Total synthesis and absolute configuration of curvularides A-E

Article abstract of DOI:10.1021/jo301264k

The first total synthesis of curvularides A-E, isolated from a culture broth of the endophytic fungus Curvularia geniculata, is described. The divergent total synthesis reported herein confirmed the absolute configurations of curvularides A-E and supported that these natural products might be obtained from a common biosynthetic pathway. The key steps involved in the synthesis were the diastereoselective hydrogenation of exo-methylene-γ-butyrolactone to α-methyl-γ-butyrolactone, Sharpless kinetic resolution, Sharpless asymmetric epoxidations, and intramolecular and intermolecular epoxide openings.

Full text of DOI:10.1021/jo301264k

Article
pubs.acs.org/joc
Total Synthesis and Absolute Configuration of Curvularides A‑E
Gangarajula Sudhakar,* Kovela Satish, and Jakka Raghavaiah
Division of Crop Protection Chemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
S
* Supporting Information
ABSTRACT: The first total synthesis of curvularides A−E, isolated from a culture broth of the endophytic fungus Curvularia
geniculata, is described. The divergent total synthesis reported herein confirmed the absolute configurations of curvularides A−E
and supported that these natural products might be obtained from a common biosynthetic pathway. The key steps involved in
the synthesis were the diastereoselective hydrogenation of exo-methylene-γ-butyrolactone to α-methyl-γ-butyrolactone, Sharpless
kinetic resolution, Sharpless asymmetric epoxidations, and intramolecular and intermolecular epoxide openings.
group could not be unambiguously established. As curvularides
A−E are closely related, they are expected to share the same
biosynthetic pathway and stereochemistry.1 Curvularide B is an
epoxide derivative of curvularide A, while curvularide C is an O-
methyl analogue. Curvularide D is a keto derivative of
curvularide B. The tetrahydrofuran ring containing curvularide
E is a derivative of curvularides A−D. They share structural
similarities with coronatine and jasmonoyl-L-isoleucine, which
are important phytohormones and signaling metabolites in
plants2,3 and contain 12-carbon polyketide conjugated with L-
isoleucine or other amino acids. Curvularides are expected to
play an ecological role by preventing phytopathogenic fungi
from growing in plant hosts. Curvularide B exhibited antifungal
activity against Candida albicans and showed synergistic activity
along with fluconazole.1
INTRODUCTION
Curvularides A−E (1−5) (Figure 1A), antifungal hybrid
peptide−polyketides, were isolated from a culture broth of
■
We became interested in the total synthesis of curvularides
because of their biological activities, structural complexity, and
incompletely assigned epoxide stereochemistry of curvularides
B (2) and D (4). From a biogenesis point of view, we
hypothesized that curvularides A−E (1−5) could be obtained
in a divergent manner if we were able to synthesize frameworks
like the epoxy α,β-unsaturated ester I or the peptide−
polyketide II (Figure 1B). The peptide−polyketide II, which
is a planar structure of curvularide B, is expected to be formed
by a peptide coupling reaction between the acid derived from I
and L-isoleucinol. Curvularide B/II can be converted to other
curvularides by appropriate transformations such as oxidation
of secondary hydroxyl to provide D (4), intermolecular epoxide
Figure 1. (A) Curvularides A−E (1−5). (B) Synthetic plan for
curvularides.
the endophytic fungus Curvularia geniculata CTOM11.1
Structure elucidation was based on spectroscopic analysis,
while the relative configurations of curvularides A and E were
determined by X-ray crystallography. The absolute config-
uration of curvularide B at C8 position was determined as R by
the Mosher method. However, the configuration of the epoxide
Received: July 12, 2012
© XXXX American Chemical Society
A
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opening to provide A (1) and C (3), and intramolecular
epoxide opening to provide E (5). Alternatively, these natural
products can also be obtained from operating the above-
mentioned transformations in I, followed by the late-stage
peptide coupling with L-isoleucinol. Herein, we describe the
first total synthesis and confirmation of the absolute
configurations of curvularides A−E (Figure 1A) through a
divergent synthetic approach.
Scheme 2. Synthesis of Lactone (+)-9
RESULTS AND DISCUSSION
■
Based on the proposed relative and absolute configurations,1 we
envisioned that α,β-unsaturated epoxy ester 6 (Scheme 1), in
Scheme 1. Retrosynthetic Plan for 6
afford the enantiomerically pure (+)-11 in 23% yield and 99%
ee.9 Treatment of (+)-11 with PTSA in toluene resulted in
(+)-10 in 86% yield, whereas under the same reaction
conditions, racemic ( )-11 yielded ( )-10. Hydrogenation of
the exo-methylene-γ-butyrolactone 10 in THF reduced the exo-
methylene group as well as the terminal olefinic bonds,
diastereoselectively furnishing α-methyl-γ-butyrolactone 9 in
1
86% yield (dr 9.1:0.9, H NMR). Employing other solvents
such as EtOH,4,5 EtOAc, MeOH, and hexane ended up
affording the desired product in lower yields due to the allylic
C−O bond cleavage.
The key fragment 6 can be accessed in an enantiomerically
pure form from (+)-9, but due to the moderate yield at kinetic
resolution step ((+)-11, 23%), we decided to proceed with the
racemic lactone ( )-9 and hoped to separate undesired isomer
after the formation of diastereomers at the Sharpless
asymmetric epoxidation step. To this end, lactone ( )-9,
which was easily obtained diastereoselectively from ( )-10 by
hydrogenation, was reduced to its corresponding lactol and
subsequently subjected to a 3C-Wittig reaction to afford α,β-
unsaturated ester10 ( )-13 (Scheme 3). After silyl ether
protection, it was reduced to allylic alcohol ( )-8. Subsequent
Sharpless asymmetric epoxidation furnished an inseparable
diastereomeric mixture 7a and 7b (dr 1:1). Oxidation of the
primary hydroxyl group of this diastereomeric mixture followed
by 2C-Wittig reaction provided epoxy esters 6a and 6b (dr
1:1), which were subjected to silyl deprotection using11−13
TBAF for 36 h, resulting in the chromatographically separable
five-membered 14 and six-membered 15 along with the epoxy
alcohol 16a in the ratio of (4.1:1:5.2) and in 93% combined
yield. Interestingly, the treatment of 6a and 6b (dr 1:1) with
HF−pyridine in THF at 0 °C to rt gave the same results,14
except that the 14 to 15 ratios (1:5.1) were reversed. Successful
acetylation only on 15 to give 15a indicated, after spectroscopic
analysis, that 14 was tetrahydrofuran derivative and 15 was a
tetrahydropyran derivative. At this stage, the isolation of an
enantiomerically pure epoxy alcohol 16a in 47% yield from 1:1
diastereomeric mixture of 6a and 6b suggested that only one of
the diastereomers was preferentially involved in the formation
of five-membered 14 and six-membered 15 in 46% combined
yield. We considered that ester hydrolysis of 14 and subsequent
coupling with L-isoleucinol would provide the peptide−
polyketide framework, whose spectral data can be compared
with the data of curvularide E (5). This comparison is expected
to disclose the stereochemistry of epoxy alcohol from which
five-membered and six-membered products resulted. Thus, 14
was subjected to an ester hydrolysis to furnish 17, which was
subsequently coupled with L-isoleucinol in the presence of
which the required epoxide can be installed, could be the
suitable framework to deliver curvularides A−E with the
necessary stereochemistry. As outlined in Scheme 1, 6 could be
obtained from the epoxy alcohol 7 via oxidation of the primary
hydroxyl and subsequent 2C-Wittig reaction. Depending upon
the requisite epoxide stereochemistry, 7 should be easily
accessed from allylic alcohol 8 by using Sharpless asymmetric
epoxidation. The key intermediate 8 could be realized from γ-
butyrolactone 9 by reduction, followed by 3C-Wittig reaction,
protection, and further reduction. The lactone 9 was expected
to be accessed diastereoselectively from hydrogenation of 10,
which, in turn, was planned from 11 by using Sharpless kinetic
resolution followed by lactonization. Allylic alcohol 11 could be
derived by reacting 12 with acrolein in Reformatsky-type
reaction conditions.
The synthetic approach we planned for γ-butyrolactone 9
was based on the literature-reported4,5 diastereoselective
hydrogenation of the exo-methylene-γ-butyrolactone to α-
methyl-γ-butyrolactone. The synthesis of enantiomerically
pure exo-methylene butyrolactone (+)-10 was commenced
from the MBH reaction between ethyl acrylate and form-
aldehyde.6 Bromination of the resultant allylic alcohol afforded
ethyl α-bromomethylacrylate7 (12) (Scheme 2), which under
Reformatsky-type reaction conditions8 with acrolein yielded
allylic alcohol ( )-11 and lactone ( )-10 in a 2:1 ratio with a
combined yield of 66%. It is interesting to note that the
formation of allylic alcohol ( )-11 was largely predominant
(>95% by TLC) in the reaction mixture, but during the
chromatographic purification, lactone ( )-10 was developed in
considerable amount. After column chromatographic separa-
tion, ( )-11 was subjected to a Sharpless kinetic resolution to
B
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Scheme 3. Synthesis of Compound 18 and Curvularide E (5)
peptide coupling reagents to produce peptide−polyketide 18 in
73% yield in two steps. Divergence of 1H and 13C NMR data of
18 from curvularide E (5) revealed that 14 and 15 might have
been obtained from the epoxy alcohol 16b, which was not
isolable in our hands. Thus, we expected that the stable epoxy
alcohol 16a should be with the required stereochemistry to
deliver the curvularide E (5). Accordingly, 16a was treated11,12
with 0.2 equiv of CSA in CH2Cl2 at 0 °C to rt for 8 h to furnish
chromatographically separable five-membered 19 and six-
membered 20 in favor of the required one (4.1:0.9) in 97%
combined yield. Finally, ester hydrolysis of 19 and subsequent
coupling with L-isoleucinol gave the desired curvularide E (5)
in 85% yield. The spectral data of the synthetic sample and
the epoxy alcohols 7a and 7b′ resulted in the corresponding
aldehydes, which were treated with the 2C-Wittig reagent to
give α,β-unsaturated esters 6a and 6b′, respectively. Here, 6a
was treated with TBAF to achieve a silyl deprotected epoxy
alcohol, which is identical in all respects with 16a, obtained
according to Scheme 3. This further confirmed the stereo-
chemistry of epoxy alcohols 6a, 16a (4S,5S,6S,8R), and 16b
(4S,5S,6R,8S).
Ester hydrolysis of 6a and 6b′ gave the corresponding acids
22 and 23, respectively. Coupling of L-isoleucinol with 22 and
23 gave corresponding peptide−polyketides 24 and 25,
respectively. Silyl deprotection of 24 provided the desired
1
curvularide B (2) in 86% yield, matched H and 13C spectra
optical rotation [[α]26 = −7.2 (c 0.48, CHCl3); lit.1 [α]28
=
and optical rotation [[α]26 = +11.3 (c 0.26, CHCl3); lit.1
D
D
D
−7.8 (c 0.33, CHCl3)] is identical with the data reported for the
natural product.
[α]28D = +10.2 (c 0.43, CHCl3)] with the natural product. The
deprotection of 2515 yielded a mixture of five-membered 26
and six-membered 27 in 1:0.3 ratio with a combined yield of
79%.
As epoxide orientation in curvularide B and D was not
conclusively defined,1 we planned the synthesis of both
enantiomerically pure epoxy esters 6a and 6b′ (Scheme 4)
from allylic alcohol (−)-8, which was synthesized from lactone
(+)-9 via (+)-13. Accordingly, epoxy alcohols 7a and 7b′ were
synthesized separately from (−)-8 by using appropriate
Sharpless asymmetric epoxidation conditions. Oxidation of
For the synthesis of curvularide D (4), primary hydroxyl in
24 was acetylated to give 28, which upon treatment with TBAF
gave the epoxy alcohol 29 in 82% yield over two steps. The
secondary hydroxyl of 29 was oxidized by using DMP16,17 to
produce acetyl derivative of curvularide D, finally acetyl
C
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Scheme 4. Synthesis of Curvularides B (2) and D (4)
deprotection with K2CO3 in MeOH achieved the anticipated
curvularide D (4) in 75% yield over two steps. The spectral
data of synthetic curvularides D agree well with the natural
product data.18
C (3) in 84% yield. The data of synthesized curvularides A
[[α]27 = −9.9 (c 0.15, CHCl3); lit.1 [α]27 = −9.3 (c 0.26,
D
D
CHCl3)] and C agree well with the data reported for natural
products, except the difference in optical rotation of curvularide
C [([α]27 = −42.9 (c 0.19, CHCl3); lit.1 [α]28 = −14.2 (c
According to our strategy, the synthesis of curvularides A−E
from a common intermediate, the next target became the
synthesis of curvularides A and C from epoxy alcohol 16a.19
The secondary hydroxyl group in 16a was protected as acetate
30 in excellent yield. After various attempts, 30 was treated with
0.2 equiv of TFA in a THF/H2O system (1:1)20 to afford the
desired diol 31 as major along with its inseparable diastereomer
(dr 9.2:0.8, 1H NMR) in 77% yield. Subsequent ester hydrolysis
followed by coupling with L-isoleucinol afforded curvularide A
(1) in 69% yield in two steps (Scheme 5).
D
D
0.32, CHCl3)].
CONCLUSION
■
In conclusion, the first total synthesis of curvularides A−E was
achieved through a divergent synthetic strategy, which
supported a common biosynthetic pathway as well as confirmed
the absolute configurations. The synthesis and biological
activity of curvularide analogues are in progress in our
laboratory and will be reported in due course.
To get a curvularide C (3), intermolecular epoxide opening
of 30 in MeOH in the presence of BF3·OEt2 afforded21,22 the
desired O-methylated tertiary hydroxyl derivative 33 as the
major product along with its inseparable diastereomer (dr
9.3:0.7, 1H NMR) in 84% yield. Under basic hydrolysis
conditions, 33 gave the corresponding secondary hydroxyl α,β-
unsaturated carboxylic acid 34 in 85% yield. Finally, coupling it
with L-isoleucinol completed the total synthesis of curvularide
EXPERIMENTAL SECTION
■
Ethyl α-Bromomethylacrylate (12):.6,7 The formaldehyde (11.4
mL, 152.46 mmol) and ethyl acrylate (46.2 g, 462.0 mmol) were
mixed with a 1:1 (v/v) mixture of 1,4-dioxane−water. To this was
added 1,4-diazabicyclo[2.2.2]octane (17.1 g, 152.46 mmol), and the
mixture was stirred for 36 h at rt. The mixture was diluted with ether
(2 × 250 mL) and washed with H2O (150 mL). The organic phase
was dried with Na2SO4, filtered, and concentrated under reduced
D
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extracted with EtOAc (2 × 50 mL), washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (12% EtOAc/
Scheme 5. Synthesis of Curvularides A (1) and C (3)
hexanes) to afford (+)-11 (230 mg, 23%) as a light yellow oil: Rf =
1
0.4, 20% EtOAc/hexanes; [α]25 = +25.1 (c 0.37, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 6.21 (s, 1H), 5.83 (m, 1H), 5.63 (s, 1H), 5.22
(d, J = 17.0 Hz, 1H), 5.02 (d, J = 10.4 Hz, 1H), 4.24 (m, 1H), 4.20 (q,
J = 7.1 Hz, 2H), 2.58 (dd, J = 13.8, 4.5 Hz, 1H), 2.44 (dd, J = 13.8, 8.1
Hz), 2.41 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 167.1, 139.9, 136.6, 127.5, 114.2, 71.1, 60.5, 39.6, 13.7; IR
(neat) νmax 3476, 2982, 1712, 1299, 1152, 1027, 946, 815 cm−1;
HRMS (ESI) calcd for C9H14O3Na [M + Na]+ 193.0835, found
193.0834.
(S)-3-Methylene-5-vinyldihydrofuran-2(3H)-one ((+)-10). To
a stirred solution of alcohol (+)-11 (230 mg, 1.352 mmol) in toluene
(4 mL) at rt was added p-toluenesulfonic acid (23.25 mg, 0.135 mmol)
and the reaction mixture allowed to stir at rt for 2 h. The reaction
mixture was quenched by the addition of H2O and extracted with
EtOAc (2 × 50 mL). The organic layer was washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (10% EtOAc/hexane)
to furnish (+)-10 (144 mg, 86%) as a light yellow oil: Rf = 0.5, 20%
EtOAc/hexanes; [α]25 = +47.6 (c 0.52, CHCl3); 1H NMR (300
D
MHz, CDCl3) δ 6.16 (t, J = 2.4 Hz, 1H), 5.83 (m, 1H), 5.59 (t, J = 2.4
Hz, 1H), 5.33 (d, J = 17.1 Hz, 1H), 5.21 (d, J = 10.4 Hz, 1H), 4.89 (q,
J = 6.6 Hz, 1H), 3.11 (ddt, J = 17.0, 8.1, 2.4 Hz, 1H), 2.65 (dm, J =
17.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 169.6, 135.5, 133.6,
121.8, 117.2, 76.9, 33.3; IR (neat) νmax 2921, 2854, 1758, 1661, 1424,
1320, 1263, 985, 938, 753 cm−1; HRMS (ESI) calcd for C7H9O2 [M +
H]+ 125.0597, found 125.0597.
pressure. The residue was purified by silica gel column chromatog-
raphy (12% EtOAc/hexane) to furnish ethyl 2-(hydroxymethyl)-
acrylate as an oily liquid (45.79 g, 75%) (Rf = 0.4, 20% EtOAc/
hexanes).
(3S,5R)-5-Ethyl-3-methyldihydrofuran-2(3H)-one ((+)-9). A
solution of lactone (+)-10 (144 mg, 1.161 mmol) in THF (12 mL)
was hydrogenated at 1 atmospheric balloon pressure in the presence of
a catalytic amount of 10% Pd/C (14.4 mg) for 1 h. The mixture was
then filtered through a pad of Celite, washed with EtOAc (50 mL),
evaporated, and purified by column chromatography (8% EtOAc/
hexane) to give a saturated syn product (+)-9 (128 mg (dr 9.1:0.9),
To a stirred solution of ethyl α-hydroxymethylacrylate (40 g, 307.69
mmol) in dry ether (650 mL) at −10 °C was added phosphorus(III)
bromide (33.31 g, 123.08 mmol). The temperature was allowed to rise
to 20 °C, and stirring was continued for 3 h. Water (150 mL) was
added at −10 °C, and the reaction mixture was extracted with hexane
(3 × 500 mL). The organic phase was washed with saturated NaCl
solution, dried with Na2SO4, and filtered. The solvents were
evaporated, and the residue was purified by column chromatography
(2% EtOAc/hexanes) to furnish ethyl α-bromomethylacrylate (12)
86%) as an oily liquid: Rf = 0.6, 20% EtOAc/hexanes; [α]25 = +10.0
D
1
(c 0.26, CHCl3); H NMR (300 MHz, CDCl3) δ 4.21 (m, 1H), 2.58
(m, 1H), 2.43 (ddd, J = 12.0, 8.3, 5.2 Hz, 1H), 1.72 (m, 1H), 1.61 (m,
1H), 1.44 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H), 0.98 (t, J = 7.5 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 179.5, 79.7, 36.7, 35.8, 28.3, 15.0, 9.3;
IR (neat) νmax 2920, 2852, 1741, 1462 cm−1; HRMS (ESI) calcd for
C7H13O2 [M + H]+ 129.0910, found 129.0912.
1
(51.5 g, 87%) as a yellow oil: Rf = 0.5, 5% EtOAc/hexanes; H NMR
(300 MHz, CDCl3) δ 6.30 (s, 1H), 5.92 (s, 1H), 4.25 (q, J = 7.1 Hz,
2H), 4.16 (s, 2H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 164.5, 137.3, 128.6, 61.0, 29.2, 13.9; IR (neat) νmax 3566,
2921, 2852, 1741, 1693, 1647, 1531,1463, 1396, 772 cm−1.
(E)-Ethyl-6-hydroxy-2,4-dimethyloct-2-enoate (( )-13). To a
solution of saturated lactone ( )-9 (1.1 g, 8.59 mmol) in toluene (42
mL) at −78 °C was added DIBAL-H (9.45 mL, 9.45 mmol). The
reaction mixture was stirred for 1 h at that temperature and was
quenched by the addition of methanol (1.73 mL). The reaction
mixture was then allowed to rt and diluted with EtOAc (20 mL), a
saturated solution of sodium potassium tartarate (24 mL) was added,
and the mixture was stirred for 1 h. The compound was filtered,
extracted with EtOAc (150 mL), washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. Column
chromatography purification (10% EtOAc/hexanes) afforded lactol
(0.945 g) as a colorless oil (Rf = 0.5, 20% EtOAc/hexanes), which was
used in the next step without any characterization.
To a solution of lactol (0.945 g, 7.27 mmol) in CH2Cl2 (36 mL)
was added (carbethoxyethylidene)triphenylphosphorane (13.19 g,
36.35 mmol). The reaction mixture was then allowed to reflux for 2
days. The reaction mixture was cooled to rt, filtered, and concentrated
in vacuo. The residue was purified by column chromatography (8%
EtOAc/hexane) to furnish ( )-13 (1.38 g, 75%) as a colorless oil (Rf =
0.6, 20% EtOAc/hexanes).
Ethyl 4-Hydroxy-2-methylenehex-5-enoate (( )-11). To ice-
cooled activated zinc (20.31 g, 312.5 mmol) was added a few drops of
α-bromomethylacrylate (12) under nitrogen. The suspension was
stirred, and the rest of the ester 12 (30.0 g, 156.25 mmol), dissolved in
THF (500 mL), was added slowly. After the mixture was stirred for 1
h, acrolein (31.28 mL, 468.75 mmol), dissolved in THF (435 mL),
was added slowly, and the mixture was allowed to stir for 5 min at 0
°C. The mixture was diluted with a saturated NH4Cl solution, filtered,
and extracted with EtOAc (2 × 1 L). The combined organic layers
were washed with H2O and brine, dried with Na2SO4, filtered, and
concentrated. Purification of residue by flash column chromatography
over silica gel (10% EtOAc/hexanes) afforded allylic alcohol ( )-11
(11.69 g, 44%) as a slightly yellow oil (Rf = 0.4, 20% EtOAc/hexanes)
and lactone ( )-10 (4.3 g, 22%) as a light yellow oil (Rf = 0.5, 20%
EtOAc/hexanes).
(S)-Ethyl 4-Hydroxy-2-methylenehex-5-enoate ((+)-11). To a
suspension of activated powdered 4 Å molecular sieves (300 mg) in
CH2Cl2 (10 mL) were added Ti(OiPr)4 (1.75 mL, 5.882 mmol) and
(−)-DIPT (1.48 mL, 7.058 mmol) sequentially at 0 °C. After being
stirred for 30 min, TBHP (3.5 mL, 3.7 M in toluene) was added and
stirring continued for another 0.5 h at the same temperature. To the
above solution was added compound ( )-11 (1.0 g, 5.882 mmol) in
CH2Cl2 (8 mL) and the mixture stirred for 9 h at 0 °C. The reaction
mixture was quenched with H2O, stirred for 2 h at rt, and filtered. The
solvent was removed under reduced pressure; the compound was
General Procedure for TBS Protection. To a stirred solution of
secondary alcohol 13 (1.36 g, 6.36 mmol) in dry CH2Cl2 (30 mL) at 0
°C was added 2,6-lutidine (2.22 mL, 19.08 mmol) and the mixture
allowed to stir for 5 min. Then TBSOTf (2.48 mL, 10.81 mmol) was
added dropwise at the same temperature. After the starting material
disappeared on TLC, the reaction mixture was quenched with H2O
E
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and extracted with EtOAc (100 mL). The organic layer was washed
with brine, dried over Na2SO4, filtered, concentrated in vacuo, and
purified by column chromatography (4% EtOAc/hexanes) to yield
TBS ether of 13 (2.01 g, 96%) as a colorless oil: Rf = 0.6, 10% EtOAc/
hexanes.
16a (131 mg, 47%) as a colorless oil were prepared from 6a and 6b
(400 mg, 1.081 mmol).
(S,E)-Ethyl 4-((2R,3R,5S)-5-Ethyl-3-methyltetrahydrofuran-2-yl)-4-
hydroxypent-2-enoate (14). Rf = 0.6, 20% EtOAc/hexanes. [α]25
=
D
1
+26.5 (c 1.05, CHCl3). H NMR (300 MHz, CDCl3): δ 6.86 (d, J =
15.6 Hz, 1H), 6.08 (d, J = 15.6 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.79
(m, 1H), 3.41 (d, J = 7.7 Hz, 1H), 2.33 (br s, 1H), 2.17 (m, 1H), 1.60
(m, 1H), 1.44 (m, 1H), 1.33 (s, 3H), 1.33−1.17 (m, 2H), 1.02 (d, J =
6.0 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
166.6, 149.9, 119.7, 90.1, 81.2, 74.5, 60.2, 41.8, 34.5, 28.7, 25.4, 19.0,
14.2, 10.1. IR (neat): νmax 3380, 2972, 2661, 1712, 1623, 1459, 1371,
1303, 1103, 1035 cm−1. HRMS (ESI): calcd for C14H24O4Na [M +
Na]+ 279.1566, found 279.1566.
General Procedure for the Reduction of Ester to Alcohol. To
a solution of TBS ether of 13 (2.0 g, 6.1 mmol) in toluene (30 mL) at
−78 °C was added DIBAL-H (12.2 mL, 12.20 mmol). The reaction
mixture was stirred for 1 h at that temperature and quenched by the
addition of methanol (1.2 mL). The reaction mixture was then allowed
to rt and diluted with EtOAc (50 mL), a saturated solution of sodium
potassium tartarate was added (17 mL), and the mixture was stirred
for 1 h and filtered. The compound was extracted with EtOAc (150
mL), washed with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by column
chromatography (14% EtOAc/hexanes) to afford allylic alcohol 8
(1.52 g, 87%) as a colorless oil: Rf = 0.3, 20% EtOAc/hexanes.
General Procedure for Sharpless Asymmetric Epoxidation
To Give 7. To a suspension of activated powdered 4 Å molecular
sieves (0.5 g) in CH2Cl2 (12 mL) were added sequentially Ti(OiPr)4
(1.56 mL, 5.24 mmol) and (+)-DIPT or (−)-DIPT (1.22 mL, 6.28
mmol) at −20 °C. After the mixture was stirred for 30 min, TBHP
(3.12 mL, 11.53 mmol, 3.7 M in toluene) was added and stirring
continued for another 0.5 h at the same temperature. To the above
solution was added allylic alcohol 8 (1.5 g, 5.24 mmol) in CH2Cl2 (15
mL) and the mixture stirred for 1 h at −20 °C. The reaction mixture
was quenched with H2O, allowed to warm to rt, and stirred for 1 h.
After the mixture was recooled to 0 °C, a solution of NaOH (30% w/
v) in saturated NaCl was added and the mixture stirred at 0 °C for 1 h.
After filtration, solvent was removed under reduced pressure, extracted
with EtOAc (2 × 100 mL), washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by column chromatography (16% EtOAc/hexanes) to afford 7
(1.41 g, 89%) as a colorless oil (Rf = 0.3, 25% EtOAc/hexanes).
General Procedure for Swern Oxidation and 2C-Wittig
Reaction To Give 6. Oxalyl chloride (0.81 mL, 9.28 mmol) in dry
CH2Cl2 (20 mL) was cooled to −78 °C under nitrogen atmosphere.
Dimethyl sulfoxide (1.31 mL, 18.56 mmol) was added dropwise. After
15 min, epoxy alcohol 7 (1.4 g, 4.64 mmol) in dry CH2Cl2 (20 mL)
was added to the reaction mixture via cannula and stirred for 30 min at
−78 °C. Then Et3N (3.23 mL, 23.2 mmol) was added and the mixture
stirred for 15 min. Further reaction was carried out at 0 °C. The
solvent was concentrated, extracted with EtOAc (2 × 100 mL), and
washed with H2O and brine, and the organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (4% EtOAc/hexanes)
to afford aldehyde (1.24 g, 89%) as a colorless oil: Rf = 0.6, 10%
EtOAc/hexanes.
To a solution of aldehyde (1.23 g, 4.1 mmol) in CH2Cl2 (20 mL)
was added (carbethoxymethylene)triphenylphosphorane (2.86 g, 8.2
mmol). The reaction mixture was stirred for 4 h at rt. After completion
of the reaction, the solvent was evaporated under reduced pressure.
The residue was filtered and purified by column chromatography (5%
EtOAc/hexane) to furnish 6 (1.45 g, 95%) as a colorless oil (Rf = 0.6,
10% EtOAc/hexanes).
General Procedure for TBS Deprotection. A solution of Bu4NF
(0.36 mL, 0.362 mmol, 1 M solution in THF) was added dropwise to a
solution of TBS ether compound (80 mg, 0.181 mmol) in THF (1
mL) at rt, and the reaction mixture was stirred at this temperature until
completion of the starting material. Then H2O was added, the mixture
was stirred for 20 min, and THF was removed under reduced pressure.
The remaining aqueous phase was extracted with EtOAc (25 mL) and
washed with brine, and the organic layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by column chromatography (EtOAc/hexanes) to afford TBS-
deprotected compound (51 mg, 86%).
(E)-Ethyl-3-((2R,3S,4R,6S)-6-Ethyl-3-hydroxy-2,4-dimethyltetrahy-
dro-2H-pyran-2-yl)acrylate (15). Rf = 0.5, 10% EtOAc/hexanes.
[α]25D = −45.8 (c 0.48, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.11
(d, J = 15.8 Hz, 1H), 6.02 (d, J = 15.8 Hz, 1H), 4.18 (q, J = 7.5 Hz,
2H), 3.51 (m, 1H), 3.01 (d, J = 9.8 Hz, 1H), 2.03 (br s, 1H), 1.77 (m,
1H), 1.66 (m, 1H), 1.55−1.36 (m, 2H), 1.30 (m, 1H), 1.28 (s, 3H),
1.01 (d, J = 6.0 Hz, 3H), 0.93 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 167.2, 152.8, 118.9, 78.0, 76.2, 70.8, 60.3, 39.2, 32.3, 28.8,
18.4, 15.5, 14.2, 9.9. IR (neat): νmax 3375, 1623, 1460, 1372, 1303,
1059, 988 cm−1. HRMS (ESI): calcd for C14H24O4Na [M + Na]+
279.1566, found 279.1562.
(E)-Ethyl-3-((2S,3S)-3-((2S,4R)-4-hydroxyhexan-2-yl)-2-methylox-
iran-2-yl)acrylate (16a). Rf = 0.4, 20% EtOAc/hexanes. [α]25
=
D
1
+36.2 (c 0.56, CHCl3). H NMR (500 MHz, CDCl3): δ 6.76 (d, J =
16.0 Hz, 1H), 6.01 (d, J = 16.0 Hz, 1H), 4.20 (q, J = 7.0 Hz, 2H), 3.65
(m, 1H), 2.64 (d, J = 9.0 Hz, 1H), 1.94 (brs, 1H), 1.72−1.62 (m, 2H),
1.55−1.44 (m, 3H), 1.48 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H), 0.99 (d, J =
6.0 Hz, 3H), 0.96 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
166.0, 149.4, 121.4, 71.0, 70.7, 60.4, 59.5, 42.4, 30.8, 30.7, 16.5, 15.1,
14.1, 9.85. IR (neat): νmax 3387, 2963, 2930, 1716, 1651, 1457, 1367,
1035, 978 cm−1. HRMS (ESI): calcd for C14H24O4Na [M + Na]+
279.1566, found 279.1564.
General Procedure for Acetylation. To a solution of primary or
secondary hydroxyl compound (80 mg, 0.312 mmol) in CH2Cl2 (2
mL) at 0 °C were added Ac2O (0.029 mL, 0.312 mmol), Et3N (0.087
mL, 0.624 mmol), and DMAP (cat amount), and the mixture was
stirred for 30 min. After completion of the reaction, H2O was added
and the mixture stirred for 10 min. The residue was extracted with
EtOAc (50 mL) and washed with water and brine, and the organic
layer was dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography
(EtOAc/hexane) to furnish acetylated product (90.5 mg, 97%).
(E)-Ethyl 3-((2R,3S,4R,6S)-3-Acetoxy-6-ethyl-2,4-dimethyltetrahy-
dro-2H-pyran-2-yl)acrylate (15a). By following the general procedure
described for acetylation, acetate 15a (17 mg, 97%) as a colorless oil
was prepared from compound 15 (15 mg, 0.058 mmol). Rf = 0.4, 10%
1
EtOAc/hexanes). [α]25 = −34.9 (c 0.81, CHCl3). H NMR (300
D
MHz, CDCl3): δ 6.74 (d, J = 15.8 Hz, 1H), 5.98 (d, J = 15.8 Hz, 1H),
4.51 (d, J = 11.3 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.54 (m, 1H), 2.09
(s, 3H), 1.92 (m, 1H), 1.72 (ddd, J = 12.8, 4.5, 2.2 Hz, 1H), 1.57−1.38
(m, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.26 (s, 3H), 0.94 (t, J = 7.5 Hz,
3H), 0.88 (t, J = 6.8 Hz, 3H). IR (neat): νmax 3620, 2967, 2933, 1741,
1721, 1516, 1462, 1371, 1274, 1036, 987, 724 cm−1. HRMS (ESI):
calcd for C16H26O5Na [M + Na]+ 321.1672, found 321.1670.
General Procedure for Ester Hydrolysis. To the ester
compound (300 mg, 1.171 mmol) in THF/MeOH/H2O (3:1:1, 5
mL) at 0 °C was added LiOH·H2O (196.5 mg, 4.684 mmol), and the
reaction was allowed to stir for 3 h. The reaction mixture was acidified
to pH 2 with 1 N HCl, the residue was extracted with EtOAc (50 mL)
and washed with H2O and brine, and the organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (EtOAc/hexane) to
furnish the acid (230 mg, 86%).
(S,E)-4-((2R,3R,5S)-5-Ethyl-3-methyltetrahydrofuran-2-yl)-4-hy-
droxypent-2-enoic Acid (17). By following the general procedure
described for ester hydrolysis, acid 17 (230 mg, 86%) as a white
amorphous solid was prepared from ester 14 (300 mg, 1.171 mmol).
Synthesis of Compounds 14, 15, and 16a. By following the
general procedure described for TBS deprotection, compound 14 (103
mg, 37%) as a light yellow oil, 15 (26 mg, 9%) as a light yellow oil, and
F
dx.doi.org/10.1021/jo301264k | J. Org. Chem. XXXX, XXX, XXX−XXX

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Rf = 0.4 (40% EtOAc/hexanes). Mp: 84−86 °C. [α]24 = +21.5 (c
described for ester hydrolysis, acid 21 (92 mg, 86%) as a white
amorphous solid was prepared from ester 19 (120 mg, 0.468 mmol).
D
1
0.72, CHCl3). H NMR (500 MHz, CDCl3): δ 6.99 (d, J = 15.8 Hz,
Rf = 0.4, 40% EtOAc/hexanes. Mp = 80 °C. [α]24 = −1.1 (c 0.27,
1H), 6.12 (d, J = 15.8 Hz, 1H), 3.82 (m, 1H), 3.44 (d, J = 7.9 Hz, 1H),
2.25−2.13 (m, 2H), 1.62 (m, 1H), 1.46 (m, 1H), 1.35 (s, 3H), 1.23
(m, 1H), 1.04 (d, J = 6.9 Hz, 3H), 0.92 (t, J = 7.9 Hz, 3H). 13C NMR
(75 MHz, CDCl3): δ 171.5, 152.3, 119.1, 90.0, 81.4, 74.6, 41.7, 34.6,
28.6, 25.3, 18.9, 10.1. IR (neat): νmax 3379, 2970, 1624, 1459, 1415,
1382, 1302, 1103, 1036 cm−1. HRMS (ESI): calcd for C12H20O4Na [M
+ Na]+ 251.1253, found 251.1250.
D
1
CHCl3). H NMR (500 MHz, CDCl3): δ 7.07 (d, J = 15.8 Hz, 1H),
6.11 (d, J = 15.8 Hz, 1H), 3.76 (m, 1H), 3.71 (d, J = 6.9 Hz, 1H), 2.34
(m, 1H), 2.12 (td, J = 12.8, 6.9 Hz, 1H), 1.67 (m, 1H), 1.52 (m, 1H),
1.37 (s, 3H), 1.26 (m, 1H), 1.06 (d, J = 6.9 Hz, 3H), 0.96 (t, J = 7.9
Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 171.7, 153.3, 119.0, 85.4,
79.6, 74.4, 40.0, 35.8, 29.0, 27.3, 16.6, 10.5. IR (neat): νmax 3443, 2930,
2871, 1699, 1379, 1287, 1173, 1029, 991, 858, 774 cm−1. HRMS (ESI)
calcd for C12H20O4Na [M + Na]+ 251.1253, found 251.1250.
General Procedure for Peptide Coupling. To a stirred solution
of the acid (50 mg, 0.219 mmol) in CH2Cl2 (1 mL) were added EDCI
(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (83.9 mg, 0.438
mmol) and HOBt (hydroxybenzotriazole) (59.18 mg, 0.438 mmol)
at 0 °C, and the mixture was stirred for 10 min. To this reaction
mixture was added L-isolucinol (30.8 mg, 0.263 mmol) followed by
Et3N (0.183 mL, 1.314 mmol). Then the reaction mixture was allowed
to stir for 3 h. The reaction mixture was diluted with EtOAc (50 mL)
and washed with 1 N HCl, aq saturated NaHCO3, and brine. The
organic layer was dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (EtOAc/hexanes) to afford peptide−polyketide (61 mg, 85%).
(S,E)-4-((2R,3R,5S)-5-Ethyl-3-methyltetrahydrofuran-2-yl)-4-hy-
droxy-N-((2S,3S)-1-hydroxy-3-methylpentan-2-yl)pent-2-enamide
(18). By following the general procedure described for peptide
coupling, compound 18 (61 mg, 85%) as a white amorphous solid was
prepared from acid 17 (50 mg, 0.219 mmol). Rf = 0.3, 50% EtOAc/
Curvularide E (5). By following the general procedure described for
peptide coupling, curvularide E (5) (76 mg, 85%) as a white solid was
prepared from acid 21 (62 mg, 0.271 mmol). Rf = 0.3, 50% EtOAc/
hexanes). Mp: 118−120 °C. [α]26D = −7.2 (c 0.48, CHCl3). 1H NMR
(500 MHz, CDCl3): δ 6.92 (d, J = 15.0 Hz, 1H), 6.26 (d, J = 9.0 Hz,
1H), 6.18 (d, J = 15.0 Hz, 1H), 3.89 (m, 1H), 3.76 (m, 1H), 3.82−
3.68 (m, 3H), 3.72 (d, J = 7.0 Hz, 1H), 2.87 (brs, 1H), 2.38 (m, 1H),
2.18 (td, J = 12.0. 7.0 Hz, 1H), 1.76−1.66 (m, 2H), 1.61−1.51 (m,
2H), 1.40 (s, 3H), 1.28 (m, 1H), 1.22 (m, 1H), 1.09 (d, J = 7.0 Hz,
3H), 1.01 (d, J = 7.0 Hz, 3H), 1.0 (t, J = 7.0 Hz, 3H), 0.97 (t, J = 7.0
Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 166.7, 146.8, 121.7, 85.4,
79.5, 74.5, 63.2, 56.0, 40.0, 35.7, 35.6, 29.2, 27.6, 25.6, 16.9, 15.5, 11.4,
10.6. IR (neat): νmax 3339, 3238, 3065, 2960, 2930, 2873, 1669, 1625,
1575, 1457, 1381, 1279, 1074, 1022, 985, 703 cm−1. HRMS (ESI):
calcd for C18H33O4NNa [M + Na]+ 350.2301, found 350.2296.
(4S,6R,E)-Ethyl 6-Hydroxy-2,4-dimethyloct-2-enoate ((+)-13).
Compound (+)- 13 (628 mg, 75%) as a colorless oil was prepared
from saturated lactone (+)-9 (500 mg, 3.906 mmol). Rf = 0.6, 20%
EtOAc/hexanes. [α]26D = +3.8 (c 0.18, CHCl3). 1H NMR (300 MHz,
CDCl3): δ 6.59 (d, J = 9.0 Hz, 1H), 4.17 (q, J = 6.7 Hz, 2H), 3.54 (m,
1H), 2.70 (m, 1H), 1.84 (s, 3H), 1.56 - 1.34 (m, 4H), 1.28 (t, J = 6.7
Hz, 3H), 1.02 (d, J = 6.7 Hz, 3H), 0.93 (t, J = 7.5 Hz, 3H). 13C NMR
(75 MHz, CDCl3): δ 168.3, 147.5, 126.0, 71.0, 60.4, 43.6, 30.3, 30.0,
19.4, 14.1, 12.2, 9.7. IR (neat): νmax 3620, 2962, 2925, 2855, 1741,
1707, 1516, 1462, 1267, 1095, 750 cm−1. HRMS (ESI): calcd for
C12H22O3Na [M + Na]+ 237.1461, found 237.1457.
hexanes). Mp: 121−123 °C. [α]24 = −23.7 (c 0.24, CHCl3). 1H
D
NMR (500 MHz, CDCl3): δ 6.87 (d, J = 15.0 Hz, 1H), 6.14 (d, J =
15.0 Hz, 1H), 6.06 (d, J = 7.0 Hz, 1H), 3.87 (m, 1H), 3.80 (m, 1H),
3.74 (dd, J = 11.0 Hz, 3.0 Hz, 1H), 3.68 (dd, J = 11.0 Hz, 6.0 Hz, 1H),
3.46 (d, J = 7.0 Hz, 1H), 2.80 (brs, 1H), 2.23−2.09 (m, 2H), 1.66 (m,
1H), 1.61 (m, 1H), 1.50 (m, 1H), 1.44 (m, 1H), 1.32 (s, 3H), 1.27−
1.10 (m, 2H), 1.02 (d, J = 6.0 Hz, 3H), 0.93 (d, J = 6.0 Hz, 3H), 0.90
(t, J = 7.0 Hz, 3H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 166.5, 146.3, 121.7, 90.2, 81.2, 74.8, 63.5, 56.1, 41.7, 35.8,
34.6, 28.7, 25.6, 25.5, 19.1, 15.4, 11.3, 10.1. IR (neat): νmax 3371, 3060,
2930, 1624, 1578, 1450, 1382, 1283, 1039 cm−1. HRMS (ESI): calcd
for C18H33O4NNa [M + Na]+ 350.2301, found 350.2296.
TBS Ether of (+)-13. By following the general procedure described
for TBS protection, TBS ether of (+)-13 (884 mg, 96%) as a colorless
(S,E)-Ethyl 4-((2R,3S,5R)-5Ethyl-3-methyltetrahydrofuran-2-yl)-4-
hydroxypent-2-enoate (19). To a stirred solution of compound 16a
(100 mg, 0.390 mmol) in CH2Cl2 (2 mL) was added 10-
camphorsulfonic acid (18.11 mg, 0.078 mmol) at 0 °C, and the
resulting solution was stirred at rt for 8 h. Then the reaction mixture
was quenched with aq Na2CO3, extracted with EtOAc (50 mL),
washed with brine, dried over Na2SO4, filtered, evaporated, and
purified by using silica gel column chromatography (8% EtOAc/
hexanes) to furnish 19 (78 mg, 78%) as a colorless oil (Rf = 0.6, 20%
EtOAc/hexanes) and compound 20 (19 mg, 19%) as a colorless oil (Rf
oil was prepared from compound (+)-13 (600 mg, 2.803 mmol). Rf =
1
0.6, 10% EtOAc/hexanes. [α]26 = +1.2 (c 0.40, CHCl3). H NMR
D
(300 MHz, CDCl3): δ 6.52 (dq, J = 10.1, 1.5 Hz, 1H), 4.17 (q, J = 7.1
Hz, 2H), 3.56 (p, J = 5.8 Hz, 1H), 2.61 (m, 1H), 1.82 (d, J = 1.5 Hz,
3H), 1.53−1.37 (m, 4H), 1.31 (t, J = 7.1 Hz, 3H), 1.0 (d, J = 6.6 Hz,
3H), 0.89 (s, 9H), 0.86 (t, J = 7.5 Hz, 3H), 0.05 (s, 3H), 0.04 (s, 3H).
13C NMR (75 MHz, CDCl3): δ 168.4, 147.9, 125.9, 71.0, 60.3, 43.4,
29.8, 29.5, 25.8, 19.6, 18.0, 14.2, 12.3, 9.3, −4.3, −4.6. IR (neat): νmax
2928, 2857, 1712, 1462, 1368, 1255, 1052, 834, 774 cm−1. HRMS
(ESI): calcd for C18H36O3SiNa [M + Na]+ 351.2325, found 351.2321.
(4S,6R,E)-6-(tert-Butyldimethylsilyloxy)-2,4-dimethyloct-2-en-1-ol
((−)-8). By following the general procedure described for a reduction
of ester to alcohol, allylic alcohol (−)-8 (608 mg, 87%) as a colorless
= 0.4, 20% EtOAc/hexanes). Data for 19. [α]24 = +12.3 (c 0.98,
D
1
CHCl3). H NMR (500 MHz, CDCl3): δ 6.94 (d, J = 15.8 Hz, 1H),
6.07 (d, J = 15.8 Hz, 1H), 4.18 (q, J = 6.9 Hz, 2H), 3.74 (m, 1H), 3.67
(d, J = 6.9 Hz, 1H), 2.38−2.28 (m, 2H), 2.11 (m, 1H), 1.65 (m, 1H),
1.51 (m, 1H), 1.35 (s, 3H), 1.31 (t, J = 6.9 Hz, 3H), 1.24 (m, 1H),
1.04 (d, J = 7.9 Hz, 3H), 0.95 (t, J = 6.9 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 166.7, 150.7, 119.5, 85.3, 79.4, 74.2, 60.2, 40.0, 35.7, 29.0,
27.4, 16.6, 14.1, 10.5. IR (neat): νmax 3380, 2977, 2934, 1712, 1623,
1460, 1373, 1300, 1278, 1182, 1033, 870 cm−1. HRMS (ESI): calcd for
C14H24O4Na [M + Na]+ 279.1566, found 279.1562.
oil was prepared from the TBS ether of (+)-13 (800 mg, 2.439 mmol).
1
Rf = 0.3, 20% EtOAc/hexanes. [α]26 = −26.0 (c 0.20, CHCl3). H
D
NMR (300 MHz, CDCl3): δ 5.21 (d, J = 9.4 Hz, 1H), 3.99 (s, 2H),
3.56 (m, 1H), 2.50 (m,1H), 1.66 (s, 3H), 1.48 (m, 1H), 1.42−1.32 (m,
3H), 0.93 (d, J = 6.6 Hz, 3H), 0.89 (s, 9H), 0.85 (t, J = 7.5 Hz, 3H),
0.04 (d, J = 4.6 Hz, 6H). 13C NMR (75 MHz, CDCl3): δ 132.9, 71.2,
69.0, 44.3, 29.9, 28.3, 25.8, 20.6, 18.1, 13.7, 9.3, −4.2, −4.4. IR (neat):
νmax 3566, 2926, 2857, 2623, 1741, 1706, 1693, 1647, 1516, 1463,
1436, 1053, 1011, 835, 774 cm−1. HRMS (ESI) calcd for
C16H34O2SiNa [M + Na]+ 309.2220, found 309.2223.
(E)-Ethyl 3-((2R,3S,4S,6R)-6-Ethyl-3-hydroxy-2,4-dimethyltetrahy-
dro-2H-pyran-2-yl)acrylate (20). [α]24 = +12.5 (c 0.87, CHCl3).
D
NMR (300 MHz, CDCl3): δ 6.88 (d, J = 15.8 Hz, 1H), 5.86 (d, J =
15.8 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.35 (brs, 1H), 1.79 (m, 1H),
1.60−1.39 (m, 2H), 1.33 (t, J = 6.7 Hz, 3H), 1.31 (s, 3H), 1.15 (m,
1H), 0.99 (d, J = 6.0 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 166.3, 150.9, 121.0, 78.2, 73.4, 73.0, 60.6, 32.3, 31.2,
29.0, 26.2, 18.2, 14.2, 9.8. IR (neat): νmax 3609, 2963, 2929, 2874,
1709, 1648, 1531, 1461, 1394, 1284, 1031, 989, 865, 658 cm−1. HRMS
(ESI): calcd for C14H24O4Na [M + Na]+ 279.1566, found 279.1561.
(S,E)-4-((2R,3S,5R)-5-Ethyl-3-methyltetrahydrofuran-2-yl)-4-hy-
droxypent-2-enoic Acid (21). By following the general procedure
((2S,3S)-3-((2S,4R)-4-(tert-Butyldimethylsilyloxy)hexan-2-yl)-2-
methyloxiran-2-yl) methanol (7a). By following the general
procedure described for Sharpless asymmetric epoxidation, epoxy
alcohol 7a (470 mg, 89%) as a colorless oil was prepared from allylic
alcohol (−)-8 (500 mg, 1.748 mmol). Rf = 0.3, 25% EtOAc/hexanes.
1H NMR (500 MHz, CDCl3): δ 3.79 (m, 1H), 3.67 (d, J = 11.5 Hz,
1H), 3.57 (d, J = 11.5 Hz, 1H), 2.74 (d, J = 9.8 Hz, 1H), 2.32 (m, 1H),
2.02 (m, 1H), 1.78−1.43 (m, 3H), 1.29 (s, 3H), 0.93 (d, J = 6.6 Hz,
G
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3H), 0.88 (s, 9H), 0.88 (t, J = 7.4 Hz, 3H), 0.06 (s, 3H), 0.05 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 70.6, 65.5, 65.0, 60.7, 41.9, 30.0, 28.9,
25.9, 18.1, 16.2, 14.2, 9.2, −4.2, −4.5. IR (neat): νmax 3444, 2923, 2854,
1462, 1252, 1038, 833 cm−1. HRMS (ESI): calcd for C16H34O3SiNa
[M + Na]+ 325.2169, found 325.2176.
= 7.7 Hz, 3H), 0.05 (s, 3H), 0.03 (s, 3H). 13C NMR (125 MHz,
CDCl3): δ 171.9, 152.6, 122.3, 71.4, 70.1, 59.5, 40.0, 30.7, 29.3, 25.8,
18.0, 17.1, 14.1, 9.2, −4.2, −4.6. IR (neat): νmax 3620, 3376, 2922,
2853, 1704, 1640, 1516, 1462, 833 cm−1. HRMS (ESI): calcd for
C18H34O4SiNa [M + Na]+ 365.2118, found 365.2120.
(E)-3-((2S,3S)-3-((2S,4R)-4-(tert-Butyldimethylsilyloxy)hexan-2-yl)-
2-methyloxiran-2-yl)-N-((2S,3S)-1-hydroxy-3-methylpentan-2-yl)-
acrylamide (24). By following the general procedure described for
peptide coupling, compound 24 (352 mg, 85%) as a colorless oil was
prepared from acid 22 (320 mg, 0.935 mmol). Rf = 0.2, 50% EtOAc/
((2R,3R)-3-((2S,4R)-4-(tert-Butyldimethylsilyloxy)hexan-2-yl)-2-
methyloxiran-2-yl)methanol (7b′). By following the general
procedure described for Sharpless asymmetric epoxidation, epoxy
alcohol 7b′ (93 mg, 88%) as a colorless oil was prepared from allylic
alcohol (−)-8 (100 mg, 0.349 mmol). Rf = 0.3, 25% EtOAc/hexanes.
[α]25D = −87.0 (c 0.14, CHCl3). 1H NMR (500 MHz, CDCl3): δ 3.67
(d, J = 11.5 Hz, 1H), 3.65 (m, 1H), 3.58 (d, J = 11.5 Hz, 1H), 2.76 (d,
J = 10.0 Hz, 1H), 2.32 (m, 1H), 2.01 (m, 1H), 1.62 (m, 1H). 1.55 (brs,
1H), 1.48 (m, 1H), 1.30 (s, 3H), 1.08 (d, J = 6.5 Hz, 3H), 0.87 (s,
9H), 0.86 (t, J = 7.8 Hz, 3H), 0.05 (s, 3H), 0.03 (s, 3H). 13C NMR
(125 MHz, CDCl3): δ 70.2, 65.5, 65.3, 61.6, 40.1, 30.7, 28.7, 25.8,
18.0, 17.2, 14.4, 9.2, −4.2, −4.5. IR (neat): νmax 3620, 2925, 2855,
1647, 1546, 1516, 1426, 833, 673 cm−1. HRMS (ESI): calcd for
C16H34O3SiNa [M + Na]+ 325.2169, found 325.2173.
hexanes. [α]26 = −6.2 (c 0.82, CHCl3). 1H NMR (500 MHz,
D
CDCl3): δ 6.69 (d, J = 15.0 Hz, 1H), 6.04 (brs, 1H), 5.97 (d, J = 15.0
Hz, 1H), 3.83 (m, 1H), 3.76 (m, 1H), 3.70 (dd, J = 11.0, 3.0 Hz, 1H),
3.63 (dd, J = 11.0, 6.0 Hz, 1H), 2.97 (brs, 1H), 2.49 (d, J = 9.0 Hz,
1H), 1.76−1.56 (m, 3H), 1.55−1.42 (m, 3H), 1.42 (s, 3H), 1.34 (m,
1H), 1.16 (m, 1H), 0.96−0.91 (m, 6H), 0.90−0.86 (m, 6H), 0.88 (s,
9H), 0.05 (s, 3H), 0.04 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 166.0,
145.7, 123.2, 71.2, 70.3, 63.0, 58.9, 55.8, 41.2, 35.6, 30.1, 29.2, 25.8,
25.5, 18.0, 15.9, 15.4, 11.2, 9.1, −4.2, −4.6. IR (neat): νmax 3367, 2960,
2930, 1624, 1540, 1462, 1383, 1254, 1073 cm−1. HRMS (ESI): calcd
for C24H48NO4Si [M + H]+ 442.3347, found 442.3335.
(E)-Ethyl 3((2S,3S)-3-((2S,4R)-4-(tert-Butyldimethylsilyloxy)hexan-
2-yl)-2-methyloxiran-2-yl)acrylate (6a). By following the general
procedure described for Swern oxidation and 2C-Wittig reaction,
unsaturated ester 6a (469 mg, 85%) as a colorless oil was prepared
from epoxy alcohol 7a (450 mg, 1.490 mmol). Rf = 0.6, 10% EtOAc/
(E)-3-((2R,3R)-3-((2S,4R)-4-((tert-Butyldimethylsilyl)oxy)hexan-2-
yl)-2-methyloxiran-2-yl)-N-((2S,3S)-1-hydroxy-3-methylpentan-2-
yl)acrylamide (25). By following the general procedure described for
peptide coupling, compound 25 (38 mg, 84%) as a colorless oil was
prepared from acid 23 (35 mg, 0.102 mmol). Rf = 0.2, 50% EtOAc/
hexanes). [α]25 = −2.8 (c 0.35, CHCl3). 1H NMR (300 MHz,
D
CDCl3): δ 6.74 (d, J = 15.6 Hz, 1H), 5.99 (d, J = 15.6 Hz, 1H), 4.18
(q, J = 7.1 Hz, 2H), 3.77 (m, 1H), 2.55 (d, J = 9.0 Hz, 1H), 1.79−1.32
(m, 5H), 1.42 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 0.92 (d, J = 6.6 Hz,
3H), 0.87 (s, 9H), 0.86 (t, J = 7.5 Hz, 3H), 0.04 (s, 3H), 0.03 (s, 3H).
13C NMR (75 MHz, CDCl3): δ 166.1, 150.0, 121.2, 70.7, 70.4, 60.4,
hexanes). [α]26 = −56.1 (c 0.23, CHCl3). 1H NMR (500 MHz,
D
CDCl3): δ 6.76 (d, J = 15.0 Hz, 1H), 6.0 (d, J = 15.0 Hz, 1H), 5.72 (d,
J = 8.0 Hz, 1H), 3.87 (m, 1H), 3.75 (dd, J = 11.0, 3.0 Hz, 1H), 3.69
(dd, J = 11.0, 6.0 Hz, 1H), 3.66 (m, 1H), 2.58 (m, 1H), 2.54 (d, J =
10.0 Hz, 1H), 1.71−1.58 (m, 3H), 1.55−1.36 (m, 3H), 1.44 (s, 3H),
1.25 (m, 1H), 1.16 (m, 1H), 1.08 (d, J = 6.0 Hz, 3H), 0.94 (d, J = 7.0
Hz, 3H), 0.91 (t, J = 7.5 Hz, 3H), 0.87 (s, 9H), 0.85 (t, J = 7.0 Hz,
3H), 0.04 (s, 3H), 0.02 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 166.1,
146.2, 122.8, 71.9, 70.1, 63.8, 59.6, 56.2, 39.9, 35.7, 30.7, 29.2, 25.8,
25.6, 18.0, 17.0, 15.8, 15.5, 11.4, 9.1, −4.2, −4.6. IR (neat): νmax 3649,
3620, 2959, 2929, 1741, 1693, 1645, 1517, 1463, 1252, 1068, 833, 773
cm−1. HRMS (ESI): calcd for C24H48O4NSi [M + H]+ 442.3347,
found 442.3339.
58.3, 41.6, 30.0, 29.4, 25.8, 18.0, 16.1, 15.1, 14.1, 9.1, −4.2, −4.6. IR
(neat): νmax 2956, 2924, 2854, 1722, 1463, 1304, 1254, 1168, 1067,
1036, 833 cm−1. HRMS (ESI): calcd for C20H38O4SiNa [M + Na]+
393.2431, found 393.2431.
(E)-Ethyl 3-((2R,3R)-3-((2S,4R)-4-((tert-Butyldimethylsilyl)oxy)-
hexan-2-yl)-2-methyloxiran-2-yl)acrylate (6b′). By following the
general procedure described for Swern oxidation and 2C-wittig
reaction, unsaturated ester 6b′ (83 mg, 85%) as a colorless oil was
prepared from epoxy alcohol 7b′ (80 mg, 0.264 mmol). Rf = 0.6, 10%
EtOAc/hexanes. [α]26D = +12.5 (c 0.12, CHCl3). 1H NMR (500 MHz,
CDCl3): δ 6.75 (d, J = 15.4 Hz, 1H), 6.01 (d, J = 15.4 Hz, 1H), 4.19
(q, J = 6.6, 7.7 Hz, 2H), 3.65 (m, 1H), 2.57 (d, J = 8.8 Hz, 1H), 1.65
(m,1H), 1.57−1.37 (m, 4H), 1.45 (s, 3H), 1.28 (t, 3H), 1.09 (d, J =
6.6 Hz, 3H), 0.87 (s, 9H), 0.85 (t, J = 7.7 Hz, 3H), 0.04 (d, J = 9.9 Hz,
6H). 13C NMR (125 MHz, CDCl3): δ 166.1, 150.0, 121.4, 70.2, 70.0,
60.5, 59.2, 40.0, 30.6, 29.2, 25.8, 18.0, 17.0, 15.3, 14.2, 9.1, −4.2, −4.6.
IR (neat): νmax 2926, 2857, 1824, 1654, 1460, 1374, 1301, 1255, 1168,
1066, 1032, 834, 775 cm−1. HRMS (ESI): calcd for C20H38O4SiNa [M
+ Na]+ 393.2431, found 393.2438.
Curvularide B (2). By following the general procedure described for
TBS deprotection, curvularide B (2) (53 mg, 86%) as a light brown oil
was prepared from compound 24 (83 mg, 0.188 mmol). Rf = 0.2, 80%
EtOAc/hexanes). [α]26 = +11.3 (c 0.26, CHCl3). 1H NMR (400
D
MHz, CDCl3): δ 6.76 (d, J = 15.0 Hz, 1H), 6.31 (brd, J = 7.5 Hz, 1H),
6.04 (d, J = 15.0 Hz, 1H), 3.87 (m, 1H), 3.72 (dd, J = 11.8, 3.2 Hz,
1H), 3.66 (dd, J = 11.8, 6.4 Hz, 1H), 3.63 (m, 1H), 3.27 (br, 1H), 2.59
(d, J = 8.6 Hz, 1H), 2.03 (br s, 1H), 1.71−1.58 (m, 3H), 1.54−1.42
(m, 3H), 1.46 (s, 3H), 1.15 (m, 1H), 0.98 (d, J = 6.5 Hz, 3H), 0.95 (t,
J = 7.5 Hz, 3H), 0.93 (d, J = 6.5 Hz, 3H), 0.89 (t, J = 7.5 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ 166.0, 145.0, 123.2, 71.6, 71.2, 63.0, 60.2,
55.8, 42.5, 35.6, 30.9, 30.7, 25.5, 16.6, 15.7, 15.4, 11.2, 9.9. IR (neat):
νmax 3289, 2962, 2927, 2876, 1667, 1626, 1545, 1459, 1345, 1069, 974,
753 cm−1. HRMS (ESI) calcd for C18H33O4NNa [M + Na]+ 350.2301,
found 350.2297.
(E)-3-((2S,3S)-3-((2S,4R)-4-(tert-Butyldimethylsilyloxy)hexan-2-yl)-
2methyloxiran-2-yl)acrylic Acid (22). By following the general
procedure described for ester hydrolysis, acid 22 (359 mg, 86%) as
a colorless oil was prepared from ester 6a (450 mg, 1.216 mmol). Rf =
1
0.4, 40% EtOAc/hexanes). [α]25 = −8.7 (c 0.25, CHCl3). H NMR
D
Synthesis of Compound 26 and 27. By following the general
procedure described for TBS deprotection, 26 (15.4 mg, 61%) and 27
(4.6 mg, 18%) as a colorless oil were prepared from compound 25 (34
mg, 0.077 mmol).
(300 MHz, CDCl3): δ 6.85 (d, J = 15.8 Hz, 1H), 5.97 (d, J = 15.8 Hz,
1H), 3.77 (dq, J = 7.5, 5.2 Hz, 1H), 2.52 (d, J = 9.0 Hz, 1H), 1.72 (m,
1H), 1.67−1.31 (m, 4H), 1.45 (s, 3H), 0.95 (d, J = 6.8 Hz, 3H), 0.89
(s, 9H), 0.88 (t, J = 7.5 Hz, 3H), 0.06 (s, 3H), 0.05 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 171.4, 152.7, 120.5, 70.9, 70.4, 58.4, 41.6, 30.0,
29.4, 25.8, 18.0, 16.1, 15.0, 9.1, −4.2, −4.6. IR (neat): νmax 3620, 3376,
2959, 2931, 1696, 1624, 1463, 1308, 1254 cm−1. HRMS (ESI): calcd
for C18H34O4SiNa [M + Na]+ 365.2118, found 365.2121.
(R,E)-4-((2S,3S,5R)-5-Ethyl-3-methyltetrahydrofuran-2-yl)-4-hy-
droxy-N-((2S,3S)-1-hydroxy-3-methylpentan-2-yl)pent-2-enamide
(26). Rf = 0.2, 80% EtOAc/hexanes. [α]26 = −15.0 (c 0.15, CHCl3).
D
1H NMR (500 MHz, CDCl3): δ 6.88 (d, J = 15.4 Hz, 1H), 6.13 (d, J =
15.4 Hz, 1H), 5.72 (d, J = 6.6 Hz, 1H), 3.88 (m, 1H), 3.81 (m, 1H),
3.77 (dd, J = 11.0, 3.3 Hz, 1H), 3.70 (dd, J = 11.0, 6.6 Hz,1H), 3.47 (d,
J = 7.7 Hz, 1H), 2.33 (m, 1H), 2.22−2.13 (m, 2H), 1.73−1.39 (m,
4H), 1.34 (s, 3H), 1.17 (m, 1H), 1.04 (d, J = 5.5 Hz, 3H), 0.95 (d, J =
6.6 Hz, 3H), 0.92 (t, J = 7.7 Hz, 3H), 0.88 (t, J = 7.7 Hz, 3H). 13C
NMR (125 MHz, CDCl3): δ 166.6, 146.5, 121.5, 90.2, 81.3, 74.7, 64.1,
56.4, 41.8, 35.9, 34.7, 28.7, 25.8, 25.6, 19.0, 15.5, 11.4, 10.2. IR (neat):
νmax 3348, 3293, 2923, 2860, 1665, 1623, 1543, 1457, 1365, 1060, 768,
(E)-3-((2R,3R)-3-((2S,4R)-4-((tert-Butyldimethylsilyl)oxy)hexan-2-
yl)-2-methyloxiran-2-yl)acrylic Acid (23). By following the general
procedure described for ester hydrolysis, acid 23 (51 mg, 85%) as a
colorless oil was prepared from ester 6b′ (65 mg, 0.149 mmol). Rf =
1
0.4, 40% EtOAc/hexanes. [α]26 = +1.9 (c 0.07, CHCl3). H NMR
D
(500 MHz, CDCl3): δ 6.85 (d, J = 15.4 Hz, 1H), 6.02 (d, J = 15.4 Hz,
1H), 3.66 (m, 1H), 2.58 (d, J = 9.9 Hz, 1H), 2.38 (m, 1H), 1.74−1.44
(m, 2H), 1.46 (s, 3H), 1.09 (d, J = 6.6 Hz, 3H), 0.87 (s, 9H), 0.85 (t, J
H
dx.doi.org/10.1021/jo301264k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
668 cm−1. HRMS (ESI): calcd for C18H34O4N [M + H]+ 328.2482,
found 328.2479.
To a stirred solution of above obtained ketone (60 mg, 0.163
mmol) in MeOH (0.8 mL) was added K2CO3 (45 mg, 0.326 mmol) at
0 °C, and the resulting solution was stirred at rt for 2 h. Then the
reaction mixture was quenched with aq NH4Cl, extracted with EtOAc
(50 mL), washed with brine, dried over Na2SO4, filtered, evaporated,
and purified by using silica gel column chromatography (50% EtOAc/
(E)-3-((2S,3R,4S,6R)-6-Ethyl-3-hydroxy-2,4-dimethyltetrahydro-
2H-pyran-2-yl)-N-((2S,3S)-1-hydroxy-3-methylpentan-2-yl)-
acrylamide (27). Rf = 0.3, 80% EtOAc/hexanes). [α]26 = −2.4 (c
D
1
0.28, CHCl3). H NMR (500 MHz, CDCl3): δ 7.0 (d, J = 14.8 Hz,
1H), 6.13 (d, J = 9.2 Hz, 1H), 6.04 (d, J = 14.8 Hz, 1H), 3.87 (m, 1H),
3.71 (dd, J = 11.1, 3.7 Hz,1H), 3.57 (dd, J = 11.1, 6.5 Hz, 1H), 3.52
(m, 1H), 2.96 (d, J = 10.2 Hz, 1H), 2.30 (m, IH), 2.03 (m, 1H), 1.78
(m, 1H), 1.72−1.60 (m, 2H), 1.55−1.34 (m, 3H), 1.27 (s, 3H), 1.16
(m, 1H), 1.01 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 7.4 Hz, 3H), 0.93 (t, J =
7.4 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ
167.3, 149.5, 120.4, 78.3, 70.9, 64.0, 56.3, 39.3, 35.8, 32.1, 28.9, 25.6,
18.5, 15.7, 15.5, 14.1, 11.4, 10.0. IR (neat): νmax 3349, 2922, 2856,
1738, 1623, 1458, 1370, 1063 cm−1. HRMS (ESI): calcd for
C18H34O4N [M + H]+ 328.2482, found 328.2482.
hexanes) to furnish curvularide D (4) (46.5 mg, 87%) as a colorless
1
oil. Rf = 0.3, 70% EtOAc/hexanes. [α]26 = +8.3 (c 0.34, CHCl3). H
D
NMR (500 MHz, CDCl3): δ 6.73 (d, J = 15.0 Hz, 1H), 6.24 (brd, J =
8.0 Hz, 1H), 6.02 (d, J = 15.0 Hz, 1H), 3.89 (m, 1H), 3.75 (dd, J =
11.0, 3.0 Hz, 1H), 3.69 (dd, J = 11.0, 6.0 Hz, 1H), 2.70 (dd, J = 16.0,
5.0 Hz, 1H), 2.63 (d, J = 10.0 Hz, 1H), 2.55−2.40 (m, 3H), 2.49 (t, J =
8.0 Hz, 1H), 2.06 (m, 1H), 1.70 (m, 1H), 1.56 (m, 1H), 1.51 (s, 3H),
1.22 (m, 1H), 1.12 (t, J = 7.5 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H), 1.0 (d,
J = 7.0 Hz, 1H), 0.97 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 210.1, 165.9, 145.4, 123.2, 70.0, 63.4, 59.5, 56.0, 46.6, 36.5,
35.6, 29.5, 25.5, 16.3, 15.4, 11.3, 7.7. IR (neat): νmax 3290, 2964, 2926,
2879, 1708, 1667,1627, 1545, 1460, 1070, 978, 753 cm−1. HRMS
(ESI): calcd for C18H31O4NNa [M + Na]+ 348.2145, found 348.2141.
(E)-Ethyl 3-((2S,3S)-3-((2S,4R)-4-Acetoxyhexan-2-yl)-2-meth-
yloxiran-2-yl)acrylate (30). By following the general procedure
described for acetylation, compound 30 (170 mg, 97%) as a gummy
(2S,3S)-2-((E)-3-((2S,3S)-3-((2S,4R)-4-(tert-Butyldimethyl-
silyloxy)hexan-2-yl)-2-methyloxiran-2-yl)acrylamido)-3-meth-
ylpentyl Acetate (28). By following the general procedure described
for acetylation, acetate 28 (234 mg, 97%) as a colorless oil was
prepared from compound 24 (220 mg, 0.498 mmol). Rf = 0.5, 30%
1
EtOAc/hexanes). [α]26 = −16.1 (c 0.82, CHCl3). H NMR (300
D
MHz, CDCl3): δ 6.71 (d, J = 15.1 Hz, 1H), 5.90 (d, J = 15.1 Hz, 1H),
5.61 (d, J = 8.8 Hz, 1H), 4.24 (dd, J = 11.1, 6.2 Hz, 1H), 4.12 (m, 1H),
4.04 (dd, J = 11.1, 3.4 Hz, 1H), 3.76 (m, 1H), 2.46 (d, J = 9.2 Hz, 1H),
2.04 (s, 3H), 1.76−1.11 (m, 8H), 1.42 (s, 3H), 0.94 (d, J = 7.3 Hz,
3H), 0.91−0.84 (m, 6H), 0.88 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 171.1, 165.0, 146.1, 122.7, 71.3, 70.3, 64.2,
58.7, 52.3, 41.4, 36.1, 30.0, 29.3, 25.8, 25.3, 20.8, 18.0, 16.0, 15.5, 15.2,
11.2, 9.1, −4.2, −4.6. IR (neat): νmax 3620, 3566, 3278, 2960, 2929,
2857, 1742, 1707, 1645, 1533, 1463, 1367, 1236, 1065, 834, 774 cm−1.
HRMS (ESI): calcd for C26H50O5NSi [M + H]+ 484.3452, found
484.3447.
liquid was prepared from compound 16a (150 mg, 0.585 mmol). Rf =
1
0.5, 15% EtOAc/hexanes). [α]26 = +23.7 (c 0.53, CHCl3). H NMR
D
(500 MHz, CDCl3): δ 6.73 (d, J = 15.8 Hz, 1H), 5.99 (d, J = 15.8 Hz,
1H), 4.98 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 2.58 (d, J = 8.5 Hz, 1H),
2.04 (s, 3H), 1.89 (m, 1H), 1.69−1.52 (m, 2H), 1.52−1.40 (m, 2H),
1.42 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 0.96 (d, J = 6.3 Hz, 3H), 0.89 (t,
J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 171.0, 166.1, 149.7,
121.4, 72.7, 70.2, 60.5, 58.5, 38.8, 30.1, 27.6, 21.2, 16.0, 15.1, 14.1, 9.4.
IR (neat): νmax 3372, 1721, 1623, 1461, 1374, 1304, 1243, 1172, 1029
cm−1. HRMS (ESI): calcd for C16H26O5Na [M + Na]+ 321.1672,
found 321.1666.
(4S,5R,6S,8R,E)-Ethyl 8-Acetoxy-4,5-dihydroxy-4,6-dimethyl-
dec-2-enoate (31). To a stirred solution of compound 30 (80 mg,
0.268 mmol) in a THF/H2O (1.5 mL, 1:1) was added TFA (0.0536
mmol) at 0 °C, and the resulting solution was stirred at rt for 18 h.
Then the reaction mixture was quenched with sodium bicarbonate,
extracted with EtOAc, washed with brine, dried over Na2SO4, filtered,
evaporated, and purified by using silica gel column chromatography
(20% EtOAc/hexanes) to furnish 31 (65.5 mg, 77%) as a liquid. Rf =
0.5, 40% EtOAc/hexanes). [α]25D = −28.1 (c 0.45, CHCl3). 1H NMR
(500 MHz, CDCl3): δ 6.96 (d, J = 15.1 Hz, 1H), 6.13 (d, J = 15.1 Hz,
1H), 4.84 (m, 1H), 4.20 (q, J = 7.0 Hz, 2H), 3.41 (s, 1H), 2.37 (m,
1H), 2.0 (s, 3H), 1.99 (m, 1H), 1.73−1.49 (m, 4H), 1.37 (s, 3H), 1.29
(t, J = 7.0 Hz, 3H), 1.22 (m, 1H), 1.02 (d, J = 7.0 Hz, 3H), 0.86 (t, J =
8.0 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 171.2, 166.4, 150.2,
119.8, 80.8, 75.9, 73.7, 60.4, 34.4, 31.4, 28.0, 26.7, 21.0, 19.1, 14.2, 9.6.
IR (neat): νmax 3620, 2967, 2925, 2855, 1708, 1648, 1546, 1462, 1372,
1265, 1176, 1030, 987, 729 cm−1. HRMS (ESI): calcd for C16H28O6Na
[M + Na]+ 339.1778, found 339.1777.
(2S,3S)-2-((E)-3-((2S,3S)-3-((2S,4R)-4-Hydroxyhexan-2-yl)-2-
methyloxiran-2-yl)acrylamido)-3-methylpentyl Acetate (29).
By following the general procedure described for TBS deprotection,
compound 29 (124 mg, 85%) as a colorless oil was prepared from 28
(190 mg, 0.393 mmol). Rf = 0.4, 50% EtOAc/hexanes). [α]26
=
D
1
−26.4 (c 0.26, CHCl3). H NMR (300 MHz, CDCl3): δ 6.74 (d, J =
15.1 Hz, 1H), 5.93 (d, J = 15.1 Hz, 1H), 5.85 (d, J = 9.0 Hz, 1H), 4.22
(dd, J = 11.3, 6.0 Hz, 1H), 4.12 (m, 1H), 4.05 (dd, J = 11.3, 3.7 Hz,
1H), 3.59 (m, 1H), 2.55 (d, J = 9.0 Hz, 1H), 2.04 (s, 3H), 1.68−1.55
(m, 3H), 1.54−1.39 (m, 3H), 1.46 (s, 3H), 1.34−1.08 (m, 2H), 1.01−
0.87 (m, 12H). 13C NMR (75 MHz, CDCl3): δ 171.1, 164.8, 145.4,
123.0, 71.5, 71.3, 64.3, 60.1, 52.3, 42.6, 36.1, 31.0, 30.7, 25.4, 20.8,
16.7, 15.7, 15.2, 11.3, 9.9. IR (neat): νmax 3620, 3566, 2961, 2924,
2855, 1741, 1707, 1693, 1646, 1546, 1572, 1516, 1426, 675 cm−1.
HRMS (ESI): calcd for C20H35O5NNa [M + Na]+ 392.2407, found
392.2410.
Curvularide D (4). To a stirred solution of alcohol 29 (88 mg,
0.238 mmol) in CH2Cl2 (2 mL) was added Dess−Martin periodinane
(DMP) (202 mg, 0.476 mmol) at 0 °C, and the resulting solution was
stirred at rt for 3 h. Then the reaction mixture was quenched with 1:1
mixture of saturated aq NaHCO3 solution (3 mL) and saturated aq
Na2S2O3 (3 mL), stirred for 20 min to get clear solution, and then
extracted with EtOAc (50 mL). The combined organic layers were
washed with brine, dried over Na2SO4, filtered, evaporated, and
purified by using silica gel column chromatography (20% EtOAc/
(4S,5R,6S,8R,E)-4,5,8-Trihydroxy-4,6-dimethyldec-2-enoic
Acid (32). By following the general procedure described for ester
hydrolysis, acid compound 32 (16.5 mg, 84%) as a colorless oil was
1
prepared from ester 31 (25 mg, 0.079 mmol). Rf = 0.2, EtOAc. H
NMR (500 MHz, CDCl3): δ 7.12 (d, J = 15.9 Hz, 1H), 6.13 (d, J =
15.9 Hz, 1H), 3.62 (m, 1H), 3.33 (d, J = 4.0 Hz, 1H), 2.31 (m, 1H),
2.02 (m, 1H), 1.62 (m, 1H), 1.48 (m, 1H), 1.38 (m, 1H), 1.31 (m,
1H), 1.05 (d, J = 6.9 Hz, 1H), 0.88 (t, J = 7.0 Hz, 1H). 13C NMR (125
MHz, CD3OD): δ 154.6, 120.7, 82.2, 77.1, 72.3, 39.4, 32.8, 32.3, 30.7,
25.2, 20.18, 10.5. HRMS (ESI): calcd for C12H22O5Na [M + Na]+
269.1364, found 269.1361.
hexanes) to furnish the ketone (76 mg, 87%) as a colorless liquid. Rf =
1
0.5, 40% EtOAc/hexanes). [α]26 = −8.3 (c 0.15, CHCl3). H NMR
D
(300 MHz, CDCl3): δ 6.69 (d, J = 15.1 Hz, 1H), 5.90 (d, J = 15.1 Hz,
1H), 5.69 (brs, 1H), 4.24 (dd, J = 11.1, 6.0 Hz, 1H), 4.12 (m, 1H),
4.04 (dd, J = 11.1, 3.4 Hz, 1H), 2.66 (dd, J = 16.2, 4.5 Hz, 1H), 2.54
(d, J = 9.6 Hz, 1H), 2.50−2.30 (m, 3H), 2.04 (s, 3H), 2.0 (m, 1H),
1.67−1.42 (m, 2H), 1.46 (s, 3H), 1.18 (m, 1H), 1.06 (t, J = 7.5 Hz,
3H), 1.01−0.88 (m, 9H). 13C NMR (75 MHz, CDCl3): δ 209.9, 171.1,
164.8, 145.5, 123.1, 70.0, 64.3, 59.6, 52.3, 46.6, 36.5, 36.1, 29.5, 25.4,
20.9, 16.4, 15.5, 15.3, 11.3, 7.7. IR (neat): νmax 3348, 2923, 2855, 1736,
1631, 1542, 1458, 1371, 1235, 977 cm−1. HRMS (ESI): calcd for
C20H34O5N [M + H]+ 368.2431, found 368.2436.
Curvularide A (1). By following the general procedure described
for peptide coupling, curvularide A (1) (10.5 mg, 83%) as a solid was
prepared from acid 32 (9 mg, 0.036 mmol). Rf = 0.5, 10% MeOH/
1
EtOAc. Mp: 123−125 °C. [α]27 = −9.9 (c 0.15, CHCl3). H NMR
D
(500 MHz, CDCl3): δ 6.82 (d, J = 15.0 Hz, 1H), 6.51 (d, J = 8.9 Hz,
1H), 6.13 (d, J = 15.0 Hz, 1H), 3.86 (m, 1H), 3.75 (m, 1H), 3.66−
3.50 (m, 3H), 3.35 (brs, 1H), 2.29 (m, 1H), 2.09 (m, 1H), 2.01 (m,
1H), 1.84 (m, 1H), 1.59 (m, 1H), 1.50−1.40 (m, 3H), 1.29 (s, 3H),
I
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The Journal of Organic Chemistry
Article
1.23 (m, 2H), 1.12 (m, 1H), 1.03 (d, J = 7.0 Hz, 3H), 0.91 (t, J = 7.0
Hz, 3H), 0.90 (d, J = 7.0 Hz, 3H), 0.87 (t, J = 7.9 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ 167.3, 149.8, 122.0, 80.6, 72.9, 62.6, 56.1, 38.9,
36.0, 31.5, 31.4, 25.7, 24.1, 21.7, 15.4, 11.4, 10.1. IR (neat): νmax 3620,
2962, 2930, 2870, 1693, 1647, 1546, 1463, 1396, 1340, 1060, 978, 771
cm−1. HRMS (ESI): calcd for C18H36O5N [M + H]+ 346.2588, found
346.2588.
ACKNOWLEDGMENTS
■
This work was funded by the Department of Science and
Technology, New Delhi, India (Grant No. SR/S1/OC-16/
2010). K.S. and J.R. thank CSIR, New Delhi, India, and UGC,
New Delhi, India, respectively, for the award of research
fellowships, and G.S. thanks Dr. J. S. Yadav, Director, IICT, for
his support and encouragement. We also thank Prof. Dr.
Kittakoop for providing authentic natural product samples and
Mr. Ramesh Babu for HPLC analysis.
(4R,5S,6S,8R,E)-Ethyl 8-Acetoxy-5-hydroxy-4-methoxy-4,6-
dimethyldec-2-enoate (33). To a stirred solution of compound
30 (100 mg, 0.335 mmol) in MeOH (1.6 mL) was added BF3·OEt3
(0.067 mmol) at 0 °C, and the resulting solution was stirred at rt for
30 min. Then the reaction mixture was quenched with water, extracted
with EtOAc (50 mL), washed with brine, dried over Na2SO4, filtered,
evaporated, and purified by using silica gel column chromatography
(20% EtOAc/hexanes) to furnish 33 (93 mg, 84%) as a colorless oil. Rf
= 0.3, 30% EtOAc/hexanes. [α]27D = −22.8 (c 0.35, CHCl3). 1H NMR
(300 MHz, CDCl3): δ 6.92 (d, J = 16.6 Hz, 1H), 5.93 (d, J = 16.6 Hz,
1H), 4.87 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.37 (dd, J = 6.0, 2.3 Hz,
0.5H), 3.20 (s, 3H), 3.17 (d, J = 3.8 Hz, 0.5H), 2.54 (d, J = 6.0 Hz,
1H), 2.04 (s, 3H), 1.93 (m, 1H), 1.69−1.46 (m, 3H), 1.33 (s, 3H),
1.30 (t, J = 7.1 Hz, 3H), 1.24 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H), 0.84
(t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 171.1, 165.8,
148.4, 122.8, 82.0, 80.3, 73.6, 60.5, 50.6, 34.5, 30.6, 28.1, 21.0, 19.3,
18.6, 14.2, 9.5. IR (neat): νmax 3379, 1716, 1623, 1462, 1374, 1304,
1246, 1178 cm−1. HRMS (ESI): calcd for C17H30O6Na [M + Na]+
353.1934, found 353.1934.
DEDICATION
■
This paper is dedicated to Dr. M. Marthanda Murthy on the
occasion of his 60th birthday.
REFERENCES
■
(1) Chomcheon, P.; Wiyakrutta, S.; Agree, T.; Sriubolmas, N.;
Ngamrojanavanich, N.; Mahidol, C.; Ruchirawat, S.; Kittakoop, P.
Chem.Eur. J. 2010, 16, 11178−11185.
(2) Fonseca, S.; Chini, A.; Hamberg, M.; Adie, B.; Porzel, A.;
Kramell, R.; Miersch, O.; Wasternack, C.; Solano, R. Nat. Chem. Biol.
2009, 5, 344−350.
(3) Thines, B.; Katsir, L.; Melotto, M.; Niu, Y.; Mandaokar, A.; Liu,
G.; Nomura, K.; He, S. Y.; Howe, G. A.; Browse, J. Nature 2007, 448,
661−665.
(4R,5S,6S,8R,E)-5,8-Dihydroxy-4-methoxy-4,6-dimethyldec-
2-enoic Acid (34). By following the general procedure described for
ester hydrolysis, acid compound 34 (27 mg, 85%) as a light yellow oil
was prepared from ester 33 (40 mg, 0.121 mmol). Rf = 0.2, EtOAc.
[α]26D = −74.4 (c 0.21, CHCl3). 1H NMR (300 MHz, CDCl3): δ 6.97
(d, J = 16.6 Hz, 1H), 5.95 (d, J = 16.6 Hz, 1H), 5.64−5.17 (br, 2H),
3.53 (m, 1H), 3.35 (d, J = 3.8 Hz, 1H), 3.21 (s, 3H), 1.93 (m, 1H),
1.70 (m, 1H), 1.51−1.39 (m, 2H), 1.36 (s, 3H), 1.24 (m, 1H), 1.0 (d, J
= 6.8 Hz, 3H), 0.90 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3):
δ 169.6, 150.4, 122.3, 82.0, 80.7, 72.1, 50.7, 39.2, 31.6, 31.0, 20.6, 18.4,
9.9. IR (neat): νmax 3378, 1624, 1462, 1304, 999 cm−1. HRMS (ESI):
calcd for C13H24O5Na [M + Na]+ 283.1516, found 283.1512.
Curvularide C (3). By following the general procedure described
for peptide coupling, curvularide C (3) (21 mg, 84%) as a yellowish oil
was prepared from acid 34 (18 mg, 0.069 mmol). Rf = 0.6, 10%
(4) Kennedy, J. W. J.; Hall, D. G. J. Org. Chem. 2004, 69, 4412−4428.
́
(5) Dumeunier, R.; Marko, I. E. Tetrahedron Lett. 2000, 41, 10219−
10222.
(6) Yu, Ch.; Liu, B.; Hu, L. J. Org. Chem. 2001, 66, 5413−5418.
(7) Villieras, J.; Rambaud, M. Synthesis 1982, 924−926.
(8) Richter, F.; Bauer, M.; Perez, C.; Mossmer, C. M.; Maier, M. E. J.
̈
Org. Chem. 2002, 67, 2474−2480.
(9) Determined by chiral HPLC (250 × 4.6) mm; MP n-hexane/IPA
(90/10, v/v); flow rate 1.0 mL/min; temp 25 °C.
(10) Ghosh, A. K.; Gong, G. J. Org. Chem. 2006, 71, 1085−1093.
(11) Katagiri, T.; Fujiwara, K.; Kawai, H.; Suzuki, T. Tetrahedron Lett.
2008, 49, 233−237.
(12) Takemura, A.; Katagiri, Y.; Fujiwara, K.; Kawai, H.; Suzuki, T.
Tetrahedron Lett. 2011, 52, 1222−1224.
(13) Initially, we expected that 6a or 6b with CSA in CH2Cl2 at 0 °C
would lead to silyl deprotection followed by in situ formation of five-
membered ring. However, this mixture of 6a and 6b displayed
formation of conjugated exo-methylene epoxide opening product with
TBS intact as major and without TBS as the minor product along with
small amounts of five-membered and six-membered products.
(14) Morimoto, Y.; Nishikawa; Ueba, C.; Tanaka, T. Angew. Chem.,
Int. Ed. 2006, 45, 810−812.
(15) We observed that after silyl ether cleavage of 25 the resulting
epoxy alcohol immediately underwent cyclization. Compounds 6b and
7b in Scheme 3 and 6b′ and 7b′ in Scheme 4, respectively, have an
enantiomeric relation. The more reactive epoxy alcohol 16b, which
was obtained from 7b via 6b in Scheme 3, and the polyketide portion
of the epoxy alcohol of 25, which was obtained from 7b′ via 6b′ in
Scheme 4, have an enantiomeric relation. This stereochemical
configuration seems to be very unstable and prone to cyclization,
apparently from quick cyclization of 16b to 14 and 15 and of 25 to 26
and 27.
MeOH/EtOAc). [α]27 = −42.9 (c 0.19, CHCl3). 1H NMR (500
D
MHz, CDCl3): δ 6.70 (d, J = 16.0 Hz, 1H), 6.36 (d, J = 8.0 Hz, 1H),
5.97 (d, J = 16.0 Hz, 1H), 3.87 (m, 1H), 3.75 (dd, J = 11.0, 3.0 Hz,
1H), 3.65 (dd, J = 11.0, 7.0 Hz, 1H), 3.44 (m, 1H), 3.37 (brd, J = 3.0
Hz, 1H), 3.22 (s, 3H), 3.04−2.72 (br, 3H), 1.88 (m, 1H), 1.71 (m,
1H), 1.66 (m, 1H), 1.51 (m, 1H), 1.47−1.38 (m, 2H), 1.33 (s, 3H),
1.25−1.11 (m, 2H), 1.03 (d, J = 7.0 Hz, 3H), 0.94 (d, J = 7.0 Hz, 3H),
0.92 (t, J = 7.0 Hz, 3H), 0.90 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 166.8, 144.0, 125.5, 81.7, 80.5, 72.2, 63.1, 56.0, 50.6, 39.0,
35.6, 31.5, 31.2, 25.6, 21.2, 18.0, 15.3, 11.3, 10.0. IR (neat): νmax 3620,
2963, 2930, 1693, 1676, 1647, 1546, 1532, 1463, 1426, 1367, 1061,
991 cm−1. HRMS (ESI): calcd for C19H37O5NNa [M + Na]+
382.2563, found 382.2569.
ASSOCIATED CONTENT
■
S
* Supporting Information
(16) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155−4156.
(17) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277−
7287.
1H and 13C NMR spectra of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(18) The specific rotation of synthesized curvularide D is ([α]26
=
D
+8.3 (c 0.34, CHCl3)) where the lit.1 is ([α]28 = −1.5 (c 0.35,
D
AUTHOR INFORMATION
■
CHCl3)). However, after repurification, the provided natural product
Corresponding Author
sample showed specific rotation ([α]29 = +8.8 (c 0.13, CHCl3)),
D
which agrees well with the synthetic product.
*E-mail: gsudhakar@iict.res.in.
(19) Our initial attempts at epoxide opening of 6a in acidic
conditions resulted in a mixture of compounds (mainly TBS
deprotected compound), and MeOH as a solvent in the presence of
Notes
The authors declare no competing financial interest.
J
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BF3OEt2 gave a mixture of five-membered 19 (minor) and six-
membered 20, (major) along with small amounts of corresponding
tertiary methoxy diol compound.
(20) Hanessian, S.; Margarita, R.; Hall, A.; Johnstone, S.; Tremblay,
M.; Parlanti, L. J. Am. Chem. Soc. 2002, 124, 13342−13343.
(21) BASF Aktiengesellschaft Patent: US5703017 A1, 1997.
(22) BASF Aktiengesellschaft Patent: US5840722 A1, 1998.
K
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