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To a solution of 735 mg (3 mmol) of N-Boc-4-hydroxyproline methyl ester in 20 mL of THF stirred at 0° C. was added 79 mg (1.1 eq, 3.3 mmol) of 60% sodium hydride in mineral oil. The mixture was stirred at 0° C. for 1 hour, and methyl iodide (0.56 mL, 3 eq, 9 mmol) was added. The mixture was stirred at room temperature overnight, quenched by addition of saturated aqueous ammonium chloride, diluted with water, and extracted with three 80 mL portions of ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated in vacuo to afford a pale yellow oil. The oil was taken up in 9 mL of CH3OH and 3 mL of water, and 378 mg (3 eq, 9 mmol) of lithium hydroxide was added. The mixture was stirred at room temperature overnight, diluted with water, acidified to pH 3 and extracted with three 80 mL portions of ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residual oil was taken up in 10 mL of TFA and the solution was stirred at room temperature for 2 hours, and concentrated in vacuo. The residual oil was diluted with 6 mL of 10% aqueous sodium carbonate and 3 mL of dioxane, and a solution of 9-fluorenylmethyl chloroformate (779 mg, 1 eq, 3 mmol) in 5 mL of dioxane was added. The mixture was stirred at room temperature overnight, diluted with water, acidified to pH 3 and extracted with three 80 mL portions of ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to afford an oil, which was purified by column chromatography over silica gel eluted with CH2Cl2/CH3OH 20:1, to afford 600 mg (55%) of N-Fmoc-4-methoxyproline: exact mass calculated for C21H21NO5 m/e 367.14 found m/e 368.4.

1. stirringThe mixture was stirred at room temperature overnight
2. customquenched by addition of saturated aqueous ammonium chloride
3. additiondiluted with water
4. extractionextracted with three 80 mL portions of ethyl acetate
5. washThe combined organic extracts were washed with brine
6. dry with materialdried (MgSO4)
7. concentrationconcentrated in vacuo
8. customto afford a pale yellow oil
9. stirringThe mixture was stirred at room temperature overnight
10. extractionextracted with three 80 mL portions of ethyl acetate
11. washThe combined organic extracts were washed with brine
12. dry with materialdried (MgSO4)
13. concentrationconcentrated in vacuo
14. stirringthe solution was stirred at room temperature for 2 hours
15. concentrationconcentrated in vacuo
16. additionThe residual oil was diluted with 6 mL of 10% aqueous sodium carbonate and 3 mL of dioxane
17. stirringThe mixture was stirred at room temperature overnight
18. extractionextracted with three 80 mL portions of ethyl acetate
19. washThe combined organic extracts were washed with brine
20. dry with materialdried (MgSO4)
21. concentrationconcentrated in vacuo
22. customto afford an oil, which
23. customwas purified by column chromatography over silica gel
24. washeluted with CH2Cl2/CH3OH 20:1