The computational analysis of the rhodium-catalyzed Pauson-Khand reaction indicates that the key transition state is highly charge-polarized, wherein different diastereoisomers have distinctively different charge polarization patterns. Experimental studies demonstrate that chloro-enynes provide the optimal σ-electron-withdrawing group to promote polarization and thereby reduce the activation barrier to provide a highly diastereoselective reaction at room temperature.

Transition metal-catalyzed [m+n+o] carbocyclization reactions provide powerful methods for the construction of complex polycyclic systems that are generally not accessible through classical pericyclic reactions. We have developed the first regio- and enantioselective crossed intermolecular rhodium-catalyzed [2+2+2] carbocyclization of carbon- and heteroatom-tethered 1,6-enynes with unsymmetrical 1,2-disubstituted alkynes. This study clearly delineates the ligand requirements for obtaining excellent regio- and enantioselectivity. Furthermore, the ability to utilize various electron-withdrawing groups, and to introduce quaternary carbon stereogenic centers, provides the level of versatility necessary for its application to target-directed synthesis. Additional studies on the development and application of this novel methodology to the total synthesis of natural products are currently underway.

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Two efficient asymmetric routes to γ-secretase modulator BMS-932481, under investigation for Alzheimer's disease, have been developed. The key step for the first route involves a challenging enantioselective hydrogenation of an unfunctionalized trisubstituted alkene to establish the benzylic stereocenter, representing a very rare case of achieving high selectivity on a complex substrate. The second route demonstrates the first example of a vinylogous dynamic kinetic resolution (VDKR) ketone reduction, where the carbonyl and the racemizable stereocenter are not contiguous, but are conjugated through a pyrimidine ring. Not only did this transformation require both catalyst and substrate control to correctly establish the two stereocenters, but it also necessitated that the nonadjacent benzylic center of the ketone substrate be more acidic than that of the alcohol product to make the process dynamic. DFT computations aided the design of this novel VDKR pathway by reliably predicting the relative acidities of the intermediates involved.

The crossed intermolecular rhodium-catalyzed [2 + 2 + 2] carbocyclization of carbon and heteroatom tethered 1,6-enynes can be accomplished with symmetrical and unsymmetrical alkynes, to afford the corresponding bicyclohexadienes in an efficient and highly selective manner.Transition metal-catalyzed carbocyclization reactions provide powerful and expeditious methods for the construction of complex polycyclic systems, which are generally not accessible via classical pericyclic reactions. 1 The metal-catalyzed [2 + 2 + 2] reaction of a tethered 1,6-diyne is representative of this class of transformations, and has been employed extensively as a tactic for the construction of various natural product skeletons. 2 Despite the myriad studies with 1,6-diynes, 3,4 the crossed intermolecular rhodium-catalyzed [2 + 2 + 2] carbocyclization with 1,6-enynes has not been forthcoming. 5-7 We envisioned that this type of carbocyclization would facilitate the rapid increase in molecular complexity, through the ability to introduce stereoelectronically orthogonal alkynes in a selective fashion. Herein, we now describe the rhodium-catalyzed intermolecular [2 + 2 + 2] carbocyclization of carbon and heteroatom tethered 1,6-enynes 1 with symmetrical and unsymmetrical alkynes, to afford the corresponding bicyclohexadienes 2 and 3 in a highly efficient and regioselective manner, respectively (Scheme 1).The mechanistic hypothesis for the desired carbocyclization outlined in Scheme 2, draws from the seminal studies of others. 2-5 It was anticipated the terminal acetylenic C-H bond of the tethered enyne i should undergo an oxidative insertion to afford ii. Coordination of the free alkyne iii followed by hydrometallation should lead to the formation of iv, en route to the key metallacyclopentadiene v. 8 Intramolecular migratory insertion across the tethered alkene, followed by a reductive elimination of metallacycle vi, should then afford the [2 + 2 + 2] carbocyclization adduct vii. We reasoned that selective intermolecular [2 + 2 + 2] carbocyclization would be feasible, since alkyne iii should preferentially undergo hydrometallation with ii, provided the concentration of alkyne iii was such that it would avoid competition with the intramolecular migratory insertion of the alkene in v.Preliminary studies tested this hypothesis by screening various reaction conditions, as outlined in Table 1. Treatment of the enyne 1a (X = NTs, R = H) with silver triflate modified Wilkinson's catalyst in the presence of excess dimethyl acetylenedicarboxylate (Y/Y = CO 2 Me) in ethanol at 60 °C, furnished the bicyclohexadiene 2a in 17% yield (Entry 1). Additional studies † Electronic supplementary information (ESI) available: experimental procedures, X-ray crystallographic analysis of 3a, and spectral data (IR, 1 H and 13 C-NMR) including High Resolution MS for 2a-i and 3a. See