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Pericyclic reactions bypass high-energy reactive intermediates by synchronizing bond formation and bond cleavage. The present work offers two strategies for uncoupling these two processes and converting concerted processes into their "interrupted" versions by combining Au(I) catalysis with electronic and stereoelectronic factors. First, we show how the alignment of the C3-C4 bond with the adjacent π systems can control the reactivity and how the concerted scission of the central σ bond is prevented in the boat conformation. Second, the introduction of a fluorine atom at C3 also interrupts the sigmatropic shift and changes the rate-determining step of the interrupted cascade from the 6-endo-dig nucleophilic attack to the fragmentation of the central C3-C4 bond. Furthermore, this effect strongly depends on the relative orientation of the C-F bond toward the developing cationic center. The equatorial C-F bond has a much greater destabilizing effect on TS2 due to the more efficient through-bond interaction between the acceptor and the cationic π system. In contrast, the axial C-F bond is not aligned with the bridging C-C bonds and does not impose an equally strong deactivating stereoelectronic effect. These differences illustrate that the competition between concerted and interrupted pericyclic pathways can be finely tuned via a combination of structural and electronic effects modulated by conformational equilibria. The combination of Au(I) catalysis and C-F-mediated stereoelectronic gating delays the central bond scission, opening access to the interrupted Cope rearrangements and expanding the scope of this classic reaction to the design of new cascade transformations.

The analysis of different layers of proximity effect in ortho-substituted aromatic compounds, using a DFT-level study, is reported. Polar and steric components of the proximity effect have been partitioned by applying multivariate regression analysis to an unusual six-electron heteroelectrocyclic reaction of the ortho-substituted nitrosostyrenes. The two pathways, 1,5- and 1,6-cyclizations, emanating from these substrates result into zwitterionic five-membered and neutral six-membered rings, respectively. The substituents at position 1, which are adjacent to the polar nitroso group, influenced the barrier primarily through electronic effect. Furthermore, a mechanistic shift from the 1,5 to 1,6 pathway, for certain substrates, is explained by the electronic repulsion. In contrast to position 1, the substituents on position 4 stereoelectronically interacted with a bulkier alkene moiety. Furthermore, unlike position 1, the position-4-substituted substrates are predicted to give only 1,5 products. A comparison of the two ortho positions with position 2, which is meta to the nitroso and para to the alkene, revealed an intriguing relationship between various electronic factors.

The combination of experiments and computations reveals unusual features of stereoselective Rh(I)-catalyzed transformation of propargyl vinyl ethers into (E,Z)-dienals. The first step, the conversion of propargyl vinyl ethers into allene aldehydes, proceeds under homogeneous conditions via a "cyclization-mediated" mechanism initiated by Rh(I) coordination at the alkyne. This path agrees well with the small experimental effects of substituents on the carbinol carbon. The key feature revealed by the computational study is the stereoelectronic effect of the ligand arrangement at the catalytic center. The rearrangement barriers significantly decrease due to the greater transfer of electron density from the catalytic metal center to the CO ligand oriented trans to the alkyne. This effect increases electrophilicity of the metal and lowers the calculated barriers by 9.0 kcal/mol. Subsequent evolution of the catalyst leads to the in situ formation of Rh(I) nanoclusters that catalyze stereoselective tautomerization. The intermediacy of heterogeneous catalysis by nanoclusters was confirmed by mercury poisoning, temperature-dependent sigmoidal kinetic curves, and dynamic light scattering. The combination of experiments and computations suggests that the initially formed allene-aldehyde product assists in the transformation of a homogeneous catalyst (or "a cocktail of catalysts") into nanoclusters, which in turn catalyze and control the stereochemistry of subsequent transformations.

A novel Rh(I)-catalyzed approach to functionalized (E,Z) dienals has been developed via tandem transformation where a stereoselective hydrogen transfer follows a propargyl Claisen rearrangement. Z-Stereochemistry of the first double bond suggests the involvement of a six-membered cyclic intermediate whereas the E-stereochemistry of the second double bond stems from the subsequent protodemetalation step giving an (E,Z)-dienal.

Curtin-Hammett analysis of four alternative mechanisms of the gold(I)-catalyzed [3,3] sigmatropic rearrangement of allenyl vinyl ethers by density functional theory calculations reveals that the lowest energy pathway (cation-accelerated oxonia Claisen rearrangement) originates from the second most stable of the four Au(I)-substrate complexes in which gold(I) coordinates to the lone pair of oxygen. This pathway proceeds via a dissociative transition state where the C-O bond cleavage precedes C1-C6 bond formation. The alternative Au(I) coordination at the vinyl π-system produces a more stable but less reactive complex. The two least stable modes of coordination at the allenyl π-system display reactivity that is intermediate between that of the Au(I)-oxygen and the Au(I)-vinyl ether complexes. The unusual electronic features of the four potential energy surfaces (PESs) associated with the four possible mechanisms were probed with intrinsic reaction coordinate calculations in conjunction with nucleus independent chemical shift (NICS(0)) evaluation of aromaticity of the transient structures. The development of aromatic character along the "6-endo" reaction path is modulated via Au-complexation to the extent where both the cyclic intermediate and the associated fragmentation transition state do not correspond to stationary points at the reaction potential energy surface. This analysis explains why the calculated PES for cyclization promoted by coordination of gold(I) to allenyl moiety lacks a discernible intermediate despite proceeding via a highly asynchronous transition state with characteristics of a stepwise "cyclization-mediated" process. Although reaction barriers can be strongly modified by aryl substituents of varying electronic demand, direct comparison of experimental and computational substituent effects is complicated by formation of Au-complexes with the Lewis-basic sites of the substrates.

Computational and experimental analysis of unusual substituent effects in the Au-catalyzed propargyl Claisen rearrangement revealed new features important for the future development of Au(I) catalysis. Despite the higher stability of Au-alkyne complexes, they do not always correspond to the catalytically active compounds. Instead, the product emanates from the higher energy Au(I)-oxygen complex reacting via a low barrier cation-accelerated oxonia Claisen pathway. Additionally, both intra and intermolecular competition from other Lewis bases present in the system, for the Au(I) catalyst, can lead to unproductive stabilization of the substrate/catalyst complex, explaining hitherto unresolved substituent effects.

Synthesis of substituted 1,3-dienes was achieved via gold(I)-catalyzed Claisen rearrangement of allenyl vinyl ethers. The N-heterocyclic carbene gold chloride catalyst (IPrAuCl) was superior in terms of activity and selectivity and afforded the 3,3-product in excellent yields. A proposed cation-π inter-action played a significant role in affecting the reaction rate.

Tandem Au(III)-catalyzed heterocyclization/Nazarov cyclizations leading to substituted carbocycle fused furans are described. An interesting dichotomy of reaction pathways as a function of solvent, confirmed by the isolation and trapping of reaction intermediates, provided a basis for computational studies that supported the experimental findings., (This journal is © The Royal Society of Chemistry 2011)

Under trialkylphosphine catalyzed Morita-Baylis-Hillman reaction conditions, epoxides react with enones to give rise to homologous aldol adducts.

An intermediate phosphonium salt has never been isolated from the Morita-Baylis-Hillman (MBH) reaction. Due to the weakly basic counterion produced in the MBH alkylation and allylation reactions, the reaction can be stopped after electrophilic attack on the zwitterionic enolate and an intermediate isolated. Upon analysis of the crystal structure, a trans geometry is observed, suggesting that there is no electrostatic interaction between phosphorus and oxygen in the zwitterionic enolate that undergoes alkylation, thus giving new mechanistic insight into the MBH reaction.

sp3 Hybridized electrophiles, never before used in the organomediated Morita-Baylis-Hillman reaction, now facilitate the formation of five- and six-membered enone cycloalkylation products.

We have developed the Morita-Baylis-Hillman reaction to include, for the first time in a completely organomediated process, intramolecular examples bearing allylic leaving groups as the electrophilic partner providing a facile, high yielding, straightforward synthesis of densely functionalized cyclic molecules.

The unprecedented reactivity of Co(4)(CO)(12) with enynes under aqueous conditions, representing the development of a mild and simple aqueous-phase cobalt-catalyzed PK reaction protocol, is described herein.

High levels of diastereoselection were achieved in the PKR of 1,6- and 1,7-cyclopropylidenynes bearing a bulky propargylic C(2)-symmetric acetal.

Unusual Pd-catalyzed cyclizations of unsymmetrical allylic acetates, where the nucleophile is tethered to the central allyl carbon, are shown for the first time to be remarkably controlled by heteroatom-mediated preassociation of the reacting partners.

Depending on the thermolytic conditions, dicobalthexacarbonyl-complexed enynes underwent cyclizations to provide different carbocyclic frameworks. Bicyclopentanones were formed from enyne-Co2(CO)6 complexes, or from enynes that were treated with Co2(CO)8, or more effectively, with Co4(CO)12 in an alcoholic solvent under a H2 or N2 atmosphere. This transformation proceeded via a sequential cyclocarbonylation and 1,4-reduction and is the first account using the cobalt carbonyl cluster. Under these conditions a cobalt hydride was presumably generated, which mediated reduction of the enone to the saturated ketone. In contrast, thermolysis of dicobalthexacarbonyl-complexed enynes under a hydrogen atmosphere in toluene resulted in their reductive cyclization to form monocyclic alkenes in moderate yields, in addition to the bicyclopentenone product. In some cases, addition of a hydrosilane to the reaction induced a complete suppression of the bicyclopentenone formation. While the former results demonstrate a reaction that occurs after the cycloaddition, the latter depicts another example of an interruption of the normal route in the Pauson-Khand reaction pathway.

The total synthesis of asteriscanolide (1) has been achieved by taking advantage on an intermolecular Pauson-Khand cycloaddition and a ring-closing metathesis as key bond-forming transformations. The approach incorporates the cyclooctane stereogenic center prior to ring formation. Interestingly, the ring-closing metathesis generates a new eight-membered ring with an "in-out" intrabridgehead relationship.

In this report we have shown that the commercially available Co(2)(CO)(8) and Co(4)(CO)(12), and enyne--Co(2)(CO)(6) complexes, are sufficiently effective in catalyzing the Pauson--Khand reaction under one atmosphere of CO pressure. It was further demonstrated that the efficiencies of these cyclization protocols could be enhanced by the presence of cyclohexylamine. These procedures have also rendered more practical and highly convenient alternatives for the catalytic Pauson--Khand reaction. Most importantly, we have dispelled the common belief that Co(4)(CO)(12) is inactive in the Pauson--Khand reaction under one atmosphere of carbon monoxide. Of mechanistic importance is that these studies have also shown that the probable formation of Co(4)(CO)(12) is not necessarily a dead end pathway in the Co(2)(CO)(8)-catalyzed Pauson--Khand reaction. It is also of interest that substoichiometric amounts of Co(2)(CO)(8), in DME and in the presence of cyclohexylamine, are sufficient for the cyclocarbonylation of enynes under a nitrogen atmosphere. Our findings have provided more practical protocols for the Pauson-Khand reaction using catalytic amounts of cobalt carbonyl complexes and a better understanding of the influence of Lewis bases on their efficiency. These reports on the activity of Co(4)(CO)(12) are anticipated to develop into a convenient and practical alternative for Co(2)(CO)(8) catalysis.