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A universal isocyanide for diverse heterocycle syntheses.

ABSTRACT: Novel scaffolds are of uttermost importance for the discovery of functional material. Three different heterocyclic scaffolds easily accessible from isocyanoacetaldehyde dimethylacetal 1 by multicomponent reaction (MCR) are described. They can be efficiently synthesized by a Ugi tetrazole multicomponent reaction of 1. We discuss the synthesis, 3D structures, and other physicochemical properties.

SUBMITTER: Patil P

PROVIDER: S-EPMC4227542 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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A universal isocyanide for diverse heterocycle syntheses.

Patil Pravin P Khoury Kareem K Herdtweck Eberhardt E Dömling Alexander A

Organic letters 20141029 21

Novel scaffolds are of uttermost importance for the discovery of functional material. Three different heterocyclic scaffolds easily accessible from isocyanoacetaldehyde dimethylacetal 1 by multicomponent reaction (MCR) are described. They can be efficiently synthesized by a Ugi tetrazole multicomponent reaction of 1. We discuss the synthesis, 3D structures, and other physicochemical properties. ...[more]

PMID: 25351886

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Project description:The combination of two or more unsaturated structural units to form cyclic organic compounds is commonly referred to as cycloaddition, and the combination of two unsaturated structural units that forms a six-membered ring is formally either a [5 + 1]-, [4 + 2]-, [2 + 2 + 2]-, or [3 + 3]-cycloaddition. Occurring as concerted or stepwise processes, cycloaddition reactions are among the most useful synthetic constructions in organic chemistry. Of these transformations, the concerted [4 + 2]-cycloaddition, the Diels-Alder reaction, is by far the best known and most widely applied. However, although symmetry disallowed as a concerted process and lacking certifiable examples until recently, stepwise [3 + 3]-cycloadditions offer advantages for the synthesis of a substantial variety of heterocyclic compounds, and they are receiving considerable attention. In this Account, we present the development of stepwise [3 + 3]-cycloaddition reactions from virtual invisibility in the 1990s to a rapidly growing synthetic methodology today, involving organocatalysis or transition metal catalysis. With origins in organometallic or vinyliminium ion chemistry, this area has blossomed into a viable synthetic transformation for the construction of six-membered heterocyclic compounds containing one or more heteroatoms. The development of [3 + 3]-cycloaddition transformations has been achieved through identification of suitable and compatible reactive dipolar adducts and stable dipoles. The reactive dipolar species is an energetic dipolar intermediate that is optimally formed catalytically in the reaction. The stepwise process occurs with the reactive dipolar adduct reacting as an electrophile or as a nucleophile to form the first covalent bond, and this association provides entropic assistance for the construction of the second covalent bond and the overall formal [3 + 3]-cycloaddition. Organocatalysis is well developed for both inter- and intramolecular synthetic transformations, but the potential of transition metal catalysis for [3 + 3]-cycloaddition has only recently emerged. The key to the rapid development of the transition metal-based methodology has been recognition that certain catalytically generated vinylcarbenes are effective dipolar adducts for reactions with stable dipolar compounds, including aryl and vinyl ylides. In particular, metallo-enolcarbenes that are generated catalytically from conveniently prepared stable enoldiazoacetates or from donor-acceptor cyclopropenes are highly effective dipolar adducts for [3 + 3]-cycloaddition. The electron-donating oxygen of the silyl ether enhances electrophilic ring closure to the metal-bound carbon of the initial adduct from vinylogous addition, and this enhancement inhibits the alternative [3 + 2]-cycloaddition across the carbon-carbon double bond of the vinylcarbene. Catalytically generated metallo-enolcarbenes react under mild conditions with a broad spectrum of compatible stable dipoles, including nitrones, azomethine imines, ylides, and certain covalent precursors of stable dipoles, to form [3 + 3]-cycloaddition products having the β-ketoester functionality (in dihydrooxazines, tetrahydropyridazines, pyrazolidinone and pyraxole derivatives, dihydroquinolines, and quinolizidines, for example) in high yield. Two ways to access these metallo-enolcarbenes, either by dinitrogen extrusion from enoldiazoacetate esters or by rearrangement of donor-acceptor cyclopropenes, enhance the versatility of the process. The [3 + 3]-cycloaddition methodology is a complementary strategy to [4 + 2]-cycloaddition for the synthesis of heterocyclic compounds having six-membered rings. High levels of enantioselectivity are obtained with the use of chiral ligands on transition metal catalysts that include those on dirhodium(II) and silver(I).

Project description:One of the grand challenges in chemical biology is identifying a small-molecule modulator for all proteins within a proteome. To expand the variety and number of ligandable proteins for drug discovery, the objective of this study was to synthesize and evaluate the protein target profiles of electrophilic and photoreactive fully functionalized small-molecule probes (FFSMPs) featuring increased scaffold-, appendage-, and protein-reactive functional group (PRFG) diversity. FFSMPs contain: (1) a protein-binding motif, (2) an electrophilic or photoreactive PRFG for target protein capture, and (3) a terminal alkyne for click chemistry-based proteomic applications. These compounds can be directly applied in phenotypic screening programs to identify ligand-protein pairs in cells unbiasedly. Herein, we highlight 17 examples from 34 structurally diverse FFSMPs featuring five electrophiles, three photoreactive groups, and 15 chemical scaffolds. Essential to the synthesis of the FFSMPs was a new minimalist bifunctional isocyanide in an "isocyanide-based multicomponent reaction-Boc deprotection-arming" synthetic sequence. To the best of our knowledge, this is the first report concerning the preparation of appendage- and scaffold-diverse FFSMPs for integrated phenotypic screening-target identification campaigns with the ability to examine either electrophilic or photoreactive PRFGs. In contrast, the status quo for such studies has been appendage-diverse FFSMPs comprised of a single chemical scaffold and a single PRFG, which limits efficient target protein capture and/or chemical space sampling significantly in the quest for discovering new drug targets and/or compounds with novel mechanisms of action. Phenotypic screening of the electrophilic members of our library identified several FFSMPs with potent antiproliferative activity against MCF10CA1a breast cancer cells. One of these FFSMPs (Compound 4a) covalently targeted and potently inhibited protein disulfide isomerase A1 (PDIA1). This study supports the continued use of minimalist bifunctional isocyanides as valuable building blocks for preparing structurally diverse FFSMPs for integrated phenotypic screening-target identification campaigns.

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A universal isocyanide for diverse heterocycle syntheses.

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A universal isocyanide for diverse heterocycle syntheses.

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