Peptides pseudodipeptides

Direct reduction of a peptide bond with diborane 59 or a thioamide bond with several reductive procedures 60 is an alternative route for the production of a reduced peptide bond in a peptide. In some cases the reductive amination does not give satisfactory results. As described earlier, preparation of Boc-Pher )[CH2N]Pro-OH by reductive amination yields two diastereomers (Scheme ll). 57 In this case treatment of Boc-Phe-Pro-OBzl by diborane yielded the reduced pseudodipeptide Boc-Pher )[CH2N]Pro-OBzl without epimerization (Scheme 12). However, in some cases diborane is not entirely selective for the amide bond and can reduce ester functions when they are present. Another procedure is to prepare endothiopeptides directly from protected dipeptides 61-66 followed by their selective reduction. 60 ... 

Peptide cyclization significantly reduces this flexibility, as shown by model studies with cyclic pseudodipeptides. When incorporated into biologically active cyclic peptides, potencies are generally retained or even enhanced. But flexibility is still a feature since pseudopeptide analogues of the p-receptor-selective opioid parent peptide, Tyr-c[-D-Lys-Gly-Phe-Leu-], were potent but nonselective with respect to activity toward p- and 6-re-ceptorsJ50]... 

In the synthesis of PMRI substance P, the slow, DCC/HOBt-mediated incorporation of the pseudodipeptide suffered from extensive formation of the Leu-Met piperazine-2,5-dione this led to about 20% loss of peptide from the resin. Two cycles of IBTFA-mediated (fourfold molar excess) rearrangement were carried out. The first one-hour cycle was followed by a second overnight cycle. 62 ... 

Further coupling of these derivatives with 2-substituted malonic acid monoester 13 using DCC-HOBt or reaction with Meldrum s acid derivatives 12 after in situ trimethylsilylation with excess N,0-bistrimethylsilyla-cetamide (BSA) gives the protected pseudodipeptide unit 28, which can be coupled to the growing peptide chain on a solid support (Scheme 10) [122]. 

The synthesis of phosphinic peptides by a reverse sequence of P-C bond formation events (N+PC approach) is a less frequently applied strategy which may offer important diversification possibilities. In particular, an amidoalkylation condensation reaction between amides, aldehydes, and alkylphosphinic acids (the three-component Kabachnik-Fields reaction) affords in a single step the main pseudopeptidic backbone, thus facilitating fast screening of the nature of Pi position. In 1996, Chen and Coward observed that a mixture of benzyl carbamates, aldehydes, and alkylphosphinic acid 23 in AcCl can lead to Cbz-protected phosphinic pseudodipeptides 24 (Scheme 10a) [53]. This method was adjusted by Matziari et al. to the synthesis of Fmoc-protected phosphinic building blocks 25 and peptides thereof (Scheme 10b) [54]. 

Several reports have dealt with the use of phosphinic pseudodipeptide building blocks in peptide couplings where both phosphinic and carboxylic acids are unprotected. Among the coupling reagents used successfully for such transformations are W,W -carbonyldiimidazole (CDl) [66-68], (benzotriazol-l-yloxy)tris (dimethylamino)phosphonium hexafluorophosphate (BOP) [69, 70],... 

Regardless of the method used to construct the main pseudodipeptidic backbone, separation of different diastereoisomers has been achieved in several cases by selective crystallization at dipeptide [74, 91], tripeptide [74, 92, 93], or even tetrapeptide level [94]. The isomer corresponding to the natural peptide is usually crystallized out selectively nevertheless, in some tripeptides it has been reported that non-natural peptide isomers are prone to selective crystallization in less polar solvents (Et20 or CHCI3), probably caused by differences in the intramolecular hydrogen bonding in these media (Scheme 16) [92, 93]. 

Kim BH, Chung YJ, Keum G, Kim J, Kim K (1992) A new peptide bond surrogate 2-isoxa-zoline in pseudodipeptide chemistry. Tetrahedron Lett 33 6811-6814... 

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