Computer-assisted Organic Synthesis Research Articles

ChemInform Abstract: Computer‐Assisted Synthetic Planning: The End of the Beginning

AbstractReview: [61 refs.

Computer-Assisted Synthetic Planning: The End of the Beginning.

Exactly half a century has passed since the launch of the first documented research project (1965 Dendral) on computer-assisted organic synthesis. Many more programs were created in the 1970s and 1980s but the enthusiasm of these pioneering days had largely dissipated by the 2000s, and the challenge of teaching the computer how to plan organic syntheses earned itself the reputation of a "mission impossible". This is quite curious given that, in the meantime, computers have "learned" many other skills that had been considered exclusive domains of human intellect and creativity-for example, machines can nowadays play chess better than human world champions and they can compose classical music pleasant to the human ear. Although there have been no similar feats in organic synthesis, this Review argues that to concede defeat would be premature. Indeed, bringing together the combination of modern computational power and algorithms from graph/network theory, chemical rules (with full stereo- and regiochemistry) coded in appropriate formats, and the elements of quantum mechanics, the machine can finally be "taught" how to plan syntheses of non-trivial organic molecules in a matter of seconds to minutes. The Review begins with an overview of some basic theoretical concepts essential for the big-data analysis of chemical syntheses. It progresses to the problem of optimizing pathways involving known reactions. It culminates with discussion of algorithms that allow for a completely de novo and fully automated design of syntheses leading to relatively complex targets, including those that have not been made before. Of course, there are still things to be improved, but computers are finally becoming relevant and helpful to the practice of organic-synthetic planning. Paraphrasing Churchill's famous words after the Allies' first major victory over the Axis forces in Africa, it is not the end, it is not even the beginning of the end, but it is the end of the beginning for the computer-assisted synthesis planning. The machine is here to stay.

In silico design of bio-based commodity chemicals: application to itaconic acid based solvents

Global issues are deeply changing the face of the chemical industry. Both the feedstock – biomass vs. oil – and the chemical transformations used are now chosen to comply with a sustainable development. In this work, a computer-assisted organic synthesis program, named GRASS (GeneratoR of Agro-based Sustainable Solvents), is proposed to help in the design of sustainable solvents from biomass feedstock. A careful selection of industrially relevant chemical transformations has been performed to propose a set that allows obtaining in a few steps (1 to 3) a large number of commodity chemicals from a chosen set of bio-based building-blocks. Emphasis has been put on solvents since this type of compound is undergoing a deep renewal due to more stringent regulatory constraints, but the same approach may be extended to other commodity chemicals. This methodology has been exemplified starting from itaconic acid, a multifunctional bio-based building block. We checked a posteriori that all itaconic acid based-solvents reported in the literature do indeed belong to the set of virtual solvents generated by GRASS, along with an extended list of new derivatives that could be of potential interest.

ChemInform Abstract: Computer-Assisted Organic Synthesis Planning: Effective Bond Polarity as a Guideline to Reactivity.

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ChemInform Abstract: A Preliminary Appraisal of Selected Problems in Computer-Assisted Organic Synthesis.

Some basic problems of contemporary computer-assisted organic synthesis are briefly dealt with. The discussion (led from the point of view of computer science) mainly concerns the question of a solution space in organic synthesis and methods of artificial intelligence used to search it. Some features of systems assisting in organic synthesis, regarded as dedicated expert systems, are also commented on. An interactive strategy for development of an optimum synthetic tree is proposed. Finally, expected future trends in computer-assisted organic synthesis and simulation (modeling) of organic reactions are briefly summarized.

ChemInform Abstract: Erythronolide B: Analysis of the Synthesis Pathway Proposed by the Lilith Program.

Computer-Assisted Organic Synthesis (CAOS) has become a common tool in synthesis pathway design. Many different approaches exist, each giving suggestions for the exploration of the synthetic space. Validation of the proposed solutions can be done both by using different programs and by experimental realization of the synthesis. To this end, a molecule of medium complexity, erythronolide B, has been used to make a three-way comparison using results obtained by the program LHASA, in the laboratory, and by the program Lilith. The importance of using different sources in studying a synthesis pathway is discussed, with respect to achieving the best result from each approach. The high level of convergence in the syntheses proposed by the Lilith program is the most interesting characteristic of the program's results. Moreover, reproduction of the syntheses proposed by the other approaches guarantees the applicability of the Lilith program to real synthetic problems. A brief outline of the Lilith program is included.

COMPASS Program - An Original Semi-Emperical Approach To Computer-Assisted Synthesis

The fundamental principle of the original “DIssection-Approximation” approach (DIA-approach) to the formal description of organic reactions are presented. It is shown that organic reactions can be considered as dissections of chemical bonds followed by the appropriate “approximations” of the reaction centers around the dissected bonds. A new original COMPASS program for computer-assisted organic synthesis (CAOS) has been developed for IBM PC on the basis of DIA-approach. The COMPASS program is shown to be a reasonable compromise between two traditional (empirical and nonempirical) directions in CAOS. We have considered the approach which has been developed as an individual semi-empirical direction in CAOS. The main feature of this semi-empirical approach is shown to be the combination of pure combinatorial methods with a small knowledge base that includes empirical rules in their most generalized form. The powerful ability of the COMPASS program to reproduce the key skeleton transformations in the total syntheses of natural compound is demonstrated for the structures quadrone and sirein.

Competing concepts in CAOS

AbstractThe evolution of Computer‐Assisted Organic Synthesis (CAOS) is briefly reviewed. The underlying concepts and strategies of the various approaches to CAOS are compared. A status report is given on bilateral synthesis design. This requires selection of suitable starting materials from a list of available compounds according to structural features of the target by correlation of substructures, augmentation of the target molecule by co‐products to yield an Ensemble of Molecules (EM) that is isomeric to the starting EM and, finally, establishment of synthesis routes that lead from the starting EM to the target EM. Despite of its apparent complexity, bilateral CAOS is a promising approach because of its combinatorial advantages.

A preliminary appraisal of selected problems in computer‐assisted organic synthesis

AbstractSome basic problems of contemporary computer‐assisted organic synthesis are briefly dealt with. The discussion (led from the point of view of computer science) mainly concerns the question of a solution space in organic synthesis and methods of artificial intelligence used to search it. Some features of systems assisting in organic synthesis, regarded as dedicated expert systems, are also commented on. An interactive strategy for development of an optimum synthetic tree is proposed. Finally, expected future trends in computer‐assisted organic synthesis and simulation (modeling) of organic reactions are briefly summarized.

Computer-assisted organic synthesis planning: effective bond polarity as a guideline to reactivity

A first section involved in reactivity prediction has been introduced in a program for computer-aided organic synthesis planning. The concepts of native polarity, induced polarity, and effective polarity have been used to determine the best electronic state for the retrosynthetic breakage of strategic bonds. The characterization obtained is used to suggest the most feasible reactive behavior for the atoms spanning the strategic bond. The procedure and the atomic and molecular physical properties used in the determination of the polarities are described. The logical component is introduced to extend the number of bonds meaningfully treated by the procedure. Results obtained show the low number of bonds that remain unresolved by the semirecursive program logic

Structures for controlling synthesis design and reaction modelling via knowledge acquisition

The performance of programs for computer-assisted organic synthesis (CAOS) is directly related to the knowledge base and to the procedures for deciding how the knowledge base should be used. The architecture of a knowledge base (text base, data base, rule base, model base and commonsense base) is discussed. The problem of knowledge acquisition is described with regard to pruning the productivity of CAOS systems. The commercial program 1stCLASS (for symbolic processing) is used with the SAAO (devised here for numeric processing) to form a commonsense base. For this purpose, knowledge was acquired by induction from the solutions provided by human experts to given problems. The general procedure is applied to the recognition of reaction sites which are crucial in the simulation of organic reactions.

COMPASS program: Combination of empirical rules and combinatorial methods for planning of organic synthesis

An original semi-empirical COMPASS program for Computer-Assisted Organic Synthesis is developed. This program is based on the combination of pure combinatorial methods with empirical rules of retrosynthetic analysis. A small knowledge base containing generalized description of synthetic methods is discussed. The principles of the DIssection-Approximation (DIA) approach to formalization of organic reactions are given. A general flow-chart of the program is presented. The rule's interpreter as well as the basic principles of the rule's construction and selection criteria are discussed. The demo version of the COMPASS program for PC-compatible computers is included on disk.

Computer-assisted organic synthesis design and reaction prediction system, “AIPHOS”

The new computer-assisted organic synthesis design and reaction prediction system AIPHOS (Artificial Intelligence for Planning and Handling Organic Synthesis) is introduced here. The system is aimed to assist the experimental chemist in the generation of all possible synthetic precursors to produce a given target molecule. Furthermore the system is also oriented to treat and predict the reaction paths and products of chemical reactions in one of the first attempts to combine this with synthesis design in one integrated system. AIPHOS unites a logic-oriented strategy with a knowledge-guided search strategy to not only give a hypothetical solution to the problem, but also the reaction conditions that would characterize its realization. This paper is an overview of the fundamental aspects of the system and developments made so far.

Computer-assisted organic synthesis of volatile heterocyclic compounds in food flavors

Revue bibliographique concernant les methodes assistees par ordinateur appliquees a la synthese d'aromatisants alimentaires. Presentation de quelques exemples de synthese de derives du maltol et de l'ammoniac

Computer-assisted organic synthesis: An undergraduate experiment

Computer-assisted organic synthesis: An undergraduate experiment