Asymmetric synthesis of (+)- and (-)-7-(3-pyridyl)-1-azabicyclo[2.2.1]heptane as conformationally restricted analogues of nicotine

Article abstract of DOI:10.1016/S0040-4039(01)01985-2

Both enantiomers of the conformationally restricted nicotine analogue 7-(3-pyridyl)-1-azabicyclo[2.2.1]heptane were prepared in a convenient, asymmetric synthetic route.

Full text of DOI:10.1016/S0040-4039(01)01985-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 177–179
Asymmetric synthesis of (+)- and
(−)-7-(3-pyridyl)-1-azabicyclo[2.2.1]heptane as conformationally
restricted analogues of nicotine
Thomas Ullrich,* Dieter Binder and Michael Pyerin
Laboratory of Medicinal Chemistry, Institute of Organic Chemistry, Vienna University of Technology, Getreidemarkt 9/154,
A-1060 Vienna, Austria
Received 30 August 2001; accepted 22 October 2001
Abstract—Both enantiomers of the conformationally restricted nicotine analogue 7-(3-pyridyl)-1-azabicyclo[2.2.1]heptane were
prepared in a convenient, asymmetric synthetic route. © 2002 Elsevier Science Ltd. All rights reserved.
Central nicotinic acetylcholine receptors (nAChRs)
have been implicated in cognitive and learning pro-
cesses, and their role in these processes allows them to
be a potential target for the treatment of Alzheimer’s
and other neurodegenerative diseases.1 Other findings
suggest that activation of these receptors also plays a
critical role in the antinociceptive effects of cholinergic
channel modulators.2 Recent reports3,4 described the
synthesis of racemic 7-(3-pyridyl)-1-azabicyclo[2.2.1]-
heptane (1), a conformationally restricted analogue of
nicotine (2), as a potential derivative for the prevention
and treatment of CNS disorders. The structural resem-
blance between nicotine (2) and its derivative is evident
in Fig. 1 (the ethylene bridge that connects the N-atom
with the C3-atom of the pyrrolidine ring accounts for
conformational restraint in 1). While the relatively low
enantioselectivity of nicotine has been an intriguing
phenomenon for many years,5 the premise that confor-
mational restraint of nicotine should enhance enan-
tioselectivity has been well established.6 We were
therefore interested in having both enantiomers of
1 available in large quantities for further biological
studies.
Caldwell et al.4 suggested several possible pathways to
generally achieve optical resolution of pyridine-substi-
tuted 1-azabicycloalkanes, including asymmetric syn-
thesis. We pondered all methods proposed, especially
those employing asymmetric addition across imine dou-
ble bonds, affording optically resolved amines. Eventu-
ally we built our enantioselective key steps on a method
described by Farkas et al.,7 who synthesized nor-doxpi-
comine from 1,3-dioxan-5-yl 3-pyridyl ketone via imine
formation with (S)-(−)-a-methylbenzylamine, dia-
stereoselective reduction to the secondary amine with
NaBH4 and catalytic cleavage of the benzyl group.
High asymmetry is attributed to distinct molecule prop-
erties which allow E,Z-stereoselectivity for imine for-
mation and—provided careful control of reaction
conditions—diastereoselectivity for reduction. By
replacement of the dioxanyl moiety with a 4-tetra-
hydropyranyl residue we provided a synthon for one-
pot cyclization to the azabicyclic compounds,
depending on a practical and high-yielding synthesis of
the ketone precursor 5 (Scheme 1).
N
N
CH3
N
N
1
2
Figure 1. Structures of 7-(3-pyridyl)-1-azabicyclo[2.2.1]-
heptane and nicotine.
Keywords: nicotine; conformational restriction; Stille coupling;
diastereoselective reduction.
* Corresponding author. Present Address: Laboratory of Medicinal
Chemistry, NIDDK, National Institutes of Health, Bethesda, MD
20817, USA. Tel.: +1-301-435-1917; fax: +1-301-402-0589; e-mail:
thomasu@intra.niddk.nih.gov
Employment of Pd(II)-salts in benzene under Stille
conditions8,9 allows for conversions of a broad range of
acyl halides to the corresponding pyridyl ketones. We
were able to improve the suggested reaction conditions
by using a catalytic amount of the Hermann–Beller
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01985-2

178
T. Ullrich et al. / Tetrahedron Letters 43 (2002) 177–179
O
O
SnBu3
ii
Cl
i
+
O
O
N
N
3
4
5
R3 R4
R6
R5
iii
R1
R2
v
N
O
N
N
7
1
O
N
a) R5 = H, R6 = 3-pyridyl
b) R5 = 3-pyridyl, R6 = H
a) R3 = H, R4 = Ph(Me)CHNH
b) R3 = Ph(Me)CHNH, R4 = H
6
a) R1 = H, R2 = Me
b) R1 = Me, R2 = H
iv
ee = 90%
c) R3 = H, R4 = NH2
d) R3 = NH2, R4 = H
Scheme 1. Reagents and conditions: (i) Pd catalyst, xylene, 120°C, 30 min, 65%; (ii) (S)- or (R)-a-methylbenzylamine, Et3N, TiCl4,
CH2Cl2, 0–25°C, 12 h, 83–86%; (iii) NaBH4, MeOH, −40°C, 86–89%; (iv) cyclohexene, 10% Pd–C, EtOH, HCl, 130°C, 6 h,
85–89%; (v) 62% HBr, 120°C (autoclave), 4 h; Na2CO3, H2O, reflux, 2 h, 65%.
palladacycle
trans-di(m-acetato)bis[o-(di-o-tolylphos-
was determined by derivatization with (S)-phenyl-
ethylisocyanate and 1H NMR interpretation. Both
enantiomers were obtained in 90% ee, matching the
result of the doxpicamine synthesis (88% ee).7 In ac-
cordance with patent literature,4 cyclization to the title
compounds (+)-1 and (−)-1 was accomplished with
ether cleavage in boiling 62% HBr and subsequent
basification (pH 9). This step could be conducted under
full retention of stereoconfiguration, and the optical
resolutions of (+)-1 and (−)-1 were confirmed to be 90%
ee, using (R)-(−)-1,1%-binaphthyl-2,2%-diyl hydrogen
phino)phenylmethyl]dipalladium(II), prepared from
palladium diacetate and tri(o-toluyl)phosphine.10 This
catalyst exhibits great temperature resistance, thus
allowing for Stille chemistry to be carried out in high-
boiling solvents rather than, for example, benzene.
(Tributylstannyl)pyridine (3) was prepared from com-
mercial tributyltin hydride and 3-bromopyridine, fol-
lowing a procedure described by Sandosham et al.,11
and reacted with tetrahydropyran-4-carbonyl chloride
(4) (prepared as reported by Radziszewskii et al.)12
under catalysis of only 0.5–1 mol% of Pd catalyst. In
order to establish a reasonable yield (65%), the cou-
pling reaction was performed at sufficiently high tem-
peratures, as the competing formation of symmetrically
coupled 3,3%-bipyridine could then be repressed. Thus,
yields decreased by more than 30% when the reaction
was carried out in xylene at 90°C or in benzene at 70°C.
Employment of the conventional catalyst PdCl2(PPh3)
at 70°C also afforded less than 30% of 5.
1
phosphate as an appropriate H NMR shift reagent.14
The absolute configurations of (+)-1 and (−)-1 were not
determined in this study. (+)-1 was obtained following
the pathway with (R)-methylbenzylamine, and (−)-1
resulted from the (S)-methylbenzylamine sequence.15
In summary, we prepared both enantiomers of 7-(3-
pyridyl)-1-azabicyclo[2.2.1]heptane (1) in 29% overall
yield, respectively, using a convenient route on a multi-
gram scale that is based on a thoroughly optimized
Stille acyl coupling reaction and diastereoselective
reduction of ketimines. The reported methodology will
be applied in the preparation of similar chiral analogues
of nicotine, and pharmacological evaluation will be
reported in due course.
Ketone 5 underwent stereoselective imine formation
with (R)- and (S)-a-methylbenzylamine, respectively,
providing single conformers 6 (anticipated syn geome-
try between the pyridyl and the a-methylbenzylamine
moieties), as suggested in the literature.7 Reduction was
carried out on both imines, using NaBH4 in MeOH.
The highest degree of stereoselectivity was found at
−40°C when 94% of the desired secondary amines 7a
and 7b were obtained in 90% de, respectively, whereas
at room temperature only 80% de resulted. Debenzyla-
tion to primary amines 7c and 7d was carried out in
cyclohexene as a catalytic hydrogen transfer reagent13
and 10% Pd–C in ethanol. No evidence of competing
hydrogenolysis of the pyridylꢀCH bond was found. The
reaction time reported in the literature (20 h)8 was
reduced by 70% when using an autoclave, thus allowing
for a higher reaction temperature (130°C) than that of
boiling cyclohexene (70°C). Optical purity of 7c and 7d
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