Corey’s oxazaborolidine

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. 

Gao and Kagan (172) reported the screening of several mixtures of ketones L25-L29, composed of compounds 9.98-9.111 (Pig. 9.40), as substrates for asymmetric catalytic reduction using Corey s oxazaborolidine 9.112 (173), establishing its general applicability to the generic reaction shown in Pig. 9.40, top. 

Since the first asymmetric reduction of ketones with chiral borohydrides by Itsuno et al. [ 1 ], a number of studies on the asymmetric reduction of ketones with chiral borane reagents have been demonstrated [2]. Corey s oxazaborolidines are some of the most successful reagents [3 ]. The effect of fluorine substituents was examined in the asymmetric reduction of acetophenone with LiBH4 by the use of chiral boronates (73) obtained from substituted phenyl boronic acid and tartaric acid [4]. Likewise, 3-nitro, fluorine, and trifluoromethyl groups on the 3- or 4-position provided enhanced stereoselection (Scheme 5.20). 

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). 

Ketone reductions. Corey s oxazaborolidine continues to be a popular catalyst for borane reduction. A cheap borane source for the reduction is LiH-BF3-OEt2. " There are also modifications, for example, using aluminum(III) ethoxide, and the sulfonamide derivative 85. ... 

Asymmetric reduction ofketimmes found to achieve high enaniioselectix of Itsuno, prepared from BH.t and (S derived from (S)-valine, (12,31). is the Like Corey s oxazaborolidines derised amounts. The highest enantioselectiv aromatic ketones (as high as 88% ce of N-r-butylimines of aryl ketones (8<> dialkyl ketones with 1 results in ( -... 

Asymmetric reduction of ketimines to sec-aminesf Of the various hydride reagents found to achieve high enantioselective reduction of ketones, the oxazaborolidine 1 of Itsuno, prepared from BH3 and (S)-(—)-2-amino-3-methyl-I,l-diphenylbutane-l-ol, derived from (S)-valine, (12,31), is the most effective in terms of asymmetric induction. Like Corey s oxazaborolidines derived from (S)-proline, 1 can also be used in catalytic amounts. The highest enantioselectivities obtain in reduction of N-phenylimines of aromatic ketones (as high as 88% ee). The enantioselectivities are lower in the case of N-t-butylimines of aryl ketones (80% ee). Reduction of N-phenylimines of prochiral dialkyl ketones with 1 results in 10-25% ees. 

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. 

Although the lipase resolution results looked promising, direct enantioselective 1,2-reduction of the enone would be much more efficient if appropriate conditions could be found. It was known that Corey s oxazaborolidine (CBS) catalyst would reduce 2-bromo-cyclopent-2-enone with high enantioselectivity (34) due to the large bromine atom being located alpha to the ketone. It was uncertain if 22 would reduce with enantioselectivity since the iodine atom was one atom further removed from the ketone. After an extensive effort at this reduction, our best conditions gave a 90% yield of enantioenriched 24 (3 1 S R) using 5 mol % (R) 5-methyl CBS catalyst.(i5)... 

An expedient and stereoselective synthesis of bicyclic ketone 30 exemplifies the utility and elegance of Corey s new catalytic system (see Scheme 8). Reaction of the (R)-tryptophan-derived oxazaboro-lidine 42 (5 mol %), 5-(benzyloxymethyl)-l,3-cyclopentadiene 26, and 2-bromoacrolein (43) at -78 °C in methylene chloride gives, after eight hours, diastereomeric adducts 44 in a yield of 83 % (95 5 exo.endo diastereoselectivity 96 4 enantioselectivity for the exo isomer). After reaction, the /V-tosyltryptophan can be recovered for reuse. The basic premise is that oxazaborolidine 42 induces the Diels-Alder reaction between intermediates 26 and 43 to proceed through a transition state geometry that maximizes attractive donor-acceptor interactions. Coordination of the dienophile at the face of boron that is cis to the 3-indolylmethyl substituent is thus favored.19d f Treatment of the 95 5 mixture of exo/endo diastereo-mers with 5 mol % aqueous AgNC>3 selectively converts the minor, but more reactive, endo aldehyde diastereomer into water-soluble... 

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%... 

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]. 

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. ... 

Asymmetric hydrogenation of either a carbonyl or an imino group to a hydroxyl group or an amino group has frequently been employed for the introduction of chirality in amino acid syntheses. Corey s catecolborane-oxazaborolidine protocol enables transformation of difluoromethyl ketone 1 into alcohol 2 with excellent enantioselectivity. The reaction of diastereoselective amination of a-hydroxyaldehyde 3 with A,A-diallylamine and 2-furyl-boronic acid provides furyl amino alcohol 4 in good chemical yield along with excellent diastereoselectivity. This protocol is applicable for the preparation of amino acids and amino alcohols with a trifluoromethyl group by the combination of /V,/V-diallyl or N,N-dibenzyl amine and aromatic, heteroaromatic and alkenyl boronic acids [7]. The usual chemical transformations as shown in steps 5 to 8 in Scheme 9.1 lead to (2S,3R) difluorothreonine 5 [8]. 

Scheme 6.51. Asymmetric cycloaddition of 2-bromoacrolein and cyclopenta-diene using Corey s indenyl oxazaborolidine catalyst [215,216]...

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... 

The second stereochemical problem, enantioselective reduction of the keto-group in the w-side-chain, was solved by Corey already in 1987. The reduction was successful with borane-THF in presence of 10 mole% of the (H)-prolme-derived (H)-oxazaborolidine (Corey-Bakshi-Shibata reduction). If the enone was reduced in presence of the corresponding (S)-oxazaborolidine, the inverse product distribution resulted. Obviously, the other stereocentres in the educt have no impact on the stereochemical course of the reduction at C-15. 

One of the most effective classes of asymmetric Diels-Alder catalysts is the family of chiral oxazaborolidines originally developed by Corey. In a recent example from Corey s lab, combining cyclopentadiene (42) with quinone 43 in the presence of catalyst 44 fiimishes cycloadduct 45 in 99% yield and 99% Yamamoto used a similar catalyst for enantioselective Diels-Alder reactions of a,p-unsaturated acetylenic ketones, and Paddon-Row and Houk reported a computational investigation into the reactivity of oxazaborolidine catalysts. 

Since our group (22) and Hehnchen s (23) independently announced a new class of chiral acyloxyboranes derive from iV-sulfonylamino acids and borane THF, chiral 1,3 -oxazaborolidines, their utility as chiral Lewis acid catalysts in enantioselective synthesis has been convincingly demonstrated (2(5). In particular, Corey s tryptophan-derived chiral oxazaborolidines 10a and 10b are highly effective for not only Mukaiyama aldol reactions (24) but also Diels-Alder reactions (25). More than 20 mol% of 10b is required for the former reaction, however. Actually, the reaction of the trimethylsilyl enol ether derived from cyclopentanone with benzaldehyde afforded the aldoI products in only 71% yield even in the presence of 40 mol%of 10b (24). We recently succeed in renewing 10b as a new and extremely active catalyst lOd using arylboron dichlorides as Lewis acid components (2(5). 

Yet another route to the popular Blechert intermediate (—)-402, by Bates and Dewey, started with an unusual conversion of tetrahydrofuian into 4-azidobutan-l-ol (411), which was oxidized to the aldehyde and treated with lithiated trimethylsilylacetylene to give the racemic adduct ( )-412 (Scheme 57). Oxidation to the ketone and reduction with cat-echolborane and the Corey (S)-2-methyl-CBS-oxazaborolidine produced (R)-(- -)-412, but in an ee of only about 75%. A further two steps afforded... 

Fig. 3 Application of strong Brpnsted acid-activated oxazaborolidine catalysts, and Corey s pretransition state assembly models...

Scheme 1.1 Generation of Corey s BLAs from the corresponding chiral oxazaborolidine (la) or (lb) and strong Bronsted acid.

The plausible generation of chiral LLA (9) is considered to be analogous to that of the CBS reduction system [18-20] and Corey s chiral BLAs [3-9]. Thus, the coordination of the achiral Lewis acid to the nitrogen atom of the chiral oxazaborolidine should serve to increase the Lewis acidity of boron atom. 

In an elegant demonstration of the versatility of Corey s chemzymes, Williams used the oxazaborolidine bromoborane 44 in an allylation with allylstannane 43, en route to a critical segment of phorboxazole (Scheme... 

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