Acyl transfer ketones

Thus, the family of azolides represents a versatile system of reagents with graduated reactivity, as will be shown in the following section by a comparison of kinetic data. Subsequent chapters will then demonstrate that this reactivity gradation is found as well for alcoholysis to esters, aminolysis to amides and peptides, hydrazinolysis, and a great variety of other azolide reactions. The preparative value of azolides is not limited to these acyl-transfer reactions, however. For example, azolides offer new synthetic routes to aldehydes and ketones via carboxylic acid azolides. In all these reactions it is of special value that the transformation of carboxylic acids to their azolides is achieved very easily in most cases the azolides need not even be isolated (Chapter 2). 

Hulshof et al. introduced 10 as an alcohol racemization catalyst [31]. Alcohol DKR was performed with 0.1mol% of 10, CALB, isopropyl butyrate as the acyl donor, potassium carbonate and about 20mol% of the corresponding ketone at 70°C (Scheme 1.23). Without the ketone, yield and optical purity of the product ester were decreased significantly. 2-Propanol produced by the acyl transfer reaction was removed at reduced pressure during the DKR to shift the equilibrium to acylated products. 

There were two more stereocenters to set. It was expected that cuprates would add to the open face of the strained cyclobutene. The control of the other stereocenter was more problematic. One solution was to prepare an a-sulfonyl lactone. To this end, the ketone was converted to the secondary carbonate. As hoped, conjugate addition was followed by intramolecular acylation, but the reaction continued to full acyl transfer, to give 10. Fortunately, desilylation of 10 proceeded with concomitant lactonization. Desulfonylation then gave 2, which could be brought to high by recrystallization. 

These chiral acyl donors can be used for quite effective kinetic resolution of racemic secondary alcohols. For example, enantiomeric aryl alkyl ketones are es-terified by the acyl pyridinium ion 8 with selectivity factors in the range 12-53 [10], In combination with its pseudo-enantiomer 9, parallel kinetic resolution was performed [11], Under these conditions, methyl l-(l-naphthyl)ethanol was resolved with an effective selectivity factor > 125 [12]. Unfortunately, the acyl donors 8 and 9 must be preformed, and no simple catalytic version was reported. Furthermore, over-stoichiometric quantities of either MgBr2 or ZnCI2 are required to promote acyl transfer. In 2001, Vedejs and Rozners reported a catalytic parallel kinetic resolution of secondary alcohols (Scheme 12.3) [13]. 

Shi and coworkers found that vinyl acetates 68 are viable acceptors in addition reactions of alkylarenes 67 catalyzed by 10 mol% FeCl2 in the presence of di-tert-butyl peroxide (Fig. 15) [124]. (S-Branched ketones 69 were isolated in 13-94% yield. The reaction proceeded with best yields when the vinyl acetate 68 was more electron deficient, but both donor- and acceptor-substituted 1-arylvinyl acetates underwent the addition reaction. These reactivity patterns and the observation of dibenzyls as side products support a radical mechanism, which starts with a Fenton process as described in Fig. 14. Hydrogen abstraction from 67 forms a benzylic radical, which stabilizes by addition to 68. SET oxidation of the resulting electron-rich a-acyloxy radical by the oxidized iron species leads to reduced iron catalyst and a carbocation, which stabilizes to 69 by acyl transfer to ferf-butanol. However, a second SET oxidation of the benzylic radical to a benzylic cation prior to addition followed by a polar addition to 68 cannot be excluded completely for the most electron-rich substrates. 

The fluorogenic hydroxyketone 14 discussed above (Scheme 1.4) can also be used to form esters such as 26 which can be used as fluorogenic substrates for lipases [37]. In this case, however, the esters are quite unstable despite being ali-phahc alcohol esters. The relatively rapid spontaneous hydrolysis in this case is probably due to an assisted mechanism involving acyl transfer in the hydrated form of the ketone. 

Alkylation products of pseudoephedrine amides are readily transformed in a single operation into highly enantiomerically enriched carboxylic acids, aldehydes, ketones, lactones or primary alcohols. Alkylated pseudoephedrine amides can be hydrolyzed under acidic or basic conditions to form carboxylic acids. Simply heating a pseudoephedrine amide at reflux in a 1 1 mixture of sulfuric acid (9-18 N) and dioxane affords the corresponding carboxylic acid in excellent chemical yield with little or no epimerization (eq 7). Under these conditions, the substrate initially undergoes a rapid N— -0 acyl transfer reaction followed by rate-limiting hydrolysis of the resulting (3-ammonium ester intermediate to form the carboxylic acid. ... 

Kochetkov and co-workers used Me2AlSeMe for direct transformation of esters into selenoesters which proved to be active acyl-transfer reagents in heavy metal-assisted reactions, producing the corresponding ketones as shown in Sch. 79 [115]. 

Comprehensive Biological Catalysis—a Mechanistic Reference Volume has recently been published. The fiiU contents list (approximate number of references in parentheses) is as follows S-adenosylmethionine-dependent methyltransferases (110) prenyl transfer and the enzymes of terpenoid and steroid biosynthesis (330) glycosyl transfer (800) mechanism of folate-requiring enzymes in one-carbon metabohsm (260) hydride and alkyl group shifts in the reactions of aldehydes and ketones (150) phosphoenolpyruvate as an electrophile carboxyvinyl transfer reactions (140) physical organic chemistry of acyl transfer reactions (220) catalytic mechanisms of the aspartic proteinases (90) the serine proteinases (135) cysteine proteinases (350) zinc proteinases (200) esterases and lipases (160) reactions of carbon at the carbon dioxide level of oxidation (390) transfer of the POj group (230) phosphate diesterases and triesterases (160) ribozymes (70) catalysis of tRNA aminoacylation by class I and class II aminoacyl-tRNA synthetases (220) thio-disulfide exchange of divalent sulfirr (150) and sulfotransferases (50). 

Roger and Mathvink reported on the extensive synthesis of ketones based on the acyl transfer reaction of acyl selenides to alkenes using tin hydride as the radical mediator (Scheme 4-24) [46]. A radical arising from the addition of an acyl radical to alkenes abstracts hydrogen from the tin hydride with the liberation of a tin radical, thus creating a chain. The addition process is in competition with de-carbonylation. In this regard, aroyl, vinylacyl, and primary alkylacyl radicals are most suitable for this reaction and secondary and tertiary acyl radicals are inferior. 

Warren has used a variation of his phosphine oxide-based olefination method to synthesise single isomers (E or Z) of unsaturated carboxylic acids.23 a-Diphenylphosphinoyl ketones (32) are reduced by sodium borohydride to give diastereomeric mixtures of the corresponding alcohols (33) and (34). These alcohols can be converted to the lactones (35) and (36) which can be separated and individually converted stereospecifically into (Z)-(37) and (E)-(38) alkenes by base treatment (Scheme 6). In many cases it is possible to reduce p-ketophosphine oxides (39) and enones (41) stereoselectively to the ery/Aro-alcohols (40) and (42), respectively, using sodium borohydride in the presence of cerium chloride (Scheme 7).24 An earlier report that reduction in the presence of cerium salts did not cause reversal of stereochemistry compared to reduction with borohydride alone appears to be true only of the compounds studied in that report. The carbanions of 3-hydroxypropylphosphine oxides (43) have been reported to undergo O- to C-acyl transfer to give the p-ketoalkylphosphine oxides... 

Ketones. These imidazolium salts (1) are acyl transfer agents that react readily with organometallic compounds to give ketones. 

Like selenol esters, tellurol esters can also serve as acyl transfer reagents, giving rise to the corresponding ketones, carboxylic acids, and esters. For example, tellurol esters react with lithium dialkylcuprates at -78 °C to give the corresponding ketones in high yields (Eq. 63) [117]. 

Enol esters such as vinyl or isopropenyl esters liberate unstable enols as coproducts, which tautomerize to give the corresponding aldehydes or ketones [151,152] (Scheme 3.4). Thus, the reaction becomes completely irreversible and this ensures that all the benefits with regard to a rapid reaction rate and a high selectivity are accrued. Acyl transfer using enol esters has been shown to be about only ten times slower than hydrolysis (in aqueous solution) and about 10-100 times faster than acyl-transfer reactions using activated esters. In contrast, when nonactivated esters such as ethyl acetate were used, reaction rates of about lO -lO of that of the hydrolytic reaction are observed (Table 3.5) [153]. 

Racemic hydroperoxides may be resolved in organic solvents via hpase-cata-lyzed acyl transfer (Scheme 3.13). Although the so-formed acetylated (R)-peroxy-species is unstable and spontaneously decomposes to form the corresponding ketone via ehmination of acetic acid, the remaining (5)-hydroperoxide was isolated in varying optical purity [213]. This concept was also applied to the resolution of a hydroperoxy derivative of an unsaturated fatty acid ester [214]. 

Four important coenzymes contain nucleotides as part of their structures. We have already mentioned coenzyme A (for its structure, see page 312), which contains ADP as part of its structure. It is a biological acyl-transfer agent and plays a key role in fat metabolism. Nicotinamide adenine dinucleotide (NAD) is a coenzyme that dehydrogenates alcohols to aldehydes or ketones, or the reverse process It reduces carbonyl groups to alcohols. It consists of two nucleotides linked by the 5 hydroxyl group of each ribose unit. 

For a long time, kinetic resolution of alcohols via enantioselective oxidation or via acyl transfer employing, for example, lipases along with dynamic kinetic resolution have been the biocatalytic methods of choice for the preparation of chiral alcohols. In recent years, however, impressive progress has been made in the use of alcohol dehydrogenases (ADHs) and ketor-eductases (KREDs) for the asymmetric synthesis of alcohols by stereoselective reduction of the corresponding ketones. Furthermore, recent remarkable multienzymatic systems have been successfully applied to the deracemisation of alcohols via stereoinversion based on an enantioselective oxidation followed by an asymmetric reduction. 

Reissert s compound (l-cyano-l,2-dihydroquinolinyl benzamide) is apparently de-protonated under phase transfer conditions at the one-carbon as expected. The condensation of the carbanion with an aldehyde or ketone leads to an N-benzoyl alk-oxide in which oxygen acylation (N ->0 acyl transfer) results in five-membered ring formation. The intermediate oxazolidine decomposes with loss of cyanide to give the benzoate ester of an isoquinolinoylcarbinol as shown in equation 10.26 [36]. 

---