Anti-Mannich reactions

Application of these principles for stereoindnction via the catalyzed Man-nich reaction led Barbas and Houk to develop 74 as a catalyst to affect the anti-Mannich reaction, to complement the use of proline as a catalyst for the ciY-Mannich reaction (Scheme 6.12). In the larger context, Houk s extensive... 

C. Wu, X. Fu, X. Ma, S. Li, C. Li, Tetrahedron Lett. 2010, 51, 5115—5111. Threonine-surfactant organocatalysis for the highly diastereo- and enantioselective direct anti-Mannich reactions of hydroxyacetone. 

Excellent enantioselectivities have also been observed by Maruoka et al. by using several other chiral secondary amines as organocatalysts for the anti-Mannich reaction between various aldehydes and A -protected hnines including a-imino esters. Therefore, the involvement of a chiral binaphthyl-based amino sulfonamide as the organocatalyst allowed a series of UM/i-Mannich products to be obtained from both iV-Boc-protected imines and A -PMP-protected a-tmino esters by reaction with aldehydes. As shown in Scheme 3.12, excellent yields and enantioselectivities (97-99% ee) were observed along with moderate to high anti diastereoselectivities of up to 90% de. 

As already discussed for aldol and Robinson annulation reactions, proline is also a catalyst for enantioselective Mannich reactions. Proline effectively catalyzes the reactions of aldehydes such as 3-methylbutanal and hexanal with /V-arylimines of ethyl glyoxalate.196 These reactions show 2,3-syn selectivity, although the products with small alkyl groups tend to isomerize to the anti isomer. 

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%. 

In a related publication, Kobayashi and his team reported on Zr-catalyzed asymmetric Mannich reactions that utilize the more electron-rich oxygenated ketene acetals shown in Scheme 6.28 [93], A noteworthy aspect of this study was that the levels of syn/anti diaste-reocontrol proved to be dependent on the nature of the alkoxide substituent whereas the (3-TBS acetals predominantly afforded the syn isomer, the OBn derivatives afforded a larger amount of the anti isomer. As before, the presence of an additive, this time 1,2-dimeth-ylimidazole (DMI), proved to be important with regard to the level of Ti-facial selectivity. The phenol activating group can be removed by the same procedure as reported previously, with essentially identical degrees of efficiency (see Scheme 6.27). 

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]... 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

It is worthy of note that - similarly to the proline catalyzed aldol reaction - the Mannich reaction can also be extended to an enantio- and diastereoselective process in which two stereogenic centers are formed in one step, although using non-chiral starting materials (Scheme 5.16) [22, 23, 26, 27, 28]. In these reactions substituted acetone or acetaldehyde derivatives, rather than acetone, serve as donor. In contrast with the anti diastereoselectivity observed for the aldol reaction (Section 6.2.1.2), the proline-catalyzed Mannich reaction furnishes products with syn diastereoselectivity [23]. A proline-derived catalyst, which led to the formation of anti Mannich products has, however, been found by the Barbas group [29]. 

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... 

Whereas the (S)-proline-catalyzed Mannich reactions afforded (2S,3S)-syn-isomers as the major products, (3R,5ft)-5-methyl-3-pyrrolidinecarboxylic acid (13) catalyzed the reactions and afforded (2S,3R)-anti-products in good yield with high, almost perfect, diastereo- and enantioselectivities (Table 2.12) [73]. The reaction rates of the 13-catalyzed Mannich reactions were approximately two- to threefold faster than the corresponding (S)-proline-catalyzed reactions that afford the syn-products. Thus, the reactions with only 0.01 or 0.02 equiv. of 13 afforded the desired products in reasonable yields within a few hours. 

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) ... 

Whereas the (S)-proline- and 13-catalyzed Mannich reactions afforded (2S,3S)-syn-products and (2S,3R)-anh-products, respectively, as shown in Scheme 2.15, with high diastereo- and enantioselectivities, the (S)-pipecolic acid (14)-catalyzed reaction afforded (2S,3S)-syn- and (2S,3.R)-anh-products with moderate diastereo-selectivities but high enantioselectivities for both the syn- and anti-products [74] (Scheme 2.16). This was explained by computational analyses indicating that (S)-pipecolic acid uses both the s-trans and s-cis conformations of the enamine similarly (the energy differences 0.2 kcal mol-1 for pipecolic acid versus 1.0 lccal mol-1 for proline) in the C-C bond-forming transition state [74]. Note that (S)-pipecolic acid was not a catalyst for the aldol reaction of acetone and... 

Scheme 2.16 (S)-Pipecolic acid (14)-catalyzed Mannich reactions afford both syn- and anti-products [74].

You may have noticed that the reaction occurred only at the 2-position on pyrrole. Though all positions react with reagents like bromine, more selective reagents usually go for the 2- (or 5-) position and attack the 3- (or 4-) position only if the 2- and 5-positions are blocked. A good example is the Mannich reaction (Chapter 27). In these two examples N-methylpyrrole reacts cleanly at the 2-position while the other pyrrole with both 2- and 5-positions blocked by methyl groups reacts cleanly at the 3-position. These reactions are used in the manufacture of the nonsteroidal anti-inflammatory compounds, lolmetin and clopirac. 

Mannich reactions were first performed using commercially available Eschen-moser s salt as the aminoalkylating agent, and enolates derived from syn and anti... 

Mitsumori, S. Zhang, H. Ha-Yeon Cheong, P Honk, K. N. Tanaka, R Barbas, C. F. Direct asymmetric anti-Mannich-type reactions catalyzed by a designed amino acid, 7. Am. Chem. Soc. 2006,128, 1040-1041. 

The proline-catalyzed asymmetric Mannich reaction between cyclohexanone, formaldehyde and an aniline has been described by Bolm and co-workers [182]. With only 0.5 mol% of homochiral catalyst, the Mannich products have been obtained with excellent ee s up to 98% after a short irradiation time using a constant low power of 10-15 W in conjunction with simultaneous cooling with compressed air. These reaction conditions allow achieving a high reaction rate and an excellent enantioselectivity. In situ reduction of the resulting ketones 129 afford the V-aryl amino alcohols 130 in high yield (syn/anti in ratio 1 5) (Scheme 101). 

Heating the mixture of isomers of 109 with TsOH equilibrates the diastereoisomers so that the required more stable syn (H and Et syn) diastereoisomer of 109 crystallises out. Treating this with (+) malic acid leads to crystals of the natural enantiomer (+)-sy -109. Both the unwanted anti-diastereoisomer and the unwanted enantiomer can be equilibrated again with TsOH. This cannot be enolisation as there are no a-hydrogens and is presumably equilibration by reversible Mannich reaction as 110 lacks either stereogenic centre and so epimerises both ... 

Though dramatic, this is an unusual example of such processes. Much more has been made of tandem aza-Cope and Mannich reactions, particularly by Overman. A typical sequence begins with the addition of a vinyl-lithium, e.g. 176, to a protected a-aminoketone 177 to give, in this case, the product 178 from Felkin-like attack (chapter 21) on the side of the ketone anti to the amino group.27... 

LLC networks containing catalytic headgroups have also been shown to be useful for heterogeneous Lewis acid catalysis. The Sc(III)-exchanged cross-linked Hu phase of a taper-shaped sulfonate-functionalized LLC monomer has been shown to be able to catalyze the Mukaiyama aldol and Mannich reactions [115] with enhanced diastereoselectivity. This Sc(III)-functionalized Hu network affords condensation products with syn-to-anti diastereoselectivity ratios of 2-to-l, whereas Sc(III) catalysts in solution or supported on amorphous polymers show no reaction diastereoselectivity at all. 

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