Synthesis LHASA

Current research in LHASA is focused on developing new methods assisting users in choosing the most appropriate strategy for their target structures. Furthermore, the development of criteria for the evaluation of synthesis routes and/or algorithms for selecting optimal synthesis routes within the tree are discussed [34]. 

In 1969 Corey and Wipke [7] reported the program OCSS (Organic Chemical Simulation of Synthesis) which was the precursor of one of the most powerful programs known at present which has been named LHASA (the acronym of Logic and Heuristics Applied to Synthetic Analysis) [5b] [8]. Since then, different... 

Process automatically the structure of the alkaloid porantherine, first with the "default-order" of disconnections and then giving priority to "consonant" over "rings" disconnections. In the latter case you should "Save" only the intermediate precursors leading to the same synthetic sequence and the same starting material (A) used in Corey s synthesis, which was actually found by LHASA (see ref. 19, Chapter 12). 

A number of different systems have been developed to conduct computer-aided organic synthesis. Of these, one of the most extensive projects is LHASA ( 3 - 11). The method starts from a target molecule and derives a set of precursor molecules which can be expected to be converted to the target by one synthetic reaction or a simple sequence of reactions. Each precursor molecule so generated serves as the next target and the procedure is repeated, thus generating a tree of synthetic intermediates. Each precursor is somewhat simpler than its parent target molecule. 

Gelernter et al (12, 13) developed a program SYNCHEM to produce reasonable problem-solving trees containing a high density of complete and satisfactory synthesis. Like LHASA, this also depends a lot on empirical chemical transforms. 

The computer-assisted synthetic analysis designated OCSS (organic chemical simulation of synthesis) and LHASA (logic and heuristics applied to synthetic analysis) were designed to assist chemists in synthetic analysis by Corey et LHASA generates trees of synthetic intermediates from a target molecule by analysis in the retrosynthetic direction. 

As a check on the effectiveness of the LHASA program, the authors performed an analysis on 14 polycyclic compounds for which a synthesis was already reported in the literature. In 10 of these cases, the LHASA program included in the set of the generated solutions the very synthetic schemes that had been successfully realized. 

Retrosynthetic Analysis. An approach to computer-assisted synthesis design that starts with the products of a reaction or sequence of reactions and works backwards toward the reactants. An example program that implements retrosynthetic analysis is the LHASA program of E. J. Corey s group. 

Simulation and Evaluation of Chemical Synthesis (SECS) was developed by Wipke and uses heuristic methods similar to LHASA but puts special emphasis on stereochemistry, topology, and energy minimization [112]. 

Logic and Heuristics Applied to Synthetic Analysis (LHASA) is an expert system for synthesis planning that assists chemists in designing efficient routes to target molecules for organic synthesis. 

Another program available form Lhasa Ltd. is Meteor, software that allows predicting metabolic pathways of xenobiotic compounds [13-15], Again, the program uses expert knowledge in form of rules to predict the metabolic pathway of compounds. The predictions are presented in metabolic trees, similar to a synthesis tree, and may be filtered according to the likelihood of metabolites. 

Figure 10.5. A sample retrosynthetic pathway generated by LHASA for the synthesis of aphidicolin.

These concepts were developed into the computer program SYNGEN147 (SYNthesis GENeration). As with Corey s LHASA program, inspection of the main principles of the program can offer useful information for a synthesis. It is emphasized that this section has only touched the surface of Hendrickson s detailed and comprehensive analysis. Once understood, any target can be analyzed in detail to provide a synthetic tree. 

The Diels-Alder reaction is one of the powerful reactions referred to by Corey in his LHASA program for synthesis (sec. 10.4.B). One of the powerful features of the Diels-Alder reaction is the stereochemical selectivity inherent to the cycloaddition and many examples exist in the total synthesis of natural products. ... 

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