P-49 Natural Product Synthesis Based on the Efficient Synthesis and Stereoselective Reaction of Epoxides

Asano Masayoshi, Takanami Tsukasa, Tokoro Hiroki, Nagasawa Chiaki, Nishiyama Shigeru, Sugai Takeshi

doi:10.24496/tennenyuki.47.0_379

Although the use of epoxides as the key intermediates in natural product syntheses has extensively been demonstrated, those examples are rather limited to stable and/or readily accessible compounds. In our poster presentation, we describe two examples towards attractive and challenging problems: 1) an in situ preparation of very unstable epoxide and the immediate regioselective opening; 2) an efficient epoxidation of α,β-unsaturated ester, which would enable the expeditious syntheses of natural products The first topic is a five-step and scalable synthesis of cytoxazone, a novel cytokine modulator, which was accomplished in a total 51% yield from p-methoxycinnamyl alcohol without any protective groups. The keystep was the new one-pot azidohydroxylation procedure by the combined use of NaN_3-H_2O_2-CH_3CN. The epoxidation of an olefin by means of an in situ-formed iminohydroperoxide worked well, accompanied by the concomitant ring opening reaction with an azide ion exclusively at the benzylic position. The desired oxazolidinone structure was obtained by the successive reduction of resulting azidoalcohol, carbamylation, and the final nitrosation-diaminocyclization of the carbamylamino diol in a regioselective manner. Throughout the synthesis, every step could effectively be performed in aqueous media. The second topic is a short-step chemoenzymatic synthesis of symbioramide, a marine-origin ceramide, which consist of the D-erythro dihydrosphingosine and long-chain (R)-β,γ-unsaturated α-hydroxycarboxylic acid. We synthesized both of the synthetic intermediates from the common α,β-epoxycarboxylic ester, which was prepared by the epoxidation of methyl 2-octadecenoate. The use of m-chloroperoxybenzoic acid in 1,2-dichloroethane was effective, and the reaction proceeded (94%) to give methyl 2,3-epoxyoctadecanoate. The addition of radical inhibitor under deoxygenated conditions was essential to prevent the autodegradation of m-CPBA. This epoxide was treated with magnesium perchlorate to give the desired β,γ-unsaturated α-hydroxy ester (60%). Two geometrical isomers were merged into pure (E)-isomer through oxidation-reduction procedure (76%). Candida antarctica lipase-mediated hydrolysis provided pure (E)-hydroxy acid. Finally, Pseudomonas cepacia lipase-mediated enantioselective acylation on (S)-isomer (E value 86) and the subsequent methylation yielded unreacted (R)-hydroxy ester (40%) with 99.5% ee. In turn, in the dihydrosphingosine synthesis, the same epoxy ester was treated with sodium azide with a preferential attack at α-position (6: 1). Under the conditions that acetic acid was added as the proton source instead of conventional ammonium chloride, the undesired in situ-epimerization at α-position could completely suppressed. Finally, an unprecedented direct coupling of dihydrosphingosine and hydroxy ester was realized without any protective groups, by means of Candida antarctica mediated aminolysis. Natural enantiomer of simbiolamide (38%), accompanied with a diastereomer derived from unnatural L-enantiomer of dihydrosphingosine (37%) were obtained.

P-49 Natural Product Synthesis Based on the Efficient Synthesis and Stereoselective Reaction of Epoxides

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P-49 Natural Product Synthesis Based on the Efficient Synthesis and Stereoselective Reaction of Epoxides

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