Synthesis and stability of a homologous series of triynol natural products and their analogues

Article abstract of DOI:10.1021/jo061588g

A series of polyyne natural products 1, 13, and 31 and analogues 14, 21, and 22 are synthesized in six steps. The key step is a Fritsch-Buttenberg- Wiechell rearrangement in which a triyne framework is formed from the appropriate dibromoolefin precursor.

Full text of DOI:10.1021/jo061588g

larvicidal properties12 and cytotoxicity toward a range of cell
lines.13 Although polyynes are commonly found in nature,
obtaining them pure and in significant quantities is often difficult
due to their kinetic instability, particularly in the case of terminal
polyynes and longer derivatives such as triynes, tetraynes, and
pentaynes.14
Polyyne natural products featuring an alcohol moiety are
frequently encountered, and these molecules also offer the
possibility of derivatization through reaction at oxygen. Over
the years, a number of metal-catalyzed hetero- and homocou-
pling reactions have been developed for the formation of
polyynols, and the most commonly used method is the Cadiot-
Chodkiewicz cross-coupling.15-17 For example, compound 1 has
been synthesized by Pre´vost et al.,18 using the cross-coupling
of diyne 2 with bromoalkyne 3 (eq 1). However, the requisite
starting material 2 and others like it are often difficult to obtain
pure and in good yield.19 Because of these challenges, a
carbenoid Fritsch-Buttenberg-Wiechell (FBW) rearrangement
has been developed as an alternative method for the formation
of biologically interesting polyynes.20-24
Synthesis and Stability of a Homologous Series of
Triynol Natural Products and Their Analogues
Thanh Luu and Rik R. Tykwinski*
Department of Chemistry, UniVersity of Alberta, Edmonton,
Alberta T6G 2G2, Canada
rik.tykwinski@ualberta.ca
ReceiVed July 31, 2006
A series of polyyne natural products 1, 13, and 31 and
analogues 14, 21, and 22 are synthesized in six steps. The
key step is a Fritsch-Buttenberg-Wiechell rearrangement
in which a triyne framework is formed from the appropriate
dibromoolefin precursor. Terminal conjugated triynes 13 and
14 are obtained as highly unstable products that rapidly
decompose under ambient conditions. The stability of triynols
increases via either the addition of methylene units (i.e., 6
f 31 f 1) or addition of terminal substituents (i.e., 13 f
21 or 31).
Toward the development of new polyynes and their deriva-
tives, we report herein on the formation and chemical stability
of conjugated triynols as a function of structure. Using the FBW
Naturally occurring polyynes (also called polyacetylenes)
have been isolated from a wide variety of plants, fungi, bacteria,
and sponges.1-6 They have proven to be important biologically
active compounds that can be used as antibacterial,7,8 antimi-
crobial,9,10 antifungal, and antiviral agents;11 they also exhibit
(12) Arnason, J. T.; Philoge`ne, B. J. R.; Berg, C.; MacEachern, A.;
Kaminski, J.; Leitch, L. C.; Morand, P.; Lam, J. Phytochemistry 1986, 25,
1609-1611.
(13) Ito, A.; Cui, B.; Cha´vez, 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.
(14) For recent examples of syntheses, see: (a) Mukai, C.; Miyakoshi,
N.; Hanaoka, M. J. Org. Chem. 2001, 66, 5875-5880. (b) Lo´pez, S.;
Ferna´ndez-Trillo, F.; Mido´n, P.; Castedo, L.; Saa´, C. J. Org. Chem. 2005,
70, 6346-6352. (c) Gung, B. W.; Kumi, G. J. Org. Chem. 2004, 69, 3488-
3492. (d) Kim, S.; Kim, S.; Lee, T.; Ko, H.; Kim, D. Org. Lett. 2004, 6,
3601-3604.
* To whom correspondence should be addressed. Fax: (780) 492-8231.
(1) Shi Shun, A. L. K.; Tykwinski, R. R. Angew. Chem., Int. Ed. 2006,
45, 1034-1057.
(2) Chemistry and Biology of Naturally Occurring Acetylenes and Related
Compounds (NOARC); Lam, J., Breteler, H., Arnason, T., Hansen, L., Eds.;
Elsevier: New York, 1988.
(3) Bohlmann, F.; Burkhardt, H.; Zdero, C. Naturally Occurring
Acetylenes; Academic Press: New York, 1973.
(4) Jones, E. R. H.; Thaller, V. The Chemistry of the Carbon-Carbon
Triple Bond; Patai, S., Ed.; John Wiley & Sons: New York, 1978; Part 2,
Chapter 14.
(5) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep,
M. R. Nat. Prod. Rep. 2003, 20, 1-48.
(6) Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1-49.
(7) Tsuge, N.; Mori, T.; Hamano, T.; Tanaka, H.; Shin-ya, K.; Seto, H.
J. Antibiot. 1999, 52, 578-581.
(8) Young, K.; Jayasuriya, H.; Ondeyka, J. G.; Herath, K.; Zhang, C.;
Kodali, S.; Galgoci, A.; Painter, R.; Brown-Driver, V.; Yamamoto, R.;
Silver, L. L.; Zheng, Y.; Ventura, J. I.; Sigmund, J.; Ha, S.; Basilio, A.;
Vicente, F.; Tormo, J. R.; Pelaez, F.; Youngman, P.; Cully, D.; Barrett, J.
F.; Schmatz, D.; Singh, S. B.; Wang, J. Antimicrob. Agents 2006, 50, 519-
526.
(15) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int.
Ed. 2000, 39, 2633-2657.
(16) Sonogashira, K. Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; Wiley-VCH: New York, 2002; pp
493-529.
(17) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere,
A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004.
(18) Pre´vost, S.; Meier, J.; Chodkiewicz, W.; Cadiot, P.; Villemart, A.
Bull. Soc. Chim. Fr. 1961, 2171-2175.
(19) Brandsma, L. PreparatiVe Acetylenic Chemistry, 2nd ed.; Elsevier:
Amsterdam, 1988; pp. 46-47.
(20) Shi Shun, A. L. K.; Tykwinski, R. R. J. Org. Chem. 2003, 68, 6810-
6813.
(21) Eisler, S.; Chahal, N.; McDonald, R.; Tykwinski, R. R. Chem. Eur.
J. 2003, 9, 2542-2550.
(9) Kobaisy, M.; Abramowski, Z.; Lermer, L.; Saxena, G.; Hancock, R.
E. W.; Towers, G. H. N.; Doxsee, D.; Stokes, R. W. J. Nat. Prod. 1997,
60, 1210-1213.
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J. Org. Chem. 2003, 68, 1339-1347.
(10) Fusetani, N.; Toyoda, T.; Asai, N.; Matsunaga, S.; Maruyama, T.
J. Nat. Prod. 1996, 59, 796-797.
(23) Luu, T.; Shi, W.; Lowary, T. L.; Tykwinski, R. R. Synthesis 2005,
3167-3178.
(11) Rashid, M. A.; Gustafson, K. R.; Cardellina, J. H.; Boyd, M. R.
Nat. Prod. Lett. 2001, 15, 21-26.
(24) Morisaki, Y.; Luu, T.; Tykwinski, R. R. Org. Lett. 2006, 8, 689-
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10.1021/jo061588g CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/13/2006
8982
J. Org. Chem. 2006, 71, 8982-8985

rearrangement as a key step, a homologous series of polyynes
terminated with a proton, methyl, or phenyl moiety has been
synthesized, including three natural products and three ana-
logues. The stability of these compounds as a function of the
terminal group and the length of the methylene tether to the
alcohol moiety has been explored in comparison with the three
model triynols 4, 5, and 6.23
Exhaustive desilylation of triynes 19 and 20 to give terminal
triynes 13 and 14 was more challenging than anticipated. Using
typical conditions, for example, triyne 20 was dissolved in wet
THF at 0 °C and TBAF was slowly added while the progress
of desilylation was monitored by TLC. Addition of Et2O and
aqueous NH4Cl, however, resulted in an intractable, insoluble
black precipitate, suggesting that the deprotected polyynol 14
decomposed during workup. All attempts to spectroscopically
determine the structure of the decomposition product(s) have
been unsuccessful. Adding a small amount of benzene to the
THF solution before the addition of TBAF helped prevent this
decomposition. TLC analysis showed that the desilylation was
quite efficient, and after quenching and workup, crude 14 was
purified on neutral alumina oxide. Upon concentration, however,
decomposition once again occurred and identification was
limited to IR and crude NMR spectroscopic analysis; no yield
could be determined. The IR data for crude 14 were consistent
with those reported by Bohlmann,28 who synthesized 14 via the
Cadiot-Chodkiewicz coupling of butadiyne and 5-bromo-4-
pentynol (no yield was reported). Chemoselective desilylation
(TBDPS versus TIPS) was also attempted but was not success-
ful. For example, the slow addition of TBAF (0.5 equiv) to a
solution of 20 in THF at either 0 or -10 °C revealed that
indiscriminant desilylation took place at both silyl groups. The
use of the desilylation reagent KF was also explored29 and gave
results similar to those obtained with TBAF.
The formation of 13 via desilylation of 19 with either TBAF
or KF was also attempted under a number of conditions, and
the results were similar to that obtained with 20. Product 13
was insufficiently stable to be concentrated to dryness, although
NMR and IR spectroscopy could be used to confirm its
formation. These results were similar to those of Tokimoto et
al., who extracted 13 from the neutral culture of Lentinus edodes
after the attack of Trichoderma polysporum30 and reported that
the triynol could be purified via preparative TLC on silica.31
The observed instability of 13 and 14 to the conditions of
purification and isolation mirrors that of the shorter homologue,
natural product 4, which has been identified and isolated from
Ramaria flaVa by Jones and co-workers.32 Thus, with only a
terminal proton, it is concluded that triynols are kinetically
unstable species regardless of the number of methylene groups
linking the alcohol moiety.
Aldehydes 7 and 8 were the targeted precursors and could
be achieved by two different methods (Scheme 1). Starting with
the known precursors 925 or 10,26 deprotonation with BuLi in
THF generated the lithium acetylide, which was then reacted
with DMF to produce either 7 or 8 in moderate yield.
Unfortunately, this transformation was often accompanied by
a side reaction that resulted from the addition of dimethyl amine
to the R,â-unsaturated product. To avoid the formation of this
byproduct, an alternative route was explored. Acetylene 9 or
10 was deprotonated with BuLi at -78 °C, followed by the
addition of excess paraformaldehyde to yield alcohols 11 and
12 in yields of 76% and 77%, respectively, as reported by Baltas
and co-workers.27 The alcohols were purified by column
chromatography and oxidized with BaMnO4 to give aldehydes
7 and 8 in good yield. The advantage of the latter route was
that the desired products were purified more easily than by the
former route, and the overall yield was also slightly higher.
SCHEME 1a
The effect of replacing a terminal proton of the triyne with
a phenyl group was then examined through the formation of
triynols 21 and 22 (Scheme 3), which are homologues of
compound 5, a natural product isolated from species of
Bidens.33,34 Thus, alcohols 23 and 24 were formed in good yield
from the reaction of lithium phenylacetylide with the appropriate
aldehyde 7 or 8. The sequence of oxidation with BaMnO4 to
ketones 25 and 26 and dibromoolefination to give 27 and 28
a Reagents and conditions: (a) BuLi, THF, -78 °C, then DMF; (b) BuLi,
THF, -78 °C, then paraformaldehyde; (c) BaMnO4, CH2Cl2, rt.
With access to aldehydes 7 and 8, terminal triynol natural
products 13 and 14 were targeted (Scheme 2). The reaction of
iPr3SiCtCLi with the appropriate aldehyde at low temperature
produced alcohols 15 and 16 in excellent yield (ca. 90%),
following workup and column chromatography. Oxidation of
the alcohols with BaMnO4 gave the corresponding ketones,
which were carried on following workup to dibromoolefination
to yield adducts 17 and 18. The conversion of the dibromoolefins
to triynes 19 and 20 was effected via the FBW reaction with
BuLi in hexanes at -78 °C.
(28) Bohlmann, F.; Herbst, P.; Gleinig, H. Chem. Ber. 1961, 94,
948-957.
(29) Stang, P. J.; Ladika, M. Synthesis 1981, 29-30.
(30) Tokimoto, K.; Fujita, T.; Takeda, Y.; Takaishi, Y. Proc. Jpn. Acad.
1987, 63, 277-280.
(31) Characterization by 1H NMR spectroscopy and HRMS was de-
scribed, but confirmation of the terminal CtC-H by IR spectroscopy was
not reported.
(32) Hearn, M. T. W.; Jones, E. R. H.; Pellatt, M. G.; Thaller, V.; Turner,
J. L. J. Chem. Soc., Perkin Trans. 1 1973, 2785-2788.
(33) Bohlmann, F.; Arndt, C.; Kleine, K.-M.; Wotschokowsky, M. Chem.
Ber. 1965, 98, 1228-1232.
(34) Bohlmann, F.; Bornowski, H.; Kleine, K.-M. Chem. Ber. 1964, 97,
2135-2138.
(25) Dineen, T. A.; Roush, W. R. Org. Lett. 2003, 5, 4725-4728.
(26) Baldwin, J. E.; Romeril, S. P.; Lee, V.; Claridge, T. D. W. Org.
Lett. 2001, 3, 1145-1148.
(27) Nacro, K.; Baltas, M.; Gorrichon, L. Tetrahedron 1999, 55, 14013-
14030.
J. Org. Chem, Vol. 71, No. 23, 2006 8983

SCHEME 2a
a Reagents and conditions: (a) iPr3SiCtCLi, THF, -78 °C; (b) BaMnO4, CH2Cl2, rt; (c) CBr4, PPh3, CH2Cl2, 0 °C; (d) BuLi, hexanes, -78 °C; (e)
TBAF, THF, 0 °C.
SCHEME 3a
a Reagents and conditions: (a) PhC≡CLi, THF, -78 °C; (b) BaMnO4, CH2Cl2, rt; (c) CBr4, PPh3, CH2Cl2, 0 °C; (d) BuLi, hexanes, -78 °C; (e) TBAF,
THF, rt. NA: the crude product was carried to the next step.
SCHEME 4a
a Reagents and conditions: (a) MeCtCLi, THF, -78 °C; (b) BaMnO4, CH2Cl2, rt; (c) CBr4, PPh3, CH2Cl2, 0 °C; (d) BuLi, hexanes, -78 °C; (e) TBAF,
THF, rt.
was accomplished in excellent yield. Although 25 and 26 were
reasonably stable intermediates that could be isolated without
problem, higher yields were obtained when the crude products
were taken on directly to the dibromoolefination step. FBW
rearrangement of each dibromoolefin with BuLi provided triynes
29 and 30 in excellent yield, and the desired triynols 21 and 22
were cleanly formed from 29 and 30, respectively, via desily-
lation with TBAF. In contrast to terminal triynes 4, 13, and 14,
the phenyl derivatives 21 and 22 are kinetically stable to
isolation under ambient conditions, as has been reported for 5.23
Furthermore, the isolated oils can be stored indefinitely under
refrigeration. It is quite clear that the phenyl end-capping groups
have a stabilizing effect for the triynols, irrespective of the length
of the methylene linker.
peronata, first by Higham35 and later from cultures of Lentinus
edodes by Tokimoto,30 as well as triynol 1, which was extracted
from the culture fluids of Psathyrella scobinacea by Taha36 and
from Tridax trilobata by Bohlmann.37 The shortest homologue
6 has been obtained from neutral fractions of cultures of the
sheathed Kuehneromyces mutabilis, Psilocybe merdaria, and
Ramaria flaVa.32 Toward the formation of 1 or 31, the reaction
of aldehyde 7 or 8 with MeCtCLi in THF produced alcohols
32 and 33 in good yields. These intermediate products were
oxidized with BaMnO4 to produce the corresponding ketones,
and dibromoolefination provided the precursors 34 and 35.
Rather modest yields were obtained in the two-step process,
(35) Higham, C. A.; Jones, E. R. H.; Keeping, J. W.; Thaller, V. J. Chem.
Soc., Perkin Trans. 1 1974, 1991-1994.
(36) Taha, A. A. Phytochemistry 2000, 55, 921-926.
(37) Bohlmann, F.; Zdero, C.; Weickgenannt, G. Liebigs Ann. Chem.
1970, 739, 135-143.
Numerous methyl terminated polyynes have been identified
as naturally occurring species.1 This includes compound 31
(Scheme 4), which was isolated from the fungus Collybia
8984 J. Org. Chem., Vol. 71, No. 23, 2006

1
3:1). H NMR (400 MHz, CDCl3) δ 7.66-7.63 (m, 4H), 7.44-
amounting to an average of ca. 60% per step. FBW rearrange-
ment yielded the triynol frameworks of 36 and 37, and liberation
of the alcohol moieties with TBAF in THF produced the free
alcohols 31 and 1. Similar to 6,23 triynol 31 was obtained as a
colorless crystalline solid that turned pink when exposed to light
at room temperature. By contrast, compound 1 remained a white,
crystalline solid under ambient conditions, with a melting point
of 68 °C, showing that the stability of the triynols improves to
some extent as a function of the number of methylene units, a
useful fact for constructing triynols for further elaboration.23
The synthesis of a series of conjugated triynols (13, 14, 21,
22, 31, and 1) has been accomplished, and their stabilities were
compared to those of three known propargylic analogues,
triynols 4, 5, and 6. It is determined that the kinetic stability of
these compounds can be generalized by three factors: (a)
terminal triynols (4, 13, and 14) are unstable regardless of the
number of methylene groups, (b) replacement of the terminal
acetylenic proton with a methyl or phenyl group affords
increasingly more stable products, and (c) within the series of
methyl-endcapped derivatives, more methylene groups is better.
Further elaboration of these and related triynols at oxygen
through the formation of esters, ethers, and carbohydrates is
underway.23
7.35 (m, 6H), 3.70 (t, J ) 6.0 Hz, 2H), 2.43 (t, J ) 6.8 Hz, 2H),
1.75 (tt, J ) 6.8 Hz, 6.0 Hz, 2H), 1.94 (s, 3H), 1.03 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 135.4, 133.5, 129.5, 127.5, 78.5, 74.7,
65.8, 64.9, 61.9, 60.3, 59.7, 30.8, 26.7, 19.1, 15.8, 4.4; IR
(microscope) 3071, 2956, 2221, 1111 cm-1; EIMS m/z 384.2 (M+,
1), 327.1 ([M - t-Bu]+, 100); HRMS calcd for C22H19OSi ([M -
t-Bu]+) 327.1205, found 327.1203.
General Desilylation Procedure. Synthesis of 3,5,7-Nonatriyn-
1-ol (31). To 36 (233 mg, 0.629 mmol) in wet THF (10 mL) was
added TBAF (0.94 mL, 1.0 M in THF, 0.94 mmol). The reaction
was stirred at room temperature until TLC analysis showed that
desilylation had taken place. Et2O (10 mL) and saturated aqueous
NH4Cl (10 mL) were added. The organic phase was separated,
washed with saturated aqueous NaCl (2 × 10 mL), and dried over
MgSO4. Solvent removal and purification by column chromatog-
raphy (CH2Cl2) afforded 31 (80 mg, 96%) as a white crystalline
solid that turned purple when exposed to light. Mp: 55-57 °C
(lit. 63.5-64 °C).35 Rf ) 0.3 (CH2Cl2). 1H NMR (500 MHz, CDCl3)
δ 3.74 (t, J ) 6.0 Hz, 2H), 2.54 (t, J ) 6.0 Hz, 2H), 1.93 (s, 3H),
1.67 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 75.4, 75.3, 67.5,
64.8, 61.2, 60.6, 59.3, 23.8, 4.5; IR (microscope) 3347, 3264, 2933,
2218, 2036(w), 1055 cm-1; HRMS calcd for C9H8O (M+) 132.0575,
found 132.0577. Spectral data were consistent with those re-
ported.30,35
4,6,8-Decatriyn-1-ol (1). Reaction of 37 (331 mg, 0.861 mmol)
in wet THF (10 mL) with TBAF (1.3 mL, 1.0 M in THF, 1.3 mmol)
as decribed above gave 1 (125 mg, 99%) as a white crystalline
Experimental Section
solid. Mp: 65-68 °C (lit. 68-70.5 °C).38 Rf ) 0.2 (CH2Cl2). H
1
General Procedure for FBW Rearrangement. Synthesis of
1-(tert-Butyldiphenylsilanyloxy)-3,5,7-nonatriyne (36). To 34
(488 mg, 0.920 mmol) in dry hexanes (10 mL) at -78 °C was
added dropwise BuLi (2.5 M in hexanes; 0.45 mL, 1.13 mmol).
The reaction was stirred at -78 °C for 30 min, and then warmed
to room temperature for 30 min. Et2O (10 mL) and saturated
aqueous NH4Cl (10 mL) were added. The organic phase was
separated, washed with saturated aqueous NaCl (2 × 10 mL), and
dried over MgSO4. Solvent removal and purification by column
chromatography (hexanes) afforded 36 (260 mg, 76%) as a colorless
NMR (500 MHz, CDCl3) δ 3.72 (t, J ) 6.0 Hz, 2H), 2.40 (t, J )
7.0 Hz, 2H), 1.77 (app. quintet, J ) 6.5 Hz, 2H), 1.40 (br s, 1H),
1.93 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 78.1, 75.1, 66.1, 64.9,
61.3, 60.7, 59.6, 30.8, 15.9, 4.5; IR (microscope) 3335, 2901, 2221,
1060 cm-1; HRMS calcd for C10H10O (M+) 146.0732, found
146.0735. Spectral data were consistent with those reported.36,38
Acknowledgment. This work has been generously supported
by the University of Alberta and the Natural Sciences and
Engineering Research Council of Canada (NSERC) through the
Discovery grant program. T.L. thanks the University of Alberta
for a Dissertation Fellowship.
1
oil. Rf ) 0.6 (hexanes/CH2Cl2, 3:1). H NMR (300 MHz, CDCl3)
δ 7.67-7.63 (m, 4H), 7.45-7.34 (m, 6H), 3.75 (t, J ) 6.6 Hz,
2H), 2.51 (t, J ) 6.6 Hz, 2H), 1.93 (s, 3H), 1.04 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 135.4, 133.2, 129.6, 127.6, 75.9, 74.9, 66.7,
64.8, 61.7, 60.5, 59.5, 26.6, 23.4, 19.1, 4.35; IR (microscope) 3071,
2932, 2222, 1112 cm-1; HRMS calcd for C25H26OSi (M+)
370.1753, found 370.1760.
Supporting Information Available: Experimental procedures
and spectroscopic data for compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
1-(tert-Butyldiphenylsilanyloxy)-4,6,8-decatriyne (37). Reac-
tion of 35 (586 mg, 1.08 mmol) in dry hexanes (10 mL) at -78 °C
with BuLi (2.5 M in hexanes; 0.52 mL, 1.30 mmol) as above gave
37 (342 mg, 83%) as a colorless oil. Rf ) 0.5 (hexanes/CH2Cl2,
JO061588G
(38) Bew, R. E.; Chapman, J. R.; Jones, E. R. H.; Lowe, B. E.; Lowe,
G. J. Chem. Soc. 1966, 129-135.
J. Org. Chem, Vol. 71, No. 23, 2006 8985