Asymmetric synthesis of functionalized cyclopropanes via .beta.-lithiation-cyclization of N-monosubstituted 3-(phenylthio)-2-[(phenylthio)methyl]propanamides

Tanaka, Kazuhiko; Funaki, I.; Kaji, Aritsune; Minami, Koichiro; Sawada, Masami; T, Tanaka

doi:10.1021/ja00229a038

Cited by 23 publications

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“…To generate cyclopropyl scaffolds 1 and 2 we envisaged the reaction of phenyl vinyl sulfide (PVS) with ethyl diazoacetate (EDA) in a transition metal‐catalyzed cyclopropanation (Scheme ). The only prior report of the cyclopropanation of PVS with EDA was in 1962; an uncatalyzed reaction requiring heating of the neat reactants at 100 to 170 °C in a sealed vessel . In search of less hazardous, lower temperature reaction conditions suitable for multi‐gram scale, transition metal catalysts were investigated.…”

Section: Resultsmentioning

confidence: 99%

Divergent Synthesis of Cyclopropane‐Containing Lead‐Like Compounds, Fragments and Building Blocks through a Cobalt Catalyzed Cyclopropanation of Phenyl Vinyl Sulfide

2017

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Cyclopropanes provide important design elements in medicinal chemistry and are widely present in drug compounds. Here we describe a strategy and extensive synthetic studies for the preparation of a diverse collection of cyclopropane‐containing lead‐like compounds, fragments and building blocks exploiting a single precursor. The bifunctional cyclopropane (E/Z)‐ethyl 2‐(phenylsulfanyl)‐cyclopropane‐1‐carboxylate was designed to allow derivatization through the ester and sulfide functionalities to topologically varied compounds designed to fit in desirable chemical space for drug discovery. A cobalt‐catalyzed cyclopropanation of phenyl vinyl sulfide affords these scaffolds on multigram scale. Divergent, orthogonal derivatization is achieved through hydrolysis, reduction, amidation and oxidation reactions as well as sulfoxide–magnesium exchange/functionalization. The cyclopropyl Grignard reagent formed from sulfoxide exchange is stable at 0 °C for > 2 h, which enables trapping with various electrophiles and Pd‐catalyzed Negishi cross‐coupling reactions. The library prepared, as well as a further virtual elaboration, is analyzed against parameters of lipophilicity (ALog P), MW and molecular shape by using the LLAMA (Lead‐Likeness and Molecular Analysis) software, to illustrate the success in generating lead‐like compounds and fragments.

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