Enantioselective a-halogenation

Maruoka reported the organocatalytic enantioselective a-halogenation of aldehydes using NIS and the binaphthyl-based catalyst shown in Scheme 13.38 [77]. Additionally, the conditions for a-brominahon of aldehydes using the C2-syrmnetric chiral pyrrohdine catalyst depicted in Scheme 13.31 were adapted for the a-iodination of two aldehyde substrates [67]. 

Aldehydes (Table 43.1) One of the most rapidly developing areas is the catalytic enantioselective a-halogenation... 

Highly enantioselective atom transfer radical cydization reactions catalyzed by chiral Lewis acids have been reported by Yang et al. [80]. Two main advantages of these enantioselective cyclizations include installing multiple chiral centers and retaining a halogen atom in the product, which allows for further functionalization. 

The enantioselective oxidative coupling of 2-naphthol itself was achieved by the aerobic oxidative reaction catalyzed by the photoactivated chiral ruthenium(II)-salen complex 73. 2 it reported that the (/ ,/ )-chloronitrosyl(salen)ruthenium complex [(/ ,/ )-(NO)Ru(II)salen complex] effectively catalyzed the aerobic oxidation of racemic secondary alcohols in a kinetic resolution manner under visible-light irradiation. The reaction mechanism is not fully understood although the electron transfer process should be involved. The solution of 2-naphthol was stirred in air under irradiation by a halogen lamp at 25°C for 24 h to afford BINOL 66 as the sole product. The screening of various chiral diamines and binaphthyl chirality revealed that the binaphthyl unit influences the enantioselection in this coupling reaction. The combination of (/f,f )-cyclohexanediamine and the (R)-binaphthyl unit was found to construct the most matched hgand to obtain the optically active BINOL 66 in 65% ee. 

Some radical reactions occur under the control of transition metal templates. The first example of asymmetric creation of an asymmetric carbon with a halogen atom is shown by the a DIOP-Rh(I) complex-catalyzed addition of bromotrichloromethane to styrene, which occurs with 32% enantioselectivity (Scheme 99) (233). Ru(II) complexes with DIOP or BINAP ligands promote addition of arenesulfonyl chlorides to afford the products in 25-40% ee (234). A reaction mechanism involving radical redox transfer chain process has been proposed. 

Asymmetric hydrohalogenation of fraws-2-butenoic acid has been achieved in a crystalline a-cyclodextrin complex using gaseous HBr at 20 °C and HC1 at 0 °C. The products were formed with 58% and 64% e.e., respectively, and were of (S )-configuration81. This contrasts with the low enantioselectivity of halogenation attempted in the same paper (vide supra). 

A similar catalytic procedure for enantioselective formation of C-Br and C-Cl bonds has been reported recently by the Lectka group [83]. The concept of this a-halogenation of carbonyl compounds is tandem asymmetric halogenation and esterification (Scheme 3.28). Inexpensive acyl halides, 74, are used as starting... 

The DE ring of camptothecin has been prepared enantioselectively in six steps from 2-fluoropyridine using a halogen dance reaction <95TL(36)7995>. The first total synthesis of dimethyl sulfomycinamate (47) was reported starting from 3-hydroxy-6-methylpyridine (48) <95TL(36)5319>. 

Organocatalysis has led to the development of new methods for the asymmetric a-halogenation of carbonyl compounds leading to the formation of stereogenic C-X centers. Hence, details of direct enantioselective fluorination, chlorination, and bromination reactions will be presented in the following sections. 

The excellent enantioselectivity and wide scope of the CBS reduction have motivated researchers to make new chiral auxiliaries [3]. Figure 1 depicts examples of in situ prepared and preformed catalyst systems reported since 1997. Most of these amino-alcohol-derived catalysts were used for the reduction of a-halogenated ketones and/or for the double reduction of diketones [16-28]. Sulfonamides [29,30], phosphinamides [31], phosphoramides [32], and amine oxides [33] derived from chiral amino alcohols were also applied. The reduction of aromatic ketones with a chiral 1,2-diamine [34] and an a-hydroxythiol [35] gave good optical yields. Acetophenone was reduced with borane-THF in the presence of a chiral phosphoramidite with an optical yield of 96% [36]. 

While the reactions ofketenes with enantiopure alcohols usually give modest selectivities [769], the use of (ethyl lactate (isopropyl lactate (/ )-2.1 (R = Me, R = i-Pr) or (R)-pantolactone 1.16 as proton donors has allowed the highly enantioselective formation of 2-arylpropionic esters. A mild hydrolysis (AcOH/HCl or LiOH) leads to the corresponding adds, which are anti-inflammatory drugs [554,923] (Figure 4.8). This method has been extended by Durst and Koh [861, 999] to the synthesis of enantioenriched a-halogenated esters, which are precursors of aminoacids (Figure 4.8). 

The initial ruthenium(II) catalyst 66 abstracts a halogen (either chlorine or bromine) from the substrate forming a ruthenium(III) species 67. This is followed by pi complexation (68), radical addition (69) and halogen atom transfer to form the desired product (70). Starting from 65a, enantioselectivities of the resulting product 70a ranged from 20 to 40% ee with excellent chemical yields [28]. Reactions with a slightly different substrate bromotrichloromethane (65b) provided 70b in 32% ee, and a poor yield of 26% [29]. 

A process of selenocatalytic a-halogenation using NBS has been reported. A catalytic enantioselective bromination of -keto esters has been achieved using a combination of NBS and TiCl2(TADDOLato) complexes as enantioselective catalyst modest enantiomeric excesses were obtained. 

In 2000, Katsuki and co-workers applied the chiral chloro nitrosyl Ru -(salen) complex developed in their own group to asymmetric aerobic oxidative biaryl coupling reactions (Scheme 3.14). The reaction was found to proceed smoothly in air under irradiation with a halogen lamp as the light source at room temperature. Examination of a series of Ru (salen) complexes revealed that the combination of (R,R)-diamine unit and (R)-BINOL scaffold in the catalyst is important for achieving higher enantioselectivity. The absolute configuration of the major product is determined by the chirality of the BINOL scaffold whereas the structural variation in the diamine part shows little influence on asymmetric induction. Under the optimal conditions, several 2-naphthols with a substituent at the C6 position of the naphthalene... 

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