First Asymmetric Total Syntheses of Fawcettimine-Type Lycopodium Alkaloids, Lycoposerramine-C and Phlegmariurine-A

Article abstract of DOI:10.1021/ol902437t

"Chemical Equation Presented" A successful asymmetric total synthesis of lycoposerramine-C involving such key steps as a cobalt-mediated Pauson-Khand reaction and vinyl Claisen rearrangement and its biomimetic transformation to phlegmariurine-A are descri

Full text of DOI:10.1021/ol902437t

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5554-5557
First Asymmetric Total Syntheses of
Fawcettimine-Type Lycopodium
Alkaloids, Lycoposerramine-C and
Phlegmariurine-A
Atsushi Nakayama, Noriyuki Kogure, Mariko Kitajima, and Hiromitsu Takayama*
Graduate School of Pharmaceutical Sciences, Chiba UniVersity, 1-33 Yayoi-cho,
Inage-ku, Chiba 263-8522, Japan
htakayam@p.chiba-u.ac.jp
Received October 22, 2009
ABSTRACT
A successful asymmetric total synthesis of lycoposerramine-C involving such key steps as a cobalt-mediated Pauson-Khand reaction and
vinyl Claisen rearrangement and its biomimetic transformation to phlegmariurine-A are described.
Lycopodium alkaloids have unique skeletal characteristics
and a variety of biological activities, such as acetylcholine
esterase (AChE) inhibition.1 These have inspired many
groups including ours2 to develop the total syntheses of
Lycopodium alkaloids.3 Lycoposerramine-C (1)4 isolated
from Lycopodium serratum by us is a new fawcettimine-
type Lycopodium alkaloid possessing a double bond at the
C-6-C-7 positions of fawcettimine (2) (Figure 1). Although
preliminary biological screening indicated that it possesses
(1) For recent reviews, see: (a) Hirasawa, Y.; Kobayashi, J.; Morita, H.
Heterocycles 2009, 77, 679. (b) Kobayashi, J.; Morita, H. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: New York, 2005; Vol. 61, p 1. (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) Ma, X.; Gang,
D. R. Nat. Prod. Rep. 2004, 21, 752.
Figure 1. Structures of fawcettimine-type (1, 2) and phlegmariurine-
type alkaloids (3, 4).
(2) (a) Nishikawa, Y.; Kitajima, M.; Kogure, N.; Takayama, H.
Tetrahedron 2009, 65, 1608. (b) Nishikawa, Y.; Kitajima, M.; Takayama,
H. Org. Lett. 2008, 10, 1987. (c) Shigeyama, T.; Katakawa, K.; Kogure,
N.; Kitajima, M.; Takayama, H. Org. Lett. 2007, 9, 4069. (d) Katakawa,
K.; Kitajima, M.; Aimi, N.; Seki, H.; Yamaguchi, K.; Furihata, K.;
Harayama, T.; Takayama, H. J. Org. Chem. 2005, 70, 658.
potent AChE inhibitory activity, further examination of the
activity has been restricted by its limited availability in
nature. To develop an efficient synthetic route to 1, directly
10.1021/ol902437t CCC: $xxxx
Published on Web 11/05/2009
 2009 American Chemical Society

confirm its absolute configuration, and investigate its bio-
mimetic chemical transformation into phlegmariurine-A (3),
we planned the asymmetric total synthesis of 1. Herein, we
report the first asymmetric total synthesis of 1, which
involves the cobalt-mediated Pauson-Khand reaction and
the vinyl Claisen rearrangement as key steps, as well as the
efficient conversion of 1 into 3.
stereoselectively obtained by vinyl Claisen rearrangement
of the allyl alcohol derivative derived from 8, which in turn
could be constructed from 1,7-enyne compound 9 via the
cobalt-mediated Pauson-Khand reaction. Substrate 9 for the
Pauson-Khand reaction would be prepared by coupling
optically active Weinreb amide 10 with alkyne 11.
We initially prepared 1,7-enyne compound 15 for the
Pauson-Khand reaction, which was synthesized from cro-
tonamide 12 via a five-step operation (Scheme 2) that
Our synthetic plan is shown in Scheme 1. Construction
of the hemiaminal function in 1 was expected by removal
Scheme 2
Scheme 1. Retrosynthetic Analysis
of the N-Boc group and epimerization at C-45 in diketone
derivative 5. Tricyclic compound 5 could be obtained through
azonane ring formation by applying the nosyl (Ns) strategy6
to compound 6 and subsequent oxidative manipulation to
prepare a cyclopentenone moiety. In the syntheses of
fawcettimine-type alkaloids, the stereoselective construction
of a bicyclic skeleton comprising an angular quaternary
carbon center (C-12) is the most important requirement. We
envisioned that this chiral center in aldehyde 7 would be
included the diastereoselective Hosomi-Sakurai allylation,7
the direct conversion of oxazolidinone into Weinreb amide
10,8 coupling with alkynyl anion prepared from 11, the
asymmetric reduction of alkynyl ketone 14 with (S)-
Corey-Bakshi-Shibata (CBS) reagent,9 and TIPS protection
of the resulting secondary hydroxyl group. Having succeeded
in the synthesis of 15, the stage was set for the intramolecular
Pauson-Khand reaction10 to construct a tetrahydroindenone
core. After several attempts, we finally found that pretreat-
ment of 15 with Co2(CO)8 in DCM at rt under Ar atmo-
sphere, followed by manipulation of the resulting coordina-
tion product with 4-methylmorpholine N-oxide (NMO) in
DCM at rt under CO atmosphere, produced the desired
bicyclo compound 16 in 87% yield as the major product after
(3) For recent reports on the total synthesis of Lycopodium alkaloids,
see: (a) Chandra, A.; Pigza, J. A.; Han, J.; Mutnick, D.; Johnston, J. N.
J. Am. Chem. Soc. 2009, 131, 3470. (b) Nilsson, B. L.; Overman, L. E.;
Read de Alaniz, J.; Rohde, J. M. J. Am. Chem. Soc. 2008, 130, 11297. (c)
Yang, H.; Carter, R. G.; Zakharov, L. N. J. Am. Chem. Soc. 2008, 130,
9238. (d) Kozak, J. A.; Dake, G. R. Angew. Chem., Int. Ed. 2008, 47, 4221.
(e) Bisai, A.; West, S. P.; Sarpong, R. J. Am. Chem. Soc. 2008, 130, 7222.
(f) Kozaka, T.; Miyakoshi, N.; Mukai, C. J. Org. Chem. 2007, 72, 10147.
(g) Linghu, X.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem., Int. Ed.
2007, 46, 7671. (h) Beshore, D. C.; Smith, A. B., III. J. Am. Chem. Soc.
2007, 129, 4148. (i) Snider, B. B.; Grabowski, J. F. J. Org. Chem. 2007,
72, 1039.
(7) Wu, M.; Yeh, J. Tetrahedron 1994, 50, 1073.
(8) The absolute configuration of the chiral center in Weinreb amide
10 ([R]22 -13.1 (c 0.23, CHCl3)) was confirmed to be (R) by direct
D
comparison with 10 ([R]22 -16.3 (c 0.08, CHCl3)) prepared from (R)-
D
(+)-citronellic acid in six steps.
(4) Takayama, H.; Katakawa, K.; Kitajima, M.; Yamaguchi, K.; Aimi,
N. Tetrahedron Lett. 2002, 43, 8307.
(9) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551. (b) Parker, K. A.; Ledeboer, M. W. J. Org. Chem. 1996, 61,
3214.
(5) (a) Heathcock, C. H.; Smith, K. M.; Blumenkopf, T. A. J. Am. Chem.
Soc. 1986, 108, 5022. (b) Heathcock, C. H.; Blumenkopf, T. A.; Smith,
K. M. J. Org. Chem. 1989, 54, 1548.
(10) (a) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E. J. Chem.
Soc., Chem. Commun. 1971, 36, 36. (b) Schore, N. E.; Croudace, M. C. J.
Org. Chem. 1981, 46, 5436. (c) Shambayati, S.; Crowe, W. E.; Schreiber,
S. L. Tetrahedron Lett. 1990, 31, 5289. (d) Jeong, N.; Chung, Y. K.; Lee,
S. H.; Yoo, S.-E. Synlett 1991, 204.
(6) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373. (b) Kurosawa, W.; Kan, T.; Fukuyama, T. Org. Synth. 2002, 79,
186. (c) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353.
Org. Lett., Vol. 11, No. 23, 2009
5555

column chromatography. The diastereomer at C-13, which
was generated by CBS reduction, could be easily separated
by column chromatography, and the enantiomeric excess of
16 was determined to be 99% ee by chiral HPLC analysis.11
The configuration at C-7 in 16 was determined by NOE
experiment, as shown in Scheme 2. The configuration at C-13
was inferred from the coupling constants of the R and ꢀ
protons on C-14 and that on C-13.
Scheme 4
Next, we turned our attention to the construction of a
quaternary center at C-12 in the fawcettimine skeleton. For
this purpose, we employed the vinyl Claisen rearrangement
by which a useful aldehyde functionality to extend the side
chain would be gained (Scheme 3). Reduction of enone 16
Scheme 3
diisopropyl azodicarboxylate (DIAD) at 0 °C. The protecting
group on the secondary amine was switched to the Boc group
to afford the desired tricyclic compound 23.
For the total synthesis of 1, compound 23 was converted
into diketone 5 as follows (Scheme 5). By the conventional
Scheme 5
with (R)-CBS reagent gave allyl alcohol 17 in good yield
with excellent selectivity (R-H:ꢀ-H ) 1:15), the stereochem-
istry of which was demonstrated by NOE experiments, as
shown in Scheme 3. By applying Mandai’s conditions,12 we
prepared sulfoxide 18, which was then heated at 170 °C in
1,2-dichlorobenzene with excess NaHCO3 to produce 19 in
59% yield. NOE experiment indicated that C-12 had the
expected (S) configuration.
Having succeeded in the synthesis of aldehyde 19, we
proceeded to perform the transformation into 1 (Scheme 4).
Conversion of 19 into R,ꢀ-unsaturated nitro compound by
the nitro-aldol reaction, followed by reduction with LiAlH4
gave primary amine 20 in 81% yield (2 steps). Substrate 21
for the intramolecular Mitsunobu reaction13 was obtained
by a one-pot operation from 20, i.e., installation of the Ns
group to the primary amine in DCM, dilution of the reaction
mixture with THF, and subsequent treatment with TBAF at
rt. Under a highly diluted condition, azonane ring compound
22 was obtained in excellent yield by treating 21 with
hydroboration-oxidation procedure14 and subsequent Dess-
Martin oxidation, 23 was transformed into ketone 25 in good
yield as colorless crystals. At this stage, X-ray crystallographic
analysis of 2515 enabled us to determine the configuration of
the chiral center at C-4 as (S). By applying the Ito-Saegusa
oxidation,16 25 was regioselectively converted into R,ꢀ-unsatur-
(11) The enantiomeric excess was determined by HPLC analysis on a
CHIRAL PACK IB column (n-hexane; flow 0.35 mL/min).
(12) (a) Mandai, T.; Ueda, M.; Hasegawa, S.; Kawada, M.; Tsuji, J.
Tetrahedron Lett. 1990, 31, 4041. (b) Kaliappan, K. P.; Ravikumar, V. Org.
Lett. 2007, 9, 2417.
(14) Brown, H. C.; Liotta, R.; Brener, L. J. Am. Chem. Soc. 1977, 99,
3427.
(15) See the Supporting Information.
(13) Mitsunobu, O. Synthesis 1981, 1.
(16) Itoh, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
5556
Org. Lett., Vol. 11, No. 23, 2009

ated ketone 26. Removal of the TIPS group in 26 with TBAF
in AcOH and successive Dess-Martin oxidation of the resulting
alcohol gave the desired diketone 5.
Scheme 6
As the final stage, we attempted removal of the Boc group
and simultaneous isomerization at C-4 to form the hemi-
aminal function. This resulted in the total synthesis of 1. As
the conventional procedure with TFA3g to remove the N-Boc
group gave only a complex mixture, we examined the
reagents and conditions. When 5 equiv of ZnBr2 was used,
a trace amount of 1 was obtained together with the depro-
tected compound. The optimum conditions were the employ-
ment of 20 equiv of ZnBr2 in EtOH at rt to furnish 1 in 91%
yield. Synthetic 1 was identical in all respects with the natural
vinyl Claisen rearrangement to construct an angular quater-
nary carbon center; (3) the construction of an azonane ring
with the Ns strategy; and (4) the formation of the
1-azabicyclo[4.3.1]decane ring system by deprotection of the
nitrogen group accompanying C4 isomerization. In addition,
we have succeeded in the efficient biomimetic transformation
of lycoposerramine-C (1) into phlegmariurine-A (3). The
synthesis of other fawcettimine-type alkaloids is underway.
product, including the optical property: synthetic, [R]24
D
+70.4 (c 0.19, CHCl3); natural, [R]24D +64.6 (c 0.21, CHCl3).
Next, we investigated the chemical transformation of 1
into 3, which would be biogenetically generated by a
C-12-C-13 bond scission in 1. According to this idea, we
treated 1 with NaOMe in MeOH at rt and obtained a mixture
of 3 and 4.4 In the present study, we found that 3 was formed
selectively in excellent yield by treating 1 with t-BuOK in
THF (Scheme 6).
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Japan Society for
the Promotion of Science and The Uehara Memorial Foun-
dation.
In conclusion, we have achieved the first asymmetric total
synthesis of lycoposerramine-C (1) (21 steps, 12.6% overall
yield), starting from crotonamide 12. The highlights of this
synthesis are the following: (1) the stereoselective construc-
tion of a 6-5 bicyclic R,ꢀ-unsaturated ketone by the cobalt-
mediated Pauson-Khand reaction; (2) the stereoselective
reduction of enone with CBS reagent and the subsequent
Supporting Information Available: Experimental pro-
1
cedures, copies of H and 13C NMR spectral data for 5 and
10-26, synthetic lycoposerramine-C (1) and phlegmari-
urine-A (3), and a CIF file for ketone 25. This material is
available free of charge via the Internet at http://pubs.acs.org.
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