Dual-Hydrogen-Bond Donor and Brønsted Acid Cocatalysis Enables Highly Enantioselective Protio-Semipinacol Rearrangement Reactions.

A catalytic protio-semipinacol ring-expansion reaction has been developed for the highly enantioselective conversion of tertiary vinylic cyclopropyl alcohols into cyclobutanone products bearing α-quaternary stereogenic centers. The method relies on the cocatalytic effect of a chiral dual-hydrogen-bond donor (HBD) with hydrogen chloride. Experimental evidence is provided for a stepwise mechanism where protonation of the alkene generates a short-lived, high-energy carbocation, which is followed by C-C bond migration to deliver the enantioenriched product. This research applies strong acid/chiral HBD cocatalysis to weakly basic olefinic substrates and lays the foundation for further investigations of enantioselective reactions involving high-energy cationic intermediates.

Concise total syntheses of (-)-jorunnamycin A and (-)-jorumycin enabled by asymmetric catalysis.

The bis-tetrahydroisoquinoline (bis-THIQ) natural products have been studied intensively over the past four decades for their exceptionally potent anticancer activity, in addition to strong Gram-positive and Gram-negative antibiotic character. Synthetic strategies toward these complex polycyclic compounds have relied heavily on electrophilic aromatic chemistry, such as the Pictet-Spengler reaction, that mimics their biosynthetic pathways. Herein, we report an approach to two bis-THIQ natural products, jorunnamycin A and jorumycin, that instead harnesses the power of modern transition-metal catalysis for the three major bond-forming events and proceeds with high efficiency (15 and 16 steps, respectively). By breaking from biomimicry, this strategy allows for the preparation of a more diverse set of nonnatural analogs.

Highly enantioselective, intermolecular hydroamination of allenyl esters catalyzed by bifunctional phosphinothioureas.

Bifunctional phosphinothiourea catalysts have been developed successfully for the highly regio- and enantioselective γ-hydroamination of allenyl and propargyl esters with N-methoxy carbamate nucleophiles to yield α,ß-unsaturated γ-amino acid ester products. In the case of propargyl ester substrates, the reaction proceeds through reversible phosphinothiourea-catalyzed isomerization to the corresponding allenyl ester. The high enantioselectivity of the process is attributed to a cooperative conjugate addition of a thiourea-bound carbamate anion to a vinyl phosphonium ion resulting from covalent activation of the allenyl ester substrate.

A broadly applicable and practical oligomeric (salen) Co catalyst for enantioselective epoxide ring-opening reactions.

The (salen) Co catalyst (4a) can be prepared as a mixture of cyclic oligomers in a short, chromatography-free synthesis from inexpensive, commercially available precursors. This catalyst displays remarkable enhancements in reactivity and enantioselectivity relative to monomeric and other multimeric (salen) Co catalysts in a wide variety of enantioselective epoxide ring-opening reactions. The application of catalyst 4a is illustrated in the kinetic resolution of terminal epoxides by nucleophilic ring-opening with water, phenols, and primary alcohols; the desymmetrization of meso epoxides by addition of water and carbamates; and the desymmetrization of oxetanes by intramolecular ring opening with alcohols and phenols. The favorable solubility properties of complex 4a under the catalytic conditions facilitated mechanistic studies, allowing elucidation of the basis for the beneficial effect of oligomerization. Finally, a catalyst selection guide is provided to delineate the specific advantages of oligomeric catalyst 4a relative to (salen) Co monomer 1 for each reaction class.

A rapid and convergent synthesis of the integrastatin core.

The tetracyclic core of the integrastatin natural products has been prepared in a convergent and rapid manner. Our strategy relies upon a palladium(II)-catalyzed oxidative cyclization to form the central [3.3.1]-dioxabicycle of the natural product core. Overall, the core has been completed in only 4 linear steps from known compounds.

Aryne acyl-alkylation in the general and convergent synthesis of benzannulated macrolactone natural products: an enantioselective synthesis of (-)-curvularin.

A general approach for the synthesis of benzannulated macrolactone natural products utilizing an aryne acyl-alkylation reaction is described. Toward this end, the total syntheses of the natural products (-)-curvularin, curvulin, and (-)-diplodialide C are reported. Furthermore, the aryne insertion technology has enabled the rapid conversion of simple diplodialide natural products to curvularin, thereby connecting these two biosynthetically distinct classes of compounds via synthetic methods.

Regioselective reactions of highly substituted arynes.

The fully regioselective reactivity of four new highly substituted silyl aryl triflate aryne precursors in aryne acyl-alkylation, acyl-alkylation/condensation, and heteroannulation reactions is reported. The application of these more complex arynes provides access to diverse natural product scaffolds and obviates late-stage functionalization of aromatic rings.

Amide-ligand hydrogen bonding in reverse micelles.

One approach to modeling the second coordination shell of metalloproteins is to pair amide-containing counterions with metal complexes to form hydrogen bonds in the solid state. In a more general approach, we have designed a surfactant counterion that can sustain hydrogen bonding interactions with metal complexes in solution. The surfactant is cationic and incorporates an amide as part of its headgroup to form hydrogen. The surfactant forms hydrogen bonding reverse micelles that accommodate anionic metal complexes in their polar core. In reverse micelles containing an iron(III) hexacyanide complex, spectroscopic evidence suggests that the anion is confined to the polar core region in solution. Single-crystal X-ray diffraction data on the surfactant ferricyanide system reveals a layered structure with interdigitated alkyl chains and an extensive network of hydrogen bonds that link amide groups to the cyanide ligands and to neighboring headgroups.