Retrosynthetic synthesis

Figure 3.3 shows a simple example of a retrosynthetic synthesis of cyclohexanol. Cyclohexanol may be disconnected to a hydride ion and a hydroxycarbocation (the synthons). Sodium borohydride and cyclohexanone are the synthetic equivalents of these two synthons. Thus, reacting cyclohexanone with NaBH will produce cyclohexanol. 

A retrosynthetic synthesis of (—)antirhine (Fig. 11) was performed through the monoacetate (1) and lactone (2) which was condensed with tryptamine. Product 3 was then finally converted, through a number of intermediates, to the tetracyclic (—)-antirhine, resulting in a remarkable overall yield of 13% (starting from the monoacetate 1), together with the 3-epimer (+)-antirhine at a yield of 6%. This strategy allowed the chemo-enzymatic synthesis of both (—) - and (+)-antirhines [82]. 

Fig. 7.22 (a) Retrosynthetic synthesis of porphyrin oligomers without amine templates. [After Sanders et ah] (b) Synthesis of porphyrin oligomers with amine templates. [After Sanders et at.] (c) Synthesis of oligomeric porphyrins binding a metal-carbonyl cluster and a chiral aluminium template. 

WORKED PROBLEM 16.26 Here is a specific example of using retrosynthetic analysis. Provide a retrosynthetic synthesis of 2-phenyl-2-butanol. Assume that you have benzene, ethanol, pyridine, and access to any inorganic reagents you might need. 

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. 

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.

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. 

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. 

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. 

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... 

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... 

Given structure 1 as a target and the recognition that it contains the retron for the Diels-Alder transform, the application of that transform to 1 to generate synthetic precursor 2 is straightforward. The problem of synthesis of 1 is then reduced retrosynthetically to the simpler... 

The frequent use of chiral controller or auxiliary groups in enantioselective synthesis (or diastereoselective processes) obviously requires the addition of such units retrosynthetically, as illustrated by the antithetic conversion 34 =i> 35. 

Methodology for the enantioselective synthesis of a broad range of chiral starting materials, by both chiral catalytic and controller-directed processes, is rapidly becoming an important factor in synthesis. The varied collection of molecules which are accessible by this technology provides another type of chiral S-goal for retrosynthetic analysis. 

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