Understanding Diastereofacial Selection in Carbohydrate-Based Domino Cycloadditions: Semiempirical and DFT Calculations

Abstract

The sequential cycloaddition of nitroalkenes with methyl vinyl ether was investigated by semiempirical (PM3) and density functional methods (B3LYP/6-31G*). The asymmetric version was also examined with a threoconfigured carbohydrate auxiliary. This produces a larger, more flexible system that complicates the calculation. Most transition structures were then fully optimized at the PM3 level and further refinement was done at ab initio levels. This study represents a model case that enables the rationalization of the high facial selectivity observed in carbohydrate-based nitrone- and nitronate-alkene cycloadditions. The selective endo orientation of the [4+2] pathway results from Coulombic attraction and secondary orbital interactions in the transition state. The stereochemical outcome is largely influenced by a combination of steric shielding from the bulky chiral substituent at C4 and the anomeric effect that places the nitronate C6-alkoxy group in a pseudoaxial arrangement. The resulting conformation favors the subsequent exo approach of methyl vinyl ether to the less hindered re face of the nitronate. It is also remarkable to note that solvation energies stabilize significantly a particular transition structure, thereby explaining the marked stereoselection observed in a polar medium.

Diastereoselective synthesis of nitroso acetals from (S,E)-γ-aminated nitroalkenes via multicomponent [4 + 2]/[3 + 2] cycloadditions promoted by LiCl or LiClO4

“…The increase in the reaction rate on employing more polar solvents can be explained through a large stabilization of the dipolar [4 + 2] transition state (TS) [9,27]. Theoretical investigations indicate that the TS of the HDA nitroalkene cycloadditions presents considerable charge transference and a large degree of asynchronicity, but remains a concerted process.…”

“…In other words, the TS presents a high zwitterionic and polar character without a zwitterionic intermediate specifically. In the second step, the TS involved in [3 + 2] nitronate cycloadditions shows lower charge transference and degree of asynchronicity, and therefore, it is expected that a lower stabilizing effect is caused by polar solvents [9,30–31]. Furthermore, when a fraction of water is present in the medium, the hydrophobic effect can lead the reaction partners to collapse to a TS that is less hydrophobic and less destabilized than the initial state, promoting an increase in the reaction rate [17,28–29].…”

“…Lithium chloride is not appreciably soluble in THF and for this reason ethanol was used as the solvent. The confirmation of the stereostructures of (+/−)- 8d , d’ was accomplished by comparison with NMR spectroscopic data available in the literature [9]. Based on these successes, 5a was reacted with EVE and methyl acrylate in LPTW or LCEW solutions (Table 2, entries 3 and 4), respectively.…”

“…In addition, Denmark’s group and others investigated the tandem [4 + 2]/[3 + 2] nitroalkene cycloaddition employing unactivated olefins or enol ethers as dienophiles and electron-deficient alkenes as 1,3-dipolarophiles to furnish nitroso acetals of type 4 in an inter- or intramolecular fashion [1–3 8–9]. These nitroso acetals can be transformed into functionalized pyrrolizidin-3-ones and in sequence into alkaloid nuclei [1,3,10–11].…”

“…In contrast, the use of a chiral pool strategy, wherein the nitroalkene is the chiral source, is still scarce. To the best of our knowledge, only Chattopadhyaya et al [18] and Cintas et al [9] utilized chiral nitroalkenes, synthesized from a nucleoside and a carbohydrate, respectively, to obtain nitroso acetals diastereoselectively.…”