Quinocarcin

The first asymmetric total synthesis of (+)-quinocarcinamide (3), an enantiomer of the natural oxidation product from antitumor antibiotic (-)-quinocarcin (1), is described. Key steps include an iridium-catalyzed asymmetric allylic amidation of racemic alcohol 9, olefin cross-metathesis followed by a SN2' to forge tetrahydroisoquinoline, and stereocontrolled 1,3-dipolar cycloaddition between a facilely generated azomethine ylide and tert-butyl acrylate to construct the diazabicyclo[3.2.1]octane ring.

The tetrahydroisoquinoline (THIQ) alkaloids are naturally occurring antibiotics isolated from a variety of microorganisms and marine invertebrates. This family of natural products exhibit broad spectrum antimicrobial and strong antitumor activities, and the potency of clinical application has been validated by the marketing of ecteinascidin 743 (ET-743) as anticancer drug. In the past 20 years, the biosynthetic gene cluster of six THIQ antibiotics has been characterized including saframycin Mx1 from Myxococcus xanthus, safracin-B from Pseudomonas fluorescens, saframycin A, naphthyridinomycin, and quinocarcin from Streptomyces, as well as ET-743 from Ecteinascidia turbinata. This review gives a brief summary of the current status in understanding the molecular logic for the biosynthesis of these natural products, which provides new insights on the biosynthetic machinery involved in the nonribosomal peptide synthetase system. The proposal of the THIQ biosynthetic pathway not only shows nature's route to generate such complex molecules, but also set the stage to develop a different process for production of ET-743 by synthetic biology.

A scalable and unified strategy is described for the synthesis of (-)-quinocarcin, an important tetrahydroisoquinoline antitumor alkaloid. The strategy allows the practical formal synthesis of (-)-quinocarcin in 13 steps and 4.8% overall yield using N-phthaloyl-l-alanine as a chiral pool. It features the gram-scale and stereoselective synthesis of the tetrahydroisoquinoline moiety (AB ring) via Pd-catalyzed C(sp3)-H arylation and Pictet-Spengler condensation and a Cu(I)-catalyzed exo-selective [C + NC + CC] coupling reaction to generate the chiral pyrrolidine motif (D ring).