scholarly journals Nature-inspired remodeling of (aza)indoles to meta-aminoaryl nicotinates for late-stage conjugation of vitamin B3 to (hetero)arylamines

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Begur Vasanthkumar Varun ◽  
Kannan Vaithegi ◽  
Sihyeong Yi ◽  
Seung Bum Park
Keyword(s):  
Biomedical Research ◽  
Late Stage ◽  
Chemical Space ◽  
Bond Cleavage ◽  
Cross Coupling ◽  
Vitamin B ◽  
Vitamin B3 ◽  
Synthetic Routes ◽  
Biomimetic Method ◽  
Pharmaceutical Agents

AbstractDespite the availability of numerous routes to substituted nicotinates based on the Bohlmann–Rahtz pyridine synthesis, the existing methods have several limitations, such as the inevitable ortho-substitutions and the inability to conjugate vitamin B3 to other pharmaceutical agents. Inspired by the biosynthesis of nicotinic acid (a form of vitamin B3) from tryptophan, we herein report the development of a strategy for the synthesis of meta-aminoaryl nicotinates from 3-formyl(aza)indoles. Our strategy is mechanistically different from the reported routes and involves the transformation of (aza)indole scaffolds into substituted meta-aminobiaryl scaffolds via Aldol-type addition and intramolecular cyclization followed by C–N bond cleavage and re-aromatization. Unlike previous synthetic routes, this biomimetic method utilizes propiolates as enamine precursors and thus allows access to ortho-unsubstituted nicotinates. In addition, the synthetic feasibility toward the halo-/boronic ester-substituted aminobiaryls clearly differentiates the present strategy from other cross-coupling strategies. Most importantly, our method enables the late-stage conjugation of bioactive (hetero)arylamines with nicotinates and nicotinamides and allows access to the previously unexplored chemical space for biomedical research.

scholarly journals Modular synthesis of α-fluorinated arylmethanes via desulfonylative cross-coupling

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Masakazu Nambo ◽  
Jacky C.-H. Yim ◽  
Luiza B. O. Freitas ◽  
Yasuyo Tahara ◽  
Zachary T. Ariki ◽  
...  
Keyword(s):  
Biological Activity ◽  
Late Stage ◽  
Recent Progress ◽  
Cross Coupling ◽  
Biologically Active Compounds ◽  
Biologically Active ◽  
Active Compounds ◽  
Arylboronic Acids ◽  
Modular Synthesis ◽  
Synthetic Routes

Abstract α-Fluoromethylarenes are common substructures in pharmaceuticals and agrochemicals, with the introduction of fluorine often resulting in improved biological activity and stability. Despite recent progress, synthetic routes to α-fluorinated diarylmethanes are still rare. Herein we describe the Pd-catalyzed Suzuki-Miyaura cross-coupling of α-fluorinated benzylic triflones with arylboronic acids affording structurally diverse α-fluorinated diarylmethanes. The ease of synthesis of fluorinated triflones as the key starting materials enables powerful late-stage transformations of known biologically active compounds into fluorinated analogs.

Enantioselective Synthesis of Azamerone

2018 ◽  
Author(s):  
Matthew L. Landry ◽  
Grace McKenna ◽  
Noah Burns
Keyword(s):  
Late Stage ◽  
Cross Coupling ◽  
Enantioselective Synthesis ◽  
Selective Synthesis

A concise and selective synthesis of the dichlorinated meroterpenoid azamerone is described. The paucity of tactics for the synthesis of chiral organochlorides motivated the development of unique strategies for accessing these motifs in enantioenriched forms. The route features a novel enantioselective chloroetherification reaction, a Pd-catalyzed cross-coupling between a quinone diazide and a boronic hemiester, and a late-stage tetrazine [4+2]-cycloaddition/oxidation cascade.

Enantioselective Synthesis of Azamerone

2018 ◽  
Author(s):  
Matthew L. Landry ◽  
Grace McKenna ◽  
Noah Burns
Keyword(s):  
Late Stage ◽  
Cross Coupling ◽  
Enantioselective Synthesis ◽  
Selective Synthesis

A concise and selective synthesis of the dichlorinated meroterpenoid azamerone is described. The paucity of tactics for the synthesis of chiral organochlorides motivated the development of unique strategies for accessing these motifs in enantioenriched forms. The route features a novel enantioselective chloroetherification reaction, a Pd-catalyzed cross-coupling between a quinone diazide and a boronic hemiester, and a late-stage tetrazine [4+2]-cycloaddition/oxidation cascade.

A Revised Modular Approach to D8-THC and Derivatives Through Late-Stage Suzuki-Miyaura Cross-Coupling Reactions

2019 ◽  
Author(s):  
Victor Bloemendal ◽  
Floris P. J. T. Rutjes ◽  
Thomas J. Boltje ◽  
Daan Sondag ◽  
Hidde Elferink ◽  
...  
Keyword(s):  
Biological Activity ◽  
Late Stage ◽  
Medicinal Chemistry ◽  
Cross Coupling ◽  
Modular Approach ◽  
Coupling Reactions ◽  
One Pot ◽  
Biologically Relevant ◽  
Cross Coupling Reactions ◽  
Chemistry Research

<p>In this manuscript we describe a modular pathway to synthesize biologically relevant (–)-<i>trans</i>-Δ<sup>8</sup>-THC derivatives, which can be used to modulate the pharmacologically important CB<sub>1</sub> and CB<sub>2</sub> receptors. This pathway involves a one-pot Friedel-Crafts alkylation/cyclization protocol, followed by Suzuki-Miyaura cross-coupling reactions and gives rise to a series of new Δ<sup>8</sup>-THC derivatives. In addition, we demonstrate using extensive NMR evidence that similar halide-substituted Friedel-Crafts alkylation/cyclization products in previous articles were wrongly assigned as the para-isomers, which also has consequence for the assignment of the subsequent cross-coupled products and interpretation of their biological activity. </p> <p>Considering the importance of the availability of THC derivatives in medicinal chemistry research and the fact that previously synthesized compounds were wrongly assigned, we feel this research is describing a straightforward pathway into new cannabinoids.</p>

The Total Synthesis of Rhabdastrellic Acid A

2018 ◽  
Author(s):  
Yaroslav Boyko ◽  
Christopher Huck ◽  
David Sarlah
Keyword(s):  
Total Synthesis ◽  
Late Stage ◽  
Cross Coupling ◽  
Side Chains ◽  
General Strategy ◽  
Modular Approach ◽  
Linear Sequence ◽  
Generating Sequence ◽  
First Time

<div>The first total synthesis of rhabdastrellic acid A, a highly cytotoxic isomalabaricane triterpenoid, has been accomplished in a linear sequence of 14 steps from commercial geranylacetone. The prominently strained <i>trans-syn-trans</i>-perhydrobenz[<i>e</i>]indene core characteristic of the isomalabaricanes is efficiently accessed in a selective manner for the first time through a rapid, complexity-generating sequence incorporating a reductive radical polyene cyclization, an unprecedented oxidative Rautenstrauch cycloisomerization, and umpolung 𝛼-substitution of a <i>p</i>-toluenesulfonylhydrazone with in situ reductive transposition. A late-stage cross-coupling in concert with a modular approach to polyunsaturated side chains renders this a general strategy for the synthesis of numerous family members of these synthetically challenging and hitherto inaccessible marine triterpenoids.</div>

ChemInform Abstract: Fe-Promoted Cross Coupling of Homobenzylic Methyl Ethers with Grignard Reagents via sp3C-O Bond Cleavage.

ChemInform ◽  
2013 ◽  
Vol 44 (52) ◽  
pp. no-no
Author(s):  
Shuang Luo ◽  
Da-Gang Yu ◽  
Ru-Yi Zhu ◽  
Xin Wang ◽  
Lei Wang ◽  
...  
Keyword(s):  
Bond Cleavage ◽  
Cross Coupling ◽  
Grignard Reagents

ChemInform Abstract: Nickel-Catalyzed Cross-Coupling of Anisoles with Alkyl Grignard Reagents via C-O Bond Cleavage.

ChemInform ◽  
2016 ◽  
Vol 47 (4) ◽  
pp. no-no
Author(s):  
Mamoru Tobisu ◽  
Tsuyoshi Takahira ◽  
Naoto Chatani
Keyword(s):  
Bond Cleavage ◽  
Cross Coupling ◽  
Grignard Reagents

scholarly journals Synthesis and Configurational Assignment of Vinyl Sulfoximines and Sulfonimidamides

2021 ◽  
Author(s):  
Gregory Craven ◽  
Edward L. Briggs ◽  
Charlotte Zammit ◽  
Alex McDermott ◽  
Stephanie Greed ◽  
...  
Keyword(s):  
Absolute Configuration ◽  
Late Stage ◽  
Chemical Biology ◽  
Chemical Space ◽  
Protein Inhibitors ◽  
Electronic Circular Dichroism ◽  
Configurational Assignment ◽  
The Absolute ◽  
Synthetic Methodologies ◽  
Circular Dichroïsm

Vinyl sulfones and sulfonamides are valued for their use as electrophilic warheads in covalent protein inhibitors. Conversely, the S(VI) aza-isosteres thereof, vinyl sulfoximines and sulfonimidamides, are far less studied and have yet to be applied to the field of protein bioconjugation. Herein, we report a range of different synthetic methodologies for constructing vinyl sulfoximine and vinyl sulfonimidamide architectures that allows access to new areas of electrophilic chemical space. We demonstrate how late stage functionalization can be applied to these motifs to incorporate alkyne tags, generating fully functionalized probes for future chemical biology applications. Finally, we establish a workflow for determining the absolute configuration of enantioenriched vinyl sulfoximines and sulfonimidamides by comparing experimentally and computationally determined electronic circular dichroism spectra, enabling access to configurationally assigned enantiomeric pairs by separation.

Retaining Alkyl Nucleophile Regiofidelity in Transition-Metal-Mediated Cross-Couplings to Aryl Electrophiles

Synthesis ◽  
2018 ◽  
Vol 50 (20) ◽  
pp. 3974-3996 ◽  
Author(s):  
Josep Cornella ◽  
Matthew O’Neill
Keyword(s):  
Transition Metal ◽  
Functional Group ◽  
Chemical Space ◽  
Cross Coupling ◽  
Transition Metal Catalysis ◽  
Metal Catalysis ◽  
Substantial Progress ◽  
Tertiary Alkyl ◽  
Metal Ligand

While the advent of transition-metal catalysis has undoubtedly transformed synthetic chemistry, problems persist with the introduction of secondary and tertiary alkyl nucleophiles into C(sp2) aryl electrophiles. Complications arise from the delicate organometallic intermediates typically invoked by such processes, from which competition between the desired reductive elimination event and the deleterious β-H elimination pathways can lead to undesired isomerization of the incoming nucleophile. Several methods have integrated distinct combinations of metal, ligand, nucleophile, and electrophile to provide solutions to this problem. Despite substantial progress, refinements to current protocols will facilitate the realization of complement reactivity and improved functional group tolerance. These issues have become more pronounced in the context of green chemistry and sustainable catalysis, as well as by the current necessity to develop robust, reliable cross-couplings beyond less explored C(sp2)–C(sp2) constructs. Indeed, the methods discussed herein and the elaborations thereof enable an ‘unlocking’ of accessible topologically enriched chemical space, which is envisioned to influence various domains of application.1 Introduction2 Mechanistic Considerations3 Magnesium Nucleophiles4 Zinc Nucleophiles5 Boron Nucleophiles6 Other Nucleophiles7 Tertiary Nucleophiles8 Reductive Cross-Coupling with in situ Organometallic Formation9 Conclusion

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