Directed lithiation on the quinuclidine ring system: the synthesis of 2,3-difunctionalised quinuclidines

Article abstract of DOI:10.1016/j.tetlet.2008.10.064

Lithiation of 3-methoxymethyl quinuclidine N-oxide occurs regioselectively to generate the 2-lithio 3-methoxymethyl derivative which can be trapped out with non-enolisable electrophiles to give 2,3-disubstituted quinuclidine N-oxide derivatives in good yi

Full text of DOI:10.1016/j.tetlet.2008.10.064

Tetrahedron Letters 49 (2008) 7416–7418
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Tetrahedron Letters
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Directed lithiation on the quinuclidine ring system:
the synthesis of 2,3-difunctionalised quinuclidines
a
a
b
b
Ian A. O’Neil a, , James Hitchin , Inder Bhamra , Alan P. Chorlton , David J. Tapolczay
*
a Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Crown Street, Liverpool L69 7ZD, UK
b Pharmorphix Ltd, 250 Milton Science Park, Cambridge CB4 0WE, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Lithiation of 3-methoxymethyl quinuclidine N-oxide occurs regioselectively to generate the 2-lithio
3-methoxymethyl derivative which can be trapped out with non-enolisable electrophiles to give 2,3-
disubstituted quinuclidine N-oxide derivatives in good yield.
Received 8 August 2008
Revised 3 October 2008
Accepted 15 October 2008
Available online 18 October 2008
Ó 2008 Published by Elsevier Ltd.
Keywords:
Amine oxide
Lithiation
Quinuclidine
The quinuclidine ring system is found in a number of natural
products including the cinchona alkaloids as exemplified by qui-
nine1 and quinidine, and in pharmacologically active compounds
such as CP-96,345,2 which is an NK1-receptor antagonist, and the
dopamine transporter inhibitor shown in Figure 1, which has po-
tential use in the treatment of cocaine addiction (Fig. 1).3 Modified
derivatives of quinine and quinidine are amongst the most widely
used and successful ligands in asymmetric synthesis.4 However,
methods for the synthesis of novel functionalised quinuclidines re-
main scarce, and to date most of them rely on the ring closure of an
appropriately functionalised piperidine derivative, as exemplified
in Stork’s synthesis of quinine.5 Historically, 2,3-disubstituted
quinuclidine systems have been synthesised from 3-quinuclidi-
none via its base-catalysed condensation with a variety of aromatic
aldehydes.6 These reactions invariably occur with concomitant
dehydration to afford the corresponding
a,b-unsaturated 3-qui-
nuclidinone systems, which then have to be manipulated in vari-
ous ways to incorporate further functionality.
As part of a programme directed towards new methods for the
synthesis of polyfunctionalised quinuclidines, we report a directed
lithiation on a functionalised quinuclidine N-oxide which gives di-
rect access to 2,3-difunctionalised quinuclidines. The lithiation of
OMe
OMe
OH
HN
OMe
Ph
Ph
H
N
N
Ph
Bu
OH
N
H
N
N
N
Quinidine
NK1-receptor antagonist
CP-96,345 (Pfizer)
Quinine
Dopamine transporter
inhibitor
Figure 1.
* Corresponding author. Tel.: +44 0 151 794 3485.
E-mail address: ion@liv.ac.uk (I. A. O’Neil).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.10.064

I. A. O’Neil et al. / Tetrahedron Letters 49 (2008) 7416–7418
-BuLi, THF, -78 o
C
7417
1. t C
-BuLi, THF, -78 o
1.
t
Ar
2. E
N
O
N
O
2. ArCHO
N
O
N
O
E
OH
Scheme 1.
quinuclidine N-oxide was reported first by Barton et al.7 Treatment
of anhydrous quinuclidine N-oxide with tert-butyllithium gave the
2-lithio derivative, which was trapped out with a range of aromatic
aldehydes. We have recently extended this methodology to the
lithiation and functionalisation of quinuclidine enamine N-oxide,
which underwent selective deprotonation at the C-2 vinylic posi-
tion.8 The resulting carbanion could be trapped out with a range
of electrophiles (Scheme 1). Furthermore, we have also shown that
2-lithio quinuclidine N-oxide can serve as a base/HMPA mimetic in
a number of important reactions.9
It was envisaged that treatment of a quinuclidine N-oxide 1,
bearing a methoxymethyl group at the C-3 position, with tert-
butyllithium would result in lithiation occurring at the C-2 carbon
adjacent to the N-oxide and the methoxymethyl group, as a conse-
quence of a directed lithiation effect, and in subsequent stabilisa-
tion of the organolithium intermediate 2 by intramolecular or
intermolecular chelation.10 The resulting carbanion could then be
trapped out with an appropriate electrophile to give the 2,3-disub-
stituted quinuclidine N-oxide 3 directly (see Scheme 2).
N-oxide as the product is produced in an anhydrous state with no
need for further purification.9 The Et2O solvent was removed in va-
cuo, anhydrous THF was added, and after brief sonication, addition
of tert-butyllithium at À78 °C resulted in lithiation at the desired
OMe
OMe
H2, Pd/C, MeOH
Ph
Ph
7a
Ph
Ph
N
O
100%
N
O
OH
8a
H
The route to the required 3-methoxymethyl quinuclidine N-
oxide (1) is shown in Scheme 3. Treatment of 3-ketoquinuclidine
(4) with the ylide derived from methoxymethylene triphenylphos-
phonium chloride gave the methyl enol ether 5 as a 2:1 mixture of
geometric isomers in 76% yield. Reduction of the enol ether 5 with
hydrogen in the presence of palladium on carbon gave the
3-methoxymethyl derivative 6. Conversion of tertiary amine 6 to
the desired N-oxide 1 was achieved using ozone in Et2O at
À78 °C. This is a superior method for the synthesis of quinuclidine
Scheme 4.
OMe
OMe
OMe
t-BuLi, THF, -78 oC
E
N
O
Li
N
O
N
O
E
1
2
3
Scheme 2.
H
O
Ph3PCH2OMe Cl
H2, Pd/C, MeOH
100%
OMe
OMe
n-BuLi, Et2O,
N
N
N
-30 oC, 76%
6
5
4
O3, Et2O, -78 o
100%
C
OMe
Ph
OMe
1. t-BuLi, THF, -78 o
2. Ph2CO
C
N
N
O
Ph
O
O
1
7a/b
H
Scheme 3.

7418
I. A. O’Neil et al. / Tetrahedron Letters 49 (2008) 7416–7418
OMe
1. t-BuLi, THF, -78 oC
OMe
O
2. RNCO
3. H2O
N
O
R = tBu, 58% 10a/b
Ph, 53% 11a/b
N
O
1
N
H
R
Scheme 5.
C-2 position. This carbanion was trapped out initially with benzo-
phenone to give the products 7a/b as a 1:1 mixture of diastereoiso-
mers in 95% yield. We did not observe any deprotonation at the
other N–CH2 positions.
References and notes
1. (a) Turner, R. B.; Woodward, R. B. The Chemistry of the Cinchona Alkaloids. In
The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1953, Vol. 3,
Chapter 16; (b) Uskokovic, M. R.; Grethe, G. The Cinchona Alkaloids. In The
Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1973, Vol. 14; (c)
Kaufmann, T. S.; Rúveda, E. A. Angew. Chem., Int. Ed. 2005, 44, 854.
2. Kacprzak, K.; Gawronski, J. Synthesis 2001, 961.
3. Sakamuri, S.; Enyedy, I. J.; Kozikowski, A. P.; Wang, S. M. Tetrahedron Lett. 2000,
41, 9949.
4. Yoon, P. T.; Jacobsen, E. N. Science 2003, 299, 1691.
5. Stork, G.; Niu, D.; Fujimoto, A.; Koft, E. R.; Balkovec, J. M.; Tata, J. R.; Dake, G. R. J.
Am. Chem. Soc. 2001, 123, 3239; See also: Raheem, I. T.; Goodman, S. N.;
Jacobsen, E. N. J. Am. Chem. Soc 2003, 126, 706; Lygo, B.; Crosby, J.; Lowde, T. R.;
Wainwright, P. G. Tetrahedron Lett. 1997, 38, 2343.
6. For selected examples see: Clemo, G. R.; Hoggarth, E. J. Chem. Soc. 1939, 1241;
Bender, D. R.; Coffen, D. L. J. Org. Chem. 1968, 33, 2504. Warawa, E. J.; Campbell,
J. R. J. Org. Chem. 1974, 39, 3511. Warawa, E. J.; Mueller, N. J.; Jules, R. J. Med.
Chem. 1974, 17, 497. Warawa, E. J.; Mueller, N. J.; Jules, R. J. Med. Chem. 1975, 18,
587. Stotter, P. L.; Friedman, M. D. J. Org. Chem. 1985, 50, 29. Jankowski, R.;
Joseph, D.; Cave, C.; Dumas, F.; Ourevitch, M.; Mahuteau, J.; Morgant, G.;
Pavlovic, N. B.; d’Angelo, J. Tetrahedron Lett. 2003, 44, 4187. Hansen, A. R.;
Badar, H. J. Heterocycl. Chem. 1966, 3, 109; Madhav, R. Synthesis 1982, 27.
7. Barton, D. H. R.; Beulgelmans, R.; Young, R. N. Nouv. J. Chem. 1978, 2, 363.
8. O’Neil, I. A.; Lai, J. Y. Q.; Wynn, D. Tetrahedron Lett. 2000, 41, 271.
9. O’Neil, I. A.; Bhamra, I.; Gibbons, P. D. J. Chem. Soc., Chem. Commun. 2006, 4545.
10. For a general review of organolithium chemistry see: Clayden, J. Organo-
lithiums: Selectivity for Synthesis. In Tetrahedron Organic Chemistry Series;
Pergamon, 2003; Vol. 23.
The product diastereoisomers 7a/b were separable by flash
chromatography, and the less polar isomer 7a was subjected to
catalytic hydrogenation using Pd/C in MeOH to give the parent ter-
tiary amine 8a, which was crystalline (Scheme 4). X-ray analysis
confirmed the structure of the product as the anti-diastereoisomer.
The carbanion 2 was also trapped out with a number of other
electrophiles. The adduct with fluoren-9-one was obtained in
84% yield, again as a 1:1 mixture of diastereoisomers 9a/b. Quench-
ing the carbanion with non-enolisable aromatic aldehydes, such as
benzaldehyde, gave the corresponding adducts as complex mix-
tures of diastereoisomers, which were inseparable by chromatog-
raphy. With tert-butyl and phenylisocyanate, the corresponding
amides 10a/b and 11a/b were generated in 58% and 53% yields,
respectively, after aqueous work-up, as 1:1 mixtures of diastereo-
isomers (Scheme 5).
In summary, we have shown that functionalised 2,3-quinucli-
dines can be prepared by the directed lithiation of 3-methoxy-
methyl quinuclidine N-oxide in good to excellent yields. To the
best of our knowledge, this is the first report of a directed lithiation
a
to a tertiary amine N-oxide.