Combination of Asymmetric Organo- and Biocatalytic Reactions in Organic Media Using Immobilized Catalysts in Different Compartments

A proof of concept for the combination of an asymmetric organocatalytic reaction with a biotransformation toward a “one-pot like” process for 1,3-diols based on immobilized organo- and biocatalysts, which are utilized in different compartments, is demonstrated. This process which runs completely in organic media consists of an initial proline-derivative-catalyzed aldol reaction and a subsequent reduction of the aldol adduct catalyzed by an alcohol dehydrogenase (ADH) without the need for intermediate isolation. Economically attractive superabsorber-based coimmobilization for the ADH and its cofactor NAD⁺ turned out to give a highly efficient biocatalyst with excellent reusability and simple product separation from the immobilizate under avoidance of any tedious extraction steps during the overall process

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>)