Cooperative Palladium/Isothiourea Catalyzed Enantioselective Formal (3+2) Cycloaddition of Vinylcyclopropanes and α,ß-Unsaturated Esters.

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,ß-unsaturated acyl ammonium species prepared from the corresponding α,ß-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,ß-unsaturated acyl ammonium intermediates has not been demonstrated previously.

α,ß-Unsaturated acyl ammonium species as reactive intermediates in organocatalysis: an update.

α,ß-Unsaturated acyl ammonium species are versatile intermediates that have been applied in a variety of transformations including Michael additions, domino reactions and cycloadditions. Many of these transformations are promoted by chiral Lewis base catalysts, enabling the rapid generation of molecular complexity with high stereochemical control. This review highlights recent developments in the generation and application of α,ß-unsaturated acyl ammonium intermediates reported since a previous review of this area in 2016. Particular emphasis will be placed on reports providing mechanistic insight into catalytic transformations and observed selectivities. A perspective on current challenges and potential future developments in the field of α,ß-unsaturated acyl ammonium catalysis is also provided.

Exploring the Scope of Tandem Palladium and Isothiourea Relay Catalysis for the Synthesis of α-Amino Acid Derivatives.

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.

Synthesis of Indazoles via N-N Bond-Forming Oxidative Cyclization from 2-Aminomethyl-phenylamines.

Herein we report a method for the synthesis of indazoles from readily available 2-aminomethyl-phenylamines via N-N bond-forming oxidative cyclization. Inspired by indazole formation initially observed as a side product by N. Coskun et al. we developed a robust protocol to access indazoles in all three tautomeric forms. The method selectively gives access to various 2-substituted 2H-indazoles which are frequently used in drug design, and we also demonstrated its applicability to less studied 3H-indazoles.

Enantioselective isothiourea-catalysed reversible Michael addition of aryl esters to 2-benzylidene malononitriles.

Catalytic enantioselective transformations usually rely upon optimal enantioselectivity being observed in kinetically controlled reaction processes, with energy differences between diastereoisomeric transition state energies translating to stereoisomeric product ratios. Herein, stereoselectivity resulting from an unusual reversible Michael addition of an aryl ester to 2-benzylidene malononitrile electrophiles using an isothiourea as a Lewis base catalyst is demonstrated. Notably, the basicity of the aryloxide component and reactivity of the isothiourea Lewis base both affect the observed product selectivity, with control studies and crossover experiments indicating the feasibility of a constructive reversible Michael addition from the desired product. When this reversible addition is coupled with a crystallisation-induced diastereomer transformation (CIDT) it allows isolation of products in high yield and stereocontrol (14 examples, up to 95 : 5 dr and 99 : 1 er). Application of this process to gram scale, plus derivatisations to provide further useful products, is demonstrated.

One-Pot Synthesis of Cereblon Proteolysis Targeting Chimeras via Photoinduced C(sp2)-C(sp3) Cross Coupling and Amide Formation for Proteolysis Targeting Chimera Library Synthesis.

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 miniaturization 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.

Catalytic enantioselective synthesis of 1,4-dihydropyridines via the addition of C(1)-ammonium enolates to pyridinium salts.

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 the 3-position allows the synthesis of a range of enantioenriched 1,4-dihydropyridines. This represents the first organocatalytic approach to pyridine dearomatisation using pronucleophiles at the carboxylic acid oxidation level. Optimisation studies revealed a significant solvent dependency upon product enantioselectivity, with only toluene providing significant asymmetric induction. Using DABCO as a base also proved beneficial for product enantioselectivity, while investigations into the nature of the counterion showed that co-ordinating bromide or chloride substrates led to higher product er than the corresponding tetrafluoroborate or hexafluorophosphate. The scope and limitations of this process are developed, with enantioselective addition to 3-cyano- or 3-sulfonylpyridinium salts giving the corresponding 1,4-dihydropyridines (15 examples, up to 95 : 5 dr and 98 : 2 er).