Synthesis of (±)-7-hydroxylycopodine

Article abstract of DOI:10.1021/jo300353t

A seven-step synthesis of (±)-7-hydroxylycopodine that proceeds in 5% overall yield has been achieved. The key step is a Prins reaction in 60% sulfuric acid that gave the key tricyclic intermediate with complete control of the ring fusion stereochemistry. A one-pot procedure orthogonally protected the primary alcohol as an acetate and the tertiary alcohol as a methylthiomethyl ether. The resulting product was converted to 7-hydroxydehydrolycopodine by heating with KO-t-Bu and benzophenone in benzene followed by acidic workup. During unsuccessful attempts to make optically pure starting material, we observed the selective Pt-catalyzed hydrogenation of the 5-phenyl group of a 4,5-diphenyloxazolidine under acidic conditions and the Pt-catalyzed isomerization of the oxazolidine to an amide under neutral conditions. In attempts to hydroxylate the starting material so that we could adapt this synthesis to the preparation of (±)-7,8-dihydroxylycopodine (sauroine) we observed the novel oxidation of a bicyclic vinylogous amide to a keto pyridine with Mn(OAc)₃ and to an amino phenol with KHMDS and oxygen.

Full text of DOI:10.1021/jo300353t

Featured Article
pubs.acs.org/joc
Synthesis of ( )-7-Hydroxylycopodine
Hong-Yu Lin,† Robert Causey,‡ Gregory E. Garcia,‡ and Barry B. Snider*,†
†Department of Chemistry MS 015, Brandeis University, Waltham, Massachusetts 02454-9110, United States
‡Research Division/Physiology & Immunology Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving
Ground, Edgewood Area, Maryland 21010-5400, United States
S
* Supporting Information
ABSTRACT: A seven-step synthesis of ( )-7-hydroxylycopodine that
proceeds in 5% overall yield has been achieved. The key step is a Prins
reaction in 60% sulfuric acid that gave the key tricyclic intermediate with
complete control of the ring fusion stereochemistry. A one-pot
procedure orthogonally protected the primary alcohol as an acetate
and the tertiary alcohol as a methylthiomethyl ether. The resulting
product was converted to 7-hydroxydehydrolycopodine by heating with
KO-t-Bu and benzophenone in benzene followed by acidic workup. During unsuccessful attempts to make optically pure starting
material, we observed the selective Pt-catalyzed hydrogenation of the 5-phenyl group of a 4,5-diphenyloxazolidine under acidic
conditions and the Pt-catalyzed isomerization of the oxazolidine to an amide under neutral conditions. In attempts to hydroxylate
the starting material so that we could adapt this synthesis to the preparation of ( )-7,8-dihydroxylycopodine (sauroine) we
observed the novel oxidation of a bicyclic vinylogous amide to a keto pyridine with Mn(OAc)3 and to an amino phenol with
KHMDS and oxygen.
Racemic lycopodine (2) was first synthesized by Stork5a and
INTRODUCTION
The lycopodium alkaloids are a large, extensively studied
■
Ayer5b in 1968, with additional syntheses by Kim,5c
Heathcock,5d Schumann,5e Wenkert,6a Kraus,5f Grieco,5g
alkaloid family that have been of interest to synthetic chemists
Padwa,5h and Mori5i over the next 30 years.5l The first
synthesis of lycopodine in optically pure form was recently
reported by Carter in 2008.5j,k 8-Hydroxylycopodine (3,
clavolonine) was synthesized in racemic form in 1984 by
Wenkert6a and more recently in optically pure form by Evans,6b
Breit,6c and Fujikoka.6d
for more than 50 years.1 Huperzine A (1), which is probably
the medicinally most significant member of this family, is an
acetylcholinesterase inhibitor that may have other important
roles including treatment of Alzheimer’s disease as discussed in
recent reviews (see Figure 1).2 We were therefore intrigued by
The bridgehead hydroxy group of sauroine (4) and 7-
hydroxylycopodine (5) is not compatible with most of the
approaches that have been used for the synthesis of lycopodine
(2) and clavolonine (3). Fortunately, the presence of a 3-
hydroxycyclohexanone suggests that this ring might be formed
by an aldol or Prins reaction. We decided to start by
synthesizing 7-hydroxylycopodine (5) and then to adapt the
route to the synthesis of sauroine (4) that contains the
additional 8-hydroxy group so that these molecules will be
available for study of their biological properties.
We envisioned that the fourth and final ring of 5 could be
constructed from dihydroxy ketone 6 by oxidation of the
primary alcohol to an aldehyde, intramolecular aldol reaction,
and dehydration and then hydrogenation as developed by
Heathcock5d in his lycopodine synthesis and later used by
Kraus5f and Carter (see Scheme 1).5j,k We hoped that we could
prepare 6 from diketone 7 with a suitable protecting group on
the primary alcohol by an intramolecular aldol reaction. We
planned to introduce the side chain ketone of diketone 7 by a
Wacker oxidation of the allyl group of ketone 8, which will be
Figure 1. Structures of huperzine A (1), lycopodine (2), clavolonine
(3), sauroine (4), and 7-hydroxylycopodine (5).
the 2009 report3a that sauroine (4, 7,8-dihydroxylycopodine),
which was first reported in 2004,3b improves memory retention
in the step-down test in male Wistar rats and significantly
improves hippocampal plasticity. The isolation of 7-hydrox-
ylycopodine (5) was also reported in 2004 without any
indication of biological activity.4
Received: February 17, 2012
Published: March 23, 2012
© 2012 American Chemical Society
7143
dx.doi.org/10.1021/jo300353t | J. Org. Chem. 2012, 77, 7143−7156

The Journal of Organic Chemistry
Featured Article
Scheme 1. Retrosynthesis of 7-Hydroxylycopodine
Scheme 2. Unsuccessful Approaches to Diketone 18
prepared by hydrolysis of enol ether 9. This approach is
intriguing because Wiesner and co-workers developed an
efficient route to 15, the analogue of 9 with an N-methyl
rather than a protected N-hydroxypropyl group, in a very early
unsuccessful approach to lycopodine synthesis.7b This route to
7-hydroxylycopodine is very short and attractive. Our one
major concern was the stereochemistry of protonation of the
enol ether of 9 which could give both the desired ketone 8 with
a trans ring fusion and the undesired stereoisomer with a cis
ring fusion that would lead to 12-epi-7-hydroxylycopodine. This
was of particular concern because related syntheses by Wiesner
led to 12-epi-lycopodine, rather than the desired target
lycopodine.7c,d The brevity of this route is appealing and the
stereochemical question is addressed early in the synthesis so
we chose to explore this route.8
RESULTS AND DISCUSSION
■
Synthesis of Tricyclic Model 26. We started with a model
study designed to prepare the tricyclic skeleton of 6 with an N-
methyl, rather than an N-hydroxypropyl, group because the
nitrogen substituent should have no effect on the stereo-
chemistry of the enol ether protonation, Wacker oxidation, or
aldol cyclization. Weisner7b prepared 129 in unspecified yield
by heating 5-methylcyclohexane-1,3-dione (11) with 3-amino-
1-propanol in benzene at reflux and then heating the resulting
vinylogous amide with 1 equiv of pyridine hydroiodide neat at
140 °C for 2 h (see Scheme 2). We prepared 12 by microwave
heating diketone 11 with 3-bromopropylammonium bromide
(10) and 2,6-lutidine in ethanol at 130 °C for 20 min in a
modification of a literature procedure for related compounds
that heated for 1 h in butanol at reflux (see Scheme 2).10a
Methylation of vinylogous amide 12 with NaH and iodo-
methane in THF gave 137b in 48% overall yield from 11. Using
Wiesner’s protocol, we converted 13 to 15 by heating 13 in
excess 2-iodopropane for 42 h at 55 °C and concentration to
give the unstable salt 14, which was immediately taken up in
THF and treated with allylmagnesium chloride in THF for 2 h
at 0 °C to give enol ether 15 as a single stereoisomer in 55%
yield from 13.
Stirring enol ether 15 in 1 M hydrochloric acid for 5 h at 25
°C afforded a ∼3:1 mixture of stereoisomeric ketones 17 in
77% yield. The major stereoisomer was easily isolated in pure
form, but the stereochemistry of the ring fusion could not be
easily assigned by analysis of the NMR spectral data. We
therefore used mixture 17 for our initial explorations of the
Wacker oxidation. Unfortunately, all attempts to carry out the
Wacker oxidation of 17 to give diketone 18 were unsuccessful.
We were somewhat concerned that the amino group might be
interfering, although Wacker oxidations of amino alkenes to
amino methyl ketones have been reported under acidic
conditions in which the amine is protonated.11
We then attempted to prepare diketone 18 by hydrolysis of
enol ether alkyne 16. Addition of propargylmagnesium bromide
to a solution of salt 14 in THF provided enol ether alkyne 16 as
a single stereoisomer in 42% yield from vinylogous amide 13.
To our surprise, hydration of the triple bond of 16 with HgO in
1:1 MeOH/1 M aqueous sulfuric acid at 65 °C provided
dienone 20 in 39% yield rather than the desired diketone 18.
Presumably, hydrolysis of the alkyne affords the desired dione
18 with a protonated amino group. Elimination of the β-amino
group leads to monocyclic amino dione 19, which condenses
with the cyclohexanone to form the fully conjugated δ-amino
dienone 20. In retrospect, the failure of the Wacker oxidation of
17 might be due to the decomposition of the desired diketone
18 under the acidic reaction conditions to give compounds that
are further oxidized by Pd(II).
Although enol ether alkyne 16 was initially prepared as a
possible precursor to diketone 18, it fortuitously allowed us to
develop a one-step route to the desired model tricyclic hydroxy
ketone 26 that does not proceed through diketone 18 (see
Scheme 3). In 1965, Wiesner and co-workers reported that
treatment of enol ether alkene 15 in 75% sulfuric acid for 12 h
at 25 °C afforded tricyclic alkene 24 in 70% yield as a single
7144
dx.doi.org/10.1021/jo300353t | J. Org. Chem. 2012, 77, 7143−7156

The Journal of Organic Chemistry
Featured Article
Scheme 3. Synthesis of Model Tricyclic Hydroxy Ketone 26
Figure 2. NOEs in tricyclic model 26.
Prins reactions with alkynes are uncommon, but known.12
The isolation of β-hydroxy ketones from Prins reactions of keto
alkynes is rarely observed because these initial products will
usually undergo dehydration to give conjugated ketones. In this
case, ring strain prevents dehydration to form a conjugated
ketone, which would have a bridgehead double bond.
We briefly explored the scope of this alkyne ketone Prins
reaction as a route to bicyclic hydroxy ketones. Stirring 3-
propargylcyclohexanone (27)13 in 60% sulfuric acid for 16 h at
25 °C provided 1-hydroxybicyclo[3.3.1]nonan-3-one (28)14 in
76% yield, indicating that the protonated nitrogen of 16 is not
necessary for the reaction (see Scheme 4). Similar treatment of
Scheme 4. Prins Reactions of Propargyl Ketones
isomer with unknown stereochemistry at the ring fusion and
unknown double bond position.7b Acidic hydrolysis of the enol
ether afforded ketone 21 (protonated form of ketone 17),
which underwent a Prins cyclization to give secondary cation
22. A facile transannular 1,5-hydride shift then took place to
form the more stable tertiary cation 23. Loss of a proton then
formed the observed product 24. The desired ring fusion
stereochemistry with a β-hydrogen, which would result from
the trans-fused stereoisomer of bicyclic ketone 21 was
suggested on the basis of kinetic and thermodynamic
conformational analysis. However later work from this group
leading to two syntheses of 12-epi-lycopodine7c,d using related
chemistry and our observation that hydrolysis of 15 with
hydrochloric acid afforded 17 as a ∼3:1 mixture of stereo-
isomers indicate that this stereochemical assignment is far from
secure. Unfortunately, the functionality is now in the wrong
ring of 24, which makes it useless for lycopodine synthesis
regardless of the stereochemistry at C12.
Enol ether alkyne 16 was treated with aqueous sulfuric acid
with the expectation that enol ether hydrolysis and Prins
cyclization would occur analogously to give alkenyl cation 25. A
1,5-hydride shift should not occur because the hydrogen is too
far from the vacant sp2 orbital on the alkenyl cation. Instead,
the alkenyl cation should react with water to give an enol that
will tautomerize to the desired tricyclic hydroxy ketone 26. We
were pleased to find that reaction of 16 in 60% sulfuric acid for
8 h at 25 °C afforded 26 in 70% yield as a single stereoisomer.
The yield was slightly lower in 75% sulfuric acid. In 50%
sulfuric acid, the enol ether hydrolyzed to give the ketone,
which did not add to the alkyne. The stereochemistry of 26 was
assigned from a series of 1D NOESY experiments as shown in
Figure 2. The stereochemistry at C12 can be unambiguously
assigned from the NOEs between H12 and H14 and between H6
and H11.
3-propargylcyclopentanone (29)13 gave a complex mixture, and
N-propargylpiperidine-4-one (30)15 was recovered unchanged
from 60%, 80%, or concentrated sulfuric acid. These initial
results suggest that this Prins reaction will be best suited for the
synthesis of 1-hydroxybicyclo[3.3.1]nonan-3-ones.
We wanted to explore the trapping of the vinyl cation
intermediate with nucleophiles other than water. We therefore
explored the reaction of 27 with EtAlCl2 in CH2Cl2 (see
Scheme 5).16 Initial reactions in which oxygen was not carefully
excluded gave chloroalkenyl ether 31 in about 50% yield.
However, when we carefully excluded oxygen, we obtained a
complex mixture of products. We hypothesized that EtAlCl2
reacted with oxygen to give EtO2AlCl2, which reacted with
second molecule of EtAlCl2 to give two molecules of EtOAlCl2,
which was responsible for the formation of 31.17,18 We
therefore treated EtAlCl2 with 1 equiv of EtOH in CH2Cl2
for 1 h to give EtOAlCl2 and ethane. Addition of 27 and stirring
for 20 h afforded 31 in 71% yield. Presumably EtOAlCl2 reacts
with 27 to give 32, which reacts further to give alkoxonium ion
The stereoisomer derived from the cis-fused bicyclic ketone
was not observed. The origin of this stereoselectivity is not
obvious. The trans-fused bicyclic ketone is calculated by
molecular mechanics to be 1.4 kcal/mol more stable than the
cis isomer, but bicyclic ketone 17 was formed as a ∼3:1 mixture
of stereoisomers by hydrolysis of enol ether alkene 15.
7145
dx.doi.org/10.1021/jo300353t | J. Org. Chem. 2012, 77, 7143−7156

The Journal of Organic Chemistry
Featured Article
unambiguously assigned from the NOEs between H12 and H14,
between H6 and H11, and between H4 and both H9 and H11.
Scheme 5. Cyclization of 3-Propargylcyclohexanone (27)
with EtOAlCl2 To Give Vinyl Chloride 31
Figure 3. NOEs of 7-hydroxylycopodine intermediate 6.
Propargylmagnesium bromide is best used immediately, and
its preparation requires the use of toxic HgCl2 in addition to
magnesium. We therefore explored the use of other propargyl
nucleophiles. Trimethylsilylpropargyllithium, which is easily
prepared by deprotonation of 1-trimethylsilylpropyne with n-
BuLi, added to cation 35 to give 36b in 51% yield. The
preparation of 36b is operationally simpler, proceeds in higher
yield, and does not produce mercury-containing waste. The
hydrolysis and cyclization of 36b in 60% sulfuric acid was
slightly slower (10 h) than that of 36a but afforded 6 in
comparable yield (50%). During the conversion of 36b to 6, the
enol ether is hydrolyzed, the TMS alkyne and TBS ether are
deprotected and the keto alkyne cyclizes to form the tricyclic
hydroxy ketone.
33, which cyclizes to give 31 after trapping of the vinyl cation
with chloride.
Synthesis of 7-Hydroxylycopodine (5). For the synthesis
of 7-hydroxylycopodine precursor 6 we needed to replace the
methyl group of 13 with a protected hydroxypropyl group. We
chose to use the TBS group because it should be stable to the
conditions needed to add the propargyl group but then be
hydrolyzed without an additional step during the sulfuric acid
catalyzed cyclization. Crude vinylogous amide 12 was treated
with NaH and then I(CH2)3OTBS19 in 1:1 THF/DMF for 18
h at 25 °C to afford 34 in 50% overall yield from 5-
methylcyclohexane-1,3-dione (11) (see Scheme 6). Heating a
Heathcock was unable to synthesize lycopodine by an
intramolecular alkylation of the analogue of 6 lacking the
tertiary hydroxy group20 and therefore used a modified
Oppenauer oxidation−aldol reaction with benzophenone and
KO-t-Bu to form dehydrolycopodine.5d,21 Unfortunately, with 6
we obtained a complex mixture containing at most 5% of the
desired enone 42 using a variety of bases (KO-t-Bu, NaO-t-Bu,
or NaH) and hydride acceptors (benzophenone or fluorenone).
We suspect that a retro-aldol reaction of the β-hydroxy ketone
took place under the very basic reaction conditions. We
therefore explored other oxidation conditions that might
oxidize the primary alcohol to the aldehyde in the presence
of an amine and tertiary alcohol. Decomposition occurs with
PCC, PDC, or excess TPAP. No reaction occurred under
Swern or Parikh−Doering conditions. Dess−Martin oxidation
formed the β-amino aldehyde which appeared to be oxidized
further to give the β-aminoenal R2NCHCHCHO based on
NMR peaks at δ 9.16 (d, 1, J = 7.6 Hz), 7.39 (br d, 1, J = 12.4
Hz), and 5.33 (dd, 1, J = 12.4, 7.6 Hz).22 Oxidation with IBX in
DMSO gave mainly recovered 6 containing a trace of β-
aminoenal. Eventually we found that the primary alcohol of 6
could be selectively oxidized to unstable amino aldehyde 37
under Narasaka−Mukaiyama conditions with t-BuOMgCl and
azodicarbonylpiperidine in THF (see Scheme 7).23 Unfortu-
nately, all attempts to carry out an intramolecular aldol reaction
with 37 to give 42 using either acid (TsOH or AcOH), base
(KO-t-Bu, K2CO3, or pyrrolidine), or salt (piperidinium
acetate, dibenzylammonium trifluoroacetate, or piperidinium
trifluoroacetate) catalysis resulted in loss of acrolein to form the
unstable tricyclic secondary amine 38.
Scheme 6. Preparation of Tricyclic Intermediate 6
solution of 34 in 2-iodopropane for 42 h at 55 °C afforded the
intermediate cation 35, which was treated with propargylmag-
nesium bromide in THF to yield 36a in 40% yield from 34.
Stirring a solution of 36a in 60% aqueous sulfuric acid for 8 h at
25 °C afforded the requisite tricyclic ketone 6 with the required
hydroxypropyl side chain in 50% yield. As in the hydrolysis and
Prins cyclization of 16, the hydrolysis and cyclization of 36a
affords 6 as a single stereoisomer whose stereochemistry was
established by a series of 1D NOESY experiments that are
summarized in Figure 3. The stereochemistry at C12 can be
We therefore decided to protect the tertiary alcohol of 6 and
to then reinvestigate the modified Oppenauer oxidation−aldol
reaction sequence. The strongly basic and high-temperature
conditions of the Oppenauer oxidation preclude the use of an
ester or silyl ether protecting group. We initially protected the
7146
dx.doi.org/10.1021/jo300353t | J. Org. Chem. 2012, 77, 7143−7156

The Journal of Organic Chemistry
Featured Article
50% yield. This reaction was carried out with an excess of
strong base suggesting that prior deprotection of the primary
acetate of 41 was unnecessary. As expected, similar treatment of
40 using an extra equivalent of KO-t-Bu afforded 42 in 47%
yield. In this step, the primary acetate is cleaved, the resulting
alcohol is oxidized to the aldehyde, the aldol reaction closes the
final ring, dehydration leads to the enone, and the protecting
group is cleaved during workup. Hydrogenation of enone 42
over PtO2 with 1 atm of H2 for 10 h afforded 7-
hydroxylycopodine (5) in 95% yield. The spectral data for
the hydrochloride salt of 5 in CD3OD are identical to those
reported for the natural product,4 thereby confirming the
stereochemical assignment of 6 made on the basis of NOE
experiments.
Scheme 7. Preparation and Decomposition of Amino
Aldehyde 37
primary alcohol with pyridine and acetic anhydride to give 39
in quantitative yield (see Scheme 8). Attempted benzylation or
Biological Activity. The crude alkaloid extract of Huperzia
Saururus, which contained no huperzine A (2), inhibited
human acetylcholinesterase (AChE) with an IC50 of 0.58 μg/
mL.3 However, the major alkaloid sauroine (1), which
constitutes 57−67% of the alkaloid mixture depending on the
harvest season, did not inhibit AChE below 10 μg/mL
indicating that there are other potent AChE inhibitors in the
crude mixture.3a Although sauroine is a weak AChE inhibitor it
did demonstrate a significant increase of hippocampal plasticity
and memory retention in rats.3c,d We found that 7-
hydroxylycopodine (5) is a weak inhibitor of eel AChE and
human erythrocyte cholinesterases with an IC50 of 1.67 and
2.08 mM (439 and 547 μg/mL), respectively (see Figure 4). At
Scheme 8. Completion of the Synthesis of 7-
Hydroxylycopodine (5)
Figure 4. Effect of 7-hydroxylycopodine (5) on eel AChE and human
whole blood ChE activities. Samples were preincubated with 7-
hydroxylycopodine before assay. Values plotted are mean SEM. The
calculated IC50 values are shown in the inset table.
allylation of the tertiary alcohol of 39 under a variety of
conditions led to complex mixtures, recovered starting material
or hydrolysis of the acetate. We were also unable to form the
tertiary ethoxyethyl or THP ether from the acid-catalyzed
reaction of 39 with ethyl vinyl ether or dihydropyran.
Eventually, we found that treatment of 39 with acetic anhydride
this concentration, 7-hydroxylycopodine does not inhibit
human butyrylcholinesterase (data not shown), indicating
that the observed IC50 of 2.08 mM is due to human erythrocyte
AChE inhibition. In contrast, huperzine A inhibits human
erythrocyte acetylcholinesterase with an IC50 of 0.09 μM.2a
Approaches to the Synthesis of Optically Pure 12. We
have developed a short, practical, six-step synthesis of ( )-7-
hydroxylcyopodine (5) from racemic 12, which is prepared
from prochiral 5-methylcyclohexane-1,3-dione (11). We briefly
explored approaches for the formation of optically pure 12
from 11. Rychnovsky found that Cu(OTf)2-catalyzed reaction
of racemic 43 with amino alcohol 44 afforded 45 in 95% yield
as a 20:1 mixture of diastereomers which he used for a synthesis
of (−)-lycoperine (see Scheme 9).25 Unfortunately, as
suggested by Rychnovsky’s work, we were unable to remove
+
in DMSO generated MeSCH2 by a Pummerer rearrange-
ment which reacted with the tertiary alcohol to give
methylthiomethyl ether 40 in 90% yield.24 Hydrolysis of the
acetate of 40 with K2CO3 in MeOH afforded primary alcohol
41 in 92% yield. This sequence was improved by carrying out
the first two steps in a single pot. A solution of 6 in Ac2O was
stirred for 12 h at 25 °C to form the primary acetate. DMSO
was added, and stirring was continued for 72 h to form 40 in
90% yield.
We were pleased to find that treatment of 41 with KO-t-Bu
(5 equiv) and benzophenone (16 equiv) in carefully degassed
benzene in a sealed tube at 110 °C for 1 h followed by workup
with 3 M hydrochloric acid to cleave the methylthiomethyl
protecting group gave 7-hydroxydehydrolycopodine (42) in
7147
dx.doi.org/10.1021/jo300353t | J. Org. Chem. 2012, 77, 7143−7156

The Journal of Organic Chemistry
Featured Article
and PtO2 in MeOH for only 10 h afforded only 5−10% of
cyclohexane 47, about 50% of amide 50, and 40−45%
unreacted 46. The facile isomerization of aminal 46 to amide
50 at 1−3 atm of H2 may be the reason that forcing conditions
(500 psi H2) were needed for the reductive removal of the
protecting group in Rychnovsky’s lycoperine synthesis.25 High
H2 pressure should accelerate hydrogenolytic cleavage of
intermediate 48 and thereby prevent the formation of amide
50.
Scheme 9. Hydrogenation and Isomerization of 46
We then turned to the resolution of racemic 12. The anion of
12 was acylated with α-acetoxy and α-methoxyphenylacetyl
chloride to give diastereomeric vinylogous imides, which were
inseparable by TLC. We then decided to react the anion of 12
with trans-stilbene oxide in the hope that the two diastereomers
of 53 with the stereocenters in closer proximity might be
separable. To our surprise, treatment of 12 with NaH and trans-
stilbene oxide in DMSO at 50 °C for 12 h gave only the N-
benzyl product 55 (12%) and unsaturated sulfoxide 56 (12%)
(see Scheme 10). The structure of 55 was confirmed by its
Scheme 10. Fragmentation of Alkoxide 53
the chiral auxiliary from 45 by hydrogenation (1−3 atm H2)
over Pd/C, Pd(OH)2/C, or PtO2. We obtained either
recovered starting material or complex mixtures, whose spectra
suggested that the tetrasubstituted double bond had been
partially reduced. We observed an apparent quartet at δ 0.43 (J
= 12 Hz) similar to that observed in 46 at δ 0.47, whereas the
most upfield ring proton of 45 is at δ 1.55.
Rychnovsky reduced 45 to 46 in 67% yield with sodium in
THF/2-propanol and found that reductive removal of the
auxiliary from 46 required forcing conditions (500 psi H2, 20%
Pd(OH)2 on carbon) to give a lycoperine precursor.25
Although the preparation of 12 from 46, which lacks both
the carbonyl group and tetrasubstituted double bond of 45,
would not be straightforward, we briefly examined hydro-
genolysis of 46 under milder conditions.
We observed two interesting reactions on attempted
hydrogenolysis of 46 over PtO2 under more moderate H2
pressures. Stirring a solution of 46 under H2 (50 psi, 3.3 atm)
with PtO2 in 10:1 MeOH/concd HCl for 40 h selectively
hydrogenated one of the two phenyl rings to give 47 in 69%
yield. This selectivity is precedented in the hydrogenation of 51
to give 52 over Rh/Al2O3 reported by Nugent.26 Under neutral
conditions and 1 atm H2 with PtO2 we observed the formation
of amide 50 in 73% yield after 40 h. Presumably, platinum
inserts in the benzylic carbon−oxygen bond to give 48, which
undergoes a β-hydride elimination to form amide 49. Reductive
elimination would then form 50. The acidic solution is
important for the selective hydrogenation of one benzene
ring to give 47, because hydrogenation of 46 under H2 (3 atm)
preparation from 12, sodium hydride and benzyl bromide.
Presumably, the anion of 12 undergoes the desired SN2
reaction with trans-stilbene oxide to give alkoxide 53, which
fragments to give benzaldehyde and carbanion 54, which is
protonated to give 55. Condensation of benzaldehyde with
DMSO is known to give 56.27
Unfortunately, we were unable to develop an efficient
synthesis of optically pure 12, but our attempts led to the
observation of the three unusual reactions, namely, the selective
hydrogenolysis of one of two benzene rings of aminal 46 to give
47, the Pt-catalyzed isomerization of 46 to amide 50, which
may explain why high-pressure conditions are needed for the
removal of this chiral auxiliary, and the unusual fragmentation
of alkoxide 53 to give benzaldehyde and 55.
Approaches To Introduce the Additional Hydroxy
Group of Sauroine. We then investigated the hydroxylation28
of 34 to give 57 (see eq 1), which could be elaborated to
7148
dx.doi.org/10.1021/jo300353t | J. Org. Chem. 2012, 77, 7143−7156

The Journal of Organic Chemistry
Featured Article
sauroine (4) by a route similar to that used for the synthesis of
7-hydroxylycopodine (5). Our initial studies were carried out
with model 13 with an N-methyl group (see Scheme 11). We
was recovered when we added MoO5·pyr·HMPA to the
enolate. Adding (8,8-dichlorocamphorylsulfonyl)oxaziridine
gave recovered starting material at −78 °C and a complex
mixture on warming to 0 °C. Silylation of the α′-enolate of 13
to give a silyl ether that could then be hydroxylated was not
practical since the required silyl ether would be a very
hydrolytically unstable 1-amino-3-silyloxy-1,3-diene. The for-
mation of phenol 59 from 13 could involve trapping of the
enolate with oxygen and a fragmentation process or more likely
an electron transfer reaction of the enolate to give an α-keto
radical which could then be oxidized further to give the phenol.
A related oxidation of a cyclohexenone to a phenol with KO-t-
Bu and oxygen that does not proceed through a hydroperoxide
has been reported.32
Scheme 11. Oxidation of 12 to Pyridine 58
We then tried to prevent formation of phenol 59 by trapping
the intermediates with TBSOTf. Vinylogous amide 13 was
treated with NaHMDS (2.2 equiv) in THF at −78 °C, oxygen
was bubbled through the solution for 50 min, and excess
TBSOTf was added. The NMR spectrum of the crude product
indicated the presence of a 1:2:2 mixture of 60, 61, and 62 in
about 50% yield. Flash chromatography provided phenyl silyl
ether 60 (10%), which was hydrolyzed with 3 M HCl to give 59
(90% yield) and 61 (22% yield). The other diastereomer 62
decomposed on chromatography. Presumably, deprotonation
occurs at the γ-position to give the thermodynamic enolate,
which is hydroxylated at the α-position to give the α-
hydroperoxy-β,γ-unsaturated ketone, which is enolized by
excess base at the α′-position. Trapping with TBSOTf will
give bis-silyl ethers 61 and 62.
MMX calculations with conformational searching were
carried out on the bis TMS ethers corresponding to bis TBS
ethers 62 and 61 using PCMODEL 9.3. The Boltzmann-
averaged coupling constants between the doubly allylic methine
hydrogen and the alkene hydrogens were calculated to be 3.1
and 3.1 Hz in the bis-TMS ether corresponding to 62, in which
the methyl and peroxy groups are trans, and 4.3 and 4.3 Hz in
the bis-TMS ether corresponding to 61, in which the methyl
and peroxy groups are cis. The stereochemistry of 62 and 61 is
tentatively assigned on the basis of the observed coupling
constants of 2 and 2 Hz in 62 and 4.4 and 4.4 Hz in 61.
We examined the deprotection of 61 as a means of
confirming the structure assignment. Treatment of 61 with
pyridine (2.5 equiv) and pyrdine·(HF)x (3 equiv) in CDCl3 for
30 min afforded a compound in 40% yield whose structure was
eventually established as 65 by careful analysis of 1D and 2D
NMR spectra (see Scheme 13). MMX calculations with
conformational searching were carried out on the analogue of
65 with TMS rather than TBS ethers using PCMODEL 9.3.
The s-trans amide conformer is calculated to be 5.4 kcal/mol
more stable than the s-cis amide conformer. The observed and
(calculated) coupling constants between H3a and H4 [13.2
(12.1) Hz], H3b and H4 [4.4 (4.1) Hz] and H4 and H5 [10.0,
(8.6)] correspond closely. A plausible pathway for the
conversion of 61 to 65 involves the hydrolysis of the peroxy
silyl ether and protonation of the enamine to give cation 63,
which cyclizes to give dioxetane 64, which fragments33 to give
hexahydro-2,7-azacinedione 65. A related oxidative cleavage of
the ring fusion double bond of 1-acetyl-1,2,3,4,5,6,7,8-
octahydro-6-methylquinoline with RuO4 afforded 1-acetyl-
(octahydro)-5-methyl-2,7-azacinedione.34
initially examined the reaction of 13 with Mn(OAc)3 in
benzene at elevated temperatures because Watt and Demir had
shown that these conditions introduce an α′-acetoxy group
onto α,β-unsaturated ketones or β-alkoxy- α,β-unsaturated
ketones.29 Unfortunately, the vinylogous amide 13 reacted
differently. Microwave heating a solution of 13 with Mn(OAc)3
in benzene at 150 °C for 20 min afforded a mixture of
recovered 13 (35%), demethylated vinylogous amide 12 (20%),
and pyridine 5830 (35%). We suspected that the slow step was
the demethylation to give 12 and confirmed this by the
oxidation of 12 with Mn(OAc)3 in benzene which proceeded
efficiently to give 58 in 65% yield with microwave heating for
20 min at only 90 °C. This facile oxidation with Mn(OAc)3 to
generate the pyridine is synthetically useful but does not
provide a procedure for the desired α′-hydroxylation.
We then attempted to form the α′-enolate and trap it with
either oxygen, MoO5·pyr·HMPA, or a sulfonyloxaziridine to
introduce the α′-hydroxy group.31 Treatment of 13 with 1.5
equiv of KHMDS in THF at −78 °C and then stirring under an
oxygen atmosphere led to phenol 59 in 20% yield rather than
the desired hydroxy compound (see Scheme 12). Similar
results were obtained with NaHMDS. Only starting material
Scheme 12
Although we have not achieved the desired α′-hydroxylation
of 34 to give sauroine precursor 57, we have found novel
procedures that oxidize vinylogous amide 12 to keto pyridine
7149
dx.doi.org/10.1021/jo300353t | J. Org. Chem. 2012, 77, 7143−7156

The Journal of Organic Chemistry
Featured Article
δ (ppm downfield from tetramethylsilane). Coupling constants are
reported in hertz with multiplicities denoted as s (singlet), d (doublet),
t (triplet), q (quartet), p (pentet), m (multiplet), and br (broad). IR
spectra were acquired on an FT-IR spectrometer and are reported in
wavenumbers (cm−1). High-resolution mass spectra were obtained
using electrospray ionization (ESI).
Scheme 13
2,3,4,6,7,8-Hexahydro-7-methyl-5(1H)-quinolinone (12).7b,9
A solution of 5-methylcyclohexane-1,3-dione (11) (1.20 g, 9.5
mmol), 3-bromopropylammonium bromide (10) (2.17 g, 9.9 mmol,
1.04 equiv), and 2,6-lutidine (3.2 mL, 2.94 g, 27.5 mmol, 3.0 equiv) in
6 mL of EtOH was heated at 130 °C for 20 min in a microwave
reactor. The reaction mixture was quenched by addition of 50 mL of 1
M NaOH and extracted with CH2Cl2 (50 mL × 3). The combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated to about 5 mL. Acetonitrile (30 mL × 2) was added, and
the resulting solution was concentrated again to give 1.50 g of crude
12 as a brown powder, which was directly used in the next step
without further purification. A small portion was purified by flash
chromatography on silica gel (100:1:1 EtOAc/MeOH/NEt3) to give
1
12 as a white solid: mp 173−174 °C; H NMR 4.56 (br s, 1, NH),
58 and N-methyl vinylogous amide 13 to phenol 59 and that
oxygenate 13 at the α- rather than α′-position to give 61 and
62. Other approaches for the synthesis of 57 are currently being
explored.
3.32−3.20 (m, 2), 2.41 (dd, 1, J = 16.8, 3.0), 2.34 (apparent t, 2, J =
6.4), 2.22−2.07 (m, 3), 2.02 (dd, 1, J = 16.8, 11.0), 1.86−1.73 (m, 2),
1.04 (d, 3, J = 6.1); 13C NMR 194.2, 158.6, 104.2, 44.8, 41.5, 37.5,
29.0, 21.2, 21.1, 18.9; IR 3239, 3081, 1573, 1526 (strong).
In conclusion, we have completed a seven-step synthesis of
( )-7-hydroxylycopodine (5) from 12 that proceeds in 5%
overall yield, making it readily available for biological
evaluation. The key step in the synthesis is the Prins reaction
of 36a or 36b in 60% sulfuric acid to give the key tricyclic
intermediate 6 with complete control of the ring fusion
stereochemistry. We also developed a one-pot procedure to
orthogonally protect the primary alcohol of 6 as an acetate and
the tertiary alcohol as a methylthiomethyl ether giving 40,
which was converted to 7-hydroxydehydrolycopodine 42 by
heating with KO-t-Bu and benzophenone in benzene followed
by acidic workup. 7-Hydroxylycopodine inhibits eel and human
acetylcholinesterase with an IC50 of 1.67 and 2.21 mM,
respectively.
We were unable to develop an efficient synthesis of optically
pure 12, but our attempts led to the observation of the three
unusual reactions, namely, the selective hydrogenolysis of one
of two benzene rings of aminal 46 to give 47, the Pt-catalyzed
isomerization of aminal 46 to amide 50, and the unusual
fragmentation of alkoxide 53 to give benzaldehyde and 55.
Although we have not achieved the desired α′-hydroxylation of
34 to give sauroine precursor 57, we have found novel
procedures that oxidize vinylogous amide 12 to keto pyridine
58 and N-methyl vinylogous amide 13 to phenol 59 and that
oxygenate 13 at the α- rather than α′-position to give 61 and
62.
2,3,4,6,7,8-Hexahydro-1,7-dimethyl-5(1H)-quinolinone
(13).7b To a suspension of NaH (60% in mineral oil, 454 mg, 11.3
mmol) in 2 mL of THF was added dropwise a solution of 750 mg of
crude 12 in 10 mL of THF at 0 °C. The mixture was stirred at 0 °C for
10 min, and 0.71 mL (1.62 g, 11.4 mmol) of MeI was added dropwise.
The reaction was warmed to room temperature and stirred for 4 h.
The reaction was quenched by addition of water (30 mL) at 0 °C. The
mixture was extracted with EtOAc (20 mL × 3). The combined
organic layers were washed with brine (60 mL), dried over Na2SO4,
and concentrated. Flash chromatography of the residue on silica gel
(100:1:1 EtOAc/MeOH/NEt3) gave 409 mg (48% from 11) of 13 as
1
a white solid: mp 46−47 °C; H NMR 3.24−3.17 (m, 2), 2.99 (s, 3),
2.55 (dd, 1, J = 15.9, 4.3), 2.46−2.23 (m, 3), 2.16−1.94 (m, 3), 1.80−
1.71 (m, 2), 1.06 (d, 3, J = 6.1); 13C NMR 193.4, 159.6, 105.6, 51.3,
43.9, 38.5, 35.1, 28.8, 21.5, 21.1, 19.5; IR 1611 (weak), 1551 (strong).
trans-1,2,3,4,6,7,8,8a-Octahydro-1,7-dimethyl-5-(1-methyle-
thoxy)-8a-(2-propynyl)quinoline (16). To a resealable tube were
added 409 mg (2.3 mmol) of 13 and 3 mL (5.1 g, 30 mmol, 13 equiv)
of 2-iodopropane. The reaction mixture was sealed and heated at 55
°C for 42 h, diluted with 9 mL of benzene, and concentrated to
remove excess 2-iodopropane to give crude cation 14.
To a solution of the residue (cation 14) in 9 mL of THF was added
4.1 mL (1.8 equiv) of propargylmagnesium bromide solution (see
below for preparation) at 0 °C. The mixture was kept at 0 °C for 1 h.
The reaction was quenched by addition of water (1 mL) at −78 °C
and filtered through a pad of Celite. The filtrate was diluted with
saturated ammonium chloride solution (20 mL) and extracted with
EtOAc (30 mL × 3). The combined organic layers were washed with
brine (100 mL), dried over Na2SO4, and concentrated. Flash
chromatography of the residue on silica gel (3:2 hexanes/EtOAc)
gave 251 mg (42% from 13) of 16 as a pale yellow oil: 1H NMR 4.08
(heptet, 1, J = 6.1), 3.01−2.93 (m, 1), 2.74 (dd, 1, J = 17.2, 2.4), 2.69−
2.57 (m, 2), 2.43 (dd, 1, J = 17.2, 2.4), 2.38 (s, 3), 2.39−2.35 (m, 1),
2.12−2.03 (m, 2), 2.03 (dd, 1, J = 2.4), 1.87−1.77 (m, 1), 1.68−1.46
(m, 3), 1.28−1.22 (m, 1), 1.20 (d, 3, J = 6.1), 1.14 (d, 3, J = 6.1), 1.01
(d, 3, J = 6.7); 13C NMR 145.3, 121.7, 82.7, 71.5, 68.7, 59.3, 50.8, 43.9,
38.7, 35.0, 25.8, 25.7, 22.9, 22.3, 22.1, 20.8, 19.5; IR 3308, 2112
(weak), 1674 (weak), 1115, 1070; HRMS (ESI) calcd for C17H28NO
(MH+) 262.2165, found 262.2168.
EXPERIMENTAL SECTION
■
General Experimental Methods. Reactions were conducted in
flame- or oven-dried glassware under a nitrogen atmosphere and were
stirred magnetically. The phrase “concentrated” refers to removal of
solvents by means of a rotary-evaporator attached to a diaphragm
pump (15−60 Torr) followed by removal of residual solvents at <1
Torr with an vacuum pump. Flash chromatography was performed on
silica gel 60 (230−400 mesh). Analytical thin-layer chromatography
(TLC) was performed using silica gel 60 F-254 precoated glass plates
(0.25 mm). TLC plates were analyzed by short wave UV illumination
or by spraying with permanganate solution (5 g KMnO4 in 495 mL
water). THF and ether were dried and purified by distillation from
sodium/benzophenone. Et3N, pyridine, acetonitrile, and benzene were
distilled from CaH2. 1H and 13C NMR spectra were obtained on a 400
MHz spectrometer in CDCl3 with tetramethylsilane as internal
standard unless specifically indicated. Chemical shifts are reported in
Propargylmagnesium Bromide. To a flame-dried flask was
added 1.0 g of Mg, 24 mg of HgCl2, and 4 mL of ether. Propargyl
bromide (0.1 mL, 80% in toluene) was added, and the reaction was
initiated by heating with a heat gun. The mixture was cooled to 0 °C,
and a solution of 1.4 mL of propargyl bromide (80% in toluene) in 8
mL of ether was slowly added over 1 h. The reaction was stirred at 0
7150
dx.doi.org/10.1021/jo300353t | J. Org. Chem. 2012, 77, 7143−7156

The Journal of Organic Chemistry
Featured Article
°C for 0.5 h and allowed to settle at 0 °C for 0.5 h to give a ∼1 M
solution.
The mixture was stirred at room temperature for 1 h. A solution of 27
(20 mg, 0.15 mmol) in 1 mL of CH2Cl2 was added dropwise. The
resulting mixture was stirred at room temperature for 20 h. The
reaction was quenched by addition of 1 M HCl solution (5 mL) and
extracted with CH2Cl2 (5 mL × 3). The combined organic layers were
dried over Na2SO4 and concentrated. Flash chromatography of the
residue on silica gel (25:1 hexanes/EtOAc) gave 21 mg (71% from 27)
of 31 as a colorless oil: 1H NMR 5.72 (s, 1), 3.55 (dq, 1, J = 9, 7), 3.45
(dq, 1, J = 9, 7), 2.60 (br dd, 1, J = 18.4, 6.8), 2.40−2.32 (m, 1), 2.02
(d, 1, J = 18.4), 1.96 (br d, 1, J = 12.0), 1.69−1.40 (m, 7), 1.19 (t, 3, J
= 7.2); 13C NMR 133.7, 130.4, 76.2, 57.5, 39.0, 35.5, 35.1, 32.7, 30.4,
20.6, 16.2; IR 1648, 1103, 1087, 1052, 945, 820, 745, 661; HRMS
(ESI) calcd for C11H18ClO (MH+) 201.1041, found 201.1039.
1-(3-(Dimethylethyl)dimethylsiloxypropyl)-2,3,4,6,7,8-hexa-
hydro-7-methyl-5(1H)-quinolinone (34). To a suspension of NaH
(60% in mineral oil, 650 mg, 16 mmol) in 12 mL of 1:1 THF/DMF at
0 °C was added dropwise a solution of crude 12 (1.50 g, from 9.5
mmol of 11) in 12 mL of 1:1 THF/DMF. The mixture was stirred at 0
°C for 10 min, and 1-((dimethylethyl)dimethylsiloxy)-3-iodopro-
pane19 (4.50 g, 15 mmol) was added dropwise. The reaction mixture
was warmed to room temperature and stirred for 18 h. The reaction
was quenched by addition of water (20 mL) at 0 °C. The mixture was
extracted with EtOAc (50 mL × 3). The combined organic layers were
washed with brine (150 mL × 5), dried over Na2SO4, and
concentrated. Flash chromatography of the residue on silica gel
(100:1:1 EtOAc/MeOH/NEt3) gave 1.60 g (50% from 11) of 34 as a
pale yellow oil: 1H NMR 3.62 (t, 2, J = 5.1), 3.40 (dt, 1, J = 14.6, 7.0),
3.30 (dt, 1, J = 14.6, 7.0), 3.27−3.12 (m, 2), 2.59 (br d, 1, J = 12.8),
2.42−2.24 (m, 3), 2.12−1.96 (m, 3), 1.86−1.72 (m, 4), 1.03 (d, 3, J =
6.1), 0.89 (s, 9), 0.05 (s, 6); 13C NMR 193.6, 159.3, 105.5, 59.6, 49.0,
47.6, 44.1, 34.5, 31.5, 28.9, 25.8 (3 C), 21.4, 21.2, 20.0, 18.1, −5.4 (2
C); IR 1613, 1551 (strong); HRMS (ESI) calcd for C19H36NO2Si
(MH+) 338.2515, found 338.2519.
1-(2,3,4,6,7,8-Hexahydro-1-methyl-5(1H)-quinolinylidene)-
2-propanone (20). To a resealable tube was added a solution of 88
mg (0.34 mmol) of 16 in 1 mL of MeOH and a solution of 12 mg
(0.055 mmol, 0.16 equiv) of HgO in 1 mL of 1 M H2SO4. The
reaction was sealed and heated at 65 °C for 10 h. The reaction was
cooled to room temperature and diluted with saturated NaHCO3
solution (20 mL). The mixture was extracted with EtOAc (20 mL ×
3). The combined organic layers were dried over Na2SO4 and
concentrated. Flash chromatography of the residue on silica gel
(100:1:0.5 EtOAc/MeOH/NEt3) gave 29 mg (39% from 16) of 20 as
a yellow oil: 1H NMR 5.64 (s, 1), 3.78 (dd, 1, J = 17.2, 2.4), 3.28−3.12
(m, 2), 2.93 (s, 3), 2.44 (dd, 1, J = 12.0, 2.9), 2.28 (ddd, 1, J = 14.0,
4.8, 4.8), 2.20−2.10 (m, 1), 2.13 (s, 3), 2.05 (dd, 1, J = 17.2, 11.6),
1.98−1.70 (m, 4), 1.05 (d, 3, J = 6.7); 13C NMR 196.4, 157.9, 153.8,
107.5, 103.3, 50.8, 38.6, 35.6, 35.1, 32.0, 28.5, 22.7, 21.7, 21.6; IR 1637
(weak), 1484 (strong), 1400 (strong); HRMS (ESI) calcd for
C14H22NO (MH+) 220.1696, found 220.1694.
( )- (4aS,5R,7S,8aS)-Octahydro-5-hydroxy-1,7-dimethyl-1H-
5,8a-propanoquinolin-10-one (26). A solution of 163 mg (0.62
mmol) of 16 in 5 mL of 3:2 concd H2SO4/H2O was stirred at room
temperature for 8 h. The reaction mixture was quenched by addition
of water (5 mL) at 0 °C and neutralized with 6 M NaOH until the pH
reached 11. The mixture was saturated with NaCl and extracted with
CH2Cl2 (30 mL × 5). The combined organic layers were dried over
Na2SO4 and concentrated. Flash chromatography of the residue on
silica gel (100:1:1 EtOAc/MeOH/NEt3) gave 104 mg (70% from 16)
1
of 26 as a white solid: mp 124−125 °C; H NMR 2.69 (br d, 1, J =
12.8, H9eq), 2.66 (br d, 1, J = 17.1, H4ax), 2.57 (dd, 1, J = 17.1, 1.4,
H6ax), 2.46 (ddd, 1, J = 12.8, 12.8, 3.1, H9ax), 2.40 (d, 1, J = 17.1, H6eq),
2.24 (s, 3, Me1), 2.18 (d, 1, J = 17.1, H4eq), 2.10 (br d, 1, J = 12.8,
H11eq), 2.09 (br d, 1, J = 12.8, H14eq), 1.85 (br dd, 1, J = 12.8, 4.4,
H8eq), 1.82 (br ddd, 1, J = 12.8, 3.2, 3.2, H10eq), 1.70 (ddddd, 1, J =
12.8, 12.8, 12.8, 4.0, 4.0, H10ax), 1.61 (br d, 1, J = 12.8, H12, showed
“W” couplings to H4eq and H6eq in COSY), 1.54−1.42 (m, 1, H15),
1.41 (br, 1, w1/2 = 5 Hz, OH), 1.34−1.22 (m, 2, H8ax, H11ax), 1.08
(ddd, 1, J = 12.8, 12.8, 1.6, H14ax), 0.92 (d, 3, J = 6.7, Me16); 13C NMR
210.0, 72.2, 58.7, 50.6, 50.5, 50.3, 50.2, 46.7, 37.22, 37.19, 25.8, 25.2,
22.4, 20.0; IR 3433 (broad), 1703 (strong), 1032; HRMS (ESI) calcd
for C14H24NO2 (MH+) 238.1807, found 238.1803.
trans-1,2,3,4,6,7,8,8a-Octahydro-1-(3-(dimethylethyl)-
dimethylsiloxypropyl)-7-methyl-5-(1-methylethoxy)-8a-(2-
propynyl)quinoline (36a). To a resealable tube were added 1.60 g
(4.7 mmol) of 34 and 9 mL (15.3 g, 90 mmol, 19 equiv) of 2-
iodopropane. The reaction mixture was sealed and heated at 55 °C for
42 h, diluted with 27 mL of benzene, and concentrated to remove
excess 2-iodopropane to give cation 35.
To a solution of the residue (cation 35) in 24 mL of THF, 8.5 mL
(1.8 equiv) of propargylmagnesium bromide solution (for the
preparation of propargylmagnesium bromide see the preparation of
16) was added at 0 °C. The mixture was kept at 0 °C for 1 h. The
reaction was quenched by addition of water (1 mL) at −78 °C and
filtered through a pad of Celite. The filtrate was diluted with saturated
ammonium chloride solution (30 mL) and extracted with EtOAc (40
mL × 3). The combined organic layers were washed with brine (100
mL), dried over Na2SO4, and concentrated. Flash chromatography of
the residue on silica gel (8:1 hexanes/EtOAc) gave 798 mg (40% from
Lycopodine numbering is used so the methyl group is carbon 1 and
there are no carbons 2 and 3. A 1D NOESY experiment with
irradiation of H6ax at δ 2.57 showed a strong NOE to H6eq at δ 2.40
and weak NOEs to H4ax at δ 2.66 and H11ax at δ 1.28. A 1D NOESY
experiment with irradiation of H4eq at δ 2.18 showed a strong NOE to
H4ax at δ 2.66 and a weak NOE to H14eq at δ 2.09. A 1D NOESY
experiment with irradiation of H14ax at δ 1.08 showed a strong NOE to
H14eq at δ 2.09 and weak NOEs to H12eq at δ 1.61, Me16 at δ 0.92, Me1
at δ 2.24, and H8ax at δ 1.28.
1-Hydroxybicyclo[3.3.1]nonan-3-one (28). A solution of
propargyl ketone 2713 (98 mg, 0.72 mmol) in 2 mL of 3:2 concd
H2SO4/H2O was stirred at room temperature for 16 h. The reaction
mixture was quenched by addition of water (10 mL) at 0 °C and
neutralized with 6 M NaOH until the pH reached 11. The mixture was
saturated with NaCl and extracted with EtOAc (20 mL × 3). The
combined organic layers were dried over Na2SO4 and concentrated.
Flash chromatography of the residue on silica gel (1:3 hexanes/
EtOAc) gave 72 mg (76% from 27) of 28 as a white solid: mp 236−
238 °C (lit.14a mp 233−240 °C; lit.14b mp 228−231 °C; lit.14c mp
220−223 °C); 1H NMR 2.60 (ddd, 1, J = 16.0, 2.0, 2.0), 2.50 (br s, 1,
OH), 2.47 (d, 1, J = 16.0), 2.42 (dd, 1, J = 16.4, 6.0), 2.32 (dd, 1, J =
16.4, 1.8), 1.98 (dddd, 1, J = 12.0, 2.8, 2.6, 1.8), 1.87−1.76 (m, 3),
1.75−1.46 (m, 4), 1.34 (ddddd, 1, J = 13.6, 13.6, 13.6, 4.4, 4.4); 13C
NMR 211.0, 71.1, 55.2, 45.6, 41.3, 40.6, 30.64, 30.58, 20.1; IR 3421
1
34) of 36a as a pale yellow oil: H NMR 4.08 (heptet, 1, J = 6.1),
3.68−3.56 (m, 2), 3.11 (ddd, 1, J = 12.8, 7.9, 7.9), 3.02−2.93 (m, 1),
2.81 (br d, 1, J = 12.2), 2.68 (dd, 1, J = 17.1, 2.4), 2.47 (dd, 1, J = 17.1,
2.4), 2.42 (ddd, 1, J = 12.2, 12.2, 2.4), 2.34 (br d, 1, J = 12.5), 2.16−
2.00 (m, 3), 1.97 (dd, 1, J = 2.4, 2.4), 1.82−1.72 (m, 1), 1.67−1.50 (m,
4), 1.48−1.37 (m, 1), 1.21 (dd, 1, J = 12.5, 12.5), 1.18 (d, 3, J = 6.1),
1.16 (d, 3, J = 6.1), 1.00 (d, 3, J = 6.1), 0.90 (s, 9), 0.05 (s, 6); 13C
NMR 145.1, 121.3, 83.1, 70.9, 68.6, 61.2, 59.8, 47.0, 46.4, 44.0, 34.7,
32.7, 26.0, 25.9 (3 C), 25.6, 22.8, 22.4, 22.3, 21.2, 20.4, 18.3, −5.26,
−5.29; IR 3311, 2113 (weak), 1673 (weak), 1253, 1097 (strong);
HRMS (ESI) calcd for C25H46NO2Si (MH+) 420.3298, found
420.3298.
trans-1,2,3,4,6,7,8,8a-Octahydro-1-(3-(dimethylethyl)-
dimethylsiloxypropyl)-7-methyl-5-(1-methylethoxy)-8a-(3-tri-
methylsilyl-2-propynyl)quinoline (36b). To a resealable tube was
added 1.60 g (4.7 mmol) of 34 and 9 mL (15.3 g, 90 mmol, 19 equiv)
of 2-iodopropane. The reaction mixture was sealed and heated at 55
°C for 42 h, diluted with 27 mL of benzene, and concentrated to
remove excess 2-iodopropane to give cation 35.
1
(broad), 1693, 1229, 1083, 991, 932, 732. The H NMR, 13C NMR,
and IR spectral data are identical to those previously reported.14a
3-Chloro-1-ethoxybicyclo[3.3.1]non-2-ene (31). To 1 mL of
CH2Cl2 were added EtAlCl2 (0.2 mL, 0.9 M in heptane, 0.18 mmol,
1.2 equiv) and EtOH (10.5 μL, 0.18 mmol, 1.2 equiv) successively.
7151
dx.doi.org/10.1021/jo300353t | J. Org. Chem. 2012, 77, 7143−7156

The Journal of Organic Chemistry
Featured Article
The residue (cation 35) was taken up in 18 mL of THF and the
resulting solution was added slowly to a solution of (trimethylsilyl)-
propargyllithium (see below) at −78 °C. The mixture was kept at −78
°C for 2 h and slowly warmed to room temperature over 4 h. The
reaction was quenched by addition of saturated ammonium chloride
solution (20 mL) and water (10 mL). The mixture was extracted with
EtOAc (50 mL × 3). The combined organic layers were washed with
brine (100 mL), dried over Na2SO4, and concentrated. Flash
chromatography of the residue on silica gel (12:1 hexanes/EtOAc)
gave 1.19 g (51% from 34) of 36b as a pale yellow oil: 1H NMR 4.07
(heptet, 1, J = 6.1), 3.68−3.56 (m, 2), 3.10 (ddd, 1, J = 13.4, 7.9, 7.9),
2.92−3.00 (m, 1), 2.83−2.76 (m, 1), 2.75 (d, 1, J = 17.4), 2.46 (d, 1, J
= 17.4), 2.40 (ddd, 1, J = 12.4, 12.4, 2.4), 2.36 (br d, 1, J = 12.2),
2.16−2.02 (m, 3), 1.82−1.71 (m, 1), 1.68−1.50 (m, 4), 1.46−1.35 (m,
1), 1.17 (d, 3, J = 6.1), 1.16 (dd, 1, J = 12.2, 12.2), 1.16 (d, 3, J = 6.1),
0.99 (d, 3, J = 6.1), 0.90 (s, 9), 0.12 (s, 9), 0.04 (s, 6); 13C NMR 144.9,
121.6, 106.3, 87.3, 68.6, 61.2, 59.9, 47.0, 46.3, 43.8, 34.6, 32.7, 26.1,
26.0 (3 C), 25.6, 22.9, 22.4, 22.3, 21.7, 21.2, 18.3, −0.1 (3 C), −5.23,
−5.25; IR 2954, 2856, 2171, 1676 (weak), 1250, 1099; HRMS (ESI)
calcd for C28H54NO2Si2 (MH+) 492.3693, found 492.3692.
CH2Cl2 (20 mL × 3). The combined organic layers were dried over
Na2SO4 and concentrated to about 5 mL. Toluene (6 mL) was added
and the resulting solution was concentrated again to give 115 mg of
crude ( )-(4aS,5R,7S,8aS)-1-(3-acetoxypropyl)-octahydro-5-hydroxy-
7-methyl-1H-5,8a-propanoquinolin-10-one (39) as a yellow sticky oil,
which was directly used in the next step without further purification.
To a solution of 115 mg of the crude primary acetate 39 in 3 mL
(3.30 g, 42.2 mmol) of DMSO was added 3 mL (3.24 g, 31.8 mmol) of
acetic anhydride. The mixture was stirred at room temperature for 72
h. The reaction was quenched by addition of saturated NaHCO3
solution (30 mL) and extracted with extracted with CH2Cl2 (30 mL ×
5). The combined organic layers were dried over Na2SO4 and
concentrated. Most of the remaining DMSO was removed by blowing
air on the compound for 6 h. Flash chromatography of the residue on
silica gel (1:1 hexanes/EtOAc) gave 136 mg (90% from 6) of 40 as a
pale yellow oil.
Alternatively, a solution of 334 mg (1.2 mmol) of 6 in 8 mL (8.64 g,
84.7 mmol, 70 equiv) of acetic anhydride was stirred overnight under
nitrogen. Eight milliliters (8.80 g, 113 mmol, 94 equiv) of DMSO was
added, and the reaction mixture was stirred for 72 h. The reaction was
quenched by addition of saturated NaHCO3 solution (80 mL) and
extracted with CH2Cl2 (100 mL × 5). The combined organic layers
were dried over Na2SO4 and concentrated. Most of the remaining
DMSO was removed by blowing air on the compound for 6 h. Flash
chromatography of the residue on silica gel (1:1 hexanes/EtOAc) gave
409 mg (90% from 6) of 40 as a pale yellow oil: 1H NMR 4.52 (s, 2),
4.19−4.06 (m, 2), 2.88 (ddd, 1, J = 13.4, 7.9, 7.9), 2.82 (br d, 1, J =
12.3), 2.75 (d, 1, J = 17.0), 2.57 (d, 1, J = 16.9), 2.54 (d, 1, J = 16.9),
2.26 (ddd, 1, J = 12.3, 12.3, 2.8), 2.19 (s, 3), 2.08 (d, 1, J = 17.0), 2.04
(s, 3), 2.05−1.86 (m, 4), 1.81−1.64 (m, 4), 1.56 (ddddd, 1, J = 12.8,
12.8, 12.8, 4.3, 4.3), 1.49−1.33 (m, 2), 1.24 (dddd, 1, J = 13.1, 13.1,
13.1, 3.7), 0.96 (dd, 1, J = 12.2, 12.2), 0.92 (d, 3, J = 5.5); 13C NMR
210.0, 171.1, 77.7, 66.0, 62.4, 58.9, 48.3, 47.8, 47.1, 46.6, 45.0, 44.6,
38.8, 27.8, 25.4, 25.2, 22.7, 21.0, 20.3, 14.6; IR 1735 (strong), 1705
(strong), 1553, 1241 (strong), 1043 (strong); HRMS (ESI) calcd for
C20H34NO4S (MH+) 384.2209, found 384.2209.
(Trimethylsilyl)propargyllithium. To 1-trimethylsilylpropyne
(1.10 mL, 7.1 mmol, 1.5 equiv) in 7 mL of THF was slowly added
n-BuLi (1.6 M, 4.70 mL, 1.6 equiv) at −78 °C. The reaction was kept
at −78 °C for 5 min, warmed to −30 °C over 15 min, and kept at 0 °C
for 1 h.
(
)-(4aS,5R,7S,8aS)-Octahydro-5-hydroxy-1-(3-hydroxy-
propyl)-7-methyl-1H-5,8a-propanoquinolin-10-one (6). A sol-
ution of 798 mg (1.9 mmol) of 36a in 27 mL of 3:2 concd H2SO4/
H2O was stirred at room temperature for 8 h. The reaction mixture
was quenched by addition of water (30 mL) at 0 °C and neutralized
with 6 M NaOH until the pH reached 11. The mixture was saturated
with NaCl and extracted with CH2Cl2 (90 mL × 5). The combined
organic layers were dried over Na2SO4 and concentrated. Flash
chromatography of the residue on silica gel (100:1:1 EtOAc/MeOH/
NEt3) gave 256 mg (48% from 36a) of 6 as a white solid.
A solution of 1.17 g (2.4 mmol) of 36b in 40 mL of 3:2 concd
H2SO4/H2O was stirred at room temperature for 10 h. The reaction
mixture was quenched by addition of water (40 mL) at 0 °C and
neutralized with 6 M NaOH until the pH reached 11. The mixture was
saturated with NaCl and extracted with CH2Cl2 (120 mL × 5). The
combined organic layers were dried over Na2SO4 and concentrated.
Flash chromatography of the residue on silica gel (100:1:1 EtOAc/
MeOH/NEt3) gave 334 mg (50% from 36b) of 6 as a white solid: mp
157−158 °C; 1H NMR 5.92 (br, 1, w1/2 = 16 Hz, OH), 3.86−3.75 (m,
2, 2 H3), 3.16−3.04 (m, 2, H1, H9eq), 2.66 (d, 1, J = 17.1, H4ax), 2.56
(d, 1, J = 16.8, H6ax), 2.49 (br, 1, w1/2 = 11 Hz, OH), 2.39 (d, 1, J =
16.8, H6eq), 2.29−2.14 (m, 4, H1, H11eq, H9ax, H14eq), 2.10 (d, 1, J =
17.1, H4eq), 2.02−1.82 (m, 3, H2, H8eq, H10eq), 1.62−1.40 (m, 4, H2,
H10ax, H12, H15), 1.35−1.22 (m, 2, H8ax, H11ax), 1.17 (dd, 1, J = 12.8,
12.8, H14ax), 0.95 (d, 3, J = 6.1, Me16); 13C NMR 209.6, 71.9, 64.3,
59.3, 51.0, 50.4, 49.9, 49.4, 46.5, 46.4, 38.2, 27.6, 25.8, 25.0, 22.4, 19.9;
IR 3372 (broad), 1702 (strong), 1055, 1032; HRMS (ESI) calcd for
C16H28NO3 (MH+) 282.2069, found 282.2067.
Lycopodine numbering is used so the hydroxypropyl group contains
carbon 1−3. A 1D NOESY experiment with irradiation of H4ax at δ
2.66 showed a strong NOE to H4eq at δ 2.10 and weak NOEs to H9ax at
δ 2.24 and H11ax at δ 1.28. A 1D NOESY experiment with irradiation
of H6ax at δ 2.56 showed a strong NOE to H6eq at δ 2.39 and a weak
NOE to H11ax at δ 1.28. A 1D NOESY experiment with irradiation of
H6eq at δ 2.39 showed a strong NOE to H6ax at δ 2.56 and a weak NOE
to H8eq at δ 1.87. A 1D NOESY experiment with irradiation of H14ax at
δ 1.17 showed a strong NOE to H14eq at δ 2.19 and weak NOEs to
H12eq at δ 1.58 and Me16 at δ 0.94.
(
)-(4aS,5R,7S,8aS)-Octahydro-1-(3-hydroxypropyl)-5-
(methylthio)methoxy-7-methyl-1H-5,8a-propanoquinolin-10-
one (41). To a solution of 136 mg (0.36 mmol) of 40 in 6 mL of
MeOH at 0 °C was added 400 mg (2.9 mmol, 8.0 equiv) of K2CO3.
The reaction was kept at 0 °C for 2 h and filtered. The filtrate was
concentrated and diluted with 10 mL of saturated NaHCO3 solution.
The mixture was extracted with CH2Cl2 (10 mL × 4). The combined
organic layers were dried over Na2SO4 and concentrated. Flash
chromatography of the residue on silica gel (100:1:1 EtOAc/MeOH/
NEt3) gave 111 mg (92%) of the primary alcohol 41 as a pale yellow
sticky oil: 1H NMR 5.47 (br, 1, w1/2 = 12 Hz, OH), 4.47 (s, 2), 3.81−
3.70 (m, 2), 3.11−2.96 (m, 2), 2.66 (d, 1, J = 17.1), 2.53 (s, 2), 2.23−
2.10 (m, 3), 2.14 (s, 3), 2.06 (d, 1, J = 17.1), 2.02 (dd, 1, J = 12.0, 2.8),
1.97−1.89 (m, 2), 1.79 (ddd, 1, J = 10.4, 2.7, 2.7), 1.70 (dd, 1, J = 12.5,
3.2), 1.52 (ddddd, 1, J = 13.2, 13.2, 13.2, 4.0, 4.0), 1.44−1.31 (m, 3),
1.22 (dddd, 1, J = 12.8, 12.8, 12.8, 3.6), 1.12 (dd, 1, J = 11.6), 0.92, (d,
3, J = 5.5); 13C NMR 209.0, 77.5, 66.0, 64.3, 59.0, 49.2, 48.2, 48.1,
46.5, 46.1, 44.5, 38.4, 27.9, 25.5, 24.9, 22.5, 20.0, 14.5; IR 3395
(broad), 1703 (strong), 1041 (strong); HRMS (ESI) calcd for
C18H32NO3S (MH+) 342.2103, found 342.2104.
( )-(8aS,9R,11S,12aR)- 3,4,6,7,8,8a,9,10,11,12-Decahydro-9-
hydroxy-11-methyl-1,9-ethanobenzo[i]quinolizin-14-one (42).
To a resealable tube was added 100 mg (0.26 mmol) of 40, 180 mg
(1.60 mmol, 6.0 equiv) of KO-t-Bu, 780 mg (4.3 mmol, 16 equiv) of
benzophenone, and 3 mL of dry benzene. The mixture was subjected
to three cycles of freeze−pump−thaw degas protocol and was sealed
and heated at 110 °C for 1 h. After cooling to room temperature, the
reaction was quenched by addition of 10 mL of 3 M HCl solution. The
mixture was extracted with ether (10 mL × 2). The aqueous layer was
neutralized with Na2CO3 powder until pH 11 was reached. The
solution was extracted with CH2Cl2 (15 mL × 5). The combined
organic layers were dried over Na2SO4 and concentrated. Flash
chromatography of the residue on silica gel (100:1:1 EtOAc/MeOH/
NEt3) gave 32 mg (47% from 40) of 42 as a white solid.
(
)-(4aS,5R,7S,8aS)-1-(3-Acetoxypropyl)-octahydro-5-
(methylthio)methoxy-7-methyl-1H-5,8a-propanoquinolin-10-
one (40). To a solution of 100 mg (0.36 mmol) of 6 in 3 mL (2.93 g,
37 mmol, 103 equiv) of pyridine was added 1.2 mL (1.30 g, 12.7
mmol, 35 equiv) of acetic anhydride. The mixture was stirred at room
temperature for 10 h. The reaction was quenched by addition of 20
mL of saturated NaHCO3 solution. The mixture was extracted with
7152
dx.doi.org/10.1021/jo300353t | J. Org. Chem. 2012, 77, 7143−7156

The Journal of Organic Chemistry
Featured Article
Alternatively, to a resealable tube was added 111 mg (0.32 mmol) of
41, 182 mg (1.63 mmol, 5.0 equiv) of KO-t-Bu, 948 mg (5.2 mmol, 16
equiv) of benzophenone, and 3 mL of dry benzene. The mixture was
subjected to three cycles of freeze−pump−thaw degas protocol and
was sealed and heated at 110 °C for 50 min. After cooling to room
temperature, the reaction was quenched by addition of 12 mL of 3 M
HCl solution. The mixture was extracted with ether (12 mL × 2). The
aqueous layer was neutralized with Na2CO3 powder until pH 11 was
reached. The solution was extracted with CH2Cl2 (20 mL × 5). The
combined organic layers were dried over Na2SO4 and concentrated.
Flash chromatography of the residue on silica gel (100:1:1 EtOAc/
MeOH/NEt3) gave 42 mg (50% from 41) of 42 as a white solid: mp
>172 °C dec; 1H NMR 7.06 (dd, 1, J = 3.7, 3.7), 3.55 (ddd, 1, J = 14.7,
11.0, 6.1), 2.75 (dd, 1, J = 14.7, 7.3), 2.70−2.50 (m, 5), 2.14 (dd, 1, J =
12.8, 2.6), 2.10−1.99 (m, 2), 1.89 (br d, 1, J = 12.2), 1.79 (ddd, 1, J =
13.2, 2.8, 2.8), 1.65 (ddddd, 1, J = 12.8, 12.8, 12.8, 4.0, 4.0), 1.64 (dd,
1, J = 12.8, 3.5), 1.49−1.36 (m, 1), 1.35 (ddd, 1, J = 12.2, 12.2, 1.6),
1.22 (dd, 1, J = 12.0, 12.0), 1.02 (dddd, 1, J = 12.8, 12.8, 12.8, 3.7),
0.93 (d, 3, J = 6.1); 13C NMR 197.5, 136.9, 136.3, 70.9, 58.4, 50.8,
50.2, 49.01, 49.00, 48.1, 43.9, 25.6, 25.1, 22.2, 21.04, 20.97; IR 3389
(broad), 1680 (strong), 1612 (strong), 1244, 1030; HRMS (ESI)
calcd for C16H24NO2 (MH+) 262.1807, found 262.1805.
match those reported in the literature.4 The 1H and 13C NMR spectra
of natural and synthetic 5·DCl are shown in Tables S1 and S2 in the
Supporting Information.
(1S,2R,3aS,5aS,6S,8S,9aR)-2-Cyclohexyldecahydro-8-methyl-
1-phenyl-5H-oxazolo[3,2-a]quinolin-6-ol (47). To a solution of
4625 (30 mg, 0.082 mmol) in 2 mL of 1:10 conc HCl/MeOH was
added 5 mg of PtO2. The mixture was shaken in a Parr apparatus at an
initial pressure of 50 psi for 40 h. The mixture was filtered through a
pad of Celite and the filtrate was concentrated. Flash chromatography
of the residue on silica gel (2:1 hexanes/EtOAc) gave 21 mg (69%) of
47 as a colorless sticky oil: [α]22D = −5.1 (c 0.25, CH2Cl2); 1H NMR
7.60−7.53 (br, 1), 7.34−7.25 (br, 1), 7.22−7.15 (br, 2), 7.12−7.05 (br,
1), 3.85 (d, 1, J = 7.9, H-1), 3.80 (dd, 1, J = 10.0, 2.5, H-3a), 3.63 (dd,
1, J = 9.2, 7.9, H-2), 3.25 (ddd, 1, J = 10.4, 10.4, 4.0, H-6), 2.33−2.22
(m, 2), 2.14 (dddd, 1, J = 11.6, 3.0, 2.9, 2.5), 1.92−1.80 (m, 2), 1.72−
1.55 (m, 2), 1.52−1.24 (m, 6), 1.19−0.90 (m, 6), 0.82 (ddd, 1, J =
12.0, 12.0, 12.0), 0.72 (d, 3, J = 6.8), 0.70−0.62 (m, 2), 0.33 (ddd, 1, J
= 12.0, 12.0, 12.0); 13C NMR 142.9, 130.2 (br), 128.6 (br), 127.6 (br),
126.9 (br), 126.6, 93.4, 86.3, 72.8, 65.5, 62.5, 49.5, 43.8, 39.8, 37.7,
29.5, 29.4, 28.9, 28.8, 26.4, 25.5, 25.4, 25.2, 21.8; IR 1453, 1096, 1029,
1009, 735, 702; HRMS (ESI) calcd for C24H36NO2 (MH+) 370.2746,
found 370.2743.
A COSY experiment showed a cross peak between H1 at δ 3.85 and
H2 at δ 3.63. A COSY experiment showed cross peaks between H3a at
δ 3.80 and the hydrogens at δ 2.14, at δ 1.64. A COSY experiment
showed cross peaks between H2 at δ 3.63 and H1 at δ 3.85, the
hydrogen at δ 1.00. A COSY experiment showed cross peaks between
H6 at δ 3.25 and the hydrogens at δ 1.82, at δ 1.11, and at δ 0.82.
(4aS,5S,7S,8aR)-5-Hydroxy-7-methyloctahydro-1-[(1R)-1,2-
diphenylethyl]-2(1H)-quinolinone (50). To a solution of 4625 (30
mg, 0.082 mmol) in 2 mL of MeOH was added 5 mg of PtO2. The
mixture was stirred under 1 atm of H2 (balloon) at room temperature
for 40 h. The mixture was filtered through a pad of Celite and the
filtrate was concentrated. Flash chromatography of the residue on silica
gel (1:1 hexanes/EtOAc) gave 22 mg (73%) of 50 as a sticky colorless
oil: [α]22D = −55 (c 0.11, CH2Cl2); 1H NMR 7.43−7.19 (m, 10), 4.75
(br, 1, PhCH), 3.87 (dd, 1, J = 13.4, 10.8, PhCH2), 3.30 (dd, 1, J =
13.4, 5.6, PhCH2), 3.02 (ddd, 1, J = 10.4, 10.4, 4.4, H-5), 2.46 (ddd, 1,
J = 18.0, 4.8, 1.4, H-3), 2.29 (ddd, 1, 18.0, 12.8, 6.0, H-3), 2.11 (br dd,
1, J = 10.8, 10.8), 1.99 (dddd, 1, J = 12.8, 6.0, 2.4, 2.4), 1.93 (br d, 1,
13.6), 1.88 (ddd, 1, J = 12.8, 4.0), 1.79−1.67 (m, 1), 1.33−1.16 (m, 1),
1.19 (dddd, 1, J = 12.4, 10.0, 10.0, 2.4), 0.92 (ddd, 1, J = 11.6, 11.6,
11.6), 0.87 (d, 3, J = 6.4), 0.83 (ddd, 1, J = 11.6, 11.6, 11.6), 0.72
(dddd, 1, J = 12.8, 12.8, 12.8, 5.2);13C NMR 171.1, 141.0 (br), 139.1,
129.4 (2 C), 128.3 (2 C), 128.1(2 C), 126.8 (2 C), 126.5, 126.4, 71.6,
63.4 (br), 62.7 (br), 48.2, 43.5, 40.0, 37.7, 33.9, 28.7, 21.8, 21.4; IR
1623, 1455, 1275, 1261, 750, 701; HRMS (ESI) calcd for C24H30NO2
(MH+) 364.2277, found 364.2275.
( )-(1S,8aS,9R,11S,12aR)-Dodecahydro-9-hydroxy-11-meth-
yl-1,9-ethanobenzo[i]quinolizin-14-one (7-Hydroxylycopo-
dine, 5). To a solution of 42 mg (0.16 mmol) of 42 in 3 mL of
MeOH was added 5 mg of PtO2. The mixture was stirred under 1 atm
of H2 (balloon) at room temperature for 10 h. The mixture was
filtered through a pad of Celite, and the filtrate was concentrated. Flash
chromatography of the residue on silica gel (40:1:1 EtOAc/MeOH/
1
NEt3) gave 40 mg (95%) of 5 as a white solid: mp 201−202 °C; H
NMR (CDCl3) 3.37 (ddd, 1, J = 14.3, 14.3, 3.7, H1ax), 3.12 (ddd, 1, J =
12.2, 12.2, 2.8, H9ax), 2.83 (br dd, 1, J = 11.6, 2.4, H4), 2.65 (br d, 1, J =
12.2, H9eq), 2.62 (br d, 1, J = 12.8, H14eq), 2.61 (br d, 1, J = 15.6, H6ax),
(The peaks at δ 2.62 ppm and δ 2.61 ppm overlap and are assigned
from analysis of the COSY spectra.), 2.56 (dd, 1, J = 14.3, 4.9, H1eq),
2.38 (dd, 1, J = 15.6, 1.5, H6eq), 2.11−2.01 (m, 2, H11eq, H3eq), 1.89
(ddd, 1, J = 12.0, 3.2, 3.2, H10eq), 1.85 (dd, 1, J = 12.0, 3.8, H8eq), 1.84
(ddddd, 1, J = 13.6, 13.6, 13.6, 4.8, 4.8, H2ax), 1.69 (ddddd, 1, J = 12.8,
12.8, 12.8, 3.8, 3.8, H10ax), 1.67 (br dd, 1, J = 12.8, 3.1, H12), 1.54
(dddd, 1, J = 13.1, 13.1, 13.1, 4.8, H3ax), 1.44 (dddd, 1, J = 12.8, 12.8,
12.8, 3.8, H11ax), 1.38 (br d, 1, J = 13.6, H2eq), 1.41−1.33 (m, 1, H15),
1.28 (ddd, 1, J = 12.0, 12.0, 2.2, H8ax), 0.91 (dd, 1, J = 12.8, 12.8,
H14ax), 0.89 (d, 3, J = 6.1, Me16); (CD3OD) 3.35 (ddd, 1, J = 14.0,
14.0, 3.5, H1ax), 3.23 (ddd, 1, J = 12.4, 12.4, 2.3, H9ax), 3.03 (br dd, 1, J
= 11.6, 2.8, H4), 2.69 (br d, 1, J = 15.6, H6ax), 2.63 (br d, 1, J = 12.4,
H14eq), 2.58 (br d, 1, J = 12.4, H9eq), 2.52 (dd, 1, J = 14.0, 4.8, H1eq),
2.25 (dd, 1, J = 15.6, 1.2, H6eq), 2.06−1.98 (m, 2, H3eq, H11eq), 1.95−
1.85 (m, 2, H2ax, H10eq), 1.79 (br d, 1, J = 12.4, H8eq), 1.73−1.46 (m, 4,
H10ax, H12, H11ax, H3ax), 1.42 (br d, 1, J = 13.6, H2eq), 1.37−1.26 (m, 1,
H15), 1.28 (ddd, 1, J = 12.4, 12.4, 1.7, H8ax), 0.91 (d, 3, J = 5.6, Me16),
0.90 (dd, 1, J = 12.6, 12.6, H14ax); (DCl salt in CD3OD) 3.82 (ddd, 1, J
= 13.2, 13.2, 2.0), 3.73 (ddd, 1, J = 13.6, 13.6, 4.4), 3.30 (m, 1,
obscured by the residual solvent peak, assigned from analysis of the
COSY spectra), 3.18 (br d, 1, J = 13.2), 3.03 (dd, 1, J = 13.6, 4.8), 2.75
(br d, 1, J = 16.0), 2.71 (dd, 1, J = 12.4, 3.0), 2.40 (dd, 1, J = 16.0, 1.2),
2.20−2.10 (m, 3), 2.06−1.80 (m, 5), 1.81 (dddd, 1, J = 12.8, 12.8,
12.8, 3.2), 1.70−1.58 (m, 1), 1.47−1.33 (m, 2), 1.33 (dd, 1, J = 12.4,
12.4), 0.98 (d, 3, J = 5.6); 13C NMR (CDCl3) 210.3, 72.5, 59.5, 51.4,
50.9, 50.4, 47.3, 47.1, 42.5, 41.8, 25.4, 25.2, 22.6, 19.6, 19.5, 18.5;
(CD3OD) 212.6, 73.1, 61.2, 52.6, 51.7, 51.1, 48.4, 48.0, 43.3, 43.1,
26.6, 26.3, 23.0, 20.6, 20.4, 19.7; (DCl salt in CD3OD) 206.6, 72.5,
66.2, 51.9, 51.0, 50.8, 44.1, 40.7, 26.6, 24.2, 22.6, 19.1, 18.9, 18.7
(carbons 1 and 9 are obscured by the residual solvent peak); IR 3458
(broad), 1702 (strong), 1312; HRMS (ESI) calcd for C16H26NO2
(MH+) 264.1964, found 264.1960.
A COSY experiment showed cross peaks between the hydrogen at δ
4.75(PhCH) and the hydrogens at δ 3.87 (PhCH2), at δ 3.30
(PhCH2). A COSY experiment showed cross peaks between H5 at δ
3.02 and the hydrogens at δ 1.88, at δ 1.19, and at δ 0.92. A COSY
experiment showed a cross peak between H3 at δ 2.46 and H3 at δ 2.29
1-Benzyl-2,3,4,6,7,8-hexahydro-7-methyl-5(1H)-quinolinone
(55) and [(1E)-2-(Methylsulfinyl)ethenyl]benzene (56). To a
suspension of NaH (60% in mineral oil, 20 mg, 0.50 mmol, 2.3 equiv)
in 1 mL of DMSO at room temperature under N2 was added dropwise
a solution of 12 (36 mg, 0.22 mmol) in 2 mL of DMSO. The mixture
was stirred at room temperature for 20 min, and a solution of stilbene
oxide (72 mg, 0.37 mmol, 1.7 equiv) in 1 mL of DMSO was added
dropwise. The resulting mixture was heated to 50 °C and stirred for 12
h. The reaction was quenched by addition of water (5 mL) at room
temperature. The mixture was extracted with EtOAc (10 mL × 3).
The combined organic layers were washed with brine (20 mL × 4),
dried over Na2SO4, and concentrated. Flash chromatography of the
residue on silica gel (100:1:1 EtOAc/MeOH/NEt3) gave 4.3 mg (12%
from 12) of 56 as a colorless oil followed by 6.7 mg (12% from 12) of
55 as a colorless sticky oil.
The data for 5 in CD3OD are referenced to the residual solvent
peaks at δ 3.31 and δ 49.15. The 1H NMR data for 5·DCl in CD3OD
(also referenced to δ 3.31 for residual CD2HOD) are identical to those
reported for 5·DCl except that all absorptions are 0.03 ppm downfield.
The 13C NMR data for 5·DCl are referenced to δ 49.3 so that the data
Data for 55: 1H NMR 7.38 (dd, 2, J = 7.3, 7.3), 7.31 (dd, 1, J = 7.3,
7.3), 7.16 (d, 2, J = 7.3), 4.58 (d, 1, J = 17.1), 4.43 (d, 1, J = 17.1),
7153
dx.doi.org/10.1021/jo300353t | J. Org. Chem. 2012, 77, 7143−7156

The Journal of Organic Chemistry
Featured Article
3.26−3.21 (m, 2), 2.56−2.30 (m, 4), 2.20−1.98 (m, 3), 1.92−1.74 (m,
2), 1.01 (d, 3, J = 6.1); 13C NMR 194.0, 159.0, 137.1, 128.9 (2 C),
127.4, 125.9 (2 C), 106.0, 54.0, 49.5, 44.0, 34.8, 29.0, 21.4, 21.1, 19.8;
IR 1674, 1607, 1550, 1275, 1263, 749, 699; HRMS (ESI) calcd for
C17H22NO (MH+) 256.1696, found 256.1702.
1,2,3,4,4a,7-hexahydro-1,7-dimethylquinoline (61), and
(
)-(4aS,7S)-5-(Dimethylethyl)dimethylsiloxy-4a-
((dimethylethyl)dimethylsilyl)dioxy-1,2,3,4,4a,7-hexahydro-
1,7-dimethylquinoline (62). To a solution of 13 (180 mg, 1.0
mmol) in 8 mL of THF at −78 °C was added a solution of NaHMDS
(1.0 M in THF, 2.2 mL, 2.2 equiv), and the mixture was stirred at the
same temperature for 50 min. Oxygen (dried over CaSO4) was
bubbled into the solution for 50 min at the same temperature. To the
solution was added TBSOTf (0.60 mL, 2.6 mmol, 2.6 equiv), and the
resulting mixture was stirred at the same temperature for 50 min. The
reaction was quenched by addition of saturated NaHCO3 solution (30
mL) and extracted with Et2O (30 mL × 3). The combined organic
layers were dried over MgSO4 and concentrated. Flash chromatog-
raphy of the residue on MeOH−deactivated silica gel (50:1 hexanes/
EtOAc) gave 30 mg (10%) of 60 as a colorless liquid, 10 mg of a
mixture of 60, 61 and 62 (1:4:10) as a pale yellow liquid, and 98 mg
(22%) of 61 as a pale yellow liquid.
Data for 56: 1H NMR 7.50−7.22 (m, 5), 7.25 (d, 1, J = 15.6), 6.90
(d, 1, J = 15.6), 2.71 (s, 3). These data are identical to those previously
reported.27
1-Benzyl-2,3,4,6,7,8-hexahydro-7-methyl-5(1H)-quinolinone
(55). To a suspension of NaH (60% in mineral oil, 65 mg, 1.6 mmol,
2.0 equiv) in 1 mL of 1:1 THF/DMF, a solution of 12 (131 mg, 0.80
mmol) in 1 mL of 1:1 THF/DMF was added dropwise at 0 °C. The
mixture was stirred at 0 °C for 20 min, and 0.15 mL (210 mg, 1.2
mmol, 1.5 equiv) of BnBr was added dropwise. The reaction was
warmed to room temperature and stirred for 18 h. The reaction was
quenched by addition of water (5 mL) at 0 °C. The mixture was
extracted with EtOAc (5 mL × 3). The combined organic layers were
washed with brine (20 mL), dried over Na2SO4, and concentrated.
Flash chromatography of the residue on silica gel (100:1:1 EtOAc/
MeOH/NEt3) gave 142 mg (70% from 12) of 55 as a colorless sticky
oil with 1H NMR, 13C NMR, and IR spectral data identical to those of
55 prepared from 12 and stilbene oxide.
1
Data for 60: H NMR 6.10 (s, 1), 6.01 (s, 1), 3.13 (t, 2, J = 5.6),
2.86 (s, 3), 2.63 (t, 2, J = 6.8), 2.22 (s, 3), 1.93 (tt, 2, J = 6.8, 5.6), 0.99
(s, 9), 0.21 (s, 6); 13C NMR 153.2, 147.9, 136.1, 110.7, 108.1, 105.4,
51.1, 39.7, 25.8 (3 C), 22.2, 21.8, 21.7, 18.3, −4.1 (2 C); IR 1606,
1576, 1269, 1191, 1135, 836, 778.
The structure of 60 was confirmed by hydrolysis of 60 (20 mg,
0.068 mmol) in 2 mL of 3 M HCl at room temperature for 2 h. The
reaction was quenched by addition of saturated NaHCO3 solution (20
mL) and extracted with EtOAc (20 mL × 3). The combined organic
layers were dried over Na2SO4 and concentrated. Flash chromatog-
raphy of the residue on silica gel (5:1 hexanes/EtOAc) gave 11 mg
7,8-Dihydro-7-methyl-5(6H)-quinolinone (58). To a solution
of 13 (15 mg, 0.084 mmol) in 1 mL of benzene was added Mn(OAc)3
(86 mg, 0.37 mmol, 4.4 equiv). The resulting mixture was heated at
150 °C for 20 min in a microwave reactor. The reaction mixture was
quenched by addition of saturated NaHSO3 solution (10 mL) and
extracted with EtOAc (10 mL × 3). The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated. Flash
chromatography of the residue on silica gel (100:1:1 EtOAc/MeOH/
NEt3) gave 4.7 mg (35%) of 58 as a colorless oil, followed by 5.3 mg
(35% recovered) of 13 as a pale yellow oil, and then 2.6 mg (20%) of
12 as a white solid.
To a solution of 12 (10 mg, 0.061 mmol) in 1 mL of benzene,
Mn(OAc)3 (60 mg, 0.26 mmol, 4.3 equiv) was added. The resulting
mixture was heated at 90 °C for 20 min in a microwave reactor. The
reaction mixture was quenched by addition of saturated NaHSO3
solution (10 mL) and extracted with EtOAc (10 mL × 3). The
combined organic layers were washed with brine, dried over Na2SO4
and concentrated. Flash chromatography of the residue on silica gel
(100:1:1 EtOAc/MeOH/NEt3) gave 6.5 mg (67%) of 58 as a colorless
oil, followed by 1.5 mg (15%) of recovered 12 as a white solid.
Data for 58: 1H NMR 8.69 (dd, 1, J = 4.8, 1.9), 8.27 (dd, 1, J = 8.0,
1.9), 7.29 (dd, 1, J = 8.0, 4.8), 3.23 (dd, 1, J = 17.0, 3.6), 2.86 (dd, 1, J
= 17.0, 10.4), 2.78 (dd, 1, J = 12.4, 1.9), 2.48−2.36 (m, 1), 2.37 (dd, 1,
J = 12.4, 12.4), 1.20 (d, 3, J = 6.4); 13C NMR 198.0, 163.0, 153.6,
134.8, 127.6, 122.2, 46.6, 40.8, 29.2, 21.2; IR 1689, 1584, 1457, 1293,
912, 731. The 1H NMR spectral data are identical to those previously
reported.30
1
(90%) of 59 as a white solid with mp, H NMR, 13C NMR, and IR
spectral data identical to those of 59 prepared from 13, KHMDS and
oxygen.
Data for 61: 1H NMR 5.01 (br d, 1, J = 4.4), 4.72 (br d, 1, J = 4.4),
2.92 (br dd, 1, J = 10.8, 5.2), 2.86−2.77 (m, 1), 2.43 (ddd, 1, J = 12.4,
10.8, 3.2), 2.43 (s, 3), 2.32−2.24 (m, 1), 2.12−1.96 (m, 1), 1.52−1.42
(m, 2), 1.09 (d, 3, J = 7.2), 0.94 (s, 9), 0.87 (s, 9), 0.19 (s, 3), 0.18 (s,
3), 0.10 (s, 6); 13C NMR 146.8, 142.5, 112.1, 108.5, 78.4, 53.9, 40.5,
30.9, 30.8, 26.2 (3 C), 25.8 (3 C), 22.4, 20.4, 18.20, 18.18, −4.4, −5.1,
−5.5, −5.8; IR 1686, 1647, 1178, 913, 835, 745; HRMS (ESI) calcd
for C23H46NO3Si2 (MH+) 440.3016, found 440.3021.
A COSY experiment showed large cross peaks between the
hydrogen at δ 2.86−2.77 and the hydrogens at δ 5.01, δ 4.72, and δ
1.09. A COSY experiment showed a small cross peak for W coupling
between the hydrogens at δ 5.01 and at δ 4.72.
The data for 62 were obtained by comparing the NMR spectra of
1
60, 61, and the mixture of all three: H NMR 4.97 (dd, 1, J = 2, 2),
4.65 (dd, 1, J = 2, 2), 2.97−2.88 (m, 2), 2.50−2.42 (m, 1), 2.45 (s, 3),
2.32−2.24 (m, 1), 2.12−1.96 (m, 1), 1.52−1.40 (m, 2), 1.02 (d, 3, J =
7.2), 0.94 (s, 9), 0.84 (s, 9), 0.20 (s, 3), 0.18 (s, 3), 0.10 (s, 6); 13C
NMR 147.0, 142.3, 113.4, 109.5, 78.1, 53.8, 40.5, 31.0, 30.8, 26.1(3 C),
25.8 (3 C), 23.5, 20.4, 18.22, 18.20, −4.4, −4.9, −5.4, −5.8.
A COSY experiment showed large cross peaks between the
hydrogen at δ 2.97−2.88 and the hydrogens at δ 4.97, δ 4.65, and δ
1.02. A COSY experiment showed a small cross peak for W coupling
between the hydrogens at δ 4.97 and at δ 4.65.
6-(Dimethylethyl)dimethylsiloxy-1,3,4,8,9,10-hexahydro-
1,4-dimethyl-2,7-azecinedione (65). To a solution of 61 (22 mg,
0.050 mmol) in 1 mL of CDCl3, pyridine (10 μL, 0.012 mmol, 2.5
equiv) and pyr·(HF)x (4 μL, 0.15 mmol, 3 equiv) were added
successively. The reaction was stirred at rt for 30 min. The solvent was
evaporated, and flash chromatography on silica gel (3:1 hexanes/
EtOAc) gave 6.5 mg (40%) of 65 as a colorless oil: 1H NMR 4.66 (d,
1, J = 10.0), 4.41 (ddd, 1, J = 13.6, 10.4, 3.6), 3.05−2.94 (m, 1), 2.82
(ddd, 1, J = 15.2, 12.0, 2.0), 2.80 (s, 3), 2.69 (dd, 1, J = 13.2, 4.4), 2.43
(ddd, 1, J = 13.6, 4.0, 4.0), 2.23−2.11 (m, 1), 2.08 (ddd, 1, J = 15.2,
8.0, 1.9), 1.94 (dd, 1, J = 13.2, 13.2), 1.94−1.84 (m, 1), 1.09 (d, 3, J =
6.8), 0.90 (s, 9), 0.21 (s, 3), 0.14 (s, 3); 13C NMR 203.2, 172.3, 150.5,
115.1, 47.0, 45.0, 37.8, 36.0, 26.2, 25.5 (3 C), 23.6, 21.0, 18.0, −4.7,
−4.8; IR 1696, 1636, 1258, 1225, 1084, 1067, 913, 837, 745; HRMS
(ESI) calcd for C17H32NO3Si (MH+) 326.2151, found 326.2150. The
fully assigned spectral data as determined by analysis of COSY, HSQC,
1,2,3,4-Tetrahydro-1,7-dimethyl-5-quinolinol (59). To a sol-
ution of 13 (8.0 mg, 0.048 mmol) in 1.5 mL of THF was added a
solution of KHMDS (0.5 M in toluene, 0.15 mL, 1.5 equiv) at −78 °C
under N2. The mixture was stirred at the same temperature for 20 min,
and O2 was introduced to the reaction container from a balloon via a
syringe. The reaction was slowly warmed to 0 °C over 50 min and
stirred at 0 °C for 30 min. The reaction was quenched by addition of
saturated Na2SO3 solution (5 mL). The mixture was extracted with
EtOAc (5 mL × 3). The combined organic layers were washed with
brine (20 mL), dried over Na2SO4, and concentrated. Flash
chromatography of the residue on silica gel (5:1 hexanes/EtOAc)
1
gave 1.6 mg (20%) of 59 as a white solid: mp 95−96 °C; H NMR
6.08 (s, 1), 6.01 (s, 1), 4.53 (br s, 1, OH), 3.16 (t, 2, J = 5.6), 2.87 (s,
3), 2.63 (t, 2, J = 6.8), 2.22 (s, 3), 1.98 (tt, 2, J = 6.8, 5.6); 13C NMR
153.2, 147.9, 136.9, 105.8, 105.0, 104.6, 50.9, 39.8, 21.9, 21.6, 20.6; IR
1618, 1580, 1517, 1273, 1124, 915, 807, 748; HRMS (ESI) calcd for
C11H16NO (MH+) 178.1232, found 178.1232. Similar results were
obtained using NaHDMS.
5-(Dimethylethyl)dimethylsiloxy-1,2,3,4-tetrahydro-1,7-di-
methylquinoline (60),
( )-(4aR,7S)-5-(Dimethylethyl)-
dimethylsiloxy-4a-((dimethylethyl)dimethylsilyl)dioxy-
7154
dx.doi.org/10.1021/jo300353t | J. Org. Chem. 2012, 77, 7143−7156

The Journal of Organic Chemistry
Featured Article
and HMBC 2D NMR spectra are shown in Table S3 in the Supporting
Information.
wrong carbon). (d) Ortega, M. G.; Vallejo, M. G.; Agnese, A. M.;
Cabrera, J. L. Recent Prog. Med. Plants 2010, 29, 345−362.
(4) (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, 1963−
1967.
(5) (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) Heath-
cock, C. H.; Kleinman, E. F.; Binkley, E. S. J. Am. Chem. Soc. 1978,
Assay for Acetylcholinesterase Activity. Inhibition of acetyl-
cholinesterase activity was determined with a modified micro-Ellman
assay.35a,b 7-Hydroxylycopodine was initially dissolved in 0.12 M HCl
to a concentration of 0.076 M and then diluted in saline (0.15 M
sodium chloride) as needed. Electric eel (Electrophorus electricus)
acetylcholinesterase (AChE) (15 U/mL) was preincubated with 7-
hydroxylycopodine for 15 min, and then 0.075 U of preincubated
enzyme was added to the reaction mixture containing 7-hydrox-
ylycopodine at the preincubation concentration, 1 mM acetylthiocho-
line (ATC), 0.1 mM 4,4′-dithiopyridine, and 50 mM pH 8.0 sodium
phosphate buffer. The reaction was monitored for 5 min at 325 nm in
a SpectraMax Plus 96 well plate reader at 24 °C. Human whole blood
was diluted initially 1:10 in saline and then 1:2 with 7-
hydroxylycopodine solution of the appropriate concentration. To
distinguish ATC hydrolysis by human blood AChE and butyrylcho-
linesterase (BChE), blood samples were first treated with 3.33 mM
tetramonoisopropyl pyrophosphortetramide (Iso-OMPA) prior to 7-
hydroxylycopodine. BChE activities were determined with 1.0 mM
butyrylthiocholine (BTC) as the substrate. IC50 values were calculated
from nonlinear regression analysis of the plotted data using GraphPad
Prism Ver. 4.0.
100, 8036−8037. 1982, 104, 1054-1068. (e) Schumann, D.; Muller,
̈
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, 78−87. (h) Greico, P. A.; Dai,
Y. J. J. Am. Chem. Soc. 1998, 120, 5128−5129. (i) Mori, M.; Hori, K.;
Akashi, M.; Hori, M.; Sato, Y.; Nishida, M. 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: Hudlicky, T.; Reed, J. W. The Way of Synthesis; Wiley-
́
VCH: Weinheim, 2007; pp 573−602.
(6) (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. (d) Nakahara, K.; Hirano, K.; Maehata, R.;
Kita, Y.; Fujioka, H. Org. Lett. 2011, 13, 2015−2017.
ASSOCIATED CONTENT
■
S
* Supporting Information
Tables of spectral data and copies of 1H and 13C NMR spectral
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
(7) (a) Valenta, Z.; Deslongchamps, P.; Ellison, R. A.; Wiesner, K. J.
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) A portion of this work was published in preliminary form: Lin,
H.-Y.; Snider, B. B. Org. Lett. 2011, 13, 1234−1237.
(9) Reinshagen, H. Angew. Chem. 1964, 76, 994.
(10) 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. (b) Zhao, Y.; Zhao, J.; Zhou, Y.; Lei, Z.; Li, L.;
Zhang, H. New J. Chem. 2005, 29, 769−772.
(11) For examples of Wacker oxidations in the presence of an amine,
see: (a) Li, W.-D. Z.; 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(39).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: snider@brandeis.edu.
ACKNOWLEDGMENTS
■
We are grateful to the National Institutes of Health (GM-
50151) for support of this work. We thank Dr. C.-H. Tan,
Shanghai Institute of Materia Medica, for a copy of his Ph.D.
thesis containing an HMQC spectrum of 7-hydroxylycopodine
(5). We thank Mr. Edward P. Dougherty for preparing the
cover art and Prof. Chang-Heng Tan, Shanghai Institute of
Materia Medica, for a photograph of Huperzia serrata.
(12) For examples of Prins additions of ketones and aldehydes to
alkynes, see: (a) Rodini, D. J.; Snider, B. B. Tetrahedron Lett. 1980, 21,
3857−3860. (b) Keirs, D.; Overton, K.; Thakker, K. J. Chem. Soc.,
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.
2005, 7, 2493−2495. (g) Jin, T.; Yamamoto, Y. Org. Lett. 2007, 9,
REFERENCES
■
(1) For recent reviews on lycopodium alkaloids, see: (a) Kobayashi,
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.
(2) For recent reviews on huperzine A for treatment of Alzheimer’s
disease, see: (a) Tang, X. C.; Han, Y. F. CNS Drug Rev. 1999, 5, 281−
300. (b) Hostettmann, K.; Borloz, A.; Urbain, A.; Marston, A. Curr.
Org. Chem. 2006, 10, 825−847. (c) 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. (d) Bai, D.
Pure Appl. Chem. 2007, 79, 469−479. (e) Little, J. T.; Walsh, S.; Aisen,
P. S. Expert Opin. Invest. Drugs 2008, 17, 209−215. (f) Desilets, A. R.;
Gickas, J. J.; Dunican, K. C. Ann. Pharmacother. 2009, 43, 514−518.
(g) Ha, G.-T.; Wong, R.-K.; Zhang, Y. Chem. Biodiversity 2011, 8,
1189−1204.
́
5259−5262. (h) Miranda, P. O.; Ramírez, M. A.; Martín, V. S.; Padron,
J. I. 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.
(13) Lee, P. H.; Kim, H.; Lee, K.; Seomoon, D; Kim, S; Kim, H; Kim,
H; Lee, M.; Shim, E; Lee, S; Kim, M; Han, M; Noh, K; Sridhar, M.
Bull. Korean Chem. Soc. 2004, 25, 1687−1691.
(14) (a) House, H. O.; Kleschick, W. A.; Zaiko, E. J. J. Org. Chem.
1978, 43, 3653−3661. (b) House, H. O.; Sieloff, R. F.; Lee, T. V.;
DeTar, M. B. J. Org. Chem. 1980, 45, 1800−1806. (c) Campbell, K. A.;
House, H. O.; Surber, B. W.; Trahanovsky, W. S. J. Org. Chem. 1987,
52, 2474−2481.
(3) (a) Ortega, M. G.; Agnese, A. M.; Cabrera, J. L. Tetrahedron Lett.
2004, 45, 7003−7005. (b) Ortega, M. G.; Agnese, A. M.; Barboza, G.
E.; Cabrera, J. L. J. Argent. Chem. Soc. 2007, 95, 1−9. (c) 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
́
́
(15) Alvarez-Perez, M.; Marco-Contelles, J. ARKIVOC 2011, No. ii,
283−296.
(16) Jackson, A. C.; Goldman, B. E.; Snider, B. B. J. Org. Chem. 1984,
49, 3988−3994.
7155
dx.doi.org/10.1021/jo300353t | J. Org. Chem. 2012, 77, 7143−7156

The Journal of Organic Chemistry
Featured Article
(17) For the related formation of Me(MeO)AlCl from Me2AlCl
leading to different chemistry than with Me2AlCl, see: Fried, J.; Sih, J.
C. Tetrahedron Lett. 1973, 3899−3902.
(18) For related formation of alkenyl chlorides, see: (a) Tanabe, Y.
Bull. Chem. Soc. Jpn. 1994, 67, 3309−3313. (b) Kim, Y.-H.; Lee, K. Y.;
Oh, C.-Y.; Yang, J.-G.; Ham, W.-H. Tetrahedron Lett. 2002, 43, 837−
841.
(19) Thompson, C. M.; Quinn, C. A.; Hergenrother, P. J. J. Med.
Chem. 2009, 52, 117−125.
(20) Heathcock, C. H.; Kleinman, E. F.; Binkley, E. S. Int. Cong. Ser.
(Stereosel. Synth. Nat. Prod.) 1979, 457, 71−82; Chem Abstr. 1980, 90,
76749.
(21) (a) Warnhoff, E. W.; Reynolds-Warnhoff, R. J. Org. Chem. 1963,
28, 1431−1433. (b) Koenig, J.-J.; de Rostolan, J.; Bourbier, J.-C.;
Jarreau, F.-X. Tetrahedron Lett. 1978, 2779−2782.
́ ́ ́ ́
(22) (a) Gomez-Sanchez, A.; Paredes-Leon, R.; Campora. J. Magn.
Reson. Chem. 1998, 36, 154−162. (b) Voskressensky, L. G.; Borisova,
T. N.; Listratova, A. V.; Kulikova, L. N.; Titov, A. A.; Varlamov, A. V.
Tetrahedron Lett. 2006, 47, 4585−4589. (c) Selig, P.; Herdtweck, E.;
Bach, T. Chem.Eur. J. 2009, 15, 3509 −3525.
(23) Narasaka, K.; Morikawa, A.; Saigo, K.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 1977, 50, 2773−2776.
(24) (a) Yamada, K.; Kato, K.; Nagase, H.; Hirata, Y. Tetrahedron
Lett. 1976, 65−66. (b) Pojer, P. M.; Angyal, S. J. Aust. J. Chem. 1978,
31, 1031−1040.
(25) Nakamura, Y.; Burke, A. M.; Kotani, S.; Ziller, J. W.;
Rychnovsky, S. D. Org. Lett. 2010, 12, 72−75.
(26) Nugent, W. A. Org. Lett. 2002, 4, 2133−2136.
(27) (a) Mikolajczyk, M; Grzejszczak, S; Zatorski, A. J. Org. Chem.
1975, 40, 1979−1984. (b) Kojima, T.; Fujisawa, T. Chem. Lett. 1978,
7, 1425−1426.
(28) For general reviews of α-hydroxylation of ketones, see:
(a) Jones, A. B. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Ley, S. V., Eds.; Pergamon: Oxford, 1991; Vol. 7, pp 151−
191. (b) Chen, B.-C.; Zhou, P.; Davis, F. A.; Ciganek, E. In Organic
Reactions; Overman, L. E., Ed.; John Wiley & Sons, Inc.: New York,
2003; Vol. 62, pp 1−356.
(29) (a) Demir, A. S.; Sayrac, T.; Watt, D. S. Synthesis 1990, 1119−
1121. (b) Demir, A. S.; Emrullahoglu, M. Curr. Org. Synth. 2007, 4,
321−350.
(30) Bohlmann, F.; Mayer-Mader, R. Tetrahedron Lett. 1965, 171−
172.
(31) (a) Bailey, E. J.; Barton, D. H. R.; Elks, J.; Templeton, J. F. J.
Chem. Soc. 1962, 1578−1591. (b) Gersmann, H. R.; Bickel, A. F. J.
Chem. Soc. B 1971, 2231−2237. (c) Frimer, A. A.; Gilinsky-Sharon, P.;
Aljadeff, G.; Gottlieb, H. E.; Hameiri-Buch, J.; Marks, V.; Philosof, R.;
Rosental, Z. J. Org. Chem. 1989, 54, 4853−4866.
(32) Crowshaw, K.; Newstead, R. C.; Rogers, N. A. J. Tetrahedron
Lett. 1964, 2307−2311.
(33) (a) Jefford, C. W.; Rimbault, C. G. J. Am. Chem. Soc. 1978, 100,
6437−6445. (b) Zhang, Z.; Foote, C. S. J. Org. Chem. 1993, 58, 5524−
5527.
(34) Torii, S.; Inokuchi, T.; Kondo, K. J. Org. Chem. 1985, 50, 4980−
4982.
(35) (a) Doctor, B. P.; Toker, L.; Roth, E.; Silman, I. Anal. Biochem.
1987, 166, 399−403. (b) Gordon, R. K.; Haigh, J. R.; Garcia, G. E.;
Feaster, S. R.; Riel, M. A.; Lenz, D. E.; Aisen, P. S.; Doctor, B. P. Chem.
Biol. Interact. 2005, 157−158, 239−246.
7156
dx.doi.org/10.1021/jo300353t | J. Org. Chem. 2012, 77, 7143−7156