Freidinger lactam

Until now, the most efficient approach to synthesize Freidinger lactams 147 started from a resin-bound cinnamylamine 144. A Fukuyama-Mitsunobu reaction to 145 followed by sulfonamide cleavage and a consecutive appropriate acylation built up the diene 146, which underwent ring-closing metathesis involving Grubb s catalyst 123 to generate the desired lactams 147 (Scheme 27, Table 5) [35d]. 

The exchange of the chiral phenylethyl amine against an optically active amino acid fragment 269 allowed the synthesis of conformationally restrained dipeptidyl lactams 271 and 272 including the so called Freidinger lactams as... 

Using again unsaturated amines and unsaturated carboxylic acids, 7-membered lactams 169 (unsaturated Freidinger lactams) have been prepared on solid phase [134]. Here a third diversity input was placed in the carboxylic acid as well, but this brought about the presence of a stereogenic centre in the starting component and hence the formation of a diastereomeric mixture of the products. 

In connection with an interest in generating /i-turn dipeptide mimetics, Piscopio and co-workers developed a solid-phase approach to the Freidinger lactam 86 via a solid-phase Ugi condensation and ring-closing metathesis (RCM) methodology [72], The resin-bound amine 85 is the equivalent of a traceless linker and the two-step protocol proceeds in good yield (Scheme 11.17). 

J. D. Peptidomimetic synthesis a novel, highly stereoselective route to substituted Freidinger lactams./. Am. Chem. Soc. 1994, 116, 2348-2355. 

The allyl alcohol linker 1.48 (106), bound to an aldehyde PS resin, has been elaborated to the pentenoic acid derivative shown. This was cyclized with cleavage using ring-closing metathesis (RCM) (Ru catalyst in DCE at 80 °C for 16 h) to give pure Freidinger lactam in solution. 

Wolfe, M. S., Dutia, D., Aube, J. Stereoselective Synthesis of Freidinger Lactams Using Oxaziridines Derived from Amino Acids. J. Org. Chem. 1997, 62, 654-663. 

Recently, a modified approach to the Freidinger lactam analogue was reported, using a novel variant of the Fukuyama-Mitsunobu process [127]. The most salient features of the new method are its simplicity and its versatility [128, 129[. The concept is not restricted to six- or seven-membered rings [130, 131]. 

Piscopio AD, Miller JF, Koch K. A second generation solid phase approach to Freidinger lactams application of Fukuyama s amine synthesis and cyclative release via ring closing metathesis. Tetrahedron Lett. 1998 39 2667-2670. 

Evidence for this conformation was provided by NMR and X-ray, but finally by synthesis of constrained analogues, including 43 which incorporates a y-lactam /3-turn mimic developed by Freidinger et al. (1989). Compound 43 was found to be 10 000 times more potent than 42 in enhancing the binding of the agonist 2-amino-6,7-dihydroxy-l,2,3,4-tctrahydronaphthalene. 

Among the various strategies available for p-tum mimics, the Freidinger y-lactam structure (1), or a spiro system [144] (2),has been found suitable for the design of a variety of medicinally relevant targets. In addition, it has been recently reported that use of a,a-disubstituted [S-lactam (3) could also be a good approach to promote a p-tum folding in a peptide chain [145] (Fig. 12). 

The lactam restriction of peptide conformation (20) (Ci -o-Ni+i) was proposed first by Freidinger et al. (58) with the aim at forcing the peptide bond (coi) to be trans and placing a severe constraint on the rj/i torsion angle. Conformational... 

Freidinger RM, Veber DF, Hirschmann R, Paege LM. Lactam restriction of peptide conformation in cychc hexapeptides which alter rumen fermentation. Int. J. Pept. Protein Res. 1980 16 464 70. 

In a very early example, Freidinger et al. developed a series of cyclic lactams that stabilized j8- and y-turn structures in linear peptides (Fig. 15.8). This strategy was applied to determine conformations of LH-RH that are consistent with the turn structure permitted by the constraint. For example, the 3-amin-olactam (18)was used to mimic a p-turn conformation. When inserted in LH-RH, com-... 

Conformational restriction can be introduced into flexible peptides by a variety of methods. For example, Marshall et al. introduced a-methyl amino acid substituents into peptides as a way to decrease the conformational space available to the resulting peptide. Freidinger et al. developed a cyclic lactam moiety (23.31) that stabilized p- and y-tum structures and applied this to LH-RH (e.g. (23.32)) to show that a p-tura about residues 6-7 was compatible with activity." Conformational restriction has been applied to determine the bioactive conformation of enzyme-inhibitor systems for which no X-ray crystal structure is available. Thorsett" synthesized conformationally restricted bicyclic lactam derivatives of the angiotensin-converting enzyme (ACE) inhibitors enalapril (2333) and enalaprilat (23.34) (Fig. 23.6) in order to characterize torsion angles in the bioactive conformation. Analog (23.35) was used to constrain... 

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