Anti-Mannich

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]. 

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... 

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. 

In 2006 Barbas III, Houk and coworkers reported the direct asymmetric anti-Mannich-type reactions catalysed by the designed amino acid 29, whereas simple (5 )-proline was known to afford the q -adduct selectively (Scheme 11.25). ... 

Scheme 11.25 Asymmetric anti-Mannich-type reactions catalysed by the designed amino acid 29.

Fustero et al. noticed that fluorinated imines lOg-h had received little attention so far in literature. In particular, the synthesis of the corresponding anti-Mannich adducts had never been explored previously. By employing Jprgensen s diphenyl-prolinol derivative 41, highly enantioselective one-pot reactions between aldehydes 2 and the fluoroaldimines lOg-h were conducted [31], leading to the fluorinated P-aUcyl-y-amino alcohols 42a-e in a highly selective anh-manner (Scheme 5.23). 

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. 

Substrate control is another approach for synthesis of anti-Mannich products. The proline-catalyzed Mannich reaction between aldehydes and pre-formed N-Boc-imines affords the syn-Mannich product with exceptionally high diastereoselectivi-ties and enantioselectivities [44]. In contrast, the reaction of aldehyde 83 with N-Boc-imines, generated in situ from the stable a-amido sulfone 84, catalyzed by the commercially available chiral secondary amine 85 provides antt-Mannich product 86 with 96% ee (Scheme 28.7a) [45]. Cyclic iminoglyoxylate 88, readily prepared from commercially available starting materials, is a useful alternative imine electrophile its configuration is locked in the (Z)-form. Because of the (Z)-configuration of imine 88, the anti-selective Mannich reaction proceeds (Scheme 28.7b) [46]. 

Quaternary ammonium betaines possessing an anion moiety have emerged as Bronsted base catalysts. The C2-symmetric axially chiral ammonium betaine 177 deprotonates the a-substituted a-nitrocarboxylates (176) to form a structured ion pair that reacts with imines (173) to furnish the corresponding anti-Mannich... 

Shibasaki et al. reported on a direct awri-selective catalytic asymmetric Mannich-type reaction of a-ketoanilides 191122 puj- ermore, they transformed the anti Mannich adduct 192 into a-hydroxy-y-amides 193, which under asymmetric alkylative cyclization produces azetidine-2-amides 194 in good yield and excellent stereoselectivity (Scheme 40.40). 

First, the carboxylic acid group is moved farther to the third position and an additional trans methyl group is introduced at the fifth position. While the later substituent would steer the enamine conformation to an s-truns arrangement, the carboxyUc acid can still participate in effective proton transfer as shown in Figure 17.15b. The relative energies of transition states indicated 95 5 anti syn diastere-oselectivity and about 98% enantiomeric excess for the (2S,3R)-Mannich product Subsequent experimental verification of these predictions yielded near quantitative agreements for the extent of both enantio- and diastereoselectivities in favor of anti-Mannich product... 

The Mannich reaction of the aldehyde or ketone with a-imino esters catalyzed by 75 under nhld conditions affords anti-Mannich products (74) with high diastereo-and enantioselectivities (Table 28.5, entries 3 and 4) [43]. Furthermore, chiral anti-1,2-amino alcohols (74) are synthesized through a Mannich reaction between the unmodified a-hydroxyketone 1 (R = Me, = OH) and imine 73 in the presence of 21 (entries 5 and 6) [16]. 

Addition of ( )-enamines 3, derived from aldehydes and ketones, to various benzylideneimini-um salts 2 has been investigated. The reaction exclusively gives the Mannich bases anti-4 in good to excellent yield (72-94%). Therefore, this method provides an efficient and highly stereoselective route to /i-amino ketones and aldehydes1415. 

The structure of the product is determined by comparison with a known compound26-27. The relative configurations of the other Mannich bases arc assigned tentatively, presuming that little variations should not be able to invert the stereochemical course of the reaction totally. f When the reaction is performed undeT reflux (10 min) the Mannich base anti-4 is obtained in 71 % yield. The minor diastereomcr syn-4 cannot be detected by H NMR. 

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. 

It has also been shown that dimethylsilyl enolates can be activated by diisopropylamine and water and exhibit a high reactivity toward iV-tosyl imines to give Mannich-type reaction products in the absence of a Fewis acid or a Bronsted acid.51 For example, the reaction of [(1-cyclohexen-l-yl)oxy]dimethylsilane with 4-methyl-A -(phenylmethylene)benzene sulfonamide gave re/-4-methyl-N- (f )-[(15)-(2-oxocyclohexyl)phenyl-methyl] benzenesulfonamide (anti-isomer) in 91% yield stereoselectively (99 1 anti syn) (Eq. 11.30). On the other hand, Fi and co-workers reported a ruthenium-catalyzed tandem olefin migration/aldol and Mannich-type reactions by reacting allyl alcohol and imine in protic solvents.52... 

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%. 

Interaction of Mannich base methyliodides (148, R = Ph, 2-Thenyl) with anti -benzaldoxime gives dinitrones (149) (Scheme 2.53) (307). 

Titanium enolates of various carbonyl compounds play an increasingly important role in Mannich-type reactions with different electrophiles. Recently, Liotta and co-workers reported a novel diastereoselective addition of chloro-titanium enolate 80 of iV-acylthiazolidinethione to various types of O-methyl oximes to afford the desired anti-azetines, precursors of a,/3-disubstituted /3-amino carbonyl derivatives 82 (Scheme 32).109... 

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 toxic potential of metabolic intermediates, of the carrier moiety, or of a fragment thereof, should never be neglected. For example, some problems may be associated with formaldehyde-releasing prodrugs such as N- and 0-[(acyloxy)methy 1] derivatives or Mannich bases. Similarly, arylacetylenes assayed as potential bioprecursors of anti-inflammatory arylacetic acids proved many years ago to be highly toxic due to the formation of an intermediate ketene. 

A few N-Mannich bases of the anti-inflammatory drug salicylamide are reported in Table 11.1. The pharmacokinetic behavior of one of these, N-(morpholinomethyl)salicylamide (11.54), was examined in the rabbit [90], Plasma concentration curves showed that the oral bioavailability of salicylamide was increased two- to sixfold by administration of the prodrug. 

Oxazolidin-5-ones (11.110) are structurally related to oxazolidines, combining the motifs of a lactone and an O-Mannich base. These derivatives have already been discussed in Sect. 8.7.5. However, they serve here as a transition to [3,1 ]benzoxazepin-4-ones as an example of potential prodrugs. Thus, [3,l]benzoxazepin-4-one derivatives (11.111, R = H or Me, R = H, Me, Et, or Ph) were prepared from diclofenac (11.112) [137]. These prodrugs were stable for at least a few hours in simulated gastric juice, but, when administered to rats elicited an anti-inflammatory response comparable to that of diclofenac. One compound (11.111, R = Me, R = Et) was even more active than diclofenac without producing the gastric mucosal injury (ulcers) caused in all rats by diclofenac itself. Here again, there was no indication of whether the mechanism of hydrolysis is chemical or enzymatic. 

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]... 

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