The dual reactivity of Weinreb amides applied to the late-stage divergent functionalisation of meso pyrrolidines

2018 ◽  
Vol 42 (15) ◽  
pp. 12403-12411 ◽  
Author(s):  
Hamza Boufroura ◽  
Laurent Sevaille ◽  
Nicolas Gigant ◽  
Emmanuelle Drège ◽  
Delphine Joseph

The dual reactivity of Weinreb amides was exploited to prepare diversified symmetrical and dissymmetrical 2,5-disubstituted pyrrolidines from simple building blocks.

2019 ◽  
Author(s):  
Patrick Fier ◽  
Kevin M. Maloney

Herein we describe the development and application of a method for the mild, late-stage conversion of primary sulfonamides to several other other functional groups. These reactions occur via initial reductive deamination of sulfonamides to sulfinates via an NHC-catalyzed reaction of transiently formed <i>N</i>-sulfonylimines. The method described here is tolerant of nearly all common functional groups, as exemplified by the late-stage derivatization of several complex pharmaceutical compounds. Based on the prevalence of sulfonamide-containing drugs and building blocks, we have developed a method to enable sulfonamides to be applied as versatile synthetic handles for synthetic chemsitry.


2019 ◽  
Author(s):  
Patrick Fier ◽  
Kevin M. Maloney

Herein we describe the development and application of a method for the mild, late-stage conversion of primary sulfonamides to several other other functional groups. These reactions occur via initial reductive deamination of sulfonamides to sulfinates via an NHC-catalyzed reaction of transiently formed <i>N</i>-sulfonylimines. The method described here is tolerant of nearly all common functional groups, as exemplified by the late-stage derivatization of several complex pharmaceutical compounds. Based on the prevalence of sulfonamide-containing drugs and building blocks, we have developed a method to enable sulfonamides to be applied as versatile synthetic handles for synthetic chemsitry.


2021 ◽  
Author(s):  
jin choi ◽  
Gabriele Laudadio ◽  
Edouard Godineau ◽  
Phil Baran

The direct position-selective C–4 alkylation of pyridines has been a longstanding challenge in heterocyclic chemistry, particularly from pyridine itself. Historically this has been addressed using pre-functionalized materials to avoid overalkylation and mixtures of regioisomers. This study reports the invention of a simple maleate-derived blocking group for pyridines that enables exquisite control for Minisci-type decarboxylative alkylation at C–4 that allows for inexpensive access to these valuable building blocks. The method is employed on a variety of different pyridines and carboxylic acid alkyl donors, is operationally simple, scalable, and is applied to access known structures in a rapid and inexpensive fashion. Finally, this work points to an interesting strategic departure for the use of Minisci chemistry at the earliest possible stage (native pyridine) rather than current dogma that almost exclusively employs Minisci as a late-stage functionalization technique.


2016 ◽  
Vol 12 ◽  
pp. 1440-1446 ◽  
Author(s):  
Markus W Weishaupt ◽  
Stefan Matthies ◽  
Mattan Hurevich ◽  
Claney L Pereira ◽  
Heung Sik Hahm ◽  
...  

Vaccines againstS. pneumoniae, one of the most prevalent bacterial infections causing severe disease, rely on isolated capsular polysaccharide (CPS) that are conjugated to proteins. Such isolates contain a heterogeneous oligosaccharide mixture of different chain lengths and frame shifts. Access to defined syntheticS. pneumoniaeCPS structures is desirable. Known syntheses ofS. pneumoniaeserotype 3 CPS rely on a time-consuming and low-yielding late-stage oxidation step, or use disaccharide building blocks which limits variability. Herein, we report the first iterative automated glycan assembly (AGA) of a conjugation-readyS. pneumoniaeserotype 3 CPS trisaccharide. This oligosaccharide was assembled using a novel glucuronic acid building block to circumvent the need for a late-stage oxidation. The introduction of a washing step with the activator prior to each glycosylation cycle greatly increased the yields by neutralizing any residual base from deprotection steps in the synthetic cycle. This process improvement is applicable to AGA of many other oligosaccharides.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shui-Jiong Wang ◽  
Wenzhong Wang ◽  
Jian-Ming Zhu ◽  
Zhongqing Wu ◽  
Jingao Liu ◽  
...  

AbstractEarth’s habitability is closely tied to its late-stage accretion, during which impactors delivered the majority of life-essential volatiles. However, the nature of these final building blocks remains poorly constrained. Nickel (Ni) can be a useful tracer in characterizing this accretion as most Ni in the bulk silicate Earth (BSE) comes from the late-stage impactors. Here, we apply Ni stable isotope analysis to a large number of meteorites and terrestrial rocks, and find that the BSE has a lighter Ni isotopic composition compared to chondrites. Using first-principles calculations based on density functional theory, we show that core-mantle differentiation cannot produce the observed light Ni isotopic composition of the BSE. Rather, the sub-chondritic Ni isotopic signature was established during Earth’s late-stage accretion, probably through the Moon-forming giant impact. We propose that a highly reduced sulfide-rich, Mercury-like body, whose mantle is characterized by light Ni isotopic composition, collided with and merged into the proto-Earth during the Moon-forming giant impact, producing the sub-chondritic Ni isotopic signature of the BSE, while delivering sulfur and probably other volatiles to the Earth.


2021 ◽  
Author(s):  
Luca Capaldo ◽  
Stefano Bonciolini ◽  
Antonio Pulcinella ◽  
Manuel Nuno ◽  
Timothy Noel

The late-stage introduction of allyl groups provides an opportunity to synthetic organic chemists for subsequent diversification, providing rapid access to new chemical space. Here, we report the development of a modular synthetic sequence for the allylation of strong aliphatic C(sp3)–H bonds. Our sequence features the merger of two distinct steps to accomplish this goal, including a photocatalytic Hydrogen Atom Transfer and an ensuing Horner-Wadsworth-Emmons reaction. This practical protocol enables the modular and scalable allylation of valuable building blocks and medicinally relevant molecules.


2020 ◽  
Author(s):  
Stephanie Greed ◽  
Edward L. Briggs ◽  
Fahima Idiris ◽  
Andrew J. P. White ◽  
Ulrich Lücking ◽  
...  

Sulfonimidamides present exciting opportunities as chiral isosteres of sulfonamides, with potential for additional directional interactions. Here we present the first modular enantioselective synthesis of sulfonimidamides, including the first stereoselective synthesis of enantioenriched sulfonimidoyl fluorides, and studies on their reactivity. A new route to sulfonimidoyl fluorides is presented from solid bench-stable, NBoc-sulfinamide salt building blocks. Enantioenriched arylsulfonimidoyl fluorides are shown to be readily racemized by fluoride ions. Conditions are developed which trap fluoride, and enable the stereospecific reaction of sulfonimidoyl fluorides with primary and secondary amines (100% es) generating sulfonimidamides with up to 99% ee. Aryl and alkyl sulfonimidoyl fluoride reagents are suitable for mild late stage functionalization reactions, exemplified by coupling with a selection of complex amines in marketed drugs.


2019 ◽  
Author(s):  
Jeffrey N. Levy ◽  
Ren-Rong Liu ◽  
Andrew McNally

Halopyridines are key building blocks for synthesizing pharmaceuticals, agrochemicals, and ligands for metal complexes, but strategies to selectively halogenate pyridine C–H precursors are lacking. We designed a set of heterocyclic phosphines that are selectively installed at the 4-position of pyridines as phosphonium salts and then displaced with halide nucleophiles. A broad range of unactivated pyridines can be halogenated, and the method is viable for late-stage halogenation of complex pharmaceuticals. The study concludes that both tuning the phosphonium electrophilicity and pyridine substitution patterns influence the efficiency of the carbon-halogen bond-forming step.<br>


2019 ◽  
Author(s):  
You-Chen Lin ◽  
Aubert Ribaucourt ◽  
Yasamin Moazami ◽  
Joshua Pierce

A concise synthesis of the tricyclic guanidinium alkaloid batzelladine D has been accomplished in a sequence of 8 steps from readily available building blocks. Highlights of the synthesis include gram-scale preparation of a late stage intermediate, pinpoint stereocontrol around the tricyclic skeleton and a modular strategy that enables analog generation. A key bicyclic b-lactam intermediate serves to not only control stereochemistry, but also serves as a pre-activated coupling partner to install the ester sidechain. The stereo-controlled synthesis allowed for the investigation of the antimicrobial activity of batzelladine D, demonstrating promising activity that is more potent for non-natural stereoisomers.


Synthesis ◽  
2021 ◽  
Author(s):  
Linda Pudnika ◽  
Ilona Domračeva ◽  
Thomas Werner ◽  
Raivis Žalubovskis ◽  
Aiga Grandane

The facile synthesis of highly functionalized building blocks with potential biological activity is of great interest to medicinal chemistry. The benzoxepinone core structures commonly exhibit biological activity. Thus, a short and efficient synthetic route towards benzoxepine containing scaffold which enables late stage modification was developed. Namely, base-free catalytic Wittig reactions enabled the synthesis of bromobenzoxepinones from readily available starting materials. Subsequent, Suzuki-Miyaura and Stille reactions proved to be suitable methods to access a variety of benzoxepinone diaryl derivatives by late stage modification in only three steps. This three step reaction sequence is suitable for high throughput applications and gives facile access to highly complex molecular structures which are suitable for further functionalization. The antiproliferative properties of selected aryl benzoxepinones were tested in vitro on monolayer tumor cell line A549. Notably, in this initial screening these compounds were found to be active in the micromolar range.


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