Nitrogen → TFA triethylsilane

Participants

Reaction Conditions

Reaction Steps

To a solution of the resorcinol 1, (5 mmol) in 25 ml of dry THF was added a 2.5 M solution of n-BuLi in hexane (5.5 mmol) at 0° C. with stirring/N2. After additional stirring for 1 h at 0° C., added a solution of the ketone (7.5 mmol) in 3 ml of dry THF all at once. The solution was stirred for 0.5 h at 0° C. and then at 23° C. for 18 h. The reaction was worked up by the addition of sat NH4Cl solution and extracted with ether. After washing (H2O) and drying (Na2SO4) the solvent was evaporated to give the crude tertiary alcohol 2, which was used as such in the subsequent reaction. A solution of the tertiary alcohol 2 (5 mmol) in 10 ml of dry CH2Cl2 was treated with CF3COOH (27.5 mmol) followed by Et3SiH (12.5 mmol). The solution was stirred/N2 for 1 h or more (followed by TLC) and then quenched by the addition of sat NaHCO3 solution. The organic layer was separated and after washing (H2O) and drying gave the crude dimethoxy precursor 3 of the target compound. This material was used as such for the demethylation step. Treatment of 3, as a solution in dry CH2Cl2 at 0° C., with 3 equivalents of 1 N BBr3 solution in CH2Cl2, using the standard procedure and work up2. gave the crude target compound, which was purified by chromatography, generally using hexane/ethyl acetate mixtures. In the case of O-1662 (Table 2), the corresponding tertiary alcohol 2 on treatment with CF3COOH/Et3SiH gave the unsaturated compound (dehydrated but not reduced) which on catalytic reduction (PtO2/C/H2) in acetic acid gave the desired dimethoxy precursor 3. The final compound was purified by chromatography using 5% Et3NH2/EtOAc mixture. The unsaturated analog O-1423 (Table 2) was prepared by treatment of the corresponding tertiary alcohol 2 with CF3COOH alone in CH2Cl2 followed by demethylation. In Table 3, compounds O-1797-A and O-1798-B were diastereomeric mixtures and showed as two distinct spots in TLC which were separated by column chromatography, whereas O-1657 was a sample of the mixture of diastereomers O-1797-A and O-1798-B. The dimethoxy compounds listed in Tables 4 and 5 were prepared (FIG. 2) from 1 and the appropriate ketones using BuLi, as in the preparation of 2, and isolating and purifying the compounds by chromatography (ethyl acetate/hexane mixtures). Deprotection of O-2092 was carried out by treatment with 10% HCl in a ether/THF (5:4) mixture for 0.5 h at 23° C. to give a mixture of O-2115 (major) and the dehydrated compound O-2114 (minor). Sodium borohydride reduction of O-2115 furnished a mixture of diastereomeric compounds which were separated by chromatography to give the target compounds O-2116-A and O-2117-B. Similarly O-1966-A and O-1967-B were separated from a diastereomeric mixture by chromatography. Epoxidation of O-2114 followed by NaBH4 reduction gave the target compound O-2122. In the preparation of O-2090 the corresponding diethoxy resorcinol derivative of 1 was used in place of 1. All compounds showed appropriate 1HNMRs (Jeol Eclipse 300 MHz) and were characterized on the basis of their 1HNMRs, TLC, and elemental analyses.

Provenance & Evidence