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

TEFDDOLs (α,α,α′,α′-Tetrakis(perfluoroaryl/alkyl)-2,2′-dimethyl-1,3-dioxolane-4,5-dimethanols): Highly Fluorinated Chiral H‑Bond Donors and Brønsted Acids with Distinct H‑Bonding Patterns and Supramolecular Architectures

The synthesis of six enantiopure α,α,α′,α′-tetrakis­(perfluoroalkyl/aryl)-2,2′-dimethyl-1,3-dioxolane-4,5-dimethanols (TEFDDOLs), by addition of perfluorinated organolithium reagents or Ruppert’s reagent (TMS-CF₃) to isopropylidene tartaric dichloride, is reported. X-ray crystal structures of the TEFDDOLs alone or in complexes with H-bond acceptors such as water and DABCO revealed that this new class of highly fluorinated chiral 1,4-diols forms distinct intra- and intermolecular H-bond patterns. Intramolecular OH–OH bonding accounts for the relatively high acidity of the perfluoroalkyl TEFDDOLs (p<i>K</i>_a in DMSO: tetrakis-CF₃, 5.7; tetrakis-C₂F₅, 2.4). For the tetrakis­(perfluorophenyl) TEFDDOL, a quite unusual “pseudo-anti” conformation of the diol, with no intramolecular (and no intermolecular) OH–OH bonds, was found both in the crystal and in solution (DOSY and NOESY NMR). The latter conformation results from a total of four intramolecular OH–F_aryl hydrogen bonds overriding OH–OH bonding. Due to their H-bonding properties, the TEFDDOLs are promising new building blocks for supramolecular and potentially catalytic applications

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>)

1,4-Bis-Dipp/Mes-1,2,4-Triazolylidenes: Carbene Catalysts That Efficiently Overcome Steric Hindrance in the Redox Esterification of α- and β‑Substituted α,β-Enals

As reported by Scheidt and Bode in 2005, sterically nonencumbered α,β-enals are readily converted to saturated esters in the presence of alcohols and N-heterocyclic carbene catalysts, e.g., benzimidazolylidenes or triazolylidenes. However, substituents at the α- or β-position of the α,β-enal substrate are typically not tolerated, thus severely limiting the substrate spectrum. On the basis of our earlier mechanistic studies, a set of <i>N</i>-Mes- or <i>N</i>-Dipp-substituted 1,2,4-triazolium salts were synthesized and evaluated as (pre)­catalysts in the redox esterification of various α- or β-substituted enals. In particular the 1,4-bis-Mes/Dipp-1,2,4-triazolylidenes overcome the above limitations and efficiently catalyze the redox esterification of a whole series of α/β-substituted enals hitherto not amenable to NHC-catalyzed transformations. The synthetic value of 1,4-bis-Mes/Dipp-1,2,4-triazolylidenes is further demonstrated by the one-step bicyclization of 10-oxocitral to (racemic) nepetalactone in diastereomerically pure form

Chemoenzymatic Synthesis of Vitamin B5-Intermediate (<i>R</i>)‑Pantolactone via Combined Asymmetric Organo- and Biocatalysis

The combination of an asymmetric organocatalytic aldol reaction with a subsequent biotransformation toward a “one-pot-like” process for the synthesis of (<i>R</i>)-pantolactone, which to date is industrially produced by a resolution process, is demonstrated. This process consists of an initial aldol reaction catalyzed by readily available l-histidine followed by biotransformation of the aldol adduct by an alcohol dehydrogenase without the need for intermediate isolation. Employing the industrially attractive starting material isobutanal, a chemoenzymatic three-step process without intermediate purification is established allowing the synthesis of (<i>R</i>)-pantolactone in an overall yield of 55% (three steps) and high enantiomeric excess of 95%