Amino proline derivatives

However, it was not until the beginning of 1994 that a rapid (<1.5 h) total resolution of two pairs of racemic amino acid derivatives with a CPC device was published [124]. The chiral selector was A-dodecanoyl-L-proline-3,5-dimethylanilide (1) and the system of solvents used was constituted by a mixture of heptane/ethyl acetate/methanol/water (3 1 3 1). Although the amounts of sample resolved were small (2 ml of a 10 inM solution of the amino acid derivatives), this separation demonstrated the feasibility and the potential of the technique for chiral separations. Thus, a number of publications appeared subsequently. Firstly, the same chiral selector was utilized for the resolution of 1 g of ( )-A-(3,5-dinitrobenzoyl)leucine with a modified system of solvents, where the substitution of water by an acidified solution... 

Early examples of enantioselective extractions are the resolution of a-aminoalco-hol salts, such as norephedrine, with lipophilic anions (hexafluorophosphate ion) [184-186] by partition between aqueous and lipophilic phases containing esters of tartaric acid [184-188]. Alkyl derivatives of proline and hydroxyproline with cupric ions showed chiral discrimination abilities for the resolution of neutral amino acid enantiomers in n-butanol/water systems [121, 178, 189-192]. On the other hand, chiral crown ethers are classical selectors utilized for enantioseparations, due to their interesting recognition abilities [171, 178]. However, the large number of steps often required for their synthesis [182] and, consequently, their cost as well as their limited loadability makes them not very suitable for preparative purposes. Examples of ligand-exchange [193] or anion-exchange selectors [183] able to discriminate amino acid derivatives have also been described. 

Aldol additions of various lithium enolates performed in the presence of (S.S)-l, 4-bisdimethyl-amino-2,3-dimethoxypentane or (.SVS )-1,2,3,4-tctramethoxybutane display only modest reagent-induced stereoselectivity (<20% ee)21. Significant improvement results from the use of the proline derived diamines 2,3 and 4 as additives in tin(II) mediated aldol additions of silyl enol ethers22 23. 

Scheme 3.1 L-Proline-derived P-amino thiol and disulfide ligands for additions of ZnEt2 to aldehydes.

The Heck reaction has proven to be an extremely useful method for the formation of C-C bond at a vinyl carbon centre. There are numerous reported examples of enantioselctive Pd catalyzed C-C bond forming reactions.10"13 Surprisingly, reports of Heck transformations using amino acid based phosphine, phosphinite ligands are rare. Recently Gilbertson reported a proline derived phosphine-oxozoline ligand in a catalytic asymmetric Heck reaction.5 In this paper we present some novel amino acids derived ligands as part of a catalytic system for use in asymmetric Heck reactions. 

Functionalized 5,6-dihydro-4// -oxazines are direct precursors of a series of useful products, for example, of proline derivatives (539), unnatural amino acids (540), and some alkaloids (541). 

In the study of Weber et al.,41 a series of proline-derived hydrazones were prepared, and the reactions of the hydrazones with organocerium reagents were examined. It is clear from the table in Scheme 2 24 that the diastereoselectivity of the examined reactions depends on the nature of the side chain. (S )-l-amino-2-(2-methoxyethoxymethyl) pyrrolidine (40) gave the highest selectivity for various nucleophiles. 

The optically active //-amino alcohol (1 / . 3 R. 5 / )-3-(di phenyl hydroxymethyl )-2-azabicyclo[3.3.0]octane [(li ,3i ,5i )-121], can be derived from a bicyclic proline analog. It catalyzes the enantioselective addition of diethylzinc to various aldehydes. Under mild conditions, the resulting chiral secondary alcohols are obtained in optical yields up to 100%. The bicyclic catalyst gives much better results than the corresponding (S )-proline derivative (S )-122 (Scheme 2-47).114... 

In the search of new methodologies for the asymmetric synthesis of nonproteinogenic amino acids, 8-methyl-4,8a-diphenyltetrahydro-17/-pyrrolo[2.1 -r l, 4 oxazinc-l, 6(7//)-dionc 62, obtained as described in Scheme 24 (Section 11.11.7.3), was selectively reduced at the lactam carbonyl with BH3 and further opened by hydrogenolysis to give syn-disubstituted proline derivative 64 in 95% yield <1997SL935> (Scheme 6). It is noteworthy that hydrogenolysis did not affect the benzylic position of bicyclic compound 63. 

Compound 331 was prepared using the free amino acid derived by coupling the product between proline and a substituted tryptophan. It was employed for studies on the biosynthesis of the anthelmintic agent paraherquamide <2001T5303>. Compound 332 was obtained by TFA-mediated reaction from the corresponding NH-/-Bu dipeptide... 

Radical cyclization of N-alkenylamino acid derivatives Proline derivatives can be obtained by cyclization of N-alkenyl amino acid derivatives. Thus the (3-iodo allylic amine 2, prepared in 54% yield from threonine, cyclizes in the presence... 

Efforts to find potent and selective DPP-4 inhibitors in the a-amino acid amide series were made in parallel with those in the (3-amino acid amides series. The structural origin of the earliest P-amino acid amide DPP-4 inhibitors traces back to two Merck HTS hits proline derivative 25 and piperazine derivative 26. These two screening leads were further progressed to P-amino acid amide DPP-4 inhibitors incorporating thiazolidine, proline and piperazine amide moieties (Figure 17.5). 

Direct electrochemical oxidation of protected a-amino acids is generally ineffective. An exception is provided by proline derivatives, which are methoxylated on carbon-5 of the pyrrolidine ring. Open chain protected a-amino acids undergo... 

Important improvement in the in vitro activity was obtained when the central proline was replaced by thiaproline (thiaPRO) to give compound 66, suggesting that modification of the central amino acid (of the proline type) could be of importance in modulating the PEP inhibitory activity, Eq. (25) [76]. In fact, replacement of the proline moiety of63 - 66 by non-natural amino acids derived from 2-perhydroindole or from 2-azabicyclo[2.2.2]octane and modulation of the side chain by replacement of the terminal phenyl ring by a dicyclopropyl-carbinyl moiety afforded derivatives such as 67 and 68 with improved activities (IC50 between 10 and 20 nM), Eq. (26). 

The chiral auxiliaries H-A developed by Evans et al. 176) were derivatives of naturally occurring amino acids. The (S)-proline-derived amide enolates (164) as well as the (S)-valine-derived amide enolates (166) and imide enolates (165) have proven to be exceptionally versatile chiral nucleophiles. 

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