Highly efficient synthesis of (+)-nimbiol and other podocarpanes derivatives from sclareol

Article abstract of DOI:10.1055/s-2007-982533

A new access to tricyclic diterpenes of podocarpane skeleton has been opened, in excellent overall yields, and an efficient synthesis of (+)-nimbiol from sclareol has been achieved. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-982533

LETTER
1589
Highly Efficient Synthesis of (+)-Nimbiol and Other Podocarpanes Derivatives
from Sclareol
H
ighly E
s
f
ficient
S
i
ynthesi
d
s of (+)-Nim
r
biol o S. Marcos,* Alvaro Beneitez, Lourdes Castañeda, Rosalina F. Moro, Pilar Basabe, David Diez, Julio G. Urones
Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caídos 1–5, 37008 Salaman-
ca, Spain
Fax +34(923)294574; E-mail: ismarcos@usal.es
Received 23 March 2007
steps from sclareol by a cheap procedure in an excellent
Abstract: A new access to tricyclic diterpenes of podocarpane
global yield requiring only one column chromatography
in the whole procedure (Scheme 1).
skeleton has been opened, in excellent overall yields, and an effi-
cient synthesis of (+)-nimbiol from sclareol has been achieved.
The transformation of sclareol (1) into methylketone 2 has
been previously used by us.9 Starting from hydroxyketone
2, the podocarpane derivative 4 can be directly obtained in
a 50% yield, but the transformation could be achieved in
a better yield in two steps. Elimination reaction of 2 by
treatment with HI at room temperature gave 3 in a nearly
quantitative yield, which on heating at 85 °C with HI led
to the podocarpane derivative 4 in an excellent yield. Both
reactions were performed on a multigram scale.
Key words: sclareol, diterpenes, podocarpanes, (+)-nimbiol
Diterpenes such as, abietane, pimarane, totarane or
cassane (Figure 1), with the podocarpane tricyclic system,
are highly distributed secondary metabolites.1
The synthesis of the diterpene (+)-nimbiol 9, known to
possess antimicrobial activity,10 was completed in the
following way: Friedel–Crafts acylation of 4 gave 5 that,
Figure 1 Diterpenes with tricyclic skeleton.
The variety and importance of the biological activities that
show these compounds as antitumour,2 antifungal,3 anti-
microbial,4 antiinflammatory,5 antiviral6 among others,
have made them important synthetic objectives for many
years.1b,7
Easy and direct access to the tricyclic system of these
compounds is a very interesting objective that will facili-
tate the synthesis of several members of these compounds
in a straightforward manner.
In this work a three-step synthesis of podocarpanes deriv-
atives starting from commercially available sclareol in
nearly quantitative yield is described. We also describe
the synthesis of the natural product (+)-nimbiol8 in six
Scheme 1 Reagents and conditions: a) KMO4, MgSO4; b) HI, C6H6,
85 °C, 6 h; c) HI, C6H6, r.t., 6 h; d) HI, C6H6, 85 °C, 3 h; e) AcCl,
SnCl4, 85 °C, 0.7 h; f) UHP, TFAA, r.t., 24 h; g) K2CO3, MeOH, H2O,
3%, r.t. 0.5 h; h) Na2CrO4, Ac2O, AcOH, 65 °C, 2 h; i) K2CO3, MeOH,
H2O, 3%, r.t. 0.7 h.
SYNLETT 2007, No. 10, pp 1589–1590
Advanced online publication: 07.06.2007
DOI: 10.1055/s-2007-982533; Art ID: D09007ST
© Georg Thieme Verlag Stuttgart · New York
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I. S. Marcos et al.
LETTER
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J., Ed.; J. Wiley and Sons: New York, 1990.
under Baeyer–Villiger conditions with urea–hydrogen
peroxide (UHP) and TFAA, led to the acetoxy derivative
6. The benzylic oxidation of 6 produced acetoxynimbiol
8, that on alkaline hydrolysis led to (+)-nimbiol 911 in an
excellent 37% global yield from sclareol. Compound 6
was hydrolyzed to give the known deoxynimbiol 712 as
well (Scheme 1).
In conclusion a new straightforward route for the synthe-
sis of diterpenes with podocarpane skeleton starting from
sclareol has been accessed. The synthesis of the natural
compound (+)-nimbiol 9 corroborates the importance of
this new route.
(8) Sengupta, P.; Choudhuri, S. N.; Khastgir, H. N. Tetrahedron
1960, 10, 45.
(9) (a) Marcos, I. S.; Basabe, P.; Laderas, M.; Díez, D.; Jorge,
A.; Rodilla, J. M.; Moro, R. F.; Lighgow, A. M.; Barata, I.
G.; Urones, J. G. Tetrahedron 2003, 59, 2333. (b) Leite, M.
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Acknowledgment
The authors are grateful to Drs. A. Lithgow and Cesar Raposo from
Servicio General de R.M.N. and Servicio General de E.M., respec-
tively and to the CICYT (CTQ2005-04406) for financial support.
We would also like to thank the Junta de Castilla y León for a grant
to L. C. and Universidad de Salamanca for a grant to A. B.
(10) Aladesanmi, A. J.; Odediran, S. A. Fitoterapia 2000, 71,
179.
(11) [a]D22 +31 (c = 0.8, CHCl3); mp 245 °C {Lit.8 [a]D22 +32.3;
mp 250 °C}. IR (film): 3291, 2929, 2869, 1655, 1578, 1458,
1287, 1162, 907, 733, 665 cm–1. 1H NMR (400 MHz,
CDCl3): d = 7.82 (s, 1 H, H-14), 6.75 (s, 1 H, H-11), 5.82 (br
s, 1 H, OH), 2.67 (dd, J = 4.4, 18.0 Hz, 1 H, H-6a), 2.58 (dd,
J = 13.6, 18.0 Hz, 1 H, H-6b), 2.23 (s, 3 H, ArCH3), 1.83 (dd,
J = 4.4, 13.6 Hz, 1 H, H-5), 1.24–1.78 (m, 6 H), 1.20 (s, 3 H,
References and Notes
(1) (a) Glasby, J. S. Encyclopedia of the Terpenoids, Vol. 1; J.
Wiley and Sons: New York, 1982. (b) Glasby, J. S.
Encyclopedia of the Terpenoids, Vol. 2; J. Wiley and Sons:
New York, 1982. (c) Hanson, J. R. Nat. Prod. Rep. 2006, 23,
875; and references cited therein.
(2) (a) Kupchan, S. M.; Karim, A.; Marcks, C. J. Org. Chem.
1969, 34, 3912. (b) Gao, J.; Han, G. Phytochemistry 1997,
44, 759. (c) Son, K.-H.; Oh, H.-M.; Choi, S.-K.; Han, D. C.;
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Ruchirawat, S. J. Nat. Prod. 2005, 68, 1632.
Me-20), 0.98 (s, 3 H, Me-19), 0.92 (s, 3 H, Me-18). 13
C
NMR (50 MHz, CDCl3): d = 38.2 (C-1), 19.1 (C-2), 41.5 (C-
3), 33.5 (C-4), 49.8 (C-5), 36.2 (C-6), 199.3 (C-7), 124.4 (C-
8), 157.3 (C-9), 38.1 (C-10), 109.8 (C-11), 159.7 (C-12),
122.4 (C-13), 131.0 (C-14), 15.4 (ArCH3), 32.8 (C-18), 21.6
(C-19), 23.5 (C-20). HRMS (ESI): m/z [M+] calcd for
C18H24O2: 272.1772; found: 272.1776.
(12) Nakano, T.; Alonso, R.; Maillo, M. A.; Martín, A.; Nuñez,
R. A. J. Chem. Soc., Perkin Trans. 1 1998, 1423.
(b) Rasoamiaranjanahary, L.; Guilet, D.; Marston, A.;
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2003, 64, 543. (c) Hostettmann, K.; Terreaux, C. Chimia
2000, 54, 652.
Synlett 2007, No. 10, 1589–1590 © Thieme Stuttgart · New York

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