Mechanistic insights into a heterobifunctional degrader-induced PTPN2/N1 complex.

PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4CRBN, and mediate potent PTPN2/N1 degradation in cells and mice. To provide mechanistic insights into the cooperative complex formation introduced by degraders, we employed a combination of structural approaches. Our crystal structure reveals how PTPN2 is recognized by the tri-substituted thiophene moiety of the degrader. We further determined a high-resolution structure of DDB1-CRBN/Cmpd-1/PTPN2 using single-particle cryo-electron microscopy (cryo-EM). This structure reveals that the degrader induces proximity between CRBN and PTPN2, albeit the large conformational heterogeneity of this ternary complex. The molecular dynamic (MD)-simulations constructed based on the cryo-EM structure exhibited a large rigid body movement of PTPN2 and illustrated the dynamic interactions between PTPN2 and CRBN. Together, our study demonstrates the development of PTPN2/N1 heterobifunctional degraders with potential applications in cancer immunotherapy. Furthermore, the developed structural workflow could help to understand the dynamic nature of degrader-induced cooperative ternary complexes.

Rhodium(II)-catalyzed nondirected oxidative alkenylation of arenes: arene loading at one equivalent.

A bimetallic Rh(II) catalyst promoted the C-H alkenylation of simple arenes at 1.0 equivalent without the use of a directing group. A phosphine ligand as well as cooperative reoxidation of Rh(II) with Cu(TFA)2 and V2O5 proved essential in providing monoalkenylated products in good yields and selectivities, especially with di- and trisubstituted arenes.

Pd(II)-catalyzed enantioselective C-H activation/C-O bond formation: synthesis of chiral benzofuranones.

Pd(II)-catalyzed enantioselective C-H activation of phenylacetic acids followed by an intramolecular C-O bond formation afforded chiral benzofuranones. This reaction provides the first example of enantioselecctive C-H functionalizations through Pd(II)/Pd(IV) redox catalysis.

Asymmetric NHC-catalyzed synthesis of α-fluoroamides from readily accessible α-fluoroenals.

The scope of the NHC-redox amidation has been expanded to include a variety of α,ß-unsaturated aldehydes, including α-fluoro α,ß-unsaturated aldehydes which give rise to enantioenriched α-fluoroamides in good to excellent yield and enantioselectivity (up to 97% ee). Enantioenriched amines may be elaborated to either diastereomer of the product in high diastereoselectivity (up to 99:1). Functionalization of the amide products to amines and fluorohydrins is also demonstrated with retention of enantioenrichment at the fluorine stereocenter.

Exploiting Acyl and Enol Azolium Intermediates via NHeterocyclic Carbene Catalyzed Reactions of Alpha-Reducible Aldehydes.

N-heterocyclic carbenes are well known for their role in catalyzing benzoin and Stetter reactions: the generation of acyl anion equivalents from simple aldehydes to react with a variety of electrophiles. However, when an aldehyde bearing a leaving group or unsaturation adjacent to the acyl anion equivalent is subjected to an NHC, a new avenue of reactivity is unlocked, leading to a number of novel transformations which can generate highly complex products from simple starting materials, many of which are assembled through unconventional bond disconnections. The field of these new reactions - those utilizing α-reducible aldehydes to access previously unexplored catalytic intermediates - has expanded rapidly in the past eight years. This review aims to provide the reader with a historical perspective on the underlying discoveries that led to the current state of the art, a mechanistic description of these reactions, and a summary of the recent advances in this area.

N-Heterocyclic carbene catalyzed asymmetric hydration: direct synthesis of alpha-protio and alpha-deuterio alpha-chloro and alpha-fluoro carboxylic acids.

Asymmetric hydration of alpha,alpha-dichloro aldehydes and alpha-halo enals via a NHC-catalyzed redox process to yield enantioenriched alpha-chloro and alpha-fluoro carboxylic acids is described herein. The developed reaction allows for installation of an alpha-deuterium to give rise to enantioenriched alpha-deutero alpha-halo acids using D(2)O as the deuteron source.

Nucleophilic carbene catalyzed synthesis of 1,2 amino alcohols via azidation of epoxy aldehydes.

We report herein a nucleophilic carbene catalyzed redox azidation of epoxyaldehydes. The intermediate beta-hydroxy acyl azides undergo thermal Curtius rearrangement followed by trapping with excess azide to form carbamoyl azides or, in a complementary sequence, by the hydroxy group to form oxazolidinones. Both products are formed in modest to good yields and diastereoselectivities. The use of an enantioenriched triazolium catalyst leads to modest asymmetric induction.