Lithium Chloride → (3aR,4R,5R,6aS)-4-((E)-3-(benzo[b]thiophen-2-yl)-3-oxoprop-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate

Temperature

-20 °C

A reactor equipped with a mechanical stirrer, under nitrogen, was charged with a mixture consisting of (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate in DCM and a mixture consisting of lithium chloride (1 molar equivalent) in THF. Diethyl 2-(2,7a-dihydrobenzo[b]thiophen-2-yl)-2-oxoethylphosphonate (1 molar equivalent) was added neat and rinsed with DCM. Some lithium chloride precipitated from solution when the THF and DCM mixtures were combined. The mixture was stirred under nitrogen and cooled to −20° C. After adding the phosphonate and further stirring and cooling, the lithium chloride dissolved. After stirring for 2.5 hours, triethylamine (1 molar equivalent) was added neat via addition funnel and the temperature was maintained at −5° C. for 19 hours. The temperature was adjusted to 0° C. and the reaction mixture was treated with 5% aqueous citric acid. The layers were separated and the organic layer was dried over magnesium sulfate and filtered. The crude product was purified on silica gel, eluted with ethyl acetate-hexanes (1:1) to afford the title intermediate 27; 1H NMR (CDCl3) δ 8.10-8.15 (m, 2H), 8.05 (s, 1H), 7.89-7.95 (m, 2H), 7.60-7.75 (m, 4H), 7.38-7.60 (m, 5H), 6.98-7.17 (m, 2H), 5.45-5.55 (m, 1H), 5.18-5.25 (m, 1H), 2.93-3.15 (m, 3H), 2.55-2.77 (m, 2H), 2.38-2.47 (m, 1H).

1. customA reactor equipped with a mechanical stirrer, under nitrogen
2. additionwas charged with a mixture
3. washrinsed with DCM
4. customSome lithium chloride precipitated from solution when the THF and DCM mixtures
5. additionAfter adding the phosphonate
6. stirringfurther stirring
7. temperaturecooling
8. dissolutionthe lithium chloride dissolved
9. stirringAfter stirring for 2.5 hours
10. additiontriethylamine (1 molar equivalent) was added neat via addition funnel
11. temperaturethe temperature was maintained at −5° C. for 19 hours
12. customwas adjusted to 0° C.
13. additionthe reaction mixture was treated with 5% aqueous citric acid
14. customThe layers were separated
15. dry with materialthe organic layer was dried over magnesium sulfate
16. filtrationfiltered
17. customThe crude product was purified on silica gel
18. washeluted with ethyl acetate-hexanes (1:1)

ORD record

ord-4da6e4db51cb490e9b536f5b53a9e5a1

Source dataset

uspto-grants-2011_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08063240B2