ORIGINAL RESEARCH Diastereoselective reaction of 1,3-dihydroxy calixarene with acylisocyanates: new and easy approach for preparing inherently chiral calyx[4]arenes V. I. Boyko 1 • A. B. Rozhenko 1 • V. V. Pirozhenko 1 • S. V. Shishkina 2,3 • O. V. Shishkin 2,3 • V. I. Kalchenko 1 Received: 14 November 2015 / Accepted: 17 November 2015 Ó Springer Science+Business Media New York 2016 Abstract The facile method of generating internal chi- rality into the calixarene with two hydroxy groups at the lower rim via an attached chiral substituent has been pro- posed. The reaction with acylisocyanates, catalyzed by a small amount of triethylamine, proceeds forming predom- inantly one of the two possible calixarene carbamates. The best diastereomeric excess (60 %) has been achieved in the reaction of trichloroacyl isocyanates with 1,3-hydroxycal- ixarene substituted with the chiral phenylethyl amide moiety. The individual diastereomers of trichloroacetyl- carbamoylcalix[4]arenas were isolated by crystallization, and their absolute configuration was determined by X-ray diffraction study. The most favored conformations pre- dicted for 1,3-dihydroxy calixarene structures by quantum chemical calculations possess very similar stability. How- ever, the triethylamine molecule preferably connects to the one hydroxyl group of the two available ones, providing the most favorable adduct, which predominantly partici- pates in the reaction with acylisocyanates. This gives rise to the observed diastereomeric excess. The subsequent treatment of the formed carbamoyl with n-propyl bromide in presence of NaH and hydrolysis of the product of alkylation easily provide a persistent internally chiral calixarene. Keywords Inherent chirality Á Calixarenes Á X-ray structure determination Á Diastereomeric excess Á DFT Introduction Calixarenes are bowl-shaped macrocycles, which are of great interest for designing highly efficient and selective receptors for cations, anions and neutral molecules [1], as well as self-assembling molecular capsules and well-de- fined functional nanostructures [2]. Over the past two decades, a considerable success has been achieved in the design and synthesis of chiral calixarenes, which are promising molecular platforms for the construction of enantioselective catalysts and receptors [3]. Of particular interest are inherently chiral calixarenes [4, 5] in which chirality originates from asymmetric arrangements of functional groups attached to the wide [6–11] and/or nar- row rim [4, 12] of macrocycles. Generating inherent chi- rality without using chiral reagents results in racemic mixtures of both enantiomers, which are hardly separable via chromatography on chiral stationary phases [12–15]. Using chiral auxiliary groups (1-phenylethyl, amino acid ester, BINOL, menthyl, etc.) usually results in mixtures with relations of diastereomers close to 1:1. They have been separated by enantioselective high-performance liq- uid chromatography [16–18], in some case, by kinetic resolution [19, 20] and crystallization [21–23]. Only in few cases, the formation of significant excesses of one of the two diastereomers was observed directly in the reaction [24–26]. & A. B. Rozhenko a_rozhenko@ukr.net & V. I. Kalchenko vik@ioch.kiev.ua 1 Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Str. 5, Kiev 02660, Ukraine 2 STC ‘‘Institute for Single Crystal’’, National Academy of Sciences of Ukraine, Lenin Ave. 60, Kharkiv 61001, Ukraine 3 V.N. Karazin Kharkiv National University, 4 Svobody sq., Kharkiv 61077, Ukraine 123 Struct Chem DOI 10.1007/s11224-015-0706-5