established.6 Totarol is approved for use as an antimicrobial
additive in several consumer products, including toothpaste
and acne treatments.7 Although several previous studies have
probed the origin of totarol’s antimicrobial activity,8 FtsZ
was only recently identified as a discrete molecular target.9
We have undertaken the synthesis of totarol and related
diterpenes as part of a broader research program aimed at
discerning the mechanism by which FtsZ can be inactivated
by small molecules. Previous syntheses of totarol include
routes to racemic material10 and semisyntheses11 from chiral
terpenoid precursors. Recent routes to related tricyclic
systems have focused on electrophile-induced cyclization of
polyene-derived precursors. Efficient syntheses of analogous
tricyclic compounds have been reported using enantioselec-
tive protonation12 and halogenation13 of alkenes to effect
polycyclization reactions. None of these efforts to date has
resulted in the synthesis of the related diterpenoids totaradiol
and totarolone. As a result, medicinal studies of totarol rely
on preparing derivatives of the natural material, largely
limiting these studies to modifications of the B and C rings.14
We recognized that an epoxide-initiated polycyclization
would provide access to all three natural products and enable
the synthesis of previously inaccessible A-ring derivatives
for biochemical studies.
Scheme 1. Retrosynthesis of Totarol, Totaradiol and Totarolone
Retrosynthetic analysis reveals that a suitable precursor (4,
Scheme 1) is produced by benzylic attachment of epoxygeraniol
to a substituted arene. Cyclizations of related substrates have
been described,15 and these substrates are produced by either
copper- or palladium-catalyzed cross-coupling reactions to
allylic acetates or halides, respectively.16,17 Alternatively, direct
coupling of Grignard reagents to allylic phosphonates has
also been employed.18 A consistent synthetic challenge is
the installation of the epoxide at one of the two trisubstituted
alkenes. The established lack of regiocontrol in the Sharpless
asymmetric dihydroxylation (SAD) reaction19 would neces-
sitate installation of the epoxide before the coupling reaction
(Scheme 1, route A). Given the liability posed by the use of
benzylic Grignard reagents, we also considered an alternate
coupling using dithiane 9 (Scheme 1, route B). The latter
route would rely on steric control of the dihydroxylation.20
This synthetic scheme provides protected totaradiol directly
from the polycyclization and totarol or totarolone by
subsequent deoxygenation or oxidation, respectively.
(6) Much of the history of totarol has been reviewed, see: Bendall, J. G.;
Cambie, R. C. Aust. J. Chem. 1995, 48, 883–917.
(7) (a) Nixon, D.; Hobbs, D. NZ Family Phys. 2006, 33, 253–255, http://
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(8) Muroi, H.; Kubo, I. Biosci., Biotechnol., Biochem. 1994, 58, 1925–
1926. (b) Muroi, H.; Kubo, I. J. Appl. Bacteriol. 1996, 80, 387–394. (c)
Kubo, I.; Muroi, H.; Himejima, M. J. Nat. Prod. 1992, 55, 1436–1440. (d)
Haraguchi, H.; Oike, S.; Muroi, H.; Kubo, I. Planta Med. 1996, 62, 122–
125. (e) Constantine, G. H.; Karchesy, J. J.; Franzblau, S. G.; LaFleur, L. E.
Fitoterapia 2001, 72, 572–574.
We initially explored route A by preparing the precursor
to 4 in seven steps (Scheme 2). Acid 10 was converted to
the amide precursor of 12 via the reaction of the mixed
anhydride with amide 11.21 The resultant amide was cyclized
to oxazoline 12 using triethylamine and methanesulfonyl
(9) Jaiswal, R.; Beuria, T. K.; Mohan, R.; Mahajan, S. K.; Panda, D.
Biochemistry 2007, 46, 4211–4220.
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2008, 56, 287–291. Additional synthetic work is described in ref 6.
(11) (a) Matsumoto, T.; Suetsugu, A. Bull. Chem. Soc. Jpn. 1979, 52,
1450–1453. (b) Marcos, I. S.; Cubillo, M. A.; Moro, R. F.; Diez, D.; Basabe,
P.; Sanz, F.; Urones, J. G. Tetrahedron Lett. 2003, 44, 8831–8835. (c)
Marcos, I. S.; Cubillo, M. A.; Moro, R. F.; Carballares, S.; Diez, D.; Basabe,
P.; Llamazares, C. F.; Beneitez, A.; Sanz, F.; Broughton, H. B.; Urones,
J. G. Tetrahedron 2005, 61, 977–1003.
(16) (a) Baeckvall, J. E.; Sellen, M. Chem. Commun. 1987, 827–829.
(b) Baeckvall, J. E.; Sellen, M.; Grant, B. J. Am. Chem. Soc. 1990, 112,
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(20) A high level of steric control has been observed in a substrate related
to 4 that is shorter by one carbon between the phenyl ring and the central
alkene, see: Neighbors, J. D.; Mente, N. R.; Boss, K. D.; Zehnder, D. W.;
Wiemer, D. F. Tetrahedron Lett. 2008, 49, 516–519.
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