P-oxoesters

Krogsgaard-Larsen and co-workers continued to utilize Claisen isoxazole chemistry in the preparation of GABAa receptor antagonists reported in 2000. In the synthesis of protected 3-isoxazolols 17a-f, P-oxoesters 16a-f were cyclized at -30°C followed by heating with concentrated hydrochloric acid at 80°C. 

Scheme 8.28 Hydrogenations of a- and P-oxoesters with diphosphine-dibenzothio-phene ligand.

Ley and Murray have developed a short synthesis of hirsutine in which the key step involves intramolecular cyclization of a P-oxoester to an alkene with N-phenylselenophthalimide and stannic chloride (Scheme LXVII) ° ... 

In addition to aldehydes and ketones, a variety of other functional groups can be used as electrophiles in Reformatsky-type reactions.1-3 Among them, nitriles play a prominent role since they lead to p-oxoesters after hydrolytic work-up (the primary enamines initially formed can only be isolated when stabilized by extended conjugation or by conformational means, cf. Table 14.1, entry 4). 

The individual products 246 were obtained in high yields and excellent purity (>95%). Since P-oxoesters 243 are readily obtained in one step and many aldehydes 244 are commercially available, this reaction is applicable to the parallel synthesis of large compound libraries. The GABA-derived acid linker increases the water solubility of the products and offers a convenient handle for additional functionalisation. 

Axially chiral guanidines with an external guanidine unit such as dinaphthoazepineamidine are effective catalysts for the enantioselective addition of p-oxoesters and a 1,3-diketone to di-ferf-butyl azodicarboxylates to yield cx-hydrazino-p-oxoesters and a-hydrazino-p-dike-tones in 54-99% yields and in 15-98% ee [44]. For example, stirring 2-oxocyclopenta-necarboxylate and di(tert-butyl) azodicarboxylate in THF in the presence of 0.05 mol% catalyst for four hours at —60° C provides an adduct in quantitative yield and in 97% ee (Scheme 4.15). The (R)-catalyst was prepared from (/ )-2,2 -dimethyl-3,3 -binaphthalene-diol ditriflate, 4-methoxyphenylboronic acid and 3.5-di(rert-butyl)phenylboronic acid in six steps. 

The key step of the synthesis of spirotryprostatin B (133) by Trost and Stiles is an enantioselective Pd-catalysed decarboxylation-allylation reaction starting from the prenyl p-oxoester 145, which serves as a pre-nucleophile (Scheme 29) [124]. 

The synthesis, thermal stability of optically pure 163 and 164 and their use as ligand in Ru(II) catalyzed hydrogenation of a- and p-oxoesters was reported. 2,2 -Bis(diphenylphosphinyl)-3,3 -bibenzo[h]furan 166 was... 

Formation of p-oxoesters by treatment of a-bromocarboxylic esters with zinc in the presence of nitriles. The intermediate organozinc compound reacts with the nitrile and the complex is hydrolyzed with 30% potassium hydroxide ... 

Hasegawa, T., Ogawa, T, Miyata, K., Karakizawa, A., Komiyama, M., Nishizawa, K., and Yoshioka, M., Photoq clisation of ((O-dialkylamino)alkyl P-oxoesters via remote hydrogen transfer,/. Chem. Soc., Perkin Trans. 1, 901, 1990. 

In contrast to oxoesters, the a-protons of thioesters are sufficiently acidic to permit continuous racemization of the substrate by base-catalyzed deprotonation at the a-carbon. Drueckhammer et al. first demonstrated the feasibility of this approach by performing DKR of a propionate thioester bearing a phenylthiogroup, which also contributes to the acidity of the a-proton (Figure 4.14) [39a]. The enzymatic hydrolysis of the thioester was coupled with a racemization catalyzed by trioctylamine. Owing to the insolubility of the substrate and base in water, they employed a biphasic system (toluene/H2O). Using P. cepacia (Amano PS-30) as the enzyme and a catalytic amount of trioctylamine, they obtained a quantitative yield of the corresponding... 

By addition of bromine at low temperature methyl 2-siloxycyclopropanecarboxylates are regioselectively cleaved to give a-bromo-y-oxoesters 126 quantitatively. These can be isolated in singular cases, but usually they are directly transformed to oe,P-unsaturated y-oxoesters 127 by subsequent elimination of hydrogen bromide with triethylamine 80). Thereby -alkenes are obtained in good overall yields, which are interesting acceptor building blocks for further synthetic operations. 

Reaction with an excess of bromine can be performed under warm-up conditions delivering the a,P-dibromo-y-oxoester 128 as a mixture of diastereomeres. Interestingly, the ratio of these stereoisomers is strongly influenced by the reaction conditions... 

The functionalized silyl enol ethers 156 are useful synthetic intermediates since electrophiles can now be introduced either directly in the P-position by known methodology 55) or in the opposition after deprotonation with LDA to an allyl anion (Eq. 70)61>. Both pathways should enormously widen the scope of specifically substituted y-oxoesters and their derivatives obtained via siloxycyclopropanes. 

Several routes to this class of compounds have been reported, such as (a) crossed Claisen condensation reactions (50-53) (b) acylation of the anion derived from ethyl fluoroacetate (54) or self-condensation of the anion derived from ethyl bromofluoroacetate (55) (c) electrophilic fluorination of the anion of p-ketoesters (56,57) (d) acylation-hydrolysis of fluoroolefins (58) and (e) acylation of fluorine-containing ketene silyl acetals (Easdon, J.C., University of Iowa, unpublished data). The limitations associated with these methods and the success achieved in the alkylation-hydrolysis of a-fluoro phosphorus ylides prompted us to examine acylation-hydrolysis of these a-fluoro ylides as a general route to 2-fluoro-3-oxoesters. 

Computer simulation of intramolecular hydrogen atom transfer to carbonyl oxygen has been achieved by a Monte Carlo method. In particular, the model has been found to give good agreement when applied to intramolecular P-, y-, 6-, -, and ( -hydrogen atom abstraction in ketones as well as q- and 0-proton transfer in oxoesters, and it has also been used to predict the reactivities of... 

A series of tricyclic annelated 1,2,3-thiadiazoles (76) have been prepared using the Hurd-Mori reaction as the key step in the sequence. Thus, treatment of the oxoesters (74) with p-toluenesulphonyl hydrazine gave hydrazones (75), which upon reaction with thionyl chloride produced fully aromatised tricycles (76) <96JHC1759>. 

Finally, it should be mentioned that the chiral DHAP equivalent (S)-2 (scheme 1) reacts after metalation with Michael acceptors, such as enoates or a,p-unsaturated phosphonates, under 1,4-addition. The resulting 3-substituted 4,6-dihydroxy-5-oxoesters and phosphonates are obtained in good overall yields and with excellent diastereo- and enantiomeric excess [35]. 

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