Comprehensive Mechanistic Analysis of Palladium- and Nickel-Catalyzed α,ß-Dehydrogenation of Carbonyls via Organozinc Intermediates.

Introducing degrees of unsaturation into small molecules is a central transformation in organic synthesis. A strategically useful category of this reaction type is the conversion of alkanes into alkenes for substrates with an adjacent electron-withdrawing group. An efficient strategy for this conversion has been deprotonation to form a stabilized organozinc intermediate that can be subjected to α,ß-dehydrogenation through palladium or nickel catalysis. This general reactivity blueprint presents a window to uncover and understand the reactivity of Pd- and Ni-enolates. Within this context, it was determined that ß-hydride elimination is slow and proceeds via concerted syn-elimination. One interesting finding is that ß-hydride elimination can be preferred to a greater extent than C-C bond formation for Ni, more so than with Pd, which defies the generally assumed trends that ß-hydride elimination is more facile with Pd than Ni. The discussion of these findings is informed by KIE experiments, DFT calculations, stoichiometric reactions, and rate studies. Additionally, this report details an in-depth analysis of a methodological manifold for practical dehydrogenation and should enable its application to challenges in organic synthesis.

Accessing Z-Enynes via Cobalt-Catalyzed Propargylic Dehydrogenation.

Alkenes constitute an enabling motif in organic synthesis, as they can be functionalized to form highly substituted molecules. Z-alkenes are generally challenging to access due to the thermodynamic preference for the formation of E-alkenes compared to Z-alkenes. Dehydrogenation methodologies to selectively form Z-alkenes have not yet been reported. Herein, we report a Z-selective, propargylic dehydrogenation that provides 1,3-enynes through the invention of a Co-catalyzed oxidation system. Observation of a kinetic isotope effect (KIE) revealed that deprotonation of the propargylic position is the rate limiting step. Additionally, isomerization experiments were conducted and confirmed that the observed Z-selectivity is a kinetic effect. A proposed stereomechanistic model for the Z-selectivity is included.

Total Synthesis of (+)-Shearilicine.

Herein we report the first total synthesis of the indole diterpenoid natural product shearilicine by an 11-step sequence via a generalizable precursor to the highly oxidized subclass of indole diterpenoids. A native chiral auxiliary strategy was employed to access the target molecule in an enantiospecific fashion. The formation of the key carbazole substructure was achieved through a mild intramolecular Heck cyclization, wherein a computational study revealed noncovalent substrate-ligand and ligand-ligand interactions that promoted migratory insertion.

Palladium-Catalyzed Carbonylative Difunctionalization of Unactivated Alkenes Initiated by Unstabilized Enolates.

This report describes the first example of palladium-catalyzed carbonylative difunctionalization of unactivated alkenes initiated by enolate nucleophiles. The approach involves initiation by an unstabilized enolate nucleophile under an atmospheric pressure of CO and termination with a carbon electrophile. This process is compatible with a diverse range of electrophiles, including aryl, heteroaryl, and vinyl iodides to yield synthetically useful 1,5-diketone products, which were demonstrated to be precursors for multi-substituted pyridines. A PdI -dimer complex with two bridging CO units was observed although its role in catalysis is not yet understood.

Pentosinane, a Post-Translational Modification of Human Proteins with Underappreciated Stability.

Pentosinane is a structurally complex nonenzymatic post-translational modification of proteins believed to be present in all living things. It falls into the category of advanced glycation end products (AGEs) and is structurally related to the other AGEs pentosidine and glucosepane. Although pentosidine and glucosepane have been widely studied for their role in wide-ranging conditions (e.g., diabetes mellitus, Alzheimer's disease, and human aging), relatively little is known about pentosinane. Interestingly, previous reports have suggested that pentosidine may derive from pentosinane. The (patho)physiological significance of pentosinane in humans is largely unexplored. As a first step to address this knowledge gap, we report herein the first total synthesis of pentosinane. Our synthesis is high yielding (1.7% over seven steps), concise, and enantioselective, and it leverages a strategy for synthesizing 2,5-diaminoimidazoles previously developed by our lab. Access to synthetic pentosinane has allowed us to perform additional studies showing that its oxidation to pentosidine is both pH and oxygen dependent and is substantially slower under physiological conditions than previously believed. Additionally, pentosinane rapidly decomposes under harshly acidic conditions typically employed for pentosidine isolation. Taken together, these results suggest that pentosinane is likely to be more abundant in vivo than previously appreciated. We believe these results represent a critical step toward illuminating the role(s) of pentosinane in human biology.

Dehydrogenative Pd and Ni Catalysis for Total Synthesis.

The development of novel synthetic methods remains a cornerstone in simplifying complex molecule synthesis. Progress in the field of transition metal catalysis has enabled new mechanistic strategies to achieve difficult chemical transformations, increased the value of abundant chemical building blocks, and pushed the boundaries of creative and strategic route design to improve step economy in multistep synthesis. Methodologies to introduce an olefin into saturated molecules continue to be essential transformations because of the plethora of reactions available for alkene functionalization. Of particular importance are dehydrogenation reactions adjacent to electron-withdrawing groups such as carbonyls, which advantageously provide activated olefins that can be regioselectively manipulated. Palladium catalysis occupies a central role in the most widely adopted carbonyl dehydrogenation reactions, but limits to the scope of these protocols persist.In this Account, we describe our group's contributions to the area of transition-metal-catalyzed dehydrogenation using palladium catalysis and more sustainable and economical nickel catalysis. These metals are used in conjunction with allyl and aryl halides or pseudohalides that serve as oxidants to access a unique mechanistic approach for one-step α,ß-dehydrogenation of various electron-withdrawing groups, including ketones, esters, nitriles, amides, carboxylic acids, and electron-deficient heteroarenes. The pivotal reaction parameters that can be modified to influence reaction efficiency are highlighted, including base and oxidant structure as well as ligand and salt additive effects. This discussion is expected to serve as a guide for troubleshooting challenging dehydrogenation reactions and provide insight for future reaction development in this area.In addition to enabling dehydrogenation reactions, our group's allyl-Pd and -Ni chemistry can be used for C-C and C-X bond-forming reactions, providing novel disconnections with practical applications for expediting multistep synthesis. These transformations include a telescoped process for ketone α,ß-vicinal difunctionalization; an oxidative enone ß-functionalization, including ß-stannylation, ß-silylation, and ß-alkylation; and an oxidative cycloalkenylation between unstabilized ketone enolates and unactivated alkenes. These bond-forming methodologies broaden the range of transformations accessible from abundant ketone, enone, and alkene moieties. Both the dehydrogenation and C-C and C-X bond-forming methodologies have been implemented in our group's total synthesis campaigns to provide step-efficient synthetic routes toward diverse natural products.Through the lens of multistep synthesis, the utility and robustness of our dehydrogenation and dehydrogenative functionalization methodologies can be better appreciated, and we hope that this Account will inspire practitioners to apply our methodologies to their own synthetic challenges.

Coordination-Controlled Nickel-Catalyzed Benzylic Allylation of Unactivated Electron-Deficient Heterocycles.

Heterocycles are widespread in pharmaceuticals but methods for their transition metal-catalyzed functionalization remain limited. This report describes a general, mild, and effective nickel-catalyzed benzylic allylation and benzylation of 14 types of heterocyclic aromatic compounds, including pyridines, pyrazines, pyrimidines, pyridazines, triazines, benzimidazoles, oxazoles, thiazoles, as well as 3,3-dimethyl-indoles. The exquisite selectivity for benzylic sites at the 2-position is hypothesized to be controlled by coordination of a heterocyclic nitrogen to Zn(TMP)2 subverting generally presumed pKa 's of benzylic protons. Furthermore, the broad range of heterocyclic substrates, the diversity of electrophiles, and excellent functional group compatibility suggest its future application to synthesis of complex molecules and library diversification in drug discovery.

An invocation for computational evaluation of isomerization transforms: cationic skeletal reorganizations as a case study.

Covering: 2010 to 2020This review article describes how cationic rearrangement reactions have been used in natural product total synthesis over the last decade as a case study for the many productive ways by which isomerization reactions are enabling for synthesis. This review argues that isomerization reactions in particular are well suited for computational evaluation, as relatively simple calculations can provide significant insight.

Copper(I)-Catalyzed Asymmetric Conjugate 1,6-, 1,8-, and 1,10-Borylation.

Catalytic asymmetric remote conjugate borylation is challenging as the control of regioselectivity is not trivial, the electrophilicity of remote sites is extenuated, and the remote asymmetric induction away from the carbonyl group is difficult. Herein, catalytic asymmetric conjugate 1,6-, 1,8- and 1,10-borylation was developed with excellent regioselectivity, which delivered α-chiral boronates in moderate to high yields with high enantioselectivity. The produced chiral boronate smoothly underwent oxidation, cross-coupling, and one-carbon homologation to give synthetically versatile chiral compounds in moderate yields with excellent stereoretention. Furthermore, a stereomechanistic analysis was conducted using DFT calculations, which provides insights into the origins of the regioselectivity. Finally, the present 1,6-borylation was successfully applied in an efficient one-pot asymmetric synthesis of (-)-7,8-dihydrokavain.

Aryl-Nickel-Catalyzed Benzylic Dehydrogenation of Electron-Deficient Heteroarenes.

This manuscript describes the first practical benzylic dehydrogenation of electron-deficient heteroarenes, including pyridines, pyrazines, pyrimidines, pyridazines, and triazines. This transformation allows for the efficient benzylic oxidation of heteroarenes to afford heterocyclic styrenes by the action of nickel catalysis paired with an unconventional bromothiophene oxidant.

Stereochemical revision of xylogranatin F by GIAO and DU8+ NMR calculations.

This manuscript describes predicted NMR shifts for the limonoid natural product xylogranatin F. The 1 H and 13 C NMR shifts of four diastereomers were evaluated by GIAO and hybrid DFT/parametric DU8+ methods. The results of the 1 H and 13 C NMR calculations for both the GIAO method and the DU8+ calculations suggest the revised structure that was recently reassigned by chemical synthesis. Furthermore, we show that while DU8+ provides superior accuracy with less computation time, GIAO points to the correct structure with more distinguishable data in this case study.

Nickel-Catalyzed Difunctionalization of Unactivated Alkenes Initiated by Unstabilized Enolates.

This report demonstrates the possibility of a nickel-catalyzed difunctionalization of unactivated alkenes initiated by an unstabilized enolate nucleophile. The process tolerates a diverse range of electrophiles, including aryl, heteroaryl, alkenyl, and amino electrophiles. An electron-deficient phosphine ligand and a tetrabutylammonium salt additive were crucial for promoting efficient vicinal difunctionalization.

Total Synthesis of (+)-Granatumine A and Related Bislactone Limonoid Alkaloids via a Pyran to Pyridine Interconversion.

We report the first total synthesis of (+)-granatumine A, a limonoid alkaloid with PTP1B inhibitory activity, in ten steps. Over the course of this study, two key methodological advances were made: a cost-effective procedure for ketone α,ß-dehydrogenation using allyl-Pd catalysis, and a Pd-catalyzed protocol to convert epoxyketones to 1,3-diketones. The central tetrasubstituted pyridine is formed by a convergent Knoevenagel condensation and carbonyl-selective electrocyclization cascade, which was followed by a direct transformation of a 2 H-pyran to a pyridine. These studies have led to the structural revision of two members of this family.

Allyl-Nickel Catalysis Enables Carbonyl Dehydrogenation and Oxidative Cycloalkenylation of Ketones.

We herein disclose the first report of a first-row transition metal-catalyzed α,ß-dehydrogenation of carbonyl compounds using allyl-nickel catalysis. This development overcomes several limitations of previously reported allyl-palladium-catalyzed oxidation, and is further leveraged for the development of an oxidative cycloalkenylation reaction that provides access to bicycloalkenones with fused, bridged, and spirocyclic ring systems using unactivated ketone and alkene precursors.

Total Synthesis of Paspaline A and Emindole PB Enabled by Computational Augmentation of a Transform-Guided Retrosynthetic Strategy.

We report the total syntheses of two indole diterpenoid natural products, paspaline A and emindole PB. Paspaline A is synthesized in a 9-step sequence from commercially available materials. The first total synthesis of emindole PB is accomplished in 13 steps and confirms a previously ambiguous structural assignment. Density functional theory calculations are utilized to interrogate the key carbocationic rearrangement in a predictive capacity to aid in the selection of the most favorable precursor substrate. This work highlights how retrosynthetic design can be augmented with quantum chemical calculations to reveal energetically feasible synthetic disconnections, minimizing time-consuming and expensive empirical evaluation.

Convergent Total Synthesis of Principinol D, a Rearranged Kaurane Diterpenoid.

The total synthesis of principinol D, a rearranged kaurane diterpenoid, is reported. This grayanane natural product is constructed via a convergent fragment coupling approach, wherein the central seven-membered ring is synthesized at a late stage. The bicyclo[3.2.1]octane fragment is accessed by a Ni-catalyzed α-vinylation reaction. Strategic reductions include a diastereoselective SmI2-mediated ketone reduction with PhSH and a new protocol for selective ester reduction in the presence of ketones. The convergent strategy reported herein may be an entry point to the larger class of kaurane diterpenoids.

Analysis of chain length, substitution patterns, and unsaturation of AM-404 derivatives as 20S proteasome stimulators.

Proteasome-mediated degradation of proteins is a vital cellular process and is performed by the ubiquitin-dependent proteasome system (UPS) and the ubiquitin-independent proteasome system (UIPS). While both systems are necessary to maintain healthy cell function, many disease states are characterized by reduced activity of the UPS, and the UIPS cannot by itself maintain proper protein levels. It has been suggested that the 20S core particle (20S CP), the isoform of the proteasome in the UIPS that can degrade proteins without a ubiquitin tag, can be stimulated with a small molecule to assist the 20S CP to accept and hydrolyze substrates more rapidly. Several small molecule stimulators of the 20S CP have since been discovered, including AM-404, an arachidonic acid derivative. AM-404 has previously been shown to inhibit fatty acid amide hydrolase activity. We wished to evaluate what structural components of AM-404 are required to stimulate the 20S CP with the long-term goal of using this information to design a stimulator with better drug-like qualities. We synthesized numerous derivatives of AM-404, varying the chain length, substitutions, and degree of unsaturation. Through this endeavor, we obtained several molecules capable of stimulating the 20S CP to various degrees. We discovered that though chain length is important, the presence of a cis-alkene in a specific location in the aliphatic chain has the greatest impact on the ability to stimulate the 20S CP. Two of the derivatives maintain modest stimulatory activity, and have improved toxicity over AM-404.

Vinylogous acyl triflates as an entry point to α,ß-disubstituted cyclic enones via Suzuki-Miyaura cross-coupling.

An alternative protocol for the B-alkyl Suzuki-Miyaura reaction to produce cyclic α,ß-disubstituted enones is reported. The use of ß-triflyl enones as coupling partners in lieu of their halogenated analogs provides enhanced substrate stability to light and chromatography without adversely affecting reactivity. This protocol allows efficient access to the synthetically challenging α,ß-disubstituted enone motif under mild conditions.

Methods Utilizing First-Row Transition Metals in Natural Product Total Synthesis.

First-row transition-metal-mediated reactions constitute an important and growing area of research due to the low cost, low toxicity, and exceptional synthetic versatility of these metals. Currently, there is considerable effort to replace existing precious-metal-catalyzed reactions with first-row analogs. More importantly, there are a plethora of unique transformations mediated by first-row metals, which have no classical second- or third-row counterpart. Herein, the application of first-row metal-mediated methods to the total synthesis of natural products is discussed. This Review is intended to highlight strategic uses of these metals to realize efficient syntheses and highlight the future potential of these reagents and catalysts in organic synthesis.

Computational chemistry strategies in natural product synthesis.

The synthesis of natural products increasingly uses computational chemistry approaches to model and understand molecular phenomena. Calculations are employed to rationalize reaction outcomes, predict how a new system will perform, and inform synthetic design. As a result, new insights into the interactions of fundamental chemical forces have emerged that advance the field of complex small molecule synthesis. This review presents ten examples of computational techniques used in the synthesis of natural products, and discusses the unique perspectives afforded by these quantitative analyses.