Previous workers in our laboratory have demonstrated that the addition of lithiated arylacetonitriles to aldehydes is anti-selective, The synthetic usefulness of the reaction would be greatly increased if we could develop an asymmetric variant. Enantiomerically pure β-hydroxynitriles are synthetic precursors to various γ-aminoalcohols, which may possess antidepressant activity. γ-Aminoalcohols can further be transformed to oxazine derivatives in good yield....[ Read more ]

Previous workers in our laboratory have demonstrated that the addition of lithiated arylacetonitriles to aldehydes is anti-selective, The synthetic usefulness of the reaction would be greatly increased if we could develop an asymmetric variant. Enantiomerically pure β-hydroxynitriles are synthetic precursors to various γ-aminoalcohols, which may possess antidepressant activity. γ-Aminoalcohols can further be transformed to oxazine derivatives in good yield.

The first chapter of this thesis begins with a brief review of progress made by other workers in asymmetric aldol reaction of carbonyl and carboxyl derivatives. We then present a discussion of the currently available methods for preparation of enantiomerically enriched β-hydroxynitriles. The chapter concludes with a discussion of the basic strategy we plan to use in inducing asymmetry in the nitrile aldol reaction: introduction of chiral ligands to complex lithiated nitriles.

Chapter 2 of this thesis describes our rationale for exploring use of chiral TMEDA analogs in conjunction with the weakly donating or non-donor solvents. Our synthesis of both known and novel chiral TMEDA analogs follows. The chiral diamine ligands were screened for ability to mediate aldol reaction of 1) acetonitrile and benzaldehyde; 2) phenylacetonitrile and pivalaldehyde. The highest %ee achieved in this study was (-)14%, using stilbenediamine derivative 5Oc as ligand to mediate addition of lithiophenylacetonitrile to pivalaldehyde. The results obtained generally demonstrated that weakly donating solvents are better than strongly donating solvent for inducing asymmetry with diamine ligands.

Chapter 3 describes attempts to mediate the nitrile aldol reaction with lithium alkoxides of chiral aminoalcohols. A wide range of both commercially available and synthetic aminoalcohols were explored; the best of these proved to be ephedrine. The effects of solvent, substrate concentration, reaction time, ligand concentration on enantioselectivity were studied in detail to establish the optimum conditions for asymmetric nitrile aldol reaction. The optimum solvent was found to be dimethoxymethane (DMM), and surprisingly %ee was found to increase with time, reaching a maximum after 12 hours at -78℃. A number of nitrile/aldehyde combinations were explored, and the best results were obtained with phenylacetonitrile/pivalaldehyde (40% ee) and 2-naphthylacetonitrile/pivalaldehyde ((-)77% ee). Subjecting the corresponding racemic aldols to the same reaction conditions results in recovery of the aldols in 31% ee and (-)86% ee respectively. The success of these "deracemization" experiments proves that the enantioselectivity of the nitrile aldol reaction is thermodynamically controlled. Our reaction is thus a rare example of an "asymmetric transformation of the first kind".