Total Synthesis of Aspidosperma and Strychnos Alkaloids through Indole Dearomatization

Monoterpenoid indole alkaloids are the major class of tryptamine-derived alkaloids found in nature. Together with their structural complexity, this has attracted great interest from synthetic organic chemists. In this Review, the syntheses of Aspidosperma and Strychnos alkaloids through dearomatization of indoles are discussed

In Situ Cyclization of Proteins (INCYPRO):Cross-Link Derivatization Modulates Protein Stability

Protein macrocyclization represents a very efficient strategy to increase the stability of protein tertiary structures. Here, we describe a panel of novel C3-symmetric tris-electrophilic agents and their use for the cyclization of proteins. These electrophiles are reacted with a protein domain harboring three solvent-exposed cysteine residues, resulting in the in situ cyclization of the protein (INCYPRO). We observe a clear dependency of cross-linking rates on the electrophilicity. All nine obtained cross-linked protein versions show considerably increased thermal stability (up to 29 °C increased melting temperature) when compared to that of the linear precursor. Most interestingly, the degree of stabilization correlates with the hydrophilicity of the cross-link. These results will support the development of novel cross-linked proteins and enable a more rational design process

Iodospirocyclization of Tryptamine-Derived Isocyanides:Formal Total Synthesis of Aspidofractinine

The N-iodosuccinimide-mediated spirocyclization of tryptamine-derived isocyanides to generate spiroindolenines is reported. The products contain both an imine and an imidoyl iodide as flexible handles for follow-up chemistry. Nucleophilic addition typically occurs chemoselectively on the imine moiety with complete diastereoselectivity, providing opportunities for the construction of complex molecular frameworks. The synthetic potential of the method was showcased in the formal total synthesis of (±)-aspidofractinine

Heterocycles and Multicomponent Polymerizations

Multicomponent reactions (MCRs) are well-recognized synthetic tools to make sets of diversely functionalized complex small-molecule scaffolds. As it has become clear from the other chapters in this book, MCRs have been widely applied for the synthesis of heterocycles. Moreover, many MCR products can undergo so-called post-reaction modifications. These can proceed either stepwise or in situ generating advanced second-generation one-pot processes. The latter deliver higher-order complexity generating reactions ideal for diversity-oriented synthesis strategies. This offers many opportunities to introduce additional desired (often predesigned) functionality in the targeted heterocyclic compounds, which accounts for the popularity of MCRs and their post-modifications in medicinal chemistry and catalysis. The utilization of MCR chemistry to access functionalized polymers for applications in advanced materials with clever properties is much less common practice. However, the use of MCRs in polymer chemistry, also known as multicomponent polymerization (MCP), has gained quite some interest in recent years. In this chapter, we highlight some of the latest examples in this area. As the main topic of this book deals with MCR applications in heterocyclic chemistry, we focused our contribution on MCPs that result in polymers that include heterocyclic fragments

BIOMIMETIC CASCADE STRATEGIES TOWARDS 2-AMINOINDOLINES FROM ALKALOIDS

The 2-aminoindoline scaffold is abundant in natural alkaloids with antibacterial, antitumor and anti-inflammatory activities. Synthetic organic chemists have developed various elegant strategies towards this heterocyclic core. These strategies often entail a cascading sequence, where two or more bonds are formed simultaneously. Potentially, these approaches drastically decrease the number of reaction steps required typically minimizing waste generation and energy consumption. These features are a requisite for the present development of new and accessible more greener pharmaceuticals. This review will uncover the synthetic cascade toolbox towards the 2-aminoindolines core focussing on synthetic applicability and discussing the different reaction mechanisms involve

Mild and Practical Indole C2 Allylation by Allylboration of in situ Generated 3-Chloroindolenines

C2 allylation of indole derivatives is a challenging but important transformation given the biological relevance of the products. Herein we report a selective C2 allylation strategy that proceeds via allylboration of in situ-generated 3-chloroindolenines. The reaction is mild, practical, and compatible with a wide range of C3-substituted indoles. As allylboronates are readily accessible from commercial precursors, various substituted allyl moieties can be introduced using the same protocol. To showcase the utility of this method we applied it to the synthesis of the natural product, tryprostatin B

Hexafluoroisopropanol as the Acid Component in the Passerini Reaction: One-Pot Access to β-Amino Alcohols

A new Passerini-type reaction in which hexafluoroisopropanol functions as the acid component is reported. The reaction tolerates a broad range of isocyanides and aldehydes, and the formed imidates can be reduced toward β-amino alcohols under mild and metal-free conditions. In addition, the imidate products were shown to undergo an unprecedented retro-Passerini-type reaction under microwave conditions, providing valuable mechanistic information about the Passerini reaction and its variations

Dearomative spirocyclization of tryptamine-derived isocyanides via iron-catalyzed carbene transfer

Abstract: Tryptamine-derived isocyanides are valuable building blocks in the construction of spirocyclic indolenines and indolines via dearomatization of the indole moiety. We report the Bu4N[Fe(CO)3NO]-catalyzed carbene transfer of \u3b1-diazo esters to 3-(2-isocyanoethyl)indoles, leading to ketenimine intermediates that undergo spontaneous dearomative spirocyclization. The utility of this iron-catalyzed carbene transfer/spirocyclization cascade was demonstrated by its use as a key step in the formal total synthesis of monoterpenoid indole alkaloids (\ub1)-aspidofractinine, (\ub1)-limaspermidine, (\ub1)-aspidospermidine, and (\ub1)-17-demethoxy-N-acetylcylindrocarine