Exploiting non-covalent π interactions for catalyst design

Neel, Andrew J.; Hilton, Margaret J.; Sigman, Matthew S.; Toste, F. Dean

doi:10.1038/nature21701

Cited by 675 publications

(475 citation statements)

References 106 publications

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“…First invoked in 1995 for the stabilization of Z-DNA, [7] it is now widely recognised as anew supramolecular bond. [14] An unprecedented intramolecular lp-p interaction between an oxygen atom of an imide group and the quinone motif in ferrocenyl QMs is reported herein.Themolecules 10-21 (Figure 1cand Table 1), in which the basic ferrocifen skeleton bears asuccinimido,glutarimido,or phthalimido substituent at the terminus of at hree-, four-, or five-membered carbon alkyl chain, and at least one of the aryl groups is aphenol, were prepared in moderate to high yields by aMcMurry coupling followed by displacement of chloride by the appropriate imide under basic conditions.T he ferrocidiphenols 4, 12,a nd 14,a nd also the ferrocimonophenols 16, 18,a nd 20,w ere initially investigated by ac ombination of 1 Ha nd 13 C2 DN MR techniques (see the Supporting Information, Figures S1-S6). [10] Thes trength and nature of lp-p interactions have been elucidated in only af ew studies, [11] mostly on simplified binding systems of two small molecules, [12] or in rigid structures.…”

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confidence: 84%

Atypical Lone Pair–π Interaction with Quinone Methides in a Series of Imido‐Ferrociphenol Anticancer Drug Candidates

et al. 2019

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Ferrociphenols,especially those possessing aheterocycle at the terminus of an aliphatic chain, displays trong anticancer activity through an ovel redox mechanismt hat generates active metabolites such as quinone methides (QMs). X-ray crystallography and UV/Vis spectroscopyreveal that the specific lone pair (lp)-p interaction between acarbonyl group of the imide and the quinone motif of the QM plays an important role in the exceptional cytotoxic behaviour of their imido-ferrociphenol precursors.T his intramolecular lp-p interaction markedly enhanced the stability of the QMs and lowered the pK a values of the corresponding phenol/phenolate couples.Asthe first example of such anon-covalent interaction that stabilizes QMs remotely,itn ot only expands the scope of the lp-p interaction in supramolecular chemistry,b ut also represents an ew mode of stabilization of aQ M. This unprecedented application of lp-p interactions in imidoferrociphenol anticancer drug candidates maya lso have great potential in drug discovery and organocatalyst design.With the goal of circumventing the drawbacks [1] associated with the widely used coordination complexes of Pt 2+ , transition-metal bioorganometallic chemistry has gradually come to the fore. [2] Antitumor agents based on iron, an abundant and inexpensive metal, occupy ap rivileged position, and mostly feature ferrocene,acompact, stable,n ontoxic metallocene showing reversible redox properties. [3] We have investigated the possible use of ferrocenes in oncology in the so-called ferrocifen family (Figure 1a), such as compounds 1 and 2,w hose IC 50 values against triple-negative breast cancer (TNBC) cell lines (MDA-MB-231) are 0.6 and 0.5 mm,r espectively.T hese singular entities possess ar edox motif of the ferrocenyl-ene-phenol type,g iving rise to reactive oxygen species (ROS) in cancer cells.T he initial reversible oxidation of the ferrocenyl antenna permits electronic delocalization, leading selectively to electrophilic quinone methides (QMs,see below), which induce senescence and/or apoptosis,d epending on the particular parameters. [3a] Functionalization of the alkyl chain of 1 by attaching aterminal hydroxy substituent [4] or aheterocyclic group, [5] as in 3 or 4,resulted in extremely low IC 50 values (0.035 mm)on TNBC MDA-MB-231 cells;m oreover,f or the epithelial ovarian cancer cell line A2780 and the cisplatin-resistant species A2780cisR, the IC 50 values were 0.035 and 0.049 mm, respectively.T he first metabolite obtained either in the chemical (Ag + )o re nzymatic oxidation of 1 in cancer cells is the quinone methide 1-QM (Figure 1a), which can react in a1 ,8-Michael addition with selective nucleophiles in the cancer cells. [6] Them echanism of action of 4 may follow asimilar pathway to that of 1.Thelone pair-p (lp-p)interaction, depicted schematically in Figure 1b,r efers to the stabilizing association between al one pair of electrons and the face of a p system. First invoked in 1995 for the stabilization of Z-DNA, [7] it is now widely recognised as anew supramolecul...

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confidence: 84%

Atypical Lone Pair–π Interaction with Quinone Methides in a Series of Imido‐Ferrociphenol Anticancer Drug Candidates

et al. 2019

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“…2–5 Additionally, the through-space non-covalent interactions between the ligand and the substrate also play a key role in influencing the reactivity of a catalyst. 6–11 Classical transition state models usually describe these through-space interactions as steric repulsion. 12–16 London dispersion, an essential type of van der Waals forces arising from the attraction between instantaneous dipoles, also contributes to the ligand-substrate interactions.…”

Section: Introductionmentioning

confidence: 99%

Ligand–Substrate Dispersion Facilitates the Copper-Catalyzed Hydroamination of Unactivated Olefins

et al. 2017

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Current understanding of ligand effects in transition metal catalysis is mostly based on the analysis of catalyst-substrate through-bond and through-space interactions, with the latter commonly considered to be repulsive in nature. The dispersion interaction between the ligand and the substrate, a ubiquitous type of attractive non-covalent interaction, is seldom accounted for in the context of transition metal-catalyzed transformations. Herein we report a computational model to quantitatively analyze the effects of different types of catalyst-substrate interactions on reactivity. Using this model, we show that in the copper(I) hydride (CuH)-catalyzed hydroamination of unactivated olefins, the substantially enhanced reactivity of copper catalysts based on bulky bidentate phosphine ligands originates from the attractive ligand-substrate dispersion interaction. These computational findings are validated by kinetic studies across a range of hydroamination reactions using structurally diverse phosphine ligands, revealing the critical role of bulky P-aryl groups in facilitating this process.

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“…16 Asymmetric induction is typically achieved from the resultant ion pair as a consequence of specific attractive non-covalent interactions between the corresponding cationic intermediate and the chiral HBD catalyst. 17,18,19 Reported examples have been limited to heteroatom-stabilized cations, due to the challenges in generating the requisite ion pair and suppressing elimination/rearrangement pathways. The ability of HBD catalysts to control enantioselective nucleophile addition into non-heteroatom stabilized carbocations has to our knowledge not been demonstrated.…”

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Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction

Wendlandt

Vangal

Jacobsen

2018

Nature

191

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The unimolecular nucleophilic substitution (SN1) mechanism figures prominently in every introductory organic chemistry course. In principle, stepwise displacement of a leaving group by a nucleophile via a carbocationic intermediate allows for the construction of highly congested carbon centers. However, the intrinsic instability and high reactivity of the carbocationic intermediates render it very difficult to control product distributions and stereoselectivity in reactions proceeding via SN1 pathways. Here we report asymmetric catalysis of an SN1-type reaction mechanism resulting in the enantioselective construction of quaternary stereocenters from racemic precursors. The new transformation relies on the synergistic action of a chiral hydrogen bond donor (HBD) catalyst with a strong Lewis acid promoter to mediate the formation of tertiary carbocationic intermediates at low temperature and achieve high levels of control over reaction enantioselectivity and product distribution. The work presented here provides a foundation for the enantioconvergent synthesis of other fully-substituted carbon stereocenters.

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Exploiting non-covalent π interactions for catalyst design

Cited by 675 publications

References 106 publications

Atypical Lone Pair–π Interaction with Quinone Methides in a Series of Imido‐Ferrociphenol Anticancer Drug Candidates

Atypical Lone Pair–π Interaction with Quinone Methides in a Series of Imido‐Ferrociphenol Anticancer Drug Candidates

Ligand–Substrate Dispersion Facilitates the Copper-Catalyzed Hydroamination of Unactivated Olefins

Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction

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