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. 2022 Nov 9;144(44):20232-20236.
doi: 10.1021/jacs.2c09583. Epub 2022 Oct 26.

Asymmetric Total Synthesis of Havellockate

Nicholas J Hafeman  1 , Melinda Chan  1 , Tyler J Fulton  1 , Eric J Alexy  1 , Steven A Loskot  1 , Scott C Virgil  1 , Brian M Stoltz  1
Affiliations

Asymmetric Total Synthesis of Havellockate

Nicholas J Hafeman et al. J Am Chem Soc. .

Abstract

The first total synthesis of the furanobutenolide-derived cembranoid diterpenoid havellockate is disclosed. Our convergent strategy employs a Julia-Kocienski olefination to join two enantioenriched fragments to produce a diene that is subsequently used in a propiolic acid esterification/Diels-Alder cascade. This sequence generates the fused carbocyclic core of the natural product in short order. A challenging Zn-mediated Barbier allylation then forges the final C-C bond and also establishes two vicinal stereogenic centers. Finally, a Cu-catalyzed aerobic oxidation facilitates the formation of the β-hydroxybutanolide to complete the total synthesis.

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Figures

Figure 1.
Figure 1.
A) Structural features of havellockate (1). B) Retrosynthetic analysis of havellockate (1).
Scheme 1.
Scheme 1.
A) Synthesis of aldehyde 6. B) Synthesis of sulfone 16.
Scheme 2.
Scheme 2.
Julia–Kocienski olefination uniting aldehyde 6 and sulfone 16, acylation and Diels–Alder of diol 5, oxidation of tricycle 3 to enone 2, and failed Grignard addition to enone 2.
Scheme 3.
Scheme 3.
Top: Zn-mediated allylation of enone 2 to forge triol 23, and failed transesterification. Bottom: Transesterification of enone 2, allylation of enone 25, and completion of the total synthesis of havellockate 1.
See this image and copyright information in PMC

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