Syntheses of Sceptrins and Nakamuric Acid and Insights into the Biosyntheses of Pyrrole-Imidazole Dimers.
Sceptrins and nakamuric acid are structurally unique antibiotics isolated from marine sponges. Recent studies suggest that the biosynthesis of these dimeric pyrrole-imidazole alkaloids involves a single-electron transfer (SET)-promoted [2+2] cycloaddition to form their cyclobutane core skeletons. We describe herein the biomimetic syntheses of racemic sceptrin and nakamuric acid. We also report the asymmetric syntheses of sceptrin, bromosceptrin, and dibromosceptrin in their natural enantiomeric form. We further provide mechanistic insights into the pathway selectivity of the SET-promoted [2+2] and [4+2] cycloadditions that lead to the divergent formation of the sceptrin and ageliferin core skeletons. Both the [2+2] and [4+2] cycloadditions are stepwise reactions, with the [2+2] pathway kinetically and thermodynamically favored over the [4+2] pathway. For the [2+2] cycloaddition, the dimerization of pyrrole-imidazole monomers is rate-limiting, whereas for the [4+2] cycloaddition, the cyclization is the slowest step.
Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Xiaolei
X
Wang
College of Chemistry, Peking University, Beijing 100871, China ; Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Hubei, Wuhan 430079, China.
Yang
Y
Gao
Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Zhiqiang
Z
Ma
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Rodrigo A
RA
Rodriguez
College of Chemistry, Peking University, Beijing 100871, China.
Zhi-Xiang
ZX
Yu
Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Chuo
C
Chen