Kang Hyun Jung. Introduction Leucascandrolide A (1, Scheme 1) was isolated in 1996 from the calcareous sponge Leucascandra caveolata, collected off the.

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Presentation transcript:

Kang Hyun Jung

Introduction Leucascandrolide A (1, Scheme 1) was isolated in 1996 from the calcareous sponge Leucascandra caveolata, collected off the east coast of New Caledonia, by Pietra and co-workers. - This polyoxygenated 18-membered macrolide features two trisubstituted tetrahydropyran rings, one of which has an unusual oxazole-bearing unsaturated side chain. - Biological studies revealed potent cytotoxic activity against a range of cancer cell lines (IC50¼0.05 and 0.25 mgmL1 against KB oral epidermoid carcinoma and P388 leukemia cell lines, respectively), as well as pronounced antifungal activity.

Retro-Synthetic Analysis

Preparation of Advanced Intermediate 18

Jacobson Asymmetric Hetero Diels-Alder Reaction [1]

Hg II -Mediated Hydration of Alkyne [2] - Alkynes are less basic than alkenes, Hg(OAc) 2 (Hg +2 is a Lewis acid) is added to ensure complete reaction

1,5-Anti Stereoindution in the Boron-Mediated Aldol Reaction [3] Org. Lett.,4, , 2002

1,3-Anti Reduction of β-Hydroxy Ketone [4] J. Am. Chem. Soc., 110, 11, , 1988

Selective Iodine(III)/TEMPO-Mediated Oxidation [5] J. Org. Chem., 62, , 1997

Elaboration to the Macrocyclic Core 24

DIBAL Reduction and in situ Acetylation [6] J. Org. Chem., 61, , 1996

1,3-Asymmetric redution [7]

Mistunobu Macrolactonization (Esterification) [8] Synthesis, 1, 1981

Preparation of the Oxazole-bearing Side Chain 3

α-Alkylation of Hydrazone and Alkyl halide [9]

Sonogashira Coupling of Functionalized Trifloyl Oxazole [10] Org. Lett.,4, , 2002

Completion of the Total Synthesis of Leucascandrolide A

Lindlar Hydrogenation [11]

Conclusion In summary, we have completed a highly stereocontrolled synthesis of the potent cytotoxic macrolide leucascandrolide A, proceeding in 23 steps from 8 (longest linear sequence) and 5.3% overall yield. Key features include a Jacobsen asymmetric hetero Diels-Alder reaction to configure the right-hand tetrahydropyran ring, a 1,5-anti aldol coupling, control over the C17 hydroxy center, and two sequential Mitsunobu reactions, to close the 18-membered macrolactone and append the oxazole-bearing side chain, respectively.