Protein engineering of lipase A from Candida antarctica to improve esterification of tertiary alcohols.

Chiral tertiary alcohols are important organic compounds in science as well as in industry. However, their preparation in enantiomerically pure form is still a challenge due to their complex structure and steric hindrances compared with primary and secondary alcohols, so kinetic resolution could be an attractive approach.  Lipase A from Candida antarctica (CAL-A) has been shown to catalyze the enantioselective esterification of various tertiary alcohols with excellent enantioselectivity but low activity. Here we report a mutagenesis study by rational design to improve CAL-A activity against tertiary alcohols. Single mutants of CAL-A were selected, expressed, immobilized and screened for esterification of the tertiary alcohol 1,2,3,4-tetrahydronaphthalene-1-ol. A double mutant V278S+S429G showed a 1.5-fold higher reaction rate than that of the wild type CAL-A, while maintaining excellent enantioselectivity.

Strategies to Design Chemocatalytic Racemization of Tertiary Alcohols: State of the Art & Utilization for Dynamic Kinetic Resolution.

The synthesis of enantiomerically pure tertiary alcohols is an important issue in organic synthesis of a range of pharmaceuticals including molecules such as the anti-HIV drug Efavirenz. A conceptually elegant approach to such enantiomers is the dynamic kinetic resolution of racemic tertiary alcohols, which, however, requires efficient racemization strategies. The racemization of tertiary alcohols is particularly challenging due to various side reactions that can occur because of their high tendency for elimination reactions. In the last few years, several complementary catalytic concepts for racemization of tertiary alcohols have been developed, characterized by efficient racemization and suppression of unwanted side-reactions. Besides resins bearing sulfonic acid moieties and a combination of boronic acid and oxalic acid as heterogeneous and homogeneous Brønsted-acids, respectively, immobilized oxovanadium and piperidine turned out to be useful catalysts. The latter two catalysts, which have already been applied to different types of substrates, also have proven good compatibility with lipase, thus leading to the first two examples of chemoenzymatic dynamic kinetic resolution of tertiary alcohols. In this review, the difficulties in racemizing tertiary alcohols are specifically described, and the recently developed complementary concepts to overcome these hurdles are summarized.

Nucleophilic Deprotection of p-Methoxybenzyl Ethers Using Heterogeneous Oxovanadium Catalyst.

Nucleophilic deprotection of p-methoxybenzyl (PMB) [p-methoxyphenylmethyl (MPM)] ethers was developed using a heterogeneous oxovanadium catalyst V-MPS4 and a thiol nucleophile. The deprotection method had a wide reaction scope, including PMB ethers of primary, secondary, and tertiary alcohols bearing various functional groups. In addition, the PMB ether of an oxidation-labile natural product was successfully removed by V-MPS4 catalysis, while a common oxidative method of PMB deprotection afforded a complex mixture. The V-MPS4 catalyst was reusable up to six times without a significant loss in the product yield. The advantages of using the heterogeneous catalyst were further demonstrated by conducting the deprotection reaction in a continuous flow process, which resulted in a 2.7-fold higher catalyst turnover number and 60-fold higher turnover frequency compared to those of the corresponding batch reaction.

First atroposelective Chan-Lam coupling for the synthesis of C-N linked biaryls.

The first atroposelective Chan-Lam coupling for the synthesis of C-N axial enantiomers is reported with good yields and ee. MnO2 additive is crucial for the success of the coupling. The longstanding problem of the lack of enantioselective synthesis to make chiral C-N linked atropisomers is solved.

Enantiodivergent Chemoenzymatic Dynamic Kinetic Resolution: Conversion of Racemic Propargyl Alcohols into Both Enantiomers.

Natural lipases typically recognize enantiomers of alcohols based on the size differences of substituents near the carbinol moiety and selectively react with the R enantiomers of secondary alcohols. Therefore, lipase-catalyzed dynamic kinetic resolution (DKR) of racemic secondary alcohols produces only R enantiomers. We report herein a method for obtaining S enantiomers by DKR of secondary 3-(trialkylsilyl)propargyl alcohols by using a well-known R-selective Pseudomonas fluorescens lipase in combination with a racemization catalyst VMPS4, in which the silyl group reverses the size relationship of substituents near the carbinol moiety. We have already reported R-selective DKR of the corresponding propargyl alcohols without substituents on the ethynyl terminal carbon, and the presence of an easily removable silyl group has enabled us to produce both enantiomers of propargyl alcohols in high chemical yields and with high enantiomeric excess. In addition, immobilization of the lipase on Celite was found to be important for achieving a high efficiency of the DKR.

Lipase-Catalyzed Kinetic Resolution of C1-Symmetric Heterocyclic Biaryls.

The highly enantioselective lipase-catalyzed kinetic resolution (KR) of racemic C1-symmetric biaryl compounds including heterocyclic moieties, such as carbazole and dibenzofuran, has been achieved for the first time. This enzymatic esterification was accelerated by the addition of disodium carbonate while maintaining its high enantioselectivities, and was particularly effective for biaryls having N-substituted carbazole moieties. Furthermore, mesoporous silica-supported oxovanadium-catalyzed cross-dehydrogenative coupling of 3-hydroxycarbazole and 2-naphthol was followed by the lipase-catalyzed KR in one-pot to synthesize the optically active heterocyclic biaryl compounds with high optical purity.

Chemo- and regioselective cross-dehydrogenative coupling reaction of 3-hydroxycarbazoles with arenols catalyzed by a mesoporous silica-supported oxovanadium.

Cross-dehydrogenative coupling between 3-hydroxycarbazoles and 2-naphthols has been achieved by using a mesoporous silica-supported oxovanadium catalyst.

Chitosan nanofiber-catalyzed highly selective Knoevenagel condensation in aqueous methanol.

A chitosan nanofiber (CsNF)-catalyzed Knoevenagel reaction in green solvent, namely aqueous methanol, was investigated. CsNFs solely catalyzed the desired C-C bond formations in high yield with high selectivity, while conventional small-molecule amines, such as n-hexylamine and triethylamine, inevitably promoted transesterification to produce a large amount of solvolysis byproducts. Structural and chemical analyses of CsNFs suggested that the unique nanoarchitecture, in which chitosan molecules were bundled to ensure the high accessibility of substrates to catalytic sites, was critical to the highly efficient Knoevenagel condensation. The products were obtained in high purity without solvent-consuming purification, and the CsNF catalyst was easily removed and recycled. This study highlights a novel and promising function of CsNFs in green catalysis as emerging polysaccharide-based nanofibers.

Nanocellulose enriches enantiomers in asymmetric aldol reactions.

Cellulose nanofibers obtained from wood pulp by TEMPO-mediated oxidation acted as a chiral enhancer in direct aldol reactions of 4-nitrobenzaldehyde and cyclopentanone with (S)-proline as an organocatalyst. Surprisingly, catalytically inactive TEMPO-oxidized cellulose nanofibers enriched the (R,R)-enantiomer in this reaction, affording 89% ee in the syn form with a very high yield (99%). Conversely, nanocellulose-free (S)-proline catalysis resulted in poor selectivity (64% ee, syn form) with a low yield (18%). Green organocatalysis occurring on nanocellulose solid surfaces bearing regularly aligned chiral carbons on hydrophobic crystalline facets will provide new insight into asymmetric synthesis strategies for interfacial catalysis.

Mechanism and Origin of Stereoselectivity in Chiral Phosphoric Acid-Catalyzed Aldol-Type Reactions of Azlactones with Vinyl Ethers.

The precise mechanism of the chiral phosphoric acid-catalyzed aldol-type reaction of azlactones with vinyl ethers was investigated. DFT calculations suggested that the reaction proceeds through a Conia-ene-type transition state consisting of the vinyl ether and the enol tautomer of the azlactone, in which the catalyst protonates the nitrogen atom of the azlactone to promote enol tautomerization. In addition, the phosphoryl oxygen of the catalyst interacts with the vinyl proton of the vinyl ether. The favorable transition structure features dicoordinating hydrogen bonds. However, these hydrogen bonds are not involved in the bond recombination sequence and hence the catalyst functions as a template for binding substrates. From the results of theoretical studies and experimental supports, the high enantioselectivity is induced by the steric repulsion between the azlactone substituent and the binaphthyl backbone of the catalyst under the catalyst template effect.

Concerted Catalysis by Nanocellulose and Proline in Organocatalytic Michael Additions.

Cellulose nanofibers (CNFs) have recently attracted much attention as catalysts in various reactions. Organocatalysts have emerged as sustainable alternatives to metal-based catalysts in green organic synthesis, with concerted systems containing CNFs that are expected to provide next-generation catalysis. Herein, for the first time, we report that a representative organocatalyst comprising an unexpected combination of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)-oxidized CNFs and proline shows significantly enhanced catalytic activity in an asymmetric Michael addition.

Interfacial Hydrolysis of Acetals on Protonated TEMPO-oxidized Cellulose Nanofibers.

2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO)-oxidized cellulose nanofibers (TOCNs), which have a high-density of exposed carboxylic acid groups on their crystalline surfaces, effectively act as acid catalysts in acetal hydrolysis. Carboxy-free cellulose nanofibers, polymeric carboxylic acids, and homogeneous acetic acid do not show significant catalytic activity under the same reaction conditions. Mercerized TOCNs differing from the original TOCNs in a crystalline structure were also ineffective, which suggests that the unique nanoarchitectural features of TOCNs, such as regularly aligned carboxylic acid groups, large specific surface areas, and structural rigidity, must be major factors in the acceleration of acetal hydrolysis. Kinetic analysis suggested that substrates and/or acid catalyst species were concentrated on the TOCN crystalline surfaces, which significantly enhanced the catalytic activity.

Cooperative catalysis of cellulose nanofiber and organocatalyst in direct aldol reactions.

Cellulose nanofibers (CNFs) are finding a wide range of applications in the forthcoming sustainable society because of their carbon-neutral renewability and superior physicochemical properties. Here, we first show a cooperative organocatalysis by combining TEMPO-oxidized cellulose nanofiber (TOCN) and proline to enhance the catalytic efficiency in a direct aldol reaction. The yields of proline-catalyzed aldol products drastically increased in the presence of catalytically-inactive TOCN. This effect was also achieved by simply adding the TOCN to the reaction conditions where various proline analogues including structurally simple pyrrolidine and piperidine were used instead of proline. TOCN was superior to physically-pulverized CNF in the organocatalytic efficiency, and the nanofibrillation of cellulose microfibrils in reaction media was essential to induce the drastic enhancement in catalytic activity. The present finding will bring a new entry in the applications of CNFs, and open up a new phase in developing highly efficient molecular transformations in green chemical industries.

Enantioselective Aza Michael-Type Addition to Alkenyl Benzimidazoles Catalyzed by a Chiral Phosphoric Acid.

Highly enantioselective Michael-type addition (MTA) reactions between N-protected alkenyl benzimidazoles and either pyrazoles or indazoles as nitrogen nucleophiles are accomplished for the first time using chiral phosphoric acid catalyst. Theoretical studies elucidated the reaction pathway and the origin of the stereochemical outcomes, where the catalyst substituent and the N-protecting group of benzimidazole contributed to the resulting high enantioselectivity.

Chiral Brønsted acid-catalyzed enantioselective Friedel-Crafts reaction of 2-methoxyfuran with aliphatic ketimines generated in situ.

An enantioselective Friedel-Crafts reaction with aliphatic ketimines generated in situ from hemiaminal ethers catalyzed by a chiral Brønsted acid was investigated. The reaction of 2-methoxyfuran with (thio)hydantoin-derived hemiaminal methyl ether proceeded under the influence of a chiral phosphoric acid catalyst to afford the corresponding adduct possessing a quaternary stereogenic center in high yield with high enantioselectivity. Theoretical studies were also conducted to clarify the mechanism of the stereochemical outcome and the major factors contributing to the efficient enantioselection.

Chiral Brønsted acid catalyzed stereoselective addition of azlactones to 3-vinylindoles for facile access to enantioenriched tryptophan derivatives.

Syn-gled out: The syn diastereo- and enantioselective addition of azlactones to 3-vinylindoles was accomplished by using a chiral, binapthol-derived, Brønsted acid catalyst (see scheme). This method enables facile access to tryptophan derivatives with adjacent quaternary and tertiary stereogenic centers, which are potentially useful for the synthesis of peptidomimetics.