Mannich synthesis with glyoxylic

N-Subst. a-aminocarboxylic acids by Mannich synthesis with glyoxylic acid... 

Cooke and coworkers reported on the synthesis of the amino acid N-benzyl-4-acetylproline (2-889) (Scheme 2.198) [453], as this might represent an interesting synthon for the preparation of bioactive compounds. These authors also used a domino iminium ion formation/aza-Cope/Mannich protocol. Thus, treatment of the secondary amine 2-885 with glyoxylic acid (2-888) primarily provided the corresponding iminium ion, which led to 2-889 in 64% yield as a mixture of diastereom-ers. 

Addition of nucleophiles to electrophilic glycine templates has served as an excellent means of synthesis of a-amino acid derivatives [2c, 4—6]. In particular, imines derived from a-ethyl glyoxylate are excellent electrophiles for stereoselective construction of optically active molecules [32], This research and retrosyn-thetic analysis led us to believe that amine-catalyzed asymmetric Mannich-type additions of unmodified ketones to glyoxylate derived imines would be an attractive route for synthesis of y-keto-ce-amino acid derivatives [33], Initially, L-proline-catalyzed direct asymmetric Mannich reaction with acetone and N-PMP-protected a-ethyl glyoxylate was examined in different solvents. The Mannich-type reaction was effective in all solvents tested and the corresponding amino acid derivative was isolated in excellent yield and enantioselectivity (ee >95 %). Direct asymmetric Mannich-type additions with other ketones afford Mannich adducts in good yield and excellent regio-, diastereo- and enantioselectivity (Eq. 8). 

Extension of this reaction toward a one-pot asymmetric Mannich-hydrocyanation reaction sequence was also reported by the Barbas group [29]. In this one-pot two-step process proline-catalyzed asymmetric Mannich reaction of unmodified aldehydes with the a-imino glyoxylate was performed first, then diastereoselective in situ cyanation. The resulting /i-cyanohydroxymethyl a-amino acids were obtained with high enantioselectivity (93-99% ee) [29]. Another one-pot two-step reaction developed by Barbas et al. is the Mannich-allylation reaction in which the proline-catalyzed Mannich reaction is combined with an indium-promoted allylation [30], This one-pot synthesis was conducted in aqueous media and is the first example of a direct organocatalytic Mannich reaction in aqueous media [28, 30]. 

Microwave acceleration of reactions is a valuable tool for organic synthesis [39], and various specialized instruments are now commercially available. Tye and co-workers have reported the microwave-assisted Petasis borono-Mannich reaction of arylboron-ic acids and primary or secondary amines with either glyoxylic acid or salicylaldehyde [40]. Optimized reaction conditions employed didiloromethane as solvent, and microwave assisted heating at 120 °C for 10 min. Products were obtained in generally modest yields (10-83%), in part due to incomplete reaction conversion imder the reported conditions. 

The successful use of the silver complex formed from an iso-leucine-derived phosphine (L2 in Scheme 11.4) as catalyst for the multicomponent Mannich reaction of silyl enol ethers 10 with in situ formed aliphatic imines allowed its application in the enantioselective synthesis of the alkaloid sedamine (56% yield, 98% ee) [17]. Also cyclic and acyclic alkenyl trichloroacetates (10, Z = EtOCO) can be used in the reaction with ethyl glyoxylate and diverse aniline derivatives 11 catalyzed by... 

Chiral 3-amino carbonyl compounds and 1,2-amino alcohols are among the most valuable building blocks for asymmetric synthesis and catalysis. Efficient enanti-oselective syntheses of these compounds were reported from 2000 to 2006 using enamine-based organocatalysts. For example, Mannich reactions employing aliphatic aldehyde as a donor with a-imino glyoxylate as an acceptor provide syn-adducts (74) as the major product with excellent enantiomeric excess in the presence of (S)-proline (13) as a catalyst (Table 28.5, entry 1) [41]. When the ketone is employed as a donor, the sy -isomer is obtained with excellent diastereo-and enantioselectivities (entry 2) [42]. 

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