Total syntheses of lyconadins A-C

Article abstract of DOI:10.1021/ja312065m

The total synthesis of the Lycopodium alkaloid lyconadin A was accomplished and it was applied to the total syntheses of the related congeners, lyconadins B and C. Lyconadin A has attracted attention as a challenging target for total synthesis due to the

Full text of DOI:10.1021/ja312065m

Article
pubs.acs.org/JACS
Total Syntheses of Lyconadins A−C
Takuya Nishimura,† Aditya K. Unni,† Satoshi Yokoshima,‡ and Tohru Fukuyama*,†,‡
†Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
‡Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan
S
* Supporting Information
ABSTRACT: The total synthesis of the Lycopodium alkaloid
lyconadin A was accomplished and it was applied to the total
syntheses of the related congeners, lyconadins B and C.
Lyconadin A has attracted attention as a challenging target for
total synthesis due to the unprecedented pentacyclic skeleton.
Our synthesis of lyconadin A features a facile construction of
the highly fused tetracyclic skeleton through a combination of
an aza-Prins reaction and an electrocyclic ring opening, followed by formation of a C−N bond. Transformation of the
bromoalkene moiety of the tetracycle to a key enone intermediate was extensively investigated, and three methods via sulfide,
oxime, or azide intermediates were established. A pyridone ring was constructed from the key enone intermediate to complete
the synthesis of lyconadin A. A dihydropyridone ring could also be formed from the same enone intermediate, leading to a
synthesis of lyconadin B. Establishment of the conditions for an electrocyclic ring opening without formation of the C−N bond
resulted in completion of the total synthesis of lyconadin C.
and co-workers5 subsequently reported the total syntheses of
INTRODUCTION
■
( )- and (+)-lyconadin A, in which a unique oxidative C−N
The Lycopodium alkaloids are a group of structurally diverse
bond-forming reaction6 was used to form the pentacyclic
skeleton. In 2011 we also reported our total synthesis of
(+)-lyconadin A, which featured a facile construction of the
tetracyclic system via a combination of an aza-Prins reaction
and an electrocyclic ring opening, and transformation of a
bromoalkene moiety to an enone.7 Herein we discuss the
synthesis of (+)-lyconadin A in detail, disclose improvement of
the transformation of the bromoalkene moiety, and describe
the synthesis of the natural congeners lyconadins B (2) and C
(3).8
compounds isolated from the Lycopodium species.1 The
complicated structures of the Lycopodium alkaloids have
provided challenging targets for total synthesis as well as
opportunities for development of synthetic methodologies.
Lyconadin A, one of the Lycopodium alkaloids, was isolated
from Lycopodium complanatum in 2001 by Kobayashi et al.2
Structural elucidation of lyconadin A (1, Figure 1) showed an
RESULTS AND DISCUSSION
■
Retrosynthesis. Our retrosynthesis of 1 is shown in
Scheme 1. Construction of the pyridone moiety in 1 would
be based on a procedure developed in our laboratory,9 which
requires enone 4 as a precursor. We envisioned that the carbon
framework of 4, bicyclo[5.4.0]undecane, could be derived from
5 via a ring expansion of the cis-decaline system. Both the
carbonyl group and the double bond in 5 would form the basis
of the unique tertiary amine moiety. Decaline 5 could in turn be
prepared by means of a Diels−Alder reaction.
Figure 1. Structure of lyconadins A−C.
Synthesis of Lyconadin A. The synthesis of lyconadin A
began with a Diels−Alder reaction performed according to
Overman’s conditions (Scheme 2).10 The known unsaturated
ketone 611 was treated with isoprene in the presence of
ethylene glycol bis(trimethylsilyl) ether and trimethylsilyl
trifluoromethanesulfonate (TMSOTf). The Diels−Alder reac-
unprecedented pentacyclic skeleton including a 2-pyridone
ring, six stereogenic centers, and a tertiary amine at a
bridgehead. The first total synthesis of (+)-lyconadin A was
accomplished by Beshore and Smith in 2007,3 featuring use of
an intramolecular aldol/conjugate addition cascade and an
aminoiodination reaction to construct the core tetracyclic
structure. In addition, Smith et al.4 developed a novel pyridone
synthesis during the course of their synthetic studies. Sarpong
Received: December 11, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja312065m | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Upon heating in pyridine, 11 underwent an electrocyclic ring
opening to form an allylic carbocation (12),14 which was
intercepted by the tertiary amine with loss of the benzyl group
to give the desired tetracyclic compound 13 (route a). This
reaction, however, was accompanied by formation of undesired
diene 14 via deprotonation of the allylic cation (route b). The
bulky benzyl group seemed to inhibit approach of the amine to
the allylic cation. The sequence was also problematic because of
the low yield of the cyclopropanation reaction, which was
presumably due to an unwanted reaction of dibromocarbene
with the tertiary amine. To solve these problems, we decided to
change the benzyl group to another protective group.
Scheme 1. Retrosynthesis
Cleavage of the benzyl group by hydrogenolysis followed by
addition of Boc2O afforded Boc-protected compound 15
(Scheme 4).15 Dibromocyclopropanation of this compound
Scheme 2. Diels−Alder Reaction and Aza-Prins Reaction
Scheme 4. Construction of Tetracyclic Skeleton
tion occurred selectively on the opposite side of the methyl
group to give 8. After cleavage of the ethylene ketal under mild
conditions,12 the resulting ketone was subjected to a reductive
amination with benzylamine to give secondary amine 9 as the
sole isomer. Upon treatment with formalin under acidic
conditions, 9 underwent an aza-Prins reaction to produce
tricyclic compound 10.13
We next focused on the ring expansion using the double
bond. Dibromocyclopropanation of tricyclic compound 10
afforded the desired product 11, albeit in low yield (Scheme 3).
proceeded in good yield to give 16 as a 5:1 diastereomeric
mixture.16 After cleavage of the Boc group by treatment with
trifluoroacetic acid (TFA), the resulting secondary amine was
heated in pyridine. As expected, interception of the allylic
cation by the amine proceeded smoothly to furnish tetracyclic
compound 13 in good yield.
Having established an efficient synthetic route to key
compound 13 containing the tetracyclic skeleton, we next
focused on transformation of 13 into enone 4. In our earlier
communication,7 we reported two different routes based on a
halogen−lithium exchange of 13 by reaction with t-butyllithium
in tetrahydrofuran (THF) at −78 °C (Scheme 5). In the first
route, treatment of the resulting alkenyllithium with diphenyl
disulfide afforded sulfide 17, which was transformed into enone
4 via a vinylogous Pummerer rearrangement.17 Oxidation of the
sulfide with m-chloroperbenzoic acid (mCPBA) gave sulfoxide
18 as the sole isomer. Upon treatment with acetic anhydride in
the presence of camphorsulfonic acid (CSA), 18 underwent the
vinylogous Pummerer rearrangement to furnish 19. Acidic
hydrolysis of 19 in the presence of mercury sulfate afforded
enone 4.
Scheme 3. Attempted Formation of Tetracyclic Core
In the second route, treatment of the alkenyllithium derived
from 13 with isoamyl nitrite afforded oxime 21 in 37% yield
(Scheme 6). This reaction is believed to proceed via formation
and isomerization of nitrosoalkene 20.18,19 Subsequent
hydrolysis of the oxime under acidic conditions afforded the
desired enone 4.
In an effort to improve the efficiency of the transformation,
we investigated the use of a variety of electrophiles including
peroxides,20,21 azo compounds,22 diazo compounds,23 and
B
dx.doi.org/10.1021/ja312065m | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Scheme 5. Transformation into Enone 4 via Vinylogous
Pummerer Rearrangement
Scheme 8. Completion of Synthesis of Lyconadin A
material. To circumvent this problem, the subsequent
cyclization step was performed in a one-pot process. Thus,
addition of 2-(phenylsulfinyl)acetamide 23 to the enone in the
presence of sodium hydride, followed by treatment with
methanolic hydrogen chloride, resulted in construction of the
pyridone ring to afford lyconadin A (1) in 90% yield.
Synthesis of Lyconadin B. The synthetic route to
lyconadin A was next applied to the synthesis of the other
lyconadins. By using the key intermediate 4, lyconadin B (2)
was prepared without much difficulty. Conjugate addition of an
anion of benzyl methyl malonate (25) furnished adduct 26 in
91% yield (Scheme 9). Cleavage of the benzyl ester by
Scheme 6. Transformation into Enone 4 through an Oxime
Scheme 9. Synthesis of Lyconadin B
nitroso compounds.24,25 After extensive investigation, we found
that the reaction of the alkenyllithium with trisyl azide, followed
by addition of acetic acid, afforded azide 22 in good yield
(Scheme 7).26 Treatment of 22 with hydrochloric acid in 1,4-
Scheme 7. Transformation into Enone 4 through an Azide
hydrogenolysis followed by treatment with aqueous ammonia
at reflux gave a mixture of primary amide 2728 and hemiaminal
28. Heating the mixture under an argon atmosphere29 induced
dehydration to furnish lyconadin B (2).
Synthesis of Lyconadin C. We next focused on the
synthesis of lyconadin C, which lacks one of the C−N bonds in
lyconadin A. In our synthesis of lyconadin A, the C−N bond
was formed by the intramolecular addition of the secondary
amine to an allylic cation generated from electrocyclic ring
opening of the dibromocyclopropane. It seemed that
introduction of an electron-withdrawing protective group on
the secondary amine could easily inhibit the C−N bond
formation. Attempted reaction of Boc-protected compound 16
dioxane induced cleavage of the N−N bond with generation of
molecular nitrogen to give an α,β-unsaturated imine,27 which
was immediately hydrolyzed in situ to afford enone 4 in 92%
yield.
To complete the synthesis, formation of the requisite
pyridone ring was conducted according to our procedure
with some modifications (Scheme 8).9 Isolation of the highly
polar diastereomeric mixture of adducts 24 caused loss of
C
dx.doi.org/10.1021/ja312065m | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(redefined as 29a in Table 1) by heating in pyridine, however,
resulted in production of a mixture of the desired diene 30a and
Scheme 10. Synthesis of Lyconadin C
Table 1. Cleavage of Dibromocyclopropane Ring
a
yield (%)
entry
R
substrate
solvent
30a−e
13
46
1
2
3
4
5
6
Boc
Ts
29a
pyridine
AcOH
AcOH
AcOH
AcOH
HCO2H
20
43
51
89
62
74
29b
51
42
p-Ns
o-Ns
H
29c
29d
trace
20
29e·HCl
29e·HCl
H
b
investigated, and three methods via sulfide, oxime, or azide
intermediates were established. The synthesis of lyconadin A
was completed after construction of a pyridone ring from key
intermediate 4. Construction of a dihydropyridone ring from
intermediate 4 led to the synthesis of lyconadin B. Establish-
ment of the conditions for an electrocyclic ring opening
without formation of the C−N bond resulted in completion of
the total synthesis of lyconadin C.
a
b
Isolated yields. Compound 13 could not be detected.
tetracyclic compound 13 (Table 1, entry 1). Since thermal
cleavage of the Boc group under the conditions was suspected,
we investigated the other substrates that had a sulfonyl group
on the nitrogen atom. To our surprise, reaction of Ts- or p-Ns-
protected compounds (29b or 29c) in refluxing acetic acid also
produced the tetracyclic compound 13 (entries 2 and 3). These
reactions might involve formation of ammonium intermediates
and subsequent cleavage of the sulfonyl groups. Although
employing the o-Ns group resulted in selective production of
30d in good yield (entry 4), selective reduction of the double
bond (vide infra) in the presence of the nitro group was
plagued with difficulties. On the other hand, protection of the
nitrogen atom as an ammonium salt proved to be effective for
the transformation (entries 5 and 6). Under optimal conditions,
heating hydrochloride 29e·HCl in formic acid selectively
produced 30e in 74% yield.
Having optimized the reaction conditions for cleavage of the
dibromocyclopropane intermediate, we turned to completion
of the synthesis of lyconadin C (Scheme 10). Compound 16
was treated with hydrochloric acid in formic acid first at room
temperature to cleave the Boc group, and the reaction mixture
was then heated to reflux to afford 30e. At this stage, the less
hindered C−C double bond was reduced with diimide to give
31 in 63% yield in two steps. After protection of the secondary
amine with a Boc group, the product was oxidized with mCPBA
to furnish enone 33.30 Finally, application of our pyridone
synthesis afforded lyconadin C (3).
ASSOCIATED CONTENT
* Supporting Information
Additional text with experimental details, characterization data,
and NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
fukuyama@mol.f.u-tokyo.ac.jp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Professor J. Kobayashi and Professor T. Kubota at
Hokkaido University for providing samples of natural products.
This work was financially supported by JSPS KAKENHI Grants
20002004 and 22590002, the Research Foundation for
Pharmaceutical Sciences, the Mochida Memorial Foundation
for Medical and Pharmaceutical Research, and the Uehara
Memorial Foundation.
REFERENCES
CONCLUSION
■
■
(1) For reviews of the Lycopodium alkaloids, see (a) MacLean, D. B.
In The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York,
1968; Vol. 10, p 305. (b) MacLean, D. B. In The Alkaloids; Manske, R.
H. F., Ed.; Academic Press: New York; 1973; Vol. 14, p 348.
(c) MacLean, D. B. In The Alkaloids; Brossi, A., Ed.; Academic Press,
New York, 1985; Vol. 26, p 241. (d) Ayer, W. A. Nat. Prod. Rep. 1991,
8, 455. (e) Ayer, W. A.; Trifonov, L. S. In The Alkaloids; Cordell, G. A.,
Brossi, A., Eds.; Academic Press: New York, 1994; Vol. 45, p 233.
We have accomplished the total synthesis of lyconadin A and
applied it to the synthesis of the related congeners, lyconadins
B and C. Our synthesis of lyconadin A features a facile
construction of the highly fused tetracyclic skeleton through a
combination of an aza-Prins reaction and an electrocyclic ring
opening, followed by formation of a C−N bond. Trans-
formation of bromoalkene 13 to enone 4 was extensively
D
dx.doi.org/10.1021/ja312065m | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(f) Ma, X.; Gang, D. R. Nat. Prod. Rep. 2004, 21, 752. (g) Kobayashi,
J.; Morita, H. In The Alkaloids; Cordell, G. A., Ed.; Academic Press:
New York, 2005; Vol. 61, p 1. (h) Hirasawa, Y.; Kobayashi, J.; Morita,
H. Heterocycles 2009, 77, 679. (i) Takayama, H. J. Syn. Org. Chem. Jpn.
2010, 68, 457.
(22) Reaction with 4-phenyl-1,2,4-triazole-3,5(4H)-dione resulted in
decomposition of the substrate. While addition to di-tert-butyl
azodicarboxylate proceeded, further transformation into enone 4
could not be achieved.
(23) Although addition to methyl 2-diazo-2-phenylacetate occurred,
the product could not be converted into enone 4.
(2) Kobayashi, J.; Hirasawa, Y.; Yoshida, N.; Morita, H. J. Org. Chem.
(24) (a) Hwu, J. R.; Huang, J. J.-T.; Tsai, F.-Y.; Tsay, S.-C.; Hsu, M.-
H.; Hwang, K. C.; Horng, J.-C.; Ho, J.-a. A.; Lin, C.-C. Chem.Eur. J.
2009, 15, 8742. (b) Yanagimoto, T.; Toyota, T.; Matsuki, N.; Makino,
Y.; Uchiyama, S.; Ohwada, T. J. Am. Chem. Soc. 2007, 129, 736.
(25) Although a variety of nitroso compounds, including N-methyl-
N-nitroso-p-toluenesulfonamide, N-nitroso-N-methylaniline, and N-
nitrosodimethylamine, were employed, either no reaction or
production of the oxime in low yield occurred.
2001, 66, 5901.
(3) (a) Beshore, D. C.; Smith, A. B., III. J. Am. Chem. Soc. 2007, 129,
4148. (b) Beshore, D. C.; Smith, A. B., III. J. Am. Chem. Soc. 2008, 130,
13778.
(4) Smith, A. B., III; Atasoylu, O.; Beshore, D. C. Synlett 2009, 2643.
(5) (a) Bisai, A.; West, S. P.; Sarpong, R. J. Am. Chem. Soc. 2008, 130,
7222. (b) West, S. P.; Bisai, A.; Lim, A. D.; Narayan, R. R.; Sarpong, R.
J. Am. Chem. Soc. 2009, 131, 11187.
(6) Gruver, J. M.; West, S. P.; Collum, D. B.; Sarpong, R. J. Am.
Chem. Soc. 2010, 132, 13212.
(7) Nishimura, T.; Unni, A. K.; Yokoshima, S.; Fukuyama, T. J. Am.
Chem. Soc. 2011, 133, 418.
(8) (a) Ishiuchi, K.; Kubota, T.; Hoshino, T.; Obara, Y.; Nakahata,
N.; Kobayashi, J. Bioorg. Med. Chem. 2006, 14, 5995. (b) Ishiuchi, K.;
Kubota, T.; Ishiyama, H.; Hayashi, S.; Shibata, T.; Kobayashi, J.
Tetrahedron Lett. 2011, 52, 289. (c) Ishiuchi, K.; Kubota, T.; Ishiyama,
H.; Hayashi, S.; Shibata, T.; Mori, K.; Obara, Y.; Nakahata, N.;
Kobayashi, J. Bioorg. Med. Chem. 2011, 19, 749.
(26) Evans, D. A.; Evrard, D. A.; Rychnovsky, S. D.; Fruh, T.;
Whittingham, W. G.; Devries, K. M. Tetrahedron Lett. 1992, 33, 1189.
́
(27) Wendt, J. A.; Aube, J. Tetrahedron Lett. 1996, 37, 1531.
(28) Compound 27 was obtained as a mixture of diastereomers. One
of the diastereomers is the known compound lyconadin F, which was
isolated by Kobayashi and co-workers.8b
(29) The presence of oxygen caused autoxidation, giving lyconadin A
as the byproduct.
(30) Attempted oxidation of 13 with a variety of oxidants did not
give the desired enone 4. The different behaviors between 13 and 32
under oxidative conditions come from the state of the nitrogen atoms
in the compounds.
(9) Koshiba, T.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2009, 11,
5354.
(10) (a) Nilsson, B. L.; Overman, L. E.; Read de Alaniz, J.; Rohde, J.
M. J. Am. Chem. Soc. 2008, 130, 11297. (b) Altman, R. A.; Nilsson, B.
L.; Overman, L. E.; Read de Alaniz, J.; Rohde, J. M.; Taupin, V. J. Org.
Chem. 2010, 75, 7519.
(11) (a) Oppolzer, W.; Petrzilka, M. Helv. Chim. Acta 1978, 61, 2755.
(b) Nangia, A.; Prasuna, G. Synth. Commun. 1994, 24, 1989.
(12) (a) Kim, K. S.; Song, Y. H.; Lee, B. H.; Hahn, C. S. J. Org. Chem.
1986, 51, 404. (b) Anderson, J. C.; Blake, A. J.; Graham, J. P.; Wilson,
C. Org. Biomol. Chem. 2003, 1, 2877.
(13) The same type of aza-Prins reaction had been reported by
Overman and co-workers10 in their total synthesis of nankakurins, and
the importance of the amine for selective formation of the double
bond was also discussed.
(14) (a) Danheiser, R. L.; Morin, J. M.; Salaski, E. J. J. Am. Chem. Soc.
1985, 107, 8066. (b) Banwell, M. G.; Harvey, J. E.; Jolliffe, K. A. J.
Chem. Soc., Perkin Trans. 1 2001, 2002. (c) Stanislawski, P. C.; Willis,
A. C.; Banwell, M. G. Chem.Asian J. 2007, 2, 1127. (d) For a recent
review of electrocyclic ring-opening reactions of dibromocyclopro-
panes, see Halton, B.; Harvey, J. Synlett 2006, 1975.
(15) When the hydrogenolysis was performed in the presence of
Boc2O, hydrogenation of the double bond also proceeded.
(16) The structure of the major isomer was confirmed by X-ray
crystallography.
(17) For a recent review of the Pummerer rearrangement, see
(a) Smith, L. H. S.; Coote, S. C.; Sneddon, H. F.; Procter, D. J. Angew.
Chem., Int. Ed. 2010, 49, 5832. For recent applications of the
vinylogous Pummerer rearrangement, see (b) Ruano, J. L. G.;
́ ́
Aleman, J.; Aranda, M. T.; Arevalo, M. J.; Padwa, A. Org. Lett. 2005, 7,
19. (c) Feldman, K. S.; Fodor, M. D. J. Am. Chem. Soc. 2008, 130,
14964. (d) Shimizu, Y.; Shi, S.-L.; Usuda, H.; Kanai, M.; Shibasaki, M.
Angew. Chem., Int. Ed. 2010, 49, 1103. (e) Halder, S.; Satyam, A.
Tetrahedron Lett. 2011, 52, 1179.
(18) Okazaki, R.; Watanabe, M.; Inagaki, Y.; Inamoto, N. Tetrahedron
Lett. 1978, 3439.
(19) The low yield of the reaction can be attributed to in situ
formation of an acidic oxime that may have caused protonation of the
alkenyllithium.
(20) (a) Dembech, P.; Ricci, A.; Seconi, G.; Taddei, M. Org. Synth.
1997, 74, 84. (b) Yoshida, M.; Kadokura, A.; Suzuki, K.; Minabe, M.
Tetrahedron 1979, 35, 2237.
(21) Reaction with peroxides did not proceed and gave instead the
protonated product.
E
dx.doi.org/10.1021/ja312065m | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX