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[This corrects the article DOI: 10.1039/D3SC04478E.].

We report the modular preparation of dihydro-1,2,5-thiodiazole dioxide heterocycles starting from methyl ketones and primary amines. This one-pot, three-component coupling employs 2,3-dimethylimidazole-1-sulfonyl azide triflate as a coupling reagent and oxidant. The transformation is scalable and various ketones and amines can be used, yielding thiodiazole dioxide products in up to 89% yield. In addition, 15N- and 13C-labeling studies suggest a mechanism involving a 1,2-nitrogen migration. Together with the mechanistic studies, DFT calculations provide insight into the reaction pathway and set the stage for further exploration of the mechanistic nuances of reactions that use sulfamoyl azides. In combination with the demonstrated modularity of the approach reported herein, the derivatization of the thiodiazole dioxide products highlights the potential of this methodology to rapidly access diverse chemical structures.

A novel synthesis of aryl-substituted, enantioenriched fulvenes from an oxidative Heck cascade and rearrangement of a carboxy-substituted spiro[4.4]nonatriene is disclosed. Mechanistic investigations with density functional theory (DFT) calculations and empirical results support the net transformation occurring through a novel Pd(ii)-mediated 1,5-vinyl shift from a vinyl-palladium intermediate that terminates with protodepalladation. This spiro-to-fused bicycle conversion tolerates a range of electron-rich and deficient arylboronic acids to give a range of mono- and diaryl substituted annulated fulvenes in moderate to good yields and enantiomeric ratios. Overall, this work connects two classes of molecules with a rich history in physical organic chemistry.

Herein, the synthesis of 1-hydroxy-2-naphthoic acid esters through an unexpected Lewis-acid-mediated 1,2-acyl shift of oxabenzonorbornadienes is reported. Using this methodology, novel substitution patterns for 1-hydroxy-2-naphtoic acid esters can be obtained. A mechanistic proposal and rationale for this transformation, the products of which had been previously incorrectly characterized, is given.

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.

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.

Herein, the diversification of tricyclo[3.2.1.03,6]octane scaffolds to afford diverse bicyclic scaffolds is described. The strained tricyclooctanes are prepared in two steps featuring a blue light-mediated [2+2] cycloaddition. Strategies for the cleavage of this scaffold were then explored resulting in the selective syntheses of the bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, and bicyclo[3.2.0]heptane cores. These findings may guide future studies of C-C cleavage reactions in strained carbon frameworks and their application in complex molecule synthesis.

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.

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.

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.

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.

Medicinal chemistry continues to be impacted by new synthetic methods. Particularly sought after, especially at the drug discovery stage, is the ability to enact the desired chemical transformations in a concise and chemospecific fashion. To this end, the field of organic synthesis has become captivated by the idea of 'molecular editing'-to rapidly build onto, change or prune molecules one atom at a time using transformations that are mild and selective enough to be employed at the late stages of a synthetic sequence. In this Review, the definition and categorization of a particularly promising subclass of molecular editing reactions, termed 'single-atom skeletal editing', are proposed. Although skeletal editing applies to both cyclic and acyclic compounds, this Review focuses on heterocycles, both for their centrality in medicinal chemistry and for the definitional clarity afforded by a focus on ring systems. A classification system is presented by highlighting methods (both historically important examples and recent advances) that achieve such transformations, with the goal to spark interest and inspire further development in this growing field.

Natural product total synthesis inspires the development of synthesis strategies to access important classes of molecules. In the 1960s, Corey and coworkers demonstrated a visionary preparation of the terpenoid longifolene, using 'strategic bond analysis' to craft a synthesis route. This approach proposes that efficient synthesis routes to bridged, polycyclic structures should be formulated to introduce the bulk of the target's topological complexity at a late stage. Subsequently, similar strategies have proved general for the syntheses of a wide variety of bridged, polycyclic molecules. Here, we demonstrate that an orthogonal strategy where topological complexity is introduced at the outset leads to the short synthesis of the longifolene-related terpenoid longiborneol. To implement this strategy, we access a bicyclo[2.2.1] starting material through scaffold remodelling of readily available (S)-carvone. We also employ a variety of late-stage C-H functionalization tactics in divergent syntheses of many longiborneol congeners. Our strategy may prove effective for the preparation of other topologically complex natural products that contain the bicyclo[2.2.1] framework.

Using calculations, we show that a proposed Cu(I)-mediated deconstructive fluorination of N-benzoylated cyclic amines with Selectfluor® is feasible and may proceed through: (a) substrate coordination to a Cu(I) salt, (b) iminium ion formation followed by conversion to a hemiaminal, and (c) fluorination involving C-C cleavage of the hemiaminal. The iminium ion formation is calculated to proceed via a F-atom coupled electron transfer (FCET) mechanism to form, formally, a product arising from oxidative addition coupled with electron transfer (OA + ET). The subsequent β-C-C cleavage/fluorination of the hemiaminal intermediate may proceed via either ring-opening or deformylative fluorination pathways. The latter pathway is initiated by opening of the hemiaminal to give an aldehyde, followed by formyl H-atom abstraction by a TEDA2+ radical dication, decarbonylation, and fluorination of the C3-radical center by another equivalent of Selectfluor®. In general, the mechanism for the proposed Cu(I)- mediated deconstructive C-H fluorination of N-benzoylated cyclic amines (LH) by Selectfluor® was calculated to proceed analogously to our previously reported Ag(I)-mediated reaction. In comparison to the Ag(I)-mediated process, in the Cu(I)-mediated reaction the iminium ion formation and hemiaminal fluorination have lower associated energy barriers, whereas the product release and catalyst re-generation steps have higher barriers.

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.

Methods that functionalize the periphery of azacylic scaffolds have garnered increasing interest in recent years. Herein, we investigate the selectivity of a solid-state Norrish-Yang cyclization (NYC) and subsequent C-C cleavage/cross-coupling reaction of a strained cyclopropane-fused azacyclic system. Surprisingly, the NYC primarily furnished a single lactam constitutional and diastereo-isomer. The regioselectivity of the C-C cleavage of the α-hydroxy-β-lactam moiety could be varied by altering the ligand set used in the coupling chemistry. Experimental and computational observations are discussed.

We report an alternative approach to the unnatural nucleobase fragment seen in remdesivir (Veklury). Remdesivir displays broad-spectrum antiviral activity and is currently being evaluated in Phase III clinical trials to treat patients with COVID-19. Our route relies on the formation of a cyanoamidine intermediate, which undergoes Lewis acid-mediated cyclization to yield the desired nucleobase. The approach is strategically distinct from prior routes and could further enable the synthesis of remdesivir and other small-molecule therapeutics.

Transition-metal-mediated cleavage of C-C single bonds can enable entirely new retrosynthetic disconnections in the total synthesis of natural products. Given that C-C bond cleavage inherently alters the carbon framework of a compound, and that, under transition-metal catalysis, the generated organometallic or radical intermediate is primed for further complexity-building reactivity, C-C bond-cleavage events have the potential to drastically and rapidly remodel skeletal frameworks. The recent acceleration of the use of transition-metal-mediated cleavage of C-C single bonds in total synthesis can be ascribed to a communal recognition of this fact. In this Review, we highlight ten selected total syntheses from 2014 to 2019 that illustrate how transition-metal-mediated cleavage of C-C single bonds at either the core or the periphery of synthetic intermediates can streamline synthetic efforts.

The construction of complex aza-cycles is of interest to drug discovery due to the prevalence of nitrogen-containing heterocycles in pharmaceutical agents. Herein we report an intramolecular C-H amination approach to afford value-added and complexity-enriched bridged bicyclic amines. Guided by density functional theory and nuclear magnetic resonance investigations, we determined the unique roles of light and heat activation in the bicyclization mechanism. We applied both light and heat activation in a synergistic fashion, achieving gram-scale bridged aza-cycle synthesis.

A key challenge in the synthesis of diterpenoid alkaloids lies in identifying strategies that rapidly construct their multiply bridged polycyclic skeletons. Existing approaches to these structurally intricate secondary metabolites are discussed in the context of a "bond-network analysis" of molecular frameworks, which was originally devised by Corey some 40 years ago. The retrosynthesis plans that emerge from a topological analysis of the highly bridged frameworks of the diterpenoid alkaloids are discussed in the context of eight recent syntheses of hetidine and hetisine natural products and their derivatives. This Minireview highlights the extent to which network analyses of the type described here sufficed for designing synthesis plans, as well as areas where they had to be amalgamated with functional group oriented synthetic planning considerations.

Saturated cyclic amines (aza-cycles) are ubiquitous structural motifs found in pharmaceuticals, agrochemicals, and bioactive natural products. Given their importance, methods that directly functionalize aza-cycles are in high demand. Herein, we disclose a fundamentally different approach to functionalizing cyclic amines which relies on C─C cleavage and attendant cross-coupling. The initial functionalization step is the generation of underexplored N-fused bicyclo α-hydroxy-β-lactams under mild, visible light conditions using a Norrish-Yang process to affect α-functionalization of saturated cyclic amines. This approach is complementary to previous methods for the C─H functionalization of aza-cycles and provides unique access to various cross-coupling adducts. In the course of these studies, we have also uncovered an orthogonal, base-promoted opening of the N-fused bicyclo α-hydroxy-β-lactams. Computational studies have provided insight into the origin of the complementary C─C cleavage processes.

We provide a full account of our synthetic studies targeting the hexacyclic calyciphylline B-type alkaloids, a subfamily of the Daphniphyllum natural products. Following an initial set of synthetic strategies focused on constructing the piperidine core of the calyciphylline B-type framework via a 6π-azaelectrocyclization, as well as exploiting the reactivity of underexplored oxazaborinine heterocycles, we ultimately designed a highly functionalized acyclic precursor which underwent carefully orchestrated and efficient cyclizations to forge the architecturally complex natural product scaffold. Our efforts have culminated in the development of the first total synthesis of (-)-daphlongamine H, provided access to its C5-epimer, (-)-isodaphlongamine H, and led to structural revision of deoxyisocalyciphylline B.

We provide a full account of our synthetic studies targeting the hexacyclic calyciphylline B-type alkaloids, a subfamily of the Daphniphyllum natural products. Following an initial set of synthetic strategies focused on constructing the piperidine core of the calyciphylline B-type framework via a 6π-azaelectrocyclization, as well as exploiting the reactivity of underexplored oxazaborinine heterocycles, we ultimately designed a highly functionalized acyclic precursor which underwent carefully orchestrated and efficient cyclizations to forge the architecturally complex natural product scaffold. Our efforts have culminated in the development of the first total synthesis of (-)-daphlongamine H, provided access to its C5-epimer, (-)-isodaphlongamine H, and led to structural revision of deoxyisocalyciphylline B.

Divergent and enantiospecific total syntheses of the indolosesquiterpenoids xiamycins A, C, F, H and oridamycin A have been accomplished. The syntheses, which commence from (R)-carvone, employ a key photoinduced benzannulation sequence to forge the carbazole moiety characteristic of these natural products. Late-stage diversification from a common intermediate enabled the first syntheses of xiamycins C and F, and an unexpected one-pot oxidative decarboxylation, which may prove general, led to xiamycin H. All synthetic intermediates and the natural products were tested for anti-fungal activity. Xiamycin H emerged as an inhibitor of three agriculturally relevant fungal pathogens.

Herein, we describe an enantiospecific route to one enantiomer of a common decalin core that is present in numerous highly oxygenated terpenoids. This intermediate is accessed in eight steps from (R)-carvone, an inexpensive, enantioenriched building block, which can be elaborated to the desired bicycle through sequential Fe(III)-catalyzed reductive olefin coupling and Dieckmann condensation. The same synthetic route may be applied to (S)-carvone to afford the enantiomer of this common intermediate for other applications.

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.

A copper-mediated conjugate addition of electron-rich aryl groups into a complex vinyl nitrile using arylmagnesium bromides is reported. The conjugate addition adducts were advanced toward the synthesis of designed aconitine-type analogues. The variation in oxygenation patterns on the arene coupling partner, introduced through the current conjugate addition approach, may ultimately provide insight into structure-activity relationships of the diterpenoid alkaloids.

The hetisine-type natural products exhibit one of the most complex carbon skeletons within the diterpenoid alkaloid family. The use of network analysis has enabled a synthesis strategy to access alkaloids in this class with hydroxylation on the A-ring. Key transformations include a benzyne acyl-alkylation to construct a key fused 6-7-6 tricycle, a chemoselective nitrile reduction, and sequential C-N bond formations using a reductive cyclization and a photochemical hydroamination to construct an embedded azabicycle. Our strategy should enable access to myriad natural and unnatural products within the hetisine-type.

Stephacidin A and its congeners are a collection of secondary metabolites that possess intriguing structural motifs. They stem from unusual biosynthetic sequences that lead to the incorporation of a prenyl or reverse-prenyl group into a bicyclo[2.2.2]diazaoctane framework, a chromene unit or the vestige thereof. To complement biosynthetic studies, which normally play a significant role in unveiling the biosynthetic pathways of natural products, here we demonstrate that chemical synthesis can provide important insights into biosynthesis. We identify a short total synthesis of congeners in the reverse-prenylated indole alkaloid family related to stephacidin A by taking advantage of a direct indole C6 halogenation of the related ketopremalbrancheamide. This novel strategic approach has now made possible the syntheses of several natural products, including malbrancheamides B and C, notoamides F, I and R, aspergamide B, and waikialoid A, which is a heterodimer of avrainvillamide and aspergamide B. Our approach to the preparation of these prenylated and reverse-prenylated indole alkaloids is bioinspired, and may also inform the as-yet undetermined biosynthesis of several congeners.

The secondary metabolites that comprise the diterpenoid alkaloids are categorized into C18, C19, and C20 families depending on the number of contiguous carbon atoms that constitute their central framework. Herein, we detail our efforts to prepare these molecules by chemical synthesis, including a photochemical approach, and ultimately a bioinspired strategy that has resulted in the development of a unifying synthesis of one C18 (weisaconitine D), one C19 (liljestrandinine), and three C20 (cochlearenine, paniculamine, and N-ethyl-1α-hydroxy-17-veratroyldictyzine) natural products from a common intermediate.

The pronounced beneficial effect of a precise amount of protic additive in an enantioselective Cu-catalysed Diels-Alder reaction is reported. This reaction, which employs a cyclic alkylidene β-ketoester as a dienophile, represents one of the first examples of a transformation where these extremely versatile, though highly unstable reaction partners participate effectively in catalytic asymmetric cycloaddition with a functionalised diene. The cycloadduct was used as an intermediate towards the synthesis of magellanine-type Lycopodium alkaloids featuring a Stille cross-coupling of a highly congested enol triflate and a unique Meinwald rearrangement/cyclopropanation sequence.

A synthetic strategy to access the fused 6-7-6 tricyclic core of hetisine-type C20-diterpenoid alkaloids is reported. This strategy employs a Diels-Alder cycloaddition to assemble a fused bicyclic anhydride intermediate, which is elaborated to a vinyl lactone-acetal bearing an aromatic ring in five steps. Aromatic iodination is followed by magnesium-halogen exchange with a trialkyl magnesiate species, which undergoes intramolecular cyclization. Subsequent oxidation provides the desired 6-7-6 tricyclic diketoaldehyde, with carbonyl groups at all three positions for eventual C-N bond formation and subsequent elaboration.

Malbrancheamide is a dichlorinated fungal indole alkaloid isolated from both Malbranchea aurantiaca and Malbranchea graminicola that belongs to a family of natural products containing a characteristic bicyclo[2.2.2]diazaoctane core. The introduction of chlorine atoms on the indole ring of malbrancheamide differentiates it from other members of this family and contributes significantly to its biological activity. In this study, we characterized the two flavin-dependent halogenases involved in the late-stage halogenation of malbrancheamide in two different fungal strains. MalA and MalA' catalyze the iterative dichlorination and monobromination of the free substrate premalbrancheamide as the final steps in the malbrancheamide biosynthetic pathway. Two unnatural bromo-chloro-malbrancheamide analogues were generated through MalA-mediated chemoenzymatic synthesis. Structural analysis and computational studies of MalA' in complex with three substrates revealed that the enzyme represents a new class of zinc-binding flavin-dependent halogenases and provides new insights into a potentially unique reaction mechanism.

Carvone is a sustainable and readily available starting material for organic synthesis. Herein, we present the syntheses of various natural product scaffolds that rely on a novel benzannulation involving the α-methyl group (C-10) of carvone to afford a versatile tetralin. The utility of our synthetic approach is highlighted by its application to a short synthesis of the ent-3,4-seco-atisane diterpenoid (-)-crotogoudin. The 13-step enantiospecific synthesis features a regioselective double oxidative dearomatization, a Diels-Alder cycloaddition with ethylene gas (to construct the bicyclo[2.2.2]octane framework), and a final acid-mediated lactonization. The versatility of this benzannulation strategy is demonstrated by its utility in the preparation of the carbon skeleton of ent-3,4-seco-abietane diterpenoids using an intramolecular oxidative dearomatization.

A unified strategy for the synthesis of congeners of the prenylated indole alkaloids is presented. This strategy has yielded the first synthesis of the natural product (-)-17-hydroxy-citrinalin B as well as syntheses of (+)-stephacidin A and (+)-notoamide I. An enolate addition to an in situ generated isocyanate was utilized in forging a key bicyclo[2.2.2]diazaoctane moiety, and in this way connected the two structural classes of the prenylated indole alkaloids through synthesis.

The enantiomers of the natural product cycloprodigiosin were prepared using an expedient five-step synthetic sequence that takes advantage of a Schöllkopf-Barton-Zard (SBZ) pyrrole annulation with a chiral isocyanoacetate and a nitrocyclohexene derivative. Using chiral HPLC and X-ray crystallographic analyses of the synthetically prepared material and natural isolate (isolated from the marine bacterium Pseudoalteromonas rubra), naturally occurring cycloprodigiosin was determined to be a scalemic mixture occurring in an enantiomeric ratio of 83:17 (R)/(S) at C4'.

A possible biosynthetic link between atropurpuran, the hetidine diterpenoid alkaloids and the alkaloid arcutine and congeners is proposed. The feasibility of aspects of this biosynthesis, especially key 1,2-rearrangements, have been examined computationally.

Substituted piperidines are emerging as important medicinally-active structural motifs. Here, we report highly stereoselective carbolithiation reactions of α-aryl piperidine enecarbamates that offer direct access to vicinally-substituted piperidine compounds. We have also demonstrated that the carbanion intermediates can be trapped with a carbon electrophile.

A general method for the formation of fused dihydroazepine derivatives from 1-sulfonyl-1,2,3-triazoles bearing a tethered diene is reported. The process involves an intramolecular cyclopropanation of an α-imino rhodium(II) carbenoid, leading to a transient 1-imino-2-vinylcyclopropane intermediate which rapidly undergoes a 1-aza-Cope rearrangement to generate fused dihydroazepine derivatives in moderate to excellent yields. The reaction proceeds with similar efficiency on gram scale. The use of catalyst-free conditions leads to the formation of a novel [4.4.0] bicyclic heterocycle.

The full details of a synthesis of the hetidine framework of the C20-diterpenoid alkaloids and its conversion to the atisine core structure are reported. The application of the hetidine framework to the synthesis of dihydronavirine, which is the formal reduction product of the natural product navirine, is also described. Key to the success of these studies is the use of a Ga(III)-catalyzed cycloisomerization reaction of alkynylindenes to prepare a [6-7-6] framework that was advanced to the hetidine skeleton. Furthermore, a Michael/aldol sequence was developed for the construction of the bicyclo[2.2.2] framework that is characteristic of the hetidines and atisines.

Catalysis and synthesis are intimately linked in modern organic chemistry. The synthesis of complex molecules is an ever evolving area of science. In many regards, the inherent beauty associated with a synthetic sequence can be linked to a certain combination of the creativity with which a sequence is designed and the overall efficiency with which the ultimate process is performed. In synthesis, as in other endeavors, beauty is very much in the eyes of the beholder. It is with this in mind that we will attempt to review an area of synthesis that has fascinated us and that we find extraordinarily beautiful, namely the combination of catalysis and sigmatropic rearrangements in consecutive and cascade sequences.

The synthesis of functionalized azepanes was accomplished through the palladium-mediated cross-coupling of α-halo eneformamides with mostly unactivated nucleophiles under mild conditions. Alkenylations proceeded with excellent stereoselectivitiy. In most cases, high yields of the coupling products were obtained.

Putting the "benz" in indolizinones: A cycloisomerization approach to benz[g]indolizinones and benz[e]indolizinones provides the first general route to these unique azacycles (see example). The utility of the benzindolizinone products was demonstrated by the application of this method to the total synthesis of the Erythrina alkaloids 3-demethoxyerythratidinone and cocculidine.

The core architecture of the citrinadin alkaloids has been prepared in racemic form by utilizing a strategy that exploits the alkylation of 2-methoxypyridines. An initially planned indolizidine to quinolizidine transformation to build the D/E rings was unsuccessful. Success was ultimately gained by a direct alkylation to establish the citrinadin core architecture.