Kagan reagent

Krief, A., Laval, A.-M. Coupling of Organic Halides with Carbonyl Compounds Promoted by Sml2, the Kagan Reagent. Chem. Rev. 1999,... 

The Sharpless epoxidation of allylic alcohols by hydroperoxides uses as mediator [45] or as catalyst [46] a chiral titanium complex obtained from the combination Ti(OPr )4/diethyl tartrate (DET) in 1 1 ratio. Kinetic resolution of P-hydroxysulfides was also observed, but without diastereoselectivity for the product P-hydroxysulfoxides [47]. We found that the Sharpless reagent deactivated by 1 equivalent of water allows the enantioselective oxidation of aryl methyl sulfides into sulfoxides to be performed with ee s up to 90% [4S-50]. The best reagent combination proved to be Ti(0Pr )4/DET/H20 = 1 2 1. Independently, Modena et al. obtained similar enantioselectivities with the combination Ti(OPr )4/DET in 1 4 ratio [51]. These two combinations are sometimes referred to as the Kagan reagent and the Modena reagent, respectively. They will be considered successively. 

Table 1.2 Some representative examples of sulfoxidation in presence of the combination Ti(OPr )4/(/ )-DET/H20 = 1 2 1 ( Kagan reagent )...

Scheme 1.7 Rule for the prediction of absolute configuration in asymmetric sulfoxidation by the Kagan reagent [54,55]...

Diethyl tartrate (compared to various tartaric acid derivatives) still remains the best ligand for the enantioselective oxidation of sulfides, as exemplified by the oxidation of methyl p-tolyl sulfide [49]. Yamamoto et al found that DET can be replaced by diols (30) or (31) in the Kagan reagent, giving sulfoxides of opposite... 

Oxidation of sulfides has been performed by TBHP in anhydrous conditions with an excess of diethyl tartarate (4 equivalents) [59]. Modena used 1,2-dichloroethane or toluene as solvent at -20°C. Some examples are listed in Table 1.3. As with the Kagan reagent, a high ee (88%) is obtained for the sulfoxidation of methyl p-tolyl sulfide in 1,2-dichloroethane, but the ee drops to 64% in toluene. 

The Kagan reagent has in a number of cases proved much more stereoselective than other systems. For example, Beckwith and Boate oxidized tetrahydrothiophene and 2-(2-bromophenyl)ethyl methyl thioether into the corresponding sulfoxides (>90% ee) [60]. Tanaka and coworkers used the method (with CHP as oxidant) to synthesize itomanindole A (80% ee) from an indolic disulfide precursor [61]. The monooxidation is fully regioselective. Both... 

Methyl vinyl sulfoxides of pharmaceutical interest, of general formula Me— S(0)—CH=C(Ar)(R), have been prepared by CHP oxidation in presence of the Kagan reagent. For example, 95% ee was obtained when Ar = m-anisyl and R =... 

Various metallocene sulfoxides of quite high ee s are now available through the asymmetric oxidation of the corresponding sulfides by the Kagan reagent (Scheme... 

A similar methodology was applied by Colonna et al. [101] to the oxidation of aryl alkyl sulfides with Bu OOH as oxidizing agent and a catalytic amount of a titanium A-salicylidene-L-amino acid complex (47) (0.1 mol equiv) in benzene at room temperature. This catalyst is not very enantioselective, and often yields mixtures of sulfoxides and sulfones. The highest enantioselectivity was achieved in the oxidation of f-butyl (p-nitrophenylthio)acetate, which gave sulfoxide in 21% ee and 25% yield. Like the Kagan reagent, but to a lesser measure, the use of a stoichiometric amount of titanium complex substantially influences the enantioselectivity, which increases from 12% (catalytic) to 21% (stoichiometric) for the oxidation of methyl p-tolyl sulfide. 

The Kagan reagent was used at Eli Lilly to resolve racemic thiazolidinone (60) (Scheme 1.16) [153]. At 60% and 80% completion, the ee s of recovered (-)-(60) were 67% and 94%, respectively. The Modena procedure (i.e. no added water in the reagent system) gave a much slower reaction, but the ee shows only a small decrease. 

The Kagan reagent allowed Ando et al. to prepare several nonracemic sulfoxides (62) by oxidation of (61) [154]. One calculates from ee s and product distribution, using the formula for kinetic resolution [148-150], that the selectivity factor s is close to 12. A P-lactam (63) has been also resolved (s = 7) using the Kagan reagent [155]. 

KAGAN-MOLANDER Samanum reagent Lanthanide reagents, speoflcally samanum, lor generation of free radicals useful in cyclizations, reductions... 

Beal and Kagan have shown that reaction of Grignard reagent with 15-ketones (45) gives the 15a-methyl carbinols (46). 

Significant improvements in asymmetric oxidations were made by Modena and, especially, by Kagan, and their coworkers. Both groups used chiral peroxotitanium complexes patterned after the Sharpless reagent as the oxidants. 

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. 

In principle, any reaction with a racemate using a chiral reagent can be used to effect a kinetic resolution. Kagan (56) has recently given an analysis of the relationship between the extent of reaction and die enantiomeric excess that can be achieved, while Sharpless (57) has applied kinetic resolution successfully to racemic allyl alcohols using his titanium alkoxide tartrate epoxidation reaction. 

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