Combinational peptide synthesis

A major trend in organic synthesis, however, is the move towards complex systems. It may happen that one needs to combine a steroid and a sugar molecule, a porphyrin and a carotenoid, a penicillin and a peptide. Also the specialists in a field have developed reactions and concepts that may, with or without modifications, be applied in other fields. If one needs to protect an amino group in a steroid, it is advisable not only to search the steroid literature but also to look into publications on peptide synthesis. In the synthesis of corrin chromophores with chiral centres, special knowledge of steroid, porphyrin, and alkaloid chemistry has been very helpful (R.B. Woodward, 1967 A. Eschenmoser, 1970). 

Mergler M, Tanner R, Gosteli J, Grogg P. Peptide synthesis by a combination of solid-phase and solution methods. I A new very acid-labile... 

A combination of SIPS with the stabilising and synthesis-favouring properties of clay minerals was studied by Rode et al. (1999) in experiments involving dry/wet cycles. The simultaneous use of both SIPS and clay minerals as catalytically active surfaces led to peptides up to and including the hexamer (Gly)6. The question as to whether this technique fulfils prebiotic conditions can (within certain limitations) be answered positively, since periodic evaporation phases in limited areas (lagoons, ponds) are conceivable. The container material could have consisted of clay minerals. Further progress in the area of peptide synthesis under conditions which could have been present on the primeval Earth can be expected. 

A possibility to overcome the time-consuming solution-phase peptide synthesis, but avoiding specific synthetic problems that cannot be addressed on tbe solid support, is to follow a combined solution-/solid-pbase approach. In such an approach the majority of the peptide sequence is typically assembled on solid support, but critical steps are performed in solution. Below, some exemplary peptides are discussed. 

DKPs may be produced without any difficulties and may form without particular activation of the carboxyl function of the dipeptide precursor. However, the cyclization reaction may be a slow process, justifying the need for specific activation of the carboxyl moiety. Kopple stated that there is no single perfect method for the cyclization of all peptides, only guidelines aiding in the judicious choice of combinations of procedures to limit the generation of unwanted by-products of peptide synthesis. 

Similarly to the methoxycarbonylsulfanyl-protected cysteine derivatives, the S-Npys compounds are stable toward strong acid treatment1 64 165 172 and thus, they can be exploited in the dual purpose of S-protection and S-activation. The Npys group has been used with considerable success in combination with Boc chemistry for the preparation of peptides. 173-175 This S-protecting/activating group, however, is labile to piperidine treatment and can, therefore, not be used in Fmoc-based peptide synthesis. 

Carbohydrates and polysaccharides, on the one hand, and peptides and proteins, on the other, have been considered as separate classes of natural products for a long time. Fundamental chemical methodology for the synthesis of both saccharides and peptides was developed by Emil Fischer et al. at the beginning of the 20th century. 1,2 However, the harsh conditions employed in early solution and solid-phase peptide synthesis hindered the combination of peptide and carbohydrate chemistry, i.e. glycopeptide synthesis. Considerable efforts were made to combine the two branches of natural product chemistry, and the state of the art within glycopeptide synthesis has improved dramatically during the last decades, as described in a number of reviews. 3 23,512"514 ... 

For the direct use of tyrosine 0-sulfate in peptide synthesis a set of -protected Tyr(S03H) derivatives were synthesized that can be combined with the most common protection schemes. In addition to Z-Tyr(S03Ba1/2)-0Ba1/2 (11)[3S1 (see Section 6.6.1.1.4), the related Boc and Fmoc derivatives have been synthesised as barium, sodium, potassium salts, and even as tetrabutylammonium salts due to their better solubility in solvents generally used for automated synthesis on solid supports.1152 154 155 ... 

Celovsky, V. and Bordusa, F. (2000). Protease-catalyzed fragment condensation via substrate mimetic strategy a useful combination of solid-phase peptide synthesis with enzymatic methods. /. Pept. Res., 55, 325-9. 

Amino acid and peptide derivatives, commonly used as substrates in peptide synthesis, form low-melting-point mixtures when combined together in the absence of bulk solvents [66]. 

An interesting example of scale-up of peptide synthesis in such low-melting point mixtures derived from eutectic melts has been described [70]. Neat combination of the pure substrates in the complete absence of water/solvent (adjuvant) provided simple heterogeneous systems consisting of the eutectic melts plus an excess of solid substrate (Figure 12.5). 

Mergler, M. Nyfeler, R. Tanner, R. Gosteli, J. Grogg, P. Peptide Synthesis by a Combination of Solid-Phase and Solution Methods. 11. Synthesis of Fully Protected Peptide Fragments on 2-Methoxy-4-alkoxybenzyl Alcohol Resin, Tetrahedron Lett. 1988, 29,4009. 

Active esters peptide synthesis. The reagent in combination with N(C2Hs)j converts N-protected amino acids into active esters (— 85% yield). It can also be used with a tertiary amine to effecl peptide formation between an N-protcctcd amino acid and an amino acid ethyl ester. CBZ-Val-Gly-OC2IIs was prepared in this way in 89% yield. 

The Fmoc group, which is very useful in peptide synthesis [32], has proved an efficient tool in glycopeptide chemistry [10], Because the Fmoc protection of the amino function is rather stable to acids, it can be combined with fert-butyl-type protecting groups and exposed to stereoselective glycosylations that require a more or less acidic milieu. 

More recent advances in the synthesis of head-to-tail cyclic peptides combine solid-phase peptide synthesis with solid-phase cyclization reactions whilst the peptide is still attached to the resin. 25 Such methods have obvious merits as they reduce manipulation of the peptides in solution. The method typically requires a suitable side-chain functional group... 

For reduction of resin 8, concerns about the possibility of traces of tin by-products contaminating subsequent assays led to the adoption of a different reduction procedure for library production.15 The tagged resins 8 are combined into one pool in a large peptide synthesis vessel, washed with methanol, filtered, and the resin left solvated. Separately, an aqueous solution of 0.5 M aqueous sodium hydrosulfite/0.5 M potassium carbonate is prepared and added to the resin (40ml/g of resin) and then the resin/solu-tion is bubbled with nitrogen at room temperature for 16 h. The resulting resin is washed with water, water/MeOH (1 1), MeOH, MeOH/NMP (1 1), NMP, DCM, MeOH, and ether, then filtered and dried overnight in vacuo prior to the next step. 

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