Glyoxylate-derived imines Mannich reactions

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). 

Other types of catalysts that are active in Mannich reactions include the Cu-bis-oxazolines.195 Most of the cases examined to date are for relatively reactive imines, such as those derived from glyoxylate or pyruvate esters. 

In 1998, a new type of Pd(II) binuclear complex was reported which was effective for Mannich reactions of an imine derived from glyoxylate and anisidine with silicon enolates [38,39]. In these reactions, use of solvents including a small amount of water was essential. It was shown that water played an important role in this system water not only activated the Pd(II) complex to generate a cation complex, but also cleaved the N-Pd bond of the intermediate to regenerate the chiral catalyst. This reaction reportedly proceeded via an optically active palladium enolate on the basis of NMR and ESIMS analyses. A unique binuclear palladium-sandwiched enolate was obtained in the reaction of the p-hydroxo palladium complex with the silyl enol ether [(Eq. (9)]. 

It was reported that proline catalyzed the direct catalytic asymmetric Mannich reactions of hydroxyacetone, aldehydes, and aniline derivatives [(Eq. (10)] [40-44]. Not only aromatic aldehydes but also aliphatic aldehydes worked well in this reaction, and good to excellent enantioselectivity and moderate to excellent yields were observed. Mannich reactions of glyoxylate imines with aldehydes or ketones were also successfully performed [45,46]. 

The Petasis method involves the use of organoboron compounds to produce a side chain on a Mannich product derived from the imine condensation product between an amine and an a-ketocarboxylic acid. Thus, as shown in Scheme 12.64, as an example of this three-component reaction, when the styrylboronic acid derived from the reaction of phenylacetylene with catecholborane was allowed to react with glyoxylic acid (CHOCO2H) and (5)-2-phenylglycinol, a single diastereomer was isolated, which gave an enantiomerically pure (7 )-homophenylalanine hydrochloride on reduction. This procedure is limited only by the availability of the components. 

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... 

Not long after List published his three-component methodology, the group of Barbas reported a fairly similar procedure [3]. Besides L-proUne (1), a penicillamine derivative appeared to effectively catalyze the reaction. Later on, various ketone donors 7b, 7e-g were successfully subjected to the preformed iV-PMP-protected a-imino ethyl glyoxylate 10a as imine acceptor, thereby yielding y-oxo-a-amino acid derivatives lla-d as the products (Scheme 5.4). Analogous to the results of List, the reactions proceeded smoothly resulting in Mannich products with excellent yn-selectivity in complete enantiomerically pure form [4],... 

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