Corey-Bakshi-Shibata reduction ketone reductions

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

The Corey-Bakshi-Shibata reduction (CBS reduction) is a highly enantioselective method for arylketones, diaryl ketones, and dialkylketones. In addition, cyclic a,p-unsaturated ketones, acyclic a,p-unsaturated ketones, and a,p-ynones are reduced enantioselectively in a 1,2-fashion. The high enantioselective nature of this reduction relies on the chiral oxazaborolidine catalyst, shown in the reaction scheme, in the presence of borane or a dialkylborane. Reviews (a) Singh, V. K. Synthesis 1992, 605-617. (b) Deloux, L. Srebnik M. Chem. Rev. 1993,93,163-1. (c) Corey, E. J. Helal, C. J. Angew. Chem. Int. Ed. 1998, 37. 1986-2012. 

The reduction of ketones by borane catalyzed by chiral oxazaborolidines such as (136), derived from the enantiomeric amino alcohols, has been applied to the synthesis of several drug candidates (127). This system is known as the CBS (Corey, Bakshi, Shibata) reduction (153), and Corey himself has applied it to the synthesis of pharmaceutical compounds (154). A further example is provided by the synthesis of MK-499 (137), a... 

Scheme 5.7 Fluorous Corey-Bakshi-Shibata reduction of ketones.

One popular method that has been apphed to industrial processes for the enantio-selective reduction of prochiral ketones, leading to the corresponding optically active secondary alcohols, is based on the use of chiral 1,3,2-oxazaborolidines. The original catalyst and reagent system [diphenyl prolinol/methane boronic acid (R)] is known as the Corey-Bakshi-Shibata reagent. Numerous examples... 

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]. 

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-... 

The Corey-Bakshi-Shibata (CBS) reduction1 employs the use of borane in conjunction with a chiral oxazaborolidine catalyst to conduct enantioselective reductions of ketones. 

The CBS (Corey-Bakshi-Shibata) reagent is a chiral catalyst derived from proline. Also known as Corey s oxazaborolidine, it is used in enantioselective bo-rane reduction of ketones, asymmetric Diels-Alder reactions and [3 + 2] cycloadditions. 

If we first consider purely organic systems, one can mention the asymmetric reduction of ketmies with borane promoted by a chiral oxazaborolidine 1 developed by Corey, Bakshi, and Shibata (CBS reduction. Scheme 1) [13,14]. In this system, the nitrogen atom of the oxazaborolidine serves as Lewis base and coordinates BH3 thus improving its nucleoplulicity, while the endocyclic boron atom acts as the Lewis acid and activates the ketone toward the reduction. This seminal work constimtes an early example of metal-free catalysis and shows that cooperative effects can emerge from ambiphilic Lewis acid/base catalytic system. 

Addition of alkenylzinc 322 to the aldehyde 321 resulted in a diastere-omer mixture (1 1) of allylic alcohol, which was oxidized to afford ketone 303. Although Terashima s asymmetric aluminum reagent did not give the desired alcohol, the asymmetric borohydride reduction catalyzed by the Corey-Bakshi-Shibata reagent gave a 5 1 mixture of separable diastereomers, in favor of the (17J )-alcohol 323. Finally, protective group manipulation and oxidations led to a seco-acid, which was subjected to Yonemitsu-modified Ya-maguchi macrolactonization to yield the macrocycle (201) (Scheme 68). 

The use of boranes has attracted considerably more interest over the last several decades and particularly the use of chiral oxazaborolidine catalysts in combination with borane as a stoichiometric reducing agent (the well-known Corey-Bakshi-Shibata (CBS) reduction) (564, 565) represents one of the most important and versatile methods for the stereoselective reduction of prochiral ketones. It is not intended to give a detailed overview of the successful applications of this versatile methodology for complex (natural product) synthesis, as this would be far beyond the scope of this volume. Instead two examples are chosen below to highlight the potential of this method, especially when used for highly selective late-stage modifications (566,567). 

A series of / -hydroxyamide derivatives of salicylic acid and chiral amino alcohols were synthesized to be used as the most effective catalyst for the enantioselective reduction of a prochiral ketone. Different substituted prochiral ketones are reduced to the corresponding secondary alcohols in yields up to 99% and enantiomeric excess up to 86%. The mechanism for this type of catalyst can be explained by considering the reaction mechanism for the Corey-Bakshi-Shibata catalyst. ... 

The pioneering work from Itsuno group [11-14] on stoichiometric 1,2-aminoalcohol-borane complex-mediated borane reduction of ketones led to the discovery of well-defined oxazaborolidine catalyzed asymmetric reduction by Corey and coworkers [15-18]. Known as Corey-Bakshi-Shibata reaction, or CBS reduction, this reaction has become a standard method for making chiral secondary alcohols for complex molecule synthesis [19]. The generally accepted mechanism of this reaction is shown in Fig. 2. Coordination of the electrophilic reductant BH3 to the nitrogen atom of... 

Borane is one of the most common agents for reducing C=0 and C=N bonds and its applications for the enantioselective reduction of ketones and imines have been extensively studied in past decades [77]. Among such agents, the Corey-Bakshi-Shibata (CBS) catalyst, a chiral oxazaborolidine complex, which was discovered by Itsuno in 1981 [78] and further developed by Corey in 1987 [79], was widely considered as the most successful catalytic system. Several excellent reviews are already available [77a, 80]. In this chapter, we only give limited coverage of the organocatalytic asymmetric reduction of ketones by catalytic systems other than chiral oxazaborolidines. 

Addition of triethylamine to the oxazaborolidine reaction system can significantly increase the enantioselectivity, especially in dialkyl ketone reductions.79 In 1987, Corey et al.80 reported that the diphenyl derivatives of 79a afford excellent enantioselectivity (>95%) in the asymmetric catalytic reduction of various ketones. This oxazaborolidine-type catalyst was named the CBS system based on the authors names (Corey, Bakshi, and Shibata). Soon after, Corey s group81 reported that another fi-methyl oxazaborolidine 79b (Fig. 6-6) was easier to prepare and to handle. The enantioselectivity of the 79b-catalyzed reaction is comparable with that of the reaction mediated by 79a (Scheme 6-36).81 The -naphthyl derivative 82 also affords high enantioselectivity.78 As a general procedure, oxazaborolidine catalysts may be used in 5-10 mol%... 

Borane reduction catalyzed by chiral oxazaborolidines (CBS reduction, CBS = Corey, Bakshi, and Shibata) exhibits excellent enantio- and chemoselectiv-ity for a wide variety of ketonic substrates (Figure 1.27). This reaction was originally developed as a stoichiometric system consisting of diphenylvalinol and borane, ° but was later extended to a useful catalytic method. Because of the high efficiency of this reaction, many chiral oxazaborolidines have been synthesized from p-amino alcohols.Among them the prolinol-derived oxazaboro-lidine is one of the most widely used catalysts. ... 

Degni, S., Wilen, C.-E. and Rosling, A. Highly Catalytic Enantioselective Reduction of Aromatic Ketones using Chiral Polymer-supported Corey, Bakshi, and Shibata Catalysts. Tetrahedron Asymmetry 2004, 15, 1495-1499. 

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. 

Enantioselective Ketone Reduction. After the pioneering work of Itsuno et al., Corey s group isolated the 1,3,2-oxazaborolidine derived from chiral a,a-diphenyl-2-pyrrolidinemethanol (2) and applied it (and also other related B-alkyl compounds) to the stereoselective reduction of ketones with borane-tetrahydrofuran, borane-dimethyl sulfide (BMS) or catecholborane.It was named the CBS method (after Corey, Bakshi, and Shibata). Since then, the CBS method has become a standard and has been extensively used, specially for aromatic and a,p-unsaturated ketones, not only in academic laboratories but also in industrial processes. ... 

Price, M. D., Sui, J. K., Kurth, M. J., Schore, N. E. Oxazaborolidines as Functional Monomers Ketone Reduction Using Polymer-Supported Corey, Bakshi, and Shibata Catalysts. J. Org. Chem. 2002, 67, 8086-8089. 

In 1987, Corey, Bakshi and Shibata demonstrated that the enantioselective reduction of ketones could be catalysed by oxazaborolidines. They showed that acetophenone was reduced only slowly by BHs-THF alone, and that oxazaborohdine (3.114) alone did not cause reduction. However, in combination they reduced acetophenone in one minute at room temperature. Using just 2.5 mol% of oxazaborolidine, and stoichiometric BHs-THF still provided excellent enantios-electivity. In the same initial commimication, proline-derived oxazaborolidine (3.115) was identified as a catalyst that was suitable for the reduction of a range of ketones, including acetophenone (3.32) and ketones (3.116) and (3.117). 

Catalyst (3.115) is often referred to as the CBS catalyst after the names of the original authors (Corey, Bakshi and Shibata). A catalytic cycle was proposed which explains the experimental observations. The oxazaborolidine interacts reversibly with borane, which then allows complexation of the ketone to give the key intermediate (3.122), as depicted in Figure 3.2. In this process the catalyst acts as both a Lewis acid and Lewis base activating the borane towards hydride delivery and the ketone towards reduction by interaction with the boron in the oxazaborolidine. This dual activation and enhanced steric bulk of the pyrrolidine moiety leads to... 

---