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. 2014 Jun 16;53(25):6519-22.
doi: 10.1002/anie.201403006. Epub 2014 May 13.

Synthesis of tetrahydropyran/tetrahydrofuran-containing macrolides by palladium-catalyzed alkoxycarbonylative macrolactonizations

Yu Bai  1 , Dexter C Davis, Mingji Dai
Affiliations

Synthesis of tetrahydropyran/tetrahydrofuran-containing macrolides by palladium-catalyzed alkoxycarbonylative macrolactonizations

Yu Bai et al. Angew Chem Int Ed Engl. .

Abstract

A novel Pd-catalyzed cascade alkoxycarbonylative macrolactonization to construct tetrahydropyran/tetrahydrofuran-containing bridged macrolactones in one step from alkendiols is described. Products with various ring sizes and substituents were obtained. Challenging macrolactones involving tertiary alcohols were synthesized smoothly as well. Mechanistically, experimental evidence to support a trans-oxypalladation step has been provided. The method was applied to the synthesis of potent anticancer compound 9-demethylneopeltolide.

Keywords: carbonylation; macrolactonization; macrolide; neopeltolide; palladium.

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Figures

Figure 1
Figure 1
Selected THP-containing macrolides and our synthetic strategy.
Scheme 1
Scheme 1
A mechanistic study of the oxypalladation step.
Scheme 2
Scheme 2
Alkoxycarbonylative macrolactonization of tertiary alcohols.
Scheme 3
Scheme 3
Alkoxycarbonylative macrolactonization of 13a and 13b and synthesis of 9-demethylneopeltolide (1a). Reagents and conditions: a) HCl (0.5 N), MeOH; then HCl (1 N), THF, RT; b) NaBH4 (3.9 equiv), MeOH, 0 °C, 74% from 14b; c) PPh3 (3.8 equiv), DIAD (3.8 equiv), 16 (4.0 equiv), benzene, RT, 56%; DIAD = diisopropyl azodicarboxylate.
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