5690
P. A. Burland et al. / Bioorg. Med. Chem. 19 (2011) 5679–5692
2.82–2.99 (3H, m, 1 ꢀ H-3, 1 ꢀ H-5, 1 ꢀ H-10), 3.04–3.10 (2H, m,
1 ꢀ H-3, 1 ꢀ H-10), 3.30–3.35 (1H, m, H-5), 3.55–3.57 (5H, m,
2 ꢀ H-8, 2 ꢀ OCH3), 3.75–3.81 (4H, m, 1 ꢀ H-9, COOCH3), 3.92–
3.94 (1H, m, H-6), 4.06–4.09 (1H, m, H-2), 4.67 (1H, d, J = 4.5 Hz,
H-7), 6.82 (2H, d, J = 8.5 Hz, Ar-H), 7.17 (2H, d, J = 8.5 Hz, Ar-H);
13C NMR (63 MHz, CD3OD) 36.66 (C-10), 52.26 (COOCH3), 52.70
(C-5), 56.61 (OCH3), 58.08 (C-3), 64.97 (C-8), 71.30 (C-9), 71.59
(C-6), 73.87 (C-2), 103.52 (C-7), 116.67 (C-12), 131.60 (C-13),
157.48 (C-14), 174.55 (COOCH3); m/z (CI) [M+H]+ requires
356.1709. Found 356.1707.
argon. Upon completion, the reaction was cooled and the solvent
removed in vacuo. The contents were partitioned between water
(100 mL) and CH2Cl2 (100 mL). The aqueous phase was further ex-
tracted with CH2Cl2 (2 ꢀ 100 mL). The organic phase was dried
(MgSO4), filtered and concentrated in vacuo. Flash column chroma-
tography on silica gel (1:1 toluene/EtOAc) yielded (17) as a white
solid (6.40 g, 66%). Mp 81–83 °C (lit.23 85–87 °C); ½a D20
ꢃ
+65.8 (c
1.0, CHCl3) (lit.35 +59.8 (c 1.1, CHCl3)); mmax (NaCl disc/cmꢁ1
)
3428 (br, s, OH), 2914 (s, CH), 1497 (m, C@C (arom)), 1454 (m,
C@C (arom)),1054 (s, C–O), 738 (s, CH (arom)), 698 (s, CH (arom));
dH (400 MHz, CDCl3) 2.92 (1H, d, J = 2.5 Hz, H-3), 2.94 (1H, d, J 3.0,
C(4)OH), 3.33 (3H, s, OCH3), 3.37 (1H, dd, J = 9.5, 3.5 Hz, H-2), 3.57
(1H, dt, J = 9.0, 3.0 Hz, H-4), 3.66–3.71 (3H, m, H-5,6), 3.90 (1H, dt,
J = 9.0, 2.5 Hz, H-3), 4.54 (1H, d, J = 12.0 Hz, OCH2Ph), 4.58–4.66
(3H, m, H-1, OCH2Ph), 4.70 (1H, d, J = 12.0 Hz, OCH2Ph), 7.32–
7.35 (10H, m, Ar-H); dC (101 MHz, CDCl3) 55.0 (OCH3), 69.2 (C-6),
69.5 (C-5), 70.8 (C-4), 72.8 (C-3), 72.8 (OCH2Ph), 73.4 (OCH2Ph),
78.9 (C-2), 97.5 (C-1), 127.4–128.3 (ArC), 137.7 (ArC); m/z (ESI)
397 ([M+Na]+, 100%). Found [M+Na]+ 397.1638, C21H26NaO6 re-
quires 397.1622.
4.2.11. Methyl 2,3,4-tri-O-benzyl-6-deoxy-6-((2R)-benzyl-
oxymethyl-(6S)-benzyloxy-(7R)-methoxy-[1,4]-oxazepan-4-yl)-
a-
D-glucopyranoside (16m)
The general procedure for the synthesis of morpholines with
purification by column chromatography (4:1 toluene/EtOAc) affor-
ded (16m) as a golden syrup in 72% yield; ½a D20
ꢃ
+13.1 (c 1.06,
CHCl3); mmax (NaCl disc/cmꢁ1) 2911 (s, CH), 1494 (s, C@C (arom)),
1453 (s, CH2), 1070 (s, C–O), 737 (s, CH (arom)), 697 (s, CH (arom));
dH (400 MHz, CDCl3) 2.68 (1H, dd, J = 13.0, 8.0 Hz, H-6), 2.71 (1H,
dd, J = 13.5, 4.5Hz, H-3a), 2.86 (1H, dd, J = 13.5, 2.5 Hz, H-5a),
2.94 (1H, d, J = 13.0 Hz, H-60), 3.00 (1H, dd, J = 13.5, 4.0 Hz, H-3a0),
3.17 (1H, dd, J = 13.5, 4.0 Hz, H-5a0), 3.25 (1H, app. t, J = 9.5 Hz,
H-4), 3.33 (3H, s, OCH3), 3.38 (3H, m, H-2, 8a), 3.44 (3H, s, OCH3),
3.56–3.60 (1H, m, H-6a), 3.80 (1H, app. t, J = 8.0 Hz, H-5), 3.99
(1H, t, J = 9.5 Hz, H-3), 4.23–4.27 (1H, m, H-2a), 4.49–4.53 (4H,
m, H-1, OCH2Ph), 4.57 (1H, d, J = 12.5 Hz, OCH2Ph), 4.60 (1H, d,
J = 12.5 Hz, OCH2Ph), 4.64 (1H, d, J = 12.0Hz, OCH2Ph), 4.75–4.81
(3H, m, H-7a, OCH2Ph), 4.89 (1H, d, J = 11.0 Hz, OCH2Ph), 4.98
(1H, d, J = 11.0 Hz, OCH2Ph), 7.15–7.33 (20H, m, Ph); dC
(101 MHz, CDCl3) 55.2 (C-5a), 55.5 (OCH3), 55.7 (OCH3), 57.5 (C-
3a), 58.8 (C-6), 68.5 (C-2a), 69.4 (C-5), 71.6 (OCH2Ph), 71.9 (C-8),
73.1 (OCH2Ph), 73.2 (OCH2Ph), 74.9 (OCH2Ph), 75.6 (OCH2Ph),
77.2 (C-6a), 79.7 (C-4), 79.9 (C-2), 81.9 (C-3), 97.8 (C-1), 100.6
(C-7a), 127.4–128.9 (ArC), 137.7–138.6 (ArC); m/z (ESI) 804
([M+H]+, 100%). Found [M+H]+ 804.4116, C49H58NO9, requires
804.4106.
4.2.14. Methyl-[O6-(toluene-4-sulfonyl)]-
a-D-glucopyranoside
(19)
Methyl
a-D-glucopyranoside (3.02 g, 15.61 mmol) was dis-
solved in pyridine (30 mL) and cooled to 0 °C under argon. Toluene
sulfonyl chloride (2.98 g, 15.6 mmol) was added and the solution
was stirred for 8 h at 0 °C. The mixture was then concentrated in
vacuo and the crude mixture was purified by flash column chroma-
tography (EtOAc) to isolate (19) as a white solid in 51% yield; mp
105–106 °C (lit.36 104–106 °C); ½a 2D0
ꢃ
+91 (c 1.01, CHCl3)) (lit.24
+104 (c 1.0, CHCl3)); mmax (NaCl disc/cmꢁ1) 3371 (br, s, OH), 1449
(m, C@C (arom)), 1361 (s, SO2 (antisymmetric)), 1176 (s, C–O),
1146 (m, SO2 (symmetric)), 1060 (m, C–O), 666 (m, CH (arom));
dH (250 MHz, CDCl3) 2.43 (3H, s, PhCH3), 3.33 (3H, s, OCH3),
3.39–3.51 (2H, m, H-2,4), 3.68–3.75 (2H, m, H-3,5), 4.22–4.33
(2H, m, H-6), 4.66 (1H, d, J = 3.5 Hz, H-1), 7.27–7.35 (2H, m, Ph),
7.77–7.85 (2H, m, Ph); dC (63 MHz; CDCl3) 22.1 (PhCH3), 55.7
(OCH3), 69.7 (C-6) 69.8 (C-5), 70.0 (C-4), 72.1 (C-2), 74.4 (C-3),
99.8 (C-1), 128.4–145.3 (ArC).
4.2.12. (2R)-(Hydroxymethyl)-(7R)-methoxy-[1,4]-oxazepan-
(6S)-ol (16n)
Compound 15e (100 mg, 0.374 mmol) was dissolved in MeOH
(2 mL) and added to Pd(OH)2/C (26.2 mg, 20% loading) in a dry
flask. TFA (0.2 mL) was added and the flask was evacuated. A
hydrogen atmosphere was then introduced. The evacuation pro-
cess was repeated three times. The contents were left to stir over-
night before filtration through CeliteÒ and washing with 1:1
CH2Cl2–MeOH. The filtrate was concentrated in vacuo to afford
4.2.15. Methyl-[O6-(toluene-4-sulfonyl)]-2,3,4-tri-O-benzyl-
a-D-
glucopyranoside (20)
Methyl-[O6-(toluene-4-sulfonyl)-
a
-D
-glucopyranoside
(19)
(364 mg, 1.04 mmol) was dissolved in anhydrous DMF (20 mL)
and cooled to 0 °C. Sodium hydride (12.5 mg, 3.13 mmol) was
added portionwise, followed by benzyl bromide (0.37 mL,
3.13 mmol). The reaction mixture was stirred under argon, warm-
ing to room temperature overnight. DMF was removed under pres-
sure and the resultant liquid was partitioned between water
(75 mL) and EtOAc (75 mL). The aqueous phase was further ex-
tracted with EtOAc (2 ꢀ 75 mL). The combined organic phases
were washed with water (75 mL), dried (MgSO4), filtered and con-
centrated in vacuo. The crude mixture was purified by flash col-
umn chromatography (4:1 hexane/EtOAc) to afford (19) as a
(16n) as a syrup (156 mg, 100%). ½a D20
ꢃ
+19.7 (c 1.35, MeOH) (lit.17a
+72.7 (c 1.0, MeOH)); mmax (NaCl disc/cmꢁ1) 3382 (br, s, OH, NH),
1677 (s, NH (bend)), 1202 (s, C–N), 1133 (s, C–O), 1076 (s, C–O);
dH (400 MHz, CD3CD) 3.06 (1H, dd, J 13.5, 10.5, C(3)H), 3.32–3.36
(1H, m, C(5)H), 3.43–3.45 (1H, m, C(30)H), 3.47–3.49 (1H, m,
C(50)H), 3.53–3.57 (4H, m, C(8)H), OCH3), 3.62 (1H, dd, J 11.5, 5.0,
C(80)H), 4.29 (1H, dd, J 6.5, 4.0, C(6)H), 4.41–4.46 (1H, m, C(2)H),
4.71 (1H, d, J 4.0, C(7)H); dC (101 MHz, CD3CD) 47.0 (C5), 50.8
(C3), 56.3 (OCH3), 63.9 (C8), 68.4 (C6), 70.1 (C2), 101.7 (C7); m/z
(ESI) 178 ([M+H]+, 100%). Found [M+H]+ 178.1079, C7H15NO4 re-
quires 178.1074.
clear oil in 100% yield; ½a D20
ꢃ
+36 (c 1.0, CHCl3) (lit.37 +25 (c 2.26,
CHCl3)); mmax (NaCl disc/cmꢁ1) 1363 (s, SO2 (antisymmetric)),
1177 (s, C–O), 1137 (s, SO2 (antisymmetric)), 1093 (s, C–O), 812
(s, CH (arom)), 738 (s, CH (arom)) 698 (s, CH (arom)); dH
(250 MHz, CDCl3) 2.05 (3H, s, PhCH3), 3.31 (3H, s, OCH3), 3.43–
3.49 (2H, m, H-2,4), 3.72–3.79 (1H, m, H-5), 3.94 (1H, t,
J = 9.0 Hz, H-3), 4.17–4.20 (2H, m, H-6), 4.42 (1H, d, J = 10.5 Hz,
OCH2Ph), 4.51 (1H, d, J = 3.5 Hz, H-1), 4.62 (1H, d, J = 12.0 Hz,
OCH2Ph), 4.75–4.84 (3H, m, OCH2Ph, OCH2Ph), 4.97 (1H, d,
J = 11.0 Hz, OCH2Ph), 7.12–7.16 (2H, m, Ph), 7.26–7.38 (15H, m,
Ph), 7.75–7.78 (2H, m, Ph); dC (63 MHz; CDCl3) 22.0 (PhCH3), 55.8
(OCH3), 68.9 (C-5), 69.0 (C-6), 73.9 (OCH2Ph), 75.4 (OCH2Ph), 76.1
4.2.13. Methyl 2,6-di-O-benzyl-
Methyl -glucopyranoside (5.04 g, 25.9 mmol) and dibutyltin
a-D
-glucopyranoside (17)23
a-D
oxide (9.69 g, 38.9 mmol) in anhydrous toluene (100 mL) were
heated at reflux at 137 °C overnight, under argon. The contents
were evaporated to dryness in vacuo. Benzyl bromide (15 mL)
and anhydrous toluene (15 mL) were added to the resultant yellow
solid, and the reaction was set to reflux overnight at 147 °C, under