Enantioselective synthesis of a hindered furyl substituted allyl alcohol intermediate: a case study in asymmetric synthesis

Abstract

In the course of the synthesis of the DEFG ring system of cneorin C 1, we were faced with the task of preparing the furyl substituted allyl alcohol 5 enantioselectively. Several different methods starting from enantioselective zinc-mediated alkylations were attempted, but none of them proved entirely satisfactory. The solution turned out to be enzymatic kinetic resolution through a highly enantioselective (E > 300) acylation in the presence of Candida antarctica lipase A.

Synthesis of DEFG ring system of cneorins

“…15 The air stability and ease of handling of Cu(MeCN) 4 PF 6 16 was reported to make the PF 6 salts superior to CuOTf. 17 We therefore decided to investigate also complexes 10a and 10b 18 the latter of which was expected to exhibit reduced Lewis acidity of copper thus making it less reactive and more selective towards the targeted double bond.…”

“…6 In this paper we disclose our results on the cyclopropanation to yield the EFG ring fragment and closing the D ring to obtain the [4.3.1]propellane structure of cneorin related natural products.…”

“…6 Retrosynthetically (Scheme 1), the structure of cneorin C can be divided into two advanced substructures, namely hydroxyketone 6, which consists of the DEFG rings of the molecule, and the A ring butenolide fragment 7. The DEFG ring system of cneorin B (6) is an ideal candidate for the intramolecular cyclopropanation [7][8][9][10][11] of diazomalonate 8, which can be conveniently prepared from the furyl substituted allylic alcohol (S)-9.…”

Biocatalytic synthesis of saphenic acid enantiomers

“…CALA shows high enantioselectivity for phenyl-(2-naphthyl)-methanol (6) (one phenyl and one naphthyl group connected to the stereocenter) which is in accordance with previous reported results. [11][12][13][14][15][16] Experimental Section…”

“…[6][7][8][9][10] Lipase A from this fungus (CALA) is reported to show broad catalytic activity towards a diversity of sterically hindered alcohols, including both secondary and tertiary alcohols. [11][12][13][14][15][16] It was interesting to investigate whether this lipase could catalyze resolutions of secondary alcohols with phenyl and naphthyl groups and other bulky groups attached to the stereocenter. The 3D structure of CALA has not been published, however, the structure of the lipase has recently been predicted by comparative modeling and site directed mutagenesis.…”