Stereodivergent Strategy in Structural Determination: Asymmetric Total Synthesis of Garcinol, Cambogin, and Related Analogues

Abstract

The asymmetric total synthesis of five biologically significant polycyclic polyprenylated acylphloroglucinols (PPAPs), including garcinol and cambogin, was achieved through a highly diastereoselective and stereodivergent strategy. Along the way, an efficient cascade Dieckmann cyclization was employed to construct the bicyclo[3.3.1]­nonane core in one step. The synthesis provided a general approach toward the chiral endo-type B PPAPs and their C-30 diastereomers in a single sequence, which resolved the challenges of the absolute configuration determination/structural revision of PPAPs bearing exocyclic stereocenters.

Polyprenylated Acylphloroglucinols With Different Carbon Skeletons From the Fruits of Garcinia multiflora

“…Recently, the absolute configuration of C-23 of the isogeranyl of PPAPs bearing exocyclic stereocenters such as guttiferone F has been determined and revised by total synthesis and X-ray diffraction, and a preliminary conclusion has been drawn that BPAP-bearing exocyclic stereocenters from natural sources mostly carries S configuration of the isogeranyl. According to this rule, all (23 R )- endo -type B BPAPs with a isogeranyl at C-5 are corrected to be (23 S )- endo -type B BPAPs, including garcimultiflorones D–F, 18-hydroxygarcimultiflorone D, isogarcimultiflorone F, and garcimultiflorone J isolated from the same plant ( Wang et al, 2021 ; Zheng et al, 2021 ). Combined with the biosynthetic pathway and this rule, the configuration of C-23 could be tentatively determined as S* .…”

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

“…The group I BPAP may then be further divided into types A and B according to the position of the acyl substituent on the phloroglucinol core at C-1 (type A) or C-3 position (type B). The exquisite chemical architectures and interesting bioactivities rendered PPAP an attractive synthetic target to chemists worldwide, including the Shibasaki, 82,83 Danishefsky, 84,85 Simpkins, [86][87][88][89][90] Porco, [91][92][93][94][95][96][97][98] Plietker, [99][100][101][102][103][104] Nakada, [105][106][107][108][109] Shair, 110,111 Barriault, 112,113 Maimone, 114,115 and Zheng [116][117][118] research groups. The elegant work reported before year 2018 was summarized by several important reviews.…”

“…Collective syntheses of numerous endo-type B PPAPs were accomplished via a diversi-ed strategy, which proved to be effective in both racemic and asymmetric manners (Scheme 24). [116][117][118]126 Starting from diesters 122, four steps of transformations including alkylation, reduction and oxidative cyclization were required to produce lactone 123. Aer methylation and halogenation, key intermediate 124 was obtained via nucleophilic substitution with dimethyl malonate and subsequent alkylation to introduce R 3 .…”

“…Notably, the asymmetric synthesis of these PPAPs along with their synthetic diastereomers enabled the absolute configuration determination and structural revision of several PPAPs bearing exocyclic stereocenters. 118…”

Enantioselective Total Synthesis of (+)‐Garsubellin A

“…In this regard, it is well to note that the C9 carbonyl bridge and the C7 prenyl or geranyl chain may be configured to be of both a-and b-orientations in the PPAP biosynthesis (2 to 1 in Scheme 1). [6] Therefore, it is difficult to infer the absolute stereochemistry of any PPAP despite the high degree of structural homology existing within the family, [7] as exemplified by the elegant chemical synthesis investigations on clusianone and nemorosone which have revealed the absolute configurational sense of these compounds to be antipodal to that of hyperforin. [8] Reported here is the first enantioselective total synthesis of garsubellin A (1) that enabled determination of its absolute stereochemistry.…”