Georgios Vassilikogiannakis

The Diels–Alder Reaction in Total Synthesis

The Diels-Alder reaction has both enabled and shaped the art and science of total synthesis over the last few decades to an extent which, arguably, has yet to be eclipsed by any other transformation in the current synthetic repertoire. With myriad applications of this magnificent pericyclic reaction, often as a crucial element in elegant and programmed cascade sequences facilitating complex molecule construction, the Diels-Alder cycloaddition has afforded numerous and unparalleled solutions to a diverse range of synthetic puzzles provided by nature in the form of natural products. In celebration of the 100th anniversary of Alders birth, selected examples of the awesome power of the reaction he helped to discover are discussed in this review in the context of total synthesis to illustrate its overall versatility and underscore its vast potential which has yet to be fully realized.

Die Diels-Alder-Reaktion in der Totalsynthese

In den letzten Jahrzehnten hat wohl keine andere Reaktion das Forschungsgebiet der Totalsynthese mehr gepragt als die Diels-Alder-Reaktion. Mit einer Vielzahl von Anwendungen dieser grosartigen pericyclischen Reaktion, oftmals als entscheidendes Element einer eleganten Kaskadenreaktion zur Herstellung komplexer Molekulstrukturen, ermoglichte die Diels-Alder-Cycloaddition die Losung einer Reihe unterschiedlicher, von der Natur in Form von Naturstoffen gestellter Syntheseprobleme. Zur Feier des hundertjahrigen Jubilaums von Alders Geburtstag soll dieser Aufsatz die ungemeine Leistungsfahigkeit der von ihm entdeckten Reaktion anhand ausgewahlter Beispiele im Kontext der Totalsynthese verdeutlichen und ihre Vielseitigkeit sowie ihr gewaltiges, noch immer nicht vollstandig erfasstes Potential unterstreichen.

Using Singlet Oxygen to Synthesize Polyoxygenated Natural Products from Furans

[Reaction: see text]. Singlet oxygen is a powerful tool in the armament of the synthetic organic chemist and possibly in that of nature itself. In this Account, we illustrate a small selection of the many ways singlet oxygen can be harnessed in the laboratory to aid in the construction of the complex molecular motifs found in natural products. A more philosophical question is also addressed: namely, how much do singlet oxygen oxidations influence the biogenesis of these natural products? All the synthetic examples surveyed in this Account can be characterized as belonging to the same class because they all involve the oxidation of a substituted furan nucleus by singlet oxygen. Readily accessible and relatively simple furans can be transformed into a host of complex motifs present in a diverse range of natural products by the action of singlet-oxygen-mediated reaction sequences. These reactions are highly advantageous because they frequently deliver a rapid and dramatic increase in molecular complexity in high yield. Furthermore, an unusually wide structural diversity is exhibited by the molecular motifs obtained from these reaction sequences. For example, relatively minor modifications to the starting substrate and to the reaction conditions may lead to products as variable as spiroketal lactones, 3-keto-tetrahydrofurans, various types of bis-spiroketals, 4-hydroxy cyclopentenones, or spiroperoxylactones. In addition, two more specialized examples are discussed in this Account. The core of the prunolide molecules and the chinensine family of natural products were rapidly synthesized using effective and short singlet oxygen mediated strategies; this adds weight to the assertion that singlet oxygen is a very effective moderator of complex cascade reaction sequences. We also show how our synthetic investigations have provided evidence that these same strategies might be used in the biogenesis of these molecules. In the cases of the chinensines and the litseaverticillols, an entire and diverse family of natural products was synthesized beginning from known naturally occurring furan-bearing terpenes. Additionally, in several cases, intermediates in our syntheses have been isolated from natural sources, which suggests that we have followed the same synthetic paths as nature. Certainly, the limit of the synthetic potential of singlet oxygen has not yet been reached, and we can look forward to seeing the boundaries expand in the future in a slew of new and interesting ways.

Total Synthesis of Colombiasin A

Colombian corals of the species Pseudopterogorgia elisabethae produce the title compound, colombiasin A (1). This structurally novel, biologically active tetracyclic compound has now been synthesized for the first time in racemic form. Preliminary studies toward the asymmetric total synthesis of both enantiomers indicate that the determination of the absolute stereochemistry can be expected soon.

Total Synthesis of Colombiasin A and Determination of Its Absolute Configuration

The total synthesis of the recently reported marine natural product colombiasin A (1) and determination of its absolute configuration are reported. Two Diels-Alder cycloadditions and a palladium-catalyzed rearrangement are employed as key reactions to construct the tetracyclic framework of the target molecule. The enantioselective synthesis of colombiasin A utilizes Mikamis [(S)-BINOL-TiCl2] catalyst to asymmetrically introduce the first chiral center during the initial Diels-Alder reaction and, in conjunction with X-ray crystallographic analysis of a bromine containing derivative, led to the assignment of the absolute configuration of the natural product.

Biomimetic Explorations Towards the Bisorbicillinoids: Total Synthesis of Bisorbicillinol, Bisorbibutenolide, and Trichodimerol**

Strikingly simple cascade dimerization sequences can be used to assemble the complex frameworks of bisorbicillinoids such as bisorbicillinol (1), bisorbibutenolide (2), and trichodimerol (3). The mechanistic facets of the biomimetic total syntheses of these bioactive natural products were also explored. Inspection of the unique molecular architecture of these compounds reveals that they are likely to be assembled in nature by a dimerization of two oxidized forms of sorbicillin.

The Total Synthesis of Coleophomones B and C

Members of the coleophomone family of natural products all possess several intriguing and challenging architectural features, as well as exhibit unusual biological activity. They, therefore, constitute attractive targets for synthesis. In this Article, we describe the total synthesis of coleophomones B (2), C (3), and D (4). The highly strained and congested 11-membered macrocycle of coleophomones B (2) and C (3) was constructed using an impressive olefin metathesis reaction. Furthermore, both of the requisite geometric isomers of the Δ16,17 within the macrocycle could be accessed from a common precursor, facilitating a divergence that lent the coleophomone B (2)/C (3) synthesis an unusually high degree of efficiency. The synthesis of coleophomone D (4) confirmed that it exists as a dynamic mixture of isomeric forms with a different aromatic substitution pattern from the other family members.

γ-Spiroketal γ-Lactones from 2-(γ-Hydroxyalkyl)furans: Syntheses of epi-Pyrenolides D and Crassalactone D

Photooxygenation of 2-(gamma-hydroxyalkyl)furans followed by dehydration affords, in one synthetic operation and in high yield, gamma-spiroketal gamma-lactones. This newly developed technology was successfully applied to the synthesis of three different epimers of pyrenolide D, as well as to the first synthesis of the anticancer natural product crassalactone D and its C4-epimer.

A Versatile Synthesis of Meyers’ Bicyclic Lactams from Furans: Singlet‐Oxygen‐Initiated Reaction Cascade

bicyclic lactams have been utilized in a myriad of different ways in the synthesis of a wide variety of natural products and nonnatural molecules possessing interesting biological activity, 4] and, also in a diverse array of other synthetic endeavors. 5] The most general method for their synthesis, introduced in the seminal work by Meyers et al., wherein a g-ketoacid is condensed with an amino alcohol under dehydrating conditions in toluene, heated to reflux, is still, by far, the most commonly employed means of accessing the bicyclic scaffold B. Modifications have been made to the Meyers lactamization with the aim of introducing milder conditions; these modifications range from using microwave energy or employing Lewis acid catalysis, to activating the acid. A second commonly employed, but stepwise, route to these bicyclic lactams, also originating from the Meyers group, relies heavily on N-acyliminium chemistry, which has been extensively elucidated by Speckamp and Hiemstra. In this case, a succinimide intermediate is substituted at the C5-position (usually by addition of a Grignard reagent) and then undergoes intramolecular cyclization under acidic conditions. Several domino reactions affording specific bicyclic lactams have also been reported recently, as well as, other stepwise approaches to the scaffold. This unceasing interest in finding new syntheses for the Meyers bicyclic lactams in itself provides testament to the usefulness of the scaffold and the diversity of potential applications there are for it. Herein, we introduce a new and mild method for the synthesis of a wide variety of Meyers bicyclic lactams. This novel approach, which uses a singlet-oxygen-mediated reaction cascade, is particularly powerful because the one-pot reaction begins from furan substrates which can be variously functionalized (A, Scheme 1) with ease, thus allowing direct access to highly substituted scaffolds of type B (frequently with excellent stereoselectivity). In this way, the new method also exhibits a very high degree of step and atom economy and utilizes the selective “green” reagent, singlet oxygen, to achieve these rapid increases in molecular complexity with precision and minimum production of waste products, thereby attaining many of the recently established criteria for an “ideal synthesis”. The idea for this new method was born from our experience in the field of furan photooxygenations, which has taught us to regard the furan motif as a readily accessible and easy-to-manipulate 1,4-enedione equivalent (or precursor). This fact led us to ask whether the intermediate C (Scheme 2) could be intercepted by an 1,2-aminoalcohol, and, subsequently rearrange and cyclize (under acid catalysis) to afford the Meyers bicyclic lactams, without the need for dehydrating conditions, or high temperatures, which have traditionally been employed. This ambitious concept is summarized, in mechanistic terms, in Scheme 2 (note: only selected steps and intermediates are shown). Thus, when a furan is oxidized upon exposure to singlet oxygen in MeOH, intermediates of type C are known to form easily from the in situ reduction (with Me2S) of a hydroperoxy functionality, which is formed after the solvent-induced collapse of the initially formed endoperoxide adduct has occurred. We hypothesized that addition of a 1,2-aminoalcohol at this stage should regioselectively afford the aminal D (via the morestable, more-substituted oxonium cation). Aminal D would ring open to imino enal E, as shown in Scheme 2, and then ring close again to afford 2-pyrrolidinone G, via 2H-pyrrol-2Scheme 1. Generalized representation of the transformation achieved with this new method. TFA = trifluoroacetic acid.

Singlet-Oxygen-Mediated One-Pot Synthesis of 3-Keto-tetrahydrofurans from 2-(β-Hydroxyalkyl) Furans

Photooxygenation of 2-(beta-hydroxyalkyl) furans affords, in one synthetic operation and in high yields, 3-keto-tetrhydrofuran motifs via intramolecular Michael-type addition to the 1,4-enedione intermediate.