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

TY - JOUR

T1 - [8+2] vs [4+2] Cycloadditions of Cyclohexadienamines to Tropone and Heptafulvenes—Mechanisms and Selectivities

AU - Chen, Xiangyang

AU - Thøgersen, Mathias Kirk

AU - Yang, Limin

AU - Lauridsen, Rune F.

AU - Xue, Xiao Song

AU - Jørgensen, Karl Anker

AU - Houk, K. N.

N1 - Funding Information: K.A.J. thanks Villum Investigator Grant (no. 25867), the Carlsberg Foundation “Semper Ardens”, and Aarhus University. Computations were performed on the Hoffman2 cluster at UCLA and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the National Science Foundation (OCI-1053575). We are grateful for financial support of the UCLA work from the National Science Foundation (CHE-1764328 to K.N.H.). Publisher Copyright: © 2021 American Chemical Society. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/1

Y1 - 2021/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85100173781&partnerID=8YFLogxK

U2 - 10.1021/jacs.0c10966

DO - 10.1021/jacs.0c10966

M3 - Journal article

C2 - 33416311

AN - SCOPUS:85100173781

SN - 0002-7863

VL - 143

SP - 934

EP - 944

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

IS - 2

ER -