TY - JOUR

T1 - Filling the Gap within 10-Membered Heteroenediynes: Thiaenediyne – an Experimental and Theoretical Study

AU - Данилкина, Наталья Александровна

AU - Хмелевская, Екатерина Алексеевна

AU - Штыров, Андрей Андреевич

AU - Рязанцев, Михаил Николаевич

AU - Хлебников, Александр Феодосиевич

AU - Тупикина, Елена Юрьевна

AU - Румянцев, Андрей Михайлович

AU - Дьяченко, Александр Сергеевич

AU - Балова, Ирина Анатольевна

PY - 2024/11/21

Y1 - 2024/11/21

N2 - The heteroatom nature in 10-membered enediynes plays a crucial role in tuning of their reactivity in the Bergman cyclization, which is a decisive factor for the biological activity of enediynes. Although benzothiophene-fused O- and N-enediynes have been identified as promising biological objects, the corresponding thiaenediyne remains unknown. To fill this gap, we synthesized the thiaanalog and studied it in both practical and theoretical terms. While the Nicholas reaction has proven to be an effective cyclization technique for the preparation of heteroenediynes, in the case of thiaenediyne it was accompanied by an unusual acid-promoted intramolecular cyclization, forming a thiepinium salt. The S-enediyne has reduced reactivity in the Bergman cyclization relative to the N- and O-enediynes, attributed to the diminished alkyne bending and extended cd-distance. The NBO analysis of the entire series, namely the evaluation of πin/out(C2-CC)→σ*(C−X) hyperconjugation, revealed that the S atom in S-enediyne provides stronger stabilization of the initial compound than the N atom in N-enediyne, while exhibiting the weakest stabilization of the Bergman cyclization transition state. NICS values were employed to examine the change in aromaticity along the Bergman cyclization coordinate. This approach, in conjunction with the NBO analysis, provides a foundation for further rational design of unnatural enediynes.

AB - The heteroatom nature in 10-membered enediynes plays a crucial role in tuning of their reactivity in the Bergman cyclization, which is a decisive factor for the biological activity of enediynes. Although benzothiophene-fused O- and N-enediynes have been identified as promising biological objects, the corresponding thiaenediyne remains unknown. To fill this gap, we synthesized the thiaanalog and studied it in both practical and theoretical terms. While the Nicholas reaction has proven to be an effective cyclization technique for the preparation of heteroenediynes, in the case of thiaenediyne it was accompanied by an unusual acid-promoted intramolecular cyclization, forming a thiepinium salt. The S-enediyne has reduced reactivity in the Bergman cyclization relative to the N- and O-enediynes, attributed to the diminished alkyne bending and extended cd-distance. The NBO analysis of the entire series, namely the evaluation of πin/out(C2-CC)→σ*(C−X) hyperconjugation, revealed that the S atom in S-enediyne provides stronger stabilization of the initial compound than the N atom in N-enediyne, while exhibiting the weakest stabilization of the Bergman cyclization transition state. NICS values were employed to examine the change in aromaticity along the Bergman cyclization coordinate. This approach, in conjunction with the NBO analysis, provides a foundation for further rational design of unnatural enediynes.

KW - Alkynes

KW - Benzo[b]thiophene

KW - Enediynes

KW - NBO

KW - Nicholas reaction

UR - https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/ejoc.202401127

UR - https://www.mendeley.com/catalogue/b468474e-4af2-326c-a61a-3e6dedb3499f/

U2 - 10.1002/ejoc.202401127

DO - 10.1002/ejoc.202401127

M3 - Article

JO - European Journal of Organic Chemistry

JF - European Journal of Organic Chemistry

SN - 1434-193X

M1 - e202401127

ER -