Synthesis of ent-ambrox from (-)-nidorellol

Article abstract of DOI:10.1016/j.tetlet.2012.07.120

Using ozonolysis of the acid-catalyzed cyclized products of (-)-nidorellol and air-autoxidation as the key steps, (+)-ambrox was obtained in 53% overall yield. In the course of our synthesis, we discovered that (-)-nidorellol provided (+)-ambrox instead of the expected product, (-)-ambrox. Thus the absolute configuration of (-)-nidorellol was proved to be trans-(5R ^*,7R^*,8R^*,9S ^*,10R^*)-labda-12,14-diene-7α,8β- diol, which is opposite to that illustrated in a previous report.

Full text of DOI:10.1016/j.tetlet.2012.07.120

Tetrahedron Letters 53 (2012) 5418–5421
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Tetrahedron Letters
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Synthesis of ent-ambroxÒ from (ꢀ)-nidorellol
Sunisa Suwancharoen a, Surachai Pornpakakul a,b, , Nongnuj Muangsin a
⇑
a Research Centre for Bioorganic Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Phayathai Road, Bangkok 10330, Thailand
b Center for Petroleum, Petrochemicals and Advanced Materials, Chulalongkorn University, Bangkok 10330, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 April 2012
Revised 7 July 2012
Accepted 27 July 2012
Available online 3 August 2012
Using ozonolysis of the acid-catalyzed cyclized products of (ꢀ)-nidorellol and air-autoxidation as the key
steps, (+)-ambrox was obtained in 53% overall yield. In the course of our synthesis, we discovered that
(ꢀ)-nidorellol provided (+)-ambrox instead of the expected product, (ꢀ)-ambrox. Thus the absolute con-
figuration of (ꢀ)-nidorellol was proved to be trans-(5R⁄,7R⁄,8R⁄,9S⁄,10R⁄)-labda-12,14-diene-7
a,8b-diol,
which is opposite to that illustrated in a previous report.
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Keywords:
Nidorellol
AmbroxÒ
Air-autoxidation
Diterpenoid
(ꢀ)-AmbroxÒ (Fig. 1) is an oxidatively degraded compound from
ambergris [a secretion of the sperm whale Physeter catodon (P.
macrocephalus L.)].1 As it has a very strong ambergris-like odor
and fixative property, it has become a highly valued fine fragrant
ingredient.2 In fact, several routes to synthesize ambroxÒ have
been developed starting from naturally occurring diterpenes.3
Among those diterpenes, labdane-type diterpenes are consid-
ered suitable synthons for ambrox synthesis due to their structural
features and ease of availability.
The key steps of the first route involve the acid-promoted cycli-
zation of 2, ozonolysis of the cyclized product and air-autoxidation,
and dehydroxylation at C-7, while the second route involves ozon-
olysis of 2 and dehydroxylation at C-7.
In the course of this seven-step synthesis an unexpected config-
uration of ambrox, that is ent-ambrox, which is the opposite to that
previously reported,4 was discovered. Thus, the configuration of
each compound in each step was carefully investigated. We found
that all the products retained their configurations, thereby con-
firming the absolute configuration of (ꢀ)-nidorellol as trans-
(ꢀ)-Nidorellol (2), a labdane-type diterpene, was first isolated
from Nidorella auriculata4 and later from Stevia sarensis.5 In 1978,
its configuration was established by Bohlmann and Fritz as trans-
(5R,7R,8R,9S,10R)-labda-12,14-diene-7
a
,8b-diol 2 ( Fig. 1). We
(5S,7S,8S,9R,10S)-labda-12,14-diene-7b,8a
-diol 20 (Fig. 1).4
Recently, we isolated 2 from Croton oblongifolius barks as a
white solid in 0.42% yield based on 380 g of powdered air-dried
bark. On the basis of spectroscopic data, including IR, 1D and 2D
NMR, and MS, the structure of 2 was established. Careful analysis
of the NOESY spectra showed an E-configuration of the conjugated
O
O
diene. Since the specific rotation of 2 was ½a D20
= ꢀ23.2 (Lit.
ꢁ
a 2D4
ꢁ
= ꢀ21.0),4 its stereochemistry was that of (ꢀ)-nidorellol as re-
H
(−)-ambrox®
½
H
ported by Bohlmann and Fritz,4 and thus is a suitable synthon for
the synthesis of (ꢀ)-ambroxÒ. However, it was unstable and
decomposed to many compounds at ambient temperature. Fortu-
nately, it was easily cyclized under acid conditions to provide more
stable products. Therefore, the synthesis of ambroxÒ was per-
formed via two routes, as summarized in Scheme 1.
ent-ambrox® (1)
12
14
13
11
15
20
17
16
9
6
1
4
10
5
8
7
2
3
OH
OH
OH
OH
H
H
2
2
19 18
Figure 1. (ꢀ)-AmbroxÒ
,
(+)-ambroxÒ (1), the previous configuration of (ꢀ)-
⇑
Corresponding author. Tel.: +66 2 218 7637/81 562 0555; fax: +66 2 218 7598.
E-mail address: psuracha@chula.ac.th (S. Pornpakakul).
nidorellol (20)4 and absolute configuration of (ꢀ)-nidorellol (2).
0040-4039/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.120

S. Suwancharoen et al. / Tetrahedron Letters 53 (2012) 5418–5421
5419
OH
20
i) O3, 5%H2O/Me2CO, -78 oC
ii) 3 weeks at r.t.
O
O
OH
NaBH4, THF,
reflux
9
1
OH
OH
10
8
7
5
4
iii) LiAlH4, THF
NNHTs
OH
7
H
33%
H
H
H
1
2
10
42% from 2
p-TsOH H2O, CH2Cl2
quant. yield
NH2NHTs,
THF, reflux
91%
TsCl, Pyridine
90%
H2NNH2 H2O,
KOH, DEG
160-200 oC, 74%
15
14
13
12
16
11
9
O
O
PCC, CH2Cl2
98%
O
O
1
4
8
7
10
17
OH
O
5
+
H
H
9
8
OH
OH
H
H
4
3
O3, 5% H2O/Me2CO
i) LiAlH4, THF
-78 oC
O
O
ii) TsCl, pyridine, 82% from 6
O
O
O
14 d
at r.t.
O
O
O
+
+
OH
90%
from 2
OH
OH
OH
H
H
H
H
5a
5b
a 3:1 mixture of and
6
6
5
6
Scheme 1. Synthesis of (+)-ambroxÒ from (ꢀ)-nidorellol; DEG = diethylene glycol.
now describe the synthesis of (+)-ambroxÒ from (ꢀ)-nidorellol and
report the absolute configuration of (ꢀ)-nidorellol.
observation of an NOE between the methyl protons of C-15 and
C-16, the configuration of the double bond was confirmed as E.
The relative configuration of 3 was determined and confirmed by
X-ray crystallographic analysis,6 as that shown in Figure 2. The
1H and 13C NMR spectra of 4 indicated that its structure was closely
related to 3. Moreover, the observed NOE in 4 between H-12 [dH
4.42 (dd, J = 2.0, 9.2 Hz)] and the methyl protons of C-17 suggested
that H-12 occupied the same face as the methyl protons of C-17.
Thus, compound 4 was an epimer of 3.
Oxidative cleavage of 3 and 4 with ozone in 5% water in ace-
tone7 at ꢀ78 °C for 3 h gave a 3:1 mixture of 5 and 6, as shown
in Figure 3a. Isolation of the mixture by silica gel column chroma-
tography [EtOAc-hexane (4:6)] gave 5a, 5b, and 6 in yields of 15%,
14%, and 19%, respectively. Surprisingly, we found that the ratio of
5 and 6 changed when the viscous mixture of 5 and 6 was stored
and exposed to air at ambient temperature. Monitoring the viscous
Acid-promoted cyclization of 2 with 20% mol p-TsOHꢂH2O in
CH2Cl2 over 3 h at room temperature gave a mixture of 3 and 4.
1H NMR data and the masses of the products obtained showed that
a 3:1 mixture of 3 and 4 had formed in quantitative yield. However,
after their separation and isolation by silica gel column chromatog-
raphy their yields were only 14% for 3 and 8% for 4, presumably
due to their decomposition during purification. Thus, the mixture
of 3 and 4 was used directly in the ozonolysis step.
The relative configurations of 3 were determined by NOE anal-
ysis. Due to the absence of any NOE between H-12 [dH 4.27 (dd,
J = 6.4, 9.2 Hz)] and the protons of C-17, the methyl protons of C-
17 are proposed to be on the opposite face to H-12. The observed
NOEs between H-12 and H-9, H-9 and H-7, and H-7 and H-5
indicated that these protons occupied the same face. Due to the
Figure 2. The ORTEP drawing of 3.

5420
S. Suwancharoen et al. / Tetrahedron Letters 53 (2012) 5418–5421
Figure 4. The ORTEP drawing of 6.
revealed that both ketones were transformed into
6 under
atmospheric air but remained unchanged under anaerobic condi-
tions. Thus, both diastereomers could be converted into 6 by
air-autoxidation. We also found that compounds 3 and 4 underwent
air oxidative degradation to give 6, but the degradation of 3 and 4
was slower than that of ketone 5. As compounds 3 and 4 could be
converted into 6, this encouraged us to investigate the direct oxida-
tive degradation of the conjugated diene of 2 under the same condi-
tions. Using 1H NMR analysis, we established signals due to
aldehyde protons (dH 9.60–10.42 ppm), olefinic protons (dH 5.10–
5.67 ppm), and a small H-7 signal due to compound 6 (Fig. 5a).
Attempts to isolate the reaction mixture were unsuccessful because
the product of the oxidative degradation consisted of many seem-
ingly unstable compounds. However, the magnitude of the H-7 sig-
nal of 6 in the 1H NMR spectrum increased when the reaction
mixture from the ozonolysis of 2 was stored under atmospheric
air and the 1H signals were unchanged after three weeks (Fig. 5b).
This suggested that the product from ozonolysis of 2 also underwent
air-autoxidation. Isolation of the air-autoxidation mixture using sil-
ica gel column chromatography gave lactone 6 in a low yield (47%).
The mechanism of air-autoxidation of ketones 5a and 5b was
investigated by GC/MS analysis of the gaseous products using the
Figure 3. 1H NMR spectra of the products from ozonolysis of a 3:1 mixture of 3 and
4: (a) after work-up; (b) under no O2 (stored in a desiccator with a GasPak) for
3 days; (c) exposed to air for 3 days, and (d) exposed to air for 14 days.
mixture of 5 and 6 by 1H NMR spectroscopy (Fig. 3), revealed that
the mixture of 5a and 5b was slowly transformed into 6, and com-
pound 6 crystallized after 14 days. Recrystallization from acetone
in the presence of a small amount of water gave lactone 6 as color-
less crystals in 90% yield. The structure of 6 was characterized by
1D and 2D NMR, and its relative configurations were determined
by NOESY analysis and further confirmed by X-ray crystallographic
analysis8 (Fig. 4).
To understand how ketones 5a and 5b were converted into lac-
tone 6, they were examined by 1H NMR spectroscopy during storage
under aerobic and anaerobic conditions. The results (Fig. 3b and 3c)
Figure 5. 1H NMR spectra of the products from ozonolysis of (ꢀ)-nidorellol: (a) after work-up; (b) exposure to air for 3 weeks.

S. Suwancharoen et al. / Tetrahedron Letters 53 (2012) 5418–5421
5421
head space technique. Since the presence of acetic acid was de-
References and notes
tected, the mechanism of air-autoxidation likely takes place by
substitution of an O2 molecule at C-12 of 5 and degradation of
the corresponding hydroperoxide to yield lactone 6 and acetic acid
as the products.
1. (a) Ohloff, G. The fragrance of ambergris. In Fragrance Chemistry; Theimer, E. T.,
Ed.; Academic Press: New York, 1982; pp 535–573; (b) Mookherjee, B. D. In
Proceedings of the 7th. International Congress on Essential Oils, Kyoto, 1977; p
479.
2. (a) Poucher, W. A., 7th ed. In Perfumes, cosmetics and soaps; Chapman and Hall,
1974; vol. 2,; (b) Barco, A; Benetti, S.; Bianchi, A.; Casolari, A.; Guarneri, M.;
Pollini, G. P. Tetrahedron 1995, 30, 8333–8338.
Reduction of lactone 6 followed by cyclization gave 8 in 82%
yield (Scheme 1). After cyclization of 7, oxidation of 8 with PCC
gave 9 in 98% yield. Reduction of the carbonyl group of 9 to a meth-
ylene was performed by Wolff-Kishner reduction,9 via heating with
hydrazine hydrate in the presence of KOH in diethylene glycol
(DEG) to give compound 1 in 74% yield (after chromatographic sep-
aration), from 9. Also, reduction of the carbonyl group of 9 was per-
formed by treatment with tosylhydrazine followed by reduction
3. (a) Coste-Manière, I. C.; Zahra, J. P.; Waegell, B. Tetrahedron Lett. 1988, 29,
1017–1020; (b) Martres, P.; Perfetti, P.; Zahra, J. P.; Waegell, B.; Giraudi, E.;
Petrzilka, M. Tetrahedron Lett. 1993, 34, 629–632; (c) Barrero, A. F.; Alvarez-
Manzaneda, E. J.; Altarejos, J.; Salido, S.; Ramos, J. M. Tetrahedron 1993, 49,
10405–10412; (d) Moulines, J.; Lamidey, A. M.; Desvergnes-Breuil, V. Synth.
Commun. 2001, 31, 749–758; (e) Barrero, A. F.; Alvarez-Manzaneda, E. J.;
Chahboun, R.; Arteaga, A. F. Synth. Commun. 2004, 34, 3631–3643; (f) Bolster,
M. G.; Jansen, B. J. M.; Groot, A. Tetrahedron 2001, 57, 5657–5662; (g) Castro, J.
M.; Salido, S.; Altarejos, J.; Nogueras, M.; Aánchez, A. Tetrahedron 2002, 58,
5941–5949; (h) Bolster, M. G.; Jansen, B. J. M.; Groot, A. Tetrahedron 2001, 57,
5663–5679; (i) Bolster, M. G.; Lagnel, B. M. F.; Jansen, B. J. M.; Morin, C.; Groot,
A. Tetrahedron 2001, 57, 8369–8379; (j) Barrero, A. F.; Alterejos, J.; Alvarez-
Manzaneda, E. J.; Ramos, J.; Salido, S. J. Org. Chem. 1996, 61, 2215–2218; (k)
Barrero, A. F.; Altarejos, J.; Alvarez-Manzaneda, E. J.; Ramos, J. M.; Salido, S.
Tetrahedron 1993, 49, 6251–6262; (l) Barrero, A. F.; Altarejos, J.; Alvarez-
Manzaneda, E. J.; Ramos, J. M.; Salido, S. Tetrahedron 1993, 49, 9525–9534; (m)
Koyama, H.; Karu, Y.; Ohno, M. Tetrahedron Lett. 1987, 28, 2863–2866; (n)
Giacomini, R. A.; Miranda, P. C. M. de L.; Baptistella, L. H. B.; Imamura, P. M.
Arkivoc 2003, 10, 314–322; (o) Hashimoto, T.; Shiki, K.; Tanaka, M.; Takaoka, S.;
Asakawa, Y. Heterocycles 1998, 49, 315–325; (p) Barrero, A. F.; Sanchez, J. F.;
Alvarez-Manzaneda, E. J.; Dorado, M. M.; Haidour, A. Phytochemistry 1993, 32,
1261–1265; (q) Cambie, R. C.; Joblin, K. N.; Preston, A. F. Aust. J. Chem. 1971, 24,
583–591; (r) Nishi, Y.; Ishihara, H. J. Jpn. Oil Chem. Soc. 1989, 38, 276–279.
4. Bohlmann, F.; Fritz, U. Phytochemistry 1978, 17, 1769–1772.
with NaBH3CN3o or with NaBH4 to give 1 in yields of 15% and
10
33%, respectively. Using 1D and 2D NMR analysis, the structure
of 1 was identified as ambroxÒ, but its specific rotation (½a 2D0
ꢁ
+23.0) was in good agreement with that of (+)-ambroxÒ synthe-
sized by Giacomini.3n This indicated that the synthesis of ambroxÒ
from (ꢀ)-nidorellol (2) gave the ent-ambroxÒ configuration instead
of the expected product, (ꢀ)-ambroxÒ (½a D20
ꢁ
-28.8)3o and so the
absolute configuration of (ꢀ)-nidorellol has been shown to be
opposite to that previously reported.4 Therefore, the correct abso-
lute configuration of (ꢀ)-nidorellol is established here to be trans-
(5R⁄,7R⁄,8R⁄,9S⁄,10R⁄)-labda-12,14-diene-7
a,8b-diol.
In conclusion, the synthesis of (+)-ambroxÒ (ent-1) was
achieved in 53% overall yield in seven steps. The absolute configu-
ration of (ꢀ)-nidorellol (2) was established and the structure iden-
tified as an ent-labdane-type diterpene.
5. Zdero, C.; Bohlmann, F.; King, R. M.; Robinson, H. Phytochemistry 1988, 27,
2835–2842.
6. Crystal data for 3 were obtained using a BRUKER SMART CCD diffractometer,
MoK radiation (k = 0.71073 Å), graphite monochromator, C20H34O2, monoclinic,
a
space group P21/c, a = 12.0921(6) Å, b = 11.7469(6) Å, c = 13.6286(7) Å,
V = 1863.68(16) Å3, Z = 4, Dc = 1.092 mg/m3, crystal size 0.30 ꢃ 0.25 ꢃ
Acknowledgments
0.18 mm, F(000) = 680,
l
= 0.068 mmꢀ1. Data were collected at 293(2) K using
x
–2h scans in the ranges h = 1.75ꢀ34.82°. A total of 14997 reflections were
collected, 5648 were unique (Rint = 0.0307). The structure was refined by full-
matrix least-squares on F2. The final refinement [I > 2
(I)] gave R1 = 0.0905,
We thank the 90th Anniversary of Chulalongkorn University
Fund, the National Research University Project of CHE (FW1022B)
and ‘Strategic Scholars Fellowships Frontier Research Networks’ fund
for financial support. Partial support from the Department of
Chemistry, the Faculty of Science, from the Rachadapiseksompoj
Endowment, and Center for Petroleum, Petrochemicals and
Advanced Materials, Chulalongkorn University are also gratefully
acknowledged. Finally, we thank the Analytical Chemistry Labora-
tory, Industrial Metrology and Testing Service Centre, Thailand Insti-
tute of Scientific and Technological Research for GC/MS analysis.
r
wR2 = 0.2542. Crystallographic data for the structure of 3 have been deposited at
the Cambridge Crystallographic Data Centre and allocated the deposition
number 823857. Copies of this information may be obtained free of charge
from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: +44 1223 336 033; email: deposit@ccdc.cam.ac.uk or http://
www.ccdc.cam.ac.uk).
7. Schiaffo, E. C.; Dussault, H. P. J. Org. Chem. 2008, 73, 4688–4690.
8. Crystal data for 6 were obtained using a BRUKER SMART CCD diffractometer,
MoK radiation (k = 0.71073 Å), graphite monochromator, C16H25O3, monoclinic,
a
space group P2(1), a = 6.2810(5) Å, b = 35.810(4) Å, c = 7.3289(9) Å, V =
14925(3) Å3, Z = 4, Dc = 1.181 mg/m3, crystal size 0.18 ꢃ 0.20 ꢃ 0.30 mm,
F(000) = 580,
l x–2h
= 0.080 mmꢀ1. Data were collected at 293(2) K using
scans in the ranges h = 2.27ꢀ26.40°. A total of 11060 reflections were collected,
5864 were unique (Rint = 0.0714). The structure was refined by full-matrix least-
squares on F2. The final refinement [I > 2
r(I)] gave R1 = 0.1077, wR2 = 0.2957.
Supplementary data
Crystallographic data for the structure of 6 have been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition number 820557.
Copies of this information may be obtained free of charge from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44
1223 336 033; email: deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk).
9. Alvarez-Manzaneda, E. J.; Romera, J. L.; Barrero, A. F.; Alvarez-Manzaneda, R.;
Chahboun, R.; Meneses, R.; Aparicio, M. Tetrahedron 2005, 61, 837–844.
10. Caglioti, L. Org. Synth., Coll. 1988, 6, 62–64.
Supplementary data (experimental procedures, spectroscopic
data, X-ray crystallographic data of 4 and 6 and GC/MS spectra fol-
lowing the air-autoxidation of compounds 5a and 5b) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2012.07.120.