Peptidomimetics synthesis

This volume brings together most of these critical issues by highlighting recent advances in a number of core areas of peptidomimetic synthesis. Section 9 focuses on side-chain-modified peptides, Section 10 describes the preparation and use of a variety of peptide main-chain modifications. Combined side-chain- and main-chain-modified peptides are covered in Section 11. Finally, Section 12 provides chemistry leading to peptides incorporating secondary structure ((1- and y-turns, helices, p-sheets) mimetics and inducers. 

J. D. Peptidomimetic synthesis a novel, highly stereoselective route to substituted Freidinger lactams./. Am. Chem. Soc. 1994, 116, 2348-2355. 

The formation of medium size rings (8-10-membered) presents challenges based on strain and entropy (Scheme Reitz utilized RCM by (2a) of diallyl glycine to give the eight-membered cyclic olefin in equation (45). Two steps convert it to a scaffold for peptidomimetic synthesis. 

In both cases, amino acids that can modulate chemical-physical properties such as lipo-philicity (like 11, present in saquinavir and nelfmavir), can produce supplementary bonds (like 12 and 13 [42]), or can induce stereochemical constraint (like 14 [43]) are frequently used (Fig. 15). The design and synthesis of conformationally constrained amino acids as scaffolds for peptidomimetics synthesis, has been recently reviewed by Hanessian [44]. 

Molteni M, Pesenti C, Sani M, Volonterio A, Zanda M (2004) Fluorinated peptidomimetics synthesis, conformational and biological features. J Fluorine Chem 125(11) 1735-1743... 

A hypervalent iodine-mediated 1,3-DC exploiting phenyliodine bis(trifluoroacetate) (PIFA) as catalyst allowed the copper-free synthesis of a novel kind of bisfiinctional nitrogen heterocycle 3 containing both 1,2,3-triazole and isoxazole rings and applied in peptidomimetic synthesis (130BC1040). 

May BCH, Abell AD (2002) a-Methylene tetiazole-based peptidomimetics synthesis and inhibition of HIV protease. J Chem Soc Perkin Trans 1 2 172-178... 

Evans has also developed an intramolecular version of the Cu(II)-assisted boronic acid O-arylation reaction and has applied it to the synthesis of macrocyclic biphenyl ether hydroxamic acid inhibitors of collagenase 1 and gelatinases A and B [65]. The reaction proceeds under sufficiently mild conditions to accommodate chemical functionalities commonly used in peptidomimetics synthesis (Scheme 3.44). 

Design and synthesis of conformationally fixed amino acids, particularly those of heterocyclic series, as peptidomimetics 97T12789. 

Scheme 6 Synthesis of peptidomimetics containing the pyrrole ring...

The 2-azadiene system of the pyrazinone scaffold undergoes inter- and intramolecular cycloaddition reactions with a variety of (functionalized) alkenes forming bicyclic adducts, leading to the stereoselective generation of a variety of natural product analogues as well as peptidomimetics [58]. These bicyclic compounds could serve as key intermediates in the synthesis... 

High throughput methods have increased our capacity for appropriate candidate compounds selection and also for developing libraries of novel compounds from which such candidates can be selected. Chapter 7 discusses the use of solid-phase synthesis for the high throughput production of peptides and other small molecules. In addition, as discussed in Chapter 6 on peptidomimetics, the swift production of novel leads holds considerable promise for future discovery of novel therapeutic agents. 

The domino process probably involves the chiral enamine intermediate 2-817 formed by reaction of ketone 2-813 with 2-815. With regard to the subsequent cy-doaddition step of 2-817 with the Knoevenagel condensation product 2-816, it is interesting to note that only a normal Diels-Alder process operates with the 1,3-bu-tadiene moiety in 2-817 and not a hetero-Diels-Alder reaction with the 1-oxa-l,3-butadiene moiety in 2-816. The formed spirocydic ketones 2-818/2-819 can be used in natural products synthesis and in medidnal chemistry [410]. They have also been used in the preparation of exotic amino adds these were used to modify the physical properties and biological activities of peptides, peptidomimetics, and proteins... 

A similar approach has been described by the same authors for the synthesis of related cyclic peptidomimetics [44]. A set often nucleophiles was employed for the substitution of the chlorine atom of the cyclic triazinyl-peptide bound to the cellulose membrane. By virtue of the aforementioned rate enhancement effects for nucleophilic substitution of the solid-supported monochlorotriazines, these reactions could be rapidly carried out by microwave heating. All products were obtained in high purity, enabling systematic modification of the molecular properties of the cyclic peptidomimetics. 

An 8000-member library of trisamino- and aminooxy-l,3,5-triazines has been prepared by use of highly effective, microwave-assisted nucleophilic substitution of polypropylene (PP) or cellulose membrane-bound monochlorotriazines. The key step relied on the microwave-promoted substitution of the chlorine atom in monochlorotriazines (Scheme 12.7) [35]. Whereas the conventional procedure required relatively harsh conditions such as 80 °C for 5 h or very long reaction times (4 days), all substitution reactions were found to proceed within 6 min, with both amines and solutions of cesium salts of phenols, and use of microwave irradiation in a domestic oven under atmospheric reaction conditions. The reactions were conducted by applying a SPOT-synthesis technique [36] on 18 x 26 cm cellulose membranes leading to a spatially addressed parallel assembly of the desired triazines after cleavage with TFA vapor. This concept was later also extended to other halogenated heterocycles, such as 2,4,6-trichloropyrimidine, 4,6-dichloro-5-nitropyrimidine, and 2,6,8-trichloro-7-methylpurine, and applied to the synthesis of macrocyclic peptidomimetics [37]. 

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