5.5- dimethylthiazolidine-4-carboxylic acid

Their previous screening of catalysts for of aldol reactions and Robinson annu-lations suggested the possibility that chiral amines might also be able to catalyze the Mannich reaction [30, 31]. Thus, screening of catalysts for Mannich-type reactions between N-OMP-protected aldimines and acetone revealed that chiral diamine salt 10, L-proline 11, and 5,5-dimethylthiazolidine-4-carboxylic acid (DMTC) 12 are catalysts of Mannich-type reactions affording Mannich adducts in moderate yields with 60-88 % ee. To extend the Mannich-type reactions to aliphatic imines, the DMTC 12-catalyzed reactions are performed as one-pot three-component procedures. The o-anisidine component has to be exchanged with p-anisidine for the one-pot reactions to occur. The DMTC 12-catalyzed one-pot three-component direct asymmetric Mannich reactions provide Mannich adducts in moderate yield with 50-86 % ee. 

Phenylalanine (1), rerf-leucine (2), 5,5-dimethylthiazolidine-4-carboxylic acid (3), and a-hydroxy-phenylalanine (4) have been chosen as models for the direct quantitative evaluation of thin-layer chromatograms. Emphasis has been placed on the evaluation of detection limits for the TLC-separated enantiomers, because exact determination of trace levels of a D- or L-enantiomer in an excess of the other is increasingly important (171,201,203-205). 

Figure 19 Application pattern for direct quantiFication of the enantiomers of phenylalanine (Ph), rm-leucine (L), 5,5-dimethylthiazolidine-4-carboxylic acid (D), and hydroxyphenylalanine (H).

Dimethylthiazolidine-4-carboxylic acid. The remission-location curve (Fig. 24) and the calibration line (Fig. 25) show that even 0.1-1% of the L-enantiomer can easily be quantitated. 

Figure 24 Remission-location curves (a) D-S,S-diinethylthiazotidine-4-carboxylic acid (b) and (c) D-5,5-dimethylthiazolidine-4-carboxylic acid + 0.1% and 0.5%, respectively, of the L-enantiomer (d) 0.1% L-5,5-dimethyIlhiazoIidine-4-carboxylic acid. Conditions eluent A X = 370 nm.

Figure 25 Calibration line for L-5,5-dimethylthiazolidine-4-carboxylic acid. I.E.=integration units 3-=-192 + 9224x r = 0.9985 S. , = 0.015 ng/spot X. = 370 nm.

Dimethylthiazolidine-4-carboxylic acid test solution (Ud). Add 500 pi of concentrated hydrochloric acid to 500 mg of D-5,5-dimethylthiazolidine-4-carboxylic acid and make up to 10 ml with isopropanol. 

Figure 15 Thin-layer chromatogram of some heterocyclics on CHIRALPLATE . Spots 1, thiazolidine-4-carboxylic acid 2,5,5-dimethylthiazolidine-4-carboxylic acid 3,3-amino-3,5,5-trimethylbutyrolactone hydro-choloride 4, pipecolic acid.

Based on early reports that 2,2-dimethylthiazolidine carboxylic acid gives rise exclusively to the ds-amide bond isomer in a model peptide [77], the (2S)-5,5-dimethylproline (Dmp, 21) was synthesized and analyzed for its propensity to stabilize the cis-isomeric state [78,79]. For Boc-Phe-Dmp-OMe and Ac-Tyr-Dmp-Asn-OH only a cis conformer was detected, while for Ac-Asn-Dmp-Tyr-OH the high content of ds-amide bond was found to slightly decrease in function of temperature from 90.3% at 6°C to 78.9% at 80 °C. This allowed the extraction of the thermodynamic parameters for the CTI (Table 11.5). In contrast to (2S)-5,5-dimethyl-proline, the (2S)-3,3-dimethylproline leads only to a slight increase of the cis isomer population of the related N-acetyl N-methylamide derivative compared with proline. However, the rates of cis-to-trans and trans-to-cis isomerization were strongly reduced, a fact that was attributed to steric interactions between the 3-methyl groups and the C-terminal amide that restrict the values away from rp 0° [80]. 

D,L-2-phenyl-5,5-dimethylthiazolidine carboxylic acid D,L-2-(2-nitrophenyl)-5,5-dimethylithiazolidinc carboxylic acid and related compounds... 

An alternative to Acm and Tr for the temporary protection of cysteine is 2,2-dimethylthiazolidine-4-carboxylic acid (H-Dmt-OH, used as the anhydride derived from Boc-Dmt-OH or as Boc-Dmt-OPfp). ... 

Heterocyclic compounds. Thiazolidine-4-carboxylic acid and 5,6-dimethylthiazolidine-4-car-boxylic acid are formed by formaldehyde condensation from cysteine and penicillamine, respectively. The derivatization of penicillamine has been published (195). Table 14 and Fig. 15 present a summary of these results. The chromatographic characteristics of the thiazolidine carboxylic acids formed by the reaction of D,L-peniciIlamine with various substituted benzaldehydes and heterocyclic aldehydes have also been studied (177). 3-Carboxy-morpholine was separated by Gunther et al. (102). 

To avoid loss of the O-labeling, trialkylammonium salts of amino acids have been t-butoxycarbonylated in dry methanol or DMF. A-/-butoxycarbonylation of an alkaline labile and hindered 2,2-dimethylthiazolidine-4-carboxylic acid has been performed in acetonitrile (eq 9). ... 

A soln of (R)-2,2-dimethylthiazolidine-4-carboxylate[961 (1.0 g, 6.2 mmol) in anhyd DMF (8mL) was reacted with Fmoc-AIa-F (0.65 g, 2.07 mmol) for 30 min at 50 °C to give a clear yellow soln. After evaporation of the volatile components, the residue was taken up in EtOAc (100 mL) and was washed with 0.1 M HC1 (3 x 50 mL) and brine (2 x 50 mL), and dried (MgS04). After removal of the solvent, the crude product was purified by flash chromatography (CHCl3/MeOH/AcOH 100 3 3) and was lyophilized from MeCN/H20 to give a white powder yield 0.62 g (66% starting from the acid fluoride) mp 108-111 °C TLC (CHCl3/MeOH/AcOH 100 7 1) Rf 0.41. 

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