[3 + 2] Cycloaddition of Nonstabilized Azomethine Ylides. 8. An Efficient Synthetic Strategy for Epiboxidine

Full text of DOI:10.1021/jo9903757

4990
J . Org. Chem. 1999, 64, 4990-4994
[3 + 2] Cycloa d d ition of Non sta bilized
Azom eth in e Ylid es. 8.† An Efficien t
Syn th etic Str a tegy for Ep iboxid in e
Ganesh Pandey,* Akhila K. Sahoo, Smita R. Gadre,
Trusar D. Bagul, and Usha D. Phalgune
Divison of Organic Chemistry (Synthesis),
National Chemical Laboratory, Pune-411 008, India
antagonist ABT 4187a,b (5) and 1 and named it epiboxi-
dine (6). Compound 6 was shown3 to be a potent nicotinic
Received March 2, 1999
In tr od u ction
Epibatidine (1), isolated by Daly et al.1a in 1992, was
found to be a member of an entirely new class of alkaloids
possessing an organochlorine compound with the 7-aza-
bicyclo[2.2.1]heptane framework. Biological and phar-
macological studies exhibited its powerful analgesic
properties in a nonopiod fashion1a and potent antinoci-
ceptive activity via activation of central nicotinic re-
ceptors.1b,2a-c The various pharmacological properties led
researchers to recognize 1 as a therapeutically important
drug target. However, due to its high toxicity (causing
death in mice at 10 µL/kg scale), its therapeutic develop-
ment has become a major impediment.3
receptor agonist and 10-fold less potent antinociceptive
agent with 20-fold less toxicity than 1. Compound 6 was
synthesized by them3 utilizing N-protected-2-exo-(car-
boalkoxy)-7-azabicyclo[2.2.1]heptane 7 as a key precur-
sor. Synthesis of 7 was achieved by the Favorskii
rearrangement of tropinone, a strategy reported by Bai
et al.4a The oxazolidine moiety was later constructed from
carbomethoxy moiety of 7 by a known protocol.7a Later,
Singh and Basmadjian8 have also reported the synthesis
of 7 in four steps by utilizing [4 + 2] cycloaddition of
N-Boc-pyrrole and methyl 3-bromopropiolate as the key
step.
However, both these approaches suffer from poor yield
during the azabicyclic formation step itself. Considering
the therapeutic potentials of 6 and the lack of syntheti-
cally viable strategy, we have devised an attractive
approach for the synthesis of 7 by the [3 + 2] cycloaddi-
tion of an in situ generated nonstabilized azomethine
ylide 9 with ethyl acrylate and its further transformation
to 6 in good yield. An alternate approach for the con-
struction of 7 utilizing azanorbornadiene 18, prepared
by a modified [4 + 2]-cycloaddition approach of pyrrole
with dimethyl acetylenedicarboxylate (DMAD), has also
been described for comparison purposes. Details of both
approaches are described herein.
Hence, there has been a renewed interest toward
searching for a pharmacophore related to the structure
of 1 that exhibits pharmacological properties similar to
1 but with better ratios of pharmacological to toxicological
activity. In this context, various groups have begun
perceiving compounds analogous to 1 by combining
structural features of the known alkaloids having high
affinity toward nicotinic receptors with that of 1 and
study their activity as well as toxicity. These studies have
led to the design and synthesis of various newer ana-
logues such as 2,4a,b 3,5 and UB 1656 (4).
Resu lts a n d Discu ssion
Daly et al.3 designed a pharmacophore by combining
the structural features of the known nicotinic receptor
[3 + 2]-Cycloa d d ition Ap p r oa ch . Our synthetic
strategy for the synthesis of 6 was envisioned through
the retrosynthetic route as shown in Scheme 1. The [3 +
2] cycloaddition of azomethine ylide 9, where whole of
the ylide conjugation is inside the ring of pyrrolidine, with
ethyl acrylate was expected to lead to azabicyclic precur-
sor 7 stereoselectively. The in situ generation of 9 from
the precursor 10 can be achieved9a-c by the sequential
one-electron oxidation of 10 employing Ag(I)F as the one-
† For part 7, see ref 9c.
(1) (a) Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh, H. J .
C.; Pannell, L.; Daly, J . W. J . Am. Chem. Soc. 1992, 114, 3475. (b)
Badio, B.; Daly, J . W. Mol. Pharmacol. 1994, 45, 563.
(2) (a) Qian, C.; Li, T.; Shen, T. Y.; Libertine-Garaham, L.; Eckman,
J .; Biftu, T.; Ip, S. Eur. J . Pharmacol. 1993, 250, R13. (b) Li, T.; Qian,
C.; Eckman, J .; Huang, D. F.; Shen, T. Y. Bioorg. Med. Chem. Lett.
1993, 3, 2759. (c) Fisher, M.; Huang, D. F.; Shen, T. Y.; Guyenet, P.
G. J . Pharmacol. Exp. Ther. 1994, 270, 702.
(3) Badio, B.; Garraffo, H. M.; Plummer, C. V.; Padgett, W. L.; Daly,
J . W. Eur. J . Pharmacol. 1997, 321, 189.
(4) (a) Bai, D.; Xu, R.; Chu, G.; Zhu, X. J . Org. Chem. 1996, 61, 4600.
(b) Malpass, J . R.; Hemmings, D. A.; Wallis, A. L. Tetrahedron Lett.
1996, 37, 3911.
(5) Zhang, C.; Gyermek, L.; Trudell, M. L. Tetrahedron Lett. 1997,
38, 5619.
(6) Wright, E.; Gallagher, T.; Sharples, C. G. V.; Wonnacott, S.
Bioorg. Med. Chem. Lett. 1997, 7, 2867.
(7) (a) Elliot, R. L.; Kopecka, H.; Lin, N.-H.; He, Y.; Garvey, D. S.
Synthesis 1995, 772. (b) Garvey, D. S.; Wasicak, J . T.; Decker, M. W.;
Brioni, J . D.; Buckley, M. J .; Sullian, J . P.; Carrera, G. M.; Holladay,
M. W.; Arneric’, S. P.; Williams, M. J . J . Med. Chem. 1994, 37, 1055.
(8) Singh, S; Basmadjian, G. P. Tetrahedron Lett. 1997, 38, 6829.
(9) (a) Pandey, G.; Lakshmaiah, G.; Ghatak, A. Tetrahedron Lett.
1993, 34, 7301. (b) Pandey, G.; Bagul, T. D.; Lakshmaiah, G. Tetra-
hedron Lett. 1994, 35, 7439. (c) Pandey, G.; Bagul, T. D.; Sahoo, A. K.
J . Org. Chem. 1998, 63, 760.
10.1021/jo9903757 CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/06/1999

Notes
J . Org. Chem., Vol. 64, No. 13, 1999 4991
Sch em e 1
Sch em e 3
Sch em e 4
Sch em e 2
electron oxidant. Ylide precursor 10 is obtained9c in 65%
yield starting from N-Boc-2-(trimethylsilyl)pyrrolidine10
(Scheme 1).
The key [3 + 2]-cycloaddition reaction was carried out
at room temperature by the slow addition of a solution
of ethyl acrylate in DCM to a stirring suspension of
vacuum-dried Ag(I)F and 10 in DCM. The reaction was
complete in 8-10 h with concomitant formation of silver
mirror on the walls of the reaction flask. Chromato-
graphic purification afforded a mixture of two stereoiso-
meric cycloadducts 11 and 12 in a 4:1 ratio in 75% yield
(Scheme 2). These cycloadducts were further separated
by careful column chromatography for spectral analysis
and were characterized by 1H NMR, 13C NMR, and mass
spectral data. The stereochemistry of the major cycload-
duct 11, indicating exo orientation of the carbethoxy
struction of oxazolidine moiety to avoid complications at
the later stage of the synthesis. In this context, N-
debenzylation of the cycloadducts (mixture of 11 and 12)
was carried out by hydrogenation over Pearlman’s cata-
lyst (10% Pd(OH)2) at 40 psi of hydrogen. The crude
mixture was treated with (Boc)2O in the presence of Et3N
in DCM at room temperature to afford the carbamates
13 and 14. The undesired endo isomer 14 was epimerized
to the required 13, quantitatively by treating with K2-
CO3 in MeOH at 80 °C12a, b.(Scheme 3).
With the key precursor 13 in hand, we transformed
its carbethoxy moiety into the 2-methyloxazolidine by
treating with the dianion of acetone oxime, obtained by
reacting 15 with 2 equiv of n-BuLi in THF at 0 °C,
followed by treating the reaction mixture with 11 M HCl
at 80 °C, which afforded product 6 in 41% yield (Scheme
1
moiety, was determined by detailed H NMR decoupling
and 1H COSY experiments. For illustration, proton H2
at δ 2.40 (dd, J ) 9.30, 4.90 Hz) was found to couple only
with the adjacent two H3exo and H3endo hydrogens at δ 2.25
(m, 1H) and δ 1.50 (dd, J ) 12.2, 9.3 Hz, 1H), respec-
tively, but not with the bridgehead proton H1 at δ 3.63
(bs, 1H). This observation is found to be in conformity
with the 1H NMR patterns of the 7-azabicyclo[2.2.1]-
heptane systems1a,11a,b where no coupling is observed
between bridgehead and adjacent endo hydrogens. This
confirms the exo orientation for the carbethoxy moiety
in major diastereomeric cycloadduct 11. As expected, in
the case of minor cycloadduct 12, the H2 hydrogen at δ
3.10 (m, 1H) was found to couple with both H3 hydrogens
at δ 1.90-2.10 (m, 1H) and δ 1.65 (m, 1H), respectively,
and also with H1 at δ 3.55 (t, J ) 4.26 Hz), confirming
the endo orientation of the carbethoxy moiety.
1
4). Product 6 was confirmed as epiboxidine by H and
13C NMR and mass spectral analysis, which was also
found to be in complete agreement with the data reported
by Badio et al.3 The retention of the exo stereochemistry
1
in 6 was once again ascertained by the detailed H NMR
decoupling and COSY experiments.
[4 + 2]-Cycloa d d ition a s a n Alter n a te Str a tegy.
The synthesis of 6 was also designed alternatively
through the azanorbornadiene 18, easily obtainable by
the [4 + 2] cycloaddition of N-carbomethoxypyrrole (19)
and dimethyl acetylenedicarboxylate (20) as shown ret-
rosynthetically in Scheme 5.
The known cycloaddition protocol by heating a neat
mixture of 19 with 20 afforded 18 in poor yield13 (42%)
due to competing Michael addition and retro-Diels-Alder
To carry out further synthetic transformations to
accomplish the synthesis of 6, it was mandatory to cleave
the N-benzyl moiety from 11 and 12 prior to the con-
(12) (a) Okabe, K.; Natsume, M. Chem. Pharm. Bull. 1994, 42, 1432.
(b) The epimerization could be achieved quantitatively; however,
hydrolysis of the carbethoxy moiety during the aqueous workup also
takes place. Therefore, the crude mixture obtained was esterified to
yield 13 quantitatively by treatment with thionyl chloride in ethanol.
(10) Beak, P.; Lee, W. K. J . Org. Chem. 1993, 58, 1109.
(11) (a) Fraser, R. R.; Swingle, R. B. Can. J . Chem. 1970, 48, 2065.
(b) Ramey, K. C.; Gopal, H.; Welsh, H. G. J . Am. Chem. Soc. 1967, 89,
2401.

4992 J . Org. Chem., Vol. 64, No. 13, 1999
Notes
Sch em e 5
Sch em e 7
Sch em e 8
Sch em e 6
corresponding acid chloride by treatment with 5 equiv
of oxalyl chloride and was subsequently transformed into
the thiohydroximate ester by stirring with 2-mercapto-
pyridine N-oxide in the presence of triethylamine in
benzene. Pyrrolysis of the resultant thiohydroximate
ester in benzene in the presence of t-BuSH affected
reductive radical monodecarboxylation to yield the ester
intermediates 23 and 17 in 65% yield. The unexpected
formation of stereoisomer 17 is possible by the epimer-
ization caused by stirring in the presence of triethylamine
for a longer period. Further epimerization of 23 gave exo
intermediate 17 quantitatively (Scheme 6).
Although we could synthesize 17 by this approach, the
moderate yield encountered in the reductive radical
decarboxylation step using t-BuSH as radical trap
prompted us to develop an indirect route. We envisaged
the use of PhSeSePh, known17 to be a better and efficient
radical trapping agent than tert-butyl mercaptan. Thus,
the photolysis (400 W tungsten lamp) of thiohydroximate
ester in the presence of PhSeSePh gave selenylated
products 24 and 25 in a 4:1 ratio in 80% yield (Scheme
7).
The mixture of these two selenides 24 and 25 was
treated with H2O2 for deselenylation purposes. As ex-
pected, 25 did not undergo oxidative elimination of the
phenylselenyl moiety, whereas the selenide 24 afforded
26 in 95% yield. It is possible to reductively remove the
phenylselenyl moiety from 25 by the known protocol18 to
afford 17 directly. Hydrogenation of 26 yielded 23
exclusively, which upon epimerization gave key precursor
17 as shown in Scheme 8.
reaction.14 Therefore, it was decided to carry out this
cycloaddition reaction at lower temperatures (40 °C)
using AlCl3 as Lewis acid.15a,b Stirring of a mixture
containing 19 and 20 in DCM at 40 °C in the presence of
AlCl3 (1 equiv) afforded 18 in 90% yield. Cycloadduct 18
was hydrogenated at 45 psi using 10% Pd/C as catalyst
to yield azanorbornane 21 in 95% yield (Scheme 6). To
obtain the required precursor 17, removal of one of the
carboxylate moieties from 21 was essential. Of the
various decarboxylation protocols available, the Barton16
reductive radical decarboxylation route by the pyrrolysis/
photolysis of the corresponding thiohydroximate ester in
the presence of radical scavengers was selected to achieve
the monodecarboxylation of azanorbornane diester 21.
To this end, the diester 21 was hydrolyzed with 1 equiv
of LiOH in MeOH/H2O (3:1) to obtain monoacid ester 22
in 90% yield. The crude 22 was converted into its
Con clu sion . From the above discussions, it appears
that the [3 + 2]-cycloaddition approach for the construc-
(13) Kitzing, R.; Fuchs, R.; J oyeux, M.; Prinzbach, H. Helv. Chim.
Acta 1968, 51, 888.
(14) Chen, Z.; Trudell, M. Chem. Rev. 1996, 96, 1179.
(15) (a) Bansal, R. C.; McCulloch, A. W.; McInnes, A. G. Can. J .
Chem. 1969, 47, 2391. (b) Bansal, R. C.; McCulloch, A. W.; McInnes,
A. G. Can. J . Chem. 1970, 48, 1472.
(16) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron
1985, 41, 3901.
(17) Barton, D. H. R.; Bridon, D.; Zard, S. Z. Tetrahedron Lett. 1984,
25, 5777.
(18) (a) Sevrin, M.; Van Ende, D.; Krief, A. Tetrahedron Lett. 1976,
2643. (b) Corey, E. J .; Pearce, H. L.; Szekely, I.; Ishiguro, M.
Tetrahedron Lett. 1978, 1023.

Notes
J . Org. Chem., Vol. 64, No. 13, 1999 4993
57.04, 58.19, 60.46, 79.63, 155.18, 172.42. MS (m/z, relative
intensity): 169 (95), 124 (85), 96 (58), 69 (100). Anal. Calcd for
tion of the 7-azabicyclo[2.2.1]heptane skeleton, required
for the synthesis of 6, is shorter and high yielding in
comparison to the related [4 + 2]-cycloaddition strategy.
C
14H23NO4: C, 62.43; H, 8.61; N, 5.20. Found: C, 62.24; H, 8.79;
N, 5.44.
Ep im er iza tion of 14 to 13. A mixture of 14 (0.25 g, 0.93
Exp er im en ta l Section
mmol) and anhydrous K2CO3 (0.26 g, 1.86 mmol) in dry methanol
(15 mL) was refluxed for 1 h. The reaction mixture was cooled
to 0 °C, quenched by the addition of saturated NH4Cl solution,
and finally extracted with CH2Cl2. The aqueous layer was
acidified by adding 6 N HCl at 0 °C to pH ) 2, extracted with
DCM, and dried over Na2SO4, and the solvent was evaporated.
The crude acid was dissolved in methanol and was treated with
SOCl2 (0.12 g, 1.02 mmol) at 0 °C. After being stirred for 10 h,
the reaction mixture was washed with NaHCO3 solution,
extracted with DCM, and dried over Na2SO4. The combined
organic layer was evaporated to afford 13 (0.24 g, 95%) as a
colorless oil.
Tr a n sfor m a tion of 13 in to Ep iboxid in e (6). A solution of
acetone oxime (0.19 g, 2.6 mmol) in 10 mL of dry THF at 0 °C
was treated dropwise with n-butyllithium (2.1 M in hexane, 2.70
mL, 5.67 mmol), and the reaction mixture was allowed to warm
to room temperature over 30 min. A solution of 13 (0.5 g, 1.86
mmol) in 10 mL of THF was introduced dropwise while the
reaction mixture was stirred at room temperature. After the
reaction mixture was refluxed for 45 min, the THF was removed
under argon atmosphere to give a crude residue that was
dissolved in 8 mL of concentrated HCl and heated at 80 °C for
4 h. The mixture was cooled, diluted with water, and washed
with ethyl acetate (2 × 10 mL). The aqueous layer was basified
with saturated NaHCO3 solution and was extracted with CH2-
Cl2 (3 × 30 mL). The combined organic layer was dried over Na2-
SO4 and evaporated. The residue was chromatographed on silica
gel, eluting with (CHCl3/MeOH/NH3 ) 97:2:1), to afford 6 (0.14
g) in 41% yield as a pale yellow oil. IR (neat): 3275, 2967, 2875,
1711, 1600, 1419, 1366, 1059, 1008, 922 cm-1. 1H NMR (CDCl3,
300 MHz): δ 1.30-1.45 (m, 2H, H5endo, H6endo), 1.55-1.75 (m,
4H, H5exo, H6exo, H3exo, H-7), 1.90 (dd, J ) 12.36, 8.71 Hz, 1H,
H3endo), 2.21 (s, 3H, 3′-methyl), 2.95 (dd, J ) 8.71, 4.85 Hz, 1H,
[3 + 2] Cycloa d d ition of N-Ben zyl-2,5-bis(tr im eth ylsi-
lyl)p yr r olid in e w ith Eth yl Acr yla te. An argon-flushed two-
neck flask equipped with a magnetic bar was charged with
Ag(I)F (1.87 g, 14.75 mmol) (dried previously under vacuum at
40 °C) and ethyl acrylate (0.78 g, 7.86 mmol) in 30 mL of dry
dichloromethane. Compound 10 (2.0 g, 6.56 mmol) dissolved in
30 mL of dry DCM was introduced into the flask dropwise over
a period of 15 min. The color of the reaction mixture gradually
turned to dark brown with concomitant deposition of silver on
the surface of the flask in the form of mirror. The reaction
mixture was periodically monitored by GC. After being stirred
for 8-10 h, the reaction mixture was filtered through a small
plug of Celite, and solvent was evaporated to give a crude brown
residue. The crude residue was purified by silica gel column
chromatography, eluting with hexane/ethyl acetate (9:1), to
afford 0.25 g of 12 (15%) as a pale yellow oil, and further elution
with the same solvent system yielded 1.02 g of 11 (60%) as a
pale yellow oil.
7-Ben zyl-2-exo-ca r b et h oxy-7-a za b icyclo[2.2.1]h ep t a n e
(Ma jor Dia ster eom er ) (11). IR (neat): 2958, 2361, 1732, 1451,
1180 cm-1. H NMR (CDCl3, 200 MHz): δ 1.25 (t, J ) 7.14 Hz,
1
3H), 1.35 (m, 2H), 1.50 (dd, J ) 12.2, 9.3 Hz, 1H), 1.85 (m, 2H),
2.25 (m, 1H), 2.40 (dd, J ) 9.3, 4.9 Hz, 1H), 3.35 (bs,1H), 3.40
(d, J ) 13.7 Hz, 1H), 3.60 (d, J ) 13.7 Hz, 1H), 3.63 (bs, 1H),
4.10 (q, J ) 7.14 Hz, 2H), 7.15-7.40 (m, 5H). 13C NMR (CDCl3,
75 MHz): δ 13.98, 26.65, 26.82, 33.2, 47.69, 51.24, 59.2, 60.1,
62.98, 126.36, 127.8, 127.93, 140.0, 174.12. MS (m/z, relative
intensity): 259 (M+, 6), 158 (24), 131 (11), 91 (100). HRMS: calcd
for C16H21NO2 259.1572, found 259.1569.
7-Be n zyl-2-en d o-ca r b e t h oxy-7-a za b icyclo[2.2.1]h e p -
ta n e (Min or Dia ster eom er ) (12). IR (neat): 2961, 2361, 1714,
1
1442, 1171 cm-1. H NMR (CDCl3, 200 MHz): δ 1.25 (t, J ) 7.9
H
2endo), 3.68 (d, J ) 4.06 Hz, 1H, H-1), 3.75 (t, J ) 4.4 Hz, 1H,
H-4), 5.77 (s, 1H, H-4′). 13C NMR (CDCl3, 75 MHz): δ 11.21,
29.14, 29.57, 38.02, 41.07, 56.03, 61.34, 100.58, 159.45, 176.07.
MS (m/z, relative intensity): 179 (M+, 23), 149 (10), 110 (24),
94 (13), 82 (19), 69 (100). HRMS: calcd for C10H14N2O 178.1106,
found 178.1103.
Hz, 3H), 1.40 (m, 2H), 1.65-1.90 (m, 3H), 1.90-2.10 (m, 1H),
3.10 (m, 1H), 3.32 (t, J ) 4.47 Hz, 1H), 3.55 (t, J ) 4.26 Hz,
1H), 3.60 (bs, 2H), 4.15 (q, J ) 7.9 Hz, 2H), 7.20-7.45 (m, 5H).
13C NMR (CDCl3, 75 MHz): δ 14.16, 24.09, 28.11, 30.99, 45.66,
51.66, 60.13, 60.21, 62.05, 126.7, 128.12, 128.31, 139.79, 173.89.
MS (m/z, relative intensity): 259 (M+, 6), 158 (27), 130 (14), 91
(100). Anal. Calcd for C16H21NO2: C, 74.09; H, 8.16; N, 5.40.
Found: C, 74.26; H, 8.39; N, 5.52.
7-Ca r bom eth oxy-2-en d o-3-en d o-d i(ca r bom eth oxy)-7-a za -
bicyclo[2.2.1]h ep ta n e (21). A solution of 18 (10.0 g, 36.36
mmol) in 70 mL of ethanol containing 10% Pd/C (0.8 g, 20 mol
%) was hydrogenated (40 psi, rt) for 8 h. The reaction mixture
was filtered, and the filtrate was evaporated and chromato-
graphed over a silica gel column, eluting with hexane/EtOAc (8:
2) to afford 8.35 g (85%) of 21 as a colorless oil. IR (neat): 2954,
Tr a n sfor m a tion of 11 a n d 12 in to 13 a n d 14. To a mixture
of 11 and 12 (0.5 g, 1.93 mmol) in 30 mL of ethanol was added
palladium hydroxide (0.1 g), and the resultant suspension was
hydrogenated (50 psi, rt) for 2 days. The reaction mixture was
filtered, the filtrate was evaporated, and the crude amine was
dissolved in 30 mL of DCM and treated with a solution of (Boc)2O
(0.5 g, 2.3 mmol) in DCM followed by triethylamine (0.8 mL)
under argon atmosphere. The resulting mixture was stirred for
18 h and concentrated. The residue was purified by silica gel
column chromatography, eluting with hexane/EtOAc (9:1), to
afford 0.09 g of 14 (18%) as a colorless oil, and further elution
with hexane/EtOAc afforded 0.37 g of 13 (72%) as a colorless
oil.
1716, 1605, 1441, 1078 cm-1 1H NMR (CDCl3, 200 MHz): δ
.
1.65-1.80 (m, 2H), 1.90-2.05 (m, 2H), 2.25 (bs, 2H), 3.65 (s,
6H), 3.68 (s, 3H), 4.45 (bs, 2H). 13C NMR (CDCl3, 75 MHz): δ
24.95, 47.26, 51.58, 52.56, 59.13, 155.65, 170.83. MS (m/z,
relative intensity): 272 (M+, 2), 146 (80), 127 (100), 114 (57).
Deca r boxyla tion of 21. A solution of 21 (5.0 g, 18.45 mmol)
in methanol-water (3:1, 80 mL) containing LiOH-H2O (0.77 g,
18.45 mmol) was stirred for 3 h at room temperature. The
solvent was evaporated, diluted with water, and washed with
CH2Cl2 (2 × 10 mL). The aqueous layer was cooled to 0 °C,
acidified with 6 N HCl to pH ) 2, and extracted with ethyl
acetate. The combined organic layer was dried over Na2SO4 and
evaporated to give 22 as a foaming white solid (4.27 g) in 90%
yield. The resultant crude acid was dissolved in 100 mL of dry
DCM, treated with oxalyl chloride (4.34 mL, 49.8 mmol) and
DMF (0.1 mL) under argon atmosphere at room temperature,
and further allowed to stir for 2 h. The mixture was evaporated
under vacuum to give the corresponding acid chloride as a brown
solid. The crude acid chloride was dissolved in dry benzene (100
mL), and to the resultant solution were added DMAP (0.2 g, 1.6
mmol), N-hydroxy-2-mercaptopyridine (2.53 g, 19.9 mmol), and
triethylamine (4.6 mL, 33.2 mmol) under argon atmosphere.
After being stirred for 4 h at room temperature, the solid
suspension was allowed to settle and the supernatant solution
was syringed out and added to a refluxing solution of tert-butyl
mercaptan (7.5 mL) in 100 mL of dry benzene. The resultant
7-(ter t-Bu t yloxyca r b on yl)-2-exo-ca r b et h oxy-7-a za b icy-
clo[2.2.1]h ep ta n e (13). IR (neat): 2979, 1738, 1706, 1368, 1156
cm-1 1H NMR (CDCl3, 200 MHz): δ 1.25 (t, J ) 7.1 Hz, 3H),
.
1.45 (s, 9H), 1.50-1.70 (m, 2H), 1.70-1.90 (m, 3H), 2.20-2.35
(m, 1H), 2.57 (dd, J ) 8.6, 3.9 Hz, 1H), 4.15 (q, J ) 7.1 Hz, 2H),
4.30 (t, J ) 4.31 Hz, 1H), 4.55 (d, J ) 4.1 Hz, 1H). 13C NMR
(CDCl3, 75 MHz): δ 13.79, 27.81 28.46, 29.12, 32.84, 47.17, 55.45,
58.89, 60.27, 79.03, 154.3, 172.73. MS (m/z, relative intensity):
269 (M+, 0.85), 196 (23), 169 (52), 96 (42), 69 (100). Anal. Calcd
for C14H23NO4: C, 62.43; H, 8.61; N, 5.20. Found: C, 62.34; H,
8.85; N, 5.52.
7-(ter t-Bu t yloxyca r b on yl)-2-en d o-ca r b et h oxy-7-a za b i-
cyclo[2.2.1]h ep ta n e (14). IR (neat): 2978, 1734, 1703, 1366,
1156 cm-1.1H NMR (CDCl3, 200 MHz): δ 1.25 (t, J ) 7.1 Hz,
3H), 1.40 (s, 9H), 1.45-1.55 (m, 2H), 1.60-1.95 (m, 4H), 2.90-
3.05 (m, 1H), 4.05-4.25 (m, 3H), 4.35 (t, J ) 4.4 Hz, 1H). 13C
NMR (CDCl3, 75 MHz): δ 14.09, 25.22, 28.12, 29.08, 32.28, 46.35,

4994 J . Org. Chem., Vol. 64, No. 13, 1999
Notes
mixture was refluxed for 4 h, cooled, washed with aqueous 1 N
NaOH solution, water, and brine, and dried over Na2SO4. The
benzene layer was concentrated, and the crude residue obtained
was chromatographed on silica gel, eluting with hexane/ethyl
acetate (8:2), to afford 17 (0.46 g, 13%) and 23 (1.84 g, 52%) as
colorless oils.
(d, J ) 10.2 Hz, 1H), 3.70 (s, 3H), 3.73 (s, 3H), 4.45 (bs, 1H),
4.65 (bs, 1H), 7.25-7.35 (m, 3H), 7.50-7.65 (m, 2H). 13C NMR
(CDCl3, 50 MHz): δ 28.46, 28.77, 48.36, 51.07, 52.06, 53.34,
58.52, 62.67, 127.19, 128.85, 130.79, 133.4, 155.16, 170.55. MS
(m/z, relative intensity): 369 (M+, 2), 212 (37), 157 (24), 126
(100). Anal. Calcd for C16 H19 NO4Se: C, 52.18; H, 5.20; N, 3.80.
Found: C, 52.34; H, 5.37; N, 3.61.
7-Ca r bom eth oxy-2-(ca r bom eth oxy)-7-a za bicyclo[2.2.1]-
h ep t-2-en e (26). To a stirring solution of 24 (2.0 g, 5.43 mmol)
in 20 mL of CH2Cl2 was added H2O2 (30%, 2 mL) dropwise at 0
°C. The resulting reaction mixture was allowed to stir at room
temperature for 30 min, washed with 5% NaHCO3 and brine,
and dried over Na2SO4. The organic layer was concentrated and
chromatographed on silica gel, eluting with hexane/EtOAc (9:
1), to afford 1.1 g (95%) of 26 as a colorless oil. IR (neat): 2955,
2879, 1721, 1603, 1284, 1080 cm-1. 1H NMR (CDCl3, 200 MHz):
δ 1.15-1.35 (m, 2H), 1.90-2.15 (m, 2H), 3.65 (s, 3H), 3.78 (s,
3H), 4.35 (bs, 1H), 5.05 (bs, 1H), 7.03 (bs, 1H). 13C NMR (CDCl3,
50 MHz): δ 23.96, 51.43, 52.36, 59.67, 61.01, 140.63, 144.12,
155.49, 163.11. MS (m/z, relative intensity): 212 (M+, 1), 183
7-Car bom eth oxy-2-exo-(car bom eth oxy)-7-azabicyclo[2.2.1]-
h ep ta n e (17). IR (neat): 2954, 2879, 1737, 1634, 1367, 1161
cm-1 1H NMR (CDCl3, 200 MHz): δ 1.30-1.55 (m, 2H), 1.63
.
(dd, J ) 12.48, 8.91 Hz, 1H), 1.75-1.95 (m, 2H), 2.17-2.35 (m,
1H), 2.55 (dd, J ) 8.91, 4.91 Hz, 1H), 3.63 (s, 3H), 3.67 (s, 3H),
4.35 (t, J ) 4.21 Hz, 1H), 4.55 (d, J ) 3.7 Hz, 1H). 13C NMR
(CDCl3, 50 MHz): δ 28.63, 29.11, 33.29, 47.18, 51.69, 52.0, 55.69,
59.08, 155.53, 173.42. MS (m/z, relative intensity): 213 (M+, 16),
184 (13), 154 (39), 126 (100), 82 (17). HRMS: calcd for C10H15
NO4 213.1001, found 213.0999.
-
7-Ca r b om et h oxy-2-en d o-(ca r b om et h oxy)-7-a za b icyclo-
[2.2.1]h ep ta n e (23). IR (neat): 2954, 1708, 1737, 1633, 1444
cm-1.1H NMR (CDCl3, 200 MHz): δ 1.40-1.55 (m, 2H), 1.70-
2.10 (m, 4H), 2.95-3.15 (m, 1H), 3.71 (s, 3H), 3.74 (s, 3H), 4.28
(t, J ) 5.5 Hz, 1H), 4.50 (t, J ) 5.5 Hz, 1H). 13C NMR (CDCl3,
75 MHz): δ 25.49, 29.24, 32.48, 46.35, 51.77, 52.36, 57.08, 58.16,
155.84, 172.72. MS (m/z, relative intensity): 213 (M+, 15), 184
(12), 154 (37), 126 (100), 82 (19). Anal. Calcd for C10H15NO4: C,
56.33; H, 7.09; N, 6.57. Found: C, 56.65; H, 7.21; N, 6.42.
Deca r boxyla tion of 21 in th e P r esen ce of P h SeSeP h . An
identical decarboxylation procedure was adopted using Ph-
SeSePh instead of tert-butyl mercaptan. The crude residue was
purified by silica gel column chromatography, eluting with
hexane/ethyl acetate (7:3), to afford 24 (64%) and 25 (16%) as
pale yellow oils.
(77), 152 (100), 108 (56), 93 (22), 59 (32). Anal. Calcd for C10H13
-
NO4: C, 56.86; H, 6.20; N, 6.63. Found: C, 56.55; H, 6.35; N,
6.93.
7-Ca r b om et h oxy-2-en d o-(ca r b om et h oxy)-7-a za b icyclo-
[2.2.1]h ep ta n e (23). A suspension of 26 (1.0 g, 4.74 mmol) and
0.2 g of 10% Pd/C in 15 mL ethanol was hydrogenated (40 psi,
rt) for 6 h. The reaction mixture was filtered, concentrated, and
chromatographed over silica gel, eluting with hexane/EtOAc (9:
1), to afford 1.0 g (100%) of 23.
Ack n ow led gm en t. T.D.B. and A.K.S. thank CSIR
for financial support. We would like to thank Dr. P
Rajmohan for the helpful discussion regarding stereo-
chemical assignments and S. K. Tiwari for scanning
NMR spectra. We are grateful to Dr. M. Vairamani
(Indian Institute of Chemical Technology, Hyderabad)
for providing HRMS data. Financial support from DST
is also gratefully acknowledged.
7-Car bom eth oxy-2-en do-(car bom eth oxy)-3-exo-(ph en ylse-
len o)-7-a za bicyclo[2.2.1]h ep ta n e (24). IR (neat): 2952, 1712,
1577, 1361, 1193 cm-1 1H NMR (CDCl3, 200 MHz): δ 1.35-
.
1.60 (m, 2H), 1.65-1.80 (m, 1H), 1.80-1.95 (m, 1H), 3.05 (t, J
) 6.5 Hz, 1H), 3.65 (s, 3H), 3.70 (s, 3H), 3.75 (d, J ) 7.1 Hz,
1H), 4.25 (bs, 1H), 4.55 (t, J ) 5.1 Hz 1H), 7.20-7.30 (m, 3H),
7.50-7.60 (m, 2H). 13C NMR (CDCl3, 75 MHz): δ 24.94, 29.65,
45.98, 52.19, 52.55, 55.48, 58.85, 62.76, 127.91, 129.24, 129.49,
134.48, 155.94, 171.39. MS (m/z, relative intensity): 369 (M+,
12), 220 (15), 212 (71), 157 (31), 127 (100). HRMS: calcd for
C16H19NO4Se 369.0479, found 369.0487.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of 6, 11-14, 17, 21, and 23-26. This material
is available free of charge via the Internet at http://pubs.acs.org.
7-Ca r bom eth oxy-2-exo-(ca r bom eth oxy)-3-exo-(p h en ylse-
len o)-7-a za bicyclo[2.2.1]h ep ta n e (25). IR (neat): 2952, 1707,
1578, 1359, 1105 cm-1 1H NMR (CDCl3, 200 MHz): δ 1.40-
.
1.55 (m, 2H), 1.65-1.95 (m, 2H), 3.05 (d, J ) 10.2 Hz, 1H), 3.50
J O9903757