Syntheses of (±)-serratine, (±)-lycoposerramine T, and (±)-lycopoclavamine B

Article abstract of DOI:10.1021/ol400628h

The first total syntheses of (±)-serratine, (±)- lycoposerramine T, and (±)-lycopoclavamine B have been accomplished. The functionalized octahydroindane skeleton of these natural products was constructed by an efficient Diels-Alder reaction of an α- alkynylcyclopentenone and the stereoselective introduction of a tertiary hydroxyl group. Two of these natural products were divergently synthesized from the same synthetic intermediate at a later stage.

Full text of DOI:10.1021/ol400628h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Syntheses of (()-Serratine,
(()-Lycoposerramine T, and
(()-Lycopoclavamine B
Hisaaki Zaimoku, Hiroshi Nishide, Asami Nishibata,† Naoya Goto,†
Tsuyoshi Taniguchi,* and Hiroyuki Ishibashi
School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health
Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
tsuyoshi@p.kanazawa-u.ac.jp
Received March 9, 2013
ABSTRACT
The first total syntheses of (()-serratine, (()-lycoposerramine T, and (()-lycopoclavamine B have been accomplished. The functionalized octahydroindane
skeleton of these natural products was constructed by an efficient DielsꢀAlder reaction of an R-alkynylcyclopentenone and the stereoselective introduction
of a tertiary hydroxyl group. Two of these natural products were divergently synthesized from the same synthetic intermediate at a later stage.
A great number of Lycopodium alkaloids have been
isolated from plant sources. These alkaloids have been
shown to have complex polycyclic structures and potential
biological activities.1 These characteristics have attracted
the attention of synthetic chemists, and many success-
ful total syntheses of Lycopodium alkaloids have been
reported.2 (ꢀ)-Serratine (1), which possesses a tetracyclic
framework with five stereocenters, was isolated from
Lycopodium serratum by Inubushi and co-workers in the
1960s (Figure 1).3 Other related alkaloids such as (ꢀ)-
serratinine (2),4 (ꢀ)-serratanidine (3),3a,5 and its deoxy
derivative6 have also been isolated in succession. Recently,
(þ)-lycoposerramine T (4),7 (ꢀ)-lycopoclavamine B (5),8
and (þ)-lycojaponicumin A (6),9 which have a tertiary
hydroxyl or acetoxy group like (ꢀ)-serratine (1), have been
(3) (a) Inubushi, Y.; Tsuda, Y.; Ishii, H.; Sano, T.; Hosokawa, M.;
Harayama, T. Yakugaku Zasshi 1964, 84, 1108–1113 (written in
Japanese). (b) Inubushi, Y.; Ishii, H.; Harayama, T. Chem. Pharm. Bull.
1967, 15, 250–252. (c) Inubushi, Y.; Harayama, T.; Akatsu, M.; Ishii, H.;
Nakahara, Y. Chem. Pharm. Bull. 1968, 16, 2463–2470. The detailed
spectroscopic data of (ꢀ)-serratine (1) have been reported by Takayama
et al.: (d) Katakawa, K.; Nozoe, A.; Kogure, N.; Kitajima, M.;
Hosokawa, M.; Takayama, H. J. Nat. Prod. 2007, 70, 1024–1028.
(4) (a) Inubushi, Y.; Ishii, H.; Yasui, B.; Hashimoto, M.; Harayama,
T. Tetrahedron Lett. 1966, 1537–1549. (b) Inubushi, Y.; Ishii, H.; Yasui,
B.; Harayama, T. Tetrahedron Lett. 1966, 1551–1559. (c) Inubushi, Y.;
Ishii, H.; Yasui, B.; Hashimoto, M.; Harayama, T. Chem. Pharm. Bull.
1968, 16, 82–91. (d) Inubushi, Y.; Ishii, H.; Yasui, B.; Hashimoto, M.;
Harayama, T. Chem. Pharm. Bull. 1968, 16, 92–100.
(5) Inubushi, Y.; Harayama, T.; Akatsu, M.; Ishii, H.; Nakahara, Y.
Chem. Pharm. Bull. 1968, 16, 561–563.
(6) (a) Inubushi, Y.; Ishii, H.; Yasui, B.; Harayama, T.; Hosokawa,
M.; Nishino, R.; Nakahara, Y. Yakugaku Zasshi 1967, 87, 1394–1404
(written in Japanese).
(7) Katakawa, K.; Kogure, N.; Kitajima, M.; Takayama, H. Helv.
Chim. Acta 2009, 92, 445–452.
(8) Katakawa, K.; Mito, H.; Kogure, N.; Kitajima, M.; Wongser-
ipipatana, S.; Arisawa, M.; Takayama, H. Tetrahedron 2011, 67, 6561–
6567.
† These authors contributed equally.
(1) Recent reviews of the Lycopodium alkaloids: (a) Ma, X.; Gang,
D. R. Nat. Prod. Rep. 2004, 21, 752–772. (b) Kobayashi, J.; Morita, H. In
The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 2005; Vol.
61, pp 1ꢀ57. (c) Hirasawa, Y.; Kobayashi, J.; Morita, H. Heterocycles
2009, 77, 679–729. (d) Kitajima, M.; Takayama, H. Top. Curr. Chem.
2012, 309, 1–31.
(2) Selected recent examples of total synthesis of the Lycopodium
alkaloids: (a) Otsuka, Y.; Inagaki, F.; Mukai, C. J. Org. Chem. 2010, 75,
3420–3426. (b) Yang, Y.-R.; Shen, L.; Huang, J.-Z.; Xu, T.; Wei, K.
J. Org. Chem. 2011, 76, 3684–3690. (c) Nakayama, A.; Katajima, M.;
Takayama, H. Synlett 2012, 2014–2024. (d) Lin, H.-Y.; Causey, R.;
Garcia, G. E.; Snider, B. B. J. Org. Chem. 2012, 77, 7143–7156. (e) Pan,
G.; Williams, R. M. J. Org. Chem. 2012, 77, 4801–4811. (f) Saha, M.;
Carter, R. G. Org. Lett. 2012, 15, 736–739. (g) Shimada, N.; Abe, Y.;
Yokoshima, S.; Fukuyama, T. Angew. Chem., Int. Ed. 2012, 51, 11824–
11826. (h) Canham, S. M.; France, D. J.; Overman, L. E. J. Org. Chem.
2013, 78, 9–34. (i) Li, H.; Wang, X.; Hong, B.; Lei, X. J. Org. Chem. 2013,
78, 800–821. (j) Nishimura, T.; Unni, A. K.; Yokoshima, S.; Fukuyama,
T. J. Am. Chem. Soc. 2013, 135, 3243–3247.
r
10.1021/ol400628h
XXXX American Chemical Society

Scheme 1. Outline of a Synthetic Strategy
Figure 1. Serratine and related natural products.
We performed some model experiments of the Dielsꢀ
Alder reaction using R-alkylcyclopentenones, but the reac-
tions with diene 11 (E/Z, 90:10) were extremely slow, even
under conditions at high temperature, hardly giving any
desired products. The use of Lewis acids induced decom-
position of these substrates.14 In 2007, Danishefsky et al.
reported that R-alkynyl dienophiles show high reactivity
and endo selectivity in DielsꢀAlder reactions.15 Encour-
aged by this report, we examined the DielsꢀAlder reaction
between diene 11 and R-alkynylcyclopentenone 13 (see the
Supporting Information) at 90 °C and obtained the desired
endo-adduct 14 in good yield, along with a small amount of
the exo-adduct 15, after 40 h (Table 1, entry 1). The use of
a microwave significantly promoted this reaction, but the
yield of 14 on a multigram scale (2ꢀ6 g) was somewhat low
(ca. 50%) (entry 2).16 Eventually, we found that heating
the neat mixture of 11 and 13 for 24 h at 80 °C gave 14 in
good yield with high reproducibility (entry 3).
Chemoselective reduction of the alkyne and hydrogeno-
lysis of the benzyl group in compound 14 with palladium
hydroxide on carbon (20%) in isopropanol for 5 h, and
subsequent treatment with citric acid, gave the unexpected
homoallyl alcohol 16 (Scheme 2). The reason for the
olefin isomerization is unclear, but fortunately, Sharpless
diastereoselective epoxidation17 of 16 succeeded, and sub-
sequent treatment of the crude epoxide with benzenethiol
(2 equiv) and cesium carbonate (2 equiv) gave the triol
compound 17 in good yield. Desulfurization of 17 with
Raney nickel (W-2) readily provided the corresponding
1,3-diol compound 18. After protection of the primary
hydroxy group by a tert-butyldiphenylsilyl group (TBDPS)
and bismuth triflate (5 mol %)-catalyzed acetylation18 of
isolated by Takayama et al. (for 4 and 5) and Yu et al.
(for 6). Surprisingly, the total synthesis of (ꢀ)-serratine (1)
has never been reported,10 though syntheses of structurally
close (ꢀ)-serratinine (2)11 and its deoxy derivatives12 have
been reported. This might be due to the existence of the
tertiary hydroxyl group, which appears to make the synth-
esis of (ꢀ)-serratine (1) difficult. With the goal of succeed-
ing in the first total synthesis of (ꢀ)-serratine (1) and
related alkaloids, we decided to try to synthesize racemic
forms of these natural products.
As shown in Scheme 1, (()-serratine (1), (()-lycoposer-
ramine T (4), and (()-lycopoclavamine B (5) could poten-
tially be synthesized from a common intermediate 7.
Azonane compounds, such as 7, are intermediates in the
synthesis of many Lycopodium alkaloids.2 Compound 7
could possibly be constructed from diol 8 by epoxidation
of an alkene and double alkylation with a protected amine
(Pg = protecting group). The ketone group of compound
9 could serve as a precursor for the introduction of a C3
unit on the right side. Sharpless diastereoselective epox-
idation of allyl alcohol 10 followed by reduction could
offer a reliable method for stereoselective introduction of
the tertiary hydroxyl group. As a starting reaction for this
synthetic study, the DielsꢀAlder reaction between diene
1113 and the R-alkylcyclopentenone 12 was envisaged for
the preparation of compound 10.
(9) Wang, X.-J.; Zhang, G.-J.; Zhuang, P. Y.; Zhang, Y.; Yu, S.-S.;
Bao, X.-Q.; Zhang, D.; Yuan, Y.-H.; Chen, N.-H.; Ma, S.-g.; Qu, J.; Li,
Y. Org. Lett. 2012, 14, 2614–2617.
(10) A synthetic study of (()-serratine (1) has been reported:
Luedtke, G.; Livinghouse, T. J. Chem. Soc., Perkin Trans. 1 1995,
2369–2371.
(14) A recent example of Lewis acid catalyzed DielsꢀAlder reactions
of R-alkylcyclopentenones: Inokuchi, T.; Okano, M.; Miyamoto, T.;
Madon, H. B.; Takagi, M. Synlett 2000, 1549–1552.
(15) Min, S.-J.; Jones, G. O.; Houk, K. N.; Danishefsky, S. J. J. Am.
Chem. Soc. 2007, 129, 10078–10079.
(16) Reviews on microwave use in organic synthesis: (a) Kappe, C. O.
Angew. Chem., Int. Ed. 2004, 43, 6250–6284. (b) Kappe, C. O.; Pieber, B.;
Dallinger, D. Angew. Chem., Int. Ed. 2012, 52, 1088–1094.
(17) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95,
6136–6137.
(11) (a) Harayama, T.; Ohtani, M.; Oki, M.; Inubushi, Y. J. Chem.
Soc., Chem. Commun. 1974, 827–828. (b) Harayama, T.; Ohtani, M.;
Oki, M.; Inubushi, Y. Chem. Pharm. Bull. 1975, 23, 1511–1515.
(12) (a) Harayama, T.; Takatani, M.; Inubushi, Y. Tetrahedron Lett.
1979, 20, 4307–4310. (b) Harayama, T.; Takatani, M.; Inubushi, Y.
Chem. Pharm. Bull. 1980, 28, 2394–2402. (c) Cassayre, J.; Gagosz, F.;
Zard, S. A. Angew. Chem., Int. Ed. 2002, 41, 1783–1785. (d) Yang, Y.-R.;
Lai, Z.-W.; Shen, L.; Huang, J.-Z.; Wu, X.-D.; Yin, J.-L.; Wei, K. Org.
Lett. 2010, 12, 3430–3433. See also ref 2b and 2i.
(18) Orita, A.; Tanahashi, C.; Kakuda, A.; Otera, J. J. Org. Chem.
2001, 66, 8926–8934.
(13) Colvin, E. W.; Thom, I. G. Tetrahedron 1986, 42, 3137–3146.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. DielsꢀAlder Reactions between 11 and 13
Scheme 2. Synthesis of Intermediate 25
yield (%)
entry
conditions
14
15
1
toluene, 90 °C, 40 h
toluene, μwave, 190 °C, 20 min
neat, 80 °C, 24 h
69
7
2
3c
75b
70
11b
7
a 90% geometrical purity (E/Z, 90:10). b On a milligram scale
(40ꢀ100 mg). c 2.0 equiv of 11 were used.
two other hydroxyl groups, reactions with various organo-
metallic reagents were examined to introduce a C3 unit into
compound 19. Through many failed attempts, we realized
that only an allyl group could be delivered as a C3 unit to
19, and Takai’s indium (20 mol %)-catalyzed allylation
using allyl bromide (4 equiv) and aluminum (4 equiv)
quantitatively afforded the adduct 20 as a single isomer
(the putative product is an R-adduct).19 After subsequent
hydroboration using 9-borabicyclo[3.3.1]nonane (9-BBN,
ca. 3 equiv) followed by oxidative treatment, 1,4-diol 21
was isolated in 82% yield. Treatment of compound 21 with
Amberlyst 15 caused elimination of the tertiary hydroxyl
group to give compound 22.20 A nitrogen atom was intro-
duced into 22 by Fukuyama’s method21 using o-nitroben-
zenesulfonamide (NsNH2) under Mitsunobu conditions
(all reagents: 1.5 equiv) with di-2-methoxyethyl azodicar-
boxylate (DMEAD)22 to give compound 23. After removal
of the TBDPS group with tetrabutylammonium fluoride
(TBAF), Fukuyama’s method was again applied to con-
struct the azonane ring of compound 25. We also tried
a direct synthesis of azonane 25 from diol 8, prepared by
one-pot dehydration and deprotection of 21 (conditions:
tetracyclic compound 28 (Scheme 4). The hydroxyl group
of 28 was oxidized into ketone 29 with 2-iodoxybenzoic
acid (IBX, 2 equiv), and the final hydrolysis of the acetyl
groups with potassium hydroxide (5 equiv) in MeOH/H2O
(10:1) afforded (()-serratine (1). Although we did not
succeed in transforming R-epoxide 27 into (()-1, 27 served
as an intermediate for the synthesis of (()-lycoposerra-
mine T (4) and (()-lycopoclavamine B (5). Epoxide 27 was
transformed into the corresponding (E)-allyl alcohol 29
by elimination with p-toluenesulfonic acid monohydrate
(20 mol %) in THF/H2O (10:1) at reflux and by replace-
ment of the protecting group (Ns f tert-butoxycarbonyl;
Boc). Finally, oxidation of the allylic hydroxy group of
compound 29 with an excess of manganese dioxide
(MnO2) and removal of the Boc group of compound 30
led to (()-lycoposerramine T (4). On the other hand, after
removal of the acetyl groups of 29, the two secondary
hydroxyl groups were oxidized with 2-iodoxybenzoic
acid (IBX, 5 equiv), and subsequent removal of the Boc
group set off cyclization upon the resultant cyclohexanone
moiety to afford (()-lycopoclavamine B (5). The spectral
data of synthetic (()-1, (()-4, and (()-5 were in accor-
dance with those of each natural product.3d,7,8
TsOH H2O, CH2Cl2, rt, then MeOH, rt, 87%) according
3
to the plan shown in Scheme 1. However, the double
Mitsunobu reaction of 8 with NsNH2 gave 25 in only a
low yield (8%).2e Efforts toward the optimization of this
transformation will be continued.
When compound 25 was treated with m-chloroperben-
zoic acid (mCPBA, 2 equiv), two epoxide diastereomers
26 and 27 were produced in similar yields (Scheme 3).
Removal of the Ns group of β-epoxide 26 using benze-
nethiol (2 equiv) and potassium carbonate (2 equiv) caused
a subsequent annulation onto the epoxide group to give
(19) Takai, K.; Ikawa, Y. Org. Lett. 2002, 4, 1727–1729.
(20) A review on reactions using Amberlyst 15: Pal, R.; Sarkar, T.;
Khasnobis, S. ARKIVOC 2012, 570–609.
(21) Review: Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353–359
and references therein.
(22) Sugimura, T.; Hagiya, K. Chem. Lett. 2007, 36, 566–567.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Epoxidation of 25
Scheme 5. Production of (Z)-Isomer 31 from 26 and
Transformation into 30
Scheme 4. Accomplishment of Total Syntheses of Three Alkaloids
In conclusion, we have achieved the first total syntheses
of three Lycopodium alkaloids, (()-serratine (1), (()-
lycoposerramine T (4), and (()-lycopoclavamine B (5).
The present syntheses feature a DielsꢀAlder reaction
promoted by an alkyne substituent and a subsequent
stereoselective introduction of a tertiary hydroxyl group
toconstruct the bicyclic systems of the three alkaloids. This
synthetic route is efficient because the total syntheses were
completed divergently from a common intermediate 25.
We anticipate that a synthesis of (()-lycojaponicumin A
(6) from intermediate 29 or 30 will be possible by intra-
molecular cycloaddition of the corresponding nitrone. In
addition, unexpected production of 16 from 14 suggested
an entry into (()-serratanidine (3) because stereoselective
introduction of the third hydroxygroup to the cyclohexane
ring should be possible by basic hydrolysis of epoxide 17.
Further synthetic studies including attempts at enantio-
selective syntheses of alkaloids 1ꢀ6 are currently underway
in our laboratory.
Acknowledgment. The authors are grateful to Professor
Dr. Hiromitsu Takayama (Chiba University) for provid-
ing us copies of NMR spectra of the natural alkaloids and
for helpful discussions. This research was supported by
a Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science and Technology of
Japan.
Interestingly, (Z)-allyl alcohol 31 was obtained from
β-epoxide 26 in almost quantitative yield by the same
procedure as that used to obtain 29 from 27 (Scheme 5).
We realized this fact by obtaining the (Z)-R,β-unsaturated
ketone 32 (80% yield) along with a small amount of
(E)-isomer 30 (7%) by oxidation of 31 with MnO2.
Apparently, the nine-membered ring of (Z)-isomer 32 is
strained. Therefore, 32 completely isomerized to the thermo-
dynamically more stable (E)-isomer30, which was converted
into (()-4, in chloroform at reflux for 7 days.
Supporting Information Available. Expermental detail
and spectroscopic data for new compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX