An asymmetric synthesis of a chiral sulfone acid with concomitant hydrolysis and oxidation to enable the preparation of a glucokinase activator

Article abstract of DOI:10.1021/op300139g

This contribution describes the demonstration of an asymmetric synthesis of a glucokinase activator via protonation of the enolate generated from an alkylaryl ketene and (R)-pantolactone. Additionally, a one-pot hydrolysis/oxidation protocol with lithium hydroperoxide was developed to afford a chiral sulfone acid without degradation of the labile stereocenter.

Full text of DOI:10.1021/op300139g

Article
pubs.acs.org/OPRD
An Asymmetric Synthesis of a Chiral Sulfone Acid with Concomitant
Hydrolysis and Oxidation to Enable the Preparation of a Glucokinase
Activator
Amy C. DeBaillie,*,† Nicholas A. Magnus,† Michael E. Laurila,† James P. Wepsiec,† J. Craig Ruble,‡
Jeffrey J. Petkus,‡ Radhe K. Vaid,† Jeffry K. Niemeier,† Joseph F. Mick,† and Thomas Z. Gunter†
†Chemical Product Research and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
‡Discovery Chemistry Research and Technologies, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
ABSTRACT: This contribution describes the demonstration of an asymmetric synthesis of a glucokinase activator via
protonation of the enolate generated from an alkylaryl ketene and (R)-pantolactone. Additionally, a one-pot hydrolysis/oxidation
protocol with lithium hydroperoxide was developed to afford a chiral sulfone acid without degradation of the labile stereocenter.
substrate to catalyst ratio (s/c) of 2000 to 1 was required.
Sulfone acid (R)-3 was obtained in 86% ee and was upgraded to
>99% ee via recrystallization. A charcoal-absorbent treatment
was required to remove residual rhodium, which led to
significant yield loss.
Since it had been reported that pantolactone adds to ketenes
to yield esters with high stereoselectivity6−8 and the reagent is
readily available,9 we investigated its utilization in the
asymmetric synthesis of glucokinase activator (R)-1. We
chose to target the synthesis of (R)-3 and utilize the amide
coupling conditions as described by Prosidion.5 To that end,
chiral sulfone acid (R)-3 would be generated from the addition
of (R)-pantolactone to the ketene produced from racemic
sulfide acid 5 and subsequent hydrolysis and oxidation of ester
4 (Figure 2).
INTRODUCTION
■
It is estimated that 346 million people worldwide have diabetes,
and the World Health Organization (WHO) anticipates that
diabetes deaths will double between 2005 and 2030.1 Of the
three types of diabetes, type 2 is the most common form and is
characterized by the body’s inability to control glucose.2 The
glucose-phosphorylating enzyme, glucokinase, has been identi-
fied as a promising drug target for type 2 diabetes and has led to
the development of several glucokinase activators.3
The glucokinase activator (GKA), (R)-1 (Figure 1), was
developed as a potential therapeutic agent for the treatment of
To investigate this approach, an efficient synthesis of racemic
sulfide acid 5 was developed from sulfide α-ketoester 710
(Scheme 2). Wittig olefination of 7 with the ylide generated
from phosphonium iodide 8 and lithium hexamethyldisilazide
(LiHMDS) gave sulfide acrylic esters 9 as a 55:45 mixture of
E:Z isomers, which contained residual triphenylphosphine
oxide that could be removed in the subsequent step. Hydrolysis
of the (E/Z)-sulfide acrylic esters, 9, cleanly gave the (E/Z)-
sulfide acrylic acids 10 in a 89% yield.11
The hydrogenation of (E/Z)-sulfide acrylic acids 10 to yield
sulfide acid 5 proved to be challenging and required less than
ideal substrate-to-catalyst loadings (Scheme 3, Table 1).12 Pd/
C required a 3:1 s/c, 150 psig (1034 kPa), and 75 °C to
completely consume 10 (entries 1 and 2). Wilkinson’s catalyst,
(RuCl(PPh3)3), (entries 3 and 4) and [Rh(dippf)(cod)]BF4
(entries 5−8) were found to be effective at reducing the olefin
without being sufficiently poisoned; however, at least one
equivalent of triethylamine was necessary to suppress hydro-
genation of the cyclopropyl moiety to give 11 (Scheme 3).12
Using preformed [Rh(dippf)(cod)]BF4 at a 200:1 s/c, 5 was
obtained in a 84% yield after recrystallization on a 100-g scale
Figure 1. Glucokinase activator (R)-1.
type 2 diabetes. It was designed to lower blood glucose levels
by increasing the uptake of glucose in the liver and increasing
insulin secretion from the pancreas. Herein, we describe the
demonstration of an asymmetric synthesis of glucokinase
activator (R)-1 via protonation of the enolate generated from
an alkylaryl ketene and (R)-pantolactone4 followed by
concomitant hydrolysis and oxidation.
RESULTS AND DISCUSSION
■
The goal of this research was to demonstrate a cost-effective,
asymmetric synthesis of glucokinase activator (R)-1 with the
potential for scale-up. Previous quantities of the active
pharmaceutical ingredient (API), (R)-1, had been prepared
via a synthesis devised by Prosidion Ltd. that utilized an
enantioselective hydrogenation to set the labile chiral center
(Scheme 1).5 In order to convert (E)-acrylic acid 2 to chiral
sulfone acid (R)-3, 750 psig (5171 kPa) of hydrogen and a
Received: May 27, 2012
Published: August 13, 2012
© 2012 American Chemical Society
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Scheme 1. Prosidion’s synthesis of (R)-1
Figure 2. Retrosynthetic analysis of glucokinase activator (R)-1.
Scheme 2. Synthesis of (E/Z)-sulfide acrylic acids 10
Scheme 3. Hydrogenation of (E/Z)-sulfide acrylic acids 10
Table 1. Hydrogenation of (E/Z)-sulfide acrylic acids 10 to yield racemic sulfide acid 5
temp
entry
catalyst
5% Pd/C Degussa type (8:1 s/c)
pressure (psig H2)
(°C)
time (h)
conversion/yield
1
1
2
3
150
150
50
75
75
50
50
24
24
24
24
12
12
24
18
24
16
16
16
1:1 mixture of 10:5 by H NMR
1
5% Pd/C Degussa type (3:1 s/c)
100% conversion by H NMR
1
RhCl(PPh3)3 (30:1 s/c)
1:0.55 mixture of 5:11 by H NMR
a
1
4
RhCl(PPh3)3 (30:1 s/c)
50
100% conversion by H NMR
b
b
b
b
,c
5
6
7
8
[Rh(dippf)(cod)]BF4 (200:1 s/c)
50
84% isolated yield
100% by HPLC
100% by HPLC
100% by HPLC
0.1 mol % Rh with dippf ligand prepared from [Rh(cod)2]CF3SO3
0.1 mol % Rh with dippf ligand prepared from [Rh(nbd)Cl]2
0.1 mol % Rh with dippf ligand prepared from [Rh(cod)2]BF4
50
50
50
a
b
c
3.0 equiv of TEA. 1.0 equiv of TEA. EtOH was utilized as the reaction solvent. Entries 1−4 and 6−8 were conducted in MeOH.
(entry 5). The substrate-to-catalyst loading was further
improved to 1000:1 via the in situ preparation of the catalyst
in MeOH with 1.0 equiv of triethylamine at 24 °C and 50 psig
(345 kPa) (entries 6−8).
With 5 in hand, the selectivity of the protonation of the
enolate generated from the sulfide alkylaryl ketene 13 and (R)-
pantolactone (6) could be evaluated. Treatment of 5 with
oxalyl chloride and catalytic DMF in toluene generated the acid
chloride 12 (Scheme 4). The reaction solution was cooled to 0
°C, and 3 equiv of dimethylethylamine6 was added to generate
13. Addition of a solution of 6 in toluene to 13 at −78 °C
generated sulfide ester 4 in 98% yield and 88% de as
determined by HPLC. Additionally, it was shown that changing
the reaction solvent to THF (instead of toluene) gave sulfide
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Scheme 4. Addition of (R)-pantolactone (6) to the ketene (13) generated from racemic sulfide acid 5
ester 4 with 82% de, whereas changing the reaction
temperature from −78 °C in toluene to −50 °C, −20 °C, or
0 °C also led to a decrease in diastereoselectivity (82%, 80%,
and 74% de, respectively) (Table 2).
sulfide oxidation state. The hydrolysis of 4 to chiral sulfide acid
14 was initially investigated with hydroxide sources (LiOH,
NaOH, or KOH in THF/H2O) (Scheme 5). Comparison of
the diastereomeric and enantiomeric excess data indicated that
∼10% erosion of the stereocenter was occurring under these
conditions. Surprisingly, upon exposure of 4 to lithium
hydroperoxide,13 oxidation of the sulfide to the sulfoxide and
sulfone was observed in addition to the desired hydrolysis.
Furthermore, a more concentrated reaction (5−7 vols) with 4
equiv of LiOH and 8 equiv of H2O2 enabled complete
hydrolysis with concomitant oxidation to yield sulfone acid (R)-
3 without erosion of the stereocenter.
Table 2. Diastereoselectivity of the protonation of the
enolate generated from 13 and 6
solvent
temperature (°C)
yield (%)
de (%)
THF
−78
−78
−50
−20 to −15
0 to 3
60
98
96
90
99
82
88
82
80
74
toluene
toluene
toluene
toluene
We hypothesize that intermediate peracids derived from
sulfide ester 4 and pantolactone are the active oxidants
generated under the lithium hydroperoxide conditions. To
test this theory, sulfide acid 5 was exposed to the lithium
hydroperoxide reaction conditions, and <20% oxidation to
sulfone 3 was observed.
Sulfide ester 4 required an ester hydrolysis and sulfide to
sulfone oxidation that avoided stereochemical erosion to
prepare chiral sulfone acid (R)-3. To minimize chiral
degradation, the ester was hydrolyzed before oxidizing the
sulfide to the sulfone since the α-proton is less acidic in the
In preparation for a multikilogram campaign,14 continuous
processing was evaluated as an option to avoid the expensive
Scheme 5. Hydrolysis and concomitant oxidation of sulfide ester 4
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cryogenic conditions required to obtain selectivity in the
protonation of the enolate generated from the sulfide alkylaryl
ketene (13) and (R)-pantolactone (6). Unfortunately, the
insolubility of 6 in toluene proved challenging and resulted in
fouling the plug flow reactors at temperatures below 0 °C.
Additionally, a safety evaluation of the lithium hydroperoxide
hydrolysis/oxidation protocol was conducted since a 20 °C
exotherm was observed during development of the process.
Heat transfer modeling of calorimetry data suggests that the
lithium hydroperoxide conditions could be scaled to a half-full
2000-gal reactor with a 5 °C solution of 4 being added to the
water/H2O2/LiOH solution over 3 h to maintain the reaction
temperature below 16 °C to lessen peroxide decomposition.
The robustness of the hydrolysis/oxidation procedure for long
addition times was not evaluated; however, this process could
be a good candidate for continuous processing as it would allow
for sufficient heat removal and would limit the potential
consequences of a runaway reaction.
isomers (∼1:1) contaminated with triphenylphosphine oxide
(84% yield by HPLC). The yellow solid was carried forward
without further purification.
2-(4-(Cyclopropylthio)phenyl)-3-(tetrahydro-2H-pyran-4-
yl)acrylic Acid (10). Under a nitrogen atmosphere at 24 °C,
crude (E/Z)-sulfide acrylic ethyl esters 9 with triphenylphos-
phine oxide (350 g of crude, 152 g (0.46 mol) of 9 as
determined by HPLC), were combined with EtOH (903 mL)
and 2 M aqueous NaOH (294 mL, 0.59 mol). The solution was
heated at 60 °C for 2.5 h until the content of the ethyl ester was
<2% by HPLC. The solution was cooled to 24 °C, and EtOH
was removed via concentration in vacuo at 60 °C to afford a
brown slurry. H2O (900 mL) was added, and the mixture was
stirred for 30 min. The mixture was filtered, and the cake was
washed with H2O (250 mL). MTBE (250 mL) was then added
to the aqueous mother liquor, followed by 1 M HCl (600 mL).
The biphasic mixture was stirred for 15 min, and then the layers
were separated. The aqueous layer was back extracted with
MTBE (2 × 250 mL), and the combined organic layers were
dried over Na2SO4. Concentration in vacuo at 45 °C gave 174 g
of a yellow solid of 2-(4-(cyclopropylthio)phenyl)-3-(tetrahy-
dro-2H-pyran-4-yl)acrylic acid 10 as a mixture of E- and Z-
isomers that contained a trace amount of triphenylphosphine
oxide. To further remove the triphenylphosphine oxide, the
solid was dissolved in 2 M NaOH (2 L) and CH2Cl2 (1.5 L).
The layers were separated, and the aqueous layer was washed
with additional CH2Cl2 (1.5 L). MTBE (1 L) followed by 1 M
HCl (600 mL) was added to the aqueous layer. The layers were
separated, and the aqueous layer was extracted with MTBE (1
L). The combined organic layers were dried over Na2SO4,
filtered, and concentrated in vacuo to yield 124 g (89%) of a
CONCLUSIONS
■
In summary, the goal of demonstrating an asymmetric route for
the synthesis of glucokinase activator (R)-1 with the potential
for scale-up was achieved. The ketene route is comparable in
selectivity (88% de vs 86% ee) and overall cost15 to the
asymmetric hydrogenation route shown in Scheme 1. In
addition, the concomitant hydrolysis and oxidation of sulfide
ester 4 without degradation of the chiral center lends to the
efficiency of the ketene route.
EXPERIMENTAL SECTION
■
1
white solid of 10 as a mixture of E- and Z-isomers. H NMR
General. HPLC conditions for diastereomeric separation of
pantolactone esters 4: Sample prep in 50:50 ACN/H2O w/
0.1% TFA. Column: Chiralpak AD-RH (0.46 cm ×15 cm, 5
μm). Flow rate: isocratic flow 1.0 mL/min, 45:55 H2O/ACN
w/0.1% TFA, 30 °C. UV detection at 259 nm, major tR = 8.79
min, minor tR = 7.35 min. HPLC for enantiomeric excess
determination of sulfone carboxylic acid (R)-3: Column:
ChiralPak AD-RH, (0.46 cm × 15 cm, 5 μm). Flow rate:
isocratic flow, 0.6 mL/min, 30 °C. UV detection: 230 nm.
Eluent: 68% H2O/32% ACN/0.1% TFA. Run time: 15 min,
major tR = 7.75 min, minor tR = 10.94 min. HPLC for reaction
monitoring: Column: Agilent Eclipse XDB-C8 (0.46 cm ×15
cm, 3.5 μm). Flow rate: 2 mL/min, A = 0.1% H3PO4, B = ACN.
Gradient: 95% A to 5% A over 10 min; change to 95% A over 1
min and hold for 4 min, 30 °C, UV detection: 220 nm.
(CDCl3, 400 mHz) E-10 δ 0.68−0.73 (m, 2H), 1.07−1.11 (m,
2H), 1.46−1.51 (m, 2H), 1.52−1.59 (m, 2H), 2.13−2.18 (m,
1H), 2.42 (qt, 1H, J = 4.2, 10.8 Hz), 3.30 (td, 2H, J = 2.0, 11.7
Hz), 3.92 (ddd, 2H, J = 1.9, 4.2, 11.7 Hz), 6.94 (d, 1H, J = 10.2
Hz), 7.08 (d, 2H, J = 8.2 Hz), 7.36 (d, 2H, J = 8.0 Hz), 11.70
(br s, 2H). 13C NMR (CDCl3, 100 mHz) 8.5, 11.7, 31.4, 35.6,
1
66.7, 125.8, 129.8, 131.0, 132.1, 138.9, 149.9, 172.2. H NMR
(CDCl3, 400 mHz) Z-10 δ 0.65−0.69 (m, 1H), 1.02−1.07 (m,
1H), 1.59−1.65 (m, 1H), 1.71 (ddd, 1H, J = 1.3, 3.5, 12.8 Hz),
2.16−2.21 (m, 1H), 3.14 (qt, 1H, J = 4.0, 11.1 Hz), 3.48 (td,
1H, J = 1.8, 11.7 Hz), 3.99 (ddd, 1H, J = 1.4, 4.2, 11.5 Hz), 6.04
(d, 1H, J = 9.8 Hz), 7.25 (d, 1H, J = 8.3 Hz), 7.31 (d, 1H, J =
8.3 Hz), 11.70 (br s, 2H). 13C NMR (CDCl3, 100 mHz) δ 8.5,
11.9, 32.1, 36.1, 67.2, 126.1, 128.1, 132.5, 134.3, 138.8, 146.2,
172.7.
Ethyl 2-(4-(Cyclopropylthio)phenyl)-3-(tetrahydro-2H-
pyran-4-yl)acrylate (9). Under a nitrogen atmosphere,
phosphonium iodide 810 (1.46 kg, 3.00 mol) was slurried in
THF (3.31 L) at 24 °C. The mixture was cooled to −5 °C, and
lithium bis(trimethylsilyl)amide (3.0 L, 3.00 mol, 1.0 M in
THF) was added over 1 h at 0 °C. The reaction was stirred at
−5 °C for 10 min before it was warmed to 24 °C and stirred for
2.5 h. The reaction was then cooled to 5 °C, and sulfide α-
ketoester 7 (625 g, 2.50 mol) in THF (625 mL) was added
over 1 h. The reaction was warmed to 24 °C. After stirring 2.5
h, H2O (2.19 L) and EtOAc (2.19 L) were added to the
reaction, and the resulting biphasic mixture was stirred
vigorously for 15 min. The mixture was filtered, and the solids
were washed with EtOAc. The layers were separated, and the
aqueous layer was extracted with EtOAc (2 × 2 L). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo to yield 1.62 kg of 9 as a mixture of E:Z
2-(4-(Cyclopropylthio)phenyl)-3-(tetrahydro-2H-pyran-4-
yl)propanoic Acid (5). Sulfide acrylic acid 10 (100 g, 328.5
mmol) was added to a hydrogenation bottle with EtOH (658
mL) and triethylamine (46 mL, 330 mmol). 1,1-Bis(di-
isopropylphosphino)ferrocene(1,5-cyclooctadiene)rhodium(I)-
tetrafluoroborate (1.18 g, 1.64 mmol) was added, and the bottle
was purged with nitrogen, followed by hydrogen at 24 °C. After
the solution stirred for 24 h at 50 psig, the reaction pH was
adjusted to 4 with 5 N HCl and treated with 100 mesh
DARCO (50 g) for 2 h at 50 °C. The mixture was then filtered,
and the filtrate was concentrated to 400 mL. After stirring at 23
°C for 12 h, a suspension was obtained. H2O (450 mL) was
added over 30 min, and the resulting thick suspension was
heated to 70 °C. The resulting solution was allowed to cool to
24 °C. The solids were filtered and rinsed with 30% EtOH/
1
H2O (500 mL) to yield 84.5 g (84%) of 5 as a tan solid. H
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NMR (CDCl3, 400 mHz) δ 0.66 (dt, 2H, J = 4.8, 6.4 Hz), 1.04
(dt, 2H, J = 4.8, 6.4 Hz), 1.23−1.33 (m, 2H), 1.37−1.45 (m,
1H), 1.54−1.62 (m, 2H), 1.71 (ddd (app dt), 1H, J = 6.8, 14
Hz), 1.98 (ddd (app dt), 1H, J = 7.2, 14.0 Hz), 2.14 (tt, 1H, J =
4.4, 7.6 Hz), 3.25−3.32 (m, 2H), 3.62 (dd (app t), 1H, J = 6.8
Hz), 3.91−3.93 (m, 2H), 7.21 (d, 2H, J = 8.4 Hz), 7.25 (d, 2H,
J = 8.4 Hz), 11.4−11.6 (br s, 1H). 13C NMR (CDCl3, 100
mHz) δ 8.5, 11.9, 32.4, 32.5, 32.9, 29.9, 47.7, 67.6, 67.7, 126.6,
128.3, 135.0, 138.3, 179.2. IR (film) 3100−2700 (br s), 2990,
2934, 1710, 1491, 1435, 1275, 1223, 1171, 1127, 1119, 1104,
1086, 1074, 1026, 1011, 978, 881, 859, 747 cm−1. HRMS (EI+)
calcd for C17H22O3S 306.12897, found 306.12858.
(R)-3 as a white solid with 82% ee as determined by chiral
HPLC.
1H NMR (DMSO-d6, 400 mHz) δ 0.99−1.05 (m, 2H),
1.06−1.19 (m, 4H), 1.26−1.33 (m, 1H), 1.50−1.60 (m, 2H),
1.63 (ddd, 1H, J = 7.2, 7.2, 14.0 Hz), 1.92 (ddd, 1H, J = 7.6, 7.6,
13.6 Hz), 2.82 (dddd (app tt), 1H, J = 4.8, 8.0 Hz), 3.11−3.18
(m, 2H) 3.73−3.80 (m, 3H), 7.57 (d, 2H, J = 8.4 Hz), 7.83 (d,
2H, J = 8.4 Hz), 12.54−12.60 (br s, 1H). 13C NMR (DMSO-d6,
100 mHz) δ 5.8, 32.4, 32.6, 32.8, 33.0, 48.0, 67.3, 127.9, 129.4,
139.6, 146.0, 174.6. IR (film) 3000−2600 (br s), 2916, 1718,
1316, 1294, 1272, 1223, 1190, 1149, 1130, 1089, 1071, 1037,
1015, 885, 855, 836, 822, 781, 758, 736 cm−1. HRMS (EI+)
calcd for C17H22O5S 338.11879, found 338.1183. [α]D24 −53.8
(MeOH, c = 2.8).
(R)-((R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl)-2-(4-
(cyclopropylthio)phenyl)-3-(tetrahydro-2H-pyran-4-yl)-
propanoate (4). Following a procedure reported in the
literature,7 to a solution of sulfide acid 5 (2.34 g, 7.64 mmol)
in toluene (46 mL) and DMF (10 μL) under a nitrogen
atmosphere was added oxalyl chloride (0.80 mL, 9.16 mmol).
The solution was stirred at 24 °C for 3 h, and then it was
cooled to 0 °C. Dimethylethylamine (2.49 mL, 22.91 mmol)
was added dropwise, and the solution was allowed to warm to
24 °C and stir for 2 h. The solution was cooled to −69 °C, and
a solution of (R)-pantolactone 6 (1.20 g, 9.16 mmol) in toluene
(37 mL) was added at such a rate to maintain the solution
temperature <−60 °C. The solution was allowed to stir and
warm to 24 °C slowly over 12 h. The reaction was quenched
with H2O, and the aqueous layer was separated. The organic
layer was washed with saturated NaHCO3 and brine, and the
aqueous layer was back extracted with EtOAc (2×). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo to give 3.14 g (98%) of 4 as a colorless
AUTHOR INFORMATION
■
Corresponding Author
*debaillie_amy_c@lilly.com
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) World Health Organization Diabetes Statistics. http://www.who.
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1
oil with 88% de as determined by chiral HPLC. H NMR
(CDCl3, 400 mHz) δ 0.62−0.66 (m, 2H), 0.98 (s, 3H), 1.01−
1.05 (m, 2H), 1.09 (s, 3H), 1.23−1.34 (m, 2H), 1.42−1.53 (m,
1H), 1.58−1.62 (m, 2H), 1.77 (ddd (app dt), 1H, J = 7.2, 14.4
Hz), 2.05 (ddd, 1H, J = 6.8, 8.0, 14.0 Hz), 2.13 (dddd (app tt),
2H, J = 4.4, 7.2 Hz), 3.28 (ddd (app dt), 2H, J = 2.0, 11.6 Hz),
3.78 (dd, (app t), 1H, J = 8.0 Hz), 3.87−3.90 (m, 2H), 3.94−
3.99 (m, 2H), 5.28 (s, 1H), 7.22 (d, 2H, J = 8.4 Hz), 7.29 (d,
2H, J = 8.4 Hz). 13C NMR (CDCl3, 100 mHz) δ 8.5, 11.9, 19.8,
23.0, 32.6, 32.7, 32.9, 39.9, 40.2, 47.9, 67.7, 75.2, 76.0, 126.6,
128.3, 134.4, 138.3, 171.8, 172.6. IR (film) 2953, 2927, 1785,
1740, 1491, 1134, 1119, 1089, 1011, 996 cm−1. HRMS (EI+)
calcd for C23H30O5S 418.18139, found 418.18161. [α]D24 +4.58
(MeOH, c = 1.2).
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(R)-2-(4-(Cyclopropylsulfonyl)phenyl)-3-(tetrahydro-2H-
pyran-4-yl)propanoic Acid ((R)-3). To a 0 °C solution of
lithium hydroxide (29.7 mg, 1.24 mmol), hydrogen peroxide
(30%) (0.25 mL, 2.48 mmol), and H2O (0.16 mL) was added
sulfide ester 4 (0.13 g, 0.31 mmol) (82% de) in THF (0.49
mL) dropwise. The mixture was stirred at 0 °C for 2 h, and
then the bath was removed and the mixture was stirred for an
additional 5.5 h at 23 °C. A solution of saturated sodium sulfite
(2 mL) was added to the reaction mixture followed by H2O,
MTBE, and 1.0 M HCl (10 mL) (pH approx 1). The layers
were separated, and the aqueous layer was extracted with
MTBE (2 × 10 mL). The combined organic layers were
washed with saturated NaHCO3 (3 × 5 mL). Then 1.0 M HCl
was added to the combined basic aqueous layers until the pH
was approximately 1. The acidic aqueous solution was extracted
with MTBE, and the organic layer was dried over Na2SO4,
filtered, and concentrated in vacuo to give 0.086 g (82%) of
(8) For the asymmetric synthesis of (R)-1 from the racemic sulfone
acid and pantolactone see: Sugawara, K.; Toshikawa, S. (Mitsubishi
Tanabe Pharma Corporation, Japan). PCT Int. Appl. WO 2009139438
A1 20091119, 2009.
(9) (a) SciFinder search lists over 50 suppliers for (R)-pantolactone.
(b) Grabowski, E. J. J. (R)-Pantolactone. In e-EROS Encylcopedia of
Reagents for Organic Synthesis; Crich, D.; Charette, A. B.; Fuchs, P. L.;
Rovis, T.; John Wiley & Sons: New York, 2010.
(10) Bertram, L. S.; Black, D.; Briner, P. H.; Chatfield, R.; Cooke, A.;
Fyfe, M. C. T.; Murray, P. J.; Naud, F.; Nawano, M.; Procter, M. J.;
Rakipovski, G.; Rasamison, C. M.; Reynet, C.; Schofield, K. L.; Shah,
V. K.; Spindler, F.; Taylor, A.; Turton, R.; Williams, G. M.; Wong-Kai-
In, P.; Yasuda, K. J. Med. Chem. 2008, 51, 4340.
(11) Residual triphenylphosphine was removed during the aqueous
workup; see the Experimental Section.
(12) For an enantioselective hydrogenation of E- sulfide acrylic acid
10 see: Zhang, Y.; Han, Z.; Li, F.; Ding, K.; Zhang, A. Chem. Commun.
2010, 46, 156.
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Organic Process Research & Development
Article
(13) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987,
28, 6141.
(14) Unfortunately, the synthesis of glucokinase activator (R)-1 via
the described ketene approach was not demonstrated on a
multikilogram scale due to the termination of the project.
(15) Comparing the cost of (R)-pantolactone to the cost of (R)-(S)-
MOD-Mandyphos and bis-(norbornadiene)-rhodium(I)-tetrafluoro-
borate at a substrate-to-catalyst ratio of 2000 to 1.
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