Synthesis and Absolute Stereochemical Assignment of (+)-Miyakolide

The first total synthesis of the marine macrolide miyakolide has been achieved, and its absolute stereochemistry has been determined. The carbon skeleton is assembled in a convergent fashion from three fragments via esterification, [3 + 2] dipolar cycloaddition, and aldol addition. The utility of â-ketoimide aldol reactions in fragment coupling was demonstrated on fully elaborated intermediates. The coupled material was transformed into a 1,3,7-triketone-containing macrocycle that underwent a facile transannular aldol reaction followed by hemiketalization to form the oxydecalin ring system of the natural product. Deprotection afforded ent-miyakolide, which was produced in 6.8% overall yield and 29 linear steps. The architecture of natural products has long provided the stimulus for the development of new reactions.1 Similarly, postulated biosynthetic pathways to natural products have focused attention on the laboratory simulation of these pivotal events.2,3 We viewed miyakolide (1) as an ideal synthetic target for these reasons (vide infra). Miyakolide was isolated in 1992 from a sponge of the genus Polyfibrospongia by Higa and coworkers.4 Its relative stereochemistry was assigned by X-ray crystallography and supported by detailed NMR spectroscopic studies. Structurally, miyakolide displays a number of features seen in several bioactive marine macrolides. The C1-C3 â-hemiketal ester/acid functionality is shared by natural products such as aplasmomycin,5 aplysiatoxin,6 callipeltoside A,7 and lonomycin A,8 while the C5 exocyclic unsaturated ester is a structural element also found in the bryostatin class of natural products.9 Synthesis Plan.10 The premise underlying the synthesis plan rested on the presumption that the C11-C19 oxydecalin subunit in miyakolide might be assembled spontaneously through an intramolecular aldol reaction (eq 1). If miyakolide is biosynthesized according to the standard polyketide model, an iterative linear chain of subunits would be assembled, followed by macrolactonization, cyclizations, and rearrangements.11 If mac(1) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1990, 29, 1320-1367. (b) Ireland, R. E. Aldrichim. Acta 1988, 21, 59-69. (c) Norcross, R. D.; Paterson, I. Chem. ReV. 1995, 95, 2041-2114. (2) Synthesis has been used as a tool to produce isotopically labeled putative biosynthetic intermediates that are fed to the producing plant or animal in order to study their incorporation into the biosynthetic pathway. Some recent examples in the field of polyketide biosynthesis include: (a) Cane, D. E.; Luo, G. J. Am. Chem. Soc. 1995, 117, 6633-6634. (b) Yue, S.; Duncan, J. S.; Yamamoto, Y.; Hutchinson, C. R. J. Am. Chem. Soc. 1987, 109, 1253-1254. (3) Proposed biosynthetic transformations have been reproduced in laboratory syntheses of natural products in order to test their practicality outside of the biological system and take advantage of the powerful transformations. Some examples include: (a) Johnson, W. S.; Gravestock, M. B.; McCarry, B. E. J. Am. Chem. Soc. 1971, 93, 4332-4334. (b) Gravestock, M. B.; Johnson, W. S.; McCarry, B. E.; Parry, R. J.; Ratcliffe, B. E. J. Am. Chem. Soc. 1978, 100, 4274-4282. (c) Chapman, O. L.; Engel, M. R.; Springer, J. P.; Clardy, J. C. J. Am. Chem. Soc. 1971, 93, 66966698. (d) Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E. J. Am. Chem. Soc. 1982, 104, 5560-5562. (e) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. J. Am. Chem. Soc. 1995, 117, 3448-3467. (f) Williams, D. R.; Coleman, P. J.; Henry, S. S. J. Am. Chem. Soc. 1993, 115, 11654-11655. (4) Higa, T.; Tanaka, J.; Komesu, M.; Gravalos, D. C.; Puentes, J. L. F.; Bernardinelli, G.; Jefford, C. W. J. Am. Chem. Soc. 1992, 114, 75877588. (5) Okazaki, T.; Kitahara, T.; Okami, Y. J. Antibiot. 1976, 29, 10191025. (6) Mynderse, J. S.; Moore, R. E. J. Org. Chem. 1978, 43, 2301-2303. (7) Zampella, A.; D’Auria, M. D.; Minale L.; Debitus, C.; Roussakis, C. J. Am. Chem. Soc. 1996, 118, 11085-11088. (8) (a) Otake, N.; Koenuma, M.; Miyamae, H.; Sato, S.; Saito, Y. Tetrahedron Lett. 1975, 4147-4150. (b) Omura, S.; Shibata, M.; Machida, S.; Sawada, J.; Otake, N. J. Antibiot. 1976, 29, 15-20. (c) Riche, C.; Pascard-Billy, C. J. Chem. Soc., Chem. Commun. 1975, 951-952. (9) Petit, G. R.; Gao, F.; Sengupta, D.; Coll, J. C.; Herald, C. L.; Doubek, D. L.; Schmidt, J. M.; Van Camp, J. R.; Rudloe, J. J.; Nieman, R. A. Tetrahedron 1991, 47, 3601-3610. (10) Progress toward the total synthesis of miyakolide has been reported: Yoshimitsu, T.; Song, J. J.; Wang, G.-Q.; Masamune, S. J. Org. Chem. 1997, 62, 8978-8979. 6816 J. Am. Chem. Soc. 1999, 121, 6816-6826 10.1021/ja990789h CCC: $18.00 © 1999 American Chemical Society Published on Web 07/14/1999 rolactonization indeed precedes the indicated intramolecular aldol construction, macrocyclic precursors such as 2 (Figure 1) could well be found along the biosynthetic pathway. If this reaction is to be integrated into a synthesis plan, the desired aldol adduct constitutes one of four possible product diastereomers, and while this process might be enzymatically mediated, it could also be simply controlled by the conformation of the macrocycle.3ef,12,13 In implementing this strategy, it was felt that macrocycle 2b might provide more conformational ordering in the aldol step than its ring-chain tautomer 2a. To assess the probability that the desired aldol macrocyclic stereocontrol might be possible in 2b, a multiconformational search of the crucial enol ketone intermediate was undertaken using the AMBER force field, restricting the C18-C13 atom distance to a maximum of 4.5 Å.14 Figure 1 depicts the lowest energy structure generated by this search, wherein the C18 and C13 diastereofaces are disposed to deliver the desired stereochemistry following an intramolecular aldol reaction. While a generic metal ion, M, has been incorporated into the 2b-Model illustration, this does not imply that the metal ion was part of the calculation. In this conformation, the chair transition state for the aldol addition is accessible. The other low-energy conformation of 2b, differing by only 0.1 kcal/mol, presents the C17-C19 (si) enol diastereoface opposite to that of the C13 carbonyl moiety; however, the resulting aldol reaction must proceed via a boat transition state. Since a spontaneous transannular aldol addition was anticipated when the three carbonyl groups at C13, C17, and C19 were revealed, we felt it was important to also have the C11 alcohol in its unprotected state prior to this bond construction. The aldol adduct would thus undergo immediate hemiketalization, masking the C17-C19 diketone moiety and suppressing elimination of the C13 hydroxyl moiety. We then elected to mask the C17-C19 diketone as its derived isoxazole,15 which might undergo spontaneous ring closure upon reduction of the N-O bond.16 While two possible isoxazole structures were entertained, we chose to employ isoxazole 3 bearing nitrogen at C19 since the reduction product of 3 might be easily hydrolyzed with assistance of the C11 alcohol following the aldol reaction (Scheme 1).17 In the event that the enaminone failed to participate in oxydecalin formation, this functionality might be hydrolyzed under conditions likely to effect the transannular aldol step.18,19 (11) For recent reviews on the biosynthesis of polyketides, see: (a) Cortes, J.; Haydock, S. F.; Roberts, G. A.; Bevitt, D. J.; Leadlay, P. F. Nature 1990, 348, 176-178. (b) Donadio, S.; Staver, M. J.; McAlpine, J. B.; Swanson, S. J.; Katz, L. Science 1991, 252, 675-679. (c) Malpartida, F.; Hopwood, D. A. Nature 1984, 309, 462-464. (d) O’Hagan, D. Nat. Prod. Rep. 1995, 1-33. (12) Transannular reactions have been postulated in a number of biosynthetic pathways. The dolabellanes are postulated to be biosynthetically converted to the clavularanes and dolastanes via transannular ringcontracting reactions: (a) Look, S. A.; Fenical, W. J. Org. Chem. 1982, 47, 4129-4134. Dactylol is postulated to be biosynthesized from humulene, via a ring-contracting cationic olefin cyclization followed by cyclopropyl cation rearrangement and solvolysis: (b) Schmitz, F. J.; Hollenbeak, K. H.; Vanderah, D. J. Tetrahedron 1978, 34, 2719-2722. (c) Hayasaka, K.; Ohtsuka, T.; Shirahama, H. Tetrahedron Lett. 1985, 26, 873-876. The endiandric acids are postulated to be biosynthesized via a cascade of electrocyclic reactions, including a ring-contracting cyclization: (d) Bandaranayake, W. M.; Banfield, J. E.; Black, D. St. C. J. Chem. Soc., Chem. Commun. 1980, 902-903. (13) Macrocyclic conformation has been employed as a control element in synthesis in several instances: (a) Still, W. C.; Romero, A. G. J. Am. Chem. Soc. 1986, 108, 2105-2106. (b) Schreiber, S. L.; Sammakia, T.; Hulin, B.; Schulte, G. J. Am. Chem. Soc. 1986, 108, 2106-2108. (c) Vedejs, E.; Gapinski, D. M. J. Am. Chem. Soc. 1983, 105, 5058-5061. Macrocyclic ring contractions have been used with success to control diastereoselectivity of the contracted ring-forming reaction. (d) Myers, A. G.; Condroski, K. R. J. Am. Chem. Soc. 1993, 115, 7926-7927. (14) All calculations were performed using the AMBER force field on structures generated by a Monte Carlo multiconformer search using MacroModel (Version 5.0) provided by Professor W. Clark Still, Columbia University. The dielectric coefficient (ELE) in the force field was set at 60 to simulate a polar solvent. Only structures with a C18 to C13 atom distance of 4.5 Å or less that were generated three or more times during the search (out of 150, 000 structures generated) were considered. The AMBER force field was selected because it generated a minimized structure of miyakolide that more closely fit the X-ray crystal structure than structures generated using the MM2 and MM3 force fields. (15) For a review on the use of isoxazoles in synthesis, see: (a) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Simoni, D. Synthesis 1987, 857-869. (b) Little, R. D. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 5 pp 239270. (c) Torssell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis; VCH Publishers: New York, 1988. (d) Caramella, P.; Grunanger, P. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; John Wiley & Sons: New York, 1984; Vol. 1, pp 291-392. (16) Although deprotonation of an enaminone (NaOH) was required to promote an aldol reaction (Yuste, F.; Sanchez-Obregon, R. J. Org. Chem. 1982, 47, 3665-3668), we hoped that the intramolecularity of our transformation would force the reacting partners together and facilitate a reaction under milder conditions. (17) The regioisomeric isoxazole containing nitrogen at C17 was deemed an inferior intermediate, as the aldol adduct would contain a C17 imine that could tautomerize, epimerizing the C16 stereocenter. (18) (a) Kato, N.; Hamada, Y.; Shioiri, T. Chem. Pharm. Bull. 1984, 32, 1679-1682. (b) Eiden, F.; Patzelt, G. Arch. Pharm. (Weinheim, Ger.) 1986, 319, 242-251. (c) Auricchio, S.; Ricca, A.; DePava, O. V. Gazz. Chim. Ital. 1980, 110, 567-570. (d) Kobuke, Y.; Kokubo, K.; Munakata, M. J. Am. Chem. Soc. 1995, 117, 12751-12758. (e) Kashima, C.; Mukai, N.; Tsuda, Y. Chem. Lett. 1973, 539-540. (19) Mineral acids are most commonly employed to achieve this transformation (see ref 18), but model studies on 3-amino-5-oxo-1phenyloct-3-ene demonstrated that this hydrolysis could be achieved under milder conditions such as 4:4:1 AcOH/THF/water; PPTS in THF/water; or CuX2 (X ) Cl, OTf, BF4) and water in a variety of organic solvents. Figure 1. Proposed miyakolide biosynthetic precursors 2a and 2b. The 2b-Model structure, less the metal ion M, minimized using the AMBER forcefield.13 C1-C9 and C21-C27 not shown. Synthesis of (+)-Miyakolide J. Am. Chem. Soc., Vol. 121, No. 29, 1999 6817