Cyclometallated Imides as Templates for the H-Bond Directed Iridium-Catalyzed Asymmetric Hydrogenation of N-Methyl, N-Alkyl and N-Aryl Imines.

A combined computational and experimental approach allowed us to develop overall the most selective catalyst for the direct hydrogenation of N-methyl, N-alkyl and N-aryl imines described to date. Iridium catalysts with a cyclometallated cyclic imide group provide selectivity of up to 99 % enantiomeric excess. Computational studies show that the selectivity results from the combined effect of H-bonding of the imide C=O with the substrate iminium ion and a stabilizing π-π interaction with the cyclometallated ligand. The cyclometallated ligand thus exhibits a unique mode of action, serving as a template for the H-bond directed approach of the substrate which results in enhanced selectivity. The catalyst (2) has been synthesized and isolated as a crystalline air-stable solid. X-ray analysis of 2 confirmed the structure of the catalyst and the correct position of the imide C=O groups to engage in an H-bond with the substrate. 19F NMR real-time monitoring showed the hydrogenation of N-methyl imines catalyzed by 2 is very fast, with a TOF of approx. 3500 h-1.

Rational optimization of a transcription factor activation domain inhibitor.

Transcription factors are among the most attractive therapeutic targets but are considered largely 'undruggable' in part due to the intrinsically disordered nature of their activation domains. Here we show that the aromatic character of the activation domain of the androgen receptor, a therapeutic target for castration-resistant prostate cancer, is key for its activity as transcription factor, allowing it to translocate to the nucleus and partition into transcriptional condensates upon activation by androgens. On the basis of our understanding of the interactions stabilizing such condensates and of the structure that the domain adopts upon condensation, we optimized the structure of a small-molecule inhibitor previously identified by phenotypic screening. The optimized compounds had more affinity for their target, inhibited androgen-receptor-dependent transcriptional programs, and had an antitumorigenic effect in models of castration-resistant prostate cancer in cells and in vivo. These results suggest that it is possible to rationally optimize, and potentially even to design, small molecules that target the activation domains of oncogenic transcription factors.

Enantioselective Ir-Catalyzed Hydrogenation of Terminal Homoallyl Sulfones: Total Synthesis of (-)-Curcumene.

A novel methodology for the preparation of chiral methyl benzylic compounds is reported. Terminal homoallyl sulfones were prepared from homoallyl alcohols, which are easily accessible through the recently reported Lewis acid isomerization of oxetanes. The iridium-catalyzed asymmetric hydrogenation of homoallylic sulfones afforded γ-chiral sulfones with excellent enantioselectivities (up to 98% ee). The synthetic potential of this novel methodology was demonstrated by the total synthesis of (R)-(-)-curcumene.

P-Stereogenic Ir-MaxPHOX: A Step toward Privileged Catalysts for Asymmetric Hydrogenation of Nonchelating Olefins.

The Ir-MaxPHOX-type catalysts demonstrated high catalytic performance in the hydrogenation of a wide range of nonchelating olefins with different geometries, substitution patterns, and degrees of functionalization. These air-stable and readily available catalysts have been successfully applied in the asymmetric hydrogenation of di-, tri-, and tetrasubstituted olefins (ee's up to 99%). The combination of theoretical calculations and deuterium labeling experiments led to the uncovering of the factors responsible for the enantioselectivity observed in the reaction, allowing the rationalization of the most suitable substrates for these Ir-catalysts.

Synthesis and Biological Activity of a VHL-Based PROTAC Specific for p38α.

We report a series of small molecule proteolysis-targeting chimeras (PROTACs) that target the protein kinase p38α for degradation. These PROTACs are based on a ligand of the VHL E3 ubiquitin ligase, which is linked to an ATP competitive inhibitor of p38α. We provide evidence that these compounds can induce the specific degradation of p38α, but not p38ß and other related kinases, at nanomolar concentrations in several mammalian cell lines. We also show that the p38α-specific PROTACs are soluble in aqueous solutions and therefore suitable for their administration to mice. Systemic administration of the PROTACs induces p38α degradation only in the liver, probably due to the PROTAC becoming inactivated in that organ, but upon local administration the PROTACs induce p38α degradation in mammary tumors. Our compounds provide an alternative to traditional chemical inhibitors for targeting p38α signaling in cultured cells and in vivo.

Design and optimization of oestrogen receptor PROTACs based on 4-hydroxytamoxifen.

In the last four decades, treatment of oestrogen receptor positive (ER+) breast cancer (BCa), has focused on targeting the estrogenic receptor signaling pathway. This signaling function is pivotal to sustain cell proliferation. Tamoxifen, a competitive inhibitor of oestrogen, has played a major role in therapeutics. However, primary and acquired resistance to hormone blockade occurs in a large subset of these cancers, and new approaches are urgently needed. Aromatase inhibitors and receptor degraders were approved and alternatively used. Yet, resistance appears in the metastatic setting. Here we report the design and synthesis of a series of proteolysis targeting chimeras (PROTACs) that induce the degradation of estrogen receptor alpha in breast cancer MCF-7 (ER+) cells at nanomolar concentration. Using a warhead based on 4-hydroxytamoxifen, bifunctional degraders recruiting either cereblon or the Von Hippel Lindau E3 ligases were synthesized. Our efforts resulted in the discovery of TVHL-1, a potent ERα degrader (DC50: 4.5 nM) that we envisage as a useful tool for biological study and a platform for potential therapeutics.

Phosphorus through the looking glass.

A key building block enables a general synthesis of chiral phosphorus drugs.

Amino acids with fluorescent tetrazine ethers as bioorthogonal handles for peptide modification.

A set of 3-bromo-1,2,4,5-tetrazines with three distinct substitutions have been used as reagents for late-stage functionalization of small molecules through nucleophilic aromatic substitution. Spectroscopic studies of the products obtained proved that tetrazine ethers are intrinsically fluorescent. This fluorescence is lost upon inverse Electron-Demand Diels-Alder (iEDDA) cycloaddition with strained alkenes. Tetrazine-phenol ethers are rather interesting because they can undergo rapid iEDDA reactions with a second order rate constant (k 2) compatible with bioorthogonal ligations. As a showcase, l-tyrosine was derivatized with 3-bromo-6-methyl-1,2,4,5-tetrazine and coupled to the peptide drug octreotide. This peptide was detected in cellular flow cytometry, and its fluorescence turned off through a bioorthogonal iEDDA cycloaddition with a strained alkene, showing for the first time the detection and reactivity of intrinsically fluorescent tetrazines in a biologically relevant context. The synthesis and characterization of fluorescent tetrazine ethers with bioorthogonal applicability pave the way for the generation of useful compounds for both detection and bioconjugation in vivo.

Iridium-Catalyzed Asymmetric Hydrogenation of 2,3-Diarylallyl Amines with a Threonine-Derived P-Stereogenic Ligand for the Synthesis of Tetrahydroquinolines and Tetrahydroisoquinolines.

Chiral compounds containing nitrogen heteroatoms are fundamental substances for the chemical, pharmaceutical and agrochemical industries. However, the preparation of some of these interesting scaffolds is still underdeveloped. Herein we present the synthesis of a family of P-stereogenic phosphinooxazoline iridium catalysts from L-threonine methyl ester and their use in the asymmetric hydrogenation of N-Boc-2,3-diarylallyl amines, achieving very high enantioselectivity. Furthermore, the synthetic utility of the 2,3-diarylpropyl amines obtained is demonstrated by their transformation to 3-aryl-tetrahydroquinolines and 4-benzyl-tetrahydroisoquinolines, which have not yet been obtained in an enantioselective manner by direct reduction of the corresponding aromatic heterocycles. This strategy allows the preparation of these types of alkaloids with the highest enantioselectivity reported up to date.

Recent Advances in the Enantioselective Synthesis of Chiral Amines via Transition Metal-Catalyzed Asymmetric Hydrogenation.

Chiral amines are key structural motifs present in a wide variety of natural products, drugs, and other biologically active compounds. During the past decade, significant advances have been made with respect to the enantioselective synthesis of chiral amines, many of them based on catalytic asymmetric hydrogenation (AH). The present review covers the use of AH in the synthesis of chiral amines bearing a stereogenic center either in the α, ß, or γ position with respect to the nitrogen atom, reported from 2010 to 2020. Therefore, we provide an overview of the recent advances in the AH of imines, enamides, enamines, allyl amines, and N-heteroaromatic compounds.

BOM-Phosphinite as an Electrophilic P-Stereogenic Transfer Reagent for the Synthesis of Bulky Phosphines: Synthesis of tert-Butyl(3,5-di-tert-butylphenyl)BisP.

BOM-tert-butylmethylphosphinite borane is an efficient electrophilic P-stereogenic transfer reagent for the synthesis of bulky tertiary phosphines. The novel methodology relies on a one-pot deprotection/substitution on the trivalent phosphinite that takes place with very high stereospecificity. The potential of this strategy is demonstrated with the synthesis of a wide scope of tertiary phosphines in excellent enantiomeric excess. The methodology was applied to the synthesis of a bulky P-stereogenic BisP* ligand analogue.

Structure-based design of a Cortistatin analogue with immunomodulatory activity in models of inflammatory bowel disease.

Ulcerative colitis and Crohn's disease are forms of inflammatory bowel disease whose incidence and prevalence are increasing worldwide. These diseases lead to chronic inflammation of the gastrointestinal tract as a result of an abnormal response of the immune system. Recent studies positioned Cortistatin, which shows low stability in plasma, as a candidate for IBD treatment. Here, using NMR structural information, we design five Cortistatin analogues adopting selected native Cortistatin conformations in solution. One of them, A5, preserves the anti-inflammatory and immunomodulatory activities of Cortistatin in vitro and in mouse models of the disease. Additionally, A5 displays an increased half-life in serum and a unique receptor binding profile, thereby overcoming the limitations of the native Cortistatin as a therapeutic agent. This study provides an efficient approach to the rational design of Cortistatin analogues and opens up new possibilities for the treatment of patients that fail to respond to other therapies.

Synthesis of 3-alkyl-6-methyl-1,2,4,5-tetrazines via a Sonogashira-type cross-coupling reaction.

1,2,4,5-Tetrazines have become extremely useful tools in chemical biology. However, the synthesis of some challenging substrates such as asymmetrically disubstituted alkyltetrazines is still a limitation for the widespread use of this class of compounds. Herein we describe an efficient route to these compounds based on the Sonogashira coupling of 3-bromo-6-methyl-1,2,4,5-tetrazine and 3-bromo-6-phenyl-1,2,4,5-tetrazine with terminal alkynes. The preparation of the starting reagents has also been optimized. The alkynyl products have been used as intermediates for the synthesis of dialkyl-tetrazines through a sequence of hydrogenation and re-oxidation with unprecedented yields. The synthetic applicability of this new approach is showcased through the preparation of several unnatural amino acids bearing alkynyl- and alkyl-1,2,4,5-tetrazine fragments.

Optimal linker length for small molecule PROTACs that selectively target p38α and p38ß for degradation.

We report the design of hetero-bifunctional small molecules that selectively target p38α and p38ß for degradation. These proteolysis targeted chimeras (PROTACs) are based on an ATP competitive inhibitor of p38α and p38ß, which is linked to thalidomide analogues to recruit the Cereblon E3 ubiquitin ligase complex. Compound synthesis was facilitated by the use of a copper catalyzed "click" reaction. We show that optimization of the linker length and composition is crucial for the degradation-inducing activity of these PROTACs. We provide evidence that these chemical compounds can induce degradation of p38α and p38ß but no other related kinases at nanomolar concentrations in several mammalian cell lines. Accordingly, the PROTACs inhibit stress and cytokine-induced p38α signaling. Our compounds contribute to understanding the development of PROTACs, and provide a useful tool to investigate functions of the p38 MAPK pathway and its involvement in diseases.

P-Stereogenic Amino-Phosphines as Chiral Ligands: From Privileged Intermediates to Asymmetric Catalysis.

Among chiral phosphines, P-stereogenic phosphines provide unparalleled activity and selectivity and have thus emerged as "state-of-the-art" ligands for asymmetric hydrogenation and other industrially relevant processes. However, the synthesis of this type of ligand implies lengthy multistep sequences, which are a hurdle for many laboratories. There is a lack of methods for the rapid construction of P-stereogenic phosphine ligands. In this respect, P-stereogenic synthons that can be rapidly incorporated into a given ligand scaffold are highly desirable. Over the last 10 years, our group has unveiled that P-stereogenic aminophosphines can be rapidly assembled in a convenient fashion from the corresponding primary aminophosphine and/or the corresponding phosphinous acid.Using cis-1-amino-2-indanol as chiral auxiliary, we devised a multigram synthesis of tert-butylmethylaminophosphine borane and tert-butylmethylphosphinous acid borane, which are key intermediate synthons. Primary aminophosphine works as nucleophilic intermediates at nitrogen. From this synthon, aminodiphosphine (MaxPHOS) and secondary imino phosphoranes (SIP) ligands were synthesized. These ligands exhibit a tautomeric equilibrium between the PH and NH forms, and because of that, they do not undergo oxidation in air. NH/PH tautomerism does not jeopardize their configurational stability, and most importantly, in the presence of a metal source, the equilibrium is shifted toward the NH form, thus allowing coordination through phosphorus. Rh-MaxPHOS and Rh-SIP complexes have been used in asymmetric hydrogenation and [2 + 2 + 2] cycloaddition reactions with outstanding results. On the other hand, P-stereogenic phosphinous acid, upon activation, serves as an electrophilic reagent with amine nucleophiles, allowing SN2 reactions at phosphorus with complete inversion of configuration. This coupling technology exhibits a great potential because it allows the incorporation of the P*-phosphine fragment in numerous ligand structures, provided there is an amino group with which to react. In a mild and efficient process, phosphinous acid has been coupled to hydrazine to yield C2 diphosphines and to chiral benzoimidazole-amines to yield P-stereogenic benzoimidazole-phosphine ligands. The most powerful ligand system, however, arises from the condensation of three independent fragments: our phosphinous acid borane, an amino acid, and an amino alcohol, which yields a library of phosphino-oxazoline ligands named MaxPHOX. The corresponding Ir-MaxPHOX catalyst library was applied with excellent results in the asymmetric hydrogenation of α,ß-unsaturated esters, 2-aryl allyl phthalimides, unfunctionalized tetrasubstituted alkenes, cyclic enamides, and N-aryl and N-methyl imines. It also has found application in asymmetric isomerization of alkenes.Overall, we developed key P-stereogenic building blocks that can be incorporated stereospecifically to ligand scaffolds and demonstrated that integration of the P*-aminophosphine fragment in a given catalytic system provides structural diversity that can be a critical contribution to obtaining optimal results and selectivity.

Synthesis and Application of 3-Bromo-1,2,4,5-Tetrazine for Protein Labeling to Trigger Click-to-Release Biorthogonal Reactions.

3-Bromo-1,2,4,5-tetrazine has been synthesized in an oxidant- and metal-free method. The synthesis is scalable and relies on inexpensive starting materials. 3-Bromo-1,2,4,5-tetrazine can undergo nucleophilic aromatic substitutions with differently substituted heteroatoms under mild conditions. In particular, its excellent reactivity has been used to attain chemoselective protein labeling. The resulting labeled lysines can react with strained dienophiles to trigger fast click-to-release (CtR) biorthogonal reactions. The characterization of the CtR reaction in physiological conditions and a therapeutically relevant example with the monoclonal antibody Trastuzumab to showcase its application is presented. Finally, 3-bromo-1,2,4,5-tetrazine has been used to achieve site-selective protein labeling through the genetic incorporation of the first unnatural amino acid bearing an unsubstituted 1,2,4,5-tetrazin-3-yl functionality, which can also undergo CtR reactions.

Catalytic Regioselective Isomerization of 2,2-Disubstituted Oxetanes to Homoallylic Alcohols.

The selective isomerization of strained heterocyclic compounds is an important tool in organic synthesis. An unprecedented regioselective isomerization of 2,2-disubstituted oxetanes into homoallylic alcohols is described. The use of tris(pentafluorophenyl)borane (B(C6 F5 )3 ), a commercially available Lewis acid was key to obtaining good yields and selectivities since other Lewis acids afforded mixtures of isomers and substantial polymerization. The reaction took place under exceptionally mild reaction conditions and very low catalyst loading (0.5 mol %). DFT calculations disclose the mechanistic features of the isomerization and account for the high selectivity displayed by the B(C6 F5 )3 catalyst. The synthetic applicability of the new reaction is demonstrated by the preparation of γ-chiral alcohols using iridium-catalyzed asymmetric hydrogenation.

Highly Enantioselective Iridium-Catalyzed Hydrogenation of 2-Aryl Allyl Phthalimides.

The iridium-catalyzed asymmetric hydrogenation of 2-aryl allyl phthalimides to afford enantioenriched ß-aryl-ß-methyl amines is presented. Recently developed Ir-MaxPHOX catalysts are used for this enantioselective transformation. The mild reaction conditions and the feasible removal of the phthalimido group makes this catalytic method easily scalable and of great interest to afford chiral amines. The importance of this new methodology is exemplified by the formal synthesis of (R)-Lorcaserin, OTS514, and enantiomerically enriched 3-methyl indolines.

Extending the Substrate Scope in the Hydrogenation of Unfunctionalized Tetrasubstituted Olefins with Ir-P Stereogenic Aminophosphine-Oxazoline Catalysts.

Air-stable and readily available Ir-catalyst precursors modified with MaxPHOX-type ligands have been successfully applied in the challenging asymmetric hydrogenation of tetrasubstituted olefins under mild reaction conditions. Gratifyingly, these catalyst precursors are able to efficiently hydrogenate not only a range of indene derivatives (ee's up to 96%) but also 1,2-dihydronapthalene derivatives and acyclic olefins (ee's up to 99%), which both constitute the most challenging substrates for this transformation.

Direct Asymmetric Hydrogenation of N-Methyl and N-Alkyl Imines with an Ir(III)H Catalyst.

A novel cationic [IrH(THF)(P,N)(imine)] [BArF] catalyst containing a P-stereogenic MaxPHOX ligand is described for the direct asymmetric hydrogenation of N-methyl and N-alkyl imines. This is the first catalytic system to attain high enantioselectivity (up to 94% ee) in this type of transformation. The labile tetrahydrofuran ligand allows for effective activation and reactivity, even at low temperatures. Density functional theory calculations allowed the rationalization of the stereochemical course of the reaction.