Chiral 1,4-dihydropyridine

Even more highly selective ketone reductions are earned out with baker s yeast [61, 62] (equations 50 and 51) Chiral dihydronicotinamides give carbonyl reductions of high enantioselectivity [63] (equation 52), and a crown ether containing a chiral 1,4-dihydropyridine moiety is also effective [64] (equation 52). 

Asymmetric reduction of ketones. Pioneering work by Ohno et al. (6, 36 7, 15) has established that l-benzyl-l,4-dihydronicotinamide is a useful NADH model for reduction of carbonyl groups, but only low enantioselectivity obtains with chiral derivatives of this NADH model. In contrast, this chiral 1,4-dihydropyridine derivative (1) reduces a-keto esters in the presence of Mg(II) or Zn(II) salts in >90% ee (equation I).1 This high stereoselectivity of 1 results from the beneficial effect... 

Considerable success has been obtained in enantiospecifk reductions using chiral 1,4-dihydropyridines. For example, keto ester (181) is reduced by the dihydropyridine (180) with a high degree of optical purity (79JA7036). At present this is a very active area of research. 

Lipase-catalyzed synthesis of chiral 1,4-dihydropyridines and barbiturates as drugs 91YGK1127. 

The use of substituted pyridines in organic synthesis has broad application. The activation of the pyridine ring toward nucleophilic attack is well known in the literature. The products of such reactions are often dihydropyridines which can serve as intermediates in more complex synthetic strategies. Rudler and co-workers have reported on the nucleophilic addition of bis(trimethylsilyl)ketene acetals to pyridine (26). The 1,4-addition product 27 was then cyclized with iodine to afford bicycle 28 in 90% overall yield <02CC940>. Yamada has elegantly shown that facial selectivity can be achieved and chiral 1,4-dihydropyridines accessed in high yield and de (29—>30) <02JA8184>. 

With this knowledge in mind, enantioselective reductions by chiral 1,4-dihydropyridines can be considered in more detail. Two types will be used to illustrate cogent points 1,4-dihydropyridines wherein C-4 of the heterocyclic ring is stereogenic, and 1,4-dihydropyridines incorporated into a macrocyclic framework that contains stereogenic centers. 

Lammerhofer, M., Gyllenhaal, O., Lindner, W. HPLC enantiomer separation of a chiral 1,4-dihydropyridine monocar-boxylic acid, J. Fharmaceut. Biomed.,... 

A STABLE CHIRAL 1,4-DIHYDROPYRIDINE EQUIVALENT FOR THE ASYMMETRIC SYNTHESIS OF SUBSTITUTED PIPERIDINES ... 

A STABLE CHIRAL 1,4-DIHYDROPYRIDINE EQUIVALENT FOR THE ASYMMETRIC SYNTHESIS OF SUBSTITUTED PIPERIDINES 2-CYANO-6-PHENYLOXAZOLOPIPERIDINE (5H-Oxazolo[3,2-aJpyridine-5-carbonltrlle, hexahydro-3-phenyl-,... 

Figure 9 Structures of chiral 1,4-dihydropyridine calcium channel blocking agents.

Reduction by a chiral 1,4-dihydropyridine derivative which contains an asymmetric center in the substituent on the nitrogen at the 1 position has also been attempted. Optical yields in the reduction o ethyl benzoylformate are shown in Table 5. It should be noted that 2 which carries a proline moiety exhibited a remarkably high e.e. value. 

The effect of synthetic polymers on the asymmetric reduction by NAD(P)H model compounds was examined. Shinkai et al. (1981) synthesized chiral 1,4-dihydropyridine derivatives bound to polystyrene beads (27-29) and subjected them to the reduction of ethyl benzoylformate in acetonitrile in the presence of magnesium perchlorate. As shown in Table 21, the optical yields from the polymeric systems were low compared to those from homogeneous systems. The reductions in homogeneous systems with 30 and 31 gave optical yields of 47 and 51, respectively. 

Table 21. Asymmetric reduction of ethyl benzoylformate with polymer-bound chiral 1,4-dihydropyridine derivatives.

De Vries JG, Kellogg RM (1979) Asymmetric reductions with a chiral 1,4-dihydropyridine crown ether. J Am Chem Soc 101 2759-2761 De Weerd RJEM, van Hal HMPJ, Buck HM (1984) A new class of chiral detergents. The formation of single micelles from N,N-dimethyl-1--dodecyl-2,4-dimethyl-3-carbamoylpyridinium bromide. A CD study. J Org Chem 49 3413-3415... 

Bard, A. J., Parsons, R. and Jordan, J., 1985. Standard Potentials in Aqueous Solutions, lUPAC Marcel Dekker, New York, USA Bonin, M., Grierson, D. S., Royer, J. and Husson, H. -P., 1992. A stable chiral 1,4-Dihydropyridine equivalent for the asymmetric synthesis of substituted piperidines 2-Cyano-6-Phenyloxazolopiperidine. Org. Synth. 70, 54-57. 

Another diarylprolinol ether has been used to catalyse several asymmetric domino Michael reactions. Therefore, Jorgensen et al. have demonstrated its efficiency for the asymmetric synthesis of 1,4-dihydropyridines, which are closely related to the NADH system, a biological system of utmost importance, and moreover these molecules are important drugs used in the treatment of a number of diseases, such as cardiovascular diseases and Alzheimer s disease. Thus, a series of chiral 1,4-dihydropyridines were prepared on the basis of a one-pot multicomponent reaction between a a,p-unsaturated aldehyde, a P-diketone... 

Yamada S, Morita C (2002) Face-selective addition to a cation-K complex of a pyridinium salt synthesis of chiral 1,4-dihydropyridines. J Am Chem Soc 124 8184—8185... 

A Lewis acid push-pull mechanism proposed for the magnesium bromide promoted Barbier-type intramolecular cyclization of Grignard reagents derived from halo-substituted acetals, ketals, and orthoesters as depicted in (Scheme 9). Stereoselective addition of chiral a-aminoorganometallics to aldehydes has been reviewed. Chiral 1,4-dihydropyridines have been synthesized with good regio- and... 

Allyltins also react with similar substrates such as pyridines or pyridiniums selectively to the a position [271]. An enantioselective approach was done with a chiral acyl chloride as activator and enantioselectivity inductor [272]. This approach was applied to heterocydes such as /3-carboline, leading to both enantiomers depending on the nature of the allyltin engaged in the reaction (Scheme 6.31) [273]. Similarly, oxazolidinones were used as chiral auxiliaries, to promote the synthesis of chiral 1,4-dihydropyridines [274]. 

---