Exploratory studies towards a total synthesis of the unusual bridged tetracyclic Lycopodium alkaloid lycopladine H

Article abstract of DOI:10.1016/j.tet.2011.04.016

A strategy for a total synthesis of the structurally novel Lycopodium alkaloid lycopladine H has been investigated. Key steps that have been tested include: 1. a regioselective DielseAlder cycloaddition of nitroethylene with an o-quinone ketal to produce the bicyclo[2.2.2]octane moiety of the alkaloid; 2. a stereoselective Henry reaction to generate the requisite functionality and configuration at C-5; 3. a stereoselective catalytic hydrogenation of a trisubstituted alkene to set the C-15 methyl configuration.

Full text of DOI:10.1016/j.tet.2011.04.016

Tetrahedron 67 (2011) 10203e10207
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Exploratory studies towards a total synthesis of the unusual bridged tetracyclic
Lycopodium alkaloid lycopladine H
*
Joshua R. Sacher, Steven M. Weinreb
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A strategy for a total synthesis of the structurally novel Lycopodium alkaloid lycopladine H has been
investigated. Key steps that have been tested include: 1. a regioselective DielseAlder cycloaddition of
nitroethylene with an o-quinone ketal to produce the bicyclo[2.2.2]octane moiety of the alkaloid; 2.
a stereoselective Henry reaction to generate the requisite functionality and configuration at C-5; 3.
a stereoselective catalytic hydrogenation of a trisubstituted alkene to set the C-15 methyl configuration.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 17 January 2011
Received in revised form 30 March 2011
Accepted 5 April 2011
Available online 13 April 2011
Keywords:
Natural product
Alkaloid
DielseAlder
Henry reaction
Catalytic hydrogenation
1. Introduction and background1
dienophiles. With the latter type of dienophile, such as acrylates and
a,b-unsaturated ketones, the regioisomeric adduct that is usually
Lycopladine H (1) is a new member of the Lycopodium family of
alkaloids that was recently isolated by Kobayashi and co-workers
from the club moss Lycopodium complanatum.1,2 The structure of
1, which was established by spectral analysis, incorporates some
novel features including a 3-piperidone spiro-fused to a bicyclo
[2.2.2]octane ring system. This structure is quite different from all
other known Lycopodium alkaloids and therefore presents a unique
synthetic challenge.2 We have recently begun to explore a strategy
directed towards a total synthesis of lycopladine H (1) based upon
a DielseAlder reaction of an o-quinone ketal to construct the
bicyclo[2.2.2]octane moiety of the alkaloid, and some of these ini-
tial studies are the subject of this report.
observed is 4 rather than 5.4 In addition, the electron withdrawing
group is in an endo position in the cycloadduct. Interestingly, it has
not been possible to rationalize the regiochemistry of this type of
cycloaddition by computation.5 However, one major drawback of
using o-quinone ketals as dienes is the tendency of some to undergo
rapid DielseAlder dimerization. Therefore, these species are com-
monly generated and trapped in situ in the presence of an appro-
priate dienophile.
Scheme 1.
o-Quinone ketals like 3 and related cyclohexadienones are easily
prepared from 2-substituted phenols 2 by oxidation, often using
hypervalent iodine compounds in alcoholic solvent, although other
methods are also available (Scheme 1).3 Dienones 3 have been used
2. Results and discussion
Our initial plan was to effect an intramolecular [4þ2]-
cycloaddition of a cyclohexadienone using a dehydroamino acid
derivative as the dienophile to establish the C-5 functionality and
bicyclo[2.2.2]octane framework of the alkaloid. Although such
dienophiles have not been utilized with o-quinone ketals and re-
lated systems, they have been applied successfully in other
as the 4p component in both inter- and intra-molecular DielseAlder
cycloadditions with a variety of electron rich and electron deficient
* Corresponding author. Tel.: þ1 (814) 863 0189; fax: þ1 (814) 863 8403; e-mail
address: smw@chem.psu.edu (S.M. Weinreb).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.016

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J.R. Sacher, S.M. Weinreb / Tetrahedron 67 (2011) 10203e10207
DielseAlder reactions.6 Therefore, known
a
,b
-unsaturated ester 67
nitro compound 16 using aqueous formaldehyde and triethylamine
was hydrogenated to produce 7 in high yield (Scheme 2). Hydro-
lysis of ester 7 gave acid 8, which was condensed with serine
methyl ester hydrochloride (9) to yield amide 10. It was then pos-
sible to cleanly dehydrate alcohol 10 using DCC and a catalytic
amount of cuprous chloride8 to afford the requisite DielseAlder
precursor 11. Phenol 11 was next treated with diacetox-
yiodobenzene (DAIB) in methanol at rt in order to generate the
cyclohexadienone intermediate 12, but under these conditions
none of the desired DielseAlder adduct 13 was detected. Rather,
only the p-quinone mono ketal 14 could be isolated in 40% yield.
Similarly, attempted oxidation of 11 with DIAB under other sets of
conditions or with lead tetraacetate did not afford a [4þ2]-
cycloadduct but only led to a complex mixture of decomposition
products containing some cyclohexadienone dimers.
as the base led to stereoselective formation of the desired endo
hydroxymethyl compound 17 in 87% isolated yield.10 The structure
of this product was again confirmed by X-ray analysis.
Based on these promising results, the correct phenolic precursor
for lycopladine
H (1) was investigated. Since the requisite
methoxyphenol 19 is commercially available but rather expensive,
we have conveniently prepared this material on a w25 g scale by
a WolffeKishner reduction of isovanillin (18) (Scheme 4).11 Treat-
ment of phenol 19 with DIAB in the presence of nitroethylene as
was done for the regioisomer 15, however, did not give any of the
desired DielseAlder adduct but led only to dimerization of the
cyclohexadienone 20. This result is not too surprising since it is well
documented that o-quinone ketals, which are unsubstituted at C-4
tend to be prone to dimerization.4bed A good solution to this
problem is to use the strategy developed by Liao and co-workers,
which involves installing a replaceable blocking group at this po-
sition of the starting phenol.4bed
Scheme 4.
Therefore, the known p-bromophenol 21, prepared as pre-
viously described via NBS halogenation of compound 19,4d was
used as the precursor for the DielseAlder step (Scheme 5). Brief
exposure of this compound to DIAB in methanol at 0 ꢀC, followed by
stirring with nitroethylene (1.5 equiv) in toluene at rt led to the
desired DielseAlder adduct 23 in high yield. It might be noted that
the 4-bromo-o-quinone ketal intermediate 22 is stable and can
even be chromatographed on silica gel. Using conditions previously
developed for the Henry reaction of 16 (cf. Scheme 3), nitro com-
pound 23 was then cleanly transformed to the endo hydroxymethyl
product 24. X-ray analysis of this compound established its struc-
ture and stereochemistry to be as shown.
Scheme 2.
In view of the disappointing results described above, at this
juncture we turned to an alternative approach involving an in-
termolecular DielseAlder reaction. We decided to first test the
chemistry with methoxyphenol 15 since it is an inexpensive com-
mercially available compound, even though we anticipated that
DielseAlder reactions of the derived o-quinone ketal with electron
deficient dienophiles would lead to the undesired C-methyl
regioisomer. Our plan here was to employ nitroethylene as the
dienophile. This compound is known to be highly reactive in [4þ2]-
cycloadditions,9 although to our knowledge it has not previously
been used with cyclohexadienones.
We were pleased to find that oxidation of phenol 15 with DIAB
in methanol in the presence of nitroethylene (3 equiv) afforded
DielseAlder adduct 16 as a single regio- and stereo-isomer in high
yield (Scheme 3). The composition of this adduct was established
by X-ray crystallography. Although the C-methyl substituent in 16 is
in the incorrect position for the alkaloid, it was decided to test the
further elaboration of this intermediate. Thus, a Henry reaction of
Scheme 5.
The unwanted bromine substituent in 24 could be easily re-
moved via the Pd-promoted procedure described by the Liao group
to give alkene 25 in good yield (Scheme 6).4d The next operation to
be investigated was the reduction of the olefin double bond of 25 to
set the correct C-15 stereochemistry of the alkaloid. Our initial
assumption was that in order to control the stereochemistry of this
Scheme 3.

J.R. Sacher, S.M. Weinreb / Tetrahedron 67 (2011) 10203e10207
10205
reduction, a metal-directed hydrogenation would have to be
employed, which makes use of the endo hydroxymethyl group in
25. Therefore, hydrogenations were attempted using [Ir(cod)(-
py)(PCy3)]PF6 or [Rh(nbd)(dppb)]BF4 as catalysts at hydrogen
pressures up to 500 psi, but in no case was any reduction product
26 observed, with only starting material being recovered. We were
surprised to find, however, that simply hydrogenating the C-8,15
alkene double bond (lycopladine H numbering) of compound 25
with 10% Pd/C at 1 atm afforded the desired C-15 exo-methyl
product 26 with >25:1 stereoselectivity in nearly quantitative
yield. The stereostructure of 26 was subsequently proven by X-ray
crystallography. Interestingly, under these hydrogenation condi-
tions, the nitro group was untouched. This hydrogenation stereo-
selectivity is undoubtedly of steric origin, although one might not
have predicted this result a priori.
methylene chloride, rt). This experiment indeed led to the forma-
tion of hemiketal 27 (w3:2 epimer mixture) in 73% yield. In-
terestingly, it was possible to detect the formation of small amounts
of hydrocinnamaldehyde by TLC during the course of this reaction.
Moreover, simply allowing a sample of alcohol 28 stand at rt led to
slow conversion to ketal 27.
3. Conclusion
We have tested the feasibility of executing a strategy for synthesis
of lycopladine H (1). Pivotal operations include an intermolecular
regioselective DielseAlder reaction of 4-bromo-o-quinone ketal (22)
with nitroethylene to construct the bicyclo[2.2.2]octane core 23 of
the alkaloid. In addition, it is possible to effect stereoselective Henry
(nitro aldol) reactions of this adduct to set the correct stereochem-
istry for C-5 of the alkaloid. Finally, the stereochemistry at the
methyl-bearing C-15 of 1 can be established by a stereoselective
catalytic hydrogenation of the C-8,15 alkene of intermediate 25. We
are currently utilizing what we have learned in the course of the
work outlined here to complete a total synthesis of lycopladine H.12
4. Experimental
Scheme 6.
4.1. General methods
In order to develop a synthetic approach to lycopladine H (1),
which is potentially more convergent than that described above, we
have examined the possibility of utilizing a more complex aldehyde
than formaldehyde in the Henry reaction. In these studies, hydro-
cinnamaldehyde was used as a model. Interestingly, we have ob-
served that the outcome of these condensations depends upon the
specific reaction conditions used. For example, to our surprise con-
densation of nitro compound 23 with hydrocinnamaldehyde under
experimental conditions similar to those used for the Henry reaction
with formaldehyde led to the undesired exo alkylation product 27
(78%), which exists as the cyclic hemiketal (inseparable w3:2 epimer
mixture) (Scheme 7). We speculated that perhaps the Henry reaction
with hydrocinnamaldehyde is reversible, and that under these con-
ditions the kinetic endo product 28 is labile, leading to formation of
the presumably more stable exo hemiketal product 27.10 It was
therefore decided to explore other conditions for the Henry reaction.
We were pleased to find that condensation of nitro compound 23
with hydrocinnamaldehyde in the presence of dry Amberlyst A21 ion
exchangeresininTHFatꢁ10 ꢀCledtothedesiredendoadduct28asan
inseparable mixture of alcohol epimers. Alcohol 28, however, was
found to be rather unstable towards chromatographic purification on
silica gel (see Experimental section). Therefore, the crude material
was directly oxidized with Jones reagent in acetone to afford stable
diketone 29 in 51% overall yield for the two steps.
All non-aqueous reactions were carried out under a positive at-
mosphere of argon in flame-dried glassware unless otherwise noted.
Anhydrous THF, CH2Cl2 and DMF were obtained from a solvent dis-
pensing system. All other solvents and reagents were used as
obtained from commercial sources without further purification. 1H
and 13C NMR spectra were recorded on Bruker DPX-300, CDPX-300,
or DRX-400 MHz spectrometers. Infrared spectraldatawere recorded
using a PerkineElmer 1600 FTIR. Flash column chromatography was
performed using Sorbent Technologies silica gel 60 (230e400 mesh).
4.2. Synthesis and characterization
4.2.1. (E)-Ethyl 3-(2-hydroxy-4-methylphenyl)acrylate (6). To a so-
lution of 2-hydroxy-4-methylbenzaldehyde (6.75 g, 49.58 mmol) in
CH2Cl2 (150 mL) was added (carbethoxymethylene)triphenyl-
phosphorane (19.0 g, 54.54 mmol). The solution was stirred for 2 h
at rt and the solvent was evaporated. The crude material was pu-
rified by flash column chromatography (1:2 EtOAc/hexanes) to give
cinnamate ester 6 (10.13 g, 99%) as a white solid: 1H NMR (400 MHz,
CDCl3)
d
8.04 (d, J¼16.1 Hz,1H), 7.41 (br s,1H), 7.34 (d, J¼8.2 Hz,1H),
6.71 (m, 2H), 6.63 (d, J¼16.1 Hz, 1H), 4.30 (q, J¼7.1 Hz, 2H), 2.29 (s,
3H), 1.35 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 169.2, 155.9,
142.5, 141.3, 129.3, 121.6, 119.1, 117.2, 117.0, 60.8, 21.5, 14.4; HRMS
(ES-TOF) [MꢁH]ꢁ calcd for C12H13O3 205.0865, found 205.0872.
4.2.2. Ethyl 3-(2-hydroxy-4-methylphenyl)propanoate (7). To a so-
lution of cinnamate ester 6 (1.70 g, 8.24 mmol) in EtOH (40 mL) was
added 10% palladium on carbon (170 mg). The suspension was
placed under hydrogen gas (1 atm) and stirred overnight. The re-
action mixture was filtered through a pad of Celite, which was
washed with EtOAc. The filtrate was evaporated to yield propanoate
ester 7 (1.71 g, 100%) as a clear oil of sufficient purity for use in the
next step: 1H NMR (300 MHz, CDCl3)
d 7.29 (br s, 1H), 6.98 (d,
J¼7.5 Hz, 1H), 6.71 (s, 1H), 6.69 (d, J¼7.6 Hz, 1H), 4.15 (q, J¼7.2 Hz,
2H), 2.88 (t, J¼6.5 Hz, 2H), 2.69 (t, J¼6.6 Hz, 2H), 2.27 (s, 3H), 1.25 (t,
J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 175.8, 154.2, 138.0, 130.4,
Scheme 7.
124.3, 121.6, 117.7, 61.3, 35.4, 24.5, 21.0, 14.2; HRMS (ES-TOF)
In order to test our postulate that the Henry reaction is re-
versible, a purified sample of the endo condensation product 28 was
exposed to the reaction conditions used for the direct formation of
the exo adduct 27 from nitro compound 23 (i.e., triethylamine,
[MꢁH]ꢁ calcd for C12H15O3 207.1021, found 207.1015.
4.2.3. 3-(2-Hydroxy-4-methylphenyl)propanoic acid (8). To a solu-
tion of propanoate ester 7 (1.00 g, 4.80 mmol) in MeOH (18 mL) and

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J.R. Sacher, S.M. Weinreb / Tetrahedron 67 (2011) 10203e10207
water (6 mL) was added lithium hydroxide hydrate (1.00 g,
23.83 mmol). The suspension was heated at 55 ꢀC and stirred
overnight. The resulting orange solution was cooled and poured
into 1 M HCl (30 mL) and ice (30 g). The aqueous mixture was
extracted with EtOAc. The organic extract was dried over MgSO4
and evaporated to give acid 8 (856 mg, 99%) as an off-white solid of
sufficient purity for use in the next step: 1H NMR (400 MHz, DMSO-
cooled to rt, and the solvent was evaporated. The residue was pu-
rified by flash column chromatography (20% EtOAc in hexanes) to
yield cycloadduct 16 (9.08 g, 85%) as a light yellow solid. X-ray
quality crystals were obtained via slow evaporation from CH2Cl2/
hexanes: 1H NMR (300 MHz, CDCl3)
d
5.65 (d, J¼6.0 Hz, 1H), 4.85
(m,1H), 3.76 (dd, J¼6.0, 2.5 Hz,1H), 3.29 (s, 3H), 3.24 (s, 3H), 2.97 (d,
J¼2.6 Hz, 1H), 2.52 (m, 1H), 2.12 (dt, J¼14.3, 3.9 Hz, 1H), 1.89 (s, 3H);
d6)
d
12.04 (br s, 1H), 9.20 (br s, 1H), 6.93 (d, J¼7.5 Hz, 1H), 6.60 (s,
13C NMR (75 MHz, CDCl3)
d 197.5, 146.6, 116.0, 93.6, 79.8, 52.1, 50.6,
1H), 6.51 (d, J¼7.5 Hz, 1H), 2.71 (t, J¼7.7 Hz, 2H), 2.45 (t, J¼7.7 Hz,
49.8, 42.7, 26.4, 21.0; HRMS (ES-TOF) [MþNH4]þ calcd for
2H), 2.18 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
d
174.3, 155.0, 136.3,
C11H18BrN2O5 337.0399, found 337.0411.
129.5, 123.9, 119.6, 115.6, 33.9, 25.2, 20.8; HRMS (ES-TOF) [MꢁH]ꢁ
calcd for C10H11O3 179.0708, found 179.0706.
4.2.8. 7-(Hydroxymethyl)-3,3-dimethoxy-5-methyl-7-nitrobicyclo
[2.2.2]oct-5-en-2-one (17). To a solution of nitro compound 16
(100 mg, 0.414 mmol) in acetonitrile (2 mL) were added aqueous
4.2.4. Methyl
anamido)propanoate (10). To a solution of acid 8(750mg, 4.16mmol)
in DMF (20 mL) were added -serine methyl ester hydrochloride (9,
3-hydroxy-2-(3-(2-hydroxy-4-methylphenyl)prop-
formaldehyde (35%, 100 mL, 1.26 mmol) and triethylamine (60 mL,
D,L
0.430 mmol). The resulting solution was stirred for 2 days and the
solvent was evaporated. The residue was purified by flash column
chromatography (40% EtOAc in hexanes) to give nitro alcohol 17
(97 mg, 87%) as a white solid. X-ray quality crystals were obtained
via slow evaporation from CH2Cl2/hexanes: 1H NMR (300 MHz,
710 mg, 4.56 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodii-
mide hydrochloride (880 mg, 4.59 mmol) and diisopropylethylamine
(2.50 mL,14.35 mmol). The resulting solutionwas stirred overnight at
rt and the reaction mixture was concentrated to w5 mL. To the crude
mixture was added 0.1 M HCl (50 mL) and EtOAc (50 mL). The layers
were separated and the aqueous layer was extracted with EtOAc. The
combined organics were washed with (0.1 M) HCl, water and brine,
dried over MgSO4 and evaporated to give amide 10 (929 mg, 79%) as
a white solid in sufficient purity for use in the next step: mp
CDCl3)
d
5.80 (dt, J¼6.9, 0.9 Hz, 1H), 4.06, 3.61 (ABq, J¼11.0 Hz, 2H),
3.92 (d, J¼7.0 Hz, 1H), 3.37 (s, 3H), 3.23 (s, 3H), 3.01 (q, J¼2.6 Hz,
1H), 2.73 (dd, J¼14.8, 3.0 Hz), 1.95 (d, J¼1.6 Hz, 3H), 1.64 (dd, J¼14.8,
2.8 Hz, 1H); HRMS (ES-TOF) [MþNH4]þ calcd for C12H20BrN2O6
367.0505, found 367.0498.
132e133 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 9.18 (s, 1H), 8.15 (d,
J¼7.5 Hz,1H), 6.91 (d, J¼7.5 Hz,1H), 6.58 (s,1H), 6.50 (d, J¼7.5 Hz,1H),
5.02(t, J¼5.3 Hz,1H), 4.34(q, J¼6.5 Hz,1H), 3.68e3.58(m, 2H), 3.62(s,
3H), 2.67 (t, J¼7.7 Hz, 2H), 2.38 (t, J¼7.7 Hz, 2H), 2.16 (s, 3H); 13C NMR
4.2.9. 2-Methoxy-5-methylphenol (19). To isovanillin (18, 10.0 g,
65.7 mmol) in ethylene glycol (130 mL) were added KOH (37 g,
659 mmol) and hydrazine hydrate (16 mL, 330 mmol). The reaction
mixture was heated at 130 ꢀC for 1 h, then at 190 ꢀC for 5 h. The
solution was cooled to rt, then poured into a mixture of concd HCl
(85 mL) and ice (300 g). The acidic aqueous layer was extracted
with Et2O. The organic extract was dried over MgSO4 and evapo-
rated to give phenol 19 (8.97 g, 99%) as a low-melting white solid in
sufficient purity for use in the next step. Spectral data were con-
sistent with literature values.4d
(75 MHz, DMSO-d6)
d 172.2, 171.3, 154.9, 136.0, 129.4, 124.3, 119.6,
115.6, 61.3, 54.7, 51.8, 35.1, 25.3, 20.8; HRMS (ES-TOF) [MþH]þ calcd
for C14H20NO5 282.1341, found 282.1332.
4.2.5. Methyl 2-(3-(2-hydroxy-4-methylphenyl)propanamido)acry-
late (11). To a solution of alcohol 10 (250 mg, 0.889 mmol) in DMF
(8 mL) were added CuCl (22 mg, 0.222 mmol) and N,N0-dicyclohex-
ylcarbodiimide (190 mg, 0.921 mmol). The reaction mixture was
stirred for 20 h at rt and the solvent was evaporated. EtOAc (40 mL),
water (20 mL) and saturated NH4Cl (20 mL) were added. The layers
were separated, and the aqueous layer was extracted with EtOAc. The
combined organics were dried over MgSO4 and evaporated. The res-
idue was purified via filtration through a silica gel plug with Et2O to
giveacrylate11 (200mg, 85%)asanoff-whitesolid:mp114e115 ꢀC;1H
4.2.10. endo-5-Bromo-3,3-dimethoxy-6-methyl-7-nitrobicyclo[2.2.2]
oct-5-en-2-one (23). To (diacetoxyiodo)benzene (24.50 g,
76.06 mmol) in MeOH (275 mL) at 0 ꢀC was added bromophenol 212
(15.00 g, 69.10 mmol). The reaction mixture was stirred for 15 min,
and water (250 mL) and brine (250 mL) were added. The aqueous
mixture was extracted with CH2Cl2, and the combined organics
were dried over MgSO4 and evaporated to give o-quinone ketal 22.
To the crude material was added a solution of nitroethylene in
PhMe (1 M, 120 mL, 120 mmol), and the resulting solution was
stirred overnight at rt. The solvent and residual nitroethylene were
removed under reduced pressure. The crude material was purified
by flash column chromatography (20% EtOAc in hexanes) to give
cycloadduct 23 (21.95 g, 99%) as a yellow oil: 1H NMR (400 MHz,
NMR (300 MHz, CDCl3)
d
8.06 (br s, 1H), 7.81 (br s, 1H), 6.95 (d, J¼7.5,
1H), 6.72 (s, 1H), 6.66 (d, J¼7.6 Hz, 1H), 6.60 (d, J¼0.8 Hz, 1H), 5.90 (d,
J¼0.8 Hz,1H), 3.82 (s, 3H), 2.91 (t, J¼6.2 Hz, 2H), 2.74 (t, J¼6.1 Hz, 2H),
2.26 (s, 3H); 13CNMR(75MHz, CDCl3)
d173.3,164.5,154.5,138.2,130.4,
127.8, 124.4, 121.5, 118.2, 110.0, 53.2, 38.4, 24.1, 21.2; HRMS (ES-TOF)
[MþH]þ calcd for C14H18NO4 264.1236, found 264.1235.
4.2.6. Methyl
2-(3-(3,3-dimethoxy-4-methyl-6-oxocyclohexa-1,4-
CDCl3)
d
4.89 (m, 1H), 3.85 (d, J¼2.4 Hz, 1H), 3.37 (s, 3H), 3.35 (t,
dien-1-yl)propanamido)acrylate (14). To a solution of phenolic
acrylate 11 (120 mg, 0.456 mmol) in MeOH (9 mL) was added
(diacetoxy)iodobenzene (160 mL, 0.498 mmol). The reaction mix-
ture was stirred for 20 h at rt and the solvent was evaporated. The
residue was purified by flash column chromatography (40% EtOAc
in hexanes) to give p-quinone ketal 14 (53 mg, 40%) as a white solid:
J¼3.0 Hz, 1H), 3.29 (s, 3H), 2.71 (ddd, J¼14.3, 9.8, 2.8 Hz, 1H), 2.33
(ddd, J¼14.4, 4.6, 3.4 Hz, 1H), 2.07 (s, 3H); 13C NMR (100 MHz,
CDCl3)
d 194.9, 131.4, 119.6, 93.8, 79.3, 59.0, 50.8, 50.6, 48.3, 28.7,
20.0; IR (thin film) 1747, 1556 cmꢁ1; HRMS (ES-TOF) [MþNH4]þ
calcd for C11H18BrN2O5 337.0399, found 337.0406.
1H NMR (300 MHz, CD3CN)
d
7.95 (br s, 1H), 6.51 (s, 1H), 6.31 (s, 1H),
4.2.11. 5-Bromo-7-(hydroxymethyl)-3,3-dimethoxy-6-methyl-7-ni-
trobicyclo[2.2.2]oct-5-en-2-one (24). To a solution of nitro com-
pound 23 (550 mg, 1.72 mmol) in MeCN (8 mL) were added aqueous
6.07 (d, J¼1.3 Hz,1H), 5.66 (d, J¼1.3 Hz,1H), 3.70 (s, 3H), 3.05 (s, 6H),
2.53e2.43 (m, 4H), 1.77 (s, 3H).
formaldehyde (35%, 410 mL, 5.15 mmol) and triethylamine (240 mL,
4.2.7. endo-3,3-Dimethoxy-5-methyl-7-nitrobicyclo[2.2.2]oct-5-en-
2-one (16). To a solution of (diacetoxy)iodobenzene (15.7 g,
48.7 mmol) and nitroethylene (9.0 mL, 132 mmol) in methanol
(175 mL) was added 2-methoxy-4-methylphenol (15, 5.6 mL,
44.3 mmol). The mixture was heated at reflux and stirred for 20 h,
1.72 mmol). The bright yellow reaction mixture was stirred for 24 h at
rt, and the solvent was evaporated. The residue was purified by flash
column chromatography (2:1 hexanes/EtOAc) to yield nitro alcohol
24 (492 mg, 82%)asawhite solid. X-ray qualitycrystals were obtained
via slow evaporation from CH2Cl2/hexanes: mp 147 ꢀC; 1H NMR

J.R. Sacher, S.M. Weinreb / Tetrahedron 67 (2011) 10203e10207
10207
(400 MHz, CDCl3)
d
4.14 (dd, J¼12.1, 4.6 Hz,1H), 3.97 (s,1H), 3.45 (dd,
81.7, 80.1, 60.3, 55.9, 51.8, 51.7, 51.6, 48.0, 47.9, 40.3, 34.0, 32.6, 32.6,
31.2, 29.9, 20.4; IR (thin film) 3493, 1538 cmꢁ1; HRMS (ES-TOF)
[MþNH4]þ calcd for C20H28BrN2O6 471.1131, found 471.1135.
J¼12.1, 5.4 Hz,1H), 3.35 (s, 3H), 3.31 (t, J¼2.9 Hz,1H), 2.69 (dd, J¼14.8,
2.8 Hz, 1H), 2.58 (br t, J¼5.3 Hz, 1H), 1.92 (s, 3H), 1.81 (dd, J¼14.7,
2.9 Hz,1H); 13C NMR (100 MHz, CDCl3)
d 193.5,132.7,120.8, 94.2, 93.3,
66.6, 58.3, 50.6, 49.9, 48.4, 32.6,19.7;HRMS(ES-TOF)[MþNH4]þ calcd
4.2.15. 5-Bromo-3,3-dimethoxy-6-methyl-7-nitro-7-(3-phenyl-
propanoyl)bicyclo[2.2.2]oct-5-en-2-one (29). To a solution of nitro
compound 23 (640 mg, 2.00 mmol) in THF (10 mL) at ꢁ10 ꢀC were
for C12H20BrN2O6 367.0505, found 367.0492.
4.2.12. 7-(Hydroxymethyl)-3,3-dimethoxy-6-methyl-7-nitrobicyclo
[2.2.2]oct-5-en-2-one (25). To a solution of bromoalkene 24 (5.50 g,
15.71 mmol) in DMF (30 mL) were added formic acid (1.20 mL,
31.80 mmol), tributylamine (11.25 mL, 47.22 mmol) and bis(-
added hydrocinnamaldehyde(400mL,3.04mmol)andAmberlystA21
ion exchange resin (400 mg). The resulting suspension was stirred
and warmed to 0 ꢀC over 6 h. The reaction mixture was filtered, and
the resin was rinsed with EtOAc. The solvent was evaporated to give
crude alcohol 28 as a 5:3 mixture of diastereomers. The alcohol was
unstable to chromatography and was directly carried on to the next
step. Alcohol 28 could be isolated by chromatography in low yield
(w33%), but isomerizes to hemiketal 27 on standing overnight.
Crude alcohol 28 was dissolved in acetone (20 mL). Jones re-
agent (2.7 M in Cr, 1.10 mL, 2.97 mmol) was added dropwise over
10 min, and the resulting solution was stirred for 12 h at rt. The
solution was quenched with i-PrOH (1 mL), and the reaction mix-
ture was filtered through a silica gel plug, eluting with EtOAc. The
combined organics were evaporated, and the residue was purified
by flash column chromatography (20% EtOAc in hexanes) to give
diketone 29 (457 mg, 51% over two steps) as a white solid: mp
triphenylphosphine)palladium(II)
dichloride
(220
mg,
0.313 mmol). The solution was heated at 80 ꢀC and stirred for 18 h.
The reaction mixture was cooled and filtered through a pad of
Celite. The pad was washed with EtOAc (150 mL), and the filtrate
was washed with water and brine. The organic phase was dried
over MgSO4 and evaporated. The resulting crude material was
purified by flash column chromatography (1:1 hexanes/EtOAc) to
give nitroalkene 25 (3.67 g, 86%) as a yellow solid: mp 141e142 ꢀC;
1H NMR (400 MHz, CDCl3)
d
6.07 (dt, J¼6.5, 1.6 Hz, 1H), 4.10, 3.47
(ABq, J¼12.2 Hz, 2H), 3.82 (d, J¼1.2 Hz, 1H), 3.27 (s, 3H), 3.17 (s, 3H),
3.08 (dt, J¼6.5, 3.1 Hz, 1H), 2.67 (dd, J¼14.6, 2.9 Hz, 1H), 2.43 (br t,
J¼7.7 Hz, 1H), 1.90 (d, J¼1.6 Hz, 3H), 1.59 (dd, J¼14.6, 2.9 Hz, 1H); 13C
NMR (100 MHz, CDCl3)
d
195.6, 136.6, 128.9, 94.2, 93.8, 66.6, 56.9,
112e113 ꢀC; 1H NMR (300 MHz, CDCl3)
d
7.32 (t, J¼6.5 Hz, 2H), 7.21
50.4, 49.2, 37.6, 32.8, 20.5; HRMS (ES-TOF) [MþNH4]þ calcd for
(m, 3H), 3.85 (d, J¼0.6 Hz, 1H), 3.44 (dd, J¼18.5, 1.7 Hz, 1H), 3.38 (s,
C12H21N2O6 289.1400, found 289.1390.
3H), 3.20 (s, 3H), 2.93e2.84 (m, 5H), 2.69 (dd, J¼14.9, 2.8 Hz, 1H),
1.60 (d, J¼0.6 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 196.1, 191.2,139.6,
4.2.13. 6-(Hydroxymethyl)-3,3-dimethoxy-7-methyl-6-nitrobicyclo
[2.2.2]octan-2-one (26). To
130.7, 128.8, 128.5, 126.8, 121.4, 97.8, 93.7, 59.7, 50.5, 50.1, 48.4, 37.9,
32.3, 29.7, 19.4; IR (neat) 1737, 1541 cmꢁ1; HRMS (ES-TOF)
[MþNH4]þ calcd for C20H26BrN2O6 469.0974, found 469.0978.
a solution of alkene 25 (1.00 g,
3.69 mmol) in EtOH (20 mL) was added 10% palladium on carbon
(100 mg). The resulting suspension was placed under a hydrogen
atmosphere (1 atm) and stirred for 24 h. The reaction mixture was
filtered through a pad of Celite and the solids were washed with
EtOAc. The organics were evaporated to give saturated nitro alcohol
26 (1.00 g, 99%) as an off-white solid as a single diastereomer
(>25:1). X-ray quality crystals were obtained via slow evaporation
Acknowledgements
We gratefully acknowledge financial support from the National
Science Foundation (CHE-0806807). We also wish to thank Dr. H.
Yennawar (Penn State Small Molecule X-ray Crystallographic Fa-
cility) for the X-ray structure determinations.13
from Et2O: mp 121e123 ꢀC; 1H NMR (400 MHz, CDCl3)
d 4.15, 3.88
(ABq, J¼12.4 Hz, 2H), 3.22 (s, 3H), 3.08 (s, 3H), 2.97 (d, J¼1.8 Hz, 1H),
2.76 (dt, J¼15.4, 3.1 Hz, 1H), 2.41 (m, 1H), 1.76 (ddd, J¼14.4, 10.7,
3.6 Hz, 1H), 1.64 (dd, J¼15.4, 2.1 Hz, 1H), 1.26 (m, 1H), 0.99 (d, 7.0 Hz,
References and notes
3H); 13C NMR (100 MHz, CDCl3)
d 202.0, 98.1, 93.5, 65.8, 52.2, 49.7,
1. Ishiuchi, K.; Kubota, T.; Hayashi, T.; Shibata, S.; Kobayashi, J. Tetrahedron Lett.
2009, 50, 6534.
2. (a) Hirasawa, Y.; Kobayashi, J.; Morita, H. Heterocycles 2009, 77, 679; (b) Ko-
bayashi, J.; Morita, H. In The Alkaloids; Cordell, G. A., Ed.; Academic: New York,
NY, 2005; Vol. 61, p 1.
3. For reviews of o-quinone ketals and related compounds see: (a) Magdziak, D.;
Meek, S. J.; Pettus, T. R. R. Chem. Rev. 2004, 104, 1383; (b) Pouysegu, L.; Deffieux,
D.; Quideau, S. Tetrahedron 2010, 66, 2235.
4. See for example: (a) Liao, C. C.; Wei, C.-P. Tetrahedron Lett. 1989, 30, 2255; (b)
Lai, C.-H.; Shen, Y.-L.; Liao, C.-C. Synlett 1997, 1351; (c) Liu, W.-C.; Liao, C.-C.
Synlett 1998, 912; (d) Lai, C.-H.; Shen, Y.-L.; Wang, M.-N.; Rao, N. S. K.; Liao, C.-C.
J. Org. Chem. 2002, 67, 6493; (e) Chang, C.-P.; Chen, C.-H.; Chuang, G. J.; Liao,
C.-C. Tetrahedron Lett. 2009, 50, 3414.
48.9, 33.6, 31.4, 28.3, 27.9, 20.8; HRMS (ES-TOF) [MþH]þ calcd for
C12H20NO6 274.1291, found 274.1282.
4.2.14. 5-Bromo-7,7-dimethoxy-4-methyl-3-nitro-2-phenethyl-
2,3,3a,6,7,7a-hexahydro-3,6-methanobenzofuran-7a-ol (27). (A) To
a solution of nitro compound 23 (320 mg, 1.00 mmol) in CH2Cl2
(2 mL) were added hydrocinnamaldehyde (90%, 160
and triethylamine (70 L, 0.50 mmol). The dark yellow solution was
stirred overnight, and then evaporated. The residue was purified by
flash column chromatography (20% EtOAc in hexanes) to give
hemiketal 27 (395 mg, 87%) as a white solid in a 3:2 mixture of
diastereomers.
mL, 1.09 mmol)
m
5. Arjona, O.; Medel, R.; Plumet, J.; Herrera, R.; Jimenez-Vazquez, H. A.; Tamariz, J.
J. Org. Chem. 2004, 69, 2348; See also: Dory, Y. L.; Roy, A.-L.; Soucy, P.; De-
slongchamps, P. Org. Lett. 2009, 11, 1197.
6. (a) Bueno, M. P.; Cativiela, C.; Finol, C.; Mayoral, J. A.; Jaime, C. Can. J. Chem. 1987,
65, 2182; (b) Crossley, M. J.; Hambley, T. W.; Stamford, A. W. Aust. J. Chem. 1990,
43, 1827; (c) Crossley, M. J.; Stamford, A. W. Aust. J. Chem. 1994, 47, 1695.
7. Bunce, R. A.; Schilling, C. L., III. Tetrahedron 1997, 53, 9477.
8. cf. Chang, Y.-A.; Chang, H. J. Heterocycl. Chem. 2009, 46, 1235.
9. (a) Ranganathan, D.; Rao, C. B.; Ranganathan, S.; Mehrotra, A. K.; Iyengar, R. J. Org.
Chem. 1980, 45, 1185; (b) Corey, E. J.; Myers, A. G. J. Am. Chem. Soc. 1985, 107, 5574.
10. For lead references to the Henry reaction see: Kurti, L.; Czako, B. Strategic Ap-
plications of Named Reactions in Organic Synthesis; Elsevier: Amsterdam, 2005,
pp 202e203.
11. For a small scale microwave-promoted WolffeKishner reduction of isovanillin see:
Chattopadhyay, S.; Banerjee, S. K.; Mitra, A. K. J. Indian Chem. Soc. 2002, 79, 906.
12. Interestingly, the skeleton of this alkaloid was constructed prior to its isolation:
Evans, D. A.; Scheerer, J. R. Angew. Chem., Int. Ed. 2005, 44, 6038.
13. X-ray data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif. CCDC 804443¼16; CCDC
804444¼17; CCDC 804445¼24; CCDC 804446¼26.
(B) To a solution of epimeric alcohols 28 (45 mg, 0.099 mmol) in
CH2Cl2 (1 mL) was added triethylamine (14 mL, 0.100 mmol). The
solution was stirred overnight at rt, and the solvent was evapo-
rated. The residue was purified by preparative TLC (25% EtOAc in
hexanes) to give hemiketal 27 (33 mg, 73%) as a white solid.
1H NMR (300 MHz, CDCl3)
d 7.28 (m, 2H), 7.19 (m, 3H), 4.74 (s,
0.4H), 4.69 (s, 0.6H), 4.44 (dd, J¼8.9, 3.2 Hz, 0.6H), 4.02 (dd, J¼10.8,
2.9 Hz, 0.4H), 3.73 (s, 0.6H), 3.62 (s, 0.4H), 3.44 (s,1.2H), 3.44 (s,1.8H),
3.38 (s, 1.2H), 3.37 (s, 1.8H), 3.05 (m, 1H), 2.92 (m, 1H), 2.67 (m, 2H),
2.20 (dd, J¼14.0, 2.6 Hz, 0.4H), 2.07(dd, J¼14.0, 2.5 Hz, 0.6H), 2.02 (m,
1H), 1.96 (s, 1.2H), 1.92 (s, 1.8H), 1.83 (m, 0.4H), 1.63 (m, 0.6H); 13C
NMR (75 MHz, CDCl3)
d 141.3, 140.8, 131.8, 131.7, 128.8, 128.7, 128.6,
128.5, 126.3, 126.2, 116.7, 116.4, 103.7, 103.6, 102.2, 101.4, 92.0, 91.1,