TY - JOUR
T1 - Studies toward the unique pederin family member psymberin
T2 - Full structure elucidation, two alternative total syntheses, and analogs
AU - Feng, Yu
AU - Jiang, Xin
AU - De Brabander, Jef K.
PY - 2012/10/17
Y1 - 2012/10/17
N2 - 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 17-18 steps (longest linear sequence, ∼14-15 isolations) from 3 fragments prepared in 7-8 (first generation) and 3-8 (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-pederin 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.
AB - 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 17-18 steps (longest linear sequence, ∼14-15 isolations) from 3 fragments prepared in 7-8 (first generation) and 3-8 (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-pederin 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.
UR - http://www.scopus.com/inward/record.url?scp=84867553335&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867553335&partnerID=8YFLogxK
U2 - 10.1021/ja3057612
DO - 10.1021/ja3057612
M3 - Article
C2 - 23004238
AN - SCOPUS:84867553335
SN - 0002-7863
VL - 134
SP - 17083
EP - 17093
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 41
ER -