Andreas Steinreiber

Regio- and stereoselective monoamination of diketones without protecting groups.

) out of six showed perfect regioselectivity forthe differentiation between the two keto groups. Hence, theamination occurred exclusively at the sterically less demand-ing w-1 ketone moiety, leading to the amino ketone 2a, whilethe w-3 position remained untouched. The intermediateamino ketone 2aspontaneously cyclized, finally giving D1-piperideine 4a. Only the w-TA from Vibrio fluvialis

High-speed microwave-promoted Mitsunobu inversions. Application toward the deracemization of sulcatol

An enantioconvergent synthesis of the aggregation pheromones (R)- and (S)-sulcatol (6-methyl-5-hepten-2-ol) is described. Key steps in the deracemization strategy are sequential combinations of enzymatic resolutions and Mitsunobu inversions. Racemization-free Mitsunobu transformations have been carried out within 5 min by microwave irradiation, providing the desired sulcatyl acetates with clean inversion of chirality.

Bacterial epoxide hydrolase-catalyzed resolution of a 2,2-disubstituted oxirane: optimization and upscaling

The epoxide hydrolase-catalyzed resolution of (±)-2-methylglycidyl benzyl ether, a versatile chiral building block for the asymmetric synthesis of bioactive compounds, mediated by whole cells of Rhodococcus ruber SM 1789 was accomplished. Among various parameters (such as temperature, buffer type, pH and catalyst/substrate-ratio) an elevated substrate-concentration proved to be particularly sensitive with respect to a significant enhancement of the enantioselectivity.

Biocatalytic asymmetric and enantioconvergent hydrolysis of trisubstituted oxiranes

Abstract Asymmetric biohydrolysis of trialkyl oxiranes (±)- 1a – 3a using the epoxide hydrolase activity of whole bacterial cells proceeded in an enantioconvergent fashion and thus led to the corresponding ( R )-configurated vicinal diols 1b – 3b in up to 97% enantiomeric excess (e.e.) as the sole product. The mechanism of this enantioconvergence was investigated by 18 O-labelling experiments and it was found that both enantiomers were hydrolysed with opposite regioselectivity.

Quantitative structure-activity relationships for the enantioselectivity of oxirane ring-opening catalyzed by epoxide hydrolases.

The enantioselective ring-opening catalyzed by epoxide hydrolases originating from seven different sources of a series of 2,2-disubstituted oxiranes containing alkyl chains of different lengths, unsaturated (alkenyl, alkinyl) and aromatic groups as well as electronegative heteroatoms at various positions within the side chain was analyzed by quantitative structure-activity relationships. Models for the enantioselectivity were derived with the aid of multiple linear regression analysis (MLR) using several steric and electronic (quantum chemical) descriptors. On the basis of the models derived by MLR nonlinear modeling with artificial neural networks (ANN) was also done. Good predictive performance was observed for both modeling approaches. The models also indicate that different steric and/or electronic features account for the enantioselectivities observed for the individual epoxide hydrolases.

Enantioselective Hydrolysis of Functionalized 2,2-Disubstituted Oxiranes with Bacterial Epoxide Hydrolases

The biohydrolysis of 2,2-disubstituted oxiranes bearing various oxygen functional groups was investigated using the epoxide hydrolase activity of 11 bacterial strains. The results show that the activity and the selectivity strongly depend on the substrate structure and the biocatalyst. Whereas substrates possessing free hydroxyl groups were not transformed, their analogs, protected as ethers, were well accepted. This allowed the convenient modulation of the enantioselectivity by proper choice of the ether group according to size and polarity. It was found that the distance of the ether-oxygen to the stereogenic quaternary carbon center of the oxirane ring had a profound influence on the enantioselectivity, and several oxiranes were resolved with good to excellent selectivities. The enantiomerically enriched epoxides and vicinal diols thus obtained contain a useful “synthetic handle” in their side chain, which allows their use as building blocks in asymmetric synthesis.

Enantio- and diastereo-convergent synthesis of (2R,5R)- and (2R,5S)-Pityol through enzyme-triggered ring closure

Abstract A short chemoenzymatic synthesis of the (2 R ,5 S )- and (2 R ,5 R )-stereoisomer of the bark beetle pheromone Pityol 1 was achieved from (±)-Sulcatol 2 in an enantio- and diastereo-convergent fashion without the formation of any ‘unwanted’ stereoisomer. The key steps include: (i) lipase-catalyzed deracemization of (±)- 2 using kinetic resolution coupled to an in-situ inversion or, alternatively, dynamic resolution using combined lipase- and Ru-catalysis; and (ii) creation of the second stereogenic center by an epoxide hydrolase-catalyzed diastereo-convergent hydrolysis of a haloalkyl oxirane, followed by spontaneous ring closure to form 1 in a stereoselective fashion.

Chemo-enzymatic enantio-convergent asymmetric total synthesis of (S)-(+)-dictyoprolene using a kinetic resolution-stereoinversion protocol

Abstract A single enantiomer of a (stereo)chemically labile allylic-homoallylic alcohol was obtained in 91% e.e. and 96% yield from the racemate by employing a lipase-catalysed kinetic resolution coupled to in situ inversion under carefully controlled (Mitsunobu) conditions in order to suppress side reactions, such as elimination and racemisation. This technique was successfully applied to an enantio-convergent asymmetric total synthesis of the algal fragrance component ( S )-dictyoprolene.

Enzyme-Triggered Enantioconvergent Transformation of Haloalkyl Epoxides

Biocatalytic hydrolysis of 2,3-disubstituted rac-cis- and rac-trans-haloalkyl epoxides 1a−8a using the epoxide hydrolase activity of whole bacterial cells furnished the corresponding vicinal diols 1b−8b as intermediates; these (spontaneously) underwent ring closure to yield cyclic products 1c−6c through an enzyme-triggered cascade reaction. In particular, cis-configured substrates (1a, 3a, 5a, 7a) were transformed in an enantioconvergent fashion, which resulted in the formation of single stereoisomeric products in 100% des and up to 92% ees from the racemates.

An enzyme-triggered enantio-convergent cascade-reaction

Abstract The biocatalytic hydrolysis of the (±)-2,3-disubstituted cis -chloroalkyl epoxides 1a and 2a using resting cells of Rhodococcus sp. did not give the corresponding chloroalkyl vic -diols 1b , and 2b , respectively, but furnished the rearranged products (2 R ,3 R )- 1c and (2 R ,3 R )- 2c in high e.e. as the sole products via an enzyme-triggered enantio-convergent cascade-reaction.