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Enantioselective synthesis of the hydroxy-lactone moiety of mevinic acids
oMo-4039m $6.00+.00 Pexgumnhrn
Temhe&m Lettars.Vol. 34,No. 23,pi. 3705-3186.1993 Primedin GreatBrimin
ENANTIOSELECTIVESYNTHES IS OF THE HYDROXY-LACIONE MOIETY OF MRVINIC ACIDS Ray McCagueP Homcio F. 0hvo.b and Stanley M. Robutah a Chiros Ltd., Science Park, MiltonRoad, Cambridge, CB4 4WE b ChemisttyDepartment,Exeter Uuiversity, Exeter, Devon EX4 4QD
Abstract: 2:Oxa-4endo-hydroxy~~~lo[3.3.0]-oct-7-en-3~one was .msolved. with Pseudomqnas jluoye~pase and one of the enanttomers was convetted mto a hey mtermedtate in the synthests of mevmr . Mevinic acids such as corn actin and mevinolin have been shown to inhibit 3-hydroxy-3enzyme in the cholesterol methylglutaryl coenxyme A & O-CoA) reductase, the rate liiting biosyntheskt Structure activity relationships revealed that the hydroxy-la&one moiety of such compounds is ease&al for biological activity.2 consequently a great amount of effort has been dimcted toward the synthesis of this enantiomekally pure moiety3 and simple dclivat.ives.~
R=H (+)-compacdn R= Me (+)-mevmolin
Water promoted hetero Diels-Alder cycloaddition of glyoxylic acid with cyclopentadiene and rearrangement of the bicyclic oleflnlc adduct yields w (S-1 aadwm-nydroxylactones in a 4: 1 ratio? The major compound is puriikd b either column chromatography, or recrystallktion from extraction liquors. This hydmxylactone has Le nshowntobeanewsyntbon,usedbyOriecoin~syn~of Sesbanimk# and by our grou in the synthesis of (-)-Carbovk.7 &Hydroxylactone W-1 hasbeen resolved using Pseudomonas& fescens lipuse (PPL) either by estuiflcation in au organic solvent. or hydrolysis of the acetyl ester in a buffer solution. Thus when hydroxylactone 1 is estuikd with FFL in tse when acetyl ester 2 is vinyl acetate, the ester (-)_2 and alcohol (+)-1 are obtain@ con hydrolyxed with PFL in an aqueous solution the ester (+)-2 and alcoholu=rw (0 -1 am obtained (Scheme I). In our previous communication the absolute stereochemistry of the resolved lactones was de&mined by the synthesis of (-)-Cmbovir starting from the (->lactone 2.7 In this communication, we show how the (+)-lactone 2 can be converted into a chiral immediate for the synthesis of hypocholestaemic agents.
oRa
aorb, B
(k) 1 R= H
(k) 2 R= AC
oRa
+
B r”,:iLg =
so a (+) 1 R= H (+) 2 R= AC
Reagents: a. PFL, vinyl aceb. PFI+ buffer solubi~n, pH=7. Scheme I. Resolution of the endo-Hydroxylactone.
3785
3786
2 R=Ac
3 R= H [a]= + 121” d ( 4 R= TBDMS [a]= + 57”
8 R= gDMS [a]= - 2.5” 7 [cc]=- 72’ 6 [cc]= - 21“ 9 R=H [a]=+ 1.2” ~~.~~,~~~~~~~~~~~~~~. DMAp, E$?za& h. m&k NB;co3. fi. Scheme II. Synthesis of the Hydroxy Lactone Moiety. Hydroxylactone (+)-1 or ester (+)-2 can be reduced to the dio13 in a three step sequence which embodies LiAUQ reduction, sodium periodate diol cleavage, and NaBb reduction (39%).7 Dio13 is selectively monopro&&& with TBDMSQ using DMAP and triethylamine c1046).8 Allylic alcohol 4 is oxidized (FCC in CH&) to tiord the cyclopentenone 5, which was stereoselectively oxidized to the epoxide 6 (66%). The a,&epoxycyclopentanone was reduced using Keck’s aluminium amalgam conditions9~10 to the B_hydroxy cyclopentanone 7 (100%). Baeyer-Villiger oxidation ofcyclopentanone 7 provided the desired lactone 8 (93%) which v the comet stereogenic centres of the mevinic aculs. In o&r to correlate this compound with a known intermediate, the protecting group was removed; the diol9 was identical to that reported by Takano.11 Other synthetic uses of the hydroxylactone enantiomers (+)_l and(-)-1 areunder investigation. Acknowledements: Wethankthe LINK Scheme (Fellowship to HFO).
SERC, DTl
chiros for support under the Biotransformations
1. D.R Sliskovic. J.A. Picard, W.H. Roark. B.D. Roth, E. Ferguson. B.R. Krause.RS. Newton.C. Sekerke. and iU.K. Shaw, 1. Med. Cheni. 1991.34,367.2. G.E. Stokker, W.F. H0ffman.A.W. Albuts,E.J. Cragoe, Jr., A.A. Deana, J.L.Gilfibn, J.W. Huff, F.C. Novello, J.D. Prugh. R.L. Smith, A.K. Willard J. Med. Chem. 198!i, 28,347. and 3. a) S. VaIven$e. J.C. Lopez, A.M. Gomez, and S. Garcia-Gchoa,J. Org. Chem. 19!&52.1613, refmccs themin. bl M. Temda. K. Mikami. and T. Nakai. Termhedron Left. 199L32.935.c) E. Baadcr, W. Barma&, G. Beck, A. Bergma&. H.-W. Fchlhber, H. Jendrah, K. K&&r, R. kit, H. Schussler, V. Teek, M. Weber, and 0. Wess, TetmhedronL&t. 1988.29.2563. d) B.D. Roth, aud W.H. Roark, Teimhedron Left. 1988 29.1255. 4. a) T. Minami and T. Hiyama, Tefraheuion Left. l992,33,7525. b) CM. Blackwell, A.H. Davidson, S.B. Launchbmy. C.N. Lewis, E.M. Morrice, MM. Reeve,J.A.R. Roffey. A.S. Tipping, and RS. Todd, J. Or . Chz. l992,57,55%. c) D.V. Pad, R.J. Schmidt, and E.M. Gordon. J. Or f&n. 1992.57.7 f43. a). F. Bennett, D.W. Kni@% and G. Fenton, J. Ckm. Sm. Per&inTmns. f Hanesslan,P.J. Ro , M. Petrim, P.J. Hodges, R Di Fahio, and G. Carganico, J. Org. ’ ~&?&O, 55.5766. r) W.i. John son, A.B. Kelson, and J.D. JZlliot, Tetmhedron Left. l988,32, A. Lubineau, J. Auge and N. L&in, Tetrahedronbtt. 1991.32.7529. :: P.A. Grieco, .K.J. Henry, J.J. Nunes an_dJ. Ematt, J. Chem. Sot. Chem. Commun., 1992,368. . 7. ~;h;ac3fCgh, R. M&ague, H.F. Ohvo, C.F. Pahner, and S.M. Roberts, 1. Chem. Sue. Perkrn Trans. 9 . Hemandez, TetrahedronLAW.1979.99. !I $2 m%t D Nickell and P Weidez Qwth Co?nmun.1979,9,281. 10. W.P. Schneider, G.L:B&y and’F.H. Lincoln, J: Chem-.Sot. Chem. Commun., 1913,254. 11. S. Takano, Y. Shhazakj Y. Sekiguchi, and K. Ggasawa, Synthesis 1989,539.
(Received in UK 2 April 1993)
Temhe&m Lettars.Vol. 34,No. 23,pi. 3705-3186.1993 Primedin GreatBrimin
ENANTIOSELECTIVESYNTHES IS OF THE HYDROXY-LACIONE MOIETY OF MRVINIC ACIDS Ray McCagueP Homcio F. 0hvo.b and Stanley M. Robutah a Chiros Ltd., Science Park, MiltonRoad, Cambridge, CB4 4WE b ChemisttyDepartment,Exeter Uuiversity, Exeter, Devon EX4 4QD
Abstract: 2:Oxa-4endo-hydroxy~~~lo[3.3.0]-oct-7-en-3~one was .msolved. with Pseudomqnas jluoye~pase and one of the enanttomers was convetted mto a hey mtermedtate in the synthests of mevmr . Mevinic acids such as corn actin and mevinolin have been shown to inhibit 3-hydroxy-3enzyme in the cholesterol methylglutaryl coenxyme A & O-CoA) reductase, the rate liiting biosyntheskt Structure activity relationships revealed that the hydroxy-la&one moiety of such compounds is ease&al for biological activity.2 consequently a great amount of effort has been dimcted toward the synthesis of this enantiomekally pure moiety3 and simple dclivat.ives.~
R=H (+)-compacdn R= Me (+)-mevmolin
Water promoted hetero Diels-Alder cycloaddition of glyoxylic acid with cyclopentadiene and rearrangement of the bicyclic oleflnlc adduct yields w (S-1 aadwm-nydroxylactones in a 4: 1 ratio? The major compound is puriikd b either column chromatography, or recrystallktion from extraction liquors. This hydmxylactone has Le nshowntobeanewsyntbon,usedbyOriecoin~syn~of Sesbanimk# and by our grou in the synthesis of (-)-Carbovk.7 &Hydroxylactone W-1 hasbeen resolved using Pseudomonas& fescens lipuse (PPL) either by estuiflcation in au organic solvent. or hydrolysis of the acetyl ester in a buffer solution. Thus when hydroxylactone 1 is estuikd with FFL in tse when acetyl ester 2 is vinyl acetate, the ester (-)_2 and alcohol (+)-1 are obtain@ con hydrolyxed with PFL in an aqueous solution the ester (+)-2 and alcoholu=rw (0 -1 am obtained (Scheme I). In our previous communication the absolute stereochemistry of the resolved lactones was de&mined by the synthesis of (-)-Cmbovir starting from the (->lactone 2.7 In this communication, we show how the (+)-lactone 2 can be converted into a chiral immediate for the synthesis of hypocholestaemic agents.
oRa
aorb, B
(k) 1 R= H
(k) 2 R= AC
oRa
+
B r”,:iLg =
so a (+) 1 R= H (+) 2 R= AC
Reagents: a. PFL, vinyl aceb. PFI+ buffer solubi~n, pH=7. Scheme I. Resolution of the endo-Hydroxylactone.
3785
3786
2 R=Ac
3 R= H [a]= + 121” d ( 4 R= TBDMS [a]= + 57”
8 R= gDMS [a]= - 2.5” 7 [cc]=- 72’ 6 [cc]= - 21“ 9 R=H [a]=+ 1.2” ~~.~~,~~~~~~~~~~~~~~. DMAp, E$?za& h. m&k NB;co3. fi. Scheme II. Synthesis of the Hydroxy Lactone Moiety. Hydroxylactone (+)-1 or ester (+)-2 can be reduced to the dio13 in a three step sequence which embodies LiAUQ reduction, sodium periodate diol cleavage, and NaBb reduction (39%).7 Dio13 is selectively monopro&&& with TBDMSQ using DMAP and triethylamine c1046).8 Allylic alcohol 4 is oxidized (FCC in CH&) to tiord the cyclopentenone 5, which was stereoselectively oxidized to the epoxide 6 (66%). The a,&epoxycyclopentanone was reduced using Keck’s aluminium amalgam conditions9~10 to the B_hydroxy cyclopentanone 7 (100%). Baeyer-Villiger oxidation ofcyclopentanone 7 provided the desired lactone 8 (93%) which v the comet stereogenic centres of the mevinic aculs. In o&r to correlate this compound with a known intermediate, the protecting group was removed; the diol9 was identical to that reported by Takano.11 Other synthetic uses of the hydroxylactone enantiomers (+)_l and(-)-1 areunder investigation. Acknowledements: Wethankthe LINK Scheme (Fellowship to HFO).
SERC, DTl
chiros for support under the Biotransformations
1. D.R Sliskovic. J.A. Picard, W.H. Roark. B.D. Roth, E. Ferguson. B.R. Krause.RS. Newton.C. Sekerke. and iU.K. Shaw, 1. Med. Cheni. 1991.34,367.2. G.E. Stokker, W.F. H0ffman.A.W. Albuts,E.J. Cragoe, Jr., A.A. Deana, J.L.Gilfibn, J.W. Huff, F.C. Novello, J.D. Prugh. R.L. Smith, A.K. Willard J. Med. Chem. 198!i, 28,347. and 3. a) S. VaIven$e. J.C. Lopez, A.M. Gomez, and S. Garcia-Gchoa,J. Org. Chem. 19!&52.1613, refmccs themin. bl M. Temda. K. Mikami. and T. Nakai. Termhedron Left. 199L32.935.c) E. Baadcr, W. Barma&, G. Beck, A. Bergma&. H.-W. Fchlhber, H. Jendrah, K. K&&r, R. kit, H. Schussler, V. Teek, M. Weber, and 0. Wess, TetmhedronL&t. 1988.29.2563. d) B.D. Roth, aud W.H. Roark, Teimhedron Left. 1988 29.1255. 4. a) T. Minami and T. Hiyama, Tefraheuion Left. l992,33,7525. b) CM. Blackwell, A.H. Davidson, S.B. Launchbmy. C.N. Lewis, E.M. Morrice, MM. Reeve,J.A.R. Roffey. A.S. Tipping, and RS. Todd, J. Or . Chz. l992,57,55%. c) D.V. Pad, R.J. Schmidt, and E.M. Gordon. J. Or f&n. 1992.57.7 f43. a). F. Bennett, D.W. Kni@% and G. Fenton, J. Ckm. Sm. Per&inTmns. f Hanesslan,P.J. Ro , M. Petrim, P.J. Hodges, R Di Fahio, and G. Carganico, J. Org. ’ ~&?&O, 55.5766. r) W.i. John son, A.B. Kelson, and J.D. JZlliot, Tetmhedron Left. l988,32, A. Lubineau, J. Auge and N. L&in, Tetrahedronbtt. 1991.32.7529. :: P.A. Grieco, .K.J. Henry, J.J. Nunes an_dJ. Ematt, J. Chem. Sot. Chem. Commun., 1992,368. . 7. ~;h;ac3fCgh, R. M&ague, H.F. Ohvo, C.F. Pahner, and S.M. Roberts, 1. Chem. Sue. Perkrn Trans. 9 . Hemandez, TetrahedronLAW.1979.99. !I $2 m%t D Nickell and P Weidez Qwth Co?nmun.1979,9,281. 10. W.P. Schneider, G.L:B&y and’F.H. Lincoln, J: Chem-.Sot. Chem. Commun., 1913,254. 11. S. Takano, Y. Shhazakj Y. Sekiguchi, and K. Ggasawa, Synthesis 1989,539.
(Received in UK 2 April 1993)