Enantiospecific reduction

Katayama T, Davin LB, Lewis NG (1992) An extraordinary accumulation of (-)-pinoresinol in cell-free extracts of Forsythia intermedia evidence for enantiospecific reduction of (+)-pinoresinol. Phytochemistry 31 3875-3881... 

Considerable success has been obtained in enantiospecific reductions using chiral 1,4-dihydropyridines. For example, keto ester (181) is reduced by the dihydropyridine (180) with a high degree of optical purity (79JA7036). At present this is a very active area of research. 

Scheme4.Antibody A5, elicited to hapten 15, catalyzes the highly enantiospecific reduction of a-ketoamide 16 (>99% de) with sodium cyanoborohydride (NaCNBHj) as a cofactor. This is a good example of an achiral hapten generating a catalyst possessing exquisite chiral discrimination...

Enantiospecific reduction of C=N bonds is of interest for the synthesis of a-amino acids and derivatives such as amines. While nonenzymatic reductive amination has been known since 192711, only recently have enzymatic procedures to L-amino acids became established. The reduction can be achieved by different enzymes following different mechanisms, e.g. by pyridoxalphosphate (PLP)-dependent transaminases (E.C. 2.6.1, discussed in Chapter 12.7) or by amino acid dehydrogenases (E.C. 1.4.1) using NADH or NADPH as the cofactor. The synthetic usefulness of the transaminase reaction is diminished by the location of the equilibrium (Keq often is close... 

Kinetic resolutions have a maximum yield of only 50%. Therefore, a second enzymatic process was added after completion of the glycolate oxidase-catalyzed kinetic resolution[131). By addition of D-lactate dehydrogenase (E.C. 1.1.1.28) together with formate dehydrogenase for NADH regeneration, enantiospecific reduction of the 2-keto acid was achieved. Overall, a quantitative transformation (deracemization) of the racemic 2-hydroxy acid into the corresponding (R)-2-hydroxy acid was achieved (Fig. 16.2-29). 

Of particular interest is the regio- and enantiospecific reduction of diketo acid with Margarlnomyces bubaki affording the keto lactone 8. The latter serves as the chiral starting point in an asymmetric total synthesis (+)-estr-4-ene-3,17-dione via key intermediate 9 (9). 

The principle pathways of lignan biosynthesis in Forsythia have been elucidated from studies using labelled precursors and cell free extracts. The sequence from coniferyl alcohol (9) to (+)-pinoresinol (10), (+)-lariciresinol (11), (-)-secoisolariciresinol (12) and (-)-matairesinol (13) is now clearly established (scheme 1) [30-33]. Lewis et al. have shown that (+)-pinoresinol (10) is formed via direct stereoselective coupling of the two coniferyl alcohol molecules, a process which requires the complimentary action of a specific protein and an auxiliary oxidase or peroxidase [34,35]. (+)-Lariciresinol (11) and (-)-secoisolariciresinol (12) are then formed by consecutive enantiospecific reduction [36], and (-)-secoisolariciresinol is further metabolised into (-)-matairesinol (13) via enantiospecific dehydrogenation, and into (-)-arctigenin (14) via regioselective 0-methylation [37]. 

Oxidative unmasking, enantiospecific reduction" of the enone (55), and stereoselective cix-hydroxylation on the allylic acetates (56a and 56b) paved the way for the first report on the synthesis of the spiro-C-linked disaccharides (57a and 57b). Extension of the same strategy to the uloses derived from d- and L-arabinose expectedly offered the enantiomeric spiro-C-linked disaccharides (58a and 58b and 59a and 59b, respectively Scheme 22.13). 

The reduction of a-keto esters has also been performed using baker s yeast [216]. Thus, different 2-oxo-2-arylacehc acid derivatives gave optically pure a-hydroxy acid derivatives [217, 218]. Ethyl p5Tuvate gave (R)-ethyl lactate efficiently [217]. Of par-hcular interest seems the synthesis of enantiomerically pure (f )-pantoyllactone 49 (Figure 21.15) via enantiospecific reduction of ketopantolactone 48. 

Enantiospecific syntheses of amino derivatives of benzo[ ]quinolizidine and indolo[2,3- ]quinolizidine compounds have also been achieved via A-acyliminium ion cyclization reactions, as an alternative to the more traditional Bischler-Napieralski chemistry (see Section 12.01.9.2.2). One interesting example involves the use of L-pyroglutamic acid as a chiral starting material to construct intermediates 240 via reaction with arylethylamine derivatives. Diisobutylaluminium hydride (DIBAL-H) reduction of the amide function in 240 and subsequent cyclization and further reduction afforded piperidine derivatives 241, which stereoselectively cyclized to benzo[ ]quinolizidine 242 upon treatment with boron trifluoride (Scheme 47) <1999JOC9729>. 

The benefits of C2-symmetry are due to the reduction of the number of possible catalyst-substrate isomers that may form, and the number of enantiospecific pathways (Helmchen, Pfaltz [9]). As they reasoned, there is no fundamental reason why a C2-symmetric ligand is superior qualitate qua to a Ci-symmetric ligand. Two different co-ordinating ligands (P-X as shown above, or P-N, discussed here) could lead to more control, as the attack may... 

The regioselective and enantiospecific allylic substitution of alkyl-substituted allyl benzoates and carbamates with (Me2PhSi)2Zn and Cul has been shown to occur by an oxidative addition - reduction elimination mechanism rather than an SN2 mechanism.16... 

Enantiospecific syntheses have utilized the chirality available in D-alanine and L-alanine. For instance, coupling and cyclization (after the necessary deprotection) of N-allyl-N-BOC-D-alanine with L-alanine methyl ester, followed by lithium aluminum hydride reduction of the diketopiperazine provided (—)-(2R,5S)-l-allyl-2,5-dimethylpiperazine (Scheme 6) [27,39], Ra-cemization was not observed during the synthesis. 

Recently, the first asymmetric cell-free application of styrene monooxygenase (StyAB) from Pseudomonas sp. VLB 120 was reported [294]. StyAB catalyses the enantiospecific epoxidation of styrene-type substrates and requires the presence of flavin and NADH as cofactor. This two-component system enzyme consists of the actual oxygenase subunit (StyA) and a reductase (StyB). In this case, the reaction could be made catalytic with respect to NADH when formate together with oxygen were used as the actual oxidant and sacrificial reductant respectively. The whole sequence is shown in Fig. 4.106. The total turnover number on StyA enzyme was around 2000, whereas the turnover number relative to NADH ranged from 66 to 87. Results for individual substrates are also given in Fig. 4.106. Excellent enantioselectivities are obtained for a- and -styrene derivatives. 

S)-reticuline to ( )-reticuline in Papver somniferum is achieved by enantiospecific oxidation of the (5 )-enantiomer (273), and it is followed by an NADPH-dependent enzymatic reduction of the dehydroreticulinium ion, which also is highly substrate specific since no reduction of 1,2-dehydronorreticuline was observed (275). 

The enantiospecific synthesis of natural and unnatural a-amino acids has been reviewed. Some of the most successful approaches involve the stereoselective hydrogenation of chiral dehydroamino acid derivatives. Many of these transformations are equivalent to the stereoselective reductive amination of a-keto acids (eq 2). For example, catalytic reduction of the imines of a-keto acids with chiral a-methylbenzylamine gives a-substituted a-amino acids with 12-80% ee (eq 3). ... 

Preparative Methods both enantiomers of dihydro-5-(hydroxymethyl)-2(3H) furanone and their trityl derivatives are commercially available but expensive. The simplest and by far most popular method for preparing (5)-dihydro-5-(hydroxymethyl)-2(3H)-furanone (2) consists of enantiospecific deamination of L-glutamic acid and subsequent selective reduction of the resulting carboxylic acid (13) (eq 1). Purification of the intermediate acid (13) by crystallization and not by distillation is recommended in order to secure an excellent optical yield (>98% ee). Likewise, (f )-dihydro-5-(hydroxymethyl)-2(3//)-furanone (1) (>98% ee) can be obtained from o-glutamic acid. As the latter is considerably more expensive than its natural antipode, an appealing option is to convert the (5)-lactone into its enantiomer (eq 2)P Also available and equally useful is an inversion route to (f )-dihydro-5-(trityloxymethyl)-2(3H)-furanone (5) by way of the Mitsunobu reaction (eq 3). ... 

The second route (272) is an enantiospecific one that starts from (+)-S-l-benzyloxycarbonyl-3-piperidein-5-ol (426), obtained from the corresponding racemate by preferential lipase-catalyzed esterification of its enantiomer by means of vinyl acetate, as in the preparation of 419. Reaction of 426 with triethyl orthoacetate, followed by Johnson-Claisen rearrangement, gave the tetrahydropyridine ester 427, which was converted by unexceptional means into the ketoamide 428. Reductive removal of the functional groups then provided another synthesis of (-I- )-R-demethoxy-carbonyl-15,16,17,20-tetrahydrosecodine (2), and Dess-Martin oxidation... 

Photosynthetic microorganisms and plant cell cultures are very important sources of enzymes for the reduction of olefins151, 2981. For example, Hirata et al. found that reduction of enone 11 with Nicotiana tabacum p90 reductase and Nicotiana tabacum p44 reductase affords (S)- and (R)-alkylcyclohexanones, respectively, with excellent enantioselectivities as shown in Fig. 15-53. They also found two enone reductases from Astasia longa, a nonchlorophyllous cell line classified in Euglenales, and studied the mechanism. Both catalyzed enantiospecific trans-addition of hydrogen atoms to carvone from the si-face at the a-position and from the re-face at the p-position. 

Stereoinversion catalyzed by two different alcohol dehydrogenases via enantiospecific oxidation followed by an asymmetric reduction. 

The alterations produced by THC and other cannabinoids in biogenic amine levels as well as on uptake, release and synthesis of neurotransmitters and effects on enzymes have been the subject of numerous investigations (for reviews see [8,52,55,114,115]). It is beyond the scope of the present summary to try to analyse and put into a proper perspective the wealth of data published so far. It is our subjective view that the mode of action of cannabi-mimetic compounds is somehow directly associated with prostaglandin metabolism (see, in particular, the series of papers by Burstein [115,116]), and/or reduction of hippocampal acetylcholine turnover observed in rats [117,118]. The latter effect is enantiospecific and follows the known SAR of the cannabinoids. This in vivo selectivity of action suggests that the THC may activate specific transmitter receptors which indirectly modulate the activity of the cholinergic neurons in the septalhippocampal pathway. 

The optically active carbinols 6 (77 85% ee) of the compounds listed in the table above are only obtained in small amounts (3-9% yield). However, the situation changes if the perfluoroalkyl group is an immediate substituent at the carbon-carbon double bond. In this case the keto group is preferably reduced affording the corresponding unsaturated optically active alcohol 7 which is further converted into the saturated optically active alcohol 8 after prolonged incubation 52. Since the carbon-carbon double bond bears, in this case, a substituent other than H, a second center of asymmetry is created during the double-bond reduction. The ratios for the two observed diastereomers (d.r. see table) are a measure of the enantiospecificity of the enzymatic reductions. 

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