Isopropenyl acetylation with

The diacylation of isopropenyl acetate with anhydrides of dicarboxylic acids is applicable for the synthesis of several other cyclic jS-triketones in moderate yield. - It has been used for the synthesis of 2-acetylcyclohexane-l,3-dione (40% yield), 2-acetyl-4-methylcyclopentane-l,3-dione (10% yield), 2-acetyl-4,4-dimethylcyclopentane-l,3-dione (10% yield), 2-acetyl-5,5-dimethylcyclohexane-l,3-dione (10% yield), 2-acetylcyclo-heptane-l,3-dione (12% yield) and 2-acetylindane-l,3-dione (26% yield). Maleic anhydrides under more drastic conditions give acetylcyclopent-4-ene-l,3-diones in yields from 5% to 12%. The corresponding acylation of the enol acetate of 2-butanone with succinic anhydride has been used to prepare 2-methylcyclopentane-l,3-dione, an important intermediate in steroid synthesis. - ... 

A-Acylation is, of course, rendered more difficult by the presence of substituents in positions 1 and 9, owing to steric effects. Massie and Kadaba observed that 1-substituted derivatives may be acetylated with acetic anhydride in pyridine, but the use of anhydrous solvents throughout the synthesis and purification is required, since the products are very readily hydrolyzed. 1-Chloro-lO-acetylpheno-thiazine, for example, loses its acyl group even on pouring the reaction mixture into water. Isopropenyl acetate has been recommended by the same authors as an acetylating agent which is able to overcome the steric hindrance in 1-substituted phenothiazines. 

House and Trost state that enol acetylation with isopropenyl acetate yields chiefly the less highly substituted isomer whereas the reverse is true of enol acetylation with acetic anhydride, but we fail to find in the paper experimental evidence in support of these generalizations. 

Racemic 217 could readily be acetylated with isopropenyl acetate catalysed by the Amano lipase PS 30. The resolution was successful only in organic solvents and heptane was the best. Any water reduced both the rate of the reaction and the ee of the product. Acetylation occurred on the wanted (R) enantiomer 218 but the product could be hydrolysed to (7 )-217 with the same enzyme with added water. The reactions were carried out on a 100 g scale using 200 g of immobilised enzyme that could be filtered off and used again and again with little diminution in ee. This sounds like a lot of enzyme but it is a polymer-supported enzyme so the bulk is polymer. 

The next key step in the sequence was the macroexpansion, smoothly executed by treatment of 142 with potassium hydride and 18-crown-6 in THF at room tenperature. Reduction of the resultant ketone and selective reduction of the least hindered olefin afforded 144. An allylic deoxygenation and deprotection of the isopropenyl group with acetyl mesylate gave the target natural product 145. 

Ketones with labile hydrogen atoms undergo enol acetylation on reaction with ketene. Strong acid catalysis is required. If acetone is used, isoptopenyl acetate [108-22-5] (10) is formed (82—85). Isopropenyl acetate is the starting material for the production of 2,4-pentanedione (acetylacetone) [123-54-6] (11). 

Acetylsucrose [63648-81-7] has been prepared in 40% yield by direct acetylation of sucrose using acetic anhydride in pyridine at 40° C (36). The 6-ester has subsequently been obtained in greater than 90% yield, by way of 4,6-cycHc orthoacetate. Other selective methods for the 6-acylated derivatives include the use of alkyl tin reagents such as dibutyl tin oxide (37) and of dibutyl stannolane derivatives (38). Selective acetylation of sucrose by an enzymic process has also been described. Treatment of sucrose with isopropenyl acetate in pyridine in the presence of Lipase P Amano gave, after chromatography, 6-0-acetylsucrose (33%) and 4/6-di-O-acetylsucrose (8%). The latter compound has been obtained in 47% yield by the prolonged treatment (39). 

Enol esterification with acetyl chloride-acetic anhydride gives the A -trien-3-acetate, but reaction with isopropenyl acetate or with hot acetic anhydride-pyridine gives A " -trien-3-acetates. " Since A"" -3-ketones react with Girard reagents, these linear dienones can be separated from A ""-3-ketones. ... 

At higher temperatures the mixture of 10 and methyl vinyl ketone yields the 1,4-carbocyclic compound as described previously. Methyl isopropenyl ketone (5), ethyl acetylacrylate (d), 2-cyclohexenone (21), and 1-acetyl-1-cyclohexene (22) also undergo this type of cyclization reaction with enamines at higher temperatures. This cycloalkylation reaction occurs with enamines made of strongly basic amines such as pyrrolidine, but the less reactive morpholine enamine combines with methyl vinyl ketone to give only a simple alkylated product (7). Chlorovinyl ketones yield pyrans when allowed to react with the enamines of either alicyclic ketones or aldehydes (23). 

In 1992, Oda et al. reported a one-pot synthesis of optically active cyanohydrin acetates from aldehydes, which were converted to the corresponding racemic cyanohydrins through transhydrocyanation with acetone cyanohydrin, catalyzed by a a strongly basic anion-exchange resin [46]. The racemic cyanohydrins were acetylated by a lipase from P. cepacia (Amano) with isopropenyl acetate as the acyl donor. The reversible nature of the base-catalyzed transhydrocyanation enabled continuous racemization of the unreacted cyanohydrins, thereby effecting a total conversion (Figure 4.21). 

A variety of enzymes (such as acetylcholine esterase, Porcine pancreatic lipase, Pseudomonas cepacia lipase, and Candida antarcita lipase) have been found useful in the preparation of enantiomerically pure cyclopentenol (+)-2 from 1. The enantiomeric (—)-2 has been prepared from diol 4 by enzymatic acetylation catalyzed by VP-345 with isopropenyl acetate in an organic medium. The key intermediate cyclopentanones (+)-6, (—)-6, 7, and 8, which are useful in the preparation of many bioactive molecules, can be obtained from 3 and 5 via routine chemical transformations.7... 

When D-gulono-1,4-lactone was treated with isopropenyl methyl ether and a catalytic amount of p-toluenes ulfonic acid in N,N-dimethyl-formamide, 5,6-0-isopropylidene-D-gulono-1,4-lactone (51) was formed in 95% yield.176 Previously, this compound was available in only low yield as a mixture of products. In addition, 51 was converted into 2,3-di-O -acetyl-5,6-0 -isopropylidene-D-gulono-1,4-lactone by treatment with acetic anhydride. 

N-Acetvlneuraminic Acid Aldolase. A new procedure has also been developed for the synthesis of 9-0-acetyl-N-acetylneuraminic acid using the aldolase catalyzed reaction methodology. This compound is an unusual sialic acid found in a number of tumor cells and influenza virus C glycoproteins (4 ). The aldol acceptor, 6-0-acetyl-D-mannosamine was prepared in 70% isolated yield from isopropenyl acetate and N-acetyl-D-mannosamine catalyzed by protease N from Bacillus subtilis (from Amano). The 6-0-acetyl hexose was previously prepared by a complicated chemical procedure (42.) The target molecule was obtained in 90% yield via the condensation of the 6-0-acetyl sugar and pyruvate catalyzed by NANA aldolase (Figure 6). With similar procedures applied to KDO, 2-deoxy-NANA and 2-deoxy-2-fluoro-NANA were prepared from NANA. 

The reaction of phenol with isoprene dibromide and sodium affords ( )-2-isopropenyl-2,3-dihydrobenzofuran (219) in high yield (78CL253) an additional formylation reaction led to fomannoxin (220), a toxin isolated from Heterobasidion annosum (77TL651). ( )-Tremetone (221) was synthesized by the same route and oxidized by selenium dioxide in acetic anhydride to give ( )-5-acetyl-2-(l-acetoxymethylvinyl)-2,3-dihydrobenzofuran. 

The direction of enohsation of steroid 3-ketones was a subject of much debate from the early 1950 s, for 5a-3-ketones give A2-enols (17), and 5ji -3-ketones give mainly A -enols (18) [12, 128]. The preference for A -enolisation in the 5j8-series was fairly easily explained [128] in terms of relief of non-bonded interactions between the qa-hydrogen and the 7a- and qa-hydrogens when a trigonal centre is formed at C 4) . Recent calculations [ 126] suggest that the A -isomer is favoured by an enthalpy difference of 1.9 kcal/mole. This would result in a A8/A2 ratio of 96 4, compared with the experimentally determined 93.5 6.5. It is interesting that kineticaUy controlled enol acetylation of a 5j5 3-ketone with isopropenyl acetate The preferential Ca-formylation of 5 j -3-ketones is discussed on p. 182. Heferences p. 214... 

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