The regio- and stereoselective addition of C(1)-ammonium enolates – generated in situ from aryl esters and the isothiourea catalyst (R)-BTM – to pyridinium salts bearing an electron withdrawing substituent in...
A thermomorphic ionic-liquid-based
microemulsion system was successfully
applied for the Ru-catalyzed asymmetric transfer hydrogenation of
ketones. On the basis of the temperature-dependent multiphase behavior
of the targeted microemulsion, simple product separation as well as
catalyst recycling could be realized. The use of water-soluble ligands
improved the immobilization of the catalyst in the microemulsion phase
and significantly decreased the catalyst leaching into the organic
layer upon extraction of the product. Eventually, the optimized microemulsion
system could be applied to a wide range of aromatic ketones that were
reduced with good isolated yields (up to 98%) and enantioselectivities
(up to 97%), while aliphatic ketones were less successful.
We
report the design and synthesis of novel ion-tagged chiral ligands
for asymmetric transfer hydrogenation (ATH) in aqueous medium. Based
on (R,R)-1,2-diphenylethylene diamine
(DPEN) as structural motif, a straightforward three-step protocol
was developed that gave access to novel chiral ligands with carbamate-substructure
and pyridinium headgroup. The careful optimization of steric and electronic
properties in combination with the adaption of solubility via choice
of the anion gave a set of chiral and water-soluble ligands for use
in ruthenium-catalyzed asymmetric transfer hydrogenations in aqueous
medium. Eventually, a pool of aliphatic and aromatic ketones as well
as two imine substrates were reduced with excellent isolated yields
up to 95% and enantioselectivities >90% ee under environmentally
benign
conditions in the absence of additional surfactants.
α,β-Unsaturated acyl ammonium species are versatile intermediates that have been applied in a variety of transformations including Michael additions, domino reactions and cycloadditions.
A protocol for the enantioselective synthesis of substituted vinylcyclopentanes has been realised using cooperative palladium and isothiourea catalysis. Treatment of vinylcyclopropanes with Pd(PPh 3 ) 4 generates a zwitterionic π-allyl palladium intermediate that intercepts a catalytically generated α,β-unsaturated acyl ammonium species prepared from the corresponding α,β-unsaturated para-nitrophenyl ester and the isothiourea (R)-BTM. Intermolecular formal (3+2) cycloaddition between these reactive intermediates generates functionalised cyclopentanes in generally good yields and excellent diastereo-and enantiocontrol (up to > 95 : 5 dr, 97 : 3 er), with the use of LiCl as an additive proving essential for optimal stereocontrol. To the best of our knowledge a dual transition metal/organocatalytic process involving α,β-unsaturated acyl ammonium intermediates has not been demonstrated previously.
The scope and limitations of a tandem N-allylation/[2,3]-rearrangement protocol are investigated through the incorporation of a variety of functional groups within an allylic phosphate precursor. This method uses readily accessible N,N-dimethylglycine aryl esters and functionalized allylic phosphates, forming quaternary ammonium salts in situ in the presence of a palladium catalyst. Subsequent enantioselective [2,3]-sigmatropic rearrangement, promoted by the chiral isothiourea tetramisole, generates α-amino acid derivatives with two contiguous stereocenters. The incorporation of electron-withdrawing ester and amide groups gave the best results, furnishing the desired products in moderate to good yields (29–70%), with low diastereocontrol (typically 60:40 dr) but high enantioselectivity (up to 90:10 er). These results indicate that substrate–catalyst interactions in the proposed transition state are sensitive to the substitution pattern of the substrates.
In this study, a one-pot synthesis via photoinduced C(sp2)–C(sp3) coupling followed by amide formation to access proteolysis targeting chimeras (PROTACs) was developed. The described protocol was studied on cereblon (CRBN)-based E3-ligase binders and (+)-JQ-1, a bromodomain inhibitor, to generate BET (bromodomain and extra terminal domain) targeting protein degraders. The generated PROTACs were profiled in-vitro and tested for their degradation ability with several potent candidates identified. Upfront, the individual reactions of the one-pot transformation were carefully optimized for CRBN binder functionalization and multiple heterobifunctional linker moieties were designed and synthesized. Separate scopes detailing the C(sp2)–C(sp3) coupling and one-pot PROTAC synthesis are described in this report as well as a library minituarization study showing the high-throughput compatibility. Overall, the developed protocol provides rapid access to PROTACs in a single process thereby allowing efficient generation of CRBN-based PROTAC libraries.
A protocol for the enantioselective synthesis of substituted vinylcyclopentanes has been realised using cooperative palladium and isothiourea catalysis. Treatment of vinylcyclopropanes with Pd(PPh3)4 generates a zwitterionic π‐allyl palladium intermediate that intercepts a catalytically generated α,β‐unsaturated acyl ammonium species prepared from the corresponding α,β‐unsaturated para‐nitrophenyl ester and the isothiourea (R)‐BTM. Intermolecular formal (3+2) cycloaddition between these reactive intermediates generates functionalised cyclopentanes in generally good yields and excellent diastereo‐ and enantiocontrol (up to >95 : 5 dr, 97 : 3 er), with the use of LiCl as an additive proving essential for optimal stereocontrol. To the best of our knowledge a dual transition metal/organocatalytic process involving α,β‐unsaturated acyl ammonium intermediates has not been demonstrated previously.
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