Asymmetric Synthesis of Chiral Aldehydes by Conjugate Additions with Bifunctional Organocatalysis by Cinchona Alkaloids

Abstract

The aldehyde is arguably the most versatile carbonyl functionality. Furthermore, it is more active than any other carbonyl functionality toward a plethora of nucleophilic reactions. This unique combination of functional versatility and activity renders chiral aldehydes highly valuable intermediates in asymmetric synthesis. The emergence of numerous catalytic enantioselective reactions that involve aldehydes as either nucleophiles or electrophiles further enhances the synthetic value of chiral aldehydes. Enantioselective transformations of the readily available prochiral aldehydes are now emerging as a fundamentally important approach toward optically active aldehydes. In particular, great strides have been made in the development of enantioselective bond formations with the a-carbon atom of prochiral aldehydes with chiral enamine catalysis, [1,2] enantioselective cycloadditions and Friedel-Crafts reactions with chiral immonium catalysis, [3] and conjugate additions of aryl boronic acids and silyl nitronates to a,b-unsaturated aldehydes by chiral transition-metal catalysis [4] and chiral phase-transfer catalysts, [5] respectively. Despite its synthetic importance, the highly enantioselective and general conjugate addition of carbonyl donors to a,b-unsaturated aldehydes remains elusive, even with considerable efforts. [6][7][8] Herein, we wish to report significant progress toward the development of such a reaction with cinchona-alkaloid-derived organic catalysts.At the outset of our investigations, we were concerned that the decomposition of 3 a could be triggered by cinchona alkaloids as nucleophilic catalysts (Scheme 1) in light of the well-documented nucleophilic catalysis of 1,4-diazabicyclo-[2.2.2]octane (DABCO) and quinuclidine in the MoritaBaylis-Hillman (MBH) reaction.[9] Indeed, 3 a was found to rapidly undergo decomposition to form insoluble oligomers or polymers in the presence of DABCO, quinuclidine, or bisocupreidine. On the other hand, mechanistic studies by us established that cinchona alkaloids, such as dihydroquinidine

Theoretical study of enantiomeric and geometric control in chiral guanidine-catalyzed asymmetric 1,4-addition of 5H -oxazol-4-ones

“…In contrast with the extensive application of conjugated alkenyl carbonyl compounds [1,2] in the synthesis of biologically active products, [3,4] the use of alkynyl carbonyl compounds in catalytic 1,4-addition is relatively few. [5,6] Moreover, in the construction of olefin product with chiral quaternary stereogenic center, the enantiomeric and geometric controls are of great significance and still remain a challenge.…”

Asymmetric Synthesis of the β-Methyl-Substituted Analogues of (+)-Tanikolide and (–)-Malyngolide

“…13 C-NMR are referenced to the residual solvent peak (CDCl 3 = δ 77. 16 NaH (60 % in mineral oil, 3.0 g, 75.0 mmol) was placed in a dry 250 mL two-neck round bottom flask containing a magnetic stirring bar under inert atmosphere and washed with anhydrous hexanes (2 × 10 mL) and dried under high vacuum. Dry THF (150 mL) was added to the reaction flask and ethyl-2-(diethoxyphosphoryl) acetate 16 (10.1 mL, 50.8 mmol) in dry THF (20 mL) was added drop-wise over 20 min to the reaction mixture with H 2 gas being evolved.…”

“…A number of different strategies have been employed in previous syntheses of (+)-tanikolide [3][4][5][6][7][8][9][10] including Sharpless asymmetric epoxidation/dihydroxylation of allylic alcohols [11][12][13][14], the use of enantiopure starting materials D-erythrulose [10], and D-erythrose [9], stereospecific C-H insertion of dichlorocarbene with a chiral secondary alcohol [15], an asymmetric α-alkylation of a β-keto ester and subsequent Bayer-Villiger oxidation [16], α-metallation of ketones and ring closing metathesis [10,12,17,18]. Domino reactions of epoxy alcohols with hypervalent iodine reagents [14,19] and asymmetric dihydroxylation of enamides have also been investigated [20].…”

Organocatalytic Conjugate Addition in Stereoselective Synthesis

“…73 Activation of the keto-ester by the tertiary amine and addition to acrolein creates the new CÀC bond controlling the challenging tetra-substituted carbon center of tanikolide with a perfect 99% ee. Only 2.5 equivalents of inexpensive acrolein were needed in the reaction despite the well-known tendency of acrolein to polymerization.…”