6-Ketoacetals

To synthesize isomeric 3-substituted isoxazoles (301) the reaction of ethylene acetals of )3-ketoaldehydes (300) (readily available from -chlorovinyl ketones (57IZV949)) with hydroxylamine was employed. Owing to the comparative stability of the dioxolane group, this reaction gave exclusively 3-substituted isoxazoles (301) (60ZOB954). The use of noncy-clic, alkyl S-ketoacetals in this reaction resulted in a mixture of 3- and 5-substituted isoxazoles (55AG395). 

Notes, (a) Using trimethyl orthoformate, -ketoacetals are obtained. 

It is worthwhile emphasising here that the observed chemoselectivity is due to the fact that enolethers are better electrophiles than the free carbonyl groups. In fact, the ketoacetal 15, obtained by chromatography, is an equilibrium 60 40 mixture of methyl epimers at C(4) in which the desired a-epimer 5 is the predominant isomer. However, the pure compound 5. could be obtained in good yields by recrystallisation from hexane (m.p. 117-118 °C) and re-equilibration-crystallisation recycling of the remaining mixmre 15 in the mother liquor. 

The next important steps to the key intermediate 30 are outlined in Scheme 13.6.5. Monoacetylation of 24 followed by oxidation with tetra-n-propylammonium perruthenateW-methylmorpholine A -oxide, afforded regioselectively in 88% overall yield, ketoacetate 21. ... 

Soon it was found that good yields of many 1-azaquinolizinium salts could be obtained by adding either the ketoacetal (250) or a /3-chlorovinyl ketone (254) to an acidic solution of 2-aminopyridine (58DOK(l 18)297). This simple one-pot reaction was extended by the use of additional ketoacetals as well as j8-diketones (253) and malonaldehyde diacetal (Scheme 124). Table 14 illustrates the scope of this [3 + 3] addition mode of the 1-azaquinolizinium synthesis. 

The preparation described 2 has been used by Nelles 3 to make a variety of /3-ketoacetals. 

The enantioselective addition of organomagnesium compounds to ketones can be most conveniently performed by using a chiral auxiliary in the substrate molecule. Primary aUsyhnagnesium reagents react with aryl and heteroaryl ketones in the presence of magnesium TADDOLate at — 100°C, yielding products with up to 98% ee (equation 143). Chiral a-ketoacetals 214, prepared in two steps from a-substituted cinnamic aldehydes, add organomagnesium species with up to 98% diastereoselectivity (equation 144). 

MeONa/HCOOEt) and ketalisation (H2SO4/CH3OH), produced the p-ketoacetal (9EIZ 80/20). A Wittig reaction with methyltriphenyl phosphorane (tBuOK/Ph3p+CH3, Br ) followed by hydrolysis of the p-methyleneketal, produced the 13-methylene isomer of retinal, as a 9E and 9Z mixture (80/20), Fig. (40). 

Recently, a novel commercially available acetoacetoxyethyl metacry-late resin (37) is finding wide applications as a selective electrophilic scavenger resin. This resin has the ability to differentiate primary amines from a mixture where secondary amines are present.64,65 An illustrative example is depicted in the synthesis of dibenzylamine (38, Fig. 16) from benzaldehyde and benzylamine. Unreacted benzylamine is selectively removed from the reaction mixture upon treatment with the ketoacetate resin (37). 

An early structural modification of FA and AP involved alkylation at C-9 and/or N-10. 10-MethylFA (447) [197] was prepared by reaction of 2,4,5-triamino-6-hydroxypyrimidine, 2,3-dibromopropionaldehyde and diethyl p-methylaminobenzoylglutamate (35), followed by alkaline hydrolysis (the Waller condensation). Analogous utilization of 2,2,3-trichlorobutyraldehyde and the requisite p-(JV-substituted amino)benzoylglutamate furnished (448a-c) (Scheme 3.88) [198]. The preparation of (450) by condensation of 2,4,5,6-tetraaminopyrimidine and the a-ketoacetal (449) was reported without details (Scheme 3.89) [199],... 

The first report concerning the synthesis of 10-deaza-10-oxafolates described the preparation of 10-deaza-10-oxaFA (498) and 10-deaza-10oxaAP (499) by condensation of the ketoacetal (497) with the appropriate pyrimidine, followed by ester hydrolysis (Scheme 3.99) [51]. An improved, unambiguous synthesis [ 174] of (498) and (499) is outlined in Scheme 3.100 and is a modification of the Boon-Leigh procedure. Reaction of (500) with methyl p-hydroxy-... 

Ketoacetals are available from the Lewis acid catalysed Michael addition of hemiacetal vinylogues to 3,4-dihydropyrans. The products are a source of hydroxy- and amino- acetals and hence give access to annulated tetrahydropyrans (95JCS(P 1)2103). 

Substituted aliphatic and aromatic a-keto ethers (Scheme 18.5) are also amenable to enantioselective hydrogenation catalyzed by cinchona-modified Pt catalysts.25 However, as opposed to the prochiral ketones discussed earlier, kinetic resolution is observed for these chiral substrates. At conversions of 20A2%, ee s of 91-98% were obtained when starting with a racemic substrate (see Table 18.5). It is somewhat surprising that a-keto ethers without substituent in the a-position, such as methoxy acetone, reacted very slowly or not at all and led to very low enantioselectivities,6 and from the results described earlier for a-ketoacetals, the same is expected if 2 substituents are present. 

White peach scale. Several scale sex pheromones have now been elucidated each of them possesses an asymmetric center and usually a trisubstituted alkene link within an isoprenoid framework (43). The structure of the white peach scale pheromone, R,Zb-II (Figure 8), lent itself to synthesis with another chiral starting material, namely limonene (44). Selective ozonlysis followed by workup with dimethyl sulfide-methanol provided a ketoacetal, III. Wittig methylenation followed by hydrolytic cleavage of the acetal gave a dienaldehyde, IV. Conversion of the aldehyde via the acid to an amide (45) with enantiomerically pure ot-methylbenzylamine permitted chromatographic assessment of the purity of the diene aldehyde (and the limonene). The required R-isomer of the diene aldehyde was >48% ee. 

Reaction between 74 and alkyl / -ketoacetates or acetylacetone under the same conditions, however, furnishes cyclic 1,1-enediamines 77 with loss of one acetyl group39. The evidence available indicates the involvement of a consecutive reaction between the initially formed 1,1-enediamines 75 and the methanethiol released at the condensation step97. The methanethiol attacks the more reactive carbonyl group of the enediamine 75 to form the intermediate 76, which undergoes elimination to give the deacetylation products 77 and methyl thioacetate (78) (Scheme 6). 75 can survive in this reaction... 

The authors used (5)-carvotanacetone (dihydrocarvone) as starting material (Scheme 34). To prepare the linearly conjugated sUylenol ether, they used the Kharash protocol and attained y-alkylation by Mukaiyama aldol reaction with trimethylorthoformate (195). The ketoacetal 295 was a-hydroxylated according to Rubottom by silylenol ether formation followed by epoxidation and silyl migration. Acid treatment transformed 296 to the epimeric cyclic acetals 297 and 298. endo-Aceta 297 was equilibrated thereby increasing the amount of exo-acetal 298. The necessary unsaturated side chain for the prospected radical cyclization was introduced by 1,4-addition of a (trimethylsilyl)butynylcopper compound. 

In 1973, it was demonstrated that 1,2-epoxystannanes, produced from vinylstannanes and MCPBA, could be isolated and characterized,in comparison with 2,3-epoxystannanes (from allylstannanes), which are extremely reactive and have not been isolated (see Section 4.2.2.3). Subsequently, useful applications of 1,2-epoxystannanes have been reported, including the internal alkyne - ketone conversion, in the carbapenem and carbacephem ( -lactam antibiotic) skeletons. Ketone (10) should be of value in the construction of the biologically interesting l-caibapoi-2-ene ring system. Syndiesis of ketoacetates of potential use in the carbacephem system (e.g. 11 and 12) was also achieved by similar sequences shown in Scheme 11. ... 

A further interesting example is the conversion of the alkynes 244 (Scheme 39) into the a-ketoacetals 247 [118]. The reaction with phenylselenyl sulfate affords the product of double addition 245, which is deselenenylated by the excess of persulfate to give the tetramethoxy alkane 246. During work up deprotection occurs and compounds 247 are produced. The reaction occurs equally well with internal alkynes. Interesting enough, methyl ketones 248 reacted, under the same experimental conditions, to afford the same a-ketoacetals... 

Scheme 39. Phenylselenyl Sulfate Catalyzed One-Pot Conversions of Alkynes and of Methyl Ketones into Ketoacetals...

As indicated in Scheme 39, the initial process is the formation of the a-phenylseleno derivative 249 tvhich gives a second addition reaction to afford products 245, identical to those formed from terminal alkynes. This reaction seems to be of general application since alkyl, vinyl, and aryl methyl ketones give the a-ketoacetals of the type 250,251 and 252 with excellent results in every case. 

The potential utility of the stereocontrol available through exo [6 + 4] cycloaddition in the tropone series can be seen in Garst s stereoselective cyclodecene syndiesis. This methodology is predicate on the efficient translation of the double bond geometry from stereochemically homogeneous ( ) and (Z)-1-acetoxybutadiene via cycloadducts (30) and (35) into ( )-cyclodecene (36) and (Z)-cyclodecene (37), respectively. Reduction of cycloadducts (30) and (35) to the corresponding fully saturated ketoacetates, followed by conversion to the mesylates and hydri reduction, led to the desired 10-membered ring products (36) and (37) in 78% and 40% yields, respectively. 

In related work, Tamura et al. [19] reported diastereoselective addition of Grignards to cyclic and acyclic a-ketoacetals to prepare mevalolactones. With high yields (>85%), the ratio of diastereomers varied from 60 40 to 100 0 [Eq. (4)]. Similar to the reaction in Eq. (2), the key step is the formation of the optically active ketoacetal, using (2S, 35)-1,4-dimethoxy-2,3-butanediol. 

---