86(P-8) 環状デプシペプチド、Callipeltin Aの全合成研究 : 異常アミノ酸部の立体選択的合成(ポスター発表の部)

抄録

Callipeltin A (1) is a cyclodepsipeptide from water sponge collected at New Caledonia. This compound shows anti-HIV and cytotoxic activities against KB and P388 cells and contains three new amino acid residues. β-methoxytyrosine (β-MeOTyr) (4), (2R,3R,4S)-4-amino-7-guanidino-2,-3-dihydroxyheptanoic acid (AGDHE) (5), (3S,4R)-3,4-dimethyl-L-glutamine (diMeGln) (6). In addition, two new truncated open-chain derivatives of Callipeltin A (1), named Callipeltin D (2) and E (3) were isolated. The unique structure and intriguing biological activities of this compound led us to explore total synthesis of Callipeltin A (1) and to elucidate stereochemistry of β-MeOTyr (4). We started to synthesize Callipeltin E (3) which contains β-MeOTyr (4). In order to synthesize four stereoisomer of β-MeOTyr (4), we attempted Evans anti or syn-Aldol reaction as a key step. Evans direct anti-aldol reaction with chiral benzyloxazolidinones (8) and p-hydroxy benzaldehyde (9) promoted by catalytic amounts of MgCl_2 in the presence of triethylamine and chlorotrimethylsilane. This proceder provide 3:1 diastereoselelctivity and 70% yield of isolated anti-aldol product (10). And Enolizalion of isocyanate oxazolidinone (13) with di-n-butylboryl trifrate and diisopropylethylamine followed by treatment with aldehyde 8 afford syn-aldol product 14 affording 88% yield and 1:5 anti: sin diastereomeric ratio. On the other hand, we tried Sharpless Asymmetric dihydroxylation (AD) and Aminohydroxylation (AA) to give all four stereoisomers of β-MeOTyr. Treatment of olefin (18) with AD-mix α provided diol (19) and the α position alcohol of 19 was converted to sulfone regioselectively followed by azidation and treatment of 20 with PPh_3 to afford aziridine (21). Addition of aziridine (21) and BF_3・Et_2O in methanol produced α-amino β-methoxy adduct (22). AA reaction protocol with t-butylcarbamate was successfully applied to afford desired 22 in single step. Now we construct Callipeltin E to determine absolute stereochemistry of β-MeOTyr (4). In addition, we report the synthesis of diMeGln (6) and (2R,3R,4S)-3-hydroxy-2-4-6-trimethyl hepanoic acid (7).