Perspective Carbohydrate-Based Azacrown Ethers in Asymmetric Syntheses István Orbán, Péter Bakó and Zsolt Rapi * Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1111 Budapest, Hungary; [email protected] (I.O.); [email protected] (P.B.) * Correspondence: [email protected] Abstract: Carbohydrate-based crown ethers represent a special group of chiral phase transfer cata- lysts. Several derivatives of these macrocycles have been synthesized in our research group. Among these compounds, monoaza-15-crown-5 lariat ethers proved to be effective phase transfer and enantioselective catalysts in certain reactions. Those chiral azacrown ethers incorporating various carbohydrate moieties in the macrocyclic structure are reviewed, which generated asymmetric in- duction in reactions, such as Michael addition, epoxidation of enones, Darzens condensation and Michael-initiated ring-closure (MIRC) reaction. Effects on the catalytic activity of the structural changes are the focus. Keywords: crown ether; carbohydrates; enantioselectivity; asymmetric synthesis 1. Introduction The modern and most economical method of preparing enantiopure compounds is asymmetric synthesis carried out in the presence of chiral catalysts or auxiliaries. An enor- Citation: Orbán, I.; Bakó, P.; Rapi, Z. mous number of catalysts have been prepared worldwide to replace the most commonly Carbohydrate-Based Azacrown applied techniques, i.e., resolution of racemic mixtures. Chiral crown ethers represent a Ethers in Asymmetric Syntheses. special type of chiral catalysts, which can generate asymmetric induction as phase transfer Chemistry 2021, 3, 550–577. https:// catalysts. The first chiral crown ethers were synthesized by Cram and co-workers using doi.org/10.3390/chemistry3020039 BINOL as the source of chirality, which proved to be effective as enantioselective catalysts in phase transfer reactions [1]. Academic Editors: Edwin Phase transfer catalysis has been recognized as one of the most useful synthetic tools Charles Constable, György Keglevich, in organic chemistry offering several advantages, such as operational simplicity, mild Réka Henyecz and Rádai Zita reaction conditions, inexpensiveness and less harmful reagents and solvents. This research field has been serving as an attractive area of green chemistry as well. Asymmetric phase Received: 28 February 2021 transfer catalysis, particularly over the past two decades or more, has become a topic of Accepted: 12 April 2021 Published: 15 April 2021 great scientific interest, and as a result of the efforts, many highly efficient enantioselective catalysts have been developed [2,3]. Publisher’s Note: MDPI stays neutral It seemed advantageous to use carbohydrates for the synthesis of crown ethers. Sugars with regard to jurisdictional claims in are a suitable source of chirality, are commercially available in enantiomerically pure form published maps and institutional affil- and are well-endowed with functionality. iations. Although several chiral crown ethers have been prepared from carbohydrates earlier, only a few of them showed (at least) moderate asymmetric induction as catalysts in asym- metric reactions [4–8]. Our research group, as a pioneer in this field, started developing new carbohydrate-based crown ethers and tested these compounds as catalysts in enan- tioselective reactions. A variety of chiral crown ethers containing one or two sugar units in Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. annulation with the macrocyclic ring from various monosaccharides and sugar alcohols This article is an open access article were synthesized in our laboratory. These compounds generated significant asymmetric distributed under the terms and induction when used as chiral phase transfer catalysts in different reactions. conditions of the Creative Commons Some carbohydrate-based azacrown ethers have also been prepared by other European Attribution (CC BY) license (https:// research groups. Diaza macrocycles derived from mannose (1a–d), glucose (2a–d) and creativecommons.org/licenses/by/ galactose (3a–d), were synthesized by Polish researchers in 1984 [9]. Application as catalysts 4.0/). or investigation of crown compounds 1–3 have not been reported to date. Chemistry 2021, 3, 550–577. https://doi.org/10.3390/chemistry3020039 https://www.mdpi.com/journal/chemistry Chemistry 2021Chemistry, 3, FOR 2021 PEER, 3, FORREVIEW PEER REVIEW 2 2 Some carbohydrate-basedSome carbohydrate-based azacrown azacrown ethers have ethers also have been also prepared been prepared by other byEuro- other Euro- Chemistry 2021, 3 pean researchpean researchgroups. Diazagroups. macrocycles Diaza macrocycles derived fromderived mannose from mannose (1a–d), glucose (1a–d), (glucose2a551–d) (2a–d) and galactoseand galactose (3a–d), were (3a– dsynthesized), were synthesized by Polish by researchers Polish researchers in 1984 [9]. in 1984Application [9]. Application as as catalysts catalystsor investigation or investigation of crown ofcompounds crown compounds 1–3 have 1not–3 havebeen notreported been reportedto date. to date. JaroszJarosz and andJarosz Lewandowski Lewandowski and Lewandowski developed developed developed the the synthesis synthesis the ofsy ofnthesis macrocyclic macrocyclic of macrocyclic compounds compounds compounds from from from sucrosesucrose (a (asucrose disaccharide). disaccharide). (a disaccharide). Among Amon others,g others,Amon azacrown gazacrown others, ethers azacrown ethers4a– 4ab ethersand-b and5 containing 4a5 -containingb and 5 sucrose containing sucrose as sucrose theas chiralthe chiral baseas the base were chiral were synthesized base synthesized were [10 synthesized]. Investigating[10]. Investigating [10]. the Investigating complexing the complexing the properties, complexing properties, enhanced properties, en- en- + + abilityhanced was abilityhanced determined was ability determined towards was determined NHtowards4 ions, NHtowards especially4 ions, NH especially4 in+ ions, the caseespecially in the of 4b case andin ofthe5 4b. case and of 5 .4b and 5. Another disaccharideAnother disaccharide was used was to build used up to buildchiral upcrown chiral derivatives crown derivatives by Porwanski by Porwanski et et al. DiazaAnother al.macrocycles Diaza disaccharide macrocycles bearing was two bear used cellobioseing to two build cellobiose units up chiral 6a– funits were crown 6a investigated– derivativesf were investigated in by complexation Porwanski in complexation et al. Diaza macrocycles bearing two cellobiose units 6a–f were investigated in complex- ation of busulfan, lysine, arginine [11], acetylsalicylic acid, 4-acetamidophenol [12] and tosylamide [13]. Quantum chemical calculations were also applied to the complex of 6b with aspirin [14]. Rhatjens and Thiem published several azamacrocycles containing the nitrogen atoms as tosylamide units. First, starting from glucose, crown ethers, e.g., 7 and 8a–b, with Chemistry 2021, 3, FOR PEER REVIEW 3 of busulfan, lysine, arginine [11], acetylsalicylic acid, 4-acetamidophenol [12] and tosyla- mide [13]. Quantum chemical calculations were also applied to the complex of 6b with Chemistry 2021, 3 aspirin [14]. 552 Rhatjens and Thiem published several azamacrocycles containing the nitrogen atoms as tosylamide units. First, starting from glucose, crown ethers, e.g., 7 and 8a-b, with larger rings in annulation of two monosaccharide moieties were prepared [15]. While in com- larger rings in annulation of two monosaccharide moieties were prepared [15]. While poundsin compounds 7 and 8, 7theand macroring8, the macroring is formed is formedin the 4 in and the 6 4 position and 6 position of the ofsugar, the sugar, in case in of crowncase ethers of crown 9–11 ethers, the ring9–11 ,was the built ring wasup in built the up2,3 invicinal the 2,3 positions vicinal positions[16]. Besides [16]. azacrowns Besides 9, azacrowns10 and 11, 9several, 10 and analogues11, several have analogues been reported. have been The reported. same authors The same also authors used manno- also furanosideused mannofuranoside as a starting ascompound a starting to compound synthesize to synthesizecrown ethers crown bearing ethers N bearing-tosyl Nmoieties,-tosyl suchmoieties, as 12a such–c [17]. as 12a To– cdate,[17]. as To far date, as aswe far know, as we no know, studies no studies have havebeen beenreported reported for com- for poundscompounds 7–12 regarding7–12 regarding the complex the complex forming forming or the or thecatalytic catalytic activity. activity. 2. Synthesis and Application of Azacrown Ethers 2. Synthesis and Application of Azacrown Ethers 2.1. Preparation of Macrocycles 2.1. Preparation of Macrocycles InIn our our research research group, group, the the first first carbohydrate-based crowncrown ethers ethers were were synthesized synthesized D in in1981. 1981. Starting Starting from from methyl methyl 4,6- 4,6-OO-benzylidene--benzylidene-αα--D-glucopyranoside,-glucopyranoside, a a few few 18-crown-6- 18-crown- 6-type macrocycles (13a–e) containing two glucose units were prepared. The complex forming ability of crown ethers 13a–e was investigated towards cations; however, catalytic activity was not examined [18]. Later, other derivatives were also synthesized to investigate complex forming ability [19]. Chemistry 2021, 3, FOR PEER REVIEW 4 ChemistryChemistry 20212021,, 33,, FORFOR PEERPEER REVIEWREVIEW 44 type macrocycles (13a–e) containing two glucose units were prepared. The complex form- typetype macrocyclesmacrocycles