Asymmetric Total Synthesis of Brasilicardins

Abstract

Brasilicardins, bacterial diterpenoid natural products that display highly potent immunosuppressive activity, are promising immunosuppressant drug candidates. Structurally, they can be described as hybrids of terpenoids, amino acids, and saccharides, and share a characteristic highly strained anti‐syn‐anti‐fused perhydrophenanthrene terpenoid scaffold (ABC‐ring system) with two quaternary asymmetric carbon atoms. A unified and stereoselective total synthesis of all four brasilicardins has been designed based on the strategic use of an intramolecular conjugate addition. The ABC‐ring system was initially constructed with high stereocontrol by novel intramolecular conjugate additions of Weinreb amides and in situ generated (Z)‐vinyl copper species. The late‐stage common intermediate was subjected to stereoselective installation of the amino acid component, followed by introduction of the saccharide unit via glycosylation to accomplish the total synthesis of brasilicardins A–D. Our synthesis offers opportunities to synthesize various brasilicardin analogues for biological and pharmacological investigations.

Beyond classical sulfone chemistry: metal- and photocatalytic approaches for C–S bond functionalization of sulfones

“…The method is exceptionally robust and finds notable application as a key step in several total syntheses. Some examples are related to the synthesis of the tricyclic skeleton of taxanes, 205 guanosine modification en route to therapeutic agents, 206 and the synthesis of brasilicardines 207 or andrastins 208 among others. Later, Nishida applied this methodology to the hydrocyanation of enamines employing the same catalytic system.…”

A Chiral-Pool-Based Strategy to Access trans-syn-Fused Drimane Meroterpenoids: Chemoenzymatic Total Syntheses of Polysin, N-Acetyl-polyveoline and the Chrodrimanins

“…In the context of target-oriented chemical synthesis, only three total syntheses of trans-syn -fused drimane terpenoids have been reported thus far (Figure C). Two of these syntheses , pertain to the brasilicardin natural products and involved lengthy synthetic sequences to generate the key trans-syn-trans -fused tricyclic intermediates. More recently, a landmark synthesis of the isomalabaricanes (e.g., stellettin E, 5 ) by the Sarlah group has enabled initial structure–activity relationship studies on the cytotoxicity of the scaffold. , To complement the aforementioned approaches, we sought to develop an alternative strategy to collectively prepare trans-syn -fused drimane meroterpenoids through the use of a chiral pool approach.…”

Chemical Synthesis of Brasilicardins

“…We achieved the total syntheses of 1 4 in 2018, including the rst total syntheses of 2 and 4. 5 Herein, our endeavor towards a uni ed total synthesis of all brasilicardins is described, focusing principally on the development of methodologies directed toward the construction of the characteristic tricyclic terpenoid core (the ABC ring).…”