Assembling the Methanoindene Cage of Phragmalin-Type Natural Products.

Phragmalin-type limonoids are highly complex natural products based on an unusual octahydro-1H-2,4-methanoindene cage. The absence of feasible routes to sufficiently functionalized methanoindene cage building blocks impedes the total synthesis of these natural products. We have developed a short and robust route to methanoindene cage compounds from the Hajos-Parrish ketone (HPK). Several stereoselective modifications of the HPK provided a substrate that underwent aldol reaction as a key step for the cage formation.

Beyond Bioisosteres: Divergent Synthesis of Azabicyclohexanes and Cyclobutenyl Amines from Bicyclobutanes.

The development of two divergent and complementary Lewis acid catalyzed additions of bicyclobutanes to imines is described. Microscale high-throughput experimentation was integral to the discovery and optimization of both reactions. N-arylimines undergo formal (3+2) cycloaddition with bicyclobutanes to yield azabicyclo[2.1.1]hexanes in a single step; in contrast, N-alkylimines undergo an addition/elimination sequence to generate cyclobutenyl methanamine products with high diastereoselectivity. These new products contain a variety of synthetic handles for further elaboration, including many functional groups relevant to pharmaceutical synthesis. The divergent reactivity observed is attributed to differences in basicity and nucleophilicity of the nitrogen atom in a common carbocation intermediate, leading to either nucleophilic attack (N-aryl) or E1 elimination (N-alkyl).

Palladium-Catalyzed Cross-Coupling of Alkenyl Carboxylates.

Carboxylate esters have many desirable features as electrophiles for catalytic cross-coupling: they are easy to access, robust during multistep synthesis, and mass-efficient in coupling reactions. Alkenyl carboxylates, a class of readily prepared non-aromatic electrophiles, remain difficult to functionalize through cross-coupling. We demonstrate that Pd catalysis is effective for coupling electron-deficient alkenyl carboxylates with arylboronic acids in the absence of base or oxidants. Furthermore, these reactions can proceed by two distinct mechanisms for C-O bond activation. A Pd0/II catalytic cycle is viable when using a Pd0 precatalyst, with turnover-limiting C-O oxidative addition; however, an alternative pathway that involves alkene carbopalladation and ß-carboxyl elimination is proposed for PdII precatalysts. This work provides a clear path toward engaging myriad oxygen-based electrophiles in Pd-catalyzed cross-coupling.

Oxidative addition of activated aryl-carboxylates to Pd(0): divergent reactivity dependant on temperature and structure.

With the exception of activated sulfonate esters, oxidative addition of Ar-O bonds to Pd(0) complexes is extremely rare. This has led to a general perception that Pd-catalyzed cross-coupling is not feasible with O-based electrophiles such as aryl esters. We report that pyrone and coumarin esters do undergo oxidative addition to Pd(PCy3)2, with Pd insertion into either the acyl-O or Ar-O bond. Addition of the acyl-O bond to Pd(0) is kinetically favoured and reversible, while addition of the Ar-O bond is thermodynamically favoured. Using a larger and more electron-rich pivalate derivative disfavours acyl-O cleavage, enabling selective oxidative addition of the Ar-O bond and corresponding catalytic cross-coupling.

High-Throughput Discovery and Evaluation of a General Catalytic Method for N-Arylation of Weakly Nucleophilic Sulfonamides.

Through targeted high-throughput experimentation (HTE), we have identified the Pd/AdBippyPhos catalyst system as an effective and general method to construct densely functionalized N,N-diaryl sulfonamide motifs relevant to medicinal chemistry. AdBippyPhos is particularly effective for the installation of heteroaromatic groups. Computational steric parametrization of the investigated ligands reveals the potential importance of remote steric demand, where a large cone angle combined with an accessible Pd center is correlated to successful catalysts for C-N coupling reactions.

The roles of Lewis acidic additives in organotransition metal catalysis.

We describe recent examples of prominent reactions in organic synthesis that involve transition metal and Lewis acid cocatalysts. Introducing Lewis acid additives to transition metal catalysis can enable new reactivity or improve activity and selectivity of an existing process. Several studies are highlighted to illustrate the possible roles of Lewis acids in catalytic mechanisms. The uses of Lewis acid additives in bond-breaking catalysis (C-C activation, C-H activation, and hydrogenolysis reactions) and bond-forming catalysis (Au-catalysed alkyne functionalisation, Pd-catalysed C-C and C-N bond formation) are reviewed.

Bis-tropolonate complexes of tungsten: scaffolds for selective side-on binding of nitriles, imines and ketones.

The chiral bis-tropolonate tungsten(ii) tricarbonyl compound, (trop)2W(CO)3 (1), has been synthesized and structurally characterized. This seven-coordinate compound readily loses two carbonyl ligands to preferentially bind a series of π-bonding substrates to form six-coordinate complexes of the type (trop)2W(CO)(L). Alkynes coordinate strongly to form (trop)2W(CO)(η(2)-RCCR) (2) in which spectroscopic data is consistent with the alkyne serving as a 4-electron donor. Compound 1 will also preferentially coordinate organic nitriles in a side-on fashion through the CN triple bond. A dramatic shift in the nitrile carbon signals to greater than 210 ppm in the (13)C NMR confirms the nitriles are coordinated in an η(2) 4-electron donating capacity. Aldehydes, ketones, and imines also react with 1 to form 4-electron donor η(2) adducts. The imine adduct (trop)2W(CO)(η(2)-MeN=C(H)(tol)) (5) was characterized crystallographically and the short 1.91 A W-N bond distance supports the postulation of 4-electron donation from the imine through C=N π-bonding and N lone pair donation. Side-on coordination of ligands of this type is rare and may provide a means towards asymmetric functionalization of these substrates. All of the tropolonate compounds are prone to oxidation in air and the alkyne compounds will oxidize to stable W(IV) oxo alkyne species, (trop)2W(O)(η(2)-RCCR) (6). This causes a 90° rotation of the alkyne ligand and a reduction in alkyne donation to approximately 3 electrons, to maintain an optimal 18 electron configuration.