Open Collections

UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Sulphur and selenium mediated cyclizations of β-keto esters : a novel synthetic approach to carotenoid… Alderdice, Margot Elaine 1980

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

Notice for Google Chrome users:
If you are having trouble viewing or searching the PDF with Google Chrome, please download it here instead.

Item Metadata

Download

Media
831-UBC_1980_A6_7 A44.pdf [ 4.41MB ]
Metadata
JSON: 831-1.0059424.json
JSON-LD: 831-1.0059424-ld.json
RDF/XML (Pretty): 831-1.0059424-rdf.xml
RDF/JSON: 831-1.0059424-rdf.json
Turtle: 831-1.0059424-turtle.txt
N-Triples: 831-1.0059424-rdf-ntriples.txt
Original Record: 831-1.0059424-source.json
Full Text
831-1.0059424-fulltext.txt
Citation
831-1.0059424.ris

Full Text

SULPHUR AND SELENIUM MEDIATED CYCLIZATIONS OF 3-KETO ESTERS - A NOVEL SYNTHETIC APPROACH TO CAROTENOID END GROUPS by MARGOT ELAINE ALDERDICE B . S c , The 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 , 1977 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n THE FACULTY OF GRADUATE STUDIES DEPARTMENT OF CHEMISTRY We a c c e p t t h i s t h e s i s as c o n f o r m i n g t o the r e q u i r e d s t a n d a r d THE UNIVERSITY OF BRITISH COLUMBIA September, 1980 (c) M a r g o t E l a i n e A l d e r d i c e , 1980 In p r e s e n t i n g t h i s t h e s i s in p a r t i a l f u l f i l m e n t o f the r e q u i r e m e n t s f o r an a d v a n c e d d e g r e e at the 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 ag ree that t h e L i b r a r y s h a l l make 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 and s t u d y . I f u r t h e r agree that 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 may be g r a n t e d by the Head o f my Department o r by h i s r e p r e s e n t a t i v e s . It 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 not be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Department of Chemistry The 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 2075 Wesbrook Place Vancouver, Canada V6T 1W5 Date - 1 1 -B r i a n and My Parents ABSTRACT The e l e c t r o p h i l i c c y c l i z a t i o n of the 8-keto e s t e r 4j3 to the s e l e n i d e 6jJ and to the s u l f i d e ET7 v i a d i f f e r e n t methods, was achieved. These two products were then e l a b o r a t e d i n an attempt 0 r ^ N r ^ C 0 2 C H 3 to produce a C - 2 s u b s t i t u t e d c a r o t e n o i d end group moiety 14_. The selenium route was d i s c o n t i n u e d , though, when d i f f i c u l t i e s in R- alkyl U a l k y l a t i n g the s e l e n i d e 8!l could not be overcome. The sulphur route proved to be more s u c c e s s f u l when the sulphoxide 98 was - iv -alkylated with two d i f f e r e n t groups in the C-2 po s i t i o n . How-ever, the ensuing elimination of the sulphoxide in the f i r s t product and the rearrangement of the second product precluded the option of f i n i s h i n g the route to a carotenoid end group moiety 14 at t h i s time. An intermediate suitable for elaboration as a C-3 hydroxy-lated carotenoid end group moiety was also prepared from both the selenium and sulphur routes. - v -TABLE OF CONTENTS Page ABSTRACT m TABLE OF CONTENTS v LIST OF FIGURES v i LIST OF ABBREVIATIONS v i i ACKNOWLEDGEMENTS v i i i A. INTRODUCTION 1. Introductory Remarks 1 2. Carotenoids 3 3. Structure and Nomenclature of Carotenoids 5 4. H i s t o r i c a l Background 7 5. Uses of Carotenoids 8 6. Biosynthesis of Carotenoids 9 7. Synthesis of Carotenoids and Irones 11 8. E l e c t r o p h i l i c Cyclizations 21 B. RESULTS AND DISCUSSION 1. Introductory Remarks 32 2. Selenium Route 3 2 3. Sulphur Route 43 4. Diene Synthesis from Selenoxide and Sulphoxide . . 58 5. Conclusion . 59 C. EXPERIMENTAL 60 D. BIBLIOGRAPHY 81 E. SPECTRAL INDEX 8 5 - v i -LIST OF FIGURES Figure T i t l e Page 1 Nomenclature for carotenoid end groups 6 2 Biosynthesis of C- n carotene from mevalonic acid (MVA) . . . . 10 3 Three strategies for synthesizing carotenoids . . 12 4 Synthesis of irones (22) from a-pinene (2_0) . . . . 16 5 Synthesis of (3-irone (1_5) from 2,3-dime t h y l -3-buten-2-ol (23) 17 6 Synthesis of irones (22) from 3,7-dimethylocta-2,6-dien-l-ol (2_6) 19 7 Synthesis of decaprenoxanthin (3_8) from 6-methyl-5-hepten-2-one (32) 20 8 Reaction of nitromethane and phenylsulphenyl tetrafluoroborate to form fluoroboric acid . . . . 45 - V l l -L I S T OF ABBREVIATIONS DECP d i e t h y l c h l o r o p h o s p h a t e DIBAL d i i s o b u t y l a l u m i n u i r i h y d r i d e e q . e q u i v a l e n t (sT" e t h e r e t h y l e t h e r ^-NMR p r o t o n n u c l e a r m a g n e t i c r e s o n a n c e IR i n f r a r e d LAH l i t h i u m a l u m i n u m h y d r i d e LDA l i t h i u m d i i s o p r o p y l a m i d e NBS N - b r o m o s u c c i n i m i d e Ph p h e n y l PPTS p y r i d i n i u m p _ - t o l u e n e s u l p h o n a t e RBF r o u n d b o t t o m f l a s k THF t e t r a h y d r o f u r a n THP 2 - t e t r a h y d r o p y r a n y l TLC t h i n l a y e r c h r o m a t o g r a p h y A b b r e v i a t i o n s f o r m u l t i p l i c i t i e s o f 1H-NMR s i g n a l s s = s i n g l e t b r s = b r o a d s i n g l e t d = d o u b l e t t = t r i p l e t q = q u a r t e t qn = q u i n t e t m = m u l t i p l e t ACKNOWLEDGEMENTS I would l i k e to thank my supervisor, Dr. Larry Weiler, for his encouragement, enthusiasm and invaluable help throughout the period of time the research for and preparation of this thesis were undertaken. In addition, I am indebted to Mr. Sam Tischler for his helpful suggestions in the preparation of t h i s thesis. - 1 -A . I N T R O D U C T I O N O v e r t h e p a s t d e c a d e , t h e r e a c t i o n o f t h e d i a n i o n o f m e t h y l a c e t o a c e t a t e " ' " w i t h v a r i o u s e l e c t r o p h i l i c r e a g e n t s h a s p r o v e n 2 t o b e a v e r s a t i l e s y n t h e t i c m e t h o d , a f a c t e x e m p l i f i e d b y t h e d i v e r s e a n d n u m e r o u s w a y s i n w h i c h g - k e t o e s t e r a d d u c t s h a v e b e e n u s e d i n o r g a n i c s y n t h e s i s . F o r i n s t a n c e , t h i s m e t h o d h a s 3 b e e n u t i l i z e d i n t h e c o n s t r u c t i o n o f t h e f r a g r a n t j a s m o n o i d s , a s w e l l a s i n t h e p r e p a r a t i o n o f a p r o s t a g l a n d i n i n t e r m e d i a t e ^ a n d m o k u p a l i d e ^ , a c o m p o u n d i s o l a t e d f r o m a m a r i n e o r g a n i s m . A l t h o u g h t h e a l k y l a t i o n o f d i a n i o n s o f g - d i k e t o n e s i s w e l l k n o w n a n d h a s b e e n s t u d i e d e x t e n s i v e l y , t h e r e a c t i o n p o s s e s s e s a s e r i o u s d r a w b a c k t h a t h a s b e e n o v e r c o m e b y t h e u s e o f ft-keto e s t e r d i a n i o n s . S i t e s e l e c t i v e a l k y l a t i o n o f t h e d i a n i o n o f a 0 - d i k e t o n e i s n o t a l w a y s f e a s i b l e , s i n c e i n m a n y c a s e s i t i s n o t p o s s i b l e t o d i f f e r e n t i a t e b e t w e e n t h e t w o c h e m i c a l l y s i m i l a r m e t h y l e n e g r o u p s ( e q u a t i o n 1). On t h e o t h e r h a n d , a 3 - k e t o e s t e r d o e s n o t s u f f e r f r o m t h i s d i s a d v a n t a g e , a n d y - a l k y l a t i o n o f t h e d i a n i o n p r o c e e d s c l e a n l y ( e q u a t i o n 2). C o u p l e d w i t h t h i s r e g i o -s e l e c t i v i t y i s t h e e a s e w i t h w h i c h t h e g - k e t o e s t e r d i a n i o n c a n b e g e n e r a t e d . One a s p e c t o f g - k e t o e s t e r c h e m i s t r y t h a t h a s r e c e i v e d m u c h a t t e n t i o n r e c e n t l y i s t h e 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 o f y - a l k y l a t e d o l e f i n i c a d d u c t s t o f o r m f i v e a n d s i x m e m b e r e d r i n g s , 7 f o r e x a m p l e , e q u a t i o n 3 . T h e s e c y c l i z a t i o n s p r o b a b l y i n v o l v e o o 2 ec'- Q o R V ^ A O R ' > R ^ V ^ O R ' base E* 0 0 E - 3 the e n o l tautomer of the g-keto e s t e r which can p a r t i c i p a t e i n the r i n g forming p r o c e s s . Once the r i n g i s formed, the r e s i d u a l e s t e r f u n c t i o n a l i t y can then be e l a b o r a t e d . The aim of the work presented i n t h i s t h e s i s i s to extend these c y c l i z a t i o n r e a c t i o n s , using other e l e c t r o p h i l i c reagents and to demonstrate how the r e s u l t i n g s u b s t i t u t e d products can be used i n the s y n t h e s i s of ir o n e s and c a r o t e n o i d end groups. 2. CAROTENOIDS Carotenoids are a group of pigments, yellow to red i n c o l o u r , which are r e s p o n s i b l e f o r many t a n t a l i z i n g c o l o u r s i n f r u i t s , v e g e t a b l e s , mushrooms, f i s h , crustaceae , p o u l t r y , eggs p and d a i r y products . For i n s t a n c e , the deep red co l o u r that develops i n r i p e n i n g tomatoes i s due to the pigment lycopene (1_) . C a r r o t s are b r i g h t orange because of the presence of a-carotene (2) and 8-carotene (3), and p a p r i k a i s red due to capsanthin (4_) and capsorubin (!5) . - 4 -- 5 -3. STRUCTURE AND NOMENCLATURE OF CAROTENOIDS Typ i c a l l y a l i p h a t i c or a l i p h a t i c - a l i c y c l i c in structure, carotenoids are usually composed of eight isoprene units. In general, the carotenoids consist of two twenty-carbon isoprene subunits linked head-to-head in the center, producing a 1,6-arrangement of methyl groups about the center of the molecule. Within each twenty-carbon subunit, the isoprene units are linked in the normal head-to-tail pattern. A l l carotenoids may be derived from the a c y c l i c C4Q H56 structure 6, which has a long chain of conjugated double bonds, by (i) hydrogenation, ( i i ) dehydrogenation, ( i i i ) c y c l i z a t i o n , (iv) oxidation or any combination of these processes. There are several compounds that arise from certain rearrangements or degradations of this basic skeleton but retaining the two cen-t r a l 1,6-methyl groups of (5. Speci f i c names of the carotenoids are based on the stem name "carotene" and the structure and numbering of 1_. By con-vention, unprimed numbers are written on the l e f t hand side, as in 7. The broken lines represent two double bond equivalents - 6 -common i n most end groups. I n d i v i d u a l compounds may have Cg a c y c l i c end groups with two double bonds at p o s i t i o n s 1,2 and 5,6 or c y c l i c end groups. Those c a r o t e n o i d s bearing a c y c l o -hexene end group with the double bond in the 5,6 p o s i t i o n are designated g, whereas e i s used to r e f e r to a 4,5 double bond. A c y c l i c c a r o t e n o i d s bear the p r e f i x \\>. The systematic names for F i g u r e 1. Nomenclature for c a r o t e n o i d end groups. a-carotene (2), g-carotene (3) and lycopene (1) would t h e r e f o r e be (6 ' R) - g , e-carotene (2) , g,g-carotene (_3) and i)j, i|j-car otene - 7 -(1), respectively. Systematic names for pigments such as capsanthin (4_) and capsorubin (_5) are somewhat more involved. 4. HISTORICAL BACKGROUND During the 19th century, research on the carotenoids dealt mainly with their i s o l a t i o n and characterization by measurement of their l i g h t absorption properties. Carotene i t s e l f was i s o -g lated by Wackenroder in 1831 and the yellow alcohol-soluble pigment of autumn leaves was c a l l e d xanthophyll by Berzelius q in 1837 . By 1902, a monograph with about 800 l i t e r a t u r e r e f e r -9 ences was published by Kohl . Despite t h i s , very few pure c r y s t a l l i n e pigments were then known. During the years 1900-1927, much work was done on the determination of empirical formulae of the carotenoids and e f f o r t was also spent attempting to uncover the role of these compounds in photosynthesis. The years 1928-1949 saw the development of the provitamin A concept, the establishment of s t r u c t u r a l formulae of several carotenoids and the development of methods to synthesize carotenoids. In 1930-1931, the symmetrical nature of the structures g-carotene 9 (3) , lycopene (_1) and zeaxanthm (8) was recognized by Karrer , and the constitution of vitamin A (B) was shown to be closely 9 related to half the g-carotene molecule . In f a c t , g-carotene . . 9 was found to be the main precursor of vitamin A in animals . From about 1950 to the present day, the increase in the number of known carotenoids has been exponential. In addition, advances have been made in t o t a l synthesis and in the determination of absolute configuration of natural carotenoids. - 8 -5. USES OF CAROTENOIDS C a r o t e n o i d s a r e d e s i r a b l e i n f o o d s n o t o n l y f o r a e s t h e t i c r e a s o n s , b u t t h e y a r e a l s o r e q u i r e d t o f u l f i l l a v i t a l r o l e a s a p r o v i t a m i n A ( p r e c u r s o r o f v i t a m i n A) t o w h i c h t h e i r s t r u c -t u r e s a r e c l o s e l y r e l a t e d . A d i e t l a c k i n g i n v i t a m i n A o r i t s p r e c u r s o r s c a n l e a d t o s e r i o u s e y e damage and e v e n b l i n d n e s s . T o day t h e g r o w i n g g l o b a l p o p u l a t i o n h a s l e d t o o u r d e p e n -d e n c e on t h e f a s t and e c o n o m i c mass p r o d u c t i o n o f f o o d w h i c h , i n many c a s e s , c o n t a i n s t h e n a t u r a l p i g m e n t s and v i t a m i n s i n o n l y s m a l l o r n e g l i g i b l e a m o u n t s . To o v e r c o m e t h i s d e f i c i e n c y , t h e m i s s i n g p i g m e n t s and v i t a m i n s must be s u p p l e m e n t e d , b u t as - 9 -natural sources could never f i l l this need, we have to rely on commercial production of many of these v i t a l compounds. For instance, c r y s t a l l i n e synthetic 0-carotene (3) was 9 introduced by Roche in 1954 as a food colourant , i t s mam application being in the colouring and f o r t i f i c a t i o n of mar-garine. Two carotenoids, the tomato pigment lycopene (JL) and an ester of the saffron pigment crocetin (1£), are undergoing t r i a l s as red and yellow food colourants, respectively. To an 10 increasing extent, these non-toxic carotenoids are replacing yellow and red azo dyes which are being prohibited by food l e g i s l a t i o n . In some cases, carotenoids are used as food addi-tives to help colour such products as butter and egg yolks. Water-soluble carotenoids also find application in such food items as j u i c e s , dry and canned soups, dairy products such as yoghurt and ice cream, and pasta products to name only a few. 6. BIOSYNTHESIS OF CAROTENOIDS In the early 1950's the ready a v a i l a b i l i t y of 1 4 C - l a b e l l e d substrates lead to the f i r s t experiments which yielded d i r e c t and unambiguous indications of how the basic carotenoid molecule HO CH2OH C0 2 H MVA ATPAT " I * ADP HO C ° 2 H Cr02H M V A P MVAPP ,ATP C O 2 * / | S A D P H 2 C * ^ C H 2 0 ® ® IPP ^ - C H 2 0 ® @ DMAPP i C H 2 0 © © 3 P P ir Ir C H 2 0 ® ® C H 2 0(§ )® GGPP i C^ Q carotene Figure 2. Biosynthesis of C.-. carotene from mevalonic acid (MVA)10. 4 0 - 11 -is b u i l t up from simple u n i t s . It was determined that caro-tenoids are biosynthesized symmetrically about the central (15,15') linkage and that each isoprene unit has the same l a b e l l i n g p a t t e r n ^ . Later i t was recognized that mevalonic acid (MVA) i s a precursor of carotenoids as well as other t e r -penoids"^. Over the course of the next decade, investigators learned that MVA i s converted v i a i t s 5-phosphate (MVAP) and 5-pyrophosphate (MVAPP), with the loss of C-l as C O 2 t into A 3-isopentenyl pyrophosphate (IPP). This molecule then isomer-izes to d i m e t h y l a l l y l pyrophosphate (DMAPP) and the condensation of these two CV units (IPP and DMAPP) in a "head-to-tail" fashion b y i e l d s geranyl pyrophosphate (GPP). Following t h i s , the addi-tion of C^ (IPP) units results in the formation of, f i r s t , farnesyl pyrophosphate (FPP) and then geranylgeranyl pyrophos-phate (GGPP). The C ^ Q carotenes are then formed by the dimer-iz a t i o n of GGPP in a "head-to-head" fashion. 7. SYNTHESIS OF CAROTENOIDS AND IRONES In general, three types of pathways can be followed to synthesize a carotenoid. In the f i r s t pathway, the end group R is synthesized and the a c y c l i c chain i s successively added on in a linear fashion u n t i l the target molecule i s obtained (Route A). The combination of two larger subunits can also lead to the desired product (Route B), as well as the reaction of a sym-metrical c e n tral component with two end group-bearing frag-ments (Route C). - 12 -F i g u r e 3. T h r e e s t r a t e g i e s f o r s y n t h e s i z i n g c a r o t e n o i d s . I n a c o m m e r c i a l s y n t h e s i s , t h e f i n a l c h o i c e o f a p a r t i c u l a r r o u t e d e p e n d s on many f a c t o r s , n o t t h e l e a s t o f w h i c h a r e t h e p r i c e and a v a i l a b i l i t y o f s t a r t i n g m a t e r i a l s , and t h e y i e l d s i n t h e v a r i o u s r e a c t i o n s t e p s . So f a r , a l l i n d u s t r i a l p r o d u c t i o n o f - 13 -c a r o t e n o i d s s t a r t s with 3-ionone (11)°. Of the more than three hundred n a t u r a l l y o c c u r r i n g c a r o t e n o i d s , o n l y f i v e are a t p r e -sent being manufactured on an i n d u s t r i a l s c a l e and these f i v e c o n t a i n o n l y two kinds of end groups, shown i n 12 and 13, of the o many t h a t e x i s t . The s y n t h e s i s of c a r o t e n o i d s bearing other end groups has a t t r a c t e d the a t t e n t i o n of many i n v e s t i g a t o r s ^ . For i n s t a n c e , the s y n t h e t i c c h a l l e n g e of p r e p a r i n g the carbon-2 s u b s t i t u t e d B - r i n g , as i n L4, has been met with v a r i a b l e success by v a r i o u s groups. T h i s p a r t i c u l a r end group appears with s e v e r a l d i f f e r -ent, but r e l a t e d s u b s t i t u e n t s a t C-2 (14). The c a r o t e n o i d s - 14 -bearing a 2-hydroxylated g-ring belong to a series of naturally 12a occurring xanthophylls f i r s t discovered in 1972 . From bio-synthetic aspects, they are believed to be clos e l y related to the C^ Q b a c t e r i a l carotenoids bearing C^-alkyl chains at the C-2 and C-2' positions . The 2-methylated carotenoids have not as yet been discovered in nature, in spite of the fact that the corresponding 2-methyl-8-ionone, or irone (lj>) , has been known 13 since 1893 . Interest in preparing these carotenoids has been c h i e f l y due to their use in c i r c u l a r dichroism studies which have made possible the stereochemical assignment of some 14 c h i r a l carotenoids. In 1974 , Andrewes, Liaaen-Jensen and Borch prepared (2R,2'R)-2,2'-dimethy1-B,g-carotene (16), st a r t i n g with o p t i c a l l y active (+)-(6R)-g-irone (1^) isolated from a mixture of natural i r o n e s ^ . The o p t i c a l l y inactive carotenoid 16^  had 16 previously been synthesized byEugster, T r i v e d i and Karrer - 15 -For synthesis of the 2-methylated end group unit 14 (P^CH-j) , one must look to the work that has been done on the synthesis of irones, which are odour components important to the perfume industry. These synthetic endeavours began in 1940 by Ruzicka and coworkers"'''7 only a few years after their studies of the structure of irone 18 In 1947, Naves and coworkers 19 reported a p r a c t i c a l synthesis of 3-methylcitrals (1/7) and 3-19 methyllinalool (18_) , from which irone (1_5) could be made , and then in 1952, Grutter, Helg and Schinz used thujacetone (19) for the synthesis of 3-methylcitrals and their isomers 20 CHO 17 18 OH In 1959, Eschinazi succeeded in transforming a-pinene (20) into 2-(2,2,3-trimethylcyclobuty1)-hepta-2,4-dien-6-one (21), which on treatment with 85% phosphoric acid resulted in forma-21 tion of a mixtures of irones (2_2) in over 50% y i e l d . The important methyl group was not introduced in the synthesis, but rather i s part of the a-pinene skeleton. Unfortunately, analy-s i s of the f i n a l irone mixture showed only 8.2% 6-irone (15) to be present. - 16 -Figure 4. Synthesis of irones (2_2) from a-pinene (2fJ) A more e f f i c i e n t synthesis of g-irone, described in 1974 22 by Ishihara, Kitahara and Matsui , involves the acid-catalyzed c y c l i z a t i o n of 9-methylpseudoionone (2_5) derived from 5,6-di-methyl-5-hepten-2-one (2£). The c r u c i a l methyl group was i n t r o -duced in this synthesis by preparing the appropriately s u b s t i -tuted a l l y l i c alcohol 23_ from the Grignard reaction of ethyl methacrylate and methylmagnesium halide. The c y c l i z a t i o n step, involving treatment of the compound 25 with acetic acid-sulphuric acid (3:7), gave almost exclusively g-irone (1J5) in good y i e l d . - 17 -Figure 5. Synthesis of B-irone (15_) from 2,3-d ime t h y l -3-buten-2-ol ( 2 3 ) 2 2 ; 23 Recently T o r n , Uneyama and Matsunami reported a stereo-sele c t i v e synthesis of (±)-irones (15) v i a the acid-catalyzed dehydration and subsequent c y c l i z a t i o n of 2,3,6-trimethyl-8-(phenylsulphonyl)-6-octen-3-ol (3£) . Introduction of the methyl group in t h i s synthesis was achieved in a three step transfor-mation, s t a r t i n g with 3,7-dimethyl-l-(phenylsulphonyl)-2,6-octadiene (2_7) . Regioselective epoxidation of the terminal double bond in this molecule is high y i e l d i n g , with no appreciable amount of diepoxide detected. This may be due to the fact that the double bond adjacent to the electron withdrawing sulphone group i s less nucleophilic and therefore less susceptible to - 18 -bromohydrin formation, which then leads to the epoxide (equa-tion 4). Treatment of the epoxide 28 in hot acid leads to the ketone _29, which when treated with methylmagnesium halide gives the t e r t i a r y alcohol 3j0_ with the methyl group in the desired po s i t i o n . Unfortunately, in the c y c l i z a t i o n step the (3-irone is produced in only 12% y i e l d , whereas 44% of each of the a isomers are obtained. Preparation of the 2-hydroxylated 3 - r i n g was attempted recently when Ito, Masahara and Tsukida carried out a regiose-l e c t i v e and stereoselective fermentative reduction of 2-oxo-12 fc) 8-ionone (3_1) using baker's yeast (equation 5) . The r e s u l t -ing o p t i c a l l y active end group was shown to have the 2S con-figuration at the c h i r a l carbon. 31 - 1 9 -Figure 6 . Synthesis of irones ( 2 2 ) from 3,7-dimethyl-o c t a - 2 , 6 - d i e n - l - o l (26) 2 3 . Although there are at least fourteen known naturally occurring and C ^ Q carotenoids bearing an isopentenyl unit 1 4 at one or both of the C - 2 positions , few syntheses of this type of end group have yet been published. Recently though, Moss and coworkers reported the synthesis of decaprenoxanthin 2 4 ( 3 8 ) , a C ^ Q carotenoid bearing a functionalized a-ionone end group. Acid treatment of 33 afforded 2-vinyl-a-ionone ( 3 £ ) in y i e l d s of up to 1 8 % . The C - 2 v i n y l group of 3 4 was then - 20 -35 R=OTHP 37 Rr CO2CH3 36 R= PPhjCf 38 R r C H 2 O H Figure 7. Synthesis of decaprenoxanthin (3_8) from 6-methyl-5-hepten-2-one ( 3 2 ) 2 4 . - 21 -transformed in a number of steps to the a ,B~unsaturated ester moiety in 3_5« Conversion of 3_5 to the s a l t 36, followed by reaction of the s a l t with the appropriate C ^ dialdehyde f u r -nished the diester 3_7. F i n a l l y , reduction of 3_7 with lithium aluminum hydride resulted in a mixture of isomers of decapre-noxanthin (_38) . 8. ELECTROPHILIC CYCLIZATIONS At this point, we were intrigued by the p o s s i b i l i t y of using cyclized (3-keto esters to prepare a common intermediate, from which a l l 2-substituted g-ring end groups could be derived. The key to synthesizing the desired precursor involved developing an electrophile-induced c y c l i z a t i o n , using an e l e c t r o p h i l e that could later serve as a handle for further elaboration of the C-2 position (equation 6). The Lewis acid catalyzed c y c l i z a t i o n of o l e f i n i c B-keto esters has been the subject of investigation in recent years. In 1976, White and coworkers reported that exposure of the ketoester 39 to one molar equivalent of stannic chloride in - 22 -dichloromethane (CH^C^) resulted in the formation of a single 25 c y c l i c product 40 in 68% p u r i f i e d y i e l d 39 40 Many a c i d - i n i t i a t e d c y c l i z a t i o n s of unsaturated B-keto esters have been attempted in our own laboratory with varying degrees of success. The a l k y l a t i o n of the dianion of methyl acetoacetate was carried out with several haloalkenes, notably l-bromo-2-propene, 3-chloro-2-methylpropene and l-bromo-3-methyl-2-butene, and the res u l t i n g o l e f i n i c adducts 41-43 were then treated with stannic chloride in CH^C^. Although the f i r s t adduct tested, 4_1, proved to be inert to treatment with Lewis or pro t i c acids (equation 7) , both 4_2 and 4_3 c y c l i z e 7 cleanly to give single products (equations 8 and 9) . However, the substitution of the o l e f i n i c bond has a major e f f e c t on the outcome of the c y c l i z a t i o n . Under acid conditions, i t i s apparent that the methyl group at C-6 in compound 4_2 s t a b i l i z e s the developing ca t i o n i c center at C-6, whereas the two methyl groups on C-7 in compound 4_3 s t a b i l i z e the carbonium ion on C-7. C-cyclization occurs to form the six-membered ring (equa-2 6 tion 9) which, according to Baldwin's rules , i s an allowed - 23 -0 41 J^\^C0 2CH 3 H -> no reaction (7) 0 H3 42 H H 3 C0 2C v ^ (8) ^ - ^ C 0 2 C H 3 H 0 ^ \ ^ C 0 2 C H : (9) process. Further, we note that intramolecular C-cyclization of 4 2 to give a five-membered ring i s disfavoured and therefore O-cyclization occurs (equation 8), in accordance with the rules From these studies i t was noted that the six-membered ring (3-keto ester 4_3 is p a r t i c u l a r l y well suited for elaboration as a carotenoid end group. However, since the elect r o p h i l e used in t h i s case i s H +, the resu l t i n g end group would not be sub-st i t u t e d at C-2 of the carotenoid system as we desired. Any other e l e c t r o p h i l e , though, i f i t could be incorporated into the ring during c y c l i z a t i o n (equation 6), might prove to be - 24 -q u i t e u s e f u l . I n o r d e r t o o b t a i n s u c h a C-2 s u b s t i t u t e d end g r o u p , we c o n s i d e r e d o t h e r e l e c t r o p h i l e m e d i a t e d c y c l i z a t i o n s , and i n p a r t i c u l a r t h o s e e m p l o y i n g t h e c a t i o n s B r + , P h S e + and PhS +. M e t h o d s d e s i g n e d t o i n c o r p o r a t e b r o m i n e i n t o a c y c l i c s y s -tern h a v e a r i s e n i n r e s p o n s e t o t h e r a p i d l y g r o w i n g number o f b r o m i n e - c o n t a i n i n g t e r p e n o i d s i s o l a t e d f r o m n a t u r a l s o u r c e s , p a r t i c u l a r l y m a r i n e o r g a n i s m s . Many d i f f e r e n t r e a g e n t s have been u s e d t o e f f e c t e l e c t r o p h i l i c B r + c y c l i z a t i o n s . A bromonium i o n c y c l i z a t i o n was f i r s t o b s e r v e d by v a n T a m e l e n and H e s s l e r i n 1966 when t h e y t r e a t e d m e t h y l f a r n e s a t e (44) w i t h N - b r o m o s u c c i n i m i d e (NBS) i n a q u e o u s t e t r a h y d r o f u r a n 27 (THF). . A l t h o u g h t h e t e r m i n a l m o n o b r o m o h y d r i n i s t h e m a j o r p r o d u c t o f t h e r e a c t i o n , t h e y s u c c e e d e d i n i s o l a t i n g t h e b i c y c l i c b r o m o e s t e r s 4_5 a s m i n o r c o m p o n e n t s . T r e a t m e n t o f t h e b r o m o h y d r i n o f m e t h y l f a r n e s a t e i n t h e same manner a s t h e o r i g i n a l NBS r e a c t i o n d i d n o t l e a d t o d e t e c t a b l e amounts o f c y c l i z e d p r o -d u c t , t h u s l e a d i n g t o t h e s u g g e s t i o n t h a t t h e b r o m o c y c l i c e s t e r s do n o t a r i s e f r o m t h e b r o m o h y d r i n . The a u t h o r s s u g g e s t e d t h a t c y c l i z a t i o n w o u l d most l i k e l y i n v o l v e r i n g f o r m a t i o n o f an - 25 -i n i t i a l l y produced t e r m i n a l bromonium i o n , f o l l o w e d by a con-c e r t e d c y c l i z a t i o n process to the b i c y c l i c bromo compound 27 (equation 10) More r e c e n t l y , Wolinsky and Faulkner have been able to bromo-cyclize g e r a n y l d e r i v a t i v e s in moderately improved y i e l d s u s ing equimolar amounts of bromine and s i l v e r t e t r a f l u o r o b o r a t e 28 i n a p o l a r a p r o t i c s o l v e n t such as nitromethane . Treatment of both g e r a n y l acetate (4_6) and g e r a n y l acetone (4J3) i n the manner i n d i c a t e d r e s u l t e d i n a 20% y i e l d of monobromo-substituted products, £7 and 4_9, i n each case. The bromine i n i t i a t e d c y c l i z a t i o n of n e r o l i d o l (5_0) was accomplished by adding the a c y c l i c a l c o h o l to a s t i r r e d s o l u -29 t i o n of tetrabromocyclohexa-2,5-dienone i n C t ^ C ^ • A f t e r e x t e n s i v e p u r i f i c a t i o n , the two bromine c o n t a i n i n g a l c o h o l s , a and 3-snyderol, were i s o l a t e d i n about 20% y i e l d each from the s t a r t i n g n e r o l i d o l (equation 11). The use of the p h e n y l s e l e n e n y l or p h e n y l s u l p h e n y l c a t i o n t o e f f e c t c y c l i z a t i o n has a l s o proven to be most advantageous, e s p e c i a l l y i n view of the f a c t t h at these groups can be a l t e r e d - 26 -- 27 -i n a v a r i e t y of ways to al l o w f o r f u r t h e r f u n c t i o n a l i z a t i o n . S e v e r a l review a r t i c l e s have been p u b l i s h e d o u t l i n i n g the v e r -s a t i l i t y of organoselenium reagents, and p a r t i c u l a r l y t h e i r e f f e c t i v e n e s s i n induci n g h e t e r o - and c a r b o c y c l i z a t i o n r e a c t i o n s e f f i c i e n t l y and under m i l d c o n d i t i o n s ^ . In 1977, N i c o l a o u and Lysenko r e p o r t e d the p r e p a r a t i o n of c y c l i c e t h e r s u s i n g a p h e n y l s e l e n e n y l c a t i o n induced c y c l i z a -31 t i o n . They found t h a t treatment of 4-cycloheptene-l-methanol (51) with p h e n y l s e l e n e n y l c h l o r i d e (PhSeCl) a f f o r d e d the ph e n y l -selenoether 52 i n 95% y i e l d . T h i s f a c i l e c y c l i z a t i o n r e a c t i o n probably proceeds v i a a r e a c t i v e i n t e r m e d i a t e such as 5_3, formed by i n i t i a l a t t a c k of p h e n y l s e l e n e n y l c h l o r i d e on the double bond to form the th r e e - c e n t e r e d s e l e n i r a n i u m i o n . Ring c l o s u r e then f o l l o w s as a r e s u l t of i n t e r n a l n u c l e o p h i l i c a t t a c k o f the hydr o x y l group. A s h o r t time l a t e r , these same i n v e s t i g a t o r s d e s c r i b e d a new method f o r i n t e r n a l l a c t o n i z a t i o n of unsaturated c a r b o x y l i c 32 a c i d s u s i n g both PhSeCl and p h e n y l s u l p h e n y l c h l o r i d e (PhSCl) In the case of p h e n y l s e l e n o l a c t o n i z a t i o n , treatment of 4-cyclo-h e p t e n e - l - c a r b o x y l i c a c i d (5_4_) with t r i e t h y l a m i n e (Et^N) , f o l -lowed by the slow a d d i t i o n of PhSeCl, l e d to the r a p i d and q u a n t i t a t i v e p r o d u c t i o n of product 55_. P h e n y l s u l p h e n o l a c t o n i -z a t i o n can be c a r r i e d out under s i m i l a r c o n d i t i o n s . In a r e c e n t s y n t h e s i s of the macrolide p h o r a c a n t h o l i d e J (58), an i n t e r n a l selenium a s s i s t e d a c e t a l formation was c a r r i e d out by s l o w l y adding a s o l u t i o n of 5_6 and N , N - d i i s o p r o p y I e t h y l -amine (iPr^EtN) t o a s o l u t i o n of p h e n y l s e l e n e n y l bromide - 28 -- 29 -(PhSeBr) . Regiospecific addition of the phenylselenenyl cation to the more nucleophilic enol ether double bond, f o l -lowed by inte r n a l attack of the a l l y l i c alcohol moiety, led to the production of the c y c l i c acetal 51_ in 71% y i e l d . Clive and coworkers have published a number of papers on cy c l o f u n c t i o n a l i z a t i o n in which both oxygen and nitrogen hetero-cycles are formed from o l e f i n i c acids, alcohols, phenols and 34 . . urethanes (equations 12 and 13) . Reaction conditions vary depending on the type of substrate, but in each case a solution of PhSeCl i s added dropwise to a solution of the s t a r t i n g mate-r i a l to i n i t i a t e the c y c l i z a t i o n . One such example i s the c y c l i z a t i o n of the ortho-alkenyl phenol 59 in 81% y i e l d . S i m i l a r l y , the heterocycle 6J) i s produced in 73% y i e l d (equa-tion 13) . In contrast to the well-studied selenium assisted syntheses of heterocycles, studies concerned with carbon-carbon bond formation using selenium reagents are very l i m i t e d . In 1971, Smit et a l . investigated 1,5-diolefin c y c l i z a t i o n s using strongly polarized sulphur cations'^. They found, for P h S e 56 57 58 - 3 0 -e x a m p l e , t h a t t r e a t m e n t o f t h e d i o n e e s t e r 6_1 w i t h p h e n y l s u l -p h e n y l t e t r a f l u o r o b o r a t e ( P h S + B F 4 ) i n n i t r o m e t h a n e ( C H - ^ N G ^ ) a f f o r d e d a 57% y i e l d o f c y c l i z e d p r o d u c t 6J2. E l e c t r o p h i l i c a t t a c k b y t h e c a t i o n i c s p e c i e s o n t h e m o r e e l e c t r o n r i c h t e r -m i n a l d o u b l e b o n d , f o l l o w e d b y n u c l e o p h i l i c p a r t i c i p a t i o n o f t h e s e c o n d d o u b l e b o n d , l e d t o c a r b o c y c l i c r i n g f o r m a t i o n . S e v e r a l y e a r s l a t e r , a n o t h e r c a r b o c y c l o f u n c t i o n a l i z a t i o n w a s a c c o m p l i s h e d w h e n C l i v e , C h i t t a t t u a n d W o n g s u c c e e d e d i n c a r r y i n g o u t a s e l e n i u m - a s s i s t e d t r a n s a n n u l a r c a r b o n - c a r b o n 3 6 b o n d f o r m a t i o n . T h e a d d i t i o n o f a n a c e t i c a c i d s o l u t i o n o f P h S e C l t o a s o l u t i o n o f t h e d i e n e 63_ a n d a n h y d r o u s s o d i u m - 3 1 -AcO" PhSeCl 63 AcOH NaOAc I ,Se i Ph AcO H SePh 64 acetate r e s u l t e d i n the formation of the h y d r i n d a n y l acetate 64. 46 PhSeCl 0 A c AcOH P h S e ^ T < ^ 0 A c OR 65a R=Ac 65b R-H CF3C00H ^ h S e - ^ ^ 66a R:Ac 66b R;H OAc To determine whether t h i s c y c l i z a t i o n was a p p l i c a b l e f o r carbon-carbon bond formation i n other c a s e s , Kametani e t a l . t r e a t e d g e r a n y l a c e t a t e (£6) with PhSeCl i n a c e t i c a c i d i n 3 7 the presence of sodium a c e t a t e . They were not able to i s o -l a t e the expected c y c l i c products 66a and 66b, but found o n l y the a d d i t i o n products 65a and 65b. However, they were able to c y c l i z e the a d d i t i o n product 65b to 66b i n 65% y i e l d by t r e a t -ment with t r i f l u o r o a c e t i c a c i d i n CH2CI2. - 32 -B. RESULTS AND DISCUSSION The aim of this project was to develop an electrophile i n i t i a t e d B-keto ester c y c l i z a t i o n which could then be used in the preparation of C-2 substituted carotenoid end groups. I n i -t i a l l y the c y c l i z a t i o n was carried out with selenium e l e c t r o -philes and work on further elaboration of the product was begun, However, problems encountered in the selenium route made the prospect of i t s completion rather u n l i k e l y . In changing to a sulphur e l e c t r o p h i l e c y c l i z a t i o n , these problems were overcome and two C-2 alkylated products were subsequently prepared. The alkenyl B-keto ester 43, prepared by alkyla t i o n of the 7 dianion of methyl acetoacetate with 1-bromo-3-methy1-2-butene , was chosen as the substrate for the e l e c t r o p h i l i c c y c l i z a t i o n studies employing phenylselenenyl and phenylsulphenyl chlorides 0 0 1 ) N a H 0 0 0 0 4 3 SELENIUM ROUTE In most of the l i t e r a t u r e examples 3 0, selenium cation i n i -t iated c y c l i z a t i o n s are carried out by adding a solution of PhSeCl dropwise to a solution of the compound to be c y c l i z e d . - 33 -This method was recently attempted on the B-keto ester 4_1, and resulted in an almost quantitative y i e l d of the addition pro-7 duct 68_ . Rapid attack by chloride ion on the intermediate phen-ylseleniranium cation 6.7 leads to addition of the reagent be-.fore i n t e r n a l c y c l i z a t i o n can occur. C 0 2 C H 3 PhSeCl C 0 2 C H 3 '-'-+SePh 68 0 0 2 C H 3 -CI ^ S e P h Thus, i t was not surprising to find that upon treatment with PhSeCl, 4_3 does not appear to c y c l i z e to the desired com-pound 69_. Inspection of the ^-NMR spectrum of the crude reac-tion material leads to the suggestion that i t may be a mixture of products, one of them being the addition product 7fJ. E v i -dence in favour of the formation of 7_0 includes the disappear-ance of the v i n y l i c absorption indicating saturation of the double bond. In addition, a new and f a i r l y strong absorption at 61.75, downfield from the unsaturated gem dimethyl signals at 61.60 and 61.65 in 4_3 suggests that the methyl groups are adjacent to a strongly electronegative atom such as chlorine. P u r i f i c a t i o n of the crude reaction mixture was not attempted 7 as previous work has shown that the addition product £8 readily rearranges on s i l i c a g e l . - 34 -0 ^ U \ ^ C 0 2 C H A t t e n t i o n was then turned to the e f f i c i e n t , but r a t h e r slow, H + c y c l i z a t i o n which i s c a r r i e d out by s t i r r i n g 43_ with 7 s t a n n i c c h l o r i d e (SnCl^) in C H 2 C I 2 f o r 17-24 hours . Coordina-t i o n of the Lewis a c i d to the two oxygen atoms in the molecule most l i k e l y promotes the formation of the e n o l tautomer 7_1 of the B-keto e s t e r . Reaction of t h i s intermediate diene s p e c i e s with H + i n s o l u t i o n then leads to r i n g c l o s u r e and formation of 72 i n good y i e l d . I t was hoped that by employing s i m i l a r c o n d i t i o n s , the c y c l i z a t i o n c o u l d be c a r r i e d out using the e l e c t r o p h i l e PhSe + i n p l a c e of H +. However, s t a n n i c c h l o r i d e r e a c t s with a B-keto e s t e r to form h y d r o c h l o r i c a c i d , hence the H + present i n s o l u -t i o n would e f f e c t c y c l i z a t i o n . In an e f f o r t to e l i m i n a t e the p o s s i b i l i t y of proton c y c l i z a t i o n , a Lewis a c i d l e s s s u s c e p t i b l e - 35 -to r e a c t i o n with a g-keto e s t e r was c o n s i d e r e d . The d e c i s i o n to use aluminum c h l o r i d e ( A l C l ^ ) was made because i t was found that i t does not r e a d i l y c a t a l y z e the c y c l i z a t i o n of 4_3. In f a c t , a f t e r s t i r r i n g 4_3 i n a suspension of A l C l ^ i n C H j C l j f o r p e r i o d s of up to three days, only s t a r t i n g m a t e r i a l was recovered. The change i n Lewis a c i d s turned out to be q u i t e oppor-tune. The dropwise a d d i t i o n of PhSeCl to a v i g o r o u s l y s t i r r e d suspension of aluminum c h l o r i d e i n CB^C^ c o n t a i n i n g 4_3, l e a d s to the immediate formation of the c y c l i z e d s e l e n i d e 69^  i n good y i e l d with l i t t l e or no a d d i t i o n product d e t e c t e d . The 1H-NMR spectrum of the crude m a t e r i a l showed a broad a b s o r p t i o n a t 67.67-7.00 due to the phenyl group, a carbomethoxy peak at 63.63, a methine a b s o r p t i o n at 63.28-3.45 and an uneven ar r a y of four sharp peaks at 61.28, 1.25, 1.22 and 1.10 due to the two methyl groups. The presence of four methyl peaks i n s t e a d - 36 -0 Q of two leads to the suggestion that 69 i s a mixture of d i a s t e r e -omers. I t was l a t e r determined that the smeared TLC spot, which had o r i g i n a l l y been a t t r i b u t e d to one compound, could be sepa-r a t e d on a l a r g e r p l a t e to give two b a r e l y d i s t i n g u i s h a b l e bands. Although a complete s e p a r a t i o n of the two compounds was not achieved, i t was p o s s i b l e to a s c e r t a i n t h a t the f a s t e r moving diastereomer c o n t a i n s the peaks at 61.25 and 61.10, while the slower moving one shows a b s o r p t i o n s at 61.28 and 61.22. The two diastereomer s, 7_4 and 7J5, probably a r i s e from e q u a t o r i a l a t t ack of the phenylseleneny1 c a t i o n on the two geo-m e t r i c isomers 73_ and 75, followed by r i n g c l o s u r e . However, compound 7_6, with an a x i a l carbomethoxy peak, may e x i s t as a r a p i d l y e q u i l i b r a t i n g p a i r of conformers 7j6 and 7_7. Compounds 74 and 7_6 are epimers, and i t i s p o s s i b l e t h at the e q u a t o r i a l methine a b s o r p t i o n of 7_6 and the a x i a l methine a b s o r p t i o n s of 74 and 11_ give r i s e to the broad peak at 63 .28-3 .45 in the JH-NMR spectrum of the mixture. U n f o r t u n a t e l y , the two diastereomers were not w e l l enough r e s o l v e d by chromatography - 37 -to allow separate determination of the d i f f e r e n t methine hydrogen absorptions. The role of aluminum chloride in the c y c l i z a t i o n is not an easy one to define. I n i t i a l l y i t was thought that the aluminum was acting much l i k e the t i n as depicted in 7_1, by coordinating to the two oxygen atoms of the g-keto ester and enhancing the formation of the enol tautomer. However, unlike stannic chloride, aluminum chloride does not dissolve in dichloromethane, nor does i t appear to react with a g-keto ester. The aluminum chloride may act as a heterogeneous reagent to provide a surface on which 38 the reaction can occur . Another suggestion i s that the alu-minum chloride may react with the phenylselenenyl chloride or any free chloride ion to ensure that any intermediate c y c l i z e s intramolecularly rather than reacting intermolecularly with chloride ions. - 38 -The f o r m a t i o n o f t h e c y c l i c s e l e n i d e s was f u r t h e r c o n f i r m e d by t h e i r r e d u c t i o n 3 ^ w i t h t r i p h e n y l t i n h y d r i d e ( P h ^ S n H ) 4 0 i n r e f l u x i n g t o l u e n e (PhCH^) t o t h e c o r r e s p o n d i n g B - k e t o e s t e r 72. 0 69 SePh Ph-.SnH PhCH-0 ^ \ . C 0 2 C H 3 72 Once t h e d e t a i l s o f t h e s e l e n i u m i n i t i a t e d c y c l i z a t i o n were w o r k e d o u t , e l a b o r a t i o n o f t h e r o u t e t o t h e c a r o t e n o i d end g r o u p c o u l d p r o c e e d . The n e x t two s t e p s , w h i c h i n v o l v e c o n v e r s i o n o f 69 t o t h e i n t e r m e d i a t e 79_ v i a t h e e n o l p h o s p h a t e 7<8, c l o s e l y 3 9 p a r a l l e l r e c e n t work done on t h e u n s u b s t i t u t e d B - k e t o e s t e r 72. P h S e X j ^ X ^ - C 0 2 C H 3 69 NaH P h S e V ^ X ^ C 0 2 C H 3 ( C 2 H 5 0 ) 2 P 0 C l ether 73. (CH 3 ) 2 CuL i PhSe ether, -23°C > OPO(OC 2 H 5 ) 2 CC>2CH3 79a D r o p w i s e a d d i t i o n o f d i e t h y l c h l o r o p h o s p h a t e (DECP) t o a s t i r r e d s u s p e n s i o n o f t h e m o n o a n i o n o f 6j) i n e t h y l e t h e r ( e t h e r ) r e -s u l t s i n good y i e l d s o f 18_. However , u n l i k e t h e a n a l o g o u s u n -39 s u b s t i t u t e d c a s e , i t was f o u n d t h a t 1.5-2 e q u i v a l e n t s o f - 39 -sodium hydride must be used to ensure complete conversion of the s t a r t i n g material to the enol phosphate 78. The IR absorption at 1725 cm ^  in the enol phosphate plus the presence of the carbornethoxy peak at 63.73 in the 1H-NMR spectrum supports the presence of the a8-unsaturated ester moiety in 7_8. The methine proton adjacent to the selenium has become evident in the *H-NMR spectrum of 78 as a multiplet at 63.00-3.30. The carbon bearing the ester group i s no longer c h i r a l due to the introduction of the double bond. There remains, then, the p o s s i b i l i t y that 78_ exi s t s as two conf ormers, 78_a and 78b, a l -though the former most l i k e l y predominates because of the pre-sence of the pseudo equatorial phenylselenide group (assuming a half-chair conformation for 78a and 78b). The methine proton S e P h 78a 78 b H R r O P O ( O C 2 H 5 ) 2 a lpha to the s e l en ium can c o u p l e w i t h the two c h e m i c a l l y d i f f e r -ent p r o t o n s on the a d j a c e n t carbon in both 78a and 78b. In each c a s e , the r e s u l t would be a d o u b l e t o f d o u b l e t s , which c o u l d account f o r the m u l t i p l e t a t 63 .00-3 .30 observed i n the 1H-NMR spectrum of 78. - 40 -Reaction of the enol phosphate 78_ with lithium dimethyl-cuprate ( (CH-^ ) 2 C u L : L ) in ether at -23°C affords very high yields of the methyl substituted product 79a. In the 'H-NMR spectrum of 79a,the ethyl absorptions of the enol phosphate are replaced by a single sharp signal at 61.65 corresponding to the v i n y l i c methyl. At this point, the intermediate 79a now contains the 5,6 double bond and C-18 methyl group present in the target end group. However, before any attempts at C-2 elaboration could be made, the ester had to be protected so that i t would not i n t e r -fere with subsequent reactions. This was achieved by reduction of the ester 79a to the a l l y l i c alcohol 80a, followed by con-version of the alcohol to the tetrahydropyrany1 (THP) ether 81. 7 41 Recent work ' has shown that a similar molecule 79b can be 79a RrPhSe 80a RrPhSe 81 79b R=H 80b R-H reduced to 80b i n two hours by treatment with l i t h i u m aluminum hydride (LAH) i n r e f l u x i n g e t h e r, but under the same c o n d i t i o n s , the c o n v e r s i o n of 79a to 80a shows only minimal p r o g r e s s . How-ever, i t was found that a d d i t i o n of an excess of d i i s o b u t y l -aluminum hydride (DIBAL) to an e t h e r e a l s o l u t i o n of 79a at 0 ° C - 41 -results in complete conversion of the ester to the alcohol. This was confirmed by loss of the IR ester absorption and the appearance of the non hydrogen-bonded and hydrogen-bonded -OH absorptions in the IR at 3620 cm ^ and 3460 cm ^ respectively. In addition, the carbomethoxy ^-NMR signal at 63.75 has been replaced by a peak at 64.10 due to the a l l y l i c methylene adja-cent to the hydroxyl group. The f a c i l e preparation of the THP ether 8_1 was carried out by s t i r r i n g a dichloromethane solution of 80a, dihydropyran and 4 2 pyridinium p_-toluenesulphonate (PPTS) at room temperature for several hours. Unfortunately, the THP group p a r t i a l l y obscures the 1H-NMR absorption of the proton adjacent to the selenium in 81. Treatment of a selenide with a base can lead to two d i f f e r -30a ent outcomes : deprotonation, which depends on proton acid-i t y , or nucleophilic attack on selenium leading to cleavage of the C-Se bond. A l k y l lithiums tend to promote Se-C cleavage whereas lithium amides appear to be more suitable for depro-t o n a t i o n 3 0 3 . The production of carbanions alpha to selenium has been achieved in several situations, but in only one case has the deprotonation of a phenyl a l k y l selenide been de-4 3 scribed . In t h i s instance, treatment of 8_2 with lithium d i -isopropylamide (LDA) results in proton abstraction in good 4 3 y i e l d (equation 14). In another case , selenium s t a b i l i z e d carbanions can be prepared by treating selenoketals, such as 84, with an a l k y l lithium to e f f e c t Se-C bond cleavage (equa-tion 15) . - 42 -LDA t J—\ / 0 H PhSeCH 3 > PhSeCH 2 >Bu-/ Y (U) 82 - 83 7 5 % BuLi, THF (PhSeWTI-U - > PhSeCH? (15) 1 L - 7 8 C > 95% 84 I t was hoped t h a t d e p r o t o n a t i o n o f 81 t o f o r m t h e a n i o n 8_5 c o u l d be a c h i e v e d by t r e a t m e n t w i t h a s u i t a b l e b a s e , i n s p i t e o f t h e s t e r i c a l l y h i n d e r e d l o c a t i o n o f t h e s e c o n d a r y p r o t o n . How-e v e r , a l l a t t e m p t s a t g e n e r a t i n g 8_5, u s i n g a v a r i e t y o f b a s e s 81 85 ( l i t h i u m d i e t h y l a m i d e , n - b u t y l l i t h i u m , t - b u t y l l i t h i u m , m e t h y l -l i t h i u m ) , d i f f e r e n t s o l v e n t s (THF, h e x a n e ) and s e v e r a l t e m p e r -a t u r e s , p r o v e d u n s u c c e s s f u l . Q u e n c h i n g t h e r e a c t i o n m i x t u r e w i t h d e u t e r i u m o x i d e ( D 0 0 ) o r m e t h y l i o d i d e l e d , i n e v e r y c a s e , - 43 -to recovery of the s t a r t i n g m a t e r i a l . T h i s c o n c l u s i o n was reached f o l l o w i n g examination of ^-NMR and mass s p e c t r a l data f o r evidence of any deuterated or methylated product. The s t e r -i c a l l y hindered t a r g e t s i t e or low proton a c i d i t y may have a t t r i b u t e d to the f a i l u r e to generate the anion 135 . Although the s t e r i c bulk of the groups surrounding the s i t e c o u l d not be a l t e r e d , some thought was given to enhancing proton a c i d i t y by o x i d i z i n g the phenylseleneny1 group to the phenylselenoxide 86. However , t h i s was not attempted because the f a c i l e fragmentation o 44 of the phenylselenoxide to an unsaturated product, even at 0 C was expected to s e v e r e l y r e s t r i c t r e a c t i o n c o n d i t i o n s . T h i s l i n e of thought, though, d i d le a d i n t o the study of sulphoxides r e p o r t e d i n the next s e c t i o n . 3. SULPHUR ROUTE Sulphoxides, l i k e s e l e n o x i d e s , can serve as a c t i v a t i n g 4 5 groups to promote de p r o t o n a t i o n with a s u i t a b l e base . How-ever, they possess the added advantage of being s t a b l e at room temperature and t h e r e f o r e , can be handled with r e l a t i v e ease without the danger of concomitant e l i m i n a t i o n . I t was f e l t t h a t i f the i n i t i a l c y c l i z a t i o n r e a c t i o n could be redesigned to i n c o r p o r a t e the p h e n y l s u l p h e n y l group, i n s t e a d of the 0 A r - S e - C H R R R base Ar-Se-C, 86 - 44 -p h e n y l s e l e n e n y l g r o u p , t h e n C-2 e l a b o r a t i o n m i g h t be a c h i e v e d v i a a l k y l a t i o n o f the s u l p h o x i d e . P r e l i m i n a r y s t u d i e s showed t h a t t r e a t m e n t o f a n i t r o m e t h a n e 3 5 s o l u t i o n o f 4_3 w i t h p h e n y l s u l p h e n y l t e t r a f l u o r o b o r a t e r e s u l t e d i n t h e r a p i d and u n e x p e c t e d p r o d u c t i o n o f t h e B - k e t o e s t e r 72. AgBF^ + PhSCl > PhS+BF4" + AgCl \ CO2CH3 R i g o r o u s d r y i n g o f the n i t r o m e t h a n e and s i l v e r t e t r a f l u o r o -b o r a t e had no e f f e c t on a l t e r i n g t h e outcome o f s u b s e q u e n t r e a c -t i o n s . However, s i l v e r t e t r a f l u o r o b o r a t e i s e x t r e m e l y h y g r o -s c o p i c , and i n s p i t e o f p r o l o n g e d h e a t i n g t o d r y the compound, m i n i m a l e x p o s u r e t o a i r c o u l d i n t r o d u c e some m o i s t u r e i n t o the r e a c t i o n f l a s k . T h i s , i n t u r n , c c u l d l e a d t o the f o r m a t i o n o f f l u o r o b o r i c a c i d (HBF^), a v e r y s t r o n g a c i d i n non-aqueous media. F l u o r o b o r i c a c i d m i g h t a l s o be p r o d u c e d i n a r e a c t i o n between p h e n y l s u l p h e n y l t e t r a f l u o r o b o r a t e and n i t r o m e t h a n e , as shown i n f i g u r e 8. I f t h i s i s the c a s e , the r e s u l t i n g p r o t o n c y c l i z a -t i o n w i t h HBF^ r e p r e s e n t s a s i g n i f i c a n t r a t e enhancement o v e r the s t a n n i c c h l o r i d e v e r s i o n o f the r e a c t i o n . - 45 -JQ-H CH 3 N0 2 CH2=NS+Q_ BR" + PhS + + CH2=N+ 0-H o-.0-H CH 2-N+ PhS 0 PhS-CH 2 -N+ + BP, + H + BR, F i g u r e 8 . R e a c t i o n o f n i t r o m e t h a n e a n d p h e n y l s u l p h e n y l t e t r a f l u o r o b o r a t e t o f o r m f l u o r o b o r i c a c i d . C y c l i z a t i o n w a s n e x t a t t e m p t e d b y a d d i n g p h e n y l s u l p h e n y l 4 7 c h l o r i d e d r o p w i s e t o a v i g o r o u s l y s t i r r e d s u s p e n s i o n o f a l u -m i n u m c h l o r i d e i n C I ^ C ^ c o n t a i n i n g 4_3. E x a m i n a t i o n o f t h e XH -NMR s p e c t r u m o f t h e c r u d e m a t e r i a l s h o w e d t h a t t h e c y c l i z e d c o m p o u n d 8_7 w a s p r e s e n t , b u t t o s u c h a s m a l l e x t e n t t h a t i s o l a -t i o n w a s i m p r a c t i c a l . 0 . A ^ C 0 2 C H 3 PhSCl , AlCl. CH 2 Cl : 43 SPh L7 - 46 -E a r l i e r i t was suggested that aluminum c h l o r i d e may be p r o v i d i n g the s u r f a c e on which the p h e n y l s e l e n e n y l c y c l i z a t i o n c o u l d occur. However, in the analogous sulphur case j u s t men-ti o n e d , t h i s heterogeneous reagent proved to be much l e s s e f f e c -t i v e . Rather than change sulphur reagents i n an attempt to im-prove y i e l d s , the d e c i s i o n to use d i f f e r e n t heterogeneous c a t a l y s t s was made. The f i r s t c h o i c e of c a t a l y s t s was s i l i c a g e l , s e l e c t e d because of the tendency of c e r t a i n compounds, such as 6^8_, to 7 rearrange on chromatography p l a t e s . I t was found, though, that the dropwise a d d i t i o n of p h e n y l s u l p h e n y l c h l o r i d e to a suspension of s i l i c a g e l i n dichloromethane c o n t a i n i n g 4_3 a f f o r d e d only the a d d i t i o n product 8_8. D i s t i n g u i s h i n g 1 H-NMR f e a t u r e s of the 0 Q r e a c t i o n product 8_8 i n c l u d e the l o s s of the v i n y l i c a b s o r p t i o n in 4_3, p l u s the presence of the phenyl a b s o r p t i o n at 67. 57-7 .03 , a carbomethoxy s i g n a l at 63.65, a methylene peak at 63.33 and a gem dimethyl s i n g l e t at 61.67. S a t u r a t i o n of the double bond would be expected to s h i f t the gem dimethyl a b s o r p t i o n u p f i e l d , as was seen i n the case of 69^ . However, the s i n g l e t at 61.67 has, i n f a c t , moved downfield s l i g h t l y , i n d i c a t i n g the presence - 47 -of an e l e c t r o n e g a t i v e atom, such as c h l o r i n e , on the carbon bearing the gem dimethyl groups. P r e p a r a t i o n of the c y c l i z e d m a t e r i a l 8_7 i n good y i e l d was e v e n t u a l l y c a r r i e d out by r e f l u x i n g a suspension of s i l i c a g e l and a s o l u t i o n of adduct 8ji_ i n d i c h l o r ome thane. Examination 0 0 / \ ^ C 0 2 C H 3 r / i l \ r x ' C 0 2 C H 3 1) PhSCl, silica gel C H 2 C l 2 43 2) A , 3 hours ^ p h §7 of the 1H-NMR spectrum of 8_7 re v e a l e d a product v i r t u a l l y i d e n -t i c a l to 6_9, except f o r a small change i n the aromatic r e g i o n . Whereas the phenyl a b s o r p t i o n i s e v i d e n t as two broad s i g n a l s in the selenium case, the same a b s o r p t i o n i n the sulphur c y c l i z e d product appears as one broad s i g n a l . The methyl s i n g l e t s at 61.32, 1.28, 1.23 and 1.15 i n the 1H-NMR spectrum of 82 i n d i -cate that i t i s a mixture of diastereomers. Separation of the two d i a s t e r e o m e r s was not attempted although, as bef o r e , they are ev i d e n t as two b a r e l y d i s t i n g u i s h a b l e spots on TLC. An obvious e x t e n s i o n of these r e s u l t s i s to attempt the phenylseleneny1 c y c l i z a t i o n u s ing s i l i c a g e l i n s t e a d of alumi-num c h l o r i d e . However, the a d d i t i o n of p h e n y l s e l e n e n y l c h l o r i d e to the double bond of 4_3 does not proceed as c l e a n l y as the s i m i l a r c onversion of 4_3 to 8H8. Since reasonable y i e l d s of 6_9 can a l r e a d y be obtai n e d , t h i s aspect of the c y c l i z a t i o n s t u d i e s was not pursued. - 48 -The next series of steps p a r a l l e l s the e a r l i e r reactions on the selenium compounds. Treatment of an ethereal solution of 8_7 with two equivalents of sodium hydride, followed by the drop-wise addition of DECP affords the enol phosphate 8_9 in good y i e l d . The 1 H-NMR spectrum of the product 8_9 exhibits a multi-plet at 62.93-3.25, which is due to the proton on the carbon bearing the sulphide group. The enol phosphate 8^9 is then con-verted to 90 by treatment with lithium dimethylcuprate in ether v ^ \ ^ C 0 2 C H 3 87 2 eq. NaH (C 2 H 5 0) 2 POCl E t 2 0 PhS •C0 2CH 3 (DPO(OC2H5)2 89 (CH 3) 2CuLi Et 2 0 / -23°C PhS C 0 2 C H 3 DIBAL E t 2 0 90 - 49 -at -23°C. Following t h i s , reduction of 9K) with excess DIBAL produces the a l l y l i c alcohol 93.. Protection of the alcohol i s achieved by converting i t to the THP ether 92. using dihydropyran 42 and PPTS in dichloromethane At this juncture, a few attempts were made at generating the anion of the sulphide 92 using n-butyllithium in THF. As in the selenium case, the sulphide multiplet in the 1H-NMR is p a r t i a l l y obscured by the THP absorptions. Enough of the signal i s discernable, though, to allow monitoring the progress of anion formation by deuterium incorporation. However, in a l l cases, only s t a r t i n g material 9_2 was recovered and no anion formation could be detected by deuterium incorporation. Failure to generate a sulphur s t a b i l i z e d carbanion was not considered a setback though, as the prime motivation in the s u l -phur work was to test, and i f possible, make use of the a c i d i t y of the sulphoxide proton. To this end, the sulphide 9_2 was oxidized to the sulphoxide 9_3 using an ice cold solution of m-chloroperbenzoic acid (MCPBA) in dichloromethane . The most noticeable change in the 1 H-NMR spectrum of 9_3, compared to the 1 H-NMR spectrum of 9 J 2 , is the narrowing and sharpening of the - 50 -p h e n y l a b s o r p t i o n , c o u p l e d w i t h a s l i g h t d o w n f i e l d s h i f t i n t h e s p e c t r u m o f 93. T h i s i s t o b e e x p e c t e d , s i n c e t h e s u l p h o x i d e i s m o r e e l e c t r o n w i t h d r a w i n g t h a n t h e s u l p h i d e . U n f o r t u n a t e l y , t h e s u l p h o x i d e p r o t o n j a p s o r p t i o n i s n o t d i s t i n c t l y v i s i b l e a n d i s m o s t l i k e l y b u r i e d u n d e r t h e T H P s i g n a l s . T h e h i d d e n s u l -p h o x i d e p r o t o n a b s o r p t i o n p r e c l u d e s t h e o p t i o n o f f o l l o w i n g a n i o n g e n e r a t i o n b y d e u t e r i u m i n c o r p o r a t i o n . I n s t e a d , p r o o f o f s u c c e s s w o u l d h a v e t o c o m e b y a l k y l a t i o n o f t h e a n i o n w i t h a r e a c t i v e a l k y l a t i n g a g e n t s u c h a s m e t h y l i o d i d e . H o w e v e r , e v e n t h i s c o u r s e c o u l d p r e s e n t a n e n i g m a . T h e s u l p h o x i d e 9_3 a l r e a d y c o n t a i n s t h r e e c h i r a l c e n t e r s , o n e o f t h e m e m b o d i e d i n t h e s u l -p h u r a t o m w i t h i t s l o n e p a i r a n d t h r e e d i f f e r e n t g r o u p s a r o u n d i t . T h e o t h e r c h i r a l c e n t e r s a r e t h e c a r b o n b e a r i n g t h e s u l -p h o x i d e g r o u p a n d t h e a c e t a l c a r b o n i n t h e T H P m o i e t y . A l l o f t h e s e c h i r a l c e n t e r s w o u l d r e m a i n c h i r a l a f t e r a l k y l a t i o n , h e n c e 94 w o u l d b e a m i x t u r e o f d i a s t e r e o m e r s . T h e c h a n c e o f t h e n e w m e t h y l p e a k a p p e a r i n g a s a s h a r p s i n g l e t w o u l d a p p e a r t o b e v e r y r e m o t e , t h u s m a k i n g i t d i f f i c u l t t o d e t e c t a n y a l k y l a t e d p r o -d u c t . F o r t h i s r e a s o n , t h e T H P g r o u p w a s r e p l a c e d b y a p r o t e c t -i n g g r o u p t h a t w o u l d n o t i n t r o d u c e i n t e r f e r i n g p e a k s i n t h e - 51 -1H-NMR and also, one that did not contain a c h i r a l atom. Treat-49 * ment of 9JL with a dichloromethane solution of 2-methoxypropene and PPTS did not produce the desired acetal 95_. Inspection of the 1H-NMR spectrum of the product revealed the presence of three v i n y l protons, one as a broad peak at 65.34-5.61, and two as a sharp peak at 65.03, which were immediately incongruous with structure 9_5, as well as was the absence of a methoxy peak. The spectral data were consistent with the formation of 96_. I t is possible that the acetal 9_5 may have indeed been formed, but then underwent a fragmentation to the diene 96. The driving force of the fragmentation could be the production of acetone and methanol (equation 16). This fragmentation must be less l i k e l y to occur in the THP case. - 52 -The next attempt at protecting the alcohol 91 was more successful. Overnight treatment of 91. with a dimethylformamide (DMF) solution of imidazole and t-butyldimethylchlorosilane 5 0 affords the s i l y l a t e d alcohol 9_7 in moderate y i e l d . However, the reaction does not proceed to completion unless a 7.5 fold excess of imidazole and a 3.5 f o l d excess of t-butyldimethyl-chlorosilane are used. The s i l y l ether 9_7 appears to circum-vent some of the problems encountered e a r l i e r with the THP ether 93. The dimethyl and t-butyl peaks occur far u p f i e l d in the ^-NMR spectrum, leaving i t unhindered for the detection of new a l k y l groups. More importantly, however, the sulphide proton multiplet i s c l e a r l y v i s i b l e at 62.93-3.28. Oxidation of the sulphide 9_V to the sulphoxide 98^  was car-r i e d out by treatment with an ice cold dichloromethane solution 48 of MCPBA . However, the res u l t i n g sulphoxide posed more - 53 -Loss of the sulph i d e proton a b s o r p t i o n at 62.93-3.28 i s accompanied by the appearance of a q u a r t e t at 63.58, v a r y i n g i n i n t e n s i t y from r e a c t i o n to r e a c t i o n . However, i f the product i s l e f t to s i t on the bench for s e v e r a l days, the qu a r t e t d i s -appears, although no other peaks i n the spectrum change. Even more i n t r i g u i n g i s the f a c t t h a t an aqueous wash of the com-pound regenerates the q u a r t e t to a c e r t a i n e x t e n t . In a d d i t i o n , the *H-NMR spectrum of the o x i d a t i o n product c o n t a i n s a broad peak at 62.97 which again v a r i e s in i n t e n s i t y depending on the r e a c t i o n . Shaking the product with D 20 r e s u l t s i n the immedi-ate disappearance of the broad peak and a very gradual l o s s of the q u a r t e t . I n s p e c t i o n of 1H-NMR evidence shows that the q u a r t e t i n 98, lo c a t e d at 63.58, i s s l i g h t l y d o wnfield of the ether q u a r t e t at 51 63.38 , which e l i m i n a t e s t h i s s o l v e n t as a p o s s i b l e source of the q u a r t e t . The o x i d a t i o n of the a l c o h o l 91. to the sulphoxide 99 e v e n t u a l l y provided the evidence needed to make a d e f i n i t i v e statement about the q u a r t e t . The 1 H-NMR spectrum of _99 c o n t a i n s a q u a r t e t at 63.58. The a d d i t i o n of a few drops of ether pro-duces a d i s t i n c t and o v e r l a p p i n g q u a r t e t at 63.38. Thus the qu a r t e t i n 99, and by analogy, the one i n 98_, i s not due to r e s i d u a l e t h e r . - 54 -The sulphoxide proton in £8 can couple with the two ad-jacent diastereotopic protons and would therefore be s p l i t into a doublet of doublets. Thus, the observed quartet i s not contrary to what m i g h t ^ i n t u i t i v e l y be expected. The variation in i n t e n s i t y of the quartet peaks seems to indicate the presence of two diastereomers. If the quartet i s due to the diastereo-topic proton as suggested, one might wonder why the absorption regularly disappears. The suggestion was made, although without precedent, that 98_ isomerizes to a compound 100 containing a 98 100 carbon-sulphur double bond. Both the proton disappearance and broad peak at 62.97 in the 1H-NMR of 98 can be explained in t h i s ease. However, th i s p o s s i b i l i t y must be discounted when one considers that the gem dimethyl absorptions of 100 should c o l -lapse to a s i n g l e t . Instead, the ^-NMR spectrum of 98_ con-tains a series of methyl peaks of varying i n t e n s i t i e s at 61.62, 1.58 , 1.46 , 1.38 , 1.32, 1.28 , 1.23, 1.16 and 1.04. The assumption that the product i s a mixture of diastereomers was confirmed when p u r i f i c a t i o n of 98_ by TLC afforded a single compound with only three of the signals at 61.62 (vin y l methyl) and 61.46, 1.32 (gem dimethyls). - 55 -Unfortunately, we cannot offer an explanation of the 1H-NMR spectrum of 98^  at th i s time. However, other spectral data were consistent with structure 98^  and various reactions to generate the sulphoxide anion and alkylate t h i s anion were attempted. Treatment of a THF solution of 98. a t ~78°C with either one or two equivalents of n-butyllithium, followed by addition of l-bromo-2-propene at -23°C, results in recovery of starting material only. However, treatment of 98^  with three equivalents of n-butyllithium and l-bromo-2-propene i n i t i a t e s a reaction, but the product i s not the desired alkylated sulphoxide 101. This i s apparent after examination of the 1H-NMR spectrum re-veals that four v i n y l protons are present instead of three, as well as the fact that the phenyl absorption of the sulphoxide i s gone. In addition, the gem dimethyl absorptions have collapsed to a single sharp peak at 61.22. This evidence would seem to indicate that the sulphoxide has eliminated to produce a second - 56 -double bond, which accounts for the extra v i n y l proton in the *H-NMR spectrum. However, i t i s possible for the elimination to proceed in either of two ways to produce an endo- or exo-c y c l i c double bond. A closer inspection of the *H-NMR spectrum shows that the v i n y l s h i f t s do not resemble the t y p i c a l pattern expected of an a l l y l system. From t h i s , and from the f a i r l y strong IR absorption at 1645 cm ^ , i t seems reasonable to sug-gest that the alkylated sulphoxide undergoes an exocyclic elim-ination to give the conjugated diene system 102. In retrospect, this is not surprising since the excess base which must be added to i n i t i a t e the reaction i s also available to abstract the a l l y l -ic proton and lead to elimination of phenyl sulphinate (equation 17) . 0 To avoid this problem of sulphoxide elimination, alkylation was next attempted using methyl iodide. It was found that treat-ment of 98_ with three equivalents of n-butyllithium, followed by addition of methyl iodide, does in fact lead to the alkylated product 103. From the series of 1H-NMR peaks ranging from 61.65 to 61.10, i t appears that 103 is a mixture of diastereo-mers, not unlike £8. However, p u r i f i c a t i o n of the crude pro-duct by TLC affords a much simpler spectrum of one diastereomer - 57 -with peaks at 61.63, 1.48, 1.37 and 1.07. The s i g n a l at 61.63 i s due to the v i n y l methyl, while the gem dimethyl a b s o r p t i o n s are assigned t o the peaks a t 61.48 and 61.37. T h i s assignment i s based on the 1 H-NMR spectrum of 98_. Hence, the remaining s i g n a l a t 61.07 i s assigned to the new methyl group. C o r r o b o r a t i o n of the s t r u c t u r e of 103 was found i n both mass s p e c t r a l and m i c r o a n a l y t i c a l evidence. The mass spectrum of 103 does not show a parent peak at 406, due to the f a c i l e e l i m i n a t i o n of the sulphoxide i n the mass spectrometer. The next h i g h e s t m/e peak at 280, corresponding to the l o s s of the sulphoxide moiety, i s four t e e n mass u n i t s higher than the h i g h e s t m/e peak found i n the mass spectrum of 98^ . C l e a r l y , i t appears t h a t a methyl u n i t has been i n c o r p o r a t e d i n t o the new s t r u c t u r e . In a d d i t i o n , the m i c r o a n a l y t i c a l r e s u l t s agree with the e m p i r i c a l formula of 103. However, the a l k y l a t e d sulphoxide 103 appeared to rearrange on st a n d i n g at room temperature f o r about a week. Lack of m a t e r i a l , though, prevented a complete c h a r a c t e r i z a t i o n of the rearranged product. - 58 -4. DIENE SYNTHESIS FROM SELENOXIDE AND SULPHOXIDE The l a s t aspect of the p r o j e c t to be explored i n v o l v e d s y n t h e s i s of two inter m e d i a t e s which could be used i n the pre-p a r a t i o n of c e r t a i n end groups, s p e c i f i c a l l y the C-3 hydroxylated moie t y . The s e l e n o x i d e 104 was prepared by treatment of an i c e 52 c o l d dichloromethane s o l u t i o n of 79a with MCPBA . Although some e l i m i n a t i o n of 104 occurred at 0°, the complete conversion 0 PhSe of 104 to the diene 105 was e f f e c t e d i n r e f l u x i n g d i c h l o r o m e t h -ane. I n s p e c t i o n of the 1H-NMR spectrum of 105 showed that the gem di m e t h y l s i g n a l s of 79a c o l l a p s e d to a s i n g l e t at 61.17. In a d d i t i o n , two a l l y l i c protons are present as a broad s i n g l e t at 62.58 and the two v i n y l protons of 105 c o i n c i d e as a s i n g l e t at 65.46. S i m i l a r l y , e l i m i n a t i o n of the sulphoxide 98_ i n r e f l u x i n g toluene a f f o r d e d the diene 106 i n good y i e l d . The 1H-NMR spec-trum of the product a l s o c o n t a i n s a gem dimethyl s i n g l e t at 61.10, as w e l l as an a l l y l i c methylene at 62.60 and two v i n y l a b s o r p t i o n s at 65.46. - 59 -O-S i - PhCH-A 0— Si-98 106 Following these steps, hydroboration of the double bond of 105 or 106 with a hindered hydroborating reagent such as thexyl-borane, should produce the desired C-3 hydroxy compound (equa-tion 18) . R 105 or 106 5. CONCLUSION 1) thexylborane 2) NaOH, H 2 0 2 (18) The e l e c t r o p h i l e induced c y c l i z a t i o n s of (3-keto esters d i s -cussed in this thesis demonstrate, only in small measure, the u t i l i t y of these esters as well as selenium and sulphur reagents in organic synthesis. The alkenyl g-keto ester 4_3 undergoes e l e c t r o p h i l i c c y c l i z a t i o n s to an intermediate p a r t i c u l a r l y well suited for elaboration as a carotenoid end group. Fortunately, the introduction of the phenylseleneny1 and phenylsulphenyl moieties into t h i s intermediate provide the means by which the end group can be substituted at cer t a i n carbons. Although the routes to natural carotenoids described in this thesis were not completed, they appear to be very promising. - 60 -C. EXPERIMENTAL A l l temperatures are reported in degrees Celsius. Kugelrohr d i s t i l l a t i o n s were carried out using a Buchi Kugelrohr thermo-stated oven, and the B o i l i n g points obtained thereof are uncor-rected. Infrared spectra were recorded in chloroform, on a Perkin Elmer 710 or 710B spectrophotometer, and were calibrated with the 1601 cm ^ band of polystyrene. The 1H-NMR spectra were recorded in deuterochloroform solution on Varian Model T-60, HA-100 and XL-100 spectrometers. Chemical s h i f t s are reported in the 6 scale using tetramethylsilane as an i n t e r n a l standard. The m u l t i p l i c i t y , coupling constants ( i f observable) and i n t e -grated peak areas are indicated in parentheses after each s i g n a l . Low resolution mass spectra were recorded on an Atlas CH-4B mass spectrometer, which was operated at an ionizing potential of 70 eV. Elemental microanalyses were performed by Mr. Peter Borda, University of B r i t i s h Columbia. The s i l i c a gel used for a n a l y t i c a l and preparative thin layer chromatography and the sulphur mediated c y c l i z a t i o n s was obtained from E. Merck and was Type PF 254 + 366. The s i l i c a gel used for column chroma-tography was of mesh size 100-200 and was obtained from Grace Co. A l l solvent systems are expressed in r a t i o s by volume (v/v). The petroleum ether used has the b o i l i n g range 30-60°. Where s p e c i f i e d , solvents were dried before use. Diethyl ether (ether) and tetrahydrofuran (THF) were d i s t i l l e d from lithium aluminum hydride. Dichloromethane (CH^Cl^) was obtained by - 61 -d i s t i l l a t i o n from phosphorus pentoxide and toluene was d i s t i l l e d from sodium metal. M e t h y l l i t h i u m (in e t h e r ) , n - b u t y l l i t h i u m (in hexane) and d i i s o b u t y l a l u m i n u m hydride (in hexane) were obtained from the A l d r i c h Chemical Company, Inc. The m e t h y l l i t h i u m and n - b u t y l -l i t h i u m s o l u t i o n s were s t a n d a r d i z e d by t i t r a t i o n a g a i n s t a 1.0 M s o l u t i o n of t - b u t a n o l i n benzene, u s i n g 1,10-phenanthroline as i n d i c a t o r . Sodium h y d r i d e , from A l f a D i v i s i o n , Ventron C o r p o r a t i o n , was weighed as a 50% d i s p e r s i o n i n m i n e r a l o i l and was washed with dry ether to remove the o i l p r i o r to use. - 62 -Methyl 7-Methyl-3-oxo-6-octenoate (43) A 250-ml two-necked round bottom f l a s k (RBF) was equipped with a stoppered, pressure e q u a l i z i n g a d d i t i o n f u n n e l on one neck and a serum cap with a n i t r o g e n i n l e t on the ot h e r . The f l a s k was charged with prewashed sodium hydride (1.86 g, 38.8 mmole) suspended i n dry THF and then placed i n an i c e bath. A s o l u t i o n of methyl a c e t o a c e t a t e (4.10 g, 35.3 mmole) i n dry THF was added dropwise through the a d d i t i o n funnel to the s t i r r e d suspension and the r e s u l t i n g mixture was s t i r r e d at 0° f o r 20 minutes. F o l l o w i n g t h i s , n - b u t y l l i t h i u m (23.5 ml, 37.0 mmole) was syr i n g e d s l o w l y i n t o the r e a c t i o n v e s s e l and the r e s u l t i n g d i a n i o n s o l u t i o n was s t i r r e d for another 20 minutes at 0°. The mixture was t r e a t e d with 1-bromo-3-methyl-2-butene (4.5 ml, 38.8 mmole) at 0°, and then s t i r r e d at room temperature for 30 minutes. The r e a c t i o n was quenched with 20 ml water and 7 ml of c o n c e n t r a t e d h y d r o c h l o r i c a c i d and then d i l u t e d with 50 ml of e t h e r . The aqueous phase was separated and washed a f u r t h e r two times with e t h e r . The e t h e r e a l e x t r a c t s were combined, washed with b r i n e and d r i e d over anhydrous magnesium sul p h a t e . Removal of s o l v e n t s under reduced pressure f u r n i s h e d 7.58 g of crude product which was d i s t i l l e d to a f f o r d 4.75 g (73%) of 4_3 as a c o l o u r l e s s l i q u i d : bp 74-76°/3 Torr ( l i t . 7 bp 67-68°/0.1 T o r r j ; IR 1745, 1718 and 1640 cm" 1; 1H-NMR 61.6 (s, 3H), 1.65 (s, 3H), 1.95-2.73 (m, 4H), 3.40 (s, 2H), 3.70 (s, 3H) and 5.0 (m, IH) . - 63 -Methyl 2,2-Dimethyl- 3-phenylselenenyl-6-oxocyclohexanecarboxy- late (69) Aluminum chloride (3.62 g, 27.2 mmole) was weighed d i r e c t -l y into a stoppered 100-ml three-necked RBF and immediately 30 ml of dry dichloromethane was added to the A l C l ^ . The flask was then f i t t e d with a pressure equalizing addition funnel on one neck and a serum cap connected to a nitrogen i n l e t on another. Following t h i s , 4_3 (5.00 g, 27.1 mmole) was syringed into the reaction mixture and then phenylselenenyl chloride (5.72 g, 29.9 mmole) in 20 ml of dry dichloromethane was added dropwise through the addition funnel to the vigorously s t i r r e d suspen-sion. The r e s u l t i n g mixture was s t i r r e d for 30 minutes and then diluted with ether. The flask was placed in an ice bath while the aluminum chloride was destroyed by the dropwise addition of cold water. The organic layer was separated, washed with brine and the aqueous washings were then combined and extracted with ether. The combined organic extracts were dried over anhydrous magnesium sulphate and subsequent solvent removal under reduced pressure yielded 9.63 g (104%) of 6_9 as a thick yellow o i l . Column chromatography of the crude material was carried out us-ing a mixture of petroleum ether and ether (4/1) to elute 7.72 g (84%) of 69 as a l i g h t yellow o i l : bp (Kugelrohr d i s t i l l a -tion) 99-102°/0.2 Torr; IR 1750, 1710 and 1590 cm - 1; 1H-NMR 61^10, 1.22, 1.25, 1.28 (s, s, s, s, 6H), 2.02-2.80 (m, 4H), 3.28-3.45 (brs, IH), 3.63 (S, 3H), 3.71-4.02 (m, IH) and 7.00-7.67 (m, 5H); mass spectrum m/e ( r e l intensity) 151 (95), - 6 4 -157 ( 9 8 ) , 183 ( 5 4 ) , 232 ( 2 2 ) , 234 ( 3 4 ) , 308 ( 2 4 ) , 309 ( 2 2 ) , 310 (54 ) , 311 ( 3 5 ) , 312 ( 9 0 ) , 313 ( 1 6 ) , 314 (1 0 0 ) , 316 (34) and 340 (29) . A n a l . C a l c d f o r C l g H 2 0 O 3 S e : C, 56.64; H, 5.94. Found: C, 56.73; H, 5.95. M e t h y l 2 - ( D i e t h y l p h o s p h o r y l o x y ) - 5 - p h e n y l s e l e n e n y 1 - 6 , 6 - d i m e t h y l -1 - c y c l o h e x e n e c a r b o x y l a t e (78) A 100-ml t h r e e - n e c k e d RBF was e q u i p p e d w i t h a s t o p p e r e d , p r e s s u r e e q u a l i z i n g a d d i t i o n f u n n e l on one neck and a serum cap w i t h a n i t r o g e n i n l e t on a n o t h e r . The f l a s k was c h a r g e d w i t h prewashed sodium h y d r i d e (0.95 g, 19.8 mmole) su s p e n d e d i n d r y e t h e r and t h e n i t was l o w e r e d i n t o an i c e b a t h . An e t h e r e a l ( d r y ) s o l u t i o n o f t h e s e l e n i d e 6_9 was s y r i n g e d s l o w l y i n t o t h e r e a c t i o n v e s s e l and the r e s u l t i n g m i x t u r e was s t i r r e d f o r 1 hour a t 0 ° . F o l l o w i n g t h i s , d i e t h y l c h l o r o p h o s p h a t e (1.71 ml, 11.9 mmole) was s y r i n g e d d r o p w i s e i n t o the f l a s k and t h e c o n t e n t s were t h e n s t i r r e d o v e r n i g h t a t room t e m p e r a t u r e . The r e a c t i o n m i x t u r e was quenched a t 0° w i t h water and the o r g a n i c phase was washed w i t h b r i n e . The aqueous w a s h i n g s were e x t r a c t e d once w i t h e t h e r and the combined o r g a n i c l a y e r s were d r i e d o v e r a n h y d r o u s magnesium s u l p h a t e . Removal o f the s o l v e n t s under r e d u c e d p r e s s u r e gave 4.63 g o f c r u d e p r o d u c t , w h i c h was p u r i -f i e d by column c h r o m a t o g r a p h y . A m i x t u r e o f p e t r o l e u m e t h e r and e t h y l a c e t a t e (4/1) was us e d t o e l u t e 3.96 g (84%) o f 78^  as a l i g h t y e l l o w o i l : bp ( K u g e l r o h r d i s t i l l a t i o n ) 1 7 3 - 1 7 6 ° / 0 . 2 - 65 -T o r r ; IR 1725, 1680, 1585, 1275 and 1030 cm" 1; 1H-NMR 61.17-1.50 (m, 12H), 1.93-2.77 (m, 4H), 3.00-3.30 (m, I H ) , 3.73 ( s , 3H), 4.10 (qn, J=7 Hz, 4H) and 7.07-7.63 (m, 5H); mass s p e c t r u m m/e ( r e l i n t e n s i t y ) 99 ( 4 5 ) , 155 ( 1 0 0 ) , 215 ( 2 7 ) , 259 ( 1 9 ) , 287 ( 6 5 ) , 288 ( 2 5 ) , 319 ( 6 ) , 320 (6), 442 ( 3 ) , 444 ( 6 ) , 472 (4) and 474 ( 8 ) . A n a l . C a l c d f o r C 2 Q H 2 9 0 6 S e P : C, 50.53; H, 6.15. Found: C, 50.36; H, 6.26. M e t h y l 2,6,6-Tr i m e t h y l - 5 - p h e n y l s e l e n e n y l - l - c y c l o h e x e n e c a r b o x y - l a t e (79a) 53 R e c r y s t a l l i z e d c u p r o u s i o d i d e (1.18 g, 6.19 mmole) was w e i ghed i n t o a 250-ml t h r e e - n e c k e d RBF, w h i c h was t h e n e q u i p p e d w i t h a p r e s s u r e e q u a l i z i n g a d d i t i o n f u n n e l and a n i t r o g e n i n l e t . The c u p r o u s i o d i d e was s u s p e n d e d i n 100 ml o f d r y e t h e r and the r e a c t i o n v e s s e l was l o w e r e d i n t o an i c e b a t h . M e t h y l l i t h i u m (7.3 ml, 12.4 mmole) was t h e n s y r i n g e d i n t o the s t i r r e d r e a c -t i o n m i x t u r e u n t i l o n l y a s m a l l amount o f y e l l o w s o l i d r e m a i n e d a t t h e b o t t o m o f t h e f l a s k . The r e s u l t i n g c l e a r l i t h i u m d i -me t h y l c u p r a t e s o l u t i o n was c o o l e d t o -23° and e n o l p h o s p h a t e 78 (1.46 g, 3.08 mmole) i n 30 ml o f d r y e t h e r was added d r o p -w i s e t o t h e r e a c t i o n m i x t u r e w i t h s t i r r i n g . The s o l u t i o n , w hich g r a d u a l l y became a deep maroon c o l o u r , was s t i r r e d f o r f o u r h o u r s a t - 2 3 ° . The r e a c t i o n m i x t u r e was t h e n warmed t o 0° and quenched w i t h a s a t u r a t e d aqueous s o l u t i o n o f ammonium c h l o r i d e . The o r g a n i c phase was s e p a r a t e d and washed w i t h a d i l u t e aqueous - 66 -ammonium h y d r o x i d e s o l u t i o n u n t i l the aqueous w a s h i n g s were no l o n g e r b l u e i n c o l o u r . The aqueous w a s h i n g s were e x t r a c t e d w i t h e t h e r and the combined e t h e r e a l e x t r a c t s were d r i e d o v e r anhy-d r o u s magnesium s u l p h a t e . S o l v e n t r e m o v a l under r e d u c e d p r e s -s u r e y i e l d e d 1.01 g (97%) o f 79 as a y e l l o w o i l . To p r e p a r e a m i c r o a n a l y t i c a l s a m p l e , 79 was p u r i f i e d by t h i n l a y e r chroma-t o g r a p h y u s i n g a s o l v e n t m i x t u r e o f p e t r o l e u m e t h e r and e t h e r ( 9 / 1 ) : bp ( K u g e l r o h r d i s t i l l a t i o n ) 1 0 9 - 1 1 2 ° / 0 . 2 T o r r ; IR 1710, 1660 and 1580 c m - 1 ; 1H-NMR 61.29 ( s , 3H), 1.33 ( s , 3H), 1.65 ( s , 3H), 1.93-2.18 (m, 4H), 3.03-3.39 (m, I H ) , 3.75 ( s , 3H) and 6.92-7.52 (m, 5H); mass s p e c t r u m m/e ( r e l i n t e n s i t y ) 77 ( 7 ) , 107 ( 2 6 ) , 121 ( 4 2 ) , 149 ( 1 0 0 ) , 150 ( 1 3 ) , 181 ( 4 3 ) , 336 (10) and 338 (15) . A n a l . C a l c d f o r C 1 7 H 2 2 0 2 S e : C, 60.53; H, 6.57. Found: C, 60.80; H, 6.60. 1 - M e t h a n o l - 5 - p h e n y l s e l e n e n y l - 2 , 6 , 6 - t r i m e t h y l - l - c y c l o h e x e n e (80a) A 50-ml s i n g l e - n e c k e d RBF e q u i p p e d w i t h a n i t r o g e n i n l e t was c h a r g e d w i t h c r u d e 7_9 (0.61 g, 1.82 mmole) d i s s o l v e d i n 20 ml o f d r y e t h e r , and was t h e n c o o l e d i n an i c e b a t h . A t w o - f o l d e x c e s s o f DIBAL (3.64 m l , 3.64 mmole) was s y r i n g e d s l o w l y i n t o the c o l d r e a c t i o n v e s s e l , and t h e r e s u l t i n g m i x t u r e was s t i r r e d and g r a d u a l l y warmed t o room t e m p e r a t u r e o v e r a t h r e e - h o u r p e r i -o d . The r e a c t i o n m i x t u r e was a g a i n c o o l e d t o 0° and quenched w i t h 1 N h y d r o c h l o r i c a c i d u n t i l b o t h the o r g a n i c and aqueous l a y e r s were c l e a r . T h i s m i x t u r e was t h e n s t i r r e d f o r 1 h o u r . - 67 -The o r g a n i c phase was washed with s a t u r a t e d aqueous sodium b i -carbonate s o l u t i o n and the aqueous washings were then e x t r a c t e d three times with e t h y l a c e t a t e . The o r g a n i c e x t r a c t s were com-bined and d r i e d over anhydrous magnesium s u l p h a t e . Solvent removal under reduced pressure y i e l d e d 0.50 g (88%) crude pro-duct as a yellow o i l . P r e p a r a t i o n of a m i c r o a n a l y t i c a l sample of 80a was c a r r i e d out by t h i n l a y e r chromatography using a s o l -vent mixture of petroleum ether and ether (1/1): bp (Kugelrohr d i s t i l l a t i o n ) 103-106°/0.1 T o r r ; IR 3620, 3460, 1655 and 1580 cm - 1; 1H-NMR 61.15 (s, 3H), 1.35 (s, 3H), 1.72 (s, 3H), 1.87-2.20 (m, 4H), 3.05-3.41 (m, IH), 4.10 (s, 2H) and 6.98-7.60 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 69 (100), 77 (68), 93 (90), 107 (80), 134 (22), 135 (92), 290 (5), 292 (7), 308 (1) and 310 (2). A n a l . C a l c d f o r C 1 6 H 2 2 O S e : C, 62.13; H, 7.17. Found: C, 6 2.28; H, 7.20. 5-Phenylselenenyl-1- Q l ' - (2"-tetrahydropyranyloxy)methyl"] -2,6,6-t r i m e t h y l - l - c y c l o h e x e n e (81) 4 2 P y r i d i n i u m p-toluenesulphonate (6 mg, 0.025 mmole) was weighed d i r e c t l y i n t o a stoppered 50-ml two-necked RBF and then immediately d i s s o l v e d i n 5 ml of dry dichloromethane. Follow-ing t h i s , the f l a s k was equipped with a n i t r o g e n i n l e t and a s o l u t i o n of crude 80a (78 mg, 0.25 mmole) in 20 ml of dry d i -chloromethane was added to the r e a c t i o n v e s s e l . Dihydropyran (0.03 ml, 0.38 mmole), f r e s h l y d i s t i l l e d from KOH, was then - 68 -s y r i n g e d dropwise i n t o the r e a c t i o n mixture and the r e s u l t i n g s o l u t i o n was s t i r r e d for three hours at room temperature. The r e a c t i o n mixture was then d i l u t e d with ether and washed s e v e r a l times with b r i n e . The aqueous washings were e x t r a c t e d once with ether and the o r g a n i c e x t r a c t s were then combined and d r i e d over anhydrous magnesium s u l p h a t e . Solvent removal under reduced pressure y i e l d e d 94 mg (95%) of crude 81. as a yellow o i l . The m i c r o a n a l y t i c a l sample was p u r i f i e d by t h i n l a y e r chromatography using a s o l v e n t mixture of petroleum ether and ether (10/1): bp (Kugelrohr d i s t i l l a t i o n ) 133-136°/0.2 T o r r ; IR 1665, 1585 and 1025 cm - 1; 1H-NMR 61.17 (s, 3H), 1.33, 1.37 (s, s, 3H), 1.48-2.28 (m, 13H), 3.12-4.47 (m, 5H), 4.47-4.73 (brs, IH) and 7.03-7.67 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 77 (71), 85 (100), 93 (84), 107 (83), 135 (93), 136 (66), 290 (24), 292 (48), 392 (1) and 394 (2) . A n a l . C a l c d f o r C 2 1 H 3 0 O 2 S e : C, 64.11; H, 7.69. Found: C, 63.99; H, 7.60. Methyl 3-Oxo-6-phenylsulphenyl-7-chloro-7-methyloctanoate (88) A 100-ml three-necked RBF was charged with _4_3 (1.01 g, 5.49 mmole) in 50 ml of dry dichloromethane. The f l a s k was then f i t t e d with a pressure e q u a l i z i n g a d d i t i o n f u n n e l on one neck 47 and a n i t r o g e n i n l e t on another. P h e n y l s u l p h e n y l c h l o r i d e (0.794 g, 5.49 mmole), as a s o l u t i o n i n 20 ml of dry d i c h l o r o -methane, was added dropwise from the a d d i t i o n f u n n e l to the v i g o r o u s l y s t i r r e d s o l u t i o n . A f t e r the r e s u l t i n g mixture was - 69 -s t i r r e d f o r 30 m i n u t e s , t h e s o l v e n t was removed under r e d u c e d p r e s s u r e t o y i e l d 1.80 g (100%) o f c r u d e 88^  as a d a r k y e l l o w o i l : IR 1745, 1720 and 1590 cm" 1; 1H-NMR 61.67 ( s , 6H), 2.33-3.05 (m, 4H), 3.33 ( s , 2H), 3.65 ( s , 3H) and 7.03-7.57 (m, 5H); mass s p e c t r u m m/e ( r e l i n t e n s i t y ) 109 ( 7 3 ) , 151 (100), 167 ( 4 7 ) , 183 ( 6 6 ) , 261 ( 1 1 ) , 292 ( 6 0 ) , 293 (15) and 294 ( 8 ) . M e t h y l 2 , 2 - D i m e t h y 1 - 3 - p h e n y l s u l p h e n y 1 - 6 - o x o c y c l o h e x a n e c a r b o x y l a t e  (87) A 250-ml two-necked RBF was c h a r g e d w i t h _43 (7. 78 g, 42.3 mmole) d i s s o l v e d i n 100 ml o f d r y d i c h l o r o m e t h a n e and was t h e n f i t t e d w i t h a p r e s s u r e e q u a l i z i n g a d d i t i o n f u n n e l and a n i t r o g e n 4 7 i n l e t . P h e n y l s u l p h e n y l c h l o r i d e (6.11 g, 42.3 mmole), as a s o l u t i o n i n 50 ml o f d r y d i c h l o r o m e t h a n e , was t h e n added d r o p -w i s e f r o m t h e a d d i t i o n f u n n e l t o t h e s t i r r e d r e a c t i o n m i x t u r e and the r e s u l t i n g s o l u t i o n was s t i r r e d a t room t e m p e r a t u r e f o r 30 m i n u t e s . F o l l o w i n g t h i s , s i l i c a g e l (7.5 g) was added i n one p o r t i o n t o the r e a c t i o n v e s s e l and t h e s u s p e n s i o n was r e f l u x e d f o r 3 h o u r s . The r e a c t i o n m i x t u r e was t h e n g r a v i t y f i l t e r e d and t h e s i l i c a g e l was r i n s e d w i t h d r y d i c h l o r o m e t h a n e . The f i l -t e r e d s o l u t i o n was d r i e d o v e r a n h y d r o u s magnesium s u l p h a t e and s u b s e q u e n t s o l v e n t r e m o v a l under r e d u c e d p r e s s u r e a f f o r d e d 11.8 g (95%) o f c r u d e p r o d u c t as an o r a n g e - y e l l o w o i l . P u r i f i c a -t i o n o f a m i c r o a n a l y t i c a l sample by t h i n l a y e r c h r o m a t o g r a p h y u s i n g a s o l v e n t m i x t u r e o f p e t r o l e u m e t h e r and e t h e r (4/1) f u r -n i s h e d a p u r e sample o f 8_7 as a l i g h t y e l l o w o i l : bp ( K u g e l r o h r - 70 -d i s t i l l a t i o n ) 119-122 u/0.15 T o r r ; IR 1750, 1710 and 1590 cm 1H-NMR 61.15, 1.23, 1.28, 1.32 ( s , s, s, s, 6H), 1.68-2.83 (m, 4H) , 3 .30-3 .46 ( b r s , IH) , 3.72 ( s , 3H) , 3 .76-3.92 (m, IH) and 7.05-7.58 (m, 5H); mass s p e c t r u m m/e ( r e l i n t e n s i t y ) 109 ( 2 4 ) , 123 ( 5 7 ) , 125 ( 1 5 ) , 151 ( 1 0 0 ) , 152 ( 1 2 ) , 183 ( 6 4 ) , 234 ( 2 0 ) , 261 ( 1 4 ) , 292 (91) and 293 ( 1 8 ) . A n a l . C a l c d f o r c 1 6 H 2 o 0 3 S : C ' 6 5 - 7 2 ; H, 6.89; S, 10.97. Found: C, 66.00; H, 6.99; S, 10.88. M e t h y l 2 - ( D i e t h y l p h o s p h o r y l o x y ) - 5 - p h e n y l s u l p h e n y 1 - 6 , 6 - d i m e t h y 1 -1 - c y c l o h e x e n e c a r b o x y l a t e (8 9) The p r o c e d u r e used h e r e was i d e n t i c a l t o the p r o c e d u r e u s e d t o make 18_. The r e a g e n t s u s e d were c r u d e 8_7 (8.30 g, 28.4 mmole), sodium h y d r i d e (2.73 g, 56.8 mmole) and d i e t h y l c h l o r o -p h o s p h a t e (5.4 m l , 37.4 mmole). A f t e r the r e a c t i o n was worked up, 11.7 g (96%) o f c r u d e p r o d u c t was i s o l a t e d as a t h i c k y e l l o w o i l . P u r i f i c a t i o n by column c h r o m a t o g r a p h y u s i n g a s o l v e n t mix-t u r e o f p e t r o l e u m e t h e r and e t h y l a c e t a t e (4/1) a f f o r d e d 9.9 g (81%) o f 8_9 as a l i g h t y e l l o w o i l : bp ( K u g e l r o h r d i s t i l l a t i o n ) l 5 8 - 1 6 1 ° / 0 . 2 T o r r ; IR 1720, 1680, 1590, 1280 and 1030 cm" 1; 1H-NMR 61.17-1.58 (m, 12H), 1.87-2.77 (m, 4H), 2.93-3.25 (m, I H ) , 3.74 ( s , 3H), 4.12 (qn, J=7 Hz, 4H) and 7.07-7.53 (m, 5H); mass s p e c t r u m m/e ( r e l i n t e n s i t y ) 136 (10 0 ) , 287 ( 5 2 ) , 288 ( 1 1 ) , 319 ( 8 ) , 383 ( 6 ) , 396 ( 9 9 ) , 397 ( 3 3 ) , 398 ( 1 5 ) , 428 ( 4 0 ) , 429 (13) and 430 (5) . A n a l . C a l c d f o r C 2 Q H 2 9 0 6 P S : C, 56.06; H, 6.82; S, 7.48. Found: C, 55.87; H, 6.77; S, 7.22. - 71 -M e t h y l 2 , 6 , 6 - T r i m e t h y l - 5 - p h e n y l s u l p h e n y l - l - c y c l o h e x e n e c a r b o x y - l a t e (90) The p r o c e d u r e u s e d h e r e was i d e n t i c a l t o t h e p r o c e d u r e used t o make _79. The r e a g e n t s u s e d were r e c r y s t a l l i z e d c u p r o u s i o d i d e 5 3 (1.28 g, 6.70 mmole), m e t h y l l i t h i u m ( 9 . 6 ml, 13.4 mmole) and e n o l p h o s p h a t e 8_9 ( 1.43 g, 3.33 mmole). A f t e r work-up, 0.93 g (96%) o f c r u d e p r o d u c t was i s o l a t e d as a t h i c k y e l l o w o i l . P u r i f i c a t i o n o f a m i c r o a n a l y t i c a l sample o f 9_0 was c a r r i e d o u t by t h i n l a y e r c h r o m a t o g r a p h y u s i n g a s o l v e n t m i x t u r e o f p e t r o l e u m e t h e r and e t h y l a c e t a t e (10/1) : bp ( K u g e l r o h r d i s -t i l l a t i o n ) 9 8 - 1 0 1 ° / 0 . 1 5 T o r r ; IR 1710, 1665 and 1590 cm" 1; 1H-NMR 61.30 ( s , 3H) , 1.32 ( s , 3H) , 1.64 ( s , 3H), 1.90-2.18 (m, 4H) , 2.92-3.28 (m, I H ) , 3.73 ( s , 3H) and 7.03-7.53 (m, 5H); mass s p e c t r u m m/e ( r e l i n t e n s i t y ) 121 ( 8 1 ) , 136 ( 9 8 ) , 149 ( 1 0 0 ) , 150 ( 1 4 ) , 180 ( 1 7 ) , 181 ( 3 7 ) , 258 ( 2 5 ) , 259 ( 1 8 ) , 290 (83) and 291 (23) . A n a l . C a l c d f o r C 1 7 H 2 2 0 2 S : C, 70.31; H, 7.64; S, 11.04. Found: C, 70.43; H, 7.58; S, 10.79. 1 - M e t h a n o l - 5 - p h e n y l s u l p h e n y l - 2 , 6 , 6 - t r i m e t h y l - l - c y c l o h e x e n e (91.) The p r o c e d u r e u s e d h e r e was i d e n t i c a l t o t h e p r o c e d u r e u s e d t o make 80a. The r e a g e n t s u s e d were c r u d e 9_0 (1.77 g, 6.11 mmole) and DIBAL (12.2 m l , 12.2 mmole). A f t e r work-up, 1.57 g (98%) o f c r u d e p r o d u c t was i s o l a t e d as a y e l l o w o i l . P u r i f i c a -t i o n o f a m i c r o a n a l y t i c a l sample o f 9_1 was a c h i e v e d by t h i n - 72 -l a y e r c h r o m a t o g r a p h y u s i n g a s o l v e n t m i x t u r e o f p e t r o l e u m e t h e r and e t h y l a c e t a t e ( 4 / 1 ) ; bp ( K u g e l r o h r d i s t i l l a t i o n ) 1 0 8 - 1 1 1 ° / 0.1 T o r r ; IR 3620, 3475, 1655 and 1585 cm" 1; 1H-NMR 61.18 ( s , 3H), 1.38 ( s , 3H), 1.76 ( s , 3H), 1.91-2.18 (m, 4H), 2.95-3.29 (m, I H ) , 4.15 ( s , 2H) and 7.03-7.53 (m, 5H); mass s p e c t r u m m/e ( r e l i n t e n s i t y ) 93 ( 2 0 ) , 109 ( 1 1 ) , 134 ( 4 3 ) , 135 (1 0 0 ) , 136 ( 3 8 ) , 244 ( 4 4 ) , 245 (1 4 ) , 262 (17) and 263 ( 7 ) . A n a l . C a l c d f o r C 1 6 H 2 2 O S : C, 73.23; H, 8.45; S, 12.22. Found: C, 73.12; H, 8.64; S, 12.10. 5-Pheny l s u l p h e n y l - 1 - Q l ' - (2 " - t e t r a h y d r o p y r a n y i o x y ) methyl^] -2,6,6-t r i m e t h y l - l - c y c l o h e x e n e (92) The p r o c e d u r e u s e d h e r e was i d e n t i c a l t o the p r o c e d u r e u s e d t o make 8_2. The r e a g e n t s u s e d were c r u d e 9_1 (350 mg, 1.33 mmole), d i h y d r o p y r a n (0.18 m l , 1.97 mmole) and p y r i d i n i u m p_-4 2 t o l u e n e s u l p h o n a t e (34 mg, 0.14 mmole). A f t e r the r e a c t i o n was worked up, 446 mg (97%) o f c r u d e p r o d u c t was i s o l a t e d as a y e l -low o i l . P u r i f i c a t i o n o f a m i c r o a n a l y t i c a l sample o f 9_2 was c a r r i e d o u t by t h i n l a y e r c h r o m a t o g r a p h y u s i n g a s o l v e n t mix-t u r e o f p e t r o l e u m e t h e r and e t h y l a c e t a t e ( 4 / 1 ) : bp ( K u g e l r o h r d i s t i l l a t i o n ) 1 2 3 - 1 2 6 ° / 0 . 2 T o r r ; IR 1665, 1590 and 1025 cm" 1; 1H-NMR 61.17 ( s , 3H), 1.33, 1.38 ( s , s, 3H), 1.48-2.25 (m, 13H), 2.98-4.49 (m, 5H), 4.49-4.74 ( b r s , IH) and 7.00-7.55 (m, 5H); mass s p e c t r u m m/e ( r e l i n t e n s i t y ) 85 (10 0 ) , 93 ( 7 7 ) , 134 (8 2 ) , 135 ( 9 2 ) , 136 ( 5 7 ) , 244 ( 6 7 ) , 245 ( 2 0 ) , 246 ( 9 ) , 262 (1) and 346 (1) . - 73 -A n a l . C a l c d f o r C 2 1 H 3 C j 0 2 S : C, 72.79; H, 8.73; S, 9.25. Found: C, 72.83; H, 8.56? S, 9.30. 5-Phenylsulphoxy-l- p i ' - (2"-tetrahydropyranyloxy) methyl"] -2,6,6- t r i m e t h y l - l - c y c l o h e x e n e (93) A 50-ml two-necked RBF was charged with crude 9_2 (228 mg, 0 . 6 6 mmole) d i s s o l v e d i n 20 ml of dry dichloromethane. The f l a s k was f i t t e d with a pressure e q u a l i z i n g a d d i t i o n f u n n e l and a n i t r o g e n i n l e t and was then lowered i n t o an i c e bath. m-Chloroperbenzoic a c i d (85%, 140 mg, 0.69 mmole) as a s o l u t i o n in 10 ml of dry dichloromethane, was added dropwise from the a d d i t i o n f u n n e l to the s t i r r e d r e a c t i o n mixture. The r e s u l t i n g s o l u t i o n was then s t i r r e d f o r a f u r t h e r 1 hour at 0°. Follow-ing t h i s , the r e a c t i o n mixture was d i l u t e d with ether and washed with a s a t u r a t e d aqueous sodium bicarbonate s o l u t i o n . The aqueous washings were e x t r a c t e d with ether and the organic ex-t r a c t s were combined and d r i e d over anhydrous magnesium s u l p h a t e . Solvent removal under reduced pressure a f f o r d e d 228 mg (95%) of crude product. The m i c r o a n a l y t i c a l sample was p u r i f i e d by t h i n l a y e r chromatography using a s o l v e n t mixture of petroleum ether and e t h y l a c etate (2.5/1): IR 1670, 1590, 1035 and 1020 cm" 1; !H-NMR 61.27-2.70 (m, 19H), 3.33-4.51 (m, 5H), 4.51-4.71 (brs, IH) and 7.47 (brs, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 85 (100), 134 (30), 135 (92), 237 (5), 260 (3) and 278 (2). A n a l . Calcd for C2iE3Q°3S: c ' 69.57; H, 8.34; S, 8.84. Found: C, 69.55; H, 8.47; S, 8.71. - 74 -1-Methylene - 5-phenylsulphenyl-2,6,6-tr imethyl-2-cyclohexene (96) 4 2 P y r i d i n i u m p_-toluenesulphonate (26 mg, 0.11 mmole) was weighed d i r e c t l y i n t o a stoppered 25-ml two-necked RBF and then immediately d i s s o l v e d i n 2 ml of dry dichloromethane. A s o l u -t i o n of crude 9_1 (276 mg, 1.05 mmole) in 15 ml of dry d i c h l o r o -methane was then added to the r e a c t i o n v e s s e l , followed by the dropwise a d d i t i o n of 2-methoxypropene (0.20 ml, 2.104 mmole). The r e s u l t i n g s o l u t i o n was s t i r r e d at room temperature f o r 3k hours, then d i l u t e d with ether and washed twice with b r i n e . The aqueous washings were e x t r a c t e d once with ether and the combined organic e x t r a c t s were d r i e d over anhydrous magnesium s u l p h a t e . Solvent removal under reduced pressure f u r n i s h e d 231 mg (90%) of crude product. P u r i f i c a t i o n of a m i c r o a n a l y t i c a l sample was c a r r i e d out by t h i n l a y e r chromatography using a s o l v e n t mixture of petroleum ether and ether (9/1); bp (Kugelrohr d i s t i l l a t i o n ) 74-76°/0.15 T o r r ; IR 3075, 1650, 1605, 1585 and 895 cm - 1; 1H-NMR 61.24 (s, 3H), 1.29 (s, 3H), 1.74-1.94 (m, 3H), 2.24-2.63 (m, 2H), 3.06-3.33 (m, IH), 5.03 (s, 2H), 5.34-5.61 (m, IH) and 7.00-7.48 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 77 (32), 93 (63), 107 (76), 110 (16), 134 (90), 135 (100), 136 (27), 244 (84), 245 (18) and 246 (7). A n a l . Calcd f o r C 1 6 H 2 Q S : C, 78.63; H, 8.25; S, 13.12. Found: C, 78.77; H, 8.32; S, 12.89. - 75 -5 - P h e n y l s u l p h e n y l - l - ' - ( t - b u t y Id ime t h y I s i l y l o x y ) me thy3~] -2,6,6-t r i m e t h y 1 - 1 - c y c l o h e x e n e (97) A 100-ml s i n g l e - n e c k e d RBF was c h a r g e d w i t h i m i d a z o l e (6.23 g, 91.4 mmole) and t - b u t y l d i m e t h y l c h l o r o s i l a n e (6.61 g, 43.9 mmole) d i s s o l v e d i n 40 ml o f d i m e t h y l f o r m a m i d e . C r u d e 91 (2.03 g, 7.73 mmole) as a s o l u t i o n i n 30 ml o f d i m e t h y l f o r m a m i d e , was t h e n added i n one p o r t i o n t o the r e a c t i o n v e s s e l and t h e r e s u l t -i n g m i x t u r e was s t i r r e d under n i t r o g e n f o r 24 h o u r s a t 4 0 - 5 0 ° . The r e a c t i o n m i x t u r e was d i l u t e d w i t h e t h e r , washed w i t h a s a t u r a t e d aqueous ammonium c h l o r i d e s o l u t i o n , 1 N h y d r o c h l o r i c a c i d and f i n a l l y b r i n e . The aqueous w a s h i n g s were e x t r a c t e d w i t h e t h e r and t h e o r g a n i c e x t r a c t s were t h e n combined and d r i e d o v e r a n h y d r o u s magnesium s u l p h a t e . S o l v e n t r e m o v a l under r e -d u c e d p r e s s u r e a f f o r d e d 8.7 g o f c r u d e p r o d u c t , w h i c h was t h e n d i s t i l l e d g i v i n g 3 . 7 6 g (60%) o f 97 as a l i g h t y e l l o w o i l : bp 1 6 0 - 1 6 2 ° / 0 . 3 T o r r . The m i c r o a n a l y t i c a l sample o f 9J_ was p u r i -f i e d by t h i n l a y e r c h r o m a t o g r a p h y u s i n g a s o l v e n t m i x t u r e o f p e t r o l e u m e t h e r and c h l o r o f o r m ( 4 / 1 ) : bp ( K u g e l r o h r d i s t i l l a -t i o n ) 8 7 - 9 0 ° / 0 . 3 T o r r ; IR 1670, 1595 and 1060 cm" 1; 1H-NMR 60.08 ( s , 6H), 0.91 ( s , 9H), 1.11 ( s , 3H), 1.32 ( s , 3H), 1.65 ( s , 3H) , 1.83-2.10 (m, 4H) , 2 .93-3.28 (m, IH) , 4.09 ( b r s , 2H) and 7.00-7.47 (m, 5H); mass s p e c t r u m m/e ( r e l i n t e n s i t y ) 75 ( 1 0 0 ) , 77 ( 4 8 ) , 93 ( 8 6 ) , 107 ( 8 5 ) , 110 ( 2 1 ) , 134 ( 7 5 ) , 135 ( 9 2 ) , 136 ( 2 1 ) , 209 ( 2 7 ) , 244 (25) and 376 ( 9 ) . A n a l . C a l c d f o r C 2 2 H 3 6 O S i S : C, 70.15; H, 9.63; S, 8.51. Found: C, 70.43; H, 9.79; S, 8.8 0. - 76 -5 - P h e n y l s u l p h o x y - l - [JL 1 - ( t - b u t y I d ime t h y I s i l y l o x y ) methyl^] -2,6,6-t r i m e t h y l - l - c y c l o h e x e n e (98) A 50-ml two-necked RBF was c h a r g e d w i t h 9_7 (263 mg, 0.70 mmole), as a s o l u t i o n i n 20 ml o f d r y d i c h l o r o m e t h a n e . The f l a s k was f i t t e d w i t h a p r e s s u r e e q u a l i z i n g a d d i t i o n f u n n e l and a n i t r o g e n i n l e t and was t h e n c o o l e d t o 0° i n an i c e b a t h . m - C h l o r o p e r b e n z o i c a c i d (85%, 150 mg, 0.74 mmole), d i s s o l v e d i n 10 ml o f d r y d i c h l o r o m e t h a n e , was added d r o p w i s e f r o m t h e a d d i -t i o n f u n n e l t o the s t i r r e d r e a c t i o n m i x t u r e . The r e s u l t i n g s o l u t i o n was t h e n s t i r r e d f o r a f u r t h e r 1 hour a t 0 ° . F o l l o w -i n g t h i s , t h e r e a c t i o n m i x t u r e was d i l u t e d w i t h e t h e r and washed w i t h a s a t u r a t e d aqueous sodium b i c a r b o n a t e s o l u t i o n . The aqueous w a s h i n g s were e x t r a c t e d w i t h e t h e r and the combined o r g a n i c e x t r a c t s were d r i e d o v e r a n h y d r o u s magnesium s u l p h a t e . Removal o f s o l v e n t s under r e d u c e d p r e s s u r e f u r n i s h e d 263 mg (96%) c r u d e p r o d u c t as a y e l l o w o i l . P u r i f i c a t i o n o f a m i c r o -a n a l y t i c a l sample o f 9_8 was a c h i e v e d by t h i n l a y e r c h r o m a t o g r a -phy, u s i n g a s o l v e n t m i x t u r e o f p e t r o l e u m e t h e r and e t h y l a c e -t a t e ( 2 . 5 / 1 ) : IR 1670, 1595 and 1030 cm" 1; 1H-NMR 60.11 ( s , 6H), 0.92 ( s , 9H), 1.03-2.12 (m, 13H), 3.58 (q, J=7 Hz, I H ) , 4.08 ( b r s , 2H) and 7.15-7.72 ( b r s , 5H); mass s p e c t r u m m/e ( r e l i n t e n s i t y ) 75 ( 1 0 0 ) , 133 ( 6 3 ) , 134 ( 6 8 ) , 135 ( 7 8 ) , 209 ( 4 7 ) , 251 (17) and 266 ( 8 ) . A n a l . C a l c d f o r C 2 2 H 3 6 0 2 S i S : C, 67.29; H, 9.24. Found: C, 67.71; H, 9.15. - 77 -5-Propylidiene-l - Q -' - (t-butyldimethylsilyloxy)methyl"] -2 ,6 ,6- trimethyl-l-cyclohexene (102) A 100-ml three-necked RBF was charged with crude 98_ (229 mg, 0.58 mmole) in 25*ml of dry tetrahydrofuran. The flask was f i t t e d with a nitrogen i n l e t and was then cooled to -78°. n-Butyllithium (1.46 ml, 1.75 mmole) was syringed dropwise into the reaction vessel and the resul t i n g solution was s t i r r e d at -78° for 2 hours. The mixture was then warmed to -23° and treated with l-bromo-2-propene (0.15 ml, 1.75 mmole). Follow-ing t h i s , the s t i r r e d solution was gradually warmed to room tem-perature over a three-hour period. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution and the aqueous washings were then extracted with ether. The combined organic extracts were dried over anhydrous magnesium sulphate, then subsequent solvent removal under reduced pressure furnished 250 mg (139%) of crude product as a yellow o i l . Since i t was evident from 1H-NMR data that the sulphoxide had already eliminated, the crude product was d i s t i l l e d at 75-85°/3 Torr to give 114 mg (64%) of 102 as a l i g h t yellow o i l . Pur i f i c a t i o n of a microanalytical sample of 102 was carried out by thin layer chromatography using petroleum ether as the developing solvent: bp (Kugelrohr d i s t i l l a t i o n ) 57-62°/u.3 Torr; IR 1645 and 1050 cm"1; 1H-NMR 60.09 (s, 6H), 0.91 (s, 9H), 1.22 (s, 6H), 1.71 (s, 3H), 1.97-2.23 (t, 3=6 Hz, 2H), 2.41-2.67 (t, J=6 Hz, 2H), 4.17 (s, 2H), 4.93-5.31 (m, 2H), 5.91-6.12 (m, IH) and - 78 -6.50-6.95 (m, I H ) ; mass s p e c t r u m m/e ( r e l i n t e n s i t y ) 73 (22), 75 ( 1 0 0 ) , 159 ( 3 3 ) , 174 ( 9 ) , 175 (10) and 306 ( 5 ) . A n a l . C a l c d f o r C 1 9 H 3 4 O S i : C, 74.44; H, 11.18. Found: C, 74.28; H, 11.36. 5 - P h e n y l s u l p h o x y - l - Q l 1 - ( t - b u t y l d i m e t h y l s i l y l o x y ) m e t h y l ^ ] -2,5,6,6-t e t r a m e t h y l - l - c y c l o h e x e n e (10 3) A 100-ml t h r e e - n e c k e d RBF was c h a r g e d w i t h c r u d e 9_8 (244 mg, 0.62 mmole) d i s s o l v e d i n 25 ml o f d r y t e t r a h y d r o f u r a n , f i t t e d w i t h a n i t r o g e n i n l e t and t h e n c o o l e d t o - 7 8 ° . n - B u t y l l i t h i u m (1.55 m l , 1.86 mmole) was s y r i n g e d d r o p w i s e i n t o the s t i r r e d r e a c t i o n m i x t u r e and t h e r e s u l t i n g s o l u t i o n was k e p t a t -78° f o r 2 h o u r s . F o l l o w i n g t h i s , the f l a s k was warmed t o -23° and m e t h y l i o d i d e (0.12 m l , 1.86 mmole) was s y r i n g e d i n t o the r e a c t i o n v e s -s e l . The s o l u t i o n was s t i r r e d a t - 2 3 ° f o r 30 m i n u t e s and t h e n s l o w l y warmed t o room t e m p e r a t u r e o v e r a 2-hour p e r i o d . The r e -a c t i o n m i x t u r e was quenched w i t h a s a t u r a t e d aqueous ammonium c h l o r i d e s o l u t i o n and the aqueous w a s h i n g s were e x t r a c t e d w i t h e t h e r . The o r g a n i c e x t r a c t s were t h e n combined and d r i e d o v e r a n h y d r o u s magnesium s u l p h a t e . S o l v e n t r e m o v a l under r e d u c e d p r e s s u r e y i e l d e d 224 mg (89%) o f c r u d e p r o d u c t as a y e l l o w o i l . P u r i f i c a t i o n o f a m i c r o a n a l y t i c a l sample o f 103 was a c h i e v e d by t h i n l a y e r c h r o m a t o g r a p h y u s i n g a s o l v e n t m i x t u r e o f p e t r o -leum e t h e r and e t h e r ( 1 / 1 ) : IR 1665, 1065 and 1025 cm" 1; 1H-NMR 60.11 ( s , 6H), 0.92 ( s , 9H), 1.05-2.12 (m, 16H), 2.33 ( i m p u r i t y ) , 4.12 ( b r s , 2H) and 7.09-7.59 (m, 5H); mass s p e c t r u m - 79 -m/e ( r e l i n t e n s i t y ) 73 ( 1 5 ) , 75 ( 1 0 0 ) , 89 ( 1 9 ) , 148 ( 1 0 ) , 223 ( 1 7 ) , 224 ( 2 ) , 265 (2) and 280 ( 1 ) . A n a l . C a l c d f o r C 2 3 H 3 g 0 2 S i S : C, 67.92; H, 9.42; S, 7.88. Found: C, 68.00; H, 9.33; S, 7.67. M e t h y l 2 , 6 , 6 - T r i m e t h y l - 1 , 4 - c y c l o h e x a d i e n e c a r b o x y l a t e (105) A 50-ml s i n g l e - n e c k e d RBF was c h a r g e d w i t h c r u d e 7_9 (887 mg, 2.63 mmole) d i s s o l v e d i n 25 ml o f d i c h l o r o m e t h a n e and was then f i t t e d w i t h an a d d i t i o n f u n n e l . F o l l o w i n g t h i s , h y d r o g e n p e r o x i d e ( 30%, 1.50 g, 13.2 mmole) was added d r o p w i s e from the a d d i t i o n f u n n e l t o t h e s t i r r e d r e a c t i o n m i x t u r e . A f t e r the r e -s u l t i n g m i x t u r e was s t i r r e d a t room t e m p e r a t u r e f o r 10 m i n u t e s , the a d d i t i o n f u n n e l was r e p l a c e d by a c o n d e n s e r , and t h e s o l u -t i o n was r e f l u x e d f o r 1 h o u r . The r e a c t i o n m i x t u r e was then d i l u t e d w i t h e t h e r and washed w i t h a s a t u r a t e d aqueous sodium c a r b o n a t e s o l u t i o n u n t i l the aqueous w a s h i n g s were no l o n g e r y e l l o w . The aqueous w a s h i n g s were t h e n e x t r a c t e d w i t h e t h e r and the combined o r g a n i c e x t r a c t s were d r i e d o v e r a n h y d r o u s magne-sium s u l p h a t e . S o l v e n t r e m o v a l under r e d u c e d p r e s s u r e a f f o r d e d 484 mg (102%) o f c r u d e 105. B e f o r e o b t a i n i n g s p e c t r a l and m i c r o a n a l y t i c a l d a t a , a sample o f 10 5 was p u r i f i e d by t h i n l a y e r c h r o m a t o g r a p h y u s i n g a s o l v e n t m i x t u r e o f p e t r o l e u m e t h e r and e t h e r ( 9 / 1 ) : bp ( K u g e l r o h r d i s t i l l a t i o n ) 4 7 - 51°/3 T o r r ; IR 1710 and 1650 c m - 1 ; 1H-NMR 61.1/ ( s , 6H), 1.70 ( s , 3H), 2.58 ( b r s , 2H), 3.73 ( s , 3H) and 5.46 ( s , 2H); mass s p e c t r u m m/e ( r e l i n t e n s i t y ) 105 ( 1 0 0 ) , 121 ( 7 9 ) , 149 ( 2 2 ) , 165 (88) and 18 0 i l l ) . - 80 -A n a l . C a l c d f o r C ] _ i H 1 5 ° 2 : C ' 73.30; H, 8.95. Found: C, 73.50; H, 8.97. 1- p i ' - ( t - B u t y l d i m e t h y l s i l y l o x y ) m e t h y l ^ ] -2 , 6 , 6-tr ime thy 1-1, 4-cyclohexadiene (106) A 50-ml si n g l e - n e c k RBF was charged with crude 98_ (294 mg, 0.75 mmole) d i s s o l v e d i n 25 ml of dry t o l u e n e . The f l a s k was then equipped with a condenser and the r e a c t i o n mixture was r e -f l u x e d for 75 minutes. F o l l o w i n g t h i s , toluene was removed under reduced pressure and the r e s i d u e was Kugelrohr d i s t i l l e d between 50 and 135° at 2 Torr to give 167 mg (84%) of crude product as a l i g h t y e l l o w o i l . P u r i f i c a t i o n of a m i c r o a n a l y t i c a l sample of 106 was achieved by t h i n l a y e r chromatography using petroleum ether as the developing s o l v e n t : bp (Kugelrohr d i s -t i l l a t i o n ) 35-40°/0.35 T o r r ; IR 1060 cm" 1; 1H-NMR 60.10 (s, 6H), 0.92 (s, 9H), 1.10 (s, 6H), 1.73 (s, 3H), 2.60 (brs, 2H), 4.18 (s, 2H) and 5.46 (s, 2H); mass spectrum m/e ( r e l i n t e n s i t y ) 73 (30), 75 (100), 134 (17), 209 (27), 251 (12) and 266 (12). A n a l . Calcd f o r C ^ H ^ O S i : C, 72.11; H, 11.35. Found: C, 72.27; H, 11.30. - 81 -D. BIBLIOGRAPHY 1. a. L. Weiler, J. Am. Chem. Soc., 92, 6702 (1970). b. S.N. Huckin and L. Weiler, J . Am. Chem. S o c , 96, 1082 (1974). 2. a. S.N. Huckin and L. Weiler, Tetrahedron Lett., 2405 (1972). b. S.N. Huckin and L. Weiler, Can. J . Chem., 52, 1379 (1974). c. S.N. Huckin and L. Weiler, Can. J . Chem., 52, 2157 (1974). d. P.E. Sum and L. Weiler, Can. J . Chem., 55, 996 (1977). 3. P.E. Sum and L. Weiler, Can. J . Chem., 56, 2301 (1978). 4. G.R. Rickards. M.Sc. Thesis, University of B r i t i s h Colum-bia, Vancouver, B.C., 1977. 5. F.W. Sum and L. Weiler, J . Am. Chem. Soc., 101, 4401 (1979). 6. T.M. Harris and CM. Harris, in "Organic Reactions"; W.G. Dauben, Ed.,; Wiley: New York, 1969; Volume 17, p. 155. 7. F.W. Sum. Ph.D. Thesis, University of B r i t i s h Columbia, Vancouver, B.C., 1979. 8. F. Kienzle, in "Carotenoids-4 (Berne 1975)"; B.C.L. Weedon, Ed. ; Pergamon Press: Oxford, 1977; p. 183. 9. 0. I s l e r , in "Carotenoids"; 0. I s l e r , Ed. ; BirkhSuser Verlag: Basel, 1971; p. 13, 19-21. 10. B.H. Davies and R.F. Taylor, in "Carotenoids-4 (Berne 1975)"; B.C.L. Weedon, Ed.; Pergamon Press: Oxford, 1977; p. 211. 11. B.C.L. Weedon, in "Carotenoids-4 (Berne 1975)"; B.C.L. Weedon, Ed.; Pergamon Press: Oxford, 1977; p. 161-171. 12. a. S. Liaaen-Jensen, Pure Appl. Chem., 47, 129 (1976). b. M. Ito, R. Masahara and K. Tsukida, Tetrahedron Lett., 2767 (1977). 13. F. Tiemann and P. Kriiger, Ber. Dtsch. Chem. Ges., 26, 2679 (1893). 14. A.G. Andrewes, S. Liaaen-Jensen and G. Borch, Acta Chem.  Scand. , B28 , 737 (1974). - 82 -15. V. Rautenstrauch and G. O h l o f f , Helv. Chim. A c t a , 54, 1776 (1971). 16. C.H. Eugster, A.H. T r i v e d i and P. Karrer , Helv. Chim. A c t a , 38 , 1360 (1955) . 17. L. Ruzicka and H. S c h i n z , Helv. Chim. A c t a , 23 , 959 (1940). 18. L. Ruzicka, C F . S e i d e l and H. Sc h i n z , Helv. Chim. A c t a , 16, 1143 (1933). 19. Y.R. Naves, A.V. Grampoloff and P. Bachmann, Helv. Chim.  A c t a , 3_0, 1599 (1947) . 20. H. G r d t t e r , R. Helg and H. S c h i n z , Helv. Chim. A c t a , 35, 771 (1952) . 21. H.E. E s c h i n a z i , J . Am. Chem. Soc., 81, 2905 (1959). 22. T. I s h i h a r a , T. K i t a h a r a and M. Matsui, Agr. B i o l . Chem., 38 , 439 (1974) . 23. S. T o r i i , K. Uneyama and S. Matsunami, J . Org. Chem., 45, 16 (1980). 24. A.K. Chopra, B.P.S. Khambay, H. Madden, G.P. Moss and B.C.L. Weedon, J . Chem. S o c , Chem. Commun. , 357 (1977). 25. R.W. Skeean, G.L. Trammell and J.D. White, Tetrahedron  L e t t . , 525 (1976) . 26. J.E. Baldwin and L . I . Kruse, J . Chem. S o c , Chem. Commun., 233 (1977). 27. E.E. van Tamelen and E . J . H e s s l e r , J . Chem. S o c , Chem.  Commun., 411 (1966). 28. L.E. Wolinsky and D.J. Faulkner, J . Org. Chem., 41, 597 (1976). 29. T. Kato, I. I c h i n o s e , A. Kamoshida and Y. K i t a h a r a , J . Chem.  S o c , Chem. Commun., 518 (1976). 30. a. D.L.J. C l i v e , Tetrahedron, 3±, 1049 (1978). b. H.J. Re i c h , Accounts Chem. Res., 12, 22 (1979). 31. K.C. N i c o l a o u and Z. Lysenko, Tetrahedron L e t t . , 1257 (1977). 32. K.C. N i c o l a o u , S.P. S e i t z , W.J. S i p i o and J.F. Bl o u n t , J . Am. Chem. S o c , 101, 3884 (1979) . - 83 -33. M. P e t r z i l k a , Helv. Chim. Acta, 61, 3075 (1978). 34. a. D.L.J. C l i v e , G. Ch i t t a t t u , N.J. C u r t i s , W.A. K i e l and C.K. Wong, J . Chem. S o c , Chem. Commun., 725 (1977). b. D.L.J. Clive and G. C h i t t a t t u , J. Chem. S o c , Chem. Commun., 484 (1977). c D.L.J. C l i v e , G. Chittattu and C.K. Wong, Can. J . Chem., 55, 3894 (1977). d. D.L.J. C l i v e , C.K. Wong, W.A. K i e l and S.M. Menchen, J. Chem. S o c , Chem. Commun., 379 (1978). 35. W.A. Smit, A.K. Semenovsky, V.F. Kucherov, T.N. Chernova, M.Z. Krimer and O.V. Lubinskaya, Tetrahedron Lett., 3101 (1971). 36. D.L.J. C l i v e , G. Chittattu and C.K. Wong, J . Chem. Soc., Chem. Commun., 441 (1978). 37. T. Kametani, K. Suzuki, H. Kurobe and H. Nemoto, J. Chem.  S o c , Chem. Commun., 1128 (1979) . 38. D.L.J. C l i v e , C.G. Russell, G. Chittattu and A. Singh, Tetrahedron, 1399 (1980). 39. F.W. Sum and L. Weiler, Can. J . Chem., 57, 1431 (1979). 40. H.G. K u i v i l a , Synthesis, 2, 499 (1970). 41. F.W. Sum and L. Weiler, Tetrahedron Lett. , 707 (1979). 42. M. Miyashita, A. Yoshikoshi and P.A. Grieco, J . Org. Chem., 42 , 3772 (1977). 43. H.J. Reich and F. Chow, J . Chem. S o c , Chem. Commun., 790 (1975). 44. D.N. Jones, D. Mundy and R.D. Whitehouse, J . Chem. Soc., Chem. Commun., 86 (1970). 45. T. Durst, M.J. LeBelle, R.V.d. Elzen and K.-C. Tin, Can.  J. Chem., 52, 761 (1974). 46. D.D. Perrin, W.L.F. Armarego and D.R. Perrin, in " P u r i f i -cation of Laboratory Chemicals"; Pergamon Press: Oxford, 1966; p. 223. 47. M. Fieser and L.F. Fieser, in "Reagents for Organic Syn-thesis"; Wiley: New York, 1975; Volume 5, p. 523. 48. CR. Johnson and D. McCants, J r . , J. Am. Chem. Soc. , 87, 1109 (1965) . - 84 -49. P.A. G r i e c o , Y. Ohfune, Y. Yokoyama and W. Owens, J . Am.  Chem. S o c , 101, 4749 (1979). 50. E . J . Corey and A. Venkateswar l u , J . Am. Chem. S o c , 94, 6190 (1972). 51. The S a d t l e r Standard S p e c t r a , NMR 3998, S a d t l e r Research L a b o r a t o r i e s , 3316 Spring Garden S t r e e t , P h i l a d e l p h i a , PA. 19104, 1968. 52. H.J. Re i c h , J.M. Renga and I.L. Reich, J . Am. Chem. S o c , 97, 5434 (1975). 53. G.B. Kauffman and L.A. T e t e r , I norganic Syntheses, 1_, 9 (1963) . SPECTRAL INDEX RELATIVE J N TENS ITT 3.0 25.0 50.0 75.0 100.0 314 - 88 -i n z £ ^ C 0 2 C H 3 -an SePh 79 Sc-arry 0.0 50.0 100.0 150.0 ~200.0 M/E 250.0 I ' 1 300.0 I ' 1 350.0 I ' 1 400.0 - I 450.0 BO 70 6 0 SO PPM 1 6 1 4 0 3 0 2 0 l O 0 MICROMETERS (nm) I • 11 o 1111 11 muni i m D i i i m i i i i m m i i - i m i m i i i i n i i i i i t a n m m n i i n i - H H H i 4000 3AOO 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400 FREQUENCY (CM1) MICf iOMfcTtHS <Mm> 2 i 3 0 3.4 4 0 5 6 7 t t V I G l l i 1 I 3 j i - i 16 18 20 25 FREQUENCY (CM") - 95 -- 100 -o P o —, i 50.0 100.0 150.0 20D.qw]/f 8 0 7 0 AO ii 0 PPM f t \ 40 30 ? 0 ID 0 M I C R O M E T E R S ( - m l FREQUENCY (CM"') 103 -CO U J S D . O 105 CO 2 CH 3 \ 1 • • ' ' 1 ir.D.0 200.0 250.0 M/F. 300.0 350.0 400,0 450.0 50 PPMI t I 40 M I C R O M E T E R S (xml 4000 ) 6 0 0 3]0O 1100 3400 1000 1100 1600 e 'REOULNCV ICM I 1400 1300 1000 100 600 400 

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}]}"
                            data-media="{[{embed.selectedMedia}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
https://iiif.library.ubc.ca/presentation/dsp.831.1-0059424/manifest

Comment

Related Items