Opposing Auxiliary Conformations Produce the Same Torquoselectivity in an Oxazolidinone-Directed Nazarov Cyclization

Abstract

Most applications of chiral oxazolidinone auxiliaries in asymmetric synthesis operate through a common set of stereocontrol principles. That is, the oxazolidinone is made to adopt a specific, coplanar conformation with respect to the prochiral substrate, and reaction occurs preferentially at whichever stereoheterotopic face is not blocked by the substituents on the oxazolidinone. In contrast to these principles, we report here the discovery of an alternative mechanism of oxazolidinone-based stereocontrol that does not require coplanarity and is driven instead by allylic strain. This pathway has been uncovered through computational studies of an asymmetric Nazarov cyclization. Chiral oxazolidinone auxiliaries provide essentially complete control over the torquoselectivity of ring closure and the regioselectivity of subsequent deprotonation. Density functional theory calculations (M06-2X//B3LYP) reveal that in the transition state of 4π electrocyclic ring closure, the oxazolidinone ring and the cyclizing pentadienyl cation are distorted from coplanarity in a manner that gives two transition state conformations of similar energy. These two conformers are distinguished by a 180° flip in the auxiliary orientation such that in one conformer the oxazolidinone carbonyl is oriented toward the OH of the pentadienyl cation (syn-conformer) and in the other it is oriented away from this OH (anti-conformer). Surprisingly, both conformations induce the same sense of torquoselectivity, with a 3-5 kcal/mol preference for the C5-β epimer of the ring-closed cation. In both conformations, the conrotatory mode that leads to the C5-α epimer is disfavored due to higher levels of allylic strain between the oxazolidinone substituent and adjacent groups on the pentadienyl cation (R(4) and OH). The excellent torquoselectivities obtained in the oxazolidinone-directed Nazarov cyclization suggest that the allylic strain-driven stereoinduction pathway represents a viable alternative mechanism of stereocontrol for reactions of sterically congested substrates that lie outside of the traditional coplanar (N-acyloxazolidinone) paradigm.

A DFT study on Diels-Alder cycloadditions oftrans-1,3-butadiene to C60and C70

“…The hybrid meta exchange‐correlation functional M06‐2X performed well in the thermochemistry as well as the kinetics and non‐covalent interactions of systems involving main‐group atoms . The computational studies proved that M06‐2X was reliable for different kinds of cycloaddition reactions when used at a suitable basis set . Recently, M06‐2X functional was employed for exploring the DA cycloaddition of cyclopentadiene to La@ C 82 , whose results were well consistent with the experimental observations …”

One-Pot Synthesis of Oxazolidinones and Five-Membered Cyclic Carbonates from Epoxides and Chlorosulfonyl isocyanate: Theoretical Evidence for the Asynchronous Concerted Pathway

“…Oxazolidinones (1), five-membered heterocyclic rings containing nitrogen atom and ester group, are important compounds in organic chemistry and pharmaceutical chemistry because of their considerable interest as antibiotics [1], immunomodulatories [2], antibacterials [3], as well as synthetic intermediates and chiral auxiliaries for various organic conversions [4][5][6][7].…”

“…Scheme 1. Oxazolidinone (1), five-membered cyclic carbonates (2) and some important compounds containing oxazolidinone ring (3,4) and five-membered cyclic carbonates (5,6).…”

A vector‐based representation of the chemical bond for predicting competitive and noncompetitive torquoselectivity of thermal ring‐opening reactions

“…Torquoselectivity is defined to be the preference for either the transition state (TS) inward conrotatory reaction pathway (TSIC) or the transition state outward conrotatory (TSOC) reaction pathway . Rondan and Houk first postulated the mechanism of torquoselectivity using orbital symmetry to understand electrocyclic reactions but only for reactions where a high degree of symmetry was present . Realistic conrotatory ring‐opening reactions are not highly symmetrical and, therefore, only reaction measures that possess directional character can correctly predict the TSIC or TSOC pathways consequently, that is, only vector‐based and not scalar measures can be used.…”