DESYPHOR · CATALYTIC ENANTIOSELECTIVE DESYMMETRIZATION OF PHOSPHORUS (V) CENTERS

CATALYTIC ENANTIOSELECTIVE DESYMMETRIZATION OF PHOSPHORUS (V) CENTERS

Compounds containing one or more phosphorous atoms in the P(V) oxidation state are important to chemistry, biology and medicine. These include marketed antiviral drugs such as Remdesivir, and Sofosbuvir; the former garnering interest as a potential treatment for COVID-19, and the latter being on the WHO list of essential medicines for the treatment of Hepatitis C (Figure 1). Accordingly, new and improved methods for the efficient synthesis of P(V) containing compounds, especially in an enantioselective fashion are essential. Although promising protocols are beginning to arise for the synthesis of racemic P(V) compounds, new strategic approaches for the stereoselective synthesis of P-stereogenic centers are limited and catalytic enantioselective approaches remain largely unknown. Despite these advances, direct enantioselective catalytic desymmetrization protocols involving reactivity directly at the P(V) remains unexplored. We envisioned a two-stage desymmetrization–derivatization strategy (Figure 2) by which enantiotopic phenolic leaving groups on a prochiral phosphonate ester are enantiodiscriminated by a suitable nucleophile under the control of a chiral catalyst, generating a new P−O bond. The resulting intermediate would retain suitable reactivity for sequential substitution of the remaining leaving group. With appropriate stereocontrol, this approach would overcome the key restrictions of previously developed protocols. Given the tunability and high basicity of our bifunctional iminophosphorane catalysts (BIMP), we expected that they would provide sufficient activation and could be suitably adapted to obtain high levels of enantiopurity in the products. Objectives: Therefore, the overall objectives of this project can be summarized as follows: a) To develop and explore the scope of the catalytic enantioselective nucleophilic desymmetrization reaction at P(V) with phenol pronucleophiles, including downstream derivatizations. b) To develop and explore the 2nd generation desymmetrization platform using thiazolidinone leaving group and application to a wide range of P(V) derivatives. Conclusion: In conclusion, a two-stage strategy for the synthesis of stereogenic P(V) compounds through an unprecedented enantioselective nucleophilic desymmetrization and subsequent enantiospecific derivatization, was developed (Scheme 1). A BIMP catalyst provided a unique chiral environment and sufficient pronucleophile/substrate activation to allow the desymmetrization to proceed with excellent yield and enantioselectivity. Through judicious choice of leaving group, facile downstream diversification of the desymmetrized P(V) ester with very high enantiospecificity was allowed. A 2nd generation enantioselective desymmetrisation at P(V) was developed (Scheme 2). Through the synergistic use of thiazolidinone leaving groups on P and fine tuning of the BIMP catalyst numerous drawbacks of previously established methods have been overcome. Now, phenols with a wide array of substitution patterns can be readily employed as nucleophiles in the desymmetrisation step with both aryl and alkyl derived P(V) electrophiles as substrates. The resulting enantioenriched intermediates could be converted to an even greater range of distinct classes P(V) of compounds.

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