Author Correction: Deconstructive diversification of cyclic amines.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Remote C-H Amination and Alkylation of Camphor at C8 through Hydrogen-Atom Abstraction.

Camphor continues to serve as a versatile chiral building block for chemical synthesis. We have developed a novel method to functionalize the camphor skeleton at C8 using an intramolecular hydrogen atom abstraction. The key advance involves the use of a camphor-derived aminonitrile, which is converted to the corresponding nitrogen-centered radical under photoredox conditions to effect the 1,5-hydrogen atom transfer at C8. The resulting carbon-centered radical at C8 was utilized in a C-H amination to access topologically complex proline derivatives. Furthermore, the total synthesis of several sesquiterpenoids was accomplished by engaging the radical generated at C8 in alkylation reactions.

Navigating Excess Complexity: Total Synthesis of Daphenylline.

Retrosynthetic analysis is a framework for designing synthetic routes to complex molecules that generally prioritizes disconnections which reduce molecular complexity. However, strict adherence to this principle can overlook pathways involving highly complex intermediates that can be easily prepared through powerful bond-forming transformations. Herein, we demonstrate this tactic of generating excess complexity, followed by strategic bond-cleavage, as a highly effective approach for the 11-step total synthesis of the Daphniphyllum alkaloid daphenylline. To implement this strategy, we accessed a bicyclo[4.1.0]heptane core through a dearomative Buchner cycloaddition, which enabled construction of the seven-membered ring after C-C bond cleavage. Installation of the synthetically challenging quaternary stereocenter methyl group was achieved through a thia-Paternò-Büchi [2 + 2] photocycloaddition followed by stereospecific thietane reduction, further illustrating how building excess complexity can enable desired synthetic outcomes after strategic bond-breaking events. This strategy leveraging bond cleavage transformations should serve as a complement to traditional bond-forming, complexity-generating synthetic strategies.

14N to 15N Isotopic Exchange of Nitrogen Heteroaromatics through Skeletal Editing.

The selective modification of nitrogen heteroaromatics enables the development of new chemical tools and accelerates drug discovery. While methods that focus on expanding or contracting the skeletal structures of heteroaromatics are emerging, methods for the direct exchange of single core atoms remain limited. Here, we present a method for 14N → 15N isotopic exchange for several aromatic nitrogen heterocycles. This nitrogen isotope transmutation occurs through activation of the heteroaromatic substrate by triflylation of a nitrogen atom, followed by a ring-opening/ring-closure sequence mediated by 15N-aspartate to effect the isotopic exchange of the nitrogen atom. Key to the success of this transformation is the formation of an isolable 15N-succinyl intermediate, which undergoes elimination to give the isotopically labeled heterocycle. These transformations occur under mild conditions in high chemical and isotopic yields.

Mechanistic Investigation, Wavelength-Dependent Reactivity, and Expanded Reactivity of N-Aryl Azacycle Photomediated Ring Contractions.

Under mild blue-light irradiation, α-acylated saturated heterocycles undergo a photomediated one-atom ring contraction that extrudes a heteroatom from the cyclic core. However, for nitrogenous heterocycles, this powerful skeletal edit has been limited to substrates bearing electron-withdrawing substituents on nitrogen. Moreover, the mechanism and wavelength-dependent efficiency of this transformation have remained unclear. In this work, we increased the electron richness of nitrogen in saturated azacycles to improve light absorption and strengthen critical intramolecular hydrogen bonding while enabling the direct installation of the photoreactive handle. As a result, a broadly expanded substrate scope, including underexplored electron-rich substrates and previously unsuccessful heterocycles, has now been achieved. The significantly improved yields and diastereoselectivities have facilitated reaction rate, kinetic isotope effect (KIE), and quenching studies, in addition to the determination of quantum yields. Guided by these studies, we propose a revised ET/PT mechanism for the ring contraction, which is additionally corroborated by computational characterization of the lowest-energy excited states of α-acylated substrates through time-dependent DFT. The efficiency of the ring contraction at wavelengths longer than those strongly absorbed by the substrates was investigated through wavelength-dependent rate measurements, which revealed a red shift of the photochemical action plot relative to substrate absorbance. The elucidated mechanistic and photophysical details effectively rationalize empirical observations, including additive effects, that were previously poorly understood. Our findings not only demonstrate enhanced synthetic utility of the photomediated ring contraction and shed light on mechanistic details but may also offer valuable guidance for understanding wavelength-dependent reactivity for related photochemical systems.

Construction of Seven-Membered Oxacycles Using a Rh(I)-Catalyzed Cascade C-C Formation/Cleavage of Cyclobutenol Derivatives.

Herein, we describe the synthesis of substituted oxepane derivatives through the skeletal remodeling of 4-hydroxy-2-cyclobutenones, which are readily prepared from commercially available dialkyl squarates upon their reaction with acrylonitrile. Mechanistically, a Rh(I)-catalyzed C-C bond formation and cleavage cascade is proposed. Specifically, a fused [3.2.0] bicycle is proposed to form from dialkyl squarate-derived cyclobutenols via an unusual Rh(I)-catalyzed intermolecular oxa-Michael addition of a tertiary alcohol with acrylonitrile, followed by an intramolecular conjugate addition/migratory insertion. Subsequent C(sp3)-C(sp3) bond cleavage through a Rh-catalyzed ß-carbon elimination is then theorized to furnish the oxepane scaffold. Computational studies support the formation of an intermediate [3.2.0] bicycle but also point to an alternative pathway for the formation of the oxepane products involving a Rh(III) intermediate. Additional studies have shown the overall process to be stereoretentive. The functional groups that are introduced in this process can be leveraged to form fused or bridged ring systems.

Site-Selective Cross-Coupling of Polyhalogenated Arenes and Heteroarenes with Identical Halogen Groups.

Methods to functionalize arenes and heteroarenes in a site-selective manner are highly sought after for rapidly constructing value-added molecules of medicinal, agrochemical, and materials interest. One effective approach is the site-selective cross-coupling of polyhalogenated arenes bearing multiple, but identical, halogen groups. Such cross-coupling reactions have proven to be incredibly effective for site-selective functionalization. However, they also present formidable challenges due to the inherent similarities in the reactivities of the halogen substituents. In this Review, we discuss strategies for site-selective cross-couplings of polyhalogenated arenes and heteroarenes bearing identical halogens, beginning first with an overview of the reaction types that are more traditional in nature, such as electronically, sterically, and directing-group-controlled processes. Following these examples is a description of emerging strategies, which includes ligand- and additive/solvent-controlled reactions as well as photochemically initiated processes.

Deconstructive diversification of cyclic amines.

Deconstructive functionalization involves carbon-carbon (C-C) bond cleavage followed by bond construction on one or more of the constituent carbons. For example, ozonolysis1 and olefin metathesis2,3 have allowed each carbon in C=C double bonds to be viewed as a functional group. Despite the substantial advances in deconstructive functionalization involving the scission of C=C double bonds, there are very few methods that achieve C(sp3)-C(sp3) single-bond cleavage and functionalization, especially in relatively unstrained cyclic systems. Here we report a deconstructive strategy to transform saturated nitrogen heterocycles such as piperidines and pyrrolidines, which are important moieties in bioactive molecules, into halogen-containing acyclic amine derivatives through sequential C(sp3)-N and C(sp3)-C(sp3) single-bond cleavage followed by C(sp3)-halogen bond formation. The resulting acyclic haloamines are versatile intermediates that can be transformed into various structural motifs through substitution reactions. In this way we achieve the skeletal remodelling of cyclic amines, an example of scaffold hopping. We demonstrate this deconstructive strategy by the late-stage diversification of proline-containing peptides.

Unified Synthesis of 2-Isocyanoallopupukeanane and 9-Isocyanopupukeanane through a "Contra-biosynthetic" Rearrangement.

Herein, we describe our synthetic efforts toward the pupukeanane natural products, in which we have completed the first enantiospecific route to 2-isocyanoallopupukeanane in 10 steps (formal synthesis), enabled by a key Pd-mediated cyclization cascade. This subsequently facilitated an unprecedented bio-inspired "contra-biosynthetic" rearrangement, providing divergent access to 9-isocyanopupukeanane in 15 steps (formal synthesis). Computational studies provide insight into the nature of this rearrangement.

Photo- and Metal-Mediated Deconstructive Approaches to Cyclic Aliphatic Amine Diversification.

Described herein are studies toward the core modification of cyclic aliphatic amines using either a riboflavin/photo-irradiation approach or Cu(I) and Ag(I) to mediate the process. Structural remodeling of cyclic amines is explored through oxidative C-N and C-C bond cleavage using peroxydisulfate (persulfate) as an oxidant. Ring-opening reactions to access linear aldehydes or carboxylic acids with flavin-derived photocatalysis or Cu salts, respectively, are demonstrated. A complementary ring-opening process mediated by Ag(I) facilitates decarboxylative Csp3-Csp2 coupling in Minisci-type reactions through a key alkyl radical intermediate. Heterocycle interconversion is demonstrated through the transformation of N-acyl cyclic amines to oxazines using Cu(II) oxidation of the alkyl radical. These transformations are investigated by computation to inform the proposed mechanistic pathways. Computational studies indicate that persulfate mediates oxidation of cyclic amines with concomitant reduction of riboflavin. Persulfate is subsequently reduced by formal hydride transfer from the reduced riboflavin catalyst. Oxidation of the cyclic aliphatic amines with a Cu(I) salt is proposed to be initiated by homolysis of the peroxy bond of persulfate followed by α-HAT from the cyclic amine and radical recombination to form an α-sulfate adduct, which is hydrolyzed to the hemiaminal. Investigation of the pathway to form oxazines indicates a kinetic preference for cyclization over more typical elimination pathways to form olefins through Cu(II) oxidation of alkyl radicals.

Skeletal Editing Approach to Bridge-Functionalized Bicyclo[1.1.1]pentanes from Azabicyclo[2.1.1]hexanes.

Azabicyclo[2.1.1]hexanes (aza-BCHs) and bicyclo[1.1.1]pentanes (BCPs) have emerged as attractive classes of sp3-rich cores for replacing flat, aromatic groups with metabolically resistant, three-dimensional frameworks in drug scaffolds. Strategies to directly convert, or "scaffold hop", between these bioisosteric subclasses through single-atom skeletal editing would enable efficient interpolation within this valuable chemical space. Herein, we describe a strategy to "scaffold hop" between aza-BCH and BCP cores through a nitrogen-deleting skeletal edit. Photochemical [2+2] cycloadditions, used to prepare multifunctionalized aza-BCH frameworks, are coupled with a subsequent deamination step to afford bridge-functionalized BCPs, for which few synthetic solutions currently exist. The modular sequence provides access to various privileged bridged bicycles of pharmaceutical relevance.

C-C Bond Cleavage of α-Pinene Derivatives Prepared from Carvone as a General Strategy for Complex Molecule Synthesis.

The preparation of complex molecules (e.g., biologically active secondary metabolites) remains an important pursuit in chemical synthesis. By virtue of their sophisticated architectures, complex natural products inspire total synthesis campaigns that can lead to completely new ways of building molecules. In the twentieth century, one such paradigm which emerged was the use of naturally occurring "chiral pool terpenes" as starting materials for total synthesis. These inexpensive and naturally abundant molecules provide an easily accessed source of enantioenriched material for the enantiospecific preparation of natural products. The most common applications of chiral pool terpenes are in syntheses where their structure can, entirely or largely, be superimposed directly onto a portion of the target structure. Less straightforward uses, where the structure of the starting chiral pool terpene is not immediately evident in the structure of the target, can be more challenging to implement. Nevertheless, these "nonintuitive" approaches illustrate the ultimate promise of chiral pool-based strategies: that any single chiral pool terpene could be applied to syntheses of an indefinite number of structurally diverse complex synthetic targets.By definition, such strategies require carefully orchestrated sequences of C-C bond forming and C-C cleaving reactions which result in remodeling of the terpene architecture. The combination of traditional rearrangement chemistry and transition-metal-catalyzed C-C cleavage methods, the latter of which were primarily developed in the early twenty-first century, provide a rich and powerful toolbox for implementing this remodeling approach. In this Account, we detail our efforts to use a variety of C-C cleavage tactics in the skeletal remodeling of carvone, a chiral pool terpene. This skeletal remodeling strategy enabled the reorganization of the carvone scaffold into synthetic intermediates with a variety of carboskeletons, which we, then, leveraged for the total syntheses of structurally disparate terpene natural products.We begin by describing our initial investigations into various, mechanistically distinct C-C cleavage processes involving cyclobutanols synthesized from carvone. These initial studies showcased how electrophile-mediated semipinacol rearrangements of these cyclobutanols can lead to [2.2.1]bicyclic intermediates, and how Rh- and Pd-catalyzed C-C cleavage can lead to a variety of densely functionalized cyclohexenes pertinent to natural product synthesis. We, then, present several total syntheses using these synthetic intermediates, beginning with the bridged, polycyclic sesquiterpenoid longiborneol, which was synthesized from a carvone-derived [2.2.1]bicycle following a key semipinacol rearrangement. Next, we discuss how several members of the macrocyclic phomactin family were synthesized from a cyclohexene derivative prepared through a Rh-catalyzed C-C cleavage reaction. Finally, we describe our synthesis of the marine diterpene xishacorene B, which was prepared using a key Pd-catalyzed C-C cleavage/cross-coupling that facilitated the assembly of the core [3.3.1]bicycle that is resident in the natural product structure.

Strategy Evolution in a Skeletal Remodeling and C-H Functionalization-Based Synthesis of the Longiborneol Sesquiterpenoids.

Detailed herein are our synthesis studies of longiborneol and related natural products. Our overarching goals of utilizing a "camphor first" strategy enabled by skeletal remodeling of carvone, and late-stage diversification using C-H functionalizations, led to divergent syntheses of the target natural products. Our initial approach proposed a lithiate addition to unite two fragments followed by a Conia-ene or Pd-mediated cycloalkylation reaction sequence to install the seven-membered ring emblematic of the longibornane core. This approach was unsuccessful and evolved into a revised plan that employed a Wittig coupling and a radical cyclization to establish the core. A reductive radical cyclization, which was explored first, led to a synthesis of copaborneol, a structural isomer of longiborneol. Alternatively, a metal-hydride hydrogen atom transfer-initiated cyclization was effective for a synthesis of longiborneol. Late-stage C-H functionalization of the longibornane core led to a number of hydroxylated longiborneol congeners. The need for significant optimization of the strategies that were employed as well as the methods for C-H functionalization to implement these strategies highlights the ongoing challenges in applying these powerful reactions. Nevertheless, the reported approach enables functionalization of every natural product-relevant C-H bond in the longibornane skeleton.

Development of a C-C Bond Cleavage/Vinylation/Mizoroki-Heck Cascade Reaction: Application to the Total Synthesis of 14- and 15-Hydroxypatchoulol.

A C-C bond cleavage/vinylation/Mizoroki-Heck cascade reaction has been developed to provide access to densely functionalized bicyclo[2.2.2]octane frameworks. The sequence proceeds through the coupling of dihydroxylated pinene derivatives, prepared from carvone, with gem-dichloroalkenes. The method was applied to 12-step total syntheses of both 14- and 15-hydroxypatchoulol, which provided unambiguous support for the structure of the natural products and corrects a misassignment in the isolation report.

Skeletal Editing of Pyrimidines to Pyrazoles by Formal Carbon Deletion.

A method for the conversion of pyrimidines into pyrazoles by a formal carbon deletion has been achieved guided by computational analysis. The pyrimidine heterocycle is the most common diazine in FDA-approved drugs, and pyrazoles are the most common diazole. An efficient method to convert pyrimidines into pyrazoles would therefore be valuable by leveraging the chemistries unique to pyrimidines to access diversified pyrazoles. One method for the conversion of pyrimidines into pyrazoles is known, though it proceeds in low yields and requires harsh conditions. The transformation reported here proceeds under milder conditions, tolerates a wide range of functional groups, and enables the simultaneous regioselective introduction of N-substitution on the resulting pyrazole. Key to the success of this formal one-carbon deletion method is a room-temperature triflylation of the pyrimidine core, followed by hydrazine-mediated skeletal remodeling.

Unified Total Syntheses of Benzenoid Cephalotane-Type Norditerpenoids: Cephanolides and Ceforalides.

Detailed herein are our synthetic studies toward the preparation of the C18- and C19-benzenoid cephalotane-type norditerpenoids. Guided by chemical network analysis, the core structure of this natural product family was constructed in a concise manner using an iterative cross-coupling, followed by a formal inverse-electron-demand [4 + 2] cycloaddition. Initial efforts to functionalize an alkene group in the [4 + 2] cycloadduct using a Mukaiyama hydration and a subsequent olefination led to the complete C18-carbon framework. While effective, this approach proved lengthy and prompted the development of a direct alkene difunctionalization that relies on borocupration to advance the cycloadduct to the natural products. Late-stage peripheral C-H functionalization facilitated access to all of the known cephanolides in 6-10 steps as well as five recently isolated ceforalides in 8-13 steps.

General Synthetic Approach to Diverse Taxane Cores.

Chemical synthesis of natural products is typically inspired by the structure and function of a target molecule. When both factors are of interest, such as in the case of taxane diterpenoids, a synthesis can both serve as a platform for synthetic strategy development and enable new biological exploration. Guided by this paradigm, we present here a unified enantiospecific approach to diverse taxane cores from the feedstock monoterpenoid (S)-carvone. Key to the success of our approach was the use of a skeletal remodeling strategy which began with the divergent reorganization and convergent coupling of two carvone-derived fragments, facilitated by Pd-catalyzed C-C bond cleavage tactics. This coupling was followed by additional restructuring using a Sm(II)-mediated rearrangement and a bioinspired, visible-light induced, transannular [2 + 2] photocycloaddition. Overall, this divergent monoterpenoid remodeling/convergent fragment coupling approach to complex diterpenoid synthesis provides access to structurally disparate taxane cores which have set the stage for the preparation of a wide range of taxanes.

Strategic elements in computer-assisted retrosynthesis: A case study of the pupukeanane natural products.

Computer-assisted synthesis planning represents a growing area of research, especially for complex molecule synthesis. Here, we present a case study involving the pupukeanane natural products, which are complex, marine-derived, natural products with unique tricyclic scaffolds. Proposed routes to members of each skeletal class informed by pathways generated using the program Synthia™ are compared to previous syntheses of these molecules. In addition, novel synthesis routes are proposed to pupukeanane congeners that have not been prepared previously.

Key Mechanistic Features of the Silver(I)-Mediated Deconstructive Fluorination of Cyclic Amines: Multistate Reactivity versus Single-Electron Transfer.

Density functional calculations have provided evidence that a Ag(I)-mediated deconstructive fluorination of N-benzoylated cyclic amines (LH) with Selectfluor [(F-TEDA)(BF4)2] begins with an association of the reactants to form a singlet state adduct {[(LH)-Ag]-[F-TEDA]2+}. The subsequent formation of an iminium ion intermediate, [L+-Ag]-HF-[TEDA]+, is, formally, a Ag(I)-mediated hydride abstraction event that occurs in two steps: (a) a formal oxidative addition (OA) of [F-TEDA]2+ to the Ag(I) center that is attended by an electron transfer (ET) from the substrate (LH) to the Ag center (i.e., OA + ET, this process can also be referred to as a F-atom coupled electron transfer), followed by (b) H-atom abstraction from LH by the Ag-coordinated F atom. The overall process involves lower-lying singlet and triplet electronic states of several intermediates. Therefore, we formally refer to this reaction as a two-state reactivity (TSR) event. The C-C bond cleavage/fluorination of the resulting hemiaminal intermediate via a ring-opening pathway has also been determined to be a TSR event. A competing deformylative fluorination initiated by hemiaminal to aldehyde equilibration involving formyl H-atom abstraction by a TEDA2+ radical dication, decarbonylation, and fluorination of the resulting alkyl radical by another equivalent of Selectfluor may also be operative in the latter step.

Total Synthesis of the Cephalotaxus Norditerpenoids (±)-Cephanolides A-D.

Concise syntheses of the Cephalotaxus norditerpenoids cephanolides A-D (8-14 steps from commercial material) using a common late-stage synthetic intermediate are described. The success of our approach rested on an early decision to apply chemical network analysis to identify the strategic bonds that needed to be forged, as well as the efficient construction of the carbon framework through iterative Csp2-Csp3 cross-coupling, followed by an intramolecular inverse-demand Diels-Alder cycloaddition. Strategic late-stage oxidations facilitated access to all congeners of the benzenoid cephanolides isolated to date.