Visible-light-mediated catalyst-free synthesis of unnatural α-amino acids and peptide macrocycles.
ABSTRACT: The visible light induced, photocatalysts or photoabsorbing EDA complexes mediated cleavage of pyridinium C-N bond were reported in the past years. Here, we report an ionic compound promote homolytic cleavage of pyridinium C-N bond by exploiting the photonic energy from visible light. This finding is successfully applied in deaminative hydroalkylation of a series of alkenes including naturally occurring dehydroalanine, which provides an efficient way to prepare β-alkyl substituted unnatural amino acids under mild and photocatalyst-free conditions. Importantly, by using this protocol, the deaminative cyclization of peptide backbone N-terminals is realized. Furthermore, the use of Et3N or PPh3 as reductants and H2O as hydrogen atom source is a practical advantage. We anticipate that our protocol will be useful in peptide synthesis and modern peptide drug discovery.
Project description:The use of pyridinium-activated primary amines as photoactive functional groups for deaminative generation of alkyl radicals under catalyst-free conditions is described. By taking advantage of the visible light absorptivity of electron donor-acceptor complexes between Katritzky pyridinium salts and either Hantzsch ester or Et<sub>3</sub> N, photoinduced single-electron transfer could be initiated in the absence of a photocatalyst. This general reactivity platform has been applied to deaminative alkylation (Giese), allylation, vinylation, alkynylation, thioetherification, and hydrodeamination reactions. The mild conditions are amenable to a diverse range of primary and secondary alkyl pyridiniums and demonstrate broad functional group tolerance.
Project description:By employing an N-heterocyclic carbene (NHC) catalyst, we developed a versatile catalytic system that enables deaminative cross-coupling reactions of aldehydes with redox-active pyridinium salts. Katritzky pyridinium salts behave as single-electron oxidants capable of generating alkyl radicals enabled by the redox properties of the enolate form of Breslow intermediates. The resultant alkyl radical undergoes efficient recombination with the NHC-bound aldehyde-derived carbonyl carbon radical for the formation of a C-C bond. The mild and transition metal-free reaction conditions tolerate a broad range of functional groups, and its utility has been further demonstrated by the modification of a series of peptide feedstocks and application to the three-component dicarbofunctionalization of olefins.
Project description:Herein, we report a radical borylation of aromatic amines through a homolytic C(sp2 )-N bond cleavage. This method capitalizes on a simple and mild activation via a pyrylium reagent (Sc Pyry-OTf) thus priming the amino group for reactivity. The combination of terpyridine and a diboron reagent triggers a radical reaction which cleaves the C(sp2 )-N bond and forges a new C(sp2 )-B bond. The unique non-planar structure of the pyridinium intermediate, provides the necessary driving force for the aryl radical formation. The method permits borylation of a wide variety of aromatic amines indistinctively of the electronic environment.
Project description:Catalysis by canonical radical <i>S</i>-adenosyl-l-methionine (SAM) enzymes involves electron transfer (ET) from [4Fe-4S]<sup>+</sup> to SAM, generating an R<sub>3</sub>S<sup>0</sup> radical that undergoes regioselective homolytic reductive cleavage of the S-C5' bond to generate the 5'-dAdo· radical. However, cryogenic photoinduced S-C bond cleavage has regioselectively yielded either 5'-dAdo· or ·CH<sub>3</sub>, and indeed, each of the three SAM S-C bonds can be regioselectively cleaved in an RS enzyme. This diversity highlights a longstanding central question: what controls regioselective homolytic S-C bond cleavage upon SAM reduction? We here provide an unexpected answer, founded on our observation that photoinduced S-C bond cleavage in multiple canonical RS enzymes reveals two enzyme classes: in one, photolysis forms 5'-dAdo·, and in another it forms ·CH<sub>3</sub>. The identity of the cleaved S-C bond correlates with SAM ribose conformation but not with positioning and orientation of the sulfonium center relative to the [4Fe-4S] cluster. We have recognized the reduced-SAM R<sub>3</sub>S<sup>0</sup> radical is a (<sup>2</sup><i>E</i>) state with its antibonding unpaired electron in an orbital doublet, which renders R<sub>3</sub>S<sup>0</sup> Jahn-Teller (JT)-active and therefore subject to vibronically induced distortion. Active-site forces induce a JT distortion that localizes the odd electron in a single priority S-C antibond, which undergoes regioselective cleavage. In photolytic cleavage those forces act through control of the ribose conformation and are transmitted to the sulfur via the S-C5' bond, but during catalysis thermally induced conformational changes that enable ET from a cluster iron generate dominant additional forces that specifically select S-C5' for cleavage. This motion also can explain how 5'-dAdo· subsequently forms the organometallic intermediate Ω.
Project description:The Cα-Cβ bond in homoallylic alcohols can be activated under basic conditions, qualifying these nonstrained acyclic systems as radical allylation reagents. This reactivity is exemplified by photoinitiated (with visible light and/or blue LEDs) allylation of perfluoroalkyl and alkyl radicals generated from perfluoroalkyl iodides and alkylpyridinium salts, respectively, with homoallylic alcohols. C-radical addition to the double bond of the title reagents and subsequent base-promoted homolytic Cα-Cβ cleavage leads to the formation of the corresponding allylated products along with ketyl radicals that act as single electron reductants to sustain the chain reactions. Substrate scope is documented and the role of base in the C-C bond activation is studied by computation.
Project description:Traditional electron-transfer dissociation (ETD) experiments operate through a complex combination of hydrogen abundant and hydrogen deficient fragmentation pathways, yielding c and z ions, side-chain losses, and disulfide bond scission. Herein, a novel dissociation pathway is reported, yielding homolytic cleavage of carbon-iodine bonds via electronic excitation. This observation is very similar to photodissociation experiments where homolytic cleavage of carbon-iodine bonds has been utilized previously, but ETD activation can be performed without addition of a laser to the mass spectrometer. Both loss of iodine and loss of hydrogen iodide are observed, with the abundance of the latter product being greatly enhanced for some peptides after additional collisional activation. These observations suggest a novel ETD fragmentation pathway involving temporary storage of the electron in a charge-reduced arginine side chain. Subsequent collisional activation of the peptide radical produced by loss of HI yields spectra dominated by radical-directed dissociation, which can be usefully employed for identification of peptide isomers, including epimers. Graphical Abstract ?.
Project description:Radical S-adenosyl-l-methionine (SAM) enzymes comprise a vast superfamily catalyzing diverse reactions essential to all life through homolytic SAM cleavage to liberate the highly reactive 5'-deoxyadenosyl radical (5'-dAdo·). Our recent observation of a catalytically competent organometallic intermediate ? that forms during reaction of the radical SAM (RS) enzyme pyruvate formate-lyase activating-enzyme (PFL-AE) was therefore quite surprising, and led to the question of its broad relevance in the superfamily. We now show that ? in PFL-AE forms as an intermediate under a variety of mixing order conditions, suggesting it is central to catalysis in this enzyme. We further demonstrate that ? forms in a suite of RS enzymes chosen to span the totality of superfamily reaction types, implicating ? as essential in catalysis across the RS superfamily. Finally, EPR and electron nuclear double resonance spectroscopy establish that ? involves an Fe-C5' bond between 5'-dAdo· and the [4Fe-4S] cluster. An analogous organometallic bond is found in the well-known adenosylcobalamin (coenzyme B<sub>12</sub>) cofactor used to initiate radical reactions via a 5'-dAdo· intermediate. Liberation of a reactive 5'-dAdo· intermediate via homolytic metal-carbon bond cleavage thus appears to be similar for ? and coenzyme B<sub>12</sub>. However, coenzyme B<sub>12</sub> is involved in enzymes catalyzing only a small number (?12) of distinct reactions, whereas the RS superfamily has more than 100?000 distinct sequences and over 80 reaction types characterized to date. The appearance of ? across the RS superfamily therefore dramatically enlarges the sphere of bio-organometallic chemistry in Nature.
Project description:An efficient, simple, and metal-free synthetic approach for the <i>N</i>- and <i>O</i>-benzoylation of various amines/benzyl alcohols with pyridinium salts of phenacyl bromides is demonstrated to generate the corresponding amides and esters. This protocol facilitates the oxidative cleavage of a C-C bond followed by formation of a new C-N/C-O bond in the presence of K<sub>2</sub>CO<sub>3</sub>. Various pyridinium salts of phenacyl bromides can be readily transformed into a variety of amides and esters which is an alternative method for the conventional amidation and esterification in organic synthesis. High functional group tolerance, broad substrate scope and operational simplicity are the prominent advantages of the current protocol.
Project description:The intriguing deactivation of the cytochrome P450 (CYP) 2B4 enzyme induced by mutation of a single residue, Phe429 to His, is explored by quantum mechanical/molecular mechanical calculations of the O-OH bond activation of the (Fe(3+)OOH)(-) intermediate. It is found that the F429H mutant of CYP 2B4 undergoes homolytic instead of heterolytic O-OH bond cleavage. Thus, the mutant acquires the following characteristics of a heme oxygenase enzyme: (a) donation by His429 of an additional NH---S H-bond to the cysteine ligand combined with the presence of the substrate retards the heterolytic cleavage and gives rise to homolytic O-OH cleavage, and (b) the Thr302/water cluster orients nascent OH(•) and ensures efficient meso hydroxylation.