Synthesis of enantiopure 1-azabicyclo[3.2.2]nonanes via stereoselective capture of chiral carbocations.

Article abstract of DOI:10.1021/ol0057378

[reaction: see text] A new class of doubly functionalized and enantiomerically pure 1-azabicyclo[3.2.2]nonanes derived from quincorine and quincoridine is described. 2,5-Disubstituted quinuclidines with a C9-mesyloxy group were easily transformed into the

Full text of DOI:10.1021/ol0057378

ORGANIC
LETTERS
2000
Vol. 2, No. 12
1661-1664
Synthesis of Enantiopure
1-Azabicyclo[3.2.2]nonanes via
Stereoselective Capture of Chiral
Carbocations
Stefanie Ro1per,† Jens Frackenpohl,† Olaf Schrake,† Rudolf Wartchow,‡ and
,†
H. M. R. Hoffmann*
Department of Organic Chemistry, UniVersity of HannoVer, Schneiderberg 1b,
D-30167 HannoVer, Germany, and Department of Inorganic Chemistry,
UniVersity of HannoVer, Callinstrasse 9, D-30167 HannoVer, Germany
hoffmann@mbox.oci.uni-hannoVer.de
Received February 29, 2000
ABSTRACT
A new class of doubly functionalized and enantiomerically pure 1-azabicyclo[3.2.2]nonanes derived from quincorine and quincoridine is described.
2,5-Disubstituted quinuclidines with a C9-mesyloxy group were easily transformed into the corresponding halides upon treatment with lithium
salts. Subsequent silver salt-mediated ring expansion stereoselectively furnished the title azabicyclics. Chiral carbocations which are
configurationally stable and nonplanar are postulated to account for the striking stereoselectivity of the capture of external nucleophile.
5-Ethynyl-2-iodomethylquinuclidines afford the r-benzoyloxy amines rather than r-methoxy amines, even in MeOH.
Azabicyclic systems1 are common building blocks in me-
dicinal chemistry and are structural motifs in natural products,
especially alkaloids including Cinchona species. Monosub-
stituted 1-azabicyclo[2.2.2]octanes play an important role in
modern medicinal chemistry as the quinuclidine nucleus has
been found to be a good mimic for the quaternary nitrogen
in acetylcholine.2 Quinuclidine derivatives are able to block
parasympathetic nervous system, thus preventing the passage
of nerve impulses.6 Anatoxin-a with a 9-azabicyclo[4.2.1]-
nonane ring system acts as a potent agonist for the nicotinic
acetylcholine receptor.7 Substituted 1-azabicyclo[3.2.2]-
(3) Flippin, L. A.; Carter, D. S.; Berger, J.; Clark, R. D.; Bonhaus, D.
W.; Leung, E.; Eglen, R. M. Bioorg. Med. Chem. Lett. 1996, 6, 477. Clark,
R. D.; Weinhardt, K. K.; Berger, J.; Lee, C.-H.; Leung, E.; Wong, E. H.
F.; Smith, W. L.; Eglen, R. M. Bioorg. Med. Chem. Lett. 1993, 3, 1375.
Langlois, M.; Soulier, J. L.; Allainmat, M.; Shen, S.; Gallais, C. Bioorg.
Med. Chem. Lett. 1993, 3, 1555.
(4) Fong, T. M.; Cascieri, M. A.; Yu, H.; Bansai, A.; Swain, C.; Strader,
C. D. Nature 1993, 362, 350. Snider, R. M.; Constantine, J. W.; Lowe, J.
A., III; Longo, K. P.; Lebel, W. S.; Woody, H. A.; Drozda, S. E.; Desai,
M. C.; Vinick, F. J.; Spencer, R. W.; Hess, H.-J. Science 1991, 251, 435.
(5) Brown, G. R.; Foubister, A. J.; Freeman, S.; McTaggart, F.; Mirrlees,
D. J.; Reid, A. C.; Smith, G. J.; Taylor, M. J.; Thomason, D. A.; Whittamore,
P. R. O. Bioorg. Med. Chem. Lett. 1997, 7, 597. McTaggart, F.; Brown, G.
R.; Davidson, R. G.; Freeman, S.; Holdgate, G. A.; Mallion, K. B.; Mirrlees,
D. J.; Smith, G. J.; Ward, W. H. J. Biochem. Pharmacol. 1996, 51, 1477.
(6) Fodor, G.; Dharanipragada, P. Nat. Prod. Rep. 1994, 11, 443.
3
5-HT3 and NK1 receptors4 and to act as squalene synthase
inhibitors.5 Tropane alkaloids with an 8-azabicyclo[3.2.1]-
octane moiety are classified as anticholinergics as they
compete with acetylcholine for the muscarinic site of the
† Department of Organic Chemistry.
‡ Department of Inorganic Chemistry.
(1) Chen, Z.; Trudell, M. L. Chem. ReV. 1996, 96, 1179.
(2) Wadsworth, H. J.; Jenkins, S. M.; Orlek, B. S.; Cassidy, F.; Clark,
M. S. G.; Brown, F.; Riley, G. J.; Graves, D.; Hawkins, J.; Naylor, C. B.
J. Med. Chem. 1992, 35, 1280.
10.1021/ol0057378 CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/24/2000

nonanes are already used as precursors for the synthesis of
rigid substance P antagonists.8 Consequently, general syn-
thetic routes to these azabicycles are of considerable interest.
Although the lower azabicyclics have been studied exten-
sively, much less is known about the higher [3.2.2]-
homologues.9 Before the advent of conformational analysis,
Prelog reported the preparation of parent 1-azabicyclo[3.2.2]-
nonane A by double intramolecular cyclization under forcing
conditions (Scheme 1).10 More recently, Pearson described
Table 1. Ring Expansion of 2-Iodomethyl-2-
azabicyclo[2.2.2]octane 2 to 3-OMe under Various Conditions
Scheme 1. Selected 1-Azabicyclo[3.2.2]nonanes Described in
the Literature
silver salt,
equiv
time
[h]
temp
[°C]
yield
[%]
entry
solvent
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH/pyr
MeOH/pyr
MeOH
Me2CO
MeOH
MeOH
MeOH
MeOH
1
2
3
4
5
6
7
8
9
10
11
12
13
AgOTf, 1.0
AgOTf, 1.0
AgOTf, 1.5
AgOTf, 1.1
AgOTf, 1.0
AgOTf, 1.0
AgOTf, 1.0
AgOAc, 1.5
AgOBz, 1.1
AgOBz, 1.0
AgOBz, 1.2
AgOBz, 1.2
AgOBz, 1.1
1
3
1
20
6
16
4
8
18
4
22
22
22
22
22
22
110
22
50
22
50
50
0
19
30
28a
39a
28
21
25a
10
76b
39
another route to these amines B via an intramolecular
Schmidt reaction involving carbocation chemistry.11 To our
knowledge most of the [3.2.2]-azabicycles reported in the
literature were either achiral or racemic mixtures.
Results and Discussion. We report herein the efficient
three-step synthesis of a variety of rearranged bridgehead
amines from functionalized 2-hydroxymethyl quinuclidines.
O-Mesylation of quincorine 1 (QCI) and quincoridine 4
(QCD) proceeds smoothly and is followed by lithium halide-
promoted SN2 displacement. The use of lithium salts in
dioxane is crucial for C9-halogenation, presumably because
the lithium cation is chelated by the â-amino mesylate moiety
exposing the rear side of CH2-OMs to external nucleophilic
attack.12 The resulting â-amino iodides were treated with a
reactive silver salt in MeOH as polar protic solvent and also
in anhydrous acetone. Reaction of â-amino iodide 2 with
AgOTf in MeOH at 22 °C provided rearranged R-amino ether
3-OMe in 19-30% yield (Table 1). Similarly, pseudoenan-
tiomeric13 QCD-based â-amino iodide 5 diastereoselectively
afforded R-amino ether 6-OMe. Longer reaction times did
not increase the yield significantly. The silver salt-mediated
synthesis of 1-azabicyclo[3.2.2]octane 3-OMe was optimized
6
68
86
68
20
2.5c
a Epimeric mixture with respect to carbon C2. b 3-OBz was obtained
instead of 3-OMe. c The reaction mixture was sonicated for 2.5 h.
with respect to solvent, silver counterion, and temperature.
Use of an excess of AgOTf promoted the epimerization of
3-OMe at carbon C2 without leading to higher yields (Table
1, entries 3 and 4).
Ring expansion with AgOTf in the presence of external
base at 22 °C was less efficient (Table 1, entries 6 and 7).
Therefore, silver salts with less reactive counterions were
examined next. While AgOAc provided only traces of
product, 3-OMe was obtained diastereoselectively in high
yield upon treatment with AgOBz in MeOH after extended
reaction times or with ultrasound at 0 °C. A change of solvent
from methanol to anhydrous acetone furnished the corre-
sponding benzoate 3-OBz (entry 9). The stereochemical
outcome of the rearrangement was not affected by this
variation of solvent.
1. Tolerance to Additional Functionality. To evaluate
the scope of this novel route to 1-azabicyclo[3.2.2]nonanes,
various functionalized 2-iodomethylquinuclidines were pre-
pared.14 Ethyl-substituted quinuclidines 7 and 9 were submit-
ted to the optimized rearrangement conditions and gave
R-amino ethers 8 and 10 in fair yield (up to 78%). Iodo ester
11 was more polar than parent â-amino iodides 2 and 5,
(7) Parsons, P. J.; Camp, N. P.; Edwards, N.; Sumoreeah, L. R.
Tetrahedron 2000, 56, 309.
(8) Lowe, J. A., III; Drozda, S. E.; McLean, S.; Bryce, D. K.; Crawford,
R. T.; Snider, R. M.; Longo, K. R.; Nagahisa, A.; Tsuchiya, M. J. Med.
Chem. 1994, 37, 2831. Lowe, J. A., III; Drozda, S. E.; Snider, R. M.; Longo,
K. P.; Rizzi, J. P. Bioorg. Med. Chem. Lett. 1993, 3, 921. Gether, U.;
Nilsson, L.; Lowe, J. A., III; Schwartz, T. W. J. Biol. Chem. 1994, 269,
23959. Lowe, J. A., III. PCT Int. Appl. WO9215585. Caruso, F. S. PCT
Int. Appl. WO 9907413.
(9) Davies, H. M. L.; Hodges, L. M.; Thornley, C. T. Tetrahedron Lett.
1998, 39, 2707. Vogel, C.; Delavier, P. Tetrahedron Lett. 1989, 30, 1789.
Bosch, J.; Bonjoch, J. Heterocycles 1980, 14, 505. Jeyaraman, R.; Avila,
S. Chem. ReV. 1981, 81, 149. Sakamoto, M.; Watanabe, S.; Fujita, T.;
Yanase, T. J. Org. Chem. 1990, 55, 2986.
(10) Prelog, V.; Cerkovnikov, E. Liebigs Ann. 1937, 532, 83. Ruggles,
C. J.; Halpern, A. M. J. Am. Chem. Soc. 1988, 110, 5692.
(11) Pearson, W. H.; Walavalkar, R.; Schkeryantz, J. M.; Fang, W.-K.;
Blickensdorf, J. D. J. Am. Chem. Soc. 1993, 115, 10183.
(12) Schrake, O.; Franz, M. H.; Wartchow, R.; Hoffmann, H. M. R.
Tetrahedron 2000, 56, in press.
(14) Schrake, O.; Rahn, V. S.; Frackenpohl, J.; Braje, W. M.; Hoffmann,
H. M. R. Org. Lett. 1999, 1, 1607. Frackenpohl, J.; Hoffmann, H. M. R. J.
Org. Chem. 2000, 65, in press.
(13) Replacement of the vinyl group by hydrogen generates enantiomeric
pairs with the 2S and 2R configurations, respectively.
1662
Org. Lett., Vol. 2, No. 12, 2000

and the ester group appeared to slow the SN1 like ring
expansion as full conversion was only observed after 40 h.
Nonetheless, the yield of the desired diastereomerically and
enantiomerically pure ester 12 remained high (75%) (Scheme
2).
proceeded spot-to-spot, affording diastereomerically pure
rearranged alkynes 18a-c and 20 in respectable yields (70-
82%) (Scheme 3, Table 3). Thus, substituents X in the
p-position of the phenylethynyl side chain affected neither
rate nor yield.
Scheme 3. Rearrangement of 10,11-Didehydroquincorine and
Scheme 2. Ring Expansion of C9-Iodinated Alkyl-Substituted
Quinuclidines and Quinuclidine Estersa
10,11-Didehydroquincoridine Iodides
a
(i) AgOBz, MeOH, 50 °C, 20 h.
We were pleased to find that even 2-iodomethyl ketones
13 and 15 afforded 1-azabicyclo[3.2.2]nonan-6-ones 14 and
16, respectively, although in a more sluggish reaction.
Surprisingly, given the high stereoselectivity exhibited by
the other silver triflate-mediated ring expansions, partial
epimerization was observed upon treatment of iodo ketones
13 and 15 with AgOTf at 22 °C (14 f 80:20 and 16 f
68:32) (Table 2). AgOBz-promoted rearrangement of
The terminal iodo alkynes 21 and 23, however, confounded
expectations by yielding, on reaction with AgOBz in MeOH,
benzoates 22-OBz and 24-OBz rather than the anticipated
R-methoxy amines 22-OMe and 24-OMe. The desired
hemiaminal 22-OMe could only be prepared upon treatment
of iodide precursors with AgNO3 in MeOH (Scheme 3). Iodo
alkynes 21 and 23 proved to be more polar than vinylic (2,
5) and ethyl analogues (7, 9): preassociation with AgOBz
seems to influence capture of the external nucleophile (OBz
versus MeOH).
Table 2. Ring Expansion of 2-Iodomethylquinuclidin-5-ones
ratio of epimers
3. Spectroscopic, Conformational and Mechanistic
Considerations. In our studies, configuration and conforma-
tion of rearranged 1-azabicyclo[3.2.2]nonanes and their
iodo
silver salt
yield
[%]
entry ketone (1.1 equiv, 50 °C)
14 [%]
16 [%]
1
2
3
4
5
13
13
15
15
15
AgOTf (i)
AgOBz (ii)
AgOTf (i)
AgOBz (ii)
1. AgOTf (i),
2. HCl
47
76
41
72
32
80
100
32
20
68
100
52
Table 3. Ring Expansion of 2-Iodomethylalkynes
48
2-iodo-
1-azabicyclo-
[3.2.2]nonane
entry
methylalkyne
X
yield [%]
1
2
3
4
5
6
7
17a
17b
17c
19
21
21
H
NO2
CO2Et
H
H
H
H
18a
18b
18c
20
22-OBz
22-OMe
24-OBz
82
77
74
70
48
61
43
â-amino keto iodides 13 and 15 gave epimerically pure (GC,
NMR) ketones 14 and 16, respectively.
2. Interception of Silver Counterion in Solvent MeOH.
Arylated alkynes 17a-c and 19 were readily available from
parent terminal alkynes15 by Sonogashira coupling16 and
subsequent C9-iodination. AgOBz-mediated ring expansions
23
Org. Lett., Vol. 2, No. 12, 2000
1663

azabicyclo[2.2.2]octane precursors were determined by NMR
spectroscopy and by X-ray analysis. The stereochemical
outcome of ring expansion reactions and the configuration
at carbon C2 could easily be assigned by NOE interactions
of protons H2, H7endo, and H8endo. QCI-based 2R-configured
[3.2.2]-azabicyclic 18b showed strong interactions between
H2 and H7endo, H3 and H4 (4 f 10%). Further evidence for
the equatorial position of the methoxy group was provided
by X-ray analysis of alkyne 18b (Scheme 4).17
ature.19 The double stereochemical label facilitates evaluation
of both leakage from QCI to pseudoenantiomeric QCD and
stereoselectivity of nucleophilic attack of the cation. It is
striking that although a carbocation is involved in our
rearrangement, the configuration at carbon C2 is retained
throughout the reaction, and equilibration between the
postulated QCI and QCD cations is not observed (Scheme
5). We suggest that iminium resonance of the cation is
Scheme 5. Mechanism of Silver-Mediated Ring Expansion via
Pseudoenantiomeric13 Carbocations
Scheme 4. NOE and X-ray Analysis of 18b
accompanied by some pyramidalization of the carbocation.
This has the effect of directing external capture of the
nucleophile to one π-face only. The carbocation of the
quinuclidin-5-one system is more prone to bridge flipping
(weaker C-N iminium bond) than the system with vinyl side
chain (stronger C-N iminium bond). The nucleophilic shift
of C3 from C2 to C9 is stereoelectronically favored if the
migrating C2-C3 bond is antiperiplanar to the C9-X bond
as well as to the nitrogen lone pair. The crystal structure of
a C9-brominated QCD analogue which is similar to iodo-
methyl precursor 15 fulfills the criterion of antiperiplanarity,
with torsion angle Φ (C3-C2-C9-X) ) 166.5°.20
Conclusion. A simple stereoselective one-pot synthesis
of a new class of azabicycles has been accomplished.
Currently, more than a dozen of the title azabicyclics have
been prepared. They are of potential therapeutic and phar-
maceutical interest. In addition, functionalized and substituted
forms of these compounds should be useful as building
blocks for asymmetric synthesis. The rearrangement proceeds
under mild SN1-like conditions and tolerates additional
functionalities such as carbonyl and ester groups and alkynes.
After optimization, no crossover from the QCI into the QCD
series and vice versa occurs. Preliminary evaluation of
biological activity suggests that our [3.2.2]-azabicyclics are
nontoxic,21 unlike quinidine and anatoxin-a.
Throughout our experiments QCI consistently gave higher
yields of ring-expanded azabicycles than the corresponding
QCD derivatives. We attribute this to interference of the C5-
side chain with the emerging ring-expanded system. The
mechanism of the silver salt-mediated rearrangement is
assumed to involve a nucleophilic shift of C3 from C2 to
C9 to generate a strained, nonplanar iminium ion instead of
an aziridinium ion which is reported to be the key intermedi-
ate in various rearrangements of â-amino alcohols such as
the ring enlargement of an L-proline derivative in the
synthesis of (-)-pseudoconhydrine.18 Bicyclic systems with
strained bridgehead imine double bonds (E and Z isomers)
have been obtained in a matrix in the dark at low temper-
(15) Schrake, O.; Braje, W. M.; Hoffmann, H. M. R.; Wartchow, R.
Tetrahedron: Asymmetry 1998, 9, 3717. Braje, W. M.; Frackenpohl, J.;
Schrake, O.; Wartchow, R.; Beil, W.; Hoffmann, H. M. R. HelV. Chim.
Acta 2000, 83, 777.
(16) Frackenpohl, J. Ph.D. Thesis, University Hannover, 2000. Braje,
W. M. Ph.D. Thesis, University Hannover, 1999.
(17) Wartchow, R.; Frackenpohl, J.; Ro¨per, S.; Hoffmann, H. M. R.
Z. Kristallogr. NCS 2000, 215, in press. Norrby, P.-O.; Kolb, H. C.;
Sharpless, K. B. J. Am. Chem. Soc. 1994, 116, 8470. Wartchow, R.; Schrake,
O.; Braje, W. M.; Hoffmann, H. M. R. Z. Kristallogr. NCS 1999, 214, 285.
von Riesen, C.; Wartchow, R.; Hoffmann, H. M. R. Z. Kristallogr. NCS
1998, 213, 483.
(18) Wilken, J.; Kossenjans, M.; Saak, W.; Haase, D.; Pohl, S.; Martens,
J. Liebigs Ann./Recueil 1997, 573. Cossy, J.; Dumas, C.; Pardo, D. G. Eur.
J. Org. Chem. 1999, 1693.
(19) Sheridan, R. S.; Ganzer, G. A. J. Am. Chem. Soc. 1983, 105, 6158.
Radziszewski, J. G.; Downing, J. W.; Wentrup, C.; Kaszynski, P.;
Jawdosiuk, M.; Kovacic, P.; Michl, J. J. Am. Chem. Soc. 1985, 107, 2799.
(20) Wartchow, R.; Frackenpohl, J.; Hoffmann, H. M. R. Submitted.
Braje, W. M.; Wartchow, R.; Hoffmann, H. M. R. Angew. Chem. 1999,
111, 2698; Angew. Chem., Int. Ed. 1999, 38, 2540.
(21) See Supporting Information and Wagner, S.; Beil, W.; Mai, U. E.
H.; Bokemeyer, C.; Meyer, H. J.; Manns, M. P. Pharmacology 1994, 49,
226.
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft (S.R.), the Fonds der Chemischen Industrie
(J.F.), and Graduiertenfo¨rderung des Landes Niedersachsen
(O.S.) for Ph.D. fellowships, Buchler GmbH Braunschweig
for a generous gift of QCI and QCD, Stefan Neumann for
experimental contributions, and Lars Ole Haustedt, Ulrike
Eggert, and Thomas Dane for their help.
Supporting Information Available: X-ray data for 18b
and spectroscopic data for each new compound. This material
is available free of charge via the Internet at http://pubs.acs.org.
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