Nitrene transfer catalysts for enantioselective C–N bond formation

Author(s):  
Minsoo Ju ◽  
Jennifer M. Schomaker
2017 ◽  
Vol 139 (6) ◽  
pp. 2216-2223 ◽  
Author(s):  
Lourdes Maestre ◽  
Ruth Dorel ◽  
Óscar Pablo ◽  
Imma Escofet ◽  
W. M. C. Sameera ◽  
...  

2019 ◽  
Author(s):  
Nicolaas P. van Leest ◽  
Martijn A. Tepaske ◽  
Jarl Ivar van der Vlugt ◽  
Bas de Bruin

The oxidation state of the redox non-innocent TAML (Tetra-Amido Macrocyclic Ligand) scaffold was recently shown to affect the formation of nitrene radical species on cobalt(III) upon reaction with PhI=NNs [J. Am. Chem. Soc. 2020, DOI: 10.1021/jacs.9b11715]. For the neutral [Co<sup>III</sup>(TAMLsq)] complex this leads to the doublet (S = ½) mono-nitrene radical species [Co<sup>III</sup>(TAMLq)(N<sup>•</sup>Ns)], while a triplet (S = 1) bis-nitrene radical species [Co<sup>III</sup>(TAML<sup>q</sup>)(N<sup>•</sup>Ns)<sub>2</sub>]<sup>‒</sup> is generated from the anionic [Co<sup>III</sup>(TAML<sup>red</sup>)]<sup>‒</sup> complex. The one-electron reduced Fischer-type nitrene radicals (N<sup>•</sup>Ns<sup>‒</sup>) are formed through single (mono-nitrene) or double (bis-nitrene) ligand-to-substrate single-electron transfer (SET). In this work we describe the reactivity and mechanisms of these nitrene radical complexes in catalytic aziridination. We report that [Co<sup>III</sup>(TAML<sup>sq</sup>)] and [Co<sup>III</sup>(TAML<sup>red</sup>)]<sup>‒</sup> are both effective catalysts for chemoselective (C=C versus C‒H bonds) and diastereoselective aziridination of styrene derivatives, cyclohexene and 1-hexene under mild and even aerobic (for [Co<sup>III</sup>(TAML<sup>red</sup>)]<sup>‒</sup>) conditions. Experimental (Hammett plots, radical inhibition, catalyst decomposition tests) and computational (DFT, CASSCF) studies reveal that [Co<sup>III</sup>(TAML<sup>q</sup>)(N<sup>•</sup>Ns)], [Co<sup>III</sup>(TAML<sup>q</sup>)(N<sup>•</sup>Ns)<sub>2</sub>]<sup>‒</sup> and [Co<sup>III</sup>(TAML<sup>sq</sup>)(N<sup>•</sup>Ns)]<sup>–</sup> are key electrophilic intermediates in the aziridination reactions. Surprisingly, the electrophilic one-electron reduced Fischer-type nitrene radicals do not react as would be expected for nitrene radicals (i.e. via radical addition and radical rebound). Instead, nitrene transfer proceeds through unusual electronically asynchronous transition states, in which (partial) styrene substrate to TAML ligand (single) electron transfer precedes C-N coupling. The actual C-N bond formation processes are best described as involving a nucleophilic attack of the nitrene (radical) lone pair at the thus (partially) formed styrene radical cation. These processes are coupled to TAML-to-cobalt and cobalt-to-nitrene single-electron transfer, effectively leading to formation of an amido-[gamma]-benzyl radical (Ns–N–CH<sub>2</sub>–<sup>•</sup>CH–Ph) bound to an intermediate spin (S = 1) cobalt(III) center. Hence, the TAML moiety can be regarded to act as a transient electron acceptor, the cobalt center behaves as a spin shuttle and the nitrene radical acts as a nucleophile. Such a mechanism for (cobalt catalyzed) nitrene transfer was hitherto unknown and complements the known concerted and stepwise mechanisms for N-group transfer.


2020 ◽  
Author(s):  
N.P. van Leest ◽  
J.I. van der Vlugt ◽  
Bas de Bruin

The cobalt species <b>PPh<sub>4</sub>[Co<sup>III</sup>(TAML<sup>red</sup>)]</b> is a competent and stable catalyst for the sulfimidation of (aryl)(alkyl)-substituted sulfides with iminoiodinanes reaching turnover numbers up to 900 and turnover frequencies of 640 min<sup>-1</sup> under mild and aerobic conditions. The sulfimidation proceeds in a highly chemoselective manner, even in the presence of alkenes or weak C-H bonds, as supported by inter- and intramolecular competition experiments. Functionalization of the sulfide substituent with various electron-donating and electron-withdrawing arenes and several alkyl, benzyl and vinyl fragments is tolerated, with up to quantitative product yields. Sulfimidation of phenyl allyl sulfide led to [2,3]-sigmatropic rearrangement of the initially formed sulfimide species to afford the corresponding <i>N</i>-allyl-<i>S</i>-phenyl-thiohydroxylamines as attractive products. Mechanistic studies suggest that the actual nitrene transfer to the sulfide proceeds via (previously characterized) electrophilic nitrene-radical intermediates that afford the sulfimide products via electronically asynchronous transition states, in which SET from the sulfide to the nitrene-radical complex precedes N-S bond formation in a single concerted process. <br>


2021 ◽  
Author(s):  
Todd Hyster ◽  
Yuxuan Ye ◽  
Jingzhe Cao ◽  
Daniel Oblinsky ◽  
Deeptak Verma ◽  
...  

The construction of C–N bonds is essential for the preparation of numerous molecules critical to modern society1,2. Nature has evolved enzymes to facilitate these transformations using nucleophilic and nitrene transfer mechanisms3,4. However, neither natural nor engineered enzymes are known to generate and control nitrogen-centered radicals, which serve as valuable species for C–N bond formation. Herein, we describe a platform for generating nitrogen-centered radicals within protein active sites, thus enabling asymmetric hydroamination reactions. Using flavin- dependent ‘ene’-reductases with an exogenous photoredox catalyst, amidyl radicals are generated selectively within the protein active site. Empowered by directed evolution, these enzymes are engineered to catalyze 5-exo, 6-endo, 7-endo, 8-endo, and intermolecular hydroamination reactions with high levels of enantioselectivity. Mechanistic studies suggest that radical initiation occurs via an enzyme-gated mechanism, where the protein thermodynamically activates the substrate for reduction by the photocatalyst. Molecular dynamics studies suggest that the enzymes bind substrates using non-canonical binding interactions, which may serve as a handle to further manipulate reactivity. This approach demonstrates the versatility of these enzymes for controlling the reactivity of high-energy radical intermediates and highlight the opportunity for synergistic catalyst strategies to unlock new enzymatic functions.


2019 ◽  
Author(s):  
Nicolaas P. van Leest ◽  
Martijn A. Tepaske ◽  
Jarl Ivar van der Vlugt ◽  
Bas de Bruin

The oxidation state of the redox non-innocent TAML (Tetra-Amido Macrocyclic Ligand) scaffold was recently shown to affect the formation of nitrene radical species on cobalt(III) upon reaction with PhI=NNs [J. Am. Chem. Soc. 2020, DOI: 10.1021/jacs.9b11715]. For the neutral [Co<sup>III</sup>(TAMLsq)] complex this leads to the doublet (S = ½) mono-nitrene radical species [Co<sup>III</sup>(TAMLq)(N<sup>•</sup>Ns)], while a triplet (S = 1) bis-nitrene radical species [Co<sup>III</sup>(TAML<sup>q</sup>)(N<sup>•</sup>Ns)<sub>2</sub>]<sup>‒</sup> is generated from the anionic [Co<sup>III</sup>(TAML<sup>red</sup>)]<sup>‒</sup> complex. The one-electron reduced Fischer-type nitrene radicals (N<sup>•</sup>Ns<sup>‒</sup>) are formed through single (mono-nitrene) or double (bis-nitrene) ligand-to-substrate single-electron transfer (SET). In this work we describe the reactivity and mechanisms of these nitrene radical complexes in catalytic aziridination. We report that [Co<sup>III</sup>(TAML<sup>sq</sup>)] and [Co<sup>III</sup>(TAML<sup>red</sup>)]<sup>‒</sup> are both effective catalysts for chemoselective (C=C versus C‒H bonds) and diastereoselective aziridination of styrene derivatives, cyclohexene and 1-hexene under mild and even aerobic (for [Co<sup>III</sup>(TAML<sup>red</sup>)]<sup>‒</sup>) conditions. Experimental (Hammett plots, radical inhibition, catalyst decomposition tests) and computational (DFT, CASSCF) studies reveal that [Co<sup>III</sup>(TAML<sup>q</sup>)(N<sup>•</sup>Ns)], [Co<sup>III</sup>(TAML<sup>q</sup>)(N<sup>•</sup>Ns)<sub>2</sub>]<sup>‒</sup> and [Co<sup>III</sup>(TAML<sup>sq</sup>)(N<sup>•</sup>Ns)]<sup>–</sup> are key electrophilic intermediates in the aziridination reactions. Surprisingly, the electrophilic one-electron reduced Fischer-type nitrene radicals do not react as would be expected for nitrene radicals (i.e. via radical addition and radical rebound). Instead, nitrene transfer proceeds through unusual electronically asynchronous transition states, in which (partial) styrene substrate to TAML ligand (single) electron transfer precedes C-N coupling. The actual C-N bond formation processes are best described as involving a nucleophilic attack of the nitrene (radical) lone pair at the thus (partially) formed styrene radical cation. These processes are coupled to TAML-to-cobalt and cobalt-to-nitrene single-electron transfer, effectively leading to formation of an amido-[gamma]-benzyl radical (Ns–N–CH<sub>2</sub>–<sup>•</sup>CH–Ph) bound to an intermediate spin (S = 1) cobalt(III) center. Hence, the TAML moiety can be regarded to act as a transient electron acceptor, the cobalt center behaves as a spin shuttle and the nitrene radical acts as a nucleophile. Such a mechanism for (cobalt catalyzed) nitrene transfer was hitherto unknown and complements the known concerted and stepwise mechanisms for N-group transfer.


2020 ◽  
Author(s):  
N.P. van Leest ◽  
J.I. van der Vlugt ◽  
Bas de Bruin

The cobalt species <b>PPh<sub>4</sub>[Co<sup>III</sup>(TAML<sup>red</sup>)]</b> is a competent and stable catalyst for the sulfimidation of (aryl)(alkyl)-substituted sulfides with iminoiodinanes reaching turnover numbers up to 900 and turnover frequencies of 640 min<sup>-1</sup> under mild and aerobic conditions. The sulfimidation proceeds in a highly chemoselective manner, even in the presence of alkenes or weak C-H bonds, as supported by inter- and intramolecular competition experiments. Functionalization of the sulfide substituent with various electron-donating and electron-withdrawing arenes and several alkyl, benzyl and vinyl fragments is tolerated, with up to quantitative product yields. Sulfimidation of phenyl allyl sulfide led to [2,3]-sigmatropic rearrangement of the initially formed sulfimide species to afford the corresponding <i>N</i>-allyl-<i>S</i>-phenyl-thiohydroxylamines as attractive products. Mechanistic studies suggest that the actual nitrene transfer to the sulfide proceeds via (previously characterized) electrophilic nitrene-radical intermediates that afford the sulfimide products via electronically asynchronous transition states, in which SET from the sulfide to the nitrene-radical complex precedes N-S bond formation in a single concerted process. <br>


2020 ◽  
Author(s):  
Rui Guo ◽  
Xiaotian Qi ◽  
Hengye Xiang ◽  
Paul Geaneoates ◽  
Ruihan Wang ◽  
...  

Vinyl fluorides play an important role in drug development as they serve as bioisosteres for peptide bonds and are found in a range of biologically active molecules. The discovery of safe, general and practical procedures to prepare vinyl fluorides remains an important goal and challenge for synthetic chemistry. Here we introduce an inexpensive and easily-handled reagent and report simple, scalable, and metal-free protocols for the regioselective and stereodivergent hydrofluorination of alkynes to access both the E and Z isomers of vinyl fluorides. These conditions were suitable for a diverse collection of alkynes, including several highly-functionalized pharmaceutical derivatives. Mechanistic and DFT studies support C–F bond formation through a vinyl cation intermediate, with the (E)- and (Z)-hydrofluorination products forming under kinetic and thermodynamic control, respectively.<br>


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>


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