Synthesis of Polyprenylated Acylphloroglucinols Using Bridgehead Lithiation:  The Total Synthesis of Racemic Clusianone and a Formal Synthesis of Racemic Garsubellin A

Abstract

The synthesis of polyprenylated phloroglucinol natural products, including clusianone, nemorosone, and garsubellin A, was pursued by a strategy involving construction of a core bicyclo[3.3.1]nonanetrione structure and subsequent elaboration via organolithium intermediates. Appropriate bridged core structures were obtained through the cyclization of a suitably substituted cyclohexanone enol ether or enol silane with malonyl dichloride. Additional substituents were then introduced by means of regioselective lithiation reactions, including the generation of bridgehead enolates, thus enabling the total synthesis of clusianone and also of an advanced intermediate toward nemorosone. In the case of garsubellin A, an additional THF-like ring was elaborated by a biomimetic 5-exo-tet cyclization of an enol ether (or enol) with a side-chain epoxide. This enabled a formal synthesis of racemic garsubellin A by accessing one of the late intermediates in the Danishefsky synthesis.

Synthesis of (±) debenzoyl analogs of norsampsones as potential anticancer agents

“…Stork-Danheiser reaction of 4, afforded the prenylated enone 5 in 89% yield as reported by Shibasaki et al and spectral data matched with those in the literature. 10 Alkylation of enone 5 with LDA and prenyl bromide afforded compound 6 (trans/cis = 9:1) as reported by Ahmad et al 11 The major trans-isomer of compound 6 was separated from cis-isomer and the 1 H and 13 C NMR spectra were found identical with those of the reported. 11 Similarly, enone 5 when treated with geranyl bromide provided the geranylated product 7 (trans/cis = 9:1) in 80% yield.…”

“…10 Alkylation of enone 5 with LDA and prenyl bromide afforded compound 6 (trans/cis = 9:1) as reported by Ahmad et al 11 The major trans-isomer of compound 6 was separated from cis-isomer and the 1 H and 13 C NMR spectra were found identical with those of the reported. 11 Similarly, enone 5 when treated with geranyl bromide provided the geranylated product 7 (trans/cis = 9:1) in 80% yield. The major trans-isomer of compound 7 was separated by column chromatography with 80% yield and its identity was confirmed by 1 H, 13 In an attempt to introduce the C6-side chain, compound 6 was alkylated with aldehyde 10 using LiHMDS to generate the enolate to give compound 11 as a diastereomeric mixture (Scheme 4).…”

Polyprenylated Phloroglucinols and Xanthones

“…The above strategy was then extended to a formal synthesis of garsubellin A [40]. Specifically, application of the Effenburger-type cyclization to 105 afforded 110, a compound isolated by the Danishefsky group en route to the synthesis of garsubellin A (Scheme 12.19) [39].…”

Synthetic efforts toward [3.3.1] bridged bicyclic phloroglucinol natural products

“…Simpkins’ formal total synthesis of garsubellin A 78 commenced with the synthesis of known enone 79 236 following the Stork-Danheiser approach. Conjugate addition and silyl enol ether trapping ( 237 ) was followed by Effenberger cyclization and esterification to afford 238 .…”