Proline-catalyzed Asymmetric Aldol Reactions Research Articles

Decoding the impact of solvents in altering the conversion rates and stereoselectivity in proline-catalyzed asymmetric aldol reaction

Decoding the impact of solvents in altering the conversion rates and stereoselectivity in proline-catalyzed asymmetric aldol reaction

Advancements and Expansions in the Proline-Catalyzed Asymmetric Aldol Reaction

Advancements and Expansions in the Proline-Catalyzed Asymmetric Aldol Reaction

Solid-Phase Synthesis of β-Hydroxy Ketones Via DNA-Compatible Organocatalytic Aldol Reactions.

One-bead one-compound (OBOC) libraries constructed by solid-phase split-and-pool synthesis are a valuable source of protein ligands. Most OBOC libraries are composed of oligoamides, particularly peptides, peptoids, and peptoid-inspired molecules. Further diversification of the chemical space covered by OBOC libraries is desirable. Toward this end, we report here that the proline-catalyzed asymmetric aldol reaction, developed by List and Barbas for solution-phase synthesis, also works well for coupling immobilized aldehydes and soluble ketones. These reaction conditions do not compromise the amplification of DNA by the polymerase chain reaction. Thus, this chemistry should be useful for the construction of novel DNA-encoded OBOC libraries by solid-phase synthesis.

Improved Conditions for the Proline-Catalyzed Aldol Reaction of Acetone with Aliphatic Aldehydes

The proline-catalyzed asymmetric aldol reaction between aliphatic aldehydes and acetone has, to date, remained underdeveloped. Challenges in controlling this reaction include avoiding undesired side reactions such as aldol condensation and self-aldolization. In recent years we have developed optimized conditions, which enable high yields and good to excellent enantioselectivities, and which are presented in this communication.

Enamine versus Oxazolidinone: What Controls Stereoselectivity in Proline‐Catalyzed Asymmetric Aldol Reactions?

Take the right path: Comparison of the oxazolidinone and enamine pathways in enantioselective aldol reactions by using density functional and ab initio transition states reveals that the oxazolidinone route does not provide the correct stereochemical outcome (see picture), whereas the enamine pathway predicts the correct stereoselectivity.

プロリン触媒不斉アルドール反応を基軸とする生理活性天然物の合成

Recent advances in the field of organocatalytic asymmetric synthesis have provided several new methods for preparing chiral compounds in an environment-friendly manner. Among them, proline-catalyzed asymmetric aldol reactions gather a considerable attention from synthetic chemists. In our recent work on the synthesis of (5R,6S)-(−)-6-acetoxy-5-hexadecanolide, we found that aldehydes bearing a 1,3-dithiane moiety at the β-position could serve as a useful synthon of straight-chain aliphatic aldehydes. This method has been successfully applied to the enantioselective synthesis of biologically interesting natural products such as (+)-boronolide, D-ribo-C18-phytosphingosine, pachastrissamine, and (+)-prosophylline.

Asymmetric Aldol Reaction in Water Catalyzed by Polystyrene-Supported Proline

The polystyrene (PS) resin supported proline-catalyzed asymmetric aldol reaction in water was described. Thus, the reaction of 4-hydroxy-l-proline with 4-chloromethylstyrene gave styrene derivative 1 in 80% yield. The radical reaction of 1 with polystyrene-supported thiol followed by cleavage of the Boc group with TFA afforded PS resin supported proline 2 (eq. 1). The asymmetric aldol reaction of cyclohexanone with 4-cyanobenzaldehyde was carried out in the presence of 10 mol% of 2 in water to give the aldol product 3 (98% conversion, anti/syn = 95:5, 98% ee) (eq. 2). Although less conversion was observed, catalyst 2 can be reused four times without loss of ­diastereoselectivity and enantio­selectivity.

Synthesis of (−)-(5 R,6 S)-6-acetoxyhexadecanolide based on l-proline-catalyzed asymmetric aldol reactions

A convenient method for proline-catalyzed asymmetric aldol reactions using synthons of straight-chain aliphatic aldehydes, and aldehydes bearing a 1,3-dithiane moiety at the β-position, has been developed. This method was successfully applied to the synthesis of (−)-(5 R,6 S)-6-acetoxyhexadecanolide, an oviposition attractant pheromone of the female Culex mosquito.

Density functional theory study of the 5-pyrrolidin-2-yltetrazole-catalyzed aldol reaction

The replacement of the carboxylic acid functionality with a tetrazolic acid in the proline-catalyzed asymmetric aldol reaction between acetone and trimethylacetaldehyde has been studied using DFT methods at the B3LYP/6-31G** computational level. For the C–C bond-formation step, four reactive channels corresponding to the syn and anti arrangement of the enamine and the re and si attack modes have been analyzed. The B3LYP/6-31G** results allowed us to explain the stereoselectivity and the increase in reactivity relative to the proline-catalyzed process in DMSO.

Proline-catalyzed asymmetric aldol reactions of tetrahydro-4 H-thiopyran-4-one with aldehydes

Proline-catalyzed enantioselective direct intermolecular aldol reactions of tetrahydro-4 H-thiopyran-4-one with various aldehydes give anti adducts with high diastereo- and enantioselectivities in moderate to excellent yields. With the aromatic aldehydes best results were obtained in wet DMF whereas dry DMSO generally was superior with the aliphatic aldehydes. Desulfurization of the adducts with Raney Ni provides products equivalent to aldols from 3-pentanone with potential applications in polypropionate synthesis.

Proline-catalyzed asymmetric aldol reactions between ketones and alpha-unsubstituted aldehydes.

[reaction: see text] With this communication we extend the methodology of proline-catalyzed direct asymmetric aldol reactions to include alpha-unsubstituted aldehydes as acceptors. This important aldehyde class gives the corresponding aldols in 22-77% yield and up to 95% ee when the reactions are performed in pure acetone or in ketone/chloroform mixtures. On the basis of these results we have developed a concise new synthesis of (S)-ipsenol.