Asymmetric synthesis of synargentolide A and its 3-epimer using the RAMP-hydrazone methodology

Article abstract of DOI:10.1055/s-0032-1316865

Synargentolide A was synthesized in 11 steps starting from the commercially available 2,2-dimethyl-1,3-dioxan-5-one, employing the SAMP/RAMP-methodology via an α,α′-bis-alkylation to generate the first two stereogenic centers with virtually complete asymmetric induction (de, ee >99%). After the asymmetric synthesis of the triol fragment of the molecule, the δ-lactone moiety was constructed using an asymmetric allylation, esterification, and ring-closing metathesis sequence. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1316865

PAPER
▌959
pAapserymmetric Synthesis of Synargentolide A and Its 3-Epimer Using the
RAMP-Hydrazone Methodology
Asymmetric Synthesis of Synargentolide A
Dieter Enders,* Linus F. Reichenbach
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received: 14.02.2013; Accepted: 15.02.2013
Once the polyacetylated triol chain of the target molecule
is synthesized, two strategies have been employed. It is ei-
ther possible to synthesize the δ-lactone in a linear se-
Abstract: Synargentolide A was synthesized in 11 steps starting
from the commercially available 2,2-dimethyl-1,3-dioxan-5-one,
employing the SAMP/RAMP-methodology via an α,α′-bis-alkyla-
tion to generate the first two stereogenic centers with virtually com- quence or the vinyl lactone 2 (Figure 1) can be
plete asymmetric induction (de, ee >99%). After the asymmetric synthesized from another chiral pool derived starting ma-
6
synthesis of the triol fragment of the molecule, the δ-lactone moiety
terial. In this case, both building blocks are then connect-
was constructed using an asymmetric allylation, esterification, and
ring-closing metathesis sequence.
ed via cross metathesis.
We envisaged a first asymmetric synthesis of the title nat-
ural product employing a chiral auxiliary approach. As the
retrosynthetic analysis in Scheme 1 shows, synargentolide
A can be traced back to the commercially available and
easily synthesized 2,2-dimethyl-1,3-dioxan-5-one (3) via
Key words: total synthesis, natural products, metathesis, hydra-
zones, asymmetric synthesis
7
Synargentolide A (1a) was first extracted by Rivett et al.
a ring-closing cross-metathesis α,α′-bis-alkylation se-
in 1997 from the aerial parts of the South African plant
8
quence.
Syncolestemon argenteus, found in the Ongoya forest in
1
the Kwazulu-Natal midlands. α,β-Unsaturated 6-substi-
OAc
OAc
tuted δ-lactones like synargentolide A are interesting tar-
RCM
gets in the field of natural product synthesis due to their
2
biological activity. Cytotoxity, antitumor activity, HIV-
OAc OAc
O
OAc OAc
O
protease inhibition, and antileukemic activity are only
some of the pharmacological properties that have been
proven for related compounds so far.3
O
O
synargentolide A (1a)
The published structure of synargentolide A (1b) was first
synthesized by Marco et al. in 2005. This structure
4
OAc
OAc
cross metathesis
proved to have one misassigned stereocenter. The revised
structure 1a (Figure 1) was later synthesized by several
groups. These published syntheses share the common fea-
ture that at least one of the stereogenic centers on the triol
OAc OAc
OAc OAc
O
moiety of the molecule is part of a starting material de-
rived from the chiral pool.5
RAMP-
hydrazone
O
OH
O
methodology
OAc
OAc
O
O
O
O
O
O
OAc OAc
O
OAc OAc
O
3
O
O
synargentolide A (1a)
first published structure of
Scheme 1 Retrosynthesis analysis for synargentolide A
synargentolide A (1b)
We now wish to present a first asymmetric synthesis of
synargentolide A employing the SAMP/RAMP-hydra-
zone methodology to create the first two stereogenic cen-
ters (Scheme 2). First the RAMP-hydrazone 4 of the
dioxanone 3 was synthesized according to the literature
O
O
(
R)-6-vinyl-5,6-dihydro-2H-pyran-2-one (2)
Figure 1 Structure of synargentolide A and a δ-lactone building
block 2
9
procedure in excellent yield (98%).
SYNTHESIS 2013, 45, 0959–0965
Advanced online publication: 07.03.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316865; Art ID: SS-2013-Z0126-OP
Georg Thieme Verlag Stuttgart · New York
©

960
D. Enders, L. F. Reichenbach
PAPER
The diastereoselective reduction of ketone 5 proved to be
difficult. None of the commonly used reducing agents
such as DIBAL-H, L-Selectride, LiAlH , NaBH , or
BINAL-H showed a good selectivity in favor of the de-
sired product, while other methods like the CBS-reduction
gave undesired side products. Because of its excellent
N
O
O
N
RAMP, CH2Cl2, r.t.
MeO
4
4
1
5 h, 4 Å MS
O
O
O
98%
yield (98%) and a simple and fast procedure NaBH was
finally chosen to reduce the ketone 5 (Scheme 3).
4
3
4
O
The diastereomers 6a and 6b (ratio 6a/6b = 45:55) were
separated by preparative HPLC and the undesired diaste-
reomer could easily be oxidized by DMP to ketone 5 for a
repeated use in very good yield (93%). The epimer 6b
was further used to synthesize the C3-epimer of synargen-
tolide A in six steps.
1. t-BuLi, THF, then MeI
2. t-BuLi, THF, then allyl bromide
3. oxalic acid, hexane
O
O
11
71%
5
de, ee >99%
Hydrolysis of the acetonide 6a was achieved under acidic
conditions and led to triol 7 in nearly quantitative yield.
This triol was not purified but directly acetylated to finish
the synthesis of the desired building block for the linear
part of synargentolide A in 87% yield over two steps.
Scheme 2 Asymmetric synthesis of ketone 5
After deprotonation of 4 with t-BuLi at –78 °C, methyl io-
dide was added first at –100 °C. In a second step, the
crude hydrazone was then allylated following the same
procedure. The removal of the chiral auxiliary could be
achieved by stirring a hexane solution of the disubstituted
hydrazone in a two-phase system with oxalic acid. For this
three-step sequence a very good overall yield of 71% was
reached under virtually complete asymmetric induction.
Thus, α,α′-bis-alkylated dioxanone 5 was obtained as a
single stereoisomer (de, ee >99%). The use of oxalic acid
is a very mild method and the possibility to recover most
of the auxiliary is another advantage making this synthesis
more cost effective.10
Cross metathesis with acrolein based on a method devel-
oped by Cossy et al. was used to expand the carbon frame-
12
work to the enal 9. The Hoveyda–Grubbs catalyst of the
2nd generation proved to be the best choice. While no re-
action occurred at room temperature, switching the sol-
vent from dichloromethane to 1,2-dichloroethane and
heating to 80 °C increased the conversion to 83% over
two days and gave the desired E-configured enal 9 in 74%
yield. The E/Z ratio was determined by NMR analysis to
be greater than 30:1.
O
OH
OH
OH
2
N HCl,
NaBH4, MeOH
THF (1:2)
−
78 °C to r.t., 1 h
1
h, r.t.
+
O
O
98%
O
O
O
O
OH OH
7
5
6b
6a
6
b/6a = 55:45
Ac2O, DMAP, Et3N
CH2Cl2, r.t., 15 h
87%
(2 steps)
DMP, CH2Cl2, 1 h, r.t.
3%
9
acrolein,
OAc
(+)-Ipc2B(allyl)
Et2O, –78 °C, 2 h
OAc
cat. A (2.5 mol%)
OAc
C2H4Cl2, 2 d, 80 °C
96%
83% conv., 74%
OAc OAc
OH
de, ee >99%
after chromatography)
OAc OAc
O
OAc OAc
10
9
dr > 30:1
8
(
nd
cat. A: Hoveyda–Grubbs 2 gen.
cat. B: Grubbs 2 gen.
acryloyl chloride
Et3N, CH2Cl2, 0 °C, 0.5 h
nd
63%
OAc
OAc
cat. B (5 mol%)
CH2Cl2, 2 h, reflux
synthesis of the C3-epimer:
6
b
epi-1a
OAc OAc
O
OAc OAc
O
77%
1
0% de, ee >99%
O
O
6 steps
11
1a
synargentolide A
de, ee >99%
Scheme 3 Asymmetric synthesis of synargentolide A (1a) and its 3-epimer 1b
Synthesis 2013, 45, 959–965
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric Synthesis of Synargentolide A
961
Asymmetric allylation with (+)-Ipc B(allyl)borane solu- (5.49 g, 45.4 mmol, 1.1 equiv) in anhyd THF (20 mL) was added
2
slowly by a syringe pump. After 2 h at –100 °C, the mixture was
stirred overnight while it warmed up to r.t. The mixture was
tion gave the desired alcohol 10 (96%). After esterifica-
tion with acryloyl chloride, the ester 11 (63%) was
obtained and used in the final step. The lactone ring was
constructed by ring-closing metathesis with the 2nd gen-
quenched with sat. aq NaHCO (50 mL) and diluted with Et O (1 L).
3
2
The organic layer was washed with sat. aq NaHCO (100 mL) and
3
brine (2 × 100 mL). The organic layer was dried (MgSO ) and con-
4
eration Grubbs catalyst and synargentolide A (1a) was centrated in vacuo. The crude hydrazone (11.5 g) in hexane (160
mL) was vigorously stirred at r.t. with sat. aq oxalic acid (60 mL)
for 14 h or until the TLC showed complete conversion. The aqueous
layer was separated, extracted with hexane (3 × 60 mL), and the or-
isolated after column chromatography in 77% yield
(
Scheme 3). A small amount of alkene 8 was detected as
a side product, due to competing intramolecular cross
metathesis.
ganic extracts were combined, dried (MgSO ), and concentrated in
4
vacuo. The residue was purified by flash chromatography (n-pen-
tane–Et O, 25:1) to give 5 (5.40 g, 71%) as a colorless liquid. The
enantiomeric excess for this compound was determined by gas
In conclusion, synargentolide A and its 3-epimer were
successfully synthesized starting from a commercially
available dioxanone and employing the SAMP/RAMP-
hydrazone methodology in 11 steps with an overall yield
of 9.2% for synargentolide A (1a), not including a possi-
ble reuse of the regenerated ketone 5. The spectral data of
2
chromatography on a chiral stationary phase and was greater than
23
9
9% while none of the syn-diastereomer was observed; [α]D +32.6
(
c 0.50, CHCl3).
IR (film): 3928 (vw), 3779 (w), 3466 (br), 3080 (m), 2988 (s), 2930
s), 2865 (s), 2309 (w), 1851 (vw), 1745 (s), 1640 (m), 1448 (s),
(
the synthesized title natural product were identical with 1380 (s), 1312 (w), 1227 (s), 1176 (s), 1120 (s), 1019 (s), 920 (s),
–1
the previously published data. In principle, eight different 834 (m), 681 (m), 608 (m), 543 (m) cm .
1
3
stereoisomers of synargentolide A may be synthesized via
H NMR (400 MHz, CDCl ): δ = 1.30 (d, J = 6.7 Hz, 3 H, CH ),
3
3
4
this approach simply by using either SAMP or RAMP as 1.44 (s, 3 H, CH ), 1.46 (s, 3 H, CH ), 2.30 (ddddd, J = 1.3 Hz,
3
3
4
3
3
2
J = 1.3 Hz, J = 6.6 Hz, J = 8.1 Hz, J = 15.0 Hz, 1 H, CH ), 2.61
ddddd, J = 1.4 Hz, J = 1.4 Hz, J = 3.9 Hz, J = 6.8 Hz, J = 15.0
Hz, 1 H, CH ), 4.27 (ddd, J = 1.3 Hz, J = 3.9 Hz, J = 8.3 Hz, 1 H,
CH), 4.32 (dq, J = 1.3 Hz, J = 6.7 Hz, 1 H, CH), 5.08 (dddd,
J = 1.3 Hz, J = 1.3 Hz, J = 1.4 Hz, J = 10.3 Hz, 1 H, CH=CH
5.13 (dddd, J = 1.4 Hz, J = 1.4 Hz, J = 1.4 Hz, J = 17.2 Hz, 1 H,
2)
CH=CH , 5.83 (dddd, J = 6.7 Hz, J = 6.7 Hz, J = 10.3 Hz
J = 17.0 Hz, 1 H, CH=CH
auxiliary, separation of the diastereomers after ketone re-
duction, and the use of different allylation reagents.
2
4
4
3
3
2
(
4
3
3
2
4
3
4
4
2
3
Unless otherwise noted, all commercially available compounds
2
),
13
4
4
2
3
were used without further purification. RAMP, 2,2-dimethyl-1,3-
9
a
9
3
3
3
dioxan-5-one (3), and the corresponding hydrazone 4 were syn-
thesized according to previously published procedures. For prepar-
ative column chromatography, SIL G-25 UV254 from Macherey-
Nagel, particle size 0.040–0.063 mm (230–240 mesh, flash) was
used. Visualization of the developed TLC plates was performed
with ultraviolet irradiation (254 nm) or by staining with a phospho-
molybdic acid, cerium sulfate stain. Mass spectra were recorded on
a Finnigan SSQ7000 spectrometer and a Finnigan MAT 95 spec-
trometer (EI 70 eV, CI 100 eV). High-resolution mass spectra were
measured using a Thermo Fisher Scientific Orbitrap XL spectrom-
eter. IR spectra were recorded on a PerkinElmer FT-IR Spectrum
3
).
2
13
C NMR (100 MHz, CDCl ): δ = 14.3 (CH ), 23.9 (CH ), 24.1
3
3
3
(
CH ), 33.0 (CH ), 70.6 (CH), 73.9 (CH), 101.1 (Cq), 117.4 (CH ),
3
2
2
133.5 (CH), 211.1 (Cq).
+
+
MS (GCMS, EI, 70 eV): m/z (%) = 184 ([M] , 2), 169 ([M – CH ],
3
1
), 140 (6), 114 (17), 86 (19), 82 (37), 54 (100).
Anal. Calcd for C H O : C, 65.19; H, 8.75. Found: C, 65.20; H,
10
16
3
8.46.
1
13
1
00 instrument. H and C NMR spectra were recorded at r.t. on
(4R,5R,6R)-4-Allyl-2,2,6-trimethyl-1,3-dioxan-5-ol (6a) and
(
4R,5S,6R)-4-Allyl-2,2,6-trimethyl-1,3-dioxan-5-ol (6b)
Ketone 5 (1.70 g, 9.24 mmol, 1.0 equiv) was dissolved in MeOH
110 mL) and cooled to –78 °C. NaBH (0.701 g, 18.48 mmol, 2.0
Varian Inova 400 (400 MHz) and Varian Inova 600 (600 MHz)
spectrometers with TMS as an internal standard. Optical rotations
were measured with a PerkinElmer P241 polarimeter. Gas chroma-
tography on a chiral stationary phase was carried out on a Siemens
Sichromat 1-4 system with a Lipodex G, 25 m × 0.25 mm ID col-
umn of Macherey & Nagel. Preparative HPLC was performed on a
LiChrosorb Si 60, 7 μm (250 × 25) mm column from Gibson.
(
4
equiv) was added and the cooling bath was removed. After the mix-
ture had reached r.t., the solvent was removed, the residue was taken
up in CH Cl (50 mL), and quenched by the addition of H O (20
2
2
2
mL). The organic phase was washed with aq NaHCO (20 mL),
3
brine (20 mL), and dried (MgSO ). The solvent was removed in
4
(
4R,6R)-4-Allyl-2,2,6-trimethyl-1,3-dioxan-5-one (5)
vacuo to yield a mixture of the alcohols 6a and 6b (1.69 g, 98%,
dr = 45:55) as a colorless liquid. They were separated by prepara-
tive HPLC [LiChrosorb Si 60, 7 μm (250 × 25) mm, n-hexane–
i-PrOH, 19:1]. The relative configuration was determined by NMR
spectroscopy.
A flame-dried 250 mL Schlenk round-bottomed flask, equipped
with a magnetic stirring bar, was charged with the RAMP-hydra-
zone 4 (10 g, 41.2 mmol, 1.0 equiv) and freshly distilled anhyd THF
(135 mL). Then, t-BuLi (28.4 mL, 1.6M in n-pentane, 45.4 mmol,
1
.1 equiv) was added dropwise by a syringe pump at –78 °C. After
(
4R,5R,6R)-4-Allyl-2,2,6-trimethyl-1,3-dioxan-5-ol (6a)
23
stirring for 2 h, the mixture was cooled to –100 °C and a solution of
MeI (2.82 mL, 45.4 mol, 1.1 equiv) in anhyd THF (20 mL) was add-
ed slowly by a syringe pump. After 2 h at –100 °C, the mixture was
further stirred overnight while it warmed up to r.t. It was then
quenched with aq NaHCO (50 mL) and diluted with Et O (1 L).
[
α]D –7.7 (c 1.00, CHCl3).
IR (film): 3450 (br), 3077 (m), 2984 (s), 2926 (s), 2716 (vw), 2167
(vw), 1836 (w), 1642 (m), 1448 (s), 1378 (s), 1228 (s), 1178 (s),
1116 (s), 1067 (s), 1023 (s), 916 (s), 831 (m), 788 (w), 751 (w), 703
3
2
–
1
The organic layer was washed with aq NaHCO (100 mL), brine
(w), 654 (w), 613 (m), 608 (m), 527 (m), 471 (m) cm .
3
(
2 × 100 mL), dried (MgSO ), and concentrated in vacuo. The crude
1
3
4
H NMR (400 MHz, CDCl ): δ = 1.29 (d, J = 6.4 Hz, 3 H, CH ),
3
3
hydrazone (10.5 g) was directly transferred into a flame-dried 250
mL Schlenk round-bottomed flask, equipped with a magnetic stir-
ring bar. It was dissolved in freshly distilled anhyd THF (135 mL).
Then, t-BuLi (28.4 mL, 1.6 M in n-pentane, 45.4 mmol, 1.10 equiv)
was added dropwise by syringe pump at –78 °C. After stirring for 2
h, the mixture was cooled to –100 °C and a solution of allyl bromide
1
.32 (s, 3 H, CH ), 1.36 (s, 3 H, CH ), 1.95 (br, 1 H, OH), 2.31 (tt,
J = 1.3 Hz, J = 7.3 Hz, 2 H, CH ), 3.43 (dd, J = 3.4 Hz, J = 6.4
3
3
4
3
3
3
2
4
3
Hz, 1 H, CH), 3.60 (dq, J = 6.4 Hz, J = 6.4 Hz, 1 H, CH), 3.84 (dt,
4
3
J = 3.4 Hz, J = 7.3 Hz, 1 H, CH), 5.03–5.08 (m, 1 H, CH=CH ),
2
3
3
5
.09–5.16 (m, 1 H, CH=CH ), 5.83 (dddd, J = 6.8 Hz, J = 6.8 Hz,
2
3
3
J = 10.2 Hz, J = 17.1 Hz, 1 H, CH=CH ).
2
©
Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 959–965

9
62
D. Enders, L. F. Reichenbach
PAPER
H NMR (600 MHz, CDCl ): δ = 1.19 (d, J = 6.4 Hz, 3 H, CH ),
13
1
3
C NMR (100 MHz, CDCl ): δ = 19.4 (CH ), 24.3 (CH ), 24.6
3
3
3
3
3
(
1
CH ), 33.5 (CH ), 70.1 (CH), 71.0 (CH), 75.6 (CH), 100.8 (Cq),
2.02 (s, 3 H, CH ), 2.04 (s, 3 H, CH ), 2.14 (s, 3 H, CH ), 2.25–2.32
3
2
3 3 3
3
3
17.1 (CH ), 134.6 (CH).
(m, 2 H, CH ), 4.99 (dq, J = 6.5 Hz, J = 6.5 Hz, 1 H, CH), 5.06–
2
2
3
3
+
5.14 (m, 3 H, CH=CH + CH), 5.17 (ddd, J = 6.4 Hz, J = 3.4 Hz,
2
MS (70 eV, EI): m/z (%) = 171 ([M – CH ], 7), 142 (3), 116 (18),
8
3
3
3
3
J = 7.5 Hz, 1 H, CH), 5.71 (dddd, J = 6.8 Hz, J = 6.8 Hz,
J = 10.2 Hz, J = 17.0 Hz, 1 H, CH=CH ).
3 (57), 59 (100).
3
3
2
+
HRMS: m/z calcd for C H O + Na : 209.1148; found: 209.1148.
1
0
18
3
13
C NMR (150 MHz, CDCl ): δ = 16.1 (CH ), 20.7 (CH ), 20.8
3
3
3
(
CH ), 21.1 (CH ), 35.6 (CH ), 67.4 (CH), 69.9 (CH), 73.9 (CH),
(
4R,5S,6R)-4-Allyl-2,2,6-trimethyl-1,3-dioxan-5-ol (6b)
3 3 2
2
3
[
α]D –13.1 (c 1.00, CHCl3).
118.6 (CH
2
), 132.4 (CH), 170.1 (Cq), 170.1 (Cq), 170.2 (Cq).
+
IR (film): 3435 (br), 2987 (s), 2911 (s), 2631 (vw), 1835 (w), 1642
MS (70 eV, EI): m/z (%) = 273 ([M + H], 2), 231 (12), 213 (100),
129 (54), 126 (22), 110 (23).
(m), 1448 (s), 1378 (s), 1228 (s), 1182 (s), 1140 (s), 1086 (s), 1040
(
s), 999 (s), 918 (s), 822 (m), 708 (w), 659 (m), 530 (m), 462 (w)
+
HRMS: m/z calcd for C H O + Na : 295.1152; found: 295.1152.
1
3
20
6
–
1
cm .
1
3
(2R,3R,4R,E)-8-Oxooct-6-ene-2,3,4-triyl Triacetate (9)
H NMR (400 MHz, CDCl ): δ = 1.15 (d, J = 6.7 Hz, 3 H, CH ),
3
3
Freshly distilled acrolein (0.27 g, 0.32 mL, 4.8 mmol, 3.0 equiv)
was added to a solution of alkene 8 (0.435 g, 1.6 mmol, 1.0 equiv)
in 1,2-dichloroethane (7 mL) in a flame-dried Schlenk flask.
Hoveyda–Grubbs II catalyst (25.0 mg, 2.5 mol%) was subsequently
added as a solid, producing a light green solution. This solution was
heated for 2 days at 80 °C. The mixture was then concentrated in
1
(
3
(
.31 (s, 3 H, CH ), 1.34 (s, 3 H, CH ), 2.00 (br, 1 H, OH), 2.27–2.46
m, 2 H, CH ), 3.42–3.47 (m, 1 H, CH), 3.47–3.54 (m, 1 H, C-4),
.93–4.00 (m, 1 H, CH), 5.02–5.07 (m, 1 H, CH=CH ), 5.08–5.16
3
3
2
2
m, 1 H, CH=CH ), 5.77–5.89 (m, 1 H, CH=CH ).
2
2
13
C NMR (100 MHz, CDCl ): δ = 14.6 (CH ), 24.3 (CH ), 24.6
CH ), 37.8 (CH ), 66.5 (CH), 74.4 (CH), 74.5 (CH), 100.7 (Cq),
3
3
3
(
1
3 2
vacuo and purified by flash chromatography (n-pentane–Et O, 2:1
2
17.1 (CH ), 134.6 (CH).
2
to 1:1, R = 0.4) to yield aldehyde 9 (0.297 g, 74%) as a yellow oil.
f
+
+
A small amount of starting material could also be recovered (0.076
MS (100 eV, CI): m/z (%) = 187 ([M + H], 100), 171 ([M – CH ],
3
3
2
3
g
,
0
.
2
7
9
m
m
o
l
,
8
3
%
c
o
n
v
e
r
s
i
o
n
)
;
[
α
]
+
1
8
.
2
(
c
1
.
2
0
,
C
H
C
l
)
.
3), 145 (19), 129 (72), 111 (91), 85 (38), 83 (42).
D
3
+
IR (film): 3468 (m), 2987 (m), 2943 (m), 2829 (w), 2738 (w), 2450
HRMS: m/z calcd for C H O + Na calcd. 209.1148; found
10
18
3
(vw), 1743 (s), 1692 (s), 1436 (m), 1374 (s), 1224 (s), 1139 (m),
209.1148.
1
060 (s), 1029 (s), 972 (m), 848 (m), 731 (w), 603 (m), 519 (w)
–
1
(2R,3R,4R)-Hept-6-ene-2,3,4-triol (7)
cm .
To a solution of alcohol 6a (0.745 g, 4.00 mmol, 1.0 equiv) in
MeOH (20 mL), was added aq 2 N HCl (10 mL) in one portion. The
mixture was stirred for 2 h, quenched with sat. aq NaHCO (10 mL),
and extracted with EtOAc (10 × 50 mL) and CH Cl (5 × 50 mL).
The combined organic layers were washed with brine (2 × 50 mL),
dried (MgSO ), and concentrated in vacuo. The crude product
0.584 g) was obtained as a colorless oil and directly used in the next
reaction without further purification; [α]D +32.6 (c 0.50, CHCl3).
1
3
H NMR (600 MHz, CDCl ): δ = 1.19 (d, J = 6.4 Hz, 3 H, CH ),
3
3
2
.02 (s, 3 H, CH ), 2.05 (s, 3 H, CH ), 2.15 (s, 3 H, CH ), 2.50–2.60
3 3 3
3
3
3
(
(
m, 2 H, CH ), 4.99 (dq, J = 7.4 Hz, J = 6.4 Hz, 1 H, CH), 5.12
dd, J = 3.2 Hz, J = 7.4 Hz, 1 H, CH), 5.32 (ddd, J = 7.5 Hz, 6.4
2
2
2
3
3
3
4
3
Hz, 3.2 Hz, 1 H, CH), 6.13 (ddt, J = 1.2 Hz, J = 7.8 Hz, 15.5 Hz,
1
4
3
H, CH), 6.72 (ddd, J = 6.7 Hz, 7.8 Hz, 15.5 Hz, 1 H, CH), 9.49
(
3
(
d, J = 7.8 Hz, 1 H, CHO).
2
3
13
C NMR (150 MHz, CDCl ): δ = 16.3 (CH ), 20.7 (CH ), 20.7
3
3
3
IR (film): 3396 (br), 3080 (s), 2975 (s), 2924 (s), 1985 (vw), 1838
w), 1718 (m), 1641 (m), 1438 (s), 1323 (m), 1257 (m), 1067 (s),
17 (s), 814 (w), 731 (m), 647 (m), 510 (w) cm .
(
1
CH ), 21.0 (CH ), 34.5 (CH ), 67.2 (CH), 68.7 (CH), 74.0 (CH),
35.5 (CH), 151.0 (CH), 169.9 (Cq), 170.1 (Cq), 170.2 (Cq), 193.3
3 3 2
(
9
–
1
(
Cq).
1
3
H NMR (400 MHz, CDCl ): δ = 1.27 (d, J = 6.5 Hz, 3 H, CH ),
.61 (br s, 1 H, OH), 2.30–2.45 (m, 3 H, CH + CHOH), 2.54–2.66
br s, 1 H, OH), 3.32–3.38 (m, 1 H, CH), 3.91–4.02 (m, 2 H,
× CH), 5.14–5.24 (m, 2 H, CH=CH ), 5.85 (dddd, J = 6.9 Hz,
3
3
+
MS (70 eV, EI): m/z (%) = 301 ([MH ], 7), 283 (11), 241 (100), 231
1
2
(
20), 181 (76), 154 (21), 138 (35), 129 (86), 121 (55), 112 (64).
(
3
+
2
HRMS: m/z calcd for C14
H
20
O
7
+ Na : 323.1103; found: 323.1101.
2
3
3
3
J = 6.9 Hz, J = 10.2 Hz, J = 17.1 Hz, 1 H, CH=CH ).
2
(
2R,3R,4R,8R,E)-8-Hydroxyundeca-6,10-diene-2,3,4-triyl Tri-
13
C NMR (100 MHz, CDCl ): δ = 19.2 (CH ), 38.3 (CH ), 69.7
CH), 70.3 (CH), 74.9 (CH), 118.5 (CH ), 134.2 (CH).
3
3
2
acetate (10)
(
To a precooled (–78 °C) solution of aldehyde 9 (0.650 g, 2.16
2
+
+
mmol, 1.0 equiv) in anhyd Et O (10 mL) was added (+)-allylB(Ipc)2
MS (100 eV, CI): m/z (%) = 147 ([M + H], 21), 129 ([M – H O],
2
2
+
(3.25 mL, 3.25 mmol, 1.5 equiv) in Et O (6 mL) under an argon at-
mosphere. The reaction mixture was stirred at –78 °C for 2 h and
was quenched by sequentially adding sat. aq NaHCO (2 mL),
6
8), 111 ([M – 2 H O], 100), 105 (29), 87 (68), 85 (88), 83 (50), 71
2
2
(98).
3
+
HRMS: m/z for C H O + Na : 169.0835; found: 169.0835.
7
14
3
MeOH (2 mL), and 30% H O (2 mL). After stirring for 30 min, the
2
2
reaction mixture was poured into aq NaHCO (10 mL) and extracted
with EtOAc (4 × 20 mL). The combined organic layers were
3
(
2R,3R,4R)-Hept-6-ene-2,3,4-triyl Triacetate (8)
Et N (2.34 mL, 16.7 mmol, 4.2 equiv), Ac O (1.59 mL, 16.8 mmol,
3
2
washed with brine (5 mL) and dried (MgSO ). The solvents were
4
4
.21 equiv), and a catalytic amount of DMAP (10 mg) were slowly
evaporated in vacuo and the crude product purified by flash chro-
added to a solution of the crude triol 7 (4.00 mmol, 1.0 equiv) in an-
matography (n-pentane–Et O, 3:2, R = 0.1) to give the alcohol 10
2
f
hyd CH Cl (32 mL) and the mixture was then stirred overnight at
r.t. The reaction mixture was quenched with aq NH Cl (16 mL) and
2
2
23
(
0.710 g, 96%) as a colorless oil; [α]D +12.5 (c 1.00, CHCl3).
4
extracted with EtOAc (3 × 50 mL). The combined organic layers
IR (film): 3779 (w), 3399 (br), 2931(s), 2839 (m), 2511 (w), 2138
(w), 1736 (s), 1443 (m), 1377 (s), 1228 (s), 1027 (s), 922 (m), 874
(w), 608 (m) cm .
were dried (MgSO ) and concentrated in vacuo. The residue was
4
–
1
purified by flash chromatography (n-pentane–Et O, 9:1) to give the
2
2
3
triacetate 8 (0.944 g, 87%) as a colorless liquid; [α]D +34.4 (c 1.00,
1
3
H NMR (400 MHz, CDCl ): δ = 1.20 (d, J = 6.3 Hz, 3 H, CH ),
3
3
CHCl3).
2
.01 (s, 3 H, CH ), 2.05 (s, 3 H, CH ), 2.13 (s, 3 H, CH ), 2.21–2.35
3 3 3
IR (film): 3469 (w), 3080 (w), 2985 (m), 2257 (w), 1744 (s), 1645
(m, 4 H, 2 × CH ), 4.09–4.16 (m, 1 H, CH), 4.95–5.07 (m, 1 H, CH),
2
(
w), 1437 (m), 1373 (s), 1226 (s), 1062 (m), 1029 (m), 960 (m), 918
5.10–5.20 (m, 4 H, 2 × CH, =CH ), 5.51–5.63 (m, 2 H, 2 × CH),
5.75–5.83 (m, 1 H, CH).
2
–1
(m), 845 (w), 734 (m), 650 (w), 604 (w), 520 (w) cm .
Synthesis 2013, 45, 959–965
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric Synthesis of Synargentolide A
963
13
+
C NMR (100 MHz, CDCl ): δ = 14.0 (CH ), 20.7 (CH ), 20.8
HRMS: m/z calcd for C H O + Na : 391.1363; found: 391.1363.
3
3
3
18 24
8
(
7
CH ), 21.0 (CH ), 33.9 (CH ), 41.5 (CH ), 67.4 (CH), 70.2 (CH),
3 3 2 2
epi-Synargentolide A (epi-1a)
1.4 (CH), 73.5 (CH), 118.0 (CH ), 124.9 (CH), 134.1 (CH), 136.6
2
To synthesize the C3-epimers of the compounds 7–11 and 1a all
steps were carried out exactly as described for synargentolide A
starting from alcohol 6b.
(
CH), 170.1 (2 × Cq), 170.2 (Cq).
+
MS (70 eV, EI): m/z (%) = 325 ([M – H O], 12), 241 (100), 181
2
(23), 163 (17), 139 (37), 121 (54).
+
(2R,3S,4R)-Hept-6-ene-2,3,4-triol (epi-7)
To a solution of alcohol 6b (0.374 g, 2.00 mmol, 1.0 equiv) in
MeOH (10 mL) was added aq 2 N HCl (5 mL) in one portion. Then
the mixture was stirred for 2 h, quenched with sat. aq NaHCO
mL) and extracted with EtOAc (10 × 25 mL) and CH Cl (5 × 25
HRMS: m/z calcd for C H O + Na : 365.1571; found: 365.1571.
1
7
26
7
(
2R,3R,4R,8R,E)-8-(Acryloyloxy)undeca-6,10-diene-2,3,4-triyl
Triacetate (11)
3
(5
Acryloyl chloride (0.145 mL, 1.75 mmol, 1.2 equiv) was added
dropwise to a solution of alcohol 10 (500 mg, 1.46 mmol, 1.0 equiv)
and Et N (0.44 mL, 3.07 mmol, 2.1 equiv) in anhyd CH Cl (36 mL)
2
2
mL). The combined organic layers were washed with brine (2 × 25
mL), dried (MgSO ), and concentrated in vacuo. The crude product
3
2
2
4
under an argon atmosphere. The mixture was stirred at 0 °C, and af-
ter 0.5 h it was poured into brine (7.5 mL) and extracted with
CH Cl (5 × 10 mL). The combined organic phases were washed
(0.293 g) was directly used in the next reaction without further pu-
rification; [α]D +9.2 (c 0.25, CHCl3).
23
2
2
IR (film): 3374 (br), 3080 (m), 2976 (s), 2923 (s), 1836 (w), 1642
with brine (10 mL), dried (MgSO ), and concentrated in vacuo. The
4
(
(
1
m), 1432 (s), 1301 (m), 1057 (s), 997 (s), 916 (m), 869 (w), 821
w), 659 (m) cm .
crude product was purified by flash chromatography (n-pentane–
Et O, 3:2, R = 0.2) to afford the acrylic ester 11 (366 mg, 63%) as
–1
2
f
3
2
3
H NMR (400 MHz, CDCl ): δ = 1.26 (d, J = 6.5 Hz, 3 H, CH ),
a colorless oil; [α]D +33.5 (c 1.02, CHCl3).
3
3
1
.58–1.70 (br, 1 H, OH), 2.24–2.45 (m, 3 H, CH + OH), 2.50–2.58
2
IR (film): 3852 (w), 3433 (br), 2949 (s), 2841 (s), 2604 (w), 2523
(
3
br, 1 H, OH), 2.58–2.70 (br, 1 H, OH), 3.30–3.36 (m, 1 H, CH),
.75–3.85 (m, 1 H, CH), 4.05–4.15 (m, 1 H, CH), 5.15–5.22 (m, 2
H, CH=CH ), 5.85 (m, 1 H, CH=CH ).
(
1
w), 2167 (w), 2032 (w), 1705 (m), 1652 (m), 1452 (m), 1384 (s),
268 (m), 1235 (m), 1112 (m), 1021 (s), 875 (w), 611 (m) cm .
–
1
2
2
1
3
H NMR (400 MHz, CDCl ): δ = 1.18 (d, J = 6.3 Hz, 3 H, CH ),
13
3
3
C NMR (100 MHz, CDCl ): δ = 19.6 (CH ), 37.7 (CH ), 66.9
3
3
2
2
.01 (s, 3 H, CH ), 2.02 (s, 3 H, CH ), 2.13 (s, 3 H, CH ), 2.20–2.29
3 3 3
(
CH), 72.8 (CH), 75.8 (CH), 118.6 (CH ), 134.3 (CH).
3
2
(
m, 2 H, CH ), 2.36–2.45 (m, 2 H, CH ), 4.97 (dq, J = 6.3 Hz,
2
2
+
+
3
MS (100 eV, CI): m/z (%) = 147 ([M + H ], 100), 129 ([M – H O],
J = 7.1 Hz, 1 H, CH), 5.03–5.12 (m, 3 H, CH, RCH ), 5.14–5.21
2
2
+
3
83), 111 ([M – 2 H O], 46), 85 (8), 83 (6).
(m, 1 H, CH), 5.31 (q, J = 6.4 Hz, 1 H, CH), 5.48–5.52 (m, 1 H,
2
3
3
CH), 5.53–5.75 (m, 2 H, CH), 5.81 (dd, J = 1.3 Hz, J = 6.4 Hz, 1
H, CH ), 6.05–6.14 (m, 1 H, CH), 6.37 (dd, J = 1.4 Hz, J = 17.4
3
3
(2R,3S,4R)-Hept-6-ene-2,3,4-triyl Triacetate (epi-8)
2
Et N (1.17 mL, 8.35 mmol, 4.2 equiv), Ac O (0.80 mL, 8.40 mmol,
3
2
Hz, 1 H, CH2).
4
.21 equiv) and a catalytic amount of DMAP (10 mg) were slowly
13
C NMR (100 MHz, CDCl ): δ = 14.0 (CH ), 20.7 (2 × CH ), 21.0
added to a solution of the crude triol epi-7 (2 mmol, 1.0 equiv) in
3
3
3
(
7
CH ), 34.0 (CH ), 38.7 (CH ), 67.4 (CH), 69.6 (CH), 73.4 (CH),
anhyd CH Cl (16 mL). The mixture was then stirred overnight at
3
2
2
2
2
3.9 (CH), 117.9 (CH ), 127.6 (CH), 128.6 (CH), 130.6 (CH ),
r.t. The reaction mixture was quenched with aq NH Cl (8 mL) and
2
2
4
131.8 (CH), 133.0 (CH), 165.2 (Cq), 170.0 (Cq), 170.1 (2 × Cq).
extracted with EtOAc (3 × 25 mL). The combined organic layers
+
were dried (MgSO ) and concentrated in vacuo. The residue was
MS (70 eV, EI): m/z (%) = 355 ([M – C H ], 2), 337 (6), 325 (5),
2
4
3
5
purified by flash chromatography (n-pentane–Et O, 9:1) to give the
95 (12), 235 (14), 193 (24), 121 (48), 55 (100).
2
2
3
triacetate epi-8 (0.346 g, 64%) as a colorless liquid; [α]D +14.2 (c
+
8
HRMS: m/z calcd for C H O : 355.1396; found: 355.1387.
1
7
28
1.03, CHCl3).
Synargentolide A (1a)
A solution of triene 11 (98 mg, 0.247 mmol, 1.0 equiv) in CH Cl
IR (film): 3467 (m), 3078 (w), 2983 (m), 2450 (w), 2107 (vw), 1744
(s), 1646 (m), 1440 (s), 1374 (s), 1228 (s), 1150 (w), 1048 (s), 938
(m), 830 (w), 659 (w), 608 (w), 535 (w) cm .
2
2
–
1
(25 mL) in a sealed tube was stirred under argon. Grubbs type II cat-
alyst (11 mg, 5 mol%) was added in one portion and the resulting
orange mixture was stirred at 40 °C for 2 h. The mixture was con-
centrated in vacuo and the crude mixture was purified by flash chro-
matography (n-pentane–Et O, 1:3, R = 0.1) to give synargentolide
A (1a) (70.5 mg, 77%) as a colorless oil; [α]D +41.7 (c 1.00,
CHCl3).
1
3
H NMR (400 MHz, CDCl ): δ = 1.17 (d, J = 6.5 Hz, 3 H, CH ),
3
3
2
(
.01 (s, 3 H, CH ), 2.04 (s, 3 H, CH ), 2.14 (s, 3 H, CH ), 2.20–2.44
3 3 3
m, 2 H, CH ), 5.03–5.06 (m, 1 H, CH), 5.06–5.11 (m, 3 H,
2
2
f
CH=CH , CH), 5.12–5.20 (m, 1 H, CH), 5.71 (m, 1 H, CH=CH ).
2
3
2
2
13
C NMR (100 MHz, CDCl ): δ = 16.4 (CH ), 20.7 (CH ), 20.8
CH ), 21.0 (CH ), 35.2 (CH ), 67.5 (CH), 69.6 (CH), 74.1 (CH),
18.3 (CH ), 132.7 (CH), 170.0 (Cq), 170.1 (Cq), 170.3 (Cq).
3
3
3
(
1
3 3 2
IR (film): 3781 (w), 3463 (br), 2928 (s), 2100 (vw), 1932 (w), 1735
2
(
6
s), 1444 (s), 1379 (s), 1230 (s), 1031 (s), 967 (m), 817 (m), 655 (w),
03 (w), 485 (vw) cm .
+
–
1
MS (70 eV, EI): m/z (%) = 273 ([M + H], 2), 231 (25), 213 (86),
1
70 (20), 152 (18), 129 (100), 126 (54), 110 (50).
1
3
H NMR (600 MHz, CDCl ): δ = 1.18 (d, J = 6.3 Hz, 3 H, CH ),
3
3
+
HRMS: m/z calcd for C H O + Na : 295.1152; found: 295.1152.
2
.02 (s, 3 H, CH ), 2.05 (s, 3 H, CH ), 2.15 (s, 3 H, CH ), 2.27–2.33
13 20
6
3
3
3
3
(m, 2 H, CH ), 2.39–2.44 (m, 2 H, CH ), 4.84 (dt, J = 9.6, 5.9 Hz,
2
2
3
3
(2R,3S,4R,E)-8-Oxooct-6-ene-2,3,4-triyl Triacetate (epi-9)
Freshly distilled acrolein (0.802g, 14.31 mmol, 3.0 equiv) was add-
ed to a solution of alkene epi-8 (1.30 g, 4.77 mmol, 1.00 equiv) in
1
H, CH), 4.95 (dq, J = 6.3 Hz, J = 7.5 Hz, 1 H, CH), 5.07 (dd,
3
3
3
3
J = 7.5 Hz, J = 3.1 Hz, 1 H, CH), 5.17 (dt, J = 6.4 Hz, J = 3.1 Hz,
3
1
H, CH), 5.66 (dd, J = 15.5, 6.4 Hz, 1 H, CH), 5.69–5.76 (m, 1 H,
1
,2-dichloroethane (21 mL) in a flame-dried Schlenk flask. Hoveyda–
3
3
CH), 6.03 (dt, J = 9.8 Hz, J = 1.1 Hz, 1 H, CH), 6.84–6.88 (m, 1
Grubbs II catalyst (74.0 mg, 2.5 mol%) was subsequently added as
a solid, producing a light green solution. This solution was heated
for 2 days at 80 °C. The mixture was then concentrated in vacuo and
purified by flash chromatography (n-pentane–Et O, 2:1) to yield al-
dehyde epi-9 (0.989 g, 69%) as a yellow oil; [α]D +3.40 (c 1.00,
H, CH).
13
C NMR (150 MHz, CDCl ): δ = 16.2 (CH ), 20.7 (CH ), 20.8
3
3
3
(
CH ), 21.0 (CH ), 29.5 (CH), 33.9 (CH ), 67.3 (CH), 69.5 (CH),
3
3
2
2
23
7
3.6 (CH), 77.6 (CH), 121.5 (CH), 128.5 (CH), 131.0 (CH), 144.5
(CH), 163.7 (Cq), 170.0 (Cq), 170.1 (Cq), 170.2 (Cq).
CHCl3).
+
+
MS (70 eV, EI): m/z (%) = 369 ([M ], 8), 309 ([M – OAc], 42), 248
36), 206 (100), 188 (76), 161 (80), 149 (25), 120 (62), 68 (74).
(
©
Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 959–965

9
64
D. Enders, L. F. Reichenbach
PAPER
H NMR (600 MHz, CDCl ): δ = 1.16 (d, J = 6.6 Hz, 3 H, CH ),
1
3
IR (film): 3470 (w), 2986 (m), 2826 (w), 2739 (w), 2256 (vw), 1743
3
3
(
(
1
s), 1692 (s), 1435 (m), 1374 (s), 1225 (s), 1144 (m), 1044 (m), 985
m), 917 (m), 834 (w), 733 (m), 649 (w), 605 (w), 533 (w) cm .
1.99 (s, 3 H, CH ), 2.03 (s, 3 H, CH ), 2.14 (s, 3 H, CH ), 2.20–2.45
3 3 3
–
1
(m, 4 H, 2 × CH ), 5.04–5.12 (m, 5 H, 2 × CH, RCH ), 5.13 (dq,
2
2
3
3
3
3
J = 6.5, J = 3.2 Hz, 1 H, CH), 5.31 (q, J = 6.5 Hz, 1 H, CH), 5.50
H NMR (600 MHz, CDCl ): δ = 1.17 (d, J = 6.6 Hz, 3 H, CH ),
3
3
3
3
(
dd, J = 6.7 Hz, J = 15.4 Hz, 1 H, CH), 5.58–5.67 (m, 1 H, CH),
2
.01 (s, 3 H, CH ), 2.04 (s, 3 H, CH ), 2.14 (s, 3 H, CH ), 2.52–2.66
3 3 3
3
3
3
3
3
5.72 (ddd, J = 6.9 Hz, J = 6.9 Hz, J = 10.3 Hz, 1 H, CH), 5.82
(dd, J = 1.4, J = 10.4 Hz, 1 H, CH ), 6.10 (dd, J = 10.4, J = 17.3
Hz, 1 H, CH), 6.39 (dd, J = 1.4, 17.4 Hz, 1 H, CH ).
2
(m, 2 H, CH ), 5.12 (dd, J = 3.1 Hz, J = 8.0 Hz, 1 H, CH), 5.15–
2
2
3
3
3
4
3
3
2
5
.22 (m, 2 H, 2 × CH), 6.11 (ddt, J = 1.2 Hz, J = 7.7 Hz, J = 15.6
3
3
3
3
Hz, 1 H, CH), 6.72 (ddd, J = 6.9 Hz, J = 7.5 Hz, J = 15.6 Hz, 1 H,
CH), 9.49 (d, J = 7.7 Hz, 1 H, CHO).
3
13
C NMR (150 MHz, CDCl ): δ = 16.4 (CH ), 20.7 (CH ), 20.8
3 3 3
1
3
(CH
3 3 2 2
), 21.0 (CH ), 33.6 (CH ), 38.8 (CH ), 67.5 (CH), 69.4 (CH),
C NMR (150 MHz, CDCl ): δ = 16.1 (CH ), 20.7 (CH ), 20.7
3
3
3
73.3 (CH), 74.1 (CH), 118.0 (CH ), 127.8 (CH), 128.1 (CH), 130.6
2
(
1
CH ), 21.0 (CH ), 34.2 (CH ), 67.2 (CH), 68.7 (CH), 73.8 (CH),
35.5 (CH), 151.5 (CH), 169.9 (Cq), 170.0 (Cq), 170.2 (Cq), 193.3
3 3 2
(
1
CH ), 131.6 (CH), 133.0 (CH), 165.2 (Cq), 169.8 (Cq), 170.1 (Cq),
70.3 (Cq).
2
(
Cq).
MS (70 eV, EI): m/z (%) = 301 ([M + H], 11), 283 (7), 257 (8), 241
54), 231 (27), 181 (84), 154 (28), 138 (53), 129 (100), 121 (71),
12 (90).
HRMS for C H O + Na : 323.1101; found: 323.1101.
+
+
+
MS (70 eV, CI): m/z (%) = 397 ([M + H], 3), 355 ([M – C
3
H
5
], 4),
37 (23), 325 (100), 295 (8), 265 (48), 205 (17), 163 (27), 145 (24),
21 (3).
3
1
(
1
+
+
HRMS: m/z calcd for C20
H O + Na : 419.1676; found: 419.1676.
28 8
14
20
7
epi-Synargentolide A (epi-1a)
(
2R,3S,4R,8R,E)-8-Hydroxyundeca-6,10-diene-2,3,4-triyl Tri-
A solution of epi-11 (75 mg, 0.188 mmol, 1.0 equiv) in anhyd
acetate (epi-10)
CH Cl (19 mL) in a sealed tube was stirred under argon. Grubbs
To a precooled (–78 °C) solution of aldehyde epi-9 (0.650 g, 2.16
mmol, 1.0 equiv) in anhyd Et O (10 mL) was added (+)-allylB(Ipc)
2
2
type II catalyst (8 mg, 0.0095 mmol, 5 mol%) was added in one por-
tion and the resulting orange mixture was stirred under argon at
2
2
(3.25 mL, 3.25 mmol, 1.5 equiv) in Et O (10 mL) under an argon
2
4
0 °C for 10 h. The mixture was concentrated in vacuo and the
atmosphere. The reaction mixture was stirred at –78 °C for 2 h and
was quenched by sequentially adding sat. aq NaHCO (2 mL),
MeOH (2 mL), and 30% H O (2 mL). After stirring for 30 min, the
mixture was poured into aq NaHCO (10 mL) and extracted with
crude mixture was purified by flash chromatography (n-pentane–
Et O, 2:3, R = 0.05) to give epi-synargentolide A (epi-1a) (61 mg,
3
2
f
2
2
23
8
8
%
)
a
s
a
c
o
l
o
r
l
e
s
s
o
i
l
;
[
α
]
+
4
5
.
8
(
c
0
.
5
0
,
C
H
C
l
)
.
D
3
3
EtOAc (5 × 20 mL). The combined organic layers were washed
IR (film): 3435 (br), 2925 (s), 2855 (s), 2610 (w), 2043 (w), 1730
(s), 1654 (s), 1546 (m), 1456 (s), 1381 (s), 1257 (m), 1156 (w), 1023
(s), 721 (m), 614 (m), 472 (w) cm .
with brine (10 mL) and dried (MgSO ). The solvents were evapo-
4
–
1
rated in vacuo and the crude product purified by column chromatog-
raphy (n-pentane–Et O, 1:2) to give alcohol epi-10 (0.481 g, 65%)
2
1
3
H NMR (600 MHz, CDCl ): δ = 1.17 (d, J = 6.5 Hz, 3 H, CH ),
23
3
3
as a colorless oil; [α]D +5.40 (c 1.03, CHCl3).
2
.03 (s, 3 H, CH ), 2.04 (s, 3 H, CH ), 2.15 (s, 3 H, CH ), 2.22–2.42
3 3 3
IR (film): 3472 (br), 3075 (w), (s), 2926 (s), 2857 (m), 2460 (vw),
(m, 4 H, 2 × CH ), 4.80–4.87 (m, 1 H, CH), 5.04–5.10 (m, 2 H,
2
3
3
2111 (vw), 1741 (s), 1642 (m), 1542 (vw), 1437 (m), 1375 (s), 1225
2 × CH), 5.12 (dq, J = 6.5 Hz, J = 3.0 Hz, 1 H, CH), 5.63 (dd,
J = 15.6, 6.2 Hz, 1 H, CH) 5.71–5.78 (m, 1 H, CH), 6.02 (dt,
J = 9.7 Hz, J = 1.7 Hz, 1 H, CH), 6.86 (dd, J = 5.1 Hz, J = 3.3
3
(
4
s), 1140 (m), 1035 (s), 920 (m), 832 (w), 757 (m), 607 (m), 523 (w),
64 (w) cm .
–
1
3
3
3
3
1
3
Hz, 1 H, CH).
H NMR (400 MHz, CDCl ): δ = 1.15 (d, J = 6.3 Hz, 3 H, CH ),
3
3
13
1
.77–1.95 (br, 1 H, OH), 2.00 (s, 3 H, CH ), 2.02 (s, 3 H, CH ), 2.13
C NMR (100 MHz, CDCl ): δ = 16.4 (CH ), 20.7 (CH ), 20.8
3 3 3
3
3
3
(
s, 3 H, CH ), 2.18–2.40 (m, 4 H, 2 × CH ), 4.10 (dt, J = 6.0 Hz,
(CH ), 21.0 (CH ), 29.6 (CH), 33.6 (CH ), 67.4 (CH), 69.4 (CH),
3
2
3
3
2
3
J = 6.1 Hz, 1 H, CH), 5.05–5.18 (m, 5 H, 3 × CH, CH=CH ), 5.44–
.63 (m, 2 H, 2 × CH), 5.70–5.82 (m, 1 H, CH).
73.9 (CH), 77.6 (CH), 121.6 (CH), 128.6 (CH), 130.6 (CH), 144.4
(CH), 163.7 (Cq), 170.0 (Cq), 170.1 (Cq), 170.2 (Cq).
2
5
1
3
+
+
C NMR (100 MHz, CDCl ): δ = 15.2 (CH ), 20.8 (CH ), 20.9
MS (100 eV, CI): m/z (%) = 369 ([M + H], 46), 309 ([M – HOAc],
3
3
3
+
+
(
7
(
CH ), 20.9 (CH ), 34.1 (CH ), 41.7 (CH ), 67.4 (CH), 69.7 (CH),
1.3 (CH), 73.7 (CH), 118.0 (CH ), 125.3 (CH), 134.1 (CH), 136.3
CH), 170.0 (Cq), 170.2 (Cq), 170.3 (Cq).
100), 249 ([M – 2 HOAc], 41), 189 ([M – 3 HOAc], 26).
3
3
2
2
2
+
HRMS: m/z calcd for C H O + Na : 391.1363; found: 391.1363.
1
8
24
8
+
+
MS (70 eV, EI): m/z = 325 ([M – H O], 1), 301 ([M – C H ], 3),
2
3
5
2
41 (77), 181 (51), 139 (65), 121 (100).
Acknowledgment
+
HRMS: m/z calcd for C H O + Na : 365.1568; found: 365.1570.
1
7
26
7
We thank the former Degussa AG and BASF SE for the donation of
chemicals.
(
2R,3S,4R,8R,E)-8-(Acryloyloxy)undeca-6,10-diene-2,3,4-triyl
Triacetate (epi-11)
Acryloyl chloride (0.087 mL, 1.05 mmol, 1.2 equiv) was added
dropwise to a solution of epi-10 (300 mg, 0.876 mmol, 1.0 equiv)
and Et N (0.264 mL, 1.84 mmol, 2.1 equiv) in anhyd CH Cl (23
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
3
2
2
mL) under an argon atmosphere. The mixture was stirred at 0 °C for
h. The mixture was poured into brine (10 mL) and extracted with
CH Cl (5 × 20 mL). The combined organic phases were washed
1
References
2
2
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