A treatment of stereochemistry in computer aided organic synthesis

This thesis describes the author’s contributions to a new stereochemical processing module constructed for the ARChem retrosynthesis program. The purpose of the module is to add the ability to perform enantioselective and diastereoselective retrosynthetic disconnections and generate appropriate precursor molecules. The module uses evidence based rules generated from a large database of literature reactions. Chapter 1 provides an introduction and critical review of the published body of work for computer aided synthesis design. The role of computer perception of key structural features (rings, functions groups etc.) and the construction and use of reaction transforms for generating precursors is discussed. Emphasis is also given to the application of strategies in retrosynthetic analysis. The availability of large reaction databases has enabled a new generation of retrosynthesis design programs to be developed that use automatically generated transforms assembled from published reactions. A brief description of the transform generation method employed by ARChem is given. Chapter 2 describes the algorithms devised by the author for handling the computer recognition and representation of the stereochemical features found in molecule and reaction scheme diagrams. The approach is generalised and uses flexible recognition patterns to transform information found in chemical diagrams into concise stereo descriptors for computer processing. An algorithm for efficiently comparing and classifying pairs of stereo descriptors is described. This algorithm is central for solving the stereochemical constraints in a variety of substructure matching problems addressed in chapter 3. The concise representation of reactions and transform rules as hyperstructure graphs is described. Chapter 3 is concerned with the efficient and reliable detection of stereochemical symmetry in both molecules, reactions and rules. A novel symmetry perception algorithm, based on a constraints satisfaction problem (CSP) solver, is described. The use of a CSP solver to implement an isomorph‐free matching algorithm for stereochemical substructure matching is detailed. The prime function of this algorithm is to seek out unique retron locations in target molecules and then to generate precursor molecules without duplications due to symmetry. Novel algorithms for classifying asymmetric, pseudo‐asymmetric and symmetric stereocentres; meso, centro, and C2 symmetric molecules; and the stereotopicity of trigonal (sp2) centres are described. Chapter 4 introduces and formalises the annotated structural language used to create both retrosynthetic rules and the patterns used for functional group recognition. A novel functional group recognition package is described along with its use to detect important electronic features such as electron‐withdrawing or donating groups and leaving groups. The functional groups and electronic features are used as constraints in retron rules to improve transform relevance. Chapter 5 details the approach taken to design detailed stereoselective and substrate controlled transforms from organised hierarchies of rules. The rules employ a rich set of constraints annotations that concisely describe the keying retrons. The application of the transforms for collating evidence based scoring parameters from published reaction examples is described. A survey of available reaction databases and the techniques for mining stereoselective reactions is demonstrated. A data mining tool was developed for finding the best reputable stereoselective reaction types for coding as transforms. For various reasons it was not possible during the research period to fully integrate this work with the ARChem program. Instead, Chapter 6 introduces a novel one‐step retrosynthesis module to test the developed transforms. The retrosynthesis algorithms use the organisation of the transform rule hierarchy to efficiently locate the best retron matches using all applicable stereoselective transforms. This module was tested using a small set of selected target molecules and the generated routes were ranked using a series of measured parameters including: stereocentre clearance and bond cleavage; example reputation; estimated stereoselectivity with reliability; and evidence of tolerated functional groups. In addition a method for detecting regioselectivity issues is presented. This work presents a number of algorithms using common set and graph theory operations and notations. Appendix A lists the set theory symbols and meanings. Appendix B summarises and defines the common graph theory terminology used throughout this thesis

Open Babel: An open chemical toolbox

Background: A frequent problem in computational modeling is the interconversion of chemical structures between different formats. While standard interchange formats exist (for example, Chemical Markup Language) and de facto standards have arisen (for example, SMILES format), the need to interconvert formats is a continuing problem due to the multitude of different application areas for chemistry data, differences in the data stored by different formats (0D versus 3D, for example), and competition between software along with a lack of vendorneutral formats. Results: We discuss, for the first time, Open Babel, an open-source chemical toolbox that speaks the many languages of chemical data. Open Babel version 2.3 interconverts over 110 formats. The need to represent such a wide variety of chemical and molecular data requires a library that implements a wide range of cheminformatics algorithms, from partial charge assignment and aromaticity detection, to bond order perception and canonicalization. We detail the implementation of Open Babel, describe key advances in the 2.3 release, and outline a variety of uses both in terms of software products and scientific research, including applications far beyond simple format interconversion. Conclusions: Open Babel presents a solution to the proliferation of multiple chemical file formats. In addition, it provides a variety of useful utilities from conformer searching and 2D depiction, to filtering, batch conversion, and substructure and similarity searching. For developers, it can be used as a programming library to handle chemical data in areas such as organic chemistry, drug design, materials science, and computational chemistry. It is freely available under an open-source license fro

Graph Symmetry Detection and Canonical Labeling: Differences and Synergies

Symmetries of combinatorial objects are known to complicate search algorithms, but such obstacles can often be removed by detecting symmetries early and discarding symmetric subproblems. Canonical labeling of combinatorial objects facilitates easy equivalence checking through quick matching. All existing canonical labeling software also finds symmetries, but the fastest symmetry-finding software does not perform canonical labeling. In this work, we contrast the two problems and dissect typical algorithms to identify their similarities and differences. We then develop a novel approach to canonical labeling where symmetries are found first and then used to speed up the canonical labeling algorithms. Empirical results show that this approach outperforms state-of-the-art canonical labelers.Comment: 15 pages, 10 figures, 1 table, Turing-10

Kinetic model construction using chemoinformatics

Kinetic models of chemical processes not only provide an alternative to costly experiments; they also have the potential to accelerate the pace of innovation in developing new chemical processes or in improving existing ones. Kinetic models are most powerful when they reflect the underlying chemistry by incorporating elementary pathways between individual molecules. The downside of this high level of detail is that the complexity and size of the models also steadily increase, such that the models eventually become too difficult to be manually constructed. Instead, computers are programmed to automate the construction of these models, and make use of graph theory to translate chemical entities such as molecules and reactions into computer-understandable representations. This work studies the use of automated methods to construct kinetic models. More particularly, the need to account for the three-dimensional arrangement of atoms in molecules and reactions of kinetic models is investigated and illustrated by two case studies. First of all, the thermal rearrangement of two monoterpenoids, cis- and trans-2-pinanol, is studied. A kinetic model that accounts for the differences in reactivity and selectivity of both pinanol diastereomers is proposed. Secondly, a kinetic model for the pyrolysis of the fuel “JP-10” is constructed and highlights the use of state-of-the-art techniques for the automated estimation of thermochemistry of polycyclic molecules. A new code is developed for the automated construction of kinetic models and takes advantage of the advances made in the field of chemo-informatics to tackle fundamental issues of previous approaches. Novel algorithms are developed for three important aspects of automated construction of kinetic models: the estimation of symmetry of molecules and reactions, the incorporation of stereochemistry in kinetic models, and the estimation of thermochemical and kinetic data using scalable structure-property methods. Finally, the application of the code is illustrated by the automated construction of a kinetic model for alkylsulfide pyrolysis

Topological Foundations of Cognitive Science

A collection of papers presented at the First International Summer Institute in Cognitive Science, University at Buffalo, July 1994, including the following papers: ** Topological Foundations of Cognitive Science, Barry Smith ** The Bounds of Axiomatisation, Graham White ** Rethinking Boundaries, Wojciech Zelaniec ** Sheaf Mereology and Space Cognition, Jean Petitot ** A Mereotopological Definition of 'Point', Carola Eschenbach ** Discreteness, Finiteness, and the Structure of Topological Spaces, Christopher Habel ** Mass Reference and the Geometry of Solids, Almerindo E. Ojeda ** Defining a 'Doughnut' Made Difficult, N .M. Gotts ** A Theory of Spatial Regions with Indeterminate Boundaries, A.G. Cohn and N.M. Gotts ** Mereotopological Construction of Time from Events, Fabio Pianesi and Achille C. Varzi ** Computational Mereology: A Study of Part-of Relations for Multi-media Indexing, Wlodek Zadrozny and Michelle Ki

Using SMILES strings for the description of chemical connectivity in the Crystallography Open Database

Computer descriptions of chemical molecular connectivity are necessary for searching chemical databases and for predicting chemical properties from molecular structure. In this article, the ongoing work to describe the chemical connectivity of entries contained in the Crystallography Open Database (COD) in SMILES format is reported. This collection of SMILES is publicly available for chemical (substructure) search or for any other purpose on an open-access basis, as is the COD itself. The conventions that have been followed for the representation of compounds that do not fit into the valence bond theory are outlined for the most frequently found cases. The procedure for getting the SMILES out of the CIF files starts with checking whether the atoms in the asymmetric unit are a chemically acceptable image of the compound. When they are not (molecule in a symmetry element, disorder, polymeric species,etc.), the previously published cif_molecule program is used to get such image in many cases. The program package Open Babel is then applied to get SMILES strings from the CIF files (either those directly taken from the COD or those produced by cif_molecule when applicable). The results are then checked and/or fixed by a human editor, in a computer-aided task that at present still consumes a great deal of human time. Even if the procedure still needs to be improved to make it more automatic (and hence faster), it has already yielded more than 160,000 curated chemical structures and the purpose of this article is to announce the existence of this work to the chemical community as well as to spread the use of its results.The authors are grateful to the Junta de Andalucía (Research Group FQM-195) for financial support of the publication costs of this article

Using SMILES strings for the description of chemical connectivity in the Crystallography Open Database

Computer descriptions of chemical molecular connectivity are necessary for searching chemical databases and for predicting chemical properties from molecular structure. In this article, the ongoing work to describe the chemical connectivity of entries contained in the Crystallography Open Database (COD) in SMILES format is reported. This collection of SMILES is publicly available for chemical (substructure) search or for any other purpose on an open-access basis, as is the COD itself. The conventions that have been followed for the representation of compounds that do not fit into the valence bond theory are outlined for the most frequently found cases. The procedure for getting the SMILES out of the CIF files starts with checking whether the atoms in the asymmetric unit are a chemically acceptable image of the compound. When they are not (molecule in a symmetry element, disorder, polymeric species,etc.), the previously published cif_molecule program is used to get such image in many cases. The program package Open Babel is then applied to get SMILES strings from the CIF files (either those directly taken from the COD or those produced by cif_molecule when applicable). The results are then checked and/or fixed by a human editor, in a computer-aided task that at present still consumes a great deal of human time. Even if the procedure still needs to be improved to make it more automatic (and hence faster), it has already yielded more than 160,000 curated chemical structures and the purpose of this article is to announce the existence of this work to the chemical community as well as to spread the use of its results.The authors are grateful to the Junta de Andalucía (Research Group FQM-195) for financial support of the publication costs of this article

Advances in Quantum Theory

The quantum theory is the first theoretical approach that helps one to successfully understand the atomic and sub-atomic worlds which are too far from the cognition based on the common intuition or the experience of the daily-life. This is a very coherent theory in which a good system of hypotheses and appropriate mathematical methods allow one to describe exactly the dynamics of the quantum systems whose measurements are systematically affected by objective uncertainties. Thanks to the quantum theory we are able now to use and control new quantum devices and technologies in quantum optics and lasers, quantum electronics and quantum computing or in the modern field of nano-technologies