Asymmetric Oxidation of a Dihydrothienopyrimidine

Article abstract of DOI:10.1021/acs.oprd.6b00400

A robust catalytic asymmetric oxidation of prochiral sulfide 1 has been achieved by the use of a chiral titanium-hydrobenzoin complex. Reproducible reaction conditions were identified by screening reaction parameters and DOE optimization. The enantioselectivity was found to be mostly influenced by the amount of water and the time the catalyst was aged before addition of the sulfide.

Full text of DOI:10.1021/acs.oprd.6b00400

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Communication
Asymmetric Oxidation of a Dihydrothienopyrimidine
Sonia Rodriguez, Nizar Haddad, Rogelio P Frutos, Nelu Grinberg, and Chris H. Senanayake
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00400 • Publication Date (Web): 25 Jan 2017
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Asymmetric Oxidation of a Dihydrothienopyrimidine
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Sonia Rodríguez,* Nizar Haddad, Rogelio Frutos, Nelu Grinberg, Chris H. Senanayake
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Chemical Development US, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd./P.O. Box
368, Ridgefield, Connecticut 06877ꢀ0368 USA
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KEYWORDS
Catalysis, DoE, asymmetric oxidation, sulfide oxidation, sulfoxide
ABSTRACT
A robust catalytic asymmetric oxidation of prochiral sulfide 1 has been achieved by the use of a chiral
titaniumꢀhydrobenzoin complex. Reproducible reaction conditions were identified by screening
reaction parameters and DOE optimization. The enantioselectivity was found to be mostly influenced by
the amount of water and the time the catalyst was aged before addition of the sulfide.
INTRODUCTION
Asymmetric sulfoxides are present as key substructures in many compounds of medicinal and
pharmaceutical importance. Thienopyrimidine oxides possess therapeutic activity that make them
attractive targets for treatment of cardiovascular, sedative, respiratory and gastrointestinal disorders,
inflammation, diseases of the peripheral or central nervous system, and cancers.1 One of the contributors
to the biological activity of these compounds is the presence of a sulfoxide group. The key challenge in
preparing such compounds is usually associated with the enantioselective synthesis of the desired
sulfoxide stereocenter. Despite the wide number of reported catalytic asymmetric methods,2 relatively
few catalytic processes are currently being applied in industry,2l,3 presumably due to poor
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reproducibility of the enantioselectivity associated with minor variations in reaction conditions. Kagan’s
group addressed reproducibility challenges in the enantioselectivity of their equimolar titaniumꢀethyl
tartrate conditions by controlling the temperature and the preparation protocol of the chiral titanium
complex.2d The highest degree of reproducibility was ensured by adding the titanium to the ligand, then
holding the resulting complex for 2.5 min before adding water dropwise over 90 seconds. The latter
operation time was found more crucial.
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As part of our program towards developing a scalable synthesis of dihydropyrimidines bearing chiral
sulfoxide groups, we became interested in the asymmetric oxidation of sulfide 1.1d We report herein our
findings to provide a robust asymmetric sulfoxidation of dihydrothienopyrimidine 1.
Scheme 1. Asymmetric sulfide oxidation of dihydrothienopyrimidine 1.
RESULTS AND DISCUSSION
The asymmetric oxidation of sulfide 1 was first examined by surveying different protocols (Table 1).4
We initially explored Kagan’s type conditions using equimolar or catalytic amounts of titanium which
afforded the sulfoxide with selectivities up to 73% ee and 2% over oxidation to the corresponding
sulfone (entries 1ꢀ3).2a,d,k When using mandelic acid as ligand, very low enantioselectivy and high
amounts of sulfone were obtained (entry 4).2g We then investigated Uemura’s type conditions using
BINOLꢀtype ligands with little success (entries 5ꢀ6).2e,5b Best results were obtained using the
methodology developed by Rosini and coꢀworkers in the presence of titanium tetraisopropoxide (5
mol%), (R,R)ꢀhydrobenzoin (10 mol%) and water (1 equiv) which gave 92% ee of 3 (entry 7).5b The
main advantage of this catalytic protocol is the high induction of enantioselectivity in the formation of
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the sulfoxides with negligible kinetic resolution due to over oxidation to sulfone.5b Evaluation of other
catalytic protocols based on metals like Mn, V, Fe or W resulted in lower yields and enantioselectivities.
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Table 1. Initial screening for the oxidation of 1
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MX
(equiv)
Additives
(equiv)
Peroxide
(equiv)
Isolated
yield
%
Sulfone
ee *
(%)
Entry
1
Ligand (equiv)
(S,S)-DET (2)
(S,S)-DET (4)
(S,S)-DET (0.6)
Solvent
CH2Cl2
CH2Cl2
toluene
CH2Cl2
CHCl3
T (°C)
-20
-20
35
23
0
time
24 h
24 h
24 h
5 h
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Ti(i-PrO)4
H2O (1)
-
CHP (2)
CHP (2)
CHP (1)
CHP (1)
99%
99%
90%
99%
71%
99%
90%
11%
82%
55%
78%
2
2
-73
-31
-1
(1)
Ti(i-PrO)4
2
(1)
Ti(i-PrO)4
(0.3)
H2O (0.1)
i-Pr2NEt (0.3)
3
7
Ti(i-PrO)4
(0.4)
(S)-mandelic acid
4
MS
H2O (2)
H2O (2)
H2O (1)
-
11
nd
14
2
15
-51
-6
(0.6)
Ti(i-PrO)4
(0.1)
aq t-BuOOH
5
(S)- BINOL (0.2 )
48 h
5 h
(2)
Ti(i-PrO)4
(0.1)
(R)-dibromo-
BINOL (0.2)
6
CHP (2)
toluene
toluene
CH3CN
CH2Cl2
CH2Cl2
THF
23
0
Ti(i-PrO)4
(0.05)
(R,R)-
hydrobenzoin (0.1)
aq. t-BuOOH
7
48 h
15 h
43 h
15 h
24 h
-92
5
(2)
8
(R,R)-Jacobsen cat. (0.02)
aq. H2O2 (6)
23
23
23
23
nd
2
VO(acac)2
(0.02)
aq. H2O2
(1.1)
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Schiff base (0.04)
Schiff base (0.04)
-
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Fe(acac)3
(0.02)
p-Anisic acid
aq. H2O2
(1.2)
10
11
nd
3
(0.01)
WO3
(0.05)
(DHQN)2-PYR
(0.1)
aq. H2O2
(1.05)
-
-59
Abbreviations: MS (molecular sieves), CHP (cumene hydroperoxide), THF (tetrahydrofuran), nd (not detected). *ee was
determined by HPLC. Positive values of ee indicate that enantiomer 2 was obtained as major isomer, while negative values
indicate the opposite enantiomer 3 was obtained as major.
Analysis of the product enantioselectivity at different enantiopurities of ligand revealed a negative nonꢀ
linear effect similar to Kagan’s catalytic system using a tartrate as ligand6 and opposite to Uemura’s
catalytic system using BINOL.7 The asymmetric depletion highlighted the importance of using ligand of
high enantiopurity to ensure high values of ee in the product (Figure 1).
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1
Non-linear effect
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100
90
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0
linear
1 eq water vs. Ti, 0.5 h
20 eq water vs. Ti, 0.5 h
Linear (linear)
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1 eq water vs. Ti, 0.5 h
20 eq water vs. Ti, 0.5 h
0
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ee ligand
Figure 1. Nonꢀlinear effect in the asymmetric oxidation of 1 at two different concentrations of water.
Further optimization of the reaction conditions was performed by screening alternative ligands,
additives, oxidants, solvents and temperatures. Evaluation of other commercially available ligands such
as (S,S)ꢀ1,2ꢀdi(1ꢀnaphthyl)ꢀ1,2ꢀethanediol and (S,S)ꢀ1ꢀ(1ꢀnaphthyl)ꢀ2ꢀ(2ꢀnaphthyl)ꢀ1,2ꢀethanediol
afforded lower selectivities of 43 and 28% ee, respectively. Addition of iꢀPr2NEt,2l Nꢀmethylmorpholine
or 1,4ꢀdimethylpiperazine to the Ti/hydrobenzoin/water catalytic system caused loss of reactivity and
enantioselectivity. tertꢀButyl hydroperoxide in water or decane proved to be a superior oxidant to
hydrogen or cumene hydroperoxide. Solvents such as fluorobenzene or dichloromethane provided lower
enantiomeric excesses of sulfoxide. When the catalyst was prepared at 0ꢀ25 °C before adding the water,
the enantioselectivity of the oxidation was consistently about 90% ee, however, when the catalyst was
prepared at 45 °C before water addition, the selectivity decreased to 68% ee. In addition, when the
peroxide was dosed to the reaction mixture at 0ꢀ25 °C, there was no effect on the enantioselectivity.
Finally, comparable results were obtained when the reaction was carried out under anaerobic or aerobic
conditions.
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Following Kagan’s reproducibility studies on ethyl tartrate as ligand,2d we evaluated the slow addition
of the water during the catalyst preparation with hydrobenzoin and found no significant impact on the
variability of the enantioselectivity. However, we identified two critical factors to insure reproducibility
of high enantioselectivity: first was stirring due to the heterogeneous nature of the reaction media at
moderately concentrated reaction (0.5 M); and secondly, the time the catalyst was hold before addition
of the sulfide. The optimized procedure is as follows: titanium and water were added sequentially
dropwise to a solution of ligand in toluene at 20ꢀ25 °C, followed by the sulfide; the resulting suspension
was stirred for 15 min before cooling to 0 °C and the peroxide was added.
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Further screening of the key factors affecting the Ti/hydrobenzoin/water catalytic system, i.e. catalyst
load, amount of water at the catalyst preparation stage, and the time the catalyst was hold before
addition of the sulfide, ꢀ was performed using statistical design of experiments (DoE)8 to develop a
robust process and to maximize the enantiomeric excess of the reaction. The procedure studied for
optimization was the following: titanium(IV) isopropoxide (5ꢀ20 mol%) was added to (S,S)ꢀ
hydrobenzoin (10ꢀ40 mol%) in toluene at 23 °C followed by water (0ꢀ1.5 equiv). After stirring for
certain time (0.5ꢀ2 h), the sulfide (1.0 equiv) was added, and the reaction mixture was cooled to 0 °C
over 30 min before addition of tertꢀbutyl hydroperoxide (2 equiv).
We utilized DOE program MODDE 8.09 and applied a 2 level full factorial design with one center
point, and complemented it with additional experiments for reproducibility evaluation. Therefore, on the
basis of nine parallel runs, plus four runs for reproducibility using 1.5 equivalents of water and 0.5 h for
catalyst preparation, it was possible to analyze the data by analysis of variance.10 In all cases, complete
conversions with 88ꢀ97% yield were obtained and 64ꢀ97% ee were observed.11 The summary plot
showed high goodness of fit, high goodness of prediction, high model validity and high reproducibility.
Analysis of the factor coefficient plot indicated that the enantiomeric excess would mostly be
maximized by minimizing the holding time of the catalyst before addition of the sulfide, and minimizing
the amount of water added during catalyst formation (Figure 2). Analysis of the response contour plot
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revealed two possible operational areas for maximum enantioselectivities: using 0ꢀ0.6 equivalents of
water at short catalyst preparation times, or using less than 0.1 equivalents of water for preparation of
the catalyst during 1.2ꢀ2 h. The reproducibility runs using 1.5 equivalents of water and stirring the
catalyst for 0.5 h before sulfide addition provided 88ꢀ95% yield and 89ꢀ93% ee.
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Figure 2. Factor coefficient plot and response contour plot at 5 mol% catalyst load.
Verification experiment on 5 g scale using 5 mol% catalyst, 1 equivalent of water and stirring the
catalyst mixture for 30 min before addition of sulfide allowed isolation of 88% of sulfoxide with 89%
ee. Catalyst loading was briefly evaluated at this point, being reduced to 2.5 mol% with no impact on
yield or enantioselectivity.
In order to further minimize the time between preparation of the catalyst and addition of sulfide, we
evaluated the formation of catalyst in the presence of sulfide. Adding the titanium and the water to a
mixture of sulfide and ligand in toluene, cooling to 0 °C over 30 min and adding the peroxide afforded
the sulfoxide in 90% ee.
The above investigations resulted in the development of the following reproducible more robust
procedure: Titanium and water were added sequentially to a slurry of ligand and sulfide in toluene at 20ꢀ
25 °C; the mixture was cooled to 0 °C over 1 h, and the peroxide was added; the reaction mixture was
stirred at 0 °C. The last protocol was also examined at lower concentration of 1 of 0.25 M instead 0.5 M
which increased solubility of the sulfide affording a quasiꢀhomogenous reaction without affecting the
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enantioselectivity. Finally, the catalyst load was reduced to 2.5 mol% without impacting the conversion
or the enantiomeric excess of the product.
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In conclusion,
a
reproducible robust procedure for the asymmetric sulfoxidation of
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dihydrothienopyrimidine 1 was developed by identifying new oxidation conditions and optimizing the
process parameters. We utilized DoE to address irreproducibility issues on the asymmetric oxidation of
sulfides using titaniumꢀhydrobenzoin complex which constitutes the first report on catalytic asymmetric
sulfoxidation. Maximum enantioselectivities were obtained at short catalyst preparation times or at low
amounts of water, achieving optimal results when preparing the catalyst in the presence of the sulfide.
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EXPERIMENTAL SECTION
Reagents were used as purchased without further purification. NMR spectra were recorded on a Bruker
400 MHz spectrometer. The chemical shift data are reported as δ (ppm) downfield from
tetramethylsilane which is used as an internal standard; coupling constants (J) are reported in Hertz, and
refer to apparent peak multiplicities. HPLC analysis was performed on an Agilent 1100 series using an
Agilent XDBꢀC18 column; flow rate 2 mL/min; with a UV detection at 215 nm; mobile phase from
48% to 97% acetonitrile in water (0.1% HClO4) in 1.3 min, then hold to 97% for 1.2 min.
Enantioselectivities were measured on an Agilent 1100 series using a chiralpak ADꢀH column; flow rate
1 mL/min; with a UV detection at 220 nm; mobile phase 20% isopropanol in heptane for 10 min.
Procedure A
To a mechanically stirred solution of (S,S)ꢀhydrobenzoin (292 mg, 1.36 mmol) in toluene (50 mL) in a
100 mL flask at 20 °C was added Ti(iꢀPrO)4 (0.20 mL, 0.68 mmol). After 2ꢀ3 min, water (0.25 mL,
13.61 mmol) was added dropwise over 1 min. The mixture was stirred at 20 °C for 30 min before
sulfide 1 (5.00 g, 90.6 wt% purity, 13.61 mmol) was added. After stirring for 15 min, the slurry was
cooled to 0 °C over 20 min and 70% aqueous tertꢀbutyl hydroperoxide (3.77 mL, 27.23 mmol) was
added. After 23 h, the reaction mixture was quenched with 5% Na2SO3 (20 mL) and extracted with
dichloromethane (50 mL). The combined organic layers were washed with water (20 mL), dried
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(MgSO4) and concentrated. 5.57 g of sulfoxide 2 was obtained as yelow solid; 88% yield by NMR, 89%
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ee; H NMR (400 MHz, CDCl3) δ 7.26ꢀ7.16 (m, 2H), 6.90ꢀ6.80 (m, 2H), 4.20ꢀ3.90 (m, 1H), 3.90ꢀ3.75
13
(m, 1H), 3.30ꢀ3.00 (m, 7H); C NMR (100 MHz, CDCl3) δ 177.5, 162.5, 160.7, 149.8, 129.4, 125.7,
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123.9, 118.2, 49.6, 46.5, 44.7, 44.4, 33.7; LCMS (ESI) for C16H17Cl2N4OS (M+H)+: calcd. 383.1,
obsvd. 383.0.
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Procedure B
To a mechanically stirred suspension of sulfide (1.0 g, 2.72 mmol) and (S,S)ꢀhydrobenzoin (58 mg, 0.27
mmol) in toluene (10 mL) at 20 °C was added Ti(iꢀPrO)4 (40 ꢀL, 0.14 mmol) followed by water (49 µL,
2.72 mmol). The mixture was cooled to 0 °C over 1 h before 70% aqueous tertꢀbutyl hydroperoxide
(0.75 mL, 5.45 mmol) was added. After 20 h, the reaction mixture was quenched with 5% Na2SO3 and
extracted with dichloromethane. The combined organic layers were washed with water, dried (MgSO4)
and concentrated. 95% conversion and 90% ee was obtained.
ASSOCIATED CONTENT
Supporting Information
Experimental procedure for DoE studies and copies of 1H and 13C NMR spectra for compound 2.
AUTHOR INFORMATION
Corresponding Author
*sonia.rodriguez@boehringerꢀingelheim.com
ORCID
Sonia Rodriguez: 0000ꢀ0003ꢀ4892ꢀ212X
ACKNOWLEDGEMENTS
We acknowledge the contributions of Dr. Xiufeng Sun to analytical methods development and support.
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(4) Configuration of the sulfide center was initially assigned by comparison with literature (see ref. 5a),
and confirmed by chemical correlation with an advanced compound which absolute configuration was
determined by XꢀRay analysis
(5) (a) Superchi, S.; Rosini, C. Tetrahedron: Asymmetry 1997, 8, 349ꢀ352. (b) Donnoli, M. I.; Superchi,
S.; Rosini, C. J. Org. Chem. 1998, 63, 9392ꢀ9395.
(6) Puchot, C.; Samuel, O.; Duñach, E.; Agami, C.; Kagan, H. G. J. Am. Chem. Soc. 1986, 108, 2353ꢀ
2357.
(7) Komatshu, N.; Hashizume, M.; Sugita, T.; Uemura, S. J. Org. Chem. 1993, 58, 4529ꢀ4533.
(6) Eriksson, L.; Johansson, E.; KettanehꢀWold, N.; Wikström, C.; Wold, S. Design of Experiments.
Principles and Applications; Umetrics: Umea (Sweden), 2000.
(9) MODDE is a registered trademark of Umetrics.
(10) Model validity and reproducibility were confirmed by complementing the model with data from
two previous experiments.
(11) Experimental data included in the Supporting Information.
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Organic Process Research & Development
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Asymmetric Oxidation of a Dihydrothienopyrimidine
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Sonia Rodríguez, Nizar Haddad, Rogelio Frutos, Nelu Grinberg, Chris H. Senanayake
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