Two efficient four-step routes to marine toxin tanikolide

Article abstract of DOI:10.1016/j.tet.2005.06.098

We have presented two facile four-step syntheses of (±)-tanikolide from ethyl 2-oxocyclopentanecarboxylate. The overall chemical yields of the two sequences reached as high as 76 and 85%, respectively. The first strategy involved alkylation, Baeyer-Villiger reaction, saponification, and reduction/lactonization. The second approach for synthesizing tanikolide took advantage of the same intermediate, the alkylated ketoester 2, which was converted to the target molecule in such three steps as deethoxycarbonylation, hydroxymethylation, and Baeyer-Villiger reaction. Our strategies are advantageous because of their high yields and suitability for the preparation of 1 in multigram or larger quantities.

Full text of DOI:10.1016/j.tet.2005.06.098

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Tetrahedron 61 (2005) 8390–8393
Two efficient four-step routes to marine toxin tanikolide
Qingshou Chen,a Haibing Deng,a Jingrui Zhao,a Yong Lu,b Mingyuan Heb and Hongbin Zhaia,
*
aLaboratory of Modern Synthetic Organic Chemistry and State Key Laboratory of Bio-Organic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
bShanghai Key Laboratory of Green Chemistry and Chemical Processes (GCCP), Department of Chemistry, East China Normal University,
Shanghai 200062, People’s Republic of China
Received 28 March 2005; revised 20 June 2005; accepted 24 June 2005
Available online 18 July 2005
Abstract—We have presented two facile four-step syntheses of (G)-tanikolide from ethyl 2-oxocyclopentanecarboxylate. The overall
chemical yields of the two sequences reached as high as 76 and 85%, respectively. The first strategy involved alkylation, Baeyer–Villiger
reaction, saponification, and reduction/lactonization. The second approach for synthesizing tanikolide took advantage of the same
intermediate, the alkylated ketoester 2, which was converted to the target molecule in such three steps as deethoxycarbonylation,
hydroxymethylation, and Baeyer–Villiger reaction. Our strategies are advantageous because of their high yields and suitability for the
preparation of 1 in multigram or larger quantities.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
of (R)-(C)-tanikolide in six steps from propargyl alcohol.2b
Afterwards, two different nine-step approaches to the
synthesis of tanikolide in the racemic form were achieved
by Chen2c and Krauss,2d respectively; both of the syntheses
featured the use of a dihydroxylation and a Grignard
addition. The powerful ring closing metathesis (RCM)
transformation has found successful applications in forming
the d-lactone framework of tanikolide.2e,f More recently,
Koumbis and co-workers2g accomplished a 10-step enantio-
selective synthesis of (R)-(C)-tanikolide starting from
D-erythrose, a useful chiron.
As a wellspring of drugs and drug leads, natural products
have been one of the most rewarding scientific research
areas for decades. In particular, marine natural products,
perpetually provided by the oceans, have gained increasing
popularity owing to their various distinct structures and
bioactivities. Gerwick and co-workers1 reported in 1999, the
isolation and structural elucidation of (R)-(C)-tanikolide, a
brine-shrimp toxic and antifungal metabolite native to the
marine cyanobacterium Lyngbya majuscula collected from
Tanikeli Island. The biological assays of this new toxin
demonstrated an LD50 of 3.6 mg/mL against brine shrimp
and 9.0 mg/mL against the snail. Moreover, a 13-mm
diameter inhibition zone (100 mg/disk) was observed when
(R)-(C)-tanikolide was tested with the fungus Candida
albicans.1 Due to the presence of a tertiary carbon center in
the d-lactone framework and the unique bioactivity, the
synthesis of tanikolide has aroused considerable interests
from the synthetic community.2 Ogasawara accomplished
an enantioselective synthesis of (R)-(C)-tanikolide in 12
steps from a known 1,2-enediol bis-silyl ether, where a
kinetic resolution based on a ruthenium-promoted catalytic
asymmetric hydrogen transfer reaction was utilized as a key
step.2a It was the remarkable optically active allene strategy
that enabled Nelson to realize the asymmetric total synthesis
Even nowadays, formulating a highly efficient synthetic
strategy for constructing biosignificant natural products
remains a tremendous challenge. The chemical community
is more willing than ever to show concern for ‘(reaction)
step economy’ in organic synthesis. In our case, a suitable
cyclopentanone derivative was envisioned as an excellent
starting point to develop synthetic avenues to tanikolide
with high efficacy. We now wish to provide a full account of
our findings regarding the syntheses of this new marine
toxin.3
Keywords: Tanikolide; Syntheses; Marine natural product.
*
Corresponding author. Tel.: C86 21 54925163; fax: C86 21 64166128;
e-mail: zhaih@mail.sioc.ac.cn
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.098

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8391
2. Results and discussion
We have developed two shorter and more efficient syntheses
of tanikolide (1). Our first synthesis,2h as outlined in
Scheme 1, commenced from the commercially available ethyl
2-oxocyclopentanecarboxylate, which was alkylated4a–c
with 1-bromoundecane in the presence of K2CO3 and KI
in refluxing anhydrous acetone for 20 h to furnish the known
intermediate4d 2 in 100% yield. Baeyer–Villiger oxidation
of 2 under typical conditions5 (MCPBA, NaHCO3,
anhydrous CHCl3, rt) led to lactone 3 (88%), in which the
monooxygenated tertiary carbon center was in place. With 3
in hand, selective reduction of the ethoxycarbonyl group in
the presence of the lactone moiety was attempted. Mild
reduction with NaBH(OAc)3 effected no reaction at all.
Treatment of 3 with excess NaBH4 in ethanol at rt for
30 min gave a ring-opened dihydroxyester, which indicated
that the lactone carbonyl was actually more reactive toward
borohydride reduction than the ethoxycarbonyl moiety. If
the above reaction mixture was heated at reflux for 1 h, a
triol was formed as a result of extensive reduction. After
several unfruitful trials, we resorted to a different strategy
that involved effecting the reduction at a later stage. Saponi-
fication6 of 3 with LiOH$H2O in THF/H2O (1:1) at K2 8C
for 4 h followed by acidification with 6 M HCl generated
the hydroxydiacid monoester 4 in almost quantitative yield
(99%). Under the reaction conditions, the ethoxycarbonyl
group was kept intact because of steric hindrance. Finally,
monoester 4 was treated with the NaBH4/CaCl2/KOH
reduction system7 to afford, after lactonization during the
acidic workup with 6 M HCl, tanikolide (1) in good yield
(87%). No reaction took place when NaBH4/CaCl2 (i.e., in
the absence of KOH) or NaBH4 alone was used instead. The
spectroscopic data of our synthetic sample of tanikolide (1)
were in accord with those reported previously.1,2
Scheme 2.
selective hydroxymethylation at C-2 took place to produce
aldol 6 with a quaternary carbon center in excellent yield
(95%, based on consumed 5).9 For this step, longer reaction
time proved detrimental to the outcome by allowing the
formation of the bis-and tris-hydroxymethylation byproducts.
Under the same Baeyer–Villiger oxidation conditions as for
2, the desired ring expansion was effected to transform 6
into (G)- tanikolide (1) in 93% yield.
3. Conclusion
In summary, we have presented two facile four-step syntheses
of (G)-tanikolide from ethyl 2-oxocyclopentanecarboxylate.
The features of the current work are as follows. (i) The
overall chemical yields of the two sequences reached as
high as 76 and 85%, respectively. (ii) The first strategy
involved alkylation, Baeyer–Villiger reaction, saponifica-
tion, and reduction/lactonization. Each step proceeds in
better than 87% yield. In addition, the net result of the last
two steps (i.e., saponification and reduction/lactonization)
is an efficient reduction of the ethoxycarbonyl of 3 while
keeping the lactone carbonyl intact. The alternative in situ
protection (LDA)–reduction (LiAlH4) strategy10 worked
with the analogues of 2 (though the chemical yields were
not so impressive, ranging from 5310c to 64%10b) and should
presumably also do with 3, but no doubt is difficult to scale
up. (iii) The second approach for synthesizing tanikolide
took advantage of the same intermediate 2 but avoided the
step of borohydride reduction in basic media. The alkylated
ketoester 2 was converted to the target molecule (1) in such
three steps as deethoxycarbonylation, hydroxymethylation,
and Baeyer–Villiger reaction. (iv) Our strategies are
advantageous because of their high yields and suitability
for the preparation of 1 in multigram or larger quantities.
4. Experimental
Scheme 1.
4.1. General
Next, an alternative, convenient approach for synthesizing
tanikolide emerged that took advantage of the same
intermediate 2 but avoided the step of calcium borohydride
(generated in situ from NaBH4 and CaCl2) reduction in
basic (KOH) media. Deethoxycarbonylative hydrolysis of 2
in refluxing concentrated HCl–HOAc (5:3, v/v) for 2 days
cleanly afforded 2-(n-undecyl)cyclopentanone8 (5) in 96%
yield (Scheme 2). Upon treatment of 5 in methanol with
formalin (105 mol%) and KOH (110 mol%) at 0 8C for 2 h,
Melting points were determined on an XT-4 apparatus and
are uncorrected. NMR spectra were recorded in CDCl3 (1H
at 300 MHz and 13C at 75.47 MHz) using TMS as the
internal standard. Column chromatography was performed
on silica gel. Acetone and CHCl3 were distilled over P2O5
and CaH2, respectively, prior to use. IR, MS, and elemental
analyses were conducted by the Analytical Laboratory at
Shanghai Institute of Organic Chemistry.

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Q. Chen et al. / Tetrahedron 61 (2005) 8390–8393
4.2. Ethyl2-oxo-1-(n-undecyl)cyclopentanecarboxylate(2)
NMR (CDCl3) d 0.88 (t, JZ6.8 Hz, 3H), 1.00–1.15 (m, 2H),
1.25–1.33 (m, 19H), 1.44–1.50 (m, 2H), 1.61–1.82 (m, 4H),
2.33–2.39 (m, 2H), 3.28 (br s, 1H), 4.25 (q, JZ7.2 Hz, 2H);
13C NMR (CDCl3) d 14.0, 14.2, 18.8, 22.6, 23.3, 29.3, 29.4,
29.4, 29.6 (very strong), 31.8, 33.8, 38.3, 39.2, 61.9, 77.2,
176.6, 179.3 (only 17 peaks shown in the spectrum). Anal.
Calcd for C19H36O5: C, 66.24; H, 10.53. Found: C, 66.32; H,
10.51.
In a dried 50-mL three-necked round-bottomed flask fitted
with a condenser and an addition funnel were placed K2CO3
(4.01 g, 29.0 mmol) and KI (0.68 g, 4.1 mmol). A solution
of ethyl 2-oxocyclopentanecarboxylate (1.90 mL,
12.8 mmol) in anhydrous acetone (30 mL) was added via
the addition funnel. After 10 min, a solution of
1-bromoundecane (2.88 mL, 12.9 mmol) in acetone
(8 mL) was added and the mixture was rapidly brought to
reflux by heating in an oil bath. After 20 h, the resultant
mixture was cooled to rt, diluted with Et2O (50 mL), and
filtered. The filtrate was concentrated at the reduced
pressure, diluted with ether, washed in succession with
water and brine, dried over MgSO4, filtered, and concen-
trated. The residue was chromatographed (SiO2, petroleum
ether–EtOAc, gradient, 100:1 to 60:1) to give 2 (3.97 g,
4.5. 2-(n-Undecyl)cyclopentanone (5)
To a mixture of 2 (1.998 g, 6.44 mmol) in HOAc (15 mL)
was added concentrated HCl (25 mL). The mixture was
rapidly brought to reflux by heating in an oil bath. After 48 h
the volatiles were evaporated at the reduced pressure. The
residue was diluted with saturated aqueous NaHCO3
solution and extracted with ether. The combined organic
layers were washed in succession with saturated aqueous
NaHCO3 solution and brine, dried over MgSO4, filtered, and
concentrated to give 5 (1.47 g, 96%) as a pale yellow oil: IR
1
100%) as a pale yellow oil: IR lmax 1725, 1747 cmK1; H
NMR (CDCl3) d 0.88 (t, JZ6.6 Hz, 3H), 1.20–1.32 (m,
21H), 1.53–1.56 (m, 1H), 1.86–2.00 (m, 4H), 2.22–2.28 (m,
1H), 2.37–2.55 (m, 2H), 4.12–4.20 (m, 2H); 13C NMR
(CDCl3) d 14.0, 14.0, 19.6, 22.6, 24.7, 29.3, 29.3, 29.5, 29.6,
29.8, 31.8, 32.6, 33.8, 38.0, 60.5, 61.2, 171.0, 215.1; (only
18 peaks shown in the spectrum); EI-MS: m/z (%) 310
(MC), 157 (61), 156 (100), 110 (100), 97 (64), 67 (58), 55
(93), 43 (85), 41 (80). Anal. Calcd for C19H34O3: C, 73.50;
H, 11.04. Found: C, 73.57; H, 11.36.
1
(film) lmax 1741 cmK1; H NMR (CDCl3) d 0.88 (t, JZ
7.2 Hz, 3H), 1.21–1.38 (m, 19H), 1.45–1.58 (m, 1H), 1.69–
1.84 (m, 2H), 1.94–2.10 (m, 2H), 2.14 (td, JZ9.8, 1.2 Hz,
1H), 2.18–2.25 (m, 1H), 2.30 (dt, JZ18, 1.2 Hz, 1H); 13C
NMR (CDCl3) d 14.1, 20.7, 22.6, 27.5, 29.3, 29.5, 29.6,
29.6, 29.6, 29.6, 29.6, 29.6, 31.9, 38.2, 49.2, 220.2; EI-MS:
m/z (%) 238 (MC), 238 (15), 156 (25), 97 (21), 84 (100), 83
(16), 55 (16), 43 (12), 41 (17). EI-HRMS: Calcd for
C16H30O 238.2297. Found: 238.2282.
4.3. 5-Ethoxycarbonyl-5-(n-undecyl)-d-valerolactone (3)
A solution of 2 (3.836 g, 12.36 mmol) in anhydrous CHCl3
(100 mL) was treated with NaHCO3 (1.922 g, 22.88 mmol)
and MCPBA (70%, 4.288 g, 17.39 mmol). The mixture was
stirred at rt for 20 h, diluted with saturated aqueous
NaHCO3 solution (120 mL), vigorously stirred for 15 min,
and extracted with CH2Cl2. The combined organic layers
were washed in succession with water and brine, dried over
Na2SO4, filtered, and evaporated at the reduced pressure.
The yellowish residue was chromatographed (SiO2,
petroleum ether–EtOAc, gradient, 20:1 to 10:1) to give 3
4.6. 2-(Hydroxymethyl)-2-(n-undecyl)cyclopentanone (6)
To a mixture of 5 (223 mg, 0.935 mmol) and KOH (58 mg,
1.0 mmol) in MeOH (2.5 mL) at 0 8C was slowly added
formalin (containing 37% HCHO, 80 mg, 0.98 mmol). The
mixture was stirred at 0 8C for 2 h, and the pH was adjusted
to 6–7 with 1 M HCl. The volatiles were evaporated under
the reduced pressure. The residue was diluted with EtOAc,
washed in succession with saturated aqueous NaHCO3
solution and brine, dried over MgSO4, filtered, and
concentrated. The residue was purified by chromatography
(SiO2, petroleum ether–EtOAc, gradient, 10:1 to 6:1) to give
recovered 5 (139 mg, 62%) and 6 (90 mg, 36%, or 95%
(3.53 g, 88%) as a colorless oil: IR (film) lmax 1750 cmK1
;
1H NMR (CDCl3) d 0.89 (t, JZ6.6 Hz, 3H), 1.19–1.34 (m,
19H), 1.61–2.21 (m, 8H), 2.43–2.64 (m, 2H), 4.23–4.31 (m,
2H); 13C NMR (CDCl3) d 14.0, 14.1, 17.0, 22.6, 22.8, 28.6,
29.2, 29.2, 29.4, 29.4, 29.5, 30.4, 31.8, 38.6, 61.8, 86.0,
170.2, 171.9 (only 18 peaks shown in the spectrum); EI-MS:
m/z (%) 326 (MC), 253 (100), 225 (44), 97 (22), 71 (22), 57
(35), 55 (76), 43 (57), 41 (46). Anal. Calcd for C19H34O4: C,
69.90; H, 10.50. Found: C, 70.04; H, 10.58.
based on consumed 5). 6: IR (film) lmax 3435, 1734 cmK1
;
1H NMR (CDCl3) d 0.88 (t, JZ6.6 Hz, 3H), 1.08–1.35 (m,
18H), 1.35–1.55 (m, 2H), 1.86–1.99 (m, 4H), 2.24–2.40 (m,
2H), 2.72 (br s, 1H, OH), 3.48 (d, JZ11.1 Hz, 1H), 3.64 (d,
JZ11.1 Hz, 1H); 13C NMR (CDCl3) d 14.0, 19.1, 22.6,
24.0, 29.3, 29.4, 29.5, 29.5, 29.6, 30.2, 30.5, 31.8, 32.4,
38.8, 53.4, 65.6, 224.7; EI-MS: m/z (%) 269 (MC1, 96),
114 (100), 96 (38), 95 (26), 68 (27), 55 (31),43 (28), 41 (43).
MALDI-HRMS: Calcd for C17H32NaO2 (MC Na)
291.2300. Found: 291.2295.
4.4. 2-Hydroxy-2-(n-undecyl)hexanedioic acid 1-ethyl
ester (4)
To a cold (K2 8C) mixture of 3 (220 mg, 0.674 mmol) and
THF/H2O (1:1, 8 mL) was added LiOH$H2O (32.5 mg,
0.774 mmol). The mixture was stirred for 4 h at K2 8C,
made acidic (pHZ2–3) with 6 M HCl, and extracted with
CHCl3. The combined organic layers were dried (MgSO4),
and the volatiles were evaporated to give 4 as a solid mass
(230 mg, 99%). The crude product was sufficiently pure and
used directly in the next reaction. Chromatography (SiO2,
petroleum ether–EtOAc, gradient, 3:1 to 1:1) furnished the
analytical sample of 4 as a colorless solid: mp 71–72 8C; 1H
4.7. Tanikolide (1)
Method A (Prepared from 4). A mixture of KOH (130 mg,
2.32 mmol), CaCl2 (516 mg, 4.65 mmol) and 4 (200 mg,
0.580 mmol) in anhydrous EtOH (10 mL) was cooled to
0 8C, then NaBH4 (176 mg, 4.65 mmol) was added in one
portion. The reaction mixture was stirred for 26 h at rt,
cooled to 0 8C, made acidic (pHZca. 1) with 6 M HCl,
evaporated, diluted with water, saturated with solid NaCl,

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Q. Chen et al. / Tetrahedron 61 (2005) 8390–8393
8393
2. For total synthesis of tanikolide, see: (a) Kanada, R. M.;
Taniguchi, T.; Ogasawara, K. Synlett 2000, 1019–1021. (b)
Wan, Z.; Nelson, S. G. J. Am. Chem. Soc. 2000, 122,
10470–10471. (c) Chang, M.-Y.; Lin, C.-L.; Chen, S.-T.
J. Chin. Chem. Soc. 2001, 48, 787–794. (d) Krauss, J. Nat.
Prod. Lett. 2001, 15, 393–399. (e) Mizutani, H.; Watanabe, M.;
Honda, T. Tetrahedron 2002, 58, 8929–8936. (f) Carda, M.;
Rodriguez, S.; Castillo, E.; Bellido, A.; Diaz, O. S.; Marco,
J. A. Tetrahedron 2003, 59, 857–864. (g) Koumbis, A. K.;
Dieti, K. M.; Vikentiou, M. G.; Gallos, J. K. Tetrahedron Lett.
2003, 44, 2513–2516. (h) Zhai, H.; Chen, Q.; Zhao, J.; Luo, S.;
Jia, X. Tetrahedron Lett. 2003, 44, 2893–2894.
and extracted with CHCl3. The combined organic layers
were dried (MgSO4), set aside for 14 h, and concentrated.
The residue was chromatographed (SiO2, petroleum ether–
EtOAc, 1:1) to provide 1 (144 mg, 87%) as a colorless oil.
Method B (Prepared from 5). A solution of 5 (62 mg,
0.23 mmol) in anhydrous CHCl3 (3 mL) was treated with
NaHCO3 (29 mg, 0.34 mmol) and MCPBA (70%, 86 mg,
0.35 mmol). The mixture was stirred at rt for 4 h, diluted
with saturated aqueous NaHCO3 solution, vigorously stirred
for 15 min, and extracted with CH2Cl2. The combined
organic layers were washed in succession with water and
brine, dried over MgSO4, filtered, and concentrated at the
reduced pressure. The residue was chromatographed (SiO2,
petroleum ether–EtOAc, 1:1) to provide 1 (61 mg, 93%) as a
3. Our preliminary results were communicated as a Letter, as
described in Ref. 2h.
4. For alkylation of ketoesters, see: (a) Venton, D. L.; Enke, S. E.;
Le Breton, G. C. J. Med. Chem. 1979, 22, 824–830. (b)
Williams, T. R.; Sirvio, L. M. J. Org. Chem. 1980, 45,
5082–5088. (c) Teixeira, L. H. P.; Barreiro, E. J.; Fraga, C. A.
M. Synth. Commun. 1997, 27, 3241–3257. (d) The alkylation
product 2 was reportedly synthesized in 55% yield from
the sodium salt of ethyl 2-oxocyclopentanecarboxylate.
Maillard, A.; Deluzarche, A.; Rudloff, A. Compt. Rend.
1995, 240, 317–319. Chem. Abstr. 1956, 50, 1615e.
5. For Baeyer–Villiger reaction, see: Nishimura, Y.; Mori, K.
Eur. J. Org. Chem. 1998, 2, 233–236.
1
colorless oil: IR (film) lmax 3424, 1721 cmK1; H NMR
(CDCl3) d 0.88 (t, JZ6.6 Hz, 3H), 1.21–1.33 (m, 18H),
1.61–1.97 (m, 6H), 2.46–2.51 (m, 2H), 2.78 (br s, 1H, OH),
3.55 (dd, JZ12.0, 2.1 Hz, 1H), 3.66 (dd, JZ12.0, 2.1 Hz,
1H); 13C NMR (CDCl3) d 14.0, 16.5, 22.5, 23.2, 26.5, 29.2,
29.3, 29.4, 29.4, 29.5, 29.6, 29.8, 31.7, 36.7, 67.1, 86.5,
172.2; EI-MS: m/z (%) 253 (MK31, 90), 225 (43), 129 (26),
71 (32), 57 (48), 55 (70), 43 (100), 41 (60). Anal. Calcd for
C17H32O3: C, 71.79; H, 11.34. Found: C, 71.64; H, 10.98.
6. For ester saponification, see: White, J. D.; Amedio, J. C., Jr.;
Gut, S.; Ohira, S.; Jayasinghe, L. R. J. Org. Chem. 1992, 57,
2270–2284.
Acknowledgements
We thank the following agencies for financial support:
National Natural Science Foundation of China; Science &
Technology Commission of Shanghai Municipality
(‘Venus’ Program); GCCP of ECNU.
7. Alexandre, F.; Legoupy, S.; Huet, F. Tetrahedron 2000, 56,
3921–3926.
8. Robertson, J.; Burrows, J. N.; Stupple, P. A. Tetrahedron
1997, 53, 14807–14820.
9. For a procedure of ketone a-hydroxymethylation, see: Cho, Y. S.;
Carcache, D. A.; Tian, Y.; Li, Y. M.; Danishefsky, S. J. J. Am.
Chem. Soc. 2004, 126, 14358–14359.
References and notes
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4262–4263. (b) Matsuo, K.; Kinuta, T.; Tanaka, K. Chem.
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Xie, Z.-F.; Sakai, K. Chem. Pharm. Bull. 1988, 36, 4337–4344.
1. For isolation of tanikolide, see: Singh, I. P.; Milligan, K. E.;
Gerwick, W. H. J. Nat. Prod. 1999, 62, 1333–1335.