Practical Stereochemistry - American Chemical Society

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Practical Stereochemistry Richard M. Kellogg* Syncom BV, Kadijk 3, Groningen 9747 AT, The Netherlands

CONSPECTUS: The relationship between fundamental and applied is often uneasy, particularly in modern political climates. A familiar political view, aimed negatively at the scientific community, is that the former is a waste of money whereas the latter gives value for investment. The answer that fundamental is required as the basis for practical suffers from the fact that the timelines between fundamental and practical are often long and the routes contorted and unexpected. This has been my experience. In this Account, examples are given from the research in which I have been involved wherein quite fundamental considerations have led to various applications. The longer the time, the clearer and broader the relationship. Fundamental can and does lead to application. They need and depend on each other. I have seen this both from the side of academia and from small companies. In the course of the past 40 plus years, I have been involved in various aspects of stereochemistry and, in particular, chirality. It has been rewarding to see that several of the developments, most originally grounded in fundamental research considerations, have been used in the chemical community and given new dimensions and often practical applications by others. In this Account, a path−not planned deliberately by mefrom orbital symmetry and Woodward−Hoffmann rules through crown ethers to conformational analysis to diastereomeric resolutions to deracemizations powered by Ostwald ripening and the Gibbs−Thomson effect to nucleation to helicenes is described. In order of discussion, the orbital symmetry aspects have via an unusual and unpredicted path has resulted in, among other things, a synthesis of hindered alkenes useful for the production of molecular motors. The crown ether aspects led to discovery of the utility of cesium salts particularly for racemization sensitive nucleophilic substitutions. Work on diastereomeric resolutions has concentrated on the mechanistic as well as practical/commercial aspects of the use of multiple resolving agents (Dutch resolution). During this work the complex relationship between nucleation and chirality in diastereomeric resolutions began to reveal itself. In general, nucleation, especially with involvement of chirality, is a topical challenge that has attracted the attention of many groups. The contribution of this knowledge to the development of attrition driven deracemizations of racemizable conglomerates is described. This remarkable technology allows, without intervention of chiral aids, conversion of certain racemates in quantitative yield and absolute enantiomeric excess to a single enantiomer. From a practical standpoint, this methodology has been used for the production in enantiomerically pure form of commercially interesting compounds like naproxen and clopidogrel (Plavix). Finally an STM investigation of the nucleation behavior of a helicene, prepared via a remarkably short and efficient route, on a metal surface is described.

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cleanly. The cis-isomer of 3 obediently provided the transisomer of 6.7,8 There are two workable routes to 1,3,4-thiadiazolines, the precursors of the thiocarbonyl ylides. They can be formed either by 1,3-dipolar reaction of a diazo compound with a thioketone (Scheme 2a) or by (oxidative) ring-closure of an azine with H2S, the route used in Scheme 1. Barton and Willis demonstrated that heavily substituted carbons can be introduced by the former route, and subsequent pyrolysis and desulfurization affords hindered alkenes.9 The conversion of 1,3,4-thiadiazolines to alkenes is sometimes referred to as the “Barton−Kellogg reaction”.10 This

In the mid-1960s, stereochemistry, chirality, synthesis, theory, and application joined hands stimulated by the Woodward− Hoffmann predictions of the stereochemical consequences of orbital symmetry.1−3 Huisgen et al. demonstrated that azomethine ylide 1 underwent reversible conrotatory ring closure to aziridine 2 in accord with the predictions of orbital symmetry (Scheme 1a).4 Interest in sulfur chemistry led to an attempt to place this element in the story.5 The conversion of trans-3 via conrotatory ring-closure of thiocarbonyl 1,3-dipole 4 to hindered cis-thiirane 5 demonstrated that an increase in steric interaction was a price readily paid to satisfy the demands of orbital symmetry (Scheme 1b).6 (Orbital symmetry allowed) desulfurization to cis-1,2-di-t-butyl ethylene 6 proceeded © 2017 American Chemical Society

Received: December 16, 2016 Published: March 1, 2017 905

DOI: 10.1021/acs.accounts.6b00630 Acc. Chem. Res. 2017, 50, 905−914

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Accounts of Chemical Research Scheme 1. From a Thiocarbonyl Ylide to an Alkene

that CsF induced the formation of crown ethers.20 The poor solubility characteristics of salts of 10 were overcome by use of Cs2CO3 in dimethylformamide (DMF). Cesium carbonate is an extremely useful solid base that has found application to form macrocyclic lactones, amines, and sulfides, as well as in other areas.21−24 With regard to stereochemistry, this includes SN2 substitutions to obtain highly racemization sensitive compounds like the ethyl ester of thiolactic acid.25,26 Cesium carbonate is widely used in cross coupling reactions.27 The effects of Cs2CO3 are due chiefly to a low degree of ion pairing and relatively high solubility in aprotic dipolar solvents. Cesium ions, paired with carbonate or bicarbonate anions, do not act as templates that preform the final ring structure of macrocycles. Ion pairing effects are involved, which also allows application to rings devoid of heteroatom coordination sites for Cs+.28 For example, the preparation of thiacrown ethers using Cs2CO3 proceeds remarkably well. Practical applications are possible owing to their affinity for transition metals.29,30 We were unable to develop a satisfactory organocatalytic version of Scheme 3. Frustration of what seemed an ideal organocatalytic reaction based on biological precedent led, stimulated by other developments in organocatalysis in Groningen,31 to investigation of the conformations of quinine 16 and quinidine 17 (Scheme 4). A combination of computational and NMR work carried out together with the Sharpless group led to the conclusion that the reactivity and mechanism of transfer of chiral information was coupled to conformational changes.32,33 These alkaloids, and derivatives thereof, continue to be applied widely for organocatalysis.34 An NMR method, developed by the Feringa group to determine enantiomeric excesses, was applied to, for example, chiral thiols and remains of practical interest.35−37 Unexpectedlyand strongly influenced by the foregoing we became involved in a discovery where the fundamental and the practical met. Commercial interest in means to obtain enantiopure compounds induced examination of the principles

Scheme 2. Thiocarbonyl Ylide Approach to Highly Hindered Alkenes

process has been adapted with impressive success by my colleague Ben Feringa and his group to prepare highly hindered chiral alkenes that may be used as molecular motors. An example is given in Scheme 2b.11,12 The excitement of crown ether chemistry led to “NADH models”, an example being 13 (Scheme 3).13−15 Crown ether 13 in the presence of Mg(ClO4)2 reduced carbonyl compounds like 13 to provide 15 in, for that time, impressive enantioselectivity. Pyridinium salt 12 could be reconverted to 13 (Scheme 3b). Note that 1,4-dihydropyridines, in particular Hantzsch esters, are currently popular reducing agents.16 A synthetic problem led to practical (stereochemical) applications. Cesium salts of organic acids often have good solubility in dipolar aprotic solvents.17 We had seen that the cesium salts of organic diacids and diphenols, formed by deprotonation with Cs2CO3, readily underwent cyclization reactions.18,19 Reinhoudt et al. demonstrated simultaneously 906


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Accounts of Chemical Research Scheme 3. Crown Ether/NADH Models

cally pure (S)-mandelic acid 20 is a poor resolving agent for amine 21. Addition of 6 mol % homochiral 22 (chiral homology) leads to almost diastereomerically pure first salt of 21. On the other hand, the (R) enantiomer of the inhibitor has virtually no effect (Scheme 6).42 This is not a one off case. We have found other potent inhibitors based on analogy with the resolving agent.42 The effect of additives is usually thought of as inhibition of crystal growth, the classical example being “tailor-made additives” as described by Lahav, Leiserowitz et al.43,44 Nucleation and crystal growth are not the same. Weissbuch, Lahav, and Leiserowitz have discussed this in detail particularly with regard to “tailor-made additives”.45,46 Nucleation in solution is of intense current interest. The status has been reviewed recently by Davey, Schroeder, and ter Horst.47 Direct observation of nucleation stretches technology to the limits. Computational methods lend support.48−53 In the classical model of nucleation, a Daltonian-like sphere forms that grows reversibly with presumably random organization of (spherical) molecules within the sphere. At a critical radius, irreversible crystallization occurs.34 These assumptions simplify the mathematics although the model lacks organizational information. However, nuclei are not necessarily spherical especially for irregularly shaped organic molecules.38 For ribbon-like long oligo(p-phenylenevinylene) derivatives that self-associate, a chiral center in the molecule can induce helicity and supramolecular chirality during nucleation.53 Current thinking about nucleation revolves around two models. In one, a cluster of molecules is formed with the molecules oriented in the fashion in which they will enter into the crystalline nucleus. These oriented clusters then associate in a nucleus that goes on to precipitation. In the other model,

Scheme 4. Quinine and Quinidine

behind “Dutch resolution”, a method whereby families, usually three members, of structurally related and homochiral (homologous absolute configurations) resolving agents are used instead of a single resolving agent.38,39 This process, discovered by Ton Vries, has a high success rate and has practical commercial value particularly for small scale first time resolutions.40 An example is the resolution of 18, the precursor of thiamphenicol 19 (Scheme 5a). Each of the structurally related and cyclic phosphoric acids 19a−c is capable of resolving this material in diastereomeric excesses for the first salts ranging from 17% to 52%. However, a 1:1:1 mixture of 19a−c provided a first salt with a diastereomeric excess of 98.8%. We now know that two major factors contribute to this peculiar effect. First, for the homochiral family of resolving agents 19a−c, the salts formed behave as a single phase (solid solution).41 This behavior is likely general. Second, nucleation inhibition is involved whereby one of the “family members” inhibits nucleation and precipitation of the more soluble diastereomer. This is a kinetic effect. For example, enantiomeri907


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Accounts of Chemical Research Scheme 5. An Example of Dutch Resolution

Scheme 6. Chirality Based Nucleation Inhibition

have an effect on a practical experimental time scale. The work on Dutch resolution, carried out together with colleagues from Nijmegen and DSM, had made this interaction clear to us. During this work, we were well aware of preferential crystallization used to resolve conglomerates, that is, those chiral compounds that crystallize in noncentrosymmetric space groups. Particularly Gerard Coquerel has demonstrated how the kinetics in the supersaturation zone interplay with the thermodynamics represented in a phase diagram based on thermodynamics.59,60 Very careful control of conditions and timing is necessary in order to remain in the kinetic window. Properly engineered preferential crystallization is used on industrial scale. Together with the groups of Elias Vlieg, Hugo Meekes, and Floris Rutjes in Nijmegen and with Bernard Kaptein at DSM, we had worked together on Dutch resolution and the nucleation inhibition that lies behind it. During a fortunate encounter, Donna Blackmond emphasized to us the uniqueness

clusters are again formed, but in this case the cluster is disoriented and has liquid-like characteristics. Crystalline nuclei then form within this liquid-like cluster.54 In such a process, one expects that the structure and properties, including chirality, of the molecules undergoing nucleation and subsequent crystallization will be important. However, outside of the work of Lahav et al.,44 little is known about chirality effects in nucleation. For the complex, multicomponent case of diastereomeric resolutions, we know that potent nucleation inhibitors can be found among “family members” of the mixtures of resolving agent. The nucleation inhibition is strongest for the more soluble diastereomer, which is held in solution longer allowing the less soluble diastereomer to precipitate. This has been interpreted on the basis of “kinetic” phase diagrams.55−57 van’t Hoff pointed out more than a hundred years ago that thermodynamic equilibrium is sometimes reached only slowly, sometimes never, in crystallization processes.58 Kinetics can 908


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Accounts of Chemical Research

Attrition induced deracemization is also referred to as Viedma ripening. Other examples were soon found, the rates of deracemization were improved and commercially interesting applications have been developed. An excellent example is the deracemization of the methyl and ethyl esters of naproxen, both conglomerates (Scheme 8). In the presence of alkoxide, deracemization occurs cleanly over a period of about 4 days to provide enantiomerically pure (R)-26 if one starts with an (R) seed. This process has been patented with a view toward the production of naproxcinod 27.65,66 A well studied case developed by us is the use of attrition in the synthesis of clopidogrel (Plavix), 29. The chiral component of 29 is 2-Cl phenyl glycine. For application of attrition, a racemizable conglomerate is needed. Condensation of the amide of 2-Cl phenyl glycine with various aromatic aldehydes gave a library of racemizable imines. Second harmonic generation experiments revealed that the imine with benzaldehyde 28 was a conglomerate. Deracemization in the presence of an (S) seed of 28 provided the (S) enantiomer in nearly 100% ee. Conversion to clopidogrel, 29, proceeded in high yield and without complications (Scheme 9).67 Prasugrel, 30, is another target. A possible chiral precursor for the synthesis would be 2-F phenyl glycine. We prepared a library of imines from the amide of 2-F phenyl glycine and found several conglomerates. Imine 31 formed from 4-Br benzaldehyde was by far the best. Deracemization by attrition in the presence of a base and a seed led to virtually enantiomerically pure (R)-31 (Scheme 10).68 Attrition combined with nucleation inhibition has also been used with success in the Pope−Peachey variation (one equivalent resolving agent) of diastereomeric resolutions.69 All these procedures are near equilibrium and do not require the extra energy input for supersaturation characteristic of, for example, preferential crystallization. How does one find a conglomerate? Recent estimates70,71 are that some 19−20% of organic chiral organic compounds occur as conglomerates, rather than the lower 5−10% estimate often quoted.55 Despite progress in analysis of crystal structures, unfortunately, we still cannot predict with certainty whether a particular structure will be a conglomerate. A laboratory approach is to search small libraries of structurally related compounds, whereby second harmonic generation (SHG) is highly useful. The library approach is pragmatic but intellectually frustrating. In view of the impressive success that organic chemists have enjoyed in the prediction of

Scheme 7. Attrition Induced Deracemization

of the discovery of Cristobal Viedma.61 Under near equilibrium conditions in saturated solution simply by application of attrition to the growing crystals, Viedma demonstrated that sodium chlorate, a conglomerate in the solid, deracemizes. Application to intrinsically chiral organic compounds was a logical step. This action was supported with keen insights from Cristobal Viedma. From work done by Kaptein at DSM, we knew that imine 25 (Scheme 7a) was a conglomerate and that it racemizes readily in the presence of the base 1,8diazabicyclounde-7-ene (DBU). Under guidance from the Blackmond, Vlieg, Kaptein, Kellogg team Wim Noorduin at Nijmegen found that under near equilibrium conditions for a saturated solution in contact the solid completely deracemized on application of mild attrition induced by glass beads. By addition of a seed of enantiomerically pure 25, the deracemization could be driven in the direction of the chirality of the seed.62 An overly simplified, but easy to visualize, explanation is that very slow primary nucleation leads, for the special case of a conglomerate, to a crystal that is either right or left handed. The attrition fragments the growing crystal and rapid secondary nucleation leads to growth of the enantiomer that first appeared (stochastic) by a process related to Ostwald ripening. Excellent discussions of the mechanism are available.63,64 Scheme 8. Attrition Based Synthesis of Naproxen

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Accounts of Chemical Research Scheme 9. Attrition for the Synthesis of Clopidogrel

Scheme 10. Attrition and a Prasugrel Precursor

Figure 1. STM analysis of racemic 5-aminohexahelicene on Au(111). Solvent 1,2,4-trichlorobenzene; Chelicene = 5.2 × 10−4 M. Reprinted from ref 85 with permission from The Royal Society of Chemistry. In panel a, enantiopure domains can be seen; these are resolved in panel b; the angle distributions for the P and M enantiomers are given in panel c, and in panel d, a model is given.

Scheme 11. Gibbs−Thomson Powered Deracemization of Omeprazole Salt

team has shown that deracemization of 28 may also be achieved in a bead mill.72 Together with the group of Mazzotti, we have examined the use of a homogenizer under high pressure for the deracemization of 28 and 31.73 Temperature jump methods have been developed by Coquerel et al. for the deracemization of a conglomerate74 and for a Mannich condensation by Vlieg, Meekes et al.75,76 These methods allow avoidance of glass beads for grinding, a handicap for bulk application. A second challenge is to develop other racemization methods. So far the emphasis has been on catalysis by base making use of an acidic proton at the chiral center. Extension to

reactivity and routes for chemical and biosynthesis based on structure of molecules and guided by chemical insight, it is disappointing that these powerful tools of insight are relatively useless for prediction of the structure of conglomerates or, for that matter, to predict solubilities of diastereomers, a necessary criterion for diastereomeric resolutions.71 For industrial purposes, a continuous process for attrition would be better. Progress has been made in this direction. Our

Scheme 12. Schematic Cross Coupling Approach to Hexahelicene 39

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Owing to the interest in conglomerates together with the knowledge that the incidence of conglomerate occurrence in helicenes is fairly high, we devised a short, scalable, efficient convergent six step synthesis of 5-aminohexa[6]helicene 39 that proceeds in up to 48% overall yield starting from 33 and 34. The strategy is based on cross coupling (Scheme 12). The amino group lends itself to attachment to surfaces as well as further substitution or possible replacement.84 Helicene 39 has been resolved into the P and M enantiomers. We were particularly interested in nucleation/deposition from solution. Using scanning tunneling microscopy (STM), the absorption of racemic 39 on the Au(111) surface was observed from 1,2,4-trichlorobenzene solution.85 The group of Steven De Feyter is skilled in this technique.86 As shown in Figure 1, conglomerate behavior is seen as the compound separates into P and M areas. On use of enantiomerically pure P enantiomer, clean selfassembly was observed whereby the characteristic “three-dot” arrangement was formed, each dot consisting of three helicenes (Figure 2). This behavior is shown by both enantiomers as illustrated in Figure 3. Virtually identical behavior has been reported for P-[7]helicene.87 From density functional theory (DFT) calculations, it was determined that the arrangement with the NH2 group pointing toward the Au surface was approximately 3.4 kcal/mol more stable than the arrangement with the NH2 group pointing away from the surface. Magali Lingenfelder and Hugo Ascolani have shown that under UHV conditions the behavior of 39 on Au(111) surfaces is different.88 The enantiomerically pure material forms rows of dimers oriented along the ⟨111̅ ⟩ crystallographic axis of Au. On the other hand, the racemate forms large enantiomorphous domains, and each unit cell apparently contains 8 molecules.89,90

Figure 2. (a) STM image of P-39, together with overlaid STM simulation (top right corner). (b) Molecular model of p3-(P3) network. Reprinted from ref 85 with permission from The Royal Society of Chemistry.

temperature induced or transition metal catalyzed or light induced processes should be possible. Subsequently it has been shown by Blackmond, Hein, and us that only application of the Gibbs−Thomson effect, that is, smaller crystals are more soluble than larger ones, is sufficient to induce deracemization under near equilibrium conditions.77 This methodology can be used for resolution of nonracemizable conglomerates such as Pasteur’s salt. A nonracemizable conglomerate salt of omeprazole has also been deracemized using the same methodology.78,79 Coquerel et al. have shown that the readily formed potassium salt ethanol solvate is a conglomerate.80 Using the Gibbs−Thomson technology and a seed, the racemic salt was readily deracemized to form the enantiomeric (R) and (S) salts (Scheme 11).78 A question that runs through these phenomena is that of nucleation and the effects of chirality thereon. We know that the effect of chirality of additives on diastereomeric resolutions can be great. These effects occur at the stage of nucleation. In order to investigate these phenomena, it is interesting to look at these processes on a molecular scale. Nucleation at surfaces is perhaps easier to study and also offers the possibility of new applications. The use of patterned surfaces to control nucleation from solution, for example, had been demonstrated by Whitesides et al.81 The use of surfaces also throws a different light on the conglomerate question. The incidence of conglomerate formation on two-dimensional surfaces is much higher. Raval has pointed out that this is the result of lowering of the number of space groups from 230 to 17, and there are only 5 possible 2D chiral space groups.82,83

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CONCLUSIONS To me “practical” means that others have used or still use the (stereo)chemistry in which I have been involved. No “blockbusters” although that would have been nice. Despite all the planning, most of which was detailed in motivated research proposals, the unexpected usually won. A synthesis of hindered alkenes, the properties of cesium ions, the use of mixtures of resolving agents, first developed by Vries and Wynberg. I didn’t predict these. The observation of Viedma that deracemization can occur under near equilibrium conditions induced only by attrition of the crystals was certainly counterintuitive. It has been possible to build and extend on this observation. There is reason to think that further expansion of this discovery and development of the necessary technology will take place.

Figure 3. STM analysis of enantiopure P- and M-39 on Au(111). Solvent: 1,2,4-trichlorobenzene. Reprinted from ref 85 with permission from The Royal Society of Chemistry. 911


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(6) Kellogg, R. M. The Molecules R2CXCR2 Including Azomethine, Carbonyl and Thiocarbonyl Ylides. Their Syntheses, Properties and Reactions. Tetrahedron 1976, 32, 2165−2184. (7) Kellogg, R. M.; Kaiser, J. K. Reaction of Singlet Oxygen with Conformationally Fixed Cyclohexylidenecyclohexanes. Failure of an All Suprafacial Mechanism. J. Org. Chem. 1975, 40, 2575. (8) Asveld, E. W. H.; Kellogg, R. M. Stereochemical Evidence for the Formation of Intermediates in the Ene Reaction of Singlet Oxygen with Tetralkyl-Substituted Alkenes. J. Org. Chem. 1982, 47, 1250. This chemistry lent itself to further test of theories. An approach analogous to that shown in Scheme 1 provided conformationally fixed cyclohexylidene cyclohexanes, which owing to their rigidity and inability to interconvert between C2h and C2v conformations provided a testing ground for stereochemical aspects of singlet oxygen reactions. (9) Barton, D. H. R.; Willis, J. Olefin Synthesis by Two-fold Extrusion Processes. Part 1 Preliminary Experiments. J. Chem. Soc., Perkin Trans. 1 1972, 305−310. (10) https://en.wikipedia.org/wiki/Barton%E2%80%93Kellogg_ reaction. (11) ter Wiel, M. K. J.; van Delden, R. A.; Meetsma, A.; Feringa, B. L. Increased Speed of Rotation for the Smallest Light-Driven Molecular Motor. J. Am. Chem. Soc. 2003, 125, 15076−15086. (12) ter Wiel, M. K. J.; Vicario, J.; Davey, S. G.; Meetsma, A.; Feringa, B. L. New Procedure for the Preparation of Highly Sterically Hindered Alkenes Using a Hypervalent Iodine Reagent. Org. Biomol. Chem. 2005, 3, 28. (13) Talma, A. G.; Jouin, P.; de Vries, J. G.; Troostwijk, C. B.; Buning, G. H. W.; Waninge, J. K.; Visscher, J.; Kellogg, R. M. Reductions of Activated Carbonyl Compounds with Chiral Bridged 1,4-Dihydropyridines. An Investigation of Scope and Structural Effects. J. Am. Chem. Soc. 1985, 107, 3981−3997. (14) Including the discovery of photoredox chemistry of dihydropyridines with sulfonium salts induced by Ru(bipy)3Cl2 and light, see Van Bergen, T. J.; Hedstrand, D. M.; Kruizinga, W. H.; Kellogg, R. M. Chemistry of Dihydropyridines. Hydride Transfer from 1,4-Dihydropyridines to sp3 Hybrized Carbon in Sulfonium Salts and Activated Halides. Studies with NAD(P)H Models. J. Org. Chem. 1979, 44, 4953−4962. (15) Ref 14 was cited recently by Shaw, M. H.; Twilton, J.; MacMillan, D. W. C. Photoredox Catalysis in Organic Chemistry. J. Org. Chem. 2016, 81, 6898−6926 in a review as one of the first examples of photoredox catalysis.. (16) Marcelli, T. Asymmetric Transfer Hydrogenations Using Hantzsch Esters. In Enantioselective Organocatalyzed Reactions I; Mahrwald, R., Ed., Springer Science: Berlin, 2011; pp 43−60. (17) Wang, S.-S.; Gisin, B. F.; Winter, D. P.; Makofske, R.; Kulesha, J. D.; Tzougraki, C.; Meienhofer, J. Facile Synthesis of Amino Acid and Peptide Esters Under Mild Conditions via Cesium Salts. J. Org. Chem. 1977, 42, 1286. (18) Piepers, O.; Kellogg, R. M. Synthesis of ‘Crown Ether’ Macrocyclic Bislactones Using Caesium Carboxylates of Pyridine and of Benzene Dicarboxylic Acids. J. Chem. Soc., Chem. Commun. 1978, 383−384. (19) van Keulen, B. J.; Kellogg, R. M.; Piepers, O. Caesium Salts in Crown Ether Synthesis. Preparation of Crown Ethers from Catechol, Resorcinol, Salicyclic Acid, and 2,3-Dihydroxypyridine. J. Chem. Soc., Chem. Commun. 1979, 285−286. (20) van der Leij, M.; Oosterink, H. J.; Hall, R. H.; Reinhoudt, D. N. A Novel Synthesis of 2′-Hydroxy-1′,3′-Xylyl Crown Ethers. Tetrahedron 1981, 37, 3661−3666. (21) Kruizinga, W. H.; Kellogg, R. M. Preparation of Macrocyclic Lactones by Ring Closure of Cesium Carboxylates. J. Am. Chem. Soc. 1981, 103, 5183. (22) Kruizinga, W. H.; Strijtveen, B.; Kellogg, R. M. Cesium Carboxylates in Dimethylformamide. Reagents for Introduction of Hydroxyl Groups by Nucleophilic Substitution and for Inversion of Configuration of Secondary Alcohols. J. Org. Chem. 1981, 46, 4321− 4323.

With regard to chiral compounds, we would now like to learn the factors that induce symmetry breaking on crystallization to form conglomerates. We would like to have guidelines that increase the chance. We can learn how to do this. Preferential crystallization allows one to resolve conglomerates without resolving agents: attrition induced deracemization permits the same thing with suitable racemizable conglomerates. Likely we can learn how to deracemize racemizable conglomerates with racemic crystal structures (the majority). We can develop continuous processes to do this that will be of industrial interest. Resolutions without the aid of resolving agents are also possible for compounds with racemic crystal structures. The Gibbs−Thomson approach, powered only by the size dependent solubility difference of crystals, as developed by Blackmond and Hein, is a powerful step in that direction. As we develop the technology, we will be pushed into the fundamental physics and chemistry. Practice and theory must go hand in hand. The road is open.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Richard M. Kellogg: 0000-0002-8409-829X Funding

Partial funding has been provided by the European Commission (seventh Framework Program NMP4-SL-2008214340) and from CONICET of Argentina (PIPS 112-20110100650 and 112-201101-00594) and the Cesar Milstein Fellowship. Notes

The author declares no competing financial interest. Biography Richard Kellogg was born in Los Angeles, California, and educated in the United States. He was professor of chemistry at the University of Groningen for many years and now works for a private company.

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ACKNOWLEDGMENTS I have had the privilege to work together with many people, many of whom are mentioned in the text. The students and postdoctoral fellows are cited in the references. Particular thanks go to Michel Leeman and Maarten van der Meijden for their work at Syncom. I am delighted that some of the chemistry that we have developed has also been used by others. In a practical fashion.

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REFERENCES

(1) Woodward, R. B.; Hoffmann, R. The Conservation of Orbital Symmetry. Angew. Chem. 1969, 81, 797−853. (2) Woodward, R. B.; Hoffmann, R. Stereochemistry of Electrocyclic Reactions. J. Am. Chem. Soc. 1965, 87, 395−397. (3) Recent review: Seeman, J. I. Woodward-Hoffmann’s Stereochemistry of Electrocyclic Reactions: From Day 1 to the JACS Receipt Date (May 5, 1964 to November 30, 1964). J. Org. Chem. 2015, 80, 11632−11671. (4) Huisgen, R.; Scheer, W.; Huber, H. Stereospecific Conversion of cis-trans Isomeric Aziridines to Open-Chain Azomethine Ylides. J. Am. Chem. Soc. 1967, 89, 1753. (5) Wynberg, H.; van Driel, H.; Kellogg, R. M.; Buter. Photochemistry of Thiophenes. IV. Scope of Arylthiophene Rearrangements. J. Am. Chem. Soc. 1967, 89, 3487−3494. 912


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Accounts of Chemical Research (23) Vriesema, B. K.; Lemaire, M.; Buter, J.; Kellogg, R. M. Chiral (Macrocyclic) Sulfide- and Sulfide/Alkylamino-Containing Ligands for Nickel-Catalyzed Grignard Cross-Coupling Reactions. J. Org. Chem. 1986, 51, 5169. (24) Kellogg, R. M. In The Science of Synthesis: Houben-Weyl Methods of Molecular Transformations; Snieckus, V., Ed.; Thieme: Stuttgart, 2006, Vol 8b, Rubidium and Cesium Halides, pp 1485−1495, and Rubidium and Cesium Carbonates, pp 1497−1515. (25) Strijtveen, B.; Kellogg, R. M. Synthesis of (Racemization Prone) Optically Active Thiols by S N 2 Substitution Using Cesium Thiocarboxylates. J. Org. Chem. 1986, 51, 3664−3671. (26) Hof, R. P.; Kellogg, R. M. Synthesis of Enantiomerically Pure (R)- and (S)-2-Sulfanylpropanoic Acids (‘Thiolactic Acid’) from Ethyl (S)-Lactate Using Pig Liver Esterase. J. Chem. Soc., Perkin Trans. 1 1995, 1247−1249. (27) The use of cesium carbonate extends over almost the entire range of cross-coupling reactions. (28) Dijkstra, G.; Kruizinga, W. H.; Kellogg, R.M. J. An Assessment of the Causes of the “Cesium Effect. J. Org. Chem. 1987, 52, 4230− 4234. (29) Lan, J.; Zheng, X. H.; Hao, H.; Wang, X. L.; Shi, X. Q.; Zeng, Z. Electrical Switching in a Fe-thiacrown Molecular Device. J. Appl. Phys. 2014, 115, 013702−1−4. (30) Fedorova, O. A.; Fedorov, Y. N.; Vedernikov, A. I.; Gromov, S. P.; Yescheulova, O. V.; Alfimov, M. V.; Woerner, M.; Bossmann, S.; Braun, A.; Saltiel, J. Thiacrown Ether Substituted Styryl Dyes: Synthesis, Complex Formation and Multiphotochromic Properties. J. Phys. Chem. A 2002, 106, 6213−6222. (31) Hiemstra, H.; Wynberg, H. Addition of Aromatic Thiols to Conjugated Cycloalkenones, Catalyzed by Chiral Beta-Hydroxy Amines. A Mechanistic Study of Homogeneous Catalytic Asymmetric Synthesis. J. Am. Chem. Soc. 1981, 103, 417−430. (32) Dijkstra, G. D. H.; Kellogg, R. M.; Wynberg, H.; Svendsen, J. S.; Marko, I.; Sharpless, K. B. Conformational Study of Cinchona Alkaloids. A Combined NMR, Molecular Mechanics, and X-ray Approach. J. Am. Chem. Soc. 1989, 111, 8069. (33) Dijkstra, G. D. H.; Kellogg, R. M.; Wynberg, H. Conformational Study of Cinchona Alkaloids. A Combined NMR and Molecular Orbital Approach. J. Org. Chem. 1990, 55, 6121−6131. (34) Conformational aspects and applications of cinchona alkaloids have, of course, been subsequently investigated in enormous detail. For recent work, see: Lam, Y-h.; Houk, K. N. Origins of Stereoselectivity in Intramolecular Aldol Reactions Catalyzed by Cinchona Amines. J. Am. Chem. Soc. 2015, 137, 2116. (35) Strijtveen, B.; Feringa, B. L.; Kellogg, R. M. Methylphosphonic Dichloride as Reagent for the Determination of the Enantiomeric Excess of Chiral Thiols. Scope and Limitations. Tetrahedron 1987, 43, 123−130. (36) The principle was first defined by Horeau37 and involves selfrecognition of chirality. An achirotopic but stereogenic central atom allows the formation of chiral and meso diastereomers, the ratio of which can be used to derive the enantioenrichment. Although modern chiral HPLC analysis has supplanted many NMR methods, the concept remains interesting and suitable for use in other situations.38 (37) Vigneron, J. P.; Dhaenens, M.; Horeau, A. Nouvelle Methode pour Porter au Maximum la Purete Optique d’un Produit Partiellement Dedouble sans l’Aide d’Aucune Substance Chirale. Tetrahedron 1973, 29, 1055. (38) Kellogg, R. M.; Kaptein, B.; Vries, T. R. Dutch Resolution of Racemates and the Roles of Solid Solution Formation and Nucleation Inhibition. Top. Curr. Chem. 2007, 269, 159−197. (39) For an excellent current discussion of enantiomeric separation, see Lorenz, H.; Seidel-Morgenstern, A. Processes to Separate Enantiomers. Angew. Chem., Int. Ed. 2014, 53, 1218−1250. (40) Syncom BV homepage http://www.syncom.nl. (41) Gervais, C.; Grimbergen, R. F. P.; Markovits, I.; Ariaans, G. J. A.; Kaptein, B.; Bruggink, A.; Broxterman, Q. B. Prediction of Solid Solution Formation in a Family of Diastereomeric Salts. A Molecular Modelling Study. J. Am. Chem. Soc. 2004, 126, 655−662.

(42) Dalmolen, J.; Tiemersma-Wegman, T. D.; Nieuwenhuijzen, J. W.; van der Sluis, M.; van Echten, E.; Vries, T. R.; Kaptein, B.; Broxterman, Q. B.; Kellogg, R. M. The Dutch Resolution Variant of the Classical Resolution of Racemates by Formation of Diastereomeric Salts: Family Behaviour in Nucleation Inhibition. Chem. - Eur. J. 2005, 11, 5619−5624. (43) Weissbuch, I.; Addadi, L.; Leiserowitz, L. Molecular Recognition at Crystal Interfaces. Science 1991, 253, 637−645. (44) Kuzmenko, I.; Rapaport, H.; Kjaer, K.; Als-Nielsen, J.; Weissbuch, I.; Lahav, M.; Leiserowitz, L. Design and Characterization of Crystalline Thin Film Architectures at the Air-Liquid Interface: Simplicity to Complexity. Chem. Rev. 2001, 101, 1659−1696. (45) Weissbuch, I.; Lahav, M.; Leiserowitz, L. Toward Stereochemical Control, Monitoring, and Understanding of Crystal Nucleation. Cryst. Growth Des. 2003, 3, 125−150. (46) For a recent example, see: Hu, L.; Yang, Y.; Aloysius, H.; Albanyan, H.; Yang, M.; Liang, J.-J.; Yu, A. C.; Shtukenberg, A. G.; Poloni, L. N.; Kholodovych, V.; Tischfield, J. A.; Goldfarb, D. S.; Ward, M. D.; Sahota, A. L-Cysteine Diamides as L-Cystine Crystallization Inhibitors for Cystinuria. J. Med. Chem. 2016, 59, 7293−7299. (47) Davey, R. J.; Schroeder, S. L. M.; ter Horst, J. H. Nucleation of Organic Crystals − A Molecular Perspective. Angew. Chem., Int. Ed. 2013, 52, 2166−2179. (48) See, for example: (a) Erdemir, D.; Lee, A. Y.; Myerson, A. S. Nucleation of Crystals from Solution: Classical and Two-Step Models. Acc. Chem. Res. 2009, 42, 621−629. (49) Wolde, P. R. t.; Frenkel, D. Enhancement of Protein Crystal Nucleation by Critical Density Fluctuations. Science 1997, 277, 1975− 1978. (50) Myerson, A. S.; Trout, B. L. Nucleation from Solution. Science 2013, 341, 855−856. (51) Nielsen, M. H.; Aloni, S.; De Yoreo, J. J. In situ TEM Imaging of CaCO3 Nucleation Reveals Coexistence of Direct and Indirect Pathways. Science 2014, 345, 1158−1162. (52) Kulkarni, S. A.; Kadam, S. S.; Meekes, H.; Stankiewicz, A. I.; ter Horst, J. H. Crystal Nucleation Kinetics from Induction Times and Metastable Zone Widths. Cryst. Growth Des. 2013, 13, 2435−2440. (53) Jonkheijm, P.; van der Schoot, P.; Schenning, A. P. H.; Meijer, E. W. Probing the Solvent-Assisted Nucleation Pathway in Chemical Self-Assembly. Science 2006, 313, 80−83. (54) Mullin, J. W. Crystallization, 4th ed; Elsevier: Amsterdam, 2001; p 109. (55) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates, and Resolutions; Krieger: Malabar, 1994. (56) Leeman, M.; Brasile, G.; Gelens, E.; Vries, T.; Kaptein, B.; Kellogg, R. Structural Aspects of Nucleation Inhibitors for Diastereomeric Resolutions and the Relationship to Dutch Resolution. Angew. Chem., Int. Ed. 2008, 47, 1287−1290. (57) In economic terms, it is may be easier to recover and purify (or reuse) a single resolving agent with a nucleation inhibitor rather than the usual 3-fold mixtures used for Dutch Resolution. (58) van t’Hoff, J. H. Physical Chemistry in the Service of Science; University Press: Chicago, 1903; p 116; cited in ref 54. (59) Coquerel, G. Crystallization of Molecular Systems from Solution: Phase Diagrams, Supersaturation and Other Basic Concepts. Chem. Soc. Rev. 2014, 43, 2286−2300. (60) Rougeot, C.; Hein, J. Application of Continuous Preferential Crystallization to Efficiently Access Enantiopure Chemicals. Org. Process Res. Dev. 2015, 19, 1809−1819. (61) Viedma, C. Chiral Symmetry Breaking During Crystallization: Complete Chiral Purity Induced by Nonlinear Autocatalysis and Recycling. Phys. Rev. Lett. 2005, 94, 065504. (62) Noorduin, W. L.; Izumi, T.; Millemaggi, A.; Leeman, M.; Meekes, H.; van Enckevort, W. J. P.; Kellogg, R. M.; Kaptein, B.; Vlieg, E.; Blackmond, D. G. Emergence of a Single Chiral Solid State from a Nearly Racemic Amino Acid Derivative. J. Am. Chem. Soc. 2008, 130, 1158−1159. 913


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Accounts of Chemical Research (63) Iggland, M.; Mazzotti, M. A Population Balance Model for Chiral Resolution via Viedma Ripening. Cryst. Growth Des. 2011, 11, 4611−4622. (64) Gherase, D.; Conroy, D.; Matar, O. K.; Blackmond, D. G. Experimental and Theoretical Study of the Emergence of Single Chirality in Attrition-Enhanced Deracemization. Cryst. Growth Des. 2014, 14, 928−937. (65) Noorduin, W. L.; Kaptein, B.; Meekes, H.; van Enckevort, W. J. P.; Kellogg, R. M.; Vlieg, E. Fast Attrition-Enhanced Deracemization of Naproxen by a Gradual in situ Feed. Angew. Chem., Int. Ed. 2009, 48, 4581−4583. (66) Kaptein, B.; Vlieg, E.; Noorduin, W. L. (DSM IP Assets) Method for the synthesis of chiral alpha-aryl propionic acid derivatives. WO 2010/089343 A1, August 12, 2010. (67) van der Meijden, M. W.; Leeman, M.; Gelens, E.; Noorduin, W. L.; Meekes, H.; van Enckevort, W. J. P.; Kaptein, B.; Vlieg, E.; Kellogg, R. M. Attrition-Enhanced Deracemization in the Synthesis of Clopidogrel − A Practical Application of a New Discovery. Org. Process Res. Dev. 2009, 13, 1195−1198. (68) Wilmink, P.; Rougeot, C.; Wurst, K.; Sanselme, M.; van der Meijden, M.; Saletra, W.; Coquerel, G.; Kellogg, R. M. Attrition Induced Deracemisation of 2-Fluorophenylglycine. Org. Process Res. Dev. 2015, 19, 302−308. (69) Leeman, M.; Kaptein, B.; Kellogg, R. M. Nucleation Inhibition in Attrition-Enhanced Pope-Peachey Type of Diastereomeric Resolutions. Tetrahedron: Asymmetry 2009, 20, 1363−1364. (70) Otero-de-la-Roza, A.; Hein, J. E.; Johnson, E. R. Reevaluating the Stability and Prevalence of Conglomerates: Implications for Preferential Crystallization. Cryst. Growth Des. 2016, 16, 6055−6059. (71) Otero-de-la-Roza, A.; Cao, B. H.; Price, I. K.; Hein, J. E.; Johnson, E. R. Predicting the Relative Solubilities of Racemic and Enantiopure Crystals by Density-Functional Theory. Angew. Chem., Int. Ed. 2014, 53, 7879−7882. (72) Noorduin, W. L.; van der Asdonk, P.; Bode, A. A. C.; Meekes, H.; van Enckevort, W. J. P.; Vlieg, E.; Kaptein, B.; van der Meijden, M. W.; Kellogg, R. M.; Deroover, G. Scaling Up Attrition-Induced Deracemization by Use of an Industrial Bead Mill in a Route to Clopidogrel (Plavix). Org. Process Res. Dev. 2010, 14, 908−911. (73) Iggland, M.; Fernández-Ronco, M. P.; Senn, R.; Kluge, J.; Mazzotti, M. Complete Solid State Deracemization by High Pressure Homogenization. Chem. Eng. Sci. 2014, 111, 106−111. (74) Suwannasang, K.; Flood, A. E.; Coquerel, G. A Novel Design Approach to Scale Up the Temperature Cycle Enhanced Deracemization Process: Coupled Mixed-Suspension Vessels. Cryst. Growth Des. 2016, 16, 6461−6467. (75) Steendam, R. R. E.; van Benthem, T. J. B.; Huijs, E. M. E.; Meekes, H.; van Enckevort, W. J. P.; Raap, J.; Rutjes, F. P. J. T.; Vlieg, E. Deracemization Controlled by Reaction-Induced Nucleation: Viedma Ripening as a Safety Catch for Total Spontaneous Resolution. Cryst. Growth Des. 2015, 15, 3917−3921. (76) Steendam, R. R.; Harmsen, B.; Meekes, H.; van Enckevort, W. J. P.; Kaptein, B.; Kellogg, R. M.; Raap, J.; Rutjes, F. P. J. T.; Vlieg, E. Controlling the Effect of Chiral Impurities on Viedma Ripening. Cryst. Growth Des. 2013, 13, 4776−4780. (77) Hein, J. E.; Huynh Cao, B.; Viedma, C.; Kellogg, R. M.; Blackmond, D. G. Pasteur’s Tweezers Revisited: On the Mechanism of Attrition-Enhanced Deracemization and Resolution of Chiral Conglomerate Solids. J. Am. Chem. Soc. 2012, 134, 12629−12636. (78) (a) Hein, J. H.; Cao, B. H.; van der Meijden, M. W.; Leeman, M.; Kellogg, R. M. Resolution of Omeprazole Using Coupled Preferential Crystallization: Efficient Separation of a Nonracemizable Conglomerate Salt under Near-Equilibrium Conditions. Org. Process Res. Dev. 2013, 17, 946−950. (79) For related technology, see: Levilain, G.; Eicke, M. J.; SeidelMorgenstern, A. Efficient Resolution of Enantiomers by Coupling of Preferential Crystallization and Dissolution. Part 1: Experimental Proof of Principle. Cryst. Growth Des. 2012, 12, 5396−5401. (80) Coquerel, G.; Petit, M. N.; Tauvel, G. Method for Resolving Omeprazole Salts. U.S. Patent 2009/0124811 A1, 2009.

(81) Aizenberg, J.; Black, A. J.; Whitesides, G. M. Control of Crystal Nucleation by Patterned Self-Assembled Monolayers. Nature 1999, 398, 495−498. (82) Raval, R. Chiral Expression from Molecular Assemblies at Metal Surfaces: Insights from Surface Science Techniques. Chem. Soc. Rev. 2009, 38, 707−721. (83) Raval, R. Mirrors in Flatland. Nature 2003, 425, 463−464. (84) van der Meijden, M. W.; Gelens, E.; Quirós, N. M.; Fuhr, J. D.; Gayone, J. E.; Ascolani, H.; Wurst, W.; Lingenfelder, M.; Kellogg, R. M. Synthesis, Properties, and Two-Dimensional Adsorption Characteristics of 5-Amino[6]hexahelicene. Chem. - Eur. J. 2016, 22, 1484. (85) Balandina, T.; van der Meijden, M. W.; Ivasenko, O.; Cornil, D.; Cornil, J.; Lazzaroni, R.; Kellogg, R. M.; De Feyter, S. Self-assembly of an Asymmetrically Functionalized [6]Helicene at Liquid/Solid Interfaces. Chem. Commun. 2013, 49, 2207−2209. (86) Mali, K. S.; Adisoejoso, J.; Ghijsens, E.; De Cat, I.; De Feyter, S. Exploring the Complexity of Supramolecular Interactions for Patterning at the Liquid-Solid Interface. Acc. Chem. Res. 2012, 45, 1309−1320. (87) Fasel, R.; Parschau, M.; Ernst, K. H. Amplification of Chirality in Two-Dimensional Enantiomorphous Lattices. Nature 2006, 439, 449. (88) Ascolani, H.; van der Meijden, M. W.; Cristina, L. J.; Gayone, J. E.; Kellogg, R. M.; Fuhr, J. D.; Lingenfelder, M. Van der Waals Interaction in the Self-Assembly of 5-Amino[6]helicene on Cu(100) and Au(111). Chem. Commun. 2014, 50, 13907−13909. (89) For a related synthesis and two dimensional studies of an acidic hexahelicene, see: van der Meijden, M. W.; Balandina, T.; Ivasenko, O.; De Feyter, S.; Wurst, K.; Kellogg, R. M. Synthesis, Properties and Two Dimensional Adsorption Characteristics of [6]Hexahelicene-7Carboxylic Acid. Chem. - Eur. J. 2016, 22, 14633−14639. (90) Together with David Amabilino and Maggie Lingenfelder, we have developed a functionalized phencyphos derivative that can be absorbed on a surface of Au and then used for microcontact printing: Lingenfelder, M.; Bejarano-Villafuerte, A.; van der Meijden, M. W.; Kellogg, R. M.; Amabilino, D. B. Localized Crystallization of Enantiomeric Organic Compounds on Chiral Micro-patterns from Various Organic Solutions. Chem. - Eur. J. 2014, 20, 10466−10474.

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