Cyclization of Hydroxyenol Ethers into Spiroacetals. Evidence for the position of the transition state and its implication on the stereoelectronic effects in acetal formation

Abstract

Acid-catalyzed cyclizations under thermodynamically and kinetically controlled conditions of the hydroxyenol ethers 18-21 are reported. Thermodynamically controllcd cyclizations of 18, 19, and 21 produced only the more stable corresponding spiroacetals 22 and 27. Thermodynamically controlled cyclization of compound 20 produced a 1:l mixture of non-epimerisable spiroacetals 24 and 26. On the other hand, kinetically controlled cyclizations of the same four hydroxyenol ethers produced, along with the more stable spiroacetals mentioned above, the less stable spiroacetals 23,25, and 28. These results show that the kinetically controlled cyclizalion takes place via an early transition state which produces a mixture of the less stable and the more stable isomers. These results are explained by an early transition state taking into account the principle of stereoelectronic control while following the antiperiplanar lone-pair hypothesis (Burgi-Dunirz angle of attack of a nucleophile on a n systcm).Introduction. -We previously reported [ 11 a study which revealed that the unsubstituted 1,7-dioxaspiro[5.5]undecane exists exclusively in conformation A, (Scheme I ), even at room temperature. This experimental observation was explained by the fact that conformation A, is stereoelectronically and sterically more stable than conformations A, and A, which were estimated to be less stable by a value of 2.4 and 4.8 kcal/mol, respectively'). This result was further confirmed experimentally by comparing the behavior of l-oxaspiro[5.5]undecane which was shown to exist as an equilibrium mixture of two conformers [2].

1994 R.U. Lemieux Award Lecture Hydrolysis of acetals and ketals. Position of transition states along the reaction coordinates, and stereoelectronic effects

“…Again, it is relatively easy to understand the exclusive formation of cis acetal 13 via an early transition state provided that the incoming hydroxyl group is properly aligned with the n-orbital of the cyclic oxocarbonium ion. Such an alignment, which corresponds closely to the Biirgi-Dunitz angle of attack of a nucleophile on a n-system (12,13), can be easily attained with 11 but not with 14, a conclusion that was supported by a molecular modelling study (6).…”

Total synthesis of spiroketal containing natural products: kinetic vs. thermodynamic approaches

“…This is consistent with the trend of a slight downfield shift of the spiro carbon in going from ax-ax to ax-eq oxygen orientations. 35 An NOE was also observed between H19 and H11 which was also seen in spirofungin B (Figure 2). …”

Evidence that Cerambycid Beetles Mimic Vespid Wasps in Odor as well as Appearance

“…An alkyl substituent adjacent to the oxygen in the tetrahydropyran substructure of a spiroacetal keeps the equatorial position (Deslongchamps et al 1981, Francke et al 1980), whereas the stabilizing anomeric effect (Perron and Albizati 1989) directs the oxygen of the alternate ring to the axial position causing ( E )-conformation. The thermodynamical stability and polarity of E / Z -isomers are different (Booth et al 2009, Pothier et al 1992), and they separate readily in gas chromatography. The ( E,E )-isomers elute first (Francke et al 1981, Heiduk et al 2015, Kitching et al 1989), because the oxygens are more shielded by the substituents, which renders these stereoisomers less polar.…”