Dipeptide isosteres, olefinic

M.T. Cox, D.W. Heaton, J. Horbury, Preparation of protected trans-olefinic dipeptide isosteres, J. Chem. Soc. Chem. Commun. (1980) 799-800. 

R. Beresis, J.S. Panek, A concise enantioselective synthesis of frans-olefin dipeptide isosteres, Bioorg. Med. Chem. Lett. 3 (1993) 1609-1614. 

Chiral (E)-crotylsilanes have been utilized with Phi = NTs for Cu(I) - catalyzed syntheses of olefinic dipeptide isosteres, examples of which are shown in Scheme 70 [191]. In this case, tosylamidation occurs with allylic inversion,probably via asymmetric tosylaziridination of the C,C-double bond. The diastereos-electivity of product formation is high (>30 1) and appears to be strongly influenced by the hydroxyl group in the starting compounds. 

Fluoro-olefins lF[CF=CH] as Dipeptide Isosteres 10.2.1 Synthetic Methods... 

Further elaboration of both (Z)- and (E)-66 led to the formation of fluoro-olefin /[CF=CH] dipeptide isosteres in enantiomerically pure form. For example, chiral imine (Z)-68 prepared by Ti(IV)-promoted condensation of a-fluoroenone 66a with Ellman s sulfonamide 67 was reduced in a highly diastereoselective manner to give the reductive amination product 69, which was converted to the dipeptide isostere 70 via several steps (see Scheme 10.24) [33]. 

To solve the inactivation issues mentioned above, the concept of conformationally restricted (Z)-fluoro-olefm dipeptide isosteres that mimic the active trans conformation of the DPP IV inhibitors was applied by Welch and co-workers to the preparation of inhibitors having Ala-T fCF CHJ-Pro structure (76 and 78) and their inhibitory activities were evaluated (see Figure 10.6) [36, 37]. DPP IV inhibitory activities and the stability of the inhibitors 76 and 77, in comparison with those of the model dipeptide Ala-Pro derivative 78 are summarized in Table 10.2. These fluoro-olefin analogues, 76 and 77, showed better DPP IV inhibitory activity than that of 78. In particular, u-76 having the same relative stereochemistry as the natural dipeptide (L-Xaa-L-X aa) configurations exhibited potent... 

Allmendinger, T., Felder, E. and Hungerbuehler, E. (1991) Fluoro-olefin dipeptide isosteres, in Selective Fluorination in Organic and Bioorganic Chemistry, ACS Symposium Series 456, American Chemical Society, Washington, D.C., pp. 186-195. 

Allylic silanes can be converted into allylic tosylamides by the reaction with PhINTs in the presence of copper salts. In particular, the copper(I)-catalyzed enantioselective amidation of the chiral ( )-crotylsilanes 659 (Scheme 3.263) has been used in the asymmetric synthesis of ( )-olefin dipeptide isosteres [806]. 

An interesting application of copper-catalyzed aziridination is the preparation of ( )-olefin dipeptide isosteres based on a diastereoselective nitrene transfer onto chiral ( )-crotylsilanes (eq 86)7 CuOTf catalyzes the formation of an aziridine whose rearrangement after spontaneous desilylation affords allylamines. Excellent levels of acyclic stereocontrol can be achieved via a hydroxyl-assisted aziridination. Copper-catalyzed aziridination of enol ethers also leads to aziridines that undergo spontaneous rearrangement. Thus, CuOTf and particularly CUCIO4 mediate the formation of an a-methylserinal derivative from a 5-methyl-4//-1,3-dioxin (eq 87). ... 

M.M. Vasbinder, S.J. Miller, Synthesis of the Pro-Gly dipeptide alkene isostere using olefin cross-metathesis, J. Org. Chem. 67 (2002) 6240-6242. 

---