Conjugate additions oxazolidinones

Enantioselectivities were found to change sharply depending upon the reaction conditions including catalyst structure, reaction temperature, solvent, and additives. Some representative examples of such selectivity dependence are listed in Scheme 7.42. The thiol adduct was formed with 79% ee (81% yield) when the reaction was catalyzed by the J ,J -DBFOX/Ph aqua nickel(II) complex at room temperature in dichloromethane. Reactions using either the anhydrous complex or the aqua complex with MS 4 A gave a racemic adduct, however, indicating that the aqua complex should be more favored than the anhydrous complex in thiol conjugate additions. Slow addition of thiophenol to the dichloromethane solution of 3-crotonoyl-2-oxazolidinone was ineffective for enantioselectivity. Enantioselectivity was dramatically lowered and reversed to -17% ee in the reaction at -78 °C. A similar tendency was observed in the reactions in diethyl ether and THF. For example, a satisfactory enantioselectivity (80% ee) was observed in the reaction in THF at room temperature, while the selectivity almost disappeared (7% ee) at 0°C. 

As is the case for aldol addition, chiral auxiliaries and catalysts can be used to control stereoselectivity in conjugate addition reactions. Oxazolidinone chiral auxiliaries have been used in both the nucleophilic and electrophilic components under Lewis acid-catalyzed conditions. (V-Acyloxazolidinones can be converted to nucleophilic titanium enolates with TiCl3(0-/-Pr).320... 

Enantioselective Reactions of Organocopper Reagents. Several methods have been developed for achieving enantioselectivity with organocopper reagents. Chiral auxiliaries can be used for example, oxazolidinone auxiliaries have been utilized in conjugate additions. The outcome of these reactions can be predicted on the basis of steric control of reactant approach, as for other applications of the oxazolidinone auxiliaries. 

The conjugate addition of (R)- or (5)-4-phenyl-2-oxazolidinone to nitroalkenes is catalyzed by t-BuOK at -78 °C to give the addition product with excellent diastereoselectivity, the products are converted into vicinal diamines (Eq. 4.28).34... 

The products of the conjugate addition of (f )-4-phenyl-2-oxazolidinone to nitroalkenes are converted into D-a-amino acids with high enantiomeric purity (Eq. 4.30).36... 

Asymmetric conjugate addition of lithium amides to alkenoates has been one of the most powerful methods for the synthesis of chiral 3-aminoalkanoates. High stereochemical controls have been achieved by using either chiral acceptors as A-enoyl derivatives of oxazolidinones (Scheme 4) 7 7a-8 chiral lithium amides (Schemes 5 and 6),9-12 or chiral catalysts.13,14... 

The asymmetric synthesis of / -branched carboxylic acid derivatives was accomplished by conjugate addition of mixed organoaluminum reagents to optically active Arabinose-derived c -unsaturated A-acyloxazolidinones (Scheme 47). Efficient stereocontrol was achieved using different optically active bicyclic oxazolidinones, yielding (.R)- or ( -configured / -branched carboxylic acid derivatives.136a... 

Scheme 33 Oxazolidinone additives in Zn(OTf)2 catalyzed conjugate additions...

TABLE 9.29. ENANTIOSELECTIVE FREE RADICAL CONJUGATE ADDITIONS TO a,p-UNSATURATED N-ACYL OXAZOLIDINONES... 

It is remarkable and impressive to find that stereochemistry in the conjugate addition of a radical species to an activated olefin is controlled by the chiral bisox-azoline ligand 98 to give a conjugate addition product 100 from 99 in quite high ee and diastereoselectivity (Scheme 12) [58]. Radical trapping by hydrogen abstraction was also shown to be possible in the reaction of 99 to 103, which was controlled by the combination of a chiral alcohol 101 and achiral oxazolidinone 102 [59]. 

The 5(2H)-oxazolones (213) present two sites, C(4) and C(5), to nucleophilic attack they usually react at the latter. The benzylidene derivative (214), the most thoroughly studied member of this class, possesses an additional electrophilic centre at the exocyclic carbon atom. However, alkaline hydrolysis of this compound affords phenylacetamide and benzoylformic acid by acyl-oxygen fission (equation 50). a-Keto acids are also obtained when 2-trifluoromethyl-5(4//)-oxazolones are hydrolyzed, the reaction involving preliminary isomerization to a 5(2//)-oxazolone. The example shown in equation (51) represents the first non-enzymatic synthesis of an optically active a-keto acid. An instance of nucleophilic attack at C(4) of a 5(2//)-oxazolone is the formation of the oxazolidinone (215) in a Grignard reaction (equation 52). However, the typical behaviour of unsaturated pseudooxazolones like (214) is conjugate addition of a nucleophile, followed by further transformations of the resulting 5(4F/)-oxazoIones. This is illustrated by the reaction of compound (214) with benzene in the presence of aluminum chloride to yield, after aqueous work-up, the acylamino acid (216 equation 53). 

The direct transmetallation of alkenyl, acyl, and alkylzirconocenes to a copper catalyst and subsequent conjugate addition is also possible without a detour via another metal like zinc. For example, Wipf and Takahashi182 reported the highly diastereoselective 1,4-addition of in situ-prepared alkylzirconocenes (e.g., 246) to chiral N-acyl oxazolidinone 245 and similar substrates in the presence of BF3 OEt2 and catalytic amount of CuBr-SMe2, giving adducts of the type 247 with moderate to good yield (Equation (13)). 

Similar chemistry using chiral sultam auxiliaries demonstrates superior yields and selectivities for specific cases of cuprate conjugate additions, but have not yet been extended to the more complex multistep transformation series illustrated above. Moderate selectivities have been obtained in alkyl cuprate additions to y-aminocrotonate equivalents where the nitrogen is derived from the oxazolidinone. ... 

The 4-phenyl-2-oxazolidinone auxiliary has also been employed in the TiCl4-mediated conjugate additions of allylsi-lanes (eq 58). Analogous reactions using the phenylalanine-derived auxiliary with dimethylaluminum chloride afforded lower selectivities. In these reactions the oxazolidinones perform better than the sultams. 

R,R)-4,6-Dibenzofiirandiyl-2,2 -bis(4-phenyloxazoline), DBFOX/Ph (5), is a novel tridentate bisoxazoline ligand developed by Kanemasa and coworkers that has been successfully used as a chiral Lewis acid in enantioselective Diels-Alder-reactions, nitrone cycloadditions and conjugate additions of radicals and thiols to 3-(2-alkenoyl)-2-oxazolidinones. Representative examples for cycloadditions using the Ni(C104)2-6H20 derived complex are shown below. 

Asymmetric conjugate addition of thiols to 3-crotonyl-2-oxazolidinone is effectively catalyzed by the aqua nickel(II) complex of (i ,l )-DBFOX/Ph to produce conjugate adducts in high chemical yields and with high enantioselectivity [125] (Sch. 27). 

Bicyclic oxazolidinones derived from carbohydrates have been used as chiral auxiliaries in conjugate addition reactions [147]. After deprotonation with MeMgBr, the D-galacto-oxazolidin-2-one 178 and the D-g/wc6>-oxazolidin-2-one 179 (Figure 10.17) were A-acylated with... 

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