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T. Velasco-Torrijos, P. V. Murphy / Tetrahedron: Asymmetry 16 (2005) 261–272
13C NMR (CDCl3, 75 MHz): d = 20.6, 20.7, 2.08 (each
q, COCH3), 39.5 (q, NCH3), 64.7 (d), 65.2 (t), 70.1,
70.3, 70.8, 94.8 (each d), 123.9 (d, ArCH), 128.0 (d,
CH@), 142.2 (s, ArC), 166.5 (s, CONCH3), 168.4,
170.0, 170.5 (each s, COCH3).
evaporated and purified by chromatography (dichloro-
methane/methanol 98:2) to give acetylated intermediate
(34 mg, 72%) as a white solid; Rf = 0.35 (dichloro-
methane/methanol 5%); [a]D = ꢁ177.6 (c 0.85, CHCl3);
1H NMR (D2O, 300 MHz): d = 0.90–0.99 (m, 2H,
CH2), 1.48–1.57 (m, 2H, CH2), 2.03 (s, 3H, OCOCH3),
2.11 (s, 6H, OCOCH3), 3.32 (m overlapping with s,
10H, NCH3 and CH2O), 4.78 (d, J = 9.6 Hz, 2H, H-5),
4.95–4.99 (dd, J = 3.3, 9.6 Hz, 2H, H-2), 5.03 (d,
J = 3.6 Hz, 2H, H-1), 5.38–5.44 (t, J = 9.6 Hz, 2H,
H-3), 5.61–5.67 (t, J = 9.3 Hz, 2H, H-4), 7.35 (s, 4H,
ArH); 13C NMR (CDCl3, 75 MHz): d = 20.6, 20.8,
20.9 (each q, COCH3), 26.3 (t, CH2), 39.5 (q, NCH3),
64.5, (d, CH), 66.4 (t, C2O), 70.2, 70.4, 70.9, 95.4 (each
d), 128.3 (d, ArCH), 142.3 (s, ArC), 166.7 (s, CONCH3),
168.4, 169.9, 170.6 (each s, COCH3); LRMS-ES:
[M+H]+ 795.3; IR (CH2Cl2): 3625, 3515, 3418, 2933,
Analytical data for 11: Rf = 0.35 (dichloromethane–
EtOAc 1:4); 1H NMR (CDCl3, 300 MHz): d = 2.02,
2.03, 2.07 (each s, each 3H, OCOCH3), 3.32 (s, 6H,
NCH3), 3.49–3.55 (m, 2H, CHCH2O), 4.05–4.09 (m,
2H, CHCH2O), 4.77 (d, J = 9.6 Hz, 2H, H-5), 4.88–
4.93 (dd, J = 3.3, 12.9 Hz, 2H, H-2), 5.03 (d,
J = 3.6 Hz, 2H, H-1), 5.38–5.48 (t, J = 9.6 Hz, 2H, H-
3), 5.48–5.51 (m, 2H, @CH), 5.52–5.56 (t, J = 9.3 Hz,
2H, H-4), 7.37 (s, 4H, ArH); 13C NMR (CDCl3,
75 MHz): d = 20.6, 20.7 (each q, COCH3), 39.3 (q,
NCH3), 64.5 (d, CH), 65.9 (t, CH2O), 69.7, 70.6, 97.5
(each d), 127.9 (d, CH@), 128.3 (d, ArCH), 142.1 (s,
ArC), 166.4 (s, CONCH3), 168.7, 169.9, 170.3 (each s,
COCH3).
1755, 1664, 1506, 1243, 1041 cmꢁ1
;
HRMS-ES:
[M+H]+ Calcd 795.2824. Found 795.2852. Sodium
methoxide from a 1 M solution freshly prepared
(0.1 mL) was added to a solution of this intermediate
(25 mg, 0.031 mmol) in methanol (2 mL) that had been
pre-cooled on ice. The reaction mixture was stirred at
0 ꢁC for 30 min. The solventwas evaporaetd under
reduced pressure to give a yellow solid that was dis-
solved in water and acidified to pH 6 by addition of
Amberlite (H+). The resin was removed by filtration
and the filtrate was freeze-dried to give 18 as a white
solid (12 mg, 70%). The mixture was partially separated
by HPLC (eluant water/acetonitrile 85:15, flow rate
10 mL/min, C4-reverse phase preparative column).
[a]D = ꢁ16 (c 0.25, MeOH); 1H NMR (D2O,
300 MHz): d = 0.92–0.97 (m, 2H, CH2), 1.41–1.59 (m,
2H, CH2), 3.33–3.39 (m overlapping with s, 10H,
NCH3 and CH2O), 3.62–3.66 (dd, J = 3 Hz,
J = 9.6 Hz, 2H, H-2), 3.72–3.78 (t, J = 9.6 Hz, 2H, H-
3), 3.87–3.93 (t, J = 9 Hz, 2H, H-4), 4.62 (d,
J = 9.6 Hz, 2H, H-5), 4.89 (d, J = 3 Hz, 2H, H-1), 7.39
(s, 4H, ArH); LRMS-ES: [M+H]+ 543.2; HRMS-ES:
[M+Na]+ Calcd 565.2009. Found 565.2006.
4.11. Macrocycles 14 and 15
Sodium methoxide from a 1 M solution freshly prepared
(0.1 mL) was added to a mixture of 10 and 11 (48 mg,
0.06 mmol) in methanol (7 mL) that was precooled on
ice. The reaction mixture was allowed to stir at 0 ꢁC
for 30 min. The solventwas evaporaetd under reduced
pressure to give a yellow solid that was dissolved in
water and acidified to pH 6 by addition of Amberlite
(H+). The resin was removed by filtration and the filtrate
was freeze-dried to give a white solid corresponding to a
mixture of title compounds (25 mg, 77%); HRMS-ES:
[M+H]+ Calcd 541.2034. Found 541.2056. The mixture
was partially separated by HPLC (eluant water/aceto-
nitrile 85:15, flow rate 3 mL/min, C4-reverse phase pre-
parative column).
1
Analytical data for 14: [a]D = ꢁ77 (c 0.2, methanol); H
NMR (D2O, 300 MHz): d = 3.18 (s, 6H, NCH3), 3.56–
3.60 (dd, J = 3, 9.6 Hz, 2H, H-2), 3.70–3.84 (m, 8H,
H-3, H-4, CHCH2O), 4.43 (d, J = 9.3 Hz, 2H, H-5),
4.86 (d, J = 3.3 Hz, 2H, H-1), 5.50 (s, 2H, @CH), 7.40
(s, 4H, ArH); 13C NMR (D2O, 125 MHz): d = 42.1 (q,
NCH3), 66.8 (t), 70.5, 74.0, 74.8, 75.3, 99.5, 125.6,
131.5 (each d), 144.7 (s, ArC), 172.8 (s, CO); IR
(KBr): 3454, 3340, 2929, 2361, 1640, 1510, 1451,
4.13. Macrocycle 16
A degassed solution of 9 (172 mg, 0.19 mmol) in dry
dichloromethane (65 mL, 3 mM) and under argon was
treated with metathesis catalyst (34 mg, 20%) for 40 h.
The solvent was evaporated to give a black solid that
was purified by column chromatography (eluant dichlo-
romethane/ethyl acetate 1:4) to give corresponding to a
2:1 mixture of the 12 and 13 (99 mg, 62%). Rf = 0.5
1400 cmꢁ1
.
Analytical data for 15: 1H NMR (D2O, 300 MHz):
d = 3.22–3.29 (m, 8H, NCH3 and CHCH2O), 3.46–3.51
(dd, J = 3.6, 9.9 Hz, 2H, H-2), 3.56–3.62 (t, J = 9.6 Hz,
2H, H-3), 3.73–3.86 (t, J = 9 Hz, 2H, H-4), 4.10–4.17
(m, 2H, CHCH2O), 4.47 (d, J = 9.9 Hz, 2H, H-5), 4.80
(d, J = 3.3 Hz, 2H, H-1), 5.45 (m, 2H, @CH), 7.53 (s,
4H, ArH).
1
(dichloromethane/ethyl acetae 1:4); H NMR (CDCl3,
300 MHz): d = 1.61–1.81 (m, 4H, CH2CH2CH), 1.98–
2.19 (m, 22H, CH2CH2CH2 and OCOCH3), 3.29–3.66
(br m, 10H, CH2CH2O– and NCH3), 4.56–4.66 (m,
2H, H-5), 4.84–4.92 (m, 2H, H-2), 5.08–5.52 (m, 8H,
H-1 and H-3 and H-4 and @CH2), 7.23 (br s, 4H,
ArH); 13C NMR (CDCl3, 75 MHz): d = 20.7, 20.8 (each
q, COCH3), 28.5, 29.8 (t), 38.5 (q, NCH3), 65.5 (d), 69.1
(t, CH2O), 69.9, 70.6, 70.9, 96.1 (each d), 127.6, 127.9 (d,
ArCH), 129.9, 130.0 (d), 142.5, 145.2 (s, ArC), 166.6,
166.9 (s, CONH), 168.6, 170.2, 170.4 (each s, COCH3);
LRMS-ES+: 849.3 [M+H]+. Sodium methoxide from a
1 M solution freshly prepared (0.1 mL) was added to a
4.12. Macrocycle 18
Pd–C (10%, 7 mg) was added to a solution of 14/15
(47 mg, 0.059 mmol) in EtOAc (2 mL) and the mixture
stirred under H2 atmosphere at rt for 18 h. The reaction
mixture was then filtered through Celite and the filtrate