[8+2] vs [4+2] Cycloadditions of Cyclohexadienamines to Tropone and HeptafulvenesMechanisms and Selectivities

The cinchona-alkaloid-catalyzed cycloaddition
reactions of 2-cyclohexenone
with tropone and various heptafulvenes give [8+2] or [4+2] cycloadducts,
depending on the substituents present on the heptafulvene. We report
the results of new experiments with heptafulvenes, containing diester
and barbiturate substituents, which in combination with computational
studies were performed to elucidate the factors controlling [8+2]
vs [4+2] cycloaddition pathways, including chemo-, regio-, and stereo­selectivities
of these higher-order cycloadditions. The protonated cinchona alkaloid
primary amine catalyst reacts with 2-cyclohexenone to form a linear
dienamine intermediate that subsequently undergoes a stepwise [8+2]
or [4+2] cycloaddition. Both tropone and the different heptafulvenes
initially form [8+2] cycloadducts. The final product is ultimately
decided by the reversibility of the [8+2] cycloaddition and the relative
thermal stability of the [4+2] products. The stereoisomeric transition
states are distinguished by the steric interactions between the protonated
catalyst and tropone/heptafulvenes. The [8+2] cycloaddition of barbiturate-heptafulvene
afforded products with an unprecedented trans-fusion
of the five- and six-membered rings, while the [8+2] cycloadducts
obtained from cyanoester-heptafulvene and diester-heptafulvene were
formed with a cis-relationship. The mechanism, thermodynamics,
and origins of stereo­selectivity were explained through DFT
calculations using the ωB97X-D density functional.