Synthons acyl anion

Again we need a reagent for an acyl anion synthon (A). We find this in the acetyhde ion since substituted acetylenes can be hydrated to ketones ... 

Terminal alkyne anions are popular reagents for the acyl anion synthons (RCHjCO"). If this nucleophile is added to aldehydes or ketones, the triple bond remains. This can be con verted to an alkynemercury(II) complex with mercuric salts and is hydrated with water or acids to form ketones (M.M.T. Khan, 1974). The more substituted carbon atom of the al-kynes is converted preferentially into a carbonyl group. Highly substituted a-hydroxyketones are available by this method (J.A. Katzenellenbogen, 1973). Acetylene itself can react with two molecules of an aldehyde or a ketone (V. jager, 1977). Hydration then leads to 1,4-dihydroxy-2-butanones. The 1,4-diols tend to condense to tetrahydrofuran derivatives in the presence of acids. 

Disconnection of the ether la now a good idea as it leaves an ct-hydroxy ketone to be made by acyl anion equivalent addition. We prefer (10) as the acetylene anion can then serve as synthon (4). 

Reagents are available nowadays for acyl anions other than (4). Thus when Heathcock made the ketone (16), which he used in stereoselective aldol reactions, he needed a-hydroxy ketone (17), This required synthon (18) for which an acetylene is not a good choice as there are as yet no means of controlling the reglo-selectivity of hydration of (19). 

Generation of Acyl Anion Equivalents (d Synthons) from Aldehydes... 

D. J. Ager, Formyl and acyl anions, in Umpoled Synthons, T. A. Hase, ed., Wiley-lnlerscience, New York, 1987, p. 19. 

Aside from the nitronates, cyanide anion and acyl anion equivalents, e.g. (219), examples of conjugate additions of a-aza-stabilized carbanions are rare. The aminomethyl synthon [ CHRNH2] is typically introduced with either nitronates or cyanide however, a-metallomethyl isocyanides (248) also show synthetic promise in conjugate additions. In addition, depending on hydrolytic conditions employed, they also serve as equivalents for the N-formamidomethyl anion ["CHRNHCHO] or the isocyanatomethyl anion ["CHRN=C ] (Scheme 84).189... 

Likewise 1,3-dithianes can be deprotonated by alkyl lithium bases and the resulting anions are strong nucleophiles. The ditliiane group can be hydrolyzed back to the carbonyl group. Thus the dithiane serves as a synthon for the acyl anion. 

Cyanohydrin derivatives have also been widely used as acyl anion synthons. They are prepared from carbonyl compounds by addition of hydrogen cyanide. A very useful variant is to use trimethylsilyl cyanide with an aldehyde to produce a trimethylsilyloxy cyanide. The cyano group acidifies the a position (pKA 25) and the a proton can be removed by a strong base. Alkylation of the anion and unmasking of the hydroxy group cause elimination of cyanide and re-formation of the carbonyl group. 

These are only three of many ways that have been reported for the formation of acyl anion equivalents, which are among the most common umpolung synthons to be found in the literature. All are prepared by a similar strategy in that they contain functional groups which can sustain a negative charge on an adjacent carbon and can be converted back to a carbonyl group. 

The acyl anion (R-C=0) is not stable as such, but when an aldehyde is converted into a 1,3-dithiane by reaction with propane-1,3-dithiol and then treated with base, it forms an acyl anion equivalent, and hence is susceptible to attack by electrophilic reagents (see Section 5.9). Two extensive compilations of formyl and acyl anion synthons together with references to their reactions... 

The retrosynthetic disconnection for the y-keto acid shown below generates an acyl anion synthon and a three-carbon carbocation. 

In chapters 19 (1,3-diCO) and 21 (1,5-diCO) we were able to use an enol(ate) as the carbon nucleophile when we made our disconnection of a bond between the two carbonyl groups. Now we have moved to the even-numbered relationship 1,2-diCO this is not possible. In the simple cases of a 1,2-diketone 1 or an a-hydroxy-ketone 4, there is only one C-C bond between the functionalised carbons so, while we can use an acid derivative 3 or an aldehyde 5 for one half of the molecule, we are forced to use a synthon of unnatural polarity, the acyl anion 2 for the other half. We shall start this chapter with a look at acyl anion equivalents (d1 reagents) and progress to alternative strategies that avoid rather than solve the problem. 

The simplest reagent for an acyl anion is cyanide ion, one of the few genuine carbanions. After addition to an aldehyde, say, the resulting cyanohydrin 7 can be converted into a range of compounds 6 and 8-10. The cyanide ion represents the synthons shown in frames next to each product. 

You might think you could escape this problem by choosing the alternative disconnection 8, but this is not so. We have more choice here we can use the a3 synthon 7 with natural polarity, in real life an enone, but then we shall have to use the acyl anion equivalents 6 that we met in chapter 23. Reversing the polarity gives us the naturally polarised electrophile, an a1 synthon 9 represented by an acylating agent and the homoenolate, or d3 synthon, 10 with unnatural polarity. 

We have met the acyl anion or d1 synthon in chapter 23 but for the disconnection 8 on 1,4-diketones we need a d1 reagent that will do conjugate additions on enones such as 36. Sadly that eliminates dithians from consideration as they are too basic (hard) and tend to add direct to carbonyl groups. 

The disconnection with opposite polarity requires a very different approach—the use of a synthon that is nucleophilic at the hydroxy carbon. The acyl anion equivalent described in Section 20.9 provides a nucleophilic carbon with a substituent that can be readily converted to a hydroxy group ... 

A sequence in which a carbonyl group has been masked as a sulfur derivative, alkylated with an electrophile, and then revealed again is a nucleophilic acylation. These nucleophilic equivalents of carbonyl compounds are known as acyl anion equivalents. In the retrosynthetic terms of Chapter 50 they are d1 reagents corresponding to the acyl anion synthon. 

The potential of the reverse polarity approach has been spectacularly demonstrated in a plethora of synthetic studies. A representative example can be found in Seebach s preparation of the antibiotic vermiculin. The key step of this synthesis involved the preparation of a polyfunctional intermediate 253 via the sequence shown in Scheme 2.102. The first stage of this sequence couples the formyl anion equivalent 244 with bromoepoxide 254. The primary bromide is more active as an electrophile than epoxide and therefore, under carefully controlled conditions, the product 255 is formed selectively. Under somewhat more stringent conditions the epoxide ring present in the latter adduct reacts as an electrophile with the second acyl anion equivalent 256 to yield adduct 257. In this sequence, 254 was used as an equivalent to the 1,4-doubly charged synthon CH2CH2CH(OH)CH. In the final step of this scheme, carbanion 258 was generated and reacted with dimethylformamide to produce the required product 253. It is remarkable that all of these sequential operations are carried out in one reaction vessel without the isolation of any intermediate products. The overall yield of 253 is rather high (approximately 52%). 

Likewise, intermolecular reactions are possible and lead to coupling products which correspond retrosynthetically to the addition of an acyl anion synthon to a ketone. The presence of a proton-donor cosolvent is crucial, otherwise j8-hydroxy nitriles are formed preferentially. The nitrile addition reaction proceeds with good stereoselectivity, e.g. preferentially one diastereoisomer is formed from the electro-reductive addition of acetonitrile (which can advantageously be used as solvent) to dihydrocarvone. 

Aldehydes and ketones RCOR react with a-methoxyvinyllithium, CH2=C(Li)OMe, to give hydroxy enol ethers, RR C(OH)C(OMe)=CH2, which are easily hydrolyzed to acyloins, RR C(OH)COMe. ° In this reaction, the CH2=C(Li)OMe is a synthon for the unavailable H3C—C=0, °" and is termed an acyl anion equivalent. The reagent also reacts with esters RCOOR to give RC(OH)(COMe=CH2)2. A synthon for the Ph—C=0 ion is PhC(CN)OSiMe3, which adds to aldehydes and ketones RCOR to give, after hydrolysis, the a-hydroxy ketones, RR C(OH) C OH)COPh. ... 

Tosylmethyl isocyanide (TosMIC) (75 R = H), a versatile reagent in synthesis, can also be used as an acyl anion equivalent. For instance symmetrical and unsymmetrical diketones were prepared by using this TosMIC synthon (equation 40). Ketones are homologated to enones by alkylating the condensation product derived from TosMIC, followed by acid hydrolysis (Scheme 46). 1-Isocyano-l-tosyl-l-alkenes (76), formed by the reaction of TosMIC with an aldehyde or ketone, react with a primary amine or ammonia to give 1,5-disubstituted (or 5-monosubstituted) imidazoles in high yield (Scheme 47). ... 

Acyl anion synthons derived from cyanohydrins may be generated catalytically by cyanide ion via the Stetter reaction " However, further reaction with electrophiles is confined to carbonyl compounds and Michael acceptors. 

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