Oxazaborolidines, chiral reductions

Chiral oxazaborolidines. Enantioselective reduction of ketones with a reagent prepared from BH, and the chiral vic-amino alcohol 1 (12,31) is now known to involve an oxazaborolidine. Thus BH3 and (S)-l, derived from valine, react rapidly in THF to form 2, m.p. 105-110°, which can serve as an efficient catalyst... 

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. ... 

The chiral reduction of phenacyl chloride (2) was run using either the methyl- or methoxy- oxazaborolidine (3) as the catalyst. After optimization of the reaction... 

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... 

In particular, reduction of unsymmetric ketones to alcohols has become one of the more useful reactions. To achieve the selective preparation of one enantiomer of the alcohol, chemists first modified the classical reagents with optically active ligands this led to modified hydrides. The second method consisted of reaction of the ketone with a classical reducing agent in the presence of a chiral catalyst. The aim of this chapter is to highlight one of the best practical methods that could be used on an industrial scale the oxazaborolidine catalyzed reduction.1 1 This chapter gives an introductory overview of oxazaborolidine reductions and covers those of proline derivatives in-depth. For the oxazaborolidine derivatives of l-amino-2-indanol for ketone reductions see Chapter 17. 

Delorme and coworkers have published a stereoselective route that is effective with a wide range of amines, including those without a stereocenter on the amine (Scheme 8) [43]. Chiral reduction of the appropriate benzophe-none (as a chromium tricarbonyl complex) using Corey s oxazaborolidine approach afforded the benzhydrol with 91% ee. Treatment with tetrafluo-roboric acid followed by the piperazine gave the desired benzhydryl piperazine without any erosion of stereochemical purity after decomplexation. In addition to simplifying analogue synthesis, these two complementary routes provide a useful base for the future development of stereoselective manufacturing routes. 

Table 1 Chiral Oxazaborolidine Catalyzed Reduction of Acetophenone and 1-Tetralone ...

Oxazaborolldines have emerged as important reagents for the enantioselective reduction of a variety of prochiral ketones. CBS reduction (chiral oxazaborolidine-catalyzed reduction)of unsymmetrical ketones with diphenyl oxazaborolidine in the presence of BH3 proceeds catalytically to provide alcohols of predicable absolute stereochemistry in high enantiomeric excess. 

The third approach to obtain diarylmethylpiperazine derivatives uses the highly stereospecific chiral oxazaborolidine-catalyzed reduction, using catecholborane as the reductant of the 4-bromobenzophenone chromium tricarbonyl complex, as described by Corey and Helal [59], followed by the stereospecific displacement of the hydroxyl benzyl group by the /V-substituted-piperazine [44]. As outlined in Scheme 2, Delorme et al. [44] used this approach for the enantioselective synthesis of compound 31, (+)-4-[ (aS)-a-(4-benzyl-l-piperazinyl)benzyl]-lV,lV-diethylben-zamide. Lithiation of the readily available benzene chromium tricarbonyl with n-BuLi in the presence of TMEDA in THF at —78 °C, followed by addition of... 

Deprotonation with n-butyllithium and addition of aldehyde 148 generated alcohol 149 as a 2 l-diastereomeric mixture. Again the stereochemistry at the newly created center was corrected by an oxidation reduction sequence via ketone 151. This time the chiral reduction had to be performed with using Corey s oxazaborolidine catalysts (19). In this way both the (31 )- and (3S)-diastereomer of alcohol were available. LAH-reduction of (3S)-149 led to the -alkene 150 which was eventually oxidized to aldehyde 154 after protection-deprotection via 152 and 153. Addition of the potassium salt of pyrone 131 gave 155 as a 4 l-epimeric mixture. Removal of the PMB protective group led to selective destruction of the minor diastereomer, so that a 95 5-mixture in favor of the desired stereoisomer 156 was obtained (Scheme 26). 

Modification of the amidine function to chiral versions has been examined. For example, C2-symmetrical chiral bicylic amidine 5 was prepared for studies on molecular recognition and were proven to differentiate analytically between the enantiomers of chiral carboxylic acids [13]. Near the same time, a mannose-based amidine 6 was synthesized as a potential mannosidase inhibitor, but not a chiral auxiliary [14]. Three enantiopure hydroxyl substituted amidines 7 of the DBN-type were synthesized from 5-(phenylsulfonyl)pyrror-idine-2-one by an oxazaborolidine-catalysed reductive desymmetrization of meso-imide followed by functionalization through N-acyliminium ion [15] (Figure 3.3). 

The most successful of the Lewis acid catalysts are oxazaborolidines prepared from chiral amino alcohols and boranes. These compounds lead to enantioselective reduction of acetophenone by an external reductant, usually diborane. The chiral environment established in the complex leads to facial selectivity. The most widely known example of these reagents is derived from the amino acid proline. Several other examples of this type of reagent have been developed, and these will be discussed more completely in Section 5.2 of part B. 

Recent advances in the asymmetric catalytic reduction of ketones using chiral oxazaborolidines as ligands 98MI64. 

Reduction of carbonyl compounds with chiral oxazaborolidine catalysts 98AG(E)1987. 

Corey, E.J. Helal, C.J. (1998) Reduction of Carbonyl Compounds with Chiral Oxazaborolidine Catalysts A New Paradigm for Enantioselective Catalysis and a Powerful New Synthetic Method. Angewandte Chemie International Edition, 37, 1986-2012. 

Other S/N ligands have been investigated in the enantioselective catalytic reduction of ketones with borane. Thus, Mehler and Martens have reported the synthesis of sulfur-containing ligands based on the L-methionine skeleton and their subsequent application as new chiral catalysts for the borane reduction of ketones." The in situ formed chiral oxazaborolidine catalyst has been used in the reduction of aryl ketones, providing the corresponding alcohols in nearly quantitative yields and high enantioselectivities of up to 99% ee, as shown in Scheme 10.60. 

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. 

Liao and Li enantioselectively synthesized and studied the antifungal activity of optically active miconazole and econazole. The key step was the enan-tioselective reduction of 2-chloro-l-(2,4-dichlorophenyl)ethanone catalyzed by chiral oxazaborolidine [10]. 

Boranes have opened the door to asymmetric reduction of carbonyl compounds. The first attempt at modifying borane with a chiral ligand was reported by Fiaud and Kagan,75 who used amphetamine borane and desoxyephedrine borane to reduce acetophenone. The ee of the 1-phenyl ethanol obtained was quite low (<5%). A more successful borane-derived reagent, oxazaborolidine, was introduced by Hirao et al.76 in 1981 and was further improved by Itsuno and Corey.77 Today, this system can provide high stereoselectivity in the asymmetric reduction of carbonyl compounds, including alkyl ketones. 

New chiral oxazaborolidines that have been prepared from both enantiomers of optically active inexpensive a-pinene have also given quite good results in the asymmetric borane reduction of prochiral ketones.92 Borane and aromatic ketone coordinate to this structurally rigid oxazaborolidine (+)- or (—)-94, forming a six-membered cyclic chair-like transition state (Scheme 6-41). Following the mechanism shown in Scheme 6-37, intramolecular hydride transfer occurs to yield the product with high enantioselectivity. With aliphatic ketones, poor ee is normally obtained (see Table 6-9). 

The reduction of dialkylketones and alkylaryl ketones is also conveniently accomplished using chiral oxazaborolidines, a methodology which emerged from relative obscurity in the late 1980s. The type of borane complex (based on (,V)-diphenyl prolinol)[39] responsible for the reductions is depicted below (10). Reduction of acetophenone with this complex gives (/ )-1 -phenylethanol in 90-95% yield (95-99% ee) [40]. Whilst previously used modified hydrides such as BiNAL-H (11), which were used in stoichiometric quantities, are generally unsatisfactory for the reduction of dialkylketones, 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). 

Surface modification of skeletal nickel with tartaric acid produced catalysts capable of enantiose-lective hydrogenation [85-89], The modification was carried out after the formation of the skeletal nickel catalyst and involved adsorption of tartaric acid on the surface of the nickel. Reaction conditions strongly influenced the enantioselectivity of the catalyst. Both Ni° and Ni2+ have been detected on the modified surface [89]. This technique has already been expanded to other modified skeletal catalysts for example, modification with oxazaborolidine compounds for reduction of ketones to chiral alcohols [90],... 

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]. 

Enantioselective borane reduction of ketones catalyzed by chiral oxazaborolidines. 

The proposed catalytic cycle for reduction of acetophenone is illustrated in Figure 1.28. The (5)-oxazaborolidine catalyst (5)-28A has both Lewis acidic and basic sites, and its borane adduct 28B acts as a chiral Lewis acid. The B center in the borolidine ring selectively interacts with a stericaUy more accessible electron... 

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