Enantiospecific synthesis of annulated nicotine analogues from D- and L- glutamic acid. Pyridotropanes

Article abstract of DOI:10.1021/jo991609p

The conformationally restricted nicotinoid 1-methyl-8- azabicyclo[3.2.1]octano[2,3-c]pyridine, pyrido[3,4-b]tropane, has been prepared enantiospecifically from both D- and L-glutamic acid. The method involved coupling of pyroglutamic acid derivatives with ortho-lithiated 4- chloropyridine, followed by intramolecular imine formation and reduction to generate the D- and L-5-substituted proline esters. Chloro-iodo exchange and side chain extension gave the precursor for the [3.2.1] system. Construction of the 8-azabicyclo[3.2.1]octano-[2,3-c]pyridine framework was achieved by an intramolecular Heck reaction. Subsequent ozonolysis gave the ketone which was reduced to the carbinol or methylene, yielding the fused nicotine analogues.

Full text of DOI:10.1021/jo991609p

J . Org. Chem. 2000, 65, 861-870
861
En a n tiosp ecific Syn th esis of An n u la ted Nicotin e An a logu es fr om
D- a n d L-Glu ta m ic Acid . P yr id otr op a n es
Sean C. Turner, Hongbin Zhai, and Henry Rapoport*
Department of Chemistry, University of California, Berkeley, California 94720
Received October 14, 1999
The conformationally restricted nicotinoid 1-methyl-8-azabicyclo[3.2.1]octano[2,3-c]pyridine, pyrido-
[3,4-b]tropane, has been prepared enantiospecifically from both D- and L-glutamic acid. The method
involved coupling of pyroglutamic acid derivatives with ortho-lithiated 4-chloropyridine, followed
by intramolecular imine formation and reduction to generate the D- and L-5-substituted proline
esters. Chloro-iodo exchange and side chain extension gave the precursor for the [3.2.1] system.
Construction of the 8-azabicyclo[3.2.1]octano-[2,3-c]pyridine framework was achieved by an
intramolecular Heck reaction. Subsequent ozonolysis gave the ketone which was reduced to the
carbinol or methylene, yielding the fused nicotine analogues.
In tr od u ction
The alkaloid (-)-nicotine (1, Figure 1), present in
tobacco at varying levels of 0.2-5%, activates nicotinic
acetylcholine receptors (nAChR)1 that are located at
neuromuscular junctions and at cholinergic synapses of
the central nervous system. Much of the interest in the
medicinal chemistry of nAChRs stems from evidence
F igu r e 1.
following nicotine administration to humans, of the
beneficial effects that have been observed with cognitive
and attention deficits,2 neuroprotection,3 and Alzheimers
disease.4 Thus there is considerable current interest in
the pharmacological effects of nicotinic analogues.5
We have recently reported6 the synthesis of conforma-
tionally restricted analogues such as 2 which possess a
pendant pyridine moiety. Fusing the pyridine ring as part
of a tricyclic skeleton would further enhance the confor-
mational restriction, and several related racemic ex-
amples have been reported.7
an intramolecular cyclization via SN2 displacement of
halide by an enolate, D to E. In the second route, an
intramolecular Heck cyclization would be conducted
between an alkene and a 4-halopyridyl group, B to C. A
particular challenge anticipated throughout was the
difficulty of retaining the labile 4-halopyridyl group
during the synthetic sequence.
Resu lts a n d Discu ssion
Our objective was to develop a synthetic route to the
enantiomerically pure pyrido[3,4-b]tropane nicotine ana-
logue 3 (Figure 1). Two routes were considered for the
key cyclization step to construct the [3.2.1] bicyclic
skeleton shown in Figure 2. The first route would employ
Earlier work had demonstrated that a pyridyl moiety
could be introduced at the γ-position of glutamic acid by
addition of 3-pyridyllithium to tert-butyl-N-tert-butyloxy-
carbonylpyroglutamic acid 4a ,6 specifically at the γ-car-
bonyl group. The lactam 4a itself is readily prepared from
D- or L-glutamic acid. To introduce the subsequently
required activation at the 4-position of pyridine, a 4-halo
group was selected. Although this functionality has not
found widespread synthetic use, nucleophilic enolate
displacement of the chloro group from 4-chloropyridine
has been reported.8 Also, it has been demonstrated that
ortho-lithiation of 4-halopyridines using LDA occurs with
high regioselectivity,9 leading to the selection of 4-chlo-
ropyridine for these dual functions. Higher metalation
yields are observed when Et2O rather than THF is
employed as the solvent.10 The addition, therefore, was
conducted using 3-lithio-4-chloropyridine generated re-
gioselectively by ortho-lithiation of 4-chloropyridine using
LDA in Et2O at -78 °C (Scheme 1).
(1) McDonald, I. A.; Cosford, N.; Vernier, J .-M. Annu. Rep. Med.
Chem. 1995, 30, 41.
(2) (a) Brioni, J . D.; Decker, M. W.; Sullivan, J . P.; Arneric, S. P.
Adv. Pharmacol. 1997, 37, 1153. (b) Perry, E. K.; Morris, C. M.; Court,
J . A.; Cheng, A.; Fairbairn, A. F.; McKeith, I. G.; Irving, D.; Brown,
A.; Perry, R. H. Neuroscience 1995, 64, 385.
(3) Akaike, A.; Tamura, Y.; Yokota, T.; Shimohama, S.; Kimura, J .
Brain Res. 1994, 644, 181.
(4) Decker, M. W.; Brioni, J . D. Neuronal Nicotinic Receptors:
Potential Treatment of Alz-heimer’s Disease with Novel Cholinergic
Channel Modulators. In Pharmacological Treatment of Alzheimer’s
Disease: Molecular and Neurobiological Foundations; Brioni, J . D.,
Decker, M. W., Eds.; Wiley-Liss: New York, 1997; p 433.
(5) Holladay, M. W.; Cosford, N. D. P.; McDonald, I. A. Natural
Products as a Source of Nicotinic Acetylcholine Receptor Modulators
and Leads for Drug Discovery. In Neuronal Nicotinic Receptors:
Pharmacology and Therapeutic Opportunities; Arneric, S. P., Brioni,
J . D., Eds.; Wiley-Liss: New York, 1999; Chapter 14.
(6) Xu, Y.-z.; Choi, J .; Calaza, M. I., Turner, S.; Rapoport, H. J . Org.
Chem. 1999, 64, 4069.
(7) (a) Catka, T. E.; Leete, E. J . Org. Chem. 1978, 43, 2125. (b)
Chavdarian, C. G.; Seeman, J . I.; Wooten, J . B. J . Org. Chem. 1983,
48, 492. (c) Kanne, D. B.; Abood, L. G. J . Med. Chem. 1988, 31, 506.
(d) Glassco, W.; Suchocki, J .; George, C.; Martin, B. R.; May, E. L. J .
Med. Chem. 1993, 36, 3381.
(8) Smith, F. X.; Evans, G. G. J . Heterocycl. Chem. 1976, 13, 1025.
(9) (a) Gribble, G. W.; Saulnier, M. G. Heterocycles 1993, 35, 151.
(b) Marsais, F.; Que´guiner, G. Tetrahedron 1983, 39, 2009.
(10) Marsais, F.; Tre´court, F.; Bre´ant, P.; Que´guiner, G. J . Hetero-
cycl. Chem. 1988, 25, 81.
10.1021/jo991609p CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/14/2000

862 J . Org. Chem., Vol. 65, No. 3, 2000
Turner et al.
F igu r e 2. Proposed syntheses of the pyrido[3,4-b]tropane nicotine analogues.
Sch em e 1. Syn th esis of 4-Ch lor op yr id in yl Keton es
Sch em e 2. Syn th esis of 5-Su bstitu ted P r olin e Der iva tives
A range of different reaction temperatures and stoi-
chiometries was examined. It was observed that when
the reaction was allowed to reach rt overnight, the initial
orange color changed to black and an intractable tar was
obtained (possibly due to polymerization of the 4-chloro-
pyridyl moiety). Favorable conditions were found giving
a 74% yield of the pyridyl ketone 5a using 150 mol % of
ortho-lithiated 4-chloropyridine at -78 °C for 14 h.
An attempt to selectively remove the N-BOC protecting
group, using 1 M HCl in EtOAc, failed due to partial
removal of the tert-butyl ester.11 Therefore, the simulta-
neous removal of both the tert-butyl ester and N-Boc
protecting groups was affected with MeOH saturated
with HCl. Subsequent treatment with aqueous NaHCO3
caused intramolecular cyclization to the imine.12 How-
ever, the product was found to be a mixture (45/55) of
imines 7 and 8, respectively (Scheme 2). The facility of
formation of 4-methoxypyridyl imine 8 probably results
from nucleophilic displacement of Cl by MeOH under the
acid hydrolysis conditions, since protonation of the py-
ridyl nitrogen activates the 4-position toward nucleophilic
attack.
To confirm the structure of 8, which was highly polar
(12) Berre´e, F.; Chang, K.; Cobas, A.; Rapoport, H. J . Org. Chem.
1996, 61, 715.
(11) Gibson, F. S.; Bergmeier, S. C. J . Org. Chem. 1994, 59, 3216.

Synthesis of Annulated Nicotine Analogues
J . Org. Chem., Vol. 65, No. 3, 2000 863
and difficult to purify, the imine was reduced using
catalytic hydrogenation (H2, 10% Pd/C) and the resulting
amine protected as its N-BOC derivative to give the
crystalline cis-pyrrolidine derivative 9, in which the
4-chloro had been replaced by methoxy. An attempt to
reduce the proportion of unwanted 4-alkoxy ether by
employing EtOH as the solvent failed to significantly
change the ratio of products. Complete removal of both
protecting groups in 5a with 4 M aqueous HCl was
successful; however, conditions for isolating the free
imino acid (resulting from subsequent base-catalyzed ring
closure) were not found.
The problem of the lack of orthogonality with respect
to the N-BOC and tert-butyl ester was avoided by
replacing the tert-butyl with a methyl ester in the initial
organometallic addition. The methyl ester is readily
prepared from pyroglutamic acid in 93% yield by reaction
with thionyl chloride in MeOH, and subsequent conver-
sion to the N-BOC derivative gives the protected pyro-
glutamate 4b (Scheme 1). Using ortho-lithiated 4-chlo-
ropyridine (110 mol %), the ketone 5b was obtained as
the sole product in 80% yield. This product is unstable
(polymerizing overnight at room temperature) and was
used with minimal delay in the next step.
The ketone 5b was treated with TFA in CH2Cl2 to
remove the N-BOC group. After basic workup (NaHCO3)
the product, isolated in 95% yield, was found to be a
mixture of 55% 4-chloro and 45% 4-trifluoroacetoxy
products. However, when 1 M HCl in EtOAc12 was used,
N-BOC deprotection occurred in essentially quantitative
yield to give the amine hydrochloride 6. Isolation after
treatment with NaHCO3 gave the imine 7 in an overall
yield of 95% (Scheme 2).
Our initial intention was to employ catalytic hydroge-
nation to reduce the imine functionality to give specifi-
cally the desired cis-proline. However, there was a
question of selectivity between reduction of the imine and
hydrogenolysis of the 4-chloropyridyl group. All attempts
using Pd/C, Pd(OH)2/C or Pd/BaSO4 either gave no
reaction or resulted in concomitant reduction of imine
and dechlorination. Hydrogenation over PtO2 resulted in
a mixture of the desired cis-amine 10 together with
dechlorinated amine.
to separate by chromatography; however, treatment of
the mixture with ClCO2Et and Et3N gave the cis- and
trans-carbamates which were separable by column chro-
matography. Alternatively, reaction of the amines with
acetic anhydride and Et3N gave the crystalline cis- and
trans-N-acetyl derivatives 12 and 13 which were sepa-
rable by either chromatography or recrystallization.
Fortuitously, a more convenient separation resulted from
treatment of the mixture with (BOC)2O and Et3N which
gave exclusively N-protection of the major diastereomer
14. Facile separation by column chromatography then
afforded a 60% yield of 14 and 32% recovery of the
unreacted minor diastereomer trans-amine 11. The re-
covered trans-amine can also be readily converted to its
N-BOC derivative using (BOC)2O when the solvent is
changed from THF to CH3CN. A similar solvent-con-
trolled cis-trans selectivity has been reported for 2,5-
dialkylpyrrolidines.16
Following from our earlier work6 we used the Arndt-
Eistert method for 1-carbon homologation of the gluta-
mate-derived R-carboxyl group. Accordingly the ester 14
was hydrolyzed to acid 15 by treatment with LiOH
(Scheme 3). Acid 15 was reacted with ethyl chloroformate
and Et3N to form the mixed anhydride which was treated
in situ with CH2N2 to give an essentially quantitative
yield of the diazoketone. Although the anticipated Wolff
rearrangement17 to the homologated ester did take place
upon treatment with Ag2O or PhCO2Ag, there was
simultaneous removal of the chloro group. Irradiation
(UV) of the diazoketone in MeOH for 36 h gave the
homologated ester 16; however, attempted intramolecu-
lar cyclization to tricycle 17 was unsuccessful. Only
starting material and polymerization products were
observed upon treatment with LDA or KHMDS in THF,
which may be due to competition between the two
possible sites of anion formation, R to the ester and R to
the pyridine.6
We then turned to the second proposed approach. In
this route, the N-bridged bicyclic targets were to be
constructed by a Heck coupling reaction that typically
takes place between an alkene and an aryl bromide or
iodide. Considering the poor reactivity of the chloro
substituent, it would be necessary to introduce either a
4-bromo- or 4-iodopyridyl functionality, more amenable
to Pd-insertion in order to employ this methodology.
Given the reported instability of ortho-lithiated 4-bromo-
or 4-iodopyridine,18 and their enhanced reactivity through-
out the synthetic sequence, these substituents would
need to be introduced at a late stage by exchange of the
4-chloro group. In addition to finding suitable conditions,
an important question would be at which point in the
synthesis to carry out the exchange reaction.
Using the key intermediate pyrrolidine 14, a variety
of methods were examined for exchange of iodo for the
chloro substituent.19 Quaternization in situ of the pyri-
dine nitrogen with TMSI, ClCO2Et, AcCl, and Ac2O were
compared using NaI or Bu4NI as sources of iodide.
Optimum conditions were found to be treatment with NaI
and AcCl in CH3CN (55 °C). Also, the 4-iodo group can
be introduced earlier in the synthesis at the imine stage;
We then turned our attention to chemical reduction
procedures. DIBAL-H and L-Selectride reduced the ester
functionality without reduction of the imine; 9-BBN gave
no reaction, and NaCNBH3 in AcOH13 gave the amines
10/11 in a 58/42 ratio. Much of the product was isolated
as a relatively nonpolar boron complex that was best
cleaved by treatment with diethanolamine. An effective
procedure involves heating the complex in EtOAc with
diethanolamine as a biphasic mixture (60 °C, 14 h),
followed by an aqueous wash to remove the diethanol-
amine-boron complex. A superior method employed
NaBH4 in AcOH/MeOH (1/4) at -40 °C14 which success-
fully reduced imine 7 in 88% yield to a mixture of
diastereomers 10 and 11 in a ratio of 68/32, respectively.
15
Identical results were obtained when NaBH(OAc)3
(thought to be the active reducing agent generated in situ
from NaBH4 in AcOH/MeOH) was used.
The resultant diastereomers were extremely difficult
(16) Kemp, D. S.; Curran, T. P. J . Org. Chem. 1988, 53, 5729.
(17) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091.
(18) (a) Mallet, M.; Que´guiner, G. Tetrahedron 1982, 38, 3035. (b)
Que´guiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J . Adv. Heterocycl.
Chem. 1991, 52, 187.
(13) Lane, C. F. Synthesis 1975, 135.
(14) Bacos, D.; Celerier, J . P.; Marx, E.; Saliou, C.; Lhommet, G.
Tetrahedron Lett. 1989, 30, 1081.
(15) Gribble, G. W.; Nutaitis, C. F. Org. Prep. Proc. Int. 1985, 17,
317.
(19) Corcoran, R. C.; Bang, S. H. Tetrahedron Lett. 1990, 31, 6757.

864 J . Org. Chem., Vol. 65, No. 3, 2000
Turner et al.
Sch em e 3. Attem p ted Syn th esis of P yr id o[3,4-b]tr op a n e An a logu e by In tr a m olecu la r En ola te Cycliza tion
Sch em e 4. Syn th esis of 1-Acetyl-2-(2-m eth oxyca r bon yleth en yl)-5-[3-(4′-iod op yr id in yl)]p yr r olid in e
however, subsequent reduction of either the imine or the
ester functionalities is not possible without simultaneous
deiodination.
A comparison reaction using (methoxycarbonylmethyl)-
triphenylphosphonium bromide/Et3N gave a similar yield,
but the triphenylphosphine oxide generated proved dif-
ficult to separate from the product.
To avoid the problem of dehalogenation during reduc-
tion, the iodo group was introduced following reduction
of the ester to alcohol. Mild reduction of the methyl ester
of 14 using Ca(BH4)2 in THF/EtOH (4/1) gave the alcohol
18 in 68% yield (Scheme 4) by direct crystallization. An
additional 11% of product can be obtained by the previ-
ously described technique of heating the crude alcohol
with diethanolamine to liberate boron-complexed mate-
rial. Application of the above conditions resulted in
concomitant 4-chloro to 4-iodo exchange, N-BOC removal,
and acetylation of the alcohol and amine functionalities
to give 19 in 89% yield. Quantitative deacetylation to the
alcohol 20 with K2CO3/MeOH20 was followed by oxidation
to aldehyde 21 using Moffatt-Swern oxidation. The
aldehyde was used in situ to avoid compromising the
stereochemical integrity at the R-position. Treatment
with potassium trimethyl phosphonoacetate provided the
olefin 22 in high yield as a mixture of E and Z isomers.
The alkene 22 was treated with Pd(OAc)2 and Ph3P in
the presence of Et3N for 5 h at 110 °C (Scheme 5).
Intramolecular Heck coupling occurred giving cyclization
to the [3.2.1] homotropane analogue 23 in 89% yield
(Scheme 5). This proved to be a mixture of E/Z isomers
in a 4/1 ratio. The alkene was oxidatively cleaved by
treatment with ozone in the presence of AcOH. It was
found that these conditions minimized the extent of
pyridine N-oxide formation that occurs to around 10-
20% under neutral conditions. Cleavage of the ozonide
with Me2S gave the ketone 24 in 91% yield. This ketone
represents a key intermediate from which a wide variety
of analogues may be derived.
Reduction of ketone of 24 with NaBH4 in MeOH gave
the alcohol 25 (83%) with high diastereoselectivity
(>9:1). The N-acetyl group was removed by heating with
1 M HCl, giving the hydrochloride salt, and treatment
with base and extraction gave the free amino alcohol 26.
The major isomer of this amino alcohol 26 is assigned
(20) Plattner, J . J .; Gless, R. D.; Rapoport, H. J . Am. Chem. Soc.
1972, 94, 8613.

Synthesis of Annulated Nicotine Analogues
J . Org. Chem., Vol. 65, No. 3, 2000 865
Sch em e 5. Syn th esis of th e (+) a n d (-) P yr id o[3,4-b]tr op a n e Nicotin e An a logu es
the R-configuration for the hydroxyl group on the basis
of the coupling patterns of the protons at C-4 (doublet)
and C-5 (triplet). Thus the bridgehead proton at C-5
(triplet) is coupled with the â-protons at C-6 and C-4,
indicating 4R stereochemistry.
31, presumably via hydroxymethylation, dehydration,
reduction, and a second hydroxymethylation at C-4.
Alternatively, reductive alkylation with formaldehyde
and NaBH(OAc)3 gave nicotine analogue 3 in high yield.
Conversion of secondary amine 26 to the N-methyl
analogue 27 was anticipated to be routine on treatment
with formaldahyde and formic acid.6 Surprisingly, the
major product was the 4-hydroxymethyl N-methylated
compound 30. Additional reaction of formaldehyde at C-4
undoubtedly results from the enhanced acidity of the
hydrogen at this position due to the pyridinium species
generated in the acidic medium. A successful and simple
method for N-methylation to 27 then was found in the
reductive alkylation with formaldehyde and NaBH
(OAc)3.21 These N-H and N-Me alcohols are in themselves
interesting constrained nicotine analogues for prospective
pharmacological evaluation. Tropanol derivatives bearing
a hydroxy substituent at the same position are known
to exhibit potent anticholinergic activity.22
Con clu sion s
We have developed an enantiospecific synthetic route
to conformationally restricted annulated analogues of
natural (-)-nicotine and unnatural (+)-nicotine from D-
and L-glutamic acid, respectively. The route proceeds by
preparing a cis-2,5-disubstituted pyrrolidine via regio-
selective addition of ortho-lithiated 4-chloropyridine to
a pyroglutamate derivative. The 8-azabicyclo[3.2.1]octano-
[2,3-c]pyridine framework is constructed by an intra-
molecular Heck cyclization. The functional versatility of
key intermediates such as the cis-5-pyridinylproline ester
5 and the ketone, pyrido-homotropane 24, should allow
access to other nicotine analogues.
Attempts were made to reduce the N-acetyl ketone 24
directly to the methylene derivative. Reaction with
LiAlH4 and AlCl3 led to a complex mixture. Application
of the Wolff-Kishner conditions (NH2NH2, triethylene
glycol, 200 °C) led to some of the desired product together
with products resulting from loss of the acetyl group. To
eliminate this complication, the ketone was deacetylated
with HCl to the free base 28 in high yield. Wolff-Kishner
reaction now occurred cleanly to give the nornicotine
analogue 29. As previously attempted, N-methylation
with formaldehyde and formic acid unexpectedly led to
Exp er im en ta l Section
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 performed using 230-400 mesh silica gel,
and TLC analyses were performed on aluminum-backed silica
gel 60 F254, 0.2 mm plates (MCN Reagents), visualized with
UV light (254 nm), followed by heating with ethanolic phos-
phomolybdic acid. 1H- and 13C-NMR spectra were recorded on
an AM-400 (300 and 75 MHz) or AM-500 (500 and 125 MHz)
instrument. These spectra were recorded, unless otherwise
stated, in CDCl3-tetramethylsilane (δ 0.0 for 1H), CDCl3 (δ
77.0 for 13C), and CD3OD (δ 49.0 for 13C) as internal references.
All chemical shifts were reported in δ ppm, and J values are
in hertz. DEPT experiments were carried out with 13C NMR
acquisition, and the carbon multiplicities were listed as (0)
quaternary, (1) methine, (2) methylene, and (3) methyl. THF
and Et2O were distilled from Na-benzophenone ketyl under
(21) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.
A.; Shah, R. D. J . Org. Chem. 1996, 61, 3849.
(22) Atkinson, E. R.; McRitchie, D. D.; Shoer, L. F.; Harris, L. S.;
Archer, S.; Aceto, M. D.; Pearl, J .; Luduena, F. P. J . Med. Chem. 1977,
20, 1612.

866 J . Org. Chem., Vol. 65, No. 3, 2000
Turner et al.
1
nitrogen; Et3N, DMF, CH3CN, and CH2Cl2 were distilled from
CaH2 under argon; and MeOH was distilled from Mg. Acetyl
chloride was distilled prior to use. Organic phases from liquid-
liquid distributions were dried over Na2SO4. Elemental analy-
ses and mass spectra were conducted by the Analytical
Laboratory at the University of California at Berkeley.
ter t-Bu tyl (2S)-2-(N-(ter t-Bu tyloxyca r bon yl)a m in o)-5-
[3-(4-ch lor op yr id in yl)]-5-oxop en ta n oa te (5a ). A solution
of LDA was prepared by the addition with stirring of n-BuLi
(1.6 M solution in hexane, 42.6 mL, 68.1 mmol) to diisopro-
pylamine (7.26 g, 71.7 mmol) in Et2O (80 mL) at -78 °C over
5 min. The resulting pale yellow solution was stirred at -78
°C for 15 min. A solution of 4-chloropyridine in Et2O was
prepared by adding portionwise 4-chloropyridinium hydro-
chloride (11.4 g, 75.6 mmol) to a mixture of Et2O (30 mL) and
saturated aqueous NaHCO3 (30 mL). Care must be taken as
vigorous effervescence takes place. The organic layer was
separated, the aqueous layer was washed with Et2O (10 mL),
the combined extract was dried and added dropwise over 10
min to the LDA solution, and the resulting yellow slurry was
stirred for 1 h, maintaining the internal temperature below
-65 °C throughout to avoid pyridyne formation, which is
characterized by the appearance of dark brown deposits. A
solution of lactam 4a (14.4 g, 50.4 mmol)6 in Et2O (15 mL)
was then added over 5 min, and the resulting mixture was
stirred at -78 °C for 14 h after which pH 7 phosphate buffer
(50 mL) was added. The aqueous layer was extracted with CH2-
Cl2 (50 mL × 2), the combined organic layer was dried and
filtered, and the filtrate was evaporated. Chromatography
(SiO2, hexane/EtOAc, 9/1-2/3) of the residue afforded ketone
5a (14.8 g, 74%) as a colorless oil. The product is susceptible
98/2-9/1]; [R]22 +79.1° (c 1.0, CHCl3). H NMR δ 2.20-2.44
D
(m, 2H), 2.98-3.11 (m, 1H), 3.14-3.30 (m, 1H), 3.78 (s, 3H),
4.91 (dd, J ) 8.7, 6.7, 1H), 7.33 (d, J ) 5.4, 1H), 8.49 (d, J )
5.4, 1H), 8.74 (s, 1H); 13C NMR δ 26.6 (2), 38.7 (2), 52.2 (3),
74.2 (1), 124.9 (1), 130.1 (0), 142.4 (0), 151.0 (1), 151.2 (1), 172.5
(0), 174.2 (0). Anal. Calcd for C11H11N2O2Cl; C, 55.5; H, 4.7;
N, 11.8. Found: C, 55.6; H, 5.0; N, 11.9.
(2R)-2-[3-(4′-Ch lor op yr id in yl)]-5-(m eth oxyca r bon yl)-1-
p yr r olin e ((2R)-7), structure not shown), was prepared from
the enantiomeric substrate in the same manner; [R]21D -80.0°
(c 1.0, CHCl3); spectral and chromatographic properties identi-
cal with (2S)-7. The enantiomeric purity was established as
>99% by chiral HPLC.
(2S)-2-[3-(4′-Meth oxyp yr id in yl)]-5-(m eth oxyca r bon yl)-
1-p yr r olin e (8). Ketone 5a (2.75 g, 6.89 mmol) was dissolved
in MeOH (50 mL) [presaturated with HCl (g)] and stirred at
room temperature for 4 h. The mixture was concentrated to a
red oil which was dissolved in H2O (10 mL) and partitioned
between EtOAc (40 mL) and saturated aqueous NaHCO3 (30
mL). The aqueous layer was extracted with EtOAc (40 mL ×
2), and the combined organic layer was dried, filtered, and
evaporated. Chromatography (SiO2, CH2Cl2/MeOH-Et3N (4/
1), 98/2-9/1) of the residue afforded imines 7 (0.62 g, 36%)
and 8 (0.75 g, 44%) as yellow oils. For characterization of 7
see above. 8: 1H NMR δ 2.38-2.10 (m, 2H), 3.04-2.90 (m,
1H), 3.25-3.10 (m, 1H), 3.76 (s, 3H), 3.88 (s, 3H), 4.82 (dd, J
) 8.6, 6.8, 1H), 6.82 (d, J ) 5.8, 1H), 8.48 (d, J ) 5.8, 1H),
8.86 (s, 1H); 13C NMR δ 26.6, 38.6, 52.1, 55.4, 73.5, 106.5,
119.8, 151.0, 152.8, 163.9, 173.2, 174.2.
(2R,5S)-N-(ter t-Bu t yloxyca r b on yl)-5-[3-(4′-m et h oxy-
p yr id in yl)]p r olin e Meth yl Ester (9). Imine 8 (1.00 g, 4.27
mmol) was dissolved in MeOH (30 mL), Pd/C (10%, 100 mg)
added, and the mixture was degassed and agitated under H2
(1 atm.) for 16 h. After filtration twice through a short plug of
Celite, the filtrate was evaporated to give amine as a yellow
oil (0.97 g, 96%): NMR δ 1.88-2.02 (m, 1H), 2.10-2.40 (m,
3H), 3.80 (s, 3H), 3.99 (s, 3H), 4.24 (m, 1H), 4.63 (dd, J ) 8.8,
6.2, 1H), 5.40 (br s, 1H), 6.93 (d, J ) 6.0, 1H), 8.51 (d, J ) 6.0,
1H), 8.76 (s, 1H); 13C NMR δ 29.4, 31.0, 52.9, 56.1, 57.3, 59.4,
106.0, 146.7, 149.0, 173.3. The amine, di-tert-butyl dicarbonate
(0.96 g, 4.42 mmol) and triethylamine (0.45 g, 4.42 mmol) were
stirred in THF (30 mL) at room temperature for 14 h.
Evaporation gave a residue which was partitioned between
EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The
aqueous layer was extracted with EtOAc (50 mL × 2), the
combined organic layer was dried and filtered, the filtrate was
evaporated, and the residue was chromatographed (SiO2;
hexanes/EtOAc, 9/1, then CH2Cl2/MeOH/ Et3N(4/1), 98/2-9/
1) to afford 9 (1.20 g, 82% from 8) as a colorless crystalline
to rapid polymerization and should be used either as the crude
1
or rapidly after purification: [R]21 +12.2° (c 1.2, CHCl3); H
D
NMR δ 1.41 and 1.47 (s, 18H), 1.95-2.05 (m, 1H), 2.20-2.33
(m, 1H), 2.97-3.15 (m, 2H), 4.25 (m, 1H), 5.11 (d, J ) 8.1,
1H), 7.36 (d, J ) 5.4, 1H), 8.55 (d, J ) 5.4, 1H), 8.74 (s, 1H);
13C NMR δ 27.4 (2), 28.2 (3), 28.5 (3), 39.4 (2), 53.5 (1), 80.1
(0), 82.5 (0), 125.6 (1), 134.5 (0), 141.5 (0), 150.4 (1), 152.4 (1),
155.8 (0), 171.6 (0), 199.8 (0).
Meth yl (2S)-2-(N-(ter t-bu tyloxyca r bon yl)a m in o)-5-[3-
(4-ch lor op yr id in yl)]-5-oxop en ta n oa te (5b) was prepared
as described for 5a , using 110 mol % of the 3-lithio-4-
chloropyridine and pyroglutamate 4b (9.00 g, 37.0 mmol).
Ketone 5b was obtained as a pale yellow oil (10.6 g, 80%). The
crude product was used directly in the next reaction: 1H NMR
δ 1.39 (s, 9H), 1.97-2.07 (m, 1H), 2.25-2.38 (m, 1H), 2.97-
3.17 (m, 2H), 3.74 (s, 3H), 4.37 (m, 1H), 5.13 (br s, 1H), 7.36
(d, J ) 5.4, 1H), 8.55 (d, J ) 5.4, 1H), 8.72 (s, 1H). HRMS
(EI): calcd for C16H21ClN2O5 (M+) 356.1121. Found 356.1217.
Meth yl (2R)-2-(N-(ter t-bu tyloxyca r bon yl)a m in o)-5-[3-
(4-ch lor op yr id in yl)]-5-oxop en ta n oa te ((2R)-5b), structure
not shown, was prepared from the enantiomeric substrate in
the same manner; 1H NMR δ and chromatographic properties
identical with (2S)-5b: [R]23D -12.0 (c 1.56, CHCl3); 13C NMR,
(400 MHz) δ 26.82, 28.17, 38.96, 52.42, 52.60, 80.02, 125.27,
134.11, 141.19, 150.10, 152.14, 155.37, 172.60, 199.27. Anal.
Calcd for C16H21CIN2O5: C, 53.9; H, 5.9; N, 7.9. Found: C,
53.8; H, 6.2; N, 8.1.
Meth yl (2S)-2-Am in o-5-[3-(4-ch lor op yr id in yl)]-5-oxo-
p en ta n oa te Hyd r och lor id e (6) a n d (2S)-2-[3-(4′-Ch lor o-
p yr id in yl)]-5-(m eth oxyca r bon yl)-1-p yr r olin e (7). Ketone
5b (2.75 g, 6.89 mmol) was dissolved in EtOAc (50 mL)
[presaturated with HCl (g) and diluted to 1 M], stirred at room
temperature for 4 h, and then evaporated to a red solid which
was washed with EtOAc (40 mL × 3) and dried to give the
amine hydrochloride salt 6 (1.92 g, 95%) as a buff solid: 1H
NMR (D2O) δ 2.32 (m, 2H), 3.38 (m, 2H), 3.76 (s, 3H), 4.22 (t,
J ) 7.5, 1H), 8.21 (d, J ) 5.4, 1H), 8.81 (d, J ) 5.4, 1H), 9.11
(s, 1H). The crude salt was partitioned between EtOAc (40 mL)
and saturated aqueous NaHCO3 (30 mL), the aqueous layer
was extracted with EtOAc (40 mL × 2), and the combined
organic layer was dried, filtered, and evaporated to afford
pyrroline 7 (1.56 g, 95%) as a red oil. The crude product was
used directly in the next reaction. An analytical sample was
prepared by chromatography [SiO2; CH2Cl2/MeOH-Et3N (4/1),
solid: mp 158 °C (EtOAc/hexane, 3/2); [R]22 +42.8° (c 1.0,
CHCl3); H NMR, rotamers, 3/2, δ 1.12 (s, minor, 3.6H), 1.17
D
1
(s, major, 5.4H), 1.73-2.08 (m, 2H), 2.14-2.35 (m, 2H), 3.78
(s, 3H), 3.82 (s, 3H), 4.29 (t, J ) 8.3, major, 0.6H), 4.43 (t, J )
5.2, minor, 0.4H), 5.08 (t, J ) 5.2, minor, 0.4H), 5.23 (d, J )
5.7, major, 0.6H), 6.71 (d, J ) 5.6, 1H), 8.37 (m, 1H), 8.87 (m,
1H); 13C NMR, rotamers, δ 27.7, 28.0, 28.2, 28.8, 32.0, 32.8,
52.0, 57.9, 58.1, 60.0, 60.9, 67.7, 80.6, 81.0, 123.6, 124.1, 135.7,
136.8, 141.5, 141.6, 148.5, 148.8, 149.0, 149.2, 149.8, 153.5,
153.8, 172.9. Anal. Calcd for C17H24N2O5: C, 60.7; H, 7.2; N,
8.3. Found: C, 60.4; H, 7.1; N, 8.2.
(2R,5S)- a n d (2S,5S)-5-[3-(4′-Ch lor op yr id in yl)]p r olin e
Meth yl Ester s ((2R,5S)-10 and (2S,5S)-11). To a stirred
solution of imine 7 (27.3 g, 0.114 mol) in glacial acetic acid/
MeOH, 4/1 (400 mL) at -40 °C was added NaBH4 (8.65 g, 0.23
mol) portionwise over 5 min. The solution was stirred for 4 h
before quenching with pH 7 1 M phosphate buffer (200 mL),
and stirring was continued for 10 min. The solution was
concentrated to 50 mL and extracted with CH2Cl2 (3 × 400
mL), and the combined organic extract was dried, filtered, and
evaporated to give an orange oil (24.2 g, 88%), shown by 1H
NMR spectroscopy to be a mixture of cis and trans diastere-
omers in the ratio 68/32. This product was used directly in
the next reaction. The pure cis diastereomer can be isolated
by chromatography on SiO2 using 60% EtOAc/hexane as
eluent; it is more readily obtained as its BOC derivative 14

Synthesis of Annulated Nicotine Analogues
J . Org. Chem., Vol. 65, No. 3, 2000 867
as described in the following procedure. Selected signals for
cis diastereomer 10: 1H NMR δ 3.74 (s, 3H), 3.98 (m, 1H),
4.68 (t, J ) 7.4, 1H), 7.16 (d, J ) 5.3, 1H), 8.28 (d, J ) 5.3,
1H), 8.97 (s, 1H).
(2S,5R)- and (2R,5R)-5-[3-(4′-Ch lor op yr id in yl)]p r olin e
m eth yl ester s ((2S,5R)-10 and (2R,5R)-11), structures not
shown, were prepared from the enantiomeric substrate in the
same manner; spectral and chromatographic properties identi-
cal with those of (2R,5S)-10 and (2S,5S)-11.
major, 0.8H), δ 2.00 (s, minor, 0.6H), 2.08-2.22 (m, 1H), 2.24-
2.50 (m, minor, 0.4H), 2.58-2.70 (m, major, 0.8H), 3.73 (s,
major, 2.4H), 3.78 (s, minor, 0.6H), 4.69 (d, J ) 8.4, minor,
0.2H), 4.75 (d, J ) 9.1, major, 0.8H), 5.45 (d, J ) 8.4, major,
0.8H), 5.56 (d, J ) 8.4, minor, 0.2H), 7.26 (d, J ) 5.3, minor,
0.2H), 7.33 (d, J ) 5.2, major, 0.8H), 8.17 (s, minor, 0.2H),
8.31 (s, major, 0.8H), 8.32 (d, J ) 5.2, minor, 0.2H), 8.44 (d, J
) 5.2, major, 0.8H); 13C NMR δ 22.5, 26.4, 32.3, 52.7, 58.7,
60.1, 125.2, 135.8, 142.2, 148.0, 150.3, 170.3, 172.6. Anal. Calcd
for C13H15N2O3Cl: C, 55.2; H, 5.3; N, 9.9. Found: C, 55.3; H,
5.5; N, 9.6.
N -(t er t -Bu t yloxyc a r b on yl)-(2R ,5S )-5-[3-(4′-c h lor o-
p yr id in yl)]p r olin e Meth yl Ester (14) a n d (2S,5S)-2-[3-(4′-
Ch lor op yr id in yl)]p r olin e Meth yl Ester (11). The mixture
of amines 10 and 11 (22.0 g, 91.5 mmol) and Et3N (12.4 mL,
89.3 mmol) were stirred in THF (200 mL) at room temperature,
di-tert-butyl dicarbonate (15.7 g, 71.8 mmol) in THF (50 mL)
was added over 30 min, and stirring was continued for 15 h.
The solution was evaporated, and the residue was partitioned
between EtOAc (500 mL) and saturated aqueous NaHCO3 (300
mL). The aqueous layer was extracted with EtOAc (300 mL ×
2), and the organic layers were combined, dried, filtered, and
evaporated. Chromatography of the residue, using EtOAc/
hexanes, 3/2-EtOAc/MeOH, 9/1, as eluent, afforded the N-BOC
amine 14 as colorless crystals (18.7 g, 60%) and the unreacted
trans-diastereomer 11 as a colorless oil (7.0 g, 32%). For 14:
(2R,5R)-1-Acetyl-5-[3-(4′-ch lor opyr idin yl)]pr olin e m eth -
yl ester ((2R,5R)-13), structure not shown, was prepared from
the enantiomeric substrate in the same manner; [R]19 +101°
D
(c 1.0, CHCl3); spectral and chromatographic properties identi-
cal with (2S,5S)-13.
(2S ,5R )-N -(t er t -Bu t yloxyc a r b on yl)-2-[3-(4′-c h lor o-
p yr id in yl)]p r olin e (15). Methyl ester 14 (340 mg, 1.00 mmol)
and LiOH (168 mg, 4.00 mmol) were stirred in MeOH/H2O (3/
1, 10 mL) at room temperature for 5 h. The solution was
poured into aqueous H3PO4 solution (0.1 M, 30 mL) and
extracted with CH2Cl2/IPA (3/1, 30 mLx3), the combined
extract was dried and filtered, and the filtrate was evaporated
to afford 15 (280 mg, 86%) as a white foam: 1H NMR,
rotamers, 3/1, δ 1.18 (s, minor, 2.25H), 1.37 (s, major, 6.75H),
1.84-1.96 (m, 1H), 2.04-2.14 (m, 1H), 2.22-2.40 (m, 1H),
2.41-2.53 (m, 1H), 4.38 (t, J ) 7.4, major, 0.75H), 4.57 (m,
minor, 0.25H), 5.23 (m, minor, 0.25H), 5.35 (m, major, 0.75H),
7.41 (d, J ) 5.4, minor, 0.25H), 7.44 (d, J ) 5.5, major, 0.75H),
8.50 (m, 1H), 9.49 (s, minor, 0.25H), 9.54 (s, major, 0.75H);
13C NMR, rotamers, δ 28.0 (3), 28.1 (3), 28.8 (2), 31.9 (2), 33.2
(2), 57.4 (1), 58.3 (1), 61.0 (1), 61.8 (1), 80.7 (0), 81.3 (0), 124.8
(1), 125.5 (1), 138.2 (0), 145.6 (0), 147.1 (0), 153.9 (0), 175.6
(0). HRMS (EI) calcd for C15H20N2O4Cl (M+ + 1) 327.1112.
Found: 327.1106.
[R]20 +23.0° (c 1.0, CHCl3); mp 95-96 °C (hexane); 1H NMR,
D
1/1 rotamers, δ 1.15 (s, 4.5H), 1.38 (s, 4.5H), 1.82-2.10 (m,
2H), 2.18-2.28 (m, 1H), 2.36-2.50 (m, 1H), 3.79 (s, 3H), 4.35
(t, J ) 7.8, 0.5H), 4.49 (dd, J ) 7.9, 5.2, 0.5H), 5.16 (t, J ) 7.0,
0.5H), 5.27 (m, 0.5H), 7.24 (m, 1H), 8.36 (m, 1H), 9.11 (s, 0.5H),
9.17 (s, 0.5H); 13C NMR, rotamers, δ 27.7 (3), 28.0 (3), 28.2
(3), 28.8 (2), 32.0 (2), 32.8 (2), 52.0 (3), 57.9 (1), 58.1 (1), 60.0
(1), 60.9 (1), 67.7 (1), 80.6 (0), 81.0 (0), 123.6 (1), 124.1 (1),
135.7 (0), 136.8 (0), 141.5 (0), 141.6 (0), 148.5 (1), 148.8 (1),
149.0 (1), 149.2 (1), 149.8 (1), 153.5 (0), 153.8 (0), 172.9 (0).
Anal. Calcd for C16H21N2O4Cl: C, 56.4; H, 6.2; N, 8.2. Found:
1
C, 56.1; H, 6.0; N, 8.2. For 11: [R]20 -110 (c 1.0, CHCl3); H
(2S,5R)-1-(ter t-Bu tyloxyca r bon yl)-2-(m eth oxyca r bon -
ylm eth yl)-5-(3-p yr id in yl)p yr r olid in e (16). The proline 15
(280 mg, 0.86 mmol) in THF (4 mL) at -15 °C was treated
with Et3N (119 µL, 0.86 mmol) followed by ethyl chloroformate
(81 µL, 0.86 mmol), and the mixture was stirred at -15 °C for
15 min, warmed to 0 °C before excess CH2N2 (0.5 M in Et2O,
4 mL, 2.0 mmol) was added, stirred for 5 h, and then warmed
to room temperature slowly. The resulting mixture was flushed
with N2 until the bright yellow color disappeared and evapo-
rated, and the residue was partitioned between EtOAc (20 mL)
and saturated aqueous NaHCO3 (20 mL). The aqueous layer
was extracted with EtOAc (20 mL × 2), and the combined
organic extract was dried, filtered, and evaporated to afford
crude diazoketone (270 mg, 90%) as a pale yellow oil which
was used directly. Crude diazoketone (100 mg, 0.28 mmol) in
MeOH (4 mL) was irradiated with UV light, the reaction
mixture was evaporated, and the residue was partitioned
between EtOAc (10 mL) and saturated aqueous NaHCO3 (5
mL). The aqueous layer was extracted with EtOAc (10 mL ×
2), and the combined organic extract was dried, filtered, and
evaporated to afford 16 (51 mg, 50% from 15) as a colorless
oil: 1H NMR δ 1.08-1.55 (9H), 1.70-1.90 (m, 2H), 2.12-2.26
(m, 1H), 2.40-2.60 (m, 2H), 3.12 (m, 1H), 3.69 (s, 3H), 4.40
(m, 1H), 5.10 (m, 1H), 7.27 (d, J ) 5.4, 1H), 8.32 (d, J ) 5.4,
1H), 8.50 (m, 1H).
(2S)-cis-1-(ter t-Bu tyloxyca r bon yl)-2-(h yd r oxym eth yl)-
5-[3-(4′-ch lor op yr id in yl)]p yr r olid in e (18). To a solution of
ester 14 (12.0 g, 35.2 mmol) in THF/EtOH (240/360 mL) at 0
°C was added CaCl2 (7.80 g, 70.4 mmol) followed by NaBH4
(5.40 g, 0.143 mol). The mixture was stirred for 18 h while it
warmed to room temperature, K2CO3 (2M, 200 mL) was added,
and it was distributed between EtOAc (500 mL) and saturated
aqueous NaHCO3 (200 mL). The aqueous layer was extracted
with EtOAc (500 mL × 2), and the combined layer was dried,
filtered, and evaporated. To the residue dissolved in EtOAc
(50 mL) was added diethanolamine (7.40 g, 70.4 mmol), the
biphasic mixture was heated to 60 °C for 16 h, and the cooled
mixture was diluted with EtOAc (200 mL), washed with H2O
(50 mL × 2), dried, and filtered. The filtrate was evaporated,
and the residue was chromatographed (SiO2, EtOAc/hexanes,
D
NMR (CDCl3) δ1.44-1.55 (m, 1H), 1.84-1.95 (m, 1H), 2.11-
2.28 (m, 2H), 2.59 (br s, 1H), 3.64 (s, 3H), 3.95 (dd, J ) 8.0,
5.1, 1H), 4.64 (t, J ) 7.1, 1H), 7.12 (d, J ) 5.3, 1H), 8.24 (d, J
) 5.3, 1H), 8.76 (s, 1H); 13C NMR δ 29.4, 32.4, 52.2, 56.7, 59.5,
123.9, 137.8, 142.4, 148.6, 149.4, 176.0. Anal. Calcd for C11 H13
-
ClN2O2: C, 54.9; H, 5.4; N, 11.6. Found: C, 55.2; H, 5.8; N,
11.3.
(2S ,5R )-N -(t er t -Bu t yloxyc a r b on yl)-5-[3-(4′-c h lor o-
p yr id in yl)]p r olin e Meth yl Ester ((2S,5R) -14), structure
not shown, was prepared from the enantiomeric substrate in
the same manner; [R]19 -22.8° (c 1.0, CHCl3); spectral and
D
chromatographic properties identical with (2R,5S)-14.
(2R,5S)-1-Acetyl-5-[3-(4′-ch lor opyr idin yl)]pr olin e Meth -
yl E st er (12) a n d (2S,5S)-1-Acet yl-5-[3-(4′-ch lor op yr i-
d in yl)]p r olin e Meth yl Ester (13). The crude mixture of
amines 10 and 11 (3.00 g, 12.5 mmol), acetic anhydride (1.53
g, 15.0 mmol), and Et3N (1.52 g, 15.0 mmol) were stirred in
THF (50 mL) at room temperature followed by evaporation of
the solvent and partitioning of the residue between EtOAc (100
mL) and saturated aqueous NaHCO3 (100 mL). The aqueous
layer was extracted with EtOAc (50 mL × 2), and the organic
layers were combined, dried, filtered, and evaporated. Chro-
matography of the residue, using EtOAc then EtOAc/MeOH,
9/1, as eluent, afforded both the cis-N-acetyl ester 12 (2.04 g,
56%) and trans-N-acetyl ester 13 (0.96 g, 26%) as colorless
crystals. For 12: mp 148-149 °C (EtOAc);[R]19D -22.7° (c 1.0,
CHCl3); 1H NMR, rotamers, 3/1, δ 1.83 (s, major, 2.25H), 1.85-
2.10 (m, 2.75H), 2.12-2.60 (m, 2H), 3.80 (s, major, 2.25H), 3.82
(s, minor, 0.75H), 4.54 (m, 1H), 5.30 (d, J ) 7.9, major, 0.75),
5.39 (t, J ) 7.1, minor, 0.25H), 7.24 (d, J ) 5.2, minor, 0.25H),
7.31 (d, J ) 5.2, major, 0.75H), 8.34 (d, J ) 5.2, minor, 0.25H),
8.47 (d, J ) 5.2, major, 0.75H), 8.88 (s, minor, 0.25H), 9.32 (s,
major, 0.75H); 13C NMR, rotamers, 22.1, 22.5, 27.3, 29.9, 31.6,
33.7, 52.3, 52.8, 58.5, 58.7, 60.6, 61.3, 79.6, 124.1, 124.3, 135.2,
135.3, 141.7, 148.7, 148.8, 149.8, 149.9, 156.0, 170.1, 170.3,
172.2, 172.3. Anal. Calcd for C13H15N2O3 Cl: C, 55.2; H, 5.3;
N, 9.9. Found: C, 55.3; H, 5.4; N, 9.8. For 13: mp 135 °C
1
(EtOAc); [R]19 -105° (c 1.0, CHCl3); H NMR, rotamers, 4/1,
D
δ 1.84 (s, major, 2.4H), 1.75-1.90 (m, 1H), 1.95-2.01 (m,

868 J . Org. Chem., Vol. 65, No. 3, 2000
Turner et al.
3/2) to afford alcohol 18 (8.70 g, 79%) as colorless crystals:
[R]20D -5.7° (c 1.0, CHCl3); mp 84-86 °C (hexane/EtOAc, 9/1);
1H NMR, rotamers, δ 1.15 (br, 9H), 1.74 (br m, 2H), 2.04 (m,
1H), 2.40 (br m, 1H), 3.85 (m, 2H), 4.12 (br, 1H), 4.65 (br, 1H),
5.18 (m, 1H), 7.25 (d, J ) 5.5, 1H), 8.38 (br, 1H), 8.60 (s, 1H);
13C NMR δ 26.2 (2), 27.0 (2), 27.9 (3), 28.3 (3), 31.8 (2), 32.3
(2), 58.0 (1), 58.7 (1), 60.8 (1), 62.0 (1), 65.2 (2), 80.5 (0), 80.8
(0), 124.5 (1), 138.1 (0), 142.0 (0), 147.2 (1), 148.3 (1), 154.8
(0). Anal. Calcd for C15H21N2O3Cl: C, 57.6; H, 6.8; N, 9.0.
Found: C, 57.5; H, 6.9; N, 9.0.
and then poured into brine (30 mL). The organic layer was
washed with H2O (20 mL) and brine (20 mL), dried, and
evaporated to afford aldehyde 21 (2.30 g) as a pale yellow oil:
1H NMR, rotamers, 9/1, δ 1.82 (s, 3H), 1.82-2.06 (m, 2H),
2.09-2.22 (m, 1H), 2.48-2.60 (m, 1H), 4.61 (d, J ) 8.0, 1H),
5.11 (dd, J ) 8.1, 3.4, 1H), 7.80 (d, J ) 5.1, 1H), 8.14 (d, J )
5.1, 1H), 8.73 (s, 1H), 9.82 (s, 1H); 13C NMR δ 22.2 (3), 24.0
(3), 27.5 (2), 34.1 (2), 46.0, 65.3 (1), 66.7 (1), 109.1 (0), 134.8
(1), 139.8 (0), 147.7 (1), 149.5 (1), 156.0 (0), 170.9 (0), 198.0
(0).
(2R)-cis-1-(ter t-Bu tyloxyca r bon yl)-2-(h yd r oxym eth yl)-
5-[3-(4′-ch lor op yr id yl)]p yr r olid in e ((2R)-18), structure not
shown, was prepared from the enantiomeric substrate in the
Aldehyde 21 (2.30 g) was dissolved in CH2Cl2 (10 mL) and
added to a preformed mixture of the sodium salt of trimethyl
phosphonoacetate [prepared by the addition of NaH (324 mg,
13.5 mmol) to a solution of trimethyl phosphonoacetate (2.83
g, 13.5 mmol) in THF (150 mL) at 0 °C, followed by stirring
for 30 min, and then cooling to -78 °C] over 30 min, followed
by stirring at -78 °C for 1 h. The reaction mixture was then
slowly warmed to -55 °C over 2 h, saturated aqueous K2HPO4
(10 mL) was added, and, after stirring for 15 min, the solution
was poured into saturated aqueous NaHCO3 (50 mL) and
distributed between CH2Cl2 (300 mL) and saturated aqueous
NaHCO3 (100 mL). The aqueous layer was extracted with CH2-
Cl2 (200 mL × 2), and the combined organic layer was washed
with brine (50 mL), dried, filtered, and evaporated. Chroma-
tography of the residue, using EtOAc as eluent, afforded R,â-
unsaturated ester 22 as colorless crystals (2.68 g, 92% from
same manner; [R]19 +7.2° (c 1.0, CHCl3); spectral and
D
chromatographic properties identical with (2S)-18.
(2S ,5R )-1-Ac e t y l-2-(a c e t o x y m e t h y l)-5-[3-(4′-io d o -
p yr id in yl)]p yr r olid in e (19). To a solution of alcohol 18 (3.70
g, 11.8 mmol) in CH3CN (100 mL) was added NaI (32.0 g, 0.213
mol) followed by acetyl chloride (6.50 g, 82.3 mmol), and the
mixture was heated to 55 °C under N2 and stirred for 40 h.
The reaction mixture was allowed to cool to room temperature,
saturated aqueous NaHCO3 (20 mL) was added, and the
mixture was distributed between CH2Cl2 (100 mL) and satu-
rated aqueous NaHCO3 (50 mL). The aqueous layer was
extracted with CH2Cl2 (50 mL × 2), and the combined organic
layer was washed with Na2S2O3 (1 M, 50 mL), dried, filtered,
and evaporated. Chromatography of the residue, using EtOAc/
hexanes, 3/2-EtOAc/MeOH, 9/1, as eluent, gave 19 (4.07 g,
20): mp 125 °C (dec); [R]21 -8.2° (c 1.0, CHCl3); 1H NMR,
D
rotamers, 6/4, δ 1.68 (s, major, 1.8H), 1.96 (s, minor, 1.2H),
1.70-1.90 (m, 2H), 2.02-2.22 (m, 1H), 2.32-2.48 (m, 1H), 3.62
(s, minor, 1.2H), 3.67 (s, major, 1.8H), 4.51 (m, minor, 0.4H),
4.72 (m, major, 0.6H), 4.97 (m, major, 0.6H), 5.07 (t, J ) 7.1,
minor, 0.4H), 5.97 (t, J ) 16.1, 1H), 6.97 (dt, J ) 16.1, 6.4,
1H), 7.64 (d, J ) 5.0, minor, 0.4H), 7.70 (d, J ) 5.1, major,
0.6H), 7.91 (d, J ) 5.0, minor, 0.4H), 8.01 (d, J ) 5.1, major,
0.6H), 8.17 (s, minor, 0.4H), 8.29 (s, major, 0.6H); 13C NMR,
rotamers, δ 22.8, 22.9, 28.7, 31.4, 32.4, 33.4, 33.7, 51.5, 51.8,
52.6, 53.1, 53.1, 53.5, 59.7, 61.0, 65.4, 66.0, 122.1, 122.8, 134.6,
134.7, 140.0, 146.4, 146.8, 146.9, 147.3, 148.3, 149.2, 166.0,
166.4, 171.0, 171.2. Anal. Calcd for C15H17IN2O3: C, 45.0; H,
4.3; N, 7.0. Found: C, 45.0; H, 4.5; N, 6.9.
89%) as colorless crystals: mp 110-112 °C (Et2O); [R]21
D
-27.2° (c 1.0, CHCl3); 1H NMR, rotamers, 7/3, δ 1.60-2.20 (m,
3H), 1.74 (s, major, 2.1H), 1.82-1.92 (m, 1H), 1.95-2.15 (m,
2H), 2.07 (s, minor, 0.9H), 2.53 (m, major, 0.7H), 2.71 (m,
minor, 0.3H), 4.17 (m, minor, 0.3H), 4.28 (m, major, 0.7H), 4.40
(m, minor, 0.6H), 4.50 (m, major, 1.4H), 5.00 (t, J ) 6.7, major,
0.7H), 5.07 (t, J ) 8.8, minor, 0.3H), 7.70 (d, J ) 5.0, minor,
0.3H), 7.76 (d, major, J 5.1, 0.7H), 7.98 (d, J ) 5.0, minor,
0.3H), 8.10 (d, major, J ) 5.1, 0.7H), 8.18 (s, minor, 0.3H),
8.61 (s, major, 0.7H); 13C NMR δ 21.3 (3), 23.4 (3), 26.6 (2),
33.9 (2), 58.6 (1), 64.8 (1), 66.4 (2), 109.2 (0), 134.9 (1), 141.2
(0), 148.0 (1), 149.4 (1), 171.1 (0), 171.9 (0). HRMS (EI) calcd
for C14H18N2O3I (M+ + 1) 389.0362. Found: 389.0370.
(2R,5S)-1-Acetyl-2-(2-(m eth oxyca r bon yl)eth en yl)-5-[3-
(4′-iod op yr id in yl)]p yr r olid in e (2R,5S-22), structure not
shown, was prepared from the enantiomeric substrate in the
(2R ,5R )-1-Ac e t y l-2-(a c e t o x y m e t h y l)-5-[3-(4′-io d o -
p yr id in yl)]p yr r olid in e ((2R,5R)-19), structure not shown,
was prepared from the enantiomeric substrate in the same
same manner; [R]19 +8.6° (c 1.0, CHCl3); spectral and
D
manner; [R]19 +26.4° (c 1.0, CHCl3); spectral and chromato-
chromatographic properties identical with (2S,5R)-22.
D
graphic properties identical with (2S,5S)-19.
(1R,5S)-8-Acetyl-4-((m eth oxyca r bon yl)m eth ylid en e)-8-
a za bicyclo[3.2.1]octa n o[2,3-c]p yr id in e (23). To a solution
of R,â-unsaturated ester 22 (500 mg, 1.25 mmol) in 10 mL of
dry DMF were added Pd(OAc)2 (10 mg, 0.044 mmol), Ph3P (20
mg, 0.076 mmol), and Et3N (150 mg, 1.48 mmol). The flask
was flushed with N2, sealed, and heated to 110 °C for 5 h; the
characteristic formation of a Pd mirror in the reaction flask
was observed. The reaction mixture was allowed to cool,
quenched with saturated aqueous NaHCO3 (5 mL), and
distributed between CH2Cl2 (50 mL) and saturated aqueous
NaHCO3 (50 mL). The aqueous extracted with CH2Cl2 (50 mL
× 2), and the combined organic layer was washed with brine,
dried, filtered, and evaporated to a crystalline solid. Chroma-
tography of the residue, using EtOAc/hexanes, 3/2, then
EtOAc/MeOH, 9/1, as eluent, afforded bicyclic R,â-unsaturated
(2S,5R)-1-Acet yl-2-(h yd r oxym et h yl)-5-[3-(4′-iod op yr i-
d in yl)]p yr r olid in e (20). The acetylated alcohol 19 (8.20 g,
21.1 mmol) was stirred in MeOH (60 mL) with K2CO3 (3.00 g,
21.7 mmol) at room temperature for 45 min, the solvent was
evaporated in vacuo, and the residue was extracted with CH2-
Cl2 (3 × 60 mL). The combined extract was dried, filtered, and
evaporated to give alcohol 20 as a colorless oil (7.30 g, 100%)
which was used directly for the next reaction: [R]21 -26.9°
D
1
(c 1.0, CHCl3); H NMR rotamers, 9/1, δ 1.62-1.72 (m, 1H),
1.81 (s, 3H), 1.78-1.88 (m, 1H), 1.97-2.10 (m, 1H), 2.38-2.50
(m, 1H), 3.85 (m, 2H), 4.30 (m, 1H), 5.06 (dd, J ) 8.3, 3.7, 1H),
5.19 (br s, 1H), 7.78 (d, J ) 5.1, 1H), 8.10 (d, J ) 5.1, 1H),
8.44 (s, 1H); 13C NMR δ 26.2 (3), 27.5 (2), 32.8 (2), 63.7 (1),
65.8 (1), 66.9 (2), 109.1 (0), 134.8 (1), 140.3 (0), 147.4 (1), 149.2
(1), 173.1 (0).
ester 23 as colorless crystals (303 mg, 89%): [R]20 +206° (c
D
(2R,5S)-1-Acet yl-2-(h yd r oxym et h yl)-5-[3-(4′-iod op yr i-
d in yl)]p yr r olid in e ((2R,5S)-20), structure not shown, was
prepared from the enantiomeric substrate in the same manner;
1.0, CHCl3); mp 195-196 °C (hexane/EtOAc, 3/2);1H NMR, E/Z
isomers or rotamers, 4/1, δ 1.52-1.82 (m, 2H), 1.86 (s, minor,
0.6H), 1.90 (s, major, 2.4H), 2.10-2.22 (m, 1H), 2.26-2.52 (m,
1H), 3.64 (s, minor, 0.6H), 3.68 (s, major, 2.4H), 4.90 (d, J )
6.0, minor, 0.2H), 5.43 (d, J ) 6.6, major, 0.8H), 6.30 (d, J )
8.0, major, 0.8H), 6.40 (s, 1H), 6.41 (d, J ) 7.4, minor, 0.2H),
7.38 (d, J ) 5.4, major, 0.8H), 7.42 (d, J ) 5.3, minor, 0.2H),
8.36 (d, J ) 5.4, major, 0.8H), 8.40 (d, J ) 5.3, minor, 0.2H),
8.42 (s, 1H); 13C NMR, E/Z isomers or rotamers, δ 14.1, 21.3,
29.4, 31.6, 51.8, 53.3, 54.7, 112.4, 117.8, 136.6, 137.4, 147.8,
149.0, 151.3, 166.2, 167.5. Anal. Calcd for C15H16N2O3: C, 66.1;
H, 5.9; N, 10.3. Found: C, 65.9; H, 6.2; N, 10.3.
[R]19 +27.4° (c 1.0, CHCl3); spectral and chromatographic
D
properties identical with (2S,5R)-20. Anal. Calcd for C12 H15
-
IN2O2: C, 41.6; H, 4.4; N, 8.1. Found: C, 42.0; H, 4.2; N, 7.8.
(2S,5R)-1-Acetyl-2-(2-(m eth oxyca r bon yl)eth en yl)-5-[3-
(4′-iod op yr id in yl)]p yr r olid in e (22). To a solution of oxalyl
chloride (1.66 g, 1.15 mL) in dry CH2Cl2 (25 mL) at -78 °C
was added DMSO (1.87 mL), the cloudy mixture was stirred
for 15 min, and a solution of alcohol 20 (2.30 g, 6.65 mmol) in
dry CH2Cl2 (25 mL) was added over 10 min. The mixture was
stirred for 1 h, triethylamine (5.5 mL) was added dropwise
over 5 min, and the mixture was stirred for an additional 1 h
(1S,5R)-8-Acetyl-4-((m eth oxyca r bon yl)m eth ylid en e)-8-
azabicyclo[3.2.1]octan o[2,3-c]-pyr idin e ((1S,5R)-23), struc-

Synthesis of Annulated Nicotine Analogues
J . Org. Chem., Vol. 65, No. 3, 2000 869
ture not shown, was prepared from the enantiomeric substrate
145.0 (1), 146.2 (1), 148.4 (0). Anal. Calcd for C10H12N2O: C,
68.1; H, 6.9; N, 15.9. Found: C, 67.8; H, 7.0; N, 15.8.
in the same manner; [R]19 -219° (c 1.0, CHCl3); spectral and
D
chromatographic properties identical with (1R,5S)-23.
(1S,4S,5R)-4-Hyd r oxy-8-a za bicyclo[3.2.1] octa n o[2,3-c]-
p yr id in e ((1S,4S,5R)-26), structure not shown, was prepared
(1R,5S)-8-Acetyl-4-oxo-8-a za bicyclo[3.2.1]octa n o[2,3-c]-
p yr id in e (24). A solution of R,â-unsaturated ester 23 (500 mg,
1.84 mmol) and acetic acid (132 mg, 2.20 mmol) in dry CH2-
Cl2 (20 mL) was stirred at -78 °C as ozone was passed through
the solution for 20 min which was then purged for 15 min with
O2. A solution of dimethyl sulfide (171 mg, 2.75 mmol) in dry
CH2Cl2 (5 mL) was added, the mixture was allowed to reach
rt over 14 h, and the organic layer was washed with saturated
aqueous NaHCO3 (20 mL) and brine (20 mL), dried, filtered,
and evaporated to give the ketone 24 (360 mg, 91%) as a
from the enantiomeric substrate in the same manner; [R]19
D
-55.5° (c 1.0, CHCl3); spectral and chromatographic properties
identical with (1R,4R,5S)-26.
(1R ,4R ,5S )-4-H yd r oxy-8-m e t h yl-8-a za b icyclo[3.2.1]-
octa n o[2,3-c]p yr id in e (27). To a mixture of alcohol 26 (22.5
mg, 0.13 mmol) and formaldehyde (37%, 84 mg, 1.03 mmol)
in dichloroethane (5.5 mL) was added sodium triacetoxyboro-
hydride (108 mg, 0.51 mmol), and the mixture was stirred
under nitrogen at room temperature for 2 h. Aqueous 1 M
NaOH (5 mL) was added, the mixture was extracted with IPA/
CHCl3 (1/3, 10 mL × 3), and the combined organic extract was
dried, filtered, and evaporated. The residue was chromato-
graphed (SiO2, MeOH saturated with NH3/CH2Cl2, 1/10) to give
22 mg (91%) of the N-methyl alcohol 27 as a colorless oil: 1H
NMR δ 1.65-1.71 (m, 1H), 1.97-2.04 (m, 2H), 2.29-2.39 (m,
1H), 2.46 (s, 3H), 3.44 (t, J ) 5.5, 1H), 3.94 (d, J ) 5.9, 1H),
5.12 (d, J ) 5.2, 1H), 7.40 (d, J ) 5.0, 1H), 8.22 (s, 1H), 8.42
(d, J ) 5.0, 1H); 13C NMR δ 19.6, 31.5, 39.9, 62.6, 65.7, 69.7,
122.5, 137.0, 145.4, 145.5, 148.4. HRMS (EI) Calcd for
colorless oil which was used directly for the next reaction:
1
[R]20 +44.0° (c 1.0, CHCl3; H NMR, rotamers, 2/1, δ 1.68-
D
1.94 (m, 2H), 2.00 (s, 2H), 2.02 (s, 1H), 2.25-2.70 (m, 2H), 4.71
(d, J ) 8.5, 0.67H), 5.17 (m, 0.67H), 5.71 (d, J ) 6.6, 0.67H),
7.73 (d, J ) 4.9, 0.67H), 7.77 (d, J ) 4.9, 0.33H), 8.71 (m, 1H),
8.75 (s, 1H); 13C NMR, rotamers, δ 21.9, 22.3, 23.6, 25.5, 30.0,
32.0, 54.0, 57.7, 62.2, 65.1, 120.5, 120.9, 135.3, 146.4, 147.8,
150.2, 150.8, 168.0, 193.1.
(1S,5R)-8-Acetyl-4-oxo-8-a za bicyclo[3.2.1]octa n o[2,3-c]-
p yr id in e ((1S,5R)-24), structure not shown, was prepared
from the enantiomeric substrate in the same manner; [R]19
D
C
11H14N2O 190.1106. Found: 190.1106. A small amount of 27
-45.2° (c 1.0, CHCl3); spectral and chromatographic properties
identical with (1R,5S)-24. Anal. Calcd for C12 H12 N2O2: C,
66.7; H, 5.6; N, 13.0. Found: C, 66.3; H, 5.7; N, 12.7.
was treated with excess 2 M HCl, and the water was removed
under reduced pressure. The residue was recrystallized from
MeOH/EtOAc to give the HCl salt of 27 as colorless crystals:
mp 208-209 °C. Anal. Calcd for C11H14N2O‚HCl: C, 58.3; H,
6.7; N, 12.4. Found: C, 57.9; H, 6.7; N, 12.1.
(1R ,4R ,5S )-8-Ace t yl-4-h yd r oxy-8-a za b icyclo[3.2.1]-
octa n o[2,3-c]p yr id in e (25). To a solution of ketone 24 (250
mg, 1.16 mmol) in MeOH (15 mL) at -20 °C was added NaBH4
(60 mg, 1.58 mmol) in portions over 10 min, and then the
mixture was allowed to reach 0 °C and, after 2 h, was
evaporated. The residue was dissolved in 1 M HCl and
evaporated again, and the residue was partitioned between
aqueous NaHCO3 (20 mL) and CH2Cl2 (20 mL). The aqueous
layer was extracted with CHCl3/IPA 3/1 (20 mL × 4), and the
combined organic layer was dried, filtered, and evaporated to
give alcohol 25 as colorless crystals (210 mg, 83%) which were
recrystallized from EtOAc before use in the next reaction:
[R]20D +22.6° (c 1.0, CHCl3); mp 174-176 °C (EtOAc); 1H NMR,
rotamers, 3/1, 1.70-1.92 (m, 1H), 2.07 (s, major, 2.25H), 2.10
(s, minor, 0.75H), 1.95-2.20 (m, 3H), 4.38 (m, minor, 0.25H),
4.90 (m, major, 0.75H), 4.87 (d, J ) 5.4, major, 0.75H), 5.07
(d, J ) 5.1, minor, 0.25H), 5.16 (d, J ) 5.0, major, 0.75H), 5.47
(d, J ) 5.3, minor, 0.25H), 7.44 (d, J ) 5.1, minor, 0.25H),
7.50 (d, J ) 5.0, major, 0.75H), 8.28, 8.32 (s, major, 0.75H),
8.32 (s, minor, 0.25H), 8.41 (d, J ) 5.1, minor, 0.25H), 8.46 (d,
J ) 5.0, major, 0.75H); 13C NMR, rotamers, 20.1, 21.9, 33.4,
35.2, 52.1, 55.9, 57.4, 59.3, 68.5, 123.6, 144.4, 149.5, 156.0,
168.0. Anal. Calcd for C12H14N2O2: C, 66.0; H, 6.5; N, 12.8.
Found: C, 65.9; H, 6.5; N, 12.9.
(1S ,4S ,5R )-4-H yd r oxy-8-m e t h yl-8-a za b icyclo[3.2.1]-
octa n o[2,3-c]p yr id in e (27) was prepared from the enantio-
meric substrate in the same manner: [R]21 -56.0 (c 0.99,
D
CHCl3); spectral and chromatographic properties identical with
(1R,4R,5S)-27.
(1R ,5S )-4-Oxo-8-a za b icyclo[3.2.1]oct a n o[2,3-c]p yr i-
d in e (28). The N-acetyl ketone 24 (300 mg, 1.39 mmol) was
converted to the hydrochloride salt of 28 (264 mg, 90%) and
then to the free base amino ketone by the procedure described
for the conversion of 25 to 26. Hydrochloride: 1H NMR (D2O)
δ 2.00-2.14 (m, 2H), 2.34-2.42 (m, 2H), 4.31 (d, J ) 7.3, 1H),
5.28 (d, J ) 5.5, 1H), 8.31 (d, J ) 5.5, 1H), 8.84 (d, J ) 5.5,
1H), 8.87 (s, 1H); 13C NMR (D2O) δ 20.6, 31.1, 56.7, 63.4, 93.2,
125.9, 134.0, 140.6, 143.8, 154.9. Free base amino ketone 28
(200 mg, 97%): mp 68-69 °C;[R]19 +75.9° (c 0.5, CHCl3); 1H
D
NMR 1.68-1.75 (m, 1H), 1.77-1.85 (m, 1H), 2.15-2.50 (m,
3H), 4.12 (d, J ) 8.0, 1H), 4.53 (d, J ) 6.1, 1H), 7.72 (d, J )
4.9, 1H), 8.63 (s, 1H), 8.67 (d, J ) 4.9, 1H); 13C NMR 24.2 (2),
31.1 (2), 55.7 (1), 64.5 (1), 119.7 (1), 134.7 (0), 142.6 (1), 146.9
(1), 149.7 (0), 197.4 (0). HRMS (EI) Calcd for C10H10N2O (M+)
174.0793. Found: 174.0792.
(1S ,5R )-4-Oxo-8-a za b icyclo[3.2.1]oct a n o[2,3-c]p yr i-
d in e ((1S,5R)-28), structure not shown, was prepared from
the enantiomeric substrate in the same manner; [R]19D -74.4°
(c 0.5, CHCl3); spectral and chromatographic properties identi-
cal with (1R,5S)-28.
(1S,4S,5R)-8-Acetyl-4-h ydr oxy-8-azabicyclo[3.2.1]octan o-
[2,3-c]p yr id in e ((1S,4S,5R)-25), structure not shown, was
prepared from the enantiomeric substrate in the same manner;
[R]19 -21.4° (c 1.0, CHCl3); spectral and chromatographic
D
properties identical with (1R,4R,5S)-25.
(1R,4R,5S)-4-Hyd r oxy-8-a za bicyclo[3.2.1]octa n o[2,3-c]-
p yr id in e (26). A solution of N-acetyl alcohol 25 (240 mg, 1.10
mmol) in 1 M HCl (10 mL) was heated at 90 °C for 12 h. The
solution was allowed to cool and evaporated to give the
hydrochloride salt of 26 as an amorphous solid (215 mg,
91%): 1H NMR (D2O) δ 2.08-2.14 (m, 1H), 2.20-2.30 (m, 2H),
2.34-2.49 (m, 1H), 4.43 (m, 1H), 5.21 (d, J ) 6.1, 1H), 5.49 (d,
J ) 4.9, 1H), 8.19 (d, J ) 6.2, 1H), 8.75 (s, 1H).
The HCl salt of 26 (200 mg, 0.94 mmol) was partitioned
between IPA/CHCl3 (1/3, 20 mL) and 1 M KOH (10 mL), the
aqueous layer was washed with IPA/CHCl3 (1/3, 50 mL × 2),
and the combined organic layer was dried, filtered, and
evaporated to give the free amino alcohol 26 as a colorless oil
(160 mg, 97%) which was used directly for the next reaction:
1H NMR 1.85-1.93 (m, 2H), 1.98-2.12 (m, 2H), 3.80 (t, J )
6.3, 1H), 4.29 (d, J ) 5.3, 1H), 5.05 (d, J ) 5.0, 1H), 7.38 (d, J
) 5.0, 1H), 8.22 (s, 1H), 8.41 (d, J ) 5.0, 1H); 13C NMR δ 21.5
(2), 35.8 (2), 56.2 (1), 59.2 (1), 70.7 (1), 122.8 (1), 137.4 (0),
(1R,5S)-8-Aza bicyclo[3.2.1]octa n o[2,3-c]p yr id in e (29).
A solution of ketone 28 (83 mg, 0.48 mmol), hydrazine (65 mg,
85%), and KOH (55 mg, 0.96 mmol) in triethylene glycol (1
mL) was heated at 100 °C for 14 h. The solution was then
heated to 200 °C for a further 30 min, allowed to cool to room
temperature, and partitioned between NaHCO3 (10 mL) and
CH2Cl2 (10 mL). The aqueous phase was washed with CH2Cl2
(20 mL × 2), and the combined organic extract was dried,
filtered, and evaporated. The residue was dissolved in 1 M HCl
(2 mL) and evaporated. The solid was washed with EtOAc (5
mL × 2) and dried in vacuo to give the hydrochloride salt of
29 (86 mg, 92%): mp 59-60 °C. Anal. Calcd for C10H12N2‚HCl;
C, 61.1; H, 6.7; N, 14.2. Found: C, 61.1; H, 6.9; N, 14.2. By
the previously described procedure, the salt was converted to
the free base nornicotine analogue 29 as a yellow oil (68 mg,
97%): 1H NMR δ 1.52-1.62 (m, 1H), 1.85-1.94 (m, 1H), 2.06-
2.18 (m, 2H), 2.54 (d, J ) 15.5, 1H), 3.11 (dd, J ) 15.5, 5.0,
1H), 3.87 (m, 1H), 4.27 (d, J ) 5.6, 1H), 6.96 (d, J ) 5.0, 1H),

870 J . Org. Chem., Vol. 65, No. 3, 2000
Turner et al.
8.22 (s, 1H), 8.29 (d, J ) 5.0, 1H); 13C NMR δ 29.1(2), 36.2(2),
37.0(2), 52.9(1), 55.5(1), 124.6(1), 137.5(0), 142.0(1), 146.1(1),
148.0(1).
× 3). The combined organic extract was dried, filtered, and
evaporated, and the residue was chromatographed (SiO2, Et3N/
MeOH saturated with NH3/CHCl3/EtOAc(6/20/100/100)) to
give 102.5 mg, 58% yield, of 30: 1H NMR (CD3OD) δ 1.60-
1.65 (m, 1H), 2.00-2.17 (m, 2H), 2.34-2.41 (m, 1H), 2.42 (s,
3H), 3.48 (d, J ) 6.9, 1H), 3.70 (d, J ) 10.4, 1H), 3.77 (d, J )
10.3, 1H), 4.14 (d, J ) 6.1, 1H), 7.51 (d, J ) 5.2, 1H), 8.23 (s,
1H), 8.38 (d, J ) 5.0, 1H); 13C NMR (CD3OD) δ 20.7, 31.0, 41.5,
64.7, 70.2, 71.7, 75.9, 124.0, 140.3, 145.5, 148.7, 148.8. By the
previously described procedure the HCl salt of 30 was obtained
as colorless crystals: mp 226-227 °C. Anal. Calcd for
(1S ,5R )-8-Aza b ic y c lo [3.2.1]o c t a n o [2,3-c]p y r id in e
((1S,5R)-29), structure not shown, was prepared from the
enantiomeric substrate in the same manner; spectral and
chromatographic properties identical with (1R,5S)-29; [R]21
-12.5 (c 0.43, CHCl3).
D
(1R,5S)-8-Meth yl-8-a za bicyclo[3.2.1]octa n o[2,3-c]p yr i-
d in e (3). To a mixture of 29 (72.7 mg, 0.45 mmol) and
formaldehyde (37%, 336 mg, 4.14 mmol) in dichloroethane (8
mL) was added sodium triacetoxyborohydride (434 mg, 2.05
mmol), and the mixture was stirred under nitrogen at room
temperature for 3 h. Aqueous 1 M NaOH (5 mL) was added,
the mixture was extracted with IPA/CHCl3 (1/3, 10 mL × 3),
and the combin‚d organic extract was dried, filtered, and
evaporated. The residue was chromatographed (SiO2, MeOH
saturated with NH3/CH2Cl2 (1/25)) to give 67 mg (85%) of the
nicotine analogue 3 as a colorless oil: 1H NMR δ 1.53-1.64
(m, 1H), 1.76-1.82 (m, 1H), 2.20-2.36 (m, 2H), 2.37 (s, 3H),
2.41 (d, J ) 17.8, 1H), 3.19 (dd, J ) 17.8, 4.9, 1H), 3.48 (dd, J
) 6.4, 5.4, 1H), 3.93 (d, J ) 5.9, 1H), 6.99 (d, J ) 5.0, 1H),
8.23 (s, 1H), 8.34 (d, J ) 5.0, 1H); 13C NMR δ 29.0, 33.0, 34.5,
36.7, 57.8, 61.1, 123.9, 136.4, 142.0, 147.1, 147.6. HRMS (EI)
calcd for C11H14N2(M+) 174,1157. Found 174.1159. By the
previously described procedure the HCl salt of 3 was obtained
as colorless crystals: mp 257-259 °C. Anal. Calcd for C11H14
N2‚2HCl‚H2O: C, 49.8; H, 6.8; N, 10.6. Found: C, 50.3; H, 6.5;
N, 10.8.
C
12H16N2O2‚HCl: C, 56.1; H, 6.7; N, 10.9. Found: C, 55.8; H,
6.6; N, 10.6.
(1S ,5R )-4-H yd r oxy-4-(h yd r oxym e t h yl)-8-m e t h yl-8-
a za bicyclo[3.2.1]octa n o[2,3-c]p yr id in e ((1S,5R)-30), struc-
ture not shown, was prepared from the enantiomeric substrate
in the same manner: [R]21 -76.7 (c 0.45, MeOH); spectral
D
and chromatographic properties identical with (1R,5S)-30.
(1R,5S-4,8-Dim eth yl-4-(h yd r oxym eth yl)-8-a za bicyclo-
[3.2.1]octa n o[2,3-c]p yr id in e ((1R,5S)-31). A solution of 29
(90 mg, 0.56 mmol), formaldehyde (37%, 574 mg, 7.07 mmol),
and formic acid (646 mg, 14.0 mmol) in water (1.5 mL) was
refluxed under nitrogen for 3 d and allowed to cool to room
temperature. Aqueous 1 M NaOH (20 mL) was added and the
mixture extracted with IPA/CHCl3 (1/3, 30 mLx 3). The
combined organic extract was dried, filtered, and evaporated,
and the residue was chromatographed (SiO2, MeOH saturated
with NH3/CH2Cl2 (6.5/100)) to give 74 mg (63%) of 31: 1H NMR
δ 1.13 (s, 3H), 1.67-1.78 (m, 2H), 2.02-2.10 (m, 1H), 2.27-
2.40 (m, 1H), 2.41 (s, 3H), 3.24 (d, J ) 7.7, 1H), 3.60 (d, J )
10.2, 1H), 3.84 (d, J ) 10.2, 1H), 4.02 (d, J ) 6.1, 1H), 7.16 (d,
J ) 5.2, 1H), 8.24 (s, 1H), 8.44 (d, J ) 5.2, 1H); 13C NMR δ
20.2, 21.8, 30.4, 40.4, 43.5, 63.3, 72.0, 76.0, 121.3, 138.0, 145.6,
147.8, 148.9. HRMS (EI) calcd for C13H18N2O (M+) 218.1419.
Found 218.1421.
(1S,5R)-8-Meth yl-8-a za bicyclo[3.2.1]octa n o[2,3-c]p yr i-
d in e ((1S,5R)-3), structure not shown, was prepared from the
enantiomeric substrate in the same manner; spectral and
chromatographic properties identical with (1R,5S)-3: [R]21
D
-77.3 (c 1.12, CHCl3). HRMS (EI) calcd for C11H14N2 (M+)
174.1157. Found: 174.1157.
(1R ,5S )-4-H yd r oxy-4-(h yd r oxym e t h yl)-8-m e t h yl-8-
a za bicyclo[3.2.1]octa n o[2,3-c]p yr id in e ((1R,5S)-30). A so-
lution of 26 (141 mg, 0.80 mmol), formaldehyde (37%, 819 mg,
10.1 mmol), and formic acid (922 mg, 20.0 mmol) in water (2
mL) was heated under nitrogen at 100 °C for 14 h and allowed
to cool to room temperature. Aqueous 2 M K2CO3 (25 mL) was
added and the mixture extracted with IPA/CHCl3 (1/3, 30 mL
(1S,5R-4,8-Dim eth yl-4-(h yd r oxym eth yl)-8-a za bicyclo-
[3.2.1]oct a n o[2,3-c]p yr id in e ((1S,5R)-31), structure not
shown, was prepared from the enantiomeric substrate in the
same manner: [R]21 -118.3 (c 0.93, CHCl3); spectral and
D
chromatographic properties identical with (1R,5S)-31.
J O991609P