PREPARATION OF ALPHA, BETA-UNSATURATED ENONES

Abstract: A process for oxidizing silyl enone ethers to alpha, beta-unsaturated enodes having formulas (I) and (II) which comprise reacting the appropriate silyl enone ether with a radical generated by the metal catalyst decomposition of a peroxide composition.

Description: PREPARATION OF alpha. beta-UNSATURATED ENONES FIELD OF THE INVENTION This invention concerns a process of oxidizing silyl enol ethers to alpha, beta-unsaturated enones by means of radical intermediates. More specifically it relates to preparing enones that are intermediates for spectinomycin and its analogs. Spectinomycin and its analogs are known antibiotics and are described in U.S. Patent 4,532,336. INFORMATION DISCLOSURE Hydroperoxides are known to decompose with metal catalyst to give radicals which can be used for abstraction of allyl hydrogen atom, A.L.J. Beckwith et al, J. Amer. Chem. Soc. 1985, 108, 8230-8234 and M. S. Kharasch et al, J. Org. Chem. 1953 18, 322-327. Oxidation of silyl enol ethers with metals and hydroperoxides has been reported to give diacids and ketoacids, K. Kaneda et al, Tet. Let. 1981, 2595-2598. SUMMARY OF THE INVENTION The present invention provides: A process from preparing an alpha, beta-unsaturated enone of Formula I which comprises oxidizing a silyl enol ether of formula II with a radical intermediate generated by the metal catalyst decomposition of a peroxide in the presence of a solvent wherein R is selected from the group consisting of (C, - C 8 ) alkyl, phenyl. and substituted phenyl, or the two R groups together can form the residue of a ring system; with the proviso that the peroxide used cannot be hydrogen peroxide. A preferred embodiment of this invention is a process for preparing an alpha, beta- unsaturated enone of a spectinomycin analog of Formula HE III which comprises oxidizing a silyl enol ether of Formula IV with a radical intermediate generated by the metal catalyst decomposition of a peroxide in the presence of a solvent wherein R ! is selected from the group consisting of alkoxycarbonyl, halogenated carbonyl, alkoxylcarbonyl and R ; is selected from the group consisting of triethylsilyl, trimethylsilyl, triphenylsilyl, and diphenylmethylsilyl. DETAILED DESCRIPTION In this process free radical intermediates are utilized to oxidize silyl enol ethers to alpha, beta-unsaturated enones. The radical intermediates are generated by the metal catalyst decomposition of peroxides. The term (C t - Cg) alkyl means methyl, ethyl, propyl butyl, pentyl, hexyl, keptyl, actyl and ϊsomeric forms thereof: The terms alkoxycarbonyl. halogenated carbonyl, and alkoxycarbonyl are terms described in the art. see U.S. Patent 4 32.336. The term residue of a ring system means any ring that has as part of its structure a silyl enol ether with a beta hydrogen. The term "metal catalyst" means the salts of the various metals including hydrates thereof. A large number of peroxides including di-t-butyl peroxide, decanoyl peroxide, benzoyl 5 peroxide, lauroyl peroxide, cumene hydroperoxide, t-butyl hydroperoxide and hydrogen peroxide can be used. The reaction can be catalyzed with metal catalyst including coprous chloride, cupric chloride cuprous acetate, cobalt carbide, maganese acetate, nickel acetate, cesium chloride and chromium acetate. It is probable that any type of acetate would work with the exception of silver acetate. The amount of catalysts used is from about 0.5 to 10% with the preferred amount being 10 about 3%. The solvent is also important. The reaction works well with any halogenated solvent dichloroethane, etc. or acetonitrile. While the acetonitrile gives the fastest reaction it also results in the loss of silyl protecting groups. The preferred solvent is methylene chloride. The water content of peroxide composition can be varied from 0 to 70%. The ratio of 15 peroxide to enone ether in the reaction is 0.01 to 3 equivalents to: 1 equivalent. The preferred ratio is about 1.5:1. Example [4a, 5a, 6, 7, 8, 9, 9a, 10a-octahydro-2-methyl-4-oxo-4a, 7, 9-tris[(trimethylsilyl)oxy]-4H-pyrano[2, 3-b][l,4]benzodioxin-6, 8-diyl]bis[methyl-, bis(phenylmethyl) ester, [4aS-(4aα, 5aα. 6α, 7α, 8α, 20 9β, 9aβ, 10aα)]-carbamic acid The enol ether, (22.0g) [4a, 5a, 6, 7, 8, 9, 9a, 10a-octahydro-2-methyl-4. 4a, 7, 9- tetrakis[(trimethylsilyl)oxyl]-2H-pyrano[2, 3-b] [1, 4]benzodioxin-6, 8-diyl]bis- [methykbis(phenylmethyl) ester, [2R-(2α, 4aβ. 5aβ, 6β, 7β, 8β, 9α, 9aα, 10aβ)]-carbamic acid 25 (38.4g) of Formula IV was dissolved in CH,C1 2 (HOmL) and CuCL, dihydrate was added. The solution was stirred magnetically in a 1 neck round bottom flask with reflux condenser and nitrogen inlet. To 70% aqueous t-butyl hydroperoxide (5.00mL) was added CHjCU (5.0mL) and the phases separated. The lower organic phase (containing t-butyl hydroperoxide and some water) was added to the enol ether solution and the mixture heated under reflux until the reaction was complete (about 30 4-5 hours). After cooling to 23-25°C solid sodium bisulfite (0.5g) was added to quench any excess peroxide. Heptane (1 lOmL) was added and the mixture concentrated to half volume under reduced _ pressure. The solution was washed with water (lOOmL) and then concentrated to a solid under ^ reduced pressure to yield the title compound 19.6g, 97% chemical yield.

Claims: A CLAΪMS 1. A process for preparing an alpha, beta-unsaturated enone of Formula I 0 which comprises oxidizing a silyl enol ether of Formula II OR, II with a radical intermediate generated by metal catalyst decomposition of a peroxide in the presence of a solvent, wherein R is selected from the group consisting of (C, - C g ) alkyl, phenyl, and substituted phenyl, or the two R groups together can form the residue of a ring system; with the proviso that the peroxide used cannot be hydrogen peroxide. 2. A process according to claim 1 for preparing a spectinomycin analog of Formula HI III which comprises oxidizing a silyl enol ether of Formula IV with a radical intermediate generated by the metal catalyst decomposition of a peroxide in the presence of a solvent, wherein R [ is selected from the group consisting of alkoxycarbonyl, halogenated carbonyl. alkoxylcarbonyl and R : is selected from the group consisting of triethylsilyl, trimethylsilyl, triphenylsilyl and dimethylphenylsilyl. 3. A process according to claim 1 wherein the peroxide contains 0 to 70% water, the equivalents of peroxide to enol ether is .01 equivalents to 3 equivalents, the reaction is conducted at a temperature of -10°C to 60°C; and the catalyst is selected from the group of metal salts consisting of cuprous, cupric, cobalt, manganese, nickel, cesium, and cromium. 4. A process according to claim 3 wherein the catalyst is selected from the group consisting of cuprous chloride, cupric chloride dihydrate and cupric chloride. 5. A process according to claim 4 wherein the catalyst is cupric chloride dihydrate. 6. A process according to claim 2 wherein the radical intermediate is generated by the metal catalyst decomposition of a peroxide. 7. A process according to claim 6 wherein the peroxide composition contains 0 to 70% water, the equivalents of peroxide to enol ether is .01 equivalents to 3 equivalents, the reaction is conducted at a temperature of -10°C to 60°C; and die catalyst is selected from the group of metal salts consisting of cuprous, cupric, cobalt, maganese, nickel, cesium, and cromium and hydrates thereof. 8. A process according to claim 7 wherein the catalyst is selected from the group consisting of cuprous chloride, cupric chloride dihydrate and cupric chloride. 9. A process according to claim 8 wherein the catalyst is cupric chloride-

Inventors: HERRINTON PAUL MATTHEW, HERRINTON, PAUL, MATTHEW
Applicants: UPJOHN CO, THE UPJOHN COMPANY
Application year: 1992
Main classification: C07C45
IPC codes: C07C45, C07C49, C07D493