Synthesis of homochiral 2-hydroxy acids

Details Synthesis of homochiral 2-hydroxy acids Synthesis of homochiral 2-hydroxy acids

1994-08-26

1997-11-11

Lilling, Herbert J.

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing oxygen-containing organic compound

435190, 435280, C12P 742, C07D30733

Patent

active

056862750

DESCRIPTION:

BRIEF SUMMARY
This invention relates to chiral synthesis; more particularly, it relates to the synthesis of certain homochiral 2-hydroxy acids using 2-oxo carboxylic acid dehydrogenases as versatile catalysts capable in many cases of preparation of both (R) and (S) isomers at the alpha hydroxy group.
The synthesis of chiral 2-hydroxy acids is of considerable importance, since these compounds are versatile synthetic intermediaries which may be converted to a variety of compounds with retention of chirality at C-2, including epoxides, alkyl esters, hydrazinyl esters, .alpha.-N-alkoxyamino esters and .alpha.-amino esters. In general, reactions involving nucleophilic substitution at the 2-position are optimally effected via the corresponding 2-triflate esters which are generated in situ and reacted directly with the chosen nucleophile.
The availability of chiral 2-hydroxy acids and esters possessing an additional prochiral functional group in the side chain, offers enormous potential for the synthesis of compounds containing two or more chiral centres. For this purpose, the hydroxyl group or C-2 is expected to provide an internal control element, facilitating stereoselective transformations of the prochiral functional group. In the case of .beta.,.gamma.-unsaturated compounds, expoxidation would give access to Sharpless-type intermediates, and dehydroxylation would produce polyols which may have utility in carbohydrate synthesis. In the case of the 4-oxo compounds, diastereoselective ketone reduction would provide either syn- or anti-1,3-diols, dependant on choice of conditions.
Chemistry offers, both in its more traditional forms and increasingly via enzyme-catalysed reactions, methods with potential for the synthesis of the compounds of particular interest.
2-hydroxy acids and esters are valuable synthetic entities and much effort has been expended in the development of methods for the preparation thereof in chiral form and examples of chemical and enzymatic methods are described below. The main limitations of the chemical procedures are technical, since the key transformations all involve the use of water-sensitive reagents at low temperature. With the exception of enone reduction, product chirality arises in a stoichiometric sense, either from chiral auxiliary (substrate control), or from a bulky chiral reductant (reagent control).
Asymmetric reduction of 2-keto esters using the chiral borane potassium 9-0-DIPGF-9-BBNH (Brown H. C., et al, J. Org. Chem., (1986), 51, 3396) requires a stoichiometric quantity of the complex reducing agent and currently only provides access to 2-hydroxy esters of (S)-absolute configuration.
Hydroxylation of chiral oxazolidone enolates with oxaziridine oxidants (Evans, D. A., et al, J. Am. Chem Soc., (1985) 102, 4346) requires that, in order to obtain homochiral 2-hydroxy esters, this chromatographic resolution of the 2-hydroxy imide be undertaken prior to methanolysis. This process gives poor yields in the case of hindered derivatives (e.g. R represents Pr, Bu.sup.t). The use of valine-derived auxiliary provides a complementary route to (S)-2-hydroxy esters.
Carboxylation of chiral .alpha.-alkoxycarbanions (Chan C. M. & Chong J. M., Tet. Lett., (1990), 31, 1985) requires a stoichiometric quantity of the costly reducing agent (S)-BINAL-H and disposal of hazardous tin residues after the transmetallation stage. The use of (R)-BINAL-H in the first stage provides a complementary route to (R)-2-hydroxy acids.
Enantioselective reduction of enones catalysed by chiral oxazaborolidines, (Coney, G. J. & Bakshi R. K., Tet. Lett., (1990), 31, 611) derives chirality from a catalytic source in contrast to the above methods. The availability of the optical antipode of the catalyst provides a complementary route to the opposite enantiomeric series. A sequence of four chemical conversions are required in order to transform initially formed chiral alcohol to the 2-hydroxy ester with obvious cost and yield implications.
The published use of enzymes found in formation of chiral .alpha.-hydroxy acids includes (R

REFERENCES:
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