Acyl anion equivalent

Acyl Anion Equivalents. The most common umpolung equivalent is that for acyl anion 339, and dithianes 344 are the most common reagent used for this purpose. Dithiane 344 is prepared from an aldehyde, but ketones are also precursors (sec. 7.3.B.ii). Removal of the hydrogen adjacent to the sulfur requires a base such as n-butyllithium and the product is a-lithiodithiane (345). The acidity of this hydrogen is largely 

A typical application is the reaction of hexanal with 1,3-propanethiol and an acid catalyst to give dithiane 346 (sec. 7.3.B.ii). Subsequent treatment with n-butyllithium to give corresponding lithio derivative (347, R = pentyl) followed by addition of 1-bromopentane gave the alkylation product, 348.343 jo complete the reversal of reactivity, the carbonyl must be unmasked, which is usually done with a Lewis acid that has a high 

Other electrophiles include H, RX, RCOX, epoxides, ketones, aldehydes, etc 

As mentioned above, many reagents have been used for hydrolysis, which is due, in part, to variations in reactivity of the dithiane as the nature of the 2-alkyl group changes. Several problems can arise during 

Chapter 8. Nucleophilic Species That Form Carbon-Carbon Bonds 

If the equivalent of a negatively charged carbonyl group is added to another carbonyl, then a 1,2-dioxygenated species is produced. The reagents that can do this are called acyl anion equivalents—they are the synthons for [XC(=0)]. We have already met a number of such species, the cyanide ion, the anions of alkynes, and dithianes. 

FIGURE 20.2 Mechanism of cyanohydrin formation using MejSiCN. 

FIGURE 20.5 Applications of the benzoin and related reactions in synthesis. 

FIGURE 20.6 Alkynyl anions as acyl anion equivalents. 

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Thiamin pyrophosphate- natures acyl anion equivalent for trans ketolization reactions... 

Allylalion of the alkoxymalonitrile 231 followed by hydrolysis affords acyl cyanide, which is converted into the amide 232. Hence the reagent 231 can be used as an acyl anion equivalent[144]. Methoxy(phenylthio)acetonitrile is allylated with allylic carbonates or vinyloxiranes. After allylation. they are converted into esters or lactones. The intramolecular version using 233 has been applied to the synthesis of the macrolide 234[37]. The /i,7-unsaturated nitrile 235 is prepared by the reaction of allylic carbonate with trimethylsilyl cyanide[145]. 

Although many carbonyl derivatives act as acyl cation equivalents, R(C=0)" in synthetic chemistry, the inherent polarity of the carbonyl group makes it much more difficult to find compounds that will act as equivalents of acyl anions, R(C=0) . Since the 1960s, major progress has been made in this area, and there are now a wide variety of compound types that can react in this way. As in so many areas of organic chemistry, heterocyclic compounds take pride of place and form the basis of many of the most useful methods. In recent years there has been particular interest in developing chiral acyl anion equivalents that will show high... 

Among the most successful classes of asymmetric acyl anion equivalents are the dioxane-containing a-amino nitriles 99 introduced by Enders and coworkers. These are deprotonated by EDA, and the resulting anions act as efficient equivalents of RCO for addition to a, (3-unsaturated esters [90AG(E)179],... 

Oxathiane 101 is readily deprotonated using s-BuLi, and the resulting anion reacts with alkyl halides, ketones, and benzonitrile (85JOC657). The majority of work in this area, however, is due to Eliel and coworkers and has involved chiral 1,3-oxathianes as asymmetric acyl anion equivalents. In the earliest work it was demonstrated that the oxathianes 102 and 103, obtained in enantiomeri-cally pure form by a sequence involving resolution, could be deprotonated with butyllithium and added to benzaldehyde. The products were formed with poor selectivity at the new stereocenter, however, and oxidation followed by addition... 

The methylenebis(boronic acid) 122 may be deprotonated and alkylated at the central position and may thus behave as an acyl anion equivalent. Monoalkylation of 122 followed by hydrolysis gives aldehydes in good yield, and a second alkylation led to a ketone in one case (77JA3196). 

The (V-methyldihydrodithiazine 125 has also been used as an effective formyl anion equivalent for reaction with alkyl halides, aldehydes, and ketones (77JOC393). In this case there is exclusive alkylation between the two sulfur atoms, and hydrolysis to give the aldehyde products is considerably easier than for dithianes. However, attempts to achieve a second alkylation at C2 were unsuccessful, thus ruling out the use of this system as an acyl anion equivalent for synthesis of ketones. Despite this limitation, the compound has found some use in synthesis (82TL4995). 

The benzodithiepines 126 and 127 have been used as formyl and acyl anion equivalents, respectively, although the range of electrophiles was restricted to alkyl halides (75S720) and epifluorohydrin (72TL1837). The carbonyl products were formed by hydrolysis with either mercury or copper salts. 

There has been recent interest in naphtho-fused dithiepines as chiral acyl anion equivalents, particularly since the starting dithiol 128 can be obtained in enan-tiomerically pure form (89TL2575). This is transformed using standard methods into the dithiepine 129, but showed only moderate diastereoselectivity in its addition to carbonyl compounds. On the other hand, as we have seen previously for other systems, formation of the 2-acyl compound 130 and reduction or addition of a Grignard reagent gave the products 131 with much better stereoselectivity (91JOC4467). 

A number of lyases are known which, unlike the aldolases, require thiamine pyrophosphate as a cofactor in the transfer of acyl anion equivalents, but mechanistically act via enolate-type additions. The commercially available transketolase (EC 2.2.1.1) stems from the pentose phosphate pathway where it catalyzes the transfer of a hydroxyacetyl fragment from a ketose phosphate to an aldehyde phosphate. For synthetic purposes, the donor component can be replaced by hydroxypyruvate, which forms the reactive intermediate by an irreversible, spontaneous decarboxylation. 

Protected cyanohydrins may be employed as acyl anion equivalents in 1,4-additions in the presence of HMPA129. For instance cyanohydrins prepared from arylaldehydes add in a 1,4-fashion under thermodynamic control (THF or THF/HMPA) to cyclohexenone, isophorone and decalone systems in the latter case c/.s-octahydro-2(l/f)-naphthalenones are exclusively obtained 130-131. 

Stork first demonstrated the utility of protected cyanohydrins as acyl anion equivalents in 1971 [2]. The acetal-protected cyanohydrin 8 was transformed into the corresponding anion with LDA in THF/HMPA, which was then alkylated with a range of alkyl halides, including secondary bromides (Scheme 2). A mild acidic hydrolysis yielded a cyanohydrin, which provided the ketone after treatment with base. The Stork cyanohydrin alkylation and its variants have become important methods in natural product synthesis [3,4]. 

In an early attempt to synthesise camphor, dlol (1) was an important intermediate. We shall want to disconnect the ring from the chain, so a preliminary disconnection of a methyl group gives an ct-hydroxy ketone (2) which can be made from ketone (3) and an acyl anion equivalent. 

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). 

Now the ether may be disconnected, diol (13) being the obvious starting material. This contains an i-hydroxy ketone so we might consider disconnecting an acyl anion equivalent from a ketone. If we use an acetylene, the starting material (14) is symmetrical so hydration presents no problems,... 

Problems of acyl anion equivalents met above in the synthesis of similar TMs disappear if (25) is made from the alkene (26), A Wittig is the obvious method to make (26) and reaction between (27) and PhgCO will probably give (26), An alternative is the dehydration of (28), made by Grignard addition to ester (20), Osmium tetroxide was used for the hydroxylation. 

Friedel-Crafts disconnection (38a) Is unambiguous because of the synunetry of (39). Further disconnection requires FGA. A carbonyl group next to the aromatic ring gives a 1,4-dicarbonyl compound (40) and allows disconnection of an acyl anion equivalent to give an enone (41). This can be made by Mannich reaction from (42). 

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

The simplest and most direct manner to generate acyl anion equivalents is through reaction of an NHC with an aldehyde, generating an enamine species 8, commonly referred to as a Breslow intermediate . Subsequent reaction with an electrophile, classically using aldehydes or enones, generates the benzoin and Stetter products 10 and 11 respectively (Scheme 12.1). 

Scheme 12.1 Generation of acyl anion equivalents with NHCs...

Asymmetric Reactions Involving Acyl Anion Equivalents... 

In 1976, Stetter extended the synthetic utility of the Breslow intermediate (1) as an acyl anion equivalent by showing that aldehydes could be coupled with Michael acceptors to generate 1,4-dicarbonyl compounds [55]. 

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