Asymmetric synthesis of stagonolide-D and stagonolide-G

Article abstract of DOI:10.1246/bcsj.20100197

First asymmetric synthesis of the naturally occurring epoxy noneolide stagonolide-D has been reported in this article. Ring-closing metathesis (RCM) by Grubbs second generation catalyst, Sharpless asymmetric epoxidation (SAE), and cis-selective HornerWads

Full text of DOI:10.1246/bcsj.20100197

© 2011 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 84, No. 5, 511–519 (2011)
511
Asymmetric Synthesis of Stagonolide-D and Stagonolide-G
Tridib Mahapatra, Tapas Das, and Samik Nanda*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
Received July 13, 2010; E-mail: snanda@chem.iitkgp.ernet.in
First asymmetric synthesis of the naturally occurring epoxy noneolide stagonolide-D has been reported in this
article. Ring-closing metathesis (RCM) by Grubbs second generation catalyst, Sharpless asymmetric epoxidation (SAE),
and cis-selective Horner-Wadsworth-Emmons (HWE) olefination by Ando method are the key reactions successfully
employed to achieve the target molecule in a divergent approach. Structurally related small ring macrolide stagonolide-G
has also been synthesized by employing RCM and a metal-enzyme combined dynamic kinetic resolution (DKR) strategy
starting from (S)-ethyl lactate as a chiral pool.
Stagonospora cirsii, a pathogenic fungus isolated from
Cirsium arvense (commonly called Canada thistle) and
proposed as a potential mycoherbicide of this perennial
noxious weed, it also produces phytotoxic secondary metab-
olites both in liquid and solid cultures. Stagonolide, being the
main phytotoxic metabolite is a noneolide, and five new
stagonolides B-F, were isolated from the fungus.1 In the same
year three more related stagonolides, named stagonolide G-I
were also isolated from the same fungal pathogen.2 Cirsium
arvense is a tall herbaceous perennial plant growing 30-100 cm
in length, forming extensive clonal colonies from an under-
ground root system. The species is widely considered a weed
even where it is native, for example being designated an
“injurious weed” in the United Kingdom. In Canada, Cirsium
arvense is classified as a primary noxious weed seed. In a
preliminary study, it was found that S. cirsii, the fungus is
capable of producing phytotoxins because culture filtrates
have demonstrated phytotoxicity to the leaves and roots of
C. arvense. Recently, with the purpose of finding new natural
potential herbicides, the main phytotoxic metabolite produced
by S. cirsii in liquid culture, named stagonolides, was isolated
and characterized as a new noneolide.
Close structural inspection on stagonolides B-I reveals that
one of the compound e.g., stagonolide-D is unique among
others. As stagonolide-D possess stereochemically pure epoxy
appendages at C7 and C8. And this kind of epoxy noneolides
has not been synthesized yet. In this article we wish to report
the first asymmetric synthesis of such an epoxy noneolide,
stagonolide-D in a divergent approach. Retrosynthetic analysis
of stagonolide-D reveals that RCM (ring-closing metathesis)
reaction is a good option to make the C5-C6 internal double
bond in the noneolide. The RCM precursor 1 was thought to be
constructed by esterification reaction between carboxylic acid
2 and epoxy alcohol 3. The hydroxy stereocenter in the
carboxylic acid 2 (C4 in stagonolide-D) was thought to be
constructed by a metal-enzyme combined DKR reaction,
whereas the stereochemically pure epoxy alcohol 3 that
constitutes the epoxide appendage at C7-C8 in the target
molecule is constructed by Sharpless asymmetric epoxidation
from the required Z-allylic alcohol 4. The Z-allylic alcohol 4 in
turn can be easily accessed from (S)-ethyl lactate by adopting a
cis-selective HWE olefination strategy (Scheme 1). The retro-
synthesis of stagonolide-G was similar to that of stagonolide-D.
The internal double bond between C6-C7 is thought to be
constructed by RCM reaction. The RCM precursor 5 can be
accessed by esterification reaction between the carboxylic acid
6 and alcohol 7. The hydroxy stereocenter in the carboxylic
acid 6 (C4 in stagonolide-G) was planned to be created by
metal-enzyme combined DKR reaction. The alcohol 7 that
constitutes other two stereocenters in stagonolide-G (C8 and
C9) was derived from (S)-ethyl lactate.
During the course of our study, the first asymmetric synthesis
of stagonolide-G was recently reported by Srihari et al.3,4
A
revised structure of stagonolide-G was then reported by
Angulo-Pachón et al.5 The revised structure of stagonolide-G
containing a £-lactone moiety is anticipated to originate from
the originally proposed 10-membered ring lactone by a
spontaneous intramolecular trans-lactonization reaction as
shown in Scheme 1.
Results and Discussion
Synthesis of Stagonolide-D. The synthesis started with
natural (S)-ethyl lactate, which was protected as its PMB (para-
methoxybenzyl) ether 9 by PMB-trichloroacetimidate.6 Reduc-
tion of compound 9 with DIBAL-H (diisobutylaluminium
hydride) in DCM (dichloromethane) at ¹78 °C afforded the
corresponding aldehyde 10 in 90% yield. cis-Selective HWE
olefination by using Ando method7 afforded the ester 11 in
88% yield (Z:E = 15:1). Reduction of compound 11 with
DIBAL-H (2 equiv) produced the corresponding Z-allylic
alcohol 4 in 87% yield. Sharpless asymmetric epoxidation8 on
compound 4 under standard condition yielded the epoxy
alcohol 12 in 92%. Epoxy alcohol 12 is then oxidized to the
corresponding aldehyde with DMP (Dess-Martin periodi-
nane),9 and the crude aldehyde was then subjected to one
carbon extension with Wittig ylide (generated from methyl
triphenylphosphonium iodide)10 to afford the epoxy olefin 13
in 78% yield (in two steps). Deprotection of the PMB group in
compound 13 was achieved by treatment of DDQ to yield the
alcohol 3. The crude alcohol 3 was esterified with carboxylic
Published on the web May 7, 2011; doi:10.1246/bcsj.20100197

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Bull. Chem. Soc. Jpn. Vol. 84, No. 5 (2011)
Symmetric Synthesis of Small Ring Macrolides
OH
OH
OPMB
4
1
6
7
9
O
5
O
O
O
+
OH
O
RCM
Esterification
HO
O
O
10
3
2
O
1
Stagonolide-D
SAE
OH
1,4-Butanediol
PMB = 4-methoxybenzyl
PMP = 4-methoxyphenyl
TBS = tert-butyldimethylsilyl
OTBS
OH
OH
OH
PMBO
4
1
6
7
9
4
O
Esterification
O
OH
RCM
OH
6
O
O
5
O
Stagonolide-G
(originally proposed structure)
intramolecular
trans-lactonization
HO
CO2Et
HO
PMPO
OTBS
OTBS
7
8
(S)-Ethyl lactate
O
O
HO
OH
Stagonolide-G
(revised structure)
Scheme 1. Retrosynthetic analysis of stagonolide-D and stagonolide-G.
acid 2, which was synthesized earlier in our laboratory by
applying metal-enzyme combined DKR as a key step.11 The
ester 14 thus obtained was then subjected to RCM reaction with
Grubbs first generation or second generation carbene complex.
No ring-closing product was, however, obtained.12 We envi-
sioned that the presence of PMB group at C-4 position might
cause some steric crowding and hence the two terminal vinyl
groups cannot reach in close proximity to inhibit an efficient
complexation with the metal catalyst, which is a prerequisite in
RCM reaction. Hence the PMB group in compound 14 was
deprotected by standard method13 to afford the compound 1 in
80% yield. When compound 1 was subjected to RCM reaction
with Grubbs second generation carbene complex 15 in benzene
as solvent, the ring-closing product (stagonolide-D) was
obtained in 60% yield (overall yield 17% from (S)-ethyl
lactate) as a single E-isomer.14 The E-geometry between C5 and
Synthesis of Stagonolide-G. At this onset we have decided
to carry out the synthesis for the originally proposed structure
of stagonolide-G by adopting the retrosynthetic strategy as
outlined in Scheme 1. For the synthesis of the required acid
fragment we have started from 1,4-butanediol. Selective
monoprotection (as its PMB ether, 16) and oxidation under
Swern condition afforded the aldehyde 17 in 88% yield.
Addition of allylmagnesium bromide on aldehyde 17 afforded
the racemic alcohol 18 in 91% yield. DKR of secondary
alcohol functionality in compound 18 was achieved by
coupling enzyme-catalyzed transesterification reaction with
metal-catalyzed (ruthenium-based catalyst shown in Scheme 3)
racemization method.15 Isopropenyl acetate was used as the
acyl donor in the DKR reaction. The DKR reaction is highly
efficient for compound 18 as it yields the corresponding acetate
19 in 92% yield with excellent enantioselection (ee = 98%).16
The acetate functionality was removed by treatment with
K2CO3 in MeOH to produce optically pure 20 in 94% yield.
The free secondary hydroxy group in 20 was protected as its
TBS ether by treatment with imidazole and TBS-Cl to afford
the compound 21 in 88% yield. Removal of the PMB group
1
C6 was confirmed by the H NMR analysis (JH ;H = 16.8 Hz)
5
6
of the final product. The similar precedence was observed by
Fürstner et al., for the synthesis of amphidinolides.14 The
spectral characteristic values of our synthesized stagonolide-D
and natural stagonolide-D are in perfect agreement (Scheme 2).

T. Mahapatra et al.
Bull. Chem. Soc. Jpn. Vol. 84, No. 5 (2011)
513
EtO2C
CHO
PMBO
CO2Et
PMBO
OH
CO2Et
HO
c
a
b
d
PMBO
10
9
11
(S)-Ethyl lactate
OPMB
H
OH
H
H
g
f
e
O
O
O
+
PMBO
PMBO
HO
OH
PMBO
H
H
H
12
2
3
4
13
O
OH
O
OH
OPMB
O
H
h
j
i
O
O
O
O
H
1
O
O
O
14
Stagonolide-D
N
N
MeS
MeS
Ph
Cl
15
Ru
Cl
PCy3
Scheme 2. Reagents and conditions: (a) PMBO (C=NH)CCl3, CSA, cyclohexane:DCM (2:1), 12 h, 92%; (b) DIBAL-H (1 equiv),
DCM, ¹78 °C, 90%; (c) (PhO)2POCH2CO2Et, NaH, 0 °C, 88%; (d) DIBAL-H (2 equiv), DCM, ¹78 °C to rt, 87%; (e) Ti(Oi-Pr)4,
(+)-DIPT, TBHP, DCM, ¹23 °C, 4 days, 92%; (f) DMP, LHMDS, Ph3P=CH2, 0 °C, 78%; (g) DDQ, DCM:H2O (19:1); (h) EDCI,
DMAP, 84%; (i) DDQ, DCM:H2O (19:1), 80%; (j) 15 (10 mol %), C6H6, 60%.
O
a
b
OH
OPMB
g
OPMB
OTBS
HO
c
HO
H
16
17
OR
OH
OTBS
d
h
O
18
6
OPMB
OPMB
OH
OH
22
19; R = Ac
20; R = H
Ph
e
f
Ph
NHiPr
21; R = TBS
Ph
Cl
Ph
CO
Ru
CO
DKR catalyst
Scheme 3. Reagents and conditions: a) NaH, PMB-Br, 82%; b) (COCl)2, DMSO, Et3N, ¹78 °C, 88%; c) CH2=CHCH2MgBr, THF,
91%; d) CAL-B, isopropenyl acetate, dicarbonylchloro[1-(isopropylamino)-2,3,4,5-tetraphenylcyclopentadienyl]ruthenium(II),
Na2CO3, KOt-Bu, 92%; e) K2CO3, MeOH, 94%; f) Imidazole, TBS-Cl, 88%; g) DDQ, DCM:H2O (19:1), 89%; h) PDC, DMF,
74%.

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Bull. Chem. Soc. Jpn. Vol. 84, No. 5 (2011)
Symmetric Synthesis of Small Ring Macrolides
b
RO
CHO
RO
a
RO
HO
CO2Et
+
OH
OH
23
24
25
(S)-Ethyl lactate
c
R = PMP (4-methoxyphenyl)
24 OTBS
OTBS
d
e
f
RO
HO
+
OTBS
OTBS
O
OH
OTBS
7
6
8
O
O
26
OH
OH
O
spontaneous
trans-lactonization
g
h
O
O
O
OH
OH
O
O
5
HO
Stagonolide-G
(originally reported)
OH
Stagonolide-G
(revised structure)
Scheme 4. Reagents and conditions: a) (i) TPP, DIAD, 4-methoxyphenol, 84%, (ii) DIBAL-H, DCM, ¹78 °C, 88%; b) CH2=
CHMgBr, THF, ¹20 °C, 86%; c) TPP, DIAD, PhCO2H, NaOH, 78%; d) 2,6-lutidine, TBS-OTf, 90%; e) CAN, pyridine,
CH3CN:H2O (4:1), 80%; f) DIC (diisopropyl carbodiimide), DMAP, 84%; g) HF-pyridine, 66%; h) 15 (10 mol %), DCM, 62%.
was achieved by treatment with DDQ to produce the compound
22 in 89% yield. Finally oxidation of the primary hydroxy
group was achieved by oxidation with PDC17 to afford the
corresponding carboxylic acid 6 in 74% yield (Scheme 3).
For the synthesis of the required alcohol fragment we
have started from (S)-ethyl lactate. The free hydroxy group
was protected as its PMP (para-methoxyphenyl) ether by
Mitsunobu strategy18 to afford the corresponding PMP-
protected lactate. Reduction of this compound with DIBAL-H
at ¹78 °C afforded the corresponding aldehyde 23 in 88%
yield. Addition of vinylmagnesium bromide on 23 at ¹20 °C
afforded two diastereomeric alcohols 24 and 25 (3:2) as
separable mixture. The absolute configuration of 24 and 25 was
confirmed by deprotecting the TBS and the PMP groups
subsequently, which yielded known (2R,3R)-pent-4-ene-2,3-
diol19 (from 24) and (2R,3S)-pent-4-ene-2,3-diol20 (from 25).
The undesired diastereomer 25 was converted to 24 by
Mitsunobu inversion and hydrolysis strategy. The free hydroxy
group in 24 was protected as its TBS ether by treatment with
2,6-lutidine and TBSOTf to afford compound 8 in 90% yield.
Deprotection of PMP group was achieved by treatment of 8
with CAN (ceric ammonium nitrate) in presence of pyridine21
to afford compound 7 in 80% yield. Addition of pyridine is
essential to make the reaction medium basic, otherwise
deprotection of TBS group was observed under the reaction
condition. Coupling with alcohol 7 and carboxylic acid 6 was
achieved by treatment with DIC and DMAP to afford coupled
ester 26 in 84% yield. Removal of TBS group in 26 was
accomplished by treatment with HF-pyridine22 to produce diol
5 in 66% yield. Ring-closing metathesis reaction of 5 with
Grubbs-II catalyst 15 in dichloromethane afforded stagonolide-
G in 62% yield (overall yield 15.6% from (S)-ethyl lactate). We
would also like to mention that TLC analysis of the RCM
reaction mixture shows one major spot (assumed 10-membered
macrolide structure for stagonolide-G, the Z-isomer) along with
one minor spot. We have separated the major spot and recorded
its spectral value (1H and 13C NMR) which resembles with the
natural stagonolide-G (Z-isomer). As the amount of the minor
spot is so little we could not able to isolate it in pure form. We
have observed a multiplet ranging from ¤ = 5.7-5.6 for the
olefinic protons (C6 and C7 in the originally proposed structure)
in 1H NMR spectrum. Careful analysis reveals that J1-2 (C6-C7)
value is 11.2 Hz, which is consistent with the Z-geometry
between C6 and C7 as reported in the literature.2 Though we do
not have any concrete logic to explain the Z-geometry between
C6 and C7, but we are boosted by a similar report by Srihari
et al.,3 for their total synthesis of stagonolide-G (originally
proposed structure). The spectral characteristic values of our
synthesized stagonolide-G and natural stagonolide-G2 are in
good agreement (Scheme 4). But little discrepancy was
observed in the chemical shift value (1H and 13C NMR) of
NMR spectra between our synthesized product and the reported
synthesized one.2,3 In the mean time, Angulo-Pachón et al.
reported the synthesis of stagonolide-G (originally proposed
structure) and indicated the difference in NMR between the
synthesized and natural stagonolide-G.5 They also indicated
that the 10-membered lactone stagonolide-G (originally pro-
posed structure) was readily isomerized by acid treatment to the
five-membered lactone, whose NMR was identical with the
reported natural stagonolide-G. The structure of stagonolide-G
was hence revised as shown in Scheme 4. The spectral value
(both 1H and 13C NMR) of our synthetic stagonolide-G

T. Mahapatra et al.
Bull. Chem. Soc. Jpn. Vol. 84, No. 5 (2011)
515
perfectly matched with the reported value for the five-member
ring lactone structure of stagonolide-G. It was anticipated that
the RCM product (supposed to be the 10-membered lactone)
underwent spontaneous intramolecular trans-lactonization to
yield stagonolide-G (revised structure, 5-membered lactone)
during the course of chromatographic separation or prolonged
exposure in CDCl3 solvent during NMR spectra recording.
celite, and the filtrate was concentrated to afford the crude
imidate. The crude imidate (15 g, 51 mmol) was taken in
cyclohexane (80 mL) and a solution of alcohol (S)-ethyl lactate
(3.0 g, 25.4 mmol) in 40 mL of DCM was added. The resulting
solution was cooled to 0 °C and CSA (0.6 g, 2.54 mmol) was
added to it. The reaction mixture was stirred overnight at room
temperature, slowly developing a white precipitate of trichloro-
acetamide. The solution was filtered off, washed with DCM.
The filtrate was washed with NaHCO3 solution, water and
brine. Purification by means of silica gel chromatography 9:1,
Conclusion
In conclusion we have described efficient asymmetric
synthesis of naturally occurring small ring macrolide, stago-
nolide-D and stagonolide-G by a divergent approach. The
crucial reaction involved in our synthetic planning for
stagonolide-D was ring-closing metathesis reaction of properly
substituted vinyl epoxide, Sharpless asymmetric epoxidation
and cis-selective HWE olefination by Ando protocol. Whereas
in case of stagonolide-G the main reaction involved is ring-
closing metathesis followed by spontaneous trans-lactonization
of properly substituted ester which in turn can be easily
accessed from (S)-ethyl lactate as a chiral pool. Synthetic
studies directed toward similar structurally related small ring
macrolides are currently in progress.
1
hexane:EtOAc) yielded compound 9 in 92% yield. H NMR:
¤H 7.30 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.2 Hz, 2H), 4.62 (d,
J = 11.2 Hz, 1H), 4.42 (d, J = 11.2 Hz, 1H), 4.2 (q, J = 7.2 Hz,
2H), 4.0 (q, J = 7.2 Hz, 1H), 3.8 (s, 3H), 1.38 (d, J = 7.2 Hz,
3H), 1.29 (t, J = 7.2 Hz, 3H). 13C NMR: ¤C 173.37, 159.41,
129.64, 129.4, 113.86, 73.77, 71.65, 60.79, 52.29, 18.70,
29
14.25. ½¡ꢀD = ¹64.39 (c 1.0, CHCl3).
(S)-2-(4-Methoxybenzyloxy)propionaldehyde (10). The
ester 9 (4.0 g, 16.8 mmol) was dissolved in DCM (30 mL) and
cooled to ¹78 °C. DIBAL-H (1 M in hexane, 1.05 equiv) was
added dropwise and the reaction mixture was allowed to stir at
¹78 °C for 2 h. The reaction was quenched by the addition of a
saturated solution of ammonium chloride (30 mL) and warmed
to room temperature producing a white precipitate. The
precipitate was filtered through a pad of Celite and washed
with DCM (3 © 100 mL). The filtrate was then dried (MgSO4)
and concentrated in vacuo. The aldehyde 10 was used without
further purification. 1H NMR: ¤H 9.6 (s, 1H), 7.25 (d, J =
8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 4.5 (s, 2H), 3.88 (m, 1H),
3.82 (s, 3H), 1.27 (d, J = 7.0 Hz, 3H). 13C NMR: ¤C 200.58,
159.54, 129.64, 129.48, 113.96, 79.11, 71.71, 55.29, 15.32.
Experimental
General. Unless otherwise stated, materials were obtained
from commercial suppliers and used without further purifica-
tion. THF and diethyl ether were distilled from sodium
diphenylketyl; dichloromethane (DCM), dimethylformamide
(DMF), and dimethyl sulfoxide (DMSO) were distilled from
calcium hydride. Diisopropyl ether (DIPE) was refluxed over
P2O5 and distilled prior to use. CAL-B (Candida antartica
lipase-B, Novozym-435, immobilized on acrylic resin) were
obtained from Sigma and used as obtained. Reactions were
monitored by thin-layer chromatography (TLC) carried out on
0.25 mm silica gel plates (Merck) with UV light, ethanolic
anisaldehyde and phosphomolybdic acid/heat as developing
agents. Silica gel 100-200 mesh was used for column
chromatography. Yields refer to chromatographically and
spectroscopically homogeneous materials unless otherwise
stated. NMR spectra were recorded on Bruker 400 MHz
spectrometers at 25 °C in CDCl3 using TMS as the internal
standard. Chemical shifts are shown in ¤. 13C NMR spectra
were recorded with a complete proton decoupling environment.
The chemical shift value is listed as ¤H and ¤C for 1H and 13C,
respectively. Elemental analysis was performed by using
Perkin-Elmer model 2400, series II CHN analyzer. Optical
rotations were measured on a JASCO P-1020 digital polar-
imeter.
(S)-2-(4-Methoxybenzyloxy)propionic Acid Ethyl Ester
(9). A solution of 4-methoxybenzyl alcohol (7.0 g, 51 mmol)
in 75 mL of ether was added to a suspension of 65% NaH
(0.305 g, 7.6 mmol) in 30 mL of ether at room temperature. The
resulting mixture was stirred at room temperature for 30 min
and cooled to 0 °C. Trichloroacetonitrile (TCA, 5.08 mL,
51 mmol) was added to it and the reaction mixture was allowed
to warm slowly to room temperature during 6 h. The solution
was evaporated to an orange syrup, which was dissolved in
anhydrous hexane (80 mL) containing few drops of MeOH.
This suspension was shaken vigorously and filtered through
29
½¡ꢀD = ¹34.5 (c 1.0, CHCl3).
Ethyl (Z)-(S)-4-(4-Methoxybenzyloxy)pent-2-enoate (11).
To a solution of ethyl (diphenoxylphosphinoxy)acetate (3.6 g,
11.27 mmol) in dry THF (40 mL) was added NaH (0.63 g, 15.5
mmol) at 0 °C. After 15 min, aldehyde 10 (2.3 g, 11.27 mmol)
in THF (10 mL) was added to the reaction mixture, and the
reaction mixture was gradually warmed to room temperature.
The reaction was quenched with saturated NH4Cl, and the
mixture was extracted with AcOEt (10 mL © 3). The combined
extracts were washed with water (15 mL © 2) followed by
brine, dried (MgSO4), and concentrated. Finally it was purified
by silica gel chromatography (hexane:EtOAc; 5:1) to afford the
pure Z-olefin 11 in 88% yield. 1H NMR: ¤H 7.24 (d, J = 8.8 Hz,
2H), 6.85 (d, J = 8.8 Hz, 2H), 6.20 (dd, J = 12.0, 8.4 Hz, 1H),
5.84 (d, J = 12.0 Hz, 1H), 5.14 (m, 1H), 4.44 (d, J = 11.2 Hz,
1H), 4.36 (d, J = 11.2 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.82
(s, 3H), 1.31 (d, J = 6.4 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H).
13C NMR: ¤C 165.91, 159.17, 152.19, 130.55, 129.54, 120.23,
29
113.78, 71.3, 70.77, 60.25, 55.25, 20.45, 14.18. ½¡ꢀD
=
¹46.75 (c 1.2, CHCl3).
(Z)-(S)-4-(4-Methoxybenzyloxy)pent-2-en-1-ol (4). The
unsaturated ester 11 (1.4 g, 5.3 mmol) was dissolved in DCM
(30 mL) and cooled to ¹78 °C. DIBAL-H (1 M in hexane, 2.2
equiv) was added dropwise and the reaction mixture was
allowed to stir at ¹78 °C for 4 h. The reaction was quenched by
the addition of a saturated solution of ammonium chloride
(25 mL) and warmed to room temperature producing a white
precipitate. The precipitate was filtered through a pad of Celite

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Bull. Chem. Soc. Jpn. Vol. 84, No. 5 (2011)
Symmetric Synthesis of Small Ring Macrolides
and washed with DCM (3 © 100 mL). The filtrate was then
dried (MgSO4) and concentrated in vacuo. Purification was
carried out by flash column chromatography eluting with ethyl
acetate/hexane (1:3) to afford the allylic alcohol 4 in 87%
yield. 1H NMR: ¤H 7.25 (d, J = 8.4 Hz, 2H), 6.87 (d, J =
8.4 Hz, 2H), 5.74 (m, 1H), 5.51 (m, 1H), 4.47 (d, J = 11.2 Hz,
1H), 4.31 (d, J = 11.2 Hz, 1H), 4.26 (m, 1H), 4.18 (m, 1H),
4.08 (m, 1H), 3.79 (s, 3H), 1.25 (d, J = 6.4 Hz, 3H). 13C NMR:
Elemental analysis for C14H18O3 Calcd: C, 71.77; H, 7.74%.
Found: C, 71.66; H, 7.70%.
(2R,3S)-1-Methyl-2,3-epoxypent-4-enyl (S)-4-(4-Methoxy-
benzyloxy)hex-5-enoate (14). The epoxy olefin 13 (0.15 g,
0.64 mmol) was taken in 5 mL of DCM:H2O (19:1). DDQ
(0.218 g, 0.96 mmol) was added to it in one portion. The
reaction mixture was stirred at room temperature for 1 h. The
reaction mixture was filtered off, and the filtrate was washed
with 5% NaHCO3 solution, water and brine. The organic layer
was dried (MgSO4) and evaporated. Evaporation of the organic
layer afforded the crude alcohol 3, which was subsequently
used for the next esterification reaction.
¤
159.17, 134.39, 130.66, 130.49, 129.55, 113.82, 69.92,
C
29
69.69, 58.68, 55.27, 21.45. ½¡ꢀD = ¹26.0 (c 1.0, CHCl3).
Elemental analysis for C13H18O3 Calcd: C, 70.24; H, 8.16%.
Found: C, 70.26; H, 8.23%.
{(2S,3R)-3-[(S)-1-(4-Methoxybenzyloxy)ethyl]oxiranyl}-
methanol (12). To a stirred solution of (+)-DIPT (0.75 mL,
3.53 mmol) in DCM (25 mL) at ¹23 °C containing 4 ¡ MS
(0.3 g), sequentially Ti(Oi-Pr)4 (0.84 mL, 2.94 mmol) and
anhydrous TBHP (tert-butyl hydroperoxide) (2.4 mL, 11.74
mmol) were added and stirred for 20 min. A solution of alcohol
4 (1.3 g, 5.87 mmol) in DCM (5 mL) was added and stirred for
72 h at ¹23 °C. The reaction mixture was quenched with 10%
KOH solution (3 g in 30 mL brine), stirred for 3 h and filtered.
The organic layers were dried over Na2SO4, evaporated and
the residue obtained was purified by column chromatography
(Silica gel, EtOAc/hexane, 2:3) to furnish epoxy alcohol 12 in
92% yield. 1H NMR: ¤H 7.27 (d, J = 8.4 Hz, 2H), 6.86 (d,
J = 8.4 Hz, 2H), 4.63 (d, J = 11.6 Hz, 1H), 4.52 (d, J =
11.6 Hz, 1H), 3.88 (m, 1H), 3.78 (s, 3H), 3.6 (m, 1H), 3.35 (m,
1H), 3.06 (m, 1H), 2.94 (m, 1H), 2.45 (br, 1H), 1.23 (d,
J = 6.8 Hz, 3H). 13C NMR: ¤C 159.09, 130.41, 129.32, 113.77,
The crude alcohol 3 (73 mg, 0.64 mmol) was taken in dry
DCM (2 mL). N-Ethyl-N¤-(3-dimethylaminopropyl)carbodi-
imide hydrochloride (EDCI¢HCl, 185 mg, 0.96 mmol), DMAP
(cat amount), and (S)-4-(4-methoxybenzyloxy)hex-5-enoic acid
(2, 160 mg, 0.64 mmol) were sequentially added to the reaction
mixture. The reaction mixture was kept at room temperature for
1
3 h. The ester was purified by flash chromatography. H NMR:
¤H 7.26 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 5.67-5.5
(m, 3H), 5.48-5.19 (m, 3H), 4.82 (m, 1H), 4.52 (d, J = 11.2
Hz, 1H), 4.42 (d, J = 11.2 Hz, 1H), 3.79 (s, 3H), 3.74 (m, 1H),
3.24 (m, 1H), 2.96 (dd, J = 6.0, 2.0 Hz, 1H), 2.46 (m, 2H), 1.8
(m, 2H), 1.22 (d, J = 6.4 Hz, 3H). 13C NMR: ¤C 172.69,
159.09, 138.29, 134.47, 130.56, 129.37, 120.07, 117.68,
113.75, 78.95, 70.0, 69.83, 61.2, 56.11, 55.26, 30.38, 30.09,
29
16.48. ½¡ꢀD = ¹2.6 (c 2.0, CHCl3). Elemental analysis for
C20H26O5 Calcd: C, 69.34; H, 7.57%. Found: C, 69.39; H,
7.51%.
29
74.81, 71.05, 61.45, 58.89, 55.19, 54.77, 17.21. ½¡ꢀD = ¹6.8
(2R,3S)-1-Methyl-2,3-epoxypent-4-enyl (S)-4-Hydroxyhex-
5-enoate (1). Ester 14 (58 mg, 0.16 mmol) was taken in 4 mL
of DCM:H2O (19:1). DDQ (55 mg, 0.24 mmol) was added to it
in one portion. The reaction mixture was stirred at room
temperature for 1 h. The reaction mixture was filtered off, and
the filtrate was washed with 5% NaHCO3 solution, water and
brine. The organic layer was dried (MgSO4) and evaporated.
The crude product was purified by flash chromatography (1:1,
hexane:EtOAc) to afford the compound 1 in 80% yield.
1H NMR: ¤H 5.9-5.81 (m, 1H), 5.6-5.5 (m, 2H), 5.4-5.2 (m,
2H), 5.12 (d, J = 10.4 Hz, 1H), 4.83 (m, 1H), 4.2 (m, 1H), 3.27
(dd, J = 6.4, 1.6 Hz, 1H), 2.98 (dd, J = 5.2, 1.6 Hz, 1H), 2.46
(t, J = 7.2 Hz, 2H), 1.8 (m, 2H), 1.21 (d, J = 6.4 Hz, 3H).
13C NMR: ¤C 173.08, 140.31, 134.39, 120.13, 115.16, 72.05,
(c 0.8, CHCl3). Elemental analysis for C13H18O4 Calcd: C,
65.53; H, 7.61%. Found: C, 65.55; H, 7.55%.
(2R,3S)-2-[(S)-1-(4-Methoxybenzyloxy)ethyl]-3-vinyloxi-
rane (13). Epoxyalcohol 12 (1.5 g, 6.3 mmol) was dissolved
in DCM (25 mL). DMP (2.76 g, 6.5 mmol) was added to it, and
the solution was stirred at room temperature for 3 h. After that
time all the starting materials have consumed, ether was added
to the reaction mixture. The reaction mixture was washed with
saturated Na2S2O3 solution and then brine. The organic layer
was dried with MgSO4 and concentrated to afford the crude
aldehyde.
Methyltriphenylphosphonium iodide (4.1 g, 10.16 mmol)
was taken in dry THF (40 mL) at 0 °C. A solution of LHMDS
(1 M in THF, 10.16 mL) was added to it at the same
temperature. A yellow-orange color develops with time. After
15 min stirring at the same temperature the crude aldehyde
(1.2 g, 5.08 mmol) was added to the reaction mixture. The
solution kept at 0 °C for 1/2 h and then allowed to warm at
room temperature. After that time, solution of NH4Cl was
added to the reaction mixture and it was extracted with ether.
Evaporation of the organic solution and purification by means
of flash chromatography the epoxy olefin 13 was obtained in
78% yield. 1H NMR: ¤H 7.29 (d, J = 8.4 Hz, 2H), 6.87 (d, J =
8.4 Hz, 2H), 5.59 (m, 1H), 5.45 (m, 1H), 5.29 (d, J = 10.0 Hz,
1H), 4.68 (d, J = 11.6 Hz, 1H), 4.53 (d, J = 11.6 Hz, 1H), 3.79
(s, 3H), 3.33 (m, 1H), 3.13 (d, J = 7.2 Hz, 1H), 2.96 (dd, J =
6.0, 2.0 Hz, 1H), 1.25 (d, J = 6.4 Hz, 3H). 13C NMR: ¤C
159.10, 134.99, 130.49, 129.31, 119.59, 113.71, 75.07, 70.84,
29
70.29, 61.18, 56.22, 31.6, 30.28, 16.5. ½¡ꢀD = ¹44.5 (c 0.5,
CHCl3). Elemental analysis for C12H18O4 Calcd: C, 63.70; H,
8.02%. Found: C, 63.66; H, 8.13%.
(E)-(1R,2S,7S,10S)-7-Hydroxy-2-methyl-3,11-dioxabicyclo-
[8.1.0]undec-8-en-4-one (Stagonolide-D). The compound 1
(30 mg, 0.081 mmol) was taken in anhydrous degassed C6H6
(80 mL). Grubbs second generation metathesis catalyst (7 mg,
0.008 mmol) was added to it and the solution was refluxed for
4 h. The solution was evaporated and the content of the flask
was directly loaded on a silica gel column. Flash chromatog-
raphy with hexane:EtOAc (3:1) afforded the pure stagonolide-
1
D in 60% yield. H NMR: ¤H 5.62 (dd, J = 16.8, 5.0 Hz, 1H),
5.5 (dd, J = 16.8, 8.4 Hz, 1H), 5.3 (m, 1H), 4.1 (m, 1H), 3.58
(dd, J = 4.8, 1.6 Hz, 1H), 3.01 (dd, J = 4.8, 2.0 Hz, 1H), 2.2-
2.1 (m, 2H), 2.05 (m, 2H), 1.34 (d, J = 6.4 Hz, 3H). 13C NMR:
¤C 173.4, 134.22, 128.15, 75.2, 65.78, 58.3, 55.52, 35.0, 31.28,
29
63.31, 55.19, 54.82, 17.29. ½¡ꢀD = ¹11.2 (c 0.5, CHCl3).

T. Mahapatra et al.
Bull. Chem. Soc. Jpn. Vol. 84, No. 5 (2011)
517
29
25
16.3. ½¡ꢀD = ¹84.4 (c 0.2, CHCl3); Literature value, ½¡ꢀD
=
(S)-4-(tert-Butyldimethylsiloxy)hept-6-en-1-ol (22). Com-
pound 21 (600 mg, 1.7 mmol) was taken in 20 mL of
DCM:H2O (19:1). DDQ (561 mg, 2.5 mmol) was added to
it in one portion. The reaction mixture was stirred at room
temperature for 1 h. The reaction mixture was filtered off, and
the filtrate was washed with 5% NaHCO3 solution, water and
brine. The organic layer was dried (MgSO4) and evaporated.
Purification by silica gel chromatography (3:1, hexane:EtOAc)
¹82.0 (c 0.2, CHCl3); Elemental analysis for C10H14O4 Calcd:
C, 60.59; H, 7.12%. Found: C, 60.56; H, 7.19%.
7-(4-Methoxybenzyloxy)hept-1-en-4-ol (18). Aldehyde 17
(5 g, 24 mmol) was taken in 40 mL of anhydrous THF. Solution
of allylmagnesium bromide (freshly prepared from allyl
bromide and Mg metal, 36 mmol) was added to it at 0 °C.
The reaction mixture was kept at the same temperature for 1 h,
after that time saturated NH4Cl solution was added to it. The
solution was extracted with EtOAc, and the organic layer was
washed with water and brine. The organic layer was dried
(MgSO4) and evaporated. Purification by silica gel chromatog-
raphy (3:1, hexane:EtOAc) afforded the alcohol 18 in 91%
yield. 1H NMR: ¤H 7.24 (d, J = 8.4 Hz, 2H), 6.87 (d, J =
8.4 Hz, 2H), 5.93-5.72 (m, 1H), 5.14-5.07 (m, 2H), 4.44 (s,
2H), 3.7 (s, 3H), 3.62 (m, 1H), 3.48 (t, J = 7.8 Hz, 2H), 2.23
(m, 2H), 1.8-1.54 (m, 4H). 13C NMR: ¤C 159.22, 135.12,
130.32, 129.35, 117.67, 113.83, 72.68, 70.6, 70.18, 55.28,
41.99, 34.1, 26.26. Elemental analysis for C15H22O3 Calcd: C,
71.97; H, 8.86%. Found: C, 71.91; H, 8.88%.
(R)-1-[3-(4-Methoxybenzyloxy)propyl]but-3-enyl Acetate
(19). In a 50 mL round bottom flask attached with a grease
free high vacuum stopcock, dicarbonylchloro[1-(isopropyl-
amino)-2,3,4,5-tetraphenylcyclopentadienyl]ruthenium(II) (DKR
catalyst, 84 mg, 0.136 mmol) was taken. The flask was
successively charged with alcohol 18 (0.86 g, 3.6 mmol) in
10 mL dry toluene, Na2CO3 (3.4 mmol), CAL-B (25 mg), and
KOt-Bu (0.17 mmol) followed by isopropenyl acetate
(5 mmol). The reaction mixture was stirred at room temperature
under argon atmosphere. After that time the reaction mixture
was filtered off and the solution was evaporated to afford the
crude acetate 19, which was subsequently purified by silica
gel chromatography (10:1, hexane:EtOAc) to afford the pure
1
afforded the pure compound 22 in 89% yield. H NMR: ¤H
5.83-5.66 (m, 1H), 5.06-4.97 (m, 2H), 3.73 (m, 1H), 3.57 (m,
2H), 2.22 (m, 2H), 1.59-1.5 (m, 4H), 0.89 (s, 9H), 0.04 (s, 6H).
13C NMR: ¤C 135.0, 116.84, 71.83, 62.86, 41.58, 33.08, 28.29,
29
25.84, 18.07, ¹4.49, ¹4.63. ½¡ꢀD = ¹3.96 (c 1.75, CHCl3).
(S)-4-(tert-Butyldimethylsiloxy)hept-6-enoic Acid (6).
The compound 22 (700 mg, 2.9 mmol) was taken in anhydrous
DMF (10 mL). Pyridinium dichromate (PDC, 5.4 g, 14.3 mmol)
was added to the reaction mixture and the reaction mixture was
stirred at room temperature till all the starting material has been
consumed as indicated by TLC. Water was added to the reaction
mixture, the water layer was extracted thrice with EtOAc
(3 © 25 mL) followed by a washing with aq. KHSO4 solution.
The organic extract was dried (MgSO4) and evaporated. The
crude acid 6 was purified by silica gel chromatography (1:1,
hexane:EtOAc). 1H NMR: ¤H 5.89-5.68 (m, 1H), 5.09-5.01 (m,
2H), 3.77 (m, 1H), 2.41 (t, J = 7.8 Hz, 2H), 2.23 (t, J = 6.2 Hz,
2H), 1.85-1.68 (m, 2H), 0.88 (s, 9H), 0.05 (s, 6H). 13C NMR: ¤C
180.18, 134.52, 117.25, 70.69, 41.78, 31.14, 29.85, 25.84,
29
18.06, ¹4.39, ¹4.70. ½¡ꢀD = ¹4.95 (c 2.0, CHCl3).
(R)-2-(4-Methoxyphenoxy)propionaldehyde (23).
A
solution of DIAD (diisopropyl azodicarboxylate) (5.4 mL,
27.56 mmol) in THF (20 mL) was added dropwise to a mixture
of (S)-ethyl lactate (2.5 g, 21.2 mmol), 4-methoxyphenol (5.3 g,
42.37 mmol), and TPP (7.2 g, 27.56 mmol) in anhydrous THF
(75 mL). The reaction mixture was stirred for overnight at
room temperature. After evaporation of THF, a mixture of
hexane:ether (1:1, 125 mL) was added to the viscous residue,
the organic layer was washed with 1 M NaOH (50 mL), water
and finally with brine. The organic extract was dried and
evaporated to afford the PMP-protected lactate.
1
acetate in 92% yield. H NMR: ¤H 7.23 (d, J = 8.6 Hz, 2H),
6.84 (d, J = 8.6 Hz, 2H), 5.82-5.62 (m, 1H), 5.1 (m, 2H), 4.91
(m, 1H), 4.39 (s, 2H), 3.76 (s, 3H), 3.4 (m, 2H), 2.28 (t, J =
6.6 Hz, 2H), 1.99 (s, 3H), 1.6 (m, 4H). 13C NMR: ¤C 170.65,
159.16, 133.69, 130.59, 129.22, 117.67, 113.76, 72.99, 72.54,
69.57, 55.2, 38.69, 30.3, 25.64, 21.15. Elemental analysis for
C17H24O4 Calcd: C, 69.84; H, 8.27%. Found: C, 69.89; H,
PMP-protected lactate (3 g, 13.4 mmol) was taken in
anhydrous DCM (70 mL). DIBAL-H (13.4 mmol, 1 M in
hexane) was added to the reaction mixture at ¹78 °C. The
reaction mixture was kept at the same temperature for further
1 h. After that time a saturated solution of Na2SO4 was added to
it, and the white gelatinous ppt was filtered off with a Celite
pad. The organic layer was evaporated and purified by means
of silica gel chromatography to afford the pure aldehyde in
88% yield. 1H NMR: ¤H 9.72 (d, J = 1.8 Hz, 1H), 6.84 (s, 4H),
4.54 (dq, J = 7.0, 1.8 Hz, 1H), 3.76 (s, 3H), 1.45 (d, J = 7.0
Hz, 3H). 13C NMR: ¤C 202.97, 154.94, 151.63, 117.0, 115.13,
79.03, 55.91, 15.83. Elemental analysis for C10H12O3 Calcd: C,
29
7.21%. ½¡ꢀD = ¹3.74 (c 2.0, CHCl3).
(S)-4-(tert-Butyldimethylsiloxy)-7-(4-methoxybenzyloxy)-
hept-1-ene (21). Compound 20 (1 g, 4 mmol) was taken in
30 mL of anhydrous DCM. Imidazole (816 mg, 12 mmol) was
added to it at room temperature. The reaction mixture was
stirred for 15 min. After that time TBS-Cl (1.2 g, 8 mmol) was
added to it and the reaction mixture was stirred overnight. After
completion of the reaction, water was added to the reaction
mixture and the organic layer was washed with excess water
and brine. The organic layer was dried (MgSO4) and
evaporated to dryness to afford the crude silylated compound
21, which was purified by silica gel chromatography (15:1,
hexane:EtOAc). 1H NMR: ¤H 7.28 (d, J = 8.6 Hz, 2H), 6.90 (d,
J = 8.6 Hz, 2H), 5.93-5.79 (m, 1H), 5.12-5.04 (m, 2H), 4.46
(s, 2H), 3.84 (m, 1H), 3.76 (s, 3H), 3.47 (t, J = 6.4 Hz, 2H),
2.27 (t, J = 6.8 Hz, 2H), 1.72-1.54 (m, 4H), 0.98 (s, 9H), 0.1
(s, 6H). 13C NMR: ¤C 159.19, 135.25, 130.81, 129.2, 116.81,
113.76, 72.5, 71.81, 70.24, 55.13, 42.05, 33.37, 26.0, 25.72,
29
66.65; H, 6.71%. Found: C, 66.69; H, 6.65%. ½¡ꢀD = +0.38
(c 1.0, CHCl3).
(3R,4R)-4-(4-Methoxyphenoxy)pent-1-en-3-ol (24). Al-
dehyde 23 (500 mg, 2.8 mmol) was taken in 40 mL of
anhydrous THF. Solution of vinylmagnesium bromide (1 M,
5.6 mL, 5.6 mmol) was added to it at ¹20 °C. The reaction
mixture was kept at the same temperature for 1 h, after that time
saturated NH4Cl solution was added to it. The solution was
29
18.17, ¹4.29, ¹4.45. ½¡ꢀD = +2.13 (c 1.0, CHCl3).

518
Bull. Chem. Soc. Jpn. Vol. 84, No. 5 (2011)
Symmetric Synthesis of Small Ring Macrolides
extracted with EtOAc, and the organic layer was washed with
water and brine. The organic layer was dried (MgSO4) and
evaporated. Purification by silica gel chromatography (3:1,
hexane:EtOAc) afforded the alcohol 24 and 25 in 86% yield
(3:2), which are separated by silica gel chromatography.
1H NMR: ¤H 6.85 (m, 4H), 5.90 (m, 1H), 5.42 (m, 1H), 5.29
(m, 1H), 4.36-4.24 (m, 2H), 3.78 (s, 3H), 1.23 (d, J = 6.2 Hz,
3H). 13C NMR: ¤C 154.46, 151.49, 136.24, 117.97, 116.99,
114.76, 78.07, 74.62, 55.71, 13.98. Elemental analysis for
C12H16O3 Calcd: C, 69.21; H, 7.74%. Found: C, 69.29; H,
172.78, 133.82, 129.62, 127.55, 117.35, 75.57, 72.55, 71.99,
40.89, 30.84, 29.86, 14.95. Elemental analysis for C12H20O4
Calcd: C, 63.14; H, 8.83%. Found: C, 63.19; H, 8.89%.
(S)-5-[(Z)-(4R,5R)-4,5-Dihydroxyhex-2-enyl]dihydrofuran-
2-one (Stagonolide-G). The diol 5 (40 mg, 0.175 mmol) was
taken in anhydrous degassed DCM (100 mL). Grubbs second
generation metathesis catalyst (15 mg, 0.0175 mmol) was added
to it and the solution was refluxed for 6 h. The solution was
evaporated and the content of the flask was directly loaded on a
silica gel column. Flash chromatography with hexane:EtOAc
29
1
7.71%. ½¡ꢀD = ¹0.36 (c 1.0, MeOH).
(1:3) afforded the pure stagonolide-G in 62% yield. H NMR:
¤ 5.65 (m, 2H), 4.84 (m, 1H), 4.11 (m, 1H), 3.68 (m, 1H),
H
(3R,4R)-4-Allyloxy-3-(tert-butyldimethylsiloxy)pent-1-
ene (8). Alcohol 24 (200 mg, 0.96 mmol) was taken in dry
DCM (2 mL). 2,6-Lutidine was (0.35 mL, 2 mmol) added to it
at 0 °C and kept for 5 min at the same temperature. TBS-OTf
(0.25 mL, 0.96 mmol) was added to the reaction mixture and
the solution warmed to attain room temperature. The reaction
mixture was kept for overnight, after that it was washed with
NaHCO3, brine and dried (Na2SO4). It was purified by flash
chromatography (10:1; hexane:EtOAc) to afford compound 8
2.37-2.14 (m, 4H), 1.79-1.72 (m, 2H), 1.10 (d, J = 6.4 Hz,
3H). 13C NMR: ¤C 178.0, 132.48, 127.89, 79.52, 72.4, 70.89,
29
33.85, 28.75, 27.5, 18.89. ½¡ꢀD = +96.2 (c 0.1, CHCl3);
25
Literature value, ½¡ꢀD = +96.0 (c 0.1, CHCl3). Elemental
analysis for C10H16O4 Calcd: C, 59.98; H, 8.05%. Found: C,
59.93; H, 8.09%.
We are Thankful to CSIR (New Delhi, India; Grant No.: 01-
2109/07/EMR-II) for providing financial support. We are also
thankful to DST (New Delhi) for providing the departmental
NMR facility under the DST-IRPHA program. Two of the
authors TM & TD is thankful to CSIR (New Delhi, India) for a
research fellowship.
1
in 90% yield. H NMR: ¤H 6.84 (m, 4H), 6.0-5.84 (m, 1H),
5.39-5.15 (m, 2H), 4.34 (m, 2H), 3.77 (s, 3H), 1.24 (d, J =
6.4 Hz, 3H), 0.95 (s, 9H), 0.07 (s, 6H). 13C NMR: ¤C 153.84,
138.49, 117.46, 117.16, 115.72, 114.63, 78.06, 75.63, 55.68,
29
25.93, 18.34, 14.43, ¹4.46, ¹4.65. ½¡ꢀD = ¹24.20 (c 1.0,
MeOH).
Supporting Information
(2R,3R)-3-(tert-Butyldimethylsiloxy)pent-4-en-2-ol
(7).
Compound (260 mg, 0.8 mmol) was dissolved in
8
1H NMR and 13C NMR spectra of selected compounds. This
material is available free of charge on the web at http://
www.csj.jp/journals/bcsj/.
CH3CN:H2O (4:1, 10 mL), followed by addition of CAN
(1.2 g, 2 mmol) and pyridine (1 mmol) at 0 °C. The solution was
kept at the same temperature for 10 min. After that time it was
extracted repeatedly with DCM. The organic layer was washed
with water and brine. It was further purified by silica gel
chromatography to afford the compound 7 in 80% yield.
1H NMR: ¤H 5.86-5.69 (m, 1H), 5.23-5.14 (m, 2H), 3.96 (m,
1H), 3.70 (m, 1H), 1.07 (d, J = 6.4 Hz, 3H), 0.87 (s, 9H), 0.04
(s, 6H). 13C NMR: ¤C 138.49, 137.30, 78.29, 70.84, 26.03,
References
1
a) A. Evidente, A. Cimmino, A. Berestetskiy, G. Mitina, A.
Andolfi, A. Motta, J. Nat. Prod. 2008, 71, 31. b) H. Greve, P. J.
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2
A. Evidente, A. Cimmino, A. Berestetskiy, A. Andolfi, A.
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P. Srihari, B. Kumaraswami, D. C. Bhunia, J. S. Yadav,
Tetrahedron Lett. 2010, 51, 2903.
For total synthesis of stagonolides see: a) P. Srihari, G.
29
18.51, 17.66, ¹4.08, ¹4.70. ½¡ꢀD = ¹4.95 (c 1.0, MeOH).
(1R,2R)-2-(tert-Butyldimethylsiloxy)-1-methylbut-3-enyl
3
(S)-4-(tert-Butyldimethylsiloxy)hept-6-enoate (26).
The
4
coupling between alcohol 7 and carboxylic acid 6 was
performed as described in the section of compound 14 to
Maheswara Rao, R. Srinivasa Rao, J. S. Yadav, Synthesis 2010,
2407. b) P. Srihari, B. Kumaraswamy, R. Somaiah, J. S. Yadav,
Synthesis 2010, 1039. c) D. K. Mohapatra, R. Somaiah, M. M.
Rao, F. Caijo, M. Mauduit, J. S. Yadav, Synlett 2010, 1223. d)
D. K. Mohapatra, U. Dash, P. R. Naidu, J. S. Yadav, Synlett 2009,
2129. e) P. Srihari, B. Kumaraswamy, G. Maheswara Rao, J. S.
Yadav, Tetrahedron: Asymmetry 2010, 21, 106. f) A. K. Perepogu,
D. Raman, U. S. N. Murty, V. J. Rao, Bioorg. Chem. 2009, 37, 46.
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1
afford the ester 26 in 84% yield. H NMR: ¤H 5.85-5.65 (m,
2H), 5.26-5.03 (m, 4H), 4.91 (m, 1H), 4.11 (m, 1H), 3.71 (m,
1H), 2.32 (m, 2H), 2.28 (m, 2H), 1.78 (m, 2H), 1.09 (d,
J = 6.4 Hz, 3H), 0.85 (s, 9H), 0.02 (s, 6H). 13C NMR: ¤C
173.06, 136.75, 134.64, 117.08, 116.52, 74.41, 72.77, 70.85,
41.78, 31.50, 30.35, 25.83, 25.72, 18.03, 14.79, ¹4.41, ¹4.66.
29
½¡ꢀD = +3.47 (c 2.0, MeOH).
(1R,2R)-2-Hydroxy-1-methylbut-3-enyl (S)-4-Hydroxy-
hept-6-enoate (5).
The ester 26 (140 mg, 0.3 mmol) was
5
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taken in CH3CN (4 mL). A solution of HF-pyridine (70% as
HF, 0.7 mmol) was added to it and the solution was kept at
room temperature for 24 h. After that time EtOAc was added to
the solution and it was washed with NaHCO3 and then brine.
Purification by means of chromatography afforded the pure diol
5 in 66% yield. 1H NMR: ¤H 5.78-5.72 (m, 1H), 5.67-5.60 (m,
1H), 5.09-4.85 (m, 5H), 4.22 (m, 1H), 3.76 (m, 1H), 2.27-2.14
(m, 4H), 1.74 (m, 2H), 1.12 (d, J = 6.8 Hz, 3H). 13C NMR: ¤C
6
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