Computer-aided synthesis design: 40 years on

Wiley Interdisciplinary Reviews: Computational Molecular Science

Volumn 2, Issue 1, 2012, Pages 79-107

  Cook, Anthony ^a   Johnson, A Peter ^a   Law, James ^b   Mirzazadeh, Mahdi ^b   Ravitz, Orr ^b   Simon, Aniko ^b  

^a UNIVERSITY OF LEEDS   (United Kingdom)

^b SimBioSys Inc   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 84859313337     PISSN: 17590876     EISSN: 17590884     Source Type: Journal    
DOI: 10.1002/wcms.61     Document Type: Review

References (129)

1. Hendrickson JB, Braun-Keller E, Toczko GA. A logic for synthesis design. Tetrahedron 1981, 37:359-370.
2. Corey EJ. General methods for the construction of complex molecules. Pure Appl Chem 1967, 14:19-38.
3. Isler O, Ronco A, Guex W, Hindley NC, Huber W, Dialer K, Kofler M. Uber die Ester und Ather des synthetischen Vitamins A. Helv Chim Acta 1949, 32:489-505.
4. Woodward RB, Sondheimer F, Taub D. The total synthesis of cortisone. J Am Chem Soc 1951, 73:4057.
5. Gates M, Tschudi G. The synthesis of morphine. J Am Chem Soc 1956, 78:1380-1393.
6. Woodward RB, Ayer WA, Beaton JM, Bickelhaupt F, Bonnett R, Buchschacher P, Closs GL, Dutler H, Hannah J, Hauck FP, et al. The total synthesis of chlorophyll. J Am Chem Soc 1960, 82:3800-3802.
7. Corey EJ. The logic of chemical synthesis: multistep synthesis of complex carbogenic molecules (Nobel Lecture). Angew Chem Int Ed Engl 1991, 30:455-465.
8. Corey EJ, Ohno M, Vatakencherry PA, Mitra RB. Total synthesis of d, l-longifolene. J Am Chem Soc 1961, 83:1251-1253.
9. Wyatt P, Warren S. Organic Synthesis: Strategy and Control. Chichester: John Wiley & Sons; 2007.
10. Warren S, Wyatt P. Organic Synthesis: The Disconnection Approach. 2nd ed. Chichester: John Wiley & Sons; 2008.
11. Corey EJ, Cheng X. The Logic of Chemical Synthesis. New York: John Wiley & Sons; 1989.
12. Corey EJ, Wipke WT. Computer-assisted design of complex organic syntheses. Science 1969, 166:178-192.
13. Corey EJ, Wipke WT, Cramer RD, Howe WJ. Techniques for perception by a computer of synthetically significant structural features in complex molecules. J Am Chem Soc 1972, 94:431-439.
14. Ugi I, Bauer J, Blomberger C, Brandt J, Dietz A, Fontain E, Gruber B, Vonscholleypfab A, Senff A, Stein N. Models, concepts, theories, and formal languages in chemistry and their use as a basis for computer assistance in chemistry. J Chem Inf Comput Sci 1994, 34:3-16.
15. Gasteiger J, Ihlenfeldt W, Röse P, Wanke R. Computer-assisted reaction prediction and synthesis design. Anal Chim Acta 1990, 235:65-75.
16. Hendrickson JB, Parks CA. A program for the FORWARD generation of synthetic routes. J Chem Inf Comput Sci 1992, 32:209-215.
17. Todd MH. Computer-aided organic synthesis. Chem Soc Rev 2005, 34:247.
18. Salatin TD, Jorgensen WL. Computer-assisted mechanistic evaluation of organic reactions. 1. Overview. J Org Chem 1980, 45:2043-2051.
19. Hanessian S, Franco J, Gagnon G, Laramee D, Larouche B. Computer-assisted analysis and perception of stereochemical features in organic molecules using the CHIRON program. J Chem Inf Comput Sci 1990, 30:413-425.
20. Hanessian S, Botta M, Larouche B, Boyaroglu A. Computer-assisted perception of similarity using the Chiron program: a powerful tool for the analysis and prediction of biogenetic patterns. J Chem Inf Comput Sci 1992, 32:718-722.
21. Wipke WT, Rogers D. Artificial intelligence in organic synthesis. SST: starting material selection strategies. An application of superstructure search. J Chem Inf Comput Sci 1984, 24:71-81.
22. Socorro IM, Taylor K, Goodman JM. ROBIA: a reaction prediction program. Org Lett 2005, 7:3541-3544.
23. Socorro IM, Goodman JM. The ROBIA program for predicting organic reactivity. J Chem Inf Model 2006, 46:606-614.
24. Chen JH, Baldi P. No electron left behind: a rule-based expert system to predict chemical reactions and reaction mechanisms. J Chem Inf Model 2009, 49:2034-2043.
25. Ihlenfeldt W, Gasteiger J. Computer-assisted planning of organic syntheses: the second generation of programs. Angew Chem Int Ed Engl 1996, 34:2613-2633.
26. Zefirov NS, Gordeeva EV. Computer-assisted synthesis. Russ Chem Rev 1987, 56:1002-1012.
27. Ugi I, Bauer J, Bley K, Dengler A, Dietz A, Fontain E, Gruber B, Herges R, Knauer M, Reitsam K, et al. Computer-assisted solution of chemical problems-the historical development and the present state of the art of a new discipline of chemistry. Angew Chem Int Ed Engl 1993, 32:201-227.
28. Corey E, Long A, Rubenstein S. Computer-assisted analysis in organic synthesis. Science 1985, 228:408-418.
29. Wipke WT. SECS-simulation and evaluation of chemical synthesis-strategy and planning. In: Computer-Assisted Organic Synthesis. Washington, D.C: American Chemical Society; 1977, 97-127.
30. Hendrickson JB. Organic synthesis in the age of computers. Angew Chem Int Ed Engl 1990, 29:1286-1295.
31. Hendrickson J. The SYNGEN approach to synthesis design. Anal Chim Acta 1990, 235:103-113.
32. Hendrickson JB, Toczko AG. Systematic synthesis design: the SYNGEN program. Pure Appl Chem 1989, 61:589-592.
33. Hendrickson JB, Toczko AG. Synthesis design logic and the SYNGEN (synthesis generation) program. Pure Appl Chem 1988, 60:1563-1572.
34. Gelernter HL, Sanders AF, Larsen DL, Agarwal KK, Boivie RH, Spritzer GA, Searleman JE. Empirical Explorations of SYNCHEM. Science 1977, 197:1041-1049.
35. Hendrickson JB, Miller TM. Reaction classification and retrieval. A linkage between synthesis generation and reaction databases. J Am Chem Soc 1991, 113:902-910.
36. Gelernter H, Rose JR, Chen C. Building and refining a knowledge base for synthetic organic chemistry via the methodology of inductive and deductive machine learning. J Chem Inf Comput Sci 1990, 30:492-504.
37. Blurock ES. Computer-aided synthesis design at RISC-Linz: automatic extraction and use of reaction classes. J Chem Inf Comput Sci 1990, 30:505-510.
38. Wang K, Wang LS, Yuan Q, Luo SW, Yao JH, Yuan SG, Zheng CZ, Brandt J. Construction of a generic reaction knowledge base by reaction data mining. J Mol Graph Model 2001, 19:427-433.
39. Satoh K, Funatsu K. A novel approach to retrosynthetic analysis using knowledge bases derived from reaction databases. J Chem Inf Comput Sci 1999, 39:316-325.
40. Law J, Zsoldos Z, Simon A, Reid D, Liu Y, Khew SY, Johnson Ap, Major S, Wade RA, Ando HY. Route designer: a retrosynthetic analysis tool utilizing automated retrosynthetic rule generation. J Chem Inf Model 2009, 49:593-602.
41. Barnard JM. Substructure searching methods: old and new. J Chem Inf Comput Sci 1993, 33:532-538.
42. Myatt GJ. Computer aided estimation of synthetic accessibility. PhD. Thesis. Leeds: University of Leeds; 1994.
43. Corey EJ, Howe WJ, Orf HW, Pensak DA, Petersson G. General methods of synthetic analysis. Strategic bond disconnections for bridged polycyclic structures. J Am Chem Soc 1975, 97:6116-6124.
44. Corey EJ, Jorgensen WL. Computer-assisted synthetic analysis. Synthetic strategies based on appendages and the use of reconnective transforms. J Am Chem Soc 1976, 98:189-203.
45. Corey EJ, Petersson GA. Algorithm for machine perception of synthetically significant rings in complex cyclic organic structures. J Am Chem Soc 1972, 94:460-465.
46. Paton K. An algorithm for finding a fundamental set of cycles of a graph. Commun ACM 1969, 12:514-518.
47. Roos-Kozel BL, Jorgensen WL. Computer-assisted mechanistic evaluation of organic reactions. 2. Perception of rings, aromaticity, and tautomers. J Chem Inf Comput Sci 1981, 21:101-111.
48. Plotkin M. Mathematical basis of ring-finding algorithms in CIDS. J Chem Doc 1971, 11:60-63.
49. Vismara P. Union of all the minimum cycle bases of a graph. Search results. Electron J Comb 1997, 4:73-87.
50. Wipke WT, Dyott TM. Use of ring assemblies in ring perception algorithm. J Chem Inf Comput Sci 1975, 15:140-147.
51. Welch JTJ. A mechanical analysis of the cyclic structure of undirected linear graphs. J ACM 1966, 13:205-210.
52. Gibbs NE. A cycle generation algorithm for finite undirected linear graphs. J ACM 1969, 16:564-568.
53. Balducci R, Pearlman RS. Efficient exact solution of the ring perception problem. J Chem Inf Comput Sci 1994, 34:822-831.
54. Syslo MM. An efficient cycle vector space algorithm for listing all cycles of a planar graph. SIAM J Comput 1981, 10:797.
55. Downs GM, Gillet VJ, Holliday JD, Lynch MF. Theoretical aspects of ring perception and development of the extended set of smallest rings concept. J Chem Inf Comput Sci 1989, 29:187-206.
56. Downs GM, Gillet VJ, Holliday JD, Lynch MF. Review of ring perception algorithms for chemical graphs. J Chem Inf Comput Sci 1989, 29:172-187.
57. Berger F, Flamm C, Gleiss PM, Leydold J, Stadler PF. Counterexamples in chemical ring perception. J Chem Inf Comput Sci 2004, 44:323-331.
58. Hopkinson GA. Computer-assisted organic synthesis design. PhD. Thesis. Leeds: University of Leeds; 1985.
59. Hoyle PLM. Computer assisted design of organic synthesis. PhD. Thesis. Leeds: University of Leeds; 1985.
60. Dewar MJS, Gleicher GJ. Ground States of Conjugated Molecules. II. Allowance for Molecular Geometry. J Am Chem Soc 1965, 87:685-692.
61. Tumber HS. Computer assisted synthesis design-selected heterocyclic systems. PhD. Thesis. Leeds: University of Leeds; 1985.
62. Seghal S. Computer assisted design of organic synthesis. PhD. Thesis. Leeds: University of Leeds; 1990.
63. Hanessian S. Total Synthesis of Natural Products: The 'Chiron' Approach. Elmsford, NY: Pergamon Press; 1983.
64. Ivanciuc O. Canonical Numbering and Constitutional Symmetry. In: Gasteiger J, ed. Handbook of Chemoinformatics. Weinheim: Wiley-VCH; 2003, 139-160.
65. Wipke WT, Dyott TM. Simulation and evaluation of chemical synthesis. Computer representation and manipulation of stereochemistry. J Am Chem Soc 1974, 96:4825-4834.
66. Corey EJ, Long AK. Computer-assisted synthetic analysis. Performance of long-range strategies for stereoselective olefin synthesis. J Org Chem 1978, 43:2208-2216.
67. Blackwood JE, Blower PE, Layten SW, Lillie DH, Lipkus AH, Peer JP, Qian C, Staggenborg LM, Watson CE. Chemical abstracts service chemical registry system. 13. Enhanced handling of stereochemistry. J Chem Inf Comput Sci 1991, 31:204-212.
68. Lipkus AH, Blower PE. Relative configurations in stereochemical substructure search. In: Chemical Structures 2: The International Language Of Chemistry. Proceedings of the second international conference, Leeuwenhorst Congress Center, Noordwijkerhout, The Netherlands. Berlin: Springer-Verlag; 1993, 137-144.
69. Gunther B, Zugge J. On the recognition of composed systems of stereocenters in molecular graph theory by wreath products [Internet]. Available at: (Accessed April 1, 2010).
70. Morgan HL. The generation of a unique machine description for chemical structures-a technique developed at chemical abstracts service. J Chem Doc 1965, 5:107-113.
71. Freeland RG, Funk SA, O'Korn LJ, Wilson GA. The chemical abstracts service chemical registry system. II. Augmented connectivity molecular formula. J Chem Inf Comput Sci 1979, 19:94-98.
72. Wipke WT, Dyott TM. Stereochemically unique naming algorithm. J Am Chem Soc 1974, 96:4834-4842.
73. Wipke WT, Krishnan S, Ouchi GI. Hash functions for rapid storage and retrieval of chemical structures. J Chem Inf Comput Sci 1978, 18:32-37.
74. Figueras J. Morgan revisited. J Chem Inf Comput Sci 1993, 33:717-718.
75. Hodgson R, Nelson A. A two-directional synthesis of the C58-C71 fragment of palytoxin. Org Biomol Chem 2004, 2:373.
76. Poss CS, Schreiber SL. Two-directional chain synthesis and terminus differentiation. Acc Chem Res 1994, 27:9-17.
77. Magnuson SR. Two-directional synthesis and its use in natural product synthesis. Tetrahedron 1995, 51:167-2213.
78. Anstiss M, Holland JM, Nelson A, Titchmarsh JR. Beyond breaking the MirrorPlane: the desymmetrisation of centrosymmetric molecules as an efficient strategy for asymmetric synthesis. ChemInform 2003, 34:1213-1220.
79. Garcia-Urdiales E, Alfonso I, Gotor V. Enantioselective enzymatic desymmetrizations in organic synthesis. Chem Rev 2005, 105:313-354.
80. Hoffmann RW. meso Compounds: stepchildren or favored children of stereoselective synthesis? Angew Chem Int Ed 2003, 42:1096-1109.
81. Agarwal KK. An algorithm for computing the automorphism group of organic structures with stereochemistry and a measure of its efficiency. J Chem Inf Comput Sci 1998, 38:402-404.
82. Shelley CA, Munk ME. An approach to the assignment of canonical connection tables and topological symmetry perception. J Chem Inf Comput Sci 1979, 19:247-250.
83. Jochum C, Gasteiger J. Canonical numbering and constitutional symmetry. J Chem Inf Comput Sci 1977, 17:113-117.
84. Fan BT, Barbu A, Panaye A, Doucet J. Detection of constitutionally equivalent sites from a connection table. J Chem Inf Comput Sci 1996, 36:654-659.
85. Fan BT, Panaye A, Doucet J. Comment on "Isomorphism, Automorphism Partitioning, and Canonical Labeling Can Be Solved in Polynomial-Time for Molecular Graphs". J Chem Inf Comput Sci 1999, 39:630-631.
86. Carhart RE. Erroneous claims concerning the perception of topological symmetry. J Chem Inf Comput Sci 1978, 18:108-110.
87. Jochum C, Gasteiger J. On the misinterpretation of our algorithm for the perception of constitutional symmetry. J Chem Inf Comput Sci 1979, 19:49-50.
88. Carhart R. Letter to the Editor. Perception of topological symmetry. J Chem Inf Comput Sci 1979, 19:56.
89. Ruecker G, Ruecker C. Computer perception of constitutional (topological) symmetry: TOPSYM, a fast algorithm for partitioning atoms and pairwise relations among atoms into equivalence classes. J Chem Inf Comput Sci 1990, 30:187-191.
90. Figueras J. Automorphism and equivalence classes. J Chem Inf Comput Sci 1992, 32:153-157.
91. Röse P, Gasteiger J. Automated derivation of reaction rules for the EROS 6.0 system for reaction prediction. Anal Chim Acta 1990, 235:163-168.
92. Wipke WT, Gund P. Simulation and evaluation of chemical synthesis. Congestion: a conformation-dependent function of steric environment at a reaction center. Application with torsional terms to stereoselectivity of nucleophilic additions to ketones. J Am Chem Soc 1976, 98:8107-8118.
93. Corey EJ, Cramer RD, Howe WJ. Computer-assisted synthetic analysis for complex molecules. Methods and procedures for machine generation of synthetic intermediates. J Am Chem Soc 1972, 94:440-459.
94. Orf HW. Computer-assisted synthetic analysis. PhD. Thesis. Cambridge, MA: Harvard University; 1976.
95. Kappos J. Computer-assisted synthetic analysis: tactical combinations of transforms and a generalised procedure for subgoal transform selection. PhD. Thesis. Cambridge, MA: Harvard University; 1991.
96. Long AK, Kappos JC. Computer-assisted synthetic analysis. Performance of tactical combinations of transforms. J Chem Inf Comput Sci 1994, 34:915-921.
97. Meehan P, Schofield H. CrossFire: a structural revolution for chemists. Online Information Review 2001, 25:241-249.
98. Fontain E, Reitsam K. The generation of reaction networks with RAIN. 1. The reaction generator. J Chem Inf Comput Sci 1991, 31:96-101.
99. Ugi I, Dengler A. The algebraic and graph theoretical completion of truncated reaction equations. J Math Chem 1992, 9:1-10.
100. Gasteiger J, Jochum C. EROS - a computer program for generating sequences of reactions. Top Curr Chem 1978, 74:93-126.
101. Hendrickson JB. Systematic synthesis design. IV. Numerical codification of construction reactions. J Am Chem Soc 1975, 97:5784-5800.
102. Ernst G, Newell A. GPS: a case study in generality and problem solving. New York: Academic Press; 1969.
103. Wipke W, Ouchi GI, Krishnan S. Simulation and evaluation of chemical synthesis-SECS: an application of artificial intelligence techniques. Artif Intell 1978, 11:173-193.
104. Corey EJ, Wipke WT, Cramer RD, Howe WJ. Computer-assisted synthetic analysis. Facile man-machine communication of chemical structure by interactive computer graphics. J Am Chem Soc 1972, 94:421-430.
105. Corey EJ, Jorgensen WL. Computer-assisted synthetic analysis. Generation of synthetic sequences involving sequential functional group interchanges. J Am Chem Soc 1976, 98:203-209.
106. Gnas Y, Glorius F. Chiral auxiliaries-principles and recent applications. ChemInform 2006, 37:1899-1930.
107. Paquette L. Chiral reagents for asymmetric synthesis. Chichester: Wiley; 2003.
108. Ojima I. Catalytic Asymmetric Synthesis. 2nd ed. New York: Wiley-VCH; 2000.
109. Corey EJ, Howe WJ, Pensak DA. Computer-assisted synthetic analysis. Methods for machine generation of synthetic intermediates involving multistep look-ahead. J Am Chem Soc 1974, 96:7724-7737.
110. Ott MA, Noordik JH. Long-range strategies in the LHASA Program: the quinone Diels-Alder transform. J Chem Inf Comput Sci 1997, 37:98-108.
111. Corey EJ, Long AK, Mulzer J, Orf HW, Johnson AP, Hewett APW. Computer-assisted synthetic analysis. Long-range search procedures for antithetic simplification of complex targets by application of the halolactonization transform. J Chem Inf Comput Sci 1980, 20:221-230.
112. Corey EJ, Johnson AP, Long AK. Computer-assisted synthetic analysis. Techniques for efficient long-range retrosynthetic searches applied to the Robinson annulation process. J Org Chem 1980, 45:2051-2057.
113. Corey EJ, Long AK. Computer-assisted synthetic analysis. Performance of long-range strategies for stereoselective olefin synthesis. J Org Chem 1978, 43:2208-2216.
114. Hendrickson JB. Systematic synthesis design. 6. Yield analysis and convergency. J Am Chem Soc 1977, 99:5439-5450.
115. Johnson AP, Marshall C, Judson PN. Starting material oriented retrosynthetic analysis in the LHASA program. 1. General description. J Chem Inf Comput Sci 1992, 32:411-417.
116. Johnson AP, Marshall C. Starting material oriented retrosynthetic analysis in the LHASA program. 2. Mapping the SM and target structures. J Chem Inf Comput Sci 1992, 32:418-425.
117. Johnson AP, Marshall C. Starting material oriented retrosynthetic analysis in the LHASA program. 3. Heuristic estimation of synthetic proximity. J Chem Inf Comput Sci 1992, 32:426-429.
118. Hart PE, Nilsson NJ, Raphael B. A formal basis for the heuristic determination of minimum cost paths. IEEE Trans Syst Sci Cybern 1968, 4:100-107.
119. Nilsson NJ. Principles of Artificial Intelligence. Palo Alto, CA: Tioga Publishing Company; 1980.
120. Pearl J. Heuristics: Intelligent Search Strategies for Computer Problem Solving. Addison-Wesley; 1984.
121. Russell SJ, Norvig P. Artificial Intelligence: A Modern Approach. Prentice Hall; 2002.
122. Corey EJ, Cheng X. The Logic of Chemical Synthesis. Wiley-Interscience; 1989.
123. Coelho F, Deprés J, Brocksom TJ, Greene AE. Direct approach to the bakkanes: a synthesis of (±)-homogynolide-B. Tetrahedron Lett 1989, 30:565-566.
124. Srikrishna A, Nagaraju S, Venkateswarlu S, Hiremath US, Reddy TJ, Venugopalan P. A formal total synthesis of (±)-homogynolide-B. J Chem Soc Perkin Trans 1 1999, (15):2069-2076.
125. Hendrickson JB, Braun-Keller E. Systematic synthesis design. 8. Generation of reaction sequences. J Comput Chem 1980, 1:323-333.
126. Jauffret P, Ostermann C, Kaufmann G. Using the COSYMA system for the discovery of synthesis strategies by analogy. Eur J Org Chem 2003, 2003:1983-1992.
127. Ellermann L, Jauffret P, Ostermann C, Kaufmann G. Evolution of the concept of synthesis strategy in the COSYMA system: introduction of the synthesis invariant. Liebigs Ann/Recl 1997, 1997:1401-1406.
128. Lee TV. Expert systems in synthesis planning: a user's view of the LHASA program. Chemometr Intell Lab 1987, 2:259-272.
129. Gund P, Grabowski EJJ, Hoff DR, Smith GM, Andose JD, Rhodes JB, Wipke WT. Computer-assisted synthetic analysis at Merck. J Chem Inf Comput Sci 1980, 20:88-93.