Carbohydrate-Based Azacrown Ethers in Asymmetric Syntheses

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 catalysts. 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 induction 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 asymmetric 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 enantioselective 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 complexation 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 tosylamide [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].

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type macrocycles (13a–e) containing two glucose units were prepared. The complex form- typetype macrocyclesmacrocycles ((13a13a––ee)) containingcontaining twotwo glucoseglucose unitsunits werewere prepared.prepared. TheThe complexcomplex form-forming ability of crown ethers 13a–e was investigated towards cations; however, catalytic ac- Chemistry 2021, 3 inging abilityability ofof crowncrown ethersethers 13a13a––ee waswas investigatedinvestigated towardstowards catications;ons; however,however, catalyticcatalytic 553ac-activity was not examined [18]. Later, other derivatives were also synthesized to investigate tivitytivity waswas notnot examinedexamined [18].[18]. Later,Later, otherother deriderivativesvatives werewere alsoalso synthesizedsynthesized toto investigateinvestigate complex forming ability [19]. complexcomplex formingforming abilityability [19].[19].

Using monoaza-15-crown-5 and anhydroallopyranoside 14 as starting materials, a UsingUsing monoaza-15-crown-5monoaza-15-crown-5 and and anhydroallopyranosideanhydroallopyranoside 1414 asas startingstartingstarting materials,materials,materials, aaa monoaza macrocycle containing an altropyranoside moiety (15) was created, in which the monoazamonoaza macrocyclemacrocycle containingcontaining anan altropyranosidealtropyranoside moiety moietymoiety ( ((151515))) was waswas created,created,created, in inin which whichwhich the thethe sugar unit was connected to the macro ring with a single bond (Scheme 1) [20]. During sugarsugar unitunit waswas connectedconnected toto thethe macromacromacro ringringring withwiwithth aaa singlesinglesingle bond bondbond (Scheme (Scheme(Scheme1 1))[1) [20].20[20].]. DuringDuringDuring the synthesis, a similar, but glucose-containing, crown compound (16) was also isolated. thethe synthesis,synthesis, a a similar,similar, butbutbut glucose-containing,glucglucose-containing,ose-containing, crown crown compound compound ( (1616)) was was also also isolated. isolated. Crown ethers 15 and 16 have not been used as phase transfer catalysts. CrownCrown ethersethers 1515 andand 16 16 havehave notnot beenbeen usedusedused as asas phase phasephase transfer transfertransfer catalysts. catalysts.catalysts.

Scheme 1. Preparation of crown ethers 15 and 16. SchemeScheme 1.1. PreparationPreparation ofof crowncrown ethersethers 15 15 and and 16. 16. A 2-amino-2-deoxy-altrose derivative, which was prepared from allopyranoside 14, AA 2-amino-2-deoxy-altrose2-amino-2-deoxy-altrose derivative, derivative, which which was was prepared prepared fromfrom allopyranosideallopyranoside 1414,, also served as the source of chirality in monoaza-15-crown-5 17 and monoaza-18-crown- alsoalso servedserved asasas thethethe sourcesourcesource of ofof chirality chiralitychirality in inin monoaza-15-crown-5 monoaza-15-crown-5monoaza-15-crown-517 1717and andand monoaza-18-crown-6 monoaza-18-crown-monoaza-18-crown- 6 18 (Scheme 2) [21]. The macro ring was formed during the multi-step synthesis, in con- 1866 1818(Scheme (Scheme(Scheme2)[ 2)2)21 [21].[21].]. The TheThe macro macromacro ring ringring was waswas formed formedformed during duringduring the thethe multi-step multi-stepmulti-step synthesis, synthesis,synthesis, in contrast inin con-contrast to the synthesis of crowns 15 and 16, where the pre-formed crown structure was totrasttrast the toto synthesis thethe synthesissynthesis of crowns ofof crownscrowns15 and 151516 ,andand where 1616,, the wherewhere pre-formed thethe pre-formedpre-formed crown structure crowncrown structurestructure was coupled waswas coupled with the sugar. withcoupledcoupled the withsugar.with thethe sugar.sugar.

Scheme 2. Synthesis of crown ethers 17 and 18. SchemeScheme 2.2. SynthesisSynthesis ofof crowncrown ethersethers 1717 and and 18. 18.

The ﬁrst carbohydrate-based monoaza-15-crown-5 lariat ethers (20a–g) were synthesized in 1995, alongside with diazacrown compounds 21 and 22 (Schemes3 and4)[ 22]. The

complexing ability of these macrocycles was examined towards various picrate salts. The Chemistry 2021, 3, FOR PEER REVIEW 5 Chemistry 2021, 3, FOR PEER REVIEW 5

Chemistry 2021, 3 554 The first carbohydrate-based monoaza-15-crown-5 lariat ethers (20a–g) were synthe- The first carbohydrate-based monoaza-15-crown-5 lariat ethers (20a–g) were synthesized in 1995, alongside with diazacrown compounds 21 and 22 (Schemes 3 and 4) [22]. sized in 1995, alongside with diazacrown compounds 21 and 22 (Schemes 3 and 4) [22]. The complexing ability of these macrocycles was examined towards various picrate salts. The complexing ability of these macrocycles was examined towards various picrate salts. Thestructure structure of compounds of compounds20 became 20 became the base the ofbase further of furthe research,r research, i.e., monoaza-15-crown- i.e., monoaza-15- The structure of compounds 20 became the base of further research, i.e., monoaza-15- crown-55 annulated annulated to a carbohydrate to a carbohydrate unit and unit bearing and bearing a side arma side on arm the nitrogen.on the nitrogen. It is known It is crown-5 annulated to a carbohydrate unit and bearing a side arm on the nitrogen. It is knownthat armed that crownarmed etherscrown (orethers lariat (or ethers) lariat ethe havers) a have unique a unique guest speciﬁcity guest specificity via the via macro the known that armed crown ethers (or lariat ethers) have a unique guest specificity via the macroring and ring side and arm side cooperativity. arm cooperativity. The three-step The th synthesis,ree-step synthesis, which can which be seen can on be Scheme seen on3, macro ring and side arm cooperativity. The three-step synthesis, which can be seen on Schemewas used 3, towas build used up to the build monoaza-15-crown-5 up the monoaza-15-crown-5 ethers bearing ethers a substituent bearing a onsubstituent the nitrogen on Scheme 3, was used to build up the monoaza-15-crown-5 ethers bearing a substituent on thefrom nitrogen different from carbohydrate different carbohydrate units. units. the nitrogen from different carbohydrate units.

Scheme 3. Synthesis of glucoseglucose-basedbased lariat ethers 20. Scheme 3. Synthesis of glucose-based lariat ethers 20.

Scheme 4. Preparation of diaza-18-crown 6 compounds 21 and 22 derived from glucose. SchemeScheme 4.4. PreparationPreparation ofof diaza-18-crowndiaza-18-crown 66 compoundscompounds21 21and and22 22derived derived fromfrom glucose.glucose. Catalyst 20h, which has been applied the most in asymmetric syntheses so far, was CatalystCatalyst 20h20h,, whichwhich hashas beenbeen appliedapplied thethe mostmost inin asymmetricasymmetric synthesessyntheses soso far,far, waswas reported 4 years later [23]. Substituents containing phosphorus were also introduced to reportedreported 44 yearsyears laterlater [[23].23]. SubstituentsSubstituents containingcontaining phosphorusphosphorus werewere alsoalso introducedintroduced toto the nitrogen of the macro ring. Methyl α-D-glucoside-based crown ethers bearing different thethe nitrogennitrogen ofof thethe macromacro ring.ring. Methyl α-D-glucoside-based crowncrown ethersethers bearingbearing differentdifferent phosphonoalkyl (20k, n = 1–5) [24] and phosphinoxidoalkyl side arms (20l, n = 1–5) were synthesized to determine the optimal distance between the N and P atoms [25]. As can

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Chemistry 2021, 3 555 phosphonoalkyl (20k, n = 1–5) [24] and phosphinoxidoalkyl side arms (20l, n = 1–5) were phosphonoalkylsynthesized (20k, n to = determine1–5) [24] and the phosphinoxidoalkyl optimal distance between side arms the N(20l and, n P= atoms1–5) were [25]. As can be synthesizedseen to determine from the theresults optimal of the distance asymmetric between reac thetions, N and the P side atoms arm [25]. strongly As can influences be the beseen seen from from thecatalytic the results results activity of of the the andasymmetric asymmetric the selectivity reac reactions,tions, of the the the crown side side arm arm ethers. strongly Substituents inﬂuencesinfluences bearing thethe different catalyticcatalytic activityactivityfunctional and and the groupsthe selectivity selectivity were ofintroduced theof the crown crown to ethers. the ethers. azacrown Substituents Substituents ring bearingin macrocycles bearing different different 20m func-–o to investi- tionalfunctional groups groupsgate were the were introducedimpact introduced of the to structural the toazacrown the azacrown changes ring onring in the macrocycles in outcome macrocycles of20m the 20m– oasyto–mmetrico investigate to investi- syntheses [26]. thegate impact the impact ofSubstituted the of structural the structural phenylethyl changes changes onside the onchai outcome thens outcomeproved of the to of asymmetricbe the effective asymmetric synthesesin case syntheses of [other26]. Sub-[26]. carbohydrate- stitutedSubstituted phenylethylbased phenylethyl catalysts, side side chains thus, chai proved crownns proved tocompounds be to effective be effective 20p in caseand in 20q of case other were of carbohydrate-basedother also carbohydrate-prepared [27]. catalysts,based catalysts, thus, crown Itthus, has crown compoundsbeen hypothesized, compounds20p and 20p that20q and onewere 20q of alsothe were influencing prepared also prepared [27 units]. [27].in addition to the side arm ItIt hashas beenbeenmay hypothesized,hypothesized,be the substituent thatthat on oneone the ofof theanomericthe inﬂuencinginfluencing center. unitsunits To investigate inin additionaddition this toto thethe idea, sideside a armseriesarm of mono- maymay bebe thethe substituentazasubstituent crown onethers on the the anomericderived anomeric from center. center. phenyl To To investigate investigate β-D-glucopyranoside this this idea, idea, a series a series(23a of–k monoazaof) weremono- synthesized crownaza crown ethers [28–30].ethers derived derived from phenylfrom phenylβ-D-glucopyranoside β-D-glucopyranoside (23a–k )( were23a–k synthesized) were synthesized [28–30]. [28–30].

To determine whether the protecting group in the 4 and 6 positions of the glucose To determine whether the protecting group in the 4 and 6 positions of the glucose unit To determineunit affects whether the activity the protecting of the crown group catalyst, in the compounds4 and 6 positions 24a–d of were the prepared,glucose in which affects the activity of the crown catalyst, compounds 24a–d were prepared, in which the unit affectsthe the benzylidene activity of the moiety crown was catalyst, replaced compounds by 4,6-di- 24aO-alkyl–d were chains prepared, (Scheme in 5)which [31]. benzylidene moiety was replaced by 4,6-di-O-alkyl chains (Scheme5)[31]. the benzylidene moiety was replaced by 4,6-di-O-alkyl chains (Scheme 5) [31].

Scheme 5. Synthesis of 4,6-di-O-alkyl glucoside-based catalysts 24a–d. SchemeScheme 5.5. Synthesis of 4,6-di-OO-alkyl-alkyl glucoside-basedglucoside-based catalystscatalysts 24a–d.24a–d. The 4,6-dibutyl-substituted 24e–h derivatives with other side chains have also been The The 4,6-dibutyl-substituted 4,6-dibutyl-substitutedprepared. For this, the 24e24e benzylidene––hh derivativesderivatives protecti withwithng otherother group sideside of chainschains the methyl havehave also alsoglucopyranoside beenbeen 19 prepared.prepared. Forwas this, removed thethe benzylidenebenzylidene and the free protectingprotecti OH groupsng groupgroup were ofof thebuthetylated methylmethyl before glucopyranosideglucopyranoside the three-step 1919 cyclization waswas removedremoved(Scheme andand thethe 6) [32]. freefree OHOH groupsgroups werewere butylatedbutylated beforebefore thethe three-stepthree-step cyclizationcyclization (Scheme(Scheme6 6))[ 32[32].].

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SchemeScheme 6.6. SynthesisSynthesisScheme of of6. crowncrownSynthesis ethersethers of crown24e–h 24e–h with etherswith 4,6-di-4,6-di- 24e–hOO -butylwith-butyl 4,6-di- glucosideglucosideO-butyl groups. groups. glucoside groups.

AsAs aa different differentAs source asource different of chirality,of chirality, sourceD-galactose of D -galactosechirality, was D alsowas-galactose usedalso toused was prepare toalso prepare monoaza used tomonoaza crownprepare monoaza compoundscrown compoundscrown26a–g [compounds 2226a,24–g,27 [22,24,27,33,34].,33, 3426a].– Galactoseg [22,24,27,33,34]. Galactose is the C-4 is Galactose the epimer C-4 epimer of isglucose, the C-4of glucose, epimer both of bothof which glucose, of both of canwhich form can pyranose formwhich pyranose can ring. form Whilering. pyranose While in the ring.in benzylidene-protected the While benzylidene-protected in the benzylidene-protected glucopyranoside, glucopyranoside, glucopyranoside, the six-the the memberedsix-membered ringssix-membered rings are inareanti in rings( transanti ()aretrans) annulation in antiannulation (trans) (planar), annulation(planar), in benzylidene in (planar),benzylidene galactopyranoside in benzylidene galactopyra- galactopyra- thenoside rings the are ringsnosidesyn -(are cisthe syn) annulatedrings- (cis) are annulated syn (L-shape).- (cis) (L-shape). annulated This structural This (L-shape). structural difference This difference structural can also can difference affectalso affect the can also affect selectivitythe selectivity inthe the in selectivity reactions.the reactions. in the reactions.

Sugar alcohol,Sugar D-mannitol alcohol, Dcan-mannitol be transformed can be transformed into a derivative, into a whichderivative, contains which two contains two Sugar alcohol, D-mannitol can be transformed into a derivative, which contains two vicinal hydroxyvicinal groups, hydroxy thus, groups, it was thus, suitable it was for suitable the three-step for the ring-closurethree-step ring-closure procedure. procedure. vicinal hydroxy groups, thus, it was suitable for the three-step ring-closure procedure. The mannitolThe moiety mannitol provides moiety a differentprovides anda different less rigid and structure less rigid to structure the catalysts. to the To catalysts. in- To in- The mannitol moiety provides a different and less rigid structure to the catalysts. To vestigate thevestigate effect of the the effect deviation of the in deviation flexibility, in lariat flexibility, ethers lariat 27a– hethers were 27a synthesized–h were synthesized by by investigate the effect of the deviation in ﬂexibility, lariat ethers 27a–h were synthesized by the previouslythe describedpreviously method described using method different using primary different amines, primary and amines, tosyl amide and tosyl for 27i amide for 27i the previously described method using different primary amines, and tosyl amide for 27i in the ring-closurein the ring-closure step. Reaction step. of Reaction27i with ofsodium 27i with amalgam sodium resulted amalgam in resultedthe formation in the formation in the ring-closure step. Reaction of 27i with sodium amalgam resulted in the formation of of 27j [35]. of 27j [35]. 27j [35]. Mannose, which is the C-2 epimer of glucose was chosen for synthesis of sugar-based Mannose,Mannose, whichwhich isis thethe C-2C-2 epimerepimer ofof glucoseglucose waswas chosenchosen forfor synthesissynthesis ofof sugar-basedsugar-based crown ethers. Whereas it has been proved previously that the sugar-based macrocycles crowncrown ethers. ethers. Whereas Whereas it it has has been been proved proved previously previously that that the sugar-basedthe sugar-based macrocycles macrocycles with with hydrocarbon-type side arms are generally ineffective in model reactions, mannose- hydrocarbon-typewith hydrocarbon-type side arms side arearms generally are generally ineffective ineffective in model in model reactions, reactions, mannose-based mannose- based crown ethers with heteroatom-containing side arms 28a–d were prepared only. crownbased etherscrown with ethers heteroatom-containing with heteroatom-containing side arms side28a– darmswere 28a prepared–d were only. prepared Compound only. 28dCompoundwas reducedCompound 28d was with reduced Na(Hg) 28d was with into reduced 28eNa(Hg)[36 with,37 into]. Na(Hg) 28e [36,37]. into 28e [36,37].

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In glucose, hydroxy groups in C-2 and C-3 positions are equatorial. In mannose, OH- function of C-2 is axial. Mannose-based catalysts 28a–e were synthesized to determine whether this has a significant impact on the selectivity. Altrose is another hexopyranoside, in which hydroxy functions in C-2 and C-3 are axial. Using altrose as a staring material, lariat ether 29 was synthesized, in which—compared to the glucose-based macrocycles 20 —a different anti (trans) annulation can be found between the macro ring and the pyranoside unit [38]. It was found that the protecting group of the sugar unit in crown ethers 24 also has an impact on the enantioselectivity, thus, other crown compounds derived from glucose were synthesized. Instead of the benzylidene group, naphthylidene (30a-b) and isoprop- Chemistry 2021, 3, FORylidene PEER moieties REVIEW (31a-b) were introduced to the macrocycles [39]. Hydrogenation of cata- 8

lysts 20h and 20j resulted in lariat ethers 32a-b bearing free OH-groups in the 4 and 6 positions (SchemeIn glucose, 7). hydroxy groups in C-2 and C-3 positions are equatorial. In mannose, OH- In glucose, hydroxy groups in C-2 and C-3 positions are equatorial. In mannose, function of C-2 is axial. Mannose-based catalysts 28a–e were synthesized to determine OH-function of C-2 is axial. Mannose-based catalysts 28a–e were synthesized to determine whether this has a significant impact on the selectivity. Altrose is another hexopyranoside, whether this has a signiﬁcant impact on the selectivity. Altrose is another hexopyranoside, in which hydroxy functions in C-2 and C-3 are axial. Using altrose as a staring material, in which hydroxy functions in C-2 and C-3 are axial. Using altrose as a staring material, lariat ether 29 was synthesized, in which—compared to the glucose-based macrocycles 20 lariat ether 29 was synthesized, in which—compared to the glucose-based macrocycles 20 —a different—aanti different(trans) annulation anti (trans) can annulation be found can between be found the macro between ring the and macro the pyranoside ring and the pyra- unit [38]. noside unit [38]. It was foundIt was that found the protecting that the groupprotecting of the grou sugarp of unit the in sugar crown unit ethers in crown24 also ethers has an 24 also has impact onan the impact enantioselectivity, on the enantioselectivity, thus, other crown thus, compounds other crown derived compounds from glucose derived were from glucose synthesized.were Instead synthesized. of the benzylidene Instead of group,the benzylidene naphthylidene group, (30a naphthylidene–b) and isopropylidene (30a-b) and isoprop- moieties (31aylidene–b) were moieties introduced (31a-b) to were the macrocyclesintroduced to [39 the].Hydrogenation macrocycles [39]. of catalystsHydrogenation20h of cata- and 20j resultedlysts 20h in lariatand 20j ethers resulted32a– binbearing lariat ethers freeOH-groups 32a-b bearing in thefree 4 OH-groups and 6 positions in the 4 and 6 (Scheme7).positions (Scheme 7).

In glucose, hydroxy groups in C-2 and C-3 positions are equatorial. In mannose, OH- function of C-2 is axial. Mannose-based catalysts 28a–e were synthesized to determine whether this has a significant impact on the selectivity. Altrose is another hexopyranoside, in which hydroxy functions in C-2 and C-3 are axial. Using altrose as a staring material, lariat ether 29 was synthesized, in which—compared to the glucose-based macrocycles 20 —a different anti (trans) annulation can be found between the macro ring and the pyranoside unit [38]. It was found that the protecting group of the sugar unit in crown ethers 24 also has an impact on the enantioselectivity, thus, other crown compounds derived from glucose were synthesized. Instead of the benzylidene group, naphthylidene (30a-b) and isopropylidene moieties (31a-b) were introduced to the macrocycles [39]. Hydrogenation of cata- SchemeScheme 7.7. Removallysts of of 20hthe the benzylidene benzylideneand 20j resulted group group ofin of catalysts lariat catalysts ethers 20h20h and and32a 20j-20jb to bearing toobtain obtain compounds free compounds OH-groups 32a32a in the 4 and 6 andand32b. 32b. positions (Scheme 7).

Scheme 7. Removal of the benzylidene group of catalysts 20h and 20j to obtain compounds 32a and 32b.

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An aldopentose,aldopentose, L-arabinose served as the sourcesource ofof chiralitychirality inin crowncrown compoundscompounds 33a–c..An When aldopentose, arabinose Lis -arabinose reacted with served acetoneacetone as the oror source benzaldehyde,benzaldehyde, of chirality a six-memberedsix-memberedin crown compounds pyra- noside33a–c .ring ringWhen can can arabinose be be formed, formed, is wh reacted whileile two twowith vicinal vicinalacetone hydroxy hydroxy or benzaldehyde, functions functions remain a remain six-membered unprotected. unprotected. After pyra- Afterthenoside three-step the ring three-step can procedure be formed, procedure of ringwhile offormation, two ring vicinal formation, the hydroxy crown the ring functions crown was ring connected remain was connectedunprotected. to the carbohy- to After the carbohydratedratethe three-step unit in syn unit procedure-annulation in syn-annulation of inring macrocycles formation, in macrocycles 33a the– ccrown [40].33a –ringc [40 was]. connected to the carbohydrate unit in syn-annulation in macrocycles 33a–c [40].

An unnatural carbohydrate, 2-deoxy-ribo-hexopyranoside was prepared from glucose,An andAn unnatural thenunnatural fused carbohydrate, carbohydrate,to the monoaza-15-crown-5 2-deoxy- 2-deoxyribo-ribo--hexopyranosidehexopyranoside ring resulting was in was preparedcatalysts prepared 34a from– dfrom glucose, [41]. glu- In andthiscose, case, then and the fused then annulation tofused the monoaza-15-crown-5to ofthe the monoaza-15-crown-5 sugar unit and ring the resultingmacro ring resulting ring in was catalysts inalso catalysts syn34a, but–d 34a[ in41 ].–thisd In [41]. case, this In case,C-3this and thecase, C-4 annulation the are annulation the connecting of the ofsugar the atoms.sugar unit unit and and the the macro macro ring ring was was also alsosyn syn, but, but in in this this case, case, C-3C-3 and Monosaccharidesand C-4 C-4 are are the the connecting connecting can form atoms. atoms.not only pyranose but furanose rings too. A few crown compoundsMonosaccharidesMonosaccharides containing cana can glucofuranoside form form not not only only pyranosemoiety pyrano (35ase but but–d furanose, 36afuranose-b) were rings rings synthesized too. too. A A few few starting crown crown compoundsfromcompounds glucose. containing containing In one type a glucofuranosidea gl(35aucofuranoside–d), the furanoside moiety moiety (35a unit(35a–d –is,d36a ,attached 36a–b-)b were) were to synthesizedthe synthesized macrocycle starting starting by a fromsinglefrom glucose. bond.glucose. while In In one one in typethe type other, (35a (35a– d–the),d), the five-memthe furanoside furanosidebered unit unitfuranoside is is attached attached is fused to to the the to macrocycle macrocyclethe crown byring by a a single(36asingle-b). bond. bond.From while whileD-xylose, in in the the catalysts other, other, the the37a ﬁve-membered -five-memb were preparedbered furanoside furanoside having isan is fused analogousfused to to the the structure crown crown ring ring to (glucofuranoside-based36a(36a–b-b).). From FromD D-xylose,-xylose, crown catalysts catalysts ethers37a 37a –36ab-bwere -wereb. When prepared prepared the complexing having having an an analogous abilityanalogous was structure structureexamined, to to glucofuranoside-basedsurprisingly,glucofuranoside-based the ion selectivity crown crown ethers ofethers crowns36a 36a– b.35a-b.When When–d towards the the complexing complexing silver was ability measuredability was was to examined, examined, be up to surprisingly,30surprisingly, times higher the the than ion ion selectivitythat selectivity for sodium of of crowns crowns [42]. 35a 35a–d–dtowards towards silver silver was was measured measured to to be be up up to to 3030 times times higher higher than than that that for for sodium sodium [42 [42].].

In addition to mannitol, another sugar alcohol, L-threitol was also used as a source of chiralityIn additionin crown to ethers mannitol [43]., Threitol-basedanother sugar alcohol,catalysts L -threitol38a–f were was prepared also used in as three a source steps of In addition to mannitol, another sugar alcohol, L-threitol was also used as a source of fromchirality 1,4-di- inO crown-alkylated ethers threitol [43]. Threitol-based derivatives, which catalysts could 38a be–f wereeasily prepared synthesized in three starting steps chirality in crown ethers [43]. Threitol-based catalysts 38a–f were prepared in three steps fromfrom diethyl 1,4-di- tartrate.O-alkylated threitol derivatives, which could be easily synthesized starting fromfrom 1,4-di- diethylO-alkylated tartrate. threitol derivatives, which could be easily synthesized starting fromIt diethyl was assumed tartrate. that the ketal groups in the mannitol moiety can have an impact on the enantioselectivity.It was assumed thatTherefore, the ketal the groups number in ofth emannitol-based mannitol moiety catalysts can have was an increased impact on the enantioselectivity. Therefore, the number of mannitol-based catalysts was increased

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It was assumed that the ketal groups in the mannitol moiety can have an impact on the enantioselectivity. Therefore, the number of mannitol-based catalysts was increased by Chemistry 2021by, 3using, FOR PEER different REVIEW protecting groups during the syntheses, resulting in compounds39a b39a-b 10 using different protecting groups during the syntheses, resulting in compounds – and 40aand– 40ab [44-b] .[44].

by using different protecting groups during the syntheses, resulting in compounds 39a-b and 40a-b [44].

As mentioned before, one of the influencing moieties may be the substituent on the As mentioned before, one of the inﬂuencing moieties may be the substituent on the anomeric center. Therefore,As mentioned additional before, glucos one ofe-based the influencin lariat gethers moieties were may synthesized be the substituent to on the anomeric center. Therefore, additional glucose-based lariat ethers were synthesized to gain further informationanomeric on center. the structure- Therefore,activity additional relationship glucose-based [27,45]. lariat Catalysts ethers were 20h synthesizedand to 20h gain42a, 41a further and information42b, gainand furtheras onwell the information asstructure-activity 41b and on 42c the are structure- epimer relationshipactivity pairs, [relationshipthe27,45 only]. Catalysts difference [27,45]. Catalysts inand the 20h and 42aabsolute, 41a andconfiguration42b, and42a, 41a asis well onand C-1. 42b as 41b, andand as well42c asare 41b epimer and 42c pairs, are epimer the only pairs, difference the only indifference the in the absolute conﬁgurationabsolute is on configuration C-1. is on C-1.

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The effectThe of effect the anomeric of the anomeric position position on the enantioselectivity on the enantioselectivity was also was studied also studied in the in the case of galactose-basedcase of galactose-based lariat ethers. lariat Crown ethers. compound Crown compound43 was synthesized 43 was synthesized from isopropyl from isopro- α-D-galactoside,pyl α-D-galactoside, while alkyl andwhile aryl alkyl 4,6- andO-benzylidene- aryl 4,6-O-benzylidene-β-galactopyranosidesβ-galactopyranosides were the were key intermediatesthe key intermediates in the synthesis in the of synthesis macrocycles of macrocycles44a–f [27,46 ].44a–f [27,46]. Xylal- (45aXylal-–b, (4645a) and-b, 46 arabinal-based) and arabinal-based (47a–b (,47a48)-b lariat, 48) lariat ethers ethers were were synthesized synthesized to to ex- examineamine the effect the ofeffect fewer of stereogenicfewer stereogenic centers center in thes sugarin the unit sugar [47 unit]. Crown [47]. catalystsCrown catalysts45a, 45a, 46, and as46, well and as as47a welland as 4847aare and enantiomeric 48 are enantiomeric pairs. Unsaturated pairs. Unsaturated monosaccharides monosaccharides bearing bear- free vicinaling OH-groups,free vicinal OH-groups, namely D- and namelyL-xylal, D- andand DL--xylal, and L -arabinaland D- and can L-arabinal be prepared can from be prepared the appropriatefrom the carbohydrates appropriate carbohydrates in four steps. in four steps.

2.2. Enantioselective2.2. Enantioselective Syntheses Syntheses 2.2.1. Michael2.2.1. Michael Addition Addition of 2-Nitropropane of 2-Nitropropane The catalyticThe catalytic properties properties of the carbohydrate-based of the carbohydrate-based crown ethers crown were ethers not investigated were not investi- in the Hungariangated in the research Hungarian group research until 1996, group only measurementsuntil 1996, only for measurements complex forming for complex ability form- were performed.ing ability Using were aperformed. few derivatives Using of a thefew two-glucose derivatives unit-containingof the two-glucose 18-crown-6 unit-containing (1), selective18-crown-6 transportation (1), selective of chiral transportation ammonium of salts chiral was ammonium examined, butsalts the was experiments examined, but the resultedexperiments in racemic mixtures resulted [ 48in ].racemic mixtures [48]. The ﬁrstThe asymmetric first asymmetric reaction, reaction, in which in carbohydrate-based which carbohydrate-based (lariat) azacrown(lariat) azacrown com- com- pounds werepounds investigated, were investigated, was the Michael was the addition Michael of addition 2-nitropropane of 2-nitropropane (50) to chalcone (50) to (49, chalcone 1 2 Ar = Ar(49,= CAr6H1 =5 )Ar (Scheme2 = C6H85))[ (Scheme49,50]. In8) the[49,50]. presence In the of presence catalysts of20a catalysts–g, the S20aenantiomer–g, the S enantio- of Michaelmer adduct of Michael51 was adduct formed 51 inwas excess. formed Lariat in excess. ether 20g Lariathaving ether a 20g (CH having2)2OH sidea (CH arm2)2OH side inducedarm 34–65% induced ee ( enantiomeric34–65% ee (enantiomeric excess), depending excess), depending on the conditions on the conditions (Table1 , entry (Table 1). 1, entry Increasing1). Increasing the distance the between distance the between nitrogen the andnitrogen the oxygen and the led oxygen to higher led to enantiomeric higher enantiomeric excess. Applicationexcess. Application of crown of ether crown20h etherbearing 20h abearing (CH2)3 aOH (CH group2)3OH resulted group resulted in an ee in value an ee value of 85% (ofTable 85%1 ,(Table entry 1, 2) entry [24]. Replacement2) [24]. Replacement of the OH of the with OH a methoxywith a methoxy group in group the hy- in the hy- droxyethyldroxyethyl chain also chain had also a positive had a positive effect on effect the selectivity, on the selectivity, 87% eewas 87% measured ee was measured in the in the α presencepresence of compound of compound20i (Table 20i1, (Table entry 4).1, entry When 4). methyl When methyl-D-glucoside-based α-D-glucoside-based crown crown ethers 20kethers(n = 20k 1–5) ( weren = 1– tested,5) were it turnedtested, outit turned that the out phosphonoalkyl that the phosphonoalkyl chain has an chain optimal has an opti- length. Using catalyst 20k (n = 4) with (CH ) spacer led to 82% enantioselectivity (Table1, mal length. Using catalyst 20k (n 2=4 4) with (CH2)4 spacer led to 82% enantioselectivity entry 5)(Table [24]. The 1, entry same phenomenon5) [24]. The same was phen observedomenon in the was case observed of 20l (n in= the 4) with case theof 20l spacer (n = 4) with (CH ) , which generated 95% ee (Table1, entry 6) [25,51]. Despite the similarity, macrocy- 2 4 the spacer (CH2)4, which generated 95% ee (Table 1, entry 6) [25,51]. Despite the similarity, cles 20l bearingmacrocycles phosphinoxidoalkyl 20l bearing phosphinoxidoalkyl groups preferred thegroups formation preferred of the theR formationenantiomer of of the R en- 51 20k S , whileantiomer using phosphonoalkyl-substituted of 51, while using phosphonoalkyl-substituted, the isomer was 20k in, excess.the S isomer was in excess.

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SchemeScheme 8.8. MichaelMichael additionaddition ofof 2-nitropropane2-nitropropane ((5050)) toto chalconeschalcones ((4949).).

TableIn 1. Effectthe Michael of crown addition, ethers in thesubs Michaeltituted addition chalcone of 2-nitropropanederivatives were (50) toalso chalcones used as (49 the). acceptor. Applying catalysts 20i and 20k (n = 4) it was observed that substituents on the 1 2 aromaticEntry rings, regardlessAr of the position,Ar led to reducedCatalyst enantiomeric Yield, excess % [52]. ee, In % the presence1 of 20h and 20j C6,H the5 addition ofC 2-nitropropane6H5 20g (50) to chalcone91 analogues 65 (49) gave similar2 results, i.e., C 6theH5 substitution ofC6 theH5 aromatic ring20h or replacement53 of the 85phenyl group 3to other aromatic Naphthalen-1-yl moieties lowered C 6theH5 enantioselectivity20h [53]. 35 87 4 C6H5 C6H5 20i 45 87 5 C H C H 20k (n = 4) 39 82 Table 1. Effect of crown ethers6 5 in the Michael addition6 5 of 2-nitropropane (50) to chalcones (49). 6 C6H5 C6H5 20l (n = 4) 43 95 Entry 7Ar1 C6H5 Ar2 C6H5 Catalyst23d Yield,78 % ee, 82% 8 C6H5 C6H5 23e 71 45 1 C6H5 C6H5 20g 91 65 9 C6H5 C6H5 23f 65 60 2 10C6H5 C6H5 C6H5 C6H5 20h 24d 53 8285 90 3 11Naphthalen-1-yl C6H 5 C6H5 C6H5 20h 24h 35 5387 55 12 C H C H 26e 34 52 4 C6H5 6 5 C6H5 6 5 20i 45 87 13 C6H5 C6H5 27e 39 40 5 C6H5 C6H5 20k (n = 4) 39 82 14 C6H5 C6H5 27j 38 67 6 15C6H5 C6H5 C6H5 C6H5 20l (n =28b 4) 43 3795 92 (S) 7 16C6 Naphthalen-1-ylH5 C6H5 C6H5 23d 28b 78 3982 84 8 C6H5 C6H5 23e 71 45 9 In the MichaelC6H addition,5 substitutedC6H5 chalcone derivatives23f were also65 used as the60 acceptor.10 Applying catalystsC6H5 20i and 20k (Cn 6=H 4)5 it was observed24d that substituents82 on the aromatic90 rings,11 regardlessC of6H the5 position, ledC to6H reduced5 enantiomeric24h excess [5253]. In the presence55 of 20h12and 20j, theC addition6H5 of 2-nitropropaneC6H5 (50) to chalcone26e analogues34 (49) gave52 similar results,13 i.e., theC substitution6H5 of theC aromatic6H5 ring or replacement27e of39 the phenyl group40 to other14 aromatic moietiesC6H5 lowered theC enantioselectivity6H5 27j [53 ]. 38 67 β 15 When the efﬁciencyC6H5 of crown ethersC6H5 derived from28b phenyl -D-glucopryanoside37 92 (S23a) –g was examined in this Michael addition, it was proven again that the enantioselectivity 16 Naphthalen-1-yl C6H5 28b 39 84 highly depends on the structure of the side arm (as well). Among the hydrocarbon substituents of the nitrogen, the phenylethyl group was the most effective; catalyst 23d When the efficiency of crown ethers derived from phenyl β-D-glucopryanoside 23a– 23e 23f generatedg was examined 82% ee in (Table this Michael1, entry 7).addition, In the it case was of provenand again ,that in which the enantioselectivity the side arm is a hydroxyethyl or a methoxyethyl group respectively, lower ee values were measured highly depends on the structure of the side arm (as well). Among the hydrocarbon sub- (45% and 60%, respectively) (Table1, entries 8 and 9) [ 28]. At lower temperature, the stituents of the nitrogen, the phenylethyl group was the most effective; catalyst 23d gen- enantiomeric excess and the yield decreased drastically [29]. erated 82% ee (Table 1, entry 7). In the case of 23e and 23f, in which the side arm is a When macrocycles 24a–d bearing alkyl substituents in the 4 and 6 positions were hydroxyethyl or a methoxyethyl group respectively, lower ee values were measured (45% applied as phase transfer catalysts, poor enantioselectivity was observed, except for com- and 60%, respectively) (Table 1, entries 8 and 9) [28]. At lower temperature, the enantio- pound 24d, which generated an ee of 90% (Table1, entry 10) [ 31]. The presence of a side meric excess and the yield decreased drastically [29]. arm in macrocycles 24e–h negatively affected the asymmetric induction, the best enan- When macrocycles 24a–d bearing alkyl substituents in the 4 and 6 positions were tioselectivity was achieved using crown ether 24h of the above-mentioned ones (55% ee) applied as phase transfer catalysts, poor enantioselectivity was observed, except for com- (Table1, entry 11) [32]. pound 24d, which generated an ee of 90% (Table 1, entry 10) [31]. The presence of a side Compared to the glucose-based analogous macrocycles, the galactose-containing arm in macrocycles 24e–h negatively affected the asymmetric induction, the best enanti- catalysts generated lower enantiomeric excess, e.g., product 51 had an optical purity of 52%oselectivity when lariat was etherachieved26e wasusing used crown (Table ether1, entry 24h 12)of the [23 ].above-mentioned ones (55% ee) (TableApplying 1, entry mannitol-based11) [32]. crown ethers (27), the less rigid structure proved to be insufﬁcientCompared to reach to the high glucose-based enantioselectivity analogous in this macrocycles, Michael addition. the galactose-containing Substitution of thecat- azacrownalysts generated structure lower on theenantiomeric nitrogen affected excess, thee.g., asymmetric product 51 inductionhad an optical negatively. purity of While 52% when lariat ether 26e was used (Table 1, entry 12) [23].

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Chemistry 2021, 3 Applying mannitol-based crown ethers (27), the less rigid structure proved to be 562in- sufficient to reach high enantioselectivity in this Michael addition. Substitution of the azacrown structure on the nitrogen affected the asymmetric induction negatively. While product 51 was formed in an ee of 67% using catalyst 27j, lariat ether 27e showed only product 51 was formed in an ee of 67% using catalyst 27j, lariat ether 27e showed only 40% 40% enantioselectivity (Table 1, entries 13 and 14) [35]. enantioselectivity (Table1, entries 13 and 14) [35]. Among the methyl α-D-mannoside-based lariat ethers, 28b was the most efficient in Among the methyl α-D-mannoside-based lariat ethers, 28b was the most efﬁcient in the Michael addition of 2-nitropropane (50) (92% ee) (Table 1, entry 15) [38]. Crown ether the Michael addition of 2-nitropropane (50) (92% ee) (Table1, entry 15) [ 38]. Crown ether 20h derived from glucose and mannose-based 28b was compared in detail in the Michael 20h derived from glucose and mannose-based 28b was compared in detail in the Michael addition of 2-nitropropane to enones [54]. In the reaction of chalcone (49, Ar1 = Ar2 = C6H5), addition of 2-nitropropane to enones [54]. In the reaction of chalcone (49, Ar1 = Ar2 = C H ), macrocycles 20h and 28b preferred the formation of opposite enantiomers. Application6 5of macrocycles 20h and 28b preferred the formation of opposite enantiomers. Application chalcone analogues resulted in lower ee values in each cases, except for compound 51 with of chalcone analogues resulted in lower ee values in each cases, except for compound 51 Ar1 = naphthalen-1-yl1 and Ar2 = C62H5 groups (87% and 84% ee, respectively) (Table 1, en- with Ar = naphthalen-1-yl and Ar = C6H5 groups (87% and 84% ee, respectively) (Table1 , triesentries 3 and 3 and 16). 16).

2.2.2. Michael Michael Addition Addition of a Phosphonoglycine Derivative InIn a a collaboration collaboration with with an an organophosphor organophosphorusus research research group, group, a new a new asymmetric asymmetric Mi- chaelMichael addition addition has has been been published. published. Synthesi Synthesiss of of chiral chiral phosphonoglycine phosphonoglycine derivatives derivatives 54 (ee up to 86%) hashas beenbeen developeddeveloped usingusing phenylphenyl ββ-glucopyranoside-based-glucopyranoside-based crown ethers 23g–i as phase transfer catalysts (Scheme 99))[ [55]55].. The The best results were obtained in the presence of lariat etherether 23i23i withwith acrylonitrileacrylonitrile ((5353,R, R11 == R22 = H, H, EWG EWG = CN) CN) and and crotonitrile 1 22 (53,,R R = CH CH33, ,RR == H, H, EWG EWG = = CN) CN) as as acceptors acceptors (75% (75% and and 86% 86% ee, ee, respectively) respectively) (Table (Table 22,, entries 1 andand 2),2), however,however, the the asymmetric asymmetric induction induction was was highly highly dependent dependent on on the the structure struc- tureof 53 of. Later, 53. Later, the number the number of applied of applied crown crown compounds compounds has been has been expanded expanded by synthesizing by synthe- sizingphenyl phenylβ-glucopyranoside-based β-glucopyranoside-based catalysts catalysts with differentwith different side armsside arms (e.g., (e.g.,23j–k 23j), as–k well), as wellas further as further Michael Michael acceptors acceptors having having been been investigated investigated [30]. [30]. Enantioselectivity Enantioselectivity was was the thehighest highest in case in case of nitrile of nitrile compounds compounds (53, EWG (53, =EWG CN). = In CN). the presenceIn the presence of lariat of ether lariat23k ether, the 1 2 23kMichael, the Michael addition addition of crotonitrile of crotonitrile (53,R = ( CH53, R3,R1 =CH= H,3, R EWG2 = H, =EWG CN) = led CN) to led a diastereomeric to a diastere- omericratio (d.r.) ratio 16:1 (d.r.) and 16:1 an eeand of an 95% ee (Table of 95%2, entry(Table 3). 2, Quantumentry 3). Quantum mechanical mechanical calculations calcula- have tionsrevealed have that revealed the side that arm the has side a veryarm has important a very important role regarding role theregarding asymmetric the asymmetric induction, induction,which is related which to isthe related distance to the of distance the sodium of the ion sodium and the ion crown and ring, the crown inﬂuenced ring,by influ- the encedsubstituent by the of substituent the nitrogen. of the nitrogen.

Scheme 9. Michael addition of phosphonoglycine derivative 52 to electron deﬁcientdeficient oleﬁnsolefins ((53).).

Table 2. Effect of crowncrown ethersethers inin thethe MichaelMichael addition addition of of phosphonoglycine phosphonoglycine derivative derivative52 52to to electron elec- trondeﬁcient deficient oleﬁns olefins (53). (53). Entry R1 R2 EWG Catalyst Yield, % d.r. ee, % Entry R1 R2 EWG Catalyst Yield, % d.r. ee, % 1 CH3 H CN 23i 76 6:1 86 1 CH H CN 23i 76 6:1 86 2 H 3 H CN 23i 84 - 75 2 H H CN 23i 84 - 75 3 33 CH CH 3 H H CN CN 23k23k 76 16:116:1 9595

2.2.3. Michael Addition of Cyanoﬂuoromethyl Phosphonate In collaboration with a research group from the ﬁeld of organophosphorous chemistry, catalysts 23h–i and 23k were applied in the Michael addition of compound 55, containing Chemistry 2021, 3, FOR PEER REVIEW 14

2.2.3. Michael Addition of Cyanofluoromethyl Phosphonate Chemistry 2021, 3 563 In collaboration with a research group from the field of organophosphorous chemistry, catalysts 23h-i and 23k were applied in the Michael addition of compound 55, containing a phosphonic ester moiety, to electron deficient olefins (Scheme 10) [56]. When a nitroolefin (56a, phosphonicEWG = NO ester2) was moiety, reacted to with electron the deficientphosphonate olefins 55 (Scheme, enantioselectivity 10)[56]. When in- a nitroolefin creased above(56 80%, EWG ee in = NOthe 2case) was of reacted lariat ethers with the 23i phosphonate and 23k (Table55, 3, enantioselectivity entries 1and 2). increasedIn above addition to the80% structural ee in the motifs case of of the lariat carboh ethersydrate-based23i and 23k catalyst,(Table 3i.e.,, entries annulation 1and 2)of the. In addition to ring and substitutionthe structural of the motifsnitrogen, of thethe carbohydrate-basedsubstrate also influenced catalyst, the asymmetric i.e., annulation induc- of the ring and tion. substitution of the nitrogen, the substrate also influenced the asymmetric induction.

SchemeScheme 10. Michael 10. Michael addition addition of diethyl of diethyl cyanofluoromethyl cyanofluoromethyl phosphonate phosphonate (55) to ( electron55) to electron deficient deficient olefins 56. olefins 56. Table 3. Effect of crown ethers in the Michael addition of diethyl cyanofluoromethyl phosphonate Table 3. Effect of crown ethers in the Michael addition of diethyl cyanofluoromethyl phosphonate (55) to electron deficient olefins 56. (55) to electron deficient olefins 56. Entry R EWG Catalyst Yield, % d.r. ee, % Entry R EWG Catalyst Yield, % d.r. ee, % 1 C H NO 23i 82 7:1 82 1 C6H5 NO2 6 5 23i 2 82 7:1 82 2 C6H5 NO2 23k 85 6:1 88 2 C6H5 NO2 23k 85 6:1 88

2.2.4. Michael2.2.4. Addition Michael of Diethyl Addition Acetamidomalonate of Diethyl Acetamidomalonate In 2011, anotherIn 2011,asymmetric another Michael asymmetric addition Michael was reported. addition Diethyl was reported. acetamidomalo- Diethyl acetamidomalonate (59) was reacted with β-nitrostyrene (58, Ar = C H ) (Scheme 11) using crown ether nate (59) was reacted with β-nitrostyrene (58, Ar = C6H5) (Scheme 611)5 using crown ether 20h as the phase transfer catalyst. Product 60 (Ar = C H ) was formed in excellent enan- 20h as the phase transfer catalyst. Product 60 (Ar = C6H5) was formed6 5in excellent enantiomeric puritytiomeric (99% ee) purity (Table (99%4, entry ee) 1). (Table Similar4, entry results 1). were Similar obtained results using were 4-chloro- obtained (58 using, 4-chloro- (58, Ar = 4-Cl-C6H4) and 4-nitro-β-nitrostyrene (58, Ar = 4-O2N-C6H4) (99% and 97%, re- Ar = 4-Cl-C6H4) and 4-nitro-β-nitrostyrene (58, Ar = 4-O2N-C6H4) (99% and 97%, respec- spectively) (Table4, entries 2 and 3) [ 57]. Later, the effect of the substituent on the aromatic tively) (Table 4, entries 2 and 3) [57]. Later, the effect of the substituent on the aromatic ring was examined using catalyst 20h. It was found that, except the above-mentioned ring was examined using catalyst 20h. It was found that, except the above-mentioned two two examples, in the reactions of substituted nitrostyrenes lower optical purity was ob- examples, in the reactions of substituted nitrostyrenes lower optical purity was observed served in the products. When the phenyl group was replaced by another aromatic ring, in the products. When the phenyl group was replaced by another aromatic ring, the asym- the asymmetric induction was also weaker [58]. Effect of some glucose-based lariat ethers metric induction was also weaker [58]. Effect of some glucose-based lariat ethers 20 with 20 with different substituents on the nitrogen atom was also systematically investigated. different substituents on the nitrogen atom was also systematically investigated. The re- The results proved that the side arm on the nitrogen highly affects the catalytic activity. sults proved that the side arm on the nitrogen highly affects the catalytic activity. While While macrocycle 20h bearing a hydroxypropyl side chain resulted in 99% optical purity, macrocycle 20h bearing a hydroxypropyl side chain resulted in 99% optical purity, its its methoxypropyl analogue, 20j gave the product in 38% ee (Table4, entry 4). Elongation methoxypropylof theanalogue, side arm 20j in gave the crownthe product ether (in20n 38%) led ee to (Table the formation 4, entry 4). of Elongation a racemic mixture of (Table4 , the side arm in the crown ether (20n) led to the formation of a racemic mixture (Table 4, entry 6). Replacement of the OH function to a N(CH3)2 group (catalyst 20m, 78% ee gener- entry 6). Replacementated) (Table of4 the, entry OH 5function) affected to the a N(CH asymmetric3)2 group induction (catalyst unfavorably 20m, 78% ee [26 gen-]. Later, the effect erated) (Tableof 4, the entry anomeric 5) affected substituent the asy ofmmetric the carbohydrate induction onunfavorably the catalytic [26]. activity Later, was the investigated, effect of the anomericglucose-based substituent crown of compounds the carbohydrate20h, 41a on–b the(α -series)catalytic and activity44a–c was(β-series) inves- were used as tigated, glucose-based crown compounds 20h, 41a-b (α-series) and 44a-c (β-series) were phase transfer catalysts in the Michael addition of β-nitrostyrene (58, Ar = C6H5). Altering used as phasethe transfer alkyl groupcatalysts in thein the axial Michael position addition of C-1 (of41a β–-nitrostyreneb) or switching (58, to Ar equatorial = C6H5). substitution Altering the (alkyl44a– cgroup), the asymmetric in the axial induction position decreasedof C-1 (41a signiﬁcantly-b) or switching (e.g., into the equatorial case of 41a to 78% ee, while using 42b led to 68% ee; Table4, entries 14 and 15).

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Chemistry 2021, 3 564 substitution (44a-c), the asymmetric induction decreased significantly (e.g., in the case of 41a to 78% ee, while using 42b led to 68% ee; Table 4, entries 14 and 15).

Scheme 11. Michael addition of diethyldiethyl acetamidomalonate (59) to nitrostyrenes ((5858).).

Table Arabinose-based 4. Effect of crown compounds ethers in the 33a Michael–c generated addition moderate of diethyl enantiomeric acetamidomalonate excess (in59 )the to Michaelnitrostyrenes addition (58). of acetamidomalonate 59. Using catalyst 33c, the R enantiomer was formed in an ee of 61% (Table 4, entry 9) [40]. Entry Ar Catalyst Yield, % ee, %

Table 4. Effect1 of crown ethers C6H in5 the Michael addition20h of diethyl acetamidomalonate60 (59 99) to ni- trostyrenes2 (58). 4-Cl-C6H4 20h 45 99 3 4-O2N-C6H4 20h 78 97 Entry4 C Ar6H 5 20j Catalyst 58 Yield, % 38 ee, % 1 5C C6HH5 20m20h 3060 7899 6 C H 20n 38 0 2 4-Cl-C6 65H4 20h 45 99 7 C6H5 26d 90 92 3 4-O2N-C6H4 20h 78 97 8 C6H5 26f 30 70 6 5 4 9C C6HH5 33c 20j 5058 61 (R38) 5 10C C6HH5 34c20m 5930 8078 6 11C C6HH5 38c20n 6538 95 0 12 C6H5 38d 22 51 7 C6H5 26d 90 92 13 C6H5 40a 57 65 8 C6H5 26f 30 70 14 C6H5 41a 67 78 9 15C C6HH5 42b33c 7150 6861 (R) 10 C6H5 34c 59 80 Arabinose-based11 compoundsC6H5 33a–c generated38c moderate enantiomeric65 excess95 in the Michael12 addition of acetamidomalonateC6H5 59. Using38d catalyst 33c,22 the R enantiomer51 was formed13 in an ee of 61% (TableC6H5 4, entry 9) [40]. 40a 57 65 Monoaza-15-crown-514 C6H ethers5 34a–d, containing41a a 2-deoxy-ribo-hexopyranoside67 78 moiety, showed15 poor enantioselectivityC6H5 in this Michael42b addition, except for71 34c bearing a68 hydroxypropyl side arm and a methoxyphenyl substituent, which generated higher asymmetric inductionMonoaza-15-crown-5 (80% ee) (Table4 ,ethers entry 34a 10)– [d41, containing]. Comparison a 2-deoxy- of the resultsribo-hexopyranoside of crown ether moi-20h ety,derived showed from poor glucose enantioselectivity and lariat ether in34c thissynthesized Michael addition, from 2-deoxy- except forribo 34c-hexopyranoside bearing a hy- droxypropylsuggests that side the interactionarm and a ofmethoxyphenyl the aromatic ring substituent, during the which reaction generated is necessary higher to asym- gain metricenantioselectivity. induction (80% ee) (Table 4, entry 10) [41]. Comparison of the results of crown ether 20h derivedGalactose-based from glucose lariat etherand lariat26d, whichether 34c is the synthesized C-4 epimer from of crown 2-deoxy- etherribo-20h,hexopyra- proved to nosidebe highly suggests effective that in thisthe Michaelinteraction addition of the (92% arom ee)atic (Table ring 4during, entry 7).the As reaction it was experiencedis necessary toearlier, gain enantioselectivity. using a catalyst bearing a methoxypropyl group, lower enantiomeric excess was measuredGalactose-based (26f, 70%) (Tablelariat 4ether, entry 26d 8), [which34]. is the C-4 epimer of crown ether 20h, proved to beAmong highly effective the threitol-based in this Michael crown addition compounds, (92% the ee) above-mentioned (Table 4, entry 7). phenomenon As it was expe- was riencedobserved earlier, again. using The highest a catalyst enantioselectivity bearing a methoxypropyl was observed group, in the lower case of enantiomeric 1,4-di-O-benzyl- ex- cesssubstituted was measured38c (95% (26f ee), 70%) (Table (Table4, entry 4, entry 11), while 8) [34]. using its methoxypropyl pair 38c, the asymmetricAmong inductionthe threitol-based has decreased crown to 51%compounds, (Table4, entrythe above-mentioned 12) [43]. phenomenon was observedLariat ethers again.27, 39Theand highest40 synthesized enantioselecti fromvity mannitol was observed showed only in the moderate case of efﬁciency1,4-di-O- benzyl-substituted(14–65% ee). As it was 38c assumed, (95% ee) ketal(Table groups 4, entry in the11), mannitol while using moiety its hadmethoxypropyl an impact on pair the 38cenantioselectivity;, the asymmetric macrocycle induction has40a bearingdecreased cyclohexylidene to 51% (Table 4, groups entry generated12) [43]. the highest ee valueLariat (65%) ethers (Table 27,4 39, entry and 13)40 synthesized [44]. from mannitol showed only moderate effi- 45 48 ciencyXylal- (14–65% and ee). arabinal-based As it was assumed, crown ketal compounds groups in the– mannitolwere poorly moiety effective had an impact in this reaction (5–34% ee), regardless of the side arm or the carbohydrate unit [47].

Chemistry 2021, 3, FOR PEER REVIEW 16

on the enantioselectivity; macrocycle 40a bearing cyclohexylidene groups generated the highest ee value (65%) (Table 4, entry 13) [44]. Chemistry 2021, 3 565 Xylal- and arabinal-based crown compounds 45–48 were poorly effective in this reaction (5–34% ee), regardless of the side arm or the carbohydrate unit [47].

2.2.5. Michael Michael Addition Addition of of Diethyl Diethyl Acetoxymalonate Michael additionaddition ofof chalconeschalcones ( 49(49)) and and diethyl diethyl acetoxymalonate acetoxymalonate (61 (61) was) was also also studied stud- iedin the in presencethe presence of carbohydrate-based of carbohydrate-based macrocycles macrocycles (Scheme (Scheme 12). Using 12). catalyst Using catalyst20h derived 20h derivedfrom glucose, from glucose, excellent excellent enantioselectivity enantioselecti wasvity measured was measured (96% ee) (Table(96% ee)5, entry (Table 1) 5, [59 entry,60] . 1)Investigating [59,60]. Investigating the substituent the substituent effect on theeffect outcome on the ofoutcome the reaction of the revealed reaction thatrevealed the selec- that thetivity selectivity of catalyst of catalyst20h depends 20h depends on the on substrate. the substrate. The highest The highest asymmetric asymmetric induction induction was wasobserved observed in the in the case case of 4-nitro-,of 4-nitro-, 4-chloro- 4-chloro- and and 4-methoxychalcone 4-methoxychalcone (89%, (89%, 88%88% and 97% ee, respectively) (Table 55,, entriesentries 2–4).2–4). Interestingly,Interestingly, when,when, insteadinstead ofof aa phenylphenyl group,group, aa heteroaromatic group (furan-2-yl or thiophen-2-yl) was introduced next to the carbonyl group of the chalcone, the Michael addition resultedresulted in enantiomerically pure products (Table5 5,, entriesentries 5 5 and and 6) 6) [ 60[60].].

Scheme 12. Michael addition of chalcones ( 49) and diethyl acetoxymalonate (61).

Table 5. EffectEffect of of crown crown ethers ethers in the in theMichael Michael addition addition of chalcones of chalcones (49) and (49 )diethyl and diethyl acetoxymalo- acetoxy- natemalonate (61). (61). Entry Ar1 Ar2 Catalyst Yield, % ee, % Entry Ar1 Ar2 Catalyst Yield, % ee, % 1 C6H5 C6H5 20h 72 96 1 C H C H 20h 72 96 2 C6H6 5 5 4-O2N-C6 6H5 4 20h 73 89 2 C6H5 4-O2N-C6H4 20h 73 89 3 C6H5 4-Cl-C6H4 20h 76 88 3 C6H5 4-Cl-C6H4 20h 76 88 4 C6H5 4-H3CO-C6H4 20h 73 97 4 C6H5 4-H3CO-C6H4 20h 73 97 5 Furan-2-yl C6H5 20h 75 99 5 Furan-2-yl C6H5 20h 75 99 66 Tiophen-2-yl Tiophen-2-yl C C6H6H5 5 20h20h 7676 9999 77 C C6H6H5 5 CC6H6H5 5 26d26d 5858 9999 88 C C6H6H5 5 CC6H6H5 5 26f26f 6767 9898 99 C C6H6H5 5 4-O4-O2N-C2N-C6H64H 4 26d26d 5555 9494 1010 C C6H6H5 5 4-O4-O2N-C2N-C6H64H 4 26f26f 8585 9999

1111 C C6H6H5 5 4-H4-H3CO-C3CO-C6H64H 4 26d26d 6969 9999 1212 C C6H6H5 5 4-H4-H3CO-C3CO-C6H64H 4 26f26f 4242 8888 1313 C C6H6H5 5 CC6H6H5 5 38a38a 6868 9696 14 C H 4-Cl-C H 38c 76 99 14 C6H6 5 5 4-Cl-C6H6 4 4 38c 76 99 15 C6H5 4-H3CO-C6H4 38e 33 99 15 C6H5 4-H3CO-C6H4 38e 33 99

InIn the the reaction of acetoxymalonate 61, lariat ethers 26d and 26f containing galactose unit showed high enantioselectivity in many many cases. The The addition addition reaction reaction of of chalcone chalcone ( (4949,, 1 2 Ar1 == Ar Ar2 =C=C6H6H5)5 resulted) resulted in in 99% 99% ee ee in in the the presence presence of of 26d26d bearingbearing a a hydroxypropyl side arm, and 98% 98% ee ee using using 26f26f havinghaving a a methoxypropyl methoxypropyl substituent substituent (Table (Table 55,, entriesentries 77 andand 8). Among the substituted products products,, the 4-nitro and 4-methoxy derivatives were prepared with the highest ee values (in the case of 26d: 94% and 99%, in the case of 26f:: 99% and 88%) (Table 5 5,, entriesentries 9–12)9–12) [[34].34]. Threitol-based crowncrown compounds compounds generated generated at leastat least moderate moderate enantioselectivity enantioselectivity when 1 2 whendifferent different chalcones chalcones were used.were Inused. the In case the of case chalcone of chalcone (49, Ar (49=,Ar Ar1 =C= Ar6H2 5=C), lariat6H5), lariat ether 38a containing the di-O-methyl threitol moiety was the most effective (96% ee) (Table5, entry 13), while catalysts 38c and 38e yielded the substituted products 62 with the highest 1 2 1 ee values (38c: 99% ee for 62 Ar = C6H5, Ar = 4-Cl-C6H4; 38e: 99% ee for 62 Ar = C6H5, 2 Ar = 4-H3CO-C6H4) (Table5, entries 14 and 15) [43]. Chemistry 2021, 3, FOR PEER REVIEW 17

ether 38a containing the di-O-methyl threitol moiety was the most effective (96% ee) (Ta- Chemistry 2021, 3 ble 5, entry 13), while catalysts 38c and 38e yielded the substituted products 62 with the566 highest ee values (38c: 99% ee for 62 Ar1 = C6H5, Ar2 = 4-Cl-C6H4; 38e: 99% ee for 62 Ar1 = C6H5, Ar2 = 4-H3CO-C6H4) (Table 5, entries 14 and 15) [43].

2.2.6. MIRC Reaction of Chalcones When an electron deficient deﬁcient olefin oleﬁn is reacted with a compound that possesses both a leaving group group and an acidic hydrogen on the same carbon atom, is a so-called Michael- initiated ringring closureclosure (MIRC)(MIRC) reaction.reaction. Applying Applying chalcones chalcones (49 (49) as) as Michael Michael acceptors, acceptors, chiral chi- ralcyclopropane cyclopropane compounds compounds64 were 64 were synthesized synthesized with with good good enantioselectivity enantioselectivity (up (up to 99% to 99% ee) ee)using using diethyl diethyl bromomalonate bromomalonate (63 )(63 (Scheme) (Scheme 13). 13). Only Only the theanti anti(trans (trans) isomer) isomer of 64 of could64 could be beisolated isolated in allin all experiments. experiments.

Scheme 13. Michael-initiated ring closure (MIRC) reaction of chalcones (61)) andand diethyldiethyl bromomalonatebromomalonate ((6464).).

In the reaction of chalcone (49, Ar1 = Ar2 =C H ), lariat ether 20h derived from glucose In the reaction of chalcone (49, Ar1 = Ar2 =C66H55), lariat ether 20h derived from glucose showed goodgood enantioselectivityenantioselectivity (88% (88% ee) ee) (Table (Table6, entry 6, entry 1). When 1). When chalcone chalcone analogues analogues were wereused underused under the same the same conditions, conditions, the substituents the substituents affected affected thecatalytic the catalytic activity activity of 20h of. Except for two compounds (49, Ar1 = 4-O N-C H , Ar2 = C H 99% ee and 49, Ar1 = C H , 20h. Except for two compounds (49, Ar12 = 4-O6 2N-C4 6H4, Ar6 2 =5, C6H5, 99% ee and 49, Ar6 1 5= Ar2 = thiophen-2-yl, 94% ee) enatiomeric excess decreased (Table6, entries 2 and 3) [ 59,61]. C6H5, Ar2 = thiophen-2-yl, 94% ee) enatiomeric excess decreased (Table 6, entries 2 and 3) [59,61]. Table 6. Effect of crown ethers in the MIRC reaction of chalcones (49) and diethyl bromomalonate (63).

TableEntry 6. Effect of crownAr ethers1 in the MIRCAr reaction2 of chalconesCatalyst (49) and diethyl Yield, %bromomalonate ee, % (63). 1 C6H5 C6H5 20h 28 88 1 2 Entry2 4-O2AN-Cr 6H4 C6HA5 r Catalyst20h Yield,77 % ee, 99 % 1 3C C66HH55 Thiophen-2-ylC6H5 20h20h 5728 9488 2 44-O2 CN-C6H56H4 C6HC56H5 26d20h 3277 9899 5 C H C H 26f 35 99 3 C66H55 Thiophen-2-yl6 5 20h 57 94 6 C6H5 C6H5 38a 31 98 4 C6H5 C6H5 26d 32 98 7 C6H5 C6H5 38c 28 99 5 C6H5 C6H5 26f 35 99 8 C6H5 C6H5 38e 33 86 6 C6H5 C6H5 38a 31 98 7 C6H5 C6H5 38c 28 99 8Applying methylC6Hα5 -D-galactoside-basedC6H5 crown ethers,38e both 26d and33 26f generated86 1 2 product 64 (Ar = Ar =C6H5) in excellent optical purity (98% and 99%, respectively) (TableApplying6, entries methyl 4 and 5) α [-34D-galactoside-based]. crown ethers, both 26d and 26f generated productLariat 64 (Ar ethers1 = Ar38a2 =C, 38c6H5and) in excellent38e with optical a hydroxypropyl purity (98% sideand 99%, arm andrespectively) threitol moiety (Table 6,proved entries to 4 be and also 5) outstanding[34]. catalysts in this cyclopropanation. Presence of methyl (38a) or benzyl Lariat ( 38c ethers) groups 38a, 38c in theandsugar 38e with unit a ledhydroxypropyl to high enantioselectivity side arm and (98%threitol and moiety 99%, provedrespectively) to be also (Table outstanding6, entries 6catalysts and 7), in while this cyclopropanation. using macrocycle Presence38e containing of methyl a 1,4-di- (38a) Oor-butyl benzyl threitol (38c) groups sub-unit, in the a somewhat sugar unit lowerled to enantioselectivityhigh enantioselectivity was observed(98% and (86%99%, ee)respectively)(Table6, entry (Table 8) [43 6,]. entries 6 and 7), while using macrocycle 38e containing a 1,4-di-O- butyl threitol sub-unit, a somewhat lower enantioselectivity was observed (86% ee) (Table 2.2.7. MIRC Reaction of Arylidenemalononitriles 6, entry 8) [43]. To simplify the outcome of the MIRC reaction (i.e., the number of possible isomers), 2.2.7.benzylidenemalononitrile MIRC Reaction of Arylidenemalononitriles (65, Ar = C6H5) was used to form new cyclopropane derivatives 66 (Scheme 14). Depending on the substituents of the aromatic ring, crown 20h generated To simplify the outcome of the MIRC reaction (i.e., the number of possible isomers), enantiomeric excess up to 99% [59,61]. Interestingly, the asymmetric induction generated benzylidenemalononitrile (65, Ar = C6H5) was used to form new cyclopropane derivatives by catalyst 20h was low (32% ee) when an unsubstituted Michael acceptor (65, Ar = C6H5) was used (Table7, entry 1). The best ee values (92% and 99%) were obtained in the reaction of 4-methyl- and 3,4-methylenedioxy-substituted benzylidenemalononitrile (65,

Ar = 4-H3C-C6H4 and 3,4-methylenedioxy-C6H3, respectively) (Table7, entries 2 and 3). Chemistry 2021, 3, FOR PEER REVIEW 18

66 (Scheme 14). Depending on the substituents of the aromatic ring, crown 20h generated enantiomeric excess up to 99% [59,61]. Interestingly, the asymmetric induction generated by catalyst 20h was low (32% ee) when an unsubstituted Michael acceptor (65, Ar = C6H5) was used (Table 7, entry 1). The best ee values (92% and 99%) were obtained in the reaction Chemistry 2021, 3 567 of 4-methyl- and 3,4-methylenedioxy-substituted benzylidenemalononitrile (65, Ar = 4- H3C-C6H4 and 3,4-methylenedioxy-C6H3, respectively) (Table 7, entries 2 and 3).

SchemeScheme 14. Michael-initiated 14. Michael-initiated ring ring closure closure reac reactiontion of of aryliden arylidenemalononitrilesemalononitriles (65 )(65 and) and diethyl diethyl bromomalonate bromomalonate (63). (63).

TableTable 7. Effect 7. Effect of crown of crown ethers ethers in in the the MIRC MIRC reaction ofof arylidenemalononitriles arylidenemalononitriles (65) ( and65) diethyland diethyl bromomalonatebromomalonate (63 (63). ). Entry Ar Catalyst Yield, % ee, % Entry Ar Catalyst Yield, % ee, % 1 C6H5 20h 82 32 1 C6H5 20h 82 32 2 4-H3C-C6H4 20h 74 92 2 34-H 3,4-OCH3C-C26O-CH4 6H3 20h20h 5974 99 92 4 C H 26f 84 78 3 3,4-OCH2O-C6 5 6H3 20h 59 99 5 4-H3C-C6H4 26f 86 98 4 6C 4-H6H3C-C5 6H4 27e26f 8184 99 78 38a 5 74-H 3-H3C-C3C-C6H64H 4 26f 7486 99 98 8 4-H3C-C6H4 38a 76 99 6 4-H3C-C6H4 27e 81 99 9 4-H3C-C6H4 39a 70 96 7 103-H 4-H3C-C3C-C6H64H 4 40a38a 8074 98 99 11 4-H3C-C6H4 40b 87 99 8 4-H3C-C6H4 38a 76 99 12 C6H5 44a 83 86 9 4-H3C-C6H4 39a 70 96 10 Galactose-based4-H macrocycles3C-C6H4 proved to be highly40a efﬁcient in this cyclopropanation.80 98 In11 the presence of crown4-H3 compoundC-C6H4 26f, the product40b66 (Ar = C6H5) was87 formed in an ee99 of12 78% (Table7, entry 4),C while6H5 using substituted 6544aderivatives, the examined83 ones were86 mostly obtained with higher enantioselectivity (e.g., in case of 66 Ar = 4-H3C-C6H4, 98% ee) (Table7, entry 5) [ 34]. Among the β-series of catalysts prepared from galactose, application Galactose-based macrocycles proved to be highly efficient in this cyclopropanation. of 44a resulted in the highest asymmetric induction (86% ee) (Table7, entry 12) [46]. In the presenceLariat ethers of crown synthesized compound from sugar 26f, alcoholsthe product (mannitol 66 (Ar or threitol) = C6H5) showed was formed diverse in an ee of 78%activity. (Table Mannitol-containing 7, entry 4), while crown using ethers substituted27e, 39a, 40a 65 andderivatives,40b gavecyclopropane the examined66 (Arones were mostly= 4-H obtained3C-C6H4 )with with excellenthigher enanti enantioselectivityoselectivity (99%, (e.g., 96%, in 98%case and of 99%66 Ar ee, = respectively) 4-H3C-C6H4, 98% ee) (Table(Table7 7,, entries entry 65) and [34]. 9–11) Among [ 44]. Usingthe β-series threitol-based of catalysts38a as prepared the catalyst, from an ee galactose, value of appli- cation99% of was 44a achieved resulted in in the the case highest of 3-methyl- asymmetric and 4-methyl-substituted induction (86% ee) Michael (Table acceptor 7, entry66 12) [46]. (Table7 , entries 7 and 8) [43]. In threitol-based compounds 38a–f, the groups attached Lariat ethers synthesized from sugar alcohols (mannitol or threitol) showed diverse to the chiral carbon atoms are rather simple, yet the outcome of the reaction is highly activity.inﬂuenced Mannitol-containing by these substituents. crown ethers 27e, 39a, 40a and 40b gave cyclopropane 66 (Ar = 4-H3C-C6H4) with excellent enantioselectivity (99%, 96%, 98% and 99% ee, respectively)2.2.8. (Table MIRC 7, Reaction entries of 6 Arylidene-1,3-Diphenylpropane-1,3-Diones and 9–11) [44]. Using threitol-based 38a as the catalyst, an ee value of Reactions99% was ofachieved arylidene-1,3-diphenylpropane-1,3-diones in the case of 3-methyl- and 4-methyl-substituted (67) and diethyl bromoma- Michael ac- ceptorlonate 66 ((Table63) resulted 7, entries in cyclopropane 7 and 8) derivatives [43]. In threitol-based68 with only one compounds stereogenic center 38a– asf, wellthe groups (Scheme 15). Replacement of the nitrile groups to benzoyl functions in the previous reac- attachedtion, resultedto the inchiral lower carbon ee values. atoms Glucose-based are rather crown simple, ether yet20h thegenerated outcome 60% of ee (Tablethe reaction8, is highlyentry influenced 1). Substitution by these on the substituents. arylidene unit had a negative impact on the enantioselectivity of crown 20h [59,61]. 2.2.8. MIRC Reaction of Arylidene-1,3-Diphenylpropane-1,3-Diones Reactions of arylidene-1,3-diphenylpropane-1,3-diones (67) and diethyl bromomalonate (63) resulted in cyclopropane derivatives 68 with only one stereogenic center as well (Scheme 15). Replacement of the nitrile groups to benzoyl functions in the previous reaction, resulted in lower ee values. Glucose-based crown ether 20h generated 60% ee (Table

Chemistry 2021, 3, FOR PEER REVIEW 19

8, entry 1). Substitution on the arylidene unit had a negative impact on the enantioselec- Chemistry 2021, 3, FOR PEER REVIEW 19 tivity of crown 20h [59,61].

Chemistry 2021, 3 568 8, entry 1). Substitution on the arylidene unit had a negative impact on the enantioselectivity of crown 20h [59,61].

Scheme 15. Michael-initiated ring closure reaction of arylidene-1,3-diphenylpropane-1,3-diones (67) and diethyl bromomalonate (63).

Macrocycle 26d, the galactose analogue of 20h, showed the same efficiency (60% ee) SchemeScheme 15. Michael-initiated 15. Michael-initiated(Table ring ring closure8, closureentry reaction reaction1), while of arylidene-1,3-diphenylpropane-1,3-dionesarylidene-1,3-diphenylpropane-1,3-diones 26f having a methoxypropyl group (67) and instead(67 diethyl) and bromoma- ofdiethyl hydroxypropyl, bromo- malonatelonate (63). ( 63). generated higher enantioselectivity (76% ee) (Table 8, entry 3 [34]). Crown ether 28b derived from mannose and threitol-based catalyst 38e, both con- Table 8. Effect of crown ethers in the MIRC reaction of arylidene-1,3-diphenylpropane-1,3-diones tainingMacrocycle hydroxypropyl 26d, the side galactose arm, had analogue similar activity of 20h, toshowed 20h (54% the and same 57% efficiency ee, respectively) (60% ee) (67) and diethyl bromomalonate (63). (Table(Table 8,8, entriesentry 1),4 and while 5) [43,61].26f having a methoxypropyl group instead of hydroxypropyl, generatedEntry higher enantioselectivity Ar (76% Catalyst ee) (Table 8, entry Yield, %3 [34]). ee, %

Table Crown8. Effect1 etherof crown 28b ethers derived C6H in5 the from MIRC mannose reaction20h andof arylidene-1,3-diphenylpropane-1,3-diones threitol-based52 catalyst 60 38e, both con- (taining67) and hydroxypropyldiethyl2 bromomalonate side C6H arm,5 (63). had similar26d activity to 20h46 (54% and 57% 60ee, respectively) 3 C H 26f 67 76 (Table 8, entries 4 and 5) [43,61].6 5 Entry 4 ArC6H 5 28b Catalyst 35 Yield, % 54 ee, % 5 C6H5 38e 38 57 Table 8.1 Effect of crown ethersC6H 5in the MIRC reaction20h of arylidene-1,3-diphenylpropane-1,3-diones52 60 2 C6H5 26d 46 60 (67) and diethylMacrocycle bromomalonate26d, the galactose (63). analogue of 20h, showed the same efﬁciency (60% ee) (Table3 8, entry 1), whileC626fH5 having a methoxypropyl26f group instead67 of hydroxypropyl,76 Entry Ar Catalyst Yield, % ee, % generated4 higher enantioselectivityC6H5 (76% ee) (Table28b8, entry 3 [34]). 35 54 1 C6H5 20h 52 60 5 Crown ether 28b derivedC6H5 from mannose and38e threitol-based catalyst3838e , both contain-57 ing2 hydroxypropyl sideC arm,6H5 had similar activity26d to 20h (54% and 57%46 ee, respectively)60 (Table8, entries 4 and 5) [43,61]. 2.2.9. MIRC3 Reaction of ArylideneC6H5 Indane-1,3-Diones26f 67 76 4 C6H5 28b 35 54 2.2.9.Cyclopropanation MIRC Reaction ofof Arylidene arylidene Indane-1,3-Diones indane-1,3-diones (69) (Scheme 16) resulted in chiral 5 C6H5 38e 38 57 compoundsCyclopropanation 70 with good of arylideneenantiomeric indane-1,3-diones excess in (the69) (Schemepresence 16 )of resulted carbohydrate-based in chiral crowncompounds ethers. When70 with glucopyranoside-based good enantiomeric excess lariat in the ether presence 20h ofwas carbohydrate-based used in the reaction of 2.2.9.crown MIRC ethers. Reaction When of glucopyranoside-based Arylidene Indane-1,3-Diones lariat ether 20h was used in the reaction of benzylidene indane-1,3-dione (69, Ar = C6H5), only moderate enantiomeric excess was benzylidene indane-1,3-dione (69, Ar = C H ), only moderate enantiomeric excess was Cyclopropanation of arylidene indane-1,3-diones6 5 (69) (Scheme 16) resulted in chiral measuredmeasured (56%) (56%) (Table (Table 9,9, entry 1).1). Altering Altering the the substrate substrate to other to other arylidene arylidene derivatives, derivatives, highercompoundshigher ee values ee 70 values with were were good obtained obtained enantiomeric in in general. general. excess Presence Presence in oftheof a a nitropresence nitro group group of in carbohydrate-based eachin each position position in- creasedcrownincreased ethers. the generated the When generated glucopyranoside-based asymmetric asymmetric induction induction (70–93%lariat ether ee) ee) (Table (Table20h9 was, entries 9, entriesused 2–4) in [2–4)61 the]. [61].reaction of benzylidene indane-1,3-dione (69, Ar = C6H5), only moderate enantiomeric excess was measured (56%) (Table 9, entry 1). Altering the substrate to other arylidene derivatives, higher ee values were obtained in general. Presence of a nitro group in each position increased the generated asymmetric induction (70–93% ee) (Table 9, entries 2–4) [61].

Scheme Scheme16. Michael-initiated 16. Michael-initiated ring ringclosure closure reacti reactionon of of arylidene arylidene indane-1,3-dionesindane-1,3-diones (69 )(69 and) and diethyl diethyl bromomalonate bromomalonate (63). (63).

Crown ether 27e synthesized from diisopropylidene mannitol showed the same efficiency (56% ee) (Table 9, entry 5) as 20h derived from glucose [44]. Scheme 16. Michael-initiated ringThe closure highest reacti enantioselectivityon of arylidene indane-1,3-diones was generated ( 69by) and β-galactoside-based diethyl bromomalonate catalysts (63). 44a, 44b and 44c (91%, 96% and 95% ee, respectively) (Table 9, entries 6–8). As can be seen, the Crown ether 27e synthesized from diisopropylidene mannitol showed the same efficiency (56% ee) (Table 9, entry 5) as 20h derived from glucose [44]. The highest enantioselectivity was generated by β-galactoside-based catalysts 44a, 44b and 44c (91%, 96% and 95% ee, respectively) (Table 9, entries 6–8). As can be seen, the

Chemistry 2021, 3 569

Chemistry 2021, 3, FOR PEER REVIEWTable 9. Effect of crown ethers in the MIRC reaction of arylidene indane-1,3-diones (69) and diethyl20

bromomalonate (63).

Entry Ar Catalyst Yield, % ee, % substituent of the anomeric center did not have a significant effect on the selectivity in this 20h MIRC reaction1 [46]. C6H5 33 54 2 2-H3C-C6H4 20h 59 79 3 3-O2N-C6H4 20h 43 70 Table 9. Effect of crown ethers in the MIRC reaction of arylidene indane-1,3-diones (69) and di- 4 4-O2N-C6H4 20h 83 93 ethyl bromomalonate (63). 5 C6H5 27e 72 56 6 C H 44a 77 91 Entry 6 Ar5 Catalyst Yield, % ee, % 7 C6H5 44b 76 96 6 5 1 8 CC6HH5 44c 20h 7133 9554 2 2-H3C-C6H4 20h 59 79 3 3-O2N-C6H4 20h 43 70 Crown ether 27e synthesized from diisopropylidene mannitol showed the same efﬁ- ciency4 (56% ee) (Table4-O9, entry2N-C6 5)H4 as 20h derived20h from glucose [44].83 93 The5 highest enantioselectivityC6H5 was generated27e by β-galactoside-based72 catalysts56 44a, 44b and6 44c (91%, 96% andC6H 95%5 ee, respectively)44a (Table 9, entries 6–8).77 As can be seen,91 the substituent7 of the anomericC6H center5 did not have a44b signiﬁcant effect on76 the selectivity96 in this MIRC8 reaction [46]. C6H5 44c 71 95

2.2.10.2.2.10. MIRC MIRC Reaction Reaction of of Arylidene Arylidene Cyanosulfones Cyanosulfones AsymmetricAsymmetric cyclopropanation cyclopropanation of of cyanosulfones cyanosulfones 7171 waswas carried carried out out in inthe the presence presence of glucose-of glucose- and and galactose-based galactose-based catalysts catalysts (Schem (Schemee 17) 17 )[[27].27]. Only Only one one of of the the diastereomers was formed formed in in all all cases. cases. Comparing Comparing the the carboh carbohydrateydrate unit, unit, the thecatalysts catalysts containing containing a ga- a lactosidegalactoside moiety moiety were were slightly slightly more more efficien efﬁcient.t. Among Among the glucose-containing the glucose-containing crown crownethers 20qethers bearing20q bearing 2-(3,4-dimethoxyphenyl)ethyl 2-(3,4-dimethoxyphenyl)ethyl substituent substituent on the on nitrogen the nitrogen proved proved to be to the be mostthe most effective effective (73% (73% ee) (Table ee) (Table 10, entry10, entry 1). 1).

SchemeScheme 17. 17. Michael-initiatedMichael-initiated ring ring closure closure reaction of arylidene cyanosulfones 71 and diethyl bromomalonate (63).

TableTable 10. EffectEffect of of crown crown ethers ethers in in the the MIRC MIRC reaction reaction of ofarylidene arylidene cyanosulfones cyanosulfones 71 and71 and diethyl diethyl bromomalonatebromomalonate ( 63).).

EntryEntry Ar Ar Catalyst Catalyst Yield, Yield, % % ee, ee, % % 1 C6H5 20q 94 73 1 C6H5 20q 94 73 2 3-Cl-C6H4 20q 91 84 2 3-Cl-C6H4 20q 91 84 3 3 3-H3-H33C-CC-C66HH44 20q 20q 9090 8181 4 4 4-O4-O22N-CN-C6H6H44 20q 20q 8787 8282 5 5Naphthalen-2-yl Naphthalen-2-yl 20q 20q 9292 8585 6 C6H5 26g 95 76 6 C6H5 26g 95 76 7 C6H5 26h 93 80 6 5 7 8 CC6HH5 44g 26h 9093 7280 8 C6H5 44g 90 72 Again, the structure of the substrate has a high impact on the enantioselectivity, Again, the structure of the substrate has a high impact on the enantioselectivity, cy- cyclopropane derivative 72 (Ar = naphthalen-2-yl) was formed with highest ee value (85%) clopropane derivative 72 (Ar = naphthalen-2-yl) was formed with highest ee value (85%) (Table 10, entry 5). Substituents on the phenyl ring of 71 in the meta or para position (Tablehad a 10, positive entry effect5). Substituents on the asymmetric on the phenyl induction ring of (e.g.,71 in 3-chlorophenylthe meta or para position72: 84% had ee; 3-a positivemethylphenyl effect 72on: 81%the ee;asymmetric 4-nitrophenyl induction72: 82% (e.g., ee) (Table 3-chlorophenyl 10, entries 2–4),72: 84% while ee;ortho 3-- methylphenylsubstituted 72 72derivatives: 81% ee; were4-nitrophenyl obtained 72 as:almost 82% ee) racemic (Tablemixtures. 10, entries 2–4), while ortho- substituted 72 derivatives were obtained as almost racemic mixtures. While catalyst 26h derived from methyl α-D-galactoside gave the best result in the reaction of 71 (Ar = C6H5) (80% ee) (Table 10, entry 7), its β-phenyl-galactopyranoside-

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While catalyst 26h derived from methyl α-D-galactoside gave the best result in the reaction of 71 (Ar = C6H5) (80% ee) (Table 10, entry 7), its β-phenyl-galactopyranoside- based analogue 44g generated a slightly lower ee value (72%) (Table 10, entry 8). In addi- based analogue 44gbasedgenerated analogue a slightly 44g generated lower ee a value slightly (72%) lower (Table ee 10value, entry (72%) 8). In (Table addition 10, entry 8). In addition to the 2-(3,4-dimethoxyphenyl)ethyl substituent, 26g with a 2-(2-methoxy- to the 2-(3,4-dimethoxyphenyl)ethyltion to the 2-(3,4-dimethoxyphenyl)ethyl substituent, 26g with a 2-(2-methoxyphenyl)ethyl substituent, 26g with side a 2-(2-methoxyphenyl)ethyl side chain was also effective (76% ee) (Table 10, entry 6). chain was also effectivephenyl)ethyl (76% ee) side (Table chain 10 was, entry also 6). effective (76% ee) (Table 10, entry 6). 2.2.11. Michael Addition of Methyl Vinyl Ketone 2.2.11. Michael Addition2.2.11. Michael of Methyl Addition Vinyl Ketoneof Methyl Vinyl Ketone Itoh and Shirakami investigated the Michael addition of a glycine derivative (73) to Itoh and ShirakamiItoh investigated and Shirakami the Michaelinvestigated addition the Michael of a glycine addition derivative of a glycine (73) to derivative (73) to methyl vinyl ketone (74) in the presence of glucose-based crown ethers (Scheme 18) [62]. methyl vinyl ketonemethyl (74) vinyl in the ketone presence (74) of in glucose-based the presence of crown glucose-based ethers (Scheme crown 18 ethers)[62]. (Scheme 18) [62]. Crown ether 24d inspired the mentioned researchers to investigate the structure-activity Crown ether 24dCrowninspired ether the mentioned24d inspired researchers the mentioned to investigate researchers the to structure-activity investigate the structure-activity relationship of monoaza-15-crown-5 compounds. Macrocycles 76 and 77 being analogous relationship of monoaza-15-crown-5relationship of monoaza-15-cr compounds.own-5 Macrocycles compounds.76 and Macrocycles77 being analogous 76 and 77 being analogous to 24d were synthesized from methyl 4,6-O-benzylidene-glucopyranoside (19) in 5–7 to 24d were synthesizedto 24d fromwere methylsynthesized 4,6-O-benzylidene-glucopyranoside from methyl 4,6-O-benzylidene-glucopyranoside (19) in 5–7 steps. (19) in 5–7 steps. In crown compound76 76, the macro ring is attached to the 3,4 positions of the sugar In crown compoundsteps. In, the crown macro compound ring is attached 76, the macro to the 3,4ring positions is attached of theto the sugar 3,4 positions unit, of the sugar whileunit, while in catalyst in catalyst77, the 77 crown, the crown and the and pyranoside the pyranoside ring isring annulated is annulated in the in 4,6 the positions. 4,6 posi- unit, while in catalyst 77, the crown and the pyranoside ring is annulated in the 4,6 posi- Comparisontions. Comparison the effect the ofeffect24d ,of76 24dand, 7677 andin the 77 reaction in the reaction of glycine of glycine derivative derivative73 and methyl73 and tions. Comparison the effect of 24d, 76 and 77 in the reaction of glycine derivative 73 and vinylmethyl ketone vinyl (ketone74) gave (74 interesting) gave interesting results. Applicationresults. Application of 24d as of the 24d phase as the transfer phase catalysttransfer methyl vinyl ketone (74) gave interesting results. Application of 24d as the phase transfer resultedcatalyst resulted in the formation in the formation of the S enantiomerof the S enantiomer of 75 (72% of 75 ee), (72% while ee), in while the presence in the presence of 76, R catalyst resulted in the formation of the S enantiomer of 75 (72% ee), while in the presence antipodeof 76, R antipode was formed was in formed excess in (60% excess ee). Surprisingly,(60% ee). Surprisingly, crown compound crown compound77 was ineffective, 77 was of 76, R antipode was formed in excess (60% ee). Surprisingly, crown compound 77 was aineffective, racemic mixture a racemic was mixture obtained. was obtained. ineffective, a racemic mixture was obtained.

Scheme 18.18. Michael addition of glycine derivative 7474 toto methylmethyl vinylvinyl ketoneketone 75.75. Scheme 18. Michael addition of glycine derivative 74 to methyl vinyl ketone 75.

2.2.12. Darzens Condensations 2.2.12. Darzens Condensations2.2.12. Darzens Condensations 1 Asymmetric Darzens reaction of 2-chloroacetophenone (78, Ar = C6H5) and benzal-1 Asymmetric DarzensAsymmetric reaction ofDarzens 2-chloroacetophenone reaction of 2-chloroacetophenone (78, Ar1 = C H ) and (78, benzalde- Ar = C6H5) and benzaldehyde (79, Ar2 = C6H5) was first investigated in the presence of glucose-based6 5 azacrown 2 dehyde (79, Ar2 = C6H5) was first investigated in the presence of glucose-based azacrown hydeethers ( 7920a, Ar–g in= 1997 C6H (Scheme5) was ﬁrst 19). investigated Catalyst 20g inbearing the presence a hydroxyethyl of glucose-based chain showed azacrown mod- 20a g ethers 20a–g in 1997 (Scheme20g 19). Catalyst 20g bearing a hydroxyethyl chain showed mod- etherserate enantioselectivity– in 1997 (Scheme (42%) (Table19). Catalyst 11, entry 1), bearingwhich could a hydroxyethyl be increased chain by lowering showed moderate enantioselectivityerate enantioselectivity (42%) (Table 11 (42%), entry (Table 1), which 11, entr couldy 1), be which increased could by loweringbe increased by lowering the temperature of the reaction to −22 °C. The synthesis was diastereoselective, only the the temperature ofthe the temperature reaction to of− 22the◦ C.reaction The synthesis to −22 °C. was The diastereoselective, synthesis was di onlyastereoselective, the only the formation of the anti (trans) product 80 was observed [50]. Replacement of the hydroxy- formation of theformationanti (trans )of product the anti80 (transwas) observedproduct 80 [50 was]. Replacement observed [50]. of Replacement the hydrox- of the hydroxyethyl moiety in compound 20g to a hydroxypropyl group led to increased enantiomeric yethyl moiety inethyl compound moiety20g in tocompound a hydroxypropyl 20g to a grouphydroxypropyl led to increased group enantiomericled to increased enantiomeric excess (20h, 62% ee) (Table 11, entry 2) [24]. The presence of the free hydroxyl group in excess (20h, 62% ee)excess (Table (20h 11, ,62% entry ee) 2) (Table [24]. The 11, presence entry 2) of[24]. the The free presence hydroxyl of group the free in the hydroxyl group in the side chain proved to be crucial, when crown ethers bearing a propyl chain with differ- side chain provedthe to side be crucial, chain proved when crown to be crucial, ethers bearingwhen crown a propyl ethers chain bearing with a different propyl chain with different functional groups at the end were tested. Methylation (20j), elongation (20n), and functional groupsent at thefunctional end were groups tested. at Methylation the end were (20j ),tested. elongation Methylation (20n), and (20j changing), elongation (20n), and changing to dimethylamino (20m) or phenylthiocarbamido (20o) groups led to a signifi- changing to dimethylamino (20m) or phenylthiocarbamido (20o) groups led to a significant decrease in enantioselectivity [26]. cant decrease in enantioselectivity [26].

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Chemistry 2021, 3, FOR PEER REVIEW 22 to dimethylamino (20m) or phenylthiocarbamido (20o) groups led to a signiﬁcant decrease in enantioselectivity [26].

SchemeScheme 19.19. Darzens condensation ofof aromaticaromatic 2-chloroketones2-chloroketones ((7878)) andand benzaldehydesbenzaldehydes ((7979).).

Table 11. Effect of crown ethersTable 11.in theEffect Darzens of crown condensation ethers in theof aromatic Darzens 2-chloroketones condensation of ( aromatic78) and benzaldehydes 2-chloroketones (79 (78). ) and benzaldehydes (79). Entry Ar1 Ar2 Catalyst Temp., °C Yield, % ee, % 1 2 ◦ 1 C6H5 Entry Ar C6H5 Ar 20g Catalyst22 Temp., C Yield,93 % ee,42 %

2 C6H5 1 C6H5 C6H5 C6H5 20h 20g 22 2274 9362 42 2 C H C H 20h 22 74 62 3 Furan-2-yl 6 5 C6H5 6 5 20h -5 55 54 3 Furan-2-yl C6H5 20h −5 55 54 4 Furan-2-yl 4 Furan-2-yl 2-Cl-C6H4 2-Cl-C6H4 20h 20h -5 −577 7770 70 − 5 Thiophen-2-yl5 Thiophen-2-yl C6H5 C6H5 20h 20h -5 563 6371 71 6 Thiophen-2-yl 3,4-OCH2O-C6H3 20h −5 57 86 6 Thiophen-2-yl 3,4-OCH2O-C6H3 20h -5 57 86 7 Thiophen-3-yl C6H5 20h −5 53 52 7 Thiophen-3-yl8 Pyrrol-2-yl C6H5 C6H5 20h 20h -5 −553 3352 36 9 1-Methyl-pyrrol-2-yl C6H5 20h −5 72 16 8 Pyrrol-2-yl C6H5 20h -5 33 36 10 4-Phenyl-C6H4 C6H5 20h 20 54 96 9 1-Methyl-pyrrol-2-yl11 C6H5 C6H5 C6H5 20h 23g -5 2272 6816 74 12 C H C H 26d 22 81 28 10 4-Phenyl-C6H4 6 5 C6H5 6 5 20h 20 54 96 13 C6H5 C6H5 30a 22 75 48 11 C6H5 14 C6H5 C6H5 C6H5 23g 40a 22 2268 5774 62 12 C6H5 15 C6H5 C6H5 C6H5 26d 41a 22 2281 9428 73 16 C6H5 C6H5 44d 22 81 64 13 C6H5 C6H5 30a 22 75 48 17 C6H5 C6H5 45a 0 65 77 14 C6H5 18 C6H5 C6H5 C6H5 40a 46 22 057 6162 72 15 C6H5 C6H5 41a 22 94 73 16 C6H5 Altering the protectiveC6H5 group in the 4,644d position of the22 carbohydrate81 inﬂuenced64 the 17 C6H5 catalytic activity of glucose-basedC6H5 crown ethers45a negatively0 (e.g., catalyst65 30a bearing77 a 1 2 18 C6H5 naphthylidene moietyC gave6H5 product 80 (Ar 46= Ar = C6H5)0 in an ee of 48%61 under the72 same conditions) (Table 11, entry 13) [39]. TheAltering substituent the protective in the anomeric group in positionthe 4,6 po ofsition glucose of the had carbohydrate only a small influenced impact on thethe enantioselectivity.catalytic activity of When glucose-based the alkoxy crown group ethers was innegative the axially (e.g., position catalyst (α-series), 30a bearing slightly a highernaphthylidene ee values moiety were measured gave product than in80 the (Ar case1 = Ar of 2β =-substituted C6H5) in an derivatives. ee of 48% under The best the result same 1 wasconditions) obtained (Table in the 11, reaction entry 2-chloroacetophenone13) [39]. (78, Ar = C6H5) and benzaldehyde (79, 2 Ar =The C6H substituent5) by using in crown the anomeric ether 41a position(73% ee) of (Table glucose 11, entryhad only 15) [a45 small]. impact on the enantioselectivity.Heteroaromatic When chloroketones the alkoxy were group synthesized was in the and axial then position investigated (α-series), in Darzens slightly condensationhigher ee values with were aromatic measured aldehydes than in in the the presence case of ofβ-substituted crown ether derivatives.20h [57,63]. TheThe tem-best perature of the reactions was lowered to −5 ◦C to reach higher enantiomeric excess. When result was obtained in the reaction 2-chloroacetophenone (78, Ar1 = C6H5) and benzalde- 2-chloroacetylfuran (78, Ar1 = furan-2-yl) and benzaldehyde was reacted (79, Ar2 = C H ), hyde (79, Ar2 = C6H5) by using crown ether 41a (73% ee) (Table 11, entry 15) [45]. 6 5 moderateHeteroaromatic asymmetric chloroketones induction was were observed synthesized (54% ee) and (Table then 11 investigated, entry 3) (Scheme in Darzens 19). Using substituted benzaldehydes, in general, the ee values were higher (e.g., 80 with condensation1 with aromatic2 aldehydes in the presence of crown ether 20h [57,63]. The Artemperature= furan-2-yl of ,the Ar reactions= 2-Cl-C was6H4 :lowered 70% ee) to (Table −5 °C 11 to, entry reach 4). higher An inverse enantiomeric trend was excess. observed for 2-chloracetylthiophene (78, Ar1 = thiophen-2-yl). In this case, a substituent on the When 2-chloroacetylfuran (78, Ar1 = furan-2-yl) and benzaldehyde was reacted (79, Ar2 = aldehyde lowered the enantioselectivity, with one exception (80 with Ar1 = thiophen-2-yl, C6H5), moderate asymmetric induction was observed (54% ee) (Table 11, entry 3) (Scheme Ar2 = C H : 70% ee; 80 with Ar1 = thiophen-2-yl, Ar2 = 3,4- methylenedioxy-C H : 86% 19). Using6 5substituted benzaldehydes, in general, the ee values were higher (e.g.,6 803 with ee) (Table 11, entries 5 and 6). Moving the chloroacetyl group to the 3 position of the Ar1 = furan-2-yl, Ar2 = 2-Cl-C6H4: 70% ee) (Table 11, entry 4). An inverse trend was ob- thiophene ring (78, Ar1 = thiophen-3-yl) led to lower optical purity (52% ee) (Table 11, served for 2-chloracetylthiophene (78, Ar1 = thiophen-2-yl). In this case, a substituent on entry 7). When pyrrol or 1-methylpyrrol analogues were reacted with benzaldehyde,1 the aldehyde lowered the enantioselectivity,1 with one exception2 (80 with Ar = thiophen- the selectivity of 20h was weak (80 with Ar = pyrrol-2-yl, Ar = C6H5: 36% ee; 80 with 2-yl, Ar2 = C6H5: 70% ee; 80 with Ar1 = thiophen-2-yl, Ar2 = 3,4- methylenedioxy-C6H3: 86% Ar1 = 1-methylpyrrol-2-yl, Ar2 = 3,4- methylenedioxy-C H : 16% ee) (Table 11, entries ee) (Table 11, entries 5 and 6). Moving the chloroacetyl group6 3 to the 3 position of the thi- 8 and 9). ophene ring (78, Ar1 = thiophen-3-yl) led to lower optical purity (52% ee) (Table 11, entry

Chemistry 2021, 3, FOR PEER REVIEW 23

7). When pyrrol or 1-methylpyrrol analogues were reacted with benzaldehyde, the selectivity of 20h was weak (80 with Ar1 = pyrrol-2-yl, Ar2 = C6H5: 36% ee; 80 with Ar1 = 1- methylpyrrol-2-yl, Ar2 = 3,4- methylenedioxy-C6H3: 16% ee) (Table 11, entries 8 and 9). Chemistry 2021, 3 572 The highest enantioselectivity was reached when 4′-phenyl-2-chloroacetophenon was reacted with benzaldehyde using glucose-based lariat ether 20h (product 80 with Ar1 = 4-phenyl-C6H4, Ar2 = C6H5: 96% ee) (Table 11, entry 10) (Scheme 19). With other aromatic 0 aldehydes,The highest lower enantioselectivity ee values were wasmeasured reached [64]. when 4 -phenyl-2-chloroacetophenon was reactedInvestigation with benzaldehyde of the efficiency using of glucose-based lariat ethers lariat23a–h ether, which20h contain(product a β80-phenylwith gluco- Ar1 = 4-phenyl-C H , Ar2 = C H : 96% ee) (Table 11, entry 10) (Scheme 19). With other side unit, demonstrated6 4 again6 5that the side chain has a significant impact on the asymmet- aromatic aldehydes, lower ee values were measured [64]. ric induction.Investigation While of the catalysts efficiency 23a of– lariatd with ethers a hydrocarbon23a–h, which substituent contain a β-phenyl on the nitrogen gluco- atom sidewere unit, ineffective demonstrated (4–12% again ee), that using the side23g chainwith hasa hydroxypropyl a significant impact group, on the 74% asymmetric ee was measured induction.(Table 11, Whileentry 11) catalysts [28,29].23a –d with a hydrocarbon substituent on the nitrogen atom were ineffectiveExperiments (4–12% with ee), galactose- using 23gcontainingwith a hydroxypropyl macrocycles group, had 74%similar ee was results. measured Catalyst 26d (Tablewith a11 hydroxypropyl, entry 11) [28,29]. side arm and a α-methyl group was inferior (26% ee) (Table 11, entryExperiments 12) to crown with compound galactose-containing 44d, which macrocycles have the hadsame similar side results.arm, but Catalyst a β-phenyl26d group within C-1 a hydroxypropyl(73% ee) (Table side 11, armentry and 16) a [46].α-methyl group was inferior (26% ee) (Table 11, entry 12) to crown compound 44d, which have the same side arm, but a β-phenyl group in In the case of mannitol-based crown compounds, it was found again that in addition C-1 (73% ee) (Table 11, entry 16) [46]. to theIn theside case arm, of mannitol-basedthe protecting crown group compounds, also influenced it was found the generated again that inenantioselectivity. addition toWith the sidethe exception arm, the protecting of compound group also40a influencedwith cyclohexylidene the generated moiety enantioselectivity. (62% ee) (Table With 11, en- thetry exception14), low ee of compoundvalues were40a measuredwith cyclohexylidene in the Darzens moiety reaction (62% ee) [44]. (Table 11, entry 14), low eeWhen values the were effect measured of xylal- in theand Darzens arabinal-based reaction [ 44crown]. ethers 45–48 were compared, cat- alystsWhen 47a, the 47b effect andof 48 xylal- derived and from arabinal-based L- and D crown-arabinal ethers were45 –ineffective.48 were compared, Application of catalystscrown ethers47a, 47b 45aand and48 46aderived, which from areL mirror- and D -arabinalimages of were each ineffective. other, resulted Application in good enan- oftiomeric crown ethersexcess45a (77%and and46a 72%,, which respectively) are mirror images(Table 11, of eachentries other, 17 and resulted 18) [47]. in good enantiomeric excess (77% and 72%, respectively) (Table 11, entries 17 and 18) [47]. In addition to 2-chloroacetyl derivatives, cyclic chloroketones were also applied in In addition to 2-chloroacetyl derivatives, cyclic chloroketones were also applied in DarzensDarzens condensations condensations in thein the presence presence of lariat of lariat ether ether20h containing 20h containing glucose glucose (Scheme (Scheme 20). 20). In the reaction of 2-chloroindanone (81, n = 0) with benzaldehyde2 (79, Ar2 = C6H5), 65% ee In the reaction of 2-chloroindanone (81, n = 0) with benzaldehyde (79, Ar = C6H5), 65% ee waswas obtained obtained (Table (Table 12 ,12, entry entry 1). In1). the In casethe case of substituted of substituted aromatic aromatic aldehydes, aldehydes, no clear no clear 2 2 tendencytendency was was observed. observed. The The best best selectivity selectivity was 85%was ee85% (79 ,ee Ar (79=,2-Cl-C Ar =6 2-Cl-CH4) (Table6H4 )12 (Table, 12, entryentry 2). 2). When When 2-chlorotetralone 2-chlorotetralone (81 ,(n81=, 1)n = was 1) tested,was tested, the highest the highest ee value ee was value 74% was in 74% in thethe productproduct82 82(Ar (Ar = C=6 HC56H) (Table5) (Table 12, entry12, entry 3). Any 3). changesAny changes on the on aromatic the aromatic part of thepart of the aldehydealdehyde decreased decreased the the measured measured optical optical purity purity [64]. [64].

SchemeScheme 20. 20.Darzens Darzens condensation condensation of of 2-chloroindanone 2-chloroindanone (81, (n81=, n 0), = and0), and of 2-chlorotetralone of 2-chlorotetralone (81, (81, n = n1).= 1).

TableTable 12. 12.Effect Effect of of crown crown ethers ethers in the in Darzensthe Darzen condensations condensation of 2-chloroindanone of 2-chloroindanone (81, n = 0), (81 and, n of= 0), and 2-chlorotetraloneof 2-chlorotetralone (81, n (=81 1)., n = 1).

◦ EntryEntry n n Ar Ar Catalyst Catalyst Temp., Temp.,C °C Yield, % Yield, ee,% % ee, % 11 0 0 C6H5 C 6H5 20h20h 00 5959 65 65 2 0 2-Cl-C6H4 20h 0 52 85 2 0 2-Cl-C6H4 20h 0 52 85 3 1 C6H5 20h −10 84 74 3 1 C6H5 20h −10 84 74 2.2.13. Epoxidations 2.2.13. Epoxidations 1 2 Asymmetric epoxidation of chalcone (49, Ar = Ar =C6H5) was ﬁrst investigated usingAsymmetric glucose- and mannose-basedepoxidation of catalystschalcone (Scheme (49, Ar 121 =)[ Ar362]. =C While6H5) screeningwas first investigated the side us- arms,ing glucose- it was found and mannose-based that a free hydroxyl catalysts group (Sch is requiredeme 21) to [36]. gain While good enantioselectivity. screening the side arms, The reaction was diastereoselective, only the anti (trans) isomer could be isolated. Catalyst

Chemistry 2021, 3, FOR PEER REVIEW 24

Chemistry 2021, 3 it was found that a free hydroxyl group is required to gain good enantioselectivity.573 The reaction was diastereoselective, only the anti (trans) isomer could be isolated. Catalyst 20g with a hydroxyethyl group generated 81% ee (Table 13, entry 1), while lariat ether 20h 20gbearingwith a a hydroxypropyl hydroxyethyl group moiety generated showed 81% even ee (Tablehigher 13 efficiency, entry 1), (92% while ee) lariat (Table ether 13, entry 20h2). Similarbearing aresults hydroxypropyl were experienced moiety showed in th evene case higher of mannose-bas efficiency (92%ed ee)crown (Table ethers, 13, com- entrypounds 2). 28a Similar and results28b proved were experiencedto be the most in theefficient case of (72% mannose-based and 80% ee, crown respectively) ethers, (Table compounds13, entries 928a andand 10).28b Itproved is interesting, to be the that most catalysts efficient derived (72% and from 80% ee,mannose respectively) preferred the (Tableformation 13, entries of the 9 and2S,3 10).R enantiomer, It is interesting, while that 2R catalysts,3S antipode derived was from in mannose excess in preferred the case of glu- the formation of the 2S,3R enantiomer, while 2R,3S antipode was in excess in the case of cose-based catalysts. It is worth to mention that glucose and mannose differs only in the glucose-based catalysts. It is worth to mention that glucose and mannose differs only in theconfiguration configuration of ofC-2, C-2, therefor thereforee in the casecase of of glucose, glucose,anti anti-annulation-annulation can can be observed be observed be- betweentween the the monosaccharide monosaccharide and and the the crown crown ring, ring, while while in the in case the of case mannose, of mannose, there is athere is a synsyn-annulation.-annulation. This This difference difference can can be thebe reasonthe reason why differentwhy different enantiomers enantiomers are formed are formed duringduring the the epoxidation epoxidation reaction. reaction.

Scheme 21. 21.Liquid-liquid Liquid-liquid two two phase phase epoxidation epoxidation of chalcones of chalcones (49). (49).

Table 13.ComparisonEffect of crown of ethers the effect in the epoxidationof catalysts of chalconescontaining (49 ).a methyl glucoside (20h), a methyl Entry Ar1 mannoside (28bAr)2 and a methylCatalyst altroside Temp.,(29) moiety◦C in Yield,the epoxidation % ee, reaction % was carried out not only with chemical experiments but using molecular modeling as well [38]. 1 C6H5 C6H5 20g 5 65 81 2 C6H5 Crown compoundC6H5 29 was ineffective20h regarding5 the asymmetric 82 induction 92 (Table 13, entry 3 4-Cl-C6H411). This is, inC 6fact,H5 very interesting;20h because0 of the anti-annulation 71 of the 97 carbohydrate 4 3-O2N-C6Hunit4 and the macroC6H5 ring, catalyst20h 29 was expected0 to be effective, 55 but as 99the results of the 5 C H 2,4-di-Cl-C H 20h 0 50 99 6 5 in silico experiments6 3revealed, that the annulation is only one of the factors that affect the 6 1-Methylpyrrol-2-yl C6H5 20h −5 80 79 7 C6H5 enantioselectivity.C6H5 23g 20 51 76 8 C6H5 ComparingC6H the5 effect of the26d protecting group20 in glucose-based 35 crown 53 ethers, macro- 28a S R 9 C6H5 cycle 20h withC 6aH benzylidene5 group was the most5 effective 70 (92% ee) (Table 72 (2 ,3 13,) entry 2), in 10 C6H5 C6H5 28b 5 72 80 (2S,3R) 11 C6H5 the case of a naphthylideneC6H5 unit29 (30a) the enantioselectivity5 51 was almost the 5 same (89% ee) 12 C6H5 (Table 13, entryC6H 12),5 but when30a an isopropylidene0 moiety (31a 46) was in the 89 4,6 position, the 13 C6H5 measured ee valueC6H5 decreased 31ato 67% (Table 13,0 entry 13) [39]. 59 67 14 C H C H 41a 20 96 94 6 5 The anomeric6 5 position also had an impact on the asymmetric induction. Selectivity 15 C6H5 C6H5 41b 20 93 93 16 C6H5 of the α-alkylC analogues6H5 of 20h42a was retained20 (41a: 94% ee; 87 41b: 93% ee) 84(Table 13, entries 17 C6H5 14 and 15), whileC6H5 catalysts of 44athe β-series were20 less selective 71 (e.g., 42a: 84% 59 ee) (Table 13, 18 C H C H 44d 20 81 64 6 5 entry 16) [45]. 6Crown5 ether 23g containing a phenoxy group in equatorial position also 19 C6H5 C6H5 45a 0 65 77 (2S,3R) 20 C6H5 generatedNaphthalen-2-yl lower enantioselectivity45a (76% ee) (Table0 13, entry 72 7) than macrocycle 96 (2S,3R) 20h [33]. 21 C6H5 C6H5 46 0 61 72 Table 13. Effect of crown ethers in the epoxidation of chalcones (49). 20h Entry Ar1 Comparison of theAr effect2 of catalysts Catalyst containing a methyl Temp., glucoside °C Yield, ( ), a% methyl ee, % mannoside (28b) and a methyl altroside (29) moiety in the epoxidation reaction was carried 1 C6H5 out not only with chemicalC6H5 experiments but using20g molecular modeling5 as well65 [38 ]. Crown 81 2 C6H5 compound 29 was ineffectiveC6H5 regarding the20h asymmetric induction5 (Table 1382, entry 11). 92 3 4-Cl-C6HThis4 is, in fact, very interesting;C6H5 because of20h the anti-annulation0 of the carbohydrate71 unit 97 4 3-O2N-C6Hand4 the macro ring, catalystC6H5 29 was expected20h to be effective,0 but as the results55 of the in 99 silico experiments revealed, that the annulation is only one of the factors that affect the 5 C6H5 2,4-di-Cl-C6H3 20h 0 50 99 enantioselectivity. 6 1-Methylpyrrol-2-yl C6H5 20h -5 80 79 Comparing the effect of the protecting group in glucose-based crown ethers, macro- 7 C6H5 cycle 20h with a benzylideneC6H5 group was the23g most effective (92%20 ee) (Table 1351, entry 2), in 76 8 C6H5 C6H5 26d 20 35 53 9 C6H5 C6H5 28a 5 70 72 (2S,3R)

Chemistry 2021, 3 574

the case of a naphthylidene unit (30a) the enantioselectivity was almost the same (89% ee) (Table 13, entry 12), but when an isopropylidene moiety (31a) was in the 4,6 position, the measured ee value decreased to 67% (Table 13, entry 13) [39]. The anomeric position also had an impact on the asymmetric induction. Selectivity of the α-alkyl analogues of 20h was retained (41a: 94% ee; 41b: 93% ee) (Table 13, entries 14 and 15), while catalysts of the β-series were less selective (e.g., 42a: 84% ee) (Table 13, entry 16) [45]. Crown ether 23g containing a phenoxy group in equatorial position also generated lower enantioselectivity (76% ee) (Table 13, entry 7) than macrocycle 20h [33]. Alteration on the anomeric center led to different ee values in the case of galactose- based crown ethers. The enantioselectivity was higher when the substituent of C-1 was equatorial. While catalyst 26d derived from methyl α-D-galactoside, which is analogous to glucose-based 20h, generated an ee of 53% (Table 13, entry 8), using its β-analogue 44a led to a slightly higher enantiomeric excess (59%) (Table 13, entry 17). In case of catalyst 1 2 44d bearing a β-phenyl group, the epoxidation of chalcone (49, Ar = C6H5, Ar = C6H5), resulted in 64% ee (Table 13, entry 18) [46]. The structure of the substrate inﬂuenced the outcome of the epoxidation as well. 0 1 Crown ether 20h showed high enantioselectivity, when 4 -chloro- (49, Ar = 4-Cl-C6H4, 2 0 1 2 Ar = C6H5), 3 -nitro- (49, Ar = 3-O2N-C6H4, Ar = C6H5) or 2,4-dichlorochalcone 1 2 (49, Ar = C6H5, Ar =2,4-di-Cl-C6H4) was used (97%, 99% and 99% ee, respectively) (Table 13, entries 3–5) [65]. In case of unsaturated ketones containing a 1-methylpyrrol subunit, lariat ether 20h generated good enantiomeric excess (e.g., 79% ee in case of 61, 1 2 Ar = 1-methylpyrrol-2-yl, Ar = C6H5) (Table 13, entry 6) [63]. From crown ethers 45–48 containing unsaturated carbohydrate units, only the xylal- based 45a and 46 resulted in an optically active product 80. While catalyst 45a derived 1 2 from D-xylal generated the 2S,3R enantiomer of 80 (Ar = C6H5, Ar = C6H5) with 77% ee, application of crown ether 46 synthesized from L-xylal led to the formation of the 2R,3S antipode in an ee value of 72% ee (Table 13, entries 19 and 21). Using chalcone analogues, various enantiomeric excess was observed in the presence of lariat ether 45a. The best 1 2 selectivity was obtained in the case of compound 80 (Ar = C6H5, Ar = naphthalen-2-yl) (96% ee) (Table 13, entry 20) [47].

3. Conclusions A variety of chiral crown ethers containing one or two sugar units in annulation with the macrocyclic ring have been synthesized from monosaccharides (such as D-glucose, D-mannose, D-galactose, D-altrose, L-arabinose, etc.) and sugar alcohols (L-threitol, D- mannitol). These chiral macrocycles were tested as phase transfer catalysts in asymmetric reactions (in liquid-liquid and solid-liquid phase systems). A few representatives of the monosaccharide-based crown ethers induced a considerable asymmetric induction in certain reactions. It turned out, that there is no universally applicable catalyst for each reaction, viz. in each asymmetric reaction, different catalysts showed the best results. It was found that the type of the carbohydrate, the substituents on the sugar unit and on the nitrogen atom of the crown ring (side arms) have significant influence on both the chemical yield and the enantioselectivity. Based on the experiments, monoaza-15-crown-5 lariat ethers incorporating a D-glucose, or a D-galactose moiety proved to be the most efficient catalysts. Sugar-based catalysts with a (CH2)3OH substituent on the nitrogen atom resulted in the best enantioselectivity in the liquid–liquid phase reactions. In solid–liquid reactions, (CH2)3OCH3 and 2-(3,4- dimethoxyphenyl)ethyl groups also enhanced the asymmetric induction. Development of novel catalysts is of practical importance, as the lariat ethers can be utilized in phase transfer catalytic reactions, a part of which is to be explored. The chiral compounds synthesized using carbohydrate-based catalysts are important intermediates in the chemical industry. Chemistry 2021, 3 575

Funding: This research received no external funding. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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