Medicinal application of many complex natural products is precluded by the impracticality of their chemical synthesis. Pactamycin, the most structurally intricate aminocyclopentitol antibiotic, displays potent antiproliferative properties across multiple phylogenetic domains, but it is highly cytotoxic. A limited number of analogs produced by genetic engineering technologies show reduced cytotoxicity against mammalian cells, renewing promise for therapeutic applications.
For decades, an efficient synthesis of pactamycin amenable to analog derivatizations has eluded researchers. Published in Science, the Johnson Group now present a short asymmetric total synthesis of pactamycin. An enantioselective Mannich reaction and symmetry-breaking reduction sequence was designed to enable assembly of the entire carbon core skeleton in under five steps and control critical three-dimensional, stereochemical, functional group relationships. This modular route totals 15 steps and is immediately amenable for structural analog synthesis.
As reported in JACS, Michael Corbett and Jeffrey Johnson in the Johnson Group observed an unexpected dichotomy in the Ru-catalyzed asymmetric transfer hydrogenation of acyl phosphonates: reduction proceeded from the opposite face relative to that observed in the analogous reduction of α-keto esters.
The first highly selective catalytic hydrogenation of acyl phosphonates was utilized in the dynamic kinetic resolution of α-aryl acyl phosphonates, providing β-stereogenic α-hydroxy phosphonic acid derivatives.