Chiral auxiliaries reaction with benzaldehyde

Z)-l-Methyl-2-butenylboronate 7 undergoes an exceptionally enantioselective reaction with benzaldehyde (99% ee), propanal (79%. 98% ee), 2-methyl-2-propenal (85%, 99% ee), and ( )-2-methyl-2-pentenal (81 %, 99% ee)10 38. Excellent enantioselectivity is also realized in reactions of the analogous chiral a-methyl-) y-disubstituted allylboronate27 40. Whether the l,2-dicyclohexyl-l,2-ethanediol auxiliary plays a beneficial role in this reaction, as suggested above for the asymmetric allylboration reactions of 6, has not yet been determined. 

A remarkable effect of the reaction temperature on the enantioselectivity of the addition of butyllithium to benzaldehyde was found with polystyrene-bound cvs-enofo-S-dimethylamino -(benzyloxy)bornane (8)12. When the soluble monomeric ligand 9 was tested, the enantioselectivity increased with decreasing temperature (53% ee at — 78 C). In contrast, the polymer-bound chiral additive 8 showed an optimum at — 20 C (32% ee). Although the enantioselectivity of this addition reaction is low, an advantage of a polymer-bound chiral auxiliary is that it can be removed by a simple filtration. 

Alkaline hydrolysis of the crude adduct formed with benzaldehyde, followed by treatment with diazomethane and column chromatography, affords methyl (2R,3S)-3-hydroxy-2-methyl-3-phenylpropanoate in 96% ee. Reduction of the crude products formed in the reactions with 2-inethylpropanal and 2,2-dimethylpropanal leads to the corresponding 1,3-diols with >96% ee. In both the hydrolysis and the reduction procedures, the chiral auxiliary reagent, 1,1,2-triphenyl-1,2-ethanediol, can be recovered and reused72. 

The addition of a-lithiomethoxyallene 144 [55] to benzaldehyde dimethylhydra-zone 145 (Eq. 13.48) leads to a mixture of pyrroline 146 and dihydroazete 147 [56]. The cydization in this case, which takes place in the same operation as the addition to the hydrazone, follows two distinct pathways, with attack of the nitrogen atom taking place at the inner, in addition to the terminal, carbon atom of the allene. A similar reaction of 144 with SAMP-hydrazone 148 (Eq. 13.49) leads to 3-pyrroline 149 in 88% yield and excellent diastereoselectivity [57]. Cleavage of the chiral auxiliary group from 149 takes place in two steps (1, methyl chloroformate 2, Raney nickel, 50 bar, 50 °C) in 74% overall yield. When the addition of 144 to 148 is conducted in diethyl ether, cydization of the adduct does not take place. Surprisingly, the hydrazones of aliphatic aldehydes react with 144 in poor yield in THF, but react quantitatively and diastereoselectively in diethyl ether to give the (uncyclized) allenyl hydrazone products. 

Amplification of Chirality. Perhaps the most striking of the nonclas-sical aspects that emerge from the enantioselective alkylation is the phenomenon illustrated in Scheme 22 (3, 14, 16, 20k, 40). A prominent nonlinear relation that allows for catalytic chiral amplification exists between the enantiomeric purity of the chiral auxiliary and the enantiomeric purity of the methylation or ethylation product (Scheme 23). Typically, when benzaldehyde and diethylzinc react in the presence of 8 mol % of (-)-DAIB of only 15% ee [(-) (+) = 57.5 42.5], the S ethylation product is obtained in 95% ee. This enantiomeric excess is close to that obtained with enantiomerically pure (—)-DAIB (98%). Evidently, chiral and achiral catalyst systems compete in the same reaction. The extent of the chiral amplification is influenced by many factors including the concentration of dialkylzincs, benzaldehyde, and chiral... 

The same chiral auxiliary has been used in the cycloaddition of an optically active azomethine ylide to benzaldehyde and to l-nitro-2-(3,4-methylenedioxyphenyl)ethylene Ae ylide was generated in situ by treating (R)-(+)-/V-(l-phenylethyl)-A -cyanomethyl-A -trimethylsilylmethylamine (33) with silver fluoride. Unfortunately, no selectivity was observed in the first case and only a 3 2 preference was expressed in the second. Use of the azomethine ylide derived in the same manner from (/ )-(-)-N-(l-phenyl-2-methoxyethyl)-/V-cyanomethyl-N-trimethylsilylmethylamine (34) displayed a modest, but potentially useful, 4 1 diastereofacial selectivity in its reaction with l-nitro-2-(3,4-methylenedioxyphenyl)ethylene. The precise structure of the major and minor product was not determined (Scheme 25). 

Early investigations of asymmetric aldol reactions with chiral carbohydrate auxliliaries were carried out by Heathcock [152] and Bandraege [159], but often only low stereoselectivities were observed. In additional studies. Banks et al. [73] used oxazinone auxiliaries for aldol reactions, which had been employed for other asymmetric reactions. The lithium enolate of the A-acylated oxazinone 226 reacted with benzaldehyde, furnishing exclusively the iyn-aldols 227A and 227B in a ratio of 10 1 (Scheme 10.76). 

Due to the importance of polypropionate antibiotics, mainy chiral auxiliaries have been introduced on propionic add derivatives in order to perform asymmetric aldol reactions. The use of esters of chiral alcohols usually gives disappointing results [147, 209]. In an important exception, Braun and Sacha [149] recommended the propionate of a trimethylsilyloxyalcohol 1.12. The reaction of the derived dicyclopentylchlorozirconium enolate with aliphatic aldehydes at -105°C leads to anti aldols with an excellent fedal stereoselectivity (Figure 6.78). The selectivity is lower with benzaldehyde. The use of titanium enolates of N-tosyl-aminoephedrine 1.61 (R = Ts) propionate has recently been advocated [1262],... 

Enantioselective alkylations have been achieved using modified MCM-41 materials.135 Mesoporous templated MCM-41s with covalently linked chiral ephedrine are active heterogeneous chiral auxiliaries in the enantioslective alkylation of benzaldehyde by diethylzinc. Lower rates, selectivities and enantioselectivities are obtained under heterogeneous conditions compared to homogeneous catalysis. This can be explained either by the participation of the uncovered surface to the racemic alkyl transfer or by a restricted accessibility to the catalytic sites in the heterogeneous reactions. 

Asymmetric aldolization of a-isocyanoacetamide and fluorinated benzaldehydes has been realized with a gold(I) salt and a ferrocenyl amine-phosphine ligand. (Salen)-Ti complexes serve well in catalyzing the condensation of diketene with aldehydes. " A camphor lactam is an adequate chiral auxiliary as its derived imide undergoes asymmetric aldol reactions. 

The presence of a chiral auxiliary can influence the stereochemistry of products formed in a Mukaiyama reaction. A stereogenic center derived from a chiral amino alcohol was incorporated in the enol ether moiety (see 445). When this reacted with benzaldehyde and TiCU. the alcoholate products were 446 and 447 (R = the chiral auxiliary) The diastereoselectivity in this reaction was quite good (95 5 favoring 446) and each product was formed with high enantioselectivity.246 It is also possible to incorporate the stereogenic center into the starting material (a chiral template, as discussed in sec. 10.9).247... 

Various magnesium oxide crystals [commercial MgO, CM-MgO (SSA 30 m /g), conventionally prepared MgO, NA-MgO (SSA 250 m /g), aerogel prepared MgO, NAP-MgO (SSA 590m /g)] were initially evaluated in the CSC and AE reactions separately in order to understand the relationship between structure and reactivity. All these MgO samples catalyzed both CSC of benzaldehyde with acetophenone to form chalcone quantitatively and selectively, and subsequent AE using (- -)-diethyl tartrate (DET) as a chiral auxiliary to obtain a chiral epoxy ketone in good yield and impressive ee. The nanocrystalline MgO (NAP-MgO) was found to be more active than the NA-MgO and CM-MgO in the condensation and epoxidation reactions (Figure 5.6). 

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