N-PMP-protected

Trost and coworkers recently reported that these dinuclear zinc complexes catalyze Mannich reactions with unmodified aromatic hydroxy ketones as donors with excellent enantioselectivity [18]. Mannich-type reactions between an N-para-meth-oxyphenyl (PMP)-protected a-ethyl glyoxalate and hydroxyacetophenone in the presence of a catalytic amount of catalyst 5a afford the desired N-PMP protected amino acid derivative in 76 % yield with a dr of 7 1 and 95 % ee (Eq.5). 

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). 

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]. 

Conditions of entries 1-2, and 4 Aldehyde (0.5 mmol, 2 equiv.), N-PMP-protected a-imino ethyl glyoxylate (0.25 mmol, 1 equiv.), 13 (0.0125 mmol, 0.05 equiv.), DMSO (2.5 mL). 

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]. 

The (S)-proline-catalyzed Mannich reactions of aldehyde donors and N-PMP-protected imines of fluorinated aldehyde, such as CF3CHO, C2F5CHO, and PI1CF2CHO, were also used for the expedient synthesis of fluorinated aminoalco-hols [81]. 

N-Phenylsulfonylprolinamide 15a was first used as organocatalyst in the reaction of cyclohexanone with the highly reactive N-PMP-protected a-imino ethyl glyoxalate (eqn. (1) in Scheme 6.5). Dodecylphenylsulfonamide-hased... 

L-proline-derived sulfonamides 15b and 15c are also effective catalysts in the Mannich reaction of cyclic ketones with N-PMP-protected cx-imino ethylglyoxylate in both classical organic solvents and ionic liquids as the reaction media. ... 

Treatment of aldehydes with N-PMP-protected a-imino ethyl glyo g late gave the Mannich adducts in good yield and high enantioselectivities. The reaction typically proceeded with high anft-selectivity. The application of... 

Furthermore, Zhang and Ying have utilized the same catalyst in an organocatalytic approach to secure a route to A-phenylisoxazolidin-5-ones, which can be converted to A-/7-methoxyphenyl (N-PMP) protected beta-amino acid esters (128) using a similar Bamberger-hke rearrangement in a mild one-pot protocol (Scheme 18.20) [67]. 

SCHEME 11.15 Awfl-selective Mannich reaction between ketones and N-PMP-protected a-imino esters. 

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... 

The same authors have designed novel chiral pyrrolidine-based amino sulfonamides, which were applied to promote a n -Mannich reactions of A/-PMP-protected a-imino esters with aldehydes, giving comparable results to those obtained with the binaphthyl-based amino sulfonamide catalyst. However, these novel pyrrolidine-based amino sulfonamides were found to be capable of promoting a //-Mannich reactions between A/-PMP-protected a-imino esters and a range of cyclic as well as acyclic ketones with excellent yields, enan-tioselectivities combined with moderate to high diastereoselectivities of up to 90% de (Scheme 3.13). 

N-PMP- and 2-N-tosyl-protected ferrocenyl imines p-tolyl sulfides were successfully allylated with tetraallyltin in the presence of a catalytic amount of Sc(OTf)3 giving the corresponding homoallylic amines in good yields with very good diastereoselectivities (respectively 72%, de > 98% and 88%, de > 98%) [121]. 

Scheme 17.14 Example of cmti-selective Mannich reaction between N-p-methoxyphenyl (PMP) protected imine catalyzed by 5-methyl-3-pyrrolidine carboxylic acid.

Trifluoromethyl-P-lactam 63 was prepared in racemic form via a ketene-imine [2 + 2] cycloaddition, following previously published methods81 with modifications.46 The subsequent oxidative cleavage of PMP, acylation of NH with (f-Boc)20, hydrogenolysis over Pd/C, and protection as 1-ethoxyethyl ether gave N-f-Boc-P-lactam 63 in good overall yield (Scheme 13). 

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