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DOI: 10.1055/s-0030-1258547
Practical Total Synthesis of Fuligocandins A and B
Publication History
Publication Date:
26 August 2010 (online)
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Abstract
Fuligocandins A and B, cycloanthranilylproline derivatives isolated from the myxomycete Fuligo candida, were synthesized efficiently by a Meyer-Schuster rearrangement, which gave Z-isomer with high selectivity. The absolute stereochemistry at C-11a of the natural products was determined to be S by comparison of the optical rotation of the natural products with synthetic counterparts derived from l-proline. This report is the first total synthesis of optically active fuligocandin B.
Key words
total synthesis - fuligocandin - Meyer-Schuster rearrangement - myxomycete - TRAIL
- Supporting Information for this article is available online:
- Supporting Information
- 1
Nakatani S.Yamamoto Y.Hayashi M.Komiyama K.Ishibashi M. Chem. Pharm. Bull. 2004, 52: 368 - 2
Hasegawa H.Yamada Y.Komiyama K.Hayashi M.Ishibashi M.Sunazuka T.Izuhara T.Sugahara K.Tsuruda K.Masuda M.Takasu N.Tsukasaki K.Tomonaga M.Kamihira S. Blood 2007, 110: 1664 - 3 For a reported synthesis of fuligocandin
A, see:
More SS.Shanmughapriya D.Lingam Y.Patel NB. Synth. Commun. 2009, 39: 2058 - 4 For the synthesis of racemic fuligocandins
A and B, see:
Pettersson B.Hasimbegovic V.Bergman J. Tetrahedron Lett. 2010, 51: 238 - 5 For a reported Meyer-Schuster
rearrangement of N-Boc lactam, see:
Sun C.Lin X.Weinreb S. J. Org. Chem. 2006, 71: 3159 - 7 A Meyer-Schuster rearrangement
of N-alkylated succinimide gave E-isomer as a main product:
Mamouni A.Daïch A.Decroix B. Synth. Commun. 1998, 28: 1839
References and Notes
NOE (5.0%) was observed between α-proton of α,β-unsaturated ketone and a proton at C-1 position in five-membered ring.
8The ee was determined by a chiral phase HPLC; CHIRALPAK AD-RH, MeOH-H2O = 75:25, flow rate: 1 mL/min, λ = 254 nm detection, t R = 11.5 min [(ent)-1)], t R = 14.3 min (1) {or CHIRALPAK IA, hexane-i-PrOH = 4:1, flow rate: 0.5 mL/min, λ = 254 nm detection, t R = 18.6 min [(ent)-1)], tR = 29.7 min (1)}. Natural product 1: >99% ee.
9Racemization was checked by comparing retention times of 8 with 9, 10 with 11 by CHIRALPAK AD-RH.
10Optical rotation of (ent)-1 (52% ee): [α]¹8 D -224 (c = 1.4, MeOH).
11Compound 1 which was synthesized at 0 ˚C was used for the synthesis of 2. Therefore, the ee of 2 was not decreased by this reaction. The ee was determined by a chiral phase HPLC; CHIRALPAK AD-RH, MeOH-H2O = 1:1, flow rate: 1 mL/min, λ = 370 nm detection, t R = 56.3 min [(ent)-2], t R = 68.1 min (2) {or CHIRALPAK IA, hexane- i-PrOH = 4:1, flow rate: 0.5 mL/min, λ = 370 nm detection, t R = 58.7 min [(ent)-2)], t R =79.1 min (2)}. Natural product 2: >99% ee.
12Optical rotation of (ent)-2 (57% ee): [α]¹8 D -181 (c = 0.6, MeOH).
13
(
S
)-1-(2-
tert
-Butoxycarbonylaminobenzoyl)pyrrolidine-2-carboxylic
Acid Methyl Ester (6): A solution of 3 (167 mg,
0.70 mmol), PyBOP (474 mg, 0.91 mmol), and DIPEA (0.48 mL, 2.80
mmol) in CH2Cl2 (7.0 mL) was cooled to 0 ˚C
under an argon atmosphere. The mixture was stirred for 10 min, and
then l-proline methyl ester hydrochloride
(4, 151 mg, 0.91 mmol) was added. The reaction
mixture was allowed to warm to r.t. and stirred for 1 h. The reaction mixture
was quenched with 5% aq KHSO4 solution and extracted
with EtOAc. The combined organic layers were washed with sat. aq
NaHCO3 solution, brine, dried over Na2SO4,
filtered and concentrated in vacuo. The residue was chromatographed
on silica gel (hexane-EtOAc, 1:1) to afford 6 (210
mg, 0.60 mmol, 86%) as a white amorphous solid. Data for 6: ¹H NMR (400 MHz,
CDCl3): δ = 8.37 (br s, 1 H), 8.18
(d, 1 H, J = 8.3 Hz), 7.36-7.40
(m, 2 H), 7.01 (t, 1 H, J = 7.6
Hz), 4.67-4.71 (m, 1 H), 3.79 (s, 3 H), 3.58-3.64
(m, 1 H), 3.48-3.54 (m, 1 H), 2.32-2.41 (m, 1
H), 1.95-2.08 (m, 2 H), 1.85-1.92 (m, 1 H), 1.50
(s, 9 H). ¹³C NMR (100 MHz, CDCl3): δ = 172.6,
168.8, 153.0, 137.3, 131.0, 127.2, 123.5, 121.6, 120.2, 80.3, 59.1,
52.5, 50.0, 29.4, 28.3, 25.3. IR (ATR): 3336, 2978, 1730, 1625,
1588, 1522, 1456, 1416, 1242, 1199, 1158 cm-¹.
EIMS: m/z = 348 [M+].
HRMS (EI): m/z [M+] calcd
for C17H24N2O5: 348.1685;
found: 348.1689.
(11a
S
)-10-
tert
-Butoxycarbonyl-2,3-dihydro-1
H
-pyrrolo-[2,1-
c
][1,4]benzodiazepine-5,11
(10H,11aH)dione (8):
To a stirred solution of 6 (210 mg, 0.60 mmol) in solvent (THF-MeOH-H2O = 3:1:1,
2.0 mL) was added LiOH×H2O (50 mg, 1.2 mmol) at 0 ˚C.
The solution was stirred for 5 h at r.t. The reaction mixture was
acidified with 1 M aq HCl to pH 2, then extracted with EtOAc. The
organic layer was washed with brine, dried over Na2SO4,
filtered and concentrated in vacuo to afford (S)-1-(2-tert-butoxycarbonyl-aminobenzoyl)pyrrolidine-2-carboxylic
acid (195 mg) as a white powder. To a solution of the carboxylic
acid and PyBOP (406 mg, 0.75 mmol) in CH2Cl2 (20
mL) was added DIPEA (0.42 mL, 2.32 mmol) at 0 ˚C under
an argon atmosphere. The reaction mixture was allowed to warm to r.t.
and stirred for 72 h. The reaction mixture was quenched with 5% aq
KHSO4 and extracted with EtOAc. The organic layer was
washed with sat. aq NaHCO3 solution, brine, dried over
Na2SO4, filtered and concentrated in vacuo.
The residue was chromatographed on silica gel (hexane-EtOAc = 1:5)
to afford 8 (148 mg, 0.47 mmol, 79% in
2 steps) as a white amorphous solid. Data for 8: [α]¹4
D +157
(c = 1.0, MeOH). ¹H
NMR (400 MHz, CDCl3): δ = 7.91 (dd,
1 H, J = 1.5, 7.8 Hz), 7.51
(dt, 1 H, J = 1.5, 7.8 Hz),
7.41 (dt, 1 H, J = 1.2, 7.8 Hz),
7.23 (dd, 1 H, J = 1.2, 7.8
Hz), 4.06-4.15 (m, 1 H), 3.82-3.87 (m, 1 H), 3.52-3.59
(m, 1 H), 2.69-2.73 (m, 1 H), 2.09-2.16 (m, 1
H), 1.94-2.07 (m, 2 H), 1.46 (s, 9 H). ¹³C NMR
(100 MHz, CDCl3): δ = 169.1, 164.9,
150.6, 135.3, 131.2, 130.9, 129.7, 127.4, 126.1, 84.6, 58.8, 46.6,
27.5, 26.3, 23.5. IR (ATR): 2979, 1773, 1748, 1716, 1646, 1457, 1416,
1238, 1144 cm-¹. EIMS: m/z = 316 [M+].
HRMS: (EI): m/z [M+] calcd
for C17H20N2O4: 316.1423;
found: 316.1431.
(11a
S
)-10-
tert
-Butoxycarbonyl-2,3-dihydro-11-hydroxy-11-prop-1-ynyl-1
H
-pyrrolo[2,1-
c
][1,4]benzodiazepine-5,11
(10H,11aH)dione (10): To a solution
of prepared LDA (9.0 mmol) in THF (90 mL) was added 1,2-dibromopropane (0.31
mL, 3.0 mmol) at -78 ˚C under an argon atmosphere. The
solution was stirred for 10 min at this temperature, and another
20 min at 0 ˚C. The resulting lithium acetylide solution
was then transferred to a THF solution of 8 (624
mg, 2.0 mmol) via cannula at -78 ˚C. The mixture
was then stirred at -78 ˚C for 40 min and sat.
aq NH4Cl solution was added slowly. The mixture was extracted
with EtOAc and the organic extracts were dried over Na2SO4,
filtered and concentrated in vacuo. The residue was chromatographed
on silica gel (hexane-EtOAc, 2:1) to afford a single isomer 10 (329 mg, 0.92 mmol, 46%) as
a white amorphous solid. Data for 10: ¹H
NMR (400 MHz, CDCl3): δ = 8.44 (br
s, 1 H), 8.21 (d, 1 H, J = 7.6
Hz), 7.38 (t, 1 H, J = 7.6 Hz),
7.02 (t, 1 H,
J = 7.6
Hz), 4.80-4.84 (m, 1 H), 3.52-3.66 (m, 2 H), 2.30-2.40
(m, 1 H), 2.06 (s, 3 H), 1.83-2.11 (m, 3 H), 1.51 (s, 9 H). ¹³C
NMR (100 MHz, CDCl3): δ = 185.6, 168.9,
153.0, 137.6, 131.2, 127.3, 123.1, 121.5, 120.2, 92.9, 80.4, 66.5, 29.7,
28.5, 28.3, 25.2, 4.3. IR (ATR): 3336, 2926, 2220, 1727, 1521, 1409,
1340, 1157, 756 cm-¹. EIMS: m/z = 356 [M+].
HRMS (EI): m/z [M+] calcd
for C20H24N2O4: 356.1736;
found: 356.1730.
Fuligocandin A (1):
To a solution of 10 (10 mg, 33.0 mmol) in
CH2Cl2 (0.8 mL) was added TFA (0.8 mL) at -20 ˚C.
The reaction mixture was stirred for 4 h at -20 ˚C.
After addition of toluene, TFA was carefully evaporated in vacuo
at r.t. To this mixture was added sat. aq NaHCO3 solution,
then the mixture was stirred at r.t. The mixture was extracted with CH2Cl2 and
the combined organic layers were dried over Na2SO4,
filtered and concentrated in vacuo. The residue was chromatographed
on silica gel (hexane-EtOAc = 1:1) to afford 1 (7.6 mg, 29.7 µmol, 90%,
70% ee). The ee value was determined by CHIRALPAK AD-RH
(46 × 150 mm); eluent: 75% MeOH; flow rate: 1.0
mL/min; t
R: (ent)-1 (14.4 min), 1 (22.6 min). Data for 1: [α]¹8
D +225
(c = 1.4, MeOH). ¹H
NMR (400 MHz, CDCl3): δ = 12.6 (br
s, 1 H), 7.97 (dd, 1 H, J = 1.5,
7.7 Hz), 7.45 (dt, 1 H, J = 1.5,
7.9 Hz), 7.21 (dt, 1 H, J = 1.5,
7.9 Hz), 7.02 (d, 1 H, J = 7.9
Hz), 5.29 (s, 1 H), 4.30 (d, 1 H, J = 7.9
Hz), 3.78-3.85 (m, 1 H), 3.61-3.69 (m, 1 H), 2.39-2.41
(m, 1 H), 2.20 (s, 3 H), 2.06-2.16 (m, 3 H). ¹³C
NMR (100 MHz, CDCl3): δ = 198.4, 165.7,
158.8, 137.1, 132.4, 131.1, 127.2, 124.4, 122.1, 91.1, 55.3, 46.9,
30.0, 27.0, 23.4. IR (ATR): 2987, 2877, 1629, 1591, 1557, 1406, 1262,
1250, 754, 733, 696, 683 cm-¹. EIMS: m/z = 256 [M+]. HRMS
(EI): m/z [M+] calcd
for C15H16N2O2: 256.1212; found:
256.1211.
Fuligocandin B (2):
To a solution of prepared LDA (0.79 mmol) in THF (4.0 mL) was added 1 (51 mg, 0.20 mmol) in THF via cannula
at -78 ˚C under an argon atmosphere. The solution
was stirred for 30 min at this temperature. The resulting solution
was then transferred to a THF solution of 20 (298
mg, 1.00 mmol) via cannula at -78 ˚C. The solution was
stirred for 20 min at this temperature. The reaction mixture was
allowed to warm to 0 ˚C. The reaction mixture was stirred
for 1 h at 0 ˚C and H2O was then added. The mixture
was extracted with EtOAc. The organic layer was washed with brine,
dried over Na2SO4, filtered and concentrated
in vacuo. The residue was chromatographed on silica gel (hexane-EtOAc = 10:1 → 1:1)
to afford a white solid. The solution of white solid in solvent
(THF-1 N aq HCl = 1:1, 5.0 mL) was stirred for
17 h at r.t. and sat. aq NaHCO3 was then added to it
and the mixture was then extracted with EtOAc. The organic layer
was washed with H2O, brine, dried over Na2SO4,
filtered and concentrated
in vacuo. The residue was chromatographed
on silica gel (hexane-EtOAc = 1:2 → 0:1)
to afford 2 (48 mg, 0.12
mmol,
63%, 61% ee). The ee value was determined by CHIRALPAK
AD-RH (46 × 150 mm); eluent: 50% MeCN; flow rate:
1.0 mL/min; t
R: (ent)-2 (56.3
min), 2 (68.1 min). Data for 2: [α]¹8
D +248
(c = 0.6, MeOH). ¹H
NMR (400 MHz, acetone-d
6): δ = 13.4
(br s, 1 H), 10.9 (br s, 1 H), 8.02 (d, 1 H, J = 8.3
Hz), 7.91 (d, 1 H, J = 15.8
Hz), 7.89 (dd, 1 H, J = 1.7,
7.8 Hz), 7.83 (d, 1 H, J = 2.7
Hz), 7.49-7.54 (m, 2 H), 7.17-7.24 (m, 3 H), 7.13
(d, 1 H, J = 8.1 Hz), 7.02 (d, 1
H, J = 15.8 Hz), 5.81 (s, 1
H), 4.44 (d, 1 H, J = 7.6 Hz), 3.67-3.72
(m, 1 H), 3.55-3.62 (m, 1 H), 2.56-2.63 (m, 1
H), 2.22-2.32 (m, 1 H), 2.05-2.16 (m, 2 H). ¹³C
NMR (100 MHz, acetone-d
6): δ = 190.2,
165.8, 160.4, 138.7, 138.6, 134.9, 133.1, 131.9, 128.2, 126.4, 124.3,
123.8, 123.4, 122.6, 121.6, 121.2, 114.4, 113.0, 93.4, 56.1, 47.4,
27.6, 24.1. IR (ATR): 3250, 1590, 1567, 1270, 1247, 1137, 1106, 754,
738 cm-¹. HRMS (ESI): m/z [M + Na]+ calcd
for C24H21O2N3Na: 406.1514;
found: 406.1526.
TRAIL-Resistance-Overcoming
Activity: To assess the sensitivity to TRAIL, cell viability
was evaluated using a fluorometric microculture cytotoxicity assay
(FMCA). Briefly, AGS cells were seeded in a 96-well plate (6 × 10³ cells
per well) in 200 µL of RPMI medium containing 10% FBS.
Cells were cultured in 24 h and then treated with test samples in
the absence or presence of TRAIL (100 ng/mL), and control
cells were treated with culture medium containing 0.1% DMSO.
After 24 h incubation, the cells were washed with PBS, and 200 µL
of PBS containing fluorescein diacetate (10 µg/mL)
was added to each well. After 1 h incubation at 37 ˚C,
fluorescence was measured in a 96-well scanning spectrofluorometer
(Thermo Electron Corporation) at 538 nm, following excitation at
485 nm.