Ethyl mandelate, reduction

In the same study, redox polymers (223) were prepared that contained pendant viologens (Scheme 108). An active reducing agent was obtained by chemical reduction with dithionite or zinc, electrochemically, or by exposure to light. Utilization of the reduced poly(viologen) (224) as an electron transfer mediator was demonstrated by addition of a catalytic amount of the polymer to a mixture of zinc powder, ethyl benzoylformate (225) and water-acetonitrile (1 5). A quantitative yield of ethyl mandelate (226) was obtained after two days at room temperature (Scheme 109). Without the polymer, no reaction was observed after a month. 

Attempts to achieve optical induction during the reduction of aromatic ketones to the secondary alcohol with the help of a single layer of chiral catalyst covalently attached to a graphite cathode have been much less successful. Reduction of 4-acetylpyridine at a graphite surface coated with (S)-phenylalanine methyl ester afforded an enantiomeric excess of the (S)-pyridinylethanol. In other experiments, ethyl glyoxylate afforded ethyl (—)-mandelate with 9.7% enantiomeric excess [101]. Results using such modified surfaces have, however, proved highly irreproducible [102]. 

A direction that redesign of the system could take was suggested by experiments with 1,4-dihydronicotinamide derivatives (55) with an optically active amine attached to the side chain such compounds in the presence of Mg are capable of reducing activated carbonyl compounds like ethyl phenylglyoxalate (53) to ethyl mandelate (54) with modest transfer of chirality (eq. 26). This approach has subsequently been developed by Ohno into an extremely efficient method for the transfer of chirality in some reductions. We felt that the selectivity... 

It is interesting to remember that ethyl i -mandelate was produced in 20 I e.e. in the reduction of ethyl benzoylformate with i -PNPH, whereas / -37 afforded ethyl -mandelate predominantly. The structures of the two reductants are similar but the stereochemical properties are quite different from each other, which indicates that the situation at the transition state of the 1,5-dihydro-5-deaza-flavin system is different from that of PNPH. This is perhaps because of the cyclic structure of 51 and of the presence of several heteroatoms in the molecule. A magnesium ion may be able to interact with these heteroatoms. 

While both the ethyl and methyl esters of R and S mandelic acids are commercially available, these can also be easily prepared in high yield. Fischer esterification of 2 affords in 91% yield the ethyl ester 88, which is then protected as the THP ether 89. Lithium aluminum hydride reduction, conversion to the tosylate, and nucleophilic substitution with cesium fluoride affords 90 characterized by 85% ee (Scheme 19) [30]. 

Thus from the sodium salt of glycolic acid (CH,OH. COOH), ethyl-glycolic acid (CH,OC,Hj.COOH), and a-lactic acid (CH3.CH(OH)COOH) the chief product obtained is acetic aldehyde, and it is quite possible that the production of hydrobenzoin and isohydrobenzoin from mandelic acid is due to the electrolytic reduction of the benzaldehyde originally formed. 

Fig. 9. Plausible molecular arrangement in the reduction with i -PNPH where dipole-dipole interaction between the ethoxycarbonyl group in ethyl benzoylformate and the carbamoyl side chain in i -PNPH is considered. Ethyl i -mandelate is produced through the approach of (a), and ethyl S-mandelate is produced through the approach of (b).

A striking dependence of the optical yield on the conversion has also been observed in other systems. Makino et al. (1980) reported that, in the reduction of ethyl benzoylformate with PNGH, the optical yield of ethyl 5-mandelate increases as the reaction proceeds (Table 9). 

Baba et al. (1980b) attempted an asymmetric reduction by 1,4-di-hydropydidine covalently bound to a cyclic peptide, bacitracin, which is an antibiotics and has large affinity to the zinc ion. They intended to enhance the reactivity of 1,4-dihydropyridine by the coordination of a cyclic peptide moiety to a metal ion as well as to achieve the asymmetric reduction by an effect of the chiral field provided by the peptide. However, neither the activity nor the ability for asymmetric induction were so high. The optical yield of ethyl i -mandelate in the reduction of ethyl benzoylformate in the presence of magnesium perchlorate was 5.4 % (7 ) in dry methanol only 1.9 % (i ) in acetonitrile. 

Some years ago, these possibilities were examined [53] with (—)-menthyl benzoylformate and ethyl benzoylformate. A simple asymmetric reduction involving either (—)-menthyl benzoylformate with an acliiral agent, liAlH4(LAH)-cyclo-hexanol, process (a), or ethyl benzoylformate with a chiral reducing agent, LAH-(+)-camphor, process (b), gave (/ )-mandelic acid after hydrolysis, in relatively low optical yields (10 and 4% e.e., respectively). On the other hand, the double asymmetric reduction , process (c), resulted in 49% asymmetric synthesis. This result is more than would be anticipated on the basis of a simple additive effect. 

From the results also shown in Table 16, the stereochemical control by the (—)-menthyl group itself was found to produce predominantly ( )-menthyl (5)-mandelate (21% e.e.), an antipode of that obtained from the lithium aluminum hydride reduction. In process (b), it was shown that a counteracting asymmetric induction by the chiral catalyst of (—)-DIOP exceeded the effect of ( )-menthyl group to give the (jR)-mandelate with rather low stereoselectivity (37% e.e.). Production of the (R)-mandelate was scarcely favored in case of the asymmetric reduction of ethyl benzoyl-... 

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