A route to large carbocycles using an alicyclic claisen rearrangement

Tetrahedron Letters,Vol.23,No.51,pp P r i n t e d in Great B r i t a i n

A ROUTE

TO LARGE

ALICYCLIC

Andrew

5455-5458,1982

Department

Summary:

A potentially

described

involving

and David W. Knight*

NG7

general

a Claisen

from a p p r o p r i a t e

USING AN

REARRANGEMENT.

of Chemistry,

Nottingham,

derived

CARBOCYCLES

CLAISEN

G. C a m e r o n

0040-4039/82/515455-04503.00/0 © 1 9 8 2 P e r g a m o n Press Ltd.

University

2RD,

route

England.

to large

rearrangement

unsaturated

Park,

carbocycles

of silyl

is

enolates

macrolides.

The C l a i s e n r e a r r a n g e m e n t of both all[l aryl and allyl vinyl ethers is an e x t r e m e l y v a l u a b l e s y n t h e t i c method. ± A u s e f u l v a r i a n t of this r e a c t i o n is the r e a r r a n g e m e n t of silyl e n o l a t e s of allyl esters, leading to ¥, 6 - u n s a t u r a t e d c a r b o x y l i c acids, d e v e l o p e d p r i m a r i l y by Ireland. 2 This m e t h o d offers the twin advantages of r e a d i l y available s t a r t i n g m a t e r i a l s and m i l d e r r e a r r a n g e m e n t conditions. Our idea was to apply this m e t h o d to the synthesis of large c a r b o c y c l e s (3) by rea r r a n g e m e n t of the e n o l a t e s (2) d e r i v e d from a p p r o p r i a t e u n s a t u r a t e d m a c r o l i d e s (i). Until recently, there were no efficient, g e n e r a l syntheses of such m a c r o l i d e s but due to the n o t a b l e efforts of Corey, Masamune, M u k a i y a m a and Gerlach, among others, a n u m b e r of m e t h o d s are now a v a i l a b l e for t h e i r e l a b o r a t i o n , u s u a l l y from the c o r r e s p o n d i n g ~ - h y d r o x y - a c i d s . 3 The t r a n s f o r m a t i o n (i) ÷ (3) has p r e v i o u s l y been shown by D a n i s h e f s k y 4a to be useful for the p r e p a r a t i o n of six- and s e v e n - m e m b e r e d c a r b o c y c l e s from ~ - v i n y l - v a l e r o l a c t o n e s and c a D r o l a c t o n e s and used in an e l e g a n t synthesis of the s e s q u i t e r p e n e widdrol. 4b A recent report by Funk et.al, w h i c h further extends this idea prompts us to report our own results in this area. As starting materials, we used the readily a v a i l a b l e e - o x o - e s t e r s (4a) and (4b). The former was o b t a i n e d by o z o n o l y s i s of m e t h y l iOu n d e c e n o a t e w h i l e (4b) was p r e p a r e d from c y c l o d o d e c a n o n e by s e q u e n t i a l B a e y e r - V i l l i g e r oxidation, m e t h a n o l y s i s and o x i d a t i o n using p y r i d i n i u m chlorochromate. T h e s e were then c o n v e r t e d into the h y d r o x y - a c i d s (5a) and (5b) by reaction with vinyl m a g n e s i u m b r o m i d e at -78oc f o l l o w e d by s a p o n i f i c a t i o n and also into the h y d r o x y - a c i d s (6a) and (6b) by W i t t i g r e a c t i o n with f o r m y l t r i p h e n y l p h o s p h o r a n e followed by b o r o h y d r i d e r e d u c t i o n and saponification. Good yields were o b t a i n e d in all these steps. We next e x a m i n e d a n u m b e r of p r o c e d u r e s 3 for the l a c t o n i s a t i o n of the h y d r o x y - a c i d s (5a,b) and (6a,b). W h i l e these were m o d e r a t e l y successful, they were not amenable for the p r e p a r a t i o n of m u l t i g r a m q u a n t i t i e s of the r e q u i r e d m a c r o l i d e s as e x p e n s i v e reagents and high d i l u t i o n conditions were required. These p r o b l e m s were o v e r c o m e by c o n v e r t i n g the h y d r o x y - a c i d s to the c o r r e s p o n d i n g allylic chlorides (5c,d) an~ (6c,d), and using the l a c t o n i s a t i o n p r o c e d u r e of Galli and M a n d o l i n i 6 (see below). Initially, a m a j o r d r a w b a c k with the approach was that both isomers of the allylic c h l o r i d e were formed from a single hydroxy-acid; for example, t r e a t m e n t of h y d r o x y - a c i d (5b) with thionyl chloride gave a m i x t u r e of (6d) and (5d) in a ratio of 77:23. However, both (6a] and (6b) could be c l e a n l y c o n v e r t e d into the 5455

5456

c o r r e s p o n d i n g chlorides (6c) and (6d) by u s i n g h e x a c h l o r o a c e t o n e and t r i p h e n y l p h o s p h i n e at -78°C + OOC in > 70% isolated yield. 7 The h y d r o x y - a c i d s (5a) and (5b) were also c o n v e r t e d into the chlorides (5c) and (5d) r e s p e c t i v e l y by using the same reagent m i x t u r e but at room temperature. In these cases, the r e g i o s e l e c t i v i t y was > 90%. The m a c r o l i d e s (7a,b) and (8a,b) were p r e p a r e d by adding a s o l u t i o n of the c o r r e s p o n d i n g chlorides in DMSO via m o t o r driven syringe to a hot s u s p e n s i o n of p o t a s s i u m c a r b o n a t e in DMSO. 6 A key factor with this m e t h o d is that the m a c r o l i d e s can be i s o l a t e d simply by continuous e x t r a c t i o n of the r e a c t i o n m i x t u r e with p e t r o l (b.p. 40-60o), thus a v o i d i n g a tedious and w a s t e f u l aqueous work-up. (The residual DMSO may be d i s t i l l e d and re-used). In this way, the d e s i r e d m a c r o l i d e s (7a,b) and (Sa,b) were o b t a i n e d in ca.60% i s o l a t e d yields, a c c o m p a n i e d by 5-10% of the c o r r e s p o n d i n g diolides. A f t e r a n u m b e r of trials, we found that the m a c r o l i d e s (7a,b) and (8a,b) could be e f f i c i e n t l y c o n v e r t e d into the c o r r e s p o n d i n g silyl enolates (c.f.2; R = SiButMeg) by r e a c t i o n with t w o 2 e q u i v a l e n t s of h e x a n e - f r e e li--6~ium d i i s o p r o p y l ~ m i d e in T H F - H M P A (3:1) for O . 7 5 h at -78°C, followed by q u e n c h i n g with [ - b u t y l d i m e t h y l s i l y l chloride. A f t e r a simple aqueous work-up, the silyl e n o l a t e s were r e f l u x e d in toluene for ca. 4h, and the p r o d u ct s h y d r o l y s e d with HF in acetonitrile, then--esterified (CHgNp) and c h r o m a t o g r a p h e d , to give the c a r b o c y c l e s (9a,b) and (iOa,5)-in 60-70% overall, isolated, yields. This m e t h o d therefore r e p r e s e n t s a r e l a t i v e l y brief, e f f i c i e n t and p o t e n t i a l l y general route to m e d i u m - s i z e d and large carbocycles. Unfortunately, the overall s t e r e o s e l e c t i v i t y in all the cases is rather low. The c a r b o c y c l e s (9a) and (9b) were i s o l a t e d as 5:1 and 3:1 m i x t u r e s of the cis and trans isomers r e s p e c t i v e l y while (iOa) and (lOb) were i s o l a t e d as 1-2:1 and 1-5:1 m i x t u r e s respectively of the trans- and cis-isomers. M o l e c u l a r models indicate that the r e a r r a n g e m e n t s of the enolates d e r i v e d from m a c r o l i d e s (7a,b) could p r o c e e d via a chair or b o a t - l i k e t r a n s i t i o n state, 4a if it is assumed that only (Z)-lithio- and hence the (E)-silyl enolates are formed~ giving rise--to the trans- or cis- c a r b o c y c l e s (9a,b) respectively. Similarly, r e a s o n a b l e chair and boat c o n f o r m a t i o n s can be c o n s t r u c t e d w h i c h account for the f o r m a t i o n of both the cis- and trans- isomers of (iOa,b) from the m a c r o l i d e s (8a,b)} Finally, we have also e x a m i n e d the r e a r r a n g e m e n t of the llm e m b e r e d m a c r o l i d e (ii), readily p r e p a r e d from 2 - m e t h y l d i m e d o n e by the m e t h o d of M a h a j a n ~ T r e a t m e n t of (ii) with 3.5 eq. of LDA f o l l o w e d by trapping of both the ketone and lactone enolates w i t h B u t M e 2 S i C l and t h e r m o l y s i s in toluene resulted, after the usual work up, in the isolation of only two, separable, d i a s t e r e o i s o m e r s in a ratio of 95:5. We have a s s i c n e d structure (12) to the m a j o r isomer on the basis of spectral data and m o l e c u l a r models~ assuming that the k i n e t i c (i.e. the less substituted) enolate of the ketone and only the (E)-silyl e n o l a t e of the lactone function are formed~ The m i n o r isomer is e p i m e r i c at the m e t h y l group ~- to the ketone group, and both are p r o b a b l y formed via a b o a t l i k e t r a n s i t i o n state. 5 Thus, in a g r e e m e n t w i t h the findings of D a n i s h e f s k y et.al. 4 and Funk et. al}, such r e a r r a n g e m e n t s seem to have c o n s i d e r ~ l e p o t e n t i a l for-internal a s y m m e t r i c induction. Acknowledgements We thank

the SERC

for financial

support

(to A.G.C.) .

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S.J~ Rhoads and N.R. Raulins, O_rrg.React., 1975, 22, i; G.B. Bennett, S y n t h e s i s , 1977, 589; F.E. Ziegler, Acc.Chem. Res., Io, 227.

1977,

5457

~

O °R

OHC (C H 2 )nC:02Me

~ T ~ ( c H2)nC%H

XL-.v~/"(C H ) CO H 2n

X

(4) a; n=8

(6) a; n = 8 ; X = O H

(5) a; n = 8 ; X = O H

b ; n=lO

2

(3)

(2)

(i)

CO H

b; n = I O ; X = O H

b; n = I O ; X = O H

c; n = 8 ; X = C I

c; n = 8 ; X = C I

d; n = I O ; X = C I

d; n = I O ; X = C I

~ (7) a; n:l;

~o /O

(8) a; n=l;

b; n=3

CO.e (9) a; n=l;

b; n=3

b; n=3

.~ H C % Me

(10)

a; n=l;

b; n=3

.h .j- co~-o (ii)

(12)

2

5458

2.

R.E. Ireland and R.H. Mueller, J.Am. Chem. Soc., 1972, 94, 5897; R.E. Ireland and A.K. Willard, T e t r a h e d r o n Lett., 1975, 3975; R.E. Ireland, A.K. Willard, and R.H. Mueller, J.Am. Chem. Soc., 1976, 98, 2868, J.Org.Chem., 1976, 41, 986; R.E. Ireland, S. Thaisrivongs, and C.S. Wilcox, J.Am. Chem. Soc., 1980, 102, 1155; R.E. Ireland, J.D. Godfrey, andS. T h a i s r i v o n g s , ibid., 1981, 103, 2446. See also, R.T. A r n o l d and C. Hoffmann, S[nth. Commun., 1972, 2,27; J.E. Baldwin and J.A. Walker, J.Chem. S o c . , C h e m . C o m m u n . , 1973, TI7; J.A. K a t z e n e l l b o g e n and K.J. Christry, [email protected]., 1974, 39, 3315; S.R. Wilson and R.S. Myers, ibid., 1975, 4__O0, 3309; G . F r a t ~ , Chimica, 1975, 29, 528.

3.

For reviews, see K.C. Nicolaou, Tetrahedron, 1977, 33, 683; S. Masamune, G.S. Bates, and J.W. Corcoran, Angew. C--hem. Int. Ed. En~l., 1977, 16, 585.

4.

(a) S. Danishefsky, R.L. Funk, and J.F. Kerwin, Jr., J.Am. Chem. Soc., 1980, 102, 6889; (b) S. D a n i s h e f s k y and K. Tsuzuki, ibid., p.6891.

5.

M.M. Abelman, R.L. Funk, and J.D. Munger, Jr., J.Am.Chem. Soc., 1982, 104, 4030. These authors have i n t r o d u c e d the term "alicyclic Claisen rearrangement" to describe t r a n s f o r m a t i o n s such as (i) + (3) .

6.

C. Galli and L. Mandolini,

7.

R.M. Magid, O.S. Fruchey, W.L. Johnson, J.Orq.Chem., 1979, 44, 359.

8.

W.C.

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J.R. Mahajan,

Still and I. Galynker, Synthesis,

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Synth.,

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1976,

ii0.

(Received in UK 14 October 1982)

1978, 58,

98.

and T.G. Allen,

1981, 37,

3981.