Streamlined Total Synthesis of Trioxacarcins and Its Application to the Design, Synthesis, and Biological Evaluation of Analogues Thereof. Discovery of Simpler Designed and Potent Trioxacarcin Analogues

Abstract

A streamlined total synthesis of the naturally occurring antitumor agents trioxacarcins is described, along with its application to the construction of a series of designed analogues of these complex natural products. Biological evaluation of the synthesized compounds revealed a number of highly potent, and yet structurally simpler, compounds that are effective against certain cancer cell lines, including a drug-resistant line. A novel one-step synthesis of anthraquinones and chloro anthraquinones from simple ketone precursors and phenylselenyl chloride is also described. The reported work, featuring novel chemistry and cascade reactions, has potential applications in cancer therapy, including targeted approaches as in antibody-drug conjugates.

Advances in the Asymmetric Total Synthesis of Natural Products Using Chiral Secondary Amine Catalyzed Reactions of α,β-Unsaturated Aldehydes

“…Between 2015 and 2017, the Nicolaou group [89,90,91] developed the elegant divergent total synthesis of five highly potent cytotoxic agents trioxacarcins DC-45-A1, DC-45-A2, A, C, and D from a common trioxacarcin precursor 119 , which was efficiently constructed using asymmetric organocatalytic epoxidation as one of the most versatile strategies (Scheme 32).…”

Streamlined Total Synthesis of Shishijimicin A and Its Application to the Design, Synthesis, and Biological Evaluation of Analogues thereof and Practical Syntheses of PhthNSSMe and Related Sulfenylating Reagents

“…Scheme 11 shows the synthesis of shishijimicin analogue 14 (the β-anomer of 11, with regards to the aminosugar glycosidic bond), whose design was intended to test the role for the αanomeric feature of the aminosugar structural motif of the molecule for bioactivity. In order to obtain desired β-glycoside disaccharide fragment 92, the Yu gold-promoted glycosylation protocol 55 was employed to couple glycosyl acceptor 84 (for preparation, see Scheme 9) and glycosyl donor 49 30 under the influence of Ph 3 PAuOTf cat. (see Scheme 11), yielding the corresponding disaccharide as a mixture of αand β-anomers (α/β ca.…”

Aza-Rubottom Oxidation: Synthetic Access to Primary α-Aminoketones

“…10 These two approaches have wide applicability, and both have been successfully used numerous times, even in the synthesis of extremely complex natural products. 11 While limited attempts have been made to mimic the first approach (i.e., the aforementioned trapping of enolates with chloramine or O-phosphinylhydroxylamine), to the best of our knowledge, no systematic studies have been dedicated to developing an amino analogue of the Rubottom oxidation (also known as "Aza-Rubottom oxidation"). Herein, we report our findings in the development of such a transformation.…”

“…Two general approaches are available, namely the trapping of an in situ generated enolate with Davis oxaziridine and the Rubottom oxidation in which silyl enol ethers are oxidized with peroxyacids, peroxides, or dioxiranes . These two approaches have wide applicability, and both have been successfully used numerous times, even in the synthesis of extremely complex natural products …”