Formation of All-Carbon Quaternary Centers via Enantioselective Pd-Catalyzed α-Vinylation of γ-Lactams.

Herein, we report an enantioselective vinylation of α-substituted γ-lactams that forges quaternary centers in up to 59% yield with 94% ee. The use of canonically inactive vinyl chloride electrophiles afforded the highest yields and levels of stereoselectivity, and a range of trisubstituted vinyl chlorides were found to be proficient in promoting this transformation. These stereogenic products could be further elaborated to functionally rich scaffolds, thereby highlighting the synthetic utility of this process.

Divergent total syntheses of pyrroloiminoquinone alkaloids enabled by the development of a Larock/Buchwald-Hartwig annulation/cyclization.

Pyrroloiminoquinone alkaloids are a large class of natural products that display a wide range of biological activities. Synthetic approaches to these natural products typically rely on a common late-stage C10-oxygenated pyrroloiminoquinone intermediate, but these strategies often lead to lengthy synthetic sequences that are not amenable to divergent syntheses. We devised an alternative approach aimed at the early introduction of the C10 nitrogen, which we hypothesized would enable late-stage diversification. This strategy hinged upon a Larock/Buchwald-Hartwig annulation/cyclization to quickly access the core of these alkaloids. We report the development of this cascade process, which was facilitated by a dual ligand system in addition to selective functionalization of the key intermediate, to provide efficient syntheses of makaluvamines A, C, and D and isobatzelline B, and the first total synthesis of makaluvamine N.

Convenient Access to a Strained Bicyclic Enone: A Concise and Improved Formal Synthesis of Ineleganolide.

The norcembranoid and cembranoid diterpenoids represent an intriguing class of natural products isolated from marine sources. Their chemical synthesis has been a challenging and exciting field of research over the past two decades, owing largely to their structural complexity. We recently disclosed a total synthesis of a member of this class, ineleganolide, in a 23 step longest linear sequence. In search of a shorter, more efficient route, we have devised a new strategy for the synthesis of a key bicyclic enone. Disclosed herein is our improved synthesis of this strained intermediate, completing the formal synthesis of ineleganolide in only 14 steps, thereby shortening our previous synthesis by 9 steps. Dedicated to Prof. Thomas Maimone on his receipt of the Tetrahedron Young Investigator Award 2024.

Enantioselective Nickel-Catalyzed α-Spirocyclization of Lactones.

Herein we report a strategy for the enantioselective synthesis of spirocycles containing all-carbon quaternary centers via nickel-catalyzed intramolecular addition of lactone enolates to aryl nitriles. The established lactone α-spirocyclization efficiently and enantioselectively forges 5-, 6-, and 7-membered rings, performing best in the synthesis of 7-membered rings (up to 90% ee). This discovery represents an expansion of the synthetic toolkit for enantioselective spirocyclization, providing access to chiral, pharmaceutically relevant spirocyclic products.

Systematic Route to Construct the 5-5-6 Tricyclic Core of Furanobutenolide-Derived Cembranoids and Norcembranoids.

Herein, we present a highly efficient method for constructing the intricate 5-5-6 fused ring system commonly found in the polycyclic furanobutenolide-derived cembranoid and norcembranoid natural product family with remarkable diastereoselectivity, utilizing an intramolecular Diels-Alder reaction as the cornerstone. Notably, employing a propargyl ether tether as the dienophile yields significant enhancements in the transformation process compared to its propargyl ester counterpart, as demonstrated in our previous total synthesis of havellockate. This advancement holds promising implications for future investigations, offering a streamlined pathway for rapidly assembling the tricyclic core characteristic of this diverse family of natural products.

Total Synthesis of Hypersampsone M.

We report the first total synthesis of hypersampsone M, an archetypal member of the homoadamantane polycyclic polyprenylated acylphloroglucinols (PPAPs). Commencing from cyclohexenone, a key cyclopentene annulation followed by ring-expansion results in an elusive hydrazulene that undergoes a series of unexpected late-stage transformations, ultimately enabling completion of the synthesis. The route detailed herein represents a potentially general strategy for the synthesis of related homoadamantane PPAPs.

Evolution of a Synthetic Strategy toward the Syntheses of Bis-tetrahydroisoquinoline Alkaloids.

ConspectusThe bis-tetrahydroisoquinoline (bis-THIQ) natural products represent a medicinally important class of isoquinoline alkaloids that exhibit broad biological activities with particularly potent antitumor properties, as exemplified by the two U.S. FDA approved molecules trabectidin and lurbinectedin. Accordingly, other members within the bis-THIQ family have emerged as prime targets for synthetic chemists, aiming to innovate an orthogonal chemical production of these compounds. With the ability of these complementary strategies to reliably and predictably manipulate molecular structures with atomic precision, this should allow the preparation of synthetic derivatives not existing in nature as new drug leads in the development of novel medicines with desired biological functions.Beyond the biological perspective, bis-THIQ natural products also possess intricate and unique structures, serving as a source of intellectual stimulation for synthetic organic chemists. Within our laboratory, we have developed an integrated program that combines reaction development and target-directed synthesis, leveraging the architecturally complex molecular framework of bis-THIQ natural products as a driving force for the advancement of novel reaction methodologies. In this Account, we unveil our synthetic efforts in a comprehensive story, describing how our synthetic strategy toward bis-THIQ natural products, specifically jorunnamycin A and jorumycin, has evolved over the course of our studies through our key transformations comprising (a) the direct functionalization of isoquinoline N-oxide to prepare the bis-isoquinoline (bis-IQ) intermediate, (b) the diastereoselective and enantioselective isoquinoline hydrogenation to forge the pentacyclic skeleton of the natural product, and (c) the late-stage oxygenation chemistry to adjust the oxidation states of the A- and E-rings. First, we detail our plan in utilizing the aryne annulation strategy to prepare isoquinoline fragments for the bis-THIQ molecules. Faced with unpromising results in the direct C-H functionalization of isoquinoline N-oxide, we lay out in this Account our rationale behind the design of each isoquinoline coupling partner to overcome these challenges. Additionally, we reveal the inspiration for our hydrogenation system, the setup of our pseudo-high-throughput screening, and the extension of the developed hydrogenation protocols to other simplified isoquinolines.In the context of non-natural bis-THIQ molecules, we have successfully adapted this tandem coupling/hydrogenation approach in the preparation of perfluorinated bis-THIQs, representing the first set of electron-deficient non-natural analogues. Finally, we include our unsuccessful late-stage oxygenation attempts prior to the discovery of the Pd-catalyzed C-O cross-coupling reaction. With this full disclosure of the chemistry developed for the syntheses of bis-THIQs, we hope our orthogonal synthetic tactics will provide useful information and serve as an inspiration for the future development of bis-THIQ pharmaceuticals.

Strategies for the Development of Asymmetric and Non-Directed Petasis Reactions.

The Petasis reaction is a multicomponent reaction of aldehydes, amines and organoboron reagents and is a useful method for the construction of substituted amines. Despite the significant advancement of the Petasis reaction since its invention in 1993, strategies for asymmetric and non-directed Petasis reactions remain limited. To date, there are very few catalytic asymmetric Petasis reactions and almost all asymmetric reports employ a chiral auxiliary. Likewise, the aldehyde component often requires a directing group, ultimately limiting the reaction's scope. In this Concept, key methods for asymmetric and non-directed Petasis reactions are discussed, focusing on how these conceptual advances can be applied to solve long-standing gaps in the Petasis literature.

Molecular Dynamics Investigations of Dienolate [4 + 2] Reactions.

We report quantum mechanics calculations and quasiclassical trajectory simulations of [4 + 2] reactions using three common dienolate substrates: siloxy dienes, Li dienolates, and conjugated Pd enolates. Asynchronous transition structures and unequal bond formation were invariably found, with average time gaps of developing bonds ranging from 26.5 to >251.0 fs. The results display a spectrum of dynamically concerted and stepwise [4 + 2] reactions, offering insights into the origin of the stereochemical outcomes of such reactions.

Enantioselective Total Synthesis of (-)-Hunterine A Enabled by a Desymmetrization/Rearrangement Strategy.

The first enantioselective total synthesis of (-)-hunterine A is disclosed. Our strategy employs a catalytic asymmetric desymmetrization of a symmetrical diketone and subsequent Beckmann rearrangement to construct a 5,6-α-aminoketone. A convergent 1,2-addition joins a vinyl dianion nucleophile and the enantioenriched ketone. The endgame of the synthesis features an aza-Cope/Mannich reaction and azide-olefin dipolar cycloaddition to complete the pentacyclic ring system. The synthesis is completed through a regioselective aziridine ring opening.

Low Part-Per-Trillion, Humidity Resistant Detection of Nitric Oxide Using Microtoroid Optical Resonators.

The nitric oxide radical plays pivotal roles in physiological as well as atmospheric contexts. Although the detection of dissolved nitric oxide in vivo has been widely explored, highly sensitive (i.e., low part-per-trillion level), selective, and humidity-resistant detection of gaseous nitric oxide in air remains challenging. In the field, humidity can have dramatic effects on the accuracy and selectivity of gas sensors, confounding data, and leading to overestimation of gas concentration. Highly selective and humidity-resistant gaseous NO sensors based on laser-induced graphene were recently reported, displaying a limit of detection (LOD) of 8.3 ppb. Although highly sensitive (LOD = 590 ppq) single-wall carbon nanotube NO sensors have been reported, these sensors lack selectivity and humidity resistance. In this report, we disclose a highly sensitive (LOD = 2.34 ppt), selective, and humidity-resistant nitric oxide sensor based on a whispering-gallery mode microtoroid optical resonator. Excellent analyte selectivity was enabled via novel ferrocene-containing polymeric coatings synthesized via reversible addition-fragmentation chain-transfer polymerization. Utilizing a frequency locked optical whispering evanescent resonator system, the microtoroid's real-time resonance frequency shift response to nitric oxide was tracked with subfemtometer resolution. The lowest concentration experimentally detected was 6.4 ppt, which is the lowest reported to date. Additionally, the performance of the sensor remained consistent across different humidity environments. Lastly, the impact of the chemical composition and molecular weight of the novel ferrocene-containing polymeric coatings on sensing performance was evaluated. We anticipate that our results will have impact on a wide variety of fields where NO sensing is important such as medical diagnostics through exhaled breath, determination of planetary habitability, climate change, air quality monitoring, and treating cardiovascular and neurological disorders.

Particle-phase accretion forms dimer esters in pinene secondary organic aerosol.

Secondary organic aerosol (SOA) is ubiquitous in the atmosphere and plays a pivotal role in climate, air quality, and health. The production of low-volatility dimeric compounds through accretion reactions is a key aspect of SOA formation. However, despite extensive study, the structures and thus the formation mechanisms of dimers in SOA remain largely uncharacterized. In this work, we elucidate the structures of several major dimer esters in SOA from ozonolysis of α-pinene and ß-pinene-substantial global SOA sources-through independent synthesis of authentic standards. We show that these dimer esters are formed in the particle phase and propose a mechanism of nucleophilic addition of alcohols to a cyclic acylperoxyhemiacetal. This chemistry likely represents a general pathway to dimeric compounds in ambient SOA.

Total Synthesis of Aleutianamine.

Aleutianamine is a recently isolated pyrroloiminoquinone natural product that displays potent and selective biological activity toward human pancreatic cancer cells with an IC50 of 25 nM against PANC-1, making it a potential candidate for therapeutic development. We report a synthetic approach to aleutianamine wherein the unique [3.3.1] ring system and tertiary sulfide of this alkaloid were constructed via a novel palladium-catalyzed dearomative thiophene functionalization. Other highlights of the synthesis include a palladium-catalyzed decarboxylative pinacol-type rearrangement of an allylic carbonate to install a ketone and a late-stage oxidative amination. This concise and convergent strategy will enable access to analogues of aleutianamine and further investigation of the biological activity of this unique natural product.

Origins of Enhanced Enantioselectivity in the Pd-Catalyzed Decarboxylative Allylic Alkylation of N-Benzoyl Lactams.

We explore the origins of the marked improvement in enantioselectivity in the inner-sphere (PHOX)Pd-catalyzed allylic alkylation of N-benzoyl lactam nucleophiles over their carbocyclic counterparts. We employ density functional theory calculations to aid in the interpretation of experimental results. Ultimately, we propose that the enhancement in enantioselectivity arises primarily from noncovalent interactions between the substrate and ligand rather than secondary substrate chelation, as previously hypothesized.

Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to α,ß-Unsaturated Lactams: Enantioselective Construction of All-Carbon Quaternary Stereocenters in Saturated Nitrogen-Containing Heterocycles.

Stereogenic nitrogen-containing heterocycles are ubiquitous in natural products and pharmaceutical compounds, but methods for their enantioselective construction have remained elusive. We report a general method for the asymmetric conjugate addition of arylboronic acids to ß-alkyl/aryl α,ß-unsaturated lactams that affords chiral ß,ß-disubstituted lactams. The transformation is operationally simple and air- and moisture-tolerant and uses a commercially available (S)-t-Bu-PyOx ligand. The method is high-yielding (up to 95% yield) and enantioselective (up to 97% ee) for a wide range of arylboronic acids and α,ß-unsaturated lactams, including those with different ring sizes.

Enantioselective 1,3-Dipolar Cycloadditions of α-Methylene Lactams to Construct Spirocycles.

Spirocyclic scaffolds are important motifs due to their potential to bestow favorable effects on pharmaceutical compounds. However, there is a need for efficient methods for their enantioselective construction. We report a method for the asymmetric 1,3-dipolar cycloaddition of diazoacetates or nitrile oxides with α-methylene lactams to prepare chiral spirocyclic heterocycles. The methodology is high yielding (up to 91% yield) and enantioselective (up to 89% ee) for a wide range of N-substituents and 6- and 7-membered ring lactam substrates.

Development of a Nickel-Catalyzed N-N Coupling for the Synthesis of Hydrazides.

A nickel-catalyzed N-N cross-coupling for the synthesis of hydrazides is reported. O-Benzoylated hydroxamates were efficiently coupled with a broad range of aryl and aliphatic amines via nickel catalysis to form hydrazides in an up to 81% yield. Experimental evidence implicates the intermediacy of electrophilic Ni-stabilized acyl nitrenoids and the formation of a Ni(I) catalyst via silane-mediated reduction. This report constitutes the first example of an intermolecular N-N coupling compatible with secondary aliphatic amines.

Recent Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002-2020).

The tetrahydroisoquinoline (THIQ) natural products constitute one of the largest families of alkaloids and exhibit a wide range of structural diversity and biological activity. Ranging from simple THIQ natural products to complex trisTHIQ alkaloids such as the ecteinascidins, the chemical syntheses of these alkaloids and their analogs have been thoroughly investigated due to their intricate structural features and functionalities, as well as their high therapeutic potential. This review describes the general structure and biosynthesis of each family of THIQ alkaloids as well as recent advancements of the total synthesis of these natural products from 2002 to 2020. Recent chemical syntheses that have emerged harnessing novel, creative synthetic design, and modern chemical methodology will be highlighted. This review will hopefully serve as a guide for the unique strategies and tools used in the total synthesis of THIQ alkaloids, as well as address the longstanding challenges in their chemical and biosynthesis.

Total synthesis of (-)-scabrolide A and (-)-yonarolide.

The complete account of the total syntheses of scabrolide A and yonarolide is disclosed. This article describes an initial approach involving a bio-inspired macrocyclization/transannular Diels-Alder cascade, which ultimately failed due to undesired reactivity during macrocycle construction. Next, the evolution of a second and third strategy, which both involve an initial intramolecular Diels-Alder reaction followed by a late-stage closure of the seven-membered ring of scabrolide A are detailed. The third strategy was first validated on a simplified system, but problems were encountered during a key [2 + 2] photocycloaddition on the fully elaborated system. An olefin protection strategy was employed to circumvent this problem, ultimately leading to the completion of the first total synthesis of scabrolide A and the closely related natural product yonarolide.

Divergent Catalysis: Catalytic Asymmetric [4+2] Cycloaddition of Palladium Enolates.

An asymmetric decarboxylative [4+2] cycloaddition from a catalytically generated chiral Pd enolate was developed, forging four contiguous stereocenters in a single transformation. This was achieved through a strategy termed divergent catalysis, wherein departure from a known catalytic cycle enables novel reactivity of a targeted intermediate prior to re-entry into the original cycle. Mechanistic studies including quantum mechanics calculations, Eyring analysis, and KIE studies offer insight into the reaction mechanism.