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(S,Z)-5-Hydroxy-N-(4-(7-(methoxymethoxy)-2,2-dimethyl-4-oxo-
4H-benzo[d][1,3]dioxin-5-yl)butyl)hex-2-enamide (15): Quinoline
(131 mg, 1.02 mmol) was added to a solution of compound 14
(388 mg, 0.926 mmol) in EtOAc (20 mL). The mixture was degassed
under nitrogen gas and then 5% Pd/CaCO3 (lead poisoned, 46 mg,
2 mol% of Pd) was added. The resulting mixture was degassed
again under H2 gas, then stirred under a H2 balloon at RT for
30 min. The catalyst was filtered through Celite and the solvent
evaporated in vacuo. The crude product was purified by silica gel
column chromatography to give cis-olefin product 15 (313 mg,
80%) as a colorless gum. 1H NMR (400 MHz, CDCl3) d=6.80 (brs,
1H, NH), 6.57 (d, J=2.3 Hz, 1H), 6.48 (d, J=2.3 Hz, 1H), 6.16–6.07
(m, 1H), 6.01 (d, J=11.6 Hz, 1H), 5.19 (s, 2H), 4.02–3.93 (m, 1H),
3.49 (s, 3H, OCH3), 3.45–3.38 (m, 2H), 3.04–2.97 (m, 2H), 2.75–2.57
(m, 2H), 1.70 (s, 6H, CH3 ꢁ2), 1.68–1.61 (m, 4H), 1.25 ppm (d, J=
6.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) d=167.0, 162.7, 160.5,
159.0, 149.7, 139.6, 126.1, 113.7, 105.4, 105.1, 102.0, 94.1, 67.1, 56.5,
38.2, 37.8, 34.0, 28.7, 28.1, 25.65, 25.64, 23.7 ppm; MS (ESI): m/z
(%): 422 [M+H]+ (100).
give a crude product which was purified by column chromatogra-
phy on silica gel (0–100% EtOAc in petroleum ether) to afford
compound 17 (347 mg, 93%) as a white solid. H NMR (400 MHz,
1
CDCl3) d=6.67 (d, J=2.2 Hz, 1H), 6.51 (d, J=2.2 Hz, 1H), 6.04 (brs,
1H, NH), 6.00 (d, J=11.8 Hz, 1H), 5.96–5.88 (m, 1H), 5.44–5.37 (m,
1H), 5.15 (s, 2H), 5.15 (d, J=6.7 Hz, 2H), 5.09 (d, J=6.7 Hz, 1H),
3.46 (s, 3H), 3.45 (s, 3H), 3.40–3.15 (m, 3H), 2.79–2.72 (m, 1H),
2.63–2.55 (m, 1H), 2.36–2.28 (m, 1H), 1.68–1.47 (m, 4H), 1.44 ppm
(d, J=6.5 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) d=167.9, 167.1,
159.0, 156.1, 142.7, 131.1, 128.8, 117.1, 111.3, 101.4, 94.7, 94.3, 70.2,
56.3, 56.2, 38.1, 35.7, 32.9, 27.1, 26.6, 18.9 ppm; HRMS (ESI-TOF)
m/z calcd for C21H29NO7Na [M+Na]+: 430.1836, found: 430.1841.
(S,Z)-8-Acetyl-14,16-bis(methoxymethoxy)-3-methyl-3,4,9,10,11,
12-hexahydro-1H-benzo[l][1,7]oxaazacyclotetradecine-1,7(8H)-
dione (18): Freshly prepared LDA (1m in THF, 184 mL) was added
dropwise to a solution of 17 (30 mg, 0.074 mol) in THF (2 mL) over
30 min at ꢀ788C. At the same time, acetic anhydride (1m in THF,
147 mL) was also added dropwise over 30–40 min. The mixture was
stirred for another 20 min at ꢀ788C then quenched by the addi-
tion of saturated aqueous NH4Cl at ~08C, warmed to RT followed
by addition of EtOAc and H2O. The mixture was extracted with
EtOAc, and the extract was washed with brine, dried over MgSO4,
and concentrated in vacuo. The crude product was purified by
column chromatography on silica gel (0–80% EtOAc in petroleum
ether) to afford compound 18 (19.5 mg, 59%) as a white solid.
1H NMR (400 MHz, CDCl3) d=6.68 (d, J=2.2 Hz, 1H), 6.53 (d, J=
2.2 Hz, 1H), 6.45–6.38 (m, 1H), 6.35 (dd, J=11.7, 1.3 Hz, 1H), 5.53–
5.45 (m, 1H), 5.19–5.12 (m, 4H), 4.00–3.93 (m, 1H), 3.54–3.49 (m,
1H), 3.49 (s, 3H, OCH3), 3.48 (s, 3H, OCH3), 3.16 (dt, J=16.5, 9.1 Hz,
1H), 2.72–2.62 (m, 2H), 2.52–2.45 (m, 1H), 2.45 (s, 3H, CH3), 1.72–
1.57 (m, 4H), 1.45 ppm (d, J=6.4 Hz, 3H, CH3); 13C NMR (100 MHz,
CDCl3) d=173.2, 169.6, 168.0, 158.8, 155.1, 143.4, 141.5, 125.2,
118.9, 109.8, 101.1, 94.7, 94.4, 70.9, 56.2, 56.1, 43.9, 36.3, 33.1, 28.8,
27.2, 26.6, 20.5 ppm; HRMS (ESI-TOF) m/z calcd for C23H31NO8Na
[M+Na]+: 472.1942, found: 472.1956.
(S,Z)-16-Hydroxy-14-(methoxymethoxy)-3-methyl-3,4,9,10,11,12-
hexahydro-1H-benzo[l][1,7]oxaazacyclotetradecine-1,7(8H)-dione
(16): A solution of 15 (7 mg, 16.6 mmol) in THF (0.5 mL) was added
to a suspension of 60% NaH in mineral oil (5 mg, 83 mmol) in anhy-
drous THF (1 mL) at 08C and the mixture was stirred for 90 min
upon being warmed to RT before being quenched by addition of
saturated NH4Cl. The organic phase was extracted with EtOAc
(2 mLꢁ3), washed with brine, dried over MgSO4, and concentrated
to give a crude product which was purified by column chromatog-
raphy on silica gel (0–100% EtOAc in petroleum ether) to afford
compound 16 (4.5 mg, 75%) as a white solid. 1H NMR (400 MHz,
CDCl3) d=11.70 (s, 1H, OH), 6.50 (d, J=2.5 Hz, 1H), 6.40 (d, J=
2.5 Hz, 1H), 5.99 (dd, J=11.5, 1.7 Hz, 1H), 5.90 (dt, J=11.4, 5.7 Hz,
1H), 5.54 (brs, 1H, NH), 5.41–5.33 (m, 1H), 5.17 (s, 2H), 3.84–3.75
(m, 1H), 3.46 (s, 3H, OCH3), 3.50–3.39 (m, 1H), 3.30–3.22 (m, 1H),
2.98–2.86 (m, 1H), 2.78–2.70 (m, 1H), 2.44–2.37 (m, 1H), 1.94–1.51
(m, 4H), 1.43 ppm (d, J=6.3 Hz, 3H, CH3); 13C NMR (100 MHz,
[D6]acetone) d=172.2, 167.9, 166.0, 162.4, 148.4, 136.3, 128.4,
128.4, 110.1, 101.9, 94.7, 73.2, 56.3, 40.7, 36.0 (2C), 28.1, 27.7,
21.1 ppm; MS (ESI): m/z (%): 362 [MꢀH]ꢀ (100).
(S,Z)-8-Acetyl-16-hydroxy-14-(methoxymethoxy)-3-methyl-3,4,9,
10,11,12-hexahydro-1H-benzo[l][1,7]oxaazacyclotetradecine-1,7
(8H)-dione (19): 1m TFA in CH2Cl2 (200 mL) was added to a solution
of 18 (2 mg, 4.5 mmol) in CH2Cl2 (1 mL). The mixture was stirred at
RT for 30 min, a few drops of saturated NaHCO3 was added to
adjust the solution to ~pH 7. After removal of CH2Cl2, EtOAc and
H2O were added. The organic phase was extracted with EtOAc and
the extracts were washed with brine, dried over MgSO4, and con-
centrated in vacuo. The crude product was purified by column
chromatography on silica gel (0–50% EtOAc in petroleum ether) to
afford compound 19 (1.3 mg, 70%) as a white solid. 1H NMR
(400 MHz, CDCl3) d=11.85 (s, 1H, OH), 6.50 (d, J=2.5 Hz, 1H), 6.33
(d, J=2.5 Hz, 1H), 6.32 (dd, J=11.6, 1.9 Hz, 1H, overlapped), 6.12
(ddd, J=11.6, 10.2, 3.7 Hz, 1H), 5.55–5.47 (m, 1H), 5.16 (s, 2H),
4.08–4.02 (m, 1H), 3.46 (s, 3H, OCH3), 3.37–3.28 (m, 1H), 3.12–2.93
(m, 2H), 2.74–2.66 (m, 1H), 2.55–2.45 (m, 1H), 2.43 (s, 3H, COCH3),
1.98–1.87 (m, 1H), 1.62–1.45 (m, 3H, overlapped), 1.43 ppm (d, J=
6.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) d=173.0, 171.3, 170.7,
165.8, 161.6, 147.1, 140.4, 127.0, 111.0, 105.7, 101.8, 93.9, 72.3, 56.3,
44.4, 36.4, 36.0, 29.8, 28.7, 26.2, 20.6 ppm; HRMS (ESI-TOF) m/z
calcd for C21H26NO7 [MꢀH]ꢀ: 404.1716, found: 404.1715.
(S,Z)-14,16-Dihydroxy-3-methyl-3,4,9,10,11,12-hexahydro-1H-
benzo[l][1,7]oxaazacyclotetradecine-1,7(8H)-dione (12): Com-
pound 12 was prepared by MOM deprotection of 16 following the
procedures for the synthesis of 11. 30 mg of 16 afforded 28.1 mg
(quant.) of 12. 1H NMR (400 MHz, MeOD) d=6.23 (d, J=2.4 Hz,
1H), 6.14 (d, J=2.4 Hz, 1H), 6.03 (dd, J=11.7, 1.5 Hz, 1H), 5.97
(ddd, J=11.7, 10.3, 4.8 Hz, 1H), 5.37–5.28 (m, 1H), 3.58–3.52 (m,
1H), 3.34–3.25 (m, 1H, overlapped), 3.18–3.07 (m, 1H), 3.02–2.95
(m, 1H), 2.72–2.63 (m, 1H), 2.52–2.45 (m, 1H), 1.81–1.55 (m, 4H),
1.40 ppm (d, J=6.3 Hz, 3H, CH3); 13C NMR (100 MHz, MeOD) d=
172.6, 170.4, 165.9, 163.6, 148.3, 137.3, 127.7, 110.3, 106.3, 101.7,
73.0, 40.9, 36.7, 36.3, 28.5 (2C), 21.0 ppm; HRMS (ESI-TOF) m/z
calcd for C17H20NO5 [MꢀH]ꢀ: 318.1347, found: 318.1339.
(S,Z)-14,16-Bis(methoxymethoxy)-3-methyl-3,4,9,10,11,12-hexa-
hydro-1H-benzo[l][1,7]oxaazacyclotetradecine-1,7(8H)-dione
(17): A solution of 16 (332 mg, 0.915 mmol) in THF (0.5 mL) was
added to a suspension of 60% NaH in mineral oil (146 mg,
3.66 mmol) in anhydrous THF (2 mL) at 08C and the mixture was
stirred for 10 min followed by addition of MOM-Cl (104 mL,
1.37 mmol). The mixture was stirred for another 90 min at 08C,
quenched by addition of saturated NH4Cl, diluted with H2O, and
extracted with EtOAc (3 mLꢁ3). The combined organic phases
were washed with brine, dried over MgSO4, and concentrated to
(S,Z)-8-Acetyl-14,16-dihydroxy-3-methyl-3,4,9,10,11,12-hexahy-
dro-1H-benzo[l][1,7]oxaazacyclotetradecine-1,7(8H)-dione
(20)
and (S,E)-8-Acetyl-14,16-dihydroxy-3-methyl-3,4,9,10,11,12-hexa-
hydro-1H-benzo[l][1,7]oxaazacyclotetradecine-1,7(8H)-dione
(21): Boron trichloride solution (0.16m in CH2Cl2, 0.5 mL) was
added to compound 17 (4.2 mg, 9.3 mmol) at ꢀ108C. The mixture
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2013, 8, 1483 – 1494 1491