Sulfur, with its multiple oxidation states, is widely present in biologically active compounds. Well-known sulfur functional groups include achiral sulfonamide, sulfone, thiol, thioether. However, chiral sulfur functional groups are often overlooked as pharmacophores. There are only limited examples of marketed drugs containing any sulfur stereogenic centers. Esomeprazole and Armodafinil are examples of chiral chiral sulfoxide drugs. Sulfoximine, a moiety with S(VI) stereocenter, has recently become a rising star in drug discovery due to its unique physicochemical and pharmacokinetic properties. Other sulfur stereogenic centers such as sulfinate ester, sulfinamide, sulfonimidate ester and sulfonimidamide have also started to attract attention. The diversity and complexity of these novel sulfur stereogenic centers have expanded the chemical space for drug discovery.
While some new methodologies have been developed for racemic synthesis of these stereogenic centers, preparation of chiral sulfur stereocenters is still a formidable challenge. The enantiomers of many bioactive compounds are usually separated for biological activity tests through preparative high-performance liquid chromatography equipped with chiral columns. Established asymmetric synthetic methods mainly rely on stoichiometric amounts of chiral reagents or kinetic resolution of racemic substrates. In the meanwhile, only a handful of catalytic approaches were reported. However, the chiral structures obtained through these methods are very limited, which is not able to meet the increasing demands for structural diversity in drug discovery. A general and efficient method to install these structures stereoselectively, into existing drug molecules, will facilitate the understanding and application of these novel chiral sulfur structures in drug discovery.
To achieve the diversification of drugs with sulfur stereogenic centers, we have focused on the enantioselective synthesis of sulfinate ester. Sulfinate ester is one linchpin structure, because a variety of approaches have been developed to convert sulfinate esters to other sulfur stereogenic centers without erosion of ee values. Reports on catalytic synthesis of enantioenriched sulfinate esters are scarce and all based upon dynamic kinetic resolution of sulfinyl chlorides with alcohols using peptides or Cinchona alkaloids as catalysts. The community is still yearning for a general and efficient method for catalytic synthesis of chiral sulfinate esters with broad substrate compatibility.
This manuscript reports the straightforward synthesis of chiral sulfinate ester through asymmetric condensation of sulfinates and alcohols. Sulfinate, a stable and easily accessible reagent, is well known as a source of carbon radical for coupling via desulfitation or as a sulfur-centered nucleophile. Less known is that sulfinate is an ambident nucleophile, and that the enantiotopic oxygen atoms are also potential nucleophilic sites. We have realized this novel pathway through the use of acyl chlorides or sulfonyl chlorides as the oxophilic electrophile. In the presence of chiral pentanidium as organocatalyst, sulfinate and ethyl chloroformate form a mixed anhydride intermediate, which in turn is converted to sulfinate ester through a replacement reaction with an alcohol. After many trials of reagents and catalysts, we found ethyl chloroformate and pentanidium with a phenol substitution gave the products with highest enantioselectivity. Later, we investigated the reaction scopes, many aromatic and alkyl sulfinates gave products with high stereoselectivity. Various alcohols with high functional group compatibility were well tolerated. Examples included cholecalciferol, cholesterol, epi-androsterone and the corresponding alcoholic intermediates of several marketed antiviral drugs such as Zidovudine, Sofosbuvir and Remdesivir.
As mentioned, the initial sulfinates are easily accessible and many synthetic methods have been developed. Therefore, we prepared several sulfinate salts of existing drugs. The asymmetric condensation of these complex sulfinates with alcohols worked well under our conditions. We also used sulfonamide drug Celecoxib as a model to show that sulfinate ester is the ideal linchpin intermediate for late-stage diversification of drugs into a plethora of sulfur stereogenic centers. Through stereospecific nucleophilic substitution and imidation, Celecoxib was diversified with various chiral S(IV)/S(V) pharmacophores, incuding sulfoxide, sulfinamide sulfonimidate ester, sulfoximine and sulfonimidamide.
In conclusion, we have presented a viable and unified synthetic strategy for the stereoselective preparation of sulfinate esters and related sulfur stereogenic centers. This methodology is mild and tolerates a wide range of functional groups, allowing it to be compatible with late-stage diversification of Celecoxib and other marketed drugs. In addition, several marketed antiviral drugs e.g. Zidovudine, Sofosbuvir and Remdesivir can be redecorated with sulfur stereogenic centers through sulfinylation of their alcoholic intermediates. This work provides new insights for the improvement of sulfur containing drugs. In view of the increasing use of sulfur stereogenic centers as pharmacophores, we believe that this new methodology will ameliorate the toolkits of drug discovery programs for the exploration of these pharmacophores.
More details on this work can be found here: “Synthesis of chiral sulfinate esters by asymmetric condensation” in Nature https://www.nature.com/articles/s41586-022-04524-4.
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