Enantiospecific synthesis of annulated nicotine analogues from D-glutamic acid. 7-Azabicyclo[2.2.1]heptano[2.3.c]pyridines

Article abstract of DOI:10.1021/jo010534y

The conformationally restricted nicotinoid (1S,4S)-7-methyl-7-azabicyclo[2.2.1]heptano[2,3-c]pyridine dihydrochloride has been prepared enantiospecifically from D-glutamic acid. The method involved a lithium cis-2,6-dimethylpiperidide-mediated intramolecular anionic cyclization of (2S,5R)-N-(tert-butyloxycarbonyl)-5-[3-(4-N-chloropyridinyl]proline methyl ester in tandem with a standard decarboxylation sequence. Reductive amination afforded the desired N-methylated [2.2.1]bicyclonicotinoid. Cyclization of the corresponding iodopyridinylproline methyl ester, obtained via ultrasound-facilitated chloro - iodo exchange, was also effected.

Full text of DOI:10.1021/jo010534y

7078
J . Org. Chem. 2001, 66, 7078-7083
En a n tiosp ecific Syn th esis of An n u la ted Nicotin e An a logu es fr om
D-Glu ta m ic Acid . 7-Aza bicyclo[2.2.1]h ep ta n o[2.3-c]p yr id in es
J oseph R. Lennox, Sean C. Turner, and Henry Rapoport*
Department of Chemistry, University of California, Berkeley, California 94720
rapoport@cchem.berkeley.edu
Received May 25, 2001
The conformationally restricted nicotinoid (1S,4S)-7-methyl-7-azabicyclo[2.2.1]heptano[2,3-c]pyridine
dihydrochloride has been prepared enantiospecifically from D-glutamic acid. The method involved
a lithium cis-2,6-dimethylpiperidide-mediated intramolecular anionic cyclization of (2S,5R)-N-(tert-
butyloxycarbonyl)-5-[3-(4-N-chloropyridinyl]proline methyl ester in tandem with a standard
decarboxylation sequence. Reductive amination afforded the desired N-methylated [2.2.1]bicycloni-
cotinoid. Cyclization of the corresponding iodopyridinylproline methyl ester, obtained via ultrasound-
facilitated chloro-iodo exchange, was also effected.
In tr od u ction
Investigative studies in pharmacology and medicinal
chemistry have spawned a virtual explosion of interest
in the development of selective compounds that target
nicotinic acetylcholine receptors (nAChRs), a family of
ligand-gated ion channels widely distributed in the
human brain.1 The egregious consequences of (S)-(-)-
nicotine 1 (Figure 1) have been well documented, but not
until recently have the surprisingly beneficial effects of
nicotine and nicotine analogues been established, includ-
ing observations of favorable results with Alzheimer’s
disease (AD), anxiety, adult attention deficit hyperactiv-
ity disorder (ADHD), depression, Parkinson’s disease,
schizophrenia, Tourette’s syndrome, and ulcerative choli-
tis.2,3
Although the antinociceptive effects of nicotine have
been known for some time,4 a limitation of its therapeutic
utility is the high doses required to achieve the desired
effects, which are modest and of short duration. The
discovery of (-)-epibatidine, however, has initiated a
resurgence of interest in developing selective nAChRs for
the treatment of chronic pain.5
F igu r e 1. Nicotine and fused-ring analogues.
and pyrrolidine rings of nicotine are skewed and nearly
perpendicular to one another7 in low energy conforma-
tions; however, the exact conformation that induces ion-
channel modulation is currently unknown.
Pursuant to these synthetic and pharmacologic objec-
tives, our laboratory has recently reported8 the synthesis
of the highly conformationally constrained nicotine ana-
logues 2, with a pendant pyridine ring, and the annulated
pyridotropane 3. We now report the synthesis of the
bicyclo[2.2.1] analogue 4.
To achieve the enantioselective synthesis of con-
strained nicotinoids 4, we have proposed a route utilizing
D-glutamic acid (Scheme 1). Paramount would be an
intramolecular cyclization of enolate 6 to bicycle 7
proceeding via an SNAr mechanism. Noncatalyzed addi-
tions of anionic carbon nucleophiles to halopyridines have
precedent,9 albeit most reported examples occur electro-
chemically10 or require substantially activated pyridine
systems.11
Synthetic efforts toward novel compounds having the
desired therapeutic indications have recently prolifer-
ated.6 Modeling studies have suggested that the pyridine
(1) (a) Paterson, D.; Nordberg, A. Prog. Neurobiol. 2000, 61, 75-
111. (b) Clementi, F.; Fornasari, D.; Gotti, C. Eur. J . Pharmacol. 2000,
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141-146. (b) Stolerman, I. P.; Mirza, N. R.; Hahn, B.; Shoaib, M. Eur.
J . Pharmacol. 2000, 393, 147-154. (c) Quik, M.; J eyarasasingam, G.
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Pharm. Acta Helv. 2000, 74, 91-101. (g) Guslandi, M. Br. J . Clin.
Pharmacol. 1999, 48, 481-484.
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407-412.
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747. (b) Glennon, R. A.; Dukat, M. Med. Chem. Res. 1996, 465-486.
(8) (a) Xu, Y.-z; Choi, J .; Calaza, M. I.; Turner, S.; Rapoport, H. J .
Org. Chem. 1999, 64, 4069-4078. (b) Turner, S. C.; Zhai, H.; Rapoport,
H. J . Org. Chem. 2000, 65, 861-870.
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(10) (a) Chahma, M.; Combellas, C.; Thie´bault, A. J . Org. Chem.
1995, 60, 8015-8022. (b) Chahma, M.; Combellas, C.; Thie´bault, A.
Synthesis 1994, 366-368.
(3) Decker, M. W.; Aneric, S. P. Neuronal Nicotinic Recept. 1999,
395-411.
(4) Davis, L.; Pollock, L. J .; Stone, T. T. Surg. Gynecol. Obstet. 1932,
55, 418.
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917-923. (b) Elgen, R. M.; Hunter, J . C.; Dray, A. Trends Pharm. Sci.
1999, 20, 337-342. (c) Bannon, A. W., et al. Science 1998, 279, 77-
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10.1021/jo010534y CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/26/2001

7-Azabicyclo[2.2.1]heptano[2.3-c]pyridines
J . Org. Chem., Vol. 66, No. 21, 2001 7079
Sch em e 1. P r op osed Rou te to 7-Aza bicyclo[2.2.1]h ep ta n o[2,3-c]p yr id in es
Sch em e 2. Syn th esis of [2.2.1] System a n d Tr a n sh a logen a tion Sequ en ce
Resu lts a n d Discu ssion
range of temperatures. The amides used included LDA,
KHMDS, LiHMDS, tetramethylpiperidine (TMP), and
cis-2,6-dimethylpiperidine (DMP). Temperature control
from -78 °C to room temperature was examined, includ-
ing a number of intermediate points for various times.
From this exhaustive examination, the best conditions
were found to be adding LiDMP to the substrate at -78
°C in THF and concluding the reaction at -20 °C. The
result was a reproducible 57% yield of 9. Evidence that
the production of bicycle 9 was ineluctably accompanied
by pyridyne formation will be discussed below.
Previous reports8 have detailed the synthesis of proline
derivative 8 (Scheme 2) from glutamic acid. The synthetic
sequence remains identical; however, the experimental
details have been modified,12 resulting in better, repro-
ducible, and scalable yields. Thus, intermediate nicotine
8 became available in quantity in 44% yield from D-
glutamic acid. The intramolecular alkylation, 8 to 9, was
exquisitely sensitive to every variable. A variety of amide
bases bearing lithium and potassium counterions in
nonpolar, ethereal, and dipolar aprotic solvents were used
for the attempted conversion. Two modes of addition,
adding a solution of substrate to the base and adding the
base to the substrate, were employed as were a wide
Since the nature of the leaving group in an SNAr
reaction impacts directly on the outcome, it was of
interest to explore the reactivity of an iodopyridine
relative to a chloropyridine to determine if there was a
leaving group effect. Known methods of pyridine trans-
halogenation were expected to be incompatible with the
(12) Modified experimental details for the synthesis of 8 from
D-glutamic acid are available in the Supporting Information.

7080 J . Org. Chem., Vol. 66, No. 21, 2001
Sch em e 3. Rea ctivity of Iod op yr id in e tow a r d [2.2.1] Cycliza tion
Lennox et al.
N-tert-butyloxycarbonyl functionality of 8; therefore, N-
BOC deprotection of proline derivative 8 (Scheme 2) was
effected in an overall 90% yield using HCl in anhydrous
EtOAc, followed by isolation of the intermediate di-HCl
salt and treatment with propylene oxide in CH2Cl2 as a
hydrogen chloride scavenger. Amine 11 was subsequently
protected in 95% yield as the ethyl carbamate 12 via
treatment with EtO2CCl and Et3N. Reported strategies13
for pyridine trans-halogenation of 12 to 13 using NaI/HI
or NaI/AcCl were ineffective. The use of NaI and AcCl in
anhydrous MeCN with moderate heat (45-50 °C) led
predominantly to de-N-carbethoxylation and N-acylation
plus decomposition products. Careful manipulation of the
reaction parameters, however, resulted in very mild,
high-yielding conditions for the trans-halogenation. Thus,
submission of chloropyridine 12 to ultrasound-facilitated
treatment with NaI and EtO2CCl/AcCl (in a 10/1 ratio,
precluding N-acylation) in anhydrous MeCN afforded
iodopyridine 13 in a 93% yield and in a fraction of the
time required by the less effective thermal process.
Exposure of iodopyridine 13 (Scheme 3) to the [2.2.1]
cyclization conditions afforded bicycle 20 in a 31% yield,
inferior to the yield from the chloride. The observation
of pyridyne formation, to some degree, in all experiments
performed with lithium amide bases raises questions as
to the nature of the mechanism of the [2.2.1] cyclization.
Interestingly, regioselective ortho-lithiation of halopy-
ridines by LDA have been independently reported14 as a
means for the generation of pyridynes.
would form more quickly from an iodopyridine and at a
lower temperature than from the corresponding chloro-
pyridine,14a iodide 13 was chosen for the trapping episode.
Furan (3300 mol %) was introduced into the reaction
mixture at -73 °C after 2h. Stirring at -73 °C was
continued while the reaction mixture was slowly warmed
to +14 °C, where it was quenched with MeOH. Positive-
ion mass spectrometry of the crude mixture under
electrospray conditions detected the following molecular
ions: [M + H]+ for the [4 + 2] furan adduct 21 m/z 345.1;
[M + H]+ for the [2.2.1] product 20 m/z 277.2; and [M +
H]+ for the starting iodide 13 m/z 405.1. Prior studies
involving the chloropyridine 24 had unambiguously veri-
fied that ortho-lithiation was occurring as established by
MeOH-d4 quench of a trial reaction at -78 °C, providing
8-d -A and 8-d -B wherein a >20% deuterium incorpora-
tion was observed ortho to the chloro group.
Elaboration to nicotine analogues 16 and 17 (Scheme
2) proceeded by methyl ester hydrolysis of 9 to carboxylic
acid 10 in 98% yield with aqueous LiOH in dioxane.
Using a previously established protocol for reductive
radical decarboxylation16 of the quaternary C-1 carboxy
group, the acid chloride of 10 (prepared via treatment
with oxalyl chloride in a pyridine-buffered medium) was
condensed with 2-mercaptopyridine N-oxide providing
the thioester 14. Completion of the sequence by irradiat-
ing 14 with two 100 W incandescent lamps in the
presence of t-BuSH afforded bicycle 15 in an overall 58%
yield from 10.
A Diels-Alder trapping reaction14,15 was invoked to
determine if the putative 3,4-pyridyne 19 was present
during the cyclization events. Projecting that a pyridyne
Removal of the N-Boc protecting group of 15 was
effected with HCl in EtOAc, affording the crystalline di-
HCl salt 16. Treatment of 16 with NaOH in MeOH
released the corresponding free base, which was submit-
ted to reductive amination to provide the desired N-
methylated bicycle 17 in a 90% yield over three steps.
Interestingly, the room-temperature 1H and 13C NMR
spectra of 17 in MeOH-d4 exhibit an unexpected doubling
of resonances, indicating the presence of two species. This
effect is not observed in the 1H NMR spectrum of the
(13) (a) Corcoran, R. C.; Bang, S. H. Tetrahedron Lett. 1990, 31,
6757-6758. (b) Newkome, G. R.; Moorfield, C. N.; Sabbaghian, B. J .
Org. Chem. 1986, 51, 953-954. (c) Sakamoto, T.; Kondo, Y.; Yamanaka,
H. Chem. Pharm. Bull. 1985, 33, 626-633. (d) Sakamoto, T.; Kondo,
Y.; Yamanaka, H. Chem. Pharm. Bull. 1985, 33, 4764-4768.
(14) (a) Gribble, G. W.; Saulnier, M. G. Heterocycles 1993, 35, 151-
169. (b) Marsais, F.; Tre´court, F.; Bre´ant, P.; Que´giner, G. J . Heterocycl.
Chem. 1988, 25, 81-87.
(15) (a) Connon, S. J .; Hegarty, A. F. J . Chem. Soc., Perkin Trans.
1 2000, 1245-1249. (b) Walters, M. A.; Shay, J . J . Synth. Commun.
1997, 27, 3573-3579. (c) Walters, M. A.; Shay, J . J . Tetrahedron Lett.
1995, 36, 7575-7578. (d) Tsukazaki, M.; Snieckus, V. Heterocycles
1992, 33, 533-536.
(16) Campbell, J . A.; Rapoport, H. J . Org. Chem. 1996, 61, 6313-
6325; Barton, D. H. R.; Herve, Y.; Potier, P.; Thierry, J . Tetrahedron
1988, 44, 5479-5486.

7-Azabicyclo[2.2.1]heptano[2.3-c]pyridines
J . Org. Chem., Vol. 66, No. 21, 2001 7081
isolations and better yields (eight steps, 44% yield from
D-glutamic acid). These improvements are delineated in detail
in the Supporting Information.
(1R,4S)-7-ter t-Bu t yloxyca r b on yl-1-m et h oxyca r b on yl-
7-a za bicyclo[2.2.1h ep ta n o[2,3-c]p yr id in e (9). It is critical
that the THF for this experiment be distilled from LAH just
prior to use to obtain reproducible results. To a solution of cis-
2,6-dimethylpiperidine (1.66 mL, 12.3 mmol) in THF (1.75 mL)
at -20 °C was added n-BuLi (2.35 M in hexanes, 5.20 mL,
12.2 mmol). The LiDMP solution was stirred for an additional
1 h at -20 °C and then cannula transferred over 15 min to a
solution of chloropyridine 8 (2.033 g, 5.965 mmol) in THF (174
mL) at -78 °C. The burgundy reaction mixture was stirred
for an additional 2 h at -78 °C, at which point it was immersed
into a -65 °C bath and warmed to -20 °C (turning brown
between -38 and -35 °C) at a rate of 0.36 °C/min. To the
reaction mixture was added MeOH (5.0 mL) followed by 1 M
pH 8 phosphate buffer (50 mL). Dilution with CH2Cl2 (150 mL)
permitted clean separation of the aqueous phase, which was
further extracted with CH2Cl2 (3 × 200 mL). The combined
extract was dried, filtered, and evaporated to a yellow oil that
on chromatography (SiO2, elution with 40% EtOAc/hexanes
+ 1% Et3N) provided bicycle 9 (1.04 g, 57%) as a pale yellow
F igu r e 2. Equilibrium between the two protonated quarter-
nary N-methyl diastereomers.
corresponding free base of 17. Comparable results are
obtained in DMSO-d6 at ambient temperature. When the
1H NMR sample is heated to 98 °C, however, a single
species is observed as indicated by coalescence of the
resonances. Upon cooling to room temperature, the
sample returns to its unchanged ambient temperature
1H NMR spectrum. These results suggest an equilibrium
(Figure 2) of two protonated quaternary N-methyl dia-
stereomers wherein the chiral nitrogen is stable to
pyramidal inversion due to the high barrier of energy
required for interconversion.
Con clu sion
oil: [R]25 -49.3° (c 0.036, CDCl3); 1H NMR (CDCl3) δ 1.32 (s,
D
A method for the enantiospecific synthesis of 7-azabi-
cyclo[2.2.1]heptano[2,3-c]pyridines 16 and 17 from D-
glutamic acid has been developed. These compounds
represent the most rigid of the conformationally con-
strained nicotine analogues reported, involving the in-
troduction only of a carbon-carbon single bond between
C-4 and C-5′ of (-)-nicotine. The key reaction, a lithium
amide promoted anionic cyclization of chloropyridine 8,
is highly dependent upon stoichiometry and steric effects
of the base used. Pyridyne formation has been detected
during the course of the reaction, although the degree to
which a pyridyne intermediate serves a role in the
transformation is currently unknown. The rigidity of this
bicyclo system is clearly demonstrated by the appearance
at room temperature of diastereomeric, protonated, qua-
9H), 1.37-1.45 (m, 1H), 1.59-1.63 (m, 1H), 2.29-2.43 (m, 1H),
2.51-2.60 (m, 1H), 3.94 (s, 3H), 5.28 (d, J ) 4.5, 1H), 8.60 (d,
J ) 4.8, 1H), 8.52 (d, J ) 5.1, 1H), 8.55 (s, 1H); 13C NMR
(CDCl3), δ 26.8 (2), 27.8 (3), 31.0 (2), 52.4 (3), 61.4 (1), 71.9
(0), 81.8 (0), 115.9 (1), 139.7(0), 140.4 (1), 148.7 (1), 151.7 (0),
155.7 (0), 168.9 (0); MS (+)-FAB [M + H]+ m/z 305. Anal. Calcd
for C16H20N2O4: C, 63.1; H, 6.6; N, 9.2. Found: C, 62.8; H,
7.0; N, 8.8.
(1R,4S)-7-ter t-Bu t yloxyca r b on yl-7-a za b icyclo[2.2.1]-
h ep ta n o[2,3-c]p yr id in e-1-ca r boxylic Acid (10). To a solu-
tion of methyl ester 9 (2.32 g, 7.61 mmol) in dioxane (38.0 mL)
was added LiOH‚H2O (958 mg, 22.6 mmol) followed by water
(38.0 mL). The reaction mixture was stirred for 12 h, where-
upon the pH was adjusted to 6 by the addition of glacial acetic
acid (871 µL, 15.2 mmol) followed by pH 4 buffer, evaporated
to approximately 40 mL, and extracted with 20% IPA/CHCl3
(15 × 100 mL). The organic extract was dried, filtered, and
evaporated. Submission of the crude material to chromatog-
raphy (SiO2, gradient elution with 0-20% MeOH-CH2Cl2)
1
ternary N-methyl species in the H NMR that coalesce
at 98 °C.
afforded 9 (2.17 g, 98%) as an off-white solid: [R]25 -36.3° (c
D
1
0.029, CDCl ); mp >230 °C dec; H NMR (CDCl3) δ 1.43 (m,
3
Exp er im en ta l Section
1H), 1.68 (ddd, J ) 12.7, 8.8, 4.1, 1H), 2.44 (ddd, J ) 14.8,
11.3, 3.9, 1H), 2.71 (ddd, J ) 14.5, 10.7, 3.6, 1H), 5.36 (d, J )
4.4, 1H), 7.95 (d, J ) 5.0, 1H), 8.64 (d, J ) 5.4, 1H), 8.69 (s,
1H); 13C NMR (CDCl3) δ 26.6 (2), 27.8 (3), 31.6 (2), 61.4 (1),
72.7 (0), 82.2 (0), 117.5 (1), 137.9 (1), 141.2 (0), 146.5 (1), 155.2
(0), 156.0 (0), 171.0 (0). Anal. Calcd for C15 H18 N2O4: C, 62.1;
H, 6.3; N, 9.6. Found: C, 61.9; H, 6.3; N, 9.6.
Meth od s a n d Ma ter ia ls. Melting points were determined
on an open capillary apparatus and are uncorrected. Column
chromatography was completed under positive pressure (N2)
using 230-400 mesh silica gel or 50-200 mesh neutral
alumina. Analytical thin-layer chromatography (TLC) was
performed on aluminum-backed silica gel 60 F254 0.2 mm plates
and visualized with UV light (254 nm) followed by heating with
commercial ethanolic phosphomolybdic acid. 1H and 13C NMR
spectra were recorded in CDCl3-tetramethylsilane (δ 0.0 for
1H), CDCl3 (δ 77.0 for 13C), CD3OD (δ 3.30 for 1H), and CD3-
OD (δ 49.0 for 13C) as internal references. DEPT experiments
were performed with 13C NMR acquisition, and the carbon
multiplicities were listed as (0) quaternary, (1) methine, (2)
methylene, and (3) methyl. The following solvents and reagents
were distilled under a blanket of dry nitrogen: THF, Et2O,
and furan were distilled from Na-benzophenone ketyl; CH2-
Cl2, diisopropylamine, cis-dimethylpiperidine, and Et3N were
distilled from CaH2; MeCN was distilled first from P2O5 and
then from CaH2; MeOH was distilled from Mg; HOAc was
distilled from anhydrous CuSO4; and EtOAc was distilled from
anhydrous CaCl2. Organic phases from liquid-liquid distribu-
tion were dried over anhydrous Na2SO4, filtered, and evapo-
rated under reduced pressure. Elemental analyses and mass
spectra were conducted by the Analytical Laboratory at the
University of California, Berkeley.
(1S,4S)-7-ter t-Bu t yloxyca r b on yl-7-a za b icyclo[2.2.1]-
h ep ta n o[2,3-c]p yr id in e (15). To a solution of carboxylic acid
10 (30.0 mg, 0.103 mmol) in 1/1 CH2Cl2/pyridine (2.0 mL) at
-15 °C was added (COCl)2 (9.9 µL, 0.114 mmol). The reaction
mixture was slowly warmed to 0 °C, at which point the cold
bath was removed and stirring was continued for 2.5 h at room
temperature. The solution of acid chloride was treated with
2-mercaptopyridine N-oxide (14.4 mg, 0.114 mmol) and then
stirred for an additional 2 h at room temperature. Evaporation
in vacuo was followed by trituration of the residue with THF
(10 mL), filtration, and addition of tert-butylthiol (1 mL). The
solution was then immersed in a bath at room temperature
and irradiated with two 100 W incandescent lamps for 3 h.
Evaporation of the volatiles in vacuo was followed by parti-
tioning of the residue between saturated NaHCO3 (10 mL) and
EtOAc (25 mL). The aqueous phase was further extracted with
EtOAc (2 × 25 mL), and the combined organic phase was dried,
filtered, and evaporated. Submission of the crude material to
chromatography (SiO2, elution with 80% EtOAc-hexanes +
1% Et3N) afforded 15 (14.8 mg, 58%) as a colorless solid: mp
(2S,5R)-N-(ter t-Bu tyloxyca r bon yl)-5-[3-(4′ch lor op yr id -
in yl)]p r olin e m eth yl ester (8) was prepared by the sequence
reported.8 A number of changes have been made, however,
particularly in larger scale reactions, that have led to easier
1
68.8-69.7 °C; H NMR (CDCl3) δ 1.25-1.37 (m, 2H), 1.39 (s,
9H), 2.14-2.20 (m, 2H), 5.14 (br d, J ) 3.0, 1H), 5.20 (br d, J
) 3.0, 1H), 7.23 (d, J ) 4.8, 1H), 8.45 (d, J ) 4.8, 1H), 8.51 (s,

7082 J . Org. Chem., Vol. 66, No. 21, 2001
Lennox et al.
1H); 13C NMR (CDCl3) δ 25.73 (2), 26.4 (2), 28.1 (3), 59.1 (1),
60.6 (1), 80.5 (0), 115.0 (1), 140.1 (1), 140.5 (0), 148.3 (1), 153.4
(0), 155.0 (0). Anal. Calcd for C14 H18 N2O2: C, 68.3; H, 7.4; N,
11.4. Found: C, 68.2; H, 7.4; N. 11.1.
1% Et3N) of the crude material afforded the ethyl carbamate
12 (273 mg, 95%) as a colorless oil: 1H NMR (CDCl3), 1:1
rotamers, δ 1.00 (t, J ) 7.5, 1.5H), 1.23 (t, J ) 7.5, 1.5H), 1.89-
1.99 (m, 1H), 2.02-2.14 (m, 1H), 2.24-2.36 (m, 1H), 2.42-
2.56 (m, 1H), 3.83 (s, 3H), 3.96-4.22 (m, 2H), 4.46-4.58 (m,
1H), 5.24-5.37 (m, 1H), 7.28 (d, J ) 5.4, 1H), 8.42 (br d, J )
4.8, 1H), 9.13 (s, 0.5H), 9.17 (s, 0.5H); 13C NMR (CDCl3) δ 14.2
(3), 14.4 (3), 28.3 (2), 29.0 (2), 32.1 (2), 33.1 (2), 52.4 (3), 58.0
(1), 58.5 (1), 60.5 (1), 60.7 (1), 61.7 (2), 61.8 (2), 123.8 (1), 124.1
(1), 315.5 (0), 136.1 (0), 141.5 (0), 141.8 (0), 184.9 (1), 149.0
(1), 149.3 (1), 149.7 (1), 145.5 (0), 155.0 (0), 172.6 (0), 172.7
(0). Anal. Calcd for C14H17 ClN2O4: C, 53.8; H, 5.5; N, 9.0.
Found: C, 53.4; H, 5.6; N, 8.7.
(2R,5S)-N-E t h oxyca r b on yl-5-[3-(4-N-iod op yr id in yl)]-
p r olin e Meth yl Ester (13). To a mixture of chloropyridine
12 (1.06 g, 3.39 mmol) and NaI (10.16 g, 67.8 mmol) in
anhydrous MeCN (34 mL) at room temperature was added
consecutively ClCO2Et (3.24 mL, 33.9 mmol) and AcCl (241
µL, 3.39 mmol). The rust-colored mixture was sonicated for
12 h, during which time the bath temperature had reached
39 °C. The yellow reaction mixture was then cooled to 0 °C
and, with magnetic stirring, was treated consecutively with
concentrated NH4OH (3.0 mL, 44.1 mmol) and 1 M pH 8
phosphate buffer (50 mL) and extracted with CH2Cl2 (3 × 150
mL). The combined organic phase was partitioned with 2 M
Na2S2O3 (100 mL), the aqueous phase was extracted with CH2-
Cl2 (60 mL), and the combined extract was dried, filtered, and
evaporated. Chromatography (SiO2, gradient elution, 40-60%
EtOAc-hexanes + 1% Et3N) afforded the iodopyridine 13 (1.26
g, 93%) as a light tan oil: 1H NMR (CDCl3) 1/1 rotamers, δ
0.99 (t, J ) 6.9, 1.5H), 1.22 (t, J ) 6.9, 1.5H), 1.83-1.95 (m,
1H), 2.05-2.16 (m, 1H), 2.23-2.36 (m, 1H), 2.43-2.57 (m, 1H),
3.84 (s, 3H), 3.99 (q, J ) 7.0, 1.0H), 4.12 (q, J ) 7.0, 1.0H),
4.46-4.57 (m, 1H), 5.01-5.13 (m, 1H), 7.74 (d, J ) 5.1, 1H),
8.08 (br d, J ) 4.8, 1H), 9.01 (s, 0.5H), 9.05 (s, 0.5H); 13C NMR
(CDCl3) δ 14.1 (3), 14.4 (3), 28.1 (2), 32.4 (2), 33.4 (2), 52.3 (3),
60.8 (1), 60.9 (1),61.6 (2), 61.7 (2), 64.9 (1), 65.2 (1), 108.7 (0),
108.9 (0), 133.8 (0), 134.0 (0), 140.1 (1), 140.8 (0), 148.1 (1),
148.2 (1), 148.3 (1), 148.6 (1), 154.4 (0), 154.9 (0), 172.5 (0),
172.6 (0). Anal. Calcd for C14H17IN2O4: C, 41.6; H, 4.2; N, 6.9.
Found: C, 41.8; H, 4.3; N, 6.8.
(1R ,4S )-7-N -E t h oxyca r b on yl-1-m e t h oxyca r b on yl-7-
a za bicyclo[2.2.1]h ep ta n o[2,3-c]p yr id in e (20). To a solution
of cis-2,6-dimethylpiperidine (687 µL, 5.1 mmol) in THF (7.06
mL) at -20 °C was added n-BuLi (2.22 M in hexanes, 2.25
mL, 5.0 mmol). The LiDMP solution was stirred an additional
1 h at -20 °C, and then an aliquot (3.30 mL, 1.65 mmol) was
added over 13 min to a solution of iodopyridine 13 (303 mg,
0.750 mmol) in THF (24.3 mL) at -72 °C. The pale reddish
orange reaction mixture was stirred an additional 2 h at -72
°C, and was then warmed to -20 °C at a rate of 0.7 °C/min.
The reaction was quenched with MeOH (0.5 mL) followed by
1 M pH 8 buffer (10 mL) and then partitioned between CH2-
Cl2 (75 mL) and 1 M Na2S2O3 (10 mL), further extracting the
aqueous phase with CH2Cl2 (3 × 50 mL). The combined extract
was dried, filtered, and evaporated to a brown oil, which was
chromatographed (SiO2, elution with 60% EtOAc/hexanes +
1% Et3N) to provide bicycle 20 (65 mg, 31%) as a pale yellow
oil: 1H NMR (CDCl3) δ 1.17 (t, J ) 7.1, 3H), 1.42 (ddd, J )
12.6, 9.0, 3.7, 1H), 1.62 (ddd, J ) 12.8, 8.9, 3.9, 1H), 2.34-
2.45 (m, 1H), 2.58 (ddd, J ) 14.2, 10.6, 3.6, 1H), 3.81 (s, 3H),
4.02 (q, J ) 7.1, 2H), 5.35 (d, J ) 4.5, 1H), 7.63 (d, J ) 5.1,
1H), 8.53 (d, J ) 5.1, 1H), 8.55 (s, 1H); 13C NMR (CDCl3) δ
14.1 (3), 27.0 (2), 31.1 (2), 52.5 (1), 61.1 (1), 62.1 (2), 71.7 (0),
116.1 (1), 139.5 (0), 140.4 (1), 148.8 (1), 151.5 (0), 156.4 (0),
168.6 (0); MS (+)-FAB [M + H]+ m/z 277. Anal. Calcd for C14
H16 N2O4: C, 60.9; H, 5.8; N, 10.1. Found: C, 60.6; H, 6.0; N.
10.0.
(1S,4S)-7-Aza bicyclo[2.2.1]h ep ta n o[2,3-c]p yr id in e Di-
h yd r och lor id e (16). To a solution of carbamate 15 (103 mg,
0.418 mmol) in MeOH (3.0 mL) was added dropwise 1 M
ethereal HCl (3.0 mL, 3.0 mmol). The homogeneous solution
was stirred for 18 h, whereupon it had become heterogeneous.
All volatiles were removed in vacuo, and the residual solid
material was triturated at 60 °C with MeOH (1.0 mL) and
MeCN (9.0 mL). The mixture was cooled to room temperature,
filtered under a blanket of dry nitrogen, washed with MeCN
(10.0 mL), and dried under high vacuum at 55 °C to afford 88
mg (96%) of a white solid: [R]25 -5.9 (c 0.028, (CD3OD); mp
D
223.5-224.6 °C; 1H NMR (CD3OD) δ 1.66-1.85 (2H, m), 2.54-
2.62 (m, 2H), 5.66 (d, J ) 4.2, 1H), 5.67 (d, J ) 3.6, 1H), 8.28
(d, J ) 5.7, 1H), 8.98 (d, J ) 5.7, 1H), 9.06 (s, 1H); 13C NMR
(CD3OD) δ 23.2 (2), 23.8 (2), 61.3 (1), 62.9 (1), 121.9 (1), 136.5
(1), 140.4 (0), 145.1 (1), 159.6 (0); MS (+)-FAB [M + H]+ m/z
147 (free base). Anal. Calcd for C9 H10 N2‚2HCl: C, 49.3; H,
5.5; N, 12.8. Found: C, 49.1; H, 5.7; N, 12.7.
(1S,4S)-7-Meth yl-7-a za bicyclo[2.2.1]h ep ta n o[2,3-c]p y-
r id in e Dih yd r och lor id e (17). Dihydrochloride 16 (156 mg,
0.714 mmol) was treated with 0.514 M NaOH (4.7 mL, 2.4
mmol) in MeOH and evaporated to dryness. To the residue
was added 37% aqueous HCHO (3.0 mL, 38 mmol) and HCO2H
(2.0 mL, 53 mmol). The resultant mixture was stirred at 95
°C for 18 h, cooled to room temperature, evaporated to dryness,
and partitioned between 1 M NaOH (20 mL) and 20% IPA/
CH2Cl2 (25 mL). The aqueous phase was saturated with solid
KCl and then further extracted with 20% IPA/CH2Cl2 (5 × 25
mL). The combined extracts were dried, evaporated, and then
submitted to flash chromatography (SiO2, elution with 5%
MeOH [saturated with NH3]/CH2Cl2).
The free base was submitted to high vacuum to remove all
traces of NH3, dissolved in EtOH (2.5 mL), and treated
dropwise with 1.0 M ethereal HCl (5.0 mL, 5 mmol) while
stirring vigorously. The mixture was further diluted with ether
(20 mL) and stirred for 18 h. Filtration of the suspension under
nitrogen followed by drying at 65 °C under high vacuum
afforded 151 mg (90%) of an off-white solid: [R]25 -4.57° (c
D
0.033, CD3OD); mp 199.8-200.4 °C; 1H NMR (CD3OD) 2/1,
quaternary diastereomers, δ 1.71-1.88 (m, 2H), 2.66 (s, 2H),
2.68-2.73 (m, 2H), 2.99 (s, 1H), 5.52 (d, J ) 3.9, 0.35H) (d, J
) 3.6, 0.35H), 5.61 (d, J ) 4.2, 0.65H), 5.63 (d, J ) 3.9, 0.65H),
8.28 (d, J ) 5.7, 0.35H), 8.32 (d, J ) 5.7, 0.65), 8.99 (d, J )
5.7, 0.35H), 9.04 (d, J ) 6.0, 0.65H), 9.07 (s, 0.35H), 9.08 (s,
0.65); 1H NMR (DMSO-d6, 98.4 °C) δ 1.46-1.59 (m, 2H), 2.49
(s, 3H), 2.54-2.56 (m, 2H), 5.21 (d, J ) 3.9, 1H), 5.25 (d, J )
3.8, 1H), 7.70 (d, J ) 5.03, 1H), 8.71 (d, J ) 5.0, 1H), 8,76 (s,
1H); 13C NMR (CD3OD), 2/1, quaternary distereomers, δ 20.9
(2), 21.5 (2), 23.6 (2), 24.2 (2), 34.3 (3), 34.5 (3) 67.4 (1), 68.7
(1), 69.0 (1), 70.2 (1), 122.0 (1), 136.7 (1), 138.1 (1), 138.4 (0),
140.5 (0), 145.2 (1), 145.6 (1), 157.6 (0), 159.5 (0); upon cooling
to room temperature, the sample showed an unchanged
ambient temperature 1H NMR spectrum. MS (+)-FAB [M +
H]+ m/z 161 (free base). Anal. Calcd for C10 H12 N2‚2HCl: C,
51.5; H, 6.1; N, 12.0. Found: C, 51.2; H, 6.2; N, 11.6.
The free base of 17 has the following spectrum: 1H NMR
(CD3OD) δ 1.23 (m, 2H), 2.03 (br, s, 3H), 2.18 (m, 2H), 4.28 (d,
1H, J ) 3.4), 4.33 (d, 1H, J ) 2.8), 7.41 (d, 1H, J ) 4.8), 8.39
(d, 1H, J ) 4.9), 8.44 (s, 1H).
(2R,5S)-N-Eth oxyca r bon yl-5-[3-(4-N-ch lor op yr id in yl)]-
p r olin e Meth yl Ester (12). To a solution of pyrrolidine 11
(222 mg, 0.92 mmol) and Et3N (390 µL, 2.8 mmol) in THF (9.2
mL) at 0 °C was added ClCO2Et (93 µL, 0.97 mmol), leading
to the formation of a white precipitate. The reaction mixture
was warmed to room temperature over 3 h, at which point all
volatiles were evaporated and the residue was partitioned
between EtOAc (30 mL) and NaHCO3 (30 mL). The aqueous
phase was further extracted with EtOAc (2 × 30 mL), and the
combined organic phase was dried, filtered, and evaporated.
Chromatography (SiO2, elution with 40%, EtOAc/hexanes +
(2R ,5S )-N -E t h oxyca r b on yl-5-[3-(oxa b icyclo[2.2.1]-
h ep ten o[4N,5N-c]p yr id in yl)]p r olin e Meth yl Ester (21).
To a solution of iodopyridine 13 (343 mg, 0.848 mmol) in THF
(25 mL) at -73 °C was added over 15 min 0.50 M LiDMP (3.56
mL, 1.78 mmol) in THF. The resultant orange red solution
was stirred 3 h at -72 °C and then treated with freshly
distilled furan (2.05 mL, 28.2 mmol). The reaction mixture was

7-Azabicyclo[2.2.1]heptano[2.3-c]pyridines
J . Org. Chem., Vol. 66, No. 21, 2001 7083
warmed to 14 °C over 18 h, treated with MeOH (2 mL), and
partitioned between pH 8 buffer (25 mL) and CH2Cl2 (75 mL).
The aqueous phase was further extracted with CH2Cl2 (3 ×
75 mL), dried over Na2SO4, and then concentrated to a viscous
orange-brown oil. The highly labile oxabicyclopyridine 21 was
not isolated, but instead submitted to (+)-ES MS (capillary,
4.16 kV; HV lens, 0.57 kV; cone, 76 V) on a VG Quattro triple
quadrupole Instrument. The following molecular ions were
detected: [M + H]+ for 21 m/z 345.1 (8% of base peak); [M +
H]+ for 20 m/z 277.2 (36% of base peak); [M + H]+ for 13 m/z
405.1 (20% of base peak).
Ack n ow led gm en t. We thank the Ruetgers Organics
Co. for their generous gift of high-quality 4-chloropyri-
dine hydrochloride.
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
mental procedures for the conversion of D-glutamic acid to
(2S,5R)-N-(tert-butyloxycarbonyl)-5-[3-(4′-chloropyridinyl)]pro-
line methyl ester (8). This material is available free of charge
via the Internet at http://pubs.acs.org.
J O010534Y