Total syntheses of clausamines A-C and clausevatine D

Article abstract of DOI:10.1021/ol703085f

The first total syntheses of clausamines A-C and clausevatine D are reported. The key step involves a Diels-Alder reaction between an imine quinone and cyclic diene, allowing for the subsequent construction of the carbazole core in a regiospecific manner. Stereochemistry of the natural products is also discussed.

Full text of DOI:10.1021/ol703085f

ORGANIC
LETTERS
2008
Vol. 10, No. 5
997-1000
Total Syntheses of Clausamines A
and Clausevatine D
−C
Terry P. Lebold and Michael A. Kerr*
Department of Chemistry, The UniVersity of Western Ontario, London,
Ontario, Canada N6A 5B7
makerr@uwo.ca
Received December 21, 2007
ABSTRACT
The first total syntheses of clausamines A
−C and clausevatine D are reported. The key step involves a Diels
−Alder reaction between an imine
quinone and cyclic diene, allowing for the subsequent construction of the carbazole core in a regiospecific manner. Stereochemistry of the
natural products is also discussed.
In 1998, Ito and co-workers reported the isolation of
clausamines A-C (Figure 1) from the dried branches of
at the 3,4-position; as such, the clausamines are given the
distinction of being the first alkaloids containing this lactonic
carbazole motif to be isolated from nature.2 Shortly after,
Wu and co-workers identified four other carbazole alkaloids
which they named clausevatines D-G, along with known
clausamine A, from the root bark of Clausena excaVata,3 a
wild shrub used in folk medicine for the treatment of
snakebites, abdominal pain, and also as a detoxificant.4
Further study of the extracts of C. excaVata by Itoigawa in
2000 yielded four new carbazoles, clausamines D-G, in
addition to previously known alkaloids. In the same account,
it was reported that clausamines A-D and F possessed
antitumor-promoting properties during short-term in vitro
assays of TPA-induced EBV-EA activation in Raji cells.5
Recently, we have reported that the Diels-Alder adducts
obtained from an imine quinone and cyclic diene allow
(1) For a comprehensive review of carbazole alkaloids see: Kno¨lker,
H. J.; Reddy, K. R. Chem. ReV. 2002, 102, 4303.
(2) Ito, C.; Katsuno, S.; Ruangrungsi, N.; Furukawa, H. Chem. Pharm.
Bull. 1998, 46, 344.
(3) Wu, T.-S.; Huang, S.-C.; Wu, P.-L. Chem. Pharm. Bull. 1998, 46,
1459.
Figure 1. Clausamines A-G and clausevatines E-G.
(4) Sasaki, S. KhoyoTaiwan Minkan Yakuyo Shokubutso Shi (khobunkan),
Taipei, 1924; p 36.
(5) Ito, C.; Katsuno, S.; Itoigawa, M.; Ruangrungsi, N.; Mukainaka, T.;
Okuda, M.; Kitagawa, Y.; Tokuda, H.; Nishino, H.; Furukawa, H. J. Nat.
Prod. 2000, 63, 125.
Clausena anisata in Thailand. Prominent structural features
of these carbazole alkaloids1 include a 1-oxygenated carba-
zole framework to which is appended a six-membered lactone
10.1021/ol703085f CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/31/2008

dihydroxylation would set the stereochemistry of the chiral
center. Intermediate 5 would in turn come from carbazole 6
via Wittig homologation of the aldehyde and carbonylation
of the triflate. Intermediate 6 would be accessible from the
aromatized Diels-Alder adduct 7 via oxidative cleavage of
the double bond and acid-catalyzed cyclization. Adduct 7
would come from a Diels-Alder cycloaddition between
imine quinone 8 and diene 9, themselves easily prepared from
commercially available starting materials.
Scheme 1. Synthesis of Carbazoles
access to functionalized carbazoles in a highly regiocontrolled
fashion (Scheme 1).6 The utility of this transformation was
demonstrated in the first total syntheses of eustifolines A-C
and alternative syntheses of eustifoline D and glycomaurrol.
Herein we report a further application of this methodology
which has enabled the first total syntheses of clausamines
A-C and clausevatine D.
Scheme 3. Synthesis of Clausamine C and Clausevatine D
To date the only reported syntheses of any of the above
compounds are the semi-syntheses of clausamines E and G
(from clausamine D) by Itoigawa and co-workers in their
attempts to confirm their assigned structures.4 Furthermore,
the absolute stereochemistry of clausamines A-C and
clausevatines D-F is not yet known. Interestingly, while
clausevatines D-F were reported to have optical rotations
of -5.7°, -92.4°, and -199.0° respectively, clausamines
A-C were reported to have no optical rotation at all.
Considering that nature does not often carry out chemistry
in a racemic fashion and the fact that clausevatines D-F
possess optical rotations, we postulated that perhaps the lack
of optical activity of clausamines A-C was due to a
combination of an inherent small optical rotation and the
low concentration used in the measurement (approximately
an order of magnitude less than that for clausevatine D) and
not because the molecules were racemic. Therefore, with the
hopes of testing this hypothesis and shedding some light on
the stereochemistry of these natural products, we set out to
synthesize clausamines A-C and clausevatine D in an
asymmetric fashion.
Scheme 2. Synthetic Strategy
Our synthetic endeavors (see Scheme 3) began with the
commercially available nitro-aryl derivative 10 which was
readily converted to the tosylated amino phenol 11 in a three-
step sequence involving nucleophilic aromatic substitution,
reduction of the nitro group, and tosylation of the resulting
amine in 82% overall yield. Treatment of the tosylated amino
phenol 11 with NaIO4/SiO2 then gave access to the desired
imine quinone 8. Treatment of 8 with diene 97 in refluxing
CH2Cl2 allowed for a facile Diels-Alder cycloaddition. The
resulting adduct was treated with catalytic DBU affording
the aromatized species 12 in 81% yield over the two steps.
Derivatization of the phenolic moiety as the triflate was then
carried out using triflic anhydride and pyridine in 90% yield.
Conversion of dihydronaphthalene 12 to the tetrahydrocar-
A brief synthetic strategy is shown in Scheme 2. We en-
visioned all four natural products coming from the elabora-
tion of an intermediate such as 5 in which an asymmetric
(7) Rodriguez, J.; Brun, P.; Waegell, B. J. Organomet. Chem. 1989, 359,
343.
(6) Lebold, T. P.; Kerr, M. A. Org. Lett. 2007, 9, 1883.
998
Org. Lett., Vol. 10, No. 5, 2008

bazole was accomplished via oxidative cleavage of the
double bond (via the diol) followed by treatment of the
resulting dicarbonyl with acid to afford 14 in 95% yield over
the three steps. Treatment of tetrahydrocarbazole 14 with
triphenylphosphonium isopropyl ylide produced the desired
prenyl moiety and alkene 15 in 73% yield. Subjecting alkene
15 to Sharpless asymmetric dihydroxylation conditions8 using
(DHQD)2PHAL resulted in diol formation in 98% yield and
45% ee.9 While the enantioselectivity for the dihydroxylation
was less then optimal, it was deemed sufficient to obtain
optical rotations and provide insight into the stereochemistry
of the natural products and was therefore carried through
the synthesis as the scalemic mixture. With the diol in hand
treatment with 2-methoxypropene under acidic conditions
provided acetonide 16 in 98% yield. Subjection of 16 to
carbonylative conditions yielded the corresponding ester in
59% yield along with unreacted starting material which could
be resubjected to the reaction conditions to give the desired
ester in 71% (96% BRSM) after two cycles.10
Detosylation was then carried out with TBAF to yield
clausamine B in 84% and 46% ee. Again the hydroxyl group
was relinquished via treatment of clausamine B with BBr3
allowing access to clausamine A in 75% yield and 35% ee.13
The stereochemistry of the diol and natural products were
assigned by using the Sharpless mnemonic8 (Scheme 5) in
Scheme 5. Assignment of Stereochemistry
With the phenoxy ester in hand treatment with DDQ
afforded the fully aromatized carbazole 17 in 94% yield.
Simple deprotection of the acetonide with TsOH in ethylene
glycol allowed for the formation of desired lactone 18 in
nearly quantitative yield. Finally, removal of the tosyl group
with TBAF11 produced clausamine C in 82% yield and 47%
ee. Treatment of clausamine C with BBr3 then revealed the
hydroxyl group, thus affording clausevatine D in 72% yield
and 49% ee.
With the completion of clausamine C and clausevatine D,
we turned our attention to the syntheses of clausamines A
and B (see Scheme 4). Our initial attempts to form the
which dihydroxylation occurs from the top face of the alkene
leading to the formation of the (R)-alcohol. With the
successful completion of clausamines A-C and clausevatine
D the optical rotations were measured. Interestingly, contrary
to what was expected, all compounds gave strong positive
rotations of 62.8°, 33.2°, 50.0°, and 50.7° for clausamines
A-C and clausevatine D, respectively, despite their modest
enantiomeric excess. Even at the low concentrations reported
in the literature for clausamines A-C a rotation was
observed. Furthermore, the optical rotation observed for
clausevatine D was an order of magnitude larger than that
which was reported (note also, opposite in sign). Although
a more detailed comparison of the rotations of the synthetic
samples to the natural products is warranted, we were unable
to obtain natural samples toward this end.
While these results may raise more questions than they
answer, several possible explanations exist. It is clear that
these molecules do not have inherently small rotations since
our samples with modest enantiomeric purities gave signifi-
cant rotations. It is possible that the natural products then,
are racemic (or nearly so). Assuming that an enzymatic
process produced enantiomerically distinct products, race-
mization may have occurred post-biosynthesis, either in
nature or during laboratory handling in the isolation process.
What is known, however, is that, based on the generally
Scheme 4. Synthesis of Clausamines A and B
required isopropenyl moiety from alcohol 18 using typical
dehydration conditions (POCl3, pyridine; SOCl2, pyridine;
MsCl, NEt3 or NEt(iPr)2) resulted in significant formation
of the undesired endo tetrasubstituted double bond being
formed. Fortunately, this could be circumvented by treatment
of the alcohol with Martin’s sulfurane12 which formed the
desired exo methylene almost exclusively in 77% yield.
(8) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu,
D.; Zhang, X. L. J. Org. Chem. 1992, 57, 2768.
(9) A modest increase to 55% ee could be obtained by cooling reaction
to 0 °C but required significantly longer reaction times.
(10) Initial attempts to carry out a carbonylative lactonization on the
unprotected diol leading directly to the lactone ring were unsucessful,
forming instead a benzodihydrofuran.
(11) Yasuhara, A.; Sakamoto, T. Tetrahedron Lett. 1998, 39, 595.
(12) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5003.
(13) The slight erosion in ee which was observed is likely due to Lewis
acid-mediated epimerization via an allylic carbocation.
Org. Lett., Vol. 10, No. 5, 2008
999

accepted mnemonic for the Sharpless dihydroxylation, the
(R)-enantiomers of these natural products possess positive
optical rotations.
In conclusion, we have reported the first total syntheses
of clausamines A-C and clausevatine D in an enantioen-
riched fashion, allowing for the assignment of a positive
rotation for the (R)-enantiomers. The overall yields for the
natural products are excellent, allowing for access to
clausamine A-C and clausevatine D in 13% (35% ee), 17%
(46% ee), 22% (47% ee), and 16% (49% ee), respectively.
Acknowledgment is made to the Donors of the American
Chemical Society Petroleum Research Fund for partial
support of this research. We thank Mr. Doug Hairsine of
the University of Western Ontario mass spectrometry facility
for performing MS analyses and Dr. Mike Chong of the
University of Waterloo for use of his polarimeter. T.P.L. is
a CGS-D awardee.
Supporting Information Available: Full experimental
procedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada for funding.
OL703085F
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Org. Lett., Vol. 10, No. 5, 2008