The advent of modern C–H functionalization chemistries has enabled medicinal chemists to consider a synthetic strategy, late stage functionalization (LSF), which utilizes the C–H bonds of drug leads as points of diversification for generating new analogs. LSF approaches offer the promise of rapid exploration of structure activity relationships (SAR), the generation of oxidized metabolites, the blocking of metabolic hot spots and the preparation of biological probes. This review details a toolbox of intermolecular C–H functionalization chemistries with proven applicability to drug-like molecules, classified by regioselectivity patterns, and gives guidance on how to systematically develop LSF strategies using these patterns and other considerations. In addition, a number of examples illustrate how LSF approaches have been used to impact actual drug discovery and chemical biology efforts.

The medicinal chemist's toolbox for late stage functionalization of drug-like molecules

Metal-ligand cooperation (MLC) has become an important concept in catalysis by transition metal complexes both in synthetic and biological systems. MLC implies that both the metal and the ligand are directly involved in bond activation processes, by contrast to "classical" transition metal catalysis where the ligand (e.g. phosphine) acts as a spectator, while all key transformations occur at the metal center. In this Review, we will discuss examples of MLC in which 1) both the metal and the ligand are chemically modified during bond activation and 2) bond activation results in immediate changes in the 1st coordination sphere involving the cooperating ligand, even if the reactive center at the ligand is not directly bound to the metal (e.g. via tautomerization). The role of MLC in enabling effective catalysis as well as in catalyst deactivation reactions will be discussed.

Metal–Ligand Cooperation

Although known for over 90 years, only in the past two decades has the chemistry of diboron(4) compounds been extensively explored. Many interesting structural features and reaction patterns have emerged, and more importantly, these compounds now feature prominently in both metal-catalyzed and metal-free methodologies for the formation of B–C bonds and other processes.

Diboron(4) Compounds: From Structural Curiosity to Synthetic Workhorse

https://pubs.rsc.org/en/Content/ArticlePDF/2017/CC/C7CC01254C

Stereospecific functionalizations and transformations of secondary and tertiary boronic esters

Easy access: An unprecedented copper-catalyzed cross-coupling reaction of the title compounds with diboron reagents is described (see scheme; Ts = 4-toluenesulfonyl). This reaction can be used to prepare both primary and secondary alkylboronic esters having diverse structures and functional groups. The resulting products would be difficult to access by other means.

Alkylboronic Esters from Copper-Catalyzed Borylation of Primary and Secondary Alkyl Halides and Pseudohalides

Enantioselective Conjugate Borylation

The B-H bond of typical boranes is heterolytically split by the polar Ru-S bond of a tethered ruthenium(II) thiolate complex, affording a ruthenium(II) hydride and borenium ions with a dative interaction with the sulfur atom. These stable adducts were spectroscopically characterized, and in one case, the B-H bond activation step was crystallographically verified, a snapshot of the σ-bond metathesis. The borenium ions derived from 9-borabicyclo[3.3.1]nonane dimer [(9-BBN)2], pinacolborane (pinBH), and catecholborane (catBH) allowed for electrophilic aromatic substitution of indoles. The unprecedented electrophilic borylation with the pinB cation was further elaborated for various nitrogen heterocycles.

Catalytic generation of borenium ions by cooperative B-H bond activation: the elusive direct electrophilic borylation of nitrogen heterocycles with pinacolborane.

The pronounced Lewis acidity of tricoordinate silicon cations brings about unusual reactivity in Lewis acid catalysis. The downside of catalysis with strong Lewis acids is, though, that these do have the potential to mediate the formation of protons by various mechanisms, and the thus released Bronsted acid might even outcompete the Lewis acid as the true catalyst. That is an often ignored point. One way of eliminating a hidden proton-catalyzed pathway is to add a proton scavenger. The low-temperature Diels–Alder reactions catalyzed by our ferrocene-stabilized silicon cation are such a case where the possibility of proton catalysis must be meticulously examined. Addition of the common hindered base 2,6-di-tert-butylpyridine resulted, however, in slow decomposition along with formation of the corresponding pyridinium ion. Quantitative deprotonation of the silicon cation was observed with more basic (Mes)3P to yield the phosphonium ion. A deuterium-labeling experiment verified that the proton is abstracted ...

Silylium ion-catalyzed challenging Diels-Alder reactions: the danger of hidden proton catalysis with strong Lewis acids.

The purpose of this systemat- ic experimental and theoretical study is to deeply understand the unique bond- ing situation in ferrocene-stabilized si- lylium ions as a function of the sub- stituents at the silicon atom and to learn about the structure parameters that determine the 29 Si NMR chemical shift and electrophilicity of these strong Lewis acids. For this, ten new members of the family of ferrocene- stabilized silicon cations were prepared by a hydride abstraction reaction from silanes with the trityl cation and char- acterized by multinuclear 1 H and 29 Si NMR spectroscopy. A closer look at the NMR spectra revealed that addi- tional minor sets of signals were not impurities but silylium ions with substi- tution patterns different from that of the initially formed cation. Careful as- signment of these signals furnished ex- perimental proof that sterically less hindered silylium ions are capable of exchanging substituents with unreacted silane precursors. Density functional theory calculations provided mechanis- tic insight into that substituent transfer in which the migrating group is ex- changed between two silicon fragments in a concerted process involving a ferro- cene-bridged intermediate. Moreover, the quantum-chemical analysis of the 29 Si NMR chemical shifts revealed a linear relationship between dA 29 Si) values and the Fe···Si distance for sub- sets of silicon cations. An electron lo- calization function and electron localiz- ability indicator analysis shows a three- center two-electron bonding attractor between the iron, silicon, and C'ipso atoms, clearly distinguishing the silicon cations from the corresponding carbe- nium ions and boranes. Correlations between 29 Si NMR chemical shifts and Lewis acidity, evaluated in terms of fluoride ion affinities, are seen only for subsets of silylium ions, sometimes with non-intuitive trends, indicating a com- plicated interplay of steric and elec- tronic effects on the degree of the Fe···Si interaction.

The family of ferrocene-stabilized silylium ions: synthesis, 29Si NMR characterization, Lewis acidity, substituent scrambling, and quantum-chemical analyses.

Trivalent silicon cations are exceptionally strong electron pair acceptors that react, either desired or undesired, with almost any σ and π basic molecule. One way of intramolecular attenuation of the Lewis acidity of these superelectrophiles is by installation of a ferrocene unit at the electron-deficient silicon atom. While well-understood for isoelectronic α-ferrocenyl-substituted carbenium ions and also boranes, the stabilizing interactions between the ferrocene backbone and a positively charged silicon atom are not clear due to the challenge of crystallizing such cations. The structural characterization of our ferrocene-stabilized silicon cation now reveals an unprecedented bonding motif different from its analogues. An extreme dip angle of the silicon atom toward the iron atom is explained by two three-center-two-electron (3c2e) bonds through participation of both the upper and the lower aromatic rings of the ferrocene sandwich structure. The positive charge is still localized at the silicon atom th...

Kristine Müther

Papers

Enantioselective Conjugate Borylation

Catalytic generation of borenium ions by cooperative B-H bond activation: the elusive direct electrophilic borylation of nitrogen heterocycles with pinacolborane.

Silylium ion-catalyzed challenging Diels-Alder reactions: the danger of hidden proton catalysis with strong Lewis acids.

The family of ferrocene-stabilized silylium ions: synthesis, 29Si NMR characterization, Lewis acidity, substituent scrambling, and quantum-chemical analyses.

A Unique Transition Metal-Stabilized Silicon Cation