Open Collections

UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Studies directed towards the synthesis of (±)-stemodin, a tetracyclic diterpenoid Abeysekera, Brian Frederick 1981

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

Item Metadata

Download

Media
831-UBC_1981_A1 A34.pdf [ 4.7MB ]
Metadata
JSON: 831-1.0060812.json
JSON-LD: 831-1.0060812-ld.json
RDF/XML (Pretty): 831-1.0060812-rdf.xml
RDF/JSON: 831-1.0060812-rdf.json
Turtle: 831-1.0060812-turtle.txt
N-Triples: 831-1.0060812-rdf-ntriples.txt
Original Record: 831-1.0060812-source.json
Full Text
831-1.0060812-fulltext.txt
Citation
831-1.0060812.ris

Full Text

C • I STUDIES DIRECTED TOWARDS THE SYNTHESIS OF (±)-STEMODIN, A TETRACYCLIC DITERPENOID B . S c , University of S r i Lanka, Colombo Campus, 1975 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA January, 1981 c") ^ Brian Fredrick Abeysekera, 1981 by BRIAN FREDRICK ABEYSEKERA i n I n p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f t h e r e q u i r e m e n t s f o r a n a d v a n c e d d e g r e e a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e t h a t t h e L i b r a r y s h a l l m a k e i t f r e e l y a v a i l a b l e f o r r e f e r e n c e a n d s t u d y . I f u r t h e r a g r e e t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s m a y b e g r a n t e d b y t h e h e a d o f m y d e p a r t m e n t o r b y h i s o r h e r r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t b e a l l o w e d w i t h o u t m y w r i t t e n p e r m i s s i o n . D e p a r t m e n t o f Ctf&"S7*y T h e U n i v e r s i t y o f B r i t i s h C o l u m b i a 2 0 7 5 W e s b r o o k P l a c e V a n c o u v e r , C a n a d a V 6 T 1W5 D a t e U~ D K - f i (2/791 i i ABSTRACT This t h e s i s describes s t u d i e s d i r e c t e d toward the s y n t h e s i s 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 represented by a p h i d i c o l i n 1_ and stemodin J5. A f e a s i b l e route to stemodin i s e s t a b l i s h e d , w h i l e the s i m i l a r route planned f o r a p h i d i c o l i n _7 i s shown to be non-viable. W e l l e s t a b l i s h e d procedures were u t i l i z e d to convert the Wleland -Miescher ketone 101 i n t o the b i c y c l i c k e t a l ketone _57. This was converted i n t o the key intermediate, the t r i c y c l i c enone j>6, u s i n g a new cyclopentenone a n n u l a t i n g sequence which compared q u i t e favourably w i t h procedures p r e s e n t l y a v a i l a b l e . This sequence was as f o l l o w s : the r e a d i l y a v a i l a b l e keto phosphonate 75 was converted i n t o i t s e n o l ether .79, > and a l l y l i c bromination w i t h N-bromosuccinimide aff o r d e d the bromo compound j51_, an e x c e l l e n t a l k y l a t i n g agent. This m a t e r i a l was used to a l k y l a t e the enolate anions of v a r i o u s ketones, i n c l u d i n g _57. The sequence i s i l l u s t r a t e d f o r cyclohexanone 82, the enolate anion of which on treatment w i t h ^81 gave 83. Acid h y d r o l y s i s of the enol ether moiety i n 83 gave the d i k e t o phosphonate 93 which was c y c l i z e d to the enone JT7 using the Horner - Emmons r e a c t i o n . The photoaddition of a l l e n e to the enone 56^ was p r e v i o u s l y s t u d i e d i n t h i s l a b o r a t o r y and was reported to y i e l d two photoadducts. While the work described i n t h i s t h e s i s supports the s t r u c t u r e p r e v i o u s l y assigned to one of the photoadducts (61), a new s t r u c t u r e (109) i s proposed f o r the other. This proposal i s based on the conversion of both photoadducts by o z o n o l y s i s and subsequent sodium methoxide treatment i n t o the same keto e s t e r 55. i i i The keto e s t e r j>5_ was subsequently elaborated i n t o the t e t r a c y c l i c dione 132 i n a number of s t e p s , the key r e a c t i o n i n t h i s sequence being a Thorpe-Ziegler condensation. i v TABLE OF CONTENTS Page TITLE PAGE i ABSTRACT i i TABLE OF CONTENTS i v ACKNOWLEDGEMENTS v ABBREVIATIONS v i INTRODUCTION I General 1 I I The I s o l a t i o n and S t r u c t u r a l E l u c i d a t i o n of A p h i d i c o l i n , Stemodin and Stemodinone. 5 I I I Previous S y n t h e t i c Approaches to A p h i d i c o l i n and Stemodin. 8 DISCUSSION I S y n t h e t i c Strategy 21 I I Synthesis of 2-Cyclopenten-l-ones 28 I I I The Synthesis of the T r i c y c l i c E s t e r 55 46 IV The Synthesis of the T e t r a c y c l i c Dione 132 59 EXPERIMENTAL 81 BIBLIOGRAPHY 119 V ACKNOWLEDGEMENTS Over the l a s t f o u r years, many people have made c o n t r i b u t i o n s towards the r e a l i z a t i o n of t h i s g o a l , and to thank them a l l i n d i v i d u a l l y i s i m p o s s i b l e . I would however l i k e to make s p e c i a l mention of a few whose c o n t r i b u t i o n s have been i n v a l u a b l e o r i n d i s p e n s a b l e . To Prof e s s o r Edward P i e r s whose enthusiasm, advice and encouragement have sustained me during the course of my s t u d i e s , I o f f e r my s i n c e r e thanks. I t was indeed a pleasure to work under h i s d i r e c t i o n . I a l s o thank the members of h i s research group f o r a l l t h e i r cooperation and camaraderie that eased the pa i n of research. I am a l s o indebted to P r o f e s s o r John Scheffer whose help and i n t e r e s t i n my work i s g r a t e f u l l y acknowledged. My s p e c i a l thanks go to Miss P a u l i n e Howell who spent many hours proofreading t h i s manuscript and i n h e l p i n g me draw a l l the diagrams, and to Mrs. Rani Theeparajah f o r her prompt and e f f i c i e n t t y p i n g . L a s t , and c e r t a i n l y not l e a s t , f i n a n c i a l a s s i s t a n c e i n the form of graduate f e l l o w s h i p s from the U n i v e r s i t y of B r i t i s h Columbia, i s g r a t e f u l l y acknowledged. v i The following abbreviations are used i n t h i s t h e s i s : NBS = N-Bromosuccinimide t-Bu = t e r t - B u t y l DMS = Dimethyl s u l f i d e HMPA = Hexamethylphosphoramide i r = i n f r a r e d LAH = Lithium Aluminum Hydride LDA = Lithium Diisopropylamide Ms = Methanesulfonyl n.m.r. = nuclear magnetic resonance pyr = Pyridine THF = Tetrahydrofuran THP = Tetrahydropyranyl Ts = para-Toluene s u l f o n y l TMS = T r i m e t h y l s i l y l 1 INTRODUCTION I . General Organic s y n t h e s i s has been going on f o r m i l l i o n s o f years i n nature on a s c a l e of ope r a t i o n that staggers the imagination. Here, va s t q u a n t i t i e s of h i g h l y e l a b o r a t e molecules are constructed s p e e d i l y and w i t h apparent ease from simple s t a r t i n g m a t e r i a l s . This p r e c i s i o n and elegance i n b i o s y n t h e s i s g r e a t l y overshadows the s t a t e of the a r t i n the l a b o r a t o r y , where s y n t h e s i s o f t e n appears cumbersome by comparison. However, much has been accomplished s i n c e the a c c i d e n t a l s y n t h e s i s of urea by Wohler i n 1828. U n t i l then, chemists b e l i e v e d t h a t a " v i t a l f o r c e " was necessary to make organic molecules and t h a t these compounds could only be made i n nature. Since then, s y n t h e t i c organic chemistry has progressed r a p i d l y and one has only to r e f e r to the l i t e r a t u r e e x p l o s i o n on the subje c t to r e a l i z e what has been achieved. Among the v a r i o u s c l a s s e s of n a t u r a l products, the terpenoids have occupied a s p e c i a l p o s i t i o n and have r e c e i v e d the a t t e n t i o n of many s y n t h e t i c chemists. Two f a c t o r s that have no doubt c o n t r i b u t e d to t h i s a r e t h e i r ease of i s o l a t i o n and p u r i f i c a t i o n and t h e i r commercial s i g n i f i c a n c e . They f i n d many uses i n perfumes and cosmetics, i n p a i n t s and p r e s e r v a t i v e s , as a r t i f i c i a l f l a v o u r i n g s i n f o o d s t u f f s and to a small extent i n medicine. S t r u c t u r a l i n v e s t i g a t i o n s revealed that the terpenoids had carbon skeletons composed of isopentane u n i t s l i n k e d i n a head to t a i l f a s h i o n , and the number of such u n i t s present i n terpenoids i s used i n t h e i r c l a s s i f i c a t i o n . Thus, monoterpenoids, s e s q u i t e r p e n o i d s , d i t e r p e n o i d s , s e s t e r t e r p e n o i d s and t r i t e r p e n o i d s are made up of two, th r e e , four, f i v e and s i x isopentane u n i t s , r e s p e c t i v e l y . 2 The d i t e r p e n o i d s are normally C^Q compounds, mainly of p l a n t and fungal o r i g i n and u s u a l l y occur as mixtures of c l o s e l y r e l a t e d compounds. They show wide v a r i a t i o n i n s t r u c t u r e though they are a l l b i o g e n e t i c a l l y derived from g e r a n y l g e r a n i o l l y The main carbon skeletons of the t e t r a c y c l i c diterpenes are the kaurane 2^, beyerane 3^, a r t i s a n e U_ and g i b b e r e l l a n e j> types. They are a l l d e r i v a b l e ^ i n p r i n c i p a l from a t r i c y c l i c precursor of the pimaradiene 6^ c l a s s . 2 3 A p h i d i c o l i n 1_ ' i s the f i r s t r eported 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 . S e v e r a l papers have appeared i n the recent 2 3 l i t e r a t u r e d e s c r i b i n g i t s i s o l a t i o n and s t r u c t u r a l e l u c i d a t i o n ' and 4-6 7 i t s t o t a l s y n t h e s i s . Recently, another two di t e r p e n o i d s , stemodin 8^  and stemodinone j) were i s o l a t e d and t h e i r s t r u c t u r e s proved to be q u i t e s i m i l a r to that of a p h i d i c o l i n 2.* The b i o s y n t h e t i c pathway to t h i s type of compounds has s t i l l to be e l u c i d a t e d , though p o s s i b l e pathways could 2 be proposed v i a the pimaradiene h_ type of t r i c y c l i c precursor . The 2 numbering systems proposed f o r the b a s i c carbon skeletons of a p h i d i c o l i n T_ and stemodin 8? are s l i g h t l y d i f f e r e n t and are i n d i c a t e d i n the s t r u c t u r a l formulas ^0 and 11, r e s p e c t i v e l y . HO' CH20H ,—CHnOH R. HO ~-H £ R = OH 9 R = 0 10 The a n t i v i r a l a c t i v i t y of a p h i d i c o l i n _7 together w i t h i t s novel s t r u c t u r e makes t h i s c l a s s of compounds an important s y n t h e t i c t a r g e t . The work described i n t h i s t h e s i s was d i r e c t e d toward the s y n t h e s i s of both a p h i d i c o l i n 7^ and stemodin j8. However, as work progressed i t became obvious that the route a c t u a l l y employed provided intermediates which are s u i t a b l e only f o r the s y n t h e s i s of stemodin j5 (or stemodinone 9) . I I . The I s o l a t i o n and S t r u c t u r a l E l u c i d a t i o n of A p h i d i c o l i n 1, Stemodin iL and Stemodinone 3_. 2 3 A p h i d i c o l i n ]_ was f i r s t i s o l a t e d ' from the f i l t r a t e s of c u l t u r e s of the fungus Cephalosporium a p h i d i c o l a Petch. I t was found to i n h i b i t the growth of Herpes simplex v i r u s e s , and to reduce the m i t o t i c r a t e of mouse 'L' c e l l s growing i n t i s s u e c u l t u r e . The absence of carbonyl and o l e f i n i c groups i n the molecule i n d i c a t e d that a p h i d i c o l i n T_, was t e t r a c y c l i c . The "^H n.m.r. s p e c t r a of a p h i d i c o l i n _7 and i t s mono-, d i - , and t r i - acetates i n d i c a t e d the presence of two t e r t i a r y methyl groups, two primary a l c o h o l groups a t quaternary p o s i t i o n s , and a secondary a l c o h o l group. A p h i d i c o l i n 7_ r e a d i l y and r e v e r s i b l y formed a b i s a c e t o n i d e 12_, i n d i c a t i n g the presence of four OH groups. Treatment of a p h i d i c o l i n 1_ w i t h p e r i o d i c a c i d i n p y r i d i n e r e s u l t e d i n the l o s s of the elements of formaldehyde and the formation of a ketone which together w i t h the data summarized above i n d i c a t e d that the f o u r t h a l c o h o l group was t e r t i a r y and v i c i n a l to one of the primary a l c o h o l f u n c t i o n s . Since a p r o t r a c t e d s e r i e s of chemical transformations would have been r e q u i r e d to unambiguously a s s i g n a s t r u c t u r e to a p h i d i c o l i n 1_, x-ray s t u d i e s were undertaken. These s t u d i e s l e d to the assignment of s t r u c t u r e VL_ to the b i s a c e t o n i d e d e r i v a t i v e and hence s t r u c t u r e and absolute c o n f i g u r a t i o n 1_ f o r a p h i d i c o l i n . HO' H CH2OH 12 Stemodin j$ and Stemodinone 9_ were f i r s t i s o l a t e d ' from the r a t e l i t t a r a l d p l a n t Stemodin maritima L found i n the Palisadoes peninsula of Jamaica.. These two new diterpenes were obtained from the l e a f c o n s t i t u e n t s < the p l a n t and were shown to possess unusual t e t r a c y c l i c carbon s k e l e t o n s . They bear a c l o s e resemblance to the s t r u c t u r e of a p h i d i c o l i n T_t d i f f e r i n g i n the stereochemistry a t C-9, C-13 and C-14 (stemodane numbering). Mass S p e c t r a l data and elemental analyses of stemodin B_ i n d i c a t e d a molecular formula o f C 20 H34°2 ^ m p 1 9 6 ~ 1 9 7 ° C » ~ 2 « 6 ° ) ' T h e i n f r a r e d spectrum of J5 i n d i c a t e d the presence of hydroxyl (3340, 3220 cm "*") and the absence of carbonyl a b s o r p t i o n . The n.m.r. spectrum (CDCl^) showed f o u r methyl groups a t 6 0.90, 0.93, 0.97 and 1.08 and a proton (<5 3.71, t of t , J = 11, 3.5 Hz) attached to a carbon bearing a hyd r o x y l group and fla n k e d by two methylene groups. The c o u p l i n g constants i n d i c a t e d that t h i s proton was i n an a x i a l o r i e n t a t i o n and hence the OH group was e q u a t o r i a l l y o r i e n t e d . A c e t y l a t i o n of stemodin 8_ gave a monoacetate which s t i l l e x h i b i t e d an i n f r a r e d a b s o r p t i o n t y p i c a l o f a hydroxyl group. Thus i t appeared that t h i s n a t u r a l product contained a secondary and a t e r t i a r y h ydroxyl group. Stemodinone j ) , C 2 0 H 3 2 ° 2 ( m p 2 1 5 ~ 2 1 6 ° C » [ a ] D +1A .3°) , was i s o l a t e d from a l e s s p o l a r f r a c t i o n of the l e a f e x t r a c t o f the p l a n t . I t s i n f r a r e d spectrum i n d i c a t e d hydroxyl (3600 - 3460 cm "S as w e l l as carbonyl (1700 cm ^) f u n c t i o n a l i t y . Oxidation of stemodin 8^  w i t h Jones' reagent gave stemodinone j) i n good y i e l d , thus e s t a b l i s h i n g the r e l a t i o n s h i p between the two compounds. The Raman spectrum of stemodinone 9_ showed no o l e f i n i c f u n c t i o n a l i t y . This o b s e r v a t i o n , taken together w i t h the f a c t that stemodinone f a i l e d to take up hydrogen when subjected to 7 c a t a l y t i c hydrogenation provided evidence f o r the t e t r a c y c l i c nature of i t s carbon s k e l e t o n . The s t r u c t u r e and absolute stereochemistry of these two n o v e l diterpenes was proved by the s i n g l e - c r y s t a l x-ray a n a l y s i s of stemodinone j ) . The curve obtained from an ORD measurement on stemodinone 9. showed a p o s i t i v e Cotton e f f e c t ( t a ^ Q g = 2460). This f a c t i s i n agreement w i t h an absolute c o n f i g u r a t i o n c o n t a i n i n g a 5a -H and a 106 -CH^. 8 I I I . Previous S y n t h e t i c Approaches to A p h i d i c o l i n 1 and Stemodin .8.. The novel carbon skeletons of both a p h i d i c o l i n ]_ and stemodin J3 along w i t h the a n t i b i o t i c nature of a p h i d i c o l i n ]_, have been strong motivators i n the choice of these molecules as t a r g e t s f o r s y n t h e s i s . When t h i s work was undertaken, the l i t e r a t u r e contained no r e p o r t of s y n t h e t i c s t u d i e s d i r e c t e d toward these t e t r a c y c l i c d i e t e r p e n o i d s . Recently, however, a number of t o t a l syntheses^ ^ and some s y n t h e t i c approaches^' 9 to a p h i d i c o l i n 7_ have been p u b l i s h e d . Stemodin 8^  (and stemodinone 9) have r e c e i v e d l e s s a t t e n t i o n and only two s y n t h e t i c approaches have thus f a r appeared i n the l i t e r a t u r e ^ ' ^ " ' ' ' . A b r i e f d i s c u s s i o n of these syntheses i s i n order. 4 5 6 Very r e c e n t l y , Trost e t . a l . , McMurry et_. a l . , and Corey £t. a l . have each published a t o t a l s y n t h e s i s of a p h i d i c o l i n 1_. A l l three research groups began by f u n c t i o n a l i z i n g the A r i n g p r i o r to b u i l d i n g the CD r i n g system which, as w i l l be seen l a t e r , i s the reverse approach t o that of 4 5 our proposed route. Trost and McMurry both began w i t h the diketone 13 and i n a s e r i e s of very s i m i l a r transformations converted i t i n t o the b i c y c l i c ketoacetonide 14 (eq. 1 ) . On the other hand, Corey^ u t i l i z e d as a key intermediate the keto aldehyde 15_ which he prepared by two routes, one of which began w i t h the diketone 13 and proceeded v i a the intermediate b i c y c l i c k e t o a c e t a l '16_, a compound very s i m i l a r to lk_ (eq. 2 ) . The s y n t h e t i c methodology u t i l i z e d i n the c o n s t r u c t i o n of the CD r i n g system, however, was approached d i f f e r e n t l y by a l l three research groups. 4 12 Trost jet. a l . u t i l i z e d t h e i r cyclopentanone a n n u l a t i o n procedure to b u i l d the C r i n g of a p h i d i c o l i n 7_. Thus, condensation of the keto-12 acetonide JL4 w i t h diphenylsulfonium c y c l o p r o p y l i d e under r e v e r s i b l e y l i d e generation c o n d i t i o n s proceeded smoothly to g i v e the oxaspiropentane 17 13 which was t r e a t e d w i t h sodium phenylselenide to give the a l k y l i d e n e -cyclopropanol 18^ (eq. 3) . 10 Thermal rearrangement v i a f l a s h vacuum p y r o l y s i s of the t r i m e t h y l s i l y l ether of t h i s m a t e r i a l (compound 19, eq. A) gave a 2:1 mixture of the epimers 20_ and 21, w i t h the major isomer 20_ having the undesired stereochemistry a t C-8. 19 20 2JL This mixture of epimers was o x i d i z e d to the enone 22 w i t h Pd(0Ac)2 i n CHgCN. D i s s o l v i n g metal r e d u c t i o n [ L i , NH 3 > THF, 0.8 equiv. of _t-C 4H g0H) of the enone 22^ f o l l o w e d by quenching of the intermediate enolate anion w i t h c h l o r o t r i m e t h y l s i l a n e gave a s i n g l e enol s i l y l ether 21. which corresponded to the minor product of the i n i t i a l rearrangement (eq. 5 ) . 11 Treatment of the enol s i l a n e 21 w i t h n - b u t y l l i t h i u m generated the enolate 23_ which was a l k y l a t e d w i t h a l l y l i o d i d e to give the keto o l e f i n 24_ i n 35% y i e l d . This was a c r i t i c a l step i n the s y n t h e s i s , e s t a b l i s h i n g the stereochemistry of the D r i n g (eq. 6 ) . 21 23 24 The remaining steps of the synt h e s i s were r a t h e r s t r a i g h t f o r w a r d . Thus hyd r o b o r a t i o n - o x i d a t i o n of the keto o l e f i n 24_ f o l l o w e d by o x i d a t i o n of the r e s u l t a n t keto a l c o h o l ,25_ gave the keto aldehyde 2j5 (eq. 7 ) . 12 A l d o l c y c l i z a t i o n of the keto aldehyde 26 gave a mixture of epimeric t e t r a c y c l i c keto a l c o h o l s 2_7 and ^8, which were converted i n t o t h e i r t e trahydropyranyl ethers 29, and 3>0_. Reduction of the l a t t e r mixture of compounds under W o l f f - K i s h n e r c o n d i t i o n s , followed by removal of the t e t r a h y d r o p y r a n y l ether p r o t e c t i n g group and o x i d a t i o n of the r e s u l t i n g mixture of a l c o h o l s 31^ and 31_ gave the keto acetonide J53 (eq. 8) 26 R = H 27 and 28 R = THP 29 and 30 31, 32 (8) 33 The ketoacetonide _33 had p r e v i o u s l y been obtained from, and reconverted 2 3 i n t o , a p h i d i c o l i n J7. ' 13 McMurry^ had a t o t a l l y d i f f e r e n t approach to the CD r i n g system of a p h i d i c o l i n ]_. A l k y l a t i o n of the enolate anion of the keto acetonide 14 w i t h m e t h a l l y l i o d i d e gave the keto o l e f i n 3_4. The o l e f i n i c bond of 3_4_ was cleaved r e a d i l y w i t h sodium meta-periodate and osmium t e t r o x i d e to g i v e the diketone 3_5 which upon treatment w i t h sodium hydride i n r e f l u x i n g benzene c o n t a i n i n g a t r a c e of t e r t - a a y l . a l c o h o l (eq. 9) underwent i n t e r n a l a l d o l c y c l i z a t i o n to a f f o r d the t r i c y c l i c enone 36. 14 Since the appropriate d i r e c t conjugate a d d i t i o n to .the enone _36 proved to be impossible, an i n d i r e c t route to the D r i n g was developed. Thus, r e d u c t i o n of the keto group of ^6_ w i t h l i t h i u m aluminum hydride gave a s i n g l e a l c o h o l 37_ which was converted i n t o i t s corresponding v i n y l ether u s i n g mercuric acetate and e t h y l v i n y l ether (eq. 10) . (10) 36 37 38 Vapour phase p y r o l y s i s of 36^ gave, i n a r a t h e r low y i e l d (20%), the C l a i s e n rearrangement product 3_9, which was reduced w i t h l i t h i u m aluminum hydride. . The r e s u l t i n g a l c o h o l 4£ was converted i n t o the corresponding t o s y l a t e _41. The C l a i s e n rearrangement served to introduce the c r u c i a l stereochemistry of the D r i n g , and d i r e c t 14 c a r b o n y l a t i o n of the t o s y l a t e 41_ 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 produced the d e s i r e d ketoacetonide 33 i n a modest y i e l d (30%, eq. 11). Corey's s y n t h e s i s of the CD r i n g system of a p h i d i c o l i n ]_ d i f f e r e d completely from the previous two syntheses, and included a number of unique steps. The keto aldehyde 15^ was t r e a t e d w i t h potassium carbonate and 1,5-diazabicyclo[5,4,0]-undec-5-ene (DBU) and subjected to a slow gaseous stream of methyl v i n y l ketone"*"^ i n argon to g i v e the Michael adduct j42. This m a t e r i a l , upon treatment w i t h p y r r o l i d i n i u m a c e t a t e ^ y i e l d e d the Robinson s p i r o a n n u l a t i o n product 43_ (eq. 12). The key intermediate 43 was converted v i a a number of steps i n t o the keto 16 0 t o s y l a t e 4^4 which could be a l k y l a t e d i n t e r n a l l y a t e i t h e r C-12 or C-15 depending on the r e a c t i o n c o n d i t i o n s . Thus a d d i t i o n of the keto t o s y l a t e 44 i n 2-methyl tetrahydrofuran to an excess of l i t h i u m d i - t e r t - b u t y l a m i d e 1 7 i n the same s o l v e n t a t -120°C to -130°C, f o l l o w e d by gradual warming of the r e s u l t a n t s o l u t i o n , produced the t e t r a c y c l i c ketone ^5 i n 90% y i e l d , a r e s u l t of a l k y l a t i o n a t C-12 (eq. 13). 17 (13) 45 The t e t r a c y c l i c ketone 4_5 was next t r e a t e d w i t h 1-ethoxyethoxymethyl 18 l i t h i u m . H y d r o l y s i s o f the adduct formed gave a 1:1 mixture of a p h i d i c o l i n ]_ and i t s C-16 epimer 4j> (eq. 14). 18 I n t e r e s t i n g l y , when the keto t o s y l a t e j44_ was allowed to r e a c t w i t h sodium methoxide i n methanol at 0°C, the product of i n t e r n a l a l k y l a t i o n at C—15 (compound 47, eq. 15) was formed e x c l u s i v e l y . This product corresponds i n stereochemistry to the stemodin jS type of carbon s k e l e t o n . 19 Stemodin j5 and stemodinone _9 have r e c e i v e d l e s s a t t e n t i o n and of the two*synthetic approaches that have appeared i n the l i t e r a t u r e , one, by C h a t t e r j e e ^ appears to conta i n a number of e r r o r s and hence w i l l not be discussed here. In the second approach, by Dutta jet. a l 19 the known ketone j48 was converted i n two steps i n t o the ketone j49_ which was a l k y l a t e d w i t h l-bromo-3,3-ethylenedioxypropane to give i n 58% y i e l d , the product _50 (eq. 16) . 49 50 The a l k y l a t i o n step i s s i m i l a r to that i n Trost's'* s y n t h e s i s of a p h i d i c o l i n J_ except t h a t the opposite stereochemistry ( c i s - B C r i n g j u n c t i o n ) i s obtained. The D r i n g i s then b u i l t up i n a s e r i e s o f 4 steps, almost i d e n t i c a l w i t h those i n Trost's s y n t h e s i s (eq. 17). * Since t h i s manuscript was prepared, Corey et a l . have published [ J . Am. Chem. S o c , 102, 7612 (1980)] a s y n t h e s i s of stemodin and stemodinone using methodology s i m i l a r to that used i n t h e i r s y n t h e s i s of a p h i d i c o l i n . 20 I t should be pointed out that a l l the syntheses discussed r e s u l t i n the preparation of a racemic mixture of the natural product. 21 DISCUSSION I . S y n t h e t i c Strategy The s t r a t e g y employed i n a chemical s y n t h e s i s depends on a number of f a c t o r s , such as f i n a n c i a l c o n s i d e r a t i o n s , the s c a l e of o p e r a t i o n , and the time f a c t o r . I n d u s t r i a l syntheses o f t e n need to be c a r r i e d out on a m u l t i - k i l o g r a m s c a l e which may preclude reagents used r o u t i n e l y i n the research l a b o r a t o r y . The p r o f i t motive i n i n d u s t r y d i c t a t e s t h a t the number of steps be kept to a minimum and o f t e n syntheses a r e b u i l t around a " t r i c k " r e a c t i o n that puts together complex s k e l e t a l elements or stereochemistry i n one step . Such syntheses have 20 been termed " i r r a t i o n a l " as opposed to syntheses i n which f u n c t i o n a l i t y and s k e l e t a l assembly i s done i n a l o g i c a l m u l t i - s t e p process. This second type of s y n t h e s i s , c a l l e d " r a t i o n a l " s y n t h e s i s , i s what i s o f t e n c a r r i e d out i n the research l a b o r a t o r y . In the design of such a s y n t h e s i s , a complex organic molecule i s broken up i n t e l l e c t u a l l y i n t o a s e r i e s of p r o g r e s s i v e l y simpler fragments u n t i l such fragments are recog n i z a b l e as being e a s i l y a v a i l a b l e . This type of breakdown i s c a l l e d a " r e t r o s y n t h e t i c a n a l y s i s " and i n theory, a t l e a s t , each fragment i n the sequence can be converted i n t o i t s precursor. Such an a n a l y s i s a p p l i e d to stemodin _8 l e d to the s e r i e s of intermediate compounds i l l u s t r a t e d i n Scheme I . The f u n c t i o n a l i t y present i n the A and D r i n g s of stemodin 8^  could be reasonably expected to be generated from two keto groups at C^ and C ^ j ' Hence the prime t a r g e t f o r our s y n t h e s i s became the t e t r a c y c l i c keto k e t a l _53. C h a t t e r j e e ^ * has i n f a c t converted the keto group a t C. , to the r e q u i r e d f u n c t i o n a l i t y i n the D r i n g , a l b e i t i n low SCHEME I 23 isomeric p u r i t y . The t e t r a c y c l i c keto k e t a l 53_ could i n theory be prepared by the r e a c t i o n of a dimesylate 54 (or d i t o s y l a t e 58) w i t h an a c y l anion 21 e q u i v a l e n t derived from methyl methylthiomethyl s u l f o x i d e or 22 23 nitromethane, * f o l l o w e d by h y d r o l y s i s or o x i d a t i v e cleavage, r e s p e c t i v e l y , of the r e s u l t a n t product (eq. 1 8 ) . R = Ms 54 5 3 R = Ts 58 The dimesylate 54 could be prepared by r e a c t i n g the d i o l _59_ w i t h methanesulfonyl c h l o r i d e i n p y r i d i n e . The stereochemistry of the secondary OH group i n the d i o l _5_9 would be of paramount importance s i n c e the o r i e n t a t i o n of t h i s group would govern the stereochemistry of the secondary OMs group i n the dimesylate j>4. The SN^ - l i k e displacement of the OMs group i n the dimesylate 54_ by thfe a c y l anion e q u i v a l e n t r e q u i r e s that the stereochemistry of the secondary OMs group be trans to the CH^CH^OMs moiety. An i d e a l precursor f o r the d i o l 5_9 would be the t r i c y c l i c keto e s t e r J55_. This could be reduced i n one step to the d i o l 59. A l t e r n a t i v e l y , the keto group could be s t e r e o s e l e c t i v e l y reduced f i r s t . Subsequent r e d u c t i o n of the r e s u l t i n g e s t e r a l c o h o l j>0 24 would then produce the d i o l 59 i n two steps from the keto e s t e r 55 (Scheme I I ) . SCHEME I I The s t e r e o s e l e c t i v e r e d u c t i o n of a carbonyl group i s a problem that r e a rs i t s ugly head ever so o f t e n i n s y n t h e s i s , and s e v e r a l 24 reviews have appeared on the s u b j e c t . One u s u a l l y employs a hydride type reducing agent and, i n gene r a l , s t e r i c a l l y bulky reagents provide a predominance of the more hindered a l c o h o l . This has been r a t i o n a l i z e d as approach of the reagent from the l e s s hindered s i d e of the molecule w i t h the consequential d e l i v e r y of hydride from that s i d e . A l a r g e number of such hindered reducing agents are r e a d i l y a v a i l a b l e . 25 If one r e q u i r e s the l e s s hindered a l c o h o l , one p o s s i b l e method i s a B i r c h - t y p e r e d u c t i o n , which can be c a r r i e d out using l i t h i u m and ammonia. Examination of a model of the t r i c y c l i c keto «ster _55 i n d i c a t e d t h a t the B face of the molecule was the l e s s hindered face and use of a bulky reducing agent would i n theory g i v e a preponderance of the a l c o h o l w i t h the c o r r e c t stereochemistry. The problem, hence, i s reduced to the p r e p a r a t i o n of the t r i c y c l i c 25 keto e s t e r _5_5. P r i o r work i n our l a b o r a t o r y i n d i c a t e d t h a t the t r i c y c l i c enone 5_6 could be converted i n t o the d e s i r e d keto e s t e r i n three steps. Thus, the photoaddition of a l l e n e to the enone 56^ gave the t e t r a c y c l i c keto o l e f i n 61 i n 39% y i e l d . Ozonolysis of t h i s m a t e r i a l i n methanol, f o l l o w e d by r e d u c t i o n of the intermediate formed w i t h dimethyl s u l f i d e gave the dione 62^. This substance, on treatment w i t h sodium methoxide i n methanol, gave the t r i c y c l i c keto e s t e r 5>5 i n good y i e l d (eq. 19). 55 26 25 P r i o r work a l s o e s t a b l i s h e d that the photoaddition of a l l e n e to enone _56 gave a second photoadduct ( i n 42% y i e l d ) which was assigned s t r u c t u r e ^ 3 . Thus, one could envisage a s i m i l a r set of transformations (as those represented i n eq. 19) to convert t h i s photoadduct to the t r i c y c l i c keto e s t e r 64_ having the keto e s t e r s i d e chain i n an a o r i e n t a t i o n . E l a b o r a t i o n of t h i s s i d e chain i n a manner s i m i l a r to that already discussed f o r stemodin 8^  (Scheme I I and eq. 18) would g i v e , i n theory,the t e t r a c y c l i c k e t a l ketone 65 which would have the a p h i d i c o l i n type of carbon sk e l e t o n (eq. 20). (20) 65 27 Thus, i t seemed that the t r i c y c l i c enone 5j5 was a v e r s a t i l e intermediate that could be used i n the sy n t h e s i s of both a p h i d i c o l i n 7_ and stemodin j5. The work described i n t h i s t h e s i s , however, proves 25 t h a t the p r e v i o u s l y assigned s t r u c t u r e j63_ to the second photoadduct i s erroneous. This w i l l be discussed i n d e t a i l elsewhere i n t h i s t h e s i s (see page 51 ). The immediate s y n t h e t i c o b j e c t i v e a t the outset of t h i s work t h e r e f o r e , was the t r i c y c l i c enone J3>5. Though t h i s compound had been 25 prepared p r e v i o u s l y i n our l a b o r a t o r y , low y i e l d s and experimental d i f f i c u l t i e s made us i n v e s t i g a t e a l t e r n a t i v e r o u t e s . Thus the problem 25 became one of c o n v e r t i n g the known ketone 57_ i n t o the d e s i r e d enone 5^5 i n as few steps as p o s s i b l e and i n reasonable y i e l d . A new s o l u t i o n to t h i s o b j e c t i v e i s described i n the next s e c t i o n of t h i s t h e s i s . 57 56 28 I I . Synthesis of 2-Cyclopenten-l-ones A l a r g e amount of research has r e c e n t l y been devoted to developing 26 s y n t h e t i c routes to s u b s t i t u t e d cyclopentenones. This i s , no doubt, l a r g e l y due to the f a c t t h a t numerous b i o l o g i c a l l y a c t i v e n a t u r a l products possess the five-membered r i n g as a major s t r u c t u r a l f e a t u r e (e.g. the 27 p r o s t a g l a n d i n s ). Our i n t e r e s t i n e f f e c t i n g the conversion of the keto k e t a l 51_ i n t o the annulated product _56 l e d us to i n v e s t i g a t e a new general method of cyclopentenone a n n u l a t i o n . In e f f e c t , the d e s i r e d o v e r a l l transformations can be represented i n general terms by eq. 21. (21) 67 6 8 69 This transformation i n v o l v e s the a l k y l a t i o n of the ketone enolate anion 66^ w i t h an "acetonyl c a t i o n e q u i v a l e n t " 67_ to g i v e , a f t e r a ppropriate m o d i f i c a t i o n of the s i d e chain i n the a l k y l a t e d m a t e r i a l , the 1,4 diketone 68, which i s subsequently converted i n t o the c y c l i c enone 69^ v i a a base-promoted i n t r a m o l e c u l a r a l d o l condensation. The d i r e c t a l k y l a t i o n w i t h haloacetones i s u s e f u l only w i t h carbon atoms c a r r y i n g very a c i d i c protons 28 due to the predominance of s i d e r e a c t i o n s . A number of reagents 29 30 (e.g. 3-halo-2-methylpropenes , 2,3-dihalopropenes , 3-bromo-l-trimethyl-31 32 33 s i l y l p r o p y n e , 3 - i o d i - 2 - t r i e t h y l s i l y l p r o p e n e , 2-nitropropene , 34 35 3-bromo-2-methoxypropene , propargyl bromide ) have been developed 29 and employed s u c c e s s f u l l y as e q u i v a l e n t s of the c a t i o n 67_ i n the a l k y l a t i o n step. However, there are c e r t a i n problems which accompany the use of these reagents. For i n s t a n c e , although a l k y l a t i o n s of enolate anions w i t h 2,3-dichloro-l-propene are q u i t e s u c c e s s f u l , the vigorous c o n d i t i o n s necessary to e f f e c t subsequent unmasking of the v i n y l 36 c h l o r i d e s i d e chain can lead to the i s o l a t i o n of furans. A l k y l a t i o n s of enolate anions w i t h propargyl bromide are t r o u b l e d by a l l e n e 31 29 formation. The use of m e t h a l l y l h a l i d e s as a l k y l a t i n g agents i s q u i t e s u c c e s s f u l , but r e q u i r e s o z o n o l y s i s f o r the subsequent conversion to the a c e t o n y l s i d e c h a i n . This of course, would be d e t r i m e n t a l to any o l e f i n i c bonds i n the s u b s t r a t e . The use of 3 - i o d o - 2 - t r i e t h y l s i l y l -32 propene as an a c e t o n y l c a t i o n synthon r e q u i r e s , during the unmasking steps, epoxidation followed by use of strong a c i d , thus l i m i t i n g i t s a p p l i c a b i l i t y . The a l k y l a t i n g agent we d e s i r e d was one t h a t , a f t e r a l k y l a t i o n , could be m o d i f i e d under m i l d c o n d i t i o n s t o the equivalent of an a c e t o n y l s i d e chain. This was important i n our s y n t h e t i c p l a n s i n c e we r e q u i r e d the keto group i n the A r i n g to be masked throughout the cyclopentenone a n n u l a t i o n sequence (eq. 22). 57 56 30 Since the k e t a l p r o t e c t i n g group i n the A r i n g i s s e n s i t i v e to s t r o n g l y 37 a c i d i c c o n d i t i o n s , i t was necessary that the unmasking of the acetonyl s i d e chain take place under m i l d l y a c i d i c , n e u t r a l , or b a s i c c o n d i t i o n s . A second p o s s i b l e problem a s s o c i a t e d w i t h the o v e r a l l conversion represented i n eq. 21 i s that the i n t r a m o l e c u l a r a l d o l condensation process (68 -*• 69) can be accompanied by an u n d e s i r a b l e base-catalyzed 38 i s o m e r i z a t i o n of the i n i t i a l l y formed product (eq. 23, j69_ to 70). (23) 68 69 70 Very r e c e n t l y , however, McMurry u t i l i z e d an i n t r a m o l e c u l a r , base-promoted a l d o l condensation of t h i s type without e f f e c t i n g i s o m e r i z a t i o n of the i n i t i a l l y formed product (eq. 9). 31 36 Recently, Heathcock and co-workers described an elegant method f o r p reparing cyclopentenones which e l i m i n a t e d the second d i f f i c u l t y mentioned above. T h e i r method i n v o l v e d a l k y l a t i o n of the enolate anion 66^ w i t h haloacetate (66 to 71), p r o t e c t i o n of the k e t o n i c carbonyl (71 to 72), and subsequent conversion o f J72 i n t o the keto phosphonate 73 (eq. 24). 32 Removal of the k e t a l p r o t e c t i n g group (73 to 74) followed by an 40 i n t r a m o l e c u l a r Horner-Emmons r e a c t i o n on the d i k e t o phosphonate 74 gave the enone _69_ (eq. 25). (25) 74 69 The i n i t i a l l y formed eyclopentenone _69 d i d not isomerize under the c o n d i t i o n s employed i n the Horner-Emmons c y c l i z a t i o n step. However, the f i r s t d i f f i c u l t y mentioned above was not e l i m i n a t e d by t h i s methodology, s i n c e the steps i n v o l v i n g formation and removal of the k e t a l p r o t e c t i n g group ( p r e p a r a t i o n of 72^ and 74) would r e q u i r e a c i d i c c o n d i t i o n s that would c l e a r l y a f f e c t an a c i d s e n s i t i v e f u n c t i o n a l group (e.g. k e t a l ) present i n the k e t o n i c s u b s t r a t e . Since the keto phosphonate _75 i s r e a d i l y a v a i l a b l e ( A l d r i c h ) , a two step conversion can be envisaged whereby the keto group of J75 i s masked as an enol ether (76), and the l a t t e r substance i s converted by a l l y l i c bromination i n t o an a c t i v e a l k y l a t i n g agent (eq. 26 , compound 77 ) . 33 Masking of the keto group of _7j5 i s e s s e n t i a l i n order to reduce the a c i d i t y of the protons on the carbon atom a to phosphorus. The unmasked a l k y l a t i n g agent 78 ( c f . w i t h compound 77) would quench the enolate anion of the ketone to be a l k y l a t e d (eq. 27). A s i l y l enol ether masking group seemed s u i t a b l e s i n c e , f o l l o w i n g the a l k y l a t i o n step, i t could be removed r e a d i l y under a v a r i e t y of m i l d r e a c t i o n c o n d i t i o n s (e.g. weak a c i d , f l u o r i d e i o n ) . However, a l l attempts to prepare a s i l y l e nol ether of 75 r e s u l t e d i n the recovery of s t a r t i n g m a t e r i a l . Since i t appeared that an a l k y l enol ether would serve j u s t as w e l l , the keto phosphonate 75 was t r e a t e d w i t h an excess of t r i e t h y l o r t h o f o r m a t e i n the presence of a c a t a l y t i c amount of 34 41 F e C l ^ ^ ^ O . Under these c o n d i t i o n s , the enol ether 79. w a s formed. The crude product was d i s s o l v e d i n dichloromethane and the s m a l l amount of remaining s t a r t i n g m a t e r i a l was conveniently removed from the mixture by the a d d i t i o n of sodium h y d r i d e , which p r e c i p i t a t e d the 42 i n s o l u b l e sodium s a l t of 75 (compound 80, eq. 28). 0 Et0\ N a °\ / A^P0(0CH3)2 — * V=CHP0(XH3)2 + V^CHPofc^ (28) 75 79 80 F i l t r a t i o n of the r e s u l t a n t mixture, followed by evaporation of the f i l t r a t e gave the enol ether 79 (bp 80°C, 0.05 t o r r ) i n 94% y i e l d . The i r spectrum of t h i s m a t e r i a l showed strong absorbances a t 1250 and 1025 cm c h a r a c t e r i s t i c of a phosphonate moiety, w h i l e a strong bond at 1605 cm ^ i n d i c a t e d a conjugated o l e f i n i c bond. The n.m.r. spectrum of 79_ was remarkably c l e a n and i n d i c a t e d that only one of the two p o s s i b l e geometric isomers (E and Z) was formed. A t r i p l e t a t 5 1.33 and a quartet a t 6 3.77 i n d i c a t e d the presence of a -OCH^CH^ group, w h i l e a t h r e e -proton doublet ( J = 2 Hz, weak c o u p l i n g to phosphorus) at 6 2.14 was assigned to the protons of the v i n y l methyl group. A doublet a t 6 3.65 was a t t r i b u t e d to the methoxy groups on phosphorus (Jg_p = H Hz) and a doublet a t 6 4.35 could be a t t r i b u t e d to the v i n y l proton ( J R _ p = 7 Hz). 43 A l l y l i c bromination of the enol ether 79_ w i t h N-bromosuccinimide 35 gave the bromo compound 81 (bp 110°C, 0.05 t o r r ) In 76% y i e l d a f t e r p u r i f i c a t i o n by column chromatography (eq. 29). I t s i r spectrum showed strong absorbance a t 1605, 1250 and 1035 cm ^ (broad) c o n s i s t e n t w i t h the presence of the phosphonate and enol ether m o i e t i e s . The n.m.r. spectrum of 81^ again i n d i c a t e d that the product was i s o m e r i c a l l y pure. No attempt was made to a s s i g n the stereochemistry of t h i s m a t e r i a l , s i n c e unmasking of the e n o l ether moiety a f t e r a l k y l a t i o n would destroy the stereochemical i n t e g r i t y of t h i s s t r u c t u r a l f e a t u r e . EtO EtO, C T U * N B S ^ = C H P 0 ( X H 3 ) 2 ^ > ^^=CHPC4XH 3) 2 (29) 79 81 In the H n.m.r. spectrum of _81, a t r i p l e t a t S 1.39 and the quartet a t 8 3.91 were assigned to the -OCH^CH^ group. A s i x - p r o t o n doublet at 6 3.76 i n d i c a t e d the methoxy groups on phosphorus (J„ = 1 1 Hz) n—r w h i l e a two-proton s i n g l e t a t 6 4.42 was c o n s i s t e n t w i t h an a l l y l i c methylene group attached to bromine. A doublet a t 6 4.57 ( J = 5 Hz) H—P was a t t r i b u t e d to the v i n y l proton. The bromo compound j51 proved to be an e x c e l l e n t a l k y l a t i n g agent. I t s general a p p l i c a b i l i t y was s t u d i e d by employing i t to a l k y l a t e the enolate anions of a number of ketones. Thus, treatment of the l i t h i u m enolate anion of cyclohexanone j$2_ (generated w i t h LDA) i n t e t r a h y d r o f u r a n 36 w i t h the bromo compound 61^ gave i n q u a n t i t a t i v e y i e l d the a l k y l a t e d product 83 (eq. 30). The i r spectrum of compound S3_ showed a sharp a b s o r p t i o n a t 1710 cm ^ c h a r a c t e r i s t i c of a s i x membered r i n g ketone. Other peaks i n the i r spectrum (1605, 1250 and 1040 cm "*") were i n d i c a t i v e of the enol ether and phosphonate m o i e t i e s . The n.m.r. spectrum showed the expected t r i p l e t and quartet (6 1.26 and 3.72, r e s p e c t i v e l y ) a r i s i n g from the - O C R ^ ^ ^ S r o u P * Th e methoxy groups on phosphorus showed up as a now f a m i l i a r doublet centered at 6 3.62 w h i l e the v i n y l proton gave r i s e to a doublet a t <S 4.36. Mass s p e c t r a l data i n d i c a t e d a molecular formula c o n s i s t e n t w i t h the assigned s t r u c t u r e . I n a s i m i l a r f a s h i o n 3-pentanone 84 was a l k y l a t e d i n q u a n t i t a t i v e y i e l d to give the product 85 (bp 140°C, 0.05 t o r r ) (eq. 31). A l l s p e c t r a l data were c o n s i s t e n t w i t h the assigned s t r u c t u r e . 37 0 1)LDA 2)81 i ' OEt 84 85 (100%) With these i n i t i a l successes, we turned our attention to structurally 44 more complicated ketones. Thus, the enolate anion of ketone £16_ , when treated with the bromo compound 81 under conditions identical with those used for cyclohexanone, gave the alkylated product j3_7 in 40% yi e l d . 45 , < However, the use of HMPA as cosolvent (added to the reaction mixture just prior to addition of the bromo compound 81) increased the yield to 78% (eq. 32). 38 S i m i l a r l y , the l i t h i u m enolate anions of ketones J$8 and 57. (see p 46 f o r p r e p a r a t i o n of t h i s substance) were reacted w i t h the bromo compound 81^ l* 1 the presence of HMPA as co s o l v e n t . The y i e l d of the pure products obtained i s as i n d i c a t e d i n pa r e n t h e s i s (eqs. 33, 34). (34) 57 90 (76%) The i r spe c t r a of compounds 87_, j89_ and j)0 showed the f a m i l i a r absorbances (at approximately 1610, 1250 and 1030 cm ^) which could be a t t r i b u t e d to the presence of the v i n y l ether and phosphonate m o i e t i e s . A d d i t i o n a l absorbances a t 1715 cm" 1 i n 87_, 1740 and 1710 cm"1 i n j89, and 1705 cm ^ i n 90 were a t t r i b u t e d to the v a r i o u s carbonyl f u n c t i o n s i n the molecules. The n.m.r. spectrum o f each of compounds J$7_, 89, and jK) showed the f a m i l i a r t r i p l e t and quartet due to the -OCH^CH^ 39 group, the doublet due to the methoxy groups on phosphorus, and a s i g n a l which could be a t t r i b u t e d to the o l e f i n i c proton resonance. In a d d i t i o n , the n.m.r. spectrum of compound J5_7 showed two s i n g l e t s at 6 0.94 and 1.01 which were assigned to the t e r t i a r y methyl groups of the k e t a l moiety w h i l e the k e t a l methylene protons gave r i s e to a s i n g l e t a t 5 3.48. A d d i t i o n a l resonances i n the n.m.r. spectrum of compound j?9_ c o n s i s t e d of a p a i r of doublet of doublets a t 6 3.11 and 3.37 which were assigned to the a l l y l i c methylene protons (AB p a i r of doublets f u r t h e r coupled to phosphorus, J . _ = 16 Hz, J . T = J T j r i = 2 Hz) and a s i n g l e t a t 6 3.74 AB A-P B—P assigned to the carbomethoxy group. I n the "^H n.m.r. spectrum of compound 9() (mp 99 - 100°C) , the three t e r t i a r y methyl groups gave r i s e to s i n g l e t s a t 6 0.93, 1.02 and 1.16. Mass s p e c t r a l data confirmed the molecular weights of s t r u c t u r e s assigned to compounds 87, 89, and 90. The work described above i n d i c a t e d t h a t , i n the a l k y l a t i o n s t e p , the bromo compound 81^ compared very favourably w i t h other a c e t o n y l c a t i o n 29-35 eq u i v a l e n t s p r e s e n t l y a v a i l a b l e . I t was now necessary to f i n d (mild) c o n d i t i o n s which would hydrolyze the enol ether f u n c t i o n a l i t y i n the s i d e chain of compounds 83_, 85, 81_, 89, and 90. The a l k y l a t e d keto k e t a l s 87 and j?0 were p a r t i c u l a r l y important examples of the present methodology s i n c e the enol ether moiety would have to be hydrolyzed under c o n d i t i o n s which would not a f f e c t the k e t a l f u n c t i o n a l groups. I t was found that treatment of an acetone s o l u t i o n of these compounds w i t h a few drops of 0.5 N h y d r o c h l o r i c a c i d f o r a short p e r i o d of time at room temperature r e s u l t e d i n complete h y d r o l y s i s of the e n o l ether f u n c t i o n a l i t y without any e f f e c t on the k e t a l groups. The h y d r o l y s i s products 91 and 92 were obtained i n 92% and 96% y i e l d , r e s p e c t i v e l y (eqs. 35, 36). 40 0 u 87 (35) 91 (92%; P0(0CH3)2 90 92 (96%) In a s i m i l a r f a s h i o n , h y d r o l y s i s of the enol ether m o i e t i e s i n compounds 83 and 85_ proceeded smoothly to give the di k e t o phosphonates 93 and 94 i n q u a n t i t a t i v e y i e l d s (eqs.37, 38). | ^ ^ Y ^ P 0 ( 0 ^ ) 2 2£ ^V"Y^P°(°^)2 (37) 83 93 (100%) P0(0CH3)2 H„0 OEt P0(XH3) 3'2 (38) 85 94 (100%) 41 The i r s p e c t r a of each of the d i k e t o phosphonates (91 - 94) showed no a b s o r p t i o n at 1605 cm \ c l e a r l y showing t h a t the enol ether moiety i n each of the corresponding s t a r t i n g m a t e r i a l s had been hydrolyzed. However, each of these s p e c t r a showed absorptions a t approx. 1710, 1250 and 1030 cm \ which were assigned to the carbonyl and phosphonate m o i e t i e s . The ^H n.m.r. spectra of these compounds showed the expected disappearance of the t r i p l e t and quartet due to the - O C H 2 C H 3 group and the absence of a v i n y l proton resonance. An unexpected d i f f i c u l t y arose d u r i n g the h y d r o l y s i s of the a l k y l a t e d m a t e r i a l 89. Thus, r o u t i n e treatment of an acetone s o l u t i o n of 89 w i t h h y d r o c h l o r i c a c i d gave a product which appeared to be homogenous (one spot by a n a l y t i c a l t h i n l a y e r chromatography). The i r spectrum of t h i s m a t e r i a l , however, showed a weak abso r p t i o n at 1605 cm \ i n d i c a t i v e of an o l e f i n i c bond. Assuming that t h i s was due to a s m a l l amount of unreacted s t a r t i n g m a t e r i a l , the crude mixture was r e d i s s o l v e d i n acetone and t r e a t e d w i t h more h y d r o c h l o r i c a c i d . A f t e r a second work-up, t h i n l a y e r chromatography of the product s t i l l i n d i c a t e d one component, but g a s - l i q u i d chromatography i n d i c a t e d a second product. Furthermore, the i r spectrum of the crude m a t e r i a l now showed a f a i r l y i n tense o l e f i n i c a b s o r p t i o n . The mass spectrum of t h i s crude m a t e r i a l showed no peak due to the s t a r t i n g m a t e r i a l (m/e 348, enol ether 8 9 ) , but d i d e x h i b i t a strong peak at m/e 330. This evidence seemed to i n d i c a t e that the f i r s t formed h y d r o l y s i s product 9_5 had undergone a t l e a s t p a r t i a l i n t r a m o l e c u l a r a l d o l condensation to g i v e the b i c y c l i c compound J36_ (eq. 39) . This compound was not f u l l y c h a r a c t e r i z e d due to experimental d i f f i c u l t i e s encountered i n i t s p u r i f i c a t i o n . 42 0 ?°2Me P0(0CH3)2 — 0 ?°2Me P0(XH3)2 C02Me (39) 89 95 96 A f t e r c o n s i d e r a b l e experimentation, i t was found t h a t the d e s i r e d r e a c t i o n (89 95) could be accomplished e f f i c i e n t l y by t r e a t i n g JJ9 w i t h 0.5 N h y d r o c h l o r i c a c i d i n acetone ( r . t . , 35 min.). The presence of a s m a l l amount of e i t h e r the s t a r t i n g m a t e r i a l or compound 9_6 seemed to be i n e v i t a b l e and hence j>5 was not p u r i f i e d f u r t h e r but was used d i r e c t l y i n the c y c l i z a t i o n step. This d i f f i c u l t y was not experienced w i t h any of the other cases s t u d i e d . Having found a m i l d and e f f i c i e n t method of unmasking the a c e t o n y l c a t i o n e q u i v a l e n t , the i n t r a m o l e c u l a r Horner-Emmons r e a c t i o n s were accomplished r o u t i n e l y by treatment of the a p p r o p r i a t e d i k e t o phosphonate 39 46 w i t h sodium hydride i n dimethoxyethane . Thus the d i k e t o phosphonates 93 and j)4_ were smoothly c y c l i z e d to g i v e the enones 97_ and j)8_ r e s -p e c t i v e l y (eq. 40, 41). 43 (40) (41) 94 98 (82%) The s p e c t r a l data derived from compounds 97"'*' (bp 45°C, 0.02 t o r r ) 47 and j)8 (bp 100°C, 15 t o r r ) were i n agreement w i t h those obtained from the chemical l i t e r a t u r e . I n a s i m i l a r f a s h i o n compounds _91, j)2_, and j)5 39 were c y c l i z e d , and i n accord w i t h previous observations , no i s o m e r i z a t i o n of the i n i t i a l l y formed cyclopentenone was observed (Scheme I I I ) . The i r spectrum of the enone 99_ (mp 73 - 74 °C) showed a band a t 1700 cm \ which was assigned to the a,8-unsaturated c a r b o n y l group, w h i l e a band a t 1620 cm was a t t r i b u t e d to the o l e f i n i c bond. The n.m.r. spectrum of j)9_ showed two s i n g l e t s a t 6 1.00 and 1.02 a r i s i n g from the t e r t i a r y methyl groups and a broad s i n g l e t centered a t 6 3.56 a t t r i b u t e d to the k e t a l methylene protons. A s i n g l e t a t 6 5.91 was assigned to the o l e f i n i c proton. The i r spectrum of enone 5_6 (mp 116 - 117 °C) had a band at 45 1680 cm ^ due to the a,8-unsaturated carbonyl group and one a t 1610 cm ^ a r i s i n g from the o l e f i n i c bond. I t s *H n.m.r. spectrum e x h i b i t e d three s i n g l e t s a t 6 0.90, 0.95 and 1.09 which were assigned to the three t e r t i a r y methyl groups. The two protons on C-13 gave r i s e to two d i s t i n c t s i g n a l s , each a doublet of doublets, centered a t 6 1.92 and 2.54. Thus, these two protons a r e m a g n e t i c a l l y non-equivalent, are geminally coupled ( J = 18 Hz) and are f u r t h e r coupled to the bridgehead proton ( J = 2 Hz, 6 Hz, r e s p e c t i v e l y ) . The broad m u l t i p l e t s a t 6 2.94, 3.3 - 3.64 and 5.76, were assigned to the bridgehead proton (C-8), the k e t a l methylene protons and the o l e f i n i c proton, r e s p e c t i v e l y . The s p e c t r a l data f o r t h i s compound 25 were i n accord w i t h those p r e v i o u s l y recorded i n our l a b o r a t o r y In a s i m i l a r f a s h i o n , the i r spectrum of enone 100 (bp 110°C, 0.05 t o r r ) showed the c h a r a c t e r i s t i c carbonyl absorptions a t 1730 and 1710 cm ^ r e s u l t i n g from the e s t e r and a,B-unsaturated ketpne m o i e t i e s , w h i l e the strong band at 1625 cm ^ was a t t r i b u t e d to the o l e f i n i c bond. The '''H n.m.r. spectrum showed a doublet of doublets a t 6 2.23 and 2.63 ( J = 18 Hz) which were assigned to the m a g n e t i c a l l y non-equivalent methylene protons adjacent to the keto group, w h i l e a doublet a t 6 5.93 ( J = 2 Hz) was assigned to the o l e f i n i c proton. Thus, the f i r s t o b j e c t i v e of t h i s work was accomplished i n that an e f f i c i e n t route t o the enone 5_6_ was e s t a b l i s h e d . The g e n e r a l i t y of t h i s methodology was a l s o i n v e s t i g a t e d and was found to compare q u i t e favourably w i t h other cyclopentenone a n n u l a t i n g procedures p r e s e n t l y a v a i l a b l e . 46 I I I . The Synthesis of the T r i c y c l i c E s t e r 55 Having l a i d the i n i t i a l ground work, we were ready to proceed towards our twin goals, a p h i d i c o l i n ]_ and stemodin jS. The t r i c y c l i c enone .56 had been e f f i c i e n t l y prepared from the k e t a l ketone 57_ by the cyclopentenone a n n u l a t i o n sequence already discussed (eq. 42). (42) 57 56 The k e t a l ketone 57_ was prepared i n a s t r a i g h t f o r w a r d manner from 48 the w e l l known Wieland-Miescher ketone 101 . Thus, r e d u c t i o n of t h i s 49 50 m a t e r i a l w i t h sodium borohydride ' gave the compound 102, which was converted i n t o i t s t e t r a h y d r o p y r a n y l ether 103**^ " u s i n g e s t a b l i s h e d procedures (eq. 43). The s p e c t r a l and p h y s i c a l data corresponding to compounds 102 and 103 were f u l l y c o n s i s t e n t w i t h those reported i n the , .„ _ 49,50 l i t e r a t u r e NaBH, (43) 101 102 103 47 52 Stork and D a r l i n g have shown that i n the metal-ammonia r e d u c t i o n of enones i n which the B-carbon i s l o c a t e d a t the f u s i o n of two s i x -membered r i n g s , the product obtained i s u s u a l l y the more s t a b l e of the two isomers ( c i s or trans) having the newly introduced 8-hydrogen a x i a l 53 to the ketone r i n g . Thus, lithium-ammonia r e d u c t i o n of enone 103, i n 54 the presence of anhydrous ether as cosolvent and t e r t - b u t y l a l c o h o l , as proton source, gave the expected b i c y c l i c ketone 104 i n 80% y i e l d (eq. 44) The physical"*^ and spectral"*** p r o p e r t i e s of t h i s compound were i n accord w i t h p u b l i s h e d v a l u e s . L i , NH, t-BuOH 103 (44) The tet r a h y d r o p y r a n y l p r o t e c t i n g group i n compound 104 was removed by treatment of t h i s substance w i t h p_-toluenesulfonic a c i d i n methanol. The crude k e t o l 105 thus obtained was d i s s o l v e d i n benzene c o n t a i n i n g 2,2-dimethyl-l,3-propanediol and a s m a l l amount of j>-toluenesulfonic a c i d . This mixture was r e f l u x e d under a Dean-Stark water trap to remove the water produced i n the r e a c t i o n . The crude k e t a l a l c o h o l 106 was o x i d i z e d t o the d e s i r e d k e t a l ketone J5_7 u s i n g p y r i d i n i u m chlorochromate^^ i n the presence of a small amount of sodium acetate as a b u f f e r . The c r y s t a l l i n e k e t a l ketone 5]_ (mp 68 - 70°C) was obtained i n 80% o v e r a l l 48 y i e l d from the b i c y c l i c ketone 104 (eq. 4 5 ) . 57 The i r spectrum of the k e t a l ketone 57_ showed a strong a b s o r p t i o n at 1705 cm \ c o n s i s t e n t w i t h the presence of a six-membered r i n g ketone, w h i l e the n.m.r. e x h i b i t e d three s i n g l e t s a t <5 0.89, 1.02 and 1.12 a r i s i n g from the three t e r t i a r y methyl groups i n the molecule. A broad m u l t i p l e t between 6 3.30 and 3.70 was assigned to the k e t a l methylene protons. The p h y s i c a l and s p e c t r a l p r o p e r t i e s of t h i s compound were 25 i d e n t i c a l w i t h those p r e v i o u s l y recorded i n our l a b o r a t o r y . The k e t a l ketone 57_ was next converted to the t r i c y c l i c enone J56 by the cyclopentenone annulation sequence, as described p r e v i o u s l y . The photoaddition of a l l e n e to the enone j>>5 had been s t u d i e d 25 p r e v i o u s l y i n our l a b o r a t o r y . A r e p e t i t i o n of t h i s r e a c t i o n gave 25 r e s u l t s very s i m i l a r to those obtained p r e v i o u s l y . Thus, i r r a d i a t i o n o f a c o l d (-78°C) s o l u t i o n of the enone j><5 and a l l e n e i n tetrahydrofuran f o r 4.5 h a f f o r d e d two main photoadducts (A and B) . This product mixture was separated by column chromatography on s i l i c a g e l , e l u t i o n being done by a 10:5:1 mixture of cyclohexane, hexane and e t h y l acetate. The f i r s t 25 photoadduct e l u t e d from the column (A, 39% y i e l d ) has been shown to possess s t r u c t u r e 61 w h i l e the second photoadduct (B, 42% y i e l d ) had 25 been assigned s t r u c t u r e 63. • H 56 63 (46) 61 (A) The p h y s i c a l and s p e c t r a l p r o p e r t i e s of these two photoadducts 25 were i n accord w i t h those p r e v i o u s l y reported i n our l a b o r a t o r y . Thus, the I r spectrum of the c r y s t a l l i n e photoadduct J51 (A, mp 134 -25 -1 135°C, l i t . mp 134 - 135°C) showed a strong a b s o r p t i o n a t 1725 cm c o n s i s t e n t w i t h the presence of a five-membered r i n g ketone. A weaker band at 1670 cm ^ was assigned to the s t r e t c h i n g v i b r a t i o n of the o l e f i n i c bond e x o c y c l i c to the four-membered r i n g . The n.m.r. spectrum 50 of 61 e x h i b i t e d three s i n g l e t s at 6 0.88, 0.95 and 0.97 a r i s i n g from the three t e r t i a r y methyl groups. In a d d i t i o n , two m u l t i p l e t s a t 6 4.82 and 4.97 were a t t r i b u t e d to the two o l e f i n i c protons. S i m i l a r l y , the i r spectrum of the photoadduct B (mp 131 - 134°C, 25 -1 l i t . mp 132 — 134°C) e x h i b i t e d a strong band a t 1725 cm and a l e s s i ntense band at 1670 cm ^ c o n s i s t e n t w i t h the presence of a five-membered r i n g ketone and an o l e f i n i c bond e x o c y c l i c to a four-membered r i n g . The *H n.m.r. spectrum of B showed three s i n g l e t s at 5 0.90, 0.95 and 1.00 due to the three t e r t i a r y methyl groups and two m u l t i p l e t s a t 6 4.80 and 4.94 a r i s i n g from the two o l e f i n i c protons. The s t r u c t u r e of the photoadduct 61 (A) was unambiguously proved 58 by an x-ray c r y s t a l l o g r a p h i c a n a l y s i s . On the other hand repeated r e c r y s t a l l i z a t i o n of the photoadduct B f a i l e d to provide c r y s t a l s which were s u i t a b l e f o r a n a l y s i s by x-ray techniques. Nevertheless, on the b a s i s of s p e c t r a l data and l i t e r a t u r e precedent regarding the photochemical c y c l o a d d i t i o n r e a c t i o n s of enones to a l k e n e s " ^ ' ^ the s t r u c t u r e of t h i s 25 substance was ( q u i t e reasonably) assigned as shown i n 63. However, during the course of t h i s work, i t became apparent that t h i s p r e v i o u s l y 25 assigned s t r u c t u r e was i n c o r r e c t . A cold (-78°C) methanol s o l u t i o n of the photoadduct 61 (A) was subjected to a stream of ozone u n t i l the s o l u t i o n remained b l u e . The r e s u l t i n g s o l u t i o n was f l u s h e d w i t h argon u n t i l the blue c o l o r had disappeared and dimethyl s u l f i d e was added to reduce the intermediate h y d r o p e r o x i d e ^ to the dione 107. The s o l v e n t s were removed under reduced pressure and the r e s i d u a l o i l was kept under reduced pressure (vacuum pump) f o r 1 h i n order to remove l a s t t races of s o l v e n t . The 51 o i l was then d i s s o l v e d i n dry methanol and the r e s u l t a n t s o l u t i o n t r e a t e d w i t h a s o l u t i o n of sodium methoxide i n methanol. In t h i s way, the dione 107 was converted i n t o the keto e s t e r J>5 (eq. 47), which was obtained i n 88% y i e l d (from 61, A). In a s i m i l a r f a s h i o n , conversion of the photoadduct B i n t o the corresponding keto e s t e r (expected to be 64, isomeric w i t h 55) could be envisaged (eq. 48). S u r p r i s i n g l y , however,treatment of the photoadduct (48) 64 B to a sequence of r e a c t i o n s ( 0 3 > CH30H; Me 2S; CH^ONa, CH^OH) i d e n t i c a l w i t h that employed f o r the photoadduct j>l (A) af f o r d e d not the new 52 (expected) keto e s t e r 64, but, Instead, gave the same keto e s t e r 55 (70% y i e l d ) as had been derived from frl (A)! The c r y s t a l l i n e keto e s t e r 55 (mp 139 - 140°C) obtained from the photoadduct j61 (A) showed a broad band between 1720 and 1740 cm ^ i n i t s i r spectrum, c o n s i s t e n t w i t h the presence of both an e s t e r moiety and a five-membered r i n g ketone. The "^H n.m.r. spectrum of t h i s m a t e r i a l showed three s i n g l e t s a t 6 0.93, 1.01 and 1.04 which were a t t r i b u t e d to the three t e r t i a r y methyl groups. A four-proton m u l t i p l e t centered at 6 3.52 was assigned to the k e t a l methylene protons w h i l e a three proton s i n g l e t a t 6 3.66 was c o n s i s t e n t w i t h a carbomethoxy moiety. Mass s p e c t r a l data i n d i c a t e d a molecular formula of C^^^^s' The keto e s t e r obtained from the photoadduct B was i d e n t i c a l ( p h y s i c a l and s p e c t r a l p r o p e r t i e s ) w i t h the keto e s t e r 55_. Mixed m e l t i n g p o i n t determinations showed no depression, i n d i c a t i n g t h a t they were one and the same compound. This a c q u i s i t i o n of the same keto e s t e r from both photoadducts would be Impossible i f the s t r u c t u r e (63) i n i t i a l l y assigned to the photoadduct B was c o r r e c t . Hence, the assignment of s t r u c t u r e j>3_ to the photoadduct B must be i n e r r o r . A minor product (20%) obtained from s u b j e c t i o n of the photoadduct B 55 53 B to the ozonolysis-sodium methoxide r e a c t i o n sequence (eq. 49) was the c r y s t a l l i n e keto a c i d 108 (mp 214 - 215°C). I t s i r spectrum showed a broad band between 2600 and 3300 cm ^ c h a r a c t e r i s t i c of the hydroxyl group of a c a r b o x y l i c a c i d . In a d d i t i o n , two sharp bands a t 1735 and 1700 cm were assigned to the five-membered r i n g ketone and the c a r b o x y l carbonyl group r e s p e c t i v e l y . The n.m.r. spectrum of 108 showed three s i n g l e t s a t 6 0.93, 1.0 and 1.07 assigned to the t h r e e t e r t i a r y methyl groups. A broad doublet a t 6 3.5 was a t t r i b u t e d to the k e t a l methylene protons. I t s s t r u c t u r e was unambiguously proved by i t s conversion i n 90% y i e l d to the keto e s t e r j>5_ on treatment w i t h diazomethane (eq. 50). (50) 108 55 54 The unusual r e s u l t s described above l e d us to the c o n c l u s i o n that the s t r u c t u r e of the photoadduct B (obtained as i n d i c a t e d i n eq. 46) 25 was not j>3 as o r i g i n a l l y b e l i e v e d , but was, i n f a c t , the h i g h l y s t r a i n e d t e t r a c y c l i c keto o l e f i n 109*. The l a t t e r s t r u c t u r e would provide the observed s p e c t r a l data and,'importantly, would account f o r the chemical data. Thus, o z o n o l y s i s of 109 ( B ) , followed by treatment of the r e s u l t i n g dione 110 w i t h sodium methoxide would produce the keto e s t e r 55 (eq. 51). The minor product of t h i s o z o n o l y s i s r e a c t i o n , the keto a c i d 108 might have a r i s e n by n u c l e o p h i l i c a t t a c k of water on the h i g h l y r e a c t i v e dione 110. A l t e r n a t i v e l y , i t might have been formed during the sodium methoxide treatment step by n u c l e o p h i l i c a t t a c k of hydroxide i o n (formed by h y d r o l y s i s of a s m a l l amount of sodium methoxide) on the dione 110 (eq. 52). * The p r e p a r a t i o n of a d e r i v a t i v e of 109 (which would be s u i t a b l e f o r x-ray a n a l y s i s ) i s planned, as a f u t u r e p r o j e c t i n t h i s l a b o r a t o r y . 55 I t i s known that trans adducts formed by the p h o t o a d d i t i o n of alkenes to cyclohexenones can be converted i n t o the corresponding c i s 59 adducts by treatment w i t h base . However, treatment of the photoadduct 109 (B) w i t h sodium methoxide i n methanol f o r 48 h a t room temperature r e s u l t e d only i n recovery of s t a r t i n g m a t e r i a l . A search of the chemical l i t e r a t u r e r e v e a l s that trans photo-c y c l o a d d i t i o n has f r e q u e n t l y been observed between alkenes and cyclohexenones"*^'^'^ . In the case of cyclopentenones however, only 59 c i s a d d i t i o n has been reported . Furthermore, a l l e n e p h o t o c y c l o a d d i t i o n s whether to cyclohexenones or cyclopentenones, have been reported to be only c i s ^ ' ^ . Hence, i f the s t r u c t u r e (109) assigned to photoadduct B i s proven c o r r e c t by the proposed x-ray a n a l y s i s , t h i s would c o n s t i t u t e the f i r s t reported trans a d d i t i o n of a l l e n e to an enone and the f i r s t reported trans a d d i t i o n of a cyclopentenone to an o l e f i n i c - t y p e bond. 63 Wiesner e t . a l . have proposed an e m p i r i c a l r u l e which allows the p r e d i c t i o n of the c o n f i g u r a t i o n of photoadducts between a l l e n e (and 56 other o l e f i n s ) and a,8-unsaturated ketones. They p o s t u l a t e that the c o n f i g u r a t i o n of the photoadduct obtained i s governed by a species ( e x c i t e d s t a t e of the enone system) which i s t r i g o n a l i n the a- and pyramidal i n the B - p o s i t i o n . This species was assumed to s e l e c t the more s t a b l e of the two p o s s i b l e epimeric c o n f i g u r a t i o n s . Thus, a l l e n e p h o t o c y c l o a d d i t i o n to the enone 111 i s reported to g i v e i n 95% y i e l d the adduct 113. S i m i l a r l y , enones 114 and 117 a f f o r d the adducts 116 and 119 r e s p e c t i v e l y (Scheme I V ) . The most s t a b l e c o n f i g u r a t i o n s of 117 118 119 SCHEME IV 57 the e x c i t e d s t a t e s of the three enones 111, 114 and 117, are rep-63b resented as 112, 115 and 118 r e s p e c t i v e l y . The enone 114, which i s the c l o s e s t approximation to our system gives the cis-ad d u c t 116 w i t h a trans-fused 6-5 r i n g j u n c t i o n . On the other hand, photoadduct A (61), obtained i n our system i s a cis - a d d u c t w i t h a c i s - f u s e d 6-5 r i n g j u n c t i o n , and does not appear to be the adduct p r e d i c t e d by the r u l e . Furthermo r e , the occurrence of photoadduct B ( i f the assigned s t r u c t u r e 109 i s c o r r e c t ) cannot be expl a i n e d by Wiesner's r u l e . The g e n e r a l i t y of t h i s r u l e i s yet to be e s t a b l i s h e d and no t h e o r e t i c a l s i g n i f i c a n c e 64 has, as y e t , been a s c r i b e d t o these Ideas. Loufty and de Mayo have c r i t i c i z e d t h i s r u l e and have suggested that the c o n t r o l of stereochemistry i n p h o t o c y c l o a d d i t i o n might depend on the s t e r i c hindrance of the approach of the o l e f i n to the e x c i t e d ketone. The proposed s t r u c t u r e 109 of the photoadduct B possesses a t r a n s -fused b i c y c l o [3.2.0] heptane r i n g system. While photoadditions to y i e l d such tra n s - f u s e d r i n g systems have not been reported, the e x i s t e n c e of such systems has been w e l l documented i n the l i t e r a t u r e ^ " * . These trans compounds are no doubt h i g h l y s t r a i n e d but t h e i r formation under the co n d i t i o n s employed i n the photoaddition i s c e r t a i n l y f e a s i b l e . Since both photoadducts j>l and 109 (A and B r e s p e c t i v e l y ) were converted i n t o the same keto e s t e r 55^, and s i n c e 55_ i s c l e a r l y a precursor only f o r stemodin jJ and not f o r a p h i d i c o l i n ]_ (Scheme V), another route to the l a t t e r n a t u r a l product w i l l have to be developed. This route c o u l d , of course, s t i l l make use of the enone ^6 as an Important intermediate. On the p l u s s i d e , however, i t was no longer necessary to e f f e c t a tedious and time consuming s e p a r a t i o n of the mixture of photoadducts j51 and 109 58 s i n c e t h i s mixture c o u l d be used d i r e c t l y i n the o z o n o l y s i s and subsequent r i n g opening (NaOMe) step. 56 61 109 1) 0 3, Me OH 2) DMS 3) NaOMe, Me OH H O ' ' " C H 2 0 H C H 2 0 H — H 8 R = OH 9 R = 0 SCHEME V 59 IV. The Synthesis of the T e t r a c y c l i c Dione 132. The next phase of t h i s work i n v o l v e d the e l a b o r a t i o n of the keto e s t e r J55 i n t o a t e t r a c y c l i c compound such as 53_ (eq. 53) . The s y n t h e t i c s t r a t e g y already discussed (page 21 ) r e q u i r e d the r e d u c t i o n of the five-membered r i n g ketone i n the keto e s t e r 5 5 to be s t e r e o s e l e c t i v e so as to produce the secondary a l c o h o l w i t h a-stereochemistry (eq. 5 4 ) . 60 Thus, r e d u c t i o n of the keto e s t e r 55 w i t h sodium borohydride i n methanol a t room temperature gave a 1:1 mixture of the d e s i r e d e s t e r a l c o h o l 60 and the lactone 120 (eq. 55). These compounds were e a s i l y separated by column chromatography on s i l i c a g e l , the eluent being a 4:1 mixture of methylene c h l o r i d e and ether. The e s t e r a l c o h o l 60, a very v i s c o u s c o l o r l e s s o i l , was obtained i n 50% y i e l d a f t e r chromatography. I t s i r spectrum showed a broad band between 3300 and 3500 cm ^ c h a r a c t e r i s t i c of the OH group of an a l c o h o l . A sharp a b s o r p t i o n a t 1725 cm ^ was assigned to the carbonyl group of the e s t e r . The ^H n.m.r. spectrum showed a three-proton s i n g l e t a t 6 0.95 and a s i x - p r o t o n s i n g l e t a t 5 0.99, s i g n a l s which could r e a d i l y be assigned to the three t e r t i a r y methyl groups. A broad m u l t i p l e t a t 6 3.58 was a t t r i b u t e d to the k e t a l methylene protons, w h i l e a sharp s i n g l e t a t 6 3.65 was assigned to the methoxy group of the e s t e r . A broad s i n g l e - p r o t o n m u l t i p l e t centered a t <5 4.54 was assigned to the proton a t C-12. 61 The c r y s t a l l i n e l a c t o n e 120 (mp 194°C), obtained i n 49% y i e l d , d i s p l a y e d bands a t 1730, 1115 and 1100 cm ^ i n i t s i r spectrum, a l l of which were c o n s i s t e n t w i t h a six-membered r i n g l a c t o n e . I t s "^H n.m.r. showed the three f a m i l i a r three-proton s i n g l e t s a t 6 0.88, 0.92 and 1.0 due to the t e r t i a r y methyl groups and a four-proton m u l t i p l e t at 6 3.5 a r i s i n g from the k e t a l methylene protons. A one-proton m u l t i p l e t a t 6 4.78 was assigned to the proton a t C-12. The n o n - s t e r e o s e l e c t i v i t y of the sodium borohydride r e d u c t i o n l e d us to examine other reducing agents. However, use of l i t h i u m aluminum hydride a l s o f a i l e d to provide any s t e r e o s e l e c t i v i t y , s i n c e r e d u c t i o n ( e t h e r , a t room temperature, overnight) w i t h t h i s reagent provided an approximately 1:1 mixture of the epimeric d i o l s 121 r e s u l t i n g from the simultaneous r e d u c t i o n of the e s t e r and ketone f u n c t i o n a l i t i e s (eq. 56). OH (56) 55 121 Although these isomers were not separated, the p r o p o r t i o n of each could be estimated on the b a s i s of an *H n.m.r. spectrum of the mixture 121, s i n c e each pure epimer was a v a i l a b l e (see pages 62, 74). 62 A c a r e f u l examination of a model of 55 i n d i c a t e d that the B-face of the molecule was more open to a t t a c k than the a-face. Therefore, a hindered reducing agent might be expected to approach the molecule p r e f e r e n t i a l l y from the B s i d e , thus g i v i n g the d e s i r e d e s t e r a l c o h o l 60. Treatment of a c o l d (-78°C) tet r a h y d r o f u r a n s o l u t i o n of 55 w i t h 66 TM l i t h i u m t r i - s e c - b u t y l b o r o h y d r i d e ( a v a i l a b l e as L - S e l e c t r i d e from A l d r i c h ) gave, a f t e r work-up, a 74% y i e l d of the e s t e r a l c o h o l 60_. A small amount of the l a c t o n e 120 (23%) was a l s o i s o l a t e d (eq. 57). 55 60 120 Having obtained the e s t e r a l c o h o l j>0 i n good y i e l d , the s y n t h e t i c p l a n r e q u i r e d i t s conversion i n t o the d i o l J 5 9 . This was e a s i l y achieved by treatment of an ether s o l u t i o n of ^0 w i t h l i t h i u m aluminum hydride at room temperature f o r 30 min (eq. 58). 63 (58) 60 59 The d i o l _5_9 was obtained i n q u a n t i t a t i v e y i e l d as a c o l o r l e s s o i l which could not be induced to c r y s t a l l i z e from a v a r i e t y of s o l v e n t s . I t s i r spectrum showed a broad band between 3200 and 3600 cm ^ c h a r a c t e r i s t i c of the OH group of an a l c o h o l . I t s ^H n.m.r. spectrum d i s p l a y e d a three-proton s i n g l e t a t 6 0.94 and a s i x - p r o t o n s i n g l e t a t 6 0.96 a r i s i n g from the three t e r t i a r y methyl groups. A broad four-proton m u l t i p l e t a t 6 3.52 was assigned to the k e t a l methylene protons, w h i l e a two-proton t r i p l e t a t 6 3.7 was a t t r i b u t e d to the methylene protons of the primary a l c o h o l moiety. A s i n g l e - p r o t o n m u l t i p l e t at 6 4.54 was assigned to the proton a t C-12. Treatment of a p y r i d i n e s o l u t i o n of d i o l 59_ w i t h methanesulfonyl c h l o r i d e gave the dimesylate j>4 i n 80% y i e l d a f t e r work-up and column chromatography (eq. 59). 64 (59) The dimesylate 54, which was obtained as a l i g h t y e l l o w o i l , d i s p l a y e d c h a r a c t e r i s t i c s u l f o n a t e e s t e r a b s o r p t i o n bands at 1360, 1340, and 1170 cm ^ i n i t s i r spectrum. Three s i n g l e t s i n i t s n.m.r. spectrum, a t 6 0.93, 0.94 and 1.0, were assigned to the three f a m i l i a r t e r t i a r y methyl groups, w h i l e two a d d i t i o n a l s i n g l e t s a t 6 3.01 and 3.04 were a t t r i b u t e d to the methyl groups of the methanesulfonyl m o i e t i e s . A four-proton m u l t i p l e t a t 6 3.5 was e a s i l y assigned to the k e t a l methylene protons. The e f f e c t of e s t e r i f i c a t i o n of the d i o l j>9_ was a downfield s h i f t o f the resonances of the protons on the carbon atoms to the primary and secondary a l c o h o l s . Thus, a two-proton t r i p l e t a t 6 4.3 was assigned to the methylene protons a t C-15 w h i l e a s i n g l e - p r o t o n m u l t i p l e t a t 6 5.28 was assigned to the proton a t C-12. With the d e s i r e d dimesylate 54 i n hand, a choice had to be made as to the a c y l anion equivalent that would be the most s u i t a b l e f o r b u i l d i n g the D-ring. A search of the l i t e r a t u r e revealed the 21 22 67 a v a i l a b i l i t y of a l a r g e number of such a c y l anion e q u i v a l e n t s ' ' and one that seemed to be q u i t e a t t r a c t i v e was that d e r i v e d from methyl 65 21 methylthiomethyl s u l f o x i d e . Thus, treatment of the dimesylate _54_ w i t h an excess of the anion of methyl methylthiomethyl s u l f o x i d e might be expected t o give an adduct 122, which, on h y d r o l y s i s , would y i e l d the d e s i r e d t e t r a c y c l i c keto fcetal _53 Ceq. 60) . 54 122 53 The anion of methyl methylthiomethyl s u l f o x i d e was prepared i n the 21 p r e s c r i b e d manner u s i n g n - b u t y l l i t h i u m as the base. This anion (2.0 - 2.5 mol-equiv.) was t r a n s f e r r e d by means of a double-tipped needle to a c o l d (-78°C) tetr a h y d r o f u r a n s o l u t i o n of the dimesylate j>4_. The r e a c t i o n mixture was s t i r r e d f o r ^ h a t 0°C and f o r 12 h a t room temperature. Methylene c h l o r i d e was added to t h i s s o l u t i o n and the p r e c i p i t a t e d s a l t s were separated by f i l t r a t i o n through a short plug of F l o r i s i l . Removal o f the s o l v e n t s (reduced pressure) from the f i l t r a t e gave a crude m a t e r i a l which was p u r i f i e d by column chromatography on s i l i c a g e l ( e l u t i o n w i t h an 8:1 hexanes-ethyl a c e t a t e m i x t u r e ) . The main compound obtained from the column was the s t a r t i n g m a t e r i a l the dimesylate 54. Although a number o f minor by-products were a l s o i s o l a t e d , none had the s p e c t r a l c h a r a c t e r i s t i c s expected f o r adduct 122. 66 A number of changes i n t h i s procedure, such as anion generation w i t h d i f f e r e n t bases (e.g. l i t h i u m d i i s o p r o p y l a m i d e , potassium hydride) and use of a more p o l a r s o l v e n t ( t e t r a h y d r o f u r a n - hexamethylphosphoramide i n the place of t e t r a h y d r o f u r a n ) , gave v a r y i n g amounts of by-products and s t a r t i n g m a t e r i a l . However, the d e s i r e d adduct 122 remained e l u s i v e , s i n c e c a r e f u l s p e c t r o s c o p i c examination of the v a r i o u s product mixtures provided l i t t l e or no evidence f o r the presence of t h i s m a t e r i a l . In t h i s connection, i t should be pointed out that the o r i g i n a l workers had used 21 only primary h a l i d e s and t o s y l a t e s i n t h e i r c y c l i c ketone s y n t h e s i s w i t h methyl methylthiomethy1 s u l f o x i d e (eq. 61). ( C H 2 ) n ^—y XSOCH3 ( C ^ C=o (61) X = Br, OTs On the b a s i s of an examination of a molecular model of the dimesylate 54_ i t seemed reasonable to propose that the f a i l u r e of the r a t h e r bulky anion of methyl methylthiomethyl s u l f o x i d e to c l e a n l y d i s p l a c e the mesylate groups In t h i s molecule (to produce 122) was l a r g e l y due to s t e r i c f a c t o r s . Therefore, i t became apparent that the displacement of the mesylate groups w i t h a s t e r i c a l l y much l e s s demanding n u c l e o p h i l e (e.g. cyanide ion) should be i n v e s t i g a t e d . A hexamethylphosphoramide s o l u t i o n of the dimesylate 54_ was t r e a t e d w i t h an excess of sodium cyanide ( s a t u r a t e d s o l u t i o n ) f o r 3 h 67 at room temperature and 48 h a t 60°C. The r e a c t i o n mixture was cooled, ether and water were added and the aqueous l a y e r was discarded. The ether l a y e r was washed twice w i t h s a t u r a t e d copper s u l f a t e (to remove hexamethylphosphoramide), d r i e d and evaporated to g i v e a y e l l o w o i l which was chromatographed on s i l i c a g e l . E l u t i o n of the column w i t h a 3:1 mixture of hexanes and e t h y l acetate gave i n 60% y i e l d , the d i n i t r i l e 123 (mp 159 - 161°C) as a white c r y s t a l l i n e s o l i d (eq. 62). The i r spectrum of the d i n i t r i l e 123 showed two sharp absorbances at 2240 and 2230 cm ^ c h a r a c t e r i s t i c of the two n i t r i l e groups, w h i l e i t s "^H n.m.r. spectrum d i s p l a y e d three s i n g l e t s a t 6 0.91, 0.98 and 1.01 a r i s i n g from the t e r t i a r y methyl groups. In a d d i t i o n , the n.m.r. spectrum e x h i b i t e d a four-proton m u l t i p l e t at 6 3.5 e a s i l y a t t r i b u t e d to the k e t a l methylene protons w h i l e a s i n g l e - p r o t o n m u l t i p l e t at 6 3.03 was assigned to the methine proton at C-12. Having obtained the d i n i t r i l e 123 i n reasonable y i e l d , a number of i n t e r e s t i n g approaches could be a p p l i e d to the D r i n g s y n t h e s i s . The 68 68 most d i r e c t route was the Thorpe-Ziegler condensation which would c y c l i z e the d i n t r i l e 123 to the e n a m i n o n i t r i l e 124 (eq. 63). I t was 123 124 a n t i c i p a t e d t h a t the r i n g c l o s u r e would occur to provide the product 124 si n c e the r e a c t i o n should be r e v e r s i b l e and the product 124 (or the corresponding anion X) would be expected to be conside r a b l y more s t a b l e than the a l t e r n a t i v e product 125 (or the corresponding anions Y or Z) (see Scheme V I ) . I f the i n t r a m o l e c u l a r condensation discussed above was s u c c e s s f u l the next step of the sy n t h e s i s would r e q u i r e the conversion of the e n a m i n o n i t r i l e 124 to the t e t r a c y c l i c keto k e t a l 53_ (eq. 64). I t was SCHEME VI 70 a t t h i s stage that the a t t r a c t i v e n e s s of the Thorpe»-Ziegler route diminished. The h y d r o l y s i s and de c a r b o x y l a t i o n of c y c l i c e n a m i n o n i t r i l e s have posed problems to some workers and B a l d w i n ^ has discussed some of these. Base h y d r o l y s i s o f t e n f a i l s and a c i d h y d r o l y s i s , w h i l e being the method of choice**^ would undoubtedly be d e t r i m e n t a l to the k e t a l a t C-3. A second p o s s i b l e approach t o the D r i n g was the Dieckmann 68 condensation which i s a much more v e r s a t i l e r e a c t i o n than the Thorpe-Z i e g l e r c y c l i z a t i o n . This would i n v o l v e conversion of the d i n i t r i l e 123 i n t o a d i e s t e r 126 which could then be c y c l i z e d (eg. 65). The d i r e c t i o n 71 of r i n g c l o s u r e would be t h a t shown s i n c e the Dieckmann condensation f a i l s when a s t a b l e enolate anion of the 8-keto e s t e r product cannot be 68 formed . The h y d r o l y s i s and d e c a r b o x y l a t i o n of the g-keto e s t e r 127 could be c a r r i e d out under c o n d i t i o n s m i l d e r than those r e q u i r e d f o r the e n a m i n o n i t r i l e 124, w i t h the r e s u l t that the k e t a l a t C-3 could remain i n t a c t t o produce the d e s i r e d keto k e t a l 53. However, s i n c e f u r t h e r m o d i f i c a t i o n of the d i n i t r i l e 123 to the d i e s t e r 126 would be r e q u i r e d i n order to t e s t the Dieckmann condensation, i t was r e s o l v e d to t r y the Thorpe-Ziegler method f i r s t . Thus, a t e r t -b u t y l a l c o h o l s o l u t i o n of the d i n i t r i l e 123 was r e f l u x e d f o r 30 h w i t h a 69 c a t a l y t i c q u a n t i t y of potassium t e r t - b u t o x i d e . A f t e r work-up and r e c r y s t a l l i z a t i o n of the crude product from methanol, the c r y s t a l l i n e e n a m i n o n i t r i l e 124 (mp 213 - 215°C) was obtained i n 90% y i e l d (eq. 63). The e n a m i n o n i t r i l e s t r u c t u r e 124 was assigned to the product ( r a t h e r than the tautomeric i m i n o n i t r i l e s t r u c t u r e 128) on the b a s i s of l i t e r a t u r e precedent . CN NH CN 124 128 72 The i r spectrum of 124 o f f e r e d the most compelling evidence i n favor of the e n a m i n o n i t r i l e s t r u c t u r e assigned. Thus, the presence of two bands a t 3490 and 3390 cm ^ was compatible w i t h a primary amino group (NH s t r e t c h ) w h i l e a band at 1642 was assigned to Wi^ d e f o r m a t i o n ^ . A band a t 1605 cm ^ was a t t r i b u t e d to the e n d o c y c l i c o l e f i n i c bond w h i l e a sharp absorbance a t 2165 cm ^ i s c h a r a c t e r i s t i c of the n i t r i l e s t r e t c h i n g frequency i n an e n a m i n o n i t r i l e ^ . The "^H n.m.r. spectrum of 124 showed the f a m i l i a r three s i n g l e t s a t 6 0.90, 0.92 and 1.01 a r i s i n g from the three t e r t i a r y methyl groups. A four-proton m u l t i p l e t at 6 3.52 was assigned to the k e t a l methylene protons w h i l e a broad two-proton s i n g l e t a t 6 4.23 was a t t r i b u t e d to the protons of the primary amino group. TM I t w i l l be r e c a l l e d that the L - S e l e c t r i d e r e d u c t i o n of the keto e s t e r 5_5 gave a 3:1 mixture of the e s t e r a l c o h o l ^0 and the l a c t o n e 120 (p 62, eq. 57). As j u s t d e s c r i b e d , the e s t e r a l c o h o l 60 was converted i n t o the e n a m i n o n i t r i l e 124, v i a the d i n i t r i l e 123, i n a number of steps. I t was p o s s i b l e to envisage a s i m i l a r set of r e a c t i o n s t h a t would convert the l a c t o n e 120 i n t o the d e s i r e d e n a m i n o n i t r i l e 124 (Scheme V I I ) . Although d i n i t r i l e 131 i s an epimer of the d i n i t r i l e 123 which was used to prepare the e n a m i n o n i t r i l e 124, i t was assumed that the b a s i c c o n d i t i o n s employed i n the Thorpe-Ziegler r e a c t i o n would cause e p i m e r i z a t i o n of 131 to 123. The removal of 123 (by the formation of the e i i a m i n o n i t r i l e ) would then s h i f t the e q u i l i b r i u m towards 123 and u l t i m a t e l y r e s u l t i n the conversion of the d i n i t r i l e 131 i n t o the d e s i r e d e n a m i n o n i t r i l e 124. SCHEME VTI 74 Thus, l i t h i u m aluminum hydride r e d u c t i o n of the lactone 120 c a r r i e d out i n r e f l u x i n g t e trahydrofuran gave, i n 99% y i e l d , the d i o l 129 (eq. 66). This c r y s t a l l i n e m a t e r i a l (mp 180 - 182°C) showed a broad band (66) 120 129 between 3200 and 3500 cm i n i t s i r spectrum, c h a r a c t e r i s t i c of the OH s t r e t c h of an a l c o h o l . I t s ^H n.m.r. spectrum d i s p l a y e d a s i x - p r o t o n s i n g l e t a t 5 0.93 and a three-proton s i n g l e t a t 6 1.0, s i g n a l s which can be assigned to the t e r t i a r y methyl groups i n the molecule. The k e t a l methylene protons showed up as a broad m u l t i p l e t centered a t 6 3.51 w h i l e a two-proton t r i p l e t a t 6 3.8 was assigned to the a protons of the primary a l c o h o l . A s i n g l e - p r o t o n m u l t i p l e t a t 6 4.55 was assigned to the proton at C-12. A s o l u t i o n of the d i o l 129 i n dry p y r i d i n e was t r e a t e d w i t h an excess of methanesulfonyl c h l o r i d e . A f t e r the r e a c t i o n mixture had been s t i r r e d a t room temperature overnight, work-up and column chromatography of the crude product on s i l i c a g e l gave, i n 95% y i e l d , the dimesylate 130 as a l i g h t y e l l o w o i l (eq. 67). 75 The i r spectrum of the dimesylate 130 d i s p l a y e d the c h a r a c t e r i s t i c s u l f o n a t e e s t e r a b s o r p t i o n bands at 1350, 1330 and 1175 cm ^. I t s n.m.r. spectrum e x h i b i t e d the three s i n g l e t s ( 6 0.93, 0.97, 1.01) expected of the three t e r t i a r y methyl groups. Two a d d i t i o n a l s i n g l e t s a t 6 3.02 and 3.03 were assigned to the two methyl groups of the methanesulfonyl m o i e t i e s , w h i l e the f a m i l i a r four-proton m u l t i p l e t a t 6 3.5 was a t t r i b u t e d to the k e t a l methylene protons. A two-proton t r i p l e t at 6 4.4 was assigned t o the methylene protons a t C-15 w h i l e a s i n g l e -proton m u l t i p l e t a t 6 5.3 was assigned to the C-12 proton. A hexamethylphosphoramide s o l u t i o n of the dimesylate 130 was t r e a t e d w i t h an excess of sodium cyanide f o r 3 h a t room temperature and 48 h at 60°C. Following work-up, the crude m a t e r i a l was chromatographed on s i l i c a g e l and the white s o l i d i s b l a t e d was r e c r y s t a l l i z e d from methanol. The c r y s t a l l i n e d i n i t r i l e 131 (mp 194°C) was obtained i n 65% y i e l d from the dimesylate 130 (eq. 68). 76 M s Q MsO — H •H HMPA NaCN -CN H (6 8) H 130 131 -1 The two sharp absorbances a t 2240 and 2230 cm i n the i r spectrum of the d i n i t r i l e 131 was c h a r a c t e r i s t i c of the two n i t r i l e groups i n the molecule. The "^H n.m.r. of 131 d i s p l a y e d a s i x - p r o t o n s i n g l e t a t S 0.95 and a three-proton s i n g l e t at 6 0.97, s i g n a l s which were assigned to the t e r t i a r y methyl groups i n the molecule. A s i n g l e - p r o t o n m u l t i p l e t a t 6 2.95 was assigned to the methine proton at C-12 w h i l e the f a m i l i a r four-proton broad m u l t i p l e t centered a t 6 3.5 was a t t r i b u t e d to the k e t a l methylene protons. With the s u c c e s s f u l s y n t h e s i s of the d i n i t r i l e 131, the hypothesis that e p i m e r i z a t i o n f o l l o w e d by c y c l i z a t i o n would occur under the co n d i t i o n s of the Thorpe-Ziegler r e a c t i o n , could be t e s t e d . Thus, a t e r t - b u t y l a l c o h o l s o l u t i o n of the d i n i t r i l e 131 was r e f l u x e d f o r 30 h w i t h a c a t a l y t i c q u a n t i t y of potassium t e r t - b u t o x i d e . The crude product, obtained i n 81% y i e l d had s p e c t r a l and p h y s i c a l p r o p e r t i e s i d e n t i c a l w i t h those of the e t t a m i n o n i t r i l e 124 obtained from the d i n i t r i l e 123 (eq. 69). 77 131 123 124 Thus the l a c k of t o t a l s t e r e o s e l e c t i v i t y i n the L - S e l e c t r i d e r e d u c t i o n of the keto e s t e r 55 d i d not r e s u l t i n a l o s s of m a t e r i a l s i n c e both the e s t e r a l c o h o l j60 and the lactone 120 could be converted i n t o the same e n a m i n o n i t r i l e 124 (eq. 70). 124 78 Good y i e l d s are of paramount importance i n a m u l t i - s t e p s y n t h e s i s and thus, t h i s saving of approximately 25% of the m a t e r i a l obtained from the r e d u c t i o n step i s of some s i g n i f i c a n c e . The sep a r a t i o n of ^ 0 from 120 though not d i f f i c u l t , could a l s o be dispensed w i t h , s i n c e the reagents employed f o r the conversion of j50 i n t o 124 are i d e n t i c a l w i t h those r e q u i r e d f o r the conversion of 120 to 124 (see Scheme V I I , p 73). At t h i s stage, i n order to prepare an intermediate which would be a p o t e n t i a l s y n t h e t i c precursor f o r stemodin i t was necessary to e f f e c t the h y d r o l y s i s and de c a r b o x y l a t i o n of the e n a m i n o n i t r i l e 124 to the t e t r a c y c l i c keto k e t a l 53_ (eq. 64) . Since the q u a n t i t y of (64) 124 53 e n a m i n o n i t r i l e 124 a v a i l a b l e a t t h i s stage of the work was r a t h e r low, i t was resolve d that the procedure most l i k e l y to succeed would be employed. Thus, B a l d w i n ' s ^ procedure was employed w i t h the f u l l knowledge that the s t r o n g l y a c i d i c c o n d i t i o n s would hydrolyze the k e t a l f u n c t i o n a l i t y i n a d d i t i o n to e f f e c t i n g the d e s i r e d t r a n s f o r m a t i o n . However, examination of a model of the dione 132 that would be produced i n d i c a t e d that the ketone i n the A r i n g was l e s s hindered than the D r i n g ketone and could probably be s e l e c t i v e l y r e p r o t e c t e d i n a 79 subsequent step (eq. 71), (71) AM 53 A s o l u t i o n of the e n a m i n o n i t r i l e 124 i n a mixture of g l a c i a l 69 a c e t i c a c i d , water and 85% phosphoric a c i d was r e f l u x e d f o r 24 h. Work-up, followed by column chromatography of the crude product gave the t e t r a c y c l i c dione 132 which was r e c r y s t a l l i z e d from ether-hexanes (eq. 72). (72) 124 132 80 The c r y s t a l l i n e dione 132 (mp 131 - 133°C) obtained i n 80% y i e l d showed a strong band at 1705 cm ^ i n i t s i r spectrum c h a r a c t e r i s t i c of a six-membered r i n g ketone. The major f e a t u r e of the ^"H n.m.r. spectrum of 132 was a s i n g l e three-proton s i n g l e t a t <5 1.16 assigned to the bridgehead methyl group. The k e t a l proton resonances were absent. Mass s p e c t r a l evidence a l s o corroborated the assigned s t r u c t u r e . With the sy n t h e s i s of the t e t r a c y c l i c dione 132, the v i a b i l i t y of t h i s s y n t h e t i c approach to the t e t r a c y c l i c d i t e r p e n o i d , stemodin 8_ has been e s t a b l i s h e d . However, the photoaddition of a l l e n e to the enone 56 under the c o n d i t i o n s described does not appear to be a v i a b l e route towards a p h i d i c o l i n 1_. The enone 56_ i s a v e r s a t i l e intermediate and other s y n t h e t i c pathways l e a d i n g through i t to a p h i d i c o l i n 7_ might s t i l l be p o s s i b l e . 81 EXPERIMENTAL General Information. M e l t i n g p o i n t s were determined on a Fisher-Johns m e l t i n g p o i n t apparatus and are uncorrected. D i s t i l l a t i o n temperatures are a l s o uncorrected and r e f e r to the mean a i r bath temperature during a short path d i s t i l l a t i o n . I n f r a r e d ( i r ) s p e c t r a were recorded on Perkin-Elmer model 710 and 710B i n f r a r e d spectrophotometers, as l i q u i d f i l m s or i n chloroform s o l u t i o n s . Nuclear magnetic resonance (^ H n.m.r.) s p e c t r a were obtained i n deuterochloroform s o l u t i o n on V a r i a n T-60, HA-100 and XL-100 spectrometers and on a Bruker WP-80 spectrometer. S i g n a l p o s i t i o n s are given i n p a r t s per m i l l i o n (6) w i t h tetramethyl s i l a n e as an i n t e r n a l r e f e r e n c e , and w i t h the m u l t i p l i c i t y , number of protons, proton assignments and coupling constants i n d i c a t e d i n parentheses. A n a l y t i c a l g a s - l i q u i d chromatography ( g . l . c . ) was done on a Hewlett Packard HP 5832 A Gas Chromatography u n i t connected to a HP 18850 A GC t e r m i n a l . The columns used were: (A) 6 f t x 0.125 i n . , 5% OV-210 on Chromosorb W (100 - 200 mesh). (B) 6 f t x 0.125 i n . , 5% OV-17 on Chromosorb W (100 - 200 mesh). Column chromatography was performed u s i n g S i l i c a Gel 60 (E. Merck, 70 - 230 mesh) and K i e s e l g e l 60 ( E. Merck, 230 - 400 mesh). A n a l y t i c a l t h i n - l a y e r chromatography ( t . l . c . ) was c a r r i e d out on commercial, pre-coated S i l i c a Gel p l a t e s w i t h f l u o r e s c e n t i n d i c a t o r (Eastman Kodak, Sheet Type 13181). V i s u a l i z a t i o n was e f f e c t e d e i t h e r by i o d i n e vapor s t a i n i n g or w i t h short-wavelength u l t r a - v i o l e t l i g h t . The alumina used i n f i l t r a t i o n columns was n e u t r a l alumina Act. I (Alumina Woelm B, Act. I ) . Low r e s o l u t i o n mass s p e c t r a were recorded w i t h a Varian/MAT CH 4 B mass spectrometer. High r e s o l u t i o n mass spectra 82 were recorded w i t h a Kratos/AEI MS 50 or a Kratos/AEI MS 902 mass spectrometer. Microanalyses were performed by Mr. P. Borda, M i c r o a n a l y t i c a l Laboratory, 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 and 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 or c a r e f u l l y flame-dried glassware. L i q u i d reagents o r s o l u t i o n s were introduced i n t o the r e a c t i o n f l a s k through a rubber septum w i t h a s y r i n g e equipped w i t h a hypodermic needle. Tetrahydrofuran and dimethoxyethane were d i s t i l l e d from a r e f l u x i n g s o l u t i o n of sodium benzophenone k e t y l i n the a p p r o p r i a t e so l v e n t under argon. Hexamethylphosphoramide was d i s t i l l e d from barium oxide; diisopropylamine and t r i e t h y l amine from calcium hydride. Carbon t e t r a c h l o r i d e and dichloromethane were d i s t i l l e d from phosphorus pentoxide, and t e r t - b u t y l a l c o h o l was d i s t i l l e d from a s o l u t i o n of potassium t e r t -butoxide i n the a l c o h o l . Dry methanol was obtained by d i s t i l l a t i o n from magnesium methoxide. Anhydrous ether was obtained commercially ( M a l l i n c k r o d t ) and dry ammonia was d i s t i l l e d from m e t a l l i c sodium. 83 P r e p a r a t i o n of Dimethyl 2-Ethoxypropenylphosphonate 7_g. EtO V=CHPO(XH3)2 7 9 To 5.10 g (37.8 mmol) of neat dimethyl 2-oxopropylphosphonate ( A l d r i c h ) was added 9.0 g (60.8 mmol) of t r i e t h y l orthbformate and .-0.20 g of FeCl 3*6H 20. The mixture was s t i r r e d b r i e f l y and then allowed to stand at room temperature f o r 3 days. The excess t r i e t h y l orthoformate and v o l a t i l e by-products were removed under reduced pressure and the r e s i d u a l m a t e r i a l was d i s s o l v e d i n 50 ml of dry dichloromethane. The s o l u t i o n was tr e a t e d w i t h 0.50 g of sodium hydride (washed f r e e of mineral o i l w i t h hexane) and the r e s u l t a n t mixture was s t i r r e d f o r 10 min and then f i l t e r e d . Removal of the s o l v e n t from the f i l t r a t e , f o l l o wed by bulb to bulb d i s t i l l a t i o n ( a i r - b a t h temperature 80°C, 0.05 t o r r ) of the r e s i d u a l m a t e r i a l gave 6.89 g (94%) of the enol ether 79 as a c o l o r l e s s l i q u i d : i r ( f i l m ) v 1605, 1250, 1050 and 1025 cm" 1; 1H n.m.r., 6 1.33 ( t , 3H, max CH 3-CH 2-0, J = 7 Hz ) , 2.14 (d, 3H, CH3-C=C, J R _ p = 2 Hz), 3.65 (d, 6H, P0(0CH 3) 2, J R _ p = 11 Hz), 3.77 (q, 2H, -0-CH 2-CH 3, J = 7 Hz), 4.35 ( d , 1H, C=CH=P, J R _ p = 7 Hz); mass spectrum: m/e 194 (M+), 179, 166, 151 (100%). Exact mass c a l c d . f o r C^^O^P: 194.0707; measured (high r e s o l u t i o n mass spectrometry): 194.0708. Ana l , c a l c d . f o r C^H^O^P: C, 43.30; H, 7.79; found: C, 43.13; H, 7.70. 84 P r e p a r a t i o n of Dimethyl 3-Bromo-2-ethoxypropenylphosphonate 31. EtO \=CHPO^CH3)2 B r — / 81 To a s o l u t i o n of the en o l ether 79 (3.0 g, 15.5 mmol) i n 150 mL of dry c a r b o n t e t r a c h l o r i d e was added 3.10 g (17.4 mmol) of N-bromosuccinimide. The w e l l s t i r r e d mixture was r e f l u x e d w h i l e i t was being i r r a d i a t e d w i t h a sun lamp (Westinghouse, 275 Watt 110-120 V) . A f t e r 15 min, the r e a c t i o n m ixture was cooled and f i l t e r e d . The f i l t r a t e was concentrated under reduced pressure to a volume of approximately 50 mL, and then was cooled i n an i c e bath to p r e c i p i t a t e r e s i d u a l s u c c i n i m i d e . The mixture was f i l t e r e d through a sm a l l amount of n e u t r a l alumina (Act. I ) . Removal of the s o l v e n t from the f i l t r a t e gave a y e l l o w o i l which was subjected to column chromatography on 160 g of s i l i c a g e l . E l u t i o n of the column w i t h e t h y l a c e t a t e , followed by d i s t i l l a t i o n ( a i r - b a t h temperature 110°C, 0.05 t o r r ) o f the crude o i l thus obtained, gave 3.2 g (76%) of dimethyl 3-bromo-2-ethoxypropenylphosphonate j$l as a c o l o r l e s s o i l . Both g a s - l i q u i d chromatography and t h i n l a y e r chromatography i n d i c a t e d one product; i r ( f i l m ) : v 1605, 1250 and 1025-1050 cm - 1; XH n.m.r., 6 1.39 ( t , max 3H, CH 3-CH 2-0, J = 7 Hz), 3.76 (d, 6H, PO(OCH 3) 2, J R _ p = 11 Hz), 3.91 (q, 2H, 0-CH2-CH3, J = 7 Hz), 4.42 ( s , 2H, Br-O^-) , 4.57 (d, 1H, OCH-P, J = 5 Hz); mass spectrum: m/e 274 and 272 (M+). Exact mass c a l c d . H—P 79 f o r C..H, ,0. Br P: 271.9813; measured (high r e s o l u t i o n mass 7 14 4 spectrometry): 271.9815. 85 General Procedure f o r the A l k y l a t i o n of Ketones w i t h Dimethyl  3-Bromo-2-ethoxypropenylphosphonate 81. To a c o l d (-78°C), s t i r r e d s o l u t i o n of l i t h i u m diisopropylamide i n tet r a h y d r o f u r a n , under an atmosphere of argon, was added the appropriate amount of the ketone. The c o o l i n g bath was removed and the r e a c t i o n mixture was allowed to warm to 0°C and l e f t a t t h i s temperature f o r 1 h. The r e a c t i o n mixture was cooled to -78°C and the r e q u i r e d amount of dimethyl 3-bromo-2-ethoxypropenylphosphonate 81 was added. A f t e r the r e a c t i o n mixture had been s t i r r e d a t -78°C f o r 30 min, at 0°C f o r 30 min and a t room temperature f o r 30 min, the tetr a h y d r o f u r a n was removed under reduced pressure. The r e s i d u a l m a t e r i a l was d i s s o l v e d i n methylene c h l o r i d e and the r e s u l t a n t s o l u t i o n was washed twice w i t h b r i n e . The s o l u t i o n was d r i e d (^£80^) and the sol v e n t was removed under reduced pressure to give the a l k y l a t e d ketone. P r e p a r a t i o n of the A l k y l a t e d Ketone 83 0 P0(0CH3)2 The general procedure o u t l i n e d above was employed to prepare t h i s compound. 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 : cyclohexanone: 98 mg (1 mmol) l i t h i u m d i i s o p r o p y l a m i d e : 128 mg (1.2 mmol) 86 te t r a h y d r o f u r a n : 2 mL 3-bromo-2-ethoxypropenylphosphonate (81): 330 mg (1.2 mmol) Following the u s u a l work-up, removal of the sol v e n t under reduced pressure gave 290 mg (100%) of the a l k y l a t e d ketone 83 as a c o l o r l e s s o i l . Both g a s - l i q u i d chromatography and t h i n l a y e r chromatography i n d i c a t e d one pure product: i r ( f i l m ) : v m a x 1710, 1605, 1250 and 1025 - 1060 cm" 1; 1H n.m.r., <S 1.26 ( t , 3H, OLj-O^-O, J = 7 Hz), 3.62 (d, 6H, PO(OCH 3) 2, J R _ p = 12 Hz), 3.72 (q, 2H, 0-CH2-CH3, J = 7 Hz), 4.36 (d, 1H, C=CH-P, J„ _ = 7 Hz); mass spectrum: m/e 290 (M+) , 244, 151, ,35 (100%). Exact mass c a l c d . f o r C 1 3 H 2 3 ° 5 P : 290.1283; measured (high r e s o l u t i o n mass spectrometry): 290.1301. P r e p a r a t i o n of the A l k y l a t e d Ketone jj5_ 0 P0(0CH3)2 The general procedure o u t l i n e d above was employed to prepare t h i s compound. 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 : 3-pentanone: 86 mg (1 mmol) l i t h i u m d i i s o p r o p y l a m i d e : 128 mg (1.2 mmol) tet r a h y d r o f u r a n : 2 mL 3-bromo-2-ethoxypropenylphosphonate (81): 330 mg (1.2 mmol) Fol l o w i n g the u s u a l work-up, removal of the solvent under reduced 87 pressure gave a yellow o i l which was d i s t i l l e d (air bath temperature 140°C, 0.05 torr) to give a quantitative yield (278 mg) of the alkylated ketone j$5_ as a colorless o i l . Both gas-liquid chromatography and thin layer chromatography indicated one pure product: i r (film): v m a x 1705, 1605, 1250 and 1025 cm"1; 1H n.m.r., <5 1.04 (t, 3H, O^O^CO, J = 7 Hz), 1.12 (d, 3H, CH3-CH-CH2, J = 6 Hz), 1.28 (t, 2H, CH3CH2-0, J = 7 Hz), 2.5 (q, 2H, CH3CH2CO, J = 7 Hz), 2.66 - 2.98 (m, 3H, CH3-CH-CH2), 3.66 (d, 6H, PO(OCH3)2, J R _ p = 12 Hz), 3.76 (q, 2H, O^-O^-O, J = 7 Hz), 4.39 (d, 1H, OCH-P, J„ _ = 6 Hz); mass spectrum: m/e 278 (M+), 221 (100%). Exact mass calcd. for C 1 2 H 2 3 ° 5 P : 2 7 8 - 1 2 8 3 5 measured (high resolution mass spectrometry): 278.1277. Preparation of the Alkylated Ketone 87 P0(0CH3)2 The general procedure outlined above, with a slight modification, was employed to prepare this compound. The quantities of materials used were as follows: 44 ketone j$6 : 198 mg (1 mmol) lithium diisopropylamide: 128 mg (.1.2 mmol) 88 tet r a h y d r o f u r a n : 2 mL 3-bromo-2-ethoxypropenylphosphonate (81) : 330 mg (1.2 mmol) hexamethylphosphoramide: 179 uL (1 mmol) The hexamethylphosphoramide was added to the r e a c t i o n mixture a t -78°C, j u s t p r i o r to adding the a l k y l a t i n g agent 81^. F o l l o w i n g the us u a l work-up, removal of the sol v e n t under reduced pressure gave a y e l l o w o i l . The hexamethylphosphoramide was removed under reduced pressure ( a i r bath temperature approx. 100°C, 0.05 t o r r ) and the residue was chromatographed on 10 g of s i l i c a g e l . E l u t i o n of the column w i t h e t h y l a c etate y i e l d e d 304 mg (78%) of the a l k y l a t e d ketone 87. as a c o l o r l e s s o i l . Both g a s - l i q u i d chromatography and t h i n l a y e r chromatography i n d i c a t e d one pure product: i r ( f i l m ) : v 1715, 1610, 1250 and r r max 1030 cm"1; ^ n.m.r., 6 0.94, 1.01 ( s , s, 6H, t e r t i a r y m e t h y ls), 1.3 ( t , 3H, CH,CH90, J = 6 Hz), 3.48 ( s , 4H, k e t a l methylene p r o t o n s ) , 3.67 (d, 6H, PO(OCH 3) 2, J R _ p - 11 Hz), 3.78 (q, 2H, C H ^ - O , J = 6 Hz), 4.43 (d, 1H, OCH-P, J = 6 Hz); mass spectrum: m/e 390 (M+), 344 (100%). Exact mass c a l c d . f o r C^H^O^: 390.1808; measured (high r e s o l u t i o n mass spectrometry): 390.1796. P r e p a r a t i o n of the A l k y l a t e d Ketone 1Q_ 0 0 90 57 89 The general procedure o u t l i n e d above, w i t h a s l i g h t m o d i f i c a t i o n , was employed to prepare t h i s compound. 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 : ketone J 5 7 : 266 mg (1 mmol) l i t h i u m d i i s o p r o p y l a m i d e : 128 mg (1.2 mmol) te t r a h y d r o f u r a n : 2 mL 3-bromo-2-ethoxypropenylphosphonate (81): 330 mg (1.2 mmol) hexamethylphosphoramide: 179 uL (1 mmol) The hexamethylphosphoramide was added to the r e a c t i o n mixture a t -78°C, j u s t p r i o r to adding thfe a l k y l a t i n g agent Jtt. F o l l o w i n g the u s u a l work-up, removal of the sol v e n t under reduced pressure gave a y e l l o w o i l . The hexamethylphosphoramide was removed under reduced pressure ( a i r bath temperature approx. 100°C, 0.05 t o r r ) and the r e s i d u e was chromatographed on 10 g of s i l i c a g e l . E l u t i o n of the column w i t h e t h y l a c e t a t e gave 348 mg (76%) of the a l k y l a t e d ketone 90 as a white s o l i d . Thin l a y e r chromatography i n d i c a t e d one pure product. This m a t e r i a l was r e c r y s t a l l i z e d from ether-hexanes: mp 99 - 100°C; i r ( C H C l _ ) v 3 3 max 1705, 1610, 1250 and 1030 cm" 1; \ n.m.r., 6 0.93, 1.02, 1.16 ( s , s, s, 9H, t e r t i a r y m e t h y ls), 1.32 ( t , 3H, OLjO^-O, J = 7 Hz), 3.72 (d, 6H, PO(OCH 3) 2, J R _ p = 12 Hz), 3.80 (q, 2H, CH 3CH 2-0, J = 7 Hz), 4.44 (d, 1H, C=CH-P, J„ _ = 6 Hz); mass spectrum: m/e 458 (M +), 412, 397, 311. Exact H—P mass c a l c d . f o r ^ 23^39^7 P : 458.2434;. measured (high r e s o l u t i o n mass spectrometry): 458.2412. 90 P r e p a r a t i o n of the A l k y l a t e d Ketone j ? j CC^Me 0 COjMe P0(0CH 3)2 88 89 The general procedure o u t l i n e d above, w i t h a few m o d i f i c a t i o n s was employed to prepare t h i s compound. 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 : 2- carbomethoxycyclohexanone j$8: 156 mg (1 mmol) l i t h i u m d i i s o p r o p y l a m i d e : 160 mg (1.5 mmol) tet r a h y d r o f u r a n : 2 mL 3- bromo-2-ethoxypropenylphosphonate (81): 413 mg (1.5 mmol) hexamethylphosphoramide: 268.5 u L (1.5 mmol) The hexamethylphosphoramide was added to the r e a c t i o n mixture at -78°C, j u s t p r i o r to adding the a l k y l a t i n g agent 81. The r e a c t i o n mixture was s t i r r e d f o r 30 min a t -78 6C, 30 min at 0°C and 6 h at room temperature. Usual work-up gave a brown o i l which was chromatographed on 10 g of s i l i c a g e l . E l u t i o n of the column w i t h e t h y l a c e t a t e fo l l o w e d by d i s t i l l a t i o n of the crude product ( a i r bath temperature 180°C, 0.05 t o r r ) gave 247 mg (71 %) of the a l k y l a t e d ketone 89 as a c o l o r l e s s o i l . Both g a s - l i q u i d chromatography and t h i n l a y e r chromatography i n d i c a t e d one pure product: i r ( f i l m ) : v 1740, 1710, 1610, 1240 phosphorus, = 16 Hz, J A _ p = J g _ p = 2 Hz), 3.72 (d, 6H, PO(OCH 3) 2, and 1020 cm ; H n.m.r., 6 1.28 ( t , 3H, CH 3-CH 2-0, J = 7 Hz), 3.11 and 3.37 ( p a i r of d of d, 2H, CH2-C=C-P, AB p a i r of d f u r t h e r coupled to 91 J R _ p = 11 Hz); mass spectrum: m/e 348 ( M + ) , 317, 302, 194 (100%). Exact mass c a l c d . f o r Ci5 H 25°7 I > : 348.1338; measured (high r e s o l u t i o n mass spectrometry): 348.1333. P r e p a r a t i o n of the Diketo Phosphonate Jj3_ 93 To a s t i r r e d s o l u t i o n of 290 mg (1 mmol) of the a l k y l a t e d ketone j83_ i n 25 mL of acetone at room temperature was added 0.50 mL of 1 N h y d r o c h l o r i c a c i d . A f t e r the r e s u l t a n t mixture had been s t i r r e d a t room temperature f o r 30 min, anhydrous potassium bicarbonate was added and the acetone was removed under reduced pressure. Methylene c h l o r i d e was added to the re s i d u e and the organic s o l u t i o n was washed twice w i t h sa t u r a t e d potassium bicarbonate and d r i e d (^£20^) . Removal of the s o l v e n t and d i s t i l l a t i o n ( a i r bath temperature 180 - 185 6C, 0.02 t o r r ) of the r e s i d u a l o i l gave 262 mg (100%) of the d i k e t o phosphonate 93 as a c o l o r l e s s o i l . Both g a s - l i q u i d chromatography and t h i n l a y e r chromatography i n d i c a t e d one pure -1 1 product: i r ( f i l m ) : v 1710, 1260, and 1030 cm ; H n.m.r., 6 r max 2.75 - 3.5 (m, 3H, C-2H and C-3'methylene p r o t o n s ) , 3.72 (d, 6H, PO(OCH 3) 2, J = 12 Hz); mass spectrum: m/e 262 ( M + ) , 244, 166, }51. Exact mass H—P c a l c d . f o r Cj_]H c^^ 5 262.0970; measured (high r e s o l u t i o n mass spectrometry): 262.0987. 92 P r e p a r a t i o n of the Diketo Phosphonate 94 0 94 To a s t i r r e d s o l u t i o n of 278 mg (1 mmol) of the a l k y l a t e d ketone 85 i n 25 mL of acetone a t room temperature was added 0.50 mL of 1 N h y d r o c h l o r i c a c i d . A f t e r the r e s u l t a n t mixture had been s t i r r e d a t room temperature f o r 30 min, anhydrous potassium bicarbonate was added and the acetone was removed under reduced pressure. Methylene c h l o r i d e was added to the re s i d u e and the organic s o l u t i o n was washed twice w i t h saturated potassium bicarbonate and d r i e d (Na 2S0^). Removal of the solv e n t a f f o r d e d the crude product which was p u r i f i e d by chromatography on 8 g of s i l i c a g e l . E l u t i o n of the column w i t h e t h y l a c e t a t e , f o l l o w e d by removal of the so l v e n t (reduced pressure) from the a p p r o p r i a t e f r a c t i o n s , gave 250 mg (100%) of the d i k e t o phosphonate j)4 as a c o l o r l e s s o i l . Both g a s - l i q u i d chromatography and t h i n l a y e r chromatography i n d i c a t e d one pure product: i r ( f i l m ) : v m a x 1710, 1270 and 1040 cm "*"; *H n.m.r., 6 1.07 ( t , 3H, CH3-CH2-CO, J = 8 Hz), 1.08 (d, 3H, CHj-CH-CO, J = 8 Hz), 2.4 - 2.88 (m, 3H, O^-O^-CO and O^-CH-CO) , 2.9 - 3.4 (m, 4H, CH.-CO-CHL-P), 3.75 (d, 6H, P0(0CH,) o, J„ = H Hz); mass spectrum:  2. Z J / n—r m/e 250 (M +), 232, 194, 193, 151 (100%). Exact mass c a l c d . f o r C 1 0 H 1 9 ^ 5 ^ : 250.0970; measured (high r e s o l u t i o n mass spectrometry): 250.0965. 93 P r e p a r a t i o n of the Diketo Phosphonate 91 0 91 To a s t i r r e d s o l u t i o n of 195 mg (0.5 mmol) of the a l k y l a t e d ketone 87_ i n 25 mL of acetone a t room temperature was added 0.5 mL of 0.5 N h y d r o c h l o r i c a c i d . A f t e r the r e a c t i o n mixture had been s t i r r e d a t room temperature f o r 2 h, anhydrous potassium bicarbonate was added and the acetone was removed under reduced pressure. Methylene c h l o r i d e was added to the residue and the organic s o l u t i o n was washed twice w i t h saturated potassium bicarbonate and d r i e d (Na2S0^). Removal of the s o l v e n t gave the crude product which was p u r i f i e d by chromatography on 8 g of s i l i c a g e l . E l u t i o n of the column w i t h e t h y l a c e t a t e , f o l l o w e d by removal of the s o l v e n t (reduced pressure) from the ap p r o p r i a t e f r a c t i o n s gave 167 mg (92%) of the d i k e t o phosphonate 9]± as a c o l o r l e s s o i l . Both g a s - l i q u i d chromatography and t h i n l a y e r chromatography i n d i c a t e d one pure product: i r ( f i l m ) : v m f , x 1710, 1260 and 1025 cm ^; n.m.r., 6 0.98, 1.04 ( s , s, 6H, t e r t i a r y methyl p r o t o n s ) , 3.4 - 3.68 (m, 4H, k e t a l methylene pr o t o n s ) , 3.81 (d, 6H, P0(0CH_) o, J„ _ = 11 Hz); J 2 n—r mass spectrum: m/e 362 (M +), 305, 259, 219. Exact mass c a l c d . f o r C.,H 0 P: 362.1494; measured (high r e s o l u t i o n mass spectrometry): 16 2.1 I 362.1491. 94 Pr e p a r a t i o n of the Diketo Phosphonate 92 0 P0(XH3)2 92 To a s t i r r e d s o l u t i o n of 229 mg (0.5 mmol) of the a l k y l a t e d ketone jK) i n 25 mL of acetone a t room temperature was added 0.50 mL of 0.5 N h y d r o c h l o r i c a c i d . A f t e r the r e s u l t a n t mixture had been s t i r r e d a t room temperature f o r 15 min, anhydrous potassium bicarbonate was added and the acetone was removed under reduced pressure. Methylene c h l o r i d e was added to the res i d u e and the organic s o l u t i o n was washed twice w i t h sa t u r a t e d potassium bicarbonate and d r i e d (^£50^) . Removal of t h e s o l v e n t gave the crude product which was p u r i f i e d by chromatography on 8 g of s i l i c a g e l . E l u t i o n of the column w i t h e t h y l a c e t a t e , followed by removal of the solvent (reduced pressure) from the appropriate f r a c t i o n s gave 206 mg (96%) of the d i k e t o phosphonate 92_ as a c o l o r l e s s o i l . Both g a s - l i q u i d chromatography and t h i n l a y e r chromatography i n d i c a t e d one pure product: i r ( f i l m ) : v m a x 1705, 1260 and 1030 cm ^; n.m.r., 6 0.85, 0.96, 1.12, ( s , s, s, 9H, t e r t i a r y methyl p r o t o n s ) , 2.8 - 3.56 (m, 9H, in c l u d e s k e t a l methylene p r o t o n s ) , 3.72 (d, 6H, P 0 ( 0 C H 3 ) 2 , J R _ p = 12 Hz); mass spectrum: m/e 430 (M +), 151, 141 (100%). Exact  mass c a l c d . f o r C2^H3^O^P; 430.2120; measured (high r e s o l u t i o n mass spectrometry): 430.2114. 95 General Procedure f o r the Intramolecular Horner-Emmons C y c l l z a t i o n  Reaction To a c o l d (0°C), s t i r r e d suspension of sodium hydride i n 2 mL of anhydrous dimethoxyethane, under an atmosphere of argon, was added dropwise a s o l u t i o n of the d i k e t o phosphonate i n 1 mL of anhydrous dimethoxyethane. A f t e r the r e a c t i o n mixture had been s t i r r e d f o r 30 min at room temperature, i t was warmed to 65°C and kept a t that temperature f o r the a p p r o p r i a t e time. The r e a c t i o n mixture was poured i n t o an aqueous sodium c h l o r i d e s o l u t i o n , and the product was i s o l a t e d by e x t r a c t i o n of the r e s u l t a n t mixture w i t h ether. The combined ether e x t r a c t was washed w i t h water and d r i e d (Na2S0^). Removal of the s o l v e n t under reduced pressure, f o l l o w e d by d i s t i l l a t i o n or column chromatography of the crude product, a f f o r d e d the d e s i r e d cyclopentenone. P r e p a r a t i o n of the B i c y c l i c Enone 31 97 The general procedure o u t l i n e d above was employed to prepare t h i s compound. 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 : sodium hydride: 14 mg (0.6 mmol) di k e t o phosphonate 9[3_: 131 mg (0.5 mmol) The r e a c t i o n mixture was maintained a t 65°C f o r 1 h, and was then 96 subjected to the usual work-up. Removal of the solvent under reduced 34 pressure and d i s t i l l a t i o n ( a i r bath temperature 45 "C, 0.02 t o r r ; l i t . 59 - 62°C, 0.05 t o r r ) of the r e s i d u e gave 51 mg (74%) of the b i c y c l i c enone 97_ as a c o l o r l e s s l i q u i d . Both g a s - l i q u i d chromatography and t h i n l a y e r chromatography i n d i c a t e d one pure product: i r ( f i l m ) : v m a x 1700 and 1620 cm ^; n.m.r., 6 5.86 ( s , 1H, o l e f i n i c p r o t o n ) ; mass  spectrum: m/e 136 (M +) , 121, 108, 107. Exact mass c a l c d . f o r C 9 H 1 2 0 : 136.0888; measured (high r e s o l u t i o n mass spectrometry): 136.0891. P r e p a r a t i o n of the Enone .9JL 98 The general procedure o u t l i n e d above was employed t o prepare t h i s compound. 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 : sodium h y d r i d e : 14 mg (0.6 mmol) d i k e t o phosphonate j)4_: 125 mg (0.5 mmol) The r e a c t i o n mixture was maintained a t 65°C f o r 3 h, and then was subjected to the usu a l work-up. Removal of the sol v e n t under reduced pressure and d i s t i l l a t i o n ( a i r bath temperature 100°C, 15 t o r r ) of the r e s i d u a l o i l a f f o r d e d 51 mg (82%) of the enone j)8 as a c o l o r l e s s l i q u i d : i r ( f i l m ) : v 1700 and 1610 cm" 1; *H n.m.r., 6 1.20 ( t , 3H, CH.-CH -< max J / J * 7 Hz, 1.21 (d, 3H, CH3-CH, J = 7 Hz), 5.94 (d, 1H, o l e f i n i c p r oton, J •» 2 Hz); mass spectrum: m/e 124 (M +), 109, 95. Exact mass c a l c d . 97 f o r C g H i 2 ° : 124.0888; measured (high r e s o l u t i o n mass spectrometry): 124.0893. Anal c a l c d . f o r CgH^O; C, 77.38, H, 9.74; found: C, 77.09, H, 9.77. P r e p a r a t i o n of the B i c y c l i c Enone 99 99 The general procedure o u t l i n e d above was employed to prepare t h i s compound. 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 : sodium hydride: 9 mg (0.38 mmol) di k e t o phosphonate .91: 118 mg (0.33 mmol) The r e a c t i o n mixture was maintained at 65°C f o r 3 h and then l e f t a t room temperature overnight. Usual work-up and product i s o l a t i o n gave an o i l which 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 w i t h e t h y l a cetate gave a y e l l o w s o l i d which was d i s t i l l e d ( a i r bath temperature 155 - 160°C, 0.05 t o r r ) to y i e l d 56 mg (72%) of the b i c y c l i c enone 99_ as a white s o l i d , which was c r y s t a l l i z e d from e t h e r -hexanes. Both g a s - l i q u i d chromatography and t h i n l a y e r chromatography i n d i c a t e d one pure product: mp 73 - 74°C; i r ( f i l m ) : v m a i i 1700 and 1620 cm 1 ; \. n.m.r., 6 1.00, 1.02 ( s , s, 6H, t e r t i a r y methyl p r o t o n s ) , 98 3.56 ( s , 4H, k e t a l methylene pr o t o n s ) , 5.91 ( s , 1H, o l e f i n i c p r o ton); mass  spectrum: m/e 236 (M +), 207, 151. Exact mass c a l c d . f o r C^H^O^: 236.1412; measured (high r e s o l u t i o n mass spectrometry): 236.1422. P r e p a r a t i o n of the T r i c y c l i c Enone 5JL 56 The general procedure o u t l i n e d above was employed to prepare t h i s compound. 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 : sodium hydride: 9 mg (0.38 mmol) dik e t o phosphonate 92_: 149 mg (0.035 mmol) The r e a c t i o n mixture was maintained a t 65°C f o r 2 h. Usual work-up affo r d e d a y e l l o w s o l i d which 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 w i t h e t h y l acetate/hexane (1:1) gave 92 mg (86%) of the t r i c y c l i c enone 5j> as a white s o l i d , which was r e c r y s t a l l i z e d from a mixture of ether and hexanes. Both g a s - l i q u i d chromatography and t h i n l a y e r chromatography i n d i c a t e d one pure product: mp 116 - 117°C; i r (CHC1-) v 1680 and 1610 cm" 1; 1H n.m.r., 6 0.90, e 3 max 0.95,.1.09 ( s , s, s, 9H, t e r t i a r y m e t h y l s ) , 1.92 (d of d, 1H, C-13 proton, J « 18 Hz, J ' = 3 Hz), 2.54 (d, of d, 1H, C-13 proton, J = 18 Hz, J ' = 6 Hz), 99 2.94 (m, 1H, C-8 pr o t o n ) , 3.30 - 3.64 (m, 4H, k e t a l methylene p r o t o n s ) , 5.76 (m, 1H, o l e f i n i c p r o t o n ) ; mass spectrum: m/e 304 (M +), 167. Exact mass c a l c d . f o r C^gH^gO^: 304.2039; measured (high r e s o l u t i o n mass spectrometry): 304.2029. P r e p a r a t i o n o f the Diketo Phosphonate 95 and the Carbomethoxy B i c y c l i c  Enone 100 95 100 To a s t i r r e d s o l u t i o n of 174 mg (0.5 mmol) of the a l k y l a t e d ketone j59_ i n 15 mL of acetone at room temperature was added 0.50 mL of 0.5 N h y d r o c h l o r i c a c i d . A f t e r the r e s u l t a n t mixture had been s t i r r e d a t room temperature f o r 35 min, anhydrous potassium bicarbonate was added and the acetone was removed under reduced pressure. Methylene c h l o r i d e was added to the r e s i d u a l m a t e r i a l and the organic s o l u t i o n was washed twice w i t h s a t u r a t e d potassium bicarbonate and d r i e d (Na2S0^). Removal of the so l v e n t a f f o r d e d the crude d i k e t o phosphonate j)5 which was not p u r i f i e d f u r t h e r but used d i r e c t l y i n the next step. The carbomethoxy b i c y c l i c enone 100 was prepared from the crude d i k e t o phosphonate J?5_ by u s i n g the general procedure f o r i n t r a m o l e c u l a r c y c l i z a t i o n s o u t l i n e d above (p 95 ) . The q u a n t i t i e s of m a t e r i a l s used 100 were as f o l l o w s : sodium h y d r i d e : 14 mg (0.6 mmol) di k e t o phosphonate j)5: a l l the crude m a t e r i a l i s o l a t e d i n the l a s t step. The r e a c t i o n mixture was maintained a t 65°C f o r 2 h. Usual work-up, f o l l o w e d by d i s t i l l a t i o n ( a i r bath temperature 110°C, 0.05 t o r r ) of the crude product gave 68 mg (70%, based on 0.5 mmol of a l k y l a t e d ketone 89) of the carbomethoxy b i c y c l i c enone 100 as a c o l o r l e s s o i l . Both gas-l i q u i d chromatography and t h i n l a y e r chromatography i n d i c a t e d one pure product: i r ( f i l m ) : v 1730, 1710 and 1625 cm" 1; hi n.m.r., 6 2.23 r 1 7 max ' ' and 2.63 (d of d, 2H, C-9 ,protons, J = 18 Hz), 3.66 ( s , 3H, 0CH 3), 5.93 (d, 1H, o l e f i n i c proton, J = 2 Hz); mass spectrum: m/e 194 (M +), 162. Exact mass c a l c d . f o r C^H^O^: 194.0944; measured (high r e s o l u t i o n mass spectrometry): 194.0944. P r e p a r a t i o n of the B i c y c l i c Ketone 1QA. 103 104 To a c o l d (-78°C), s t i r r e d s o l u t i o n of 3 g (0.43 mol) of l i t h i u m w i r e i n 600 mL of anhydrous ammonia was added a s o l u t i o n of 20 g (0.08 mol) 101 of the b i c y c l i c enone 1 0 3 5 1 i n 200 mL of anhydrous ether and 10 mL 54 (0.10 mol) of anhydrous t e r t - b u t y l a l c o h o l . The c o o l i n g bath was removed and the r e a c t i o n mixture was allowed t o r e f l u x f o r 1 h. S o l i d ammonium c h l o r i d e was added u n t i l the blue c o l o r of the s o l u t i o n was discharged. The ammonia was allowed to evaporate (warm water bath) and ether and water were added to the r e s i d u e . The aqueous phase was e x t r a c t e d thoroughly w i t h e t h e r . The combined organic e x t r a c t s were washed w i t h saturated sodium c h l o r i d e and d r i e d (Na 2S0^). The s o l v e n t s were removed i n vacuo to y i e l d a y e l l o w o i l which c r y s t a l l i z e d upon a d d i t i o n of a few mL of high b o i l i n g (60 - 100°C) petroleum ether. The powdery white c r y s t a l s were r e c r y s t a l l i z e d from hexanes to g i v e 16.1 g (80%) of the b i c y c l i c ketone 104 . Thin l a y e r chromatography i n d i c a t e d one pure product: mp 97 - 99°C ( l i t . 5 5 mp 98 - 99°C); i r ( n u j o l m u l l ) , v 1715 cm"1: 3"H n.m.r., 6 1.07 ( s , 3H, t e r t i a r y methyl), 4.74 (m, 1H, max -0CH0-); mass spectrum: m/e 266 ( M + ) , 182, 165, 85 (100%). Exact mass c a l c d . f o r C, ,H„,0 : 266.1882; measured (high r e s o l u t i o n mass l b 2o 3 spectrometry): 266.1875. This compound had p r e v i o u s l y been prepared i n t h i s l a b o r a t o r y by 25 D.J. Herbert u t i l i z i n g a d i f f e r e n t procedure . 102 P r e p a r a t i o n of the K e t a l Ketone 5J_ 0 57 A s o l u t i o n of 15 g (56 mmol) of the b i c y c l i c ketone 104 and 600 mg of _p_-toluenesulfonic a c i d i n 500 mL of methanol was s t i r r e d a t room temperature f o r 3 h. The methanol was removed i n vacuo and 100 mL of ether added to the r e s i d u e . This e t h e r e a l s o l u t i o n was washed w i t h aqueous sodium bicarbonate and b r i n e p r i o r to being d r i e d (^£20^) . Removal of the ether i n vacuo gave a gummy white s o l i d which was d i s s o l v e d i n 500 mL of benzene. To t h i s s o l u t i o n was added 18.7 g (180 mmol) of 2,2-dimethyl-1,3-propanediol and 200 mg of j>-toluenesulfonic a c i d , and the r e s u l t i n g mixture was r e f l u x e d f o r 2 h under an atmosphere of argon usi n g a Dean-Star k trap to remove the water produced. The mixture was cooled and then d i l u t e d w i t h 200 mL of ether and s u c c e s s i v e l y washed w i t h s a t u r a t e d aqueous sodium bicarbonate, water and b r i n e . The organic phase was d r i e d (Na2S0^) and the s o l v e n t s removed i n vacuo to y i e l d a l i g h t y e l l o w s o l i d . This was d i s s o l v e d i n 100 mL of dry methylene c h l o r i d e and the r e s u l t i n g s o l u t i o n was c a r e f u l l y added to a suspension of 23.6 g (110 mmol) of p y r i d i n i u m chlorochrornate"*^ and 1.6 g (21.4 mmol) of sodium acetate i n 100 mL of dry methylene c h l o r i d e . The r e s u l t i n g mixture was s t i r r e d a t room temperature f o r 3h h a f t e r which 100 mL of anhydrous ether was 103 added and the ensuing s o l u t i o n was passed through a short column of n e u t r a l alumina ( a c t i v i t y I ) . The column was f l u s h e d w i t h s e v e r a l p o r t i o n s of ether and the combined eluents were concentrated. The r e s i d u e was r e c r y s t a l l i z e d from a mixture of ether and hexanes to g i v e 12 g (80% from 104) of the b i c y c l i c keto k e t a l 57*: mp 68 - 70°C ( l i t . 2 5 mp 6 8 -72°C); i r (CHC1,), v 1705 cm - 1; XH n.m.r., 6 0.89, 1.02, 1.12 J max ( s , s, s, 9H, t e r t i a r y m e t h y l s ) , 3.30 - 3.70 (m, 4H, methylene p r o t o n s ) ; mass spectrum: m/e 266 ( M + ) . Exact mass c a l c d . f o r C.,H_,0_: 266.1881; measured (high r e s o l u t i o n mass spectrometry): 266.1881. A n a l , c a l c d . f o r C 1 6 H 2 6 0 3 : C, 72.14, H. 9.84; found: C, 71.95, H, 9.94. Pr e p a r a t i o n of the Photoadducts A and B + 61 (A) 109 =B This compound had p r e v i o u s l y been prepared i n t h i s l a b o r a t o r y by 25 D.J. Herbert u t i l i z i n g s i m i l a r procedures The photoadducts A and B were p r e v i o u s l y prepared i n t h i s l a b o r a t o r y 25 (by a s i m i l a r procedure) by D.J. Herbert 104 A c o l d (-78°C) s o l u t i o n of 1.0 g (3.29 mmol) of the t r i c y c l i c enone 5_6 and 10 mL of a l l e n e i n 60 mL of dry, deoxygenated tetrahydrofuran, contained i n a pyrex tube under n i t r o g e n , was i r r a d i a t e d (450 Watt Hanovia lamp) f o r 4.5 h. The r e a c t i o n mixture was t r a n s f e r r e d to a l a r g e beaker and allowed to warm to room temperature. The sol v e n t s were removed and the r e s u l t i n g o i l was subjected to f l a s h chromatography ( s i l i c a g e l ; 25 x 4 cm column). E l u t i o n of the column w i t h a 10:5:1 mixture of cyclohexane, hexane and e t h y l a c e t a t e 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 ether-hexane to gi v e 437 mg (39%) of the photoadduct 61 (A). Thin l a y e r chromatography i n d i c a t e d one product: mp 134 - 135°C ( l i t . 2 5 mp 134 - 135°C); i r (CHC1-), v 1725 and r c 3 max 1670 cm"1; " S i n.m.r., 6 0.88, 0.95, 0.97 ( s , s, s, 9H, t e r t i a r y m e t h y ls), 3.29 ( s , 1H, C - l l p r o t o n ) , 3.45 - 3.69 (m, 4H, k e t a l methylene p r o t o n s ) , 4.82, 4.97 (m, m, 2H, o l e f i n i c p r o t o n s ) ; mass spectrum: m/e 344 ( M + ) . Exact mass c a l c d . f o r ^ 22^32^3 ! 344.2351; measured (high r e s o l u t i o n mass spectrometry): 344.2349. Further e l u t i o n of the column w i t h the same eluent gave the isomeric photoadduct 109 (B) which on r e c r y s t a l l i z a t i o n from ether-hexanes y i e l d e d 473 mg (42%). Thin l a y e r chromatography i n d i c a t e d one product: mp 131 - 134°C ( l i t . 2 5 mp 132 - 134°C); i r (CHC1-), v 1725 and r r 3 max 1670 cm"1; ^ n.m.r., 6 0.90, 0.95, 1.00 ( s , s, s, 9H, t e r t i a r y methyls), 2.78 (broad s, 2H, unassigned), 3.12 (m, 1H, C - l l p r o t o n ) , 3.48 - 3.60 (m, 4H, k e t a l methylene p r o t o n s ) , 4.80, 4.94 (m, m, 2H, o l e f i n i c p r o t o n s ) ; mass spectrum: m/e 344 (M +). Exact mass c a l c d . f o r ^ 2^32^3 • 344.2351; measured (high r e s o l u t i o n mass spectrometry): 344.2349. 105 P r e p a r a t i o n of the T r i c y c l i c Keto E s t e r 55 55 A. By Ozonolysis of the Photoadduct A 61 (A) A c o l d (-78°C), s t i r r e d s o l u t i o n of 295 mg (0.86 mmol) of the photoadduct j61 (A) i n 50 mL of methanol was subjected to a stream of ozone u n t i l the s o l u t i o n remained b l u e . While s t i l l a t -78°C, the r e s u l t i n g s o l u t i o n was f l u s h e d w i t h argon u n t i l the bl u e c o l o r disappeared and 100 yL (1.36 mmol) of dimethyl s u l f i d e was added. The r e a c t i o n mixture was s t i r r e d a t -78°C f o r 15 min, -15°C f o r 30 min, 0°C f o r 30 min and a t room temperature f o r 1 h. The methanol was removed under reduced pressure and the res i d u e was kept under reduced pressure (vacuum pump) f o r 1 h. The re s i d u e was d i s s o l v e d i n 30 mL of dry methanol and a s o l u t i o n of 51 mg (0.94 mmol) of sodium methoxide i n 20 mL of dry methanol was added. The r e s u l t a n t s o l u t i o n was s t i r r e d a t room temperature f o r 106 1 h. The methanol was removed under reduced pressure and ether and water were added to the r e s i d u e . A f t e r e x t r a c t i o n , the ether l a y e r was washed w i t h water and d r i e d (^£50^). Removal of the sol v e n t gave a c o l o r l e s s o i l which c r y s t a l l i z e d upon a d d i t i o n of a few drops of methanol. Re-c r y s t a l l i z a t i o n from methanol gave 285 mg (88%) of the t r i c y c l i c keto e s t e r 55 as white needles. Thin l a y e r chromatography i n d i c a t e d one pure product: mp 139 - 140°C; i r (CHCl ) , v 1720 - 1740 cm" 1 (broad); hi n.m.r., 6 0.93, 1.01, 1.04 ( s , s, s, 9H, t e r t i a r y m ethyls), 3.52 (m, 4H, k e t a l methylene p r o t o n s ) , 3.66 ( s , 3H, OCHg); mass spectrum: m/e 378 (M +), 305, 219, 167, 141 (100%). Exact mass c a l c d . f o r C ^ H ^ O ^ 378.2406; measured (high r e s o l u t i o n mass spectrometry): 378.2408. 6. By Ozonolysis of the Photoadduct B 108 109HB The procedure described i n s e c t i o n A, above, was used to prepare the t r i c y c l i c keto e s t e r 55 from the photoadduct B. The q u a n t i t i e s o f ma t e r i a l s used were the same. The i s o l a t e d crude product was r e c r y s t a l l i z e d from methanol to give 227 mg (70%) of the t r i c y c l i c keto e s t e r 55 as white needles. Thin l a y e r chromatography i n d i c a t e d one pure product. A l l s p e c t r a l data matched those given i n s e c t i o n A, above. In a d d i t i o n , 107 m e l t i n g p o i n t and mixed m e l t i n g point determination gave i d e n t i c a l values to that obtained i n S e c t i o n A. The aqueous washings from the work-up step were combined and a c i d i f i e d w i t h 1 N h y d r o c h l o r i c a c i d . The r e s u l t a n t s o l u t i o n was e x t r a c t e d s u c c e s s i v e l y w i t h ether and the combined ether e x t r a c t s were d r i e d (Na2S0^). Evaporation of the ether under reduced pressure gave 63 mg (20%) of the t r i c y c l i c keto a c i d 108 as white powdery c r y s t a l s . Thin l a y e r chromatography i n d i c a t e d one pure product: mp 214 - 215°C; i r (CHC1-), v 2600 - 3300 cm - 1 (broad), 3 max 1735 and 1700 cm - 1; 1H n.m.r., 6 0.93, 1.0, 1.07 ( s , s, s, 9H, t e r t i a r y m e t h y l s), 3.5 (broad d, 4H, k e t a l methylene p r o t o n s ) ; mass spectrum: m/e 364 (M +) . Exact mass c a l c d . f o r ^21^32^5 : 364.2250; measured (high r e s o l u t i o n mass spectrometry): 364.2226. C. By Ozonolysis of a Mixture of the Photoadducts A and B An approximately 1:1 mixture of 295 mg of the photoadduct A and B was subjected to the same c o n d i t i o n s as o u t l i n e d i n s e c t i o n A, above. The q u a n t i t i e s of m a t e r i a l s used were the same. The crude product was r e c r y s t a l l i z e d from methanol to give 178 mg (55%) of the t r i c y c l i c keto e s t e r 5f> as white needles. Thin l a y e r chromatography i n d i c a t e d one pure product. A l l s p e c t r a l data matched those given i n s e c t i o n A, above. The aqueous washings from the work-up step were combined and a c i d i f i e d w i t h 1 N h y d r o c h l o r i c a c i d . The r e s u l t a n t s o l u t i o n was e x t r a c t e d s u c c e s s i v e l y w i t h ether and the combined ether l a y e r s were d r i e d (^£50^) . Evaporation of the ether under reduced pressure gave 94 mg (30%) of the t r i c y c l i c keto a c i d 108 as white powdery c r y s t a l s . Thin l a y e r chromatography i n d i c a t e d one pure product. A l l s p e c t r a l data matched those given i n 108 s e c t i o n B, above. D. By E s t e r i f i c a t i o n of the T r i c y c l i c Keto A c i d 1D_8_ To a c o l d (0°C), s t i r r e d s o l u t i o n of approximately 23.1 mg (0.55 mmol) of diazomethane 7 1 i n 20 mL of ether was added dropwise a s o l u t i o n of 20 mg (55 u mol) of the t r i c y c l i c keto a c i d 108 i n 3 mL of ether. A f t e r the s o l u t i o n had been s t i r r e d a t 0"C f o r 30 min, argon was bubbled through the s o l u t i o n to get r i d of the excess diazomethane. Evaporation of the ether under reduced pressure, followed by r e c r y s t a l l i z a t i o n of the crude product from methanol gave 18.7 mg (90%) of the t r i c y c l i c keto e s t e r 55 as white needles. Thin l a y e r chromatography i n d i c a t e d one pure product. A l l s p e c t r a l data matched those given i n s e c t i o n A, above. Reduction of the T r i c y c l i c Keto E s t e r 5_5_ 55 109 A. With Sodium Borohydrlde 60 120 To a s t i r r e d s o l u t i o n of 240 mg (0.63 mmol) of the t r i c y c l i c keto e s t e r 5_5 i n 25 mL of methanol a t room temperature was added 190 mg (5 mmol) of s o l i d sodium borohydride. A f t e r the r e a c t i o n mixture had been s t i r r e d a t room temperature f o r 30 min, the methanol was removed under reduced pressure. Ether was added to the r e s i d u e and the r e s u l t a n t mixture was washed twice w i t h water. The ether e x t r a c t was d r i e d (Na 2S0^). Removal of the ether i n vacuo gave a c o l o r l e s s o i l , which was chromatographed on 10 g of s i l i c a g e l . E l u t i o n of the column w i t h a 4:1 mixture of methylene c h l o r i d e and ether gave 108 mg (49%) of the l a c t o n e 120. This m a t e r i a l was r e c r y s t a l l i z e d from methanol to g i v e an a n a l y t i c a l sample: mp 194°C; i r (CHC1„), v 1730, 1115, 1100 cm" 1; *H n.m.r., 6 0.88, ' 3_ max — 0.92, 1.0 ( s , s, s, 9H, t e r t i a r y methyls), 3.5 (m, 4H, k e t a l methylene p r o t o n s ) , 4.78 (m, 1H, -CH-0C0); mass spectrum: m/e 348 ( M + ) , 167, 154, 141 (100%). Exact mass c a l c d . f o r C 2 1 H 3 2 0 4 : 348.2301; measured (high r e s o l u t i o n mass spectrometry): 348.2304. A n a l , c a l c d . f o r < - 2 l H 3 2 ^ 4 : C, 72.38; H, 9.26; found: C, 71.97; H, 8.95. Further e l u t i o n of the column w i t h the same sol v e n t mixture gave 121 mg (50%) of the compound ^0 as a very v i s c o u s , c o l o r l e s s o i l . Thin l a y e r chromatography i n d i c a t e d one pure product: i r (CHC1,), v 110 -1 1-3300 - 3500, (broad), 1725, .1115 and 1095 cm"1; n.m.r., S 0.95 ( s , 3H, t e r t i a r y methyl), 0.99 ( s , 6H, t e r t i a r y methyls), 3.58 (broad d, 4H, k e t a l methylene p r o t o n s ) , 3.65 ( s , 3H, 0-CH 3), 4.54 (m, 1H, -CH-OH); mass  spectrum: m/e 380 ( M + ) , 167, 141 (100%). Exact mass c a l c d . f o r C 22 H36°5 : 380.2562; measured (high r e s o l u t i o n mass spectrometry): 380.2561. B. With L i t h i u m T r i - s e c - b u t y l b o r o h y d r i d e (L-Selectride™) To a c o l d (-78°C), s t i r r e d s o l u t i o n of 25 mg (66 y mol) of the t r i c y c l i c keto e s t e r _5_5 i n 5 mL of anhydrous tet r a h y d r o f u r a n was added TM dropwise 100 yL of a 1 M s o l u t i o n (100 y mol) of L - S e l e c t r i d e ( A l d r i c h ) i n t e t r a h y d r o f u r a n . The r e a c t i o n mixture was s t i r r e d a t -78°C f o r 3 h, a f t e r which 1 mL of water, 100 yL of 1 M aqueous sodium h y d r i d e , and 25 yL of 30% hydrogen peroxide were added c o n s e c u t i v e l y . A f t e r the r e s u l t a n t mixture had been s t i r r e d at room temperature f o r 15 min, i t was e x t r a c t e d thoroughly w i t h e t h e r . The combined or g a n i c e x t r a c t was washed w i t h water and d r i e d over anhydrous sodium s u l f a t e . Evaporation of the s o l v e n t gave a c o l o r l e s s o i l which was chromatographed on 1 g of s i l i c a g e l . E l u t i o n of the column w i t h a 4:1 mixture of methylene c h l o r i d e - e t h e r gave 5.3 mg (23%) of the l a c t o n e 120 and 18.6 mg (74%) of the compound 60_. A l l s p e c t r a l data f o r the two compounds were i d e n t i c a l w i t h those given i n s e c t i o n A, above. I l l P r e p a r a t i o n of the T r i c y c l i c D i o l 129 129 To a c o l d (0°C), s t i r r e d s o l u t i o n of 13.3 mg (0.35 mmol) of l i t h i u m aluminum hydride i n 5 mL of anhydrous tetrahydrofuran was added a s o l u t i o n of 50 mg (0.14 mmol) of the la c t o n e 120 i n 5 mL of anhydrous t e t r a h y d r o -furan. The r e a c t i o n mixture was s t i r r e d v i g o r o u s l y and r e f l u x e d f o r 2.5 h. The excess l i t h i u m aluminum hydride was destroyed by c a r e f u l a d d i t i o n of s o l i d Na 2S0^.10H 20. The s o l u t i o n was f i l t e r e d and the c o l l e c t e d s a l t s were washed thoroughly w i t h ether. Removal of the s o l v e n t from the combined f i l t r a t e gave a white powder. This m a t e r i a l was r e c r y s t a l l i z e d from methanol to give 50 mg (99%) of the t r i c y c l i c d i o l 129 as f i n e white powdery c r y s t a l s . Thin l a y e r chromatography i n d i c a t e d one pure product: mp 180 - 182°C; i r (CHCl,); v 3200 - 3500 (broad), 1120 r r 3_ max ' and 1100 cm" ; H n.m.r., 6 0.93 ( s , 6H, t e r t i a r y methyls), 1.00 ( s , 3H, t e r t i a r y methyl) 3.51 (broad s, 4H, k e t a l methylene p r o t o n s ) , 3.8 ( t , 2H, -CH20H, J = 7 l z ) , 4.55 (m, 1H, -CHOH); mass spectrum: m/e 352 (M +). Exact mass c a l c d . f o r C o.H o,0.: 352.2613; measured (high z i JO r e s o l u t i o n mass spectrometry): 352.2623. 112 P r e p a r a t i o n of the T r i c y c l i c D i o l To a c o l d (0°C), s t i r r e d s o l u t i o n of 14.4 mg (0.38 mmol) of l i t h i u m aluminum hydride i n 3 mL of anhydrous ether was added a s o l u t i o n of 57 mg (0.15 mmol) of the e s t e r 6_0_ i n 3 mL of anhydrous ether. The r e a c t i o n mixture was s t i r r e d v i g o r o u s l y f o r 15 min at 0°C and f o r 30 min at room temperature. The excess l i t h i u m aluminum hydride was destroyed by c a r e f u l a d d i t i o n of s o l i d Na„S0..10H_0. The s o l u t i o n was f i l t e r e d and 2 4 2 the c o l l e c t e d s a l t s were washed thoroughly w i t h ether. Removal of the solv e n t from the combined f i l t r a t e gave 53 mg (100%) of the t r i c y c l i c d i o l 5_9 as a c o l o r l e s s o i l . Thin l a y e r chromatography i n d i c a t e d one pure product: i r (CHC1-); v 3200 - 3600 (broad), 1120 and 1100 cm - 1; n.m.r., 6 0.94 ( s , 3H, t e r t i a r y methyl), 0.96 ( s , 6H, t e r t i a r y m e t h y ls), 3.52 (broad d, 4H, k e t a l methylene p r o t o n s ) , 3.7 ( t , 2H, -CH^OH, J = 8 Hz), 4.54 (m, 1H, -CH0H); mass spectrum: m/e 352 ( M + ) . Exact mass c a l c d . f o r C_.H 0 : 352.2613; measured (high r e s o l u t i o n mass spectrometry): 21 36 4 352.2613. 113 P r e p a r a t i o n of the T r i c y c l i c Dimesylate 130 To a w e l l s t i r r e d s o l u t i o n of 50 mg (0.14 mmol) of the t r i c y c l i c d i o l 129 i n 10 mL of dry p y r i d i n e was added 54 yL (0.70 mmol) of methane-s u l f o n y l c h l o r i d e . The r e a c t i o n mixture was s t i r r e d at room temperature overnight a f t e r which I t was poured onto 10 g of crushed i c e . The r e s u l t a n t mixture was e x t r a c t e d w i t h ether and the combined ether e x t r a c t s were d r i e d ( N a 2 S 0 4 ) . Removal of the s o l v e n t i n vacuo gave a ye l l o w o i l which was chromatographed on 2 g of s i l i c a g e l . E l u t i o n of the column w i t h a 9:1 mixture of methylene c h l o r i d e - e t h e r gave 68.5 mg (95%) of the t r i c y c l i c dimesylate 130 as a l i g h t y e l l o w o i l . Thin l a y e r chromatography i n d i c a t e d one pure product: i r (CHCl^); v m a x 1350, 1330 and 1175 cm"1; " S i n.m.r., 6 0.93, 0.97, 1.01 ( s , s, s, 9H, t e r t i a r y m e t h y l s), 3,02, 3.03 ( s , s, 6H, CH 3S0 2~), 3.5 (m, 4H, k e t a l methylene p r o t o n s ) , 4.4 ( t , 2H, -CH^-OMs, J = 9 Hz), 5.3 (m, 1H, -CH-OMs); mass  spectrum: m/e 508 (M +), 412, 316. Exact mass c a l c d . f o r ^ 23 H40^8^2 : 508.2165; measured (high r e s o l u t i o n mass spectrometry): 508.2167. 114 P r e p a r a t i o n of the T r i c y c l i c Dimesylate 5Jt Ms( -OMs 54 This compound was prepared from the t r i c y c l i c d i o l 5_9_, by a procedure i d e n t i c a l w i t h t h a t used f o r the p r e p a r a t i o n of t r i c y c l i c dimesylate 130. The q u a n t i t i e s of m a t e r i a l s used were the same. The y i e l d of the t r i c y c l i c dimesylate _54_ ( a l i g h t y e l l o w o i l ) , a f t e r column chromatography of the crude product, was 57.7 mg (80%). Thin l a y e r chromatography i n d i c a t e d one pure product: i r (CHC1-); v 1360, 1340 and 1170 cm r v 3 max \L n.m.r., 6 0.93, 0.94, 1.0 ( s , s, s, 9H, t e r t i a r y m e t h y ls), 3.01, 3.04 ( s , s, 6H, CH 3-S0 2-), 3.5 (m, 4H, k e t a l methylene p r o t o n s ) , 4.3 ( t , 2H, -CH2-0Ms, J = 9 Hz), 5.28 (m, 1H, -CH-OMs) ; mass spectrum: m/e 508 ( M + ) , 412, 316. Exact mass c a l c d . f o r C23 H 4 o°8 S2 : 5 0 8 - 2 1 6 5 5 measured (high r e s o l u t i o n mass spectrometry): 508.2160. Pr e p a r a t i o n of the T r i c y c l i c D i n i t r i l e H I 115 To a s t i r r e d s o l u t i o n of 30 mg (59 u mol) of the t r i c y c l i c dimesylate 130 i n 3 mL of hexamethylphosphoramide at room temperature, was added s o l i d sodium cyanide u n t i l an excess of the s o l i d was l e f t u n d i s s o l v e d . The r e a c t i o n mixture was s t i r r e d a t room temperature f o r 3 h and then maintained a t 60°C f o r 48 h. Ether was added and the organic l a y e r was washed once w i t h water and twice w i t h a s a t u r a t e d s o l u t i o n of copper s u l f a t e , and then d r i e d (Na 2S0^). Removal of the ether gave a y e l l o w o i l which was chromatographed on 1 g of s i l i c a g e l . E l u t i o n of the column w i t h a 3:1 mixture of hexanes-ethyl a c e t a t e gave a white c r y s t a l l i n e s o l i d , which was r e c r y s t a l l i z e d from methanol to g i v e 14.2 mg (65%) of the t r i c y c l i c d i n i t r i l e . Thin l a y e r chromatography i n d i c a t e d one pure product: mp 194°C; i r (CHCl,); v ; 2240 and 2230 3 max cm"1; *H n.m.r., 6 0.95 ( s , 6H, t e r t i a r y m e t h y l s ) , 0.97 ( s , 3H, t e r t i a r y methyl ), 2.95 (m, 1H, -CH-CN), 3.5 (broad s, 4H, k e t a l methylene p r o t o n s ) ; mass spectrum: m/e 370 (M +), 285, 195, 167, 141 (100%). Exact  mass c a l c d . f o r ^23 H34 N2^2 : 370.2620; measured (high r e s o l u t i o n mass spectrometry): 370.2618. Pr e p a r a t i o n of the T r i c y c l i c D i n i t r i l e 123 123 116 This compound was prepared from the t r i c y c l i c dimesylate j>4_ by a procedure i d e n t i c a l w i t h that used f o r the p r e p a r a t i o n of the t r i c y c l i c d i n i t r i l e 131. The q u a n t i t i e s of m a t e r i a l s used were the same. As b e f o r e , column chromatography, followed by r e c r y s t a l l i z a t i o n of the crude product from methanol, gave 13.1 mg (60%) of the t r i c y c l i c d i n i t r i l e 123 as a white c r y s t a l l i n e s o l i d . Thin l a y e r chromatography i n d i c a t e d one pure product: mp 159 - 161°C; i r (CHC1_); v 2240 and 2230 cm" 1; \l n.m.r., 6 0.91, 3 max ' 0.98, 1.01 ( s , s, s, 9H, t e r t i a r y m ethyls), 3.03 (m, 1H, -CH-CN), 3.5 (m, 4H, k e t a l methylene p r o t o n s ) ; mass spectrum: m/e 370 (M +), 285, 195, 167, 141 (100%). Exact mass c a l c d . f o r C 2 3 H 3 4 N 2 ° 2 : 3 ?0.2620; measured (high r e s o l u t i o n mass spectrometry): 370.2611. P r e p a r a t i o n of the T e t r a c y c l i c E n a m i m m i t r i l e .124.. 124 A. From the T r i c y c l i c D i n i t r i l e 123. To a s t i r r e d s o l u t i o n of 20 mg (54 u mol) of the t r i c y c l i c d i n i t r i l e 123 i n 1 mL of t e r t - b u t y l a l c o h o l under argon, was added a C a t a l y t i c q u a n t i t y of potassium t e r t - b u t o x i d e ( A l d r i c h ) . The r e a c t i o n mixture was r e f l u x e d f o r 30 h a f t e r which the t e r t - b u t y l a l c o h o l was removed i n vacuo. Ether 117 and water were added and the ether e x t r a c t was d r i e d (^£50^) and concentrated to give a c o l o r l e s s o i l which c r y s t a l l i z e d upon a d d i t i o n of a few drops of methanol. This m a t e r i a l was r e c r y s t a l l i z e d from methanol to give 18 mg (90%) of 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 124 as white needles. Thin l a y e r chromatography i n d i c a t e d one pure product: mp 213 -215°C; i r (CHCl.); v 3490, 3390, 2165, 1642 and 1605 cm" 1; h n.m.r. , 3 max ' 6 0.90, 0.92, 1.01 ( s , s, s, 9H, t e r t i a r y methyls), 3.52 (m, 4H, k e t a l methylene pr o t o n s ) , 4.23 (broad s, 2H, - N I L p ; mass spectrum: m/e 370 (M +). Exact mass c a l c d . f o r ^ 23^34^2^2* 370.2620; measured (high r e s o l u t i o n mass spectrometry): 370.2613. B. From the T r i c y c l i c D i n i t r i l e 131 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 124 was prepared from the t r i c y c l i c d i n i t r i l e 131 by a procedure i d e n t i c a l w i t h that employed as described i n s e c t i o n A, above. 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 : t r i c y c l i c d i n i t r i l e 131: 5 mg (13.5 u mol) t e r t - b u t y l a l c o h o l : 0.5 mL The crude product was obtained i n 81% y i e l d and a l l s p e c t r a l data corresponded to those obtained f o r 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 124 as summarized i n s e c t i o n A, above. 118 P r e p a r a t i o n of the T e t r a c y c l i c Dione 132 i H 132 To a w e l l s t i r r e d s o l u t i o n of 18 mg (49 u mol) of 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 124 i n 1 mL of g l a c i a l a c e t i c a c i d and 100 yL of water, was added 400 yL of 85% phosphoric a c i d ^ 9 . The s o l u t i o n was r e f l u x e d f o r 24 h, and, a f t e r being cooled to room temperature, was poured onto 2 g of crushed i c e . S o l i d sodium bicarbonate was added u n t i l the mixture was b a s i c to l i t m u s , and the r e s u l t a n t mixture was e x t r a c t e d thoroughly w i t h ether. The combined organic e x t r a c t s were d r i e d (Na 2S0^). Removal of the s o l v e n t i n vacuo gave a c o l o r l e s s o i l which was chromatographed on 1 g of s i l i c a g e l . E l u t i o n of the column w i t h a 1:1 mixture of hexane-ethyl acetate gave 10.1 mg (80%) of the t e t r a c y c l i c dione 132 as a white powder. This m a t e r i a l was r e c r y s t a l l i z e d from ether-hexanes. Thin l a y e r Chromatography i n d i c a t e d one pure product: mp 131 - 133°C; i r (CHC1 3) ; v 1705 cm"1; n.m.r., 6 1.16 ( s , 3H, t e r t i a r y m e t h y l s ) ; mass spectrum: m/e 260 (M +) (100%). Exact mass c a l c d . f o r C^7 H24°2 : 260.1777; measured (high r e s o l u t i o n mass spectrometry): 260.1778. 119 BIBLIOGRAPHY 1. E. Wenkert, Chem. and Ind., 282 (1955). 2. K.M. Brundret, W. D a l z i e l , B. Hesp, J.A. J a r v l s , and S. Meidle, J . Chem. Soc. Chem. Commun., 1027 (1972). 3. W. D a l z i e l , B. Hesp, K.M. Stevenson, and J.A. J a r v i s , J . Chem. Soc. P e r k i n I , 2841 (1973). 4. B.M. Trost, Y. Nishimura, K. Yamamoto and S.S. McElvain, J . Am.  Chem. S o c , 101, 1328 (1979). 5. J.E. McMurry, A. Andrus, G.M. Ksander, J.H. Musser and M.A. Johnson, J . Am. Chem. S o c , 101, 1330 (1979). 6. E.J. Corey, M.A. Tius and J . Das, J . Am. Chem. S o c , 102, 1742 (1980). 7. P.S. Manchand, J.D. White, H. Wright, and J . Clardy, J . Am. Chem. S o c , j)5, 2705 (1973). 8. R.E. I r e l a n d and P.A. A r i s t o f f , J . Org. Chem., 44, 4323 (1979). 9. T. Kametani, T. Honda, Y. S h i v a t o r i , and K. Fukumoto, Tetrahedron  L e t t . , 1665 (1980). 10. P.K. Ghosal, D. Mukherjee and P.C. Dutta, Tetrahedron L e t t . , 2997 (1976). 11. Samir C h a t t e r j e e , J . Chem. S o c Chem. Commun., 622 (1979). 12. B.M. Trost and M.J. Bogdanowicz, J . Am. Chem. S o c , 95, 5311 (1973). B. M. Trost and S. Kurozumi, Tetrahedron L e t t . , 1929 (1974). 13. B.M, Trost and P.H. Scudder, J . Am. Chem. S o c , 99, 7601 (1977). 14. J.P. Collman, Acc. Chem. Res., 8, 342 (1975). J.Y. Merour, J.L. Roustan, C. C h a r r i e r , J . C o l l i n and J . Benaim, J . Organomet. Chem., 51, C24 (1973). 15. CD. De Boer, J . Org. Chem., 3_9, 2426 (1974). 16. A. de Groot and B.J.M. Jansen, Tetrahedron L e t t . , 2709 (1976). 17. T.G. Back and D.H.R. Barton, J . Chem. Soc. P e r k i n Trans. I , 924 (1977). 18. | W.C S t i l l , J . Am. Chem. S o c , 100, 1481 (1978). 19. P. McClosky, J . Chem. S o c , 3811 (1965). 20. S. Turner, The Design of Organic S y n t h e s i s , E l s e v i e r , 1976. 21. K. Ogura, M. Yamashita, S. Farukawa, M. Suzuki and G. Tsuchihashi, Tetrahedron L e t t . , 2767 (1975). 120 22. D. Seebach and F. Lehr, Helv. Chem. Acta. , 62, 2239 (1979). 23. C.F. B a r t l e t t , Tetrahedron L e t t . , 331 (1977). 24. D.C. W i g f i e l d , Tetrahedron, 35, 449 (1979). H.C. Brown and s. Krishnamurthy, Tetrahedron, 35, 567 (1979). 25. D.J. Herbert, Ph.D. Thesis, U n i v e r s i t y of B r i t i s h Columbia (1979). 26. For a recent review see R.A. E l l i s o n , S y n t h e s i s , 397 (1973). 27. S. Bergstrom, Science, 157, 382 (1967). 28. A.W. Dox and B. Houston, J . Am. Chem. S o c , 46, 252 (1924). 29. M. Miyano and C.R. Porn, J . Org. Chem., 37, 268 (1972); E. Brown and M. Regault, Tetrahedron L e t t . , 1927 (1973); D.A. Evans, C L . Sims, and G.C Andrews, J . Am. Chem. S o c , 99, 5453 (1977). 30. Y. Fukuyama, T. Tokoroyama, and T. Kubota, Tetrahedron L e t t . , 4869 (1973); T. Curigmy, M. Larcheveque, and H. Normant, i b i d . , 1237 (1974). 31. R.B. M i l l e r , Synth. Commun., 2, 267 (1972); D.A. McCrae and L. Dolby J . Org. Chem., 42, 1607 (1977); P.E. Sum and L. W e i l e r , Can. J . Chem., 56, 2301,(1978). 32. G. Stork and M.E. Jung, J . Am. Chem. S o c , 96, 3682 (1974). 33. M. M i y a s h i t a , T. Yanami, and A. Y o s h i k o s h i , J . Am. Chem. S o c , 98, 4679 (1976). 34. P.M. Jacabson, R.A. Raths, and J.H. McDonald I I I , J . Org. Chem., 42, 2-5.45 T1977) . 35. W.G. Dauben and D.J. H a r t , J . Org. Chem., 42, 3787 (1977). 36. E.J. Nienhouse, R.M. Irwin, and G.R. F i n n i , J . Am. Chem. Soc., 89, 4557 (1967). 37. M.S. Newman and R.J. Harper, J r . , J . Am. Chem. S o c , 80, 6350 (1958). 38. For the e f f e c t of p r o t i c and a p r o t i c c o n d i t i o n s on isomer r a t i o see E. Brown and M. Ragault, Tetrahedron L e t t . , 1927 (1973). 39. R.D. C l a r k , L.G. Kozar, and C.H. Heathcock, Synth. Commun., 5_, 1 (1975). 40. W.S. Wadsworth, J r . , and W.D. Emmons, J . Am. Chem. S o c , 83, 1733 (1961); L. Horner, H. Hoffmann, H.G. Wippel, and G. K l a h r e , Chem. Ber., 92, 2499 (1959). 41. A. Michael and G.H. Carlson, J . Am. Chem. S o c , 57, 162 (1935). 121 42. F.A. Cotton and R.A. Schunn, J . Am. Chem. S o c , 85, 2394 (1963). 43. L. Horner and E.H. Winkelmann, Newer Methods of P r e p a r a t i v e Organic Chemistry, V o l . I l l , p. 151, Academic P r e s s , 1964. 44. J.A. M a r s h a l l and G.A. Flynn, Synth. Commun., j9» 1 2 3 (1979). We are g r a t e f u l to Mr. M. Burmeister f o r supplying a sample of t h i s compound. 45. H.O. House, Modern S y n t h e t i c Reactions, 2nd Ed., p. 527, W.A. Benjamin Inc., 1972. 46. P.A. Grieco and C.S. Pogonowski, S y n t h e s i s , 425 (1973). 47. J.M. Conia and M.L. L e r i v e r e n d , B u l l . Soc. Chim. F r . , 2981 (1970). 48. P. Wieland and K. Miescher, Helv. Chem. Acta., 33, 2215 (1950). S. Ramachandran and M.S. Newman, Org. Syn., 41, 38 (1961). 49. J.D. Cocker and T.G. H a l s a l l , J . Chem. S o c , 3441 (1957). 50. E. P i e r s , W. de Waal, and R.W. B r i t t o n , J . Am. Chem. S o c , 93, 5113 (1971). 51. N. M i y a s h i t a , A. Y o s h i k o s h i and P.A. Grieco, J . Org. Chem., 42, 3772 (1977). 52. G. Stork and S.D. D a r l i n g , J . Am. Chem. S o c , 82, 1512 (1960); 86, 1761 (1964). 53. D. Caine, Org. Reactions, 23, 1 (1976). 54. H.A. Smith, B.J.L. Huff, W.J. Powers, and D. Caine, J . Org. Chem., 32_, 2851 (1967). 55. R.H. Jaeger, Tetrahedron, 2_, 326 (1958). 56. Y.Y. L i n and J.B. Jones, J . Org. Chem., 38, 3575 (1973). 57. E.J. Corey and J.W. Suggs, Tetrahedron L e t t . , 2647 (1975). 58. R. P a u p t i t and J . T r o t t e r , i n press. 59. P.G. Bauslaugh, Synthesis, 287 (1970). 60. E.J. Corey, J.D. Bass, R. LeMahieu, and R.B. M i t r a , J . Am. Chem. S o c , 86, 5570 (1964). 61. J . J . Pappas, W.P. Keareney, E. Gancher, and M. Berger, Tetrahedron  L e t t . , 4273 (1966). 122 62. G. Lenz, Tetrahedron, 31, 1587 (1975). 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). 63. a. K. Wiesner, Tetrahedron, 31, 1655 (1975); b) G. M a r i n i - B e t t o l o , S.P. Sahoo, G.A. Poulton, T.Y.R. T s a i , and K. Wiesner, Tetrahedron, 36, 719 (1980); c) J.F. Blount, G.D. Gray, K.S. A l w a l , T.Y.R. T s a i , and K. Wiesner, Tetrahedron L e t t . , 4413 (1980). 64. R.O. Loufty and P. de Mayo, J . Am. Chem. S o c , 99, 3559 (1977). 65. K.B. Wiberg, B.L. Furtekj and L.K. O l l i , J . Am. Chem. S o c , 101, 7675 (1979); K.B. Wiberg, J.E. H i a t t , and K. Hseih, J . Am. Chem. Soc., 92, 544 (1970); J . Meinwald, J . J . T u f a r i e l l o , and J . J . Hurst, J . Org. Chem., 29, 2914 (1964). 66. H.C. Brown and S. Krishnamurthy, J . Am. Chem. S o c , 94, 7159 (1972). 67. O.W. Lever, J r . , Tetrahedron, 1943 (1976); G. Stork and L. Maldonado, J . Am. Chem. S o c , 93, 5286 (1971); T. Mukaiyama, K. Narasaka, and M. Furu.sato, J . Am. Chem. S o c , 94, 8641 (1972); D. Seebach and E.J. Corey, J. Org. Chem., 40, 231 (1975); S. Hunig and G. Wehner, Synthesis, 180, 391 (1975); B.M. Trost and Y. Tamaru, Tetrahedron L e t t . , 3797 (1975). 68. J.P. Schaefer and J . J . B l o o m f i e l d , Org. Reactions, 15, 1 (1967). 69. S. Baldwin, J . Org. Chem/, 26, 3280 (1961). 70. S. Baldwin, J. Org. Chem., 26, 3288 (1961). 71. T.J. De Boer and H.J. Backer, Org. Syn., C o l l . V o l . IV, 250 (1963); C D . Gutsche, Org. Reactions, 8, 392 (1954) . 

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
http://iiif.library.ubc.ca/presentation/dsp.831.1-0060812/manifest

Comment

Related Items