Proline mimics

DPP IV inhibitors, access to potent c/ s-proline mimics, (E)-fluoroolefin isosteres, is convenient. The utility of (Z)-alkene amide isosteres in such applications has been established [106],... 

F.A. Etzkorn, J.M. Travins, S.A. Hart, Rare protein turns y-turn, helix-turn-helix, and cis-proline mimics, Adv. Amino Acid Mimet. Peptidomimet. 2 (1999) 125-163. 

Fig. 1.2.4. Bulky substituents attached to the heterocyclic scaffold make 5-tert-butylproline (a) and pseudoprolines (X = O or S) (b) efficient syn-proline mimics, (c) Imide isomerism N-terminal to pipecolyl residues.

The homo proline mimic 38 has been synthesized by standard means and incorporated into peptides. Conformational aspects of the products were determined by H NMR and molecular dynamics simulation. ... 

The overall synthetic strategy toward the tetrapeptide scaffold of telaprevir requires four key amino acid building blocks (45-49, Scheme 8), which can be coupled using standard peptide coupling methods. As in the synthesis of boceprevir, the P2 domain (48), which contains the bicyclic proline mimic, is the most synthetically challenging fragment of telaprevir, particularly in the context of a scalable route for commercialization. Likewise, the synthesis of the PI ketoamide domain (49) has required significant revision and optimization in the transition from discovery to process scale. 

M. W. Albeis, C. T. Walsh, and S. L. Schreiber,/. Org. Chem., 55,4984 (1990). Substrate Specificity for the Human Rotamase FKBP A View of FK506 and Rapamycin as Leu-cine-(Twisted Amide)-Proline Mimics. 

FIGURE 16.7 The proline racemase reaction. Pyrrole-2-carboxylate and A-l-pyrroline-2-carboxylate mimic the planar transition state of the reaction. 

Cyproase 1 is in effect a new enzyme, produced by systematic protein engineering firmly based on sound chemical principles. Its status as an enzyme mimic may be debatable its efficiency is not. It was shown to hydrolyze 25% of bonds to proline in a (denatured) peptide toxin in two hours at pH 70, with some 400 turnovers. It is one of the two most efficient enzyme mimics we will encounter in this article1131... 

Robust peptide-derived approaches aim to identify a small drug-like molecule to mimic the peptide interactions. The primary peptide molecule is considered in these approaches as a tool compound to demonstrate that small molecules can compete with a given interaction. A variety of chemical, 3D structural and molecular modeling approaches are used to validate the essential 3D pharmacophore model which in turn is the basis for the design of the mimics. The chemical approaches include in addition to N- and C-terminal truncations a variety of positional scanning methods. Using alanine scans one can identify the key pharmacophore points D-amino-acid or proline scans allow stabilization of (i-turn structures cyclic scans bias the peptide or portions of the peptide in a particular conformation (a-helix, (i-turn and so on) other scans, like N-methyl-amino-acid scans and amide-bond-replacement (depsi-peptides) scans aim to improve the ADME properties." ... 

X.J. Wang, S.A. Hart, B. Xu, M.D. Mason, J.R. Goodell, F.A. Etzkorn, Serine-c/s-proline and Serine-frans-proline isosteres Stereoselective synthesis of (Z)- and ( )-alkene mimics by still-wittig and ireland-claisen rearrangements, J. Org. Chem. 

Most of the fluoro derivatives of proline described in the literature are fluorinated in the 4 position. 4-Fluoroprolines are able to mimic 4-hydroxyproline, present in some proteins and polypeptides. On the other hand, 4-fluorination could suppress oxidative metabolism or modified ring conformation of ligands.The labeled analogues may be used as probes in PET (positron emission tomography) for localization of tumors... 

Figure 7.11 2-Pyridyl analogs (pyridinium salts) closely mimic the carboxyl of proline.

As in the case of the five-membered proline analogues, besides pipecolic acid (6) as the six-membered homologue of proline, related aza-, oxa-, and thia-analogues are used to mimic the conformationally restricting properties of proline in the peptidomimetic design of bioactive compounds.1202 ... 

In 2008 Resmini et al. [76] presented their work on the synthesis of novel molecularly imprinted nanogels with Aldolase type I activity in the cross-aldol reaction between 4-nitrobenzaldehyde and acetone. A polymerisable proline derivative was used as the functional monomer to mimic the enamine-based mechanism of aldolase type I enzymes. A 1,3-diketone template, used to create the cavity, was... 

In the synthesis of l,2,5-triazepine-l,5-diones, which are expected to mimic the structural features of or-peptidyl prolin-amides, the preparation of N2,N3-disubstituted derivatives 213a from the reaction of (Z)-alanine with the N2-substituted triazepines 213 resulted in lower yields. It has been reported that these fused triazepinediones could be elaborated to give constrained rir-peptidyl proline peptide mimetics of defined stereochemistry and sequence <1997J(P1)2297>. 

The mechanism similarities to enzymatic processes In principle, L-proline acts as an enzyme mimic of type I metal-free aldolases. Similar to this enzyme, L-proline catalyzes the direct aldol reaction according to an enamine mechanism. Thus, for the first time a mimic of type I aldolases has been found. The close similarity of... 

In principle, L-proline acts as an enzyme mimic of the metal-free aldolase of type I. Similar to this enzyme L-proline catalyzes the direct aldol reaction according to an enamine mechanism. Thus, for the first time a mimic of the aldolase of type I was found. The close relation of the reaction mechanisms of the aldolase of type 1 [5b] and L-proline [4] is shown in a graphical comparison of both reaction cycles in Scheme 3. In both cases the formation of the enamines Ila and lib, respectively, represents the initial step. These reactions are carried out starting from the corresponding ketone and the amino functionality of the enzyme or L-proline. The conversion of the enamine intermediates Ha and lib, respectively, with an aldehyde, and the subsequent release of the catalytic system (aldolase of type I or L-proline) furnishes the aldol product. 

In conclusion, the aldol reaction with L-proline as an enzyme mimic is a successful example for the concept of using simple organic molecules as chiral catalysts. However, this concept is not limited to selected enzymatic reactions, but opens up a general perspective for the asymmetric design of a multitude of catalytic reactions in the presence of organocatalysts [1, 3]. This has been also demonstrated by very recent publications in the field of asymmetric syntheses with amino acids and peptides as catalysts. In the following paragraphs this will be exemplified by selected excellent contributions. 

In conclusion, the recent contributions by several groups in the field of asymmetric syntheses with amino acids and short-chain peptides as efficient chiral catalysts appear to be very interesting for chemists from academia as well as from industry. In addition, those new syntheses are promising alternatives to existing asymmetric technologies. Without any doubts it is surprising to observe that a simple amino acid molecule - as shown in case of proline - can in principle act like an enzymatic system, thus representing an efficient enzyme mimic. 

For the proline- and proline congener-catalyzed aldol reaction [23, 24], a mechanism based on enamine formation is proposed [25], Scheme 7. The catalytic process starts with condensation of the secondary amino group of proline with a carbonyl substrate leading to a nucleophilic enamine intermediate, which mimics the condensation of the active-site lysine residue with a carbonyl substrate in type I aldolases. The adjacent carboxylic acid group of the enamine intermediate... 

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