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extracted with CH2Cl2 (3 × 10 mL). The combined organic phases
were concentrated under reduced pressure. The residue was dissolved
in Et2O (10 mL), and 30% aqueous NaOH solution (1 mL) was
added. The biphasic mixture was stirred vigorously at 0 °C for 1 h. The
organic phase was separated, dried (MgSO4), and concentrated.
Purification of the residue by flash chromatography on silica gel
(hexane/EtOAc 3.5:1) afforded epoxy alcohol 9 (180 mg, 77%, dr
>20:1) as a colorless oil. The dr value was determined by analysis of
the corresponding (S)-MTPA esters:19 [α]D28 +41.6 (c 0.7, THF); 1H
NMR (500 MHz, CDCl3) δ 0.87 (t, J = 7.0 Hz, 3H), 1.16−1.57 (m,
26H), 1.67−1.79 (m, 2H), 2.65 (s, 1H), 2.68 (dd, J = 2.1, 5.8 Hz, 1H),
2.81−2.85 (m, 1H), 3.27−3.33 (m, 1H), 3.53 (dd, J = 3.4, 10.6 Hz,
1H), 3.56−3.60 (m, 1H), 3.68 (dd, J = 2.8, 5.9 Hz, 1H), 3.94 (dd, J =
2.9, 4.5 Hz, 1H), 3.99−4.15 (m, 3H), 4.42−4.68 (m, 8H), 7.18−7.34
(m, 20H); 13C NMR (125 MHz, CDCl3) δ 14.1, 22.7, 25.1, 29.3,
29.60, 29.61, 29.63, 29.67, 31.9, 34.0, 54.8, 61.5, 66.6, 70.8, 72.5, 72.7,
73.0, 73.2, 73.4, 73.9, 75.4, 76.6, 127.5, 127.6, 127.7, 127.8, 127.9,
128.0, 128.2, 128.35, 128.36, 128.37, 128.39, 137.80, 138.84, 138.1,
138.3; ESI-HRMS [M + NH4]+ calcd for m/z C52H74NO7+ 824.5460,
found 824.5453.
1H), 4.06−4.20 (m, 3H), 4.43−4.74 (m, 8H), 6.64 (d, J = 6.9 Hz,
1H), 7.22−7.36 (m, 20H); 13C NMR (125 MHz, CDCl3) δ 14.1, 22.7,
25.7, 25.9, 29.3, 29.4, 29.5, 29.7, 31.9, 33.4, 36.5, 73.1, 73.2, 73.4,
127.5, 127.7, 127.9, 128.01, 128.03, 128.10, 128.37, 128.43, 128.49,
137.3, 137.90, 137.97, 138.3, 174.2; ESI-HRMS [M + Na]+ calcd for
+
m/z C78H123NNaO8 1224.9141, found 1224.9139.
To the other half of solution A (2 mL) were added p-nitrophenyl
ester 19b (46 mg, 0.135 mmol) and DMAP (0.5 mg, 4.0 μmol). After
the mixture was stirred at rt for 48 h, the solvent was removed under
reduced pressure. The residue was purified by flash chromatography
on silica gel (hexane/EtOAc 2:1) to provide amide 20b (15 mg, 49%,
1
based on the mixture of 18 and its C-3 regioisomer) as a wax: H
NMR (500 MHz, CDCl3) δ 0.88 (t, J = 7.1 Hz, 3H), 1.12−1.74 (m,
36H), 1.93−2.03 (m, 3H), 2.12−2.20 (m, 1H), 2.57 (t, J = 7.7 Hz,
2H), 3.32−3.43 (m, 3H), 3.62 (dd, J = 2.8, 7.5 Hz, 1H), 3.77−3.81
(m, 1H), 3.83 (t, J = 3.0 Hz, 1H), 3.89−3.97 (m, 1H), 4.06−4.19 (m,
3H), 4.43−4.74 (m, 8H), 6.63 (d, J = 6.9 Hz, 1H), 7.14−7.36 (m,
25H); 13C NMR (125 MHz, CDCl3) δ 14.1, 22.7, 29.4, 29.67, 29.71,
31.9, 35.9, 72.1, 73.1, 73.3, 73.4, 74.1, 127.5, 127.7, 127.86, 127.88,
127.98, 128.00, 128.1, 128.2, 128.37, 128.42, 128.43, 128.49, 137.4,
137.9, 138.0, 138.3, 142.8, 174.1; ESI-HRMS [M + Na]+ calcd for m/z
(2′S,3′S,4′R)-1-(2′-Azido-3′,4′-dihydroxyoctadecyl)-(2,3,4,6-
tetra-O-benzyl)-α-C-D-galactopyranoside (18). Oil bath heating:
NH4Cl (50 mg, 0.935 mmol) and NaN3 (120 mg, 1.85 mmol) were
added to epoxy alcohol 9 (100 mg, 0.124 mmol) in 9 mL of
MeOCH2CH2OH/H2O (8/1). The reaction mixture was stirred at
110 °C for 20 h. The reaction mixture was allowed to cool to rt, and
the solvents were removed under reduced pressure. The residue was
extracted with EtOAc (3 × 10 mL). The combined organic phases
were dried (Na2SO4), filtered, and concentrated under reduced
pressure. Purification of the residue by flash chromatography on silica
gel (EtOAc/hexane 1:4) afforded a mixture of 18 and its C-3 azide
regioisomer (3:1, 77 mg, 73%). Microwave heating: To a solution of
epoxy alcohol 9 (10 mg, 0.0124 mmol) in 1.8 mL of
MeOCH2CH2OH/H2O (8/1) in a 10 mL microwave reaction test
tube were added NH4Cl (6.6 mg, 0.124 mmol) and NaN3 (16 mg,
0.248 mmol). The tube was placed in a microwave reactor. The
reaction was conducted at 140 °C for 1 h. The workup and purification
followed the above procedure to afford a mixture of 18 and its C-3
+
C66H91NNaO8 1048.6637, found 1048.6643.
(2′S,3′S,4′R)-2′-N-Hexacosanoylamino-3′,4′-dihydroxyocta-
decyl-α-C-D-galactopyranoside (1). A solution of 20a (12 mg, 10
μmol) in EtSH/BF3·OEt2 (3:1, 1.3 mL) was stirred at rt for 24 h. The
solvent was evaporated under reduced pressure, and the residue was
purified by flash chromatography on silica gel (CHCl3/MeOH 10:1)
and then was lyophilized with benzene to afford 1 (8 mg, 95%) as a
1
white powder: H NMR (500 MHz, C5D5N) δ 0.85−0.90 (m, 6H),
1.12−1.49 (m, 66H), 1.66−1.74 (m, 1H), 1.81−1.89 (m, 2H), 1.89−
2.02 (m, 2H), 2.29−2.39 (m, 1H), 2.45−2.58 (m, 2H), 2.80 (dt, J =
8.5, 14.7 Hz, 1H), 3.08 (dt, J = 4.3, 14.7 Hz, 1H), 4.25−4.30 (m, 1H),
4.36−4.40 (m, 1H), 4.42−4.48 (m, 2H), 4.52−4.57 (m, 1H), 4.69 (t, J
= 3.0 Hz, 1H), 4.71 (dd, J = 7.6, 11.1 Hz, 1H), 4.79 (dd, J = 4.8, 7.8
Hz, 1H), 5.01−5.06 (m, 1H), 5.32−5.38 (m, 1H), 8.62 (d, J = 8.5 Hz,
1H); 13C NMR (125 MHz, C5D5N) δ 14.8, 23.4, 27.0, 27.1, 30.1,
30.27, 30.34, 30.37, 30.40, 30.42, 30.5, 30.68, 30.9, 32.6, 34.8, 37.5,
51.7, 62.4, 70.3, 71.4, 72.9, 73.3, 73.8, 76.0, 78.7, 174.0; ESI-HRMS [M
+ Na+] calcd for m/z C50H99NNaO8 864.7263, found 864.7271.
+
1
azide regioisomer (3:1, 7.5 mg, 71%). Data for the mixture: H NMR
(2′S,3′S,4′R)-2′-N-8″-Phenyloctanoylamino-3′,4′-dihydroxy
octadecyl-α-C-D-galactopyranoside (1′). A solution of 20b (5 mg,
4.9 μmol) in EtSH/BF3·OEt2 (3:1, 1.3 mL) was stirred at rt for 24 h.
The solvent was evaporated under reduced pressure, and the residue
was purified by flash chromatography on silica gel (CHCl3/MeOH
10:1) and then was lyophilized with benzene to afford 1′ (3 mg, 92%)
as a white powder: 1H NMR (500 MHz, C5D5N) δ 0.87 (t, J = 6.9 Hz,
3H), 1.15−1.53 (m, 30H), 1.65−1.74 (m, 1H), 1.77−1.85 (m, 2H),
1.89−2.01 (m, 2H), 2.31−2.39 (m, 1H), 2.42−2.55 (m, 4H), 2.80 (dt,
J = 8.5, 14.7 Hz, 1H), 3.08 (dt, J = 4.5, 14.7 Hz, 1H), 4.26−4.30 (m,
1H), 4.35−4.40 (m, 1H), 4.42−4.49 (m, 2H), 4.52−4.57 (m, 1H),
4.69 (t, J = 3.1 Hz, 1H), 4.72 (dd, J = 7.6, 11.1 Hz, 1H), 4.79 (dd, J =
4.7, 7.8 Hz, 1H), 5.01−5.06 (m, 1H), 5.33−5.39 (m, 1H), 7.23−7.27
(m, 3H), 7.33−7.38 (m, 2H), 8.58 (d, J = 8.5 Hz, 1H); 13C NMR
(100 MHz, C5D5N) δ 14.8, 23.4, 26.9, 27.1, 29.9, 30.03, 30.08, 30.12,
30.39, 30.46, 30.49, 30.6, 30.9, 32.3, 32.6, 34.9, 36.6, 37.4, 51.7, 62.4,
70.2, 71.5, 72.9, 73.3, 73.8, 76.0, 78.7, 126.5, 129.2, 129.3, 143.7, 174.0;
ESI-HRMS [M + Na]+ m/z calcd for C38H67NNaO8+ 688.4759, found
688.4759.
(S,E)-1-(4′-Hydroxyoctadec-2′-en-5′-ynyl)-(2,3,4,6-tetra-O-
benzyl)-α-C-D-galactopyranoside (35a). A flame-dried 100 mL
round-bottom flask was charged with commercially available
ProPhenol ligand (R,R)-347 (123 mg, 0.192 mmol), 1-tetradecyne
(1.12 g, 5.76 mmol), and toluene (25 mL); see Scheme S1. After the
solution was degassed by two freeze−pump−thaw cycles and filled
with N2, a solution of Me2Zn in toluene (4.8 mL, 1.2 M, 5.76 mmol)
was added rapidly via syringe. The reaction mixture was stirred for 90
min at rt, and gas slowly evolved. A solution of α,β-unsaturated
aldehyde 331 (1.14 g, 1.92 mmol) in 10 mL of toluene, which was
degassed by two freeze−pump−thaw cycles, was added via syringe
over 10 s. The reaction mixture was sealed and cooled to 4 °C for 13
(500 MHz, CDCl3) δ 0.87 (t, J = 7.0 Hz, 3H), 1.15−1.34 (m, 24H),
1.35−1.50 (m, 2H), 1.92−1.99 (m, 1H), 2.18−2.26 (m, 1H), 3.32 (d,
J = 9.8 Hz, 1H), 3.50−3.57 (m, 1H), 3.59−3.66 (m, 2H), 3.69−3.75
(m, 1H), 3.77−3.85 (m, 2H), 3.90−4.02 (m, 2H), 4.40−4.83 (m, 9H),
7.19−7.39 (m, 20H); 13C NMR (125 MHz, CDCl3) δ 14.1, 22.7, 25.9,
29.3, 29.61, 29.63, 29.7, 31.2, 31.9, 61.1, 70.5, 72.02, 72.05, 72.6, 73.16,
73.26, 73.45, 73.65, 74.4, 76.3, 127.6, 127.7, 127.82, 127.84, 128.0,
128.05, 128.15, 128.20, 128.34, 128.40, 128.43, 137.1, 137.9, 138.0,
138.3; ESI-HRMS [M + Na]+ calcd for m/z C52H71N3NaO7
+
872.5184, found 872.5187.
(2′S,3′S,4′R)-2′-N-Hexacosanoylamino-3′,4′-dihydroxyocta-
decyl-(2,3,4,6-tetra-O-benzyl)-α-C-D-galactopyranoside (20a)
and (2′S,3′S,4′R)-2′-N-8″-Phenyloctanoylamino-3′,4′-dihy-
droxyoctadecyl-(2,3,4,6-tetra-O-benzyl)-α-C-D-galactopyrano-
side (20b). To a solution of azido diol 18 and its C-3 azide
regioisomer (3:1, 50 mg, 0.059 mmol) in MeOH (2 mL) were added
Et3N (200 μL, 1.44 mmol) and 1,3-propanedithiol (120 μL, 1.19
mmol). The solution was heated at reflux for 20 h and allowed to cool
to rt. The solvent was removed in vacuo to give a residue, which was
dissolved in anhydrous THF (4 mL, solution A). Solution A was
divided into two 10 mL round-bottom flasks, which were directly used
in the amidation reaction. p-Nitrophenyl ester 19a (46 mg, 0.089
mmol) and DMAP (0.5 mg, 4.0 μmol) were added to the first half of
solution A (2 mL). After the mixture was stirred at rt for 48 h, the
solvent was removed under reduced pressure. The residue was purified
by flash chromatography on silica gel (hexane/EtOAc 3:1 to 5:2) to
provide amide 20a (25 mg, 72%, based on the mixture of 18 and its C-
1
3 regioisomer) as a wax: H NMR (500 MHz, CDCl3) δ 0.85−0.90
(m, 6H), 1.12−1.80 (m, 72H), 1.94−2.07 (m, 3H), 2.11−2.21 (m,
1H), 3.32−3.38 (m, 2H), 3.39−3.44 (m, 1H), 3.62 (dd, J = 2.7, 7.5
Hz, 1H), 3.77−3.81 (m, 1H), 3.83 (t, J = 3.0 Hz, 1H), 3.90−3.96 (m,
8593
dx.doi.org/10.1021/jo201450s|J. Org. Chem. 2011, 76, 8588−8598