62 機能性複素五員環を活用するVirginiamycin M2の全合成研究

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Virginiamycin M2 (V-M2) (1) is an antibiotic isolated from Streptomyces species. Its molecular structure has been shown to be a macrocyclic (27-membered ring) lactone-lactam derivative containing four asymmetric carbon atoms, a trisubstituted E,E-diene, an E-α,β-unsaturated carboxylic acid amide, and an oxazole ring. Our synthetic strategy is synthesis of four segments shown in the text followed by their condensation: in other words, this is a convergent method. We developed functional five-membered heterocycles (2〜5) and utilized them effectively to solve all of the problems for the total synthesis of V-M2 (1). The segment A was synthesized through the Cornforth's procedure as shown in Scheme-1. The synthesis of the β-hydroxy carboxylic acid part in the segment B was achieved by a model experiment, i.e., an asymmetric aldol condensation between the N-acetyl derivative of MPOT (3) and an aldehyde in the presence of Sn(OTf)_2 and N-ethylpiperidine (see Table 1). The aldehyde moiety in the segment B was synthesized through a sequence of reactions shown in Scheme-2. Model experiments for the C-C bond formation between segments A and B was tried with success using a reaction of a mixed acid anhydride or a carboxylic acid amide with BSMBO anion (see Schemes-4 and 5). The segment C was synthesized via successive reactions: an asymmetric aldol condensation between the N-propionyl derivative of MPOT (3) and isobutyraldehyde in the presence of Sn(OTf)_2 and N-ethylpiperidine, protection of the hydroxy group, reduction with DIBAL, and the Wittig-Honer reaction, as shown in Schemes-6 and 7 and also in Table 2. The esterification of segment D with segment C was successful using DCC and DMAP: almost quantitative yield of the product was given (Scheme-8). The amide formation between the segments B and C was achieved in a model experiment utilizing TTPPA (5) as shown in Scheme-9. The amide formation between the segments A and D was similarly successful in a model experiment utilizing TTPPA (5) as shown in Scheme-11. Thus, we solved all of the important questions for the total synthesis of V-M2 (1) by the model experiments. The total synthesis of V-M2 itself is now in progress.
天然有機化合物討論会の論文
1983-09-15

62 機能性複素五員環を活用するVirginiamycin M2の全合成研究

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