Thianthrenation-promoted photoinduced alkene difunctionalization and aryl allylation with Morita-Baylis-Hillman adducts.

An organophotoredox-catalyzed alkoxyallylation of feed-stock olefins, through thianthrenation using a Morita-Baylis-Hillman adduct as an allylating agent, is described. Site-selective addition of MeOH to an alkene-thianthrenium salt and its subsequent conversion into a nucleophilic radical species forms the basis of this unique difunctionalization strategy. The scope is also expanded into radical aryl allylation.

Hydrogen bonding-promoted tunable approach for access to aza-bicyclo-[3.3.0]octanes and cyclopenta[b] pyrroles.

A unified strategy is disclosed that builds on successfully engaging the aniline nitrogen of 1,3-amphoteric γ-aminocyclopentenone for a tandem annulation with electron-poor alkynes, solely assisted by the H-bonding network of HFIP. This metal-free mild strategy provides access to medicinally relevant aza-bicyclo-octanes en route to another important scaffold: cyclopenta[b]pyrrole.

Hydroxamate-directed access to ß-Kdo glycosides.

The reaction repertoire for forming transient aziridinone or azaoxyallyl cations from α-halohydroxamate is conceptually extended to design Kdo-glycosyl donors by installing the hydroxamate moiety at an anomeric centre, which is shown to be highly effective for stereoselective access to ß-Kdo glycosides. The pivotal roles of hydroxamate over amide are revealed in control experiments.

Fe-Catalyzed Hydroallylation of Unactivated Alkenes with Vinyl Cyclopropanes.

Catalytic, reductive C-C bond formation between alkenes and vinyl cyclopropane (VCP) through hydrogen atom transfer (MHAT) is developed. Despite VCP's use as probes in radical-clock experiments, translation of this manifold into synthetic methods for accessing elusive C-C bonds remains largely unexplored. This work represents the first foray into this front where the high chemoselectivity of MHAT for alkene over VCP was pivotal for realizing the strategy. This method exhibits a broad scope, high functional group tolerance, and useful applications.

Cation-Promoted Strain-Release-Driven Access to Functionalized Azetidines from Azabicyclo[1.1.0]butanes.

Access to 1,3-functionalized azetidines through a diversity-oriented approach is highly sought-after for finding new applications in drug-discovery. To this goal, strain-release-driven functionalization of azabicyclo[1.1.0]-butane (ABB) has generated significant interest. Through appropriate N-activation, C3-substituted ABBs are shown to render tandem N/C3-fucntionalization/rearrangement, furnishing azetidines; although, modalities of such N-activation vis-à-vis N-functionalization remain limited to selected electrophiles. This work showcases a versatile cation-driven activation strategy of ABBs. And capitalizes on the use of Csp3 precursors amenable to forming reactive (aza)oxyallyl cations in situ. Herein, N-activation leads to formation of a congested C-N bond, and effective C3 activation. The concept was extended to formal [3+2] annulations involving (aza)oxyallyl cations and ABBs, leading to bridged bicyclic azetidines. Besides the fundamental appeal of this new activation paradigm, operational simplicity and remarkable diversity should engender its prompt use in synthetic and medicinal chemistry.

Experimental and Theoretical Investigation of an Azaoxyallyl Cation-Templated Intramolecular Aryl Amination Leading to Oxindole Derivatives.

Herein, development and detailed investigation of a SN '-type intramolecular aromatic substitution reaction involving α-arylazaoxyallyl cation intermediate, is disclosed. The study showcased that while α-aryl-α-chlorohydroxamate could be activated by a combination of base and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) into the corresponding azaoxyallyl cations, it could further emerge into a π-extended species involving the adjacent α-aryl moiety, and this transition is contingent on electronic effects of the aromatic ring as well as on α-substituents. An effective activation of the α-aromatic ring could pave the path for intramolecular Ar(Csp2 )-N bond formation towards oxindoles. Control experiments and DFT calculations suggested that a non-pericyclic nucleophilic amination pathway is most likely operative and precluded the possibility of concerted or electrophilic amination mechanism. HFIP as the reaction solvent plays pivotal roles in the transformation.

Access to 3,3'-disubstituted peroxyoxindole derivatives and α-peroxyamides via azaoxyallyl cation-guided addition of hydroperoxides.

Herein, a transition metal-free approach for access to 3,3'-disubstituted peroxyoxindole is disclosed, which harnesses a transient azaoxyallyl cation. This strategy is also applicable to the synthesis of structurally diverse α-peroxycarboxylic acid surrogates. The method exhibits good functional group tolerance and is suitable for generating a library of peroxy-containing compounds.

Access to densely functionalized spirocyclopentenonyl oxindole frameworks via aza- and carbo-Piancatelli rearrangement.

A new strategy for access to spirocyclopentenonyl oxindole frameworks is disclosed. Suitably anchored furfuryl alcohol at C3 of an oxindole was used for the aza-Piancatelli rearrangement, which furnished spirocyclic aminocyclopentenone frameworks with catalytic phosphomolybdic acid. The scope of the transformation was extended to the carbo-Piancatelli rearrangement with various indole derivatives.

An acid-promoted pseudocine substitution manifold of γ-aminocyclopentenone enables divergent access to polycyclic indole derivatives.

We demonstrated γ-aminocyclopentenones to be a suitable surrogate for reactive cyclopentadienone via a pseudocine-substitution manifold. This approach enabled its orchestrated annulation with "tailored" bis-nucleophiles and to furnish complex ß,γ-annulated cyclopentanoids or indole-based polycyclic architectures. This strategy represents a generalized means for direct, regioselective and stereoselective ß,γ-functionalization of monosubstituted or unsubstituted aminocyclopentenones.

Leveraging the Domino Skeletal Expansion of Thia-/Selenazolidinones via Nitrogen-Atom Transfer in Hexafluoroisopropanol: Room Temperature Access to Six-Membered S/Se,N-Heterocycles.

Herein, a highly regioselective domino skeletal-expansion process that transforms 2-aminothiazolidinone into six-membered S,N-heterocycle is developed with the aid of TMS-azide in hexafluoroisopropanol (HFIP) at ambient temperature. Functioning of the C2 tertiary amine as latent reactive group on thiazolidinone moiety was the key to this development, which allowed relay substitution with azide and imparted subsequent ring-expansion under metal/acid free-conditions. The reaction also underscored an intermolecular nitrogen-atom transfer process from TMS-azide leading to final products, where any intermediary azidothiazolidinone was absent. The strategy was extendable to analogous synthesis of Se,N-heterocycles, and furthermore, late-stage drug-modification and follow-up transformations were also performed. Density functional theory calculations and control experiments provided important mechanistic insights and highlighted potential roles of HFIP in the transformation.

Unprecedented Reactivity of γ-Amino Cyclopentenone Enables Diversity-Oriented Access to Functionalized Indoles and Indole-Annulated Ring Structures.

Observation of an unexpected, Lewis acid promoted displacement of latent reactive γ-amino group on cyclopentenone presented unparalleled opportunity for enone functionalization and annulations with indole derivatives, which is developed in the current study. Herein, a vast range of C3/N-indolyl enones and indole alkaloid-like compound were accessed in excellent yields (up to 99 %) and selectivity through a one-pot operation. The mechanism most likely involves an unprecedented trait of Piancatelli-type rearrangement where influence of the gem-diaryl group appeared crucial.

Multicomponent, Tandem 1,3- and 1,4-Bisarylation of Donor-Acceptor Cyclopropanes and Cyclobutanes with Electron-Rich Arenes and Hypervalent Arylbismuth Reagents.

A tandem catalytic process for 1,3- and 1,4-bisarylation of donor-acceptor (D-A) cyclopropanes and cyclobutanes is disclosed. This strategy capitalizes on the use of two distinct sources of nucleophilic and electrophilic arylating agents, affording the formation of two new C-C bonds in an orchestrated multicomponent fashion with the aid of a catalytic Lewis acid. Mechanistic investigations have revealed it to be a stereoselective process, and products could be easily elaborated into other useful compounds.

One-Step Assembly of Functionalized Morpholinones and 1,4-Oxazepane-3-ones via [3 + 3]- and [3 + 4]-Annulation of Aza-Oxyallyl Cation and Amphoteric Compounds.

A new [3 + 3]- and [3 + 4]-annulation strategy involving azaoxyallyl cation and [1,m]-amphoteric compounds (m = 3,4) is presented. This concise method enables easy assembly of functionalized saturated N-heterocycles, comprised of six-and seven-membered rings and is of high significance in the context of drug discovery approaches. This reaction also represents a new trapping modality of the azaoxyallyl cation with amphoteric agents of different chain lengths that consist of a heteroatom nucleophilic site and a π-electrophilic site.

[3 + 2]-Annulation of Azaoxyallyl Cations and Thiocarbonyls for the Assembly of Thiazolidin-4-ones.

A base-promoted, efficient [3 + 2] annulation between azaoxyallyl cations and thiocarbonyls is reported for flexible access to highly functionalized thiazolidin-4-one derivatives in good to excellent yields. An intriguing feature of this method is the metal or Lewis acid free late-stage entry of distinct set of functional groups at C2 of thiazolidin-4-ones via substitution of a latent amino functional group. Overall, this approach constitutes a general platform for convenient access to this medicinally important scaffold.

Lewis acid catalyzed annulation of spirocyclic donor-acceptor cyclopropanes with exo-heterocyclic olefins: access to highly functionalized bis-spirocyclopentane oxindole frameworks.

Lewis acid catalyzed highly efficient [3+2] annulation of spirocyclic Donor-Acceptor cyclopropanes (DACs) with exo-heterocyclic olefins is reported to furnish various biologically relevant dispiro-2,3-dioxopyrrolidine[cyclopentane]oxindole and dispiropyrazolone[cyclopentane]oxindole frameworks. This report highlights the use of oxindole-activated spiro-DACs as potential synthons to access complex dispirocarbocyclic oxindoles via ring-enlargement of the former, with high yields and diastereoselectivity.

Lewis Acid Catalyzed Nucleophilic Ring Opening and 1,3-Bisfunctionalization of Donor-Acceptor Cyclopropanes with Hydroperoxides: Access to Highly Functionalized Peroxy/(α-Heteroatom Substituted)Peroxy Compounds.

The Lewis acid catalyzed ring opening reaction of Donor-Acceptor (D-A) cyclopropanes with alkyl hydroperoxides is reported to furnish various peroxycarbonyls and 1,3-haloperoxygenated compounds in good to excellent yields. This method adds another instance to scarcely reported noncyclilizing 1,3-bisfunctionalization of D-A cyclopropanes with two different functional groups and relies on the dual role of peroxide as nucleophile and oxidant through an orchestrated reaction sequence. The products obtained, including α-heterosubstituted peroxy compounds, are amenable to useful synthetic elaboration.

Hypoxia-Activated, Small-Molecule-Induced Gene Expression.

Hypoxia, a condition of reduced oxygen, occurs in a wide variety of biological contexts, including solid tumors and bacterial biofilms, which are relevant to human health. Consequently, the development of chemical tools to study hypoxia is vital. Here we report a hypoxia-activated, small-molecule-mediated gene expression system using a bioreductive prodrug of the inducer isopropyl 1-thio-ß-d-galactopyranoside. As a proof-of-concept we have placed the production of a green fluorescent protein under the control of hypoxia. Our system has the potential to be extended to regulate the production of any given protein of choice.

Design, synthesis and evaluation of molecularly targeted hypoxia-activated prodrugs.

Regions of insufficient oxygen supply-hypoxia-occur in diverse contexts across biology in both healthy and diseased organisms. The difference in the chemical environment between a hypoxic biological system and one with normal oxygen levels provides an opportunity for targeting compound delivery to hypoxic regions by using bioreductive prodrugs. Here we detail a protocol for the efficient synthesis of (1-methyl-2-nitro-1H-imidazol-5-yl)methanol, which is a key intermediate that can be converted into a range of 1-methyl-2-nitro-1H-imidazole-based precursors of bioreductive prodrugs. We outline methods for attaching the bioreductive group to a range of functionalities, and we discuss the strategy for positioning of the group on the biologically active parent compound. We have used two parent checkpoint kinase 1 (Chk1) inhibitors to exemplify the protocol. The PROCEDURE also describes a suite of reduction assays, of increasing biological relevance, to validate the bioreductive prodrug. These assays are applied to an exemplar compound, CH-01, which is a bioreductive Chk1 inhibitor. This protocol has broad applications to the development of hypoxia-targeted compounds.

An uncharged oxetanyl sulfoxide as a covalent modifier for improving aqueous solubility.

Low aqueous solubility is a common challenge in drug discovery and development and can lead to inconclusive biological assay results. Attaching small, polar groups that do not interfere with the bioactivity of the pharmacophore often improves solubility, but there is a dearth of viable neutral moieties available for this purpose. We have modified several poorly soluble drugs or drug candidates with the oxetanyl sulfoxide moiety of the DMSO analog MMS-350 and noted in most cases a moderate to large improvement of aqueous solubility. Furthermore, the membrane permeability of a test sample was enhanced compared to the parent compound.

Copper-catalyst-controlled site-selective allenylation of ketones and aldehydes with propargyl boronates.

A practical and highly site-selective copper-PhBPE-catalyst-controlled allenylation with propargyl boronates has been developed. The methodology has shown to be tolerant of diverse ketones and aldehydes providing the allenyl adducts in high selectivity. The BPE ligand and boronate substituents were shown to direct the site selectivity for which either propargyl or allenyl adducts can be acquired in high selectivity. A model is proposed that explains the origin of the site selectivity.