RESEARCH ARTICLE Steric interactions controlling the syn diastereofacial selectivity in the [3 + 2] cycloaddition reaction between acetonitrile oxide and 7‐ oxanorborn‐5‐en‐2‐ones: A molecular electron density theory study A. I. Adjieufack 1 | I.M. Ndassa 2 | J. Ketcha Mbadcam 1 | M. Ríos‐Gutiérrez 3 | L.R. Domingo 3 1 Physical and Theoretical Chemistry Laboratory, Faculty of Science, University of Yaoundé I, Yaoundé, Cameroon 2 Department of Chemistry, High Teacher Training College, University of Yaoundé I, Yaoundé, Cameroon 3 Department of Organic Chemistry, University of Valencia, Burjassot, Valencia, Spain Correspondence Luis R. Domingo, Department of Organic Chemistry, University of Valencia, Dr. Moliner 50, 46100 Burjassot, Valencia, Spain. Ibrahim M. Ndassa, Department of Chemistry, High Teacher Training College, University of Yaoundé I, P.O. Box 47, Yaoundé, Cameroon. Email: domingo@utopia.uv.es Funding information MINECO and EUROPEAN Social fund, Grant/Award Number: (CTQ2016‐78669‐P). and (BES‐2014‐068258). A Molecular Electron Density Theory study of the zw‐type 32CA reactions of acetonitrile oxide (NO) with two 7‐oxanorborn‐5‐en‐2‐ones (ONBs) has been performed at the DFT B3LYP/6‐31G(d) computational level. These cycloadditions proceed through one‐step mechanisms with high activation energies and present low para regio and complete syn diastereofacial selectivities. While the non‐polar character of these zw‐type 32CA reactions, which is the consequence of the insuffi- cient electrophilic activation of ONBs, according to the analysis of the conceptual DFT reactivity indices, accounts for the high activation energies, and low para regioselectivity, NCI topological analyses at the anti/syn pairs of para TSs reveal that the steric hindrance encountered between the NO framework and the ONB side containing the carbonyl group along the anti approach mode is responsible for the complete syn diastereofacial selectivity. 1 | INTRODUCTION [3 + 2] Cycloaddition (32CA) reactions have emerged as a powerful synthetic tool for the construction of five‐mem- bered heterocyclic compounds [1] after the great effort made by Huisgen and coworkers. [2] 32CA reactions are bimolecu- lar in nature and involve the 1,3‐addition of an ethylene derivative to a three‐atom‐component (TAC), leading to the formation of five‐membered heterocycles (see Scheme 1). TACs can be structurally classified into two categories: allylic type (A‐TAC) and propargylic type (P‐TAC) struc- tures. [3] While A‐TACs such as nitrone 1 are bent, P‐TACs such as nitrile oxide (NO) 2 have a linear structure (see Scheme 1). Many TACs are readily available and react with a variety of multiple bond systems in a highly regioselective and stereoselective manner. [2] Weygand's group was the first to perform the first 32CA reaction between NOs 3 and olefins 4. [4] Huisgen later categorised NOs 3 as members of a broader class of TACs able to undergo 32CA reactions. [5] In particular, the 32CA reactions of NOs 3 with asymmetric alkenes 4 lead to the formation of 4‐isoxazoline 5 and 5‐ isoxazoline 6 mixtures (Scheme 2), which are versatile inter- mediates for the synthesis of natural products and biologi- cally, medically active compounds. [6] Very recently, Domingo has proposed a new reactivity theory in organic chemistry, the Molecular Electron Density Theory (MEDT), [7] in which changes in the electron density Received: 11 January 2017 Revised: 31 March 2017 Accepted: 4 April 2017 DOI: 10.1002/poc.3710 J Phys Org Chem. 2017;e3710. https://doi.org/10.1002/poc.3710 Copyright © 2017 John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/poc 1 of 11