Anti-Selective Mannich Reactions

Isayama described the coupling reaction of N-methylimine 157 and ethyl crotonate catalyzed by Co(acac)2 and mediated by PhSiH3 to produce Mannich product 158 in 82% with syn-selectivity (Scheme 41) [71]. The (i-laclam 159 was readily synthesized by heating 158. In 2002, Matsuda et al. reported cationic Rh complex [Rh(COD) P(OPh)3 2]OTf (1 mol%) as an active catalyst for the reductive Mannich reaction [72]. N-Tosylaldiminc 160 was coupled with methyl acrylate and Et2MeSiH (200 mol%) at 45 °C to give the b-amino ester 161 in 96% with moderate anti-selectivity 68%. 

The scope of the enamine-catalyzed Mannich reaction can be considerably expanded by the use of preformed imines. These two-component Mannich reactions can be either syn selective [91, 94, 136, 220, 222, 230-233, 245, 248-258] (proline or its simple derivatives as catalysts) or anti selective [220, 259-268]... 

Chiral palladium complexes have been employed as enantio- and diastereo-selective catalysts of a Mannich-type addition of /3-kclo esters to aldimines and imino esters, q. in a strategy which activates both reactants 28 anti-Selective direct enantioselective Mannich reactions use a BINAP-derived axi- ally chiral aminosulfonamide as organocatalyst.29... 

High anti-diastereoselectivity is observed for several aromatic imines for ortho-substituted aromatic imines the two newly formed stereocenters are created with almost absolute stereocontrol. Aliphatic imines can also be used as substrates and the reaction is readily performed on the gram scale with as little as 0.25 mol% catalyst loading. Furthermore, the Mannich adducts are readily transformed to protected a-hydroxy-/8-amino acids in high yield. The absolute stereochemistry of the Mannich adducts revealed that Et2Zn-linked complex 3 affords Mannich and aldol adducts with the same absolute configuration (2 R). However, the diastereoselectiv-ity of the amino alcohol derivatives is anti, which is opposite to the syn-l,2-diol aldol products. Hence, the electrophiles approach the re face of the zinc enolate in the Mannich reactions and the si face in the aldol reactions. The anti selectivity is... 

Note that catalyst 13 was designed for anti-selective Mannich reactions based on the study of proline-catalyzed Mannich reactions. Four considerations are key for the diastereo- and enantioselectivities observed in the (S)-proline-catalyzed reactions (Scheme 2.15a) ... 

Matsunaga S, Kumagai N, Harada S, Shibasaki M (2003) anti-Selective direct catalytic asymmetric Mannich-type reaction of hydroxyketone providing beta-amino alcohols. J Am Chem Soc 125 4712—4713 Mayer S, List B (2006) Asymmetric counteranion-directed catalysis. 

The highly enantioselective and diastereoselective asymmetric Mannich-type reaction of N-phosphinoylimines (487) with hydroxyketone (488) was catalysed by (S,S) linked BINOL, affording N-phosphinylated aminoalcohols (489). The observed complementary anti-selectivity, in combination with the facile removal of diphenylphosphinoyl group make this reaction synthetically attractive (Figure 92). ... 

Silylserine 63, the catalyst for aldol reaction, also actively promotes enantioselective Mannich reaction. Excellent asymmetric induction and anti-selectivity are found in the Mannich reaction using 3-pyrrolidinecarboxylic acids 99 and 3-triflylaminopyrrolidine 100. ° Since emphasis is placed on the importance of the carboxyl group of 99, the acidic TfNH group of 100 must be similarly implicated. 

It is interesting that the condensation between electron-rich phenol, amine, and a chiral a -A, A -dibenzylamino aldehyde has been reported to be temperature sensitive, with high syn selectivity at high reaction temperatures while high anti selectivity is observed at low reaction temperatures. Similar to the Aldol Condensation, the Mannich reaction can be promoted or catalyzed by either acid or base. Furthermore, different protic acids or Lewis acid alone or in combination with a different chiral ligand or auxiliary group is used to enhance the stereoselectivity of the Mannich reaction, such as proline, (,S )-amino sulfonamide, BINOL phosphate," At-spiro chiral quaternary ammonium bromide, and dodecylbenzenesulfonic acid" as well as Lewis acids, such as Cu(OAc)2, CuC104, " Cu(OTf)2-chiral diamine complexes,... 

Thus far only procedures to acquire the i y/t-Mannich adducts have been described. Equally valuable and perhaps more appealing are protocols that broaden the versatility of the former methodology by providing the Mannich bases in a highly anti-selective manner. The preparation of a/tft-Mannich adducts was initially conducted by Barbas et al. by means of a direct (5)-2-methoxymethylpyrroMine (34, SMP) catalyzed asymmetric Mannich-type reaction [26]. A variety of unmodified aliphatic aldehydes 2 were treated with A-PMP-protected iminoglyoxylate 10a in DMSO to afford the P-formyl-functionalized amino acid derivatives 35a-f in moderate to good ee s and with a dr that increased with the bulkiness of the aldehyde (Scheme 5.19). 

If enamine/iminium activation promotes the direct asymmetric Mannich reaction with jyn-selectivity, the complementary anti-selectivity is also accessible using chiral primary amino acids [84] or phosphoric acids as catalysts [85]. 

This catalyst was also employed by Melchiorre et al. to promote the first aminocatalysed anti-selective Mannich reaction of aldehydes with A-Cbz-and A-Boc-protected imines generated in situ from stable a-amido sulfones (Scheme 3.11). Besides the high level of efficiency and stereocontrol achieved, this approach introduced important synthetic advantages, by avoiding the requirement to perform the A-carbamoyl imines. 

Using ZrOCl2 as a catalyst, direct Mannich reaction was performed under solvent-free conditions. Treatment of the three components aldehydes, amines, and ketones with the catalyst at room temperature afforded the corresponding P-amino ketones with high anti selectivity (Equation 11) [16]. It is interesting to note that product yields and selectivity were higher under solvent-free conditions than those with solvents. 

Mannich-type reactions of aryl, heteroaryl, and isomerizable alkyl N-Eoc imines and ot-substituted nitroacetates gave products in 91% to >99% ee and high anti-selectivity (Scheme 4) [22], which were successfully converted into ot,p-diamino acids with a-tetrasubstituted stereocenter. Catalyst loading was successfully... 

Scheme 10 Anti-selective catalytic asymmetric nitro-Mannich-type reaction with a Yb/K hetero-bimetallic catalyst...

In the approaches toward a direct asymmetric Mannich reaction by enolate formation with the metal of the catalyst also, the well-proved systems of the analogous aldol reactions were widely applied. Here, it is referred to some of these protocols wherein a metal enolate is involved, as least as assumed and plausible intermediate [183]. Shibasaki and coworkers used a dinuclear zinc complex derived from linked BINOL ligand 371 for catalyst in direct Mannich reactions of a-hydroxy ketones 370 with Af-diphenylphosphinoyl imines 369 to give ti-configured a-hydroxy-P-amino ketones 372 in high yield, diastereoselectivity, and enantioselectivity (Scheme 5.97) [184]. The authors postulate the metal to form a chelated zinc enolate by double deprotonation of the a-hydroxy ketone. This enolate approaches with its Si-face to the Si-face of the imine, as illustrated by the transition state model 373, in agreement with the observed stereochemical outcome. It is remarkable that opposite simple diastereoselectivity arises from the Mannich reaction (anti-selective) and the previously reported syn-selective aldol reaction [185], although the zinc enolates... 

EIGURE 113 Examples of highly anti-selective catalysts for the asymmetric Mannich reaction. 

For the same purpose, various chiral pyrroUdine catalysts such as 50-54 have also been introduced [242-250]. The versatile nature of pyrrolidine catalysts has been recognized by other transformations aldol reaction [251], Mannich-type reaction [252, 253], and oxa-Michael reaction [254]. Among these, Maruoka s work on anti-selective Mannich reactions is noteworthy (Scheme 1.19, compare with Scheme 1.8) [253]. In this case, the remote hydrogen-bonding form 57 derived from catalyst 56 can overcome the steric preference so that the opposite sense of stereochemistry should be observed. 

C6rdova and Dziedzic [45] examined the catalytic effects of primary 3-amino acids in the direct Mannich-type reaction in sea water. Highly anti-selective Mannich products were obtained with excellent enantiomeric excesses, and the diastereoselectivity of the reaction was opposite to that of L-alanine-catalyzed reaction (Scheme 3.12). 

Anti-selective Mannich reactions have been developed using (R)-3-pyrrolidine-carboxylic acid (75) or primary amine-containing amino acid 21 these catalysts were designed through consideration of mechanism and transition state models. 

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