4‐Aminothiourea Prolinol tert‐Butyldiphenylsilyl Ether: A Chiral Secondary Amine‐Thiourea as Organocatalyst for Enantioselective anti‐Mannich Reactions

Abstract

anti-Selective Mannich reactions of N-pmethoxyphenyl (PMP)-protected a-iminoglyoxylate with unmodified aldehydes or ketones were effectively catalyzed by 4-aminothiourea prolinol tert-butyldiphenylsilyl ether. The reactions led to chiral bamino carbonyl compounds in high yields (up to 94%), excellent diastereo-and enantioselectivities (up to 98% de and > 99% ee). The study demonstrated for the first time that direct Mannich-type reactions of unmodified aldehydes or ketones to aiminoglyoxylate can be promoted by secondary amine-thiourea chiral organocatalyst.Keywords: b-amino carbonyl compounds; 4-aminothiourea prolinol tert-butyldiphenylsilyl ether; asymmetric anti-Mannich reactions; secondary amine-thiourea organocatalyst Direct catalytic asymmetric Mannich reactions are highly effective carbon-carbon bond forming reactions, [1] to build b-amino acids, amino alcohols, amino carbonyls, and their derivatives that contain two adjacent stereocenters. Due to the wide utility of these synthons, especially in pure syn-or anti-form, it is highly desirable to develop stereoselective methods. In this respect, the catalytic asymmetric Mannich-type reaction has recently been the subject of intense research, [2][3][4][5][6][7][8] and tremendous efforts have been focused on the development of an organocatalytic asymmetric version of the reaction. Great success has been achieved in the development of syn-selective direct organocatalytic asymmetric Mannich-type reactions [3,4] wile anti-selective Mannich reactions are considerably more challenging and only a limited number of reports were documented. [5][6][7][8] In this context, pyrrolidine-based derivatives were found to be generally more effective catalysts, as demonstrated by the work of the Barbas group: pyrrolidine derivatives (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and 3-pyrrolidinecarboxylic acid as effective catalysts for anti-selective Mannich-type reactions with unmodified aldehydes and ketones as nucleophiles; [5b-d] Blanchets group has developed 3-trifluoromethanesulfonamidopyrrolidine [5g] and Maruokas group has discovered that chiral cyclic amines were effective catalysts with high diastereoselectivity and enantioselectivity; [5h-l] Good results were also achieved by using other organocatalysts, including acyclic primary amino acids, [6] chiral Brønsted acids [7] and primary amine-thioureas [8] in direct anti-selective Mannich reactions. In these catalytic systems, solvents such as DMSO and DMF were often chosen as the reaction media, because most of the catalysts, especially chiral amino acids and some chiral amino sulfonamides were hardly soluble in less polar solvents. Although these reactions are highly enantioselective, removal of such high boiling-point solvents has engendered inconveniency, especially in practical synthesis. Thiourea-based organocatalysts have been widely used in asymmetric catalysis due to their strong activation efficiency through double hydrogen-bonding. [9] Among them, Chens group has successfully used chiral secon...

Asymmetric Organocatalysis

“…Peng and co-workers have developed a chiral secondary amine-thiourea organocatalyst, 4-aminothiourea prolinol tert-butyldiphenylsilyl ether 26, which was applied to the direct anti-selective asymmetric Mannich reaction (Scheme 6) [45]. The direct Mannich reaction of cyclohexanone with N-p-methoxyphenyl a-iminoglyoxylate proceeded smoothly in the presence of 5-10 mol% of 26 in CH 2 ClCH 2 Cl to afford anti-product in a high yield and with excellent diastereo-and enantioselectivity.…”

A 4‐Hydroxypyrrolidine‐Catalyzed Mannich Reaction of Aldehydes: Control of anti‐Selectivity by Hydrogen Bonding Assisted by Brønsted Acids

“…Pyrrolidines 17 26 and 18 27 that work through the same model have also been reported by Blanchet and Maruoka, independently. More recently, the thiourea‐based catalyst 19 that combines structural features of catalysts 13 and 18 has been reported by Peng for the same reaction 28. Accordingly, the main limitation of all these contributions is that only α‐imino esters appear to be sufficiently reactive to give Mannich adducts with both chemical and stereochemical efficiency 29.…”

“…More recently, the thiourea-based catalyst 19 that combines structural features of catalysts 13 and 18 has been reported by Peng for the same reaction. [28] Accordingly, the main limitation of all these contributions is that only aimino esters appear to be sufficiently reactive to give Mannich adducts with both chemical and stereochemical efficiency. [29] One solution has been recently presented by Maruoka who has revealed that N-Boc (tert-butoxycarbonyl) imines from arylaldehydes may be utilized in the Mannich reaction by using chiral sulfonamide 14.…”

Asymmetric Synthesis with Silicon‐Based Bulky Amino Organocatalysts

“…When ketones were used as substrates, moderate to good yields were obtained but the enantioselectivities are excellent (up to 99% ee). [20] With realization of the importance of the Mannich reaction in the synthesis of b-amino acid derivatives, Gellman [21a] and Córdova [21b] successfully exploited the enantioselective organocatalytic method for the Mannich reaction between formaldehyde-derived Nbenzyl-N-(methoxymethyl)A C H T U N G T R E N N U N G (phenyl)methanamine (35) and aldehydes. Formaldehyde does not form stable imines, so the use of N-benzyl-N-(methoxymethyl)-A C H T U N G T R E N N U N G (phenyl)methanamine (35) as a precursor of the methylene iminium species is practical.…”