ABSTRACT
Unprotected, highly substituted morpholines were obtained through a copper-catalyzed three-component reaction utilizing amino alcohols, aldehydes, and diazomalonates. The transformation was effective for diversely substituted aldehydes and for a broad range of readily available vicinal amino alcohols, including those derived from glycine, α-substituted, and α,α-disubstituted amino acids. Epimerization of morpholines using light-mediated stereochemical editing was demonstrated, and the unprotected morpholine products were readily elaborated through efficient transformations.
ABSTRACT
A general one-pot approach to diverse N-acylsulfenamides from a common S-phenethylsulfenamide starting material is reported. This approach was demonstrated by C-S bond formation utilizing commercially abundant (hetero)aryl iodides and boronic acids to provide sulfilimine intermediates that undergo thermal elimination of styrene. In contrast, all prior approaches to N-acylsulfenamides rely on thiol inputs to introduce sulfenamide S-substituents. A broad scope of reaction inputs was demonstrated including for approved drugs and drug precursors with dense display of functionality. Several different types of sulfur functionalization were performed on a sulfenamide derived from a complex precursor of the blockbuster anticoagulant drug apixaban, highlighting the utility of this approach for the introduction of high oxidation state sulfur groups in complex bioactive compounds. Mechanistic studies established that the key styrene elimination step proceeds by a concerted elimination that does not require reagents or catalysts, and therefore, this one-pot approach should be applicable to the synthesis of N-acylsulfenamides utilizing diverse electrophiles and reaction conditions for C-S bond formation.
ABSTRACT
Stereoselective α-amino C-H epimerization of exocyclic amines is achieved via photoredox catalyzed, thiyl-radical mediated, reversible hydrogen atom transfer to provide thermodynamically controlled anti/syn isomer ratios. The method is applicable to different substituents and substitution patterns about aminocyclopentanes, aminocyclohexanes, and a N-Boc-3-aminopiperidine. The method also provided efficient epimerization for primary, alkyl and (hetero)aryl secondary, and tertiary exocyclic amines. Demonstration of reversible epimerization, deuterium labeling, and luminescence quenching provides insight into the reaction mechanism.
ABSTRACT
Herein is reported a robust and general method for the preparation of N-acylsulfenamides, important functionalities that have recently been utilized as central inputs for the asymmetric synthesis of high oxidation state sulfur compounds. This straightforward transformation proceeds by reaction of primary amides, carbamates, sulfonamides, sulfinamides, and ureas with stable N-thiosuccinimides or N-thiophthalimides, which in turn are prepared in a single step from commercial thiols. The use of stable N-thiosuccinimide and N-thiophthalimide reactants is desirable because it obviates the use of highly reactive sulfenyl chlorides.
ABSTRACT
Sulfur-(hetero)arylation of sulfenamides with commercially abundant (hetero)aryl iodides by Ullmann-type coupling with inexpensive copper(I) iodide as the catalyst is reported. A broad scope of reaction inputs was demonstrated, including both aryl and alkyl sulfenamides and highly sterically hindered aryl and 5- and 6-membered ring heteroaryl iodides. Relevant to many bioactive high oxidation state sulfur compounds, the (hetero)arylation of S-methyl sulfenamides is reported, including for complex aryl iodides. Smiles rearrangement of electron-deficient S-heteroaryl sulfilimines is also disclosed.
Subject(s)
Iodides , Sulfamerazine , Sulfur , Sulfur Compounds , CatalysisABSTRACT
Unprotected, α,ß-disubstituted tryptamines and phenethylamines are obtained by a one-pot, metal-free sequence that proceeds by the in situ formation of aziridinium salts followed by Friedel-Crafts reaction with electron-rich (hetero)arenes. Both steps are facilitated by hexafluoroisopropanol as the solvent. The one-pot sequence was effective for diversely substituted indoles and 1,3,5-trimethoxybenzene, for cyclic and acyclic alkenes, and proceeded in a stereospecific fashion for both (E)- and (Z)-1,2-disubstituted alkenes. Moreover, one-pot morpholine addition to an aziridinium salt provided a diamine.
ABSTRACT
Sulfur alkylation of N-acyl sulfenamides with alkyl halides provides sulfilimines in 47% to 98% yields. A broad scope was established with a variety of aryl and alkyl sulfenamides, including for different N-acyl groups. Alkyl halides with different steric and electronic properties were effective inputs, including methyl, primary, secondary, benzyl, and propargyl halides. A proof-of-concept asymmetric phase-transfer alkylation was also demonstrated. A sulfilimine product was readily converted to an N-acyl and to a free sulfoximine, which represent important motifs in medicinal chemistry.
ABSTRACT
Sulfur-arylation of sulfenamides is reported. This reaction proceeds via a Chan-Lam-type coupling with commercially abundant boronic acids to give sulfilimines. A broad scope was established with a variety of readily accessible aryl and alkyl sulfenamide and boronic acid inputs. Synthetic utility and functional group compatibility were further demonstrated through the direct late-stage introduction of sulfilimines into approved drugs. Derivatization of the sulfilimine products provided access to medicinally relevant sulfoximines and sulfondiimines.
ABSTRACT
A multicomponent annulation that proceeds by imine directed Cp*RhIII -catalyzed N-H functionalization is disclosed. The transformation affords piperazinones displaying a range of functionality and is the first example of transition metal-catalyzed multicomponent N-H functionalization. A broad range of readily available α-amino amides, including those derived from glycine, α-substituted, and α,α-disubstituted amino acids, were effective inputs and enabled the incorporation of a variety of amino acid side chains with minimal racemization. Branched and unbranched alkyl aldehydes and various stabilized diazo compounds were also efficient reactants. The piperazinone products were further modified through efficient transformations. Mechanistic studies, including X-ray crystallographic characterization of a catalytically competent five-membered rhodacycle with imine and amide nitrogen chelation, provide support for the proposed mechanism.
Subject(s)
Aldehydes , Rhodium , Aldehydes/chemistry , Amides , Imines , Rhodium/chemistry , Catalysis , Azo CompoundsABSTRACT
All carbon α-quaternary aldehydes are prepared via Co(iii)-catalysed sequential C-H bond addition to dienes and acetic formic anhydride, representing a rare example of intermolecular carboformylation. A wide range of internally substituted dienes containing diverse functionality can be employed in this reaction, affording complex α-quaternary aldehydes that would not be accessible via hydroformylation approaches. Mechanistic investigations, including control reactions and deuterium labeling studies, establish a catalytic cycle that accounts for formyl group introduction with an uncommon 1,3-addition selectivity to the conjugated diene. Investigations into the role of the uniquely effective additive Proton Sponge® were also conducted, leading to the observation of a putative, intermediate Co(i) tetramethylfulvene complex at low temperatures via NMR spectroscopy. The synthetic utility of the aldehyde products is demonstrated by various transformations, including proline-catalysed asymmetric aldol addition, reductive amination, and the asymmetric synthesis of amines using tert-butanesulfinamide technology.
ABSTRACT
We report a photocatalyzed epimerization of morpholines and piperazines that proceeds by reversible hydrogen atom transfer (HAT) and provides an efficient strategy for editing the stereochemical configurations of these saturated nitrogen heterocycles, which are prevalent in drugs. The more stable morpholine and piperazine isomers are obtained from the more synthetically accessible but less stable stereoisomers, and a broad scope is demonstrated in terms of substitution patterns and functional group compatibility. The observed distributions of diastereomers correlate well with the relative energies of the diastereomer pairs as determined by density functional theory (DFT) calculations. Mechanistic studies, including luminescence quenching, deuterium labeling reactions, and determination of reversibility support a thiyl radical mediated HAT pathway for the epimerization of morpholines. Investigation of piperazine epimerization established that the mechanism is more complex and led to the development of thiol free conditions for the highly stereoselective epimerization of N,N'-dialkyl piperazines for which a previously unrecognized radical chain HAT mechanism is proposed.
ABSTRACT
Mitogen-activated protein kinase (MAPK) phosphatase 5 (MKP5) is responsible for regulating the activity of the stress-responsive MAPKs and has been put forth as a potential therapeutic target for a number of diseases, including dystrophic muscle disease a fatal rare disease which has neither a treatment nor cure. In previous work, we identified Compound 1 (3,3-dimethyl-1-((9-(methylthio)-5,6-dihydrothieno[3,4-h]quinazolin-2-yl)thio)butan-2-one) as the lead compound of a novel class of MKP5 inhibitors. In this work, we explore the structure-activity relationship for inhibition of MKP5 through modifications to the scaffold and functional groups present in 1. A series of derivative compounds was designed, synthesized, and evaluated for inhibition of MKP5. In addition, the X-ray crystal structures of six enzyme-inhibitor complexes were solved, further elucidating the necessary requirements for MKP5 inhibition. We found that the parallel-displaced π-π interaction between the inhibitor three-ring core and Tyr435 is critical for modulating potency, and that modifications to the core and functionalization at the C-9 position are essential for ensuring proper positioning of the core for this interaction. These results lay the foundation from which more potent MKP5 allosteric inhibitors can be developed for potential therapeutics towards the treatment of dystrophic muscle disease.
Subject(s)
Structure-Activity RelationshipABSTRACT
There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally1-4. Efforts have focused on readily synthesizable molecules, inevitably leaving many chemotypes unexplored. Here we investigate structure-based docking of a bespoke virtual library of tetrahydropyridines-a scaffold that is poorly sampled by a general billion-molecule virtual library but is well suited to many aminergic G-protein-coupled receptors. Using three inputs, each with diverse available derivatives, a one pot C-H alkenylation, electrocyclization and reduction provides the tetrahydropyridine core with up to six sites of derivatization5-7. Docking a virtual library of 75 million tetrahydropyridines against a model of the serotonin 5-HT2A receptor (5-HT2AR) led to the synthesis and testing of 17 initial molecules. Four of these molecules had low-micromolar activities against either the 5-HT2A or the 5-HT2B receptors. Structure-based optimization led to the 5-HT2AR agonists (R)-69 and (R)-70, with half-maximal effective concentration values of 41 nM and 110 nM, respectively, and unusual signalling kinetics that differ from psychedelic 5-HT2AR agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HT2AR. The favourable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioural assays. Notably, neither had psychedelic activity, in contrast to classic 5-HT2AR agonists, whereas both had potent antidepressant activity in mouse models and had the same efficacy as antidepressants such as fluoxetine at as low as 1/40th of the dose. Prospects for using bespoke virtual libraries to sample pharmacologically relevant chemical space will be considered.
Subject(s)
Antidepressive Agents , Pyrrolidines , Receptor, Serotonin, 5-HT2A , Animals , Mice , Antidepressive Agents/pharmacology , Cryoelectron Microscopy , Fluoxetine/administration & dosage , Fluoxetine/pharmacology , Hallucinogens/administration & dosage , Hallucinogens/pharmacology , Ligands , Pyrrolidines/administration & dosage , Pyrrolidines/pharmacology , Receptor, Serotonin, 5-HT2A/metabolism , Small Molecule LibrariesABSTRACT
Sulfoximines are increasingly incorporated in agrochemicals and pharmaceuticals, with the two enantiomers of chiral sulfoximines often having profoundly different binding interactions with biomolecules. Therefore, their application to drug discovery and development requires the challenging preparation of single enantiomers rather than racemic mixtures. Here, we report a general and fundamentally new asymmetric synthesis of sulfoximines. The first S-alkylation of sulfenamides, which are readily accessible sulfur compounds with one carbon and one nitrogen substituent, represents the key step. A broad scope for S-alkylation was achieved by rhodium-catalyzed coupling with diazo compounds under mild conditions. When a chiral rhodium catalyst was utilized with loadings as low as 0.1 mol %, the S-alkylation products were obtained in high yields and with enantiomeric ratios up to 98:2 at the newly generated chiral sulfur center. The S-alkylation products were efficiently converted to a variety of sulfoximines with complete retention of stereochemistry. The utility of this approach was further demonstrated by the asymmetric synthesis of a complex sulfoximine agrochemical.
Subject(s)
Rhodium , Agrochemicals , Alkylation , Carbon , Catalysis , Molecular Structure , Nitrogen , Pharmaceutical Preparations , Rhodium/chemistry , Stereoisomerism , Sulfamerazine , Sulfur/chemistryABSTRACT
Sequential multicomponent C-H bond addition is a powerful approach for the rapid, modular generation of molecular complexity in a single reaction. In this approach, C-H bonds are typically added across π-bonds or π-bond isosteres, followed by subsequent coupling to another type of functionality, thereby forming two σ-bonds in a single reaction sequence. Many sequential C-H bond addition reactions have been developed to date, including additions across both conjugated and isolated π-systems followed by coupling with reactants such as carbonyl compounds, cyanating reagents, aminating reagents, halogenating reagents, oxygenating reagents, and alkylating reagents. These atom-economical reactions transform ubiquitous C-H bonds under mild conditions to more complex structures with a high level of regiochemical and stereochemical control. Surprising connectivities and diverse mechanisms have been elucidated in the development of these reactions. Given the large number of possible combinations of coupling partners, there are enormous opportunities for the discovery of new sequential C-H bond addition reactions.
Subject(s)
Catalysis , Indicators and ReagentsABSTRACT
Most known methods to access δ-lactams with stereogenic centers at the α- and ß-positions are highly selective for the contra-thermodynamic syn diastereomer, typically via hydrogenation of the corresponding pyridinones or quinolinones. We describe here the development of a photoredox-mediated hydrogen atom transfer (HAT) approach for the epimerization of δ-lactams to access the more stable anti diastereomers from the contra-thermodynamic syn isomers. The reaction displays broad functional group compatibility, including acid, ester, 1°, 2° and 3° amide, carbamate, and pyridyl groups, and was effective for a range of differently substituted monocyclic and bicyclic lactams. Experimentally observed diastereoselectivities are consistent with the calculated relative stabilities of lactam diastereomers. Convergence to the same diastereomer ratio from the syn- and anti- diastereomers establishes that reversible epimerization provides an equilibrium mixture of diastereomers. Additionally, deuterium labeling and luminescence quenching studies shed further light on the mechanism of the reaction.
ABSTRACT
An efficient and stereoselective CoIII -catalyzed sequential C-H bond addition to 1,3-enynes and aldehydes is disclosed. This transformation represents the first example of sequential C-H bond additions to 1,3-enynes and a second coupling partner and provides the first example of preparing allenes by C-H bond addition to 1,3-enynes. A wide range of aldehydes, C-H bond substrates and 1,3-enynes with large substituents on the alkynes are effective substrates. The allenyl alcohol products can be further converted to dihydrofurans with high stereoselectivity either in situ or under Ag-mediated cyclization conditions. The allenyl silyl group can also be transferred to the adjacent alcohol by a Brook rearrangement. Moreover, a mechanism for the transformation is proposed supported by X-ray structural characterization of a cobaltacycle intermediate.
Subject(s)
Aldehydes , Cobalt , Alcohols , Aldehydes/chemistry , Catalysis , Cobalt/chemistry , Molecular StructureABSTRACT
Straightforward and mild hexafluoroisopropanol (HFIP)-mediated, metal-free, three-component Friedel-Crafts approaches are reported for the synthesis of alkenyl and alkyl trifluoromethyl sulfides from arenes, (PhSO2)2NSCF3, and alkynes or alkenes, respectively. The transformations proceed with high regio- and stereochemical control via the initial formation of cationic thiirenium and thiiranium intermediates, respectively, followed by Friedel-Crafts reactions with the arene. A mechanistically related three-component synthesis of alkenyl iodides from arenes, alkenes, and N-iodosuccinimide is also reported.
ABSTRACT
Efficient syntheses of α-branched amines by three- and four-component C-H functionalization employing a diversifiable hydrazone directing group have been developed. The hydrazone in the α-branched amine products has been readily converted to multiple desirable functionalities such as a nitrile, a carboxylic acid, alkenes, and heterocycles using diverse heterolytic chemistry and homolytic transition metal- or photoredox-catalyzed processes. This study represents the first example of a four-component C-H functionalization reaction.