Two classes of heterocycles—6,8‐dioxabicyclo[3.2.1]octanes and cyclopentenols from the same reagents: A quantum‐chemical comparison of mechanism

Abstract

Most of the strategies for the synthesis of 6,8‐dioxabicyclo[3.2.1]octanes (BCO) and cyclopentenols (CP), which show high biological and pharmaceutical activity, are multistage and/or require hardly accessible starting materials and catalysts. The general method for BCO and CP preparation in a single preparative stage from two simple reagents, ketones and acetylene, under the action of an available super‐basic catalytic system KOH/DMSO becomes promising for the development of general approaches to the design of these classes of biologically active compounds. The mechanism of competing reactions yielding both 7‐methylene‐6.8‐dioxabicyclo[3.2.1]‐octanes and functionalized cyclopentenoles from their common intermediate 1,5‐diketones and acetylene in the KOH/DMSO superbasic media is investigated using the B2PLYP/6‐311++G**//B3LYP/6‐31+G* calculations with particular attention to the diastereoselectivity aspects of individual stages.

Quantum‐chemical models of KOH(KOBut)/DMSO superbasic systems and mechanisms of base‐promoted acetylene reactions

“…Among all the studied reactions 1 to 9 , the highest activation barriers were found for nucleophilic additions to the triple bond. The PENTA GAS model predicts these activation energies in the range of 26 to 20 kcal/mol, which is consistent with their rate‐determining role in the formation of 6,8‐dioxabicyclo[3.2.1]octanes, cyclopentenols, and furans . Notably, the O ‐vinylation does not occur during the interaction of enolate ion with the acetylene molecule.…”

“…Indeed, in this case, the yield of dioxabicyclooctane amounts to 86%, while an analogous reaction of 1‐(thiophen‐2‐yl)ethanone (R = Th) results in 55% of the corresponding cyclopentenol . Recently, we have estimated the activation energies of the dioxabicyclooctane and cyclopentenol formation for R = Th as 19.1 and 17.8 kcal/mol, respectively, using a larger basis set (6‐311++G**) in the final B2PLYP single‐point calculation . Using the B2PLYP/6‐311+G** approach gives the same activation barriers, as expected.…”

Base‐Promoted Formation of an Annelated Pyrrolo‐1,4‐oxazine Ensemble from 1H‐pyrrol‐2‐ylmethanol and Propargyl Chloride: A Theoretical and Experimental Study

“…This model does not take into account the influence of alkali metal cation, which plays a significant role. Nevertheless, despite obvious shortcomings, the anionic model is actively employed for the analysis of superbase‐catalyzed reactions since it allows studying the systems with a large number of atoms …”

“…This approach shows good agreement with the high-precision CCSD (T)/6-311 + G**//CCSD/6-31 + G* method. [54] In this paper, the B2PLYP/6-311 + + G** method is used for the description of transformations involving the pentasolvate KOH•5DMSO complex.…”

“…Nevertheless, despite obvious shortcomings, the anionic model is actively employed for the analysis of superbase-catalyzed reactions since it allows studying the systems with a large number of atoms. [52][53][54]…”