Abstract
The brasilinolides are an architecturally complex family of 32-membered macrolides, characterised by potent immunosuppressant and antifungal properties, which represent challenging synthetic targets. By adopting a highly convergent strategy, a range of asymmetric aldol/reduction sequences and catalytic protocols were employed to assemble a series of increasingly elaborate fragments. The controlled preparation of suitable C1-C19 and C20-C38 acyclic fragments 5 and 6, containing seven and 12 stereocentres respectively, was first achieved. An adventurous C19-C20 fragment union was then explored to construct the entire carbon chain of the brasilinolides. This pivotal coupling step could be performed in a complex boron-mediated aldol reaction to install the required C19 hydroxyl stereocentre when alternative Mukaiyama-type aldol protocols proved unrewarding. A protected C1-C38 polyol 93 was subsequently prepared, setting the stage for future late-stage diversification toward the various brasilinolide congeners. Throughout this work, asymmetric boron-mediated aldol reactions of chiral ketones with aldehydes proved effective both for controlled fragment assembly and coupling with predictable stereoinduction from the enolate component.
Highlights
The polyketides represent a diverse array of structurally elaborate natural products having a wide range of biological activity, with many members having important therapeutic utility in human and veterinary medicine.[1]
The brasilinolides (Fig. 1), isolated by Mikami and Kobayashi and co-workers in 1996 from the pathogenic actinomycetes Nocardia brasiliensis, constitute a unique family of immunosuppressive and antifungal polyketides based on a highly hydroxylated macrolide scaffold, which presumably arises in the biosynthesis from a PKSmediated cyclisation of a linear 38-carbon chain.[2]
A carefully planned protecting group regime was devised for the purposes of achieving predictable stereoinduction, along with enabling the late-stage introduction of the defining brasilinolide substituents, and to ensure the necessary control in progressing the synthetic route
Summary
The polyketides represent a diverse array of structurally elaborate natural products having a wide range of biological activity, with many members having important therapeutic utility in human and veterinary medicine.[1]. With some of the desired epoxide in hand, the synthesis of the planned northern fragment 6 (86%, two steps) was completed by TBS ether formation (TBSOTf, 2,6-lutidine) followed by a dihydroxylation–oxidative diol cleavage step (OsO4; NaIO4–SiO2) to reveal the methyl ketone functionality.[35] Following this route, the preparation of the C20–C38 northern fragment 6 was achieved in 13% overall yield over 16 linear steps from ethyl ketone 36.
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