reaction solvent was removed under reduced pressure, and replaced with a deoxygenated mixture of a c e t i c acid, phosphoric acid and water (32,82). The r e s u l t i n g s o l u t i o n was heated at r e f l u x for 40 hours under an i n e r t atmo-sphere. Workup and chromatography of the crude product afforded an 83% y i e l d of the dione 63. The physical and spectral properties of t h i s dione 63_, mp 132°C ( l i t . (32) mp 131-133°C), were i d e n t i c a l with those reported previously (32). The i r spectrum of 63_ showed a band at 1700 cm - 1 which was a t t r i b u t e d to the two 6-membered ring ketones, while the *H nmr spectrum showed a 3-proton s i n g l e t at 6 1.15 assigned to the angular methyl group and a broad t r i p l e t at 6 2.70 (J_ = 7 Hz) assigned to the methine proton at C-14. Subsequent experiments, which w i l l not be discussed in t h i s t h e s i s , i n d i c a t e d that, under anhydrous a c i d i c conditions, the dione 63_ rearranged - 89 -i n t o a number of other products. One p o s s i b l e a c i d - c a t a l y z e d rearrangement i s shown i n equation [28], This observation led us to ask a c r u c i a l question. Since the h y d r o l y s i s of the e n a r a i n o n i t r i l e 78_ to the dione 63_ i n v o l v e d the use of f a i r l y s t r o n g l y a c i d i c c o n d i t i o n s , was the s t r u c t u r e 63_, which we had assigned to the t e t r a c y c l i c dione, i n f a c t c o r r e c t ? While chemical t r a n s -formations, i n combination w i t h spectroscopic evidence, could be envisaged to r u l e out s t r u c t u r e s such as 154, i t was decided to obt a i n a d e f i n i t i v e answer to t h i s question by X-ray c r y s t a l l o g r a p h y . We were r e l i e v e d to f i n d that the s t r u c t u r e of the dione was J33_, as o r i g i n a l l y assigned (85). I f oxygen was not r i g o r o u s l y excluded from t h i s c y c l i z a t i o n - h y d r o l y s i s r e a c t i o n sequence (77 •»• 7_8_ -> 63) a minor product (up to =40%), assigned s t r u c t u r e 155, was obtained. Separation of the t e t r a c y c l i c dione 63_ from t h i s product 155 was troublesome. While i t proved impossible to i s o l a t e the t r i k e -- 90 -HO P O P HO O 155 156-a 156-b tone 155, the corresponding product 156, with the k e t a l function s t i l l present i n the A-ring, could be separated chromatographically from the enaminonitrile 78, as an unstable viscous o i l . This sample of the oc-diketone 156 (C22^Z2°ky HRMS) exhibited, i n the i r spectrum, a band at 3460 cm - 1, a strong broad band at 1670 cm - 1 and a weaker band at 1720 cm - 1. The former two bands may be a t t r i b u t e d to the 1,2-diketone i n i t s eno l i c form 156b, while the l a t t e r band was attributed to the ketonic form 156a. The *H nmr spectrum of t h i s o i l showed a 1-proton multiplet at 6 3.00 a t t r i b u t e d to the C-14 methine proton, a broad s i n g l e t at 6 5.66 (exchangeable with D 20) assigned to the enol proton of 156b and a doublet at 6 6.38 (J = 2 Hz) a t t r i b u t e d to the C - l l proton of 156b. While the mechanism by which the a-diketone 156 forms i s not cle a r , i t presumably involves reaction of the enaminonitrile 7^ with molecular oxygen along the l i n e s shown i n equation [29]. NC NH, HOO H,0 O P - 91 -7 . Attempted Synthesis of the T e t r a c y c l i c Keto K e t a l 160 v i a a Dieckmann Condensation As discussed p r e v i o u s l y , the major problem w i t h the Thorpe-Ziegler condensation of the d i n i t r i l e s 7_7_ was t h a t , i n the h y d r o l y s i s of the enamino-n i t r i l e 78_, the k e t a l f u n c t i o n on the A - r i n g was a l s o hydrolyzed. An a l t e r -n a t i v e and somewhat longer route, which could p o t e n t i a l l y circumvent t h i s problem, i s shown i n Scheme XV. This sequence i n v o l v e s f i r s t converting the d i n i t r i l e s 7_7_ i n t o the epimeric d i e s t e r s 158. On treatment w i t h an N C 160 159 Scheme XV - 92 -appropriate base, these diesters 158 should undergo a Dieckmann condensation (80) to generate the B-keto ester 159. This c y c l i z a t i o n reaction should lead to compound 159, and not to the other possible 6-keto ester 161, since the d r i v i n g force for t h i s condensation i s the formation of the stable enolate anion of the c y c l i z e d 8-keto ester. Such anion formation i s not possible i n compound 161. Decarbomethoxylation of compound 159 to a f f o r d the t e t r a c y c l i c ketone 160, with the k e t a l i n the A-ring s t i l l i n t a c t , should be possible using some of the more recently-developed Sjj2-type methods for the cleavage of p-keto esters (equation [29], e.g. NaCl, DMS0-H20, heat (86), or 1,4-diazabicyclo-[2.2.2]octane (DABCO), xylene, heat (87)). Thus, a solution of the mixed d i n i t r i l e s 77_ i n 40% aqueous potassium hydroxide and ethylene g l y c o l was heated under re f l u x for 16 h. The reaction mixture was cooled, c a r e f u l l y a c i d i f i e d , and extracted quickly with ether. Concentration of the ether extracts afforded a mixture of the diacids 157 as a viscous colourless o i l ( i r : 3600-2500 and 1700 (br) cm - 1). This o i l was dissolved in ether and the resultant s o l u t i o n was treated with an excess of ethereal diazomethane. After an appropriate workup, and chromatography of the - 93 -r e s u l t a n t o i l , an 81% y i e l d of a mixture of the epimeric d i e s t e r s 158 was obtained as a c o l o u r l e s s o i l . The s p e c t r a l data of t h i s o i l corroborated the assigned s t r u c t u r e s . For example, the i r spectrum e x h i b i t e d a strong broad band at 1720 cm - 1 a t t r i b u t e d to the two es t e r m o i e t i e s , while the *H nmr spec-trum showed a 6-proton s i n g l e t at 6 3.68, a t t r i b u t e d to the two es t e r methoxy groups. The presence of more than three t e r t i a r y methyl group s i g n a l s i n the *H nmr spectrum of t h i s o i l i n d i c a t e d that a mixture of epimeric (at C-2) d i e s t e r s was present. Because the d i e s t e r s 158 were formed as a mixture of epimers, any co n d i t i o n s used to carry out the desired Dieckmann condensation ( i . e . 158 •*• 159) must a l s o be able to e f f e c t e q u i l i b r a t i o n at the C-2 centre of 158, and theref o r e allow both epimers to be c y c l i z e d . We were u n f o r t u n a t e l y unable, usi n g a v a r i e t y of r e a c t i o n c o n d i t i o n s , to e f f e c t the desi r e d Dieckmann c y c l i -z a t i o n of 158. The f o l l o w i n g r e a c t i o n c o n d i t i o n s were employed without success: ( i ) NaOMe, MeOH, r e f l u x , 2.5 days ( i i ) NaOMe, MeOH-HMPA (=1:5), room temperature, 20h - 94 -( i i i ) t-BuOK, _t-BuOH, r e f l u x , 1 day ( i v ) NaH, benzene, r e f l u x , 2.5 h These experiments led ei t h e r to recovery of s t a r t i n g material 158, or even-t u a l l y , because of the small scale of the reactions, to the diacids 157 (by base-catalyzed ester h y d r o l y s i s ) . We have no explanation for the f a i l u r e of t h i s c y c l i z a t i o n . However, i n t h e i r review of the Dieckmann condensation Schaefer and Bloomfield (80) note: "It i s probable that esters that have so far r e s i s t e d attempts at c y c l i z a t i o n w i l l c y c l i z e when the proper choice of base and reaction conditions i s made". 8. Synthesis of the Bis Enone 75 As has already been discussed i n Section 1, i t was necessary at t h i s stage in the synthetic sequence to introduce two methyl groups at C-4 in the t e t r a c y c l i c dione 63. The way we intended to do t h i s was to f i r s t block both C-2 and C-12 to deprotonation by generating the A ^ ' ^ ' ^ ' ^ - b i s enone 7_5_ (see eq. [8], reproduced below). In t h i s compound the only enolizable protons remaining are those at C-4. As mentioned i n Section 1, C-14 i s already "blocked" to deprotonation by the nature of the carbon skeleton. Dimethyla-t i o n of 75_ at C-4, followed by hydrogenation of the double bonds i n the a l k y l a t e d bis enone 7_5_, should then a f f o r d the required alkylated dione 62. Our immediate target then became the bis enone 75. It was expected that deprotonation of 63_ under k i n e t i c a l l y c o n t r o l l e d conditions would generate r e g i o s e l e c t i v e l y the A » ' » - b i s enolate anion 162, which could then be trapped with phenylselenyl chloride to generate 163 - 95 -- 96 -(88). Oxidation of th i s compound, followed by elimination of phenylselenic acids should then generate the desired bis enone 75 (89). The k i n e t i c a l l y c o n t r o l l e d deprotonation of the diketone 63_ was expected, by analogy with s i m i l a r s t e r o i d a l systems, to occur at C-2 i n preference to C-4. For example, Trost (90) has reported that k i n e t i c a l l y c o n t r o l l e d deprotonation of 5a-cholestan-3-one 164 occurred r e g i o s e l e c t i v e l y at C-2, to aff o r d , a f t e r 164 164 165 81% 12% trapping of the resultant enolate anion with diphenyl d i s u l f i d e , an 81% y i e l d of compound 165. This product was accompanied by 12% of the s t a r t i n g m aterial. Consequently, we were somewhat surprised to find that deprotonation of the dione j63_ under k i n e t i c a l l y c ontrolled conditions (91) (dropwise addition of a sol u t i o n of 63_ i n tetrahydrofuran to a cold (-78°C) solution of l i t h i u m diisopropylamide (4 equivalents) i n tetrahydrofuran; s t i r for 15 min at -78°C, and 1 hour at 0°C), followed by trapping of the resultant bis enolate anions with t e r t - b u t y l d i m e t h y l s i l y l chloride (TBDMSC1) afforded an approximately 1:1 mixture of 166 and 167. The 1H nmr spectrum of th i s mixture showed two signals at 6 0.84 and 0.86 i n the approximate r a t i o of 1:1 (3 protons i n - 97 -63 166 167 t o t a l ) which were at t r i b u t e d to the angular methyl groups of 166 and 167, as well as signals at 6 0.11, 0.12 and 0.13 (12 protons) and 0.91 (18 protons) consistent with compounds 166 and 167 being bis t e r t - b u t y l d i m e t h y l s i l y l enol ethers. The low f i e l d region of the *H nmr spectrum of t h i s mixture exhibited 3 s i g n a l s , a broad ( w i / 2 = ^ H z ) 1-proton s i n g l e t at 64.42 which was assigned to the C-12 protons of both 166 and 167, a si n g l e t (W^/2= ^ a t 6 4.50 (=0.5 proton) attributed to the C-4 o l e f i n i c proton of 167 and a broad doublet at 6 4.76 (J_ = 6 Hz, =0.5 proton) which was assigned to the C-2 alkene proton of 166. When t h i s reaction was repeated using the more hindered base, l i t h i u m 2,2,6,6-tetramethylpiperidide (92), i n place of lithium d i i s o p r o p y l -amide, a s i m i l a r r a t i o of 166 to 167 was obtained. Since the deprotonation of 63_ under k i n e t i c a l l y c ontrolled conditions was not r e g i o s e l e c t i v e , we turned our attention to other ways of generating the desired bis selenyl ketone 163. Sharpless (93) has reported that, a f t e r s t i r r i n g a mixture of 5a-cholestan-3-one 164 and phenylselenyl chloride i n ethyl acetate, and ox i d a t i v e l y eliminating phenylselenic acid from the r e s u l t -1 9 ing crude oc-selenyl ketone, an 84% y i e l d of A x • -cholesten-3-one 168 was - 98 -obtained. Only 3% of the regioisomeric A » -cholesten-3-one was obtained. 164 168 The rate determining step i n the selenation of ketones under these conditions i s the (acid catalyzed) e n o l i z a t i o n of the appropriate ketone. Consequently, the p o s i t i o n taken by the entering phenylselenyl group i n unsymmetrical ketones such as 164 i s a r e f l e c t i o n of the r e l a t i v e ease with which the two possible regioisomeric enols of 164 are formed. We investigated the use of th i s d i r e c t selenation procedure (93) with our dione 63. Thus, the t e t r a c y c l i c dione J53_ was s t i r r e d for 1 h i n ethy l acetate containing 2.4 equivalents of phenylselenyl chloride, and the resultant reaction mixture was worked up by washing i t with water. T i c of the r e s u l t i n g yellow viscous o i l indicated the presence of a number of compounds. Oxidative elimination of phenylselenic acid from t h i s mixture of a-selenyl ketones, using either the H2O2/THF procedure reported by Sharpless (93), or Reich's ozonolysis procedure (88) (excess O3 i n CH 2Cl2, -78°C; blow off excess O3; add 5 equivalents of diisopropylamine; transfer the cold (-78°C) solution i n t o r e f l u x i n g hexanes) afforded a mixture containing many products. One of the two major products present i n th i s mixture (27% i n the best case) was t e n t a t i v e l y i d e n t i f i e d as the desired bis enone 75. A sample containing mainly t h i s component was i s o l a t e d by chromatography, and the *H nmr spectrum - 99 -p 75 of t h i s o i l showed four o l e f i n i c s i g n a l s . This s t r u c t u r a l assignment was subsequently confirmed by comparison with an authentic sample of 7_5 (vide  i n f r a ) . The other major product (38% of the reaction mixture) was not i d e n t i f i e d . Another method which has been used to generate a-phenylselenyl ketones involves f i r s t forming the enol acetate of the ketone. The enol acetate can then be converted into the corresponding a-selenyl ketone either d i r e c t l y by reaction with PhSeBr/Ag0 2CCF 3 (94), or PhSe0 2CCF 3 (88), or by conversion into the corresponding l i t h i u m enolate anion with methyllithium, followed by quenching with PhSeBr (88). In these procedures, the regiochemistry of the selenation w i l l be determined by the step involving formation of the enol acetates. Going back once again to 5<x-cholestan-3-one 164, treatment of t h i s ketone with a c e t i c anhydride and a c a t a l y t i c amount of p e r c h l o r i c acid i s known to a f f o r d r e g i o s e l e c t i v e l y the A 2 » ^ enol acetate 169 (95). These a c e t y l a t i o n conditions normally lead to a thermodynamic mixture of enol acetates. Attempted formation of the thermodynamic mixture of bis enol acetates of the dione 63_ using either the procedure of House (96) (Ac 20 (excess), CCl^, HCIO^ ( c a t . ) , r t , 30 min or 20 h), or that of Edwards and Rao (95b) (Ac 20, - 100 -C g H ) 7 O HC101+ ( t r a c e ) , EtOAc, r t , 20 min or 20 h) gave mixtures of u n i d e n t i f i e d products. The unexpectedly large number of products obtained, both i n the attempted d i r e c t p h enylselenation of the dione 63_, and i n the attempted forma-t i o n of the b i s enol acetates of the same compound, can be r a t i o n a l i z e d by proposing that a c i d - c a t a l y z e d rearrangement of the carbon skeleton i s occur-r i n g during both these r e a c t i o n s . We next attempted to make r e g i o s e l e c t i v e l y the b i s t r i m e t h y l s i l y l enol ether 170. I f t h i s compound 170 could be formed from the dione 63, e i t h e r e x c l u s i v e l y , or as the major product i n a mixture of 170 and 171, a number of p o s s i b l e routes to the b i s enone 75 could be envisaged. Some of these p o s s i -b i l i t i e s are presented i n Scheme XVI. - 101 -Scheme XVI Since the formation of the b i s s i l y l enol ethers of _63_ under k i n e t i -c a l l y c o n t r o l l e d c o n d i t i o n s i s n o n - r e g i o s e l e c t i v e , i t was suggested that perhaps the thermodynamic mixture of b i s s i l y l enol ethers formed from the same diketone 63_ might be more u s e f u l . A number of procedures are a v a i l a b l e f o r generating "thermodynamic" mixtures of s i l y l enol ethers from unsymmetri-c a l ketones. Several of these methods are presented i n Table I I . The r e g i o -s e l e c t i v i t y of these various s i l y l a t i o n procedures i s f r e q u e n t l y judged by - 102 -Table I I . The P r e p a r a t i o n of "Thermodynamic M i x t u r e s " of S i l y l Enol Ethers from 2-Methylcylohexanone 172. 172 173 174 Reagents (Reference) R a t i o 173 : 174 Y i e l d Comments E t 3 N , TMSC1, DMF, 130°C (91) 78 : 22 — For improvements and r e l a t e d methods see r e f s . (100,101) p_-BuitNF, TMSCH2C00Et (102) 82 : 18 -NaH, DME; TMSC1 (97) 73 : 27 - KH i s l e s s s e l e c t i v e (103) B r M g N ( i - P r ) 2 , E t 2 0 ; TMSC1, HMPA (104) 97 : 3 95% Gives a l d o l products w i t h unhindered ketones e.g. c y c l o -octanone. TMSI, (TMS) 2NH (105) 90 : 10 90% a l s o see r e f . (106) TMS0S0 2CF 3, E t 3 N (107) - -H2C=CHCH2TMS, CF 3C00H (108) 65 : 35 84% i n s i t u TMS0S0 9 C F c , Ph 2MeSiH, py, C o 2 ( C 0 ) 8 (109) 92 : 8 89% TMSH a l s o works. Reaction wi t h 172 not reported. - 103 -examining the r e s u l t obtained i n the reaction of 2-methylcyclohexanone 172 with the various reagent systems. For t h i s ketone 172, 174 i s considered to be the " k i n e t i c " and 173 the "thermodynamic" ( i . e . thermodynamically more stable) s i l y l enol ether. As can be seen from Table I I , the c o n s t i t u t i o n of the "thermodynamic mixture" of s i l y l enol ethers varies s i g n i f i c a n t l y with the procedure used to generate i t . Of the methods shown i n Table I I , one of the more a t t r a c t i v e procedures involves the use of t r i m e t h y l s i l y l iodide and a base (105,106). Thus, a s o l u t i o n of the ketone j>3_, hexamethyldisilazane and t r i m e t h y l s i l y l iodide (formed i n s i t u from sodium iodide and t r i m e t h y l s i l y l chloride (106)) in a c e t o n i t r i l e was s t i r r e d for 1 h at -20°C and 2 h at room temperature. After an appropriate workup, glc analysis of the i s o l a t e d material indicated that two major products, assigned structures 170 and 171, were present i n the r a t i o of 73:27. The oxidation of t h i s mixture of s i l y l enol ethers to a 73:27 mixture of 75_ and 175 with palladium(II) acetate (99) (vide i n f r a ) served to confirm the structures of 170 and 171. As the r e s u l t discussed above appeared promising, a series of further experiments were ca r r i e d out to try to further improve the r a t i o of 170 to 171. Some of these r e s u l t s are presented i n Table I I I . From Table III i t can be seen that the "thermodynamic mixture" of s i l y l enol ethers 170 and 171, at l e a s t for the t r i m e t h y l s i l y l iodide/base system, i s approximately 2:1 i n favour of compound 170 (Entries 3,5). However, better product r a t i o s (170:171) could be obtained by not allowing the mixture of s i l y l enol ethers to reach i t s equilibrium composition (e.g. Entry 1). In an attempt to further improve the r a t i o of 170 to 171, the solvent, base and reaction temperature - 104 -Table I I I . The Pr e p a r a t i o n of the B i s T r i m e t h y l s i l y l Enol Ethers 170 and 171 from 63 0 T M S O T M S O 63 170 171 Entry Reagents and c o n d i t i o n s 3 R a t i o b 170 : 171 1 TMSC1 (20=) C, Nal (20=), (TMS) 2NH (22=), MeCN; -20°C l h , room temperature 2h d 73 27 2 TMSOS0 2CF 3 (20=), E t 3 N (25=), e i t h e r benzene; 80°C 3h or MeCN; 0°C l h , room temperature 4h 63 37 3 TMSI (20=), (TMS)2NH (25=), CH 2C1 2; -20°C 30 min, room temperature 4h 66 34 4 TMSCH2C00Et (excess), (n-Bu) 4NF ( c a t . ) , THF; 0°C 2h, room temperature 16h only 63 (1 attempt) 5 TMSI (20=), E t 3 N or ( i - P r ) 2 N E t (25=) MeCN; -20°C 15 min, 0VC 30 min 66 34 6 TMSI (20=), E t 3 N (25=), CH 2C1 2; -78°C 3h 78 22 7 TMSI (20=), E t 3 N (25=), CH 2C1 2; -95°C 1.5h 84 16 8 TMSI (20=), ( i - P r ) 2 N E t (25=), CH 2C1 2; -78°C 30 min 59 41 Reactions were c a r r i e d out with 30-70 uraol of 63. 'Product r a t i o s were determined by g l c . In a l l cases 170 and 171 accounted f o r greater than 90% of the crude r e a c t i o n mixture. For conciseness the number of equiv a l e n t s of reagents used are shown i n parentheses as (X=). This r e a c t i o n was incomplete i n shorter times. - 105 -were varied. Not too s u r p r i s i n g l y , lowering the reaction temperature improved the r a t i o of 170 to 171 (e.g. Entry 7 versus Entry 6). The base used also has a very s i g n i f i c a n t e f f e c t (Entry 6 versus Entry 8, also see Entry 1 versus Entry 5), but the reasons for t h i s observation are not at a l l clear ( c f . r e f . 106). The solvent may also be important i n t h i s reaction, although t h i s i s not clear from the experiments reported here ( c f . r e f . 105). Two other s i l y l a t i o n systems, TMS0S0 2CF 3/Et 3N (107) and TMSCH2C00Et/n-BultNF (102), were less s a t i s f a c t o r y (Entries 2 and 4, r e s p e c t i v e l y ) . As can be seen from Table III the best conditions found (Entry 7) involve the use of triethylamine as base i n dichloromethane at low tempera-tures (-95°C). This afforded the two s i l y l enol ethers 170 and 171 i n the r a t i o of 5:1. Because of the directness of the procedure, and the t y p i c a l l y high y i e l d s which have been reported i n i t s use, i t was decided to f i r s t try o x i d i -zing the mixture of bis s i l y l enol ethers 170 and 171 with palladium(II) acetate d i r e c t l y to a mixture of the bis enones 75_ and 175 (99). Small scale experiments indicated that t h i s oxidation proceeded cleanly, and that the two isomeric bis enones 75_ and 175 could be chromatographically separated. The large scale s i l y l enol ether formation reactions were, unfortunate-l y , s l i g h t l y less r e g i o s e l e c t i v e than the small scale reactions. Thus, 5 equivalents of f r e s h l y prepared t r i m e t h y l s i l y l iodide (110) were slowly added to a -95°C solution of the dione 63_ and triethylamine (6 equivalents) i n dichloromethane. The r e s u l t i n g mixture was s t i r r e d at t h i s temperature for 1 hour and worked up to provide a mixture of the two s i l y l enol ethers 170 and 171 i n the r a t i o of 4:1. Oxidation of t h i s crude mixture i n a c e t o n i t r i l e - 106 -p o containing 2.2 equivalents of palladium(II) acetate afforded a mixture composed mainly of the two bis enones 75. and 175. After chromatography and r e c r y s t a l l i z a t i o n , the enones 75 and 175 were i s o l a t e d i n y i e l d s of 67% and 19%, r e s p e c t i v e l y . Both bis enones, 75_, mp 155-157°C, and 175., mp 147-149°C, exhibited s p e c t r a l data i n accord with the assigned structures. For example, both showed bands i n the i r spectrum consistent with the presence of at least one a, B-unsaturated ketone function (75: 1680, 1660 cm - 1, and 175: 1680, 1665, 1650, 1605 cm - 1). The 1H nmr spectrum of 75 exhibited 4 signals due to o l e f i n i c protons while 175 showed only 3 signals i n the o l e f i n i c region of i t s *H nmr spectrum. A more detai l e d discussion of the % nmr spectra of these, and related enones, w i l l be deferred to Section 9. Attempts to recycle the undesired A ^ ' - * > » 1 2 - b i s enone 175 back to the diketone 63_, either by Li/NH 3 reduction (Li/NH 3, THF, t-BuOH; -33°C, lh; - 107 -then PCC, NaOAc, CH2CI2; room temperature, 2 h), or by c a t a l y t i c hydrogenation (H2, 1 Atmosphere, 5% Pd/C, dioxane; room temperature, 2 h) were unsuccess-f u l . Both methods generated the t e t r a c y c l i c dione 63_ along with another chromatographically inseparable dione, presumably i t s C-5 epimer 176. 9 . P r e p a r a t i o n of the A l k y l a t e d Dione 62 9.1 Dimethylation of the A 1 ' Z ; 1 1 » 1 Z - B i s Enone 75 A number of methods have been used to geminally diraethylate or perraethylate ketones. These procedures include: potassium (or sodium) t e r t -butoxide, methyl iodide, t e r t - b u t y l alcohol (111); sodium tert-amyloxide, methyl iodide, benzene (112); sodium hydride, methyl iodide, dimethoxyethane (113); and potassium hydride, methyl iodide, tetrahydrofuran (114). The dimethylation of the bis enone 7_5_ proved to be more d i f f i c u l t than a n t i c i p a t e d . Eventually the following method was found to give a s a t i s f a c t o r y r e s u l t . The l i t h i u m enolate of 75_ was generated i n the normal manner i n dimethoxyethane at 0°C using 6 equivalents of l i t h i u m b i s ( t r i m e t h y l s i l y l ) -- 108 -amide. A vast excess (=330 equivalents) of methyl iodide was added ra p i d l y and the resultant s o l u t i o n was s t i r r e d at 0°C for 30 min and at room tempera-ture for 1 hour. A f t e r workup as described i n the experimental section, a white s o l i d was obtained. A small amount of the major (95%) component present i n t h i s s o l i d , which was assigned structure 177, was i s o l a t e d by chromatography. The spectral data exhibited by t h i s compound (mp 149-150.5°C) i s f u l l y consistent with the 75 177 76 assigned structure 177. In p a r t i c u l a r the % nmr spectrum of 177 exhibited a 3-proton doublet at 6 1.17 (J_ = 7 Hz), assigned to the methyl group at C-4. I r r a d i a t i o n of t h i s signal collapsed the doublet of quartets (J_ = 13,7 Hz) at 6 2.38 to a doublet, J = 13 Hz. This s i g n a l at 6 2.38 must therefore be assigned to the proton at C-4. Furthermore, because of the large (13 Hz) coupling constant between t h i s proton and the adjacent a x i a l C-5 methine proton, these two protons must be t r a n s - d i a x i a l l y related to one another. Thus the proton at C-4 must be assigned the 6-confIguration and hence the methyl group i s a-oriented. If large amounts of methyl iodide were not added to the reaction mixture, then, i n addition to the desired product 177, s i g n i f i c a n t amounts of both the s t a r t i n g material 75_ and the d i a l k y l a t e d product 76^ were i s o l a t e d i n - 109 -nearly equal amounts. The recovery of s t a r t i n g material i s presumably due to deprotonation of the i n i t i a l l y formed monoalkylated ketone 177 by some of the as-yet-unreacted enolate anion of 75. A l k y l a t i o n of the newly formed enolate anion of 177 w i l l give the di a l k y l a t e d product 76, while the o r i g i n a l enolate anion, which has acted as the base, w i l l be recovered as s t a r t i n g material 75. Addition of a vast excess of methyl iodide circumvents t h i s problem by speeding up the rate of methylation of the enolate anion of 75. The d i a l k y l a t e d bis enone _76_ was obtained by submitting the crude monoalkylated product 177, prepared as described above, to a second a l k y l a t i o n reaction under e s s e n t i a l l y the same conditions. The only difference was that the a l k y l a t i o n with methyl iodide was ca r r i e d out for 6 hours at room tempera-ture, rather than for 1 hour as before. The d i a l k y l a t e d product 76_ was obtained i n a y i e l d of 77% (from 75) as colourless c r y s t a l s , mp 154-156°C. The i r spectrum of t h i s s o l i d showed a broad band centered at 1660 cm - 1, assigned to the two a, 8-unsaturated ketone systems i n 76_, while the *H nmr spectrum exhibited three 3-proton s i n g l e t s at 6 1.16, 1.20 and 1.44, assigned to the three t e r t i a r y methyl groups, and four o l e f i n i c s i g n a l s . Some of the a d d i t i o n a l features observed i n the *H nmr spectrum of 76_ w i l l be discussed l a t e r . A number of other la r g e l y u n i d e n t i f i e d products were also formed i n small amounts during t h i s d i a l k y l a t i o n reaction. As with the f i r s t step of t h i s sequence, the use of a large amount of a l k y l a t i n g agent i n the second methylation step led to the formation of fewer side products. If care was not taken to wash out the small amount of iodine formed during the f i r s t a l k y l a t i o n step, then a product, ascribed structure 178, - 110 -could be i s o l a t e d as a colourles s o l i d , mp 167-169°C (Ci 8H 2o02, HRMS), a f t e r 177 178 [32] the second a l k y l a t i o n step. The formation of 178 can be r e a d i l y r a t i o n a l i z e d i n terms of equation [32]. The most compelling evidence for the structure 178 assigned to th i s s o l i d comes from i t s *H nmr spectrum. In addition to the four o l e f i n i c s i g n a l s , s i m i l a r to those observed i n compounds 75_, 76_ and 177 (assigned to the protons on C—1,2,11 and 12), two further l o w - f i e l d , 1-proton signals at 6 5.28 (observed as a t r i p l e t , J_ = 1 Hz), and at 6 6.18 (doublet of doublets, J_ = 2.5, 1 Hz) were observed. These signals were assigned to the two protons on the exocyclic methylene group. Both these protons exhibited a small coupling with one another, as well as an a l l y l i c coupling to the C-5 proton (6 2.90). Some of the attempted methods which f a i l e d to provide s y n t h e t i c a l l y u s e f u l y i e l d s of the dimethylated bis enone 76_ included: ( i ) Potassium tert-butoxide (= 10 equivalents) was added to a solut i o n of the bis enone 75_ i n dry t e r t - b u t y l alcohol (115). After the resultant solution had been s t i r r e d for 3 minutes, 20 equivalents of methyl iodide were added and the solution was - I l l -heated under reflux for 1 hour. Analysis of an aliquot of th i s reaction by glc showed that 72% of the s t a r t i n g material remained. While heating t h i s mixture for a further hour did not change the s t a r t i n g material to product r a t i o , addition of more base and methyl iodide gave a l i t t l e more alkylated material. Presumably here, the base was being consumed fas t e r by reaction with the methyl iodide than i t was being used to al k y l a t e the ketone. ( i i ) A sol u t i o n of 8 equivalents of f r e s h l y sublimed potassium tert-butoxide i n tetrahydrofuran was added dropwise (syringe pump) over a period of approximately 1 hour to a -78°C solution of the ketone 75_ and excess methyl iodide (= 30 equivalents) i n tetrahydrofuran containing 1% hexamethylphosphoramide ( c f . r e f . 116). After the resultant solution had been s t i r r e d for a further hour at -78°C, analysis of an aliquot indicated the presence of a mixture containing mainly the mono- and di a l k y l a t e d bis enones 177 and 76. Further iodomethane was added to the cold s o l u t i o n and then another 8 equivalents of base, dissolved i n tetrahydrofuran, were added over a period of 1 hour. Af t e r an appropriate workup, g l c analysis of the r e s u l t i n g o i l showed the presence of 70% of the desired d i a l k y l a t e d bis enone Jb_, 20% of a compound assigned structure 179 plus a number of other minor components. The desired dimethylated bis enone 76_ was i s o l a t e d i n a y i e l d of 45% by column chromatography. - 112 -A small amount of compound 179, mp 206-209°C, was p u r i f i e d by a combination of chromatography and c r y s t a l l i z a t i o n . This .0 179 s o l i d ( C 1 8 H 220 3 , HRMS) exhibited bands i n the i r spectrum at 1680, 1660 and 1610 cm - 1 consistent with the presence of two a,8-unsaturated ketone functions. The lVL nmr spectrum of 179 showed two 3-proton s i n g l e t s at 6 1.33 and 1.49 assigned to the two t e r t i a r y methyl groups, a 1-proton exchangeable si n g l e t at 6 3.42 assigned to the C-4 hydroxyl group proton, as well as four o l e f i n i c protons. The o r i g i n of 179 i s not c l e a r . A number of attempts to further improve the y i e l d of the dimethylated product 76^  and to avoid the formation of 179 were l a r g e l y unsuccessful. ( i i i ) To a so l u t i o n of the l i t h i u m enolate of 75_ i n tetrahydrofuran, generated by addition of the bis enone 7_5 to an excess of li t h i u m diisopropylamide, was added, at -78°C, approximately 25 equivalents of methyl iodide. After the reaction mixture had been s t i r r e d for 30 min at -78°C, 30 min at 0°C and 1 h at room temperature, and then worked up, glc analysis of the crude product indicated the presence of 65% of the monoalkylated - 113 -ketone 177, along w i t h s u b s t a n t i a l amounts of both s t a r t i n g m a t e r i a l 7_5 and the d i a l k y l a t e d ketone 76. This r e a c t i o n was repeated twice more 6 on the same m a t e r i a l to give an o i l which was composed mainly of the des i r e d d i a l k y l a t e d m a t e r i a l 76_ (69%, g l c ) and an unknown product (13%). This procedure was not pursued f u r t h e r . ( i v ) F o l l o w i n g e s s e n t i a l l y the procedure of Rathke (114), a s o l u t i o n of 75_ i n tetrahydrofuran was added to a s t i r r e d suspension of potassium hydride (= 7 e q u i v a l e n t s ) i n t e t r a h y d r o f u r a n , and the r e s u l t i n g mixture was s t i r r e d f o r a f u r t h e r 5 minutes at room temperature. Four e q u i v a l e n t s of methyl i o d i d e were then added over a period of 15 minutes, at room temperature. A f t e r the r e s u l t i n g mixture had been s t i r r e d f o r a f u r t h e r 30 minutes at room temperature, the r e a c t i o n mixture was worked up. Glc a n a l y s i s of the r e s u l t i n g o i l showed the presence of a number of components i n c l u d i n g s t a r t i n g m a t e r i a l 75_ (44%), the monoalky-l a t e d product 1T7_ (41%), the d i a l k y l a t e d product 76 ( 8 % ) , and compound 179 ( 4 % ) . 9.2 The AH nmr Spectra of Compounds 75, 177, 76 and 175 Because of t h e i r s i m i l a r i t y , i t i s convenient to discuss the *H nmr spectra of compounds 7_5» 177, 76 and 175 together. Table IV shows the chemical s h i f t s assigned to many of the protons i n these compounds. R e p a r a t i o n of the mono- and d i a l k y l a t e d enones 177 and 76 by chromatography was found to be very d i f f i c u l t . Hence t h i s r e a c t i o n was repeated twice more to ensure that a l l the s t a r t i n g m a t e r i a l 75, i s o l a t e d from the f i r s t methylation r e a c t i o n , was dimethylated. - 114 -Table IV. The Chemical S h i f t s of Selected Protons i n Compounds 75, 177, 76 and 175. 75 177 76 175 Proton Compound 75 177 76 175 C-l 6.72 6.65 6.66 -C-2 5.89 5.87 5.89 -C-4 - 2.38 - 5.86 C - l l 7.33 7.32 7.35 7.26 C-12 6.00 5.98 5.99 5.93 C-14 2.94 2.91 2.92 2.91 C-15o 1.75 1.73 1.74 -C-15B 1.84 1.84 1.83 -C-16a 2.29 2.27 2.30 -C-168 1.70 1.68 1.68 -- 115 -4 H 6 H i H H 75 177 76 175 The two doublets (J_ = 10 or 10.5 Hz) observed at 6 6.65-6.72 and 6 5.87-5.89 i n the 1H nmr spectra of compounds 75_, 177 and 76_ were assigned to the protons on C-l and C-2, re s p e c t i v e l y , i n these substances. The o l e f i n i c proton at C-4 i n the A^»^>* *»* 2-bis enone 175 was observed as a doublet, J_ = 1.5 Hz, at 6 5.86. This proton i s presumably a l l y l i c a l l y coupled to one of the protons on C-6. The C - l l and C-12 protons of these four compounds were assigned to the signals at 6 7.26-7.35 (d of d, J = 10-10.5, 3 Hz) and at 6 5.93-6.00 (d of d, J_ = 10 - 10.5, 2-3 Hz) r e s p e c t i v e l y . The broad t r i p l e t (J = 7 Hz) centred at 6 2.91-2.94 was assigned to the C-14 proton, which i s both t e r t i a r y and a- to the carbonyl group. A s i m i l a r s i g n a l i s observed at 6 2.70 i n the t e t r a c y c l i c dione 63. I r r a d i a t i o n of t h i s s i g n a l i n compound 7_5_ collapsed the o l e f i n i c s i g n a l at 6 6.00 to a doublet, J_ = 10 Hz. This 2-3 Hz long range coupling observed between the two protons on C-12 and C-14 was not unexpected, since these two protons and carbons 12, 13 and 14 are situated i n a plane. However the o r i g i n of the 3 Hz coupling constant observed in the signal assigned to the C - l l proton (6 7.26-7.35) was not c l e a r from examination of molecular models. I r r a d i a t i o n of the s i g n a l assigned to t h i s C - l l proton (6 7.35 i n 76) removed a 3 Hz coupling constant - 116 -from the signal at 6 2.30 (d of d of d, J = 12, 6, 3 Hz), which was assigned to the C-16a proton. This C-16a proton would be expected to show a geminal coupling to the C-16B proton as well as a coupling to the C-14 proton. Thus, i r r a d i a t i o n of the signal assigned to the C-14 proton (6 2.94 i n 75) removed the 6 Hz coupling from the si g n a l at 6 2.29. The doublet (J_ = 12 Hz) observed at 6 1.68-1.70 i n the spectra of compounds _75_, 177 and 76_ was assigned to the C-168 proton. Examination of molecular models indicates that i n these compounds the C-168 proton i s ortho-gonal to the C-14 proton and hence would be expected to be coupled only to i t s geminal partner. The other signals which could be assigned i n the *H nmr spectra of compounds 7_5, 177 and 76_ are the two 1-proton signals at 6 1.84-1.83 and 6 1.75-1.73. These were at t r i b u t e d to the two protons on C-15. These two C-15 protons are t i g h t l y coupled (Av/J_ = 3 ) to each other with a coupling constant of 14 Hz. The low f i e l d s i g n a l (d of d, J = 14, 7-8 Hz) exhibits a 7-8 Hz coupling, presumably to the C-8 methine proton, while the high f i e l d s i g n a l e x h i b i t s a 14 Hz geminal coupling, an 8 Hz coupling to the C-14 methine proton, as well as an a d d i t i o n a l 2 Hz long range coupling. Since examination of molecular models indicates that the C-15a proton i s perpendicular to the h - 117 -C-8 proton, and the C-156 proton i s perpendicular to the C-14 proton, the u p f i e l d s i g n a l was a t t r i b u t e d to the a-proton on C-15, while the downfield s i g n a l was assigned to the 8-proton. 9.3 Preparation of 62 C a t a l y t i c hydrogenatlon of the d i a l k y l a t e d b i s enone 76_ at atmospheric pressure i n dry dioxane, using 5% palladium-on-charcoal as the c a t a l y s t , proceeded smoothly to generate the d e s i r e d a l k y l a t e d dione 62_, mp 151-152°C, i n an e s s e n t i a l l y q u a n t i t a t i v e y i e l d . The s p e c t r a l data e x h i b i t e d by t h i s compound was c o n s i s t e n t with the assigned s t r u c t u r e 62. In p a r t i c u l a r , the *H nmr spectrum e x h i b i t e d no s i g n a l s due to o l e f i n i c protons, while the i r spectrum of 62_ showed a strong band at 1700 cm - 1 c o n s i s t e n t w i t h the presence of the two saturated ketone carbonyl groups. 10. Synthesis of the Keto Alcohol 61^  With a good route to the a l k y l a t e d dione 62_, the next target i n our s y n t h e t i c sequence was the keto a l c o h o l 61. As already mentioned i n S e c t i o n - 118 -1, t h i s transformation posed two problems. F i r s t l y , i t was necessary to d i f f e r e n t i a t e between the two ketone carbonyl groups at C-3 and C-13. It was ant i c i p a t e d that, since the carbonyl group at C-3 i n 62_ was adjacent to a quaternary centre, i t should be possible to e f f e c t some sort of a s e l e c t i v e reaction at the s t e r i c a l l y more accessible C-13 carbonyl group. Secondly, we needed to develop a method to s t e r e o s e l e c t i v e l y add the C-17 methyl group to the carbonyl group at C-13, so that, i n the product, the hydroxyl group would be a x i a l l y oriented and the methyl group would be e q u a t o r i a l l y positioned on the 6-membered D-ring. At the st a r t of th i s project the solution to th i s problem was not at a l l obvious. As can be seen from structure 62_ the s t e r i c a c c e s s i b i l i t y to both sides of the carbonyl group i s comparable. Therefore we could not expect the d i r e c t i o n of addition of an organometallic reagent (e.g. - 119 -MeLi)> to the carbonyl group of 62_ to be r e a d i l y controlled by s t e r i c a c c e s s i -b i l i t y f a c t o r s . In r i g i d cyclohexanones such as 4-tert-butylcyclohexanone, i n which s t e r i c a c c e s s i b i l i t y does not c l e a r l y i n d i c a t e a preferred mode of carbonyl addition, the observed s t e r e o s e l e c t i v i t y i n such additions i s frequently low (44). Since our eventual so l u t i o n to the problem posed by the generation of the C-13 stereocentre was influenced to a cer t a i n extent by work reported i n e a r l i e r syntheses of the stemodane-type diterpenoids 3_ - 6_ (12,23-25), i t i s appropriate here to look b r i e f l y at how these groups have solved t h i s stereochemical problem. In the f i r s t synthesis of (i)-stemodin _3 and (i)-stemodinone 4_, Corey and co-workers (22) made, as one of t h e i r intermediates, the ketone 181. Addition of the following reagents to th i s ketone 181 was not s t e r o s e l e c t i v e : MeLi, E t 2 0 , 0°C (55_:_182 1:1); Me3AI (117); LiMe^Al (118); LiMe 3Mn (118); and MeMgBr, E t 2 0 , 25°C (55:182 2:1). However, i t was eventually found that i f 181 was reacted with dimethylsulfoxonium methylide (119) i n dimethyl sulfoxide at 23°C, and the r e s u l t i n g crude mixture of spiro epoxides was reduced with l i t h i u m triethylborohydride (120), a 5:1 mixture of 55 and 182 was formed i n - 120 -an unspecified y i e l d . Recently the I t a l i a n group (23) has reported that i f t h i s sequence i s c a r r i e d out on the very s i m i l a r ketone 183, then (±)-maritimol _5 and (±)-13-epimaritimol 184 were i s o l a t e d i n y i e l d s of 69 and 11% r e s p e c t i v e l y . - 121 -osmium tetroxide occurred both r e g i o s e l e c t i v e l y and s t e r e o s e l e c t i v e l y to generate the d i o l 185. This compound was hydrogenated (H 2, Pt black, 1 atm) to generate the saturated d i o l 186 i n a y i e l d of 41%. The a d d i t i o n a l primary hydroxyl group present at C-17 i n compound 186 was removed by conversion of t h i s d i o l into the monotosylate 187, followed by reduction with lithium triethylborohydride (120). F i n a l l y the benzyl ether protecting group at C-3 was removed (Li-NR^) to give a 49% y i e l d of (±)-maritiraol _5. The t h i r d s o l u t i o n to the problem posed by the C-13 stereocentre comes from K e l l y and co-workers (12,25), i n t h e i r synthesis of (±)-2-desoxystemodi-none 6_ and (i)-stemodinol 7. The alkene 188 was epoxidized s t e r e o s e l e c t i v e l y from the less hindered a-face to afford the epoxide 189. Reduction of t h i s [33] 188 - 122 -compound 189 with lithium aluminium hydride afforded (±)-stemodinol 7 i n a y i e l d of 44% (from 188). The f i r s t approach we investigated to set up the stereocentre at C-13 i s presented i n equation [34], Addition of methylenetriphenylphosphorane to 76 190 I Li ,NH, , EtOH j [34] H 0 ! the alkylated bis-enone 7_6_ was predicted to occur r e g i o s e l e c t i v e l y at the less hindered C-13 carbonyl group, to generate the diene enone 190. Reduction of th i s compound with lithium i n ammonia containing an excess of a proton donor such as ethanol, was then expected to generate the alkene alcohol 191. F i n a l l y , epoxidation of t h i s alkene 191 with meta-chloroperbenzoic acid and reduction of the r e s u l t i n g epoxide ( c f . eq. [33] (12,25)) should then generate - 123 -(±)-maritimol _5. The proposed reduction of the diene enone 190 with Li-NH 3~ EtOH perhaps warrants further mention. Reduction of conjugated dienes such as 190 with an a l k a l i metal i n ammonia containing a proton donor normally proceeds i n a 1,4 manner to generate the A 2' 3-alkene (121) (eq. [35]). In the presence of an a c i d i c proton donor such as ethanol, Li-NH3 reduction of enones normally leads to the corresponding thermodynamically more stable satu-rated alcohol (69). In the case of compound 190 we would therefore expect the e q u a t o r i a l l y - o r i e n t e d , and hence 8 hydroxyl group at C-3 to be favoured i n the reduction step. A so l u t i o n of 1.2 equivalents of methylenetriphenylphosphorane i n tetrahydrofuran was added to a -78°C solution of 76_ i n tetrahydrofuran. A f t e r the mixture had been s t i r r e d for 30 min at -78°C and 1 hour at 0°C, analysis of an aliquot of the r e s u l t i n g mixture showed that substantial amounts of s t a r t i n g material s t i l l remained. Consequently the mixture was re-cooled to -78°C and a further 0.9 equivalents of the W i t t i g reagent were added. The reaction mixture was s t i r r e d at -78°C and 0°C, as described above, and then worked up. Chromatography of the r e s u l t i n g o i l afforded a 63% y i e l d (87% based on unrecovered 76) of the desired diene enone 190, plus some recovered s t a r t i n g material (27%). If t h i s reaction was allowed to proceed u n t i l less s t a r t i n g material remained then another sideproduct, presumably the bis diene 192, began to form. [35] - 124 -192 The diene enone 190, mp 98-99.5°C, exhibited spectral data consistent with the assigned structure. In p a r t i c u l a r the i r spectrum of 190 exhibited a broad strong band centred at 1660 cm - 1 and a much weaker band at 1580 cm - 1 consistent with the presence of both an a,8-unsaturated ketone and a conjuga-ted diene i n the molecule. Furthermore the *H nmr spectrum of 190 exhibited s i x 1-proton o l e f i n i c s i g n a l s . The two doublets (J_ = 10 Hz) at 6 5.84 and 6.76 were assigned, by analogy with compounds 7_5, 177 and 76_, to the C-2 and C-l protons re s p e c t i v e l y , while the two signals at 6 4.54 (d, J_ = 1.5 Hz) and 6 4.66 (s) were attributed to the two o l e f i n i c protons on C-l7. The two remaining signals at 6 6.08 (d of d, J = 10, 1.5 Hz) and 6.20 (d, J = 10 Hz) were attributed to the two protons at C - l l and C-12. Reduction of the diene enone 190 with an excess of l i t h i u m i n a mixture of ammonia, ether and ethanol (= 1.5%), at -33°C for 1 hour, produced a - 125 -mixture of products. This mixture was separated by chromatography into two groups of components, present i n the r a t i o of approximately 2:1 i n favour of the le s s polar f r a c t i o n . Glc of these f r a c t i o n s showed that, in each case, three components were present i n the r a t i o of approximately 4:2:1. The *H nmr spectrum of the more polar f r a c t i o n showed a broad 1-proton mul t i p l e t centred at 6 3.20. This signal suggested that the three components present i n t h i s f r a c t i o n contained a proton attached to a carbon also bearing a hydroxyl group. Consequently i t was suggested that the more polar f r a c t i o n was a mixture of products containing a hydroxyl group at C-3, while the less polar f r a c t i o n was the corresponding mixture of products containing a C-3 carbonyl group. Examination of the o l e f i n i c region of the 1H nmr spectrum of the le s s polar f r a c t i o n showed a broad s i n g l e t at 6 4.97 (= 0.25 H) and two broad 190 193 R ' .R -^O 1 9 4 R ' , R « = O 195 R' = OH,R"=H 191 R'=OH,R»=H doublets U = 10 Hz) at 6 5.20 and 5.78 (= 0.7 H each), as well as some further minor s i g n a l s . This *H nmr evidence, along with the glc data, led to the suggestion that the less polar f r a c t i o n was a mixture of the two possible epimeric A**»* 2-ketones 193 (4/7 and 1/7 of the mixture, sterochemistry at C-13 unknown) and the A ^ ' ^ - k e t o n e 194 (2/7 of the mixture). No signals - 126 -were observed i n the v i c i n i t y of 6 4.6. This indicated that l i t t l e , i f any, 13 17 of the A ' -alkene 196 was generated. The presence of a doublet, J_ = 7 Hz, at 6 0.81 (= 2.3 H) i n the *H nmr spectrum of t h i s mixture provides some 6 -4-6 51 193 194 196 support for the proposal that one of the epimers of 193 i s the major component in t h i s less polar f r a c t i o n . The C-17 protons of 193 would be expected to resonate as a doublet, showing a coupling to the C-13 proton. Since the o l e f i n i c region of the H^ nmr spectrum of the more polar f r a c t i o n was e s s e n t i a l l y i d e n t i c a l with that of the less polar f r a c t i o n , the components of t h i s mixture were assigned structures 195 (both epimers at C-13) and 191. Although, as mentioned previously, Li-NH3 reduction of conjugated dienes normally occurs i n a 1,4 manner, precedent e x i s t s for the 1,2 reduction of dienes, leading to products such as 193 (121). A recent review by Weidmann and Seebach (122) on the chemistry of organotitaniura and organozirconium compounds of the type R-Ti(0R') 3 and R-Zr(0R') 3 mentioned that reagents such as MeTi(Of-Pr) 3 _19_7 (123) exhibit remarkable s e l e c t i v i t y i n t h e i r addition to carbonyl groups. Equation [36] shows that t h i s reagent 197 can cleanly d i s t i n g u i s h between two aldehydes - 127 -having d i f f e r e n t degrees of s t e r i c hindrance (124). Furthermore, as shown i n .CHO 44 197 95% conversion CHO 1 [36] CHO 46 equation [37], the s t e r e o s e l e c t i v i t y found i n the a d d i t i o n of methyl t r i i s o -propoxytitaniura to r i g i d ketones i s high, favouring e q u a t o r i a l a t t a c k (45). T y p i c a l r e s u l t s f o r the a d d i t i o n of MeLi and MeMgBr to the same ketone are Included f o r comparison. HO OH [37] Reagent MeLi, E t 2 0 (125) MeMgBr, E t 2 0 (125,126) M e T i ( C a - P r ) 3 , E t 2 0 65 68 86 35 32 14 - 128 -The r e s u l t s presented above l e d us to look at the r e a c t i o n of MeTi(Oi-Pr) 3 w i t h the a l k y l a t e d diketone 62. We were pleased to f i n d that s t i r r i n g 62 i n a 2:1 mixture of ether and MeTi(Oi-Pr) 3, at room temperature f o r 10 hours, af f o r d e d an 82% y i e l d of an 86:13 mixture of the keto a l c o h o l s 61 and 180. 62 61 180 U n f o r t u n a t e l y , however, the two epimers 61_ and 180 were v i r t u a l l y i n separable by chromatography, so i t was often more convenient to carry out a separation at a l a t e r stage i n the s y n t h e t i c sequence. A sample co n t a i n i n g mainly the desi r e d epimer _61_ was, however, i s o l a t e d as a c o l o u r l e s s o i l by chromatography on s i l i c a g e l , e l u t i n g w i t h 30% tetrahydrofuran i n hexanes. Pure 61_ was obtained as a white s o l i d , mp 93°C ( l i t . (23) mp 90-91 °C), by c r y s t a l l i z a t i o n of t h i s o i l from hexanes. The i r spectrum of t h i s s o l i d showed bands at 3570 and 3320 cm - 1, a t t r i b u t e d to the t e r t i a r y hydroxyl group, and a strong band at 1690 cm - 1, assigned to the 6-membered r i n g ketone. The 1H nmr spectrum of J31_ e x h i b i t e d four 3-proton s i n g l e t s at 6 1.09, 1.10, 1.12 and 1.14, a t t r i b u t e d to the four t e r t i a r y methyl groups, as w e l l as two 1-proton s i n g l e t s at 6 2.29 (d of d of d, J = 16, 4.5, 3.5 Hz) and 6 2.57 (d of d of d, J = 16, 14, 6 Hz), assigned to the C-2oc and C-28 protons. The conversion of j>l_ i n t o (±)-maritimol _5 served to confirm the stereochemistry at C-13. - 129 -11. Synthesis o f (±)-Maritlmol _5 and (+)-Stemodin 2 With the a c q u i s i t i o n of the keto alcohol JS1_, we were i n a p o s i t i o n to complete our synthesis of the various stemodane-type diterpenoids 3_ - 6_. The D-ring was complete, and a l l that remained to be done was to use the carbonyl group at C-3 as a handle to introduce the f u n c t i o n a l i t y required i n the A-ring of the four natural products 3^  - j>. Before proceeding to a discussion of our r e s u l t s , we should perhaps consider b r i e f l y some of the work ca r r i e d out in previous syntheses of the stemodane-type diterpenoids 3_ - b_ (22,23). The relevant work i s summarized i n Scheme XVII. Corey and co-workers (22) completed the f i r s t t o t a l synthesis of racemic stemodin 3^  and stemodinone k_ v i a the A 2»^-alkene alcohol 55. Reaction of th i s alkene 55_ with an excess of N-broraoacetamide i n water genera-ted e x c l u s i v e l y the bromohydrin 199. This broraohydrin was then oxidized to the corresponding a-bromo ketone 200 (PCC), and the l a t t e r substance was debrominated with zinc dust In ether-aqueous ammonium chlor i d e , to afford synthetic (i)-stemodinone 4 i n a y i e l d of 80% (from _5_5). This ketone h_ was f i n a l l y reduced to (i)-stemodin 3_, i n a y i e l d of 54%, using sodium i n a mixture of ethanol and tetrahydrofuran. The I t a l i a n group (23) oxidized (±)-maritiraol 5_ into the intermediate keto alcohol ^1_ (PCC, 91%). This compound ^1_ was then converted, i n 63% y i e l d , into (±)-2-desoxystemodinone 6_ by reduction of the intermediate t o s y l -hydrazone 198 with sodium cyanoborohydride. To complete a formal t o t a l synthesis of stemodin 3^  and stemodinone 4_, the keto alcohol 61_ was converted, Scheme XVII - 1 3 1 -v i a a Shapiro r e a c t i o n ( 1 2 7 ) on the tosylhydrazone 1 9 8 , i n t o Corey's o l e f i n i c a l c o h o l 5 5 . Thus, w i t h a sample of our keto a l c o h o l 61_ i n hand, we had already completed, at l e a s t f o r m a l l y , a synthesis of (±)-stemodin 3_, (±)-stemodinone 4_ and ( ± ) - 2-desoxystemodinone j>. However, the work from M a r i n i B e t t o l o and co-workers ( 2 3 ) d i d not appear u n t i l s h o r t l y a f t e r we had completed our syn t h e s i s of (±)-maritiraol _5 and (i)-stemodin 3_. To convert the keto a l c o h o l 6_1_ i n t o (±)-maritimol 5_ we needed to reduce the carbonyl group at C - 3 i n such a manner that the 8 - , e q u a t o r i a l l y - o r i e n t e d hydroxyl group was produced. In s u b s t i t u t e d cyclohexanones such as 6 J _ , i n which the s t e r i c environment on both sides of the carbonyl group i s not s u b s t a n t i a l l y d i f f e r e n t , r eduction w i t h unhindered reducing agents such as sodium borohydride and l i t h i u m aluminium hydride normally leads to a prepon-derance of the product possessing the more s t a b l e e q u a t o r i a l hydroxyl group ( 1 2 8 ) . In c o n t r a s t , r e d u c t i o n of the keto a l c o h o l j>l_ w i t h a hindered reducing - 132 -agent, l i t h i u m tri(sec-butyl)borohydride, was reported (23) to afford (±)-3-epimaritimol 201. A sol u t i o n of the keto alcohol 6l_ i n methanol was s t i r r e d at 0°C for 2 hours i n the presence of an excess of sodium borohydride. After the reaction 61 5 201 95 5 mixture had been worked up, g l c analysis of the material thus obtained i n d i -cated the presence of (±)-maritimol 5_ and, another component, presumably 201, i n the r a t i o of =95:5. Although these compounds, _5 and 201, were inseparable by t i c with a number of solvent systems, maritimol 5_ could be p u r i f i e d from t h i s mixture by c r y s t a l l i z a t i o n from ethyl acetate. In t h i s manner, (±)-maritimol 5_ was i s o l a t e d i n a y i e l d of 73% as cubes, mp 220-221 °C ( l i t . mp 212.5-214°C (24), 211.5-212.5°C (23)). These c r y s t a l s of (±)-maritimol 5_ exhibited a broad band i n the i r spectrum centred at 3340 cm - 1 which was assigned to the two hydroxyl groups. The *H nmr spectrum of this compound showed two 1-proton signals at 6 1.75 (s) and 2.04 (d, £ = 6 Hz), both exchangeable with D 20, a t t r i b u t e d to the hydroxyl group protons at C-13 and C-3 re s p e c t i v e l y , and a 1-proton signal at 6 3.18 (d of d of d, J_ = 13, 6, 5 Hz) which was assigned to the proton at C-3. The - 133 -coupling constants (12, 5 Hz) observed between the proton on C-3 and the two adjacent protons on C-2 are consistent only with t h i s C-3 proton being a x i a l to the A-ring. If the A-ring of _5 e x i s t s In a chair conformation, t h i s means that the hydroxyl group at C-3 i s 6-oriented, as i s required i n (±)-raaritimol _5. The a d d i t i o n a l 6 Hz coupling observed i n the s i g n a l at 6 3.18 i s due to coupling of the C-3 proton with the proton on the hydroxyl group. Our sample of synthetic (±)-maritimol _5 was i d e n t i c a l with an authentic sample of (+)-maritimol 7 by g l c , t i c i n four d i f f e r e n t solvent systems, *H nmr and mass spectrometry. Both (±)- and (+)-maritimol were i n s u f f i c i e n t l y soluble i n chloroform for a meaningful comparison to be made by i r spectro-scopy. In an o v e r a l l sense, what i s required for the conversion of the keto alcohol 61_ into (l)-stemodin 3_ or (±)-stemodinone 4_ i s removal of the carbonyl group at C-3 and introduction of an oxygen-containing functional group at C-2, either at the oxidation l e v e l of a ketone (to give (i)-stemodinone), or at the l e v e l of an alcohol (to give (i)-stemodin, provided the stereochemistry i s c o r r e c t ) . The two natural products 3_ and 4^  are interconvertable by e i t h e r oxidation (10) or reduction (22), as appropriate. While a number of methods could be envisaged for e f f e c t i n g the desired transformation, 61_ + 3 or 4, based on 1,2-carbonyl group transposition metho-dology (129), the most a t t r a c t i v e approach appeared to involve conversion of the keto alcohol 61_ into Corey's alkene 55, followed by elaboration of t h i s compound into (i)-stemodin 3_ and/or (i)-stemodinone 4_. We are g r a t e f u l to Professor CD. Hufford (University of M i s s i s s i p p i ) for kindly providing a sample of (+)-maritimol. - 135 -One of the most widely used methods for transforming a ketone such as 61 into the corresponding alkene i s the Shapiro reaction (127). This proce-dure, i l l u s t r a t e d i n equation [38], involves generating the _p_-toluene s u l f o n y l -[38] hydrazone (tosylhydrazone) of the ketone, and then t r e a t i n g t h i s product with an excess of a strong base. Examination of the chemical l i t e r a t u r e indicated that 4,4-dimethyl-cholestan-3-one 202, a compound having an A-ring s i m i l a r to that of j>l_, had been transformed, v i a a Shapiro reaction, into the corresponding alkene 204, 202 203 204 as shown i n equation [39] (130). These workers looked at the e f f e c t d i f f e r e n t bases (NaH, t-amylONa, LiH and BuLi, a l l in toluene or benzene) had on t h i s Shapiro reaction (203 •*• 204), and found that, at least i n t h i s case, sodium hydride gave the best y i e l d . A s o l u t i o n of 1.3 equivalents of p-toluensulfonylhydrazide and an 86:14 mixture of the two epimeric keto alcohols 61_ and 180 i n a small volume of absolute ethanol was heated under re f l u x for 3 hours. The crude mixture of - 136 -products (mainly 198 and 205), obtained from t h i s reaction by removal of the solvent, was suspended i n toluene and then treated with an excess of o i l - f r e e sodium hydride. The resultant mixture was heated under re f l u x for 3 hours and worked up to afford a viscous o i l , which, on the basis of glc analysis, contained mainly the two alkenes 55_ and 182, along with minor amounts of a number of other u n i d e n t i f i e d components. Chromatography of th i s o i l afforded the two pure epimeric alkenes 55_ and 182 i n y i e l d s of 58 and 14% re s p e c t i v e l y . Shortly a f t e r we had c a r r i e d out th i s reaction, i t was reported (23) that the conversion of the tosylhydrazone 198 into Corey's alkene 55_ could be accomplished more e f f i c i e n t l y (87%) by treatment of a tetrahydrofuran so l u t i o n of the former substance with an excess of methyllithium. - 137 -The alkene 55, mp 129.5-131°C ( l i t . mp 119-122°C (22), 128-129°C (23)), exhibited s p e c t r a l data i n accord with the assigned structure, and consistent with that reported e a r l i e r for t h i s compound (23). The i r spectrum of 55 showed a band at 3600 cm - 1 a t t r i b u t e d to the hydroxyl group, while the *H nmr spectrum of this compound exhibited two l o w - f i e l d signals at 6 5.32 (d of d, £ = 10, 2.5 Hz) and 6 5.50 (d of d of d, J = 10, 6.5, 2.5 Hz) which were assigned to the o l e f i n i c protons at C-3 and C-2 r e s p e c t i v e l y . The epimeric alkene 182 was obtained as a white powder, mp 153-154.5°C ( l i t . (22) mp 147-149°C). The i r spectrum of t h i s compound showed the expected band at 3300 cm - 1 due to the hydroxyl group. The H^ nmr spectrum of 182 exhibited two s i n g l e t s at 6 0.91 (3H) and 6 0.95 (6H) assigned to the three t e r t i a r y methyl groups on C-4 and C-10, a 3-proton s i n g l e t at 6 1.24 a t t r i b u t e d to the C-17 methyl group and a 2-proton multiplet between 6 5.18 and 5.62 assigned to the two o l e f i n i c protons on C-2 and C-3. - 138 -While the alkene 5_5 had been converted previously into (±)-stemodin 3_ v i a a 4-step sequence (22), we thought that i t should be possible to e f f e c t t h i s transformation d i r e c t l y by hydroboration. Examination of molecular models of 55_ suggested that, i f th i s alkene was treated with a hindered hydroborating agent such as disiamylborane (131) or 9-borabicyclo[3.3.1]nonane (9-BBN) (132), addition of the reagent to 5_5_ would occur, for s t e r i c reasons, both r e g i o s e l e c t i v e l y so as to attach the boron atom to the C-2 carbon, and st e r e o s e l e c t i v e l y from the a-face. The reagent of choice for the conversion of _55_ into (t)-stemodin 3_ appeared to be 9-BBN, since i t i s a f a i r l y reactive reagent and yet i s one of the most regio- and stereoselective hydroborating agents presently a v a i l a b l e (132). A s o l u t i o n of the alkene 5_5 and a large excess of 9-BBN i n tetrahydrofuran was heated under re f l u x for 2 days. The r e s u l t i n g solution was treated with a l k a l i n e hydrogen peroxide and subjected to work-up. The o i l thus obtained was chromatographed to provide an 88% y i e l d of (i)-stemodin 3. The large excess of hydroborating agent, elevated temperature, and long reaction time were necessary to drive t h i s reaction to completion. The sample of synthetic (i)-stemodin 3_> mp 220.5-222°C ( l i t . (22) mp 218-220°C), showed i n i t s i r spectrum a broad band at 3300 cm - 1 assigned to the hydroxyl groups. The % nmr spectrum of th i s d i o l 3_ showed, i n addition to the expected four 3-proton s i n g l e t s , two exchangeable 1-proton signals at 6 2.47 and 2.87, assigned to the protons on the two hydroxyl groups, and a 1-proton multiplet centred at 6 3.67 which was assigned to the C-28 proton. Our sample of (i)-steraodin 3_ was i d e n t i c a l with an authentic sample of - 139 -(-)-stemodin a by g l c , t i c i n 4 d i f f e r e n t solvent systems, 1H nmr and mass spectrometry. Since the keto alcohol 61_ had been converted previously into (±)-2-desoxystemodinone 6_ (23), and the alkene 55_ had been converted into (±)-stemodinone 4_ (22) (see Scheme XVII), the work described i n th i s thesis also constitutes a formal t o t a l synthesis of these two stemodane-type d i t e r -penoids, 4^  and j>. We are g r a t e f u l to Dr. P.S. Manchand (Hoffman-LaRoche Inc.) for kindly providing a sample of (-)-stemodin. - 140 -EXPERIMENTAL General Information Melting points were determined using a Fisher-Johns melting point apparatus and are uncorrected. Infrared ( i r ) spectra were recorded on a Perkin Elmer model 710B i n f r a r e d spectrophotometer, and were ca l i b r a t e d using the 1601 cm - 1 band of polystyrene. Proton nuclear magnetic resonance (*H nmr) spectra were determined i n deuterochloroform unless otherwise stated, and recorded at 80 MHz on a Bruker WP-80 spectrometer, at 400 MHz on a Bruker WP-400 instrument, or at 270 MHz on a unit composed of an Oxford Instruments 63.4 KG magnet, Nicolet 16K computer, and a Bruker TT-23 console. Signal positions are given i n parts per m i l l i o n (6) downfield from tetramethyl-s i l a n e . In the case of compounds containing t r i a l k y l s i l y l groups the chemical s h i f t s were determined r e l a t i v e to the chloroform s i g n a l (6 7.25). The multi-p l i c i t y , number of protons, coupling constants, and assignments ( i f possible) of selected signals are indicated i n parentheses. A l l chemical s h i f t s and coupling constants are those measured from the spectrum, i . e . assuming f i r s t order behaviour. A n a l y t i c a l gas l i q u i d chromatography (glc) was c a r r i e d out, unless otherwise stated, on a Hewlett Packard 5880A gas chromatograph with a 25 m x 0.31 mm crosslinked 5% phenylmethyl s i l i c o n e column, using helium (=2.5 mL/rain) as c a r r i e r gas. A n a l y t i c a l thin layer chromatography ( t i c ) was c a r r i e d out on commercial pre-coated S i l i c a Gel 60 plates (Merck No. 5554). Preparative t i c was c a r r i e d out e i t h e r on 20 x 20 cm glass plates coated with 0.7 mm of S i l i c a Gel 60 (E. Merck No. 7730), or, for small samples, on the commercial pre-coated a n a l y t i c a l plates described above. Column chromato-- 141 -graphy was c a r r i e d out on S i l i c a Gel 60 (E. Merck, 7 0 - 2 3 0 mesh). F l a s h chromatography was c a r r i e d out on S i l i c a Gel 60 (E. Merck, 2 3 0 - 4 0 0 mesh) according to the procedure described by S t i l l ( 1 3 3 ) . The solvent and column diameter ( i f appropriate) are given i n parentheses. Low r e s o l u t i o n mass spectra were recorded w i t h a Varian/MAT CH 4 B mass spectrometer, and high r e s o l u t i o n mass spectra (HRMS) were measured on a Kratos MS-50 mass spectr o -meter. A l l compounds c h a r a c t e r i z e d by high r e s o l u t i o n mass spectrometry e x h i b i t e d 1 peak by g l c and/or 1 spot on t i c . Microanalyses were performed by the M i c r o a n a l y t i c a l Laboratory at the U n i v e r s i t y of B r i t i s h Columbia. A l l r e a c t i o n s i n v o l v i n g a i r or moisture s e n s i t i v e reagents were c a r r i e d out under an atmosphere of argon using e i t h e r oven-, vacuum-, or flame-dried glassware. The solvents and reagents used were p u r i f i e d as f o l l o w s : Tetrahydro-fu r a n , d i e t h y l ether, dimethoxyethane, dioxane, and toluene were f r e s h l y d i s t i l l e d from sodium benzophenone k e t y l ; ammonia was d i s t i l l e d from m e t a l l i c sodium; benzene was f r e s h l y d i s t i l l e d from calcium hydride; hexamethyl-phosphoramide (HMPA), t r i e t h y l a m i n e , hexamethyldisilazane, diisopropylamine, t e r t - b u t y l a l c o h o l and tert-amyl a l c o h o l were d i s t i l l e d from calcium hydride and stored over a c t i v a t e d 3A molecular s i e v e s ; dichloromethane was d i s t i l l e d from phosphorous pentoxide or calcium hydride; a c e t o n i t r i l e was d i s t i l l e d from phosphorus pentoxide; methanol was d i s t i l l e d from f r e s h l y prepared magnesium methoxide j u s t p r i o r to use; dimethyl s u l f i d e was d r i e d w i t h a c t i v a t e d 3A molecular s i e v e s ; and methyl i o d i d e was passed through a plug of b a s i c alumina immediately p r i o r to use. Petroleum ether r e f e r s to the hydrocarbon f r a c t i o n bp 35-60°C. Aqueous ammonium c h l o r i d e , sodium bicarbonate, sodium t h i o s u l f a t e and copper s u l f a t e - 142 -re f e r to saturated solutions of the appropriate s a l t i n water. Preparation of the 1,4-Dione 83 To a cold (-78°C), s t i r r e d , solution of lithium diisopropylamide (22.5 mmol) i n 50 mL of dry tetrahydrofuran, under an atmosphere of argon, was added dropwise v i a syringe a sol u t i o n of 5.0 g (18.8 mmol) of the keto k e t a l 67_ i n 10 mL of dry tetrahydrofuran. A f t e r the resultant s o l u t i o n had been s t i r r e d for 30 min at 0°C, i t was again cooled to -78°C and 8 mL ( = 70 mmol) of neat methallyl iodide (50) was added i n one portion. After the reaction mixture This i s a modification of a reaction previously c a r r i e d out in t h i s laboratory by D.J. Herbert (31). - 143 -had been s t i r r e d at 0°C for 2 h and at room temperature for 1 h, the v o l a t i l e materials were removed under reduced pressure. The residual viscous o i l was dissolved i n 50 mL of methanol and s t i r r e d under an atmosphere of argon with a small amount of sodium methoxide. After 15 min the methanol was removed under reduced pressure and the r e s u l t i n g s o l i d was dissolved i n ether. The ethereal so l u t i o n was washed once with aqueous ammonium chloride, and three times with brine, dried (MgS0 4), and concentrated under reduced pressure to afford 6.34 g of a white s o l i d . Glc analysis of th i s s o l i d (using a 6 f t x 0.125 in column with 5% 0V17 on Chromosorb W (100-120 mesh) as the stationary phase) showed i t to be a mixture of the s t a r t i n g material 67_ (0.5%), the monoalkylated keto k e t a l 82 (94%) and the di a l k y l a t e d keto k e t a l 98 (5%). Flash chromatography (10% ethyl acetate i n hexanes) of a small amount of t h i s material provided samples of the two major components. E l u t i o n of the column afforded i n i t i a l l y the d i a l k y l a t e d keto k e t a l 98_ as a colourless viscous o i l : XH nmr (80 MHz) 6: 0.91, 1.03, 1.08 (s, s, s, 3H each, t e r t i a r y methyl groups), 1.61, 1.71 (br s, br s, 3H each, v i n y l methyl groups), 3.27-3.73 (m, 4H, ke t a l methylene protons), 4.64, 4.86 (m, m, 2H each, alkene protons). Exact Mass calcd. for C24H33O3: 374.2821; measured: 374.2821. Further e l u t i o n of the column afforded the alkylated keto k e t a l 82_ as a white s o l i d . R e c r y s t a l l i z a t i o n of a small amount of th i s material provided an a n a l y t i c a l sample of 82, mp 87°C; i r (CHCI3): 1700, 1630, 1105, 1095 cm"1; XH nmr (400 MHz) 6: 0.90, 1.03, 1.15 (s, s, s, 3H each, t e r t i a r y methyl groups), 1.69 (br s, 3H, v i n y l methyl group), 1.93 (d of t, IH, J = 13, 2.5 Hz), 2.08 (m, IH), 2.36 (d of d of d, IH, J = 14, 6, 3 Hz), 2.54 (d of d, IH, J = 15, 5 Hz), 2.80 (m, IH, C-2 proton), 3.39, 3.44 (d of d, d of d, IH each, J = 11, 1 - 144 -Hz i n each case, equatorial k e t a l methylene protons), 3.51, 3.59 (d, d, IH each, J_ = 11 Hz in each case, a x i a l k e t a l methylene protons), 4.63, 4.75 (br s, br s, IH each, alkene protons). Exact Mass calcd. for C20H32O3: 320.2351; measured: 320.2353. To a s t i r r e d mixture (room temperature) of 24.13 g (112.8 mmol) of sodium metaperiodate ( f r e s h l y r e c r y s t a l l i z e d from water), 1.54 g (18.8 mmol) of sodium acetate, a c a t a l y t i c amount of osmium tetroxide and 200 mL of d i s t i l l e d water, was added i n one portion a solution of the mixture of 67, 82, and 98_, prepared as described above, i n 150 mL of d i s t i l l e d t e r t - b u t y l a l c o h o l . The mixture was stoppered and s t i r r e d for 2 h, a f t e r which time the i n i t i a l l y - f o r m e d brown col o r a t i o n had discharged. A further 150 mL of d i s t i l l e d water were added and the mixture was s t i r r e d for a further 4 h. The r e s u l t i n g reaction mixture was then extracted three times with 300 mL of ether. The combined organic extracts were washed with brine, dried (MgS0i+), and concentrated under reduced pressure. The r e s u l t i n g brown o i l was dissolved i n ether, and the solution was f i l t e r e d through a plug of s i l i c a gel to remove much of the coloured material. Removal of the solvent, followed by c r y s t a l l i z a t i o n of the remaining o i l from hexanes, afforded 4.51 g (74%) of the dione 83_, as off-white c r y s t a l s , which exhibited: mp 89-91 °C. Flash chromatography of the material from the mother liquo r (20% ethyl acetate i n hexanes, 5 cm column) afforded a further 0.80 g of 83_, as an off-white s o l i d , for a t o t a l y i e l d of 5.31 g (88%). R e c r y s t a l l i z a t i o n of a small amount of t h i s material from hexanes afforded an a n a l y t i c a l sample of J33_ as colourless needles, mp 90-91°C; i r (CHC1 3): 1700 cm"1; XH nmr (400 MHz) 6: 0.88, 1.02, 1.17 (s, s, s, 3H each, t e r t i a r y methyl groups), 1.91 (d of t, IH, £ = 13, 3 - 145 -Hz), 2.03 (m, IH), 2.09 (d of d, IH, J = 17, 5 Hz, C - l ' p r o t o n ) , 2.20 ( s , 3H, C-3' p r o t o n s ) , 2.35 (d of q, IH, J = 14, 3.5 Hz), 2.92 (d of d, IH, J = 17, 8 Hz, C - l ' proton), 3.32 (m, IH, C-2 p r o t o n ) , 3.36-3.60 (m, 4H, k e t a l methylene protons). Exact Mass c a l c d . f o r C 1 9H 3 0O H: 322.2144; found: 322.2147. A n a l , c a l c d . f o r C^HgoO^: C 70.77, H 9.38; found: C 70.73, H 9.45. P r e p a r a t i o n of the T r i c y c l i c Enone 6 6 83 66 88 Sodium hydride (490 mg of a 57% d i s p e r s i o n i n o i l , 11.6 mmol) was placed i n a dry 2-necked round-bottomed f l a s k under an argon atmosphere. The o i l was removed from the sodium hydride by washing i t with dry ether ( 3 x 5 mL), and the r e s i d u a l solvent was then evaporated under reduced pressure. Dry benzene (200 mL) and dry ter t - a m y l a l c o h o l (500 uL, 4.7 mmol) were added. A f t e r the mixture had been s t i r r e d at room temperature f o r 20 min, 3.00 g (9.30 mmol) of the s o l i d 1,4-dione 83_ were added, and the mixture was heated under r e f l u x f o r 1 h. The cooled r e a c t i o n mixture was quenched with aqueous ammonium c h l o r i d e and d i l u t e d with ether. The organic e x t r a c t was washed with b r i n e , d r i e d (MgSO^) and concentrated to a f f o r d a yellow o i l . Glc a n a l y s i s of t h i s o i l showed i t to be a mixture of the s t a r t i n g m a t e r i a l 83 (13%), the - 146 -t r i c y c l i c enone 66 (82%) and the isomeric enone 88 (4%). Separation of t h i s mixture by preparative high performance l i q u i d chromatography (Waters Prep. 500 HPLC, = 30% ethyl acetate i n petroleum ether) and rechromatography of the mixed f r a c t i o n s by f l a s h chromatography (solvent as above, 5 cm column) afforded 333 mg (11%) of recovered s t a r t i n g material 83_ as the f i r s t eluted component, 2.08 g (73%, 83% based on unrecovered s t a r t i n g m a t erial), a f t e r r e c r y s t a l l i z a t i o n from ether-hexanes, of the desired enone 66_, mp 115-117°C, followed by 139 mg (5%) of a mixture of the two isomeric enones 66_ and 88. R e c r y s t a l l i z a t i o n of a small portion of the major f r a c t i o n afforded an a n a l y t i c a l sample of the enone 66, mp 115-116°C; i r (CHC1 3): 1690, 1670, 1600 cm - 1; XH nmr (400 MHz) 6: 0.94, 1.00 (s, s, 3H each, k e t a l methyl groups), 1.13 (s, 3H, angular methyl group), 1.18 (m, IH), 1.39-1.67 ( d i f f u s e , 6H), 1.73 (q of d, IH, J = 14, 4 Hz), 1.96 (d of d, IH, J = 18, 2 Hz, C-3a proton), 1.99 (d of t, IH, J = 13, 3 Hz), 2.18 (m, IH), 2.34 (d of d of d, IH, J = 13.5, 6.5, 3 Hz), 2.57 (d of d, IH, J = 18, 7 Hz, C-3B proton), 2.98 (m, IH, C-3a proton), 3.42-3.61 (m, 4H, k e t a l methylene protons), 5.80 (d, IH, J_ = 1.5 Hz, C-l proton). I r r a d i a t i o n at 6 5.80 sharpens the multiplet at 6 2.98. I r r a d i a t i o n at 6 2.98 causes the doublet at 6 5.80 to collapse to a s i n g l e t and the signals at 6 2.57 and 6 1.96 to collapse to doublets, J = 18 Hz. I r r a d i a t i o n at 6 2.57 sharpens the multiplet at 6 2.98 and the signal at 6 1.96 collapses to a doublet (J_ = 2 Hz). Exact Mass calcd. for C 1 9 H 2 8 0 3 : 304.2038; found: 304.2038. Anal, calcd. for C 1 9 H 2 8 0 3 : C 74.96, H 9.27; found: C 74.76, H 9.47. Flash chromatography of the mixed f r a c t i o n (4:2:3 cyclohexane-hexanes-ethyl acetate, 3 cm column) followed by c r y s t a l l i z a t i o n of - 147 -the material from the appropriate f r a c t i o n s from ether-hexanes provided a sample of the isomeric enone 88, mp 139-140°C; i r (CHCI3): 1690, 1665, 1610, 1105 cm"1; XH nmr (400 MHz) 6: 0.64 (s, 3H, angular methyl group), 0.93, 1.04 (s, s, 3H each, keta l methyl groups), 1.31-1.49 ( d i f f u s e , 5H), 1.62 (m, IH), 1.77 (t of t, IH, J = 13, 3.5 Hz), 1.96 (d of t, IH, J = 13, 3.5 Hz), 2.17 (d of d, IH, J = 19, 2 Hz, C-la proton), 2.24-2.41 (m, 2H), 2.30 (d of d, IH, J = 19, 7 Hz, C-1B proton), 2.54 (br d, IH, J = 7 Hz, C-9b proton), 2.80 (br d of d, IH, J_ = 15, 5 Hz), 3.45-3.65 (m, 4H, ke t a l methylene protons), 5.90 (d of d, IH, J = 2, 2 Hz, C-3 proton). I r r a d i a t i o n at 6 5.90 sharpens the signal at 6 2.54. I r r a d i a t i o n at 6 2.54 collapses the signal at 6 5.90 to a doublet, J_ = 2 Hz, and collapses the signals at 6 2.17 and 6 2.30 to doublets, J_ = 19 Hz. I r r a d i a t i o n at 6 2.17 sharpens the signal at 6 2.54. Exact Mass calcd. for C 1 9H 280 3: 304.2039; found: 304.2039. - 148 -Photoaddition of Allene to the Enone 66 108 109 A cold (-78°C), s t i r r e d , s o l u t i o n of 3.00 g (9.89 mmol) of the t r i c y c l i c enone 66_ and approximately 5 mL of allene i n 55 mL of dry tetrahydrofuran, contained i n a Pyrex tube, was i r r a d i a t e d (450 Watt Hanovia lamp) for 7 h while a slow stream of argon was bubbled through the so l u t i o n . The r e s u l t i n g solution was allowed to warm to room temperature while being vigorously s t i r r e d , and the tetrahydrofuran was then removed under reduced pressure. Flash chromatography (20% ethyl acetate i n hexanes, 5 cm column) of the residue afforded 3.25 g (96%) of a mixture of the four possible This reaction was car r i e d out e s s e n t i a l l y as described e a r l i e r by D.J. Herbert (31). Also see r e f . (32). - 149 -photoadducts 79_, 80, 108 and 109 i n the r a t i o of 40:51:6:3 ( g l c ) , as a viscous foaming o i l . As has been described previously (31,32) the two major photoadducts 79 and 80_ could be i s o l a t e d by chromatography of t h i s mixture on s i l i c a gel (10:5:2 cyclohexane-hexanes-ethyl acetate), followed by c r y s t a l l i z a t i o n of the material from the appropriate f r a c t i o n s from ether-hexanes. Samples i s o l a t e d i n t h i s manner were Ide n t i c a l ( t i c , nmr, mp) with those prepared previously (31,32). The following XH nmr data i s included for completeness: Compound 79 exhibited: XH nmr (400 MHz) 6: 0.87, 0.95, 0.97 (s, s, s, 3H each, t e r t i a r y methyl groups), 1.73 (br m, IH), 1.89 (d of d, IH, J_ = 17, 1 Hz, C-2a proton), 1.95 (d of t, IH, J - 14, 3 Hz), 2.12-2.27 (m, 2H), 2.66 (br d of d, IH, J = 17, 3 Hz, C-9 proton), 2.83 (br d of d, IH, J_ = 17, 2.5 Hz, C-9 proton), 2.93 (d of d, IH, J_ = 17, 6 Hz, C-2 proton), 3.26 (br s, IH, C-10a proton), 3.41-3.55 (m, 4H, k e t a l methylene protons), 4.80 (br d, IH, J = 2.5 Hz, alkene proton), 4.95 (br d, IH, J_ = 2 Hz, alkene proton). Compound 80 exhibited: *H nmr (400 MHz) 6: 0.90, 0.95, 1.00 (s, s, s, 3H each, t e r t i a r y methyl groups), 1.90 (d of t, IH, J_ = 13, 3 Hz), 2.19 (d of d of d, IH, J = 15, 6, 1 Hz, C-2 proton), 2.23 (m, IH), 2.38 (m, IH, C-2a proton), 2.45 (m, IH, C-2 proton), 2.68-2.83 (br AB system, 2H, J^g = 17 Hz, C-9 protons), 3.09 (br s, IH, C-lOa proton), 3.43-3.58 (m, 4H, k e t a l methylene protons), 4.78 (br d, IH, J_ = 2.5 Hz, alkene proton), 4.92 (br d, IH, J_ = 2 Hz, alkene proton). I r r a d i a t i o n at 6 3.09 s i m p l i f i e s the si g n a l at 6 2.19 to a doublet of doublets, J = 15, 6 Hz. I r r a d i a t i o n at 6 2.22 (6 2.19 and 6 2.23 signals) s i m p l i f i e s the multiplet at 6 2.45. - 150 -I s o l a t i o n of the Minor Photoadducts 108 and 109 1 0 8 1 0 9 Flash chromatography (10:5:2 cyclohexane-hexanes-ethyl acetate, 2.5 cm column) of 119 mg of a mixture containing mainly the regioisomeric photo-adducts 108 and 109, i s o l a t e d as a minor high Rf component from ozonolysis-methoxide treatment of a mixture of a l l four photoadducts 7_9_, 80_, 108 and 109, (vide i n f r a : preparation of the keto ester 65, D), afforded i n i t i a l l y 62 rag of the a-photoadduct 109. R e c r y s t a l l i z a t i o n from ether-hexanes provided a pure sample of 109, mp 146-148°C; i r (CHC1 3): 1720, 1660, 1100 cm - 1; XH nmr (400 MHz) 6: 0.89 (m, IH, C-8a proton), 0.97, 1.00 (s, s, 6H, 3H, t e r t i a r y methyl groups), 1.71 (m, IH), 1.88 (d of d, IH, J = 17, 2 Hz), 1.98 (d of t, IH, J = 13, 3 Hz), 2.16 (d of q, IH, J = 13, 3 Hz), 2.26-2.35 (m, 2H), 2.67 (br d, IH, J - 10 Hz), 2.88 (d of d, IH, J = 17, 6 Hz), 2.90 (m, IH,) 3.47, 3.52 (s, s, 2H each, k e t a l methylene protons), 5.00 ( t , IH, J_ = 2.5 Hz, alkene proton), 5.01 ( t , IH, J_ = 2 Hz, alkene proton). I r r a d i a t i o n at 6 0.91 showed no NOE enhancement of the signals at 6 5.00 or 6 5.01 (N0E difference experiment). Exact Mass calcd. for C 2 2 H 3 2 O 3 : 344.2351; measured: 344.2347. Further e l u t i o n of the column afforded 31 mg of the 8-photoadduct 108, - 151 -which, a f t e r r e c r y s t a l l i z a t i o n from hexanes, exhibited the following proper-t i e s : mp 132-133.5°C; i r ( C H C 1 3 ) : 1720, 1650, 1100 cm - 1; *H nmr (400 MHz) 6: 0.89, 0.94, 0.99 (s, s, s, 3H each, t e r t i a r y methyl groups), 1.85 (t of d, IH, J - 14, 4 Hz), 1.90-2.00 (m, 2 H ) , 2.13-2.29 (m, 4 H ) , 2.46 (d, IH, J = 15 Hz), 2.52 (br d, IH, J - 10 Hz), 2.78 (d of d of t, IH, J = 16, 11, 3 Hz), 3.43-3.58 (m, 4H, k e t a l methylene protons), 5.11 (br s, IH, alkene proton), 5.26 ( t , IH, J = 3 Hz, alkene proton). I r r a d i a t i o n at 6 0.94 showed NOE enhancement of the signal at 6 5.26 (NOE difference experiment). Exact Mass calcd. for C22H32O3: 344.2351; measured: 344.2359. Reduction of the a-Photoadduct 80 80 206 107 To a cold (0°C), s t i r r e d , s o l u t i o n of 67 mg (0.195 mmol) of the ct-photoadduct 80_ in 20 mL of methanol was added an excess of sodium boro-hydride. The r e s u l t i n g mixture was then allowed to warm to room temperature and s t i r r e d for a further 40 min at t h i s temperature. After the solvent had been removed, the residue was pa r t i t i o n e d between ether and water. The - 152 -organic phase was washed with brine, dried (MgSO^) and concentrated, to afford 63 mg (93%) of the alcohol 206 as a viscous colourless o i l : i r (CHC1 3 ) : 3540, 3450, 1660 cm - 1; XH nmr (80 MHz) 6: 0.85, 0.93, 0.98 (s, s, s, 3H each, methyl groups), 3.31-3.67 (m, 4H, k e t a l methylene protons), 4.10 (br m, IH, C-l proton), 4.86 (m, 2H, alkene protons). Exact Mass calcd. for C 2 2 H 3i40 3 : 346.2508; measured: 346.2509. A l l attempts to c r y s t a l l i z e t h i s o i l from a v a r i e t y of solvents f a i l e d . The corresponding p_-bromobenzoate 107 (p_-bromobenzoyl chloride, p y r i d i n e , room temperature, 16 h) , a f t e r p u r i f i c a t i o n by preparative t i c (10:5:4 cyclohexane-hexanes-ethyl acetate), was c r y s t a l l i z e d from ethanol as cubes, mp 184-185°C; i r (CHC1 3 ) : 1700, 1665, 1590 cm - 1; *H nmr (270 MHz) 6: 0.89, 0.92, 0.99 (s, s, s, 3H each, t e r t i a r y methyl groups), 2.44, 2.65 (br d, br d, IH each, J = 19 Hz i n each case) 3.29 (br d, IH, J = 9 Hz, C-lOa proton), 3.39-3.60 (m, 4H, k e t a l methylene protons), 4.58, 4.74 (br d, br d, IH each, J_ = 2 Hz,. alkene protons), 5.15 (m, IH, C-l proton), 7.54 (br d, 2H, J_ = 8 Hz, aromatic protons m- to e s t e r ) , 7.86 (br d, 2H, J_ = 8 Hz, aromatic protons o_- to e s t e r ) . Exact Mass calcd. for C29H37 BrO^: 528.1875; measured: 528.1871. - 153 -Hydrogenatlon of the T r i c y c l i c Enone 66 6 6 118 A mixture of 35.3 mg (116 umol) of the t r i c y c l i c enone 66, 3 mL of methanol and 10 mg of 5% palladium-on-charcoal was s t i r r e d vigorously at room temperature and at atmospheric pressure under an atmosphere of hydrogen. A f t e r 6 h t i c indicated that no s t a r t i n g material remained. The mixture was d i l u t e d with ether and f i l t e r e d through a short plug of Celite®. Concentra-t i o n of the f i l t r a t e afforded a white s o l i d , which *H nmr indicated contained almost e x c l u s i v e l y the cis-fused ketone 118, along with a trace of the trans-fused ketone 117. R e c r y s t a l l i z a t i o n of t h i s s o l i d from pentane gave 34.2 mg (96%) of the cis-fused ketone 118, as colourless needles, mp 152-153°C; i r (CHCI3): 1725 cm - 1; XH nmr (400 MHz) 6: 0.94, 1.00 (s, s, 3H each, k e t a l methyl groups), 1.04 (s, 3H, bridgehead methyl group), 1.08 (q of d, IH, J_ = 14, 6 Hz, C-4a proton), 1.36 (d, IH, J = 13 Hz), 1.52 (t of d, IH, Jf = 13.5, 4 Hz), 1.57-1.69 (m, 2H), 1.95 (d of t , IH, J = 13, 3Hz), 2.00-2.12 (ra, 3H), 2.19-2.29 (m, 2H), 2.31 (d of d, IH, J = 18, 7 Hz, C-3 proton), 2.50 (d of q, IH, J_ = 14, 7 Hz, C-3a proton), 3.42-3.57 (m, 4H, k e t a l methylene protons). Exact Mass calcd. for C 1 9H 3 0O 3: 306.2195; measured: 306.2200. - 154 -Lithium/Ammonia Reduction of the Enone 66 6 6 117 118 To a cold (-33°C), s t i r r e d , solution of 107 mg (0.35 mmol) of the t r i c y c l i c enone 66_ and 33 uL (0.35 mmol) of dry t e r t - b u t y l alcohol i n 25 mL of anhydrous ammonia and 3 mL of dry ether, was added approximately 6 mg ( = 0.9 mmol) of lit h i u m metal. An immediate reaction occurred and the r e s u l t i n g blue solution was s t i r r e d at -33°C for a further hour. The excess lithium was quenched with a few drops of isoprene (violent r e a c t i o n ) , and s o l i d ammonium chloride was then c a r e f u l l y added to the white reaction mixture. After the ammonia had been allowed to evaporate, the residue was par t i t i o n e d between ether and waters The aqueous phase was extracted thoroughly with ether and the combined organic extracts were washed with brine, dried (MgSO^) and concentrated to y i e l d 105 mg of a colourless viscous o i l . Flash chromato-graphy (4:2:3 cyclohexane-hexanes-ethyl acetate, 2.5 cm column) gave 82 mg (76%) of a white s o l i d which *H nmr (80 MHz) indicated was a mixture of 117 (6 0.85) and 118 (6 1.04) i n the r a t i o of approximately 7:3. The values given i n parentheses are the chemical s h i f t s of the angular methyl groups. These peaks - 155 -were used to estimate the product r a t i o . F r a c t i o n a l r e c r y s t a l l i z a t i o n from pentane afforded a small amount of the pure cis-fused isomer 118, i d e n t i c a l with a sample prepared as described e a r l i e r . For the i s o l a t i o n and character-i z a t i o n of the trans-fused ketone 117, see l a t e r . P h o t o a d d i t i o n of A l l e n e to the Enone 88 A cold (-78°C), s t i r r e d , s o l u t i o n of 100 mg (0.329 mmol) of the enone 88 and approximately 5 mL of allene i n 50 mL of dry tetrahydrofuran, contained i n a Pyrex tube, was i r r a d i a t e d (450 Watt Hanovia lamp) for 2 h while a slow stream of argon was bubbled through the s o l u t i o n . Concentration, as previously described, and f l a s h chromatography (= 20% e t h y l acetate i n petroleum ether, 2.5 cm column) afforded 108 mg (96%) of a colourless viscous - 156 -o i l . Glc analysis (220°C, SE 54) showed 3 peaks with retention times of 7.00 (10%, 113), 7.37 (87%, 110_ and 111), and 7.54 rain (4%, 112). Examination of the l o w - f i e l d region of the 400 MHz *H nmr spectrum of t h i s o i l gave the following product r a t i o : 1_10 (6 4.77, 4.94), 48%; 1_11_ (6 4.81, 5.00), 37%; 113 (6 4.84, 4.94), 12%; and J_12_ (6 5.01, 5.31), 3%. The values given i n parentheses here are the chemical s h i f t s of the two alkene protons. I s o l a t i o n of small samples of the two major photoadducts was c a r r i e d out as follows: Flash chromatography (10:5:2 cyclohexane-hexanes-ethyl acetate) of the photoadduct mixture afforded, as the f i r s t eluted component, a mixture containing mainly 110. Preparative t i c (same solvent, Rf 0.32), followed by r e c r y s t a l l i z a t i o n from pentane afforded the 8-photoadduct 110 as colourless needles, mp 151-152°C; i r (CHC1 3): 1720, 1665, 1110, 1100 cm - 1; *H nmr (270 MHz) 6: 0.84 (s, 3H, angular methyl group), 0.93, 0.99 (s, s, 3H each, k e t a l methyl groups), 1.71 (d of d, IH, J_ = 15, 7 Hz), 1.90 (d of t, IH, J = 13, 3 Hz), 2.00 (d of t, IH, J = 12, 3 Hz), 2.15-2.28 (m, 2H), 2.36 (br d, IH, J_ = 16 Hz, C-4a proton), 2.51 (br d, IH, J_ = 16 Hz, C-l proton), 2.94 (br s, IH, C-2a proton), 3.11 (br d, IH, J = 16 Hz, C-48 proton), 3.42-3.60 (m, 4H, k e t a l methylene protons), 4.77 (br d, IH, J_ = 1 Hz, alkene proton), 4.94 (br d, IH, J_ = 2 Hz, alkene proton). Exact Mass calcd. for C 22H32°3 : 344.2351; measured: 344.2352. Further e l u t i o n of the column afforded a mixture containing mainly the photoadduct 111. Submission of t h i s mixture to conventional column chromato-graphy (same solvent), followed by r e c r y s t a l l i z a t i o n of the cleaner f r a c t i o n s from ether-hexanes, and then from pentane, afforded a sample of the a-photo-adduct 111, as fin e colourless needles, mp 163-165°C; i r (CHC1 3): 1720, 1660 cm - 1; XH nmr (400 MHz) 6: 0.61 (s, 3H, angular methyl group), 0.93, 1.00 (s, - 157 -s, 3H each, k e t a l methyl groups), 1.77 (d, IH, £ = 8 Hz, C-lOb proton), 1.92 (d of t, IH, J = 13, 3 Hz), 2.13-2.24 (m, 2H), 2.34 (d, IH, J = 18 Hz, C-1B proton), 2.43 (d of d of d, IH, J = 16, 5, 2 Hz, C-4 proton), 2.82 (d of d, IH, J_ = 18, 8 Hz, C-lcc proton), 2.90 (d of d of d, IH, J = 16, 6, 3 Hz, C-4 proton), 3.01 (br s, IH, C-2a proton), 3.42-3.60 (m, 4H, ket a l methylene protons), 4.81 (d of d, IH, J_ = 4, 2 Hz, alkene proton), 5.00 (d of d, IH, J = 4, 3 Hz, alkene proton). Exact Mass calcd. for C 2 2 H 3 2 ° 3 : 344.2351; measured: 344.2342. Hydrogenatlon of the T r i c y c l i c Enone 88 8 8 117 119 A mixture of 9.1 mg (30 umol) of the t r i c y c l i c enone 88, 1 ml of dry dioxane and a small amount of 5% palladium-on-charcoal was s t i r r e d vigorously at room temperature and atmospheric pressure, under an atmosphere of hydrogen. A f t e r 8 h t i c indicated that a small amount of s t a r t i n g material s t i l l remained, but that side products were being formed. After a further hour the mixture was d i l u t e d with ether and f i l t e r e d through a plug of Celite®. Concentration of the f i l t r a t e afforded 10.3 mg of a white s o l i d , which was submitted to chromatography on 2.5 g of s i l i c a g e l . E l u t i o n with a 10:5:2 mixture of cyclohexane, hexanes and ethyl acetate yielded 8.1 mg (88%) - 158 -of a 95:5 mixture (glc) of the ketones 119 and 117. R e c r y s t a l l i z a t l o n of th i s s o l i d from ether-hexanes afforded an a n a l y t i c a l sample of 119, as needles, mp 126-128°C; i r (CHC1 3): 1730, 1120, 1100 cm - 1; XH nmr (400 MHz) 6: 0.73 (s, 3H, angular methyl group), 0.93, 1.00 (s, s, 3H each, k e t a l methyl groups), 1.72-1.84 (m, 2H), 1.93 (d of t, IH, J = 13, 3 Hz), 1.98 ( t , IH, J = 8 Hz, C-9b proton), 2.13-2.21 (m, 3H), 2.19-2.37 (AB part of ABX system, 2H, J^g = 18 Hz, C-l protons), 2.55 (m, IH), 3.44-3.57 (m, 4H, k e t a l methylene protons). Exact Mass calcd. for C 1 9H3 0O 3: 306.2195; measured: 306.2197. Lithium/Ammonia Reduction of the Enone 88 8 8 117 119 To a cold (-33°C), s t i r r e d , solution of 50.1 mg (0.165 mmol) of the t r i c y c l i c enone 88_ and 15.5 al, (0.165 mmol) of dry t e r t - b u t y l alcohol i n 30 mL of anhydrous ammonia and 5 mL of dry ether was added approximately 4 mg (=0.58 mmol) of lithium metal. The r e s u l t i n g blue so l u t i o n was s t i r r e d at -33°C for a further hour. After the reaction had been quenched and worked up as described e a r l i e r (L1/NH3 reduction of 66), t i c analysis of the r e s u l t i n g o i l - 159 -Indicated that some over-reduction had occurred. This residue was dissolved i n 3 mL of dry dichloromethane and the resultant s o l u t i o n was treated with 56 mg (0.260 mmol) of pyridinium chlorochromate and a small amount of anhydrous sodium acetate. The mixture thus obtained was s t i r r e d at room temperature for 13 h, d i l u t e d with ether and f i l t e r e d through a short column containing Florisil® and Celite®. The f i l t r a t e was evaporated and the residue was submitted to f l a s h chromatography (4:2:3 cyclohexane-hexanes-ethyl acetate, 1 cm column) to afford 33.2 mg (66%) of a white s o l i d , which glc indicated was a 99:1 mixture of 117 and 119. R e c r y s t a l l i z a t i o n of th i s s o l i d from ether-hexanes provided a sample of the pure trans-fused ketone 117, mp 91.5-92°C; i r (CHC1 3): 1730, 1110 cm"1; *H nmr (400 MHz) 6: 0.85 (s, 3H, angular methyl group), 0.94, 1.00 (s, s, 3H each, k e t a l methyl groups), 1.18-1.62 (d i f f u s e m, 9H), 1.79 (d of d, IH, J = 17, 12 Hz), 1.85-2.04 (m, 4H), 2.14-2.25 (m, 2H), 2.34 (d of d, IH, J = 17, 6 Hz). Exact Mass calcd. for C 1 9H3 0O 3: 306.2195; measured: 306.2195. Ozonolysis-Methoxide Treatment of the a-Photoadduct 80 - 160 -A cold (-78°C), sol u t i o n of 88 mg (0.255 mmol) of the a-photoadduct 80 in 15.6 uL (0.383 mmol) of dry methanol and 15 mL of dry dichloromethane was subjected to a stream of ozone i n oxygen (dried by passage through a cold trap (-78°C)) u n t i l the solution remained blue. The -78°C sol u t i o n was flushed with a stream of dry oxygen u n t i l c olourless, and 200 uL of dry dimethyl s u l f i d e was then added. After the solution had been s t i r r e d under argon for 15 min at -78°C and 2 h at room temperature, the v o l a t i l e materials were removed with the aid of a stream of argon and f i n a l l y on the pump. The r e s u l t i n g p a r t l y c r y s t a l l i n e viscous o i l was dissolved i n 20 mL of dry methanol. The methanolic solution was cooled to 0°C and treated with a small amount of methanolic sodium methoxide. Af t e r the solution had been s t i r r e d at 0°C for 5 min, 2 drops of ac e t i c acid were added and the r e s u l t i n g mixture was concentrated under reduced pressure. The residue was taken up i n ether and the r e s u l t i n g ethereal solution was washed with 10% aqueous sodium carbonate and brine, dried (MgSO^), and concentrated under reduced pressure to give 85 mg of a viscous o i l . Flash chromatography (4:2:3 cyclohexane-hexanes-ethyl acetate, 3 cm column) of t h i s o i l gave 32 mg (33%) of the cyclobutanone ester 144. An a n a l y t i c a l sample of 144, r e c r y s t a l l i z e d from ether-hexanes, e x h i b i -ted the following properties: mp 157-158°C; i r (CHC1 3): 1760, 1720 cm - 1; LH nmr (400 MHz) 6: 0.91, 0.98, 1.00 (s, s, s, 3H each, t e r t i a r y methyl groups), 1.77 (d of d of d, IH, J = .14, 7, 4 Hz), 1.89 ( d of t, IH, J = 14, 3 Hz), 2.01 (d of d, IH, J = 15, 10 Hz, C - l " proton), 2.26 (d of d of d, IH, J_ = 13, 7, 4 Hz), 2.45 (d of d, IH, J = 15, 3 Hz, C - l " proton), 2.55 (m, IH, C-2' proton), 2.57-2.78 (AB part of ABMN system, 2H, protons on C-2 and C-4), 2.91-3.08 (MN part of ABMN system, 2H, protons on C-2 and C-4), 3.41-3.62 (m, 4H, k e t a l methylene protons), 3.69 (s, 3H, - C O O C H 3 ) . I r r a d i a t i o n at 6 2.01 - 161 -removes the 15 Hz coupling from the si g n a l at 6 2.45, and s i m p l i f i e s the multiplet at 6 2.55. I r r a d i a t i o n at 6 2.71 almost removes the large (J_ = 18 Hz) couplings from the 6 2.91-3.08 MN part of the ABMN system. Exact Mass calcd. for C 2 2 H 3 1 4 O 5 : 378.2406; measured: 378.2410. Further e l u t i o n of the column gave 13 mg (13%) of a mixture of the three keto esters 65, 8j_, and 144, in the approximate r a t i o of 1:6:4 (*H nmr). Further e l u t i o n of the column yielded 38 mg (39%) of the keto ester 3 81.' R e c r y s t a l l i z a t i o n of t h i s s o l i d from hexanes gave j$l_ as colourless needles, mp 156-157°C; i r (CHCI3): 1725 (br) cm - 1; *H nmr (400 MHz) 6: 0.89, 1.03, 1.04 (s, s, s, 3H each, t e r t i a r y methyl groups), 1.65-1.75 (m, 2H), 1.84-1.96 (m, 2H), 2.03-2.21 (AB part of ABX system, 2H, = 18 Hz), 2.15 (d, IH, J - 18 Hz), 2.30 (m, IH), 2.34 (d, lH, J = 15 Hz), 2.43 (m, IH), 2.49 (d, IH, J - 18 Hz), 2.73 (d of d, IH, J = 15, 1 Hz), 3.42-3.62 (m, 4H, k e t a l methylene protons), 3.59 (s, 3H, -COOCH3). Exact Mass calcd. for 022^1+05: 378.2407; measured: 378.2407. Anal, calcd. for C22H34O5: C 69.81, H 9.05; found: C 69.84, H 8.96. This compound has been prepared previously i n our laboratory using a d i f f e r e n t procedure (31). - 162 -P r e p a r a t i o n of the Keto E s t e r 65 65 A. From the p-Photoadduct 79 The procedure used f o r the ozonolysis-methoxide treatment of the a-photoadduct 80_ was followed. The q u a n t i t i e s of m a t e r i a l s used were as f o l l o w s : This compound has been prepared p r e v i o u s l y i n t h i s l a b o r a t o r y u t i l i z -i n g procedures s i m i l a r to those described i n Experiments A (31,32) and D (32). - 163 -6-photoadduct 79 58 mg 0.168 mmol methanol 10.2 uL 0.253 mmol dichloromethane 20 mL dimethyl s u l f i d e 400 uL methanol 15 mL sodium methoxide c a t a l y t i c amount Workup, as described before, gave 60 mg (94%) of the keto ester 65. R e c r y s t a l l i z a t i o n from ether-hexanes afforded an a n a l y t i c a l sample of 65, mp 138.5-139.5°C; i r (CHC1 3): 1720 (br) cm - 1; XH nmr (400 MHz) 6: 0.92, 1.00, 1.02 (s, s, s, 3H each, t e r t i a r y methyl groups), 1.70-1.80 (m, 2H), 1.88 (d, IH, J - 19 Hz), 1.93 (d of t, IH, J = 14, 3 Hz), 2.17 (d of d of d, IH, J = 13, 6, 3 Hz), 2.33-2.44 (m, 3H), 2.46-2.61 (m, 3H), 3.40-3.57 (m, 4H, ke t a l methylene protons), 3.63 (s, 3H, - C O O C H 3 ) . Exact Mass calcd. for C 2 2 H 3 4 ° 5 : 378.2406; measured 378.2410. Anal, calcd. f o r 0 * 2 2 ^ 0 5 : C 69.81, H 9.05; found: C 69.65, H 8.94. B. By I s o m e r i z a t i o n of the Keto E s t e r j$l 81 65 - 164 -To a s t i r r e d s o l u t i o n of 54 mg (0.143 mmol) of the keto ester 81_ In 20 mL of dry methanol, was added, at room temperature, a c a t a l y t i c amount of sodium methoxide i n 1 mL of dry methanol. Af t e r the so l u t i o n had been s t i r r e d for 2.5 h at room temperature, i t was concentrated under reduced pressure. The residue was p a r t i t i o n e d between ether and water and the organic phase was washed with brine, dried (MgSO^) and concentrated to y i e l d 49 mg (91%) of the keto ester 65_, as a white s o l i d , mp 138-139°C (methanol), i d e n t i c a l ( t i c , 1H nmr) with a sample prepared as described previously. C. By I s o m e r i z a t i o n of the Cyclobutanone E s t e r 144 O 144 65 A procedure i d e n t i c a l with that used i n the isomerization of the keto ester 81_ was followed here. Thus, 36 mg (95 umol) of the cyclobutanone ester 144 i n 20 mL of dry methanol, gave, a f t e r workup, 29 mg (81%) of the keto ester 65_, as a white s o l i d , mp 137-138°C (hexanes), which was i d e n t i c a l ( t i c , % nmr) with a sample prepared as described e a r l i e r . - 165 -D. From a Mixt u r e of the Photoadducts 79, 80, 108 and 109 The ozonolysis procedure outlined e a r l i e r was employed i n t h i s experi-ment. The s t a r t i n g material i n t h i s case was a mixture of the four possible photoadducts 79_, 80_, 108 and 109, which had been prepared as described previously. The quantities of materials used were as follows: photoadduct mixture 3.11 g 9.02 mmol methanol 550 uL 13.53 mmol dichloromethane 100 mL dimethyl s u l f i d e 3 mL The semi-solid residue obtained a f t e r workup of the ozonolysis reaction was dissolved i n 80 mL of dry methanol. The resultant solution was treated with a small amount of a fr e s h l y prepared so l u t i o n of sodium methoxide i n dry methanol, and then s t i r r e d at room temperature for 15 h. The methanol was removed under reduced pressure and the residue was redissolved i n ether. The re s u l t i n g ethereal solution was washed with brine, dried (MgS0i+) and concent-rated to give a colourless s o l i d . Flash chromatography (4:2:2 cyclohexane-hexanes-ethyl acetate, 5 cm column) of th i s s o l i d gave, as the f i r s t eluted component, 88 mg of a mixture containing mainly the photoadducts 108 and 109 (see e a r l i e r for the separation and characterization of these two photo-adducts) . Further e l u t i o n of the column gave a white s o l i d which was r e c r y s t a l -l i z e d from hexanes to give 2.39 g (70%) of the keto ester 65, as colourless needles, mp 135-138°C. This s o l i d was i d e n t i c a l ( t i c , g l c , 1H nmr) with a sample of 65_, prepared as described e a r l i e r . The aqueous (brine) washings from the workup were a c i d i f i e d with 1 N hydrochloric acid, and extracted thoroughly with ether. The combined ether - 166 -extracts were washed with brine u n t i l the washings were neutral, dried (MgSO^) and concentrated, to afford 322 mg of a p a r t l y s o l i d viscous o i l . This material was dissolved i n 10 mL of dry ether and treated at 0°C with an excess of ethereal diazomethane. The yellow so l u t i o n was s t i r r e d at 0°C for 20 min, and the excess diazomethane and ether were then allowed to evaporate at room temperature, with the aid of a stream of argon. The viscous yellow o i l which remained was dissolved i n 20 mL of dry methanol and treated, as described above, with sodium methoxide. The resultant solution was worked up and chromatographed, as described e a r l i e r , to give a further 108 mg (3%) of the keto ester 65. P r e p a r a t i o n of the D i n i t r i l e s 77 153 152 77 The compounds 146, 64, and 7_7_ have been prepared previously i n our laboratory (32) as pure epimers (at C-2) using procedures s i m i l a r to those employed here. - 167 -To a cold (0°C), s t i r r e d , suspension of 361 mg (9.50 mmol) of lithium aluminium hydride i n 50 mL of dry ether was added dropwise a solution of 2.40 g (6.33 mmol) of the keto ester j>5_ i n 100 mL of dry ether. The r e s u l t i n g mixture was allowed to warm to room temperature and was s t i r r e d for a further 4 h at th i s temperature. The excess l i t h i u m aluminium hydride was then destroyed by the ca r e f u l addition of s o l i d Na 2S0 1 +» 10H20 to the cold (0°C) react i o n mixture. The r e s u l t i n g mixture was f i l t e r e d through a plug of Florisil® and the co l l e c t e d material was thoroughly washed with ethyl acetate. Concentration of the eluate gave 2.17 g of a mixture of the epimeric alcohols 146, as a white s o l i d . This s o l i d exhibited: i r (CHC1 3): 3590, 3370, 1110, 1090 cm - 1; lH nmr (80 MHz) 6: 0.92, 0.96, 0.99 (s, s, s, 9H i n t o t a l , t e r t i a r y methyl groups), 2.86 (br s, 2H, -OH), 3.30-3.63 (m, 4H, ke t a l methyl-ene protons), 3.75 (br t, 2H, J_ = 7 Hz, C-2' protons), 4.50 (br m, IH, C-2 protons). The t i c behaviour, and spe c t r a l data exhibited by th i s s o l i d were consistent with t h i s material being a mixture of the two d i o l s 146, both epimers of which have been prepared previously (32). To a cold (0°C), s t i r r e d , solution of the epimeric d i o l s 146, prepared as described above, and 2.55 mL (18.3 mmol) of dry triethylamine i n 30 mL of dry dichloromethane, was added dropwise (=5 min) 1.03 mL (13.3 mmol) of methanesulfonyl ch l o r i d e . The re s u l t i n g solution was s t i r r e d at th i s tempera-ture for 1 h, a f t e r which time t i c indicated that no s t a r t i n g material remained. The reaction mixture was d i l u t e d with dichloromethane, washed successively with i c e - c o l d water and brine, dried (MgS0i+), and concentrated. The yellowish residue was dissolved i n dichloromethane and the r e s u l t i n g s o l u t i o n was f i l t e r e d through a plug of s i l i c a g e l , using ethyl acetate as - 168 -eluant. Removal of the solvent from the r e s u l t i n g solution afforded 3.15 g of the epimeric dimesylates 64_ as a colourless foam, i r (CHCI3): 1360, 1340, 1180 cm"1; XH nmr (80 MHz) 6: 0.90, 0.93, 0.94, 0.95, 1.00 (s, s, s, s, s, 9H i n t o t a l , t e r t i a r y methyl groups), 2.98, 3.00, 3.02 (s, s, s, 6H i n t o t a l , CH 3-S0 2-), 3.30-3.68 (m, 4H, k e t a l methylene protons), 4.30, 4.38 ( t , t, 2H i n t o t a l , J_ = 8 Hz, J = 8 Hz, C-2' protons), 5.27 (br m, IH, C-2 protons). This s p e c t r a l data, plus the t i c behavior of this foam, was consistent with a mixture of the isomeric dimesylates 64_, both epimers of which had been prepared previously (32). A mixture of the epimeric dimesylates 64, prepared as described above, 25 mL of dry hexamethylphosphoramide and enough sodium cyanide to saturate the solvent was s t i r r e d at 62°C for 16 h. The cooled reaction mixture was p a r t i -tioned between ether and water, and the aqueous phase was extracted twice more with ether. The combined organic extracts were washed twice with aqueous copper s u l f a t e , once with brine, and then were dried (MgSO^) and concentrated to y i e l d 2.48 g of a yellowish semi-solid. Flash chromatography of t h i s m aterial, e l u t i n g i n i t i a l l y with a mixture of 25% ethyl acetate in hexanes, gave 142 mg (6%) of a mixture (= 1:1, glc) of the regioisomeric o l e f i n i c n i t r i l e s 152 and 153, as a colourless viscous o i l , which exhibited: i r (CHCI3): 2230, 1100 cm"1; hi nmr (80 MHz) 6: 0.92, 0.95, 1.00 (s, s, s, 9H i n t o t a l , t e r t i a r y methyl groups), 3.34-3.70 (m, 4H, keta l methylene protons), 5.43-5.93 (m, 2H, alkene protons). Exact Mass calcd. for C 2 2H 33N0 2: 343.2511; measured: 343.2513. Further e l u t i o n of the column with 35% ethyl acetate i n hexanes afforded 1.39 g (63%) of a mixture (a: B-CN, = 2:1, glc) of the epimeric - 169 -d i n i t r i l e s 77_, as a white s o l i d . This s o l i d exhibited the following proper-t i e s : i r (KBr): 2220, 2210 cm - 1; *H nmr (80 MHz) 6: 0.91, 0.96, 0.98, 1.00 (s, s, s, s, 9H i n t o t a l , t e r t i a r y methyl groups), 2.98 (br m, IH, C-2 protons), 3.35-3.68 (m, 4H, k e t a l methylene protons). Exact Mass calcd. for C 23H 3i +N202: 370.2620; measured: 370.2620. Preparation of the Tetracyclic Dione 63 6 77 78 63 To a s t i r r e d solution of 602 mg (1.62 mmol) of a mixture of the epimeric d i n i t r i l e s 7_7_ i n 10 mL of dry t e r t - b u t y l alcohol, was added a small amount of potassium tert-butoxide. The reaction mixture was heated under reflux for 5 h, a f t e r which time the solvent was removed ( o i l pump). To the r e s u l t i n g s o l i d was added a deoxygenated mixture (by three times evacuating (a s p i r a t o r , 5 min) a f l a s k containing this mixture, and then r e f i l l i n g i t with argon) of 10 mL of a c e t i c acid, 4 mL of 85% phosphoric acid and 1 mL of water. The r e s u l t i n g solution was heated at r e f l u x , with s t i r r i n g , for 40 h, This compound has been prepared previously i n our laboratory u t i l i z i n g s i m i l a r procedures (32). - 170 -under an atmosphere of argon. The cooled reaction mixture was p a r t i t i o n e d between water and dichloromethane, and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine, twice with aqueous sodium bicarbonate, and then again with brine. The dichloromethane so l u t i o n was dried (MgSOi^) and the v o l a t i l e materials were then removed under reduced pressure to afford 444 mg of a pale brown s o l i d . F l a s h chromatography (ether, 5 cm column) afforded 351 mg (83%) of the t e t r a -c y c l i c dione 63_ as a white s o l i d . R e c r y s t a l l i z a t i o n of a small amount of t h i s material from ether-hexanes provided an a n a l y t i c a l sample of 63_ as colourless cubes, mp 132°C; i r (KBr): 1700 (br) cm - 1; XH nmr (400 MHz) 6: 1.15 (s, 3H, angular methyl group), 1.73 (br m, IH), 1.85 (br m, IH), 1.90-2.05 (m, 4H), 2.09 (br m, IH), 2.14-2.44 (m, 7H), 2.52 (d of d of t, IH, J = 18, 9, 1 Hz), 2.70 (br t, IH, J_ = 7 Hz, C-14 proton). Exact Mass calcd. for C 1 7H 2 l +0 2: 260. 1776; measured: 260. 1774. Anal, calcd. for C 1 7 H 2 i t 0 2 : C 78.42, H 9.29; found: C 78.29, H 9.28. Preparation of the Westers 158 - 171 -A s t i r r e d solution of 52.0 mg (0.40 mmol) of the epimeric d i n i t r i l e s 77, i n 1.5 mL of 40% aqueous potassium hydroxide and 1.5 mL of ethylene g l y c o l was heated under reflux for 20 h. The cooled reaction mixture was dilu t e d with water and extracted twice with ether. The aqueous phase was a c i d i f i e d to pH =2 with a c e t i c acid and rapidly extracted three times with ether. The combined organic extracts were washed three times with brine, dried (MgSO^) and concentrated to give 56 mg of the diacids 157 as a colourless o i l , i r (CHC1 3): 3600-2500 (br), 1700 (br) cm - 1. This o i l was dissolved i n 10 mL of ether and the resultant solution was cooled to 0°C, and treated with an excess of ethereal diazomethane. After the s o l u t i o n had been s t i r r e d f o r 20 min at 0°C, i t was warmed to room temperature and the excess diazomethane was allowed to evaporate with the aid of a stream of argon. Concentration of t h i s solution afforded an o i l , which was submitted to f l a s h chromatography (30% ethyl acetate i n hexanes, 2.5 cm column) to a f f o r d 49.8 mg (81%) of the epimeric diesters 158 as a colourless o i l , i r (CHCI3): 1720 (br) cm"1; XH nmr (80 MHz) 6: 0.91, 0.95, 0.98, 1.02 (s, s, s, s, 9H i n t o t a l , t e r t i a r y methyl groups), 2.93 (br m, IH, C-2 protons), 3.49 (br s, 4H, k e t a l methylene protons), 3.68 (s, 6H, -COOCH3). Exact Mass calcd. f or C 2 5H 4 0O 6: 436.2825; measured: 436.2821. P r e p a r a t i o n of the B i s S i l y l Enol Ethers 166 and 167 0< T B D M S O H TBDMSO H + TBDMSO 4 H T B D M S O H 63 166 167 - 172 -To a cold (-78°C), s t i r r e d , solution of lithium diisopropylamide (161 nmol) in 2 mL of dry tetrahydrofuran, under an atmosphere of argon, was added, dropwise, a solution of 10.5 mg (40 umol) of the t e t r a c y c l i c dione 63_ i n 2 mL of dry tetrahydrofuran. The r e s u l t i n g solution was s t i r r e d for 15 min at -78°C and 1 hour at 0°C. The reaction mixture was cooled to -78°C and a sol u t i o n of approximately 25 mg (166 uraol) of fres h l y sublimed t e r t - b u t y l -d i m e t h y l s i l y l chloride in 1.5 mL of dry tetrahydrofuran was added. This was followed immediately by the addition of 28 pL (161 umol) of dry hexaraethyl-phosphoramide. After the r e s u l t i n g solution had been s t i r r e d for 15 min at -78°C and 2 h at room temperature, a few drops of aqueous sodium bicarbonate were added. The reaction mixture was then d i l u t e d with ether and washed successively with aqueous sodium bicarbonate, twice with aqueous copper s u l f a t e and f i n a l l y with brine. The r e s u l t i n g ethereal solution was dried (MgSOit) and concentrated, to give 17.3 mg of a colourless o i l . T i c indicated that no s t a r t i n g dione S3_ remained. Chromatography on =2 g of triethylamine-deactivated a c t i v i t y III neutral alumina (Woelm), e l u t i n g with n-hexane, gave 14.9 mg (76%) of an approximately 1:1 (*H nmr) mixture of 166 and 167, as a colourless s o l i d . This s o l i d exhibited: *H nmr (400 MHz) 6: 0.11, 0.12, 0.13 (s, s, s, 12H i n t o t a l , Si-CH 3), 0.84, 0.86 (s, s, =1.5H each, angular methyl groups), 0.91 (s, 18H, S i - C ( C H 3 ) 3 ) , 2.30 (br d, = 0.5H, J = 13 Hz, C-l proton of 166), 2.37 (overlapping d of d, IH i n t o t a l , J_ = 18, 4 Hz in each case, C - l l protons of both 166 and 167), 4.42 (br s, IH, wx/2 = 1 0 H z » c ~ 1 2 protons of both _166_ and 167), 4.50 (br s, = 0.5H, C-4 proton of 167), 4.76 (br d, =0.5H, J_ = 6 Hz, C-2 proton of 166). I r r a d i a t i o n at 6 4.42 collapses the s i g n a l at 6 2.37 to an overlapping pair of doublets, J_ = 18 Hz. Mass  Spectrum: m/e 488 (M +), 473, 431, 187, 73 (100%). - 173 -P r e p a r a t i o n of the B i s Enones 75 and 175 4 175 To a cold (-95°C), s t i r r e d , solution of 251 mg (0.964 mmol) of the t e t r a c y c l i c dione 63_ and 806 oL (5.78 mmol) of dry triethylamine i n 20 mL of dry dichloromethane was added, dropwise, 686 uL (4.82 mmol) of fr e s h l y prepared t r i m e t h y l s i l y l iodide (109). The r e s u l t i n g orange sol u t i o n was s t i r r e d for 1 h at this temperature, was di l u t e d with petroleum ether, and was then allowed to warm to room temperature. This reaction mixture was washed with cold aqueous sodium bicarbonate, dried (^ 280 )^ and concentrated under reduced pressure, to afford a yellow o i l . Glc analysis indicated that the two - 174 -isomeric s i l y l enol ethers 170 and 171 were present i n the r a t i o of 79:21. An ali q u o t of th i s o i l exhibited: *H nmr (80 MHz) 6: 0.18 (s, 18H, - S i ( C H 3 ) 3 ) , 0.85 (br s, 3H, angular methyl groups of both isomers), 2.36 (d of d, IH, £ = 17, 4 Hz, C - l l proton of both isomers), 4.45, 4.78 (br s, br s, 2H i n t o t a l , alkene protons). Mass Spectrum: m/e 404 (M +), 155, 73 (100%). The mixture of s i l y l enol ethers 170 and 171 was dissolved i n 20 mL of dry a c e t o n i t r i l e and the resultant solution was s t i r r e d at room temperature for 14 h with 472 mg (2.12 mmol) of palladium(II) acetate. The r e s u l t i n g reaction mixture was f i l t e r e d through a short column of s i l i c a gel to remove the m e t a l l i c palladium and much of the coloured material. After thoroughly washing the column with ether, the combined eluates were concentrated to afford a brown viscous o i l . Flash chromatography (ether, 3 cm column) of t h i s o i l gave, as the f i r s t eluted component, 182 mg of a white s o l i d . R e c r y s t a l -l i z a t i o n of th i s s o l i d from ethyl acetate-hexanes (or ether) (to remove = 6% of a mono enone) gave 165 mg (67%) of the A 1 » 2 » ^ » 1 2 - b i s enone 75. A sample of 7_5, which had been r e c r y s t a l l i z e d from ether, exhibited: mp 155-157°C; i r (KBr): 1680, 1660 cm - 1; *H nmr (400 MHz) 6: 1.34 (s, 3H, angular methyl group), 1.70 (d, IH, J = 12 Hz, C-166 proton), 1.75 (d of d of d, IH, J = 14, 8, 2 Hz, C-15a proton), 1.84 (d of d, IH, J = 14, 8 Hz, C-158 proton), 1.99 (m, IH), 2.15 (m, IH), 2.29 (d of d of d, IH, J = 12, 6, 2.5 Hz, C-16a proton), 2.30-2.49 (m, 3H), 2.94 (br t , IH, J = 7 Hz, C-14 proton), 5.89 (d, IH, J_ = 10.5 Hz, C-2 proton), 6.00 (d of d, IH, J_ = 10, 2 Hz, C-12 proton), 6.72 (d, IH, J_ = 10.5 Hz, C-l proton), 7.33 (d of d, IH, J = 10, 2.5 Hz, C - l l proton). On i r r a d i a t i o n at 6 2.94 the si g n a l at 6 6.00 collapses to a doublet, J_ = 10 Hz, the signal at 6 2.29 collapses to a d of d, J_ = 12, 2.5 Hz - 175 -and the si g n a l at 6 1.75 s i m p l i f i e s to a d of d, J_ = 14, 2 Hz. Exact Mass calcd. for C17H20O2: 256.1464; measured: 256.1463. Anal, calcd. for C17H20O2: C 79.65, H 7.86; found: C 79 .49 , H 7.88. Further e l u t i o n of the column afforded 47 mg (19%) of the ^4,5;11,12_^^ s e n o n e 175 a s a white s o l i d . R e c r y s t a l l i z a t i o n of a small amount of t h i s material from ether afforded an a n a l y t i c a l sample of 175, mp 147-149°C; i r (KBr): 1680, 1665, 1650, 1605 cm"1; XH nmr (400 MHz) 6: 1.50 (m, IH), 1.55 (s, 3H, angular methyl group), 1.71-1.97 ( d i f f u s e m, 4H) , 2.01 (d, IH, J - 12 Hz, C-168 proton), 2.04-2.15 (m, 2H), 2.27-2.61 ( d i f f u s e m, 4H) , 2.91 (br t, IH, J = 7 Hz, C-14 proton), 5.86 (d, IH, J = 1.5 Hz, C-4 proton), 5 .93 (d of d, IH, J = 10, 2 Hz, C-12 proton), 7.26 (d of d, IH, J = 10, 3 Hz, C - l l proton). Exact Mass calcd. for C 1 7H 2 o 0 2 : 256.1463; measured: 256.1459. P r e p a r a t i o n of 17-^lor-stemoda-l, ll-diene-3,13-dione 76^ To a cold (0°C), s t i r r e d , solution of lithium b i s ( t r i m e t h y l s i l y l ) a m i d e (3.77 mmol) i n 30 mL of dry dimethoxyethane, under an atmosphere of argon, was added, dropwise, a solution of 186 mg (0.73 mmol) of the bis enone 75 i n 5 mL - 176 -of dry dimethoxyethane. A f t e r the r e s u l t a n t s o l u t i o n had been s t i r r e d f o r 1 h at 0°C, 15 mL of dry methyl i o d i d e was r a p i d l y added. The r e a c t i o n mixture was s t i r r e d f o r 30 min at 0°C and 1 h at room temperature and then was quenched w i t h a few drops of aqueous ammonium c h l o r i d e . The v o l a t i l e m a t e r i a l s were removed under reduced pressure and the r e s u l t i n g residue was partioned between ether and aqueous ammonium c h l o r i d e . The organic phase was washed w i t h aqueous sodium t h i o s u l f a t e and then b r i n e , d r i e d and concentrated to a f f o r d 206 mg of a white s o l i d . F l a s h chromatography (35% hexanes i n ether) of a small amount of t h i s m a t e r i a l followed by r e c r y s t a l l i z a t i o n of the m a t e r i a l by contained i n appropriate f r a c t i o n s from e t h y l acetate-hexanes, provided a pure sample of the major component 177, as c o l o u r l e s s p l a t e s , mp 149-150.5°C; i r (CHC1 3): 1675, 1660 cm - 1; *H nmr (400 MHz) 6: 1.17 (d, 3H, J = 7 Hz, C-4 methyl group), 1.25-1.48 (m, 2H), 1.37 ( s , 3H, angular methyl group), 1.68 (d, IH, J = 12 Hz, C-166 proton), 1.71 (m IH), 1.73 (d of d of d, IH, J = 14, 8, 2 Hz, C-15a p r o t o n ) , 1.84 (d of d, IH, J = 14, 7 Hz, C-15B proton), 1.91-2.07 (m, 2H), 2.15 (m, IH), 2.27 (d of d of d, IH, J = 12, 6, 3 Hz, C-16a pro t o n ) , 2.38 (d of q, IH, J = 13, 7 Hz, C-4 proton), 2.91 (br t , IH, J = 7 Hz, C-14 proton) 5.87 (d, IH, J = 10.5 Hz, C-2 proton), 5.98 (d of d, IH, J = 10.5, 2.5 Hz, C-12 pro t o n ) , 6.65 (d, IH, J = 10.5 Hz, C-l pr o t o n ) , 7.32 (d of d, IH, J = 10.5, 3 Hz, C - l l proton). I r r a d i a t i o n at 6 1.17 c o l l a p s e s the s i g n a l at 6 2.38 to a doublet, J_ - 13 Hz. Exact Mass c a l c d . f o r C18 H22°2 : 270.1620; measured: 270.1621. The white s o l i d , prepared as described above, was a l k y l a t e d again under i d e n t i c a l c o n d i t i o n s , except t h a t , a f t e r a d d i t i o n of the methyl i o d i d e , the r e a c t i o n mixture was s t i r r e d f o r 6 h at room temperature. A f t e r workup as - 177 -described above, the r e s u l t i n g white s o l i d was r e c r y s t a l l i z e d from ether-hexanes to give 126 mg of 76. Flas h chromatography (35% hexanes i n ether) of the material from the mother liquo r afforded a further 34 mg of _76_, for a t o t a l y i e l d of 160 mg (77%). The c r y s t a l l i n e 76_ exhibited: mp 154-156°C; i r (CHC13): 1660 (br) cm - 1; XH nmr (400 MHz) 6: 1.16, 1.20 (s, s, 3H each, C-4 methyl groups), 1.37 (m, IH), 1.44 (s, 3H, angular methyl group), 1.68 (d, IH, J - 12 Hz, C-16B proton), 1.74 (d of d of d, IH, J = 14, 8, 2 Hz, C-15o proton), 1.83 (d of d, IH, J = 14, 7.5 Hz, C-15B proton), 2.04-2.21 (m, 3H), 2.30 (d of d of d, IH, J = 12, 6, 3 Hz, C-16cc proton), 2.92 (br t, IH, _J = 7 Hz, C-14 proton), 5.89 (d, IH, J = 10.5 Hz, C-2 proton), 5.99 (d of d, IH, J = 10.5, 2.5 Hz, C-12 proton), 6.66 (d, IH, J = 10.5 Hz, C-l proton), 7.35 (d of d, IH, J_ = 10.5, 3 Hz, C - l l proton). I r r a d i a t i o n at 6 7.35 collapses the si g n a l at 6 5.99 to a doublet, J_ = 2.5 Hz, and the si g n a l at 6 2.30 s i m p l i f i e s to a d of d, J_ = 12, 6 Hz. Exact Mass calcd. for C 1 9H 2 i<0 2: 284.1776; measured: 284.1778. Anal, calcd. for C 1 9H 2 1 |0 2: C 80.24, H 8.51; found: C 80.08, H 8.40. P r e p a r a t i o n of 17-Nor-stemodane—3,13-dione 62_ - 178 -A mixture of 77.5 mg (0.273 mmol) of the d i a l k y l a t e d b i s enone 76_, 3 mL of dry dioxane and a small amount of 5% palladium-on-charcoal c a t a l y s t was s t i r r e d v i g o r o u s l y , at room temperature and atmospheric pressure, under an atmosphere of hydrogen. A f t e r 2 h t i c i n d i c a t e d that no s t a r t i n g m a t e r i a l remained. The mixture was d i l u t e d w i t h e t h y l acetate and f i l t e r e d through a short plug of Celite®. The f i l t r a t e was concentrated, under reduced pressure, to a f f o r d 77.6 mg (99%) of J52_ as a c o l o u r l e s s s o l i d . R e c r y s t a l l i z a t i o n of a sm a l l amount of t h i s m a t e r i a l from e t h y l acetate-hexanes provided an a n a l y t i -c a l sample of 62, mp 151-152°C; i r (CHC1 3): 1700 cm"1; *H nmr (400 MHz) 6: 1.10, 1.12, 1.18 ( s , s, s, 3H each, t e r t i a r y methyl groups), 1.26 (m, IH), 1.46-1.79 ( d i f f u s e m, 7H), 1.89-1.99 (m, 4H), 2.04 (m, IH), 2.18-2.30 (m, 2H), 2.34 (d of d of d, IH, J = 16, 5, 3 Hz), 2.50 (br d of d of d, IH, J_ = 17, 9, 9 Hz), 2.58 (d of d of d, IH, J = 16, 13, 6 Hz), 2.69 (br t , IH, J = 7 Hz, C-14 proton). Exact Mass c a l c d . f o r C 1 9 H 2 8 0 2 : 288.2089; measured: 288.2086. An a l , c a l c d . f o r C 1 9H280 2: C 79.12, H 9.78; found: C 79.03, H 9.80. P r e p a r a t i o n o f S t e m o d a - 1 , 1 1 , 1 3 ( 1 7 ) - t r i e n - 3 - o n e 1 9 0 i H H O' H H 7 6 190 - 179 -To a cold (-78°C), s t i r r e d , solution of 12.9 mg (45 ^imol) of the alkylated bis enone 76_ in 1 mL of dry tetrahydrofuran was added a solution of methylenetriphenylphosphorane (55 umol) i n 1.4 mL of dry tetrahydrofuran. Af t e r the solution had been s t i r r e d for 30 min at -78°C and 2 h at 0°C, glc analysis of an aliquot showed that a substantial amount of s t a r t i n g material remained. The reaction mixture was recooled to -78°C and a further 40 |imol of methylenetriphenylphosphorane i n 1 mL of dry tetrahydrofuran was added. The r e s u l t i n g mixture was s t i r r e d for 30 min at -78°C and 1 h at 0°C. Glc analy-s i s of an aliquot showed that, although some s t a r t i n g material remained, other products appeared to be forming. The reaction mixture was then d i l u t e d with ether and f i l t e r e d through a plug of Florisil®. The colourless o i l remaining a f t e r removal of the solvent from the f i l t r a t e was chromatographed on 4 g of s i l i c a g e l . E l u t i o n of the column with dichloromethane gave, as the f i r s t eluted component, 8.1 mg (63%, 87% based on unrecovered 76) of the diene enone 190 as a colourless s o l i d . R e c r y s t a l l i z a t i o n from hexanes provided an analy-t i c a l sample of 190, mp 98-99.5°C; i r (GHC1 3): 1660 ( b r ) , 1580 cm"1; :H nmr (400 MHz) 6: 1.14, 1.18 (s, s, 3H each, C-4 methyl groups), 1.20-1.33 (m, 2H), 1.30 (d, IH, J_ = 12 Hz, C-166 proton), 1.34 (s, 3H, angular methyl group), 1.47-1.72 (m, 4H), 1.87 (d of d of t, IH, J = 14, 7, 3.5 Hz), 2.06-2.24 (m, 3H), 2.88 (br t, IH, J = 7 Hz, C-14 proton), 4.54 (d, IH, J = 1.5 Hz, exo-c y c l i c o l e f i n i c proton), 4.65 (s, IH, exocyclic o l e f i n i c proton), 5.84 (d, IH, J = 10 /Hz, C-2 proton), 6.08 (d of d, IH, J = 10, 1.5 Hz, C - l l or C-12 proton), 6.20 (d, IH, J = 10 Hz, C - l l or C-12 proton), 6.76 (d, IH, J = 10 Hz, C-l proton). Exact Mass calcd. for C 2rjH260 : 282. 1983; measured 282.1982. Further e l u t i o n of the column with ether afforded 3.5 mg (27%) of - 180 -recovered s t a r t i n g m a t e r i a l 76, as a white s o l i d . Preparation of 13<z- and 13B-Hydroxystemodan-3-one, 61 and 180 p HO HO H H O + O H H 6 2 61 180 To a s t i r r e d s o l u t i o n of 20.8 mg (72 u-raol) of the a l k y l a t e d dione 62_ i n 2 mL of dry ether was added, at room temperature, 1 mL (= 4 mmol) of neat m e t h y l t r i i s o p r o p o x y t i t a n i u m (121), and the r e s u l t i n g yellow s o l u t i o n was s t i r r e d at t h i s temperature f o r 10 h. The s o l u t i o n was c a r e f u l l y poured onto ether - I N h y d r o c h l o r i c a c i d (copious white p r e c i p i t a t e ) and the aqueous phase was ex t r a c t e d twice more w i t h ether. The combined organic e x t r a c t s were washed w i t h aqueous sodium bicarbonate followed by b r i n e , d r i e d (MgSO^) and concentrated.. F l a s h chromatography (30% tetrahydrofuran i n hexanes, 1 cm column) gave 18.0 mg (82%) of an 86:13 mixture ( g l c ) of 6l_ and 180, as a c o l o u r l e s s viscous o i l . This o i l e x h i b i t e d : i r (CHC1 3): 3580, 3400, 1690 cm"1; *H nmr (80 MHz) 6: 1.09, 1.12, 1.13, 1.24 ( s , s, s, s, t e r t i a r y methyl groups). Exact Mass c a l c d . f o r 0 2 0 ^ 3 2 0 2 * 304.2403; measured: 304.2405. In another r e a c t i o n , c a r r i e d out as described above, concentration of the l a t e r f r a c t i o n s obtained during chromatography ( c o n d i t i o n s as above) of - 181 -the crude r e a c t i o n product, afforded a viscous o i l co n t a i n i n g mainly (94%) compound 61. A pure sample of 61_, obtained by c r y s t a l l i z a t i o n of the o i l from hexanes, e x h i b i t e d : mp 93°C ( l i t . (23) mp 9C~91°C); i r (CHC1 3): 3570, 3320, 1690, 905 cm - 1; TH nmr (400 MHz) 6: 1.09, 1.10, 1.12, 1.14 ( s , s, s, s, 3H each, t e r t i a r y methyl groups), 1.91-2.03 (m, 3H), 2.29 (d of d of d, IH, J = 16, 4.5, 3.5 Hz, C-2a proton), 2.57 (d of d of d, IH, J = 16, 14, 6 Hz, C-2B proton). Exact Mass c a l c d . f o r C 2oH3 20 2: 304.2402; measured: 304.2404. Preparation of (±)-Maritimol 5 61 5 To a co l d (0°C), s t i r r e d , s o l u t i o n of 11.7 mg (38 umol) of the keto a l c o h o l 6l_ i n 2 mL of methanol was added an excess of s o l i d sodium boro-hydride. The r e s u l t i n g mixture was s t i r r e d f o r 2 h at 0°C and the solvent was then removed under reduced pressure. The residue was p a r t i t i o n e d between e t h y l acetate and b r i n e . The organic phase was d r i e d (MgSOi,) and concentrated to y i e l d a viscous o i l . C r y s t a l l i z a t i o n of t h i s o i l from e t h y l acetate gave 5.6 mg of (±)-maritimol J>. Chromatography of the mother l i q u o r on 2.5 g of s i l i c a g e l e l u t i n g w i t h a 1:1 mixture of e t h y l acetate and hexanes a f f o r d e d , - 182 -after crystallization of the appropriate fractions from ethyl acetate (to remove the (±)-3-epimaritimol 201), a further 3.0 mg of (±)-maritimol _5, for a total yield of 8.6 mg (73%). The crystalline (±)-maritimol J5 exhibited: mp 220-221°C (ethyl acetate) and 221-222°C (ether-hexanes) ( l i t . mp 212.5-214°C (24); 211.5-212.5°C (ether-hexane) (23)); i r (KBr): 3340 (br) cm"1; XH nmr (400 MHz, CDC13 - (CD3)2S0) 6: 0.84, 0.95, 1.02, 1.11 (s, s, s, s, 3H each, tertiary methyl groups), 1.75 (s, IH, C-13 -OH), 1.83 (d, IH, J = 12 Hz), I. 88-1.98 (m, 2H), 2.04 (d, IH, J = 6 Hz, C-3 -OH), 3.18 (d of'd of d, IH, J = 13, 6, 5 Hz, C-3 proton). On addition of D20 the signals at 6 1.75 and 2.04 disappeared and the signal at 6 3.18 simplified. Exact Mass calcd. for C 2 0 H 3 4 ° 2 : 306.2559; measured: 306.2560. Anal, calcd. for C2oH3402: C 78.38, H II. 18; found: C 78.26, H 11.28. This material was identical with an authentic sample of (+)-maritimol (11) by glc (coinjection, retention time 5.86 min at 225°C), *H nmr (400 MHz), mass spectrometry and t i c in four solvent systems. P r e p a r a t i o n o f S t e m o d - 2 - e n - 1 3 a - o l 55 a n d S t e m o d - 2 - e n - 1 3 B - o l 1 8 2 61 ,180 5 5 182 A solution of 61.1 mg (0.201 mmol) of an 86:14 mixture of 61_ and 180, and 48.6 mg (0.261 mmol) of j>-toluenesulfonylhydrazide in approximately 1 mL - 183 -of absolute ethanol was heated under re f l u x , with s t i r r i n g , for 3 h. A white p r e c i p i t a t e formed. The r e s u l t i n g mixture was concentrated and dried i n vacuo f o r 3 h. Sodium hydride (5.34 mmol, 225 mg of a 57% dispersion i n mineral o i l , freed of o i l by washing three times with ether) was added, at room tempera-ture, to a s t i r r e d suspension of the crude tosylhydrazones i n 15 mL of dry toluene. The r e s u l t i n g mixture was heated under re f l u x for 3 h and then cooled to room temperature. After the excess base had been destroyed by the cautious addition of water, the reaction mixture was part i t i o n e d between ether and aqueous ammonium chloride. The aqueous phase was extracted once more with ether and the combined ethereal extracts were washed with brine, dried (MgSOi+) and concentrated. The r e s u l t i n g o i l was chromatographed on 15 g of s i l i c a g e l , e l u t i n g with 15% ethyl acetate i n hexanes, to af f o r d 33.5 mg (58%) of 5_5_ as a white s o l i d . R e c r y s t a l l i z a t i o n of a portion of th i s s o l i d from hexanes gave an a n a l y t i c a l sample of 55, mp 129.5-131°C ( l i t . mp 119-122°C (22); 128-129°C (23)); i r (CHC1 3): 3600 cm - 1; XH nmr (400 MHz) 6: 0.92, 0.96, 0.97, 1.12 (s, s, s, s, 3H each, t e r t i a r y methyl groups), 2.08 (br d, IH, = 17 Hz), 5.32 (d of d, IH, J = 10, 2.5 Hz, C-3 proton), 5.50 (d of d of d, IH, J = 10, 6.5, 2.5 Hz, C-2 proton). Exact Mass calcd. for C20H32O: 288.2453; measured 288.2455. Anal, calcd. for C 2 0H 3 2O: C 83.27, H 11.18; found: C 83.27, H 11.10. Further e l u t i o n of the column afforded 8.3 mg (14%) of stemod-2-en-13B-ol 182 as a white s o l i d . R e c r y s t a l l i z a t i o n from heptane provided a pure sample of 182, mp 153-154.5°C ( l i t . (22) mp 147-149°C); i r (KBr): 3300 cm - 1; *H nmr (80 MHz) 6: 0.90 (s, 3H, C-4 or C-10 methyl group), 0.95 (s, 6H, C-4 - 184 -and/or C-10 methyl groups), 1.23 (s, 3H, C-17 methyl group), 5.18-5.62 (m, 2H, alkene protons). Exact Mass calcd. for C20H32O: 288.2453; measured: 288.2456. P r e p a r a t i o n of (±)-Stemodin 3 55 A solution of 33.3 mg (116 umol) of the alkene 55_ and an excess ( = 200 mg) of 9-borabicyclo[3.3.1]nonane (Aldrich) i n 3 mL of dry tetrahydrofuran was heated under r e f l u x f or 48 h. The cooled reaction mixture was treated succes-s i v e l y with 3 mL of ethanol, 3 mL of 7 M sodium hydroxide and 3 mL of 30% aqueous hydrogen peroxide, and was then heated at 50°C (oilbath) for 1 h. The r e s u l t i n g mixture was p a r t i t i o n e d between ethyl acetate and aqueous sodium bicarbonate. . The aqueous phase was extracted with e t h y l acetate and the combined organic extracts were then washed with brine, dried (MgSO^) and concentrated to give 200 mg of a colourless o i l . Chromatography of t h i s o i l on 25 g of s i l i c a g e l , e l u t i n g with a 3:1 mixture of ethyl acetate and hexanes, afforded 31.3 mg (88%) of (i)-stemodin 3_, as a white s o l i d . Recrys-t a l l i z a t i o n from acetone-hexanes (or ethyl acetate) provided 3_ as colourless p l a t e s , mp 220.5-222°C ( l i t . (22) mp 218-220°C); i r (KBr): 3300 cm"1; XH nmr - 185 -(400 MHz, CDCI3 - (CD 3) 2S0) 6: 0.90, 0.94, 0.97, 1.08 (s, s, s, s, 3H each, t e r t i a r y methyl groups), 1.59-1.76 (m, 5H), 1.85-2.00 (m, 4H), 2.87 (br s, IH, -OH), 3.41 (br s, IH, -OH), 3.67 (m, IH, C-2B proton). On addition of D 20 the signals at 6 2.87 and 3.41 disappeared, and the signal at 6 3.67 s i m p l i f i e d . Exact Mass calcd. for C2Q^2^°2: 306.2558; measured: 306.2548. This material was i d e n t i c a l with an authentic sample of (-)-stemodin (10) by g l c , *H nmr (400 MHz), mass spectrometry, and t i c i n four solvent systems. - 186 -BIBLIOGRAPHY 1. K.M. Brundret, W. D a l z i e l , B. Hesp, J.A.J. J a r v i s , and S. Neidle, J . Chem. Soc. Chem. Commun., 1027 (1972). 2. W. D a l z i e l , B. Hesp, K.M. Stevenson, and J.A.J. J a r v i s , J . Chem. Soc. Perkin I, 2841 (1973). 3. A.N. S t a r r a t t , and S.R. Loschiavo, Can. J . M i c r o b i o l . , 20, 416 (1974). 4. M.R. Adams, and J.D. Bu'Lock, J . Chem. Soc. Chem. Commun., 389 (1975). 5. M.J. Ackland, J.R. Hanson, A.H. R a t c l i f f e , and I.H. Sadler, J . Chem. Soc. Chem. Commun., 165 (1982). 6. R.A. Bucknall, H. Moores, R. Simms, and B. Hesp, Antimicrob. Agents  Chemother., 4_, 294 (1973); S. Ikegami, T. Taguchi, M. Ohashi, M. Oguro, H. Nagano, and Y. Mano, Nature, 275, 458 (1978). 7. J . Douros, and M. Suffness, i n New Anticancer Drugs, S.K. Carter, and Y. Sakurai Eds., Springer Verlag, B e r l i n , 1980, p. 29. 8. G. Pedrali-Noy, G. Mazza, F. Focher, and S. Spadari, Biochem. Biophys. Res. Commun., 93, 1094 (1980). 9. M. Ohashi, T. Taguchi, and S. Ikegami, Biochem. Biophys. Res. Commun., 82, 1084 (1978); G. Pedrali-Noy, and S. Spadari, Biochem. Biophys. Res.  Commun., 88, 1194 (1979); J.A. Huberman, C e l l , 23, 647 (1981). 10. P.S. Manchand, J.D. White, H. Wright, and J . Clardy, J . Am. Chem. S o c , 95, 2705 (1973). 11. CD. Hufford, R.O. Guerrero, and N.J. Doorenbos, J . Pharm. S c i . , 65, 778 (1976). — 12. R.B. K e l l y , M.L. Harley, S.J. Alward, R.N. Rej, G. Gowda, A. Mukhopadhyay, and P.S. Manchand, Can. J . Chem., 61, 269 (1983). 13. P.S. Manchand, and J.F. Blount, J . Chem. Soc. Chem. Commun., 894 (1975). 14. Huang-Minion, J . Am. Chem. S o c , 71, 3301 (1949). 15. B.M. Trost, Y. Nishimura, K. Yamamoto, and S.S. McElvain, J . Am. Chem.  Soc., 101, 1328 (1979). 16. J.E. McMurry, A. Andrus, G.M. Ksander, J.H. Musser, and M.A. Johnson, J . Am. Chem. S o c , 101, 1330 (1979). 17. J.E. McMurry, A. Andrus, G.M. Ksander, J.H. Musser, and M.A. Johnson, Tetrahedron, 37, Supplement 1, 319 (1981). - 187 -18. E.J. Corey, M.A. Tius, and J . Das, J . Am. Chem. Soc., 102, 1742 (1980). 19. R.E. Ireland, and P.A. A r i s t o f f , J . Org. Chem., 44_, 4323 (1979). 20. R.E. Ireland, J.D. Godfrey, and S. Thaisrivongs, J . Am. Chem. Soc. , 103, 2446 (1981). 21. E.E. van Tamelen, S.R. Zawacky, R.K. R u s s e l l , and J.G. Carlson, J . Am.  Chem. S o c , 105, 142 (1983). 22. E.J. Corey, M.A. Tius, and J . Das, J . Am. Chem. Soc., 102, 7612 (1980). 23. R. Marini Bettolo, P. T a g l i a t e s t a , A. Lupi, and D. B r a v e t t i , Helv. Chim.  Acta, 66, 760 (1983). 24. E.E. van Tamelen, J.G. Carlson, R.K. R u s s e l l , and S.R. Zawacky, J . Am.  Chem. S o c , 103, 4615 (1981). 25. R.B. K e l l y , M.L. Harley, S.J. Alward, and P.S. Manchand, Can. J . Chem., 60, 675 (1982). 26. T. Kametani, T. Honda, Y. S h i r a t o r i , and K. Fukumoto, Tetrahedron L e t t . , 21, 1665 (1980); T. Kametani, T. Honda, Y. S h i r a t o r i , H. Matsumoto, and K. Fukumoto, J . Chem. Soc. Perkin I, 1386 (1981). 27. K.C. Nicolaou, and R.E. Zipki n , Angew. Chem., Int. Ed. Engl., 20, 785 (1981) . 28. R.L. C a r g i l l , D.F. Bushey, J.R. Dalton, R.S. Prasad, R.D. Dyer, and J . Bordner, J . Org. Chem., 46, 3389 (1981). 29. D. B a r v e t t i , R. Marini Bettolo, and A. Lupi, Helv. Chim. Acta, 65, 371 (1982) . 30. P.K. Ghosal, D. Mukherjee, and P.C. Dutta, Tetrahedron L e t t . , 2997 (1976). 31. D.J. Herbert, Ph.D. Thesis, University of B r i t i s h Columbia (1979). 32. B.F. Abeysekera, Ph.D. Thesis, U n i v e r s i t y of B r i t i s h Columbia (1981). 33. E. Pi e r s , B.F. Abeysekera, D.J. Herbert, and I.D. Suckling, J . Chem.  Soc. Chem. Commun., 404 (1982). 34. B.M. Trost, and M.J. Bogdanowicz, J . Am. Chem. Soc., 95, 5311 (1973); B.M. Trost, and S. Kurozumi, Tetrahedron L e t t . , 1929 (1974). - 188 -35. J.P. Collman, Acc. Chem. Res., 8, 342 (1975); J.Y. Merour, J.L. Roustan, C. Charrier, J . C o l l i n , and J . Benaim, J . Organomet. Chem., 51, C24 (1973). 36. A.J. Pearson, G.C. Heywood, and M. Chandler, J . Chem. Soc. Perkin I_, 2631 (1982). 37. T.G. Crandall, and R.G. Lawton, J . Am. Chem. S o c , 91, 2127 (1969); E.J. Corey, N. G i r o t r a , and C.T. Mathew, i b i d . , 91_ 1557 (1969). 38. M.P. Cava, and E. Moroz, J . Am. Chem. Soc., 84, 115 (1962); J . Meinwald, G.G. C u r t i s , and P.G. Gassman, i b i d . , 84, 116 (1962). 39. K. Wiesner, Chem. Soc. Rev., 6_, 413 (1977). 40. R.B. K e l l y , M.L. Harley, and S.J. Alward, Can. J . Chem., 58, 755 (1980). 41. H.L. Goering, and M.F. Sloan, J . Am. Chem. S o c , 83, 1397, 1992 (1961). 42. G. K5brich, Angew. Chem., Int. Ed. Engl. 1_2, 464 (1973). 43. G.L. Buchanan, Chem. Soc. Rev., _3» 4 1 (1974). 44. E.C. Ashby, and J.T. Laemmle, Chem. Rev., 75, 521 (1975). 45. B. Weidmann, and D. Seebach, Helv. Chim. Acta., 63, 2451 (1980). 46. P. Wieland, and K. Miescher, Helv. Chim. Acta., 33, 2215 (1950); S. Ramachandran, and M.S. Newman, Org. Synthn., 41, 38 TT961). 47. E. Piers and B. Abeysekera, Can. J . Chem., 60, 1114 (1982). 48. E. Brown, and M. Ragault, Tetrahedron L e t t . , 1927 (1973). 49. E. Brown, and N. Ragault, B u l l . Chem. Soc. Jpn., 47, 1729 (1974); idem, Tetrahedron, 37, Supplement 1, 61 (1981). 50. L.H. Sarett, W.F. Johns, R.E. Beyler, R.M. Lukes, G.I. Poos, and G.E. Arth, J . Am. Chem. S o c , 75, 2112 (1953). 51. L.M. Jackman, and S. S t e r n h e l l , Applications of Nuclear Magnetic  Resonance Spectroscopy i n Organic Chemistry, 2nd ed., Pergamon Press, New York, 1969. 52. M. Winter, Ph.D. Thesis, University of B r i t i s h Columbia (1980). 53. D.A. Evans, C L . Sims, and G.C. Andrews, J . Am. Chem. S o c , 99, 5453 (1977). - 189 -54. a) P.G. Bauslaugh, Synthesis, 287 (1970); b) W.L. D i l l i n g , Photochem.  Photobiol., 25, 605 (1977); c) J . Kossanyi, Pure Appl. Chem., 51, 181 (1979). 55. K. Wiesner, Tetrahedron, 31_, 1655 (1975). 56. R.A. Pauptit, and J . Tr o t t e r , Can. J . Chem., 59, 524 (1981). 57. E.J. Corey, J.D. Bass, R. LeMahieu, and R.B. Mitra, J . Am. Chem. Soc., 86, 5570 (1964). 58. P. Singh, J . Org. Chem., 36_, 3334 (1971); R.M. Bowman, C. Calvo, J . J . McCullough, P.W. Rasmussen, and F.F. Snyder, J . Org. Chem., 37, 2084 (1972); G.R. Lenz, Tetrahedron, 3j_, 1587 (1975); idem, J . Chem. Soc.  Chem. Commun., 803 (1982). 59. R.L. C a r g i l l , G.H. Morton, and J . Bordner, J . Org. Chem., 45, 3929 (1980). 60. G. Marini-Bettolo, S.P. Sahoo, G.A. Poulton, T.Y.R. T s a i , and K. Wiesner, Tetrahedron, 36, 719 (1980). 61. R.A. Pauptit, and J . Tro t t e r , Can. J . Chem., 61, 63 (1983). 62. L.D. H a l l , and J.K.M. Sanders, J . Am. Chem. S o c , 102, 5703 (1980). 63. F.E. Z i e g l e r , G.R. Reid, W.L. Studt, and P.A. Wender, J . Org. Chem., 42, 1991 (1977). — 64. R.L. Augustine, Adv. Ca t a l . , 25, 56 (1976). 65. E.J. Corey, and J.W. Suggs, Tetrahedron L e t t . , 2647 (1975). 66. R.O. Loutfy, and P. de Mayo, J._ Am. Chem. Soc., 9_9, 3559 (1977). 67. J.F. Blount, G.D. Gray, K.S. Atwal, T.Y.R. T s a i , and K. Wiesner, Tetrahedron L e t t . , 21, 4413 (1980). 68. G. Stork, and S.D. Darling, J . Am. Chem. S o c , 82, 1512 (1960); 86_, 1761 (1964). 69. D. Caine, Org. React., 2_3, 1 (1976). 70. N.J. Turro, Modern Molecular Photochemistry, Benjarain-Cumraings, Menlo Park, 1978, pp. 458-465. 71. K. Wiesner, unpublished work, quoted i n r e f . (59). 72. K. Valenta, and F. Grein, Can. J . Chem., 60, 601 (1982). 73. R.A. Caldwell, and D. Creed, Acc. Chem. Res., 13, 45 (1980). - 190 -74. D.H.R. Barton, and C.H. Robinson, J . Chem. S o c , 3045 (1954). 75. F.E. Zi e g l e r , and J.A. Kloek, Tetrahedron, 33, 373 (1977); idem, Tetrahedron L e t t . , 315 (1974). 76. J . J . Pappas, W.P. Keaveney, E. Gancher, and M. Berger, Tetrahedron L e t t . , 4273 (1966). 77. P.L. Stot t e r , and J.B. Eppner, Tetrahedron L e t t . , 2417 (1973). 78. I. Fleming, and D.H. Williams, Tetrahedron, 23, 2747 (1967). 79. K. Ogura, M. Yamashita, S. Furukawa, M. Suzuki, and G. Tsuchihashi, Tetrahedron L e t t . , 2767 (1975). 80. J.P. Schaefer, and J . J . Bloomfield, Org. React., 15, 1 (1967). 81. E.C. Taylor, and A. McKillop, The Chemistry of C y c l i c Enaminonitriles and £-Aminonitriles, Wiley, New York, 1970, p. 1. 82. S. Baldwin, J . Org. Chem., 2_6, 3280 (1961). 83. R.K. Crossland, and K.L. Servis, J . Org. Chem., 35, 3195 (1970). 84. K. F r i e d r i c h , and K. Wallenfels, i n The Chemistry of the Cyano Group, Z. Rappoport, Ed., Wiley, New York, 1970, p. 77; J.E. Shaw, D.Y. Hsia, G.S. Par r i e s , and T.K. Sawyer, J . Org. Chem., 43, 1017 (1978). 85. S.V. Evans, and J . T r o t t e r , unpublished r e s u l t s . 86. A.P. Krapcho, and A.J. Lovey, Tetrahedron L e t t . , 957 (1973). 87. B.S. Huang, E.J. Parish, and D.H. Miles, J . Org. Chem., 39, 2647 (1974). 88. H.J. Reich, J.M. Renga, and I.L. Reich, J . Am. Chem. S o c , 97, 5434 (1975). 89. D.L.J. C l i v e , Tetrahedron, 34, 1049 (1978). 90. B.M. Trost, and G.S. Massiot, J . Am. Chem. Soc., 99, 4405 (1977). 91. H.O. House, L.J. Czuba, M. G a l l , and H.D. Olmstead, J . Org. Chem. , 34, 2324 (1969). 92. R.A. Olofson, and CM. Dougherty, J . Am. Chem. S o c , 95, 581, 582 (1973). 93. K.B. Sharpless, R.F. Lauer, and A.Y. Te r a n i s h i , J . Am. Chem. S o c , 95, 6137 (1973). - 191 -94. D.L.J. C l i v e , J . Chem. Soc. Chem. Commun., 695 (1973). 95. a) C.C. Beard, i n Organic Reactions i n Steroid Chemistry, Vol. 1, J . Fr i e d , and J.A. Edwards Eds., van Nostrand Reinhold, New York, 1972, p. 271; b) B.E. Edwards and P.N. Rao, J . Org. Chem. , 31_, 324(1966). 96. H.O. House, and B.M. Trost, J . Org. Chem., 30, 2502 (1965). 97. G. Stork, and P.F. Hudrlik, J . Am. Chem. S o c , 90, 4462 (1968). 98. I. Ryu, S. Murai, I. Niwa, and N. Sonoda, Synthesis, 874 (1977). 99. Y. Ito, T. Hirao, and T. Saegusa, J. Org. Chem., 43, 1011 (1978). 100. I. Fleming, and I. Paterson, Synthesis, 736 (1979). 101. S. Danishefsky, and T. Kitahara, J . Am. Chem. Soc., 96, 7807 (1974); G.M. Rubottom, and J.M. Gruber, J . Org. Chem., 42, 1051 (1977); G.A. Olah, B.G.B. Gupta, S.C. Narang, and R. Malhotra, J . Org. Chem., 44, 4272 (1979); Y. Taniguchi, J. Inanaga, and M. Yamaguchi, B u l l . Chem. Soc. Jpn., 54, 3229 (1981). 102. E. Nakamura, T. Murofushi, M. Shimizu, and I. Kuwajima, J . Am. Chem.  S o c , 98, 2346 (1976). 103. C A . Brown, J . Org. Chem., 39_, 3913 (1974). 104. M.E. K r a f f t , and R.A. Holton, Tetrahedron L e t t . , 24, 1345 (1983). 105. R.D. M i l l e r , and D.R. McKean, Synthesis, 730 (1979). 106. P. Cazeau, F. Moulines, 0. Laporte, and F. Duboudin, J . Organomet. Chem., 201, C9 (1980). 107. G. Simchen, and W. Kober, Synthesis, 259 (1976). 108. G.A. Olah, A. Husain, B.G.B. Gupta, G.F. Salem, and S.C.Narang, J . Org.  Chem., 46, 5212 (1981). 109. H. Sakurai, K. Miyoshi, and Y. Nakadaira, Tetrahedron L e t t . , 2671 (1977). 110. D.E. S e i t z , and L. F e r r e i r a , Synth. Commun., 2» 931 (1979). 111. D.E. Pearson, and C A . Buehler, Chem. Rev., 74, 45 (1974). 112. J.M. Conia, Record of Chem. Progr., 24, 43 (1963). 113. Cf. H.O. House, Modern Synthetic Reactions, 2nd ed. , W.A. Benjamin, Menlo Park, 1972, pp. 546-570. - 192 -114. A.A. Millard, and M.W. Rathke, J. Org. Chem., 43, 1834 (1978). 115. R.B. Woodward, A.A. Patchett, D.H.R. Barton, D.A.J. Ives, and R.B. Kelly, J. Chem. Soc, 1131 (1957). 116. L. Nedelec, J.C. Gasc, and R. Bucourt, Tetrahedron, 30, 3263 (1974). 117. J. Laemmle, E.C. Ashby, and P.V. Roling, J. Org. Chem., 38, 2526 (1973). 118. G.H. Posner, Ph.D. Thesis, Harvard University (1968). 119. E.J. Corey, and M. Chaykovsky, J. Am. Chem. Soc, 87, 1353 (1965). 120. S. Krishnamurthy, R.M. Schubert, and H.C. Brown, J. Am."Chem. Soc., 95, 8486 (1973). 121. H. Smith, Organic Reactions in Liquid Ammonia, Chemistry in Non-aqueous  Ionizing Solvents, Vol. 1, Part 2, Interscience, New York, 1963, pp. 223-6; M. Cais, in The Chemistry of Alkenes, S. Patai Ed., Interscience, London, 1964, p. 999. 122. B. Weidmann, and D. Seebach, Angew. Chem., Int. Ed. Engl., 22, 31 (1983). 123. M.D. Rausch, and H.B. Gordon, J. Organomet. Chem., 74, 85 (1974). 124. M. Reetz, Chem. Ind. (London), 541 (1981). 125. W.J. Haulihan, J. Org. Chem. , 2J_, 3860 (1962). 126. H.O. House, and W. Respress, J. Org. Chem., 30, 301 (1965). 127. R.H. Shapiro, Organic Reactions, 23, 405 (1976). 128. D.M.S. Wheeler, and M.M. Wheeler, in Organic Reactions in Steroid  Chemistry, Vol. 1, J. Fried, and J.A. Edwards Eds., van Nostrand Reinhold, New York, 1972, p. 66. 129. V.V. Kane, V. Singh, A. Martin, and D.L. Doyle, Tetrahedron, 39, 345 (1983). — 130. J.F. Biellmann, and J.P. Pete, Bull. Soc. Chim. Fr., 675 (1967). 131. H.C. Brown, and G. Zweifel, J. Am. Chem. Soc, 83, 1241 (1961). 132. H.C. Brown, E.F. Knights, and C.G. Scouten, J . Am. Chem. Soc, 96, 7765 (1974); H.C. Brown, R. Liotta, and L. Brener, J. Am. Chem. Soc. "99", 3427 (1977). 133. W.C. S t i l l , M. Kahn, and A. Mitra, J . Org. Chem., 43, 2923 (1978). 

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