Protected Dipeptide Derivatives

The fully protected dipeptide derivative, BOC-L-alanyl-D-isogluta-mine benzyl ester, was synthesized by conventional methods (Fig. 3). 

The ot-amino and y-carboxyl functions are blocked by t-butyloxy-carbonyl and benzyl ester groups respectively. The coupling is performed using the N,N -dicyclohexylcarbodiimide with N-hydroxysuccinimide (55), mixed anhydride (55, 43), or activated ester 43) methods. The key intermediate, BOC-D-isoglutamine benzyl ester, is prepared by a process which allows the non-equivocal synthesis of this isoglutamine derivative (Fig. 3) 43). 

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Initially, the cytotoxicity against chick embryo fibroblasts of BPA, tyrosine, tyrosine dipeptide, and the dipeptide derivatives used in the synthesis of the polymers shown in Fig. 7 were evaluated in a comparative experiment (43). The surface of standard tissue culture wells was coated with 5 mg of each test substance. Then the adhesion and proliferation of the fibroblasts was followed over a 7-day period. Among all test substances, BPA was clearly the most cytotoxic material. Monomeric tyrosine derivatives containing the ben-zyloxycarbonyl group were also cytotoxic, while tyrosine itself, tyrosine dipeptide, and most of the protected dipeptide derivatives did not noticeably interfere with cell growth and adhesion and were therefore classified on a preliminary basis as possibly "nontoxic."... 

A crystal structure determination of a protected dipeptide derivative of (-)l-aminoethanephosphonous acid showed the (-)aminophosphonous acid to have R stereochemistry. 

Intramolecular rearrangement of symmetrical anhydrides gives bis-protected dipeptide derivatives, which can again be activated, leading to the incorporation of an extra residue. This side reaction is most favored when relatively unhindered amino acids such as Gly and Ala are incorporated... 

Endotoxin and Muramyl Dipeptide Derivatives. Bacterial cell wall constituents such as the Hpopolysaccharide endotoxin and muramyl dipeptide, which stimulate host defense systems, show radioprotective activity in animals (204). Although endotoxin is most effective when given - 24 h before irradiation, it provides some protection when adrninistered shortiy before and even after radiation exposure. Endotoxin s radioprotective activity is probably related to its Hpid component, and some of its properties may result from PG and leukotriene induction (204). 

After 7 days, the acute inflammatory response at the implantation site was evaluated. Bisphenol A resulted in a moderate level of irritation at the implantation site and was clearly the least biocompatible test substance. Tyrosine derivatives containing the benzyloxycar-bonyl group caused a slight inflammatory response, while all other tyrosine derivatives produced no abnormal tissue response at all. These observations indicate that tyrosine dipeptide derivatives, even if fully protected, are more biocompatible than BPA, a synthetic diphenol. ... 

Amino acid derivatives can be examined for enantiomeric purity by the same procedures after removal of the protecting groups. Another approach is to couple them directly with another derivative to give protected dipeptides whose diastereomeric forms are usually easy to separate by HPLC (see Section 4.11). An A-protected amino acid is coupled with an amino acid ester, and vice versa. Use of soluble carbodiimide as reagent (see Section 1.16), followed by aqueous washes, gives clean HPLC profiles. It is understood that the derivative that serves as reagent must have been demonstrated to be enantiomerically pure.43 84-89... 

The traditional method for preparing activated esters of A -protected dipeptides is combination of the A-protected amino acid with the amino acid ester (Figure 7.16). The latter is obtained by A-deprotection of the diprotected amino acid in an acidic milieu. Coupling is achievable using the carbodiimide, mixed-anhydride, and acyl-azide methods. Success with this approach indicates that the esterified residues react preferentially with the other derivatives and not among themselves. The chain cannot be extended to the protected tripeptide ester because the dipeptide ester cyclizes too... 

As mentioned above, thiazolidine-4-carboxylic acid is characterized by an anomalously low basicity and thus difficult acylation in peptide synthesis. 189 Therefore, the incorporation of this amino acid residue into a growing peptide chain is preferentially preformed via dipeptide derivatives. 139 Suitably N-protected amino acids are coupled directly to the thiazolidine-4-carboxylic acid by the acid fluoride 139 or iV-carboxyan hydride 1392111 methods. The resulting dipeptides are used as building blocks without risk of racemization 139 and standard coupling procedures are applied as pentachlorophenyl esters prepared by the mixed anhydride procedure 121 or PyBOP. 171 ... 

The development of chiral peptide-based metal catalysts has also been studied. The group of Gilbertson has synthesized several phosphine-modified amino adds and incorporated two of them into short peptide sequences.[45J,71 They demonstrated the formation of several metal complexes, in particular Rh complexes, and reported their structure as well as their ability to catalyze enantioselectively certain hydrogenation reactions.[481 While the enantioselectivities observed are modest so far, optimization through combinatorial synthesis will probably lead to useful catalysts. The synthesis of the sulfide protected form of both Fmoc- and Boc-dicyclohexylphosphinoserine 49 and -diphenylphosphinoserine 50 has been reported, in addition to diphenylphosphino-L-proline 51 (Scheme 14).[49 To show their compatibility with solid-phase peptide synthesis, they were incorporated into hydrophobic peptides, such as dodecapeptide 53, using the standard Fmoc protocol (Scheme 15).[451 For better results, the phosphine-modified amino acid 50 was coupled as a Fmoc-protected dipeptide 56, rather than the usual Fmoc derivative 52.[471 As an illustrative example, the synthesis of diphe-nylphosphinoserine 52 is depicted in Scheme 16J45 ... 

Following preparation of the protected thiol derivative 29 (overall retention of configuration is observed when using Val), a mixed anhydride was prepared and converted into the amide 30 with ammonia. The acetyl group of 30 was then removed and the resulting thiol compound condensed with Z-Arg-OH to give the thioester dipeptide 31. 

The synthesis of the starting aminoacyl nitrile 39 was carried out by the modified method of Lowe and Yuthavong 91,92 as shown in Scheme 19. The dipeptide derivative 43 was produced by simple chloroformate-mediated condensation of 42 with aminoacetonitrile formally derived from Gly. This example uses the TV-methoxycarbonyl protection group, presumably to avoid steric interference in the target enzyme active site. 

The alkylation products are synthetically useful because simple subsequent transformations furnishes precursors of important natural products as illustrated in Scheme 8E.23. Simple oxidative cleavage of allylic phthalimide 45 generates protected (5)-2-aminopimelic acid, whose dipeptide derivatives have shown antibiotic activity. The esterification via deracemization protocol is not limited to the use of bulky pivalic acid. The alkylation with sterically less hindered propionic acid also occurs with high enantioselectivity to give allylic ester 116, which has been utilized as an intermediate towards the antitumor agent phyllanthocin and the insect sex excitant periplanone. Dihydroxylation of the enantiopure allylic sulfone gives diol 117 with complete diastereoselectivity. Upon further transformation, the structurally versatile y-hydroxy-a,(f-un-saturated sulfone 118 is readily obtained enantiomerically pure. 

Chen and co-workers at Procter and Gamble developed a traceless synthesis of 2,5-diketopiperazines [18b] by employing the universal Rink-isocyanide resin. The Ugi-4CR between the resin, aldehydes, amines, and N-Fmoc-protected a-amino acids afforded the resin-bound dipeptide derivatives 131 which were N-deprotected on treatment with piperidine in DMF. Cyclization by heating with 10% AcOH in DCE smoothly provided the desired diketopiperazines 132 in good yields (Scheme 2.47). 

With racemic a-alkylated amino acids an enzymatic racemate resolution is possible. There are several methods to access racemic a-alkylated amino acids in high yields [38]. Different microorganisms have been applied, and the products are obtained in very high enantiomeric purities [39]. Because a-alkylated amino acids are used as building blocks for different active substances, methods for the synthesis of large quantities have been developed, especially in industry [40]. Other effective racemic resolution techniques have been described recently. Disubstituted azlactones of type 28 can react with the phenylalanine derivative 29 [41]. The diastereo-mers of the protected dipeptide 30 are then separated. The easy access of compounds of type 28, together with the optimized reagent 29, ensures... 

Photolysis of 36 in the presence of the carbonyl-protected alanine derivative 37 allows the diastereoselective assembly of the dipeptide 38 in a one pot synthesis [13]. This process is remarkable for several reasons on the one hand the peptide bond and one new stereogenic center are established in a single preparative step on the... 

An example of the use of a symmetrical disulfide as a protecting group can be seen in a synthesis of compound 30.4 [Scheme 5.30], a key intermediate in Bristol-Myers Squibb s Omapatrilat.60 The tethered dipeptide derivative 30.2 of homocysteine was cleaved with dithiothreitol and the thiol intermediate treated with methanesulfonic acid to cause a double cyclisation reaction. 

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