scholarly journals The role of allyl ammonium salts in palladium-catalyzed cascade reactions towards the synthesis of spiro-fused heterocycles

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Fei Ye ◽  
Yao Ge ◽  
Anke Spannenberg ◽  
Helfried Neumann ◽  
Matthias Beller
Keyword(s):  
Cascade Reactions ◽  
Synthetic Methods ◽  
Ammonium Salts ◽  
One Pot ◽  
Pd Catalysts ◽  
Complex Molecules ◽  
Fused Heterocycles ◽  
Palladium Catalyzed ◽  
Ideal Tool

Abstract There is a continuous need for designing new and improved synthetic methods aiming at minimizing reaction steps while increasing molecular complexity. In this respect, catalytic, one-pot cascade methodologies constitute an ideal tool for the construction of complex molecules with high chemo-, regio-, and stereoselectivity. Herein, we describe two general and efficient cascade procedures for the synthesis of spiro-fused heterocylces. This transformation combines selective nucleophilic substitution (SN2′), palladium-catalyzed Heck and C–H activation reactions in a cascade manner. The use of allylic ammonium salts and specific Pd catalysts are key to the success of the transformations. The synthetic utility of these methodologies is showcased by the preparation of 48 spiro-fused dihydrobenzofuranes and indolines including a variety of fluorinated derivatives.

scholarly journals A hidden catalysis: metal-, and organocatalyst-free one-pot assembly of chiral aza-tricyclic molecules containing six contiguous stereocenters

2020 ◽  
Author(s):  
Dung Do
Keyword(s):  
Chemical Space ◽  
Structural Diversity ◽  
Therapeutic Agents ◽  
Chiral Molecules ◽  
One Pot ◽  
Complex Molecules ◽  
Chiral Complex ◽  
Enamine Catalysis ◽  
Daunting Challenge

<p></p><p>Chiral molecules with their defined 3-D structures are of paramount importance for the study of chemical biology and drug discovery. Having rich structural diversity and unique stereoisomerism, chiral molecules offer a large chemical space that can be explored for the design of new therapeutic agents.<sup>1</sup> In practice, chiral architectures are usually prepared from organometallic and organocatalytic processes where a transition metal or an organocatalyst is tailor-made for a desired reaction. As a result, developing a method that enables rapid assembly of chiral complex molecules under a metal- and organocatalyst-free condition represents a daunting challenge. Here we developed a straightforward one-pot procedure to create a chiral 3-D structure from 2-D structures and an amino acid without any chiral catalyst. The center of this research is the design of a <a>special chiral spiroimidazolidinone cyclohexadienone intermediate</a>, a merger of a chiral reactive substrate with multiple nucleophillic/electrophillic sites and a transient organocatalyst. <a>This unique substrate-catalyst (“sub-catalyst”) dual role of the intermediate was displayed in its aza-Michael/Michael cascade reaction with an </a>α,β-unsaturated aldehyde under an iminium/enamine catalysis. <a>The enhanced co-ordinational proximity of the chiral substrate and catalyst</a> in the transition state resulted in a substantial steric discrimination and an excellent overall diastereoselectivity. Aza-tricylic molecules with six contiguous stereocenters were assembled from <i>N</i>-alkylated aminophenols, α,β-unsaturated aldehydes and chiral α-amino acids under a hidden “sub-catalysis” where the strategically produced “sub-catalyst” does not present in initial components of the reaction. The success of this methodology will pave the way for many efficient preparations of chiral complex molecules.</p><br><p></p>

Palladium-Catalyzed Stereoselective Aza-Wacker–Heck Cyclization: One-Pot Stepwise Strategy toward Tetracyclic Fused Heterocycles

2020 ◽  
Vol 22 (23) ◽  
pp. 9337-9341
Author(s):  
Rong-Shiow Tang ◽  
Li-Yuan Chen ◽  
Chin-Hung Lai ◽  
Ta-Hsien Chuang
Keyword(s):  
One Pot ◽  
Heck Cyclization ◽  
Fused Heterocycles ◽  
Palladium Catalyzed

scholarly journals A hidden catalysis: metal-, and organocatalyst-free one-pot assembly of chiral aza-tricyclic molecules containing six contiguous stereocenters

2020 ◽  
Author(s):  
Dung Do
Keyword(s):  
Chemical Space ◽  
Structural Diversity ◽  
Therapeutic Agents ◽  
Chiral Molecules ◽  
One Pot ◽  
Complex Molecules ◽  
Chiral Complex ◽  
Enamine Catalysis ◽  
Daunting Challenge

<p></p><p>Chiral molecules with their defined 3-D structures are of paramount importance for the study of chemical biology and drug discovery. Having rich structural diversity and unique stereoisomerism, chiral molecules offer a large chemical space that can be explored for the design of new therapeutic agents.<sup>1</sup> In practice, chiral architectures are usually prepared from organometallic and organocatalytic processes where a transition metal or an organocatalyst is tailor-made for a desired reaction. As a result, developing a method that enables rapid assembly of chiral complex molecules under a metal- and organocatalyst-free condition represents a daunting challenge. Here we developed a straightforward one-pot procedure to create a chiral 3-D structure from 2-D structures and an amino acid without any chiral catalyst. The center of this research is the design of a <a>special chiral spiroimidazolidinone cyclohexadienone intermediate</a>, a merger of a chiral reactive substrate with multiple nucleophillic/electrophillic sites and a transient organocatalyst. <a>This unique substrate-catalyst (“sub-catalyst”) dual role of the intermediate was displayed in its aza-Michael/Michael cascade reaction with an </a>α,β-unsaturated aldehyde under an iminium/enamine catalysis. <a>The enhanced co-ordinational proximity of the chiral substrate and catalyst</a> in the transition state resulted in a substantial steric discrimination and an excellent overall diastereoselectivity. Aza-tricylic molecules with six contiguous stereocenters were assembled from <i>N</i>-alkylated aminophenols, α,β-unsaturated aldehydes and chiral α-amino acids under a hidden “sub-catalysis” where the strategically produced “sub-catalyst” does not present in initial components of the reaction. The success of this methodology will pave the way for many efficient preparations of chiral complex molecules.</p><br><p></p>

scholarly journals A hidden catalysis: metal-, and organocatalyst-free one-pot assembly of chiral aza-tricyclic molecules

2021 ◽  
Author(s):  
Dung Do
Keyword(s):  
Amino Acid ◽  
Michael Reaction ◽  
Chemical Change ◽  
Building Blocks ◽  
One Pot ◽  
Complex Molecules ◽  
Enamine Catalysis ◽  
Amino Acid Precursor ◽  
Acid Precursor

<p></p><p> Development of a rapid synthesis of complex molecules from simple building blocks under a metal-and organocatalyst-free condition is both conceptually and chemically challenging. Here, we developed a hidden catalysis that allow the straightforward assembly of enantiopure aza-tricyclic molecules containing six contiguous stereocenters from <a>aminophenols, α,β-unsaturated aldehydes </a>and α-amino acids. <a>Without using a metal or an organocatalyst, our approach relies on a temporary formation of a spiroimidazolidinone intermediate and its participation in a sequential aza-Michael/Michael reaction as both a substrate and a catalyst</a> under an iminium/enamine catalysis. The formation of the putative iminium intermediate was supported by spectroscopic data and its interruptive reduction derivative was isolated and fully characterized. Whereas a conventional catalyst is always present and does not undergo a permanent chemical change in a classic catalysis, the spiroimidazolidinone intermediate is conceptualized as a sub-catalyst as it is only temporary produced from precursors and catalyzes its own consumption. This unique substrate-catalyst (sub-catalyst) dual role of the spiroimidazolidinone induces a substantial steric discrimination in the transition state and an excellent overall diastereoselectivity (>20:1 dr). It allows the use of an amino acid precursor as the sole chirality genesis and avoids the use of transition metals or organocatalysts. An enantiomer of an aza-tricyclic imidazolidinone can be prepared from a commercially available amino acid precursor. The aqueous-based reaction is practical and scalable for multi-gram synthesis. The success of implementing this sub-catalysis concept in the synthesis will pave the way for many efficient chiral catalyst-free preparations of chiral complex molecules.<br></p><br><p></p>

Tunable synthesis of quinolinone-fused isoquinolines through sequential one-pot nucleophilic addition and palladium-catalyzed intramolecular C–H alkenylation

2019 ◽  
Vol 17 (2) ◽  
pp. 321-332 ◽  
Author(s):  
Xue Li ◽  
Yunyun Bian ◽  
Xin Chen ◽  
Hang Zhang ◽  
Wei Wang ◽  
...  
Keyword(s):  
Nucleophilic Addition ◽  
One Pot ◽  
One Pot Synthesis ◽  
Fused Heterocycles ◽  
Biological Interest ◽  
Palladium Catalyzed

An efficient sequential one-pot synthesis of N-fused heterocycles based on 4-quinolinone and isoquinoline scaffolds of biological interest has been developed.

scholarly journals Engineering Dirhodium Artificial Metalloenzymes for Diazo Coupling Cascade Reactions

2021 ◽  
Author(s):  
David M. Upp ◽  
Rui Huang ◽  
Ying Li ◽  
Maxwell J. Bultman ◽  
Benoît Roux ◽  
...  
Keyword(s):  
Large Scale ◽  
Md Simulations ◽  
Cascade Reactions ◽  
Cascade Reaction ◽  
Side Reactions ◽  
One Pot ◽  
Diazo Coupling ◽  
Reaction With Water ◽  
Artificial Metalloenzymes

<p>Artificial metalloenzymes (ArMs) are now commonly used to control the stereoselectivity of catalytic reactions, but controlling ArM chemoselectivity remains challenging. In this study, we engineer a dirhodium ArM to catalyze diazo cross-coupling to form an alkene that, in a one-pot cascade reaction, is reduced to an alkane with high enantioselectivity (typically >99% e.e.) by an alkene reductase. The numerous protein and small molecule components required for the cascade reaction had minimal effect on ArM catalysis, while the dirhodium cofactor itself provided only O-H insertion products from reaction with water and glucose under the same conditions. Directed evolution of the ArM led to improved yields and E/Z selectivities for a variety of substrates, which translated well to cascade reaction yields. MD simulations of ArM variants were used to understand the structural role of the cofactor on large-scale scaffold structural dynamics. These results highlight the ability of ArMs to control both catalyst stereoselectivity and chemoselectivity to enable reactions in complex media that would otherwise lead to undesired side reactions.</p>

scholarly journals A Multi-Enzyme Cascade Reaction for the Production of 2’3’‑cGAMP

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 590
Author(s):  
Martin Becker ◽  
Patrick Nikel ◽  
Jennifer N. Andexer ◽  
Stephan Lütz ◽  
Katrin Rosenthal
Keyword(s):  
Cyclic Gmp ◽  
Reaction Rate ◽  
Atp Synthesis ◽  
Cascade Reactions ◽  
Single Step ◽  
One Pot ◽  
Complex Molecules ◽  
Complex Products ◽  
Enzyme Cascade ◽  
Enzyme Cascades

Multi-enzyme cascade reactions for the synthesis of complex products have gained importance in recent decades. Their advantages compared to single biotransformations include the possibility to synthesize complex molecules without purification of reaction intermediates, easier handling of unstable intermediates, and dealing with unfavorable thermodynamics by coupled equilibria. In this study, a four-enzyme cascade consisting of ScADK, AjPPK2, and SmPPK2 for ATP synthesis from adenosine coupled to the cyclic GMP-AMP synthase (cGAS) catalyzing cyclic GMP-AMP (2’3’-cGAMP) formation was successfully developed. The 2’3’‑cGAMP synthesis rates were comparable to the maximal reaction rate achieved in single-step reactions. An iterative optimization of substrate, cofactor, and enzyme concentrations led to an overall yield of 0.08 mole 2’3’-cGAMP per mole adenosine, which is comparable to chemical synthesis. The established enzyme cascade enabled the synthesis of 2’3’-cGAMP from GTP and inexpensive adenosine as well as polyphosphate in a biocatalytic one-pot reaction, demonstrating the performance capabilities of multi-enzyme cascades for the synthesis of pharmaceutically relevant products.

One-Pot Assembly of Fused Heterocycles via Oxidative Palladium-Catalyzed Cyclization of Arylols and Iodoarenes

2016 ◽  
Vol 358 (3) ◽  
pp. 353-357 ◽  
Author(s):  
Fenglin Hong ◽  
Yingwen Chen ◽  
Beili Lu ◽  
Jiajia Cheng
Keyword(s):  
One Pot ◽  
Fused Heterocycles ◽  
Palladium Catalyzed

scholarly journals Engineering Dirhodium Artificial Metalloenzymes for Diazo Coupling Cascade Reactions

2021 ◽  
Author(s):  
David M. Upp ◽  
Rui Huang ◽  
Ying Li ◽  
Maxwell J. Bultman ◽  
Benoît Roux ◽  
...  
Keyword(s):  
Large Scale ◽  
Md Simulations ◽  
Cascade Reactions ◽  
Cascade Reaction ◽  
Side Reactions ◽  
One Pot ◽  
Diazo Coupling ◽  
Reaction With Water ◽  
Artificial Metalloenzymes

<p>Artificial metalloenzymes (ArMs) are now commonly used to control the stereoselectivity of catalytic reactions, but controlling ArM chemoselectivity remains challenging. In this study, we engineer a dirhodium ArM to catalyze diazo cross-coupling to form an alkene that, in a one-pot cascade reaction, is reduced to an alkane with high enantioselectivity (typically >99% e.e.) by an alkene reductase. The numerous protein and small molecule components required for the cascade reaction had minimal effect on ArM catalysis, while the dirhodium cofactor itself provided only O-H insertion products from reaction with water and glucose under the same conditions. Directed evolution of the ArM led to improved yields and E/Z selectivities for a variety of substrates, which translated well to cascade reaction yields. MD simulations of ArM variants were used to understand the structural role of the cofactor on large-scale scaffold structural dynamics. These results highlight the ability of ArMs to control both catalyst stereoselectivity and chemoselectivity to enable reactions in complex media that would otherwise lead to undesired side reactions.</p>

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