Practical Syntheses of Enantiomerically Enriched γ-Lactones and γ-Hydroxy Ketones by the Alkylation of Pseudoephedrine Amides with Epoxides and Their Derivatives

Abstract

Pseudoephedrine amide enolates are shown to undergo efficient alkylation reactions with epoxides as electrophiles. Reactions with monosubstituted epoxides are subject to stereochemical matching such that the pairing leading to the 1,3-syn diastereomer is a highly selective, synthetically useful process, while the pairing forming the 1,3-anti diastereomer is not. Reactions with the 1,1-disubstituted epoxide isobutylene oxide are also highly diastereoselective and synthetically useful, but ethylene oxide exhibits poor diastereoselectivity. As an alternative to the use of ethylene oxide, 2-(tert-butyldimethylsilyloxy)ethyl iodide is shown to undergo highly diastereoselective and efficient alkylation reactions with pseudoephedrine amide enolates. Interestingly, epoxides and alkyl halides are found to attack opposite π-faces of pseudoephedrine amide enolates. The products of each of these alkylation reactions are transformed efficiently into γ-lactones by acidic hydrolysis and into methyl ketones by the addition of methyllithium. The methodology described provides useful procedures for the synthesis of enantiomerically enriched γ-lactones and γ-hydroxy ketones.

Reactivity of Oxiranes with Organolithium Reagents

“…The reaction of the chiral amide enolate 100 with the chiral oxiranes 101 and 102 occurs with a good diastereoselectivity (in the matched case 217 ); interestingly, the stereochemical course is opposite to the one observed with alkyl iodides. The same reversal is found in the reaction of the amide enolate 103 218 . By contrast, this reversal in diastereoselectivity compared to alkyl iodides was not found in the reaction of the lithium enolate 104 with the chiral oxiranes 105 219 and 106 220 .…”

Total Syntheses of Amphidinolides B1, B4, G1, H1 and Structure Revision of Amphidinolide H2

“…This extremely scarce metabolite of a recently collected Amphidinium strain (Y-100) exhibits exceptional potency, although only two cancer cell lines have been screened so far. [15] The modified polyhydroxylated Eastern sector to be incorporated into its frame was again obtained by a syn-selective glycolate aldol reaction [29] between 23 and aldehyde 69, which was prepared by alkylation of 35 with (R)-propenoxide [57] as the matched electrophile, [58] followed by appropriate oxidation state management (Scheme 8). The subsequent elaboration of product 70 followed the established route, except that the attachment of the ester moiety to C-25 had to occur with inversion of configuration (74 !…”

First Asymmetric Synthesis of (+)‐Sordidin and (–)‐7‐epi‐Sordidin, Aggregation Pheromones of the Banana Weevil Cosmopolites sordidus

“…as additive according to a modified literature procedure for enolate oxirane ring openings. [16] In our case, a large excess of aza-enolate (9.2 equiv. ), generated from 3-pentanone SAEP-hydrazone 4 and LDA (11.0 equiv.…”