A Study On Alicyclic Secondary Amines Catalyzed Aldol Reaction Of Aldehydes

The asymmetric aldol reaction is one of the most important methods of forming carbon-carbon bonds. It has been known that small organic molecules can catalyze the direct aldol reaction between aldehydes or between aldehyde and ketone. However, the substrate scope of this catalytic reaction is still narrow up to now. There are few reports refered to the aldol reaction converned on reactive or functionalized aldehydes, although the aldol products with various functional groups are very useful. In this thesis, the cross aldol reactions of aliphatic ketones or aldehydes with reactive aldehydes or 3-phthalimidopropanal were studied by using alicyclic secondary amines as catalysts.In view ofα-trichloromethyl alcohols, especiallyβ-trichloromethyl-β-hydroxy aldehydes are easily converting into biologically important compounds and natural products, in the second part of the thesis, direct catalytic cross aldol reaction of chloral with aliphatic aldehydes was investigated. Through screening the organocatalysts in different solvents, we found that both piperidine and L-prolinamide are the efficient catalysts for the cross aldol reaction, while the competitive self-aldol reacrion of aliphatic aldehyde is markedly restrained. In fact, in the presence of 20 mol% of piperidine, the cross aldol reaction undergoes smoothly when equimolar amounts of aliphatic aldehyde and chloral are used, givingβ-trichloromethyl-β-hydroxy aldehydes in high yield (up to 87%). In the case of L-prolinamide, the aldol products 118 were isolated in up to 95% yield with 88% ee. In addition, the baker's yeast mediated reduction of chiral 118a (80% ee) underwent smoothly and afforded the higher enantioselective primary alcohol 122a (95% ee).Due to the usefulness ofα-trifluoromethylated in drugs and materials, it becomes an interesting task to search for a suitable approach to such compounds for synthetic chemists. The synthesis ofβ-hydroxy-β-trifluoromethyl ketones was commonly performed through the reaction of trifluoroacetaldehyde ethyl hemiacetal with enamines or silyl enolates. In the third part of the thesis, we described that the direct aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with ketones or aldehydes catalyzed by alicyclic secondary amines. Chosing the aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with cyclohexanone as a model system, the catalytic reactivity of secondary amines was investigated and the reaction progress was followed by GC analysis. The results clearly demonstrated that pyrrolidine was an appropriate catalyst for this reaction and the catalytic reactivity of pyrrolidine was much higher than piperidine. Three interesting phenomena were also observed. 1) the concentration of hemiaminal formed in situ was almost kept constant at the initial stage, and started to decrease slowly when the hemiacetal was completely consumed. 2) the reaction preferentially gave anti-138b initially, and was gradually converted in situ into syn-138b during the reaction. 3) the concentration of the catalyst and the enamine intermediates were kept extremely low during the reaction. Based on these observations, we suggested that formation of the enamine would be a rate-determining step for the catalytic aldol reaction.Pyrrolidine-catalyzed aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with other ketones such as linear aliphatic ketones, alicyclic ketones and aromatic ketones as well as aliphatic aldehydes were tested under similar conditions and the reaction proceeded smoothly to afford the aldol products in good yields. Among all the ketones, cyclopentanone was the most reactive. In fact, piperidine, a poor catalyst, can effectively catalyze the aldol reaction of hemiacetal with cyclopentanone. In addition, the asymmetric aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with cyclohexanone catalyzed by L-prolinamide was also discussed. The aldol product 138b was afforded in 92% yield with high enantioselectivity (88% ee).Since L-prolinamide was an efficient catalyst for the direct cross aldol reactions of chloral or fluoral, in the fourth part of the thesis, we continued to explore the cross aldol reaction of another reactive aldehyde, glyoxylate with aliphatic ketones and aldehydes. For the direct cross aldol reaction of glyoxylate with branched aldehydes was not reported hitherto and the cross adduct was easily converted into pantolactone and pantolactam. The L-prolinamide catalyzed asymmetric cross aldol reaction of benzyl glyoxylate with isobutanal was investigated, and afforded the cross adducts 151 in good yield (93%) with moderate enantioselectivity (52%). The aldol product 151 was easily converted into pantolactam in high yield through a reductive amination.In the fifth part of the thesis, base on the observations for the L-proline catalyzed asymmetric aldol reaction ofβ-amino aldehyde, we have developed a highly enantioselective approach for preparing optically active bicyclic piperidines. The L-proline catalyzed asymmetric aldol or Mannich reaction of 3-phthalimidopropanal with aliphatic ketones was investigated in details. The cross adducts 171 were afforded in good yields in the reactions with alicyclic ketones. A high enantioselectivity up to 99 % ee was also observed. Then, the possible synthetic routes and the reaction conditions were evaluated, and a workable synthetic route to the target bicyclic 4-hydroxypiperidine 176 was found. After treating 171 with excess NaBH4, the reduction mixture was heated in acetic acid at 80 oC. The obtained amino alcohol was further benzoylated without isolation with benzoyl chloride, affording the desired amino protective product 180. When the tosylation of 180 was performed with tosyl chloride, almost only the desired tosylates 181 was given. Subsequent cyclization carried out by treatment with NaH produced 182. Deprotection of 182a was achieved by refluxing in NaOH aqueous solution, and the target bicyclic 4-hydroxypiperidine 176a obtained in 18% overall yield. The application of 176 to the catalytic direct aldol reaction is underway.