Utilization of the intramolecular cycloaddition-cationic π-cyclization of an isomunchnone derivative for the synthesis of (±)-lycopodine

Article abstract of DOI:10.1021/jo960829p

A new annulation sequence leading to the tetracyclic skeleton of the Lycopodium family of alkaloids is effected by using the tandem cycloaddition-cationic π-cyclization reaction of an isomunchnone dipole as the key strategic element. Synthesis of the required α-diazo imide precursor involved treating 5-methylcyclohex-2-en-1-one with the organocopper reagent derived from 3-methoxybenzyl chloride in the presence of chlorotrimethylsilane. Ozonolysis of the resulting silyl enol ether followed by a Wittig reaction and conversion to the desired α-diazo imide was carried out using standard malonylacylation and diazotization procedures. Treatment of the α-diazo imide with rhodium(II) perfluorobutyrate afforded a transient 1,3-dipole which subsequently cycloadded across the tethered π-bond. The resulting cycloadduct was treated with BF₃9.2AcOH to give a rearranged tetracyclic compound derived from a Pictet-Spengler-type cyclization of an N-acyliminium ion. The rearranged product was subsequently converted into a key intermediate previously used for the synthesis of (±)-lycopodine.

Full text of DOI:10.1021/jo960829p

78
J . Org. Chem. 1997, 62, 78-87
Utiliza tion of th e In tr a m olecu la r Cycloa d d ition -Ca tion ic
π-Cycliza tion of a n Isom u1 n ch n on e Der iva tive for th e Syn th esis of
(()-Lycop od in e†
Albert Padwa,* Michael A. Brodney, J oseph P. Marino, J r., and Scott M. Sheehan
Department of Chemistry, Emory University, Atlanta, Georgia 30322
Received May 6, 1996X
A new annulation sequence leading to the tetracyclic skeleton of the Lycopodium family of alkaloids
is effected by using the tandem cycloaddition-cationic π-cyclization reaction of an isomu¨nchnone
dipole as the key strategic element. Synthesis of the required R-diazo imide precursor involved
treating 5-methylcyclohex-2-en-1-one with the organocopper reagent derived from 3-methoxybenzyl
chloride in the presence of chlorotrimethylsilane. Ozonolysis of the resulting silyl enol ether followed
by a Wittig reaction and conversion to the desired R-diazo imide was carried out using standard
malonylacylation and diazotization procedures. Treatment of the R-diazo imide with rhodium(II)
perfluorobutyrate afforded a transient 1,3-dipole which subsequently cycloadded across the tethered
π-bond. The resulting cycloadduct was treated with BF3‚2AcOH to give a rearranged tetracyclic
compound derived from a Pictet-Spengler-type cyclization of an N-acyliminium ion. The rearranged
product was subsequently converted into a key intermediate previously used for the synthesis of
(()-lycopodine.
In tr od u ction
Earlier reports from our laboratories8 have described
a general method for the synthesis of complex nitrogen
polyheterocycles (i.e., 7) from readily available R-diazo
imides (i.e., 5). As shown in Scheme 1, isomu¨nchnone
cycloadducts such as 6 were employed as masked N-
acyliminium9 ions for cationic π-cyclizations10 as an
approach to B-ring homologues of erythrinane alkaloids.11
As an extension of our earlier work dealing with tandem
cyclization-cycloadditions,12 we planned to use this
method as the key sequence in the synthesis of (()-
lycopodine (2).
Hexahydrojulolidine (1) contains the basic ring skel-
eton of many Lycopodium alkaloids,1 and numerous
synthetic routes toward this class of compounds have
been described in the literature.2 The Lycopodium
alkaloids continue to be of interest as synthetic targets
due to the wide range of biological properties they
exhibit.3-5 For example, lycopodine (2) was first recog-
nized as a medicinal agent as early as the 19th century
and was utilized in Chinese folk medicine for the treat-
ment of skin disorders.6 Recently, huperzine B (4)
(Huperzia serrata), the structural analog of lycodine (3),
has been shown to be a potent reversible inhibitor (IC50
) 10-7 M) of acetylcholine esterase and thus shows
promise in the treatment of Alzheimer’s disease.7
To date, there have been seven independent syntheses
of (()-lycopodine,13-19 the first by Stork13 and Ayer14 in
1968. The strategy utilized in these approaches has
generally been divided into three distinct classes. The
(5) Szychowski, J .; MacLean, D. B. Can. J . Chem. 1979, 57, 1631.
(6) Yang, C. Zhongyao Tongbao 1981, 6, 12.
(7) Campiani, G.; Sun, L.; Kozikowski, A. P.; Augoard, P.; McKinney,
M. J . Org. Chem. 1993, 58, 7660. Kozikowski, A. P.; Xia, Y.; Reddy, E.
R.; Tu¨ckmantel, W.; Hanin, I.; Tang, X. C. J . Org. Chem. 1991, 56,
4636. Tang, X. C.; Lu, C. Z.; Ying, Z. L.; Ni, W. Y.; Zhang, C. L.; Sang,
G. W. New Drugs Clin. Rem. 1986, 5, 2560. Tang, X. C.; Hann, Y. F.;
Chen, X. P.; Zhu, X. D. Acta Pharm. Sin. (Yaoxure Xuebao) 1986, 7,
507.
(8) Marino, J . P., J r.; Osterhout, M. H.; Padwa, A. J . Org. Chem.
1995, 60, 2704. Osterhout, M. H.; Nadler, W. R.; Padwa, A. Synthesis
1994, 123. Padwa, A.; Hertzog, D. L.; Nadler, W. R.; Osterhout, M.
H.; Price, A. T. J . Org. Chem. 1994, 59, 1418. Hertzog, D. L.; Austin,
D. J .; Nadler, W. R.; Padwa, A. Tetrahedron Lett. 1992, 4731.
(9) Hiemstra, H.; Speckamp, W. N. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 2, pp 1047-1082.
(10) Mondon, A.; Hansen, K. F.; Boehme, K.; Faro, H. P.; Nestler,
H. J .; Vilhuber, H. G.; Bo¨ttcher, K. Chem. Ber. 1970, 103, 615. Mondon,
A.; Seidel, P. R. Chem. Ber. 1971, 104, 2937. Mondon, A.; Nestler, H.
J . Chem. Ber. 1979, 112, 1329.
(11) Marino, J . P., J r.; Osterhout, M. H.; Price, A. T.; Semones, M.
A.; Padwa, A. J . Org. Chem. 1994, 59, 5518.
(12) Padwa, A.; Brodney, M. A.; Marino, J . P.; J r.; Osterhout, M.
H.; Price, A. T. J . Org. Chem. 1997, 62, 67.
(13) Stork, G.; Kretchmer, R. A.; Schlessinger, R. H. J . Am. Chem.
Soc. 1968, 90, 1647. Stork, G. Pure Appl. Chem. 1968, 17, 383.
(14) Heathcock, C. H.; Kleinman, E. F.; Binkley, E. S. J . Am. Chem.
Soc. 1982, 104, 1054. Heathcock, C. H.; Kleinman, E. F. Tetrahedron
Lett. 1979, 4125. Heathcock, C. H.; Kleinman, E. F.; Binkley, E. S. J .
Am. Chem. Soc. 1978, 100, 8036.
† This paper is dedicated to William G. Dauben on the occasion of
his 78th birthday.
X Abstract published in Advance ACS Abstracts, November 1, 1996.
(1) Wiesner, K.; Valenta, Z.; Ayer, W. A.; Bankiewicz, C. Chem. Ind.
(London) 1956, 1019. Wiesner, K.; Valenta, Z.; Ayer, W. A.; Fowler, L.
R.; Francis, J . E. Tetrahedron 1958, 4, 87. Kim, S. W.; Bando, Y.; Horii,
Z. Tetrahedron Lett. 1978, 2293. Ayer, W. A.; Altenkirk, B.; Valverde-
Lopez, S.; Douglas, B.; Raffauf, R. F.; Weisbach, J . A. Can. J . Chem.
1968, 46, 15.
(2) For other syntheses of hydrojulolidines, see: Protiva, M.; Prelog,
V. Helv. Chim. Acta 1949, 32, 621. Mann, F. G.; Smith, B. B. J . Chem.
Soc. 1951, 1898. Leonard, N. J .; Middleton, W. J . J . Am. Chem. Soc.
1952, 74, 5114. Wiesner, K.; Poon, L.; J irkovsky, I.; Fishman, M. Can.
J . Chem. 1969, 47, 433. Martin, S. F.; Desai, S. K.; Phillips, G. W.;
Miller, A. C. J . Am. Chem. Soc. 1980, 102, 3294.
(3) McLean, D. B. In The Alkaloids: Chemistry and Physiology;
Manske, R. H. F., Ed.; Academic Press: New York, 1973. Blumenkopf,
T. A.; Heathcock, C. H. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1985; Vol. 3, pp
185-240. Stevens, R. V. In Total Synthesis of Natural Products;
ApSimon, J ., Ed.; Wiley: New York, 1977; Vol. 3, pp 489-515.
(4) Schumann, D.; Naumann, A. Liebigs Ann. Chem. 1979, 57, 1631.
(15) Wenkert, E.; Broka, C. A. J . Chem. Soc., Chem. Commun. 1984,
714.
(16) Ayer, W. A.; Bowman, W. R.; J oseph, T. C.; Smith, P. J . Am.
Chem. Soc. 1968, 90, 1648.
(17) Schuman, D.; Mu¨ller, H. J .; Naumann, A. Liebigs Ann. Chem.
1982, 1700.
S0022-3263(96)00829-8 CCC: $14.00 © 1997 American Chemical Society

Intramolecular Cycloaddition-Cationic π-Cyclization
J . Org. Chem., Vol. 62, No. 1, 1997 79
Sch em e 1
Sch em e 3a
Sch em e 2
a
Reagents: (a) pyrrolidine, K2CO3; (b) CH2dCHCN, CH3CN,
10% HCl; (c) Ph3PdCH2; (d) KOH; (e) Im2CO, PhCH2NH2; (f)
ClCOCH2CO2Et; (g) MsN3, NEt3.
the tandem sequence of reactions, (ii) to demonstrate that
intramolecular dipolar cycloaddition would provide rings
A and D of the lycopodine skeleton, and (iii) to utilize
the dipolar cycloadduct as a masked N-acyliminium ion
for cationic π-cyclization with the neighboring aromatic
ring. Toward this end, diazo imide 15 was synthesized
as a model system (Scheme 3) because it could be
prepared easily from the readily available 3-(3,4-dimeth-
oxyphenyl)propionaldehyde (12). Conjugate addition of
the pyrrolidine enamine derived from 12 to acrylonitrile
followed by aqueous hydrolysis afforded nitrile 13 in 81%
yield. The resultant alkene derived from Wittig meth-
ylenation was hydrolyzed under basic conditions to give
hexenoic acid 14 in 65% yield for the two-step sequence.
Treatment of 14 with 1,1-carbonyldiimidazole followed
by quenching with benzylamine afforded the correspond-
ing N-benzylamide in 90% yield. Using a modified
literature procedure,21 the benzylamide we subjected to
N-malonylacylation to afford the corresponding mal-
onamic acid ethyl ester in 88% yield. The imido ester
was treated with mesyl azide in the presence of triethyl-
amine22 to provide R-diazo imide 15 in 95% yield as a
pale yellow oil.
Addition of rhodium(II) perfluorobutyrate (Rh2pfb4) to
a solution of 15 in CH2Cl2 at 25 °C effected loss of
nitrogen and cyclization to the isomu¨nchnone dipole,
which underwent an intramolecular cycloaddition with
the alkene function to give cycloadduct 16 in 80% isolated
yield (Scheme 4). The assignment of the stereochemistry
of 16 was based on the comparison of NMR signals of 16
with related substrates.12,23 The formation of the endo-
cycloadduct with respect to the carbonyl ylide dipole is
in full accord with molecular mechanics calculations
which show a large ground state energy difference
between the two diastereomers. In the previous article,12
we identified BF3‚OEt2 as the Lewis acid that routinely
gave the highest yield of rearranged product from the
isomu¨nchnone cycloadduct. This also proved to be the
case with cycloadduct 16. Thus, treatment of 16 with
BF3‚OEt2 afforded the tetracyclic lactam 17 in 80% yield
as a single diastereomer. Once again, the assignment
original Stork synthesis closely resembled the proposed
biosynthesis and involved an intramolecular cationic
π-cyclization onto a tetrasubstituted octahydroquinoline
iminium ion derivative to create the ABD-ring skeleton.20
Another approach relies on the further functionalization
of an all-cis hexahydrojulolidine ABC-ring skeleton,15-18
whereas the third approach makes use of a bridgehead
olefin from a preassembled BD-ring system.19 The in-
tramolecular isomu¨nchnone cycloadduct 10 was envis-
aged as the precursor of the key Stork intermediate 8
(via 9) (Scheme 2). The heart of our plan was the
formation of the latter intermediate by a Pictet-Spengler
cyclization of the N-acyliminium ion derived from 10 (vide
infra). Central to this strategy was the expectation that
the bicyclic iminium ion originating from 10 would exist
in a chairlike conformation. Cyclization of the aromatic
ring onto the iminium ion center should take place most
readily from the axial position.13,14 The readily available
heptenoic acid 11 would serve as the precursor for the
R-diazo imide, the direct progenitor of the isomu¨nchnone
dipole. In this paper, we detail the extension of our
tandem cycloaddition-cationic π-cyclization protocol to
the formal synthesis of (()-lycopodine (2).
Resu lts a n d Discu ssion
Our initial set of goals was (i) to develop a synthesis
of the prerequisite R-diazo imide system necessary for
(18) Kim, S. W.; Bando, Y.; Horii, Z. I. Tetrahedron Lett. 1978, 2293.
Momose, T.; Uchida, S.; Imanishi, T.; Kim, S.; Takahashi, N.; Horii,
Z. I. Heterocycles 1977, 6, 1105.
(19) Kraus, G. A.; Hon, Y. S. Heterocycles 1987, 25, 377. Kraus, G.
A.; Hon, Y. S. J . Am. Chem. Soc. 1985, 105, 4341.
(20) Nyembo, L.; Goffin, A.; Hootele´, C.; Braekman, J . C. Can. J .
Chem. 1975, 53, 41. Gupta, R. N.; Castillo, M.; MacLean, D. B.;
Spenser, I. D.; Wrobel, J . T. J . Am. Chem. Soc. 1968, 90, 1360.
(21) Sato, M.; Kanuma, N.; Kato, T. Chem. Pharm. Bull. 1982, 30,
1315.
(22) Taber, D. F.; Ruckle, R. E., J r.; Hennesy, M. J . J . Org. Chem.
1986, 51, 1663.
(23) Marino, J . P., J r.; Osterhout, M. H.; Price, A. T.; Semones, M.
A.; Padwa, A. J . Org. Chem. 1994, 59, 5518.

80 J . Org. Chem., Vol. 62, No. 1, 1997
Padwa et al.
Sch em e 4
Sch em e 6
Sch em e 5
Sch em e 7a
a
Reagents: (a) m-MeOC6H4CH2MgC, CuI, HMPA, TMSCl; (b)
O3; (c) Ph3PdCH2; (d) Im2CO; (e) BnNH2; (f) ClCOCH2CO2Et; (g)
MsN3, NEt3.
sibility of performing a similar tandem cycloaddition-
cyclization with the closely related diazo imide 21. In
the case of 21, it is not clear whether the monosubstituted
aromatic ring, a synthon for the lycopodine B ring,13 is
capable of undergoing the desired 6-exo-trig cyclization.
Therefore, R-diazo imide 21 was synthesized starting
from 2-cyclopenten-1-one using a procedure similar to
that outlined in Scheme 6 (vide infra) and was subjected
to rhodium(II)-catalyzed decomposition. The highest
yield of intramolecular cycloaddition was achieved using
1 mol % of Rh2(pfb)4 in CH2Cl2 at 25 °C. Exposure of 21
to these conditions for 24 h provided the expected
isomu¨nchnone cycloadduct 22 in 89% yield (Scheme 6).
Substrate 22 was then subjected to BF3‚2AcOH in CH2-
Cl2 at 25 °C, effecting cyclization to the desired azacycle
23 in 93% yield. In this case, BF3‚2AcOH was found to
be the most effective Lewis acid for the cyclization.
In light of the successful π-cyclization of isomu¨nchnone
adduct 22 to yield the octahydroethanobenzo[h]quinoline
derivative 23, we next tried to perform the tandem
cycloaddition-cyclization process to produce the corre-
sponding propanobenzo[h]quinoline derivative. There-
fore, substrate 28, a one-carbon homologue of diazo imide
21, was synthesized by the seven-step process outlined
in Scheme 7. Treatment of cyclohexenone 24 with the
organocopper24 reagent derived from 3-methoxybenzyl
chloride in the presence of chlorotrimethylsilane25 fol-
of stereochemistry was based (NMR) on related sub-
strates previously synthesized in these laboratories.12,23
To account for the syn relationship of the ring junction
proton of 17 with the newly formed hydroxyl group, we
suggest that the two diastereomeric N-acyliminium ions
18 and 20 equilibrate under the reaction conditions. The
intermediate N-acyliminium ion 18 derived from the
initial Lewis acid-assisted ring opening of 16 undergoes
rapid proton loss to produce the transient tetrasubsti-
tuted enamide 19 (Scheme 5). Intramolecular axial
reprotonation of 19 from the â-face generates the dia-
stereomeric iminium ion 20. This species then undergoes
intramolecular cationic π-cyclization with the dimethoxy-
substituted aromatic ring, through a transition state in
which the bridgehead hydrogen atom and the tethered
aromatic group on the cyclopentane ring possess a
preferred anti arrangement in the cyclopentane ring.
Having established the feasibility of intramolecular
π-cyclization from an isomu¨nchnone cycloadduct contain-
ing a diactivated aryl group, we investigated the pos-

Intramolecular Cycloaddition-Cationic π-Cyclization
J . Org. Chem., Vol. 62, No. 1, 1997 81
Sch em e 8
single diastereomer. The relative stereochemistry of 38
was established by a single-crystal X-ray analysis.27
Similarly, the critical rearrangement of diazo imide 32
to the oxabicyclic amide was effected by exposure to Rh2-
(pfb)4 which resulted in the isolation of the expected
cycloadduct as a 3:2 mixture of endo-diastereomers (34
and 35) in 97% yield. Exposure of the diastereomeric
mixture to BF3‚2AcOH generated the tetracyclic amide
9 as a 4:1 mixture of diastereomers (71%) about the
tertiary hydroxyl center. The stereoselection of this
cyclization may be understood in terms of an argument
put forth by Stork to account for the stereochemical
outcome of a related cyclization.13 The bridgehead
hydrogen atom and the tethered aromatic ring possess
an anti arrangement in the cyclohexylidene ring of the
bicyclic iminium ion when cyclization occurs. Cyclization
of the diastereomeric N-acyliminium salt, in which the
bridgehead hydrogen atom and the tethered aromatic
ring are in a syn arrangement, to give the epi-derivative
of 9 is not observed because the cyclohexylidene ring
must adopt an unfavorable boat conformation. Conse-
quently, the initially formed iminium ion derived from
35 can easily cyclize, but the isomeric iminium ions
obtained from 33 or 34 must first undergo proton loss to
give the corresponding enamides 36 and 37. This is
followed by reprotonation and a subsequent π-cyclization
to give 9. It is also interesting to note that cyclization of
both 34 and 35 occurs regiospecifically to give the product
derived from para attack with respect to the methoxy
group. In contrast, cyclization of 39 in the Stork syn-
lowed by ozonolysis of the silyl enol ether 25 afforded
carboxylic acid 26 in 73% yield. Wittig olefination
followed by reaction with 1,1-carbonyldiimidazole and
quenching of the reaction with benzylamine produced the
substituted amide 27 in 80% yield. Conversion to the
desired R-diazo imide system 28 was straightforward
using established malonylacylation21 and diazotization22
procedures. Preparation of the closely related methyl
analogue 32, necessary for the lycopodine synthesis, was
accomplished in an analogous manner. In the case of
cyclohexenone 29, the conjugate addition is highly ste-
reoselective with respect to the C-5 methyl group,26
thereby establishing an anti relationship between the
methyl and p-methoxybenzyl substituents.
The reaction of R-diazo imide 28 with a catalytic
quantity of rhodium(II) perfluorobutyrate in CH2Cl2 at
25 °C provided cycloadduct 33 (95%) as a single diaste-
reomer in which cycloaddition of the isomu¨nchnone dipole
occurred anti to the 3-methoxybenzyl substituent. (See
Scheme 8). Assignment of the stereochemistry was based
(NMR) on related substrates previously synthesized in
these laboratories.12,23 Formation of the endo-cycloadduct
with respect to the carbonyl ylide dipole is in full accord
with molecular mechanics calculations which show a
large energy difference between the two diastereomers.
When 33 was exposed to BF3‚2AcOH in CH2Cl2 at 0 °C,
the cyclized product 38 was isolated in 90% yield as a
thesis gives the corresponding mixture of regioisomers
(i.e., 40 and 41). Apparently, the steric effect of the
N-benzyl group directs cyclization away from the meth-
oxy group.
Lactam 9 contains the proper ring skeleton needed for
lycopodine except that it is overfunctionalized. Before
attempting to convert 9 into the Stork relay intermediate
8, we decided to first examine the deoxygenation of a
related model system (i.e., 38). A modification28 of the
original Barton-McCombie deoxygenation reaction29 was
found to be the method of choice. Treatment of 38 with
NaH and phenyl chlorothionoformate gave the stable,
easily handled phenyl thiocarbonate derivative. Heating
this ester in toluene at 75 °C with slow addition of a
solution of 2,2′-azobis(isobutyronitrile) (AlBN) and tribu-
tyltin hydride afforded the deoxygenated lactam 42,
which was isolated as a 3:2 mixture of diastereomers in
80% yield (Scheme 9). Substrate 42 was hydrolyzed to
the corresponding carboxylic acid which was readily
decarboxylated upon heating in p-xylene at 160 °C to give
N-benzyl lactam 43 in 87% yield. To our surprise,
subjection of 43 to catalytic (PtO2) hydrogenation gave
(24) Oppolzer, W.; Petrzilka, X. Helv. Chim. Acta 1978, 61, 2755.
Regitz, M.; Hocker, J .; Leidhergener, A. Organic Syntheses; J ohn
Wiley: New York, 1973; Collect. Vol. 5, pp 179-183.
(27) The authors have deposited atomic coordinates for structures
38 and 46 with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, CB2 1EZ, U.K.
(28) Robins, M. J .; Wilson, J . S. J . Am. Chem. Soc. 1981, 103, 932.
(29) Barton, D. H. R.; McCombie, S. W. J . Chem. Soc., Perkin Trans.
1 1975, 1574.
(25) Corey, E. J .; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6015.
J ohnson, C. R.; Marren, T. J . Tetrahedron Lett. 1987, 28, 27. Bertz, S.
H.; Smith, R. A. J . Tetrahedron 1990, 46, 4091.
(26) House, H. O.; Fischer, W. F. J . Org. Chem. 1968, 33, 949.
Allinger, N. L.; Riew, C. K. Tetrahedron Lett. 1966, 1269.

82 J . Org. Chem., Vol. 62, No. 1, 1997
Padwa et al.
Sch em e 9a
over MgSO4 and concentrated under reduced pressure. The
residue was purified by flash silica gel chromatography to give
the malonamic acid ethyl ester. A variation of the procedure
described by Taber and co-workers22 was used to prepare the
diazo imide system. To a solution containing 2 mmol of the
appropriate imide and 2.2 mmol of mesyl azide in 5 mL of
acetonitrile or CH2Cl2 was added 4.0 mmol of NEt3 under N2
at rt. After the mixture was stirred for 3 h, the solvent was
removed under reduced pressure and the residue was sub-
jected to flash silica gel chromatography.
4-(3,4-Dim eth oxyben zyl)h ex-5-en oic Acid (14). To a
solution containing 9.92 g (47.19 mmol) of 3-(3,4-dimeth-
oxyphenyl)propionic acid in 100 mL of a 1:1 mixture of Et2O/
THF was added 26 mL (51.9 mmol) of BH3‚SMe2 dropwise at
0 °C. After the addition was complete, the reaction was heated
at 75 °C for 1.5 h. The reaction was cooled to rt and filtered
through a Celite plug using CH2Cl2, and the filtrate was
concentrated under reduced pressure to provide 9.26 g (100%)
of 3-(3,4-dimethoxyphenyl)propanol (lit.30 ) as a clear oil which
was used in the next step without further purification.
A suspension of 14.24 g (66.06 mmol) of pyridinium chlo-
rochromate and 14.0 g of Celite in 300 mL of CH2Cl2 was
vigorously stirred for 30 min. The mixture was cooled to 0
°C, and 9.26 g (47.19 mmol) of the above alcohol in 100 mL of
CH2Cl2 was added dropwise over 20 min. The reaction was
stirred for 2 h at 0 °C, warmed to 25 °C, filtered through a
Florisil plug, and washed with EtOAc. The filtrate was
concentrated under reduced pressure to provide 7.3 g (80%)
of 3-(3,4-dimethoxyphenyl)propionaldehyde (12) (lit.31 ) as a
thick yellow oil: IR (neat) 2932, 2833, 1722, 1514, 1260 cm-1
;
a
Reaction conditions: (a) C6H5OCSCl, NaH, n-Bu3SnH, AlBN,
1H NMR (CDCl3, 300 MHz) δ 2.76 (t, 2H, J ) 7.2 Hz), 2.90 (t,
2H, J ) 7.2 Hz), 3.85 (s, 3H), 3.86 (s, 3H), 6.72 (m, 2H), 6.79
(d, 1H, J ) 8.4 Hz), 9.81 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ
26.2, 44.0, 54.5, 110.0, 110.3, 118.7, 131.5, 146.0, 147.4, 200.3.
To a solution containing 5.30 g (27.28 mmol) of the above
aldehyde in 200 mL of benzene were added 6.83 mL (81.85
mmol) of pyrrolidine and 11.31 g (81.85 mmol) of K2CO3. The
reaction was stirred at rt for 3 h, filtered through a Celite plug,
and concentrated under reduced pressure. The resulting oil
was taken up in 100 mL of acetonitrile, and to this solution
were added 10.80 mL (163.7 mmol) of acrylonitrile and 0.50 g
of 4 Å molecular sieves. After the mixture was heated at 105
°C for 24 h and cooled to rt, 200 mL of ether was added. The
organic layer was washed with H2O, followed by 10% aqueous
HCl and brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude residue was subjected to
flash silica gel chromatography to give 5.48 g (81%) of 5-(3,4-
dimethoxyphenyl)-4-formylpentanenitrile (13) as a clear oil:
45 °C; (b) KOH, H2O, 160 °C; (c) H2, PtO2; (d) LiAlH4, ether/THF;
(e) H2, Pd/C.
only the cyclohexyl derivative 44 in almost quantitative
yield. We were able, however, to effect debenzylation of
the related structure 46 (R ) Me) by a different proce-
dure. Lactam 46 was synthesized from the Barton-
McCombie reaction of 9 which gave 45 (96%) as a 3:2
mixture of diastereomers. The mixture was hydrolyzed
to the corresponding carboxylic acids which, upon ther-
mal decarboxylation, gave N-benzyl lactam 46 (85%
overall yield) as a single diastereomer whose structure
was unequivocally established by a single-crystal X-ray
analysis.27 Reduction of 46 with LiAlH4 (81%) followed
by debenzylation via catalytic hydrogenation (Pd/C)
afforded the key Stork intermediate 8.13 The preparation
of 8 constitutes a formal total synthesis of (()-lycopodine
(2).13
In summary, a new strategy for the synthesis of (()-
lycopodine has been developed which is based on a
sequential dipolar cycloaddition-N-acyliminium ion cy-
clization. This approach is particularly attractive as the
starting R-diazo imide can be prepared efficiently on a
large scale, and the cycloaddition and cyclization reac-
tions are highly stereospecific. We are currently inves-
tigating the application of the methodology outlined here
to other alkaloidal targets.
1
IR (neat) 2936, 2244, 1721, 1514 cm-1; H NMR (CDCl3, 300
MHz) δ 1.73 (m, 1H), 2.01 (m, 1H), 2.38 (t, 2H, J ) 6.6 Hz),
2.71 (dd, 1H, J ) 13.6, 7.8 Hz), 2.83 (m, 1H), 3.03 (dd, 1H, J
) 13.6, 7.8 Hz), 3.86 (s, 6H), 6.68-6.71 (m, 2H), 6.81 (d, 1H,
J ) 8.1 Hz), 9.73 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.8,
23.4, 34.4, 51.3, 55.6, 111.2, 111.6, 118.8, 120.7, 129.4, 147.7,
148.9, 202.4.
To a flask charged with 4.12 g (11.56 mmol) of methyltri-
phenylphosphonium bromide in 100 mL of THF at 0 °C was
added 5.52 mL (12.16 mmol) of 2.2 M n-BuLi, and the solution
was stirred at rt for 30 min. To this solution was added 1.44
g (5.76 mmol) of the above aldehyde in 20 mL of THF. The
reaction mixture was stirred for 2 h and warmed to rt, the
reaction was quenched with brine, and 80 mL of H2O was
added to the mixture. The aqueous solution was extracted
with ether, and the organic extracts were dried over Na2SO4.
Removal of the solvent under reduced pressure followed by
flash silica gel chromatography afforded 1.20 g (65%) of 4-(3,4-
dimethoxybenzyl)hex-5-enenitrile as a yellow oil: IR (neat)
2240, 1590, 1254, 763 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.52
(m, 1H), 1.81 (m, 1H), 2.18-2.47 (m, 3H), 2.54-2.70 (m, 2H),
3.86 (s, 3H), 3.87 (s, 3H), 5.04 (d, 1H, J ) 16.5 Hz), 5.08 (d,
1H, J ) 9.6 Hz), 5.53 (dt, 1H, J ) 16.5 and 9.6 Hz), 6.65 (s,
1H), 6.67 (d, 1H, J ) 7.8 Hz), 6.78 (d, 1H, J ) 7.8 Hz); 13C
NMR (CDCl3, 75 MHz) δ 14.6, 28.7, 40.6, 44.4, 55.4, 110.7,
112.0, 116.5, 119.2, 120.7, 131.3, 139.4, 147.0, 148.3.
Exp er im en ta l Section
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in flame-dried glassware under
an atmosphere of dry nitrogen. Solutions were evaporated
under reduced pressure with a rotary evaporator, and the
residue was chromatographed on a silica gel column using an
ethyl acetate-hexane mixture as the eluent unless specified
otherwise.
Gen er a l P r oced u r e for th e Syn th esis of Dia zo Im id es.
A solution containing 5.0 mmol of the appropriate amide and
10.0 mmol of ethyl malonyl chloride in 15 mL of anhydrous
benzene was heated at reflux for 1 h. After being cooled to rt,
the reaction mixture was diluted with ether and washed with
10% aqueous NaOH and brine. The organic layer was dried
(30) Frydman, B.; Deulofev, V. Tetrahedron 1962, 18, 1063.
(31) Denniff, P.; Whiting, D. A. J . Chem. Soc., Chem. Commun. 1976,
712.

Intramolecular Cycloaddition-Cationic π-Cyclization
J . Org. Chem., Vol. 62, No. 1, 1997 83
To a solution of 1.10 g (4.49 mmol) of the above nitrile in 50
mL of a 3:2 EtOH/H2O mixture was added 2.52 g (44.9 mmol)
of KOH. The mixture was heated at 95 °C for 12 h, cooled to
0 °C, and acidified with 10% aqueous HCl. The aqueous
mixture was extracted with ether, dried over Na2SO4, and
concentrated under reduced pressure. The crude residue was
subjected to flash silica gel chromatography to give 4-(3,4-
dimethoxybenzyl)hex-5-enoic acid (14) as a clear oil: IR (neat)
3295, 1707, 1513, 1259, 1029 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.54 (m, 1H), 1.80 (m, 1H), 2.24-2.40 (m, 3H), 2.60 (d, 2H,
J ) 6.9 Hz), 3.85 (s, 6H), 4.93 (d, 1H, J ) 17.1 Hz), 5.01 (d,
1H, J ) 10.2 Hz), 5.56 (dt, 1H, J ) 17.1 and 10.2 Hz), 6.66 (s,
1H), 6.67 (d, 1H, J ) 8.4 Hz), 6.77 (d, 1H, J ) 8.4 Hz), 11.17
(brs, 1H); 13C NMR (CDCl3, 75 MHz) δ 28.5, 31.8, 41.2, 45.1,
55.7, 111.0, 112.4, 115.8, 121.1, 132.4, 141.0, 147.2, 148.5,
179.9. Anal. Calcd for C15H20O4: C, 68.15; H, 7.63. Found:
C, 68.09; H, 7.72.
Hz), 1.43 (m, 1H), 1.55-1.61 (m, 2H), 1.88-2.04 (m, 5H), 2.35
(dd, 1H, J ) 13.3 and 6.9 Hz), 2.46 (dd, 1H, J ) 13.3 and 6.9
Hz), 3.79 (s, 3H), 3.80 (s, 3H), 4.31 (q, 2H, J ) 7.2 Hz), 4.36
(d, 1H, J ) 15.6 Hz), 4.46 (d, 1H, J ) 15.6 Hz), 6.48 (s, 1H),
6.49 (d, 1H, J ) 8.4 Hz), 6.69 (d, 1H, J ) 8.4 Hz), 7.24 (m,
5H); 13C NMR (CDCl3, 75 MHz) δ 14.0, 24.4, 31.9, 34.5, 39.9,
43.4, 45.9, 53.6, 55.6, 62.0, 88.4, 106.6, 111.0, 111.6, 120.5,
127.5, 127.7, 128.6, 132.2, 136.3, 147.3, 148.6, 165.7, 170.5;
HRMS calcd for C27H31NO6 465.2151, found 465.2122.
1-B e n z y l-8,9-d i m e t h o x y -3-h y d r o x y -2-o x o -1,2,3,4,
4a ,5,6,10b-octa h yd r o-5,10b-eth a n oben zo[h ]qu in olin e-2-
ca r boxylic Acid Eth yl Ester (17). To a solution containing
0.21 g (0.45 mmol) of cycloadduct 16 in 12 mL of CH2Cl2 at rt
was added 0.11 mL (0.90 mmol) of BF3‚OEt2. After being
warmed to rt, the reaction mixture was stirred for 5 h, the
reaction was quenched with MeOH, and the reaction mixture
diluted with CH2Cl2. After the solution was extracted with
H2O, the organic extracts were dried over Na2SO4 and con-
centrated under reduced pressure and the resulting crude
residue was subjected to flash silica gel chromatography to
give 0.17 g (80%) of 1-benzyl-8,9-dimethoxy-3-hydroxy-2-oxo-
1,2,3,4,4a,5,6,10b-octahydro-5,10b-ethanobenzo[h]quinoline-2-
carboxylic acid ethyl ester (17) as a white solid: mp 151-152
N -Be n zyl-2-d ia zo-N-[4-(3,4-d im e t h oxyb e n zyl)h e x-5-
en oyl]m a lon a m ic Acid Eth yl Ester (15). To a solution of
0.57 g (2.18 mmol) of carboxylic acid 14 in 15 mL of CH2Cl2
was added 0.42 g (2.61 mmol) of 1,1-carbonyldiimidazole at
rt. The solution was stirred for 2 h, was cooled to 0 °C, and
was treated with 0.31 mL (2.83 mmol) of benzylamine, and
the reaction mixture was stirred overnight at rt. Concentra-
tion under reduced pressure followed by flash silica gel
chromatography gave 0.61 g (90%) of 4-(3,4-dimethoxybenzyl)-
hex-5-enoic acid benzylamide as a clear oil: IR (neat) 1642,
°C; IR (neat) 3438, 1748, 1647, 1509, 1258 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 0.94 (t, 3H, J ) 7.5 Hz), 1.50 (m, 1H),
2.03-2.18 (m, 5H), 2.48 (m, 1H), 2.55-2.65 (m, 2H), 2.90 (dd,
1H, J ) 16.9 and 3.6 Hz), 3.79 (s, 3H), 3.83 (s, 3H), 3.94 (s,
1H), 3.96 (m, 2H), 4.45 (d, 1H, J ) 15.3 Hz), 5.55 (d, 1H, J )
15.3 Hz), 6.58 (s, 1H), 6.63 (s, 1H), 7.21-7.33 (m, 5H); 13C NMR
(CDCl3, 75 MHz) δ 13.4, 28.8, 31.1, 34.5, 35.1, 39.3, 42.8, 49.9,
55.7, 55.8, 61.7, 68.4, 75.3, 107.9, 111.7, 124.6, 126.2, 126.7,
128.4, 133.7, 137.8, 147.4, 147.8, 170.5, 172.0; Anal. Calcd for
C27H31NO6: C, 69.66; H, 6.71; N, 3.01. Found: C, 69.58; H,
6.71; N, 2.95.
4-(3-Met h oxyb en zyl)h ex-5-en oic Acid Ben zyla m id e.
To a solution of 2.96 g (121.8 mmol) of magnesium mesh in 15
mL of THF at -20 °C was added 3.89 mL (26.79 mmol) of
3-methoxybenzyl chloride. After the Grignard reagent was
stirred for 30 min at -20 °C, the solution was warmed to rt
and was added to a mixture containing 4.64 g (24.36 mmol) of
CuI and 5.09 mL (29.2 mmol) of HMPA in 25 mL of THF at
-78 °C. The organocopper species was stirred for 1 h at -78
°C. To this solution was added 15.46 mL (121.8 mmol) of
chlorotrimethylsilane followed by 1.0 g (12.18 mmol) of 2-cy-
clopenten-1-one. The reaction mixture was stirred for 30 min
at -78 °C, and the reaction was quenched with 16.97 mL
(122.8 mmol) of Et3N and 2 mL of H2O. The mixture was
filtered through a Celite plug with EtOAc, and the extracts
were washed with cold H2O, dried over Na2SO4, filtered, and
concentrated under reduced pressure to provide the crude silyl
enol ether which was used in the next step without purifica-
tion.
1
1548, 1028, 914 cm-1; H NMR (CDCl3, 300 MHz) δ 1.56 (m,
1H), 1.86 (m, 1H), 2.09 (m, 1H), 2.20-2.32 (m, 2H), 2.59 (d,
2H, J ) 6.9 Hz), 3.83 (s, 6H), 4.38 (m, 2H), 4.86 (d, 1H, J )
17.1 Hz), 4.96 (d, 1H, J ) 10.2 Hz), 5.55 (m, 1H), 5.66 (brs,
1H), 6.64 (s, 1H), 6.65 (d, 1H, J ) 8.7 Hz), 6.75 (d, 1H, J ) 8.7
Hz), 7.23-7.34 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 29.4, 33.4,
40.9, 42.9, 45.0, 55.3, 110.7, 112.2, 115.1, 120.8, 126.8, 127.1,
128.0, 132.3, 138.1, 141.1, 146.7, 148.1, 172.6; Anal. Calcd for
C22H27NO3: C, 74.75; H, 7.70; N, 3.96. Found: C, 74.68; H,
7.72; N, 3.89.
N-Malonylacylation of 0.5 g of the above amide was carried
out in the standard manner to give 0.55 g of N-benzyl-N-[4-
3,4-dimethoxybenzyl)hex-5-enoyl]malonamic acid ethyl ester
(88%) as a clear oil: IR (neat) 2932, 1738, 1699, 1515, 1028
1
cm-1; H NMR (CDCl3, 300 MHz) δ 1.27 (t, 3H, J ) 7.2 Hz),
1.47 (m, 1H), 1.77 (m, 1H), 2.18 (m, 1H), 2.43 (m, 1H), 2.53 (d,
2H, J ) 7.2 Hz), 2.56 (m, 1H), 3.84 (s, 6H), 3.89 (s, 2H), 4.19
(q, 2H, J ) 7.2 Hz), 4.77 (d, 1H, J ) 17.1 Hz), 4.88 (d, 1H, J
) 10.2 Hz), 4.98 (s, 2H), 5.43 (dt, 1H, J ) 17.1 and 10.2 Hz),
6.60 (d, 1H, J ) 8.7 Hz), 6.61 (s, 1H), 6.74 (d, 1H, J ) 8.7 Hz),
7.17 (d, 2H, J ) 6.9 Hz), 7.22-7.35 (m, 3H); 13C NMR (CDCl3,
75 MHz) δ 14.0, 28.2, 34.5, 41.2, 44.9, 46.4, 46.8, 55.7, 61.1,
110.8, 112.3, 115.7, 121.0, 126.0, 127.3, 128.7, 132.3, 136.4,
141.1, 147.1, 148.5, 167.2, 168.7, 175.9; Anal. Calcd for
C27H33NO6: C, 69.34; H, 7.12; N, 3.00. Found: C, 69.25; H,
7.05; N, 2.98.
A solution of the above compound in 100 mL of a 3:1 mixture
of MeOH/CH2Cl2 at -78 °C was saturated with ozone for 30
min. After the reaction mixture was purged wtih oxygen, 4.47
mL (60.9 mmol) of dimethyl sulfide was added and the solution
was allowed to warm to rt. After being stirred for 5 h, the
reaction mixture was concentrated under reduced pressure and
subjected to flash silica gel chromatography to give 1.53 g
(53%) of 5-(3-methoxyphenyl)-4-formylpentanoic acid as a
A 0.48 g sample of the above compound was subjected to
the standard diazo transfer conditions to give 0.45 g of
N-benzyl-2-diazo-N-[4-(3,4-dimethoxybenzyl)hex-5-enoyl]ma-
lonamic acid ethyl ester (15) (95%) as a yellow oil: IR (neat)
2136, 1717, 1648, 1323, 1028 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.27 (t, 3H, J ) 6.9 Hz), 1.50 (m, 1H), 1.80 (m, 1H), 2.21 (m,
1H), 2.40-2.53 (m, 2H), 2.54 (d, 2H, J ) 6.9 Hz), 3.84 (s, 6H),
4.22 (q, 2H, J ) 6.9 Hz), 4.82 (d, 1H, J ) 16.8 Hz), 4.86 (s,
2H), 4.91 (d, 1H, J ) 10.5 Hz), 5.47 (m, 1H), 6.63 (m, 2H),
6.74 (d, 1H, J ) 8.4 Hz), 7.28 (m, 5H); 13C NMR (CDCl3, 75
MHz) δ 14.1, 28.7, 33.9, 41.3, 42.6, 45.0, 49.0, 55.7, 61.6, 110.8,
112.4, 115.6, 121.0, 127.0, 127.3, 128.5, 132.4, 136.9, 141.2,
147.0, 148.4, 160.4, 166.1, 175.5.
yellow oil: IR (neat) 3100 (broad), 2939, 1709, 1595, 1253 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.89 (m, 1H), 1.96 (m, 1H), 2.35
(m, 2H), 2.70 (m, 2H), 2.95 (m, 1H), 3.75 (s, 3H), 6.71 (m, 3H),
7.18 (t, 1H, J ) 7.8 Hz), 9.64 (s, 1H); 13C NMR (CDCl3, 75
MHz) δ 23.0, 30.1, 31.0, 35.0, 55.0, 111.7, 114.6, 121.1, 129.5,
139.4, 159.6, 178.3, 203.6; Anal. Calcd for C26H29O5: C, 66.07;
H, 6.83. Found: C, 65.92; H, 6.79.
9-Ben zyl-4-(3,4-d im eth oxyben zyl)-8-oxo-10-oxa -9-a za -
tr icyclo-[5.2.1.01,5]d eca n e-7-ca r boxylic Acid Eth yl Ester
(16). A solution of 1.15 g (2.33 mmol) of diazo imide 15 in 20
mL of CH2Cl2 at rt was treated with 5 mg of rhodium(II)
perfluorobutyrate. The reaction mixture was stirred for 6 h
at rt and was concentrated under reduced pressure. The
resulting residue was subjected to flash silica gel chromatog-
raphy to give 0.91 g (80%) of 9-benzyl-4-(3,4-dimethoxybenzyl)-
8-oxo-10-oxa-9-azatricyclo[5.2.1.01,5]decane-7-carboxylic acid
ethyl ester (16) as a clear oil: IR (neat) 1749, 1721, 1259, 1029,
To a flask charged with 2.56 g (7.17 mmol) of methyltri-
phenylphosphonium bromide in 100 mL of THF at 0 °C was
added 3.0 mL (7.50 mmol) of 2.5 M n-BuLi, and the solution
was stirred at 0 °C for 35 min. To this solution was added
0.77 g (3.26 mmol) of the above aldehyde in 50 mL of THF.
The reaction mixture was stirred for 3 h at 0 °C, the reaction
was quenched with brine, the reaction mixture was recooled
to 0 °C, and 50 mL of a 5% aqueous HCl solution was added.
After being stirred for 15 min, the reaction mixture was
extracted with ether and the organic extracts were dried over
1
731 cm-1; H NMR (CDCl3, 300 MHz) δ 1.30 (t, 3H, J ) 7.2

84 J . Org. Chem., Vol. 62, No. 1, 1997
Padwa et al.
Na2SO4, filtered, and concentrated under reduced pressure.
The crude hexenoic acid obtained was used in the next step
without further purification.
mL (2.30 mmol) of BF3‚2AcOH, and the solution was stirred
at rt for 24 h. The reaction was quenched with 5 mL of EtOH,
and the reaction mixture was extracted with water. The
organic extracts were concentrated under reduced pressure,
and the crude residue was subjected to flash silica gel
chromatography to give 0.093 g of 1-benzyl-3-hydroxy-8-
methoxy-2-oxo-1,2,3,4,4a,5,6,10b-octahydro-5,10b-ethanoben-
zo[h]quinoline-2-carboxylic acid ethyl ester (23) (93%) as a
white solid: mp 172-173 °C; IR (neat) 3438, 2932, 1744, 1637,
To a solution of the above compound in 30 mL of CH2Cl2
was added 0.79 g (4.89 mmol) of 1,1′-carbonyldiimidazole at
rt. The solution was stirred for 2 h and cooled to 0 °C, 0.89
mL (8.15 mmol) of benzylamine was added, and the reaction
mixture was stirred for 12 h at rt. The solution was concen-
trated under reduced pressure and subjected to flash silica gel
chromatography to give 0.54 g (51%) of 4-(3-methoxybenzyl)-
hex-5-enoic acid benzylamide as a clear oil: IR (neat) 3288
1
1246 cm-1; H NMR (CDCl3, 300 MHz) δ 0.97 (t, 3H, J ) 7.2
Hz), 1.49 (m, 1H), 2.03-2.17 (m, 5H), 2.49 (m, 1H), 2.60-2.69
(m, 2H), 2.96 (dd, 1H, J ) 17.4 and 3.9 Hz), 3.79 (s, 3H), 3.98
(s, 1H), 4.00 (q, 2H, J ) 7.2 Hz), 4.39 (d, 1H, J ) 15.6 Hz),
5.61 (d, 1H, J ) 15.6 Hz), 6.65 (d, 1H, J ) 2.7 Hz), 6.74 (dd,
1H, J ) 8.7 and 2.7 Hz), 7.10 (d, 1H, J ) 8.7 Hz), 7.23-7.35
(m, 5H); 13C NMR (CDCl3, 75 MHz) δ 13.6, 28.9, 31.2, 35.1,
39.1, 42.8, 50.2, 55.1, 61.8, 68.4, 75.5, 112.2, 113.9, 125.6, 126.2,
126.7, 128.5, 134.2, 134.3, 138.1, 158.4, 170.5, 172.2; Anal.
Calcd for C26H29NO5: C, 71.69; H, 6.72; N, 3.22. Found: C,
71.64; H, 6.70; N, 3.18.
1
(broad), 1637, 1253 cm-1; H NMR (CDCl3, 300 MHz) δ 1.56
(m, 1H), 1.84 (m, 1H), 2.01-2.12 (m, 1H), 2.18-2.30 (m, 2H),
2.60 (dd, 2H, J ) 7.0 and 3.9 Hz), 3.75 (s, 3H), 4.36 (d, 2H, J
) 5.7 Hz), 4.85 (d, 1H, J ) 17.1 Hz), 4.94 (dd, 1H, J ) 10.2
and 1.5 Hz), 5.54 (m, 1H), 5.88 (brs, 1H), 6.68 (m, 3H), 7.15 (t,
1H, J ) 7.8 Hz), 7.20-7.32 (m, 5H); 13C NMR (CDCl3, 75 MHz)
δ 29.7, 34.2, 41.8, 43.3, 45.1, 54.9, 111.0, 114.9, 115.5, 121.5,
127.2, 127.6, 128.5, 128.9, 138.3, 141.3, 141.5, 159.3, 172.6;
Anal. Calcd for C21H25NO2: C, 77.97; H, 7.80; N, 4.33.
Found: C, 77.84; H, 7.75; N, 4.18.
5-(3-Met h oxyb en zyl)h ep t -6-en oic Acid Ben zyla m id e
(27). To a mixture containing 2.53 g (104 mol) of magnesium
metal in 12 mL of THF at -20 °C was added 3.32 mL (10.4
mmol) of 3-methoxybenzyl chloride. After being stirred for 30
min at -20 °C, the solution was allowed to warm to rt over
1.5 h. The resulting benzyl Grignard reagent was transferred
via cannula into a flask containing 3.96 g (20.8 mmol) of CuI
and 4.34 mL (24.9 mmol) of HMPA in 25 mL of THF at -78
°C. The organocopper reagent was stirred for 1 h at -78 °C,
and then 7.92 mL (62.4 mmol) of chlorotrimethyl silane was
added followed by 1.01 mL (10.4 mmol) of 2- cyclohexen-1-one.
The mixture was stirred for 30 min at -78 °C, and the reaction
was quenched by the addition of 8.69 mL (62.4 mmol) of Et3N
and 2 mL of H2O. The mixture was filtered through Celite
using EtOAc, and the organic extracts were washed with H2O,
dried over Na2SO4, and concentrated under reduced pressure.
The above silyl enol ether was dissolved in 100 mL of a 3:1
mixture of MeOH/CH2Cl2 at -78 °C and was saturated with
an ozone stream for 30 min. After the mixture was purged
with oxygen, 4 mL (50.0 mmol) of dimethyl sulfide was added
and the solution was slowly allowed to warm to rt. After being
stirred at rt for 5 h, the reaction mixture was concentrated
under reduced pressure and subjected to flash silica gel
chromatography to give 2.4 g (92%) of 5-(3-methoxybenzyl)-
6-oxohexanoic acid (26) as a yellow oil: IR (neat) 3174, 2939,
N-Ben zyl-2-d ia zo-N-[4-(3-m eth oxyben zyl)h ex-5-en oyl]-
m a lon a m ic Acid Eth yl Ester (21). N-Malonylacylation of
0.52 g of 4-(3-methoxybenzyl)hex-5-enoic acid benzylamide was
carried out in the normal manner to give 0.55 g of N-benzyl-
N-[4-(3-methoxybenzyl)hex-5-enoyl]malonamic acid ethyl ester
(90%) as a clear oil: IR (neat) 3068, 1737, 1694, 1154 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.27 (t, 3H, J ) 7.2 Hz), 1.48
(m, 1H), 1.76 (m, 1H), 2.21 (m, 1H), 2.42 (dd, 1H, J ) 8.8 and
6.3 Hz), 2.50 (dd, 1H, J ) 8.8 and 5.4 Hz), 2.55 (d, 2H, J ) 6.9
Hz), 3.77 (s, 3H), 3.89 (s, 2H), 4.20 (q, 2H, J ) 7.2 Hz), 4.77
(d, 1H, J ) 17.1 Hz), 4.88 (dd, 1H, J ) 10.2 and 1.8 Hz), 4.97
(s, 2H), 5.43 (m, 1H), 6.63-6.72 (m, 3H), 7.12-7.19 (m, 3H),
7.25-7.35 (m, 3H); 13C NMR (CDCl3, 75 MHz) δ 13.8, 28.0,
34.2, 41.4, 44.4, 46.1, 46.5, 54.7, 60.8, 110.8, 114.6, 115.4, 121.2,
125.8, 127.1, 128.5, 128.7, 136.3, 140.7, 141.1, 159.1, 167.0,
168.4, 175.6; Anal. Calcd for C26H31NO5: C, 71.36; H, 7.15;
N, 3.20. Found: C, 71.28; H, 7.03; N, 3.27.
A 0.58 g sample of the above compound was subjected to
the standard diazo transfer conditions to give 0.6 g of N-benzyl-
2-diazo-N-[4-(3-methoxybenzyl)hex-5-enoyl]malonamic acid eth-
yl ester (21) (99%) as a yellow oil: IR (neat) 3060, 2128, 1709,
1
1645 cm-1; H NMR (CDCl3, 300 MHz) δ 1.26 (t, 3H, J ) 7.2
Hz), 1.50 (m, 1H), 1.79 (m, 1H), 2.24 (m, 1H), 2.42 (dd, 1H, J
) 9.0 and 6.6 Hz), 2.49 (dd, 1H, J ) 9.3 and 5.4 Hz), 2.57 (dd,
2H, J ) 6.9 and 2.7 Hz), 3.77 (s, 3H), 4.22 (q, 2H, J ) 7.2 Hz),
4.82 (d, 1H, J ) 17.1 Hz), 4.86 (s, 2H), 4.91 (dd, 1H, J ) 10.3
and 1.8 Hz), 5.47 (m, 1H), 6.65-6.72 (m, 3H), 7.15 (t, 1H, J )
7.8 Hz), 7.21-7.32 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 14.0,
28.7, 33.8, 41.6, 42.4, 44.6, 48.9, 54.8, 61.6, 110.9, 114.7, 115.5,
121.4, 126.9, 127.2, 128.4, 128.8, 136.8, 141.0, 141.3, 159.2,
160.3, 166.0, 175.4.
1
1712, 1599, 1488 cm-1; H NMR (CDCl3, 300 MHz) δ 1.49-
1.73 (m, 4H), 2.34 (t, 2H, J ) 6.6 Hz), 2.61-2.66 (m, 1H), 2.71
(dd, 1H, J ) 13.5 and 6.9 Hz), 2.97 (dd, 1H, J ) 13.5 and 6.9
Hz), 3.78 (s, 3H), 6.73 (m, 3H), 7.19 (t, 1H, J ) 7.8 Hz), 9.66
(s, 1H), 10.65 (bs, 1H); 13C NMR (CDCl3, 75 MHz) δ 21.9, 27.7,
33.7, 34.9, 52.9, 55.0, 111.6, 114.7, 121.2, 129.5, 139.9, 159.6,
179.1, 204.0.
To a flask containing 2.57 g (7.19 mmol) of methyltri-
phenylphosphonium bromide in 60 mL of THF at 0 °C was
added 3.42 mL (7.52 mmol) of a 2.2 M n-BuLi solution, and
the mixture was stirred at 0 °C for 35 min. To the red-colored
Wittig anion was added 0.82 g (3.27 mmol) of aldehyde 26 in
10 mL of THF. The mixture was stirred for 3 h at rt, the
reaction was quenched with brine, the mixture was cooled to
0 °C, and 50 mL of 5% aqueous HCl was added. After being
stirred for 15 min, the mixture was extracted with ether and
the ether layer was dried over Na2SO4. Concentration under
reduced pressure afforded the expected heptenoic acid as a
yellow oil which was used in the next step without further
purification.
To a solution of the above compound in 30 mL of CH2Cl2
was added 0.79 g (4.90 mmol) of 1,1′-carbonyldiimidazole at
rt. The mixture was stirred for 2 h and cooled to 0 °C, and
0.71 mL (4.90 mmol) of benzylamine was added. The solution
was stirred overnight and then concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography to give 0.88 g (80%) of 5-(3-methoxybenzyl)hept-
6-enoic acid benzylamide (27) as a clear oil: IR (neat) 3288,
3068, 2918, 1644, 697 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.29
(m, 1H), 1.45 (m, 1H), 1.59 (m, 1H), 1.72 (m, 1H), 2.16 (m,
2H), 2.29 (m, 1H), 2.59 (d, 2H, J ) 6.9 Hz), 3.78 (s, 3H), 4.41
(d, 2H, J ) 5.4 Hz), 4.90 (d, 1H, J ) 18.0 Hz), 4.95 (d, 1H, J
9-Be n zyl-4-(3-m e t h oxyb e n zyl)-8-oxo-10-oxa -9-a za -
tr icyclo[5.2.1.01,5]d eca n e-7-ca r boxylic Acid Eth yl Ester
(22). A 0.57 g (1.22 mmol) sample of diazo imide 21 in 10 mL
of CH2Cl2 at rt was treated with 5 mg of rhodium(II) perfluo-
robutyrate for 24 h. The reaction mixture was concentrated
under reduced pressure, and the residue was subjected to flash
silica gel chromatography to give 0.47 g (89%) of 9-benzyl-4-
(3-methoxybenzyl)-8-oxo-10-oxa-9-azatricyclo[5.2.1.01,5]decane-
7-carboxylic acid ethyl ester (22) as a clear oil: IR (neat) 2932,
1716, 1744, 1588, 1225 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
1.34 (t, 3H, J ) 7.2 Hz), 1.48 (m, 1H), 1.60 (t, 1H, J ) 4.0 Hz),
1.64 (d, 1H, J ) 4.2 Hz), 1.92-2.10 (m, 5H), 2.43 (dd, 1H, J )
16.6 and 6.9 Hz), 2.52 (dd, 1H, J ) 13.2 and 6.9 Hz), 3.77 (s,
3H), 4.35 (q, 2H, J ) 7.2 Hz), 4.38 (d, 1H, J ) 15.6 Hz), 4.51
(d, 1H, J ) 15.6 Hz), 6.55 (d, 1H, J ) 1.9 Hz), 6.60 (d, 1H, J
) 7.5 Hz), 6.72 (dd, 1H, J ) 8.1 and 1.9 Hz), 7.15 (t, 1H, J )
8.1 Hz), 7.26-7.35 (m, 5H);13C NMR (CDCl3, 75 MHz) δ 14.0,
24.4, 31.9, 34.4, 40.3, 43.3, 45.6, 53.5, 54.9, 61.9, 88.4, 106.5,
111.2, 114.2, 120.8, 127.4, 127.6, 128.6, 129.1, 136.2, 141.2,
159.4, 165.6, 170.5; HRMS calcd for C26H29NO5 435.2045, found
435.2053.
1-Ben zyl-3-h yd r oxy-8-m eth oxy-2-oxo-1,2,3,4,4a ,5,6,10b-
oct a h yd r o-5,10b -et h a n ob en zo[h ]q u in olin e-2-ca r b oxyl-
ic Acid Eth yl Ester (23). To a flask containing 0.10 g (0.23
mmol) of cycloadduct 22 in 5 mL of CH2Cl2 was added 0.32

Intramolecular Cycloaddition-Cationic π-Cyclization
J . Org. Chem., Vol. 62, No. 1, 1997 85
) 11.4 Hz), 5.59 (m, 2H), 6.68 (s, 1H), 6.70 (s, 1H), 6.73 (s,
1H), 7.16 (t, 1H, J ) 7.8 Hz), 7.25-7.35 (m, 5H); 13C NMR
(CDCl3, 75 MHz) δ 23.3, 33.4, 36.5, 41.6, 43.4, 45.2, 55.0, 110.9,
114.9, 115.0, 121.6, 127.3, 127.6, 128.5, 128.9, 138.3, 141.7,
141.9, 159.3, 172.6; Anal. Calcd for C22H27NO2: C, 78.29; H,
8.07; N, 4.15. Found: C, 78.03; H, 7.89; N, 4.18.
J ) 15.9 Hz), 6.64 (d, 1H, J ) 2.7 Hz), 6.75 (dd, 1H, J ) 8.7
and 2.7 Hz), 7.17 (d, 1H, J ) 8.7 Hz), 7.21-7.35 (m, 5H); 13C
NMR (CDCl3, 75 MHz) δ 13.6, 18.7, 31.7, 32.6, 33.7, 34.2, 37.9,
39.4, 47.9, 55.1, 61.9, 63.4, 75.1, 112.3, 112.4, 126.0, 126.4,
126.5, 128.5, 131.3, 137.8, 138.7, 158.2, 170.0, 172.1; Anal.
Calcd for C27H31NO5: C, 72.13; H, 6.96; N, 3.11. Found: C,
72.15; H, 6.96; N, 3.14.
5-(3-Meth oxyben zyl)-3-m eth ylh ep t-6-en oic Acid Ben -
zyla m id e (31). To a mixture containing 2.21 g (98.80 mol) of
magnesium metal in 12 mL of THF at -20 °C was added 3.13
mL (9.97 mmol) of 3-methoxybenzyl chloride. After being
stirred for 30 min at -20 °C, the solution was allowed to warm
to rt over a 1.5 h interval. The resulting Grignard reagent
was transferred via cannula into a flask containing 4.15 g
(21.79 mmol) of CuI and 3.91 mL (21.79 mmol) of HMPA in
25 mL of THF at -78 °C. The organocopper reagent was
stirred for 1 h at -78 °C, and then 8.07 mL (63.56 mmol) of
chlorotrimethylsilane (at -30 °C) was added, followed by 1.0
g (9.08 mmol) of 5-methylcyclohex-2-en-1-one24 (at -30 °C).
The mixture was stirred for 30 min at -78 °C, and the reaction
was quenched with 8.86 mL (63.6 mmol) of Et3N and 2 mL of
H2O. The mixture was filtered through Celite using EtOAc,
and the extracts were washed with cold H2O, dried over Na2-
SO4, and concentrated under reduced pressure.
N-Ben zyl-2-diazo-N-[5-(3-m eth oxyben zyl)h ept-6-en oyl]-
m a lon a m ic Acid Eth yl Ester (28). N-Malonylacylation of
0.8 g of the above amide was carried out in the normal manner
to give 0.85 g of N-benzyl-N-[5-(3-methoxybenzyl)hept-6-enoyl]-
malonamic acid ethyl ester as a clear oil (98%): IR (neat) 2932,
1738, 1700, 1602, 1154, 698 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.17 (m, 1H), 1.26 (t, 3H, J ) 6.9 Hz), 1.31 (m, 1H), 1.47 (m,
1H), 1.62 (m, 1H), 2.18 (m, 1H), 2.43 (m, 2H), 2.53 (d, 2H, J )
7.2 Hz), 3.76 (s, 3H), 3.88 (s, 2H), 4.18 (q, 2H, J ) 6.9 Hz),
4.80 (d, 1H, J ) 17.1 Hz), 4.89 (d, 1H, J ) 10.2 Hz), 4.97 (s,
2H), 5.50 (m, 1H), 6.65 (m, 3H), 7.12-7.18 (m, 3H), 7.23-7.34
(m, 3H); 13C NMR (CDCl3, 75 MHz) δ 14.0, 21.9, 33.0, 36.5,
41.6, 45.1, 46.4, 46.8, 55.0, 61.2, 110.8, 115.0, 121.5, 125.9,
127.3, 128.8, 128.9, 136.4, 141.5, 141.7, 159.3, 167.2, 168.7,
175.9; Anal. Calcd for C27H33NO5: C, 71.80; H, 7.37; N, 3.10.
Found: C, 71.65; H, 7.29; N, 3.02.
A 0.8 g sample of the above compound was subjected to the
standard diazo transfer conditions to give 0.85 g of N-benzyl-
2-diazo-N-[5-(3-methoxybenzyl)hept-6-enoyl]malonamic acid
ethyl ester (28) as a yellow oil (96%): IR (neat) 2932, 2134,
1715, 1650, 1601, 1491, 779 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.20 (m, 1H), 1.28 (t, 3H, J ) 7.2 Hz), 1.35 (m, 1H), 1.50 (m,
1H), 1.65 (m, 1H), 2.22 (m, 1H), 2.44 (m, 2H), 2.55 (m, 2H),
3.78 (s, 3H), 4.24 (q, 2H, J ) 7.2 Hz), 4.83 (d, 1H, J ) 17.1
Hz), 4.88 (s, 2H), 4.89 (d, 1H, J ) 10.2 Hz), 5.53 (ddt, 1H, J )
17.1, 10.2, 8.7 Hz), 6.65-6.73 (m, 3H), 7.16 (t, 1H, J ) 7.8
Hz), 7.24-7.31 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 22.3,
33.2, 36.0, 41.6, 45.2, 49.0, 55.0, 61.7, 72.8, 110.9, 114.9, 115.0,
121.6, 127.0, 127.4, 128.5, 128.8, 136.9, 141.6, 141.8, 159.3,
160.4, 166.2, 175.5.
The above silyl enol ether was dissolved in 100 mL of a 3:1
mixture of MeOH/CH2Cl2 at -78 °C and was saturated with
an ozone stream for 30 min. After the solution was purged
with oxygen, 4 mL (50.0 mmol) of dimethyl sulfide was added,
and the solution was slowly allowed to warm to rt. After being
stirred at rt for 5 h, the mixture was concentrated under
reduced pressure and subjected to flash silica gel chromatog-
raphy to give 1.51 g (63%) of 5-(3-methoxybenzyl)-3-methyl-
6-oxohexanoic acid (11) as a light yellow oil: IR (neat) 3274,
1707, 1599, 1488, 1262 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
0.99 (d, 3H, J ) 6.6 Hz), 1.43 (m, 1H), 1.63 (quin, 1H, J ) 6.9
Hz), 2.07 (m, 1H), 2.17 (m, 1H), 2.32 (dd, 1H, J ) 15.0 and 5.7
Hz), 2.69 (m, 1H), 2.73 (dd, 1H, J ) 19.6 and 6.6 Hz), 2.91 (m,
1H), 3.78 (s, 3H), 6.73 (m, 3H), 7.19 (t, 1H, J ) 7.8 Hz), 9.65
(d, 1H, J ) 2.1 Hz), 10.65 (brs, 1H); 13C NMR (CDCl3, 75 MHz)
δ 19.7, 27.8, 35.1, 35.2, 40.9, 50.9, 55.0, 111.6, 114.7, 121.1,
129.4, 139.8, 159.5, 178.1, 204.2; Anal. Calcd for C15H20O4:
C, 68.15; H, 7.63. Found: C, 68.06; H, 7.46.
10-Ben zyl-5-(3-m et h oxyb en zyl)-9-oxo-11-oxa -10-a za -
tr icyclo[6.2.1.01,6]u n d eca n e-8-ca r boxylic Acid Eth yl Es-
ter (33). A 1.60 g (3.35 mmol) sample of diazo imide 28 in 30
mL of CH2Cl2 was treated with 5 mg of rhodium(II) perfluo-
robutyrate, and the mixture was stirred at rt for 24 h. The
solution was concentrated under reduced pressure, and the
residue was subjected to flash silica gel chromatography to
give 1.44 g (95%) of 10-benzyl-5-(3-methoxybenzyl)-9-oxo-11-
oxa-10-azatricyclo[6.2.1.01,6]undecane-8-carboxylic acid ethyl
ester (33) as a clear oil: IR (neat) 1749, 1721, 1599, 1105, 697
To a 8.37 g (23.43 mmol) sample of methyltriphenylphos-
phonium bromide in 150 mL of THF at 0 °C was added 9.40
mL (23.4 mmol) of 2.5 M n-BuLi, and the mixture was stirred
at 0 °C for 35 min. To the red-colored Wittig anion was added
2.95 g (11.16 mmol) of aldehyde 11 in 25 mL of THF. The
reaction mixture was stirred for 3 h at rt, the reaction was
quenched with brine, the reaction mixture was cooled to 0 °C,
and then 100 mL of 5% aqueous HCl was added. After being
stirred at rt for 15 min, the reaction mixture was extracted
with ether and the organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The resulting heptenoic
acid that was isolated was used in the next step without
further purification.
To a solution of the above heptenoic acid in 50 mL of CH2-
Cl2 at rt was added 2.71 g (16.74 mmol) of 1,1′-carbonyldiimi-
dazole. The solution was stirred for 2 h, cooled to 0 °C, and
3.06 mL (27.90 mmol) of benzylamine was added. After being
stirred at rt overnight, the solution was concentrated under
reduced pressure and subjected to flash silica gel chromatog-
raphy to give 2.82 g (72%) of 5-(3-methoxybenzyl)-3-methyl-
hept-6-enoic acid benzylamide as a yellow oil: IR (neat) 3288,
1643, 1453, 1259, 697 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.94
(d, 3H, J ) 6.6 Hz), 1.18-1.40 (m, 2H), 1.82 (dd, 1H, J ) 13.5
and 8.7 Hz), 2.07 (m, 1H), 2.25 (dd, 1H, J ) 13.5 and 5.1 Hz),
2.38 (m, 1H), 2.51 (m, 1H), 2.62 (m, 1H), 3.76 (s, 3H), 4.39 (d,
2H, J ) 5.7 Hz), 4.87 (d, 1H, J ) 17.4 Hz), 4.93 (d, 1H, J )
10.5 Hz), 5.59 (m, 1H), 5.77 (m, 1H), 6.69 (m, 3H), 7.15 (t, 1H,
J ) 7.8 Hz), 7.23-7.33 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ
20.4, 28.5, 41.4, 41.7, 43.0, 43.5, 43.6, 55.0, 110.9, 114.7, 115.1,
121.7, 127.4, 127.7, 128.6, 128.9, 138.4, 141.9, 142.2, 159.3,
172.1; Anal. Calcd for C23H29NO2: C, 78.58; H, 8.32; N, 3.99;
Found: C, 78.37; H, 8.42; N, 3.84.
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.85 (m, 1H), 1.39 (t, 3H,
J ) 6.9 Hz), 1.45-1.66 (m, 5H), 1.74 (dd, 1H, J ) 13.5 and 5.1
Hz), 1.83 (dd, 1H, J ) 12.9 and 7.3 Hz), 2.13 (m, 2H), 2.26
(dd, 1H, J ) 12.9 and 7.3 Hz), 2.60 (dd, 1H, J ) 13.5 and 3.6
Hz), 3.78 (s, 3H), 4.40 (s, 2H), 4.42 (m, 2H), 6.56 (s, 1H), 6.61
(d, 1H, J ) 7.5 Hz), 6.72 (dd, 1H, J ) 8.1 and 2.1 Hz), 7.15 (t,
1H, J ) 8.1 Hz), 7.26-7.31 (m, 5H); 13C NMR (CDCl3, 75 MHz)
δ 14.1, 20.5, 27.7, 29.6, 36.2, 40.9, 43.1, 44.7, 47.7, 55.0, 62.1,
86.1, 97.3, 111.1, 115.0, 121.5, 127.5, 127.7, 128.6, 129.1, 136.6,
140.8, 159.4, 165.9, 170.9; HRMS calcd for C27H31NO5 449.2202,
found 449.2195.
1-Ben zyl-3-h yd r oxy-8-m eth oxy-2-oxo-1,2,3,4,4a ,5,6,10b-
oc t a h y d r o-5,10b -p r o p a n o b e n zo [h ]q u in o lin e -2-c a r b -
oxylic Acid Eth yl Ester (38). To a flask containing 1.20 g
(2.67 mmol) of cycloadduct 33 in 100 mL of CH2Cl2 was added
3.72 mL (26.7 mmol) of BF3‚2AcOH, and the mixture was
stirred at rt for 24 h. The reaction was quenched with 5 mL
of EtOH, and the mixture was washed with 100 mL of H2O.
The organic layer was dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude residue was
subjected to flash silica gel chromatography to give 1.05 g
(88%) of 1-benzyl-3-hydroxy-8-methoxy-2-oxo-1,2,3,4,4a,5,6,
10b-octahydro-5,10b-propanobenzo[h]quinoline-2-carboxylic acid
ethyl ester (38) as a crystalline solid: mp 154-155 °C; IR
(neat) 3445, 1748, 1642, 1499, 1240, 728 cm-1; 1H NMR (CDCl3,
300 MHz) δ 0.98 (t, 3H, J ) 7.2 Hz), 1.23 (m, 1H), 1.43-1.47
(m, 1H), 1.54-1.64 (m, 2H), 1.68-1.72 (m, 1H), 1.85 (dd, 1H,
J ) 13.8 and 3.3 Hz), 1.98-2.02 (m, 1H), 2.15-2.24 (m, 2H),
2.44 (dt, 1H, J ) 13.2 and 3.0 Hz), 2.60 (d, 1H, J ) 18.3 Hz),
3.04 (dd, 1H, J ) 18.3 and 7.2 Hz), 3.79 (s, 3H), 3.99 (q, 2H, J
) 7.2 Hz), 4.02 (s, 1H), 4.69 (d, 1H, J ) 15.9 Hz), 5.66 (d, 1H,
N-Ben zyl-2-diazo-N-[5-(3-m eth oxyben zyl)-3-m eth ylh ept-
6-en oyl]m a lon a m ic Acid E t h yl E st er (32). N-Malonyl-
acylation of a 0.8 g sample of the above amide was carried out

86 J . Org. Chem., Vol. 62, No. 1, 1997
Padwa et al.
in the normal manner to give 0.9 g of N-benzyl-N-[5-(3-
methoxybenzyl)-3-methylhept-6-enoyl]malonamic acid ethyl
ester as a clear oil (96%): IR (neat) 1739, 1698, 1602, 1487,
137.4, 138.6, 158.0, 169.9, 171.9; HRMS calcd for C28H33NO5
470.2518, found 470.2519.
1-Ben zyl-8-m eth oxy-2-oxo-1,2,3,4,4a ,5,6,10b-octa h yd r o-
5,10b-p r op a n oben zo[h ]qu in olin e-2-ca r boxylic Acid Eth -
yl Ester (42). To a solution containing 0.50 g (1.15 mmol) of
benzo[h]quinoline 38 in 20 mL of THF was added 0.055 g (2.30
mmol) of NaH (60% dispersion in mineral oil), and the mixture
was stirred at rt for 30 min. To this mixture was added 0.48
mL (3.45 mmol) of phenyl chlorothionocarbonate via syringe,
and the reaction mixture was stirred overnight at rt. The
reaction was quenched with an aqueous NH4Cl solution, and
the reaction mixture was extracted with ether. The ether
extracts were washed with brine, dried over Na2SO4, and
filtered. The solution was concentrated under reduced pres-
sure, and the residue was subjected to flash silica gel chro-
matography to give 0.58 g (88%) of 1-benzyl-8-methoxy-2-oxo-
2-((phenoxy(thiocarbonyl))oxy)-1,2,3,4,4a,5,6,10b-octahydro-
5,10b-propanobenzo[h]quinoline-2-carboxylic acid ethyl ester
as a white solid: mp 75-76 °C; IR (neat) 1746, 1661, 1495,
1
1033 cm-1; H NMR (CDCl3, 300 MHz) δ 0.85 (d, 3H, J ) 6.3
Hz), 1.19 (m, 1H), 1.28 (t, 3H, J ) 7.2 Hz), 2.07-2.21 (m, 3H),
2.43-2.61 (m, 4H), 3.78 (s, 3H), 3.90 (d, 2H, J ) 3.9 Hz), 4.20
(q, 2H, J ) 7.2 Hz), 4.69 (d, 1H, J ) 17.1 Hz), 4.86 (d, 1H, J
) 10.2 Hz), 4.98 (d, 2H, J ) 4.8 Hz), 5.51 (dt, 1H, J ) 17.1
and 10.2 Hz), 6.64-6.67 (m, 2H), 6.72 (d, 1H, J ) 8.1 Hz),
7.14-7.19 (m, 2H), 7.27 (m, 2H), 7.34 (t, 2H, J ) 6.9 Hz); 13
C
NMR (CDCl3, 75 MHz) δ 14.0, 20.4, 27.2, 41.1, 41.7, 42.9, 43.0,
46.4, 46.8, 55.0, 61.2, 110.8, 114.7, 115.1, 121.5, 125.9, 127.3,
128.7, 128.9, 136.5, 141.7, 141.9, 159.3, 167.2, 168.7, 175.4;
Anal. Calcd for C28H35NO5: C, 72.22; H, 7.58; N, 3.01.
Found: C, 72.11; H, 7.46; N, 3.04.
A 0.8 g sample of the above compound was subjected to the
standard diazo transfer conditions to give 0.82 g of N-benzyl-
2-diazo-N-[5-(3-methoxybenzyl)-3-methylhept-6-enoyl]malonam-
ic acid ethyl ester (32) as a yellow oil (98%): IR (neat) 2128,
1720, 1648, 1323, 696 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.81
(d, 3H, J ) 6.6 Hz), 1.38 (m, 1H), 1.25 (t, 3H, J ) 7.2 Hz),
2.04 (m, 1H), 2.15 (dd, 1H, J ) 15.6 and 8.4 Hz), 2.22 (m, 1H),
2.37-2.46 (m, 2H), 2.50-2.60 (m, 2H), 3.74 (s, 3H), 4.21 (q,
2H, J ) 7.2 Hz), 4.71 (d, 1H, J ) 17.1 Hz), 4.83 (m, 3H), 5.48
(dt, 1H, J ) 17.1 and 10.2 Hz), 6.61-6.69 (m, 3H), 7.12 (t, 1H,
J ) 7.8 Hz), 7.19-7.30 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ
14.1, 20.3, 27.7, 41.2, 41.5, 42.3, 42.6, 42.9, 49.0, 54.9, 61.7,
110.8, 114.6, 115.0, 121.6, 127.1, 127.2, 127.3, 128.5, 128.8,
137.0, 141.9, 159.2, 160.3, 166.3, 174.7.
1
729 cm-1; H NMR (CDCl3, 300 MHz) δ 1.12 (t, 3H, J ) 7.2
Hz), 1.18 (m, 1H), 1.40-1.44 (m, 1H), 1.52-1.61 (m, 2H), 1.66-
1.71 (m, 1H), 1.96-2.00 (m, 1H), 2.16 (m, 1H), 2.43 (dt, 1H, J
) 12.6 and 3.3 Hz), 2.54-2.70 (m, 2H), 3.02-3.15 (m, 2H),
3.75 (s, 3H), 4.00 (m, 2H), 4.70 (d, 1H, J ) 15.9 Hz), 5.69 (d,
1H, J ) 15.9 Hz), 6.62 (d, 1H, J ) 2.4 Hz), 6.72 (dd, 1H, J )
8.7 and 2.4 Hz), 7.10-7.30 (m, 10H), 7.38 (t, 1H, J ) 7.8 Hz);
13C NMR (CDCl3, 75 MHz) δ 13.6, 18.6, 30.9, 31.6, 32.3, 33.5,
38.1, 39.4, 48.9, 55.0, 60.2, 62.4, 63.1, 85.5, 112.3, 112.4, 121.8,
126.2, 126.3, 126.4, 126.5, 128.4, 129.4, 130.5, 137.9, 138.7,
153.1, 158.2, 163.7, 165.8, 191.2.
10-Ben zyl-5-(3-m eth oxyben zyl)-3-m eth yl-9-oxo-11-oxa -
10-a za tr icyclo[6.2.1.01,6]u n d eca n e-8-ca r boxylic Acid Eth -
yl Ester (34). A sample containing 0.90 g (1.86 mmol) of diazo
imide 32 in 30 mL of CH2Cl2 was treated with 5 mg of
rhodium(II) perfluorobutyrate at rt for 24 h. The mixture was
concentrated under reduced pressure, and the residue was
subjected to flash silica gel chromatography to give 0.82 g
(95%) of 10-benzyl-5-(3-methoxybenzyl)-3-methyl-9-oxo-11-oxa-
10-azatricyclo[6.2.1.01,6]undecane-8-carboxylic acid ethyl ester
(34 and 35) as a 3:2 mixture of diastereomers. The minor
diastereomer was a crystalline solid: mp 142-143 °C; IR (neat)
1750, 1722, 1599, 1454, 732 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 0.73 (m, 1H), 0.82 (d, 3H, J ) 6.6 Hz), 1.35 (t, 3H, J ) 7.2
Hz), 1.37-1.53 (m, 3H), 1.85 (m, 1H), 1.97-2.07 (m, 2H), 2.18
(d, 1H, J ) 13.5 Hz), 2.30 (dd, 1H, J ) 13.2 and 3.3 Hz), 2.50
(dd, 1H, J ) 13.5 and 10.5 Hz), 2.67 (dd, 1H, J ) 13.8 and 5.4
Hz), 3.73 (s, 3H), 4.38 (q, 2H, J ) 7.2 Hz), 4.30 (d, 1H, J )
15.6 Hz), 4.48 (d, 1H, J ) 15.6 Hz), 6.60 (m, 2H), 6.68 (dd,
1H, J ) 8.1 and 2.4 Hz), 7.13 (t, 1H, J ) 7.8 Hz), 7.25 (m,
5H); 13C NMR (CDCl3, 75 MHz) δ 14.2, 21.8, 22.0, 30.8, 35.1,
35.3, 35.4, 36.1, 43.2, 44.4, 55.0, 62.1, 85.3, 98.0, 111.0, 114.3,
121.0, 127.6, 127.7, 128.7, 129.2, 136.5, 142.6, 159.5, 165.8,
171.1; Anal. Calcd for C28H33NO5: C, 72.54; H, 7.19; N, 3.02.
Found: C, 72.29; H, 7.18; N, 2.96.
1-B e n z y l-3-h y d r o x y -8-m e t h o x y -12-m e t h y l-2-o x o -
1,2,3,4,4a ,5,6,10b-octa h yd r o-5,10b-p r op a n oben zo[h ]qu in -
olin e-2-ca r boxylic Acid Eth yl Ester (9). To a flask con-
taining 0.77 g (1.66 mmol) of the above mixture of diastereo-
meric cycloadducts (34/35) in 100 mL of CH2Cl2 was added
2.31 mL (16.6 mmol) of BF3‚2AcOH, and the solution was
stirred at rt for 36 h. The reaction was quenched with 5 mL
of EtOH, and the reaction mixture was washed with water.
The organic extracts were concentrated under reduced pres-
sure, and the crude residue was subjected to flash silica gel
chromatography to give 0.51 g (71%) of 1-benzyl-3-hydroxy-
8-methoxy-12-methyl-2-oxo-1,2,3,4,4a,5,6,10b-octahydro-5,10b-
propanobenzo[h]quinoline-2-carboxylic acid ethyl ester (9) as
a crystalline solid: mp 73-74 °C; IR (neat) 1744, 1641, 1259,
1119, 729 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.67 (d, 3H, J )
6.0 Hz), 0.95 (t, 3H, J ) 7.2 Hz), 1.23-1.37 (m, 3H), 1.70 (m,
1H), 1.84 (dd, 1H, J ) 13.8 and 2.7 Hz), 1.98 (m, 1H), 2.13-
2.21 (m, 2H), 2.37 (m, 1H), 2.58 (d, 1H, J ) 18.3 Hz), 3.01 (dd,
1H, J ) 18.3 and 7.2 Hz), 3.75 (s, 3H), 3.96 (q, 2H, J ) 7.2
Hz), 4.03 (s, 1H), 4.70 (d, 1H, J ) 15.9 Hz), 5.59 (d, 1H, J )
15.9 Hz), 6.60 (s, 1H), 6.72 (d, 1H, J ) 8.4 Hz), 7.14 (d, 1H, J
) 8.7 Hz), 7.19-7.29 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ
13.4, 21.5, 24.9, 31.9, 32.9, 33.8, 39.0, 42.4, 46.3, 47.8, 55.0,
61.7, 63.5, 75.0, 112.2, 112.3, 125.9, 126.2, 126.4, 128.3, 131.9,
To a solution containing 0.43 g (0.74 mmol) of the above
thionocarbonate in 10 mL of toluene was added 0.12 g (0.74
mmol) of AIBN, followed by 1.0 mL (3.71 mmol) of tributyltin
hydride. The solution was heated at 75 °C for 5 h, cooled to
rt, and concentrated under reduced pressure. The residue was
subjected to flash silica gel chromatography to give 0.26 g
(80%) of 1-benzyl-8-methoxy-2-oxo-1,2,3,4,4a,5,6,10b-octahy-
dro-5,10b-propanobenzo[h]quinoline-2-carboxylic acid ethyl
ester (42) as a 3:2 inseparable mixture of diastereomers: mp
51-55 °C; IR (neat) 1736, 1642, 1496, 730 cm-1
;
1H NMR
(CDCl3, 300 MHz) δ 1.26 (t, 3H, J ) 7.2 Hz), 1.39-1.69 (m,
5H), 1.75-2.03 (m, 2H), 2.07-2.16 (m, 2H), 2.29 (m, 1H), 2.53
(d, 1H, J ) 18.3 Hz), 3.00-3.17 (m, 2H), 3.76 (s, 3H), 4.19 (m,
2H), 4.59 (d, 0.7H, J ) 16.2 Hz), 4.61 (d, 0.3H, J ) 16.2 Hz),
5.71 (d, 0.7H, J ) 16.2 Hz), 5.74 (d, 0.3H, J ) 16.2 Hz), 6.61
(s, 1H), 6.72 (d, 1H, J ) 8.7 Hz), 7.08 (d, 1H, J ) 8.7 Hz),
7.14-7.31 (m, 5H); HRMS calcd for C27H31NO4 433.2253, found
433.2254.
1-Ben zyl-8-m eth oxy-2-oxo-1,2,3,4,4a ,5,6,10b-octa h yd r o-
5,10b-p r op a n oben zo[h ]qu in olin e (43). A solution contain-
ing 0.40 g (0.92 mmol) of the ester 42 in 8 mL of a 2 M aqueous
KOH solution was heated at 95 °C for 24 h. The reaction
mixture was cooled to rt and acidified with concentrated HCl.
The solution was poured into 10 mL of H2O and extracted with
EtOAc. The EtOAc extracts were dried over Na2SO4, filtered,
and concentrated under reduced pressure. The crude residue
was taken up in xylene and heated at 160 °C for 3 h. After
being cooled to rt, the reaction mixture was concentrated under
reduced pressure and subjected to flash silica gel chromatog-
raphy to give 0.30 g (87%) of 1-benzyl-8-methoxy-2-oxo-1,2,3,4,
4a,5,6,10b-octahydro-5,10b-propanobenzo[h]quinoline (43) as
a crystalline solid: mp 155-156 °C; IR (neat) 1642, 1605, 1495,
728 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.15 (dt, 1H, J ) 13.5
and 4.2 Hz), 1.40-1.81 (m, 6H), 1.96-2.09 (m, 2H), 2.16-2.30
(m, 2H), 2.52 (t, 1H, J ) 8.1 Hz), 2.58 (t, 1H, J ) 8.1 Hz), 3.11
(dd, 1H, J ) 18.1 and 7.2 Hz), 3.77 (s, 3H), 4.59 (d, 1H, J )
15.9 Hz), 5.76 (d, 1H, J ) 15.9 Hz), 6.63 (s, 1H), 6.73 (dd, 1H,
J ) 8.7 and 2.4 Hz), 7.12 (d, 1H, J ) 8.7 Hz), 7.19-7.34 (m,
5H); 13C NMR (CDCl3, 75 MHz) δ 18.8, 22.8, 31.1, 31.6, 33.2,
33.8, 38.1, 42.8, 47.0, 55.0, 62.3, 112.3, 112.4, 125.9, 126.2,
126.3, 128.3, 132.6, 138.1, 140.0, 157.9, 172.1; Anal. Calcd for
C24H27NO2: C, 79.73; H, 7.54; N, 3.87. Found: C, 79.76; H,
7.56; N, 3.91.
1-Cycloh exyl-8-m eth oxy-2-oxo-1,2,3,4,4a,5,6,10b-octah y-
d r o-5,10b-p r op a n oben zo[h ]qu in olin e (44). To a solution
containing 0.26 g (0.71 mmol) of amide 43 in 5 mL of a 4:1
mixture of MeOH/AcOH was added 40 mg (0.17 mmol) of PtO2.

Intramolecular Cycloaddition-Cationic π-Cyclization
J . Org. Chem., Vol. 62, No. 1, 1997 87
The mixture was hydrogenated at 40 psi for 24 h. At the end
of this time, the mixture was filtered through Celite and
washed with EtOAc. The filtrate was concentrated under
reduced pressure and subjected to flash silica gel chromatog-
raphy to give 0.20 g (99%) of 1-cyclohexyl-8-methoxy-2-oxo-
1,2,3,4,4a,5,6,10b-octahydro-5,10b-propanobenzo[h]quinoline
(44) as a crystalline solid: mp 136-137 °C; IR (neat) 2925,
2847, 1641, 1498, 729 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.02
(m, 2H), 1.20 (m, 4H), 1.47-1.86 (m, 12H), 1.96-2.08 (m, 3H),
2.17 (m, 1H), 2.35 (dt, 1H, J ) 16.8 and 7.8 Hz), 2.53 (d, 1H,
J ) 18.3 Hz), 3.11 (dd, 1H, J ) 18.3 and 7.5 Hz), 3.20 (dd, 1H,
J ) 13.5 and 7.5 Hz), 3.75 (s, 3H), 4.13 (dd, 1H, J ) 13.5 and
7.5 Hz), 6.58 (d, 1H, J ) 2.4 Hz), 6.66 (dd, 1H, J ) 8.7 and 2.4
Hz), 6.97 (d, 1H, J ) 8.7 Hz);13C NMR (CDCl3, 75 MHz) δ 19.2,
22.8, 26.1, 26.3, 30.8, 31.4, 31.5, 33.5, 33.9, 38.6, 38.8, 42.1,
49.5, 54.9, 61.5, 112.1, 112.2, 125.9, 133.3, 138.0, 157.7, 172.4;
Anal. Calcd for C24H33NO2: C, 78.42; H, 9.07; N, 3.81.
Found: C, 78.50; H, 9.05; N, 3.89.
1-Ben zyl-8-m eth oxy-12-m eth yl-2-oxo-1,2,3,4,4a ,5,6,10b-
oc t a h y d r o-5,10b -p r o p a n o b e n zo [h ]q u in o lin e -2-c a r b -
oxylic Acid Eth yl Ester (45). To a solution containing 0.51
g (1.09 mmol) of alcohol 9 in 20 mL of THF was added 0.11 g
(2.73 mmol) of NaH (60% dispersion in mineral oil), and the
mixture was stirred at rt for 30 min. To this mixture was
added 0.45 mL (3.28 mmol) of phenyl chlorothionocarbonate
via syringe, and the reaction mixture was stirred overnight
at rt. The reaction was quenched with an aqueous NH4Cl
solution and the mixture was extracted with ether. The ether
extracts were washed with brine, dried over Na2SO4, and
filtered. The solution was concentrated under reduced pres-
sure, and the residue was subjected to flash silica gel chro-
matography to give 0.52 g (80%) of 1-benzyl-8-methoxy-12-
methyl-2-oxo-2-((phenoxy(thiocarbonyl))oxy)-1,2,3,4,4a,5,6,10b-
octahydro-5,10b-propanobenzo[h]quinoline-2-carboxylic acid
ethyl ester as a white solid: mp 70-71 °C; IR (neat) 2911,
1741, 1661, 1495, 728 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.70
(d, 3H, J ) 5.7 Hz), 1.15 (t, 3H, J ) 7.2 Hz), 1.31 (m, 3H),
1.74 (m, 1H), 2.01 (m, 1H), 2.22 (m, 1H), 2.41 (m, 1H), 2.58-
2.72 (m, 2H), 3.08-3.17 (m, 2H), 3.78 (s, 3H), 4.03 (q, 2H, J )
7.2 Hz), 4.75 (d, 1H, J ) 15.6 Hz), 5.67 (d, 1H, J ) 15.6 Hz),
6.63 (s, 1H), 6.73 (d, 1H, J ) 8.7 Hz), 7.12-7.22 (m, 3H), 7.28-
7.44 (m, 8H).
(CDCl3, 300 MHz) δ 0.70 (d, 3H, J ) 6.3 Hz), 1.24 (m, 2H),
1.34 (m, 1H), 1.56-1.81 (m, 4H), 2.02 (m, 1H), 2.18-2.28 (m,
2H), 2.52 (dd, 1H, J ) 17.2 and 8.1 Hz), 2.56 (d, 1H, J ) 18.6
Hz), 3.11 (dd, 1H, J ) 18.6 and 7.5 Hz), 3.78 (s, 3H), 4.62 (d,
1H, J ) 15.9 Hz), 5.71 (d, 1H, J ) 15.9 Hz), 6.61 (s, 1H), 6.71
(dd, 1H, J ) 8.7 and 2.7 Hz), 7.11 (d, 1H, J ) 8.7 Hz), 7.19-
7.34 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 21.7, 22.5, 25.1,
31.1, 31.9, 33.6, 42.5, 42.6, 46.8, 47.0, 55.0, 62.5, 112.2, 112.5,
125.9, 126.3, 126.4, 128.3, 133.4, 137.8, 139.9, 158.0, 172.1;
Anal. Calcd for C25H29NO2: C, 79.95; H, 7.79; N, 3.72.
Found: C, 80.06; H, 7.70; N, 3.63.
8-Meth oxy-12-m eth yl-1,2,3,4,4a ,5,6,10b-octa h yd r o-1H-
5,10b-p r op a n oben zo[h ]qu in olin e (8). To a flask containing
0.21 g (0.55 mmol) of benzo[h]quinoline 46 in 8 mL of a 1:1
mixture of Et2O/THF was added 5.51 mL (5.51 mmol) of a 1
M solution of LiAlH4 in THF at 0 °C. The solution was slowly
warmed to rt, was stirred for 1 h at 25 °C, and was then heated
at 75 °C for an additional 48 h. After being cooled to rt, the
mixture was cooled to 0 °C and the reaction was quenched
with 10 mL of a 5% aqueous NaOH solution. The aluminum
salts were filtered and washed with ether. The filtrate was
poured into 20 mL of H2O, and the mixture was extracted with
ether. The ether extracts were dried over Na2SO4, filtered,
and concentrated under reduced pressure. The crude residue
was subjected to flash silica gel chromatography to give 0.127
g (81%) of 1-benzyl-8-methoxy-12-methyl-1,2,3,4,4a,5,6,10b-
octahydro-5,10b-propanobenzo[h]quinoline as a tan oil: IR
1
(neat) 1604, 1491, 1237, 906, 730 cm-1; H NMR (CDCl3, 300
MHz) δ 0.79 (d, 3H, J ) 5.1 Hz), 0.93 (m, 1H), 1.19 (m, 1H),
1.36 (m, 2H), 1.40-1.61 (m, 3H), 1.74-1.84 (m, 2H), 1.90 (dt,
1H, J ) 12.6 and 3.3 Hz), 2.04 (m, 1H), 2.48-2.54 (m, 2H),
2.66 (m, 1H), 3.13 (dd, 1H, J ) 16.9 and 6.9 Hz), 3.82 (s, 3H),
4.22 (d, 2H, J ) 7.8 Hz), 6.66 (s, 1H), 6.83 (dd, 1H, J ) 8.7
and 2.4 Hz), 7.27 (m, 1H), 7.39 (t, 2H, J ) 7.2 Hz), 7.55 (d,
2H, J ) 7.2 Hz), 7.76 (d, 1H, J ) 8.7 Hz); 13C NMR (CDCl3, 75
MHz) δ 21.6, 22.5, 26.6, 27.1, 32.6, 34.6, 39.4, 44.1, 45.7, 48.2,
51.1, 54.9, 59.9, 111.9, 112.0, 126.2, 127.4, 127.8, 128.0, 134.7,
139.6, 142.9, 157.3; HRMS calcd for C25H31NO 361.2405, found
361.2393.
To a solution containing 0.13 g (0.35 mmol) of the above
amine in 5 mL of a 4:1 mixture of CH2Cl2/MeOH was added
50 mg of 10% Pd/C. The mixture was hydrogenated at 30 psi
for 20 h. At the end of this time, the mixture was filtered
through Celite and washed with EtOAc. The filtrate was
concentrated under reduced pressure and subjected to flash
silica gel chromatography to give 89 mg (90%) of 8-methoxy-
12-methyl-1,2,3,4,4a,5,6,10b-octahydro-1H-5,10b-propanoben-
zo[h]quinoline (8) as a yellow oil: IR (neat) 2705, 1602, 1502,
To a solution containing 0.51 g (0.85 mmol) of the above
thionocarbonate in 10 mL of toluene was added 0.14 g (0.85
mmol) of AIBN, followed by 1.14 mL (4.25 mmol) of tributyltin
hydride. The solution was heated at 45 °C for 5 h, cooled to
rt, and concentrated under reduced pressure. The residue was
subjected to flash silica gel chromatography to give 0.37 g
(96%) of 1-benzyl-8-methoxy-12-methyl-2-oxo-1,2,3,4,4a,5,6,
10b-octahydro-5,10b-propanobenzo[h]quinoline-2-carboxylic acid
ethyl ester (45) as a 3:2 inseparable mixture of diastereo-
mers: mp 48-49 °C; IR (neat) 1731, 1643, 1495, 1265, 730
1
1253, 784 cm-1; H NMR (CDCl3, 300 MHz) δ 0.79 (m, 3H),
0.85 (m, 2H), 1.24-1.41 (m, 3H), 1.54-1.79 (m, 3H), 1.87 (m,
1H), 2.05 (m, 1H), 2.09 (m, 2H), 2.53 (d, 1H, J ) 18.0 Hz),
2.81 (t, 1H, J ) 12.9 Hz), 3.07 (dd, 1H, J ) 18.0 and 6.6 Hz),
3.19 (d, 1H, J ) 12.3 Hz), 3.78 (s, 3H), 6.64 (s, 1H), 6.85 (dd,
1H, J ) 8.7 and 2.1 Hz), 7.77 (d, 1H, J ) 8.7 Hz); 13C NMR
(CDCl3, 75 MHz) δ 21.5, 23.6, 24.6, 25.8, 31.9, 33.3, 40.3, 41.8,
42.8, 47.9, 54.9, 60.1, 112.7, 113.0, 126.4, 126.9, 139.0, 158.2;
HRMS calcd for C18H25NO 271.1936, found 271.1930.
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.71 (d, 3H, J ) 5.4 Hz),
1.28 (t, 3H, J ) 7.2 Hz), 1.34 (m, 2H), 1.67 (m, 2H), 1.85 (m,
1H), 2.00 (m, 2H), 2.21 (m, 2H), 2.56 (d, 0.67H, J ) 18.3 Hz),
2.59 (d, 0.33H, J ) 18.3 Hz), 3.03 (d, 0.33H, J ) 7.2 Hz), 3.09
(d, 0.67H, J ) 7.2 Hz), 3.15 (m, 1H), 3.78 (s, 3H), 4.22 (m,
2H), 4.64 (d, 0.67H, J ) 15.9 Hz), 4.66 (d, 0.33H, J ) 15.9
Hz), 5.68 (d, 0.67H, J ) 15.9 Hz), 5.71 (d, 0.33H, J ) 15.9
Hz), 6.61 (s, 1H), 6.73 (d, 1H, J ) 8.4 Hz), 7.09 (d, 1H, J ) 8.4
Hz), 7.19-7.33 (m, 5H); HRMS calcd for C28H33NO4 447.2409,
found 447.2349.
Ack n ow led gm en t. We gratefully acknowledge the
National Cancer Institute (Grant CA-26751), DHEW,
for generous support of this work. Use of the high-field
NMR spectrometer used in these studies was made
possible through equipment grants from the NIH and
NSF.
1-Ben zyl-8-m eth oxy-12-m eth yl-2-oxo-1,2,3,4,4a ,5,6,10b-
octa h yd r o-5,10b-p r op a n oben zo[h ]qu in olin e (46). A solu-
tion containing 0.38 g (0.85 mmol) of ester 45 in 8 mL of a 2
M aqueous KOH solution was heated at 95 °C for 24 h. The
reaction mixture was cooled to rt and acidified with concen-
trated HCl. The solution was poured into 10 mL of H2O and
extracted with EtOAc. The EtOAc extracts were dried over
Na2SO4, filtered, and concentrated under reduced pressure.
The crude residue was taken up in xylene and heated at 160
°C for 3 h. After being cooled to rt, the reaction mixture was
concentrated under reduced pressure and subjected to flash
silica gel chromatography to give 0.27 g (85%) of 1-benzyl-8-
methoxy-12-methyl-2-oxo-1,2,3,4,4a,5,6,10b-octahydro-5,10b-
propanobenzo[h]quinoline (46) as a crystalline solid: mp 131-
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for all compounds with high-resolution mass
spectra together with ORTEP drawings for structures 38 and
46 (9 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
1
132 °C; IR (neat) 1641, 1606, 1496, 1266, 729 cm-1; H NMR
J O960829P