| Budget Amount *help |
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2000: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1999: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
Macrocyclic lactams containing a biogenetic base such as apermine and spermidine represent a new class of polyamine alkaloids which have a framework of β-amino acid and are of particular interest as synthetic targets in view of the broad biological activity, for instance as antibiotics and antihypertensives. (S)-dihydroperiphylline (1) is one of six alkaloids isolated from the leaves of Peripterygia marginata by Husson et al. All these alkaloids contain a 13-membered ring system derived from dicinnamoylspermidine. We recently reported the conjugate addition reaction of 6-and 5-membered cyclic hydrazines such as piperidazine and pyrazolidine to chiral vinyl sulfoxides and synthesized the chiral 9-and 8-membered lactams with high optical purity (up to 95% ee). The asymmetric syntheses of a 13-membered lactam alkaloid, celacinnine, and an 8-membered lactam alkaloid, homaline, were accomplished by this method. The present study provides a facile route to the synthesis of 13-membered alkaloid, (S)-dihydroperiphylline (1), starting from (S)-4-phenyl-2-azetidinone. A total synthesis of 1 involves a six-step sequence by successive ring expansions of smaller heterocyclic units. Our procedure permits clear-cut differentiation of the two secondary amino groups in the 13-membered lactam system by selective acylation in an early step. This method utilizes, as key steps, the condensation of (S)-4-phenyl-2-azetidinone with a 9-membered cyclic imino ether and following reductive ring-expansion of 4-oxotetrahydropyrimidine derivative. Both of these reaction process proceeded with retention of configuration around the chiral center to give an optical pure lactam. This is the first example of 13-membered lactam alkaloids using a chiral β-lactam as a chiral synthon, and this method can be applicable to the synthesis of other polyamine alkaloids containing a framework of β-amino acids.
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