Synthesis of the C4–C16 Polyketide Fragment of Portimines A and B

Abstract

Stereoselective synthesis of the C4−C16 polyketide fragment of portimines A and B is reported, enabled by our previously established method for the stereoselective synthesis of syn-α,α′-dihydroxyketones. The preparation of this advanced fragment provides insights useful for the total synthesis of portimines A and B. An asymmetric Evans aldol reaction was used to install the C10−C11 adjacent stereogenic centers before incorporation of indantrione, followed by epoxidation and epoxide opening to forge the challenging syn-α,α′-dihydroxyketone functionality.

Synthesis of the spiroimine fragment of portimines A and B

“…Our synthetic strategy towards the polyketide domain, including assembly of the challenging dihydroxyketone motif, has been detailed in previous publications. 23,27 Herein, we describe the development of our synthesis of the spiroimine fragment.…”

“…A growing body of work dedicated to this goal illustrates the challenges associated with a chemical synthesis of 1-2, which has resulted in methodological advances with application beyond this context. [23][24][25] Most recently, Baran and co-workers described the total synthesis of portimines A (1) and B (2) over 15 steps, which enabled correction of the initially assigned structure for portimine B and an in-depth study of their biological activity. 26 Additionally, through chemical proteomic experiments, the primary target of portimine A (1) was identified as the 60S ribosomal export protein NMD3.…”

A Scalable Total Synthesis of Portimine A and B Reveals the Basis of Their Potent and Selective Anti-cancer Activity

“…This pioneering approach was first accomplished by Kishi et al in the 1998 total synthesis of pinnatoxin A (16). In the case of the portimines, approaches thus far have followed this dogma (21)(22)(23)(24). Thus, Brimble et al (22,23) and Harran et al (24) aimed for a bio-inspired synthesis that mimics the polyketide synthases (PKSs), featuring bold intramolecular cyclizations of densely functionalized polyketides 3 and 4 respectively (Fig 1A).…”

“…In the case of the portimines, approaches thus far have followed this dogma (21)(22)(23)(24). Thus, Brimble et al (22,23) and Harran et al (24) aimed for a bio-inspired synthesis that mimics the polyketide synthases (PKSs), featuring bold intramolecular cyclizations of densely functionalized polyketides 3 and 4 respectively (Fig 1A). The former approach demonstrated that the ketalization of linear 3 was not facile, even with the well-functionalized skeleton.…”

Remote Stereocontrol in the Ireland–Claisen Rearrangement by δ-Alkoxy Group

“…Seeking to further capitalize on the advantages of this methodology, we initiated a project directed at the total synthesis of portimine A, − a member of the cyclic imine family of marine natural products (Figure ). This natural product is discovered from a marine benthic dinoflagellate Vulcanodinium rugosum and is the most potent known selective chemical inducer of apoptosis, with an LC 50 to P388 cells of 2.7 nM. , The structure presents opportunities to utilize a related strategy, with additional challenges that include the installation of the strained internal spiroketal and intricate functional group arrangement, and a more effective approach to stereocontrol in the Ireland–Claisen rearrangement.…”