Open Collections

UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Studies directed toward a synthesis of the sesquiterpene zizanoic acid Skinner, Frank W. B. 1976

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_1976_A1 S49_5.pdf [ 9.29MB ]
Metadata
JSON: 831-1.0060995.json
JSON-LD: 831-1.0060995-ld.json
RDF/XML (Pretty): 831-1.0060995-rdf.xml
RDF/JSON: 831-1.0060995-rdf.json
Turtle: 831-1.0060995-turtle.txt
N-Triples: 831-1.0060995-rdf-ntriples.txt
Original Record: 831-1.0060995-source.json
Full Text
831-1.0060995-fulltext.txt
Citation
831-1.0060995.ris

Full Text

Studies Directed Toward a Synthesis of the Sesquiterpene Zizanoic Acid by Frank W. B. Skinner University of B r i t i s h Columbia, Vancouver, 3, A THESIS .SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENT FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n the Department of Chemistry We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA May, 197 6 (o) Prank ¥. B. Skinner, 1976 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 requirements fo r an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, i agree that the 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 fo r reference and study. I f u r t h e r agree t h a t permiss ion for e x t e n s i v e copying o f t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the Head of my Department or by h i s r e p r e s e n t a t i v e s . It i s understood that copying or 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 ga in s h a l l not be a l lowed without my w r i t t e n p e r m i s s i o n . Department of The U n i v e r s i t y of B r i t i s h Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 Date ABSTRACT 1A/ The most i n t e r e s t i n g s t r u c t u r a l feature of the t r i c y c l i c sesquiterpene zizanoic acid i s the bicycio[3,2,1]octane system. With the view of synthesizing a bicycio[3,2,1]octane system capable of elaboration to zizanoic acid, the c y c l i z a -t i o n of compound 220 to compound 131 was investigated. 2 2 0 131 o-Methoxybenzaldehyde was condensed with d i e t h y l succinate to give ethyl hydrogen cis-y-o-methoxyphenylitaconate. After hydrogenation, the ethyl hydrogen 6-methoxybenzyl-succinate was c y c l i z e d with aluminum chloride to give - i i -5 - m e t h o x y - l - t e t r a l o n e - 3 - c a r b o x y l i c a c i d e t h y l e s t e r . T h i s was d i m e t h y l a t e d t o y i e l d 2 , 2 - d i m e t h y l - 5 - m e t h o x y - l - t e t r a l o n e -3 - c a r b o x y l i c a c i d e t h y l e s t e r . H y d r o l y s i s o f the e s t e r and e x t e n s i o n of the c a r b o x y l i c a c i d s i d e c h a i n by use of the A r n d t - E i s t e r t r e a c t i o n gave 2,2-dimethy1-5-methoxy-l-t e t r a l o n e - 3 - a c e t i c a c i d methyl e s t e r . The methoxy group was removed w i t h p y r i d i n e hydrogen c h l o r i d e , and the r e s u l t -i n g phenol a c e t y l a t e d t o g i v e 2 , 2 - d i m e t h y l - 5 - a c e t o x y - l -t e t r a l o n e - 3 - a c e t i c a c i d . The c a r b o x y l i c a c i d was then reduced w i t h d i b o r a n e to g i v e 2 , 2 - d i m e t h y l - 3 - e t h y l ( 2 -h y d r o x y ) - 5 - a c e t o x y - l - t e t r a l o n e . The a l c o h o l was c o n v e r t e d t o the mesylate and the a c e t a t e removed t o g i v e compound 220 where X=OMs. A l l attempts t o c y c l i z e t h i s compound f a i l e d . Attempted c y c l i z a t i o n of the reduced s p e c i e s 2 , 2 - d i m e t h y l - 3 - e t h y l ( 2 -methanesulphonate e s t e r ) - 1 , 2 , 3 , 4 - t e t r a - h y d r o n a p h t h a l e n e - l , 5 -d i o l a l s o f a i l e d . 2,2-Dimethyl-3-ethyl(2-bromo-l-oxo)-5-h y d r o x y - l - t e t r a l o n e was prepared, but t h i s too f a i l e d t o r e a c t . The bromide 220 where x = Br on treatment w i t h sodium methoxide f o l l o w e d by s o l i d s t a t e t h e r m o l y s i s was observed t o undergo the d e s i r e d t r a n s f o r m a t i o n i n up to 20% y i e l d , depending on the s o l i d support used. More pro m i s i n g r e s u l t s were observed i n the c y c l i z a t i o n o f the model compound 7-ethyl(2-methanesulphonate e s t e r ) - 5 , 6 , 7 , 8 - t e t r a h y d r o - l -n a p h t h o l t o the t r i c y c l i c compound 1,2,3,4-tetrahydro-3,4a-ethanonaphthalen-5(4aH)-one. - i i i -T A B L E OF CONTENTS P a g e T i t l e P a g e A b s t r a c t i T a b l e o f C o n t e n t s i i i L i s t o f S c h e m e s i v L i s t o f F i g u r e s v i A c k n o w l e d g e m e n t v i i I n t r o d u c t i o n 1 R e s u l t s a n d D i s c u s s i o n 3 5 E x p e r i m e n t a l 91 B i b l i o g r a p h y 147 S p e c t r a l A p p e n d i x 151 - i v -LIST OF SCHEMES Scheme 1. Proposed Z i z a n o i c A c i d B i o s y n t h e s i s V i a the Cedrene Pathway. Scheme 2. Proposed B i o s y n t h e t i c Pathway to Zizaene and Other V e t i v e r Sesquiterpenes. Scheme 3. Proposed B i o g e n e t i c Route t o Zizaene, P r e z i z a e n e , and (+)-a-Cedrene. Scheme 4. I n i t i a l Biomimetic Formation of the Zizane Ring System. Scheme 5. The I n i t i a l Biomimetic S y n t h e s i s of Methyl Zizanoate. Scheme 6. Coates Route t o Zizaene. Scheme 7. Attempted S y n t h e s i s o f Zizaene w i t h T e r m i n a l Formation of Ring A. Scheme 8. A S y n t h e t i c Route t o Zizaene Using Terminal Formation of Ring C. Scheme 9. S y n t h e s i s of the B i c y c i o [ 3 , 2 , 1 ] o c t a n e System V i a Phenol C y c l i z a t i o n . Scheme 10. Proposed S y n t h e s i s of a Compound P o s s e s s i n g the Zizane Ring System. Scheme 11. P r o j e c t e d S y n t h e s i s of the Phenol T o s y l a t e 124  Scheme 12. T r a n s f o r m a t i o n of Phenol T o s y l a t e to Z i z a n o i c A c i d . S c h e m e 1 3 . P o s s i b l e R o u t e s f r o m t h e E s t e r 158 t o t h e P h e n o l T o s y l a t e 124 o r t h e P h e n o l M e s y l a t e 170_. Scheme 1 4 . R e d u c t i o n o f t h e P h e n o l M e s y l a t e a n d B a s e T r e a t m e n t o f t h e P r o d u c t . S c h e m e 1 5 , E l u c i d a t i o n o f t h e . S t e r e o c h e m i s t r y o f R e d u c t i o n o f E s t e r 1 5 8 . Scheme 1 6 . P r e p a r a t i o n o f t h e B r o m o k e t o n e 190 a n d A t t e m p t e d C y c l i z a t i o n , Scheme 1 7 . P r e p a r a t i o n o f t h e M o d e l P h e n o l M e s y l a t e 2 0 4 . Scheme .18. S u g g e s t e d F r a g m e n t a t i o n o f t h e D i e n e d i o n e 1 3 1 . Scheme 1 9 . A S y n t h e t i c R o u t e F r o m t h e M o d e l D i e n o n e 117 t o t h e D e s i r e d D i e n e d i o n e 1 3 1 . - v i -LIST OF FIGURES Page Figure 1. S t e r i c Hindrance About the Double Bond i n Compound 117. 31 Figure 2. Confcrmers of the Phenoxide of Compounds 109 and 171. 60 Figure 3. S t e r i c Hindrance in the Two Ketals 192 and 193. 74 Figure 4. Some of the Resonance Forms Available to the Phenoxide. 8 8 Figure 5. Comparison of the Environment About the Inactive Methylene i n Yuan's Ketone 88 and the Possible Product 218. 89 ACKNOWLEDGEMENT I w o u l d l i k e t c t h a n k D r . L a r r y W e i l e r f o r t h e e x c e l l e n t g u i d a n c e a n d e n c o u r a g e m e n t h e h a s g i v e n me t h r o u g h o u t t h e r e s e a r c h a n d t h e p r e p a r a t i o n o f t h i s m a n u s c r i p t . I w o u l d l i k e t o e x p r e s s my g r a t i t u d e t o D r . R. B a l a j i R a o f o r h i s a i d a n d c o l l a b o r a t i o n i n t h e i n i t i a l s t a g e s o f t h i s w o r k . I w o u l d f u r t h e r l i k e t o t h a n k D r . S t u a r t N . H u c k i n , D r . J o h n F . K i n g s t o n , D r . K e n P a i s l e y , M r . G o r d o n R i c k a r d r a n d Sam a n d P h a i k - E n g Sum f o r t h e i r g o o d f e l l o w s h i p a n d many h e l p f u l d i s c u s s i o n s , a n d P h y l l i s M o o r e f o r t y p i n g t h i s m a n u s c r i p t . INTRODUCTION Is o l a t i o n and. Structure of Zizanoic Acid (1) C0 2 H 1 The i s o l a t i o n and p a r t i a l s t r u c t u r a l determination of zizanoic acid- (1) from the es s e n t i a l o i l of vetiver (vetiver zizanoides) was reported i n 19 67 by Yoshikoshi and h i s coworker'--^. In t h e i r i n i t i a l paper they noted zizanoic acid on reduction gave an unsaturated alcohol (2_) which was found 2 to be i d e n t i c a l to khusimol , also reported i n vetiver o i l and t e n t a t i v e l y assigned structure 3_ or 4_. Shortly there-3 af t e r , Nigam and his coworkers showed that t r i c y c l o v e t i v e n o l , 4 also found i n vetiver o i l and assigned structure 5_ , was i d e n t i c a l to the reduction product of zizanoic acid. Thus there were three proposed structures for the zizane skeleton. A closer look at the s t r u c t u r a l determination of zizanoic acid by Yoshikoshi i s therefore of i n t e r e s t . IR and NMR spectral evidence indicated the presence of a terminal - 2 -methylene (1640 cm - 1, 892 cm - 1) (4.53 and 4.70 6, t, 1 H each), one proton on the carbon adjacent to the acid function (2.62 6, quartet, 1 H), and two methyl groups (1.05 6, 1.08 6, s i n g l e t s , 3 H each). (2) 4 5 Hydrogenation of the methyl ester of zizanoic acid resulted i n the uptake of one mole of hydrogen to give methyl dihydrozizanoate (6_) . This implies a t r i c y c l i c structure. Dihydrozizanoic acid 7_, obtained by basic hydrolysis of the ester 6_, was treated with methyllithium to give an epimeric mixture of methyl ketones 8_. After peracid oxida-t i o n and hydrolysis, t h i s product gave an epimeric mixture of alcohols 9_, which aft e r Jones oxidation gave a single ketone .10. The IR frequency (17 3 5 cm "*') indicated that the - 3 -ketone was i n a five-membered r i n g . Peracid oxidation of the ketone 10_ gave the 6-lactone LI, whose NMR spectrum showed no protons or methyl groups on the carbon adjacent to the lactone oxygen. 6 R= C 0 2CH 3 7 R ~ C 0 2 H 8 R = COCH, 11 R 9 R = H,OH 1 0 R = 0 ;O 2CH 3 Methyl zizanoate was ozonized to the ketoester 12, whose IR spectrum (1705 cm - 1) indicated that the ketone was st r a i n - f r e e , and the NMR spectrum showed no methyl or methylene adjacent to the ketone. The reduction of t h i s ketone to the hydroxyester 1_3, and dehydration by phosphorus oxychloride i n pyridine gave the unsaturated ester 1_4, which by i t s NMR and IR spectra contained a t r i s u b s t i t u t e d double bond. The compound was oxidized with osmium tetroxide to a d i o l 15, which was further oxidized with lead tetra-acetate followed C02H 20 21 by Jones oxidation to the keto half-ester 16_. Chloro-decarboxylation with lead acetate and lithium chloride gave the chloroketoester 17_, whose NMR spectrum (1. 55 6 , s, 6 H) indicated a gem-dimethyl group on the same carbon as chlorine. This was confirmed by the mass spectrum of the diest e r 18, which had a strong peak at m/e 102 corresponding to the species 19_. Also, as no strong peak appeared at m/e 115, which would correspond to species 20, the carbon corresponding t o d l i n z i z a n o i c a c i d cannot be a methylene. The o n l y s t r u c t u r e s t h a t f i t a l l t h i s data are the one proposed f o r ' z i z a n o i c a c i d and i t s d i a s t e r e o m e r s , and the s t r u c t u r e 21. S t r u c t u r e 2_1 was d i s c o u n t e d on mass s p e c t r a l d a t a . 22 23 The ketone 10 showed a s t r o n g n e g a t i v e C o t t o n e f f e c t , s u g g e s t i n g a t r a n s A/B r i n g j u n c t i o n and the a b s o l u t e s t e r e o c h e m i s t r y shown i n 2_2. The k e t o e s t e r 12 showed a s t r o n g p o s i t i v e C o t t o n e f f e c t c o n f i r m i n g a t r a n s A/B r i n g j u n c t i o n . The s t e r e o c h e m i s t r y o f the a c i d f u n c t i o n was determined when the a c i d o b t a i n e d from the d i o l - e s t e r 15_ was t r e a t e d w i t h DCC t o g i v e the y l a c t o n e 2_3. S i n c e the osmium t e t r o x i d e a t t a c k on the p r e c u r s o r 1_4 i s exo, the r e s u l t i n g d i o l and thus the a c i d f u n c t i o n s should be 8. T h i s s t r u c t u r e was 5 subsequently confirmed by X-ray s t u d i e s . S i n c e then, the z i z a n e f a m i l y has been expanded t o i n c l u d e z i z a e n e or t r i c y c l o v e t i v e n e ^ (2_4) and e p i z i z a n o i c a c i d 7 (25). Because z i z a n o i c a c i d has a n o n - i s o p r e n o i d s t r u c t u r e , the s p e c u l a t i o n s c o n c e r n i n g the b i o g e n e t i c pathway l e a d i n g to i t s f o r m a t i o n are o f i n t e r e s t . In h i s i n i t i a l p a p e r \ - 6 -C02H 2 4 2 5 Yoshikoshi proposed a biosynthetic pathway for zizanoic acid related to cedrene biosynthesis as shown i n Scheme 1. Farnesol (26_) can c y c l i z e to the cyclohexene 2_7, which after a 1,2-hydride s h i f t gives 2_8. This undergoes further c y c l i z a t i o n s tc give the t r i c y c l i c intermediate 29_. If bond "a" s h i f t s to the carbonium ion centre, the product a f t e r deprotonation i s (-) -a-cedrene (3_0) or a similar species. However, i f bond "b" s h i f t s , the product i s the intermediate 31. By one methyl migration, t h i s can give a compound 3_2 whose gross structure corresponds to zizaene. This proposal had to be abandoned when the absolute stereo-chemistry of zizanoic acid was elucidated. Q MacSweeney, Ramage and Sutter then proposed a series of biogenetic reactions that explained not only the formation of zizanoic acid, but also of a- and 6-vetivone, both present i n the ess e n t i a l o i l of vetiver, and ce r t a i n other sesquiterpenes. Farnesol can undergo c y c l i z a t i o n and rearrangement to the cyclodeca-1,6-diene 3_3, shown i n two conformers 33a and 33b i n Scheme 2. These can undergo further intramolecular c y c l i z a t i o n to y i e l d intermediates _34 and 35_ respectively. Scheme 1. Proposed Z i z a n o i c A c i d B i o s y n t h e s i s V i a the Cedrene Pathway. - 8 -Scheme 2. Proposed B i o s y n t h e t i c Pathway to Zizaene and Other V e t i v e r S e s q u i t e r p e n e s . - 9 -4 4 2 4 Scheme 2 (continued) A 1 , 2 - h y d r i d e s h i f t f o l l o w e d by l o s s o f a proton would rearrange 3_4 and 3_5 to the A ' eudesmols 3_7 and 3_8 r e s p e c t i v e l y . H o m o a l l y l i c p a r t i c i p a t i o n of the double bond i n 37_ w i t h displacement o f the a l c o h o l , f o l l o w e d by r e a r r a n g e -ment, l e a d s t o c a l a r e n e (39.) . On the other hand p r o t o n a t i o n - 1 0 -of the double bond i n 3_7, followed by s i m i l a r rearrangement, leads to the alcohol 4_0, which can be oxidized to a-vetivone ( 4 1 ) • The intermediate 3_5 on deprotonation would y i e l d a mixture of a-, 8-, and Y~eudesmols ( 3 6 ) . Protonation of the double bond of 38_\ followed by a ring-contraction and deprotonation, leads to hinesol ( 4 2 ) . Loss of water by hinesol y i e l d s B-vetivene (43_) . A l t e r n a t i v e l y , i n t e r a c t i o n of the double bond i n hinesol with the departing alcohol y i e l d s the intermediate carbonium ion 4_4, which i s p e r f e c t l y set up for rearrangement and deprotonation to zizaene (2_4) . The f e a s i b i l i t y of t h i s rearrangement has been proven by i t s successful use i n syntheses, as v / i l l be discussed below. Recently, a new biogenetic pathway bearing a resemblance to Yoshikoshi's o r i g i n a l proposal has been suggested and i s 9 shown i n Scheme 3 . Andersen and Falcone discovered a sesquiterpene prezizaene (4_5) , which bore a marked s i m i l a r i t y to zizaene. Assuming that both these sesquiterpenes were formed by the same biogenetic pathway, and further assuming that prezizaene was formed f i r s t along t h i s pathway, they proposed that ( + ) -y-curcumene (4_6) , after protonation, under-went c y c l i z a t i o n f i r s t to the B-acorenyl cation 4_7, and then to the a l l o c e d r y l cation 4J8. This intermediate can then rearrange to the prezizanyl cation 49_. Immediate loss of a proton y i e l d s prezizaene (4J5) , while a methyl migration followed by - I I -Scheme 3. Proposed Biogenetic Route to Zizaene, Prezizaene, and (+)-a-Cedrene. - 12 -proton loss y i e l d s zizaene (24_). Complimentary evidence for t h i s proposal was reported by Kaiser and Naegeli"^ who i s o l a t e d B-bisabolol (5_0) , an obvious precursor to ( + )-y-curcumene, from vetiver o i l . They also i s o l a t e d (+)-a-cedrene {51) , which they suggested could be formed from (+)-y-curcumene by protonation and c y c l i z a t i o n to the a-acorenyl cation 52, followed by a further c y c l i z a t i o n and proton loss to give the product 51. are possible derivatives of the intermediates 47. and 52. The Synthetic Motivation The zizanes possess a unique feature not found i n other sesquiterpenes i n t h e i r bicyclo[3,2,l]octane system, and the synthesis of t h i s unusual carbon skeleton poses an i n t e r e s t -ing challenge to the synthetic chemist. The s i m i l a r i t y - 13 -between the structure of zizanoic acid and of c e r t a i n plant growth hormones such as g i b b e r e l l i n A^^ (5_5) suggests the p o s s i b i l i t y of preparing substituted zizanes i n an e f f o r t to mimic the a c t i v i t y of such growth hormones. Furthermore, studies directed toward the preparation of the bicyclo[3,2,l] octane system of zizanoic acid could f i n d a p p l i c a t i o n i n the syntheses of such diverse compounds as the aforementioned g i b b e r e l l i n A ^ (55), the diterpene kaurene (56), and the a l k a l o i d garryine (57_) . A f i n a l consideration i s the possible economic value of the synthetic zizanes i n the perfume industry. 5 7 - 1 4 -Synthetic Approaches In fused t r i c y c l i c r i n g systems such as zizanoic acid, setting up the correct carbon framework must take precedence over other considerations. Usually the carbon skeleton i s set up by either a rearrangement i n a preformed t r i c y c l i c system, which merely s h i f t s the problem to an e a r l i e r step, or by an intramolecular c y c l i z a t i o n to what subsequently becomes a bridgehead carbon. The various possible methods 1 applicable to zizanoic acid are examined below. The i n t e r n a l rearrangement r e s u l t i n g i n formation of the C 9 - C 2 Q bond as shown i n equation 1 i s of great i n t e r e s t as i t would correspond to the biogenetic route proposed by Ramage. - 15 -A n o t h e r r e a r r a n g e m e n t o f i n t e r e s t i s t h e f o r m a t i o n o f t h e b i c y c l o [ 3 , 2 , l j o c t a n e s y s t e m f r o m a b i c y c l o [ 2 , 2 , 2 ] o c t a n e s y s t e m , v i a a s h i f t o f C„ f r o m C 2 t o C-^1 a s shown i n e q u a t i o n 2. T h i s w o u l d c o r r e s p o n d t o A n d e r s e n ' s b i o g e n e t i c p r o p o s a l . The p o s s i b i l i t i e s o f 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 t o c o m p l e t e r i n g A c a n be e x p e c t e d t o c e n t r e o n C_-C Q bond f o r m a t i o n . The a l t e r n a t i v e a p p r o a c h , a C ^ - C ^ Q bond f o r m a t i o n , w o u l d i n v o l v e c y c l i z a t i o n t o a b r i d g e h e a d c a r b o n on a b i c y c l o [ 3 , 2 , l - J o c t a n e s y s t e m , a much l e s s v i a b l e a p p r o a c h . To f o r m r i n g B, e i t h e r t h e C-^-Cg b o n d o r t h e C 2 - C n b o n d m u s t be c o m p l e t e d . The p r e c u r s o r w o u l d be a s p i r o - • s y s t e m , w i t h t h e f i n a l c y c l i z a t i o n t a k i n g p l a c e ct and 3 t o t h e q u a t e r n a r y c e n t r e , r e s p e c t i v e l y . N e i t h e r o f t h e s e a p p r o a c h e s a p p e a r t o h a v e a n y f u n d a m e n t a l d i f f i c u l t y , a l t h o u g h t h e s p i r o - s y s t e m m u s t be s e t up c a r e f u l l y . The c o m p l e t i o n o f r i n g C c a n a l s o be done i n two w a y s — e i t h e r a t and C ^ , o r a t and C^g. E i t h e r a p p r o a c h i s i n e s s e n c e t h e a t t a c h m e n t o f a two c a r b o n s i d e - c h a i n t o a s i x - m e m b e r e d r i n g r e s u l t i n g i n a b i c y c l o [ 3 , 2 , l j o c t a n e s y s t e m . - 16 -58 R = C0 2CH 3 59 R=CHO 65 66 Scheme 4. I n i t i a l Biomimetic Formation o f the Zizane Ring System. Three of the f i r s t syntheses of z i z a n o i c a c i d and other c l o s e l y r e l a t e d s e s q u i t e r p e n e s used a rearrangement almost - 17 -e x a c t l y c o r r e s p o n d i n g to Ramage 1s proposed b i o g e n e t i c r o u t e . Using the rou t e shown i n Scheme 4, Y o s h i k o s h i and h i s co-workers''""'" reduced the e s t e r 5_8_ wit h l i t h i u m aluminum h y d r i d e , and o x i d i z e d the r e s u l t i n g a l c o h o l to the aldehyde 5_9. T h i s was condensed w i t h acetone i n presence of base t o y i e l d the a, ^ -unsaturated ketone 6_0. M i c h a e l a d d i t i o n of cyanide to the oi, g-unsaturated ketone gave compound 6_1, and o z o n o l y s i s of t h i s y i e l d e d the dik e t o n e 62. T h i s was c y c l i z e d w i t h f o r m i c a c i d to compound 6_3, and the cyanide was co n v e r t e d to c a r b o x y l i c a c i d y i e l d i n g , a f t e r e s t e r i f i c a t i o n , compound 64. I t was determined at t h i s stage t h a t the e s t e r group was i n the a c o n f i g u r a t i o n , whereas the B form i s r e q u i r e d f o r z i z a n o i c a c i d . The ketone was then removed w i t h ethane d i t h i o l and Raney n i c k e l , and the alkene o x i d i z e d to the d i o l 6_5 w i t h osmium t e t r o x i d e . T h i s d i o l was t r e a t e d w i t h methanesulphonyl c h l o r i d e and potassium t - b u t o x i d e , y i e l d -i n g the rearranged ketone 66_ a f t e r e p i m e r i z a t i o n . The mechanism of t h i s p i n a c o l - t y p e rearrangement, except f o r the s u b s t i t u t i o n o f an a l c o h o l f o r a methyl group, i s i d e n t i c a l to Ramage's proposed r o u t e . T h i s k e t o e s t e r was then converted t o methyl e p i z i z a n o a t e by a W i t t i g r e a c t i o n . Ramage and h i s coworkers succeeded i n a somewhat more 12 g e n e r a l s y n t h e t i c route , as shown i n Scheme 5. Camphor (67) was e l a b o r a t e d by a s e r i e s of r e a c t i o n s to the d i k e t o -- i a -Scheme 5. The I n i t i a l Biomimetic S y n t h e s i s of Methyl Z i z a n o a t e . e s t e r 68_. C y c l i z a t i o n of t h i s .compound w i t h potassium t - b u t o x i d e gave a mixture o f 6_4 and 6_9 i n a r a t i o of 3:2. The product 69_ b e a r i n g the d e s i r e d s t e r e o c h e m i s t r y o f the e s t e r f u n c t i o n was c a r r i e d forward to the d i o l 70_ u s i n g the same methods as Y o s h i k o s h i . A f t e r m e s y l a t i o n , the mono-mecylate was rearranged t o compound 12_ using p y r i d i n e i n t r i e t h y l a m i n e . U n f o r t u n a t e l y the ketone 12_ was r e s i s t a n t t o the W i t t i g r e a c t i o n , so the c o r r e s p o n d i n g a c i d was t r e a t e d w i t h methyl-magnesium bromide, which a f t e r t r e a t -ment w i t h phosphorus o x y c h l o r i d e gave methyl z i z a n o a t e and methyl i s d z i z a n o a t e 7_2 i n the r a t i o of 2:3. The t h i r d s y n t h e s i s i n t h i s group shown i n Scheme 6 13 by Coates and h i s coworkers , y i e l d s z i z a e n e . B i c y c l o [2,2, l]heptanone (7_3) was e l a b o r a t e d to the ketoamide 74. N i t r o s a t i o n o f compound 7_4 w i t h d i n i t r o g e n t e t r o x i d e f o l l o w e d by treatment w i t h sodium methoxide y i e l d e d the diazoketone 75. T h i s immediately c y c l i z e d t o the i n t e r m e d i a t e 7_6, which r e a r r a n g e d to the ketone 77. The ketone i s a-formylated, and the formyl group was c o n v e r t e d t o the t h i o e t h e r 78. T h i s compound was reduced under B i r c h c o n d i t i o n s , and the r e s u l t i n g e n o l a t e a l k y l a t e d w i t h methyl i o d i d e t o y i e l d compound 7_9. T h i s ketone was ep i m e r i z e d w i t h base t o y i e l d the d e s i r e d s t e r e o c h e m i s t r y _80, and t h i s compound was con-v e r t e d t o z i z a e n e (24) u s i n g procedures d i s c u s s e d a l r e a d y . 8 0 2 4 Scheme 6. Coates' Route to Zizaene. In each of the p r e c e d i n g syntheses, the r i n g system i s s e t up by the s h i f t o f a carbon to a d e v e l o p i n g carbonium i o n produced by the d e p a r t u r e o f , i n two cases, a mesylate group, o r , i n one case, n i t r o g e n . The f a c i l i t y and high y i e l d s (65%, 93%, and 67% r e s p e c t i v e l y ) of the r e a r r a n g e -ment s t r o n g l y support the f e a s i b i l i t y of the- l a s t stage of Ramage's suggested b i o s y n t h e t i c pathway. 81 82 Thus f a r , no attempts t o p a r a l l e l Andersen's proposed b i o g e n e t i c pathway have been made. However, the Wagner-Meerwein rearrangement of a b i c y c i o [ 2 , 2 , 2 ] o c t a n e system to 14 a b i c y c l o [ 3 , 2 , 1 J o c t a n e system has been observed f o r h e t i s i n e (81), which undergoes an a c i d c a t a l y s e d r e a r r a n g e -ment t o form the hemiketal of the ketone 8_2_. The 1,2-carbon s h i f t and subsequent p r o t o n l o s s correspond e x a c t l y to the proposed methyl s h i f t and p r o t o n l o s s from carbon, c o n v e r t i n g i n t e r m e d i a t e 4_8 to z i z a e n e (24) (see Scheme 3, page 1 1 ) . - 22 -That z i z a n e s themselves can e a s i l y undergo r e a r r a n g e -9 ment was shown by Andersen when he found the a c i d - c a t a l y s e d 8 3 8 4 formation of " e p i i s o z i z a e n e " S4_ from z i z a e n e (24_) v i a the i n t e r m e d i a t e 83. 8 7 8 8 Scheme 7. Attempted S y n t h e s i s of Zizaene With Te r m i n a l Formation of Ring A. - 23 -The generation of the t r i c y c l i c structure v i a C_-C / y bond formation creating r i n g A has been employed i n an 15 attempt by S. Yuan to synthesize zizaene . Compound 8_5 underwent rearrangement of i t s b i c y c l o [ 2 , 2 , 2 ] o c t a n e system to give the [ 3 , 2 , 1 ] system i n compound- 8 6 . This compound was elaborated using normal methods to the dimethyl ketone ketal 8_7. Attempts were made to alkylate at C^ of compound 8 7 , but these f a i l e d , probably because of s t e r i c hindrance from the adjacent gem-dimethyl group. The compound was then c y c l i z e d to the enone 8J8, which contains a l l the carbons of zizaene except the exocyclic. methylene at Cg. Again, attempts to f u n c t i o n a l i z e at t h i s location were unsuccessful. Although the synthesis of zizaene was not successful, t h i s approach" i s useful i n that i t shows the p r a c t i c a l i t y of forming ring A l a s t , and by i t s f a i l u r e i t points out the need to introduce the f u n c t i o n a l i t y adjacent to the gcm-diraethyl group at an early stage i n the synthetic sequence. Up to the present, there have been no reported syntheses employing the closure of a [ 5 , 5 ] - s p i r o system to generate ring B of the zizane skeleton, nor has any attempt been made to carry out a c y c l i z a t i o n employing a [ 6 , 5 ] - s p i r o system to p a r a l l e l Ramage1s proposed biosynthetic route from hinesol (4_2) to the intermediate AA_. However, a very 16 17 s i m i l a r plan has been used by two groups of workers ' to prepare the sesquiterpene cedrene ( 3 0 ) . - 24 -In the f i r s t , Corey and1 h i s coworkers exposed the d i o l 89 to anhydrous formic a c i d , and i s o l a t e d 10 to 20 percent of cedrene 3_0 (equation 5). A l t e r n a t i v e l y , the u n s a t u r a t e d d i o l 9_0, a f t e r treatment under s i m i l a r c o n d i t i o n s and sub-sequent t h e r m o l y s i s , gave the diene 91 i n 80% y i e l d (equation 6) . T h i s was reduced to cedrene by l i t h i u m i n ' e t h y l a m i n e . In the second, Lawton d i s s o l v e d the u n s a t u r a t e d a l c o h o l 9_2 i n 88% formic a c i d and i s o l a t e d cedrene i n 80% y i e l d (equation 7) . (5) 89 30 (6) (7) 92 - 25 -The success o f these b i o g e n e t i c - t y p e c y c l i z a t i o n s i n the case of cedrene s t r o n g l y supports the f e a s i b i l i t y of u s i n g s p i r a n e s as b i c y c l i c p r e c u r s o r s to the f i n a l t r i c y c l i c s p e c i e s . Thus use of [5,5] or [ 6 , 5 ] - s p i r a n e s f o l l o w e d by rea.vrangement i n the s y n t h e s i s of the z i z a n e s e s q u i t e r p e n e s c o u l d be an i n t e r e s t i n g approach f o r the f u t u r e . C l o s u r e of r i n g C as the f i n a l c y c l i z a t i o n i s the s i m p l e s t s y n t h e t i c method i n concept. The p r e c u r s o r i s a hydrindane system w i t h a two carbon s i d e - c h a i n t h a t can l i n k a c r o s s the six-membered r i n g to form e i t h e r the C2~C11 bond or the C ^ - C ^ Q bond o f the z i z a n e s and g i v e a b i c y c i o [ 3 , 2 , l ] o c t a n e system. T h i s corresponds c l o s e l y to the requirements of g i b b e r e l l i n s y n t h e s i s . Many of the s y n t h e t i c approaches to the [3,2,1] g i b b e r e l l i n system would be a p p l i c a b l e to the z i z a n e s , were i t not f o r the d i f f e r e n t s u b s t i t u e n t s i n the two c l a s s e s of compounds. For example, 18 Stork and coworkers were ab l e to c y c l i z e the a c e t y l e n e 93 by r e d u c t i o n w i t h l i t h i u m i n l i q u i d ammonia to y i e l d compound 9_4 (equation 8) . However the a d d i t i o n a l f u n c t i o n a l - 26 -1 0 2 101 Scheme 8. S y n t h e t i c Route to Zizaene Using T e r m i n a l Formation of Ring C. groups p r e s e n t , namely the t e r t i a r y a l c o h o l and the e x o c y c l i c methylene, make these methods l e s s a t t r a c t i v e f o r the z i z a n e s . - 27 -The other promising l i n e o f a t t a c k on the formation of r i n g C i s to form the f i n a l bond between and C^g. T h i s 19 approach has been used by Wiesner and h i s coworkers i n a s y n t h e s i s of zizaene as shown i n Scheme 8. The sub-s t i t u t e d indan 9_5 was e l a b o r a t e d to the methoxy k e t a l 96. On exposure to a c e t i c a c i d , t h i s compound c y c l i z e d t o the a, g-unsaturated ketones 9_7_, w i t h the d e s i r e d s t e r e o c h e m i s t r y , and 9_8, i n a 2:3 r a t i o . These were converted by a c e t o l y s i s , hydrogenation, and O'ones o x i d a t i o n t o the ketones 9_9 and 100 r e s p e c t i v e l y . I t appears t h a t the o r i e n t a t i o n of the methyl group c o n t r o l s the approach o f the hydrogen, f o r c i n g i t to enter from the o p p o s i t e , l e s s crowded s i d e . S i n c e zizaene bears both proton and methyl on the 6 s i d e , n e i t h e r of the above ketones i s s a t i s f a c t o r y i n t h i s r e s p e c t . Both compounds were subsequently transformed to the z i z a e n e -type s p e c i e s 101 and 102 r e s p e c t i v e l y . Compound 101 was then transformed to z i z a e n e v i a o x i d a t i o n of the t e r m i n a l methylene to g i v e the ketone 7_9, which was transformed to zizaene using techniques a l r e a d y d i s c u s s e d (see Scheme 6). Two p o i n t s are i l l u s t r a t e d by t h i s s y n t h e s i s . F i r s t , the f e a s i b i l i t y of forming r i n g C v i a c y c l i z a t i o n t o the subsequent quaternary carbon has been demonstrated. Second, the need to m a i n t a i n good s t e r e o c h e m i c a l c o n t r o l over any r e a c t i o n s a f f e c t i n g the C q p r o t o n has been underscored. The Present Approach 0R 2 OTs 1 0 5 R,=CH 3 ,R 2 -H 106R,= H,R2=H 1 0 9 1 0 7 R,= Bz,R2=H 1 0 8 Ri= Bz,R2=Ts Scheme 9. S y n t h e s i s of the B i c y c l o [ 3 , 2 , l ] o c t a n e System V i a 20 Phenol C y c l i z a t i o n . 20 In 1961, Masamune developed a h i g h - y i e l d i n g c y c l i z a -t i o n r e a c t i o n g i v i n g the b i c y c l o [ 3 , 2 , l j o c t a n e system as - 29 -shown i n Scheme 9. In d e t a i l , the Reformatsky reaction of 6~methoxy-3-tetralone 103 with ethyl bromoacetate produced compound 104. After dehydration and hydrogenation, the HO' 113 compound was reduced with lithium aluminum hydride to give compound 105. Pyrolysis of the methylmagnesium iodide complex afforded the hydroxyphenol 106, which was converted to the benzyl ether 107, and then to the corresponding t o s y l ester 108. This was hydrogenated to give the phenol tosylate 109. Refluxing compound 109 i n t-butanol with potassium t-butoxide afforded the t r i c y c l i c compound 110 i n 90% y i e l d . - 30 -21 A t about the same time Mandel and coworkers demon-s t r a t e d t h a t a c y c l i z a t i o n i n v o k i n g a r y l p a r t i c i p a t i o n c o u l d occur a t the o r t h o p o s i t i o n as w e l l as the para. Compound 111 on c y c l i z a t i o n gave the products 112 and 113 i n 18% and 9% y i e l d r e s p e c t i v e l y . H < X ^ \ Ov I, (10) 1 1 4 115 More r e c e n t l y , an a c i d c a t a l y s e d decomposition of the diazoketone 114 has been found to g i v e compound 115, a r e a c t i o n which forms the b i c y c i o [ 3 , 2 , l j o c t a n e system ( r e a c t i o n 22 10). C0 2 H 118 119 Scheme 10. Proposed S y n t h e s i s of a Compound P o s s e s s i n g the Zizane Ring System. - 31 -T h i s suggests a p o s s i b l e approach to the zi z a n e s k e l e t o n (see Scheme 10). The phenol t o s y l a t e 116 when t r e a t e d w i t h base should c y c l i z e to the dieneone 117. Hydrogenation of t h i s compound c o u l d g i v e two p r o d u c t s , o f which compound 113 would be s l i g h t l y favoured, as can be seen by comparing the s t e r i c hindrance between top- and bottom-side a t t a c k , as shown i n F i g u r e 1. F i g u r e 1. S t e r i c Hindrance About the Double Bond i n Compound 117. The ketone 118, i f s u b j e c t e d to the F a v o r s k i i r e a c t i o n , would g i v e the c a r b o x y l i c a c i d 119, w i t h no s t e r e o c h e m i s t r y i m p l i e d f o r the a c i d f u n c t i o n a l i t y . •Although i t was p r e d i c t e d t h a t hydrogenation o f compound. 117 should g i v e the d e s i r e d compound 118 as the major product, 20 the hydrogenation of a s i m i l a r compound 120 by Masamune y i e l d e d both isomers i n a 7:3 r a t i o i n favour of the u n d e s i r e -a b l e product 122 over the p r e f e r e d 121. Thus e i t h e r a ketone or a f u n c t i o n a l i t y t h a t can e a s i l y be e l a b o r a t e d t o a ketone c o u l d be adjacent t o the newly i n t r o d u c e d hydrogen, t h a t i s , - 32 -120 121 + (11) Ph 122 on C* of compound 118. T h i s would bypass the d i f f i c u l t i e s encountered by Yuan i n attempting to f u n c t i o n a l i z e a t a l a t e stage i n the s y n t h e s i s . I f a ketone was p r e s e n t a t t h i s l o c a t i o n , i t would be b e t t e r t o have the gem-dimethyl group pres e n t on the a-carbon to prevent u n d e s i r a b l e e n o l a t e f o r m a t i o n of the ketone under the s t r o n g l y b a s i c c y c l i z a -t i o n c o n d i t i o n s . Other l e s s important p o s s i b i l i t i e s are the placement of e l e c t r o n - d o n a t i n g a c t i v a t i n g groups on the aromatic r i n g meta t o the phenol i n order to a i d forma-t i o n of the d e s i r e d c a r b a n i o n , or placement of groups a d j a c e n t to the l e a v i n g group to f a c i l i t a t e f o r m a t i o n of the carbonium - 33 -i o n . A l l of these f e a t u r e s are i l l u s t r a t e d i n 123. Necessary f e a t u r e s : 1. Presence of a good l e a v i n g group at A. 2. Presence of a f u n c t i o n a l i t y c o n v e r t i b l e t o a ketone or t e r m i n a l methylene at B. 3. Presence of a gem-dimethyl group a t C. . P o s s i b l e a d d i t i o n a l f e a t u r e s : 1. Presence o f an a c t i v a t i n g group a t D. 2. Presence of an a c t i v a t i n g group a t E. A p o s s i b l e t a r g e t f u l f i l l i n g a l l of the necessary B 123 o OTs 124 - 34 -requirements i s compound 124. T h e r e f o r e t h i s molecule was made the i n i t i a l t a r g e t of s y n t h e s i s . - 35 -RESULTS AND DISCUSSION The S y n t h e t i c Approach The s y n t h e t i c r o u t e t o the d e s i r e d phenol t o s y l a t e 124 was planned as f o l l o w s . O-Methoxybenzaldehyde 125 would be condensed w i t h d i e t h y l s u c c i n a t e to g i v e the u n s a t u r a t e d h a l f e s t e r 126. Hydrogenation of t h i s compound to 127, and F r i e d e l - C r a f t s c y c l i z a t i o n of 127 would produce the t e t r a l o n e 128. D i m e t h y l a t i o n adjacent t o the ketone would g i v e compound 129. C h a i n - l e n g t h e n i n g and r e d u c t i o n a t the e s t e r s i t e would y i e l d the a l c o h o l 130, which a f t e r cleavage of the methyl ether and t o s y l a t i o n would y i e l d the d e s i r e d phenol t o s y l a t e 124. The t r a n s f o r m a t i o n of the phenol t o s y l a t e t o z i z a n o i c a c i d would then f o l l o w the l i n e s d i s c u s s e d i n the I n t r o d u c t i o n . C y c l i z a t i o n o f compound 124 would produce the dienedione 131. Hydrogenation a t t h i s stage should y i e l d compound 132, p o s s e s s i n g the d e s i r e d s t e r e o c h e m i s t r y , as the major product. However, i f the u n d e s i r a b l e s t e r e o c h e m i s t r y d i d predominate, the ketone a d j a c e n t to the hydrogen i n q u e s t i o n would ensure i t s easy e p i m e r i z a t i o n . The ketone a d j a c e n t t o the gem-di m e t h y l group i n 132 should now be p r o t e c t e d , g i v i n g compound 133. Then, bromination would y i e l d the a-bromo ketone 134, which on treatment w i t h s t r o n g base should undergo a F a v o r s k i i -type rearrangement to y i e l d , a f t e r removal of the p r o t e c t i n g - 36 -- 3 7 -131 132 R=0 133 R = Protecting group P > 1 134 12 R^COaCHa. R2=H 66R,= H.Ra=C02CH3 Scheme 12. T r a n s f o r m a t i o n o f Phenol T o s y l a t e t o Z i z a n o i c A c i d . group, the ep i m e r i c e s t e r s 1_2 and 6_6, which have been 11 12 e l a b o r a t e d t o z i z a n o i c a c i d and e p i z i z a n o i c a c i d r e s p e c t i v e l y . The Stobbe Condensation o-Methoxybenzaldehyde was condensed w i t h d i e t h y l s u c c i n a t e by potassium t - b u t o x i d e i n t - b u t a n o l a c c o r d i n g t o the c o n d i t i o n s 23 o f El-Abbady and E l - A s s a l t o y i e l d the d e s i r e d h a l f e s t e r 126 i n up t o 75% y i e l d . - 38 -This product was always accompanied by a small amount (10 to 15% yield) of the corresponding d i a c i d 135, which was presumably formed i n the workup. This d i a c i d was very re s i s t a n t to c a t a l y t i c hydrogenation, and on r e c r y s t a l l i z a t i o n from nitromethane, c y c l i z e d to give the naphthoic acid 136, 23 a compound previously prepared by Ei-Abbady and El - A s s a l The ease of t h i s c y c l i z a t i o n suggested that the analogous reaction on the hydrogenated species should proceed e a s i l y . Hydrogenation The half ester 126 was hydrogenated to give the desired compound 127, which was i d e n t i f i e d by IR (the disappearance of the absorption at 16 4 0 cm 1 , and the s h i f t of the ester absorption from 1705 cm - 1 to 17 20 cm - 1), NMR (the disappear-ance of the v i n y l proton at 6.9 6 , and the appearance of protons between 2.4 6 and 3.0 6 ) , and UV (the disappearance of the styrene chromophore at 264 nm and 302 nm, and the emergence of a spectrum si m i l a r to anisole, with t r a n s i t i o n s - 39 -COaEt C O a E t at 272 nm, 278 nm, and 315 nm). The hydrogenation conditions used i n i t i a l l y , three atmospheres hydrogen pressure, platinum oxide catalyst-:. and ethanol as solvent, gave a small amount of the diester 137 as a side product, so ethyl acetate containing 5% acetic acid was substituted as solvent. However the NMR of the hydrogenation products indicated, by the presence of excess protons i n the range of 1 to 2 6, that reduction of the aromatic ri n g had taken place to some extent. This agrees 24 with the findings of H. C. Brown and C. A. Brown , who were able to hydrogenate benzene at atmospheric pressure using platinum on a carbon support. These workers also found that benzene was not reduced at a l l by palladium on charcoal, so t h i s c a t a l y s t was substituted for platinum oxide, thereby eliminating reduction of the aromatic ri n g and allowing a clean hydrogenation of compound 126 to compound 127. - 40 -F r i e d e l - C r a f t s C y c l i z a t i o n The i n i t i a l method used t o e f f e c t the F r i e d e l - C r a f t s c y c l i z a t i o n , d i s s o l u t i o n of the h a l f e s t e r 127 i n commercial p o l y p h o s p h o r i c a c i d a t 70°, gave only s m a l l amounts of the d e s i r e d t e t r a l o n e 128. The y i e l d of the r e a c t i o n never exceeded 12%. Use of f r e s h l y prepared p o l y p h o s p h o r i c a c i d brought some i n c r e a s e i n y i e l d , and f i n a l l y high d i l u t i o n -about 1% - of the r e a c t a n t r a i s e d the y i e l d again, t o 3 0% i n one case. However the l a c k o f r e p r o d u c i b i l i t y i n y i e l d s , 25 and other d i f f i c u l t i e s r e p o r t e d i n l a r g e s c a l e r e a c t i o n s made t h i s method u n a t t r a c t i v e . COCI C0 2Et 138 .While these s t u d i e s were i n p r o g r e s s , o t h e r methods of c y c l i z a t i o n were explo r e d . Phosphorus pentoxide i n benzene c y c l i z e d the h a l f e s t e r i n h a l f the y i e l d of the p o l y -phosphoric a c i d method. Phosphorus o x y c h l o r i d e i n t e t r a -c hloroethane, hydrogen f l u o r i d e s o l u t i o n , sodium a c e t a t e i n a c e t i c anhydride, a c e t y l c h l o r i d e , and boron t r i f l u o r i d e - 41 -e t h e r a t e a l l f a i l e d to g i v e any more than t r a c e s o f the d e s i r e d t e t r a l o n e . S i n c e the a c i d would o n l y c y c l i z e w i t h d i f f i c u l t y , i t was d e c i d e d t o prepare the more a c t i v e a c i d c h l o r i d e 138. T h i s was done u s i n g o x a l y l c h l o r i d e . T h i s method was found to be s u p e r i o r to both phosphorus p e n t a c h l o r i d e and t h i o n y l c h l o r i d e because o f the ease o f r e a c t i o n . The product, e a s i l y i d e n t i f i e d by i t s IR spectrum (appearance of a c i d c h l o r i d e at 177 0 cm , was t r e a t e d w i t h aluminum c h l o r i d e i n 26 methylene c h l o r i d e u s i n g a procedure developed by House to g i v e the d e s i r e d t e t r a l o n e 128 i n 20 t o 3 0% y i e l d . The t e t r a l o n e ' s s t r u c t u r e was confirmed by i t s IR (disappearance of the a c i d c h l o r i d e , and appearance of a ketone a b s o r p t i o n C02H O A O C H 3 O 140 a t 1693 cm ^ ) , UV (appearance of an a r y l ketone a b s o r b t i o n at 255 nm, c l o s e t o the v a l u e 256 nm c a l c u l a t e d by use of 27 S c o t t ' s r u l e s - 24 6 f o r the a r y l ketone, p l u s 3 f o r the o - a l k y l group, p l u s 7 f o r the m-methoxy f u n c t i o n a l i t y ) and mass spectrum (parent mass 248 m/e). - 42 -F u r t h e r c o n f i r m a t i o n was g i v e n when the t e t r a l o n e a c i d 139, the product of s a p o n i f i c a t i o n of e s t e r 128, was found to correspond to the l i t e r a t u r e compound, p r e v i o u s l y prepared by c y c l i z a t i o n of the anhydride 140 w i t h aluminum c h l o r i d e i n n itrobenzene. Although y i e l d s from 27% to 45% were r e p o r t e d f o r t h i s t r a n s f o r m a t i o n , our attempts t o d u p l i c a t e t h i s r e a c t i o n f a i l e d t o produce 139 i n g r e a t e r than 20% y i e l d , and as the t e t r a l o n e e s t e r was p r e f e r r e d t o the a c i d , these s t u d i e s were not pursued. 2 6 House has d i s c u s s e d causes f o r the d i f f i c u l t y i n f o r c i n g a c y c l i z a t i o n t o go meta to a methoxy group.. He po i n t e d out t h a t the aluminum c h l o r i d e c a t a l y s t can now complex wi t h the methoxy group on the aromatic r i n g , as shown 1 4 1 i n 141, d e a c t i v a t i n g the aromatic r i n g . Because of t h i s , he recommends us i n g o n l y one e q u i v a l e n t of c a t a l y s t . S i n c e the c a t a l y s t should p r e f e r e n t i a l l y c o o r d i n a t e w i t h the a c i d c h l o r i d e f u n c t i o n a l i t y , the methoxy-aluminum c h l o r i d e complex would not form. Furthermore the aluminum c h l o r i d e should be - 43 -added to the a c i d c h l o r i d e , r a t h e r than the r e v e r s e , t o prevent formation of the u n d e s i r a b l e complex i n the i n i t i a l l y i n t r o d u c e d p o r t i o n of a c i d c h l o r i d e . T h i s l a s t p o i n t i s i n d i r e c t disagreement w i t h the 29 f i n d i n g s of W. S. Johnson , who found t h a t the i n v e r s e F r i e d e l - C r a f t s procedure, t h a t i s , adding a c i d c h l o r i d e t o an aluminum c h l o r i d e suspension, gave enhanced y i e l d s of meta-methoxy a r y l ketones. However our use o f Johnson's procedure f o r the a c i d c h l o r i d e 138 gave y i e l d s markedly lower than the procedure f i n a l l y adopted. Johnson a l s o suggested t h a t use of a l e s s a c t i v e Lewis a c i d such as C O C I CH 3 o o 1 4 2 + 1 4 3 (12) 1 4 4 n=4 1 4 5 n= l a r g e s t a n n i c c h l o r i d e would e l i m i n a t e the f o r m a t i o n of the unwanted complex, but attempts to c y c l i z e the a c i d c h l o r i d e 138 w i t h t h i s reagent f a i l e d . House also noted that as the uncomplexed methoxy group activates the aromatic ring s p e c i f i c a l l y at the ortho and para positions, an important side reaction to intramolecular c y c l i z a t i o n at the meta po s i t i o n would be polymerization v i a intermolecular ortho or para attack. This was confirmed during the c y c l i z a t i o n of the acid chloride 142 to the indanone 143, when the desired indanone was accompanied by up to 4 0% of polymer made up of the c y c l i c tetramer 144, and a higher molecular weight portion of indeterminate length 2 6 (145) (reaction 12) . Very d i l u t e reaction conditions (13) (14) 1 4 9 150 - 45 -(1% acid chloride i n methylene chloride) reduced polymers to a n e g l i g i b l e y i e l d . This procedure was adopted i n our work for the same reason. The only other attempt to improve the y i e l d of the c y c l i z a t i o n was based on the work of Chatterjee and Banerjee"^, who found that the bromo-acid 146 c y c l i z e d i n polyphosphoric acid to give the two products 147 and 148 i n 35% y i e l d each (reaction 13). The half ester 126 was treated with bromine i n acetic acid to y i e l d the mono bromo-compound, presumably the 4-bromo species 149. However attempts to c y c l i z e t h i s com-pound to the bromo-tetralone 150 using polyphosphoric acid, Chatterjee's method of choice, were large l y unsuccessful. The corresponding acid chloride also f a i l e d to undergo Fr i e d e l - C r a f t s c y c l i z a t i o n with aluminum chloride c a t a l y s t i n methylene chloride (reaction 14). The lack of r e a c t i v i t y could be attributed to s t e r i c factors-attack ortho to both a bromine and an a l k y l group, or to the deactivating influence of the bromine, but Chatterjee's success with a s i m i l a r system make t h i s explana-t i o n less s a t i s f a c t o r y . No further work was done on the bromo species. Dimethylation Attempts to dimethylate the tetralone 128 with sodium hydride and methyl iodide i n dimethoxyethane to produce - 46 -compound 129 returned only s t a r t i n g material. As a l k y l a t i o n conditions with non-hydroxylic polar solvents and bases con-. . . 31 taming a large cation promote O-alkylation , the enol ether 151 was i n a l l l i k e l i h o o d formed i n the reaction, and promptly hydrolysed during the workup. To promote C-alkylation, one or more of the following options are available: use of a hydroxylie solvent; use of a non-polar non-hydroxylic solvent; or use of a base with a small cation. Addition of a small amount of ethanol to the above-mentioned reaction conditions f a i l e d to a l t e r the course 1 5 1 1 5 2 of the reaction. F i n a l l y , use of potassium t-butoxide i n a 32 1:4 mixture of benzene and ;t-butanol succeeded i n producing the methylated product 129 i n y i e l d s approaching 90%. The i d e n t i t y of the product 129 was confirmed by IR (appearance of gem-dimethyl doublet at 137 0 and 138 5 cm"1) and NMR (appearance of a s i n g l e t at 1.3 6, 6 protons). An i n t e r e s t i n g s i d e product of the m e t h y l a t i o n r e a c t i o n i s the t r i r a e t h y l a t e d t e t r a l o n e 152. T h i s compound, v i r t u a l l y i d e n t i c a l t o the d i m e t h y l a t e d t e t r a l o n e i n IR and UV c h a r a c t e r i s t i c s , can be q u i c k l y i d e n t i f i e d by i t s s t r i k i n g l y simple NMR spectrum--the ABC system of the d i m e t h y l t e t r a l o n e has c o l l a p s e d t o a c l a s s i c AB system, and another methyl s i n g l e t has appeared a t 1.15 6. E x t e n s i o n of the E s t e r Group A l l the carbons t h a t are to c o n s t i t u t e r i n g s A and B of z i z a n o i c a c i d , w i t h the e x c e p t i o n of the e x o c y c l i c methylene, have now been assembled. To complete the requirements f o r r i n g C, the e s t e r group must be extended by one carbon, as 3 3 i n the A r n d t - E i s t e r t r e a c t i o n . T h e e s t e r 129 was h y d r o l y s e d 1 3 3 « —uniMj 156 R = CH 2CI ~ 48 -to the acid 153 by sodium hydroxide i n aqueous dioxane at 80°. In comparison, the trimethylated compound 152, being a t e r t i a r y ester, was completely r e s i s t a n t to hydrolysis under these conditions. This chemical separation was far more e f f i c i e n t on a preparative scale than physical means such as gas chromatography. The acid 153 was now treated with o x a l y l chloride to give the acid chloride 154, and then with diazomethane to y i e l d the diazoketone 155. On the f i r s t attempt, diazomethane. in ether was added to the acid chloride, and the major pro-duct was the chloroketone 156, normally present i n very small amounts. This resulted from the reactions: RCOC1 + CK,N2 > RCOCHN2 + HC1 (15) RCOCHN2 + HC1 > RC0CH2C1 + N 2 (16) When the procedure was reversed, that i s , the acid chloride was added to the excess diazomethane, another reaction (17) - 49 -r e m o v e d t h e h y d r o c h l o r i c a c i d b e f o r e i t c o u l d r e a c t s i g n i -f i c a n t l y w i t h t h e d i a z o k e t o n e : C H 2 N 2 + HC1 > C H 3 C 1 + N 2 (18) T h i s i n v e r s e a d d i t i o n r e s u l t e d i n y i e l d s o f d i a z o k e t o n e o f u p t o 75%. T h e p r e s e n c e o f t h e d i a z o k e t o n e was c o n f i r m e d b y t h e IR s p e c t r u m (2120 a n d 164 5 cm "*") . T h e d i a z o k e t o n e was p u r i f i e d s a t i s f a c t o r i l y b y t h i n l a y e r c h r o m a t o g r a p h y ; c o l u m n c h r o m a t o g r a p h y on s i l i c a g e l c a u s e d s l o w d e c o m p o s i t i o n o f t h e d i a z o k e t o n e w i t h e v o l u t i o n o f n i t r o g e n , a p r o c e s s w h i c h d a m a g e d t h e c o l u m n s o t h a t n o s e p a r a t i o n was a c h i e v e d . 2 I n a n a t t e m p t t o p a r a l l e l t h e w o r k o f B e a m e s a n d M a n d e r m e n t i o n e d i n t h e I n t r o d u c t i o n , t h e d i a z o k e t o n e 155 was i r r a d i a t e d w i t h UV l i g h t w i t h t h e o b j e c t o f p r o d u c i n g t h e t r i k e t o n e 1 6 0 . H o w e v e r t h e p r o d u c t s h o w e d n o c h a n g e i n t h e a r o m a t i c c h r o m o p h o r e i n e i t h e r t h e IR o r t h e UV s p e c t r a . I n f u r t h e r e x p e r i m e n t s t h e d i a z o k e t o n e 155 was t r e a t e d w i t h s e v e r a l p r o t o n o r L e w i s a c i d s , n a m e l y t r i f l u o r o a c e t i c a c i d , 34 c u p n c s u l p h a t e , s t a n n i c c h l o r i d e a n d b o r o n t r i f l u o r i d e , w i t h u n i f o r m l y n e g a t i v e r e s u l t s . Some o f t h e e x p e r i m e n t s w e r e d u p l i c a t e d l a t e r o n t h e v e r y s i m i l a r d i a z o k e t o n e 1 5 7 , w i t h n o s u c c e s s . T h e f a i l u r e o f t h e s e e x p e r i m e n t s s u g g e s t s t h a t t h e a r o m a t i c r i n g i s n o t v e r y n u c l e o p h i l i c e v e n t o w a r d s v e r y r e a c t i v e c a r b o n i u m i o n s s u c h a s t h e o n e f o r m e d h e r e f r o m a d i a z o k e t o n e . - 50 -The diazoketone was then t r e a t e d w i t h s i l v e r o x i de i n r e f l u x i n g methanol, and i t smoothly underwent the Wolff rearrangement to g i v e the ch a i n - l e n g t h e n e d e s t e r 158 i n q u a n t i t a t i v e y i e l d . As an a l t e r n a t i v e , treatment of the diazo k e t o n e w i t h sodium t h i o s u l p h a t e and s i l v e r o x i de i n aqueous dioxane gave the c o r r e s p o n d i n g a c i d 159, but y i e l d s were about 60%, so t h i s method was not f u r t h e r s t u d i e d . E t h e r Cleavage and Reduction At t h i s p o i n t , w i t h the e x c e p t i o n of the e x o c y c l i c methylene, a l l of the carbons necessary to c o n s t r u c t z i z a n o i c a c i d are p r e s e n t . In o r d e r to s y n t h e s i z e the d e s i r e d phenol t o s y l a t e 124 from the e s t e r 158, t h r e e o p e r a t i o n s must be c a r r i e d out. The methyl e t h e r must be c l e a v e d , the e s t e r reduced t o an a l c o h o l , and t h a t a l c o h o l c o n v e r t e d t o a t o s y l a t e . While f o r m a t i o n of the t o s y l a t e must o b v i o u s l y f o l l o w r e d u c t i o n , the a l t e r n a t i v e sequences of r e a c t i o n s , a f t e r i n c l u d i n g p o s s i b l e a d d i t i o n o f p r o t e c t i n g groups a t v a r i o u s times, c r e a t e a number of r o u t e s t o be c o n s i d e r e d , as shown i n Scheme 13. The e s t e r 158', on treatment w i t h sodium b i s ( 2 -methoxyethoxy)aluminum h y d r i d e (Redal), y i e l d e d the e s t e r a l c o h o l 167 i n s t e a d of the k e t o a l c o h o l 130. The most obvious method t o prevent t h i s u n d e s i r a b l e ketone r e d u c t i o n i s t o p r o t e c t the ketone, f o r example as the k e t a l o f e t h y l e n e g l y c o l o r 2,2-dimethyl p r o p a n e d i o l . However, - 51 -Q 163 164R = Ts 169 R = M s Scheme 13. P o s s i b l e Routes from the E s t e r 158 to the Phenol T o s y l a t e 124 or the Phenol Mesylate 170. - 52 -a t t e m p t s t o f o r m t h e k e t a l s o f t h i s e s t e r a n d t h e v e r y s i m i l a r e s t e r 129 h a d n o s u c c e s s a t a l l b e c a u s e o f t h e s t e r i c h i n d r a n c e o f t h e a d j a c e n t g e m - d i m e t h y l g r o u p . A t t e n t i o n now t u r n e d t o t h e a c i d 1 5 9 . I t was s u c c e s s -f u l l y r e d u c e d t o t h e a l c o h o l 130 i n 50% y i e l d w i t h d i b o r a n e , 3 5 u s i n g a w e l l e s t a b l i s h e d p r o c e d u r e . H o w e v e r , a t t e m p t s t o c l e a v e t h e a r y l e t h e r t o y i e l d t h e p h e n o l a l c o h o l 165 f a i l e d a t t h i s t i m e , a s d i d a l l e f f o r t s o n t h e c o r r e s p o n d i n g t o s y l a t e 1 6 6 . T h i s i n i t i a l r e d u c t i o n o f t h e a c i d o r e s t e r f u n c t i o n was f o u n d t o b e a d e a d e n d . T h e r e f o r e , i n t e r e s t now f o c u s e d o n t h e i n i t i a l c l e a v a g e o f t h e a r y l e t h e r . I t was f e l t t h a t t h e c o m m o n l y u s e d c o n d i t i o n s o f e x t r e m e l y s t r o n g a q u e o u s a c i d ( s u c h a s 48% h y d r o b r o m i c a c i d ) c o u l d a d v e r s e l y a f f e c t o u r p r o d u c t , s o a m i l d e r m e t h o d was s o u g h t . S o d i u m t h i o p h e n o x i d e i n r e f l u x i n g d i e t h y l e n e g l y c o l , p r e v i o u s l y c o n s i d e r e d t h e r e a g e n t o f c h o i c e f o r t h e d e m e t h y l a t i o n o f q u a t e r n a r y ammonium s a l t s , - 53 -h a s b e e n u s e d t o c l e a v e a n a r y l m e t h y l e t h e r t o a p h e n o l i n 37 g o o d y i e l d s . H o w e v e r i n o u r c a s e , t h e a t t e m p t e d c l e a v a g e o f t h e e t h e r f a i l e d o n b o t h t h e e s t e r 158 a n d t h e a c i d 159. T h i s r e a c t i o n was m o n i t o r e d b y U V . A n o t h e r r e c e n t l y d e v e l o p e d m e t h o d f o r e t h e r c l e a v a g e 3 8 i s t r e a t m e n t w i t h l i t h i u m i o d i d e i n r e f l u x i n g c o l l i d i n e T r e a t m e n t o f t h e e s t e r 158 u n d e r t h e s e c o n d i t i o n s f o r 20 h o u r s g a v e t h e p h e n o l a c i d 161 i n a b o u t 40% y i e l d , a c c o m p a n i e d b y a 2 0% y i e l d o f t h e m e t h o x y a c i d 159. T h e m e t h o x y a c i d was s i m i l a r l y t r e a t e d , a n d p r o d u c e d t h e d e s i r e d p r o d u c t 161 i n t h e same 4 0% y i e l d , w i t h a b o u t 50% r e c o v e r y o f s t a r t i n g m a t e r i a l . T h e p o s s i b i l i t y o f c o n t i n u a l p u r i f i c a t i o n o f p r o -d u c t s a n d r e c y c l i n g o f t h e r e c o v e r e d m e t h o x y a c i d o n a s y n t h e t i c s c a l e was c o n s i d e r e d , b u t i t was h e l d i n a b e y a n c e u n t i l o t h e r m e t h o d s o f e t h e r c l e a v a g e h a d b e e n e x p l o r e d . 39 W o r k b y P r a g e r a n d T a n s u g g e s t e d t h r e e m e t h o d s t h a t c o u l d b e a p p l i c a b l e t o o u r c a s e . T h e f i r s t , r e f l u x w i t h a l u m i n u m c h l o r i d e i n b e n z e n e , f a i l e d t o g i v e a n y r e a c t i o n , a s j u d g e d b y T L C . T h e s e c o n d m e t h o d , b o r o n t r i b r o m i d e i n r e f l u x i n g b e n z e n e , y i e l d e d u p t o 6 0% o f t h e d e s i r e d p r o d u c t 161 f r o m t h e e s t e r 158. T h e f i n a l m e t h o d , p y r i d i n e h y d r o -c h l o r i d e a t 200°, was f o u n d t o b e s u p e r i o r t o a l l p r e v i o u s m e t h o d s , g i v i n g t h e d e s i r e d p h e n o l a c i d 161 i n e s s e n t i a l l y q u a n t i t a t i v e y i e l d s . T h e s t r u c t u r e was c o n f i r m e d b y IR (3415 c m - 1 ( p h e n o l ) , 3200-2400 a n d 1710 c m - 1 ( a c i d ) ) a n d m a s s s p e c t r a l d a t a . - 54 -From Scheme 13, i t can be seen that two routes from the phenol acid 161 to the phenol tosylate 124 must be considered. The simpler route involved reduction of compound 161 to the d i o l 165, and subsequent formation of the tosylate 124. However i t was f e l t that s e l e c t i v e t o s y l a t i o n of the primary alcohol of compound 165 i n preference to the phenol could be d i f f i c u l t . Thus when the acid 161 was found to be re s i s t a n t to reduction i n preliminary experiments using both diborane and sodium bis(2-methoxyethoxy)aluminum hydride, attention turned to the longer route, i n i t i a l protection of the phenol of compound 161. The protecting group to be employed i n compound 16 2 must be unaffected by conditions used to reduce the acid. As 35 esters are reduced quite slowly by diborane , the obvious candidate was the acetate group. The phenol acid 161 was treated w:\th ac e t i c anhydride i n ethyl acetate with a 40 c a t a l y t i c amount of perc h l o r i c acid present , and the pro-O 1 6 8 - 55 -duct which usually contained large amounts of the anhydride 168, was hydrolysed to the desired acetate 162, where P i s acetate, i n 90% y i e l d . This compound was i d e n t i f i e d by i t s IR (carbonyl absorptions at 168 5 cm ^ for the ketone, 1705 cm ^ for the acid, and 1780 cm ^ for the acetate) and NMR (appearance of a( s i n g l e t at 2.4 6, 3 H). This compound was reduced without d i f f i c u l t y using diborane according to Brown's procedure to give up to 91% of the desired alcohol acetate 163, where P i s acetate. The expected changes occurred i n the IR (disappearance of the 17 05. cm ^ absorption, and the appearance of an alcohol absorption at 33 00 cm ~) and i n the NMR (disappearance of the acid absorption at 10.7 6 ) . Treatment of t h i s compound with p-toluenesulphonyl chloride i n pyridine gave the tosylate 164, which P i s acetate, i n quantitative y i e l d . In the IR, the alcohol absorption disappeared, and a strong absorption at 1380 cm ^, a t t r i b u t a b l e to tosylate, appeared. Removal of the acetate was accomplished i n 80% y i e l d using an 22 aqueous carbonate-bicarbonate buffer to give the phenol tosylate 124. This was accompanied by the expected changes i n the IR (disappearance of the acetate absorption, and appearance of a hydroxyl absorption at 33 50 cm "*") and NMR (disappearance of the acetate s i n g l e t ) . Reaction of the alcohol acetate 163 with methanesulphonyl chloride yielded the corresponding mesylate 169 which a f t e r buffer treatment gave the phenol mesylate 170. C y c l i z a t i o n (19) 1 2 4 R=Ts 1 3 1 1 7 0 R=Ms The most c r u c i a l step, v.he formation of the t r i c y c l i c dienedione 131 from the phenol tosylate 124 or some si m i l a r compound (reaction 19), now remained. In order"to conserve the supply of the precious tosylate or mesylate s t a r t i n g material, the majority of the reactions were carried out using very small amounts (1-5 mg.), and followed by UV and a n a l y t i c a l TLC. Only i f the r e s u l t was po s i t i v e were larger scale experiments c a r r i e d out. The tosylate 124 was treated with potassium t-butoxide i n r e f l u x i n g t-butanol—Masamune's conditions—however, a f t e r 18 hours r e f l u x i n g , the UV absorbtion at 256 nm was unchanged. The desired dienedione was expected to have a maximum at around 33 0 nm, based on the adjusted UV absorption 41 at 276 nm or octa-3,5-diene-2,7-dione (onto the 276 nm for base, add 10 nm for an a- a l k y l group, 5 nm for an exocyclic 27 double bond, and 39 nm for the homodiene component ). - 57 -A n a l y t i c a l TLC data, on the oth e r hand, i n d i c a t e d t h a t the s t a r t i n g m a t e r i a l was no longer p r e s e n t . R e p e t i t i o n of t h i s experiment on a l a r g e r s c a l e u s i n g the phenol mesylate 170 r e s u l t e d i n the i s o l a t i o n of the t - b u t y l e t h e r 171 and i t s c h a r a c t e r i z a t i o n by IR (unsymmetrical d o u b l e t a t 1385 cm (medium) and 1360 cm 1 (strong) and mass s p e c t r a l data ( r e a c t i o n 2 0 ) ) . In view of the l a c k o f n u c l e o p h i l i c i t y u s u a l l y , a s s o c i a t e d w i t h the t - b u t o x i d e anion, t h i s product was unexpected, and f u r t h e r u n d e r l i n e d the extreme l a c k of n u c l e o p h i l i c i t y of the aromatic system i n 170. (20) A wide range of experimental c o n d i t i o n s to e f f e c t the c y c l i z a t i o n was now ex p l o r e d . The same new product was observed on a n a l y t i c a l TLC a f t e r treatment of the phenol t o s y l a t e 124 or the phenol mesylate 170 wit h e i t h e r t r i -f l u o r o a c e t i c a c i d , l i t h i u m o r sodium d i s i l a z a n e ^ ' i n t e t r a h y d r o f u r a n or benzene r e s p e c t i v e l y , base-washed alumina i n benzene, sodium methoxide i n di m e t h y l sulphoxide, - 58 -O or sodium hydride i n dimethyl formamide. The l a t t e r two methods were ca r r i e d out i n larger scale, and f i n a l l y the mesylate was treated with sodium hydride i n dimethyl sulphoxide, conditions normally conducive to the formation 43 of the dimsyl anion . The mass spectrum of the p u r i f i e d product showed a small peak at 216 m/e, corresponding to the desired dienedione, but further inspection showed a large peak at 432 m/e, a strong i n d i c a t i o n that the dimer of the desired compound was present. Two sources of a dimer are possible. Assuming the dienedione 131 did form, i t i s possible that i t immediately underwent an intermolecular Diels-Alder c y c l i z a t i o n reaction to y i e l d a dimeric product such as 172. If t h i s was the case, the spectral properties of the product should be 59 -r a d i c a l l y d i f f e r e n t from the s t a r t i n g mesylate. However the s p e c t r a l p r o p e r t i e s of the dimer were ve r y s i m i l a r to s t a r t -i n g m a t e r i a l , showing o n l y the disappearance of the phenol and mesylate a b s o r b t i o n s i n the IR, and no change i n the UV spectrum. T h i s p o i n t s to the fourteen-membered r i n g s p e c i e s 173 as the product. As h i g h d i l u t i o n techniques have been used i n s i m i l a r 44 cases to minimize u n d e s i r a b l e m t e r m o l e c u l a r r e a c t i o n s , the phenol mesylate was t r e a t e d w i t h potassium t - b u t o x i d e i n benzene at a c o n c e n t r a t i o n of 0.5 mg mesylate per ml of s o l v e n t , but no change i n the UV was d e t e c t e d . C o n s i d e r a t i o n of the D i f f e r e n c e s Between Compounds 109 and 170 T h i s s t a r t l i n g r e s u l t , whereby the mesylate was d i s p l a c e d by the i n t e r m o l e c u l a r a t t a c k by oxygen i n s t e a d of the d e s i r e d i n t r a m o l e c u l a r a t t a c k by carbon, l e d us to compare compound 170, which had c o n s i s t e n t l y f a i l e d to c y c l i z e , w i t h the very s i m i l a r t o s y l a t e 109, which as mentioned i n the I n t r o d u c t i o n had been c y c l i z e d by Masamune i n 90% y i e l d . There are f o u r p o i n t s of d i f f e r e n t i a t i o n between these compounds. The most obvious i s the presence of a ketone adjacent to the aromatic r i n g . The ketone i s u n l i k e l y to enter d i r e c t l y i n t o the r e a c t i o n — i t i s too hindered to be e a s i l y a t t a c k e d by a n u c l e o p h i l e — a n d i t has no a-protons to - 60 -O HO, 109 170 l o s e . However i t c o u l d s t i l l i n f l u e n c e the p r e f e r r e d mode of r e a c t i o n of the i n t e r m e d i a t e phenoxide by e i t h e r s t e r i c o r e l e c t r o n i c means. The most important o f these p o s s i b i l -i t i e s appeared t o be the s t e r i c e f f e c t s of the presence of an a d d i t i o n a l - p l a n a r carbon i n the B r i n g . 109e 109a 109b 170e 170a F i g u r e 2. Conformers of the Phenoxides of Compounds 109 and 17 0. - 61 -In order for the leaving group to be displaced by the i n c i p i e n t carbanion i n the aromatic r i n g , a close approach between the carbon of the aromatic r i n g and the carbon bearing the leaving group i s necessary. The two conformers i n which the side-chain bearing the leaving group i s equatorial, that i s , 109e and 170e, can be dismissed at once. I f , however, the side-chain i s f l i p p e d into the a x i a l position, i n both the conformers 109a and 170a the carbon bearing the leaving group can be positioned almost d i r e c t l y below the p o t e n t i a l carbanion i n the aromatic r i n g . Measurement of o t h i s distance on models yielded a separation of 2.4 A for o compound 109a and 2.2 A for the unreactive 170a. This r e s u l t , assuming that the less the separation, the greater the ease of reaction, would predict that 170a would react more quickly than 109a, i n d i r e c t contradiction to the observed r e s u l t s . Further inspection of the conformg.tional p o s s i b i l i t i e s of compound 109, however, show a t h i r d conformer, the skewed o boat 109b, i n which the closest approach i s now 2.0 A. Furthermore, due to the conformational r e s t r i c t i o n s placed upon compound 170 by the presence of an a d d i t i o n a l planar 2 . sp hybridized carbon, there i s no comparable s t e r i c arrange-ment for t h i s compound. This analysis reinforces the theory that the c l o s e s t possible approach between reacting centres i s a requirement of t h i s reaction. Thus experiments on the c y c l i z a t i o n of compounds bearing an sp"' hybridized carbon i n place of the ketone were indicated. - 62 -The second p o i n t of d i f f e r e n t i a t i o n between Masamune's compound 109 and our mesylate 170 i s the r e l a t i v e p o s i t i o n of the phenol, para to the r e a c t i n g c e n t r e i n h i s case (109), and ortho i n our case (170). However the ease w i t h 21 which Mandel and h i s coworkers o b t a i n e d the products of both ortho and para a t t a c k , as mentioned i n the I n t r o d u c t i o n , made the p o s s i b i l i t y t h a t the p o s i t i o n of the phenol c o u l d a f f e c t the r e a c t i o n appear remote. Thus a t t h a t time, no c o n s i d e r a t i o n was g i v e n to comparative s t u d i e s of the r e a c t i v i t y of o r t h o - and para-phenols. The t h i r d and f o u r t h p o i n t s of d i f f e r e n c e , namely the presence of the gem-dimethyl group, and the s u b s t i t u t i o n of the mesyl group f o r the t o s y l group, were d i s m i s s e d as p o s s i b l e causes f o r the l a c k of r e a c t i v i t y of the mesylate 170, i n the f i r s t case because of no v i s i b l e s t e r i c e f f e c t s , and i n the second case because of the g r e a t s i m i l a r i t y between the t o s y l and mesyl group. Reduction of the A r y l Ketone and R e l a t e d S t u d i e s 174 - 63 -A t t e n t i o n now turned t o the p r e p a r a t i o n o f a compound 3 b e a r i n g an sp h y b r i d i z e d carbon i n p l a c e of the ketone i n r i n g B of compound 170. The phenol a c i d 165 was t r e a t e d w i t h sodium borohydride, but r e t u r n e d o n l y s t a r t i n g m a t e r i a l . T h i s r e s u l t was not unexpected c o n s i d e r i n g i t s p r e v i o u s l y mentioned r e s i s t a n c e t o r e d u c t i o n by both Redal and diborane. I t was then d e c i d e d t o attempt the r e d u c t i o n of the phenol mesylate 170. On treatment w i t h sodium borohydride i n methanol, t h i s compound gave up to 77% y i e l d s o f the a l c o h o l mesylate 174, as c h a r a c t e r i z e d by IR (disappearance of the ketone a b s o r p t i o n , and appearance of a hydroxy a t 3400 cm "*") . Attempts to c y c l i z e t h i s compound w i t h base were immedi-a t e l y made. The compound was d i s s o l v e d i n di m e t h y l formamide and t r e a t e d w i t h sodium h y d r i d e , but the IR spectrum of the product f a i l e d t o e x h i b i t the d e s i r e d conjugated c a r b o n y l a b s o r p t i o n . S i m i l a r l y treatment o f compound 17 4 w i t h a l a r g e excess of potassium t - b u t o x i d e i n a r e f l u x i n g s o l u t i o n of t - b u t a n o l c o n t a i n i n g 6% di m e t h y l formamide f a i l e d t o g i v e any k e t o n i c product. However, both p r o d u c t s showed a new ab s o r p t i o n i n t h e i r IR s p e c t r a a t 1080 cm an i n d i c a t i o n of a C-0 bond. The f a i l u r e of t h i s attempted c y c l i z a t i o n f o r c e d a c a r e f u l e v a l u a t i o n o f the mechanism by which the d i o l 174 was produced. The phenol mesylate 170 c o u l d e x i s t i n two conformers, 170a and 170e, but the presence o f the l a r g e s i d e - c h a i n should make the p r e f e r r e d conformation 17 Oe. - 64 -\ 1 7 5 O M s 1 7 4 a (cis) Scheme 14. Reduction of the Phenol Mesylate and Base T r e a t -ment of the Product. During the r e d u c t i o n w i t h sodium borohydride, the borohydride' would tend to approach from the l e s s h i n d e r e d s i d e . S i n c e the 1 , 3 - d i a x i a l i n t e r a c t i o n between the a r r i v i n g borohydride - 65 -and the hydrogen on the same carbon as the side chain should be d i s t i n c t l y less than the 1,2 i n t e r a c t i o n with the adjacent a x i a l methyl group, the reducing agent should d e l i v e r the hydride from the side opposite to the a x i a l methyl, r e s u l t -ing i n formation of the equatorial alcohol 1.74e, c i s to the side chain, as shown i n Scheme 14. During the subsequent base treatment, t h i s could f l i p to the d i a x i a l conformer 174a, which would e a s i l y be able to undergo an a l t e r n a t i v e i n t e r n a l c y c l i z a t i o n to form the t r i c y c l i o ether 175. Indirect evidence i n favour of t h i s hypothesis was provided by the observation chat the major product i n the reduction of 1,l-dimethyl-4-t^butylcyclohexanone (176) with 45 lithium aluminum hydride was the equatorial alcohol 177 As the bulky t-butyl group holds the cyclohexanone ring i n (21) 96 per cent 4 per cent 1 7 6 1 7 7 1 7 8 the indicated conformation, most of the hydride attacked from the topside i n t o t a l disregard of the 1,3-axial proton s t e r i c e f f e c t , but i n accordance with the s t e r i c demands of the a x i a l methyl group a to the ketone. - 6 6 -Scheme 15. E l u c i d a t i o n of the S t e r e o c h e m i s t r y of Reduction of E s t e r 158. There are, however, d i f f e r i n g c onformation requirements between the simple cyclohexanone 176 2nd the mesylate 17 0, the most important of which are a t t r i b u t a b l e to the presence 2 of two more sp h y b r i d i z e d carbons i n compound 170. There-f o r e , i n order to check the v a l i d i t y o f our a n a l y s i s , a compound s i m i l a r to the mesylate 170 should be reduced, and i t s s t e r e o c h e m i s t r y proven unambiguously. - 67 -The compound chosen for the reduction was the ester 158. Treatment with sodium borohydride i n methanol gave a s a t i s -factory y i e l d of the al c o h o l i c ester 167. On saponification with sodium hydroxide solution i n methanol, the ester 167 was converted into the hydroxy acid 179. The crude compound 179 was refluxed i n benzene i n the presence of 4 A molecular sieves and a c a t a l y t i c amount of p-toluenesulphonic acid 46 for 18 hours , giving up to 8 0% y i e l d of a compound contain-ing a lactone absorption at 1730 cm i n d i c a t i n g that 17 9 i s the c i s isomer. The high y i e l d of the c i s reduction product confirmed our reasoning as to the f a i l u r e of the reduced mesylate 174 to c y c l i z e i n the desired fashion. Since the reduction of the ketone with a hydride reducing agent produced an alcohol with the correct configuration to i n t e r f e r e i n the c y c l i z a t i o n process by pre-empting the less nucleophilic carbanion, the next l o g i c a l step was to remove the oxygen e n t i r e l y . The Clemmensen reduction of the s t e r i c a l l y s imilar compound 181 has been c a r r i e d out, but the y i e l d of compound 182 was very small, about 1%, and was 181 - 68 -overshadowed by rearrangement products such as 183 , so o n l y the W o l f f - K i s h n e r r e d u c t i o n was ex p l o r e d s y n t h e t i c a l l y . A r e c e n t m o d i f i c a t i o n of the W o l f f - K i s h n e r has been used 48 by Nagata w i t h good e f f e c t on s e v e r a l f a i r l y h indered ketones. These methods, which i n v o l v e a c i d c a t a l y s e d f o r m a t i o n of the hydrazone f o l l o w e d by treatment w i t h s t r o n g base, f a i l e d to g i v e more than 22% y i e l d of the d e s i r e d a c i d 184. Furthermore, s i n c e the ketone would have t o be r e p l a c e d w i t h some f u n c t i o n a l i t y a t a l a t e r stage, i n order t o p r o v i d e a handle f o r the i n t r o d u c t i o n of the e x o c y c l i c methylene of z i z a n o i c a c i d , i t was deci d e d t o abandon t h i s r o u t e . T h i s pathway c o u l d s t i l l be i n v e s t i g a t e d a t some f u t u r e time. (23) 158 184 S u b s t i t u t i o n o f a H a l i d e as a Leaving Group Throughout a l l the attempted c y c l i z a t i o n s , the l a c k of r e a c t i v i t y o f the car b a n i o n had been the main cause f o r the f o r m a t i o n o f the prod u c t s t h a t were i s o l a t e d , a l l of which appeared to i n v o l v e O - a l k y l a t i o n . T h i s caused us to r e c o n s i d e r the mechanism of displacement o f the l e a v i n g group. - 69 -As mentioned e a r l i e r , l a r g e c a t i o n s such as potassium, which have a tendency to d i s s o c i a t e from the anion, favour O - a l k y l a t i o n over C - a l k y l a t i o n " ^ . Furthermore, the use of p o l a r a p r o t i c s o l v e n t s such as d i m e t h y l sulphoxide o r dimethylformamide a l s o promotes O - a l k y l a t i o n by a i d i n g the 4 9 formation o f a f r e e e n o l a t e i o n . i n s o l u t i o n . These two c o n s i d e r a t i o n s , e s p e c i a l l y the e f f e c t o f the s o l v e n t , h e l p e x p l a i n the s u r p r i s i n g a c t i v i t y o f the oxygen anion. However, among the e x p l o r a t o r y experiments, use was made of the small l i t h i u m c a t i o n , and i n another case, of the non-polar s o l v e n t benzene. In both ca s e s , a-compound i d e n t i f i e d by TLC data t o be the dimer 173 was formed, a l b e i t i n low y i e l d . T h e r e f o r e other p o s s i b l e reasons f o r the a c t i v i t y of the oxygen should be c o n s i d e r e d . The nature o f the l e a v i n g group on the a l k y l a t i n g s p e c i e s has been found to have a d e f i n i t e e f f e c t on product 30 f o r m a t i o n . T h i s can be e x p l a i n e d by the p r i n c i p l e o f hard 50 and s o f t a c i d s and bases , which s t a t e s t h a t hard Lewis a c i d s p r e f e r t o bond t o hard Lewis bases, and, v i c e v e r s a , t h a t s o f t a c i d s p r e f e r t o bond t o s o f t bases. Hard a c i d s and bases are c h a r a c t e r i z e d by low p o l a r i z a b i l i t y , and a hard base i s h i g h l y e l e c t r o n e g a t i v e (fluox-ide i s thus an extreme example). S o f t a c i d s and bases are h i g h l y p o l a r -i z a b l e , w i t h the s o f t base being l a r g e and of low e l e c t r o -n e g a t i v i t y (such as t r i e t h y l phosphine). Thus a l i s t of common l e a v i n g groups i n order from h a r d e s t to s o f t e s t i s : - 70 -sulphonate, chloride, bromide, and iodide. S i m i l a r l y , a comparison between the small highly electronegative phenoxide oxygen and the much more polarizable carbon shows the oxygen to be far harder. Using the p r i n c i p l e stated above, i t can be seen that 0-alkylation i s favoured by use of a sulphonate leaving group (hard to hard c o r r e l a t i o n ) , whereas C-alkylation i s favoured by use of an iodide or perhaps a bromide (soft to soft c o r r e l a t i o n ) . Thus our u t i l i z a t i o n of the t o s y l or mesyl leaving group greatly aided the observed oxygen attack. I t was therefore decided to prepare a compound with a halide i n place of the less desirable sulphonate, and as the iodide leaving group should best promote nucleophilic attack by carbon, compound 185 was chosen as a target. The acetate alcohol 163 was treated with hydroiodic 51 acid at temperatures up to 120° for times up to 24 hours, but the only i d e n t i f i a b l e product was the phenol alcohol 165, formed by hydrolysis of the acetate group. Treatment - 71 -of compound 163 w i t h i o d i n e and a l a r g e excess of diborane . * 52 m benzene s o l u t i o n , a r e c e n t l y developed i o d i n a t i o n procedure , r e s u l t e d o n l y i n the p a r t i a l r e d u c t i o n o f the ketone. S i m i l a r l y treatment of compound 163 w i t h sodium i o d i d e i n dimethylformamide a t 75° f a i l e d t o g i v e any of the d e s i r e d product. Treatment of the reduced phenol mesylate 174 under the l a t t e r c o n d i t i o n s f a i l e d to g i v e any i o d i n a t e d product. Attempts to prepare the c o r r e s p o n d i n g c h l o r i d e 186 wi t h t h i o n y l c h l o r i d e i n benzene were not s u c c e s s f u l . As the d i r e c t s u b s t i t u t i o n of h a l i d e f o r a l c o h o l seemed d i f f i c u l t t o a c h i e v e , an i n d i r e c t r o u t e was adopted. The e s t e r 129 was t r e a t e d w i t h p y r i d i n e h y d r o c h l o r i d e a t 200° to g i v e the phenol a c i d 187 i n high y i e l d . T h i s product was a c e t y l a t e d i n the same manner as d e s c r i b e d f o r the o r i g i n a l r o u t e t o y i e l d compound 188• Treatment of t h i s a c i d w i t h o x a l y l c h l o r i d e i n benzene gave the a c i d c h l o r i d e , which on a d d i t i o n t o diazomethane s o l u t i o n gave the d i a z o -ketone 157 i n 24% y i e l d from the e s t e r 129. A s o l u t i o n of the diazoketone i n methylene c h l o r i d e was t r e a t e d w i t h ether 54 s a t u r a t e d w i t h hydrogen bromide t o g i v e the bromoketone 189. The a c e t a t e was then removed w i t h b u f f e r t o g i v e compound 190. In an e f f o r t t o c y c l i z e t h i s compound to the d i e n e t r i o n e 160, i t was t r e a t e d w i t h potassium carbonate i n both d i m e t h y l -formamide and t - b u t a n o l s o l u t i o n , but the products showed no - 72 -1 5 7 C0 2 Et 1 8 7 R = H 188R=Ac 1 8 9 C0 2H 1 9 0 1 6 0 Scheme 16. P r e p a r a t i o n o f the Bromoketone 190 and Attempted C y c l i z a t i o n . change i n e i t h e r the i n f r a r e d aromatic a b s o r b t i o n or i n the UV s p e c t r a . Attempts t o c y c l i z e compound 190 u s i n g potassium t - b u t o x i d e i n t - b u t a n o l at both room temperature and 60° l i k e w i s e met w i t h no success. - 73 -The probable cause of t h i s f a i l u r e can be a t t r i b u t e d to the d e a c t i v a t i n g e f f e c t s of the ketone adjacent to the bromide l e a v i n g group. T h i s same l a c k of r e a c t i v i t y was 20 . noted by Masamune i n the s i m i l a r compound 191, which bears a s i m i l a r i t y to our product. He a l s o found t h a t the c o r r e s -ponding e t h y l e n e g l y c o l k e t a l 192 f a i l e d t o c y c l i z e , a r e s u l t which can be a s c r i b e d to s t e r i c i n t e r a c t i o n between the k e t a l oxygen and a p r o t o n on the s a t u r a t e d r i n g , as shown i n F i g u r e 3. Because o f the f a r g r e a t e r s t e r i c e f f e c t s expected i n our analogous k e t a l product 193 due to the s u b s t i t u t i o n o f a methyl i n p l a c e of a hydrogen, a p r o p o s a l to prepare t h i s compound was abandoned. The f a i l u r e of t h i s r o u t e l e d us to r e t u r n to our o r i g i n a l o b j e c t i v e of s u b s t i t u t i n g a halogen f o r the a l c o h o l i n compound 16 3. Using a r e c e n t procedure by Weiss 55 and Snyder , the a l c o h o l was t r e a t e d w i t h carbon t e t r a b r o m i d e 1 9 1 R = 0 • 1 9 2 R = k e t a l 193 - 74 -O 1 9 2 1 9 3 F i g u r e 3. S t e r i c Hindrance i n the Two K e t a l s 192 and 193. and t r i p h e n y l phosphine i n e t h e r i n an u n s u c c e s s f u l attempt to produce the bromo a c e t a t e 194. T h i s t r a n s f o r m a t i o n was s u c c e s s f u l l y accomplished i n low y i e l d u s i n g an improved (24) 1 6 3 R = H 1 9 4 R = A C 1 6 9 R = M S 1 9 5 R-H procedure by H o o z ^ , i n which t r i - n - o c t y l p h o s p h i n e i s s u b s t i t u t e d f o r t r i p h e n y l phosphine. While these s t u d i e s were being c a r r i e d out, i t was found t h a t the c o r r e s p o n d i n g mesylate 169 gave the d e s i r e d bromide i n up to 63% y i e l d by - 75 -r e f l u x i n g an acetone s o l u t i o n of the mesylate i n the presence 57 of anhydrous l i t h i u m bromide . The s t r u c t u r e was confirmed by IR (disappearance o f the mesylate a b s o r b t i o n ) , NMR ( s h i f t o f a two p r o t o n m u l t i p l e t from 4.3 6 t o 3.5 6), and mass s p e c t r a l data. The a c e t a t e p r o t e c t i n g group was then removed w i t h b u f f e r t o g i v e the d e s i r e d phenol bromide 195 i n up t o 95% y i e l d . In c hoosing the c o n d i t i o n s to e f f e c t the d e s i r e d c y c l i z a -t i o n , i t was f e l t tr, i t a s o l i d phase r e a c t i o n would e l i m i n a t e some of the d i f f i c u l t i e s encountered i n e a r l i e r experiments, such as s o l v o l y t i c a t t a c k . Furthermore, s o l i d s t a t e r e a c t i o n 31 c o n d i t i o n s have been found t o favour C - a l k y l a t i o n . P y r o l y s i s (25) 196R=H 1 9 7 R = H 198 R = CH3 199R=CH3 of the sodium phenoxides 196 and 198 g i v e s the dieneone products 197 and 199, as a r e s u l t of the A ^ - 5 p a r t i c i p a t i o n r e a c t i o n i n 20% and 80% y i e l d r e s p e c t i v e l y . The mesylate - 76 -170 was not c o n s i d e r e d f o r t h i s procedure because of i t s tendency to d i m e r i z e , and a l s o because o f the r e p o r t e d ease of p y r o l y s i s of mesylates to a l k e n e s * ^ . The phenol bromide 195 was t h e r e f o r e t r e a t e d w i t h sodium methoxide i n methanol, the methanol evaporated, and the product was heated to 20 0° i n a h i g h vacuum s u b l i m a t i o n apparatus. The sublimed product was examined and found to be l a r g e l y dimer by i t s IR and UV s p e c t r a . Assuming t h a t the dimer was formed d u r i n g the p y r o l y s i s , i t can be seen t h a t even i n t h i s s o l i d s t a t e r e a c t i o n , d i m e r i z a t i o n v i a 0-a l k y l a t i o n was s t i l l the predominant r e a c t i o n . In f a c t , the d i m e r i z a t i o n might even have been a i d e d by the c l o s e m o l e c u l a r c o n t a c t i n the t h i n l a y e r of s o l i d phenoxide on the bottom of * the s u b l i m a t i o n apparatus. In o r d e r to i n c r e a s e the d i s p e r s a l of the phenoxide, a few grams of c e l i t e were added to the phenol bromide s o l u t i o n , and the experiment was repeated. A very s m a l l amount of product w i t h an IR a b s o r p t i o n a t 1660 cm and a UV a b s o r p t i o n a t 314 nm was i s o l a t e d . However both the s m a l l y i e l d and the d i f f e r e n c e of the s p e c t r a l p r o p e r t i e s from those expected (1660 and 1620 cm i n the IR, and 330 nm i n the UV) l e d us to abandon t h i s procedure f o r some time. Recent work w i t h t r i f l u o r o e t h a n o l ' has shown i t to be an e x c e l l e n t s o l v e n t f o r a s s i s t i n g the formation of carbonium ions by s o l v a t i n g the l e a v i n g group, w h i l e a t the same time i t s extremely low n u c l e o p h i l i c i t y prevents u n d e s i r a b l e - 77 -products of s o l v e n t a t t a c k . 2 0 0 S o l v e n t A c e t i c a c i d T r i f l o u r o e t h a n o i 2 0 1 Y i e l d 97 0 2 0 2 % Y i e l d 3 100 (26) For i n s t a n c e , i n r e a c t i o n 26, when-the t o s y l a t e 200 was t r e a t e d w i t h the .indicated s o l v e n t s and t h e i r r e s p e c t i v e sodium s a l t s , the product a t t r i b u t i b l e t o s o l v e n t a t t a c k was dominant i n the case of a c e t i c a c i d and n e g l i g i b l e i n 6 2 the case of t r i f l u o r o e t h a n o l (27) 1 9 5 2 0 3 However, treatment of the phenol 195 wi t h t r i f l u o r o e t h a n o l alone, or i n the presence of base ( l i t h i u m carbonate and l i t h i u m d i m e t h y l s i l a z a n e ) f a i l e d to g i v e any products showing the s p e c t r a l p r o p e r t i e s expected f o r the c y c l i c d i e n e d i o n e . - 78 -As s i l v e r has a s p e c i a l a f f i n i t y f o r a l l the h a l i d e s , i t was f e l t t h a t treatment w i t h a s i l v e r s a l t would form the primary carbonium i o n which c o u l d then c y c l i z e . Treatment of compound 195 w i t h s i l v e r p e r c h l o r a t e i n t r i f l u o r o e t h a n o l , however, produced a compound i d e n t i f i e d by mass spectrometry as the t r i f l u o r o e t h y l e t h e r 203 ( r e a c t i o n 27)". The f o r m a t i o n of t h i s s o l v o l y s i s product re-emphasized the i n a d v i s a b i l i t y of u s i n g a p r o t o n i c s o l v e n t because of the p r o b a b i l i t y of a t t a c k . Consequently the r e a c t i o n was repeated u s i n g n i t r o -6 3 methane and s i l v e r p e r c h l o r a t e , and the s m a l l s c a l e r e a c t i o n f o l l o w e d by TLC. The major components p r e s e n t a f t e r up to 18 hours at 40° were dimer and s t a r t i n g m a t e r i a l . The sub-s t i t u t i o n of benzene f o r nitromethane showed s i m i l a r r e s u l t s by TLC. P r e p a r a t i o n and C y c l i z a t i o n of a Model Compound HO. 1 0 9 2 0 4 The c o n t i n u a l f a i l u r e of the v a r i o u s p h e n o l i c compounds to c y c l i z e i n d i c a t e d t h a t a s u b t l e e f f e c t not y e t p r o p e r l y accounted f o r must be o p e r a t i n g to prevent the d e s i r e d i n t r a -- 79 -molecular a t t a c k . One p o s s i b i l i t y t h a t had. been c o n s i d e r e d and d i s m i s s e d e a r l i e r was the d i f f e r e n c e i n r e a c t i v i t y between a c a r b a n i o n e i t h e r para (as i n Masamune's compound 109) or ortho (as i n our compounds) to the phenol. I t was t h e r e f o r e decided to make a model compound 204 i d e n t i c a l to compound 109, except f o r the a l t e r e d p o s i t i o n o f the phenol, and the s u b s t i t u t i o n o f the mesylate f o r the t o s y l a t e l e a v i n g group. T h i s p r e p a r a t i o n was c a r r i e d out a c c o r d i n g to Scheme 17. Naphthalene-1,7-diol 205 was reduced w i t h l i t h i u m i n l i q u i d ammonia to the tet r a h y d r o n a p h t h a l e n e 206, and without i s o l a t i o n t h i s was a l k y l a t e d w i t h d i m e t h y l s u l p h a t e t o g i v e 64 the methoxy. a l c o h o l 207 i n 4 2% y i e l d o v e r a l l . T h i s compound was o x i d i z e d w i t h p y r i d i n i u m c h l o r o c h r o m a t e 6 ^ to g i v e the ketone 208 in-52% y i e l d . A minor s i d e product 209 was i s o l a t e d i n up to 4% y i e l d i n e a r l y experiments employing 64 pyridine-chromium t r i o x i d e complex . The ketone 208 was t r e a t e d w i t h the anion of t r i m e t h y l phosphonoacetate, and 6 6 Wadsworth-Emmons m o d i f i c a t i o n of the W i t t i g r e a c t i o n , t o y i e l d the i s o m e r i c compounds 210 and 211 i n 4 0% and 22% y i e l d r e s p e c t i v e l y . Normally the mixture was not separated, but hydrogenated t o g i v e compound 212. From t h i s p o i n t on, the procedures are analogous to those used to prepare the phenol mesylate 170. Thus the e s t e r 212 was t r e a t e d w i t h p y r i d i n e h y d r o c h l o r i d e to g i v e the phenol a c i d 213 i n 61% y i e l d , which i n t u r n was a c e t y l a t e d i n 98% y i e l d to g i v e compound 214. T h i s compound was reduced w i t h d i b o r a n e -- 80 -2 0 5 2 0 6 R=H 207R = CH 3 OCH, 2 0 9 OR 2 1 2 R=CH 3 2 1 3 R= H + C02R OCH 2 1 1 OAc 2 1 4 OMs 2 0 4 C0 2 CH 3 0,H 215R=H 2 1 6 R=Ms S c h e m e 1 7 . P r e p a r a t i o n o f t h e M o d e l P h e n o l M e s y l a t e 204, - 81 -dimethyl sulphide complex to give the acetoxy alcohol 215 i n 98% y i e l d . Treatment of t h i s compound with methanesulphonyl chloride i n pyridine gave the product 216 i n 4 9% y i e l d . The acetate was removed with buffer to give the desired model compound, the phenol mesylate 204. For the c y c l i z a t i o n of t h i s compound, i t was decided to use conditions very s i m i l a r to Masamune's o r i g i n a l experi-ment. Therefore the mesylate 204 was treated with potassium t-butoxide i n r e f l u x i n g t-butanol and a product showing a a, 8-unsaturated carbonyl absorbtion. at 1660 and 1620 cm (28) 204 1 1 7 i n the IR spectrum was i s o l a t e d . The product a l s o e x h i b i t e d the expected UV a b s o r p t i o n a t 325 nm (the parent v a l u e , 215 nm, p l u s the increments f o r a double bond extending c o n j u g a t i o n (30 nm), a homo-annular diene (39 nm), an exo-c y c l i c double bond (5 nm), and two 6 - a l k y l groups (18 nm 27 each) gxves a t o t a l of 3 24 nm ) and the expected p a r e n t i n the mass spectrum c o r r e s p o n d i n g to the dieneone 117. The success of the c y c l i z a t i o n attempt on the model system l e d us to attempt p a r a l l e l experiments under Masamune* c o n d i t i o n s u t i l i z i n g the model 20j4 and the o r i g i n a l 170. As expected, the model compound smoothly c y c l i z e d , w h i l e the more complex s p e c i e s g r a d u a l l y gave r i s e to a s e r i e s o f minor compounds, a l l of which r e t a i n e d the a r y l ketone f u n c t i o n a l i t y by IR and UV. R e p e t i t i o n of the p a r a l l e l experiments u s i n g potassium J t-butoxide i n r e f l u x i n g benzene brought s i m i l a r r e s u l t s , a l t h o u g h the y i e l d o f the dieneone was somewhat lower. The success of r e a c t i o n 28 proved t h a t n e i t h e r the r e l a t i v e p o s i t i o n o f the phenol nor the s u b s t i t u t i o n of " mesylate f o r t o s y l a t e was c r u c i a l . T h e r e f o r e the l a c k of r e a c t i v i t y c o u l d be t r a c e d back t o the ketone f u n c t i o n a l i t y (the e f f e c t o f the gem-dimethyl was agai n d i s c o u n t e d ) . The S u c c e s s f u l C y c l i z a t i o n A t t h i s p o i n t i t was noted t h a t the UV a b s o r b t i o n spectrum o f the dieneone 117 was almost superimposable on t h a t of the minor p r o d u c t of the t h e r m o l y s i s of the sodium s a l t o f compound 195. The t h e r m o l y s i s was repeated, and the product i n v e s t i -gated. As noted e a r l i e r , the s i n g l e a b s o r p t i o n (1660 cm - 1) i n the c a r b o n y l r e g i o n , and the d i f f e r e n c e of the observed UV a b s o r b t i o n (315 nm) from t h a t c a l c u l a t e d (330 nm) tended t o r a i s e doubts as to the product's i d e n t i t y . The mass - 83 -(29) 195 131 spectrum, on the oth e r hand, gave ample conformation t o the assignment of s t r u c t u r e 131 to the product. The parent peak appeared a t 216 m/e, and the h i g h r e s o l u t i o n a n a l y s i s o f the parent corresponded to the c o r r e c t atomic composition. The lower mass v a l u e s f i t the expected fragmentation p a t t e r n of the parent i o n , as shown i n Scheme 18. The parent can fragment i n t h r e e p o s s i b l e ways. The f i r s t and most common rou t e i n v o l v e s l o s s o f carbon monoxide to y i e l d the peak a t 188 m/e i n 57% abundance. T h i s daughter i o n can then fragment i n t h r e e ways as w e l l . In the f i r s t , a methyl i s l o s t to g i v e an i o n a t 173 m/e w i t h 100% abundance. In the second, e t h y l e n e and a pro t o n are l o s t t o g i v e an i o n a t 159 m/e. The t h i r d f r a g m e n t a t i o n of t h i s daughter i o n i s by l o s s of propylene and a proton to g i v e the i o n a t 14 5 m/e. In the second mode of fragmentation, the parent i o n l o s e s propylene t o y i e l d a second i o n a t 174 m/e. I t can - 84 -Scheme 18. Suggested Fragmentation of the Dienedione 131: R e l a t i v e I n t e n s i t i e s are Shown i n Parentheses. - 85 -then l o s e carbon monoxide and a proton to y i e l d the same s p e c i e s a t 14 5 m/e as from the i n i t i a l r o u t e of fragmentation. In the f i n a l r o u t e of fragmentation of the parent i o n , e t h y l e n e and a proton are l o s t to g i v e the i o n a t 187 m/e. T h i s i o n can then l o s e carbon monoxide t o y i e l d the s p e c i e s a t 159 m/e which arose from the i n i t i a l f r agmentation pathway. The F o u r i e r Transform NMR spectrum gave f u r t h e r c o n f i r m a -t i o n t o the proposed s t r u c t u r e . The aromatic m u l t i p l e t of the s t a r t i n g m a t e r i a l 195 had broken down i n t o t h r e e w e l l 6 7 separated o l e f i n i c p roton peaks c l o s e to the expected v a l u e s (6.35 6' f o r C-6, 7.2 6 f o r C-7, 6. 95 <5 f o r C-8; expected, 6.36 6, 7.36 6, and 7.33 6 r e s p e c t i v e l y ) . The a b s o r p t i o n s of the methylene groups a d j a c e n t to the aromatic r i n g (2.8 o) and the bromide (3.5 <5) p r e s e n t i n the s t a r t i n g m a t e r i a l had both d i s a p p e a r e d , to be r e p l a c e d w i t h a broad envelope at 1.6 6. Now t h a t a r o u t e to the dienedione 131 had been e s t a b l i s h e d , e f f o r t s were made to i n c r e a s e the amount of product on hand (the average amount produced per run from about 10 mg of the phenol 195 was 1 mg). The s i m p l e s t method t o get u s e f u l amounts of the dienedione would be to s c a l e up the procedure, but the requirements of the r e a c t i o n , a s m a l l amount of compound spread over a l a r g e area of support i n a s u b l i m a t i o n apparatus, made t h i s approach extremely d i f f i c u l t . - 86 -During the removal o f the s o l v e n t a f t e r f o r m a t i o n of the phenoxide i n the s u b l i m a t i o n apparatus, the c e l i t e formed a hard cake, which, i t was f e l t , c o u l d l a t e r t r a p newly formed molecules of the d i e n e d i o n e d u r i n g the t h e r m o l y s i s , thereby l e a d i n g to decomposition or d i m e r i z a t i o n under co n t i n u e d h e a t i n g . T h e r e f o r e i n order to ensure easy escape f o r any newly formed product d u r i n g the t h e r m o l y s i s , w h i l e a t the same time m a i n t a i n i n g an adequate s u r f a c e area, g l a s s beads were s u b s t i t u t e d f o r c e l i t e i n the procedure. T h i s , however, f a i l e d to i n c r e a s e the y i e l d . I t was d e c i d e d to t r y again u s i n g s m a l l e r g l a s s beads, xn order to i n c r e a s e the a v a i l a b l e s u r f a c e area. But as g l a s s beads s m a l l e r than 4mm i n diameter were u n a v a i l a b l e , sand was used i n s t e a d . The y i e l d u n f o r t u n a t e l y showed no improvement. I t was f e l t t h a t use of a b a s i c s o l i d support might h e l p r a i s e the y i e l d . In the i n i t i a l experiment, s u b s t i t u t i o n of l i t h i u m carbonate f o r sand r e s u l t e d i n a s l i g h t i n c r e a s e i n y i e l d from 16% to 20%. Use of c a l c i u m carbonate as a support gave a comparable r e s u l t — 1 7 % y i e l d . As n e i t h e r an i n e r t support nor an i o n i c support had r e s u l t e d i n y i e l d s over 20%, i t was d e c i d e d to e x p l o r e the use of s t r o n g absorbents which, i t was hoped, would p r e f e r -e n t i a l l y b i n d the charged s t a r t i n g m a t e r i a l . However, no dienedione was i s o l a t e d a f t e r a t h e r m o l y s i s u s i n g a c t i v a t e d c h a r c o a l support, and o n l y t r a c e s of the d e s i r e d product were d e t e c t e d a f t e r use of alumina as s o l i d support. - 87 -T a b l e 1. P r o d u c t i o n of the Dienedione 131. S o l i d Support Y i e l d (percent) None 0 C e l i t e 7 G l a s s beads 7 Sand 16 L i t h i u m carbonate 20 Calcium carbonate 17 M o r i t ( a c t i v a t e d c h a r c o a l ) 0 Alumina (Woelm B a s i c I) l e s s than 1 C o n c l u s i o n (30) 123 217 The use of an Ar^-5 p a r t i c i p a t i o n r e a c t i o n t o y i e l d a t r i c y c l i c s p e c i e s b e a r i n g the d e s i r a b l e f u n c t i o n a l groups i n d i c a t e d i n the I n t r o d u c t i o n ( r e a c t i o n 30) has been shown to be extremely p r o b l e m a t i c a l . The main reason f o r the f a i l u r e of the phenol mesylate 170 and s i m i l a r s p e c i e s to undergo smooth c y c l i z a t i o n can be t r a c e d to the presence of the ketone, which c o u l d d e a c t i v a t e the p o t e n t i a l c a r b a n i o n - 38 -as d e p i c t e d i n the u n d e s i r a b l e resonance form (b) not a v a i l a b l e t o the s a t u r a t e d s p e c i e s (see F i g u r e 4). A l t e r -n a t i v e l y , the i n a c t i v i t y of the phenoxide c o u l d be blamed on the e l e c t r o n - w i t h d r a w i n g i n d u c t i v e e f f e c t of the ketone. F i g u r e 4. Some of the Resonance Forms A v a i l a b l e to the Phenoxide. To e l i m i n a t e t h i s d i f f i c u l t y , the ketone must be removed. The r e d u c t i o n o f the ketone t o an a l c o h o l removed t h i s problem, but then the s t e r e o c h e m i s t r y of r e d u c t i o n ensured t h a t the a l c o h o l would be abl e t o i n t e r f e r e i n the c y c l i z a -t i o n by d i s p l a c i n g the l e a v i n g group b e f o r e the carbanion c o u l d a t t a c k . The p o s s i b i l i t i e s of p r o t e c t i n g the a l c o h o l to ensure i t s i n a c t i v i t y or i t s replacement w i t h another f u n c t i o n a l group must be c o n s i d e r e d , but the bulk of the adja c e n t gem-dimethyl.group would p r o b a b l y make such r e a c t i o n s extremely d i f f i c u l t to c a r r y out s a t i s f a c t o r i l y - 89 -as shown by our i n a b i l i t y to form the k e t a l o f the ketone. The complete removal of the ketone to leave a methylene group would e l i m i n a t e both the u n d e s i r a b l e e l e c t r o n i c e f f e c t s of the ketone, and the u n d e s i r a b l e chemical e f f e c t s of the a l c o h o l , thereby e n s u r i n g the s u c c e s s f u l c y c l i z a t i o n t o g i v e compound 218, but a f u n c t i o n a l i t y capable of e l a b o r a t i o n t o the e x o c y c l i c methylene of z i z a n o i c a c i d would have t o be i n t r o d u c e d a t C(*) a t a l a t e r time. The i n a b i l i t y of Yuan t o f u n c t i o n a l i z e the c o r r e s p o n d i n g p o s i t i o n (*) of a very s i m i l a r compound 8_8, suggests t h a t t h i s c o u l d be extremely d i f f i c u l t ( F i g u r e 5). F i g u r e 5. Comparison of the Environment About the I n a c t i v e Methylene i n Yuan's Ketone 8_8 and the P o s s i b l e Product 218. One of the p o s s i b i l i t i e s remaining i s to i n t r o d u c e the gem-dimethyl f u n c t i o n a l i t y a f t e r f o r m a t i o n of the t r i c y c l i c system. Thus a r o u t e based on the model compound 117 would i n v o l v e a l l y l i c o x i d a t i o n o f the methylene group t o y i e l d 88 218 ~ 90 -the d i k e t o n e 219, which c o u l d then be a l k y l a t e d to g i v e compound 131, as shown i n Scheme 19. 0 1 3 1 Scheme 19. A Synthetic Route From the Model Dieneone 117 to the Desired Dienedione 131. This route was not investigated due to lack of time. However, i n any further studies of the possible synthesis of zizanoic acid v i a the dienedione 131, t h i s route should c e r t a i n l y be pursued. - 91 -EXPERIMENTAL Spectral Data A l l IR spectra were taken i n chloroform solution unless otherwise noted. They were recorded on a Perkin Elmer model 700 spectrophotometer and were ca l i b r a t e d with the 1601 cm 1 band of polystyrene. The assignment of each band i s noted i n parentheses a f t e r i t . A l l absorptions are given i n cm The NMR spectra were taken i n deuterochloroform unless otherwise noted, and were recorded on a Varian model T-60 or nodel XL-100. Tetramethylsilane was used as an i n t e r n a l standard. Chemical s h i f t s are reported on the 6 scale. Coupling constants are quoted i n Hz. A l l UV spectra were recorded on either a Unicam model SP 800 or a Carey Model .14 spectrophotometer, and unless otherwise noted, the spectra were taken i n methanol. A l l absorptions are given i n nm. The mass spectra were recorded with either an Atlas CH-4b or, for high r e s o l u t i o n , an AEI MS--50 mass spectro-meter. In both cases, the spectra were obtained at 70 eV. The value i n parentheses a f t e r each mass i s i t s r e l a t i v e i n t e n s i t y . Masses below 100 m/e are usually omitted. Physical Data Melting points were obtained on a Kofler hot stage micro-scope and are uncorrected. - 92 -Elemental a n a l y s e s were performed by Mr. Peter Borda, U n i v e r s i t y of B r i t i s h Columbia. Chromatography S i l i c a g e l was o b t a i n e d from E. Merck. P r e p a r a t i v e t h i n l a y e r chromatography (TLC) was done u s i n g 0.9 mm. t h i c k n e s s PF-254 + 366 on e i t h e r 20 x 20 cm. or 5 x 20 cm. g l a s s p l a t e s . Small a n a l y t i c a l p l a t e s were prepared by d i p p i n g microscope s l i d e s i n t o a s t i r r e d s l u r r y o f s i l i c a g e l i n c h l o r o f o r m . Column chromatography was c a r r i e d out w i t h s i l i c a g e l f i n e r than 200 mesh. Gas. chromatography was c a r r i e d out on a V a r i a n Aerograph model 9OP. S o l v e n t s S o l v e n t s termed 'dry' have been t r e a t e d as f o l l o w s . E t h y l ether and t e t r a h y d r o f u r a n were d r i e d by r e f l u x i n g over l i t h i u m aluminum h y d r i d e . Benzene was d r i e d by storage over sodium. P y r i d i n e was d r i e d by storage over sodium hydroxide p e l l e t s . Methanol was d r i e d by r e f l u x i n g over magnesium methoxide. Techniques Anhydrous magnesium su l p h a t e was used t o dry chemical s o l u t i o n s , and was removed by f i l t r a t i o n through a s i n t e r e d g l a s s f u n n e l , g l a s s wool, or c o t t o n wool. - 93 -A l l s t i r r i n g , u n l e s s otherwise s t a t e d , was c a r r i e d out m a g n e t i c a l l y u s i n g t e f l o n coated s t i r r e r s . E t h y l hydrogen c i s - y - o - m e t h o x y p h e n y l i t a c o n a t e (126) A s o l u t i o n of 28.0 g. (0.2 mole) of o-methoxybenzaldehyde and 42 g. (0.24 mole) of d i e t h y l s u c c i n a t e i n 40 ml. t - b u t a n o l was added to a r e f l u x i n g s o l u t i o n of 36 g. (0.32 mole) potassium t - b u t o x i d e i n 20 0 ml. t_-butanol over 2 0 minutes, and the r e s u l t i n g r e a c t i o n mixture r e f l u x e d a fu-rther^ 3 hours. Mechanical s t i r r i n g was necessary f o r the v i s c o u s s o l u t i o n . Concentrated h y d r o c h l o r i c a c i d was then added to the c o o l e d s o l u t i o n u n t i l i t was a c i d i c . The o r g a n i c s o l v e n t was removed under reduced p r e s s u r e , and the r e s u l t i n g o i l taken up i n e t h y l a c e t a t e . The o r g a n i c s o l u t i o n was washed w i t h t h r e e 100 ml. p o r t i o n s of s a t u r a t e d sodium c h l o r i d e s o l u t i o n , and the o r g a n i c s o l v e n t a g a i n removed under reduced p r e s s u r e . The o i l was d i s s o l v e d i n 50 0 ml. of c o n c e n t r a t e d sodium b i c a r b o n a t e s o l u t i o n , and e x t r a c t e d w i t h two 100 ml. p o r t i o n s of e t h e r . The o r g a n i c s o l v e n t was l a t e r removed under reduced p r e s s u r e to y i e l d 11.2 g. (0.065 mole) of unreacted s t a r t i n g m a t e r i a l . The aqueous l a y e r was then a c i d i f i e d w i t h concen-t r a t e d h y d r o c h l o r i c a c i d , and e x t r a c t e d w i t h 200 ml. of e t h y l a c e t a t e . The o r g a n i c l a y e r was washed wit h s a t u r a t e d sodium c h l o r i d e s o l u t i o n u n t i l n e u t r a l , d r i e d , and the s o l v e n t - 94 -removed under reduced p r e s s u r e . In order to remove the c r y s t a l l i n e d i a c i d 135 (m.p.,. 210-212° ( l i t . 2 3 210-211°)), the crude product was d i s s o l v e d i n benzene, and f i l t e r e d through a s i n t e r e d g l a s s f u n n e l . The s o l v e n t was removed to g i v e 39.5 g. (73% y i e l d ) of crude compound 126, a t h i c k y e l l o w o i l . A s m a l l sample was p u r i f i e d by p r e p a r a t i v e T L C ( s i l i c a g e l ; c h l o r o f o r m : acetone: a c e t i c a c i d - 90: 10: 1 ) , the band a t 0.5 being removed and e x t r a c t e d w i t h e t h y l a c e t a t e . IR: 3600 - 2400 (acid), 1705 ( a c i d and conjugated e s t e r ) , 1640 (conjugated a l k e n e ) . NMR: 1.2 ( t , J = 7 , 3 H), 3.4 (s, 2 H), 3.8 (s, 3 H), 4.2 (q, J = 7, 2 H), 6.7 - 7.5 (m, 5 H), 7.8 (s, 1 H). UV: 214 (9,600), 264 (7,500), 302 (4,500). Mass Spectrum; c a l c u l a t e d f o r c i 4 H i g ° 5 : 264.0997 m/e. Found: 264.1001 m/e. Low r e s o l u t i o n : 265 (8), 264 (55), 233 (11), 220 (53), 218 '(21), 217 (13), 191 (15), 190 (15), 189 (59), 187 (11), 175 (21), 174 (30), 161 (20), 159 (16), 147 (20), 146 (98), 145 (69), 131 (100), 115 (38). - 95 -E t h y l Hydrogen 6-methoxybenzylsuccinate (127) A s o l u t i o n of 21.9 g. (.083 mole) o f the unsaturated h a l f a c i d 126 i n 200 ml. of 10% a c e t i c a c i d i n e t h y l a c e t a t e was p l a c e d . w i t h 0.8 g. of 10% p a l l a d i u m on c h a r c o a l i n a P a r r hydrogenation apparatus. The hydrogen p r e s s u r e was set at 40 p s i , and the s o l u t i o n was shaken f o r 4 days. At the end of t h i s time, a p r e s s u r e drop of 3.5 p s i (60% of the expected amount) had o c c u r r e d . A f u r t h e r 0.58 g. of c a t a l y s t was added, and shaking was resumed f o r a f u r t h e r 4 8 hours, at which time the t o t a l p r e s s u r e drop equaled the expected 6 p s i . The s o l u t i o n was f i l t e r e d through a s i n t e r e d g l a s s f u n n e l , and the s o l v e n t was removed under reduced p r e s s u r e t o y i e l d 23.0 g. of c o l o u r l e s s o i l . The excess weight d i s c r e p a n c y was due to a s m a l l amount of a c e t i c a c i d , which c o u l d be c a r r i e d forward without i n t e r f e r i n g with l a t e r r e s u l t s . Washing an e t h y l a c e t a t e s o l u t i o n of the product w i t h f o u r f r a c t i o n s of d e i o n i z e d water removed the a c e t i c a c i d . IR ( CC1 4): 3600 - 2400 ( a c i d ) , 1730 ( e s t e r ) , 1705 ( a c i d ; . NMR: 1.1 ( t , J = 7, 3 H), 2.4 - 3.2 (m, 5 H), 3.6 (s, 3 H), 4.1 (q, J = 7, 2 H), 6.6 - 7.2 (m, 4 H), 11.0 (s, 1 H). UV: 217 (6,300), 272 (1,900), 278 (1,600), 315 (50) - 96 -Mass Spectrum; c a l c u l a t e d f o r C^H^gOc-: 266.1154 m/e. Found: 266.1145 m/e. Low r e s o l u t i o n : 266 (26), 249 (16), 238 (8), 220 (49), 207 (21), 203 (23), 192 (25), 175 (36), 174 (11), 161 (44), 147 (31), 128 (27), 121 (100). 5 - M e t h o x y - l - t e t r a l c n e - 3 - c a r b o x y l i c a c i d e t h y l e s t e r (128) To a s t i r r e d s o l u t i o n of 21.0 g. of the h a l f a c i d 127 i n 200 ml- d r y benzene was added 26 ml. (0.30 moles) o x a l y l c h l o r i d e . The r e s u l t i n g b r i g h t y e l l o w s o l u t i o n was s t i r r e d w i t h e x c l u s i o n of moisture f o r 14 hours, and the s o l v e n t was then removed under reduced p r e s s u r e . An IR spectrum confirmed the presence of the a c i d c h l o r i d e . IR ( C H 2 C 1 2 ) : 1790 ( a c i d c h l o r i d e ) , 1730 cm - 1 ( e s t e r ) . The a c i d c h l o r i d e was d i s s o l v e d i n 1500 ml. methylene c h l o r i d e and 30 g. (0.23 moles) o f aluminum c h l o r i d e was added i n one l o t . W i t h i n seconds the s o l u t i o n deepened i n c o l o u r u n t i l n e a r l y b l a c k . The s o l u t i o n was s t i r r e d f o r 72 hours, and then a mixture o f 200 g. i c e , 200 ml. water, and 10 ml. 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 was added to the r e a c t i o n mixture, and s t i r r i n g maintained f o r 30 minutes. The methylene c h l o r i d e was removed under reduced p r e s s u r e , and the product taken up i n 200 ml. e t h e r . The o r g a n i c - 97 -l a y e r was washed wi t h t h r e e 50 ml. p o r t i o n s of 5% sodium hydroxide s o l u t i o n (small amounts of benzene and e t h y l a c e t a t e were added to break up e m u l s i o n s ) , and then with four 50 ml. p o r t i o n s of s a t u r a t e d sodium c h l o r i d e s o l u t i o n . The s o l u t i o n was d r i e d , and the s o l v e n t removed under reduced p r e s s u r e to y i e l d 16.2 g. crude product. In o r d e r to remove the s m a l l amount of the anhydride 140, a l l of the crude product was d i s s o l v e d i n 200 ml. 95% e t h a n o l , r e f l u x e d f o r 12 hours, and the s o l v e n t removed under reduced p r e s s u r e . The r e s u l t i n g o i l was taken up i n ether and washed with two 50 ml. p o r t i o n s of 5% sodium hydroxide s o l u t i o n , f o l l o w e d by t h r e e 50 ml. p o r t i o n s of s a t u r a t e d sodium c h l o r i d e s o l u t i o n . A f t e r d r y i n g , the s o l v e n t was removed under reduced p r e s s u r e . The o i l was p u r i f i e d by column chromatography (150 g. s i l i c a g e l , chloroform) to y i e l d 6.8 g. product. T h i s product was then d i s t i l l e d on a Kugelrohr apparatus. A f t e r a very s m a l l f o r e r u n (38°-55°/ .05 mm.), the main f r a c t i o n (134°-144°/.05 mm.) y i e l d e d 4.75 g. (24%) of the d e s i r e d t e t r a l o n e 12 8, a t h i c k o i l . IR (CC1 4): 1735 ( e s t e r ) , 1693 (aromatic ketone). NMR: 1.2 ( t , J = 7, 3 H), 2.8 - 3.4 (m, 5 H), 3.9 (s, 3 H)., 4.2 (q, J = 7, 2 H) , 7.0 - 7.8 (m, 3 H) . 27 UV ( c a l c u l a t e d , 256 nm.): 207 ( c o n c e n t r a t i o n depen-d e n t ) , 223 (18,000), 255 (7,700), 313 (2,700). - 98 -Mass Spectrum; c a l c u l a t e d f o r C,.H,r0A: 248.1048 m/e. 14 l o 4 Found: 248.1035 m/e. Low r e s o l u t i o n : 248 (12), 176 (12), 175 (100), 174 (22), 160 (18), 147 (19), 131 (16), 115 (20), 103 (18), 91 (21) , 77 (22) . A n a l y s i s c a l c u l a t e d , f o r C^H^O^: C, 67.73; H, 6.50. Found: C, 68.00; H, 6.56. 2 , 2 - D i m e t h y l - 5 - m e t h o x y - l - t e t r a l o n e - 3 - c a r b o x y l i c a c i d e t h y l  e s t e r (129) In a f l a s k equipped w i t h a serum cap and magnetic s t i r r e r , and p r e v i o u s l y f l u s h e d w i t h n i t r o g e n , 3.66 g. (32.6 mmoles) of potassium t - b u t o x i d e was suspended i n 20 ml. of d r y benzene and c o p i e d t o 10°. To t h i s suspension was added a s o l u t i o n of 4.05 g. (16.3 mmoles) of the t e t r a l o n e 128 i n 100 ml. of d r y benzene. The dark brown s o l u t i o n was s t i r r e d f o r 5 minutes, a f t e r which 10 ml. (160 mmoles) of methyl iod.ide was added, and the s t i r r i n g was continued a t room temperature f o r 24 hours, d u r i n g which a p r e c i p i t a t e of potassium i o d i d e appeared. The r e a c t i o n s o l u t i o n was washed wi t h 2 0 ml. of tap water, f o l l o w e d by t h r e e 50 ml. p o r t i o n s of s a t u r a t e d sodium c h l o r i d e s o l u t i o n . The benzene l a y e r was d r i e d , f i l t e r e d , and the s o l v e n t removed under r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t was p u r i f i e d b y c o l u m n c h r o m a t o g r a p h y (150 g . s i l i c a g e l , c h l o r o f o r m ) . A t o t a l o f 3 . 2 g . (7 2% y i e l d ) o f a t a n c o l o u r e d o i l was o b t a i n e d . T h i s p r o d u c t was s a t i s f a c t o r y f o r f u r t h e r s y n t h e t i c w o r k , t h e s m a l l a m o u n t o f t r i m e t h y l a t e d p r o d u c t 152 ( 0 . 2 4 g . , 5% y i e l d ) b e i n g s e p a r a t e d i n the. n e x t s t e p . A n a n a l y t i c a l s a m p l e o f 1 2 9 was p r e p a r e d b y p r e p a r a t i v e g a s c h r o m a t o g r a p h y (10% c a r b o w a x o v e r c h r o m o s o r b W s u p p o r t , 2 0 0 ° , 60 m l / m i n u t e f l o w r a t e , 1 7 . 5 m i n u t e s r e t e n t i o n ) . i I R : 1 7 2 0 ( e s t e r ) , 1 6 8 5 ( k e t o n e ) , 1 3 8 5 a n d 1 3 7 0 (gem-d i m e t h y l ) . NMR: 1 . 2 0 ( t , J = 7 , 3 H ) , 1 2 1 ( s , 3 H ) , 1 . 2 2 ( s , 3 H ) , 2 . 8 - 3 . 2 (m, 3 H ) , 3 . 8 8 ( s , 3 H ) , 4 . 1 ( q , 3=1,2 H) , 6 . 9 - 7 . 7 (m, 3 H ) . U V : 2 1 0 ( 3 2 , 7 0 0 ) , 2 5 5 ( 1 0 , 7 0 0 ) , 310 ( 3 , 5 0 0 ) . M a s s S p e c t r u m ; c a l c u l a t e d f o r C ^ g ^ g O ^ : 2 7 6 . 1 3 6 1 m/e F o u n d : 2 7 6 . 1 4 2 0 m / e . Low R e s o l t u i o n : 276 ( 3 3 ) , 2 0 3 ( 7 0 ) , 2 0 2 ( 4 5 ) , 1 8 9 ( 3 7 ) , 1 7 5 ( 3 2 ) , 1 6 1 ( 1 9 ) , 148 ( 3 4 ) , 1 2 0 ( 5 3 ) , 91 ( 4 3 ) . A n a l y s i s c a l c u l a t e d f o r c i 6 H 2 o ° 4 : C ' 6 9 - 5 4 ' H ' 7 - 2 9 . F o u n d : C , 6 9 . 2 6 ; H , 7 . 3 4 . Attempted Formation of the Ethylene Glycol Ketal of the Tetralone 129 A solution of 0.070 g. of the tetralone 129, 0.200 g. ethylene g l y c o l , and a c a t a l y t i c amount of p-toluenesulphonic acid i n 4 0 ml. benzene was refluxed with a Dean-Stark condenser and drying tube for 24 hours. The solution v/as washed with sodiiim bicarbonate solution and three 50 ml. portions of saturated sodium chloride solution, dried, and the solvent removed under reduced pressure. The crude product was found to be i d e n t i c a l to s t a r t i n g material by IR, NMR, and a n a l y t i c a l TLC. Attempted Formation of the 2,2-Dimethyl-l,3-propanediol ketal  of the Tetralone 129 F i r s t method; a solution of 0.144 g. of the tetralone 129, 0.600 g. 2,2-dimethyl-l,3-propanediol, and a c a t a l y t i c amount of benzoic acid i n 8 0 ml. benzene was refluxed with a Dean-Stark condenser and drying tube for 3 days. The reaction mixture was washed with sodium bicarbonate solution and f i n a l l y with saturated sodium chloride solution. The organic layer was dried and the solvent removed under reduced pressure. The r e s u l t i n g product was found to be i d e n t i c a l to s t a r t i n g material by both IR and TLC. Second method; the r e a c t i o n was c a r r i e d out as above, except t o l u e n e was s u b s t i t u t e d f o r benzene, and p - t o l u e n e -s u l p h o n i c a c i d f o r benzoic a c i d . A f t e r 24 hours r e f l u x , t h e r e a c t i o n was worked up as d e s c r i b e d above and the product a g a i n found t o be s t a r t i n g m a t e r i a l . 2, 2-Dimethyl-5-methoxy-l-tetralone-3--carboxylic a c i d (153) To 1.95 g. (7.05 mmoles) of the d i m e t h y l a t e d e s t e r 129 i n 30 ml. dioxane was added 30 ml. of 10% sodium' hydroxide s o l u t i o n , and the r e a c t i o n mixture was s t i r r e d f o r 18 hours at r e f l u x . The c o o l e d s o l u t i o n was taken up i n 100 ml. e t h e r , and washed w i t h t h r e e 5 0 ml. p o r t i o n s of water. The combined aqueous l a y e r s were washed again w i t h e t h e r , and the ether e x t r a c t s combined. Concentrated h y d r o c h l o r i c a c i d was added t o the aqueous l a y e r u n t i l i t was a c i d i c , and the s o l u t i o n was e x t r a c t e d twice with e t h y l a c e t a t e . The combined e t h y l a c e t a t e l a y e r s were washed wi t h two 20 ml. p o r t i o n s of water, d r i e d , and the s o l v e n t removed under reduced pressure to y i e l d 1.48 g. (85%) of white c r y s t a l l i n e product. The pro-duct was of s a t i s f a c t o r y p u r i t y f o r f u r t h e r experimental work. MP: 156 - 157°. IR: 3550 - 2400 ( a c i d ) , 1710 ( a c i d ) , 1690 (ketone). - 102 -NMR: 1-4 (s, 6 H), 2.8 - 3.4. (m, 3 H), 3.8 (s, 3 H), 6.8 - 7.3 (m, 3 H), 11.2 (s, 1 H) . UV: 219, 254, 308. Mass Spectrum; c a l c u l a t e d f o r ci4 H2.6°4 : 248.1049 m/e. Found: 248.1041 m/e. Low r e s o l u t i o n : 249 (15), 248 (100), 234 (13), 233 (15), 203 (57), 202 (21), 201 (10), 189 (39), 188 (14), 187 (12), 175 (14), 174 (23), 161 (20), 149 (11), 148 (72), 120 (66), 105 (26), 90 (27). The ether s o l u t i o n c o n t a i n i n g base i n s o l u b l e s p e c i e s from the above r e a c t i o n was d r i e d and the s o l v e n t removed under reduced p r e s s u r e t o y i e l d 0.14 g. (7% y i e l d ) of 2 , 2 , 3 - t r i m e t h y l - 5 - m e t h o x y - l - t e t r a l o n e - 3 - c a r b o x y l i c a c i d e t h y l e s t e r (152), a tan c o l o u r e d o i l . IR: 1720 ( e s t e r ) , 1690 (ketone), 1390 and 1375 (gem-dim e t h y l group). NMR: 108 ( t , J = 7, 3 H), 1.13 (s, 3 H), 125 (s, 3 H), 1.33 (s, 3 H), 3.1 (AB q u a r t e t , J = 19, .6 = 29, 2 H), 3.8 (s, 3 H), 4.0 (q, J = 7, 2 H), 6.8 - 7.7 (m, 3 H). Mass Spectrum; c a l c u l a t e d f o r C^H^O^: 290.1518 m/e. Found: 290.1513 m/e. Low r e s o l u t i o n : 290 (42), 217 (100), 202 (22), 175 (32), 174 (27), 148 (11), 133 (15), 120 (19), 91 (32). - 103 -3-Di a z o a c e t y l - 2 , 2 - d i m e t h y l - 5 - m e t h o x y - l - t e t r a l o n e (155) To 1.13 g. (4.6 mmoles) of the t e t r a l o n e a c i d 153 i n 15 ml. benzene was added 7.0 ml. (8.3 mmoles) of o x a l y l c h l o r i d e , and the y e l l o w s o l u t i o n was s t i r r e d f o r 18 hours. The s o l v e n t was removed under reduced p r e s s u r e , and an IR of the crude a c i d c h l o r i d e was taken: IR (CH 2C1 2); 1785 ( a c i d c h l o r i d e ) , 1690 (ketone). The a c i d c h l o r i d e was d i s s o l v e d i n 30 ml. of d r y e t h e r , and added over 5 minutes t o 100 ml. o f f r e s h l y prepared 0.1 M s o l u t i o n (10 mmoles) of diazomethane i n ether a t 0°. The b r i g h t y e l l o w s o l u t i o n was s t i r r e d f o r 24 hours, d u r i n g which a s m a l l amount o f polymethylene p r e c i p i t a t e appeared. The s o l v e n t was removed under reduced p r e s s u r e , and the crude product was p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l ; c h l o r o -form: e t h y l a c e t a t e - 9: 1). The band at R f 0.4 was e x t r a c t e d w i t h e t h y l a c e t a t e , and the s o l v e n t removed to y i e l d 0.7 6 g. (62%) of y e l l o w c r y s t a l l i n e compound 155. MP: 104 - 106°. IR: 2120 (diazoketone), 1690 (ketone), 1645 (diazoketone). NMR: 1.25 (s, 6 H) , 2.7 - 3.4 (m, 3 H) , 3.8 (s, 3 Fl) , 5.3 (s, 1 H), 6.8 - 7.7 (m, 3 H). UV (dioxane): 260, 309. - 104 Mass Spectrum; c a l c u l a t e d f o r C ^ H ^ O ^ (parent l e s s N 2 ^ : 244.1099 m/e. Found: 244.1100 m/e. Low r e s o l u t i o n : 244 (8), 204 (8), 203 (41), 202 (21), 201 (5), 189 (5), 187 (7), 175 (11), 174 (7), 161 (7), 148 (9), 146 (5), 120 (8), 115 (8). 2,2-Dimethyl-5-methoxy-l-tetralone-3-acetic a c i d methyl  e s t e r (158) To 0.72 g. (2.6 mmoles) of the diazoketone 155 i n 20 ml. a b s o l u t e methanol was added 1.0 g. (4.3 mmoles) of s i l v e r o x i d e , and the s o l u t i o n was r e f l u x e d f o r 1 hour. An a d d i t i o n a l 1.0 g. s i l v e r oxide was added t o the s i l v e r e d f l a s k , and the s o l u t i o n was r e f l u x e d f o r a f u r t h e r hour. The s o l u t i o n was then v a c u u m - f i l t e r e d through a s i n t e r e d g l a s s f u n n e l , and the s o l v e n t removed under reduced p r e s s u r e , y i e l d i n g 0.633 g. (95%) of white c r y s t a l l i n e compound 158, of s u f f i c i e n t p u r i t y f o r f u r t h e r use. An a n a l y t i c a l sample was sublimed a t 85/0.05 mm. MP: 94 - 95°. IR; 1735 ( e s t e r ) , 1690 (ketone). - 105 -NMR: 1.1 (s, 3 H), 1.3 (s, 3 H), 2.1 - 3.1 (m, 3 H), 3.70 (s, 3 H), 3.81 (s, 3 H), 6.8 - 7.7 (ra, 3 H). UV: 222 (18,700), 254 (6,800), 312 (2,200). Mass Spectrum; c a l c u l a t e d f o r c ^ g H 2 0 ° 4 : 276.1361 m/e. Found: 276.1378 m/e. Low r e s o l u t i o n : 277 (15), 276 (75), 261 (6), 258 (5), 245 (6), 233 (26), 229 (7), 217 (7), 216. (8), 204 (14), 203 (100), 202 (66), 201 (20), 188 (11), 187 (22), 174 (19), 159 (10), 151 (13), 148 (25), 120 (32). A n a l y s i s c a l c u l a t e d f o r c i g H 2 o ° 4 : C ' 69.55; H, 7.30. Found: C,69.13; H,7.30. 2,2-Dimethyl-5-methoxy-l-tetralone-3-acetic a c i d (159) To a s o l u t i o n o f 2.1 g. (13 mmoles) of sodium t h i o s u l p h a t e , 12 g. sodium carbonate, and a suspension of 1.5 g. (6.5 mmoles) of s i l v e r oxide i n 150 ml. water was added 0.70 g. (2.6 mmoles) of the diazoketone 155 i n 15 ml. dioxane. The r e a c t i o n mixture was r e f l u x e d f o r 70 minutes. A f t e r c o o l i n g , i t was e x t r a c t e d w i t h 50 ml. of a 1:1 benzene:ether.mixture to remove base i n s o l u b l e p r o d u c t s . The aqueous s o l u t i o n was then a c i d i f i e d w i t h 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 e x t r a c t e d with e t h y l a c e t a t e . The o r g a n i c l a y e r was washed wit h two 50 ml. p o r t i o n s o f co n c e n t r a t e d sodium c h l o r i d e - 106 -s o l u t i o n , d r i e d , and the s o l v e n t removed under reduced p r e s s u r e to y i e l d 0.48 g. (70% y i e l d ) o f the d e s i r e d a c i d , a white c r y s t a l l i n e s o l i d . An a n a l y t i c a l sample was sublimed a t 150°/0.05 mm. MP: 156 - 157°. IR: 3500 - 2400 ( a c i d ) , 1700 ( a c i d ) , 1685 (ketone). NMR (deuteroacetone): 1.0 (s, 3 H), 1.3 (s, 3 H), 2.1 - 3.0 (HI, 5 H) , 3.8 (s, 3 H) , 4.5 (br. s, 1 H) , 7.1 - 7.6 (m, 3 H). UV: 223 (18,000), 255 (6,500), 313 (2,000). -Mass Spectrum; c a l c u l a t e d f o r C, CH, o0.: 262.1204 m/e. 1_) 1 o 4 Found: 262.1170 m/e. Low r e s o l u t i o n : 263 (22), 262 (100), 244 (6), 219 (43), 203 (90), 202 (67), 187 (16), 174 (8), 159 (11), 148 (18), 120 (26). A n a l y s i s c a l c u l a t e d f o r c i 5 H 1 g ° 4 : c » 68.69; H, 6.92. Found: C, 68.40; H, 6.91. P y r i d i n i u m H y d r o c h l o r i d e A s o l u t i o n of 10 g. of p y r i d i n e i n 300 ml. of d r y e t h e r was p l a c e d i n a f l a s k equipped with a d r y i n g tube and an i n l e t - 107 -tube f o r hydrogen c h l o r i d e gas r e a c h i n g t o near the bottom. Under an atmosphere of n i t r o g e n , hydrogen c h l o r i d e gas was bubbled i n t o the c o o l e d (ice-bath) w e l l - s t i r r e d s o l u t i o n u n t i l no f u r t h e r white p r e c i p i t a t e appeared. The h i g h l y h y g r o s c o p i c p y r i d i n i u m h y d r o c h l o r i d e was f i l t e r e d u s i n g p o s i t i v e n i t r o g e n p r e s s u r e , washed w i t h t h r e e 10 ml. p o r t i o n s of dry e t h e r , t r a n s f e r r e d t o a l a r g e round bottom f l a s k i n a glove bag, and the l a s t t r a c e s o f ether were removed under vacuum. The product was s t o r e d i n a d e s s i c a t o r u n t i l used. 2 , 2 - D i m e t h y l - 5 - h y d r o x y - l - t e t r a l o n e - 3 - a c e t i c a c i d (161) In a 5 ml. round bottom f l a s k was p l a c e d 0.429 g. (1.55 mmoles) o f t h e e s t e r 158. The f l a s k was t h e n f i l l e d w i t h a t o t a l o f 4.1 g. of p y r i d i n i u m h y d r o c h l o r i d e w h i l e under n i t r o g e n , and a serum cap f i t t e d and s e c u r e l y wired on. The f l a s k was then plunged i n t o an o i l bath a t 215° f o r 3 hours. During the i n i t i a l minutes of h e a t i n g , the p r e s s u r e i n s i d e the f l a s k was r e l e a s e d twice w i t h a hypo-dermic s y r i n g e . The brown r e a c t i o n mixture was then allowed to c o o l u n t i l i t c r y s t a l l i z e d , and the r e s u l t i n g s o l i d d i s s o l v e d i n water. The f l a s k was washed out w i t h e t h e r , w h i l e the aqueous s o l u t i o n was e x t r a c t e d w i t h e t h e r f o l l o w e d by e t h y l a c e t a t e . The combined o r g a n i c l a y e r s were then washed w i t h t h r e e 20 ml. p o r t i o n s of s a t u r a t e d sodium c h l o r i d e - 108 -solution, dried, and the solvent removed under reduced pressure to y i e l d 0.330 g. (86% yield) of white c r y s t a l l i n e product, of s a t i s f a c t o r y purity for further synthetic work. An a n a l y t i c a l sample was r e c r y s t a l l i z e d from nitromethane. MP: 175.5 - 177°. IR (nujol mull): 3415 (phenol), 3200 - 2400 (acid), 1710 (acid), 1670 (ketone). UV: 221 (15,000), 256 (6,700), 315 (2,300); (after base addition) 240 (16,000), 270 (3,800), 356 (1,800). Mass Spectrum: 248 (49), 205 (33), 189 (58), 188 (49), 187 (22), 173 (13), 160 (12), 159 (13), 145 (22), 134 (97), 131 (13), 155 (24), 106 (100). Analysis calculated for C. .H,' O. : C, 67.72; H, 6.49. 14 i o 4 Found: C, 67.57; H, 6.40. 2, 2-Dimethyl-5-acetoxy-l-tetralone-3--acetic acid (162) To a solution of 0.068 g. (0.27 mmoles) of the phenol acid 161 i n 2 ml. absolute ethyl acetate was added 7 ml. acetylating reagent (9.6 ml. acetic anhydride and 0.1 ml. 38 perchloric acid i n 90 ml. dry ethyl acetate ), and the brown solution s t i r r e d for 10 minutes. The reaction mixture was then washed wit h t h r e e 10 ml. p o r t i o n s o f s a t u r a t e d sodium c h l o r i d e s o l u t i o n and the e t h y l a c e t a t e removed under reduced p r e s s u r e . To the r e s i d u e thus o b t a i n e d 10 ml. of water was added, and f l a s k was equipped w i t h a r e f l u x con-denser and heated on a steam bath f o r 20 minutes. The o r g a n i c m a t e r i a l was e x t r a c t e d i n t o 2 0 ml. e t h e r , and the aqueous l a y e r washed wit h 20 ml. e t h y l a c e t a t e . The com-bined o r g a n i c l a y e r s were washed wit h two 2 0 ml. p o r t i o n s of s a t u r a t e d sodium c h l o r i d e s o l u t i o n , d r i e d , and the s o l v e n t removed under reduced p r e s s u r e . The crude product was pur . f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l ; e t h e r : petroleum e t h e r : a c e t i c a c i d - 100: 50: 1). The band wi t h R f 0.2 -0.3 was e x t r a c t e d w i t h e t h e r , and the s o l v e n t removed to y i e l d 0.075 g. (97% y i e l d ) of the white c r y s t a l l i n e product. An a n a l y t i c a l sample was sublimed a t 14 0°/0.5 mm. MP: 132 - 134°. IR: 3550 - 2450 ( a c i d ) , 1760 ( a r y l a c e t a t e ) , 1705 ( a c i d ) , 1685 (ketone). NMR: 1.1 (s, 3 H), 1.3 (s, 3 H), 2.1 - 3.2 (m, 8 H), 2.33 (s, 3 H), 7.2 - 8.2 (m, 3 H), 10.65 (s, 1 H). UV: 246 (10,000), 294 (1,900). Mass Spectrum: 290 (94), 248 (100), 233 (30), 231 (40), 225 (54), 189 (78), 134 (76), 106 (34), 77 (20). - 110 -A n a l y s i s c a l c u l a t e d f o r C 1 6 H 1 8 ° 5 : C, 66.19; H, 6.24. Found: C, 65.98; H, 6.25. 2 , 2 - D i m e t h y l - 3 - e t h y l ( 2 - h y d r o x y ) - 5 - a c e t o x y - l - t e t r a l o n e (163) A s o l u t i o n of 0.500 g. (1.72 mmoles) of the acetoxy a c i d 162 i n dry t e t r a h y d r o f u r a n was c o o l e d t o 15°, 3 ml. of 1.6 M diborane (4.2 mmoles) i n t e t r a h y d r o f u r a n was added, and the mixture was s t i r r e d a t 15° f o r 2 hours. The excess diborane was then decomposed w i t h e v o l u t i o n of gas, by dropwise a d d i t i o n of 1 M h y d r o c h l o r i c a c i d , and the a d d i t i o n of 3 0 ml. o f water. The homogeneous s o l u t i o n was e x t r a c t e d w i t h two 30 ml. p o r t i o n s of e t h e r , and the combined ether l a y e r s were washed wit h f i v e 20 ml. p o r t i o n s o f s a t u r a t e d sodium c h l o r i d e s o l u t i o n . The ether l a y e r was then d r i e d , and the s o l v e n t removed under reduced p r e s s u r e . The o i l y r e s i d u e was p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l ; e t h e r : petroleum e t h e r : a c e t i c a c i d - 100: 50: 1), the band a t R^ 0.6 being e x t r a c t e d with ether to y i e l d 0.454 g. (91% y i e l d ) of the d e s i r e d product, a t h i c k o i l . An e q u i v a l e n t amount of the d i m e t h y l s u l p h i d e complex of diborane can be s u b s t i t u t e d f o r the t e t r a h y d r o f u r a n s o l u t i o n . The y i e l d of t h i s a l t e r e d procedure has not been maximized. - I l l -IR: 3300 ( a l c o h o l ) , 1765 ( a c e t a t e ) , 1685 (ketone). NMR: 1.1 (s, 3 H), 1.3 (s, 3 H), 1.4 - 1.6 (m , 3 H), 2.3 (s, 3 H), 2.7 (d, J = 8, 1 H), 2.9 (d, J = 5, 1 H), 3.7 ( t , J = 6, 2 H), 7.2 - 8.0 (m, 3 H). UV: 207 (16,500), 244 (9,700), 290 (1,500). Mass Spectrum: 276 (50), 234 (34), 219 (16), 216 (15), 209 (28), 192 (32), 191 (20), 190 (51), 189 (34), 173 (16), 134 (100), 106 (28), 85 (58), 83 (98), 78 (70), 70 (56). A n a l y s i s c a l c u l a t e d f o r c 1 6 H 2 o ° 4 : C ' 6 9 - 5 5'* H ' 7.30. Found: C, 6 9.27; H, 7.45. 2,2-Dimethyl-3-ethyl(2-methanesulphonate)-5-acetoxy-l- t e t r a l o n e (169) A s o l u t i o n of 0.389 g. (1.41 mmoles) of the a l c o h o l 163 i n 0.5 ml. p y r i d i n e was c o o l e d to 0°, and 0.5 ml. methane-sul p h o n y l c h l o r i d e was added i n one l o t . The s o l u t i o n was s t i r r e d f o r 5 minutes at 0°, then s t o r e d at 0° f o r 14 hours. The r e a c t i o n mixture was then d i s s o l v e d i n 50 ml. e t h e r , and washed wi t h two 20 ml. p o r t i o n s of 1 M h y d r o c h l o r i c a c i d f o l l o w e d by fo u r 20 ml. p o r t i o n s o f s a t u r a t e d sodium c h l o r i d e s o l u t i o n . The ether l a y e r was d r i e d , the s o l v e n t removed, - 112 -and the crude product was p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l ; c h l o r o f o r m : e t h y l a c e t a t e - 2: 1). The band a t 0.5 was e x t r a c t e d with ether and y i e l d e d 0.428 g. (90% y i e l d ) of the d e s i r e d product, a t h i c k o i l . IR: 1760 ( a c e t a t e ) , 1685 (ketone), 1340 and 1170 (sulphonate). NMR: 1.1 (s, 3 H), 1.3 (s, 3 H), 1.9 - 2.3 (m, 2 H), 2.4 (s, 3 H), 2.7 - 3.2 (m, 2 H), 3.0 (s, 2 H), 4.3 (dd, J = 7 and J = 5, 2 H), 7.25 - 8.0 (m, 3 H). UV: 210, 239, 290. Mass Spectrum; c a l c u l a t e d f o r c i 7 H 2 2 ° 6 S : 354.1136 m/e. Found: 354.1129 m/e. Low r e s o l u t i o n s : 354 (5), 312 (29), 216 (31), 201 (21), 189 (18), 188 (34), 159 (19), 134 (100), 113 (29). 2 , 2 - D i m e t h y l - 3 - e t h y l ( 2 - t o l u e n e s u l p h o n a t e ) - 5 - a c e t o x y - l - t e t r a l o n e  (164) The t o s y l a t e 164 was prepared i n a s i m i l a r way t o the mesylate 169. 0.045 g. of the a l c o h o l 163 w i t h 0.047 g. t o l u e n e s u l p h o n y l c h l o r i d e y i e l d e d 0.061 g. pure t o s y l a t e 164 (88% y i e l d ) a f t e r p u r i f i c a t i o n by p r e p a r a t i v e TLC ( s i l i c a g e l ; c h l o r o f o r m : e t h y l a c e t a t e - 2: 1). - 113 -IR: 1765 ( a c e t a t e ) , 1685 (ketone), 1370 and 1170 (sulphonate). NMR: 1.0 (s, 3 H), 1.2 (s, 3 H), 1.7 - 2.1 (m, 2 H), 2.40 (s, 3 II) , 2.45 (s, 3 H) , 2.5 - 2.9 (m, 2 H) , 4.1 (dd, J = 7 and J = 5, 2 H) , 7.2 - 8.0 (m, 7 H). UV: 220, 245, 290 2,2-Dimethyl-3-ethyl(2-methanesulphonate)-5-hydroxy-l- t e t r a l o n e (170) To a s o l u t i o n o f 0.428 g. (1.2 mmole) of the acetoxy mesylate 169 i n 20 ml. methanol at 0° was added 5 ml. b u f f e r (0.2 g. sodium carbonate, 1.0 g. sodium b i c a r b o n a t e , and 4 ml. water). The r e s u l t i n g suspension was s t i r r e d f o r 90 minutes, then d i l u t e d w i t h 150 ml. o f water and e x t r a c t e d w i t h 4 0 ml. of e t h e r . The aqueous l a y e r was e x t r a c t e d w i t h a f u r t h e r 40 ml. of et h e r , and the separate e t h e r l a y e r s were each washed wi t h 20 ml. water and 20 ml. s a t u r a t e d sodium c h l o r i d e s o l u t i o n , combined, and dr i e d . 1 The s o l v e n t was removed under reduced p r e s s u r e , and the crude product was p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l ; c h l o r o f o r m : e t h y l a c e t a t e - 2: 1) t o y i e l d 0.343 g. (92% y i e l d ) o f a c o l o u r l e s s o i l . - 1 1 4 -IR; 3 6 0 0 and 3 4 0 0 ( h y d r o x y l ) , 1 6 9 0 (ketone), 1 3 4 0 and 1 1 7 0 (sulphonate). NMR: 1 . 1 (s, 3 H ) , 1 . 3 (s, 3 H ) , 1 . 8 - 2 . 9 (m, 3 H ) , 3 . 0 (s, 3 H ) , 4 . 4 (ra, 2 H ) , 4 . 9 (br. s, 1 H ) , 7 . 0 -7 . 8 (m, 3 H ) . UV: 2 2 0 , 2 5 7 , 3 1 5 ; a f t e r base a d d i t i o n , 2 4 1 , 2 7 0 ( s h o u l d e r ) , 3 5 4 . Mass Spectrum; c a l c u l a t e d f o r C ^ H ^ Q O J - S : 3 1 2 . 1 0 3 0 m/e. Found: 3 1 2 . 1 0 6 0 m/e. Low r e s o l u t i o n : 3 1 2 ( 3 0 ) , 2 1 6 ( 1 4 ) , 2 0 2 ( 2 0 ) , 1 8 8 ( 3 8 ) , 1 7 3 ( 3 0 ) , 1 3 4 ( 1 0 0 ) , 1 0 6 ( 3 0 ) , 8 4 ( 2 2 ) , 7 8 ( 6 8 ) , 7 7 ( 2 0 ) , 7 0 ( 4 4 ) , 5 5 ( 3 4 ) . 2 , 2 - D i m e t h y l - 3 - e t h y l ( 2 - t o l u e n e s u l p h o n a t e ) - 5 - h y d r o x y - l - t e t r a l o n e ( 1 2 4 ) The phenol t o s y l a t e 1 2 4 was prepared and p u r i f i e d i n a manner s i m i l a r t o the phenol mesylate 1 7 0 . Thus 1 8 mg. o f the a c e t a t e 1 6 4 gave 1 3 mg. o f compound 1 2 4 ( 8 0 % y i e l d ) , a c o l o u r l e s s o i l . IR: 3600 and 3400 ( h y d r o x y l ) , 1690 (ketone), 1360 and 1170 (sulphonate) . - 115 -NMR: 1.0 (s, 3 H), 1.2 (s, 3 H), 1.6 - 3.0 (m, 3 H), 2.4 (s, 3 H), 4.1 - 4.4 (m, 2 H), 7.1 - 7.9 (m, 7 H). UV: 222, 257, 315; a f t e r base a d d i t i o n , 226, 240, 271, 353. 388.1343 m/e. (63), 201 (31), Mass Spectrum; c a l c u l a t e d f o r ^ -^^^O^S: Found: 388.1335 m/e. Low r e s o l u t i o n : 388 (37), 216 (32), 202 188 (85), 173 (37), 146 (35), 134 (81). 2 , 2 - D i m e t h y l - 3 - e t h y l ( 2 - t - b u t o x y ) - 5 - h y d r o x y - l - t e t r a l o n e (171) A t o t a l o f 320 mg. (0.0082 gm-atoms) of potassium was d i s s o l v e d i n 10 ml. o f dry t - b u t a n o l . To the s t i r r e d s o l u t i o n of potassium t_-butoxide was addecl 12 mg. (0. 038 mmole) of the phenol mesylate 170 d i s s o l v e d i n 0.5 ml. dry benzene. The l i g h t green r e a c t i o n mixture was s t i r r e d f o r 14 hours, at which time the base was n e u t r a l i z e d w i t h 1 M h y d r o c h l o r i c a c i d . The s o l u t i o n was e x t r a c t e d w i t h two 20 ml. p o r t i o n s of e t h e r , and the et h e r l a y e r was washed w i t h two 20 ml. p o r t i o n s o f s a t u r a t e d sodium c h l o r i d e s o l u t i o n , d r i e d , and the s o l v e n t removed under reduced p r e s s u r e . The r e s i d u e was p u r i f i e d on p r e p a r a t i v e TLC ( s i l i c a g e l ; c h l o r o f o r m : e t h y l a c e t a t e - 9: 1). The major product at R^ 0.3 was e x t r a c t e d w i t h e t h y l a c e t a t e t o y i e l d 8 mg. (70% y i e l d ) of compound 171, an o i l . IR: 3600 and 3400 ( h y d r o x y l ) , 1680 (ketone), 1590 ( a r y l ) , 1385 and 1360 ( t - b u t y l ) . Mass Spectrum: 290 (16), 274 (14), 234 (34), 219 (8), 217 (8), 201 (8), 191 (10), 189 (20), 145 (40), 129 (68), 100 (26), 71 (100). (2,2-Dimethyl-3-ethyl-5-oxy-l-tetralone)5,16';16,5'-dimer (173) A s o l u t i o n of 42 mg. (0.134 mmole) of the phenol mesylate 170 was d i s s o l v e d i n 5 ml. of d i m e t h y l sulphoxide and added by s y r i n g e to 6.6 mg. (0.165 mmole) sodium h y d r i d e suspension i n m i n e r a l o i l c o n t a i n e d i n a n i t r o g e n - f i l l e d serum cap equipped f l a s k . The s o l u t i o n was s t i r r e d f o r 75 hours, d u r i n g which the c o l o u r g r a d u a l l y darkened to red-brown. Then 10 ml. of water and 2 0 ml. of e t h e r were added to the r e a c t i o n mixture. The two l a y e r s were separated, the aqueous l a y e r e x t r a c t e d w i t h 10 ml. petroleum e t h e r , and the combined o r g a n i c l a y e r s washed w i t h f i v e 20 ml. p o r t i o n s o f water. The o r g a n i c l a y e r was then d r i e d and the s o l v e n t removed t o y i e l d a white c r y s t a l l i n e s o l i d . T h i s was p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l ; e t h e r : petroleum e t h e r : a c e t i c a c i d - 100: 50: 1) t o y i e l d 12 mg. (41% y i e l d ) of white c r y s t a l l i n e compound 173. - 117 -MP: 202 - 212°. IR: 1680 (aromatic ketone), 1595 (aro m a t i c ) . NMR ( d e s c r i b e d as monomer): 1.15 (d, J = 1.5, 3 H), 1.3 (s, 3 H), 1.8 - 2.1 (m, 3 H), 3.2 - 4.6 (m, 3 or 4 H) , 6.9 - 7.5 (m, 3 H) . UV ( a c e t o n i t r i l e ) : 254 (8,000), 313 (3,000). Mass Spectrum; c a l c u l a t e d f o r ^ g H ^ O ^ : 432. 2299 m/e. Found: 4 32.2263 m/e. Low r e s o l u t i o n : 432 (11), 368 (7), 340 (13), 284 (17), 201 (17), 173 (8), 167 (13), 151 (16). 2,2-Dimethyl-3-ethyl(2-methanesulphonate e s t e r ) - 1 , 2 , 3 , 4 - t e t r a - hydronaphthalene-1,5-diol (17 4) To a s o l u t i o n o f 22 mg. (0.070 mmole) of the p h e n o l i c mesylate 170 i n 5 ml. methanol was added 6.5 mg. (0.18 mmole) of sodium bor o h y d r i d e . The mixture was s t i r r e d a t 10° f o r 20 hours, a f t e r which 10 drops of 1 M h y d r o c h l o r i c a c i d were added. The s o l u t i o n was d i l u t e d w i t h 50 ml. water, and e x t r a c t e d t wice w i t h a 1:1 benzene:ether s o l v e n t mixture. The o r g a n i c e x t r a c t was washed w i t h two 10 ml. p o r t i o n s of s a t u r a t e d sodium c h l o r i d e s o l u t i o n , and the s o l v e n t removed under reduced p r e s s u r e t o g i v e 24 mg. of the crude product. - 118 -T h i s was p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l ; c h l o r o f o r m : e t h y l a c e t a t e - 2: 1) to g i v e 17 mg. o f compound 174 (77% y i e l d ) , an o i l . IR: 3640 and 3400 ( h y d r o x y l ) , 1590 ( a r y l ) , 1330 (mesylate). Base treatment of the reduced mesylate 174  Method A A t o t a l of 4 mg. (0.012 mmole) o f compound 174 was d i s s o l v e d i n 4 ml. o f a 6:1 t-butanol:dimethylformamide s o l v e n t mixture (the dimethylformamide was necessary t o ensure d i s s o l u t i o n o f the s t a r t i n g m a t e r i a l ) . Then 8 mg. (0.10 mmole.) of potassium t - b u t o x i d e were added, and the s o l u t i o n was r e f l u x e d f o r 18 hours. Then 10 drops o f 1 M h y d r o c h l o r i c a c i d were added, and the r e a c t i o n mixture was d i l u t e d w i t h 50 ml. water. T h i s s o l u t i o n was e x t r a c t e d w i t h two 20 ml. p o r t i o n s o f et h e r , and the combined o r g a n i c f r a c t i o n s washed w i t h t h r e e 2 0 ml. p o r t i o n s o f s a t u r a t e d sodium c h l o r i d e s o l u t i o n . The s o l u t i o n was d r i e d and the s o l v e n t was removed to g i v e the crude product, which s t i l l c o n t a i n e d the p h e n o l i c r i n g . IR: 3620 and 3350 ( h y d r o x y l ) , 1590 ( a r y l ) , 1080 ( e t h e r ) . - 119 -M e t h o d B A 2 m g . s a m p l e o f c o m p o u n d 174 was d i s s o l v e d i n 2 m l . d i m e t h y l f o r m a m i d e , a n d 1 m g . o f s o d i u m h y d r i d e (6 0% i n o i l s u s p e n s i o n ) was a d d e d . T h e s o l u t i o n w a s s t i r r e d f o r 18 h o u r s a t r o o m t e m p e r a t u r e , a n d w o r k e d u p a s d e t a i l e d i n M e t h o d A. T h e I R s p e c t r a o f t h e c r u d e p r o d u c t was a l m o s t s u p e r i m p o s i b l e o n t h a t o f t h e p r o d u c t o f M e t h o d A. 2,2 - D i m e t h y l - 5 - m e t h o x y - l , 2 , 3 , 4 - t e t r a h y d r o - l - n a p h t h o l - 3 - a c e t i c a c i d m e t h y l e s t e r (167) A t o t a l o f 15 mg. (0.40 mmole) o f s o d i u m b o r o h y d r i d e was a d d e d t o a s o l u t i o n o f 60 mg. (0.22 mmole) o f t h e k e t o n e 158 i n 6 m l . m e t h a n o l , a n d t h e r e a c t i o n m i x t u r e was s t i r r e d f o r 90 m i n u t e s . A few d r o p s o f 1 M h y d r o c h l o r i c a c i d was a d d e d , a f t e r w h i c h t h e s o l u t i o n was t a k e n up i n t o 40 m l , e t h e r . T h e o r g a n i c l a y e r was w a s h e d w i t h t w o 2 0 m l . p o r t i o n s o f w a t e r a n d t w o 2 0 m l . p o r t i o n s o f s a t u r a t e d s o d i u m c h l o r i d e s o l u t i o n , d r i e d , a n d t h e s o l v e n t r e m o v e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t was p u r i f i e d b y p r e p a r a t i v e T L C ( s i l i c a g e l ; c h l o r o f o r m : a c e t o n e - 20: 1 ) . T h e b a n d a t 0.4 was r e m o v e d a n d e x t r a c t e d w i t h e t h y l a c e t a t e t o g i v e 39 m g . (65% y i e l d ) o f c o m p o u n d 167 , a c o l o u r l e s s o i l . IR: 3600 a n d 3400 ( h y d r o x y l ) , 1725 ( e s t e r ) . - 120 -NMR: 0.7 (s, 3 H), 1.1 (s, 3 H), 1.2 - 1.5 (m, 1 H), 2.0 - 3.0 (m, 5 H) , 3.7 (s, 3 H), 3.8 (s, 3 H), 4.4 (s, 1 H), 6 . 6 - 7 . 2 (m, 3 H). UV: 214, 272, 279, 308. Mass Spectrum; c a l c u l a t e d f o r C, _H„„0.: 278.1518 m/e. 16 22 4 Found: 278.1518 m/e. Low r e s o l u t i o n : 278 (1), 260 (37), 246 (10), 201 (5), 187 (52), 186 (100), 185 (52), 172 (10), 159 (14), 150 (27) , 149 (14) , 91 (13) . 2,2-Dimethyl-5-methoxy-l,2,3,4-tetrahydro-l-naphthol-3- a c e t i c a c i d (179) A t o t a l o f 25 mg. (0.090 mmole) o f compond 167 was d i s s o l v e d i n 2 ml. methanol. Then 5 ml. of 10% sodium hydroxide s o l u t i o n was added, and the r e a c t i o n mixture was s t i r r e d f o r 7 hours. The aqueous l a y e r was washed w i t h e t h e r , a c i d i f i e d w i t h 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 e x t r a c t e d w i t h 20 ml. of e t h y l a c e t a t e . The o r g a n i c l a y e r was then washed w i t h two 2 0 ml. p o r t i o n s o f s a t u r a t e d sodium c h l o r i d e s o l u t i o n , d r i e d , and the s o l v e n t removed under reduced p r e s s u r e t o g i v e 22 mg. (93% y i e l d ) o f white c r y s t a l l i n e product. T h i s was used without f u r t h e r p u r i f i c a -t i o n . - 121 -MP: 167 - 169°. IR: 3600 - 2500 ( a c i d ) , 1705 ( a c i d ) . NMR: 0.7 (s, 3 H), 1.1 (s, 3 H), 1.2 (m, 1 H), 1.9 -3.0 (m, 5 H), 4.8 (s, 3 H), 4.1 (br. s, 2 H), 4.3 (s, 1 H), 6.5 - 7.2 (m, 3 H). Mass Spectrum; c a l c u l a t e d f o r C]_5 H20°4 : 264.1362 m/e. Found: 264.136 9 m/e. Low r e s o l u t i o n : 247 (12), 246 (83), 189 (9), 188 (7), 187 (34), 186 (20), 185 (12), 173 (15), 172 (19), 161 (11), 160 (16), 159 (100), 158 (22), 146 (14), 144 (21), 129 (11), 128 (12), 115 (13), 91 (10). 2,2-Dimethyl-l-hydroxy-5-methoxy-l,2,3,4-tetrahydronaphthalene- a c e t i c a c i d l a c t o n e (180) A s o l u t i o n o f 20 mg. (0.075 mmole) of the a c i d 179 and a c a t a l y t i c amount (about 2 mg.) of p - t o l u e n e s u l p h o n i c a c i d i n 10 ml. dry benzene was r e f l u x e d f o r 12 hours. The s o l u t i o n was washed w i t h a s a t u r a t e d s o l u t i o n o f sodium b i c a r b o n a t e , and f i n a l l y w i t h two 20 ml. p o r t i o n s of s a t u r a t e d sodium c h l o r i d e s o l u t i o n . A f t e r d r y i n g , the s o l v e n t was removed under reduced p r e s s u r e t o g i v e 9 mg. of compound 180 (50% y i e l d ) , an o i l . A c i d i f i c a t i o n and e x t r a c t i o n o f the b i c a r b o n a t e - 122 -solution yielded less than a nig. of residue. IR: 1720 (lactone). NMR: 1.0 (s, 3 H), 1.3 (s, 3 H), 2.1 (m, 2 H), 2.4 (br. s, 1 H), 2.8 (m, 2 H), 3.8 (s, 3 H), 4.6 (s, 1 H), 6.6 -7.1 (m, 3 H). UV: 220, 275, 283. Mass Spectrum; calculated for ci5 H-L3°3 : 246.1256 m/e. Found: 246.1260 m/e. • Low re s o l u t i o n : 247 (16), 246 (100), 187 (21), 173 (10), 161 (10), 160 (14), 159 (85), 158 (13), 146 (13), 144 (13). 3,3-Dimethyl-3-methoxy-l,2,3,4-tetrahydronaphthalene-2-acetic  acid (184) Method A: a f l a s k containing 28 mg. (0.10 mmole) of the ester 158, 280 mg. (8.3 mmole) hydrazine (95% i n water), and 82 mg. (0.8 mmole) hydrazine dihydrogen chloride i n 3 ml. diethylene g l y c o l was f i t t e d with a reflux condenser, and s t i r r e d at 130° i n an o i l bath. After 4 hours heating, 125 mg. (2.2 mmoles) of s o l i d potassium hydroxide was added to the reaction mixture, and the fl a s k was f i t t e d with a d i s t i l l a t i o n head and condenser. The o i l bath temperature was raised to 210° over 30 minutes and maintained there for 2 hours while the hydrazine was d i s t i l l e d o f f . After cooling, 20 ml. ether and 20 ml. water were added to the reaction f l a s k , and the organic layer was subsequently washed with three 20 ml. portions of water. The combined aqueous extracts were a c i d i f i e d with concentrated hydrochloric acid, and extracted with ethyl acetate. The solution was washed with two 20 ml. portions of saturated sodium chloride solution, and the solvent removed under reduced pressure to y i e l d 11 mg. of crude product. This product was p u r i f i e d by preparative TLC ( s i l i c a g e l; ether: petroleum ether: acetic acid- 66: 33: 1), the band at 0.5 being removed and extracted with ethyl acetate to y i e l d 4 mg. (16% yield) of white c r y s t a l l i n e compound 184• Method B: a t o t a l of 56 mg. (0.20 mmole) of the ester 158, 3 g. (85 mmoles) hydrazine, and 640 mg. (6.4 mmoles} of hydrazine dihydrogen chloride i n 4 ml. diethylene g l y c o l was treated i n a s i m i l a r fashion to the reaction described above. After the i n i t i a l heating, 800 mg. (14 mmoles) of s o l i d potassium hydroxide was added, and the temperature was raised to 220° for 3 hours. The reaction was then worked up as described above. After p u r i f i c a t i o n , a t o t a l of 11 mg. (22% yield) of white c r y s t a l s of compound 18 4 was i s o l a t e d . MP: 130 - 139°. IR: 3600 - 2400 (acid), 1700 ( a c i d ) . - 124 -UV: 223, 269, 277. Mass Spectrum; c a l c u l a t e d f o r c i 5 H 2 o ° 3 : 248.1412 m/e. Found: 248.1411 m/e. Low r e s o l u t i o n : 248 (34), 189 (14), 188 (86), 174 (14), 173 (100), 158 (10), 134 (21), 104 (11). 2 , 2 - D i m e t h y l - 5 - h y d r o x y - l - t e t r a l o n e - 3 - c a r b o x y l i c a c i d (187) To a 10 ml. f l a s k c o n t a i n i n g 92 mg. (0.32 mmole) o f the e s t e r 129 was added 2.7 g. of p y r i d i n e h y d r o c h l o r i d e . A serum cap was wired onto the f l a s k , and the f l a s k was heated to 2 0 0 ° f o r 15 minutes. A f t e r c o o l i n g , the r e s u l t -i n g s o l i d was d i s s o l v e d i n water, and the f l a s k was washed out with e t h y l a c e t a t e . The aqueous l a y e r was e x t r a c t e d w i t h e t h y l a c e t a t e , and the combined o r g a n i c l a y e r s were washed w i t h two 2 0 ml. p o r t i o n s of 1 M h y d r o c h l o r i c a c i d and two 20 ml. p o r t i o n s o f s a t u r a t e d sodium c h l o r i d e s o l u t i o n . The s o l v e n t was removed under reduced p r e s s u r e to y i e l d 90 mg. of crude product. T h i s was normally used without f u r t h e r p u r i f i c a t i o n . An a n a l y t i c a l sample was sublimed twice a t 1 7 5 ° / 0 . 4 mm. t o y i e l d a hy g r o s c o p i c white c r y s t a l l i n e s o l i d . MP: 197 - 1 9 8 ° . - 125 -IR ( n u j o l m u l l ) : 3350 ( h y d r o x y l ) , 3200 - 2400 ( a c i d , 1700 ( a c i d ) , 1675 (ketone). A n a l y s i s c a l c u l a t e d f o r c i 3 H i 4 ° 4 : C ' 66.66; H , 6.02. Found: C, 66.84; H , 6.11. 2 , 2 - D i m e t h y l - 5 - a c e t o x y - l - t e t r a l o n e - 3 - c a r b o x y l i c a c i d (188) 90 mg. (0.38 mmoles) o f crude compound 187 i n 10 ml. e t h y l a c e t a t e was t r e a t e d w i t h 5 ml. of a c e t y l a t i n g reagent, and the r e a c t i o n was c a r r i e d out u s i n g the same procedure as f o r compound 162. The 90 mg. of crude product (85% y i e l d ) , a t h i c k o i l which c r y s t a l l i z e d on s t a n d i n g , was normally used without f u r t h e r p u r i f i c a t i o n . A sample was p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l ; c h l o r o f o r m : e t h y l a c e t a t e : a c e t i c a c i d - 90: 10: 1) and the band a t R^ 0.4 removed. MP: 62 - 65°. IR: 3600 - 2400 ( a c i d ) , 1760 ( a c e t a t e ) , 1705 ( a c i d ) , • 1690 (ketone). NMR: 1.30 (s, 3 H ) , 1.33 (s, 3 H ) , 2.0 (d, J = 2, 1 H ) , 2,3 (s, 3 H ) , 3.0 (br. s, 2 H ) , 7.2 (m, 2 H ) , 7.9 (dd, J = 6 and J = 3, 1 H). , 10.3 (br. s, 1 H) . UV: 211 (13,500), 246 (8,900), 290 (1,400). - 126 -Mass Spectrum; c a l c u l a t e d f o r C^H^gO,.: 276.0998 m/e. Found: 276.0994 m/e. Low r e s o l u t i o n : 276 (25), 246 (50), 234 (60), 219 (12), 192 (10), 189 (32), 188 (21), 187 (13), 175 (11), 159 (44) , 134 (60). 5 - A c e t o x y - 3 - d i a z o a c e t y l - 2 , 3 - d i m e t h y i - l - t e t r a l o n e (157) To 90 mg. (0.34 mmole) crude compound 188 i n 5 ml. dry benzene was added 0.5 ml. o x a i y l c h l o r i d e , and the s o l u t i o n was s t i r r e d f o r 90 minutes. A f t e r removal o f the s o l v e n t under reduced p r e s s u r e , the crude a c i d c h l o r i d e (IR; 1770 ( a c i d c h l o r i d e and a c e t a t e ) , 1695 (ketone)) was d i s s o l v e d i n 25 ml. dry ether and added over 5 minutes to 25 ml. of 0.1 M diazomethane s o l u t i o n a t 0°. The b r i g h t y e l l o w s o l u t i o n was s t i r r e d a t room temperature f o r 18 hours, the s o l v e n t removed under reduced p r e s s u r e , and the crude diazoketone p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l ; c h l o r o f o r m : e t h y l a c e t a t e - 4: 1). The band a t R^ 0.5 was removed and e x t r a c t e d w i t h e t h y l a c e t a t e t o y i e l d 24 mg. (24% y i e l d from compound 129) of the diazoketone 157, a y e l l o w o i l . IR: 2140 (d i a z o k e t o n e ) , 1770 ( a c e t a t e ) , 1690 (ketone), 1640 ( d i a z o k e t o n e ) . NMR: 1.1 (s, 3 H) , 1.15 (s, 3 H), 2.3 (s, 3 H) , 3.0 (m, 3 H), 5.3 (s, 1 H), 7.1 (m, 2 H), 8.0 (dd, J = 3 and J = 6, 1 H). - 127 -5-Acetoxy-2,3-dimethyl-3-ethyl(2-bromo-l-oxo)-1-tetralone (189) To a c o o l e d (0°) s o l u t i o n o f 20 mg. (0.070 mmole) of the diazoketone 157 i n 5 ml. methylene c h l o r i d e s o l u t i o n was added 1 ml. of et h e r s a t u r a t e d w i t h hydrogen bromide gas. The s o l u t i o n was s t i r r e d f o r 5 minutes, and the s o l v e n t was removed under reduced p r e s s u r e . The crude product was p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l ; c h l o r o f o r m : e t h y l a c e t a t e - 4: 1), the band a t 0.5 being e x t r a c t e d with e t h y l a c e t a t e t o g i v e 3 mg. (15% y i e l d ) of the hy d r o l y s e d p h e n o l i c bromo ketone 190.. The band a t R^ 0.6 was s i m i l a r l y e x t r a c t e d t o g i v e 14 mg. (60% y i e l d ) of the d e s i r e d Product, a t h i c k o i l . IR: 1765 ( a c e t a t e ) , 1720 (bromoketone), 1695 ( a r y l k e tone). NMR." 1.20 (s, 3 H) , 1.25 (s, 3 H) ,. 2.3 (s, 3 H) , 3.0 (d, 2 H), 3.5 ( t , 1 H), 3.9 (s, 2 H), 7.2 - 8.1 (m, 3 H). UV: 209, 247, 290. Mass Spectrum; c a l c u l a t e d f o r C ^ H ^ O ^ B r : 352. 0310 m/e. Found: 352.0326 m/e. Low r e s o l u t i o n : 354 (2), 352 (2), 312 (7), 310 (7), 273 (8), 232.(8), 231 (44), 190 (13), 189 (100), 161 (15), 149 (10), 134 (26). - 128 -2, 2--Dimethyl-3-ethyl (2-bromo-l-oxo) - 5 - h y d r o x y - l - t e t r a l o n e (190) A s o l u t i o n o f 14 mg. (0.040 mmole) of compound 189 was h y d r o l y s e d i n a manner s i m i l a r to t h a t used t o prepare compound 170. A f t e r workup, 13 mg. (100% y i e l d ) o f crude compound 190, a t h i c k o i l , was i s o l a t e d . IR: 3600 and 3300 ( h y d r o x y l ) , 1720 (bromoketone), 1685 ( a r y l ketone). NMR: 1.18 (s, 3 H), 1.20 (s, 3 H), 3.1 (br. d, J = 6, 2 H), 3.5 (d. d, J = 5, J = 7, 1 H), 3.9 (s, 2 H), 6.8 -7.7 (m, 3 H). UV: 222, 257, 315; a f t e r base a d d i t i o n , 241, 270 ( s h o u l d e r ) , 371. Mass Spectrum; c a l c u l a t e d f o r C,,H, cO,Br: 310.0224 m/e. 14 l b 3 Found: 310.0214 m/e. Low r e s o l u t i o n : 312 (6), 310 (6), 284 (12), 256 (13), 248 (13), 231 (12), 189 (100), 161 (13), 147 (39), 134 (52), 105 (40). Attempted c y c l i z a t i o n o f the Bromide 190 Method A: To 3 mg. (0.01 mmole) of the bromide 190 i n 1 ml. of t - b u t a n o l was added 50 mg. of anhydrous potassium carbonate. The r e a c t i o n mixture was s t i r r e d a t room - 129 -t e m p e r a t u r e f o r 18 h o u r s . T h e s o l u t i o n was d i l u t e d w i t h 2 0 m l . e t h e r , a n d w a s h e d w i t h s i x 20 m l . p o r t i o n s o f s a t u r a t e d s o d i u m c h l o r i d e s o l u t i o n . T h e o r g a n i c l a y e r was d r i e d a n d t h e s o l v e n t was r e m o v e d u n d e r r e d u c e d p r e s s u r e . T h e 2 mg. o f c r u d e p r o d u c t t h u s o b t a i n e d h a d a UV s p e c t r u m i d e n t i c a l t o t h a t o f t h e b r o m i d e 1 9 0 . T h e a r y l r e g i o n o f t h e IR s p e c t r u m a l s o s h o w e d no c h a n g e . M e t h o d B : T o 9 m g . ( 0 . 0 8 mmole) o f p o t a s s i u m t - b u t o x i d e u n d e r n i t r o g e n i n 1 m l . t - b u t a n o l was a d d e d 10 mg. ( 0 . 0 3 mmole) o f t h e b r o m i d e 190 i n 1 m l . t - b u t a n o l . T h e s o l u t i o n was s t i r r e d a t 6 0 ° f o r 72 h o u r s , u n t i l a n a l y t i c a l T L C i n d i c a t e d t h a t m o s t o f t h e b r o m i d e 190 h a d d i s a p p e a r e d . T h e n 5 m l . o f a b u f f e r , pH 6 . 5 , w e r e a d d e d t o t h e c o o l e d r e a c t i o n m i x t u r e , a n d t h e s o l u t i o n was d i l u t e d w i t h 20 m l . e t h e r . U s i n g t h e same p r o c e d u r e a s i n M e t h o d A , a t o t a l o f 8 mg. o f c r u d e p r o d u c t was t h e n i s o l a t e d . T h i s p r o d u c t was p u r i f i e d b y p r e p a r a t i v e T L C ( s i l i c a g e l ; c h l o r o f o r m : e t h y l a c e t a t e -4 : 1) t o y i e l d two p r o d u c t s , e a c h o f 2 m g . B o t h o f t h e s e p r o d u c t s a n d t h e s t a r t i n g m a t e r i a l h a d v e r y s i m i l a r IR a n d UV s p e c t r a . - 130 -5 - A c e t o x y - 2 , 2 - d i m e t h y l - 3 - e t h y l ( 2 - b r o m o ) - 1 - t e t r a l o n e (194) A s o l u t i o n o f 57 m g . ( 0 . 1 6 mmole) o f t h e m e s y l a t e 16 9 a n d 0 . 1 9 g . o f a n h y d r o u s l i t h i u m b r o m i d e i n 10 m l . d r y a c e t o n e was r e f l u x e d f o r 18 h o u r s . T h e s o l v e n t was r e m o v e d u n d e r r e d u c e d p r e s s u r e , a n d t h e r e s i d u e was t a k e n u p i n 2 0 m l . w a t e r a n d 20 m l . e t h e r . T h e o r g a n i c l a y e r was w a s h e d w i t h t w o 2 0 m l . p o r t i o n s o f s a t u r a t e d s o d i u m c h l o r i d e s o l u t i o n , d r i e d , a n d t h e s o l v e n t r e m o v e d u n d e r r e d u c e d p r e s s u r e . T h i s g a v e 46 mg. 085% y i e l d ) o f c r u d e c o m p o u n d 1 9 4 . A n a n a l y t i c a l s a m p l e was d i s t i l l e d a t 1 2 0 ° / 0 . 5 mm. t o y i e l d a c o l o u r l e s s o i l . I R : 1770 ( a c e t a t e ) , 1690 ( k e t o n e ) . NMR: 1 . 0 ( s , 3 H ) , 1 . 2 ( s , 3 H ) , 1 .7 (m, 1 H ) , 2 . 1 (m, 2 H ) , 2 . 3 ( s , 3 H ) , 1 . 6 ( d , J = 7 , 1 H ) , 1 .8 ( d , J = 5 , 1 H- , 3 . 4 (m, 2 H) , 7 . 1 - 7 . 9 (m, 3 H).. U V : 210 ( 1 5 , 3 0 0 ) , 242 ( 1 0 , 0 0 0 ) , 292 ( 1 , 7 0 0 ) . M a s s s p e c t r u m ; c a l c u l a t e d f o r C^gH-^gO^Br: 3 3 8 . 0 5 1 6 m / e . F o u n d : 3 3 8 . 0 4 8 5 m / e . Low r e s o l u t i o n : 340 ( 2 . 2 ) , 338 ( 2 . 6 ) , 298 ( 3 7 ) , 296 ( 3 9 ) , 216 ( 2 0 ) , 203 ( 1 2 ) , 189 ( 1 0 ) , 145 ( 1 8 ) , 134 ( 7 3 ) , 106 ( 2 8 ) . - 131 -Analysis calculated for C 1 6 H 1 9 0 3 B r : C, 56.64; H, 5.66. Found: C , 57 . 31; II, 5. 90 . 2,2-Dimethyl-3-ethyl(2-bromo)-5-hydroxy-l-tetralone (195) A 46 mg. sample (0.14 mmole) of crude compound 194 was hydrolysed using s i m i l a r conditions to those by which compound 169 was hydrolysed. The crude product was p u r i f i e d by pre-parative TLC ( s i l i c a gel; chloroform: ethyl acetate- 9: 1), and. the band at 0.5 was removed and extracted with ethyl acetate to- give 26 mg. of compound 195, a thick o i l (84% y i e l d from compound 169). IR: 3600 and 3300 (hydroxy), 1675 (ketone). NMR: 1.2 (s, 3 H), 1.3 (s, 3 H), 1.8 - 2.4 (m, 3 H) , 2.8 (d, J = 7, 1 H), 3.1 (d, J =4, 1 H), 3.4 - 3.7 (m, 2 H), 6.0 (br. s, 1 H), 7.0 - 7.7 (m, 3 H). UR: 222 (15,200), 257 (6,800), 315 (2,300); aft e r base •addition, 241 (18,800), 270 (3,000), 356 (2,200). Mass Spectrum; calculated for C-^H^CUBr: 296.0413 m/e. Found: 296.0413 m/e. Low r e s o l u t i o n : 298 (18), 296 (19), 252 (12), 189 (10), 186 (5), 185 (5), 145 (5), 135 (11), 134 (100), 106 (28). - 132 -Attempted C y c l i z a t i o n of Compound 195 w i t h S i l v e r P e r c h l o r a t e  i n T r i f l u o r o e t h a n o l A s o l u t i o n of 3 mg. (0.01 mmole) of compound 195 i n 5 ml. o f t r i f l u o r o e t h a n o l was added to 9 mg. (0.04 mmole) of s i l v e r p e r c h l o r a t e d i s s o l v e d i n 0.02 ml. water. The s o l u t i o n was s t i r r e d a t room temperature f o r 6 hours, a t the end of which a n a l y t i c a l TLC i n d i c a t e d o n l y unchanged s t a r t i n g m a t e r i a l was p r e s e n t . The r e a c t i o n mixture was t h e r e f o r e r e f l u x e d f o r 16 hours. At t h i s time, a n a l y t i c a l TLC i n d i c a t e d the absence of s t a r t i n g m a t e r i a l and the presence of a new product. The s o l u t i o n was d i l u t e d w i t h 2 0 ml. e t h e r , and washed wit h f o u r 20 ml. p o r t i o n s of s a t u r a t e d sodium c h l o r i d e s o l u t i o n . The o r g a n i c l a y e r was d r i e d , and the s o l v e n t was removed under reduced p r e s s u r e t o y i e l d the crude product. T h i s was p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l ; ethanol) to y i e l d 3 mg. (100% y i e l d ) of 2 , 2 - d i m e t h y l - 3 - e t h y l ( 2 - t r i f l u o r o e t h o x y ) -5 - h y d r o x y - l - t e t r a l o n e (203), an o i l . IR: 1705 (ketone), 1600 ( a r y l ) . Mass Spectrum; c a l c u l a t e d f o r C l c H , Q 0 o F _ : 316.1286 m/e. Found: 316.1279 m/e. Low r e s o l u t i o n : 316 (4), 284 (4), 257 (4), 256 (17), 223 (6), 213 (4), 205 (4), 185 (4), 150 (9), 149 (100), 97 (17), 85 (16), 83 (19), 71 (22), 57 (43). - 13 3 -1,2,3,4-Tetrahydro-8-methoxy-2-naphthol (207) To a s o l u t i o n o f 16.0 g. (0.100 moles) of naphthalene-1 , 7 - d i o l i n a mixture of 4 0 ml. t e t r a h y d r o f u r a n , 19 ml. t - b u t y l a l c o h o l , and 30 0 ml. of recondensed l i q u i d ammonia under a n i t r o g e n atmosphere was added. 4.3 g. (0.62 moles) of l i t h i u m metal i n s m a l l p i e c e s . The deep bl u e s o l u t i o n was s t i r r e d f o r 2 1/2 hours, then 60 ml. methanol was added over 5 minutes, and the ammonia was d r i v e n o f f wi t h a stream o f n i t r o g e n w h i l e h e a t i n g the o u t s i d e o f the f l a s k w i t h a hot a i r gun. A f t e r completion of t h i s o p e r a t i o n , on i n t r o -d u c t i o n o f a i r the y e l l o w s o l u t i o n t u r n e d a deep red-brown. Concentrated h y d r o c h l o r i c a c i d was added u n t i l t he s o l u t i o n was a c i d i c , and the s o l u t i o n was e x t r a c t e d w i t h 2 00 ml. of e t h y l a c e t a t e . The o r g a n i c l a y e r was washed w i t h f i v e 200 ml. p o r t i o n s o f s a t u r a t e d sodium c h l o r i d e s o l u t i o n , d r i e d , and the s o l v e n t removed under reduced p r e s s u r e to y i e l d 16 g. of crude 5 , 6 , 7 , 8 - t e t r a h y d r o n a p h t h a l e n e - l , 7 - d i o l . 13.8 g. of t h i s crude product was d i s s o l v e d i n 80 ml. of 1.5 N (5%) sodium hydroxide s o l u t i o n , the system f l u s h e d with n i t r o g e n , and 30 ml. (0.32 moles) of di m e t h y l sulphate added. A l i g h t c o l o u r e d p r e c i p i t a t e appeared almost immediately, and a f t e r 30 minutes s t i r r i n g , the s o l u t i o n was c o l o u r l e s s . The s o l u t i o n was e x t r a c t e d w i t h 100 ml. e t h y l a c e t a t e , and the o r g a n i c l a y e r washed wi t h 50 ml. of 1.5 N sodium hydroxide s o l u t i o n , f i v e 50 ml. p o r t i o n s o f s a t u r a t e d sodium c h l o r i d e s o l u t i o n , and d r i e d . On removal o f the s o l v e n t under reduced p r e s s u r e , - 134 -and the s o l i d product d r i e d under h i g h vacuum f o r 4 hours t o y i e l d 9.75 g. of crude compound 207. In a t y p i c a l s m a l l s c a l e p u r i f i c a t i o n , 0.321 g. was p l a t e d ( s i l i c a g e l ; c h l o r o -form: acetone- 9: 1) and the band a t R f 0.5 e x t r a c t e d w i t h e t h y l a c e t a t e t o y i e l d 0.228 g. (68% o f crude, 42% o v e r a l l y i e l d ) o f white c r y s t a l l i n e compound 207. An a n a l y t i c a l sample was sublimed a t 80°/0.04 mm. MP: 104.5 - 106°. IR: 3650 - 3100 ( a l c o h o l ) , 1590 ( a r o m a t i c ) . NMR: 1.6 (s, 1 H), 1.9 (m, 2 H), 2.8 (m, 4 H), 3.7 (s, 3 H), 4.1 (m, 1 H), 6.5 - 7.1 (m, 3 H). UV: 224 (7,000), 268 (1,300), 277 (1,350). Mass Spectrum; c a l c u l a t e d f o r c i ^ H 1 0 ° 2 : I 7 8 - 0 9 9 3 m/e. Found: 178.0996 m/e. Low r e s o l u t i o n : 179 (15), 178 (94), 160 (100), 159 (48), 150 (26), 145 (25), 134 (64), 115 (19), 104 (51). A n a l y s i s c a l c u l a t e d f o r C 1 1 H 1 4 ° 2 : C ' 7 4 - 1 3 ; H ' 7 - 9 2 -Found: C, 73.99; H, 7.94. - 135 -8-Methoxy-2-tetralone (208) To a s t i r r e d suspension o f 0.755 g. (3.8 mmoles) p y r i d i n i u m chlorochromate D ; : ) i n 3 ml. methylene c h l o r i d e was added 0.318 g. (1.8 mmoles) of the a l c o h o l 207 i n 7 ml. methylene c h l o r i d e . The s o l u t i o n was s t i r r e d at room temperature and the p r o g r e s s o f the r e a c t i o n was f o l l o w e d by a n a l y t i c a l TLC. A f t e r 4 hours, 20 ml. of dry et h e r was added t o the r e a c t i o n mixture, and the r e s u l t a n t dark g r a n u l a r s o l i d was removed by f i l t r a t i o n of the s o l u t i o n through a s i n t e r e d g l a s s f u n n e l . The g r a n u l a r s o l i d was washed wit h a f u r t h e r 20 ml. of e t h e r , and the f i l t r a t e s combined. The o r g a n i c s o l v e n t was then removed under reduced p r e s s u r e t o y i e l d 0.21 g. of crude product. T h i s was p u r i f i e d by p r e -p a r a t i v e TLC ( s i l i c a g e l ; c h l o r o f o r m ) . The band a t 0.5 was removed and e x t r a c t e d w i t h e t h y l a c e t a t e t o g i v e 0.162 g. of white c r y s t a l l i n e compound 208 (52% y i e l d ) . A s m a l l sample was sublimed a t 75°/0.02 mm. MP: 55.5 - 57° ( l i t e r a t u r e 55 - 5 6 . 5 ° 6 4 ) . IR: 1710 (ketone). NMR: 2.4 - 3.2 (m, 4 H), 3.5 (s, 2 H), 3.8 (s, 3 H), 6. 5 - 7.2 (m. 3 H) . UV. 212, 245, 305 ( s h o u l d e r ) . - 136 -Mass spectrum; 177 (13) , 176 (100) , 161 (17) , 147 (24) , 131 (91), 117 (61). A n a l y s i s c a l c u l a t e d f o r cnEi2°2: C' 7 4 , 9 6 ; H ' 6.88. Found: C, 74.86; H, 6.90. 5,6-Dihydronaphthalene-l-methoxy-7-acetic a c i d methyl e s t e r  (210) In a glo v e bag, 24 mg. (0.60 mmole) o f sodium h y d r i d e suspension i n m i n e r a l o i l was p l a c e d i n a f l a s k , the f l a s k f i t t e d w i t h a serum cap, and 5 ml. of dry benzene added. The s o l u t i o n was s t i r r e d , and 90 mg. (0.55 mmole) of t r i -methyl piiosphonoacetate was added by s y r i n g e . The s o l u t i o n was s t i r r e d a t room temperature f o r 45 minutes, w i t h gas e v o l u t i o n observed i n t h e e a r l y minutes. Then 70 mg. (0.40 mmole) o f the ketone 208 i n 1 ml. d r y benzene was added, and an a d d i t i o n a l ml. of benzene w i t h washings was added. The s o l u t i o n was s t i r r e d at room temperature f o r 30 minutes, and then at 60° f o r 3 hours. A f t e r c o o l i n g , 10 ml. sodium c h l o r i d e s o l u t i o n and 10 ml. et h e r were added, the o r g a n i c l a y e r separated, washed w i t h t h r e e 10 ml. p o r t i o n s o f s a t u r a t e d sodium c h l o r i d e , d r i e d , and the s o l v e n t removed under reduced p r e s s u r e . The crude product was p u r i f i e d by - 137 -p r e p a r a t i v e TLC ( s i l i c a g e l ; c h l o r o f o r m ) . The band a t R^ 0. was removed and e x t r a c t e d w i t h e t h y l a c e t a t e t o y i e l d 3 6 mg. (40% y i e l d ) o f compound 210, a t h i c k o i l . IR: 1725 ( e s t e r ) , 1650 (conjugated a l k e n e ) . NMR: 2.0 - 3.o (m, 4 H) , 3.2 (s, 2 H), 3.7 (s, 3 H) , 3.8 (s, 3 H), 6.7 - 7.3 (m, 4 H). UV: 222, 272, 293, 308. The TLC band a t R f 0.75 was a l s o removed and e x t r a c t e d w i t h e t h y l a c e t a t e t o g i v e 20 mg. (22% y i e l d ) o f 2,3-dihydro 8-methoxy-2(1H)naphthylidene a c e t i c a c i d methyl e s t e r (211) , a l s o a t h i c k o i l . IR: 1710 (a, 8-unsaturated e s t e r ) , 1650 (conjugated a l k e n e ) . NMR: 2.6 - 3.3 (m, 4 H), 3.5 (s, 2 H), 3.7 (s, 3 H), 3.8 (s, 3 H), 5.9 ( t , J = 2, 1 H), 6.5 - 7.3 (m, 3 H). UV ( q u a l i t a t i v e o n l y ) : 221, 264, 277. An unseparated sample of the Wadsworth-Emmons product was analyzed. A n a l y s i s c a l c u l a t e d f o r c 1 4 H 1 g ° 3 : c> 72.39; H, 6.94. Found: C, 72.00; H, 6.73. - 138 -8-Methoxy-l, 2,3,4-tetrahydronaphthaiene-2-acetic a c i d methyl  e s t e r (212) A s o l u t i o n o f 73 mg. (0.31 mmole) of an unseparated mixture o f the un s a t u r a t e d s p e c i e s 210 and 211 wit h 90 mg. of 10% p a l l a d i u m on c h a r c o a l i n suspension i n 10 ml. e t h y l a c e t a t e was s t i r r e d under 1 atomsphere of hydrogen p r e s s u r e f o r 3 hours. A t o t a l of 6.9 ml. of hydrogen (0.29 mmole) was absorbed. The s o l u t i o n was vacuum f i l t e r e d through a s i n t e r e d g l a s s f u n n e l , and the s o l v e n t was removed under-reduced p r e s s u r e t o g i v e 7 0 mg. of the crude product 212. T h i s was p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l ; c h l o r o f o r m ) , c t h e band a t 0.6 being e x t r a c t e d w i t h e t h y l a c e t a t e t o y i e l d 68 mg. (92% y i e l d ) o f a t h i c k c o l o u r l e s s o i l . IR: 1720 ( e s t e r ) . NMR: 1.2 - 3.2 (m, 9 H), 3.7 (s, 3 H), 3.8 (s, 3 H), 6.5 - 7.2 (m, 3 H). UV: 218 (7,500), 270 (1,300), 277 (1,350). Mass Spectrum; c a l c u l a t e d f o r C-^H^gO^: 234.1255 m/e. Found: 234.1255 m/e. Low r e s o l u t i o n : 235 (3), 234 (21), 204 (5), 203 (3), 161 (12), 160 (100), 159 (25), 145 (12), 129 (20). - 139 -8-Hydroxy-l,2,3,4-tetrahydronaphthalene-2-acetic a c i d (213) A t o t a l o f 56 mg. (0.24 mmole) of the e s t e r 213 was t r e a t e d w i t h p y r i d i n e h y d r o c h l o r i d e under the same c o n d i t i o n s used t o t r a n s f o r m the e s t e r 158 to compound 161. A f t e r the workup, 41 mg. of crude product was i s o l a t e d . T h i s was p u r i f i e d by preparative. TLC ( s i l i c a g e l ; c h l o r o f o r m : acetone: a c e t i c a c i d - 80: 20: 1) and the band a t 0.4 removed and e x t r a c t e d with e t h y l a c e t a t e t o g i v e 30 mg. (61% y i e l d ) o f compound 213, a white c r y s t a l l i n e s o l i d . MP: 110.5 - 112°. IR: 3600 ( a l c o h o l ) , 3500 - 2400 ( a c i d ) , 1705 ( a c i d ) . NMR: 1.0 - 1.5 (m, 2 H), 1.6 - 1.8 (m, 1 H), 2.2 (d. d, J = 5 and J = 6, 2 H), 2.6 (d. d, J = 4 and J = 8, 2 H), 4.5 - 7.5 (v. b r . s, 2 H), 6.3 - 6.9 (m, 3 H). UV: 210, 270; a f t e r base a d d i t i o n , 213, 243, 253, 290 ( s h o u l d e r ) . Mass Spectrum; c a l c u l a t e d f o r c i 2 H 1 4 ° 3 : 206.0943 m/e. Found: 206.0943 m/e. Low r e s o l u t i o n : 207 (8), 206 (25), 186 (5), 159 (6), 147 (21), 146 (100), 145 (45), 144 (15), 131 (21). - 140 -8 - A c e t o x y - l , 2 , 3 , 4 - t e t r a h y d r o n a p h t h a l e n e - 2 - a c e t i c a c i d (214) A 27 mg. sample ( 0 . 1 1 mmole) of compound 213 was t r e a t e d w i t h 1 ml. of a c e t y l a t i n g reagent under the same c o n d i t i o n s by which compound 161 was a c e t y l a t e d , y i e l d i n g 32 mg. (98% y i e l d ) of crude compound 214. As o n l y one spot was v i s i b l e on a n a l y t i c a l TLC, t h i s product, a t h i c k o i l , was used without f u r t h e r p u r i f i c a t i o n . IR: 3600 - ^ 2 4 0 0 ( a c i d ) , 1750 ( a c e t a t e ) , 1705 ( a c i d ) . NMR: 1 . 3 (m, 2 H), 1 . 7 - 2 . 2 (m, 3 H), 2 . 3 (s, 3 H), . 2 . 4 (m, 2 H) , 2 . 9 (d. d, J = 5 , J = 7 , 2 H) , 6 . 8 - 7 . 3 (m, 3- H) , 8 . 6 (br. s, 1 H) . UV: 211 ( 7 , 1 0 0 ) , 259 ( 3 8 0 ) . Mass Spectrum; c a l c u l a t e d f o r c i 4 H i g 0 4 : 2 4 8 . 1 0 4 8 m/e. Found: 2 4 8 . 1 0 4 8 m/e. Low r e s o l u t i o n : 248 ( 1 ) , 230 ( 7 ) , 206 ( 2 1 ) , 188 ( 6 ) , 147 ( 1 4 ) , 146 ( 1 0 0 ) , 145 ( 2 9 ) , 144 ( 1 8 ) , 131 ( 1 2 ) , 127 ( 6 ) , 120 ( 6 ) , 115 ( 9 ) , 91 ( 1 0 ) . l - A c e t o x y - 7 - e t h y l ( 2 - h y d r o x y ) - 5 , 6 , 7 , 8 - t e t r a h y d r o n a p h t h a l e n e (215) To a serum cap equipped flask, c o n t a i n i n g 29 mg. ( 0 . 1 2 mmole) o f compound 214 i n 10 ml. dry t e t r a h y d r o f u r a n under a n i t r o g e n atomosphere was added 0 . 0 8 0 ml. (64 mg., 0 . 8 6 mmole) of d i b o r a n e - d i m e t h y l s u l p h i d e complex. Hydrogen was evolved - 141 -f o r 5 m i n u t e s a f t e r t h i s a d d i t i o n , a n d t h e r e s u l t a n t p r e s s u r e was r e l e a s e d v i a a s y r i n g n e e d l e , a f t e r w h i c h t h e r e a c t i o n m i x t u r e was s t i r r e d f o r 90 m i n u t e s . T h e n 10 d r o p s o f 1 M h y d r o c h l o r i c a c i d w e r e a d d e d c a r e f u l l y , w i t h a c c o m p a n y i n g r a p i d e v o l u t i o n o f h y d r o g e n . T h e s o l u t i o n was t a k e n u p i n t o 20 m l . e t h e r , a n d w a s h e d w i t h f i v e 20 m l . p o r t i o n s o f s a t u r a t e d s o d i u m c h l o r i d e s o l u t i o n . T h e o r g a n i c l a y e r was d r i e d , a n d t h e s o l v e n t r e m o v e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t was p u r i f i e d b y p r e p a r a t i v e T L C ( s i l i c a g e l ; c h l o r o f o r m : a c e t o n e - 9 : 1 ) . T h e b a n d a t R f 0 . 4 was r e m o v e d a n d • e x t r a c t e d w i t h e t h y l a c e t a t e t o g i v e 27 mg. (98% y i e l d ) o f c o m p o u n d 2 1 5 , a c o l o u r l e s s o i l . I R : 3 6 4 0 a n d 3450 ( h y d r o x y l ) , 1750 ( a c e t a t e ) . NMR: 1 . 5 - 2 . 2 (m, 5 H p l u s i m p u r i t y ) , 2 . 4 ( s , 3 H ) , 2 . 8 (m, 4 H ) , 3 . 8 ( t , J = 6 , 2 H ) , 6 . 8 - 7 . 3 (m, 3 H ) . U V : 218 ( 7 , 5 0 0 ) , 270 ( 3 0 0 ) . M a s s S p e c t r u m ; c a l c u l a t e d f o r c i 4 H i g ° 3 : 2 3 4 . 1 2 5 6 m / e . F o u n d : 2 3 4 . 1 2 6 0 m / e . Low r e s o l u t i o n : 234 ( 1 0 ) , 193 ( 8 ) , 192 ( 5 7 ) , 174 ( 2 2 ) , 159 ( 1 4 ) , 147 ( 1 2 ) , 146 ( 1 0 0 ) , 145 ( 7 0 ) , 131 ( 1 3 ) , 128 ( 8 ) , 127 ( 8 ) , 120 ( 1 7 ) , 117 ( 1 0 ) , 115 ( 1 3 ) , 91 ( 1 5 ) . - 142 -l-Acetoxy-7-ethyl(2-methanesulphonate e s t e r ) - 5 , 6 , 7 , 8 - t e t r a - hydronaphthalene (216) To a s o l u t i o n of 24 mg. (0.10 mmole) o f the a l c o h o l 215 i n 1 ml. of dry p y r i d i n e a t 0° was added 0.1 ml. methane-s u l p h o n y l c h l o r i d e . The r e a c t i o n mixture was s t i r r e d at 0° f o r 18 hours. The s o l u t i o n was d i l u t e d w i t h 20 ml. e t h e r , and washed w i t h 10 ml. 1 M h y d r o c h l o r i c a c i d , f o l l o w e d by t h r e e 20 ml. p o r t i o n s of s a t u r a t e d sodium c h l o r i d e s o l u t i o n . The s o l u t i o n was.dried, and the s o l v e n t was removed under reduced p r e s s u r e . The crude product was p u r i f i e d by p r e p a r a -tive. TLC ( s i l i c a g e l ; c h l o r o f o r m : acetone- 19: 1), and the band at 0.5 was removed and e x t r a c t e d w i t h e t h y l a c e t a t e . From t h i s , 15 mg. (47% y i e l d ) of a t h i c k c o l o u r l e s s o i l was i s o l a t e d . IR; 1750 ( a c e t a t e ) , 1340 (mesylate). NMR: 1 . 5 - 2 . 2 (m, 5 H), 2.4 (s, 3 H), 2 . 6 - 3 . 0 (m, 2 H), 3.0 (s, 3 H), 4.4 ( t , J = 6, 2 H), 6.7 - 7.2 (m, 3 H) . UV: 213, 259. Mass Spectrum; c a l c u l a t e d f o r C ^ 5 H 2 0 ° 5 S : 312.1032 m/e. Found: 312.1020 m/e. Low r e s o l u t i o n : 312 (12), 284 (9), 271 (14), 270 (100), 256 (13), 248 (15), 203 (10), 174 (47), 173 (10), 159 (18), 147 (19), 146 (91), 145 (60), 129 (24), 120 (16). - 143 -7-Ethyl(2-methanesulphonate e s t e r ) - 5 , 6 , 1 , 8 - t e t r a h y d r o - l - n a p h t h o l (204) A s o l u t i o n of 11 mg. (0.035 mmole) o f compound 216 was h y d r o l y s e d i n a manner s i m i l a r t o t h a t used t o prepare com-pound 170. The crude product thus o b t a i n e d was p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l ; c h l o r o f o r m : acetone- 80: 20) to g i v e 6 mg. (63% y i e l d ) of a c o l o u r l e s s o i l . IR: 3400 (hydroxy), 1590 (ar o m a t i c ) , 1340 (sulphonate e s t e r . UV: 217, 272, 279; a f t e r base a d d i t i o n , 244, 281 289. Mass Spectrum; c a l c u l a t e d f o r c i 3 H i 8 ° 4 S : 270.0926 m/e. Found: 270.0926 m/e. Low r e s o l u t i o n : 270 (37), 174.(21), 159 (24), 149 (12), 147 (16), 146 (97), 145 (80), 133 (7), 131 (18), 129 (11), 127 (11), 120 (12), 117 (11), 115 (10). 1,2,3, 4-Tet.rahydro-3 , 4a-ethanonaphthalen-5 (4aH) -one (117 ) An 11 mg. (0.040 mmole) sample of the mesylate 204 was d i s s o l v e d i n 2 ml. o f t - b u t a n o l , and added t o a r e f l u x i n g s o l u t i o n o f 10 mg. (0.090 mmole) of potassium t-butoxide i n 12 ml. t - b u t a n o l . The r e f l u x i n g was con t i n u e d f o r 2 hours, by which time none of the mesylate 204 c o u l d be d e t e c t e d by a n a l y t i c a l TLC. Then 3 drops o f 1 M h y d r o c h l o r i c a c i d were - 144 -added to the r e a c t i o n mixture, and the s o l u t i o n was tkane up i n 20 ml. e t h y l a c e t a t e . The o r g a n i c l a y e r was washed w i t h f o u r 20 ml. p o r t i o n s o f s a t u r a t e d sodium c h l o r i d e s o l u t i o n , d r i e d , and the s o l v e n t removed under reduced p r e s s u r e . The crude product was p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l ; c h l o r o f o r m : e t h y l a c e t a t e - 12: 1). The band at 0.5 was removed and e x t r a c t e d w i t h e t h y l a c e t a t e t o g i v e 1.7 mg. (25% y i e l d ) of compound 117, a l i g h t y e l l o w o i l . IR: 1660 (ketone), 1620 (conjugated a l k e n e ) , 1560 (diene) . NMR (100 MHz, F T ) : 1.5 - 2.6 (envelope), 6.0 (d, J = 6, 1 H), 6.15 (d, J = 9, 1 H), 7.1 (dd, J = 6 and J = 9, 1 H) . UV: 210, 323 Mass Spectrum; c a l c u l a t e d f o r c j 2 H l 4 0 : 174.1044 m/e. Found: 174.1066 m/e. Low r e s o l u t i o n : 174 (35), 159 (24), 145 (73), 133 (32), 131 (44) , 128 (45) , 115 (61) . 14 5 -3,4-Dihydro-2, 3-dimethyl-3,4a-ethanonaphthalen-5(4aH),  l ( 2 H ) - d i o n e (131) A t o t a l of 2 g. of l i t h i u m carbonate was p l a c e d i n the s bottom of a l a r g e (2 cm x 2 cm 2 8 cm) s u b l i m a t i o n apparatus, and the system was f l u s h e d w i t h n i t r o g e n . A s o l u t i o n of 7 mg. (0.033 mmole) o f the p h e n o l i c bromide 195 i n 5 ml. o f dry methanol was t r e a t e d w i t h 0.25 ml. (0.038 mmole) of 0.15 M sodium methoxide s o l u t i o n , and p l a c e d i n the sub-l i m a t i o n apparatus. The s o l v e n t was removed over 1 hour by a stream of n i t r o g e n . The c o l d f i n g e r was s e t i n p l a c e , the system was evacuated, and a d r y i c e - a c e t o n e mixture was added t o the c o l d f i n g e r . The s u b l i m a t i o n apparatus was heated i n an o i l bath at 180 - 200°/0.02 mm. f o r 80 minutes. A f t e r the c o l d f i n g e r had been warmed to room temperature, i t was removed and washed w i t h methylene c h l o r i d e , y i e l d i n g 1.7 mg. of crude product. T h i s was p u r i f i e d by p r e p a r a t i v e TLC ( s i l i c a g e l ; c h l o r o f o r m : e t h y l a c e t a t e - 9: 1). The b r i g h t o y e l l o w band a t 0.6 was removed and e x t r a c t e d w i t h e t h y l a c e t a t e to y i e l d 1.0 mg. (20% y i e l d ) o f compound 131, a y e l l o w o i l . IR: 1650 (conjugated ketone). NMR ( F o u r i e r t r a n s f o r m ) : 0.8 ( i m p u r i t y ) , 1.14 (s, 3 H), 1.21 (s, 3 H), 1.28 ( i m p u r i t y ) , 1.6 (m, 7 to 10 H), 2.0 - 2.4 ( i m p u r i t y ) , 6.35 (dd, J = 9 and J = 1, 1 H), 6.95 (dd, J = 6 and IJ = 1, 1 H) , 7.20 (dd, J = 9 and J = 6, 1 H), 7.25 (CHC1 3). - 146 -UV: 215, 317. Mass Spectrum; c a l c u l a t e d f o r c i 4 H i g ° 2 : 216.1149 m/e. Found: 216.117 6 m/e. Low r e s o l u t i o n : 216 (3), 189 (10), 188 (57), 174 (11), 173 (100), 159 (14), 158 (5), 146 (39), 145 (71), 144 (15), 133 (9), 132 (24), 131 (13), 115 (11). - 147 -REFERENCES F. Kido, H. Uda, and A. Y o s h i k o s h i , Tetrahedron L e t t e r s , 2815 (1967); Tetrahedron L e t t e r s , 1247 (1968). D. C. Umarani, K. G. Gore, and K. K. C h a k r a v a r t i , T e t rahedron L e t t e r s , 1255 (1966). I. C. Nigam, H. Komae, G. A. N e v i l l e , C. Radecka, and S. K. Paknikar, Tetrahedron L e t t e r s , 2497 (1968). G. C h i u r d o g l u and J . Decot, Tetrahedron, |, 1 (1958). R. M. Coates, F. R. Farney, S. M. Johnson, and I. C. P a u l , Chem. Commun., 999 (1969). R. Sakuma and A. Y o s h i k o s h i , Chem. Commun., 41 (1968). N. Hanayama, F. Kido, R. Sakuma, H. Uda, and A. Y o s h i k o s h i , Tetrahedron L e t t e r s , 6099 (1968). D. F. MacSweeney, R. Ramage, and A. S a t t a r , Tetrahedron  L e t t e r s , 557 (1970). N, H. Andersen and M. S. Fa l c o n e , Chem. Ind., 62 (1971); N. H. Andersen, S. E. Smith, and Y. Ohta, Chem. Commun., 447 (1973). R. K a i s e r and P. N a e g e l i , Tetrahedron L e t t e r s , 2009 (1972). F. Kido, H. Uda, and A. Y o s h i k o s h i , Chem. Commun., 1335 (1969); J . Chem. S o c , P e r k i n I, 17 55 (1972). D. F. MacSweeney and R. Ramage, Tetrahedron, 27, 1481 (1971) R. M. Coates and R. L. Sowerby, J . Am. Chem. Soc., 94, 5386 (1972). — K. Wiesner, Z. V a l e n t a , and L. G. Humber, Tetrahedron  L e t t e r s , 621 (1962). S. Yuan, D i s s . Abst., 33B, 126 (1972). E. J . Corey, N. N. G i r o t r a , and C. T. Mathew, J . Am. Chem. Soc. , <|1, 1557 (1969) . T. G. C r a n d a l l and R. G. Lawton, J . Am. Chem. Soc., 91, 2129 (1969). - 148 -18. G. St o r k , S. Ma l h a t r a , H. Thompson, and M. U c h i b a y a s h i , J . Am. Chem. Soc., 8J, 1148 (1965). 19. A. D e l j a c , W. D. MacKay, C. S. J . Pan, K. J . Wiesner, and K. Wiesner, Can. J . Chem., 50, 726 (1972). 20. S. Masamune, J . Am. Chem. S o c , 83 , 1009 (1961); 86, 288 (1964) . 21. L. Mandell, D. Caine, and G. E. K i l p a t r i c k , J . Am. Chem. Soc., 83, 4457 (1961) . 22. D. J . Beames and L. N. Mander, Aust. J . Chem., 24, 343 (1971); D. J . Beames, T. R. K l o s e , and L. N. Mander, Chem. Commun., 773 (1971). 23. A. M. El-Abbady and L. S. E l - A s s a l , J . Chem. S o c , 1024 (1959) . 24. H. C. Brown and C. A. Brown, Tetrahedron, Suppl. 8, P a r t I, .149. 25. L. F. F i e s e r and M. F i e s e r , Reagents f o r Organic S y n t h e s i s , Wiley, New York, 1967, p. 890. 26. H. O, House and C. B. Hudson, J . Org. Chem., 35, 647 (1970). 27. A. I. S c o t t , I n t e r p r e t a t i o n o f the U l t r a v i o l e t S p e c t r a of  N a t u r a l P r o ducts, Pergamon P r e s s , Oxford, 1974, pp. 45-134. 28. A. S i e g l i t z and C. J o r d a n i d e s , J u s t u s L i e b i g s Ann. Chem., 663, 123 (1963). 29. W. S. Johnson and H. J . Glenn, J . Am. Chem. Soc., 71, 1092 (1949). ~~ 30. A. C h a t t e r j e e and D. Banerjee, J . Chem. Soc., C, 1859 (1971). 31. H. O. House, Modern S y n t h e t i c R e a c t i o n s , .Benjamin, New York, 2nd ed. 1972, pp. 510-546. 32. W. Nagata, T. Sugasawa, M. N a r i s a d a , T. Wakabayashi, and Y. Hayase, J . Am. Chem. Soc., 89, 1483 (1967). 33. W. E. Bachmann and W. S. Stru v e , Organic R e a c t i o n s , 1, 38 (1942). 34. W. F. Erman and L. C. Stone, J . Am. Chem. Soc., 93, 2821 (1971). ~~ 35. H. C. Brown and B. S. C. Rao, J . Am. Chem. Soc., 82, 681 (1960). ~~ 1 - 149 -36. M. Shamma, N. C. Deno, and J . F. Remar, Tetrahedron L e t t e r s , 1375 (1966); L. F. F i e s e r and M. F i e s e r , Reagents f o r  Organic S y n t h e s i s , Wiley, New York, 1967, p. 1106. 37. J . W. Wildes, N. H. M a r t i n , C. C. P i t t , and M. E. W a l l , J . Org. Chem. , 3J, 721 (1971). 38. I. T. H a r r i s o n , Chem. Commun., 616 (1969). 39. R. H. Prager and Y. T. Tan, Tetrahedron L e t t e r s , 3661 (1967). 40. B. E. Edwards and P. N. Rao, J . Org. Chem., 3^, 324 (1966). 41. H. J . Kabbe, E. T r u s c h e i t , and K. E i t e r , J u s t u s L i e b i g s  Ann. Chem., 684, 14 (1965). 42. C. R. Kruger and E. G. Rochow, J . Organometal. Chem., 1, 474 (1964); M. W. Rathke, J . Am. Chem. Soc., 2 J , 3222 (1970) . 43. E. J . Corey and M. Chaykovsky, J . Am. Chem. Soc., 87, 1345 (1965). 44. G. I. I l l u m i n a t i , L. M a n d o l i n i , and B. M o s l i , J . Am. Chem. Soc. , 9_§, 1422 (1974) . 45. J . C. R i c h e r , J . Org. Chem., 2Q, 324 (1965). 46. H. 0. House, H. Badod, R. B. T o o t h i l l , and A. W. N o l t e s , J . Org. Chem., 2J, 4141 (1962). 47. T. Nakabayashi, J . Am. Chem. Soc., §2, 3906 (1960). 48. W. Nagata and H. I t a y a k i , Chemistry and In d u s t r y , 1194 (1964). 49. W. J . LeNoble, S y n t h e s i s , g, 1 (1970). 50. R. G. Pearson and J . Songstad, J . Am. Chem. S o c , 89, 1827 (1967). 51. W. L. Mock and K. A. Rumon, J . Org. Chem., 22, 400 (1973). 52. G. F. Freeguard and L. H. Long, Chemistry and I n d u s t r y , 1582 (1964). 53. H. Gilman and J . E. K i r b y , J . Am. Chem. Soc., 51, 3475 (1929). ~~~ 54. S. Nimigirawath, E. R i t c h i e , and W. C. T a y l o r , Aust. J . Chem., 26, 183 (1973). - 1 5 0 -5 5 . R. G. Weiss and E. K. Snyder, J . Org. Chem., 3 6 , 4 0 3 ( 1 9 7 1 ) . ~ ~ 5 6 . J . Hooz and S. S. N. G i l a n i , Can. J . Chem., 4 6 , 8 6 ( 1 9 6 8 ) . ~ ~ 5 7 . R. L. C a r g i l l , D. F. Busby, P. D. E l l i s , S. W o l f f , and W. C. Augusta, J . Org. Chem., 3 J , 5 7 3 ( 1 9 7 4 ) . 5 8 . S. D o r l i n g and J . Harley-Mason, Chemistry and I n d u s t r y , 1 5 5 1 ( 1 9 5 9 ) . 5 9 . A. Ogiso, M. Kurabayashi, H. Nagakori, and H. Mishima, Ch. Pharm. B u l l . , l j , 1 2 8 3 ( 1 9 7 0 ) . 6 0 . I. D. E n t w i s t l e and R. A. W . Johnstone, Chem. Commun., 2 9 ( 1 9 6 5 ) . 6 1 . D. J . Raber, M. D. Dukes, and J . Gregory, Tetrahedron  L e t t e r s , 6 6 7 ( 1 9 7 4 ) . 6 2 . J . L. M a r s h a l l , Tetrahedron L e t t e r s , 7 5 3 ( 1 9 7 1 ) . 6 3 . P. B o l d t and W. T h i e l e c k e , Angew. Chem., I n t e r n . Ed. E n g l . , J , 1 0 4 4 ( 1 9 6 6 ) . 6 4 . D. W. Johnson and L. N. Mander, Aust. J . Chem., 2 7 , 1 2 7 7 ( 1 9 7 5 ) . 6 5 . E. J . Corey and J . W. Suggs, Tetrahedron L e t t e r s , 2 6 4 7 ( 1 9 7 5 ; . 6 6 . W. S. Wadsworth and W. D. Emmons, J . Am. Chem. S o c , 8 3 , 1 7 3 3 ( 1 9 6 1 ) ; Org. Syn., 4 J , 4 4 ( 1 9 6 5 ) . ~ ~ - 151 -S P E C T R A L A P P E N D I X ~ 152 -- 153 -CD •9 a i n cn LU a . a cn W 2 -a . i n CM 022 a . a CM eat a . in 3b r rec-r o r 0 * 0 0 1 — i i — r~ o's/. o ' a s o'Sc JULISN3iNJ 3MicJ13d I i n 0 * 0 - 154 -6-- SSI -- 156 -100' DO 3600 FHOUENCY (CM ') . 3300 3000 3400 3000 1800 1600 1400 1300 1000 tOO 6SO t - 157 -ON wn*ii:>3dS CO LU t — t a in U J _ _ l a T 1 I T — r 50.0 100.0 1 I 1 150.0 > i — f — , — i — i — i — | — i — r - h — i — | — i — i — i — i — | — i — i — i — i — | 200.0 250.0 300.0 350.0 400 M/E - 1 G 1 -CO LU in LU J a a 50.0 I 1 100.0 - T - r -150.0 o a V - L O . CO L U £=. * — ' a . L U > C E Q-C\J a i i i — i — i — r r—i—T—r—r 8 i i i 50.0 T T — i — i — i — I — i — i — i — r — I — i — i — i i 100.0 150.0 200.0 250.0 300.0 350.0 400.0 M/E cs o to 8 CO UJ tu 0 2 CH, CO CE LTICM 50.0 100.0 i i—i1 i i i 150.0 200.0 250.0 i |—i—i i 300.0 M/E 350.0 400.0 - 169 -- 171 -- 173 -- v£T -transmittancc 01 + <o a % o o g o £ - 177 -I FKIOUENCY I tM- l 4000 3600 3700 J800 1400 3000 1600 1600 1400 1200 1000 600 650 WAVtUNGOt MIUIMICRONS - 6LT -~ T8T -- 182 -£-1 o o - £8T -- S8T -- 186 -- 187 -FREQUENCY (CM-') 4CO0 3600 3300 3800 3400 3000 1800 1600 1400 1300 1000 800 650 - 188 -- 681 -- 190 -- T6I -- 192 -| FREQUENCY (CM1) WAVCKNCTM MIll lMICRONJ - £61 -i - 1 9 4 - • i I F B E O U E N C Y ( C M 1 tfOO 1 A 0 0 J 3 0 0 3 8 0 0 3 4 0 0 7000 I BOO 1 4 0 0 1 4 0 0 1 3 0 0 1 0 0 0 8 0 0 W A V I if N rim M M ii M I C ii O N S - L6T -- 66T -- 200 -- 201 -I I FREQUENCY (CM-') 4000 3600 3200 3800 2400 2000 1800 1600 1400 1700 1000 800 600 - £0Z -- 204 -- 90S -- 209 -WAVfUNCIM MIUIMICRONS i ' i o I i .1 i • | 50.0 100.0 2 0 7 i "i i i T — i — r 7~"~ 350.0 400 150.0 200.0 250.0 300.0 M/E - 211 -WAVcUNGJII MIUIMICRONS RELATIVE INTENSITY 0.0 25.0 50.0 75.0 100.0 i i i : i 104 ill :J34 J76 - ZTZ -- 213 -I FRCOUHNC* (CM-'I 4C00 3600 320C 3800 3400 3000 1800 1600 K 0 0 1200 ICOO 800 600 i i i | ' I I i | ' i i i | I I I I | i : i I | I—r i I I i I I I I I I I I I i ~ i i i | |' WAVCICNGTH MILLIMICRONS - 214 -V/AVtlfNOTH MIlllMICRONS - 215 -C3__ 50.Q 100.0 150.0 200.0 250.0 300.0 350.0 400.0 M/E - 217 -C J H2-CO ~2L L U I— 2 ° i n L U :> O H 2 1 3 C0 2 H to CO CE lo 11 i • o T i l l 50.0 100.0 T— i—r i i I I T— i— i—r T—i—i—r ~i—r 150.0 200.0 250.0 300.0 -l—i—i—r 350.0 400.Q M/E - 219 -FREQUENCY (CM-1 WAVttfNCIH MIUIMICRONS 0.0 RELRTIVE INTENSITY 25.0 50.0 75.0 100, O H o • o 115 o o o • •205 o J-218 LO o • o 3: rn LO LTI' O 6-o o - 022 -- 221 -FRSOUEHCY (CM-1 4000 3600 3300 3800 3400 3000 1800 1600 1400 1300 1000 800 600 WAVtlCNGTH MILLIMICRONS transmittancc ? 8 ro eg cs I Z ODUcqjosqc - vZZ -- 226 -FREQUENCY (CM-<) 4000 3600 3300 3800 3400 3000 1800 1600 1400 1300 1000 000 600 WAVftfNGl l l MIUIMICRONS LZZ -- 228 -o o - ezz -

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.831.1-0060995/manifest

Comment

Related Items