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

Abstract

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.

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

“…As eries of studies by Nelson and co-workersc ombined the abovementioned idea and the methodology of DOS to generate dozens of scaffolds capable of generating lead-like compound libraries;s everalo ther groups have also contributed to this area. [210][211][212][213] For example, as ynthetic strategy very similar to the B/C/P approach was used to obtain over 20 structurally diversel ead-like scaffolds from only 4 a,a-disubstituted amino acids and 6t ypical transformations. [214] In another example, over 50 lead-like scaffolds were generated by using only 13 startingc ompounds and at oolkit of 6c yclization reactions, which werea pplied sequentially in 2s teps.…”

Mild Homologation of Esters through Continuous Flow Chloroacetate Claisen Reactions

“…Notably,the aliphatic homologation product 1m shows regioselectivity opposite to that of analogous halogenation reactions. [17] Furthermore,the cyclopropane trans-diester [18] 5ab furnished the stereoisomerically pure cyclopropanoate 2q in 61 %y ield. Ar elated reaction with ethyl glycidate 5ac (d.r.…”

“…More electron-rich benzoic esters 5rt required the use of more than 1.1 equiv of dianion 4 to furnish the desired products 1i and 2k-m in satisfying yields of 60-76 %( entries 18-21). Furthermore,b yc hoosing between different quench methods,t he acetal of ester 5r could be largely preserved (1i,60%) [16] or removed in situ to give the aldehyde (2k, 71 %; entries [18][19]. Finally,b romopyridine 5u and quinoline 5v furnished the heterocyclic chloroketones 2n-o in 66-80 %yield.…”

“…More electron-rich benzoic esters 5rt required the use of more than 1.1 equiv of dianion 4 to furnish the desired products 1i and 2k-m in satisfying yields of 60-76 %( entries 18-21). [17] Furthermore,the cyclopropane trans-diester [18] 5ab furnished the stereoisomerically pure cyclopropanoate 2q in 61 %y ield. Finally,b romopyridine 5u and quinoline 5v furnished the heterocyclic chloroketones 2n-o in 66-80 %yield.…”

Stereoselective Enzymatic Synthesis of Heteroatom-Substituted Cyclopropanes

“…For cis-selective cyclopropanation of phenyl vinyl sulfide, an A328N mutation improved diastereoselectivity from 59:41 dr to 84:16 dr while increasing the ee from 39% to 90%, thereby delivering a cyclopropane core allowing extensive further functionalization with high selectivity. 47 Moreover, this approach yielded P411-VAC cis variants with good to excellent diastereoselectivities and enantioselectivities for the trans-selective cyclopropanation of phenyl vinyl ether and phenyl vinyl sulfide, through a V87I and V87F mutation, respectively (Table 1, Figure S6). We thereby generated a panel of P411 variants delivering diverse heteroatom-substituted cyclopropanes with good to excellent dr and ee (Table 1).…”