The enantioselective synthesis of both caprolactam and enone synthons for the DEFG ring system of zoanthenol are described. The evolution of this approach proceeds first through a synthesis using the chiral pool as a starting point. Challenges in protecting-group strategy led to the modification of this approach beginning with (±)-glycidol. Ultimately, an efficient approach was developed by employing an asymmetric hetero-Diels–Alder reaction. The caprolactam building block can be converted by an interesting selective Grignard addition into the corresponding enone synthon. Addition of a model alkyne provides support for the late-stage addition of a hindered alkyne to the caprolactam building block.

Donor−acceptor cyclopropanes are convenient precursors to reactive and versatile 1,3-dipoles, and have found application in the synthesis of a variety of carbo- and heterocyclic scaffolds. This perspective review details our laboratory's use of donor−acceptor cyclopropanes as intermediates toward the total synthesis of various natural products. We also discuss our work in the development of novel cycloadditions and rearrangements of donor−acceptor cyclopropanes and aziridines, as well as an example of an aryne insertion proceeding via fragmentation of a transient donor−acceptor cyclobutane.

An efficient and exceptionally mild intramolecular nickel-catalyzed carbon–oxygen bond-forming reaction between vinyl halides and primary, secondary, and tertiary alcohols has been achieved. Zinc powder was found to be an essential additive for obtaining high catalyst turnover and yields. This operationally simple method allows direct access to cyclic vinyl ethers in high yields in a single step.

An efficient and exceptionally mild intramolecular nickel-catalyzed carbon–oxygen bond-forming reaction between vinyl halides and primary, secondary, and tertiary alcohols has been achieved. Zinc powder was found to be an essential additive for obtaining high catalyst turnover and yields. This operationally simple method allows direct access to cyclic vinyl ethers in high yields in a single step.

The use of Oxone and a palladium(II) catalyst enables the efficient allylic CH oxidation of sterically hindered α-quaternary lactams which are unreactive under known conditions for similar transformations. This simple, safe, and effective system for CH activation allows for unusual tunable selectivity between a two-electron oxidation to the allylic acetates and a four-electron oxidation to the corresponding enals, with the dominant product depending on the presence or absence of water. The versatile synthetic utility of both the allylic acetate and enal products accessible through this methodology is also demonstrated.

The use of Oxone and a palladium(II) catalyst enables the efficient allylic CH oxidation of sterically hindered α-quaternary lactams which are unreactive under known conditions for similar transformations. This simple, safe, and effective system for CH activation allows for unusual tunable selectivity between a two-electron oxidation to the allylic acetates and a four-electron oxidation to the corresponding enals, with the dominant product depending on the presence or absence of water. The versatile synthetic utility of both the allylic acetate and enal products accessible through this methodology is also demonstrated.

The asymmetric palladium-catalyzed decarboxylative allylic alkylation of differentially N-protected piperazin-2-ones allows the synthesis of a variety of highly enantioenriched tertiary piperazine-2-ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogues. The introduction of these chiral tertiary piperazines resulted in imatinib analogues which exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts.

The asymmetric palladium-catalyzed decarboxylative allylic alkylation of differentially N-protected piperazin-2-ones allows the synthesis of a variety of highly enantioenriched tertiary piperazine-2-ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogues. The introduction of these chiral tertiary piperazines resulted in imatinib analogues which exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts.

Alkyl and aryl isothiocyanates and carbodiimides are effective substrates in (3+2) cycloadditions with N-sulfonyl-2-substituted aziridines and 2-phenylaziridine for the synthesis of iminothiazolidines and iminoimidazolidines. Additionally, the stereoselective (3+2) cycloaddition of N-H- and N-sulfonylaziridines with isothiocyanates can be accomplished, allowing for the synthesis of highly enantioenriched iminothiazolidines. Evidence for an intimate ion-pair mechanism is presented herein in the context of these chemo-, regio-, and diastereoselective transformations. The demonstrated ability to remove the sulfonyl group from the heterocyclic products displays the utility of these compounds for further derivatization and application.

Presilphiperfolanols constitute a family of biosynthetically important sesquiterpenes which can rearrange to diverse sesquiterpenoid skeletons. While the origin of these natural products can be traced to simple linear terpene precursors, the details of the enzymatic cyclization mechanism that forms the stereochemically dense tricyclic skeleton has required extensive biochemical, computational, and synthetic investigation. Parallel efforts to prepare the unique and intriguing structures of these compounds by total synthesis have also inspired novel strategies, thus resulting in four synthetic approaches and two completed syntheses. While the biosynthesis and chemical synthesis studies performed to date have provided much insight into the role and properties of these molecules, emerging questions regarding the biosynthesis of newer members of the family and subtle details of rearrangement mechanisms have yet to be explored.

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.1 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.

Presilphiperfolanole bilden eine biosynthetisch bedeutende Klasse von Sesquiterpenen, die sich zu verschiedenen weiteren Sesquiterpen-Grundgerüsten umlagern können. Ihr Ursprung lässt sich auf einfache lineare Terpenvorstufen zurückverfolgen. Durch umfassende biochemische, theoretische und synthetische Arbeiten gelang es, ein mechanistisches Verständnis für die enzymatische Cyclisierung zu gewinnen. Um die ungewöhnliche und bemerkenswerte Grundstruktur der Presilphiperfolanole synthetisch zu erhalten, wurde ebenfalls intensiv an Totalsynthesen dieser Naturstoffe gearbeitet. Die dabei entwickelten Strategien mündeten in zwei Syntheseansätzen sowie zwei vollständigen Totalsynthesen. Während biosynthetisch und durch chemische Synthese schon viel zur Aufklärung der Moleküle und ihrer Mechanismen beigetragen wurde, tauchen Fragen zur Biosynthese von neueren Presilphiperfolanolen auf. Auch die Umlagerungsmechanismen sind im Detail noch unklar.

All-carbon quaternary stereocenters have posed significant challenges in the synthesis of complex natural products. These important structural motifs have inspired the development of broadly applicable palladium-catalyzed asymmetric allylic alkylation reactions of unstabilized non-biased enolates for the synthesis of enantioenriched α-quaternary products. This microreview outlines key considerations in the application of palladium-catalyzed asymmetric allylic alkylation reactions and presents recent total syntheses of complex natural products that have employed these powerful transformations for the direct, catalytic, enantioselective construction of all-carbon quaternary stereocenters.

Access to the bicyclo[5.3.0]decane core found in the daucane and sphenolobane terpenoids via a key enone intermediate enables the enantioselective total syntheses of daucene, daucenal, epoxydaucenal B, and 14-para-anisoyloxydauc-4,8-diene. Central aspects include a catalytic asymmetric alkylation followed by a ring contraction and ring-closing metathesis to generate the five- and seven-membered rings, respectively.

α-Quaternary ketones are accessed through novel enantioselective alkylations of allyl and propargyl electrophiles by unstabilized prochiral enolate nucleophiles in the presence of palladium complexes with various phosphinooxazoline (PHOX) ligands. Excellent yields and high enantiomeric excesses are obtained from three classes of enolate precursor: enol carbonates, enol silanes, and racemic β-ketoesters. Each of these substrate classes functions with nearly identical efficiency in terms of yield and enantioselectivity. Catalyst discovery and development, the optimization of reaction conditions, the exploration of reaction scope, and applications in target-directed synthesis are reported. Experimental observations suggest that these alkylation reactions occur through an unusual inner-sphere mechanism involving binding of the prochiral enolate nucleophile directly to the palladium center.

A concise and versatile approach toward the preparation of the cyanthiwigin family of cyathane natural products is described. By leveraging a unique double asymmetric catalytic alkylation procedure it is possible to quickly establish two of the most critical stereocenters of the cyanthiwigin framework with high levels of selectivity and expediency. The synthetic route additionally employs both a tandem ring-closing cross-metathesis reaction, and an aldehyde-olefin radical cyclization process, in order to rapidly arrive at the tricyclic cyathane core of the cyanthiwigin molecules. From this unifying intermediate, the preparations of cyanthiwigins B, F, and G are attained swiftly and without the need for protecting groups.

The first palladium-catalyzed enantioselective oxidation of secondary alcohols has been developed, utilizing the readily available diamine (−)-sparteine as a chiral ligand and molecular oxygen as the stoichiometric oxidant. Mechanistic insights regarding the role of the base and hydrogen-bond donors have resulted in several improvements to the original system. Namely, addition of cesium carbonate and tert-butyl alcohol greatly enhances reaction rates, promoting rapid resolutions. The use of chloroform as solvent allows the use of ambient air as the terminal oxidant at 23 °C, resulting in enhanced catalyst selectivity. These improved reaction conditions have permitted the successful kinetic resolution of benzylic, allylic, and cyclopropyl secondary alcohols to high enantiomeric excess with good-to-excellent selectivity factors. This catalyst system has also been applied to the desymmetrization of meso-diols, providing high yields of enantioenriched hydroxyketones.

Marine Naturstoffe spielen schon lange eine wichtige Rolle in der Naturstoffchemie und bei der Wirkstoffentwicklung. Die Artenvielfalt und das facettenreiche Wechselspiel im Lebensraum Meer spiegeln sich in den Eigenschaften der Substanzen wider, die aus marinen Lebensformen isoliert werden: Sie zeigen unwahrscheinlich vielseitige Molekülstrukturen und biologische Aktivitäten. Die Naturstoffe aus den Polypen der marinen Zoanthidea bilden darin keine Ausnahme. Die Zoanthamin-Alkaloide, deren erste Vertreter vor über zwanzig Jahren isoliert wurden, erregten besonderes Interesse als Syntheseziele, weil sie sich durch eine große Bandbreite an biologischen Aktivitäten auszeichnen. Hier fassen wir die wichtigsten Beiträge zur Isolierung und strukturellen Charakterisierung der natürlichen Zoanthamine zusammen und führen Studien zu ihrer biologischen Aktivität und Totalsynthese an.

Marine natural products have long played an important role in natural products chemistry and drug discovery. Mirroring the rich variety and complicated interactions of the marine environment, the substances isolated from sea creatures tend to be incredibly diverse in both molecular structure and biological activity. The natural products isolated from the polyps of marine zoanthids are no exception. The zoanthamine alkaloids, the first of which were isolated over 20 years ago, are of particular interest to the synthetic community because they feature a novel structural framework and exhibit a broad range of biological activities. In this Review, we summarize the major contributions to understanding the zoanthamine natural products with regard to their isolation and structure determination, as well as studies on their biological activity and total synthesis.