Synthon Analysis

Figure 9.17 A snapshot of Synthons Analysis for the primary amine query.

Mosley R.T., Culberson J.C., Kraker B., Feuston B.P., Sheridan R.P., Conway J.F., Forbes J.K., Chakravorty S.J., Kearsley S.K., Reagent selector using synthon analysis to visualize reagent properties and assist in basis set selection. J. Chem. Inf. Model. 2005, 45, 1439-1446. 

The recently developed logit hydrogen-bonding propensity (LHP) model is another knowledge-based approach that aims to build a predictive model from what is observed in known crystal structures. In contrast to the supramolecular synthon analysis in the methodology described above, which addresses elaborate arrangements of intermolecular interactions that are specific to a small family of very closely related molecules, the LHP model focuses on... 

Analysis It may be tempting to disconnect bond a but this would giye the unknown and presumably yery unstable PhC=0 synthon. The better disconnection is bond b giying two carbonjd compounds. 

Analysis Marking the common atoms we find there are three possible disconnections of bonds between them, but only a or c give us simpler precursors. Both also are logical in that we can immediately write reagents for the synthons. 

Analysis The carbene synthon is easy it can be ethyl diazoacetate NiCHCOiEt. The diene can be made by the Wittig reaction from a familiar aUylic bromide (TM 31). 

PLE catalyzes the hydrolysis of a wide range of meso-diesters (Table 2). This reaction is interesting from both theoretical and practical standpoints. Indeed, the analysis of a large range of kinetic data provided sufficient information to create a detailed active site model of PLE (31). From a practical standpoint, selective hydrolysis of y j (9-cyclo-I,2-dicarboxylates leads to chiral synthons that are valuable intermediates for the synthesis of a variety of natural products. 

The second edition of this extremely successful guidebook for planning organic syntheses is addressed to advanced undergraduate, graduate and research chemists. Retrosynthetic analysis and the synthon approach are presented. This new, extensively revised and enlarged edition takes account of recent developments, such as nanometer-size architecture, while emphasizing the essentials. 

If a target aminodicarboxyl units bears an aryl group in one of its side chains, retrosynthetic analysis indicates that a bromoamide synthon 12, bearing an aliphatic side-chain, should react with a nucleophilic partner carrying the aromatic side chain. In the alternative bromoamide 21, HBr elimination to cinnamic derivatives competes with the desired bromine substitution. 

The stereochemistry of the first step was ascertained by an X-ray analysis [8] of an isolated oxazaphospholidine 3 (R = Ph). The overall sequence from oxi-rane to aziridine takes place with an excellent retention of chiral integrity. As the stereochemistry of the oxirane esters is determined by the chiral inductor during the Sharpless epoxidation, both enantiomers of aziridine esters can be readily obtained by choosing the desired antipodal tartrate inductor during the epoxidation reaction. It is relevant to note that the required starting allylic alcohols are conveniently prepared by chain elongation of propargyl alcohol as a C3 synthon followed by an appropriate reduction of the triple bond, e. g., with lithium aluminum hydride [6b]. 

Retrosynthetic analysis may identify a need to use synthetic equivalent groups. These groups are synthons that correspond structurally to a subunit of the target structure, but in which the reactivity of the functionality is masked or modified. As an example, suppose the transformation shown below was to be accomplished. 

Trimethylenemethane is a special type of alkene that does not exist as the free compound. Various synthetic equivalents to the synthon 43 shown below have been reported. Trost, in particular, has exploited these compounds in 1,3-dipolar cycloaddition reactions.138 139 A metal-bound, isolated trimethylenemethane species was recently reported by Ando (Scheme 6). It resulted from the complexation of an ero-methylenesila-cyclopropene with group 8 carbonyls (Fe, Ru).140,140a The structure was proved by X-ray crystal structure analysis.29Si NMR data were consistent with the -structure shown. 

Treatment of the CH-acidic carbonyl compound with 1.5-2.5 equivalents of D M F D EA in N, N-dimethylformamide at 180 °C resulted in full conversion to the enam-ine synthons within 5 min. The enamines were obtained in 53-93% yield (based on LC-MS analysis) and were used without further purification in the next step. 

Easily available advanced synthons, such as the carbohydrates, amino acids, hydroxyacids, and terpenoids, make the synthetic task easier than the complexity metrics of the target suggests this is especially true for the glycosides, if the carbohydrate portion can be introduced intactly. It must also be borne in mind that the S metric is counted in a linearly additive hion, neglecting interactions between the functional groups (Whitlock 1998) such interactions are not treated adequately by any method so far proposed to calculate the molecular complexity. Moreover, no attention was paid here to the graphic analysis of the synthesis plan based on the molecular complexity of the intermediates these aspects have recently been reviewed (Bertz 1993 Whitlock 1998 Chanon 1998). 

A retrosynthetic analysis leads to one synthon with reversed polarity and another with normal polarity ... 

The simple addition reaction in Scheme 19 illustrates how the notation is used. Ester (1) can be dissected into synthons (2), (3) and (4). Synthons for radical precursors (pro-radicals) possess radical sites ( ) A reagent that is an appropriate radical precursor for the cyclohexyl radical, such as cyclohexyl iodide, is the actual equivalent of synthon (2). By nature, alkene acceptors have one site that reacts with a radical ( ) and one adjacent radical site ( ) that is created upon addition of a radical. Ethyl acrylate is a reagent that is equivalent to synthon (3). Atom or group donors are represented as sites that react with radicals ( ) Tributyltin hydride is a reagent equivalent of (4). In practice, such analysis will usually focus on carbon-carbon bond forming reactions and the atom transfer step may be omitted in the notation for simplicity. 

Section 3.2.1 covers a similar area of synthesis planning as S. Warren s (1978) book Designing Organic Synthesis . This book contains many examples of antitheses of achiral carbo-and heterocyclic compounds that are largely ignored in this chapter (but see sections 2.5,4.6, and 4.7 for heterocycles). Warren s much more elaborate introduction into the "synthon approach to rerro-synthetic analysis is based on E.J. Corey s work (1967A, 1971) and is highly recommended for further study. 

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