Facile total synthesis of (±)-nimbiol

Article abstract of DOI:10.1002/jccs.200400075

A facile total synthesis of (±)-nimbiol 1 has been achieved. In order to decrease the dioxo byproduct 2a, an improved oxidation system of CrO₃/H₂O/HOAc/NaOAc was used.

Full text of DOI:10.1002/jccs.200400075

Journal of the Chinese Chemical Society, 2004, 51, 505-508
505
Facile Total Synthesis of (±)-Nimbiol
Zhen-Ting Dua (
Jun-Ying Maa (
Xue-Gong Shea (
), Guo-Ren Yuea,b
(
), An-Pai Lia (
),
), Tong-Xing Wua (
) and Xin-Fu Pana* (
),
)
aDepartment of Chemistry, National Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou, Gansu 730000, P. R. China
bDepartment of Chemistry, Hexi University, Zhangye, Gansu 734000, P. R. China
A facile total synthesis of (±)-nimbiol 1 has been achieved. In order to decrease the dioxo byproduct 2a,
an improved oxidation system of CrO3/H2O/HOAc/NaOAc was used.
Keywords: Abietane; Nimbiol; Diterpene; Steric hindrance.
INTRODUCTION
(±)-Nimbiol 1 is a member of the aromatic tricyclic
nimbiol to solve the A/B fusion configuration problem but it
involved too many steps.8 Meyer synthesized (±)-nimbiol
through a A®AB®ABC strategy by 14 steps in low yield.9
As an extension of our previous work,10,11 herein we report an
efficient total synthesis of (±)-nimbiol. The salient feature of
our approach lies in that the A/B ring was all trans fusion. At
the same time, if chiral starting material 6 was used, (+)-
nimbiol can be obtained correspondingly.
diterpenes1 and was isolated first from the trunk bark of
Melia azadirachta Linn, which is used as an antiseptic agent
and a medicine for curing a variety of skin diseases in rural
India.2 It is different from the other abietic diterpenes in that
the substituent at C-13 is a methyl group, not an isopropyl
group.3,4 As (±)-nimbiol bears a unique structure and modest
biological activities, it arouses the interest of chemists. Using
podocarpic acid as starting material, Bible and Wenkert gave
a partial synthesis to nimbiol.5,6 Fetizon and Delobelle gave
an approach to (±)-nimbiol, but their route had a fatal defect
in that the A/B ring configuration contained two ismoers.7
Very recently, Karpha described a total synthesis of (±)-
RESULTS AND DISCUSSION
As shown in Scheme I, based on the synthetic works
published before,10 through the synthetic route of AC®ABC,
the tricyclic compound 6 was obtained.10a,10b Through the lit-
Scheme I
OMe
CH3
OMe
OMe
CHO
OMe
CH2OH
11
13
10
i
ii
iii
14
3
6
4
5
OMe
O
OMe
OH
CHO
iv
O
O
2
2a
1
v
i: BuLi, THF, and then DMF, -78 °C; ii: NaBH4, MeOH, r.t. 1 h; iii: (a) MsCl, TEA, CH2Cl2, -20 °C; (b) LiAlH4, THF, reflux,
6 h; iv: CrO3/H2O/HOAc/NaOAc, r.t. 1.5 h; v: NaSEt, DMF, 130 °C

506 J. Chin. Chem. Soc., Vol. 51, No. 3, 2004
Du et al.
erature, if the chiral (S)-a-cyclocitral was used as starting
material, (5S,10S)-12-Methoxy-podocarpane-8,11,13-triene
6 can be obtained.11
EXPERIMENTAL
Melting points were measured on a Kofler apparatus
and were uncorrected. The 1H-NMR and 13C-NMR data were
recorded in CDCl3 solution with a Bruker AM-400 MHz
spectrometer. The chemical shifts are referenced on TMS in
ppm on the ‘d’ scale if not noted otherwise. Mass spectra
were reported on a HP-5988 mass spectrometer (EI).
In order to introduce a functionality at C-13, com-
pound 6 was treated with BuLi and subsequent DMF at -78
°C to afford the formylated product 5. After purification and
careful characterization of the resulting product, only the
C-13 formylated product was found; no C-11 formylated
product was observed. This result can be explained by steric
hindrance. As shown in Fig. 1 (The geometry was optimized
by semi-empirical quantum chemistry AM1 method in
HyperChem 6.0), the methyl group at C-10 held back the ap-
proach of the DMF molecule at very low temperatures.
Therefore, the DMF molecule was more favorable to
approach C-13 and led to compound 5. And this result is con-
sistent with the X-ray.12
(±)-12-Methoxy-13-formylpodocarpane-8,11,13-trene (5)
At argon, to a solution of 6 (820 mg, 3.2 mmol) in anhy-
drous THF (10 mL) was added BuLi in hexane (1.6 N, 2.2
mL) at -20 °C dropwise. The mixture was stirred for 1 h at this
temperature and another 3 h at room temperature, and then
the temperature of the reaction system was cooled to -78 °C.
Then anhydrous DMF (1.2 mL) was added to the above solu-
tion. The reaction mixture was stirred at this temperature for
2 h and then quenched with water and then extracted with
ether (3 × 50 mL). The combined organic layer was washed
with saturated NH4Cl, brine, and dried over anhydrous
MgSO4. The solvent was distilled in a vacuum, and the resi-
due was purified through chromatography to afford 5 (820
mg, 89%) as yellow oil. 1H-NMR: 0.93 (s, 3H), 0.95 (s, 3H),
1.20 (s, 3H), 1.26-1.65 (m, 6H), 1.70-1.94 (m, 3H), 2.80-2.94
(m, 2H), 3.88 (s, 3H), 6.88 (s, 1H), 7.49 (s, 1H), 10.36 (s, 1H).
13C-NMR: 18.74, 19.04, 21.52, 24.27, 27.52, 29.04, 33.07,
38.68, 41.34, 49.07, 49.70, 55.53, 107.23, 111.52, 128.78,
135.87, 158.81, 159.85, 189.30. MS (EI): 286 (M+, 100), 271
(70), 243 (6), 229 (25), 203 (70), 201 (56), 189 (69), 149 (36)
and 115 (28). Found: C, 79.66; H, 9.17. C19H26O2 requires C,
79.68; H, 9.15.
After reduction of compound 5 by NaBH4, the corre-
sponding alcohol 4 was obtained. This alcohol was protected
by methyl sulphonyl chloride in CH2Cl2 and triethylamine at
-20 °C. Compound 3 was readily available after the subse-
quent reduction of the above sulfonate by LiAlH4.
To obtain the C-7 oxo compound 2 in high yield, Jones’
oxidation system was used, but the ratio of dioxo 2a and com-
pound 2 is 1:4. This is mainly because the oxidizing ability of
Jones’ reagent was in harmony with the acidity of the system.
To decrease oxidizing ability of the Jones’ reagent, anhy-
drous sodium acetate and water was added carefully to buffer
the above system. Finally, the oxidation system of CrO3/
H2O/HOAc/NaOAc (90 mg/0.2 mL/1 mL/80 mg) was used.
Through this ameliorated system, the ratio of target com-
pound 2 and dioxo compound 2a decreased to 8:1.
With the compound 2 in hand, (±)-nimbiol 1 was af-
forded after a very effective demethylation method by so-
dium ethylthiolate13 was employed.
(±)-12-Methoxy-13-hydroxymethylpodocarpane-8,11,13-
trene (4)
In summary, we have developed a simple and efficient
route to (±)-nimbiol in high yield. In addition, the formyl-
ating reaction gave excellent regioselectivity at low tempera-
ture and this result can be explained by a geometric model.
Significantly, we found a mild oxidation system, which can
be used to achieve target compound 2 in a high ratio.
To a solution of 5 (600 mg, 2.1 mmol) in methanol (15
mL) was added NaBH4 (100 mg) and CeCl3×7H2O (10 mg)
and the reaction mixture was stirred for 1 h at room tempera-
ture. Then cold water was added; the mixture was extracted
with ether (3 ´ 50 mL), and the combined organic layer was
washed with brine, and then dried with Na2SO4. Evaporation
of the solvent and then purification of the residue by column
chromatography gave the alcohol (570 mg, 95%). 1H-NMR:
0.96 (s, 3H), 0.98 (s, 3H), 1.24 (s, 3H), 1.22-1.67 (m, 6H),
1.66-1.88 (m, 2H), 2.28 (m, 1H), 2.75-2.92 (m, 2H), 3.85 (s,
3H), 4.63 (s, 2H), 6.79 (s, 1H), 6.95 (s, 1H). 13C-NMR: 19.13,
20.95, 21.45, 24.56, 29.39, 34.42, 37.87, 38.77, 41.46, 49.17,
50.25, 55.10, 61.56, 106.03, 109.89, 129.07, 135.31, 150.33,
Fig. 1

Facile Total Synthesis of (±)-Nimbiol
J. Chin. Chem. Soc., Vol. 51, No. 3, 2004 507
155.28. MS (EI): 288 (M+, 38), 273 (37), 243 (9), 203 (20),
191 (36), 187 (38), 177 (37) and 151 (100). Found: C, 79.13;
H, 9.71. C19H28O2 requires C, 79.12; H, 9.78.
Nimbiol (1)
To a solution of ethylthiol (0.4 mL, 5.5 mmol) in anhy-
drous DMF was added NaH (132 mg, 5.5 mmol) and the mix-
ture was stirred for 30 minutes. Then a solution of nimbiol
methyl ether 2 (89 mg, 0.3 mmol) in DMF (5 mL) was added,
and the mixture was heated to 130 °C for 4 h. After cooling,
the mixture was quenched with diluted HCl and extracted
with ethyl acetate (3 ´ 20 mL). The combined organic layers
were washed with brine and dried over Na2SO4. The solvent
was evaporated and the residue was purified through column
chromatography to give nimbiol 1 (82 mg, 96%). Mp:
248-249 (lit3, 250-251 °C), 1H-NMR (400 MHz, DMSO-d6):
0.87 (s, 3H), 0.93 (s, 3H), 1.13 (s, 3H), 2.08 (s, 3H), 6.67 (s,
1H), 7.57 (s, 1H), 10.23 (s, 1H). 13C-NMR: 15.36, 18.45,
21.10, 23.03, 32.28, 32.84, 35.43, 37.45, 38.08, 41.81, 49.13,
108.89, 122.26, 122.42, 129.40, 156.16, 160.94, 196.37. MS
(EI): 272 (M+, 48), 257 (47), 189 (62), 175 (64), 149 (47) and
121 (50). Found: C, 79.35; H, 8.82. C18H24O2 requires C,
79.37; H, 8.88.
(±)-Nimbiol methyl ether (2)
To a solution of the above alcohol (570 mg, 1.97 mmol)
in CH2Cl2 (20 mL) was added triethylamine (0.5 mL) and
methyl sulphonyl chloride (0.5 mL) at -20 °C. The mixture
was stirred for 3 h at this temperature, and then quenched
with water, extracted with ether, and the combined organic
layer was washed with brine and then dried with Na2SO4.
Evaporation of the solvent gave the sulfonate. This sulfonate
was dissolved in anhydrous THF (10 mL) directly. LiAlH4
(40 mg) was added to the above solution, and the mixture was
refluxed for 6 h. The reaction mixture was quenched with a
few drops of saturated Na2SO4 and extracted with ether (3 ´
50 mL); the combined organic layer was washed with brine
and then dried with Na2SO4. The solvent was evaporated to
afford crude 3 as yellow oil (530 mg, 98%). This compound
was not purified further for the next step. To a solution of 3
(200 mg, 0.74 mmol) in acetic acid (3 mL) was added the
mixture of CrO3/H2O/HOAc/NaOAc (90 mg/0.2 mL/1 mL/
80 mg) at room temperature. The mixture was stirred for 1.5
h, and then diluted with water. After extraction with dichloro-
methane, the combined organic layer was washed with satu-
rated sodium bicarbonate, brine and then dried with Na2SO4.
The solvent was evaporated and the residue was purified by
flash column chromatography affording (±)-nimbiol methyl
ether 2 (165 mg, 80%) and 2a (30 mg, 10%).
ACKNOWLEDGEMENT
Support from the National Natural Science Foundation
of China (No. 20172023) is gratefully acknowledged.
Received June 16, 2003.
2: White needle crystals, Mp: 142-143 °C (lit3, 142-143
°C), 1H-NMR (400 MHz, CDCl3): 0.94 (s, 3H), 1.00 (s, 3H),
1.25 (s, 3H), 1.27-1.53 (m, 1H), 1.52-1.88 (m, 5H), 2.19 (s,
3H), 2.31 (d, J = 12 Hz, 1H), 2.58-2.70 (m, 2H), 3.90 (s, 3H),
6.74 (s, 1H), 7.81 (s, 1H). 13C-NMR: 15.57, 18.88, 21.32,
23.24, 32.55, 33.27, 35.94, 37.99, 38.30, 41.33, 49.72, 55.34,
104.01, 123.84, 124.86, 129.66, 156.78, 162.48, 198.37. MS
(EI): 286 (M+, 25), 271 (12), 203 (24), 189 (33), 175 (26) and
153 (100). Found: C, 79.66; H, 9.17. C19H26O2 requires C,
79.68; H, 9.15.
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