skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Explore Research Products in the PAR
It may take a few hours for recently added research products to appear in PAR search results.


Title: Recent advances in enzymatic carbon–carbon bond formation
Enzymatic carbon‒carbon (C–C) bond formation reactions have become an effective and invaluable tool for designing new biological and medicinal molecules, often with asymmetric features. This review provides a systematic overview of key C–C bond formation reactions and enzymes, with the focus of reaction mechanisms and recent advances. These reactions include aldol reaction, Henry reaction, Knoevenagel condensation, Michael addition, Friedel-Crafts alkylation and acylation, Mannich reaction, Morita–Baylis–Hillman (MBH) reaction, Diels-Alder reaction, acyloin condensations via Thiamine Diphosphate (ThDP)-dependent enzymes, oxidative and reductive C–C bond formation, C–C bond formation through C1 resource utilization, radical enzymes for C–C bond formation, and other C–C bond formation reactions.  more » « less
Award ID(s):
2244638
PAR ID:
10639833
Author(s) / Creator(s):
 
Publisher / Repository:
Royal Society of Chemistry
Date Published:
Journal Name:
RSC Advances
Volume:
14
Issue:
36
ISSN:
2046-2069
Page Range / eLocation ID:
25932 to 25974
Subject(s) / Keyword(s):
carbon-carbon bond formation, enzymatic carboligation, aldol reaction, Michael addition, Friedel-Crafts alkylation and acylation, Knoevenagel condensation, catalytic promiscuity
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. ; ; (, Chemical Science)
    null (Ed.)
    Microdroplets display distinctive interfacial chemistry, manifested as accelerated reactions relative to those observed for the same reagents in bulk. Carbon dioxide undergoes C–N bond formation reactions with amines at the interface of droplets to form carbamic acids. Electrospray ionization mass spectrometry displays the reaction products in the form of the protonated and deprotonated carbamic acid. Electrosonic spray ionization (ESSI) utilizing carbon dioxide as nebulization gas, confines reaction to the gas–liquid interface where it proceeds much faster than in the bulk. Intriguingly, trace amounts of water accelerate the reaction, presumably by formation of superacid or superbase at the water interface. The suggested mechanism of protonation of CO 2 followed by nucleophilic attack by the amine is analogous to that previously advanced for imidazole formation from carboxylic acids and diamines. 
    more » « less
  2. ; (, Journal of Chemical Technology & Biotechnology)
    Abstract BACKGROUNDKnoevenagel condensation is an important tool for building carbon–carbon (CC) bonds, especially when catalyzed by enzymes to enable a potentially high chemo‐, regio‐ and/or stereoselectivity. Although many Knoevenagel condensation reactions are carried out in aqueous solutions, insoluble hydrophobic substrates often lead to poor catalytic efficiencies. The use of water‐miscible organic solvents improves the substrate solubilization, but usually induces activity suppression or inactivation of enzymes. There is a great need to develop alternative solvents for both substrate dissolution and enzyme compatibility in CC bond formation reactions. RESULTSOur group previously developed dual‐functionalized water‐mimicking ionic liquids (ILs) for the activation and stabilization of hydrolases (e.g. lipase and protease). In the present study, we evaluated the Knoevenagel condensation of 4‐chlorobenzaldehyde with acetylacetone, and found that porcine pancreas lipase in water‐mimicking ILs carrying ammonium, imidazolium and benzimidazolium cations enabled higher reaction rates (up to 3.22 μmol min−1 g−1lipase) and better yields thantert‐butanol, glymes and [BMIM][Tf2N]. Interestingly, tertiary amide solvents such asN‐methyl‐2‐pyrrolidone (NMP),N,N‐dimethylformamide (DMF) andN,N‐dimethylacetamide (DMAc) led to 8.2‐ to 11.1‐fold increases in the initial rate (up to 35.66 μmol min−1 g−1lipase) when compared with dual‐functionalized ILs, which is likely due to some synergistic effect of these tertiary amides with the lipase. CONCLUSIONDual‐functionalized ILs based on ammonium, imidazolium and benzimidazolium cations improved Knoevenagel condensation reaction rates and yields when compared withtert‐butanol and glymes. Tertiary amides (NMP, DMF and DMAc) significantly increased the reaction rate. © 2024 The Authors.Journal of Chemical Technology and Biotechnologypublished by John Wiley & Sons Ltd on behalf of Society of Chemical Industry (SCI). 
    more » « less
  3. ; ; ; ; ; ; (, Nature Communications)
    null (Ed.)
    Abstract Despite remarkable recent advances in transition-metal-catalyzed C(sp 3 )−C cross-coupling reactions, there remain challenging bond formations. One class of such reactions include the formation of tertiary -C(sp 3 )−C bonds, presumably due to unfavorable steric interactions and competing isomerizations of tertiary alkyl metal intermediates. Reported herein is a Ni-catalyzed migratory 3,3-difluoroallylation of unactivated alkyl bromides at remote tertiary centers. This approach enables the facile construction of otherwise difficult to prepare all-carbon quaternary centers. Key to the success of this transformation is an unusual remote functionalization via chain walking to the most sterically hindered tertiary C(sp 3 ) center of the substrate. Preliminary mechanistic and radical trapping studies with primary alkyl bromides suggest a unique mode of tertiary C-radical generation through chain-walking followed by Ni–C bond homolysis. This strategy is complementary to the existing coupling protocols with tert -alkyl organometallic or -alkyl halide reagents, and it enables the expedient formation of quaternary centers from easily available starting materials. 
    more » « less
  4. (, ACS catalysis)
    null (Ed.)
    Ergothioneine, a natural longevity vitamin and antioxidant, is a thiol-histidine derivative. Recently, two types of biosynthetic pathways were reported. In the aerobic ergothioneine biosyntheses, non-heme iron enzymes incorporate a sulfoxide into an sp2 C–H bond from trimethyl-histidine (hercynine) through oxidation reactions. In contrast, in the anaerobic ergothioneine biosynthetic pathway in a green-sulfur bacterium, Chlorobium limicola, a rhodanese domain containing protein (EanB), directly replaces this unreactive hercynine C–H bond with a C–S bond. Herein, we demonstrate that polysulfide (HSSnSR) is the direct sulfur source in EanB catalysis. After identifying EanB’s substrates, X-ray crystallography of several intermediate states along with mass spectrometry results provide additional mechanistic details for this reaction. Further, quantum mechanics/molecular mechanics (QM/MM) calculations reveal that the protonation of Nπ of hercynine by Tyr353 with the assistance of Thr414 is a key activation step for the hercynine sp2 C–H bond in this trans-sulfuration reaction. 
    more » « less
  5. ; ; ; (, Dalton Transactions)
    Interest in O 2 -dependent aliphatic carbon–carbon (C–C) bond cleavage reactions of first row divalent metal diketonate complexes stems from the desire to further understand the reaction pathways of enzymes such as DKE1 and to extract information to develop applications in organic synthesis. A recent report of O 2 -dependent aliphatic C–C bond cleavage at ambient temperature in Ni( ii ) diketonate complexes supported by a tridentate nitrogen donor ligand [(MBBP)Ni(PhC(O)CHC(O)Ph)]Cl ( 7-Cl ; MBBP = 2,6-bis(1-methylbenzimidazol-2-yl)pyridine) in the presence of NEt 3 spurred our interest in further examining the chemistry of such complexes. A series of new TERPY-ligated Ni( ii ) diketonate complexes of the general formula [(TERPY)Ni(R 2 -1,3-diketonate)]ClO 4 ( 1 : R = CH 3 ; 2 : R = C(CH 3 ) 3 ; 3 : R = Ph) was prepared under air and characterized using single crystal X-ray crystallography, elemental analysis, 1 H NMR, ESI-MS, FTIR, and UV-vis. Analysis of the reaction mixtures in which these complexes were generated using 1 H NMR and ESI-MS revealed the presence of both the desired diketonate complex and the bis-TERPY derivative [(TERPY) 2 Ni](ClO 4 ) 2 ( 4 ). Through selective crystallization 1–3 were isolated in analytically pure form. Analysis of reaction mixtures leading to the formation of the MBBP analogs [(MBBP)Ni(R 2 -1,3-diketonate)]X (X = ClO 4 : 5 : R = CH 3 ; 6 : R = C(CH 3 ) 3 ; 7-ClO4 : R = Ph; X = Cl: 7-Cl : R = Ph) using 1 H NMR and ESI-MS revealed the presence of [(MBBP) 2 Ni](ClO 4 ) 2 ( 8 ). Analysis of aerobic acetonitrile solutions of analytically pure 1–3 , 5 and 6 containing NEt 3 and in some cases H 2 O using 1 H NMR and UV-vis revealed evidence for the formation of additional bis-ligand complexes ( 4 and 8 ) but suggested no oxidative diketonate cleavage reactivity. Analysis of the organic products generated from 3 , 7-ClO4 and 7-Cl revealed unaltered dibenzoylmethane. Our results therefore indicate that N 3 -ligated Ni( ii ) complexes of unsubstituted diketonate ligands do not exhibit O 2 -dependent aliphatic C–C bond clevage at room temperature, including in the presence of NEt 3 and/or H 2 O. 
    more » « less
  • Citation Formats
  • MLA
  • APA
  • Chicago
  • BibTeX
  • Save / Share this Record
  • Send to Email