SCHEME 1. Synthesis of Bicyclic Tropinone via
Domino Reaction
Novel Domino Reactions for Diterpene
Synthesis
Shanta S. Bhar and M. M. V. Ramana*
Department of Chemistry, University of Mumbai,
Mumbai-400098, India
Received March 9, 2004
Abstract: New types of concerted domino acylation-
cycloalkylation/alkylation-cycloacylation reactions have been
described. These processes promoted by methanesulfonic
acid-phosphorus pentoxide and concentrated H2SO4, re-
spectively, provide efficient, elegant, and expeditious routes
for biologically active naturally occurring diterpenoids,
namely (()-ferruginol (1), (()-nimbidiol (2), (()-nimbiol (3),
(()-totarol (4), and ar-abietatriene (5).
SCHEME 2. The Common Synthon,
2,6,6-Trimethyl-1-cyclohexane-1-acetic Acid,
Synthesized from the Acyclic Mooterpene Citral
In recent years, the need to improve synthetic effi-
ciency with the aim of generating diversified molecules
has led to the development of domino processes.1-3 The
term domino reaction in organic chemistry was coined
by Tietze4 in 1990. The significant feature of domino pro-
cesses is the formation of complex compounds starting
from simple substrates in two or more steps which occur
in succession in the same pot without isolation of inter-
mediates. In nature domino reactions are rather common,
although a direct comparison to the reactions in a flask
is not possible because of the involvement of multien-
zymes.
The oldest known example of a domino type of reaction
was performed by Robinson5 in the synthesis of a natural
product, a bicyclic tropinone, which is a structural com-
ponent of several alkaloids such as cocaine and atropine
(Scheme 1). The biosyntheses of fatty acids6 and proges-
terone7 are also characteristic examples of the domino
type of reactions.
A domino reaction is therefore defined as a process
involving two or more bond transformations (usually
involving C-C bonds) which take place under the same
reaction conditions without adding additional reagents
and/or catalysts, and in which the second and any
subsequent reactions result as a consequence of the
functionality formed in the previous step.
In this Note, we disclose the strategy designed to
achieve convenient, expeditious, stereocontrolled total
syntheses of several naturally occurring diterpenoids, viz.
(()-ferruginol (1), (()-nimbidiol (2), (()-nimbiol (3), (()-
totarol (4), and ar-abietatriene (5), via a concerted
mechanism of domino acylation-cycloalkylation/alkyla-
tion-cycloacylation as the principal step to construct the
basic carbocyclic framework required for the trans-fused
octahydrophenanthrene nucleus, starting from the readily
available acyclic monoterpene, citral (Scheme 2).
As depicted in Scheme 2, citral (6) was cyclized8 to
2,6,6-trimethyl-1-cyclohexene-1-carboxaldehyde(â-cycloci-
tral) (7), which was then reduced to (2,6,6-trimethylcy-
clohex-1-enyl)methanol (8).9 This was reacted with PBr3
to give 2-(bromomethyl)-1,3,3-trimethylcyclohexene (9),10
which was converted to (2,6,6-trimethylcyclohex-1-enyl)-
acetonitrile (10).11 Nitrile 10 was hydrolyzed with dilute
alkali to give the important intermediate (2,6,6-trimeth-
ylcyclohex-1-enyl)acetic acid (11).12
Acid 11 was subjected to CH3SO3H-P2O5 (10:1) pro-
moted domino acylation-cycloalkylation with anisole (12)
to yield the tricyclic ketone (13), which was subsequently
transformed, as depicted in Scheme 3, to the diterpene
(()-ferruginol (1), known to have antihepatomic, antitu-
mour, antibacterial, and fungicidal13 properties.
Similarly, the acid (11) was subjected to CH3SO3H-
P2O5 promoted domino acylation-cycloalkylation with
veratrole (18) to yield the tricyclic ketone (19), which was
* To whom the correspondence should be addressed. Fax: (91) (22)
26528547.
(8) Heather, J. B.; Mittal, R. S. D.; Sih, C. J. J. Am. Chem. Soc.
1976, 98, 3661-9.
(1) (a) Tietze, L. F.; Beifuss, U. Angew. Chem. 1993, 105 (2), 137-
70. (b) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32
(2), 131-63.
(9) Kuhn, R.; Hoffer, M. Berichte 1934, 67, 357-9.
(10) Andrewes, A. G.; Borch, G.; Liaaen-Jensen, S. Acta Chim.
Scand., Ser. B 1984, B38 (10), 871-5.
(2) Tietze, L. F. Chem. Rev. 1996, 96, 115-36.
(3) Tietze, L. F.; Haunert, F.; Ott, C. Can. J. Chem. 2001, 79 (11),
1511-4.
(11) Kato, T.; Ichinose, I.; Kumazawa, S.; Kitahara, Y. Bioorg. Chem.
1975, 4, 188-93.
(4) Tietze, L. F. J. Heterocycl. Chem. 1990, 27, 47-69.
(5) Robinson, R. J. J. Chem. Soc. 1917, 111, 862-76.
(6) Lynen, F. Pure Appl. Chem. 1967, 14, 137.
(7) Johnson, W. S. Angew. Chem., Int. Ed. Engl. 1976, 15, 9.
(12) Branca, S. J.; Lock, R. L.; Smith, A. B. J. Org. Chem. 1977, 42
(19), 3165-8.
(13) Nishino, C.; Kobayashi, K.; Shiobara, Y.; Kodama, M. Agric.
Biol. Chem. 1988, 52 (1), 77-84.
10.1021/jo049616n CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/11/2004
J. Org. Chem. 2004, 69, 8935-8937
8935