Synthons illogical

Clearly other combinations of logical and illogical synthons could be used to make 1,4-dioxygenated compounds. How could you use cyanide ion (as the CO2H synthon) to make a y-keto acid such as... 

You will meet other combinations of logical and illogical synthons in review problems later. 

Although all these strategies imply, in some respect, a reactivity inversion of some of the starting reagents or synthons, the term "reactivity inversion" (or Umpolung as proposed by Seebach in 1979) [1] is commonly used in the context of the strategy known as "illogical disconnections" [2]. 

The obvious disconnection on a 1, 4-dicarbonyl compound gives us a logical nuclec philic synthon (an enolate anion) A but an illogical electrophilic synthon B ... 

The nature of the problem is now revealed. We have many candidates for the synthon (3), the most obvious being an aldehyde (Y = OH). But what of synthon (2> This synthon has unnatural polarity (illogical) and the usual strategy will be to devise a reagent for (2) or to avoid it altogether by some alternative strategy. 

The problem of an unnatural (illogical) synthon arises here too (cf. Chapter 23). A 1,4-diketone (1) can be disconnected at its central bond into the natural enolate (2) but that requires also an unnatural synthon, the a-carbonyl cation (3). We shall need reagents for this synthon as well as for related synthons at different oxidation levels. We met some of these reagents—a-halo carbonyl compounds and epoxides—in Chapter 6. 

Disconnecting that same carbon-oxygen bond in the other direction (with both electrons going to the carbon) would be an illogical disconnection, since it leads to an electrophilic oxygen synthon for which there is no reasonable equivalent reagent. 

Disconnection of an a-hydroxy carboxylic acid results in an illogical synthon a carboxylic acid moiety that is nucleophilic at the carbonyl carbon. 

Disconnection of the TM at the newly formed C-C bond gives an illogical synthon (an acyl anion, for which a 1,3-dithiane anion is the synthetic equivalent). An alternate, stepwise approach to the retrosynthesis involves first doing a functional group interconversion, followed by a logical disconnection. Either... 

The disconnection of a y-hydroxy carbonyl at the alpha carbon seems illogical because it is different from the aldol disconnection of a P-hydroxy carbonyl. The alpha carbon is the nucleophile as expected, but the electrophilic synthon has a positive charge not on the same carbon as the hydroxyl, but on the adjacent carbon. This reactivity can be achieved by using an epoxide ring, because when a nucleophile attacks an epoxide, the hydroxyl group of the product is on the carbon next to the carbon that was attacked. 

Since attempting to disconnect a 1,6-dicarbonyl leads to illogical synthons, a retrosynthesis involving a functional group interconversion should be considered instead. 

On the other hand, the carbethoxy cation, a seemingly illogical synthon, has an available synthetic equivalent in diethyl carbonate. Diethyl carbonate is produced by oxidative carbonylation of ethanol, promoted by various heterogeneous catalysts one of the most effective is the mixed catalyst CuCl2/PdCl2 deposited on charcoal (Scheme 4.20). 

Abstract Compounds with a 1,2-, 1,4- and 1,6-dioxygen pattern and related bifunctional structures are presented. Disconnection of the internal bonds results in illogical synthons because of the mismatch of charges in the patterns with an even number of C atoms between the functional groups. Three-membered heterocyclic rings are presented as an important class of illogical nucleophiles in the retrosyn-thesis of the 1,2-difunctional pattern. Retrosynthesis of the 1,6-dicarbonyl pattern by reconnection and rctro-Birch reduction of the aromatic building block is related to chemoselective Birch reduction and ozonolysis in the synthetic route. The retrosynthesis and synthesis of salbutamol and asymmetric synthesis of —)-frontalin are presented. 

Disconnection (a) corresponds to the synthesis of I, a-halogenation of carboxylic acid or its derivative followed by hydrolysis of halogen (Scheme 5.2). Disconnection (b) envisages building a carbon framework from C + Ci synthons but looks unacceptable since illogical synthon COOH with a negative charge on the carbonyl C atom appears. Let us, however, consider the next example. 

Completing the disconnection of the internal C-C bond with participation of the hydroxy group, we generate the simple building block acetophenone and illogical synthon COOH (Scheme 5.3). 

Cyanide salts are also used in the Strecker synthesis of a-amino acids. This well-known name reaction generates compounds with a 1,2-disubstimted pattern whose disconnection results in one illogical synthon. Example 5.3 presents some mechanistic details of this reaction, suggested by rcfra-Strecker disconnection. 

In the first step, we perform 1,2-disconnection with participation of the neighboring amino group and formation of an illogical anionic synthon (Scheme 5.7). 

Such 1,2-CO disconnection results in ketone and an illogical synthon, the acetyl anion. Since we discovered sodium acetylide as the proper reagent for anionic C2 synthons, a short and elegant synthetic scheme for TM 5.5 can be proposed (Scheme 5.15). 

The next example confirms the importance of retrosynthetic analysis of the a-hydroxycarbonyl pattern conceiving sodium acetylide as a reagent for the acetyl anion as an illogical synthon. 

The following examples illustrate the practicability of syntheses of tricycles with reagents based on illogical synthons. First we discuss the epoxidation of the C=C bond in its achiral and chiral variant. 

As presented in Sect. 5.1, an even number of C atoms between oxygen functionalities results in a mismatch of partial charges on the atoms of the central C-C bond. Accordingly, disconnection of the central C-C bond in 1,4-dicarbonyl compounds results in an acceptable anionic synthon and illogical cationic synthon with a positive charge on the a-C atom (Scheme 5.38). 

In this 1,4-dioxygenated pattern, we can expect that all disconnections of central bonds will result in one preferred and one illogical synthon. Let as first consider two variants of 1,4-CO disconnection a (Scheme 5.47). 

A surprising solution is offered by rcfro-Mannich type disconnection b where the acidic C-H group participates and the carbanion appears as an illogical synthon on the acyl C atom. We showed the transformation of the nitro to a carbonyl group already in Sect. 2.4. For the illogical C3 synthon, an unexpected reagent exists, 1-nitropropane, whose a-C-H atom has a of ca. 10. Taking into account this... 

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