Peloruside B, a potent antitumor macrolide from the New Zealand marine sponge Mycale hentscheli: isolation, structure, total synthesis, and bioactivity

Abstract

Peloruside B (2), a natural congener of peloruside A (1), was isolated in sub-milligram quantities from the New Zealand marine sponge Mycale hentscheli. Peloruside B promotes microtubule polymerization and arrests cells in the G(2)/M phase of mitosis similar to paclitaxel, and its bioactivity was comparable to that of peloruside A. NMR-directed isolation, structure elucidation, structure confirmation by total synthesis, and bioactivity of peloruside B are described in this article. The synthesis features Sharpless dihydroxylation, Brown's asymmetric allylboration reaction, reductive aldol coupling, Yamaguchi macrolactonization, and selective methylation.

Figure 1

Structures of peloruside A (1) and peloruside B (2).

Figure 2

Key COSY, 2D TOCSY and HMBC correlations for peloruside B (2).

Figure 3

Retrosynthetic analysis of peloruside B (2).

Scheme 1

Synthesis of fragment 5.

Scheme 2

Reductive aldol reaction and synthesis of seco-acid 14.

Scheme 3

Revised route to macrolactone 16.

Scheme 4

Completion of total synthesis of peloruside B (2).

Figure 4

Typical MTT cell proliferation assay for pelorusides A (1) and B (2). HL-60 cells were treated for 96 h (n = 3 replicates from a single preparation).

Figure 5

G₂/M arrest of 1A9 cells by natural and synthetic peloruside B (2).