Discovery and Development of the Enantioselective Minisci Reaction.

ConspectusThe class of reactions now known as Minisci reactions is broadly defined as the addition of nucleophilic carbon-based radicals to basic heteroarenes with subsequent rearomatization to form a new carbon-carbon bond. Since the pioneering work of Minisci in the 1960s and 1970s, these reactions are now widely used in medicinal chemistry due to the ubiquity of basic heterocycles in druglike molecules. One of the long-standing challenges of Minisci chemistry has been that of regioselectivity due to the mixtures of positional isomers commonly obtained on many substrates if there is a choice between similarly activated sites. At the outset of the work described herein, we hypothesized that it may be possible to tackle this using a catalytic strategy whereby a bifunctional Brønsted acid catalyst simultaneously activates the heteroarene and engages attractive non-covalent interactions with the incoming nucleophile, resulting in a proximal attack. Using chiral BINOL-derived phosphoric acids, we not only were able to achieve this goal of regiocontrol but also discovered that we could control the absolute stereochemistry at the new stereocenter formed when prochiral α-amino radicals were employed. At the time, this discovery was unprecedented in the context of Minisci reactions.This Account details the discovery of this protocol and the further development, expansion, and investigations into the mechanism that we have carried out since then, several in collaboration with other research groups. Collaborative efforts have involved an expansion of the scope to diazines guided by multivariate statistical analysis through the development of a predictive model (collaboration with Sigman). Also, a mechanistic study involving detailed DFT analysis (collaboration with Goodman and Ermanis) unveiled the selectivity-determining step as being the deprotonation of a key cationic radical intermediate by the associated chiral phosphate anion. We have additionally carried out a number of synthetic developments of the protocol such as removing the need to prefunctionalize the radical nucleophile; hydrogen-atom transfer can be used to enable a formal coupling of two C-H bonds to form a C-C bond while retaining high enantio- and regioselectivity. Most recently, we have been able to expand the protocol so that α-hydroxy radicals can be used: until this point, all examples had concerned α-amino radicals. Again, HAT was used to generate the α-hydroxy radicals, and DFT studies carried out in collaboration (Ermanis) provided mechanistic insights.Since our original report, there have appeared a number of exciting developments from other research groups whereby the protocol has been applied to new substrates or using different precursors to generate the requisite α-amino radical. There have also been several examples in which alternative photocatalyst systems have been used to reduce the redox-active esters in the original enantioselective Minisci protocol. While primarily an Account, these contributions from other research groups will be covered briefly for context toward the end of the article.

Enantioselective Giese Additions of Prochiral α-Amino Radicals.

Amines featuring an adjacent stereocenter are important building blocks, and recent years have seen remarkable growth in methods forming these via prochiral α-amino radical intermediates. However, very few can exert control over the newly formed stereocenter. We disclose a strategy to overcome this in the context of one of the most widely used radical carbon-carbon bond forming reactions, the Giese reaction. Incorporation of a removable basic heteroarene into the substrate enables a network of attractive noncovalent interactions between a phosphoric acid catalyst, the subsequently formed α-amino radical, and the Giese acceptor, allowing the catalyst to exert control during the C-C bond forming step. Deprotection of the products leads to analogues of γ-aminobutyric acid. We anticipate that this strategy will be applicable to other asymmetric radical transformations in which catalyst control is presently challenging.

Hydrogen Atom Transfer Driven Enantioselective Minisci Reaction of Alcohols.

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.

Enantioselective remote C-H activation directed by a chiral cation.

Chiral cations have been used extensively as organocatalysts, but their application to rendering transition metal-catalyzed processes enantioselective remains rare. This is despite the success of the analogous charge-inverted strategy in which cationic metal complexes are paired with chiral anions. We report here a strategy to render a common bipyridine ligand anionic and pair its iridium complexes with a chiral cation derived from quinine. We have applied these ion-paired complexes to long-range asymmetric induction in the desymmetrization of the geminal diaryl motif, located on a carbon or phosphorus center, by enantioselective C-H borylation. In principle, numerous common classes of ligand could likewise be amenable to this approach.

Hydrogen-Bond-Enabled Dynamic Kinetic Resolution of Axially Chiral Amides Mediated by a Chiral Counterion.

Non-biaryl atropisomers are valuable in medicine, materials, and catalysis, but their enantioselective synthesis remains a challenge. Herein, a counterion-mediated O-alkylation method for the generation of atropisomeric amides with an er up to 99:1 is outlined. This dynamic kinetic resolution is enabled by the observation that the rate of racemization of atropisomeric naphthamides is significantly increased by the presence of an intramolecular O-H⋅⋅⋅NCO hydrogen bond. Upon O-alkylation of the H-bond donor, the barrier to rotation is significantly increased. Quantum calculations demonstrate that the intramolecular H-bond reduces the rotational barrier about the aryl-amide bond, stabilizing the planar transition state for racemization by approximately 40 kJ mol-1 , thereby facilitating the observed dynamic kinetic resolution.