C?H Activation Enables a Concise Total Synthesis of Quinine and Analogues with Enhanced Antimalarial Activity

Article abstract of DOI:10.1002/anie.201804551

We report a novel approach to the classical natural product quinine that is based on two stereoselective key steps, namely a C?H activation and an aldol reaction, to unite the two heterocyclic moieties of the target molecule. This straightforward and flexible strategy enables a concise synthesis of natural (?)-quinine, the first synthesis of unnatural (+)-quinine, and also provides access to unprecedented C3-aryl analogues, which were prepared in only six steps. We additionally demonstrate that these structural analogues exhibit improved antimalarial activity compared with (?)-quinine both in vitro and in mice infected with Plasmodium berghei.

Full text of DOI:10.1002/anie.201804551

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Accepted Article
Title: C−H Activation Enables a Concise Total Synthesis of Quinine
and Analogues with Enhanced Antimalarial Activity
Authors: Daniel H O' Donovan, Paul Aillard, Martin Berger, Aurelien
de la Torre, Desislava Petkova, Christian Knittl-Frank, Danny
Geerdink, Marcel Kaiser, and Nuno Maulide
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804551
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C−H Activation Enables a Concise Total Synthesis of Quinine and
Analogues with Enhanced Antimalarial Activity
Daniel H. O’ Donovan,[d,+] Paul Aillard,[a,+] Martin Berger,[a,+] Aurélien de la Torre,[a] Desislava Petkova,[a]
Christian Knittl-Frank,[a] Danny Geerdink,[a] Marcel Kaiser[b,c] and Nuno Maulide*[a]
Abstract: We report a novel approach to the classical natural
product Quinine based on two stereoselective key steps, namely a
C−H activation and an aldol reaction to unite the two heterocyclic
moieties of the target molecule. This straightforward and flexible
strategy enables a concise synthesis of natural (−)-Quinine, the first
synthesis of unnatural (+)-Quinine and also provides access to
unprecedented C3-aryl analogues that can be prepared in only 6
steps. We additionally demonstrate that these structural analogues
exhibit improved antimalarial activity compared with (−)-Quinine both
in vitro and in mice infected with Plasmodium berghei.
analogue Quinidine is typically employed as a “pseudo”
enantiomer.
Herein we report a straightforward and flexible strategy enabling
a concise stereoselective synthesis of both enantiomers of
Quinine, based on a selective C(sp3)−H activation step and a
novel C8−C9 disconnection via aldol addition. Furthermore, we
disclose a short route towards novel C3-aryl analogues and their
in vivo biological evaluation, resulting in significantly enhanced
antimalarial activity.
Among the many natural products described throughout the
chemical literature, Quinine has undoubtedly one of the most
vivid and colorful histories. For over a century, this Cinchona
alkaloid has attracted the attention of a plethora of researchers.[1]
Its potent antimalarial activity, especially against resistant
strains,[2] along with its privileged role in catalysis,[3] rendered it a
highly coveted target. The first (formal) synthesis of the alkaloid,
widely regarded as a milestone in total synthesis, was achieved
by Woodward and Doering in 1944 and was heralded in the
5]
popular media.[4, Taken together, virtually all the successful
approaches to this natural product share as a common trait
(Figure 1a) the late-stage construction of the quinuclidine moiety,
namely via a C8−N1 disconnection.[6] Despite the apparent
structural simplicity of Quinine, the first enantioselective
synthesis was reported by Stork et al. as late as in 2001,[7] with a
longest linear sequence of 14 steps and featuring an innovative
C6−N1 disconnection (Figure 1b). Notably, no reported
synthesis demonstrated the introduction of structural diversity at
the C3 position, despite studies which suggest that this site can
modulate antimalarial activity.[8] Furthermore, to the best of our
knowledge there are no reports on either the synthesis or the
biological activity of the unnatural enantiomer (+)-Quinine.
Indeed, this enantiomer is conspicuously absent throughout the
vast literature of organocatalysis, where the diastereoisomeric
[a]
Dr. P. Aillard [+], M. Berger [+], Dr. A. de la Torre, Dr. D. Petkova, C.
Knittl-Frank, Dr. D. Geerdink and Prof. Dr. N. Maulide*
Institute of Organic Chemistry, University of Vienna
Währinger Straße 38, 1090 Vienna, Austria
E-mail: nuno.maulide@univie.ac.at
Web: https://organicsynthesis.univie.ac.at
Dr. M. Kaiser
[b]
Figure 1. An overview of previous retrosynthetic approaches to Quinine (1) (a,
b) and our synthetic plan (c). For a comprehensive review of prior syntheses,
see references [1a–d].
Swiss Tropical and Public Health Institute
Socinstrasse 57, CH-4002 Basel, Switzerland
and
[c]
[d]
University of Basel
CH-4003 Basel, Switzerland
Dr. D. H. O’ Donovan [+]
AstraZeneca, Oncology, IMED Biotech Unit
1 Francis Crick Avenue, Cambridge, CB2 0RE, United Kingdom
These authors contributed equally.
Our synthetic plan predicated the use of a preformed
quinuclidine A bearing a C7 (Quinine numbering) substituent X
(Figure 1c). This substituent should simultaneously (i) embody
the directing group to guide our planned C(sp3)−H activation
step, while also (ii) serving as a masked ketone to facilitate the
[+]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201804551
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aldol event and ultimately (iii) being amenable to removal of this
redundant functionality at the end of the synthesis.
epimerization -to the aldehydic carbon was observed during
this transformation, likely
a
fortuitous consequence of
We elected to use the picolinamide directing group
pioneered by Daugulis et al. for the C(sp3)−H activation
reaction.[9, 10] This moiety was readily introduced via a coupling
reaction using commercially available 3-aminoquinuclidine (2)
(Scheme 1).[11] From intermediate 3, we found that C(sp3)−H
arylation using Pd-catalysis[12] can be achieved with complete
regio- and diastereocontrol. The observed selectivity is likely the
result of preferential formation of a 5-membered palladacyclic
intermediate, combined with preclusion of C(sp3)−H activation at
C8 via the inductive effect of the adjacent nitrogen. Although
direct C(sp3)−H vinylation and alkenylation eluded our efforts
despite extensive investigation,[13] we established the C(sp3)−H
arylation to be a general transformation, as shown in Scheme 1.
hemiaminal formation.
Scheme 2. Conversion of arylated (−)-4c to quinuclidone building block 10.
Reagents and conditions: (3) RuCl3, NaIO4, H2O, EtOAc, CH3CN, r.t., 18 h. (4)
HATU, MeNHOMe.HCl, Et3N, DMF, r.t., 18 h. (5) DIBAL-H, DCM, −78 °C, 1.5
h. (6) Ph3PMeBr, LiHMDS, DMSO, THF, −78 °C. (7) Zn, HCl, Zn(OTf)2, H2O,
r.t., 1.5 h. (8) IBX, pTsOH, CH3CN, 70 °C, 2 h.
The desired vinyl moiety was then completed via Wittig
olefination to afford alkenyl-quinuclidine 8 (Scheme 2).[16] We
now sought to remove the directing group and set the stage for
an aldol-type reaction to introduce the quinoline portion of the
natural product. Having served its purpose, the picolinamide
moiety was removed under reducing conditions affording free
amine 9.[17] After extensive experimentation, we found that
oxidation of this free amine to the corresponding ketone using
IBX led to the desired building block 10 (Scheme 2).[18] The
amine-to-ketone functional group interconversion is seldom
utilized in total synthesis, despite several methods being
reported.[19] In this case, protonation of the nucleophilic
quinuclidine nitrogen with pTsOH as an additive proved to be
crucial to achieve oxidation in good yield. In the absence of the
acid additive, competing fragmentation of the bicyclic framework
took place.
With ketone 10 in hand, the stage was set for the aldol
reaction with 6-methoxyquinoline-4-carbaldehyde 12. We noted
that an early attempt toward the synthesis of Quinine via an
aldol addition between an unsubstituted quinuclidinone and
benzaldehyde was previously reported by Stotter et al. more
than 30 years ago.[20] In that study, preliminary experiments with
3-quinuclidone and benzaldehyde as model substrates revealed
rapid epimerization (i.e. configurational instability) of the aldol
product. Although the authors overcame this undesired
isomerization through in situ reduction of the newly-formed
addition product, this approach to the synthesis of Quinine
ultimately proved unsuccessful. More recently, Williams et al.
made similar observations in the course of their synthesis of 7-
hydroxy-quinine.[21]
Scheme 1. Scope of divergent C(sp3)‒H arylation on quinuclidine 3. Reagents
and conditions: (1) Picolinic acid, CDI, DMF, r.t., 16 h. (2) ArI, Pd(OAc)2,
Ag2CO3, DMF, 100 °C, 16 h. * - 1:1 mixture of diastereoisomers starting from
(±)-3.
Thus, arenes bearing electron-donating (Me, OMe) as well
as electron-withdrawing groups (CF3, Cl, CO2Me, NO2) could be
efficiently appended to 3. Notably, 4-chloro-iodobenzene proved
to be a suitable partner for the reaction without affecting the
chloride moiety and esters were also well-tolerated. Ortho-
substituted aromatics could be introduced, albeit in lower yield.
The successful reaction using a complex estradiol derivative is
particularly noteworthy (4j).
In the event, the availability of intermediate 4c in
enantiomerically pure (‒)-form (starting from (‒)-2) enabled a
route towards the natural product (Scheme 2). This was
accomplished by Ru-catalyzed oxidative degradation of the
anisole moiety to a carboxylic acid,[14] isolated as zwitterion 5.
Formation of Weinreb amide 6 was accomplished by HATU-
mediated coupling, and subsequent reduction by DIBAL-H
afforded the masked aldehyde 7.[15] It is noteworthy that no
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10.1002/anie.201804551
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demanding, methanesulfonyl-hydrazone 14 (Scheme 3b) along
with the more reactive reducing system LiAlH4/MeOH
(presumably generating trimethoxyaluminum hydride) was
capable of finally delivering (−)-Quinine (1) in 53% yield
(Scheme 3b). Our synthesis of this natural product thus stands
at 10 steps from (‒)-2 and 5.4% overall yield.
The flexibility of this synthetic approach allowed us to
apply an analogous synthetic sequence to prepare the unnatural
enantiomer (+)-Quinine. To the best of our knowledge, no study
exists on the biological activity of the unnatural antipode of this
natural product.[24] Furthermore, when applied to C‒H activation
products (±)-4b and (±)-4c, the synthetic sequence outlined
herein resulted in two novel analogs of Quinine (±)-15b and (±)-
15c in only four additional steps (Table 1; for details, see SI). All
these compounds were tested for antimalarial activity in vitro
(see Supplementary Table 1). The activity of (+)-Quinine is
slightly decreased against Plasmodium falciparum (P.
falciparum) compared to (−)-Quinine, whereas novel C3-aryl
analogs (±)-15b and (±)-15c showed improved activity. Based
on these results, in vivo experiments using the aryl analogs on
mice infected with Plasmodium berghei (P. berghei) were
performed (Table 1).
Scheme 3. a) Model studies towards a stereoselective aldol reaction. b)
Endgame for the total synthesis of (‒)-Quinine. Reagents and conditions: (9)
LiHMDS, THF, −78 °C, 1 h, then aldehyde 12, then Ti(O-i-Pr)3Cl, MsNHNH2,
r.t., 3 h. (10) LiAlH4, MeOH, THF, r.t., 10 min.
In our initial studies, we prepared racemic aryl-substituted
quinuclidone 11c (see SI for details) as a readily available model
substrate. As shown in Scheme 3a, the aldol reaction of 11 with
aldehyde 12 proceeded in very good yield. In analogy to the
studies of Stotter,[20] the product
B
underwent rapid
Table 1. In vivo activity of racemic aryl analogs (±)-15b and (±)-15c, and (‒)-
Quinine hydrochloride as reference against P. berghei in mice.
epimerization to the undesired C8 diastereoisomer upon
attempted purification. Recognizing that the acidity at C8
(marked * in Scheme 3a) must be rapidly curtailed following the
aldol reaction, we eventually found that epimerization could be
suppressed by in situ treatment of the nascent aldol addition
product with Ti(O-i-Pr)3Cl followed by conversion of the ketone
functionality into a sulfonylhydrazone in a one-pot operation.
This sequence of operations facilitated the isolation of 13 in 86%
yield with a high level of diastereoselectivity (d.r. > 16:1, relative
configuration assigned by X-ray structure analysis after TBS-
protection).[22]
Applying these same aldol reaction conditions using vinyl-
substituted Quinine precursor 10 proved similarly successful; the
desired tosylhydrazone was obtained in high yield and excellent
diastereoselectivity (see SI), leaving its removal as the final
remaining step. Despite its apparent simplicity, this proved to be
a very challenging endeavor. A plethora of common reductants
(NaBH4, DIBAL-H, NaBH3CN among others) led either to no
reaction or to undesired byproducts. Various modifications of the
Wolff-Kishner reduction (such as Myers or Cram)[23] were also
investigated but failed to afford the desired product, while
alternative approaches to trap the configurationally labile aldol
product (e.g. as dithiane or diol) likewise proved unsuccessful.
Consideration of molecular models of hydrazone 13 revealed
severe steric congestion around the hydrazone C=N carbon and
suggested that this might be responsible for its experimentally
observed slow reduction and sluggish sulfonyl elimination. We
eventually found that the critical choice of a less sterically
Parasitemia
Survivalb (in
days)
Substance
Dose (mg/kg)
reduction (in %)a
30
100
30
42
80
98
99
0
euthan
7 ± 0
(−)-Quinine
hydrochloride
8 ± 1
(±)-15bc
(±)-15cc
100
30
21 ± 7
euthan
7 ± 1
100
98
[a] Blood for parasitemia determination was collected on day 3 (72 h after
infection). [b] Mean survival time in days ± standard deviation. Mice with
parasitemia reduction < 50% were euthanized on day 3 postinfection in order
to prevent death otherwise occurring on day 6. [c] Purity of > 99% determined
by HPLC.
The compounds were orally administered in a single dose
24 hours after infection and subsequently both parasitemia after
3 days and survival time were recorded. CF3-aryl analog (±)-15b
exhibits high antimalarial activity in both doses tested and also
significantly increases the survival time of the infected mice,
while (−)-Quinine exhibited only moderate activity at an oral
dose of 100 mg/kg. Remarkably, single dose administration of
100 mg/kg of (±)-15b reduced the amount of parasitized red
blood cells to only 1 percent and therefore prolonged the
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M. Sarkar, Y. Taira, A. Nakano, K. Takahashi, J. Ishihara, S.
Hatakeyama, Tetrahedron Lett. 2011, 52, 923.
average lifespan of the mice to 21 days, compared to 7 days for
(−)-Quinine. Based on these results, replacement of the vinyl
group with a more lipophilic aryl moiety seems to increase the
efficacy of the drug.
[7]
[8]
[9]
G. Stork, D. Niu, A. Fujimoto, E. R. Koft, J. M. Balkovec, J. R. Tata, G.
R. Dake, J. Am. Chem. Soc. 2001, 123, 3239.
T. Dinio, A. P. Gorka, A. McGinniss, P. D. Roepe, J. B. Morgan, Bioorg.
Med. Chem. 2012, 20, 3292.
In summary, herein we have presented a flexible and
concise approach to Quinine which begins from commercially
available 3-aminoquinuclidine and makes use of its lone
aminostereocenter to achieve introduction of all the necessary
functionalities of the natural product with excellent regio- and
stereoselectivity. This enabled the synthesis of both natural (−)-
and unnatural (+)-Quinine as well as two analogues bearing
aromatic groups at the C3 position.[25] The latter are available in
only 6 synthetic steps from aminoquinuclidine and, given their
significantly enhanced antimalarial activity in vitro and in vivo,
imply potential therapeutic applications for the chemistry
presented herein.
a) V. G. Zaitsev, D. Shabashov, O. Daugulis, J. Am. Chem. Soc. 2005,
127, 13154; b) E. T. Nadres, G. I. F. Santos, D. Shabashov, O.
Daugulis, J. Org. Chem. 2013, 78, 9689.
[10] For selected examples of the picolinamide directing group in synthesis,
see: a) G. He, G. Chen, Angew. Chem. Int. Ed. 2011, 50, 5192; G. He,
G. Chen, Angew. Chem. 2011, 123, 5298; b) S.-Y. Zhang, G. He, Y.
Zhao, K. Wright, W. A. Nack, G. Chen, J. Am. Chem. Soc. 2012, 134,
7313; c) D. S. Roman, A. B. Charette, Org. Lett. 2013, 15, 4394; d) W.
Cui, S. Chen, J.-Q. Wu, X. Zhao, W. Hu, H. Wang, Org. Lett. 2014, 16,
4288.
[11] Both racemic and enantiopure 3-aminoquinuclidine dihydrochloride are
commercially available from more than 100 sources (according to
SciFinder) and offered often in bulk quantities. For instance, and at the
time of writing, the racemic form is available in 25 g quantities for 153 €
(TCI Chemicals) or 130 USD (Ark Pharm). The enantiopure material is
supplied by more than 100 common vendors as well (e.g. Oakwood
Chemical offers 100 g quantities for 450 USD ((S)-enantiomer) or
995 USD ((R)-enantiomer).
Acknowledgements
Generous support by the University of Vienna and the Max-
Planck-Institut für Kohlenforschung, where parts of this research
were carried out, is acknowledged. We are thankful to the ERC
(StG FLATOUT and CoG VINCAT), the FWF (graduate program
MolTag W1232), the DFG (Grants MA 4861/3-1, 4-1 and 4-2) for
support, to Dr. X. Chen (UVienna) for material throughput, to Ing.
A. Roller (UVienna) for X-ray crystallography and Prof. W.
Lindner (UVienna) for the chromatographic separation of the
enantiomers of (±)-Quinine.
[12] For selected reviews on palladium-catalyzed, directed C−H activation,
see: a) X. Chen, K. M. Engle, D.-H. Wang, J.-Q. Yu, Angew. Chem. Int.
Ed. 2009, 48, 5094; X. Chen, K. M. Engle, D.-H. Wang, J.-Q. Yu,
Angew. Chem. 2009, 121, 5196; b) O. Daugulis, H.-Q. Do, D.
Shabashov, Acc. Chem. Res. 2009, 42, 1074; c) T. W. Lyons, M. S.
Sanford, Chem. Rev. 2010, 110, 1147; d) H. Li, B.-J. Li, Z.-J. Shi, Catal.
Sci. Technol. 2011, 1, 191; e) G. Rouquet, N. Chatani, Angew. Chem.
Int. Ed. 2013, 52, 11726; G. Rouquet, N. Chatani, Angew. Chem. 2013,
125, 11942; f) Z. Chen, B. Wang, J. Zhang, W. Yu, Z. Liu, Y. Zhang,
Org. Chem. Front. 2015, 2, 1107; g) J. He, M. Wasa, K. S. L. Chan, Q.
Shao, J.-Q. Yu, Chem. Rev. 2016, 117, 8754.
Keywords: Quinine • C−H activation • malaria • total synthesis
[13] See SI for a summary of attempted catalytic C−H functionalizations of
compound 3.
[1]
a) K. C. Nicolaou, S. A. Snyder, Quinine, in Classics in Total Synthesis
II: More Targets, Strategies, Methods, Wiley-VCH, Weinheim, 2003; b)
T. S. Kaufman, E. A. Rúveda, Angew. Chem. Int. Ed. 2005, 44, 854; T.
S. Kaufman, E. A. Rúveda, Angew. Chem. 2005, 117, 876; c) J. I.
Seeman, Angew. Chem. Int. Ed. 2007, 46, 1378; J. I. Seeman, Angew.
Chem. 2007, 119, 1400; d) K. C. Nicolaou, T. Montagnon, Quinine, in
Molecules That Changed the World, Wiley-VCH, Weinheim, 2008.
J. Achan, A. O. Talisuna, A. Erhart, A. Yeka, J. K. Tibenderana, F. N.
Baliraine, P. J. Rosenthal, U. D’Alessandro, Malar. J. 2011, 10, 144.
a) E. N. Jacobsen, I. Marko, W. S. Mungall, G. Schroeder, K. B.
Sharpless, J. Am. Chem. Soc. 1988, 110, 1968; b) S. France, D. J.
Guerin, S. J. Miller, T. Lectka, Chem. Rev. 2003, 103, 2985; c) S.-K.
Tian, Y. Chen, J. Hang, L. Tang, P. McDaid, L. Deng, Acc. Chem. Res.
2004, 37, 621; d) M. J. Gaunt, C. C. C. Johansson, Chem. Rev. 2007,
107, 5596; e) T. Ooi, K. Maruoka, Angew. Chem. Int. Ed. 2007, 46,
4222; T. Ooi, K. Maruoka, Angew. Chem. 2007, 119, 4300.
[14] a) J. A. Caputo, R. Fuchs, Tetrahedron Lett. 1967, 8, 4729; b) P. H. J.
Carlsen, T. Katsuki, V. S. Martin, K. B. Sharpless, J. Org. Chem. 1981,
46, 3936; c) L. N. Mander, C. M. Williams, Tetrahedron 2003, 59, 1105.
[15] S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815.
[16] a) G. Wittig, U. Schöllkopf, Chem. Ber. 1954, 87, 1318; b) G. Wittig, W.
Haag, Chem. Ber. 1955, 88, 1654.
[17] D. H. O’ Donovan, C. D. Fusco, D. R. Spring, Tetrahedron Lett. 2016,
57, 2962.
[2]
[3]
[18] K. C. Nicolaou, C. J. N. Mathison, T. Montagnon, Angew. Chem. Int. Ed.
2003, 42, 4077; K. C. Nicolaou, C. J. N. Mathison, T. Montagnon,
Angew. Chem. 2003, 115, 4211.
[19] a) E. J. Corey, K. Achiwa, J. Am. Chem. Soc. 1969, 91, 1429; b) A.
Miyazawa, K. Tanaka, T. Sakakura, M. Tashiro, H. Tashiro, G. K. S.
Prakash, G. A. Olah, Chem. Commun. 2005, 2104; c) D. Knowles, C.
Mathews, N. Tomkinson, Synlett 2008, 2008, 2769; d) J. Srogl, S.
Voltrova, Org. Lett. 2009, 11, 843.
[4]
[5]
a) R. B. Woodward, W. E. Doering, J. Am. Chem. Soc. 1944, 66, 849;
b) R. B. Woodward, W. E. Doering, J. Am. Chem. Soc. 1945, 67, 860.
For racemic syntheses of Quinine, see: a) J. Gutzwiller, M. R.
Uskokovic, J. Am. Chem. Soc. 1978, 100, 576; b) M. R. Uskokovic, J.
Gutzwiller, T. Henderson, J. Am. Chem. Soc. 1970, 92, 203; c) M.
Gates, B. Sugavanam, W. L. Schreiber, J. Am. Chem. Soc. 1970, 92,
205.
[20] P. L. Stotter, M. D. Friedman, D. E. Minter, J. Org. Chem. 1985, 50, 29.
[21] D. M. Johns, M. Mori, R. M. Williams, Org. Lett. 2006, 8, 4051.
[22] See SI for X-ray structure details.
[23] a) D. J. Cram, M. R. V. Sahyun, J. Am. Chem. Soc. 1962, 84, 1734; b)
M. E. Furrow, A. G. Myers, J. Am. Chem. Soc. 2004, 126, 5436.
[24] In historical studies both the natural and non-natural enantiomer of
dihydroquinine have been tested on mice infected with P. berghei;
showing similar activity. See: A. Brossi, M. Uskokovic, J. Gutzwiller, A.
U. Krettli, Z. Brenner, Experientia 1971, 27, 1100.
[6]
For asymmetric syntheses of Quinine, see: a) I. T. Raheem, S. N.
Goodman, E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 706; b) J.
Igarashi, M. Katsukawa, Y.-G. Wang, H. P. Acharya, Y. Kobayashi,
Tetrahedron Lett. 2004, 45, 3783; c) O. Illa, M. Arshad, A. Ros, E. M.
McGarrigle, V. K. Aggarwal, J. Am. Chem. Soc. 2010, 132, 1828; d) S.
[25] Furthermore, when starting from racemic 3-aminoquinuclidine (+)- and
(−)-Quinine can be separated using chiral chromatography (see SI for
conditions).
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Entry for the Table of Contents
COMMUNICATION
Revisiting an old friend: Herein we
Daniel H. O’Donovan, Paul Aillard,
Martin Berger, Aurélien de la Torre,
Desislava Petkova, Christian Knittl-
Frank, Danny Geerdink, Marcel Kaiser
and Nuno Maulide*
report
a
novel approach to the
classical natural product Quinine
based on two stereoselective key
steps, namely a C(sp3)−H activation
and an aldol reaction. This strategy
enables the preparation of both
antipodes of the target as well as
novel synthetic analogues that display
enhanced in vivo antimalarial activity.
((insert TOC Graphic here))
Page No. – Page No.
C−H Activation Enables a Concise
Total Synthesis of Quinine and
Analogues
with
Enhanced
Antimalarial Activity
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