Nonenzymatic acylative kinetic resolution of Baylis-Hillman adducts

The first efficient nonenzymatic acylative kinetic resolution of Baylis-Hillman adducts is reported. Chiral pyridine catalyst 1a and an optimized analogue 1e are capable of promoting the synthetically useful enantioselective acylation (the efficiency of which is outstanding for sp(2)-sp(2) carbinol substrates, s = 3.5-13.1, ee up to 97%) of Baylis-Hillman adducts derived from recalcitrant precursors which are currently difficult to synthesize utilizing benchmark asymmetric Baylis-Hillman reaction catalyst technology. A novel one-pot synthesis-kinetic resolution process involving a DBU-catalyzed Baylis-Hillman reaction and subsequent 1e/DBU-mediated enantioselective acylation has also been developed.     

Dynamic kinetic resolution of atropisomeric amides

[reaction: see text] Using L-proline as catalyst in the asymmetric aldol reaction and a series of benzamides and naphthamides, we have accomplished a dynamic kinetic resolution that simultaneously establishes the stereochemistry of the atropisomeric amide's chiral axis and a stereogenic center. The enantioselectivities ranged from 82% to 95% and the diastereoselectivities from 2.1:1 to 7.0:1.     

Enzymatic kinetic resolution of sec-alcohols using an ionic liquid anhydride as acylating agent

A task-specific ionic liquid bearing an anhydride moiety was synthesized for the first time in good yield (83%) through a carbodiimide-mediated coupling reaction. The enantiomeric separation of a series of sec-alcohols was performed via enzymatic kinetic resolution, employing an ionic anhydride as acylating agent and Candida antarctica Lipase B as a biocatalyst. A fast and efficient recovery of both enantiomers was achieved separately due to the ionic nature of the acyl donor, combined with the possibility of carrying out the enzymatic step in an organic solvent.     

The preparation and resolution of 2-phenyl-Quinazolinap,a new atropisomeric phosphinamine ligand for asymmetric catalysis

The preparation and resolution of an axially chiral quinazoline-containing phosphinamine ligand is described. The biaryl linkage was formed in a Pd-catalysed coupling of 4-chloro-2-phenylquinazoline 10 with 2-methoxy-1-naphthylboronic acid 11. Demethylation of the product ether 12 afforded alcohol 13 which was converted into the corresponding triflate 14 by treatment with trifluoromethanesulphonic anhydride. An Ni-catalysed phosphinylation gave the required phosphinamine ligand 9 as a racemate. Diastereomeric palladacycles 16, formed from 9 and (+)-di-μ-chlorobis[(R)-dimethyl(1-(1-naphthyl)ethyl)aminato-C₂,N]dipalladium(II) 15 were separated to give diastereomerically pure materials. An X-ray crystal structure of the (R,R)-16 palladacycle was determined and is discussed. Displacement of the resolving agent by reaction with 1,2-bis(diphenylphosphino)ethane gave enantiopure 2-phenyl-Quinazolinap 9, a new atropisomeric phosphinamine ligand for asymmetric catalysis.     

Enantiomerically enriched atropisomeric N,N′-diaryl ureas by oxidative kinetic resolution of their 2-sulfanyl derivatives

Atropisomeric N-methyl-N,N′-diaryl ureas may be obtained in enantiomerically enriched form by oxidative kinetic resolution of their sulfide derivatives. The atropisomeric sulfides may be obtained in up to 97:3 er and display high stability to racemisation (half-lives at 25 °C of up to 500 years). Unlike related fully alkylated ureas, the product sulfoxides exhibit relatively weak thermodynamic conformational selectivity.     

Dynamic kinetic resolution of benzoins by lipase-metal combo catalysis

The synthesis of some noncommercial racemic 1,2-diaryl-2-hydroxyethanones (benzoins) is described, optimizing the previously reported methodologies. In a further step, the kinetic resolution of these substrates is reported, obtaining conversions of around 50% and ee(p) higher than 99% in very short reaction times. As enzymatic catalyst, after screening of several enzymes, the lipase TL (from Pseudomonas stutzeri) was the most efficient, working in an organic solvent with a very low log P value, such as THF. Finally, the dynamic-kinetic resolution of different benzoins using a lipase-ruthenium-catalyzed transesterification in organic solvents is described for the first time, obtaining conversions up to 90% maintaining the excellent enantioselectivity in all cases.     

Enantiomers of all-cis-5-(4-bromophenyl)-4-tert-butoxycarbonyl-2-methoxycarbonylpyrrolidine: preparative HPLC separation and acylative kinetic resolution of the racemate

The fundamental possibility of acylative kinetic resolution of racemic heterocyclic amines was demonstrated by the example of all-cis-5-(4-bromophenyl)-4-tert-butoxycarbonyl-2-methoxycarbonylpyrrolidine. Individual enantiomers (ee >99%) were obtained in high yields via preparative chiral HPLC.     

Dynamic resolution of atropisomeric amides using proline-derived imidazolines and ephedrine-derived oxazolidines

Condensation of atropisomeric tertiary 2-formyl naphthamides or 2-formyl benzamides with some chiral diamines and amino alcohols leads, via a dynamic resolution process, to single atropisomers of tertiary amides bearing chiral imidazolidines or oxazolidines. Hydrolysis of the new heterocycle competes a dynamic thermodynamic resolution of the starting aldehyde, and rapid reduction allows the isolation of atropisomeric amides bearing 2-hydroxymethyl substituents in enantiomerically enriched form. Evidence that the reactions are under thermodynamic control is presented.     

Development of a rapid,room-temperature dynamic kinetic resolution for efficient asymmetric synthesis of alpha-aryl amino acids

[reaction: see text] A rapid, highly efficient and general dynamic kinetic resolution (DKR) of racemic alpha-aryl UNCAs with the dual-function catalysis of modified cinchona alkaloid was accomplished at room temperature. This DKR led to the development of a highly enantioselective catalytic method for the practical synthesis of a wide range of alpha-aryl and alpha-heteroaryl amino acids in 89-92% ee and 86-95% yield from racemic UNCAs.     

Development of porous materials for heterogeneous catalysis: kinetic resolution of epoxides

Template copolymerization methods have been utilized to prepare porous materials with immobilized cobalt complexes that catalyze the hydrolytic kinetic resolution of epoxides.     

Kinetic resolution of sec-alcohols using a new class of readily assembled (S)-proline-derived 4-(pyrrolidino)-pyridine analogues

We report the development of a new class of readily prepared chiral 4-(pyrrolidino)-pyridine catalysts capable of exploiting both van der Waals (pi) and H-bonding interactions, thus allowing remote chiral information to stereochemically control the kinetic resolution of sec-alcohols.     

Efficient,scalable kinetic resolution of cis-4-benzyloxy-2,3-epoxybutanol

A new enzyme catalysed kinetic resolution of cis-4-benzyloxy-2,3-epoxybutanol has been reported. Efficient, scalable separation of the optically active alcohol from its ester derivative has been solved with liquid–liquid and solid–liquid extraction methods using commercial organic solvents and supercritical carbon dioxide. cis-4-Benzyloxy-2,3-epoxy-1-butanol enantiomers were applied for the enantioselective synthesis of (2S,3S,1′S)- and (2R,3R,1′R)-3-[2′-(dibenzylamino)-1′-hydroxyethyl]-2-phenyloxetane.     

Determination of absolute configuration using kinetic resolution catalysts

A new method was developed to assign the absolute configuration of molecules using kinetic resolution catalysts. Secondary alcohols were acylated in the presence of Birman's S-HBTM and R-HBTM catalysts, and the fast-reacting catalyst was identified by NMR analysis of the reaction mixture. A mnemonic was developed to assign configuration based on the identity of the fast-reacting catalyst. The method uses only 1-3 mg of alcohol, and it is more convenient than the Mosher method. The kinetic resolution strategy may be extended to other classes of molecules.     

Enzymatic kinetic resolution of racemic 4-tetrahydropyranols by Candida rugosa lipase

Enzymatic kinetic resolution of (±)-hydroxytetrahydropyrans has been achieved for the first time by means of lipase-mediated transesterification to afford optically active (2S,4R)-tetrahydropyranyl acetates and (2R,4S)-tetrahydropyranols in excellent yields with high enantioselectivity. Absolute configurations of the tetrahydropyranyl acetates were assigned as (S) by chemical correlation.     

Resonantly enhanced two photon ionization and zero kinetic energy spectroscopy of jet-cooled 4-aminopyridine

We report studies of supersonically cooled 4-aminopyridine (4-AP) using two-color resonantly enhanced multiphoton ionization (REMPI) and two-color zero kinetic energy (ZEKE) photoelectron spectroscopy. With the aid of ab initio and density functional calculations, vibrational modes of the first electronically excited state (S1) of the neutral species and those of the cation have been assigned, and the adiabatic ionization potential has been determined to be 62291+/-6 cm(-1). The REMPI spectrum of the S1 state is dominated by ring deformation modes and the inversion mode of the amino group, while the ZEKE spectra demonstrate a strong propensity of Deltav=0, where v is the vibrational quantum number of the intermediate vibronic state from S1. In addition, the ZEKE spectra obtained via different vibrational levels of the S1 state contain four common features, corresponding to the activation of four different vibrational modes of the cation. These observations are explained in terms of the structural changes from the ground state to S1 and further to the cation. The vibrational mode distributions in both the REMPI and the ZEKE spectra, the excitation energy of the S1 state, and the ionization potential of 4-AP, are remarkably similar to those of aniline, suggesting that the electronic activity is centered on the ring.     

Enzyme-catalyzed kinetic resolution of N-Boc-trans-3-hydroxy-4-phenylpyrrolidine

The first enzyme-catalyzed kinetic resolution of tert-butyl-3-hydroxy-4-phenylpyrrolidine-1-carboxylate is presented. Enzyme, solvent and temperature optimization resulted in a new resolution method with E = 40 enantioselectivity. The acetate derivative of the (+)-(3S,4R) enantiomer formed while the (?)-(3R,4S) isomer remained intact. Very good enantioselectivities (E > 200) were achieved in the enzyme-catalyzed alcoholysis of the racemic acetate in i-propanol and t-butanol where the (+)-(3S,4R) enantiomer was prepared in pure form (ee > 99.7%). Absolute configuration of the (?)-(3R,4S)-enantiomer was determined by single crystal X-ray diffraction method.      

Manifestation of felkin-anh control in enantioselective acyl transfer catalysis: kinetic resolution of carboxylic acids

Under control: The classical polar Felkin-Anh model has been applied for the first time to the analysis of diastereoselectivity in acylation reactions. Computational studies demonstrate that stereoelectronic effects control the enantioselectivity in asymmetric catalytic alcoholysis of acyclic anhydrides.     

Rapid, highly diastereoselective addition of dialkylzinc reagents to atropisomeric 2-formyl arylamides

We have observed that dialkylzinc reagents add to atropisomeric 2-formyl arylamides many times faster than they react with other substituted benzaldehyde derivatives. Additionally, with diethylzinc the products were formed with very high diastereoselectivity, affording the syn product (d.r. greater than 95:5), except in one case where epimerization of the product is rapid. In contrast, Grignard and trialkylaluminum reagents afforded the anti diastereomers, with diminished stereoselectivity and formation of reduction products.