A new, iterative strategy for the synthesis of unsymmetrical polyynes: Application to the total synthesis of 15,16-dihydrominquartynoic acid

Article abstract of DOI:10.1021/ol0484963

(Chemical Equation Presented) A new iterative strategy for the synthesis of unsymmetrically substituted polyynes has been developed. The starting bromoalkyne is homologated by one acetylene unit through palladium-catalyzed cross-coupling with a TIPS-prote

Full text of DOI:10.1021/ol0484963

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3601-3604
A New, Iterative Strategy for the
Synthesis of Unsymmetrical Polyynes:
Application to the Total Synthesis of
15,16-Dihydrominquartynoic Acid
Sanghee Kim,*,†,‡ Shinae Kim,†,‡ Taeho Lee,‡ Hyojin Ko,‡ and Deukjoon Kim†
College of Pharmacy, Seoul National UniVersity, San 56-1, Shilim, Kwanak,
Seoul 151-742, Korea, and Natural Products Research Institute, College of Pharmacy,
Seoul National UniVersity, 28 Yungun, Jongro, Seoul 110-460, Korea
pennkim@snu.ac.kr
Received July 30, 2004
ABSTRACT
A new iterative strategy for the synthesis of unsymmetrically substituted polyynes has been developed. The starting bromoalkyne is homologated
by one acetylene unit through palladium-catalyzed cross-coupling with a TIPS-protected terminal acetylene and a subsequent in situ one-pot
AgF-mediated desilylative bromination. The utility of this new synthetic method is demonstrated by its application to the total synthesis of
(S)-(E)-15,16-dihydrominquartynoic acid.
Unsymmetrically substituted conjugated diyne and polyyne
units continue to attract widespread interest because of their
unusual electrical, optical, and structural properties.1 In
addition to their potential applications in materials science,
they are also key structural moieties present within a large
number of natural products that exhibit a variety of interest-
ing biological activities.2 Consequently, the development of
efficient synthetic approaches toward these rigid units re-
mains an important challenge to synthetic organic chemists.1-3
The oxidative homocoupling of two different terminal
alkynes under CuI/CuII catalysis is not a suitable process for
the synthesis of unsymmetrically substituted 1,3-butadiynes
and polyynes, because this approach usually leads to the
simultaneous and rather predominant formation of the
corresponding symmetrical products. One solution to this
problem is the CuI-catalyzed cross-coupling of terminal
alkynes with 1-haloalkynes in the presence of a suitable
amine, i.e., the so-called Cadiot-Chodkiewicz coupling.4
This method has been used extensively for the preparation
of unsymmetrical diynes and polyynes; a number of varia-
tions have been developed, including palladium-catalyzed
heterocoupling reactions.3b,5 The major limitation of these
reactions, however, is that the vast majority of terminal
diynes and higher polyynes required as coupling partners or
(2) For a recent paper that includes a discussion of this topic, see: (a)
Heuft, M. A.; Collins, S. K.; Yap, G. P. A.; Fallis, A. G. Org. Lett. 2001,
3, 2883-2886. (b) Shi Shun, A. L. K.; Chernick, E. T.; Eisler, S.; Tykwinski,
R. R. J. Org. Chem. 2003, 68, 1339-1347.
(3) For recent reviews, see: (a) Hartung, R.; Paquette, L. Chemtracts
2002, 15, 106-116. (b) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew.
Chem., Int. Ed. 2000, 39, 2632-2657.
(4) Cadiot, P.; Chodkiewicz, W. In Chemistry of Acetylenes; Viehe, H.
G., Ed., Marcel Dekker: New York, 1969; pp. 597-647.
† College of Pharmacy.
‡ Natural Products Research Institute.
(1) (a) Ginsburg, E. J.; Gorman, C. B.; Grubbs, R. H. In Modern
Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH: Weinheim,
1995. (b) Brandsma, L. PreparatiVe Acetylenic Chemistry; Elsevier:
Amsterdam, 1988.
10.1021/ol0484963 CCC: $27.50
© 2004 American Chemical Society
Published on Web 08/26/2004

precursors of 1-haloalkynes are highly sensitive molecules
that are prone to rapid decomposition.1,2,6
mination of 3. Repeating this reaction sequence sequentially
would allow the rapid construction of polyyne systems.
Finally, cross-coupling with a monosubstituted acetylene or
another type of coupling partner should afford the desired
unsymmetrical polyyne 5. The key to the success of this
iterative scheme lies in the in situ one-pot desilylative bro-
mination, which avoids the complication encountered with
isolating sensitive terminal alkynes. One of the salient fea-
tures of this protocol is that it allows the preparation of even-
and odd-numbered polyynes10 by controlling the number of
iterations of the chain growth cycle.
The instability of terminal diynes and higher polyynes can
be circumvented, for the preparation of symmetrical polyynes,
by employing an in situ generation/dimerization protocol.2a,3,6c
In the case of unsymmetrical polyynes, the rather limited
synthetic approaches have been reviewed.3 For example,
Tykwinski and co-worker7 employed an alkylidene carbenoid
rearrangement toward the synthesis of naturally occurring
unsymmetrical polyynes. Their protocol eliminates the need
for unstable acetylenic precursors required for coupling
approaches. Gung and co-workers8 reported the successful
one-pot three-component Cadiot-Chodkiewicz reaction to
construct the unsymmetrical tetrayne unit. Very recently,
Gung9 also reported the successful preparation of an unsym-
metrical 1,3,5-polyyne ((S)-(E)-15,16-dihydrominquartynoic
acid) via an in situ generated terminal alkyne/cross-coupling
protocol. In addition, Mori and co-workers5b reported the
CuI-catalyzed cross-coupling of chloroalkynes with alkynyl-
silanes, which are generally more stable than their corre-
sponding terminal alkynes. Although this method seems to
be promising for the future preparation of unsymmetrical
higher polyynes, an appropriate combination of chloroalkynes
and alkynylsilanes is essential for clean formation of the
desired cross-coupled products. Herein we report an alterna-
tive protocol for the synthesis of unsymmetrical polyynes
that uses a two-step homologation sequence.
To test the feasibility of our approach, we conducted our
initial studies with the simple terminal alkyne 6 (Scheme
2). Conversion of alkyne 6 to the known bromoalkyne 711
Scheme 2. Synthesis of Unsymmetrical Polyynes
Scheme 1 depicts a general outline of our iterative pro-
tocol. We envisioned that the bromoalkyne 2, which can be
Scheme 1. General Iterative Protocol for Synthesis of
Unsymmetrical Polyynes
was achieved readily in good yield (82%) with AgNO3 and
NBS12 in acetone. At this point, we decided to employ bulky
(trialkylsilyl)acetylenes as the cross-coupling partners for the
homologation reactions because it had previously been
reported that trimethylsilyl (TMS) acetylene decomposes,
possibly by a desilylation pathway, under the basic conditions
of the coupling reaction such that no desired cross-coupling
product can usually be isolated.13 When we used the bulkier
triisopropylsilyl (TIPS) acetylene, the desired cross-coupling
product 8 was obtained under standard Cadiot-Chodkiewicz
obtained from the simple terminal alkyne 1, could be ho-
mologated by one acetylene unit through cross-coupling with
the trialkylsilylacetylene 4 and subsequent desilylative bro-
(5) (a) Alami, M.; Ferri, F. Tetrahedron Lett. 1996, 37, 2763-2766. (b)
Nishihara, Y.; Ikegashira, K.; Mori, A.; Hiyama, T. Tetrahedron Lett. 1998,
39, 4075-4078. (c) Sinclair, J. A.; Brown, H. C. J. Org. Chem. 1976, 41,
1078-1079. (d) Miller, J. A.; Zweifel, G. Synthesis 1983, 128-130. (e)
Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20, 3437-
3440. (f) Wityak, J.; Chan, J. B. Synth. Commun. 1991, 21, 977-979.
(6) (a) Haley, M. M.; Bell, M. L.; English, J. J.; Johnson, C. A.; Weakley,
T. J. R. J. Am. Chem. Soc. 1997, 119, 2956-2957. (b) Patel, G. N.; Chance,
R. R.; Turi, E. A.; Khanna, Y. P. J. Am. Chem. Soc. 1978, 100, 6644-
6649. (c) Haley, M. M.; Bell, M. L.; Brand, S. C.; Kimball, D. B.; Pak, J.
J.; Wan, W. B. Tetrahedron Lett. 1997, 38, 7483-7486.
(7) Shi Shun, A. L. K.; Tykwinski, R. R. J. Org. Chem. 2003, 68, 6810-
6813.
(8) (a) Gung, B. W.; Dickson, H. Org. Lett. 2002, 4, 2517-2519. (b)
Gung, B. W.; Kumi, G. J. Org. Chem. 2003, 68, 5956-5960.
(9) Gung, B. W.; Kumi, G. J. Org. Chem. 2004, 69, 3488-3492.
(10) For the synthesis of odd-numbered polyynes, see: Rubin, Y.; Lin,
S. S.; Knobler, C. B.; Anthony, J.; Boldi, A. M.; Diederich, F. J. Am. Chem.
Soc. 1991, 113, 6943-6946.
(11) (a) Hoshi, M.; Shirakawa, K. Synlett 2002, 1101-1104. (b) Abele,
E.; Rubina, K.; Abele, R.; Gaukhman, A.; Lukevics, E. J. Chem. Res., Synop.
1998, 618-619.
(12) (a) Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, H. Angew.
Chem., Int. Ed. Engl. 1984, 23, 727-729. (b) Basak, S.; Srivastava, S.; le
Noble, W. J. J. J. Org. Chem. 1987, 52, 5095-5099.
3602
Org. Lett., Vol. 6, No. 20, 2004

coupling conditions (CuCl, HONH2‚HCl, EtNH2, MeOH),
but only in modest yield (40%). However, under the modi-
fied Sonogashira conditions (Pd(PPh3)2Cl2, CuI, diisopro-
pylamine, THF),5f,14 the yield of the product was improved
to 88%.
Scheme 3. Total Synthesis of
(S)-(E)-15,16-Dihydrominquartynoic Acid
Our first attempts to effect the in situ one-pot desilylative
bromination of 8 used the standard NBS/AgNO3 conditions
developed by Isobe and co-workers for the conversion of
TMS-protected acetylenes to bromoacetylenes.15 Unfortu-
nately, these conditions led only to the recovery of the
starting material, presumably because of the increased
stability of the bulky silyl group. Consequently, we needed
to develop alternative conditions for the one-pot desilylative
bromination of bulkier (trialkylsilyl)acetylenes. We ex-
amined the use of different silver sources and solvents for
this reaction and found the results of using an AgF/NBS/
CH3CN system to be superior to those from the use of other
combinations. When using this system, the reaction occurred
at room temperature to give the desired bromodiyne 9 in
86% yield.
With the optimal reaction conditions in hand, we per-
formed the second iteration in the same manner as just
described. We encountered no difficulties when converting
bromodiyne 9 into bromotriyne 11 through this two-step
sequence. The palladium-catalyzed cross-coupling of 9 with
TIPS-acetylene provided TIPS-triyne 10 in 75% yield, and
the subsequent AgF-mediated desilylative bromination af-
forded bromotriyne 11 successfully in 77% yield.
The obtained bromotriyne 11 could be further converted
to TIPS-tetrayne 12 under the same cross-coupling reaction
conditions in 53% yield, implying that our iterative protocol
could be applicable to the synthesis of higher polyynes. The
iterative process can be terminated in a number of ways by
reactions with various coupling partners. For example, the
palladium-catalyzed cross-coupling of bromotriyne 11 with
2-penten-4-yn-1-ol (13) led to the formation of the unsym-
metrical tetrayne 14 in 50% yield.
We further demonstrated the utility of this iterative
protocol by applying it in the total synthesis of a polyacety-
lenic natural product, (S)-(E)-15,16-dihydrominquartynoic
acid16 (15, Scheme 3), which exhibits potent cytotoxic
activity against human hormone-dependent prostate and
ovarian cancer cell lines.
The starting material for our synthesis was the com-
mercially available 8-bromooctanoic acid (16). Treatment of
16 with an excess of lithium trimethylsilylacetylide at -78
°C furnished the known17 TMS-protected acetylene 17
smoothly in 72% yield, and then esterification with diazo-
methane gave 18 in nearly quantitative yield. In situ de-
silylative bromination of 18 to the known8a bromoacetylene
19 was achieved in 90% yield under standard NBS/AgNO3
conditions. With bromoacetylene 19 in hand, repeating the
two-step homologation sequence twice generated the desired
bromotriyne 20 readily in 47% overall yield. The cross-
coupling of 20 with a slight excess of the vinylstannane
(S)-2118 (>99% ee, 1.1 equiv), mediated by Pd(PPh3)4 and
CuI,19 gave enetriyne 22 successfully in 69% yield. Finally,
hydrolysis of methyl ester with LiOH afforded the (S)-(E)-
15,16-dihydrominquartynoic acid (15) in 90% yield, whose
spectroscopic data were in agreement with those reported in
the literature.9,16,20
In summary, we have developed a new iterative strategy
for the synthesis of unsymmetrically substituted polyynes
that uses a two-step homologation sequence. In this process,
the starting bromoalkyne is homologated by one acetylene
unit through palladium-catalyzed cross-coupling with a TIPS-
protected terminal acetylene followed by an in situ one-pot
AgF-mediated desilylative bromination. We have also ac-
complished the total synthesis of (S)-(E)-15,16-dihydrom-
inquartynoic acid from a simple stating material in high
overall yield. These results demonstrate that our approach
can be applied efficiently to the synthesis of various
unsymmetrical polyynes. Further developments and applica-
tions of this strategy are now under investigation.
(13) (a) Marino, J. P.; Nguyen, H. N. J. Org. Chem. 2002, 67, 6841-
6844. (b) Eastmond, R.; Walton, D. R. M. Tetrahedron 1972, 28, 4591-
4599. (c) Johnson, T. R.; Walton, D. R. M. Tetrahedron 1972, 28, 5221-
5236. (d) Eaborn, C.; Walton, D. R. M. J. Organomet. Chem. 1965, 4,
217-228.
(14) Sonogashira K. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; Wiley: New York, 2002; Vol. 1, pp
493-549.
(15) Nishikawa, T.; Shibuya, S.; Hosokawa, S.; Isobe, M. Synlett 1994,
485-486.
(16) Ito, A.; Cui, B. L.; Chavez, D.; Chai, H. B.; Shin, Y. G.; Kawanishi,
K.; 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.
(17) Robertson, J.; Burrows, J. N. Synthesis 1998, 63-66.
Acknowledgment. This research was supported by a
grant (PF0321201-01) from Plant Diversity Research Center
(18) Lee, T.; Kim, S. Tetrahedron: Asymmetry 2003, 14, 1951-1954.
(19) (a) Palmisano, G.; Santagostino, M. Tetrahedron 1993, 49, 2533-
2542. (b) Ma, Y.; Huang, X. Synth. Commun. 1997, 27, 3441-3447.
(20) The optical rotation value measured for the synthetic 15 {[R]D -32.2
(c 1.0 MeOH)} is higher than that of the natural product16 {[R]D -12.8 (c
0.05 MeOH)}.
Org. Lett., Vol. 6, No. 20, 2004
3603

of 21st Century Frontier Research Program funded by
Ministry of Science and Technology of Korean government.
1H NMR and 13C NMR spectra of compounds 12, 14, and
15. This material is available free of charge via the Internet
at http://pubs.acs.org.
Supporting Information Available: Full experimental
procedures and analytical data of compounds and copies of
OL0484963
3604
Org. Lett., Vol. 6, No. 20, 2004