Asymmetric aldol reactions stereoselective synthesis

T. Nakata et al. developed a simple and efficient synthetic approach to prepare (+)-methyl-7-benzoylpederate, a key intermediate toward the synthesis of mycalamides. The key steps were the Evans asymmetric aldol reaction, stereoselective Claisen condensation and the Takai-Nozaki olefination. The diastereoselective Claisen condensation took place between a 5-lactone and the lithium enolate of a glycolate ester. 

The stereoselectivities seem to be kinetically controlled. In fact, the ee of the aldol product was constant during the course of the reaction. Thus, we have succeeded in performing the first catalytic asymmetric aldol reaction between aldehydes and unmodified ketones by using heterobimetallic or heteropolymetallic catalysts. Several reactions have already been synthetically useful especially for tertiary aldehydes, leading to the catalytic asymmetric synthesis of key intermediates en route to natural products [63]. Further studies are currently in progress. 

Direct organocatalytic asymmetric aldol reaction of a-aminoaldehydes 35 with other substituted aldehydes furnishes S-hydroxy-a-aminoaldehydes with high anti-stereoselectivity. This procedure is of importance for the synthesis of a-aminosugars and derivatives. Additionally, the oxidation of aldehydes gives rise to highly enantiomerically enriched ant/-/3-hydroxy-a-amino acids (O Scheme 28) [156]. 

The aldol condensation is a powerful tool for the stereoselective synthesis of acyclic molecules with contiguous chiral centers. The catalytic asymmetric aldol reaction of ( )-2-rerr-butyldimethylsiloxy-2-phenylacetaldehyde (121) with the achiral silyl enol ether 1-ethylthio-l-trimethylsilyloxyethene (134) in the presence of tin(II) trifluoride and the chiral promotor ( S)-l-methyl-2-[(7V-naphthylamino)methyl]pyrrolidine (135) in propionitrile at — 78 °C proceeds smoothly to give a 94 6 mixture of diastereomeric aldol adducts 136 and 137 in 85% yield (Scheme 32). When performed on ( S)-129 this same reaction affords in 85% yield a 96 4 mixture of diastereomers 138 and 139. It is noteworthy that the newly created chiral centers in both of the major diastereomers 136 and 138 has the S configuration, suggesting that the stereochemistry of the aldol reaction is controlled by the chiral promotor and not the chiral aldehydes. 

The asymmetric aldol reaction using the Evans oxazolidinone auxiliary has been used in a number of syntheses. Suggest reagents for the preparation of the imide 2, used in a synthesis of cytovaricin and explain the stereoselectivity of this reaction. Suggest how you would obtain the other syn aldol product and explain the difference in the stereoselectivity. 

Chen J-R, Liu X-P, Zhu X-Y, Qiao Y-F, Zhang J-M, Xiao W-J (2007) Organocatalytic Asymmetric Aldol Reaction of Ketones with Isatins Straightfmward Stereoselective Synthesis of 3-Alkyl-3-hydroxyindolin-2-ones. Tetrahedron 63 10437... 

The synthesis of a novel Merrifield resin-supported dipeptide Pro-Ala-O-P, derived from proline and alanine, was reported by Wang and Yan with the aim of being used as an organocatalyst in asymmetric aldol reactions of ketones with aldehydes. " Indeed, this supported dipeptide was found to be an efficient catalyst to promote the asymmetric aldol reaction under neat conditions between aromatic aldehydes and cyclic ketones, generating the corresponding aldol products with moderate to high yields and diastereoselectivities of up to 80% de combined with good enantioselectivities of up to 95% ee, as shown in Scheme 2.18. Moreover, this catalyst could be used for seven times with only a minor decrease in product yields, but maintained stereoselectivities. 

Conventional asymmetric aldol reactions have been performed by using chiral enolates and achiral carbonyl compounds. A chiral boron enolate generated from a chiral oxazolidone derivative (26 and 28), dialkylboron tri-fiate, and diisopropylethylamine reacts stereoselectively with aldehydes to afford the corresponding syn aldol adducts (27 and 29) in good yields with excellent diastereoselectivity (Eqs. (8) and (9)) [12]. The opposite sense of asymmetric induction is achieved by changing the chiral auxiliary. Several other chiral auxiliaries have also been developed for highly diastereoselec-tive synthesis of syn aldol adducts (Eqs. (10)-(13)) [13]. 

Stereoselective Synthesis of 1,3-Diols Asymmetric Aldol Reactions... 

Chen JR, Liu XP, Zhu XY, Li L, Qiao YF, Zhang JM, Xiao WJ. Organocatalytic asymmetric aldol reaction of ketones with isatins straightforward stereoselective synthesis of 3-alkyl-3-hydroxyindolin-2-ones. Tetrahedron 2007 63 10437-10444. 

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