Enantioselective Hydrogenation of α‐Dehydroamino Acid Esters Catalyzed by Rhodium Complexes with Chiral Bisaminophosphine Ligands

A highly efficient strategy for the synthesis of a series of chiral bisaminophosphine ligands was well established with several remarkable features. The synthetic utility of these ligands was explored for rhodium‐catalyzed asymmetric hydrogenations of α‐dehydroamino acid esters. Up to 98% ee values were achieved for the enantioselective synthesis of aminocarboxylic acids and their derivatives, which are very important chiral building blocks for the synthesis of a variety of natural products and biologically active molecules.     

Efficient Lipase‐Catalyzed Kinetic Resolution and Dynamic Kinetic Resolution of β‐Hydroxy Nitriles. Correction of Absolute Configuration and Transformation to Chiral β‐Hydroxy Acids and γ‐Amino Alcohols

Chemoenzymatic dynamic kinetic resolution of β‐hydroxy nitriles 1 has been carried out using Candida antarctica lipase B and a ruthenium catalyst. The use of a hydrogen source to depress ketone formation in the dynamic kinetic resolution yields the corresponding acetates 2 in good yield and high enantioselectivity. It is shown that the ruthenium catalyst and the enzyme can be recycled when used in separate reactions. We also report on the preparation of various enantiomerically pure β‐hydroxy acid derivatives and γ‐amino alcohols from 1 and 2. The latter compounds were also used to establish the correct absolute configuration of 1 and 2.     

Organocatalytic Asymmetric Synthesis of Protected α,β‐Diamino Acids

In the presence of the readily available quinine‐derived catalyst 4d , highly diastereo‐ and enantioselective Mannich reactions of tosyl‐protected imines and α‐isothiocyanato imides proceeded to afford the protected α,β‐diamino acids, useful building blocks for natural products and biologically active compounds, in good to excellent yields.     

A General Approach to the Synthesis of β2‐Amino Acid Derivatives via Highly Efficient Catalytic Asymmetric Hydrogenation of α‐Aminomethylacrylates

A new strategy was developed for the synthesis of a valuable class of α‐aminomethylacrylates via the Baylis–Hillman reaction of different aldehydes with methyl acrylate followed by acetylation of the resulting allylic alcohols and S_N2′‐type amination of the allylic acetates. Asymmetric hydrogenation of these diverse olefinic precursors using rhodium(Et‐Duphos) catalysts provided the corresponding β²‐amino acid derivatives with excellent enantioselectivities and exceedingly high reactivities (up to >99.5% ee and S/C=10,000). The first hydrogenation of (Z)‐configurated substrates was studied for the synthesis of β²‐amino acid derivatives. The high influence of the substrate geometry and steric hindrance on the reactivity and enantioselectivity was also disclosed for this reaction. This protocol provides a highly practical, facile and scalable method for the preparation of optically pure β²‐amino acids and their derivatives under mild reaction conditions.     

Bis(3,5‐dimethylphenyl)‐(S)‐pyrrolidin‐2‐ylmethanol: an Improved Organocatalyst for the Asymmetric Epoxidation of α,β‐Enones

The asymmetric epoxidation of α,β‐enones by the readily available bis(3,5‐dimethylphenyl)‐(S)‐pyrrolidin‐2‐ylmethanol and tert‐butyl hydroperoxide (TBHP) is described. Stereoelectronic substitution on the aryl moiety of diaryl‐2‐pyrrolidinemethanols was found to significantly affect the efficiency with respect to the previously reported (S)‐diphenyl‐2‐pyrrolidinemethanol. Improved reactivity and enantioselectivity were achieved with bis(3,5‐dimethylphenyl)‐(S)‐pyrrolidin‐2‐ylmethanol at reduced catalyst loading (20 mol %) with ees up to 94% for chalcone epoxides under mild reaction conditions, whereas (S)‐diphenyl‐2‐pyrrolidinemethanol afforded a maximum ee of 80%. Interestingly, the methodology is applicable to the epoxidation of more challenging aliphatic or enolizable enones with good control of the asymmetric induction (up to 87% ee).     

Asymmetric Synthesis of 3,4‐Dihydrocoumarins Bearing an α,α‐Disubstituted Amino Acid Moiety

An organocatalytic approach for the stereoselective synthesis of 3,4‐dihydrocoumarins with an α,α‐disubstituted amino acid moiety incorporated is presented. The developed methodology is based on the cascade reaction between α‐substituted azlactones and 2‐hydroxychalcones. It is initiated by a chiral Brønsted base‐catalyzed enantio‐ and diastereoselective Michael reaction followed by the azlactone ring opening to construct a 3,4‐dihydrocoumarin framework. Products bearing two adjacent stereogenic centers, one being quaternary, were formed with high enantioselectivities and excellent diastereoselectivities. Furthermore, the complete regioselectivity of the new cascade reactivity is worthy of notice.

     

Organocatalytic Enantioselective Aziridination of α‐Substituted α,β‐Unsaturated Aldehydes: Asymmetric Synthesis of Terminal Aziridines

The first example of a highly enantioselective organocatalytic aziridination of α‐substituted α,β‐unsaturated aldehydes is presented. The reaction is catalyzed by simple chiral amines and gives access to highly functional terminal azirdines containing an α‐tertiary amine stereocenter in high yields and enantiomeric ratios (95.5:4.5–98:2).     

Multi‐Enzymatic Synthesis of Optically Pure β‐Hydroxy α‐Amino Acids

A novel enzymatic production system of optically pure β‐hydroxy α‐amino acids was developed. Two enzymes were used for the system: an N‐succinyl L ‐amino acid β‐hydroxylase (SadA) belonging to the iron(II)/α‐ketoglutarate‐dependent dioxygenase superfamily and an N‐succinyl L ‐amino acid desuccinylase (LasA). The genes encoding the two enzymes are part of a gene set responsible for the biosynthesis of peptidyl compounds found in the Burkholderia ambifaria AMMD genome. SadA stereoselectively hydroxylated several N‐succinyl aliphatic L ‐amino acids and produced N‐succinyl β‐hydroxy L ‐amino acids, such as N‐succinyl‐L ‐β‐hydroxyvaline, N‐succinyl‐L ‐threonine, (2S,3R)‐N‐succinyl‐L ‐β‐hydroxyisoleucine, and N‐succinyl‐L ‐threo‐β‐hydroxyleucine. LasA catalyzed the desuccinylation of various N‐succinyl‐L ‐amino acids. Surprisingly, LasA is the first amide bond‐forming enzyme belonging to the amidohydrolase superfamily, and has succinylation activity towards the amino group of L ‐leucine. By combining SadA and LasA in a preparative scale production using N‐succinyl‐L ‐leucine as substrate, 2.3 mmol of L ‐threo‐β‐hydroxyleucine were successfully produced with 93% conversion and over 99% of diastereomeric excess. Consequently, the new production system described in this study has advantages in optical purity and reaction efficiency for application in the mass production of several β‐hydroxy α‐amino acids.

     

Efficient Tandem Biocatalytic Process for the Kinetic Resolution of Aromatic β‐Amino Acids

We describe a simple and efficient enzymatic tandem reaction for the preparation of enantiomerically pure β‐phenylalanine and its analogues from the corresponding racemates. In this process, phenylalanine aminomutase (PAM) catalyzes the stereoselective isomerization of (R)‐β‐phenylalanines to (S)‐α‐phenylalanines, which are in situ transformed to cinnamic acids by phenylalanine ammonia lyase (PAL). Preparative scale conversions are done with a mutated PAM with enhanced catalytic activity.     

Chemoenzymatic Preparation of Enantiopure Homoadamantyl β‐Amino Acid and β‐Lactam Derivatives

Racemic cis‐10‐azatetracyclo[7.2.0.1^2,6.1^4,8]tridecan‐11‐one was prepared from homoadamant‐4‐ene by chlorosulfonyl isocyanate addition. The transformation of the β‐lactam to the corresponding β‐amino ester followed by Candida antarctica lipase A‐catalyzed enantioselective (E>>200) N‐acylation with 2,2,2‐trifluoroethyl butanoate afforded methyl (1R,4R,5S,8S)‐5‐aminotricyclo[4.3.1.1^3,8]undecane‐4‐carboxylate and the (1S,4S,5R,8R)‐butanamide with>99% ee at 50% conversion. Alternatively, transformation of the β‐lactam to the corresponding N‐hydroxymethyl‐β‐lactam and the following Pseudomonas cepacia (currently Burkholderia cepacia) lipase‐catalyzed enantioseletive O‐acylation provided the (1S,4S,6R,9R)‐alcohol (ee=87%) and the corresponding (1R,4R,6S,9S)‐butanoate (ee>99%). In the latter method, competition for the enzyme between the (1R,4R,6S,9S)‐butanoate, 2,2,2‐trifluoroethyl butanoate and the hydrolysis product, butanoic acid, tended to stop the reaction at about 45% conversion and finally gave racemization in the (1S,4S,6R,9R)‐alcohol with time.     

Chiral Amino Diol Derivatives as New Modular Organocatalysts for the Enantioselective α‐Chlorination of Cyclic β‐Keto Esters

Highly modular chiral amino diol derivatives have been used as organocatalysts in the enantioselective α‐chlorination of cyclic β‐keto esters. Optimization of the catalyst structure and the reaction conditions has allowed the synthesis of optically active α‐chlorinated products with high enantioselectivities (up to 96% ee) using inexpensive commercially available N‐chlorosuccinimide (NCS) as the chlorine source under mild conditions.     

A Triazole Organocatalyst with Spiropyrrolidine Framework and its Application to the Catalytic Asymmetric Addition of Nitromethane to α,β‐Unsaturated Aldehydes

A series of new water‐compatible “spiropyrrolidine triazole” catalysts was designed and synthesized. The asymmetric Michael addition of nitromethane and α,β‐unsaturated aldehydes in an aqueous system was investigated to evaluate these new catalysts, and the resulting adducts were obtained with excellent enantioselectivity (up to 95.5% ee) and moderate to good yield (63–88%).

     

Asymmetric Aza‐Morita–Baylis–Hillman‐Type Reactions: The Highly Enantioselective Reaction between Unmodified α,β‐ Unsaturated Aldehydes and N‐Acylimines by Organo‐co‐catalysis

The highly enantioselective organo‐co‐catalytic aza‐Morita–Baylis–Hillman (MBH)‐type reaction between N‐carbamate‐protected imines and α,β‐unsaturated aldehydes has been developed. The organic co‐catalytic system of proline and 1,4‐diazabicyclo[2.2.2]octane (DABCO) enables the asymmetric synthesis of the corresponding N‐Boc‐ and N‐Cbz‐protected β‐amino‐α‐alkylidene‐aldehydes in good to high yields and up to 99% ee. In the case of aza‐MBH‐type addition of enals to phenylprop‐2‐ene‐1‐imines, the co‐catalytic reaction exhibits excellent 1,2‐selectivity. The organo‐co‐catalytic aza‐MBH‐type reaction can also be performed by the direct highly enantioselective addition of α,β‐unsaturated aldehydes to bench‐stable N‐carbamate‐protected α‐amidosulfones to give the corresponding β‐amino‐α‐alkylidene‐aldehydes with up to 99% ee. The organo‐co‐catalytic aza‐MBH‐type reaction is also an expeditious entry to nearly enantiomerically pure β‐amino‐α‐alkylidene‐amino acids and β‐amino‐α‐alkylidene‐lactams (99% ee). The mechanism and stereochemistry of the chiral amine and DABCO co‐catalyzed aza‐MBH‐type reaction are also discussed.     

Iridium‐Catalyzed Enantioselective Hydrogenation of β,β‐Disubstituted Nitroalkenes

A highly efficient, iridium‐catalyzed, enantioselective hydrogenation of β,β‐disubstituted nitroalkenes has been developed. Using a complex consisting of iridium and (S,S)‐f‐spiroPhos as the catalyst, a variety of β,β‐disubstituted nitroalkenes were successfully hydrogenated to the corresponding chiral nitroalkanes with excellent enantioselectivities (up to 98% ee) and high turnover numbers (TON=1000).

     

Optically Pure 1,2‐Bis[(o‐alkylphenyl)phenylphosphino]ethanes and Their Use in Rhodium‐Catalyzed Asymmetric Hydrogenations of α‐(Acylamino)acrylic Derivatives

Optically pure (S,S)‐1,2‐bis[(o‐alkylphenyl)phenylphosphino]ethanes 1a–d were prepared in four steps from phenyldichlorophosphine via phosphine‐boranes as the intermediates. The rhodium complexes 5a–d of these diphosphines were used for the asymmetric hydrogenations of α‐(acylamino)acrylic derivatives including β‐disubstituted derivatives. Markedly high enantioselectivity (78–>99%) was observed for the reduction of β‐monosubstituted derivatives. β‐Disubstituted derivatives were also reduced in considerably high enantioselectivity (up to 90%). The single crystal X‐ray analysis of the rhodium complex 5c of (S,S)‐1,2‐bis[phenyl(5′,6′,7′,8′‐tetrahydronaphthyl)phosphino]ethane ( 1c) revealed its δ‐type structure with face orientation of the two tetrahydronaphthyl groups and edge orientation of the two phenyl groups. This conformation corresponds to that of the rhodium complex of 1,2‐bis[(o‐methoxyphenyl)phenylphosphino]ethane (DIPAMP); the rhodium complex of (R,R)‐DIPAMP, whose chirality at phosphorus is opposite that of 5c , exhibits a λ‐type structure with the face orientation of the two o‐methoxyphenyl groups and the edge orientation of the two phenyl groups. The conformational similarity of these rhodium complexes as well as the stereochemical outcome in the asymmetric hydrogenations means that the coordinative interaction of the methoxy group of DIPAMP with rhodium metal is not the main factor that affects asymmetric induction.     

A Simple Organocatalytic Enantioselective Cyclopropanation of α,β‐Unsaturated Aldehydes

A highly chemo‐ and enantioselective organocatalytic cyclopropanation of α,β‐unsaturated aldehydes with bromomalonate and 2‐bromoacetoacetate esters is presented. The reaction is catalyzed by chiral amines and gives access to 2‐formylcyclopropanes in high yields and up to 99 % ee.     

Organocatalytic Enantioselective Michael Reaction of Malononitrile with β,β‐Disubstituted Nitroalkenes

We have developed and optimized an enantioselective Michael reaction of malononitrile with β,β‐disubstituted nitroalkenes. This reaction was catalyzed by a cinchona alkaloid derived thiourea catalyst, producing products of high yields (up to 98 %) and stereoselectivities (up to 93 % ee). One of the adducts was used as an intermediate for the synthesis of dihydropyrrole derivative bearing a synthetically valuable quaternary chiral center.

     

Copper‐Catalyzed Addition of Alkylboranes to Iminoacetates: Access to α‐Alkyl Branched α‐Amino Acids

A copper(I)‐catalyzed addition of alkylborane reagents to α‐iminoacetates has been developed to assemble both acyclic and cyclic α‐branched α‐amino carboxylic acid derivatives in good yields. A wide variety of unactivated alkenes are well tolerated in this transformation.