Sulfones a-amido

An additional means of performing a selective cross-benzoin was reported in 2001 when Mnrry and co-workers expanded benzoin methodology to include trapping of acyl imines XIX formed in situ (Scheme 6) [53], The authors chose to use a-amido sulfones due to their stability and the relative ease of acyl imine liberation. The parent reaction combines pyridine 4-carboxaldehyde 51 and tosylamide 52 in 98% yield in the presence of pre-catalyst 54 and triethylamine (Scheme 6). 

Scheme 6.132 Representative Mannich adducts obtained from the base-catalyzed in situ generation of N-protected aldimines from N-Boc- and N-Cbz-protected a-amido sulfones and subsequent 121- and 124-catalyzed addition of dibenzyl malonate. The product configurations were not determined.

Scheme 3.23 Asymmetric Strecker synthesis using a-amido sulfones with acetone cyanohydrin.

This phase-transfer-catalyzed asymmetric Strecker reaction is further elaborated by the use of a-amido sulfone as a precursor of N-arylsulfonyl imine. In this system, the reaction can be conducted with a slight excess of potassium cyanide (1.05 equiv.), and the reaction leads to completion within 2h (Table 5.15) [46b],... 

Table 5.15 Direct asymmetric Strecker reaction of a-amido sulfones under phase-transfer conditions.

Values in parentheses refer to the use of sulfonylimines in place of a-amido sulfones. 

Another catalytic application of chiral ketene enolates to [4 + 2]-type cydizations was the discovery of their use in the diastereoselective and enantioselective syntheses of disubstituted thiazinone. Nelson and coworkers described the cyclocondensations of acid chlorides and a-amido sulfones as effective surrogates for asymmetric Mannich addition reactions in the presence of catalytic system composed of O-TM S quinine lc or O-TMS quinidine Id (20mol%), LiC104, and DIPEA. These reactions provided chiral Mannich adducts masked as cis-4,5 -disubstituted thiazinone heterocycles S. It was noteworthy that the in situ formation of enolizable N-thioacyl imine electrophiles, which could be trapped by the nucleophilic ketene enolates, was crucial to the success of this reaction. As summarized in Table 10.2, the cinchona-catalyzed ketene-N-thioacyl-imine cycloadditions were generally effective for a variety of alkyl-substituted ketenes and aliphatic imine electrophiles (>95%ee, >95%cis trans) [12]. 

However, cycloaddition involving aryl a-amido sulfone afforded modestly attenuated yields due to competing formation of the P-lactam adducts, possessing the unanticipated trans diastereoselection that was not observed for alkyl imine electrophiles (Eq. (10.1)). 

Herrera and Bernard have developed a new catalyhc enantioselechve approach to the asymmetric nucleophilic addition of nitromethane to N-carbamoyl imines generated from a-amido sulfones (aza-Henry reachon) [64]. The chiral phase-hansfer catalyst 85a acts in a dual fashion, first promohng the formation of the imine under mild reachon condihons and then achvahng the nucleophile for asymmetric addihon. This new strategy for the catalyhc aza-Henry reaction was... 

The highly enanhoselective phase-transfer-catalyzed Mannich reachon of malo-nates with in situ-generated, Cbz-protected azomethines has been developed by Ricci (Scheme 11.23) [65]. This approach gives a straightforward access to ophcally achve [1-alkyl N-carbanoyl acids, starhng from readily available and stable a-amido sulfones. 

A related example of an organocatalytic asymmetric Mannich reaction that makes use of an aqueous biphasic system (aq. K2CO3/toluene) was reported by Ricci et al. Catalysts 19 derive from quinine and act as typical phase-transfer reagents. Active methylene compounds are used as donors, and 7V-Boc and A-Cbz protected a-amido sulfones as precursors of TV-prolcclcd imines (Scheme 1.9). ... 

Nelson and co-workers reported cinchona alkaloid-catalyzed [4-1-2] cycloaddition of ketenes and N-thioacyl imine, affording the 4,5-cw-disubstituted l,3-thiazin-6-one derivatives 146 with high enantioselectivities (>95% ee) and diastereoselectivities (>95 5 cis. trans). Scheme 3.47 [63], Ketene, in situ generated from acyl halide 143 and base, followed by addition to imine which was generated in situ via basic elimination of a-amido sulfone 144, providing the ketene-imine addition pathway toward the cycloadducts. 

Shortly after, the same authors proposed a more convenient protocol for this CN promoted Mannich reaction. Employing a-amido sulfones as imine... 

Scheme 14.16 Mannich reactions of 1,3-dicarbonyl compounds with imines generated in situ from a-amido sulfones catalysed by cinchonine CN.

It is also noteworthy that Ricci and co-workers have disclosed phase nitro-Mannich (or aza-Henry) reaction using Al-Carbamoyl imines generated in situ from a-amido Sulfones using phase-transfer catalysts [78]. Ricci s direct use of a-amido sulfones as acceptors has also inspired developments in aminocatalysis as described vide infra. Here the 7/-benzyl quininium chloride catalyst has a dual function by generating the corresponding Al-carbamoyl imines in situ and next activate the nucleophile for the highly stereoselective addition (Scheme 4.17). 

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. 

A second method to achieve the synthesis of the enantioenriched dihy-dropyrimidone core of SNAP-7941 was based on the cinchona alkaloid-catalysed Mannich reaction of p-keto esters with acylimines. Therefore, the reaction of a p-keto ester with an a-amido sulfone performed in the presence of cinchonine produced the Mannich product as a mixture of two diastereomers in an excellent yield (Scheme 3.20). This diastereomeric mixture was transformed in high yield into a key intermediate of the synthesis of SNAP-7941, showing a good enantioselectivity. This compound was finally converted into desired SNAP-7941, which is an inhibitor of MCHl-R in a G protein-coupled receptor. 

Another cinchona alkaloid-catalysed Mannich reaction was reported by Barbas et al, occurring between a thioester and an a-amido sulfone, leading in the presence of KOH to the unti-Mannich product in 79% yield, with both moderate diastereo- and enantioselectivity of 64% de and 45% ee, respectively. Finally, Akiyama et al. have developed a new method for the enantioselec-tive synthesis of y-butenolide derivatives, which involved the vinylogous Mannich-type reaction catalysed by a novel chiral phosphoric acid bearing iodine groups at the 6,6 -positions. Aliphatic as well as aromatic aldimines... 

On the other hand, Palomo et al. have developed efficient organocatalytic asymmetric aza-Henry reactions under phase-transfer conditions. This method was based on the reaction of a nitroalkane with an azomethine generated from an a-amido sulfone promoted by CSOH.H2O as a base in toluene and in the presence of cinchonine-derived ammonium catalysts. The corresponding. syw-products were obtained in good yields, moderate to good diastereoselectivities (10-86% de) and moderate to excellent enantioselectivities... 

N-Benzotriazole derivatives of quinine and quinidine were applied as phase-transfer catalysts for the nitro-Mannich reaction between a-amido-sulfones and nitroalkanes (Scheme 6.57) [119]. The products were formed in good yields and high enantioselechvihes and could be transformed efficiently into either a diamine... 

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]. 

Scheme 29.28 Proposed mechanism for the aza-Henry reaction involving a-amido sulfones under chiral PTC conditions.

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