N, N-dibenzyl-¦Á-amino Aldehydes As A Substrate Asymmetric Nucleophilic Addition Reactions

In the modern organic synthesis, one of the most attractive approaches is synthesis of enantiopure compounds using either catalytic asymmetric reactions or chiral pools. As a frequently used chiral pool, (-amino acids have been found extensive applications in the organic synthesis. N,N-dibenzyl (-amino aldehydes are a class of relatively new compounds that are ready to be transformed into a variety of synthetically useful intermediates. Discovery of new reactions based on these starting materials would prompt their further utilization. In this thesis, we wish to describe our efforts toward the development of asymmetric nucleophilic addition reaction to N,N-dibenzyl (-amino aldehydes catalyzed by chiral reagents.In the first part of the thesis, we first synthesized 14 chiral guanidines started from chiral amines or natural amino acids, and then checked their suitabilities as the chiral catalysts. The first reaction we tested was asymmetric Henry reaction of N,N-dibenzyl (-amino aldehydes with nitromethane. We found that for this reaction moderate to good diastereoselectivity was obtained under the catalysis of chiral guanidines. Highest d.e. values (>90%) were observed when L-valine or L-isoleucine derived N,N-dibenzyl (-amino aldehyde 15b and 15d were used as the substrates and (R)-1-(1-naphthyl)ethylamine derived guanidine 85c was employed as the catalyst. The second reaction we tested was diastereoselective Michael-Aldol annulation of (-keto ester 121 with methacrolein to give a key intermediate for synthesizing (-)-Huperzine A. The best result (73.2% de) was obtained in case of benzyl (S)-lactate derived (-keto ester 121i as the substrate and (1R,2R)-diaminocyclohexane derived guanidine 85i as the catalyst.In the second part of the thesis, we discussed a L-proline-catalyzed direct Aldol reaction between L-amino acid-derived N,N-dibenzyl (-amino aldehydes 15 and acetone, cyclopentanone or hydroxyacetone, which afforded (-amino-(-hydroxy- or (-amino-(,(-dihydroxy-ketones in good to excellent yields (up to 94%) and diastereoseletivities (up to 94.9%).We also converted (-amino-(,(-dihydroxy-ketone 171d, a major Aldol product of hydroxyacetone with L-leucine derived N,N-dibenzyl (-amino aldehyde 15g, into an amino acid segment 184 via oxidative cleavage with sodium hypobromite. This intermediate is suitable to synthesize PM-94128, a natural antitumor agent.