Acyl anions, synthetic equivalents

Additional examples of the use of a dithiane to generate an acyl anion synthetic equivalent are provided by tire following equations ... 

In Scheme 1.3, hexanal on reaction with 1,3-propanedithiol gives the 1,3-dithiane derivative 1.8. A strong base such as u-butyllithium abstracts the proton to give the corresponding 2-lithio-1,3-dithiane 1.9, which reacts with 1-bromopentane to give alkylated product 1.10. Treatment of 1.10 with FIgO and BF3 (boron trifluoride) in aqueous THF (tetrahydrofuran) yields the dipentyl ketone (the corey-seebach reaction ). Thus, dithianyllithium (2-lithio-1,3-dithiane) 1.9 is an acyl anion synthetic equivalent. 

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... 

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. 

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]. 

Scheme 13.1 summarizes some examples of synthetic sequences that employ acyl anion equivalents. Another synthetic equivalent that has been extensively developed... 

Scheme 13.1. Synthetic Sequences Using Acyl Anion Equivalents...

An example where the presence of a counterion makes a difference between the gas phase and solution phase pathways involves the intriguing carbanion produced on deprotonation of 1,3-dithiane at C-2. In solution, this species, almost invariably produced by reaction of the dithiane with butyllithium, is widely used as an acyl anion equivalent in synthetic chemistry. Its importance for the present work is that this is a configurationally stable lithiated species in solution the carbanion stays sp -hybridized, and the lithium prefers the equatorial position, even to the extent of driving a terr-butyl group on the same acidic C-2 carbanion to the axial position in the lithiocarbon species. The carbanion is thought to be stabilized primarily by orbital overlap with the C-S antibonding orbitals, as opposed to more conventional polar and 7t-resonance stabilization. ... 

The use of masked acyl anion equivalents in a synthetic protocol requires additional steps to unmask the carbonyl unit. Sometimes the deprotection procedures are incompatible with sensitive compounds thus, a direct nucleophilic acylation protocol is desirable. While C-nucleophilic carbonyl groups do not... 

The synthetic utility of a-phosphorus- and a-thio-stabilized carbanions is the subject of numerous reviews.21 Notable are additions of phosphonium ylides (237),183 sulfonium ylides (238),l84 ° oxosulfo-nium ylides (239)184 " and sulfoximine ylides (240)184,1 to electron-deficient alkenes which afford nucleophilic cyclopropanation products. In contrast, with a-(phenylthio)-stabilized carbanions, which are not acyl anion equivalents, either nucleophilic cyclopropanation or retention of the hetero substituent occurs, depending on the acceptor and reaction conditions used. For example, carbanion (241) adds to 1,1-... 

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... 

The possibilities for assembling carbogenic structures have sharply increased in recent years with the advent of various synthetic strategies for generating the equivalents of carbon electrophiles and nucleophiles which are unavailable in structures containing simple core functional groups such as carbonyl, amino, or hydroxyl. For example, acyl anions (RCO), which for various reasons are not readily available, can be utilized in synthesis in modified or equivalent forms. Several acyl anion... 

Umpolung. Show how each of the following compounds can be prepared from the given starting material using either a formyl or an acyl anion equivalent in the synthetic scheme. 

Fig. 3.6.9. Synthetic pathways (A-C) involving polymer-supported acyl anion equivalents.

In the case of vinyl radical cyclizations of 49E , the intermediate silacycle could be oxidized under Tamao conditions to afford ketone 51 (2) [124], The consequence is an umpolung installation of an acetyl group, with the vinyl radical serving as an acyl anion equivalent, further expanding the synthetic potential of the Si-tethered radical additions. 

The nucleophile obtained by deprotonation of a dithiane serves as the synthetic equivalent of an acyl anion, a species that is too unstable to be prepared directly. 

Silylated cyanohydrins have also been prepared via silylation of cyanohydrins themselves9 and by the addition of hydrogen cyanide to silyl enol ethers.10 Sllylated cyanohydrins have proved to be quite useful 1n a variety of synthetic transformations, including the regiospecific protection of p-quinones,11 as Intermediates in an efficient synthesis of a-aminomethyl alcohols,6 and for the preparation of ketone cyanohydrins themselves.1 The silylated cyanohydrins of heteroaromatic aldehydes have found extensive use as acyl anion equivalents, providing general syntheses of ketones13 and acyloins.1 ... 

In 1971 Stork and Maldonado214 showed that anions derived from 0-pro tec ted cyanohydrins of aldehydes could be efficiently metallated and the resultant anions could serve as synthetically useful acyl anion equivalents. Other develop-... 

Addition of an acyl anion or its equivalmt to a,p-unsaturated ketones is an important synthetic mediod for 1,4-dicaibonyl compounds. In the palladium method for 1,4-dicartxHiyl compounds, a vinyl Grignard or vinyllithium reagent is used as a synthetic equivalent of the acetyl anion. Reaction of lithium divinylcuprate with 2-cyclohexenone (44) afforded 3-vinylcyclohexanone (45). which was oxidized to the 1,4-diketone (46 Scheme 12). ° ... 

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%). 

The most systematically investigated acyl anion equivalents have been the IMS ethers of aromatic and heteroaromatic aldehyde cyanohydrins, TBDMS-protected cyanohydrins, - benzoyl-protected cyanohydrins, alkoxycaibonyl-protected cyanohydrins, THP-protected cyanohydrins, ethoxyethyl-protect cyanohydrins, a-(dialkylamino)nitriles, cyanophosphates, diethyl l-(trimethylsiloxy)-phenyimethyl phosphonate and dithioacetals. Deprotonation di these masked acyl anions under the action of strong basie, usually LDA, followed by treatment with a wide varies of electrophiles is of great synthetic value. If the electrophUe is another aldehyde, a-hydroxy ketones or benzoins are formed. More recently, the acyl caibanion equivalents formed by electroreduction of oxazolium salts were found to be useful for the formation of ketones, aldehydes or a-hydroxy ketones (Scheme 4). a-Methoxyvinyl-lithium also can act as an acyl anion equivalent and can be used for the formation of a-hydroxy ketones, a-diketones, ketones, y-diketones and silyl ketones. - - ... 

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