Pseudodipeptides

The results for conjugate additions to pseudodipeptides 83 and 86 may be interpreted along similar lines. Thus, addition of the fairly slim lithium dimethyl-cuprate nucleophile proceeded non-selectively (84, Scheme 6.17) [34, 35]. Con-... 

Acylation of 186 with an oc-substituted ethyl succinyl chloride generates the expected 4-acyl-5(4//)-oxazolones 187 that serve as precursors to ketomethylene and dehydro ketomethylene pseudodipeptides (Scheme 7.56). ... 

The presence of an NH group is essential, since the Boc-p-amino sulfone derived from Pro could only be coupled with lower yields (-20%). This method is also suitable for the preparation of pseudodipeptides having functionalized side chains such as those of Ser and AsnJ72l The p-oxo sulfone 51, which was obtained by reacting Boc-pAla-OMe with the dilithium anion of methyl phenyl sulfone, cleanly reacted with ethyl bromoacetate to give the p-oxo sulfone 52 (86%). The latter was reduced using LLAIH4, which on reductive elimination produced the over-reduced Boc-Alai)i(CH2—CH2]Gly-OMe isostere (80%). 

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 ... 

Protected Xaa1i()[CH(CN)NH]Xaa2 Pseudodipeptides General Procedure 179 ... 

TEA (0.55 mL, 4 mmol) was added to a stirred soln of the corresponding a-amino acid methyl ester hydrochloride 27-HC1 (PG2=Me) (4 mmol) in MeOH (25 mL). After 15 min at rt, the mixture was cooled to -20 °C. ZnCl2 (0.27 g, 2 mmol) and the appropriate freshly prepared N -protected a-amino aldehyde 26 (2 mmol) were added and stirring was continued for lh at this temperature. TMSCN (0.30 mL, 2.4 mmol) was added and the mixture was stirred at 0°C for 24 h. The solvent was removed under reduced pressure, the residue dissolved in EtOAc (25 mL), and the resulting soln was washed with H20 (20 mL), brine (20 mL), and then dried (Na2S04). After removal of the solvent and flash chromatography (EtOAc/hexane), the protected pseudodipeptide 28 was obtained as a mixture of two diastereomers (R)-28 and (S)-28 which could be separated in some cases (28e, 28j). The results are summarized in Table 5. Analytical and spectroscopic data for compounds (R)-28e, (S)-28e, (R)-28j, and (S)-28j are reported in Table 6. 

Table 5 Yields and Stereoisomeric Ratio of Pseudodipeptides PCd-XaahpfCH-...

Preparation of [NHCHj] pseudodipeptides from a A-acetyl gem-diamine 88 and an a-aldehydo ester 89 was unsuccessful.185 The desired pseudodipeptide was unstable and eliminated the acetamide moiety. To overcome this instability a pseudotripeptide was prepared that incorporates the reduced retro isostere from a retro-inverso pseudodipeptide 85 the synthesis of this compound is shown in Scheme 16. Coupling of Z-L-Phe-OH with 32 using the mixed anhydride method afforded the retro-inverse pseudodipeptide 33. Reaction of 33 after hydrogenation with an a-aldehydo ester provides the reduced-retro pseudotripeptide 35 as a pair of diastereomers. 

If the C-terminal component of a t t[CH2-S] pseudodipeptide derives from Gly, such compounds can be prepared by the simpler approach shown in Scheme 6. Borane treatment reduces the amino acid 14 to the amino alcohol 15 which is then further converted into the tosylate 16 with retention of the chirality in the N-terminal component 36 as described previously. Reaction of 16 with the disodium salt 17 of the commercially available sulfe-nylacetic acid yields the pseudodipeptide 18. 

Synthesis of a i >[CH2—S] Pseudodipeptide with a C-Terminal Gly (18) 3g-401 O-Benzyl-flV-ferf-butoxycarbonylltyrosinol (15) 40 ... 

Scheme 7 Synthetic Route to the Pseudodipeptide H-D-Senj)[CH2-S]-Leu-OHl38l...

In this approach cysteine (19) was reduced to Cys(ol) (20) which was isolated as the triacetyl derivative 21. This compound was hydrolyzed with hydrochloric acid, the resulting hydrochloride 22 treated with 3 equivalents of NaOEt followed by addition of the a-bromo acid 24 derived from D-leucine (23). The resulting product 25 can then be /V-Boc-protected to yield the pseudodipeptide in a form suitable for solid-phase chain elongation. 

A report involving the solid-phase preparation of Fmoc-protected t t[CH2—S] pseudodipeptides revealed that the expected stereochemical patterns did not hold.147 It is known that the conversion of an a-bromo acid into the a-thioacid does not always occur with quantitative inversion of chirality, since it is side-chain dependent.146] With side chains such as benzyl (Phe) or butyl (Leu, lie), exceptions are not expected. But when the Fmoc-protected amino thiol 26 was condensed to a support-bound bromo acid 27, as shown in Scheme 8, the (S,R)-product 28 was obtained instead of the expected (S,S)-isomer. 

Another potential problem involving stereochemistry concerns the epimerization of the C-terminal chiral center of the pseudodipeptide unit, which is observed during the resin attachment step when using the cesium salt derivative.]36]... 

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 ... 

The pseudodipeptide amides represented a major advance in the substrate-based design of FTIs. They removed the metabolic liability of the prodrug, were cell active, and were considerably simpler chemically. However, the majority of pseudodipeptide amides were not potent enough and too cytotoxic to demonstrate activity in cell culture. Although the potency issue was perceived as solvable, the dark cloud of nonspecific cytotoxicity hovered over this particular class of compounds like an unwelcome visitor. Changes to the molecule which virtually destroyed FTase activity had no effect on the level of cytotoxicity, indicating that the observed toxicity was unlikely to be mechanism related. 

Martin, O.R., Zhou, W., Wu, X., Front-Deschamps, S., Moutel, S., Schindl, K., Jeandet, R, Zbaeren, C., Bauer, J.A. Synthesis and immunobiological activity of an original series of acyclic lipid A mimics based on a pseudodipeptide backbone. J Med Chem 49 (2006) 6000-6014. 

Heidelberg and Martin described the first synthesis of the polar mycoside C 252 (O Scheme 38) [131]. The synthesis was based on the disconnection of the final structure into three saccharidic building blocks, an L-rhamnosyl pseudodipeptide 254, a 6-deoxy-L-talosyl... 

A nonaqueous CEC method for an efficient, simultaneous separation of the four stereoisomers of N-Z-phosphinic pseudodipeptides 54 has been developed... 

A similar approach published by Zhang and Taylor [82] was based on a combination of Boc/Bzl and Fmoc/tBu methods as well as the use of a preformed pseudodipeptide building block, which was previously proposed... 

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]. 

Kaboudin et al. have developed a simple and efficient method for the synthesis of a-aminophosphinic acids (577) in reaction of aromatic aldehydes (576) with ammonia solution and hypophosphorus acid in good yields (40-71%). Novel C2-symmetric phosphinic acid pseudodipeptides (578) have been also synthesized by the Michael addition of (577) to methyl acrylate (Scheme 141). 

The NP+C approach (Fig. 4) is undoubtedly the predominant strategy for the preparation of the main pseudodipeptidic unit. This approach usually involves the mild reaction of phosphorus nucleophiles (2 or 3) derived in situ from amino-protected aminophosphinic acids with carbon electrophiles such as acrylic... 

Scheme 1 Main synthetic routes toward phosphinic pseudodipeptides by the NP+C approach...

Scheme 2 Main synthetic routes toward phosphinic pseudodipeptides by the NP+C approach (Cbz benzyloxycarbonyl, Brv. benzyl, Tf. trifluoromethanesulfonyl, THF tetrahydrofuran, LDA lithium diisopropylamide)...

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