Selectivity in Cationic Cyclizations Involving Alkynes: A Computational Study on the Biomimetic Synthesis of Steroids

• Published in: Chemistry : a European journal Vol. 29; no. 19; pp. e202204028 - n/a
• Main Authors: Cózar, Abel, Arrieta, Ana, Cossío, Fernando P.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 03.04.2023
• Subjects: Alkynes; Biomimetics; Chemistry; computational chemistry; Computer applications; cyclization reactions; distortion/Interaction activation strain model; Epoxides; reaction mechanisms; Stereochemistry; Steroid hormones; Steroids; reaction mechanisms; cyclization reactions; distortion/Interaction activation strain model; computational chemistry
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202204028

Computational studies on the electrophilic cyclization between alkynes and transient carbocations or Lewis‐acid‐activated epoxides show that the regiochemistry of the reaction depends on the terminal or internal position of the triple bond. Reactants possessing terminal alkynyl groups lead to six‐membered rings, whereas internal alkynes yield five‐membered rings through 6‐endo‐dig and 5‐exo‐dig electrophilic cyclizations, respectively. The regiochemistry of the reaction is not determined by two‐electron interactions, but by the minimization of Pauli repulsion. This scenario is preserved in related biomimetic reactions leading to steroid scaffolds. In this latter case, the stereochemistry of the cyclization reaction is oriented towards the formation of equatorial C−C bonds connecting the new six‐six‐ and six‐five‐membered fused rings. Inside out: Computational analysis of electrophilic cyclization reactions involving terminal or internal alkynes and electrophilic centers (cations and Lewis‐acid‐activated epoxides) provide insights into the different interactions that determine the 6‐endo‐dig or 5‐exo‐dig regioselectivity of terminal and internal alkynes, respectively.