The first total synthesis of naturally occurring (+)-gymnasterkoreayne F and its enantiomer

Article abstract of DOI:10.1016/j.tetasy.2005.06.015

The first total synthesis of naturally occurring (+)-gymnasterkoreayne F and its enantiomer is reported. The seven-step route to these two polyacetylenes in enantiomerically pure form involves the use of (+)-2,3-O-isopropylidene-l- threitol and (-)-2,3-O-isopropylidene-d-threitol, respectively, as the starting material and a Cadiot-Chodkiewicz reaction as a key step. The absolute configuration of (+)-gymnasterkoreayne F has been confirmed to be (2E,8S,Z). The natural product and its enantiomer have been found to exhibit modest cytotoxicity against the 60 human tumor cell lines of the National Cancer Institute.

Full text of DOI:10.1016/j.tetasy.2005.06.015

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2501–2508
The first total synthesis of naturally occurring
(+)-gymnasterkoreayne F and its enantiomer
Adriano Carpita,* Silvia Braconi and Renzo Rossi*
Dipartimento di Chimica e Chimica Industriale, University of Pisa, via Risorgimento 35, I-56126 Pisa, Italy
Received 1 June 2005; accepted 7 June 2005
Abstract—The first total synthesis of naturally occurring (+)-gymnasterkoreayne F and its enantiomer is reported. The seven-step
route to these two polyacetylenes in enantiomerically pure form involves the use of (+)-2,3-O-isopropylidene-L-threitol and (ꢀ)-2,3-
O-isopropylidene-D-threitol, respectively, as the starting material and a Cadiot–Chodkiewicz reaction as a key step. The absolute
configuration of (+)-gymnasterkoreayne F has been confirmed to be (2E,8S,Z). The natural product and its enantiomer have been
found to exhibit modest cytotoxicity against the 60 human tumor cell lines of the National Cancer Institute.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
In 2002, Jung et al.13 isolated six new polyacetylenes,
gymnasterkoreaynes A–F, (ꢀ)-1, (+)-2, (+)-3, (+)-4,
(+)-5, and (+)-6, respectively (Fig. 1), from the roots
of Gymnaster koreaiensis (Nakai) Kitamura (Composi-
tae), an endemic species in Korea, by bioassay-guided
fractionation of an 80% EtOH extracts of these roots
using L1210 mouse leukemia tumor cell line as a model
for cytotoxicity. These authors also elucidated the struc-
ture of compounds 1–6 by spectroscopic methods and
assigned their absolute stereochemistry. However, only
in the case of compound (ꢀ)-1 did they specify that
the absolute stereochemistry had been determined using
the modified Mosher method.14 In fact, they assigned
Polyacetylenes are widely recognized as one of the most
frequently encountered groups of metabolites of basidio-
mycete fungi1 and higher plants, such as Compositae
(Asteraceae),2 Olacaceae,3 Santalaceae,4 Umbelliferae
(Apiaceae),5 Araliaceae,6 and Loranthaceae.7 Moreover,
in recent years several polyacetylenes have been isolated
from marine sponges.8 The biological properties of these
metabolites, which include antifungal,9 antimicrobial,10
cytotoxic,11 and enzyme-inhibitory activities,12 make
them to be of particular interest to pharmacologists
and plant pathologists.
CH3
H
R1
CH3
R2
H
OH
H
HO
(–)-1
OH
H
(+)-2 : R1, R2 = O
(+)-5 : R1 = R2 = OH
AcO
H
R
OH
OH
H
H
(+)-3
(+)-4 : R = OAc
(+)-6 : R = OH
Figure 1. Gymnasterkoreaynes A–F.
*
Corresponding authors. Tel.: +39 050 2219203; fax: +39 050 2219260; e-mail: rossi@dcci.unipi.it
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.06.015

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A. Carpita et al. / Tetrahedron: Asymmetry 16 (2005) 2501–2508
the (10S)- and (3S,8S)-configurations to (+)-2 and (+)-3,
respectively, on the basis of their 13C NMR data and
specific rotations, which resembled analogous data of
well-known natural products,13 but they did not men-
tion on which basis it had been possible to establish
the absolute configurations of (+)-4, (+)-5, and (+)-6.
2-penten-4-yn-1-ol 8 and (3S,4Z)-dodeca-4,11-dien-1-
yn-3-ol (3S,4Z)-9. Compound 8 can be prepared from
commercially available 1015b while (3S,4Z)-9 is available
from (2R,3S,4Z)-1-chloro-2,3-(isopropylidenedioxyl)-do-
deca-4,11-diene (2R,3S,4Z)-11, which in turn can be
synthesized by a Wittig reaction between aldehyde
(2R,3S)-12 and the ylide derived from phosphonium
bromide 13. Conversely, (2R,3S)-12 can be prepared
from (2S,3S)-7, which is commercially available or can
be prepared from L-tartaric acid.17
Interestingly, compounds (+)-2, (+)-3, and (+)-6 were
found to exhibit significant cytotoxicity against the
L1210 tumor cell line with ED50 values of 3.3, 2.1, and
3.1 lg/mL, respectively.13
A very similar retrosynthetic analysis involving the use
of commercially available (2R,3R)-7 as the starting
material and (3R,4Z)-9 as the key intermediate was envi-
sioned for the synthesis of (ꢀ)-6 (Fig. 2).
Motivated by the biological activity of these polyacetyl-
enes, their low availability from natural sources and our
interest in the synthesis of naturally occurring com-
pounds and their analogues, which exhibit cytotoxic
activity against tumor cell lines,15 we decided to investi-
gate the total synthesis of compounds (+)-3 and (+)-6.
In fact, we wished also to verify their structural and con-
figurational assignment and to evaluate their cytotoxic
activity against the entire panel of 60 human tumor cell
lines of the National Cancer Institute (NCI). Herein, we
report a concise and efficient synthesis of naturally
occurring (+)-6 and (ꢀ)-6 in enantiomerically pure
forms starting from (+)-2,3-O-isopropylidene-L-threitol,
(+)(2S,3S-)-7, and (ꢀ)-(2R,3R)-7, respectively.
O
H
HO
OH
O
OH
(2R,3R)-7
(3R,4Z)-9
16
4
HO
2
9
Additionally, we also report the cytotoxicity data of the
natural product and its enantiomer against the NCIꢀs 60
tumor cell lines.
OH
(–)-6
Figure 2.
2. Results and discussion
Scheme 2 provides details of the synthetic route followed
to prepare (+)-6. In particular, compound (2S,3S)-14
was prepared in 72% yield by the reaction of (2S,3S)-7
with 1.07 equiv of NaH in a 1:1 mixture of THF and
Our synthetic approach to the synthesis of naturally
occurring (+)-6 was envisioned through the retrosyn-
thetic analysis shown in Scheme 1.
HO
HO
O
a, b
c
d
MPMO
(2S,3S)-7
(2R,3S)-12
OH
Br
H
8
10
O
(2S,3S)-14
(+)-6
+
e
f
O
O
H
O
MPMO
HO
Cl
O
O
O
OH
(2S,3S,4Z)-15
(2S,3S,4Z)-16
(3S,4Z)-9
(2R,3S,4Z)-11
h or i or j
g
(3S,4Z)-9
(+)-6
(2R,3S,4Z)-11
Scheme 2. Reagents and conditions: (a) NaH (1.07 equiv), DMF/THF
(1:1), 0 ꢁC, 1.5 h; (b) MPMCl (1.05 equiv), 0–20 ꢁC, 18 h (72%); (c)
DMSO (3 equiv), (COCl)2 (1.5 equiv), Et3N (1.7 equiv), CH2Cl2,
ꢀ78 ꢁC, 10 min; (d) 13 (1.2 equiv), t-BuOK (1.2 equiv), THF,
ꢀ78 ꢁC, 2 h, then 20 ꢁC, 12 h (87% from (2S,3S)-14); (e) DDQ
(1.5 equiv) CH2Cl2/H2O (20:1), 20 ꢁC, 2.5 h (85%); (f) PPh3 (2 equiv),
CCl4, 90 ꢁC, 16 h (91%); (g) LDA (5 equiv), THF, ꢀ78 ꢁC, 3 h, 0 ꢁC,
30 min, then aq NH4Cl (55%); (h) 8 (1.1 equiv), CuCl (6 mol %),
NH2OHÆHCl (0.3 equiv), EtNH2, H2O, CH3OH, 0 ꢁC, 45 min (76%);
(i) 8, (1.0 equiv), CuCl (10 mol %), NH2OHÆHCl (0.3 equiv), Et3N
(1 equiv), DMF, 0 ꢁC, 30 min, then 20 ꢁC, 23 h (13%); (j) 8 (1 equiv),
CuCl (10 mol %), NH2OHÆHCl (0.3 equiv), 2,2,6,6-tetramethylpiperi-
dine (TMP) (2.1 equiv), DMF, 0 ꢁC, 30 min, then 20 ꢁC, 5 h (51%).
O
O
HO
MPMO
CHO
+
OH
Br Ph3P
O
O
13
(2R,3S)-12
(2S,3S)-7
(MPM = p-methoxybenzyl)
Scheme 1.
In particular, (+)-6 should be accessible through a Cad-
iot–Chodkiewicz-type reaction16 between (E)-5-bromo-

A. Carpita et al. / Tetrahedron: Asymmetry 16 (2005) 2501–2508
2503
DMF followed by treatment of the so-obtained mono-
sodium salt with a molar excess of p-methoxybenzyl
chloride (MPMCl). Swern oxidation of (2S,3S)-14 pro-
vided aldehyde (2R,3S)-12, which was subsequently
reacted with the ylide derived from treatment of phos-
phonium bromide 13 with t-BuOK in THF to afford
92% stereoisomerically pure (2S,3S,4Z)-15 in 87% yield
from (2S,3S)-14 after chromatographic purification. It
should be noted that freshly prepared crude (2R,3S)-12
was employed in the Wittig reaction. In fact, we ob-
served that this compound easily undergoes epimeriza-
tion at ꢀ23 ꢁC. Moreover, we found that the crude
product of the Wittig reaction was contaminated by
three stereoisomers of the required (2S,3S,4Z)-15, which
presumably corresponded to (2S,3R,4Z)-, (2S,3S,4E)-,
and (2S,3R,4E)-15. We also noticed that the chromato-
graphic purification of this crude reaction product did
not allow us to obtain (2S,3S,4Z)-15 in its stereoisomer-
ically pure form.
which involves the use of 6 equiv of BuLi in HMPA at
ꢀ35 ꢁC.22
Finally,
a
Cadiot–Chodkiewicz reaction between
(3S,4Z)-9 and (E)-1-bromo-3-en-1-yne 8 under standard
conditions20b,23 gave (+)-6 in 76% yield. This same com-
pound could be prepared in 51% yield employing a mod-
ification of the Cadiot–Chodkiewicz reaction, which we
developed for the synthesis of a chiral precursor of nat-
urally occurring (ꢀ)-nitidon and its enantiomer.15b This
modification involves the CuCl-catalyzed coupling of 8
with (3S,4Z)-9 in DMF in the presence of 0.3 equiv of
NH2OHÆHCl and 2,2,6,6-tetramethylpiperidine (TMP)
as a base. On the other hand, we found that the CuCl-
catalyzed reaction of 8 with (3S,4Z)-9 in DMF in the
presence of Et3N and 0.3 equiv of NH2OHÆHCl
furnished chemically pure (+)-6 only in 13% yield.
Compound (+)-6, which was so prepared in seven steps
and 20% overall yield from (2S,3S)-7 and 8, was esti-
mated to have 98.5% enantiomeric excess on the basis
of HPLC analyses on a Chiracel OD-H column. This
compound had physical and spectral properties in satis-
Crude compound 13 was prepared in a quantitative
yield by reaction of PPh3 with a CH3CN solution of 8-
bromo-1-octene 18 at 90 ꢁC for 140 h (Scheme 3). On
the other hand, this halide was obtained in 39% yield
by the reaction of 1,8-dibromooctane 17 with t-BuOK
in THF at room temperature for 1.5 h (Scheme 3). On
the contrary, the procedure reported in the literature
for the preparation of 18, which involves treatment of
17 with t-BuOK in THF under reflux,18 provided the de-
sired monobromide in a very low yield.
factory agreement with those of the natural product,13
20
D
CH3OH), was higher than that reported for naturally
but its specific rotatory power, ½aꢁ ¼ þ370 (c 0.525,
20
D
occurring (+)-6, ½aꢁ ¼ þ296 (c 0.5, CH3OH).13 It
should also be noted that this stereospecific synthesis
of (+)-6 from (2S,3S)-7 allowed us to confirm that the
natural product has a (2E,8S,9Z)-configuration.
Finally, we used a reaction sequence very similar to that
reported in Scheme 2 to prepare (ꢀ)-6, which had
Br
20
D
a
b
(2E,8R,9Z)-configuration and ½aꢁ ¼ ꢀ380 (c 0.50,
13
Br
Br
CH3OH), from (ꢀ)-2,3-O-isopropylidene-D-threitol
(ꢀ)-(2R,3R)-7 in 16% overall yield. Compound (ꢀ)-6
was estimated to have 97% enantiomeric excess on the
basis of HPLC analyses on a Chiracel OD-H column.
17
18
Scheme 3. Reagents and conditions: (a) t-BuOK (1.15 equiv), THF,
20 ꢁC, 1.5 h, then H2O; (b) PPh3 (1.2 equiv), CH3CN, 90 ꢁC, 140 h.
Finally, compounds (+)-6 (NSC 735472) and (ꢀ)-6
(NSC 735473) were evaluated over a 5-log dose range
in the NCIꢀs in vitro human disease-oriented tumor cell
line screening panel that consisted of 60 human tumor
cell lines. The natural product and its enantiomer were
found to exhibit modest cytotoxicity. In fact, their
MG–MID Log GI50 values were ꢀ4.44 and ꢀ4.27,
respectively. Nevertheless, (+)-6 had Log GI50 ꢀ5.44
against the HL-60 leukemia cell line, but (ꢀ)-6 had
Log GI50ꢀ4.95.
Deprotection
of
92%
stereoisomerically
pure
(2S,3S,4Z)-15 with 2,3-dichloro-5,6-dicyanobenzoqui-
none (DDQ)19 in a CH2Cl2–H2O system followed by
chromatographic purification of the crude reaction
product provided alcohol (2S,3S,4Z)-16 in 85% yield.
This compound was smoothly converted to stereoiso-
merically pure chloride (2R,3S,4Z)-11 in 91% yield by
reaction with PPh3 and CCl4.20 Treatment of
(2R,3S,4Z)-11 with 5 equiv of LDA in THF at
ꢀ78 ꢁC21 gave 1-alkyne (3S,4Z)-9 in 55% yield. On the
other hand, this alkyne was obtained in a negligible
yield, when we used the procedure reported in the liter-
ature to prepare 1-alkyne 20 from chloride 19 (Fig. 3),
3. Conclusions
We have developed a route for the preparation of natu-
rally occurring (+)-gymnasterkoreayne F and its enan-
tiomer, which involves the use of an inexpensive
derivative of L- and D-tartaric acid, respectively, as the
starting material. The natural product was found to
exhibit cytotoxic activity against the HL-60 leukemia
cell line higher than that of the corresponding enantio-
mer. It should also be noted that (3S,4Z)-dodeca-4,
11-dien-1-yn-3-ol, which we used as a key intermediate
for the synthesis of (+)-gymnasterkoreayne F, can
O
H
H
O
Cl
HO
H
19
20
Figure 3.

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A. Carpita et al. / Tetrahedron: Asymmetry 16 (2005) 2501–2508
represent a useful intermediate for the preparation of
other cytotoxic gymnasterkoreaynes, such as those of
B and C. Studies on the synthesis of (+)-gymnas-
terkoreayne C are in progress.
(60:40) as eluent, to give (2S,3S)-14 (10.9 g, 72%) as a
light yellow liquid. EI-MS, m/z (%): 282 (0.5) [M+],
163 (7), 162 (13), 137 (19), 135 (5), 131 (8), 122 (12),
121 (100), 77 (6). IR (film): m 3463, 1612, 1514, 1371,
1249, 1171, 1082, 1036, 846 cmꢀ1
.
1H NMR
(300 MHz, CDCl3): d 1.41 (6H, s, CMe2), 2.60 (1H, s,
OH), 3.48–3.80 (4H, m, H-1 and H-4), 3.79 (3H, s,
OMe), 3.91 (1H, dt, J = 8.4 and 4.5 Hz, H-2), 4.02
(1H, ddd, J = 8.4, 5.6, and 4.5 Hz, H-3), 4.51 (2H, s,
ArCH2O), 6.87 (2H, d, J = 9.0 Hz, Harom), 7.25 (2H,
d, J = 9.0 Hz, Harom) ppm. 13C NMR (75 MHz, CDCl3):
d 26.82, 26.84, 55.1, 62.3, 69.9, 73.2, 76.6, 79.6, 109.2,
113.7 (2C), 129.3 (2C), 129.5, 159.2 ppm. The spectral
properties of this compound were in good agreement
with those previously reported.25 Compound (2R,3R)-
14 was synthesized in 74% yield from (2R,3R)-7, accord-
ing to the procedure used to prepare (2S,3S)-14. The
spectral properties of (2R,3R)-14 were in good agree-
ment with those of the corresponding enantiomer.
4. Experimental
4.1. General
Pre-coated Merk 60 F254 aluminum silica gel sheets
were used for TLC analyses. GLC analyses were per-
formed on a Dani GC 1000 instrument with a PTV
injector, which was equipped with a Dani DDS 1000
data station. Two types of capillary columns were used:
an
Alltech
AT-35
bonded
FSOT
column
(30 m· 0.25 mm i.d.) and an Alltech AT-1 bonded Fsot
column (30 m· 0.25 mm i.d.). Purifications by MPLC
on silica gel (Merk 60 silica gel, particle size 0.015–
0.040 mm) were performed on a Buchi B-680 system
¨
with a Knauer K-2400 differential refractometer as
detector. GLC/EI-MS analyses were performed with
an Agilent Technologies 5973 Network mass selective
detector interfaced with an Agilent Technologies
6890N Network GC system. The MS spectrum of com-
pound (+)-6 was recorded with a Perkin–Elmer SCIEX
API III triple quadrupole mass spectrometer by the
atmospheric pressure photoionization (APPI) technique
by a tandem mass spectrometry approach. HPLC anal-
yses were performed on a Waters system with a 1525 LC
pump and a 2996 photodiode array detector. IR spectra
were recorded with a Perkin–Elmer 1725 FT-IR spectro-
photometer. NMR spectra were recorded with a Varian
Gemini 200 MHz and Varian Gemini 300 MHz spec-
trometers with TMS as the internal standard. Measure-
ments of optical activity were performed with a Perkin–
Elmer 142 spectropolarimeter in 1 dm tubes. All
reactions involving air- and water-sensitive materials
were performed in flame-dried glassware under argon
by standard syringe, cannula, and septa techniques.
(+)-2,3-O-Isopropylidene-L-threitol (2S,3S)-7 and (ꢀ)-
2,3-O-isopropylidene-D-threitol (2R,3R)-7 were com-
mercially available. The following compounds were
prepared according to the literature: PdCl2(PhCN),24
(E)-5-bromo-2-penten-4-yn-1-ol 8.15b
4.3. 8-Bromo-1-octene, 18
To
a solution of 1,8-dibromooctane 17 (27.2 g,
100 mmol) in THF (53 mL) maintained at room temper-
ature, was added during 0.5 h a solution of t-BuOK
(13.0 g, 115 mmol) in THF (100 mL) and the resulting
mixture stirred at room temperature for 1.5 h. It was
then poured into water (200 mL) and extracted with
ether (5 · 50 mL). The combined organic phase was
washed with brine (3 · 50 mL), dried, and concentrated.
The residue was fractionally distilled to give 18 (7.4 g,
39%) as a colorless liquid: bp 86–87 ꢁC/20 mbar (lit.18
bp 92 ꢁC/24 mmHg).
4.4. 7-Octenyl triphenylphosphonium bromide, 13
A mixture of 18 (11.1 g, 58.2 mmol) and triphenylphos-
phine (18.3 g, 69.9 mmol) in CH3CN (150 mL) was re-
fluxed for 140 h and then cooled at room temperature.
Most of the solvent was removed under reduced pres-
sure and the residue thoroughly washed with anhydrous
ether (2 · 70 mL) and then with hexane (2 · 70 mL). It
was then dried under reduced pressure to give 13
(26.3 g, 100%) as a pale brown gummy mass, which
was used in the next step without any further purifica-
tion and characterization.
4.2. (2S,3S)- and (2R,3R)-4-(p-Methoxybenzyloxy)-2,3-
(isopropylidendioxy)-butan-1-ol, (2S,3S)-14 and (2R,3R)-
14, respectively
4.5. (2R,3S)- and (2S,3R)-2,3-(Isopropylidenedioxy)-
4-(p-methoxybenzyloxy)-butanale, (2R,3S)- and
(2S,3R)-12, respectively
To a solution of (2S,3S)-7 (8.75 g, 53.9 mmol) in a 1:1
mixture of THF and DMF (70 mL) was added portion-
wise, in 20 min, a 60% dispersion of NaH in mineral oil
(2.32 g, 58.0 mmol) at 0 ꢁC. After 1.5 h stirring, p-meth-
oxybenzyl chloride (7.68 mL, 56.7 mmol) was added
dropwise to the solution at 0 ꢁC and the mixture stirred
overnight at room temperature. It was then treated with
water (20 mL), poured into a saturated aqueous NaCl
solution (150 mL) and extracted with AcOEt
(6 · 50 mL). The combined organic solution was washed
with brine (3 · 50 mL), dried, and concentrated under
reduced pressure. The residue was purified by MPLC
on silica gel, with a mixture of hexane and AcOEt
Dimethyl sulfoxide (8.42 mL, 0.118 mmol) was added
dropwise to a solution of oxalyl chloride (5.17 mL,
59.2 mmol) in CH2Cl2 (88 mL) at ꢀ78 ꢁC. After stirring
for 15 min, a solution of (2S,3S)-14 (11.2 g, 39.5 mmol)
in CH2Cl2 (21 mL) was added dropwise and the mixture
stirred for 40 min at ꢀ78 ꢁC. Triethylamine (27.5 g,
197 mmol) in CH2Cl2 was then added over 15 min,
and the resulting mixture stirred for another 10 min at
ꢀ78 ꢁC and then allowed to warm to room temperature.
It was then poured into a saturated aqueous NaCl solu-
tion (500 mL) and extracted with CH2Cl2 (5 · 200 mL).

A. Carpita et al. / Tetrahedron: Asymmetry 16 (2005) 2501–2508
2505
The collected organic phase was washed with 1% HCl
(200 mL), brine (2 · 200 mL), and water (200 mL),
dried, and concentrated under reduced pressure to give
crude (2R,3S)-12 (14.0 g) as a pale yellow liquid. EI-
MS, m/z (%): 280 (4) [M+], 179 (8) 178 (14), 137 (6),
136 (5), 122 (9), 121 (100), 78 (5), 77 (6). GLC analyses
showed that crude (2R,3S)-12 was contaminated by ca.
4% of a compound, which had an EI-MS spectrum very
similar to that of the major component. This crude com-
pound was directly used in the next reaction without any
further purification and characterization since this alde-
hyde undergoes significant epimerization also at room
temperature. In fact, GLC analysis of a sample of crude
(2R,3S)-12 maintained at ꢀ23 ꢁC for 48 h showed that
the amount of the stereoisomer contaminating the de-
sired compound now figured to more than 10%.
sumably correspond to (2S,3R,4Z)-, (2S,3S,4E)-, and
(2S,3R,4E)-15.
The procedure employed to prepare (2S,3S,4Z)-15 was
also used for the synthesis of 94% stereoisomerically
pure (2R,3R,4Z)-15 in 78% yield starting from 13 and
28
D
(2S,3R)-12. Compound (2R,3R,4Z)-15 had ½aꢁ
¼
ꢀ8.1 (c 3.09, CHCl3). The spectral properties of this
compound were in good agreement with those of the
corresponding enantiomer.
4.7. (2S,3S,4Z)- and (2R,3R,4Z)-2,3-(Isopropylidenedi-
oxy)-dodeca-4,11-dien-1-ol, (2S,3S,4Z)-16 and
(2R,3R,4Z)-16, respectively
To a stirred solution of 92% stereoisomerically pure
(2S,3S,4Z)-15 (11.9 g, 31.8 mmol) in CH2Cl2 (154 mL)
and water (8 mL) was added DDQ (10.8 g, 47.7 mmol).
After the initially dark solution was stirred for 2 h at
room temperature, a saturated aqueous NaHCO3 solu-
tion (150 mL) was added and the brown mixture filtered
over Celite and extracted with CH2Cl2 (5 · 70 mL). The
organic extract was washed with a saturated aqueous
NaHCO3 solution (3 · 50 mL) and brine (2 · 70 mL),
dried, and concentrated under reduced pressure. The
residue was purified by MPLC on silica gel, with a mix-
ture of toluene and AcOEt (90:10) as eluent, to give
(2S,3S,4Z)-16 (6.84 g, 85%) as a pale yellow liquid.
EI-MS, m/z (%): 254 (1) [M+], 239 (11), 179 (8), 123
(8), 97 (47), 95 (25), 81 (32), 67 (29), 59 (100). IR (film):
m 3482, 2929, 2856, 1640, 1380, 1242, 1165, 1054, 907,
This same procedure was used to prepare crude (2S,3R)-
12 (14.1 g) starting from (2R,3R)-14 (12.2 g, 43.2 mmol).
This crude product was also used directly in the next
step without any further purification.
4.6. (2S,3S,4Z)- and (2R,3R,4Z)-2,3-(Isopropylidenedi-
oxy)-1-(p-methoxybenzyloxy)-dodeca-4,11-diene,
(2S,3S,4Z)-15 and (2R,3R,4Z)-15, respectively
To a solution of 13 (21.4 g, 47.4 mmol) in THF
(263 mL) was added a 1M THF solution of t-BuOK
(47.4 mL, 47.4 mmol) and the mixture was stirred at
room temperature for 1 h and then cooled to ꢀ78 ꢁC.
To this mixture was added a solution of crude
(2R,3S)-12 (14.0 g) in THF (110 mL) and the resulting
mixture stirred for another 2 h at ꢀ78 ꢁC and then for
12 h at room temperature. The reaction was quenched
with a saturated aqueous NH4Cl solution (500 mL)
and the resulting mixture extracted with ether
(5 · 200 mL). The collected organic phase was washed
with brine (3 · 100 mL), dried, concentrated under re-
duced pressure and the residue was purified by MPLC
on silica gel, with a mixture of petroleum ether and
AcOEt (94:6) as eluent, to give (2S,3S,4Z)-15 (12.9 g,
87%) as a yellow oil. EI-MS, m/z (%): 374 (0.3) [M+],
137 (37), 136 (4), 135 (5), 122 (10), 121 (100), 97 (10),
81 (6), 77 (7). IR (film): m 2929, 1613, 1514, 1369,
856 cmꢀ1 1H NMR (200 MHz, CDCl3): d 1.23–1.40
.
(6H, m, H-7, H-8, and H-9), 1.41 (6H, s, CMe2), 1.92–
2.20 (4H, m, H-6 and H-10), 3.45–3.83 (3H, m, H-1
and H-2), 4.67 (1H, pseudo-t, J = 8.8 Hz, H-3), 4.89
(1H, dm, J = 10.2 Hz, H-12Z), 4.95 (1H, dm,
J = 16.8 Hz, H-12E), 5.35 (1H, dd, J = 10.8 and
8.8 Hz, H-4), 5.66 (1H, dt, J = 10.8 and 7.2 Hz, H-5),
5.76 (1H, ddt, J = 16.8, 10.2, and 6.8 Hz, H-11) ppm.
13C NMR (50 MHz, CDCl3): d 27.0, 27.2, 27.7, 28.6
(2C), 29.4, 33.7, 60.5, 72.5, 81.3, 108.9, 114.2, 125.8,
136.6, 138.9 ppm. Anal. Calcd for C15H26O3: C, 70.83;
28
D
H, 10.30. Found: C, 70.65; H, 10.10. ½aꢁ ¼ ꢀ11.3 (c
3.14, CHCl3). GLC and EI-GLC–MS analyses showed
that compound (2S,3S,4Z)-16 was 97% stereoisomeri-
cally pure.
1248, 1171, 1081, 1036, 861, 821 cmꢀ1
.
1H NMR
(300 MHz, CDCl3): d 1.21–1.42 (6H, m, H-7, H-8, H-
9), 1.44 (6H, s, CMe2), 1.92–2.17 (4H, m, H-6 and H-
10), 3.47–3.59 (2H, m, H-1), 3.80 (3H, s, Ome), 3.80–
3.88 (1H, m, H-2), 4.52 (2H, s, ArCH2O), 4.61 (1H,
pseudo-t, J = 8.7 Hz, H-3), 4.93 (1H, d, J = 10.2 Hz,
H-12Z), 5.00 (1H, d, J = 16.8 Hz, H-12E), 5.38 (1H,
dd, J = 11.1 and 8.7 Hz, H-4), 5.65 (1H, dt, J = 11.1
and 7.4 Hz, H-5), 5.79 (1H, ddt, J = 16.8, 10.2, and
6.7 Hz, H-11), 6.86 (2H, d, J = 8.2 Hz, Harom), 7.25
(2H, d, J = 8.2 Hz, Harom) ppm. 13C NMR (75 MHz,
CDCl3): d 26.9, 27.1, 27.6, 28.60, 28.64, 29.3, 33.6,
55.1, 68.8, 73.1, 73.4, 80.4, 109.1, 113.6 (2C), 114.2,
The procedure employed to prepare (2S,3S,4Z)-16 was
also used for the synthesis of 99% stereoisomerically
pure (2R,3R,4Z)-16 in 88% yield from (2R,3R,4Z)-15.
28
D
Compound (2R,3R,4Z)-16 had ½aꢁ ¼ þ11.0 (c 3.09,
CHCl3). Its spectral properties were in good agreement
with those of the corresponding enantiomer.
4.8. (2R,3S,4Z)- and (2S,3R,4Z)-1-Chloro-2,3-(iso-
propylidenedioxy)-dodeca-4,11-diene, (2R,3S,4Z)-11
and (2S,3R,4Z)-11, respectively
126.2, 128.2 (2C), 130.0, 136.1, 138.8, 159.1 ppm.
28
D
½aꢁ ¼ þ7.0 (c 3.17, CHCl3). Anal. Calcd for
Triphenylphosphine (12.0 g, 45.8 mmol) was added to a
solution of (2S,3S,4Z)-16 (5.83 g, 22.9 mmol) in CCl4
(110 mL) and the mixture stirred under reflux for 16 h.
It was then cooled to room temperature, poured into
petroleum ether (550 mL) and left at 0 ꢁC for 6 h. The
C23H34O4: C, 73.76; H 9.15. Found: C, 73.47; H, 9.33.
GLC and GLC–MS analyses showed that (2S,3S,4Z)-
15 had stereoisomeric purity higher than 92% and
was contaminated by three stereoisomers, which pre-

2506
A. Carpita et al. / Tetrahedron: Asymmetry 16 (2005) 2501–2508
mixture was filtered and the filtrate concentrated under
reduced pressure. The residue was purified by MPLC
on silica gel, with a mixture of petroleum ether and
AcOEt (97:3) as eluent, to give (2R,3S,4Z)-11 (5.70 g,
91%) as a pale yellow liquid. EI-MS, m/z (%): 272
(0.3) [M+], 257 (5), 179 (8), 120 (15), 97 (34), 95 (15),
94 (4), 85 (100), 79 (17), 67 (18). IR (film): m 2930,
The procedure used for the preparation of (3S,4Z)-9 was
also used for the synthesis of (3R,4Z)-9 in 53% yield
from (2S,3R,4Z)-11. Compound (3R,4Z)-9 had
28
½aꢁ ¼ ꢀ127.5 (c 1.22, CHCl3). Its spectral properties
D
were in good agreement with those of the corresponding
enantiomer.
1
1640, 1371, 1241, 1163, 1112, 1061, 900, 747 cmꢀ1. H
4.10. (+)-Gymnasterkoreayne F [(S,2E,9Z)-heptadeca-
2,9,16-trien-4,6-diyne-1,8-diol], (+)-6
NMR (200 MHz, CDCl3): d 1.32–1.45 (6H, m, H-7,
H-8, H-9), 1.46 (6H, s, CMe2), 1.98–2.24 (4H, m, H-6
and H-10), 3.56 (1H, dd, J = 12.2 and 4.5 Hz, H-1),
3.70 (1H, dd, J = 12.2 and 4.5 Hz, H-1), 3.84–3.94
(1H, m, H-2), 4.70 (1H, pseudo-t, J = 9.2 Hz, H-3),
4.93 (1H, dm, J = 10.2 Hz, H-12Z), 5.00 (1H, dm,
J = 17.0 Hz, H-12E), 5.39 (1H, dd, J = 10.8 and
9.2 Hz, H-4), 5.73 (1H, dt, J = 10.8 and 7.8 Hz, H-5),
5.81 (1H, ddt, J = 17.0, 10.2, and 6.8 Hz, H-11) ppm.
13C NMR (50 MHz, CDCl3): d 26.9, 27.3, 27.8, 28.7
This compound was prepared by three different proce-
dures (Methods A, B, and C).
4.10.1. Method A. To a suspension of CuCl (10.9 mg,
0.11 mmol), NH2OHÆHCl (38.8 mg, 0.568 mmol), and
65% EtNH2 (82.10 mL) in methanol (2.7 mL) at 0 ꢁC
were added successively a solution of (E)-5-bromo-2-
penten-4-yn-1-ol 8 (365 mg, 2.05 mmol) in methanol
(2C), 29.4, 33.7, 43.1, 74.3, 80.0, 109.5, 114.3, 125.4,
(1.4 mL) and
a
solution of (3S,4Z)-9 (300 mg,
28
D
137.1, 138.9 ppm. ½aꢁ ¼ ꢀ7.65 (c 3.11, CHCl3). Anal.
1.86 mmol) in methanol (1.4 mL). After being stirred
for 45 min at 0 ꢁC, the mixture was treated with water
(20 mL) and extracted with CH2Cl2 (6 · 15 mL). The or-
ganic extract was washed with brine (2 · 10 mL), dried,
and concentrated under reduced pressure. The residue
was purified by MPLC on silica gel, with a mixture of
hexane and THF (65:35) as eluent, to give (+)-6
(365 mg, 76%) as a pale yellow liquid, which proved to
be homogeneous to TLC and MPLC analyses. MPLC
purification on silica gel of this liquid, with a mixture
of hexane and THF (70:30) as eluent, provided an ana-
lytically pure sample of (+)-6. MS (Tandem Mass Spec-
trometry on the 281 [M++Na] ion), m/z (%): 281 (100),
242 (2), 241 (9), 197 (2), 171 (4), 159 (2), 143 (2), 135
(2), 129 (2). IR (film): m 3350, 2927, 2855, 2230, 1640,
Calcd for C15H25ClO2: C, 66.04; H, 9.24. Found: C,
65.94; H, 9.12. GLC and EI-MS analyses showed that
compound (2R,3S,4Z)-11 was stereoisomerically pure.
The procedure employed to prepare (2R,3S,4Z)-11 was
also used in the synthesis of (2S,3R,4Z)-11 in 80% yield
from (2R,3R,4Z)-16. Compound (2S,3R,4Z)-11, which
28
was stereoisomerically pure, had ½aꢁ ¼ þ8.1 (c
D
3.12, CHCl3). Its spectral properties were in good agree-
ment with those of the corresponding enantiomer.
4.9. (3S,4Z)- and (3R,4Z)-Dodeca-4,11-dien-1-yn-3-ol,
(3S,4Z)-9 and (3R,4Z)-9, respectively
A
1.72 M solution of n-butyllithium (36.3 mL,
1435, 1384, 1092, 909 cmꢀ1 1H NMR (200 MHz,
.
62.5 mmol) was added to a solution of diisopropylamine
(6.32 g, 62.5 mmol) in THF (105 mL) at 0 ꢁC. After
being stirred for 70 min, the mixture was cooled to
ꢀ78 ꢁC. To this mixture was added a solution of
(2R,3S,4Z)-11 (3.41 g, 12.5 mmol) in THF (10 mL).
Stirring was continued for 3 h, then the mixture was
warmed to 0 ꢁC, stirred for 30 min, quenched with a sat-
urated aqueous NH4Cl solution (100 mL) and extracted
with ether (5 · 60 mL). The organic extract was washed
with brine (3 · 40 mL), dried, and concentrated under
reduced pressure. The residue was purified by MPLC
on silica gel, with a mixture of hexane and ether
(80:20) as eluent, to give (3S,4Z)-9 (1.23 g, 55%) as a
pale yellow liquid. EI-MS, m/z (%): 177 (0.5) [M+ꢀ1],
117 (20), 107 (23), 95 (40), 93 (24), 91 (41), 81 (100),
79 (45), 67 (54). IR (film): m 3306, 2928, 2856, 2116,
CDCl3): d 1.22–1.45 (6H, m, H-12, H-13, H-14), 1.97–
2.17 (4H, m, H-11 and H-15), 4.21 (2H, dd, J = 4.6
and 1.8 Hz, H-1), 4.93 (1H, dm, J = 10.2 Hz, H-17Z),
4.99 (1H, dm, 16.8 Hz, H-17E), 5.20 (1H, d,
J = 7.8 Hz, H-8), 5.49 (1H, dd, J = 10.8 and 7.8 Hz,
H-9), 5.58 (1H, dt, J = 10.8 and 7.0 Hz, H-10) 5.80
(1H, ddt, J = 16.8, 10.2, and 6.7 Hz, H-16), 5.81 (1H,
d, J =15.8 Hz, H-3), 6.40 (1H, dt, J = 15.8 and 4.6 Hz,
H-2) ppm. 13C NMR (50 MHz, CDCl3): d 27.5, 28.6
(2C), 29.0, 33.6, 58.4, 62.2, 69.4, 73.7, 77.3, 81.8,
108.3, 114.2, 127.8, 133.8, 138.8, 145.8 ppm.
28
28
½aꢁ ¼ þ370.0 (c 0.525, CH3OH) lit.13 ½aꢁ ¼ þ296 (c
D
D
0.5, CH3OH). Anal. Calcd for C17H22O2: C, 79.03; H,
8.58; Found: C, 78.97; H, 8.40.
The enantiomeric excess of (+)-6 was estimated as 98.5%
by HPLC analysis [column: Chiracel OD-H; solvent:
1
1639, 1438, 1018, 910, 652 cmꢀ1. H NMR (200 MHz,
CDCl3): d 1.15–1.50 (6H, m, H-7, H-8, and H-9), 1.85
(1H, br s, OH), 1.92–2.20 (4H, m, H-6 and H-10), 2.51
(1H, d, J = 2.2 Hz, H-1), 4.93 (1H, dm, J = 10.2 Hz,
H-12Z), 5.00 (1H, dm, J = 16.8 Hz, H-12E), 5.15 (1H,
dd, J = 7.6 and 2.2 Hz, H-3), 5.50–5.62 (2H, m, H-4
and H-5), 5.81 (1H, ddt, J = 16.8, 10.2, and 6.6 Hz,
H-11) ppm. 13C NMR (50 MHz, CDCl3): d 27.5, 28.7
methanol/H2O
(70:30);
flow
rate:
1 mL/min];
1
tr = 8.33 min; RS = 2.5. The H and 13C NMR spectra
of (+)-6 were in good agreement with those of the natu-
ral product.13
4.10.2. Method B. A solution of (3S,4Z)-9 (270 mg,
1.68 mmol) in DMF (2.5 mL) and Et3N (234 lL,
1.68 mmol), were sequentially added to a suspension of
CuCl (16.8 mg, 0.168 mmol), NH2OHÆHCl (35.0 mg,
0.504 mmol), and 8 (300 mg, 1.68 mmol) in DMF
(3 mL) at 0 ꢁC and the resulting mixture stirred at
(2C), 29.1, 33.7, 58.0, 72.9, 84.0, 114.3, 128.6, 133.9,
28
D
138.9 ppm. ½aꢁ ¼ þ132.4 (c 1.14, CHCl3). Anal. Calcd
for C12H18O: C, 80.85; H, 10.18. Found: C, 81.05; H,
10.13.

A. Carpita et al. / Tetrahedron: Asymmetry 16 (2005) 2501–2508
2507
M. T.; Vincente, F.; Dorso, K.; Abruzzo, G.; Wilson, K.
J. Nat. Prod. 2004, 67, 1900–1902.
0 ꢁC for 30 min. It was then warmed to room tempera-
ture, stirred at this temperature for 23 h and subse-
quently poured into 5% HCl (25 mL). The mixture
was extracted with CH2Cl2 (8 · 10 mL) and the organic
extract washed with brine until neutrality (4 · 6 mL) and
dried. It was then concentrated under reduced pressure,
and the residue purified by MPLC on silica gel, with a
mixture of hexane and THF (65:35) as eluent, to give
(+)-6 (55 mg, 13%) as a pale yellow liquid. The spectral
properties of this compound were in agreement with
those of (+)-6 prepared with Method A.
2. (a) Bohlmann, F.; Burkhardt, T.; Zdero, C. Naturally
Occurring Acetylenes; Academic Press: New York, 1973;
(b) Christensen, L. P. Phytochemistry 1991, 31, 7–49; (c)
Wu, L.; Bae, J.; Kraus, G.; Wurtele, E. S. Phytochemistry
2004, 2477–2484.
3. (a) Marles, R. J.; Farnsworth, N. R.; Neill, D. A. J. Nat.
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Prod. 1989, 52, 261–266; (b) Kraus, C. M.; Neszmelyi, A.;
Holly, S.; Wiedemann, B.; Nenninger, A.; Torssell, K. B.;
Bohlin, L.; Wagner, H. J. Nat. Prod. 1988, 61, 422–427; (c)
Fort, D. M.; King, S. R.; Carlson, J. T.; Nelson, S. T.
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´
Chavez, D.; Chai, H.-B.; Shin, Y. G.; Kawanishi, K.;
4.10.3. Method C. A solution of (3S,4Z)-9 (270 mg,
1.68 mmol) in DMF (2.5 mL) and 2,2,6,6-tetramethyl-
piperidine (TMP) (600 lL, 3.53 mmol) were sequentially
added to a mixture of CuCl (16.8 mg, 0.168 mmol),
Kardono, L. B. S.; Riswan, S.; Farnsworth, N. R.;
Cordell, G. A.; Pezzuto, J. M.; Kinghorn, A. D. J. Nat.
Prod. 2001, 64, 246–248.
4. (a) Spitzer, V.; de L. Bordignon, S. A.; Schenkel, E.-P.;
Marx, F. J. Am. Oil Chem. Soc. 1994, 71, 1343–1348; (b)
Liu, Y. D.; Longmore, R. B.; Boddy, M. R.; Fox, J. E. D.
J. Am. Oil Chem. Soc. 1997, 74, 1269–1272; (c) El-Jaber,
NH2OHÆHCl (35.0 mg, 0.504 mmol),
8
(300 mg,
1.68 mmol), and DMF (3 mL), which was stirred at
0 ꢁC. After stirring for 30 min at 0 ꢁC, the mixture was
warmed to room temperature for 5 h and then worked
up as described for the preparation of (+)-6 by Method
B. The crude product obtained was purified by MPLC
on silica gel, with a mixture of hexane and THF
(65:35) as eluent, to give (+)-6 (221 mg, 51%) as a pale
yellow liquid. The spectral properties of this chemically
pure compound were in agreement with those of (+)-6
prepared by Methods A and B.
´
N.; Estevez-Braun, A.; Ravelo, A. G.; Mun˜oz-Mun˜oz, O.;
Rodrıguez-Alfonso, A.; Murguia, J. R. J. Nat. Prod. 2003,
66, 722–724.
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5. (a) Konoshima, T.; Lee, K. H. J. Nat. Prod. 1986, 49,
1117–1121; (b) Nakano, Y.; Matsunaga, H.; Saita, T.;
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553–557.
6. (a) Kwon, B. M.; Ro, S. H.; Kim, M. K.; Nam, J. Y.;
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1997, 63, 552–553; (b) Park, B.-Y.; Min, B.-S.; Oh, S.-R.;
Kim, J.-H.; Kim, T. J.; Kim, D.-H.; Bae, K.-H.; Lee, H.-K.
J. Ethnopharm. 2004, 90, 403–408.
4.11. (ꢀ)-Gymnasterkoreayne F [(R,2E,9Z)-heptadeca-
2,9,16-trien-4,6-diyne-1,8-diol], (ꢀ)-6
This compound was synthesized by reaction of (3R,4Z)-
9 (400 mg, 224 mmol) with 8 (328 mg, 2.04 mmol) by a
procedure very similar to that described for the prepara-
7. Ohashi, K.; Winarno, H.; Mukai, M.; Shibuya, H. Chem.
Pharm. Bull. 2003, 51, 463–466.
8. (a) For some reviews, see: Faulkner, D. J. Nat. Prod. Rep.
1997, 14, 259–302; (b) van Soest, R. W. M.; Fusetani, N.;
Anderse, R. J. In Sponge Sciences Multidisciplinary
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Tokyo, 1997, pp 3–30; (c) Faulkner, D. J. Nat. Prod. Rep.
2002, 19, 1–48; (d) Blunt, J. W.; Copp, B. R.; Munro, M.
H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep.
2005, 22, 15–61.
9. (a) Fusetani, N.; Li, H.-J.; Tamura, K.; Matsunaga, S.
Tetrahedron 1993, 49, 1203–1210; (b) Li, H.-Y.; Matsu-
naga, S.; Fusetani, N. J. Nat. Prod. 1994, 57, 1464–1467.
10. Fusetani, N.; Shiragaki, T.; Matsunaga, S.; Hashimoto,
K. Tetrahedron Lett. 1987, 28, 4313–4314.
tion of its enantiomer according to Method A. The com-
28
D
pound (ꢀ)-6 obtained (408 mg, 77%) had ½aꢁ ¼ ꢀ380.0
(c 0.500, CH3OH). Its spectral properties were in very
good agreement with those of (+)-6 synthesized from
(2S,4Z)-9. The enantiomeric excess of (+)-6 was esti-
mated to be 97% by HPLC analysis [column: Chiracel
OD-H; solvent: methanol/H2O (70:30); flow rate:
1 mL/min]; tr = 7.18 min; RS = 2.5.
Acknowledgments
11. (a) Youssef, D. T. A.; Yoshida, W. Y.; Kelly, M.; Scheuer,
P. J. J. Nat. Prod. 2000, 63, 1406–1410; (b) Youssef, D. T.
A.; van Soest, R. W. M.; Fusetani, N. J. Nat. Prod. 2003,
66, 679–681; (c) Dai, J.-R.; Hallock, Y. F.; Cardellina, J.
H., II; Gray, G. N.; Boyd, M. R. J. Nat. Prod. 1996, 59,
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Im, K. S.; Jung, J. H. J. Nat. Prod. 2001, 64, 1059–1063.
12. (a) Nakao, Y.; Uehara, T.; Matunaga, S.; Fusetani, N.;
van Soest, R. W. M. J. Nat. Prod. 2002, 65, 922–924; (b)
Liu, J. H.; Zschocke, S.; Reininger, E.; Bauer, R. Pharm.
Biol. 1998, 36, 207–216.
This work was supported by the MIUR (Rome) and the
University of Pisa. We are grateful to Prof. Piero Salva-
dori for the use of the Perkin–Elmer Sciex API III triple
quadrupole mass spectrometer. We also wish to thank
Mr. Piergiorgio Vergamini for recording IR spectra
and Dr. Angela Cuzzola for recording the mass spectra
by tandem mass spectrometry.
13. Jung, H.-J.; Min, B.-S.; Park, J.-Y.; Kim, Y.-H.; Lee, H.-K.;
Bae, K.-H. J. Nat. Prod. 2002, 65, 897–901.
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