Stereoselective C9 arylation and vinylation of Cinchona alkaloids

Article abstract of DOI:10.1021/ol7026625

A simple and efficient method for the highly stereoselective C-9 arylation and vinylation of Cinchona alkaloids was developed. Both 9S- and 9R-chloroquinine with PhMgBr yielded 9S-phenylquinine (X-ray structure). The reactions with various aryl and vinyl

Full text of DOI:10.1021/ol7026625

ORGANIC
LETTERS
2008
Vol. 10, No. 3
385-388
Stereoselective C9 Arylation and
Vinylation of Cinchona Alkaloids
Przemysław J. Boratyn´ski,† Ilona Turowska-Tyrk,‡ and Jacek Skarzewski*,†
3
Department of Organic Chemistry, Faculty of Chemistry, Wrocław UniVersity of
Technology, 50-370 Wrocław, Poland, and Institute of Physical and Theoretical
Chemistry, Faculty of Chemistry, Wrocław UniVersity of Technology,
50-370 Wrocław, Poland
jacek.skarzewski@pwr.wroc.pl
Received November 2, 2007
ABSTRACT
A simple and efficient method for the highly stereoselective C-9 arylation and vinylation of Cinchona alkaloids was developed. Both 9S- and
9R-chloroquinine with PhMgBr yielded 9S-phenylquinine (X-ray structure). The reactions with various aryl and vinyl Grignard reagents resulted
in the series of 9S-aryl and vinyl alkaloid derivatives. The stereochemical outcome was rationalized by coordination of the magnesium atom
to the quinuclidine nitrogen, thus directing the nucleophilic attack at the C-9 stereogenic center.
In the last two decades, Cinchona alkaloids (Figure 1) have
gained much interest because of their successful applications
catalyst class.2 The most often used selective synthetic
modifications of Cinchona alkaloids were based on the
replacement of C-9 hydroxy group by other functionalities,
including those with nitrogen,3 halogen,4 and chalcogen5
heteroatoms.
However, the stereochemistry of some of these transfor-
mations was not so obvious. The stereochemical outcome
of the reaction of thionyl chloride with quinine was not a
retention as believed,6 but rather inversion of configuration,
as it was proved by X-ray crystallography.7 Another example
is the acidic hydrolysis of methanesulfonyl esters derived
from alkaloids of native and inversed (epi) configuration at
Figure 1. Major Cinchona alkaloids.
(2) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691.
(3) (a) Brunner, H.; Buegler, J.; Numer, B. Tetrahedron: Asymmetry
1995, 6, 1699. (b) Vakulya, B.; Varga, S.; Csa´mpai, A.; Soo´s, T. Org. Lett.
2005, 7, 1967. (c) Chen, W.; Du, W.; Duan, Y.-Z.; Wu, Y.; Yang, S.-Y.;
Chen, Y.-C. Angew. Chem., Int. Ed. 2007, 46, 7667.
(4) (a) Ko¨nigs, W. Chem. Ber. 1880, 13, 285. (b) Pouwels, H.; Veldstra,
H. Rec. TraV. Chem. 1955, 74, 795. (c) Braje, W. M.; Wartchow, R.;
Hoffmann, H. M. R. Angew. Chem., Int. Ed. 1999, 38, 2539.
(5) (a) Zielin´ska-Błajet, M.; Kucharska, M.; Skarz˘ewski, J. Synthesis
2006, 1176. (b) Zielin´ska-Błajet, M.; Siedlecka, R.; Skarz˘ewski, J.
Tetrahedron: Asymmetry 2007, 18, 131.
in asymmetric synthesis.1 For their prominent role as chiral
bases, ligands, phase-transfer catalysts, and surface modifiers,
they were even considered as belonging to a priVileged
† Department of Organic Chemistry.
‡ Institute of Physical and Theoretical Chemistry.
(1) For reviews, see: (a) Kacprzak, K.; Gawronski, J. Synthesis 2001,
961. (b) Tian, S. K.; Chen, Y. G.; Hang, J. F.; Tang, L.; McDaid, P.; Deng,
L. Acc. Chem. Res. 2004, 37, 621. (c) Hoffmann, H. M. R.; Frackenpohl,
J. Eur. J. Org. Chem. 2004, 4293. (d) Palomo, C.; Oiarbide, M.; Laso, A.
Eur. J. Org. Chem. 2007, 2561.
(6) Dijkstra, G. D. H.; Kellog, R. M.; Wynberg, H. J. Org. Chem. 1990,
55, 6121.
(7) Mazhar-ul-Haque; Ahmed, J.; Horne, W.; Miana, G. A.; Al-Hazimi,
H. M. G.; Amin, H. B. J. Cryst. Spectr. Res. 1986, 16, 169.
10.1021/ol7026625 CCC: $40.75
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Published on Web 01/08/2008

the C-9 stereogenic center. Both substrates gave a product
of the same epi-configuration only. The authors suggested
that a hydrogen-bound water molecule was one of the
possible causes of such a course.8
To the best of our knowledge, there is only a single, nearly
60-year-old report on the effective building of the new C-C
bond by the replacement of the C-9 hydroxy group.9 A
coupling reaction between 9-chloroquinine and phenylmag-
nesium bromide was described by Ochiai et al. However,
the authors made no statement on the stereochemistry at
position 9 of either the substrate or the product of the
reaction.
product (70%) was identical to the previous one; i.e., in this
case, 9S-Ph-QN (7) was obtained with the inversion of
configuration (Scheme 1). The product of different config-
uration, 9R-Ph-QN, was neither isolated nor observed in the
spectra.
Scheme 1. Synthesis of 9S-Ph-QN and 9R-Ph-QD
In the present paper, we report an unexpected stereochem-
ical course of this reaction and its use for the efficient
synthesis of a series of new 9-aryl and 9-vinyl derivatives
of Cinchona alkaloids.
The alkaloids and their C-9 epimers8 were transformed to
the corresponding chloro derivatives with inversion of
configuration by treatment with thionyl chloride.4b Thus, we
obtained both epimers of chloroquinine and cloroquinidine:
9R-Cl-QN (6), 9S-Cl-QN (5), 9R-Cl-QD (8), 9S-Cl-QD
(9), as well as 9S-Cl-CD and 9S-Cl-CN. Additionally,
9S-Br-QN was obtained through the known procedure of
Apel reaction.4c
9S-Chloroquinine (5) was reacted with the Grignard
reagent obtained from bromobenzene and magnesium as
described before.9 The product was isolated by chromatog-
raphy (65% yield) or, as reported,9 by crystallization of the
thiocyanate salt. A single crystal of this salt was submitted
to X-ray analysis (Figure 2), and the structure of 9S-Ph-QN
(7) was proved unambiguously.
The same procedure was applied for 9-chloro derivatives
of quinidine. Here again the reaction of either 9R-Cl-QD
(8) and 9S-Cl-QD (9) with phenylmagnesium bromide
yielded one and the same product, 9R-Ph-QD (10) (Scheme
1). Its relative configuration was confirmed by 2D 1H NMR
experiment (NOESY) (Figure 3).
Figure 2. X-ray structure of 9S-Ph-QN (7) thiocyanate salt.
Accordingly, the configuration at the substitution cen-
ter was retained. Interestingly, when a different isomer,
9R-Cl-QN (6), was used in the same reaction, the isolated
Figure 3. Selected NOE correlations for 9S-C2H3-QN (18) and
9R-Ph-QD (10).
(8) Braje, W. M.; Holzgrefe, J.; Wartchow, R.; Hoffmann, H. M. R.
Angew. Chem., Int. Ed. 2000, 39, 2085.
(9) Ochiai, E.; Tsunashima, K.; Kobayashi, Y. J. Pharm. Soc. Jpn. 1949,
69, 10; Chem. Abstr. 1950, 44, 3508D.
Thus, when the configurations at the C-9 and C-8
stereogenic centers of chloro derivatives were the same (like-
386
Org. Lett., Vol. 10, No. 3, 2008

isomers) the reaction proceeded with the retention of
configuration. On the other hand, the substrates with different
configurations at C-9 and C-8 (unlike-isomers) reacted with
inversion. Generally better yields were observed for chlo-
roderivatives of unlike-configuration. The additional yield
improvement (up to 88%) was achieved when a 2-fold excess
of arylmagnesium compound was used.
It seems that binding of magnesium species by the
quinuclidine nitrogen is essential to achieve such unexpected
stereoselectivity (Scheme 2). A similar effect has already
phenylmagnesium bromide. Additionally, when the reaction
of 9S-Cl-QN with phenylmagnesium bromide was quenched
before completion, the recovered chloro derivative was
identical to the substrate used; therefore, a rapid isomerization
between 5 and 6 can be ruled out under these conditions.
Attempted reactions with phenyllithium or lithium di-
phenylcuprate instead of the Grignard reagent gave 4%
9S-Ph-QN or complete substrate recovery, respectively. Cin-
chonine (4) and cinchonidine (3) were transformed to the
corresponding 9-phenyl derivatives 12 and 11 in 23-39%
yield. Because of the higher yield observed in the series of
the 6′-methoxy-bearing compounds 7 and 10 vs those without
this substituent 11 and 12, we suppose that the additional
complexation of one of the magnesium atoms may facilitate
the substitution. Such an effect has already been observed
for reactions involving Grignard reagents.13 Moreover, an
inspection of the corresponding molecular model does not
exclude a similar interaction in our case.
Scheme 2. Suggested Mechanism of the Substitution Reaction
Several other aryl derivatives were prepared in fair to good
yields by reaction of 9S-Cl-QN with various aryl Grignard
reagents. Both 2-naphthylmagnesium bromide as well as
hindered 1-naphthylmagnesium bromide reacted easily,
producing 13 and 14, respectively (Figure 4).
been postulated in order to explain the observed diastereo-
selectivities of DIBALH reduction of quinidinone10 as well
as the addition of alkyl group to quinine’s quinoline.11 In
our case, in the most stable conformation of like-isomers
(9S-Cl-QN and 9R-Cl-QD) the chlorine atom is located very
closely to the quinuclidine-bound magnesium atom. The
reaction that follows requires the participation of the two-
metal center and proceeds according to SNi mechanism
leading to retention of configuration. In the case of unlike-
isomers (9R-Cl-QN and 9S-Cl-QD), the chlorine atom is
preferably oriented antiperiplanar to the quinuclidine nitro-
gen. Here, similar binding of magnesium structure is fol-
lowed by the SN2-like attack and usual inversion of config-
uration. This explanation is valid for both quinine and
quinidine, since apart from the location and orientation of a
vinyl group they can be regarded as enantiomers.
Otherwise, a common intermediate would, in the case of
Cinchona alkaloids, require an extremely strained aziridinium
ion, which is unlikely.4c Moreover, it would be responsible
for a limited diastereoselectivity only and high content of
the elimination and ring-expansion products. None of these
products were formed in more than trace amounts. Also,
contrary to the reported stereoselectivity of nucleophilic
substitution by organomagnesium compounds attributed to
anchimeric assistance,12 in our case no difference was found
between the reactions of 9S-Cl-QN and 9S-Br-QN with
Figure 4. Cinchona alkaloid derivatives.
An attempted substitution of 9-chloroquinine with ethyl-
magnesium bromide gave a complex mixture, and we could
not obtain the desired product. However, when a THF
solution of either 9S-Cl-QN or 9R-Cl-QN was treated with
vinylmagnesium bromide, 9S-vinylquinine (18) was formed
as the only isomer. The reaction was complete within 1 h at
room temperature. The NOESY experiments for 18 revealed
a conformation very similar to that found in the crystal
structure of 7 thiocyanate. Hydrogen H-8 shows no cross-
(10) Gutzwiller, J.; Uskovic´, M. R. HelV. Chim. Acta 1973, 56, 1494.
(11) Hintermann, L.; Schmitz, M.; Englert, U. Angew. Chem., Int. Ed.
2007, 46, 5164.
(12) Converso, A.; Saaidi, P. I.; Sharpless, K. B.; Finn, M. G. J. Org.
Chem. 2004, 69, 7336.
(13) Le Bail, M.; Pe´rard, J.; Aitken, F. J.; Husson, H. P. Tetrahedron
Lett. 1999, 40, 5309.
Org. Lett., Vol. 10, No. 3, 2008
387

peak with hydrogen H-9, suggesting their antiperiplanar
orientation. Strong correlations of H-9 with quinoline’s H-5′
and H-7b were observed. Three hydrogens, H-7a, H-8, and
H-3′, correlate with each other. This averaged conformation
cannot be justified by 9R-vinylquinine, but it fits to the
9S-epimer (Figure 3).
When less than 1.2 equiv of vinylmagnesium bromide was
added, nearly 50% of substrate was recovered, while the use
of more than 1.5 equiv led to a pronounced nucleophilic
substitution at the quinoline 2′-carbon atom11,14 (Scheme 3).
we prepared the products bearing free phenolic hydroxy
groups as a hydrogen bond donor.15 The methoxymethyl
ether of p-iodophenol16 was converted to the corresponding
Grignard reagent and subsequently coupled with 9S-Cl-QN.
The product was deprotected with 95% trifluoroacetic acid
giving 16. The phenolic group can also be uncovered by
cleavage of the 6′-methyl ether inherited from the quinine
structure. Sodium ethylthiolate in DMF15b was found to
provide the most satisfactory results, giving 15 from 13 in
75% yield. In order to obtain chiral building blocks suitable
for further selective transformations, compound 20 with a
single vinyl group only was obtained from the corresponding
dihydro derivative (17).
Scheme 3. Synthesis of Vinyl Derivatives
In conclusion, 9-chloro-substituted derivatives of Cinchona
alkaloids were arylated and vinylated in a highly stereose-
lective manner. The outcome depended on the relative
configurations at C-8 and C-9 centers. The reaction with aryl-
and vinylmagnesium halides gave a series of the respective
9-aryl and 9-vinyl compounds with the retention for like-
and inversion for unlike-C8,C9-configurations. The products
are amenable for further conversion to the prospective
catalysts, and these transformations are underway in our
laboratory.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
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OL7026625
We did not observe such byproducts with arylmagnesium
halides, unless they were used in more than 2-fold excess.
With the intention of examining transformation of the
obtained 9-arylalkaloids into the prospective organocatalysts,
(15) (a) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J.
Am. Chem. Soc. 1999, 121, 10219. (b) Li, H.; Wang, B.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 732. (c) Marcelli, T.; van Marseveen, J. H.; Hiemstra,
H. Angew. Chem., Int. Ed. 2006, 62, 11402. (d) Mandal, T.; Samanta, S.;
Zhao, C.-G. Org. Lett. 2007, 9, 943.
(14) Mead, J. F.; Rapport, M. M.; Koepfli, J. B. J. Am. Chem. Soc. 1946,
68, 2704.
(16) Takatori, K.; Nisihara, M.; Nishiyama, Y.; Kajiwara, M. Tetrahedron
1998, 54, 15861.
388
Org. Lett., Vol. 10, No. 3, 2008