Propanoic acid, 2-[[(trifluoromethyl)sulfonyl]oxy]-, methyl ester, (2R)-

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add 2(R)-trifluoromethanesulfonyloxypropionic acid methyl ester (6 g, 25.42 mmol) to a solution of (2R,3S,4S)-2-amino-3-benzyloxy-4-dibenzylamino-5-(3,5-difluorophenyl)-pentan-1-ol bishydrochloride (4.7 g, 7.94 mmol) and triethylamine (5 mL, 35.87 mmol) in dichloromethane (150 mL). Stir the reaction mixture at room temperature for 68-hours. Dilute with dichloromethane and wash with 5% aqueous citric acid, saturated aqueous sodium chloride, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate:hexanes) to give the desired compound (2.93 g, 65%). wash with 5% aqueous citric acid, saturated aqueous sodium chloride dry (magnesium sulfate) filter concentrate purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate:hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add 2(R)-trifluoromethanesulfonyloxypropionic acid methyl ester (6 g, 25.42 mmol) to a solution of (2R,3S,4S)-2-amino-3-benzyloxy-4-dibenzylamino-5-(3,5-difluorophenyl)-pentan-1-ol bishydrochloride (4.7 g, 7.94 mmol) and triethylamine (5 mL, 35.87 mmol) in dichloromethane (150 mL). Stir the reaction mixture at room temperature for 68-hours. Dilute with dichloromethane and wash with 5% aqueous citric acid, saturated aqueous sodium chloride, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate:hexanes) to give the desired compound (2.93 g, 65%). wash with 5% aqueous citric acid, saturated aqueous sodium chloride dry (magnesium sulfate) filter concentrate purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate:hexanes)

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of triflate 14 (5.00 g, 0.021 mol) in anhydrous CH2Cl2 (80 mL) under an N2 atmosphere, was cooled to −40° C. and was treated with a solution of 2-amino-2-methyl-1-propanol (2.5 folds, 4.68 g, 0.0525 mol) in anhydrous CH2Cl2 (10 mL). After stirring for 2 h at −40° C., the reaction mixture was warmed slowly to 0° C. then to room temperature and stirred overnight. The reaction mixture was treated with saturated aqueous NaHCO3 solution (100 mL). The organic phase was washed (water, brine), separated, and dried (Na2SO4). The aqueous layer was extracted with EtOAc (twice). The organic layer was separated, washed (water, brine) and dried (Na2SO4). The organic extracts were combined and concentrated to give a yellow oil. Column chromatography on silica gel using hexanes-EtOAc (1:2) to EtOAc gave 1.88 g (63%) of 15 as a light yellow oil: [α]23D −75° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 4.11 (s, 2H), 3.71 (q, 1H, J=6.8), 1.39 (d, 3H, J=6.8 Hz), 1.26 (s, 3H), 1.18 (s, 3H); 13C NMR (CDCl3) δ 229.2, 77.6, 49.5, 49.3, 27.2, 24.2, 18.4; LCMS (APCI) m/z 144.3 [(M+H)+, M=C7H13NO2]; Anal. (C7H13NO2) calcd: C, 58.72; H, 9.15; N, 9.78. found: C, 58.60; H, 9.35; N, 9.79. Note: 1H NMR data is similar with the data reported in the literature for the racemic compound (Koch, T. H.; Olesen, J. A.; DeNiro, J., J. Am. Chem. Soc. 1975, 97, (25), 7285-7288). the reaction mixture was warmed slowly to 0° C. to room temperature and stirred overnight The organic phase was washed (water, brine) separated dried (Na2SO4) The aqueous layer was extracted with EtOAc (twice) The organic layer was separated washed (water, brine) dried (Na2SO4) concentrated to give a yellow oil

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In some embodiments, various compounds of the present invention (e.g., 4h-m and 4o) were prepared by a novel convergent synthetic approach for the preparation of 2-substituted morpholinols as outlined in Scheme 3. This new approach utilized a nucleophilic addition of Grignard reagents to (3S)-3,5,5-trimethylmorpholin-2-one (15). Treatment of methyl (R)-(+)-lactate (13) with trifluoromethanesulfonic anhydride and 2,6-lutidine at 0° C., gave methyl (2R)-2-{[(trifluoromethyl)sulfonyl]oxy}propionate (14) in 77% yield. The alkylation of 2-amino-2-methyl-1-propanol with triflate 14 at −40° C. for 2 h and overnight at room temperature, and subsequent cyclization afforded 15 in 63% yield. To test the approach, reaction of lactone 15 with 3-chlorophenylmagnesium bromide resulted in the formation of (2S,3S)-trimethyl-2-(3′-chlorophenyl)morpholin-2-ol [(2S,3S)-4-a] in 32% yield (98% ee), 16% overall from (R)-(+)-lactate (13). The addition of the appropriate arylmagnesium bromide to 15 provided the desired compounds (e.g., 4h-m and 4o).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In some embodiments, various compounds of the present invention may be prepared by a novel convergent synthetic approach for the preparation of 2-substituted morpholinols as outlined in Scheme 3. This approach utilizes a nucleophilic addition of Grignard reagents to (35)-3,5,5-trimethylmorpholin-2-one (15). Treatment of methyl (R)-(+)-lactate (13) with trifluoromethanesulfonic anhydride and 2,6-lutidine at 0° C., gives methyl (2R)-2-{[(trifluoromethyl)sulfonyl]oxy}propionate (14) in 77% yield. The alkylation of 2-amino-2-methyl-1-propanol with triflate 14 at −40° C. for 2 h and overnight at room temperature, and subsequent cyclization affords 15. The addition of the appropriate arylmagnesium bromide to 15 provides the desired compounds. The C-3 stereocenter of these compounds is derived from the lactate, rather than created by a synthetic transformation such as the Sharpless hydroxylation used in Scheme 1. In some embodiments, this center was then leveraged to create the second C-2 stereocenter. The resulting stereochemistry at C-2 was a result of either facial selectivity during the Grignard addition anti to the C-3 methyl group and/or a thermodynamic equilibrium of the final product to the S,S-configuration since the resulting product can ring open and close. The ring opened form loses its C-2 stereochemistry, forming a ketone. This route is more convergent than the Sharpless hydroxylation route, and in some embodiments, may be more reliable, requiring far less analytical work.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add 2(R)-trifluoromethanesulfonyloxypropionic acid methyl ester (6 g, 25.42 mmol) to a solution of (2R,3S,4S)-2-amino-3-benzyloxy-4-dibenzylamino-5-(3,5-difluorophenyl)-pentan-1-ol bishydrochloride (4.7 g, 7.94 mmol) and triethylamine (5 mL, 35.87 mmol) in dichloromethane (150 mL). Stir the reaction mixture at room temperature for 68-hours. Dilute with dichloromethane and wash with 5% aqueous citric acid, saturated aqueous sodium chloride, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate:hexanes) to give the desired compound (2.93 g, 65%). wash with 5% aqueous citric acid, saturated aqueous sodium chloride dry (magnesium sulfate) filter concentrate purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate:hexanes)