scholarly journals Late-stage trifluoromethylthiolation of benzylic C-H bonds

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Wentao Xu ◽  
Wenliang Wang ◽  
Tao Liu ◽  
Jin Xie ◽  
Chengjian Zhu

Abstract The benzylic positions in drugs are sites that readily react with cytochrome P450 oxidases via single-electron oxidation. New synthetic methodologies to incorporate a fluoroalkyl group at the benzylic site are continually being developed, and in this paper, we report a metal-free and site-selective organophotoredox-catalyzed trifluoromethylthiolation of benzylic C-H bonds for a wide variety of alkyl arenes and heteroarenes. The precise and predictive regioselectivity among various C(sp3)-H bonds originates from an inner-sphere benzylic radical initiation mechanism, and avoids the use of external oxidants or hydrogen atom abstractors. Its practicality stems from the trifluoromethylthiolation of a series of drugs and complex organic molecules, which is overwhelmingly selective for benzyl groups. This operationally simple protocol can provide a general and practical access to structurally diverse benzylic trifluoromethyl sulfides produced from ubiquitous benzylic C-H bonds. Large scale trifluoromethylthiolation can be achieved with continuous flow photoredox technology.

2019 ◽  
Vol 629 ◽  
pp. A29 ◽  
Author(s):  
Steffen K. Jacobsen ◽  
Jes K. Jørgensen ◽  
James Di Francesco ◽  
Neal J. Evans ◽  
Minho Choi ◽  
...  

Context. Observations of the innermost regions of deeply embedded protostellar cores have revealed complicated physical structures as well as a rich chemistry with the existence of complex organic molecules. The protostellar envelopes, outflow, and large-scale chemistry of Class 0 and Class I objects have been well studied, but while previous works have hinted at or found a few Keplerian disks at the Class 0 stage, it remains to be seen if their presence in this early stage is the norm. Likewise, while complex organics have been detected toward some Class 0 objects, their distribution is unknown as they could reside in the hottest parts of the envelope, in the emerging disk itself, or in other components of the protostellar system, such as shocked regions related to outflows. Aims. In this work, we aim to address two related issues regarding protostars: when rotationally supported disks form around deeply embedded protostars and where complex organic molecules reside in such objects. We wish to observe and constrain the velocity profile of the gas kinematics near the central protostar and determine whether Keplerian motion or an infalling-rotating collapse under angular momentum conservation best explains the observations. The distribution of the complex organic molecules is used to investigate whether they are associated with the hot inner envelope or a possible Keplerian disk. Methods. We observed the deeply embedded protostar, L483, using Atacama Large Millimeter/submillimeter Array (ALMA) Band 7 data from Cycles 1 and 3 with a high angular resolution down to ~0.1′′ (20 au) scales. We present new HCN J = 4–3, HCO+ J = 4–3, CS J = 7–6, and H13CN J = 4–3 observations, along with a range of transitions that can be attributed to complex organics, including lines of CH3OH, CH3OCHO, C2H5OH, NH2CHO, and other species. Results. We find that the kinematics of CS J = 7–6 and H13CN J = 4–3 are best fitted by the velocity profile from infall under conservation of angular momentum and not by a Keplerian profile. The only discernible velocity profile from the complex organics, belonging to CH3OCHO, is consistent with the infall velocity profile derived from CS J = 7–6 and H13CN J = 4–3. The spatial extents of the observed complex organics are consistent with an estimated ice sublimation radius of the envelope at ~50 au, suggesting that the complex organics exist in the hot corino of L483, where the molecules sublimate off the dust grain ice mantles and are injected into the gas phase. Conclusions. We find that L483 does not harbor a Keplerian disk down to at least 15 au in radius. Instead, the innermost regions of L483 are undergoing a rotating collapse and the complex organics exist in a hot corino with a radius of ~40–60 au. This result highlights that some Class 0 objects contain only very small disks, or none at all, and the complex organic chemistry take place on scales inside the hot corino of the envelope in a region larger than the emerging disk.


2021 ◽  
Vol 118 (8) ◽  
pp. e2005164118
Author(s):  
Dillon T. Flood ◽  
Jordi C. J. Hintzen ◽  
Kyle W. Knouse ◽  
David E. Hill ◽  
Chenxi Lu ◽  
...  

Site-selective chemical bioconjugation reactions are enabling tools for the chemical biologist. Guided by a careful study of the selenomethionine (SeM) benzylation, we have refined the reaction to meet the requirements of practical protein bioconjugation. SeM is readily introduced through auxotrophic expression and exhibits unique nucleophilic properties that allow it to be selectively modified even in the presence of cysteine. The resulting benzylselenonium adduct is stable at physiological pH, is selectively labile to glutathione, and embodies a broadly tunable cleavage profile. Specifically, a 4-bromomethylphenylacetyl (BrMePAA) linker has been applied for efficient conjugation of complex organic molecules to SeM-containing proteins. This expansion of the bioconjugation toolkit has broad potential in the development of chemically enhanced proteins.


2020 ◽  
Author(s):  
Dillon T. Flood ◽  
Jordi C.J. Hintzen ◽  
Chenxi Lu ◽  
Philip A. Cistrone ◽  
Jason Chen ◽  
...  

<b>Site-selective chemical protein ligation reactions are enabling tools for chemical biology. Herein, we employ a physical organic study to refine the selenomethionine (SeM) benzylation as a practical protein bioconjugation strategy. SeM is readily introduced through auxotrophic expression and exhibits unique nucleophilic properties that allow it to be selectively modified even in the presence of cysteine. The resulting benzylselenonium adduct is stable at physiological pH, selectively labile to glutathione and embodies a broadly tuneable reactivity profile. Guided by a mechanistic analysis of the reaction, a 4-bromomethylphenylacetyl linker is identified for efficient conjugations of complex organic molecules to SeM containing proteins. This optimized benzyl linker exhibits a rate constant of 3x10<sup>-1</sup> M<sup>-1</sup>s<sup>-1</sup>, facilitating efficient conjugation at micromolar concentrations. The selenonium conjugate is further advanced through a linker that can be selectively photo-locked or reductively cleaved on demand. This tool-kit of selenonium forming reagents have broad potential in the development of chemically enhanced proteins.</b>


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qing-Yuan Meng ◽  
Lena Lezius ◽  
Armido Studer

AbstractMethods that enable site selective acylation of sp3 C-H bonds in complex organic molecules are not well explored, particularly if compared with analogous transformations of aromatic and vinylic sp2 C-H bonds. We report herein a direct acylation of benzylic C-H bonds by merging N-heterocyclic carbene (NHC) and photoredox catalysis. The method allows the preparation of a diverse range of benzylic ketones with good functional group tolerance under mild conditions. The reaction can be used to install acyl groups on highly functionalized natural product derived compounds and the C-H functionalization works with excellent site selectivity. The combination of NHC and photoredox catalysis offers options in preparing benzyl aryl ketones.


2020 ◽  
Author(s):  
Dillon T. Flood ◽  
Jordi C.J. Hintzen ◽  
Chenxi Lu ◽  
Philip A. Cistrone ◽  
Jason Chen ◽  
...  

<b>Site-selective chemical protein ligation reactions are enabling tools for chemical biology. Herein, we employ a physical organic study to refine the selenomethionine (SeM) benzylation as a practical protein bioconjugation strategy. SeM is readily introduced through auxotrophic expression and exhibits unique nucleophilic properties that allow it to be selectively modified even in the presence of cysteine. The resulting benzylselenonium adduct is stable at physiological pH, selectively labile to glutathione and embodies a broadly tuneable reactivity profile. Guided by a mechanistic analysis of the reaction, a 4-bromomethylphenylacetyl linker is identified for efficient conjugations of complex organic molecules to SeM containing proteins. This optimized benzyl linker exhibits a rate constant of 3x10<sup>-1</sup> M<sup>-1</sup>s<sup>-1</sup>, facilitating efficient conjugation at micromolar concentrations. The selenonium conjugate is further advanced through a linker that can be selectively photo-locked or reductively cleaved on demand. This tool-kit of selenonium forming reagents have broad potential in the development of chemically enhanced proteins.</b>


2020 ◽  
Author(s):  
Dillon T. Flood ◽  
Jordi C.J. Hintzen ◽  
Chenxi Lu ◽  
Philip A. Cistrone ◽  
Jason Chen ◽  
...  

<b>Site-selective chemical protein ligation reactions are enabling tools for chemical biology. Herein, we employ a physical organic study to refine the selenomethionine (SeM) benzylation as a practical protein bioconjugation strategy. SeM is readily introduced through auxotrophic expression and exhibits unique nucleophilic properties that allow it to be selectively modified even in the presence of cysteine. The resulting benzylselenonium adduct is stable at physiological pH, selectively labile to glutathione and embodies a broadly tuneable reactivity profile. Guided by a mechanistic analysis of the reaction, a 4-bromomethylphenylacetyl linker is identified for efficient conjugations of complex organic molecules to SeM containing proteins. This optimized benzyl linker exhibits a rate constant of 3x10<sup>-1</sup> M<sup>-1</sup>s<sup>-1</sup>, facilitating efficient conjugation at micromolar concentrations. The selenonium conjugate is further advanced through a linker that can be selectively photo-locked or reductively cleaved on demand. This tool-kit of selenonium forming reagents have broad potential in the development of chemically enhanced proteins.</b>


2020 ◽  
Author(s):  
Sukdev Bag ◽  
Sadhan Jana ◽  
Sukumar Pradhan ◽  
Suman Bhowmick ◽  
Nupur Goswami ◽  
...  

<p>Despite the widespread applications of C–H functionalization, controlling site selectivity remains a significant challenge. Covalently attached directing group (DG) served as an ancillary ligand to ensure proximal <i>ortho</i>-, distal <i>meta</i>- and <i>para</i>-C-H functionalization over the last two decades. These covalently linked DGs necessitate two extra steps for a single C–H functionalization: introduction of DG prior to C–H activation and removal of DG post-functionalization. We introduce here a transient directing group for distal C(<i>sp<sup>2</sup></i>)-H functionalization <i>via</i> reversible imine formation. By overruling facile proximal C-H bond activation by imine-<i>N</i> atom, a suitably designed pyrimidine-based transient directing group (TDG) successfully delivered selective distal C-C bond formation. Application of this transient directing group strategy for streamlining the synthesis of complex organic molecules without any necessary pre-functionalization at the distal position has been explored.</p>


Organics ◽  
2021 ◽  
Vol 2 (2) ◽  
pp. 107-117
Author(s):  
Mattia Forchetta ◽  
Valeria Conte ◽  
Giulia Fiorani ◽  
Pierluca Galloni ◽  
Federica Sabuzi

Owing to the attractiveness of organic phosphonic acids and esters in the pharmacological field and in the functionalization of conductive metal-oxides, the research of effective synthetic protocols is pivotal. Among the others, ω-bromoalkylphosphonates are gaining particular attention because they are useful building blocks for the tailored functionalization of complex organic molecules. Hence, in this work, the optimization of Michaelis–Arbuzov reaction conditions for ω-bromoalkylphosphonates has been performed, to improve process sustainability while maintaining good yields. Synthesized ω-bromoalkylphosphonates have been successfully adopted for the synthesis of new KuQuinone phosphonate esters and, by hydrolysis, phosphonic acid KuQuinone derivatives have been obtained for the first time. Considering the high affinity with metal-oxides, KuQuinones bearing phosphonic acid terminal groups are promising candidates for biomedical and photo(electro)chemical applications.


2021 ◽  
Vol 9 (1) ◽  
pp. 163
Author(s):  
Jeanine Rismondo ◽  
Lisa Maria Schulz

ATP-binding cassette (ABC) transporters are usually involved in the translocation of their cognate substrates, which is driven by ATP hydrolysis. Typically, these transporters are required for the import or export of a wide range of substrates such as sugars, ions and complex organic molecules. ABC exporters can also be involved in the export of toxic compounds such as antibiotics. However, recent studies revealed alternative detoxification mechanisms of ABC transporters. For instance, the ABC transporter BceAB of Bacillus subtilis seems to confer resistance to bacitracin via target protection. In addition, several transporters with functions other than substrate export or import have been identified in the past. Here, we provide an overview of recent findings on ABC transporters of the Gram-positive organisms B. subtilis and Listeria monocytogenes with transport or regulatory functions affecting antibiotic resistance, cell wall biosynthesis, cell division and sporulation.


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