Efficient and practical asymmetric synthesis of isopropyl (R)-3-(3′,4′-dihydroxyphenyl)-2-hydroxypropanoate and its enantiomer

Article abstract of DOI:10.1016/j.tetasy.2010.11.030

The highly enantioselective synthesis of (R)-isopropyl 3-(3′, 4′-dihydroxyphenyl)-2-hydroxypropanoate and its enantiomer has been achieved starting from 3,4-dihydroxybenzaldehyde. The stereogenic centers were established through asymmetric dihydroxylation of (E)-isopropyl 3,4-bis(benzyloxy) cinnamate. A convenient manipulation in selective catalytic hydrogenation and deprotection was also accomplished in HCl-ⁱPrOH employing 10% Pd/C catalyst.

Full text of DOI:10.1016/j.tetasy.2010.11.030

Tetrahedron: Asymmetry 22 (2011) 4–7
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Efficient and practical asymmetric synthesis of isopropyl
(R)-3-(30,40-dihydroxyphenyl)-2-hydroxypropanoate and its enantiomer
Ming Chen a, , Hui Chen a, , Yuzhen Wang a, Haibo Wang a, Yefei Nan b, Xiaohui Zheng b, , Ru Jiang a,
⇑
⇑
a Department of Medicinal Chemistry and Pharmaceutical analysis, School of Pharmacy, Fourth Military Medical University, Xi’an 710032, China
b Key Laboratory of Resource Biology and Biotechnology in Western China and College of Life Sciences, Northwest University, Xi’an 710069, China
a r t i c l e i n f o
a b s t r a c t
The highly enantioselective synthesis of (R)-isopropyl 3-(30,40-dihydroxyphenyl)-2-hydroxypropanoate
and its enantiomer has been achieved starting from 3,4-dihydroxybenzaldehyde. The stereogenic centers
were established through asymmetric dihydroxylation of (E)-isopropyl 3,4-bis(benzyloxy) cinnamate. A
convenient manipulation in selective catalytic hydrogenation and deprotection was also accomplished in
HCl–iPrOH employing 10% Pd/C catalyst.
Article history:
Received 19 October 2010
Accepted 24 November 2010
Available online 31 January 2011
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
O
HO
HO
O
Danshen, the dried root of Salvia miltiorrhiza, is a traditional Chi-
nese medicine widely used for the treatment of cardiovascular dis-
eases in China and other countries.1 The extract of danshen was
approved by the Chinese State Food and Drug Administration as an
activating blood circulation agent with the trade name of Danshen
Tablet (state drug permit doc: Z20055235). More than 50 chemical
constituents of danshen have been identified and shown to possess
various biological and pharmacological effects, including improve-
ment of microcirculation, anti-blood coagulation, anti-oxidation,
anti-myocardial ischemia, anti-inflammation, and anti-neoplastici-
ty.2–8 In 2007, we found a new metabolite of danshen after oral
administration of the compound Danshen Dripping pills (state drug
permit doc: Z10950111), a novel compound, namely isopropyl 3-
(30,40-dihydroxyphenyl)-2-hydroxypropanoate (IDHP, Fig. 1).9 Fur-
ther studies have proved that IDHP exerts a vasorelaxant effect by
inhibiting both Ca2+ release from intracellular stores and Ca2+ influx
through voltage-dependent calcium channels and receptor-oper-
ated calcium channels in vascular smooth muscle cells.10 Moreover,
it also exhibited a significant neuroprotective effect on MCAO-in-
duced focal cerebral ischemia by inhibiting lipid peroxidation,
increasing endogenous antioxidant defense enzymes, and improv-
ing brain mitochondrial energy metabolism.11 These findings
indicated that IDHP might be developed as a new medicine for the
treatment of cardiovascular and cerebrovascular diseases.
Therefore, it is necessary to assess the contributions of the different
OH
Figure 1. Structure of IDHP.
stereoisomers to the pharmacodynamics and pharmacokinetics,
respectively, for IDHP. The aim of the present study was, therefore,
to establish a concise and practical synthesismethod of (R)/(S)-IDHP.
2. Results and discussion
The strategies for the preparation of chiral
involve the stereoselective oxidation of a pro-chiral ester by a cam-
phoryl-sulfonyloxaziridine, alkylation of chiral glycolate enolates,
a-hydroxy esters
and catalytic hydrogenation of enol esters, and
a-keto acid
derivatives.12–15 The method we adopted is based on the Sharpless
catalytic asymmetric dihydroxylation (AD) reaction of substituted
(E)-cinnamates.16–18 Cinnamates, which can be readily prepared
from aldehyde, have proven to be exceptionally good substrates
for the AD reaction. The resulting
a,b-dihydroxy esters are
obtained with high enantiomeric excesses and good yield. The
subsequent selective deoxygenation of the b-hydroxyl group pro-
vides the desired product. Therefore, we designed the following
synthetic route to (R)-IDHP (Scheme 1).
Our asymmetric synthesis of (R)-IDHP commenced with com-
mercially available 3,4-dihydroxybenzaldehyde 1, which was
transformed into (E)-isopropyl 3,4-bis(benzyloxy) cinnamate 4 by
benzylation, Knoevenagel condensation, and esterification. Next,
asymmetric dihydroxylation of 4 proceeded in the presence of
K2[OsO2(OH)4] (0.2 mol %) and the chiral ligand (QN)2PHAL
⇑
Corresponding authors. Tel.: +86 29 88302686 (X.H.Z.); tel.: +86 29 84776775
(R.J.).
E-mail addresses: zhengxh@nwu.edu.cn, jiangrufmmu@yahoo.com (X. Zheng),
jiangru@fmmu.edu.cn (R. Jiang).
Co-first author.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.11.030

M. Chen et al. / Tetrahedron: Asymmetry 22 (2011) 4–7
5
BnO
BnO
COOPri
BnO
BnO
COOH
BnO
BnO
CHO
HO
HO
CHO
c
b
a
3
4
2
1
OH
HO
HO
COOPri
BnO
BnO
COOPri
e
d
OH
(R)-IDHP
OH
5
Scheme 1. Synthesis of (R)-IDHP. Reagents and conditions: (a) BnCl, K2CO3, DMF, 75 °C; (b) malonic acid, 1,4-dioxane, reflux; (c) iPrOH, H2SO4, reflux; (d) K3Fe(CN)6, K2CO3,
CH3SO2NH2, (QN)2PHAL, K2[OsO2(OH)4], 0 °C; (e) H2, Pd/C, HCl–iPrOH, 0 °C.
(1.0 mol %) with K3Fe(CN)6 as co-oxidant, and the desired (2R,3S)-
2,3-dihydroxy ester 5 was obtained in 86% yield with >99.9% ee.
Next, selective deoxygenation of the 3-hydroxyl group employing
10% Pd/C catalyst in HCl–iPrOH (0.5 mol Lꢀ1) provided (R)-IDHP,
while also allowing for the deprotection of phenolic hydroxyl
groups.19 Although the desired product was obtained in good yield,
the enantiomeric purity was only 16.3% ee. Because almost enan-
tioimerically pure 5 was obtained in the AD reaction, we specu-
lated that racemization might have occurred in the last step.
Therefore, we attempted to optimize the conditions for the hydro-
genation of 5.
fect neither the enantiomeric purity nor the chemical yield (entries
10 and 11). Finally, good enantiomeric purity of (R)-IDHP (97.8%
ee) was obtained by hydrogenation of 5 in the presence of 10%
Pd/C catalyst and 0.05 mol Lꢀ1 HCl at 0 °C under 5 bar H2 pressure
(entry 4).
In the same fashion, the (S)-enantiomer was synthesized from
(E)-isopropyl 3,4-bis(benzyloxy) cinnamate 4 (Scheme 2). (2S,3R)-
2,3-Dihydroxy ester 6 was obtained in >99.9% ee in the AD reaction
adopting (QD)2PHAL as the chiral ligand. After hydrogenation,
(S)-IDHP was prepared in 97.8% ee and 65% yield.
The concentration of HCl was observed to play an important
role in the reaction. The ees of the product increased as the HCl
concentration dropped from 0.5 to 0.05 mol Lꢀ1 (Table 1, entries
1–4), and the chemical yield did not change even though the reac-
tion time increased. Decreasing the concentration of HCl to
0.03 mol Lꢀ1 gave no benefit to the enantiomeric purity but low-
ered the chemical yield significantly (entry 5). Next, the effect of
reaction temperature on the chemical yield and enantiomeric pur-
ity was also investigated, and 0 °C was found to be optimal (Table 1,
entry 4). When the temperature was increased, the chemical yield
increased, but the ees of the product dropped (entries 6–8). Lower
temperatures resulted in a significant drop in the chemical yield
(entry 9). When the reaction temperature was lowered to ꢀ20 °C,
no product formed. Moreover H2 pressure was not observed to af-
3. Conclusions
In summary, we have developed a novel and efficient route to
(R)/(S)-IDHP starting from 3,4-dihydroxybenzaldehyde 1. The
essential stereocenters were constructed by AD reaction of (E)-iso-
propyl 3,4-bis(benzyloxy) cinnamate 4. Convenient manipulation
to both selective catalytic hydrogenation and deprotection was
also accomplished in HCl–iPrOH employing 10% Pd/C catalyst.
The method described herein could be an attractive alternative
for the synthesis of chiral a-hydroxyl esters.
4. Experimental
4.1. General
In general, reagents and solvents were used as purchased with-
out further purification. K2[OsO2(OH)4] was purchased from Al-
drich Chemical Co. (QN)2PHAL and (QD)2PHAL were prepared
according to literature procedures.21 NMR spectra were recorded
on Bruker Avance-400 and 500 spectrometers. High-Resolution
Mass Spectroscopy (HRMS) was carried out on a BRUKER APEX-II.
High performance liquid chromatography (HPLC) was performed
by an Agilent 1100 interfaced to an HP 71 series computer work-
station with Daicel Chiralpak AD chiral column. Optical rotations
were obtained on a Perkin–Elmer 343 polarimeter.
Table 1
Optimization of the reaction conditions in hydrogenation of 5
Entry
HCl (mol Lꢀ1
)
Temperature (°C)
H2 (bar)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
0.50
0.10
0.08
0.05
0.03
0.05
0.05
0.05
0.05
0.05
0.05
0
0
0
0
0
50
40
10
ꢀ10
0
5
5
5
5
5
5
5
5
5
4
6
71
69
70
68
32
78
73
65
29
65
68
16.3
88.5
92.4
97.8
97.5
60.2
79.5
93.7
97.8
97.5
97.6
10
11
4.2. 3,4-Dibenzyloxybenzaldehyde 2
0
a
A 500 mL three-necked round-bottomed flask was charged with
3,4-dihydroxybenzaldehyde 1 (8.30 g, 60 mmol), K2CO3 (41.4 g,
Yield of isolated product 5.
Determined by HPLC using a Chiracel AD column.20
b
OH
HO
HO
COOPri
OH
(S)-IDHP
COOPri
BnO
BnO
COOPri
BnO
BnO
b
a
OH
4
6
Scheme 2. Synthesis of (S)-IDHP. Reagents and conditions: (a) K3Fe(CN)6, K2CO3, CH3SO2NH2, (QD)2PHAL, K2[OsO2(OH)4], 0 °C; (b) H2, Pd/C, HCl–iPrOH, 0 °C.

6
M. Chen et al. / Tetrahedron: Asymmetry 22 (2011) 4–7
300 mmol), BnCl (17.3 mL, 150 mmol) and dry DMF (120 mL). The
mixture was stirred at 75 °C until TLC indicated that 1 had disap-
peared. The resultant mixture was cooled to room temperature, fil-
tered, and concentrated in vacuo. The crude oil residue was poured
into water and the obtained solid was triturated, filtered, and
washed with water giving 18.8 g of light yellow solid 2 (yield:
90%). Mp 90–91 °C [lit.22 mp 88 °C].
2H), 5.19–5.18 (d, J = 8.8 Hz, 4H), 5.14–5.06 (m, 1H), 4.88–4.86
(m, 1H); 4.28–4.26 (m, 1H), 3.14–3.12 (d, J = 6.0 Hz, 1H), 2.75–
2.73 (d, J = 6.4 Hz, 1H), 1.28–1.26 (d, J = 6.4 Hz, 3H), 1.21–1.20 (d,
J = 6.0 Hz, 3H); 13C NMR (125 MHz, CDCl3), d 172.4, 149.1, 149.0,
137.4, 137.3, 133.5,128.6, 128.0,127.9, 127.6, 127.4, 119.7, 115.0,
113.7, 74.7, 74.5, 71.5, 71.4, 70.3, 21.9, 21.8; HRMS calcd for
C
26H31NO6 (M+ NH4+) 454.2184, found 454.2228.
4.3. (E)-3,4-Bis(benzyloxy)cinnamic acid 3
4.6. (R)-IDHP
To a solution of 2 (15.0 g, 47.3 mmol) and malonic acid (14.7 g,
142.5 mmol) in 1,4-dioxane (75 mL) were added 1 mL pyridine and
piperidine. Then the mixture was refluxed for 5 h. After being
cooled to room temperature, the reaction mixture was poured into
ice water, and concentrated HCl was added slowly until no more
precipitate formed. The precipitate was collected and recrystal-
lized from 95% EtOH to afford 14.3 g (yield: 85%) of 3 as a white so-
lid. Mp 201–202 °C; 1H NMR (500 MHz, CDCl3), d 7.67–7.63 (d,
J = 15.85 Hz, 1H), 7.46–7.43 (m, 4H), 7.39–7.36 (m, 4H), 7.33–
7.30 (m, 2H), 7.14–7.13 (d, J = 1.95 Hz, 1H), 7.10–7.08 (dd,
J1 = 1.9 Hz, J2 = 2.0 Hz, 1H), 6.94–6.92 (d, J = 8.35 Hz, 1H), 6.25–
6.22 (d, J = 15.85 Hz, 1H), 5.21–5.19 (d, J = 10.6 Hz, 4H); 13C NMR
(125 MHz, CDCl3), d 171.3, 151.6, 149.1, 147.0, 136.9, 136.8,
128.8, 128.1, 127.6, 127.4, 127.3, 123.5, 114.9, 114.4, 114.1, 71.5,
71.1; HRMS calcd for C23H20O4 (M+H+) 361.1395, found 361.1439.
To a solution of 5 (1.5 g, 3.44 mmol) in isopropanol (36 mL) was
added HCl–iPrOH (1.1 mol Lꢀ1, 1.3 mL) and 10% Pd/C hydrogena-
tion catalyst (130 mg). Under vigorous stirring, the suspension
was hydrogenated at 0 °C under 5 bar H2 pressure for 16 h. The
suspension was filtered, and the clear filtrate was evaporated in va-
cuo. (R)-IDHP was obtained as brown oil in 68% yield after purifica-
tion
by
column
chromatography
(hexane/AcOEt = 3:2).
½
a 2D5
ꢂ
¼ ꢀ9:72 (c 1, MeOH). The ee value was 97.8%.20 1H NMR
(500 MHz, CDCl3), d 6.72–6.69 (m, 2H), 6.52–6.50 (d, J = 7.65 Hz,
1H), 5.32 (br, 3H), 5.03–4.98 (m, 1H), 4.31 (s, 1H), 2.95–2.91 (dd,
J1 = 3.45 Hz, J2 = 3.30 Hz, 1H), 2.76–2.71 (dd, J1 = 6.95 Hz,
J2 = 6.95 Hz, 1H), 1.23–1.22 (d, J = 6.25 Hz, 6H); 13C NMR
(125 MHz, CDCl3), d 174.0, 143.8, 143.1, 128.6, 121.6, 117.1,
115.6, 71.5, 69.8, 39.6, 21.8, 21.7; HRMS calcd for C12H16O5
(M+H+) 241.1031, found 241.1073.
4.4. (E)-Isopropyl 3,4-bis(benzyloxy) cinnamate 4
4.7. (2S,3R)-Isopropyl-3-(30,40-bis(benzyloxy)phenyl)-2,3-
dihydroxy propanoate 6
To a solution of 3 (12.0 g, 33.2 mmol) in isopropanol (200 mL)
was added concentrated H2SO4 (4 mL) via dropping funnel. Then
the solution was refluxed for 15 h. After being cooled to room tem-
perature, satd aq NaHCO3 was added and the mixture was ex-
tracted with toluene (3 ꢁ 30 mL). The combined organic phases
were washed with brine and dried over Na2SO4. After filtration,
the solvent was removed in vacuo. The residue was purified by
recrystallization (hexanes/AcOEt = 3:1) to give 2.7 g (yield: 80%)
of 4 as a white solid. Mp 114–115 °C. 1H NMR (400 MHz, CDCl3),
d 7.59–7.55 (d, J = 16 Hz, 1H), 7.49–7.45 (m, 5H), 7.41–7.35 (m,
5H), 7.14 (s, 1H), 7.10–7.08 (d, J = 8.4 Hz, 1H), 6.95–6.93 (d, J =
8.4 Hz, 1H), 6.27–6.23 (d, J = 15.6 Hz, 1H), 5.22–5.20 (d, J = 8.8 Hz,
4H), 5.16–5.11 (m, 1H), 1.33–1.32 (d, J = 6.4 Hz, 6H); 13C NMR
(125 MHz, CDCl3), d 166.8, 151.1, 149.1, 144.2, 137.0, 136.9,
128.7, 128.1, 128.0, 127.4, 127.3, 122.9, 116.9, 114.4, 113.8, 71.4,
71.1, 67.7, 22.1; HRMS calcd for C26H26O4 (M+H+) 403.1865, found
403.1912.
The preparation of 6 was carried out as described for 5, using
(QD)2PHAL as the chiral ligand in place of (QN)2PHAL. The desired
compound was obtained as a white powder (2.13 g, yield: 80%). Mp
107 °C. ½a 2D5
ꢂ
¼ þ2:0 (c 1, MeOH). The ee value was >99.9%.23
4.8. (S)-IDHP
(S)-IDHP was prepared from 6 in 65% yield employing the same
procedure as described for the preparation of (R)-IDHP.
½
a 2D5
ꢂ
¼ þ9:7 (c 1, MeOH). The ee value was 97.8%.20 1H NMR
(500 MHz, CDCl3), d 6.75–6.72 (m, 2H), 6.62–6.60 (d, J = 8.0 Hz,
1H), 5.90–5.70 (br, 3H), 5.09–5.04 (m, 1H), 4.37–4.35 (m, 1H),
3.02–2.98 (dd, J1 = 4.25 Hz, J2 = 4.25 Hz, 1H), 2.85–2.80 (dd,
J1 = 6.65 Hz, J2 = 6.65 Hz, 1H), 1.27–1.26 (d, J = 6.25 Hz, 6H); 13C
NMR (125 MHz, CDCl3) d 173.9, 143.7, 142.9, 128.5, 121.7, 116.9,
115.4, 71.5, 70.0, 21.8, 21.7.
4.5. Isopropyl (2R,3S)-3-(30,40-bis(benzyloxy)phenyl)-2,3-
dihydroxy propanoate 5
Acknowledgments
This work was financially supported by the National Natural
Science Foundation of China (Nos: 20972189, 30901883 and
81001398) and Major Program of Ministry of Science and Technol-
ogy of China (No: 2009ZXJ09004-081).
A 250 mL round-bottomed flask was charged with tert-butyl
alcohol (36 mL), water (36 mL), K3Fe(CN)6 (5.88 g, 18.0 mmol),
K2CO3 (2.46 g, 18.0 mmol), CH3SO2NH2 (0.57 g, 6.0 mmol),
K2[OsO2(OH)4] (4.5 mg, 0.012 mmol), and (QN)2PHAL (46.8 mg,
0.06 mmol). Stirring at room temperature produced two clear
phases. After the solution was cooled to 0 °C, 4 (2.4 g, 6.0 mmol)
was added, and the mixture was stirred vigorously at 0 °C until
TLC indicated that 4 had disappeared. Na2SO3 (7.5 g) was added
and the mixture was stirred for an additional 30 min. The mixture
was extracted with AcOEt (3 ꢁ 30 mL), and then the combined or-
ganic phases were washed successively with 2 mol Lꢀ1 KOH
(30 mL) and with H2O (2 ꢁ 30 mL) and dried over Na2SO4. After
the solvent was removed in vacuo, the residue was purified by col-
umn chromatography (hexane/AcOEt = 7:3) to afford 2.3 g (yield:
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