Ketones enantioselective reduction using oxazaborolidines

For aryl ketones the Corey-Bakshi-Shibata (CBS) reduction using oxazaborolidines as catalysts for the boron hydride mediated hydrogenation is particularly useful, with maximum selectivities up to 99 % ee (see Scheme 4) [34]. The excellent review by Corey et al. [35] also shows clearly the power for chemo- and enantioselective reduction of purely aliphatic a,//-enones and -ynones only on the carbonyl group. In the re-... 

Chiral Ligand of LiAlH4 for the Enantioselective Reduction of a,p-Unsaturated Ketones. Enantioselective reductions of a,p-unsaturated ketones afford optically active ally lie alcohols which are useful intermediates in natural product synthesis. Enantioselective reduction of a,p-unsaturated ketones with LiAlH4 modified with chiral amino alcohol (1) affords optically active (S)-allylic alcohols with high ee s. When 2-cyclohexen-l-one is employed, (5)-2-cyclohexen-l-ol with 100% ee is obtained in 95% yield (eq 2). This is comparable with the results obtained using LiAlH4-chiral binaphthol and chiral 1,3,2-oxazaborolidine. ... 

Enantioselective Ketone Reduction. Following Itsuno s lead for enantioselective reductions using diphenylvalinol, Kraatz was the first to describe the use of a 1 2 mixture of (5)-diphenylprolinol (1) and Borane-Tetrahydrofuran for the stoichiometric enantioselective reduction of ketone (2) to obtain the plant growth regulator triapenthenol (3) (eq 1). Although not characterized at the time, the species responsible for the enantiose-lectivity observed was presumed to be an oxazaborolidine-borane complex. ... 

Corey-Bakshi-Shibata reduction Enantioselective reduction of ketones with BH3 using oxazaborolidines as catalysts. 100... 

Other aromatic ketones are also reduced highly enantioselectively by using oxazaborolidine catalyst. Representative data for the reduction of other aromatic ketones (53 to 58) are collected in Fig. 2. 

Catalytic Enantioselective Reduction of Ketones. An even more efficient approach to enantioselective reduction is to use a chiral catalyst. One of the most developed is the oxazaborolidine 18, which is derived from the amino acid proline.148 The enantiomer is also available. These catalysts are called the CBS-oxazaborolidines. 

Scheme 5.6. Enantioselective Reduction of Ketones Using CBS-Oxazaborolidine... 

Enantioselective reduction of ketones using n-arylsulfonyl oxazaborolidines... 

ENANTIOSELECTIVE REDUCTION OF KETONES USING N-ARYLSULFONYL OXAZABOROLIDINES... 

Enantioselective reduction of ketones.1 The ability of diborane in combination with the vic-amino alcohol (S)-2-amino-3-methyl-l,l-diphenyl-l-butanol (12, 31) to effect enantioselective reduction of alkyl aryl ketones involves formation of an intermediate chiral oxazaborolidine, which can be isolated and used as a catalyst for enantioselective borane reductions (equation I). 

As an example of non-enzymatic catalyst using oxazaborolidines [10], Corey and his associates have described an efficient synthesis of (-i-)-l(S),5(R),8(S)-8-phenyl-2-azabicyclo[3.3.0]octan-8-ol (2.) and its enantiomer. The B-methyloxazaborolidine derivatives (3) of these amino alcohols are excellent catalysts -or chemzymes- for the enantioselective reduction of a variety of achiral ketones to chiral secondary alcohols [11]. 

The enantioselective reduction of ketones using oxazaborolidine-borane complexes is a useful synthetic route to chiral alcohols (equation 63). Additives such as simple alcohols have been found to enhance the enantioselectivity of the process, and the reaction has been used in the large-scale synthesis of an important drug with anti arrhythmic properties249. 

The use of oxazaborolidines as asymmetric reduction catalysts257 and the enantioselectivity of diphcnyloxazaborolidinc reduction of ketones have been reviewed.258 Large-scale practical enantioselective reduction of prochiral ketones has been reviewed with particular emphasis on the Itsuno-Corey oxazaborolidinc and Brown s 5-chlorodiisopinocampheylborane (Ipc2BCl) as reagents.259 Brown himself has also reviewed the use of Ipc2BCl.260 Indolinoalkylboranes in the form of dimers have been confirmed by 11B NMR as the products of the reduction of trifluoroacetylindoles by diborane.261... 

The enantioselective reduction of ketones using borane and a chiral oxazaborolidine as catalyst (CBS Catalyst). Usually, MeCBS... 

Reduction of ketones. Merck chemists3 have used oxazaborolidine-catalyzed reduction of a ketone for introduction of chirality in a synthesis of MK-927 (4), a carbonic anhydrase inhibitor. They found that even traces of water decreases the enantioselectivity in reductions of 2. Highest enantioselectivity (98 2) is obtained by... 

Building on the excellent work of Itsuno,9 10 who first described the use of oxazaborolidine as a chiral ligand, and of Kraatz,11 Corey was the first to report the enantioselective reduction of ketones to chiral secondary alcohols in the presence of an oxazaborolidine in substoichiometric amounts.12 13 This general method was named the CBS method (Scheme 16.1). 

The organocatalytic enantioselective reduction of C=C, C=0, and C=N double bonds is a relatively young area for which many new and exciting developments can be expected in the near future. Hantzsch esters are useful organic hydrides, and a recent review has summarized the results obtained to date in organocataly-sis [27]. The case of silicon hydrides is convenient for imine or ketone reductions, as a chiral base can act as an organic catalyst. The asymmetric reductions of ketones catalyzed by oxazaborolidines and pioneered by Itsuno [28] and Corey [29] could not be included in this chapter. 

The pioneering studies by Itsuno [1] and Corey [2] on the development of the asymmetric hydroboration of ketones using oxazaborolidines have made it possible to easily obtain chiral secondary alcohols with excellent optical purity [3]. Scheme 1 shows examples of Corey s (Corey-Bakshi-Shibata) CBS reduction. When oxazaborolidines 1 were used as catalysts (usually 0.01-0.1 equiv), a wide variety of ketones were reduced by borane reagents with consistently high enan-tioselectivity [2]. The sense of enantioselection was predictable. Many important biologically active compounds and functional materials have been synthesized using this versatile reaction [2-4]. 

In 1987, Corey and co-workers proved that highly enantioselective reduction of ketones could be achieved by using stoichiometric borane in the presence of catalytic amounts of the oxazaborolidine 28a11 (Scheme 4.3j). Compound 28a, synthesized by heating (S)-(-)-2-(diphenylhydroxymethyl)pyrrolidine at reflux in THF with 3 equivalents of BH3 THF, shows excellent catalytic activity for the asymmetric reduction of acetophenone and other ketones. The B -methylated analog 28b was later synthesized to improve the air and moisture sensitivity associated with 28a. The third analog, 28c, with a 2-naphthyl substituent on the oxazaborolidine ring, has proven to be the best to afford the alcohol 29 with superb levels of enantioselectivity. 

The oxazaborolidine-catalyzed enantioselective reduction of aryl alkyl ketones was used in the asymmetric synthesis of the naturally occurring molecule (15 )-(—)-salsolidine 4119 (Scheme 4.3o). The ketone 42 underwent oxazaboroli-dine-mediated reduction to furnish the alcohol 43 in excellent yield and greater than 95% ee. The alcohol 43 was then coupled with the reagent 44 under Mit-sunobu conditions to produce the aminoacetal 45. 

C. The reported procedure provides a practical preparation of (S)-tetrahydro-i-methyl-3,3-diphenyl-lH,3H-pyrrolo[i,2-c][l,3,2]oxazaboroie and conversion to its more stable borane complex.13 The oxazaborolidine-borane complex has also been prepared by treatment of a toluene solution of the free oxazaborolidine with gaseous fiborane followed by recrystallization from a dichloromethane-hexane bilayer.14 This nd other chiral oxazaborolidines have been used to catalyze the enantioselective eduction of prochiral ketones.15 The yield and enantioselectivity of reductions using catalytic amounts of the oxazaborolidine-borane complex are equal to or greater than those obtained using the free oxazaborolidine.13... 

D. The use of chiral oxazaborolidines as enantioselective catalysts for the reduction of prochiral ketones, imines, and oximes, the reduction of 2-pyranones to afford chiral biaryls, the addition of diethylzinc to aldehydes, the asymmetric hydroboration, the Diels-Alder reaction, and the aldol reaction has recently been reviewed.15b d The yield and enantioselectivity of reductions using stoichiometric or catalytic amounts of the oxazaborolidine-borane complex are equal to or greater than those obtained using the free oxazaborolidine.13 The above procedure demonstrates the catalytic use of the oxazaborolidine-borane complex for the enantioselective reduction of 1-indanone. The enantiomeric purity of the crude product is 97.8%. A... 

Several novel catalysts in which borohydride is complexed with a difiinctional chiral ligand have been developed and used for the enantioselective reduction of prochiral ketones to chiral alcohols. Corey-Bakshi-Shibatareduction (CBS reduction) is an organic reaction which reduces ketones enantioselectively into alcohols by using chiral oxazaborolidines and BHs-THF or catecholborane as stoichiometric reductants (CBS reagent, 1.64) (also see Chapter 6, section 6.4.2). 

Enantioselective reduction of ketones by boranes and an enantiomeric catalyst oxazaboro-lidine (the CBS catalyst) is known as the Corey, Bakshi and Shibata method . Both enantiomers of 2-methyl-CBS-oxazaborolidine (6.52 and 6.53) are used for the reduction of prochiral ketones, imines and oximes to produce chiral alcohols, amines and amino alcohols in excellent yields and enantiomeric excesses. 

Recently, Katz employed oxazaborolidine (2) to catalyze the enantioselective reduction of ketone (7) (eq 6). The resultant carbinol was used for the synthesis of optically active helical metallocene oligimers. ... 

Enantioselective Reduction of Oxime 0-Ethers. In addition to the reduction of prochiral ketones, oxazaborolidine (3) has been used (both stoichiometrically and catalytically with borane-THF) to catalyze the enantioselective reduction of prochiral ketoxime O-ethers to the corresponding amine (eq Unlike the ketone reduction described above, the... 

Corey demonstrated that oxazaborolidine (6) can be used cat-alytically (2.5-100 mol %) with excess borane (60-200 mol %) for the enantioselective reduction of prochiral ketones (eq 3 Table 1). ... 

Table 1 Catalytic Enantioselective Reduction of Ketones using Oxazaborolidine (5)-(6)...

Enantioselective Reduction of a,p-Enones. Oxazaborolidine catalyst Ic was also found to be a superior catalyst compared to la and lb for the reducdon of a,p-unsaturated ketone derivatives (eq 5). It is interesdng to note that the presence of a bulky substituent at the p-posidon is mandatory for high enandocon-trol. This reaction has been used as a key step in the synthesis of atractyligenin. This catalyst has also been used to reduce a,p-unsaturated ketones bearing a trifluoromethyl group in 87% ee. ... 

The use of membrane reactors is favorable not only with respect to an increase in the total turnover number. In certain cases the selectivity can also be increased by applying high concentrations of the soluble catalyst together with making use of the behavior of a continuously operated stirred-tank reactor. Basically, this is also possible with a catalyst coupled to an insoluble support, but here the maximum volumetric activity is limited by the number of active sites per mass unit of the catalyst. This has been shown for the enantioselective reduction of ketones (eq. (2)) such as acetophenone 5 with borane 6 in the presence of polymer-enlarged oxazaborolidines 8 and 9 [65-67]. 

Nevalainen, V. Quantum chemical modeling of chiral catalysis. Part 17. On the diborane derivatives of chiral oxazaborolidines used as catalysts in the enantioselective reduction of ketones. Tetrahedron Asymmetry 1994, 5, 395-402. 

For the enantioselective reduction of cyclic meso-imides and 1 -siloxy-2-alkanones, 1,2-reduction of other enones,the prototypal chiral bicyclic oxazaborolidine is adequate, although 81 has been used to reduce a-phenylthio-p-phenyl ketones to obtain precursors of a-hydroxy thioesters. The enantiomer of 81 mediates reduction of enediones to the corresponding chiral diols. ... 

---