Reagents. Equivalents. Synthons

An impressive number of alkaloids has been generated from the synthon (202), which is accessible by an acid catalyzed rearrangement of the appropriately substituted cyclopropyl-imine. The endocyclic enamine (202) should react with electrophiles on the /8-carbon in a process which simultaneously renders the a-carbon electrophilic and therefore susceptible to capture by nucleophilic reagents. The application of this methodology to the synthesis of ipalbidine (191a) and septicine (204) is shown in Scheme 30. Here, the unusual 3-phenylthio-2-pyrroline intermediate (203) serves as a relatively stable equivalent synthon of the unsubstituted 2-pyrroline analogue which is notoriously unstable (77ACR193). 

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. 

Re, R-0=0, CH2-C02R. These synthons have unnatural , or reversed polarity (originally called umpolung ).23 However, they are perfectly valid though their reagent equivalents are sometimes not immediately obvious. Some illustrative examples are noted below. 

Target molecules which contain a carbon-carbon double bond, in the presence of other functionality or not, may be treated as in a one- or two-group disconnection strategy, as noted above. However, disconnection at the double bond may be a valuable retrosynthetic transform, since the synthons may then be related to reagent equivalents for a Wittig-type (Section 5.2.3, p.495 and Section 5.18) or aldol-type (Section 5.18) synthesis. 

The synthetic methods described below illustrate the use of various reagent equivalents to such synthons which give a good yield of the required product. 

One of the most important reagent equivalents of the donor formyl synthon is 1,3-dithiane (see Chapter 1, p. 21). However the use of this reagent equivalent is not widely found for the synthesis of simple aldehydes since other methods may be economically more appropriate. An example of specific formylation by the use of 1,3-dithiane is illustrated in Expt 6.66. Disodium tetracarbonylferrate(n)... 

Synthon Some reagent equivalents Cross-references... 

A C—N disconnection of a primary amine gives rise to the carbocation and amide anion synthons. It might be predicted therefore that treatment of an alkyl halide with ammonia (reagents equivalent to the above synthons) under pressure would constitute a suitable synthesis of a primary amine. In practice, however, the yield is poor since a mixture of all three classes of amines, together with some of the quaternary ammonium salt, is obtained, owing to more ready further alkylation of the sequentially formed products. 

An alternative reagent equivalent for the amide anion synthon is the potassium salt of phthalimide which can only react with one molecular proportion of alkyl halide. The resulting JV-alkylphthalimide is then cleaved to the primary amine (the Gabriel synthesis). The preliminary preparation of potassium phthalimide (from a solution of phthalimide in absolute ethanol and potassium hydroxide in 75% ethanol) may be avoided in some cases by boiling phthalimide with the halide in the presence of anhydrous potassium carbonate. The cleavage of the JV-substituted phthalimide is best effected by reaction with hydrazine hydrate and then heating the reaction mixture with hydrochloric acid. The insoluble phthalylhydrazide is filtered off, leaving the amine hydrochloride in solution from which the amine may be liberated and isolated in the appropriate manner. 

A retrosynthetic analysis of an a,/J-unsaturated aldehyde or ketone involves an initial functional group interconversion into a /1-hydroxycarbonyl compound, followed by a disconnection into the carbocation (12) and the carbanion (13) synthons. The reagent equivalents of these two synthons are the corresponding carbonyl compounds. 

In the case of (11), retrosynthetic functional group interconversion into the aldol followed by disconnection of the a, /3-bond gives the dipolar synthon (15), of which the reagent equivalent is the 1,4-dicarbonyl compound, hexane-2,5-dione (i.e. a refro-aldol condensation). The action of base on this diketone effects the forward aldol reaction followed by spontaneous dehydration (see Expt 7.4 for formulation). 

Disconnection of the cylic j8-keto ester (23) gives the dipolar synthon (25), the reagent equivalent of which is diethyl adipate. 

A similar disconnection for indane-l,3-dione (24) gives the dipolar synthon (26), from which it may be inferred that the reagent equivalent could be o-ethoxycarbonylacetophenone. 

The synthesis of this starting material may prove troublesome, but if an activating group (C02Et) is formally added to the methyl group, further disconnection leads to the recognition of diethyl phthalate and ethyl acetate as the reagent equivalents of the synthons (27) and (28) respectively. 

This time-honoured view of ring construction preceded the retrosynthetic approach it is still of value since it provides an indication of which bonds could be selected for disconnection. The more rigorous application of the principles of retrosynthetic analysis leads of course to the formulation of synthons and their reagent equivalents. 

Urea may be recognised as a structural unit in 5,5-diphenylhydantoin (57) and it constitutes one of the reagents in the synthesis. Although it is not obvious, the appropriate reagent equivalent corresponding to the accompanying synthon is in fact benzil. 

Chloroacetone is also a recognisable reagent equivalent following disconnection of 2,4-dimethylthiazole (60) the reagent equivalent of the other synthon is thioacetamide, which is formed in situ from acetamide and phosphorus penta-sulphide (Expt 8.20). 

A retrosynthetic analysis for coumarin reveals salicylaldehyde and acetic anhydride (under basic conditions) as suitable reagent equivalents of the derived synthons. 

Synthon Some reagent equivalents (masked or latent functionality, LF) Page ref. 

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