Enantioselective Diels–Alder reactions catalyzed by hydrogen bonding

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, ␣,␣,␣ ,␣ -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 , -stacking plays an central role in the overall catalytic cycle, in particular, the enantioselective step.M ost biomolecules are asymmetric (chiral), that is, they are not superimposable on their mirror image. Likewise, small molecules that might be used to modulate the response of the biomolecule are also frequently chiral. One mirrorimage form (enantiomer) of the small molecule may elicit a desirable response, such as stimulation or inhibition of a particular function, whereas the other image might produce no response or a completely different response. It is, in part, for this reason that a tremendous effort has been put into the development of methods for the selective synthesis of one enantiomer. In 2002, single enantiomer drugs comprised 37% ($152 billion) of the total market of Ϸ$400 billion. This number is projected to increase steadily, such that chiral drugs will constitute a market of Ͼ$200 billion by 2008. The growing economic importance of chiral compounds has spurred major research efforts from many laboratories, academic and industrial, directed at the selective preparation of chiral compounds. In this report, we describe our results on the hydrogenbonding-mediated catalysis of the all-carbon Diels-Alder reaction.The premier process for forming functionalized cyclohexenes, with up to four new stereogenic centers (1), the Diels-Alder reaction plays a pivotal strategic role in the synthesis of numerous complex natural products (2). The steady evolution of this reaction...

Recent Progress in Chiral Brønsted Acid Catalysis

“…[42] The TADDOL catalyst 11 proved to be effective for the vinylogous Mukaiyama aldol reaction to give the corresponding aldol products highly enantioselectively (Scheme 24). The aldol products should be useful for the preparation of polyketides.…”

Computational design of a lipase for catalysis of the Diels-Alder reaction

“…[34] These values are expected to be similar using lipase oxyanion holes, so the main concern for the viability of lipases such as CALB therefore lies in the ligandreceptor dynamics. From data on molecular catalysis reported in the literature, we can conclude that rather high catalyst concentrations are required for a reasonable activation, typically around 1-20 mol-%, [35,36,37,38] which is not possible with enzymes. Thus the binding constant between the enzyme and both substrate must be sufficiently low.…”

Development of New Chiral Br^|^oslash;nsted Acid Catalysis

“…16 After the two step transformations from the initial cycloadducts, a variety of chiral cyclohexenones were obtained with high enantioselectivies (up to 92% ee). Furthermore, our group and the Rawal group have found that the axially chiral BAMOL (1,1 biaryl 2,2 dimethanol) scaffold to be highly effective for the catalysis of the hetero Diels Alder reactions of a wide range of aliphatic and aromatic aldehydes (Scheme 7).…”