Scalable synthesis of methyl ent-isocopalate and its derivatives

Article abstract of DOI:10.1016/j.tet.2010.12.008

An efficient and convenient synthetic route was developed to prepare the tricycle diterpene intermediates 1-3 starting from commercially available (-)-sclareol. This improved approach involving four-step reactions provides large-scale (30-40 g) methyl ent-isocopalate in 61% overall yield, which could supply sufficient material for the synthesis of marine natural products containing tricyclic diterpenes.

Full text of DOI:10.1016/j.tet.2010.12.008

Tetrahedron 67 (2011) 1142e1144
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Scalable synthesis of methyl ent-isocopalate and its derivatives
Si-Kai Hua b, Jing Wang a b, Xi-Bo Chen a b, Zhong-Yu Xu , Bu-Bing Zeng a
a
,
,
,
a
,b,
*
a
Shanghai Key Laboratory of Chemical Biology, 130 Meilong Road, Shanghai 200237, People’s Republic of China
School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, People’s Republic of China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 October 2010
Received in revised form 29 November 2010
Accepted 3 December 2010
Available online 9 December 2010
An efficient and convenient synthetic route was developed to prepare the tricycle diterpene in-
termediates 1e3 starting from commercially available (ꢀ)-sclareol. This improved approach involving
four-step reactions provides large-scale (30e40 g) methyl ent-isocopalate in 61% overall yield, which
could supply sufficient material for the synthesis of marine natural products containing tricyclic
diterpenes.
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Keywords:
Methyl ent-isocopalate
(
ꢀ)-Sclareol
Tricycle diterpene
Spongiane
1. Introduction
Spongiane diterpenoids are a class of natural products pos-
sessing broad spectrum of biological properties including antifun-
gal, antiinflammatory, antihypertensive, antimicrobial, cytotoxic,
1
antitumor, and anti-HIV activities. Due to their unique stereo-
chemical features, the tricyclic diterpenes intermediates 1e3 are
frequently used as excellent precursors in the total synthesis of
2
e4
1b
these marine natural products, such as (ꢀ)-hyrtiosal,
luffolide,
1h
and (þ)-scalarolide (Fig. 1).
To the best of our knowledge, three synthetic approaches to
methyl ent-isocopalate 1 have been presented in the literatures. The
5
a
first route was described by Minale, which required five-step
reactions starting from the uncommercial grindelic acid. Sub-
sequently, Urones and co-workers published other two approaches.
One involved five-step reactions with 45% overall yield from labda-
nolic acid5b and the other embodied eight-step reactions with 49%
5
c
overall yield using (ꢀ)-sclareol as starting material. However, these
procedures mentioned above have some significant drawbacks, such
as the use of scarce starting materials (labdanolic acid), long synthetic
route (eight steps) and the utilization of hazardous chemicals
(
diazomethane and organoselenium reagent), which severely limited
their applications in the total synthesis of marine natural products.
Hence, we developed a practical and convenient synthetic route to
prepare methyl ent-isocopalate 1 on a large scale. Afterward, iso-
copalic alcohol 2 and the corresponding aldehyde 3 were readily
Fig. 1. Tricyclicditerepeneintermediates1e3 andthe naturalproductsstarting fromthem.
2. Results and discussion
5
d
prepared from methyl ent-isocopalate via reduction and oxidation.
Considering the tricyclic framework and stereochemistry of 1,
our improved route chose commercially available (ꢀ)-sclareol as
starting material. This novel synthetic strategy involving four-step
reactions was shown in Schemes 1 and 2.
*
Corresponding author. Tel./fax: þ86 21 64253689; e-mail address: zengbb@
ecust.edu.cn (B.-B. Zeng).
0
040-4020/$ e see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.008

S.-K. Hua et al. / Tetrahedron 67 (2011) 1142e1144
1143
HO
O
O
9
1
7
a
O
b
+
8
7
OH
OH
see table 1
H
H
H
H
8
, 9
Sclareol
4
5
6
7
8
7
, 8
Silica gel
8, 17
ꢁ
Scheme 1. The synthesis of compound 6. Reagents and conditions: (a) KMnO
4
and MgSO
4
, acetone, 0 C to rt, 90%; (b) I
2
, PhMe, reflux, 78%.
ester. At this stage, we were disappointed to find that all attempts to
afford ester 9 from compound 6 and stable ylide methyl (triphenyl-
phosphoranylidene)-acetate were unsuccessful. However, the re-
placement of methyl (triphenyl-phosphoranylidene)-acetate with
methyl diethylphosphonoacetate via HornereEmmons reaction
could smoothly provide the expected
a,b-unsaturated ester 9 in
nearly quantitative yield with high regioselectivity (E/Z¼11:1, de-
termined by HPLC), which was superior to the result by using iso-
12
drimenol as starting material (E/Z¼7:2). Finally, the unsaturated
ester 9 was readily cyclized with formic acid to obtain methyl ent-
isocopalate 1 in 88% yield, whose physical properties were identical
5
a
to those previously reported (details were described in the
Supplementary data). The corresponding alcohol 2 and aldehyde 3
5
d
were prepared according to the reference from 1.
. Conclusion
3
In summary, a practical and concise approach has been de-
veloped to synthesize methyl ent-isocopalate 1, isocopalic alcohol
2
, and the corresponding aldehyde 3 from (ꢀ)-sclareol in short
Scheme 2. Synthesis of methyl ent-isocopalate and the corresponding alcohol and
steps. Each step proceeds to give high yields, which are adequate
for large-scale (30e40 g) preparation.
aldehyde. Reagents and conditions: (a) NaH, (EtO)
2
P(O)CH
2
CO
2
Me, THF, ꢀ15 ꢁC, quant.;
ꢁ
(
b) HCOOH, 80 C, 88%; (c) and (d) see Ref. 5d.
4
4
. Experimental section
Our approach commenced with a degradative oxidation of
(
ꢀ)-sclareol to afford methyl ketone 4 according to the established
.1. General information
6
procedure. Furthermore, we found that using finelygroundpowder
of KMnO
4 4
and MgSO could greatlyimprove theyield from80 to 90%.
Commercial reagents and solvents were used without further
Compound 4 is unstable, which can easily cyclize and dehydrate to
afford sclareol oxide 5 in petroleum ether, benzene or pyridine.
And the facile conversion of 4 to 5 also takes place in the presence
purification unless otherwise mentioned. All anhydrous solvents
were prepared according to the reported procedures and distilled
under argon prior to use. All the stable compounds were char-
7
8
9
7
10
8
of mineral acid, on silica gel, or at a higher tempertaure.
The furtherdehydration of 4 and 5 was liable to provide a mixture
8-labden-13-one 6 and 7-labden-13-one 7 in moderate overall
yield according to the known procedure.
1
13
acterized by IR, MS, H, and C NMR. Melting points were de-
termined on a digital melting point apparatus WRS-113 and are
of
D
D
1
13
uncorrected. H and C NMR spectra were determined on Bruker
00 instruments in CDCl using tetramethylsilane as internal
6
a,11
Hoping to achieve
4
3
a more desirable result, we screened the reaction conditions to
optimize the yield and regioselectivity of the product. To our delight,
refluxing of 4 and 5 in toluene for 3 h in the presence of catalytic
amount of iodine was found to be the most favorable dehydration
condition, which afforded 6 as a single product in 78% yield. The
optimized conditions and results were outlined in Table 1.
reference. Mass spectra were recorded on a Micromass GCT
CA055. Infrared spectra were collected on Thermo FT-IR 200
Spectrometer. Optical rotations were measured using Rudolph
Research Analytical Automatic Polarimeter III at ambient tem-
perature and 589 nm. HPLC analyses were performed on Agilent
Technologies 1200 Series equipped with a Diamonsil C18 column,
With a reliable preparation to obtain the single compound 6 in
ꢁ
using a mixture of acetonitrile/water as a mobile phase, at 25 C.
Chiral HPLC analyses were performed on Agilent Technologies
hand, we turned our attention to the formation of
a
,b
-unsaturated
1
100 Series equipped with a chiral OD-H column, using a mixture
Table 1
ꢁ
Optimization for dehydration of compound 4 and 5
of n-hexane/isopropyl alcohol (IPA) as a mobile phase, at 25 C.
Yielda (%)
The analytical data for the known compounds were found to
match with the literature data.
Entry
Conditions
SOCl /Py/CH
HI/C
Temp
1
2
3
4
2
2
Cl
2
ꢀ78 ꢁ
C
61 (6þ7þ8)
55 (6þ7)
75 (6þ7)
78 (6)
6
H
6
rt
I
I
2
/C
6
H
6
Reflux
Reflux
4.1.1. (þ)-8
solution of (ꢀ)-sclareol (30.8 g, 0.1 mol) in acetone (400 mL), the
finely ground powder of KMnO (55.3 g, 0.35 mol) and MgSO
(60.2 g, 0.5 mol) was added in portions for 2 h. The reaction mixture
a-Hydroxy-14,15-bisnorlabda-13-one (4). To an ice cooled
2
/PhMe
a
Isolated yield through flash chromatograph, and the ratio of 6:7 was determined
4
4
by 1H NMR.

1144
S.-K. Hua et al. / Tetrahedron 67 (2011) 1142e1144
was stirred at ambient temperature overnight. The slurry mixture
3
(400 MHz, CDCl ) d 0.82 (s, 3H), 0.87 (s, 3H), 0.92 (s, 3H), 0.95 (s, 3H),
was filtered through a pad of Celite, and the filter cake was washed
1.10e1.18 (m, 2H), 1.25e1.45 (m, 5H), 1.54e1.58 (m, 3H), 1.61 (s, 3H),
with acetone (3ꢂ200 mL). The combined organic phase was con-
1.65e1.74 (m, 2H), 1.96 (br s, 2H), 2.93 (s, 1H), 3.68 (s, 3H), 5.53 (s,
ꢁ
13
centrated under reduced pressure below 20 C, to afford (þ)-8
a-
1H); C NMR (100 MHz, CDCl
3
)
d
15.5,15.8,18.5,18.6, 21.2, 21.7, 22.7,
hydroxy-14,15-bisnorlabda-13-one (4), (25.1 g, 90%) as a white solid,
which was directly used for the next step reaction without further
purification. The pure sample for data collection was recrystallized
33.2, 33.4, 36.5, 37.4, 39.8, 41.8, 51.0, 54.3, 56.4, 62.6, 124.1, 129.0,
þ
173.4; MS (EI, m/z): 318 [M ]. The de value of the product was de-
termined by chiral HPLC analysis (Chiralcel OD-H, n-hexane/i-
ꢁ
13
ꢁ
12
ꢁ
from hexane. Mp 77.8e78.9 C (lit. mp 78e80 C); [
a
]
D
þ5.1 (c
PrOH¼30:1, 230 nm, 1 mL/min, 25 C), 82% de.
8
ꢀ1
1
.03, CH
Cl
2 2
), lit. þ6.7; IR (neat)
nmax 3498, 1698, 1114 cm ; MS (EI,
þ
m/z): 280 [M ].
Acknowledgements
4
.1.2. (þ)-14,15-Bisnorlabda-8-ene-13-one (6). The pink solution of
We are grateful for the financial support by the national ‘863’
Project of China (2006AA609Z447 and 2007AA02Z301), 111 Project
(B07023), and Shanghai Foundation of Science and Technology
(09JC1404200).
hydroxyl ketone 4 (22.4 g, 0.08 mol) and I (1.0 g, 4.0 mmol) in
anhydrous toluene (500 mL) was refluxed with a DeaneStark trap
for 3 h. The solution was diluted with ethyl acetate (200 mL) and
2
washed with 5% Na
2
S
2
O
3
(3ꢂ50 mL), H
2
O (3ꢂ30 mL), and brine
Supplementary data
(
3ꢂ30 mL), the organic phase was dried over anhydrous Na
2
SO
4
and concentrated in vacuum to provide the crude product that
was purified through flash chromatography in petroleum ether to
afford (þ)-14,15-bisnorlabda-8-ene-13-one (6), (16.4 g, 78%) as
Copies of 1H NMR, 13C NMR and HPLC spectra associated with
this article can be found in the supplementary content. Supple-
mentary data associated with this article can be found in online
version at doi:10.1016/j.tet.2010.12.008. These data include MOL
files and InChIKeys of the most important compounds described in
this article.
1
3
14
a light yellow oil. [
a
]
D
þ74.5 (c 1.05, CHCl
3
), lit. þ78; IR (neat)
ꢀ
1
1
n
max 2937, 1716, 1461, 1360, 1159, 999 cm
CDCl
.09 (d, J¼11.6 Hz, 1H), 1.12e1.17 (m, 1H), 1.37e1.40 (m, 1H),
.42e1.45 (m, 1H), 1.47e1.48 (m, 1H), 1.53 (s, 3H), 1.58e1.61 (m,
; H NMR (400 MHz,
3
) d 0.83 (s, 3H), 0.88 (s, 3H), 0.94 (s, 3H), 0.96e1.05 (m, 1H),
1
1
References and notes
1
H), 1.63e1.66 (m, 1H), 1.78 (br d, J¼12.4 Hz, 1H), 1.91e2.02 (m,
2
H), 2.14 (s, 3H), 2.16e2.19 (m, 1H), 2.25e2.33 (m, 1H), 2.49 (t,
13
1. (a) Basabe, P.; Delgado, S.; Marcos, I. S.; Diez, D.; Diego, A.; de Roman, M.; Sanz,
F.; Urones, J. G. Tetrahedron 2007, 63, 8939; (b) Basabe, P.; Delgado, S.; Marcos, I.
S.; Diez, D.; Diego, A.; De Roman, M.; Urones, J. G. J. Org. Chem. 2005, 70, 9480;
J¼8.4 Hz, 2H); C NMR (100 MHz, CDCl
3
) 19.0, 19.4, 19.9, 21.6, 21.7,
2
9.8, 33.3, 33.6, 36.9, 39.1, 41.7, 44.6, 52.0, 126.6, 139.2, 209.1; MS
þ
(c) Basabe, P.; Gomez, A.; Marcos, I. S.; Martin, D. D.; Broughton, H. B.; Urones, J.
(
EI, m/z): 262 [M ].
G. Tetrahedron Lett. 1999, 40, 6857; (d) Gonzalez-Sierra, M.; Kaufman, T.; Ru-
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Sierra, M. G.; Ruveda, E. A. J. Org. Chem. 1984, 49, 2035; (f) Gonzalez, M. A.
Tetrahedron 2008, 64, 445; (g) Sierra, G.; Mischne, M. P.; Ruveda, E. A. Synth.
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W. P. Tetrahedron Lett. 2009, 50, 4983.
2. (a) Lunardi, I.; Santiago, G. M. P.; Imamura, P. M. Tetrahedron Lett. 2002, 43,
3609; (b) Basabe, P.; Diego, A.; Diez, D.; Marcos, I. S.; Mollinedo, F.; Urones, J. G.
Synthesis 2002, 1523; (c) Basabe, P.; Diego, A.; Diez, D.; Marcos, I. S.; Urones, J. G.
Synlett 2000, 1807.
4.1.3. Labda-8,13-diene-15-oic acid, methyl ester (9). To a mixture of
sodium hydride (9.3 g, 0.24 mmol, 60% in mineral oil) in anhydrous
ꢁ
THF (100 mL) at ꢀ25 C, methyl diethylphosphonoacetate (38 mL,
0
.20 mol) was added under nitrogen atmosphere. The reaction was
ꢁ
continued to stir at 0 C for another 30 min. Then a solution of 6
17.9 g, 0.07 mol) in anhydrous THF (40 mL) was added dropwise
over 2 h, the reaction was stirred at ambient temperature overnight,
then quenched with saturated NH Cl solution, and extracted with
ethyl acetate (3ꢂ50 mL). The combined organic phase was dried
over anhydrous Na SO and concentrated under reduce pressure to
afford
by HPLC) as a yellowliquid. [
(
3
4
5
. Du, L.; Shen, L. L.; Yu, Z. G.; Chen, J.; Guo, Y. W.; Tang, Y.; Shen, X.; Jiang, H. L.
ChemMedChem 2008, 3, 173.
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4
2
4
. (a) Cimino, G.; De Rosa, D.; De Stefano, S.; Minale, L. Tetrahedron 1974, 30, 645; (b)
Urones, J. G.; Sexmero, M. J.; Lithgow, A. M.; Basabe, P.; Gomez, A.;
Marcos, I. S.; Estrella, A.; Diez, D.; Carballares, S.; Broughton, H. B. Nat. Prod. Lett.
1995, 6, 285; (c) Urones, J. G.; Marcos, I. S.; Basabe, P.; Gomez, A.;
Estrella, A.; Lithgow, A. M. Nat. Prod. Lett. 1994, 5, 217; (d) Gonzalez Sierra, M.;
Cravero, R. M.; Laborde, L. A.; Ruveda, E. A. J. Chem. Soc., Chem. Commun.1984, 417.
. (a) Marcos, I. S.; Beneitez, A.; Castaneda, L.; Moro, R. F.; Basabe, P.; Diez, D.;
Urones, J. G. Synlett 2007, 1589; (b) Marcos, I. S.; Basabe, P.; Laderas, M.; Díez,
D.; Jorge, A.; Rodilla, J. M.; Moro, R. F.; Lithgow, A. M.; Barata, I. G.; Urones, J. G.
Tetrahedron 2003, 59, 2333; (c) Leite, M. A. F.; Sarragiotto, M. H.; Imamuna, P.;
Marsaidi, A. J. J. Org. Chem. 1986, 51, 5409.
a,
b-unsaturated ester 9 (21.6 g, 99.6%, E/Z¼11:1 determined
2
0
5a
a
]
D
þ58.7 (c 3.09, CHCl
3
), lit. þ50.8; IR
ꢀ
1
1
(
neat)
n
max 2945, 1725, 1650, 1387, 1148, 864 cm
;
H NMR
(
400 MHz, CDCl ) d 0.85 (s, 3H), 0.90 (s, 3H), 0.96 (s, 3H), 1.11e1.20
3
6
(
m, 3H),1.27e1.31 (m,1H),1.39e1.44 (m, 2H),1.47e1.53 (m, 2H),1.59
(
4
d
s, 3H), 1.64e1.70 (m, 2H), 1.82 (br d, J¼12.0 Hz, 1H), 1.93e2.17 (m,
1
3
3
H), 2.20 (s, 3H), 3.70 (s, 3H), 5.71 (s,1H); C NMR (100 MHz, CDCl )
18.9, 19.0, 19.5, 20.1, 21.7, 26.4, 33.3, 33.6, 39.1, 41.6, 41.8, 50.8, 51.9,
þ
7. Bigley, D. B.; Rogers, N. A. J.; Barltrop, J. A. J. Chem. Soc. 1960, 4613.
114.5, 126.7, 139.5, 161.1, 167.4; MS (EI, m/z): 318 [M ].
8. Barrero, A. F.; Alvarez-Manzaneda, E. J.; Altarejos, J.; Salido, S.; Ramos, J. M.
Tetrahedron 1993, 49, 10405.
4
.1.4. Methyl ent-isocopalate (1). A solution of 2.7 g (8.6 mmol) of
9. Bendall, J. G.; Cambie, R. C.; Moratti, S. C.; Rutledge, P. S.; Woodgate, P. D. Aust. J.
Chem. 1995, 48, 1747.
ꢁ
compound 9 in anhydrous formic acid (30 mL) was heated at 80 C
for 3 h. After removal of formic acid under reduced pressure, the
yielding solid was recrystallized from MeOH or petroleum ether to
give methyl ent-isocopalate (1), (2.4 g, 88%) as a white solid. Mp
10. Marcos, I. S.; Laderas, M.; Diez, D.; Basabe, P.; Moro, R. F.; Garrido, N. M.; Urones,
J. G. Tetrahedron Lett. 2003, 44, 5419.
11. Gray, C. A.; Davies-Coleman, M. T.; Rivett, D. E. A. Tetrahedron 2003, 59, 165.
1
2. Arima, Y.; Kinoshita, M.; Akita, H. Tetrahedron: Asymmetry 2007, 18, 1701.
3. Barltrop, J. A.; Littlehailes, J. D.; Rushton, J. D.; Rogers, N. A. J. Tetrahedron Lett.
962, 10, 429.
14. Mangoni, L.; Belardini, M. Gazz. Chim. Ital. 1963, 93, 465.
1
ꢁ
5a
ꢁ
10
102.2e105.1 C (lit. mp 103e105 C); [
a
]
D
ꢀ59.4 (c 2.61, CHCl
3
),
1
5
a
ꢀ1
;
1
lit. ꢀ50.4; IR (neat)
n
max 3438, 2936, 1729 cm
H NMR