44 糖質を出発原料としたα,α-2置換α-アミノ酸構造を有する天然物の合成研究 : ラクタシスチンの全合成(口頭発表の部)

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The novel natural products containingα,α-disubstituted α-amino acid structures, sphingofungin E and F, myriocin, conagenin (1), and lactacystin (2), attracted significant attention because of their interesting biological activities such as neurotrophic factor, immunomodulation, immunosuppressive and enzyme inhibitory activities. We report here preparation of precursors of α,α-disubstituted α-amino acids by way of rearrangement of allylic trichloroacetimidates (Overman rearrangement) derived from carbohydrates, and total synthesis of lactacystin (2) and its analogs starting from D-glucose. The allyl alcohol derivative (4Z) prepared from diacetone-D-glucose was transformed into trichloroacetimidate (5), which was heated in toluene at 140℃ afforded rearranged products 6a and 6b (8.3:1.0) in 78% yield. It was revealed that Overman rearrangement of trichloroacetimidates derived carbohydrates proceeded generally in good yields and in moderate stereoselectivities. The rearranged product 6a was successfully converted into (S)-methylserine derivative (10), which is an amino acid part of conagenin (1). Its enantiomer (11) was also synthesized from compound 6a. Lactacystin (2), reported to show neurotrophic activity as well as inhibitory activity against proteosome, was synthesized stereoselectively using Overman rearrangement as the key transformation. Thermal rearrangement of imidate (17), followed by removal of the acetonide group provided R-19 as the major product (43% from 16). Periodate oxidation afforded aminal (20), which was transformed into γ-lactam (21). Stereoselective introduction of an isopropyl group and oxidation of vinyl function gave 28, whose coupling with N-acetyl cysteine and subsequent deprotection furnished the total synthesis of 2. The analogs of lactacystin containing hydrogen (31) and phenyl group (33) in place of the isopropyl group were prepared from compounds 21 and 24, respectively. This work revealed that the Overman rearrangement of imidates derived from carbohydrates should be an effective approach to α,α-disubstituted α-amino acids.
天然有機化合物討論会の論文
1996-09-02

44 糖質を出発原料としたα,α-2置換α-アミノ酸構造を有する天然物の合成研究 : ラクタシスチンの全合成(口頭発表の部)

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