Asymmetric Direct Aldol Reaction Catalyzed By L-proline

The aldol addition reaction is one of the most widely used synthetic reactions for the construction of stereochemically complex, natural and unnatural products. As a result of this reaction, a new carbon-carbon bond is formed and one or two new stereogenic centers can be generated simultaneously. The real breakthrough about direct asymmetric aldol addition came from the pioneering work by List and Barbas and their co-wokers over recent years. In this respect, they have identified that proline, which is an abundant chiral molecule that is inexpensive and available in both enantiomeric forms, is a privileged molecule for diversity enantioselective aldol reactions. Traditionally, the substrates as acceptors or electrophiles in intermolecular asymmetric aldol reactions are mostly aldehydes, which have higher activity than ketones. To broaden the applicability of the present method is a significant challenge.In this thesis, we described the aldol reaction of activated ketones, includingα-ketoamides andα-ketoesters with an aliphatic methyl ketone, such as acetone, and their Henry reaction. In the presence of L-proline, acetone and butanone could add toα-ketoamides orα-ketoesters to form the corresponding tertiary alcohols in the yields of 21%~99% with enantioselectivities up to 81% e.e. The Henry reaction of cyclicα-ketoamides andα-ketoesters was achieved using triethylamine as a promoter. New multi-functionalβ-nitroalcohols were produced in high yield under mild reaction conditions.More interestingly, addition of acetone to 2-oxo-3-aryl-succinates under L-proline catalysis in acetonitrile at room temperature, realized dynamic kinetic resolution of the substituted succinates, providing the desired adduct in good yield with up to 87 : 13 dr and high e.e. up to 99% for both the major and the minor diastereomers. Similarly,β-Cyano-α-oxoesters were found to undergo asymmetric aldol addition reaction with acetone in the presence of 10 mol% of L-proline. With the racemic starting material, dynamic kinetic resolution (DKR) was achieved in quantitative yields with good diastreroselectivity of up to 85 : 15 dr and excellent e.e. up to 99% for the major diastereomer.1 Asymmetric aldol reaction between methyl ketones andα-ketoamides catalyzed by L-prolineElevenα-ketoamides, which contain moderately electron-withdrawing amido groups to increase the positive charge density on the carbonyl carbon and hence increase their reactivities in proline catalyzed intermolecular aldol addition, were synthesized as aldol acceptors. Unfortunatedly, enantioselectivities of the aldol reactions betweenα-aroylamides 1a-1e and methyl ketones are very low. The reactions of isatin derivatives 4a-4e showed improved reactivity, provided better yields, however, the enantioselectivities were also low. When aliphatic amide 6a was employed as an acceptor, an improved enantioselectivity of 43% e.e. was observed. The causes of low enantioselectivities may include spatial and electronic factors of structures of acceptors. Probably, designing and synthesizing novel substrates and developing more efficient catalysts will be helpful to improving the enantioselectivity of the reaction.2 L-proline catalyzed asymmetric aldol reaction between methyl ketones andα-ketoestersConsidering that the ester group is stronger electron-withdrawing than amido group, We supposed that the aldol reaction betweenα-ketoesters and methyl ketones should occur more readily than that ofα-ketoamides. Compared to the reaction ofα-ketoamides, improved results were obtained. Thorough studies of these reactions manifested that there were several factors which affected the results of the reactions. Firstly, the reaction of butanone was much slower than the corresponding reaction of acetone and provided lower yield, but improved e.e. was found. Secondly, the structure of the substrate plays an important role in determining whether the reaction can occur easily or not, and whether the reaction can be enantioselective. Thirdly, theα-ketoester 12a, which has a fused aromatic system in the molecule, did not show any enantioselectivity in its reaction with acetone and its reaction with butanone did not occur. In conclusion, using 10 mol% of L-proline as the catalyst, acetone and butanone could add toα-ketoesters to form the corresponding tertiary alcohols in the yields of 43%~93% with enantioselectivities up to 81% e.e. Further studies focus on looking for more activated acceptors based on the structure ofα-ketoesters.3 Henry reaction ofα-ketoesters andα-ketoamides α-Ketoesters,α-Ketoamides and their derivatives have been used as key intermediates in the syntheses of complex organic and medicinal molecules. The Henry reaction may generateβ-nitroalcohols, which can further be converted to various valuable structural motifs. The Henry reaction of cyclicα-ketoesters andα-ketoamides was achieved using triethylamine as a promoter. Twelve new multi-functionalβ-nitroalcohols were synthesized. Their structures were confirmed by elemental analyses, IR, 1H NMR or 13C NMR spectroscopy.4 Dynamic kinetic resolution of 2-oxo-3-aryl-succinates by L-proline catalyzed asymmetric aldol reactionHere we designed and synthesizedα-ketoesters 18a-18m as aldol acceptors which exist as an equilibrium mixture of keto- and enol-form. Dynamic kinetic resolution (DKR) of this kind of compounds has been achieved in their asymmetric aldol reaction. We chose the addition of acetone to 2-Oxo-3-phenyl-succinic acid diethyl ester 18a in the presence of 10 mol% of L-proline as our research model. Among various solvents explored, acetonitrile was found most suitable for this reaction. In this solvent, the reaction proceeded smoothly and completed within 24 h, providing the adducts in good yield with 79 : 21 dr. Excellent e.e. for both the major (97%) and the minor product (96%) were observed. Research on the influence of temperature on the DKR of 18a in acetonitrile demonstrated the strong influence of temperature on the diastreroselectivity. A steady improvement in diastereomeric ratio can be observed as the temperature was being lowered. Long reaction time was required while the reaction was performed at–20°C. DKR reactions of many other 2-oxo-3-arylsuccinates 18b-18m were then investigated at rt using acetonitrile as the solvent. Data showed that for all ethyl and methyl 2-oxo-3-phenylsuccinates the reaction exhibited high selectivity, both syn- and anti-products were obtained in almost enantiopure form. Substituent on 3-phenyl did not affect the reaction a lot, although substrates with o- and p-chloro- and p-methoxy substituent on the 3-phenyl gave enantiopure syn- and anti-products. In the reaction of benzyl esters, the ee in both syn- and anti-product was dropped.For the absolute configuration asignment, single crystals of the minor diastereomer of 19l and the major diastereomer of 19h, were prepared and X-ray crystallographed. According to the results of the minor diastereomer of 19l, there are two independent molecules in the asymmetric unit. These have the same absolute cofigurations of (2R, 3R), but differ in the orintation of a carboxyl group. From the X-ray analysis of the major diastereomer of 19h, which consists of all-light-atom, only the relative configuration of syn, could be established. In this molecule, the hydroxyl and the aryl groups are on the same side of the C-C skeleton, Based on the known mechanism of L-proline-catalyzed asymmetric aldol reaction, these two compounds should have the same configuration at C-2, and hence the absolute configuration of the major diastereomer of 19h should be (2R, 3S). Considering the mechanistic similarity, in all reactions, the major and the minor diastereomers were considered as of (2R, 3S) and (2R, 3R), respectively.In this chapter, we have demonstrated the first highly enantio- and diastereoselective organocatalytic dynamic kinetic resolution (DKR) of 2-oxo-3-arylsuccinates. The reaction proceeds for a number of 2-oxo-3-arylsuccinates and acetone, forming adducts with two adjacent stereogenic centers. This work represents a rare use of organocatalysts in a dynamic kinetic resolution.5 Addition of acetone towardsβ-cyano-α-oxoesters catalyzed by L-proline: Dynamic kinetic resolutionBased on the similar consideration in the former Chapter,β-cyano-α-oxoesters 20a-20j were designed and synthesized as aldol acceptors. After optimization of the reaction conditions with 20a, DKR reactions of substrates 20b-20j were then conducted at 20°C in acetone, using 10 mol% of L-proline as the catalyst. In all reactions, the combined yields of diastereomers was quantitative, and high ee for the major adduct could be achieved. Substituent on 3-phenyl did not affect the reaction a lot. It looks likely that, small alkyl in the ester group tended to provide higher stereoselectivity than the larger ones.In summary, we have developed an efficient method for the dynamic kinetic resolution ofβ-cyano-α-oxoesters via L-proline catalyzed asymmetric aldol reaction, which proceeded well for a number of substrates in various solvents providing quantitative yield with high e.e. of the major diastereomeric isomer up to 99%.