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. 2004 Apr 20;101(16):5846-50.
doi: 10.1073/pnas.0308545101. Epub 2004 Apr 6.

Enantioselective Diels-Alder reactions catalyzed by hydrogen bonding

Avinash N Thadani  1 , Ana R Stankovic, Viresh H Rawal
Affiliations

Enantioselective Diels-Alder reactions catalyzed by hydrogen bonding

Avinash N Thadani et al. Proc Natl Acad Sci U S A. .

Abstract

Like molecules of life (e.g., proteins and DNA), many pharmaceutical drugs are also asymmetric (chiral); they are not superimposable on their mirror images. One mirror image form (enantiomer) of a drug can have desirable activity, the other not. Consequently, the development of methods for the selective synthesis of one enantiomer is of great scientific and economic importance. We report here that a simple, commercially available chiral alcohol, alpha,alpha,alpha',alpha'-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL), catalyzes the all-carbon Diels-Alder reactions of aminosiloxydienes and substituted acroleins to afford the products in good yields and high enantioselectivities (up to 92% enantiomeric excess). It is remarkable that the reactions are promoted by hydrogen bonding, the ubiquitous "glue" that helps to keep water molecules together and holds up the 3D structures of proteins. Hydrogen bond catalysis is little used in chemical synthesis, wherein most reactions are promoted by complexes of Lewis acidic metal salts coordinated to chiral ligands. As it does for enzymes, hydrogen bonding not only organizes TADDOL into a well defined conformation, but, functioning as a Brønsted acid catalyst, it also activates the dienophile toward reaction with the diene. The gross structure of the TADDOL has been found to have a profound influence on both the rate and the enantioselectivity of the cycloadditions. These structure-function effects are rationalized by evaluating the conformation adopted by the TADDOLs in the crystal state. It is suggested that pi,pi-stacking plays an central role in the overall catalytic cycle, in particular, the enantioselective step.

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Figures

Fig. 1.
Fig. 1.
Solid-state structures of TADDOL 4a–c.
Fig. 2.
Fig. 2.
Plot of enantioselectivity (ee) versus temperature for the TADDOL-catalyzed Diels–Alder reaction of aminosiloxydiene 1. Shown is the effect of temperature on enantioselectivity.
Fig. 3.
Fig. 3.
Structures of compounds 8f and 9f.
Fig. 4.
Fig. 4.
A proposed working model for the TADDOL-catalyzed Diels–Alder reactions
See this image and copyright information in PMC

References

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