Enantioselective Total Synthesis of (+)‐Garsubellin A

Abstract

Garsubellin A is a meroterpene capable of enhancing the enzyme choline acetyltransferase whose decreased level is believed to play a central role in the symptoms of Alzheimers disease. Due to the potentially useful biological activity together with the novel bridged and fused cyclic molecular architecture, garsubellin A has garnered substantial synthetic interest, but its absolute stereostructure has been undetermined. We report here the first enantioselective total synthesis of (+)-garsubellin A. Our synthesis relies on stereoselective fashioning of a cyclohexanone framework and double conjugate addition of 1,2-ethanedithiol that promotes aldol cyclization to build the bicyclic [3.3.1] skeleton. The twelvestep, protecting group-free synthetic route has enabled the syntheses of both the natural (À)-garsubellin A and its unnatural (+)-antipode for biological evaluations.Scheme 1. Structure and retrosynthesis of Garsubellin A.

Recent advances in the synthesis of natural products containing the phloroglucinol motif

“…The key oxidative Although garsubellin A was the rst example of PPAP total synthesis (in year 2005), 82 it was not until very recently that the rst asymmetric total synthesis of (+)-garsubellin A was realised by the Lee group through diastereoselective multifunctionalization of cyclohexanone moiety followed by latestage construction of the bicyclic framework (Scheme 23). 125 Isobutyrylation and reductive prenylation of 117 (obtained from known enol ether 116) happened with exclusive trans selectivity with respect to the sterically more demanding allyl substituent. Alkynylation of the resulting intermediate with 118 gave a mixture of a and b-isobutyryl group, but the a-epimer tended to isomerize into the more stable b-product (as shown in 119) upon warming, leading to 119 aer reduction of the ester moiety.…”

Evolution of a Synthetic Strategy for Garsubellin A

“…These synthetic feats, however, were achieved only in racemic settings in contrast to related BPAPs such as hyperforin, nemorosone and clusianone, of which the asymmetric total syntheses had been performed to elucidate their absolute configuration [5] . The absolute stereostructure of 1 had remained unknown until 2021 when we disclosed the first enantioselective total synthesis [15] . We report here a full account of our synthetic investigations directed toward the enantioselective total synthesis of garsubellin A.…”

“…[5] The absolute stereostructure of 1 had remained unknown until 2021 when we disclosed the first enantioselective total synthesis. [15] We report here a full account of our synthetic investigations directed toward the enantioselective total synthesis of garsubellin A.…”

Copper-catalyzed 1,2-Borylacylation of 1,3-Enynes: synthesis of β-Alkynyl ketones

“…1 Among them, functionalized α,α-disubstituted β-alkynyl carbonyl compounds are important synthetic synthons that serve as tremendous intermediates in chemical synthesis. 2 A series of methods have been developed for their synthesis, but most of them were based on α-alkynylation of ketones. 3 The development of synthetic methods for functionalized β-alkynyl carbonyl compounds is still highly desirable.…”