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1.
J Org Chem ; 89(14): 9979-9989, 2024 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-38970491

RESUMEN

The release of strain energy is a fundamental driving force for organic reactions. However, absolute strain energy alone is an insufficient predictor of reactivity, evidenced by the similar ring strain but disparate reactivity of cyclopropanes and cyclobutanes. In this work, we demonstrate that electronic delocalization is a key factor that operates alongside strain release to boost, or even dominate, reactivity. This delocalization principle extends across a wide range of molecules containing three-membered rings such as epoxides, aziridines, and propellanes and also applies to strain-driven cycloaddition reactions. Our findings lead to a "rule of thumb" for the accurate prediction of activation barriers in such systems, which can be easily applied to reactions involving many of the strained building blocks commonly encountered in organic synthesis, medicinal chemistry, polymer science, and bioconjugation. Given the significance of electronic delocalization in organic chemistry, for example in aromatic π-systems and hyperconjugation, we anticipate that this concept will serve as a versatile tool to understand and predict organic reactivity.

2.
Org Lett ; 26(14): 2843-2846, 2024 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-38251922

RESUMEN

A route toward heterocycle-functionalized bicyclo[3.1.1]heptanes (BCHeps) and aza-bicyclo[3.1.1]heptanes (aza-BCHeps) has been developed, using mild, photocatalytic Minisci-like conditions to introduce various heterocycles at the bridgehead position from readily available N-hydroxyphthalimide esters of the corresponding carboxylic acids. This chemistry enables access to heterocycle-functionalized BCHep-containing structures that are highly relevant in medicinal chemistry research as potential bioisosteres of meta-substituted arenes and pyridines.

3.
Angew Chem Int Ed Engl ; 62(3): e202213508, 2023 01 16.
Artículo en Inglés | MEDLINE | ID: mdl-36226350

RESUMEN

Sulfonylated aromatics are commonplace motifs in drugs and agrochemicals. However, methods for the direct synthesis of sulfonylated non-classical arene bioisosteres, which could improve the physicochemical properties of drug and agrochemical candidates, are limited. Here we report a solution to this challenge: a one-pot halosulfonylation of [1.1.1]propellane, [3.1.1]propellane and bicyclo[1.1.0]butanes that proceeds under practical, scalable and mild conditions. The sulfonyl halides used in this chemistry feature aryl, heteroaryl and alkyl substituents, and are conveniently generated in situ from readily available sulfinate salts and halogen atom sources. This methodology enables the synthesis of an array of pharmaceutically and agrochemically relevant halogen/sulfonyl-substituted bioisosteres and cyclobutanes, on up to multidecagram scale.


Asunto(s)
Butanos , Halógenos , Indicadores y Reactivos , Butanos/química
4.
Nature ; 611(7937): 721-726, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36108675

RESUMEN

Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design1. The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions4. By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors5. Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes.


Asunto(s)
Compuestos Bicíclicos con Puentes , Diseño de Fármacos , Heptanos , Aniones/química , Benceno/química , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/química , Descubrimiento de Drogas , Heptanos/síntesis química , Heptanos/química , Pentanos/síntesis química , Pentanos/química , Solubilidad
5.
J Am Chem Soc ; 143(26): 9729-9736, 2021 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-34161076

RESUMEN

Bicyclo[1.1.1]pentylamines (BCPAs) are of growing importance to the pharmaceutical industry as sp3-rich bioisosteres of anilines and N-tert-butyl groups. Here we report a facile synthesis of 1,3-disubstituted BCPAs using a twofold radical functionalization strategy. Sulfonamidyl radicals, generated through fragmentation of α-iodoaziridines, undergo initial addition to [1.1.1]propellane to afford iodo-BCPAs; the newly formed C-I bond in these products is then functionalized via a silyl-mediated Giese reaction. This chemistry also translates smoothly to 1,3-disubstituted iodo-BCPs. A wide variety of radical acceptors and iodo-BCPAs are accommodated, providing straightforward access to an array of valuable aniline-like isosteres.

6.
J Med Chem ; 63(6): 2915-2929, 2020 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-32134643

RESUMEN

To identify Janus kinase (JAK) inhibitors that selectively target gastrointestinal tissues with limited systemic exposures, a class of imidazopyrrolopyridines with a range of physical properties was prepared and evaluated. We identified compounds with low intrinsic permeability and determined a correlation between permeability and physicochemical properties, clogP and tPSA, for a subset of compounds. This low intrinsic permeability translated into compounds displaying high colonic exposure and low systemic exposure after oral dosing at 25 mg/kg in mouse. In a mouse PK/PD model, oral dosing of lead compound 2 demonstrated dose-dependent inhibition of pSTAT phosphorylation in colonic explants post-oral dose but low systemic exposure and no measurable systemic pharmacodynamic activity. We thus demonstrate the utility of JAK inhibitors with low intrinsic permeability as a feasible approach to develop gut-restricted, pharmacologically active molecules with a potential advantage over systemically available compounds that are limited by systemic on-target adverse events.


Asunto(s)
Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Inhibidores de las Cinasas Janus/farmacología , Inhibidores de las Cinasas Janus/farmacocinética , Piridinas/farmacología , Piridinas/farmacocinética , Administración Oral , Animales , Perros , Descubrimiento de Drogas , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/metabolismo , Inhibidores de las Cinasas Janus/administración & dosificación , Inhibidores de las Cinasas Janus/química , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Células de Riñón Canino Madin Darby , Ratones , Ratones Endogámicos C57BL , Permeabilidad , Fosforilación/efectos de los fármacos , Piridinas/administración & dosificación , Piridinas/química
7.
Chem Sci ; 11(19): 4895-4903, 2020 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-34122945

RESUMEN

[1.1.1]Propellane is the ubiquitous precursor to bicyclo[1.1.1]pentanes (BCPs), motifs of high value in pharmaceutical and materials research. The classical Lewis representation of this molecule places an inter-bridgehead C-C bond along its central axis; 'strain relief'-driven cleavage of this bond is commonly thought to enable reactions with nucleophiles, radicals and electrophiles. We propose that this broad reactivity profile instead derives from σ-π-delocalization of electron density in [1.1.1]propellane. Using ab initio and DFT calculations, we show that its reactions with anions and radicals are facilitated by increased delocalization of electron density over the propellane cage during addition, while reactions with cations involve charge transfer that relieves repulsion inside the cage. These results provide a unified framework to rationalize experimental observations of propellane reactivity, opening up opportunities for the exploration of new chemistry of [1.1.1]propellane and related strained systems that are useful building blocks in organic synthesis.

8.
J Org Chem ; 84(12): 7722-7746, 2019 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-31066273

RESUMEN

Late-stage synthetic efforts to advance the enatio- and diastereoselectively constructed [6,7,5,5]-fused tetracyclic scaffold toward the polycyclic norditerpenoid ineleganolide are disclosed. The described investigations focus on oxidation-state manipulation around the central cycloheptane ring. Computational evaluation of ground-state energies of dihydroineleganolide is used to rationalize empirical observations and provide insight for further synthetic development, enhancing the understanding of the conformational constraints of these compact polycyclic structures. Advanced synthetic manipulations generated a series of natural product-like compounds termed the ineleganoloids.


Asunto(s)
Diterpenos/química , Diterpenos/síntesis química , Furanos/química , Lactonas/química , Compuestos Policíclicos/química , Técnicas de Química Sintética , Ciclización , Oxidación-Reducción , Estereoisomerismo
9.
Org Lett ; 21(8): 2918-2922, 2019 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-30942600

RESUMEN

Ynamides are accessed via copper-catalyzed coupling of Grignard or organozinc nucleophiles with chloroynamides, formed in situ from 1,2-dichloroenamides. The reaction exhibits a broad substrate scope, is readily scaled, and overcomes typical limitations in ynamide synthesis such as the use of ureas, carbamates, and bulky or aromatic amide derivatives. This modular approach contrasts with previous routes by installing both the N- and C-substituents of the ynamide as nucleophilic components.

10.
Chem Sci ; 10(4): 1254-1255, 2019 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-30774926

RESUMEN

[This corrects the article DOI: 10.1039/C6SC03347D.].

11.
Psychiatry ; 81(1): 22-27, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29799362

RESUMEN

OBJECTIVE: This is a follow-up study of a pilot project first reported on in 2006. A group model was developed for a state psychiatric hospital setting to assist residents who had displayed characteristics of "institutionalism." This includes an aversion or ambivalence to discharge efforts and an acceptance of prolonged life in the hospital. The pilot project, while small, was promising, with five of seven people entering the community successfully within a year and a half. METHOD: The current project expanded the scope to include three groups with a total of 25 participants. Additional refinement included a standardized group curriculum, expanding outcome measures to include participant attitudes toward change, a protocol to inform and meaningfully involve clinical treatment teams in the participants' progress, and enhanced training for group facilitators. RESULTS: Of the original participants, 32% achieved discharge in the first year of participation in the group. In addition, participants who were not discharged within the first year developed more positive attitudes toward making changes in their life. DISCUSSION: The guiding principles of this model-including personal reflection, a team approach for sharing life experiences, and encouragement from participants and staff-seem conducive for supporting the attitudinal change and motivation necessary for successful discharge after prolonged hospital stays.


Asunto(s)
Hospitales Psiquiátricos , Alta del Paciente/estadística & datos numéricos , Rehabilitación Psiquiátrica/métodos , Adulto , Femenino , Estudios de Seguimiento , Humanos , Institucionalización , Masculino , Persona de Mediana Edad
12.
J Org Chem ; 83(7): 3467-3485, 2018 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-29464957

RESUMEN

An enantioselective and diastereoselective approach toward the synthesis of the tetracyclic scaffold of the furanobutenolide-derived polycyclic norditerpenoids is described. Focusing on synthetic efforts toward ineleganolide, the synthetic approach utilizes a palladium-catalyzed enantioselective allylic alkylation for the construction of the requisite chiral tertiary ether. A diastereoselective cyclopropanation-Cope rearrangement cascade enabled the convergent assembly of the ineleganolide [6,7,5,5]-tetracyclic scaffold. Investigation of substrates for this critical tandem annulation process is discussed along with synthetic manipulations of the [6,7,5,5]-tetracyclic scaffold and the attempted interconversion of the [6,7,5,5]-tetracyclic scaffold of ineleganolide to the isomeric [7,6,5,5]-core of scabrolide A and its naturally occurring isomers. Computational evaluation of ground-state energies of late-stage synthetic intermediates was used to guide synthetic development and aid in the investigation of the conformational rigidity of these highly constrained and compact polycyclic structures.


Asunto(s)
Diterpenos/síntesis química , Furanos/química , Lactonas/química , Diterpenos/química , Conformación Molecular , Estereoisomerismo
13.
J Org Chem ; 82(24): 13051-13067, 2017 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-29111725

RESUMEN

Recently, we reported a convergent cyclopropanation-Cope approach to the core of ineleganolide, which was the first disclosed synthesis of the core of the norditerpene natural product ineleganolide. In this complementary work, a model system for the core of ineleganolide has been prepared through a series of tandem cyclopropanation-Cope and translactonization-Cope rearrangements. Work with this model system has enriched our understanding of the cyclopropanation-Cope rearrangement sequence. Additionally, research into this model system has driven the development of tandem translactonization-Cope rearrangements.


Asunto(s)
Alquenos/química , Diterpenos/química , Lactonas/química , Modelos Biológicos , Propano/química , Ciclización , Estructura Molecular
14.
Chem Sci ; 8(1): 507-514, 2017 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-28239443

RESUMEN

An enantioselective and diastereoselective approach toward the synthesis of the polycyclic norditerpenoid ineleganolide is disclosed. A palladium-catalyzed enantioselective allylic alkylation is employed to stereoselectively construct the requisite chiral tertiary ether and facilitate the synthesis of a 1,3-cis-cyclopentenediol building block. Careful substrate design enabled the convergent assembly of the ineleganolide [6,7,5,5]-tetracyclic scaffold by a diastereoselective cyclopropanation-Cope rearrangement cascade under unusually mild conditions. Computational evaluation of ground state energies of late-stage synthetic intermediates was used to guide synthetic development and aid in the investigation of the conformational rigidity of these highly constrained and compact polycyclic structures. This work represents the first successful synthesis of the core structure of any member of the polycyclic norcembranoid diterpene family of natural products. Advanced synthetic manipulations generated a series of natural product-like compounds that were shown to possess selective secretory antagonism of either interleukin-5 or interleukin-17. This bioactivity stands in contrast to the known antileukemic activity of ineleganolide and suggests the norcembranoid natural product core may serve as a useful scaffold for the development of diverse therapeutics.

16.
J Am Chem Soc ; 137(19): 6200-18, 2015 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-25945516

RESUMEN

Through the combination of reaction kinetics (both stoichiometric and catalytic), solution- and solid-state characterization of arylpalladium(II) arylsilanolates, and computational analysis, the intermediacy of covalent adducts containing Si-O-Pd linkages in the cross-coupling reactions of arylsilanolates has been unambiguously established. Two mechanistically distinct pathways have been demonstrated: (1) transmetalation via a neutral 8-Si-4 intermediate that dominates in the absence of free silanolate (i.e., stoichiometric reactions of arylpalladium(II) arylsilanolate complexes), and (2) transmetalation via an anionic 10-Si-5 intermediate that dominates in the cross-coupling under catalytic conditions (i.e., in the presence of free silanolate). Arylpalladium(II) arylsilanolate complexes bearing various phosphine ligands have been isolated, fully characterized, and evaluated for their kinetic competence under thermal (stoichiometric) and anionic (catalytic) conditions. Comparison of the rates for thermal and anionic activation suggested, but did not prove, that intermediates containing the Si-O-Pd linkage were involved in the cross-coupling process. The isolation of a coordinatively unsaturated, T-shaped arylpalladium(II) arylsilanolate complex ligated with t-Bu3P allowed the unambiguous demonstration of the operation of both pathways involving 8-Si-4 and 10-Si-5 intermediates. Three kinetic regimes were identified: (1) with 0.5-1.0 equiv of added silanolate (with respect to arylpalladium bromide), thermal transmetalation via a neutral 8-Si-4 intermediate; (2) with 1.0-5.0 equiv of added silanolate, activated transmetalation via an anionic 10-Si-5 intermediate; and (3) with >5.0 equiv of added silanolate, concentration-independent (saturation) activated transmetalation via an anionic 10-Si-5 intermediate. Transition states for the intramolecular transmetalation of neutral (8-Si-4) and anionic (10-Si-5) intermediates have been located computationally, and the anionic pathway is favored by 1.8 kcal/mol. The energies of all intermediates and transition states are highly dependent on the configuration around the palladium atom.


Asunto(s)
Hidrocarburos Aromáticos/química , Paladio/química , Silanos/química , Aniones/síntesis química , Aniones/química , Bromuros/síntesis química , Bromuros/química , Catálisis , Hidrocarburos Aromáticos/síntesis química , Cinética , Ligandos , Modelos Moleculares , Silanos/síntesis química , Termodinámica
17.
J Am Chem Soc ; 137(19): 6192-9, 2015 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-25945390

RESUMEN

Through the combination of reaction kinetics (both catalytic and stoichiometric) and solid-state characterization of arylpalladium(II) alkenylsilanolate complexes, the intermediacy of covalent adducts containing Si-O-Pd linkages in the cross-coupling reactions of organosilanolates has been unambiguously established. Two mechanistically distinct pathways have been demonstrated: (1) transmetalation via a neutral 8-Si-4 intermediate that dominates in the cross-coupling of potassium alkenylsilanolates, and (2) transmetalation via an anionic 10-Si-5 intermediate that dominates in the cross-coupling of cesium alkenylsilanolates. Arylpalladium(II) alkenylsilanolate complexes bearing various phosphine ligands (both bidentate and monodentate) have been isolated, fully characterized, and evaluated for their kinetic competence under thermal (stoichiometric) and anionic (catalytic) conditions. Comparison of the rates for thermal and anionic activation demonstrates that intermediates containing the Si-O-Pd linkage are involved in the cross-coupling process.


Asunto(s)
Alquenos/química , Hidrocarburos Aromáticos/química , Compuestos Organometálicos/química , Paladio/química , Silanos/química , Alquenos/síntesis química , Catálisis , Hidrocarburos Aromáticos/síntesis química , Modelos Moleculares , Compuestos Organometálicos/síntesis química , Silanos/síntesis química
18.
Bioorg Med Chem Lett ; 24(23): 5489-92, 2014 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-25455490

RESUMEN

During the course of our efforts toward the discovery of human histamine H4 antagonists from a series of 2-aminiopyrimidines, it was noted that a 6-trifluoromethyl group dramatically reduced affinity of the series toward the histamine H4 receptor. This observation was further investigated by synthesizing a series of ligands that varied in pKa of the pyrimidine derived H4 ligands by over five orders of magnitude and the effect on histamine H4 affinity. This trend was then extended to the discovery of C-linked piperidinyl-2-amino pyridines as histamine H4 receptor antagonists.


Asunto(s)
Antagonistas de los Receptores Histamínicos/farmacocinética , Piridinas/química , Pirimidinas/química , Receptores Acoplados a Proteínas G/efectos de los fármacos , Receptores Histamínicos/efectos de los fármacos , Antagonistas de los Receptores Histamínicos/uso terapéutico , Humanos , Ligandos , Estructura Molecular , Receptores Histamínicos H4
19.
Org Lett ; 14(22): 5716-9, 2012 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-23101616

RESUMEN

A brief, enantioselective synthesis of a hydroxymethyl-cis-1,3-cyclopentenediol building block is presented. This scaffold allows access to the cis-1,3-cyclopentanediol fragments found in a variety of biologically active natural and non-natural products. This rapid and efficient synthesis is highlighted by the utilization of the palladium-catalyzed enantioselective allylic alkylation of dioxanone substrates to prepare tertiary alcohols.


Asunto(s)
Alcoholes/síntesis química , Ciclopentanos/síntesis química , Dioxanos/química , Paladio/química , Alcoholes/química , Alquilación , Catálisis , Ciclopentanos/química , Estructura Molecular , Estereoisomerismo
20.
Tetrahedron ; 67(24): 4391-4396, 2011 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-21731114

RESUMEN

The electronic characteristics of coupling partners in the transmetalation step for the cross-coupling reaction of arylsilanolates have been investigated. The ability to interrogate the transmetalation event by in situ preparation of the arylpalladium(II) silanolate intermediate has enabled a Hammett analysis for both the aryl electrophile and arylsilanolate to be conducted. These studies reveal that electron-donating groups on the silicon nucleophile and electron-withdrawing groups on the electrophile accelerate the transmetalation process.

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