10 放線菌の生産する神経突起伸長物質ラクタシスチンの合成研究(口頭発表の部)

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Neurotrophic agents such as nerve growth factor (NGF), a well-characterized protein, are required for the survial and function of neurons. In 1991 we reported the isolation and characterization of the first non-protein neurotrophic factor, (+)-lactacystin, a novel sulfur-containing γ-lactam produced by a culture broth of Streptomyces sp. OM-6519. Lactacystin induces neuritogenesis and causes a transient increase in the intracellular cAMP level in Neuro 2a neuroblastoma cells. Corey and Reichard recently reported the first total synthesis of lactacystin. Herein we describe a concise alternative approach, designed to afford easy access to both the natural product and a variety of analogues. Key steps in the elaboration of the lactam moiety include the stereoselective hydroxymethylation of oxazoline 11 and an asymmetric allylboration which introduces the hydroxyl and methyl substituted at C(6) and C(7), respectively. As our point of departure, 2(R), 3(S)-γ-hydroxyleucine methyl ester (10) was treated with methly benzimidate to furnish the trans-disubstituted oxazoline 11. Aldol condensation with formaldehyde via the Seebach protocol then gave 12 exclusively (>98% de). Moffat oxidation of 12 afforded aldehyde 13, which was subjected without purification to allylboration with (E)-crotyldiisopinocampheylborane as described by Brown. The desired γ-methly homoallylic alcohol 15 was thus obtained. Conversion of 16 to carboxylic acid 17 entailed ozonolysis and reductive workup followed by selective oxidation. The key γ-lactam 18 could be elaborated by catalytic transfer hydrogenation of 16 and ester hydrolysis. The amino side chain was incorporated via thioesterification of 18 with BOPCl and N-acetyl-L-cystein allyl ester. Finally, deallylation of 19 gave pure (+)-lactacystin as colorless needles. In summary, the development of an economic and versatile synthetic approach to lactacystin (10 steps, 13% overall yield) should permit the preparation of useful quantities of (+)-lactacystin and its analogues, greatly facilitatin the on going pharmacological studies of neurotrophic factors.
天然有機化合物討論会の論文
1993-09-10

10 放線菌の生産する神経突起伸長物質ラクタシスチンの合成研究(口頭発表の部)

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