Asymmetric Enamide–Imine Tautomerism in the Kinetic Resolution of Tertiary Alcohols

Abstract

An efficient protocol for kinetic resolution of tertiary alcohols has been developed through an unprecedented asymmetric enamide‐imine tautomerism process enabled by chiral phosphoric acid catalysis. A broad range of racemic 2‐arylsulfonamido tertiary allyl alcohols could be kinetically resolved with excellent kinetic resolution performances (with s‐factor up to >200). This method is particularly effective for a series of 1,1‐dialkyl substituted allyl alcohols, which produced chiral tertiary alcohols that would be difficult to access via other asymmetric methods. Facile and versatile transformations of the chiral α‐hydroxy imine and enamide products, especially the efficient stereodivergent synthesis of all four stereoisomers of β‐amino tertiary alcohols using one enantiomer of the catalyst, demonstrated the value of this kinetic resolution method.

Asymmetric Enamide–Imine Tautomerism in the Kinetic Resolution of Tertiary Alcohols

“…[29] Thea bsolute configurations of these b-amino alcohols were assigned by X-ray crystallography of product (2R,3R)-10 a. [24] It is worth noting that only one enantiomer of the CPAcatalyst was used in this protocol to provide access to all four stereoisomers of the b-amino tertiary alcohol products,which highlighted the power of this protocol.…”

“…Thea bsolute configurations of the chiral imine and enamide products were assigned by analogy to recovered (S)-1j,w hose structure was unambiguously determined by X-ray crystallography. [24] With the excellent KR results for 1,1-dialkyl-substituted allylic alcohols,w et urned our attention to 1-aryl-1-alkyldisubstituted allylic alcohols,whose disubstitutions should be easier to be differentiated in general sense (Table 3). Treatment of racemic 1o with CPA( S)-A7 (10 mol %) in benzene [25] at 25 8 8Cp rovided the imine product 2o with 98:2 er and recovered 1o with 82.5:17.5 er after 3h,corresponding to an excellent s-factor (s = 100).…”

A Statistical Modeling Approach to Catalyst Generality Assessment in Enantioselective Synthesis

“…Where additional comparison data is available, several other studies involving imine-type electrophiles (C=N-R) have shown the importance of including TCYP in a catalyst evaluation despite the structural similarities with TRIP. [32][33][34][35][36][37][38][39][40][41] By performing this type of analysis with similarly related electrophiles, azo compounds, [42][43][44][45][46] precedent shows TCYP to be a top performer. Continued expansion of this comparative analysis demonstrates TCYP to be effective in condensation, 47,48 halogenation [49][50][51][52] and organometallic reactions.…”

Recent Advances in Catalytic Nonenzymatic Kinetic Resolution of Tertiary Alcohols

“…The KR of 2-arylsulfonamido tertiary allylic alcohols 38 enabled by chiral phosphoric acid 23 catalyzed asymmetric enamide-imine tautomerism process was disclosed by Yang and co-workers in 2021 (Scheme 7a). 22 This protocol did not involve the transformation of the hydroxy group and, thus, led to the formation of two enantiomeric tertiary alcohols. Both dialkyl-and aryl,alkyl-disubstituted tertiary allylic alcohols were well resolved by this protocol, generating chiral -hydroxy enamides 38 and imines 39 with selectivity factors up to 200.…”