Treatment of (E)-1-(methoxymethylene)-1,2,3,4-tetrahydronaphthalene with styryl diazoacetates in the presence of catalytic amounts of the dirhodium complex Rh2(S-DOSP)4 provides a highly enantioenriched hexacyclic product with 10 new stereogenic centers. The transformation proceeds by a cascade sequence starting with a double cyclopropanation of a benzene ring, followed by a Cope rearrangement of a divinylcyclopropane and then an intramolecular Diels–Alder cycloaddition.

Cu-catalyzed three-component coupling of imines with benzoyl chloride and terminal arylalkynes followed by enyne ring-closing metathesis (RCM) and Heck cyclization afforded medicinally relevant benzoindolines, cyclopropane-fused indenopyridines, pyrroloquinolines, or 1,7-tetrahydrophenanthrolines via divergent cyclization pathways. Unexpectedly, the Pd-catalyzed cyclization of heterocyclic dienes proceeded via regiodivergent 5-exo or 6-endo pathways depending on the ring size (n = 1, 2) or the presence of isosteric groups (CH vs N). A one-pot protocol for the enyne-RCM/Heck annulation featuring a sequential addition of the Ru and Pd catalysts was developed maximizing the synthetic efficiency.

The synthesis of trisubstituted pyrrolidines and tetrahydrofurans from boronic acids, allenes, and imines or aldehydes via a five-and a three-step protocol, respectively, is described. The assignment of the relative stereochemistry in the pyrrolidines and tetrahydrofurans confirmed the mechanistically significant stereochemical divergence of the palladium-catalyzed three-component coupling reaction. The methodology is applicable to the preparation of combinatorial libraries of pyrrolidines related to pharmaceutical agents and bioactive natural products.Substituted pyrrolidines and tetrahydrofurans constitute structural cores of a variety of medicinally significant natural products and synthetic pharmaceutical agents. 1 Among these heterocycles, structures featuring an α-aryl functionality 2 as well as the neuroexcitatory amino acids 3 present particularly challenging targets for diastereocontrolled syntheses ( Figure 1).Most frequently, various [3+2] cycloadditions are applied towards the synthesis of substituted pyrrolidines and tetrahydrofurans. 4 Alternatively, the functionalization of heterocyclic precursors, including the directed metalation of pyrrolidines 5 or additions to cyclic imines, 6 provides access to these structural motifs. In contrast, strategies relying on the construction of an acyclic precursor featuring all the requisite stereocenters followed by a ring-closure reaction remain less explored 7 owing to the challenges posed by acyclic stereocontrol. Herein, we report a protocol for the synthesis of contiguously trisubstituted pyrrolidines and tetrahydrofurans that are structurally related to bioactive natural products and selected pharmaceutical agents (Figure 1). Our work demonstrates the synthetic potential of a modular palladiumcatalyzed coupling of boronic acids I, allenes II, and imines or aldehydes III affording homoallylic amines or alcohols IV, respectively, which we previously developed in our laboratories. 8,9 We cyclized the homoallylic amines and alcohols IV to give pyrrolidines or tetrahydrofurans V, respectively, in four (for pyrrolidines) or two (for tetrahydrofurans) straightforward synthetic steps (Scheme 1). The relative stereochemistry observed in pyrrolidines and tetrahydrofurans V confirmed the operation of stereochemically divergent mechanistic pathways in the palladium-catalyzed coupling step. Figure 1 Biologically active pyrrolidines and tetrahydrofuransAlthough the preparation of tetrahydrofurans V proved less diastereoselective than the synthesis of pyrrolidines V, good yields of single diastereomers of tetrahydrofurans V were obtained using the synthetically practical route. The described methodology is well suited for the diastereocontrolled synthesis of libraries of substituted pyrrolidines 10 structurally related to the ETA antagonist atrasentan and allows for independent variations in all three C-substituents on the heterocyclic ring. 11

Starting with the Pd‐catalyzed condensation of boronic acids with allenes and imines or aldehydes, multistep routes to trisubstituted pyrrolidines and tetrahydrofurans are developed.

Modular Strategy for the Synthesis of Functionalized Aryl-Fused Azabicyclo[2.2.2]octanes via Radical-Mediated Cascade Cyclization. -Phenylidene (IVa) gives exclusively the (Z)-diastereoisomer, whereas electron rich groups in the arylidene substituent [e.g. (IVb)] afford product mixtures. -(MALINAKOVA*, H. C.; RAIKAR, S. N.; MCCORMICK, L. F.; Tetrahedron Lett. 55 (2014) 30, 4152-4155, http://dx.