USOO7709632B2

(12) United States Patent (10) Patent No.: US 7,709,632 B2 Johnson et al. (45) Date of Patent: May 4, 2010

(54) METHODS, COMPOSITIONS, AND 2005, 0096475 A1 5/2005 Ikemoto et al. APPARATUSES FOR FORMING MACROCYCLIC COMPOUNDS OTHER PUBLICATIONS A Simplified Synthesis for meso-Tetraphenylporphyrin, Adler, A.D., (76) Inventors: Thomas E. Johnson, 100 Snapfinger et al., J. Org. Chem. vol. 32 (1967) 476. Dr. Athens, GA (US) 30605; Billy T. Condensation of Pyrrole with Aldehydes in the Presence of Y Fowler, 9711 Wildcat Bridge Rd., Zeolites and Mesoporous MCM-41 Aluminosilicate: on the Encap Danseville, GA (US) 30633 sulation of Porphyrin Precursors, Algarra, F., et al., New J. Chem. (1998) 333-338. (*) Notice: Subject to any disclaimer, the term of this Interlocked and Intertwined Structures and Superstructures, patent is extended or adjusted under 35 Amabilino, D.B., et al., Chem. Rev. vol. 95 (1995) 2725-2828. U.S.C. 154(b) by 1478 days. Rapid Communication. Imidazolium-Linked Cyclophanes, Baker, M.V., et al., Aust. J. Chem. vol. 52 (1999) 823-825. (21) Appl. No.: 11/059,796 Self-Assembly of Novel Macrocyclic Aminomethylphosphines with Hydrophobic Intramolecular Cavities, Balueva, A.S., et al., J. Chem. (22) Filed: Feb. 17, 2005 Soc. Dalton Trans. (2004) 442-447. Chelation-Controlled Bergamin Cyclization: Synthesis and Reactiv (65) Prior Publication Data ity of Enediynyl Ligands, Basak, A., et al., Chem. Rev. vol. 103 (2003) 4077-4094. US 2007/0217965 A1 Sep. 20, 2007 Macrocyclic Aromatic Thioether Sulfones, Baxter, I., et al., Chem. Commun. (1998) 283-284. Related U.S. Application Data Cyclic Oligomers of Poly(ether ketone) (PEK): Synthesis, Extraction from Polymer, Fractionation and Characterization of the Cyclic (60) Provisional application No. 60/545,131, filed on Feb. Trimer, Tetramerand Pentamer, Ben-Haida, A., et al., J. Mater: Chem. 17, 2004. vol. 10 (2000) 2011-2016. Porphyrin Synthesis in Surfactant Solution: Multicomponent Assem (51) Int. Cl. bly in Micelles, Bonar-Law, R.P. J. Org. Chem. vol. 61 (1996) C07B 47/00 (2006.01) 3623-3634. (52) U.S. Cl...... 540/145 5, 10-Diphenyltripyrrane. A Useful Building Block for the Synthesis (58) Field of Classification Search ...... 540/145 of meso-Phenyl Substituted Expanded Macrocycles, Brickner, C., et al., Chem. Commun. (1997) 1689-1690. See application file for complete search history. Synthesis of Phosphorus-Containing Macrocycles and Cryptands, (56) References Cited Caminade, A.-M., et al., Chem. Rev. vol. 94 (1994) 1183-1213. Nanoscale Borromean Rings, Cantrill, S.J., et al., Accts. Chem. Res. U.S. PATENT DOCUMENTS vol. 38 (2005) 1-9. 4,980,453 A 12/1990 Brunelle et al. (Continued) 5,206,362 A 4, 1993 Speranza et al. 5,214,158 A 5, 1993 Brunelle et al. Primary Examiner James O. Wilson Assistant Examiner Paul V. Ward 5,231,161 A 7, 1993 Brunelle et al. (74) Attorney, Agent, Of Firm—Intellectual 5,357,029 A 10, 1994 Takekoshi et al. Property/Technology Law; Steven J. Hultquist; David Bradin 5,512,675 A 4, 1996 Tang et al. 5,587,451 A 12/1996 Athey et al. (57) ABSTRACT 5,936,100 A 8, 1999 Furstner et al. 5.948,693. A 9, 1999 Rich et al. This invention relates to methods, compositions, and appara 5,955,603 A 9, 1999 Therien et al. tuses for producing macrocyclic compounds. First, one or 6,072,054 A 6, 2000 Abd-El-Aziz et al. more reactants are provided in a reaction medium, which are 6,080,826 A 6, 2000 Grubbs et al. capable of forming the macrocyclic compound through a 6,130,330 A 10, 2000 Nestler et al. desired reaction pathway that includes at least cyclization, 6,310,180 B1 10/2001 Tam and which are further capable of forming undesired oligo 6,333,391 B1 12/2001 Laycocket al. mers through a undesired reaction pathway that includes 6,337,395 B1 1/2002 Ercolani et al. undesirable oligomerization. Oligomerization of Such reac 6,433,162 B1 8, 2002 Nickel et al. tions in the reaction medium is modulated to reduce forma 6,610,351 B2 8/2003 Shchegolikhin et al. tion of undesired oligomers and/or to reduce separation of the undesired oligomers from the reaction medium, relative to a 6,712,972 B2 3, 2004 Pothuri et al. corresponding unmodulated oligomerization reaction, 6,762,315 B1 7/2004 Scherer et al. thereby maximizing yields of the macrocyclic compound. 6,822,092 B2 11/2004 Osuka The macrocyclic compound so formed is then recovered from 6,849,730 B2 2/2005 Lindsey et al. the reaction medium. Preferably, the macrocyclic compound 6,855,798 B2 2, 2005 Faler spontaneously separates from the reaction medium via phase 2002fOO37560 A1 3/2002 Chappell et al. separation. More preferably, the macrocyclic compound 2002.0137924 A1 9, 2002 Robinson et al. spontaneous precipitates from the reaction medium and 2004/O115724 A1 6, 2004 Lowik et al. therefore can be easily recovered by simple filtration. 2004/O132934 A1 7/2004 Grubbs et al. 2004/0206940 A1 10, 2004 Boschetti et al. 64 Claims, 24 Drawing Sheets US 7,709,632 B2 Page 2

OTHER PUBLICATIONS Intramolecular Reaction in Polycondensations II. Ring Chain Equi librium in Polydecamethylene Adipate, Jacobson, H., et al., J. Chem. Synthesis of Cyclic Peptides from Unprotected Precursors. Using Phys. vol. 18 (1950) 1607-1612. Removable N(alpha)-(1-(4-methoxyphenyl)-2-mercaptoethyl) A One-Pot Four-Component (ABC) Synthesis of Macrocycles, Auxiliary, Cardona, V.M.F., et al., J. Peptide Res, vol. 61 (2003) Janvier, P. et al., Angew: Chem. Int. Ed. vol. 42 (2003) 811-814. 152-157. Ring Closure Reactions of Bifunctional Chain Molecules, Illuminati, Temperature Regiocontrol of Intramolecular Cyclization of G. et al., Acc. Chem. Res, vol. 14 (1981) 95-102. Di-HydroxySecoacids, Caruso, T., et al., Org. Biomol. Chem. vol. 2 The Synthesis and Characterization of a Novel vic-Dioxime and its (2004) 3425-3426. Mononuclear Complexes Bearing an 18-Membered NOS Ring-Chain Equilibrium in Reversibly Associated Polymer Solu Macrocycle and their Characteristics as Extractants for Transition tions: Monte Carlo Simulations, Chen, C.-C., et al., Macromolecules, Metal Ions, Kantekin, H., et al., J. Inc. Phenom. vol. 48 (2004) vol. 37 (2004)3905-3917. 95-101. A New method for the Synthesis of Boronate Macrocycles, Dynamic Combinatorial Libraries of Metalloporphyrins: Templated Christinat, N., et al., Chem. Commun. (2004) 1158-1159. Amplification of Disulfide-Linked Oligomers, Kieran, A.L., et al., A Convenient Procedure for Moderate-Scale Rothemund Synthesis Chem. Commun. (2003) 2674-2675. of Lipophilic Porphyrins: An Alternative to the Adler-Longo and Dynamic Synthesis of a Macrocycle Containing a Porphyrin and an Lindsey Methodologies, Crossley, M.J., et al., J. Porphyrins Electron Donor, Kieran, A.L., et al., Chem. Commun. (2005) 1842 Phthalocyanines, vol. 2 (1998) 511-516. 1844. Modulation of Reactivity in Native Chemical Ligation through the Biomimetic Synthesis and Optimization of Cyclic Peptide Antibiot Use of Thiol Additives, Dawson, P.E., et al., J. Am. Chem. Soc. vol. ics, Kohli, R.M., et al., Nature vol. 418 (2002) 658-661. 119 (1997) 4325-4329. One-Step Syntheses of Macrocyclic Compounds: A Short Review, Synthesis of Oxygen- and Nitrogen-Containing Heterocycles by Krakowiak, K.E., et al., J. Heterocyclic Chem. vol. 38 (2001) 1239 Ring-Closing Metathesis, Deiters, A., et al., Chem. Rev. vol. 104 1248. (2004) 2199-2238. Calixphyrins: Novel Macrocycles at the Intersection between Interlocking of Molecular Threads: From the Statistical Approach to Porphyrins and Calixpyrroles, Kral, V., et al., Angew: Chem. Int. Ed. the Templated Synthesis of Catenands, Dietrich-Buchecker, C.O., et vol. 39 (2000) 1055-1058. al., Chem. Rev. vol. 87 (1987) 795-810. Macrocyclic Dibutyltin Dicarboxylates via Thermodynamically Samarium(II)-Iodide-Mediated Cyclizations in Natural Product Syn Controlled Polycondensations, Kricheldorf, H.R., Macromol. Chem. thesis, Edmonds, D.J., et al., Chem. Rev. vol. 104 (2004)3371-3403. Phys. vol. 203 (2002) 313-318. Macrocyclization Under Thermodynamic Control. A Theoretical Cyclic Polymers by Kinetically Controlled Step-Growth Polymer Study and Its Application to the Equilibrium Cyclooligomerization ization, Kricheldorf, H.R., et al., Macromol. Rapid Commun, vol. 24 of beta-Propiolactone, Ercolani, G., et al., J. Am. Chem. Soc. vol. 115 (2003) 359-381. (1993)3901-3908. Macrocycles. 21. Role of Ring-Ring Equilibria in Thermodynami Novel Porphyrinoids for Chemistry and Medicine by Biomimetic cally Controlled Polycondensations, Kricheldorf, H.R., et al., Mac Syntheses, Franck, B., et al., Angew. Chem. Int. Ed. Engl. vol. 34 romolecules vol. 36 (2003) 2302-2308. (1995) 1795-1811. The Synthesis of Cyclic Peptides, Lambert, J.N., et al., J. Chem. Soc., Cyclization Strategies for the Synthesis of Macrocyclic Perkin Trans. 1 (2001) 471-484. Bisindolylmaleimides, Faul, M.M., et al., J. Org. Chem. vol. 66 Cyclization Reactions of Dianions in Organic Synthesis, Langer, P. (2001) 2024-2033. et al., Chem. Rev. vol. 104 (2004) 4125-4149. Amplification of Dynamic Chiral Crown Ether Complexes. During Cryptates: The Chemistry of Macropolycyclic Inclusion Complexes, Cyclic Acetal Formation, Fuchs, B., et al., Angew. Chem. Int. Ed. vol. Lehn, Jean-Marie, Acc. Chem. Res. Vol. 11 (1978) 49-57. 42 (2003) 4220-4224. Self-Assembly of Discrete Cyclic Nanostructures Mediated by Tran Supramolecular Templating in Thermodynamically Controlled Syn sition Metals, Leininger, S., et al., Chem. Rev. vol. 100 (2000) 853 thesis, Furlan, R.L.E., et al., Proc. Nat. Acad. Sci., vol. 99 (2002) 908. 4801-4804. Beneficial Effects of Salts on an Acid-Catalyzed Condensation Lead Synthetic Cyclic Oligosaccharides, Gattuso, G. et al., Chem. Rev. ing to Porphyrin Formation, Li, F., et al., Tetrahedron vol. 53 (1997) vol. 98 (1998) 1919-1958. 12339-1236O. Clays as a Host Matrix in the Synthesis of Organic Macrocycles, Rothemund and Adler-Longo Reactions Revisited: Synthesis of Georgakilas, V., et al., Chem. Eur: J. vol. 9 (2003)3904-3908. Tetraphenylporphyrins Under Equilibrium Conditions, Lindsey, J.L., Selective Host Amplification from a Dynamic Combinatorial Library et al., J. Org. Chem. vol. 52 (1987) 827-836. of Oligoimines for the Synthesis of Different Optically Active Diyl Trapping and Electoreductive Cyclization Reactions, Little, R. Polyazamacrocycles, Gonzalez-Alvarez, A., et al., Eur: J. Org. Chem. Daniel, Chem. Rev. vol. 96 (1996) 93-114. (2004) 1117-1127. Synthesizing Macrocycles Under Thermodynamic Control-Dy Novel Synthesis of 5,10,15,20-Tetraarylporphyrins Using High namic Combinatorial Libraries and Templates, Lining, U., J. Inc. Valent Transition Metal Salts, Gradillas, A., et al., J. Chem. Soc. Phenom. vol. 49 (2004) 81-84. Perkin Trans. I (1995) 2611-2613. Synthesis of Phosphorous and Sulfur Heterocycles via Ring-Closing Ring-Closing Metathesis and Related Processes in Organic Synthe Olefin Metathesis, McReynolds, M.D., et al., Chem. Rev. vol. 104 sis, Grubbs, R.H., et al., Acc. Chem. Res. vol. 28 (1995) 446-452. (2004) 2239-2258. Synthesis of a Series of Cyclic Oligo(alkylidene isophthalate)s by Difficult Macrocyclizations: New Strategies for Synthesizing Highly Cyclo-Depolymerisation, Hall, A.J., et al., Polymer vol. 41 (2000) Strained Cyclic Tetrapeptides, Meutermans, W.D.F., et al., Org. Lett. 1239-1249. vol. 5 (2003)2711-2714. 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Studies Directed Toward the Synthesis of Vancomycin and Related Porphyrins with Record-Breaking Long-Wavelength Electronic Cyclic Peptides, Rama Rao, A.V., et al., Chem. Rev. vol. 95 (1995) Absorptions, Spence, J.D., et al., J. Org. Chem. vol. 65 (2000) 1530 2135-2167. 1539. Novel Synthesis of Macrocycles with Chalcone Moieties through How to Synthesize Macrocycles Efficiently Using Virtual Mixed Aldol Reaction, Rao, M.L.N., et al., Tetrahedron Lett. vol. 42 Combinatorial Libraries, Storm. O., et al., Chem. Eur: J. vol. 8 (2002) (2001) 8351-83.55. 793-798. Building Thermodynamic Combinatorial Libraries of Quinine A Biomimetic Strategy for the Synthesis and Fragmentation of Macrocycles, Rowan, S.J., et al., Chem. Commun. (1997) 1407-1408. Cyclic Protein, Tam, J.P. et al., Protein Sci., vol. 7 (1998) 1583-1592. Dynamic Covalent Chemistry, Rowan, S.J., et al., Angew. Chem. Int. Thia Zip Reaction for Synthesis of Large Cyclic Peptides: Mecha Ed. vol. 41 (2002) 898-952. nisms and Applications, Tam, J.P. et al., J. Am. Chem. Soc. vol. 121 (1999) 4316-4324. Chiral Heterocycles by Iminium Ion Cyclization, Royer, J., et al., Orthogonal Ligation Strategies for Peptide and Protein, Tam, J.P., et Chem. Rev. vol. 104 (2004) 2311-2352. al., Biopolymers vol. 51 (1999) 311-332. Template Condensation Reactions of Formaldehyde with Amines RCM Approach for the Total Synthesis of Crytophycin-24 and 2, 3-Butanedihydrazone: Preparation and Properties of (Arenastatin A), Tripathy, N. K., et al., Tetrahedron Lett. vol. 45 Nickel(II) Complexes of 18-Membered Decaaza Macrocycles, (2004) 5309-5311. Salavati-Niasari, M., et al., Polyhedron vol. 23 (2004) 1325-1331. Anion-Templated Synthesis, Vilar, R., Angew: Chem. Int. Ed. vol. 42 Interlacing Molecular Threads on Transition Metals: Catenands, Cat (2003) 1460-1477. enates, and Knots, Sauvage, Jean-Pierre. Acc. Chem. Res. Vol. 23 End-to-End Cyclization of Polymer Chains, Winnik, Mitchell A., (1990) 319-327. Acc. Chem. Res. vol. 18 (1985) 73-79. Efficient Diastereoselective Synthesis of Chiral Macrocycles via Metal-Mediated Synthesis of Medium-Sized Rings, Yet, Larry, Zirconocene Coupling. Synthetic Control of Size and Geometry, Chem. Rev. vol. 100 (2000) 2963-3007. Schafer, L.L., J. Am. Chem. Soc. vol. 123, (2001) 2683-2684. Highly Efficient, One-Step Macrocyclizations Assisted by the Fold Synthetic Expanded Porphyrin Chemistry, Sessler, J.L., et al., Angew: ing and Preorganization of Precursor Oligomers, Yuan, L., et al., J. Chem. Int. Ed. vol. 42 (2003) 5.134-5175. Am. Chem. Soc. vol. 126 (2004) 11120-11 121. Advances in Modern Synthetic Porphyrin Chemistry, Synthesis and Application of Unprotected Cyclic Peptides as Build Shanmugathasan, S., et al., Tetrahedron vol. 56, (2000) 1025-1046. ing Blocks for Peptide Dendrimers, Zhang, L., et al., J. Am. Chem. Soc. vol. 119 (1997) 2363-2370. Efficient Synthesis of Macrocyclic Diamides, Sharghi, H., Tetrahe Lactone and Lactam Library Synthesis by Silver Ion-Assisted dron vol. 51 (1995) 9 13-922. Orthogonal Cyclization of Unprotected Peptides, Zhang, L., et al., J. Syntheses of Large-Membered Macrocycles Having Multiple Am. Chem. Soc. vol. 121 (1999) 3311-3320. Hydrogen Bonding Moieties, Shimakoshi, H., et al., Tetrahedron Arylene Ethynylene Macrocycles Prepared by Precipitation-Driven Lett. vol. 43 (2002) 8261-8264. Alkyne Metathesis, Zhang, W., et al., J. Am. Chem. Soc. vol. 126 The Synthesis of Large Ring Compounds, Roxburgh, C.J. Tetrahe (2004) 12796. dron vol. 51 (1995) 9767-9822. Sharghi, H. et al., “Novel Sythesis of meso-tetraarylporphyrins using Porphyrins with Exocyclic Rings. 14. Synthesis of CF3SO2C1 under aerobic oxidation”, “Tetrahedron', Feb. 16, 2004, Tetraacenaphthoporphyrins, a New Family of Highly Conjugated pp. 1863-1868, vol. 60, Publisher: Elsevier. U.S. Patent May 4, 2010 Sheet 1 of 24 US 7,709,632 B2

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FIG.7B U.S. Patent May 4, 2010 Sheet 11 of 24 US 7,709,632 B2

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FIG.1 O U.S. Patent May 4, 2010 Sheet 15 of 24 US 7,709,632 B2

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N R ON N - 3 ...) 1 - C) R

R R R s e RN Br

R Br

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U.S. Patent May 4, 2010 Sheet 18 of 24 US 7,709,632 B2 U.S. Patent May 4, 2010 Sheet 19 of 24 US 7,709,632 B2

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SINVLOWER!! SINEATOS US 7,709,632 B2 1. 2 METHODS, COMPOSITIONS, AND Conceptually, the synthesis of cyclic molecules begins APPARATUSES FOR FORMING with the preparation of open-chained starting materials which MACROCYCLIC COMPOUNDS are cyclized by a ring closure reaction. In contrast to the efficient formation of five- or six-member rings, however, CROSS REFERENCE TO RELATED problems are encountered when cyclization of compounds of APPLICATIONS other sizes, both Smaller and larger, is carried out in practice: yields of small rings (3-4 atoms) are low and even lower for This claims priority to U.S. Provisional Patent Application medium rings (8-12 carbon atoms) and macrocycles (>12 No. 60/545,131 filed Feb. 17, 2004 in the name of Thomas E. atoms). Due to ring strain effects, Small rings are less stable Johnson and Billy T. Fowler for “METHODS AND COM 10 than five- or six-member rings, and thus they are more diffi POSITIONS FOR FORMING CYCLIC COMPOUNDS cult to obtain. However, most macrocycles are unstrained and their enthalpy of formation is comparable to that of five- or FIELD OF THE INVENTION six-member rings. Thus, there are nothermodynamic barriers to the formation of unstrained macrocycle. Nonetheless, the The present invention relates generally to methods, com 15 kinetics of the formation of macrocycles greatly complicates positions, and apparatuses for synthesizing a wide variety of their formation. For entropic reasons, it is more difficult to macrocyclic compounds. synthesize macrocycles than Small and medium ring com pounds because macrocyclic ring formation involves a low probability for coincident positioning of the two ends of the BACKGROUND OF THE INVENTION open chain starting material, as required for cyclization to At a time when the small-molecule pipeline of the phar occur. Further, intermolecular reactions of the reactive ends maceutical industry is beginning to run dry, the number of of the linear precursor compete with the cyclization reaction. macrocycles has increased in an explosive manner. This fast Such intermolecular reactions lead to formation of undesired growing phenomenon is due to the discovery of an impressive oligomers and polymers. number of new families of natural, semi-synthetic, and Syn 25 In order to circumvent these undesirable oligomerization thetic compounds, which possess extraordinary properties. reactions, cyclization is generally carried out under relatively The macrocyclic structure is a particularly desirable feature dilute conditions (typically less than 10 mM). The rationale for the pharmaceutical industry. The cyclic structure stabi for the high dilution synthesis method is that if the concen lizes the molecule against destruction by the human body and tration of the reactants is sufficiently low, then the ring closure increases its effectiveness in comparison with its linear ana 30 reaction will be favored, since the reactive ends thereby are log, by constraining it to a biologically active form. Accord isolated from the reactants and therefore more likely to react ingly, macrocycles constitute a major class of pharmaceutical in an intramolecular fashion to effect ring formation. How agents that are currently under wide-spread clinical investi ever, the high dilution principle is most effective if the gation. cyclization reaction is an irreversible reaction and the rate of 35 cyclization is greater than the rate of polymerization. In con Moreover, macrocycles are key components in many other trast to this kinetic approach, in a thermodynamically con fields, including nanotechnology. Nanoscale devices Such as trolled, reversible reaction, the relative stabilities of all prod chemical noses for the detection of land mines, sensors for the ucts, macrocyclic or acyclic, determine the product detection of chemical weapons, light rods for Solar energy distribution. If the macrocycle is the most stable compound in conversion, photovoltaic cells, light emitting diodes, mag 40 such reversible reaction system, then the macrocycle will be netic materials, multi-bit storage devices, and semi-conduct formed in good yield. Indeed, some examples exist where ing materials have already been fashioned using macrocyclic macrocycles are in fact formed as the most stable products in compounds. a reversible reaction. However, in most cyclization reactions, In spite of their great potential, however, macrocycles have macrocycles and undesired oligomers and polymers are of remained relatively under-explored and unexploited. Current 45 comparable thermodynamic stabilities and therefore, all of methods used for the preparation of macrocycles severely them will exist as a complex mixture, which requires exten limit their use in medicine and other important industries. sive and complicated purification procedures in order to While some of these compounds are available from biological obtain the desired macrocyclic material. Furthermore, high Sources in quantities sufficient for basic research or initial dilution methods can only provide limited quantities of the clinical studies, others need to be produced by semi- or total 50 macrocyclic material and are therefore inappropriate for synthesis. The present methodologies for producing macro high-volume commercial production. cycles require hundreds of man-hours of work, produce large In order to overcome or mediate the above-described dif amounts of toxic waste, require expensive manufacturing ficulties and complications, a wide variety of modifications facilities, and still produce frustratingly low quantities of the and improvements have been made to the high dilution meth desired material. Low production yield renders the profit 55 ods, by adapting Such methods to the individual requirements margins of these molecules too small for commercial produc of specific target molecules. These approaches have achieved tion. Consequently, due to the high costs and low profit mar a wide variety of levels of success, on a molecule by molecule gins associated with production of macrocycles by conven basis. For example, it is now possible to prepare modest tional chemical manufacturing approaches, many important quantities of certain macrocycles by appropriate choice of discoveries are not commercialized. More importantly, the 60 starting material, Solvent, temperature, catalyst and dilution staggering potential of macrocyclic research and develop conditions, often with the assistance of other effects, e.g., the ment is largely unrealized, as the result of the inability of the template effect, the rigid group principle, and other pseudo art to provide a practical method for making Such compounds. dilution phenomenon. Thus, the inability to obtain large quantities of macrocyclic In Supramolecular chemistry, for example, the use of an molecules has been, and still is, the major stumbling block for 65 appropriate template can greatly improve cyclization steps. their commercial exploitation, as well as the stimulus for For those examples where the building blocks for the macro efforts to improve existing methods or to discover new ones. cycle and its oligomers are the same, an organic or inorganic US 7,709,632 B2 3 4 guest material (i.e., a template) may be found which binds of backbone peptide bonds. Unlike other methods, chemical complementarily into the cavity formed by the macrocycle. ligation methods do not require coupling reagents or protec Under reversible conditions, the resulting Supramolecular tion schemes, but are achieved through a variable chemose complex will be more stable than the macrocyclic component lective capture step followed by an invariable intramolecular and thus favored, which is known as the template effect. In 5 acyl transfer reaction. addition to mixtures in equilibrium, the template effect can Despite the development of the above-discussed synthesis also be useful in kinetically controlled reactions when the techniques and other high-dilution or pseudo-dilution meth template facilitates the intramolecular reaction by pre-orga ods, however, the practical aspects of the synthesis principle, nizing the reactive ends. Important features in high yield viz., the selection of starting materials and reaction param template-assisted cyclization reactions include the geometry 10 eters, still have to be determined empirically, and the cycliza of the template material, and the number of heteroatoms in the tion step still remains as the fundamental synthetic challenge. interior cavity of the macrocycle that are available for coor The requirements for complex multi-step processes, specific dinating with the template. reaction conditions, templates, selective protection/deprotec In addition to template materials that bind to a cavity tion steps, and high dilution of the reaction materials continue formed by the macrocycle, other materials with microporous 15 to restrict commercial production of macrocyclic com structures can pre-organize the reactive ends of the reactants pounds, even after extensive optimization, and the modified and thereby facilitate the ring closure reaction, by providing a or improved methods still suffer from many limitations of the localized environment defined by the microporous structure original high-dilution procedure. that is highly favorable to the ring closure reaction. For A general method that does not depend on high dilution of example, Smectite clays have been used to provide Substan the reaction materials or otherwise suffer the deficiencies of tial improvements in yield and/or selectivity of macrocyclic high dilution techniques and is useful for synthesis of a wide compounds. The predetermined architectures of the variety of macrocyclic compounds on a commercial scale microporous structures in the clays can be effectively used to would be of immense value. pre-organize the reactive Substances in a manner that controls the extent of oligomerization and the geometry of the macro 25 SUMMARY OF THE INVENTION cycle so formed. Subsequently, the final macrocyclic product can be removed from the clay framework. The present invention relates to a new method for produc Further, some structural elements have emerged that show ing macrocyclic compounds, which can be generally applied a propensity to bend linear structures and form pre-organized to increase the production yield and the Volumetric produc ring structures, Suggesting that such pre-organization can be 30 tion efficiency of a wide variety of different classes of mac used to favor intramolecular processes over the intermolecu rocyclic compounds. lar ones and provide simple routes for the preparation of The present invention also relates to new compositions and macrocyclic structures. This predisposition of certain mol to apparatuses for automated synthesis of a wide variety of ecules to bending or folding has been widely studied, e.g., the macrocyclic compounds for scale-up commercial production Thorpe-Ingold effect, and several structural elements, such as 35 of macrocyclic compounds at significantly reduced cost. urea and proline residues, have been identified as being asso In one aspect, the present invention relates to a process for ciated with the formation of U-turns in natural products. manufacturing at least one macrocyclic compound, which Consequently, sterically encumbering groups can be added to comprises the steps of: (a) providing a reaction system com acyclic precursors to effectuate bending thereof and to facili prising one or more reactants in a reaction medium, wherein tate ring closure, when the target macrocyclic compound does 40 Such reactants are capable of forming the macrocyclic com not normally contain such sterically encumbering groups. pound in the reaction medium at a first set of reaction condi Recent years have witnessed a renaissance in the field of tions through at least one desired reaction pathway that peptides. At present, more than 40 peptides are on the market, includes at least cyclization reaction(s), and wherein Such many more are in registration processing, hundreds are in reactants are further capable of forming undesired oligomers clinical trials and more than 400 are in advanced preclinical 45 at the first set of reaction conditions through at least one studies. The enhanced biological specificity, activity, and undesired reaction pathway that includes undesirable oligo metabolic stability of cyclopeptides in comparison with those merization reactions; and (b) modulating oligomerization of the linear peptides, as a result of the constrained structural reactions of Such one or more reactants in the reaction features of the cyclic peptides, have attracted much attention. medium, so as to reduce formation of the undesired oligomers Cyclic peptidomimetic scaffolds and templates have been 50 by Such one or more reactants and/or to reduce separation of widely used to assemble a wide variety of spatially defined the undesired oligomers from the reaction medium, relative to functional groups for molecular recognition and drug discov corresponding unmodulated oligomerization reactions. ery. There is a vigorous, on-going effort to device and develop The present invention in another aspect relates to a process commercially applicable synthetic methods for preparation for manufacturing at least one macrocyclic compound, com of cyclic peptides and peptidomimetics. 55 prising the steps of: (a) providing a reaction system compris Cyclic peptides can be synthesized from partially protected ing one or more reactants in a reaction medium, wherein Such linear precursors formed in Solution or by Solid-phase tech reactants are capable of forming an intermediate macrocyclic niques involving cyclization of such linear precursors in solu compound in the reaction medium at a first set of reaction tion under high or pseudo-dilution conditions. Alternatively, conditions through at least one desired reaction pathway that cyclic peptides can be prepared by Solid-phase assembly of 60 includes at least cyclization reaction(s), and wherein Such the linear peptide sequence, followed by cyclization while the reactants are further capable of forming undesired oligomers peptide remains anchored to a polymeric Support. This at the first set of reaction conditions through at least one method takes advantage of the pseudo-dilution phenomenon undesired reaction pathway that includes undesirable oligo attributed to the solid-phase, which favors intramolecular merization reactions; and (b) modulating oligomerization reactions over intermolecular side reactions. More recently, 65 reactions of Such one or more reactants in the reaction chemical ligation methods have also shown some Success in medium, so as to reduce formation of undesired oligomers by the formation of cyclic peptides, specifically in the formation Such one or more reactants and/or to reduce separation of the US 7,709,632 B2 5 6 undesired oligomers from the reaction medium, relative to ear functional groups, branched functional groups, and/or corresponding unmodulated oligomerization reactions; and arched functional groups that bridge across a plane defined by (c) modifying the intermediate macrocyclic compound to a ring structure. In the case of multi-cyclic compounds having form a macrocyclic compound of interest. two or more ring structures, any pair of Such ring structures In a further aspect, the present invention relates to a reac- 5 may be separated from each another by a non-cyclic spacing tion composition for forming a macrocyclic compound, com structure, or the rings can be in side-by-side relationship to prising: each another, sharing one chemical bond or one atom, or (1) one or more reactants, wherein Such reactants are alternatively, the rings may partially overlap with each other, capable of forming the macrocyclic compound at a first or one ring structure can be enclosed by or intertwined with set of reaction conditions through at least one desired 10 the other ring. The three-dimensional structures of Such com reaction pathway that includes at least cyclization reac pounds can be characterized by any geometric shape, either tion(s), and wherein such reactants are further capable of regular or irregular, including, but not limited to, planar, forming undesired oligomers at the first set of reaction cylindrical, semispherical, spherical, ovoidal, helical, pyri conditions through at least one undesired reaction path amidyl, etc. Specifically, such macrocyclic compounds may way that includes undesirable oligomerization reac- 15 include, but are not limited to porphyrinogens, porphyrins, tions; Saphyrins, texaphyrins, bacteriochlorins, chlorins, copropor (2) one or more reacting solvents for dissolving the reac phyrin I, corrins, corroles, cytoporphyrins, deuteroporphy tants; and rins, etioporphyrin I, etioporphyrin III, hematoporphyrins, (3) one or more oligomerization control additives that pheophorbide a, pheophorbide b, phorbines, phthalocya modulate oligomerization reactions of such reactants by 20 nines, phyllochlorins, phylloporphyrins, phytochlorins, phy reducing formation of undesired oligomers and/or sepa toporphyrins, protoporphyrins, pyrrochlorins, pyrroporphy ration of the undesired oligomers from Such reaction rins, rhodochlorins, rhodoporphyrins, uroporphyrin I, calix composition, relative to a corresponding reaction npyrroles, calixnerines, cycloalkanes, cycloalkenes, composition lacking such oligomerization control addi cycloalkynes, piperidines, morpholines, pyrrolidines, aziri tive(s). 25 dines, anilines, thiophenes, quinolines, isoquinolines, naph In a still further aspect, the present invention relates to a thalenes, pyrimidines, purines, benzofurans, oxiranes, pyr system for manufacturing at least one macrocyclic com roles, thiazides, oZazoles, imidazoles, indoles, furans, pound, comprising at lease one reaction Zone having: (1) one benzothiophenes, polyazamacrocycles, carbohydrates, or more Supply vessels for Supplying one or more reactants acetals, crown ethers, cyclic anhydrides, lactams, lactones, and/or one or more solvents, wherein Such reactants are 30 cyclic peptides, phenylthiohydantoins, thiazolinones, succin capable of forming the macrocyclic compound in a reaction imides, coronenes, macrollides, carbocyclics, cyclodextrins, medium comprising such one or more solvents at a first set of squalene oxides, ionophore antibiotics, cyclic bis-NO-ac reaction conditions through at least one desired reaction path etals, cyclic disulfides, terpenoids, spirocycles, resorcinarene way that includes at least cyclization reaction(s), and wherein macrocycles, cyclic oligo(siloxane)S. stannylated cyclic oli Such reactants are further capable of forming undesired oli- 35 go(ethyleneoxide)S. cyclic poly(dibutyltindicarboxylate)S. gomers at the first set of reaction conditions through at least cyclic poly(pyrrole), cyclic poly(thiophene)S. cyclic poly(a- one undesired reaction pathway that includes undesirable mide)S. cyclic poly(ether)s, cyclic poly(carbonate)S. cyclic oligomerization reactions, (2) a reaction chamber coupled poly(etherSulfone)S. cyclic poly(etherketone)S. cyclic poly with Such Supply vessels for receiving the reactants and sol (urethane)S. cyclic poly(imide)S. cyclic poly(decamethylene vents and effectuating reactions of the reactants therein to 40 fumarate)S. cyclic poly(decamethylethylene maleate)s, etc. form the macrocyclic compound, and (3) an oligomerization The phrase “desired oligomer as used herein refers to the modulation unit for modulating oligomerization reactions of oligomeric or polymeric compound formed by the reactants Such one or more reactants in the reaction chamber, so as to in the reaction composition of the present invention, which reduce formation of undesired oligomers by Such one or more has the appropriate oligomer number (number of mer units) reactants or to reduce separation of the undesired oligomers 45 for forming the desired macrocyclic compound by cycliza from the reaction medium, relative to corresponding tion reaction. unmodulated oligomerization reactions. The phrase “desired oligomerization” as used herein refers Another aspect of the present invention relates to a process to the oligomerization reaction(s) that form the desired oli for synthesizing a macrocyclic compound through cycliza gomers. tion reaction(s), including the use of an oligomerization con- 50 The phrase “undesired oligomers' as used herein refers to trol agent to control undesired oligomerization reactions that a wide variety of oligomeric and/or polymeric compounds compete with said cyclization reaction(s). other than the desired oligomer, which are also formed by the Other aspects, features and embodiments of the invention reactants in the reaction composition of the present invention, will be more fully apparent from the ensuing disclosure and and which have oligomeric or polymeric numbers (number of appended claims. 55 mer units) that are either smaller or larger than that of the desired oligomer. DEFINITIONS The phrase “undesired oligomerization' as used herein refers to the oligomerization reactions that form the undesired The words “a” and “an as used herein are not limited to oligomers. their singular senses, but also covers the plural. 60 The phrase “modulating or “modulation” as used herein The phrases "macrocycles.” “macrocyclic compounds.” in reference to oligomerization reactions is intended to be and "cyclic compounds are used interchangeably herein to broadly construed, to encompass any type of intervention refer to both single cyclic and multi-cyclic compounds having affecting the oligomerization reactions to cause reduction in one or more ring structures. The total number of atoms on formation of the undesired oligomers and/or separation of the each of Such ring structures may be widely varied, e.g., in a 65 already formed undesired oligomers from the reaction range of from 3 to about 100 or more. Such single cyclic or medium, relative to corresponding oligomerization reactions multi-cyclic compound may further contain one or more lin carried out without such intervention. Such intervention in US 7,709,632 B2 7 8 specific embodiments of the invention can include, for when different concentrations of extraneous oligomerization example, one or more of addition of any agent or additive; byproduct are introduced to the reaction system. removal of any reaction byproduct; and change of any reac FIG. 3 shows a high-performance liquid chromatograph tion condition, whereby the oligomerization reactions takes (HPLC) of the products produced by reaction of benzalde place with reduced formation of undesired oligomers and/or hyde and pyrrole in an absolute ethanol solution without reduced separation of the undesired oligomers from the reac oligomerization control. tion medium. Conventional techniques, such as templating FIGS. 4A and 4B show HPLC chromatographs of the prod and other pseudo-dilution techniques, while they may be ucts produced by reaction of benzaldehyde and pyrrole in additionally employed in the overall process of the present Solutions containing precipitating solvent and oligomeriza invention to maximize yield of desired macrocycle, form no 10 tion control additive species. part of modulation or modulating as contemplated by the FIG. 4A shows a HPLC of the products produced by reac present invention. tion of benzaldehyde and pyrrole in a solution containing The phrase “byproducts” and “reaction byproducts are 50% methanol and 50% water by volume. used interchangeably herein to encompass any inorganic FIG. 4B shows a HPLC of the products produced by reac compounds, organic compounds, organometallic com 15 tion of benzaldehyde and pyrrole in a solution containing pounds, chemical elements, radicals, ions (cations/anions/ methanol and water at a volume ratio of 3:5 with about 0.014 Zwitterions), neutral particles, energized particles, or other g/ml NaCl. applicable species that are produced by a specific reaction in FIGS. 5-19 show processes for manufacturing a wide vari the method of the present invention. Specifically, reaction ety of macrocyclic compounds, according to illustrative steps that may produce byproducts include, but are not lim embodiments of the present invention. ited to, condensation reactions, oligomerization reactions, FIG.20 is a schematic representation of a system for manu cyclization reaction(s). Substitution reaction(s), metathesis facturing macrocyclic compounds, according to one embodi reaction(s), etc. ment of the present invention. The term “phase separation” as used herein broadly refers to separation of material from its Surrounding environment 25 DETAILED DESCRIPTION OF THE INVENTION due to physical and/or chemical differences between the material and its environment, or otherwise as a result of The contents of U.S. Provisional Patent Application No. differences in properties between the material and its envi 60/545,131 filed Feb. 17, 2004 in the names of Thomas E. ronment. Such term specifically covers, but is not limited to, Johnson and Billy T. Fowler for “METHODS AND COM the spontaneous separation of an insoluble or weakly soluble 30 POSITIONS FOR FORMING CYCLIC COMPOUNDS Solid or gas from a liquid, or of an immiscible liquid from are incorporated herein by reference in their entirety for all another liquid, or of a liquid or solid from a gas, due to a purposes. density differential therebetween. Such term, for example, In general, synthesis of a macrocyclic compound involves encompasses any separation based on differences in size, cyclization of a linear precursor. The linear precursor can shape, mass, density, solubility, Volatility, permeability, dif 35 either be formed in situ from one or more starting materials, fusion rate, charge distribution, mass/charge ratio, binding e.g., by oligomerization reaction, or the linear precursor be affinity, adsorption/absorption potential, reactivity, or the provided directly as the starting material for macrocyclic like. compound synthesis. The term “phase transfer” as used herein broadly refers to FIG. 1A illustratively shows a process by which a macro transfer of material in a multi-phase environment (e.g., an 40 cyclic compound C can be formed by oligomerization and environmental that contains two or more distinct, immiscible cyclization reaction(s). Specifically, such process includes: components as respect of phases), from one phase into (a) condensation reaction of two or more reactants A and B, another phase. The phases thus differ from one another in one forming a monomeric intermediate product AB; (b) reversible or more physical and/or chemical characteristics, or in other oligomerization of Such monomeric intermediate product differentiating properties. Such term specifically encom 45 AB, forming a desired oligomer AB, of length n, and (c) passes, but is not limited to, the transfer of one material from reversible cyclization of such desired oligomer AB, form a first liquid component into a second liquid component that ing the macrocyclic compound C. The oligomerization of AB is distinct from and immiscible with Such first liquid compo that forms the desired oligomer AB, necessary for Subse nent. Such term further encompasses any transfer of material quent cyclization and formation of the compound C is the from one phase component to another based on differences in 50 desired oligomerization. The condensation reaction, the size, shape, mass, density, Solubility, Volatility, permeability, desired oligomerization reaction and the cyclization reaction diffusion rate, charge distribution, mass/charge ratio, binding therefore define a desired reaction pathway 1 in which the affinity, adsorption/absorption potential, and/or reactivity reactants A and B form the macrocyclic compound C. Fur between such respective phase components. ther, the desired oligomer AB, is susceptible to further, 55 undesired oligomerization in forming undesired oligomers The term “spontaneous” as used herein refers to a process AB, of length (n+k). Such further oligomerization of the that proceeds under internal force(s) and requires no external desired oligomer AB defines an undesired reaction path force(s) or intervention. A spontaneous process is not limited way 2, which directly competes with the desired reaction by any specific time frame, i.e., it may occur instantaneously pathway 1 by reducing availability of the desired oligomer or over a relatively long period of time. 60 AB, for the cyclization reaction and causing significant reduction in the production yield of the macrocyclic com BRIEF DESCRIPTION OF THE DRAWINGS pound C. FIG. 1B illustratively shows another process for forming a FIGS. 1A-1D illustrate a wide variety of generalized reac macrocyclic compound C, which includes: (a) condensation tion processes for forming macrocyclic compounds. 65 reaction of two or more reactants A and B, forming a linear FIG. 2 is a graph of intensity as a function of average intermediate product AB; and (b) reversible cyclization of oligomer length, showing shifts in oligomer distributions Such linear intermediate product AB, forming the macrocy US 7,709,632 B2 10 clic compound C. No oligomerization is required for forma Sulfate ester, peroxide, peracid, anhydride, alkaloids, grig tion of the macrocyclic compound C in this process. Instead, nard reagents, ketone acetals, ylides, keto esters, keto acids, the condensation reaction and the cyclization reaction define N-acylamino acids, acychlorides, acylnitrenes, hydrazones, the desired reaction pathway 1 in which the reactants A and B enamines, ketenes, thiophens, furans, pyrides, allyllic alco form the desired macrocyclic compound C. The linear inter hol, aromatic nitrogen, aromatic alcohol, beta lactam fused, mediate product AB, however, is susceptible to undesired lactam, lactone, aromatic ketone, aromatic oxygen, oxime oligomerization in forming undesired oligomers AB, of ether, urea, urethane, trihalide, cyclic ether, arylhalide, acetal length m. Such undesired oligomerization of the linear inter ketal, Sulfonamide, acyl halide, bismaleimides, alditols, mediate product therefore defines the undesired reaction aldotetroses, alkadienes, amidomalonic esters, alkatrienes, pathway 2, which directly competes with the desired reaction 10 alkene oxides, alkenylbeZenes, alkyl halides, alkyl Sulfates, pathway 1 by reducing availability of the linear intermediate alkyl tosylates, alkyl triflates, allenes, allylic halides, and product AB for the cyclization reaction and causing signifi amine oxides. cant reduction in the production yield of the macrocyclic Although the above-described processes of FIGS. 1A-1D compound C. differ in the number of starting materials (i.e., reactants) and FIG. 1C illustratively shows a further process through 15 the specific reaction steps, they share the following common which a macrocyclic compound C can be formed through features: oligomerization and cyclization. Specifically, Such process (1) all processes form the macrocyclic compound C includes: (a) reversible oligomerization of a single reactant A, through cyclization of a linear precursor, e.g., the forming desired oligomer A, of length n, and (b) reversible desired oligomer AB, in the process illustrated by FIG. cyclization of Such desired oligomer A, forming the macro 1A, the linear intermediate AB in the process illustrated cyclic compound C. The oligomerization of A that forms the by FIG. 1B, the desired oligomer A in the process illus desired oligomer A, necessary for Subsequent cyclization and trated by FIG. 1C, and the reactant A in the process formation of the compound C is the desired oligomerization. illustrated by FIG. 1D; and The desired oligomerization reaction and the cyclization (2) Such linear precursor is Susceptible to undesired reaction therefore define the desired reaction pathway 1 in 25 oligomerization in forming undesired oligomers, e.g., which the reactant A forms the desired macrocyclic com AB, in the process illustrated by FIG. 1A, AB, in pound C. In this reaction scheme, the desired oligomer A, is the process illustrated by FIG. 1B, A, in the process Susceptible to further, undesired oligomerization in forming illustrated by FIG.1C, and A in the process illustrated undesired oligomers A of length (n+k). Such further, by FIG. 1D. undesired oligomerization of the desired oligomer A, defines 30 The undesired oligomerization reaction competes with the an undesired reaction pathway 2, which directly competes cyclization reaction, thus reducing the availability of the lin with the desired reaction pathway 1 by reducing availability ear precursor for cyclization reaction and causing reduction of the desired oligomer A, for the cyclization reaction and in the production yield of the macrocyclic compound of inter causing significant reduction in the production yield of the est. Moreover, when the undesired oligomers reach certain macrocyclic compound C. 35 critical length, they may become insoluble or weakly soluble FIG. 1D illustratively shows another process for forming a and will precipitate from the reaction medium or otherwise macrocyclic compound C, which includes only reversible separate from the reaction medium, thereby converting the cyclization of a single reactant A, forming the macrocyclic reversible oligomerization reaction into a virtually irrevers compound C. No condensation or oligomerization is required ible reaction that dominates over the cyclization reaction. In for formation of the macrocyclic compound C in this process. 40 Such event, the amount of undesired oligomers will far exceed Instead, the cyclization reaction alone defines the desired the amount of macrocycles in the product mixture. reaction pathway 1 in which the reactant A forms the desired The present invention provides a solution to Such problem, macrocyclic compound C. The reactant A, however, is sus by modulating the oligomerization reaction, so as to reduce ceptible to undesired oligomerization in forming undesired formation of the undesired oligomers and/or to reduce sepa oligomers A, of length m. Such undesired oligomerization of 45 ration of the already-undesired oligomers from the reaction the reactant Atherefore defines the undesired reaction path medium, relative to an unmodulated oligomerization reac way 2, which directly competes with the desired reaction tion. pathway 1 by reducing availability of the reactant A for the In one embodiment of the present invention, such oligo cyclization reaction and causing significant reduction in the merization modulation is achieved by adding one or more production yield of the macrocyclic compound C. 50 oligomerization control additives into the reaction medium. The reactants as mentioned hereinabove may contain any Such oligomerization control additives can include any Suit structure or functional groups, and they may include, but are able materials whose addition affects the oligomerization not limited to, functional groups derived from methane, reactions in Such manner as to reduce formation of the undes alkane primary, alkane secondary, alkane tertiary, ired oligomers and/or separation of the already undesired cycloaliphatic ring, bicycloaliphatic ring, tricycloaliphatic 55 oligomers from the reaction medium, relative to correspond ring, alkene, alkyne, monocyclic aromatic hydrocarbon, ing oligomerization reactions carried out without addition of polycyclic aromatic hydrocarbon, biphenyl-type benzenoid Such oligomerization control additives. ring, oxygen ether, thioether, S-heterocyclic ring, N-hetero For example, for those oligomerization reactions in which cyclic ring, saturated, N-heterocyclic ring, unsaturated, an oligomerization byproduct is also formed in addition to the O-heterocyclic ring, epoxide, thioketone, alcohol, thiol, 60 undesired oligomers, extraneous oligomerization byproduct amine primary, amine secondary, amine tertiary, aldehyde, can be added into the reaction medium to increase the overall carboxylate ions, carboxylic acid, carboxylic acid ester, car oligomerization byproduct concentration in Such reaction boxylic thioester, dicarboxylic and tricarboxylic acids, medium, thereby directing the reactionaway from production amide, nitrile, oxime, thiocyanate, cyanamide, nitro, nitrate of the undesired oligomers. ester, diazo, organohalide, organomercurial, organoarsenical, 65 More importantly, the overall oligomerization byproduct organosilicon, organotin, organophosphate ester, thiophos concentration in the reaction medium can be adjusted to pro phate ester, phosphonic acid, phosphinic acid, Sulfonic acid, vide a product distribution of desired oligomers of selected US 7,709,632 B2 11 12 lengths. In general, the higher the oligomerization byproduct this manner, the undesired oligomers are kept in the reaction concentration, the shorter the average length of the oligomers medium and may be reversibly converted to the desired oli formed in the reaction medium. FIG. 2 illustrates the shift in gomers or other linear precursors for the cyclization reaction. oligomer distributions, when different amounts of extraneous Further, the oligomerization control additive may include a oligomerization byproduct are added. For example, when compound or solvent species that interacts with the reactants 14% extraneous oligomerization byproduct (based on the or one or more intermediate products of Such reactants to total volume of the reaction medium) is added, the distribu affect the oligomerization reactions in Such a manner that tion of the average oligomer length peaks at about 5, which formation of the undesired oligomers is reduced. means that the oligomerization reaction as thus modulated In addition to the use of oligomerization control additives favors formation of pentamers. As another example, when 8% 10 as described hereinabove, oligomerization modulation within (by Volume) extraneous oligomerization byproduct is added, the broad practice of the present invention may further the peak of the average oligomer length distribution shifts to include removal of one or more reaction byproducts, to affect about 10, which means that the modulated oligomerization the oligomerization reactions so that formation of the undes reaction now favors formation of longer oligomers of about ired oligomers is reduced, and/or formation of the desired length 10. As a still further example, when only 2% (by 15 oligomer is favored, relative to a corresponding reaction Volume) extraneous oligomerization byproduct is added, the scheme lacking such byproduct removal. peak of the average oligomer length distribution further shifts Oligomerization modulation can also be achieved by to about 15, which means that the modulated oligomerization changing the reaction conditions in Such a manner that the reaction now favors formation of oligomers of about length reaction equilibria change to favor the desired reaction path 15. way over the reaction pathway yielding undesired oligomers, Therefore, by adjusting the amount of added extraneous thereby forming more macrocyclic compound instead of oligomerization byproduct, the extent of the oligomerization undesired oligomers. For example, by change of reaction reaction can be controlled to favor formation of the desired temperature, pressure, pH value, energetic State, magnetic oligomers of a specific length (n) for cyclization to form the state, and/or photonic state, the equilibria of the oligomeriza macrocyclic compound. 25 tion and cyclization reaction(s) can be changed to stimulate The extraneous oligomerization byproduct used for modu formation of the macrocyclic compound and Suppress forma lating the oligomerization reaction is selected based on the tion of the undesired oligomers. Such techniques can be used specific oligomerization reaction involved. For example, Suit either in conjunction with, or independent of the use of able extraneous oligomerization byproducts that can be used oligomerization control additives. in specific instances within the broad Scope of the present 30 Modulation of the oligomerization reaction according to invention include, but are not limited to, adenosine 5'-mono the present invention can be used to effectively minimize or phosphate (AMP), cytidine 5'-monophosphate (CMP), gua other significantly reduce the impact of the undesired oligo nosine 5'-monophosphate (GMP), thymidine 5'-monophos merization, and thereby achieve significantly increased yield phate (TMP), uridine 5'-monophosphate (UMP), adenosine of the macrocyclic compound. di-phosphate (ADP), cytidine di-phosphate (CDP), gua 35 In certain reaction systems, multiple macrocyclic com nosine di-phosphate (GDP), thymidine di-phosphate (TDP), pounds of different sizes can be formed via different reaction uridine di-phosphate (UDP), pyrophosphoric acid, alkyl pathways that include cyclization reaction(s) of different oli pyrophosphates, pyridine, aniline, benzyl alcohol, water, gomers. Suitable oligomerization modulation techniques can dihydrogen Sulfide, methanol, ethanol, propanol, butanol, therefore be selected to reduce formation of the undesired bromide, alkylthiol, thiophenol, 2-butyne, acetic acid, 40 oligomers, thereby reducing formation of those macrocyclic acetone, carbon dioxide, carbon monoxide, deuterium oxide, compounds that are undesired and achieving improved prod fructose, galactose, gallic acid, glycerol, glucose, hydrochlo uct distribution that favors the formation of one or more ric acid, hydrogen cyanide, hydrobromic acid, hydroiodic macrocyclic compound(s) of desired size(s). acid, iodoform, lactic acid, nitrogen, nitrous acid, ammonia, Macrocyclic compounds formed by the cyclization reac methyl amine, ethylamine, propyl amine, butyl amine, dim 45 tion(s) under the influence of the above-mentioned oligomer ethylamine, diethylamine, dipropylamine, trimethylamine, ization modulation process can be recovered by any Suitable triethylamine, hydrogen, phenol, Sulfur dioxide, phosphoric methods or techniques now known or hereinafter discovered acid, ethylene, Sulfuric acid, silanes, silylethers, Sulfonic in the art. Preferably, Such macrocyclic compound is selec acids, Sulfite esters, Sulfenic acids, Sulfinic acids, disulfides, tively separated from the reaction medium, based on differ peroxides, boronic acids, borate ethers, triflates, meSylates, 50 ences in one or more physical and/or chemical characteristics, Sulfates, alkyl halides, perchloric acid, periodic acid, Sul or other material properties, between such macrocyclic com fones, Sulfoxides, succinimide, N,N-diisopropylurea, amino pound and other components of the reaction medium. acids, methylthiocyanate, and N-hydroxysuccinimide. For example, the macrocyclic compound can be selectively For those oligomerization reactions in which the undesired separated from the reaction medium based on permeability oligomers formed are insoluble or weakly soluble in the reac 55 difference therebetween, by passing the reaction medium tion medium, oligomerization modulation can beachieved by through a semi-permeable membrane that is selectively per providing an oligomerization control additive that includes meable to such macrocyclic compound but is impermeable to one or more solubilizing functional groups and functions as a the starting materials, the desired/undesired oligomers, and solubilizing agent. One or more oligomerization additives other components of the reaction medium, or which, alterna can be employed, as necessary or desirable, in a specific 60 tively, is impermeable to the macrocyclic compound but is application of the methodology of the invention. The solubi permeable to all other components of the reaction medium. lizing agent participates in the undesired oligomerization As another example, the macrocyclic compound can be selec reaction to form modified undesired oligomers that incorpo tively separated from the reaction medium based on affinity rate the solubilizing functional group(s). Such modified difference therebetween, by passing the reaction medium undesired oligomers, due to incorporation of the solubilizing 65 through an affinity column that has selective binding affinity functional group(s) therein, become more soluble in the reac for the macrocyclic compound but not for the other compo tion medium and less Susceptible to separation therefrom. In nents of the reaction medium. As a further example, the US 7,709,632 B2 13 14 macrocyclic compound can be selectively separated from the phase component immiscible or weakly immiscible in Such reaction medium by application of an electric field, if Such reaction medium is provided as a liquid layer or Volume macrocyclic compound carries a charge that is different from adjacent to the reaction medium. The macrocyclic compound those carried by the other components of the reaction to be formed is insoluble or weakly soluble in the first liquid medium. As a still further example, the macrocyclic com phase component defined by the reaction medium but is pound can be selectively separated from the reaction medium soluble or moderately soluble in the second liquid phase by application of a magnetic field, if the macrocyclic com component. Therefore, macrocyclic compound that forms in pound exhibits a different magnetic state from those of the the reaction medium and contacts the liquid-liquid interface other components of the reaction medium. of these two liquid phase components will spontaneously The physical and/or chemical characteristic differences 10 transfer from the reaction medium into the adjacent second that can be used for separating the macrocyclic compound liquid phase component, thereby separating from the reaction from the reaction medium include, but are not limited to, medium. differences in size, shape, mass, density, Solubility, Volatility, The spontaneous separation of the macrocyclic compound permeability, diffusion rate, charge distribution, mass/charge as described hereinabove advantageously provides a driving ratio, binding affinity, adsorption/absorption potential, reac 15 force that continuously drives the cyclization reaction toward tivity (e.g., metal coordination, electrostatic interactions, the macrocyclic compound, and Such mode of reaction and hydrogen bonding, donor-acceptor interactions, and covalent separation therefore is a particularly preferred approach in the bond formation), etc., which have been widely used in a wide practice of the present invention. variety of well-known separation methods, such as filtration, The spontaneous separation of the macrocyclic compound evaporation, flash expansion, distillation, stripping, absorp from the reaction medium can be effectuated by selecting tion, extraction, crystallization, adsorption, ion exchanging, Suitable solvents and/or additives, and/or by adjusting the drying, leaching, washing, clathration, osmosis, reverse reaction conditions, to maximize the production of the mac osmosis, bubble fractionation, magnetic separation, chroma rocyclic compound. Preferably, the composition of the reac tography, freeze drying, condensation, gel filtration, gaseous tion medium and the reaction conditions are adjusted so that diffusion, Sweep diffusion, thermal diffusion, mass spectrom 25 the reactants and at least the desired oligomers are soluble in etry, dialysis, electrodialysis, electrophoresis, ultra-centrifu Such reaction medium, and the macrocyclic compound is gation, ultra-filtration, molecular distillation, demisting, set insoluble or only weakly soluble in the reaction medium, tling, centrifugation, cyclone flow separation, electrostatic thereby selectively separating the macrocyclic compound precipitation, etc. from the reaction medium. It is to be emphasized that the above-listed physical and 30 In one specific embodiment of the present invention, the chemical characteristic differences and separation techniques reaction medium comprises a single solvent for dissolving the are only illustrative of some of the vast numbers of separation reactants and selectively separating the macrocyclic compo characteristics and techniques that can be usefully employed nent. in the broad practice of the present invention. Accordingly, In an alternative embodiment, a reacting solvent and a the foregoing should not be construed as an exhaustive listing 35 co-solvent are provided in the reaction medium, with the and should not be interpreted in any manner as limiting the reacting solvent functioning to dissolve the reactants, and the broad scope of applicability of the present invention. co-solvent functioning to effectuate spontaneous separation In a preferred embodiment of the present invention, the of the macrocyclic compound from the reaction medium. reaction medium composition and the reaction conditions are Preferably, Such reacting solvent and co-solvent operate to adjusted so that the macrocyclic compound formed by the 40 define a reaction medium in which the reactants and the cyclization reaction spontaneously separates from the reac desired oligomers are soluble, and the macrocyclic com tion medium via phase separation or phase transfer, without pound is insoluble or only weakly soluble. requirement for external force or energy. As mentioned hereinabove, when the undesired oligomers For example, when the reaction medium is in a liquid reach certain lengths, they may become insoluble or only phase, the reaction medium composition and the reaction 45 weakly soluble in the reaction medium and start to precipitate conditions can be selected to form the macrocyclic compound out of the reaction medium. Such problem can be effectively as a solid that is insoluble or weakly soluble in such reaction dealt with by employing Suitable oligomerization control medium, so that Such macrocyclic compound precipitates out techniques as described hereinabove to reduce formation of of the reaction medium upon formation. Such macrocyclic Such undesired oligomers and/or reduce separation of the compound can alternatively be a liquid phase material that is 50 undesired oligomers from the reaction medium. immiscible or weakly miscible in the reaction medium, so Suitable co-solvents that can be used in the broad practice that it spontaneously separates into a different liquid layer, of the present invention for effectuating spontaneous separa e.g., on top of or underneath the reaction medium layer, tion of the macrocyclic compound from the reaction medium depending on its specific gravity characteristics. Such mac include, but are not limited to, water, methanol, ethanol, iso rocyclic compound as a further alternative can be a gaseous 55 propanol, tert-butanol, n-propanol, iso-butanol, n-butanol, product that is insoluble or weakly soluble in said reaction ethylene glycol, propylene glycol, formic acid, limonene, medium, so that it spontaneously bubbles out of the reaction dipropylene glycol, monomethyl ether, diethylene glycol, medium upon formation. As yet another alternative, the reac ethyl ether, tripropylene glycol, monomethyl ether, dimethyl tion medium can be provided in a gaseous state, in which the Sulfoxide, phenol, polypropylene glycol, N-methyl-2-pyr macrocyclic compound is formed as a liquid or alternatively 60 rolidone, acetone, ethyl acetate, glycolfurol, Solketal, glyc a solid that spontaneously separates from the gaseous reac erol, formol, formamide, nitrobenzene, tetrahydrofuryl alco tion medium by condensation or Solidification, respectively. hol, polyethylene glycol, dimethyl isosorbide, dimethyl Multiphase reaction systems can also be employed in the acetamide, methyl ethyl ketone, 1,4-dioxane, hydroSolv, present invention to achieve spontaneous separation of the acetonitrile, ammonia, methyl amine, ethyl amine, propyl macrocyclic compound via phase transfer. For example, the 65 amine, butyl amine, dimethylamine, diethylamine, dipropyl reaction medium can be provided as a first liquid phase com amine, trimethylamine, triethylamine, dimethylformamide, ponent of a multiphase reaction system, while a second liquid tetrahydrofuran, glycol ethers, methyl cellosolve, cellosolve, US 7,709,632 B2 15 16 butyl cellosolve, hexyl cellosolve, methyl carbitol, carbitol, oxalate, arsenate, arsenite, hydride, fluoride, chloride, bro butyl carbitol, hexyl carbitol, propasol solvent B, propasol mide, iodide, Sulfide, nitride, Hexanoate, cyclohexanecar solvent P. propasol solvent M, propasol solvent DM, meth boxalyte, benzenesulfate, 1-butanide, 1-butyn-1-ide, ben oxytriglycol, ethoxytriglycol, butoxytriglycol, 1-butoxy Zenide, triphenylmethanide, diphenylmethanediide, ethoxy-2-propanol, phenyl glycol ether, glymes, cyclopentadienide, 1,4-dihydro-1,4-naphthalenediide, Eth monoglyme, ethylglyme, diglyme, ethyl diglyme, triglyme, ylide or ethene anion, Dihydronaphthylide or naphthalene butyl diglyme, tetraglyme, aminoalcohols, Sulfolane, hexam anion, p-benzosemiquinone anion, methanide, but-1-yn-1- ethylphosphorictriamide (HMPA), nitromethane, methyleth ide, propan-2-ide, diphenylmethanediide, tetramethylbo ylether, carbon disulfide, methale chloride, chloroform, tet ranuide, benzenesulfonate, dibenzylphosphinite, methano rahydrofuran, toluene, and benzene. 10 late, benzene-1,4-bis(thiolate), cyclohexaneselenolate, In addition to, or independent of Such co-solvent, one or 3-hydroxybenzene-1,2-bis(olate), carboxylato, phospho more separation additives can be provided in the reaction nato, Sulfonato, oxido, methanidyl, amidylidene, disul medium for effectuating spontaneous separation of the mac fanidyl, phosphanida, boranuida, methyl anion, acetyl anion, rocyclic compound from the reaction medium. phenyl anion, benzenesulfinyl anion, methanaminyl anion, For example, such separation additives may encompass 15 methylazanyl anion, cyclopenta-2,4-dien-1-yl anion, diphe salts with cations selected from the group consisting of alu nylmethylene dianion, 1.4-dihydronaphthalene-1,4-diyl minum, ammonium, barium, calcium, chromium(II), chro dianion, methylamide, methylazanide, dimethylphos mous, chromium(III), chromic, copper(I), cuprous, copper phanide, dimethylphosphinide, tributylstannanide, methyli (II), cupric, iron(II), ferrous, iron(III), ferric hydrogen, dynesilanide, (diphenylboryl)methanide, tricyanomethanide, hydronium, lead(II), lithium, magnesium, manganese(II), propan-2-ide, but-1-yn-1-ide, 1,3-diphenylprop-2-en-1-ide manganous manganese(III), manganic, mercury(I), mercu 1,1,2-tricyano-2-(3,4-dicyano-5-imino-1,5-dihydro-2H-pyr rous, mercury(II), mercuric, nitronium, potassium, silver, rol-2-ylidene)ethan-1-ide, 4-chlorobenzen-1-ide, cyclo Sodium, strontium, tin(II), Stannous, tin(IV), Stannic, Zinc penta-2,4-dien-1-ide, 7bH-indeno1,2,3-kfluoren-7b-ide, Oxonium, Sulfonium, selenonium, chloronium, bromonium, 1,5-di-p-tolylpentaaza-1,4-dien-3-ide, 1H-benzotriazol-1- iodonium, tetramethylammonium, dimethyloxonium, diphe 25 ide, C.H. N-phenylimide, diphenylmethanediide, nyliodonium, ethylenebromonium, anilinium, guanidinium, 9H-fluorene-9,9-diide, 1,4-dihydronaphthalene-1,4-dide, 2-phenylhydrazinium, 1-methylhydrazinium, acetohy 1.1.1.5.5.5-hexamethyltrisilazane-2,4-dide, 1,3-diphenyl drazidium, benzamidium, acetonium, 1,4-dioxanium, ethy propane-1,2,3-tride, 1.4.6.9-tetrahydropyrene-1,4,6,9-tet lium or ethenium, phenylium, 2-cyclohexen-1-ylium, 9-an raide. thrylium, neopentylium, triphenylmethylium O 30 Preferably, such salts comprise an anion such as F, Cl, triphenylcarbenium, methanediylium, cyclopropenylium, Br, I, SO, HSO, Ph.B., NO, SO, and BO, or a ethane-1,1-diylium, ethane-1,2-diylium, acetylium, methyl cation such as ammonium, copper(II), iron(III), magnesium, Sulfanylium or methanesulfenylium, methanesulfonylium, potassium, Sodium, Zinc, guanidinium, triphenylmethylium, benzylideneaminylium, quinolizinyum, 1,2,3-benzodithiaz and tetramethylphosphonium. olylium, methyliumyl ethan-2-ium-1-yl, 3-methyl-1-(trim 35 Such salts can interact with the solvents contained in the ethylsilyl)triaz-2-en-2-ium-1-id-2yl, 1.2.2.2-tetramethyldia reaction medium, and/or interact with the macrocyclic com Zan-2-ium-1-ide, azanylium, aminylium, nitrenium, pound, in Such a manner that the macrocyclic compound phenylsulfanylium, tetramethyl-, -phosphanylium, tetram becomes less Soluble in Such reaction medium and spontane ethylphosphoranylium, tetramethylphosphonium, 3-methyl ously separates from the reaction medium upon its formation. triaZ-1-en-1-ylium, heptamethyltrisilan-2-ylium, 4-cyclo 40 Further, such salts may interact with the other components of propyltetrasulfan-1-ylium, cyclooct-3-en-1-ylium, furan-2- the reaction medium to reduce separation of such components ylium, 1.2-bis(4-methoxyphenyl)-2-phenylethen-1-ylium, from the reaction medium. bicyclo2.2.2]heptan-2-ylium, Spiro4.5 decan-8-ylium, pro By selecting the appropriate oligomerization control addi pane-1,3-bis(ylium), 2.2-dimethyldiazane-1,1-bis(ylium), tive(s), reacting solvent(s), co-solvent(s), and/or separation 2,2-dimethylhydrazine-1,1-bis(ylium), propane-2.2-bis 45 additive(s), one can readily adjust the product distribution of (ylium) 1-methylethane-1,1-bis(ylium), cyclobut-3-ene-1,2- the oligomerization and/or cyclization reactions and improve bis(ylium), propane-1,2,3-tris(ylium), ammonium, meth the production yield of the macrocyclic compound. anediazonium, methyldiazenylium, benzothiazole-2- For example, FIG. 3 is a HPLC chromatograph for the diazonium, benzothiazol-2-yldiazenylium, 2,4- products formed by reacting benzaldehyde and pyrrole dioxopentane-3-diazonium, (2,4-dioxopentan-3-yl) 50 (which are used to form tetraphenylporphyrinogen) in abso diazenylium, (1-acetyl-2-oxopropyl)diaZenylium, benzene lute ethanol (which functions as a precipitating solvent for 1,4-bis(diazonium), 1,4-phenylenebis(diazenylium), 3.5- selectively precipitating the non-polar tetraphenylporphy dimethyl-1,4-dihydropyridin-1-ylium, 3,5-dimethylpyridin rinogen so formed), without any oligomerization control. The 1(4h)-ylium, acetylium, hexanethioylium, lack of oligomerization control in Such reaction results in cyclohexanecarbonylium, ethenesulfonylium, dimeth 55 formation of a wide variety of reaction products, as indicated ylphosphinoylium, methylphosphonoylium, glutarylium, by the Gaussian distribution. Majority of such reaction prod pentanedioylium, pyridine-2,6-dicarbony. ucts were linear extended oligomers that were formed and Such separation additives may further encompass salts precipitated out of the reaction solution concurrently with the including anions selected from the group consisting of tetraphenylporphyrinogen, with only a small amount of tet hydride, oxide, fluoride, sulfide, chloride, nitride, bromide, 60 raphenylporphyrinogen (as represented by the peak at iodide, nitrate, nitrite, chromate, chlorate, chlorite, dichro 29.153), approximately less than 1%. mate, Sulfate, Sulfite, phosphate, phosphite, carbonate, By reacting benzaldehyde and pyrrole in a reaction com acetate, hydroxide, cyanate, cyanide, hydrogen Sulfate, position that comprises ethanol (i.e., the precipitating Sol hydrogen Sulfite, hydrogen carbonate, hydrogen phosphate, Vent) and water (i.e., the oligomerization control additive) at hypochlorite, dihydrogen phosphate, perchlorate, oxalate, 65 a volumetric ratio of 1:1, approximately 30% of the reaction permanganate, silicate, thiocyanate, iodate, Bromate, hypo products were tetraphenylporphyrinogen, as mixed with bromate, formate, amide, hydroxide, peroxide, oxide, undesired oligomers. FIG. 4A is a HPLC chromatograph for US 7,709,632 B2 17 18 the products formed by reacting benzaldehyde and pyrrole in the template material functions both as a cyclization agent a reaction composition that comprises methanol (i.e., a dif and a stabilizing agent. As another example, the cyclization ferent precipitating solvent) and water (i.e., the oligomeriza agent can include a material with microporous structure. Such tion control additive) at a volumetric ratio of 1:1. About 75% as Smectite clay, which provides a localized environment that of the reaction products were tetraphenylporphyrinogen (as is highly favorable to the ring closure reaction. Further, the represented by the peak at 29.261). FIG. 4B is a HPLC chro cyclization agent can include certain structural elements that matograph for the products formed by reacting benzaldehyde function to bend the linear structures of the desired oligomers and pyrrole in a reaction composition that contained about and form pre-organized ring structures, as discussed herein 37.5% by volume of methanol (i.e., the precipitating solvent), above. 62.5% by volume of water (i.e., the oligomerization control 10 The reaction medium in the practice of the present inven additive), and 0.014 g/ml of NaCl (i.e., the separation addi tion can further include any Suitable catalyst materials now or tive). The reaction composition used in FIG. 4B contained a hereafter discovered for catalyzing one or more reactions in higher concentration of oligomerization control additive for the reaction medium. more effective modulation of the oligomerization reactions, The methodology of the present invention can also be used and the separation additive NaCl functioned to further adjust 15 to synthesize a macrocyclic compound of interest, by first the solvent strength of the reaction composition for more forming a macrocyclic intermediate compound through a selective separation of the macrocyclic compound. Conse desired reaction pathway involving at least cyclization reac quently, the production yield of the tetraphenylporphyrino tion(s) as described hereinabove, and then modifying Such gen (as represented by the peak at 29.004) was further macrocyclic intermediate compound to form the macrocyclic improved to about 85%. Addition of water in the synthesis of compound of interest. The modification of the macrocyclic non-polar porphyrinogens is completely opposite to the intermediate compound may comprise one or more steps such teachings of the conventional wisdom, which advocates as oxidation, reduction, Substitution of at least one functional removal of water instead, and it surprisingly and unexpect group, removal of at least one functional group, addition of at edly improves the production yield of the non-polar porphy least one functional group, further cyclization, isomeric rear rinogen (e.g., tetraphenylporphyrinogen) by almost a hun 25 rangement, and/or purification. Such modification can be car dred fold. ried out either in situ in the same reaction medium as In another embodiment of the present invention, a solid employed for the cyclization reaction(s), without separation phase Substrate can be employed for immobilizing at least one of the macrocyclic compound, or Subsequently in a different of the reactants and facilitating Solid-phase reactions, to reaction medium, by first separating the macrocyclic com thereby form a macrocyclic compound that is also immobi 30 pound from the cyclization reaction medium. lized on Such solid-phase Substrate. In this circumstance, The present invention in a further aspect provides a system separation of the macrocyclic compound can be carried out by for manufacturing a macrocyclic compound, which may be removing the solid-phase Substrate from the reaction medium employed to carry out the synthesis methodology of the and Subsequently releasing the immobilized macrocyclic invention in a highly effective manner. compound from Such Substrate. Such solid-phase substrate 35 technique is amenable to automation, and it is particularly FIG. 20 shows a schematic representation of one such Suitable for producing libraries of macrocycles in the practice system, which includes a reaction Zone having: (1) one or of the method of the present invention. more Supply vessels for Supplying one or more reactants As mentioned hereinabove, in a thermodynamically con and/or one or more solvents that are needed for forming the trolled, reversible reaction, the relative stabilities of all prod 40 macrocyclic compound, (2) a reaction chamber coupled with ucts, macrocyclic or acyclic, determine the product distribu Such supply vessels for receiving the reactants and solvents tion. Therefore, the reaction medium of the present invention and effectuating reactions of the reactants therein to form the may further comprise a stabilizing agent that selectively sta macrocyclic compound, and (3) an oligomerization modula bilizes the macrocyclic compound, so as to increase the rela tion unit for modulating oligomerization reactions of the tive proportion of the macrocyclic compound in the reaction 45 reactants in the reaction chamber, so as to reduce formation of end product mixture. Such stabilizing agent can be of any undesired oligomers by the reactants and/or to reduce sepa Suitable type, as for example including, organic, inorganic, or ration of the undesired oligomers from the reaction medium, organometallic compounds, ions, or chemical elements. Pref relative to corresponding unmodulated oligomerization reac erably, the stabilizing agent is a salt with metallic or inorganic tions. ions that bind to the macrocyclic compound and form a more 50 The reaction chamber may include one or more reactors of stable complex than the macrocyclic compound. Alterna Suitable type(s), as for example selected from among: con tively, the macrocyclic compound itself can be engineered to tinuous reactors, batch reactors, fixed-bed reactors, fluidized undergo intramolecular rearrangement after the ring closure bed reactors, bubbling fluid reactors, circulating fluid bed reaction, thereby forming a different macrocyclic form that is reactors, slurry-phase reactors, packed-bed reactors, trickle more stable than the original macrocyclic compound. Further, 55 bed reactors, multi-tubular fixed-bed reactors, quench reac an electric and/or magnetic field can be applied to the reaction tors, double-wall heat-exchanging reactors, radial flow reac composition for selectively stabilizing the macrocyclic com tors, plug flow reactors, continually stirred tank reactors, pound. semi-batch reactors, semi-continuous reactors, bypass reac The reaction medium of the present invention may further tors, differential reactors, Swing reactors, continuous regen comprise a cyclization agent that facilitates the ring closure or 60 eration reactors, multi-stage reactors, and membrane-based cyclization reaction(s). For example, such cyclization agent reactors. The reaction chamber may include a single reactor can include a template material, which pre-organizes the in which all the reactions are carried out, or multiple reactors reactive ends of the desired oligomers for more effective arranged in parallel or in series for carrying out multiple cyclization. A template material, as mentioned hereinabove, processes. can be employed to complementarily bind to a cavity formed 65 The oligomerization modulation unit may include one or by the macrocyclic compound and to form a more stable more additive Supply vessels for adding one or more oligo complex with Such macrocyclic compound. In such manner, merization control additives to the reaction chamber, or it US 7,709,632 B2 19 20 may include one or more process controllers for changing the porphyrins, pheophorbide a, pheophorbide b, phorbines, reaction conditions in the reaction chamber, consistent with phthalocyanines, phyllochlorins, phylloporphyrins, phy the description hereinabove. tochlorins, phytoporphyrins, protoporphyrins, pyrrochlorins, Further, Such reaction system of the present invention can pyrroporphyrins, rhodochlorins, rhodoporphyrins, uropor include a recovery Zone, either downstream of or within the phyrin I, calixnlpyrroles, calixnerines, cycloalkanes, reaction Zone, which is arranged and constructed for either cycloalkenes, cycloalkynes, piperidines, morpholines, pyrro Subsequent or in situ recovery of the macrocyclic compound. lidines, aziridines, anilines, thiophenes, quinolines, isoquino Alternatively, such reaction system may include multiple lines, naphthalenes, pyrimidines, purines, benzofurans, reaction Zones and multiple recovery Zones that are arranged oxiranes, pyrroles, thiazides, oZazoles, imidazoles, indoles, in series, parallel, or combined forms for carrying out multi 10 furans, benzothiophenes, polyazamacrocycles, carbohy stage reaction/recovery processes. drates, acetals, crown ethers, cyclic anhydrides, lactams, lac The recovery Zone may comprise one or more separation tones, cyclic peptides, phenylthiohydantoins, thiazolinones, units for selectively separating the macrocyclic compound Succinimides, coronenes, macrollides, carbocyclics, cyclo from the reaction medium, based on differences between the dextrins, squalene oxides, ionophore antibiotics, cyclic bis macrocyclic compound and other components of the reaction 15 N.O-acetals, cyclic disulfides, terpenoids, spirocycles, resor medium, Such as differences in one or more physical and/or cinarene macrocycles, cyclic oligo(siloxane)S. stannylated chemical characteristics thereof, as for example size, shape, cyclic oligo(ethyleneoxide)S. cyclic poly(dibutyltindicar mass, density, Solubility, Volatility, permeability, diffusion boxylate)S. cyclic poly(pyrrole), cyclic poly(thiophene)S. rate, charge distribution, mass/charge ratio, binding affinity, cyclic poly(amide)S. cyclic poly(ether)s, cyclic poly(carbon adsorption/absorption potential, magnetic state, and/or reac ate)S. cyclic poly(etherSulfone)S. cyclic poly(etherketone)S. tivity. A purification unit may also be included in the recovery cyclic poly(urethane)S. cyclic poly(imide)S. cyclic poly Zone to further purify the recovered macrocyclic compound. (decamethylene fumarate)s, cyclic poly(decamethylethylene Such separation and/or purification arrangement may maleate)s, etc. include one or more of evaporation units, flash expansion The following examples are provided to further illustrate units, distillation units, Stripping units, absorption units, 25 the broad applicability of the present invention, as applicable extraction units, crystallization units, adsorption units, ion to synthesis of a wide variety of macrocyclic compounds. exchange units, drying units, leaching units, washing units, clathration units, osmosis units, reverse osmosis units, bubble EXAMPLES fractionation units, magnetic separation units, chromatogra phy units, freeze drying units, condensation units, gel filtra 30 Example 1 tion units, gaseous diffusion units, Sweep diffusion units, thermal diffusion units, mass spectrometry units, dialysis Formation of Macrocyclic Aminomethylphosphine units, electrodialysis units, gas permeation units, electro phoresis units, ultra-centrifugation units, ultra-filtration As shown in FIG. 5, two reactants can be used for forming units, molecular distillation units, filtration units, demisting 35 a macrocyclic aminomethylphosphine compound. The first units, settling units, centrifugation units, cyclone flow units, reactant comprises a bis(hydroxymethyl)-organylphosphine and electrostatic precipitation units. 1, and the second reactant comprises an aromatic diamine 2. Furthermore, a recycling unit may be coupled with the The macrocyclic aminomethylphosphine compound is reaction Zone and the recovery Zone, for recycling used reac formed through a desired reaction pathway that comprises: (i) tion medium by collecting at least a portion of the used 40 condensation reaction of four molecules of 1 and two mol reaction medium from the recovery Zone, treating the used ecules of 2, forming a linear intermediate product 3 with reaction medium, and recirculating the treated reaction oligomerization number of two (where n=1), and cyclization medium back to the reaction Zone. of the linear intermediate product 3, forming a macrocyclic It may be desirable in some applications to further modify aminomethylphosphine compound 4. The intermediate prod the macrocyclic compound for Subsequent processing or ulti 45 uct 3 is also susceptible to further undesired oligomerization mate use. Such as by oxidation, reduction, Substitution/addi in forming undesirable oligomers (where n1). tion/removal of functional groups, further cyclization, and/or In the practice of the present invention, the above-de isomeric rearrangement, and Such modification can be carried scribed reactions can be carried out in a solvent system that out either in situ in the reaction medium within the reaction contains: (1) dimethylforamide (DMF) as the reacting solvent chamber, in a modification Zone inside the reaction chamber, 50 for dissolving the starting materials 1 and 2, (2) formamide as or Subsequently in a modification Zone downstream of the the co-solvent for facilitating phase-separation of the cyclic reaction chamber. end product 4 from the starting materials 1 and 2, the linear The specific arrangement and configuration of the reaction intermediate product 3 (where n=1), and undesirable oligo system depend on a wide variety of factors including require mers (where n>1), and (3) water as the oligomerization con ments imposed by the specific reactions and products 55 trol additive to modulate formation of the undesirable oligo involved, and are readily determinable by a person ordinarily mers. The concentrations of the starting materials 1 and 2 are skilled in the art, based on the disclosure herein without preferably higher than 0.25 M. The reaction temperature is undue experimentation. preferably within a range of from about -15°C. to about 120° The present invention can be used for synthesis of a wide C., and the reaction duration is within a range of from about variety of macrocyclic compounds, e.g., macrocyclic com 60 4 hours to about 60 hours. pounds that fit the reaction profiles illustrated in FIGS. The identity of the R group, or any substituent for that 1A-1D. Illustrated examples of macrocyclic compounds that matter, may be hydrogen, aryl, phenyl, alkyl, cycloalkyl, may be synthesized in accordance with the method of the spiroalkyl, alkenyl, alkynyl, halogen, alkoxy, alkylthio, per invention include, but are not limited to, porphyrinogens, fluoroalkyl, perfluoroaryl, pyridyl, cyano, thiocyanato, nitro, porphyrins, Saphyrins, texaphyrins, bacteriochlorins, chlor 65 amino, alkylamino, acyl, Sulfoxyl, Sulfonyl, imido, amido, ins, coproporphyrin I, corrins, corroles, cytoporphyrins, deu and carbamoyl; or as a protected or unprotected reactive teroporphyrins, etioporphyrin I, etioporphyrin III, hemato Substituent selected from the group consisting of hydroxy, US 7,709,632 B2 21 22 thio. Seleno, telluro, ester, carboxylic acid, boronic acid, phe erably higher than 0.03 M. The reaction temperature is pref nol, silane, Sulfonic acid, phosphonic acid, alkylthiol, formyl. erably within a range of from about -15°C. to about 120°C., halo, alkenyl, alkynyl, haloalkyl, dialkyl phosphonate, alkyl and the reaction duration is within a range of from about 4 Sulfonate, alkyl carboxylate, acetylacetone, and dialkyl bor hours to about 60 hours. The identity of the Argroup is the onate groups, or of any suitable chemical moiety appropriate same as described hereinabove for the R group in Example 1. to the synthesis of the macrocyclic product desired, while any In this reaction, the added water breaks the boron-oxygen two or more of R groups can be further linked together to form bond in the oligomers 4 and therefore modulates the oligo a loop or other intramolecular structure. merization reactions.

Example 2 10 Example 4 Formation of Macrocyclic Imine Alternative Process for Formation of Macrocyclic Boronate Compound As shown in FIG. 6, two reactants 1 and 2 can be used for formation of the macrocyclic imine. The first reactant 1 com 15 FIG.7B shows an alternative process for forming the mac prises a diamine, and the second reactant 2 comprises a dial rocyclic boronate compound in addition to the process dehyde. Such reactants 1 and 2 form the macrocyclic imine described in FIG. 7A, wherein the same reactants 1 and 2 can through a desired reaction pathway that comprises: (i) con be used for forming the macrocyclic boronate compound in densation reaction of one molecule of 1 and one molecule of the same manner as described in Example 3, with the excep 2, forming a linear intermediate product (not shown), and (ii) tion that pyridine, instead of water, is used as the oligomer cyclization of said linear intermediate product, forming a ization control additive to modulate formation of the unde macrocyclic imine compound 4 via Schiff-base formation. sirable oligomers. In this reaction, the added pyridine The linear intermediate product is also susceptible to further interruptes formation of the boron-nitrogen required for oli undesired oligomerization in forming undesirable oligomers gomerization and therefore modulates the oligomerization 3 (where n21). reactions. Pyridine as used herein provides additional control In the practice of the present invention, the above-de 25 over the oligomerization reactions, which is not available in scribed reactions can be carried out in a solvent system that FIG. 7A. contains: (1) ethanol as the reacting solvent for dissolving the Further, a mixture of pyridine and water can be used as the starting materials 1 and 2, (2) formamide as the co-solvent for oligomerization control additives for more effective modula facilitating phase-separation of the cyclic end product 4 from tion of the oligomerization reactions. It is also within the the starting materials, the linear intermediate product, and 30 Scope of the present invention to add pyridine and remove undesired oligomers 3 (where n-1), and (3) water as the water for controlling the oligomerization reactions. Removal oligomerization control additive to modulate formation of the of water drives the condensation reaction and prevents undesired oligomers 3. The concentrations of the starting decomposition of the monomeric intermediate 3. Further, it materials 1 and 2 are preferably higher than 0.02 M. The prevents hydrolysis of the boron-oxygen bonds in the oligo reaction temperature is preferably within a range of from 35 mers and limits the oligomer decomposition to the extent only about -15° C. to about 80° C., and the reaction duration is caused by boron-nitrogen bond disruption. within a range of from about 4 hours to about 60 hours. The identity of the R group is the same as described hereinabove Example 5 in Example 1. 40 Formation of Macrocyclic Calix4 pyrrole Example 3 Compound Formation of Macrocyclic Boronate Compound As shown in FIG. 8A, two reactants 1 and 2 can be used for forming the macrocyclic calix4pyrrole compound. Specifi As shown in FIG. 7A, two reactants 1 and 2 can be used for 45 cally, the first reactant 1 comprises a ketone, and the second forming a macrocyclic boronate compound. The first reactant reactant 2 comprises a pyrrole, which can form the macrocy 1 comprises an arylboronic acid, and the second reactant 2 clic calix4pyrrole compound through a desired reaction comprises a 2,3-dihydroxy-pyridine. Such reacants 1 and 2 pathway that comprises: (i) condensation reaction of 1 and 2. can form the macrocyclic boronate compound through a forming a monomeric intermediate product (not shown); (2) desired reaction pathway that comprises: (i) condensation 50 desired oligomerization of Such monomeric intermediate, reaction of one molecule of 1 and one molecule of 2, forming forming a desired oligomer 3 with oligomerization number of a monomeric intermediate product 3, (ii) desired oligomer four (where n=3); and (iii) cyclization of said desired oligo ization of such monomeric intermediate product 3, forming a mer 3, forming the macrocyclic calix4pyrrole compound 4. desired oligomer 4 with oligomerization number of four Such desired oligomer 3 is also susceptible to further undes (where n=3), and (iii) cyclization of said desired oligomer 4, ired oligomerization in forming undesirable oligomers with forming the desired boronate macrocyclic compound 5. Such 55 n>3. desired oligomer 4 is Susceptible to further undesired oligo In practicing of the present invention, the above-described merization in forming undesirable oligomers with n>3. reactions can be carried out in a solvent system that contains: In practicing of the present invention, the above-described (1) dimethylacetamide as the reacting solvent for dissolving reactions can be carried out in a solvent system that contains: starting materials 1 and 2, (2) formamide as the co-solvent for (1) dimethylacetamide as the reacting solvent for dissolving 60 facilitating phase-separation of the cyclic end product 4 from starting materials 1 and 2, (2) formamide as the co-solvent for the starting materials 1 and 2, the desired oligomer 3 (where facilitating phase-separation of the cyclic end product 5 from n=3), and undesirable oligomers (where n>3), and (3) water the starting materials, monomeric intermediate product 3, the as the equilibrium control agent to modulate formation of the desired oligomer 4 (where n=3), and undesirable oligomers undesirable oligomers. The concentrations of the starting (where n-3), and (3) water as the oligomerization control 65 materials 1 and 2 are preferably higher than 0.01 M. The additive to modulate the formation of undesirable oligomers. reaction temperature is preferably within a range of from The concentrations of the starting materials 1 and 2 are pref about -15° C. to about 120° C., and the reaction duration is US 7,709,632 B2 23 24 within a range of from about 4 hours to about 60 hours. The In practice of the present invention, the above-described identity of the R group is the same as described hereinabove reaction can be carried out in a solvent system that contains: in Example 1. (1) an aqueous 0.2 M sodium phosphate pH 7.4 buffer as the reacting solvent for dissolving the starting material 1, and (2) Example 6 thiophenol as the equilibrium control agent to modulate for mation of undesired oligomers 2. The concentration of the Alternative Process for Formation of Macrocyclic starting material 1 is preferably higher than 0.001 M. The Calix4pyrrole Compound reaction temperature is preferably within a range of from about -15° C. to about 100° C., and the reaction duration is within a range of from about 2 hours to about 48 hours. No FIG. 8B shows an alternative process for forming the mac 10 co-solvent is used herein. Instead, Solvent removal process is rocyclic calix4pyrrole compound in addition to the process used for facilitating phase-separation of the cyclic end prod described in FIG. 8A, wherein a different reactant 1 is used, uct3 from the starting material 1 and the undesired oligomers which causes generation of a different oligomerization 2. The identity of the R group is —CH2CH2C(O) byproduct (i.e., methanol instead of water). Consequently, NHCH2COOH, but may it be any suitable chemical moiety methanol, instead of water, is used as the oligomerization 15 control additive to modulate formation of the undesirable appropriate to the synthesis of the product desired. oligomers. Example 9 This example shows that by manipulating the starting materials, different oligomerization byproducts can be gen Formation of Imidazolium-Linked Bicyclic erated, enabling oligomerization control by different oligo Compound merization control additives, and one ordinarily skilled in the art can readily select the Suitable starting materials and the oligomerization control additives for optimizing the macro As shown in FIG. 11, two reactants 1 and 2 can be used for cyclic production, consistent with the principle and spirit of forming an imidazolium-linked bicyclic compound. Specifi the present invention. cally, the first reactant 1 comprises an (imidazol-1-ylmethyl) 25 benzene, and the second reactant 2 comprises a (bromometh yl)benzene, which can form the imidazolium-linked bicyclic Example 7 compound through a desired reaction pathway that com prises: (i) condensation reaction of one molecule of 1 and one Formation of Macrocyclic Crown Ether molecule of 2, forming a linear intermediate product (not shown); (ii) cyclization of said linear intermediate produc As shown in FIG. 9, two reactants 1 and 2 can be used for 30 tion, forming a cyclic intermediate product with one ring formation of the macrocyclic crown ether. The first reactant 1 structure (not shown); and (iii) further cyclization of the comprises a diacetal, and the second reactant 2 comprises a cyclic intermediate product to form the imidazolium-linked diacetonide, which can form the macrocyclic crown ether bicyclic compound 4 with two ring structures. The linear through a desired reaction pathway that comprises: (i) con intermediate product is Susceptible to undergo undesired oli densation reaction of one molecule of 1 and one molecule of 35 gomerization informing undesired linear oligomers 3 (where 2, forming a monomeric intermediate product (not shown); n>1), and the cyclic intermediate product is also Susceptible (ii) oligomerization of such monomeric intermediate product, to undesired oligomerization informing undesired oligomers forming a desired oligomer 3 with oligomerization number of (not shown) with ring structures. two (where n=2), and (iii) cyclization of the desired oligomer In practicing the present invention, the above-described 3, forming the macrocyclic crown ether compound 4. Such 40 reactions can be carried out in a solvent system that contains: desired oligomer 3 is also susceptible to further undesired (1) dimethylformamide as the reacting solvent for dissolving oligomerization in forming undesirable oligomers (wherein the starting materials 1 and 2, (2) acetone as the co-solvent for n>2). facilitating phase-separation of the cyclic end product 4 from In practice of the present invention, the above-described the starting materials, the linear and cyclic intermediate prod reactions can be carried out in a solvent system that contains: 45 ucts, the undesired linear oligomers 3 (where n-1), and the (1) acetonitrile as the reacting solvent for dissolving the start undesirable oligomers with ring structures, and (3) bromide ing materials 1 and 2, (2) formamide as the co-solvent for as the equilibrium control agent to modulate formation of the facilitating phase-separation of the cyclic end product 4 from undesirable oligomers, either linear or with ring structures. the starting materials 1 and 2, the desired oligomer 3 (where The concentrations of the starting materials 1 and 2 are pref n=2), and undesirable oligomers (where n>2), and (3) a mix erably higher than 0.03 M. The reaction temperature is pref ture of acetone and methanol as the equilibrium control erably within a range of from about -15°C. to about 120°C., agents to modulate formation of the undesirable oligomers. and the reaction duration is within a range of from about 4 The concentrations of the starting materials 1 and 2 are pref hours to about 168 hours. The identity of the R group is erably higher than 0.04M. The reaction temperature is pref methyl, but it may be of any suitable chemical moiety appro erably within a range of from about -15°C. to about 60°C., priate to the synthesis of the product desired as listed in and the reaction duration is within a range of from about 4 55 Example 1. hours to about 72 hours. Example 10 Example 8 Formation of Macrocyclic Lactone Formation of Cyclic Peptide 60 As illustrated in FIG. 12, a single reactant 1 that comprises As shown in FIG. 10, a single reactant 1 that comprises a a carboxylic acid terminal group and an ether terminal group peptide chain flanked by a terminal thioester group and a can be used for forming the macrocyclic lactone compound 2 terminal thiol group is used for formation of a cyclic peptide through cyclization. Such reactant 1 is susceptible of undes 3 with a thiolactone linker through cyclization of such reac 65 ired self-oligomerization informing undesirable oligomers3. tant. The reactant 1 is susceptible of undesired self-oligomer The identity of the R group is the same as described herein ization in forming undesirable oligomers 2 (where n21). above in Example 1. US 7,709,632 B2 25 26 In practicing the present invention, the above-described In the present invention, this reaction is carried out in a reaction can be carried out in a solvent system that contains: Solvent system that contains: (1) dimethylacetamide as the (1) dimethylacetamide as the reacting solvent for dissolving reacting solvent for dissolving the starting materials 1 and 2. the starting material 1, (2) formamide as the co-solvent for (2) formamide as the co-solvent for facilitating phase-sepa facilitating phase-separation of the cyclic end product 2 from 5 ration of the cyclic end product 4 from the starting materials, the starting material 1 and the undesirable oligomers 3 (where linear intermediate product 3, where n=0, and undesired oli n>1), and (3) methanol as the equilibrium control agent to gomers where n>0, and (3) water as the equilibrium control modulate formation of the oligomers. The concentration of agent to modulate formation of the undesirable oligomers the starting material 1 is preferably higher than 0.1 M. The where no-0. The concentration of the starting materials 1 and reaction temperature is preferably within a range of from 10 2 is preferably higher than 0.1 M. The reaction temperature is about -15° C. to about 120° C., and the reaction duration is preferably within a range of from about -15°C. to about 80° within a range of from about 4 hours to about 72 hours. C., and the reaction duration is within a range of from about Example 13 4 hours to about 60 hours. 15 Example 15 Formation of Arylene Ethynylene Macrocycle Formation of Porphyrinogen As shown in FIG. 13, a single reactant 1 that comprises a dialkyne can be used for forming the arylene ethynylene As shown in FIG. 15, a macrocyclic porphyrinogen can be macrocyclic compound 2 through a desired reaction pathway formed by using two reactants 1 (an aldehyde) and 2 (a that comprises: (i) oligomerization reaction of six molecules pyrrole) through a desired reaction pathway that comprises: of 1, forming a desired oligomer 3 with oligomerization num (i) condensation reaction of four molecules of 1 and four ber of six (where n=5) that is susceptible to further undesired molecules of 2, forming a linear intermediate product with oligomerization in forming undesirable oligomers with n>5. oligomerization number of four that is susceptible to further and (ii) cyclization of said desired oligomer 3, forming an 25 undesired oligomerization informing undesirable oligomers, arylene ethynylene macrocyclic compound. and (ii) cyclization of said linear intermediate product, form In the present invention, this reaction can be carried out in ing a macrocyclic porphyrinogen compound. a solvent system that contains: (I) CC1 as the reacting solvent for dissolving the starting material 1 and catalyst system, (2) In the present invention, this reaction can be carried out in nitrobenzene as the co-solvent for facilitating phase-separa a solvent system that contains: (1) dimethylacetamide as the tion of the cyclic end product 2 from the starting material 1, 30 reacting solvent for dissolving starting materials 1 and 2, (2) the desired oligomer 3 (where n=5), and the undesired oligo formamide as the co-solvent for facilitating phase-separation mers (where n>5), and (3) 2-butyne as the equilibrium control of the cyclic end product 4 from the starting materials, linear agent to modulate formation of the undesired oligomers. The intermediate product 3, where n=3, and the undesired oligo concentration of the starting material 1 is preferably higher mers where n>3, and (3) water as the equilibrium control 35 agent to modulate formation of the undesired oligomers 3, than 0.04 M. The reaction temperature is preferably within a where n-3. The concentration of the starting materials 1 and range of from about -15°C. to about 80°C., and the reaction 2 is preferably higher than 0.01 M. The reaction temperature duration is within a range of from about 4 hours to about 24 hours. is preferably within a range of from about -15°C. to about Alternatively, this reaction can be carried out in a solvent 120° C., and the reaction duration is within a range of from system that contains: (1) CH2Cl as the reacting solvent for 40 about 4 hours to about 60 hours. The identity of the Argroup dissolving the starting material 1 and catalyst system, and (2) is 4-(iodo)phenyl and the R group is H, but, may be of any 2-butyne as the equilibrium control agent to modulate forma Suitable chemical moiety appropriate to the synthesis of the tion of the undesirable oligomers. The concentration of the product desired. starting material 1 is preferably higher than 0.04 M. The 45 Example 16 reaction temperature is preferably within a range of from about -15° C. to about 80° C., and the reaction duration is Formation of Resorcinarene within a range of from about 4 hours to about 24 hours. No co-solvent is used. Instead, Solvent removal method is used for facilitating phase-separation of the cyclic end product 2 As shown in FIG. 16, a macrocyclic resorcinarene can be 50 formed by using two reactants 1 (an aldehyde) and 2 (a from the starting materials, linear intermediate product 3, resorcinol) through a desired reaction pathway that com where n=5 and the undesired oligomers 3, where n-5. prises: (i) condensation reaction of four molecules of 1 and Example 14 four molecules of 2, forming a linear intermediate product with oligomerization number of four that is susceptible to Formation of the Macrocyclic Compound via Mixed 55 further undesired oligomerization informing undesirable oli Aldol Reaction gomers, and (ii) cyclization of said linear intermediate prod uct, forming a macrocyclic resorcinarene compound. As shown in FIG. 14, two reactants 1 (a dialdehyde) and 2 In the present invention, this reaction can be carried out in (a diketone) are used for forming a macrocyclic compound a solvent system that contains: (1) dimethylacetamide as the through a desired reaction pathway that comprises: (i) con 60 reacting solvent for dissolving starting materials 1 and 2, (2) densation reaction of one molecule of said first reactant and formamide as the co-solvent for facilitating phase-separation one molecule of said second reactant, forming a linear inter of the cyclic end product 4 from the starting materials, linear mediate product3 with oligomerization number of two that is intermediate product 3, where n=3, and undesired oligomers Susceptible to further undesired oligomerization in forming 3, where no3, and (3) water as the equilibrium control agent undesirable oligomers, and (ii) cyclization of said linear inter 65 to modulate formation of the undesired oligomers 3, where mediate product, forming a macrocyclic compound via a n>3. The concentration of the starting materials 1 and 2 is mixed Aldol reaction. preferably higher than 0.01 M. The reaction temperature is US 7,709,632 B2 27 28 preferably within a range of from about -15°C. to about 120° offrom about 4 hours to about 72 hours. The identity of the Ar C., and the reaction duration is within a range of from about group is phenyl, but, may be of any Suitable chemical moiety 4 hours to about 60 hours. The identity of the Ar group is appropriate to the synthesis of the product desired as listed in p-tolyl, but, may be of any suitable chemical moiety appro Example 1. priate to the synthesis of the product desired as listed in Example 1. Example 19 Example 17 Formation of Macrocyclic Dibutyltin Dicarboxylate Compound Formation of Macrocyclic Heteroheptaphyrin 10 As shown in FIG. 19, a macrocyclic dibutyltin dicarboxy As shown in FIG. 17, a macrocyclic heteroheptaphyrin late compound can be formed by using two reactants 1 (a compound can be formed by two reactants 1 (a trithiophene dicarboxylic acid) and 2 (a dibutyltin bisacetate) through a diol) and 2 (a linear heterotetrapyrrole) through a desired desired reaction pathway that comprises: (i) condensation reaction pathway that comprises: (i) condensation reaction of 15 reaction of one molecule of 1 and one molecule of 2, forming one molecule of 1 and one molecule of 2, forming a linear a linear intermediate product with oligomerization number of intermediate product with oligomerization number of one one that is susceptible to further undesired oligomerization in that is susceptible to further undesired oligomerization in forming undesirable oligomers, and (ii) cyclization of said forming undesirable oligomers, and (ii) cyclization of said linear intermediate product, forming a macrocyclic dibutyltin linear intermediate product, forming a macrocyclic hetero dicarboxylate compound. heptaphyrin compound. In the present invention, this reaction can be carried out in In the present invention, this reaction is carried out in a a solvent system that contains: (1) chlorobenzene as the react Solvent system that contains: (1) dimethylacetamide as the ing solvent for dissolving the starting materials 1 and 2, (2) reacting solvent for dissolving starting materials 1 and 2, (2) dimethylacetamide as the co-solvent for facilitating phase formamide as the co-solvent for facilitating phase-separation 25 separation of the cyclic end product 4 from the starting mate of the cyclic end product 4 from the starting materials, linear rials, linear intermediate product3, where n=1, and undesired intermediate product 3, where n=1, and undesired oligomers oligomers 3, where n>1, and (3) acetic acid as the equilibrium 3, where n-1, and (3) water as the equilibrium control agent control agent to modulate formation of undesired oligomers to modulate formation of the undesired oligomers 3, where 3, where n>1. The concentration of the starting materials 1 n>1. The concentration of the starting materials 1 and 2 is 30 and 2 is preferably higher than 0.4 M. The reaction tempera preferably higher than 0.01 M. The reaction temperature is ture is preferably within a range of from about -15° C. to preferably within a range of from about -15°C. to about 120° about 120° C., and the reaction duration is within a range of C., and the reaction duration is within a range of from about from about 4 hours to about 72 hours. 4 hours to about 60 hours. The identity of the Ar group is While the invention has been described herein with refer Mesity1, but, may be of any suitable chemical moiety appro 35 ence to a wide variety of specific embodiments, it will be priate to the synthesis of the product desired as listed in appreciated that the invention is not thus limited, and extends Example 1. to and encompasses a wide variety of other modifications and embodiments, as will be appreciated by those ordinarily Example 18 skilled in the art. Accordingly, the invention is intended to be 40 construed and interpreted broadly, in accordance with the Formation of Macrocyclic Thioether Sulfone ensuing claims. Compound What is claimed is: 1. A process for manufacturing at least one macrocyclic As shown in FIG. 18, a macrocyclic thioether sulfone com compound, comprising the steps of pound can be formed by using two reactants 1 (a bisthiophe 45 (a) providing a reaction system comprising one or more nol) and 2 (a bisthiophenylether) through a desired reaction reactants in a reaction medium, wherein the reactants pathway that comprises: (i) condensation reaction of two participate in both cyclization and oligomerization reac molecules of said first reactant and two molecules of said tions, and wherein cyclization is desired and oligomer second reactant, forming a linear intermediate product with ization is undesired, oligomerization number of two that is susceptible to further 50 and (b) modulating oligomerization reactions in the reac undesired oligomerization informing undesirable oligomers, tion medium, so as to reduce formation of the undesired and (ii) cyclization of said linear intermediate product, form oligomers by said one or more reactants, relative to ing a macrocyclic aromatic thioether Sulfone compound via corresponding unmodulated oligomerization reactions, thioether exchange. wherein modulation of the oligomerization reactions to In the present invention, this reaction can be carried out in 55 reduce formation of the undesired oligomers com a solvent system that contains: (1) benzene as the reacting prises adding one or more oligomerization control Solvent for dissolving the starting materials 1 and 2, (2) dim additives into the reaction medium, ethylacetamide as the co-solvent for facilitating phase-sepa the oligomerization control additives comprise one or ration of the cyclic end product 4, where n=4, from the start more extraneous oligomerization byproducts, and ing materials, linear intermediate product 3, where n=3, 60 the macrocycle is a macrocycle with a range of from 3 to linear intermediate 5, where n23, and the undesirable oligo about 100 atoms, prepared by cyclization of a linear mers 3, where n-3 and 5, where nod3, and (3) thiophenol as precursor, using one or more reaction steps that pro the equilibrium control agent to modulate formation of the duce byproducts, and undesirable oligomers 3 and 5. The concentration of the start the reaction steps are selected from the group consisting ing material 1 is preferably higher than 0.1 M. The reaction 65 of condensation reactions, oligomerization reactions, temperature is preferably within a range of from about -15° cyclization reaction(s), Substitution reaction(s), and C. to about 100°C., and the reaction duration is within a range metathesis reaction(s). US 7,709,632 B2 29 30 2. The process of claim 1, wherein the macrocyclic com 12. The process of claim 11, wherein said reaction medium pound is selected from the group consisting of porphyrino is in a liquid phase, and wherein said macrocyclic compound gens, porphyrins, Saphyrins, texaphyrins, bacteriochlorins, is a solid that is insoluble or weakly soluble in said reaction chlorins, coproporphyrin I, coffins, corroles, cytoporphyrins, medium. deuteroporphyrins, etioporphyrin I, etioporphyrin III, 5 13. The process of claim 11, wherein said reaction medium hematoporphyrins, pheophorbidea, pheophorbide b, phorb is in a liquid phase, and wherein said macrocyclic compound ines, phthalocyanines, phyllochlorins, phylloporphyrins, is a liquid that is immiscible or weakly miscible in said phytochlorins, phytoporphyrins, protoporphyrins, pyrrochlo reaction medium. rins, pyrroporphyrins, rhodochlorins, rhodoporphyrins, and 14. The process of claim 11, wherein said reaction medium uroporphyrin I. 10 is in a liquid phase, and wherein said macrocyclic compound is a gas that is insoluble or weakly soluble in said reaction 3. The process of claim 1, wherein the reaction steps com medium. prise at least one condensation reaction. 15. The process of claim 11, wherein said reaction medium 4. The process of claim 1, wherein said extraneous oligo is in a gaseous phase, and wherein said macrocyclic com merization byproduct is water. 15 pound is a liquid. 5. The process of claim 1, wherein said extraneous oligo 16. The process of claim 11, wherein said reaction medium merization byproducts are selected from the group consisting is in a gaseous phase, and wherein said macrocyclic com of adenosine 5'-monophosphate (AMP), cytidine 5'-mono pound is a solid. phosphate (CMP), guanosine 5'-monophosphate (GMP), thy 17. The process of claim 11, wherein said reaction medium midine 5'-monophosphate (TMP), uridine 5'-monophosphate 20 comprises a first liquid phase component, and wherein a (UMP), adenosine di-phosphate (ADP), cytidine di-phos second liquid phase component immiscible or weakly immis phate (CDP), guanosine di-phosphate (GDP), thymidine di cible in said first liquid phase component is provided adjacent phosphate (TDP), uridine di-phosphate (UDP), pyrophos to said reaction medium, wherein said macrocyclic com phoric acid, alkyl pyrophosphates, pyridine, aniline, benzyl pound is insoluble or weakly soluble in the first liquid phase alcohol, water, dihydrogen sulfide, methanol, ethanol, pro- 25 component but is soluble or moderately soluble in the second panol, butanol, bromide, alkylthiol, thiophenol, 2-butyne, liquid phase component, and is thereby separated from said acetic acid, acetone, carbon dioxide, carbon monoxide, deu reaction medium by phase transfer. terium oxide, fructose, galactose, gallic acid, glycerol, glu 18. The process of claim 1, wherein said reaction medium cose, hydrochloric acid, hydrogen cyanide, hydrobromic comprises: (1) one or more solvents in which one or more acid, hydroiodic acid, iodoform, lactic acid, nitrogen, nitrous 30 reactants are soluble, and (2) one or more co-solvents for acid, ammonia, methyl amine, ethyl amine, propyl amine, effectuating spontaneous separation of the macrocyclic com butylamine, dimethylamine, diethylamine, dipropylamine, pound from the reaction medium. trimethyl amine, triethyl amine, hydrogen, phenol, Sulfur 19. The process of claim 18, wherein said one or more dioxide, phosphoric acid, ethylene, Sulfuric acid, silanes, co-solvents are selected from the group consisting of water, silylethers, Sulfonic acids, Sulfite esters, Sulfenic acids, 35 methanol, ethanol, isopropanol, tert-butanol, n-propanol, iso Sulfinic acids, disulfides, peroxides, boronic acids, borate butanol, n-butanol, ethylene glycol, propylene glycol, formic ethers, triflates, mesylates, Sulfates, alkyl halides, perchloric acid, limonene, dipropylene glycol, monomethyl ether, dieth acid, periodic acid, Sulfones, Sulfoxides. Succinimide, N.N- ylene glycol, ethyl ether, tripropylene glycol, monomethyl diisopropylurea, amino acids, methylthiocyanate, and N-hy ether, dimethyl sulfoxide, phenol, polypropylene glycol, droxysuccinimide. 40 N-methyl-2-pyrrolidone, acetone, ethyl acetate, glycolfurol, 6. The process of claim 1, further comprising the step of Solketal, glycerol, formol, formamide, nitrobenzene, tetrahy recovering the macrocyclic compound by selectively separat drofuryl alcohol, polyethylene glycol, dimethyl isosorbide, ing the macrocyclic compound from the reaction medium. dimethyl acetamide, methyl ethyl ketone, 1,4-dioxane, 7. The process of claim 6, wherein said macrocyclic com hydrosolv, acetonitrile, ammonia, methylamine, ethylamine, pound is selectively separated from the reaction medium by 45 propyl amine, butyl amine, dimethyl amine, diethyl amine, using a semi-permeable membrane, based on permeability dipropylamine, trimethylamine, triethylamine, dimethylfor difference between the macrocyclic compound and other mamide, tetrahydrofuran, glycol ethers, methyl celloSolve, components of the reaction medium. cellosolve, butyl cellosolve, hexyl cellosolve, methyl carbi 8. The process of claim 6, wherein said macrocyclic com tol, carbitol, butyl carbitol, hexylcarbitol, propasol solvent B, 50 propasol solvent P. propasol solvent M, propasol solvent DM, pound is selectively separated from the reaction medium by methoxytriglycol, ethoxytriglycol, butoxytriglycol, 1-bu an affinity column, based on binding affinity difference toxyethoxy-2-propanol, phenyl glycol ether, glymes, between the macrocyclic compound and other components of monoglyme, ethylglyme, diglyme, ethyl diglyme, triglyme, the reaction medium. butyl diglyme, tetraglyme, aminoalcohols, Sulfolane, hexam 9. The process of claim 6, wherein said macrocyclic com 55 ethylphosphorictriamide (HMPA), nitromethane, methyl eth pound is selectively separated from the reaction medium by ylether, carbon disulfide, methale chloride, chloroform, tet an electrical field, based on charge difference between the rahydrofuran, toluene, and benzene. macrocyclic compound and other components of the reaction 20. The process of claim 1, wherein said reaction medium medium. comprises: (1) one or more solvents in which one or more 10. The process of claim 6, wherein said macrocyclic com- 60 reactants are soluble, and (2) one or more separation additives pound is selectively separated from the reaction medium by a for effectuating spontaneous separation of the macrocyclic magnetic field, based on magnetic state difference between compound from the reaction medium, the macrocyclic compound and other components of the reac wherein the separation additives are salts with cations tion medium. Selected from the group consisting of aluminum, ammo 11. The process of claim 1, wherein said macrocyclic com- 65 nium, barium, calcium, chromium(II), chromous, chro pound spontaneously separates from the reaction medium via mium(III), chromic, copper(I), cuprous, copper(II), phase separation or phase transfer. cupric, iron(II), ferrous, iron(III), ferric hydrogen, US 7,709,632 B2 31 32 hydronium, lead(II), lithium, magnesium, manganese thalene-1,4-diyl dianion, methylamide, methylazanide, (II), manganous manganese(III), manganic, mercury(I), dimethylphosphanide, dimethylphosphinide, tributyl mercurous, mercury(II), mercuric, nitronium, potas Stannanide, methylidynesilanide, (diphenylboryl)meth sium, silver, Sodium, strontium, tin(II), Stannous, tin anide, tricyanomethanide, propan-2-ide, but-1-yn-1- (IV), Stannic, Zinc oxonium, Sulfonium, selenonium, ide, 1,3-diphenylprop-2-en-1-ide1,1,2-tricyano-2-(3,4- chloronium, bromonium, iodonium, tetramethylammo dicyano-5-imino-1,5-dihydro-2H-pyrrol-2-ylidene) nium, dimethyloxonium, diphenyliodonium, ethylene ethan-1-ide, 4-chlorobenzen-1-ide, cyclopenta-2,4- bromonium, anilinium, guanidinium, 2-phenylhy dien-1-ide, 7bH-indeno 1,2,3-kfluoren-7b-ide, 1.5- drazinium, 1-methylhydrazinium, acetohydrazidium, di-p-tolylpentaaza-1,4-dien-3-ide, 1H-benzotriazol-1- benzamidium, acetonium, 1,4-dioxanium, ethylium or 10 ide, C.H. N-phenylimide, diphenylmethanediide, ethenium, phenylium, 2-cyclohexen-1-ylium, 9-anthry 9H-fluorene-9,9-dide, 1,4-dihydronaphthalene-1,4-di lium, neopentylium, triphenylmethylium or triphenyl ide, 1.1.1.5.5.5-hexamethyltrisilazane-2,4-dide, 1,3- carbenium, methanediylium, cyclopropenylium, diphenylpropane-1,2,3-tride, and 1.4.6.9-tetrahydropy ethane-1,1-diylium, ethane-1,2-diylium, acetylium, rene-1,4,6,9-tetraide. methylsulfanylium or methanesulfenylium, methane 15 21. The process of claim 20, wherein said salt is character Sulfonylium, benzylideneaminylium, quinolizinyum, ized by an anion selected from the group consisting of F, Cl, 1,2,3-benzodithiazolylium, methyliumyl, ethan-2-ium Br, I, SO, HSO, Ph.B., NO, SO, and BO. 1-yl, 3-methyl-1-(trimethylsilyl)triaz-2-en-2-ium-1-id 22. The process of claim 20, wherein said salt is character 2yl, 1.2.2.2-tetramethyldiazan-2-ium-1-ide, azanylium, ized by a cation selected from the group consisting of ammo aminylium, nitrenium, phenylsulfanylium, tetramethyl nium, copper(II), iron (III), magnesium, potassium, Sodium, -phosphanylium, tetramethylphosphoranylium, tet Zinc, guanidinium, triphenylmethylium, and tetrameth ramethylphosphonium, 3-methyltriaZ-1-en-1-ylium, ylphosphonium. heptamethyltrisilan-2-ylium, 4-cyclopropyltetrasulfan 23. The process of claim 1, wherein a stabilizing agent is 1-ylium, cyclooct-3-en-1-ylium, furan-2-ylium, 1,2-bis provided for selectively stabilizing the macrocyclic com (4-methoxyphenyl)-2-phenylethen-1-ylium, bicyclo 25 pound, wherein the stabilizing agent is a salt with metallic or 2.2.1]heptan-2-ylium, Spiro 4.5 decan-8-ylium, pro inorganic ions that bind to the macrocyclic compound and pane-1,3-bis(ylium), 2,2-dimethyldiazane-1,1-bis form a more stable complex than the macrocyclic compound. (ylium), 2.2-dimethylhydrazine-1,1-bis(ylium), pro 24. The process of claim 1, wherein a cyclization agent is pane-2.2-bis(ylium) 1-methylethane-1,1-bis(ylium), provided for facilitating the cyclization reaction(s), wherein cyclobut-3-ene-1,2-bis(ylium), propane-1,2,3-tris 30 the cyclization agent is a template material that pre-organizes (ylium), ammonium, methanediaZonium, methyldiaz the reactive ends of the desired oligomers for more effective enylium, benzothiazole-2-diazonium, benzothiazol-2- cyclization or a material with microporous structure. yldiazenylium, 2,4-dioxopentane-3-diazonium, (2,4-di 25. The process of claim 1, wherein at least one catalyst is oXopentan-3-yl)diaZenylium, (1-acetyl-2-oxopropyl) provided for catalyzing the cyclization reaction, wherein the diazenylium, benzene-1,4-bis(diazonium), 1,4- 35 catalyst is a protic acid selected from the group consisting of phenylenebis (diazenylium), 3,5-dimethyl-1,4- hydrochloric acid, hydrobromic acid, sulfuric acid, boron dihydropyridin-1-ylium, 3,5-dimethylpyridin-1 (4h)- trifluoride etherate, acetic acid, propionic acid, benzoic acid, ylium, acetylium, hexanethioylium, methane Sulfonic acid, trichloroacetic acid, trifluoroacetic cyclohexanecarbonylium, ethenesulfonylium, dimeth acid, triflic acid, Sulfoni acid, benezenesulfonic acid, p-tolu ylphosphinoylium, methylphosphonoylium, glutary 40 enesulfonic acid, camphor Sulfonic acid, and trifluo lium, pentanedioylium, and pyridine-2,6-dicarbony, and romethane Sulfonic acid, or a Lewis acid selected from the anions selected from the group consisting of hydride, group consisting of BF-etherate, BF-methanol, AlCl oxide, fluoride, sulfide, chloride, nitride, bromide, CsC1, SmC1-6H.O., InCls, CrF, AlF. Sc(OTf), YTiF, iodide, nitrate, nitrite, chromate, chlorate, chlorite, BEt, GeCla. EuCl-nHO, LaCl, and Ln(OTf), where Ln is dichromate, Sulfate, Sulfite, phosphate, phosphite, car 45 a lanthamide. bonate, acetate, hydroxide, cyanate, cyanide, hydrogen 26. The process of claim 1, wherein a solid-phase substrate Sulfate, hydrogen Sulfite, hydrogen carbonate, hydrogen is provided for immobilizing at least one of said one or more phosphate, hypochlorite, dihydrogen phosphate, per reactants and facilitating Solid-phase reactions thereof. chlorate, oxalate, permanganate, silicate, thiocyanate, 27. The process of claim 1, wherein said reactants are iodate, Bromate, hypobromate, formate, amide, hydrox 50 capable of forming multiple macrocyclic compounds in said ide, peroxide, oxide, oxalate, arsenate, arsenite, hydride, reaction medium at said first set of reaction conditions. fluoride, chloride, bromide, iodide, sulfide, nitride, Hex 28. The process of claim 1, wherein two or more reactants anoate, cyclohexanecarboxalyte, benzenesulfate, 1-bu are used, and wherein said desired reaction pathway com tanide, 1-butyn-1-ide, benzenide, triphenylmethanide, prises: (i) condensation reaction of said two or more reac diphenylmethanediide, cyclopentadienide, 1,4-dihydro 55 tants, forming monomeric intermediate product, (ii) desired 1,4-naphthalenediide, Ethylide or ethene anion, Dihy oligomerization of said monomeric intermediate product, dronaphthylide or naphthalene anion, p-benzosemi forming desired oligomers, and (iii) cyclization of said quinone anion, methanide, but-1-yn-1-ide, propan-2- desired oligomers, forming the macrocyclic compound. ide, diphenylmethanediide, tetramethylboranuide, 29. The process of claim 1, wherein two or more reactants benzenesulfonate, dibenzylphosphinite, methanolate, 60 are used, and wherein said desired reaction pathway com benzene-1,4-bis(thiolate), cyclohexaneselenolate, 3-hy prises: (i) condensation reaction of said two or more reac droxybenzene-1,2-bis(olate), carboxylato, phospho tants, forming a linear intermediate product, and (ii) cycliza nato, Sulfonato, oxido, methanidyl, amidylidene, disul tion of said linear intermediate product, forming the fanidyl, phosphanida, boranuida, methyl anion, acetyl macrocyclic compound. anion, phenylanion, benzenesulfinyl anion, methanami 65 30. The process of claim 1, wherein a single reactant is nyl anion, methylazanyl anion, cyclopenta-2,4-dien-1- used, and wherein said desired reaction pathway comprises: yl anion, diphenylmethylene dianion, 1,4-dihydronaph (i) desired oligomerization of said reactant, forming desired US 7,709,632 B2 33 34 oligomers, and (ii) cyclization of said desired oligomers, amine, butyl amine, dimethylamine, diethylamine, dipropyl forming the macrocyclic compound. amine, trimethyl amine, triethyl amine, hydrogen, phenol, 31. The process of claim 1, wherein a single reactant is Sulfur dioxide, phosphoric acid, ethylene, Sulfuric acid, used, and wherein said desired reaction pathway comprises silanes, silylethers, Sulfonic acids, Sulfite esters, Sulfenic cyclization of said single reactant, forming the macrocyclic acids, sulfinic acids, disulfides, peroxides, boronic acids, compound. borate ethers, triflates, meSylates, Sulfates, alkyl halides, per 32. The process of claim 1, further comprising modifying chloric acid, periodic acid, Sulfones, Sulfoxides, succinimide, the macrocyclic compound, wherein modification of the mac N,N-diisopropylurea, amino acids, methyl thiocyanate, and rocyclic compound includes one or more process steps N-hydroxysuccinimide. selected from the group consisting of (i) oxidation, (ii) reduc 10 38. The process of claim 33, further comprising the step of tion, (iii) further cyclization, (iv) isomeric rearrangement, recovering the macrocyclic compound by selectively separat and (v) purification. ing the macrocyclic compound from the reaction medium. 33. A process for manufacturing at least one macrocyclic 39. The process of claim 18, wherein said macrocyclic compound, comprising the steps of compound is selectively separated from the reaction medium (a) providing a reaction system comprising one or more 15 by using a semi-permeable membrane, based on permeability reactants in a reaction medium, wherein the reactants difference between the macrocyclic compound and other participate in both cyclization and oligomerization reac components of the reaction medium. tions, and wherein cyclization is desired and oligomer 40. The process of claim 38, wherein said macrocyclic ization is undesired, and compound is selectively separated from the reaction medium (b) modulating oligomerization reactions in the reaction by an affinity column, based on binding affinity difference medium, so as to reduce separation of the undesired between the macrocyclic compound and other components of oligomers from said reaction medium, relative to corre the reaction medium. sponding unmodulated oligomerization reactions, 41. The process of claim 38, wherein said macrocyclic wherein modulation of the oligomerization reactions to compound is selectively separated from the reaction medium reduce formation of the undesired oligomers com 25 by an electrical field, based on charge difference between the prises adding one or more oligomerization control macrocyclic compound and other components of the reaction additives into the reaction medium, medium. the oligomerization control additives comprise one or 42. The process of claim 38, wherein said macrocyclic more extraneous oligomerization byproducts, and compound is selectively separated from the reaction medium the macrocycle is a macrocycle with a range of from 3 to 30 by a magnetic field, based on magnetic state difference about 100 atoms, prepared by cyclization of a linear between the macrocyclic compound and other components of precursor, using one or more reaction steps that pro the reaction medium. duce byproducts, and 43. The process of claim 33, wherein said macrocyclic the reaction steps are selected from the group consisting compound spontaneously separates from the reaction of condensation reactions, oligomerization reactions, 35 medium via phase separation or phase transfer. cyclization reaction(s), Substitution reaction(s), and 44. The process of claim 43, wherein said reaction medium metathesis reaction(s). is in a liquid phase, and wherein said macrocyclic compound 34. The process of claim33, wherein the macrocyclic com is a solid that is insoluble or weakly soluble in said reaction pound is selected from the group consisting of porphyrino medium. gens, porphyrins, Saphyrins, texaphyrins, bacteriochlorins, 40 45. The process of claim 43, wherein said reaction medium chlorins, coproporphyrin I, corrins, corroles, cytoporphyrins, is in a liquid phase, and wherein said macrocyclic compound deuteroporphyrins, etioporphyrin I, etioporphyrin III, is a liquid that is immiscible or weakly miscible in said hematoporphyrins, pheophorbidea, pheophorbide b, phorb reaction medium. ines, phthalocyanines, phyllochlorins, phylloporphyrins, 46. The process of claim 43, wherein said reaction medium phytochlorins, phytoporphyrins, protoporphyrins, pyrrochlo 45 is in a liquid phase, and wherein said macrocyclic compound rins, pyrroporphyrins, rhodochlorins, rhodoporphyrins, and is a gas that is insoluble or weakly soluble in said reaction uroporphyrin I. medium. 35. The process of claim 33, wherein the reaction steps 47. The process of claim 43, wherein said reaction medium comprise at least one condensation reaction. is in a gaseous phase, and wherein said macrocyclic com 36. The process of claim 33, wherein said extraneous oli 50 pound is a liquid. gomerization byproduct is water. 48. The process of claim 43, wherein said reaction medium 37. The process of claim 33, wherein said extraneous oli is in a gaseous phase, and wherein said macrocyclic com gomerization byproducts are selected from the group consist pound is a solid. ing of adenosine 5'-monophosphate (AMP), cytidine 49. The process of claim 43, wherein said reaction medium 5'-monophosphate (CMP), guanosine 5'-monophosphate 55 comprises a first liquid phase component, and wherein a (GMP), thymidine 5'-monophosphate (TMP), uridine second liquid phase component immiscible or weakly immis 5'-monophosphate (UMP), adenosine di-phosphate (ADP), cible in said first liquid phase component is provided adjacent cytidine di-phosphate (CDP), guanosine di-phosphate to said reaction medium, wherein said macrocyclic com (GDP), thymidine di-phosphate (TDP), uridine di-phosphate pound is insoluble or weakly soluble in the first liquid phase (UDP), pyrophosphoric acid, alkyl pyrophosphates, pyridine, 60 component but is soluble or moderately soluble in the second aniline, benzyl alcohol, water, dihydrogen Sulfide, methanol, liquid phase component, and is thereby separated from said ethanol, propanol, butanol, bromide, alkylthiol, thiophenol, reaction medium by phase transfer. 2-butyne, acetic acid, acetone, carbon dioxide, carbon mon 50. The process of claim 33, wherein said reaction medium oxide, deuterium oxide, fructose, galactose, gallic acid, glyc comprises: (1) one or more solvents in which one or more erol, glucose, hydrochloric acid, hydrogen cyanide, hydro 65 reactants are soluble, and (2) one or more co-solvents for bromic acid, hydroiodic acid, iodoform, lactic acid, nitrogen, effectuating spontaneous separation of the macrocyclic com nitrous acid, ammonia, methyl amine, ethyl amine, propyl pound from the reaction medium. US 7,709,632 B2 35 36 51. The process of claim 50, wherein said one or more yldiazenylium, 2,4-dioxopentane-3-diazonium, (2,4-di co-solvents are selected from the group consisting of water, OXopentan-3-yl)gliaZenylium, (1-acetyl-2-oxopropyl) methanol, ethanol, isopropanol, tert-butanol, n-propanol, iso diazenylium, benzene-1,4-bis(diazonium), 1,4- butanol, n-butanol, ethylene glycol, propylene glycol, formic phenylenebis (diazenylium), 3,5-dimethyl-1,4- acid, limonene, dipropylene glycol, monomethyl ether, dieth dihydropyridin-1-ylium, 3,5-dimethylpyridin-1 (4h)- ylene glycol, ethyl ether, tripropylene glycol, monomethyl ylium, acetylium, hexanethioylium, ether, dimethyl sulfoxide, phenol, polypropylene glycol, cyclohexanecarbonylium, ethenesulfonylium, dimeth N-methyl-2-pyrrolidone, acetone, ethyl acetate, glycolfurol, ylphosphinoylium, methylphosphonoylium, glutary Solketal, glycerol, formol, formamide, nitrobenzene, tetrahy lium, pentanedioylium, and pyridine-2,6-dicarbony, and drofuryl alcohol, polyethylene glycol, dimethyl isosorbide, 10 anions selected from the group consisting of hydride, dimethyl acetamide, methyl ethyl ketone, 1,4-dioxane, oxide, fluoride, sulfide, chloride, nitride, bromide, hydroSolv, acetonitrile, ammonia, methylamine, ethylamine, iodide, nitrate, nitrite, chromate, chlorate, chlorite, propyl amine, butyl amine, dimethyl amine, diethyl amine, dichromate, Sulfate, Sulfite, phosphate, phosphite, car dipropylamine, trimethylamine, triethylamine, dimethylfor bonate, acetate, hydroxide, cyanate, cyanide, hydrogen mamide, tetrahydrofuran, glycol ethers, methyl celloSolve, 15 Sulfate, hydrogen Sulfite, hydrogen carbonate, hydrogen cellosolve, butyl cellosolve, hexyl cellosolve, methyl carbi phosphate, hypochlorite, dihydrogen phosphate, per tol, carbitol, butyl carbitol, hexylcarbitol, propasol solvent B, chlorate, oxalate, permanganate, silicate, thiocyanate, propasol solvent P. propasol solvent M, propasol solvent DM, iodate, Bromate, hypobromate, formate, amide, hydrox methoxytriglycol, ethoxytriglycol, butoxytriglycol, 1-bu ide, peroxide, oxide, oxalate, arsenate, arsenite, hydride, toxyethoxy-2-propanol, phenyl glycol ether, glymes, fluoride, chloride, bromide, iodide, sulfide, nitride, Hex monoglyme, ethylglyme, diglyme, ethyl diglyme, triglyme, anoate, cyclohexanecarboxalyte, benzenesulfate, 1-bu butyl diglyme, tetraglyme, aminoalcohols, Sulfolane, hexam tanide, 1-butyn-1-ide, benzenide, triphenylmethanide, ethylphosphorictriamide (HMPA), nitromethane, methyleth diphenylmethanediide, cyclopentadienide, 1,4-dihydro ylether, carbon disulfide, methale chloride, chloroform, tet 1,4-naphthalenediide, Ethylide or ethene anion, Dihy rahydrofuran, toluene, and benzene. 25 dronaphthylide or naphthalene anion, p-benzosemi 52. The process of claim33, wherein said reaction medium quinone anion, methanide, but-1-yn-1-ide, propan-2- comprises: (1) one or more solvents in which one or more ide, diphenylmethanediide, tetramethylboranuide, reactants are soluble, and (2) one or more separation additives benzenesulfonate, dibenzylphosphinite, methanolate, for effectuating spontaneous separation of the macrocyclic benzene-1,4-bis(thiolate), cyclohexaneselenolate, 3-hy compound from the reaction medium, 30 droxybenzene-1,2-bis(olate), carboxylato, phospho wherein the separation additives are salts with cations nato, Sulfonato, oxido, methanidyl, amidylidene, disul selected from the group consisting of aluminum, ammo fanidyl, phosphanida, boranuida, methyl anion, acetyl nium, barium, calcium, chromium(II), chromous, chro anion, phenyl anion, benzenesulfinyl anion, methanami mium(III), chromic, copper(I), cuprous, copper(II), nyl anion, methylazanyl anion, cyclopenta-2,4-dien-1- cupric, iron(II), ferrous, iron(III), ferric hydrogen, 35 yl anion, diphenylmethylene dianion, 1.4-dihydronaph hydronium, lead(II), lithium, magnesium, manganese thalene-1,4-diyl dianion, methylamide, methylazanide, (II), manganous manganese(III), manganic, mercury(I), dimethylphosphanide, dimethylphosphinide, tributyl mercurous, mercury(II), mercuric, nitronium, potas Stannanide, methylidynesilanide, (diphenylboryl)meth sium, silver, Sodium, strontium, tin(II), Stannous, tin anide, tricyanomethanide, propan-2-ide, but-1-yn-1- (IV), Stannic, Zinc oxonium, Sulfonium, selenonium, 40 ide, 1,3-diphenylprop-2-en-1-ide1,1,2-tricyano-2-(3,4- chloronium, bromonium, iodonium, tetramethylammo dicyano-5-imino-1,5-dihydro-2H-pyrrol-2-ylidene) nium, dimethyloxonium, diphenyliodonium, ethylene ethan-1-ide, 4-chlorobenzen-1-ide, cyclopenta-2,4- bromonium, anilinium, guanidinium, 2-phenylhy dien-1-ide, 7bH-indeno1,2,3-jk fluoren-7b-ide, 1.5- drazinium, 1-methylhydrazinium, acetohydrazidium, di-p-tolylpentaaza-1,4-dien-3-ide, 1H-benzotriazol-1- benzamidium, acetonium, 1,4-dioxanium, ethylium or 45 ide, C.H. N-phenylimide, diphenylmethanediide, ethenium, phenylium, 2-cyclohexen-1-ylium, 9-anthry 9H-fluorene-9,9-dide, 1,4-dihydronaphthalene-1,4-di lium, neopentylium, triphenylmethylium or triphenyl ide, 1.1.1.5.5.5-hexamethyltrisilazane-2,4-dide, 1,3- carbenium, methanediylium, cyclopropenylium, diphenylpropane-1,2,3-tride, and 1.4.6.9-tetrahydropy ethane-1,1-diylium, ethane-1,2-diylium, acetylium, rene-1,4,6,9-tetraide. methylsulfanylium or methanesulfenylium, methane 50 53. The process of claim 52, wherein said salt is character Sulfonylium, benzylideneaminylium, quinolizinyum, ized by an anion selected from the group consisting of F, Cl, 1,2,3-benzodithiazolylium, methyliumyl, ethan-2-ium Br, I, SO, HSO, Ph.B., NO, SO, and BO. 1-yl, 3-methyl-1-(trimethylsilyl)triaz-2-en-2-ium-1-id 54. The process of claim 52, wherein said salt is character 2yl, 1.2.2.2-tetramethyldiazan-2-ium-1-ide, azanylium, ized by a cation selected from the group consisting of ammo aminylium, nitrenium, phenylsulfanylium, tetramethyl 55 nium, copper(II), iron (III), magnesium, potassium, Sodium, -phosphanylium, tetramethylphosphoranylium, tet Zinc, guanidinium, triphenylmethylium, and tetrameth ramethylphosphonium, 3-methyltriaZ-1-en-1-ylium, ylphosphonium. heptamethyltrisilan-2-ylium, 4-cyclopropyltetrasulfan 55. The process of claim 33, wherein a stabilizing agent is 1-ylium, cyclooct-3-en-1-ylium, furan-2-ylium, 1,2-bis provided for selectively stabilizing the macrocyclic com (4-methoxyphenyl)-2-phenylethen-1-ylium, bicyclo 60 pound, wherein the stabilizing agent is a salt with metallic or 2.2.1]heptan-2-ylium, Spiro 4.5 decan-8-ylium, pro inorganic ions that bind to the macrocyclic compound and pane-1,3-bis(ylium), 2,2-dimethyldiazane-1,1-bis form a more stable complex than the macrocyclic compound. (ylium), 2.2-dimethylhydrazine-1,1-bis(ylium), pro 56. The process of claim33, wherein a cyclization agent is pane-2.2-bis(ylium) 1-methylethane-1,1-bis(ylium), provided for facilitating the cyclization reaction(s), wherein cyclobut-3-ene-1,2-bis(ylium), propane-1,2,3-tris 65 the cyclization agent is a template material that pre-organizes (ylium), ammonium, methanediaZonium, methyldiaz the reactive ends of the desired oligomers for more effective enylium, benzothiazole-2-diazonium, benzothiazol-2- cyclization or a material with microporous structure. US 7,709,632 B2 37 38 57. The process of claim 33, wherein at least one catalyst is forming desired oligomers, and (iii) cyclization of said provided for catalyzing the cyclization reaction, wherein the desired oligomers, forming the macrocyclic compound. catalyst is a protic acid selected from the group consisting of 61. The process of claim 33, wherein two or more reactants hydrochloric acid, hydrobromic acid, sulfuric acid, boron are used, and wherein said desired reaction pathway com trifluoride etherate, acetic acid, propionic acid, benzoic acid, prises: (i) condensation reaction of said two or more reac methane Sulfonic acid, trichloroacetic acid, trifluoroacetic tants, forming a linear intermediate product, and (ii) cycliza acid, triflic acid, Sulfoni acid, benezenesulfonic acid, p-tolu tion of said linear intermediate product, forming the enesulfonic acid, camphor Sulfonic acid, and trifluo macrocyclic compound. romethane Sulfonic acid, or a Lewis acid selected from the 62. The process of claim 33, wherein a single reactant is group consisting of BFs-etherate, BF-methanol. AlCls, 10 used, and wherein said desired reaction pathway comprises: CsCl SmC1-6H.O., InCls, CrF, AlF. Sc(OTf), YTiF, (i) desired oligomerization of said reactant, forming desired BEt, GeOl. EuCl-nHO, LaCl, and Ln(OTf), where Ln is oligomers, and (ii) cyclization of said desired oligomers, a lanthamide. forming the macrocyclic compound. 58. The process of claim 33, wherein a solid-phase sub 63. The process of claim 33, wherein a single reactant is strate is provided for immobilizing at least one of said one or 15 used, and wherein said desired reaction pathway comprises cyclization of said single reactant, forming the macrocyclic more reactants and facilitating Solid-phase reactions thereof. compound. 59. The process of claim 33, wherein said reactants are 64. The process of claim 33, further comprising modifying capable of forming multiple macrocyclic compounds in said the macrocyclic compound, wherein modification of the mac reaction medium at said first set of reaction conditions. rocyclic compound includes one or more process steps 60. The process of claim33, wherein two or more reactants selected from the group consisting of (i) oxidation, (ii) reduc are used, and wherein said desired reaction pathway com tion, (iii) further cyclization, (iv) isomeric rearrangement, prises: (i) condensation reaction of said two or more reac and (v) purification. tants, forming monomeric intermediate product, (ii) desired oligomerization of said monomeric intermediate product, UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 7,709,632 B2 Page 1 of 1 APPLICATIONNO. : 11/059796 DATED : May 4, 2010 INVENTOR(S) : Thomas E. Johnson It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

IN THE SPECIFICATIONS: Column 15, line 43: “bicyclo[2.2.2]heptan-2-ylium should be -- bicyclo[2.2.1]heptan-2-ylium --. Column 21, line 31 : “(where n>1) should be -- (where n-1)--.

Signed and Sealed this Second Day of November, 2010

David J. Kappos Director of the United States Patent and Trademark Office