Recent Developments in Asymmetric Aziridination

This review updates the recent developments in asymmetric aziridination using chiral substrates as well as chiral catalysts, covering the literature since the beginning of 2010. It clearly demonstrates that this reaction constitutes an important tool in organic synthesis, still attracting considerable interest due to the potential use of enantiopure aziridines as useful intermediates in the synthesis of complex important molecules, and to the intriguing biological activities of numerous aziridine‐containing compounds including natural products. Abbreviations: Ar: aryl; BINOL: 1,1′‐bi‐2‐naphthol; Bn: benzyl; Boc: tert‐butoxycarbonyl; BUDAM: tetra‐tert‐butyldianisylmethyl; Bz: benzoyl; Cbz: benzyloxycarbonyl; Cy: cyclohexyl; DAM: dianisylmethyl; DBN: 3,5‐dinitrobenzoyl; DCE: 1,2‐dichloroethane; de: diastereomeric excess; DEAD: diethyl azodicarboxylate; DIAD: diisopropyl azodicarboxylate; DMAP: 4‐dimethylaminopyridine; DMF: N,N‐dimethylformamide; DMSO: dimethyl sulfoxide; dr: diastereomeric ratio; ee: enantiomeric excess; esp: α,α,α′,α′‐tetramethyl‐1,3‐benzenedipropionate; FG: functional group; Hex: hexyl; HMDS: hexamethyldisilazide; LDA: lithium diisopropylamide; M: metal; MEDAM: tetramethyldianisylmethyl; MEDPM: tetramethyldiphenylmethyl; Mes: mesyl; MS: molecular sieves; Naph: naphthyl; NCS: N‐chlorosuccinimide; Ns: nosyl; PG: protecting group; Phth: phthalimido; Piv: pivalate; PMB: para‐methoxybenzoyl; PMP: para‐methoxyphenyl; PNNP: N,N′‐bis[ortho‐(diphenylphosphino)benzylidene]cyclohexane‐1,2‐diamine; r.t.: room temperature; SES: trimethylsilylethanesulfonyl; TBS: tert‐butyldimethylsilyl; TEA: triethylamine; Tf: trifluoromethanesulfonyl; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TMG: 1,1,3,3‐tetramethylguanidine; TMS: trimethylsilyl; Tol: tolyl; TPS: triphenylsilyl; Troc: 2,2,2‐trichloroethoxycarbonyl; Ts: 4‐toluenesulfonyl (tosyl).

     

Molecular Basis for the Enantio‐ and Diastereoselectivity of Burkholderia cepacia Lipase toward γ‐Butyrolactone Primary Alcohols

Burkholderia cepacia lipase (BCL) shows high enantioselectivity toward chiral primary alcohols, but this enantioselectivity is often unpredictable, especially for substrates that contain an oxygen at the stereocenter. For example, BCL resolves β‐substituted‐γ‐acetyloxymethyl‐γ‐butyrolactones (acetates of a chiral primary alcohol) by hydrolysis of the acetate, but the enantioselectivity varies with the nature and orientation of the β‐alkyl substituent. BCL favors the (R)‐primary alcohol when the β‐alkyl substituent is hydrogen (E=30) or trans methyl (E=38), but the (S)‐primary alcohol when it is cis methyl (E=145). To rationalize this unusual selectivity, we used a combination of experiments to show the importance of polar interactions and modeling to reveal differences in orientations of the enantiomers. Removal of either the lactone carbonyl in the substrate or the polar side chains in the enzyme by using a related enzyme without these side chains decreased the enantioselectivity at least four‐fold. Modeling revealed that the slow enantiomers do not bind by exchanging the location of two substituents relative to the fast enantiomer. Instead, three substituents remain in the same region, but the fourth substituent, hydrogen, inverts to a new location, like an umbrella in a strong wind. In this orientation the favored stereoisomers have similar shapes, thus accounting for the unusual stereoselectivity. The ratio of catalytically productive orientations for the fast vs. slow enantiomers in a molecular dynamic simulation correlated (R²=0.82) with the degree of enantioselectivity including the case where the enantioselectivity reversed. Weighting this ratio by the ratio of H‐bonds in the polar interaction to account for different binding strengths improved the correlation with the measured enantioselectivity to R²=0.97. The modeling identifies key interactions responsible for high enantioselectivity in this class of substrates.

     

Enantioselective Construction of the Biologically Significant Dibenzo[1,4]diazepine Scaffold via Organocatalytic Asymmetric Three‐Component Reactions

The first catalytic asymmetric construction of the biologically important dibenzo[1,4]diazepine scaffold has been established via SPINOL‐derived chiral phosphoric acid‐catalyzed three‐component reactions of aldehydes, 1,2‐phenylenediamines and cyclohexane‐1,3‐diones, which afforded structurally complex and diverse dibenzo[1,4]diazepines in high yields and good enantioselectivities (up to 98% yield, 92:8 er). This transformation also represents the first catalytic asymmetric version of this three‐component reaction and provides an easy access to structurally rigid seven‐membered chiral heterocycles.

     

Simultaneous Use of in Silico Design and a Correlated Mutation Network as a Tool To Efficiently Guide Enzyme Engineering

In order to improve the efficiency of directed evolution experiments, in silico multiple‐substrate clustering was combined with an analysis of the variability of natural enzymes within a protein superfamily. This was applied to a Pseudomonas fluorescens esterase (PFE I) targeting the enantioselective hydrolysis of 3‐phenylbutyric acid esters. Data reported in the literature for nine substrates were used for the clustering meta‐analysis of the docking conformations in wild‐type PFE I, and this highlighted a tryptophan residue (W28) as an interesting target. Exploration of the most frequently, naturally occurring amino acids at this position suggested that the reduced flexibility observed in the case of the W28F variant leads to enhancement of the enantioselectivity. This mutant was subsequently combined with mutations identified in a library based on analysis of a correlated mutation network. By interrogation of <80 variants a mutant with 15‐fold improved enantioselectivity was found.     

Enantioselective hydrogenation of (E)-α-phenylcinnamic acid with cinchonidine-modified Pd/TiO2: influence of solvents and additives

Both the enantioselectivity and activity of the hydrogenation of (E)-α-phenylcinnamic acid with cinchonidine-modified Pd catalysts are strongly solvent dependent; polar solvents with higher solubility for the substrate are preferable. The simultaneous increases in the enantioselectivity and activity, also induced by the addition of either a small amount of water to aprotic solvents or an amine such as benzylamine, indicate that preferential acceleration of the selective reaction has occurred, thus strongly suggesting the importance of the product desorption step on the modified sites. This revised version was published online in June 2006 with corrections to the Cover Date.     

Selectivity from a kinetic point of view: nonlinear behavior of logarithmic product ratios as a function of the reciprocal temperature

The influence of the temperature on selectivity is described under special consideration of nonlinearities in the corresponding modified Eyring plots. Reasons for the experimentally well-known behavior are discussed. Furthermore, the conditions for nonlinear temperature behavior are quantified and a concept is described which allows the determination of the temperature dependence of a single reaction pathway in a selection process. This revised version was published online in June 2006 with corrections to the Cover Date.     

Clean-up to Chirality—Liquid Membranes as a Facilitating Technology?

Liquid membranes have been suggested as a clean technology due to characteristics such as high specificity, intensity and productivity as well as low emissions and energy utilisation. However when applying liquid membrane systems to real problems, in this paper chiral extraction of phenylalanine and lactic acid extraction from an industrial effluent, problems have been encountered with the specificity of the liquid membrane system used. Relatively low enantioselectivities (maximum 2·4) were observed with the chiral emulsion liquid membrane system investigated (maximum 1·6), although this was in excess of an analogous solvent extraction system studied. In lactic acid extraction, although batch extraction from model solutions was in excess of 75% in 2 min, when a real lactic acid containing industrial effluent was used the extent of extraction was reduced to around 20%. This effect was found to result from the co-extraction of other anions present in the effluent. In the case of chloride ions, a co-transport mechanism was noted. Thermal and photometric back-extraction strategies have been suggested as a means of enhancing overall liquid membrane extraction selectivities. © 1997 SCI.     

Molecular Basis for the Enantioselective Ring Opening of β‐Lactams Catalyzed by Candida antarctica Lipase B

Lipase B from Candida antarctica (CAL‐B) catalyzes the slow, but highly enantioselective (E>200), ring‐opening alcoholysis of two bicyclic and two 4‐aryl‐substituted β‐lactams. Surprisingly, the rate of the reaction varies with the nature of the alcohols and was fastest with either enantiomer of 2‐octanol. A 0.5‐g scale reaction with 2‐octanol as the nucleophile in diisopropyl ether at 60 °C yielded the unreacted β‐lactam in 39–46% yield (maximum yield is 50%) with ≥96% ee. The product β‐amino acid esters reacted further by polymerization (not isolated or characterized) or by hydrolysis due to small amounts of water in the reaction mixture yielding β‐amino acids (7–11% yield, ≥96% ee). The favored enantiomer of all four β‐lactams had similar 3‐D orientation of substituents, as did most previously reported β‐lactams and β‐lactones in similar ring‐opening reactions. Computer modeling of the ring opening of 4‐phenylazetidin‐2‐one suggests that the reaction proceeds via an unusual substrate‐assisted transition state, where the substrate alcohol bridges between the catalytic histidine and the nitrogen of the β‐lactam. Computer modeling also suggested that the molecular basis for the high enantioselectivity is a severe steric clash between Ile189 in CAL‐B and the phenyl substituent on the slow‐reacting enantiomer of the β‐lactam.     

Enzymes in Organic Chemistry, 11:[1] Hydrolase‐Catalyzed Resolution of α‐ and β‐Hydroxyphosphonates and Synthesis of Chiral,Non‐Racemic β‐Aminophosphonic Acids

The enantioselective acylation of racemic diisopropyl α‐ and β‐hydroxyphosphonates by hydrolases in t‐butyl methyl ether with isopropenyl acetate as acyl donor is limited by the narrow substrate specificity of the enzymes. High enantiomeric excesses (up to 99%) were obtained for the acetates of (S)‐diisopropyl 1‐hydroxy‐(2‐thienyl)methyl‐, 1‐hydroxyethyl‐ and 1‐hydroxyhexylphosphonate and (R)‐diisopropyl 2‐hydroxypropylphosphonate. The hydrolysis of a variety of β‐chloroacetoxyphosphonates by the lipase from Candida cylindracea and protease subtilisin in a biphasic system gives (S)‐β‐hydroxyphosphonates (ee 51–92%) enantioselectively. (S)‐2‐Phenyl‐2‐hydroxyethyl‐ and (S)‐3‐methyl‐2‐hydroxybutylphosphonates (ee 96% and 99%, respectively) were transformed into (R)‐2‐aminophosphonic acids of the same ee.