Some Examples of Non-catalytic, Catalytic and Biocatalytic Preparations of Chiral Molecules

Practical solutions for the preparation of enantiomerically pure compounds (EPC) by enantioselective synthesis have now been found for most important organic reactions, and for a number of economically important classes of organic compounds. This author-review, therefore, covers only representative examples of those methods to which the author\u27s group made some contribution. Non-catalytic preparation of chiral molecules can be achieved either by separation of racemic mixtures, or by enantioselective synthesis using stoichiometric quantities of a chiral auxiliary agent. Examples of various separations of racemic 1,4-benzodiazepines will be given. Non-catalytic enantioselective preparation of specific a-amino acids and some therapeutically important compounds, will examplify the use of chiral auxiliaries, derived from the »chiral pooh of Nature. Biocatalytic transformations of chiral molecules that are not natural substrates of the enzymes, represent a rapidly growing field of application of enzymes and microorgasnisms in organic synthesis. Recently, we successfully used microbial lipases for enantioselective hydrolysis of some precursors of C3 and C4 chiral synthons, for kinetic resolution of rac 3-(2-nitrophe- noxy) butanoates, precursors for l,5-benzoxazepin-4(5H)-ones with ACH inhibitory activity, and also in chemoenzymatic syntehsis of S-fenpropimorph, the biologically active enantiomer of a commercially important fungicide. Complete stereoselectivity in the hydrolysis and acylation of resorcyclic acid macrocyclic lactones, intermediates in the production of a-zearanol, a commercially important growth-promoting agent, catalyzed by microbial lipases, prompted us to propose a new »helical model« for interaction of substrates with the Pseudomonas sp. lipase active site

Effect of distant groups on the enantioselectivity in kinetic resolution of sec-alcohols catalyzed by microbial lipases

A short series of racemic phenoxyalkyl-alkycarbinols, possessing perturbing groups at different distances from the stereogenic center, was prepared. The sec-alcohols (+/-)-1-phenoxy-2-hydroxybutane (6), (+/-)-1-phenoxy-3-hydroxyhexane (11), (+/-)-1-phenoxy-4-hydroxyoctane (15) and (+/-)-1-phenoxy-5-hydroxydecane (19) were prepared. The enantioselectivity of their acetylation by vinylacetate catalyzed by microbial lipases in n-hexane was determined. The products of this acetylation were (+/-)-1-phenoxy-2-acetoxybutane (7), (+/-)-1-phenoxy-3-acetoxyhexane (12), (+/-)-1-phenoxy-4-acetoxyoctane (16), and (+/-)-1-phenoxy-5-acetoxydecane (20). The efficacy of kinetic resolution, expressed as E-value, generally diminishes with the distance of the perturbing phenoxy (R-L) and methyl (R-M) groups. Twenty lipases from commercial sources were screened for their enantioselectivity; for two lipases with broadest substrate selectivity, Geotrichum candidum (GCL) and Candida cyclindracea (CCL (S), from Sigma), non-monotonous correlation between E-value and the distance (n) of the perturbing group was observed. With GCL lipase, a remarkable turnover of enantioselectivity from preferred acetylation of (R)-enantiomers in 6, 11, 15 to (S)-enantiomer of 19 was observed, indicating that relative steric requirements of the distant perturbing groups in the latter do not control the enantioselective bias. The herewith reported results are correlated with the previously observed stereoselective acetylation of (S)-sec-alcohols (3S, 7S)-trans-3,4,5,6,9,10-octahydro-7,14,16-trihydroxy-3-methyl-1H-2-benzoxacyclotetradecene-1-one (1) and (3S,7S)-3,4,5, 6,9,10,11, 12-decahydro-7,14,16-trihydroxy-3-methyl-1H-2-benzoxacyclotetradecane-1-one (3), macrocyclic derivatives of resorcyllic acid, and also with the results of MM2 calculations for some low energy conformations

Effect of Distant Groups on the Enantioselectivity in Kinetic Resolution of sec-Alcohols Catalyzed by Microbial Lipases

A short series of racemic phenoxyalkyl-alkycarbinols, possessing perturbing groups at different distances from the stereogenic center, was prepared. The sec-alcohols (±)-1-phenoxy-2-hydroxybutane (6), (±)-1-phenoxy-3-hydroxyhexane (11), (±)-1-phenoxy-4-hydroxyoctane (15) and (±)-1-phenoxy-5-hydroxydecane (19) were prepared. The enantioselectivity of their acetylation by vinylacetate catalyzed by microbial lipases in n-hexane was determined. The products of this acetylation were (±)-1-phenoxy-2-acetoxybutane (7), (±)-1-phenoxy- 3-acetoxyhexane (12), (±)-1-phenoxy-4-acetoxyoctane (16), and (±)-1-phenoxy-5-acetoxydecane (20). The efficacy of kinetic resolution, expressed as E-value, generally diminishes with the distance of the perturbing phenoxy (RL) and methyl (RM) groups. Twenty lipases from commercial sources were screened for their enantioselectivity; for two lipases with broadest substrate selectivity, Geotrichum candidum (GCL) and Candida cyclindracea (CCL (S), from Sigma), non-monotonous correlation between E-value and the distance (n) of the perturbing group was observed. With GCL lipase, a remarkable turnover of enantioselectivity from preferred acetylation of (R)-enantiomers in 6, 11, 15 to (S)-enantiomer of 19 was observed, indicating that relative steric requirements of the distant perturbing groups in the latter do not control the enantioselective bias. The herewith reported results are correlated with the previously observed stereoselective acetylation of (S)-sec-alcohols (3S,7S)-trans-3,4,5,6,9,10-octahydro-7,14,16-trihydroxy-3-methyl-1H-2-benzoxacyclotetradecene-1-one (1) and (3S,7S)-3,4,5, 6,9,10,11,12-decahydro-7,14,16-trihydroxy-3-methyl-1H-2-benzoxacyclotetradecane-1-one (3), macrocyclic derivatives of resorcyllic acid, and also with the results of MM2 calculations for some low energy conformations

Foreword

SPECIAL SUBJECT ISSUE ON CHIROPTICAL METHODS Part

Effect of Distant Groups on the Enantioselectivity in Kinetic Resolution of sec-Alcohols Catalyzed by Microbial Lipases

A short series of racemic phenoxyalkyl-alkycarbinols, possessing perturbing groups at different distances from the stereogenic center, was prepared. The sec-alcohols (±)-1-phenoxy-2-hydroxybutane (6), (±)-1-phenoxy-3-hydroxyhexane (11), (±)-1-phenoxy-4-hydroxyoctane (15) and (±)-1-phenoxy-5-hydroxydecane (19) were prepared. The enantioselectivity of their acetylation by vinylacetate catalyzed by microbial lipases in n-hexane was determined. The products of this acetylation were (±)-1-phenoxy-2-acetoxybutane (7), (±)-1-phenoxy- 3-acetoxyhexane (12), (±)-1-phenoxy-4-acetoxyoctane (16), and (±)-1-phenoxy-5-acetoxydecane (20). The efficacy of kinetic resolution, expressed as E-value, generally diminishes with the distance of the perturbing phenoxy (RL) and methyl (RM) groups. Twenty lipases from commercial sources were screened for their enantioselectivity; for two lipases with broadest substrate selectivity, Geotrichum candidum (GCL) and Candida cyclindracea (CCL (S), from Sigma), non-monotonous correlation between E-value and the distance (n) of the perturbing group was observed. With GCL lipase, a remarkable turnover of enantioselectivity from preferred acetylation of (R)-enantiomers in 6, 11, 15 to (S)-enantiomer of 19 was observed, indicating that relative steric requirements of the distant perturbing groups in the latter do not control the enantioselective bias. The herewith reported results are correlated with the previously observed stereoselective acetylation of (S)-sec-alcohols (3S,7S)-trans-3,4,5,6,9,10-octahydro-7,14,16-trihydroxy-3-methyl-1H-2-benzoxacyclotetradecene-1-one (1) and (3S,7S)-3,4,5, 6,9,10,11,12-decahydro-7,14,16-trihydroxy-3-methyl-1H-2-benzoxacyclotetradecane-1-one (3), macrocyclic derivatives of resorcyllic acid, and also with the results of MM2 calculations for some low energy conformations

Preparation of the Chiral Diol (2R,3R)-2-Hydroxymethyl-3-hydroxy-tetrahydropyran from D-Glucose via Reductive Rearrangement of Pseudo-D-glucal Triacetate

Hydrogenation of n-glutal triacetate (1) and pseudo-n-glucal triacetate (2) into (2R,3R)-2-acetoxymethyl-3-acetoxy-tetrahydropyran (4) and the rearrangement of 1 into 2 were investigated. On. hydrogenation, at high catalyst-to-substrate ratio and in the presence of a great excess of diethylamine, compound 1 afforded diacetate 4 in a mixture with triacetate 6, while 2 was quantitatively converted into 4 under standard catalyst-to-substrate (- 1 : 80) ratio. It was established that hydrogenation of both isomers proceeds through the same intermediate 4,6-di-O-acetyl-l,2,3-trideoxy- n-erythro-hex-J-enitol (3) which was fully characterised from its lH_ and 13C-NMRspectra. When hydrogenation of 2 was performed with platinum on carbon in acetonitrile, compound 3 was isolated in 83010yield. The thermal and Lewis acid catalysed rearrangement of 1 into 2 was examined; only zinc(II) chloride in acetic anhydride gave preparatively acceptable yields (60- -70010) of 2. It was demonstrated that with Zn(II) or Mo(VI) ions in AC20 an 1 =:; 2 equilibrium in favour of 2 was attained