Synthetic studies on quinine: Quinuclidine construction via a ketone enolate regio- and diastereoselective Pd-mediated allylic alkylation

Article abstract of DOI:10.1021/ol061524s

7-Hydroxy-quinine was synthesized by an asymmetric aldol reaction that establishes the C8 and C9 stereochemistry, followed by construction of the 3-vinyl-quinuclidine azabicyclo[2.2.2]octane by C3-C4 ring closure using an intramolecular palladium-mediated

Full text of DOI:10.1021/ol061524s

ORGANIC
LETTERS
2006
Vol. 8, No. 18
4051-4054
Synthetic Studies on Quinine:
Quinuclidine Construction via a Ketone
Enolate Regio- and Diastereoselective
Pd-Mediated Allylic Alkylation
Deidre M. Johns, Makoto Mori, and Robert M. Williams*
Department of Chemistry, Colorado State UniVersity,
Fort Collins, Colorado 80523-1872
rmw@lamar.colostate.edu
Received June 21, 2006
ABSTRACT
7-Hydroxy-quinine was synthesized by an asymmetric aldol reaction that establishes the C8 and C9 stereochemistry, followed by construction
of the 3-vinyl-quinuclidine azabicyclo[2.2.2]octane by C3 C4 ring closure using an intramolecular palladium-mediated allylic alkylation with
−
excellent regio- and diastereoselectivity. This is the first report of a ketone-enolate-stereocontrolled allylic alkylation mediated by palladium.
The title compound and a dehydro-quinine analogue were evaluated for antimalarial activity.
The Cinchona alkaloid, quinine (1),1 was the first known
effective treatment for malaria and has attracted considerable
attention from synthetic chemists since its formula was
determined by Strecker in 1854.2 Initially, interest in quinine
was driven by the need for a domestically produced malaria
remedy and more recently because of its challenging
architecture and utility as a catalyst or ligand for asymmetric
synthesis.3 Malaria kills over 1 million people every year,
and this is projected to increase as a result of the ineffectivity
of available treatments against widespread drug-resistant
strains of the parasite. The first stereocontrolled synthesis
of quinine was elegantly accomplished by Stork and co-
workers in 2001 deploying a novel N1-C6 disconnection
strategy.4 Jacobsen5 and Kobayashi6 in 2004 completed the
stereocontrolled synthesis of quinine via the historic Rabe
N1-C8 disconnection strategy. In this communication, we
report the first synthetic approach to quinine via a stereo-
controlled C3-C4 ring-closure reaction to construct the
quinuclidine azabicyclo[2.2.2]octane ring system (Scheme
1). This was accomplished using a modified Pd-mediated
allylic alkylation to enable a TMS-enol ether (preformed
ketone enolate equivalent) to participate as the nucleophile
in an intramolecular cyclization. The observed diastereose-
lectivity at C3 suggests the reaction proceeds by a mechanism
in which the C7-oxygen influences the forming vinyl
(1) For reviews, see: (a) Kaufman, T. S.; Ru´veda, E. A. Angew. Chem.,
Int. Ed. 2005, 44, 854-885. (b) Nicoloau, K. C.; Snyder, S. A. Classics in
Total Synthesis II: More Targets, Strategies, Methods; Wiley-VCH:
Weinheim, Germany, 2003; Chapter 15. (c) 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. (d) Grethe,
G.; Uskokovic, M. R. In The Chemistry of Heterocyclic Compounds; Sexton,
J. E., Ed.; Wiley-Interscience: New York, 1983; Vol. 23, Part 4, p 279.
(2) Strecker, A. Justus Leibigs Ann. Chem. 1854, 91, 155.
(3) For recent reviews of Cinchona alkaloids in asymmetric synthesis,
see: (a) Kacprzak, K.; Gawronski, J. Synthesis 2001, 7, 961-998. (b)
Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719-724. (c) Tian, S. K.;
Chen, Y. G.; Hang, J. F.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res.
2004, 37, 621-631.
(4) Stork, G.; Niu, D.; Fujimoto, A.; Koft, E. R.; Balkovec, J. M.; Tata,
J. R.; Dake, G. R. J. Am. Chem. Soc. 2001, 123, 3239-3242.
(5) Raheem, I. T.; Goodman, S. N.; Jacobsen, E. N. J. Am. Chem. Soc.
2004, 126, 3706-3707.
(6) (a) Igarashi, J.; Katsukawa, M.; Wang, Y.-G.; Acharya, H. P.;
Kobayashi, Y. Tetrahedron Lett. 2004, 45, 3783-3786. (b) Igarashi, J.;
Kobayashi, Y. Tetrahedron Lett. 2005, 46, 6381-4638.
10.1021/ol061524s CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/04/2006

Scheme 1. Retrosynthetic Analysis
Scheme 2. Asymmetric Aldol Reaction
syn-isomer as illustrated by the decreased syn/anti selectivity
for 9 when the reaction is maintained at -78 °C (1:1 to 2:1
dr). Optimal yields are obtained when the reaction is
quenched at low temperature to minimize retro-aldol product
formation. Protection of the C9-hydroxyl as a triethylsilyl
ether (TES) (the largest silyl ether that it was found possible
to install) provided compound 10. Standard conditions for
reductive cleavage of the chiral template (H2, Pd-C) were
sluggish as a result of the presence of the quinoline moiety
and merely cleaved the N-Cbz group. The resulting free
amine intermediate was converted in three steps to the desired
R-amino-â-silyloxy-ester 11 in excellent yield.
substituent. Preformation of the silyl enol ether facilitates
regiocontrol; alkylation at elevated temperature occurs
exclusively at the site of kinetic enolization. Another novel
aspect of our approach is the establishment of the C8 and
C9 stereogenic centers early in the synthesis through the use
of an asymmetric aldol reaction.
With 11 in hand, the next task was to form the piperidine
ring system (Scheme 3). Ester 11 was directly reduced to
the corresponding aldehyde, and treatment with 3-(benzyl-
Scheme 3. Preparation of Piperidine Derivative 20
The piperidinone 3 can be further disconnected to an
R-amino-â-hydroxy ester (5), for which our laboratory has
developed methods to prepare using the commercially
available chiral, nonracemic 5,6-diphenylmorpholine-2-one
templates (Williams lactones).7 Lactone template (6) is
known to participate in boron-mediated aldol reactions and
provide anti-aldol products, which are well suited for
preparing the historically challenging C8 and C9 stereogenic
centers of quinine as illustrated in Scheme 2.8 The boron-
mediated aldol reaction of 6 with quinolinecarboxaldehyde
79 resulted in an unsatisfactory yield (42% yield). However,
the TBAF-promoted reaction of 7 with silyl enol ether 8
provided a significantly improved yield and excellent dias-
tereoselectivity (>30:1 dr) of 9, the relative configuration
of which was secured by X-ray crystallography.10 The desired
anti-aldol product (9) is thermodynamically favored over the
(7) Dastlik, K. A.; Sundermeier, U.; Johns, D. M.; Chen, Y.; Williams,
R. M. Synlett 2005, 4, 693-696.
(8) (a) Reno, D. S.; Lotz, B. T.; Miller, M. M. Tetrahedron Lett. 1990,
31, 827-830. (b) Williams, R. M.; Yuan, C. J. Org. Chem. 1992, 57, 6519-
6527.
(9) Prepared as described in Supporting Information. For previous syn-
theses, see: (a) Wilson, S. R.; Grandi, M. J. J. Org. Chem. 1991, 56, 4766-
4772. (b) Biot, C.; Delhaes, L.; Maciejewski, L. A.; Mortuaire, M.; Camus,
D.; Dive, D.; Brocard, J. S. Eur. J. Med. Chem. 2000, 35, 707-714.
(10) (a) Mukaiyama, T.; Matsuo, J.-i. Boron and Silicon Mediated
Enolates in Cross Aldol Reaction. In Modern Aldol Reactions; Mahrwald,
R., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany,
2004; Chapter 1, pp 127-160.
4052
Org. Lett., Vol. 8, No. 18, 2006

oxypropyl)magnesium bromide11 resulted in the (R)-alcohol
(12) selectively. This was converted to mesylate 13, which
resisted cyclization to piperidine 14. We reasoned that gauche
interactions preclude this substance from adopting the
conformation required for cyclization as depicted in Figure
1. Fortunately, the epimeric C7-acetate (16) could be
Scheme 4. Allylic Alkylation of Malonic Ester Derivative
functionality was prepared in 8:1 dr using chiral, nonracemic
catalysts.14
Figure 1. Conformations of 13 and 16.
The regio- and diastereselective allylic alkylation of ketone
enolates is a versatile yet challenging synthetic transforma-
tion. Limited examples using ketone enolates have been
reported.15 The carbon nucleophiles used are predominantly
stabilized carbanions, such as malonates, or enolate equiva-
lents formed by the decarboxylation of allyl-â-keto carboxy-
lates.16 Ketone enolates as nucleophiles in this reaction offer
several synthetic advantages as illustrated by our system
(Scheme 5). The product C8-hydrogen is less prone to
prepared from alcohol 12 via an oxidation-reduction
sequence affording 15 (>20:1 dr). Indeed, the epimeric
mesylate 16 cyclized to 17 when treated with NaH. Since
removal of the C7-acetate required LiAlH4, it was replaced
with an O-TMS ether prior to N-alkylation. A five-step
sequence involving first reductive cleavage of the acetate,
followed by silylation of the C7-hydroxyl with simultaneous
N-Boc deprotection,12 N-alkylation, acid hydrolysis of the
C7-OTMS, and finally Swern oxidation yielded piperidinone
20.
Scheme 5. Regio- and Diastereoselective Allylic Alkylation of
Ketone-Derived TMS Enol Ether
Our laboratory has previously demonstrated the powerful
directing ability of sodium enolates in stereoselective SN2’
cyclizations for the synthesis of complex prenylated indole
alkaloid natural products such as the brevianamides and
paraherquamides.13 We envisioned a similar tight contact ion-
pair, closed transition state between the enolate and forming
vinyl group to control the C3-vinyl stereochemistry. The
stereochemistry at C4 would be concomitantly established
by facial control derived from the stereogenic center at C8.
After initial efforts to induce enolate species derived from
ketones related to 20 (allylic halide substrates as opposed to
the allylic benzoate were evaluated) to cyclize using various
SN2’ conditions failed, we turned to palladium-mediated
cyclizations. Piperidinone 20 was converted to the corre-
sponding â-keto ester and subjected to Tsuji-Trost condi-
tions (Scheme 4). Encouragingly, this provided quinuclidine
products 21-24 after optimization. Attempts to decarboxy-
late, reduce, and deprotect all resulted in decomposition. This
and the lack of stereoselectivity at C3 prompted us to
investigate alternative substrates. Shortly after our initial
studies, Trost reported a similar transformation in which a
quinuclidine heterocycle lacking the problematic quinine C8
equilibration, and the need for subsequent decarboxylation
is eliminated. Preformation of a silylenol ether enables
alkylation exclusively at C4. After significant optimization,
it was found that treatment of silylenol ether 25 with Pd2-
(dba)3, P(2-furyl)3, and Bu3SnF in toluene at 85 °C provides
the desired quinuclidine ketone 26 having two additional
(14) Trost, B. M.; Sacchi, K. L.; Schroeder, G. M.; Asakawa, N. Org.
Lett. 2002, 4, 3427-3430.
(15) (a) Braun, M.; Laicher, F.; Meier, T. Angew. Chem., Int. Ed. 2000,
39, 3494-3497. (b) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc.
1999, 121, 6759-6760. (c) Trost, B. M.; Schroeder, G. M. Chem.- Eur.
J. 2005, 11, 174-184. (d) Hou, D. R.; Reibenspies, J. H.; Burgess, K. J.
Org. Chem. 2001, 66, 206-215. (e) Trost, B. M.; Lee, C. B. J. Am. Chem.
Soc. 1998, 120, 6818-6819. (f) Trost, B. M.; Keinen, E. Tetrahedron Lett.
1980, 21, 2591-2594. (g) Trost, B. M.; Self, C. R. J. Org. Chem. 1984,
49, 468-473. (h) Kazmaier, U. Curr. Org. Chem. 2003, 7, 317-328. (i)
Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2003, 125, 8974-8975.
(16) (a) Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 4113-4115. (b)
Tsuji, J. Transition Metal Reagents and Catalysis; John Wiley & Sons
Ltd.: New York 2000; p 109. (c) Tsuji, J. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; John Wiley & Sons:
New York, 2000; Vol. 2, p 1669.
(11) For the preparation of BnO(CH2)3Br, see: Bessodes, M.; Boukarim,
C. Synlett 1996, 11, 1119-1120.
(12) Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870-876.
(13) (a) Williams, R. M.; Cao, J.; Tsujishima, H.; Cox, R. J. J. Am. Chem.
Soc. 2003, 125, 12172-12178. (b) Cushing, T.; Sanz-Cervera, J. F.;
Williams, R. M. J. Am. Chem. Soc. 1996, 118, 557-579. (c) Williams, R.
M.; Glinka, T.; Kwast, E.; Coffman, H.; Stille, J. K. J. Am. Chem. Soc.
1990, 112, 808-821. (d) Williams, R. M.; Glinka, T.; Kwast, E. J. Am.
Chem. Soc. 1988, 110, 5927-5929. (e) Williams, R. M.; Glinka, T.
Tetrahedron Lett. 1986, 27, 3581-3584.
Org. Lett., Vol. 8, No. 18, 2006
4053

stereogenic centers established between C3-C4. Tributyltin
fluoride is required to facilitate transmetalation of the silyl
enol ether. Ketone 26 was immediately reduced to avoid
equilibration at C8 and â-elimination. This provided the
desired quinuclidine 27 and the diols 2 and 28. Surprisingly,
none of the undesired C3-vinyl stereoisomer was observed.
Product 27 exists predominantly as two rotamers about C9
as determined by ROESY NMR and confirmed by variable
temperature NMR (∆G° ) 1.8 kcal/mol). Removal of the
silyl ether from 27 provided (R)-7-hydroxy-quinine 2.
The mechanism of the net SN2’-type cyclization reaction,
particularly with respect to the diastereoselectivity observed,
is interesting and deserves comment. The standard π-allyl
Pd-based allylic alkylation mechanism fails to explain the
observed stereoselectivity.16 Two mechanisms can be envi-
sioned (Scheme 6): (1) formation of a Pd-sandwich com-
the [5.3.1] AB ring system of taxane, which was conversely
prepared from bicyclo[2.2.2]octanes by sigmatropic rear-
rangements.20
We were also interested to see if 7-oxygenated derivatives
of quinine are effective against malaria parasites, as ana-
logues of quinine of this type have not been reported. Diol
2 and dehydro-keto-quinine 29 (isolated as a cyclization
byproduct during optimization studies; Figure 2) were
Scheme 6. (1) Pd-Sandwich Complex. (2) Pd-Mediated
Etherification Followed by Claisen Rearrangement Mechanism
Figure 2. Structures of 7-oxy-quinine analogues 2 and 29 evaluated
for antimalarial activity.
evaluated against two strains of Plasmodium falciparum;
surprisingly, both analogues were found to be inactive.
In conclusion, the asymmetric synthesis of 7-hydroxy-
quinine (2) has been accomplished via a novel quinuclidine-
forming construction involving a C3-C4 Pd-mediated SN2’-
type cyclization reaction. Two 7-oxy analogues of quinine
were evaluated and found to be inactive against malaria
parasites. The application of this new conceptual approach
to the total synthesis of the Cinchona alkaloids is currently
under study in these laboratories.
Acknowledgment. We thank the National Institutes of
Health (GM068011) for financial support. We are very
grateful to Prof. Daniel Goldberg for evaluating the biological
activity of analogues 2 and 29, to Prof. L. S. Hegedus
(Colorado State University) for helpful discussions, and to
Dr. Chris Rithner for help with NMR spectroscopy. D.M.J.
thanks the American Cancer Society, New England Division
Broadway on Beachside for a postdoctoral fellowship, and
M.M. thanks Sankyo Co., Ltd. for financial support.
plex17 involving an η3 Pd-enolate and a π-allyl Pd species
undergoing allylic alkylation, which could favor the desired
C3 isomer; and (2) Pd-mediated etherification,18 followed
by a Claisen rearrangement.19 The latter mechanism can only
result in a single observed and desired stereoisomer (Scheme
5). Furthermore, the ethereal intermediate is reminiscent of
Supporting Information Available: Experimental pro-
cedures and characterization of all key compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Lord, P.; Olmstead, M. M.; Balch, A. L. Angew. Chem., Int. Ed.
1999, 38, 2761-2763.
OL061524S
(18) (a) Review of Pd-mediated etherifications: Muzart, J. Tetrahedron
2005, 61, 5955-6008. (b) Bosch, M.; Schlaf, M. J. Org. Chem. 2003, 68,
5225-5227.
(20) Martin, S. F.; Assercq, J.-M.; Austin, R. E.; Dantanarayana, A. P.;
Fishpaugh, J. R.; Gluchowski, C.; Guinn, D. E.; Hartmann, M.; Tanaka,
T.; Wagner, R.; White, J. B. Tetrahedron 1995, 51, 3455-82.
(19) Review of Claisen rearrangements: Castro, A. A. M. Chem. ReV.
2004, 104, 2939-3002.
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Org. Lett., Vol. 8, No. 18, 2006