Total synthesis of (-)-Lycoperine a

Article abstract of DOI:10.1021/ol902389e

Chemical Equation Presented Lycoperine A was synthesized through a highly convergent route in which a double alkylation of 2,6-dicyano-N-benzylpiperidine with the octahydroquinoline moiety gave the lycoperine skeleton. The octahydroquinoline was prepared by a desymmetrization reaction of 5-methylcyclohexane-1,3-dione. Hydrolysis, reductive amination, and cyclization gave lycoperine A in 13 steps and 3% overall yield. The absolute configuration of lycoperine A was assigned as 6R,6′R,8′,R,13S,17R.

Full text of DOI:10.1021/ol902389e

ORGANIC
LETTERS
2010
Vol. 12, No. 1
72-75
Total Synthesis of (-)-Lycoperine A
Yoshitaka Nakamura, Anthony M. Burke, Shunsuke Kotani, Joseph W. Ziller, and
Scott D. Rychnovsky*
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California,
IrVine, California 92697-2025
srychnoV@uci.edu
Received October 16, 2009
ABSTRACT
Lycoperine A was synthesized through a highly convergent route in which a double alkylation of 2,6-dicyano-N-benzylpiperidine with the
octahydroquinoline moiety gave the lycoperine skeleton. The octahydroquinoline was prepared by a desymmetrization reaction of
5-methylcyclohexane-1,3-dione. Hydrolysis, reductive amination, and cyclization gave lycoperine A in 13 steps and 3% overall yield. The
absolute configuration of lycoperine A was assigned as 6R,6′R,8R,8′R,13S,17R.
Lycopodium alkaloids are an important class of natural
products due to their diversity and their varied biological
activities.1 Several of these alkaloids inhibit acetylcholines-
terase (AChE), which is responsible for the breakdown of
the neurotransmitter acetylcholine. After the discovery of this
significant biological activity around 1986,2 there was a surge
of interest in Lycopodium alkaloids, and subsequently
numerous new alkaloids in this class were discovered and
characterized.1 In the time span from 1993 to 2004, 81 new
Lycopodium alkaloids had been reported.1 Of the Lycopodium
alkaloids discovered in the 1980s, huperzine A (HupA)
demonstrated the greatest inhibition of acetylcholinesterase,
and its synthesis was first reported by Qian and Ji in 1989.3
Recent studies subjecting rats to HupA have demonstrated
increased efficiency in learning and memory and have been
considered potential lead compounds for the treatment of
Alzheimer’s disease.4
Lycopodium alkaloids have also attracted significant inter-
est from synthetic chemists due to their unique and complex
structures. The four classes of Lycopodium alkaloids are the
phelgmarine, lycodine, lycopodine, and fawcettimine (Figure
1).1,5,6 Lycopodine was the first of this class discovered in
1881 by Bodecker.7 Phlegmarine8 is a representative of the
most recently discovered class, described as the “miscel-
laneous group”.5 They are structurally related through their
common quinolizine, quinoline, pyridine, or R-pyridone ring
systems. They generally contain 16 carbons or as dimers 32
carbons.
(4) (a) Zhang, R. W.; Tang, X. C.; Han, Y. Y.; Sang, G. W.; Zhang,
Y. D.; Ma, Y. X.; Zhang, C. L.; Yang, R. M. Acta Pharmacol. Sin. 1991,
12, 250–252. (b) Jiang, H. L.; Luo, X. M.; Bai, D. L. Curr. Med. Chem.
2003, 10, 2231–2252.
(5) Ayer, W. A.; Trifonov, L. S. Lycopodium Alkaloids; Academic Press:
San Diego, 1994
.
(1) Ma, X.; Gang, D. R. Nat. Prod. Rep. 2004, 21, 752–772.
(2) (a) Tang, X. C.; Han, Y. F.; Chen, X. P.; Zhu, X. D. Acta Pharmacol.
Sin. 1986, 7, 507–511. (b) Tang, X. C.; De Sarno, P.; Sugaya, K.; Giacobini,
E. J. Neurosci. Res. 1989, 24, 276–285.
(6) Bisai, A.; West, S. P.; Sarpong, R. J. Am. Chem. Soc. 2008, 130,
7222–7223
.
(7) Bodeker, K. Justus Liebigs Ann. Chem. 1881, 208, 363.
(8) Nyembo, L.; Goffin, A.; Hootele, C.; Jean Claude, B. Can. J. Chem.
1978, 56, 851–856.
(3) Qian, L.; Ji, R. Tetrahedron Lett. 1989, 30, 2089–2090.
10.1021/ol902389e  2010 American Chemical Society
Published on Web 11/30/2009

Preparation of the octahydroquinoline segment was based
on precedent from Lhommet and from Bosch.11,12 Diketone
6 was combined with acrolein to produce hemiacetal 7, a
cyclic version of the underlying symmetric dione. Desym-
metrization by condensation with amino alcohol auxiliaries
8 and 9 led to the formation of vinylogous amides 10 and
11, respectively (Table 1). The condensation with 8 was
Figure 1. Classes of lycopodium alkaloids.
Table 1. Desymmetrization of Hemiacetal 7 with Amino
Alcohols
Lycoperine A (1) was recently isolated from the club moss
Lycopodium hamiltonii in Japan by Kobayashi and co-
workers from Hokkaido University.9 This compound exhib-
ited a moderate inhibitory activity against acetylcholine
esterase from bovine erythrocyte. The structure and the
relative stereochemistry of lycoperine A were determined
by detailed 2D NMR studies after conversion to the N-diethyl
analogue by the reduction of the acetamide moieties, but its
absolute configuration was not determined. This compound
has a characteristic pseudosymmetric structure in which two
identical octahydroquinoline rings are linked to a central 2,6-
cis-disubstituted piperidine ring. We report here the total
synthesis of lycoperine A and its absolute configuration.
entry auxiliary
Lewis acida
conditions
yield drb
1
2
3
4
5
8 (2 equiv) Zn(ClO4)2 · 6H2O rt, 15 h
100c 2.7:1
96c 2.7:1
92c 4:1
8 (2 equiv) Sc(OTf)3
8 (2 equiv) Cu(OTf)2
9 (2 equiv) Cu(OTf)2
9 (1.1 equiv) Cu(OTf)2
0 °C, 2 d
0 °C, 2 d
0 - 10 °C, 16 h 95d 20:1f
e
0 °C, 22 h
96d 20:1f
Our retrosynthetic analysis for lycoperine A is shown in
Scheme 1. The plan called for the generation of lycoperine
a The Lewis acid was used in 5 mol % quantities unless otherwise noted.
b The dr between C1 and C8 is reported and was estimated from NMR
spectroscopy. Epimers at C3a were also observed in roughly a 10:1 dr with
amino alcohol 8. c The product was 10. d The product was 11. e Only 3
mol % of the Lewis acid was used. f The crude mixture was ca. 92:5:2:1
by NMR analysis, but the two minor isomers were removed on
chromatography.
Scheme 1. Retrosynthetic Analysis for Lycoperine A
efficient using several different Lewis acids, but the desym-
metrization to set the C8 methyl center resulted in very
modest selectivities (entries 1-3). Switching to the amino
alcohol 9 led to much more effective desymmetrization, with
ca. 95:5 dr at the C8 stereogenic center. Copper triflate was
the best catalyst, and 3 mol % of the catalyst was effective
(entry 5). Minor diastereomers were produced with both
auxiliaries, but in the case of 9 they could be separated on
silica gel chromatography to deliver the vinylogous amide
11 in 96% yield. The relative configuration of compound
11 was confirmed by X-ray crystallography.13 This unusual
desymmetrization strategy12d allowed the C8 stereogenic
center to be introduced efficiently from a racemic precursor.
Synthesis of the octahydroquinoline 4 is presented in
Scheme 2. Optimized conditions for the desymmetrization
A by reductive decyanation of the dinitrile 2 and is based
on precedent from Husson’s program.10 The dinitrile 2 would
arise from a double alkylation of 2,6-dicyano-N-benzylpi-
peridine (3) with the octahydroquinoline 4. The synthesis
of 4 was envisioned to come from elaboration of vinylogous
amide 5, which itself would be prepared by a desymmetri-
zation reaction. The starting material for the synthesis was
5-methylcyclohexane-1,3-dione (6). The configuration of the
natural product would be derived from a chiral amino alcohol
auxiliary.
(11) (a) Noe¨l, R.; Vanucci-Bacque, C.; Fargeau-Bellassoued, M.-C.;
Lhommet, G. J. Org. Chem. 2005, 70, 9044–9047. (b) Noel, R.; Fargeau-
Bellassoued, M. C.; Vanucci-Bacque, C.; Lhommet, G. Synthesis 2008,
1948–1954. (c) Noel, R.; Vanucci-Bacque, C.; Fargeau-Bellassoued, M. C.;
Lhommet, G. Eur. J. Org. Chem. 2007, 476–486
.
(12) (a) Amat, M.; Fabregat, R.; Griera, R.; Bosch, J. J. Org. Chem.
2009, 74, 1794–1797. (b) Amat, M.; Perez, M.; Minaglia, A. T.; Bosch, J.
J. Org. Chem. 2008, 73, 6920–6923. (c) Amat, M.; Griera, R.; Tabregat,
R.; Molins, E.; Bosch, J. Angew. Chem., Int. Ed. 2008, 47, 3348–3351. (d)
Amat, M.; Bassas, O.; Llor, N.; Canto, M.; Perez, M.; Molins, E.; Bosch,
J. Chem.sEur. J. 2006, 12, 7872–7881. (e) Escolano, C.; Amat, M.; Bosch,
(9) Hirasawa, Y.; Kobayashi, J.; Morita, H. Org. Lett. 2006, 8, 123–
126.
J. Chem.sEur. J. 2006, 12, 8198–8207.
(13) Details of the X-ray structures for compounds 11, 12, and 13 are
(10) Husson, H.-P.; Royer, J. Chem. Soc. ReV. 1999, 28, 383–394.
included in Supporting Information.
Org. Lett., Vol. 12, No. 1, 2010
73

nitrogen.16 Stille carbonylation was uneventful, and reduction
delivered the allylic alcohol 15.17 Generation of the alkylating
agent 4 used standard PPh3 and CBr4 conditions.18 Allyl
bromide 4 was set up to couple with the central piperidine
ring.
Scheme 2. Synthesis of Allyl Bromide 4 for Double Alkylation
The original plan called for the introduction of the two
identical octahydroquinoline segments by alkylation of a
piperidine dinitrile 3, followed by reductive decyanation and
deprotection. A single reductive decyanation has ample
precedent from Husson’s piperidine assembly.10 Model
studies for the double alkylation and reductive decyanation
are outlined in Scheme 3. Dinitrile 3 was prepared from
Scheme 3. Alkylation and Decyanation of Dinitrile 3
led to vinylogous amide 11 with excellent diastereoselec-
tivity. Attempts to reduce the tetrasubstituted double bond
by hydrogenation were unsuccessful, and so we turned to
dissolving metal conditions. On the basis of Palmieri’s
precedent, we investigated sodium and isopropanol.14 Op-
timized conditions delivered the amine 12 in 67% yield with
>95:5 dr. The relative configuration of amine 12 was
established by X-ray crystallography.13 Hydrogenolysis of
the auxiliary was accomplished under forcing conditions with
20% Pd(OH)2/C in acidic methanol. The resulting amine was
directly acylated to give an acetamide in 70% yield over
two steps. Oxidation with Dess-Martin periodinane pro-
duced the crystalline ketone 13 as a single diastereomer. The
relative configuration of 13 was confirmed by X-ray crystal-
lography.13 The octahydroquinoline 13 was assembled in six
steps and 27% overall yield from commercially available
diketone 6.
glutaraldehyde following Husson’s procedure.19 After some
optimization, the double alkylation using just 2.2 equiv of
allyl bromide worked extremely well, delivering predomi-
nantly the cis-16 diastereomer in >90% yield.20 Surprisingly,
the reductive decyanation was not straightforward. Numerous
attempts to cleave the nitriles did not produce the expected
cis-2,6-disubstituted piperidine (17 cis) but rather led to
complex mixtures of products. A representative example is
shown in Scheme 3, where the expected decyanation product
17 was produced in only 4% yield as a mixture of
stereoisomers. Reductive coupling of the two nitriles gener-
ated diketone 18, and addition of lithium amide and
cyclization led to compound 19. Clearly the reduction does
not proceed one nitrile at a time, but rather the two nitriles
interact and generate a variety of side products. The
alkylation reaction was very effective, but the reductive
decyanation was an utter failure.
The next goal was to introduce the tetrasubstituted double
bond and a one-carbon substituent onto ketone 13. A
thermodynamic enolate is required, and a number of condi-
tions were investigated to generate it. KHMDS and PhNTf2
gave predominantly the less substituted enol triflate.15
Potassium tert-butoxide led to more of the desired enol
triflate, but it was accompanied by epimerization adjacent
to nitrogen, presumably due to a reversible Michael addition
of the amide. Selection of the solvent and reaction temper-
ature turned out to be important, and going from THF to
2:1 DMF/THF gave predominantly the more hindered enol
triflate 14 with no detectable epimerization adjacent to
(16) No epimerization was detected in the generation of enol triflate 14
at -78 °C, but significant epimerization was observed at -35 °C.
(17) Baillargeon, V. P.; Stille, J. K. J. Am. Chem. Soc. 2002, 108, 452–
461.
(18) Mori, M.; Chiba, K.; Okita, M.; Kayo, I.; Ban, Y. Tetrahedron
1985, 41, 375–385.
(14) Bartoli, G.; Cimarelli, C.; Palmieri, G. J. Chem. Soc., Perkin Trans.
1 1994, 537–543. Hsung et al. utilized Palmieri’s method for the total
synthesis of (()-tangutorine; see: (b) Luo, S.; Zificsak, C. A.; Hsung, R. P.
Org. Lett. 2003, 5, 4709–4712.
(19) Bonin, M.; Chiaroni, A.; Riche, C.; Beloeil, J.-C.; Grierson, D. S.;
Husson, H.-P. J. Org. Chem. 1987, 52, 382–385.
(20) Takahashi et al. reported the bisalkylation of 1-benzyl-2,6-dicyano-
piperidine in a stepwise manner; see: Takahashi, K.; Kurita, H.; Ogura, K.;
Iida, H. J. Org. Chem. 1985, 50, 4368–4371.
(15) Mori, M.; Nakanishi, M.; Kajishima, D.; Sato, Y. J. Am. Chem.
Soc. 2003, 125, 9801–9807.
74
Org. Lett., Vol. 12, No. 1, 2010

An alternative approach to the central piperidine ring
would be a reductive amination of a 1,5-diketone. A number
of different routes to the desired 1,5-diketone 20 can be
envisioned, but we decided to build upon the successful
alkylation reaction in Scheme 3. The double alkylation was
accomplished in good yield by mixing 1.0 equiv of 3 with
2.2 equiv bromide 4 in THF/DMPU and adding an excess
of LiHMDS at reduced temperature. The dinitrile piperidine
2 was isolated in good yield. Deprotection to give the
diketone 20 was initially attempted by treatment with HCl
in MeOH, but the conditions led to subsequent alkene
isomerization. Using AgNO3 as a Lewis acid to promote the
hydrolysis gave the desired diketone 20 in good overall
yield.21
Scheme 4. Double Alkylation and Preparation of Lycoperine A
Reductive amination was first attempted using sodium
cyanoborohydride as described by Abe and co-workers,22
but the reaction was very slow and provided a mixture of
the desired product and an undesired side product, the
tetrahydropyran ring corresponding to piperidine 1, which
arose from reduction of the ketone and cyclization. Ketone
reduction could be avoided by using a more selective
reducing agent, sodium triacetoxyborohydride.23 The reduc-
tive amination was still slow, gave incomplete conversion,
and produced 28% yield of the piperidine 1 along with 50%
of recovered diketone 20. The NMR spectra and other
physical data for piperidine 1 matched that reported for
lycoperine A, including optical rotation.24 LAH reduction
of diamide 1 gave the diethyl compound, and its spectra
compared favorably with that reported by Kobayashi’s.25
Synthesis of lycoperine A was accomplished using a
desymmetrization reaction that led to an efficient synthesis
of the octahydroquinoline 4. A double alkylation reaction
and subsequent piperidine ring formation completed the
synthesis and allowed the configuration of the natural product
to be assigned as 6R,6′R,8R,8′R,13S,17R.
Acknowledgment. This work was supported by a gift from
the Schering-Plough Research Institute and by the S. T. Li
foundation. Financial support was also provided by Daiichi-
Sankyo (Y.N.) and the Japan Society for the Promotion of
Science (S.K.).
(21) (a) Boucher, J.-L.; Stella, L. Tetrahedron 1985, 41, 875–887. (b)
Enders, D.; Shilvock, J. P.; Raabe, G. J. Chem. Soc., Perkin Trans. 1 1999,
1617–1619.
(22) Abe, K.; Okumura, H.; Tsugoshi, T.; Nakamura, N. Synthesis 1984,
597–598.
(23) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.;
Shah, R. D. J. Org. Chem. 1996, 61, 3849–3862.
Supporting Information Available: Characterization data
and experimental procedures for all compounds described
are included. This material is available free of charge via
the Internet at http://pubs.acs.org.
(24) Reported (ref 9): [R]24D -238 (c 0.1 MeOH). Observed: [R]24D -196
(c 0.14 MeOH).
(25) 1H NMR data and 13C NMR data for the diethyl compound show
discrepancies with the reported values, presumably due to the variable
protonation state of the triamine. The 13C NMR data shows all peaks within
0.5 ppm of reported values and an average difference of 0.14 ppm.
OL902389E
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