Enantioselective Synthesis of Pactamycin, a Complex Antitumor Antibiotic

Abstract

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 anti-prolific properties across multiple phylogenetic domains, but 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. Herein, we present a short asymmetric total synthesis of pactamycin. An enantioselective Mannich reaction/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 fifteen steps and is immediately amenable for structural analog synthesis.

Highly stereoselective synthesis of cyclopentanes bearing four stereocentres by a rhodium carbene-initiated domino sequence

“…26,27 Synthetic cyclopentanes are a central motif common to prostaglandin antagonist antiglaucoma agents. 28–32 Indeed, the convergent, asymmetric synthesis of a cyclopentane nucleus bearing multiple chiral centers presents a distinct challenge for modern synthetic chemists.…”

Stereoselective synthesis and molecular modeling of chiral cyclopentanes

“…[1][2][3] Moreover, the significance of the development of new synthetic strategies leading to construct such diverse complex molecular structures arises due to their essential need in total synthesis of natural products and the high demand for synthetic strategies, which can provide alternative and practical methods for the synthesis of pharmaceuticals and agrochemicals. Pactamycin (1) and pactamycin derivative (2) have been shown to possess antitumor and antibacterial activities 4 whereas CCR5 (3) has been reported as an anti-HIV drug candidate. 5 Viridenomycin (4) have shown potent antimicrobial activities 6 against Gram positive and negative organisms (Fig.…”

Asymmetric Synthesis of the Aminocyclitol Pactamycin, a Universal Translocation Inhibitor

“…17 Herein, we present a full account of our studies on pactamycin encompassing a modification of our original route to accommodate early-stage incorporation of the C2 amine functionality. A symmetry-breaking reduction for rapid access to the C1/C2/C7 stereotriad was developed, and an emphasis was placed on incorporating pactamycin’s unique functionality in its final form to obviate downstream functional group adjustment or protecting group manipulation.…”