Asymmetric Synthesis of Potential Precursors of the HIV Drug MC1220 and Its Analogues by Hydrogenation of (1-Arylvinyl)pyrimidines

Article abstract of DOI:10.1002/jhet.3168

Because MC1220 is a promising microbicide with anti-HIV-1 activity, the possibility for asymmetric synthesis of its potential precursors is explored. Here, we investigate asymmetric reduction of the vinyl double bond of 6-(1-arylvinyl)pyrimidine derivativ

Full text of DOI:10.1002/jhet.3168

Month 2018
Asymmetric Synthesis of Potential Precursors of the HIV Drug MC1220
and Its Analogues by Hydrogenation of (1-Arylvinyl)pyrimidines
Yasser M. Lokshaa,b
and Erik B. Pedersena
*
aNucleic Acid Centre, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55,
DK-5230 Odense M, Denmark
bDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Sinai University, Al-Arish, North Sinai, Egypt
*
E-mail: yml@su.edu.eg
Received November 19, 2017
DOI 10.1002/jhet.3168
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
Because MC1220 is a promising microbicide with anti-HIV-1 activity, the possibility for asymmetric
synthesis of its potential precursors is explored. Here, we investigate asymmetric reduction of the vinyl
double bond of 6-(1-arylvinyl)pyrimidine derivatives to their corresponding ethylidene analogues. Catalysts
with ligands bearing trivalent phosphorus ligating the soft metals rhodium(I), ruthenium(II), or iridium(I) are
used for asymmetric reduction of the vinyl derivatives 5a–e. The enantioselective reduction reaches 92% ee
and about 71% conversion for reduction of the 6-(1-(3,5-dimethylphenyl)vinyl)pyrimidine derivative 5b
using the asymmetric catalyst catASium M(R)Rh (7m). However, for the more sterically hindered double
bond in the corresponding 2,6-difluorophenyl derivative 5e, the enantioselective reduction dropped to
30% ee and 14% conversion.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
tested; the R-enantiomer was over 2500 times more
active than the S-enantiomer on MT-4 wild type strain.
Analysis of the docking of R-enantiomer in the RT
protein X-ray structure (1RT1) suggested that the
difference in activity could be due to a more favorable
binding energy of the methyl substituent at the benzylic
position [18]. In the light of this remarkable difference in
the biological activity, we were interested in investigating
the possibility of an asymmetric synthesis of MC1220.
Transition metal catalyzed enantioselective hydro-
genation has been established as one of the most favorable
strategies for the synthesis of optically active compounds
in academia and on the industrial scale [19]. In particular,
chiral ligands bearing trivalent phosphorus as the ligating
atom for soft metals like rhodium(I) [20–26],
ruthenium(II) [27–31], or iridium(III) [32–34] play a
pivotal role in this area. Among electron-rich chiral
phosphines, chiral phospholanes have emerged as one of
the most efficient classes of ligands in metal catalyzed
enantioselective reactions. Prominent examples are
bisphospholane ligands like DuPHOS and BPE. In
general, these compounds are synthesized by a linear
approach, where the phospholane is constructed by
condensation of a primary phosphine with the sulfate or
As the HIV pandemic continues to grow, particularly
among young women in many parts of the developing
world, new prevention technologies are urgently needed.
A female-initiated microbicide applied vaginally to
interrupt the initial steps of viral transmission could
complement efficiently the preexisting treatments.
Microbicides are currently being designed in formulations
such as gels, creams, or emulsions that are delivered by
vaginal applicators. Biologically, women are more
vulnerable than men to HIV infection during a single
sexual encounter, and microbicides would provide a
convenient and readily available method of self-
protection against HIV. The class of non-nucleoside
reverse transcriptase inhibitors featuring potent and
selective anti-HIV-1 activity have recently emerged [1–8].
Some of these showed potential as microbicides to
prevent sexual HIV-1 transmission/acquisition [9–14].
One of the most important lead compounds of this series
of tight-binding non-nucleoside reverse transcriptase
inhibitors is MC1220, which is used in racemic form
[9,14–17]. After chiral resolution and X-ray
characterization, both enantiomers of MC1220 were
© 2018 Wiley Periodicals, Inc.

Y. M. Loksha and E. B. Pedersen
Vol 000
Scheme 1. Synthetic route for compounds 5a,b.
Figure 1. MC1220.
sulfonates derived from the appropriate chiral diols in the
presence of strong bases. This tedious approach is
restricted by low tolerance of the functional groups and,
therefore, strongly limits the possible variations of the
backbone [20–26].
Evonik Degussa GmbH has developed a modular
synthesis of diverse arrays of chiral vicinal
bisphospholanes in collaboration with the Leibniz-Institute
of Organic Catalysis in Rostock [20]. These ligands, which
are now commercially available on a multikilogram scale
under the trademark catASium M, are characterized by
varied “bite-angle” and electronic properties of the
bridging unit [21]. A rhodium(I) catalyst based on the new
chiral bisphospholane ligand is one of the most effective
catalytic systems for the hydrogenation of olefins [22–26].
This has recently been extended to asymmetric hydro-
genation of 1,1-diarylethylene in high enantiomeric yields
using cobalt, copper, iridium, and rhodium metalorganic
catalysts [25–39]. We therefore found it interesting to
explore the possibility of asymmetric hydrogenation when
starting with corresponding (1-arylvinyl)pyrimidines in
order to device a synthetic route to enantiomerically
pure/enantioenriched MC1220 (Fig. 1).
Compounds 4a,b were hydrolyzed under strong acidic
conditions to afford 2-(dimethylamino)-6-(1-arylvinyl)-5-
methylpyrimidin-4(3H)-ones 5c,d in 70% and 89%
yields, respectively. The unreported 5e was prepared in
61% yield by methylation of the sodium salt of
compound 5c using methyl iodide in dimethylformamide
(Scheme 2).
The racemic compounds 6a–e were synthesized to be
used as reference compounds for the assessment of the
enantiomeric excesses (by chiral HPLC). MC1220 (6c)
and 2-(dimethylamino)-6-[1-(3,5-dimethylphenyl)ethyl]-
5-methylpyrimidin-4(3H)-one (6d) were obtained as
racemic mixtures by treating compounds 5c,d with 10%
Pd/C under 3.5 bar of hydrogen [16]. Compound 6c was
methylated by treatment of their sodium salts with methyl
iodide to afford the corresponding methoxy derivative 6e
in 86% yield [16]. The unreported racemic compound 6a
was synthesized by refluxing compound 6c with
phosphorus oxychloride (Scheme 2).
Asymmetric hydrogenation of the vinyl group in
compounds 5a–e (the structures of compounds 5c,d
are drawn in their tautomeric enol forms) was
performed under hydrogen (10–100 bar) in the presence
of the asymmetric catalyst 7a–m in methanol
or dichloromethane during 24–96 h (Scheme 3, Table 1).
However, hydrogenation was not observed using the
catalyst (S)-BINAP-Ru(OAc)2 (7a, Fig. 2) for hydro-
genation of 5a–c,e although different condition were tried
by increasing the pressure of hydrogen from 10 bar to
100 bar and the time of the reaction from 24 to 96 h. The
iridium(III) catalyst (7b, Fig. 2) gave 50% ee with 10%
conversion from 5b to 6b but no observed conversion
were obtained for reduction of 5a using the same catalyst
7b. The latter result could be explained by the steric
hindrance to planarity around the vinyl group in 5a due
RESULTS AND DISCUSSION
The diarylethenes (5a–e) for the enantioselective
hydrogenation were prepared by our previously described
procedure [16]. Treatment compound 1 with the sodium
salt of the appropriate arylmethyl cyanides (2,6-
difluorobenzyl cyanide and 3,5-dimethylbenzyl cyanide)
afforded the corresponding 2-[6-chloro-2-(dimethylamino)-5-
methylpyrimidin-4-yl]-2-(aryl)acetonitriles 2a,b in high
yields (86%, 98%). Nucleophilic substitution of
compound 1 under the same conditions as mentioned
earlier to obtain 2a,b without separation, followed by
oxidation with a stream of oxygen bubbled through the
reaction mixture for 3 h afforded the 4-(arylcarbonyl)-6-
chloro-N,N-5-trimethylpyrimidin-2-amines 3a,b in 52%
and 99% yields, respectively. Reaction of 3a,b with
methylmagnesium bromide afforded the tertiary alcohols
4a,b that were dehydrated into the vinyl compounds
5a,b in 65% and 74% yields using phosphorus
pentoxide or phosphorus oxychloride, respectively
(Scheme 1).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Asymmetric Synthesis of Potential Precursors of the HIV Drug MC1220
and Its Analogues
Scheme 2. Synthetic route for compounds 5c–e and the racemic mixture of 6a–e.
Table 1
Scheme 3. Asymmetric reduction of 5a–e to 6a–e.
Data for asymmetric reduction of 5a–e to 6a–e.
Entry
No.
H2
Time
Conv.
(%)
%
ee
Cpd. Cat.
Solv.
(bar) (hours)
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5c
5c
5c
5e
5e
5e
5e
5e
7a MeOH
7b MeOH
7b CH2Cl2
7c CH2Cl2
7d CH2Cl2
7d CH2Cl2
7a MeOH
7b CH2Cl2
7b CH2Cl2
7d CH2Cl2
7e CH2Cl2
7f MeOH
7g MeOH
7h MeOH
7i CH2Cl2
7j CH2Cl2
7k MeOH
7l CH2Cl2
7m MeOH
7a MeOH
7a MeOH
7a MeOH
7a MeOH
7d CH2Cl2
7d CH2Cl2
7f MeOH
7m MeOH
100
50
50
50
20
50
100
50
50
20
20
20
20
20
20
20
20
20
20
10
100
100
100
20
60
20
20
24
24
96
96
96
96
24
24
96
96
96
96
96
96
96
96
96
96
96
24
24
96
24
96
96
96
96
—
—
—
45
—
5
—
10
10
5
—
—
—
0
—
0
—
50
50
22
2
72
71
84
14
19
64
11
92
—
—
—
—
—
6
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
5
63
32
33
12
14
54
12
71
—
—
—
—
—
4
to the presence of fluoro atoms in the ortho position of the
phenyl ring in compound 5a. Instead, rather good results
were obtained for the compound 5b without
ortho substituents when performing the asymmetric
hydrogenation with rhodium(I) catalysts 7c–m (Fig. 2).
The best one was catASium M(R)Rh (7m) that afforded a
conversion of 71% with 92% ee from 5b to 6b. It was
also the best catalyst for reduction of the highly steric
hindered vinyl group by the aryl group with fluoro
atoms in the ortho positions. So 14% of compound 5e
converted by the catalyst 7m into 6e with 30% ee
(Fig. 3). It is assumed that a more suitable 3D structure
of the catalyst catASium M(R)Rh (7m) better makes
complexation possible of rhodium(I) to the vinyl group in
compounds 5a–e.
26
14
12
30
asymmetric rhodium(I), ruthenium(II), or iridium(III)
catalysts. The rhodium(I) catalysts 7c–m were found to
be superior to ruthenium(II) and iridium(III) catalysts.
Using the asymmetric rhodium(I) catalyst catASium
M(R)Rh (7m), we observed a 92% ee with 71%
conversion upon hydrogenation of 5b that has no ortho
substituents in the aryl group. On the other hand,
CONCLUSION
Asymmetric synthesis of MC1220 and related
compounds
were
investigated
by
asymmetric
hydrogenation of (1-arylvinyl)pyrimidines 5a–e using
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Y. M. Loksha and E. B. Pedersen
Vol 000
Figure 2. Transition-metal catalysts used in the hydrogenation arylvinyl pyrimidines.
substrates containing highly sterically hindered ortho,
ortho disubstituted aryl group could not be efficiently
hydrogenated under these conditions, as exemplified by
compound 5e with ortho fluorine atoms in where only
30% ee with 14% conversion was observed upon
hydrogenation to 6e using the catalyst 7m.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Asymmetric Synthesis of Potential Precursors of the HIV Drug MC1220
and Its Analogues
found 306.1409. Anal. Calcd for C16H17F2N3O (305.32):
C, 62.94; H, 5.61; N, 13.76. Found: C, 62.85; H, 5.69;
N, 13.64.
4-Chloro-6-[1-(2,6-difluorophenyl)ethyl]-N,N,5-
trimethylpyrimidin-2-amine (6a). Compound 6c (293 mg,
1 mmole) was refluxed in phosphorus oxychloride (10 mL)
for 1 h. The mixture was left to reach room temperature
and poured on ice-cold water (50 mL). The precipitate
was filtered off, washed with 10% aqueous solution
sodium bicarbonate (10 mL) to afford 250 mg of
compound 6a; yield: 80%, mp 84–86°C; 1H NMR
(duteriochloroform): δ 1.66 (d, 3H, J = 7.2 Hz, CH3CH),
2.05 (s, 3H, CH3─C5), 3.13 [s, 6H, (CH3)2N], 4.60 (q,
1H, J = 7.2 Hz, CH3CH), 6.82 (t, 2H, J = 8.4 Hz, Harom),
7.10–7.20 (m, 1H, Harom); 13C NMR (duteriochloroform)
δ: 13.12 (CH3─C5), 17.72 (CH3CH), 34.84 (CH3CH),
36.83 [(CH3)2N], 111.44 (dd, J = 7.8, 18.9 Hz, Carom),
112.50 (C5), 128.11 (t, J = 10.6 Hz, Carom), 159.64 (C2),
161.10 (C4), 161.41 (dd, J = 8.3, 248.4 Hz, Carom),
169.91 (C6); HRMS (MALDI): m/z Calcd for
C15H17ClF2N3 (MH+) 312.1074, found 312.1076.
Figure 3. Chromatographic enantioresolution of compound 6e resulted
from asymmetric reduction of 5e using catalyst 7m (entry 27): (a) 5b;
(b) enantiomer of 6e at time of 6.34 min; (c) the other enantiomer of 6e
at time of 3.32 min.
Asymmetric reduction procedure.
Under argon, the
asymmetric catalyst 7a–m (2 mg) was shaken with a
solution of 5a–e (20 mg) in methanol or dichloromethane,
1.5 mL. The mixture was left under hydrogen (10–100 bar
for 24–96 h). The conditions and results for 27 trials are
summarized in Table 1. After filtration, the solution was
monitored on HPLC using a chiral column.
EXPERIMENTAL
NMR spectra were recorded on a Varian Gemini 2000
1
NMR spectrometer at 300 MHz for H and 75 MHz for
13C with TMS as internal standard. MALDI mass spectra
were recorded on a 4.7 Tesla Ultima (IonSpec, Irvine,
CA) Fourier Transform Ion Cyclotron Resonance Mass
Spectrometer. Melting points were determined on a Büchi
melting point apparatus. Solvents were bought as HPLC
grade or distilled prior to use. All asymmetric catalyst
(7a–m) were bought from Sigma-Aldrich.
Chromatographic analysis. The enantiomeric separation
was carried out with a Hitachi HPLC LaChrom with L-7100
pump and L-7400 UV detector. The enantioseparation of
compounds 6a–e as racemic mixtures or in enantiomeric
excess was carried out using a commercial CHIRALCEL
OD-H column [cellulose tris(3,5-dimethylphenylcarbamate)
coated on 5 μm silica-gel, 250 × 4.6 mm ID)] bought
from Chiral Technologies Europe. n-Hexane:2-propanol
(95:5 v/v) was used as mobile phase at flow rate of
0.7 mL/min for enantiomeric resolution of 6a,b and
n-hexane:diethyl amine (99.9:0.1, v/v) was used as mobile
phase at flow rate of 1 mL/min. For enantiomeric resolution
of 6c–e. The injection volume for each run was 20 μL.
4-[1-(2,6-Difluorophenyl)vinyl]-6-methoxy-N,N,5-
trimethylpyrimidin-2-amine (5e). Sodium hydride (50 mg,
55% suspension in paraffin oil, 1.2 mmole) was added
portionwise to a solution of 5a (291 mg, 1.0 mmole) in
dry N,N-dimethylformamide (5 mL) at room temperature,
stirred for 0.5 h followed by addition of methyl iodide
(0.07 mL, 1.1 mmole). The mixture was stirred for 2 h
then poured onto cold water (20 mL) and stirred for
0.5 h. The resulted solid product was filtered off and
dried to afford 185 mg of compound 5e; yield 61%; mp
Acknowledgments. This work received funding from the
European Community’s Sixth Framework Programme under
contract number LSHP-CT-2004-503162 (Selection and
development of microbicides for mucosal use to prevent sexual
HIV transmission/acquisition).
1
78–80°C; H NMR (deuteriochloroform): δ 1.96 (s, 3H,
CH3), 3.04 [s, 6H, (CH3)2N], 3.91 (s, 3H, OCH3), 5.79
(s, 1H, HCH═C), 5.91 (s, 1H, HCH═C), 6.85 (t, 2H,
J = 8.0 Hz, Harom), 7.14–7.25 (m, 1H, Harom); 13C NMR
(duteriochloroform): δ 10.66 (CH3), 36.58 [(CH3)2N],
53.17 (OCH3), 101.23 (C5), 111.10 (dd, J = 8.0, 17.6 Hz,
Carom), 124.81 (CH2═C), 128.60 (t, J = 10.3 Hz, Carom),
136.11 (CH2═C), 159.88 (C4), 160.46 (dd, J = 7.4,
248.7 Hz, Carom), 164.09 (C2), 168.82 (C6); HRMS
(MALDI): m/z Calcd for C16H18F2N3O (MH+) 306.1413,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet