Study towards bioactive pyrone derivatives from the marine red alga Phacelocarpus labillardieri

Article abstract of DOI:10.1016/S0040-4020(03)00815-9

Red algae of the genus Phacelocarpus labillardieri produce a structurally rather unique class of macrocyclic pyrone derivatives with phospholipase A ₂ inhibiting properties and potential neuromuscular blocking activity. They were also shown to be potent feeding inhibitors for various marine herbivorous gastropods. Described herein is the first preparative study towards these conspicuous secondary metabolites. Their carbon skeleton has been assembled in a few straightforward steps using ring closing alkyne metathesis (RCAM) catalyzed by the Schrock alkylidyne complex (tBuO) ₃W≡CCMe₃ to forge the meta-cyclophane core with high efficiency.

Full text of DOI:10.1016/S0040-4020(03)00815-9

Tetrahedron 59 (2003) 6899–6904
Study towards bioactive pyrone derivatives from the marine red
alga Phacelocarpus labillardieri
*
¨
Dschun Song, Gaelle Blond and Alois Fu¨rstner
¨ ¨
Max-Planck-Institut fur Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mulheim an der Ruhr, Germany
Received 2 April 2003; revised 14 May 2003; accepted 14 May 2003
This paper is dedicated with respect and admiration to Professor K. C. Nicolaou as the recipient of the 2003 Tetrahedron Prize
Abstract—Red algae of the genus Phacelocarpus labillardieri produce a structurally rather unique class of macrocyclic pyrone derivatives
with phospholipase A2 inhibiting properties and potential neuromuscular blocking activity. They were also shown to be potent feeding
inhibitors for various marine herbivorous gastropods. Described herein is the first preparative study towards these conspicuous secondary
metabolites. Their carbon skeleton has been assembled in a few straightforward steps using ring closing alkyne metathesis (RCAM)
catalyzed by the Schrock alkylidyne complex (tBuO)3WuCCMe3 to forge the meta-cyclophane core with high efficiency.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
The red alga Phacelocarpus labillardieri commonly found
in South Australian waters turned out to be a unique source
of the acetate-derived secondary metabolites 1–4 featuring
a pyrone ring embedded into a polyunsaturated macrocyclic
skeleton.1,2 While the somewhat variable ratio of the
individual members of this family in different collections
is deemed to reflect seasonal and/or regional variations in
the algae’s metabolism, there is little doubt that all of them
derive from a common linear diketoacid precursor that can
cyclize along two different pathways to give either the a- or
the g-pyrone motif.2
Compound 3 acts as potent deterrent to herbivorous shells,
snails and other gastropods and is therefore likely involved
in the chemical defense of the algae against predators.3 The
crude extracts of P. labillardieri were also found to exhibit
neuromuscular blocking activity, which might be caused by
pyrones of this type.1a Moreover, compound 4 exhibits
promising phospholipase A2 inhibiting properties (93%
inhibition of bee venom PLA2 at 4.4 mM).4 This interesting
biological profile together with the rather unusual structures
prompted us to target these marine natural products as part
of our investigations on the synthesis and evaluation of
bioactive heterocycles.5,6 Outlined below is a preliminary
study showing that ring closing alkyne metathesis (RCAM)7
is an adequate tool for the construction of their meta-
cyclophane skeleton.8
2. Results and discussion
The highly conserved triple bond within the core structures
of 1–4 suggests the use of RCAM for the construction of the
macrocyclic scaffold.7,9 Though discovered only recently,
RCAM has already borne scrutiny in target oriented
Keywords: alkynes; macrocycles; marine natural products; metathesis;
pyrone.
*
Corresponding author. Tel.: þ49-208-306-2342; fax: þ49-208-306-2994;
e-mail: fuerstner@mpi-muelheim.mpg.de
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00815-9

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D. Song et al. / Tetrahedron 59 (2003) 6899–6904
syntheses on several occasions,10,11 not least because of the
exceedingly high tolerance of the commonly used
catalysts12 – 14 towards many polar functional groups.
Moreover, these catalysts are distinguished by a remarkable
chemoselectivity profile in that they select exclusively for
alkynes while leaving pre-existing olefins in a given
substrate unaffected.15 – 17 This ability to differentiate
between different p-bonds promises a successful appli-
cation of RCAM to the present series as well (Scheme 1).
However, since no secured information on the relative and
absolute configuration of compounds 2 and 4 is available to
date, only a highly flexible approach to this class of pyrone
ether derivatives can ultimately be successful as it might be
necessary to prepare the full set of stereoisomers for
comparison with the natural products. Therefore, an interim
goal consists in establishing an efficient and concise route to
their common core structure.
This model study commenced with commercial 6-heptynoic
acid, which was C-alkylated with MeI prior to esterification
of the resulting acid 5 with (trimethylsilyl)-diazomethane.
Reaction of ester 6 thus formed with dianion 7 gave the
tricarbonyl compound 8; thereby, an extra equivalent of
base (n-BuLi) was necessary to ensure that the product
formed does not quench the reagent via proton transfer.18
Attempts to use methyl acetoacetate resulted in lower yields
(ca. 30%) of the corresponding tricarbonyl derivative 9 due
to competing attack of residual nucleophile to the emerging
product.
Scheme 2. [a] TMSCHN2, pentane–MeOH, 85%; [b] tert-butyl aceto-
acetate, LDA (2 equiv.), TMEDA, THF, then BuLi (see text), 08C, 58%;
[c] (i) F3CCOOH, CH2Cl2; (ii) TMSCHN2, MeOH, 71%; [d] (i) F3CCOOH,
CH2Cl2; (ii) Ac2O; [e] K2CO3 cat., MeOH, 70% (over three steps);
[f] 12-bromo-2-dodecyne 13, Et3N, MeCN, 56%; [g] (i) DBU, toluene,
reflux; (ii) bromide 13, MeCN, rt, 53%.
For the sake of brevity, we envisaged conversion of
compound 8 to the required metathesis precursor 12 by a
cascade combining the cyclization of the b,d-diketoester to
the corresponding a-pyrone19 with a subsequent in situ
O-alkylation reaction. Unfortunately, however, the tert-
butyl ester 8 remained completely unchanged under the
standard reaction conditions (DBU, toluene, reflux). Cycli-
zation of this compound could only be achieved in a
stepwise fashion by cleavage of the tert-butyl group
followed by dehydration of the resulting diketoacid with
Ac2O.20 Since this procedure leads to a concomitant
acetylation of the 4-OH group on the heterocyclic ring,
the alkylation had to be carried out separately (10!11!12,
cf. Scheme 2). In marked contrast, however, the correspond-
ing methyl ester 9 was converted to the 4-alkylated pyrone
derivative 12 in one-pot on treatment with DBU followed by
addition of 12-bromo-2-dodecyne 13. Since the direct
synthesis of 9 from 6 and methyl acetoacetate is
unsatisfactory (see above), access to this key intermediate
had to be secured by transesterification of 8 under standard
conditions.21
occurred smoothly on exposure of the substrate to catalytic
amounts of Schrock’s tungsten alkylidyne complex
12
(tBuO)3WuCCMe3 in toluene at 808C (Scheme 3).
Thereby, the yield of the resulting cycloalkyne 13 strongly
correlated with the chosen dilution, with best results being
obtained at c¼0.001 M (84% isolated yield). This fact is
deemed to reflect the strain inherent to the meta-pyrono-
phane skeleton of this particular compound. Its molecular
structure in the solid state is depicted in Figure 1. In contrast
to the excellent results obtained with Schrock’s complex,
applications of the ‘in situ’ catalyst system (comprising
Mo(CO)6 and phenol additives) pioneered by Mortreux et al.
and subsequently modified by others14 invariably gave
rather poor results (,40% yield) which could not be
improved any further by lowering the concentration.
With diyne 12 in hand, the formation of the macrocyclic
ring by RCAM was investigated. Gratifyingly, this reaction
Scheme 3. Ring closing alkyne metathesis of diyne 13. [a] (tBuO)3-
WuCCMe3 cat., toluene, 808C, 50 min, 84%.
Scheme 1. Basic principle of ring closing alkyne metathesis (RCAM).

D. Song et al. / Tetrahedron 59 (2003) 6899–6904
6901
the solvent was evaporated, and the residue was purified by
flash chromatography (hexanes–EtOAc, 6:1þ3% AcOH) to
give acid 5 as a colorless solid (5.45 g, 98%). Mp 43–448C;
1H NMR (CD2Cl2, 300 MHz) d 2.37 (t, J¼7.6 Hz, 2H),
2.18–2.10 (m, 2H), 1.75 (t, J¼2.5 Hz, 3H), 1.80–1.66 (m,
2H), 1.56–1.48 (m, 2H); 13C NMR (CD2Cl2, 75 MHz) d
180.2, 78.6, 75.9, 33.7, 28.5, 24.0, 18.5, 3.2; IR (neat) 2947,
2875, 1707, 1415, 1269, 936 cm21; MS (EI) m/z (rel.
intensity) 140 (Mþ, 9), 95 (35), 81 (100), 67 (32), 53 (52),
41 (54), 39 (40); HRMS (CI): (C8H12O2þH) calcd
141.0916, found 141.0916; C8H12O2 (140.18) calcd C
68.54, H 8.63; found C 68.28, H 8.54.
3.1.2. 6-Octynoic acid methyl ester (6). To a solution of
acid 5 (900 mg, 0.64 mmol) in MeOH (10 mL) and pentane
(5 mL) was added (trimethylsilyl)-diazomethane (2.0 M in
hexanes, 9.6 mL, 1.93 mmol). After stirring for 30 min, the
solution was quenched with acetic acid (2 mL). Evaporation
of the solvents and flash chromatography of the residue
(hexanes–EtOAc, 4:1) afforded ester 6 as a colorless liquid
(841 mg, 85%); 1H NMR (CDCl3, 300 MHz) d 3.57 (s, 3H),
2.26–2.21 (m, 2H), 2.08–2.01 (m, 2H), 1.67 (t, J¼2.6 Hz,
3H), 1.70–1.58 (m, 2H), 1.45–1.41 (m, 2H); 13C NMR
(CDCl3, 75 MHz) d 173.7, 78.4, 75.6, 51.3, 33.4, 28.3, 24.0,
18.3, 3.2; IR (neat) 2951, 2922, 2862, 1740, 1437, 1204,
1174, 1152 cm21; MS (EI) m/z (rel. intensity) 154 (Mþ,
,1), 95 (23), 94 (100), 79 (60), 67 (29), 69 (31), 55 (23), 53
(29), 41 (25); HRMS (CI) (C9H14O2þH) calcd 155.1072,
found 155.1072; C9H14O2 (154.21) calcd C 70.10, H 9.15,
found C 70.19, H 9.11.
Figure 1. Molecular structure of cycloalkyne 13 obtained from single-
crystal structure determination. Anisotropic displacement parameters are
shown at the 50% probability level.
In summary, a model for the core structure of the marine
pyrone derivatives isolated from P. labillardieri has been
prepared by a route which comprises only six steps,
including the crucial RCAM reaction forging the macro-
cyclic ring with high efficiency. Due to its brevity and
flexibility, this entry should qualify for the envisaged total
synthesis of these bioactive natural products and derivatives
thereof. Studies along these lines are currently in progress
and will be reported in due course.
3.1.3. 3,5-Dioxo-dodec-10-ynoic acid tert-butyl ester (8).
To a solution of freshly prepared LDA (from diisopropyl-
amine (280 mL, 2 mmol) and n-BuLi (1.25 mL, 2 mmol,
1.6 M in hexane)) at 08C were added TMEDA (166 mL,
1.1 mmol) followed by tert-butylacetoacetate (182 mL,
1.1 mmol). After stirring for 15 min, a first portion of
ester 6 (77 mg, 0.5 mmol) was introduced and stirring was
continued for 15 min before n-BuLi (690 mL, 1 mmol,
1.6 M in hexane) was added to ensure complete deprotona-
tion of the resulting product. After stirring for another
15 min, a second portion of tert-butylacetoacetate (250 mg,
1.62 mmol) was added and stirring was continued for 6 h
until GC showed complete conversion of the starting
material. The reaction was then quenched with aq. HCl
(6 M), the aqueous layer was repeatedly extracted with
CH2Cl2, the combined organic phases were consecutively
washed with aq. HCl, aq. sat. NaHCO3 and brine before
being dried over Na2SO4. Evaporation of the solvent and
flash chromatography of the residue (pentane–EtOAc, 10:1)
gave the tricarbonyl compound 8 as a pale yellow liquid
(161 mg, 58%). The product consists of a mixture of the
keto- and the enol tautomers (ca. 21:79) in solution.
3. Experimental
3.1. General
All reactions were carried out under Ar. The solvents used
were purified by distillation over the drying agents indicated
and were transferred under Ar: THF, Et2O, DME (Mg–
anthracene), CH2Cl2 (P4O10), MeCN, Et3N, pyridine, DMF
(CaH2), MeOH (Mg), hexane, pentane, toluene (Na/K).
Flash chromatography: Merck silica gel 60 (230–400
mesh). NMR: Spectra were recorded on a Bruker DPX
300 or AV 400 spectrometer in the solvents indicated;
chemical shifts (d) are given in ppm relative to TMS,
coupling constants (J) in Hz. IR: Nicolet FT-7199
spectrometer, wavenumbers in cm21. MS (EI): Finnigan
MAT 8200 (70 eV), HRMS: Finnigan MAT 95. Melting
points: Bu¨chi melting point apparatus (uncorrected).
Elemental analyses: H. Kolbe, Mu¨lheim/Ruhr. All com-
mercially available compounds (Lancaster, Fluka, Aldrich)
were used as received.
3.1.1. 6-Octynoic acid (5). Hept-6-ynoic acid (5 mL,
39.8 mmol) was added dropwise to a solution of LDA
(freshly prepared from diisopropylamine (11.7 mL,
83.3 mmol) and n-BuLi (52.2 mL, 83.3 mmol, 1.6 M in
hexane)) in THF (800 mL) at 2788C. After stirring for
1.5 h, DMPU (9.6 mL, 79.3 mmol) was introduced followed
by the addition of MeI (3.7 mL, 59.5 mmol). The reaction
mixture was allowed to warm to ambient temperature and
stirring was continued for 10 h. After quenching with aq.
HCl (6 M), the aqueous layer was repeatedly extracted with
Et2O, the combined organic phases were dried over Na2SO4,
1
Characteristic data: H NMR (CDCl3, 300 MHz) d 15.12
(s), 5.56 (s), 3.67 (s), 3.42 (s), 3.21 (s), 2.50 (t, J¼7.2 Hz),
2.28 (t, J¼7.3 Hz), 2.14–2.08 (m, 2H), 1.73 (t, J¼2.4 Hz,
3H), 1.73–1.62 (m, 2H), 1.49–1.39 (m, 2H), 1.44 (s, 9H);
13C NMR (CDCl3, 75 MHz, signals of the enol-form) d
192.9, 187.7, 166.7, 99.7, 81.9, 78.5, 75.9, 46.4, 37.3. 28.4,
27.9 (3C), 24.7, 18.4, 3.4; IR (neat) 2979, 2934, 2864, 1734,
1610, 1456, 1411, 1394, 1369, 1148; MS (EI) m/z (rel.
intensity) 224 (18), 165 (53), 162 (19), 129 (18), 95 (16), 69
(16), 57 (100), 41 (27); HR-MS (CI) calcd (C16H24O4þH)

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D. Song et al. / Tetrahedron 59 (2003) 6899–6904
281.1754, found 281.1753; C16H24O4 (280.36) calcd C
68.54, H 8.63, found C 68.54, H 8.58.
combined organic phases were dried over Na2SO4 and
evaporated, and the crude product was purified by flash
chromatography (hexanes–EtOAc, 4:1) to furnish pyrone
1
3.1.4. 3,5-Dioxo-dodec-10-ynoic acid methyl ester (9). To
a solution of the tert-butyl ester 8 (360 mg, 1.3 mmol) in
CH2Cl2 (5 mL) was added trifluoroacetic acid and the
resulting mixture was stirred for 2 h at ambient temperature.
After all volatiles had been evaporated, the residue was
dissolved in MeOH (5 mL) and (trimethylsilyl)-diazo-
methane (0.96 mL, 1.9 mmol, 2.0 M in hexanes) was slowly
added. The reaction was then quenched by AcOH, the
solvent was evaporated and the residue was purified by flash
chromatography to give product 9 as a colorless liquid
(216.4 mg, 71%). The product consists of a mixture of the
12 as a colorless solid (113.2 mg, 53%). Mp 47–488C; H
NMR (CD2Cl2, 300 MHz) d 5.78 (d, J¼2.2 Hz, 1H), 5.33
(d, J¼2.2 Hz, 1H), 3.93 (t, J¼6.5 Hz, 2H), 2.44 (t,
J¼7.3 Hz, 2H), 2.13–2.05 (m, 4H), 1.79–1.67 (m, 4H),
1.75 (t, J¼2.5 Hz, 3H), 1.74 (t, J¼2.5 Hz, 3H), 1.55–1.29
(m, 14H); 13C NMR (CD2Cl2, 75 MHz) d 171.8, 166.5,
165.7, 100.9, 88.8, 80.3, 79.5, 76.9, 76.2, 70.1, 34.3, 30.5,
30.32, 30.29, 30.2, 30.0, 29.6, 29.4, 27.0, 26.9, 19.8, 19.5,
4.3 (2C); IR (KBr) 2927, 2855, 1736, 1717, 1650, 1565,
1441, 1260, 1146, 1031, 868, 812 cm21; MS (EI) m/z (rel.
intensity) 370 (Mþ, 18), 326 (35), 162 (100), 147 (51), 111
(72), 81 (58), 67 (52), 55 (62); HRMS (EI) (C24H34O3) calcd
370.2508, found 370.2504; C24H34O3 (370.52) calcd C
77.80, H 9.25, found C 77.68, H 9.20.
1
keto- and the enol tautomers in solution (ca. 14:86). H
NMR (CDCl3, 300 MHz) d 15.03 (s), 5.24 (s), 3.65 (s, 3H),
3.64 (s), 3.49 (s), 3.16 (s), 2.45 (t, J¼7.2 Hz), 2.23 (t,
J¼7.8 Hz), 2.09–2.02 (m, 2H), 1.68 (t, J¼2.3 Hz, 3H),
1.68–1.57 (m, 2H), 1.48–1.35 (m, 2H); 13C NMR (75 MHz,
CDCl3, enol-form) d 192.8, 187.0, 99.2, 77.2, 75.5, 52.2,
49.0, 44.7, 37.1, 28.2 24.6, 18.2, 3.2; IR (neat) 2952, 2922,
1862, 1745, 1606, 1437, 1330, 1262, 1202, 1156, 1017, 915,
776 cm21; MS (EI) m/z (rel. intensity) 238 (Mþ, 2), 220
(48), 143 (39), 165 (78) 101 (100), 69 (69), 55 (34), 43 (41);
HRMS (CI) (C13H18O4þH) calcd 239.1284, found
239.1283; C13H18O4 (238.28) calcd C 65.53, H 7.61,
found C 65.38, H 7.62.
3.1.7. 2,19-Dioxa-bicyclo[16.3.1]docosa-1(21),18(22)-
dien-12-yn-20-one (13). To a solution of diyne 12
(49 mg, 0.12 mmol) in toluene (100 mL) was added
(tBuO)3WuCCMe3 (10 mg, 16 mol%)12 and the resulting
solution was stirred for 50 min at 808C. Evaporation of the
solvent followed by flash chromatography of the residue
(pentane–EtOAc, 5:1) gave cycloalkyne 13 as colorless
1
needles (33.3 mg, 84%). Mp 83–848C; H NMR (CDCl3,
400 MHz) d 5.81 (d, J¼2.1 Hz, 1H), 5.38 (d, J¼2.1 Hz,
1H), 4.02 (t, J¼5.2 Hz, 2H), 2.48 (t, J¼5.2 Hz, 2H), 2.19–
2.13 (m, 4H), 1.79–1.72 (m, 4H), 1.56–1.29 (m, 14H); 13C
NMR (CDCl3, 100 MHz) d 170.4, 165.7, 165.1, 99.9, 88.0,
81.4, 79.4, 69.4, 32.3, 29.3, 29.2, 28.4, 28.0, 27.4, 26.9, 26.8
(2C), 25.1, 18.7, 18.4; IR (KBr) 3074, 2933, 2896, 2854,
1714, 1651, 1572, 1437, 1340, 1257, 1133, 1033, 848,
806 cm21; MS (EI) m/z (rel. intensity) 316 (Mþ, 21), 272
(83), 192 (45), 162 (87), 146 (41), 111 (86), 69 (100), 55
(69); HRMS (EI) (C20H28O3) calcd 316.2039, found
316.2039; C20H28O3 (316.43) calcd C 75.91, H 8.92,
found C 76.05, H 8.87.
3.1.5. 6-Hept-5-ynyl-4-hydroxypyran-2-one (11). To a
solution of tert-butyl ester 8 (509 mg, 1.8 mmol) in CH2Cl2
(11 mL) was added TFA (4 mL) and the resulting mixture
was stirred for 2 h at ambient temperature. The solvent was
then removed in vacuo and the residue was dissolved in
Ac2O (11 mL). After stirring for 24 h, the solvent was
evaporated, the residue was dissolved in MeOH (5 mL), and
K2CO3 (25 mg, 0.18 mmol) was added. The reaction was
quenched after 8 h with sat. aq. NH4Cl. The aqueous layer
was extracted with CH2Cl2, the combined organic phases
were successively washed with sat. aq. NH4Cl and brine
before being dried over Na2SO4. Evaporation of the solvent
followed by flash chromatography (pentane–EtOAc, 4:1)
gave pyrone 11 (260 mg, 70%) as a colorless solid. Mp 96–
3.2. X-Ray crystallographic study
Crystal data for compound 13: C20H28O3, M¼
316.42 g mol21, colorless, crystal dimensions 0.34£0.08£
0.02 mm, Monoclinic P21/c (no. 14), at 293 K a¼
1
978C; H NMR (CDCl3, 400 MHz) d 5.93 (d, J¼2.0 Hz,
1H), 5.52 (d, J¼2.0 Hz, 1H), 2.44 (t, J¼7.5 Hz, 2H), 2.12–
2.06 (m, 2H), 1.70 (t, J¼2.5 Hz, 3H), 1.68–1.57 (m, 2H),
1.51–1.42 (m, 2H); 13C NMR (CDCl3, 100 MHz) d 172.7,
168.4, 167.2, 101.6, 90.0, 78.5, 76.3, 33.3, 28.3, 25.9, 18.5,
3.6; IR (KBr) 3000, 2935, 2861, 1647, 1571, 1249,
837 cm21; MS (EI) m/z (rel. intensity) 206 (Mþ, 6), 189
(5), 178 (19), 163 (20), 150 (22), 136 (25), 121 (18), 111
(76), 69 (100), 55 (45), 41 (37); HR-MS (EI) calcd
206.0943, found 206.0944; C12H14O3 (206.24) calcd C
69.88, H 6.84, found C 69.86, H 6.90.
˚
˚
˚
˚
14.8897(6) A, b¼5.3874(2) A, c¼23.4353(12) A, a¼908,
3
b¼103.8460(10)8, g¼908, V¼1825.28(14) A , Z¼4,
r¼1.151 mg m23, m¼0.076 mm21, l¼0.71073 A. X-Ray
˚
diffraction data were collected using a Bruker–Nonius
KappaCCD diffractometer employing CCD scans to cover
reciprocal space up to 26.538 with 90.1% completeness,
integration of raw data yielded a total of 9115 reflections,
merged into 3416 unique reflections with Rint¼0.20 after
applying Lorentz, polarisation and absorption correction.
The structure was solved by the direct method using
SHELXS-97,22 and atomic positions and displacement
parameters were refined using full matrix least-squares
based on Fsqd using SHELXL-97.23 Refinement of 208
parameters using all reflections converged at R¼0.069,
3.1.6. 4-Dodec-10-ynyloxy-6-hept-5-ynyl-pyran-2-one
(12). To a solution methyl ester 9 (137.2 mg, 0.58 mmol)
in toluene (10 mL) was added 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU, 172.2 mL, 1.15 mmol) and the mixture
was refluxed for 2 h. After reaching ambient temperature,
MeCN (5 mL) and 12-bromo-dodec-2-yne 13 (169.4 mg,
6.91 mmol) were introduced and stirring was continued for
16 h. The reaction was quenched with aq. sat. NH4Cl
solution, the aqueous layer was extracted with Et2O, the
3
˚
wR¼0.19, highest residual electron density peak 0.35 A .
Crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 206171. Copies of the data
can be obtained free of charge on application to CCDC,

D. Song et al. / Tetrahedron 59 (2003) 6899–6904
6903
Marel, G. A.; van Boom, J. H. J. Org. Chem. 2001, 66,
3584–3589.
12 Union Road, Cambridge CB2 1EZ, UK, e-mail:
deposit@ccdc.cam.ac.uk.
12. (a) Schrock, R. R.; Clark, D. N.; Sancho, J.; Wengrovius, J. H.;
Rocklage, S. M.; Pedersen, S. F. Organometallics 1982, 1,
1645–1651. (b) Freudenberger, J. H.; Schrock, R. R.;
Churchill, M. R.; Rheingold, A. L.; Ziller, J. W. Organo-
metallics 1984, 3, 1563–1573. (c) Listemann, M. L.; Schrock,
R. R. Organometallics 1985, 4, 74–83. (d) Schrock, R. R.
Polyhedron 1995, 14, 3177–3195.
Acknowledgements
Generous financial support by the Deutsche Forschungs-
gemeinschaft (Leibniz award to A. F.), the Fonds der
Chemischen Industrie, the Arthur C. Cope Funds
administered by the ACS, and the Merck Research Council
is gratefully acknowledged. We thank Dr C. W. Lehmann
for solving the X-ray structure of cycloalkyne 13.
13. Fu¨rstner, A.; Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc.
1999, 121, 9453–9454.
14. (a) Mortreux, A.; Blanchard, M. J. Chem. Soc., Chem.
Commun. 1974, 786–787. (b) Mortreux, A.; Dy, N.;
Blanchard, M. J. Mol. Catal. 1975/76, 1, 101–109. (c) Du
Plessis, J. A. K.; Vosloo, H. C. M. J. Mol. Catal. 1991, 65,
51–54. (d) Villemin, D.; Cadiot, P. Tetrahedron Lett. 1982,
23, 5139–5140. (e) Pschirer, N. G.; Bunz, U. H. F.
Tetrahedron Lett. 1999, 40, 2481–2484. (f) Kaneta, N.;
Hirai, T.; Mori, M. Chem. Lett. 1995, 627–628. (g) Grela, K.;
Ignatowska, J. Org. Lett. 2002, 4, 3747–3749. (h) Villemin,
References
1. (a) Kazlauskas, R.; Murphy, P. T.; Wells, R. J.; Blackman, A. J.
Aust. J. Chem. 1982, 35, 113–120. (b) Blackman, A. J.;
Bremner, J. B.; Paano, A. M. C.; Skerratt, J. H.; Swann, M. L.;
Aust, Aust. J. Chem. 1990, 43, 1133–1136. (c) Murray, L.;
Currie, G.; Capon, R. J. Aust. J. Chem. 1995, 48, 1485–1489.
2. Shin, J.; Paul, V. J.; Fenical, W. Tetrahedron Lett. 1986, 27,
5189–5192.
´
D.; Heroux, M.; Blot, V. Tetrahedron Lett. 2001, 42,
3701–3703.
15. The first indication of this striking chemoselectivity is found in
an early publication of Schrock showing that tungsten
alkylidyne complexes will metathezise 3-heptyne in the
presence of admixed cis-2-pentene, cf.: Sancho, J.; Schrock,
R. R. J. Mol. Catal. 1982, 15, 75–79.
3. Sakata, K.; Iwase, Y.; Kato, K.; Ina, K.; Machiguchi, Y.
Nippon Suisan Gakkaishi 1991, 57, 261–265.
4. Mayer, A. M. S.; Paul, V. J.; Fenical, W.; Norris, J. N.; de
Carvalho, M. S.; Jacobs, R. S. Hydrobiologia 1993, 260–261,
521–529.
16. For more elaborate examples see the total syntheses of
epothilone C, various prostaglandin derivatives, and the
butenolide dehydrohomoancepsenolide: (a) Fu¨rstner, A.;
Mathes, C.; Lehmann, C. W. Chem. Eur. J. 2001, 7,
5299–5317. (b) Fu¨rstner, A.; Mathes, C.; Grela, K. Chem.
Commun. 2001, 1057–1059. (c) Fu¨rstner, A.; Grela, K.;
Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc. 2000, 122,
11799–11805. (d) Fu¨rstner, A.; Grela, K. Angew. Chem., Int.
Ed. 2000, 39, 1234–1236. (e) Fu¨rstner, A.; Dierkes, T. Org.
Lett. 2000, 2, 2463–2465. (f) Fu¨rstner, A.; Mathes, C. Org.
Lett. 2001, 3, 221–223.
5. For representative examples see: (a) Fu¨rstner, A.; Leitner, A.
Angew. Chem., Int. Ed. 2003, 42, 308–311. (b) Fu¨rstner, A.;
Krause, H.; Thiel, O. R. Tetrahedron 2002, 58, 6373–6380.
(c) Fu¨rstner, A.; Gastner, T. Org. Lett. 2000, 2, 2467–2470.
(d) Fu¨rstner, A.; Thiel, O. R. J. Org. Chem. 2000, 65,
1738–1742. (e) Fu¨rstner, A.; Grabowski, J.; Lehmann, C. W.
J. Org. Chem. 1999, 64, 8275–8280. (f) Fu¨rstner, A.;
Weintritt, H. J. Am. Chem. Soc. 1998, 120, 2817–2825.
(g) Fu¨rstner, A.; Weintritt, H.; Hupperts, A. J. Org. Chem.
1995, 60, 6637–6641. (h) Fu¨rstner, A.; Hupperts, A. J. Am.
Chem. Soc. 1995, 117, 4468–4475.
17. (a) Brizius, G.; Bunz, U. H. F. Org. Lett. 2002, 4, 2829–2831.
(b) Brizius, G.; Pschirer, N. G.; Steffen, W.; Stitzer, K.; zur
Loye, H.-C.; Bunz, U. H. F. J. Am. Chem. Soc. 2000, 122,
12435–12440.
6. (a) Fu¨rstner, A.; Grabowski, J.; Lehmann, C. W.; Kataoka, T.;
Nagai, K. ChemBioChem. 2001, 2, 60–68. (b) Fu¨rstner, A.;
Grabowski, E. J. ChemBioChem. 2001, 2, 706–709.
7. Fu¨rstner, A.; Seidel, G. Angew. Chem., Int. Ed. 1998, 37,
1734–1736.
18. Huckin, S. N.; Weiler, L. Can. J. Chem. 1974, 52,
1343–1351.
19. For leading applications see: (a) Hagiwara, H.; Kobayashi, K.;
Miya, S.; Hoshi, T.; Suzuki, T.; Ando, M.; Okamoto, T.;
Kobayashi, M.; Yamamoto, I.; Ohtsubo, S.; Kato, M.; Uda, H.
J. Org. Chem. 2002, 67, 5969–5976. (b) Oikawa, H.;
Kobayashi, T.; Katayama, K.; Suzuki, Y.; Ichihara, A.
J. Org. Chem. 1998, 63, 8748–8756. (c) Smith, A. B.; Kinsho,
T.; Sunazuka, T.; Omura, S. Tetrahedron Lett. 1996, 37,
6461–6464. (d) Fehr, M. J.; Consiglio, G.; Scalone, M.;
Schmid, R. J. Org. Chem. 1999, 64, 5768–5776. (e) Ishibashi,
Y.; Ohba, S.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett.
1996, 37, 2997–3000. (f) Cervello, J.; Marquet, J.; Moreno-
Man˜as, M. Tetrahedron 1990, 46, 2035–2046. (g) Cervello, J.;
Marquet, J.; Moreno-Man˜as, M. J. Chem. Soc., Chem.
Commun. 1987, 644–645. (h) Oppolzer, W.; Moretti, R.;
Bernardinelli, G. Tetrahedron Lett. 1986, 27, 4713–4716, and
literature cited therin.
8. For another synthesis of a pyrone embedded into a meta-
cyclophane structure from our laboratory see: Fu¨rstner, A.;
Krause, H. J. Org. Chem. 1999, 64, 8281–8286.
9. For general reviews on metathesis see: (a) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29. (b) Fu¨rstner,
A. Angew. Chem., Int. Ed. 2000, 39, 3012–3043.
10. (a) Fu¨rstner, A.; Stelzer, F.; Rumbo, A.; Krause, H. Chem. Eur.
J. 2002, 8, 1856–1871. (b) Fu¨rstner, A.; Guth, O.; Rumbo, A.;
Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108–11113.
(c) Fu¨rstner, A.; Radkowski, K.; Grabowski, J.; Wirtz, C.;
Mynott, R. J. Org. Chem. 2000, 65, 8758–8762. (d) Fu¨rstner,
A.; Rumbo, A. J. Org. Chem. 2000, 65, 2608–2611.
(e) Fu¨rstner, A.; Seidel, G. J. Organomet. Chem. 2000, 606,
75–78. (f) Fu¨rstner, A.; Castanet, A.-S.; Radkowski, K.;
Lehmann, C. W. J. Org. Chem. 2003, 68, 1521–1528.
11. Aguilera, B.; Wolf, L. B.; Nieczypor, P.; Rutjes, F. P. J. T.;
Overkleeft, H. S.; van Hest, J. C. M.; Schoemaker, H. E.;
Wang, B.; Mol, J. C.; Fu¨rstner, A.; Overhand, M.; van der
20. (a) Lygo, B. Tetrahedron 1995, 51, 12859–12868. (b) Lygo,
B.; Bhatia, M.; Cooke, J. W. B.; Hirst, D. J. Tetrahedron Lett.
2003, 44, 2529–2532.

6904
D. Song et al. / Tetrahedron 59 (2003) 6899–6904
¨
of Crystal Structures; University of Gottingen: Germany,
1997.
23. Sheldrick, G. M. SHELXL-97: Program for Least-squares
21. (a) Genin, M. J.; Biles, C.; Keiser, B. J.; Poppe, S. M.; Swaney,
S. M.; Tarpley, W. G.; Yagi, Y.; Romero, D. L. J. Med. Chem.
2000, 43, 1034–1040. (b) Harris, T. M.; Carney, R. L. J. Am.
Chem. Soc. 1967, 89, 6734–6741.
¨
Refinement of Crystal Structures; University of Gottingen:
Germany, 1997.
22. Sheldrick, G. M. SHELXS-97: Program for the Determination