Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

Abstract

SummaryIn the recent past, the design and synthesis of peptide mimics (peptidomimetics) has received much attention. This because they have shown in many cases enhanced pharmacological properties over their natural peptide analogues. In particular, the incorporation of cyclic constructs into peptides is of high interest as they reduce the flexibility of the peptide enhancing often affinity for a certain receptor. Moreover, these cyclic mimics force the molecule into a well-defined secondary structure. Constraint structural and conformational features are often found in biological active peptides. For the synthesis of cyclic constrained peptidomimetics usually a sequence of multiple reactions has been applied, which makes it difficult to easily introduce structural diversity necessary for fine tuning the biological activity. A promising approach to tackle this problem is the use of multicomponent reactions (MCRs), because they can introduce both structural diversity and molecular complexity in only one step. Among the MCRs, the isocyanide-based multicomponent reactions (IMCRs) are most relevant for the synthesis of peptidomimetics because they provide peptide-like products. However, these IMCRs usually give linear products and in order to obtain cyclic constrained peptidomimetics, the acyclic products have to be cyclized via additional cyclization strategies. This is possible via incorporation of bifunctional substrates into the initial IMCR. Examples of such bifunctional groups are N-protected amino acids, convertible isocyanides or MCR-components that bear an additional alkene, alkyne or azide moiety and can be cyclized via either a deprotection–cyclization strategy, a ring-closing metathesis, a 1,3-dipolar cycloaddition or even via a sequence of multiple multicomponent reactions. The sequential IMCR-cyclization reactions can afford small cyclic peptide mimics (ranging from four- to seven-membered rings), medium-sized cyclic constructs or peptidic macrocycles (>12 membered rings). This review describes the developments since 2002 of IMCRs-cyclization strategies towards a wide variety of small cyclic mimics, medium sized cyclic constructs and macrocyclic peptidomimetics.

A Multicomponent Conjugation Strategy to Unique N‐Steroidal Peptides: First Evidence of the Steroidal Nucleus as a β‐Turn Inducer in Acyclic Peptides

“…[25] As shown in Scheme 1, the strategy comprises the deprotection of the N and C termini of the Ugi-derived N-steroidal peptide, followed by cyclization to afford a cyclopeptide scaffold having the steroid as exocyclic amide appendage. As detailed information was already gained regarding the efficiency of the conjugation, a sequential approach could be implemented that avoids isolation of pure intermediate peptidosteroids, which were only identified by ESI-MS, and then directly subjected to further deprotection and cyclization.…”

The Synthesis of Macrocycles for Drug Discovery

“…However, exploiting the power of MCR in assembling complex frameworks from simpler precursors in tandem with a variety of other reactions for the construction of macrocycles has been more fruitful. 300 In one of the initial such examples, Dömling and coworkers have reported both Ugi and Passerini-type MCR in concert with RCM. 301 The general approach is outlined in Scheme 11.25, with the linear precursor (186) obtained from the MCR then subjected to standard RCM to give the macrocyclic products 187 or 188.…”

“…Indeed, as already noted, one of the first macrocyclic library efforts actually used the Heck reaction for solid phase construction of small collections of 20-to 24-membered semipeptidic macrocycles (299, Figure 11.26, site of ring closure and chemistry indicated). 198 In addition, modest-sized libraries of RGD mimic macrocycles (300) 230 and macrosphelide analogues (301) 392 were prepared using palladium-catalysed cyclocarbonylation on resin. This particular method proved to be tolerant of a variety of functional groups, including halides, ethers, ketones and esters.…”

Leuckart–Wallach Route Toward Isocyanides and Some Applications

“…Ugi and Passerini reactions are the most famous IMCRs with extended application in drug discovery. 6 It is unquestionable that IMCRs are based on the isocyanide moiety and therefore preparative isocyanide synthesis is extremely important. The majority of isocyanide syntheses use the classical 2-step sequence described by Ugi: primary amine formamide isocyanide.…”