Chloromethyl Methyl Ether

Used Chemicals

• Methoxymethyl Chloride (= MOM-Cl) [C0202]
• Z-Ser-OMe [C1403]
• N,N-Diisopropylethylamine (= DIEA) [D1599]
• Dichloromethane

Procedure

To a solution of Z-Ser-OMe (200 mg, 0.79 mmol) in dichloromethane (3.9 mL) were added DIEA (0.6 mL, 3.55 mmol, 4.5 eq.) and MOM-Cl (214 µL, 2.84 mmol, 3.6 eq.) at room temperature and the mixture was stirred for overnight. The reaction mixture was quenched with sat. NaHCO₃ aq. (5 mL) and the water layer was extracted with dichloromethane (3 x 5 mL). The combined organic layer was washed with brine, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate:hexane = 10:90 - 25:75 on silica gel), giving 1 as a colorless liquid (181 mg, 77% yield).

Experimenter’s Comments

The reaction mixture was monitored by TLC (ethyl acetate:hexane = 1:1, Rf = 0.55).
Since MOM-Cl is known to be carcinogenic, this experiment was conducted in a draft chamber with appropriate protective equipment.
About 18% of Z-Ser-OMe was recovered.

Analytical Data

Compound 1

¹H NMR (270 MHz, CDCl₃); δ 7.38-7.29 (m, 5H), 5.71 (brd, J = 8.6 Hz, 1H), 5.14 (s, 2H), 4.59 (s, 2H), 4.54 (m, 1H), 4.04 (dd, J = 3.0, 10.3 Hz, 1H), 3.78 (s, 3H), 3.76 (dd, J = 3.0, 10.0 Hz, 1H), 3.31 (s, 3H).

Other Reference

• Total synthesis of (+)-sparsomycin. Approaches using cysteine and serine inversion
• D. R. Hwang, P. Helquist, M. S. Shekhani, J. Org. Chem. 1985, 50, 1264.

Reference

• Protection for the Hydroxyl Group, Including 1,2- and 1,3-Diols
  • P. G. M. Wuts, in Greene’s Protective Groups in Organic Synthesis, 5th ed., ed. by P. G. M. Wuts, John Wiley & Sons, Inc., Hoboken, New Jersey, 2014, Chap. 2, 17.