'Wake-Up Call of A Sleeping Beauty': Straightforward Synthesis of Functionalized β-(2-Pyridyl) Ketones from 2,6-Lutidine

Article abstract of DOI:10.1055/s-0036-1588154

β-(2-Pyridyl) ketones are a unique class of heterocycles with valuable physicochemical properties and emerging relevance as pharmacophores. Herein we report a one-step process for the preparation of various substituted β-(2-pyridyl) ketones from the common starting material, 2,6-lutidine. Furthermore, we demonstrate the utility of this building block by synthesizing of a small set of antimalarial natural products.

Full text of DOI:10.1055/s-0036-1588154

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
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L. C. Bouchez et al.
Letter
Synlett
‘Wake-Up Call of A Sleeping Beauty’: Straightforward Synthesis of
Functionalized β-(2-Pyridyl) Ketones from 2,6-Lutidine
O
O
Laure C. Bouchez*
Cyril Gerbeaux
Marion Rusch
O
O
N
Maude Patoor
Madeleine Livendahl
Neil J. Press
racemic Cladosporin analogue
X
Ar
N
N
Ar
O
O
X = Cl, OH, OMe, N(Me)OMe
Novartis Institutes for Biomedical Research,
Fabrikstrasse 22-1.051.17, 4054 Basel, Switzerland
laure.bouchez@novartis.com
N
O
up to 90% yield
key building block
O
F
Cassiarin C, D, E precursor
Received: 10.02.2017
Accepted after revision: 13.02.2017
Published online: 22.03.2017
blood- and liver-stage proliferation. Cladosporin (1)5 and
cassiarin D (2) were both identified as being potent anti-
parasitic compounds (Figure 1).
DOI: 10.1055/s-0036-1588154; Art ID: st-2017-b1728-l
Abstract β-(2-Pyridyl) ketones are a unique class of heterocycles with
valuable physicochemical properties and emerging relevance as phar-
macophores. Herein we report a one-step process for the preparation
of various substituted β-(2-pyridyl) ketones from the common starting
material, 2,6-lutidine. Furthermore, we demonstrate the utility of this
building block by synthesizing of a small set of antimalarial natural
products.
HO
O
O
OH
OH
O
O
O
O
N
HO
HO
O
1, Cladosporin
3, Cassiarin C
Key words β-(2-pyridyl) propanone, acylation, malaria, small-mole-
cule natural-product analogues
O
O
O
O
N
O
N
OH
Heterocyclic compounds play an important role in me-
dicinal chemistry and drug synthesis.1 Like any important
functional class of compounds, developments that facilitate
their preparation or elucidate their reaction mechanisms
are significant for process chemists in the pharmaceutical
industry. Over the last decades, β-(2-pyridyl) ketones have
emerged as attractive precursors not only for heterocyclic
bioactive molecules2 but also for advanced materials such
as organic semiconductors.3
Indeed, in a continuing search for bioactive molecules
which display curative possibilities for many human ail-
ments such as cancer, Alzheimer’s disease, malaria, and
pain, among others, we focused our attention on plants of
medicinal importance. The vast diversity of plants on the
planet gives a promising journey ahead in the quest for
knowledge and represents a valuable source of new drug
leads and novel scaffolds.
2, Cassiarin D
4, Cassiarin E
Figure 1 Structure of cladosporin and cassiarin C–E
Unlike cladosporin, which can be isolated from different
fungal sources6 (for instance: Aspergillus flavus, and several
Eurotium genus), cassiarin D was extracted from a plant;
Cassia siamea Lam. (Leguminosae) that has been used wide-
ly in traditional medicine, particularly for treatment of pe-
riodic fever and malaria in Indonesia. Notably, in 2009,
three novel alkaloids, cassiarin C (3), D (2), and E (4), exhib-
iting a moderate antiplasmodial activity against Plasmodi-
um falciparum 3D7 (24.2 μM, 3.6 μM, and 7.3 μM, respec-
tively), were isolated and characterized by the group of
Morita.7 Cassiarin C–E display an unprecedented tricyclic
skeleton where an elaborated pyridyl-propanone could
serve as a starting point for their total synthesis. Similarly,
observing the structure of cladosporin and evaluating pos-
sible medicinal chemistry development of the molecule, we
envisioned the synthesis of a series of analogues with pyr-
With renewed calls for malaria eradication, next-gener-
ation antimalarials will need to be active against drug-
resistant parasites and efficacious against both liver- and
blood-stage infections.4 We screened a natural product li-
brary to identify inhibitors of Plasmodium falciparum
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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L. C. Bouchez et al.
Letter
Synlett
idyl-propanone being our key building block. Notably, the
synthesis of β-(2-pyridyl) propanones and their picolylde-
rivative homologues, as it stands today, largely relies on the
use of rather dangerous and toxic starting materials and are
often accessible only via a multistep synthesis.8
With this in mind, we embarked on the development of
an acylation reaction that should be robust, productive,
scalable, and flexible. We started by developing the acyla-
tion conditions with Weinreb amides9 bearing two specific
types of electron-withdrawing groups (EWG), for which we
had a synthetic preference, as they offer potential late-stage
functionalization of drug-like molecules10 (Scheme 1;
EWG = F and NO2).
presence of s-BuLi could give rise to the corresponding β-
(2-pyridyl) ketone in 20% and 90% yield, respectively (Table
1).
Table 1 Exploration of the Conditions for the Synthesis of Fluoro- and
Nitro-β-ketopyridyl
Entrya
X
Conditions
Yield (%)b
1
2
3
4
5
6
7
8
9
NO2
n-BuLi (2 equiv), –80 °C for 1 h
–
–
NO2
NO2
NO2
NO2
F
s-BuLi (2 equiv), –80 °C for 1 h
s-BuLi (2 equiv), –80 °C to –30 °C for 2 h
s-BuLi (2 equiv), –30 °C for 1 h
6a 8
6a 20
–
KHMDS (2.1 equiv), –80 °C for 30 min
LDA (2.1 equiv), –80 °C for 30 min
LiHMDS (2.1 equiv), –80 °C for 15 min
n-BuLi (2.1 equiv), –80 °C for 10 min
s-BuLi (2 equiv), –80 °C for 1 h
O
6b 60
–
N
N
F
O
O
N
X
X
F
6b 77
6b 90
base (Table 1)
THF (15 min to 3 h)
–80 to –30 °C
6a: X = NO2
6b: X = F
5a: X = NO2
5b: X = F
F
a Reactions were performed in THF on a 0.5–1 mmol scale.
b Yield of isolated products.
10–90%
Scheme 1 Synthesis of fluoro- and nitro-β-ketopyridyl
To further explore the scope of the reaction, a series of
potential acylating agents of varying softness and reactivity
were studied: acyl chloride, esters, Weinreb amides, and al-
dehydes.14 As predicted, Weinreb amides were less prob-
lematic over its acyl chloride and the esters counterparts in
terms of potential for overalkylation and were further car-
ried on for the preparation of a small collection of pyridyl
derivatives in moderate to good yields (9a–l). Interestingly,
it should be noted that all the β-(2-pyridyl) ketones exist as
a mixture of keto–enol tautomers, whose ratio depends on
the carbonyl substitution15 (9′, Scheme 2). Particularly
noteworthy, are the examples shown in entry 9m and 9n, in
which Weinreb amides were replaced by their correspond-
ing aldehydes 8m (2-cyclohexylacetaldehyde) and 8n [(R)-
citronellal], to afford the desired alcohols in high yield and
without any further decomposition (Figure 2).
A literature search for additional acylation conditions in
the presence of Weinreb amides returned only very limited
references, indicating that this beautiful reaction,11 asleep
for many years, was due to for a revival. Indeed, to awake
this ‘sleeping beauty’ we took a look at the 1977 paper pub-
lished by H. Anderson et al.,13 which investigated the acyla-
tion of the pyrrolyl ambident anion and rationalized most
of their results using the principle of Pearson around hard
and soft acids and bases. Based on this work, we postulated
that direct acylation should proceed via deprotonation of
the 2,6-lutidine, with a range of organolithium reagents
(e.g., LDA, n-BuLi, s-BuLi, LiHMDS, and eventually KHMDS),
according to the same principle. Pleasingly, we here demon-
strated that in contrast to previous reports,5 unreactive acy-
lating agents such as 5a and to a greater extent 5b, in the
O
O
O
c) see Figure 2
a) or b)
R
R
+
N
N
O
R
N
X
7
8a–l
9a–l
X = OH, Cl, OMe
O
R'
H
8m–n
OH
OH
R'
R
N
N
9m–n
9a'–l
Scheme 2 Synthesis a small collection of β-ketopyridyls and racemic 1-(6-methylpyrdin-2-yl) alcohols. Reagents and conditions: a) SOCl2, reflux followed
by Weinreb amine in pyridine–CH2Cl2 at r.t., or b) DIPEA, EDCI, Me(MeO)NH·HCl in CH2Cl2 at r.t.; for c) see Figure 2; 8m corresponds to 2-cyclohexyl-
acetaldehyde and 8n to (R)-citronellal.
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L. C. Bouchez et al.
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This methodology also enables the synthesis of asym-
metric β-(2-pyridyl) alcohol (9m,n, dr = 2:1), reacting
the enantiopure (R)-citronellal and cyclohexanal with the
2,6-lutidine under standard conditions, as exemplified in
Figure 2.16
a) s-BuLi (2.3 equiv), THF
–78 °C, 30 min
N
N
O
OH
b)
O
O
OH
2 equiv
12
OH
F
Finally, more elaborated arylketones were also investi-
gated. Substrates bearing multiple functionalities (11 and
14) were successfully prepared.
Addition of 2-pyridylmethyl lithium to the 5-(4-fluoro-
phenyl)-5-oxopentanoic acid (11) commercially available
under optimized conditions (Scheme 3) followed by Lewis
acid catalyzed cyclization in the presence of BF3·OEt2
opened a convenient entry into the fluorophenyl-pyridinyl-
substituted lactone 13 [78% for 12 (ref. 16), quantitative for
13 (see supporting information)].
F
11 (1 equiv), THF
–78 °C, 1 h
78%
BF3·OEt2
CH2Cl2, RT, 16 h
quantitative
N
O
O
With this methodology established, compound 1417 was
swiftly elaborated into the pyridinyl-isocoumarin 15 (60%),
mimicking the signature tetrahydropyran-isocoumarin mo-
tif as a first racemic cladosporin natural product analogue
(Scheme 4). This compound is currently being evaluated for
its antimalarial properties.
F
13
Scheme 3 Synthesis of a novel functionalized lactone 13
O
O
a) s-BuLi (2.3 equiv), THF
N
–78 °C, 30 min
The results of this venture and of a first round of chemi-
cal synthesis of elaborated scaffolds are summarized. A
range of β-(2-pyridyl) ketones and their picolylderivative
homologues were successfully synthesized in a single-step
process. Our group is currently exploring the enantiomeric
aspect of this fundamental reaction. This method may
O
b)
O
N
O
O
15
2 equiv
OMe
O
O
14 (1 equiv)
THF, –78 °C, 1 h then –20 °C
60%
Scheme 4 Synthesis of a racemic non-natural cladosporin analogue 15
F
O
O
O
S
N
N
N
N
F
9a, 79%
9c, 82%
9b, 55%
NH2
CF3
O
O
O
N
N
N
N
9f, 35%
9e, 45%
9d, 77%
O
O
O
NH
O
9h, 93%
O
N
N
O
9g, 63%
9i, 35%
F
O
SO2Me
O
O
N
N
N
9j, 84%
9k, 89%
9l, 67%
OH
OH
N
N
9m, 85%
9n, 69% (dr 2:1)
Figure 2 Scope of the acylation reaction. Yields of isolated compounds after column chromatography are given.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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L. C. Bouchez et al.
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Synlett
prove highly useful in the context of the synthesis of clado-
sporin analogues and other cassiarin natural products. Fur-
ther results will be reported in due course.
and stirred under reflux over a period of 5 h. The excess of SOCl2
was then removed under reduced pressure. Under inert atmo-
sphere, the crude residue was taken into CH2Cl2, added drop-
wise to a solution of N,O-dimethylhydroxylamine hydrochloride
(1.1 equiv) and pyridine (2.2 equiv) at 0 °C (NB: final concentra-
tion must not exceed 0.1 mol/L) and slowly warmed to r.t. After
completion of the reaction, the crude mixture was diluted with
CH2Cl2, and rinsed three times with water. The organic phase
was decanted and was washed with a sat. solution of NaHCO3,
and neutralized with a solution HCl (1 M) until pH 7. The
organic layers were dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified
by flash chromatography (gradient of eluent from 100% heptane
to 100% EtOAc) to afford the corresponding Weinreb amide.
Method B
Diisopropylethylamine (4 equiv, 0.1 mmol), followed by 1-ethyl-
3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1 equiv
were sequentially added to a dry solution of the corresponding
carboxylic acid (1 equiv) in CH2Cl2 and stirred for 10 min at r.t.
N,O-Dimethylhydroxylamine hydrochloride (2 equiv) was
added, and the resulting mixture was stirred until all starting
materials were consumed (TLC and LC–MS monitoring). The
crude reaction was quenched with a sat. aq NH4Cl solution and
extracted with EtOAc. The organic layers were washed with a
sat. solution of NaCl, dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. The residue was purified by
flash chromatography (gradient of eluent from 100% heptane to
100% EtOAc) affording the desired Weinreb amides.
Acknowledgment
This work was supported by the Global Discovery Chemistry (GDC)
department at the Novartis Institute for BioMedical Research (NIBR).
We would like to thank specifically Prof. Fabrice Denes and Prof. Mary
J. Sever for constructive discussions.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588154.
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References and Notes
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cited therein.
See the Supporting Information for full characterization and
spectra.
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M. J.; Bradbury, J. J. Med. Chem. 2006, 49, 39. (d) Birchler, A. G.;
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(14) (a) Ho, T.-. L. Chem. Rev. 1975, 75, 1. (b) Pearson, R. G. J. Am.
Chem. Soc. 1963, 85, 3533.
(15) A ratio in favor of the enol form compared to the ketone form
was observed in the case of carbonyls bearing electron-with-
drawing aromatic groups. When reacting in the presence of het-
eroaromatic rings, such as thiophene, pyridine, and indole
rings, the equilibrium was in favor of the ketone form.
(16) General Procedure for the Preparation of β-Keto-Pyridyls
In a 50 mL dry three-neck round-bottom flask was introduced a
solution of 2,6-lutidine (2 equiv, 0.09 mmol) in THF under
argon. The solution was cooled to –78 °C and a solution of s-BuLi
(1.4 M in cyclohexane, 2.3 equiv) was added dropwise to the
reaction mixture, which was then stirred for 15–30 min at –78 °C.
A solution of the electrophile of choice (1 equiv) in THF was
then added dropwise and stirred for 15–60 min at –78 °C.
The crude reaction was quenched with a sat. aq NH4Cl solution
(8) (a) Press, N. J.; Taylor, R. J.; Fullerton, J. D.; Tranter, P.; McCarthy,
C.; Keller, T. H.; Arnold, N.; Beer, D.; Brown, L.; Cheung, R.;
Christie, J.; Denholm, A.; Haberthuer, S.; Hatto, J. D. I.; Keenan,
M.; Mercer, M. K.; Oakman, H.; Sahri, H.; Tuffnell, A. R.; Tweed,
M.; Trifilieff, A. J. Med. Chem. 2015, 58, 6747. (b) Li, B.; Wei, H.;
Li, H.; Pereshivko, O. P.; Peshkov, V. A. Tetrahedron Lett. 2015,
56, 5231. (c) Crawford, J. J.; Young, W. B. WO 2013067277, 2013.
(d) Elsner, J.; Harris, R. L.; Lee, B.; Mortensen, D.; Packard, G.;
Papa, P.; Perrin-Ninkovic, S.; Riggs, J.; Sankar, S.; Sapienza, J. WO
2010062571, 2010.
(9) General Procedure for the Preparation of Weinreb Amide
Method A
In a dry round-bottom flask, the corresponding carboxylic acid
(1 equiv, 0.5 mmol) was added to a solution of SOCl2 (20 equiv),
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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L. C. Bouchez et al.
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Synlett
at –78 °C and allowed to warm up to r.t. The aqueous phase was
then extracted three times with EtOAc. The combined organic
layers were washed with a sat. solution of NaCl, dried over
anhydrous MgSO4, and concentrated under reduced pressure.
The crude residue was purified by flash chromatography (gradi-
ent of eluent from 100% heptane to 100% EtOAc) to afford the
desired products (6a,b, 9 and 9′ series, and 12; for 15 see the
Supporting Information).
See the Supporting Information for full characterization and
spectra.
(±)-(4R)-4,8-Dimethyl-1-(6-methylpyridin-2-yl)non-7-en-2-
ol (9n)
Compound 9n was obtained in 69% yield as a colorless oil. The
compound was isolated as a mixture of two diastereoisomers
(dr = 2:1). 1H NMR (400 MHz, CDCl3): δ = 7.54 (d, J = 7.4 Hz, 1 H),
7.05 (d, J = 7.6 Hz, 1 H), 6.97 (d, J = 7.3 Hz, 1 H), 5.18–5.06 (m, 1
H), 4.19–4.06 (m, 1 H), 2.96–2.76 (m, 2 H), 2.56 (s, 3 H), 2.13–
1.91 (m, 2 H), 1.70 (s, 3 H), 1.62 (s, 3 H), 1.55–1.39 (m, 2 H),
1.34–1.11 (m, 3 H), 0.96 (dd, J = 6.6, 4.7 Hz, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 159.1, 156.7, 136.8, 130.6, 124.4, 120.6,
120.1, 68.6, 68.2, 44.3, 44.2, 43.1, 42.4, 37.5, 36.4, 28.8, 28.3,
25.2, 25.0, 24.9 ppm. LC–MS (tR = 1.00 min for a 2 min run): m/z
calcd for [C17H27NO + H+]: 262.4 [M + H]+.
= 8.8, 5.6 Hz, 2 H), 7.09–6.98 (m, 3 H), 6.90 (d, J = 7.6 Hz, 1 H),
3.26–3.08 (m, 2 H), 2.39 (s, 3 H), 2.08 (td, J = 7.8, 2.5 Hz, 2 H),
1.89–1.74 (m, 1 H), 1.67 (td, J = 13.4, 12.5, 4.7 Hz, 1 H), 1.51 (qd,
J = 12.3, 7.5 Hz, 1 H), 1.18 (dt, J = 12.0, 5.8 Hz, 1 H) ppm. 13C NMR
(101 MHz, (CD3)2SO): δ = 174.37, 161.65, 159.25, 157.89,
156.18, 142.80, 136.82, 127.41/127.34, 121.62, 120.78, 114.16,
113.95, 75.83, 47.93, 41.83, 33.93, 23.85, 18.94 ppm. LC-MS (tR =
0.74 min for a 2 min run): m/z calcd for [C18H20FNO3+H+]: 318.3
[M + H]+.
(±)-6,8-Dimethoxy-3-[(6-methyl-pyridin-2-yl)methyl]iso-
chroman-1-one (15)
Compound 15 was obtained in 60% yield as a yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 7.57 (t, J = 7.5 Hz, 1 H), 7.17 (d, J = 7.4 Hz,
1 H), 7.07 (d, J = 7.6 Hz, 1 H), 6.41 (d, J = 2.2 Hz, 1 H), 6.30 (d, J =
2.2 Hz, 1 H), 4.92–4.83 (m, 1 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.36–
3.30 (m, 1 H), 3.23–3.12 (m, 1 H), 3.02–2.86 (m, 2 H), 2.57 (s, 3
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 169.8, 166.3, 162.8,
158.3, 157.7, 143.1, 137.0, 122.4, 119.5, 108.6, 104.1, 98.5, 79.9,
55.8, 55.2, 39.8, 33.3, 24.6 ppm. LC–MS (tR = 0.73 min for a 2
min run): m/z calcd for [C18H19NO4+H+]: 314.3 [M + H]+.
(17) (a) The work around the design, synthesis and biological evalu-
ation of analogues of cladosporin will be reported in a separated
publication. (b) Mohapatra, D. K.; Maity, S.; Rao, T. S.; Yadav, J.
S.; Sridhar, B. Eur. J. Org. Chem. 2013, 2859. (c) Zheng, H.; Zhao,
C.; Fang, B.; Jing, P.; Yang, J.; Xie, X.; She, X. J. Org. Chem. 2012,
77, 5656.
(±)-5-(4-Fluorophenyl)-5-hydroxy-6-(6-methylpyridin-2-
yl)hexanoic Acid (12)
Compound 12 was obtained in 78% yield as a white solid. 1H
NMR (400 MHz, (CD3)2SO): δ = 7.49 (t, J = 7.7 Hz, 1 H), 7.40 (dd, J
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E