2017-01- Synthetic strategies towards mycolactone A/B, an exotoxin secreted by Mycobacterium ulcerans
Saint-Auret, S.; Abdelkafi, H.; Le Nouen, D.; Bisseret, P.; Blanchard, N. Org. Chem. Front. 2017, 4, 2380-2386.
Mycolactone A/B, a complex polyketidic macrolide secreted by Mycobacterium ulcerans, has been synthesized using catalytic and/or asymmetric reactions. Several palladium-catalyzed reactions were investigated for forging key σ-bonds as well as a particularly challenging hydroboration reaction of a functionalized and sterically demanding 1,1-disubstituted exo-alkene. The full account of these investigations is discussed.
A modular total synthesis of mycolactone A/B, the exotoxin produced by Mycobacterium ulcerans, has been achieved through the orchestration of several Pd-catalyzed key steps. While this route leads to a mixture of the natural product and its C12 epimer (4 : 1 ratio), this was inconsequential from the biological activity standpoint. Compared to the previously reported routes, this synthetic blueprint allows the late-stage modification of the toxin, as exemplified by the preparation of [22,22,22-2H3]-mycolactone A/B
2017-03- Diels–Alder and Formal Diels–Alder Cycloaddition Reactions of Ynamines and Ynamides
Duret, G.; Le Fouler, V.; Bisseret, P.; Bizet, V.; Blanchard, N. Eur. J. Org. Chem. 2017, 6816-6830.
Nitrogen-substituted alkynes such as ynamines and ynamides are competent partners in [4+2] cycloaddition reactions. This microreview aims to discuss in a historical context the main achievements in the work on this class of reactions that leads to valuable nitrogen-containing heterocycles in a single-step fashion. In the last section, our own work in the field of inverse-electron-demand Diels–Alder reactions between ynamides and pyrimidines is discussed.
2017-04- Intramolecular Inverse Electron-Demand [4+2] Cycloadditions of Ynamides with Pyrimidines: Scope and DFT Insights
Duret, G.; Quinlan, R.; Yin, B.; Martin, R. E.; Bisseret, P.; Neuburger, M.; Gandon, V.; Blanchard, N. J. Org. Chem.2017, 82, 1726-1742.
We report herein a collection of structurally diverse polycyclic fused and spiro-4-aminopyridines that are prepared in only three steps from commercially available pyrimidines. The key step of this short sequence is a [4 + 2]/retro-[4 + 2] cycloaddition between a pyrimidine and an ynamide, which constitutes the first examples of ynamides behaving as electron-rich dienophiles in [4 + 2] cycloaddition reactions. In addition, running the ihDA/rDA reaction in continuous mode in superheated toluene, to overcome the limited scalability of MW reactions, results in a notable production increase compared to batch mode. Finally, density functional theory investigations shed light on the energetic and geometric requirements of the different steps of the ihDA/rDA sequence.
2017-05- Intramolecular inverse electron-demand [4+2] cycloadditions of ynamidyl-tethered pyrimidines: Comparative studies in trifluorotoluene and sulfolane
Donnard, M.; Duret, G.; Bisseret, P.; Blanchard, N. C. R. Acad. Sci. 2017, 20, 643-647.
Three representative 6,7-dihydro-5H-cyclopenta[b]pyridin-4-amines were synthesized using an intramolecular inverse electron demand hetero–Diels–Alder/retro–Diels–Alder sequence between pyrimidines (acting as azadienes) and ynamides (acting as dienophiles). Two solvents of this reaction, sulfolane and trifluorotoluene, were compared at 210 °C and the former consistently led to higher yields. In addition, these studies confirmed the importance of the steric bulk of the C5-position of the pyrimidinyl cycloaddition precursor.
Buruli ulcer, classified as a neglected tropical disease by the World Health Organization, is caused by a mycobacterium which secretes a macrolidic exotoxin called mycolactone A/B. In this article, several synthetic strategies for the preparation of this toxin are discussed, highlighting the importance of total synthesis for the exploration of biological mechanism underpinning relevant human diseases.
2017-07- Acid-Catalyzed Ring-Opening Reactions of Cyclopropanated 3-Aza-2-oxabicyclo[2.2.1]hept-5-enes with Alcohols
Tam, W.; Tait, K.; Horvath, A.; Blanchard, N. Beilstein J. Org. Chem. 2017, 13, 2888-2894.
The acid-catalyzed ring-opening reactions of a cyclopropanated 3-aza-2-oxabicylic alkene using alcohol nucleophiles were investigated. Although this acid-catalyzed ring-opening reaction did not cleave the cyclopropane unit as planned, this represent the first examples of ring-openings of cyclopropanated 3-aza-2-oxabicyclo[2.2.1]alkenes that lead to the cleavage of the C–O bond instead of the N–O bond…
