Large-Scale Synthesis of Singh’s Catalyst in a One-Pot Procedure Starting from Proline

A practical one-pot procedure for the preparation of Singh’s catalyst from either l-/d-proline or Boc-proline is described. The coupling partner, a chiral amino alcohol, can be prepared and used directly without purification from the corresponding amino acid ester. Moreover, a procedure for <i>tert</i>-butoxycarbonyl (Boc) group removal using concentrated HCl in MeOH–DCM was developed and utilized for the multigram-scale synthesis of Singh’s catalyst

Highly Enantioselective Organocatalytic Trifluoromethyl Carbinol SynthesisA Caveat on Reaction Times and Product Isolation

Aldol reactions with trifluoroacetophenones as acceptors yield chiral α-aryl, α-trifluoromethyl tertiary alcohols, valuable intermediates in organic synthesis. Of the various organocatalysts examined, Singh’s catalyst [(2<i>S</i>)-<i>N</i>-[(1<i>S</i>)-1-hydroxydiphenylmethyl-3-methylbutyl]-2-pyrrolidinecarbox­amide] was found to efficiently promote this organocatalytic transformation in a highly enantioselective manner. Detailed reaction monitoring (¹⁹F-NMR, HPLC) showed that, up to full conversion, the catalytic transformation proceeds under kinetic control and affords up to 95% ee in a time-independent manner. At longer reaction times, the catalyst effects racemization. For the product aldols, even weak acids (such as ammonium chloride) or protic solvents, can induce racemization, too. Thus, acid-free workup, at carefully chosen reaction time, is crucial for the isolation of the aldols in high (and stable) enantiomeric purity. As evidenced by ¹⁹F-NMR, X-ray structural analysis, and independent synthesis of a stable intramolecular variant, Singh’s catalyst reversibly forms a catalytically inactive (“parasitic”) intermediate, namely a <i>N</i>,<i>O</i>-hemiacetal with trifluoroacetophenones. X-ray crystallography also allowed the determination of the product aldols’ absolute configuration (<i>S</i>)

Highly Enantioselective Organocatalytic Trifluoromethyl Carbinol SynthesisA Caveat on Reaction Times and Product Isolation

Aldol reactions with trifluoroacetophenones as acceptors yield chiral α-aryl, α-trifluoromethyl tertiary alcohols, valuable intermediates in organic synthesis. Of the various organocatalysts examined, Singh’s catalyst [(2<i>S</i>)-<i>N</i>-[(1<i>S</i>)-1-hydroxydiphenylmethyl-3-methylbutyl]-2-pyrrolidinecarbox­amide] was found to efficiently promote this organocatalytic transformation in a highly enantioselective manner. Detailed reaction monitoring (¹⁹F-NMR, HPLC) showed that, up to full conversion, the catalytic transformation proceeds under kinetic control and affords up to 95% ee in a time-independent manner. At longer reaction times, the catalyst effects racemization. For the product aldols, even weak acids (such as ammonium chloride) or protic solvents, can induce racemization, too. Thus, acid-free workup, at carefully chosen reaction time, is crucial for the isolation of the aldols in high (and stable) enantiomeric purity. As evidenced by ¹⁹F-NMR, X-ray structural analysis, and independent synthesis of a stable intramolecular variant, Singh’s catalyst reversibly forms a catalytically inactive (“parasitic”) intermediate, namely a <i>N</i>,<i>O</i>-hemiacetal with trifluoroacetophenones. X-ray crystallography also allowed the determination of the product aldols’ absolute configuration (<i>S</i>)

Highly Enantioselective Organocatalytic Trifluoromethyl Carbinol SynthesisA Caveat on Reaction Times and Product Isolation

Aldol reactions with trifluoroacetophenones as acceptors yield chiral α-aryl, α-trifluoromethyl tertiary alcohols, valuable intermediates in organic synthesis. Of the various organocatalysts examined, Singh’s catalyst [(2<i>S</i>)-<i>N</i>-[(1<i>S</i>)-1-hydroxydiphenylmethyl-3-methylbutyl]-2-pyrrolidinecarbox­amide] was found to efficiently promote this organocatalytic transformation in a highly enantioselective manner. Detailed reaction monitoring (¹⁹F-NMR, HPLC) showed that, up to full conversion, the catalytic transformation proceeds under kinetic control and affords up to 95% ee in a time-independent manner. At longer reaction times, the catalyst effects racemization. For the product aldols, even weak acids (such as ammonium chloride) or protic solvents, can induce racemization, too. Thus, acid-free workup, at carefully chosen reaction time, is crucial for the isolation of the aldols in high (and stable) enantiomeric purity. As evidenced by ¹⁹F-NMR, X-ray structural analysis, and independent synthesis of a stable intramolecular variant, Singh’s catalyst reversibly forms a catalytically inactive (“parasitic”) intermediate, namely a <i>N</i>,<i>O</i>-hemiacetal with trifluoroacetophenones. X-ray crystallography also allowed the determination of the product aldols’ absolute configuration (<i>S</i>)

Highly Enantioselective Organocatalytic Trifluoromethyl Carbinol SynthesisA Caveat on Reaction Times and Product Isolation

Aldol reactions with trifluoroacetophenones as acceptors yield chiral α-aryl, α-trifluoromethyl tertiary alcohols, valuable intermediates in organic synthesis. Of the various organocatalysts examined, Singh’s catalyst [(2<i>S</i>)-<i>N</i>-[(1<i>S</i>)-1-hydroxydiphenylmethyl-3-methylbutyl]-2-pyrrolidinecarbox­amide] was found to efficiently promote this organocatalytic transformation in a highly enantioselective manner. Detailed reaction monitoring (¹⁹F-NMR, HPLC) showed that, up to full conversion, the catalytic transformation proceeds under kinetic control and affords up to 95% ee in a time-independent manner. At longer reaction times, the catalyst effects racemization. For the product aldols, even weak acids (such as ammonium chloride) or protic solvents, can induce racemization, too. Thus, acid-free workup, at carefully chosen reaction time, is crucial for the isolation of the aldols in high (and stable) enantiomeric purity. As evidenced by ¹⁹F-NMR, X-ray structural analysis, and independent synthesis of a stable intramolecular variant, Singh’s catalyst reversibly forms a catalytically inactive (“parasitic”) intermediate, namely a <i>N</i>,<i>O</i>-hemiacetal with trifluoroacetophenones. X-ray crystallography also allowed the determination of the product aldols’ absolute configuration (<i>S</i>)