Asymmetric total synthesis of clavolonine

Article abstract of DOI:10.1021/ol200376z

The asymmetric total synthesis of clavolonine (1) has been achieved based on chiral auxiliary multiple-use methodology. Our synthetic route features stereoselective transformations on the cyclohexane ring utilizing the steric environment of the chiral aux

Full text of DOI:10.1021/ol200376z

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2015–2017
Asymmetric Total Synthesis of Clavolonine
Kenji Nakahara, Kie Hirano, Ryota Maehata, Yasuyuki Kita,† and Hiromichi Fujioka*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka,
Suita, Osaka, 565-0871 Japan
fujioka@phs.osaka-u.ac.jp
Received February 9, 2011
ABSTRACT
The asymmetric total synthesis of clavolonine (1) has been achieved based on chiral auxiliary multiple-use methodology. Our synthetic route
features stereoselective transformations on the cyclohexane ring utilizing the steric environment of the chiral auxiliary and an intramolecular
Mannich reaction to construct the fused ring system.
The Lycopodium alkaloids have received significant atten-
tion because of their architectural complexity and wide-
ranging biological properties.1 Recently, the asymmetric total
synthesis of various structural types of Lycopodium alkaloids
have been achieved by many research groups.2 Clavolonine
(1) was first isolated in 1960 from the club moss Lycopodium
clavatum by Burnell and co-workers.3 This alkaloid is struc-
turally categorized into the lycopodine (2)4,5 class.1a Our
interest in the synthesis of 1 was stimulated by its intriguing
structure, a tetracyclic framework with six contiguous stereo-
genic centers (Figure 1), as well as potential anticholinesterase
activity.6 The development of a facile entry to 1 would set the
stage for allowing a total synthesis of other structurally
related alkaloids.7 To date, three total syntheses of 1 have
been reported. One was in racemic form,8 the other two were
in enantiomerically pure form.9
† Present address: College of Pharmaceutical Sciences, Ritsumeikan
University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan.
(1) (a) Ma, X.; Gang, D. R. Nat. Prod. Rep. 2004, 21, 752. (b)
Hirasawa, Y.; Kobayashi, J.; Morita, H. Heterocycles 2009, 77, 679.
(c) Ayer, W. A.; Trifonov, L. S. In The Alkaloids; Cordell, G. A., Brossi,
A., Eds.; Academic Press: New York, 1994; Vol. 45, p 233. (d) Kobayashi,
J.; Morita, H. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New
York, 2005; Vol. 61, p 1.
(2) For recent reports of asymmetric synthesis of Lycopodium alka-
loids, see: (a) Ramharter, J.; Weinstabl, H.; Mulzer, J. J. Am. Chem. Soc.
2010, 132, 14338. (b) Nakamura, Y.; Bruke, A. M.; Kotani, S.; Ziller,
J. W.; Rychnovsky, S. D. Org. Lett. 2010, 12, 72. (c) Fischer, D. F.;
Sarpong, R. J. Am. Chem. Soc. 2010, 132, 5926. (d) Liau, B. B.; Shair,
M. D. J. Am. Chem. Soc. 2010, 132, 9594. (e) Altaman, R. A.; Nilsson,
B. L.; Overman, L. E.; de Alaniz, J. R.; Rohde, J. M.; Taupin, V. J. Org.
Chem. 2010, 75, 7519. (f) Canham, S. M.; France, D. J.; Overman, L. E.
J. Am. Chem. Soc. 2010, 132, 7876. (g) Yuan, C.; Chang, C.-T.; Axelrod,
A.; Siegel, D. J. Am. Chem. Soc. 2010, 132, 5924. (h) Nishimura, T.;
Unni, A. K.; Yokoshima, S.; Fukuyama, T. J. Am. Chem. Soc. 2011, 133,
418.
Figure 1. Structures of clavolonine (1) and lycopodine (2).
As a part of our ongoing study on the development of
asymmetric reactions using C2-symmetric diols as chiral
auxiliaries, we have described
a
diastereoselective
(6) Ortega, M. R.; Agnese, A. M.; Cabrera, J. L. Phytomedicine 2004,
11, 539.
(3) (a) Burnell, R. H.; Taylor, D. R. Chem. Ind. 1960, 1239. (b)
Burnell, R. H.; Mootoo, B. S. Can. J. Chem. 1961, 39, 1090.
(7) A number of structurally related analogues have been isolated
(see ref 1a). In fact, Breit et al. converted 1 into the two natural products
(-)-deacetylfawcettiine and (þ)-acetylfawcettiine (see, ref 9b).
(8) Wenkert, E.; Broka, C. A. J. Chem. Soc., Chem. Commun. 1984,
714.
€
(4) (a) Bodeker, K. Justus Liebigs Ann. Chem. 1881, 208, 363. (b)
Achmatowicsz, O.; Uzieblo, W. Rocz Chem. 1938, 18, 88. (c) Ayer,
W. A.; Iverach, G. G. Tetrahedron Lett. 1962, 3, 87. (d) Rogers, D.;
Quick, A.; Hague, M. Acta Crystallogr. 1974, B30, 552. (e) Hague, M.;
Rogers, D. J. Chem. Soc., Perkin Trans. 2 1975, 93.
(5) For asymmetric synthesis of lycopodine, see: (a) Yang, H.; Carter,
R. G. J. Org. Chem. 2010, 75, 4929. (b) Yang, H.; Carter, R. G.;
Zakharov, L. N. J. Am. Chem. Soc. 2008, 130, 9238.
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6038. (b) Laemmerhold, K. M.; Breit, B. Angew. Chem., Int. Ed. 2010,
49, 2367.
r
10.1021/ol200376z
2011 American Chemical Society
Published on Web 03/09/2011

desymmetrization of symmetric dienes10 that leads to many
stereogenic centers being installed in a one-pot reaction. This
chemistry has been applied in natural product synthesis.11
During our studies, we have recently developed a new
strategy for the asymmetric synthesis of natural products,
known as chiral auxiliary multiple-use methodology.12
Usually, chiral auxiliaries work only during asymmetric
reactions to induce asymmetric centers, and they are then
removed from the substrates as stoichiometric waste or
recyclable molecules. In contrast, we have utilized a single
chiral auxiliary not only for asymmetric induction but also as
a regio- or stereochemical directing group and a protective
group for hydroxyl functions during further transformations,
and achieved a concise synthesis of (þ)-Sch 642305.12 As an
extension of this concept, we now report an expeditious
asymmetric total synthesis of clavolonine.
Scheme 2. Synthesis of 10
Scheme 1. Retrosynthetic Analysis
cyclohexadiene acetal 3 by sequential bromoetherification
and hydroboration/oxidation using (S,S)-hydrobenzoin as a
chiral auxiliary (Scheme 2).12 The bulky eight-membered
acetal moiety of 4 shields the R-face of the cyclohexane ring
to prevent ring inversion, since the two phenyl groups prefer
to occupy an equatorial position which restricts the con-
formational flexibility. We assumed that stereoselective in-
troduction of the alkyl chains on the cyclohexane in 4 could
then occur. The coupling of the lithium enolate of 4 with
3-chloropropyl triflate13 gave poor results due to the low
reactivity of the resulting conjugated enolate. After extensive
experimentation, we chose KHMDS as the base to afford 5
in a moderate yield (48%), along with a competitive O-
alkylative product. A Michael addition to 5with MeMgBr in
the presence of CuI gave 6. It was followed by azidation
(NaN3, NaI) to provide 7 in 73% in two steps. The azide 7
was obtained as a single diastereomer, suggesting that the
alkylations (4f5, 5f6) proceeded with a facial selectivity
from the sterically less-hindered side (the upper side of the
cyclohexane ring). Hydrolysis of the acetal in 7 with DDQ14
afforded the corresponding aldehyde 8 in 83% yield.
A chemoselective Grignard reaction was accomplished with
4-methoxybutanemagnesium chloride15 to provide the diol 9
in 45% yield (73% yield based on the consumed starting
material 8) (dr = ca. 5:1). Finally, treatment of 9 with
Our retrosynthetic analysis is outlined in Scheme 1. In
principle, construction of the tetracyclic structure in 1 could
be achieved from 13, which could be formed through a
Staudinger/aza-Wittig reaction, an isomerization at the R-
position of the ketone, and an intramolecular Mannich reac-
tion on 10. The synthesis of the cyclization precursor 10 was
envisioned to come from the acetal 7, which could be obtained
from 4 by stereoselective introduction of alkyl units on the
cyclohexane ring utilizing the steric environment of the eight-
membered acetal. The cyclohexenone 4 has already been
synthesized through stereoselective bromoetherification of
the C2-symmetric diene acetal 3 in our laboratory.11a,12
Our synthesis commenced with the enone 4, which
is readily prepared in multigram quantities from the
(10) For reviews, see: (a) Rahman, N. A.; Landais, Y. Curr. Org.
Chem. 2002, 6, 1369. (b) Hoffmann, R. W. Synthesis 2004, 2075. (c)
Nakahara, K.; Fujioka, H. Symmetry 2010, 2, 437.
(11) (a) Fujioka, H.; Kotoku, N.; Sawama, Y.; Kitagawa, H.; Ohba,
Y.; Wang, T.-L.; Nagatomi, Y.; Kita, Y. Chem. Pharm. Bull. 2005, 53,
952. (b) Fujioka, H.; Ohba, Y.; Hirose, H.; Murai, K.; Kita, Y. Angew.
Chem., Int. Ed. 2005, 44, 734. (c) Fujioka, H.; Ohba, Y.; Hirose, H.;
Nakahara, K.; Murai, K.; Kita, Y. Tetrahedron 2008, 64, 4233. (d)
Fujioka, H.; Nakahara, K.; Hirose, H.; Hirano, K.; Oki, T.; Kita, Y.
Chem. Commun. 2011, 47, 1060. (e) Fujioka, H.; Sawama, Y.; Kotoku,
N.; Ohnaka, T.; Okitsu, T.; Murata, N.; Kubo, O.; Li, R.; Kita, Y.
Chem.;Eur. J. 2007, 13, 10225. (f) Fujioka, H.; Nakahara, K.; Oki, T.;
Hirano, K.; Hayashi, T.; Kita, Y. Tetrahedron Lett. 2010, 51, 1945.
(12) Fujioka, H.; Ohba, Y.; Nakahara, K.; Takatsuji, M.; Murai, K.;
Ito, M.; Kita, Y. Org. Lett. 2007, 9, 5605.
(13) Gmeiner, P.; Feldman, P. L.; Chu-Moyer, M. Y.; Rapoport, H.
J. Org. Chem. 1990, 55, 3068.
ꢀ
(14) Fernandez, J. G.; Mellet, C. O.; Marın, A. M.; Fuentes, J.
´
Carbohydr. Res. 1995, 274, 263.
(15) Hara, Y.; Matsuda, M. J. Org. Chem. 1975, 40, 2786.
2016
Org. Lett., Vol. 13, No. 8, 2011

Dess-Martin periodinane gave the cyclization precursor 10
in 94% yield.
Scheme 3. Completion of the Total Synthesis of 1
Figure 2. NOE experiment of 10.
The stereochemistry of 10 was assigned based on an NOE
experiment. NOEs between 11-H and 14-βH, 14-βH and16-
CH3, 14-βH and 8-H, and 16-CH3 and 8-H were observed as
shown in Figure 2. This supported the stereochemical out-
come in Figure 2, with 14-βH, 8-H, 11-H, and 16-CH3, all
situated on the same face of the cyclohexane ring in 10.
For completion of the total synthesis of 1, we envisioned
that the intramolecular Mannich reaction would construct
the tricyclic ring system, inspired by Heathcock’s pioneering
work (Scheme 3).16 The Staudinger/aza-Wittig reaction of
10 with PPh3 quantitatively led to the imine 11.9b Direct
exposure of the crude product 11 to methanolic HCl
afforded the tricyclic amine 13 (dr = ca. 4:1) in an 83%
overall yield from 11. We speculated that this reaction
would proceed via the intermediate 12, which is the 12-C
epimerization compound of 11. The Mannich reaction of 11
would not be expected to proceed through the kinetically
disfavored boat-like transition state, whereas the chairlike
transition state from 12 would be predicted to smoothly
produce 13.17 Surprisingly, treatment of 13 with HBr in
AcOH effected conversion of the methoxy group to the
bromide with concomitant cleavage of the auxiliary unit
and protection as an acetate. Intramolecular nucleophilic
substitution and saponification under basic conditions
(aqueous NaOH in MeOH) thereafter afforded clavolonine
yield). Our synthetic route requires fewer steps for
achieving the total synthesis than previous reports.9
The key feature is that a chiral auxiliary subunit in the
molecules plays an important role in the construction of
the asymmetric centers on the cyclohexane ring and it
also serves as a protective group for the hydroxyl func-
tions. The tetracyclic structure was assembled through
the Staudinger/aza-Wittig reaction and subsequent in-
tramolecular Mannich reaction. Our synthetic approach
also provides potential access to related Lycopodium
alkaloids and various designed analogues for biological
studies. Further synthetic work is currently underway in
our laboratory.
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research (A) and (B), Grant-
in-Aid for Scientific Research for Exploratory Research
from Japan Society for the Promotion of Science, and
Grant-in-Aid for Scientific Research on Priority Areas
(17035047) from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
(1) in 63% yield. The spectroscopic data and optical rota-
28.3
tion [[R]D
þ22.8 (c 0.36, EtOH), lit.9a [R]D þ21.3 (c 0.5,
EtOH), lit.9b [R]D þ28.3 (c 0.50, EtOH)] were identical
20
with the reported data.9
In conclusion, we have described a concise asymmetric
total synthesis of clavolonine with a longest linear
sequence of 10 steps from the enone 4 (10.4% overall
Supporting Information Available. Experimental details
and detailed spectroscopic data of all new compounds and
synthetic clavolonine. This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) (a) Heathcock, C. H.; Kleinman, E. F. J. Am. Chem. Soc. 1981,
103, 222. (b) Heathcock, C. H.; Kleinman, E. F.; Binkley, E. S. J. Am.
Chem. Soc. 1982, 104, 1054.
(17) (a) Stevens, R. V.; Lee, A. W. M. J. Am. Chem. Soc. 1979, 101,
7032. (b) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289.
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