The stereoselective total synthesis of (+)-stagonolide B

Article abstract of DOI:10.1055/s-0029-1218638

The stereoselective total synthesis of the nonenolide, (+)-stagonolide B is described. The key steps involve epoxide homologation, hydrolytic kinetic resolution and ring-closing metathesis.

Full text of DOI:10.1055/s-0029-1218638

PAPER
1039
The Stereoselective Total Synthesis of (+)-Stagonolide B
S
tereoselectiv
a
Total Syn
b
thesis of (+)
-
b
Stagonolide
a
B
raja Srihari,* Boyapelly Kumaraswamy, Ragam Somaiah, Jhillu S. Yadav
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
Fax +91(402)7160512; E-mail: Srihari@iict.res.in
Received 9 November 2009; revised 16 November 2009
HO
HO
HO
HO
HO
Abstract: The stereoselective total synthesis of the nonenolide,
(+)-stagonolide B is described. The key steps involve epoxide ho-
mologation, hydrolytic kinetic resolution and ring-closing metathe-
sis.
O
O
O
OH
O
O
O
herbarumin I (1)
herbarumin II (2)
herbarumin III (3)
Key words: macrolide, ring-closing metathesis, antifungal, phyto-
toxic, kinetic resolution
OH
OH
HO
HO
O
O
O
O
Ten-membered macrolides have attracted significant at-
tention due to their interesting biological properties.1 A
few recent examples include herbarumins I–III and
stagonolides A–I (Figure 1). The herbarumins, isolated
from the fungus Phoma herbarum,2 display antifungal ac-
tivity and phytotoxic effects. They also interact with bo-
vine brain caldmodulin and inhibit the calmodulin-
dependent enzyme cAMP phosphodiesterase. While there
are several reports on the synthesis of herbarumins,3 only
a few contributions on stagonolides have been published
which describe total syntheses and biological activity.
Stagonolides A–I were isolated from the fungus Stagono-
spora cirsii, a pathogen of the perennial weed Cirsium ar-
vense,4 which results in necrotic lesions on leaves.
Stagonolide F displays antifungal, antibacterial and cyto-
toxic properties.5 As the biological activity of the other
members of this group has not been fully explored due to
their limited availability, we decided to target these mole-
cules in order to investigate their biological properties. In
continuation of our work on the total syntheses of biolog-
ically active lactone-containing natural products,6 we de-
scribe herein a stereoselective total synthesis of
stagonolide B (5).7
HO
HO
O
O
O
stagonolide A (4)
stagonolide B (5)
stagonolide C (6)
OH
OH
OH
O
O
O
O
O
O
O
stagonolide D (7)
stagonolide E (8)
stagonolide F (9)
OH
OH
OH
OH
O
O
O
O
OH
O
O
O
stagonolide G (10)
stagonolide H (11)
stagonolide I (12)
Figure 1 Examples of naturally occurring ten-membered macro-
lides
OH
OH
O
OH
OH
O
O
O
O
O
Our retrosynthesis of stagonolide B (5) is based on a con-
vergent approach wherein two intermediate fragments, 14
and 15, are coupled by esterification followed by an olefin
metathesis to give the required ten-membered cyclic skel-
eton 13. Carboxylic acid 14 can be obtained from com-
mercially available butane-1,4-diol or pent-4-en-1-ol.
Fragment 15, with three stereogenic centers, is obtained
utilizing a chiral pool approach starting from D-ribose
(Scheme 1).
13
5
O
OH
O
+
HO
OTBDPS
O
14
15
O
HO
O
OH
HO
pent-4-en-1-ol
Our initial strategy toward fragment 15 departs from prior
work at the readily available epoxide 16 obtained from D-
ribose in four steps.8 Epoxide 16 was treated with ethyl-
butane-1,4-diol
O
16
D-ribose
Scheme 1 Retrosynthesis of stagonolide B (5)
SYNTHESIS 2010, No. 6, pp 1039–1045
x
x
.
x
x
.2
0
1
0
Advanced online publication: 08.01.2010
DOI: 10.1055/s-0029-1218638; Art ID: Z24109SS
© Georg Thieme Verlag Stuttgart · New York

1040
P. Srihari et al.
PAPER
magnesium bromide in the presence of copper(I) iodide to was protected as the corresponding tert-butyldiphenylsi-
yield the key intermediate 15 in good yield (Scheme 2).
lyl ether to yield 25 which was subjected to debenzylation
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
to give the alcohol 26 (Scheme 4).
O
ref. 8
O
D-ribose
4 steps, 61%
NaH, BnBr
O
HO
BnO
16
THF, 0 °C to r.t.
5 h, 96%
OH
O
CuI, EtMgBr
22
THF, –40 °C
3 h, 92%
O
O
MCPBA, NaHCO3
BnO
15
CH2Cl2, 0 °C to r.t.
2 h, 87%
23
Scheme 2 Synthesis of fragment 15
(salen)Co(III)(OAc) (0.005 mol%)
The other key fragment, acid 14, was obtained starting
from commercially available butane-1,4-diol as shown in
Schemes 3– 5. Accordingly, butane-1,4-diol was mono-
protected as the benzyl ether 17. Oxidation of 17 under
Swern conditions9 gave the corresponding aldehyde
which on Wittig homologation with ethyl (triphenylphos-
phoranylidene)acetate yielded a,b-unsaturated ester 18.
Reduction of the ester functionality with diisobutylalumi-
num hydride gave alcohol 19, which was subjected to
Sharpless asymmetric epoxidation to yield chiral epoxy
alcohol 20.10 The epoxy alcohol 20 was treated with io-
dine, triphenylphosphine and imidazole to give the corre-
sponding epoxy iodide which reacted with zinc in ethanol
at reflux temperature to yield the chiral allylic alcohol 2111
(Scheme 3).
23
H2O (0.55 equiv)
45% yield, 98% ee
OH
O
BnO
BnO
+
OH
24
24a
TBDPSCl
imidazole
OH
Me3SI, n-BuLi
BnO
24
THF, –20 °C
5 h, 81%
CH2Cl2, 4 h, 95%
21
OTBDPS
OTBDPS
DDQ
HO
BnO
CH2Cl2–H2O (19:1)
4 h, reflux, 92%
26
25
Scheme 4 Synthesis of alcohol 26
Alternatively, the alcohol 21 could be prepared from com-
mercially available pent-4-en-1-ol as shown in Scheme 4.
Thus, pent-4-en-1-ol was protected as the corresponding
benzyl ether 22 using sodium hydride and benzyl bro-
mide. Next, the alkene group of 22 was subjected to ep-
oxidation with m-chloroperoxybenzoic acid to afford the
racemic epoxide 23. Solvent-free hydrolytic kinetic
resolution12 of 23 employing 0.55 equivalents of water in
the presence of 0.005 equivalents of (R,R)-(–)-N,N¢-
bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediami-
nocobalt(III) acetate [(salen)Co(III)(OAc)] afforded
chiral epoxide 24 in 45% yield along with the chiral diol
24a (42%). The diol 24a could be converted into the ep-
oxide 24 in three steps.13 Treatment of epoxide 24 with tri-
methylsulfonium iodide and n-butyllithium provided the
chiral secondary allylic alcohol 21.14 The hydroxy group
The alcohol 26 was sequentially oxidized to aldehyde 27
with 2-iodoxybenzoic acid (IBX), and then to acid 14 with
sodium chlorite (NaClO2) and sodium dihydrogen phos-
phate (NaH2PO4) in tert-butanol–water, in an overall 96%
yield (Scheme 5).15 With the two key intermediates, acid
14 and alcohol 15 in hand, the stage was set for coupling
these fragments.
Initially, we used the standard procedure to couple acid 14
and alcohol 15 employing N,N¢-dicyclohexylcarbodi-
imide and 4-(N,N-dimethylamino)pyridine to give the
corresponding ester 28 (Scheme 6). Ring closing metathe-
sis (RCM) on substrate 28 did not proceed to our expecta-
tions with both the Grubbs first- and second-generation
catalysts. The starting material was recovered even after
heating the reaction mixture at reflux for more than 12
NaH, BnBr
HO
i. Swern oxidation
BnO
OH
OH
THF, r.t.,
4 h, 95%
ii. Ph3P=CHCO2Et
benzene, reflux, 8 h
17
overall yield 92%
(–)-DET, Ti(Oi-Pr)4
TBHP, CH2Cl2
DIBAL-H
BnO
BnO
CO2Et
BnO
OH
4 Å MS
16 h, –25 °C, 88%
CH2Cl2, 0 °C to r.t.
4 h, 95%
18
19
OH
i. I2, Ph3P, imidazole
benzene, 1 h
O
BnO
OH
ii. Zn, EtOH, reflux
6 h, 96%
20
21
Scheme 3 Synthesis of chiral allylic alcohol 21 starting from butane-1,4-diol
Synthesis 2010, No. 6, 1039–1045 © Thieme Stuttgart · New York

PAPER
Stereoselective Total Synthesis of (+)-Stagonolide B
1041
Table 1 Investigation of the Reaction Conditions for the Desilylation of 28
OH
OTBDPS
O
O
OH
O
O
O
O
O
OH
O
O
28
30
31
Entry
Reagents and conditions
HF–py, THF, 0 °C to r.t.
Bu4NF, THF, 0 °C to r.t.
Products (yield)
1
2
3
4
5
mixture of 15 and 31
mixture of 15, 31 and 28
mixture of 15 and 31
30 (91%), 31 (5%)
30 (85%)
NaH, HMPA, THF, 0 °C to r.t.
Et3N·3HF, THF, reflux
NH4F, MeOH, reflux
However, formation of 31 (5%) was observed in the case
of the reaction with triethylamine tris(hydrogen fluoride).
O
IBX, DMSO, THF
r.t., 3.5 h, 98%
H
26
Having established the free hydroxy group at the allylic
position in compound 30, the ring-closing metathesis was
studied further. Unfortunately, cyclization using the
Grubbs first-generation catalyst did not succeed and 70%
of the starting material 30 was recovered along with other
unidentified by-products. Attempts with Hoveyda catalyst
ended up with uncharacterized by-products. However, the
reaction was successful using the Grubbs second-genera-
tion catalyst to yield the desired acetonide-protected ten-
membered macrolide 137 along with ketone 32 as a by-
product. On increasing the concentration of the catalyst
from 0.2 mol% to 20 mol%, the percentage of the met-
athesis product was enhanced significantly (25% to 50%).
Finally, cleavage of the acetonide group of crude 13 was
achieved using hydrochloric acid to yield the target natu-
ral product (+)-stagonolide B (5) (Scheme 7). The analyt-
ical data of the synthetic product was found to be identical
with that reported for the natural product.4a,7
OTBDPS
27
O
NaClO2, NaH2PO4
HO
t-BuOH–H2O (9:1)
2 h, 98%
OTBDPS
14
Scheme 5 Preparation of acid fragment 14
hours in dichloromethane. We reasoned that the presence
of the tert-butyldiphenylsilyl moiety might be responsible
for the failure of the ring-closing metathesis. Hence, we
investigated the ring-closing metathesis using deprotected
hydroxy compound 30. Our attempts to desilylate the
hydroxy group of 28 with hydrogen fluoride–pyridine,
tetrabutylammonium fluoride, or sodium hydride in hexa-
methylphosphoramide (entries 1–3, Table 1) resulted in
ester hydrolysis to return the acid 15 along with the hy-
droxy acid by-product 31. After further careful investiga-
tions, we found that 28 could be desilyated using
triethylamine tris(hydrogen fluoride) (Et3N·3HF) in tet-
rahydrofuran or with ammonium fluoride in methanol
(entries 4 and 5, Table 1) to yield the desired product 30.
In conclusion, the stereoselective total synthesis of
stagonolide B (5) has been achieved. The key steps were
Sharpless epoxidation, epoxide homologation, Jacobsen
hydrolytic kinetic resolution and Grubbs olefin metathe-
sis. Application of this strategy to the preparation of other
G-1 (20 mol%)
OTBDPS
O
OTBDPS
O
CH2Cl2, reflux
O
O
O
DCC, DMAP
O
14 + 15
CH2Cl2, 12 h
0 °C to r.t., 90%
G-2 (20 mol%)
CH2Cl2, reflux
O
28
O
29
G-1: Grubbs 1st-generation catalyst
G-2: Grubbs 2nd-generation catalyst
Scheme 6 Synthesis of diene 28 and attempted ring-closing metathesis
Synthesis 2010, No. 6, 1039–1045 © Thieme Stuttgart · New York

1042
P. Srihari et al.
PAPER
hyd Na2SO4, filtered and concd. The residue was purified by
column chromatography on silica gel (30% EtOAc–hexane) to give
20 (7.60 g, 88%, 90% ee) as a colorless syrup.
[a]D27 +12.0 (c 2.0, CHCl3).
G1 (20 mol%)
uncharacterized
by-products
30
+
CH2Cl2, reflux, 24–72 h
70%
30%
IR (neat): 3409, 2920, 2854, 1452, 1364, 1099 cm–1.
Hoveyda catalyst
(20 mol%)
1H NMR (300 MHz, CDCl3): d = 7.38–7.26 (m, 5 H), 4.50 (s, 2 H),
3.84 (qd, J = 12.6, 2.6 Hz, 1 H), 3.63–3.46 (m, 3 H), 2.97 (dt,
J = 6.0, 2.3 Hz, 1 H), 2.93–2.88 (m, 1 H), 2.19 (s, 1 H), 1.95 (s, 1
H), 1.85–1.58 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 138.3, 128.3, 127.6, 127.5, 72.9,
69.6, 61.6, 58.4, 55.7, 28.4, 26.1.
uncharacterized
by-products
CH2Cl2, reflux, 10 h
30
OH
O
O
O
G2 (0.2 mol%)
benzene, reflux
+
MS (ES): m/z = 245 [M + Na]+.
O
O
O
O
HRMS (ESI): m/z [M + Na]+ calcd for C13H18O3Na: 245.1148;
O
found: 245.1151.
O
13
32
25% (crude)
45%
(3R)-6-(Benzyloxy)hex-1-en-3-ol (21)
From butane-1,4-diol according to Scheme 3: To a soln of alcohol
20 (8.0 g, 21.5 mmol) in anhyd benzene (100 mL) were added imi-
dazole (4.39 g, 64.5 mmol), Ph3P (8.47 g, 32.30 mmol) and I2 (8.22
g, 32 mmol) at 0 °C. After 5 min, the cold bath was removed and the
reaction mixture was stirred for 1 h at r.t. during which time the col-
or changed from brown to bright-yellow and the mixture became
highly viscous. The mixture was quenched with sat. aq Na2S2O3
soln (50 mL) and extracted with Et2O (3 × 100 mL). The combined
organic layer was washed with sat. aq Na2S2O3 soln (100 mL) and
brine (100 mL), dried over anhyd Na2SO4 and concd under reduced
pressure. Purification of the crude product by column chromatogra-
phy on silica gel (20% EtOAc–hexane) afforded the iodo compound
(6.88 g, 96%) as a colorless oil. The iodide was heated at reflux with
Zn (5.41 g, 82.0 mmol) in EtOH (70 mL) for 6 h after which the re-
action mixture was filtered through a pad of Celite which was then
rinsed with EtOH. The combined ethanolic layer was dried over an-
hyd Na2SO4, filtered and evaporated. The residue was purified by
column chromatography on silica gel (20% EtOAc–hexane) to give
21 (4.09 g, 96%) as a colorless syrup.
G2 (20 mol%)
13
+
32
benzene, reflux
25%, pure
isolated product
50%
(crude)
OH
OH
OH
1 M HCl
13
(crude)
O
THF, 55 °C
45%
O
5
Scheme 7 Completion of the synthesis of stagonolide B
stagonolide analogues in order to study their biological
activity is currently being pursued.
Column chromatography was performed using silica gel (60–120
mesh, Acme). All solvents were dried and distilled prior to use. IR
spectra were obtained on a Perkin-Elmer Infrared spectrophotome-
ter. 1H and 13C NMR spectra were recorded on a Bruker Avance 300
MHz instrument at 300 MHz and 75 MHz, respectively, using TMS
as an internal standard. Mass spectra (EI) were recorded on a Micro-
mass VG 7070H mass spectrometer. HRMS (ESI) spectra were ob-
tained using a Micromass Quattro LC triple quadrupole mass
spectrometer. The optical rotations were recorded on a JASCO DIP-
360 digital polarimeter. Enantiomeric excess values were deter-
mined by HPLC techniques using a ChiralPak IC 250 × 4.6 mm (5
mm) column. The mobile phase was 10% IPA in hexane with a flow
rate of 1.0 mL/min for compound 20 and 20% IPA in hexane for
compound 24.
From pent-4-en-1-ol according to Scheme 4: A soln of trimethylsul-
fonium iodide (3.2 g, 15.6 mmol) (predried by azeotroping with an-
hyd toluene) in THF (25 mL) was cooled to –20 °C, and n-BuLi (8.8
mL, 14.0 mmol, 1.6 M in hexane) was added. The mixture was
stirred for 30 min at –20 °C, then epoxy benzyl ether 24 (1 g, 5.2
mmol) in THF (10 mL) was added via syringe, over 20 min, at the
same temperature. After addition was complete, the cooling bath
was removed and the reaction was allowed to warm to r.t. over 30
min, and then stirred at r.t. for 5 h. The reaction was quenched by
the addition of H2O and then diluted with Et2O (60 mL). The organ-
ic layer was separated, washed with brine (25 mL), dried over anhyd
Na2SO4, filtered and concd. The residue was purified by column
chromatography on silica gel (20% EtOAc–hexane) to give 21 (0.86
g, 81%) as colorless syrup.
[a]D29 –2.7 (c 2.0, CHCl3).
IR (neat): 3430, 2922, 2858, 1644, 1454, 1095, 1027 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.37–7.24 (m, 5 H), 5.85 (ddd,
J = 17.2, 10.4, 6.0 Hz, 1 H), 5.21 (td, J = 17.2, 1.5 Hz, 1 H), 5.08
(td, J = 10.4, 1.3 Hz, 1 H), 4.50 (s, 2 H), 4.15–4.06 (m, 1 H), 3.50
(t, J = 5.8 Hz, 2 H), 2.57 (br s, 1 H), 1.79–1.53 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 141.0, 138.0, 128.3, 127.6, 127.5,
114.3, 72.8, 72.5, 70.2, 34.0, 25.6.
MS (ES): m/z = 229 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C13H18O2Na: 229.1199;
{(2R,3R)-3-[(Benzyloxy)propyl]oxiran-2-yl}methanol (20)
To a cooled (–25 °C) suspension of activated, powdered 4 Å MS (4
g) in CH2Cl2 (50 mL) were added (–)-DET (1.23 mL, 5.8 mmol),
Ti(Oi-Pr)4 (1.38 mL, 4.6 mmol) and TBHP (21.25 mL, 85.0 mmol).
After 20 min, a soln of allylic alcohol 19 (8.0 g, 38.8 mmol) in
CH2Cl2 (80 mL) was added at –25 °C over 15 min. The resulting
mixture was stirred at –25 °C for 12 h and then quenched with a cold
soln of FeSO4–tartaric acid (stoichiometric amount) in deionized
H2O. The mixture was stirred vigorously for 30 min and then ex-
tracted with Et2O (3 × 100 mL). The combined organic layer was
treated with a cold (0 °C) soln of 30% NaOH (30 mL, w/v) in brine
and the mixture stirred for 2 h at r.t. The two layers were separated
and the aq layer was extracted with Et2O (3 × 100 mL). The com-
bined organic layer was washed with brine (100 mL), dried over an-
found: 229.1197.
Synthesis 2010, No. 6, 1039–1045 © Thieme Stuttgart · New York

PAPER
Stereoselective Total Synthesis of (+)-Stagonolide B
1043
(3R)-{[6-(Benzyloxy)hex-1-en-3-yl]oxy}tert-butyldiphenylsi-
lane (25)
3.48 (t, J = 6.6 Hz, 2 H), 2.15 (q, J = 7.2 Hz, 2 H), 1.78–1.65 (m, 2
H).
To a stirred soln of alcohol 21 (5.0 g, 24 mmol) and imidazole (2.47
g, 29 mmol) in anhyd CH2Cl2 (50 mL) at 0 °C was added TBDPSCl
(8.0 g, 29 mmol) dropwise, and stirring was continued for 4 h at r.t.
The reaction mixture was quenched with H2O and extracted with
CH2Cl2 (3 × 100 mL). The combined organic layer was washed with
brine (50 mL), dried over anhyd Na2SO4 and concd under reduced
pressure. Purification by column chromatography using silica gel
(2% EtOAc–hexane) furnished silyl ether 25 (10.19 g, 95%) as a
colorless liquid.
13C NMR (75 MHz, CDCl3): d = 138.7, 138.2, 128.3, 127.6, 127.4,
114.7, 72.8, 69.7, 30.3, 28.9.
2-[3-(Benzyloxy)propyl]oxirane (23)
To a soln of alkene 22 (18.0 g, 102.3 mmol) in anhyd CH2Cl2 (150
mL) was added NaHCO3 (17.2 g, 204.6 mmol) followed by
MCPBA (26.5 g, 153.4 mmol) and the resulting mixture was stirred
at r.t. for 2 h. The mixture was diluted with H2O (150 mL) and ex-
tracted with CH2Cl2 (3 × 130 mL). The combined organic layer was
washed with brine (200 mL) and dried over anhyd Na2SO4. The sol-
vent was removed under reduced pressure and the crude product
was purified by column chromatography on silica gel (10% EtOAc–
hexane) to afford the epoxide 23 (17.0 g, 87%) as a colorless oil.
[a]D25 –17.1 (c 0.8, CHCl3).
IR (neat): 2970, 2925, 1639, 1217 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.73–7.59 (m, 5 H), 7.43–7.23 (m,
10 H), 5.77 (ddd, J = 17.0, 10.4, 6.4 Hz, 1 H), 4.98 (td, J = 10.4, 1.3
Hz, 1 H), 4.95–4.92 (m, 1 H), 4.40 (s, 2 H), 4.17 (q, J = 5.3 Hz, 1
H), 3.37–3.26 (m, 2 H), 1.64–1.46 (m, 4 H), 1.06 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 140.6, 136.0, 135.9, 134.8, 129.6,
129.56, 129.5, 128.3, 127.7, 127.54, 127.48, 127.41, 127.39, 114.5,
74.3, 72.7, 70.3, 34.0, 27.1, 26.6, 19.4.
(2S)-2-[3-(Benzyloxy)propyl]oxirane (24)
A mixture of (R,R)-(–)-N,N¢-bis(3,5-di-tert-butylsalicylidene)-1,2-
cyclohexanediaminocobalt(II) (0.26 g, 0.43 mmol), toluene (1 mL)
and AcOH (0.1 mL, 1. 73 mmol) was stirred for 1 h at r.t. open to
the air. The solvent was removed under reduced pressure and the re-
maining brown residue was dried under high vacuum. Oxirane 23
(17.0 g, 86.7 mmol) was added in one portion and the mixture was
cooled using an ice-bath. H2O (0.87 mL, 48.7 mmol) was added
slowly whilst maintaining the temperature of the reaction mixture
below 20 °C. After 1 h, the addition was complete; the ice-bath was
removed and the reaction stirred for 24 h at r.t. The product 24 was
isolated by column chromatography on silica gel (20% EtOAc–
hexane) as a colorless liquid (7.65 g, 45%, 98% ee).
[a]D25 –5.12 (c 2.3, CHCl3).
IR (neat): 2929, 2836, 1630, 1347, 1210, 1109, 771 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.41–7.20 (m, 5 H), 4.50 (s, 2 H),
3.58–3.44 (m, 2 H), 2.96–2.88 (m, 1 H), 2.72 (t, J = 4.9 Hz, 1 H),
2.45 (q, J = 2.6 Hz, 1 H), 1.85–1.50 (m, 4 H).
MS (ES): m/z = 467 [M + Na]+.
HRMS (ESI): m/z [M + NH4]+ calcd for C29H40NO2Si: 462.2823;
found: 462.2831.
(4R)-4-(tert-Butyldiphenylsilyloxy)hex-5-en-1-ol (26)
To a stirred soln of 25 (5.0 g, 11.3 mmol) in CH2Cl2–H2O (60 mL,
19:1) was added DDQ (10.27 g, 45.2 mmol) and the mixture stirred
at reflux for 4 h. Sat. aq NaHCO3 soln (30 mL) was added and the
mixture was extracted with CH2Cl2 (3 × 100 mL). The combined or-
ganic layer was washed with H2O (100 mL) and brine (30 mL),
dried over anhyd Na2SO4 and concd. The crude residue was purified
by column chromatography on silica gel (20% EtOAc–hexane) to
afford alcohol 26 (3.66 g, 92%) as a colorless syrupy liquid.
[a]D25 –18.1 (c 1, CHCl3).
IR (neat): 3375, 2931, 2857, 1466, 1427, 1111, 1057 cm–1.
13C NMR (75 MHz, CDCl3): d = 138.3, 128.2, 127.4, 127.38, 72.7,
69.6, 51.9, 46.9, 29.1, 26.0.
1H NMR (300 MHz, CDCl3): d = 7.74–7.61 (m, 4 H), 7.47–7.30 (m,
6 H), 5.79 (ddd, J = 16.8, 10.6, 6.4 Hz, 1 H), 5.02 (td, J = 10.0, 1.3
Hz, 1 H), 4.99–4.95 (m, 1 H), 4.21 (q, J = 4.9 Hz, 1 H), 3.49 (t,
J = 5.8 Hz, 2 H), 1.65–1.41 (m, 4 H), 1.07 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 140.3, 135.9, 135.8, 134.2, 134.0,
129.6, 129.5, 127.5, 127.3, 114.6, 74.2, 62.9, 33.7, 27.5, 27.0, 19.3.
MS (ES): m/z = 377 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C22H30O2SiNa: 377.1907;
(4R)-4-(tert-Butyldiphenylsilyloxy)hex-5-enoic acid (14)
To a stirred soln of IBX (3.6 g, 12.80 mmol) in DMSO (7 mL) was
added alcohol 26 (3 g, 8.5 mmol) in THF (30 mL) at r.t. After 3 h,
the reaction mixture was diluted with Et2O (50 mL), stirred for 30
min and then filtered through a pad of Celite. The organic layer was
washed with sat. aq NaHCO3 soln (50 mL) and brine (50 mL), dried
over anhyd Na2SO4 and concd to give the crude aldehyde 27 (2.93
g, 98%). Crude 27 was dissolved in t-BuOH–H2O (30 mL, 9:1),
cooled to 0 °C, and after 10 min, treated with 2-methyl-2-butene fol-
lowed by an aq soln of NaClO2 (0.92 g, 9.98 mmol) and NaH2PO4
(1.58 g, 9.98 mmol) in H2O (10 mL). After 2 h, the reaction mixture
was quenched with KHSO4 (15 mL, 1 mol/L) and H2O (10 mL) and
extracted with EtOAc (3 × 100 mL). The combined organic layer
was washed with brine (10 mL), dried over anhyd Na2SO4, filtered
and concd in vacuo. Flash chromatography of the residue over silica
gel (20% EtOAc–hexane) afforded 14 as a colorless oil (3.0 g,
98%).
[a]D29 –19.1 (c 1.4, CHCl3).
IR (neat): 3457, 2925, 1710, 1643, 1427, 1112 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.76–7.60 (m, 4 H), 7.50–7.30 (m,
6 H), 5.74 (ddd, J = 10.4, 7.0, 6.0 Hz, 1 H), 5.02 (dd, J = 17.0, 4.9
Hz, 2 H), 4.26 (q, J = 5.3 Hz, 1 H), 2.35 (q, J = 7.4 Hz, 2 H), 1.79
(q, J = 7.4 Hz, 2 H), 1.06 (s, 9 H).
found: 377.1915.
[(Pent-4-enyloxy)methyl]benzene (22)
To a vigorously stirred suspension of freshly activated NaH (3.48 g,
139.5 mmol, 60% w/v dispersion in mineral oil) in anhyd THF (50
mL) was added a soln of pent-4-en-1-ol (10 g, 116.2 mmol) in an-
hyd THF (70 mL), dropwise at 0 °C. After 30 min, benzyl bromide
(16.6 mL, 139.5 mmol) was added and the reaction mixture was
stirred at r.t. for 5 h. The reaction was quenched with crushed ice
and the product was extracted with Et2O (3 × 100 mL). The com-
bined organic layer was washed with H2O (100 mL) and brine (100
mL), and then dried over anhyd Na2SO4. After removing the vola-
tiles under reduced pressure, the crude benzyl ether was purified by
column chromatography on silica gel (5% EtOAc–hexane) to afford
the pure product 22 (19.6 g, 96%) as a colorless liquid.
IR (neat): 3069, 3031, 1640, 1495, 1454, 1362, 1028, 995, 910, 736,
613 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.38–7.23 (m, 5 H), 5.82 (dddd,
J = 16.8, 13.2, 10.0, 6.6 Hz, 1 H), 5.07–4.91 (m, 2 H), 4.50 (s, 2 H),
13C NMR (75 MHz, CDCl3): d = 179.2, 139.5, 135.9, 135.8, 133.9,
133.8, 129.7, 129.5, 127.5, 127.4, 115.4, 73.1, 31.7, 28.9, 27.0,
19.3.
Synthesis 2010, No. 6, 1039–1045 © Thieme Stuttgart · New York

1044
P. Srihari et al.
PAPER
MS (ES): m/z = 391 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C33H46O5SiNa: 573.3012;
found: 573.2999.
HRMS (ESI): m/z [M + Na]+ calcd for C22H28O3SiNa: 391.1705;
found: 391.1708.
{(1R)-1-[(4R,5S)-2,2-Dimethyl-5-ethenyl-1,3-dioxolan-4-yl]bu-
tyl} (4R)-4-hydroxyhex-5-enoate (30)7
(1R)-1-[(4R,5S)-2,2-Dimethyl-5-ethenyl-1,3-dioxolan-4-yl]bu-
tan-1-ol (15)
To a soln of 28 (1.2 g, 2.2 mmol) in anhyd THF (15 mL) under an
N2 atm was added Et3N·3HF (7.1 mL, 43.6 mmol), and the reaction
mixture was heated at reflux for 8 h. The mixture was quenched
with aq NH4Cl soln (30 mL), the phases were separated, and the aq
phase was extracted with CH2Cl2 (3 × 40 mL). The combined organ-
ic extract was dried over anhyd Na2SO4 and concd in vacuo to af-
ford an oil which was purified by silica gel column chromatography
(20% EtOAc–hexane) to yield 30 (0.62 g, 91%) as a colorless oil.
[a]D27 +20.1 (c 2.5, CHCl3).
IR (neat): 3425, 2976, 2860, 1717, 1630, 1378, 1199 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.90–5.73 (m, 2 H), 5.40–5.10 (m,
4 H), 4.93 (dt, J = 7.4, 3.6 Hz, 1 H), 4.61 (t, J = 7.0 Hz, 1 H), 4.23–
4.11 (m, 2 H), 2.48–2.33 (m, 2 H), 2.00 (br s, 1 H), 1.94–1.75 (m, 2
H), 1.74–1.54 (m, 2 H), 1.49 (s, 3 H), 1.37 (s, 3 H), 1.35–1.20 (m, 2
H), 0.91 (t, J = 7.4 Hz, 3 H).
To a soln of epoxide 16 (0.6 g, 3.5 mmol) in THF (8 mL) at –40 °C
was added CuI (0.13 g, 0.7 mmol) and the mixture was stirred at the
same temperature for 15 min. After this time, a cold (22 °C) soln of
ethylmagnesium bromide (10.5 mL, 10.5 mmol, 1 M soln in THF)
was added via a cannula. The resulting mixture was stirred at –40
°C for 3 h, quenched by the addition of aq NH4Cl soln and then
warmed to 23 °C. The aq layer was separated and extracted with
EtOAc (2 × 20 mL), and the combined organic layer was washed
with brine (25 mL), dried over anhyd Na2SO4 and concd to give the
crude product. Silica gel column chromatography (15% EtOAc–
hexane) afforded pure 15 (0.649 g, 92%) as a colorless oil.
[a]D30 +8.8 (c 1.6, CH2Cl2) [Lit.16 [a]D20 +8.8 (c 1.2, CH2Cl2)].
IR (neat): 3467, 2983, 2959, 2932, 2873, 1642, 1217, 1065, 872
cm–1.
1H NMR (300 MHz, CDCl3): d = 6.04 (ddd, J = 17.2, 10.4, 7.4 Hz,
1 H), 5.43 (d, J = 17.2 Hz, 1 H), 5.31 (d, J = 10.4 Hz, 1 H), 4.63 (t,
J = 7.4 Hz, 1 H), 3.97 (dd, J = 8.1, 6.4 Hz, 1 H), 3.67 (dt, J = 2.6,
2.3 Hz, 1 H), 1.80 (br s, 1 H), 1.69 (m, 1 H), 1.57 (m, 1 H), 1.48 (s,
3 H), 1.45 (m, 1 H), 1.37 (s, 3 H), 1.37 (m, 1 H), 0.94 (t, J = 7.2 Hz,
3 H).
13C NMR (75 MHz, CDCl3): d = 172.9, 140.4, 133.2, 118.5, 115.1,
108.8, 78.8, 78.4, 72.1, 71.9, 33.4, 31.5, 30.3, 27.5, 25.2, 17.9, 14.0.
MS (ES): m/z = 335 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C17H28O5Na: 335.1834;
found: 335.1836.
13C NMR (75 MHz, CDCl3): d = 134.7, 118.9, 108.6, 80.7, 78.9,
69.7, 35.8, 27.8, 25.3, 18.3, 14.0.
Stagonolide B (5)
Ester 30 (0.04 g, 0.12 mmol) was dissolved in freshly distilled and
degassed anhyd benzene (90 mL), then treated with Grubbs 2nd gen-
eration catalyst (0.022 mg, 0.025 mmol) and heated at reflux for 6
h under an inert atm. The reaction mixture was evaporated under re-
duced pressure to give a brown residue which was purified by col-
umn chromatography on silica gel (20% EtOAc–hexane) to afford
impure 13 (0.018 g, 50%) as a colorless syrup. To a stirred soln of
crude 13 (0.018 g, 0.06 mmol) in anhyd THF (5 mL) was added aq
HCl (1 M, 0.25 mL) and the mixture was stirred at 55 °C for 10 h
(TLC showed complete consumption of the starting material). The
mixture was diluted with aq NaOH (1 M, 0.3 mL). The organic layer
was separated, dried over anhyd Na2SO4, evaporated, and the resi-
due was purified by column chromatography over silica gel (50%
EtOAc–hexane) to afford stagonolide B (5) (0.007 g, 45%) as a vis-
cous liquid.
MS (ES): m/z = 223 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C11H20O3Na: 223.1305;
found: 223.1304.
{(1R)-1-[(4R,5S)-2,2-Dimethyl-5-ethenyl-1,3-dioxolan-4-yl]bu-
tyl} (4R)-4-(tert-butyldiphenylsilyloxy)hex-5-enoate (28)
A soln of acid 14 (1.0 g, 29.4 mmol) in CH2Cl2 (12 mL) was cooled
to 0 °C and DCC (0.79 g, 38.2 mmol) was added in several portions
during which a white precipitate formed rapidly. After 15 min, a
soln of alcohol 15 (0.65 g, 32.34 mmol) in CH2Cl2 (8 mL) was add-
ed followed by a catalytic amount of DMAP (15 mg). The cooling
bath was removed and stirring was continued for 12 h. The soln was
filtered and the solvent was removed under reduced pressure. The
resulting oil was purified by silica gel column chromatography (2%
EtOAc–hexane) to afford ester 28 [0.96 g, 90%, yield based on re-
covered 14 (0.3 g) and 15 (0.23 g)] as a colorless oil.
[a]D27 +16.0 (c 0.2, CHCl3) [Lit.4a [a]D +20 (c 0.1, CHCl3)].
IR (neat): 3422, 2933, 2861, 2350, 1734, 1424, 1370, 1251, 1217,
1109, 1069 cm–1.
[a]D26 –3.2 (c 1.8, CHCl3).
IR (neat): 2933, 2861, 2360, 1737, 1427, 1376, 1251, 1217, 1109,
1069 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.97 (br t, J = 16.2 Hz, 1 H), 5.65–
5.57 (m, 1 H), 4.92 (td, J = 9.8, 2.3 Hz, 1 H), 4.63 (br s, 1 H), 4.54
(br s, 1 H), 3.63–3.53 (m, 1 H), 2.44 (br dd, J = 14.1, 13.6 Hz, 1 H),
2.20–2.02 (m, 1 H), 1.99–1.81 (m, 1 H), 1.74–1.45 (m, 3 H), 1.41–
1.25 (m, 2 H), 0.92 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 176.5, 128.0, 127.2, 73.6, 73.1,
70.3, 68.6, 33.6, 31.7, 27.9, 18.0, 13.8.
MS (ES): m/z = 267 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C12H20O5Na: 267.1203;
found: 267.1217.
1H NMR (300 MHz, CDCl3): d = 7.78–7.59 (m, 4 H), 7.46–7.28 (m,
6 H), 5.86–5.66 (m, 2 H), 5.27 (d, J = 17.0 Hz, 1 H), 5.14 (d,
J = 10.4 Hz, 1 H), 5.07–4.94 (m, 2 H), 4.87 (dt, J = 7.5, 4.0 Hz, 1
H), 4.56 (t, J = 7.2 Hz, 1 H), 4.31–4.18 (m, 1 H), 4.13 (t, J = 7.5 Hz,
1 H), 2.38–2.11 (m, 2 H), 1.75 (q, J = 5.7 Hz, 2 H), 1.68–1.51 (m, 2
H), 1.47 (s, 3 H), 1.37 (s, 3 H), 1.35–1.19 (m, 2 H), 1.07 (s, 9 H),
0.89 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 172.6, 139.6, 135.9, 135.8, 135.8,
133.8, 133.2, 129.6, 129.5, 127.5, 127.4, 118.4, 115.2, 108.7, 78.9,
78.3, 73.3, 71.4, 33.4, 32.0, 29.3, 27.5, 27.0, 25.2, 18.4, 17.9, 14.1.
MS (ES): m/z = 573 [M + Na]+.
Acknowledgment
B.K. and R.S. thank the CSIR, New Delhi for financial assistance.
Synthesis 2010, No. 6, 1039–1045 © Thieme Stuttgart · New York

PAPER
Stereoselective Total Synthesis of (+)-Stagonolide B
1045
Yadav, J. S. Synlett 2009, 2129. (c) Srihari, P.; Rajendar,
G.; Srinivasa Rao, R.; Yadav, J. S. Tetrahedron Lett. 2008,
49, 5590. (d) Srihari, P.; Kumar, B. P.; Subbarayudu, K.;
Yadav, J. S. Tetrahedron Lett. 2007, 48, 6977. (e) For 10-
membered ring lactones, see: Srihari, P.; Bhasker, E. V.;
Harshavardhan, S. J.; Yadav, J. S. Synthesis 2006, 4041.
(f) Nagaiah, K.; Sreenu, D.; Rao, R. S.; Yadav, J. S.
Tetrahedron Lett. 2007, 48, 7173. (g) Yadav, J. S.; Pratap,
T. V.; Rajender, V. J. Org. Chem. 2007, 72, 5882. (h) Ref.
3e.
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Synthesis 2010, No. 6, 1039–1045 © Thieme Stuttgart · New York