Asymmetric total syntheses of cyclic nitrone-containing phlegmarine-type Lycopodium alkaloids, lycoposerramines-X and -Z

Article abstract of DOI:10.1021/jo9018182

(Figure Presented) The total syntheses of cyclic nitrone-containing phlegmarine-type Lycopodium alkaloids, lycoposerramines-X and -Z, were accomplished starting from (R)-3-methylcyclohexanone via Pd-catalyzed Suzuki-Miyaura coupling, Johnson-Claisen rearr

Full text of DOI:10.1021/jo9018182

pubs.acs.org/joc
Asymmetric Total Syntheses of Cyclic Nitrone-Containing
Phlegmarine-Type Lycopodium Alkaloids, Lycoposerramines-X and -Z
Tomoyuki Tanaka, 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 25, 2009
The total syntheses of cyclic nitrone-containing phlegmarine-type Lycopodium alkaloids, lycoposerra-
mines-X and -Z, were accomplished starting from (R)-3-methylcyclohexanone via Pd-catalyzed Suzuki-
Miyaura coupling, Johnson-Claisen rearrangement, stereoselective hydroboration-oxidation reaction,
and Mitsunobu reaction, thereby establishing the structures including the absolute configuration.
Introduction
many groups including ours2 to investigate the alkaloidal
constituents in Lycopodium plants and to synthesize structu-
rally unique Lycopodium alkaloids.3,4 We have reported
recently the isolation and structure elucidation of new alka-
loids, lycoposerramines-Z (1) and -X (2) (Figure 1), from
Lycopodium serratum.2f From spectroscopic analyses, we
found that they were diastereomers of phlegmarine-type
alkaloids5 at the C13 position, but could not establish their
absolute configuration. 1 and 2 consist of a piperidine ring
with a novel nitrone residue and an decahydroquinoline ring
with four chiral centers. Some Lycopodium alkaloids having
the nitrone residue were also isolated from other Lycopodium
and Huperzia plants in recent years.6 However, as far as we
know, synthetic studies on these types of alkaloids have
never been reported. In this paper, we describe the first
asymmetric total syntheses of 1 and 2 which assign the
absolute stereochemistry as shown and confirm the structure
assignment.
Lycopodium alkaloids have highly diverse, complex struc-
tures and a variety of biological activities.1 This has inspired
(1) For recent reviews, see: (a) Hirasawa, Y.; Kobayashi, J.; Morita, H.
Heterocycles 2009, 77, 679–729. (b) Kobayashi, J.; Morita, H. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: New York, 2005; Vol. 61, pp 1-57. (c) Ayer,
W. A.; Trifonov, L. S. In The Alkaloids; Cordell, G. A., Brossi, A., Eds.;
Academic Press: New York, 1994; Vol. 45, pp 233-266. (d) Ma, X.; Gang,
D. R. Nat. Prod. Rep. 2004, 21, 752–772.
(2) (a) Nishikawa, Y.; Kitajima, M.; Kogure, N.; Takayama, H. Tetrahedron
2009, 65, 1608–1617. (b) Katakawa, K.; Nozoe, A.; Kitajima, M.; Takayama, H.
Helv. Chim. Acta 2009, 92, 445–452. (c) Nishikawa, Y.; Kitajima, M.; Takayama,
H. Org. Lett. 2008, 10, 1987–1990. (d) Shigeyama, T.; Katakawa, K.; Kogure, N.;
Kitajima, M.; Takayama, H. Org. Lett. 2007, 9, 4069–4073. (e) Katakawa, K.;
Nozoe, A.; Kogure, N.; Kitajima, M.; Hosokawa, M.; Takayama, H. J. Nat. Prod.
2007, 70, 1024-1028 and references cited therein. (f) Katakawa, K.; Kitajima, M.;
Yamaguchi, K.; Takayama, H. Heterocycles 2006, 69, 223-229.
(3) For recent reports of 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, 3470–3471. (b) Nilsson, B. L.; Overman, L. E.; Read de
Alaniz, J.; Rohde, J. M. J. Am. Chem. Soc. 2008, 130, 11297–11299. (c) Yang,
H.; Carter, R. G.; Zakharov, L. N. J. Am. Chem. Soc. 2008, 130, 9238–9239.
(d) Kozak, J. A.; Dake, G. R. Angew. Chem., Int. Ed. 2008, 47, 4221–4223.
(e) Bisai, A.; West, S. P.; Sarpong, R. J. Am. Chem. Soc. 2008, 130, 7222–
7223. (f) Kozaka, T.; Miyakoshi, N.; Mukai, C. J. Org. Chem. 2007, 72,
10147–10154. (g) Linghu, X.; Kennedy-Smith, J. J.; Toste, F. D. Angew.
Chem., Int. Ed. 2007, 46, 7671–7673. (h) Beshore, D. C.; Smith, A. B., III
J. Am. Chem. Soc. 2007, 129, 4148–4149. (i) Snider, B. B.; Grabowski, J. F.
J. Org. Chem. 2007, 72, 1039–1042.
(4) For recent reports of the structure elucidation of Lycopodium alka-
loids, see: (a) He, J.; Chen, X.; Li, M.; Zhao, Y.; Xu, G.; Cheng, X.; Peng, L.;
Xie, M.; Zheng, Y.; Wang, Y.; Zhao, Q. Org. Lett. 2009, 11, 1397–1400.
(b) Sun, Y.; Yan, J.; Meng, H.; He, C.; Yi, P.; Qiao, Y.; Qiu, M. Helv. Chim.
Acta 2008, 91, 2107–2109. (c) Hirasawa, Y.; Kato, E.; Kobayashi, J.;
Kawahara, N.; Goda, Y.; Shiro, M.; Morita, H. Bioorg. Med. Chem. 2008,
16, 6167–6171. (d) Ishiuchi, K.; Kubota, T.; Mikami, Y.; Obara, Y.;
Nakahata, N.; Kobayashi, J. Bioorg. Med. Chem. 2007, 15, 413–417.
The retrosynthesis of lycoposerramine-Z (1) is outlined in
Scheme 1. The formation of a characteristic piperidine ring
with a nitrone residue in 1 was expected by reacting hydro-
xylamine with keto-mesylate 7, which would be derived from
(5) For the total synthesis of phlegmarine-type alkaloids, see: (a) Comins,
D. L.; Libby, A. H.; Al-awar, R. S.; Foti, C. J. J. Org. Chem. 1999, 64, 2184–
2185. (b) Leniewski, A.; Szychowski, J.; MacLean, D. B. Can. J. Chem. 1981,
59, 2479–2490.
(6) (a) Gao, W.; Li, Y.; Jiang, S.; Zhu, D. Helv. Chim. Acta 2008, 91,
1031–1035. (b) Choo, C. Y.; Hirasawa, Y.; Karimata, C.; Koyama, K.;
Sekiguchi, M.; Kobayashi, J.; Morita, H. Bioorg. Med. Chem. 2007, 15,
1703–1707. (c) Gao, W.; Li, Y.; Jiang, S.; Zhu, D. Planta Medica 2000, 66,
664–667.
DOI: 10.1021/jo9018182
r
Published on Web 10/30/2009
J. Org. Chem. 2009, 74, 8675–8680 8675
2009 American Chemical Society

Tanaka et al.
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SCHEME 2
FIGURE 1. Structures of lycoposerramines-Z (1) and -X (2).
SCHEME 1. Retrosynthesis of lycoposerramine-Z (1)
SCHEME 3
aldehyde 6 via installation of a C4 unit at C5. The stereo-
selective construction of the cis-decahydroquinoline skele-
ton in 6 would be achieved via the intramolecular Mitsunobu
reaction7 of sulfonamide 5, which could be formed from
cyclohexanol derivative 4. Compound 4 was also expected to
be a common intermediate for the divergent synthesis of
lycoposerramine-X (2), which has a trans-decahydroquino-
line skeleton, by manipulating the hydroxy group at C13.
Compound 42d can be constructed from (R)-3-methylcyclo-
hexanone (3) with the procedure previously developed by us,
which included Pd-catalyzed Suzuki-Miyaura coupling,8
Johnson-Claisen rearrangement,9 and stereoselective
hydroboration-oxidation reaction.10 The chiral ketone 3
has the same absolute configuration as that at C15 in 1 and 2,
which was deduced to be R based on biogenetic considera-
tion of common Lycopodium alkaloids.
Results and Discussion
Synthesis of Lycoposerramine-Z. cis-Decahydroquinoline
11 was obtained from common synthetic intermediate 4 via a
five-step sequence. Acetylation of the secondary alcohol and
deprotection of the silyl group of the primary alcohol in 4
gave alcohol 9 in good yield. Replacement of the hydroxy
group at C9 in 9 with 2-nitrobenzenesulfonamide under
Mitsunobu conditions (diethyl azodicarboxylate (DEAD),
PPh3, THF, quant), followed by removal of the acetyl group
of the secondary hydroxy group at C13 (NaOEt, EtOH,
quant), afforded sulfonamide 5. Compound 5 was subjected
to intramolecular Mitsunobu reaction with di-tert-butyl
azodicarboxylate (DTAD) and PPh3 in THF to give cis-
decahydroquinoline 11in quantitative yield. The stereochemistry
(7) Mitsunobu, O. Synthesis 1981, 1–28.
(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) Brown, H. C.; Liotta, R.; Brener, L. J. Am. Chem. Soc. 1977, 99,
3427–3432.
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SCHEME 4
SCHEME 5
respects (1H and 13C NMR, mass, CD) with natural lycopo-
serramine-Z. Therefore, the structure including the absolute
configuration was established to be formula 1.
Synthesis of Lycoposerramine-X. Next, we turned our
attention to the synthesis of lycoposerramine-X (2), the key
step of which was the introduction of a nitrogen function at
C13R to construct the trans-decahydroquinoline skeleton.
For this purpose, sulfonamide 20 was initially prepared from
common intermediate 4 utilizing the Mitsunobu reaction
two times, as follows (Scheme 4). The R-hydroxy group at
C13 in 4 was converted into a β-acetoxy group by treatment
with AcOH, DTAD, and PPh3 in THF in 65% yield. After
removal of the TBDPS group, the resulting primary alcohol
was treated with NsNH2 under Mitsunobu conditions
(DTAD, PPh3, THF, 93% yield). This was followed by
alkaline hydrolysis of the acetyl group to give the desired
sulfonamide 20. Attempts to perform the intramolecular
Mitsunobu reaction of 20 with DEAD (5 equiv) and PPh3
in THF gave a 1:1 mixture of trans-decahydroquinoline 21
and E2 elimination product 22 in 86% yield. Use of DTAD
instead of DEAD gave a similar result. Then, the route for
the construction of the trans-decahydroquinoline skeleton
was modified. Secondary alcohol 23, which was formed by
hydrolysis of the acetyl group in 18, was treated with DPPA,
DEAD, and PPh3 in THF to give 13R-azido compound 24 in
81% yield. The stereochemistry of 24 was confirmed from
the coupling constants of H13 (ddd, J=11.2, 11.2, 4.0 Hz), as
depicted in Scheme 4. The TBDPS group was changed to an
Ms group in 95% yield (two steps). Reduction of the azide
group in 26 (H2, Pd/C, EtOH) led to the spontaneous
cyclization, followed by protection of the resulting second-
ary amine by the Teoc group to give trans-decahydroquino-
line 27 in 89% yield (two steps).
of product 11 was confirmed from the coupling constants of H13
(ddd, J=12.2, 4.6, 4.6 Hz) and by NOE experiments, as depicted
in Scheme 2.
Next, aldehyde 6 was prepared from cis-decahydroquino-
line 11 via a four-step sequence, as follows (Scheme 3).
Switching of the protecting group on the amine function
from Ns to Teoc [(i) PhSH, K2CO3, DMF; (ii) 2-trimethylsi-
lylethyl 4-nitrophenyl carbonate (Teoc-carbonate), 4-(N,N-
dimethylamino)pyridine (DMAP), toluene] provided 13 in
80% overall yield. Then, reduction of the ester group in 13
with LiAlH4 in THF and subsequent oxidation with
2-iodoxybenzoic acid (IBX) in DMSO gave aldehyde 6 in
good yield. The installation of a C4 unit at C5 was accom-
plished by treating 6 with an alkynyl anion that was prepared
from 3-butyn-1-ol and n-BuLi in the presence of HMPA in
THF, to afford diol 15 in 90% yield. Selective oxidation of
the hydroxy group on the propargyl position with MnO2
in CH2Cl2 gave R,β-unsaturated ketone 16 in 75% yield.
Mesylation of the primary alcohol and subsequent catalytic
reduction of the alkyne function yielded keto-mesylate 7.
Next, compound 7 was treated with NH2OH HCl in the
3
presence of 0.5 equiv of K2CO3 in EtOH/H2O11 to give the
expected cyclic nitrone 17 in 68% yield. Finally, removal of
the Teoc group with tris(dimethylamino)sulfonium difluor-
otrimethylsilicate (TASF) in THF afforded 1 in 78% yield.
Synthetic 1 ([R]18D þ9.6 (c 0.34, MeOH)) with 7R, 12R, 13S,
and 15R stereochemistry was completely identical in all
According to the method for the synthesis of 1 described
above, trans-decahydroquinoline 27 was converted into 2 in
eight steps, including the installation of a C4 unit at C5 and
(11) Brandman, H. A.; Conley, R. T. J. Org. Chem. 1973, 38, 2236–2238.
J. Org. Chem. Vol. 74, No. 22, 2009 8677

Tanaka et al.
JOCArticle
the formation of a cyclic nitrone residue (Scheme 5). Syn-
1.68-1.57 (5H, overlapped), 1.47-1.43 (1H, m, H-10), 1.25
(3H, t, J=7.1 Hz, -OCH2CH3), 1.19 (1H, ddd, J=13.2, 4.7, 4.7
Hz, H-14), 1.11 (1H, ddd, J=13.7, 6.9, 6.9 Hz, H-8), 1.01 (3H, d,
J=7.1 Hz, H3-16); 13C NMR (CDCl3, 150 MHz) δ (ppm) 172.9
(-CO2Et), 147.8 (Ph), 134.1 (Ph), 133.2 (Ph), 131.6 (Ph), 130.7
(Ph), 124.2 (Ph), 60.3 (-OCH2CH3), 49.7 (C-13), 41.2 (C-9),
40.7 (C-6), 39.1 (C-12), 36.7 (C-7), 32.2 (C-8), 29.4 (C-14), 27.4
(C-15), 25.9 (C-11), 25.1 (C-10), 21.9 (C-16), 14.2 (-OCH2CH3);
EI-MS m/z (%) 424 (2, Mþ), 407 (25), 367 (32), 337 (38), 325
(41), 238 (67), 237 (61), 186 (51), 150 (100); HREI-MS calcd for
C20H28N2O6S (Mþ) 424.1668, found 424.1678; IR νmax (ATR)
(cm-1) 2928, 2875, 1726 (CdO), 1542 (NO2).
thetic 2 ([R]21 þ50.9 (c 0.20, MeOH)) with 7R, 12R, 13R,
D
and 15R stereochemistry was completely identical in all
respects (1H and 13C NMR, mass, CD) with natural lycopo-
serramine-X. Therefore, the structure including the absolute
configuration was established to be formula 2. Recently,
Morita and co-workers reported the isolation of a nitrone-
containing alkaloid named carinatumin C from L. carina-
tum.6b Comparison of NMR data and the optical properties
of synthetic 2 with those of carinatumin C ([R]25 þ35
D
(c 0.30, MeOH)) demonstrated that the two natural products
are identical.
Preparation of Diol 15. To a stirred solution of 3-butyn-1-ol
(140 μL, 1.85 mmol) and HMPA (0.26 mL, 1.48 mmol) in dry
THF (7.5 mL) was added dropwise n-BuLi (1.59 mmol/L in
n-hexane, 2.46 mL, 3.88 mmol) at -78 °C under argon atmo-
sphere. The mixture was stirred for 1 h at -78 °C, and then a
solution of 6 (156.7 mg, 0.462 mmol) in dry THF (15.0 mL) was
added at -78 °C. After being stirred for 1.5 h at -78 °C and for
1.5 h at room temperature, the reaction mixture was quenched
with sat. aq. NH4Cl and the whole was extracted three times
with CHCl3. The combined organic layers were dried over
MgSO4 and evaporated. The residue was purified by silica gel
flash column chromatography (AcOEt/n-hexane=3:1) to afford
15 (169.7 mg, 90%) as a colorless oil: 1H NMR (CDCl3,
400 MHz) δ (ppm) 4.43-4.34 (4H, overlapped, H-5, H-13),
4.22-4.11 (4H, overlapped), 3.98-3.94 (2H, overlapped, H-9),
3.73-3.70 (4H, overlapped, H2-1), 2.84-2.78 (6H, overlapped),
2.48-2.45 (4H, overlapped, H2-2), 2.02-1.51 (18H, over-
lapped), 1.45-1.41 (2H, overlapped), 1.17-0.92 (14H, over-
lapped), 0.04 (18H, s, -CO2CH2CH2Si(CH3)3); 13C NMR
(CDCl3, 100 MHz) δ (ppm) 155.9, 83.4, 83.2, 82.2, 82.0, 63.3,
61.2, 61.0, 46.54, 46.49, 44.7, 39.2, 39.0, 38.9, 36.6, 33.0, 32.5,
29.02, 28.99, 27.53, 27.46, 26.2, 25.3, 23.0, 22.04, 21.97,
17.7, -1.5; EI-MS m/z (%) 409 (1, Mþ), 308 (8), 101 (17), 73
(100); HREI-MS calcd for C22H39NO4Si (Mþ) 409.2648, found
409.2648; IR νmax (ATR) (cm-1) 3361 (OH), 2952, 2925, 2875,
1663 (CdO).
Preparation of r,β-Unsaturated Ketone 16. To a stirred solu-
tion of 15 (165.2 mg, 0.404 mmol) in dry CH2Cl2 (25.0 mL) was
added MnO2 (826 mg, 9.50 mmol) at 0 °C under argon atmo-
sphere. After being stirred for 21 h at room temperature, the
reaction mixture was filtered through Celite and the filtrate was
concentrated under reduced pressure. The residue was purified
by silica gel flash column chromatography (AcOEt/n-hexane=
2:1) to afford 16 (123.8 mg, 75%) as a colorless oil: [R]19D þ1.3
(c 0.65, CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm) 4.37 (1H,
br ddd, J=11.2, 4.6, 4.6 Hz, H-13), 4.20-4.11 (2H, overlapped),
3.96 (1H, br dd, J=13.4, 2.7 Hz, H-9), 3.81 (2H, q, J=6.1 Hz,
H2-1), 2.82 (1H, ddd, J=10.0, 10.0, 3.2 Hz, H-9), 2.80 (1H, dd,
J=16.8, 7.8 Hz, H-6), 2.65 (2H, t, J=6.3 Hz, H2-2), 2.59 (1H, dd,
J=16.3, 6.6 Hz, H-6), 2.16 (1H, t, J=6.1 Hz, -OH), 2.10-2.06
(1H, m), 2.05-1.95 (2H, overlapped), 1.72-1.49 (5H, over-
lapped), 1.42-1.36 (1H, m), 1.17 (1H, dd, J=9.8, 4.6 Hz, H-
12), 1.10 (1H, q, J=6.6 Hz), 1.06 (3H, d, J=6.8 Hz, H3-16), 1.00
(2H, dd, J = 9.0, 7.6 Hz, -CO2CH2CH2Si(CH3)3), 0.04 (9H,
s, -CO2CH2CH2Si(CH3)3; 13C NMR (CDCl3, 100 MHz) δ
(ppm) 187.4 (C-5), 155.9 (-CO2CH2CH2Si(CH3)3), 90.7 (C-3),
82.3 (C-4), 63.3 (-CO2CH2CH2Si(CH3)3), 60.2 (C-1), 52.0
(C-6), 46.3 (C-13), 39.0 (C-12), 38.9 (C-9), 35.7 (C-7), 32.5 (C-
8), 28.8 (C-14), 27.4 (C-15), 26.0 (C-11), 25.2 (C-10), 23.3 (C-2),
21.9 (C-16), 17.7 (-CO2CH2CH2Si(CH3)3), -1.5 (-CO2CH2-
CH2Si(CH3)3); EI-MS m/z (%) 407 (1, Mþ), 224 (6), 101 (15), 73
(100); HREI-MS calcd for C22H37NO4Si (Mþ) 407.2492, found
407.2487; IR νmax (ATR) (cm-1) 3430 (OH), 2949, 2867, 2212
(CtC), 1664 (CdO).
Conclusion
We have achieved the first asymmetric total syntheses of
lycoposerramines-Z (1) and -X (2) using common intermedi-
ate 4, which enabled us to determine unambiguously the
structures including the absolute configurations of the two
new phlegmarine-type alkaloids possessing a cyclic nitrone
residue.
Experimental Section
Preparation of Sulfonamide 10. To a stirred solution of 9 (593
mg, 1.97 mmol) in dry THF (40.0 mL) were added PPh3 (1.00 g,
3.95 mmol), NsNH2 (800 mg, 3.95 mmol), and DEAD (1.73 mL,
3.95 mmol) at 0 °C under argon atmosphere. The reaction
mixture was stirred for 13 h at room temperature. After removal
of the solvent under reduced pressure, the residue was purified
by silica gel flash column chromatography (AcOEt/n-hexane=
1:1 and then MeOH/CHCl3=1:50) to afford 10 (1.03 g, quant)
as a colorless oil: [R]15 -10.4 (c 0.62, CHCl3); 1H NMR
D
(CDCl3, 400 MHz) δ (ppm) 8.12-8.10 (1H, m, Ph-H),
7.86-7.84 (1H, m, Ph-H), 7.76-7.72 (2H, overlapped, Ph-H),
5.38 (1H, br t, J=5.7 Hz, NH), 4.65 (1H, ddd, J=10.9, 10.9, 4.4
Hz, H-13), 4.14 (2H, q, J=7.1 Hz, -OCH2CH3), 3.07-3.03 (2H,
m, H2-9), 2.44 (1H, dd, J=15.0, 3.5 Hz, H-6), 2.09-2.01 (2H,
overlapped), 2.06 (3H, s, -OCOCH3), 1.95 (1H, br d, J=12.2
Hz), 1.77-1.67 (2H, overlapped), 1.51-1.24 (3H, overlapped),
1.27 (3H, t, J=7.1 Hz, -OCH2CH3), 0.98 (1H, q, J=11.8 Hz,
H-14), 0.89 (3H, d, J=6.3 Hz, H3-16), 0.75 (1H, q, J=12.0 Hz,
H-8); 13C NMR (CDCl3, 100 MHz) δ (ppm) 172.8 (-CO2Et),
170.9 (-OCOCH3), 148.0 (Ph), 133.54 (Ph), 133.45 (Ph), 132.6
(Ph), 130.9 (Ph), 125.2 (Ph), 73.7 (C-13), 60.4 (-OCH2CH3),
44.5 (C-7), 44.0 (C-9), 40.4 (C-6), 40.1 (C-14), 38.4 (C-8), 35.1
(C-12), 29.7 (C-15), 24.1 (C-11), 24.0 (C-10), 21.7 (C-16), 21.2
(-OCOCH3), 14.2 (-OCH2CH3); FAB-MS (NBA) m/z 485
[M þ H]þ; HRFAB-MS (NBA/PEG) calcd for C22H32N2O8S-
Na [M þ Na]þ 507.1777, found 507.1779; IR νmax (ATR) (cm-1
)
3307 (NH), 2950, 2918, 2867, 1722 (CdO), 1540 (NO2).
Preparation of cis-Octahydroquinoline 11. To a stirred solu-
tion of 5 (120.5 mg, 0.272 mmol) in dry THF (5.4 mL) were
added PPh3 (357 mg, 1.36 mmol) and DTAD (313 mg, 1.36
mmol) at 0 °C under argon atmosphere. The reaction mixture
was stirred for 16 h at room temperature. After removal of the
solvent under reduced pressure, the residue was purified by silica
gel flash column chromatography (AcOEt/n-hexane=1:1 and
then MeOH/CHCl3=1:50) to afford 11 (120.8 mg, quant) as a
colorless oil: [R]16 þ38.2 (c 0.51, CHCl3); H NMR (CDCl3,
1
D
400 MHz) δ (ppm) 8.08-8.05 (1H, m, Ph-H), 7.70-7.61 (3H, m,
Ph-H), 4.18 (1H, ddd, J=12.2, 4.6, 4.6 Hz, H-13), 4.12 (2H, q,
J=7.1 Hz, -OCH2CH3), 3.59 (1H, br d, J=11.0 Hz, H-9), 3.11
(1H, ddd, J=12.7, 12.7, 2.7 Hz, H-9), 2.51 (1H, dd, J=15.6,
7.8 Hz, H-6), 2.37 (1H, dd, J=15.6, 7.1 Hz, H-6), 2.11 (1H, ddd,
J = 12.9, 12.9, 6.9 Hz, H-14), 1.97-1.90 (2H, overlapped),
Preparation of Cyclic Nitrone 17. To a stirred solution of 7
(29.8 mg, 0.073 mmol) in EtOH/H2O (1:1, 1.2 mL) were added
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Tanaka et al.
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K2CO3 (4.0 mg, 0.037 mmol) and NH2OH HCl (6.4 mg,
q-like, J=7.1 Hz, -OCH2CH3), 3.61 (2H, t, J=6.1 Hz, H2-9),
2.52 (1H, dd, J=13.7, 2.7 Hz, H-6), 2.05 (3H, s, -OCOCH3),
2.03-1.91 (3H, overlapped), 1.75-1.49 (4H, overlapped),
1.44-1.33 (1H, m), 1.26 (3H, t, J = 7.1 Hz, -OCH2CH3),
1.22-1.15 (2H, overlapped), 1.03 (9H, s, -tBu), 1.05-0.97 (1H,
m), 0.85 (3H, d, J=6.3 Hz, H3-16), 0.75 (1H, q, J=12.9 Hz, H-8);
13C NMR (CDCl3, 100 MHz) δ ppm: 173.3 (-CO2Et), 170.6
(-OCOCH3), 135.6 (Ph), 134.0 (Ph), 129.5 (Ph), 127.6 (Ph), 70.9
(C-13), 63.9 (C-9), 60.2 (-OCH2CH3), 43.7 (C-7), 41.0 (C-6),
39.0 (C-14), 38.6 (C-8), 34.4 (C-12), 29.8 (C-11), 26.9
(-C(CH3)), 26.2 (C-15), 24.9 (C-10), 22.0 (C-16), 21.2
(-OCOCH3), 19.2 (-C(CH3)), 14.3 (-OCH2CH3); FAB-MS
(NBA) m/z: 539 [MþH]þ; HRFAB-MS (NBA/PEG): calcd
for C32H47O5Si [M þ H]þ: 539.3193, found: 539.3201; IR νmax
(ATR) cm-1: 2930, 2858, 1732 (CdO).
Preparation of 13r-Azido Compound 24. To a stirred solution
of 23 (138.2 mg, 0.279 mmol) in dry THF (1.9 mL) were added
PPh3 (351 mg, 1.40 mmol), DPPA (0.29 mL, 1.40 mmol), and
DEAD (40 wt % in toluene, 0.58 mL, 1.40 mmol) at -20 °C
under argon atmosphere. The reaction mixture was stirred for
24 h at -20 °C. After removal of the solvent under reduced
pressure, the residue was purified by silica gel flash column
3
0.110 mmol) at room temperature under argon atmosphere.
After being stirred for 1 h and 15 min at 90 °C, the reaction
mixture was quenched with sat. aq. NaHCO3/H2O (1:1) and the
whole was extracted three times with CHCl3. The combined
organic layers were dried over MgSO4 and evaporated. The
residue was purified by silica gel flash column chromatography
(MeOH/CHCl3=1:10) to afford 17 (16.5 mg, 68%) as a colorless
oil: [R]19D -17.2 (c 0.19, CHCl3); 1H NMR (CDCl3, 400 MHz)
δ (ppm) 4.34 (1H, br ddd, J=11.7, 4.9, 4.9 Hz, H-13), 4.22-4.11
(2H, overlapped), 3.97 (1H, br d, J=13.4 Hz, H-9), 3.80 (2H,
br t, J=5.9 Hz, H2-1), 2.81 (1H, ddd, J=12.4, 12.4, 2.7 Hz, H-9),
2.67 (1H, dd, J=13.2, 6.3 Hz, H-6), 2.46-2.41 (3H, overlapped),
2.09-1.83 (5H, overlapped), 1.78-1.71 (2H, overlapped),
1.68-1.59 (2H, overlapped), 1.55-1.39 (4H, overlapped),
1.14-1.06 (2H, overlapped), 1.03 (3H, d, J=7.1 Hz, H3-16),
1.00 (2H, t, J = 8.5 Hz, -CO2CH2CH2Si(CH3)3), 0.04 (9H,
s, -CO2CH2CH2Si(CH3)3; 13C NMR (CDCl3, 100 MHz)
δ (ppm) 155.9 (-CO2CH2CH2Si(CH3)3), 148.0 (C-5), 63.2
(-CO2CH2CH2Si(CH3)3), 58.3 (C-1), 47.3 (C-13), 39.5, 39.1,
38.3, 36.2, 34.0 (C-7), 30.8 (C-8), 29.5 (C-14), 27.2, 26.4 (C-11),
24.8, 23.1, 22.5 (C-16), 18.9 (C-2), 17.7 (-CO2CH2-
CH2Si(CH3)3), -1.5 (-CO2CH2CH2Si(CH3)3); EI-MS m/z
(%) 408 (2, Mþ), 268 (28), 97 (54), 84 (85), 73 (100); HRFAB-
MS calcd for C22H41N2O3Si [M þ H]þ 409.2886, found
409.2871; IR νmax (ATR) (cm-1) 3362, 2948, 1684 (CdO),
1611 (NdC).
chromatography (AcOEt/n-hexane=1:15) to afford 24 (117.3
1
mg, 81%) as a colorless oil: [R]24 -19.5 (c 1.93, CHCl3); H
D
NMR (CDCl3, 400 MHz) δ (ppm) 7.68-7.66 (4H, overlapped,
Ph-H), 7.44-7.36 (6H, overlapped, Ph-H), 4.12 (2H, q, J=7.1,
-OCH2CH3), 3.69-3.60 (2H, overlapped, H2-9), 3.09 (1H, ddd,
J=11.2, 11.2, 4.0 Hz, H-13), 2.57 (1H, dd, J=15.2, 3.3 Hz, H-6),
2.08-1.98 (2H, overlapped), 1.80-1.67 (3H, overlapped),
1.61-1.43 (4H, overlapped), 1.25 (3H, t, J=7.1 Hz, -OCH2-
CH3), 1.14-1.05 (2H, overlapped), 1.05 (9H, s, -tBu), 0.94 (3H,
d, J=6.4 Hz, H3-16), 0.75 (1H, q, J=12.1 Hz, H-8); 13C NMR
(CDCl3, 100 MHz) δ (ppm) 172.8 (-CO2Et), 135.5 (Ph), 133.9
(Ph), 129.5 (Ph), 127.6 (Ph), 64.0 (C-9), 62.7 (C-13), 60.2
(-OCH2CH3), 45.0 (C-7), 40.3 (C-6), 39.9 (C-14), 38.3 (C-8),
35.8 (C-12), 30.4 (C-15), 27.4 (C-11), 26.8 (-C(CH3)3), 24.1
(C-10), 21.9 (C-16), 19.1 (-C(CH3)), 14.2 (-OCH2CH3); FAB-
MS (NBA) m/z 522 [M þ H]þ; HRFAB-MS (NBA/PEG) calcd
for C30H44N3O3Si [M þ H]þ 522.3152, found 522.3137; IR νmax
(ATR) (cm-1) 2926, 2855, 2091 (N3), 1732 (CdO).
Preparation of Lycoposerramine-Z (1). To a stirred solution of
17 (17.1 mg, 0.042 mmol) in dry THF (0.4 mL) was added
dropwise TASF (2.0 M in DMF, 0.21 mL, 0.420 mmol) at 0 °C
under argon atmosphere. The reaction mixture was stirred for
14 h at 0 °C and then quenched with MeOH. After removal of
the solvent under reduced pressure, the residue was purified by
silica gel flash column chromatography (MeOH/CHCl3/concd
NH4OH=1:2:0.1) and amino-silica gel open column chroma-
tography (CH3CN/H2O=15:1) to afford synthetic 1 (8.4 mg,
78%) as a colorless amorphous solid: [R]18 þ9.6 (c 0.34,
D
1
MeOH); H NMR (CDCl3, 500 MHz) δ (ppm) 3.82 (2H, br t,
J=5.8 Hz, H2-1), 3.12 (1H, br d, J=11.9 Hz, H-9), 2.91 (1H, br s,
H-13), 2.72-2.67 (2H, overlapped, H-6, H-9), 2.53-2.39 (3H,
overlapped, H2-4, H-7), 2.34 (1H, dd, J=13.1, 10.7 Hz, H-6),
2.03 (1H, br d, J=13.4 Hz, H-11), 1.97-1.92 (2H, overlapped,
H2-2), 1.79-1.71 (3H, overlapped, H2-3, H-15), 1.68-1.60 (2H,
overlapped, H-10, H-14), 1.55 (1H, br d, J=12.8 Hz, H-8), 1.44
(1H, dddd, J=13.7, 13.7, 4.3, 4.3 Hz, H-11), 1.36-1.25 (2H,
overlapped, H-10, H-12), 1.19 (1H, ddd, J=13.4, 13.4, 3.7 Hz,
H-14), 0.83 (3H, d, J=6.7 Hz, H3-16), 0.79 (1H, q, J=12.2 Hz,
H-8); 13C NMR (CDCl3, 125 MHz) δ (ppm) 148.7 (C-5), 58.3
(C-1), 56.6 (C-13), 47.9 (C-9), 41.6 (C-14), 41.4 (C-8), 40.9 (C-
12), 35.8 (C-6), 29.84 (C-4), 29.81 (C-7), 26.9 (C-11), 26.7 (C-15),
23.3 (C-3), 22.7 (C-16), 21.2 (C-10), 18.9 (C-3); FAB-MS (NBA)
m/z 265 [M þ H]þ; HRFAB-MS (NBA/PEG) calcd for
C16H29N2O [M þ H]þ 265.2280, found 265.2295; IR νmax
(ATR) (cm-1) 3275 (NH), 2940, 2914, 1604 (NdC); CD
(MeOH, 24 °C, c 0.496 mmol/L), λ (nm) (Δε) 277 (0), 255
(-1.2), 245 (0), 229 (þ2.7), 208 (0).
Preparation of trans-Octahydroquinoine 27. To a stirred solu-
tion of 26 (280.5 mg, 0.777 mmol) in dry EtOH (10.0 mL) was
added Pd/C (10%, 56.7 mg) at room temperature under H2
atmosphere. After being stirred for 12 h at room temperature,
the reaction mixture was filtered through Celite and the filtrate
was concentrated under reduced pressure. To a stirred solution
of the crude product (190.6 mg) in dry toluene (5.0 mL) were
added DMAP (455 mg, 1.60 mmol) and Teoc-carbonate (197 mg,
1.60 mmol) at 0 °C under argon atmosphere. After being stirred
for 24 h at room temperature, the reaction mixture was poured
into H2O and the whole was extracted three times with AcOEt.
The combined organic layers were washed with sat. aq. NaH-
CO3, dried over MgSO4, and evaporated. The residue was
purified by silica gel flash column chromatography (AcOEt/n-
hexane=1:7) to afford 27 (264.2 mg, 89%) as a colorless oil:
1
[R]18 -37.2 (c 1.04, CHCl3); H NMR (CDCl3, 400 MHz) δ
D
Preparation of 13β-Acetate 18. To a stirred solution of 4
(140 mg, 0.282 mmol) and PPh3 (222 mg, 0.846 mmol) in dry
THF (1.9 mL) were added DTAD (195 mg, 0.846 mmol) and dry
AcOH (48 μL, 0.846 mmol) at 0 °C under argon atmosphere.
The reaction mixture was stirred for 3 h at room temperature.
After removal of the solvent under reduced pressure, the residue
was purified by silica gel flash column chromatography (AcOEt/
n-hexane=1:9) to afford 18 (98.1 mg, 65%) as a pale yellow oil
(ppm) 4.15-4.07 (4H, overlapped, -OCH2CH3, -CO2CH2-
CH2Si(CH3)3), 3.56 (1H, ddd, J = 13.9, 6.6, 3.9 Hz, H-9),
3.22-3.12 (2H, overlapped, H-9, H-13), 2.46 (1H, dd, J =
14.9, 4.6 Hz, H-6), 2.05-2.00 (1H, overlapped), 2.01 (1H, dd,
J=14.9, 8.3 Hz, H-6), 1.86-1.73 (2H, overlapped), 1.71-1.47
(4H, overlapped), 1.27-1.14 (2H, overlapped), 1.04-0.94 (3H,
overlapped), 1.23 (3H, t, J=7.1 Hz, -OCH2CH3), 0.88 (3H, d,
J=6.6 H, H3-16), 0.77 (1H, q, J=12.2 Hz, H-8), 0.01 (9H, s,
-CO2CH2CH2Si(CH3)3); 13C NMR (CDCl3, 100 MHz) δ
(ppm) 173.1 (-CO2Et), 156.1 (-CO2CH2CH2Si(CH3)3), 63.0
(-CO2CH2CH2Si(CH3)3), 61.0 (C-13), 60.3 (-OCH2CH3),
42.1 (C-12), 41.2 (C-9), 39.5 (C-6), 39.3 (C-8), 38.7 (C-7), 38.6
along with the starting material 4 (37.2 mg, 27%). 18: [R]23
D
1
þ42.0 (c 1.29, CHCl3); H NMR (CDCl3, 400 MHz) δ ppm:
7.66-7.63 (4H, overlapped, Ph-H), 7.42-7.36 (6H, over-
lapped, Ph-H), 5.10 (1H, br-q, J = 2.7 Hz, H-13), 4.12 (2H,
J. Org. Chem. Vol. 74, No. 22, 2009 8679

Tanaka et al.
JOCArticle
(C-14), 31.0 (C-15), 23.9 (C-11), 23.1 (C-10), 22.1 (C-16),
17.8 (-CO2CH2CH2Si(CH3)3), 14.2 (-OCH2CH3), -1.5
(-CO2CH2CH2Si(CH3)3); EI-MS m/z (%) 383 (11, Mþ), 355
(11), 340 (25), 282 (33), 268 (35), 252 (93), 224 (52), 101 (51), 73
(100); HREI-MS calcd for C20H37NO4Si (Mþ) 383.2492, found
383.2497; IR νmax (ATR) (cm-1) 2950, 2900, 1733 (CdO), 1689
(CdO).
Preparation of Lycoposerramine-X (2). To a stirred solution
of 32 (14.0 mg, 0.034 mmol) in dry THF (0.3 mL) was added
dropwise TASF (2.0 M in DMF, 0.17 mL, 0.340 mmol) at
0 °C under argon atmosphere. The reaction mixture was
stirred for 16 h at 0 °C and then quenched with MeOH. After
removal of the solvent under reduced pressure, the residue
was purified by silica gel flash column chromatography
(MeOH/CHCl3/concd NH4OH = 1:2:0.1) and amino-silica
gel open column chromatography (CH3CN/H2O=15:1) to
(1H, dddd, J=12.4, 12.4, 12.4, 3.8 Hz, H-11), 0.96-0.88 (1H,
m, H-12), 0.93 (1H, q, J=12.4 Hz, H-14), 0.93 (3H, d, J=6.6
Hz, H3-16), 0.84 (1H, q, J = 12.4 Hz, H-8); 13C NMR
(CD3OD, 150 MHz) δ (ppm) 157.0 (C-5), 61.6 (C-13), 58.9
(C-1), 47.9 (C-12), 47.2 (C-9), 42.4 (C-8), 41.9 (C-14), 39.2 (C-
7), 36.5 (C-6), 32.0 (C-15), 31.4 (C-4), 29.3 (C-11), 27.1 (C-10),
23.9 (C-2), 22.7 (C-16), 19.3 (C-3); FAB-MS (NBA) m/z 265
[M þ H]þ; HRESI-MS calcd for C16H29N2O [M þ H]þ
265.2274, found 265.2270; IR νmax (ATR) (cm-1) 3281
(-NH), 3231, 2924, 2849, 2789, 1619 (NdC); CD (MeOH,
24 °C, c 0.617 mmol/L), λ (nm) (Δε) 283 (0), 254 (-1.17), 241
(0), 228 (þ1.59).
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 Founda-
tion.
afford synthetic 2 (6.9 mg, 76%) as a colorless amorphous
1
solid: [R]21 þ50.9 (c 0.20, MeOH); H NMR (CD3OD, 600
D
MHz) δ (ppm) 3.75 (2H, br t, J=5.8 Hz, H2-1), 3.02 (1H, br d,
J=11.8 Hz, H-9), 2.80 (1H, br dd, J=12.9, 4.1 Hz, H-6), 2.62
(1H, br t, J=12.6 Hz, H-9), 2.57-2.49 (2H, overlapped, H2-
4), 2.31-2.25 (1H, m, H-13), 2.25 (1H, dd, J=13.2, 10.4 Hz,
H-6), 2.04 (1H, br d, J = 12.9 Hz, H-11), 1.98-1.94 (2H,
overlapped, H2-3), 1.80-1.74 (5H, overlapped, H2-3, H-7, H-
10, H-14), 1.59-1.49 (3H, overlapped, H-8, H-10, H-15), 1.06
Supporting Information Available: Additional procedures
and spectral data for all new compounds 5-9, 12-14, 23, 25, 26,
28-32, and S1-S3, and copies of NMR spectra of compounds
5-18, 23-32, S1-S3, and synthetic lycoposerramines-Z (1)
and -X (2). This material is available free of charge via the
Internet at http://pubs.acs.org.
8680 J. Org. Chem. Vol. 74, No. 22, 2009