Dichloromethane → Diisopropylethylamine

As shown in the reaction Scheme 1, aldehyde 1 (prepared as described in Goulet, M. T.; Boger, J. Tetrahedron Lett. 1990, 31, 4845) in an inert organic solvent such as toluene is treated with a disopropyl tartrate-modified allyl boronate at about -78° C. for a period of one to twelve hours to give the homoallylic alcohol 2 with a high degree of diastereoselection. Epoxidation of the olefin contained in 2 is conducted by treatment of a solution 2 in an inert organic solvent such as benzene, toluene, methylene chloride, or tetrahydrofuran with an alkyl hydroperoxide such as tertbutyl hydroperoxide and a catalytic amount of vanadyl acetylacetonate at room temperature for a period of ten to twenty-four hours to give the cis epoxy-alcohol 3 as the major product. Alcohol 3 is protected as the benzyloxymethyl ether by treatment of a methylene chloride solution with benzyl chloromethyl ether and an amine base such as diisopropylethyl amine or triethylamine at room temperature for a period of ten to twenty-four hours to give the protected analog 4. The extended alcohol 5 is prepared by subjection of a solution of epoxide 4 in an inert organic solvent such as diethyl ether or tetrahydrofuran to the cyanocuprate prepared from 4-pentenyl lithium at about -20° C. for one to three hours. Alcohol 5 is protected as the tert-butyldimethylsilyl ether by subjection of a solution in methylene chloride to tert-butyldimethylsilyl trifluoromethanesulfonate and an amine base such as 2,6-lutidine at room temperature for fifteen minutes to one hour giving the protected derivative 6. Selective hydroboration of olefin 6 to the primary alcohol 7 is accomplished by treatment of a solution of 6 in ethylene glycol dimethyl ether with 9-borabicyclo[3.3.1]nonane a 0° C. for a period of one to eight hours, followed by addition of saturated sodium bicarbonate and hydrogen peroxide. This mixture is stirred at room temperature for thirty minutes to two hours to give alcohol 7. Treatment of alcohol 7 as a mixed solution in carbon tetrachloride, acetonitrile, and water with periodic acid and a catalytic amount of ruthenium (III) chloride at room temperature for two to five hours, followed by treatment of the crude reaction product with diazomethane in ether gives methyl ester 8. The benzyloxymethyl ether protecting group is removed from 8 by treatment of an ethyl acetate solution with hydrogen and a catalytic amount of palladium hydroxide on carbon to produce the free alcohol. Treatment of this crude product with an excess of the lithium anion of methyl diethylphosphonate in tetrahydrofuran at -40° C. for a period of thirty minutes to two hours is followed by acidification with a weak acid such as aqueous ammonium chloride to give the β-keto-phosphonate 9.

ORD record

ord-f0eb8b1738e7498a9e9f5acaa13b19a9

Source dataset

uspto-grants-1992_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05147877