Retrosynthetic

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... 

The aim of a retrosynthetic analysis is the transformation of a synthesis target into progressively simpler structures, following a pathway to commercially available starting materials. 

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). 

Figure 10.3-30. The retrosynthetic point of view the transform of a Michael addition. The structure fragment with a gray background is the retron of the Michael addition transforin.

A siynthestis tree is the graphical representation of the result of a retrosynthetic analysis. The target compound (T) is set to the top of a tree that is turned upside down (Figure 10..3-3.3). 

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.). 

The retrosynthetic analysis is performed in two steps in a first step, SYNGEN dissects the skeleton to find all fully convergent bondsets which utili2e starting material skeletons found in two successive levels of cuts. A bondset is a set of skeletal bonds that is cut during the retrosynthetic analysis or formed in any given synthesis. 

The Japanese program system AlPHOS is developed by Funatsu s group at Toyo-hashi Institute of Technology [40]. AlPHOS is an interactive system which performs the retrosynthetic analysis in a stepwise manner, determining at each step the synthesis precursors from the molecules of the preceding step. AlPHOS tries to combine the merits of a knowledge-based approach with those of a logic-centered approach. 

Figure 10.3-34. The plajiiiing of a synthesis is neither a classical bottom-up nor a top-down search, ft is an array of different methods for searching and planning, applied In both the retrosynthetic and the synthetic directions.

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 retrosynthetic analysis of a target compound is a systematic approach in developing a synthesis plan starting with the target structure and working backward to available starting materials. 

Most programs take a retrosynthetic approach. This is a means for systematically working backward from the target compound to available precursors... 

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]. 

The oxidative generation of o-aminophenylacetaldehydes can be done by ozonolysis (retrosynthetic path d in Scheme 2.2) but this requires an elec-... 

Retrosynthetic path e in Scheme 2.2 requires a regioselective oxidation of an o-nitrostyrene to the corresponding phenylacetaldehyde. This transformation has been accomplished hy Wacker oxidation carried out in such a way as to ensure the desired regioselectivity. The required o-nitrostyrenes can be prepared by Heck vinylation. One procedure for oxidation uses 1,3-propaiiediol to trap the product as a l,3-dioxane[15]. These can then be hydrogenated over Rh/C and cyclized by treatment with dilute HCl,... 

Category Ih cyclizations effect closure of the C2 C3 bond. Scheme 3.1 depicts retrosynthetic transformations corresponding to syntheses in category lb. Included are three variations of the intramolecular aldol condensation and reductive coupling of o,/V-diacylanilines,... 

Retrosynthetic path b in Scheme 3.1 corresponds to reversal of the electrophilic and nucleophilic components with respect to the Madelung synthesis and identifies o-acyl-iV-alkylanilines as potential indole precursors. The known examples require an aryl or EW group on the iV-alkyl substituent and these substituents are presumably required to facilitate deprotonation in the condensation. The preparation of these starting materials usually involves iV-alkyla-tion of an o-acylaniline. Table 3.3 gives some examples of this synthesis. 

Rctrosynthetic path a corresponds to Pd-catalysed exo-trig cyclization of o-halo-JV-allylanilines. Path b involves the endo-trig cyclization of o-halo-JV-vinyl anilines. Path c is a structurally similar cyclization which can be effected photochemically in the absence of an o-substituent. Retrosynthetic path d involves intramolecular Friedel-Crafts oxyalkylation followed by aromatiz-ation. 

A symbol used to indicate a retrosynthetic step is an open arrow written from prod uct to suitable precursors or fragments of those precursors... 

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... 

A number of compounds of the type represented by compound A were prepared for evalu ation as potential analgesic drugs Their preparation is described in a retrosynthetic format as shown... 

On the basis of this retrosynthetic analysis design a synthesis of N methyl 4 phenylpipendine (compound A where R = CH3 R = C6H5) Present your answer as a series of equations show ing all necessary reagents and isolated intermediates... 

---