Tetrahedron Letters,Vol.29,No.38,pp 4865-4868,1988 0040-4039/88 $3.00 + .OO Printed in Great Britain Pergamon Press plc

CHIRAL SYNTHONS FOR THE ELABORATION OF MEVINIC ACID ANALOGUES

Frank Bennett and David W. Knight*

Chemistry Department, University of Nottingham, Nottingham, NG7 2RD, U.K.

Garry Fenton

May and Baker Limited, Dagenham, Essex, RMlO 7XS, U.K.

Summary: Baker's yeast reduction of methyl 3-oxo-5-hexenoate (6b) affords

the (R)-hydroxy-ester (7b) (76% ee) which is converted into the lactones

(15) and epoxy-ester (19), synthons of the lactone part of the mevinic

acids.

The discovery1 that the natural products Compactin (la), Mevinolin (lb)

and close relatives, collectively the mevinic acids, are capable of signifi-

cantly reducing serum cholesterol levels in man has resulted in considerable

interest in syntheses of both the natural compounds and of more biologically-

active analogues, 2

a basic tenet being to retain the hydroxy-valerolactone

portion, the function which is primarily responsible for the biological

activity, while replacing the decalin fragment with more readily available and

(2)

(5) (6)

easily variable aromatic functions; 3

thus, many series of 6-styryl and

6-arylethyl-valerolactones (2) have been prepared. To enable rapid access to

such compounds, the availability of lactones (3) or epoxy-esters (4)2'4'5 would

be of considerable benefit, given that such compounds could be prepared easily

4865

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in quantity, with the absolute configuration which mimics that of

mevalonolactone and Compactin. We reasoned that the valerolactone synthons (3)

and (4) could be obtained from the hydroxy-esters (5) which in turn should be

available from asymmetric reduction of the keto-esters (6). 6 A variety of

methods, both chemical and biochemical are available for effecting such

transformations; we were attracted to the possibility of using a Baker's yeast

reduction for which B-keto-esters are especially suitable substrates. 7 We were

pleased to discover that yeast reductions (Dried yeast, sucrose, tap water,

3O"C, ca. - 24h) of the keto-esters (6) proceeded smoothly to give 60-70% isolated

yields of the desired alcohols [(7a) and (7b)l. Analysis of the derived Mosher's

esters 8 by lH n.m.r. revealed enantiomer ratios of 71.5:28.5 (43% ee) for the

ethyl ester (7a) and 88:12 (76% ee) in the same sense for the methyl ester

(7b).'

(6) ii a=Et; b=Me; c=H

PhSe PhSe (‘3) (9)

Selenolactonisation 11 of the hydroxy-acid (7c), [a], -27.3" (c 1.0,

CHC13) (76% ee), derived from ester (7b) [2M NaOH, 20°C, 24 hl, under

kinetic conditions provided a modest 40% yield of the selenolactones L(8) and

(9)] but in a highly stereoselective manner in favour of the trans-lactone (8).

In contrast, lactonisation under thermodynamic conditions afforded ca. 65% of a -

mixture of lactones L(8) and (9) I containing slightly more of the e-isomer

(9). The relative stereochemistries of the two lactones were determined by

reductive removal of the phenylseleno group [Ph3SnH, toluene, reflux, 2.5 hl 12

and chromatographic separation of the resulting lactones [(lo) and (11)l. The

less polar isomer exhibited resonances at 64.38 (app. pentet, J 3.7 Hz) and

64.87 (ddq, J 11.3, 6.4, and 3.1 Hz) assigned to the 4- and 6- protons

respectively by decoupling experiments; these data are consistent with the

trans stereochemistry (lo), in which the 4-H is equatorial, especially when

contrasted with the equivalent data for the more polar cis-isomer (11): 64.25

(dddd, J 9.1, 7.6, 5.8, and 5.6 Hz, 4-H) and 64.37 (ddq, J 11.7, 6.2, and 3.OHz,

6-H). The marked downfield shift of the 6-H resonance in the trans-isomer is

also consistent with a [1.31-diaxial relationship between this proton and the

4-hydroxyl group. The (R)-absolute configuration of the reduction products (7)

4867

was confirmed by conversion of both hydroxy-lactones into Parasorbic acid, the

naturally occurring enantiomer of which has the (S)-configuration (13),13 by

dehydration using POC13 in pyridine [65'C; 50 mins]. The natural product has

[aID =+206"; therefore the maximum possible optical rotations of our samples are

+159o, based on the 16% ee of reduction product (7b). The trans-lactone (10) -

afforded the non-natural enantiomer (12) ([a], -112') while e-lactone (11)

lead to natural Parasorbic acid (13) ([al, +98"). The lower than expected

rotations indicate that some racemisation may have occurred but are more likely

associated with difficulties in handling and purifying small samples of this

lactone. 14

We then turned to the preparation of other precursors of Compactin

analogues from the ester (7b), noting that this contained an excess of the

(R)-enantiomer corresponding to the natural stereochemistry of the mevinic

acids. Treatment of the derived silyl ether (14a) with iodine under kinetic

$Jo- $& k; ~ ,,,,,z f (10) (12) / CO,H

0 0 H

(14)

Hao-Hoo

(11) (13)

a: R='BuSiMq 3 1

b: R ='BuSiPh2 4 1 c: R=?r,Si 5.5 1

conditions [12, NaHC03, CH3CN, O"C, 3h1 15

gave, (80%) a 3:l mixture of the

iodo-lactones [(15a) and (16a) I in favour of the trans-isomer (15a) which could

be obtained isomerically pure by fractional crystallisation from pentane. The

relative stereochemistries were determined in the same way as those of the

foregoing selenolactones. Increases in the size of the silyl protecting group

resulted in higher stereoselectivities; the t-butyldiphenyl derivative (14b)

afforded a 4:l mixture of lactones [(15b) and (16b)l (87%) while the tri-

isopropyl homologue (14~) gave a 5.5:1 ratio of products [(15c) and (16c)l (81%)

The major trans-isomers have the correct absolute configuration for the

synthesis of mevinic acid analogues [cf. (2)l; one direct method for achieving -

(17) (15a+ 160) (18) (19)

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this is by radical mediated coupling reactions with various stannanes. Thus,

treatment of the mixture of iodo-lactones [(15a) and (16a)], with allyltri-

n-butylstannane [AIBN, toluene, 8O"C, 16hl 16 and separation gave an isomerically -

pure sample of the trans-homologue (17), while a similar reaction17 with

8-tri-n-butylstannylstyrene gave the homologue (18). Both reactions proceeded

in unoptimised yields of ca. 40% and both products could be cleanly deprotected - using HF in acetonitrile. Finally, treatment of the iodo-lactone (15a) with

sodium carbonate in methanol (2O"C, 24h) gave the (3g,52)-epoxide (24) in 91%

yield, [a]: -23" (c 1, CHC13). Closely related chiral epoxy-esters, differing in

the nature of the alcohol protecting group, couple very efficiently with

benzylic Grignard reagents,

(2) I of Compactin.4'5

in the presence of CuBr.SMe2, to give analogues [cf.

In summary, we have prepared three types of chiral synthon [(13), (20),

and (24)] for the elaboration of mevinic acid analogues; efforts to convert

these into other mevinic acid analogues and related natural systems will be

reported later.

Acknowledgements: We thank the SERC and May and Baker Limited for financial

support.

References

1.

2.

3.

4.

5. 6.

7.

8.

9.

10. 11. 1'2.

13.

14.

15. 16. 17.

A. Endo, J.Med.Chem., 1985, 28, 401; L. Vega and S. Grundy, J.Am.Med. ASSOC., 1987, 257, 33, and references therein. For a comprehensive review, see T. Rosen and C.H. Heathcock,Tetrahedron, 1986, 18, 4909. See, for example, G.E. Stokker, A.W. Alberts, J.L. Gilfilan, J.W. Huff, and R.L. Smith, J.Med.Chem., 1986, 29, 852, and references therein. Y. Guindon, C. Yoakin, M.A. Bernstein, and H.E. Morton, Tetrahedron Lett., 1985, 26, 1185. B.D. Roth and W.H. Roark, Tetrahedron Lett., 1988, 2, 1255. G.W. Anderson, I.R. Halvstadt, W.H. Miller, and R.O. Roblin, jun., J.Am.Chem.Soc., 1948, 70, 500; H. Hamara and T. Sugawasa, Chem.Lett., 1985, 921. Recent Reviews: T. Oshii and Nakata, Acc.Chem.Res., 1984, 11, 338; C.J. Sih and C.S. Chen, Angew.Chem.Int.Ed.Engl., 1984, 22, 556. S. Butt and S.M. Roberts, Nat.Prod.Rpts., 1986, 2, 489; D. Seebach, M.A. Sutter, R.H. Weber and M.F. Zuger, Org.Synth., 1984, 63, 1. J.A. Dale, D.L. Dull, and H.S. Mosher, J.Org.Chem., 1969, 34, 2543.

Ester (7b) showed [ct12n5 =-23.5" (c 1.1, CHC13). While our studies were in 1o

progress, Tamm and co-workers reported an alternative preparation of

(R)-(7b), based on the use of porcine liver esterase; these authors quote

[a]]r't'=-12.6" (c 1.3, CHC13). P. R MO r, L. Rosslein, and C. Tamm, Helv.Chim.Acta., 1987, 70, 142. K.C. Nicolaou and 2. Lysenko, J.Am.Chem.Soc., 1977, 2, 3185. D.L.J. Clive, G. Chittattu, and C.K. Wong, J.Chem.Soc., Chem.Commun., 1978, 41. L. Crombie and P.A. Firth, J.Chem.Soc., (Cl, 1968, 2852 and references therein. See, for example A.T. Russell and G. Procter, Tetrahedron Lett., 1987, 2, 2041. P.A. Bartlett, D.P. Richardson, and J. Myerson, Tetrahedron, 1984, 40, 2317 G.E. Keck and J.B. Yates, J.Am.Chem.Soc., 1982, 104, 5829. J.E. Baldwin and D.R. Kelly, J.Chem.Soc., Chem.Commun., 1985, 682

(Received in UK 27 July 1988)