Oxazaborolidine synthesis

SCHEME 23.38 Chiral oxazaborolidine synthesis via reaction of n-BuBClj with (5)-l,l-diphenyl-... 

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... 

The synthesis of the trisubstituted cyclohexane sector 160 commences with the preparation of optically active (/ )-2-cyclohexen-l-ol (199) (see Scheme 49). To accomplish this objective, the decision was made to utilize the powerful catalytic asymmetric reduction process developed by Corey and his colleagues at Harvard.83 Treatment of 2-bromocyclohexenone (196) with BH3 SMe2 in the presence of 5 mol % of oxazaborolidine 197 provides enantiomeri-cally enriched allylic alcohol 198 (99% yield, 96% ee). Reductive cleavage of the C-Br bond in 198 with lithium metal in terf-butyl alcohol and THF then provides optically active (/ )-2-cyclo-hexen-l-ol (199). When the latter substance is treated with wCPBA, a hydroxyl-directed Henbest epoxidation84 takes place to give an epoxy alcohol which can subsequently be protected in the form of a benzyl ether (see 175) under standard conditions. 

In the same area, a (5)-tryptophan-derived oxazaborolidine including a p-tolylsulfonylamide function has been used by Corey et al. to catalyse the enantioselective Diels-Alder reaction between 2-bromoacrolein and cyclo-pentadiene to form the corresponding chiral product with an unprecedented high (> 99% ee) enantioselectivity (Scheme 5.27)." This highly efficient methodology was extended to various 2-substituted acroleins and dienes such as isoprene and furan. In addition, it was applied to develop a highly efficient total synthesis of the potent antiulcer substance, cassiol, as depicted in Scheme 5.21... 

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. 

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 chiral oxazaborolidines introduced in Section 2.1.3.5 as enantioselective aldol addition catalysts have also been found to be useful in Diels-Alder reactions. The tryptophan-derived catalyst A, for example, can achieve 99% enantioselectivity in the Diels-Alder reaction between 5-benzyloxymethyl-l,3-cyclopentadiene and 2-bromopro-penal. The adduct is an important intermediate in the synthesis of prostaglandins.64... 

Highly enantioenriched 4-alken-l-yn-3-ol moieties present in many bioactive acetylenic metabolites from sponges have been efficiently obtained by reduction of the parent 1-trimethylsilyI-4-alken-l-yn-3-one 18 with Alpine-borane or with BH3-SMe2 in the presence of chiral oxazaborolidines, followed by desilylation of the resulting alcohol. This strategy has been applied to the first stereoselective synthesis of petrofuran 19 <99SL429>. 

The first described synthesis of the enantiomeric cetirizine employed resolution of a ( )-chlorobenzhydrylainine as the salt with tartaric acid. Later, an asymmetric synthesis was reported by the Corey group in 1996 (Scheme 7). The pivotal step involved a chiral oxazaborolidine (CBS)-catalyzed reduction of an unsymmetrical chlorobenzophenone with a Tt-chromium tricarbonyl group serving as an effective... 

Organometallic compounds asymmetric catalysis, 11, 255 chiral auxiliaries, 266 enantioselectivity, 255 see also specific compounds Organozinc chemistry, 260 amino alcohols, 261, 355 chirality amplification, 273 efficiency origins, 273 ligand acceleration, 260 molecular structures, 276 reaction mechanism, 269 transition state models, 264 turnover-limiting step, 271 Orthohydroxylation, naphthol, 230 Osmium, olefin dihydroxylation, 150 Oxametallacycle intermediates, 150, 152 Oxazaborolidines, 134 Oxazoline, 356 Oxidation amines, 155 olefins, 137, 150 reduction, 5 sulfides, 155 Oxidative addition, 5 amine isomerization, 111 hydrogen molecule, 16 Oxidative dimerization, chiral phenols, 287 Oximes, borane reduction, 135 Oxindole alkylation, 338 Oxiranes, enantioselective synthesis, 137, 289, 326, 333, 349, 361 Oxonium polymerization, 332 Oxo process, 162 Oxovanadium complexes, 220 Oxygenation, C—H bonds, 149... 

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. 

Y. Y. Chu, Y. Synthetic studies on d-biotin, part 6 an expeditious and enantiocontrolled approach to the total synthesis of d-biotin via a polymer-supported chiral oxazaborolidine-cata-lyzed reduction of meso-cyclic imide strategy. Synthesis 2003, 2155-2160. 

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... 

The asymmetric reduction of ketones by borane catalyzed by oxazaborolidines has been widely studied since the beginning of the 1980s. Despite the use of borane complexes, which are hazardous chemicals, this reaction is an excellent tool to introduce the chirality in a synthesis and has demonstrated its usefulness in industrial preparation of chiral pharmaceutical intermediates. As a result of its performance, versatility, predictability, and scale up features, this method is particularly suitable for the rapid preparation of quantities of complex chiral molecules for clinical trials. 

Many chiral auxiliaries are derived from 1,2-amino alcohols.7 These include oxazolidinones (l),7-9 oxazolines (2),10 11 bis-oxazolines (3),1213 oxazinones (4),14 and oxazaborolidines (5).15-17 Even the 1,2-amino alcohol itself can be used as a chiral auxiliary.18-22 Other chiral auxiliaries examples include camphorsultams (6),23 piperazinediones (7),24 SAMP [(S)-l-amino-2-methoxy-methylpyrrolidine] (8) and RAMP (ent-8),25 chiral boranes such as isopinocampheylborane (9),26 and tartaric acid esters (10). For examples of terpenes as chiral auxiliaries, see Chapter 5. Some of these auxiliaries have been used as ligands in reagents (e.g., Chapters 17 and 24), such as 3 and 5, whereas others have only been used at laboratory scale (e.g., 6 and 7). It should be noted that some auxiliaries may be used to synthesize starting materials, such as an unnatural amino acid, for a drug synthesis, and these may not have been reported in the primary literature. 

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. 

After the identification of aprepitant as a clinical candidate, Merck invested considerable process research toward an improved synthesis of aprepitant, which culminated in the elegant manufacturing process shown in Scheme 6.21,22 The key step relies on displacement of a trifluoroacetate from intermediate 48 by the optically active alcohol intermediate 49. The synthesis of 49 was accomplished via an oxazaborolidine-catalyzed borane reduction of the corresponding acetophenone. Although the displacement resulted in an almost equal mixture of the two diastereomers 50 and 51, the desired diastereomer 50 could be recovered in high yield by base-catalyzed equilibration of the mixture and crystallization. Addition of p-fluorophenyl magnesium bromide followed by hydrogenolysis afforded the key intermediate 40, which can be readily converted to 1 as detailed in the previous synthesis. 

In the synthesis of (—)-hennoxazole (37), Wipf and Lim used a CBS reagent to prepare the chiral allylic alcohol 3918 (Scheme 4.3n). The enantioselective reduction of the enone 38 using a catalytic amount of the oxazaborolidine 28b... 

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