Substituted deracemization

Other racemization systems that may be amenable to conversion to deracemization processes in future have recently been reported by Faber and coworkers [33]. Resting cells of L. paracasei have been used for biocatalytic racemization of open-chain and cyclic dialkyl-, alkyl-aryl-, and diaryl-substituted acyloins (29/30) (Figure 5.20). Both... 

In a subsequent study using a resting cell system of N. diaphanozonaria JCM3208, deracemization of 4-substituted-2-thiopropanoic adds (34) were... 

For the deracemization of phenylethanol derivatives using G. candidum under aerobic conditions (Figure 8.41b), the (S)-specific enzyme was reversible and (R) enzyme was irreversible, so (R)-alcohol accumulated when the cell and racemic alcohols were mixed [31b,c]. Para-substituted phenylethanol derivatives gave better results than meta-substituted derivatives. Sphingomonas was used for... 

In a time course study on the conversion of ( )-l-phenylethanol 13 (X=H), formation of acetophenone was observed to a maximum of around 20% during the conversion of (S)- to (R)- alcohol which occurred over 24 h to give (R)-13 in 96 % yield, 99% e.e. The effect of ring substitution on the efficiency of the dera-cemization was notable. While para substituents (Cl, OMe, Me) gave good results, ortho derivatives could not be deracemized and the biocatalyst showed little activity towards meta substituted compounds. On addition of allyl alcohol, improvements in e.e. were obtained, particularly for the conversion of l-(m-methylphenyl)ethanol (from 21 to 94% e.e.). However these improvements did appear to be at the expense of yield (89% diminished to 55%). The authors sug-... 

Substituted acrylates (which reseitible the enamide substrates employed 1n asymmetric hydrogenation) may be deracemized by reduction with an optically active catalyst, especially DIPAMPRh . Selectivity ratios of 12 1 to 22 1 have been obtained for a variety of reactants with compounds of reasonable volatility, separation of starting material and product may be effected by preparative GLC. Recovered starting material can then be reduced with an achiral catalyst to give the optically pure anti product. Examples of kinetic resolutions by this method are given in Table II. More recently very successful kinetic resolutions of allylic alcohols have been carried out with Ru(BINAP) catalysts. 

An application of the deracemization strategy has provided efficient entry to a novel amino acid substituent of the antifungal agents, polyoxins and nikkomycins, as shown in Scheme 8E.20. The versatile five-carbon building block was obtained from phthalimidation of the hydroxymethyl-substituted epoxide in 87% yield and 82% ee. Straightforward synthesis of polyoxamic acid was then accomplished by subsequent dihydroxylation and selective oxidation of the alkylation product. 

The obligatory enantiofacial exchange for efficient deracemization also occurs in a very congested allylic system giving high enantioselectivity (86% ee) as shown in Eq. 8E.8 [145]. The silyl groups in the alkylation product could be removed without loss of stereochemical integrity to effect a nct-benzylic substitution. 

Kato, D., Mitsuda, S., and Ohta, H. 2002. Microbial deracemization of a-substituted carboxylic acids. Org. Lett., 4, 371-373.107. 

Recently the microorganism Candida parapsilosis was used for the deracemization of a- and P-hydroxy esters. A series of racemic aryl and aryl substituted... 

The generality of the reaction was established by using different substituents in the standard substrate ethyl 3-hydroxy 3-phenyl propionate. The presence of electron donating and electron withdrawing groups in the para position does not affect the deracemization reaction, while substitution in the ortho position hinders the same. On a preparative scale, up to 500 mg of racemic substrate incubated with the cells were deracemized with isolated yields close to 80%. 

Hydantoinase-Carbamoylase System for t-Amino Acid Synthesis Despite a number of reports of strains with L-selechve hydantoin-hydrolyzing enzymes [38] the commercial application of the hydantoinase process is stiU restricted to the production of D-amino acids. Processes for the production of L-amino acids are Umited by low space-time yields and high biocatalyst costs. Recently, a new generation of an L-hydantoinase process was developed based on a tailor-made recombinant whole cell biocatalyst. Further reduction of biocatalyst cost by use of recombinant Escherichia coli cells overexpressing hydantoinase, carbamoylase, and hydantoin racemase from Arthrohacter sp. DSM 9771 were achieved. To improve the hydan-toin-converting pathway, the level of expression of the different genes was balanced on the basis of their specific activities. The system has been appUed to the preparation of L-methionine the space-time yield is however still Umited [39]. Improvements in the deracemization process from rac-5-substituted hydantoins to L-amino acids still requires a more selective L-hydantoinase. 

Thus, using L-amino add oxidase from P. myxcfaciens and various amine-borane complexes or D-amino acid oxidase from porcine kidney and sodium cyanoboro-hydride, the preparation of several natural and non-natural enantiopure D- and L-amino adds was achieved, respectively [51]. In a more recent report, several P- and y-substituted a-amino adds were deracemized using D-amino add oxidase from Trigonopsis variahilis and sodium cyanoborohydride or sodium borohydride [52] (Scheme 13.20). 

The resulting derivatives were applied with success in the standard asymmetric allylic alkylation (up to 97 % ee) [134, 136] or in transformations involving either specific allylic substrates (2-cycloalkenyl derivatives, up to >99% ee) [135, 137], unsymmetrical substrates (monosubstituted allyl acetate, up to 83% ee) [140], or especial nucleophiles (nitroalkanes [141], iminoesters [138 a], or diketones [139, 140, 142]). Such ligands were also effective in the formation of quaternary chiral carbon through allylic substitution (eq. (6)) [138, 143], deracemiza-tion of vinyl epoxides (up to 99% ee) [144], or alkylation of ketone enolates [138 b], and deracemization of allylic derivatives [145]. 

Enzymatic oxidations of carbon-nitrogen bonds are as diverse as the substances containing this structural element. Mainly amine and amino acid oxidases are reported for the oxidation of C-N bonds. The steroespecificity of amine-oxidizing enzymes can be exploited to perform resolutions and even deracemizations or stereoinversions (Fig. 16.7-1 A). Analogous to the oxidation of alcohols, primary amines are oxidized to the corresponding imines, which can hydrolyze and react with unreacted amines (Fig. 16.7-1 B). In contrast to ethers, internal C-N bonds are readily oxidized, yielding substituted imines. This can be exploited for the production of substituted pyridines (Fig. 16.7-1 C). Furthermore, pyridines can be oxidized not only to N-oxides but also to a-hydroxylated products (Fig. 16.7-1 D). 

The approach can be coupled with other methods to prepare amino acids, such as to access [3-substituted a-amino acids. The methodology gives a way to prepare all four possible isomers of (3-aryl a-amino acids by a combination of asymmetric hydrogenation and the use of the deracem-ization process to invert the a-center (Scheme 9.36)." "°... 

Kinetic resolutions. Baylis-Hillman adducts are deracemized by exploiting their reactivity toward Pd(0)-catalyzed substitution, using chiral ligand 2. Both the planar chiral DMAP derivative 3 and the axially chiral analogue (4) ° and 5" have been developed as catalysts for enantioselective acylation. Benzylic alcohols undergo enantioselective acylation with the aid of 6. Methanolysis of meio-anhydrides in the presence of a cinchona alkaloids is a good way to desymmetrize such compounds. ... 

Use of a chiral proton source, a chiral base or base/chiral ligand complex circumvents the problem of incorporation and removal of a chiral auxiliary. Simpkins and coworkers opened the possibility of enantioselective protonation as a method for the asymmetric syntheses of 1-substituted tetrahydroisoquinolines [77]. Using the chiral amine 98 as a proton source, deracemization of 97 proceeded in up to 93 7 er, alleviating the requirement for a chiral auxiliary (Scheme 28). 

Deracemization of 3-nonyl-3,4-epoxybut-l-ene (119) occurred by the EtsB-assisted reaction with p-methoxybenzyl alcohol (PMB) to afford the chiral product 120 with 99 % ee by using (/ ,/ )-Trost L-1. In addition to high enantioselectiv-ity, unusual exclusive 1,2-addition of the alcohol at the more substituted terminus occurred to generate a chiral center. The reaction is a key step in total synthesis of (—)-malyngolide [44]. 

Enantioenriched a-substituted carboxylic acids have been prepared using the growing cell system of Nocardia diaphanozonaria JCM3208. Racemic 2-aryl and 2-aryloxypropanoic acid could be deracemized leading to the recovery of the (R)-enantiomer in high yield (>50%) and 69% ee (Scheme 4.44). A new biocatalytic... 

K. and Ohta H., Microbial deracemization of a-substituted carboxylic acids control of the reaction path. Tetrahedron Asymmetry, 2004, 15, 2965-2973 (h) Kato, D., Mitsuda S. and Ohta, H., Microbial deracemization of a-substituted carboxylic acids substrate specificity and mechanistic investigation, /. Org. Chem., 2003, 68, 7234-7242 (i) Mitsukura, K., Yoshida, T. and Nagasawa T., Synthesis of (R)-2-phenylpropanoic acid from its racemate through an isomerase-involving reaction by Nocardia diaphanozonaria, Biotechnol Lett., 2002, 24, 1615-1621. 

Even though this concept has been proven to be effective, the toxicity of NaCNBHj led to the search for alternative reagents whereby amine-boranes turned out to be competent substitutes [117]. They are stable in water at neutral or basic pH and soluble and unreactive toward a wide range of protic and aprotic solvents. Deracemization of several natural and nonnatural AAs with an L-amino acid deaminase (l-AAD)... 

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