Asymmetric Aldol and Asymmetric Alkylation-Olefin Metathesis: Enantioselective Synthesis of Carbocycles and Heterocycles
Asymmetric Aldol Additions with Acyloxazolidinethiones
A new paradigm is currently being utilized for the enantioselective synthesis of carbocycles and heterocycles. Studies in asymmetric enolate technology are at the center of this area of research. The development of highly selective methods for control of acyclic stereochemistry, such as the asymmetric aldol addition of titanium enolates of acyl oxazolidinethiones and the asymmetric glycolate alkylation, are being combined with the ring-closing metathesis reaction for the efficient, enantioselective synthesis of carbon and heterocyclic rings.
The chlorotitanium enolates of N-acylaoxazolidinones 1, N-acyloxazolidinethiones 2, N-acylthiazolidinethiones 3 generated by treatment with titanium tetrachloride and (-)-sparteine undergo highly selective and efficient aldol reactions with aldehydes. The N-acyloxazolidinethione and N-acylthiazolidinethione auxiliaries are also significantly easier to cleave and can be recovered by simple base extraction. This minor alteration of the Evans aldol can reduce the cost of the reaction and improve its utility and potential for scale up.(1)
The asymmetric glycolate alkylation reaction of N-glycolyloxazolidinones provides a highly selective method for the synthesis of selectively protected homoallylic alcohols. A variety of protecting groups can be tolerated and the reaction is highly selective even with complex glycolates with other preexisting stereogenic centers.(2)
The combination of the olefin metathesis reaction with these two powerful methods for the control of acyclic stereochemistry has allowed rapid entry into a variety of carbocycles and heterocycles. A short, enantioselective synthesis of the anti-AIDS agent 1592U89 (3) has been accomplished through the asymmetric aldol-metathesis strategy and a highly efficient synthesis of the marine metabolite laurencin has been completed using the asymmetric glycolate alkylation-olefin metathesis combination.4
The outlined strategy is currently being applied to the synthesis of a variety of naturally occurring compounds. These include the antitumor agent mucocin, the marine toxin brevetoxin A and other medium ring ethers such as obtusenyne and trans-isoprelaurefucin.
Crimmins, M.T.; King, B.W. J. Am. Chem. Soc. 1998, 120, 9084-9085. Crimmins, M.T.; King, B.W.; Tabet, E.A., Chaudhary, K. J. Org. Chem. 2001, 65, 0000.
Crimmins, M.T.; Emmitte, K.A., Katz, J.D. Organic Lett. 2000, 2, 2165.
Crimmins, M.T., King, B.W. J. Org. Chem. 1996, 61, 4192-4193.
Crimmins, M.T.; Emmitte, K.A. Organic Lett. 1999, 1, 2029-2032. Crimmins, M.T.; Choy, A.L. J. Am. Chem. Soc. 1999, 121, 5663-5660.
Applications of Stereoselective Photocycloadditions in Synthesis
Stereoselective intramolecular photocycloadditions are under development for their application to the synthesis of polycyclic natural products such as ginkgolide B and CP-263,114. The strategy for these syntheses relies on a highly stereoselective intramolecular photocycloaddition in which the stereochemistry of the photoaddition of enone is controlled by the stereogenicity of the substituents on the tether between the enone and the olefin. Some important general implications in the mechanism and predictability of stereochemistry of photocycloadditions have been discovered during the studies on the photoaddition of 10 and similar substrates. A chairlike transition state, with the substituents equatorially positioned on the initially formed five membered ring, generally predicts the experimentally observed product. Molecular mechanics calculations of the various conformers correlate well with experimental product ratios.
This general approach has been utilized in a highly selective synthesis of the PAF antagonist ginkgolide B. (1) The preparation of photosubstrate 10 takes advantage of a tandem conjugate addition cycloacylation reaction of zinc-copper homoenolates on acetylenic esters recently developed in our laboratory. (2) The stereochemistry of the photoaddition of enone 10 is controlled by the stereogenicity of the triethylsilyloxy substituent on the tether.
These basic principles are being expanded to prepare crossed photoaddition products. Under normal circumstances, enone-olefins tethered by three atoms give exclusively straight adducts leading to fused tricyclic systems, however, if a temporary, removable linker is incorporated into the photosubstrate, the equivalent of the crossed adducts can be obtained with high selectivity. (3)
Crimmins, M.T.; Pace, J.M.; Nantermet, P.G.; Kim-Meade, A.S.; Thomas, J.B.; Wagman, A.S.; Watterson, S.H. J. Am. Chem. Soc. 2000, 122, 8453-8463.
Crimmins, M.T.; Nantermet, P.G.; Trotter, B.W.; Vallin, I.M.; Watson, P.S.; McKerlie, L.A.; Reinhold, T.L.; Cheung, A.W.H.; Stetson, K.A.; Dedopoulou, D.; Gray, J.L. J. Org. Chem. 1993, 58, 1038-1047. Crimmins, M.T.; Guise, L.E.; Lacy, D.B.; Huang, S.J. Tetrahedron Lett. 1995, 36, 7061-7065.
Crimmins, M.T.; Hauser, E.B. Organic Lett. 2000, 2, 281-284.
Synthesis and Applications of Spiroketals
The studies in spiroketal chemistry center around the addition of metalated pyrones to beta-alkoxy aldehydes followed by acid catalyzed cyclization for the synthesis of 6,6-spiroketals. These spiroketals can be further functionalized and used as stereochemical templates for the control of stereochemistry on the rigid spiroketal template. Once properly functionalized, the spiroketals can be used directly or selectively converted to 2,6-tetrahydropyrans by a regio and stereoselective reductive cleavage, which has recently been developed.
Pyrones as Polyketide Equivalents: Synthesis of Spongistatin and Leucascandrolide A
A synthesis of the extraordinary tumor inhibitor spongistatin, which exploits pyrones as a fundamental building block, was recently initiated in our laboratory. Spongistatin has been found to be extraordinarily effective against a variety of highly chemoresistant tumor types, which comprise the NCI panel of 60 human cancer cell lines. Human melanoma, lung, brain, and colon cancers were found to be especially sensitive to spongistatin. The activity of spongistatin correlates well with the class of microtubule interactive antimitotics. Because of the extremely limited availability of spongistatin from natural sources, [400 kg wet weight of Spongia sp. provided only 13.8 mg of spongistatin], synthesis may be essential for providing adequate quantities of the substance for biological studies.
The basic approach to the C1 to C28 fragment is illustrated below. γ-Pyrones such as 2-methylpyrone 11 shown below are equivalent to 1,3,5-tricarbonyls and as such are polyketide equivalents. Addition of the lithium anion of 2-methylpyrone with the chiral aldehyde provides the pyrone 12 in high yield. Exposure of 13 to trifluoroacetic acid in benzene gives good yields of the spiroketal 14. This basic strategy has been used to construct the AB1 and the CD2 spiroketals of spongistatin.
Reductive Cleavage of Spiroketals
The majority of these studies have centered on the synthesis of stereochemically complex spiroketals for their direct incorporation into complex molecules. Applications involving reductive cleavage of the anomeric center also have significant potential utility. The exploitation of a regio and stereocontrolled reductive cleavage of unsymmetrical spiroketals such as 15 could be a valuable method for the synthesis of both 2,6-disubstituted tetrahydropyrans similar to 16 and acyclic stereochemical arrays as found, for example, in leucascandrolide A, a known antitumor agent. Spiroketal alcohol 15 was exposed to aluminum trichloride or tin tetrachloride and triethyl silane to produce a single detectable product 16. This highly selective reductive cleavage arises from bidentate coordination of the Lewis acid with the hydroxyl oxygen and the proximal anomeric oxygen. (3,4)
The formation of a spiroketal as a template for stereocontrol followed by a reductive cleavage to produce a 2,6-disubstituted tetrahydropyran is currently being evaluated for a synthesis of the antitumor agent leucascandrolide A.
Crimmins, M.T.; Washburn, D.G. Tetrahedron Lett. 1998, 39, 7487-7490.
Crimmins, M.T.; Katz, J.D. Organic Lett. 2000, 2, 957-960.
Crimmins, M.T.; Rafferty, S. W. Tetrahedron Lett. 1996, 37, 5649-5652.
Crimmins, M.T.; Carroll, C.A.; King, B.W. Organic Lett. 2000, 2, 597-599.