P-50 (+)-Martinellineの全合成研究(ポスター発表の部)

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Martinelline (1) and martinellic acid (2) were isolated by Witherup et al. at Merck Resarch Laboratories from the roots of the South American plant Martinella iquitosensis. These are the first naturally occurring non-peptide bradykinin B_1 and B_2 receptor antagonist, and are the first alkaloids with the hexahydropyrrolo[3,2-c]quinoline ring system. The biological activities of 1 and 2 coupled with their intriguing molecular frame have spurred intense synthetic efforts which culminated in the several total syntheses. To date, however, there have been reported a limited number of methodologies that allow facile construction of the tricyclic core in an enantiocontrolled manner. We envisaged a convergent route, involving an intramolecular hetero Diels-Alder reaction of an o-quinone methide imide formed in situ via isomerization of an imine. After considerable experimentations, we eventually found that LiBF_4 promoted conversion of TBS enol ether 12c to furnish pyrrolo[3,2-c]quinoline 14 as a single stereoisomer in a moderate yield, probably via a stepwise sequence involving an iminium ion intermediate but not via the expected concerted manner. Adduct 16, derived from an advanced building block 17, was successfully transformed into the known intermediate 23 through a diastereoselective Hosomi-Sakurai allylation and a set of conventional functional group transformations, thereby establishing the stereoselectivity of the key [4+2]-cyclization. We then applied this cycloisomerization reaction to a chiral substrate 24 having TBDPSoxymethyl group as a stereocontrolling element. It was found that BF_3・OEt_2 worked nicely in this particular case to give two diastereoisomers in a moderate yield with a 33: 9 ratio, in which the major isomer was confirmed to possess the suitable stereochemistries for synthesis of (+)-martinelline.
天然有機化合物討論会の論文
2005-09-15

P-50 (+)-Martinellineの全合成研究(ポスター発表の部)

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