Stereoseletive total synthesis of 11-α- and 11-β- methoxycurvularins

Article abstract of DOI:10.1055/S-0029-1218621

Total synthesis of 11-α-methoxycurvularin and 11-β- methoxycurvularin has been accomplished in a highly stereoselective manner by utilizing Jacobsen hydrolytic kinetic resolution, Maruoka asymmetric allylation and intramolecular Friedel-Crafts acylation as key steps. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/S-0029-1218621

PAPER
797
Stereoseletive Total Synthesis of 11-a- and 11-b-Methoxycurvularins
11-a-
and
.
11-
b
-Methox
S
ycurvularins . Yadav,* A. Raju, K. Ravindar, B. V. Subba Reddy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500607, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 19 October 2009; revised 24 November 2009
O
3
O
15
O
3
O
15
Abstract: Total synthesis of 11-a-methoxycurvularin and 11-b-
methoxycurvularin has been accomplished in a highly stereoselec-
tive manner by utilizing Jacobsen hydrolytic kinetic resolution,
Maruoka asymmetric allylation and intramolecular Friedel–Crafts
acylation as key steps.
1
1
HO
HO
5
5
11
11
9
9
8
8
7
7
OH
OH
O
OMe
OH
O
OMe
Key words: 11-a-methoxycurvularin,
11-b-methoxycurvularin,
1
2
Jacobsen resolution, Maruoka asymmetric allylation, intramolecu-
lar Friedel–Crafts acylation
O
3
O
15
O
R
O
1
HO
5
11-a-Methoxycurvularin (1) and 11-b-methoxycurvularin
(2) were isolated from the mycelium of the hybrid strain
ME005, which is derived from Penicillium citreoviride
4692 and 6200 (Figure 1).1 These substances showed con-
siderable cytotoxicity against four types of human cancer
cell lines (NCI-H460, MCF-7, SF-268, MIA. Pa Ca-2).2
They have also been found to be specific inhibitors of sea
urchin embryogenesis by acting on components of the mi-
totic apparatus,3 90 (HSP90),4 which is a promising target
for anticancer drug development.5
11
9
HO
8
O
4: R = H
5: R = OH (S)
6: R = OH (R)
7
OH
O
3
Figure 1 11-a-Methoxycurvularin (1), 11-b-methoxycurvularin
(2), curvularin (3) and xestodecalactones A, B and C (4, 5 and 6)
In a continuation of our interest in the total synthesis of
biologically active natural products, we herein report the
total synthesis of 11-a-methoxycurvularin (1) and 11-b-
methoxycurvularin (2) using Jacobsen hydrolytic kinetic
resolution (HKR) and Maruoka asymmetric allylation re-
actions to create the two stereogenic centres. An intramo-
lecular Friedel–Crafts acylation strategy was used to
construct the macrolide.
Structurally, these natural products are 12-membered
macrolides with a fused 1,3-dihydroxy benzene ring; they
are related to a number of compounds isolated from ter-
restrial fungi such as xestodecalactone A, B and C (4, 5
and 6; Figure 1).6 The absolute configurations of 11-a-
methoxycurvularin (1) and 11-b-methoxycurvularin (2)
were determined by Xinfu Pan et al. by their stereoselec-
tive syntheses.7
In our retrosynthetic analysis (Scheme 1), we envisioned
that the construction of 11-a-methoxycurvularin (1) and
O
O
O
O
MeO
OTBS
OH
HO
HO2C
OMe
9
OMe
OH
O
OMe
O
7
11-α-methoxycurvularin (1)
11
O
O
O
O
HO
MeO
OTBS
OH
HO2C
OMe
10
OH
O
OMe
OMe
11-β-methoxycurvularin (2)
8
Scheme 1 Retrosynthetic analysis of 11-a-methoxycurvularin (1) and 11-b-methoxycurvularin (2)
SYNTHESIS 2010, No. 5, pp 0797–0802
x
x
.
x
x
.2
0
1
0
Advanced online publication: 08.01.2010
DOI: 10.1055/s-0029-1218621; Art ID: Z21909SS
© Georg Thieme Verlag Stuttgart · New York

798
J. S. Yadav et al.
PAPER
to give 13a, which was hydrogenated with Pd/C to pro-
vide the primary alcohol 14 in good yield. Alcohol 14 was
oxidized to aldehyde 15 under Swern oxidation condi-
tions.9 Aldehyde 15 was used as a common intermediate
for the synthesis of both 11-a-methoxycurvularin (1) and
11-b-methoxycurvularin (2). Thus, aldehyde 15 was sub-
jected to the Maruoka asymmetric allylation reaction to
establish the C-11 stereocentre of both the natural prod-
ucts by using different 1,1-binaphthol (BINOL) ligands;
we synthesised diastereomers 9 and 10 using (R)-binol
and (S)-binol, respectively (Scheme 2).10
OH
O
OBn
b
c–e
OBn
13
12
A
OTBS
OH
f
9
OTBS
O
H
OTBS
OH
15
g
10
The synthesis of 11-a-methoxycurvularin (1) began with
the secondary alcohol 9, which was protected as its methyl
ether (9a) using sodium hydride and methyl iodide. Sub-
sequently, the TBS protecting group was removed with
tetrabutylammonium fluoride (TBAF) in tetrahydrofuran
to afford compound 16 in good yield. The latter secondary
alcohol was then treated with 3,5-dimethoxyphenyl acetic
acid in the presence of N,N-dicyclohexylcarbodiimide
(DCC) and 4-(N,N-dimethylamino)pyridine (DMAP) to
afford ester 17,11 which was subsequently converted into
carboxylic acid 7 using dihydroxylation followed by sodi-
um metaperiodate (NaIO4) mediated cleavage and oxida-
tion with sodium chlorite (NaClO2). The desired
macrolide 18 was obtained by an intramolecular Friedel–
Crafts acylation reaction with a mixture of trifluoroacetic
acid (TFA) and trifluoroacetic anhydride (TFAA).12 Se-
lective deprotection of the aromatic methoxy groups of
macrolide 18 with freshly prepared aluminium iodide
(AlI3) gave the target natural product 11-a-methoxycur-
vularin (1) in good yield (Scheme 3).13 11-b-Methoxycur-
vularin (2) was synthesized from compound 10 by the
same strategy described for the preparation of 11-a-meth-
oxycurvularin (1). The analytical and spectral data of
Scheme 2 Reagents and conditions: (a) (S,S)-Jacobsen catalyst,
H2O, r.t., 12 h; (b) n-BuLi, BF3·OEt2, THF, –78 °C, 3 h, 65%; (c)
TBSCl, imidazole, CH2Cl2, r.t., 2 h, 95%; (d) 10% Pd/C, H2, EtOAc,
r.t., 10 h, 92%; (e) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C, 1 h, 80%;
(f) allyltri-n-butyltin, Ti(Oi-Pr)4, Ag2O, (R)-BINOL, CH2Cl2, 24 h,
65%; (g) allyltri-n-butyltin, Ti(Oi-Pr)4, Ag2O, (S)-BINOL, CH2Cl2,
24 h, 75%.
11-b-methoxycurvularin (2) could be achieved from car-
boxylic acids 7 and 8. These key acids could be synthe-
sized from compounds 9 and 10, respectively, which, in
turn, could be prepared from propylene oxide (11) by us-
ing Jacobsen resolution and Maruoka asymmetric allyla-
tion.
Accordingly, the synthesis of 11-a-methoxycurvularin (1)
and 11-b-methoxycurvularin (2) began with the Jacobsen
hydrolytic kinetic resolution of propylene oxide (11) to af-
ford (S)-propylene oxide (12).8 The resulting chiral propy-
lene oxide (12) was regioselectively opened with 1-[(2-
propynyloxy)methyl]benzene (A) to provide the second-
ary alcohol (13) in good yield (Scheme 2). Compound 13
was subjected to tert-butyldimethylsilyl (TBS) protection
MeO
CO2H
O
O
MeO
OH
OMe
OTBS
OH
OMe
c
a,b
17
16
9
OMe
OMe
O
O
O
O
O
O
MeO
MeO
HO
g
d–f
h
HO2C
OMe
OMe
a–f
OMe
O
OMe
OH
O
OMe
7
1
18
O
O
O
O
OTBS
OH
HO
MeO
g,h
HO2C
OMe
10
OH
O
OMe
OMe
8
2
Scheme 3 Reagents and conditions: (a) NaH, MeI, THF, 0 °C→r.t., 2 h, 90%; (b) TBAF, THF, 0 °C→r.t., 90%; (c) DCC, DMAP, Et2O, r.t.,
95%; (d) OsO4, NMO, acetone–H2O (8:2), r.t., 2 h, 90%; (e) NaIO4, THF–H2O (2:1), 0 °C→r.t., 1 h, 80%; (f) NaClO2, NaH2PO4·2H2O,
2-methylbut-2-ene, t-BuOH–H2O (4:1), 0 °C→r.t., 12 h, 85%; (g) TFA, TFAA, r.t., 40%; (h) AlI3, TBAI, benzene, 10 °C, 65%.
Synthesis 2010, No. 5, 797–802 © Thieme Stuttgart · New York

PAPER
11-a- and 11-b-Methoxycurvularins
799
TBDMSCl (0.6 g, 8.73 mmol) and the mixture was allowed to stir
at r.t. for 1 h. The reaction mixture was treated with sat. aq NH4Cl
(15 mL), extracted with CH2Cl2 (2 × 20 mL) and the combined or-
ganic layers were washed with H2O (20 mL) and brine (20 mL),
dried over anhydrous Na2SO4 and concentrated in vacuo. The re-
sulting crude residue was purified by column chromatography (sil-
ica gel; EtOAc–hexane, 0.2:9.8) to give 13a.
compounds described here were in agreement those re-
ported in the literature.7
In conclusion, we have demonstrated the stereoselective
total synthesis of 11-a-methoxycurvularin (1) and 11-b-
methoxycurvularin (2) by using the Jacobsen hydrolytic
kinetic resolution,8 Maruoka asymmetric allylation10 and
intramolecular Friedel–Crafts reaction as key steps. Both
of the natural products can be obtained through this sim-
ple, convenient and straightforward synthetic route by
merely changing the chiral ligand in the allylation step.
Yield: 2.4 g (95%); colourless oil; [a]D25 –3.7 (c 1.0, CHCl3).
IR (neat): 2954, 2930, 2889, 2856, 1464, 1356, 1253, 1128, 1092,
998, 833, 775, 738, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.21–7.35 (m, 5 H), 4.56 (s, 2 H),
4.11 (t, J = 2.2 Hz, 2 H), 3.94 (m, 1 H), 2.32 (m, 2 H), 1.23 (d,
J = 6.0 Hz, 3 H), 0.89 (s, 9 H), 0.07 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 137.7, 128.4, 128.0, 127.7, 84.5,
77.4, 71.4, 67.6, 57.7, 29.5, 25.4, 23.3, 18.1, –4.6, –4.7.
Melting points were recorded with a Büchi R-535 apparatus and are
uncorrected. IR spectra were recorded with a Perkin–Elmer FT-IR
240-c spectrophotometer using KBr optics. 1H and 13C NMR spec-
tra were recorded in CDCl3 with either a Gemini-200 or a Varian
Bruker-300 spectrometer using TMS as internal standard. Mass
spectra were recorded with a Finnigan MAT 1020 mass spectrome-
ter operating at 70 eV.
MS (ESI): m/z = [M + Na]+ 341.
HRMS: m/z [M + Na]+ calcd for C19H30O2NaSi: 341.1912; found:
341.1913.
(5S)-5-[1-(tert-Butyl)-1,1-dimethylsilyl]oxyhexan-1-ol (14)
To a stirred solution of 13a (2.36 g, 7.43 mmol) in EtOAc (10 mL),
10% Pd/C (0.037 g) was added and the mixture was stirred under a
H2 atmosphere at r.t. for 12 h. When the reaction was complete the
mixture was filtered through Celite and the filtrate was concentrated
under reduced pressure to furnish 14.
Yield: 1.6 g (92%); colourless oil; [a]D25 +10.7 (c 1.0, CHCl3).
IR (neat): 3347, 2932, 2859, 1465, 1372, 1253, 1057, 834, 774 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.74–3.80 (m, 1 H), 3.62 (t,
J = 6.4 Hz, 2 H), 1.23–1.60 (m, 6 H), 1.11 (d, J = 6.0 Hz, 3 H), 0.88
(s, 9 H), 0.03 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 68.5, 62.9, 39.1, 32.7, 25.8, 23.7,
21.9, 18.0, –4.5, –4.8.
(2S)-2-Methyloxirane (12)
A mixture of (S,S)-(–)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-
cyclohexanediaminocobalt(II) (0.120 g, 0.20 mmol) in toluene (0.3
mL) and AcOH (0.24 g, 0.40 mmol) was stirred under air at r.t. for
1 h. The reaction mixture was concentrated under reduced pressure
and the resulting brown residue was dried under vacuum. The race-
mic epoxide (5.8 g, 100 mmol) was added in one portion at 0 °C
then H2O (1.0 mL, 55 mmol) was added dropwise over 5 min. The
reaction mixture was allowed to stir at r.t. for 16 h. Pure (S)-propy-
lene oxide 12 was isolated by distillation from the reaction mixture
at atmospheric pressure.
Yield: 2.50 g (43%); bp 37 °C; [a]D25 +10.8 (c 1.0, CHCl3).
(2S)-6-(Benzyloxy)-4-hexyn-2-ol (13)
n-BuLi (1.6 M in hexane, 9.45 mL, 15.07 mmol) was added drop-
wise to a solution of 1-[(2-propynyloxy)methyl]benzene (A; 2.0 g,
13.7 mmol) in anhydrous THF (30 mL) at –78 °C under an N2 atmo-
sphere. The mixture was allowed to stir for 30 min, then treated with
BF3·OEt2 (1.9 mL, 15.07 mmol). After 10 min, a solution of (S)-pro-
pylene oxide (12; 2.0 g, 34.48 mmol) in anhydrous THF (10 mL)
was added and the mixture was allowed to stir for a further 3 h at
–78 °C. The reaction mixture was quenched with sat. NaHCO3 (20
mL) then sat. NH4Cl (20 mL) was added at –78 °C. The mixture was
allowed to warm to r.t. then extracted with EtOAc (3 × 20 mL),
washed with H2O (20 mL) and dried over Na2SO4. Removal of sol-
vent followed by purification on silica gel (EtOAc–hexane, 1.5:8.5)
gave 13.
MS (ESI): m/z = 233 [M + H]+.
(5S)-5-[1-(tert-Butyl)-1,1-dimethylsilyl]oxyhexanal (15)
To a stirred solution of oxalyl chloride (0.92 mL, 9.6 mmol) in
CH2Cl2 at –78 °C was added DMSO (0.92 mL,12.8 mmol) followed
by 13b (1.5 g, 6.4 mmol) in CH2Cl2 (10 mL) and the resulting mix-
ture was stirred for 1 h at –78 °C. The reaction was quenched with
Et3N (2.8 mL, 19.2 mmol) and then extracted with CH2Cl2 (3 × 40
mL). The combined organic layers were washed with brine (2 × 10
mL), dried over Na2SO4, and concentrated in vacuo to give the cor-
responding aldehyde 14, which was used directly for further reac-
tion.
Yield: 1.19 g (80%).
Yield: 1.81 g (65%); colourless oil; [a]D25 +9.3 (c 1.0, CHCl3).
IR (neat): 3416, 2970, 2953, 2857, 1452, 1354, 1070, 1026, 938,
741, 698 cm–1.
(4R,8S)-8-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-1-nonen-4-ol
(10)
To a stirred solution of TiCl4 (0.03 mL, 0.25 mmol) in CH2Cl2 (5
mL), was added anhydrous Ti(Oi-Pr)4 (0.19 mL, 0.646 mmol) at
0 °C under an N2 atmosphere and the mixture was allowed to warm
to r.t. After 1 h, (S)-binaphthol (0.24 g, 0.86 mmol) was added at r.t.
and the resulting mixture was stirred for 3 h. The mixture was
cooled to 0 °C, treated with Ag2O (0.09 g, 0.42 mmol) and allowed
to stir at r.t. for 5 h in the dark to furnish chiral bis{[(S)-binaphth-
oxyisopropoxy]titanium}oxide, which was subsequently treated
with compound 15 (0.5 g, 2.15 mol) and allyl-n-tributyltin (0.73
mL, 2.37 mol) at –15 °C. The mixture was warmed to 0 °C and
stirred for 36 h, then quenched with sat. NaHCO3 (5 mL) and ex-
tracted with CH2Cl2 (4 × 30 mL). The combined organic extracts
were washed with brine (10 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. The resulting residue was purified over silica
gel (EtOAc–n-hexane, 1:3.5) to give the allylated product 10.
1H NMR (300 MHz, CDCl3): d = 7.22–7.33 (m, 5 H), 4.56 (s, 2 H),
4.13 (t, J = 2.2 Hz, 2 H), 3.87–3.97 (m, 1 H), 2.27–2.47 (m, 2 H),
1.97 (br s, 1 H), 1.25 (d, J = 5.9 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 137.2, 128.3, 127.9, 127.7, 83.3,
78.1, 71.3, 66.1, 57.1, 29.1, 22.2.
MS (ESI): m/z = 227 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C13H16O2Na: 227.1047; found:
227.1056.
(1S)-5-(Benzyloxy)-1-methyl-3-pentynyloxy[(tert-butyl)dimeth-
ylsilane] (13a)
To an ice-cold solution (0 °C) of 13 (1.62 g, 7.95 mmol) in CH2Cl2
(15 mL), was added imidazole (1.8 g, 11.92 mmol) followed by
Synthesis 2010, No. 5, 797–802 © Thieme Stuttgart · New York

800
J. S. Yadav et al.
PAPER
Yield: 0.46 g (75%); colourless oil; [a]D25 +17.0 (c 1.0, CHCl3).
13C NMR (75 MHz, CDCl3): d = 134.9, 116.7, 80.4, 68.5, 56.5, 39.7,
37.7, 33.4, 25.8, 23.7, 21.6, 0.99, –4.4, –4.7.
IR (neat): 3388, 2956, 2930, 2857, 1464, 1375, 1218, 1137, 1042,
999, 912, 834, 773, 661 cm–1.
MS (ESI): m/z = 287 [M + H]+.
1H NMR (200 MHz, CDCl3): d = 5.70–5.85 (m, 1 H), 5.03–5.12 (m,
2 H), 3.67–3.80 (m, 1 H), 3.51–3.62 (m, 1 H), 2.02–2.30 (m, 2 H),
1.32–1.46 (m, 6 H), 1.07 (d, J = 6.0 Hz, 3 H), 0.85 (s, 9 H), 0.04 (s,
6 H).
HRMS: m/z [M + Na]+ calcd for C16H34O2NaSi: 309.2225; found:
309.2235.
(2S,6S)-6-Methoxy-8-nonen-2-ol (16)
To an ice-cold solution of silyl ether 9a (178 mg, 0.62 mmol) in
THF (10 mL), was added TBAF (1.0 M in THF, 0.80 mL, 0.74
mmol). The resulting solution was stirred at r.t. for 5 h and then di-
luted with sat. NH4Cl (2 mL) and EtOAc (20 mL). The organic layer
was separated and the aqueous layer was extracted with EtOAc
(2 × 20 mL). The combined organic layers were dried over MgSO4
and concentrated under reduced pressure to obtain an oily residue,
which was purified by chromatography (hexane–EtOAc) to afford
16.
13C NMR (75 MHz, CDCl3): d = 134.7, 117.7, 70.4, 68.5, 41.7, 39.5,
36.5, 25.8, 23.7, 21.8, 18.0, –4.5, –4.7.
MS (ESI): m/z = 295 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C15H32O2NaSi: 295.2069; found:
295.2068.
(4S,8S)-8-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-1-nonen-4-ol (9)
To a stirred solution of TiCl4 (0.03 mL, 0.10 mmol) in CH2Cl2 (5
mL), was added anhydrous Ti(Oi-Pr)4 (0.19 mL, 0.64 mmol) at 0 °C
under an N2 atmosphere. After 1 h, (R)-binaphthol (248 mg, 0.87
mmol) was added at r.t. and the resulting solution was stirred for
3 h. The mixture was cooled to 0 °C, treated with Ag2O (99 mg,
0.43 mmol) and stirred at r.t. for 5 h in the dark to furnish chiral
bis{[(R)-binaphthoxyisopropoxy]titanium}oxide, which was then
treated with compound 15 (0.5 g, 2.15 mol) and allyl-n-tributyltin
(0.73 mL, 2.374 mol) at –15 °C. The mixture was warmed to 0 °C
and allowed to stir for 36 h. When the reaction was complete, sat.
NaHCO3 (5 mL) was added and the mixture was extracted with
CH2Cl2 (4 × 30 mL). The organic extracts were washed with brine
(10 mL), dried over anhydrous Na2SO4 and concentrated in vacuo.
The resulting crude residue was purified by column chromatogra-
phy using silica gel (EtOAc–n-hexane, 1:3.5) to give the allylated
product 9.
Yield: 95 mg (90%); colourless oil; [a]D25 +5.7 (c 1.0, CHCl3).
IR (neat): 3408, 3076, 2927, 2857, 1641, 1460, 1372, 1096, 995,
913, 770 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.59–5.82 (m, 1 H), 4.90–5.08 (m,
2 H), 3.61–3.81 (m, 1 H), 3.33 (s, 3 H), 3.11–3.22 (m, 1 H), 2.03–
2.29 (m, 2 H), 1.26–1.49 (m, 6 H), 1.18 (d, J = 6.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 134.7, 116.8, 80.3, 68.8, 56.5, 39.2,
37.6, 33.2, 23.4, 21.7.
MS (ESI): m/z = 173 [M + H]+.
HRMS: m/z [M + Na]+ calcd for C10H20O2Na: 195.1360; found:
195.1365.
(1S,5S)-5-Methoxy-1-methyl-7-octenyl 2-(3,5-Dimethoxyphe-
nyl)acetate (17)
Yield: 0.40 g (65%); colourless oil; [a]D25 +5.7 (c 0.5, CHCl3).
To a solution of 16 (88 mg, 0.51 mmol) and 3,5-dimethoxyphenyl-
acetic acid (120 mg, 0.61 mmol) in anhydrous Et2O (20 mL) at r.t.,
was added DCC (127 mg, 0.613 mmol) and DMAP (7 mg, 0.3
mmol). After stirring for 3 h at r.t., the mixture was filtered. The fil-
trate was diluted with Et2O (100 mL) and washed with brine (3 × 10
mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography (hexanes–EtOAc,
10:1) to afford compound 17.
IR (neat): 3388, 2956, 2930, 2857, 1464, 1375, 1218, 1137, 1042,
999, 912, 834, 773, 661 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.70–5.87 (m, 1 H), 5.03–5.13 (m,
2 H), 3.68–3.79 (m, 1 H), 3.55–3.65 (m, 1 H), 1.74–1.53 (m, 2 H),
1.32–1.46 (m, 6 H), 1.08 (d, J = 6.0 Hz, 3 H), 0.84 (s, 9 H), 0.05 (s,
6 H).
13C NMR (75 MHz, CDCl3): d = 134.7, 118.3, 70.5, 68.3, 41.9, 39.5,
36.7, 25.7, 23.7, 21.6, 17.4, –4.4, –4.7.
Yield: 160 mg (90%); colourless oil; [a]D25 +8.3 (c 1.0, CHCl3).
MS (ESI): m/z = 295 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C15H32O2NaSi: 295.2069; found:
IR (neat): 3446, 2932, 1787, 1728, 1602, 1461, 1294, 1206, 1154,
1095, 915, 770, 687 cm–1.
295.2068.
1H NMR (300 MHz, CDCl3): d = 6.37 (d, J = 1.8 Hz, 2 H), 6.29 (t,
J = 2.0 Hz, 1 H), 5.61–5.81 (m, 1 H), 4.92–5.06 (m. 2 H), 4.77–4.91
(m, 1 H), 3.71 (s, 6 H), 3.45 (s, 2 H), 3.25 (s, 3 H), 3.01–3.13 (m,
1 H), 2.07–2.28 (m, 2 H), 1.24–1.63 (m, 6 H), 1.17 (d, J = 6.2 Hz,
3 H).
13C NMR (75 MHz, CDCl3): d = 170.9, 160.7, 136.3, 134.7, 116.8,
107.1, 99.4, 80.3, 71.4, 56.5, 55.2, 42.0, 37.6, 35.8, 33.0, 21.0, 19.8.
tert-Butyl[(1S,5S)-5-methoxy-1-methyl-7-octenyl]oxydimethyl-
silane (9a)
To a suspension of NaH (60 mg, 2.34 mmol) in THF (10 mL), was
added alcohol 9 (0.32 g, 1.17 mmol) at 0 °C. After stirring for 20
min, MeI (0.2 g, 1.41 mmol) was added slowly and the resulting
mixture was stirred for a further 2 h. After completion, the reaction
was quenched with ice-cold H2O (10 mL) and extracted with EtOAc
(3 × 10 mL). The combined organic layers were dried over anhy-
drous Na2SO4, the solvent was evaporated under reduced pressure,
and the residue was purified by column chromatography (EtOAc–
n-hexane, 1:3.5) to afford 9a.
MS (ESI): m/z = 368 [M + NH4]+.
HRMS: m/z [M + Na]+ calcd for C20H30O5Na: 373.1990; found:
373.1993.
(3S,7S)-7-[2-(3,5-Dimethoxyphenyl)acetyl]oxy-3-methoxyoc-
tanoic Acid (7)
Yield: 0.3 g (90%); pale-yellow oil; [a]D25 +7.7 (c 0.75, CHCl3).
To a solution of the alkene 17 (150 mg, 0.42 mmol) in a mixture of
t-BuOH (16 mL) and H2O ( 4 mL), was added NMO (50% by wt. in
H2O, 1.12 mL, 2.13 mmol) and OsO4 (10 mg, 0.042 mmol) and the
resulting mixture was stirred at r.t. for 12 h. The mixture was
quenched by addition of granular NaHSO4 (100 mg). After stirring
for 15 min, the mixture was filtered and the filtrate was concentrated
in vacuo. The crude residue was diluted with EtOAc (150 mL) and
brine (50 mL), the organic layer was separated and the aqueous lay-
IR (neat): 3450, 2928, 2857, 1734, 1639, 1462, 1372, 1255, 1097,
1035, 911, 832, 804, 767, 408 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.83–5.95 (m, 1 H), 5.11–5.21 (m,
2 H), 3.82–3.92 (m, 1 H), 3.22 (s, 3 H), 3.12–3.19 (m, 1 H), 2.17–
2.29 (m, 2 H), 1.31–1.47 (m, 6 H), 1.10 (d, J = 5.8 Hz, 3 H), 0.88 (s,
9 H), 0.03 (s, 6 H).
Synthesis 2010, No. 5, 797–802 © Thieme Stuttgart · New York

PAPER
11-a- and 11-b-Methoxycurvularins
801
er was extracted with EtOAc (3 × 50 mL). The combined organic
layers were dried over anhydrous MgSO4 and concentrated in vac-
uo. The crude diol was taken into a mixture of acetone (14 mL) and
H2O (4 mL) and solid NaIO4 (184 mg, 0.84 mmol) was added. The
resulting white suspension was stirred at r.t. for 1 h, filtered, and the
filtrate was concentrated in vacuo. The residue was diluted with
Et2O (25 mL) and H2O (10 mL), the layers were separated and the
aqueous layer was extracted with Et2O (3 × 20 mL). The combined
organic layers were dried over anhydrous MgSO4 and concentrated
in vacuo. The crude product was purified by flash column chroma-
tography (hexanes–EtOAc, 9:1) to give the aldehyde (68 mg, 80%),
which was used directly for further reaction. To a stirred solution of
the crude aldehyde (60 mg, 0.19 mmol) were added 2-methylbut-2-
ene (5 mL), t-BuOH (10 mL) and a solution of NaClO2 (50 mg, 0.57
mmol, 80%), NaH2PO4 (70 mg, 0.57 mmol) and H2O (5 mL). After
stirring at r.t. for 1.5 h, the reaction mixture was diluted with H2O
(50 mL) and extracted with Et2O (3 × 50 mL). The combined organ-
ic layers were dried over anhydrous Na2SO4 and evaporated in vac-
uo to give 7.
Yield: 73 mg (85%); colourless oil; [a]D25 +9.3 (c 1.0, CHCl3).
IR (neat): 3449, 2930, 1726, 1599, 1462, 1295, 1258, 1204, 1156,
1064, 771, 683 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.38 (s, 2 H), 6.29 (s, 1 H), 4.83–
4.96 (m, 1 H), 3.76 (s, 6 H), 3.51 (m, 1 H), 3.47 (s, 2 H), 3.32 (s,
3 H), 2.48 (dd, J = 15.2, 6.9 Hz, 1 H), 2.37 (dd, J = 15.2, 5.4 Hz,
1 H), 1.24–1.63 (m, 6 H), 1.21 (d, J = 6.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 175.6, 171.2, 170.3, 160.9, 136.2,
107.3, 99.2, 77.3, 71.2, 56.8, 55.2, 41.9, 38.9, 35.6, 33.3.
MS (ESI): m/z = 286 [M + NH4]+.
HRMS: m/z [M + Na]+ calcd for C19H28O7Na: 391.1732; found:
391.1714.
(4S,8S)-11,13-Dihydroxy-8-methoxy-4-methyl-1,4,5,6,7,8,9,10-
octahydro-2H-3-benzoxacyclododecine-2,10-dione (1)
Iodine (542 mg, 1.54 mmol) was added to a mixture of aluminium
(77 mg, 3 mmol) in anhydrous benzene (4 mL). The mixture was re-
fluxed for 0.5 h and cooled to 0 °C, then TBAI (2 mg) and com-
pound 18 (25 mg, 0.07 mmol) in benzene (2 mL) were added. The
mixture was stirred for 15 min at 0 °C, then quenched with 2 N HCl
(5 mL) at 0 °C and extracted with EtOAc (3 × 20 mL). The organic
phase was washed with sat. NaHCO3 (3 mL) and brine (5 mL), dried
over anhydrous Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography (hexanes–EtOAc, 2:1) to af-
ford the target molecule 1.
Yield: 70 mg (85%); colourless oil; [a]D25 +9.7 (c 1.0, CHCl3).
IR (neat): 3449, 2930, 1726, 1599, 1462, 1295, 1258, 1204, 1156,
1064, 771, 683 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.38 (s, 2 H), 6.29 (s, 1 H), 4.83–
4.96 (m, 1 H), 3.76 (s, 6 H), 3.51 (m, 1 H), 3.47 (s, 2 H), 3.32 (s,
3 H), 2.48 (dd, J = 15.2, 6.9 Hz, 1 H), 2.37 (dd, J = 15.2, 5.4 Hz,
1 H), 1.24–1.63 (m, 6 H), 1.21 (d, J = 6.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 175.6, 171.2, 170.3, 160.9, 136.2,
107.3, 99.2, 77.3, 71.2, 56.8, 55.2, 41.9, 38.9, 35.6, 33.3.
MS (ESI): m/z = 286 [M + NH4]+.
Yield: 15 mg (65%); colourless oil; [a]D25 –16.3 (c 1.0, EtOH).
IR (neat): 3393, 2924, 2854, 1714, 1622, 1454, 1320, 1260, 1170,
1030, 844, 758, 645 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.30 (d, J = 2.0 Hz, 1 H), 6.23 (d,
J = 2.0 Hz, 1 H), 4.90 (t, J = 6.9 Hz, 1 H), 3.87 (d, J = 15.7 Hz,
1 H), 3.82 (d, J = 3.6 Hz, 1 H), 3.72 (dd, J = 15.6, 6.9 Hz, 1 H), 3.40
(d, J = 12.0 Hz, 1 H), 3.35 (s, 3 H), 3.04 (dd, J = 14.8, 8.8 Hz, 1 H),
1.52–1.65 (m, 6 H), 1.20 (d, J = 7.2 Hz, 3 H).
HRMS: m/z [M + Na]+ calcd for C19H28O7Na: 391.1732; found:
391.1714.
(4S,8S)-8,11,13-Trimethoxy-4-methyl-1,4,5,6,7,8,9,10-octahy-
dro-2H-3-benzoxacyclododecine-2,10-dione (18)
13C NMR (75 MHz, CDCl3): d = 205.0, 172.0, 160.2, 159.1, 135.3,
120.0, 113.4, 102.9, 77.0, 74.0, 55.6, 49.1, 39.7, 32.7, 31.8, 20.8,
17.2.
MS (ESI): m/z = 345 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C17H22O6Na: 345.1309; found:
Compound 7 (50 mg, 0.21 mmol) was dissolved in a mixture of
TFA (6 mL) and TFAA (1 mL) under an argon atmosphere. The so-
lution was stirred overnight at r.t. and then poured into sat. NaHCO3
(50 mL), extracted with Et2O (3 × 50 mL), dried over anhydrous
Na2SO4 and concentrated in vacuo. The residue was purified by col-
umn chromatography (hexanes–EtOAc, 5:1) to give the metabolite
18.
345.1315.
Yield: 30 mg (40%); colourless oil; [a]D25 –4.7 (c 1.0, CHCl3).
(4S,8R)-11,13-Dihydroxy-8-methoxy-4-methyl-1,4,5,6,7,8,9,10-
octahydro-2H-3-benzoxacyclododecine-2,10-dione (2)
Compound 2 was obtained from 10 by the same procedure as de-
scribed for 7.
IR (neat): 3383, 2929, 1729, 1657, 1603, 1471, 1317, 1163, 1085,
1022, 849 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.46 (d, J = 1.8 Hz, 1 H), 6.44 (d,
J = 1.8 Hz, 1 H), 6.30 (d, J = 15.0 Hz, 1 H), 4.89 (t, J = 6.4 Hz,
1 H), 3.86 (s, 2 H), 3.84 (s, 3 H), 3.77 (s, 3 H), 3.40 (d, J = 4.2 Hz,
3 H), 2.35 (dd, J = 13.0, 6.4 Hz, 1 H), 2.30 (t, J = 6.4 Hz, 1 H), 2.20
(dd, J = 15.0, 8.4 Hz, 1 H), 1.80–1.93 (m, 1 H), 1.41–1.60 (m, 4 H),
1.17 (d, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 197.3, 170.1, 162.0, 160.0, 156.7,
133.7, 132.8, 123.9, 107.2, 97.6, 78.1, 66.0, 55.9, 54.3, 40.3, 34.3,
34.0, 24.2, 20.1.
Yield: 12.9 mg (70%); colourless oil; [a]D25 –3.2 (c 1.0, EtOH).
IR (neat): 3392, 2925, 2853, 1711, 1620, 1454, 1321, 1268, 1169,
1031, 844, 758, 644 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.37 (d, J = 2.4 Hz, 1 H), 6.13 (d,
J = 2.4 Hz, 1 H), 5.12 (t, J = 6.0 Hz, 1 H), 3.97 (d, J = 15.7 Hz,
1 H), 3.79 (d, J = 14.1 Hz, 1 H), 3.58 (d, J = 16.5 Hz, 1 H), 3.33 (d,
J = 5.2 Hz, 1 H), 3.25 (s, 3 H), 3.12 (dd, J = 14.1, 8.1 Hz, 1 H),
1.53–1.85 (m, 6 H), 1.24 (d, J = 5.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 204.2, 171.8, 160.1, 159.4, 135.0,
118.3, 113.4, 102.7, 74.9, 72.8, 54.1, 49.3, 41.0, 31.3, 30.6, 19.0,
17.3.
MS (ESI): m/z = 373.0 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C19H26O6Na: 373.1627; found:
373.1623.
MS (ESI): m/z = 345 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C17H22O6Na: 345.1309; found:
(3R,7S)-7-[2-(3,5-Dimethoxyphenyl)acetyl]oxy-3-methoxyoc-
tanoic Acid (8)
Compound 8 was obtained from 10 by the same procedure as de-
scribed for 7.
345.1313.
Synthesis 2010, No. 5, 797–802 © Thieme Stuttgart · New York

802
J. S. Yadav et al.
PAPER
(6) Edrada, R. A.; Heubes, M.; Brauers, G.; Wray, V.; Berg, A.;
Gräfe, U.; Wohlfarth, M.; Mühlbacher, J.; Schaumann, K.;
Sudarsono, S.; Bringmann, G.; Proksch, P. J. Nat. Prod.
2002, 65, 1598.
Acknowledgment
A.R. and K.R. thank the CSIR, New Delhi, for the award of fel-
lowships.
(7) (a) Liang, Q.; Sun, Y.; Yu, B.; She, X.; Pan, X. J. Org. Chem.
2007, 72, 9846. (b) Reddy, G. V.; Kumar, S. C. R.; Babu, K.
S.; Rao, J. M. Tetrahedron Lett. 2009, 50, 4117.
(8) (a) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga,
M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen,
E. N. J. Am. Chem. Soc. 2002, 124, 1307. (b) Louis, J. T.;
Nelson, W. L. J. Org. Chem. 1987, 52, 1309.
(9) Corey, E. J.; Marafat, A.; Laguzza, B. C. Tetrahedron Lett.
1981, 22, 3339.
(10) Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc.
2003, 125, 1708.
References
(1) Lai, S.; Shizuri, Y.; Yamamura, S.; Kawai, K.; Furukawa, H.
Bull. Chem. Soc. Jpn. 1991, 64, 1048.
(2) (a) He, J.; Wijeratne, E. M. K.; Bashyal, B. P.; Zhan, J.;
Seliga, C. J.; Liu, M. X.; Pierson, E. E.; Pierson, L. S. III.;
VanEtten, H. D.; Gunatilaka, A. A. L. J. Nat. Prod. 2004, 67,
1985. (b) Zhan, J.; Wijeratne, E. M. K.; Seliga, C. J.;
Pierson, E. E.; Pierson, L. S. III; VanEtten, H. D.;
Gunatilaka, A. A. L. J. Antibiot. 2004, 57, 341.
(3) Kobayashi, A.; Hino, T.; Yata, S.; Itoh, T. J.; Sato, H.;
Kawazu, K. Agric. Biol. Chem. 1988, 52, 3119.
(4) Matsushita, N.; Akinaga, S.; Agatsuma, T. International
Patent No. WO 2004/024141, 2004.
(11) Liang, Q.; Zhang, J.; Quan, W.; Sun, Y.; She, X.; Pan, X.
J. Org. Chem. 2007, 72, 2694.
(12) (a) Bracher, F.; Schulte, B. Liebigs Ann./Recl. 1997, 1979.
(b) Liang, Q.; Zhang, J.; Quan, W.; Sun, Y.; She, X.; Pan, X.
J. Org. Chem. 2007, 72, 2694. (c) Bringmann, G.; Lang, G.;
Michel, M.; Heubes, M. Tetrahedron Lett. 2004, 45, 2829.
(13) Kreipl, A. T.; Reid, C.; Steglich, W. Org. Lett. 2002, 4, 3287.
(5) Whitesell, L.; Bagatell, R.; Falsey, R. Curr. Cancer Drug
Targets 2003, 3, 349.
Synthesis 2010, No. 5, 797–802 © Thieme Stuttgart · New York