Enantioselective total syntheses of (+)- and (-)-ottelione A and (+)- and (-)-ottelione B. Absolute configuration of the novel, biologically active natural products

Article abstract of DOI:10.1016/S0040-4039(03)01643-5

Following our recent total synthesis of the biologically potent natural products otteliones A and B in racemic form, we have now accomplished the total synthesis of both the enantiomers of otteliones A and B through an enantiodivergent strategy emanating from the readily available Diels-Alder adduct of cyclopentadiene and p-benzoquinone. These endeavors have led to the elucidation of the absolute configuration of naturally occurring otteliones A and B.

Full text of DOI:10.1016/S0040-4039(03)01643-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6733–6736
Enantioselective total syntheses of (+)- and (−)-ottelione A and
(+)- and (−)-ottelione B. Absolute configuration of the novel,
biologically active natural products
Goverdhan Mehta* and Kabirul Islam
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 12 May 2003; revised 20 June 2003; accepted 27 June 2003
Abstract—Following our recent total synthesis of the biologically potent natural products otteliones A and B in racemic form, we
have now accomplished the total synthesis of both the enantiomers of otteliones A and B through an enantiodivergent strategy
emanating from the readily available Diels–Alder adduct of cyclopentadiene and p-benzoquinone. These endeavors have led to the
elucidation of the absolute configuration of naturally occurring otteliones A and B.
© 2003 Published by Elsevier Ltd.
Otteliones A and B are two structurally novel natural
products, first reported in 1998 from the widely occur-
ring freshwater plant ottelia alismoides, which exten-
sively lines irrigation canals and rice fields in south east
Asia and Africa.1a Collaborative efforts between the US
and Egyptian scientists1a and subsequent reinvestiga-
tions at Rhone–Poulenc Rorer (now Aventis)1b have led
to the establishment of structures 1 and 2 for ottelione
A (RPR 112378)1b and B, respectively, based mainly on
absolute configuration of otteliones has not yet been
determined though this is an important requirement
vis-a`-vis their biological activity profile. This could
possibly be due to the inability to apply directly chiro-
optical probes to this system. We therefore decided to
settle the absolute configuration of otteliones through
enantioselective synthesis and considering the lack of
consistency5 regarding the specific rotation of the natu-
rally occurring otteliones, it was decided to undertake
the total synthesis of both the enantiomers. These stud-
ies have led to the establishment of the absolute
configuration of ottelione A as (+)-1 and ottelione B as
(−)-2 and these results form the subject matter of this
letter.
1
high field H NMR studies. Otteliones exhibit quite a
remarkable biological activity profile. While the Chi-
nese scientists2a have reported on the anti-tuberculor
effect of the extract of ottelia alismoides rich in otte-
liones, screening against a panel of 60 human cancer
cell lines at the National Cancer Institute has revealed
cytotoxicity of ottelione A at nM–pM levels.1a,2b More
recently, it has been shown that ottelione A is an
efficient inhibitor of tubulin polymerization (IC50=1.2
mM) and is able to disassemble preformed microtubules
in a manner reminiscent of colchicine and vinblastin.1b
These promising biological activity attributes, the pres-
ence of an unusual and reactive 4-methylenecyclohex-2-
enone moiety and the biogenetically interesting
framework make otteliones attractive synthetic
targets.3,4 Several synthetic studies directed towards
otteliones have appeared in the literature3 and we have
recently described the first total synthesis4 of ottelione
A 1 and ottelione B 2 in racemic form, which also
unambiguously settled their structures. However, the
Our total synthesis of rac-otteliones had commenced
from the readily available Diels–Alder adduct 36 of
cyclopentadiene and p-benzoquinone and involved the
terminal olefin 4 as an intermediate.4 In order to
achieve the synthesis of both (+)- and (−)-otteliones A
and B, access to both the enantiomers of 4 from 3 was
* Corresponding author.
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/S0040-4039(03)01643-5

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G. Mehta, K. Islam / Tetrahedron Letters 44 (2003) 6733–6736
required through an enantiodivergent route. This was
accomplished employing enzymatic desymmetrization
as the key step. Adduct 3 on LAH reduction furnished
hydroxy-ketone 5 which was oxidized with PCC to the
dione 6 (Scheme 1).7 DIBAL-H reduction of 6 was
stereoselective and led to the endo,endo-diol 7. The
meso-diol 7 was subjected to lipase catalysed transester-
ification, as described earlier by Ogaswara et al.8 to
furnish enantiopure monoacetate (+)-8 (Scheme 1).
TBS-protection of the hydroxyl group in (+)-8 gave
(+)-9 and the acetate group was hydrolyzed to (−)-10
and further oxidized to the ketone (+)-11. Lombardo
methylation9 of (+)-11 led to (+)-12, and TBS deprotec-
tion furnished enantiomerically pure (+)-4, the key
starting material for our ottelione synthesis.10
The hydroxy-methylene compound (+)-4 was elabo-
rated to ottelione A essentially following the route
outlined by us4 for the racemic synthesis of otteliones
and is schematically represented in Scheme 2. Success-
ful implementation of Scheme 2 led to (+)-ottelione A 1
which had a specific rotation of +19.2 (c 0.52, CHCl3).5
The observed rotation of our synthetic ottelione A was
a good match with that reported for the natural
product. We also compared the CD spectrum11 of the
synthetic ottelione A with that of the natural product
and found them to be identical, thus establishing the
absolute configuration of ottelione A as (+)-1.11,12
Scheme 2. Reagents and conditions: (a) i. O3, MeOH, −78°C,
n
ii. Me2S, rt 72%; (b) Ph3PCH3+I−, BuLi, THF, 0°C, 86%; (c)
PCC, DCM, 0°C, 90%; (d) 4-bromo-1-methoxy-2-(tert-
n
butyldimethylsiloxy)benzene, BuLi, THF, −78°C–rt, 88%; (e)
Otteliones A and B have a diastereomeric relationship
with respect to the C9 stereogenic center and we have
shown4 that the former can be isomerized to the latter
Li, liq. NH3, THF, −33°C, 65%; (f) PCC, DCM, 0°C, 87%;
(g) i. LHMDS, PhSeCl, THF, −78°C; ii. 30% H2O2, DCM,
0°C, 70% (two steps); (h) TBAF, THF, 0°C, 72%.
on exposure to base. Consequently, synthetic (+)-otte-
lione A 1 on treatment with DBU resulted in C9
epimerization to furnish (−)-ottelione B 2 having a
specific rotation of −250 (c 0.24, CHCl3) similar to that
reported5,11 for ottelione B and led to confirmation of
the absolute configuration (−)-2 for the natural product
(Scheme 3).
Initially, not having any inkling of the absolute configu-
ration of otteliones and also in the backdrop of confl-
icting information5 about the specific rotation of the
natural products, we decided to undertake simulta-
neously the synthesis of both the enantiomers of otte-
liones. Consequently, the starting Diels–Alder adduct 3
was elaborated to the key intermediate (−)-4 in enan-
tiomerically pure form10 through an adaptation of an
earlier described procedure (Scheme 4).8
Scheme 1. Reagents and conditions: (a) LiAlH4, ether, 0°C,
78%; (b) PCC, DCM, 0°C, 82%; (c) DIBAL-H, DCM, −78°C,
83%; (d) Lipase PS (amano), vinyl acetate, THF, rt 85%; (e)
TBSCl, imidazole, DMAP, DCM, 90%; (f) K2CO3, MeOH,
0°C, 80%; (g) PDC, DCM, rt 86%; (h) Zn-TiCl4-CH2Br2,
DCM, 0°C, 79%; (i) TBAF, THF, rt 88%.
Scheme 3. Reagents and conditions: (a) DBU, benzene, 65°C,
83%.

G. Mehta, K. Islam / Tetrahedron Letters 44 (2003) 6733–6736
6735
The hydroxy-acetate (+)-8 was oxidized to the acetoxy-
ketone (−)-13 and Lombardo methylenation9 led to the
terminal olefin (+)-14 (Scheme 4). Acetate deprotection
in 14 delivered the desired key intermediate (−)-4.10
Following the synthetic sequence outlined in Scheme 2
for the synthesis of (+)-ottelione A 1, (−)-4 was elabo-
rated to (−)-ottelione A 1 (ent-ottelione A), [h]D −17 (c
0.4, CHCl3), Scheme 5. Finally, (−)-ottelione A 1 was
epimerized with DBU to furnish (+)-ottelione B 2 (ent-
ottelione B), [h]D +246 (c 0.4, CHCl3), Scheme 6.5
In short, we have outlined enantioselective syntheses of
both the enantiomers of otteliones A and B from the
Diels–Alder adduct 3 of cyclopentadiene and p-benzo-
quinone, following an enantiodivergent strategy. Our
synthetic studies have established the absolute configu-
ration of the naturally occurring otteliones A and B as
(+)-1 and (−)-2, respectively.
Scheme 4. Reagents and conditions: (a) PDC, DCM, 0°C,
80%; (b) Zn-TiCl4-CH2Br2, DCM, 0°C, 76%; (c) K2CO3,
MeOH, 0°C, quant.
Acknowledgements
K.I. thanks CSIR, India for the award of a research
fellowship. This work was supported by the Chemical
Biology Unit of JNCASR at the Indian Institute of
Science, Bangalore. The lipase used in this study was a
gift from Dr. Y. Hirose of Amano Pharmaceutical Co.
Ltd, Japan.
References
1. (a) Ayyad, S. E. N.; Judd, A. S.; Shier, W. T.; Hoye, T.
R. J. Org. Chem. 1998, 63, 8102; (b) Combeau, C.;
Provost, J.; Lanceli, F.; Tournoux, Y.; Prod’homme, F.;
Herman, F.; Lavelle, F.; Leboul, J.; Vuilhorgne, M. Mol.
Pharm. 2000, 57, 553.
2. (a) Li, H.; Li, H.; Qu, X.; Shi, Y.; Guo, L.; Yuan, Z.
Zhongguo Zhongyao Zazhi (Chin. J. Chin. Mat. Med.)
1995, 20, 128; (b) Leboul, J.; Prevost, J. French Patent
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3. (a) Mehta, G.; Reddy, D. S. Chem. Commun. 1999, 2193;
(b) Mehta, G.; Islam, K. Synlett 2000, 1473; (c) Trem-
bleau, L.; Patiny, L.; Ghosez, L. Tetrahedron Lett. 2000,
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2881; (e) Clive, D. L. J.; Fletcher, S. P. Chem. Commun.
2002, 1940; (f) Hoye, T. R., private communication.
4. Mehta, G.; Islam, K. Angew. Chem., Int. Ed. Engl. 2002,
41, 2396.
Scheme 5. Reagents and conditions: (a) i. O3, MeOH, −78°C,
n
ii. Me2S, rt 70%; (b) Ph3PCH3+I−, BuLi, THF, 0°C, 85%; (c)
5. The two full papers1a,b dealing with the structure elucida-
tion of otteliones do not report the specific rotation of
these natural products. However, in response to our
queries, Professor Hoye from the University of
Minnesota1a informed us that the two samples of otte-
lione A isolated by his group exhibited specific rotations
of +22 (c 1.25, CDCl3) and +14 (c 0.87, CHCl3), respec-
tively. On the other hand, Dr. H. Bouchard of Aventis
(formerly RPR)1b informed us that their sample of otte-
lione A had a specific rotation of −20.8 (c 0.5, CH2Cl2).
This was quite intriguing and spurred us to undertake the
total synthesis of both the enantiomers of ottelione A.
Professor Hoye has also informed us that a sample of
ottelione B prepared by them had a rotation of −276 (c
2.0, CHCl3). We are most grateful to Professor Hoye and
Dr. Bouchard for information regarding the rotations of
otteliones.
PCC, DCM, 0°C, 91%; (d) 4-bromo-1-methoxy-2-(tert-
n
butyldimethylsiloxy)benzene, BuLi, THF, −78°C–rt, 87%; (e)
Li, liq. NH3, THF, −33°C, 85%; (f) PCC, DCM, 0°C, 86%;
(g) i. LHMDS, PhSeCl, THF, −78°C; ii. 30% H2O2, DCM,
0°C, 68% (two steps); (h) TBAF, THF, 0°C, 77%.
Scheme 6. Reagents and conditions: (a) DBU, benzene, 65°C,
81%.

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G. Mehta, K. Islam / Tetrahedron Letters 44 (2003) 6733–6736
6. (a) Diels, O.; Blom, J. M.; Koll, W. Ann. 1925, 443, 247;
information with Professor Hoye that proved crucial
in arriving at the correct absolute configuration of
otteliones. Hoye’s group has independently arrived at
the same conclusion about the absolute configuration
of otteliones on the basis of the Mosher ester studies
with the alcohol derived from the reduction of ottelione
A.
(b) Cookson, R. C.; Crundwell, E.; Hill, R. R.; Hudec, J.
J. Chem. Soc. 1964, 3062.
7. All compounds reported here were characterized through
spectral comparison with their racemic counterparts pre-
pared earlier by us.4
8. Konno, H.; Ogasawara, K. Synthesis 1999, 1135.
9. Lombardo, L. Tetrahedron Lett. 1982, 23, 4293.
10. Enantiomeric purity of the key intermediates (+)-4, [h]D
+93.7 (c 2.23, CHCl3) and (−)-4, [h]D −93.6 (c 1.72,
CHCl3) was determined through comparison of the spe-
cific rotation of the enzymatically desymmetrized com-
mon precursor (+)-8, [h]D +48.2 (c 1.7, CHCl3), [lit. [h]D
+44.2 (c 1.6, CHCl3)],8 >99% ee, with the literature
values.
12. While we have unambiguously determined the absolute
configuration of otteliones through enantiodivergent syn-
thesis of both the enantiomers of otteliones A and B, the
observed specific rotation of −20.8 by the Aventis group
remains puzzling. One possible explanation could be that
their sample of (+)-ottelione A was contaminated with
ottelione B, [h]D −276 having high negative (opposite)
rotation and thus leading to the observation of net nega-
tive rotation for ottelione A.
11. We greatly appreciate the free and helpful exchange of