Otilie E. Vercillo

Multiple Multicomponent Macrocyclizations (MiBs): A Strategic Development Toward Macrocycle Diversity

Macrocycles are of high significance in areas as diverse as drug development and supramolecular chemistry. They can be considered as privileged molecules because they can combine flexibility and conformational bias. They allow a certain conformational adaptation for binding and at the same time can have an improved overall energy term while binding, compared to linear molecules. Recently, a diversityoriented macrocyclization strategy termed multiple multicomponent macrocyclization including bifunctional building blocks (MiB) was developed which allows producing constitutionally diverse and complex macrocycles from simple building blocks in one pot. The efficient search for novel molecular ligands of biological targets remains a continuing goal in drug discovery and chemical biology.1-3 In the past, the predominant interest of medicinal chemists in synthetic ligands has been devoted to small rings (especially heterocycles) because of their known capability to interact with defined protein motifs and their ease of preparation. Huge libraries, including combinatorial ones,4,5 have been synthesized by means of wellestablished processes and screened for biological activity. Lately, macrocycles have attracted increasing attention also by virtue of both their high success rate in medicinal and recognition chemistry and their widespread occurrence in nature.6-10 The demand for bioactive compounds with new application profiles has triggered the search for molecules with biological features that simple 5/6/7-ring (hetero)cycles do not bear.8-12 Macrocycles are usually endowed with a proper combination of more than one binding domain, conformational preorganization, and flexibility.8,13,14 Their structural, physicochemical, and biological features provide recognition and binding properties not found in linear or small ring counterparts.14 For example, their often increased biological stability compared to acyclic analogues (e.g., cyclopeptides compared to peptides) makes them a fascinating paradigm to design biologically active molecules.8-14 Combinatorial synthetic chemistry in the macrocycle field does not yet reflect the tremendous impact of naturally occurring macrocycles in areas such as antibiotics, immunosuppressants, ion chelators, or membrane active compounds, where their success rate appears to be overproportional (in relative terms) compared to other drug types.6-9,15

Fast and efficient microwave-assisted synthesis of functionalized peptoids via Ugi reactions.

A wide range of N-alkylglycines (peptoids) can be efficiently prepared via Ugi reactions using microwave irradiations. The results confirm the versatility and efficiency of the methodology for the preparation of functionalized peptoids. The products can be used in consecutive Ugi reactions to yield cyclic peptoids of potential biological interest.

Cyclic Peptidomimetics and Pseudopeptides from Multicomponent Reactions

Multicomponent reactions (MCRs) that provide in the final product amides are suitable to produce peptides and peptide-like moieties. The Passerini and Staudinger reactions provide one amide bond, and the Ugi-four-component reaction generates two amides from three or even four (or more) components, respectively. The Ugi-reaction thus is most important to produce peptides and peptoids while the Passerini reaction is useful to generate depsipeptoid moieties. In order to produce cyclic peptides and pseudopeptides, the linear peptidic MCR products have to be cyclized, usually with the help of bifunctional or activatable building blocks. Orthogonal but cyclizable secondary functionalities that need no protection in isonitrile MCRs commonly include alkenes (for ring closing metathesis), azide/alkyne (for Huisgen click reactions) or dienes and enoates (Diels-Alder) etc. If MCR-reactive groups are to be used also for the cyclisation, monoprotected bifunctional building blocks are used and deprotected after the MCR, e.g. for Ugi reactions as Ugi-Deprotection-Cyclisation (UDC). Alternatively one of the former building blocks or functional groups generated by the MCR can be activated. Most commonly these are activated amides (from so-called convertible isonitriles) which can be used e.g. for Ugi-Activation-Cyclisation (UAC) protocols, or most recently for a simultaneous use of both strategies Ugi-Deprotection/Activation-Cyclisation (UDAC). These methods mostly lead to small, medicinally relevant peptide turn mimics. In an opposing strategy, the MCR is rather used as ring-closing reaction, thereby introducing a (di-)peptide moiety. Most recently these processes have been combined to use MCRs for both, linear precursor synthesis and cyclisation. These multiple MCR approaches allow the most efficient and versatile one pot synthesis of macrocyclic pseudopeptides known to date.

Consecutive isocyanide-based multicomponent reactions: synthesis of cyclic pentadepsipeptoids.

Summary The synthesis of six cyclic depsipeptoids inspired by the natural depsipeptide sansalvamide A is described. An efficient and fast synthetic strategy was developed using a combination of consecutive isocyanide-based multicomponent reactions (Ugi and Passerini reactions). This methodology can be used to access a variety of cyclic oligodepsipeptoids.

Microwave-assisted Passerini reactions under solvent-free conditions

Various a-acyloxy carboxyamides were easily obtained combining three building blocks in one step: a carboxylic acid, an aldehyde and an isonitrile (Passerini reaction), using microwave irradiation under solvent-free conditions. The products were obtained in good yields (61-90%) and in short reaction times (≤ 5 min), using two different temperatures (60 and 120 °C). At 120 °C, the yields were higher and the reactions faster (≤ 1 min). Most of the obtained products are multifunctional allowing their application in consecutive Passerini reactions.

Intramolecular ene reactions catalyzed by NbCl5, TaCl5 and InCl3

Pentacloreto de niobio, pentacloreto de tântalo e tricloreto de indio catalisaram eficientemente a ciclizacao do (R)-citronelal a uma mistura de isopulegol e neoisopulegol, em bons rendimentos. Um estudo comparativo foi realizado demonstrando que NbCl5 e o acido de Lewis mais ativo enquanto que InCl3 e o mais seletivo. A seletividade das reacoes variou de acordo com o acido de Lewis utilizado e o solvente. NbCl5 e TaCl5 mostraram ausencia de seletividade enquanto que o InCl3 apresentou seletividade moderada em favor do isopulegol. A reacao ene de um 1,7-dieno tambem foi investigada. Neste caso, todos os acidos de Lewis testados apresentaram excelente seletividade.