Application Study Of Asymmetric Allylation Of Aldehydes

This work, concentrated on the asymmetric allylation of aldehydes controlled by different chiral auxiliaries prepared from rotational pure tartaric acid, can be divided into three parts.The first part aims to review the developments of chiral drugs and asymmetric synthesis, from which derived the present research topic backgrounds and works.Synthesis and applications of allylation from aldehydes are the second part of the thesis. By optimizing the reaction conditions, such as solvents, temperature, time and chiral auxiliaries like N,N'-dibenzyl tartamide, N,N'-p-dimethylphenyl tartamide, N,N'-o-dimethylphenyl tartamide, N,N'-o-dichlorophenyl tartamide, N,N'-a-dinaphyl tartamide, N,N'-dicyclohexyl tartamide and N,N'-diphenyl tartamide, ideal experimenttal conditions are obtained according to HPLC monitoring, as well as the auxiliaries' recoveries experiments. Starting from benzaldehyde and 3-bromopropaldehyde, N,N'-dibenzyl tartamide is considered the best auxiliary in this reaction. The homoallylic alcohol product, (4R)-4-hydroxy-6-bromo-1-hexylene, can be easily synthesized into (3R,5S)-3-hydroxy-5-iodomethyl-d-valerolactone, a very important intermediate of Atorvastatin, in excellent enantiomeric excess (94.1%e.e.). In a similar way, using N,N'-dibenzyl tartamide as auxiliary, (S)-(2-methyl)allyl-2-chloro-phenyl-methyl azide, a vital intermediate of Repaglinide, can be prepared via asymmetric allylation of o-chlorobenzaldehyde in 87.7%e.e. The auxiliary can be recovered in high yield (81%) only by filtering and recrystallization. Besides, some other aldehydes have been chosen to test the enantioselectivity of N,N'-dibenzyl tartamide, in comparison with two other allylaborates reagents developed previously by Roush and Brown, respectively. The results show that %e.e. of homoallylic alcohol is superior to that of the former, and approaches the Brown reagent.The third part of this thesis is reactive simulating calculation In this section, some well-known auxiliaries are selected to compute in density functional theory B3LYP on Gaussian 03, from which the relationship between reaction active energies of transition states and enantiomeric excess of chiral products homoallylic alcohols isobtained based on relative reactive ratio theory. Using this relationship, calculations on the reaction of more than eight auxiliaries with four other aldehydes are carried out in AMI and MNDO, proving that N,N'-dibenzyl tartamide has higher enantioselectivity than others in this reaction.