Alkynyl Halo-Aza-Prins Annulative Couplings.

This article is a comprehensive report describing our studies in the field of aza-alkynyl Prins chemistry, comparing and contrasting the different reaction partners and reactivities observed during method development. The synthetic strategies combine an alkynyl aza-Prins coupling with an annulation, enabling the preparation of different nitrogen-containing heterocycles. Different iminium ions are explored as viable electrophiles for an alkynyl Prins cyclization, terminated by capture with a halogen nucleophile to form a vinyl halide. The synthetic utility of this functional handle is exploited through a number of Suzuki cross-couplings, allowing for the preparation of a modest library of compounds. In most cases, the Prins couplings are highly selective for the vinyl halides with E geometry, resulting from anti-addition across the alkyne.

Merging Strategy, Improvisation, and Conversation to Solve Problems in Target Synthesis.

Total synthesis has long been depicted as the quest to conquer the structures created by nature, requiring an unflinching, single-minded devotion to the task. The goal is achieved by chemists with grit, strength of will, and a competitive spirit. While there is some truth to this viewpoint, it does not fully capture the rich experiences gained in this research realm. In our lab, strategic planning, improvisation, and conversation have worked in concert to enable progress. This Account summarizes our efforts to synthesize four different bioactive targets: merrilactone A, rocaglamide, phomactin A, and tetrapetalone A. Certain missteps were integral to success in these synthetic projects. As such, we include the hiccups, and their roles in the evolution of the strategies, along with the results that aligned with our expectations.Two of these projects (merrilactone A and rocaglamide) culminated in the total synthesis of the targets. The challenges presented by merrilactone A spawned a new design strategy for pentannulation using Nazarov cyclization chemistry. This work demonstrated that Lewis acid catalysis is often a viable electrocyclization strategy in activated, polarized pentadienyl cation intermediates. We sought to apply the same logic to the rocaglamide target, but precursors we prepared did not behave according to plan. This situation pushed us to adapt our approach to match the innate reactivity of the substrate, resulting in an on-the-spot improvisation that was not only integral to the success of the project but also expanded our understanding of pentadienyl cation chemistry. In the other two projects (phomactin A and tetrapetalone A), we did not complete a total synthesis but did build the polycyclic core of the target. Even though the hetero [4 + 2] cycloaddition plan for assembling the macrocyclic oxadecalin ring system of phomactin A failed, the original experimental design still enabled us to solve the problem. Through a wholly unanticipated series of events, our focus on the oxadecalin ring system primed us for the discovery of a sequential iodoaldol/oxa-Michael sequence, using the original [4 + 2] building blocks. Then, the bridging ring present in phomactin A demanded we implement this sequence in a transannular fashion. Finally, our successful synthesis of the tetrapetalone core was enabled by consultations with others in the community. Each bond formation seemed to require different expertise, and in three separate instances (C-N cross-coupling, diastereoselective ring-closing metathesis, and oxidative dearomatization) synthetic challenges were overcome through conversation and collaboration.In our experience, the amount of creative power we summon during a target synthesis project correlates directly with the magnitude of the structural challenges we face. When reactivity surprises us, we analyze the problem anew, consult with colleagues, and improvise with the tools at hand. The inevitable misbehavior of a complex system is a strong motivating force, and one that has helped to shape our research program for nearly two decades.

Divergent Reactivity of Triaryldivinyl Ketones: Competing 4π and Putative 6π Electrocyclization Pathways.

This work describes an acid-promoted cyclization of triaryldivinyl ketones containing a thiophene moiety in the α-position. Two cyclization pathways are accessible: one a 4π-Nazarov cyclization and the other we propose to proceed through a 6π electrocyclic mechanism. The relative proportion of products from these divergent pathways is affected by reaction conditions and steric bulk in the substrate. We present experimental and computational evidence that when using HCl in dioxane, the 4π-conrotatory electrocyclization is more favorable, whereas GaCl3 in methylene chloride shifts the chemoselectivity toward a putative 6π-disrotatory electrocyclization. DFT calculations suggest that a complex interplay between kinetic and thermodynamic factors is implicated in the chemodivergent behavior.

Approach to High-Nitrogen Materials with Dual-Use Properties via Tetraaza-Nazarov Cyclization.

In this report, we describe the application of an electrocyclization toward the synthesis of a high-nitrogen heterocycle. It entails the synthesis of a novel, high-nitrogen, 2-3-disubstituted tetrazolium salt via the tetraaza-Nazarov cyclization (4π electrocyclization) of 3-bromo-1,5-bis(3-nitro-1,2,4-triazole-1H-5-yl)-formazan (BDNF). The cyclization takes place under mild conditions using the oxidant phenyliodine(III) diacetate (PIDA). The proposed electrocyclic mechanism is supported by density functional theory (DFT) calculations and data from previous studies of formazan cyclizations. This is noteworthy because while 4π electrocyclizations with one or two nitrogen atoms have been documented previously, this case represents the first example of generation and cyclization of a conjugated intermediate with four nitrogen atoms. The experimental behavior of electrocyclization is consistent with the predictions of DFT.

New Twists in Nazarov Cyclization Chemistry.

The defining feature of the Nazarov cyclization is a 4π-conrotatory electrocyclization, resulting in the stereospecific formation of functionalized cyclopentanones. The reaction provides access to structural motifs that are found in many natural products and drug targets. Harnessing the full potential of the Nazarov cyclization broadens its utility by enabling the development of new methodologies and synthetic strategies. To achieve these goals through efficient cyclization design, it is helpful to think of the reaction as a two-stage process. The first stage involves a 4π-electrocyclization leading to the formation of an allylic cation, and the second stage corresponds to the fate of this cationic intermediate. With a complete understanding of the discrete events that characterize the overall process, one can optimize reactivity and control the selectivity of the different Stage 2 pathways.In this Account, we describe the development of methods that render the Nazarov cyclization catalytic and chemoselective, focusing specifically on advances made in our lab between 2002 and 2015. The initial discovery made in our lab involved reactions of electronically asymmetric ("polarized") substrates, which cyclize efficiently in the catalytic regime using mild Lewis acidic reagents. These cyclizations also exhibit selective eliminative behavior, increasing their synthetic utility. Research directed toward catalytic asymmetric Nazarov cyclization led to the serendipitous discovery of a 4π-cyclization coupled to a well-behaved Wagner-Meerwein rearrangement, representing an underexplored Stage 2 process. With careful choice of promoter and loading, it is possible to access either the rearrangement or the elimination pathway. Additional experimental and computational studies provided an effective model for anticipating the migratory behavior of substiutents in the rearrangements. Problem-solving efforts prompted investigation of alternative methods for generating pentadienyl cation intermediates, including oxidation of allenol ethers and addition of nucleophiles to dienyl diketones. These Nazarov cyclization variants afford cyclopentenone products with vicinal stereogenic centers and a different arrangement of substituents around the ring. A nucleophilic addition/cyclization/elimination sequence can be executed enantioselectively using catalytic amounts of a nonracemic chiral tertiary amine.In summary, the discovery and development of several new variations on the Nazarov electrocyclization are described, along with synthetic applications. This work illustrates how strongly substitution patterns can impact the efficiency of the 4π-electrocyclization (Stage 1), allowing for mild Lewis acid catalysis. Over the course of these studies, we have also identified new ways to access the critical pentadienyl cation intermediates and demonstrated strategies that exploit and control the different cationic pathways available post-electrocyclization (Stage 2 processes). These advances in Nazarov chemistry were subsequently employed in the synthesis of natural product targets such as (±)-merrilactone A, (±)-rocaglamide, and (±)-enokipodin B.

Tuning Mechanism through Buffer Dependence of Hydrogen Evolution Catalyzed by a Cobalt Mini-enzyme.

Cobalt-mimochrome VI*a (CoMC6*a) is a synthetic mini-protein that catalyzes aqueous proton reduction to hydrogen (H2). In buffered water, there are multiple possible proton donors, complicating the elucidation of the mechanism. We have found that the buffer pKa and sterics have significant effects on activity, evaluated via cyclic voltammetry (CV). Protonated buffer is proposed to act as the primary proton donor to the catalyst, specifically through the protonated amine of the buffers that were tested. At a constant pH of 6.5, catalytic H2 evolution in the presence of buffer acids with pKa values ranging from 5.8 to 11.6 was investigated, giving rise to a potential-pKa relationship that can be divided into two regions. For acids with pKa values of ≤8.7, the half-wave catalytic potential (Eh) changes as a function of pKa with a slope of -128 mV/pKa unit, and for acids with pKa of ≥8.7, Eh changes as a function of pKa with a slope of -39 mV/pKa unit. In addition, a series of buffer acids were synthesized to explore the influence of steric bulk around the acidic proton on catalysis. The catalytic current in CV shows a significant decrease in the presence of the sterically hindered buffer acids compared to those of their parent compounds, also consistent with the added buffer acid acting as the primary proton donor to the catalyst and showing that acid structure in addition to pKa impacts activity. These results demonstrate that buffer acidity and structure are important considerations when optimizing and evaluating systems for proton-dependent catalysis in water.

Cationic Cascade for Building Complex Polycyclic Molecules from Simple Precursors: Diastereoselective Installation of Three Contiguous Stereogenic Centers in a One-Pot Process.

An expedient strategy for the synthesis of polycyclic small molecules is described. The method first joins together two achiral building blocks (an enyne and an aldehyde or a ketone) using an alkynyl halo-Prins protocol. Then, in the same reaction vessel, acidic conditions initiate a cationic cascade that includes a stereospecific halo-Nazarov electrocyclization and a diastereoselective Friedel-Crafts allylation. The entire sequence forms three carbon-carbon bonds and a carbon-halogen bond, generating halocyclopentene adducts in one pot from simple precursors. The process occurs with excellent diastereocontrol, providing highly functionalized polycycles containing three tertiary or quaternary stereogenic centers in a linear array. It is even possible to install three contiguous all-carbon quaternary centers using this method.

Leveraging the Halo-Nazarov Cyclization for the Chemodivergent Assembly of Functionalized Haloindenes and Indanones.

In this report, we describe a halo-Prins/aryl halo-Nazarov cyclization strategy that employs readily available starting materials, inexpensive reagents, and convenient reaction procedures to generate functionalized haloindenes and indanones. The scope and limitations of the method are outlined, demonstrating that aromatic systems readily react under mild, catalytic conditions when this strategy is implemented. Furthermore, we present both experimental and computational data supporting the notion that cyclizations of 3-halopentadienyl cationic intermediates are more kinetically accessible, as well as more thermodynamically favorable, than cyclizations of the analogous 3-oxypentadienyl cationic systems. The energetic advantage imparted by the halo-Nazarov cyclization design was found to be especially valuable in the cyclizations of arylallyl cationic intermediates, which require disruption of aromaticity.

Diastereoselective Construction of Densely Functionalized 1-Halocyclopentenes Using an Alkynyl Halo-Prins/Halo-Nazarov Cyclization Strategy.

A diastereoselective two-step strategy for the synthesis of densely functionalized 1-halocyclopentenes with several chiral centers has been developed. In the first step, a multicomponent alkynyl halo-Prins reaction joins an enyne, a carbonyl derivative, and either a chloride, bromide, or iodide to produce a cyclic ether intermediate. In the subsequent step, the intermediate is ionized to generate a halopentadienyl cation, which undergoes an interrupted halo-Nazarov cyclization. The products contain three new contiguous stereogenic centers, generated with a high level of stereocontrol, as well as a vinyl halide allowing for additional functionalization. The strategy creates two new carbon-carbon bonds, one carbon-halide bond, and one carbon-oxygen bond.

Studies toward the AB ring system of the tetrapetalone natural products.

Synthetic efforts toward the rapid assembly of the AB ring system of the tetrapetalones is described. Key to this work was the use of [3+2] cycloaddition/oxidative extrusion methodology to furnish functionalized aryl enones. The Nazarov cyclization of these substrates was examined, and optimized to generate the AB ring carbon skeleton. Then, Pd-catalyzed cross-coupling were conducted, and conditions were identified that enabled installation of the requisite C14-N bond.

Enantioselective Nazarov Cyclization Catalyzed by a Cinchona Alkaloid Derivative.

Nucleophilic catalysts for a 1,6 addition/Nazarov cyclization/elimination sequence were evaluated for their ability to induce enantioselectivity in the electrocyclization step. Of the tertiary amines examined, it was found that a cinchona alkaloid derivative was able to generate substituted 5-hydroxy γ-methylene cyclopentenones with excellent enantioselectivity. The study results suggest that successful cyclization depends upon the ability of the dienyl diketone substrate to readily adopt an s-cis conformation.

No acid required: 4π and 6π electrocyclization reactions of dienyl diketones for the synthesis of cyclopentenones and 2H-Pyrans.

The 1,6-conjugate addition of nucleophiles to dienyl diketones produces either cyclopentenone or 2H-pyran products with high selectivity through either Nazarov (4π) or 6π electrocyclization, respectively. The outcome of the reaction is dependent upon the nature of the nucleophile used. Nucleophiles that are anionic or easily deprotonated exclusively produce cyclopentenones via Nazarov cyclization, whereas the neutral nucleophile DABCO promotes 6π cyclization to afford 2H-pyrans. Experimental evidence is presented for both retro-4π and -6π electrocyclization in these systems, lending support to the bifurcated mechanistic hypothesis proposed for these cyclizations.

Synthesis of (±)-tetrapetalone A-Me aglycon.

The first synthesis of (±)-tetrapetalone A-Me aglycon is described. Key bond-forming reactions include Nazarov cyclization, a ring-closing metathesis promoted with complete diastereoselectivity by a chiral molybdenum-based complex, tandem conjugate reduction/intramolecular aldol cyclization, and oxidative dearomatization.

Hydroxychloroquine and a low activity bisphosphonate conjugate prevent and reverse ovariectomy-induced bone loss in mice through dual antiresorptive and anabolic effects.

Osteoporosis is incurable because there are no dual antiresorptive and anabolic therapeutic agents that can be administered long-term. The most widely used antiresorptive agents, bisphosphonates (BPs), also inhibit bone formation and thus have limited effect in preventing osteoporotic fracture. Hydroxychloroquine (HCQ), which is used to treat rheumatoid arthritis, prevents the lysosomal degradation of TNF receptor-associated factor 3 (TRAF3), an NF-κB adaptor protein that limits bone resorption and maintains bone formation. We attempted to covalently link HCQ to a hydroxyalklyl BP (HABP) with anticipated low antiresorptive activity, to target delivery of HCQ to bone to test if this targeting increases its efficacy to prevent TRAF3 degradation in the bone microenvironment and thus reduce bone resorption and increase bone formation, while reducing its systemic side effects. Unexpectedly, HABP-HCQ was found to exist as a salt in aqueous solution, composed of a protonated HCQ cation and a deprotonated HABP anion. Nevertheless, it inhibited osteoclastogenesis, stimulated osteoblast differentiation, and increased TRAF3 protein levels in vitro. HABP-HCQ significantly inhibited both osteoclast formation and bone marrow fibrosis in mice given multiple daily PTH injections. In contrast, HCQ inhibited fibrosis, but not osteoclast formation, while the HABP alone inhibited osteoclast formation, but not fibrosis, in the mice. HABP-HCQ, but not HCQ, prevented trabecular bone loss following ovariectomy in mice and, importantly, increased bone volume in ovariectomized mice with established bone loss because HABP-HCQ increased bone formation and decreased bone resorption parameters simultaneously. In contrast, HCQ increased bone formation, but did not decrease bone resorption parameters, while HABP also restored the bone lost in ovariectomized mice, but it inhibited parameters of both bone resorption and formation. Our findings suggest that the combination of HABP and HCQ could have dual antiresorptive and anabolic effects to prevent and treat osteoporosis.

Reagent control of [1,2]-Wagner-Meerwein shift chemoselectivity following the Nazarov cyclization: application to the total synthesis of enokipodin B.

An approach toward the carbon framework of various sesquiterpenes from the herbertane and cuparane families is described, including the concise total synthesis of enokipodin B. The key step is the construction of the vicinal quarternary centers of the skeleton through a tandem Nazarov cyclization/Wagner-Meerwein rearrangement mediated by a copper(II) complex. During this study, it was also found that changing the ligand architecture on the copper(II) promoter improved the chemoselectivity of the cationic rearrangement.

Efficient Nazarov cyclization/Wagner-Meerwein rearrangement terminated by a Cu(II)-promoted oxidation: synthesis of 4-alkylidene cyclopentenones.

The discovery and elucidation of a new Nazarov cyclization/Wagner-Meerwein rearrangement/oxidation sequence is described that constitutes an efficient strategy for the synthesis of 4-alkylidene cyclopentenones. DFT computations and EPR experiments were conducted to gain further mechanistic insight into the reaction pathways.

Gold (III) Chloride-Catalyzed 6-endo-trig Oxa-Michael Addition Reactions for Diastereoselective Synthesis of Fused Tetrahydropyranones.

Alkynones were treated with boron trifluoride diethyl etherate to generate ß-iodoallenolates, which underwent intramolecular aldol reactions to produce cycloalkenyl alcohols. Diastereoselective oxa-Michael ring closure could then be induced by treatment with a catalytic amount of gold(III) chloride, affording highly functionalized tetrahydropyran-containing ring systems.

Cascade cyclizations of acyclic and macrocyclic alkynones: studies toward the synthesis of phomactin A.

A study of the reactivity and diastereoselectivity of the Lewis acid promoted cascade cyclizations of both acyclic and macrocyclic alkynones is described. In these reactions, a ß-iodoallenolate intermediate is generated via conjugate addition of iodide to an alkynone followed by an intramolecular aldol reaction with a tethered aldehyde to afford a cyclohexenyl alcohol. The Lewis acid magnesium iodide (MgI2) was found to promote irreversible ring closure, while cyclizations using BF3·OEt2 as promoter occurred reversibly. For both acyclic and macrocyclic alkynones, high diastereoselectivity was observed in the intramolecular aldol reaction. The MgI2 protocol for cyclization was applied to the synthesis of advanced intermediates relevant to the synthesis of phomactin natural products, during which a novel transannular cation-olefin cyclization was observed. DFT calculations were conducted to analyze the mechanism of this unusual MgI2-promoted process.

Beyond the Divinyl Ketone: Innovations in the Generation and Nazarov Cyclization of Pentadienyl Cation Intermediates.

The requirement for new strategies for synthesizing five-membered carbocycles has driven an expansion in the study of the Nazarov cyclization. This renewed interest in the reaction has led to the discovery of several interesting new methods for generating the pentadienyl cation intermediate central to the cyclization. Methods reviewed include carbon-heteroatom ionization, functionalization of a double bond, nucleophilic addition, or electrocyclic ring opening. Additional variations employ unconventional substrates to produce novel pentacycles, such as the iso- and imino-Nazarov. Herein, we provide an overview of these unconventional, yet highly useful versions of the Nazarov cyclization.

Nitrogen-interrupted halo-Prins/halo-Nazarov fragment coupling cascade for the synthesis of indolines.

The nitrogen-interrupted Nazarov cyclization can be a powerful method for the stereocontrolled synthesis of sp3-rich N-heterocycles. However, due to the incompatibility between the basicity of nitrogen and the acidic reaction conditions, examples of this type of Nazarov cyclization are scarce. Herein, we report a one-pot nitrogen-interrupted halo-Prins/halo-Nazarov coupling cascade that joins two simple building blocks, an enyne and a carbonyl partner, to furnish functionalized cyclopenta[b]indolines with up to four contiguous stereocenters. For the first time, we provide a general method for the alkynyl halo-Prins reaction of ketones, thus enabling the formation of quaternary stereocenters. Additionally, we describe the outcomes of secondary alcohol enyne couplings, which exhibit helical chirality transfer. Furthermore, we investigate the impact of aniline enyne substituents on the reaction and evaluate the tolerance of different functional groups. Finally, we discuss the reaction mechanism and demonstrate various transformations of the prepared indoline scaffolds, highlighting their applicability in drug discovery campaigns.