With synthesis planning systems

In this paper we describe how the ORAC reaction database system has been integrated with the LHASA synthesis planning program. This interface allows literature precedents for synthetic steps proposed by LHASA to be retrieved from ORAC and displayed to the user. The problem of sequence searching in reaction database systems is also explored and approaches to this problem are described. Finally, the potential use of synthesis planning systems to identify and classify links between reactions in ORAC for use during sequence searching is considered. 

In the retrosynthetic plan (Scheme 14), the key step was based on the crucial supposition that the truns-fused bicyclic hemiacetal Dill would undergo a reversible ring tautomerization with the monocyclic system DII, the skeletal and functionalization of which are well correlated with both actinobolin 1 and bactobolin 2 (vide infra). Further retrosynthesis of Dill led to unsaturated hemiacetal DIV which is reminiscent of a 2,3-unsaturated pyranose (i.e., a pseudo glycal) [46], and thence to lactone DV. The construction of the unsaturated bicyclic lactone therefore constituted the first plateau of this synthesis. 

The first task can be done very conveniently with the available reaction retrieval systems. The second task is either a synthesis retrieval or a S3mthesis proposal task. The reaction retrieval systems cannot yet handle the synthesis retrieval job, but the synthesis proposal task can be done with one of the synthesis planning programs. 

Suppose a chemist wishes to propose a new synthesis for quinine that was different strategically from prior published plans. The goal is to come up with a plan that is different from past published plans that demonstrates novelty in building up the ring system in a different way than earlier published plans, and hopefully that this new methodology translates into a more material efficient plan. 

The primary purpose of a reaction database system is to provide quick and easy access to the reaction literature. Users of synthesis planning programs have a need for such access to the literature in elaborating routes suggested by an analysis. An interface between LHASA and ORAC has recently been developed to provide such a link. The interface allows literature precedents for synthetic steps proposed by LHASA to be retrieved automatically from ORAC s database of over 120,000 reactions and to be displayed to the user on an ORAC Display Form. Company databases can also be accessed to search and display in-house preparative methods and processes in conjunction with databases supplied by ORAC Ltd. 

The synthesis of modhephene (54), which proceeds according to plan in an overall yield of >16%, with complete control of relative stereochemistry, demonstrates the ability of radical cyclisations to form propellane systems and generate highly crowded neopentyl quaternary centres. The accepted pathway for the cyclisation of the vinyl trimethylstannane is shown in Scheme 7.25. The chair-like transition state in which the methyl substituent on the radical is pseudoequatorial, accounts for the observed endo stereoselectivity. 

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