The enantioselective, organocatalytic aziridination of small, medium and macro‐cyclic enals is reported using (S)‐2‐(fluorodiphenyl methyl)‐pyrrolidine. Central to the reaction design is the ...reversible formation of a β‐fluoroiminium ion intermediate, which is pre‐organised on account of the fluorine‐iminium ion gauche effect. This conformational effect positions the fluorine substituent synclinal‐endo to the electropositive nitrogen centre thus benefiting from favourable stereoelectronic and electrostatic interactions (σC−H→σC−F*; Fδ−…︁N+). Consequently, one of the shielding groups on the fluorine‐bearing carbon atom is positioned above the π‐system, forming the basis of an enantioinduction strategy. Treatment of this intermediate with a “nitrene” source furnished a series of novel, optically active aziridines (e.r. up to 99.5:0.5). Further derivatisation of the product aziridines gives facile access to various amino acid derivatives, including β‐fluoroamino acids. Crystallographic analyses of both the aziridines and their derivatives are disclosed.
The enantioselective, organocatalytic aziridination of small, medium and large cyclic enals is reported using (S)‐2‐(fluorodiphenylmethyl)pyrrolidine. Central to the reaction design is the reversible formation of the β‐fluoroiminium ion intermediate, which is pre‐organised on account of the fluorine‐iminium ion gauche effect (see figure). Treatment of this intermediate with a nitrene source furnished a series of novel, optically active aziridines (up to e.r. 99.5:0.5).
The fluorine‐iminium ion gauche effect is triggered upon union of a secondary β‐fluoroamine and an α,β‐unsaturated aldehyde, providing a useful strategy for controlling the molecular topology of ...intermediates that are central to organocatalytic processes. The β‐fluoroamine (S)‐2‐(fluorodiphenylmethyl)pyrrolidine (1) is an effective catalyst for the enantioselective epoxidation of α,β‐unsaturated aldehydes. A process of structural editing has revealed that the efficiency of this catalyst is due to the (fluorodiphenyl)methyl group when it is embedded in a β‐fluoroiminium motif. Epoxidations of challenging cyclic α,β‐disubstituted, β,β‐disubstituted and α,β,β‐trisubstituted enals catalysed by 1 proceed with excellent levels of enantiocontrol (up to 98 % ee).
Fluorine finesse! The β‐fluoroamine (S)‐2‐(fluorodiphenylmethyl)pyrrolidine (1) is an effective catalyst for the enantioselective epoxidation of α,β‐unsaturated aldehydes (see scheme). Application of this catalyst to challenging cyclic α,β‐disubstituted enals, β,β‐disubstituted enals, and an α,β,β‐trisubstituted enal proceeds in a highly enantioselective fashion (up to 98 % ee).
The C9 position of cinchona alkaloids functions as a molecular hinge, with internal rotations around the C8C9 (τ1) and C9C4′ (τ2) bonds giving rise to four low energy conformers (1; anti‐closed, ...anti‐open, syn‐closed, and syn‐open). By substituting the C9 carbinol centre by a configurationally defined fluorine substituent, a fluorine‐ammonium ion gauche effect (σC−H→σC−F*; Fδ−⋅⋅⋅N+) encodes for two out of the four possible conformers (2). This constitutes a partial solution to the long‐standing problem of governing internal rotations in cinchonium‐based catalysts relying solely on a fluorine conformational effect.
Fixed with fluorine! The C9 position of cinchona alkaloids functions as a molecular hinge, with internal rotations around the C8C9 (τ1) and C9C4′ (τ2) bonds giving rise to four low‐energy conformers. By substituting the C9 carbinol centre by a configurationally defined fluorine, a fluorine‐ammonium gauche effect encodes for two out of the four possible conformers. This constitutes a partial solution to the long‐standing problem of governing internal rotations in cinchonium‐based catalysts.
Accurate ranking of compounds with regards to their binding affinity to a protein using computational methods is of great interest to pharmaceutical research. Physics-based free energy calculations ...are regarded as the most rigorous way to estimate binding affinity. In recent years, many retrospective studies carried out both in academia and industry have demonstrated its potential. Here, we present the results of large-scale prospective application of the FEP+ method in active drug discovery projects in an industry setting at Merck KGaA, Darmstadt, Germany. We compare these prospective data to results obtained on a new diverse, public benchmark of eight pharmaceutically relevant targets. Our results offer insights into the challenges faced when using free energy calculations in real-life drug discovery projects and identify limitations that could be tackled by future method development. The new public data set we provide to the community can support further method development and comparative benchmarking of free energy calculations.
Acyclic conformational control often relies on destabilising noncovalent interactions to give rise to predictable conformer populations. Pertinent examples of such strategies include allylic strain ...(A1,2 and A1,3) and syn‐pentane interactions. However, the incorporation of fluorine vicinal to an electron‐withdrawing group (F–Cβ–Cα–X) can lead to predictable conformations as a consequence of stabilising hyperconjugative and/or electrostatic interactions. Herein, we describe the application of a fluorine gauche effect to predictably control torsional rotation in a class of fluorinated 4‐(dimethylamino)pyridine (DMAP) analogues. Intramolecularisation, such as protonation or acylation, generates an electropositive nitrogen centre vicinal to the fluorine atom at a molecular hinge (F–Cβ–Cα–N+); this is the only rotatable sp3–sp3 bond. In so doing, this “substrate binding” triggers a conformational change akin to the induced fit process inherent to enzymatic systems. Herein, we validate this design approach to control molecular space. A number of X‐ray structures are documented that display this gauche preference (φNCCF ≈ 60°). Preliminary catalysis experiments are disclosed together with a kinetic and reactivity analysis.
The fluorine gauche effect was used to control torsional rotation in fluorinated dimethylamino pyridine (DMAP) analogues. Upon “substrate binding” an electropositive nitrogen centre vicinal to the fluorine atom at a molecular hinge (F–Cβ–Cα–N+) triggers a conformational change akin to those induced in enzymatic systems. Catalysis experiments and kinetic and reactivity studies are disclosed.
We report the first total synthesis of the proposed structure of ardimerin, which was achieved in 14 steps starting from 2,3,4‐trimethoxybenzoic acid. The key steps include the β‐selective formation ...of the crucial C‐glycoside linkage and stepwise construction of the strained eight‐membered salicylide core. The synthesis revealed that the proposed structure 1 does not match the natural product. A proposal is made for reassigning the isolated natural product to the already known structure of bergenin. Interesting properties of the synthetic eight‐membered salicylides are documented, including their susceptibility toward nucleophilic ring opening and the bowl chirality.
A novel one-pot procedure for the stereoselective synthesis of α-hydroxy esters from ortho esters was developed. Key steps were multi-heteroatom Cope rearrangements of O-acylated ...N-hydroxy-l-tert-leucinol-derived oxazoline N-oxides leading to α-acyloxy oxazolines and, after methanolysis, to the target molecules in 67−80% yield and 94−98% ee.
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Hematopoietic progenitor kinase 1 (HPK1) is regarded as a highly validated target in pre-clinical immune oncology. HPK1 has been described as regulating multiple critical signaling ...pathway in both adaptive and innate cells. In support of this role, HPK1 KO T cells show enhanced sensitivity to TCR activation and HPK1 KO mice display enhanced anti-tumor activity. Taken together, inhibition of HPK1 has the potential to induce enhanced anti-tumor immune response. Herein, we described the discovery of highly potent HPK1 inhibitors starting form a weak HTS hit. Using a structure-based drug design, HPK1 inhibitors exhibiting excellent cellular single-digit nanomolar potency in both proximal (pSLP76) and distal (IL-2) biomarkers along with sustained elevation of IL-2 cytokine secretion were discovered.
Fluorinated groups are essential for drug design, agro-che-micals, and materials science. The bis(trifluoro-methyl)--amino group is an example for a stable group that has a high potential. While the ...number of molecules containing per-fluoro-alkyl, perfluoro-alkoxy, and other fluorinated groups is steadily increasing, exampl-es with the N(CF3)2 group are rare. One reason is that transfer reagents are scarce and metal-based storable reagents are unknown. Here, we present a set of CuI and AgI bis(trifluoromethyl)amido complexes stabilized by N- and P-donor ligands with un-pre-ce--dented stability. The complexes are stable solids that can even be manipulated in air for a short time. They are bis(trifluoro-methyl)amination reagents as shown by nucleo-philic substitution and Sandmeyer reactions. In addition to a series of benzylbis(trifluoromethyl)amines, 2-bis(trifluoro-methyl)--amino acetate was obtained that upon hydrolysis gives the fluorinated amino acid N,N-bis(trifluoromethyl)glycine.
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