Increasing enatioselectivity in reductions with borane reagents

Details Increasing enatioselectivity in reductions with borane reagents Increasing enatioselectivity in reductions with borane reagents

2000-04-20

2001-04-17

Barts, Samuel (Department: 1621)

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

Organic compounds

Oxygen containing

C568S881000

Reexamination Certificate

active

06218585

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to increasing enantioselectivity in reactions with borane reagents, and especially, to increasing enantioselectivity in the reduction of a prochiral substrate with a borane reagent and a chiral catalyst.
BACKGROUND OF THE INVENTION
Borane reagents such as borane-tetrahydrofuran complex (sometimes referred to as THFB) are valuable reagents for the reduction of functional groups and for hydroboration reactions with carbon-carbon double and triple bonds. For example, functional groups reduced by borane-tetrahydrofuran complex include aldehyde, ketone, acyl chloride, lactone, epoxide, ester, amide, oxime, imine, and nitrile. Borane-tetrahydrofuran complex is a very selective and clean reducing agent. Because the borane is complexed to the low-boiling (65° C.), common solvent, tetrahydrofuran, no byproduct residues are generated. Typically a reduction is quenched with excess methanol to deactivate any remaining borane-tetrahydrofuran complex and distilled to remove the boron from the desired products as the methylborate/methanol azeotrope.
The enantioselective reduction of prochiral ketones with borane-tetrahydrofuran complex in the presence of an oxazaborolidine chiral catalyst such as (R)-MeCBS (a methyl-substituted chiral oxazaborolidine named after Corey, Bakshi, and Shibata) is a very important tool for the synthesis of alcohols in high optical purity. See, for example, Corey, E. J. and Helel, C. J., “Reduction of Carbonyl Compounds with Chiral Oxazaborolidine Catalysts: A New Paradigm for Enantioselective Catalysis and a Powerful New Synthetic Method,”
Angew. Chem. Int. Ed
., 37, 1986-2012 (1998); U.S. Pat. No. 4,943,635; and Franot, C. et al., A Polymer-Bound Oxazaborolidine Catalysts: “Enantioselective Borane Reductions of Ketones,” Tetrahedron: Asymmetry, 6:11, 2755-2766 (1995).
However, the selectivity of the reaction has been found to be affected by a number of parameters including, for example, temperature and borane source/batch. In that regard, the enantioselectivity of (R)-MeCBS catalyzed reductions has been found to be quite low for various commercial samples of THFB. Several researchers have presumed that the widely variable results achieved with commercially available THFB were a result of decomposition thereof. See Jones, T. K. et al., “An Asymmetric Synthesis of MK-0417. Observations on Oxazaborolidine-Catalyzed Reductions,”
J. Org. Chem
., 56, 763-769 (1991).
In that regard, although THFB is a very valuable reagent, THFB complexes are known to decompose during transportation and storage at ambient temperature and to thermally decompose during reaction. To prevent decomposition during transportation and storage, stabilizers are typically added to borane-tetrahydrofuran complex. Typically, a hydride source such as a metal hydride (for example, potassium hydride, sodium hydride or lithium hydride) or sodium borohydride (NaBH
4
) is added to THFB. Sodium borohydride and other hydrides have been shown to be quite effective in stabilizing THFB. At least one study has also shown that sodium borohydride leads to strongly enhanced activity in the reduction of ketones. Jockel, H. and Schmidt, R., “Kinetics of Direct Borane Reduction of Pinacolone in THF,”
J. Chem. Soc
., Perkin Trans. 2, 2719-2723 (1997). Other borohydride sources include, for example, potassium borohydride, lithium borohydride, and tetraalkylammonium borohydride. Moreover, metal alkoxides (for example, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium tert-amylate, potassium tert-amylate, lithium tert-amylate, sodium isopropoxide, potassium isopropoxide, lithium isopropoxide, sodium methoxide, potassium methoxide and lithium methoxide) can be added to generate a borohydride stabilizing agent within THFB.
It is very desirable to develop borane compositions and methods of reaction that improve enantioselectivity.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a method of increasing enantioselectivity in a reduction reaction of a prochiral substrate with a borane reagent including or containing a borohydride species (for example, a borohydride stabilized borane-tetrahydrofuran complex) catalyzed by a chiral catalyst. As used herein, the term “borohydride species” refers to compounds of boron and hydrogen and includes, for example, anionic borohydrides. The method includes generally the step of limiting the concentration of borohydride species in the borane reagent (for example, borane-tetrahydrofuran complex). In the case of borane-tetrahydrofuran complex, the method includes generally the step of maintaining the concentration of borohydride species in the borane-tetrahydrofuran complex below approximately 0.005 moles per mole of BH
3
during the reduction of the prochiral substrate. More preferably, the concentration of borohydride species in the borane-tetrahydrofuran complex is below approximately 0.0015 moles per mole of BH
3
during the reduction of the prochiral substrate. Most preferably, the concentration of borohydride speicies in the borane-tetrahydrofuran complex is below approximately 0.0005 moles per mole of BH
3
during the reduction of the prochiral substrate. Prochiral substrates suitable for use in the present invention include, for example, ketones, imines and oximes.
As used herein and as used commonly in the chemical arts, the term “ketone” refers generally to a compound having the formula:
The term “imine” refers generally to a compound having the formula:
The term “oxime” refers generally to a compound having the formula:
In the above formulas, R and R′ are preferably independently different, an alkyl group or an aryl group (Ar). R″ is preferably H, —SiR
3
or an alkyl group. Reductions of such prochiral substrates are discussed, for example, in Tilyer, R. D. et al., “Asymmetric Reduction of Keto Oxime Ethers Using Oxazaborolidine Reagents. The Enantioselective Synthesis of Cyclic Amino Alcohols,”
Tetrahedron Letters
, 36:25, 4337-4440 (1995); Cho, B. T. and Ryu, M. H., “Asymmetric Borane Reduction of Ketoxime O-Trimethylsilyl Ethers Mediated by a Chiral 1,3,2-Oxazaborolidine Derived from (−)-Ephedrine,”
Bull. Korean Chem. Soc
., 15:3, 191-192 (1994); and Shimizu, M. et al., “Stereocontrol in the Reduction of 1,2-Diimine with an Oxazaborolidine Catalyst. Highly Stereoselective Preparation of (R,R)-1,2-Diphenylethylenediamine,”
Tetrahedron Letters
, 36:47, 8607-8610 (1995).
Borane-tetrahydrofuran complex and other borane reagents may be prepared in a manner to maintain the concentration of borohydride species in the borane-tetrahydrofuran complex below a desired level (for example, below approximately 0.005 moles per mole of BH
3
in the case of borane-tetrahydrofuran complex. For example, borane-tetrahydrofuran complex may be prepared by the addition of diborane to tetrahydrofuran with a known amount of a borohydride stabilizer. In that regard, a known amount of a borohydride stabilizer can be added. As used herein, the term “borohydride stabilizer” refers generally to borohydride compounds such as sodium borohydride and to compound(s) that generate a borohydride species within the borane-tetrahydrofuran complex. Alternatively, borane-tetrahydrofuran complex can be made without using a borohydride stabilizer. Preferably, borane-tetrahydrofuran complex is stored at or below 20° C. before the reduction reaction to reduce decomposition.
Borane-tetrahydrofuran complex and other borane reagents may also be prepared with a concentration of borohydride species greater than a desired threshold concentration (for example 0.005 moles per mole of BH
3
in the case of borane-tetrahydrofuran complex), and the concentration of borohydride species decreased before the reduction reaction. The concentration of borohydride species may, for example, be decreased by the addition of a Lewis acid. Example of a suitable Lewis acid include BF
3
, BF
3
etherate complex (for example, BH
3
—THE), ZrCl
4
, AlCl
3
, FeCl
3
or TiCl
4
.
In the case of borane-tetrahydrofuran complex,

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