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

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.


[e]
Method used is the same as that detailed for the synthesis of 1 and 2 on page S14. [f] Yield was determined using 1 H NMR spectroscopy through comparison to an internal standard (dibenzyl ether or 1,3,5-trimethoxybenzene).

Cyclopropanation of phenyl vinyl sulfide: product purification
With the larger scale cyclopropanation reactions, using EDA and PVS with cobalt catalyst 3, flash chromatography was not successful in separating cyclopropanes 1 and 2 from a catalyst derived impurity. This impurity coeluted with the products in all eluent systems tested. An oxidative work-up was developed that allowed removal of this impurity through simple filtration. Initial observations were made on the addition of iso-hexane to the reaction mixture on small scale, leading to a change in the nature of the impurity so it could be easily removed. This was ascribed to the dissolved O 2 in the iso-hexane likely forming a peroxo-bridged dimeric Co-species, resulting in a very deep brown mixture. [1] On larger scales, more O 2 was required for the same effect. Various solvents were tested for effectiveness in oxidation of the catalyst, and hence facile removal, by adding O 2 (from either an O 2 or compressed air cylinder) for approximately 15 minutes. The resulting mixture was then filtered through a pad of silica (size dependant upon the amount of salen-based material being removed), washing with CH 2 Cl 2 . i-Hexane was chosen as the most effective solvent as it has a relatively high oxygen permeability, [2] it solubilises the Co-salen-based species, and allows the mixture to be directly filtered through a silica pad without the solvent eluting impurities.    Figure  S1: Physicochemical properties for the synthesized compounds deemed relevant to drug discovery Molecular properties were calculated using LLAMA (Lead-Likeness and Molecular Analysis) software, available freely online at https://llama.leeds.ac.uk. [8]

Virtual scaffold decoration and LLAMA compound analysis
The LLAMA software was used to perform a virtual decoration of the synthesized cyclopropyl compounds. The 56 compounds (all 50 compounds shown in Figure  S1 plus 19a, 19k, 19l, 19m, 20a and 20l) were utilized as scaffolds, along with the 44 reagents from the 'LLAMA Default' reactant set ( Figure  S2).

Figure S2: 'LLAMA Default' reaction set
The following reactions were enabled for the virtual scaffold functionalization: BOC deprotection, reductive amination, Suzuki-Miyaura cross-coupling, Buchwald-Hartwig amination, sulfonamide formation, urea formation, alcohol alkylation, carbamate formation, secondary amide alkylation, secondary amide arylation, amide formation, alcohol arylation, urea alkylation, urea arylation, esterification and ester hydrolysis. The reaction for ester hydrolysis to the corresponding carboxylic acid was not present in the default reaction library and so was added via 'Advanced settings > Add a new reaction to the library' and using the below SMARTS code as the reaction description:

Optimization of an enantioselective cyclopropanation of phenyl vinyl sulfide
Enantiopure ligands were applied to the cyclopropanation of phenyl vinyl sulfide and ethyl diazoacetate towards an asymmetric cyclopropanation. A range of BOX and PyBOX ligands were investigated in the CuOTf-catalyzed protocol, that give high yields and ee on styrene substrates. [23] However, all gave low yields, dr and ee with PVS. Following the success of the Co-catalyzed reaction, several enantiopure Co II (salen)-type complexes were prepared (see below) to probe a variety of steric and electronic effects (Table  S3). The best results were achieved using commercial complex 3 (Table  S3, entry 1), which gave a quantitative yield and showed moderate and good enantioselectivity for the trans-and cis-cyclopropane products, respectively. Other variations in catalyst structure were not advantageous. Synthesis of enantiopure C 2 -symmetric Co II -(salen)-type complexes General procedure for tetradentate Schiff base synthesis A solution of the enantiopure chiral diamine (1.0 equiv) in EtOH (0.20 M) was added to a solution of the salicylaldehyde derivative (2.0 equiv) in EtOH (0.17 M) and the solution refluxed for 3-20 h. Filtration and recrystallization from ethanol gave the desired tetradentate Schiff bases. The observed data was consistent with that previously reported for the tetradentate Schiff base ligands for complexes 26, [24] 27, [25] and 28. [26] N,N'-Bis[(E)-(3,5-di-iodo)-2-hydroxyphenylmethylene]-[(1R,2R)-1,2-