Understanding Stereoinduction in Catalysis via Computer: New Tools for Asymmetric Synthesis

Abstract

An overview of new concepts, new algorithms, and new computational protocols directed at synthetic chemists interested in generating chiral catalysts is presented in this report. A new mapping tool called stereocartography is described, which allows one to locate the most stereoinducing region around a proposed catalyst. Extant QSAR methods including Comparative Molecular Field Analysis (CoMFA) and a new technique called QM-QSAR are tools for modeling stereoinduction and for making predictions about whether a proposed chiral catalyst will be effective or not. Database mining with the intention of locating unbiased, unique ligand motifs for use in catalysis is described. Functionality mapping of transition states is introduced with the idea of locating where around that transition structure, functional groups assist or interfere with a given reaction coordinate. Functionality mapping in combination with database mining is shown to be an effective way to generate new catalysts for asymmetric induction. Beyond these new tools, more advanced treatments of chirality are investigated - the relationship between the chirality content of a catalyst and its ability to induce asymmetry is discussed along with the concept of distorting a ligand to make it more or less chiral.

• 1 Introduction

• 1.1 Background

• 1.2 Computational Chemistry

• 2 New Concepts in Asymmetric Synthesis

• 2.1 Stereocartography

• 2.2 Comparative Molecular Field Analysis (CoMFA)

• 2.3 QM-QSAR

• 2.4 Database Mining

• 2.5 Functionality Mapping

• 2.6 Functionality Mapping + Database Mining

• 2.7 Chirality Content and Stereoinduction

• 2.8 Chirality Content and Ligand Distortion

• 3 Future Prospects

Key words

asymmetric synthesis - chirality - computational chemistry - chiral catalysts

References

• 1a Cover story and feature article: ‘Chiral Roundup’ Rouhi AM. Chem. Eng. News  2002,  80(23):  43 
• 1b Cover story and feature article, ‘2D Stereoselectivity’: Jacoby M. Chem. Eng. News  2002,  80(12):  43 
• 1c Cover story and feature article, ‘Chiral Pharmaceuticals’: Stinson SC. Chem. Eng. News  2001,  79(41):  79 
• 1d ‘Chiral Drugs’: Stinson SC. Chem. Eng. News  2000,  78(43):  55 
• 1e Cover story and feature report ‘Chiral Drugs: Market Growth in Single-Isomer Forms Spurs Research Advances’: Stinson SC. Chem. Eng. News  1995,  73(40):  44 
• 1f Cover story and feature article, ‘Chiral Drugs: Single-Isomer Products Drive Development of New Syntheses and Separation Technologies’: Stinson SC. Chem. Eng. News  1994,  72(38):  38 
• 1g Cover story and feature article, ‘Chiral Drugs: Wave of New Enantiomer Products Set to Flood Market’: Stinson SC. Chem. Eng. News  1993,  71(39):  38 
• 2 Comprehensive Asymmetric Catalysis   Jacobsen EN. Pfaltz A. Yamamoto H. Springer-Verlag; New York: 1999. 
• 3a Jensen F. Introduction to Computational Chemistry   Wiley; New York: 1999. 
• 3b Leach AR. Molecular Modeling. Principles and Applications   2nd Ed.:  Prentice Hall; Harlow: 2001. 
• 3c Schlick T. Molecular Modeling and Simulation. An Interdisciplinary Guide   Springer-Verlag; New York: 2002. 
• 3d Cramer CJ. Essentials of Computational Chemistry. Theories and Models   Wiley; Chichester: 2002. 
• 4 Reviews in Computational Chemistry   Vol. 1-19:  Lipkowitz KB. Boyd DB. Wiley-VCH; New York: 1990-2003. 
• 5 Encyclopedia of Computational Chemistry   Vol. 1-5:  von Ragué Schleyer P. Wiley; Chichester: 1998. 
• 6 Lipkowitz KB. D’Hue CA. Sakamoto T. Stack JN. J. Am. Chem. Soc.  2002,  124:  14255 
• 7 Kanemasa S. Oderaotashi Y. Yamamoto H. Tanaka J. Wada E. Curran DP. J. Org. Chem.  1997,  62:  6454 
• 8 Transition State Modeling for Catalysis, ACS Symposium Series 721   Truhlar DG. Morokuma K. American Chemical Society; Washington D.C.: 1999. 
• 9 El-Bahraoui J. Wiest O. Feichtinger D. Plattner DA. Angew. Chem. Int. Ed.  2001,  40:  2073 
• 10 Linde C. Akermark B. Norrby P.-O. Svensson M. J. Am. Chem. Soc.  1999,  121:  5083 
• 11 Abashkin YG. Collins JR. Burt SK. Inorg. Chem.  2001,  40:  4040 
• 12 Brandt P. Norrby P.-O. Daly AM. Gilheany DG. Chem.-Eur. J.  2002,  8:  4299 
• 13a Kubinyi H. 3D QSAR in Drug Design: Theory Methods and Applications   ESCOM; Leiden: 1993. 
• 13b QSAR: Hansch Analysis and Related Approaches   Kubinyi H. VCH; Weinheim: 1994. 
• 13c Hansch C. Leo A. Exploring QSAR Fundamentals and Applications in Chemistry and Biology   American Chemical Society; Washington D. C.: 1995. 
• 14 To our knowledge the first paper that used QSAR in the area of chiral catalysis was published by Helquist and Norrby: Oslob JD. Åkermark B. Helquist P. Norrby P.-O. Organometallics  1997,  16:  3015 
• 15 Comparative Molecular Field Analysis (CoMFA): Kubinyi, H.; In Encyclopedia of Computational Chemistry; von Ragu˛ Schleyer, P.; Wiley: New York, 1998; Vol. 1, 448-460
• 16 Lipkowitz KB. Pradahn M. J. Org. Chem.,  2003,  68:  4648 
• 17 Kozlowski MC. Dixon S. Panda M. Lauri G. J. Am. Chem. Soc.,  2003,  125:  6614 
• 19 Dixon SL. Merz KM. J. Chem. Phys.  1997,  107:  879 
• 20 Kitamura M. Suga S. Kawai K. Noyori R. J. Am. Chem. Soc.  1986,  108:  6071 
• 21 Pu L. Yu H.-B. Chem. Rev.  2001,  101:  757 ; and references therein
• 22 See for example reference 2
• 23 Kozlowski MC. Panda M. J. Mol. Graphics Modell.  2002,  20:  399 
• 24 Masamune S. Sata T. Kim BM. Wollmann TA. J. Am. Chem. Soc.  1986,  108:  8279 
• 25 Short RP. Masamune S. J. Am. Chem. Soc.  1989,  11:  1892 
• 26 Corey EJ. Imwinkelried R. Pikul S. Xiang YB. J. Am. Chem. Soc.  1989,  11:  5493 
• 27 Corey EJ. Yu C.-M. Kim SS. J. Am. Chem. Soc.  1989,  11:  5495 
• For the design of a boron aldol chiral auxiliary see:
• 28a Gennari C. Hewkin CT. Molinari F. Bernardi A. Comotti A. Goodman JM. Paterson I. J. Org. Chem.  1992,  57:  5173 
• 28b Paterson I. Pure Appl. Chem.  1992,  64:  1821 
• 28c Gennari C. Moresca D. Vieth S. Vulpetti A. Angew. Chem., Int. Ed. Engl.  1993,  32:  1618 
• 28d Bernardi A. Comotti A. Gennari C. Hewkin CT. Goodman JM. Schlapbach A. Paterson I. Tetrahedron  1994,  50:  1227 
• 28e Bernardi A. Gennari C. Goodman JM. Paterson I. Tetrahedron: Asymmetry  1995,  6:  2613 
• 28f Gennari C. Pure Appl. Chem.  1997,  69:  507 
• 28g Gennari C. Ceccarelli S. Piarulli U. Aboutayab K. J. Braz. Chem. Soc.  1998,  9:  319 
• 29 Lauri G. Bartlett PA. J. Comput.-Aided Mol. Design  1994,  8:  51 
• 31 Allen FH. Kennard O. Taylor R. Acc. Chem. Res.  1983,  26:  146 
• 32 Berman HM. Westbrook J. Feng Z. Gilliland G. Bhat TN. Weissig H. Shindyalov IN. Bourne PE. Nucleic Acids Res.  2000,  28:  235 
• 33 Soderquist JA. Matos K. Burgos CH. Lai C. Vaquer J. Medina JR. Huang SD. In Organoboranes for Syntheses, ACS Symposium Series 783   American Chemical Society; Washington D.C.: 2001.  p.176 
• 34 Kozlowski MC. Panda M. J. Org. Chem.  2003,  68:  2061 
• For seminal studies see:
• 35a Miranker A. Karplus M. Proteins: Struct. Funct. Genetics  1991,  11:  29 
• 35b Hart TN. Read RJ. Proteins: Struct. Funct. Genetics  1992,  13:  206 
• 36 For recent work on transition state placement in antibody binding sites see: Tantillo DJ. Houk KN. J. Comput. Chem.  2002,  23:  84 
• 37a Roush WR. Walts AE. Hoong LK. J. Am. Chem. Soc.  1985,  107:  8186 
• 37b Roush WR. Banfi L. J. Am. Chem. Soc.  1988,  110:  3979 
• 37c Roush WR. Hoong LK. Palmer MAJ. Park JC. J. Org. Chem.  1990,  55:  4109 
• 37d Roush WR. Hoong LK. Palmer MAJ. Straub JA. Palkowitz AD. J. Org. Chem.  1990,  55:  4117 
• 37e Roush WR. Ando K. Powers DB. Palkowitz A. Halterman RL. J. Am. Chem. Soc.  1990,  112:  6339 
• 38 Ahrendt KA. Borths CJ. MacMillan DWC. J. Am. Chem. Soc.  2000,  122:  4243 
• 39 Kozlowski MC. Waters SP. Skudlarek JW. Evans CA. Org. Lett.  2002,  4:  4391 
• 40a Li X. Schenkel LB. Kozlowski MC. Org. Lett.  2000,  2:  875 
• 40b Li X. Yang J. Kozlowski MC. Org. Lett.  2001,  3:  1137 
• 40c Kozlowski MC. Li X. Carroll PJ. Xu Z. Organometallics  2002,  21:  4513 
• 40d Xie X. Phuan P.-W.. Angew. Chem. Int. Ed.  2003,  42:  2168 
• 40e Li X. Hewgley JB. Mulrooney CA. Yang J. Kozlowski MC. J. Org. Chem.  2003,  68:  5500 
• 40f Mulrooney CA. Yang J. Kozlowski MC. J. Am. Chem. Soc.,  2003,  125:  6856 
• 41 New Developments in Molecular Chirality   Mezey PG. Kluwer; Dordrecht: 1991. and chapters therein
• For additional review articles on quantifying chirality see:
• 42a Buda AB. Auf der Heyde T. Mislow K. Angew. Chem., Int. Ed. Engl.  1992,  31:  989 
• 42b Gilat G. In Concepts in Chemistry: A Contemporary Challenge   Rouvray DH. Research Studies Press; Taunton: 1996.  Chap. 10. p.325-354  
• 42c Avnir D. Katzenelson O. Keinan S. Pinsky M. Pinto Y. Salomon Y. Zabrodsky Hel-Or H. In Concepts in Chemistry: A Contemporary Challenge   Rouvray DH. Research Studies Press; Taunton: 1996.  Chap. 10. p.283-324  
• 43 Zabrodsky H. Avnir D. J. Am. Chem. Soc.  1995,  117:  462 
• 44 Harada T. Takeuchi M. Hatsuda M. Ueda H. Oku A. Tetrahedron: Asymmetry  1996,  7:  2479 
• 45 Gao D. Schefzick S. Lipkowitz KB. J. Am. Chem. Soc.  1999,  121:  9481 
• 46 Zhang W. Loebach JL. Wilson SR. Jacobsen EN. J. Am. Chem. Soc.  1990,  112:  2801 
• 47 Irie R. Noda K. Ito Y. Matsumoto N. Katsuki T. Tetrahedron Lett.  1990,  31:  7345 
• 48 Strassner T. Houk KN. Org. Lett.  1999,  1:  419 
• 49 Jacobsen H. Cavallo L. Chem.-Eur. J.  2001,  7:  800 
• 50 Ito YN. Katsuki T. Bull. Chem. Soc. Jpn.  1999,  72:  603 ; and references therein to earlier work
• 51 Punniyamurthy T. Irie R. Katsuki T. Munetaka A. Moro-oka Y. Synlett  1999,  1049 
• 52 Hashihayata T. Punniyamurthy T. Irie R. Katsuki T. Akita M. Moro-oka Y. Tetrahedron  1999,  55:  14599 
• 53 Pospisil PJ. Carsten DH. Jacobsen EN. Chem.-Eur. J.  1996,  2:  974 
• 54 Denmark SE. Stiff CM. J. Org. Chem.  2000,  65:  5875 
• 55 Davies IW. Deeth RJ. Larsen RD. Reider PJ. Tetrahedron Lett.  1999,  40:  1233 
• 56 Davies IW. Gerena L. Castonguay L. Senanayake CH. Larsen RD. Verhoeven TR. Reider PJ. Chem. Commun.  1996,  1753 
• 57 Pérollier C. Pécaut J. Ramasseul R. Marchon J.-C. Inorg. Chem.  1999,  38:  3758 
• 58 Pécaut J. Pérollier C. Ramasseul R. Marchon J.-C. C. R. Acad. Sci. Paris Sér. IIc Chimie/Chemistry  2000,  3:  743 
• 59 Gazeau S. Pécaut J. Haddad R. Shelnutt JA. Marchon J.-C. Eur. J. Inorg. Chem.  2002,  2956 
• 60 Saito T. Yokozawa T. Ishizaki T. Moroi T. Sayo N. Miura T. Kumobayashi H. Adv. Synth. Catal.  2001,  343:  264 
• 61 Claver C. Fernandez E. Gillon A. Heslop K. Hyett DJ. Martorell A. Orpen AG. Pringle PG. Chem. Commun.  2000,  961 
• 62 Becker JJ. White PS. Gagné MR. J. Am. Chem. Soc.  2001,  123:  9478 
• 63 Davis TJ. Balsells J. Carroll PJ. Walsh PJ. Org. Lett.  2001,  3:  2161 
• 64 Balsells J. Betancort JM. Walsh PJ. Angew. Chem, Int. Ed.  2000,  39:  3428 
• 65 Mikami K. Terada M. Korenga T. Matsumoto Y. Matsukawa S. Acc. Chem. Res.  2000,  33:  391 
• 66 Ringwald M. Stürmer R. Brintzinger HH. J. Am. Chem. Soc.  1999,  121:  1524 
• 67a Davies IW. Gerena L. Castonguay L. Senanayake CH. Larsen RD. Verhoeven TR. Reider PJ. Chem. Commun.  1996,  1753 
• 67b Davies IW. Deeth RJ. Larsen RD. Reider PJ. Tetrahedron Lett.  1999,  40:  1233 
• 68 Lipkowitz KB. Schefzick S. Avnir D. J. Am. Chem. Soc.  2001,  123:  6710 
• 69 Reviews in Computational Chemistry   Vol. 6:  Lipkowitz KB. Boyd DB. VCH Publishers; New York: 1996.  p.v-ix  
• 70 Martin EJ. Spellmeyer DC. Critchlow RE. Blaney JM. In Reviews in Computational Chemistry   Vol. 10:  Lipkowitz KB. Boyd DB. VCH; New York: 1997.  Chap. 2. p.97 
• 71 Murcko MA. In Reviews in Computational Chemistry   Vol. 11:  Lipkowitz KB. Boyd DB. Wiley-VCH; New York: 1997.  Chap. 1. p.1 
• 72 Clark DE. Murray CW. Li J. In Reviews in Computational Chemistry   Vol. 11:  Lipkowitz KB. Boyd DB. Wiley-VCH; New York: 1997.  Chap. 2. p.67 

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For a complete description of this methodology see: Dixon, S. L.; Lauri, G.; Merz, K. M. Jr. in preparation.

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CAVEAT V2.2, Bartlett, P. A. U.; C. Berkeley.

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Email: [e-mail].