Dipeptide mimics

T. Allmendinger, E. Felder, E. Hungerbuehler, Fluoroolefin dipeptide isosteres. II. Enantioselective synthesis of both antipodes of the Phe-Gly dipeptide mimic. Tetrahedron Lett. 31 (1990) 7301-7304. 

Figure 7.21 Charge distribution of fluoroolefins as dipeptide mimics. ...

Spiro lactam 15 (Scheme 9), a dipeptide mimic with C (/)<-+Na(/ + l) cyclization, was used to replace the Pro-Tyr segment of an immunogenic peptide. 69 Comprehensive conformational analysis led to the conclusion that a type-II p-turn conformation was adopted in solution. 

Because the aldehyde in 11 or 12 can be converted into different side-chain functionalities, a range of different dipeptides is accessible. It should, furthermore, be noted that ring sizes of the cyclic amino add scaffold, and stereochemistry in bicyclics like 13, can be readily changed by varying the aza-Diels-Aldcr input. This in turn, enables one to systematically screen a certain set of backbone dihedral angles in dipeptide mimics. 

Design, synthesis, conformational analysis, and application of azabicycloalkane amino acids as constrained dipeptide mimics 04SL1499. 

Single crystal X-ray crystallographic analysis established that the constrained dipeptide mimic 192 (prepared from 189 and 190 via 191) adopts a type II P-tum in the solid state <05TL3733>. 

Polyak, F., and Lubell, W.D. (1998)Rigid dipeptide mimics - Synthesis of enanti-opure 5- and 7-benzyl and 5,7-dibenzyl indolizidinone amino acids via enolization and alkylation of delta-oxo alpha,omega-di-[N-(9-(9-phenylfluorenyl))amino] azelate esters. J. Org. Chem. 63, 5937-5949. 

Fig. YI.9 General framework of dipeptide mimics with a trans-amide conformation X and Y represent possible heteroatoms in the fused rings which can vary in the size and bear additional substitutents to mimic the amino acid side-chains. A stereocontrol of the ring-fusion center Z is difficult to achieve.

Two general routes to a new class of dipeptide mimics, the fluoroolefin dipeptide isosteres, will be presented. They allow the preparation of compounds of formula 2 with a wide variety of residues R, and r3 in racemic or enantiomerically pure form. Some of the mimics have been introduced into small peptides of biological interest. Some preliminary results will also be discussed. 

With catalytic amounts of sodium hydride and two equivalents of trichloro-acetonitrile, one could get the bis-iminoesters 24, which were rearranged in refluxing xylene to 25. The unaffected primary iminoester group was cleaved with sulfuric acid in methanol affording 26. Replacing the N-trichloro acetyl by the BOC group and finally Jones oxidation gives the protected Phe-Gly fluoroolefin dipeptide mimics 28a in optically pure form. 

Peptides containing the Fluoroolefin Dipeptide Mimic and their Biological Activity... 

Flynn, G.A., Giroux, E.L. and Dage, R.C. (1987) An acyl-iminium ion cycUzation route to a novel conformationally restricted dipeptide mimic applications to angiotensin-converting enzyme inhibition. J. Am. Chem. Soc. 109 7914-7915. 

Currently, six HMGRIs are approved tor therapeutic use in the United States. Chemically, they can be divided into two groups, natural products and synthetic agents. All of these compounds effectively block the conversion of HMG-CoA to mevalonic acid and have similar effects on plasma cholesterol levels. The compounds differ somewhat in their indications, potencies, and pharmacokinetic profiles. They often are referred to as statins or, more recently, vastatins. Because of the potential confusion of the terms statin and statine" (i.e., a stable dipeptide mimic [see Chapter 28]), it is suggested here that classifying an HMGRI as a vastatin is preferable to classifying it as a statin. 

G. A. Flynn, E. L. Giroux, and R. C. Dage,/. Am. Chem. Soc., 109, 7914 (1987). An Acyl-Iminium Ion Cyclization Route to a Novel Conformationally Restricted Dipeptide Mimic Applications to Angiotensin-Converting Enzyme Inhibition. 

The synthesis, spectral characteristics, and the reactions of electrophiles with 1//- and (mesoionic) 2//-pyrrolotetrazoles were studied <01JCS(P1)720, 729>. The synthesis and crystal structure of a a-keto tetrazole-based dipeptide mimics has been reported <01TL5641>. Novel tetrazol-5-yl-isoquinolinium zwitterions have been synthesized and confirmed by X-ray diffraction analysis <01JHC199>. Application of natural bond orbital analysis to delocalization and aromaticity in C-substituted tetrazoles has been investigated <01JOC8737>. 

Similar in approach to linear methods discussed previously, the cyclodehydration of a-amido ketones is an alternative strategy for preparation of the oxazole nucleus. Treatment of the ketone with PPhs and I2 results in cyclization to provide the fully substituted oxazole nucleus in excellent yield. This strategy was recently used in the synthesis of oxazole-modified glycopeptides, designed to target two classes of arthritis-associated proteins. The oxazole was probed as a conformationally locked dipeptide mimic. 

Scheme 5.25 Incorporation of derivatives of 1,1 ferrocenyl-fc/s-alanine 42 as dipeptide mimics into substance P (top, 48) and enkephalin (bottom, 49).

The dipeptide mimic (100), a constituent of the orally-active renin inhibitor BW-175, has been prepared from 3-0-benzyl-1,2 5,6-di-O-isopropylidene-D-allose (sugar carbons numbered).76... 

This strategy has been also employed for the synthesis of a dipeptide mimic,as illustrated in eq 14. 

Figure 10.2 Dipeptide mimics containing a 1,4- or 1,5-substituted triazole were produced by a thermal or cop per ( )-catalyzed 1,3-dipolar cycloaddition reaction...

The pseudodipeptide 55 (see Scheme 10.16) was regarded as a conformationally restricted Xaa-Pro dipeptide and Scolastico et al. functionalized the azido-group by copper(l)-catalyzed dipolar cycloaddition with an alkynylated sugar, biotin or fluorescein to afford substituted triazolyl-Xaa-Pro-dipeptide mimics 56 in good to excellent yields. ... 

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