The Stoichiometry, Structure and Possible Formation of Crystalline Diastereomeric Salts

S S symmetry

Article The Stoichiometry, Structure and Possible Formation of Crystalline Diastereomeric Salts

Dorottya Fruzsina Bánhegyi and Emese Pálovics *

Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary; [email protected] * Correspondence: [email protected]

Abstract: Knowing the eutectic composition of the binary melting point phase diagrams of the

diastereomeric salts formed during the given resolution, the achievable F (F = eeDia*Y) value can be calculated. The same value can also be calculated and predicted by knowing the eutectic compositions of the binary melting point phase diagrams of enantiomeric mixtures of the racemic compound or the resolving agent. An explanation was sought as to why and how the crystalline precipitated diastereomeric salt—formed in the solution between a racemic compound and the corresponding resolving agent—may be formed. According to our idea, the self-disproportionation of enantiomers (SDE) has a decisive role when the enantiomers form two nonequal ratios of conformers in solution. The self-organized enantiomers form supramolecular associations having M and P helicity, and double helices are formed. Between these double spirals, with the formation of new double spirals, a dynamic equilibrium is achieved and the salt crystallizes. During this process between acids and bases, chelate structures may also be formed. Acids appear to have a crucial impact on these structures. It is assumed that the behavior of each chiral molecule is determined by its own code. This code validates the combined effect of constituent atoms, bonds, spatial structure, charge distribution, ﬂexibility and complementarity. Citation: Bánhegyi, D.F.; Pálovics, E. The Stoichiometry, Structure and Keywords: predictable resolution; supramolecular associations; helical structure; eutectic Possible Formation of Crystalline composition Diastereomeric Salts. Symmetry 2021, 13, 667. https://doi.org/10.3390/ sym13040667

Academic Editor: Takashiro Akitsu 1. Introduction When a racemic mixture (SR) reacts in a solution with a suitable chiral compound (R*), Received: 25 March 2021 depending on the solvent, one of the diastereomers precipitates (e.g., crystalline SR*) and Accepted: 9 April 2021 the other remains in solution (RR* solution). The multiplication of the purity (eeDia) and Published: 13 April 2021 yield (Y) of the enantiomeric mixture, which is isolated from the precipitated diastereomer, gives the selectivity (F = eeDia*Y). F corresponds to the enantiomeric ratio of the mixture Publisher’s Note: MDPI stays neutral (in addition to the racemic ratio). with regard to jurisdictional claims in When the binary melting point phase diagram of the racemic mixture is constructed, published maps and institutional afﬁl- a relationship between the eutectic composition (eeEu) and the results can be observed iations. (Figure1)[1]. We have also shown experimentally [1] that under certain conditions the purity of the enantiomeric mixtures separable from the precipitated diastereomeric salt is approximately equal to the eutectic composition of the enantiomeric mixtures of the racemic compound or Copyright: © 2021 by the authors. the eutectic composition of the enantiomeric mixtures of the resolving agent (eeDia~eeEuRac Licensee MDPI, Basel, Switzerland. or eeDia~eeEuRes). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Symmetry 2021, 13, 667. https://doi.org/10.3390/sym13040667 https://www.mdpi.com/journal/symmetry Symmetry 2021, 13, x FOR PEER REVIEW 2 of 13 Symmetry 2021, 13, 667 2 of 12

𝐹= 𝑒𝑒 ∙𝑌∙10

1−2𝑒𝑒 𝐹= 𝑒𝑒 ∙𝑌= 1−𝑒𝑒

𝑒𝑒 𝑐𝑟𝑦𝑠𝑡. ≈𝑒𝑒 𝑜𝑟 𝑒𝑒

FigureFigure 1.1.Binary Binary melting melting point point phase phase diagram diagram of diastereomeric of diastereomeric mixtures and mixtures stoichiometry and of stoichiometry of diastereomers (eeeuRac: ee of an enantiomer at the eutectic composition of the racemic compound; diastereomers (eeeuRac: ee of an enantiomer at the eutectic composition of the racemic compound; eeeuRes: ee of the resolving agent enantiomer (R) at the eutectic composition; eeDia: ee of the enan- eeeuRes: ee of the resolving agent enantiomer (R) at the eutectic composition; eeDia: ee of the enantio- tiomer of the original racemic compound at the eutectic composition of the diastereoisomeric salt). mer of the original racemic compound at the eutectic composition of the diastereoisomeric salt). The enantiomers—whose separation possibilities are summarized in this article—have been usedWe have for the also synthesis shown of active experimentally pharmaceutical ingredients[1] that under (Jumex, certain prostaglandins, conditions the purity of aspartame, Chlorocid, antibiotics). During the resolution of these compounds, further theinsights enantiomeric have been added mixtures to our previous separable knowledge. from the precipitated diastereomeric salt is approximately equal to the eutectic composition of the enantiomeric mixtures of the racemic com- 2. The Stoichiometry of the Crystalline Diastereomeric Salt May Be Determined by poundthe Eutectic or Compositionthe eutectic of composition Either the Racemic of the Compound enantiomeric or the Resolving mixtures Agent of the resolving agent (eeDiaBased~eeEuRac on our or owneeDia [2~ee–4] andEuRes others’). experimental results regarding the self- dispropor- tionationThe of enantiomers—whose enantiomers (SDE) [5–16], weseparation were looking possibili for an explanationties are ofsummarized the possible in this article— havemechanism been forused the for distribution the synthesis of the enantiomericof active pharmaceutical diastereomeric mixtures ingredients between (Jumex, prostaglan- solid–liquid phases. dins,However, aspartame, there wasChlorocid, no explanation antibiotics). of how it Duri is possibleng the to formresolution the eutectic of these com- compounds, fur- therposition insights of the singlehave enantiomerbeen added resolving to our agent previous from the knowledge. enantiomers of the racemic compound present. We believe that this is only possible if at least two reactive conformers of the single enantiomer resolving agent react with the enantiomers of the racemic 2.compound. The Stoichiometry of the Crystalline Diastereomeric Salt May Be Determined by the EutecticIt was demonstrated Composition that two of typesEither of the conformers Racemic are involvedCompound in the or crystalline the Resolving Agent structureBased of the on enantiomers, our own roughly [2–4] mimickingand others’ the stabilityexperi ofmental the corresponding results regarding racemic the self-dispro- structure [17]. Racemic toﬁzopam tends to form an 82:18 (major/minor) conformer ra- portionationtio immediately of in enantiomers chloroform solution. (SDE) The [5–16], single we enantiomer were looking is also capable for an of explanation this of the pos- siblephenomenon, mechanism but it takes for the 48 h distribution if its enantiomeric of the pair en is notantiomeric present [18 ].diastereomeric mixtures between solid–liquidIt was also phases. shown that in the crystal structure of the diastereomeric salt, the resolving agent (sodium salt of cis-2-hydroxycyclopent-4-enyl acetic acid (CPN) intermediate of the prostaglandinHowever, F2α synthesis)there was participates no explanation with two conformers of how it in is a possible ratio of 59:41 to and form thus the eutectic compo- sitionachieves of high the purity single of theenantiomer corresponding resolving enantiomer agent from from the racemic the enantiomers compound in the of the racemic com- pounddiastereomer present. (Figure We2)[ 19believe]. that this is only possible if at least two reactive conformers of the single enantiomer resolving agent react with the enantiomers of the racemic compound. It was demonstrated that two types of conformers are involved in the crystalline structure of the enantiomers, roughly mimicking the stability of the corresponding racemic structure [17]. Racemic tofizopam tends to form an 82:18 (major/minor) conformer ratio immediately in chloroform solution. The single enantiomer is also capable of this phenomenon, but it takes 48 h if its enantiomeric pair is not present. [18]. It was also shown that in the crystal structure of the diastereomeric salt, the resolving agent (sodium salt of cis-2-hydroxycyclopent-4-enyl acetic acid (CPN) intermediate of the prostaglandin F2α synthesis) participates with two conformers in a ratio of 59:41 and thus achieves high purity of the corresponding enantiomer from the racemic compound in the diastereomer (Figure 2) [19]. Symmetry 2021, 13, x FOR PEER REVIEW 3 of 13 Symmetry 2021, 13, 667 3 of 12

Figure 2. Separation of 1-phenylethan-1-amine hydrochloride (PhEA) enantiomers by the sodium salt of (1S,5R)-CPN Figure 2. Separationand perspective of 1-phenyletha view of the asymmetricn-1-amine unit hydrochloride in the (R)-PhEA. (PhEA)(1S-5R)- enantiomersCPN salt aggregate. by the Thick sodium lines indicatesalt of ( major1S,5R)-CPN and perspective (conformerview of the A with asymmetric 59% population) unit whilein the thin (R lines)-PhEA. the minor(1S-5R (conformer)-CPN salt B with aggregate. 41% population) Thick orientationlines indicate in the major (conformer A withhydroxycyclopentenyl 59% population) part while of the anion. thin lines the minor (conformer B with 41% population) orientation in the hy- droxycyclopentenyl part of the anion. Accordingly, the assumption has been proved that the stoichiometry of the diastereomeric salts formed by the reaction of the racemic compound with the resolving agent Accordingly,can be determined the by assumption the racemic compound has been or proved the resolving that the agent. stoichiometry It may also provide of the diastere- omericthe salts stoichiometry formed by of the the diastereomer reaction of by the the racemic ratio of the compound resolving agent with conformers the resolving (eeDia agent can value). This is illustrated by a generalized example and ﬁgure (Figure3). be determinedTwo conformers by the racemic (M and P) compound of each chiral or molecule the resolving are formed agent. in the reaction It may mixture also provide the stoichiometryof the resolution of the and diastereomer form supramolecular by the helicalratio structures.of the resolving The ratio agent of conformers conformers (eeDia value).depends This is on illustrated the eutectic compositionby a generalized (M:P~ee Diaexample). Therefore, and ee figureEuRes have (Figure the potential 3). to determine the stoichiometry of the crystalline precipitation. The reaction of racemic methamphetamine (2-methylamino-1-phenylpropane, MeAn) with (R,R)-tartaric acid (TA) (Figure4) produces the ( R)-MeAn.(R,R)-TA diastereomeric salt from an aqueous solution. From the diastereomeric salt, (R)-MeAn (eeDia: 95%) can be isolated with high purity. Based on single-crystal X-ray diffraction of the diastereomeric salt (Figure5), the crystalline ( R)-MeAn.(R,R)-TA forms an antiparallel double helix. SymmetrySymmetry2021 2021, 13, 13, 667, x FOR PEER REVIEW 4 of4 of13 12

FigureFigure 3. 3.Possibilities Possibilities of of reactions reactions between between thethe racemicracemic compoundcompound (SR) and the resolving resolving agent agent (R*) (R*) for for putative putative eutectic eutectic compositions—acompositions—a hypothetical hypothetical example. example. SymmetrySymmetry 2021 2021, 13, ,13 x FOR, x FOR PEER PEER REVIEW REVIEW 5 of5 13of 13

TwoTwo conformers conformers (M (M and and P) P)of ofeach each chiral chiral mo moleculelecule are are formed formed in inthe the reaction reaction mixture mixture of ofthe the resolution resolution and and form form supramolecular supramolecular he helicallical structures. structures. The The ratio ratio of ofconformers conformers de- de- pendspends on on the the eutectic eutectic composition composition (M:P~ (M:P~ ee Diaee).Dia Therefore,). Therefore, ee eeEuResEuRes have have the the potential potential to tode- de- terminetermine the the stoichiometry stoichiometry of ofthe the crystalline crystalline precipitation. precipitation. TheThe reaction reaction of ofracemic racemic methamphetam methamphetamineine (2-methylamino-1-phenylpropane, (2-methylamino-1-phenylpropane, MeAnMeAn) with) with (R,R (R,R)-tartaric)-tartaric acid acid (TA (TA) (Figure) (Figure 4) 4)produces produces the the (R ()-RMeAn)-MeAn.(R,R.(R,R)-TA)-TA diastere- diastere- omericomeric salt salt from from an an aqueous aqueous soluti solution.on. From From the the diastereomeric diastereomeric salt, salt, (R ()-RMeAn)-MeAn (ee (eeDia:Dia 95%): 95%) cancan be be isolated isolated with with high high purity. purity. Based Based on on si ngle-crystalsingle-crystal X-ray X-ray diffraction diffraction of ofthe the diastere- diastere- Symmetry 2021, 13, 667 5 of 12 omericomeric salt salt (Figure (Figure 5), 5), the the crystalline crystalline (R ()-RMeAn)-MeAn.(R,R.(R,R)-TA)-TA forms forms an an antiparallel antiparallel double double he- he- lix.lix.

FigureFigure 4. Resolution4. Resolution of of methamphetamine methamphetamine (2-methylamino-1-phenylpropane) (2-methylamino-1-phenylpropane) with with (R,R (RR,R)-tartaric,R)-tartaric)-tartaric acid. acid.acid.

FigureFigure 5. The5. TheThe packing packing packing arrangement arrangement arrangement of of(R of )-(RMeAn (R)-MeAn)-MeAn.(R,R.(R,R.()-RTA,)-RTA)- viewedTA viewedviewed along along along the the b the axis. b axis. b axis.Dotted Dotted Dotted lines lines lines representrepresent C-H…O C-H…O C-H . .contacts . Ocontacts contacts 1–5 1–5 [20]. 1–5 [20]. [20 ].

TheThe reaction reaction mixture mixture contains contains the the supr supr supramolecularamolecularamolecular helical helical associates associates of of(R ()-RMeAn)-MeAn and and (S)-(SMeAn)-MeAn and andand associates associates associates of of(R,R of (R,R (R)-,TAR)-)-TA,TA which, which, which form form form head-to-foot head-to-foot head-to-foot supramolecular supramolecular supramolecular helical helical helical asas- sociates.sociates.associates. The The Thereaction reaction reaction produces produces produces acidic acidic acidic salt saltsalt forming forming forming supramolecular supramolecular supramolecular helical helical helical associates associates of of (R()-RMeAn)-MeAn and and (R,R ( R,RR)-,RTA)-TA, which,, whichwhich then thenthen form formform an anan antiparallel antiparallelantiparallel double doubledouble helix. helix.helix. Simultaneously,Simultaneously, the the resulting resulting double double helices, helices, also also with with an an antiparallel antiparallel orientation, orientation, reactreact with with the the acidic acidic salt salt forming forming helical helical structures structures and and disintegrate disintegratedisintegrate into into further further double double heliceshelices by by replication. replication. When When the the concentration concentration of of the the double double helix helix structures structures reaches reaches the the limit of the solubility, the crystallization of the (R)-MeAn.(R,R)-TA diastereomeric salt begins (Figures3 and6), which may become autocatalytic. It is reasonable to assume that the structure (code) of the chiral molecules determines the stoichiometry of crystallization and replication of helical supramolecular structures. Simultaneously, it also proves that the formation and replication of antiparallel double helices can occur not only by the formation of covalent bonds but also with secondary binding forces. In addition to the resolution of the racemic bases shown so far, we present the resolutions of other racemic compounds with chiral acids (Table1). It can be seen that the racemic MeAn may be resolved with both (R,R)-DPTA and (R,R)-TA (Table1, Entries 1 and 2); however, in the case of (R,R)-DPTA, lower resolvability was achieved. SymmetrySymmetry 2021 2021, 13, 13, x, FORx FOR PEER PEER REVIEW REVIEW 6 6of of 13 13

SymmetrySymmetry 2021 2021, 13, 13, x, xFOR FOR PEER PEER REVIEW REVIEW 6 6of of 13 13

SymmetrySymmetry 2021 2021, 13, 13, x ,FOR x FOR PEER PEER REVIEW REVIEW 6 of6 of13 13 SymmetrySymmetry 2021 2021, 13, 13, x, FORx FOR PEER PEER REVIEW REVIEW limit limit of of the the solubility, solubility, the the crystallization crystallization of of the the ( R(R)-)-MeAnMeAn.(.(R,RR,R)-)-TATA diastereomeric diastereomeric6 6ofsalt of salt13 13 beginsbegins (Figures (Figures 3 3and and 6), 6), which which may may become become autocatalytic. autocatalytic. Symmetry Symmetry 2021 2021, 13, 13, x ,FOR x FOR PEER PEER REVIEW REVIEW limit limit of of the the solubility, solubility, the the crystallization crystallization of of the the ( R(R)-)-MeAnMeAn.(.(R,RR,R)-)-TATA diastereomeric diastereomeric6 of 6salt of13salt 13 ItIt is is reasonable reasonable to to assume assume that that the the structur structure e(code) (code) of of the the chiral chiral molecules molecules determines determines beginsbegins (Figures (Figures 3 3 and and 6), 6), which which may may become become autocatalytic. autocatalytic. limitthelimitthe stoichiometry ofstoichiometry of the the solubility, solubility, of of crystallization crystallizationthe the crystallization crystallization and and replication ofreplication of the the (R ()-R ofMeAn)- ofMeAn helical helical.(R,R.( R,Rsupramolecular supramolecular)-TA)-TA diastereomeric diastereomeric structures. structures. salt salt ItIt is is reasonable reasonable to to assume assume that that the the structur structure e(code) (code) of of the the chiral chiral molecules molecules determines determines beginslimitSimultaneously,limitbeginsSimultaneously, of (Figuresof (Figuresthe the solubility, solubility, 3 and3it it andalso also 6), 6),the provesthewhich proves which crystallization crystallization maythat thatmay becomethe thebecome formation formationof of autocatalytic.the autocatalytic.the ( R( Rand)- and)-MeAnMeAn replication replication .( .(R,RR,R)-)-TA TAof of diastereomericantiparallel diastereomericantiparallel double double salt salt thethe stoichiometryIt stoichiometry is reasonable of toof crystallization assumecrystallization that the and and structur replication replicatione (code) of of ofhelical helical the chiral supramolecular supramolecular molecules determines structures. structures. beginshelicesbeginshelicesIt (Figures can is (Figurescan reasonable occur occur 3 3 and not andnot to 6),only 6), onlyassume which which by by the maythatthe may formation formation thebecome become structur autocatalytic. of autocatalytic.of ecovalent (code)covalent of bonds thebonds chiral but but moleculesalso also with with secondarydetermines secondary limittheSimultaneously,limitSimultaneously, stoichiometry of of the the solubility, solubility, it ofit also alsocrystallization the provesthe proves crystallization crystallization that that and the the replicationformation formationof of the the (R ( )- Rand ofMeAnand)- MeAnhelical replication replication.(R,R.( supramolecularR,R)-TA)- TAof of diastereomericantiparallel diastereomericantiparallel structures. double double salt salt bindingthebinding ItstoichiometryIt is is forces.reasonable forces.reasonable of to to crystallizationassume assume that that the the and structur structur replicatione e(code) (code) of of helicalof the the chiral chiral supramolecular molecules molecules determines determinesstructures. beginsSimultaneously,helicesbeginshelices (Figures can (Figurescan occur occur 3 itand3 notalso andnot 6), only 6),provesonly which which by by thethatmay the may formation theformationbecome become formation autocatalytic. of autocatalytic.of covalent covalent and replication bonds bonds but but of also antiparallelalso with with secondary secondary double thetheSimultaneously, stoichiometry InstoichiometryIn addition addition to toitof the of also thecrystallization crystallization resolution resolutionproves that of of and the andthethe racemireplication formationracemireplicationc cbases bases ofand of helicalshown helicalshownreplication supramolecularso supramolecularso far, far, ofwe we antiparallel present present structures. structures. the the double reso- reso- helicesbindingbindingIt Itis can is reasonableforces. forces.reasonable occur not to to onlyassume assume by thatthe that formationthe the structur structur ofe (code)covalente (code) of of thebonds the chiral chiral but molecules alsomolecules with determines secondary determines Simultaneously,lutionsSimultaneously,heliceslutions of canof other other occur racemicit racemicit alsonot also onlyproves provescompounds compounds by that thethat formationthe thewith with formation formation chiral chiral of covalentacids andacids and replication (Table replication(Table bonds 1). 1). but It of It ofcan alsocanantiparallel antiparallel be bewith seen seen secondary that double thatdouble the the thebindingthe stoichiometry InstoichiometryIn additionforces. addition to ofto theof crystallizationthe crystallization resolution resolution of ofand the andthe replicationracemi racemireplicationc cbases bases of of helical shown shownhelical supramolecular so supramolecularso far, far, we we present present structures. structures. the the reso- reso- helicesracemicbindinghelicesracemic can MeAncan forces.MeAn occur occur may may not not be beonly onlyresolved resolved by by the the with withformation formation both both ( R,R (ofR,R of )-covalent )-covalentDPTADPTA and bonds andbonds ( R,R(R,R but )-but)-TA TAalso also (Table (Table with with 1, secondary 1, secondaryEntries Entries 1 1 Simultaneously,lutionsSimultaneously,lutionsIn addition of of other other toitracemic racemic italsothe also resolution proves provescompounds compounds that thatof thethe thewith withformationracemi formation chiral chiralc bases acidsand acids and shown replication (Table replication(Table so 1). 1).far, Itof It weof can antiparallelcan antiparallel present be be seen seen the thatdouble that doublereso- the the bindingandbindingand 2); 2);In however, forces.additionhowever, forces. into in thethe the caseresolution case of of ( R,R(R,R of)-)-DPTA theDPTA racemi, lower, lowerc bases resolvability resolvability shown so was was far, achieved. achieved.we present the reso- heliceslutionsracemichelicesracemic canof MeAncan MeAnother occur occur mayracemic maynot not be onlybe only resolved compoundsresolved by by the the with formationwith formation with both both chiral ( R,R(ofR,R of covalent)- )-acidscovalentDPTADPTA (Table andbonds and bonds ( R,R1).( R,Rbut It)-but)- TAcanalsoTA also (Table (Tablebewith withseen 1,secondary 1, secondaryEntriesthat Entries the 1 1 lutionsInIn addition additionof other to racemicto the the resolution resolution compounds of of the the with racemi racemi chiralc cbases bases acids shown shown (Table so so 1). far, far, It we canwe present presentbe seen the the that reso- reso- the bindingracemicandbindingand 2); 2); however,forces.MeAn however, forces. may in in thebe the resolved case case of of ( R,R(withR,R)-)-DPTA bothDPTA (,R,R ,lower lower)-DPTA resolvability resolvability and (R,R was )-wasTA achieved. achieved.(Table 1, Entries 1 lutionslutionsracemicTableTable of1. of 1.MeAn Resolutionsother Resolutionsother racemicmay racemic of beof racemic racemicresolvedcompounds compounds compounds compounds with with withboth with chiralwith chiral(R,R chiral chiral )-acids DPTAacids acids. acids. (Table (Table and (1).R,R 1). It )-It TAcan can (Tablebe be seen seen 1, thatEntries that the the 1 and 2);InIn additionhowever, addition to in to the the the resolution case resolution of (R,R of )-of theDPTA the racemi racemi, lowerc basesc basesresolvability shown shown so sowas far, far, achieved.we we present present the the reso- reso- racemicandracemic 2); MeAnhowever, MeAn may may in bethe be resolved caseresolved of ( R,Rwith with)- DPTAboth both ( R,R,( R,Rlower)-)-DPTADPTA resolvability and and ( R,R(R,R was)-)-TATA achieved. (Table (Table 1, 1, Entries Entries 1 1 EntryEntry RacemicRacemic Bases Baseslutions lutions TableTable of 1. of 1. otherResolutions Resolutionsother Resolving Resolving racemic racemic of of Agentracemic Agentcompoundsracemic compounds compounds compounds with with withchiral with chiral Diastereomer chiral Diastereomer chiral acids acids acids. acids. (Table (Table 1). 1). It Itcan can ee eebeDia Diabe (%)seen (%)seen that thatF F the the Symmetry 2021, 13, 667 andand 2); 2); however, however, in in the the case case of of ( R,R(R,R)-)-DPTADPTA, lower, lower resolvability resolvability was was achieved. achieved.6 of 12 racemicracemicTable 1.MeAn ResolutionsMeAn may may beof be racemicresolved resolved compounds with with both both with (R,R (R,R chiral)-DPTA)-DPTA acids. and and (R,R (R,R)-TA)-TA (Table (Table 1, 1,Entries Entries 1 1 EntryEntry RacemicRacemic Bases Bases Table 1. Resolutions Resolving Resolving of Agent Agentracemic compounds with Diastereomer Diastereomer chiral acids. ee eeDiaDia (%) (%) FF andand 2); 2); however, however, in in the the case case of of (R,R (R,R)-DPTA)-DPTA, lower, lower resolvability resolvability was was achieved. achieved. TableTable 1. 1. Resolutions Resolutions of of racemic racemic compounds compounds with with chiral chiral acids. acids. EntryEntry RacemicRacemic Bases Bases Resolving Resolving Agent Agent Diastereomer Diastereomer ee eeDiaDia (%) (%) F F TableTable 1. 1.Resolutions Resolutions of ofracemic racemic compounds compounds with with chiral chiral acids. acids. 1 1Entry[21–23] Entry[21–23] RacemicRacemicTable Bases Bases 1. Resolutions Resolving of Resolving racemic compoundsAgent Agent with chiral(R( acids.R)- Diastereomer)-MeAn DiastereomerMeAn.(.(R,RR,R)-)-TA TA ee eeDia95Dia95 (%) (%) 0.64F0.64F

1Entry [21–23]Entry RacemicRacemic Bases Bases Resolving Resolving Agent Agent (R Diastereomer)-MeAn Diastereomer.(R,R)- TA ee eeDia95Dia (%) (%) 0.64F F Entry1 [21–23] Racemic Bases Resolving Agent Diastereomer(R)-MeAn.(R,R)-TA ee Dia (%)95 F 0.64

1 [21–23]1 [21–23] (R()-RMeAn)-MeAn.(R,R.(R,R)-TA)-TA 9595 0.640.64

1 1[21–23] [21–23] (R(R)-)-MeAnMeAn.(.(R,RR,R)-)-TATA 9595 0.640.64

1 [211 [21–23]1–23 [21–23]] (R)-MeAn(R()-RMeAn)-.(MeAnR,R)-.(TAR,R.(R,R)-TA)-TA 959595 0.64 0.640.64

2 2[21–23] [21–23] (R(R)-)-MeAnMeAn.(.(R,RR,R)-)-DPTADPTA 68.868.8 0.460.46

2 [21–23] (R)-MeAn.(R,R)-DPTA 68.8 0.46 2 [21–23] (R)-MeAn.(R,R)-DPTA 68.8 0.46

2 [21–23]2 [21–23] (R()-RMeAn)-MeAn.(R,R.(R,R)-DPTA)-DPTA 68.868.8 0.460.46

2 [212 –2[21–23]23 [21–23]] (R)-MeAn(R(R)-)-MeAn.(MeAnR,R)-.(DPTA.(R,RR,R)-)-DPTADPTA 68.8 68.868.8 0.46 0.460.46

2 [21–23]2 [21–23] (R()-RMeAn)-MeAn.(R,R.(R,R)-DPTA)-DPTA 68.868.8 0.460.46

3 3[24] [24] (R(R)-)-FAFA.(.(R,RR,R)-)-DPTADPTA 9696 0.860.86

33 [24] [24] (R(R)-)-FAFA.(.(R,RR,R)-)-DPTADPTA 9696 0.860.86

3 [243 ][24] (R)-FA(R.()-RFA,R)-.(DPTAR,R)-DPTA 9696 0.86 0.86 3 [24] (R)-FA.(R,R)-DPTA 96 0.86

3 3[24] [24] (R(R)-)-FAFA.(.(R,RR,R)-)-DPTADPTA 9696 0.860.86

3 [24]3 [24] (R()-RFA)-FA.(R,R.(R,R)-DPTA)-DPTA 9696 0.860.86

4 [24] (S)-FA.(R)-BFA 99 0.80 4 [24] (S)-FA.(R)-BFA 99 0.80

4 [244] [24] (S)-FA(S.()-R)FA-BFA.(R)-BFA 9999 0.80 0.80 4 [24] (S)-FA.(R)-BFA 99 0.80 Symmetry 2021, 13, x FOR PEER REVIEW 7 of 13 4 [24]4 [24] (S()-SFA)-FA.(R).(R)-BFA-BFA 9999 0.800.80

Symmetry 2021, 13, x FOR PEER REVIEW 7 of 13 4 4[24] [24] (S(S)-)-FAFA.(.(R)R)-BFA-BFA 9999 0.800.80

Symmetry 2021, 13, x FOR PEER REVIEW 7 of 13 Symmetry4 [24]4 [24] 2021 , 13, x FOR PEER REVIEW (S()-SFA)-FA.(R).(R)-BFA-BFA 9999 0.800.807 of 13

5 [255, 526[25,26] [25,26]] (R,R)-(R,RAD(R,R.()-R)-AD,ADR)-.(DPTAD.(R,RR,R)-)-DPTADDPTAD 97 9797 0.93 0.930.93

55 [25,26] [25,26] (R,R(R,R)-)-ADAD.(.(R,RR,R)-)-DPTADDPTAD 9797 0.930.93

5 [25,26] (R,R(R,R)-AD)-AD.(R,R.(R,R)-DPTAD)-DPTAD 97 0.93 5 6[25,26] [27] (R)-ASG.(R,R)-DPTA 86.397 0.930.69

5 5[25,26] [25,26] (R,R(R,R)-)-ADAD.(.(R,RR,R)-)-DPTADDPTAD 9797 0.930.93 6 [27] (R)-ASG.(R,R)-DPTA 86.3 0.69

5 [25,26]5 [25,26] (R,R(R,R)-AD)-AD.(R,R.(R,R)-DPTAD)-DPTAD 9797 0.930.93 6 [27] (R)-ASG.(R,R)-DPTA 86.3 0.69 6 [276] [27] (R)-ASG(R)-.(RASG,R)-DPTA.(R,R)-DPTA 86.386.3 0.69 0.69

7 [19] (R)-FEA.(1S,5R)-CPN 95 0.51 7 [197 ][19] (R)-FEA(R)-.(1FEAS,5.(1R)-S,CPN5R)-CPN 9595 0.51 0.51

7 [19] (R)-FEA.(1S,5R)-CPN 95 0.51 7 [19] (R)-FEA.(1S,5R)-CPN 95 0.51

SymmetrySymmetry 2021, 13, x 667 FOR PEER REVIEW 78 ofof 1213

Figure 6. Retro-synthesis of the crystalline diastereomeric salt.salt.

Another phenylisopropyl derivative (AD) allowed excellent enantiomeric separation using (R,R)-DPTAD (Entry 5). However, free amino acids (FA, ASG) may be resolved effectively using (R,R)-DPTA (Entries 3 and 6), although the carboxyl group was not protected. The free racemic FA also allows good separation with its benzoylated enantiomer Symmetry 2021, 13, x FOR PEER REVIEW 9 of 13

Another phenylisopropyl derivative (AD) allowed excellent enantiomeric separation Symmetry 2021, 13, 667 using (R,R)-DPTAD (Entry 5). However, free amino acids (FA, ASG) may8 of 12 be resolved effectively using (R,R)-DPTA (Entries 3 and 6), although the carboxyl group was not protected. The free racemic FA also allows good separation with its benzoylated enantiomer (Entry 4). In the seven resolutions presented, the stoichiometry of the diastereomeric salts (Entry 4). In the seven resolutions presented, the stoichiometry of the diastereomeric salts (eeDia) was clearly determined by the eutectic composition of the enantiomeric mixtures of (eeDia) was clearly determined by the eutectic composition of the enantiomeric mixtures the resolving agent (eeDia~eeResAg). It is surprising how similar the structures of these dia- of the resolving agent (ee ~ee ). It is surprising how similar the structures of these stereomeric saltsDia are,ResAg as if they were seven-membered ring structures (chelate structure) diastereomeric salts are, as if they were seven-membered ring structures (chelate structure) (Figure 5 and Table 2). (Figure5 and Table2). Based on the calculated results of the diastereomeric bitartrate (Figure 5), sterically Based on the calculated results of the diastereomeric bitartrate (Figure5), sterically determined antiparallel tartrate chains recognize the corresponding enantiomers to form determined antiparallel tartrate chains recognize the corresponding enantiomers to form the double helix structure. Using molecular simulation1 based on the X-ray diffraction, the the double helix structure. Using molecular simulation1 based on the X-ray diffraction, the formedformed spatial spatial structure structure is illustrated is illustrated (Figure (Figure7). It can 7). be It can seen be that seen this that structure this structure can can only only be formedbe formed if the acidif the (resolving acid (resolving agent) agent) and the and base the arebase located are located in the in form the ofform double of double helix helix associates.associates.

Figure 7.Figure Top and 7. Topside andviews side of the views double of the helix double structure helix on structure the (R)-MeAn on the.(R,R (R)-)-MeAnTA diastereomeric.(R,R)-TA diastere- salt. omeric salt. The reaction of helical acid and base associates produces helical salt associates that The reactionhave antiparallel of helical acidorientation and base and associates form helical produces double helical spirals. salt Helical associates double that spirals can be have antiparallelduplicated orientation by replication and form from helical their double helical spirals. salts (Figure Helical 6). double spirals can be duplicated by replicationFurther, the from resolution their helical results salts of (Figure racemic6). acids (mainly N-acetylated amino acids) Further,were the introduced resolution (Table results 3, of Entries racemic 8–16) acids with (mainly a single N-acetylated base resolving amino agent. acids) It is striking were introducedthat the (Table environment3, Entries of 8–16) the withdiastereomeric a single base salt resolvings of these agent. resolutions It is striking is essentially that the same the environmentas described of the diastereomericabove (Tables 1 salts and of2, Entries these resolutions 1–7). is essentially the same as described aboveIn (Tables these 1cases, and2 the, Entries X substituent 1–7). has the greatest effect on the result of the separation. SymmetrySymmetrySymmetry 2021 2021 2021,, 13,, 1313,, x,x, xFORFORx FOR FOR PEERPEER PEER PEER REVIEWREVIEW REVIEW REVIEW In these cases, the X substituent has the greatest effect on the result of the separation.101010 of ofof 13 13 13 Although (eeDia ~ eeResAg) is also valid for these resolutions, clearly more modest separa- Although (eetionsDia~ee (F)ResAg were) isobtained also valid with for thesethe basic resolutions, resolving clearly agents. more It modestis likely separations that the acid compo- (F) were obtained with the basic resolving agents. It is likely that the acid components of nents of the diastereomers allow for weaker secondary bonds (Table 2). the diastereomers allow for weaker secondary bonds (Table2). It was known that the resolvability of enantiomeric mixtures into single enantiomeric TableTableTable 2. 2.2. Seven-membered Seven-memberedSeven-membered ring ringring structure structurestructure of ofof the thethe dias diasdiastereomerictereomerictereomeric salts saltssalts from fromfrom Tables TablesTables 1 1 1and andand 3. 3.3. and racemic fractions is a nonlinear function of the initial enantiomeric ratio. From the TableDiastereomersDiastereomersDiastereomers 2. Seven-membered ring structure of the diastereomeric salts from Tables1 and3. DiastereomerDiastereomerDiastereomer 7 7 7 mixtureDiastereomerDiastereomerDiastereomer of enantiomers 5 5 5 Diastereomerpurer Diastereomer Diastereomer than the 4 eutectic 4 4 composition, Diastereomers Diastereomers Diastereomers the enantiomer 8–16 8–168–16 crystallizes, Diastereomer 7 Diastereomers1–3,1–3,1–3, 6 6 6 1–3, 6while Diastereomer the racemic 5 fraction crystallizes Diastereomer when 4 the mixture Diastereomers of enantiomers 8–16 is below this level of purity. This phenomenon has been explained by some of the different reactions of supramolecular associates, while other studies [16–23] have explained it by the self-disproportionation of enantiomeric mixtures (SDE). 1Molecular modeling software: Spartan’18 v.1.4.4/2019

TableTableTable 3. 3.3. Resolutions ResolutionsResolutions of ofof racemic racemicracemic compounds compoundscompounds with withwith chiral chiralchiral bases. bases.bases.

EntryEntryEntry Racemic Racemic Racemic acids acidsacids Resolving Resolving Resolving agent agentagent Diastereomer Diastereomer Diastereomer ee ee eeDiaDiaDia (%) (%) (%) FF F

8[28]8[28]8[28] (1(1(1SS,5S,5,5RRR)-)-)-CPN.CPN.CPN.(R((RR)-)-)-FEAFEAFEA 81.581.581.5 0.550.550.55

99 9[29] [29][29] (R((RR)-)-)-FoEAFoEAFoEA.(.(R.(RR)-)-)-FEAFEAFEA 919191 0.400.400.40

101010 [29] [29][29] (R((RR)-)-)-AcEAAcEAAcEA.(.(R.(RR)-)-)-FEAFEAFEA 898989 0.550.550.55

111111 [30] [30][30] (S((S)-S)-)-AcEAAcEAAcEA.(.(R,R.(R,RR,R)-)-)-ADADAD 767676 0.510.510.51

121212 [29] [29][29] (S((S)-S)-)-PEAPEAPEA.(.(.(R,RR,RR,R)-)-)-ADADAD 535353 0.330.330.33

SymmetrySymmetry 2021 2021, ,13 13, ,x x FOR FOR PEER PEER REVIEW REVIEW 1010 of of 13 13

SymmetrySymmetry 2021 2021, ,13 13, ,x xFOR FOR PEER PEER REVIEW REVIEW 1010 of of 13 13

SymmetrySymmetry 2021 2021, 13, 13, x, FORx FOR PEER PEER REVIEW REVIEW 1010 of of 13 13 Table 2. Seven-membered ring structure of the diastereomeric salts from Tables 1 and 3. Table 2. Seven-membered ring structure of the diastereomeric salts from Tables 1 and 3. SymmetrySymmetry 2021 2021, 13, 13, x, xFOR FOR PEER PEER REVIEW REVIEW 1010 of of 13 13 DiastereomersDiastereomers DiastereomerDiastereomer 77 TableTable 2. 2. Seven-membered Seven-membered Diastereomerring Diastereomerring structure structure of of 5 5the the dias dias Diastereomer Diastereomertereomerictereomeric salts salts 44 from from Tables Tables Diastereomers Diastereomers1 1 and and 3. 3. 8–168–16 SymmetrySymmetry 2021 2021, 13, 13, x, xFOR FOR PEER PEER REVIEW REVIEW1–3,1–3, 66 1010 of of 13 13 DiastereomersDiastereomers DiastereomerDiastereomer 7 7 TableTable 2. 2. Seven-membered Seven-membered DiastereomerringDiastereomer ring structure structure of 5of 5 the the dias dias Diastereomer Diastereomertereomerictereomeric salts salts 4 4 from from Tables Tables Diastereomers Diastereomers1 1and and 3. 3. 8–16 8–16 1–3,1–3, 6 6 DiastereomersDiastereomers DiastereomerDiastereomer 7 7 TableTable 2. 2. Seven-membered Seven-memberedDiastereomer ringDiastereomer ring structure structure of 5of 5the the dias dias Diastereomer Diastereomertereomerictereomeric salts salts 4 4from from Tables Tables Diastereomers Diastereomers1 1and and 3. 3. 8–16 8–16 1–3,1–3, 6 6 TableDiastereomersDiastereomers 2. Seven-membered ring structure of the diastereomeric salts from Tables 1 and 3. SymmetryDiastereomerDiastereomer2021, 13, 667 7 7 Table 2. Seven-memberedDiastereomer ringDiastereomer structure of 5 5the dias Diastereomer Diastereomertereomeric salts 4 4from Tables Diastereomers Diastereomers1 and 3. 8–16 8–16 9 of 12 1–3,1–3, 6 6 DiastereomersDiastereomers DiastereomerDiastereomer 7 7 DiastereomerDiastereomer 5 5 Diastereomer Diastereomer 4 4 Diastereomers Diastereomers 8–16 8–16 1–3,1–3, 6 6

It was known that the resolvability of enantiomeric mixtures into single enantiomeric

and racemicTableTable 3. 3. Resolutions fractionsResolutions is of of a racemic nonlinearracemic compounds compounds function with with of thechiral chiral initial bases. bases. enantiomeric ratio. From the mixture ofenantiomers purer than the eutectic composition, the enantiomer crystallizes, EntryEntry Racemic Racemic acidsacidswhile TableTable the 3. racemic3. Resolutions Resolutions Resolving Resolving fraction of of racemic agentracemicagent crystallizes compounds compounds when with with the Diastereomerchiral Diastereomer chiral mixture bases. bases. of enantiomers ee eeDia isDia (%) below(%) thisFF

level of purity. This phenomenon has been explained by some of the different reactions EntryEntry Racemic Racemic acids acids TableTable 3. 3. Resolutions Resolutions Resolving Resolving of of racemicagent agentracemic compounds compounds with with Diastereomer chiral Diastereomer chiral bases. bases. ee eeDiaDia (%) (%) FF of supramolecular associates, while other studies [16 – 23] have explained it by the self-

EntryEntry Racemic Racemic acids acidsdisproportionation TableTable 3. 3. Resolutions Resolutions Resolving Resolving of enantiomeric of of racemicagent racemicagent compounds compounds mixtures with (SDE).with Diastereomer chiral Diastereomer chiral bases. bases. ee eeDiaDia (%) (%) F F

Entry8[28]Entry8[28] Racemic Racemic acids acids TableTable 3. 3. Resolutions Resolutions Resolving Resolving of of racemicagent racemicagent compounds compounds with (1with(1SS,5 Diastereomer ,5chiral DiastereomerRchiralR)-)-CPN.CPN. bases. bases.((RR )- )-FEA FEA ee eeDia81.581.5Dia (%) (%) 0.550.55FF Table 3. Resolutions of racemic compounds with chiral bases.

Entry8[28]Entry8[28] Racemic Racemic acids acids Resolving Resolving agent agent (1(1SS,5 Diastereomer,5 DiastereomerRR)-)-CPN.CPN.(R(R)-)-FEA FEA ee eeDia81.581.5Dia (%) (%) 0.550.55FF Entry Racemic acids Resolving agent Diastereomer eeDia (%) F 8[28]8[28] (1(1S,5S,5RR)-)-CPN.CPN.(R(R)-)-FEAFEA 81.581.5 0.550.55

8[28]8[28] (1(1SS,5,5RR)-)-CPN.CPN.(R(R)-)-FEAFEA 81.581.5 0.550.55

8[28] (1S,5R)-CPN.(R)-FEA 81.5 0.55 88[28] [28] (1S,5(1RS)-,5CPN.R)-CPN.(R)-FEA(R)-FEA 81.581.5 0.550.55

99 [29][29] ((RR)-)-FoEAFoEA.(.(RR)-)-FEAFEA 9191 0.400.40

99 [29] [29] (R(R)-)-FoEAFoEA.(.(RR)-)-FEAFEA 9191 0.400.40

9 9[29] [29] (R(R)-)-FoEAFoEA.(.(RR)-)-FEAFEA 9191 0.400.40

99 [ 929[29] [29]] (R)-(FoEAR(R)-)-FoEAFoEA.(R)-FEA.(.(RR)-)-FEAFEA 919191 0.400.400.40

9 [29] (R)-FoEA.(R)-FEA 91 0.40 9 [29] (R)-FoEA.(R)-FEA 91 0.40

1010 [29][29] ((RR)-)-AcEAAcEA.(.(RR)-)-FEAFEA 8989 0.550.55

1010 [29] [29] (R(R)-)-AcEAAcEA.(.(RR)-)-FEAFEA 8989 0.550.55

10 [29] (R)-AcEA.(R)-FEA 89 0.55 1010 [29] [29] (R(R)-)-AcEAAcEA.(.(RR)-)-FEAFEA 8989 0.550.55

1010 [29] [29] (R(R)-)-AcEAAcEA.(.(RR)-)-FEAFEA 8989 0.550.55

10 [29] (R)-AcEA.(R)-FEA 89 0.55 10 [29] (R)-AcEA.(R)-FEA 89 0.55

1111 [30][30] ((SS)-)-AcEAAcEA.(.(R,RR,R)-)-ADAD 7676 0.510.51

11 [30] (S)-AcEA.(R,R)-AD 76 0.51 1111 [30] [30] (S(S)-)-AcEAAcEA.(.(R,RR,R)-)-ADAD 7676 0.510.51

1111 [30] [30] (S()-S)-AcEAAcEA.(.(R,RR,R)-)-ADAD 7676 0.510.51

1111 [30] [30] (S(S)-)-AcEAAcEA.(.(R,RR,R)-)-ADAD 7676 0.510.51

SymmetrySymmetry 2021 2021, 13, 13, x, xFOR FOR PEER PEER REVIEW REVIEW 1111 of of 13 13

12 1212 [29 [29][29]] (S)-PEA((SS)-)-.(PEAPEAR,R)-.(.(ADR,RR,R)-)-ADAD 535353 0.330.330.33

1212 [29] [29] (S(S)-)-PEAPEA.(.(R,RR,R)-)-ADAD 5353 0.330.33

1212 [29] [29] (S()-S)-PEAPEA.(.(R,RR,R)-)-ADAD 5353 0.330.33

1212 [29] [29] (S(S)-)-PEAPEA.(.(R,RR,R)-)-ADAD 5353 0.330.33

1212 [29] [29] (S(S)-)-PEAPEA.(.(R,RR,R)-)-ADAD 5353 0.330.33 131313 [ 29[29] [29]] (R)-(FoEAR(R)-)-FoEAFoEA.(R)-FGM.(.(RR)-)-FGMFGM 727272 0.390.390.39

1414 [29] [29] (S(S)-)-AcEAAcEA.(.(RR)-)-FGMFGM 5555 0.260.26

1515 [29] [29] (S(S)-)-AcEGAcEG.(.(RR)-)-FGMFGM 7979 0.400.40

1616 [29] [29] (R(R)-)-PEGPEG.(.(RR)-)-FGMFGM 4343 0.290.29

ItIt has has been been found found that that enantiomeric enantiomeric mixtures, mixtures, i.e i.e.,. ,the the racemic racemic compound compound and and the the resolvingresolving agent agent (a (a third third chiral chiral molecule), molecule), are are also also capable capable of of self-disproportionation self-disproportionation in in a a commoncommon solution solution by by the the interactions interactions (reaction) (reaction) of of supramolecular supramolecular helical helical associates associates formform- inging the the conformers conformers of of the the chiral chiral molecules molecules present. present.

3.3. Conclusions Conclusions AsAs a a result, result, the the eutectic eutectic composition composition of of th the eenantiomeric enantiomeric mixture mixture isolated isolated from from the the crystallinecrystalline diastereomeric diastereomeric salt salt (depending (depending on on the the solvent, solvent, crystallization crystallization conditions, conditions, and and time)time) agrees agrees well well with with the the eutectic eutectic compositio compositionsns of of the the racemic racemic compound compound or or enantiomeric enantiomeric mixturesmixtures of of the the resolving resolving agent agent (ee (eeDiaDia~ee~eeEuRacEuRac or or ~ee ~eeEuRacEuRac).). AlthoughAlthough the the resolving resolving agent agent is is present present only only in in single single enantiomeric enantiomeric form form during during the the resolution,resolution, it it is is able able to to force force a a ratio ratio corresponding corresponding to to its its eutectic eutectic composition composition on on the the dia- dia- stereomericstereomeric salt. salt. ThisThis is is made made possible possible by by the the fact fact that that th the echiral chiral molecules molecules present present form form homo- homo- and and heterochiralheterochiral supramolecular supramolecular associates associates (corre (correspondingsponding to to their their eutectic eutectic composition) composition) and and reactreact with with each each other. other. The The salts salts corresponding corresponding to to the the diastereomer diastereomer thus thus form form an an antipar- antipar- allelallel helical helical double double spiral spiral structure, structure, which which is is capable capable of of replication. replication. Crystallization Crystallization begins begins fromfrom a a supersaturated supersaturated solution solution of of the the structures structures thus thus formed, formed, which which maintain maintain an an active active equilibriumequilibrium with with the the solution solution until until they they are are separated. separated. Simultaneously,Simultaneously, all all this this also also proves proves that that a a chiral chiral molecule molecule validates validates the the code code of of its its reactionreaction with with other other chiral chiral molecules molecules with with its its molecular molecular geometry. geometry. SymmetrySymmetry 2021 2021, ,13 13, ,x xFOR FOR PEER PEER REVIEW REVIEW 1111 of of 13 13 SymmetrySymmetry 2021 2021, 13, 13, x, FORx FOR PEER PEER REVIEW REVIEW 1111 of of 13 13

SymmetrySymmetry 2021 2021, ,13 13, ,x xFOR FOR PEER PEER REVIEW REVIEW 1111 of of 13 13

1313 [29] [29] (R(R)-)-FoEAFoEA.(.(RR)-)-FGMFGM 7272 0.390.39 Symmetry1313 [29]2021 [29] , 13 , 667 (R(R)-)-FoEAFoEA.(R.(R)-)-FGMFGM 7272 100.39 of0.39 12 1313 [29] [29] (R(R)-)-FoEAFoEA.(.(RR)-)-FGMFGM 7272 0.390.39

Table 3. Cont.

Entry Racemic acids Resolving agent Diastereomer ee (%) F Dia

1414 [29] [29] (S(S)-)-AcEAAcEA.(.(RR)-)-FGMFGM 5555 0.260.26 1414 [29] [29] (S()-S)-AcEAAcEA.(R.(R)-)-FGMFGM 5555 0.260.26 141414 [29 [29] [29]] (S)-AcEA(S(S)-)-AcEAAcEA.(R)-FGM.(.(RR)-)-FGMFGM 555555 0.260.260.26

1515 [29] [29] (S(S)-)-AcEGAcEG.(.(RR)-)-FGMFGM 7979 0.400.40 151515 [ 29[29] [29]] (S)-AcEG(S()-S)-AcEGAcEG.(R)-FGM.(R.(R)-)-FGMFGM 797979 0.400.400.40 1515 [29] [29] (S(S)-)-AcEGAcEG.(.(RR)-)-FGMFGM 7979 0.400.40

161616 [29 [29] [29]] (R)-(PEGR(R)-)-PEG.(PEGR)-FGM.(.(RR)-)-FGMFGM 434343 0.290.290.29 1616 [29] [29] (R(R)-)-PEGPEG.(R.(R)-)-FGMFGM 4343 0.290.29 1616 [29] [29] (R(R)-)-PEGPEG.(.(RR)-)-FGMFGM 4343 0.290.29

1 MolecularItIt hashas beenbeen modeling foundfound that software:that enantiomeric enantiomeric Spartan’18 mixtures,mixtures, v.1.4.4/2019 i.e i.e.,. , thethe racemicracemic compoundcompound and and thethe It has been found that enantiomeric mixtures, i.e., the racemic compound and the resolvingresolvingIt hasIt has been agent agentbeen found (a found(a third third that that chiral chiral enantiomeric enantiomeric molecule), molecule), mixtures, are mixtures,are also also i.e.,capable capable i.e the., the racemicof of racemicself-disproportionation self-disproportionation compound compound and and the in thein a a resolving agent (a third chiral molecule), are also capable of self-disproportionation in a resolvingresolvingcommoncommonItIt has agenthas solution agentsolution beenbeen (a (athird found found by thirdby the chiralthe that chiralthatinteractions interactions molecule),enantiomeric enantiomeric molecule), (reaction) (reaction) are are mixtures, alsomixtures, also of capableof supramolecular capablesupramolecular i.e i.e.,. of , thethe self-disproportionationof racemicself-disproportionationracemic helical helical compoundcompound associates associates and and in formform- ina thethe a common solution by the interactions (reaction) of supramolecular helical associates form- commoncommoningresolvingingresolving the the solution conformers conformers solution agent agent by (a (a theby third ofthird of the interactionsthe the chiral interactions chiralchiral chiral molecule), molecule),molecules molecules (reaction) (reaction) are present.are ofpresent. supramolecularalso also of supramolecular capable capable of of self-disproportionation helicalself-disproportionation helical associates associates forming form- in in a a theingcommoncommon conformersing the the conformers conformers solution solution of the by by chiralof ofthe the the interactions moleculesinteractionschiral chiral molecules molecules present. (reaction) (reaction) present. present. of of supramolecular supramolecular helical helical associates associates formform- 3.ing3.ing Conclusions Conclusions the the conformers conformers of of the the chiral chiral molecules molecules present. present. 3. Conclusions3.3. Conclusions Conclusions AsAs a a result, result, the the eutectic eutectic composition composition of of th thee enantiomeric enantiomeric mixture mixture isolated isolated from from the the 3.3. ConclusionsAs Conclusions aAs result, a result, the eutecticthe eutectic composition composition of the of enantiomericthe enantiomeric mixture mixture isolated isolated from from the the crystallinecrystallineAs a result, diastereomeric diastereomeric the eutectic salt salt composition (depending (depending ofon on th the thee enantiomeric solvent, solvent, crystallization crystallization mixture isolated conditions, conditions, from and theand crystallinecrystalline diastereomeric diastereomeric salt salt (depending (depending on theon solvent,the solvent, crystallization crystallization conditions, conditions, and and crystallinetime)time)As Asagrees agrees a a result, result,diastereomeric well well the with thewith eutectic eutectic the the eutectic salteutectic composition composition(depending compositio compositio of onof nsth nsththe eof e ofenantiomeric solvent,enantiomericthe the racemic racemic crystallization compound compoundmixture mixture isolated isolated orconditions, or enantiomeric enantiomeric from from and the the time)time)crystallinecrystallinetime) agrees agrees agrees well diastereomeric diastereomeric well well with with with the the eutecticthe eutectic salt eutecticsalt (depending (depending compositions compositio compositio on onns of thens the of the of solvent,the solvent, racemicthe racemic racemic crystallization crystallization compound compound compound or orconditions, enantiomeric conditions,or enantiomeric enantiomeric and and mixturesmixtures of of the the resolving resolving agent agent (ee (eeDiaDia~ee~eeEuRacEuRac or or ~ee ~eeEuRacEuRac).). mixturesmixtures of the of resolvingthe resolving agent agent (eeDia (eeDia~eeDia~eeEuRacEuRacEuRacor or ~ee ~eeEuRacEuRacEuRac).). mixturestime)time)Although Althoughagrees agrees of the well well the resolvingthe with with resolving resolving the the agenteutectic eutectic agent agent (ee compositio iscompositio is ~eepresent present or onlyns onlyns ~ee of of inthe inthe single singleracemic ).racemic enantiomeric enantiomeric compound compound form orform or enantiomeric enantiomeric during during the the AlthoughAlthough the the resolving resolving agent agent isDiaDia presentis presentEuRacEuRac only only inEuRac EuRacin single single enantiomeric enantiomeric formform duringduring the resolution,mixturesresolution,mixturesAlthough of of it theit theis is the ableresolving ableresolving resolving to to force force agent agent agenta a ratio ratio(ee (ee is corresponding corresponding~eepresent~ee or onlyor ~ee ~ee in to to single its ).its). eutectic eutectic enantiomeric composition composition form on duringon the the dia- thedia- theresolution, it is able to force a ratio corresponding to to its its eutectic eutectic composition composition on on the the dia- resolution,stereomericstereomericAlthoughAlthough it salt. salt.is the ablethe resolving resolving to force aagent agent ratio is iscorresponding present present only only in into single singleits eutectic enantiomeric enantiomeric composition form form onduring during the dia- the the diastereomericstereomeric salt.salt. stereomericresolution,resolution,ThisThis is is it madesalt.it madeis is able able possible possible to to force force by by a a theratio theratio fact fact corresponding corresponding that that th thee chiral chiral to to molecules its moleculesits eutectic eutectic present presentcomposition composition form form homo- on homo-on the the dia-and dia-and ThisThis is made is made possible possible by theby factthe fact that that the chiralthe chiral molecules molecules present present form form homo- homo- and and heterochiralstereomericheterochiralstereomericThis is madesalt. supramolecular salt.supramolecular possible by associates associatesthe fact that (corre (corre thspondingesponding chiral molecules to to their their eutectic eutecticpresent composition) composition)form homo- and and heterochiralheterochiral supramolecular supramolecular associates associates (corresponding (corresponding to their to their eutectic eutectic composition) composition) and and heterochiralreactreactThis withThis with is iseach each made supramolecularmade other. other. possible possible The The salts by saltsby associates the thecorresponding corresponding fact fact that (correthat th thspondingee chiralto chiralto the the moleculesdiastereomer moleculesdiastereomer to their eutectic present present thus thus composition) form form anhomo- anhomo- antipar- antipar- and and reactreactheterochiralheterochiralreact with with with each each each supramolecular other.supramolecular other. other. The The saltsThe salts correspondingsalts associates associates corresponding corresponding (corre (corre to thespondingsponding to to diastereomer the the diastereomer diastereomerto to their their thus eutectic eutectic formthus thus composition) ancomposition)form form antiparallel an an antipar- antipar- and and helicalallelallel helical doublehelical double double spiral spiral structure,spiral structure, structure, which which which is capable is is capable capable of replication. of of replication. replication. Crystallization Crystallization Crystallization begins begins begins allelreactreactallel helical with helicalwith each eachdouble double other. other. spiral spiral The The structure, structure,salts salts corresponding corresponding which which is is capable capable to to the the of diastereomer ofdiastereomer replication. replication. Crystallizationthus thusCrystallization form form an an antipar- antipar- begins begins fromfromfrom a supersaturateda a supersaturated supersaturated solution solution solution of of theof the the structures structures structures thus thus thus formed, formed, formed, which which which maintain maintain maintain an an activean active active fromallelallelfrom helical ahelical asupersaturated supersaturated double double spiral spiral solution solution structure, structure, of of the which thewhich structures structures is is capable capable thus thus of of formed, replication. formed,replication. which which Crystallization Crystallization maintain maintain an an begins activebegins active equilibriumequilibriumequilibrium with with with the the the solution solution solution until until until they they they are are are separated. separated. separated. equilibriumfromfromequilibrium a a supersaturated supersaturated with with the the solution solutionsolution solution until until of of the theythe they structures structures are are separated. separated. thus thus formed, formed, which which maintain maintain an an active active Simultaneously,Simultaneously,Simultaneously, all all thisall this this also also also proves proves proves that that that a chirala a chiral chiral molecule molecule molecule validates validates validates the the the code code code of of itsof its its equilibriumequilibriumSimultaneously,Simultaneously, with with the the solution allsolution all this this also until alsountil proves theyproves they are arethat that separated. separated. a achiral chiral molecule molecule validates validates the the code code of of its its reactionreactionreaction with with with other other other chiral chiral chiral molecules molecules molecules with with with its its molecularits molecular molecular geometry. geometry. geometry. reactionreactionSimultaneously,Simultaneously, with with other other chiral chiral all all this moleculesthis molecules also also proves proves with with itsthat thatits molecular moleculara a chiral chiral molecule geometry.molecule geometry. validates validates the the code code of of its its reactionreaction with with other other chiral chiral molecules molecules with with its its molecular molecular geometry. geometry. Author Contributions: D.F.B. and E.P. wrote the paper together, and it is based on their own experimental results. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Symmetry 2021, 13, 667 11 of 12

Acknowledgments: The authors thank Emeritus Elemér Fogassy for his valuable and constructive suggestions during the planning and development of this research work. His willingness to give his time so generously has been very much appreciated. This work was supported by the National Research, Development and Innovation Office-NKFIH through OTKA grants 124180. Conflicts of Interest: The authors declare no conflict of interest.

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