Tamsyn Montagnon

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.

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.

Methylene Blue as a Photosensitizer and Redox Agent: Synthesis of 5‐Hydroxy‐1H‐pyrrol‐2(5H)‐ones from Furans

A highly efficient and general singlet-oxygen-initiated one-pot transformation of readily accessible furans into 5-hydroxy-1H-pyrrol-2(5H)-ones has been developed. The methodology was extended to the synthesis of other high-value α,β-unsaturated γ-lactams. This useful set of transformations relies not only on the photosensitizing ability of methylene blue, but also on its redox properties: properties that have until now been virtually ignored in a synthetic context.

One-pot synthesis of the tetracyclic framework of the aromatic erythrina alkaloids from simple furans.

Conversion of a simple furan into the intact erythrinane skeleton in one synthetic operation has been accomplished. The one-pot reaction sequence begins with singlet oxygen photooxygenation of the furan and proceeds via a 2-pyrrolidinone formation, cyclization of the pendant aldehyde moiety and an N-acyliminium ion formation and terminates with a Pictet-Spengler-type aromatic substitution. The method has been used to achieve a rapid and highly effective formal synthesis of erysotramidine.

Using water, light, air and spirulina to access a wide variety of polyoxygenated compounds

A new set of completely green methods utilising air, light, water and spirulina to transform readily accessible furan substrates into a diverse range of synthetically useful polyoxygenated motifs commonly found in natural products is presented herein.

From Simple Furans to Complex Nitrogen‐Bearing Aromatic Polycycles by Means of a Flexible and General Reaction Sequence Initiated by Singlet Oxygen

All-in-one: A new and general one-pot reaction sequence initiated by singlet oxygen that transforms simple furan substrates into complex nitrogen-bearing aromatic polycycles having all the structural features of a number of important natural products (for example, the erythrina alkaloids; see scheme, RB = rose Bengal) is reported. The reaction sequence itself uses mild conditions and has wide functional group tolerance.

Photooxidations of 2-(γ,ε-dihydroxyalkyl) furans in water: synthesis of DE-bicycles of the pectenotoxins.

Photooxygenations of 2-(γ,ε-dihydroxyalkyl) furans in H(2)O followed by in situ reduction and ketalization affords, in one synthetic operation, DE-bicyclic ketals of the pectenotoxins.

Using singlet oxygen to synthesise a [6,6,5]-bis-spiroketal in one-pot from a simple 2,5-disubstituted furan.

Singlet oxygen (1O2) proves to be a powerful tool in mediating the one-pot synthesis of a salinomycin-type [6,6,5]-bis-spiroketal unit starting from a suitably substituted furan nucleus.

Total synthesis of coleophomone DElectronic supplementary information (ESI) available: selected physical data for compound 18. See http://www.rsc.org/suppdata/cc/b2/b208236p/

A concise total synthesis of coleophomone D that exists as a dynamic mixture of four isomeric compounds, using a strategy based on a benzoyl cyanide coupling reaction to assemble the key tricarbonyl motif, is reported.