A highly stereoselective and efficient synthesis of enantiomerically pure sitagliptin

Article abstract of DOI:10.1016/j.tetasy.2016.10.010

A highly stereoselective and efficient synthesis of sitagliptin 1 consisting of a chiral β-amino acid unit has been achieved through 6 steps from commercially available 2,4,5-trifluorobenzaldehyde 4. The chiral antidiabetic drug was obtained with almost perfect enantiomeric purity (>99.9% ee) in 40.9% overall yield. The key feature of the synthesis is the addition of a malonate enolate to a chiral sulfinylimine in more than 99:1 dr. Our synthetic procedure proved to be highly efficient, economical, and sustainable.

Full text of DOI:10.1016/j.tetasy.2016.10.010

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A highly stereoselective and efficient synthesis of enantiomerically
pure sitagliptin
Sung Kwon Kang a,b, Gyeong Hi Cho b, Hyung Joon Leem b, Bong Kwan Soh b, Jaehoon Sim a,
Young-Ger Suh a,
⇑
a College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea
b Department of Synthetic Chemistry, Chong Kun Dang Research Institute, 315-20, Dongbaekjukjeon-daero, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly stereoselective and efficient synthesis of sitagliptin 1 consisting of a chiral b-amino acid unit has
been achieved through 6 steps from commercially available 2,4,5-trifluorobenzaldehyde 4. The chiral
antidiabetic drug was obtained with almost perfect enantiomeric purity (>99.9% ee) in 40.9% overall
yield. The key feature of the synthesis is the addition of a malonate enolate to a chiral sulfinylimine in
more than 99:1 dr. Our synthetic procedure proved to be highly efficient, economical, and sustainable.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 9 August 2016
Revised 10 October 2016
Accepted 18 October 2016
Available online xxxx
1. Introduction
equipment for the transition metal-mediated hydrogenation, the
unsatisfactory stereoselectivity and an extra procedure to remove
Fluorine-containing compounds have been used in a variety of
medicines, such as anti-cancer, anti-hyperlipidemia, anti-diabetes
and in many other applications over recent years,1–3 as shown by
the representative drugs in Figure 1. Especially, amino acid motifs
containing fluorine4–7 are of particular interest and medicinal
potential in pharmaceutical industry. The representative fluori-
nated b-amino acid derivative is sitagliptin 1, which has been
approved for the treatment of type 2 diabetes.8,9
the metal catalyst remained as drawbacks for the economical pro-
cess. Recently, chiral resolution for enantiomerically pure sitaglip-
tin and
a highly enantioselective process using an optimal
biocatalyst for the direct amination of b-keto amide were also
reported although unsatisfactory yields for the resolution, high
cost and limited susceptibility to substrates or products
remained.14,20 Thus, there has been continuing interests in the effi-
cient and practical synthesis of sitagliptin.
Sitagliptin inhibits the activity of dipeptidyl peptidase IV (DPP-
4) that breaks down incretins,10 which play a key role in stimulat-
ing insulin release and inhibiting glucagon secretion. Since this
first dipeptidyl peptidase IV (DPP-4) inhibitor was launched, it
has been widely used around the world and has become a leading
drug for the treatment of type 2 diabetes. Due to its tremendous
value and unique structure, many pharmaceutical companies have
been interested in the development of more efficient and econom-
ical synthetic routes to sitagliptin.11–18
Herein we report an environmentally friendly, economical, and
practical approach for the preparation of optically pure sitagliptin.
The key part of our strategy involves a highly stereoselective eno-
late addition of an malonate derivatives to sulfinyl imine 3 to afford
the key amine intermediate 2, as outlined in Scheme 1.21–24 The
tert-butyl sulfinyl aldimine 3, prepared by direct condensation of
aldehyde
4 with tert-butanesulfinamide, was anticipated to
undergo a facile nucleophilic addition by an enolate for the chiral
b-amino acid moiety of sitagliptin. The metal coordination capabil-
ity of the enantiomerically pure tert-butyl sulfinyl moiety was
anticipated to induce the diastereoselective addition of an enolate
to 3.25–27
In 2005, the first commercial process12,19 involved an asymmet-
ric hydrogenation of a b-keto ester using Ru catalyst followed by
the Mitsunobu reaction to provide the chiral amino acid unit. How-
ever, the reaction conditions, including high pressure for hydro-
genation and the use of an expensive ruthenium catalyst, limited
this process for commercial production. An improved process13
2. Results and discussion
included
a one-pot, three-step synthesis of a key dehy-
We first explored the reactivity of various esters for the enolate
addition to sulfinyl imine 3, which was obtained from commer-
cially available 4.28 The experimental investigation for the enolate
drositagliptin intermediate and a Rh-catalyzed asymmetric hydro-
genation of enamine. However, the requirement of high-pressure
addition to (R)-tert-butanesulfinamide
3 is summarized in
Table 1.29 Meldrum’s acid 6 and menthyl ester 7 gave poor
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.tetasy.2016.10.010
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
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2
S. K. Kang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
N
F
OH
F
N
N
OH
NH2
O
N
N
HO
N
N
N
N
F
N
F
O
F
F
F
CF3
F
voriconazole
ezetimibe
F
sitagliptin 1
OH
OH
O
O
O
HN
N
Cl
N
OH
N
H
N
O
O
N
F
gefitinib
atorvastatin
Figure 1. Fluorine-containing pharmaceutical drugs.
F
F
The reaction temperature significantly affected the diastereoselec-
tivity, although the reactions generally produced the desired prod-
ucts in good yields. The diastereoselectivity decreased as the
reaction temperature increased (entries 4–8). Considering the sat-
isfactory diastereoselectivities and conversions, we attempted to
improve the rate of the addition reaction using a rate accelerating
additive. It is noteworthy that the diastereoselectivity dramatically
improved to 99.4% upon the addition of NaI (entries 9 and 10). We
further confirmed the crucial coordination effect of the metal ion
for high diastereoselectivity with the help of the cation-capturing
ability of crown ether (entries 11 and 12). A plausible transition
state for the highly stereoselective enolate addition is depicted in
Figure 2.
O
F
F
F
F
F
S
t-Bu
F
NH2
O
HN
O
N
N
OR
N
N
O
N
OR'
sitagliptin 1
CF3
2
F
O
F
F
S
O
t-Bu
H
H
F
3
4
With the chiral sulfinamide 8, acid-catalyzed hydrolysis fol-
lowed by decarboxylation with 2 M HCl was attempted to obtain
the b-amino ester 10. However, small amounts of by-products 11
(3%) and 12 (1%) were consistently detected (Scheme 2). We
assumed that the presence of the acid by-product causes instability
in the sulfinamide group. Thus, complete separation of the by-
products was considered crucial because even small amounts of
by-products influence the purity of the final sitagliptin. In order
to overcome the decarboxylation problem, we investigated the
Pd-catalyzed decarboxylation of the 1,3-diester consisting of an
allyl ester.21,30 We anticipated that the functional groups of 8 were
tolerable in the presence of palladium catalysts and triethylamine-
formic acid salt.
Scheme 1. Synthetic strategy for the synthesis of sitagliptin.
conversions, while tert-butyl acetate 5 afforded a high conversion.
Diethyl malonate 8 provided the best yield of 96.4%, which is likely
due to the steric hindrance and geometry of enolates and the low
pKa of the malonate.
Next, we focused on the optimization of the malonate addition
to 3, as summarized in Table 2. In order to develop a sustainable
and economical process, we explored the effect of the base, tem-
perature, and additives at the solvent-free condition in reference
to the previously reported literature.23 All bases afforded high
diastereoselectivities of greater than 90.9% dr with high conver-
sions (entries 1–4). However, a relatively long reaction time was
required to complete the addition reaction for NaHCO3 and KHCO3.
We examined the reactivity and selectivity of the enolate addi-
tion for various allyl malonates (Table 3). All substrates produced
Table 1
Pre-screening results for enolate addition to sulfinyl imine 3 with various esters
F
F
F
O
S
O
S
F
F
N
HN
t-Bu
t-Bu
esters
conditionsa
H
R1
F
3 (Rs)
5 - 8 (R, Rs)
O
O
O
O
O
O
O
O
R1=
O
O
O
6
O
5
7
8
Conversionb
88.0%
Trace
Trace
96.4%
a
Reaction conditions: 3 (1.0 equiv, 1.08 mmol), LHMDS (10.0 equiv, 10.8 mmol), esters (10.0 equiv, 10.8 mmol), À78 °C, THF.
b
Conversion is given based on the disappearance of the starting compound by HPLC analysis.
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S. K. Kang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
Table 2
Optimization of the enolate addition reactions
O
O
F
F
t-Bu
O
t-Bu
O
S
S
F
O
H
F
F
HN
HN
diethyl malonatea
conditions
F
N
t-Bu
O
O
+
F
F
O
O
O
O
F
3
8 (R,Rs)
9 (S,Rs)
Entry
Base (equiv)
Temperature (°C)
Additive (equiv)
Time (h)
Conversionb
drc
(8:9)
1
2
3
4
5
6
7
8
NaHCO3 (5)
KHCO3 (5)
Na2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
Na2CO3 (5)
K2CO3 (5)
Na2CO3 (5)
Na2CO3 (5)
K2CO3 (5)
40
40
40
40
25
5
0
0
0
0
—
—
—
—
—
—
—
—
20
22
12
1.5
0.5
2.5
4
17.5
4
12.5
4
80
91
91
98
94
94
94
94
94
90
84
96
98.0:2.0
97.2:2.8
97.5:2.5
90.9:9.1
96.2:3.8
97.8:2.2
97.9:2.1
98.8:1.2
99.4:0.6
99.7:0.3
74.3:25.7
46.8:53.2
9
NaI (0.1)
NaI (0.1)
15-Crown-4
18-Crown-6
10
11
12
0
0
1
a
b
c
Diethyl malonate was used as solvent (5.0 equiv, 18.0 mmol).
Conversion is given based on the disappearance of the starting compound by HPLC analysis.
Diastereoselectivity was determined by HPLC analysis of crude reaction mixture.
F
F
F
Pd-catalyzed decarboxylation to provide the b-amino ester 10 with
excellent diastereoselectivity. Hydrolysis of the terminal ester
afforded pure b-amino acid 16. Coupling of 16 with the piperazine
unit with the assistance of HBTU produced amide 17. To complete
the synthesis, the sulfinyl chiral auxiliary was removed by HCl to
produce sitagliptin 1, which exhibited almost perfect enantioselec-
tivity (>99.9% ee). We did not detect the enantiomeric sitagliptin.
Ar
OEt
M
O
OEt
OM
H
N
S
EtO2C
+
O
H
N
S
EtO
t-Bu
O
O
F
3
O
S
HN
F
F
3. Conclusion
t-Bu
O
M
S
O
N
O
H+
In conclusion, a highly stereoselective and concise synthesis of
enantiomerically pure sitagliptin was accomplished in 40.9% over-
all yield over six steps from the commercially available aldehyde 4.
The key step of the synthesis includes elaboration of the chiral b-
amino acid moiety of sitagliptin via a highly stereoselective enolate
addition of allyl ethyl malonate to the chiral sulfinyl imine 3. Our
synthetic procedure proved to be highly efficient, economical,
and environmentally friendly. We believe that it could be widely
utilized by synthetic and medicinal chemists.
H
OEt
OEt
OEt
OEt
Bn
O
O
8
Figure 2. The enolate addition reaction of
transition state.
3
through the chelate-controlled
the desired products with high diastereoselectivities greater than
99.3% and in high conversions. Allyl ethyl malonate afforded the
best results in terms of selectivity and reactivity (entry 2).
As shown in Scheme 3, enantiomerically pure chiral sulfinamide
14, prepared by the selective enolate addition, was subjected to
4. Experimental
4.1. General
1H NMR spectra and 13C NMR spectra were measured using a
Bruker DPX 400 Spectrometer. All purity values were obtained by
HPLC analysis. HPLC was 1200 Series available from Agilent Tech-
nologies. Melting points were determined on an open capillary
apparatus. All NMR spectra were measured using 400 UltraShield
NMR in CDCl3, NMR chemical shifts are reported in ppm referenced
to the solvent peaks of CDCl3 (7.26 ppm for 1H and 77.0 ppm for
13C, respectively). High resolution mass spectra were obtained
with Synapt G2 instrument.
O
F
O
F
F
S
t-Bu
O
F
S
t-Bu
O
HN
F
2M HCl
HN
OEt
OEt
MeOH
r.t.
OEt
F
O
8
10 (91%)
F
F
F
F
NH2
O
NH2
O
4.2. Preparation of compounds
+
OEt
OH
4.2.1. (R,E)-2-Methyl-N-[2-(2,4,5-trifluorophenyl) ethylidene]
propane-2-sulfinamide 3
F
F
11 (~ 3%)
12 (~ 1%)
To a suspension of compound 4 (45.8 g, 262.9 mmol) in DCM
(115 mL) were added (R)-(+)-2-methyl-2-propanesulfinamide
Scheme 2. Acid-catalyzed hydrolysis and decarboxylation.
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4
S. K. Kang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Table 3
Stereoselective enolate addition to sulfinyl imine 3 with allyl malonates
F
F
O
S
F
O
S
O
O
F
F
HN
t-Bu
CO2R1
R1O
OR2
conditionsa
N
t-Bu
H
CO2R2
F
13 - 15
3
Entry
R1
R2
Time
Conversionb
drc
1 13d
2 14d
3 15
Allyl
Allyl
Allyl
Methyl
Ethyl
Allyl
4
7
4
89.1
94.0
91.6
99.3:0.7
99.5:0.5
99.3:0.7
a
b
c
Reaction conditions: 3 (1.0 equiv, 3.6 mmol), K2CO3 (5.0 equiv, 18.0 mmol), NaI (0.1 equiv, 0.4 mmol), 0 °C, malonates were used as solvent (5.0 equiv, 18.0 mmol).
Conversion is given based on the disappearance of the starting compound by HPLC analysis.
Diastereoselectivity was determined by HPLC.
d
Compounds 13 and 14 were obtained as a 1:1 mixture of a-diastereomers.
O
F
F
F
F
O
S
S
t-Bu
O
F
Pd(OAc)2, PPh3,
HCO2H, TEA
allyl ethyl malonate,
K2CO3, NaI
HN
F
N
t-Bu
O
0 oC, 7 hr
ethyl acetate
reflux, 3 hr
H
O
O
3
14
N
N
O
F
F
HN
N
O
F
CF3
S
t-Bu
F
S
t-Bu
O
F
HN
O
5M NaOH
HBTU, TEA
HN
THF
OH
DCM
O
40 oC
0 oC to r.t.
F
10
16
3 steps 57%
84%
F
O
F
F
S
t-Bu
O
F
NH2
O
HN
conc. HCl
N
N
N
MeOH
r.t.
N
N
N
F
N
F
N
17
89%
sitagliptin 1
CF3
CF3
Scheme 3. Completion of sitagliptin synthesis.
(33.4 g, 276.1 mmol), pyridinium-p-toluenesulfonic acid (3.30 g,
13.1 mmol), and anhydrous sodium sulfate (186.8 g, 1.32 mol)
and then stirred for 16 h at room temperature. The completion of
the reaction was confirmed by TLC. To the reaction mixture was
added DCM (230 mL), after which it was filtered with Celite, and
washed with DCM (90 mL Â 2). The filtered DCM solution was con-
centrated to give compound 3 as yellow oil (70.0 g, 96%). 1H NMR
(400 MHz, CDCl3): d 1.16 (s, 9H), 3.79 (d, 2H, J = 4.2 Hz), 6.92–6.94
(m, 1H), 6.96–6.98 (m, 1H), 8.09 (t, 1H, J = 4.3 Hz). HRMS: Calcd for
À78 °C. Approximately 1.0 mL of the reaction sample was sub-
jected to HPLC analysis.
HPLC methods. Kromasil C18, 4.6 mm  250 mm (5
lm),
k = 268 nm, flow rate 1.2 mL/min, column temperature: 25 °C,
mobile phase: water/acetonitrile.
Time (min)
Water (%)
Acetonitrile (%)
0
48
30
5
48
48
52
70
95
52
52
15.5
20.5
20.6
27
C
12H14F3NOS [M+H]+ 278.0826; Found 278.0827.
4.2.2. Pre-screening results for enolate addition to sulfinimine
(sulfinylimine) 3 with various esters (Table 1)
4.2.2.1. General procedure for the synthesis of compound 5, 6, 7
4.2.2.2. tert-Butyl-(R)-3-[((R)-tert-butylsulfinyl)amino]-4-(2,4,5-
trifluorophenyl)butanoate 5.
1H NMR (400 MHz, CDCl3): d
and 8.
To a reaction flask were added ester (10.8 mmol), and
THF (15.0 mL). The reaction mixture was cooled to À78 °C, and
then was slowly added dropwise LHMDS (10.8 mmol) in droplet.
The reaction mixture was stirred for 1 h at À78 °C. To the reaction
slurry was added a solution of compound 3 (1.08 mmol) dissolved
in THF (9.0 mL), and the reaction mixture was stirred for 3 h at
1.12 (s, 9H), 1.38 (s, 9H), 2.30–2.34 (m, 2H), 2.89 (dd, 1H, J = 7.5,
6.5 Hz), 3.07 (dd, 1H, J = 8.5, 5.4 Hz), 3.74 (d, 1H, J = 8.4 Hz), 3.82–
3.87 (m, 1H), 6.87 (q, 1H, J = 9.4 Hz, 6.8 Hz), 7.04 (q, 1H,
J = 8.7 Hz, 7.8 Hz). HRMS: Calcd for
394.1664; Found 394.1664.
C
18H26F3NO3S [M+H]+
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S. K. Kang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
4.2.2.3.
Diethyl-2-{(R)-1-[((R)-tert-butylsulfinyl)amino]-2-
8. NMR
1H
was cooled to 0 °C. Next, K2CO3 (18.0 mmol) and NaI (53.0 mg,
0.36 mmol) were added to the reaction mixture and then stirred
at 0 °C. The completion of the reaction was confirmed using
HPLC and TLC. The solution was allowed to room temperature,
and then purified water (10 mL) was added to the reaction mix-
ture. The slurry was extracted with ethyl acetate (10 mL) and the
organic layer was vacuum distilled to afford the desired products
13, 14 and 15 as yellow oil. HPLC method was the same as com-
pound 8.
(2,4,5-trifluorophenyl)ethyl}malonate
(400 MHz, CDCl3): d 1.06 (s, 9H), 1.26–1.33 (m, 6H), 2.92 (d, 2H,
J = 7.3 Hz), 3.89 (d, 1H, J = 3.6 Hz), 3.97–4.01 (m, 1H), 4.23–4.29
(m, 4H), 4.57 (d, 1H, J = 10.0 Hz), 6.85–6.91 (m, 1H), 7.02–7.08
(m, 1H). HRMS: Calcd for C19H26F3NO5S [M+H]+ 438.1562; Found
438.1563.
4.2.3. Optimization of the enolate addition reactions (Table 2)
4.2.3.1. General procedure for the synthesis of compound 8
(entries 1–4).
To a reaction flask were added compound 3
4.2.4.2.
1-Allyl-3-methyl-{(R)-1-[((R)-tert-butylsulfinyl)-
13.
1H
(3.60 mmol), diethyl malonate (18.0 mmol), and bases (18.0 mmol)
and then stirred at 40 °C. The completion of the reaction was con-
firmed by HPLC and TLC. The solution was cooled to room temper-
ature, and then purified water (10 mL) was added to the reaction
mixture. The slurry was extracted with ethyl acetate (10 mL) and
the organic layer was vacuum distilled to afford compound 8 as a
yellow oil.
amino]-2-(2,4,5-trifluorophenyl)-ethyl)malonate
NMR (400 MHz, CDCl3): d 1.02 (s, 9H), 2.88–2.91 (m, 2H), 3.77 (s,
3H), 3.89–4.02 (m, 2H), 4.50 (dd, 1H, J = 16.8, 9.9 Hz), 4.65–4.69
(m, 2H), 5.21–5.36 (m, 2H), 5.86–5.93 (m, 2H), 6.82–6.88 (m,
1H), 6.99–7.04 (m, 1H). HRMS: Calcd for C19H24F3NO5S [M+H]+
436.1406; Found 436.1405. dr = 99.3:0.7.
4.2.4.3. 1-Allyl-3-ethyl-{(R)-1-[((R)-tert-butylsulfinyl)-amino]-
4.2.3.2. General procedure for the synthesis of compound 8
2-(2,4,5-trifluorophenyl)-ethyl}malonate
14.
1H
NMR
(entries 5–7).
To a reaction flask were added compound 3
(400 MHz, CDCl3): d 1.09 (s, 9H), 1.31–1.36 (m, 3H), 2.96 (d, 2H,
J = 7.2 Hz), 3.97–4.04 (m, 2H), 4.30–4.31 (m, 2H), 4.59 (t, 1H,
J = 9.4 Hz), 4.74 (t, 2H, J = 6.0 Hz), 5.31 (t, 1H, J = 10.9 Hz), 5.41
(dd, 1H, J = 9.6, 7.6 Hz), 5.93–5.99 (m, 1H), 6.88–6.94 (m, 1H),
7.05–7.11 (m, 1H). 13C NMR (175 MHz, CDCl3): d 167.8, 156.8,
155.4, 156.8, 155.4, 149.5, 148.1, 147.2, 145.8, 131.3, 121.6,
119.2, 119.0, 105.4, 66.5, 66.2, 62.1, 61.8, 62.1, 61.8, 60.3, 57.3,
56.1, 55.7, 32.6, 28.0, 22.3, 13.9. HRMS: Calcd for C20H26F3NO5S
[M+H]+ 450.1562; Found 450.1562. dr = 99.5:0.5.
(3.60 mmol), diethyl malonate (18.0 mmol), and K2CO3
(18.0 mmol) and then stirred. The completion of the reaction was
confirmed using HPLC and TLC. Purified water (10 mL) was then
added to the reaction mixture. The slurry was extracted with ethyl
acetate (10 mL) and the organic layer was vacuum distilled to
afford compound 8 as a yellow oil.
4.2.3.3. Synthesis of compound 8 (entry 8).
To a reaction
flask were added compound 3 (1.0 g, 3.60 mmol), diethyl malonate
(2.74 mL, 18.0 mmol), and Na2CO3 (1.91 g, 18.0 mmol) and then
stirred for 17.5 h at 0 °C. The completion of the reaction was con-
firmed using HPLC and TLC. The solution was allowed to return
to room temperature, and then purified water (10 mL) was added
to the reaction mixture. The slurry was extracted with ethyl acet-
ate (10 mL) and the organic layer was vacuum distilled to afford
compound 8 as a yellow oil.
4.2.4.4. Diallyl-{(R)-1-[((R)-tert-butylsulfinyl)amino]-2-(2,4,5-
trifluorophenyl)ethyl}malonate 15.
1H NMR (400 MHz,
CDCl3,) : d 1.06 (s, 9H), 2.93 (d, 2H, J = 7.5 Hz), 3.99–4.04 (m, 2H),
4.52 (d, 1H, J = 9.8 Hz), 4.69–4.72 (m, 4H), 5.25–5.38 (m, 4H),
5.89–5.94 (m, 2H), 6.85–6.91 (m, 1H), 7.01–7.08 (m, 1H). HRMS:
Calcd for
dr = 99.3:0.7.
C
21H26F3NO5S [M+H]+ 462.1562; Found 462.1561.
4.2.3.4. General procedure for the synthesis of compound 8
4.2.5. Completion of sitagliptin synthesis (Scheme 3)
(entries 9, 10).
To a reaction flask were added compound 3
4.2.5.1. Ethyl-(R)-3-[((R)-tert-butylsulfinyl)amino]-4-(2,4,5-tri-
(3.60 mmol) and diethyl malonate (18.0 mmol), and then the reac-
tion mixture was cooled to 0 °C. Base (18.0 mmol) and NaI
(53.0 mg, 0.36 mmol) were added to the reaction mixture and stir-
red at 0 °C. The completion of the reaction was confirmed using
HPLC and TLC. The solution was allowed to room temperature,
and then purified water (10 mL) was added to the reaction mix-
ture. The slurry was extracted with ethyl acetate (10 mL) and the
organic layer was vacuum distilled to afford compound 8 as a yel-
low oil.
fluorophenyl)butanoate 10.
To a reaction flask were added
compound 14 (113.5 g, 252.4 mmol), palladium acetate (0.23 g,
1.01 mmol), triphenyl phosphine (1.06 g, 4.04 mmol), and ethyl
acetate (230 mL). The reaction slurry was stirred until it dissolved
clearly at room temperature. To the reaction mixture were added
formic acid (11.9 mL, 315 mmol) and triethylamine (45.7 mL,
328 mmol), and then stirred for 3 h at reflux. The completion of
the reaction was confirmed using HPLC. The reaction mixture
was cooled to room temperature. Subsequently, a 2 M HCl solution
(120 mL) was slowly added to the reaction mixture, and then stir-
red for 5 min. The slurry was extracted with ethyl acetate
(565 mL). The organic layer was washed with 20% NaCl solution
(565 mL), 5% NaHCO3 solution (565 mL), and 5% NaCl solution
(565 mL). Vacuum distillation of the organic layer afforded com-
pound 10 as a yellow oil. 1H NMR (400 MHz, CDCl3): d 1.08 (s,
9H), 1.27 (t, 3H, J = 7.1 Hz), 2.62–2.92 (m, 4H), 3.74–3.78 (m, 1H),
4.14 (q, 2H, J = 6.1 Hz), 4.25 (d, 1H, J = 8.9 Hz), 6.86–6.92 (m, 1H),
7.00–7.07 (m, 1H). 13C NMR (175 MHz, CDCl3): d 171.6, 170.7,
169.8, 156.8, 155.4, 149.5, 148.1, 147.2, 145.8, 121.6, 119.2,
106.0, 61.6, 60.9, 59.2, 56.0, 54.3, 49.0, 39.8, 34.9, 34.4, 31.2, 28.1,
22.4, 14.3. HRMS: Calcd for C16H22F3NO3S [M+H]+ 366.1351; Found
366.1353. dr = 99.4:0.6.
4.2.3.5. General procedure for the synthesis of compound 8
(entries 11, 12).
To a reaction flask were added compound 3
(3.60 mmol), diethyl malonate (18.0 mmol), base (18.0 mmol),
and additive (18.0 mmol) and then stirred at 0 °C. The completion
of the reaction was confirmed using HPLC and TLC. The solution
was allowed to room temperature, and then purified water
(10 mL) was added to the reaction mixture. The slurry was
extracted with ethyl acetate (10 mL) and the organic layer was vac-
uum distilled to afford compound 8 as a yellow oil. The HPLC
method was the same as compound 8.
4.2.4. Stereoselective enolate addition to sulfinyl imine 3 with
allyl malonates (Table 3)
4.2.4.1. General procedure for the synthesis of compound 13, 14
HPLC methods. Kromasil C18
,
4.6 mm  250 mm (5
lm),
k = 268 nm, flow rate 1.0 mL/min, column temperature: 40 °C,
mobile phase: buffer/acetonitrile (buffer: 0.1% HClO4 aqueous
solution).
and 15.
To a reaction flask were added compound 3
(3.60 mmol) and malonates (18.0 mmol). The reaction mixture
Please cite this article in press as: Kang, S. K.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.10.010

6
S. K. Kang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
4.2.5.2.
rophenyl)butanoic acid 16.
compound 10 (92.2 g, 252.4 mmol), 5 M-NaOH solution (126 mL),
and THF (370 mL), and then stirred for 2 h at 40 °C. The completion
of the reaction was confirmed using HPLC. The reaction mixture
(R)-3-[((R)-tert-Butylsulfinyl)amino]-4-(2,4,5-trifluo-
To a reaction flask were added
basified to pH 9.0 with 5 M-NaOH solution. To the solution was
added DCM (594 mL), and the organic layer was separated, com-
bined. The residue was dissolved with IPA (180 mL) at 60 °C, and
then cooled to room temperature. The solution was stirred for
12 h at room temperature. To the solution was added n-hexane
(1,200 mL), and stirred for 2 h at room temperature. The solid pre-
cipitate was filtered, and then dried to afford compound 1 (sita-
Time (min)
Buffer (%)
Acetonitrile (%)
gliptin) as
a
white solid (42.1 g, 89.0%). Mp 117.4 °C;
0
10
12.5
15
60
25
25
60
40
75
75
40
[a]
20 = À22.7 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3): d 2.40–2.56
D
(m, 2H), 2.64–2.69 (m, 1H), 2.76–2.81 (m, 1H), 3.57 (m, 1H),
3.94–4.21 (m, 4H), 4.92–5.12 (m, 2H), 6.88–6.94 (m, 1H), 7.03–
7.09 (m, 1H). 13C NMR (175 MHz, CDCl3): d 170.5 (major), 170.1
(minor), 156.8 (ddd, JC–F = 243.9, 9.1, 2.1 Hz) 150.3, 149.5 (dt, JC–
F = 250.0, 13.0, 13.0 Hz), 146.0 (dd, JC–F = 244.8, 12.2 Hz), 143.7 (q,
major, JC–F = 80.2, 40.1 Hz), 143.6 (q, minor, JC–F = 40.1 Hz), 121.6
(d, major, JC–F = 15.5 Hz), 120.6 (d, minor, JC–F = 15.5 Hz), 119.0
(dd, JC–F = 18.8, 5.8 Hz), 117.4 (d, minor), 116.5 (d, major), 105.7
(dd, JC–F = 28.7, 20.6 Hz), 48.5, 43.5 (s, minor), 43.2 (s, major),
42.4 (s, major), 41.6 (s, minor), 40.0, 39.1, 37.99, 36.1. HRMS: Calcd
for C16H15F6N5O [M+H]+ 408.1259; Found 408.1257. HPLC purity:
99.76%. Enantiomeric sitagliptin: not detected.
was cooled to room temperature, after which were added water
(370 mL) and n-hexane (370 mL) to the solution. The aqueous layer
was separated (the organic layer was discarded) and washed with
ethyl acetate/hexane solution (1:1, 370 mL). The aqueous solution
was adjusted to pH 5.0 with a 2 M HCl solution, and stirred for
2 h at room temperature and then for 1 h at 0 °C. The solid precip-
itate was filtered, washed with purified water (90 mL), and then
dried to give compound 16 as a white solid (48.4 g, 57% for 3 steps).
Mp. 117.4 °C. 1H NMR (400 MHz, CDCl3): d 1.15 (s, 9H), 2.55 (dd, 1H,
J = 12.1, 4.9 Hz), 2.83–2.89 (m, 2H), 3.02–3.08 (m, 1H), 3.77 (br, 1H),
5.01 (d, 1H, J = 7.6 Hz), 6.88–6.95 (m, 1H), 7.03–7.09 (m, 1H). 13C
NMR (175 MHz, CDCl3): d 173.4, 156.9 149.5, 147.3, 121.7, 119.3,
56.8, 55.0, 39.0, 34.4, 22.6. HRMS: Calcd for C14H18F3NO3S [M+H]+
338.1038; Found 338.1038. dr = 99.8: 0.2. HPLC method was the
same as compound 10.
HPLC methods (purity). YMC ODS-AM, 4.6 mm  250 mm
(5 lm), k = 215 nm, flow rate 1.0 mL/min, column temperature:
30 °C, mobile phase: buffer/acetonitrile (buffer: 0.2% H3PO4 aque-
ous solution).
Time (min)
Buffer (%)
Acetonitrile (%)
0
5
85
85
65
25
25
85
85
15
15
35
75
75
15
15
4.2.5.3. (R)-2-Methyl-N-((R)-4-oxo-4-(3-(trifluoromethyl)-5,6-
dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluo-
15
25
30
32
45
rophenyl)butan-2-yl)propane-2-sulfinamide 17.
To a sus-
pension of compound 16 (48.0 g, 142.3 mmol) in DCM (960 mL)
were added HBTU (56.6 g, 149.4 mmol), piperazine (34.0 g,
149.4 mmol), and TEA (60.0 mL, 426.0 mmol) at 0 °C. The reaction
mixture was allowed to return to room temperature, and stirred
for 2 h. The completion of the reaction was confirmed using HPLC.
To the reaction mixture was added purified water (960 mL) and
then stirred for 20 min. The organic layer was separated and
washed with purified water (960 mL). The organic solution was
washed with a solution of 0.5% NaHCO3 (960 mL), 0.2 M HCl
(960 mL), and purified water (960 mL) and combined using a
rotary evaporator. The residue was dissolved with ethyl acetate
(480 mL) at reflux. The clear solution was cooled to room temper-
ature, and stirred for 12H, and then stirred for 2 h at 0 °C. The solid
precipitate was filtered, and then dried to afford compound 17 as a
white solid (61.1 g, 84.0%). Mp 189.5 °C. 1H NMR (400 MHz, CDCl3):
d 1.07 (s, 9H), 2.73–3.02 (m, 4H), 3.84–4.26 (m, 5H), 4.45 (d, 1H,
J = 10.4 Hz), 4.91–5.13 (m, 2H), 6.86–6.88 (m, 1H), 7.01–7.08 (m,
1H). 13C NMR (175 MHz, CDCl3): d 171.5, 170.2, 169.7, 156.8,
155.4, 150.2, 149.6, 148.0, 147.3, 145.9, 143.9, 143.6, 121.8,
120.5, 119.2, 119.1, 119.0, 118.9, 117.4, 115.9, 110.4, 105.4, 64.4,
56.1, 50.0, 55.2, 55.1, 49.0, 43.5, 43.2, 42.5, 41.7, 41.2, 39.1, 38.4,
HPLC methods (enantiomeric purity). Chiralpak IC, 4.6 mm  250 mm
(5 m), k = 268 nm, flow rate 1.0 mL/min, column temperature:
l
25 °C, mobile phase: buffer (n-hexane:isopropyl alcohol:ethanol:
diethylamine = 70:10:20:0.1).
Acknowledgements
This work was supported by the National Research Foundation of
Korea (NRF) grant for the Global Core Research Center (GCRC)
funded by the Korea government (MSIP) (No. 2011-0030001) and
by the Global Frontier Project grant of National Research Foundation
funded by Korea government (MSIP) (NRF-2015M3A6A4065798).
We acknowledge the Korea Basic Science Institute, Ochang, Korea,
for providing HRMS.
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C
20H23F6N5O2S [M+H]+
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O
O
O
O
F
F
F
F
(Ss
)
(Ss)
S
S
t-Bu
t-Bu
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(Ss
H
F
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NaHMDS
N
) t-Bu
(S)
(R)
O
O
+
toluene
-15 oC
O
O
O
O
(S,Ss)
(R,Ss)
88%
12%
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Please cite this article in press as: Kang, S. K.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.10.010