Journal of Natural Products
Article
To a stirred solution of the crude residue in THF (20 mL) at 0 °C
was added TEA (0.56 mL, 4.00 mmol) and propionyl chloride (3.06
mL, 35.0 mmol). The reaction mixture was stirred at 0 °C for 3 h.
After addition of saturated NaHCO3 (20 mL), the separated aqueous
layer was extracted with EtOAc (3 × 30 mL). The combined organic
extract was washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated in vacuo. The crude residue was purified by silica gel
flash chromatography eluting with hexanes/EtOAc (5:1) to afford 30
(960 mg, 1.85 mmol) as a colorless oil in a yield of 59%: [α]20D +1.80
(c 1.11, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.0 Hz,
4H), 7.30−7.47 (m, 11H), 6.02 (d, J = 7.6 Hz, 1H), 5.18 (m, J = 6.4,
31.1 Hz, 2H), 4.70 (td, J = 5.2, 7.8 Hz, 1H), 3.64 (td, J = 2.1, 6.1 Hz,
2H), 2.23 (q, J = 7.6 Hz, 2H), 1.94−2.07 (m, 1H), 1.74−1.85 (m,
1H), 1.46−1.64 (m, 2H), 1.15 (t, J = 7.6 Hz, 3H), 1.04 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 173.7, 172.8, 135.7, 133.8, 129.8, 128.8,
128.6, 128.4, 127.9, 67.3, 63.2, 52.1, 29.7, 29.2, 28.4, 27.0, 19.4, 9.9
(31.8 s missing); ESIMS m/z 540.2 [M + Na]+; HRESIMS m/z
540.2546 [M + Na]+ (calcd for C31H39NO4NaSi, 540.2548).
for an additional 3 h. To the reaction mixture was added AcOH (0.5
mL); then the solvent was evaporated in vacuo. The crude residue was
purified by silica gel flash chromatography eluting with hexanes/
EtOAc (60:1 → 10:1) to afford coupling product 33 (168 mg, 0.182
mmol) as a colorless oil in a yield of 50%: [α]20 +46 (c 1.66,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.56−7.76 (m, 8H), 7.31−
7.46 (m, 12H), 5.83 (dd, J = 5.6, 9.0 Hz, 1H), 5.03 (s, 1H), 4.68 (dd,
J = 2.7, 5.5 Hz, 1H), 3.80 (s, 3H), 3.68 (t, J = 6.5 Hz, 2H), 3.61−3.66
(m, 1H), 3.54−3.61 (m, 1H), 2.81 (q, J = 7.3 Hz, 2H), 2.14−2.29 (m,
2H), 1.97−2.14 (m, 3H), 1.68−1.80 (m, 1H), 1.55−1.66 (m, 2H),
1.49 (s, 9H), 1.13 (t, J = 7.5 Hz, 3H), 1.01−1.05 (m, 18H); 13C NMR
(100 MHz, CDCl3) δ 179.1, 177.5, 170.0, 169.5, 135.6, 153.6, 135.7,
134.2, 134.0, 129.8, 129.7, 127.8, 127.8, 94.0, 83.3, 64.0, 63.5, 59.6,
59.6, 58.8, 31.7, 30.1, 28.1, 27.3, 27.1, 27.0, 25.8, 25.7, 19.4, 10.0;
ESIMS m/z 941.9 [M + Na]+; HRESIMS m/z 941.4578 [M + Na]+
(calcd for C53H70N2O8Na28Si2, 941.4568).
tert-Butyl ((R)-5-Hydroxy-1-((S)-2-(3-hydroxypropyl)-3-methoxy-
5-oxo-2,5-dihydro-1H-pyrrol-1-yl)-1-oxopentan-2-yl)(propionyl)-
carbamate (34). To a stirred solution of 33 (166 mg, 0.180 mmol) in
THF (5 mL) in a Nalgene bottle at 0 °C was added HF/pyridine
complex (1 mL, 20 mmol, ∼70% HF in pyridine) in pyridine (1 mL).
The reaction mixture was stirred at rt for 5 h, then cooled to 0 °C
again. After carefully neutralizing with saturated NaHCO3, the
aqueous layer was extracted with CH2Cl2 (3 × 30 mL). The
combined organic extract was washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. The crude
residue was purified by silica gel flash chromatography eluting with
Benzyl (R)-2-(N-(tert-Butoxycarbonyl)propionamido)-5-((tert-
butyldiphenylsilyl)oxy)pentanoate (31). To a stirred solution of 30
(513 mg, 0.991 mmol), DIPEA (0.35 mL, 2.00 mmol), and DMAP
(12 mg, 0.098 mmol) in THF (5 mL) at 0 °C was added Boc2O (432
mg, 1.98 mmol). The reaction mixture was refluxed for 1 h. After
addition of brine (5 mL), the separated aqueous layer was extracted
with ether (3 × 20 mL). The combined ethereal extract was dried
over anhydrous MgSO4, filtered, and concentrated in vacuo. The
crude residue was purified by silica gel flash chromatography eluting
with hexanes/EtOAc (30:1 → 1:1) to afford 31 (391 mg, 0.632
hexanes/EtOAc (5:1 → 1:4) to afford diol 34 (69.1 mg, 0.156 mmol)
1
as a colorless oil in a yield of 86%: [α]20 +59 (c 0.47, CHCl3); H
mmol) as a colorless oil in a yield of 63%: [α]20 +9.4 (c 1.06,
D
D
1
NMR (400 MHz, CDCl3) δ 5.96 (dd, J = 6.5, 8.1 Hz, 1H), 5.06 (s,
1H), 4.71 (dd, J = 3.0, 5.5 Hz, 1H), 3.86 (s, 3H), 3.64−3.74 (m, 2H),
3.53−3.64 (m, 2H), 2.70−2.88 (m, 2H), 2.19−2.27 (m, 2H), 2.11−
2.19 (m, 2H), 1.85−1.97 (m, 2H), 1.62−1.74 (m, 1H), 1.54−1.60
(m, 1H), 1.48−1.54 (m, 9H), 1.13 (t, J = 7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 179.6, 177.7, 170.2, 169.8, 153.6, 93.9, 83.7,
62.2, 61.3, 59.2, 59.1, 58.7, 31.8, 29.3, 28.1, 26.2, 25.9, 25.5, 10.0;
ESIMS m/z: 465.3 [M + Na]+; HRESIMS m/z 465.2204 [M + Na]+
(calcd for C21H34N2O8Na, 465.2213).
CHCl3); H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 6.7 Hz, 4H),
7.30−7.45 (m, 11H), 5.33 (dd, J = 5.2, 9.1 Hz, 1H), 5.10−5.20 (m, J
= 1.2, 27.4 Hz, 2H), 3.67 (t, J = 5.9 Hz, 2H), 2.90 (q, J = 7.1 Hz, 2H),
2.25−2.36 (m, 1H), 1.91−2.03 (m, 1H), 1.56−1.66 (m, 1H), 1.47−
1.54 (m, 1H), 1.41 (s, 9H), 1.14 (t, J = 7.3 Hz, 3H), 1.05 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 176.9, 170.8, 152.5, 135.7, 134.1, 129.8,
128.7, 128.4, 128.3, 127.8, 84.0, 67.0, 63.6, 55.9, 31.8, 29.6, 28.0, 27.1,
26.5, 19.4, 9.7; ESIMS m/z 640.2 [M + Na]+; HRESIMS m/z
640.3076 [M + Na]+ (calcd for C36H47NO6NaSi, 640.3070).
tert-Butyl ((R)-5-Chloro-1-((S)-2-(3-chloropropyl)-3-methoxy-5-
oxo-2,5-dihydro-1H-pyrrol-1-yl)-1-oxopentan-2-yl)(propionyl)-
carbamate (35). To a stirred solution of deprotected coupling
intermediate 34 (22 mg, 0.497 mmol) in CCl4 (2 mL) at rt was added
triphenyl phosphine (52.1 mg, 0.198 mmol). The mixture was
refluxed overnight. After addition of hexanes (50 mL), the white
precipitate formed was filtered off; then the filtrate was dried in vacuo.
The crude residue was purified by silica gel flash chromatography
eluting with CH2Cl2/EtOAc (300:1) to afford bis-monochlorinated
coupling intermediate 35 (14.5 mg, 0.030 mmol) as a colorless oil in a
Perfluorophenyl (R)-2-(N-(tert-Butoxycarbonyl)propionamido)-
5-((tert-butyldiphenylsilyl)oxy)pentanoate (32). To a stirred sol-
ution of 31 (220 mg, 0.356 mmol) in MeOH (10 mL) was added Pd/
C (50 mg, 10%). The reaction mixture was hydrogenated under
atmospheric pressure at rt for 1.5 h. The catalyst was removed
through a pad of Celite with MeOH (20 mL), and the filtrate was
concentrated in vacuo. The crude residue was used directly for the
next step without further purification.
To a stirred solution of the crude residue and pentafluorophenol
(73.6 mg, 0.399 mmol) in EtOAc (5 mL) was added DCC (88.1 mg,
0.427 mmol) at 0 °C. The reaction mixture was stirred at rt for 3 h.
After addition of hexanes (15 mL), the white precipitate formed was
filtered off; then the filtrate was dried in vacuo. The crude residue was
purified by silica gel flash chromatography eluting with hexanes/
acetone (30:1) to afford active ester 32 (209 mg, 0.302 mmol) as a
colorless oil in a yield of 84%: [α]20D +4.7 (c 1.27, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.67 (d, J = 6.8 Hz, 4H), 7.33−7.49 (m, 6H),
5.61 (dd, J = 5.5, 8.9 Hz, 1H), 3.70 (t, J = 6.0 Hz, 2H), 2.85−3.07 (m,
2H), 2.30−2.43 (m, 1H), 2.01−2.14 (m, 1H), 1.55−1.71 (m, 2H),
1.52 (s, 9H), 1.19 (t, J = 7.3 Hz, 3H), 1.06 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 176.6, 167.0, 152.0, 135.8, 134.0, 129.8, 127.9, 85.2,
63.4, 55.3, 31.7, 29.3, 28.0, 27.1, 26.5, 19.4, 9.6; 19F NMR (282 MHz,
CDCl3) δ −152.1 (d, J = 18.4 Hz, 2F), −158.2 (t, J = 22.9 Hz, 1F),
−162.7 (t, J = 20.6 Hz, 2F); ESIMS m/z 716.3 [M + Na]+; HRESIMS
m/z 716.2454 [M + Na]+ (calcd for C35H40F5NO6NaSi, 716.2443).
tert-Butyl ((R)-5-((tert-Butyldiphenylsilyl)oxy)-1-((S)-2-(3-((tert-
butyldiphenylsilyl)oxy)propyl)-3-methoxy-5-oxo-2,5-dihydro-1H-
pyrrol-1-yl)-1-oxopentan-2-yl)(propionyl)carbamate (33). To a
stirred solution of methyl tetramate 28 (297.5 mg, 0.726 mmol) in
THF (5 mL) at −50 °C was dropwise added LiHMDS (0.54 mL, 0.54
mmol, 1.0 M in THF). After dropwise addition of 32 (252 mg, 0.363
mmol) in THF (2.5 mL), the reaction mixture was stirred at −40 °C
yield of 61%: [α]20 +71 (c 0.7, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 5.83 (t, J = 7.2 Hz, 1 H), 5.07 (s, 1H), 4.65 (dd, J = 3.1, 5.8
Hz, 1H), 3.87 (s, 3H), 3.52−3.65 (m, 2H), 3.50 (td, J = 2.7, 6.5 Hz,
2H), 2.81 (q, J = 7.4 Hz, 2H), 2.25−2.35 (m, 2H), 1.96−2.06 (m,
2H), 1.88−1.96 (m, 1H), 1.82 (m, 1H), 1.63−1.73 (m, 1H), 1.57−
1.62 (m, 1H), 1.54 (s, 9H), 1.13 (t, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 179.0, 177.6, 169.8, 169.4, 153.5, 94.1, 83.8, 59.2,
59.1, 58.9, 44.9, 44.6, 31.7, 30.0, 28.2, 28.2, 27.0, 26.3, 10.0; ESIMS
m/z 501.4 [M + Na]+; HRESIMS m/z 501.1525 [M + Na]+ (calcd
for C21H32N2O6Na35Cl2, 501.1535).
N-((R)-5-Chloro-1-((S)-2-(3-chloropropyl)-3-methoxy-5-oxo-2,5-
dihydro-1H-pyrrol-1-yl)-1-oxopentan-2-yl)propionamide (19).
Compound 35 (14.0 mg, 0.0292 mmol) was dissolved in TFA/
CH2Cl2 (2 mL, 25%) and stirred at 0 °C for 1 h. The solvent was
evaporated in vacuo. After addition of saturated NaHCO3 (2 mL), the
aqueous layer was extracted with EtOAc (3 × 5 mL). The combined
organic extract was washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The crude residue was purified by
silica gel flash chromatography eluting with hexanes/EtOAc (2:1 →
1:1) to afford 19 (9.4 mg, 0.0247 mmol) as a colorless oil in a yield of
85%: [α]20D +66 (c 0.3, CHCl3); 1H NMR (600 MHz, CDCl3) δ 6.23
(d, J = 8.2 Hz, 1H), 5.72 (td, J = 3.6, 8.4 Hz, 1H), 5.12 (s, 1H), 4.71
L
J. Nat. Prod. XXXX, XXX, XXX−XXX