[Rh(CO)2Cl]2 is as an effective catalyst for endoselective cyclizations and cascades of epoxy-(E)-enoate alcohols, thus enabling the synthesis of oxepanes andoxepane-containing polyethers from di- and trisubstituted epoxides. Syntheses of the ABC and EF ring systems of (−)-brevisin via all endo-diepoxide-opening cascades using this method constitute a formal total synthesis and demonstrate the utility of this methodology in the context of the synthesis of marine ladder polyether natural products.
A new and highly selective method for the synthesis of hydroxyl-substituted tetrahydropyrans is described. This method utilizes titanium(IV) isopropoxide and diethyl tartrate to perform a diastereoselective epoxidation followed by in situ epoxide activation and highly selective endocyclization to form the desired tetrahydropyran ring. The HIJ ring fragment of the marine ladder polyether yessotoxin was synthesized using this two-stage tactic that proceeds with high efficiency and excellent regioselectivity
Among the numerous approaches and reagents employed for electrophilic amination, nitrenoids have long stayed out of the limelight. Here, we systematically review the discovery, structural features and chemical reactivity of these promising reagents. We highlight advances in applying the chemistry of nitrenoids as well as outline current limitations and future directions.
Despite the myriad of selective enzymatic reactions that occur in water, chemists have rarely capitalized on the unique properties of this medium to govern selectivity in reactions. Here we report detailed mechanistic investigations of a water-promoted reaction that displays high selectivity for what is generally a disfavored product. A combination of structural and kinetic data indicates not only that synergy between substrate and water suppresses undesired pathways but also that water promotes the desired pathway by stabilizing charge in the transition state, facilitating proton transfer, doubly activating the substrate for reaction, and perhaps most remarkably, reorganizing the substrate into a reactive conformation that leads to the observed product. This approach serves as an outline for a general strategy of exploiting solvent-solute interactions to achieve unusual reactivity in chemical reactions. These findings may also have implications in the biosynthesis of the ladder polyether natural products, such as the brevetoxins and ciguatoxins.
Herein we describe in full our investigations leading to the first total syntheses of ent-dioxepandehydrothyrsiferol and armatol A. Discovery of a bromonium-initiated epoxide-opening cascade enabled novel tactics for constructing key fragments found in both natural products and have led us to revise the proposed biogeneses. Other common features found in the routes include convergent fragment coupling strategies to assemble the natural products' backbones and the use of epoxide-opening cascades for rapid constructions of the fused polyether subunits. Through de novo synthesis of armatol A, we elucidate the absolute and relative configuration of this natural product.
Reversed selectivity: 1,3-Dioxan-5-ol templated epoxy alcohols undergo a remarkably selective cyclization, which occurs with near complete endo selectivity that is opposite to that predicted by Baldwin's rules. This endo preference in water near pH 7.0 is an order of magnitude larger relative to that of a previously disclosed THP-templated cyclization (see scheme), suggesting that “templates” may be important in the biosynthesis of marine ladder polyethers.
A new photochemical flow reactor has been developed for the photo-induced electron-transfer deoxygenation reaction to produce 2′-deoxy and 2′,3′-dideoxynucleosides. The continuous flow format significantly improved both the efficiency and selectivity of the reaction, with the streamlined multi-step sequence directly furnishing the highly desired unprotected deoxynucleosides.
A continuous protocol for the two-carbon homologation of esters to α,β-unsaturated esters is described. This multireactor homologation telescopes an ester reduction, phosphonate deprotonation, and Horner–Wadsworth–Emmons olefination, thus converting a three-operation procedure into a single, uninterrupted system that eliminates the need for isolation or purification of the aldehyde intermediates. The homologated products are obtained in high yield and selectivity.
A continuous flow system for the multiparameter (flow rate, temperature, residence time, stoichiometry) optimization of the DIBALH reduction of esters to aldehydes is described. Incorporating an in-line quench (MeOH), these transformations are generally complete in fewer than 60 s. Mixing of the DIBALH and ester solutions was observed to be an exceptionally critical parameter for optimum results. This system thus provides general guidelines based on the structure of the ester for selective reduction of an ester without overreduction.
A continuous-flow microreactor is applied for a kinetic study of a model β-amino alcohol formation by epoxide aminolysis. A large number of experiments are performed in a short time with minimal reagent consumption. The kinetics of formation of secondary aminolysis between starting epoxide and product are decoupled from the primary synthesis, constructing a complete model for desired product formation. The activation energy for the formation of desired product is observed to be higher than those for regioisomer formation and for secondary aminolysis, indicating that increasing temperature improves selectivity in addition to accelerating the reaction. A set of optimized conditions is then selected for best reaction performance, and the process is scaled up to a 100-fold larger reactor volume with model predictions in good agreement with measured process performance.