Synthesis of (±)-7-hydroxylycopodine

Article abstract of DOI:10.1021/ol200119h

A six step synthesis of (±)-7-hydroxylycopodine has been achieved in 5% overall yield. In the key step, a Prins cyclization of a bicyclic keto alkyne in 60% H₂SO₄ forms a tricyclic dihydroxy amino ketone.(Figure Presented)

Full text of DOI:10.1021/ol200119h

ORGANIC
LETTERS
2
011
Vol. 13, No. 5
234–1237
Synthesis of (()-7-Hydroxylycopodine
Hong-Yu Lin and Barry B. Snider*
1
Department of Chemistry MS 015, Brandeis University, Waltham,
Massachusetts 02454-9110, United States
snider@brandeis.edu
Received January 14, 2011
ABSTRACT
A six step synthesis of (()-7-hydroxylycopodine has been achieved in 5% overall yield. In the key step, a Prins cyclization of a bicyclic keto alkyne
in 60% H SO forms a tricyclic dihydroxy amino ketone.
2
4
Sauroine (3, 7,8-dihydroxylycopodine), from Huperzia
Wenkert in racemic form and recently by Evans and Breit
5
in optically pure form. 7-Hydroxylycopodine (4) was
1
a
saururus, was reported in 2004 and shown in 2009 to
improve memory retention in the step-down test in male
Wistar rats, significantly increasing hippocampal plasticity
(
2) For recent reviews on lycopodium alkaloids, see: (a) Kobayashi,
1
b
J.; Morita, H. In The Alkaloids: Chemistry and Biology; Cordell, G. A.,
Ed.; Elsevier: San Diego, CA, 2005; Vol. 61, pp 1-57. (b) Ma, X.; Gang,
D. R. Nat. Prod. Rep. 2004, 21, 752–772. (c) Hirasawa, Y.; Kobayashi,
J.; Morita, H. Heterocycles 2009, 77, 679–729.
(
see Scheme 1). The lycopodium alkaloids are a large and
2
extensively studied alkaloid family. Huperzine A, the medic-
inally most significant lycopodine alkaloid as a potential
treatment for Alzheimer’s disease, functions as an acetyl-
cholinesterase inhibitor but may have other roles as has
(
3) For recent reviews on huperzine A for treatment of Alzheimer’s
disease, see: (a) Hostettmann, K.; Borloz, A.; Urbain, A.; Marston, A.
Curr. Org. Chem. 2006, 10, 825–847. (b) Zhu, D.-Y.; Tan, C.-H.; Li,
Y.-M. In Medicinal Chemistry of Bioactive Natural Products; Liang,
X.-T., Fang, W.-S., Eds.; WILEY-VCH: New York, 2006; pp 143-182.
3
been addressed in several recent reviews.
(
c) Bai, D. Pure Appl. Chem. 2007, 79, 469–479. (d) Little, J. T.; Walsh,
S.; Aisen, P. S. Exp. Opin. Invest. Drugs 2008, 17, 209–215. (e) Desilets,
A. R.; Gickas, J. J.; Dunican, K. C. Ann. Pharmacother. 2009, 43,
5
14–518.
(
4) (a) Stork, G.; Kretchmer, R. A.; Schlessinger, R. H. J. Am. Chem.
Soc. 1968, 90, 1647–1648. (b) Ayer, W. A.; Bowman, W. R.; Joseph,
T. C.; Smith, P. J. Am. Chem. Soc. 1968, 90, 1648–1650. (c) Kim, S.;
Bando, Y.; Horii, Z. Tetrahedron Lett. 1978, 2293–2294. (d) Heathcock,
C. H.; Kleinman, E. F.; Binkley, E. S. J. Am. Chem. Soc. 1982, 104,
1
054–1068. (e) Schumann, D.; M u€ ller, H.-J.; Naumann, A. Liebigs Ann.
Chem. 1982, 1700–1705. (f) Kraus, G. A.; Hon, Y. S. J. Am. Chem. Soc.
1985, 107, 4341–4342. Heterocycles 1987, 25, 377–386. (g) Padwa, A.;
Brodney, M. A.; Marino, J. P.; Sheehan, S. M. J. Org. Chem. 1997, 62,
Lycopodine (1) has been synthesized many times over
4
the past 40 years but is still a significant target with the
first synthesis in optically pure form reported by Carter in
7
8–87. (h) Greico, P. A.; Dai, Y. J. J. Am. Chem. Soc. 1998, 120, 5128–
5
129. (i) Mori, M.; Hori, K.; Akashi, M.; Hori, M.; Sato, Y.; Nishida, M.
4
008. 8-Hydroxylycopodine (2, clavolonine) has been
j
Angew. Chem., Int. Ed. 1998, 37, 636–637. (j) Yang, H.; Carter, R. G.;
Zakharov, L. N. J. Am. Chem. Soc. 2008, 130, 9238–9239. (k) Yang, H.;
Carter, R. G. J. Org. Chem. 2010, 75, 4929–4938. (l) For a review of
lycopodine syntheses, see: Hudlick ꢀy , T.; Reed, J. W. The Way of
Synthesis; Wiley-VCH: Weinheim, 2007; pp 573-602.
(5) (a) Wenkert, E.; Broka, C. A. J. Chem. Soc., Chem. Commun.
1984, 714–715. (b) Evans, D. A.; Scheerer, J. R. Angew. Chem., Int. Ed.
2005, 44, 6038–6042. (c) Laemmerhold, K. M.; Breit, B. Angew. Chem.,
Int. Ed. 2010, 49, 2367–2370.
2
known for many years and has been synthesized by
(
1) (a) Ortega, M. G.; Agnese, A M.; Cabrera, J. L. Tetrahedron Lett.
2
004, 45, 7003–7005. (b) Vallejo, M. G.; Ortega, M. G.; Cabrera, J. L.;
Carlini, V. P.; Rubiales de Barioglio, S.; Almiron, R. S.; Ramirez, O. A.;
Agnese, A. M. J. Nat. Prod. 2009, 72, 156–158; note that the methyl
group of sauroine is attached to the wrong carbon.
1
0.1021/ol200119h r 2011 American Chemical Society
Published on Web 01/27/2011

Scheme 1. Retrosynthesis of 7-Hydroxylycopodine
Scheme 2. Unsuccessful Approach to Diketone
6
reported in 2004. The bridgehead hydroxy group of
sauroine (3) and 7-hydroxylycopodine (4) precludes the
use of most of the methods that have been developed for
lycopodine and clavolonine synthesis, but they also make
aldol and Prins approaches more attractive. We decided to
synthesize 7-hydroxylocopodine (4) first and then modify
that route to prepare sauroine (3) with the additional
8-hydroxy group so that these molecules will be available
for further biological evaluation.
We planned to construct the final ring of 4 from dihy-
droxy ketone 5 by a modified Oppenauer oxidation-aldol
reaction sequence as developed by Heathcock in his lyco-
4
d
podine synthesis (see Scheme 1) and later used by Kraus
4
f,j,k
and Carter.
We planned to prepare the β-hydroxycy-
bromide (9), 5-methyl-1,3-cyclohexanedione (10), and 2,6-
lutidine in ethanol at 130 °C afforded the enamide which
underwent an intramolecular alkylation to give racemic 11
clohexanone of 5 from diketone 6 by an intramolecular
aldol reaction. The 2-oxopropyl side chain of 6 should be
available by Wacker oxidation of the allyl side chain of 7,
which will be prepared by hydrolysis of enol ether 8. This
route is appealing because Wiesner reported an efficient
synthesis of 15, the analogue of 8 with an N-methyl sub-
7
b,8,9
(see Scheme 2).
Alkylation of 11 with iodomethane
using NaH in THF gave 12 in 48% yield from 10. Follow-
ing Wiesner’s procedure, vinylogous amide 12 was heated
in isopropyl iodide at 55 °C for 42 h to provide cation 13,
which was treated with allylmagnesium bromide to give 15
in 55% yield from 12. Hydrolysis of the enol ether of 15
with 1 M hydrochloric acid afforded a 1.7:1 mixture of
stereoisomeric ketones in 77% yield. Unfortunately, we
were unable to prepare 18 by a Wacker oxidation of keto
amino alkene 15, although amino alkenes have been
7
b
stituent. We were concerned about the stereochemistry
of the ring fusion that will be introduced by protonation
of the enol ether of 8 because related work from Wiesner’s
7
c,d
laboratory led to the synthesis of 12-epilycopodine.
Nevertheless, the brevity of this approach was very appealing.
Before addressing the synthesis of 5, we chose to carry
out a model study for the preparation of the tricylic frame-
work with an N-methyl rather than a protected N-hydro-
xypropyl group. Reaction of 3-bromopropylamine hydro-
1
0
successfully oxidized to amino methyl ketones.
We then attempted to prepare methyl ketone 18 by hy-
drolysis of alkyne 14. Addition of propargylmagnesium
bromide to cation 13 gave ketone 14 in 42% yield from 12.
Hydration of the triple bond of 14 with HgO in 1:1 MeOH/
(
6) (a) Tan, C.-H. Ph. D. Thesis, Shanghai Institute of Materia
Medica, 2001. (b) Tan, C.-H.; Zhu, D.-Y. Helv. Chim. Acta 2004, 87,
963–1967.
7) (a) Valenta, Z.; Deslongchamps, P.; Ellison, R. A.; Wiesner, K. J.
1
M aqueous H SO at 65 °C also failed to give the desired
2
4
1
methyl ketone 18. Instead we obtained dienone 16 in 39%
yield. A plausible mechanism for the formation of 16
involves the desired hydration of the alkyne to give 18,
which under the acidic conditions undergoes a retro con-
jugate addition to give amino diketone 17. Condensation
(
J. Am. Chem. Soc. 1964, 86, 2533–2534. (b) Dugas, H.; Ellison, R. A.;
Valenta, Z.; Wiesner, K.; Wong, C. M. Tetrahedron Lett. 1965, 1279–
1286. (c) Dugas, H.; Hazenberg, M. E.; Valenta, Z.; Wiesner, K.
Tetrahedron Lett. 1967, 4931–4936. (d) Wiesner, K.; Musil, V.; Wiesner,
K. J. Tetrahedron Lett. 1968, 5643–5646.
(8) Reinshagen, H. Angew. Chem. 1964, 76, 994.
(9) For the preparation of related vinylogous amides by this method,
see: (a) Rohloff, J. C.; Dyson, N. H.; Gardner, J. O.; Alfredson, T. V.;
Sparacino, M. L.; Robinson, J., III. J. Org. Chem. 1993, 58, 1935–1938.
(10) For examples of Wacker oxidations in the presence of an amine,
see: (a) Li, W.-D.; Wang, Y.-Q. Org. Lett. 2003, 5, 2931–2934. (b) Berry,
M. B.; Craig, D.; Jones, P. S.; Rowlands, G. J. Beilstein J. Org. Chem.
2007, 3, no. 39.
(b) Zhao, Y.; Zhao, J.; Zhou, Y.; Lei, Z.; Li, L.; Zhang, H. New J. Chem.
2005, 29, 769–772.
Org. Lett., Vol. 13, No. 5, 2011
1235

Scheme 3. Synthesis of Model Tricyclic Hydroxy Ketone 24
Scheme 4. Synthesis of 7-Hydroxylycopodine (4)
of the amine with the cyclohexanone will then give the fully
conjugated δ-amino dienone 16. This suggests that decom-
position of 18 might be responsible for the failure of the
Wacker oxidation of 15.
Fortunately, the alkyne of 14 provided us with another
method to form the desired tricyclic hydroxy ketone 5.
Wiesner reported that reaction of 15 in 75% H SO for
2
4
12 h afforded 22 in 70% yield as a single isomer with unknown
regio- and stereochemistry. Hydrolysis of enol ether 15
afforded ketone 19, which underwent a Prins cyclization to
give secondary cation 20 (see Scheme 3). A 1,5-hydride
shift afforded tertiary cation 21, which lost a proton to give
2
2. The desired stereochemistry with a β-hydrogen, which
would result from formation of trans-fused bicylic ketone
9, was suggested on the basis of kinetic and thermody-
1
2
sp orbital. Cation 23 should react with water to give an
namic conformational arguments. However, later work
from this group leading to two syntheses of the undesired
1
mical suggestion. Amino alkene 22 is not useful for lyco-
podine synthesis because the functionality is now in the
wrong ring.
enol that will tautomerize to the desired tricylic ketone 24.
We were delighted to find that reaction of 14 in 60%
aqueous H SO for 8 h afforded tricylic amino hydroxy
7
2-epi-lycopodine raises questions about this stereoche-
c,d
2
4
ketone 24 in 70% yield. Prins reactions with alkynes are
1
1
uncommon but known. The isolation of β-hydroxy
ketones from Prins reactions of keto alkynes is not usually
observed but occurs here because ring strain prevents
dehydration to form the enone with a bridgehead double
bond. The stereochemistry of 24 was assigned from NOE
studies as described in detail in the Supporting Informa-
tion. The stereoisomer derived from the cis-fused bicyclic
ketone was not formed, possibly because the trans-fused
bicyclic ketone is 1.4 kcal/mol more stable than the cis iso-
mer as determined by molecular mechanics calculations.
For the synthesis of 7-hydroxylycopodine precursor 5
we simply needed to replace the methyl group of 14 with a
3-hydroxypropyl group. Crude enaminoketone 11 was
We decided to subject alkyne 14 to these acidic condi-
tions with the hope that hydrolysis of the enol ether and
cyclization would give vinyl cation 23 analogously to the
formation of secondary cation 20. A 1,5-hydride shift cannot
occur in 23 because the hydrogen is too far from the vacant
(
11) For examples of Prins additions of ketones and aldehydes to
alkynes, see: (a) Rodini, D. J.; Snider, B. B. Tetrahedron Lett. 1980, 21,
857–3860. (b) Keirs, D.; Overton, K.; Thakker, K. J. Chem. Soc.,
3
Chem. Commun. 1990, 310–311. (c) Harding, C. E.; King, S. L. J. Org.
Chem. 1992, 57, 883–886. (d) Wempe, M. F.; Grunwell, J. R. J. Org.
Chem. 1995, 60, 2714–2720. (e) Balog, A.; Geib, S. J.; Curran, D. P. J.
Org. Chem. 1995, 60, 345–352. (f) Rhee, J. U.; Krische, M. J. Org. Lett.
2
005, 7, 2493–2495. (g) Jin, T.; Yamamoto, Y. Org. Lett. 2007, 9, 5259–
5262. (h) Miranda, P. O.; Ramırez, M. A.; Martı
´
´
n, V. S.; Padr oꢀ n, J. I.
12
alkylated with I(CH ) OTBS using NaH in 1:1 THF/
2
3
Chem.;Eur. J. 2008, 14, 6260–6268. (i) Chavre, S. N.; Choo, H.; Lee,
J. K.; Pae, A. N.; Kim, Y.; Cho, Y. S. J. Org. Chem. 2008, 73, 7647–7471.
DMF for 18 h at 25 °C to give 25 in 50% yield from
1
236
Org. Lett., Vol. 13, No. 5, 2011

cyclohexanedione 10 (see Scheme 4). A solution of 25 in
-iodopropane was heated at 55 °C for 42 h to give the
reaction sequence. Both alcohol groups of 5 were differ-
ently protected in a single reaction to give 28 in 90% yield
by stirring 5 for 12 h in Ac O to form the primary acetate
2
intermediate cation 26, which was treated with propargyl-
magnesium bromide to give 27a in 40% yield from 25.
Stirring 27a in 60% aqueous H SO for 8 h at 25 °C
2
and adding DMSO and continuing stirring for 72h toform
1
5
the methylthiomethyl ether of the tertiary alcohol. Keto
acetate 28 was treated with KO-t-Bu (6 equiv) and benzo-
phenone (16 equiv) in carefully degassed benzene at 110 °C
for 1 h. Under these conditions, the acetate is cleaved,
the resulting primary alcohol is oxidized to the alde-
hyde, and the aldol reaction occurs to form the enone.
The methylthiomethyl protecting group is cleaved with
3 M hydrochloric acid during the workup to give 29 in
2
4
afforded the desired tricylic dihydroxy ketone 5 in 48%
yield. The sequence was improved by adding trimethylsi-
lylpropargyllithium, prepared by deprotonation of 1-tri-
methylsilylpropyne with n-BuLi, to cation 26 to give 27b in
5
2
1% yield. Stirring 27b in 60% sulfuric acid for 10 h at
5°C afforded 5 in 50%yield. The stereochemistry of 5 was
established by NOE studies as detailed in the Supporting
Information. During the conversion of 27b to 5, the enol
ether is hydrolyzed, the TBS ether and TMS alkyne are
deprotected, and the keto alkyne undergoes the Prins
reaction to form the third ring.
47% yield. Hydrogenation of enone 29 over PtO with
2
1 atm of H for 10 h afforded 7-hydroxylycopodine (4)
2
in 95% yield. The spectral data for the hydrochloride
salt of 4 in CD OD are identical to those reported for
3
6
The modified Oppenauer oxidation-aldol reaction of 5
with benzophenone and KO-t-Bu using conditions devel-
oped by Heathcock in his lycopodine synthesis for the
oxidation of the analogue of 5 lacking the tertiary hydroxy
group gave a complex mixture containing ∼5% of the
the natural product.
In conclusion, we have developed a practical six step
synthesis of (()-7-hydroxylycopodine (4) that proceeds in
a 5% overall yield making it readily available for further
biological evaluation. The key step is the Prins reaction of
27a or 27b that proceeds in 60% H SO to give tricyclic
4
d,13
desired enone 29.
Wesuspectthata retro aldolreaction
2
4
of the β-hydroxy ketone occurred under the strongly basic
conditions. We eventually found that the primary alcohol
could be selectively oxidized to the aldehyde with t-
BuOMgCl and azodicarbonyldipiperidine in THF, but
all attempts to carry out the aldol reaction resulted in a
retro conjugate addition with loss of acrolein to form the
tricyclic secondary amine.
dihydroxy amino ketone 5. We are currently investigating
methods to prepare the starting vinylogous amide 11 in
optically pure form and to introduce a hydroxy group
adjacent to the carbonyl group of 25 to give an intermedi-
ate that will be elaborated analogously to sauroine (3, 7,8-
dihydroxylycopodine).
1
4
We therefore decided to protect the tertiary alcohol
and re-examine the modified Oppenauer oxidation-aldol
Acknowledgment. We are grateful to the National In-
stitutes of Health (GM-50151) for generous financial sup-
port. We thank Dr. C.-H. Tan, Shanghai Institute of Materia
Medica, for a copy of his Ph.D. thesis containing an
HMQC spectrum of 4.
(
12) Thompson, C. M.; Quinn, C. A.; Hergenrother, P. J. J. Med.
Chem. 2009, 52, 117–125.
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Lett. 1976, 65–66. (b) Pojer, P. M.; Angyal, S. J. Aust. J. Chem. 1978, 31,
031–1040.
(
1
Supporting Information Available. Complete experi-
(
1
13
mental procedures and copies of H and C NMR
spectral data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(
1
Org. Lett., Vol. 13, No. 5, 2011
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