Hydrogen Atom Transfer-Driven Enantioselective Minisci Reaction of Amides.

Minisci-type reactions constitute one of the most powerful methods for building up complexity around basic heteroarenes. The most desirable variants involve formal oxidative coupling of a C-H bond on each partner, leading back to the simplest possible starting materials. We herein disclose a method that enables such a coupling of linear amides and heteroarenes with full control of enantioselectivity at the newly formed stereocenter as well as site selectivity on both the heteroarene and the amide. This is achieved by the use of a chiral phosphoric acid catalyst in conjunction with diacetyl as a combined hydrogen atom transfer reagent and oxidant. Diacetyl is directly photoexcitable, and thus, no extraneous photocatalyst is required: an added feature that contributes to the simplicity and practicality of the protocol.EPSRC, GlaxoSmithKline, ER

A Computational and Experimental Investigation of the Origin of Selectivity in the Chiral Phosphoric Acid Catalyzed Enantioselective Minisci Reaction.

The Minisci reaction is one of the most valuable methods for directly functionalizing basic heteroarenes to form carbon-carbon bonds. Use of prochiral, heteroatom-substituted radicals results in stereocenters being formed adjacent to the heteroaromatic system, generating motifs which are valuable in medicinal chemistry and chiral ligand design. Recently a highly enantioselective and regioselective protocol for the Minisci reaction was developed, using chiral phosphoric acid catalysis. However, the precise mechanism by which this process operated and the origin of selectivity remained unclear, making it challenging to develop the reaction more generally. Herein we report further experimental mechanistic studies which feed into detailed DFT calculations that probe the precise nature of the stereochemistry-determining step. Computational and experimental evidence together support Curtin-Hammett control in this reaction, with initial radical addition being quick and reversible, and enantioselectivity being achieved in the subsequent slower, irreversible deprotonation. A detailed survey via DFT calculations assessed a number of different possibilities for selectivity-determining deprotonation of the radical cation intermediate. Computations point to a clear preference for an initially unexpected mode of internal deprotonation enacted by the amide group, which is a crucial structural feature of the radical precursor, with the assistance of the associated chiral phosphate. This unconventional stereodetermining step underpins the high enantioselectivities and regioselectivities observed. The mechanistic model was further validated by applying it to a test set of substrates possessing varied structural features.EPSRC GSSK ERC Leverhulme Trust Isaac Newton Trus

Benzylation Reactions in DMF Lead to an Impurity Which Acts as an Organocatalyst Poison in Thiourea-Catalyzed Glycosylations

The benzylation of alcohols with the commonly used combination of benzyl bromide and sodium hydride in DMF can lead to the formation of an amine side product, N,N′-dimethyl-1-phenyl-1-(o-tolyl)methanamine. This amine coeluted with benzylated galactal during column chromatography and was found to be a catalyst poison in thiourea-catalyzed glycosylations of galactals. It may also be problematic for other base-sensitive reactions involving benzylated substrates. Solutions to this problem are described.Irish Research CouncilScience Foundation IrelandMarie-Curie Action COFUN

Benzylation Reactions in DMF Lead to an Impurity Which Acts as an Organocatalyst Poison in Thiourea-Catalyzed Glycosylations

The benzylation of alcohols with the commonly used combination of benzyl bromide and sodium hydride in DMF can lead to the formation of an amine side product, N,N′-dimethyl-1-phenyl-1-(o-tolyl)methanamine. This amine coeluted with benzylated galactal during column chromatography and was found to be a catalyst poison in thiourea-catalyzed glycosylations of galactals. It may also be problematic for other base-sensitive reactions involving benzylated substrates. Solutions to this problem are described.Irish Research CouncilScience Foundation IrelandMarie-Curie Action COFUN

Benzylation Reactions in DMF Lead to an Impurity Which Acts as an Organocatalyst Poison in Thiourea-Catalyzed Glycosylations

The benzylation of alcohols with the commonly used combination of benzyl bromide and sodium hydride in DMF can lead to the formation of an amine side product, <i>N</i>,<i>N</i>′-dimethyl-1-phenyl-1-(<i>o</i>-tolyl)­methanamine. This amine coeluted with benzylated galactal during column chromatography and was found to be a catalyst poison in thiourea-catalyzed glycosylations of galactals. It may also be problematic for other base-sensitive reactions involving benzylated substrates. Solutions to this problem are described

DFT calculation Data From the Computational and Experimental Investigation of the Origin of Selectivity in the Chiral Phosphoric Acid-Catalyzed Enantioselective Minisci Reaction

This dataset contains Gaussian DFT output files of the key ground-states and transition state DFT optimized structures. The data is organised in one archive containing 95 separate folders. The hierarchical folder structure follows the convention of ‘substrate’/’mechanistic step’/ ’intermediate or TS stereochemistry’/’activation mode (if applicable)’. The substrate, mechanistic step and activation mode naming conventions follow that in the associated paper. Thus, ‘Subst3_QuinValine\II-III_TS\ RS\INT_sol’ folder contains the computational data of the substrate 3 R,S-INT deprotonation solvent transition states. Each of these lower level folders contain at least the output of a frequency calculation at B3LYP/6-31g** level with or without SMD(1,4-dioxane) solvent model (*_freq.out files), as well as at least one single point calculation at a higher level, usually at M06-2X/def2-TZVP/SMD(1,4-dioxane) or M06-2X/def2-TZVPD/ SMD(1,4-dioxane) level (*_sp.out files). All optimized geometries are also provided as *.sdf files for even better usability. All of the files can be opened in any text editor. Gaussian output structures can be viewed and the frequency modes visualised in GausView, Avogadro, jmol and in most other molecular viewers/editors. *.sdf files can be viewed in essentially all 3D molecular editors and viewers.We are grateful to the EPSRC and GlaxoSmithKline for PhD studentships (to R.S.J.P. and B.W.H.), the Royal Society for a University Research Fellowship (to R.J.P.), the Leverhulme Trust (RPG-2018-081) and the European Research Council (Starting Grant 757381, NonCovRegioSiteCat). We also thank Leverhulme Trust (ECF-2017-255) and Isaac Newton Trust (17.08(d)) for Early Career Fellowship (to K.E.). The computational work has been performed using resources provided by the Cambridge Tier-2 system operated by the University of Cambridge Research Computing Service (http://www.hpc.cam.ac.uk) funded by EPSRC Tier-2 capital grant EP/P020259/1

Hydrogen Atom Transfer Driven Enantioselective Minisci Reaction of Alcohols

Abstract: Catalytic enantioselective Minisci reactions have recently been developed but all instances so far utilize α‐amino radical coupling partners. We report a substantial evolution of the enantioselective Minisci reaction that enables α‐hydroxy radicals to be used, providing valuable enantioenriched secondary alcohol products. This is achieved through the direct oxidative coupling of two C−H bonds on simple alcohol and pyridine partners through a hydrogen atom transfer (HAT)‐driven approach: a challenging process to achieve due to the numerous side reactions that can occur. Our approach is highly regioselective as well as highly enantioselective. Dicumyl peroxide, upon irradiation with 390 nm light, serves as both HAT reagent and oxidant whilst selectivity is controlled by use of a chiral phosphoric acid catalyst. Computational and experimental evidence provide mechanistic insight as to the origin of selectivity, revealing a stereodetermining deprotonation step distinct from the analogous reaction of amide‐containing substrates