Hetero-Diels–Alder Reactions of Quinone Methides: The Origin of the α-Regioselectivity of 3-Methylene-1,2,4-naphthotriones

Abstract

The regioselective formation of αand β-lapachone via hetero-Diels−Alder reactions was investigated by experimental and computational approaches. The experimentally observed α-selectivity was explored in detail, revealing that the lower energy barrier for the formation of α-lapachone is a result of lower Pauli repulsion throughout the reaction path, when compared to the β-isomer. By comparing equivalent points on both αand β-lapachone potential energy surfaces (PES), according to the activation strain model (ASM) and energy decomposition analysis (EDA), we were able to demonstrate that the Pauli repulsion term increases more significantly when going from reactants to TS β than to TS α , resulting in lower interaction energy in the early stages of the reaction path and in a later transition state for βlapachone. Moreover, we confirmed that regio-and diastereoselectivity trends previously reported for other quinone methide intermediates are also observed for 3-methylene-1,2,4-naphthotriones, such as small endo/exo diastereoselectivity, as well as pronounced ortho/meta regioselectivity for reactions performed with dienophile containing electron-releasing groups. The results presented here provide a deeper understanding of the reactivity of quinone methide derivatives, aiding the future rational design of the reaction condition, structural modification of possible quinone methide intermediates, and the development of more selective synthetic routes for quinone derivatives.

Regioselectivity Switch Towards the Development of Innovative Diels‐Alder Cycloaddition and Productive Applications in Organic Synthesis

“…In this regards, quinone methide intermediates and their derivatives are a versatile synthon and are well explored to access diversified and functionalized naphthoquinone derivatives [128,129] . In line, Carneiro disclosed an experimental and computational techniques to the regioselective synthesis of naturally occurring α ‐ and β ‐lapachone in 2020 [130] . The formation of α ‐ and β ‐lapachones, was a noteworthy feature of their discovery, as many natural products and bioactive molecules could be synthesized due to its incredible capacity to create both the regioisomers.…”

“…However, characterization of the β ‐ isomer was unfeasible in many cases (see Scheme 14a) [132] . Interestingly, the result of computational technique emerged into an eight potential transition states for the developed hetero Diels‐Alder reaction, depending on the reactivity site and the type of the substituents as shown in Scheme 14 [130] . These findings undoubtedly provides insight on quinone methide reactivity, paving the way for future rational reaction condition design, structural modification of intermediates, and the development of more selective quinone derivative synthesis methods.…”

“…[128,129] In line, Carneiro disclosed an experimental and computational techniques to the regioselective synthesis of naturally occurring αand β-lapachone in 2020. [130] The formation of αand β-lapachones, was a noteworthy feature of their discovery, as many natural products and bioactive molecules could be synthesized due to its incredible capacity to create both the regioisomers. The hetero-DA reaction of quinone methide 89 (in situ generated by Knoevenagel condensation of lawsone with paraformaldehyde) [131] with a variety of dienophiles 90 a-c, constructed a mixture of both the isomers (α-isomer 91 a-c and βisomer 92 a-c) in promising yields as shown in Scheme 14a.…”