Stereocontrolled and time-honored access to piperidine- and pyrrolidine-fused 3-methylenetetrahydropyrans using lactam-tethered alkenols.

Polycyclic oxygen-heterocycles bearing the 3-methylenetetrahydropyran (i.e., 3-MeTHP) motif are resident in bioactive molecules such as hodgsonox and iridoid. Meanwhile, the δ- and γ-lactam topologies as well as their reduced variants (i.e., piperidines and pyrrolidines) are at the core of several pharmaceuticals and fragrances. A stereocontrolled, time-honored, and cost-effective strategy that merges a 3-MeTHP motif with the aforementioned azaheterocyclic scaffolds could exponentially expand the 3D-structural space for the discovery of new small molecules with medicinal value. In these studies, readily affordable lactam-tethered alkenols have been interrogated in two complementary cascade approaches, leading to the regioselective and stereocontrolled synthesis of lactam-fused 3-MeTHPs. The first approach hinges on regioselective 6-endo-trig bromoetherification of the alkenols and concomitant elimination to arrive at the desired 3-MeTHPs. The methylene portion of the 3-MeTHP is unveiled at a late stage, which is noteworthy since all existing approaches to 3-MeTHPs rely on early-stage introduction of the methylene group. The second strategy involves transition metal-catalyzed alkoxylation of the tethered alkenol followed by base-induced double bond isomerization. The lactam-fused 3-MeTHPs are obtained in high site- and diastereo-selectivities. Post-modification of the bicycles has led to the construction of 3-MeTHP-fused saturated piperidines and pyrrolidines as well as 3-MeTHPs bearing four contiguous stereocenters.

Harnessing the 1,3-azadiene-anhydride reaction for the regioselective and stereocontrolled synthesis of lactam-fused bromotetrahydropyrans by bromoetherification of lactam-tethered trisubstituted tertiary alkenols.

Halo-cycloetherification of lactam-tethered alkenols enables the construction of oxygen-heterocycles that are fused to nitrogen heterocycles via intramolecular halonium-induced nucleophilic addition. Specifically, tetrahydropyrans (THPs) that are fused to a nitrogen heterocycle constitute the core of several bioactive molecules, including tachykinin receptor antagonists and alpha-1 adrenergic antagonists. Although the literature is replete with successful examples of the halo-cycloetherification of simple mono- or disubstituted primary alkenols, methods for the modular, efficient, regioselective, and stereocontrolled intramolecular haloetherification of sterically encumbered trisubstituted tertiary alkenols are rare. Here, we describe a simple intramolecular bromoetherification strategy that meets these benchmarks and proceeds with exclusive 6-endo regioselectivity. The transformation employs mild and water-tolerant conditions, which bodes well for late-stage diversification. The hindered ethers contain four contiguous stereocenters as well as one halogen-bearing tetrasubstituted stereocenter.

Revisiting the 1,3-azadiene-succinic anhydride annulation reaction for the stereocontrolled synthesis of allylic 2-oxopyrrolidines bearing up to four contiguous stereocenters.

Polysubstituted 2-oxopyrrolidines bearing at least two contiguous stereocenters constitute the core of several pharmaceuticals, including clausenamide (antidementia). Here, we describe a flexible annulation strategy, which unites succinic anhydride and 1,3-azadienes to produce allylic 2-oxopyrrolidines bearing contiguous stereocenters. The approach is chemoselective, efficient, modular, scalable, and diastereoselective. The scalable nature of the reactions offers the opportunity for post-diversification, leading to incorporation of motifs with either known pharmaceutical value or that permit subsequent conversion to medicinally relevant entities.

Diastereospecific arylation and cascade deconstructive amidation/thioesterification of readily available lactam-fused bromolactones.

An intrinsic goal when designing synthetic methodology is to identify approaches whereby readily accessible precursors are converted into an array of products, which efficiently tap into new 3D-chemical space. In these studies, readily available bicyclic lactam-bromolactones have been interrogated in several fragment growth protocols by utilizing the halogen and lactone motifs as versatile linchpins for strategic construction of C-C, C-N, C-O, and C-S bonds. Diastereospecific C(sp3)-C(sp2) Kumada coupling of sterically imposing [5,5]-bicyclic lactam-bromolactones with several aryl Grignard reagents, under palladium catalysis, furnishes diarylmethane-tethered lactam-lactones in synthetically attractive yields, stereoinvertive fashion, and with a tolerance for many functional groups. When [5,6]-bicyclic lactam-bromolactones, which are prone to ß-hydride elimination are employed, efficient arylation is observed only under Co(acac)3-catalyzed conditions. Importantly, these [5,6]-bicyclic lactam-bromolactones undergo retentive arylation, independent of the transition metal catalyst. A base-mediated cascade deconstructive amidation of the [5,6]-bicyclic lactam-bromolactones with primary aliphatic amines proceeds efficiently to afford epoxide-tethered lactam carboxamides, which bear four contiguous stereocenters. Furthermore, an unusual route to homoallylic thioesters has been uncovered through deconstructive contra-thermodynamic thioesterification of the lactam-fused bromolactone precursors.

Regiodivergent synthesis of sulfone-tethered lactam-lactones bearing four contiguous stereocenters.

Sulfone-tethered lactones/amides/amines display a diverse spectrum of biological activities, including anti-psychotic and anti-hypertensive. Sulfones are also widely present in functional materials and fragrances. We therefore reasoned that a regiodivergent and stereocontrolled strategy that merges the sulfone, lactone, and lactam motifs would likely lead to the discovery of new pharmacophores and functional materials. Here, we report mild conditions for the sulfonyllactonization of γ-lactam-tethered 5-aryl-4(E)-pentenoic acids. The annulation is highly modular, chemoselective, and diastereoselective. With respect to regioselectivity, trisubstituted alkenoic acids display a preference for 5-exo-trig cyclization whereas disubstituted alkenoic acids undergo exclusive 6-endo-trig cyclization. The lactam-fused sulfonyllactones bear angular quaternary as well as four contiguous stereocenters. The products are post-modifiable, especially through a newly developed Co-catalyzed reductive cross-coupling protocol.

Introducing a sulfone-embedded anhydride to the anhydride-imine reaction for the modular synthesis of N-heterocyclic sulfones bearing vicinal stereocenters.

N-heterocyclic sulfones constitute the core of several pharmaceuticals, including the antityrpanosomal drug Nifurtimox. Their biological relevance and architectural complexity makes them valued targets and inspires the development of more selective and atom-economical strategies for their construction and post-modification. In this embodiment, we describe a flexible approach to sp3-rich N-heterocyclic sulfones, which hinges on the efficient annulation of a novel sulfone-embedded anhydride with 1,3-azadienes and aryl aldimines. Further elaboration of the lactam esters has facilitated the construction of a library of vicinally functionalized sulfone-embedded N-heterocycles.

Serendipitous synthesis of cross-conjugated dienes by cascade deconstructive esterification of thiomorpholinone-tethered alkenoic acids.

Functionalized 1,3-dienes are ubiquitous structural motifs in biologically pertinent molecules. They are frequently employed as precursors for a broad range of chemical transformations, including Diels-Alder reactions. The stereoselective construction of highly decorated 1,3-dienes therefore represents an important research objective. Medicinal chemists are becoming increasingly interested in synthetic methodologies that not only achieve expedient construction and peripheral editing of heterocycles, but also seek to modify their core framework in order to achieve skeletal remodeling. In a succinct manifestation of this 'scaffold hopping' concept, we herein describe a cascade reaction, which converts thiomorpholinone-tethered alkenoic acids to 1,1-disubstituted amino-1,3-dienes. This domino process involves esterification of the acid, base-assisted ring-opening, and concomitant 1,2-migration of the α-amino alkenyl group. Several control experiments have revealed that the alkenyl substituent is necessary for deconstruction to occur. Inherently more activated N-aryl-substituted thiomorpholinone acids react significantly faster than their less activated N-alkyl congeners.

Contra-thermodynamic halolactonization of lactam-tethered 5-aryl-4(E)-pentenoic acids for the flexible and stereocontrolled synthesis of fused lactam-halolactones.

Halolactonization of alkenoic acids enables the construction of oxygen-heterocycles via intramolecular halonium-induced nucleophilic addition. Although the literature is currently inundated with halolactonizations of 5-aryl-4(E)-pentenoic acids that predictably afford the 6-endo cyclization adducts, methods that reliably alter the innate regioselectivity bias to instead deliver the thermodynamically less favored 5-exo cyclization products are relatively rare. Here, we attempt to bridge this gap and have found mild conditions for contra-thermodynamic halolactonization of lactam-tethered 5-aryl-4(E)-pentenoic acids that lead to the formation of trans-fused lactam-γ-lactones. The natural proclivity for these 5-aryl-4(E)-pentenoic acids to undergo 6-endo cyclization is overridden and 5-exo-trig cyclization predominates. The success of the approach hinges on the use of N,N-dimethylformamide (DMF) as the solvent and N-methylmorpholine oxide as the catalyst. The lactam-lactone products are synthesized in high diastereoselectivity, modularity, and chemoselectivity. Notably, most of the bicycles contain one benzylic quaternary stereocenter as well as an α-alkoxy quaternary stereocenter.

Stereocontrolled access to δ-lactone-fused-γ-lactams bearing angular benzylic quaternary stereocenters.

C-fused γ-lactam-lactones are resident in several bioactive molecules, including anticancer agents such as omuralide. In this embodiment, we report mild conditions for the catalytic halolactonization of lactam-tethered 5-aryl-4(E)-pentenoic acids. The use of dichloromethane as the solvent and Ph3P[double bond, length as m-dash]S as the catalyst led to predominant 6-endo-trig cyclization and furnished the trans-fused-γ-lactam-δ-lactones. The transformation is modular, regioselective, chemoselective, and diastereoselective. The γ-lactam-δ-lactones bear angular quaternary benzylic stereocenters, which is noteworthy since the presence of a quaternary carbon in bioactive small molecules often promotes an element of conformational restriction that imparts potency, selectivity, and metabolic stability. The generated halogen and lactone motifs are important functional handles for late-stage diversification.

Leveraging the 1,3-azadiene-anhydride reaction for the synthesis of functionalized piperidines bearing up to five contiguous stereocenters.

A modular and scalable strategy, which remodels 3-methylglutaric anhydride to 2-oxopiperidines bearing at least three contiguous stereocenters is described. The approach relies on the chemoselective and stereocontrolled annulation of 1,3-azadienes with the anhydride component. The resulting acid-tethered allylic 2-oxopiperidines are then engaged in several selective fragment growth processes, including catalytic denitrative alkenylation, halolactonization, and Vilsmeier-Haack functionalization.

Direct access to vicinally functionalized and N-trifluoroacetylated (bicyclic)ketopiperazines using a readily affordable N-heterocyclic anhydride.

Functionalized 2-piperazinones play essential roles as conformationally-constrained peptidomimetics by mimicking inverse γ-turns in peptides. Here, we describe an efficient, scalable, stereoselective, modular, and chemoselective annulation protocol between a novel N-trifluoroacetyl anhydride and several reactive partners, including lactim ethers, imidoyl chlorides, aryl aldimines, and 1,3-azadienes, leading to vicinally functionalized (bicyclic) 2-piperazinones.

Catalytic, selective, and stereocontrolled construction of C4 quaternary and homobenzylic dihydroisoquinolones by sp3 C-H benzylation.

C1 benzylated isoquinoline derivatives constitute the core of benzylisoquinoline alkaloids (BIAs). However, their C4 congeners remain elusive. Here, we describe a diastereoselective, catalytic, and modular C(sp3)-C(sp3) coupling protocol wherein ß-amino sp3 C-H bonds of readily affordable vicinally functionalized dihydroisoquinolones are replaced by sp3 C-benzyl bonds. The method provides expedient access to C4 quaternary and homobenzylic dihydroisoquinolones, which are attractive fragments for potential drug discovery.

Transition metal-free domino acyl substitution/Michael addition of alkenyl Grignard reagents to lactam esters: synthesis of lactam-bearing homoallylic ketones.

A solvent-controlled protocol for the direct and transition metal-free addition of alkenyl Grignard reagents to vicinally functionalized sp3-rich morpholinones has been developed, leading to the chemo and regioselective synthesis of lactam-bearing homoallylic ketones. The addition of lithium chloride proved to be essential. In cases where a new stereocenter is generated, the doubly branched homoallylic ketones are obtained in unexpectedly high diastereoselectivities. Efforts to extend the methodology to other heterosubstituted lactams revealed some important reactivity and selectivity differences.

Site-selective, catalytic, and diastereoselective sp3 C-H hydroxylation and alkoxylation of vicinally functionalized lactams.

The C-H bond functionalization of sp3 carbon centres presents a significant challenge due to the inert nature of hydrocarbons as well as the need to selectively functionalize one of the numerous aliphatic C-H bonds embodied in organic molecules. Here, we describe catalytic, diastereoselective, and site-selective sp3 C-H hydroxylation/alkoxylation protocols featuring dihydroisoquinolones, γ-, and δ-lactams, which bear vicinal stereocenters. The hydroxylation strategy utilizes oxygen, a waste-free oxidant and affords attractive fragments for potential drug discovery. Fe-catalyzed dehydrative coupling of the resulting tertiary alcohols with simple primary alcohols has led to the construction of highly versatile unsymmetrical dialkyl ethers.

Modular synthesis and transition metal-free alkynylation/alkenylation of Castagnoli-Cushman-derived N,O- and N,S-heterocyclic vinyl chlorides.

A modular and functional group-tolerant protocol for the transition metal-free coupling of novel N,O- and N,S-heterocyclic vinyl chlorides with terminal acetylenes and styrenes has been developed, leading to the epimerization-free synthesis of fully carbofunctionalized dihydro-1,4-oxazines/thiazines. Bicyclic morpholines have also been prepared through the interrogation of newly synthesized cross-conjugated dienes in Diels-Alder reactions. The use of environmentally benign reaction media endows the current strategy with a practical advantage.

Expedient and modular access to 2-azabicyclic architectures by iron-catalyzed dehydrative coupling of alcohol-bearing allylic lactams.

A high-yielding, cost-effective, modular and environmentally benign approach to [5,5]- or [6,5]-2-azabicyclic architectures bearing vicinal stereocenters, by Fe-catalyzed intramolecular dehydrative coupling of readily affordable alcohol-bearing allylic lactams is presented.

Modular access to vicinally functionalized allylic (thio)morpholinonates and piperidinonates by substrate-controlled annulation of 1,3-azadienes with hexacyclic anhydrides.

A modular substrate-controlled hexannulation of inherently promiscuous 1,3-azadienes with hexacyclic anhydrides, which affords versatile vicinally functionalized allylic lactams, in high yields, regio- and stereoselectivities is described.

Regiocontrolled synthesis of (hetero)aryl and alkenyl dehydropyrrolidines, dehydropiperidines and azepenes by Ru-catalyzed, heteroatom-directed α-C-H activation/cross-coupling of cyclic enamides with boronic acids.

The synthesis of α-aryl and alkenyl pyrrolidine-, piperidine-, and azepane derivatives, through the intermediacy of cyclic enamides is described. The desired outcome is achieved through ruthenium-catalyzed, site-selective sp(2) C-H activation/cross-coupling with aryl and alkenyl boronic acids. The regioselectivity (α-sp(2)vs. α-sp(3)vs. ß-sp(2) C-H functionalization) is governed by the rate differences between sp(2) and sp(3) C-H activation and the necessity for chelation between the ruthenium metal and the carbonyl directing group.

One-shot access to α,ß-difunctionalized azepenes and dehydropiperidines by reductive cross-coupling of α-selenonyl-ß-selenyl enamides with organic bromides.

The synthesis of α- and α,ß-functionalized azepenes and dehydropiperidines from readily prepared α-selenonyl eneformamides or enecarbamates has been achieved through Fe-catalyzed α-substitutive deselenonation, ß-regioselective lithiation/trapping, and Co-catalyzed reductive cross-coupling protocols.

Trapping of carbolithiation-derived tertiary benzylic α-lithio piperidines with carbon electrophiles: Controlling the formation of α-amino quaternary and vicinal stereocenters.

The interception of carbolithiation-derived tertiary benzylic α-lithio piperidines with carbon electrophiles, under HMPA-mediated conditions, has led to the diastereoselective synthesis of vicinally functionalized piperidines bearing α-amino quaternary stereocenters.