A concise and practical stereoselective synthesis of ipragliflozin L-proline

Article abstract of DOI:10.3762/bjoc.13.105

A concise and practical stereoselective synthesis of ipragliflozin L-proline was presented starting from 2-[(5-iodo-2-fluorophenyl)methyl]-1-benzothiophene and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide without catalyst via iodine–lithium–zinc exchange. The overall yield was 52% in three steps and the product purity was excellent. Two key diastereomers were prepared with efficient and direct access to the α-C-arylglucoside.

Full text of DOI:10.3762/bjoc.13.105

A concise and practical stereoselective synthesis of
ipragliflozin L-proline
Shuai Ma, Zhenren Liu, Jing Pan, Shunli Zhang and Weicheng Zhou*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 1064–1070.
State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key
Lab of Anti-Infectives, Shanghai Institute of Pharmaceutical Industry,
China State Institute of Pharmaceutical Industry, No. 285, Gebaini
Rd., Shanghai 201203, P. R. of China
doi:10.3762/bjoc.13.105
Received: 02 March 2017
Accepted: 15 May 2017
Published: 01 June 2017
Email:
Weicheng Zhou* - zhouweicheng58@163.com
Associate Editor: T. P. Yoon
* Corresponding author
© 2017 Ma et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
arylzinc derivative; β-C-arylglucoside; diastereomer impurity;
ipragliflozin L-proline; stereoselective synthesis
Abstract
A concise and practical stereoselective synthesis of ipragliflozin L-proline was presented starting from 2-[(5-iodo-2-
fluorophenyl)methyl]-1-benzothiophene and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide without catalyst via iodine–lithi-
um–zinc exchange. The overall yield was 52% in three steps and the product purity was excellent. Two key diastereomers were pre-
pared with efficient and direct access to the α-C-arylglucoside.
Introduction
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new Only a few methods have been found in the literature about the
class of antidiabetes drugs, and dapagliflozin [1], canagliflozin synthesis of 1. It was reported that aryllithium reacted with per-
[2], empagliflozin [3], ipragliflozin [4], tofogliflozin [5], hydroxy-protected D-glucono-1,5-lactone at −78 °C to obtain
luseogliflozin [6] have been approved for the treatment of Type the lactol, followed by reduction with a large bulk silyl hydride
2 diabetes mellitus (T2DM). One of them, (ipragliflozin in order to get high β-selectivity [9,10]. This approach included
L-proline 1, (1S)-1,5-anhydro-1-C-{3-[(1-benzothiophen-2- six steps such as addition, methyl etherification, acetylation,
yl)methyl]-4-fluorophenyl}-D-glucitol (2S)-pyrrolidine-2- reduction, deprotection and cocrystallization with L-proline to
carboxylic acid (1:1), Figure 1), was launched into the Japanese get 1 with a total yield of 32.89%. The subsequent improve-
market in January 2014 [7,8]. Due to its efficacy and safety, 1 ment reported included the replacement of aryllithium by aryl
can be used as monotherapy or in combination with other hypo- Grignard reagents, raising the reaction temperature up to −20 °C
glycemic agents.
[11]. However, the yield was not obviously improved.
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Beilstein J. Org. Chem. 2017, 13, 1064–1070.
Scheme 1: Stereoselective synthesis of C-aryl glycoside by Lemarie.
sequence. Cryogenic temperatures and catalysts were not re-
quired.
Figure 1: Structure of ipragliflozin L-proline.
SGLT-2 inhibitors have the common pharmacophore of β-C- The key step was the diastereoselective synthesis of pivaloyl-
arylglucoside, and the synthesis of β-C-arylglucoside including protected 5 (Scheme 2). Thus, this reaction was studied in more
the usage of arylzinc [12], arylalane [13], and anomeric stan- detail to screen the best conditions, and the results were
nane [14] were applied to prepare dapagliflozin and presented in Table 1.
canagliflozin. However, these approaches might be difficult to
scale up because of the involvements of complex synthetic pro- On the basis of literature [12], 2-[(5-bromo-2-fluorophenyl)-
cedures, chromatographic purification or expensive catalysts methyl]-1-benzothiophene (4b) [9] was converted to the
and ligands. Gong et al. [15] reported an approach to synthesise arylzinc species by the reaction with n-BuLi in the mixed sol-
C-aryl glycosides based on a Negishi cross-coupling of arylzinc vent (toluene/DBE), followed by transmetalation with ZnBr/
with protected glycosyl bromide in the presence of Ni-catalysts. LiBr complex in DBE, and then the active species reacted with
An improved procedure with high stereoselectivity and in the 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (2b) [16].
absence of catalysts was reported subsequently by Lemarie et But the reaction gave only 35% of desired 5 although it had a
al. (Scheme 1) [12] to construct the anomeric chiral center of high diastereomeric excess (de) value (97%). The main byprod-
dapagliflozin and canagliflozin. But so far, it has not been found uct was the debrominated compound 5” determined by NMR
that this method was applied to synthesize 1. In this paper, we and MS analysis (Table 1, entry 1). The reaction between 2-[(5-
report an efficient and practical method for the preparation of 1 iodo-2-fluorophenyl)methyl]-1-benzothiophene (4a) [9] and
through an arylzinc reagent.
pivaloyl-protected glycosyl halides 2 were further explored. The
reaction of chloride 2c [17] with 4a provided a better result
(Table 1, entry 2). With respect to the iodide 2a [18], due to its
Results and Discussion
Herein, a concise and practical stereoselective synthesis of 1 thermal and chemical instability, there was only 2% of 5
with three steps was developed. The route initiated from com- detected, and the content of 5” was up to 60% (Table 1, entry
pound 4a and pivaloyl-protected glycosyl bromide 2b, the β-C- 3). Fortunately, the reaction of 4a with 1.0 equiv 2b gave a
arylglucoside 5 was obtained with high stereoselectivity in one good result, the amount of 5” was greatly reduced (Table 1,
step after a halogen–lithium exchange/transmetalation/coupling entry 4), while the content of 5 in the crude product was in-
Scheme 2: Stereoselective synthesis of β-C-arylglucoside 5.
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Beilstein J. Org. Chem. 2017, 13, 1064–1070.
Table 1: Conditions for the stereoselective synthesis of β-C-arylglucoside 5.
Entry
Reactants
Zinc halide salt
Solvent
T (°C) Crude producta (5:5’:5”) deb (%) Yieldc (%)
1
4b, 2b
4a, 2c
4a, 2a
4a, 2b
4a, 2b
4a, 2b
4a, 2b
4a, 2b
4a, 2b
4a, 2b
4a, 2b
4a, 2b
4a, 2b
4a, 2b
ZnBr2/LiBr (0.55 equiv) Toluene/DBEd (5:3)
ZnBr2/LiBr (0.55 equiv) Toluene/DBE (5:3)
−20
−20
−20
−20
−20
−10
−30
−20
−20
−20
−20
−20
−20
−20
35%:0.5%:46%
50%:4%:36%
2%:0.3%:60%
68%:2%:21%
65%:2%:24%
34%:1%:46%
67%:2%:23%
55%:2%:32%
68%:2%:20%
2%:0%:14%
97
85
74
94
94
94
94
93
94
0g
0g
98
94
93
48.4
63.8
−
2
3
ZnI2/LiI (0.55 equiv)
ZnBr2/LiBr (0.55 equiv) Toluene/DBE (5:3)
ZnBr2/LiBr (1.0 equiv) Toluene/DBE (5:3)
Toluene/DBE (5:3)
4
77.7
75.6
46.7
76.5
78.9
77.9
–
5
6
ZnBr2/LiBr (0.55 equiv) Toluene/DBE (5:3)
ZnBr2/LiBr(0.55 equiv) Toluene/DBE (5:3)
ZnBr2/LiBr (0.55 equiv) Toluene/DBE (5:3)
ZnBr2/LiBr (0.55 equiv) Toluene/DBE (5:3)
ZnBr2/LiBr (0.55 equiv) Toluene/THF (5:3)
ZnBr2/LiBr (0.55 equiv) Toluene/MTBEh (5:3)
ZnBr2/LiBr (0.55 equiv) Toluene/CPMEi (5:3)
ZnBr2/LiBr (0.55 equiv) Toluene/DBE (5:3)
ZnBr2/LiBr (0.55 equiv) Toluene/DBE (5:3)
7
8e
9f
10
11
12
13j
14l
5%:0%:67%
6.5
33%:0.4%:49%
66%:2%:22%
68%:2.5%:21%
47
62.8k
65.3k
aDetermined by HPLC at 263 nm, the content of 5’’ might be over-estimated since the different UV response between compound 5 and 5’’. This may
explain why the isolated yield after chromatography was higher than the content of 5 in the crude; bdiastereomeric excess of 5 and 5’; cisolated yield
for 5 after column chromatography (entries 1–12); ddi-n-butyl ether; e4a was added in 1.2 equiv; f2b was added in 1.2 equiv; gno diastereomer was
detected; hmethyl tert-butyl ether; icyclopentyl methyl ether; j20 g of 4a was added; kisolated by recrystallization; l50 g of 4a was added.
creased to 68% and the isolated yield was 77.7%. It was The protecting groups of 5 were removed in presence of sodi-
presumable that a iodine–lithium–zinc exchange and the trans- um methoxide in refluxing methanol, and then recrystallized to
metalation proceeded better than a bromide–lithium–zinc give ipragliflozin 6 in 95.3% yield. Compound 6 and L-proline
exchange and transmetalation to produce the arylzinc deriva- was converted to the L-proline complex 1 as a cocrystal form in
tive in situ in this reaction. However, further increasing the ethanol (Scheme 3). After filtration and drying, compound 1
amount of zinc bromide to 1.0 equiv did not improve the reac- was produced with 83.7% yield and 99.92% purity. The mp
tion (Table 1, entry 5) and elevation of the reaction temperature (dec) and optical rotation value of compound 1 was consistent
to −10 °C (Table 1, entry 6) worsened the reaction, resulting in with those in the literature reported [19], and the structure was
more formation of 5’’. Additionally, no significant improve- confirmed by MS and NMR.
ment was achieved by further decreasing the temperature
(Table 1, entry 7).
The α-anomers of 5 and 6 were the key impurities during the
synthetic process. Pure compounds of 5’ and 6’ were prepared
In entries 1–7 (Table 1), the feed ratio of two reagents (4 and 2) for the analytical references (Scheme 4). Compound 4a was
was set as 1:1. From the above data, it was seen that the reac- converted to the corresponding arylzinc derivative in situ, and
tion was acccompanied by the deiodination of 4a, but to our the latter coupled with pivaloyl-protected 1,2-anhydroglucal 7
surprise, neither elevation of the ratio to 1.2 of compound 4a [20] to get the α-C-arylglucoside 8. After removing the
(Table 1, entry 8) nor 2b (Table 1, entry 9) improved the reac- protecting groups in the presence of sodium methoxide, the
tion. When other solvents were tested (Table 1, entries 10–12), α-anomer 6’ of ipragliflozin was obtained. The hydroxy group
the results showed that the reaction in toluene/DBE mixed sol- in 2-position of 8 was protected by pivaloyl chloride to generate
vent afforded the best result. Interestingly, it was also found that 5’. In the 1H NMR, the coupling constant of the anomeric
the reaction of 2b with 4a gave a similar de (Table 1, entries 1, proton for 6’ was 4.0 Hz, while the corresponding constant for 6
4–9 and 12–14) in different conditions although the content of 5 was 9.6 Hz, which was similar with those of canagliflozin [20].
was greatly varied. According to the methodology in entry 4,
the reaction was scaled up (50 g 4a) (Table 1, entry 14), and the Conclusion
crude product was purified by recrystallization from methanol, In conclusion, a concise and practical stereoselective synthesis
and the desired product in 65.3% yield with HPLC of 1 starting from 4a and 2b was developed in a 52% overall
purity 99.79% was obtained; the diastereomer 5’ was not yield with a purity of 99.92% over three steps. This method was
detected.
easy to perform in large scale, and both the purity and yield
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Beilstein J. Org. Chem. 2017, 13, 1064–1070.
Scheme 3: Synthesis of 1.
Scheme 4: Synthesis of diastereomer 6’ and 5’.
were excellent. In addition, two key diastereomers were pre- measured on a Büchi Melting Piont M-565 apparatus. Optical
pared with efficient and direct access to α-C-arylglucoside and rotations were measured with an Autopol IV laboratory
they may be served as the references both in the monitoring the polarimeter.
reaction and the quality control of the drug.
Preparation of (1S)-1,5-anhydro-1- {3-[(1-benzothiophen-2-
Experimental
yl)methyl]-4-fluorophenyl}-2,3,4,6-tetra-O-pivaloyl-D-
All solvents and reagents were of reagent grade and used with- glucitol (5): A dry round-bottle flask was charged with solid
out further purification. HPLC analyses were recorded using a ZnBr2 (16.8 g, 0.55 equiv), LiBr (6.5 g, 0.55 equiv) and an-
Waters Arc HPLC System with 2998 PDA Detector or an hydrous n-dibutyl ether (120 mL) under a nitrogen atmosphere.
Agilent 1260 HPLC System with DAD Detector. NMR spectra The resulting mixture was stirred at 50 °C until the solid dis-
were recorded on a Bruker AV III 400 MHz spectrometer with solved, and then the mixture cooled back to room temperature
TMS as an internal standard. Chemical shifts are quoted in parts and used as such for the next step. Compound 4a (50 g,
per million (ppm). HRMS were recorded on a Waters Q-Tof 135.8 mmol) was dissolved in anhydrous toluene (150 mL) and
Micro LCMS apparatus. Melting points were uncorrected and n-dibutyl ether (90 mL) under nitrogen atmosphere, and then
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Beilstein J. Org. Chem. 2017, 13, 1064–1070.
the mixture was cooled to −20 °C, n-butyllithium in hexane cooled to room temperature, and crystallized to get a white solid
2.5 M (57.6 mL, 1.06 equiv) was added dropwise over 20 min. 21.5 g. Yield 83.7%; purity (HPLC): 99.92%; decomposition
After beeing stirred for 3 h, a solution of ZnBr2–LiBr in temperature 203.3–205 °C; [α]D25 = −9.2° (c 1, acetonitrile/
n-dibutyl ether was added dropwise over 20 min at 0 °C. After H2O 7:3); 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.0 Hz,
stirring for 1 h, a solution of compound 2b (78.7 g, 1.0 equiv) in 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.45 (d, J = 7.6 Hz, 2.4 Hz, 1H),
toluene (120 mL) was added to the reaction mixture. The mix- 7.39–7.36 (m, 1H), 7.31–7.23 (m, 2H), 7.10 (t, J = 9.2 Hz, 1H),
ture was stirred at 100 °C for about 3 h until the reaction was 7.07 (s, 1H), 4.32–4.23 (m, 2H), 4.14 (d, J = 9.2 Hz, 1H),
completed (TLC detection). The mixture was quenched with 4.00–3.97 (m, 1H), 3.89 (dd, J = 12.0 Hz, 1.6 Hz, 1H), 3.71 (dd,
1 M HCl (300 mL), and then stirred for about 10 min and J = 12.0 Hz, 5.2 Hz, 1H), 3.50–3.31 (m, 5H), 3.27–3.20 (m,
extracted. The organic phase was washed with water (300 mL), 1H), 2.35–2.26 (m, 1H), 2.17–2.09 (m, 1H), 2.01–1.94 (m, 2H);
followed by concentration under reduced pressure to get a 13C NMR (100 MHz, CDCl3) δ 172.6, 161.6, 159.2, 143.6,
brown oil. The crude oil was crystallized from methanol to get a 139.9, 135.9, 130.4, 127.9, 126.0, 123.8, 123.4, 122.6, 121.5,
white solid 65.7 g. Yield 65.3%; purity (HPLC): 99.79%; 114.5, 81.5, 80.8, 78.4, 75.1, 70.5, 61.5, 45.6, 29.2, 23.7; MS
mp 133–134.7 °C; [α]D25 = +14° (c 1, CHCl3); 1H NMR (ES+) m/z: 427.16 [M + Na]+.
(400 MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.4
Hz, 1H), 7.31–7.22 (m, 4H), 7.04 (t, J = 9.2 Hz, 1H), 6.97 (s, Preparation of (1R)-1,5-anhydro-1-{3-[(1-benzothiophen-2-
1H), 5.40 (t, J = 9.6 Hz, 1H), 5.33–5.23 (m, 2H), 4.36 (d, J = yl)methyl]-4-fluorophenyl}-3,4,6-tri-O-pivaloyl-D-glucitol
10.0 Hz, 1H), 4.25–4.16 (m, 3H), 4.10 (dd, J = 12.4 Hz, 4.0 Hz, (8): A dry round-bottom flask was charged with solid ZnBr2
1H), 3.84–3.80 (m, 1H), 1.19 (s, 9H), 1.16 (s, 9H), 1.11 (s, 9H), (2.59 g, 1.15 equiv), LiBr (1 g, 1.15 equiv) and anhydrous
0.84 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.1, 177.3, n-dibutyl ether (15 mL) under nitrogen atmosphere, the result-
176.4, 162.2, 159.8, 142.9, 139.9, 132.4, 130.7, 128.3, 126.6, ing mixture was stirred at 50 °C for 2 h. After cooling to room
124.2, 123.8, 123.0, 122.0, 115.6, 80.3, 73.6, 72.0, 67.9, 61.7, temperature, the mixture was used as such for the next step. A
38.7, 30.0, 27.1; HRMS (ES+) m/z: [M + Na]+ calcd for solution of compound 4a (4.05 g, 1.1 equiv) dissolved in an-
C41H53O9NaSF, 763.3292; found, 763.3310.
hydrous toluene (20 mL) under nitrogen atmosphere was cooled
to 0 °C, n-butyllithium in hexane 1.6 M (7.2 mL, 1.15 equiv)
Preparation of (1S)-1,5-anhydro-1-{3-[(1-benzothiophen-2- was added dropwise over 8 min. After beeing stirred for 2 h, a
yl)methyl]-4-fluorophenyl}-D-glucitol (6): A round-bottom solution of ZnBr2–LiBr in n-dibutyl ether was added dropwise
flask was charged with compound 5 (20 g, 27 mmol) and meth- over 10 min at 0 °C. After being stirred for 1.5 h, a solution of
anol (100 mL), then, sodium methoxide (2.92 g, 2.0 equiv) was compound 7 (4.15 g, 10 mmol) in toluene (10 mL) was added to
added and the mixture was heated at 65 °C for 3 h. After cool- the reaction mixture. The mixture was stirred at room tempera-
ing down to room temperature, water (300 mL) was added to ture for about 14 h, then saturated ammonium chloride (50 mL)
the resulting mixture, followed by addition of a seed crystal was added (quenched the reaction), the organic phase was
(50 mg) and stirred for 4 h. The crystals were filtered and dried washed with water, dried over Na2SO4 and concentrated under
to obtain a white solid 10.4 g. Yield 95.3%; purity (HPLC): reduced pressure. The residue was purified by column chroma-
99.78%; mp 155–156.5 °C; [α]D25 = +24.5° (c 1, CH3OH); tography to afford the title compound as light yellow oil
1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.6 Hz, 1H), 7.65 (d, 1.316 g. Yield 20%; purity (HPLC): 98.2%; [α]D25 = +21.5°
J =7.6 Hz, 1H), 7.45 (dd, J =7.2 Hz, 2.0Hz, 1H), 7.39–7.36 (m, (c 1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.0
1H), 7.31–7.22 (m, 2H), 7.10 (t, J = 9.6 Hz, 1H), 7.05 (s, 1H), Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.46–7.39 (m, 2H), 7.30–7.23
4.31–4.22 (m, 1H), 4.14 (d, J = 9.6 Hz, 1H), 3.89 (dd, J = 12.4 (m, 2H), 7.07 (t, J = 9.2 Hz, 1H), 7.01 (s, 1H), 5.24 (t, J = 6.0
Hz, 2.0 Hz, 1H), 3.72 (dd, J = 12.0 Hz, 5.6 Hz, 1H), 3.51–3.33 Hz, 1H), 5.06 (d, J = 2.8 Hz, 1H), 4.96 (t, J = 4.8 Hz, 1H), 4.57
(m, 4H); 13C NMR (100 MHz, CDCl3) δ 161.6, 159.2, 143.6, (m, 1H), 4.29–4.20 (m, 2H), 4.05–3.97 (m, 3H), 2.51 (brs, 1H),
140.1, 139.7, 135.8, 130.4, 128.0, 126.1, 123.8, 123.4, 122.6, 1.24 (s, 9H), 1.19 (s, 9H), 1.14 (s, 9H); 13C NMR (100 MHz,
121.6, 114.5, 81.5, 80.8, 78.4, 75.1, 70.5, 61.7, 29.3; HRMS CDCl3) δ 178.1, 177.4, 176.6, 161.5, 159.1, 143.3, 140.0,
(ES+) m/z: [M + Na]+ calcd for C21H21O5NaSF, 427.0991; 139.7, 133.0, 130.1, 127.7, 126.6, 123.9, 123.0, 122.1, 121.8,
found, 427.0983.
115.5, 72.8, 71.9, 71.0, 69.9, 67.2, 60.7, 38.8, 30.2, 27.1; MS
(ES−) m/z: 691.09 [M + Cl]−.
Preparation of ipragliflozin L-proline (1): A round-bottom
flask was charged with compound 6 (20 g, 49.4 mmol), and Preparation of (1R)-1,5-anhydro-1-{3-[(1-benzothiophen-2-
filled up with ethanol (100 mL), and then L-proline (5.7 g, yl)methyl]-4-fluorophenyl}-D-glucitol (6’): A round-bottom
1.0 equiv) and water (10 mL) were added. The mixture was flask was charged with compound 8 (1.316 g, 2 mmol) and
stirred at 100 °C for 0.5 h. Thereafter, the reaction solution was filled up with methanol (7 mL), and then sodium methoxide
1068

Beilstein J. Org. Chem. 2017, 13, 1064–1070.
References
(0.324 g, 3.0 equiv) was added, the resulting mixture was
heated at 65 °C for 3 h. After cooling down to room tempera-
ture, the reaction was quenched with a solution of ammonium
chloride (10 wt %, 15 mL). The aqueous layer was extracted
with ethyl acetate (15 mL). The organic layer was washed with
water, dried over Na2SO4 and concentrated under reduced pres-
sure. The residue was purified by column chromatography to
afford the title compound as light yellow solid 0.602 g. Yield
74.4%; purity (HPLC): 99.8%; mp 164.5–167.6 °C;
[α]D25 = +55.5° (c 1, MeOH); 1H NMR (400 MHz, CD3OD) δ
7.74 (d, J = 7.6 Hz, 2H), 7.70–7.66 (m, 2H), 7.31–7.22 (m, 2H),
7.10–7.06 (m, 2H), 5.08 (d, J = 4.0 Hz, 1H), 4.26 (s, 2H),
3.90–3.83 (m, 2H), 3.79–3.69 (m, 2H), 3.48–3.42 (m, 2H);
13C NMR (100 MHz, CD3OD) δ 161.1, 158.6, 143.7, 140.1,
139.7, 134.8, 130.9, 128.6, 126.0, 123.8, 123.4, 122.6, 121.5,
114.4, 75.7, 73.7, 72.9, 61.1, 29.4; MS (ES+) m/z: 427.33
[M + Na]+.
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Preparation of (1R)-1,5-anhydro-1-{3-[(1-benzothiophen-2-
yl)methyl]-4-fluorophenyl}-2,3,4,6-tetra-O-pivaloyl-D-
glucitol (5’): In a round-bottom flask, a mixture of compound 8
(1 g, 1.52 mmol), DCM (5 mL), DMAP (10 mg, 0.05 equiv)
and TEA (0.46 g, 3.0 equiv) were stirred at room temperature.
Then, pivaloyl chloride (0.55 g, 3.0 equiv) was added dropwise
and the mixture was stirred at room temperature for 5 days, the
reaction was diluted with DCM (10 mL) and quenched with
saturated ammonium chloride (10 mL), the organic layer was
washed with water, dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by column chroma-
tography to afford the title compound as light yellow solid
0.596 g. Yield 52.84%; purity (HPLC): 95.7%;
mp 159.2–162.3 °C; [α]D25 = +78.9° (c 1, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.72 (d, J = 8 Hz, 1H), 7.65 (d, J = 7.6 Hz,
1H), 7.59 (dd, J = 6.8 Hz, 1.6 Hz, 1H), 7.52–7.48 (m, 1H),
7.30–7.22 (m, 2H), 7.12–7.07 (m, 2H), 5.69 (t, J = 9.2 Hz, 1H),
5.35 (dd, J = 9.2 Hz, 5.6 Hz, 1H), 5.29 (d, J = 6.0 Hz, 1H), 5.16
(t, J = 9.2 Hz, 1H), 4.31–4.23 (m, 2H), 4.11–4.02 (m, 2H),
3.64–3.60 (m, 1H), 1.18 (s, 9H), 1.17 (s, 9H), 1.13 (s, 9H), 0.92
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.0, 177.1, 176.6,
161.6, 159.1, 142.8, 139.9, 131.4, 129.0, 126.9, 124.0, 123.1,
122.1, 115.7, 73.1, 70.6, 68.4, 62.1, 38.7, 30.0, 27.0; MS (ES+)
m/z: 763.44 [M + Na]+.
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Supporting Information
Supporting Information File 1
1H NMR, 13C NMR and HRMS spectra of compounds 1, 5,
6, 5’, 6’ and 8, and HPLC diagram of 5.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-105-S1.pdf]
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Beilstein J. Org. Chem. 2017, 13, 1064–1070.
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