Glycine 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). 

Bagley MC, Brace C, Dale JW, Ohnesorge M, Phillips NG, Xiong X, Bower J (2002) J Chem Soc [Perkin 1] 1663 Belattar A, Saxton JE (1992) J Chem Soc [Perkin 1] 679 Bernardi L, Gothelf AS, Hazell RG, Jprgensen KA (2003) Catalytic asymmetric Mannich reactions of glycine derivatives with imines. A new approach to optically active alpha,beta-diamino acid derivatives. J Org Chem 68 2583-2591... 

Enolates from A-(diphenylmethylene)glycine esters (211) were also used as nucleophiles in Mannich reactions with chiral A-sulhnyl imines (212), as reported by Davis and coworkers (equation 56f. They found that the simple antUsyn selectivity of the formed 2,3-diamino esters 213 and 214 was strongly influenced by the water content in the THE solvent. In the absence of water both 2,3-diamino ester isomers were equally obtained (first entry of Table 18), but by changing the H2O/LDA ratio the formation of the... 

Barbas et al. described highly enantio- and diastereoselective organocatalytic Mannich reactions of the glycine-derived Schiff base 63 with in situ generated aromatic A -Boc-protected imines from 64 (Scheme 5.31) [42]. Several thiourea-... 

Readily available chiral cyclopropenimine (13) catalyses Mannich reactions of A-Boc-aldimines (14) and glycine imines (15), with yields/rZe/ee up to 97/98/95%." The vicinal diamino stereoarray of the products (16) allows access to many useful derivatives, and the t-butyl ester of the product (16, = BuO is amenable to acidic deprotection. In the... 

Recently, Kanai and co-workers developed a novel catalytic system for oxidation of benzyl amines and anilines to the corresponding imines with molecular ojg gen under mild conditions (Scheme 7.11). Inspired by Iwa-buchi s 2-azaadamantane-AI-03grl (AZADO) oxidation, they designed 9-azabi-cyclo[3.3.1]nonan-3-one AT-ojgrl (ketoABNO) as a more electron-deficient redox mediator and found that the combination with Cu(I) was effective for efficient aerobic oxidation of amines. Based on this result, they successfully applied their oxidation chemistry to CDC reactions. When the chiral Box ligand was used, an aerobic nitro-Mannich reaction between N-PMP glycine and 1-nitropropane proceeded with excellent diastereo- and enantioselectivity (20 1 diastereomeric ratio (dr) and 95% ee of the major syn isomer). In this case, EtgN was used as a co-catalyst to accelerate the addition reaction, because tertiary amines are inert to the ketoABNO/Cu(i) system. 

Zhang HL, Syed S, Barbas CFI. Highly enantio- and diaster-eoselective Mannich reactions of glycine Schiff bases with in situ generated A-Boc-imines catalyzed by a cinchona alkaloid thiourea. Org. Lett. 2010 12(4) 708-711. 

After a thorough screening of different TaDiAS for the Mannich reaction of glycine Schiff base 14 with Boc-protected imines 134 it was found beneficial... 

Some chiral phase-transfer catalysts can also promote enantioselective aldol and Mannich condensations of glycine imine donors with aldehyde and imine acceptors. These reactions provide important tools for the asymmetric constmction of P-hydroxy-a-amino acid and a,p-diamino acid derivatives, which are extremely interesting chiral units in the synthesis of pharmaceutical and natural products. For... 

Maruoka and coworkers described a direct phase-transfer-catalyzed Mannich reaction of the glycine imine ester 65a with a-imino ester. N-spiro quaternary ammonium bromide (S,S)-31c was identified as an efficient catalyst under LL (aqueous NaOH-mesitylene) phase-transfer conditions (Scheme 12.12) [114]. The usefulness of the Mannich adduct 86 was further demonstrated by the conversion into an optically pure precursor 87 of streptolidine lactam. 

Scheme 12.12 Asymmetric phase-transfer catalytic Mannich reaction of glycine imine ester 65a with a-amino ester and its further conversion into streptolidine lactam precursor 87.

Chiral two-center phase-transfer catalyst 202 possessing 2,6-disubstituted cyclohexane spiroacetal catalyzes the syn-selective Mannich-type reaction of glycine Schiff base 186 with N-Boc-protected aromatic imines as weU as enoUzable aUcyl imines (201) in high yields with moderate to good enantioselectivities (Scheme 28.24) [103],... 

Optically active, a,p-diamino acid derivatives are key structures in medicinally important compounds. Direct synffiesis of these segments has been reported using a Mannich-type reaction of a glycine Schiff base with imines. Shibasaki and co-workers obtained 5y -a,p-diamino acid... 

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