scholarly journals Bio-Inspired Primary Amine α-C–H Functionalization

2018 ◽  
Author(s):  
Dhananjayan Vasu ◽  
Ángel L. Fuentes de Arriba ◽  
Jamie A. Leitch ◽  
Antoine de Gombert ◽  
Darren J. Dixon
Keyword(s):  
Drug Discovery ◽  
Late Stage ◽  
Primary Amine ◽  
Amine Oxidase ◽  
Primary Amines ◽  
Reverse Polarity ◽  
Copper Amine Oxidase ◽  
Drug Molecules ◽  
Organolithium Reagents

<div>The selective manipulation of complex amine architectures has received great attention in recent years with widespread applications including inter alia drug discovery. Inspired by an enzymatic copper amine oxidase process, a synthetic quinone co-factor mediated general platform for the construction of α-fully substituted primary amines from abundant α-branched primary amine starting materials is described. This procedure pivots on the efficient generation of reactive ketimine intermediates in situ which are primed to react with carbon-centered nucleophiles such as organomagnesium and organolithium reagents, and TMSCN. Extension to reverse polarity photoredox catalysis enables reactivity with electrophiles. Subsequent oxidative hydrolysis releases the unprotected α-fully substituted primary amine product. This efficient, broadly applicable and scaleable amine-to-amine synthetic platform was successfully applied to library and API synthesis and in the late stage functionalization of drug molecules.</div>

Bio-Inspired Primary Amine α-C–H Functionalization

2018 ◽  
Author(s):  
Dhananjayan Vasu ◽  
Ángel L. Fuentes de Arriba ◽  
Jamie A. Leitch ◽  
Darren J. Dixon
Keyword(s):  
Drug Discovery ◽  
Late Stage ◽  
Primary Amine ◽  
Amine Oxidase ◽  
Primary Amines ◽  
Reverse Polarity ◽  
Copper Amine Oxidase ◽  
Drug Molecules ◽  
Organolithium Reagents

<div>The selective manipulation of complex amine architectures has received great attention in recent years with widespread applications including inter alia drug discovery. Inspired by an enzymatic copper amine oxidase process, a synthetic quinone co-factor mediated general platform for the construction of α-fully substituted primary amines from abundant α-branched primary amine starting materials is described. This procedure pivots on the efficient generation of reactive ketimine intermediates in situ which are primed to react with carbon-centered nucleophiles such as organomagnesium and organolithium reagents, and TMSCN. Extension to reverse polarity photoredox catalysis enables reactivity with electrophiles. Subsequent oxidative hydrolysis releases the unprotected α-fully substituted primary amine product. This efficient, broadly applicable and scaleable amine-to-amine synthetic platform was successfully applied to library and API synthesis and in the late stage functionalization of drug molecules.</div>

Bio-Inspired Primary Amine α-C–H Functionalization

2018 ◽  
Author(s):  
Dhananjayan Vasu ◽  
Ángel L. Fuentes de Arriba ◽  
Jamie A. Leitch ◽  
Darren J. Dixon
Keyword(s):  
Drug Discovery ◽  
Late Stage ◽  
Primary Amine ◽  
Amine Oxidase ◽  
Primary Amines ◽  
Reverse Polarity ◽  
Copper Amine Oxidase ◽  
Drug Molecules ◽  
Organolithium Reagents

<div>The selective manipulation of complex amine architectures has received great attention in recent years with widespread applications including inter alia drug discovery. Inspired by an enzymatic copper amine oxidase process, a synthetic quinone co-factor mediated general platform for the construction of α-fully substituted primary amines from abundant α-branched primary amine starting materials is described. This procedure pivots on the efficient generation of reactive ketimine intermediates in situ which are primed to react with carbon-centered nucleophiles such as organomagnesium and organolithium reagents, and TMSCN. Extension to reverse polarity photoredox catalysis enables reactivity with electrophiles. Subsequent oxidative hydrolysis releases the unprotected α-fully substituted primary amine product. This efficient, broadly applicable and scaleable amine-to-amine synthetic platform was successfully applied to library and API synthesis and in the late stage functionalization of drug molecules.</div>

scholarly journals Primary α-Tertiary Amine Synthesis via α-C–H Functionalization

2018 ◽  
Author(s):  
Dhananjayan Vasu ◽  
Ángel L. Fuentes de Arriba ◽  
Jamie Leitch ◽  
Antoine de Gombert ◽  
Darren J. Dixon
Keyword(s):  
Tertiary Amine ◽  
Late Stage ◽  
Tertiary Amines ◽  
Reverse Polarity ◽  
Subsequent Reaction ◽  
Quaternary Centers ◽  
Drug Molecules ◽  
Organolithium Reagents ◽  
In Situ Generation

<i>A quinone-mediated general platform for the construction of primary α-tertiary amines from abundant primary α-branched amine starting materials is described. This procedure pivots on the efficient in situ generation of reactive ketimine intermediates and subsequent reaction with carbon-centered nucleophiles such as organomagnesium and organolithium reagents, and TMSCN, creating quaternary centers. Furthermore, extension to reverse polarity photoredox catalysis enables reactivity with electrophiles. This efficient, broadly applicable and scalable amine-to-amine synthetic platform was successfully applied to library and API synthesis and in the late stage functionalization of drug molecules. </i><br>

scholarly journals Primary α-Tertiary Amine Synthesis via α-C–H Functionalization

2018 ◽  
Author(s):  
Dhananjayan Vasu ◽  
Ángel L. Fuentes de Arriba ◽  
Jamie Leitch ◽  
Antoine de Gombert ◽  
Darren J. Dixon
Keyword(s):  
Tertiary Amine ◽  
Late Stage ◽  
Tertiary Amines ◽  
Reverse Polarity ◽  
Subsequent Reaction ◽  
Quaternary Centers ◽  
Drug Molecules ◽  
Organolithium Reagents ◽  
In Situ Generation

<i>A quinone-mediated general platform for the construction of primary α-tertiary amines from abundant primary α-branched amine starting materials is described. This procedure pivots on the efficient in situ generation of reactive ketimine intermediates and subsequent reaction with carbon-centered nucleophiles such as organomagnesium and organolithium reagents, and TMSCN, creating quaternary centers. Furthermore, extension to reverse polarity photoredox catalysis enables reactivity with electrophiles. This efficient, broadly applicable and scalable amine-to-amine synthetic platform was successfully applied to library and API synthesis and in the late stage functionalization of drug molecules. </i><br>

The Total Synthesis of Rhabdastrellic Acid A

2018 ◽  
Author(s):  
Yaroslav Boyko ◽  
Christopher Huck ◽  
David Sarlah
Keyword(s):  
Total Synthesis ◽  
Late Stage ◽  
Cross Coupling ◽  
Side Chains ◽  
General Strategy ◽  
Modular Approach ◽  
Linear Sequence ◽  
Generating Sequence ◽  
First Time

<div>The first total synthesis of rhabdastrellic acid A, a highly cytotoxic isomalabaricane triterpenoid, has been accomplished in a linear sequence of 14 steps from commercial geranylacetone. The prominently strained <i>trans-syn-trans</i>-perhydrobenz[<i>e</i>]indene core characteristic of the isomalabaricanes is efficiently accessed in a selective manner for the first time through a rapid, complexity-generating sequence incorporating a reductive radical polyene cyclization, an unprecedented oxidative Rautenstrauch cycloisomerization, and umpolung 𝛼-substitution of a <i>p</i>-toluenesulfonylhydrazone with in situ reductive transposition. A late-stage cross-coupling in concert with a modular approach to polyunsaturated side chains renders this a general strategy for the synthesis of numerous family members of these synthetically challenging and hitherto inaccessible marine triterpenoids.</div>

Reductive Cleavage of Secondary Sulfonamides: Converting Terminal Functional Groups into Versatile Synthetic Handles

2019 ◽  
Author(s):  
Patrick Fier ◽  
Suhong Kim ◽  
Kevin M. Maloney
Keyword(s):  
Functional Groups ◽  
Late Stage ◽  
Reductive Cleavage ◽  
Bioactive Molecules ◽  
General Method

Sulfonamides are pervasive in drugs and agrochemicals, yet are typically considered as terminal functional groups rather than synthetic handles. To enable the general late-stage functionalization of secondary sulfonamides, we have developed a mild and general method to reductively cleave the N-S bonds of sulfonamides to generate sulfinates and amines, components which can further react <i>in-situ</i> to access a variety of other medicinally relevant functional groups. The utility of this platform is highlighted by the selective manipulation of several complex bioactive molecules.

scholarly journals DEER and RIDME Measurements of the Nitroxide-Spin Labelled Copper-Bound Amine Oxidase Homodimer from Arthrobacter Globiformis

2021 ◽  
Author(s):  
Hannah Russell ◽  
Rachel Stewart ◽  
Christopher Prior ◽  
Vasily S. Oganesyan ◽  
Thembaninkosi G. Gaule ◽  
...  
Keyword(s):  
Dipolar Coupling ◽  
Amine Oxidase ◽  
Spin Labels ◽  
Arthrobacter Globiformis ◽  
Copper Amine Oxidase ◽  
Dipole Interactions ◽  
Nitroxide Spin Labels ◽  
Double Electron Electron Resonance ◽  
Dipolar Modulation ◽  
Paramagnetic Centres

AbstractIn the study of biological structures, pulse dipolar spectroscopy (PDS) is used to elucidate spin–spin distances at nanometre-scale by measuring dipole–dipole interactions between paramagnetic centres. The PDS methods of Double Electron Electron Resonance (DEER) and Relaxation Induced Dipolar Modulation Enhancement (RIDME) are employed, and their results compared, for the measurement of the dipolar coupling between nitroxide spin labels and copper-II (Cu(II)) paramagnetic centres within the copper amine oxidase from Arthrobacter globiformis (AGAO). The distance distribution results obtained indicate that two distinct distances can be measured, with the longer of these at c.a. 5 nm. Conditions for optimising the RIDME experiment such that it may outperform DEER for these long distances are discussed. Modelling methods are used to show that the distances obtained after data analysis are consistent with the structure of AGAO.

Late-stage C–H functionalization offers new opportunities in drug discovery

2021 ◽  
Author(s):  
Lucas Guillemard ◽  
Nikolaos Kaplaneris ◽  
Lutz Ackermann ◽  
Magnus J. Johansson
Keyword(s):  
Drug Discovery ◽  
Late Stage

scholarly journals Metal-Free Air Oxidation in a Convenient Cascade Approach for the Access to Isoquinoline-1,3,4(2H)-triones

Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2177
Author(s):  
Antonia Di Mola ◽  
Consiglia Tedesco ◽  
Antonio Massa
Keyword(s):  
Heterocyclic Compounds ◽  
Aromatic Ketone ◽  
Primary Amines ◽  
Cascade Process ◽  
Staudinger Reaction ◽  
Caspase Inhibitor ◽  
Air Oxidation ◽  
Metal Free ◽  
Free Air

Herein we describe a very useful application of the readily available trifunctional aromatic ketone methyl-2-(2-bromoacetyl)benzoate in reactions with primary amines. An unexpected in situ air oxidation that follows a cascade process allowed the access to a series of isoquinoline-1,3,4(2H)-triones, a class of heterocyclic compounds of great interest containing an oxygen-rich heterocyclic scaffold. A modification of the original protocol, utilizing a Staudinger reaction in the presence of trimethylphosphine, was necessary for the synthesis of Caspase inhibitor trione with free NH group.

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