Hantsch ester

Phosphoric acid catalysts, bearing bulky groups, have been devised for the asymmetric transfer hydrogenation of imines with Hantsch ester. With the catalyst (14), (g) enantioselectivity up to 93% has been achieved in the reduction of aromatic imines. 

However, if we look at the LUMO, we find that it has the form 4.65, namely that of ift4 of benzene, but polarised by the nitrogen atom. This polarisation has reduced the coefficient at C-3, and the coefficient at C-4 is larger than that at C-2, as can be seen from the simple Hiickel calculation for pyridine itself in Fig. 4.11, which gives LUMO coefficients of 0.454 and —0.383, respectively, and an energy of 0.56/3 (compare benzene with 1/3 for this orbital). Thus, soft nucleophiles should attack at C-4, where the frontier orbital term is largest. Again this is the case cyanide ion, bisulfite, enolate ions, and hydride delivered from the carbon atom of the Hantsch ester 4.67 react faster at this site. 

In contrast to asymmetric oxidation chemistry, cinchona-catalyzed asymmetric reduction reactions have been explored very little, despite the importance of this reaction. Previous reports on this topic are restricted to the reduction of aromatic ketones, and the enantioselectivities achieved to date remain far from satisfactory when compared with metal catalysis. Moreover, Hantsch esters, another type of useful organic hydrides, have not yet been studied in combination with cinchona catalysts. However, as is well known, the structures of cinchona alkaloids are easily modifiable, thus permitting the easy tuning of the reaction course. The successful use of cinchona catalysts for this reaction will therefore likely be reported in the very near future. 

Loss of the OH from a racemic 2//-chromen-2-ol derivative on reaction with a chiral phosphoric acid in toluene affords the corresponding achiral 1-benzopyrylium ion intermediate which is then reduced by diallyl l,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (Hantsch ester) to give the final product 4//-chromene in good yields with moderate enantioselectivity." ... 

Hantsch esters, such as (89), having monosaccharide substituents, have been synthesised from sugar aldehydes as chiral NADH models, and used in the asymmetric reduction of several prochiral ketones with ee s up to 79% being attained. ... 

The Hantsch pyridine synthesis provides the final step in the preparation of all dihydrop-yridines. This reaction consists in essence in the condensation of an aromatic aldehyde with an excess of an acetoacetate ester and ammonia. Tlie need to produce unsymmetrically subsrituted dihydropyridines led to the development of modifications on the synthesis. (The chirality in unsymmetrical compounds leads to marked enhancement in potency.) Methyl acetoacetate foniis an aldol product (30) with aldehyde 29 conjugate addition of ethyl acetoacetate would complete assembly of the carbon skeleton. Ammonia would provide the heterocyclic atom. Thus, application of this modified reaction affords the mixed diester felodipine 31 [8]. 

Nicardipine Nicardipine, l,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-methyl-2-[(methyl-phenylmethyl)-amino]ethyl ester 3,5-pirididincarboxylic acid (19.3.7), is synthesized in a manner analogous to the synthesis of nifedipine, the only difference being that in the Hantsch synthesis, two different )3-dicarbonyl compounds are used simultaneously with o-nitrobenzaldehyde. During this, one of these in the enamine form of acetoacetic ester is simultaneously used as an amine component. A heterocycUzation reaction is accomplished by reacting, the methyl ester of 8-aminocrotonic acid with the 2-methyl-2-benzyl-aminoethyl ester of acetoacetic acid [24-27]. 

Polysubstituted dihydropyridines were also considered as targets. Condensation of LI with enamino ester 9.16 and enamino nitrile 9.17 under standard Hantsch conditions only proved successful for the latter, furnishing the pyridine library L6 (1280 members). Oxidation of the initially formed dihydropyridines is presumably favored due to the highly conjugated system formed (Fig. 9.12). Hantsch condensation with cyclic enamino esters 9.18 and 9.19a-f was also successful, providing respectively the bicyclic libraries L7 (1280 members) and L8 (7680 members. Fig. 9.12). 

Scheme 8.24 Photoinduced electron transfer from ketone 56 to the iridium complex occurs coti-certedly with protonation by the chiral phosphate. In the process, the ketyl radical becomes significantly more basic than phosphoric acid, and rapid radical cyciization from the neutral ketyl as an H-bonded adduct to the chiral phosphate occurs. Asymmetric induction results, due to the rapid radical cyciization. Hantsch dihydropyridine esters provide the required proton and hydrogen atoms...

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