Cyclic enol acetals

The hydrogenation of enamides and enol acetates without acid function is often more demanding, and at present is not applied widely. Besides a bench-scale application by Roche with a Ru-biphep catalyst [55], two examples are of interest a pilot process for a cyclic enol acetate by Roche [55], and a feasibility study by Bristol-Myers Squibb [56], both using Rh-DuPhos catalysts (Fig. 37.11). In the latter case, despite very good ee-values, a chiral pool route was finally chosen. Chiral Quests Rh-f-KetalPhos (see Fig. 37.9) has been shown to hydrogenate a variety of substituted aryl enamide model substrates at r.t., 1 bar, with very promising catalyst performance (ee 98-99%, TON 10000) [47]. 

Vinyl acetate fails to react with dihalocarbenes, but reacts with the trihalo-methyl anion precursor to produce the l,l,l-trihalo-2-acetoxypropane [33, 166-168], In contrast, where the a-position is substituted by an alkyl group, normal cyclopropanation occurs. Cyclic enol acetates behave in a similar fashion to the enol ethers [12, 88], e.g. bicyclo[3,2,l]oct-2-enyl acetate and its 3-isomer... 

Rhodium( I)-catalyzed hydroformylation of cyclic enol acetals 1 leads to acetal-protected syn-3,5-dihydroxyalkanals 2 with extraordinarily high levels (>50 1) of diastereoselectivity (Scheme 5.2) [2]. The diastereoselectivity cannot be ascribed to any obvious steric bias, and serves as a powerful demonstration that the hydroformylation reaction may be subject to exquisite stereoelectronic control. Indeed, while the addition of a pseudo-axial methyl group to the acetal carbon (as in acetonide 3) has a deleterious effect on the rate of the reaction, the sy -diastereomer 4 is still produced selectively, in what is surely a contra-steric hydroformylation reaction. 

Highly enantioselective hydrogenation of cyclic enol acetates was achieved using the complex Rh-PennPhos (XIII), offering a good synthetic method for optically pure alcohols [23a],... 

Five research groups have investigated fluorination of enol acetates and silyl ethers with xenon difluoride, and mainly a-fluoroketones were formed22"24, 78-81. HF-catalyzed fluorination of cyclic enol acetates with xenon difluoride at room temperature gave a-fluorocycloalkanones, while the yield and contamination with cycloalkanones depend on... 

Zeaxanthin Hydrogenation of cyclic enol acetate with Rh-duphos multi kg Roche [29]... 

There have been many other independent reports of excellent S/C ratios using rhodium DuPHOS systems. For the synthesis of an (R)-metalaxyl intermediate 19 [21], a turnover number of 50000 has been demonstrated using Me-DuPHOS-Rh. Hoffmann la Roche have reported the Et-DuPHOS-Rh-catalyzed hydrogenation at S/C 10000-20000 of a cyclic enol acetate 21 to provide an intermediate 22 to Zeaxanthin in 98% ee [22] (Fig. 12). 

The asymmetric hydrogenation of cyclic enol acetate has also proven to be a challenging problem. In this respect, Me-PennPhos 125 was shown to be an effective ligand in the rhodium-catalyzed asymmetric hydrogenation of five- or six-membered cyclic enol acetates such as 172. " In addition, Tang et al. found that the TangPhos-Rh catalyst system provided good-to-excellent (92%-99%) enantioselectivities for a diverse set of aryl enol acetates. ... 

The photochemical reactivity of P-ketoesters is different form that of P-diketones. Irradiation of a P-ketoester in the presence of an alkene produces oxetane via the ketone carbonyl instead of the desired cyclobutane ring system. Therefore, it is necessary to covalently lock the ketoesters as the enol tautomers. To this end, silyl enol ethers, 129 and 132a, and enol acetates, 130 and 132b, were prepared, but these substrates still fail to undergo the desired intramolecular [2 + 2] photocycloaddition with olefins. The only new products observed in these reactions result from the photo-Fries rearrangement of the cyclic enol acetate (130 to 131) and cis-trans isomerization of both acyclic substrates 132a/b. However, tetronates are appropriate substrates for both intermolecular and intramolecular photocycloadditions with olefins. In addition, enol acetates and silyl enol ethers of p-keto esters are known to undergo [2 + 2] photoaddition with cyclic enones (vide infra). 

Room temperature fluorination of cyclic enol acetates by (1) gives cK-fluorocycloalkanones in high yield (70-90%). p-Diketones and barbituric acid give the corresponding gem-difluorinated derivatives. Room temperature fluorination of uridine in methanol followed by treatment with EtsN gives 5-fluorouridine (79%). Similarly, 1,3-dimethyluracil gives the 5-fluoro derivative (89%). ... 

In the cyclic enol acetal of Eq. 14.72, this has the great advantage of being highly diastereoselective, producing the 1,3-sy/i-diol derivative. The bulky phosphine, P(o-r-BuC6H40)3 proved the most effective. 

Cyclic enol-acetates and a-acetoxy-ketones are converted into keto-esters by electro-oxidative ring-cleavage. Keto-esters are prepared (in good yield) by the reduction of acyl ylides (107) with aluminium amalgam (Scheme 60). ... 

The oxidation of the cyclic enol ether 93 in MeOH affords the methyl ester 95 by hydrolysis of the ketene acetal 94 formed initially by regioselective attack of the methoxy group at the anomeric carbon, rather than the a-alkoxy ketone[35]. Similarly, the double bond of the furan part in khellin (96) is converted ino the ester 98 via the ketene acetal 97[l23],... 

The isoflavone 406 is prepared by the indirect a-phenylation of a ketone by reaction of phenylmercury(II) chloride with the enol acetate 405, prepared from 4-chromanone[371]. A simple synthesis of pterocarpin (409) has been achieved based on the oxypalladation of the oriho-mercurated phenol derivative 408 with the cyclic alkene 407[372,373]. 

The cyclic enol ether 255 from the functionalized 3-alkynoI 254 was converted into the furans 256 by the reaction of allyl chloride, and 257 by elimination of MeOH[132], The alkynes 258 and 260, which have two hydroxy groups at suitable positions, are converted into the cyclic acetals 259 and 261. Carcogran and frontalin have been prepared by this reaction[124]. 

Three possible mechanisms for the Serini reaction were originally suggested. These proceed via (a) a A -enol acetate, (b) a A -epoxide, or (c) a cyclic orthoester ... 

In order to construct the thiepin conjugation, the seven-membered cyclic ketones containing sulfur could be converted to either their enol ethers or enol acetates. The resulting thiepins should have a number of substituents. The first stable 3,5-diacetoxy-4-phenylbenzo[6]thiepin (15) has been obtained by Hofmann et al. from the diketone (14) by acetylation with acetic anhydride in pyridine in good yield 13). By this methodo-... 

Nitration of the potassium enolates of cycloalkanones with pentyl nitrate81 or nitration of silyl enol ethers with nitronium tetrafluoroborate82 provides a method for the preparation of cyclic a-nitro ketones. Trifluoroacetyl nitrate generated from trifluoroacetic anhydride and ammonium nitrate is a mild and effective nitrating reagent for enol acetates (Eq. 2.41).83... 

Katsuki et al. have reported that high enantioselectivity can be obtained in the oxidation of nonconjugated cyclic enol ethers by using Mn(salen) (34) as the catalyst.138 The reactions were performed in an alcoholic solvent to obtain a-hydroxy acetals as the products, because a-hydroxy acetals are tolerant to a weak Lewis acid like Mn(salen) and do not racemize during the reaction and the isolation procedure (Scheme 29). 

Tetrabutylammonium peroxydisulfate-mediated oxidative cycloaddition was recently discovered to be a convenient method for the realization of fused acetal derivatives. It is believed that the reactive intermediate is the cyclic enol ethers of the 1,3-diketones. An example is presented below <00S1091>. 

DuPhos. The exception for rhodium-catalyzed reductions are CnrPhos and BPE-4 [168, 264—268]. MalPhos has proven useful for the reductions of yS-acylamino-acrylates [260]. The ferrocene hybrid (FerroTANE) was referred to earlier (see Section 23.4.1) [167, 222]. The PennPhos ligand is useful for the reductions of cyclic enamides and enol acetates both classes of compounds are difficult for DuPhos itself to reduce with high selectivity [269, 270]. 

Camell, A.J., Swain, S.A. and Bickley, J.E., Chiral enol acetates derived from prochiral oxabi-cyclic ketones using enz3mies. Tetrahedron Lett., 1999, 40, 8633. 

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. - ... 

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