Oxazaborolidine, complex with

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). 

Oxazaborolidine catalyzed reductions are generally performed in an aprotic solvent, such as dichloromethane, THF, or toluene. When the reactions are run in a Lewis basic solvent, such as THF, the solvent competes with the oxazaborolidine to complex with the borane, which can have an effect on the enantioselectivity and/or rate of the reaction. The solubility of the oxazaborolidine-borane complex can be the limiting factor for reactions run in toluene, although this problem has been circumvented by using oxazaborolidines with more lipophilic... 

Treatment of the amino alcohol with borane provides the oxazaborolidine catalyst, which presumably complexes with borane to provide the reducing agent. 

The enantioselective reduction of acylpyridines has been improved by the addition of trimethoxyborane to the oxazaborolidine reagent <97SL273, 97T12405>. An alkyl pyridyl sulfoxide is resolved by complexation with a chiral host compound derived from tartaric acid <97TA2505>. 

Enantiomerically pure boron-based Lewis acids have also been used successfully in catalytic aldol reactions. Corey s catalyst (7.10a) provides good enantioselectivity with ketone-derived silyl enol ethers, including compound (7.11). Other oxazaborolidine complexes (7.13) derived from a,a-disubstituted a-amino acids give particularly high enantioselectivity, especially with the disubstituted ketene... 

Based on this strategy, Garcia et al. have used oxazaborolidine, (R)-2, and effectively reduced several a,p-acetylenic ketones. The e.e. value of the products was in the range 90 to 97%. To improve the results further, the monobranched ketones were complexed with hexacarbonyl dicobalt complexes and snbjected to reduction. Unfortunately, the reactions were sluggish and under forced conditions or modifications of oxazaborolidine resnlled only in low yields and enantioselectives (Table 21.3). 

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... 

The characteristic feature of the aforementioned oxazaborolidine catalyst system consists of a-sulfonamide carboxylic acid ligand for boron reagent, where the five-membered ring system seems to be the major structural feature for the active catalyst. Accordingly, tartaric acid-derived chiral (acyloxy)borane (CAB) complexes can also catalyze the asymmetric Diels-Alder reaction of a,P-unsaturated aldehydes with a high level of asymmetric induction [10] (Eq. 8A.4). Similarly, a chiral tartrate-derived dioxaborolidine has been introduced as a catalyst for enantioselective Diels-Alder reaction of 2-bromoacrolein [11] (Eq. 8A.5). 

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 mechanism of the atroposelective ring opening of a lactone-bridged biaryl, dinaphtho[2,l-t l, 2 -< ]oxepin-3(5//)-one, with a chiral oxazaborolidine-BH3 complex (Scheme 2) was studied using semi-empirical AMI calculations <2000JOC2517>. 

The mechanism A very detailed mechanistic study of this phosphoramide-catalyzed asymmetric aldol reaction was conducted by the Denmark group (see also Section 6.2.1.2) [59, 60], Mechanistically, the chiral phosphoramide base seems to coordinate temporarily with the silicon atom of the trichlorosilyl enolates, in contrast with previously used chiral Lewis acids, e.g. oxazaborolidines, which interact with the aldehyde. It has been suggested that the hexacoordinate silicate species of type I is involved in stereoselection (Scheme 6.15). Thus, this cationic, diphosphoramide silyl enolate complex reacts through a chair-like transition structure. 

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. 

The CBS reduction has also proven to be an efficient method for asymmetric reduction of a,ft-unsaturated enones14 and ynones15 (Scheme 4.31). The asymmetric reduction of alkynyl ketones affords propargylic alcohols 30 with high levels of enantioselectivity and in moderate to good yields. Optimized reaction conditions for the reduction are the use of THF at — 30° C, 2 equivalents of chiral oxazaborolidine 28b, and 5 equivalents of borane methyl sulfide complex. 

The product is stored at room temperature protected from moisture. A nitrogen atmosphere is recommended for long term storage. Unlike the free oxazaborolidine that readily reacts with and is decomposed by atmospheric moisture, the oxazaborolidine-borane complex is significantly more stable, allowing it to be handled briefly in the open. 

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... 

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