Synthetic studies on lycopodine: Construction of hexahydrojulolidine core by intramolecular Mannich reaction

Article abstract of DOI:10.1016/j.tetlet.2014.10.150

The tricyclic core skeleton of lycopodine was constructed by the intramolecular Mannich reaction of a 12-membered cyclic amine. The concise assembly of the macrocyclic intermediate was executed by the sequential inter- and intramolecular N-alkylation of a

Full text of DOI:10.1016/j.tetlet.2014.10.150

Tetrahedron Letters 55 (2014) 7177–7180
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic studies on lycopodine: construction of hexahydrojulolidine
core by intramolecular Mannich reaction
⇑
Takanao Sato, Hirofumi Ueda, Hidetoshi Tokuyama
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The tricyclic core skeleton of lycopodine was constructed by the intramolecular Mannich reaction of a 12-
membered cyclic amine. The concise assembly of the macrocyclic intermediate was executed by the
sequential inter- and intramolecular N-alkylation of a linear diol using Ns-amide. The fully functionalized
diol was prepared via Michael reaction of enone and malonate. The key Mannich reaction proceeded
smoothly in the presence of silica gel to provide the tricyclic core skeleton of lycopodine.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 29 September 2014
Revised 27 October 2014
Accepted 30 October 2014
Available online 5 November 2014
Keywords:
Mannich reaction
Cascade reaction
Oxidation
Lycopodine
Alkaloid
As a number of polycyclic alkaloids possessing attractive bioac-
tivities are found in nature, the development of an efficient syn-
thetic strategy for this class of compounds has become an
important topic in synthetic organic chemistry and drug discovery.
Polycyclic structures are usually assembled by stepwise cycliza-
tions, however, this conventional synthetic strategy requires
lengthy synthetic route. Recently, a cascade reaction has gained
1
much attention for the construction of polycyclic structures. This
powerful tool increases the efficiency of multistep synthesis by
reducing the reaction steps. In addition, cascade reactions are
2
3
advantageous with regard to atom economy and green chemistry
due to their simplification of experimental operations and genera-
tion of less hazardous waste.
Recently, we demonstrated the construction of the tricyclic
aminoketone 2 by intramolecular Mannich reaction of a macrocy-
4
clic secondary amine bearing two carbonyl groups (Scheme 1).
Scheme 1. Intramolecular Mannich reaction and application to the total syntheses
of (+)-haplophytine (3) and related compounds.
This cascade cyclization proceeded under mild acidic conditions,
in the presence of silica gel to give the tricyclic compound 2 as a
single diastereomer. The tricyclic aminoketone 2 served as a key
intermediate for the synthesis of the aspidosperma class of indole
alkaloids, allowing the completed total syntheses of a series of
4a
4b
H
alkaloids including (+)-haplophytine (3), (–)-aspidophytine (4),
N
N
l OHC
N
N
H
H
4
b
4b
(
+)-cimicidine (5),
and (+)-cimicine (6).
With the high
m
l
m
l
m
stereoselectivity and mildness of the reaction conditions, we
predicted the general strategy (from 7 to 9) depicted in Scheme 2
n
n
n
O
O
O
O
7
8
9
lycopodine (10)
⇑
Corresponding author.
E-mail address: tokuyama@mail.pharm.tohoku.ac.jp (H. Tokuyama).
Scheme 2. General strategy and target compound in this study.
http://dx.doi.org/10.1016/j.tetlet.2014.10.150
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
0

7
178
T. Sato et al. / Tetrahedron Letters 55 (2014) 7177–7180
Our study was initiated by preparing fragments 14 and 15 for
Michael addition (Scheme 4). After mono-benzylation of 1,5-pen-
tanediol 16, the remaining hydroxyl group was oxidized to alde-
hyde. 1,2-Addition of lithium acetylide to aldehyde afforded
4
propargyl alcohol 19, which was then reduced with LiAlH .
Subsequent oxidation with PCC gave Michael acceptor 14. Michael
donor 15, on the other hand, was obtained by alkylation of
1
2
dimethyl malonate with alkyl bromide 22, which was prepared
from 1,3-propanediol (20) by mono-benzylation and bromination.
With these two fragments in hand, we then examined the
Michael addition (Table 1). First, we tested several bases such as
DBU and NaH, however, these reaction conditions resulted in only
trace amounts of the desired Michael adduct 23 (entries 1–2).
Treatment with sodium methoxide slightly improved the Michael
adduct yield (entry 3). After further optimization, we found the
yield of the Michael adduct strongly depended on the concentra-
tion of the reaction mixture. Finally, we obtained the desired
adduct 23 in a 57% yield when the reaction was conducted in
solvent free conditions (entry 4).
Scheme 3. Synthetic strategy for the tricyclic core of lycopodine (10).
to be applicable to the synthesis of a wide variety of polycyclic
alkaloids. As such we initiated synthetic studies on lycopodine
Next, we conducted functional group manipulations of ketoes-
ter 23 in preparation for the 12-membered cyclic amine formation
by double Mitsunobu reaction (Scheme 5). After protection of the
(
10) featuring the intramolecular Mannich reaction cascade.
5
Lycopodine (10) is a representative Lycopodium alkaloid iso-
6
lated from Lycopodium complanatum by Bödeker. The Lycopodium
species has been utilized in Chinese folk medicine for the treat-
7
ment of muscle and skin disorders. In addition, its congeners are
Table 1
Optimization of the Michael reaction
expected to be lead compounds for the remedy of Alzheimer’s dis-
8
ease. To date numerous synthetic studies and total syntheses of
9
a–h
lycopodine (10), including many racemic total syntheses,
two
9
i,j
formal syntheses, and only one asymmetric total synthesis of
1
0 by Carter and co-workers10 were reported.
The synthetic strategy for the tricyclic aminoketone 11, a model
compound of a lycopodine synthetic intermediate, is shown in
Scheme 3. For construction of the tricyclic skeleton, we planned
to apply the intramolecular Mannich reaction to 12-membered
cyclic amine 12. The macrocyclic secondary amine derivative
would be then synthesized by sequential inter- and intramolecular
Mitsunobu reaction of diol 13 using 2-nitrobenzenesulfonamide
Entry
Base (equiv)
Solvent
Temp
Time (h)
Yield
1
2
3
DBU (4)
NaH (4)
NaOMe (1.2)
NaOMe (0.3)
THF
DMF
MeOH (1.0 M)
None
rt
12
1
1.5
3
Trace
Trace
10%
50 °C
50 °C
rt
1
1
(
Ns-amide). A concise assembly of 13 could then be executed
a
4
57%
via Michael addition with enone 14 and aldehyde 15.
a
Michael donor 15 (1.2 equiv) was used.
Scheme 4. Preparation of Michael accepter 14 and donor 15.
Scheme 5. Preparation of diol 28.

T. Sato et al. / Tetrahedron Letters 55 (2014) 7177–7180
7179
Table 2
Macrocyclization
Entry
Substrate
Reagents (equiv)
DEAD (3.0) Ph P (3.0)
DEAD (3.0) n-Bu P (3.0)
DEAD (10) Ph P (10)
DEAD (3.0) Ph P (3.0)
Cs CO (10)
Solvent
Temp
Time
Yield (%)
1
2
3
4
5
28
28
28
28
30
3
Benzene (0.1 M)
Benzene (0.1 M)
Benzene (0.005 M)
Benzene (0.1 then 0.02 M)
MeCN (0.005 M)
rt
rt
Reflux
rt
Reflux
40 min
2 days
24 h
15 min + 1 h
1 h
7
3
Trace
0
3
3
21
41
a
2
3
a
The Yield was for three steps from 28.
We then investigated the formation of a 12-membered cyclic
amine by the double Mitsunobu reaction of Ns-amide (Table 2).15
Disappointingly, the initial trial using DEAD and triphenylphos-
phine gave the desired cyclic product 29 in only a 7% yield (entry
1
). Conditions using tri-n-butylphosphine instead of triphenyl-
phosphine were not effective (entry 2). To avoid polymerization,
we examined high-dilution conditions (entry 3). Generation of
the desired cyclic amine 29 was not observed, possibly due to an
insufficient reaction rate of the initial intermolecular Mitsunobu
reaction. The yield of the 12-membered cyclic amine derivative
was substantially improved to 21% when the reaction was con-
ducted with a stepwise decrease in the concentration (entry 4).
Thus, the reaction was initially conducted using one equivalent
of DEAD at a 0.1 M concentration. The mixture was then diluted
to 0.02 M with benzene and stirring was continued after addition
of two equivalents of DEAD. Finally, we decided to employ the
sequential inter- and intramolecular N-alkylation after the conver-
sion of diol 28 to diiodide 30. The desired 12-membered cyclic
amine derivative 29 was successfully obtained in an acceptable
yield (41%) by treatment of diiodide 30 with Ns-amide in the pres-
Scheme 6. Key intramolecular Mannich reaction.
ketone, the diester was subjected to Krapcho decarboxylation13
with sodium cyanide, to produce a mixture of monoester 25 and
a small amount of the corresponding carboxylic acid. This mixture
was then treated with MeI to transform 25 as a 1:1 mixture of dia-
2 3
ence of Cs CO
under highly diluted condition in MeCN (entry 5).16
Having successfully constructed the 12-membered cyclic amide
29, we subsequently examined the key Mannich reaction. Accord-
ing to our previously developed methodology, the 12-membered
cyclic amide 29 (a 2:1 mixture of diastereomers) was subjected
to the sequential reaction. Initially, two acetal protective groups
were removed by acidic hydrolysis to give the corresponding
1
4
stereomers. After conversion of the methyl ester 25 to aldehyde
6 by a reduction–oxidation sequence, the formyl group was pro-
2
tected as an acetal and the removal of two benzyl groups under
Birch reduction conditions was subsequently executed to give
the desired diol 28.
Table 3
Oxidation of the tricyclic aminoketone
N
N
H
H
H
H
conditions
H
O
n-Pr
O
n-Pr
H
11
31
Entry
Reagents
Fe(CN)
Solvent
t-BuOH/H
CH Cl
Benzene
EtOAc
Temp
Time (h)
Yield (%)
1
2
3
4
5
6
K
3
6
NaHCO
3
2
O
90 °C
rt
50 °C
rt
rt
80 °C
1
48
4
0.5
0.5
2
0
0
0
0
0
DDQ
2
2
Pb(OAc)
Mn(OAc)
4
3
Á2H
O NaIO
Hg(OAc)
EDTAÁ2NaÁ2H
2
O t-BuOOH
RuO
2
ÁH
2
4
EtOAc/H
2
O
a
2
2
O
EtOH/H
2
O
36 (50 )
a
The Yield was based on recovered starting material.

7
180
T. Sato et al. / Tetrahedron Letters 55 (2014) 7177–7180
ketoaldehyde. Cleavage of the Ns group and removal of MeCN then
gave a crude intermediate. Finally, by treatment of the intermedi-
ate with silica gel in CH Cl , the expected Mannich reaction
2 2
2006, 45, 7134; (g) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun.
003, 551; (h) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(a) Trost, B. M. Science 1991, 254, 1471; (b) Trost, B. M. Angew. Chem., Int. Ed.
995, 34, 259.
2
2.
1
proceeded quite smoothly to produce the desired tricyclic aminok-
etone 11 in excellent yields as a single isomer. The stereochemistry
of 11 was unambiguously determined by NOESY experiments. Sub-
stantial NOE was observed between the methyne protons depicted
in Scheme 6.
3. (a) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford
University Press: Oxford, 2000; p 135; (b) Matlack, A. S. Introduction to Green
Chemistry; Marcel Dekker: New York, 2001; p 570.
4.
(a) Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama,
H. Angew. Chem., Int. Ed. 2009, 48, 7600; (b) Satoh, H.; Ueda, H.; Tokuyama, H.
Tetrahedron 2013, 69, 89.
5.
For recent reviews on Lycopodium alkaloids, see: (a) Murphy, R. A.; Sarpong, R.
Chem.-Eur. J. 2014, 20, 42; (b) Siengalewicz, P.; Mulzer, J.; Rinner, U. In The
Alkaloids; Knölker, H.-J., Ed.; Elsevier: Amsterdam, 2013; Vol. 72, pp 1–151; (c)
Kitajima, M.; Takayama, H. In Topics in Current Chemistry; Knölker, H.-J., Ed.;
Springer: Berlin, 2012; Vol. 309, pp 1–31; (d) Nakayama, A.; Kitajima, M.;
Takayama, H. Synlett 2012, 2014; (e) Hirasawa, Y.; Kobayashi, J.; Morita, H.
Heterocycles 2009, 77, 679.
For construction of the final lycopodine ring, we next examined
the regioselective oxidation of amine 11 (Table 3). First, we evalu-
3 6
ated the conditions using K FeCN according to the procedure
17
reported by Corey and co-workers, however, the expected oxida-
tion was not observed (entry 1). Similarly, no oxidation was
6.
Bödeker, K. Justus Liebigs Ann. Chem. 1881, 208, 363.
4
observed using DDQ and Pb(OAc) (entries 2–3). When Mn or Ru
1
8
7. (a) Nikonorow, M. Acta Polon. Pharm. 1939, 3, 23; (b) Ma, X.; Gang, D. R. Nat.
Prod. Rep. 2004, 21, 752; (c) Kobayashi, J.; Morita, H. Alkaloids 2005, 61, 1.
8. Ortega, M. G.; Agnese, A. M.; Cabrera, J. L. Phytomedicine 2004, 11, 539.
9. (a) Stork, G.; Kretchmer, R. A.; Schlessinger, R. H. J. Am. Chem. Soc. 1968, 90,
reagents were used, the expected vinylogous amide was not
obtained, but an undesired oxidized product was generated
1
9
(
entries 4–5). After extensive screening of various oxidants, we
1647; (b) Ayer, W. A.; Bowman, W. R.; Joseph, T. C.; Smith, P. J. Am. Chem. Soc.
found that vinylogous amide 31 was afforded via oxidation and
isomerization of the allylic methine proton with recovery of the
starting material 11 by treatment with mercury (II) acetate in
1968, 90, 1648; (c) Kim, S.; Bando, Y.; Horii, Z. Tetrahedron Lett. 1978, 19, 2293;
(
d) Heathcock, C. H.; Kleinman, E.; Binkley, E. S. J. Am. Chem. Soc. 1978, 100,
8036; (e) Heathcock, C. H.; Kleinman, E. F.; Binkly, E. S. J. Am. Chem. Soc. 1982,
1054, 104; (f) Schumann, D.; Mueller, H. J.; Naumann, A. Lebigs Ann. Chem. 1982,
20
the presence of EDTAÁ2Na (entry 6).
1700; (g) Kraus, G. A.; Hon, Y. S. Heterocycles 1987, 25, 377; (h) Grieco, P. A.;
In summary, we developed a concise construction of the tricy-
clic core skeleton of lycopodine (10). This was conducted by facile
assembly of a 12-membered secondary amine derivative through
Michael addition and sequential inter- and intramolecular N-alkyl-
ation of Ns-amide, and the subsequent construction of the tricyclic
structure by silica gel-promoted stereoselective intramolecular
Mannich reaction. In addition, we succeeded in performing an
Dai, Y. J. Am. Chem. Soc. 1998, 120, 5128; For formal syntheses of lycopodine,
see: (i) Padwa, A.; Brodney, M. A.; Marino, J. P., Jr.; Sheehan, S. M. J. Org. Chem.
1997, 62, 78; (j) Mori, M.; Hori, K.; Akashi, M.; Hori, M.; Sato, Y.; Nishida, M.
Angew. Chem., Int. Ed. 1998, 37, 637; For synthetic studies towards lycopodine,
see: (k) Colvin, E. W.; Martin, J.; Parker, W.; Raphael, R. A.; Shroot, B.; Doyle, M.
J. Chem. Soc., Perkin Trans. 1 1972, 860; (l) Wenkert, E.; Broka, C. A. J. Chem. Soc.,
Chem. Commun. 1984, 714; (m) Saha, M.; Carter, R. G. Org. Lett. 2013, 15, 736;
(
n) Zhang, J.; Wang, Y.-Q.; Wang, X.-W.; Li, W.-D. J. Org. Chem. 2013, 78, 6154.
1
1
0. (a) Yang, H.; Carter, R. G.; Zakharov, L. N. J. Am. Chem. Soc. 2008, 130, 9238; (b)
Yang, H.; Carter, R. G. J. Org. Chem. 2010, 75, 4929.
1. (a) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353; (b) Kan, T.; Kobayashi, H.;
Fukuyama, T. Synlett 2002, 697; (c) Fukuyama, T.; Jow, C.-K.; Cheung, M.
Tetrahedron Lett. 2001, 36, 6373.
oxidation at a-position of nitrogen atom. Further synthetic studies
toward lycopodine (10) are currently in progress.
Acknowledgments
12. Frankowski, K. J.; Golden, J. E.; Zeng, Y.; Lei, Y.; Aube J. Am. Chem. Soc. 2008, 130,
018.
6
1
1
1
3. Krapcho, A. P. Synthesis 1982, 805.
This work was financially supported by the Cabinet Office,
Government of Japan through its Funding Program for Next
Generation World-Leading Researchers (LS008), a Grant-in-aid
for Scientific Research (A) (26253001) and for Young Scientists
4. The structures of the diasteromers were not determined.
5. (a) Sumi, S.; Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Tetrahedron 2003, 59,
8571; (b) Kaburagi, Y.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2004, 126,
10246.
1
6. The difference of diastereomeric ratio between 28 and 29 or 30 and 29
indicates that one of the two diastereomers of 28 or 30 seems to be easily
cyclized to give 12-membered compound in higher yields.
7. He, F.; Bo, Y.; Altom, J. D.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 6771.
8. Murahashi, S.; Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem. Soc. 2003, 125,
15312.
(
B) (24790003), and Platform for Drug Discovery, Informatics,
and Structural Life Science from the MEXT, Japan.
1
1
Supplementary data
1
9. The structure of the by-product was tentatively determined as below.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.10.
1
50.
References and notes
1
.
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C.; Walji, A. M. Synthesis 2007, 1477; (e) Chapman, C. J.; Frost, C. G. Synthesis
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1
2
007, 1; (f) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed.