Process for selective reduction

Details Process for selective reduction Process for selective reduction

2000-07-14

2002-03-12

Shaver, Paul F. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Silicon containing

C552S004000, C549S214000, C554S077000

Reexamination Certificate

active

06355822

ABSTRACT:

Chirally functionalized alcohols are very important synthetic intermediates, for example for potential enzyme inhibitors for anticancer therapy, such as, for example, protein kinase C inhibitors, or for anti-HIV agents.
For this reason, many experiments have already been undertaken to obtain these compounds from prochiral ketones.
One of the most customary methods for the preparation of optically active &agr;-hydroxy esters is the asymmetric reduction of the corresponding &agr;-keto esters. Thus the asymmetric reduction of prochiral ketones with chiral systems derived from NaBH
4
, which are obtained by reaction NaBH
4
with, for example, monosaccharides or &agr;-amino acid derivatives, in particular L-proline derivatives, has already been more closely investigated. However, this method only produces moderate optical purities, as is known from Bull. Chem. Soc. Jpn., 64, 175-182 (1991). For this reason, other chiral systems derived from NaBH
4
were investigated in this reference. Thus ethyl 2-(3,4-isopropylidenedioxyphenyl)-2-oxoacetate was reduced to the corresponding (R)-hydroxy compound using a system obtained by reaction of NaBH
4
with (R,R)-tartaric acid, an ee of up to 78% being obtained. In contrast to this, the asymmetric reduction of propiophenone with the reaction product of NaBH
4
and (S,S)-tartaric acid afforded (S)-1-phenyl-1-propanol in an optical yield of only 10%.
EP-A1-0 320 096 likewize describes the reduction of prochiral keto esters or ketones by means of NaBH
4
and tartaric acid. In the examples, it is shown here that the use of (R,R)-tartaric acid yields the corresponding (R)-hydroxy compounds in an optical yield of only 15 to at most 85%.
In Synthetic Communications, 14(10), 955-959 (1984), the efficiency of the NaBH
4
/tartaric acid system in the reduction of cyclic ketones was investigated. In the course of this, ketones, such as 2-methyl-, 3-methyl-, 4-methyl- and 4-t-butylcyclohexanone were reduced to the corresponding alcohols, markedly higher proportions of the more stable equatorial alcohols being obtained with the NaBH
4
/tartaric acid system than with NaBH
4
alone. A change in the optical activity of the tartaric acid had no detectable effect on the stereochemical result of the reduction.
Rather, it can be derived from the literature that the stereoselectivity is strongly dependent on the structure of the substrate and that chiral centers present in the substrate, and/or the nature and size of the substituents of the substrate, have a strong influence on the course of the reduction. This is confirmed, for example, by J. Org. Chem. 1999, 64, 2172-2173. In this reference, the stereoselectivity in the reduction of &bgr;-hydroxy or &bgr;-alkoxy ketones by means of SmI
2
was investigated, it being found that it was possible to reduce substituents having the &bgr;-hydroxy substituent in high yield and good optical purity, the hydroxyl group to a significant extent determining both the stereoselectivity and the reaction rate. Substrates which had a protected &bgr;-hydroxyl group, for example a &bgr;-OBn or OTBS group, were almost completely inert in comparison with compounds having the free hydroxyl group. In the case of these substrates, no reduction was achieved. It also follows from J. Org. Chem., Vol. 56, No. 24, 1991 that the size of the substituents has a great influence on the stereoselectivity.
Unexpectedly, it has now been found that &agr;- or &bgr;-ketoesters which have a chiral center in the &ggr; position can be reduced with NaBH
4
and (D)- or (L)-tartaric acid to the corresponding diastereomeric hydroxy esters in each case in high optical purity and high yield, the chiral center present in the starting compound having no influence on the formation of the diastereomers.
The invention accordingly relates to a process for the stereoselective reduction of chiral &agr;- or &bgr;-keto esters, which comprizes reducing &agr;- or &bgr;-ketoesters which have a chiral center in the &ggr; position in an inert solvent at temperatures from −80 to +50° C. using a reductant obtained by reaction of NaBH
4
and (D)- or (L)-tartaric acid to the corresponding diastereomeric hydroxy compounds in each case.
Chiral &agr;- or &bgr;-keto esters which have a chiral center in the &ggr; position are reduced in the process according to the invention. Suitable substrates accordingly preferably have an open-chain, optionally branched alkyl or alkenyl chain. The alkyl or alkenyl chain consists here of 4 to 30, preferably 4 to 15, C atoms. In the case of an alkenyl chain, this can have 1 to 3 double bonds. The chain is substituted in position 1 by a carboxylate group. The ester group is derived here from a primary, secondary or tertiary alcohol. Esters of primary alcohols are preferred. These are accordingly C
1
-C
20
-, preferably C
3
-C
6
-, alkyl esters, such as methyl, ethyl, propyl, butyl, hexyl esters, etc. A keto group is found either in the &agr; or &bgr; position to the carboxylate, preferably in the &agr; position. The substrates have a chiral center in the &ggr; position. A protected OH group, for example a t-butyldiphenylsilyloxy group, a trimethylsilyloxy group, a benzyloxy group or another customary protective group, is preferably found as a substituent in the &ggr; position.
Particularly preferred substrates are those which can be prepared from unsaturated cyanohydrins by means of the Blaise reaction. Methyl (4S)-3-oxo-4-tert-butylsilyloxyundec-5-enoate is very particularly preferred.
According to the invention, the corresponding substrate is reduced using a reductant which is obtained by reaction of NaBH
4
with (D)- or (L)-tartaric acid.
Depending on which diastereomer of the corresponding hydroxy compound is desired, NaBH
4
is reacted here either with (D)- or with (L)-tartaric acid. The preparation of the actual reductant (the sodium acyloxyborohydride derived from (D)- or (L)-tartaric acid) is preferably carried out in situ, as described, for example, in Synthetic Communications, 14(10), 955-959 (1984); Bull. Chem. Soc. Jpn., 64, 175-182 (1991) or J. Chem. Soc. Perkin Trans I, 1827 (1990) etc. Preferably, the corresponding tartaric acid and NaBH
4
are suspended here in a suitable inert diluent which preferably also serves as a solvent for the reduction, NaBH
4
in turn preferably being added in portions to a solution of the tartaric acid and the suspension thus obtained being heated to reflux temperature for 0.5 to 6 hours. Suitable diluents or solvents are, for example, alcohols, such as, for example, 2-propanol, t-butanol, etc., ethers, such as tetrahydrofuran (THF), dioxane, diethyl ether etc., aromatics, such as benzene, toluene, xylene, etc. or other solvents which are inert under the reaction conditions. Optionally, the above solvents can also be employed as a solvent mixture. THF or 2-propanol is preferably employed. The molar ratio of NaBH
4
to (D)- or (L)-tartaric acid is between 1:0.5 to 1:1.5, the molar ratio preferably being 1:1.
Following the warming of the suspension, the mixture is cooled down to −50° C., preferably to −30° C. and particularly preferably to −20° C. A solution of the substrate to be reduced is then introduced into the solution of the reductant thus obtained. Suitable solvents are once again the solvents listed above. Preferably, the same solvent is employed in the in situ preparation of the reductant and in the reduction. Preferably, the substrate solution is added in a number of portions, particularly preferably dropwise, so that the temperature is kept constant at, particularly preferably, −20° C.
The reductant is present here in an excess relative to the substrate. A molar ratio of substrate to reductant of 1:2 to 1:6, particularly preferably of approximately 1:4, is preferred. The reaction mixture is stirred in the course of this. After reduction is complete, i.e. depending on the selected substrate after 1 to 60 hours, hydrochloric acid or sulfuric acid, for example, is added to the reaction mixture for the isolation of the corresponding diastereomer, or for the termination

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