Conformationally constrained nicotines. 1-Pyridinyl-7- azabicyclo[2.2.1]heptane and 1-pyridinyl-8-azabicyclo[3.2.1] octane analogues

Article abstract of DOI:10.1021/jo990130u

Conformationally constrained bicyclo analogues of natural (-)-nicotine and unnatural (+)-nicotine have been synthesized from D- and L-glutamic acid, respectively. Regioselective addition of 3-lithiopyridine to the γ-carbonyl of a protected glutamate was followed by intramolecular imine formation and stereospecific catalytic hydrogenation of the resultant pyrroline to give cis-5-pyridinylproline. A sequence of transformations to convert the ester to bromide was followed by the key intramolecular anionic cyclization at the benzylic position to form the 1-pyridinyl-7-azabicyclo[2.2.1]heptane analogue. Alternatively, homologation of the ester of cis-5-pyridinylproline and conversion to bromide allowed cyclization to the 1-pyridinyl-7- azabicyclo[3.2.1]octane analogues.

Full text of DOI:10.1021/jo990130u

J . Org. Chem. 1999, 64, 4069-4078
4069
Con for m a tion a lly Con str a in ed Nicotin es.
1-P yr id in yl-7-a za bicyclo[2.2.1]h ep ta n e a n d
1-P yr id in yl-8-a za bicyclo[3.2.1]octa n e An a logu es
Ying-zi Xu, J aesung Choi, M. Isabel Calaza, Sean Turner, and Henry Rapoport*
Department of Chemistry, University of California, Berkeley, California 94720
Received J anuary 25, 1999
Conformationally constrained bicyclo analogues of natural (-)-nicotine and unnatural (+)-nicotine
have been synthesized from D- and L-glutamic acid, respectively. Regioselective addition of
3-lithiopyridine to the γ-carbonyl of a protected glutamate was followed by intramolecular imine
formation and stereospecific catalytic hydrogenation of the resultant pyrroline to give cis-5-
pyridinylproline. A sequence of transformations to convert the ester to bromide was followed by
the key intramolecular anionic cyclization at the benzylic position to form the 1-pyridinyl-7-
azabicyclo[2.2.1]heptane analogue. Alternatively, homologation of the ester of cis-5-pyridinylproline
and conversion to bromide allowed cyclization to the 1-pyridinyl-7-azabicyclo[3.2.1]octane analogues.
Ch a r t 1
In tr od u ction
Nicotinic acetylcholine receptors are a group of ion
channel receptors1 that play an important role in many
biological processes related to a number of nervous
system disorders. As ligands for the nicotinic acetylcho-
line receptor,2,3 many groups of compounds have been
isolated from natural sources or synthesized, of which
(-)-nicotine (1, Chart 1) and its analogues represent an
important class. In particular, nicotine analogues with
rigid structures have become interesting targets stimu-
lated by the isolation of the very active but highly toxic
epibatidine4 from the skin of a South American frog.
The targets in the work we are now reporting have
been to synthesize nicotine analogues 2 and 3, which
possess azabicyclo ring systems with an apical nitrogen.
The synthetic plan involves coupling of glutamic acid
derivatives with 3-metalated pyridine, followed by cy-
clization to form proline A. By subsequent side-chain
manipulation, A can afford bromide B or C (Figure 1).
The key step then becomes generation of the carbanion
at the benzylic position R to the pyridine followed by
intramolecular cyclization to construct the bridged sys-
tem. Depending on the number of carbons in the side
chain of the bromide, either a [2.2.1]- or [3.2.1]azabicy-
clonicotine analogue will result. Although Beak’s pio-
neering work has presented many examples of metalation
and electrophilic substitution at the R-position of an
amine derivative5,6 (e.g., Boc-protected secondary amines),
there were certain unexplored factors introduced by our
system. Thus, there has been no report of application of
this method to pyridines or to the deprotonation of a
tertiary carbon R to the nitrogen. Also, after deprotona-
tion, although an intramolecular cyclization seems to be
preferred judging from the ring size, steric effects at the
quaternary carbon in forming the bicyclo system might
lead to competitive intermolecular reaction, including
quaternization of the pyridine.
Resu lts a n d Discu ssion
Syn th esis of th e P yr id in yl Keton e. Using a number
of glutamic acid derivatives and 3-metallopyridines, a
variety of conditions and combinations were examined
for pyridinyl ketone formation. The first substrate was
N-tert-butyloxycarbonyl-L-glutamic acid R-tert-butyl ester
(4)7 as its tetrahydrofuranyl ester.8 In its reaction with
the original Grignard reagent derived from 3-bromopy-
ridine, a disappointing 30% yield of pyridinyl ketone 8
was obtained.
Since a quite satisfactory yield of the corresponding
anisolyl ketone had resulted when the isoxazolidide 5 was
treated with anisolyllithium,7 this combination was ap-
plied to the preparation of the pyridinyl ketone. With
3-pyridinyllithium9,10 and isoxazolidide 5, an improved
yield of 69% of ketone 8 was realized. Substitution of the
3-pyridinyl Grignard reagent led to a decreased yield of
50%.
The most convenient and efficacious process was found
to be the coupling of 3-pyridinyllithium with the readily
available N-Boc pyroglutamate esters11 6 and 7. With
tert-butyl ester 6, a 73% yield of pyridinyl ketone 8 was
realized, while methyl ester 7 gave the corresponding
(1) Galzi, J .-L., Changeux, J .-P. Neuropharmacology 1995, 34, 563.
(2) Glennon, R. A.; Dukat, M. Med. Chem. Res. 1996, 465.
(3) McDonald, I. A.; Cosford, N.; Vemier, J .-M. Ann. Rep. Med. Chem.
1995, 30, 41.
(4) Spande, T. F.; Garraffo, M. W.; Edwards, M. W. H.; Yeh, H. J .
C.; Pannell, L.; Daly, J . W. J . Am. Chem. Soc. 1992, 114, 3475.
(5) Beak, P.; Zajdel, W. J .; Reitz, D. B. Chem. Rev. 1984, 84, 471.
(6) Beak, P.; Lee, W. K. J . Org. Chem. 1993, 58, 1109.
(7) Berre´e, F.; Chang, K.; Cobas, A.; Rapoport, H. J . Org. Chem.
1996, 61, 715.
(8) Mattson, M. N.; Rapoport, H. J . Org. Chem. 1996, 61, 6071.
(9) Murahashi, S.-I.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe,
S. J . Org. Chem. 1990, 55, 1736.
(10) Guthikonda, R. N.; Cams, L. D.; Quesada, M.; Woods, M. F.;
Salzmann, T. N.; Christensen, B. G. J . Med. Chem. 1987, 30, 871.
10.1021/jo990130u CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/01/1999

4070 J . Org. Chem., Vol. 64, No. 11, 1999
Xu et al.
F igu r e 1. Proposed synthesis of the [2.2.1] and [3.2.1] azabicyclonicotine analogues.
Sch em e 1. Syn th esis of P yr id in yl Keton es
ketone 9 in 59% yield. These results are collated in
Scheme 1.
Sid e Ch a in Exten sion . With pyridinyl proline 13 in
hand, the next task was to extend the carboxylate side
chain at the 5-position. For this purpose, the nitrogen
was protected as its Boc derivative and the methyl ester
was hydrolyzed with LiOH to the acid 16. A stepwise
route utilizing the Arndt-Eistert synthesis13,14 was ap-
plied to obtain the homologated ester 18. In this se-
quence, a mixed anhydride intermediate15 was superior
to the acid chloride for diazoketone formation. Reduction
of the ester with Ca(BH4)2 afforded both the desired
alcohol 19 plus the borane complex of 19. Use of a large
amount of EtOH as solvent instead of a mixture of THF/
EtOH16 suppressed formation of this complex, which can
also be broken up by refluxing in EtOH with 400 mol %
of diethanolamine.
Our intention was to obtain bromide 21 directly from
alcohol 19 using carbon tetrabromide and triphenylphos-
phine;17 however, only poor yields of 21 were isolated.
An alternative was to prepare the mesylate 20 and to
use it directly in the alkylation step or convert it to
bromide 21 as the alkylation reagent. All attempts at
standard mesylate formation, requiring base, failed;
elimination was the major product. A milder way to effect
mesylation under essentially neutral conditions is to use
the very active mesylating reagent 2-mesyl-5-methylimi-
dazonium triflate.18 When this reagent was used mesy-
late 20 was the sole product and treatment with LiBr in
acetone afforded bromide 21 in 73% yield. A minor and
In tr a m olecu la r Cycliza tion to th e P r olin e De-
r iva tives. Our initial intention was to selectively remove
the N-Boc group without affecting the tert-butyl ester of
8.12 The free amine and the ketone functionalities thus
could undergo intramolecular condensation to form the
pyrroline under treatment with mild base, and subse-
quent reduction would produce the proline derivative.
Removal of the N-Boc group, however, was not suf-
ficiently selective and a partial removal of the tert-butyl
ester was observed under various conditions. As a result,
the plan was to remove both the N-Boc and tert-butyl
ester groups under more strongly acidic conditions, then
to re-esterify the acid. This was accomplished by treat-
ment of 8 with saturated HCl in MeOH from which a
75% yield of keto-methyl ester 10 was obtained. A major
side product was the ketal-methyl ester 11, which could
be easily hydrolyzed to ketone 10 at pH 1-2 with
aqueous HCl. On the other hand, when methyl ester 9
was used, treatment with 3 M HCl in EtOAc afforded
the single product 10. After isolation using base, the
pyrroline 12 was obtained in 87% yield. Catalytic hydro-
genation of the imine gave the cis-proline derivative 13
as the sole product in 95% yield. In another experiment,
with NaCNBH3 as the reducing agent, a mixture of both
diastereoisomers with a cis to trans ratio of 5/4 was
1
isolated, as determined by H NMR. These experiments
are summarized in Scheme 2.
(13) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091.
(14) Arndt, F.; Eistert, B.; Partale, W. Chem. Ber. 1927, 60, 1364.
(15) Podlech, J .; Seebach, D. Liebigs Ann. 1995, 1217.
(16) Kang, M.; Park, J .; Konradi, A. W.; Pedersen, S. F. J . Org.
Chem. 1996, 61, 5528.
(17) Campell, J . A.; Rapoport, H. J . Org. Chem. 1996, 61, 6313.
(18) O’Connell, J . F.; Rapoport, H. J . Org. Chem. 1992, 57, 4775.
(11) (a) Ohta, T.; Hosoi, A.; Kimura, T.; Nozoe, S. Chem. Lett. 1987,
2091. (b) Ezquerra, J .; Pedregal, C.; Rubio, A.; Valenciano, J .; Navio,
J . L. G.; Alvarez-Builla, J .; Vaquero, J . J . Tetrahedron Lett. 1993, 34,
6317.
(12) Gibson, F. S.; Bergmeier, S. C.; Rapoport, H. J . Org. Chem.
1994, 59, 3216.

Conformationally Constrained Nicotines
J . Org. Chem., Vol. 64, No. 11, 1999 4071
Sch em e 2. Syn th esis of 5-Su bstitu ted P r olin e Der iva tives
Sch em e 3. Syn th esis of 5-P yr id in yl-2-br om oeth ylp yr r olid in e 21
unexpected product was cyclic carbamate 22, resulting
used, a small amount of olefin 23 was isolated together
with recovered starting material 21. The structure of the
olefin was confirmed by an alternative synthesis: methyl
ester 15 was reduced with Ca(BH4)2, and the resulting
alcohol 25 was oxidized to the aldehyde 26 and treated
with methyltriphenylphosphonium bromide/n-Buli to af-
ford the olefin 23. When s-BuLi was used, two products
were obtained, the desired [2.2.1] structure 2a and 24,
in which the bromine had been replaced by hydrogen.
The structure of 24 was established by catalytic hydro-
genation (Pd/C) of olefin 23 to 24. Apparently, under the
reaction conditions, metal-halogen exchange and R-depro-
from attack at the carbonyl oxygen of the Boc group by
the very active mesylated side chain during bromide
formation. Bromide 21 was not stable, due to alkylation
of the pyridine nitrogen by the side chain bromide. This
is probably an intermolecular process since dilution with
solvent significantly slows this process. These reactions
are depicted in Scheme 3.
Con str u ction of th e Bicyclo [2.2.1] Rin g System .
Anion formation and closure of bromide 21 to the bicyclo
[2.2.1] ring system was surprisingly sensitive to the
specific base, as shown in Scheme 4. When KHMDS was

4072 J . Org. Chem., Vol. 64, No. 11, 1999
Sch em e 4. Syn th esis of th e [2.2.1] Aza bicyclo Nicotin e An a logu e
Xu et al.
tonation are competitive processes, one leading to forma-
tion of the ethyl analogue 24 (after quenching and
isolation) and the other yielding the desired bicyclo[2.2.1]
product 2a .
system is less favorable than formation of the [2.2.1]
system, thus permitting intermolecular side reactions to
occur. To reduce the extent of any competing intermo-
lecular reactions, higher dilution conditions were applied.
Bromide 31 was added to the solution of n-Buli in THF
via a syringe pump over a period of 1 h. Indeed, an
improved yield of 48% was obtained. When the same
technique was applied to bromide 21, the yield of the
[2.2.1] system product 2a was improved from 55% to 64%.
Deprotection and methylation gave the final [3.2.1]
azabicyclo (-)-3 analogue. To obtain the enantiomer (+)-
3, exactly the same sequence of reactions was applied to
D-glutamic acid.
Although n-BuLi is known to add to the 1,2 double
bond of pyridine,19 the intramolecular cyclization of 21
to 2a proceeded very rapidly at -78 °C, thus avoiding
this potential addition. Under these conditions, metal-
halogen exchange was not observed and 2a was the only
product, isolated in 55% yield. Treatment of 2a with 3
M HCl in EtOAc removed the Boc group, and the amine
2b was methylated (formic acid/formaldehyde)20 to the
target nicotine analogue 2. Since 2 is a symmetric
molecule it was unnecessary to carry out a parallel
sequence from D-glutamic acid.
Con clu sion
Con str u ction of th e Bicyclo [3.2.1] Rin g System .
From ester 15, the intermediate needed for cyclization
to the [3.2.1] system was constructed. Reduction of this
ester and oxidation of the resulting alcohol 25 gave
aldehyde 26. Treatment with the sodium salt of trimethyl
phosphono- acetate afforded olefin 27 as a mixture of the
E and Z isomers (Scheme 5). This mixture of isomers was
reduced to propionic ester 28. Following the same pro-
cedure used for the formation of bromide 21, ester 28 was
reduced to the alcohol 29, which was treated with the
imidazolium mesylating reagent followed by LiBr to yield
the desired bromide 31.
We report a process for the enantiospecific synthesis
of nicotine analogues in which the pyrrolidine ring is
conformationally constrained into an azabicyclo ring
system. The specific systems prepared are the 1-(3-
pyridinyl)-7-azabicyclo[2.2.1]heptanes and the 1-(3-py-
ridinyl)-8-azabicyclo[3.2.1] octanes. Enantiospecificity is
achieved by basing the synthetic sequence on L- or
D-glutamic acid to which the metallopyridine is attached.
Conceivably, the method could be extrapolated to other
substitution patterns and structural types.
Employing the same conditions used for formation of
the [2.2.1] system, 31 was treated with n-BuLi at -78
°C in THF. Only a small amount of the desired [3.2.1]
structure 3a (<10%) was formed; the major products
consisted of unidentified polar material. A possible
explanation for this difference in behavior is that depro-
tonation at the R-carbon to the pyridine in 31 did occur
but that the intramolecular cyclization to the [3.2.1]
Exp er im en ta l Section
Gen er a l P r oced u r es. All melting points are uncorrected.
1H NMR and 13C spectra were recorded in CDCl3 unless
otherwise specified, and chemical shifts are reported in ppm
from internal tetramethylsilane; 13C chemical shifts are re-
ported in ppm from CDCl3 or CD3OD, followed by multiplicity
as determined from DEPT; J values are given in Hz. Reagents
and solvents were dried and purified by distillation before
use: CH2Cl2 from CaH2; THF and Et2O from Na; MeOH from
Mg. Reactions were conducted under N2 and organic extracts
were dried over Na2SO4 prior to evaporation. Chromatography
(19) Gilman, H.; Spatz, S. M. J . Org. Chem. 1951, 16, 1485.
(20) Glenn, D. F.; Edwards, W. B., III. J . Org. Chem. 1978, 43, 2860.

Conformationally Constrained Nicotines
J . Org. Chem., Vol. 64, No. 11, 1999 4073
Sch em e 5. Syn th esis of th e (+)- a n d (-)-[3.2.1] a za bicyclon icotin e An a logu es
was carried out on gravity-grade SiO2. Elemental analyses
were determined by Microanalytical Laboratory, University
of California at Berkeley.
dried, filtered, and evaporated to a residue, which was chro-
matographed (SiO2, CH2Cl2/EtOAc, 7/3), yielding a mixture of
8 and 5 (85/15, 293 mg); 69% yield of 8.
ter t-Bu tyl (2S)-2-(N-(ter t-Bu tyloxyca r bon yl)a m in o)-5-
oxo-5-(3-p yr id in yl)p en ta n oa te ((+)-8). Meth od A. To a
solution of 3-iodopyridine (123 mg, 0.6 mmol) in THF (5 mL)
was added EtMgBr (0.72 mL of a 1.0 M THF solution, 0.72
mmol) at room temperature, and the mixture was stirred for
25 min. To a solution of N-(tert-butyloxycarbonyl)-L-glutamic
acid R-tert-butyl ester (4, 152 mg, 0.5 mmol) in dichlo-
romethane (2 mL) at -20 °C were added 2,3-dihydrofuran
(38.5 mg, 0.55 mmol) and a solution of methanesulfonic acid
in dichloromethane (5 µL, 0.5 M solution, 2.5 µmol). The
mixture was allowed to warm to 0 °C over 4 h and then
recooled to -20 °C, and to this mixture was added the
3-pyridinyl Grignard reagent dropwise over 5 min to yield a
clear, colored solution. After 30 min at -20 °C, the mixture
was very slowly warmed to room temperature over 18 h and
then recooled to 0 °C and added dropwise to aqueous 1 M K2-
CO3. The mixture was extracted with dichloromethane (3 ×
20 mL), and the combined organic layer was dried, filtered,
and evaporated to a residue that was chromatographed (CH2-
Cl2/EtOAc, 7/3) to afford 8 (55 mg, 30% yield) as a white solid:
mp 89-90 °C; [R]22D +8.7 (c 1, CHCl3); 1H NMR δ 1.42 (s, 9H),
1.48 (s, 9H), 2.01-2.13 (m, 1H), 2.28-2.40 (m, 1H), 3.01-3.30
(m, 2H), 4.28 (m, 1H), 5.26 (d, J ) 7.5, 1H), 7.43 (dd, J ) 7.9,
4.8, 1H), 8.24 (dt, J ) 7.9, 1.7, 1H), 8.79 (d, J ) 4.8, 1H), 9.17
(s, 1H); 13C NMR δ 27.0, 27.9, 28.1, 34.7, 53.3, 79.7, 82.1, 123.5,
131.9, 135.2, 149.4, 153.4, 155.4, 171.3, 197.7. Anal. Calcd
for C19H28N2O5: C, 62.6; H, 7.7; N, 7.7. Found: C, 62.8; H,
7.8; N, 7.6.
Meth od B. 3-Bromopyridine (0.241 mL, 2.5 mmol) in ether
(3.5 mL) was added dropwise to a solution of n-BuLi (1.56 mL
of a 1.6 M solution in hexane, 2.5 mmol) in ether (10 mL) at
-78 °C in 5 min. The resulting yellow slurry was stirred at
-78 °C for 30 min, and a solution of N-(tert-butoxycarbonyl)-
L-glutamic acid R-tert-butyl ester â-isoxazolidide (5, 354 mg,
1 mmol) in THF (5 mL) was added over 5 min. The resulting
mixture was warmed to room temperature over 6 h, stirred at
room temperature for 12 h, diluted with ether (30 mL), and
quenched with H2O (40 mL). The aqueous layer was extracted
with ether (3 × 30 mL), and the combined organic layer was
Meth od C. To a solution of isoxazolidide 5 (177 mg, 0.5
mmol) in THF (2 mL) at room temperature was added the
3-pyridinyl Grignard reagent (0.72 mmol) dropwise over 5 min
to yield a clear, colored solution (0.72 mmol) that was stirred
for 9 h at room temperature. Aqueous K2CO3 was added, the
mixture was extracted with dichloromethane (3 × 20 mL), and
the combined organic layer was dried, filtered, and evaporated.
Chromatography (CH2Cl2/EtOAc, 7/3) of the residue afforded
a mixture of 8 and 5 (63/37, 143 mg); 50% yield of 8.
Meth od D. 3-Bromopyridine (7.23 mL, 74.7 mmol) in Et2O
(57 mL) was added dropwise to a solution of n-BuLi (1.6 M
solution in hexane, 47 mL, 74.7 mmol) in Et2O (167 mL) at
-78 °C over 30 min. The resulting yellow slurry was stirred
at -78 °C for 30 min, and a solution of tert-butyl N-(tert-
butyloxycarbonyl)-L-pyroglutamate (6, 14.3 g, 50 mmol) in
Et2O/THF (70 mL, 1/1) was added over 10 min. The resulting
mixture was stirred at -78 °C for 1 h, poured into H2O (60
mL), and extracted with Et2O (50 mL). The combined organic
layer was dried, filtered, and evaporated, and the residue was
chromatographed (CH2Cl2/EtOAc, 7/3) to afford 8 (13.1 g, 72%).
Meth yl (2S)-2-(N-(ter t-Bu tyloxyca r bon yl)a m in o)-5-oxo-
5-(3-p yr id in yl)p en ta n oa te ((+)-9). 3-Bromopyridine (7.23
mL, 74.7 mmol) in Et2O (57 mL) was added dropwise to a
solution of n-BuLi (1.6 M solution in hexane, 47 mL, 74.7
mmol) in Et2O (167 mL) at -78 °C over 30 min. The resulting
yellow slurry was stirred at -78 °C for 30 min, and a solution
of methyl N-(tert-butyloxycarbonyl)-L-pyroglutamate (7, 16.4
g, 67.3 mmol) in THF/Et2O (80 mL, 1/1) was added over 20
min. The resulting mixture was stirred at -78 °C for 1 h and
then poured into H2O (60 mL), the aqueous layer was extracted
with Et2O (50 mL), and the combined organic layer was dried,
filtered, and evaporated. The residue was chromatographed
(CH2Cl2/EtOAc, 7/3) to afford 9 (12.9 g, 59%) as a white solid:
mp 90-92 °C; [R]22 +13.5 (c 1, CHCl3); 1H NMR δ 1.40 (s,
D
9H), 2.06 (m, 1H), 2.34 (m, 1H), 3.01-3.19 (m, 2H), 3.75 (s,
3H), 4.40 (m, 1H), 5.22 (d, J ) 7.5, 1H), 7.41 (dd, J ) 7.7, 4.9,
1H), 8.22 (dt, J ) 7.7, 1.7, 1H), 8.77 (d, J ) 4.9, 1H), 9.15 (d,
J ) 1.7, 1H); 13C NMR δ 26.6, 28.1, 34.6, 52.3, 52.7, 80.0, 123.5,

4074 J . Org. Chem., Vol. 64, No. 11, 1999
Xu et al.
131.8, 135.2, 149.4, 153.4, 155.3, 172.6, 197.5. Anal. Calcd for
saturated NaHCO3 in H2O (25 mL) and extracted with CHCl3/
IPA (3/1, v/v, 3 × 30 mL). The combined organic layer was
dried, filtered, and evaporated. The residue was chromato-
graphed (CH2Cl2/MeOH saturated with NH3, 95/5) to afford
first 14 (121 mg, 40%) and then 13 (153 mg, 51%), both as
colorless oils. For 14: 1H NMR δ 1.60-1.80 (m, 1H), 1.90-
2.05 (m, 1H), 2.05-2.28 (m, 1H), 2.30-2.38 (m, 1H), 2.64 (br,
1H), 3.75 (s, 3H), 4.03 (dd, J ) 8.4, 5.7, 1H), 4.39 (t, J ) 7.2,
1H), 7.23 (dd, J ) 7.8, 4.7, 1H), 7.80 (dt, J ) 7.8, 1.7, 1H),
8.47 (dd, J ) 4.7, 1.4, 1H), 8.59 (d, J ) 1.9, 1H); 13C NMR δ
29.7 (CH2), 34.6 (CH2), 52.2 (CH3), 59.2 (CH), 59.4 (CH), 123.3
(CH), 134.1 (CH), 139.8 (C), 148.4 (CH), 148.5 (CH), 176.2 (C).
Anal. Calcd for C11H14N2O2‚1/4H2O: C, 62.7; H, 6.9; N, 13.3.
Found: C,62.9; H,7.1; N, 13.3.
C
16H22N2O5: C, 59.6; H, 6.9; N, 8.7. Found: C, 59.7; H, 6.9; N,
8.6.
Meth yl (2R)-2-(N-(ter t-bu tyloxyca r bon yl)a m in o)-5-oxo-
5(3-p yr id in yl)p en ta n oa te ((-)-9, structure not shown) was
prepared from the corresponding D-pyroglutamate: mp 91-
93 °C; [R]22D -14.1 (c 1, CHCl3); spectral and chromatographic
properties identical with those of (+)-9.
Meth yl (2S)-Am in o-5-oxo-5-(3-pyr idin yl)pen tan oate Di-
h yd r och lor id e (10), (2S)-2-(3-P yr id in yl)-5-m eth oxyca r -
bon yl-1-p yr r olin e (12), a n d (2S)-cis-5-(3-P yr id in yl)p r o-
lin e Meth yl Ester ((+)-13). To pyridinyl ketone (+)-9 (2.65
g, 8.24 mmol) was added slowly, while stirring, HCl in EtOAc
(3 M, 30 mL) at room temperature. The mixture was stirred
overnight while precipitate formed; concentration under re-
duced pressure gave crude dihydrochloride 10 as a pale yellow
solid: 1H NMR δ 2.25-2.50 (m, 2H), 3.41 (q, J ) 6.6, 2H),
3.79 (s, 3H), 4.26 (t, J ) 6.9, 1H), 8.22 (t, J ) 7.0, 1H), 8.98 (d,
J ) 4.2, 1H), 9.09 (d, J ) 8.2, 1H), 9.33 (s, 1H). The crude 10
was dissolved in H2O (20 mL) and shaken with EtOAc (100
mL) and saturated NaHCO3 in H2O (20 mL). The aqueous
layer was extracted with EtOAc (2 × 60 mL), and the combined
organic layer was dried, filtered, and evaporated to afford
crude pyrroline 12 (1.46 g, 87%) as a yellow oil: 1H NMR δ
2.15-2.40 (m, 2H), 2.85-3.05 (m, 1H), 3.08-3.20 (m, 1H), 3.74
(s, 3H), 4.89 (dd, J ) 8.7, 6.6, 1H), 7.31 (dd, J ) 7.9, 4.8, 1H),
8.19 (dt, J ) 7.9, 1.8, 1H), 8.62 (dd, J ) 4.8, 1.6, 1H), 8.97 (d,
J ) 2.0, 1H); 13C NMR δ 26.1 (CH2), 35.2 (CH2), 52.2 (CH3),
74.5 (CH), 123.3 (CH), 129.4 (C), 135.0 (CH), 149.2 (CH), 151.7
(CH), 172.9 (C), 173.8 (C). Pyrroline 12 (1.2 g, 5.88 mmol) in
IPA (15 mL) was treated with H2 at 1 atm in the presence of
10% Pd/C (0.12 g, 10% w/w) at room temperature overnight.
The resulting mixture was filtered and evaporated to give 13
(1.2 g, 95%) as a colorless oil. This crude product was suitable
for further reactions. An analytic sample was obtained by
chromatography (CH2Cl2/MeOH saturated with NH3, 95/5):
(2S)-cis-1-(ter t-Bu tyloxyca r bon yl)-5-(3-p yr id in yl)p r o-
lin e Meth yl Ester ((+)-15). Proline (+)-13 (3.4 g, 16.5 mmol)
in THF (160 mL) at room temperature was treated with Et3N
(2.5 g, 24.8 mmol) followed by (BOC)2O (4.32 mg, 19.8 mmol).
The mixture was stirred at room temperature for 1 h and
evaporated, and the residue was distributed between EtOAc
(100 mL) and saturated NaHCO3 in H2O (50 mL). The aqueous
layer was extracted with EtOAc (2 × 50 mL), the combined
organic layer was dried, filtered, and evaporated, and the
residue was chromatographed (CH2Cl2/EtOAc, 4/6) to afford
15 (4.9 g, 97%) as a colorless oil: [R]22 +27.1 (c 1.2, CHCl3);
D
1H NMR (298 K, rotamer ratio, 60/40, *denotes minor rotamer)
δ 1.16 (s, 5.4H), 1.41* (s, 3.6H), 1.90-2.18 (m, 2H), 2.20-2.30
(m, 1H), 2.32-2.42 (m, 1H), 3.82 (s, 3H), 4.39* (t, J ) 8.4,
0.4H), 4.51-4.58 (m, 0.6H), 4.78 (t, J ) 7.4, 0.6H), 4.98-5.03*
(m, 0.4H), 7.20-7.40 (m, 1H), 8.01* (d, J ) 7.7, 0.4H), 8.15 (d,
J ) 7.7, 0.6H), 8.50 (br, 1H), 8.60 (bs, 0.6H), 8.69* (bs, 0.4H);
1H NMR (C6D6, 298 K, rotamer ratio 70/30) δ 1.09 (s, 6.3H),
1.32* (s, 2.7H), 1.40-1.60 (m, 4H), 3.30 (s, 2.1H), 3.34* (s,
0.9H), 4.15* (br, 0.3H), 4.28 (br, 0.7H), 4.41 (br, 0.7H), 4.72*
(br, 0.3H), 6.75-6.85 (m, 1H), 8.00* (bd, J ) 7.8, 0.3H), 8.21
(d, J ) 7.8, 0.7H), 8.42 (br, 1H), 8.70 (bs, 0.7H), 8.84* (bs,
0.3H); 1H NMR (C6D6, 343 K) δ 1.20 (s, 9H), 1.45-1.58 (m,
4H), 3.38 (s, 3H), 4.33 (br, 1H), 4.53 (br, 1H), 6.86 (dd, J )
7.8, 4.7, 1H), 7.97 (d, J ) 7.8, 1H), 8.41 (dd, J ) 4.7, 1.6, 1H),
8.73 (s, 1H); 13C NMR very complex because of rotamers. Anal.
Calcd for C16H22N2O2: C, 62.7; H, 7.2; N, 9.1. Found: C, 62.4;
H, 7.1; N, 9.2.
[R]22 +34.2 (c 1.1, CHCl3); 1H NMR δ 1.58-1.71 (m, 1H),
D
2.01-2.25 (m, 3H), 2.41 (bs, 1H), 3.70 (s, 3H), 3.90 (dd, J )
8.2, 4.9, 1H), 4.19 (dd, J ) 9.0, 6.0, 1H), 7.20 (dd, J ) 7.8, 4.8,
1H), 7.80 (dt, J ) 7.8, 1.8, 1H), 8.43 (dd, J ) 4.8, 2.5, 1H),
8.54 (d, J ) 2.0, 1H); 13C NMR δ 30.0 (CH2), 34.0 (CH2), 51.9
(CH3), 59.7 (CH), 60.6 (CH), 123.3 (CH), 134.1 (CH), 138.9 (C),
148.4 (CH), 148.6 (CH), 175.1 (C). Anal. Calcd for
(2R)-cis-1-(ter t-Bu tyloxyca r bon yl)-5-(3-p yr id in yl)p r o-
lin e m eth yl ester ((-)-15, structure not shown) was prepared
C
11H14N2O2: C, 64.1; H, 6.8; N, 13.6. Found: C, 63.7; H, 6.9;
N, 13.5.
(2R)-cis-5-(3-P yr id in yl)p r olin e m eth yl ester ((-)-13,
from the corresponding proline (-)-13: [R]22 -27.3 (c 1.1,
D
CHCl3); spectral and chromatographic properties identical with
those of (+)-15.
(2S)-cis-1-(ter t-Bu tyloxyca r bon yl)-5-(3-p yr id in yl)p r o-
lin e (16), (2S,5R)-1-(ter t-Bu tyloxy-ca r bon yl)-2-(1-d ia zo-
m et h ylca r b on yl)-5-(3-p yr id in yl)p yr r olid in e (17), a n d
(2S,5R)-1-(ter t-Bu tyl-oxyca r bon yl)-2-(m eth oxyca r bon yl-
m eth yl)-5-(3-p yr id in yl)p yr r olid in e (18). To methyl ester
15 (3.0 g, 9.8 mmol) in MeOH/H2O (3/1, v/v, 100 mL) at room
temperature was added LiOH‚H2O (1.65 g, 39.2 mmol). The
solution was stirred at room temperature for 5 h, poured into
aqueous H3PO4 solution (0.1 M, 150 mL), and extracted with
CHCl3/IPA (3/1, v/v, 3 × 150 mL). The combined organic layer
was dried, filtered, and evaporated to afford acid 16 (2.8 g,
97%) as a white solid that is suitable for the next reaction
without further purification: 1H NMR (298 K, rotamer ratio
60/40) δ 1.14 (s, 9H), 1.36 (s, 9H), 1.80-2.40 (m, 4H), 4.39 (t,
J ) 7.4, 0.6H), 4.56* (dd, J ) 7.0, 5.0, 0.4H), 4.81* (t, J ) 7.5,
0.4H), 5.04 (dd, J ) 7.5, 4.2, 0.6H), 7.38* (m, 0.4H), 8.42 (dd,
J ) 7.8, 5.3, 0.6H), 7.82 (d, J ) 7.8, 0.6H), 7.86* (d, J ) 7.7,
0.4H), 8.59 (br, 1H), 9.19* (bs, 0.4H), 9.22 (bs, 0.6H). To acid
16 (0.93 g, 3.17 mmol) in THF (15 mL) at -15 °C was added
Et3N (440 µL, 3.17 mmol) followed by ethyl chloroformate (300
µL, 3.17 mmol). The mixture was stirred at -15 °C for 15 min
then warmed to 0 °C followed by addition of excess CH2N2 (0.5
M in Et2O, 20 mL, 10.0 mmol). The reaction mixture stayed
bright yellow and was stirred for 5 h, warmed to room
temperature slowly, and stirred vigorously until the bright
yellow color disappeared. The mixture was evaporated, and
the residue was distributed between EtOAc (50 mL) and
saturated aqueous NaHCO3 (25 mL). The aqueous layer was
structure not shown) was prepared from the corresponding
pyridinyl ketone (-)-9: [R]D22-35.0 (c 1.3, CHCl3); spectral
and chromatographic properties identical with those of (+)-
13.
Met h yl (2S)-(N-(ter t-Bu t yloxyca r b on yl)a m in o)-5,5-
d im eth oxy-5-(3-p yr id in yl)p en ta n oa te (11). Pyridinyl ke-
tone 8 (0.3 g, 0.824 mmol) was treated with saturated HCl in
MeOH (10 mL) at room temperature for 4 h. The mixture was
evaporated, and the residue was dissolved in H2O (5 mL) and
distributed between EtOAc (20 mL) and saturated NaHCO3
in H2O (10 mL). The aqueous layer was extracted with EtOAc
(2 × 20 mL), and the combined organic layer was dried,
filtered, and evaporated. The residue was chromatographed
(CH2Cl2/MeOH saturated with NH3, 97/3) to afford first 12 (126
mg, 75%) then 11 (38 mg, 18%) both as colorless oils. For 11:
1H NMR δ 1.05-1.45 (m, 2H), 1.92-2.15 (m, 2H), 3.14 (s, 3H),
3.15 (s,3H), 3.63 (s, 3H), 7.27 (dd, J ) 7.9, 4.8, 1H), 7.73 (dt,
J ) 7.9, 2.0, 1H), 8.53 (dd, J ) 4.8, 1.7, 1H), 8.67 (d, J ) 2.2,
1H); 13C NMR δ 28.5, 33.1, 48.6, 51.8, 53.9, 102.2, 122.9, 134.6,
135.8, 148.7, 149.0, 175.9. Treatment of 11 with aqueous HCl
at pH 1.5 for 2 h, concentration of the mixture, and partition
between saturated NaHCO3 in H2O and EtOAc as above, led
to complete conversion to 12.
(2S)-tr a n s-5-(3-P yr id in yl)p r olin e Meth yl Ester (14).
Pyrroline 12 (300 mg, 1.47 mmol) in MeOH/Acetate buffer (25
mL, 1/1, v/v) was treated with NaCNBH3 (110 mg, 1.76 mmol)
at room temperature overnight. The mixture was poured into

Conformationally Constrained Nicotines
J . Org. Chem., Vol. 64, No. 11, 1999 4075
extracted with EtOAc (2 × 25 mL), and the combined organic
layer was dried, filtered, and evaporated, affording crude diazo
ketone 17 (0.95 g) as a pale yellow oil that is suitable for the
next reaction without further purification: 1H NMR (298 K,
rotamers) δ 1.00-1.50 (br, 9H), 1.90-2.40 (m, 4H), 4.45 (br,
1H), 4.60-5.10 (br, 1H), 5.35-5.75 (br, 1H), 7.29 (dd, J ) 7.8,
4.7, 1H), 8.02 (bd, J ) 7.8, 1H), 8.49 (dd, J ) 4.7, 2.0, 1H),
59.1, 61.0, 79.7, 122.7, 132.2, 139.7, 148.2, 148.4, 155.7. Anal.
Calcd for C16H24N2O3: C, 65.7; H, 8.3; N, 9.6. Found: C, 65.5;
H, 8.2; N, 9.6.
(2S,5R)-1-(ter t-Bu tyloxyca r bon yl)-2-(2-m eth ylsu lfon yl-
oxyeth yl)-5-(3-p yr id in yl)p yr r olid in e (20), (2S,5R)-1-(ter t-
Bu tyloxyca r bon yl)-2-(2-br om oeth yl)-5-(3-p yr id in yl)p yr -
r olid in e (21), a n d Cyclic Ca r ba m a te 22. To a solution
1-methanesulfonylimidazolide (180 mg, 1.2 mmol) in THF (12
mL) at 0 °C was added methyl triflate (127 µL, 1.2 mmol)
dropwise, the mixture was stirred at 0 °C for 30 min, and then
a mixture of alcohol 19 (300 mg, 1.03 mmol) and 1-methylimi-
dazole (84 µL, 1.03 mmol) in THF (3 mL) was added dropwise
at 0 °C. After addition, the ice bath was removed, the mixture
was stirred overnight and evaporated, and the residue was
dissolved in EtOAc (10 mL) and washed with H2O (5 mL). The
organic layer was dried and evaporated to afford crude
mesylate 20 (containing a small amount of 1-mesylimida-
zolide): 1H NMR (298 K, rotamers) δ 1.00-1.50 (br, 9H), 1.75-
(br, 1H), 1.80-2.00 (m, 2H), 2.13 (m, 1H), 2.27-2.44 (m, 2H),
3.00 (s, 3H), 4.12 (bs, 1H), 4.37 (bs, 2H), 4.60-4.80 (br, 1H),
7.25 (br, 1H), 7.55 (bd, J ) 7.9, 1H), 8.51 (bs, 2H). Crude
mesylate 20 was dissolved in acetone (12 mL), LiBr (358 mg,
4.12 mmol) was added, and the mixture was heated under
reflux for about 1 h, with monitoring by TLC. After evapora-
tion, the residue was distributed between CH2Cl2 (10 mL) and
saturated aqueous NaHCO3 (5 mL), the aqueous layer was
extracted with CH2Cl2 (2 × 10), and the combined organic layer
was dried, filtered, and evaporated. The residue was chro-
matographed (CH2Cl2/EtOAc 4/6) to afford bromide 21 (260
mg, 73%) as a colorless oil; elution with EtOAc gave cyclic
carbamate 22 (23 mg, 11% yield) as a white solid with a broad
(60-80 °C) mp. For bromide 21: 1H NMR (298 K, rotamers) δ
1.00-1.60 (br, 9H), 1.65-1.79 (br, 1H), 1.80-1.95 (m, 1H),
1.91-2.20 (m, 2H), 2.28-2.40 (m, 1H), 2.43-2.60 (br, 1H),
3.37-3.60 (m, 2H), 4.10-4.20 (m, 1H), 4.60-5.00 (br, 1H), 7.27
(dd, J ) 7.9, 4.9, 1H), 7.52 (dt, J ) 7.9, 1.8, 1H), 8.51 (bs, 2H);
1H NMR (C6D6, 298 K, rotamers) δ 0.90-1.80 (br, 14H), 2.20-
2.40 (br, 1H), 2.95-3.25 (br, 2H), 3.89 (br, 1H), 4.20-4.80 (br,
1H), 6.74 (dd, J ) 7.8, 4.6, 1H), 7.15 (overlap with solvent,
1
8.55 (br, 1H); H NMR (323 K) δ 1.27 (s, 9H), 1.95-2.05 (m,
2H), 2.20-2.40 (m, 2H), 4.84 (br, 1H), 4.80 (br, 1H), 5.58 (bs,
1H), 7.27 (dd, J ) 7.9, 4.7, 1H), 7.96 (d, J ) 7.9, 1H), 8.50 (d,
J ) 4.7, 1H), 8.58 (s, 1H). To diazoketone 17 (0.95 g, 3 mmol)
in MeOH (12 mL) at -25 °C was added a solution of PhCO2-
Ag (80 mg, 0.33 mmol) in Et3N (880 mg, 8.7 mmol) with the
exclusion of light. The mixture was warmed to 0 °C over 3 h
and was stirred overnight while it warmed to room tempera-
ture. The reaction mixture was evaporated, the residue was
distributed between EtOAc (50 mL) and saturated aqueous
NaHCO3 (25 mL), the aqueous layer was extracted with EtOAc
(2 × 20 mL), and the combined organic layer was dried and
filtered. The filtrate was evaporated and the residue chro-
matographed (CH2Cl2/EtOAc, 4/6) to afford homologous ester
18 (700 mg, 70% from 15) as a colorless oil: 1H NMR (298 K,
rotamers) δ 1.00-1.60 (br, 9H), 1.70-1.95 (m, 2H), 1.90-2.18
(m, 2H), 2.08-2.25 (m, 1H), 2.25-2.41 (m, 1H), 2.48 (dd, J )
14.8, 9.5, 1H), 3.08 (br, 1H), 3.90 (s, 3H), 4.40 (br, 1H), 4.65-
5.00 (br, 1H), 7.27 (br, 1H), 7.56 (bd, J ) 7.8, 1H), 8.50 (br,
1
2H); H NMR (C6D6, 298 K, rotamers) δ 1.14 (br, 9H), 1.10-
1.40 (m, 2H), 1.60-1.80 (m, 2H), 2.26 (dd, J ) 14.8, 9.3, 1H),
3.02 (br, 1H), 3.36 (s, 3H), 4.28 (br, 1H), 4.41 (br, 1H), 6.82
(dd, J ) 4.9, 6.7, 1H), 7.29 (dt, J ) 7.9, 1.8, 1H), 8.45 (d, J )
1
4.7, 1H), 9.11 (br, 1H); H NMR (C6D6, 329 K) δ 1.21 (s, 9H),
1.35.1.50 (m, 2H), 1.60-1.80 (m, 2H), 2.30 (dd, J ) 14.7, 9.2,
1H), 3.03 (dd, J ) 14.7, 4.4, 1H), 3.39 (s, 3H), 4.35 (br, 1H),
4.50 (br, 1H), 6.84 (dd, J ) 7.8, 4.8, 1H), 7.31 (d, J ) 7.8, 1H),
8.43 (d, J ) 4.8, 1H), 8.57 (s, 1H); 13C NMR (C6D6, 298 K,
rotamers) δ 28.2, 30.2 (br), 33.8 (br), 40.1 (br), 51.2, 56.2, 60.8,
79.5, 123.2, 132.6, 140.0 (br), 148.6, 148.7, 154.3, 171.3; 13C
NMR (C6D6, 328 K) δ 28.2 (CH3), 30.2 (CH2), 33.8 (CH2), 40.1
(CH2), 51.0 (CH3), 56.3 (CH), 60.9 (CH), 79.5 (C), 123.0 (CH),
132.7 (CH), 140.0 (C), 148.5 (CH), 148.7 (CH), 154.4 (C), 171.2
(C). Anal. Calcd for C17H24N2O4: C, 63.7; H, 7.5; N, 8.7;
Found: C, 63.6; H, 7.5; N, 8.7.
1
1H), 8.47 (d, J ) 4.6, 1H), 8.59 (br, 1H); H NMR (C6D6, 333
K) δ 1.05-1.20 (m, 1H), 1.24 (s, 9H), 1.15-1.28 (m, 2H), 1.60-
1.80 (m, 2H), 2.38 (p, J ) 6.9, 1H), 3.10-3.29 (m, 2H), 3.91
(m, 1H), 4.50 (dt, J ) 7.4, 1H), 6.79 (dd, J ) 7.7, 4.6, 1H), 7.21
(bd, J ) 7.7, 1H), 8.44 (d, J ) 4.6, 1H), 8.58 (s, 1H); 13C NMR
(C6D6, 298 K) δ 28.3 (CH3), 29.8 (CH2), 30.0 (CH2), 33.8 (CH2),
39.6 (CH2), 58.4 (CH), 60.9 (CH), 79.7 (C), 123.0 (CH), 132.7
(CH), 139.7 (C), 148.6 (CH), 148.7 (CH), 154.9 (C). For cyclic
carbamate 22: 1H NMR δ 1.70-1.86 (m, 2H), 1.93-2.04 (m,
1H), 2.12 (m, 1H), 2.20-2.40 (m, 2H), 3.75 (ddt, J ) 3.0, 5.1,
11.1, 1H), 4.28 (ddd, J ) 3.3, 11.3, 12.8, 1H), 4.51 (ddd, J )
1.4, 5.1, 11.3), 5.05 (d, J ) 8.9, 1H), 7.24 (dd, J ) 4.9, 7.9,
1H), 7.46 (dt, J ) 1.9, 7.9, 1H), 8.48 (bs, 2H); 13C NMR (CDCl3)
δ 28.4 (CH2), 29.9 (CH2), 32.6 (CH2), 57.4 (CH), 59.4 (CH), 67.4
(CH2), 123.2 (CH), 133.1 (CH), 138.1 (C), 147.3 (CH), 148.3
(CH), 155.7 (C). Anal. Calcd for C12H14N2O2: C, 66.0; H, 6.5;
N, 12.8. Found: C, 66.1; H, 6.5; N, 12.7.
(2S,5R)-1-(ter t-Bu tyloxyca r bon yl)-2-(2-h yd r oxyeth yl)-
5-(3-p yr id in yl)p yr r olid in e (19). To a solution of ester 18 (2.0
g, 6.25 mmol) in EtOH (200 mL) at 0 °C was added CaCl2 (1.47
g, 12.5 mmol) followed by NaBH4 (950 mg, 25 mmol). The
mixture was stirred overnight while it warmed to room
temperature, and then aqueous K2CO3 (2M, 50 mL) was added
and the mixture was evaporated. The residue was distributed
between EtOAc (100 mL) and H2O (50 mL), the aqueous layer
was extracted with EtOAc (2 × 40 mL), and the combined
organic layer was dried, filtered, and evaporated. The residue
was chromatographed (CH2Cl2/EtOAc 2/8) to afford alcohol 19
(1.3 g, 71%) as a colorless oil: [R]22 +39.6 (c 1, CHCl3); 1H
(2S,5R)-1-(ter t-Bu tyloxyca r bon yl)-2-vin yl-5-(3-p yr id i-
n yl)p yr r olid in e (23). Methyltriphenylphosphonium bromide
(2.64 g, 7.38 mmol) was suspended in 30 mL of THF, and with
stirrring at 25 °C, a solution of n-BuLi (2.5 M in hexane, 2.95
mL, 7.38 mmol) was added dropwise over 15 min and the
mixture was stirred for 3 h at 25 °C. An aliquot of this
suspension (1.0 mL, 0.22 mmol) was placed in another flask,
to it a solution of aldehyde 26 (0.18 mmol) in THF was added
dropwise at 0 °C, and the resulting mixture stirred overnight.
To the mixture, after being stirred overnight, was added pH
7 phosphate buffer (1 mL) followed by evaporation. The residue
was distributed between EtOAc (10 mL) and H2O (5 mL), the
organic layer was dried, filtered, and evaporated, and the
residue was chromatographed (CH2Cl2/EtOAc 4/6) to afford
D
NMR (298 K, rotamer ratio, 60/40) δ 1.22 (bs, 5.4H), 1.25* (bs,
3.6H), 1.60-2.00 (m, 4H), 2.00-2.20 (m, 1H), 2.25-2.40 (m,
1H), 3.80 (bm, 2H), 4.19 (br, 0.6H), 4.38 (br, 0.6H), 4.49* (br,
0.4H), 4.55-4.67* (br, 0.4H), 4.71 (bt, J ) 7.6, 0.6H), 4.86*
(bt, J ) 7.1, 0.4H), 7.25 (br, 1H), 7.51 (d, J ) 7.9, 0.6H), 7.61*
(d, J ) 7.9, 0.4H), 8.50 (br, 2H); 1H NMR (C6D6, 298 K,
rotamers) δ 1.07 (bs, 9H), 1.20-1.70 (bm, 4H), 3.60-3.85 (br,
2H), 4.21 (br, 2H), 4.66 (br, 1H), 6.75 (dd, J ) 7.9, 4.7, 1H),
1
7.13 (br, 1H), 8.42 (bd, J ) 4.7, 1H), 8.51 (br, 1H); H NMR
(C6D6, 329 K) δ 1.22 (s, 9H), 1.25-1.38 (m, 1H), 1.40-1.72 (m,
4H), 1.75-1.83 (m, 1H), 3.70-3.90 (m, 2H), 3.80-4.20 (br, 1H),
4.28 (bq, J ) 7.0, 1H), 4.45 (dt, J ) 7.4, 1H), 6.89 (bd, J ) 7.9,
4.7, 1H), 7.31 (d, J ) 7.9, 1H), 8.51 (d, J ) 4.7, 1H), 8.63 (s,
1H); 13C NMR (C6D6, 298 K) δ 28.0 (CH3), 30.0 (CH2), 34.8
(CH2), 39.2 (CH2), 55.9 (CH), 59.2 (CH2), 61.3 (CH), 80.1 (C),
123.2 (CH), 132.6 (CH), 140.1 (C), 148.6 (CH), 148.8 (CH),
156.3 (C); 13C NMR (C6D6, 329 K) δ 27.7, 30.4, 34.2, 39.1, 55.9,
vinyl pyrrolidine 23 (46 mg, 91%) as a colorless oil: [R]22
D
1
+52.0 (c 1.3, CHCl3); H NMR (298 K, rotamers) δ 1.00-1.60
(br, 9H), 1.85-1.95 (m, 2H), 2.09 (m, 1H), 2.28 (m, 1H), 4.20-
4.50 (br, 1H), 4.60-4.95 (br, 1H), 5.17 (bd, 1H), 5.26 (bd, 1H),
5.95 (br, 2H), 7.22 (dd, J ) 7.9, 4.9, 1H), 7.56 (dt, J ) 7.9, 1.8,

4076 J . Org. Chem., Vol. 64, No. 11, 1999
Xu et al.
1H), 8.42 (dd, J ) 4.7, 1.4, 1H), 8.54 (d, J ) 1.9, 1H); 1H NMR
(328 K) δ 1.27 (s, 9H), 1.75-1.95 (m, 2H), 2.07 (m, 1H), 2.27
(m, 1H), 4.45 (bs, 1H), 4.81 (bt, J ) 6.8, 1H), 5.14 (d, J ) 10.3,
1H), 5.23 (d, J ) 17.1, 1H), 5.94 (m, 1H), 7.17 (dd, J ) 7.9,
4.9, 1H), 7.53 (dt, J ) 7.9, 1.8, 1H), 8.42 (d, J ) 4.7, 1H), 8.51
(s, 1H); 13C NMR (328 K) δ 28.2, 30.4, 34.0, 60.7, 60.8, 79.8,
115.1, 122.9, 133.3, 139.1, 139.4, 148.0, 148.2, 154.6. Anal.
Calcd for C16H22N2O2: C, 70.0; H, 8.1; N, 10.2. Found: C, 70.0;
H, 8.1; N, 10.1.
aqueous layer was extracted with EtOAc (2 × 10 mL). The
combined organic layer was dried, filtered, and evaporated,
and the residue was chromatographed (CH2Cl2/MeOH satu-
rated with NH3, 97/3) to afford 2 (51 mg, 94%) as a colorless
oil: 1H NMR δ 1.30-2.80 (br, 11H, with s at 2.04, 3H), 3.46
(t, J ) 4.3, 1H), 7.28 (dd, J ) 7.9, 4.8, 1H), 7.78 (dt, J ) 7.9,
1.7, 1H), 8.50 (d, J ) 4.8, 1H), 8.62 (s,1H); 13C NMR (two CH2
obscured by pyramidyl inversion) δ 32.3, 63.2, 70.1, 123.4,
135.2, 137.7, 148.2, 149.0. Anal. Calcd for C11H14N2‚0.5H2O:
C, 73.1; H, 8.7; N, 14.2. Found: C, 73.2; H, 8.7; N, 13.9.
(2S,5R)-1-(ter t-Bu tyloxyca r bon yl)-2-h yd r oxym eth yl-5-
(3-p yr id in yl)p yr r olid in e ((+)-25). To a solution of (+)-15
(400 mg, 1.3 mmol) in EtOH (40 mL) at 0 °C was added CaCl2
(433 mg, 3.9 mmol) followed by NaBH4 (296 mg, 7.8 mmol).
The mixture was stirred overnight as it warmed to room
temperature. Aqueous K2CO3 (2 M, 5 mL) was added, the
mixture was partitioned between EtOAc (50 mL) and satu-
rated aqueous NaHCO3 (20 mL), the aqueous layer was
extracted with EtOAc (2 × 40 mL), and the combined organic
layer was dried, filtered, and evaporated. The residue was
chromatographed (EtOAc) to afford 25 (315 mg, 87%) as a
(2S,5R)-1-(ter t-Bu tyloxyca r bon yl)-2-eth yl-5-(3-p yr id i-
n yl)p yr r olid in e (24). Vinyl pyrrolidine 23 (20 mg, 0.073
mmol) in IPA (1 mL) was treated with H2 at 1 atm in the
presence of 10% Pd/C (2 mg, 10% w/w) at room temperature
overnight. The resulting mixture was filtered and evaporated
to give ethyl pyrrolidine 24 (20 g, 99%) as a colorless oil:
[R]22D +40.5 (c 1, CHCl3); 1H NMR (298 K, rotamers) δ 0.95 (t,
J ) 7.4, 3H), 1.00-1.60 (bm, 10H), 1.69 (br, 1H), 1.81 (m, 1H),
1.98 (m, 2H), 2.29 (m, 1H), 3.86 (br, 1H), 4.69 (br, 1H), 7.20
(dd, J ) 7.9, 4.9, 1H), 7.51 (dt, J ) 7.9, 1.8, 1H), 8.44 (d, J )
4.7, 1H), 8.48 (s, 1H); 1H NMR (328 K) δ 0.96 (t, J ) 7.4, 3H),
1.28 (s, 9H), 1.46 (m, 1H), 1.69 (m, 1H), 1.85 (m, 1H), 1.98 (m,
2H), 2.29 (m, 1H), 3.89 (m, 1H), 4.78 (t, J ) 7.4,1H), 7.19 (dd,
J ) 7.9, 4.9, 1H), 7.52 (dt, J ) 7.9, 1.8, 1H), 8.44 (d, J ) 4.7,
1H), 8.50 (d, J ) 1.8, 1H); 13C NMR (328 K) δ 11.0, 28.3, 28.5,
29.3, 34.1, 60.7, 60.8, 79.6, 123.0, 133.1, 140.1, 148.0, 148.1,
155.0. Anal. Calcd for C16H24N2O2: C, 69.5; H, 8.7; N, 10.1.
Found: C, 69.1; H, 8.7; N, 10.1.
white solid: mp 75-78 °C; [R]22 +17.4 (c 1, CHCl3); 1H NMR
D
δ 1.20 (bs, 9H), 1.69 (br, 1H), 1.87 (m, 1H), 2.07 (m, 1H), 2.34
(m, 1H), 3.80 (m, 2H), 4.18 (br, 1H), 4.55 (br, 1H), 4.83 (bt,
1H), 7.6 (m, 1H), 7.39 (d, J ) 4.8, 1H), 8.52 (m, 2H); 1H NMR
(C6D6, 298 K, rotamers) δ 1.07 (bs, 9H), 1.20-1.70 (bm, 4H),
3.60-3.85 (br, 2H), 4.21 (br, 2H), 4.66 (br, 1H), 6.75 (dd, J )
7.9, 4.7, 1H), 7.13 (br, 1H), 8.42 (bd, J ) 4.7, 1H), 8.51 (br,
1H); 1H NMR (C6D6, 329 K) δ 1.22 (s, 9H), 1.25-1.38 (m, 1H),
1.40-1.72 (m, 4H), 1.75-1.83 (m, 1H), 3.70-3.90 (m, 2H),
3.80-4.20 (br, 1H), 4.28 (bq, J ) 7.0, 1H), 4.45 (dt, J ) 7.4,
1H), 6.89 (bd, J ) 7.9, 4.7, 1H), 7.31 (d, J ) 7.9, 1H), 8.51 (d,
J ) 4.7, 1H), 8.63 (s, 1H); 13C NMR (C6D6, 328 K) δ 27.2, 28.1,
34.1, 61.2, 61.6, 65.9, 80.0, 123.1, 132.9, 140.1, 148.4, 148.7,
156.0. Anal. Calcd for C15H22N2O3: C, 64.7; H, 8.0; N, 10.1.
Found: C, 65.0; H, 8.0; N, 10.4.
7-(ter t-Bu tyloxyca r bon yl)-1-(3-p yr id in yl)-7-a za bicyclo-
[2.2.1]h ep ta n e (2a ). To a solution of bromide 21 (90 mg, 0.25
mmol) in THF (5 mL) at -78 °C was added n-BuLi (1.6 M in
hexane, 0.55 mL) dropwise. The mixture was stirred at -78
°C for 30 min, and then pH 7 buffer (10 mL) was added. The
mixture was allowed to warm to room temperature and
extracted with EtOAc (2 × 20 mL), and the combined organic
layer was dried, filtered, and evaporated. The residue was
chromatographed (hexanes/EtOAc, 1/1) to afford 2a (45 mg,
(2R,5S)-1-(ter t-Bu tyloxyca r bon yl)-2-h yd r oxym eth yl-5-
(3-p yr id in yl)p yr r olid in e ((-)-25, structure not shown) was
1
64%) as a white solid: mp 83-85 °C; H NMR δ 1.13 (s, 9H),
prepared from (-)-15 in the same way: [R]22 -17.0 (c 1,
D
1.58 (tm, J ) 11.5, 2H), 1.85-2.10 (m, 6H), 4.49 (t, J ) 4.4,
1H), 7.26 (overlap with solvent, 1H), 7.71 (d, J ) 8.0, 1H), 8.48
(br, 1H), 8.64 (br, 1H); 13C NMR (CDCl3) δ 27.7 (CH3), 29.3
(CH2), 37.4 (CH2), 59.8 (CH), 68.4 (C), 79.7 (C), 122.8 (CH),
134.5 (CH), 138.3 (C), 147.3 (CH), 148.0 (CH), 156.8 (C). Anal.
Calcd for C16H22N2O2: C, 70.0; H, 8.1; N, 10.2. Found: C, 69.8;
H, 8.2; N, 9.9.
CHCl3); spectral and chromatographic properties identical with
those of (+)-25.
(2S,5R)-1-(ter t-Bu tyloxyca r bon yl)-2-for m yl-5-(3-p yr id i-
n yl)p yr r olid in e (26) a n d (2S,5R)-1-(ter t-Bu tyloxyca r bo-
n yl)-2-(2-m eth oxyca r bon ylvin yl)-5-(3-p yr id in yl)p yr r oli-
d in e (27). To a solution of oxalyl chloride (0.75 g, 5.9 mmol)
in CH2Cl2 (10 mL) at -78 °C was added DMSO (0.84 mL, 11.8
mmol), the mixture was stirred for 15 min, a solution of 25
(0.82 g, 2.95 mmol) in CH2Cl2 (10 mL) was added over 10 min,
the mixture was stirred for 1 h, and triethylamine (2.5 mL,
17.7 mmol) was added dropwise over 5 min. The mixture was
stirred for an additional 1 h and poured into H2O (30 mL).
The organic layer was washed with H2O (20 mL) and brine
(20 mL), dried, filtered, and evaporated to afford crude
aldehyde 26: 1H NMR (298 K, rotamers) δ 1.00-1.50 (br, 9H),
1.70-2.45 (bm, 4H), 4.26 (br, 0.5H), 4.46 (br, 0.5H), 4.78 (br,
0.5H), 5.02 (br, 0.5H), 7.26 (br, 1H),7.60-7.80 (br, 1H),8.40-
8.70 (br, 2H). To a suspension of NaH (85 mg, 3.54 mmol) in
THF (40 mL) at 0 °C was added a solution of trimethyl
phosphonoacetate (0.57 mL, 3.54 mmol) dropwise, the resulting
mixture was stirred at 0 °C for 30 min, and the crude 26 in
THF (40 mL) was added via cannula. The resulting solution
was stirred for another 30 min, pH 7 phosphate buffer (5 mL)
was added, the mixture was concentrated to about 20 mL, and
the residue was partitioned between EtOAc (25 mL) and H2O
(25 mL). The aqueous phase was extracted with EtOAc (2 ×
25 mL), and the combined organic phase was dried and
evaporated, leaving a residue that was chromatographed
(EtOAc/hexanes, 6/4) to give the unsaturated ester 27 (0.73 g,
73% from 25) as a mixture of cis and trans isomers: 1H NMR
(298 K) δ 1.10-1.51 (br, 9H major, 9H minor), 1.68 (br, 1H
minor), 1.86 (m, 2H major, 1H minor), 2.13 (m, 1H major), 2.30
(m, 1H major, 2H minor), 3.67 (s, 3H minor), 3.71 (s, 3H major),
4.30-4.70 (br, 1H major), 4.70-5.10 (br, 1H major, 1H minor),
5.43 (bq, J ) 7.2, 1H minor), 5.80 (bd, J ) 11.1, 1H minor),
6.00 (br, 1H major), 6.23-6.57 (br, 1H minor), 6.95 (br, 1H
1-(3-P yr id in yl)-7-a za bicyclo[2.2.1]h ep ta n e (2b). To 2a
(39 mg, 0.14 mmol) was added a solution of HCl in EtOAc (3
M, 2 mL), the resulting solution was stirred at room temper-
ature for 1 h and then evaporated. The residue was distributed
between saturated aqueous Na2CO3 (10 mL) and EtOAc (2 ×
10 mL), the combined organic layer was dried and filtered,
and the filtrate was evaporated to afford 2b (24 mg, 95%) as
a colorless oil: 1H NMR δ 1.70-2.10 (m, 8H), 3.15 (br, 1H),
3.82 (t, J ) 4.7, 1H), 7.26 (dd, J ) 7.9, 4.8, 1H), 7.79 (dt, J )
7.9, 1.7, 1H), 8.50 (dd, J ) 4.8, 1.6, 1H), 8.71 (d, J ) 1.6, 1H);
13C NMR (CDCl3) δ 31.8 (CH2), 37.3 (CH2), 57.0 (CH), 67.5
(C),123.0 (CH), 133.4 (CH), 139.3 (C), 147.5 (CH), 147.9 (CH).
The hydrogen fumarate of 2b was formed by mixing 2b (20
mg, 0.115 mmol) in CH2Cl2 (2 mL) with fumaric acid (15 mg,
0.129 mmol) in MeOH (2.47 mL) and evaporating the solution
to an amorphous white solid (35 mg, 99%): 1H NMR (CD3OD)
δ 1.99 (tm, J ) 11.5, 2H), 2.05-2.30 (m, 4H), 2.38 (tm, J )
11.5, 2H), 4.38 (t, J ) 4.7, 1H), 6.67 (s, 2H), 7.54 (dd, J ) 8.0,
4.7, 1H), 7.98 (d, J ) 8.0, 1H), 8.59 (br, 1H), 8.68 (bs, 1H); 13
C
NMR (CD3OD) δ 29.3 (CH2), 35.3 (CH2), 60.8 (CH), 73.0 (C),-
125.5 (CH), 134.8 (C), 135.8 (CH), 136.1 (CH), 147.4 (CH),-
150.4 (CH), 171.0 (C). Anal. Calcd. for C11H14N2‚1.1C4H4O4:
C, 61.3; H, 6.1; N, 9.3. Found: C, 61.1; H, 6.4; N, 9.2.
7-Meth yl-1-(3-pyr idin yl)-7-azabicyclo[2.2.1]h eptan e (2).
A mixture of 2b (50 mg) in H2O (0.5 mL), formic acid (0.25
mL), and formaldehyde (0.25 mL) was heated at reflux for 14
h. The solution was evaporated, the residue was partitioned
between EtOAc (10 mL) and 2 M K2CO3 (10 mL), and the

Conformationally Constrained Nicotines
J . Org. Chem., Vol. 64, No. 11, 1999 4077
major), 7.22 (m, 1H major, 1H minor), 7.53 (m, 1H major, 1H
minor), 8.45 (m, 1H major, 1H minor), 8.49 (s, 1H major), 8.51
(s, 1H minor); H NMR (328 K) δ 1.27 (s, 9H major), 1.28 (s,
overnight and then evaporated, and the residue was parti-
tioned between EtOAc (2 × 20 mL) and H2O (20 mL). The
organic layer was dried, filtered, and evaporated to afford
crude mesylate 30 containing a small amount of mesylimida-
zolide: 1H NMR (298 K, rotamers) δ 1.00-2.40 (m, 17H), 2.98
(s, 3H), 3.95 (bs, 1H), 4.28 (bs, 2H), 4.75 (br, 1H), 7.20 (br,
1H), 7.49 (bd, J ) 7.9, 1H), 8.48 (bs, 2H). Crude 30 was
dissolved in acetone (12 mL), LiBr (358 mg, 4.12 mmol) was
added, and the mixture was refluxed for 1 h. Evaporation left
a residue that was partitioned between EtOAc (10 mL) and
H2O (5 mL). The aqueous layer was extracted with EtOAc (2
× 10 mL), and the combined organic layer was dried, filtered,
and evaporated. The residue was chromatographed (CH2Cl2/
EtOAc, 4/6) to afford bromide 31 (270 mg, 73%) as a colorless
oil: 1H NMR (298 K, rotamers) δ 1.00-1.50 (br, 9H), 1.55-
1.78 (br, 2H), 1.85-2.10 (m, 5H), 2.20-2.28 (m, 1H), 3.44 (m,
2H), 4.02 (br, 1H), 4.60-5.00 (br, 1H), 7.27 (dd, J ) 7.9, 4.7,
1H), 7.57 (d, J ) 7.9, 1H), 8.47 (d, J ) 4.7, 1H), 8.57 (s, 1H);
1H NMR (323 K) δ 1.28 (bs, 9H), 1.55-1.78 (m, 2H), 1.85-
2.10 (m, 5H), 2.20-2.28 (m, 1H), 3.44 (m, 2H), 4.02 (br, 1H),
4.79 (bt, 1H), 7.23 (dd, J ) 7.9, 4.7, 1H), 7.54 (d, J ) 7.9, 1H),
8.47 (d, J ) 4.7, 1H), 8.54 (s, 1H); 13C NMR (328 K) δ 28.2,
30.1, 30.3, 33.3, 34.0, 34.5, 58.4, 61.8, 79.9, 123.1, 133.2, 139.6,
147.8, 147.9, 154.8. Bromide 31 is unstable and was used
immediately after a short period of drying under vacuum.
1
9H minor), 1.68 (m, 1H minor), 1.90 (m, 2H major, 1H minor),
2.15 (m, 1H major), 2.31 (m, 1H major, 2H minor), 3.69 (s, 3H
minor), 3.72 (s, 3H major), 4.55 (br, 1H major), 4.85 (br, 1H
major), 4.96 (br, 1H minor), 5.44 (bq, J ) 7.2, 1H minor), 5.80
(dd, J ) 11.5, 1.2, 1H minor), 6.00 (d, J ) 15.7, 1H major),
6.37 (bt, J ) 9.6, 1H minor), 6.96 (dd, J ) 15.7, 6.5, 1H major),
7.21 (m, 1H major, 1H minor), 7.53 (m, 1H major, 1H minor),
8.44 (d, J ) 4.7, 1H major, 1H minor), 8.51 (s, 1H major), 8.53
(s, 1H minor); 13C NMR (328 K) δ 28.1 × 2, 30.4, 30.5, 33.6,
33.9, 51.0, 51.4, 57.4, 59.5, 60.4, 60.8, 80.2, 80.4, 118.5, 121.5,
123.1, 123.2, 133.2, 138.8, 139.1, 147.8, 148.1 × 2, 148.2 × 2,
152.2, 154.6, 154.8, 166.1, 166.5. Anal. Calcd for C18H24N2O4:
C, 65.0; H, 7.3; N, 8.4. Found: C, 64.7; H, 7.5; N, 8.2.
(2S,5R)-1-(ter t-Bu tyloxyca r bon yl)-2-(2-â-m eth oxyca r -
bon yleth yl)-5-(3-p yr id in yl)p yr r olid in e (28). Unsaturated
ester 27 (1.0 g, 3.0 mmol) in MeOH (10 mL) was treated with
H2 at 1 atm in the presence of 10% Pd/C (100 mg, 10% w/w)
at room temperature for 4 h. The resulting mixture was filtered
through Celite and evaporated to give 28 (1.0 g, 99%) as a
colorless oil: 1H NMR (298 K, rotamers) δ 1.00-1.50 (br, 9H),
1.65 (m, 1H), 1.70-1.92 (m, 2H), 2.00 (m, 1H), 2.13-2.37 (m,
2H), 2.41 (br, 1H), 3.64 (s, 3H), 3.97 (br, 1H), 4.60-5.20 (br,
1H), 7.21 (dd, J ) 7.8, 4.7, 1H), 7.51 (d, J ) 7.8, 1H), 8.43 (d,
J ) 4.8, 1H), 8.45 (s, 1H); 1H NMR (328 K) δ 1.26 (s, 9H), 1.68
(m, 1H), 1.80 (m, 1H), 1.88 (m, 1H), 2.07 (m, 1H), 2.15-2.35
(m, 2H), 2.41 (t, J ) 7.8, 2H), 3.65 (s, 3H), 4.00 (m, 1H), 4.77
(t, J ) 7.6, 1H), 7.19 (dd, J ) 7.8, 4.8, 1H), 7.52 (dt, J ) 7.8,
1.8, 1H), 8.43 (d, J ) 4.8, 1H), 8.48 (d, J ) 1.8, 1H); 13C NMR
(328 K) δ 28.2, 29.8, 31.0, 31.5, 33.9, 51.3, 58.6, 60.8, 79.9,
123.1, 133.1, 139.6, 147.9, 148.0, 154.9, 173.4.
8-ter t-Bu tyloxyca r bon yl-1-(3-p yr id in yl)-8-a za bicyclo-
[3.2.1]octa n e ((-)-3a ). To a solution of n-BuLi (0.21 mmol,
1.6 M in hexane, 0.13 mL) in THF (15 mL) at -78 °C was
added bromide 31 (27 mg, 0.083 mmol) in THF (2 mL) slowly
(syringe pump) over 1 h. The mixture was stirred at -78 °C
for 30 min, and then pH 7 phosphate buffer (20 mL) was added
and the reaction mixture was allowed to warm to room
temperature. The mixture was extracted with EtOAc (2 × 20
mL), and the combined organic layer was dried, filtered, and
evaporated. The residue was chromatographed (hexanes/
(2S,5R)-1-(ter t-Bu tyloxycar bon yl)-2-(3-h ydr oxypr opyl)-
5-(3-p yr id in yl)p yr r olid in e ((+)-29). To a solution of ester
28 (1 g, 3 mmol) in EtOH (30 mL) at 0 °C was added CaCl2 (1
g, 9 mmol) followed by NaBH4 (0.68 g, 18 mmol). The mixture
was stirred overnight as it warmed to room temperature,
aqueous K2CO3 (2 M, 20 mL) was added, and the mixture was
evaporated. The residue was partitioned between EtOAc (100
mL) and H2O (50 mL), the aqueous layer was extracted with
EtOAc (2 × 100 mL), and the combined organic layer was
dried, filtered, and evaporated. The residue was chromato-
graphed (EtOAc) to afford alcohol 29 (0.65 g, 71%) as a
EtOAc, 1/1) to afford 3a (10 mg, 48%) as a white solid: mp
1
104-106 °C; [R]22 -46.1 (c 1, CHCl3); H NMR δ 1.50-2.40
D
(m, 10H), 3.49 (s, 3H), 4,47 (bs, 1H), 7.22 (dd, J ) 7.8, 4.8,
1H), 7.63 (d, J ) 7.8, 1H), 8.43 (bs, 1H), 8.60 (s, 1H); 13C NMR
δ 17.6, 26.7, 27.9, 29.0, 30.9, 41.9, 57.8, 63.7, 79.4, 122.7, 132.9,
141.9, 147.0, 154.4. Anal. Calcd for C17H24N2O2: C, 70.8; H,
8.4; N, 9.7. Found: C, 70.4; H, 8.8; N, 9.7.
8-(ter t-Bu t oxyca r bon yl)-1-(3-p yr id in yl)-8-a za b icyclo-
[3.2.1]octa n e ((+)-3a ) was prepared from the enantiomeric
substrate in the same manner: [R]22 +45.8 (c 0.93, CHCl3);
D
spectral and chromatographic properties identical with those
colorless oil: [R]22 +16.5 (c 1, CHCl3); 1H NMR (298 K) δ
D
of (-)-3a .
1.18-1.45 (br s, 9H), 1.45-1.76 (m, 4H), 1.87 (m, 1H), 2.00
(m, 2H), 2.26 (m, 1H), 2.40-3.50 (br, 1H), 3.67 (bs, 2H), 3.98
(br, 1H), 4.69 (br, 1H), 7.19 (dd, J ) 7.8, 4.8, 1H), 7.51 (dt, J
) 7.8, 1.8, 1H), 8.41 (d, J ) 4.8, 1H), 8.45 (d, J ) 1.8, 1H); 1H
NMR (328 K) δ 1.23 (s, 9H), 1.48-1.72 (m, 4H), 1.87 (m, 1H),
2.01 (m, 2H), 2.28 (m, 1H), 2.66 (br, 1H), 3.69 (bs, 2H), 4.02
(br, 1H), 4.74 (dt, J ) 7.2, 1H), 7.18 (dd, J ) 7.9, 4.7, 1H),
7.51 (d, J ) 7.9, 1.8, 1H), 8.42 (dd, J ) 4.7, 1.8, 1H), 8.47 (d,
J ) 1.8, 1H); 13C NMR (328 K) δ 28.2, 29.7, 29.8, 32.1, 34.1,
58.9, 60.7, 62.4, 79.7, 123.1, 133.1, 140.0, 147.9, 154.9. Anal.
Calcd for C17H26N2O3: C, 66.6; H, 8.6; N, 9.1. Found: C, 66.4;
H, 8.8; N, 9.0.
1-(3-P yr id in yl)-8-a za bicyclo[3.2.1]octa n e ((-)-3b). To
3a (39 mg, 0.14 mmol) was added HCl in EtOAc (3 M, 2 mL),
and the resulting mixture was stirred at room temperature
for 30 min. After evaporation, the residue was partitioned
between saturated aqueous Na2CO3 (10 mL) and EtOAc (2 ×
10 mL). The combined organic layer was dried, filtered, and
evaporated to afford (-)-3b (23 mg, 93%) as a colorless oil:
[R]22 -7.0 (c 1.1, CHCl3); 1H NMR δ 1.50-2.10 (m, 10H),
D
2.20-2.32 (m, 1H), 3.72 (m, 1H), 7.24 (dd, J ) 7.9, 4.8, 1H),
7.73 (dt, J ) 7.9, 1.7, 1H), 8.46 (dd, J ) 4.8, 1.6, 1H), 8.65 (d,
J ) 1.6, 1H); 13C NMR δ 18.7, 30.1, 31.6, 35.8, 41.1, 55.5, 64.1,
123.1, 132.8, 143.7, 146.3, 147.6. Anal. Calcd for C12H16N2‚1/
4H2O: C, 74.8; H, 8.6; N, 14.5. Found: C, 75.1; H, 8.8; N, 14.7.
(2R,5S)-1-(ter t-Bu tyloxycar bon yl)-2-(3-h ydr oxypr opyl)-
5-(3-p yr id in yl)p yr r olid in e ((-)-29, structure not shown)
1-(3-P yr id in yl)-8-a za bicyclo[3.2.1]octa n e ((+)-3b) was
prepared from the enantiomeric substrate in the same man-
ner: [R]22D +6.8 (c 0.96, CHCl3); spectral and chromatographic
properties identical with those of (-)-3b.
was prepared in the same manner from ester (-)-28: [R]22
D
-17.0 (c 1.2, CHCl3); spectral and chromatographic properties
identical with (+)-29.
(2S,5R)-1-(ter t-Bu tyloxyca r bon yl)-2-(3-m eth ylsu lfon yl-
oxyp r op yl)-5-(3-p yr id in yl)p yr r olid in e (30) a n d (2S,5R)-
1-(ter t-Bu tyloxyca r bon yl)-2-(3-br om op r op yl)-5-(3-p yr id i-
n yl)p yr r olid in e (31). To a solution of 1-methansulfonyl-
imidazolide (180 mg, 1.2 mmol) in THF (12 mL) at 0 °C was
added methyl triflate (127 µL, 1.2 mmol) dropwise, and the
mixture was stirred at 0 °C for 30 min followed by the dropwise
addition at 0 °C of a mixture of 29 (315 mg, 1.03 mmol) and
1-methylimidazole (84 µL, 1.03 mmol) in THF (3 mL). After
the addition, the ice bath was removed, the mixture was stirred
7-Me t h yl-1-(3-p yr id in yl)-8-a za b icyclo[3.2.1]oct a n e
((-)-3). A mixture of (-)-3b (50 mg) in H2O (0.5 mL), formic
acid (0.25 mL), and formaldehyde (0.25 mL) was heated at
reflux for 14 h and then evaporated, and the residue was
partitioned between EtOAc (5 mL) and 2 M K2CO3 (5 mL).
The aqueous layer was extracted with EtOAc (2 × 5 mL), and
the combined organic layer was dried and evaporated. The
residue was chromatographed (CH2Cl2/MeOH saturated with
NH3, 97/3) to afford (-)-3 (48 mg, 90%) as a colorless oil: [R]22
D
-10.9

4078 J . Org. Chem., Vol. 64, No. 11, 1999
Xu et al.
(c 1, CHCl3); 1H NMR δ 1.20-1.35 (m, 1H), 1.55-2.20 (m, 13H,
with singlet at 2.10), 3.39 (m, 1H), 7.24 (dd, J ) 7.9, 4.8, 1H),
7.75 (dt, J ) 7.9, 1.7, 1H), 8.45 (dd, J ) 4.8, 1.6, 1H), 8.65 (d,
J ) 1.6, 1H); 13C NMR (328 K) δ 18.3, 26.4, 27.3, 33.0, 34.2,
35.4, 61.9, 66.0, 123.0, 134.5, 141.8, 147.7, 148.7. Anal. Calcd.
for C13H18N2‚1/4H2O: C, 75.5; H, 9.0; N, 13.6. Found: C, 75.6;
H, 9.0; N, 13.8.
manner: [R]22 +11.2 (c 1.3, CHCl3); spectral and chromato-
D
graphic properties identical with those of (-)-3.
Ack n ow led gm en t. J . Choi thanks the Korea Sci-
ence and Engineering Foundation for partial fellowship
support. M.I.C. is grateful to the Xunta de Galicia for
an internship.
7-Meth yl-1-(3-pyr idin yl)-8-a za bicyclo[3.2.1]octa n e ((+)-
3) was prepared from the enantiomeric substrate in the same
J O990130U