Development of a Practical, Safe, and High-Yielding Process for the Preparation of Enantiomerically Pure trans-Cyclopropane Carboxylic Acid

Abstract

A practical, safe, and high-yielding process for the cyclopropanation of a chiral epoxide has been developed using the inexpensive and nonhazardous reagents triethylphosphonoacetate and sodium tert-butoxide. IntroductionCyclopropane ring systems are ubiquitous in nature and are contained in a large number of natural products, insecticides, and pharmaceutical drug candidates. 1 In conjunction with our work on the melatonergic agent 1 2 (Scheme 1), we needed to develop a cost-effective process for the large-scale preparation of the enantiomerically pure transcyclopropane carboxylic acid 2b.The reaction of epoxides with the anion of triethylphosphonoacetate (TEPA) in the synthesis of cyclopropane derivatives has been known for over four decades, 3 and there has been occasional additional application of the reaction between epoxides and phosphonates (either R-phosphono esters or phosphono ketones). 4 However, the utility of this reaction for the large-scale preparation of cyclopropane derivatives has not been explored. We were attracted toward developing the use of TEPA for the conversion of 3 to 2a due to its low cost, ease of availability and handling onscale. Most of the cited procedures use NaH as the base and afford the cyclopropane derivatives in fair yields (20-60%). Therefore, to make such a procedure scale-worthy, we needed to find a suitable substitute for NaH (dust hazard, hydrogen evolution, moisture sensitivity, etc.) and to identify reaction conditions to significantly improve the overall yield of the reaction.Herein, we wish to report the development of a safe, practical, and high-yielding process for the conversion of 3 to 2a by using the chemistry of TEPA anion and subsequent isolation of 2b.

Validation of Diethoxyphosphonate as an Effective Agent for Charge Transfer in Anion Relay Chemistry (ARC)

“…The most common prototype, orginally reported by Wadsworth and Emmons, 9 entails the reaction of stabilized phosphonate anions with epoxides to form cyclopropanes (Figure 2A), a reaction process that typically requires both high temperature and prolonged reaction time. Independent studies by Singh, 11 Merschaert, 12 and Ghirardelli 5 suggested that the reaction proceeds through a mechanism similar to what we now term Type I ARC, involving a stepwise “Brook-like” rearrangement involving initial explusion of an ethoxide anion. Readdition of the ethoxide and completion of the C→O phosphorus migration furnishes a stabilized anion that undergoes intramolecular displacement of the diethoxyphosphate to generate the trans cyclopropane.…”

Microbial hydroxylation of o-bromophenylacetic acid: synthesis of 4-substituted-2,3-dihydrobenzofurans

“…In these programs, several interesting syntheses of dihydrobenzofurans have been reported. During our melatonin receptor agonist [7,8,21,24] and sodium hydrogen exchange (NHE) programs [1,2], we needed to develop 2,3-dihydrobenzofuran as a core structure which would allow facile access to 4-substituted-2,3-dihydrobenzofurans. We envisioned accomplishing this by microbial hydroxylation [14] of 2-bromophenylacetic acid (7), thus providing a suitable substrate (9).…”

Catalytic Enantioselective Synthesis of Highly Functionalized Difluoromethylated Cyclopropanes

“…By combining the features of the fluorine atom and cyclopropanes,f luorinated cyclopropyl motifs have become highly important. [7] Forexample,trifluoromethyl cyclopropane is well recognized as a tert-butyl bioisostere, [8a] and its synthesis has been well studied over the last years. [8] Notably,the difluoromethylated cyclopropane motif has already found applications in medicinal chemistry and agrochemistry with some bioactive molecules ( Figure 1).…”