J. Am. Chem. SOC.1990, 112, 3018-3028
3018
Total Synthesis of Both (+)-Compactin and (+)-Mevinolin. A General Strategy Based on the Use of a Special Titanium Reagent for Dicarbonyl Coupling Derrick L. J. Clive,**'K. S. Keshava Murthy, Andrew G. H. Wee,J. Siva Prasad, Gil V. J. da Silva, Marek Majewski, Paul C. Anderson, Claire F. Evans,2 Richard D. Haugen? Louis D. Heerze, and James R. Barrie2 Contribution from the Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2. Received June 26, 1989
Abstract: A strategy is described for stereocontrolled synthesis of hypocholesterolemic compounds, (+)-compactin and (+)-mevinolin, by an approach (Scheme 11) based on 6,7,4-pentenal (9a),and (R)-3-methyl-4-pentenal (9b). The Evans asymmetric Diels-Alder technique was used (Scheme 111) to prepare 13, which was converted into the cis ester 17. Chain extension, iodolactonization, and elimination of HI then gave optically pure 6. The homochiral epoxide 24, made (Scheme IV) from (.!$)-malic acid, was converted into 25 and then, by iodocarbonation, hydrolysis, and ketalization, into the iodo ketal 7. Evans asymmetric alkylation was used (Scheme V) to prepare 9b. Ozonolysis, ketalization, and reduction (LiAIH,) of 28 gave 31,which was transformed by Swern oxidation, Wittig methylenation, and acid hydrolysis into 9b. An optically pure intermediate (8), common to both syntheses, was assembled (Scheme VI) by alkylation of 6 with 7, reduction to a mixture of lactols, allylic oxidation, and decarbonylation. Aldol condensation (Scheme VII) of 8 with 4-pentena1, triethylsilylation, and ozonolysis gave the enone aldehydes 39,epimeric at C-1. A modified McMurry reaction requiring an excess of a reagent prepared from C8K and Tic& (2:l molar ratio) in DME, produced the ethers 40, which were converted into (+)-compactin by appropriate modification of the oxygen functionality. The strategy is general and was applied with minor modifications (Scheme VIII) to the synthesis of (+)-mevinolin.
Scheme I
Introduction3
R,SiO
The fungal metabolites (+)-compactin (la)4*5and (+)-mevinolin (1b)6 are the best-known of a small groupsb+'of natural products that have attracted much attention on account of their usefulness as metabolic probes for studying cholesterol homeostasis*and their
0
0
(a) i aldol ii siIyIation
P
/
1
(b) ozone
( I ) Dedication: To the memory of my father. (2) Summer Undergraduate Research Student. (3) Preliminary communication: Clive, D. L. J.; Keshava Murthy, K. S.; Wee, A. G.H.; Siva Prasad, J.; da Silva, G. V. J.; Majewski, M.;Anderson, P. C.; Haugen, R. D.; Heerze, L. D. J. Am. Chem. Soc. 1988, 110, 6914. (4) Nonsystematic numbering is used in this publication, except in the experimental section. (5) (a) Brown, A. G.;Smale, T. C.; King, T. J.; Hasenkamp, R.; Thompson, R. H. J . Chem. Soc., Perkin Trans. I 1976,1165. (b) Endo, A,; Kuroda, M.; Tsujita, Y. J . Anfibiot. 1976, 29, 1346. (6) (a) Alberts, A. W.; Chen, J.; Kuron, G.; Hunt, V.;Huff, J.; Hoffman, C.; Rothrock, J.; Lopez, M.; Joshua, H.; Harris, E.; Patchett, A.; Monaghan, R.; Currie, S.;Stapley, E.; Albers-SchGnberg, G.; Hensens, 0.; Hirshfield, J.; Hoogsteen, K.; Liesch, J.; Springer, J. Proc. Narl. Acad. Sci. U S A . 1980, 77, 3957. (b) Endo, A. J. Anfibiof.1979, 32, 852. (7) E.g.: (a) Lam, Y. K. T.; Gullo, V. P.; Goegelman, R. T.; Jorn, D.; Huang, L.; DeRiso, C.; Monaghan, R. L.; Putter, I. J. Anfibior. 1981,34,614. (b) Albers-SchGnberg, G.; Jashua, H.; Lopez, M. B.; Hensens, 0. D.; Springer, J. P.; Chen, J.; Ostrove, S.;Hoffman, C. H.; Alberts, A. W.; Patchett, A. A. J. Anribior. 1981, 34, 507. (c) Endo, A,; Hasumi, K.; Negishi, S . J . Anfibiof. 1985, 38, 420. (d) Endo, A.; Hasumi, K.;Nakamura, T.; Kunishima, M.; Masuda, M. J. Anribior. 1985, 38, 321. (e) Serizawa, N.; Nakagawa, K.; Hamano, K.;Tsujita, Y.; Terahara, A.; Kuwano, H. J . Antibioi. 1983, 36, 604. (f) Serizawa, N.; Nakagawa, K.; Tsujita, Y.; Terahara, A.; Kuwano, H. J. Anribiof. 1983, 36, 608. (8) Serizawa, N.; Nakagawa, K.; Tsujita, Y.; Terahara, A.; Kuwano, H.; Tanaka, M. J. Anribiof. 1983, 36, 918. (h) Yamashita, H.; Tsubokawa, S.; Endo, A. J. Antibiot. 1985, 38,605. (i) Endo, A.; Yamashita, H.; Naoki, H.; Iwashita, T.; Mizukawa, Y. J. Anribiof. 1985, 38, 328. G) Komagata, D.; Yamashita, H.; Endo, A. J. Anribior. 1986, 39, 1574. (k) Serizawa, N.; Nakagawa, K.; Tsujita, Y.; Terahara, A. Agdc. Biol. Chem. 1984.48, 2581. (I) Sato, S.; Furukawa, Y. J. Anfibiof.1988,41, 1265. (m) Endo, A.; Komagata, D.; Shimada, H. J . Anribior. 1986,39, 1670. (n) Serizawa, N.; Serizawa, S.; Nakagawa, K.; Fuuya, K.;Okazaki,T.; Terahara, A. J . Anfibiof.1986, 36, 887. ( 0 ) Chem. Absrr. 1982,97,4664~. (p) Chem. Absrr. 1983, 99,68799s. (4) Chem. Absrr. 1983, 99,70288t. (r) Chem. Absrr. 1984, 101, 282922. (s) Chem. Absrr. 1988, 108, 166115q. (8) (a) Brown, M. S.; Goldstein, J. L. Angew. Chem.,Int. Ed. Engl. 1986, 25, 583. (b) Grundy, S. M. West. J. Med. 1978, 128, 13.
Ti 0
potential value in the treatment of hypercholesterolemic individuals. The primary characteristic of the two compounds is their
la R = H lb R=Me ability9 to lower blood levels of cholesterol, specifically plasma low density lipoprotein (LDL)Io cholesterol, in man. This is a significant property because high blood levels of LDL cholesterol are associated" with coronary atherosclerosis,'* a majorI3 cause (9) (a) Tobert, J. A.; Bell, G.D.; Birtwell, J.; James, I.; Kukovetz, W. R.; Pryor, J. S.; Buntinx, A.; Holmes, I. B.; Chao, Y.-S.; Bolognese, J. A. J. Clin. Inuesr. 1982, 69, 913. (b) Mabuchi, H.; Haba, T.; Tatami, R.; Miyamoto, s.; Sakai, Y.;Wakasugi, T.; Watanabe, A,; Koizumi, J.; Takeda, R. N.Engl. J. Med. 1981, 305, 478. (10) (a) Goldstein, J. L.; Brown, M. S . Annu. Reu. Biochem. 1977, 46, 897. (b) Havel, R. J.; Goldstein, J. L.; Brown, M. S . In Metabolic Conrrol and Disease, 8th ed.; Bondy, P. K., Rosenberg, L. E.; Eds; Saunders: Philadelphia, PA, 1980; p 393.
0002-7863/90/ 15 12-3018$02.50/0 0 1990 American Chemical Society
J . Am. Chem. SOC.,Vol. 112, No. 8, 1990 3019
Synthesis of Compactin and Mevinolin
of death in Western industrialized societies. Scheme 11 The development of drugs14 to treat hypercholesterolemia is, OR' of course, regarded as a very important problem. Compactin and mevinolin represent lead compounds for one approach that is being investigated intensively. The compounds are reversible, competitive 7 inhibitorskJ5 of 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMG CoA reductase), the enzyme involvedi6 in the committing step of cholesterol biosynthesis. A significant portion of total body d cholesterol is generated by endogenous synthesis,sb mainly in the liver, and the ability to perturb the biosynthetic process has turned 5 6 out to be helpful in lowering blood cholesterol, although the mechanism is indirect. The biologically active forms of compactin and mevinolin are the corresponding hydroxy a ~ i d resulting ~ ~ ~ J ~ ~ from hydrolysis of the lactone substructure. A cell respond~&~@'~ % G O R ' in a variety of ways to inhibition of HMG CoA reductase. More P H of the enzyme is synthesized, so that steroid production continues but, in addition, an increased number of LDL receptors is formed on the cell surface, and it is these additional receptors that are directly responsible for mediating the observed reduction in plasma LDL levels of the steroid. The supply of cholesterol to a cell is not seriously impaired; the essential difference is that it now occurs lOa,b 9a,b 8 at a lower plasma LDL Our selection of compactin and the stereochemically more intricate mevinolin as targets for total synthesis was based in part la,b R' = SiPh,Bu-t; R = H or Me on the fact that synthetic contributions might prove to be of value in the design of new inhibitors for HMG CoA reductase. We were until we were already committed to an approach which, from our aware that mevinolin l b is several times as powerfuP in its point of view, appeared sufficiently promising to warrant combiochemical action as compactin la, and, since the only difference pletion. Accordingly, our plan was not influenced by any need between the two substances is the presence in one of a methyl to avoid similarity with other routes, and the method we used group to replace a hydrogen, it was clear that the biological activity turned out to be quite different from those developed elsewhere.*z can be improved by modifications to ring A. There was little else We considered first the means by which ring A could be built in the way of structure-activity correlations available to us at the onto the ring B portion. The presence of the C-l4 oxygen function time,I9 and so we wanted to devise a synthesis that was sufficiently and the oxidation level of C-4a was very suggestive to us of an general to afford a variety of analogues without extensive modaldol condensation, and that thought led to the question of how ification of the approach for each compound. Our primary aim to generate the 4,4a double bond. Posed in this way, the problem was to make analogues differing in the substitution pattern of ring immediately brought to mind the idea of using an intramolecular A because we knew that such alterations could be useful. McMurry reaction, and so we decided to attach the left-hand Development of the Synthetic Plan. No total synthesis had been portion of ring A by the aldol and McMurry processes outlined published in this area when we began, and none was to appear in Scheme I. This was the only plan we considered seriously, because our commitment to it was reinforced by model studies (1 I ) (a) Grundy, S. M. J . Am. Med. Assoc. 1986,256,2849. (b) Castelli, which quickly suggested it would work. However, the preliminary W. P.; Garrison, R. J.; Wilson, P. W. F.; Abbott, R. D.; Kalousdian, S.; experiments failed to indicate the difficulties we would encounter Kannel, W. B. J . Am. Med. Assoc. 1986,256, 2835. (c) Strong, J. P. J. Am. when the titanium-induced coupling (Scheme I, step c) was applied Med. Assoc. 1986, 256,2863. (d) Stamler, J.; Wentworth, D.; Neaton, J. D. J . Am. Med. Assoc. 1986, 256, 2823. (e) PyBrllii, K. Eur. Heart J . 1987, to sensitive and highly oxygenated materials. In retrospect, this 8, (Suppl. E), 23. situation was fortunate because it prompted us to develop a (12) (a) Fuster, V. Scand. J. Haematol., Suppl. 1981,27 (Suppl. 38), 1. modification of the classical McMurry reagent, with the result (b) Ross, R. Annu. Rev. Med. 1979, 30, 1. (c) Smith, E. B. Adu. Lipid Res. that the annulation process used here (see Scheme I) represents 1974, 12, 1. (13) (a) Thom, T. J.; Epstein, F. H.; Feldman, J. J.; Leaverton, P. E. Inr. a general method of ring c o n s t r u c t i ~ n . ~ ~ J. Epidemiol. 1985, 14, 510. Our preliminary experimentsz4involved testing the above plan (14) (a) Suckling, K. E.; Grwt, P. H. E. Chem. Br. 1988,24 (5). 436. (b) and dealt also with the synthesisz5of the lactone portion (ring C) Brown, M. S.; Goldstein, J. L. In The Pharmaceutical Basis of Therapeutics,
:1
LJ
-
d4 1
sGoR'
7th ed.; Gilman, A. G., Goodman, L. S., Rall, T. W., Murad, F., Eds.; Macmillan: New York, 1985; p 827. (15) (a) Endo, A.; Kuroda, M.; Tanzawa, K. FEBS Lea. 1976, 72, 323. (b) Endo, A. J . Med. Chem. 1985,28,401. (c) Brown, M. S.; Faust, J. R.; Goldstein, J. L.; Kaneko, I.; Endo, A. J . Biol. Chem. 1978, 253, 1121. (d) Kita, T.; Brown, M. S.; Goldstein, J. L . J. Clin. Irwest. 1980,66, 1094. (e) Nakamura, C. E.; Abeles, R. H. Biochemistry 1985,24, 1364. (f) Endo, A. J. Antibiot. 1980,33,334. (g) Tanzawa, K.; Endo, A. Eur. J. Biochem. 1979, 98, 195. (h) Kaneko, 1.; Hazama-Shimada, Y.; Endo, A. Eur. J . Biochem. 1978, 87, 313. (i) Schloss, J. V. Acc. Chem. Res. 1988, 21, 348. (16) (a) Rodwell, V. W.; Nordstrom, J. L.; Mitschellen, J. J. Adu. Lipid Res. 1976, 14, 1. (b) Rodwell, V. W.; McNamara, D. J.; Shapiro, D. J. Adu. Enzymol. 1973, 38, 373. (c) Stryer, L. Biochemistry; Freeman: New York, 1988; p 556. (d) Brown, M. S.; Goldstein, J. L. J. LipidRes. 1980, 21, 505. (17) Brown, M. S.; Goldstein, J. L. Sci. Am. 1984, 251 (3,58. (18) (a) Brown, M. S.; Goldstein, J. L. N . Engl. J . Med. 1981, 305,515. (b) Grundy, S. M.; Bilheimer, D. W. Proc. Natl. Acad. Sci. U.S.A. 1984,81, 2538. (c) Hoeg, J. M.; Brewer, H. B., Jr. J. Am. Med. Assoc. 1987, 258,3532, and references therein. (19) For recent structure-activity studies, see, for example: (a) Stokker, G. E.; Alberts, A. W.; Anderson, P. S.; Cragoe, E. J., Jr.; Deana, A. A,; Gilfillan, J. L.; Hirshfield, J.; Holtz, W. J.; Hoffman, W. F.; Huff, J. W.; Lee, T. J.; Novello, F. C.; Prugh, J. D.; Rwney, C. S.; Smith, R. L.; Willard, A. K. J. Med. Chem. 1986, 29, 170 and earlier parts of this series. (b) Heathcock, C. H.; Hadley, C. R.; Rosen, T.; Theisen, P. D.; Hecker, S. J. J . Med. Chem. 1987, 30, 1858. (c) Heathcock, C. H.; Davis, B. R.; Hadley, C. R. J . Med. Chem. 1989, 32, 197. (d) Reference 15b.
>"
(20) Synthesis of (+)-mevinolin: (a) Hirama, M.; Iwashita, M. Tetrahedron Lett. 1983,24, 181 1. (b) Wovkulich, P. M.; Tang, P. C.; Chadha, N. K.; Batcho, A. D.; Barrish, J. C.; UskokoviE, M. R. J . Am. Chem. Soc. 1989, 111, 2596. (21) Synthesis of (+)-compactin: (a) Hsu, C.-T.; Wang, N.-Y.; Latimer, L. H.; Sih, C. J. J . Am. Chem. SOC.1983, 105, 593. (b) Girotra, N. N.; Wendler, N. L. Tetrahedron Lett. 1982,23, 5501. Girotra, N. N.; Wendler, N. L. Tetrahedron Lett. 1983, 24, 3687. Girotra, N. N.; Reamer, R. A,; Wendler, N. L. Tetrahedron Lett. 1984,25, 5371. (c) Hirama, M.; Uei, M. J . Am. Chem. SOC.1982, 104, 4251. (d) Grieco, P. A.; Lis, R.; Zelle, R. E.; Finn, J. J . Am. Chem. SOC.1986, 108, 5908. (e) Rosen, T.; Heathcock, C. H. J . Am. Chem. SOC.1985,107, 3731. (f) Keck, G. E.; Kachensky, D. F. J. Org. Chem. 1986,51,2487. (g) Kozikowski, A. P.; Li, C.4. J . Org. Chem. 1987,52,3541. (h) Danishefsky, S. J.; Simoneau, B. J . Am. Chem. SOC.1989, I l l , 2599. (22) Review of synthetic work: Rosen, T.; Heathcock, C. H. Tetrahedron 1986,42,4909. Synthesis of (+)-dihydrmmpactin: (a) Yang, Y.-L.; Manna, S.; Falck, J. R. J. Am. Chem. SOC.1984, 106, 3811. Synthesis of (+)-di-
hydromevinolin: (a) Davidson, A. H.; Jones, A. J.; Floyd, C. D.; Lewis, C.; Myers, P. L. J. Chem. SOC.,Chem. Commun. 1987, 1786. (b) Hecker, S. J.; Heathcock, C. H. J. Am. Chem. Soc. 1986,108,4586. (c) Falck, J. R.; Yang, Y.-L. Tetrahedron Lett. 1984, 25, 3563. (23) Clive, D. L. J.; Keshava Murthy, K. S.; Zhang, C.; Hayward, W. D.; Daigneault, S. J. Chem. SOC.,Chem. Commun. In press. (24) Anderson, P. C.; Clive, D. L. J.; Evans, C. F. Tetrahedron Lett. 1983, 24, 1373.
CIiue et al.
3020 J . A m . Chem. SOC..Vol. 112, No. 8, 1990 Scheme IiI'
Scheme IV"
0
0
0
20 R' = H
21 R' = SiPhzBu-t Id
COOMe
-. 25 R' = SiPh,Bu-t
R' = SiPh2Bu-t 23 R = Ms R' = SiPh2Bu-t
HO
HOOC
5 18 6 " (a) BuLi, THF, -78 OC; crotonyl chloride, -78 OC, 30 min; 79%; (b) butadiene, Et,AICI (3.15 mol per mol 12), -10 "C, 16 h; 56%; (c) BnOLi, THF, 0 OC, 5 h; 87%; (d) MeOLi, MeOHCH2CI2,reflux, 46 h; 87%; (e) LDA, THF, -78 "C; add 15, -78 OC, 45 min; AcOH, -78 OC; 90%;(f) spinning band distillation; ( 9 ) LiAIH4, THF, reflux, 15 h; 99%; (h) ( I ) TsCI, CH,CI,, pyridine, DMAP (catalyst), room temperature, 24 h; 90%; (2) NaCN, DMSO, 75 OC, 10 h; 92%; (3) aqueous NaOH, reflux, 24 h; 92%; (i) ( I ) NaI, 18-crown-6, CH2CIz, MCPBA, ca. 0 OC, 1.25 h; 91%; (2) DBU, PhMe, reflux, 2 h; 79%.
and the problem of joining it to the other segments. This work which is described in the Supplementary Material, led to racemic 2 and 3 and to the optically pure lactone 4.
i
26 R = SiPh,Bu-t
7qgosiph2Bu-t 7
"(a) BH3-Me2S, (MeO),B, THF, -5 OC, 51 h; ca. 100%; (b) 3,3dimethoxypentane, CH2CI2,TsOH-H20,room temperature, overnight; 71%; (c) r-BuPh,SiCI, CH2C12, Et,N, DMAP (catalyst), room temperature, 18 h; 96%; (d) 80% v/v aqueous AcOH, 50 OC, 4 h; 84%; (e) MsCI, CH2CI2, pyridine, -30 OC, 3 h; room temperature, 40 h; 68%; (f) BnMe,N+OH-, MeOH-ether, room temperature, 30 min; 91%;(g) CH2=CHLi, CuCN, THF, -60 OC; add 24, -10 "C, 4 h; 96%; (h) BuLi, THF, 0 OC; pass in C 0 2 at 0 "C, 1 h; I,, 0 "C, 15 min, room temperature 2 h; 74%; (i) ( I ) dry acetone, TsOH.H,O (0.61 mol per mol 26), room temperature, 91 h; (2) t-BuPh,SiCI, CH2CIz, Et,N, DMAP, room temperature, 2 h; 67% overall.
metric Diels-Alder technique27(Scheme 111). The chiral auxiliary 11,28easily prepared in optically pure29form, was converted into 12 by acylation with the acid chloride of (,!?)-crotonic acid.27 Diels-Alder reaction with butadiene then yielded the adduct 1330 from which the auxiliary was displaced (13 14) by the action of lithium benzyloxide. As we needed the methyl ester, we did try to displace the heterocyclic unit directly with lithium methoxide, but the reaction does not work. In contrast, ester exchange (14 15)with lithium methoxide proceeds smoothly, and, from this point, deprotonation and reprotonation generated a mixture of epimeric methyl esters 16 (cis:trans, 65:35). The desired cis isomer 17 was isolated by spinning band di~tillation.~'Reduction gave alcohol 5, and this was transformed into the bicylic lactone 6 by the reactions summarized in Scheme 111. The process involved converting the hydroxyl function of 5 into a leaving group by tosylation followed by displacement with cyanide ion. Hydrolysis of the resulting homologated nitrile then took the sequence as far as acid 18. Finally, iodolact~nization~~ and elimination of hydrogen halide with 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) completed our synthesis of the bicyclic lactone 6. It should be explained that in the Diels-Alder reaction, use of a (2)-crotonyl unit in the dienophile (cf. 12) would be expected to produce a cis disubstituted cyclohexene directly and so remove
-
2
3
4
These experiments were carefully designed to explore a stereocontrolled and flexible approach to compactin and mevinolin with the serious intention of subsequently making both compounds. Our experience in preparing the model compounds served to define a plan in the form shown by Scheme 11, and this is the manner in which the natural products were actually assembled. The approach is built around the homochiral bicyclic lactone 6,to which were attached the atoms destined to became the lactone subunit. This was achieved by alkylating 6 at C-9 with iodide 7. Several more operations then gave the enone 8-a key intermediate since it represents, in suitably protected form, the BC ring system of both natural products. The aldehydes %,b provided the left-hand portion of ring A, and this unit was attached to enone 8 by aldol condensation (Scheme 11, Robinson curved arrow). Then, at a slightly later stage (see lOa,b), ozonolysis of the pendant olefin and intramolecular dicarbonyl coupling (Scheme 11, dotted arrow), using a special titanium reagent, served to complete the diene chromophore. Construction of the Homochiral Subunits. Preparation of the Ring B Precursor 6. The bicyclic lactone 6 was made from the homochiral cyclohexenemethanol 5 (Scheme II), which was constructed by two independent routes. The first involved elaboration of D-ghCal triacetate and has already been described26 in detail; however, for large scale work we used the Evans asym(25) Majewski, M.; Clive, D. L. J.; Anderson, P. C. Tetrahedron Lerr. 1984, 25, 2101. (26) Siva Prasad, J.; Clive, D. L.J.; da Silva, G. V. J. J . Org. Chem. 1986, 51, 2717.
-
(27) (a) Evans, D. A.; Chapman, K. T.; Bisaha, J. J . Am. Chem. SOC. 1984,106,4261. (b) Evans, D. A.; Chapman, K. T.; Bisaha, J. J . Am. Chem. SOC.1988,110, 1238. (28) Evans, D. A.; Weber, A. E. J. Am. Chem. SOC.1986, 108, 6757. (29) rac-11 was prepared from dl-phenylalanine. The Mosher imides formed from roc-11 with (R)-a-methoxy-a-(trifluoromethyl)phenylacetyl chloride were examined by 'HNMR (200 MHz). The two diastereoisomers were readily distinguished, and examination of the Mosher imide from optically active 1 1 showed it to be optically pure. (30) Formation of 13 proceeds with de >95%. Pure 13 is easily isolated. (3 1 ) In principle, the trans isomer and the mixed fractions, which together amount to ca. 36%of the initial still pot charge, can be recycled. The desired cis isomer amounts to ca. 50% of the initial still pot charge. (32) Srebnik, M.; Mechoulam, R. J . Chem. Soc., Chem. Commun. 1984, 1070.
J . Am. Chem. SOC.,Vol. 112, No. 8, 1990 3021
Synthesis of Compactin and Meoinolin
-
the need for e p i m e r i ~ a t i o n(cf. ~ ~ 16 17). This approach was not tried because we suspected from other experiments that the Z geometry would not be preserved during cycloaddition, and, indeed, the unsuitability of (Z)crotonyl systems was subsequently reported.27b Attempts to gain access to optically pure ester 17 by chemical resolution starting from appropriate racemic precursors, such as the racemic acid34 corresponding to 15 (see Scheme 111), were not successful, and, in any case, only an unusually efficient resolution would have been a c ~ e p t a b l e . ~ ~ Preparation of the Ring C Precursor 7. The iodide 7, which would provide the constituent atoms of the ring C lactone of both natural products, was prepared by reactions summarized in Scheme IV. The method is very similar to that used earlier in our model s t ~ d y , but ~ ~ aJ number ~ of significant improvements were introduced and a more felicitous choice of protecting group was made for the primary hydroxyl function. In this series of compounds we also verified the optical purity for the key intermediate, 24; in the model ~ o r optical k ~ purity ~ ~was~taken ~ for granted, based on the mode of synthesis.37 Reduction37bof (S)-malic acid to (S)-l,2,4-butanetriol (19) was accomplished with borane-methyl sulfide complex. This method is far more convenient, at least in our experience, than other procedures that have been reported,38 and it provides the triol in almost quantitative yield. Ketalization by a literature procedure39then gave alcohol 20. The use of diethyl ketone here, instead of acetone, which is the obvious choice, is based on the fact that with the former ketone the product is not contaminated by the isomeric ketal involving the oxygens on C- 13 and C- 15.40 The primary hydroxyl of 20 was protected (20 21) by silylation, and the ketal was then hydrolyzed (21 22) under conditions that do not disturb the silicon substituent. Selective mesylation afforded the primary mesylate 23, and this led to optically pure epoxide 24 when treated with base. We were careful to ensure that our mesylate was free of isomeric material carrying the methanesulfonyloxy group on C-13 and the hydroxyl at C-12, as such a compound would generate the enantiomer of epoxide 24. Fortunately, the secondary mesylate, which was formed to some extent, could be removed by chromatography, but, as a precaution, we proved that our epoxide was optically pure by the simple method described in the Supplementary Material. The remaining carbons for the ring C subunit were introduced with dilithium (cyan0)divinylcuprate (24 25). At this stage, iodocarb~nation~~ (25 26), followed by acid-catalyzed hydrolysis in acetone and ketalization in the same mixture (26 7), completed our preparation of the subunit destined to become the lactone ring. The product of iodocarbonation contained ('HNMR) 11% of the C-11 epimer, but the iodo ketal 7 was pure. The conditions needed for hydrolysis and ketalization of 26 caused some loss of the silicon-protecting group; however, this problem was easily corrected by resilylating the crude product. The desired material was obtained in 67% overall yield from the carbonate. Preparation of the Ring A Precursors, Aldehydes 9a and 96. Aldehyde 9a is a known4*compound, but the methyl-substituted
--
-
-
-
(33) The enantiomer of 12 would, of course, have to be used. (34) Green, N.; Beroza, M. J . Org. Chem. 1959, 24, 761. (35) Cf.: Sonnet, P. E.; McGovern, T. P.; Cunningham, R. T. J. Org. Chem. 1984, 49, 4639. The route (Scheme 111) to optically pure 17 also constitutes a synthesis of the active isomer of trimedlure, a synthetic attractant for the Mediterranean fruit fly. (36) See Supplementary Material. (37) Reduction of @)-malic acid is known to give optically pure triol. Cf.: (a) Tandon, V. K.;van Leusen, A. M.; Wynberg, H. J . Org. Chem. 1983,#8, 2767. (b) Hanessian, S.; Ugolini, A.; Dub€, D.; Glamyan, A. Con. J . Chem. 1984, 62, 2146. (38) For a list of methods, see literature cited in refs 37a and 37b. (39) Masamune, S.; Ma, P.; Okumoto, H.; Ellingboe, J. W.; Ito, Y . J. Org. Chem. 1984, 49, 2834. (40) (a) Cf.: Meyers, A. I.; Lawson, J. P. Tetrahedron Lett. 1982, 23, 4883. (b) Presumably, increased nonbonded interactions further destabilize the six-membered ketal with respect to the five-membered isomer when diethyl ketone is used. (41) (a) Bongini, A.; Cardillo, G.; Orena, M.; Porzi, G.; Sandri, S . J. Org. Chem. 1982, 47, 4626. (b) Bartlett, P. A.; Meadows, J. D.; Brown, E. G.; Morimoto, A.; Jernstedt, K. K. J . Org. Chem. 1982, 47, 4013.
Scheme Va
I1 0
i
Ph
27
f? \
