Dipeptides proline-based

In 2011, the group of Chen reported the application of proline-based reduced dipeptides in the asymmetric Michael addition of cyclic ketones to tra s-p-nitrostyrenes. Comparative studies revealed that the presence of the carbonyl moiety at the N-terminal L-proline unit results in a lower enantioselectivity compared to the corresponding amine analogues. Thus, a series of reduced dipeptides was tested on the above-mentioned Michael addition unveiling reduced dipeptide 17, derived from L-proline and L-phenylalanine, as the optimal catalyst generating the desired products in... 

Based on the observations obtained for i-proline-based dipeptides Gong and coworkers were the first to report an efficient catalytic protocol for the asymmetric direct aldol reaction of aldehydes with hydroxyacetone yielding a series of 1,4-diols as major product (1,2-diols just as minor product) in aqueous media providing good yields and excellent enantioselectivities. " ... 

The group of Zhang designed a series of L-proline-based dipeptides eom-prising a C-terminal amino-piperidyl pyridine moiety (Scheme 13.22a). The asymmetric aldol reaction between various aldehydes and cyelie ketones, catalysed by peptide 34 in 10 mol% loading, was performed in brine since... 

Simple A/-proline-based dipeptides catalyse direct aldols of aldehydes with a wide range of ketones, giving yield/de/ee up to 99/>98 (syn)/97%, at room temperature in 0 brine, with 2,4-dinitrophenol as co-catalyst. A simple organocatalyst, the methyl 0 ester of (S)-proline-(S)-phenylalanine, promotes high-yielding aldols with up to 95% ee and 82% de (anti-) under solvent-free conditions at —20 °C. Lack of solvent should 0 maximize substrate-catalyst noncovalent interactions. 0... 

A series of new robust proline-based dipeptides with two amide units were evaluated by Peng et al. as organocatalysts for the asymmetric aldolisation of cyclohexanone in organic solvents. The reactions proceeded smoothly in the presence of an additive, such as AcOH or 0-T0ICO2H, providing high yields and enantio- and diastereoselectivities of up to 98% ee and 98% de, respectively (Scheme 2.17). In order to explain the enantioselectivity of the reaction,... 

Aldolisations of cyclohexanone with aldehydes catalysed by proline-based dipeptide. 

Unsupported dipeptides such as 43 were active only in the presence of NMM/ SDS or DABCO/PEG400. Immobilization of several proline-based dipeptides showed that there is no need for such additives. For instance, resin 67 (Figure... 

Two examples of unsupported proline-based catalysts are compounds 88 and 89 (Figure 24.30). Dipeptide 88 was used in water in the presence of NaOH in the addition of ketones to nitroalkenes. The presence of sodium hydroxide additive was crucial for the success of the reaction [109]. Catalyst 89 was designed on the structurally rigid hexahydropyrrolo[2,3]indole skeleton and efficiently catalyzed the enantioselective addition of aldehydes to nitroalkenes both in methanol and water [110]. The same catalyst was also used in the addition of aldehydes to vinyl sulfone followed by reduction with sodium borohydride. In this case water was a better reaction medium than methanol [111]. 

Once it is part of a cyclic dipeptide, the prolyl residue becomes susceptible to enantiomerization by base (see Section 7.22). The implication of the tendency of dipeptide esters to form piperazine-2,5-diones is that their amino groups cannot be left unprotonated for any length of time. The problem arises during neutralization after acidolysis of a Boc-dipeptide ester and after removal of an Fmoc group from an Fmoc-dipeptide ester by piperidine or other secondary amine. The problem is so severe with proline that a synthesis involving deprotection of Fmoc-Lys(Z)-Pro-OBzl produced only the cyclic dipeptide and no linear tripeptide. The problem surfaces in solid-phase synthesis after incorporation of the second residue of a chain that is bound to the support by a benzyl-ester type linkage. There is also the added difficulty that hydroxymethyl groups are liberated, and they can be the source of other side reactions. 

Cyclic dipeptides, especially when N-alkylated, undergo extremely fast epimerization (79JA1885). For example, cyclo(L-Pro-L-Phe) is rapidly converted to its diastereomer, cyclo(D-Pro-L-Phe) (80% conversion), by treatment with 0.5 N NaOH at 25°C for 15 min. This diastereomer is the one in which the proline residue has epimerized and not the more activated phenylalanine. CNDO/2 calculations seem to provide a rationale for this. It is not yet completely clear why such base-catalyzed epimerizations of piperazinediones are so easy the conformation of the molecule may play a role in this (79MI1). It is also worth noting that even in linear peptides, rm-amides of N-alkyl-amino acids, which consist of s-trans and s-cis rotamers of almost equal energy, are more prone to racemization than the sec-amides, which exist only in the s-trans configuration. Of course, the amide functions of piperazine-2,5-diones are obliged to assume the s-cis conformation. 

The development of chiral peptide-based metal catalysts has also been studied. The group of Gilbertson has synthesized several phosphine-modified amino adds and incorporated two of them into short peptide sequences.[45J,71 They demonstrated the formation of several metal complexes, in particular Rh complexes, and reported their structure as well as their ability to catalyze enantioselectively certain hydrogenation reactions.[481 While the enantioselectivities observed are modest so far, optimization through combinatorial synthesis will probably lead to useful catalysts. The synthesis of the sulfide protected form of both Fmoc- and Boc-dicyclohexylphosphinoserine 49 and -diphenylphosphinoserine 50 has been reported, in addition to diphenylphosphino-L-proline 51 (Scheme 14).[49 To show their compatibility with solid-phase peptide synthesis, they were incorporated into hydrophobic peptides, such as dodecapeptide 53, using the standard Fmoc protocol (Scheme 15).[451 For better results, the phosphine-modified amino acid 50 was coupled as a Fmoc-protected dipeptide 56, rather than the usual Fmoc derivative 52.[471 As an illustrative example, the synthesis of diphe-nylphosphinoserine 52 is depicted in Scheme 16J45 ... 

Lisinoprii has been prepared by the scheme outlined in Figure 1 (7,8). The dipeptide, Ng-trifluoroacetyl-L-lysyl-L-proline (D is subjected to reductive alkyiation with ethyl 2-oxo-4-phenylbutanoate over Raney Nickel via a Schiff base to yield a diastereomeric mixture 4 (SSS and RSS). Hydrolysis of the N -trifluoroacetyl moiety and saponification of the ethyl ester followed by crystallization in ethanol/water and final recrystallization in water yield lisinopril (SSS, 5) of greater than 98% purity in about 65% yield (based on In addition to this synthetic route, others have also been described in the literature (9-12). 

Based on the observations and quantum mechanical calculations for proline-catalysed asymmetric aldol reactions Li and coworkers synthesised a series of L-proline-hased dipeptides for the direct asymmetric aldol reaction between substituted aldehydes and acetone in DMSO. Dipeptide 31 was successfully employed yielding the desired adducts in excellent yield and good to excellent enantioselectivity. Additionally, PGME 5000 was used as a surfactant additive in catalytic amounts, since prior reports showed an acceleration of aldol reactions hy such additives Xheme 13.20b). 

---