Asymmetrie total syntheses of two phlegmarine-type alkaloids, lycoposerramines-V and -W, newly isolated from lycopodium serratum

Article abstract of DOI:10.1021/ol701871v

Two new Phlegmarine-type alkaloids, lycoposerramines-V and -W, were isolated from Lycopodium serratum, and their structures including the absolute configuration were established by asymmetric total synthesis involving such key steps as Johnson-Claisen rea

Full text of DOI:10.1021/ol701871v

ORGANIC
LETTERS
2007
Vol. 9, No. 20
4069-4072
Asymmetric Total Syntheses of Two
Phlegmarine-Type Alkaloids,
Lycoposerramines-V and -W, Newly
Isolated from Lycopodium serratum
Takahide Shigeyama, Kazuaki Katakawa, 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 August 3, 2007
ABSTRACT
Two new Phlegmarine-type alkaloids, lycoposerramines-V and -W, were isolated from Lycopodium serratum, and their structures including the
absolute configuration were established by asymmetric total synthesis involving such key steps as Johnson Claisen rearrangement, asymmetric
allylation, and ring-closing metathesis (RCM)- or SmI2-mediated stereoselective piperidine ring construction.
−
Plants belonging to genus Lycopodium are known to contain
alkaloids having unique skeletal characteristics and biological
activities, such as acetylcholine esterase (AChE) inhibition.1
This has inspired many groups to investigate the alkaloid
constituents in those plants, and a number of novel alkaloids
were discovered in recent years.2 We have reported the
isolation and structure elucidation of novel alkaloids having
various kinds of skeleton from L. serratum.3 Further inves-
tigation of the alkaloidal fraction of this plant has led to the
isolation of two new Phlegmarine-type alkaloids:4 lycopos-
erramines-V (1) and -W (3). In this paper, we describe the
structure determination based on spectroscopic analyses and
asymmetric total syntheses.
Lycoposerramine-V. The crude base fraction obtained by
means of a previously reported procedure3c,4d was purified
(3) (a) Takayama, H.; Katakawa, K.; Kitajima, M.; Seki, H.; Yamaguchi,
K.; Aimi, N. Org. Lett. 2001, 3, 4165-4167; 2002, 4, 1243. (b) Takayama,
H.; Katakawa, K.; Kitajima, M.; Yamaguchi, K.; Aimi, N. Tetrahedron
Lett. 2002, 43, 8307-8311. (c) Takayama, H.; Katakawa, K.; Kitajima,
M.; Yamaguchi, K.; Aimi, N. Chem. Pharm. Bull. 2003, 51, 1163-1169.
(d) Katakawa, K.; Kitajima, M.; Aimi, N.; Seki, H.; Yamaguchi, K.;
Furihata, K.; Harayama, T.; Takayama, H. J. Org. Chem. 2005, 70, 658-
663. (e) Katakawa, K.; Nozoe, A.; Kogure, N.; Kitajima, M.; Hosokawa,
M.; Takayama, H. J. Nat. Prod. 2007, 70, 1024-1028.
(4) Isolation of Phlegmarine-type alkaloids: (a) Nyembo, L.; Goffin, A.;
Hootele´, C.; Braekman, J.-C. Can. J. Chem. 1978, 56, 851-865. (b) Morita,
H.; Hirasawa, Y.; Shinzato, T.; Kobayashi, J. Tetrahedron 2004, 60, 7015-
7023. (c) Choo, C. Y.; Hirasawa, Y.; Karimata, C.; Koyama, K.; Sekiguchi,
M.; Kobayashi, J.; Morita, H. Bioorg. Med. Chem. 2007, 15, 1703-1707.
(d) Katakawa, K.; Kitajima, M.; Yamaguchi, K.; Takayama, H. Heterocycles
2006, 69, 223-229. Synthetic studies on Phlegmarine-type alkaloids: (e)
Leniewski, A.; Szychowski, J.; Maclean, D. B. Can. J. Chem. 1981, 59,
2479-2490. (f) Comins, D. L.; Libby, A. H.; Al-awar, R. S.; Foti, C. J. J.
Org. Chem. 1999, 64, 2184-2185. (g) Comins, D. L.; Williams, A. L. Org.
Lett. 2001, 3, 3217-3220.
(1) (a) Kozikowski, A. P.; Tu¨ckmantel, W. Acc. Chem. Res. 1999, 32,
641-650. (b) Bai, D. L.; Tang, X. C.; He, X. C. Curr. Med. Chem. 2000,
7, 355-374. (c) Wong, D. M.; Greenblatt, H. M.; Dvir, H.; Carlier, P. R.;
Han, Y.-F.; Pang, Y.-P.; Silman, I.; Sussman, J. L. J. Am. Chem. Soc. 2003,
125, 363-373.
(2) (a) Kobayashi, J.; Morita, H. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: New York, 2005; Vol. 61, pp 1-57. (b) Ayer, W. A.;
Trifonov, L. S. In The Alkaloids; Cordell, G. A., Brossi, A., Eds.; Academic
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Nat. Prod. Rep. 2004, 21, 752-772.
10.1021/ol701871v CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/08/2007

by repeated chromatography over SiO2 gel to afford new
alkaloids 1 and 3 (0.64 and 1.75% yields based on the crude
base, respectively). Compound 1, named lycoposerramine-
it was not possible to elucidate the relative stereochemistry
between C7 and C5 by spectroscopic analysis. Then, we
attempted the total synthesis of lycoposerramine-V to reveal
its relative and absolute configurations.
V, was obtained as a colorless amorphous powder ([R]23
D
+17.7 (c 0.24, CHCl3)), and its molecular formula was
The retrosynthetic analysis of lycoposerramine-V is shown
in Scheme 1. The absolute configuration at C15 was deduced
to be R based on the biogenesis of common Lycopodium
alkaloids, and therefore C7 could be R from the NOE data
described above. However, as the asymmetric center at C5
could not be determined from spectroscopic analyses, we
planned the synthesis of both stereoisomers with 5S or 5R
configuration in a stereoselective manner from key interme-
diate 4, which would be constructed from chiral ketone 7
via Johnson-Claisen rearrangement and Knoevenagel py-
ridine synthesis.
Our synthesis began with the preparation of known
cyclohexenone 85 from commercially available (R)-3-meth-
ylcyclohexanone 7 through sulfenylation, followed by oxida-
tion and dehydrosulfenylation. R-Iodination of cyclohexenone
8 with I2/pyridine gave iodide 9.6 Next, the installation of a
3-hydroxypropane side chain to 9 was accomplished with a
tandem sequence involving the regioselective hydroboration
of alkene 107 with 9-BBN, followed by coupling of the
resulting borane under Pd-catalyzed Suzuki-Miyaura condi-
tions.8 Reduction of thus obtained enone 11 under Luche
conditions gave allyl alcohol 6 as a single isomer, the
stereochemistry of which was demonstrated by the coupling
constant of the proton bearing a secondary hydroxyl group
(δ 4.16, dd, J ) 9.3 and 5.4 Hz, â-axial proton). Allylic
alcohol 6 was subjected to Johnson-Claisen rearrangement9
to attach the acetic acid residue to C7 by heating xylene with
triethyl orthoacetate in the presence of a small amount of
o-nitrophenol to give stereoselectively cyclohexene 5 in 92%
yield (Scheme 2).
established to be C16H24N2 by HRFAB-MS analysis. In
1
addition to H and 13C NMR data (Table 1), 2D NMR
Table 1. 1H and 13C NMR Data for Natural
Lycoposerramine-V (1) and Lycoposerramine-W (3) (in CDCl3)
Lycoposerramine-V (1)
Lycoposerramine-W (3)
δH
δC
δH
δC
(400 MHz)
(100 MHz)
(400 MHz)
(125 MHz)
1R
2.76 (ddd, 12.6, 44.8
12.6, 3.1)
2.80-2.77
49.5
31.0
(2H, m)
1â
2R
3.34 (br d, 13.2)
1.50-1.43 (m)
22.6a
1.71-1.60
(2H, m)
2â
3
1.91-1.66 (m)
1.91-1.66
(2H, m)
22.3a
30.3
54.8
4.08 (dddd, 4.9, 65.0
4.9, 3.7, 3.7)
4
1.91-1.66
1.71-1.60
(2H, m)
37.7
(2H, m)
5
6
3.15-3.10 (m)
2.89-2.85 (m)
55.7
2.68 (ddd, 13.5, 41.1
2.30 (ddd, 14.6, 40.0
9.5, 3.3)
6.4, 4.2)
1.53 (ddd, 14.8,
11.1, 3.8)
1.36-1.25 (m)
7
8R
3.44-3.36 (m)
33.3
2.98-2.93 (m)
35.9
0.90 (ddd, 11.9, 37.9
1.08 (ddd, 11.9, 39.0
11.9, 11.9)
11.9, 11.9)
8â
2.22-2.17 (m)
2.13 (dddd, 12.8,
5.5, 2.6, 2.6)
9
10
8.26 (d, 4.0)
6.91 (dd, 7.9,
4.8)
146.8
121.1
8.34 (d, 4.2)
7.07 (dd, 7.9,
4.6)
146.6
121.1
11
7.73 (d, 7.7)
135.0
133.9
157.3
41.7
7.61 (d, 7.9)
134.6
135.7
157.6
42.0
12
13
14R
2.48 (dd, 16.8,
12.1)
2.53 (dd, 16.8,
11.9)
14â
2.92 (ddd, 16.8,
2.96 (ddd, 16.7,
By conventional hydroboration-oxidation procedure, 5
was converted into diastereomeric alcohol 12 as the major
product in 75% yield.10 Removal of the TBDPS group and
subsequent Swern oxidation of the resultant diol gave keto-
aldehyde 13, which was subjected to Knoevenagel condi-
tions11 with slight modification using NH2OMe to afford the
5,6,7,8-tetrahydroquinoline skeleton. Reduction of the ester
in 14 with LiAlH4 and subsequent oxidation under Swern
conditions gave aldehyde 4 in good yield (Scheme 3).
Next, we turned our attention to the enantioselective
construction of 2-substituted piperidine from aldehyde 4. For
4.4, 1.8)
4.4, 2.2)
15
16
N-CH3
2.02-1.96 (m)
28.6
1.92-1.88 (m)
29.2
1.11 (3H, d, 6.6) 22.2
1.10 (3H, d, 6.6) 22.3
2.46 (3H, s)
41.1
a Interchangeable.
correlations indicated that compound 1 had a Phlegmarine
skeleton with the 5,6,7,8-tetrahydroquinoline moiety, which
is the first example of Lycopodium alkaloid, and a piperidine
ring (see the structure in Scheme 1). The stereochemistry at
H7 and H15 was found to be cis by NOE analysis. However,
(5) (a) Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem. Soc. 1976,
98, 4887-4902. (b) Oppolzer, W.; Petrzilka, M. HelV. Chim. Acta 1978,
61, 2755-2762.
Scheme 1. Retrosynthesis of Lycoposerramine-V (1 and 2)
(6) Scott, T. L.; So¨derberg, B. C. G. Tetrahedron 2003, 59, 6323-6332.
(7) Saygili, N.; Brown, R. J.; Day, P.; Hoelzl, R.; Kathirgamanathan,
P.; Mageean, E. R.; Ozturk, T.; Pilkington, M.; Qayyum, M. M. B.; Turner,
S. S.; Vorwerg, L.; Wallis, J. D. Tetrahedron 2001, 57, 5015-5026.
(8) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (b)
Ridgway, B. H.; Woerpel, K. A. J. Org. Chem. 1998, 63, 458-460.
(9) (a) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T.
J.; Li, T.-T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92,
741-743. (b) Sayo, N.; Kimura, Y.; Nakai, T. Tetrahedron Lett. 1982, 23,
3931-3934. (c) Fukazawa, T.; Shimoji, Y.; Hashimoto, T. Tetrahedron:
Asymmetry 1996, 7, 1649-1658.
(10) Brawn, H. C.; Liotta, R.; Brener, L. J. Am. Chem. Soc. 1977, 99,
3427-3432.
(11) (a) Frankowski, A. Tetrahedron 1977, 33, 427-432. (b) Tanida,
H.; Irie, T. J. Org. Chem. 1987, 52, 5218-5224.
4070
Org. Lett., Vol. 9, No. 20, 2007

was conducted, which enabled the unambiguous assignment
of all chiral centers. RCM14 using first-generation Grubbs’
ruthenium catalyst proceeded smoothly to generate unsatur-
ated lactam 19.
Scheme 2
Finally, reduction of the double bond with H2/Pd/C and
subsequent reduction of lactam with BH3-THF afforded
desired compound 1 with 5S,7R,15R configuration (Scheme
4). Starting from common intermediate 4, we achieved the
Scheme 4
this purpose, we employed Brown’s asymmetric allylation
with B-allyldiisopinocampheylborane,12 which would enable
us to prepare both diastereomeric homoallylic alcohols,
followed by RCM. Treatment of aldehyde 4 with B-
allyldiisopinocampheylborane prepared from (+)-B-chloro-
diisopinocampheylborane and allylmagnesium bromide yielded
Scheme 3
asymmetric synthesis of compound 2 possessing 5R,7R,15R
configuration via a sequence similar to that described above
by employing B-allyldiisopinocampheylborane prepared from
(-)-B-chlorodiisopinocampheylborane in the asymmetric
allylation reaction (see the Supporting Information).
Having both target compounds (1 and 2) in hand, we
compared their physicochemical data with those of the
natural product. As a result, compound 1 was completely
identical in all respects (chromatographic behavior, mass,
1
IR, UV, H and 13C NMR, [R]23 +29.2 (c 0.35, CHCl3))
D
with natural lycoposerramine-V. Therefore, the structure
including the absolute configuration of the chiral center was
established to be 1.
homoallylic alcohol 16 in 97% yield with good diastereo-
selectivity (92% de). The absolute configuration of the newly
generated chiral center was assigned as R based on a well-
established reaction mechanism and confirmed later by X-ray
crystallographic analysis (see compound 18). The alcohol
thus obtained was converted into azide 17 accompanying
the stereoinversion via an O-mesylated derivative. Using
Staudinger reaction with PPh3-H2O,13 azide 17 was trans-
formed into primary amine, which was directly acylated with
acryloyl chloride in the presence of TEA to give 18 in 65%
yield. At this stage, X-ray crystallographic analysis of 18
Lycoposerramine-W. Compound 3, named lycoposer-
ramine-W, was obtained as a colorless amorphous powder
([R]25 +22.4 (c 0.14, CHCl3)), and its molecular formula
D
was established to be C17H27N2O1 by HRFAB-MS analysis.
1H and 13C NMR (Table 1) spectra and 2D NMR correlations
indicated the presence of two additional functional groups
(i.e., a N-methyl group and a secondary hydroxyl group) at
C3 of the piperidine ring, compared with the structure of
lycoposerramine-V (1). Although the stereochemistry at the
four chiral centers (C3, C5, C7, and C15) was obscure from
the spectroscopic analyses, we deduced that the absolute
configuration at C5, C7, and C15 would be the same as that
of 1 based on biogenetic consideration, and the remaining
chiral center (C3) would be S, that is, R-axial orientation,
(12) (a) Brown, H. C.; Jadhav, P. K. J. Org. Chem. 1984, 49, 4089-
4091. (b) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org.
Chem. 1986, 51, 432-439. (c) Felpin, F. X.; Girard, S.; Thanh, G. V.;
Robins, R. J.; Villie´ras, J.; Lebreton, J. J. Org. Chem. 2001, 66, 6305-
6312.
(13) (a) Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron
1981, 37, 437-472. (b) Danieli, B.; Lesma, G.; Passarella, D.; Sacchetti,
A.; Silvani, A.; Virdis, A. Org. Lett. 2004, 6, 493-496.
(14) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.
(b) Phillips, A. J.; Abell, A. D. Aldrichimica Acta 1999, 32, 75-89.
Org. Lett., Vol. 9, No. 20, 2007
4071

from the coupling constant of the proton on C3 (dddd, J )
4.9, 4.9, 3.7, 3.7 Hz). Then, we focused on the asymmetric
synthesis of the compound having 3S,5R,7R,15R configu-
ration to elucidate the structure of lycoposerramine-W. In
the key step of the synthesis of lycoposerramine-W, we
employed the intramolecular Reformatsky reaction promoted
by samarium(II) iodide, which led to 1,3-asymmetric induc-
tion in a C-C bond-forming process. However, as far as
we know, this reaction has been applied only to â-halo-
acetoxy carbonyl substrates, forming a lactone ring. None
of the studies that employed this reaction used substrates
that contained nitrogen atom (i.e., â-haloacetamide-carbonyl
compound) to produce a 4-hydroxy-2-substituted piperidine
ring.15 Then, we prepared key substrate 23 and investigated
the reaction conditions for this new type of substrate.
The primary amine prepared from azide 17, which was
an intermediate for the synthesis of lycoposerramine-V, was
directly converted into methyl carbamate derivative 20
(Scheme 5). Reduction of the carbamate with LiAlH4 gave
amount of OsO4 and 4 equiv of NaIO4 produced â-chloro-
acetamine-aldehyde 23 in 84% yield. After several attempts
at the investigation of the reaction conditions of samarium-
(II)-promoted stereoselective intramolecular Reformatsky
reaction,17 we found that the use of samarium(II) iodide18
freshly prepared from samarium metal and diiodomethane
in THF gave the best result, producing lactam 24 in 40%
yield with good diastereoselectivity (79% de). The relative
stereochemistry between C3 and C5 was demonstrated by
careful NMR analysis (δ 2.81, 1H, dd, J ) 17.4, 5.5 Hz,
H-2; δ 2.39, 1H, dd, J ) 17.4, 7.0 Hz, H-2; δ 4.24, 1H,
dddd, J ) 7.0, 7.0, 5.8, 5.5, H-3) and NOE experiments.
The stereochemical control of the reaction could be due to
a chair-like transition structure as described by Molander.17a,b
Finally, reduction of lactam 24 with BH3-THF afforded
target compound 3, which was completely identical in all
1
respects (chromatographic behavior, mass, IR, UV, H and
13C NMR, [R]25 +21.5 (c 0.07, CHCl3)) with natural
D
lycoposerramine-W. Therefore, the structure including the
absolute configuration of the four chiral centers was estab-
lished for 3.
In conclusion, we have achieved the asymmetric total
syntheses of lycoposerramine-V (1) (22 steps, 4.3% overall
yield) and lycoposerramine-W (3) (23 steps, 1.4% overall
yield) starting from (R)-3-methylcyclohexanone, which
enabled us to determine unambiguously the structures
including the absolute configurations of two novel Phleg-
marine-type alkaloids newly isolated from Lycopodium
serratum.
Scheme 5
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan.
Supporting Information Available: Experimental pro-
cedures for isolation of lycoposerramine-V and -W, and
preparation of compounds 1-6, 9-24, and S1-S6, and
copies of 1H and 13C NMR spectral data for natural
lycoposerramine-V, -W, and compounds 1-3, 5, 14, 16, 17,
22, 24, and S3. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL701871V
N-methyl derivative 21, which was then acylated with
chloroacetylchloride to yield amide 22 in 63% overall yield
from 20. Oxidative cleavage of the terminal double bond in
22 with the Johnson-Lemieux16 protocol using a catalytic
(16) (a) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J.
Org. Chem. 1956, 21, 478-479.
(17) (a) Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96, 307-338.
(b) Molander, G. A.; Etter, J. B.; Harring, L. S.; Thorel, P.-J. J. Am. Chem.
Soc. 1991, 113, 8036-8045. (c) Reddy, P. P.; Yen, K.-F.; Uang, B.-J. J.
Org. Chem. 2002, 67, 1034-1035. (d) Sawant, K. B.; Jennings, M. P. J.
Org. Chem. 2006, 71, 7911-7914.
(15) Diastereoselective pinacol coupling of acyclic dicarbonyl compounds
leading to N-heterocyclic diols by using samarium iodide was reported;
see: Handa, S.; Kachala, M. S.; Lowe, S. R. Tetrahedron Lett. 2004, 45,
253-256.
(18) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980,
102, 2693-2698.
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