CBS catalysts

Since the discovery of the CBS catalyst system, many chiral //-amino alcohols have been prepared for the synthesis of new oxazoborolidine catalysts. Compounds 95 and 96 have been prepared93 from L-cysteine. Aziridine carbi-nols 97a and 97b have been prepared94 from L-serine and L-threonine, respectively. When applied in the catalytic borane reduction of prochiral ketones, good to excellent enantioselectivity can be attained (Schemes 6-42 and 6-43). 

In a 250 mL round-bottomed flask with an argon inlet equipped with a magnetic stirring bar the CBS-catalyst (1.85 g) was dissolved in tetrahydrofuran (10 mL) and cooled to 0°C in an ice bath. From a syringe filled with borane dimethyl sulfide-complex (2.00 mL dissolved in 10 mL THF) 20% of the volume (2.40 mL) were added and the solution was stirred for 5 minutes. A solution of the diketone (3.00 g dissolved in 30 mL THF) was added from a second syringe simultaneously with the rest of the borane dimethyl sulfide-complex over 2 hours. The resulting yellow solution was stirred for another... 

Scheme 19. Corey s utilization of B-methyl CBS catalyst in the asymmetric reduction of a ketone en route to wodeshiol (1999), and Nicolaou s application of the Corey technology to a total synthesis of rapa-mycin (1993).

Spivey and coworkers have applied the CBS catalyst to the reduction of centro-symmetric imides. The efficiency of this catalyst system leaves room for improvement, but the reaction is capable of forming up to four stereocenters in a single operation with good enantioselectivity ... 

For a recovery of (S)-a,a-diphenylprolinol, which is the hydrolysis product of the CBS-catalyst (S)-5 (and likewise its synthetic precursor ), the aqueous phase is carefully adjusted to pH 10 with concentrated ammonia and extracted with diethyl ether (3 x 50 ml). The combined organic layers are washed with brine (50 mL) and dried over MgS04. Removal of the solvent by rotary evaporation yields 1.68 g (79%) of crude (S)-a,a-diphenylprolinol. This material is dissolved in dichloromethane / methanol 9 1 (3 ml) and filtered over Alox B (act. Ill, 80 g) with dichloromethane / methanol 9 1 as the eluent, to yield 1.64 g (77%) of (S)-a,a-diphenylprolinol as a white solid. 

The CBS-catalyst [(S)-2-methyl-CBS-oxazaborolidine] (S)-5 (1.0 M in toluene) (The CBS catalyst is named after Corey, Bakshi, and Shibata) and the borane-THF complex (1.0 M in THF) were obtained from Aldrich Chemical Co., Inc. and used as received. THF was distilled from potassium directly before use. 

The enantioselective reduction of ketones using borane and a chiral oxazaborolidine as catalyst (CBS Catalyst). Usually, MeCBS... 

The mechanism depicted portrays the rationale for the enantioselectivity and high reaction rates, which are influenced only by the CBS catalyst. This catalyst is a combination of both a Lewis acid and a chiral auxiliary ... 

Corey and Roberts reported a total synthesis of the dysidiolide 46, a marine sponge metabolite with biological activities against A-549 human lung carcinoma and P388 murine leukemia cancer cell lines20 (Scheme 4.3p). The unwanted alcohol (47) was converted to the ketone 48 via Dess-Martin periodinane oxidation. The asymmetric reduction of 48 with the CBS catalyst 28b efficiently gave the alcohol 49, which was transformed into the dysidiolide 46 via photochemical oxidation. 

However, in this section, the total synthesis of yingzhaosu A, the lead compound of a particular class of antimalarial 1,2-dioxocins, is reported. The synthesis involves eight steps and a 7.3% overall yield starting from (A)-limonene (Scheme 64). Besides the TOCO procedure that allowed the formation of five bonds in one step, the most intriguing steps involved the selective hydrogenation of a C-C double bond in the presence of a peroxide and an aldehyde functionalities (step vi) and the stereoselective reduction of the side-chain carbonyl with (R)-CBS catalyst (step viii). Last but not least, the old classical fractional recrystallization allowed the separation of yingzhaosu A from its C-14 epimer and saved two synthetic steps <2005JOC3618>. 

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. 

The first step of the mechanism is the coordination of BFI3 (Lewis acid) to the tertiary nitrogen atom (Lewis base) of the CBS catalyst from the -face. This coordination enhances the Lewis acidity of the endocyclic boron atom and activates the BH3 to become a strong hydride donor. The CBS catalyst-borane complex then binds to the ketone at the sterically more accessible lone pair (the lone pair closer to the smaller substituent) via the endocyclic boron atom. At this point the ketone and the coordinated borane in the vicinal position are cis to each other and the unfavorable steric interactions between the ketone and the CBS catalyst are minimal. The face-selective hydride transfer takes... 

The asymmetric total synthesis of prostaglandin Ei utilizing a two-component coupling process was achieved in the laboratory of B.W. Spur. The hydroxylated side-chain of the target was prepared via the catalytic asymmetric reduction of a y-iodo vinyl ketone with catecholborane in the presence of Corey s CBS catalyst. The reduction proceeded in 95% yield and >96% ee. The best results were obtained at low temperature and with the use of the B-n-butyl catalyst. The 6-methyl catalyst afforded lower enantiomeric excess and at higher temperatures the ee dropped due to competing non-catalyzed reduction. 

E.J. Corey and co-workers synthesized the cdc25A protein phosphatase inhibitor dysidiolide enantioselectively. In the last phase of the total synthesis, the secondary alcohol functionality of the side-chain was established with a highly diastereoselective oxazaborolidine-catalyzed reduction using borane-dimethylsulfide complex in the presence of the (S)-6-methyl CBS catalyst. Finally, a photochemical oxidation generated the y-hydroxybutenolide functionality. This total synthesis confirmed the absolute stereochemistry of dysidiolide. 

Nowadays much less catalyst is needed. This is particularly important in large scale syntheses as of the intermediate needed by Merck16 for the drug intermediate 79. The starting material is ketone 75 easily made by a Friedel-Crafts reaction. Reduction using only 0.5% CBS catalyst 60 gave alcohol 76 of 98.9% ee. Even with only 0.1% 60, the ee of the product 76 was still 94.2%. 

Scheme 47 shows a case 2 example for double stereodifferentiation, the problem being to reduce enone 47-1 preferentially to alcohol 47-2 or 47-3 [110]. The substrate control (DIBAH or L-selectride) is essentially zero, so that the chiral hydride donor must do the job. It can be seen that BINAL-H [ 111 ] is ineffective whereas diborane plus the CBS catalyst [112] shows a very pronounced reagent control so that either one of 47-2 and 47-3 may be generated selectively for the formation of 47-3 the reagent control is much higher than for 47-2, which is surprising in view of the low substrate control of the process. 

The CBS catalyst, devised by Corey, Bakshi and Shibata, has proven to be very useful in synthesis. The Schore group has prepared two polymer-supported... 

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