Studies toward the Unique Pederin Family Member Psymberin: Full Structure Elucidation, Two Alternative Total Syntheses, and Analogs

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• 作者：Yu Feng ; Xin Jiang ; Jef K. De Brabander
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：October 17, 2012
• 年：2012
• 卷：134
• 期：41
• 页码：17083-17093
• 全文大小：844K
• 年卷期：v.134,no.41(October 17, 2012)
• ISSN：1520-5126

文摘

Two synthetic approaches to psymberin have been accomplished. A highly convergent first generation synthesis led to the complete stereochemical assignment and demonstrated that psymberin and irciniastatin A are identical compounds. This synthesis featured a diastereoselective aldol coupling between the aryl fragment and a central tetrahydropyran core and a novel one-pot procedure to convert an amide, via intermediacy of a sensitive methyl imidate, to the N-acyl aminal reminiscent of psymberin. The highlights of the second generation synthesis include an efficient iridium-catalyzed enantioselective bisallylation of neopentyl glycol and a stepwise Sonogashira coupling/cycloisomerization/reduction sequence to construct the dihydroisocoumarin unit. The two synthetic avenues were achieved in 17鈥?8 steps (longest linear sequence, 14鈥?5 isolations) from 3 fragments prepared in 7鈥? (first generation) and 3鈥? (second generation) steps each. This convergent approach allowed for the preparation of sufficient amounts of psymberin ( 0.5 g) for follow-up biological studies. Meanwhile, our highly flexible strategy enabled the design and synthesis of multiple analogs, including a psymberin鈥損ederin hybrid, termed psympederin, that proved crucial to a comprehensive understanding of the chemical biology of psymberin and related compounds that will be described in a subsequent manuscript.