Retrosynthetic reactions

CHAOS is a program for the computer-assisted design of organic synthesis. CHAOSBASE is an auxiliary program, which makes it possible to create retrosynthetic reactions data bases that can then be used by the CHAOS program. 

The CHAOSBASE program has been designed to create retrosynthetic reactions data bases, i.e. transforms data bases. These transforms can be used by the CHAOS program to create synthetic pathways. As many data bases as are needed can be created, but CHAOS can only use a maximum of 10 data bases simultaneously. 

Fragment analysis is based on the RECAP algorithm, published in 1998 [55], This retrosynthetic combinatorial analysis starts with a collection of active molecules and then fragments these molecules using any set of retrosynthetic reactions (Figure 8.12). For example, Cisapride is cleaved into four fragments based on three different bond cleavage types. 

Transform-based strategy searches for simplifying retrosynthetic reactions. 

Topological strategy to identify strategic bonds that can lead to major simplifications of retrosynthetic reactions. 

To recognize the different levels of representation of biochemical reactions To understand metabolic reaction networks To know the principles of retrosynthetic analysis To understand the disconnection approach To become familiar with synthesis design systems... 

Since a reaction is considered during a retrosynthetic analysis in a direction opposite to its actual course, it is called a retro-reaction or transform (Figure 10.3-30). 

Tran orm-based or long-range strategies The retrosynthetic analysis is directed toward the application of powerful synthesis transforms. Functional groups are introduced into the target compound in order to establish the retion of a certain goal transform (e.g., the transform for the Diels-Alder reaction, Robinson annulation, Birch reduction, halolactonization, etc.). 

In order to verify a retrosynthetic step suggested by WODCA, a direct connection to reaction databases (e.g., Theilheimer [62] has been established in the most recent version of WODCA. 

The position of the ehosen strategic bond locates the reaction center. To derive the reaction siibstrncture, the user can select the number of bond, spheres around the strategic bond which should be included. The reaction substructure obtained is then n.scd as the query for a reaction substructure search in the database. Figure 10,3-42 illustrates the first and second bond spheres around a selected strategic bond of a retrosynthetic step. 

The number of bond spheres chosen influences the specificity of tlie reaction substructure query and the result of the search. In Figure 10.3-43 the reaction substructure queiy including the first bond sphere of the retrosynthetic step of Figure 10,3-42 is shown. 

Reaction prediction treats chemical reactions in their forward direction, and synthesis design in their backward, retrosynthetic direction,... 

The vitamin D3 metabolite la,25-dihydroxycholecalciferol is a lifesaving drug in treatment of defective bone formation due to renal failure. Retrosynthetic analysis (E.G. Baggjolint, 1982) revealed the obvious precursors shown below, a (2-cyclohexylideneethyl)diphenylphosphine oxide (A) and an octahydro-4f/-inden-4-one (B), to be connected in a Wittig-Homer reaction (cf. section 1.5). 

In the last fifteen years macrolides have been the major target molecules for complex stereoselective total syntheses. This choice has been made independently by R.B. Woodward and E.J. Corey in Harvard, and has been followed by many famous fellow Americans, e.g., G. Stork, K.C. Nicolaou, S. Masamune, C.H. Heathcock, and S.L. Schreiber, to name only a few. There is also no other class of compounds which is so suitable for retrosynthetic analysis and for the application of modem synthetic reactions, such as Sharpless epoxidation, Noyori hydrogenation, and stereoselective alkylation and aldol reactions. We have chosen a classical synthesis by E.J. Corey and two recent syntheses by A.R. Chamberlin and S.L. Schreiber as examples. 

The reactant corresponding to retrosynthetic path b in Scheme 2.2 can be obtained by Meerwein arylation of vinyl acetate with o-nitrophcnyldiazonium ions[9], Retrosynthetic path c involves oxidation of a 2-(o-nitrophenyl)ethanol. This transformation has also been realized for 2-(o-aminophenyl)ethanols. For the latter reaction the best catalyst is Ru(PPhj)2Cl2. The reaction proceeds with evolution of hydrogen and has been shown to be applicable to a variety of ring-substituted 2-(o-aminophenyl)ethanols[10]. 

When planning the synthesis of a compound using an organometallic reagent or indeed any synthesis the best approach is to reason backward from the product This method is called retrosynthetic analysis Retro synthetic analysis of 1 methylcyclohexanol suggests it can be prepared by the reaction of methylmagnesmm bromide and cyclohexanone... 

It is useful to think about synthetic processes which can be used together in a specific sequence as multistep packages. Such standard reaction combinations are typified by the common synthetic sequences shown in Chart 13. In retrosynthetic analysis the corresponding transform groupings can be applied as tactical combinations. 

The direct goal of stereochemical strategies is the reduction of stereochemical complexity by the retrosynthetic elimination of the stereocenters in a target molecule. The greater the number and density of stereocenters in a TGT, the more influential such strategies will be. The selective removal of stereocenters depends on the availability of stereosimplifying transforms, the establishment of the required retrons (complete with defined stereocenter relationships), and the presence of a favorable spatial environment in the precursor generated by application of such a transform. The last factor, which is of crucial importance to stereoselectivity, mandates a bidirectional approach to stereosimplification which takes into account not only the TGT but also the retrosynthetic precursor, or reaction substrate. Thus both retrosynthetic and synthetic analyses are considered in the discussion which follows. 

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