*3.6. Synthesis of an Optically Active Synthetic Ceramide*

*(S)-3-Azidopropane-1,2-diol* ((*S*)-**8**). To a solution of (*R*)-**2** (246 mg, 1.0 mmol) in CH3CN (10 mL) was successively added 15-crown-5 (22.1 mg, 0.10 mmol) and NaN3 (130 mg, 2.0 mmol) at room temperature. After refluxing for 24 h, the reaction mixture was filtered using celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH = 12/1) to afford (*S*)-**8** (114 mg, 0.974 mmol, 97% yield) as a colorless oil; [α]D<sup>23</sup> −16.2 (*<sup>c</sup>* 1.10, MeOH); 1H NMR (400 MHz, CDCl3): *δ* 3.92–3.86 (m, 1H), 3.74–3.72 (m, 1H), 3.65–3.61 (m, 1H), 3.47–3.38 (m, 2H), 2.49 (d, *J* = 4.1 Hz, 1H), 1.95 (br s, 1H); 13C{1H} NMR (100 MHz, CDCl3): *δ* 70.9, 63.9, 53.4; IR (ATR): 3333, 2924, 2855, 2093, 1443, 1272, 1103, 1038, 928 cm−1; HRMS (EI) *m*/*z*: [M]+ calcd for C3H7N3O2 117.0538, found 117.0546. The absolute configuration of **8** was established by comparing the sign of the specific rotation of **8** with the literature value ([α]D<sup>20</sup> −17.4 (*<sup>c</sup>* 1.00, MeOH) for (*S*)-**8**) [71].

*(S)-1-Azido-3-(hexadecyloxy)propan-2-ol* ((*S*)-**9**). To a solution of (*S*)-**8** (46.8 mg, 0.40 mmol) in *N*-methylpyrrolidone (0.80 mL) was successively added 2-methoxyphenylboronic acid (6.0 mg, 0.040 mmol) and K2CO3 (82.9 mg, 0.60 mmol). The resulting mixture was stirred

for 30 min at room temperature, and then cetyl bromide (183 mg, 0.60 mmol) was added. After stirring for 24 h at 95 ◦C, the reaction mixture was diluted with H2O and extracted with AcOEt. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/Et2O = 8/2) to afford (*S*)-**9** (87.3 mg, 0.256 mmol, 64% yield) as a white solid; mp = 37–39 ◦C; [α]D<sup>24</sup> −11.8 (*<sup>c</sup>* 1.00, MeOH); 1H NMR (400 MHz, CDCl3): *δ* 3.97–3.91 (m, 1H), 3.51–3.33 (m, 6H), 2.42 (d, *J* = 5.0 Hz, 1H), 1.61–1.54 (m, 2H), 1.32–1.26 (m, 26H), 0.88 (t, *J* = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): *δ* 71.8, 71.7, 69.6, 53.5, 31.9, 29.68, 29.66, 29.64, 29.59, 29.57, 29.5, 29.4, 29.3, 26.1, 22.7, 14.1; IR (ATR): 3429, 2914, 2876, 2846, 2088, 1466, 1337, 1290, 1113, 989 cm−1; HRMS (DART) *m*/*z*: [M + H]<sup>+</sup> calcd for C19H40N3O2 342.3121, found 342.3171.

*(S)-1-Amino-3-(hexadecyloxy)propan-2-ol* ((*S*)-**10**). To a reaction vessel charged with 10% Pd/C (24.9 mg, 10% w/w) was added a solution of (*S*)-**9** (249 mg, 0.73 mmol) in MeOH (7.3 mL) at room temperature under argon atmosphere. The reaction vessel was charged with H2 gas, and then the mixture was stirred for 4 h at room temperature. The reaction mixture was filtered using celite, and then the filtrate was concentrated under reduced pressure. The residue was dissolved in 10% aqueous HCl and washed with AcOEt. The aqueous layer was basified with saturated aqueous NaHCO3 and then extracted with CHCl3. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (*S*)-**10** (211 mg, 0.67 mmol, 92% yield) as a white solid; mp = 60–61 ◦C; [α]D<sup>24</sup> −3.2 (*<sup>c</sup>* 0.50, CHCl3); 1H NMR (400 MHz, CDCl3): *<sup>δ</sup>* 3.76–3.70 (m, 1H), 3.50–3.43 (m, 3H), 3.38 (dd, *J* = 9.5, 6.5 Hz, 1H), 2.83 (dd, *J* = 12.7, 3.1 Hz, 1H), 2.72 (dd, *J* = 12.5, 6.7 Hz, 1H), 1.61–1.54 (m, 2H), 1.32–1.26 (m, 26H), 0.88 (t, *J* = 6.7 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): *δ* 73.0, 71.7, 71.1, 44.4, 31.9, 29.7, 29.64, 29.59, 29.58, 29.5, 29.3, 26.1, 22.7, 14.1; IR (ATR): 2912, 2827, 1470, 1130, 1032, 924 cm−1; HRMS (FAB) *m*/*z*: [M + H]+ calcd for C19H42NO2 316.3216, found 316.3200.

*(S)-2,2,3,3-Tetramethyl-4,11-dioxa-7-aza-3-silaheptacosan-9-ol* ((*S*)-**11**). To a solution of 2-(*tert*-butyldimethylsilyloxy)acetaldehyde (34.9 mg, 0.20 mmol) [72] in MeOH/CH2Cl2 (5:2, 1.4 mL) was added (*S*)-**10** (69.4 mg, 0.22 mmol) at room temperature. After stirring for 10 min at the same temperature, 2-picoline borane (256 mg, 0.24 mmol) was added, and then the reaction mixture was stirred for an additional 10 h. The reaction mixture was diluted with H2O and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH = 12/1) to afford (*S*)-**11** (55.8 mg, 0.117 mmol, 59% yield) as a colorless amorphous; [α]D<sup>25</sup> −3.6 (*<sup>c</sup>* 1.00, CHCl3); 1H NMR (400 MHz, CDCl3): *δ* 3.86–3.81 (m, 1H), 3.75–3.67 (m, 2H), 3.49–3.39 (m, 4H), 2.78–2.64 (m, 4H), 1.60–1.54 (m, 2H), 1.33–1.25 (m, 26H), 0.90–0.86 (m, 12H), 0.06 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): *δ* 73.3, 71.7, 68.7, 62.2, 51.7, 51.5, 31.9, 29.7, 29.62, 29.58, 29.5, 29.3, 26.1, 25.9, 22.7, 18.3, 14.1, −5.4; IR (ATR): 2914, 2849, 1472, 1464, 1256, 1119, 1080, 968, 937, 831 cm<sup>−</sup>1; HRMS (FAB) *m*/*z*: [M + H]<sup>+</sup> calcd for C27H60NO3Si 473.4342, found 473.4300.

*(S)-N-(3-(Hexadecyloxy)-2-hydroxypropyl)-N-(2-hydroxyethyl)palmitamide* ((*S*)-**12**). To a solution of (*S*)-**11** (135 mg, 0.28 mmol) and *i*-Pr2NEt (77.0 mg, 0.60 mmol) in CH2Cl2 (1.4 mL) was added palmitoyl chloride (81.9 mg, 0.30 mmol) at room temperature. After stirring for 1 h at the same temperature, all volatile was removed under reduced pressure. The residue was dissolved in THF (2.8 mL), and then a 1.0 M solution of TBAF in THF (0.57 mL) was added at room temperature. After stirring for 30 min at the same temperature, the reaction mixture was diluted with H2O and extracted with CHCl3. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt = 1/1) to afford (*S*)-**<sup>12</sup>** (144 mg, 0.241 mmol, 85% yield) as a white solid; mp = 67–68 ◦C; [α]D<sup>25</sup> −4.4 (*<sup>c</sup>* 1.00, CHCl3); 1H NMR (400 MHz, CDCl3, mixture of rotamers): *δ* 4.16–3.93 (m, 1H), 3.85–3.74 (m, 2H), 3.67–3.25 (m, 8H), 2.46–2.30 (m, 2H), 1.67–1.52 (m, 4H), 1.28 (m, 50H), 0.88 (app t, *J* = 6.9 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3): *δ* 175.8, 72.4, 72.1, 71.8, 71.6, 69.8, 69.4, 61.7, 60.6, 53.3, 52.5, 51.4, 51.1, 33.6, 33.5, 31.9, 29.7, 29.62, 29.60, 29.59, 29.56, 29.53, 29.47, 29.44, 29.42, 29.3, 26.1, 26.0, 25.29, 25.26, 22.7, 14.1; IR (ATR): 3320, 2916, 2849, 1611, 1464, 1437, 1375, 1306, 1290, 1261, 1206, 1165, 1109, 1094, 1059, 1040, 955, 845, 814 cm−1; HRMS (FAB) *m*/*z*: [M + H]<sup>+</sup> calcd for C37H76NO4 598.5773, found 598.5800.
