Total synthesis of (±)tanikolide

Article abstract of DOI:10.1081/SCC-120005428

A total synthesis of (±)tanikolide 1 is described. The six-membered lactone moiety of the title compound was completed through oxidation of α,δ-dihydroxyl compound by PDC.

Full text of DOI:10.1081/SCC-120005428

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TOTAL SYNTHESIS OF (±)TANIKOLIDE
Ruzhou Zhang a , Zhiqin Wang a , Fengping Wei b & Yongren Huang b
a Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu,
Shanghai, 200032, China
b Key Laboratory of Education Ministry for Optical and Magnetic Resonance Spectroscopy,
Easy China Normal University, Shanghai, 200062, China
To cite this article: Ruzhou Zhang , Zhiqin Wang , Fengping Wei & Yongren Huang (2002) TOTAL SYNTHESIS OF (±)TANIKOLIDE,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:14,
2187-2194, DOI: 10.1081/SCC-120005428
To link to this article: http://dx.doi.org/10.1081/SCC-120005428
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 14, pp. 2187–2194, 2002
TOTAL SYNTHESIS OF (1)TANIKOLIDE
2
,
y
Zhiqin Wang,1 Fengping Wei,2,
Ruzhou Zhang,1,
*
*
and Yongren Huang2
1Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Lu,
Shanghai 200032, China
2Key Laboratory of Education Ministry for Optical and
Magnetic Resonance Spectroscopy, Easy China Normal
University, Shanghai 200062, China
ABSTRACT
A total synthesis of (ꢀ)tanikolide 1 is described. The
six-membered lactone moiety of the title compound was
completed through oxidation of ꢀ,ꢁ-dihydroxyl compound
by PDC.
Key Words: Tanikolide; Lactonization; Synthesis
INTRODUCTION
The Cyanobacteria (blue–green algae) are an exciting source of
novel bioactive natural products, many structurally diverse metabolites
exhibit
a a new
rich variety of biological activity.[1] Recently,
*Corresponding authors.
yE-mail: zhangrz_1999@yahoo.com
2187
DOI: 10.1081/SCC-120005428
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

2188
ZHANG ET AL.
Figure 1. The structure of (R)-tanikolide.
brine-shrimp toxic and antifungal compound, (þ)tanikolide 1 has been
isolated from the lipid extract of a Madagascan collection of the marine
cyanobacterium Lyngbya majuscula by Gerwick et al.[2] (Figure 1).
The structure of tanikolide and its absolute configuration at C-5 was
determined as R by 1H NMR analysis of its derivatives. Quickly,
Ogasawara et al.[3] reported the total synthesis of (þ)tanikolide by employ-
ing a catalytic asymmetric hydrogen transfer reaction as the key step. Trost
finished the total synthesis of (À)malyngolide by using the deracemization of
3-nonyl-3,4-epoxybut-1-ene with Pd(0) in the presence of chiral N, P-ligand
as key step.[4] Herein, we report a new route to (ꢀ)tanikolide.[5]
RESULTS AND DISCUSSION
The synthesis began with monobenzylation of 1,5-pentanediol 2,
followed by oxidation of the primary alcohol 3 to give 5-benzyloxypentanal
4 in 73%, then treated with undecyl magnesium bromide to afford 1-benzyl-
oxy-5-hexadecanol 5 in 66% (Scheme 1), After oxidation of 5 with PDC, the
transformation of 1-benzyloxy-5-hexadecanone 6 to the corresponding com-
pound 7 was achieved by reacting with triphenylmethylphosphonium iodide
in the presence of potassium tert-butoxide in THF (99% yield).[6]
Asymmetric dihydroxylation with AD-mix-ꢀ or AD-mix-ꢂ of 7
afforded diol 8 in excellent yield, but the ee. of the products is very low.
Maybe the substrate don’t match with catalyst,[7] so we decide to finish the
total synthesis of (ꢀ)tanikolide, firstly.
Dihydroxylation of 7 with OsO4/NMO gave diol 8 in 79%,
then monobenzoylation of the primary alcohol of 8 afforded 2-(n-undecy)-
6-benzyloxy-l-benzoyloxy-2-hexanol 9 in 97%. Alcohol 9 was converted to
2-(n-undecy)-1-benzoyloxy-2,6-hexanediol 10 by hydrogenation. In selective
oxidation and lactonization of the ꢀ,ꢁ-diol of 10, conventional Fetizon
reagents (Ag2CO3/Celite)[8] treatment resulted in unsatisfactory yields of
the 6-(n-undecyl)-6-benzoyloxymethyl-2-pyraone 11. Upon treatment with
PDC in methylene dichloride, however, 11 was obtained in high yield (80%).
Removal of the benzoyl group furnished (ꢀ)tanikolide 1. It’s spectroscopic

TOTAL SYNTHESIS OF (1)TANIKOLIDE
2189
2
Scheme 1. Reagents and conditions: a. BnCl/NaOH, rt, 50%; b. PCC,73%; c.
n-C11H23MgBr, 66%; d. PDC,71%; e. CH3PþPhIꢀ/tBuOK, 99%; f. OsO4/NMO,
79%; g. BzCl/Py, ꢀ 60ꢁC to rt, 97%; h. 10% Pd/C, H2, 1 atm., 86%; i. PDC, 80%;
j. NaCN(cat.)/MeOH, 93%.
data (IR, 1H NMR, 13C NMR and Mass) were virtually identical with those
reported.
In summary, (ꢀ)tanikolide 1 was synthesized in an efficient way. The
asymmetric synthesis of (þ)tanikolide 1 is in progress.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian AM-90 and a Brucker
AM-300-spectrometer using CDCl3 or CCl4. 13C NMR was reported at
75 MHz (Brucker AM-300). All chemical shifts (ꢁ) were reported relative
to TMS. Mass spectra were recorded on an HP5989 A mass spectrometer.
IR spectra and EA was recorded on a Perkin-Elmer 983 and Italian Carlo-
Erba 1106, respectively. TLC was performed on precoated plates of silica gel
HF254 (0.5 mm, Yantai, China). Flash column chromatography was carried
out on silica gel (300–400 mesh, Yantai, China).

2190
ZHANG ET AL.
5-Benzyloxy-1-pentanol (3)
To a stirred solution of 2 (10 g, 96 mmol) and NaOH (4.8 g, 120 mmol)
in DMSO (30 mL) was added benzyl chloride (12.2 g, 96 mmol) slowly. The
resulting mixture was stirred at rt for additional 6 h and then poured into
ice-water (300 mL), extracted with EtOAc (3 Â 50 mL). The organic layer
was washed with water, brine, dried over Na2SO4 and concentrated
in vacuo. The residue was purified by flash chromatography to give a color-
less oil 3 (9.3 g, 50%). ꢁH (90 MHz, CCl4): 7.50–7.10 (m, 5H), 4.48 (s, 2H),
3.70–3.30 (m, 4H), 1.80–1.30 (m, 6H).
5-Benzyloxy-pentanal (4)
A solution of 3 (4.0 g, 20.6 mmol) in CH2Cl2 (15 mL) was added to a
solution of PCC (13 g, 3 equiv.) in CH2Cl2 (100 mL). The reaction mixture
was stirred at rt for 1 h. The upper phase was separated and the precipitate
was washed with CH2Cl2. The combined organic phase was concentrated
in vacuo and purified by flash chromatography to afford 4 (2.9 g, 73%). ꢁH
(90 MHz, CCl4): 9.83 (s, 1H, -CHO), 7.50–7.0 (m, 5H), 4.50 (s, 2H, PhCH2-),
3.48 (t, J ¼ 6.0 Hz, 2H, BnO-CH2-), 2.60–2.20 (m, 2H, -CH2CHO), 2.0–1.45
(m, 4H).
1-Benzyloxy-5-hexadecanol (5)
A solution of 4 (1.35 g, 7.0 mmol) in Et2O (20 mL) was added dropwise
to a solution of n-undecyl magnesium bromide [9.6 mmol in Et2O (15 mL)]
at 0ꢁC under stirring. After being stirred for 30 min at this temperature, the
resulting mixture was stirred at rt for additional 1 h and quenched by satu-
rated aqueous NH4Cl solution. The organic phase was separated and the
aqueous phase was extracted with EtOAc (100 mL). The combined organic
phase was washed with brine, dried over anhy. Na2SO4 and concentrated
under reduced pressure. The residue was purified by flash chromatography
to provide a colorless oil 5 (1.6 g, 66%). ꢃmax: 3402 (w, OH), 2928 (s), 2855
(s), 1455 (s), 1363 (m), 1102 (s), 967 (m), 734 (s), 697 (s). ꢁH: 7.47–7.20
(m, 5H, Ar-H), 4.51 (s, 2H, PhCH2-), 3.58 (m, IH, CHOH), 3.48 (t,
J ¼ 6.2 Hz, 2H, BnOCH2-), 2.12–1.88 (m, 2H), 1.75–1.57 (m, 2H),
1.57–1.15 (m, 22H), 0.89 (t, J ¼ 6.5 Hz, 3H, -CH3). m/z (%): 349 (Mþþ1,
0.36), 313 (3.5), 239 (10), 107 (23), 91 (100). Anal. C23H40O2. Calcd: C,
79.25; H, 11.57. Found: C, 79.33; H, 11.32.

TOTAL SYNTHESIS OF (1)TANIKOLIDE
2191
2
1-Benzyloxy-5-hexadecanone (6)
PDC (623 mg, 2 equiv.) was added in one portion to a solution of 5
(277 mg, 079 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred
for 24 h at rt. and filtered on Celite. The solvent was evaporated under
reduced pressure. The residue was purified by flash chromatography to pro-
vide 6 (195 mg, 71%). ꢃmax: 2918 (s), 2850 (s), 1700 (s), 1469 (s), 1455 (m), 1126
(s), 730 (s), 694 (s). ꢁH: 7.41–7.25 (m, 5H, Ar-H), 4.49 (s, 2H, PhCH2-), 3.47
(t, J ¼ 6.1 Hz, 2H, BnOCH2-), 2.42 (t, J ¼ 6.8 Hz, 2H, -CH2CO-), 2.37
(t, J ¼ 7.5 Hz, 2H, -COCH2-), 1.75–1.49 (m, 6H,), 1.40–1.19 (m, 16H),
0.88 (t, J ¼ 6.2 Hz, 3H, -CH3). m/z (%): 347 (Mþ þ 1, 4.35), 255 (4.8), 239
(50), 107 (8), 91 (100). Anal. C23H38O2. Calcd: C, 79.71; H, 11.05. Found:
C, 79.68; H, 10.97.
Compound 7
Triphenylmethylphosphonium iodide (1.l g, 4 equiv.) was suspensioned
in THF (10 mL) and cooled to 0ꢁC. Solid BuOK(273 mg, 4 equiv.) was
t
added and the resulting mixture was stirred for 30 min before ketone 6
(240 mg, 0.61 mmol) in THF (3 mL) was added at same temperature.
Stirring was continued for another 30 min at this temperature, and then,
the reaction mixture was quenched with saturated aqueous NH4Cl solution.
The biphase layer was separated and the aqueous phase was extracted with
EtOAc (50 mL). The combined organic phase was washed in sequence with
water and brine, dried over Na2SO4 and concentrated in vacuo. The crude
product was purified by flash chromatography to afford 7 (236 mg, 99%).
ꢃmax: 2927 (s), 2855 (s), 1455 (br), 1362 (m), 1105 (w), 887 (m), 733 (m), 697
(m). ꢁH: 7.40–7.23 (m, 5H, Ar-H), 4.70 (s, 2H, ¼CH2-), 4.50 (s, 2H,
PhCH2-), 3.48 (t, J ¼ 6.4 Hz, 2H, OCH2-), 2.10–1.93 (m, 4H, -CH2-),
1.71–1.47 (m, 4H, -CH2-), 1.47–1.19 (m, 18H), 0.88 (t, J ¼ 6.2 Hz, 3H,
-CH3). m/z (%): 344 (Mþ, 3.10), 263 (29), 253 (16), 235 (20), 145 (8), 109
(21), 95 (33), 91 (100). Anal. C24H40O. Calcd: C, 83.66; H, 11.70. Found:
C, 83.69; H, 11.32.
Diol (8)
To a cooled (0ꢁC) stirred solution of NMO (22 mg, 1.1 equiv.) in
acetone (2 mL) was added a solution of OSO4 [2 mg, 0.2 mL solution of
tBuOH/H2O (1/1)]. Stirring was continued for additional 15 min at 0ꢁC.

2192
ZHANG ET AL.
Olefin 7 (38 mg, 0.11 mmol) in acetone (l mL) was added to the above men-
tioned solution and the resulting mixture was stirred at rt. for 9 h and then
quenched with Na2SO3 (100 mg) under stirring for 30 min. The mixture was
extracted with EtOAc. The organic phase was washed with water, brine,
dried over anhy. Na2SO4, and concentrated in vacuo. The residue was
purified by flash chromatography to give alcohol 8 (33 mg, 79%). ꢃmax
:
3404 (w), 2926 (s), 2854 (s), 1455 (s), 1103 (br), 733 (m), 697 (m). ꢁH:
7.45–7.21 (m, 5H, Ar-H), 4.50 (s, 2H, PhCH2-), 3.49 (t, J ¼ 6.2 Hz, 2H,
BnOCH2-), 3.42 (s, 2H, -CH2OH), 2.20 (s, 1H, OH), 2.0 (s, 1H, OH),
1.78–1.57 (m, 2H), 1.57–1.10 (m, 24H), 0.88 (t, J ¼ 5.9 Hz, 3H, -CH3). m/z
(%): 347 (Mþ -CH2OH, 0.95), 239 (16), 205 (3), 107 (5), 91 (100). Anal.
C24H42O3. Calcd: C, 76.14; H, 11.18. Found: C, 76.14; H, 11.00.
2-(n-Undecyl)-6-benzoyloxy-1-benzoyloxy-2-hexanol (9)
Pyridine (0.13 mL, 5 equiv.) and PhCOCl (38 ul, l equiv.) in CH2Cl2
(2 mL) was added successively to a stirred solution of 8 (126 mg,
0.33 mmol) in CH2Cl2 (8 mL) at À60ꢁC. The resulting mixture was allowed
to warm to rt. and stirred for 4 h at this temperature. After quenching with
saturated aqueous NH4Cl, this mixture was diluted with EtOAc. The organic
phase was separated and the aqueous phase was extracted with EtOAc. The
combined organic phase was washed with water, brine, dried over Na2SO4
and concentrated. The residue was purified by flash chromatography (PE :
acetone ¼ 5 : 1) to afford 9 (155 mg, 97%). ꢃmax: 3480 (w), 2927 (s), 2855 (s),
1723 (s), 1453 (m), 1274 (s), 1114 (s), 1027 (m), 711 (s). ꢁH: 8.10–7.97 (m, 2H,
Ar-H), 7.63–7.53 (m, 1H, Ar-H), 7.53–7.37 (m, 2H, Ar-H), 7.37–7.23 (m, 5H,
OAr-H), 4.50 (s, 2H, PhCH2-), 4.25 (s, 2H, BzO-CH2-), 3.50 (t, J ¼ 6.2 Hz,
2H, BnOCH2-), 1.92 (s, 1H, -OH), 1.73–1.43 (m, 4H), 1.43–1.10 (m, 22H),
0.88 (t, J ¼ 6.2 Hz, 3H, -CH3). m/z (%): 465 (1.61), 343 (23.45), 239 (34), 219
(19), 105 (69), 91 (100). Anal. C31H46O4. Calcd: C, 77.14; H, 9.60. Found:
C, 76.82; H, 9.41.
2-(n-Undecyl)-1-benzoyloxy-2,6-hexanediol (10)
9 (155 mg, 0.32 mmol) and Pd/C (10%, 15 mg) was added to EtOAc
(10 mL) and the solution was reduced with hydrogen for 4h at room tem-
perature under a hydrogen pressure of 1 atm. The resulting mixture was
filtered, concentrated and the residue was purified by flash chromatography
to give diol 10 (108 mg, 86%). ꢃmax: 3378 (w), 2926 (s), 2855 (s), 1724 (s),
1452 (m), 1274 (s), 1116 (m), 1028 (m), 711(s). ꢁH: 8.10–7.95 (m, 2H, Ar-H),

TOTAL SYNTHESIS OF (1)TANIKOLIDE
2193
2
7.60–7.50 (m, 1H, Ar-H), 7.50–7.30 (m, 2H; Ar-H), 4.25 (s, 2H, BzO-CH2-),
3.66 (t, J ¼ 6.0 Hz, 2H, HOCH2-), 2.13 (brs, 2H, -OH), 1.70–1.37 (m, 8H),
1.37–1.13 (m, 18H), 0.86 (t, J ¼ 6.3 Hz, 3H, -CH3); ꢁc: 166.65, 133.16, 129.61,
128.46, 73.73, 69.79, 62.46, 36.90, 36.30, 33.0, 31.89, 30.18, 29.63, 29.60,
29.58, 29.53, 29.32, 23.36, 22.66, 19.42, 14.09. m/z (%): 393 (Mþ þ 1,
0.14), 375 (Mþ-H2O, 16), 253 (18), 239 (100), 219 (15), 105 (88), 97 (27);
Anal. C24H40O4: Calcd: C, 73.42; H, 10.72. Found: C, 73.17; H, 10.23.
6-(n-Undecyl)-6-benzoyloxymethyl-2-pyranone (11)
A solution of diol 10 (56 mg, 0.14 mmol ) and PDC (268 mg, 5 equiv.)
in CH2Cl2 (5 mL) was stirred overnight at room temperature, filtered on
Celite and concentration in vacuo. The residue was purified by flash chro-
matography to provide 11 (44 mg, 80%). ꢃmax: 2926 (s), 2855 (s), 1726 (s),
1452 (m), 1270 (s), 1116 (s), 711 (s); ꢁH: 8.13–7.97 (m, 2H, Ar-H), 7.69–7.52
(m, 1H, Ar-H), 7.52–7.39 (m, 2H, Ar-H), 4.38 (dd, J ¼ 11.6 Hz, 2H, -
CH2OBz), 2.53 (t, J ¼ 6.7 Hz, 2H, -CH2COO-), 2.01–1.53 (m, 6H),
1.53–1.35 (m, 2H), 1.35–1.20 (m, 16H), 0.88 (t, J ¼ 6.4 Hz, 3H, -CH3); ꢁc:
170.74, 166.05, 133.35, 129.68, 128.56, 83.96, 67.91, 37.90, 31.91, 29.89,
29.78, 29.62, 29.59, 29.52, 29.42, 29.33, 27.77, 23.15, 22.69, 16.70, 14.12.
m/z (%): 389 (Mþ þ 1, 12.51), 267 (3), 253 (89), 225 (63), 105 (100), 97 (10).
Anal. C24H36O4: Calcd: C, 74.19; H, 9.34. Found: C, 74.54; H, 9.46.
(1)Tanikolide (1)
2
A solution of 11 (80 mg, 0.2 mmol) and NaCN (33 mg, 0.07 mmol) in
MeOH (3 mL) was stirred for 5 h at room temperature and diluted with
EtOAc (20 mL). The resulting mixture washed with diluted FeCl3, water,
brine, dried over anhyd. Na2SO4 and evaporated under reduced pressure.
The residue was purified by flash chromatography to give (ꢀ)tanikolide 1
(53 mg, 93%). ꢃmax: 3395 (w), 2921 (s), 2851 (s), 1700 (s, C¼O), 1469 (m),
1264 (m), 1046 (m), 931 (m), 721 (m), 643 (m); ꢁH: 3.66 (d, J ¼ 11.9 Hz, 1H),
3.54 (d, J ¼ 11.9 Hz, 1H), 2.50–2.45 (m, 2H, OCOCH2-), 1.93–1.85 (m, 3H,
-CH2-), 1.75–1.67 (m, 3H), 1.37–1.17 (m, 18H), 0.88 (t, J ¼ 6.3 Hz, 3H,
-CH3); 13C: 171.9 (-COO-), 86.5, 67.5, 36.73, 31.9, 29.97, 29.78, 29.59,
29.57, 29.52, 29.44, 29.30, 26.65, 23.41, 22.65, 16.68, 14.07. m/z (%): 253
(100), 225 (51.8), 129 (27); Anal. C17H32O3: Calcd: C, 71.79; H, 11.34.
Found: C, 71.93, H, 10.88.

2194
ZHANG ET AL.
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Received in Japan March 26, 2001