Combining two-directional synthesis and tandem reactions. Part 21: Exploitation of a dimeric macrocycle for chain terminus differentiation and synthesis of an sp3-rich library

Abstract

. (2015) Combining two-directional synthesis and tandem reactions. Part 21: Exploitation of a dimeric macrocycle for chain terminus differentiation and synthesis of an sp3-rich library. Bioorganic and Medicinal Chemistry, 23 (11 A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. Get rights and content AbstractThe application of a tandem condensation/cyclisation/[3+2]-cycloaddition/elimination reaction gives an sp 3 -rich tricyclic pyrazoline scaffold with two ethyl esters in a single step from a simple linear starting material. The successive hydrolysis and cyclisation (with Boc anhydride) of these 3-dimensional architectures, generates unprecedented 16-membered macrocyclic bisanhydrides (characterised by XRD). Selective amidations could then be achieved by ring opening with a primary amine followed by HATU-promoted amide coupling to yield an sp 3 -rich natural product-like library. Graphical abstractFigure options

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

“…[58] Thec entral ketone moiety in 124 was transformed into ar ange of nucleophilic functional groups (e.g., oxime,i mine,a zomethine ylide,o re nolate), which then reacted with the tethered a,bunsaturated esters at the termini of the chain (e.g., various [3+ +2] cycloadditions or amine/ enolate conjugate addition). [59] In another cascade reaction based design, our group explored the various electrophilic moieties of ac ommon precursor to generate scaffold diversity. [60] Va rious mono-and bisnucleophiles as well as nucleophilic zwitterions were identified during reaction optimization and successfully reacted with 136 to yield thirteen diverse scaffolds (Scheme 12).…”

Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

“…Indeed, a significant number of unprecedented spiro, bridged, and fused polycycles with different degrees of saturation, conjugation, and substitution have been synthesized and expanded to a library format. This has been recently exemplified by several publications from the ELF chemistry groups detailing the associated design and validation aspects [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]. Given that most theoretical ring systems remains unexplored [39], the synthesis of novel rings represents one of the strategies embraced by the ELF chemistry consortium to expand the available chemical space.…”

Gerüstdiversitätsbasierte Synthese und ihre Anwendung bei der Sonden‐ und Wirkstoffsuche

“…Mit dem Ziel, diverse dreidimensionale Gerüste mit zahlreichen sp 3 -Zentren zu synthetisieren, entwarfen Stockman et al eine bidirektionale Methode unter Verwendung eines symmetrischen linearen "Seil-ähnlichen" Ketodienolats,d as für den Aufbau von zwçlf naturstoffähnlichen Gerüsten zwçlf gesonderten Tandemreaktionen unterworfen wurde.Die so erhaltenen Gerüste trugen bereits funktionelle Gruppen für weitere Umwandlungen (Schema 11). [59] In einem weiteren auf einer Kaskadenreaktion basierenden Ansatz erforschte unsere Arbeitsgruppe die Eignung verschiedener elektrophiler Reste einer gemeinsamen Vorstufe zur Erzeugung von Gerüstdiversität. [59] In einem weiteren auf einer Kaskadenreaktion basierenden Ansatz erforschte unsere Arbeitsgruppe die Eignung verschiedener elektrophiler Reste einer gemeinsamen Vorstufe zur Erzeugung von Gerüstdiversität.…”