Total Synthesis of Berkelic Acid

Abstract

A productive total synthesis of both enantiomers of berkelic acid (1) is outlined that takes the structure revision of this bioactive fungal metabolite previously proposed by our group into account. The successful route relies on a fully optimized triple-deprotection/1,4-addition/spiroacetalization cascade reaction sequence, which delivers the tetracyclic core 32 of the target as a single isomer in excellent yield. The required cyclization precursor 31 is assembled from the polysubstituted benzaldehyde derivative 20 and methyl ketone 25 by an aldol condensation, in which the acetyl residue in 20 transforms from a passive protecting group into an active participant. Access to fragment 25 takes advantage of the Collum-Godenschwager variant of the ester enolate Claisen rearrangement, which clearly surpasses the classical Ireland-Claisen procedure in terms of diastereoselectivity. Although it is possible to elaborate 32 into the target without any additional manipulations of protecting groups, a short detour consisting in the conversion of the phenolic -OH into the corresponding TBS-ether is beneficial. It tempers the sensitivity of the compound toward oxidation and hence improves the efficiency and reliability of the final stages. Orthogonal ester groups for the benzoate and the aliphatic carboxylate terminus of the side chain secure an efficient liberation of free berkelic acid in the final step of the route.

Lithium Hexamethyldisilazide-Mediated Enolization of Highly Substituted Aryl Ketones: Structural and Mechanistic Basis of the E/Z Selectivities

“…By contrast, enolization using ≥2.0 equiv of [ 6 Li, 15 N]LiHMDS afforded lithium enolate–LiHMDS mixed aggregate 8 E -15 along with traces of Z -15 , consistent with the 65:1 E/Z selectivity observed with tosylation. 6 The dimeric mixed aggregates displayed characteristic 6 Li– 15 N coupling (3.6 Hz) and offered an independent measure of the E / Z selectivity.…”

“…They differed quantitatively from analogous complexes formed from 2-methylcyclohexanone or 3-pentanone owing to weaker binding. 8 …”

“…6 The dependencies in such uncongested cases derive from markedly different mechanisms corresponding to monomer- and dimer-based transition structures 5 and 6 , 7,8 which offered the possibility that the stereoselectivity would extend to the stereochemically demanding case in Scheme 1. Indeed, 65:1 E/Z selectivity exceeded expectations.…”

A Diastereoselective Formal Synthesis of Berkelic Acid

“…Their observations led to the revision of three stereocenters and an assignment of the relative stereochemistry including the quaternary stereocenter (Figure 1). 9 This landmark effort paved the way for future synthetic successes, and soon afterward, Snider reported the first total synthesis establishing the absolute structure of berkelic acid as its enantiomer (−)- 1 '. 10 The Snider synthesis, which involved an acid-catalyzed coupling of two chiral components followed by late-stage chromatographic resolution of the quaternary center, is masterful in its overall efficiency.…”

Synthesis of 5,6- and 6,6-Spirocyclic Compounds

“…An oxa-Michael initiated spirocyclization cascade sequence has been used in the synthesis of berkelic acid by both Fürstner et al [128] and Brimble et al [129] (Scheme 59).…”