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Journal of the American Chemical Society Dec 2022The amide is one of the most prevalent functional groups in all of pharmaceuticals, and for this reason, reactions that introduce the amide moiety are of particular...
The amide is one of the most prevalent functional groups in all of pharmaceuticals, and for this reason, reactions that introduce the amide moiety are of particular value. Intermolecular hydroamidation of alkenes remains an underexplored method for the synthesis of amide-containing compounds. The majority of hydroamidation procedures exhibit Markovnikov regioselectivity, while current methods for anti-Markovnikov hydroamidation are somewhat limited to activated alkene substrates or radical processes. Herein, we report a general method for the intermolecular anti-Markovnikov hydroamidation of unactivated alkenes under mild conditions, utilizing Rh(III) catalysis in conjunction with dioxazolone amidating reagents and isopropanol as an environmentally friendly hydride source. The reaction tolerates a wide range of functional groups and efficiently converts electron-deficient alkenes, styrenes, and 1,1-disubstituted alkenes, in addition to unactivated alkenes, to their corresponding linear amides. Mechanistic studies reveal a reversible rhodium hydride migratory insertion step, leading to exquisite selectivity for the anti-Markovnikov product.
Topics: Rhodium; Alkenes; Indicators and Reagents; Molecular Structure; Catalysis; Amides
PubMed: 36453859
DOI: 10.1021/jacs.2c10552 -
Angewandte Chemie (International Ed. in... Jun 2021A colorimetric indicator displacement assay (IDA) amenable to high-throughput experimentation was developed to determine the percentage of cis and trans alkenes. Using...
A colorimetric indicator displacement assay (IDA) amenable to high-throughput experimentation was developed to determine the percentage of cis and trans alkenes. Using 96-well plates two steps are performed: a reaction plate for dihydroxylation of the alkenes followed by an IDA screening plate consisting of an indicator and a boronic acid. The dihydroxylation generates either erythro or threo vicinal diols from cis or trans alkenes, depending upon their syn- or anti-addition mechanisms. Threo diols preferentially associate with the boronic acid due to the creation of more stable boronate esters, thus displacing the indicator to a greater extent. The generality of the protocol was demonstrated using seven sets of cis and trans alkenes. Blind mixtures of cis and trans alkenes were made, resulting in an average error of ±2 % in the percentage of cis or trans alkenes, and implementing E and Wittig reactions gave errors of ±3 %. Furthermore, we developed variants of the IDA for which the color may be tuned to optimize the response for the human eye.
Topics: Alkenes; Colorimetry; Molecular Structure; Stereoisomerism
PubMed: 33723888
DOI: 10.1002/anie.202101004 -
Nature Communications May 2022The chain-walking of terminal alkenes (also called migration or isomerization reaction) is currently carried out in industry with unselective and relatively costly...
The chain-walking of terminal alkenes (also called migration or isomerization reaction) is currently carried out in industry with unselective and relatively costly processes, to give mixtures of alkenes with significant amounts of oligomerized, branched and reduced by-products. Here, it is shown that part-per-million amounts of a variety of commercially available and in-house made ruthenium compounds, supported or not, transform into an extremely active catalyst for the regioselective migration of terminal alkenes to internal positions, with yields and selectivity up to >99% and without any solvent, ligand, additive or protecting atmosphere required, but only heating at temperatures >150 °C. The resulting internal alkene can be prepared in kilogram quantities, ready to be used in nine different organic reactions without any further treatment.
Topics: Alkenes; Catalysis; Ruthenium
PubMed: 35595741
DOI: 10.1038/s41467-022-30320-9 -
Nature Communications May 20222 + 2 Photocycloadditions are idealized, convergent construction approaches of 4-membered heterocyclic rings, including azetidines. However, methods of direct...
2 + 2 Photocycloadditions are idealized, convergent construction approaches of 4-membered heterocyclic rings, including azetidines. However, methods of direct excitation are limited by the unfavorable photophysical properties of imines and electronically unbiased alkenes. Here, we report copper-catalyzed photocycloadditions of non-conjugated imines and alkenes to produce a variety of substituted azetidines. Design principles allow this base metal-catalyzed method to achieve 2 + 2 imine-olefin photocycloaddition via selective alkene activation through a coordination-MLCT pathway supported by combined experimental and computational mechanistic studies.
Topics: Alkenes; Azetidines; Catalysis; Copper; Imines
PubMed: 35589714
DOI: 10.1038/s41467-022-30393-6 -
Angewandte Chemie (International Ed. in... Mar 2020We report a Rh -catalyzed regio- and diastereoselective synthesis of δ-lactams from readily available acrylamide derivatives and unactivated alkenes. The reaction...
We report a Rh -catalyzed regio- and diastereoselective synthesis of δ-lactams from readily available acrylamide derivatives and unactivated alkenes. The reaction provides a rapid route to a diverse set of δ-lactams in good yield and stereoselectivity, which serve as useful building blocks for substituted piperidines. The regioselectivity of the reaction with unactivated terminal alkene is significantly improved by using Cp ligand on the Rh catalyst. The synthetic utility of the reaction is demonstrated by the preparation of a potential drug candidate containing a trisubstituted piperidine moiety. Mechanistic studies show that the reversibility of the C-H activation depends on the choice of Cp ligand on the Rh catalyst. The irreversible C-H activation is observed and becomes turnover-limiting with [Cp RhCl ] as catalyst.
Topics: Acrylamides; Alkenes; Catalysis; Lactams; Molecular Structure; Organometallic Compounds; Rhodium
PubMed: 32045098
DOI: 10.1002/anie.201916332 -
Chemistry (Weinheim An Der Bergstrasse,... Aug 2021Herein is given a full account of the evolution of the first total synthesis of (+)-cornexistin. Initial efforts were based on masking the reactive maleic anhydride...
Herein is given a full account of the evolution of the first total synthesis of (+)-cornexistin. Initial efforts were based on masking the reactive maleic anhydride moiety as a 3,4-substituted furan and on forming the nine-membered carbocycle in an intramolecular Conia-ene or Nozaki-Hiyama-Kishi (NHK) reaction. Those strategies suffered from low yields and were jeopardized by a late-stage installation of the Z-alkene, as well as the stereocenters along the eastern periphery. These issues were addressed by employing a chiral-pool strategy that involved construction of the crucial stereocenters at C2, C3 and C8 at an early stage with installation of the maleic anhydride as late as possible. The successful approach featured an intermolecular NHK coupling to install the Z-alkene, a syn-Evans-aldol reaction to forge the stereocenters along the eastern periphery, an intramolecular allylic alkylation to close the nine-membered carbocycle, and a challenging stepwise hydrolysis of a β-keto nitrile to furnish the maleic anhydride.
Topics: Alkenes; Furans
PubMed: 34105834
DOI: 10.1002/chem.202101849 -
Proceedings of the National Academy of... May 2023The enzymatic decarboxylation of fatty acids (FAs) represents an advance toward the development of biological routes to produce drop-in hydrocarbons. The current...
The enzymatic decarboxylation of fatty acids (FAs) represents an advance toward the development of biological routes to produce drop-in hydrocarbons. The current mechanism for the P450-catalyzed decarboxylation has been largely established from the bacterial cytochrome P450 OleT. Herein, we describe OleTP, a poly-unsaturated alkene-producing decarboxylase that outrivals the functional properties of the model enzyme and exploits a distinct molecular mechanism for substrate binding and chemoselectivity. In addition to the high conversion rates into alkenes from a broad range of saturated FAs without dependence on high salt concentrations, OleTP can also efficiently produce alkenes from unsaturated (oleic and linoleic) acids, the most abundant FAs found in nature. OleTP performs carbon-carbon cleavage by a catalytic itinerary that involves hydrogen-atom transfer by the heme-ferryl intermediate Compound I and features a hydrophobic cradle at the distal region of the substrate-binding pocket, not found in OleT, which is proposed to play a role in the productive binding of long-chain FAs and favors the rapid release of products from the metabolism of short-chain FAs. Moreover, it is shown that the dimeric configuration of OleTP is involved in the stabilization of the A-A' helical motif, a second-coordination sphere of the substrate, which contributes to the proper accommodation of the aliphatic tail in the distal and medial active-site pocket. These findings provide an alternative molecular mechanism for alkene production by P450 peroxygenases, creating new opportunities for biological production of renewable hydrocarbons.
Topics: Fatty Acids; Alkenes; Decarboxylation; Cytochrome P-450 Enzyme System; Oxidation-Reduction
PubMed: 37216508
DOI: 10.1073/pnas.2221483120 -
Applied and Environmental Microbiology Jan 1996The inducible nature of the alkene oxidation system of Xanthobacter strain Py2 has been investigated. Cultures grown with glucose as the carbon source did not contain...
The inducible nature of the alkene oxidation system of Xanthobacter strain Py2 has been investigated. Cultures grown with glucose as the carbon source did not contain detectable levels of alkene monooxygenase or epoxidase, two key enzymes of alkene and epoxide metabolism. Upon addition of propylene to glucose-grown cultures, alkene monooxygenase and epoxidase activities increased and after an 11-h induction period reached levels of specific activity comparable to those in propylene-grown cells. Addition of chloramphenicol or rifampin prevented the increase in the enzyme activities. Comparison of the banding patterns of proteins present in cell extracts revealed that polypeptides with molecular masses of 43, 53, and 57 kDa accumulate in propylene-grown but not glucose-grown cells. Pulse-labeling of glucose-grown cells with [35S]methionine and [35S]cysteine revealed that the 43-, 53-, and 57-kDa proteins, as well as two additional polypeptides with molecular masses of 12 and 21 kDa, were newly synthesized upon exposure of cells to propylene or propylene oxide. The addition to glucose-grown cells of a variety of other aliphatic and chlorinated alkenes and epoxides, including ethylene, vinyl chloride (1-chloroethylene), cis- and trans-1,2-dichloroethylene, 1-chloropropylene, 1,3-dichloropropylene, 1-butylene, trans-2-butylene, isobutylene, ethylene oxide, epichlorohydrin (3-chloro-1,2-epoxypropane), 1,2-epoxybutane, cis- and trans-2,3-epoxybutane, and isobutylene oxide stimulated the synthesis of the five propylene-inducible polypeptides as well as increases in alkene monooxygenase and epoxidase activities. In contrast, acetylene, and a range of aliphatic and chlorinated alkanes, did not stimulate the synthesis of the propylene-inducible polypeptides or the increase in alkene monooxygenase and epoxidase activities.
Topics: Alkenes; Bacterial Proteins; Chloramphenicol; Enzyme Induction; Epoxy Compounds; Gram-Negative Aerobic Bacteria; Hydrocarbons, Chlorinated; Molecular Weight; Oxidation-Reduction; Oxidoreductases; Oxygenases; Protein Synthesis Inhibitors; Rifampin
PubMed: 8572713
DOI: 10.1128/aem.62.1.61-66.1996 -
Organic Letters Oct 2018The first total synthesis of asperphenins A and B has been accomplished in a concise, highly stereoselective fashion from commercially available materials (15 steps,...
The first total synthesis of asperphenins A and B has been accomplished in a concise, highly stereoselective fashion from commercially available materials (15 steps, 9.7% and 14.2% overall yields, respectively). The convergent route featured the judicious choice of protecting groups, fragment assembly strategy and a late-stage iron-catalyzed Wacker-type selective oxidation of an internal alkene to the corresponding ketone.
Topics: Alkenes; Amides; Amines; Aspergillus; Catalysis; Cycloaddition Reaction; Ketones; Molecular Structure; Oxidation-Reduction; Palladium; Stereoisomerism
PubMed: 30232896
DOI: 10.1021/acs.orglett.8b02652 -
Molecules (Basel, Switzerland) Mar 2020Alkene cleavage is a possibility to generate aldehydes with olfactory properties for the fragrance and flavor industry. A dye-decolorizing peroxidase (DyP) of the...
Alkene cleavage is a possibility to generate aldehydes with olfactory properties for the fragrance and flavor industry. A dye-decolorizing peroxidase (DyP) of the basidiomycete (PsaPOX) cleaved the aryl alkene -anethole. The PsaPOX was semi-purified from the mycelium via FPLC, and the corresponding gene was identified. The amino acid sequence as well as the predicted tertiary structure showed typical characteristics of DyPs as well as a non-canonical Mn-oxidation site on its surface. The gene was expressed in GS115 yielding activities up to 142 U/L using 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) as substrate. PsaPOX exhibited optima at pH 3.5 and 40 °C and showed highest peroxidase activity in the presence of 100 µM HO and 25 mM Mn. PsaPOX lacked the typical activity of DyPs towards anthraquinone dyes, but oxidized Mn to Mn. In addition, bleaching of -carotene and annatto was observed. Biotransformation experiments verified the alkene cleavage activity towards the aryl alkenes ()-methyl isoeugenol, -methylstyrene, and -anethole, which was increased almost twofold in the presence of Mn. The resultant aldehydes are olfactants used in the fragrance and flavor industry. PsaPOX is the first described DyP with alkene cleavage activity towards aryl alkenes and showed potential as biocatalyst for flavor production.
Topics: Aldehydes; Alkenes; Allylbenzene Derivatives; Anisoles; Anthraquinones; Biocatalysis; Bixaceae; Bleaching Agents; Carotenoids; Coloring Agents; Gene Expression; Hydrogen Peroxide; Hydrogen-Ion Concentration; Manganese; Oxidation-Reduction; Peroxidase; Plant Extracts; Pleurotus; Saccharomycetales; Styrenes; beta Carotene
PubMed: 32230972
DOI: 10.3390/molecules25071536