Mannich glyoxylate imines

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]. 

Mannich-Type Reactions of Aldehyde Donors with Glyoxylate Imines... 

S)-Proline has been used to catalyze Mannich-type reactions of enolizable carbonyl donors. Reactions of unmodified aldehydes and N-p-methoxyphenyl (PMP)-protected glyoxylate imine in the presence of a catalytic amount of (S)-proline at room temperature afforded enantiomerically enriched / -aminoaldehydes, as... 

Table 2.10 (S)-Proline-catalyzed Mannich-type reactions of aldehyde donors and /N/-PMP-protected glyoxylate imine [71 a,b].

Table 2.12 ont/ -Mannich-type reactions of aldehyde donors and N-PMP-protected glyoxylate imine catalyzed by (3/ ,5/ )-5-methyl-3-pyrrolidine-carboxylic acid (13) [73]. 

Fig. 2.3 Catalysts for the Mannich-type reactions of aldehydes and glyoxylate imines that use m-s/tu-gene rated enamine intermediates and that selectively afford (a) syn-products or (b) ont/ -products with high enantioselectivities.

S)-Proline also catalyzed the Mannich-type reactions of unmodified aldehydes and N-PMP-protected imines to afford the corresponding enantiomerically enriched / -aminoaldehydes at 4 °C (Table 2.13) [71b]. The products were isolated after reduction with NaBH4, though oxidation to the / -amino acid is also possible. These reactions also provided the syn-isomer as the major diastereomer with high enantioselectivities, and proceeded well in other solvents (e.g., dioxane, THF, Et20). In the reaction of propionaldehyde and the N-PMP-imine of 4-nitrobenzaldehyde in DMF, the addition of water (up to 20%, v/v) did not affect the enantioselectivity. Similar results were obtained for the (S)-proline-catalyzed Mannich-type reactions with the glyoxylate imine where water did not reduce enantioselectivity [71b]. However, the enantioselectivity of the reaction of propionaldehyde and the N-PMP-imine of benzaldehyde in DMF was decreased by the addition of water or MeOH [71b]. 

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)]. 

An interesting extension of this Mannich reaction was reported very recently by the Barbas group [26]. An a-imino glyoxylate 33 was used as a (preformed imine) starting material. The corresponding Mannich reaction furnished directly functionalized a-amino acids of type (S)-34 (see also the selected example in Scheme 5.15) which are difficult to synthesize by other synthetic routes. 

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). 

The similarity between mechanisms of reactions between proline- and 2-deoxy-ribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggests that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes, which could add to different electrophiles such as imines [36, 37]. In fact, proline is able to mediate the direct catalytic asymmetric Mannich reaction with unmodified aldehydes as nucleophiles [38]. The first proline-catalyzed direct asymmetric Mannich-type reaction between aldehydes and N-PMP protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantioselectivity (Eq. 9). 

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],... 

Diastereoselective aza-Diels-Alder or Mannich reaction of furan with the imine formed in situ from ethyl glyoxylate and (lii,2R)-l, 2-diamino-cyclohexane gave rise to enantiopure polycyclic nitrogen heterocycles (13JOC2808). 

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. 

Microwave-assisted Petasis borono-Mannich reactions of arylboronic acids, secondary amines and salicylaldehyde have been carried out in CH2CI2 at 120 °C for 10 min [40], The main problem encountered here was incomplete conversions, resulting in modest adduct yields (23-76%). The reaction of a primary amine (p-ani-sidine) under the same conditions failed to produce the desired adducts, giving instead only the imines (cf. reactions with glyoxylic acid). 

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... 

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