Unified Approach to Deamination and Deoxygenation Through Isonitrile Hydrodecyanation: A Combined Experimental and Computational Investigation.

Herein, we describe a general hydrodefunctionalization protocol of alcohols and amines through a common isonitrile intermediate. To cleave the relatively inert C-NC bond, we leveraged dual hydrogen atom transfer (HAT) and photoredox catalysis to generate a nucleophilic boryl radical, which readily forms an imidoyl radical intermediate from the isonitrile. Rapid ß-scission then accomplishes defunctionalization. This method has been applied to the hydrodefunctionalization of both amine and alcohol-containing pharmaceuticals, natural products, and biomolecules. We extended this approach to the reduction of carbonyls and olefins to their saturated counterparts, as well as the hydrodecyanation of alkyl nitriles. Both experimental and computational studies demonstrate a facile ß-scission of the imidoyl radical, and reconcile differences in reactivity between nitriles and isonitriles within our protocol.

A General Strategy for the Asymmetric Preparation of α-Stereogenic Allyl Silanes, Germanes, and Boronate Esters via Dual Copper Hydride- and Palladium-Catalysis.

α-Stereogenic allyl metalloids are versatile synthetic intermediates which can undergo various stereocontrolled transformations. Most existing methods to prepare α-stereogenic allyl metalloids involve multi-step sequences that curtail the number of compatible substrates and are limited to the synthesis of boronates. Here, we report a general method for the enantioselective preparation of α-stereogenic allyl metalloids utilizing dual CuH- and Pd-catalysis. This approach leverages a stereoretentive Cu-to-Pd transmetalation of an in situ generated alkyl copper species to allow access to enantioenriched allyl silanes, germanes, and boronate esters with broad functional group compatibility.

Dual-Gradient Unified Chromatography: A New Paradigm for Versatility in Simultaneous Multicomponent Analysis.

Generality in analytical chemistry can be manifested in impactful platforms that can streamline modern organic synthesis and biopharmaceutical processes. We herein introduce a hybrid separation technique named Dual-Gradient Unified Chromatography (DGUC), which is built upon an automated dynamic modulation of CO2 , organic modifier, and water blends with various buffers. This concept enables simultaneous multicomponent analysis of both small and large molecules across a wide polarity range in single experimental runs. After a careful investigation of its fundamental aspects, a DGUC-DAD-MS screening workflow that combines multiple orthogonal column and mobile phase choices across a far-reaching universal elution profile is also reported. The power of this framework is demonstrated with new analytical applications guiding academic and industrial laboratories in the development of new (bio)pharmaceutical targets (e.g. synthetic intermediates, nucleosides, cyclic and linear peptides, proteins, antibody drug conjugates).

Confronting the Challenging Asymmetric Carbonyl 1,2-Addition Using Vinyl Heteroarene Pronucleophiles: Ligand-Controlled Regiodivergent Processes through a Dearomatized Allyl-Cu Species.

The selective reductive coupling of vinyl heteroarenes with aldehydes and ketones represents a versatile approach for the rapid construction of enantiomerically enriched secondary and tertiary alcohols, respectively. Herein, we demonstrate a CuH-catalyzed regiodivergent coupling of vinyl heteroarenes with carbonyl-containing electrophiles, in which the selectivity is controlled by the ancillary ligand. This approach leverages an in situ generated benzyl- or dearomatized allyl-Cu intermediate, yielding either the dearomatized or exocyclic addition products, respectively. The method exhibits excellent regio-, diastereo-, and enantioselectivity and tolerates a range of common functional groups and heterocycles. The dearomative pathway allows direct access to a variety of functionalized saturated heterocyclic structures. The reaction mechanism was probed using a combination of experimental and computational approach. Density functional theory studies suggest that the ligand-controlled regioselectivity results from the C-H/π interaction and steric repulsion in transition states, leading to the major and minor regioisomers, respectively. Hydrocupration of vinyl heteroarene pronucleophile is the enantiodetermining step, whereas the diastereoselectivity is enforced by steric interactions between the benzylic or allyl-Cu intermediate and carbonyl-containing substrates in a six-membered cyclic transition state.

Unified Total Synthesis of the Limonoid Alkaloids: Strategies for the De Novo Synthesis of Highly Substituted Pyridine Scaffolds.

Highly substituted pyridine scaffolds are found in many biologically active natural products and therapeutics. Accordingly, numerous complementary de novo approaches to obtain differentially substituted pyridines have been disclosed. This article delineates the evolution of the synthetic strategies designed to assemble the demanding tetrasubstituted pyridine core present in the limonoid alkaloids isolated from Xylocarpus granatum, including xylogranatopyridine B, granatumine A and related congeners. In addition, NMR calculations suggested structural misassignment of several limonoid alkaloids, and predicted their C3-epimers as the correct structures, which was further validated unequivocally through chemical synthesis. The materials produced in this study were evaluated for cytotoxicity, anti-oxidant effects, anti-inflammatory action, PTP1B and Nlrp3 inflammasome inhibition, which led to compelling anti-inflammatory activity and anti-oxidant effects being discovered.

Synthesis of (-)-melazolide B, a degraded limonoid, from a natural terpene precursor.

Degraded limonoids are a subclass of limonoid natural products that derive from ring-intact or ring-rearranged limonoids. Establishment of robust synthetic routes to access them could provide valuable materials to identify the simplest active pharmacophore responsible for the observed biological activities of the parent molecules. This communication delineates the development of a divergent strategy to furnish melazolide B and several other related congeners from a common keto-lactone intermediate, which was rapidly assembled from α-ionone. A chemoselective carbonyl α,ß-dehydrogenation and a Wharton reduction were key strategic steps in this synthetic pathway.

A Dual CuH- and Pd-Catalyzed Stereoselective Synthesis of Highly Substituted 1,3-Dienes.

Conjugated dienes are versatile building blocks and prevalent substructures in synthetic chemistry. Herein, we report a method for the stereoselective hydroalkenylation of alkynes, utilizing readily available enol triflates. We leveraged an in situ-generated and geometrically pure vinyl-Cu(I) species to form the Z,Z- or Z,E-1,3-dienes in excellent stereoselectivity and yield. This approach allowed for the synthesis of highly substituted Z-dienes, including pentasubstituted 1,3-dienes, which are difficult to prepare by existing approaches.

Enantioselective Hydroalkenylation of Olefins with Enol Sulfonates Enabled by Dual Copper Hydride and Palladium Catalysis.

The catalytic enantioselective synthesis of α-chiral olefins represents a valuable strategy for rapid generation of structural diversity in divergent syntheses of complex targets. Herein, we report a protocol for the dual CuH- and Pd-catalyzed asymmetric Markovnikov hydroalkenylation of vinyl arenes and the anti-Markovnikov hydroalkenylation of unactivated olefins, in which readily available enol triflates can be utilized as alkenyl coupling partners. This method allowed for the synthesis of diverse α-chiral olefins, including tri- and tetrasubstituted olefin products, which are challenging to prepare by existing approaches.

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.

Improved Process for the Palladium-Catalyzed C-O Cross-Coupling of Secondary Alcohols.

An improved protocol for the Pd-catalyzed C-O cross-coupling of secondary alcohols is described. The use of biaryl phosphine L2 as the ligand was key to achieving efficient cross-coupling of (hetero)aryl chlorides with only a 20% molar excess of the alcohol. Additionally, we observed an unusual reactivity difference between an electron-rich aryl bromide and the analogous aryl chloride, and deuterium-labeling suggested that currently unidentified pathways for reduction play an important role in explaining this disparity.

Enantioselective Olefin Hydrocyanation without Cyanide.

The enantioselective hydrocyanation of olefins represents a conceptually straightforward approach to prepare enantiomerically enriched nitriles. These, in turn, comprise or are intermediates in the synthesis of many pharmaceuticals and their synthetic derivatives. Herein, we report a cyanide-free dual Pd/CuH-catalyzed protocol for the asymmetric Markovnikov hydrocyanation of vinyl arenes and the anti-Markovnikov hydrocyanation of terminal olefins in which oxazoles function as nitrile equivalents. After an initial hydroarylation process, the oxazole substructure was deconstructed using a [4 + 2]/retro-[4 + 2] sequence to afford the enantioenriched nitrile product under mild reaction conditions.

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.

Copper-Catalyzed Vinylogous Aerobic Oxidation of Unsaturated Compounds with Air.

A mild and operationally simple copper-catalyzed vinylogous aerobic oxidation of ß,γ- and α,ß-unsaturated esters is described. This method features good yields, broad substrate scope, excellent chemo- and regioselectivity, and good functional group tolerance. This method is additionally capable of oxidizing ß,γ- and α,ß-unsaturated aldehydes, ketones, amides, nitriles, and sulfones. Furthermore, the present catalytic system is suitable for bisvinylogous and trisvinylogous oxidation. Tetramethylguanidine (TMG) was found to be crucial in its role as a base, but we also speculate that it serves as a ligand to copper(II) triflate to produce the active copper(II) catalyst. Mechanistic experiments conducted suggest a plausible reaction pathway via an allylcopper(II) species. Finally, the breadth of scope and power of this methodology are demonstrated through its application to complex natural product substrates.

Total Synthesis of (-)-Xylogranatopyridine B via a Palladium-Catalyzed Oxidative Stannylation of Enones.

We report a total synthesis of the pyridine-containing limonoid alkaloid (-)-xylogranatopyridine B in 11 steps from commercially available dihydrocarvone. The central pyridine ring was assembled by a late-stage fragment coupling approach employing a modified Liebeskind pyridine synthesis. One fragment was prepared by an allyl-palladium catalyzed oxidative enone ß-stannylation, in which the key bimetallic ß-stannyl palladium enolate intermediate undergoes a ß-hydride elimination. This methodology also allowed introduction of alkyl and silyl groups to the ß-position of enones.

Scalable synthesis of enaminones utilizing Gold's reagents.

Several Gold's reagents were synthesized from cyanuric chloride and N,N-dialkylformamides. These synthetic equivalents of N,N-dimethylformamide dimethyl acetal were used in an optimized and scalable procedure for the regioselective synthesis of a variety of enaminones from ketone starting materials, whose utility was demonstrated by the stereoselective synthesis of Rawal-type dienes.

Assembly of the Limonoid Architecture by a Divergent Approach: Total Synthesis of (±)-Andirolide N via (±)-8α-Hydroxycarapin.

We report the first total synthesis of the limonoid andirolide N using a 12-step sequence from commercially available materials. The final step of this route demonstrates the chemical feasibility of our biosynthetic proposal that andirolide N arises from 8α-hydroxycarapin. The strategic use of a degraded limonoid as a platform for the synthesis of more structurally complex congeners may be a general approach to obtain limonoids with diverse functional properties.

Scalable procedure for the fragmentation of hydroperoxides mediated by copper and iron tetrafluoroborate salts.

An improved protocol for the formal elimination of propene from organic substrates is reported. This process entails the ozonolytic conversion of an alkene to a methoxy hydroperoxide which undergoes fragmentation mediated by copper and iron. The use of soluble Cu(BF4)2 and Fe(BF4)2 results in reproducible results up to a 100 gram scale.