Synthesis of marine polyacetylenes callyberynes A-C by transition-metal- catalyzed cross-coupling reactions to sp centers

Article abstract of DOI:10.1021/jo052609u

Efficient total syntheses of the sponge-derived hydrocarbon polyacetylenes callyberynes A-C have been achieved using metal-catalyzed cross-coupling reactions of highly unsaturated 1,3-diyne fragments as the key steps, namely: Cadiot-Chodkiewicz reaction u

Full text of DOI:10.1021/jo052609u

Synthesis of Marine Polyacetylenes Callyberynes A-C by
Transition-Metal-Catalyzed Cross-Coupling Reactions to sp Centers
Susana Lo´pez,* Francisco Ferna´ndez-Trillo, Pilar Mido´n, Luis Castedo, and Carlos Saa´
Departamento de Qu´ımica Orga´nica, Facultade de Qu´ımica, UniVersidade de Santiago de Compostela,
15782 Santiago de Compostela, Spain
qosuslop@usc.es
ReceiVed December 20, 2005
Efficient total syntheses of the sponge-derived hydrocarbon polyacetylenes callyberynes A-C have been
achieved using metal-catalyzed cross-coupling reactions of highly unsaturated 1,3-diyne fragments as
the key steps, namely: Cadiot-Chodkiewicz reaction under Alami’s optimized conditions (sp-sp),
sequential Sonogashira reaction of a cis,cis-divinyl dihalide (sp2-sp), and Kumada-Corriu reaction of
an unactivated alkyl iodide (sp3-sp). This last approach constitutes the first application of a metal-
catalyzed sp3-sp Kumada-Corriu cross-coupling reaction to the synthesis of a natural product.
Introduction
Transition-metal-catalyzed cross-coupling reactions are widely
recognized as selective, high-yielding methods for the synthesis
of organic compounds and have proven to be one of the most
powerful arsenals for the formation of carbon-carbon bonds
to sp centers.5 However, the highly reactive nature of the
intermediates involved in the total synthesis of conjugated
polyacetylenes often presents a major challenge.
The carbon-carbon triple bond is a ubiquitous structural
feature of organic molecules.1 Conjugated polyacetylenes are
common structural units in a large number of natural products,
many of which exhibit potent and varied biological activities
and play important ecological roles.2 In addition, they are also
key structural moieties in synthetic compounds with unusual
electrical, optical, or structural properties, which have found
applications in materials science.3 Consequently, renewed
interest has recently appeared in the synthetic studies of both
natural and unnatural acetylenic compounds.4
The vast majority of the metal-catalyzed acetylenic cross-
coupling processes requires substrates having an sp or sp2 carbon
(3) (a) Luu, T.; Elliott, E.; Slepkov, A. D.; Eisler, S.; McDonald, R.;
Hegmann, F. A.; Tykwinski, R. R. Org. Lett. 2005, 7, 51-54. (b) Eisler,
S.; Slepkov, A. D.; Elliot, E.; Luu, T.; McDonald, R.; Hegmann, F. A.;
Tykwinski, R. R. J. Am. Chem. Soc. 2005, 127, 2666-2676. (c) Umeda,
R.; Morinaka, T.; Sonoda, M.; Tobe, Y. J. Org. Chem. 2005, 70, 6133-
6136. (d) Marsden, J. A.; Haley, M. M. J. Org. Chem. 2005, 70, 10213-
10226.
(4) For a recent review on the synthesis of naturally occurring polyyynes,
see: Shi Shun, A. L. K.; Tykwinski, R. R. Angew. Chem., Int. Ed. 2006,
45, 1034-1057.
(1) Stang, P. J., Diederich, F., Eds. Modern Acetylene Chemistry; Wiley-
VCH: Weinheim, 1995.
(2) (a) Bohlmann, F.; Burkhart, F, T,; Zero, C. Naturally Occurring
Acetylenes; Academic Press: New York, 1973. (b) Blunt, J. W.; Copp, B.
R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep.
2005, 22, 15-61 and previous reports in this series.
10.1021/jo052609u CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/04/2006
2802
J. Org. Chem. 2006, 71, 2802-2810

Synthesis of Marine Polyacetylenes Callyberynes A-C
at or immediately adjacent to an electrophilic center. Poly-
acetylenic compounds are usually obtained through coupling
of two acetylenic fragments.6 Symmetrical 1,3-diynes can be
prepared by oxidative coupling of terminal alkynes. Unsym-
metrically disubstituted 1,3-diynes are more often obtained by
the Cadiot-Chodkiewicz cross-coupling of a bromoacetylene
with a terminal alkyne in the presence of a copper(I) salt and
an aliphatic amine.7 Some catalytical versions have been
described together with examples of Pd-Cu cocatalysis.8 Alami9
has reported improved conditions for the coupling of terminal
alkynes with 1-iodoalkynes in pyrrolidine that employ a copper
catalyst and do not require a palladium cocatalyst. This
optimized version can be advantageously used in the case of
aliphatic 1-alkynes, which are known to give low yields of cross-
coupling products under classical Cadiot-Chodkiewicz condi-
tions.
The transition-metal-catalyzed cross-coupling reaction of
metal acetylides with vinyl/aryl halides is an important reaction
in organic synthesis since it provides a straight method for sp2-
sp carbon-carbon coupling.10 The palladium-catalyzed cross-
coupling reactions of terminal alkynes with sp2 halides/triflates,
in the presence (Sonogashira-Hagihara alkynylation)11 or in
the absence (Heck alkynylation)12 of a copper cocatalyst, are
even more useful synthetically and have been extensively used
in the stereospecific synthesis of conjugated enynes.13
recently to enhance the reactivity of the aliphatic C-X bonds
and/or to stabilize the resulting organometallic intermediate so
that the desired coupling can be achieved.15 Regarding alkyn-
ylation, to the best of our knowledge, only two examples are
described in the literature employing terminal alkynes and
electrophilic sp3 centers.16 Luh17 has reported that Pd2(dba)3-
Ph3P-catalyzed Kumada-Corriu coupling reactions of unacti-
vated alkyl bromides or iodides with an alkynyl nucleophile
(Mg or Li) led to Csp3-Csp bond formation in good yields;
the source of palladium appears to be decisive (palladium acetate
is not an effective catalyst), and Ph3P performs as the best ligand
in what seems to be a reductive elimination-controlled process.
On the other hand, Fu18 has developed a Pd/N-heterocyclic
carbene-based catalyst that achieves Sonogashira coupling of
terminal alkynes with an array of fuctionalized, unactivated,
â-hydrogen-containing alkyl bromides and iodides, under mild
conditions.
As part of our ongoing projects on developing efficient and
selective routes to natural and synthetic polyenes and poly-
enynes,19 we became interested in a synthetically unexplored,
rapidly growing group of linear, bioactive marine polyacetylenes
isolated from the family Callyspongiidae. Fusetani20 and Um-
eyama21 have independently reported the isolation, from Japa-
nese Callyspongia sp., of three C21 hydrocarbon polyacety-
lenes: callyberyne A (also referred to as callypentayne) (1),
callyberyne B (2), and callyberyne C (also referred to as
callytetrayne) (3) (Scheme 1). The three metabolites were
structurally related to the known (-)-siphonodiol (4),22 and
biogenetically, they were considered most likely to be produced
by decarboxylation of a C22 fatty acid precursor in the sponge.
As some other members of this family,23 callyberynes A (1)
and C (3) exhibited potent metamorphosis-inducing activity in
the ascidian Halocynthia roretzi, with ED100 values of 0.25 µg/
mL.20
Palladium-catalyzed couplings in which the electrophile is
sp3-hybridized have been, however, rather uncommon.14 Slow
oxidative addition of the alkyl halide/triflate to palladium and
facile intramolecular â-hydride elimination of the alkylmetal
intermediate are two likely causes for this comparative lack of
attention. However, a number of conditions have been developed
(5) (a) Miyaura, N. Cross-Coupling Reactions. In Topics in Current
Chemistry; Springer-Verlag: Berlin, 2000; Vol. 219. (b) Schlosser, M.
Organometallics in Synthesis, 2nd ed.; John Wiley & Sons: Chichester,
2002. (c) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004. (d) Nicolaou, K. C.;
Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442-4489.
(6) (a) Sonogashira, K. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 551-562. (b)
Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000,
39, 2633-2657.
(14) (a) Billington, D. C. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 413-434.
(b) Tamao, K. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 435-480. (c) Ca´rdenas, D.
J. Angew. Chem., Int. Ed. 1999, 38, 3018-3020. (d) Luh, T.-Y.; Leung,
M.-K.; Wong, K.-T. Chem. ReV. 2000, 100, 3187-3204. (e) Ca´rdenas, D.
J. Angew. Chem., Int. Ed. 2003, 42, 384-387.
(15) (a) Netherton, M. R.; Fu, G. C. AdV. Synth. Catal. 2004, 346, 1525-
1532. (b) Fu, G. C. J. Org. Chem. 2004, 69, 3245-3249. (c) Netherton,
M. R.; Fu, G. C. In Topics in Organometallic Chemistry; Springer GmbH:
Heidelberg, 2005; Vol. 14, pp 85-108. (d) Frisch, A. C.; Beller, M. Angew.
Chem., Int. Ed. 2005, 44, 674-688.
(16) Examples of metal-catalyzed cross-coupling reactions of alkynyl
stannanes with alkyl halides have been already described; see, for instance,
ref 14d.
(17) Yang, L.-M.; Huang, L.-F-; Luh, T.-Y. Org. Lett. 2004, 6, 1461-
1463.
(18) Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 13642-
13643.
(19) For some recent publications of our group in the chemistry and
biology of polyenes and polyenynes, see: (a) Mart´ınez-Espero´n, M. F.;
Rodr´ıguez, D.; Castedo, L.; Saa´, C. Org. Lett. 2005, 7, 2213-2216. (b)
Lo´pez, S.; Rodr´ıguez, V.; Montenegro, J.; Saa´, C.; Alvarez, R.; Lo´pez, C.
S.; de Lera, A. R.; Simo´n, R.; Lazarova, T.; Padro´s, E. ChemBioChem 2005,
6, 2078-2087.
(20) Tsukamoto, S.; Kato, H.; Hirota, H.; Fusetani, N. J. Nat. Prod. 1997,
60, 126-130.
(21) Umeyama, A.; Nagano, C.; Arihara, S. J. Nat. Prod. 1997, 60, 131-
133.
(7) Cadiot, P. C. R.; Chodkiewicz, W. Coupling of Acetylenes in
Chemistry of Acetylenes; Viehe, H. G., Ed.; Marcel Dekker: New York,
1969.
(8) (a) Wityak, J.; Chan, J. B. Synth. Commun. 1991, 21, 977-979. (b)
Cai, C.; Vasella, A. HelV. Chim. Acta 1995, 78, 2053-2064.
(9) Alami, M.; Ferri, F. Tetrahedron Lett. 1996, 37, 2763-2766.
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B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 521-549.
(b) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions; Dieder-
ich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; pp 203-229. (c)
Tykwinski, R. R. Angew. Chem., Int. Ed. 2003, 42, 1566-1568. (d) Negishi,
E.-i.; Anastasia, L. Chem. ReV. 2003, 103, 1979-2017.
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4467-4470. (b) Rossi, R.; Carpita, A.; Bellina, F. Org. Prep. Proced. Int.
1995, 27, 127-160. (c) Sonogashira, K. J. Organomet. Chem. 2002, 653,
46-49. (d) Sonogashira, K. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E.-i., Ed.; Wiley: New York, 2002; pp 493-
529.
(12) Dieck, H. A.; Heck, F. R. J. Organomet. Chem. 1975, 93, 259-
263.
(13) For some recent applications in the synthesis of natural products,
see: (a) Guilford, W. J.; Bauman, J. G.; Skuballa, W.; Bauer, S.; Wei, G.
P.; Davey, D.; Schaefer, C.; Mallari, C.; Terkelsen, J.; Tseng, J.-L.; Shen,
J.; Subramanyam, B.; Schottelius, A. J.; Parkinson, J. F. J. Med. Chem.
2004, 47, 2157-2165. (b) Murakami, Y.; Nakano, M.; Shimofusa, T.;
Furuichi, N.; Katsumura, S. Org. Biomol. Chem. 2005, 3, 1372-1374. Some
recent applications in the chemistry of materials, see: (c) Miljanic, O. S.;
Holmes, D.; Vollhardt, K. P. C. Org. Lett. 2005, 7, 4001-4004. (d)
Golovkova, T. A.; Kozlov, D. V.; Neckers, D. C. J. Org. Chem. 2005, 70,
5545-5549.
(22) (a) Tada, H.; Yasuda, F. Chem. Lett. 1984, 779-780. (b) Fusetani,
N.; Sugano, M.; Matsunaga, S.; Hashimoto, K. Tetrahedron Lett. 1987,
28, 4311-4312.
(23) The family includes around 20 structurally related compounds,
among them four C21 hydrocarbons, four C22 alcohols, five triols, two
sulfates, one dihydro derivative, and one tetrahydro derivative. See refs
2b, 25, 26, and references cited therein.
J. Org. Chem, Vol. 71, No. 7, 2006 2803

Lo´pez et al.
SCHEME 1. Retrosynthetic Analysis
The highly unsaturated nature of these new marine poly-
acetylenes prompted us to investigate their synthesis by routes
that would allow us to apply new cross-coupling reactions and/
or to test standard cross-coupling reactions by employing
structurally complex building blocks.24 As a result, we have
already reported a communication on the synthesis of hydro-
carbon callyberynes A (1) and B (2),25 and we have recently
described the first, stereoselective total synthesis of the parent
compound (-)-siphonodiol (4)26 using highly convergent ap-
proaches that involved optimized Cadiot-Chodkiewicz and
sequential Sonogashira cross-coupling reactions as the key steps.
We want to disclose herein the full account of our efforts toward
the total synthesis of callyberynes A-B together with the first
total synthesis of the related callyberyne C (3).
The overall retrosynthetic analysis is summarized in Scheme
1. The convergent approaches to the three polyacetylenes rely
on bond disconnections at the central sp centers and employ
transition-metal-catalyzed alkynylation reactions (sp-sp, sp2-
sp, or sp3-sp) as the pivotal steps. The high structural
resemblance of the three natural products will allow the use of
common synthetic building blocks. The strategy requires the
preparation of several highly unsaturated, monoprotected in-
termediates so the choice of suitable acetylenic protecting groups
will be critical to successfully achieve monodeprotection of both
symmetrically and orthogonally diprotected polyynes.
Results and Discussion
Synthesis of Callyberyne A (1). We envisioned that the
skeletal framework of callyberyne A (1) could be constructed
through two alternative routes involving either Cadiot-Chod-
kiewicz (sp-sp) or Sonogashira (sp2-sp) cross-coupling reac-
tions as key steps (Scheme 1).
Initial efforts led us to consider the Cadiot-Chodkiewicz
reaction between the iodotriyne 6 and the monoprotected
dienediynes 13 or 17 as the most straightforward disconnection.
Thus, 9-iodo-1-triisopropylsilylnona-1,3,8-triyne (6) was easily
available from 1-triisopropylsilylnona-1,3,8-triyne (5)25 by treat-
ment with n-BuLi/iodine (89%) (Scheme 2).
The monoprotected (3Z,9Z)-1-trimethylsilyldodeca-3,9-diene-
1,11-diyne (13) and (5Z,11Z)-2-methyltetradeca-5,11-diene-3,-
13-diyn-2-ol (17) were chosen as suitable building blocks since
they could a priori be synthesized by monodeprotection of
readily available symmetrically disubstituted precursors (12 and
16, respectively) (Scheme 3). It is well established that bis-
(trimethylsilyl)acetylenes can be monodesilylated by treatment
with MeLi‚LiBr complex in THF followed by hydrolysis.27
Selective unmasking of silyl groups has also been described by
employing NaBH(OMe)3.28 As an alternative, partial deprotec-
(24) For some recent syntheses of natural polyacetylenes, see: (a) Carpita,
A.; Braconi, S.; Rossi, R. Tetrahedron: Asymmetry 2005, 16, 2501-2508.
(b) Gung, B. W.; Gibeau, C.; Jones, A. Tetrahedron: Asymmetry 2005,
16, 3107-3114. (c) Kirkham, J. E. D.; Courtney, T. D. L.; Lee, V.; Baldwin,
J. E. Tetrahedron 2005, 61, 7219-7232. (d) Pereira, A. R.; Cabezas, J. A.
J. Org. Chem. 2005, 70, 2594-2597. (e) Yun, H.; Chou, T.-C.; Dong, H.;
Tian, Y.; Li, Y.-m.; Danishefsky, S. J. J. Org. Chem. 2005, 70, 10375-
10380. For a recent review, see ref 4.
(25) Lo´pez, S.; Ferna´ndez-Trillo, F.; Castedo, L.; Saa´, C. Org. Lett. 2003,
5, 3725-3728.
(26) Lo´pez, S.; Ferna´ndez-Trillo, F.; Mido´n, P.; Castedo, L.; Saa´, C. J.
Org. Chem. 2005, 70, 6346-6352.
(27) (a) Holmes, A B.; Jennings-White, C. L. D.; Schulthess, A. H.;
Akinde, B.; Walton, D. R. M. J. Chem. Soc., Chem. Commun. 1979, 840-
842. (b) Holmes, A. B.; Jones, G. E. Tetrahedron Lett. 1980, 21, 3111-
3112. (c) Eaton, P. E.; Galoppini, E.; Gilardi, R. J. Am. Chem. Soc. 1994,
116, 7588-7596.
2804 J. Org. Chem., Vol. 71, No. 7, 2006

Synthesis of Marine Polyacetylenes Callyberynes A-C
SCHEME 2
SCHEME 3
tion of bis-tert-propargyl alcohols can be successfully achieved
by heating in benzene or toluene solution under basic conditions
for short reaction times, a base-catalyzed “retro-Favorsky”
elimination of acetone being the driving-force of the reaction.29
Accordingly, the synthesis of the target monoprotected diene-
diyne 13 started with the preparation of the putative precursor
(3Z,9Z)-1,12-bis(trimethylsilyl)dodeca-3,9-diene-1,11-diyne (12),
which was obtained in excellent yield by double Sonogashira
cross-coupling reaction of dibromide 1025,26 with an excess of
trimethylsilylacetylene (11) [PdCl2(Ph3P)2, CuI, piperidine,
95%]. Selective monoprotodesilylation of 12 proved, however,
to be discouraging. In fact, the first attempt using 1 equiv of
MeLi‚LiBr complex (1.5 M in ether, rt) gave rise to a complex
mixture of mono and bis-desilylated products (13 and 14)
together with some recovered starting material; the three
compounds showed a very similar chromatographic mobilities
and product purification was therefore extremely difficult.
Disappointingly, the same problem was found when NaBH-
(OMe)3 or 1 equiv of CsF was used, and therefore, compound
13 could not be prepared efficiently.
(5Z,11Z)-2-methyltetradeca-5,11-diene-3,13-diyn-2-ol
(17)
(Scheme 3). Palladium-catalyzed double alkynylation of (1Z,7Z)-
1,8-dibromoocta-1,7-diene (10) with an excess of 2-methyl-3-
butyn-2-ol (15), under the same above conditions, afforded
(5Z,11Z)-2,15-dimethylhexadeca-5,11-diene-3,13-diyne-2,15-
diol (16) in 84% yield. Rewardingly, partial deprotection of 16
could be achieved by heating its benzene solution at 70 °C for
2 h in the presence of potassium hydroxide, leading to the
desired 17 in a moderate 56% yield. Monodeprotected 17
appeared also accompanied by small amounts of fully depro-
tected (3Z,9Z)-dodeca-3,9-diene-1,11-diyne (14) (14%) and
some recovered starting material, but in this case, the polarity
of the protecting hydroxyl group allowed an easy chromato-
graphic separation. Attempts to improve the yield by employing
longer reaction times, higher temperatures or by changing the
solvent (toluene, methanol, i-PrOH) were fruitless, the harshness
of the conditions leading to an increase of deprotection or
decomposition.
With subunits 6 and 17 in hand, Cadiot-Chodkiewicz cross-
coupling was carried out under Alami’s improved conditions
[CuI, piperidine] to afford (5Z,11Z)-2-methyl-23-triisopropyl-
silyltricosa-5,11-diene-3,13,15,20,22-pentayn-2-ol (20) in a 60%
yield (Scheme 4).30 Unfortunately, the subsequent deprotection
step proved again to be troublesome. Attempts to carry out
Due to the difficulties found in the preparation of pure
examples of fragment 13, we next focused on the synthesis of
(28) (a) Myers, A. G.; Harrington, P. M.; Kuo, E. Y. K. J. Am. Chem.
Soc. 1991, 113, 694-695. (b) Wright, J. M.; Jones, G. B. Tetrahedron Lett.
1999, 40, 7605-7609.
(29) (a) Ma, L.; Hu, Q.-S.; Pu, L. Tetrahedron: Asymmetry 1996, 7,
3103-3106. (b) Khatyr, A.; Ziessel, R. J. Org. Chem. 2000, 65, 3126-
3134.
(30) The use of Cadiot-Chodkiewicz classical conditions (5% CuCl,
30% NH2OH, EtNH2, MeOH-H2O) led to a lower yield of cross-coupling
product 33 (<25%).
J. Org. Chem, Vol. 71, No. 7, 2006 2805

Lo´pez et al.
SCHEME 4
simultaneous deprotection of both silyl and hydroxyl protecting
groups by base-treatment (KOH/benzene/MeOH, 70 °C, 31 h)
gave rise to only a very low yield of callyberyne A (1) (9%);
instead, the partially deprotected (3Z,9Z)-1-triisopropylsilyl-
henicosa-3,9-diene-1,11,13,18,20-pentayne (21) (9%) and
(5Z,11Z)-2-methyltricosa-5,12-diene-3,13,15,20,22-pentayn-2-
ol (22) (25%) were also obtained, the latter being the major
product of this reaction.
Consequently, in light of the numerous difficulties found in
the designed Cadiot-Chodkiewicz (sp-sp) route to callyberyne
A, we turned our attention to the alternative sp2-sp discon-
nection which would disassemble the target molecule into two
fragments of similar size, employing a Sonogashira cross-
coupling reaction to join the subunits C1-C10 (18) and C11-
C21 (9) (Scheme 1).
The skeleton would be constructed by succesive replacement
of the bromine atoms of (1Z,7Z)-1,8-dibromoocta-1,7-diene (10)
by alkynes. The cis-bromovinyl moiety 18 could be available
through reaction of 10 with the novel [(3-cyanopropyl)-
dimethylsilyl]acetylene (CPDMSA) (7) (Scheme 3).31 After
optimization of the reaction conditions, we found that the use
of substoichiometric amounts of the alkyne reactant (3:1 molar
ratio) and the employment of dilute solutions (0.05 M for the
alkyne) were clearly in favor of the monocoupled product
(3Z,9Z)-10-bromo-1-[(3′-cyanopropyl)dimethylsilyl]deca-3,9-
dien-1-yne (18) (75% isolated yield). The polarity of the
CPDMS protecting group allowed the easy separation of the
dicoupled side product (3Z,9Z)-1,12-bis-[(3′-cyanopropyl)di-
methylsilyl]dodeca-3,9-diene-1,11-diyne (19), which was ob-
tained in less than 10% yield.32
On the other side, the right-hand segment tetrayne 9 was
easily prepared from iodotriyne 6 through a two-step sequence
involving coupling with CPDMSA (7) under Alami’s conditions
(CuI, piperidine) to produce the differentially protected tetrayne
8 in 63% yield and basic methanolysis (K2CO3 in wet THF/
MeOH) to remove selectively the cyanopropyldimethylsilyl
moiety in 71% yield (Scheme 2).
The assembly of the skeleton of callyberyne A (1) requires
the Sonogashira cross-coupling reaction between fragments 9
and 18 (Scheme 4). In comparison with 1-alkynes, the use of
1,3-diynes as the acetylenic component in such coupling is
scarce, mainly due to difficulties associated with the synthesis
and especially the stability of these intermediates.33,34 However,
despite its highly unsaturated structure, 1-triisopropylsilylun-
deca-1,3,8,10-tetrayne (9) was shown to be remarkably stable,
and reaction with (3Z,9Z)-10-bromo-1-[(3′-cyanopropyl)di-
methylsilyl]deca-3,9-dien-1-yne (18) proceeded smoothly [PdCl2-
(PPh3)2, CuI, pyrrolidine, rt, 2 h] to furnish the skeletal
framework (3Z,9Z)-1-[3′-cyanopropyl) dimethylsilyl]-21-triiso-
propylsilylhenicosa-3,9-diene-1,11,13,18,20-pentayne (23) in a
(32) For other mono-cross-coupling reaction conditions, see: (a) Khatyr,
A.; Ziessel, R. J. Org. Chem. 2000, 65, 7814-7824. (b) Kosinki, C.; Hirsch,
A.; Heinemann, F. W.; Hampel, F. Eur. J. Org. Chem. 2001, 3879-3890.
(c) Hu, Q.-S.; Sun, C.; Monoghan, C. E. Tetrahedron Lett. 2002, 43, 927-
930. (d) Kitamura, C.; Saito, K.; Nakagawa, M.; Ouchi, M.; Yoneda, A.;
Yamashita, Y. Tetrahedron Lett. 2002, 43, 3373-3376.
(33) (a) Balova, I. A.; Morozkina, S. N.; Knight, D. W.; Vasilevsky, S.
F. Tetrahedron Lett. 2003, 44, 107-109. (b) Fiandanese, V.; Bottalico, D.;
Marchese, G.; Punzi, A. Tetrahedron Lett. 2003, 44, 9087-9090. (c)
Sabitha, G.; Reddy, Ch. S.; Srihari, P.; Yadav, J. S. Synthesis 2003, 2699-
2704. (d) Balova, I. A.; Sorokoumov, V. N.; Morozkina, S. N.; Vinogradova,
O. V.; Knight, D. W.; Vasilevsky, S. F. Eur. J. Org. Chem. 2005, 882-
888.
(31) CPDMS-acetylene combines the mild conditions necessary to
remove the TMS protecting group with the high polarity of the hydroxyl-
containing protecting groups, allowing for the simple and high yield
chromatographic separation of its palladium-catalyzed coupling products.
See: Ho¨ger, S.; Bonrad, K. J. Org. Chem. 2000, 65, 2243-2245.
(34) To avoid the use of highly reactive terminal diyne or triyne
intermediates in the synthesis of polyyne natural products, Gung has recently
developed a new approach based on a three-component one-pot Cadiot-
Chodkiewicz cross-coupling reaction; see: Gung, B. W.; Kumi, G. J. Org.
Chem. 2004, 69, 3488-3492.
2806 J. Org. Chem., Vol. 71, No. 7, 2006

Synthesis of Marine Polyacetylenes Callyberynes A-C
SCHEME 5
remarkable 76% yield. It must be noted that the choice of the
amine had a significant impact on the efficiency of this cross-
coupling and the use of pyrrolidine, instead of piperidine (the
standard amine used for coupling of 1-alkynes), appeared to be
crucial for the success of the reaction with 1,3-diynes.35
Finally, fluoride-induced cleavage of both terminal silyl-
protecting groups led to the target callyberyne A (1) in
quantitative yield. Following this highly convergent sp2-sp
route, the total synthesis of callyberyne A (1) was completed
in three steps with a 57% overall yield from [(3′-cyanopropyl)
dimethylsilyl]acetylene (7).
Synthesis of Callyberyne B (2). Since the successful sp2-
sp disconnection for the synthesis of callyberyne A (1), the
preparation of callyberyne B (2) was performed following a
parallel route (Scheme 1). The required left-hand fragment,
(1Z,7Z)-1-bromo-10-[(3′-cyanopropyl)dimethylsilyl]deca-1,7-
dien-9-yne (18), was common to both metabolites. The synthesis
of the right-hand fragment, protected enetriyne 30, is outlined
in Scheme 5. Cadiot-Chodkiewicz cross-coupling of 6-iodo-
5-hexyn-1-ol (24) with trimethylsilylacetylene (6), under modi-
fied Alami’s conditions [CuCl, piperidine, 0 °C], gave the TMS-
protected diynol 25 (87% yield) which was quantitatively
oxidized using Dess-Martin periodinane.36 Aldehyde 26 was
subjected to a Stork/Zhao37 modified Wittig reaction [(Ph3P+-
CH2I)I-, NaN(TMS)2, HMPA, THF, -78 °C] to give, stereo-
selectively, the homologated (Z)-1-iodo-9-trimethylsilylnon-1-
ene-6,8-diyne (27) in 66% yield (12:1 Z/E ratio). Sonogashira
cross-coupling [PdCl2(PPh3)2, CuI, piperidine] of the Z-vinylio-
dide 27 with triisopropylsilylacetylene (28) afforded, after
purification, the orthogonally protected Z-enetriyne 29 in 70%
yield as a single isomer. Finally, basic methanolysis allowed
selective removal of TMS group to obtain (Z)-1-triisopropyl-
silylundec-3-ene-1,8,10-triyne (30) in 95% yield.
proceeded again uneventfully to give rise to (3Z,12Z,18Z)-21-
[(3′-cyanopropyl)dimethylsilyl]-1-triisopropylsilylhenicosa-3,-
12,18-triene-1,8,10,20-tetrayne (31) in a good yield (72%).
Deprotection of both silyl groups with TBAF in THF led to
callyberyne B (2) in 90% yield.
Following this highly convergent sp2-sp route, the total
synthesis of callyberyne B (2) was completed in three steps with
a 49% overall yield, again from [(3′-cyanopropyl)dimethylsilyl]-
acetylene (7).
Synthesis of Callyberyne C (3). At the time that we initiated
our approaches to this family of marine polyacetylenes, there
were no reports in the literature regarding metal-catalyzed cross-
coupling reactions of alkynes with alkyl electrophiles. The
obvious strategy for the synthesis of callyberyne C, at that
moment, implied the dissection of the skeleton into two major
fragments C1-C11 (30) and C12-C21 (37) to be joined by an
SN2 displacement (Scheme 1).
The nucleophilic fragment, (Z)-1-triisopropylsilylundec-3-ene-
1,8,10-triyne (30), had been previously employed in the
synthesis of callyberyne B (2). The electrophilic subunit 37,
either as a triflate or halide, could be easily prepared from Z-10-
triisopropylsilyldec-7-en-9-yn-1-ol (36), which could in turn be
synthesized from the known 7-tert-butyldiphenylsilyloxyhep-
tanal (32),38 as depicted in Scheme 6. Following this sequence,
the vinyl gem-dibromoolefin 33 was obtained, in excellent yield
(96%), by Wittig homologation of 32 in the presence of PPh3
and CBr4. Palladium-catalyzed stereoselective hydrogenolysis
of 33 with n-Bu3SnH was then performed,39 yielding the desired
Z-vinyl bromide 34 (93% yield) which, on treatment with TBAF
at 0 °C, furnished the alcohol 35 in 83% yield. Sonogashira
cross-coupling reaction of 35 with triisopropylsilylacetylene (28)
[PdCl2(PPh3)2, CuI, piperidine] delivered enynol 36 in 79%
yield.
Cross-coupling reaction of the cis-vinyl bromide 18 with the
1,3-diyne unit 30, under the same Sonogashira conditions
described above [PdCl2(PPh3)2, CuI, pyrrolidine] (Scheme 4),
Initially, we chose a triflate as the alkylating agent since
alkynylation of alkyl triflates with alkynyllithiums is known to
(38) Jones, G. B.; Huber, R. S.; Chapman, B. J. Tetrahedron: Asymmetry
1997, 8, 1797-1809.
(39) (a) Uenishi, J.; Kawahama, R.; Shiga, Y.; Yonemitsu, O.; Tsuji, J.
Tetrahedron Lett. 1996, 37, 6759-6762. (b) Uenishi, J.; Kawahama, R.;
Yonemitsu, O.; Tsuji, J. J. Org. Chem. 1996, 61, 5716-5717. (c) Uenishi,
J.; Kawahama, R.; Yonemitsu, O.; Tsuji, J. J. Org. Chem. 1998, 63, 8965-
8975.
(35) The influence of the amine in the success of copper-catalyzed cross-
coupling reactions is well-known: Alami, M.; Ferri, F.; Linstrumelle, G.
Tetrahedron Lett. 1993, 34, 6403-6406 and ref 9.
(36) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
(37) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173-2174.
J. Org. Chem, Vol. 71, No. 7, 2006 2807

Lo´pez et al.
SCHEME 6
SCHEME 7
occur under relatively mild conditions.40 Therefore, Z-10-
trifluoromethanesulfonyloxy-1-triisopropylsilyldec-3-en-1-yne
(37a) was prepared from alcohol 36 by treatment with Tf2O
and pyridine in toluene at 0 °C (Scheme 6). The isolated yield
of crude triflate was nearly quantitative (96%) but the product
proved to be unstable and showed decomposition upon column
chromatography; so, it had to be prepared inmediately before
alkynylation and used without purification.
Deprotonation of the terminal 1,3-diyne 30 with n-butyl-
lithium at -78 °C, followed by addition of the lithiated acetylene
to an excess of triflate 37a in THF led to the expected
condensation product (3Z,18Z)-1,21-bis(triisopropylsilyl)heni-
cosa-3,18-diene-1,8,10,20-tetrayne (38), although in a modest
yield (43%) (Scheme 7). Since the unstable nature of the triflate
appeared as the most likely cause of this diminished yield, we
decide to use an iodide as the leaving group. Consequently,
enynol 36 was converted to (Z)-10-iodo-1-triisopropylsilyldec-
3-en-1-yne (37b) [I2/Ph3P/imidazole, 85% yield] (Scheme 6),
which was reacted with the lithium acetylide generated from
30. However, the halide displacement did not improve the
previous yield, even when an excess of HMPA was used as
cosolvent and the reaction mixture was heated at 65 °C for 48
h, affording 38 in practically the same yield (42%) (Scheme
7).41
coupling reactions, reporting the first successful examples of
palladium-catalyzed sp3-sp cross-coupling of alkynes with
unactivated, â-hydrogen-containing alkyl halides. In view of
the unsatisfactory results obtained in the SN2 displacement, we
decided to apply these new conditions (which would imply the
same subunits 30 and 37b) to the synthesis of callyberyne C
(3).
We first faced the modified Sonogashira reaction, which use
N-heterocyclic carbene ligands, developed by Fu. Following this,
to a solution of 1,3-bis(1-adamantyl)imidazolium chloride, CuI,
[(π-allyl)PdCl]2, and Na2CO3 in a mixture of Et2O-DMF
(2:1) were added sequentially, under argon atmosphere, solutions
of the diyne 30 and the iodide 37b in the same solvent. The
heterogeneous mixture was vigorously stirred at 40 °C, but after
16 h of reaction, only traces of 38 were detected, recovering
most of the starting materials.
We then tried the Kumada-Corriu reaction of alkyl halides
with alkynyl nucleophiles recently described by Luh. In this
case, we were pleased to find that, by adding dropwise the
lithium acetylide (prepared from 30 by treatment with n-BuLi
at -78 °C in THF), under argon, to a heated (65 °C) solution
of Pd2(dba)3, Ph3P, and iodide 37b in THF, compound 38 could
be obtained, after 23 h of reaction, in an excellent 86% yield
(Scheme 7). Finally, subsequent TBAF desilylation cleanly
provided the target natural product, as a yellow oil, in 89% yield.
As we have anticipated, Luh17 and Fu18 have recently
expanded the scope of the metal-catalyzed alkynylation cross-
(41) Yields of SN2 reactions using terminal 1,3-diynes and alkyl halides
as partners are often modest even when simpler fragments than used in
this manuscript are employed, see, for example: Fiandanese, V.; Bottalico,
D.; Cardellicchio, C.; Marchese, G.; Punzi, A. Tetrahedron 2005, 61, 4551-
4556.
(40) For a recent application of triflates in SN2 displacements, see:
Armstrong-Chong, R. J.; Matthews, K.; Chong, J. M. Tetrahedron 2004,
60, 10239-10244.
2808 J. Org. Chem., Vol. 71, No. 7, 2006

Synthesis of Marine Polyacetylenes Callyberynes A-C
Following this highly convergent sp3-sp route, the total
synthesis of callyberyne C (3) was completed in seven steps
with a 38% overall yield from 7-tert-butyldiphenylsilyloxy-
heptanal (32).
(hexane/ethyl acetate 95:5) afforded the title compound (0.030 g,
quantitative yield) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ
1.4-1.5 (4H, m), 1.78 (2H, q, J ) 6.9 Hz), 1.98 (1H, s), 2.3-2.5
(8H, m), 3.08 (1H, d, J ) 1.7 Hz), 5.4-5.5 (2H, m), 5.99 (1H, dt,
J ) 10.8, 7.5 Hz), 6.04 (1H, dt, J ) 10.8, 7.5 Hz); 13C NMR (75
MHz, CDCl3) δ 18.2 (CH2), 18.7 (CH2), 26.7 (CH2), 28.1 (CH2),
28.2 (CH2), 30.0 (CH2), 30.5 (CH2), 64.9 (CH), 65.5 (C), 66.2 (C),
68.2 (C), 72.5 (C), 76.8 (C), 77.9 (C), 80.4 (C), 81.3 (CH), 82.9
(C), 108.2 (CH), 108.3 (CH), 145.7 (CH), 147.7 (CH); IR (CsI) ν
3296 (≡C-H), 2226 (CtC) cm-1; MS (CI) m/z 273 (MH+, 4),
272 (M+, 5), 229 (67), 215 (75), 203 (71), 165 (66), 28 (100);
HRMS (CI) calcd for C21H21 273.1643, found 273.1634.
Conclusions
In summary, efficient total syntheses of the marine hydro-
carbon polyacetylenes callyberynes A-C (1-3) have been
achieved using highly convergent routes,42 which involved
metal-catalyzed cross-coupling reactions to sp centers as the
key steps, namely: Alami’s optimized conditions of the classical
Cadiot-Chodkiewicz reaction (sp-sp), sequential Sonogashira
reactions of a cis,cis-divinyl dihalide (sp2-sp), and Kumada-
Corriu reaction of an unactivated alkyl iodide under the
conditions recently reported by Luh (sp3-sp).
It is noteworthy that the acetylenic counterparts were, in all
the cases, highly unsaturated 1,3-diyne moieties which were
shown to be remarkably stable and could be isolated, purified,
and coupled effectively.
In particular, we want to emphasize that the Kumada-Corriu
alkynylation cross-coupling reaction between an sp3-hybridized
iodide and the lithium acetylide of a terminal 1,3-diyne turned
out in high yields as compared with the equivalent SN2
displacement reaction. To our knowledge, this approach to
callyberyne C constitutes the first application of a metal-
catalyzed sp3-sp Kumada-Corriu reaction to the synthesis of
a natural product.
(3Z,12Z,18Z)-21-[(3′-Cyanopropyl)dimethylsilyl]-1-triiso-
propylsilylhenicosa-3,12,18-triene-1,8,10,20-tetrayne (31). Fol-
lowing the same procedure described for 23, treatment of (1Z,7Z)-
1-bromo-10-[(3′-cyanopropyl)dimethylsilyl]deca-1,7-dien-9-yne (18)
(0.060 g, 0.18 mmol) and (Z)-1-triisopropylsilylundec-3-ene-1,8,-
10-triyne (30) (0.110 g, 0.37 mmol) with PdCl2(PPh3)2 (0.014 g,
0.02 mmol) and CuI (0.004 g, 0.02 mmol) in degassed pyrrolidine
(4 mL) for 1 h afforded, after purification by flash chromatography
(hexane/ethyl acetate 98:2), the title compound (0.072 g, 72% yield)
as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 0.22 (6H, s), 0.7-
0.8 (2H, m), 1.0-1.1 (21H, m), 1.4-1.5 (4H, m), 1.70 (2H, q, J )
7.3 Hz), 1.8-1.9 (2H, m), 2.3-2.5 (10H, m), 5.48 (2H, d, J )
10.3 Hz), 5.55 (1H, d, J ) 11.0 Hz), 5.9-6.1 (3H, m); 13C NMR
(75 MHz, CDCl3) δ -1.2 (2 × CH3), 11.8 (3 × CH), 16.3 (CH2),
19.1 (6 × CH3), 19.8 (CH2), 20.9 (CH2), 21.2 (CH2), 28.1 (CH2),
28.6 (CH2), 29.0 (CH2), 30.0 (CH2), 30.1 (CH2), 31.0 (CH2), 65.9
(C), 72.5 (C), 78.7 (C), 84.6 (C), 95.8 (C), 96.8 (C), 103.7 (2xC),
108.7 (CH), 109.5 (CH), 111.0 (CH), 120.0 (C), 143.4 (CH), 145.9
(CH), 147.5 (CH); IR (CsI) ν 2245 (CtN), 2146 (CtC) cm-1
;
MS (CI) m/z 557 (MH+, 1), 556 (M+, 3), 512 (4), 279 (7), 167
(19), 149 (57), 126 (96), 29 (100); HRMS (EI) calcd for C36H54-
NSi2 556.3795, found 556.3803.
Experimental Section
(3Z,9Z)-1-[(3′-Cyanopropyl)dimethylsilyl]-21-triisopropyl-
silylhenicosa-3,9,diene-1,11,13,18,20-pentayne (23). A solution of
1-triisopropylsilylundeca-1,3,8,10-tetrayne (9) (0.250 g, 0.84 mmol)
in degassed pyrrolidine (1 mL) was added to a solution of (1Z,7Z)-
1-bromo-10-[(3′-cyanopropyl)dimethylsilyl]deca-1,7-dien-9-yne (18)
(0.140 g, 0.42 mmol), PdCl2(PPh3)2 (0.030 g, 0.04 mmol), and CuI
(0.008 g, 0.04 mmol) in the same solvent (4 mL), and the reaction
mixture was stirred for 2 h. Saturated aqueous solution of NH4Cl
(20 mL) was then added, and the organic phase was extracted with
ether (3 × 20 mL). The ethereal fractions were washed with brine
(3 × 60 mL), dried over anhydrous Na2SO4, and concentrated. Flash
chromatography (hexane/ethyl acetate 90:10) afforded the title
compound (0.175 g, 76% yield) as a brown oil: 1H NMR (300
MHz, CDCl3) δ 0.22 (6H, s), 0.8-0.9 (2H, m), 1.0-1.1 (21H, m),
1.4-1.5 (4H, m), 1.7-1.8 (4H, m), 2.3-2.5 (10H, m), 5.49 (2H,
d, J ) 10.8 Hz), 5.98 (1H, dt, J ) 10.8, 7.5 Hz), 6.05 (1H, dt, J )
10.8, 7.5 Hz); 13C NMR (75 MHz, CDCl3) δ -1.6 (2 × CH3),
11.4 (3 × CH), 15.9 (CH2), 18.5 (CH2), 18.7 (6 × CH3), 18.9 (CH2),
20.6 (CH2), 20.7 (CH2), 26.9 (CH2), 28.2 (CH2), 28.4 (CH2), 30.3
(CH2), 30.6 (CH2), 66.1 (C), 66.7 (C), 72.4 (C), 77.1 (C), 77.9
(C), 80.6 (C), 83.1 (C), 89.7 (C), 96.4 (C), 103.3 (C), 108.1 (CH),
109.1 (CH), 119.6 (C), 145.5 (CH), 147.5 (CH); IR (CsI) ν 2244
(CtN), 2224, 2147, 2104 (CtC) cm-1; MS (CI) m/z 554 (MH+,
3), 510 (3), 279 (6), 167 (22), 149 (70), 126 (100); HRMS (CI)
calcd for C36H52NSi2 554.3638, found 554.3641.
(3Z,12Z,18Z)-Henicosa-3,12,18-triene-1,8,10,20-tetrayne
[Callyberyne B] (2). Following the same procedure described for
1, treatment of a solution of 31 (0.050 g, 0.09 mmol) in THF (1
mL) with n-Bu4NF (1.0 M in THF, 0.36 mL, 0.36 mmol) for 25
min afforded, after purification by flash chromatography (hexane/
ethyl acetate 95:5), the title compound (0.022 g, 90%) as a colorless
oil: 1H NMR (250 MHz, CDCl3) δ 1.4-1.5 (4H, m), 1.68 (2H, q,
J ) 7.3 Hz), 2.3-2.5 (8H, m), 3.09 (2H, t, J ) 2.8 Hz), 5.4-5.5
(3H, m), 5.9-6.1 (3H, m); 13C NMR (100 MHz, CDCl3) δ 19.2
(CH2), 27.4 (CH2), 28.1 (CH2), 28.2 (CH2), 29.4 (CH2), 30.0 (CH2),
30.4 (CH2), 65.6 (C), 72.2 (C), 78.2 (C), 80.1 (C), 80.4 (C), 81.3
(CH), 81.8 (CH), 84.2 (C), 108.2 (CH), 108.3 (CH), 109.3 (CH),
144.2 (CH), 145.7 (CH), 147.4 (CH); IR (CsI) ν 3294 (≡C-H),
2233, 2146 (CtC) cm-1; MS (CI) m/z 275 (MH+, 3), 181 (50),
179 (77), 156 (21), 155 (72), 92 (16), 91 (100), 79 (88); HRMS
(CI) calcd for C21H23 275.1800, found 275.1794.
(3Z,18Z)-1,21-Bis(triisopropylsilyl)henicosa-3,18-diene-1,8,10,-
20-tetrayne (38). To a well-stirred solution of (Z)-1-triisopropyl-
silylundec-3-ene-1,8,10-triyne (30) (0.050 g, 0.17 mmol) in THF
(0.30 mL), cooled at -78 °C, was added n-BuLi (1.6 M in hexanes,
0.10 mL, 0.16 mmol), and the mixture was allowed to react for 5
min at that temperature. It was then added, dropwise, to a solution
of (Z)-10-iodo-1-triisopropylsilyldec-3-en-1-ynol (37b) (0.030 g,
0.07 mmol), Pd2dba3‚CHCl3 (0.010 g, 0.01 mmol), and PPh3 (0.010
g, 0.04 mmol) in THF (0.20 mL), and the mixture was allowed to
react for 23 h at 65 °C. It was diluted with saturated aqueous
solution of NH4Cl (2 mL), and the organic phase was extracted
with Et2O (3 × 2 mL). The combined ethereal fractions were
washed with brine (2 × 5 mL), dried over anhydrous Na2SO4,
filtered, and concentrated. Purification by flash chromatography
(hexane) afforded the title compound (0.036 g, 86%) as a colorless
oil: 1H NMR (300 MHz, CDCl3) δ 1.0-1.1 (42H, m), 1.3-1.6
(8H, m), 1.6-1.7 (2H, m), 2.2-2.3 (4H, m), 2.36 (2H, dc, J )
1.2, 7.2 Hz), 2.45 (2H, dc, J ) 1.1, 7.4 Hz), 5.51 (1H, dt, J )
10.9, 1.2 Hz), 5.55 (1H, dt, J ) 10.9, 1.1 Hz), 5.93 (1H, dt, J )
(3Z,9Z)-Henicosa-3,9-diene-1,11,13,18,20-pentayne [Cally-
beryne A, Callypentayne] (1). To a solution of 23 (0.061 g, 0.11
mmol) in anhydrous THF (2 mL) was added n-Bu4NF (1.0 M
solution in THF, 0.36 mL, 0.36 mmol), and the mixture was allowed
to react for 5 h at room temperature. The mixture was diluted with
ether (3 mL), washed with brine (3 × 3 mL), dried over anhydrous
Na2SO4, and concentrated. Purification by flash chromatography
(42) The spectroscopic and physical data (1H NMR, 13C NMR) of the
synthetic compounds were found to be identical to those published for the
natural products (see refs 20 and 21).
J. Org. Chem, Vol. 71, No. 7, 2006 2809

Lo´pez et al.
10.9, 7.4 Hz), 5.95 (1H, dt, J ) 10.9, 7.2 Hz); 13C NMR (75 MHz,
CDCl3) δ 11.4 (6 × CH), 18.8 (12 × CH3), 19.0 (CH2), 19.3 (CH2),
27.8 (CH2), 28.3 (CH2), 28.7 (2 × CH2), 28.8 (CH2), 29.7 (CH2),
30.2 (CH2), 65.3 (C), 65.6 (C), 76.8 (C), 77.6 (C), 94.7 (C), 95.4
(C), 103.4 (C), 103.8 (C), 109.6 (CH), 110.6 (CH), 143.1 (CH),
144.8 (CH); IR (CsI) ν 2146 (CtC) cm-1; MS (CI) m/z 589 (MH+,
28), 588 (M+, 18), 545 (50), 461 (12), 431 (11), 270 (22), 157
(100), 129 (50), 115 (89); HRMS (CI) calcd for C39H65Si2 589.4625,
found 589.4622.
(3Z,18Z)-Henicosa-3,18-diene-1,8,10,20-tetrayne (Callyberyne
C, Callytetrayne) (3). Following the same procedure as described
for 1, treatment of a solution of 38 (0.016 g, 0.028 mmol) in THF
(0.28 mL) with n-Bu4NF (1.0 M solution in THF, 0.12 mL, 0.12
mmol) for 1 h afforded, after purification by flash chromatography
(hexane), the title compound as a colorless oil (0.007 g, 89%
yield): 1H NMR (300 MHz, CDCl3) δ 1.3-1.6 (8H, m), 1.6-1.7
(2H, m), 2.2-2.4 (6H, m), 2.44 (2H, c, J ) 7.3 Hz), 3.08 (1H, d,
J ) 2.0 Hz), 3.10 (1H, d, J ) 2.1 Hz), 5.45 (1H, dd, J ) 11.0, 2.0
Hz), 5.49 (1H, dd, J ) 11.3, 2.1 Hz), 5.9-6.0 (2H, m); 13C NMR
(75 MHz, CDCl3) δ 18.9 (CH2), 19.3 (CH2), 27.6 (CH2), 28.3 (CH2),
28.6 (2 × CH2), 28.7 (CH2), 29.5 (CH2), 30.2 (CH2), 65.3 (C),
65.7 (C), 76.8 (C), 77.6 (C), 80.2 (C), 80.5 (C), 81.2 (CH), 81.7
(CH), 108.1 (CH), 109.1 (CH), 144.2 (CH), 145.8 (CH); IR (CsI)
ν 3293 (≡C-H), 2097 (CtC) cm-1; MS (CI) m/z 277 (MH+, 7),
276 (M+, 14), 251 (19), 233 (37), 219 (66), 205 (98), 193 (83),
179 (98), 155 (100), 129 (77), 91 (66); HRMS (EI) calcd for C21H24
276.1878, found 276.1884.
Acknowledgment. We thank the Ministerio de Ciencia y
Tecnolog´ıa and the European Regional Development Fund
(Project No. CTQ2005-08613) and the Xunta de Galicia (Project
No. PGIDT00PXI20901PR) for supporting this research.
Supporting Information Available: General methods, experi-
1
mental procedures for selected intermediates, and H-13C NMR
for all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO052609U
2810 J. Org. Chem., Vol. 71, No. 7, 2006