Dual Lewis Acid/Lewis Base Catalyzed Acylcyanation of Aldehydes: A Mechanistic Study.

A mechanistic investigation, which included a Hammett correlation analysis, evaluation of the effect of variation of catalyst composition, and low-temperature NMR spectroscopy studies, of the Lewis acid-Lewis base catalyzed addition of acetyl cyanide to prochiral aldehydes provides support for a reaction route that involves Lewis base activation of the acyl cyanide with formation of a potent acylating agent and cyanide ion. The cyanide ion adds to the carbonyl group of the Lewis acid activated aldehyde. O-Acylation by the acylated Lewis base to form the final cyanohydrin ester occurs prior to decomplexation from titanium. For less reactive aldehydes, the addition of cyanide is the rate-determining step, whereas, for more reactive, electron-deficient aldehydes, cyanide addition is rapid and reversible and is followed by rate-limiting acylation. The resting state of the catalyst lies outside the catalytic cycle and is believed to be a monomeric titanium complex with two alcoholate ligands, which only slowly converts into the product.

Synthesis of the ß3-adrenergic receptor agonist solabegron and analogous N-(2-ethylamino)-ß-amino alcohols from O-acylated cyanohydrins - expanding the scope of minor enantiomer recycling.

A novel methodology to produce highly enantioenriched N-(2-ethylamino)-ß-amino alcohols was developed. These compounds were obtained from O-(α-bromoacyl) cyanohydrins, which were synthesized by the minor enantiomer methodology employing a Lewis acid and a biocatalyst, followed by nucleophilic substitution with amines and reduction. The importance of the developed methodology was demonstrated by completing a highly enantioselective total synthesis of the ß3-adrenergic receptor agonist Solabegron.

Enantioselective acylphosphonylation-dual Lewis acid-Lewis base activation of aldehyde and acylphosphonate.

Acetoxyphosphonates were obtained by a one-step procedure consisting of reaction of diethyl acetylphosphonate with prochiral aldehydes in the presence of a catalytic system comprising a chiral Lewis acid, an achiral Lewis base, and a Brønstedt base. Best results were obtained using a tridentate Schiff base aluminum(III) Lewis acidic complex, 1H-1,2,3-benzotriazole, and a tertiary amine such as DBU. The target compounds were in most cases obtained in high yields, but with moderate enantiomeric ratios (up to 78:22).

Minor enantiomer recycling: application to enantioselective syntheses of beta blockers.

Continuous recycling of the minor product enantiomer obtained from the acetylcyanation of prochiral aldehydes provided access to highly enantiomerically enriched products. Cyanohydrin derivatives, which under normal conditions are obtained with modest or poor enantiomeric ratios, were formed with high enantiomeric purity by using a reinforcing combination of a chiral Lewis acid catalyst and a biocatalyst. The primarily obtained products were transformed into ß-adrenergic antagonists (S)-propanolol, (R)-dichloroisoproterenol, and (R)-pronethalol by means of a two-step procedure.

One-step preparation of O-(α-bromoacyl) cyanohydrins by minor enantiomer recycling: synthesis of 4-amino-2(5H)-furanones.

O-(α-Bromoacyl) cyanohydrins were prepared in a single step from a range of different aldehydes in combination with α-bromoacyl cyanides. By the use of a cyclic procedure where the two minor diastereoisomers from a chiral Lewis acid-catalyzed reaction undergo Candida antarctica lipase B (CALB)-catalyzed hydrolysis followed by dehydrocyanation to regenerate the starting material, the products were obtained in good to high yields and in most cases with excellent diastereoselectivites. The synthetic importance of these compounds was demonstrated by the synthesis of 4-amino-2(5H)-furanones, a class of compounds that have shown both biological activity and utility as synthetic intermediates. This transformation was achieved by an intramolecular Blaise reaction, which gave the products in high to excellent yields and enantiomeric ratios.