Intermolecular rhodium-catalyzed [2 + 2 + 2] carbocyclization reactions of 1,6-enynes with symmetrical and unsymmetrical alkynes

Abstract

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

Transition metals in organic synthesis: Highlights for the year 2005

“…Rhodium catalyzed regioselective eyne-diyne[2 + 2 + 2]cycloadditions to give paracyclophanes [1304]. Rhodium-catalyzed intermolecular [2 + 2 + 2]cycloaddition of 1,6-enynes with alkynes to give bicyclic cyclohexadienes [1305]. Rhodium catalyzed [2 + 2 + 2]cycloadditions of 1,6-, 1,7-, and 1,8-diynes with isocyanates to give fused 2-pyridones [1306].…”

New metal-catalyzed carbocyclization reactions for the construction of complex natural products

“…Gratifyingly, the non-coordinating solvent benzene (0.05 M) at 60 °C proved optimum, affording 21a in 95% yield (Entry 5). 35 Interestingly, the homodimerization adduct was not observed, whereas the product resulting from the competitive trapping of the metallacyclopentadiene D with a second equivalent of dimethyl acetylenedicarboxylate was produced in varying amounts, depending upon the concentration. Furthermore, the terminal acetylenic proton of the 1,6-enyne 7a proved to be crucial for catalytic activity, since the corresponding substituted derivatives, where R = Me, Ph or TMS, did not afford any of the carbocyclization adduct.…”

“…Previous studies demonstrated that the overall efficiency could be improved dramatically by simply adjusting the nature of the solvent and/or counter-ion. 35 In light of this fact, we probed the effect of coordinating solvents, and silver salts with progressively weaker coordinating counter ions (Entries 2-5). Gratifyingly, the ethereal solvent tetrahydrofuran in combination with the tetrafluoroborate counter ion proved optimal in terms of efficiency (Entry 5), since these conditions completely suppressed the undesired homo-coupling of 1,6-enyne 7a.…”

Rhodium‐Catalyzed Asymmetric [2+2+2] Cycloaddition Reactions of 1,6‐Enynes and Oxabenzonorbornadienes

“…[2] For this transformation, the complexes of cationic rhodium-(I) with biaryl diphosphine complexes are well established as highly active catalysts. Elegant examples of the asymmetric [2 + 2 + 2] cycloadditions of 1,6enynes and alkynes were pioneered by the groups of Evans [3] and Shibata (Figure 1). [4] By using activated alkenes instead of alkynes, the group of Tanaka has accomplished the produce of chiral substituted cyclohexenes.…”