Asymmetric synthesis of the HMG-CoA reductase inhibitor atorvastatin calcium: An organocatalytic anhydride desymmetrization and cyanide-free side chain elongation approach

Article abstract of DOI:10.1021/jo402829b

An efficient asymmetric synthesis of atorvastatin calcium has been achieved from commercially available diethyl 3-hydroxyglutarate through a novel approach that involves an organocatalytic enantioselective cyclic anhydride desymmetrization to establish C(

Full text of DOI:10.1021/jo402829b

Note
pubs.acs.org/joc
Asymmetric Synthesis of the HMG-CoA Reductase Inhibitor
Atorvastatin Calcium: An Organocatalytic Anhydride
Desymmetrization and Cyanide-Free Side Chain Elongation
Approach
Xiaofei Chen,†,‡ Fangjun Xiong,† Wenxue Chen,† Qiuqin He,† and Fener Chen*,†,‡
‡
†Department of Chemistry and Institutes of Biomedical Science, Fudan University, Shanghai 200433, People’s Republic of China
S
* Supporting Information
ABSTRACT: An efficient asymmetric synthesis of atorvastatin calcium has been achieved from commercially available diethyl 3-
hydroxyglutarate through a novel approach that involves an organocatalytic enantioselective cyclic anhydride desymmetrization
to establish C(3) stereogenicity and cyanide-free assembly of C7 amino type side chain via C5+C2 strategy as the key
transformations.
ardiovascular disease (CVD) poses a serious threat to
Cworld public health and continues to be the growing
concern. The strong association between low-density lip-
oprotein cholesterol (LDL-c) as well as lipoprotein [LP(a)]
levels and cardiovascular risk is well-defined and underlines
their central role in the pathogenesis of arteriosclerotic plague.1
Medications used for the treatment of hyperlipidemia are
numerous, but no class of drugs is as widely prescribed as those
that inhibit 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-
CoA) reductase (Statins).2 The reason for extensive use of
statins is their favorable efficiency, safe profiles, and long-term
clinical benefits in reducing the risk for cardiovascular events
and death in patients with or without established CVD.
Atorvastatin calcium (Lipitor, 1, Figure 1) was first introduced
to the market in 1997 by Pfizer as an effective HMG-CoA
reductase inhibitor for the treatment of hypercholesterolemia
and arteriosclerosis and now ranks at the top of the drugs best
sold in the world.3 To date, joint synthetic development efforts
led to a number of strategies that make use of chemoenzymatic
resolution4 or chiral auxiliary5 at an appropriate stage,
enantioselective catalysis,6 or starting from the chiral pool.7
However, to the best of our knowledge, none of the known
synthetic routes appears to have a commercial advantage over
the long used Paal−Knorr pyrrole approach via two advanced
building blocks of diketone 2 and C7 amino type side chain 3
with a syn-1,3-diol pattern developed by the Warner-Lambert
company in 1989 (Scheme 1).7a−c
Figure 1. Structures of 1 and its important intermediate 2 and 3.
route (the equivalent of C1 synthon is NaCN or KCN). In
addition, the dependence on a single synthetic process for the
supply of such an important drug is unwise. As a result,
development of alternative synthetic approaches toward 3,
which use cyanide-free material to complete asymmetric
synthesis of 1, is an urgent demand. Herein we report a new,
The major drawback of this large-scale synthesis lies in the
manipulation of a large excess of high toxic cyanide in
lengthening this C7 statin skelton through a C3 + C1 + C2 + C1
Received: December 27, 2013
Published: February 27, 2014
© 2014 American Chemical Society
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Note
Scheme 1. Outline of the Industrial Process and the Current Process
short, enantiocontrolled route to 1 starting from easily available
diethyl 3-hydroxyglutarate.
As is seen from entries 1−4 in Table 1, the catalyst 9b afforded
the desired hemiester 5 of the highest enantioselectivity (80%
Our approach toward this statin side chain 3 was designed
with the view that its 3R-chirality and C7 amino type side chain
could be assembled through the use of an enantioselective
desymmetrization and C5 + C2 strategy, respectively. As
indicated in our synthetic plan (Scheme 1), the enantioselective
alcoholysis using our developed bifunctional sulfonamide
catalysts would be expected to set the requisite 3R stereo-
chemistry from cyclic anhydride 6, while the cyanide-free
installation of C7 cyano type side chain 4 could be reached
through a DEPC-promoted condensation of chiral hemiester 5
(C5 synthon) with methyl cyanoacetate (C2 synthon), which
would in turn be converted into 3 by a Krapcho
decarboxylation, deprotection, Narasaka’s reduction, protection,
and reduction sequence.
Table 1. Condition Optimization of the Enantioselective
Methanolysis of Cyclic Anhydride 6
a
Given the importance of enantiomerically pure hemiester 5
to the success of our planned asymmetric synthesis, we sought
an efficient method to access the desired 5. With this idea in
mind, we paid our attention to organocatalytic enantioselective
desymmetrization8 of 6 by alcoholysis employing our
developed bifunctional sulfonamide catalysts 9a−d.9 As
delineated in Scheme 2, we initially prepared cyclic anhydride
c
d
e
entry
cat.
solvent
concn
T (h) yield (%) ee (%)
1
9a
9b
9c
9d
9b
9b
9b
9b
9b
9b
9b
9b
MTBE
MTBE
MTBE
MTBE
CH2Cl2
toluene
CH3CN
THF
0.1
96
96
93
92
91
87
89
89
90
90
93
92
92
92
93
79
80
52
54
42
70
36
76
78
85
88
88
90
2
0.1
3
0.1
120
120
72
4
0.1
5
0.1
Scheme 2. Synthesis of Cyclic Anhydride 6
6
0.1
120
120
96
7
0.1
8
0.1
9
Et2O
0.1
96
10
11
12
13
MTBE
MTBE
MTBE
MTBE
0.05
0.025
96
120
168
168
0.0125
0.0125
b
9b
a
Unless otherwise noted, all reactions were carried out with 6 (0.5
b
mmol), 9 (0.025 mmol), and MeOH (5.0 mmol). The catalyst
loading was 10 mol %. The concentration of 6 (mol/L). Yield of
isolated product. Determined by HPLC.
c
d
e
6 from commercially available diethyl 3-hydroxyglutarate.
Treatment of diethyl 3-hydroxyglutarate with benzyl trichlor-
oacetimidate in the presence of a catalytic amount of
trifluoromethanesulfonic acid in cyclohexane and methylene
chloride afforded the corresponding benzyl ether 7 in 79%
yield,10 which was subjected to LiOH-hydrolysis and
dehydration with acetyl chloride in methylene chloride to
yield 6 in 91% overall yield (over two steps).
With 6 in hand, we were poised to examine the desired
catalytic enantioselective methanolysis under different reaction
conditions. First, our developed bifunctional sulfonamide
organocatalysts 9a−d were screened for this transformation.
ee) when the reaction of 6 with excess methanol was performed
in methyl tert-butyl ether (MTBE) in the presence of 5 mol %
organocatalysts 9a−d at room temperature. The influence of
solvent on enantioselectivity is very crucial. Very low
enantioselectivities (42% and 36% ee) were detected in
methylene chloride and acetonitrile using 5 mol % 9b, and
moderate enantioselectivities (70%, 76%, and 78% ee) were
obtained in toluene, tetrahydrofuran, and diethyl ether,
respectively (entries 5−9). MTBE is the best choice for this
methanolysis. A slightly improvement in enantioselectivity
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Note
(from 80% to 88% ee) was observed by decreasing the
concentration of substrate from 0.1 to 0.0125 mol/L in the
presence of 5 mol % 9b (entries 10−12). A tiny increase in
enantioselectivity (90% ee) was achieved by enhancing catalyst
loading from 5 to 10 mol % (entry 13). The absolute
configuration of 5 was determined to be the required R by
comparing the measured specific rotation with reported data.11
The remaining key step is the elongation of C7 side chain 4
possessing a cyano functional group from C5 side chain 5.
Treatment of 5 (90% ee) with methyl cyanoacetate in the
presence of diethyl pyrocarbonate (DEPC) and excess
triethylamine furnished the diester 4 in 86% yield under
McClure’s reaction condition.12 Decarboxylation of 4 in wet
DMSO at 130 °C was smoothly converted into the ketoester
10 in 79% yield. Cleavage of benzyl ether in 10 upon treating
anhydrous ferric trichloride in anhydrous CH2Cl2 at 5 °C for 48
h gave rise to debenzyl product 11 in 81% yield (Scheme 3).
Finally, the Paal−Knorr condensation7c of diketone 2 and
amine 3 was carried out in the presence of pivalic acid at 90 °C
for 36 h to provide pyrrolic compound 14 in 74% yield (brsm
2) with 91% ee, which was upgraded to 99% ee after
recrystallization using EtOAc/PE (1:8) in 81% recovered
yield. The deprotection of 14 by treatment with hydrochloric
acid (1.0 M) in methanol at room temperature afforded diol 15
in 94% yield. Hydrolysis of 15 with sodium hydroxide (1.0 M)
in methanol at 0 °C and salification with 5% aqueous calcium
acetate at 0 °C in sequence furnished 1 in an overall yield of
91% over two steps (Scheme 4). In addition, we have
Scheme 4. Synthesis of Atorvastatin Calcium (1)
Scheme 3. Synthesis of Key Intermediate 3
determined the crystalline form of 1 by X-ray powder
diffraction. The crystalline form observed is consistent with
Form I reported by the Warner-Lambert company.17
In conclusion, the organocatalytic anhydride desymmetriza-
tion and cyanide-free side chain elongation strategy detailed in
this paper represents an efficient and practical process for the
asymmetric synthesis of atorvastatin calcium (1) starting from
readily available and cheap diethyl 3-hydroxyglutarate. We
believe that our approach would be of great benefit to industrial
application after further optimization of reaction conditions in
each step.
Diastereoselective reduction of 11 using the procedure of the
Narasaka group13 gave the corresponding diol 12, which was
then protected with 2,2-dimethoxypropane in the presence of
p-toluenesulfonic acid to furnish 1,3-dioxane 13 in an overall
yield of 73% with excellent diastereoselectivity [(4R,6R)-1,3-
dioxane 13a/(4R,6S)-1,3-dioxane 13b = 95/5, determined by
GC−MS analysis). The stereochemistry of 13a and 13b
confirmed by using NOESY experiments is consistent with
the mechanism proposed by Narasaka et al. for the reduction of
acyclic β-hydroxyketones via boron chelate with sodium
borohydride in the stereoselective preparation of 1,3-diols
(Figure 2).13,16 Catalytic hydrogenation of 13 with a mixture of
Raney-Ni and methanolic ammonia proceeded smoothly to
afford the desired amine 3 in almost quantitative yield.7c
EXPERIMENTAL SECTION
■
Diethyl 3-(Benzyloxy)-glutarate (7).10 To a stirred solution of
diethyl 3-hydroxyglutarate (20.4 g, 0.10 mol) and benzyltrichlor-
oacetimidate (20.3 mL, 0.11 mol) in 500 mL of 4:1 c-hexane/CH2Cl2
at 0 °C was added TfOH (0.44 mL, 5 mmol). The reaction mixture
was stirred at 0 °C for 24 h before being quenched by Et3N and
filtered. The filtrate was concentrated and purified by column
chromatography (silica gel, PE/EtOAc 20:1) to afford 7 (23.3 g,
79%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.25 (t, J = 7.2
Hz, 6H), 2.60 (dd, J = 5.6, 15.6 Hz, 2H), 2.67 (dd, J = 6.8, 15.6 Hz,
2H), 4.14 (q, J = 7.2 Hz, 4H), 4.31−4.37 (m, 1H), 4.59 (s, 2H), 7.24−
7.34 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 14.1, 39.7, 60.5, 72.1,
72.8, 127.6, 127.7, 128.3, 138.0, 170.9; IR (thin film) 2980, 1732,
1453, 822, 742 cm−1; MS (EI) m/z (%) = 249.0 [M − EtO] (1), 91.1
[Bn] (100).
3-(Benzyloxy)-glutaric Acid (8).10 To a stirred solution of 7
(14.7 g, 0.05 mol) in 100 mL of 4:1 THF/H2O was added LiOH·H2O
(5.25 g, 0.125 mol) at 20 °C. The reaction mixture was stirred at 20
°C for 48 h before the THF was evaporated. The aqueous layer was
washed with EtOAc (50 mL), acidified with 2.0 M HCl, and then
Figure 2. NOESY correlations of 13a and 13b.
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Note
extracted with EtOAc (3 × 200 mL). The organic layer was washed
with brine, dried over Na2SO4, and concentrated to afford 8 (11.4 g,
96%) as a white solid that was pure enough to be used in next step
directly: mp 147.8−151.2 °C (EtOAc); 1H NMR (400 MHz, DMSO-
d6) δ 2.54 (d, J = 6.4 Hz, 4H), 4.13−4.20 (m, 1H), 4.52 (s, 2H), 7.24−
7.34 (m, 5H), 12.30 (brs, 2H); 13C NMR (100 MHz, DMSO-d6) δ
39.1, 70.8, 73.0, 127.4, 127.5, 128.2, 138.6, 172.4; IR (KBr) 3063,
1709, 1427, 923, 754, 701 cm−1; MS (ESI) m/z = 261 (M + Na+).
3-(Benzyloxy)-glutaric Anhydride (6).14 To a stirred suspension
of 8 (11.4 g, 48 mmol) in 50 mL of CH2Cl2 at 0 °C was added AcCl
(16.9 mL, 240 mmol). The reaction mixture was stirred at rt for 12 h
before being concentrated. The crude anhydride was dissolved in 300
mL of CH2Cl2, washed with 5% aq NaHCO3 and brine, dried over
Na2SO4, and concentrated to afford 6 (10.0 g, 95%) as a white solid
that was pure enough to be used in next step directly: mp 82.6−84.8
128.5, 137.3, 170.9, 195.9; IR (thin film) 3033, 2262, 1732, 1627,
1498, 885, 770 cm−1; HRMS (ESI-TOF) m/z calcd for C15H18NO4
(M + H)+ 276.1230, found 276.1246.
(R)-Methyl 3-Hydroxy-6-isocyano-5-oxohexanoate (11). To a
stirred suspension of anhydrous FeCl3 (1.36 g, 8 mmol) in 30 mL of
anhydrous CH2Cl2 under argon atmosphere at 0 °C was added a
solution of 10 (560 mg, 2 mmol) in 20 mL of anhydrous CH2Cl2. The
reaction mixture was stirred at 5 °C for 48 h before being quenched by
water, concentrated, and then purified by column chromatography
(silica gel, PE/EtOAc 3:2) to afford 11 (300 mg, 81%) as a pale yellow
oil; [α]25.8D +8.6 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.55
(d, J = 6.0 Hz, 2H), 2.75 (dd, J = 4.0, 16.0 Hz, 1H), 2.79 (brs, 1H),
2.82 (dd, J = 8.0, 16.0 Hz, 1H), 3.60 (s, 2H), 3.72 (s, 3H), 4.46−4.52
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 33.1, 40.2, 47.8, 52.0, 64.2,
113.5, 172.2, 196.9; IR (thin film) 3442, 2962, 2263, 1730, 1442, 1065
cm−1; HRMS (ESI-TOF) m/z calcd for C8H12NO4 (M + H)+
186.0761, found 186.0763.
°C (EtOAc), lit.14 mp 79−80 °C (CHCl3); H NMR (400 MHz,
1
CDCl3) δ 2.75 (dd, J = 2.0, 16.8 Hz, 2H), 3.08 (dd, J = 2.8, 16.8 Hz,
2H), 4.07 (m, 1H), 4.55 (s, 2H), 7.27−7.37 (m, 5H); 13C NMR (100
MHz, CDCl3) δ 35.6, 66.9, 70.8, 127.6, 128.1, 128.5, 136.5, 165.0; IR
(KBr) 2939, 1819, 1773, 1427, 934, 739 cm−1; MS (ESI) m/z = 243
(M + Na+).
Methyl 2-((4R)-6-(Cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-
yl)acetate (13). To a stirred solution of 11 (1.84 g, 10 mmol) in 100
mL of anhydrous THF and 20 mL of methanol under argon
atmosphere at −10 °C was added Et2BOMe (12 mL, 1.0 M in THF).
The reaction mixture was stirred for 30 min at −10 °C before being
cooled to −78 °C, and then NaBH4 (456 mg, 12 mmol) was added in
batches. The mixture was stirred at −78 °C for 6 h before being
quenched by HOAc. The solvent was removed, then extracted with
EtOAc (3 × 100 mL), dried over Na2SO4, and concentrated. The
residue was coevaporated with MeOH to afford the diol 12 (1.6 g,
86%) as a colorless oil. To a stirred solution of 12 (1.6 g, 8.6 mmol)
and 2,2-dimethoxypropane (5.3 mL, 43.0 mmol) in 20 mL of acetone
under argon atmosphere at rt was added p-TsOH·H2O (0.16 g, 0.86
mmol). The reaction mixture was stirred at 20 °C for 6 h before being
quenched by Et3N, and solvents were removed to obtain 13 (1.6 g,
73% from 11) as a colorless oil that was pure enough to be used in
next step directly. The dr of the residue was measured by GC−MS:
Agilent, HP-5MS column (30 m × 0.25 mm × 0.25 μm), injector
temperature 280 °C, oven temperature program from 80 °C (2 min)
to 280 °C at 10 °C/min, carrier gas He, flow rate 0.9 mL/min,
ionization energy 70 eV in the electronic ionization (EI) mode, tR
(minor) = 13.0 min, tR (major) = 13.4 min. The analytic sample was
purified by column chromatography (silica gel, PE/EtOAc 8:1) to
afford the 13a4e and 13b; 13a: [α]22.9D +1.2 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 1.26−1.35 (m, 1H), 1.36 (s, 3H), 1.45 (s, 3H),
1.74 (dt, J = 2.4, 12.8 Hz, 1H), 2.40 (dd, J = 6.0, 15.6 Hz, 1H), 2.50
(dd, J = 4.0, 6.0 Hz, 2H), 2.56 (dd, J = 6.8, 15.6 Hz, 1H), 3.67 (s, 3H),
4.13 (ddt, J = 2.4, 6.0, 11.6 Hz, 1H), 4.32 (ddt, J = 2.0, 6.4, 11.6 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 19.5, 24.9, 29.6, 35.3, 40.8, 51.7,
64.9, 65.3, 99.5, 116.7, 171.0; IR (thin film) 2998, 2255, 1740, 1442,
(R)-3-(Benzyloxy)-5-methoxy-5-oxopentanoic Acid (5).11 To
a stirred solution of 6 (110 mg, 0.5 mmol) and catalysts 9a−d (0.025
mmol) in anhydrous solvent (see Table 1) under argon atmosphere at
rt was added MeOH (0.2 mL, 5.0 mmol). The reaction was stirred
until the starting material was consumed before being concentrated
and then purified by column chromatography (silica gel, PE/EtOAc/
AcOH 5:1:0.05 to EtOAc/MeOH 20:1) to afford 5 (pale yellow oil,
yields 87−93%) and recover 9a−d (white solid, recovered yields 88−
92%), ee of 5: 36−90%, determined by HPLC analysis, Daicel,
Chiralpak AS-H column (25 cm × 4.6 mm × 5 μm), n-hexane/
isopropanol = 95/5, 0.5 mL/min, 258 nm, 30 °C, tR (major) = 45.8
min, tR (minor) = 71.5 min; [α]12.3D +2.3 (c 1.0, CHCl3, 90% ee), lit.11
1
(S)-5: [α]25 −0.3 (c 10.0, CHCl3, 40% ee); H NMR (400 MHz,
D
CDCl3) δ 2.62−2.76 (m, 4H), 3.69 (s, 3H), 4.30−4.36 (m, 1H), 4.61
(s, 2H), 7.26−7.35 (m, 5H), 10.80 (brs, 1H); 13C NMR (100 MHz,
CDCl3) δ 39.2, 39.3, 51.8, 72.1, 72.3, 127.8, 127.8, 128.3, 137.7, 171.3,
176.9; IR (thin film) 3530, 1732, 1712, 1495, 746, 693 cm−1; MS
(ESI) m/z = 251 (M − H+).
(5R)-Dimethyl 5-(Benzyloxy)-2-cyano-3-oxoheptanedioate
(4). To a stirred solution of 5 (12.6 g, 50 mmol, 90% ee) and methyl
cyanoacetate (4.4 mL, 50 mmol) in 75 mL of anhydrous DMF under
argon atmosphere at 0 °C was added triethylamine (20.8 mL, 150
mmol). The reaction mixture was stirred at 0 °C for 15 min before
diethyl pyrocarbonate (8.7 mL, 60 mmol) was added. The mixture was
then stirred at 20 °C for 24 h before being quenched by brine and
addition of dilute HCl to adjust to pH = 5 at 0 °C. The mixture was
extracted with 1000 mL of EtOAc and washed with brine, dried over
Na2SO4, concentrated, and then purified by column chromatography
(silica gel, PE/EtOAc/AcOH 4:1:0.05) to afford 4 (14.3 g, 86%) as a
pale brown oil. 1H NMR (400 MHz, CDCl3) δ 2.61 (dd, J = 6.0, 16.0
Hz, 1H), 2.74 (dd, J = 7.2, 16.0 Hz, 1H), 2.90 (dd, J = 6.0, 14.0 Hz,
1H), 2.97 (dd, J = 6.8, 14.0 Hz, 1H), 3.68 (s, 3H), 3.88 (s, 3H), 4.30−
4.36 (m, 1H), 4.59 (s, 2H), 7.27−7.34 (m, 5H), 13.56 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 39.4, 39.5, 51.8, 53.0, 72.1, 72.9, 82.6,
114.4, 127.8, 127.9, 128.3, 137.4, 170.2, 170.9, 187.2; IR (thin film)
2956, 2228, 1737, 1660, 879, 750, 696 cm−1; HRMS (ESI-TOF) m/z
calcd for C17H20NO6 (M + H)+ 334.1285, found 334.1290.
(R)-Methyl 3-(Benzyloxy)-6-cyano-5-oxohexanoate (10). A
stirred solution of 4 (1.3 g, 4 mmol) in 12 mL of DMSO and 3 mL of
H2O under argon atmosphere was heated to 130 °C for 45 min. The
mixture was added to 200 mL of EtOAc and washed with brine, dried
over Na2SO4, concentrated, and then purified by column chromatog-
raphy (silica gel, PE/EtOAc 3:1) to afford 10 (0.86 g, 79%) as a pale
yellow oil; [α]14.7D +27.7 (c 1.0, CHCl3, 90% ee); 1H NMR (400 MHz,
CDCl3) δ 2.59 (dd, J = 6.4, 15.6 Hz, 1H), 2.67 (dd, J = 5.6, 15.6 Hz,
1H), 2.82 (dd, J = 4.8, 16.4 Hz, 1H), 2.90 (dd, J = 7.2, 16.4 Hz, 1H),
3.45 (s, 2H), 3.68 (s, 3H), 4.29−4.35 (m, 1H), 4.49 (d, J = 11.2 Hz,
1H), 4.60 (d, J = 11.2 Hz, 1H), 7.27−7.36 (m, 5H); 13C NMR (100
MHz, CDCl3) δ 33.0, 38.4, 46.7, 51.8, 71.8, 72.1, 113.5, 127.9, 128.0,
987, 937, 884 cm−1; MS (ESI) m/z = 228 (M + H+); 13b: [α]19.0
+27.5 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 1.35 (s, 3H),
D
1
1.38 (s, 3H), 1.75−1.86 (m, 2H), 2.46 (dd, J = 5.6, 15.6 Hz, 1H), 2.53
(d, J = 6.0 Hz, 2H), 2.57 (dd, J = 8.0, 15.6 Hz, 1H), 3.69 (s, 3H),
4.05−4.12 (m, 1H), 4.28−4.35 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 24.2, 24.3, 24.6, 36.7, 40.2, 51.7, 62.6, 63.1, 101.4, 116.9,
170.9; IR (thin film) 2991, 2252, 1737, 1442, 994 cm−1; HRMS (ESI-
TOF) m/z calcd for C11H17NNaO4 (M + Na)+ 250.1050, found
250.1056.
Methyl 2-((4R,6R)-6-(2-(2-(4-Fluorophenyl)-5-isopropyl-3-
phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl) ethyl)-2,2-di-
methyl-1,3-dioxan-4-yl)acetate (14). A high pressure steel
autoclave was filled with 13 (240 mg, 1.0 mmol) and 0.2 g of
Raney-Ni suspended in MeOH (10 mL) saturated with ammonia gas.
The autoclave was pressurized to 10 atm with H2 and stirred at 40 °C
for 4 h. The mixture was filtered and concentrated to afford crude
amine 3 (240 mg, 99%) as a pale yellow oil. To a stirred solution of
diketone 2 (340 mg, 0.8 mmol) and amine 3 (240 mg, 1.0 mmol) in
heptane (8 mL)/toluene (1 mL)/THF (1 mL) at rt was added pivalic
acid (92 mg, 0.9 mmol). The reaction mixture was heated to 90 °C for
36 h before solvents were removed. The residue was purified by
column chromatography (silica gel, PE/EtOAc 6:1) to afford 14 [320
mg, 63%, (74%, brsm 2)] as a white solid: mp 78.3−80.6 °C (EtOAc).
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Note
The ee of 14 was upgraded from 91% to over 99% by a single
recrystallization using EtOAc/PE (1:8), determined by HPLC analysis,
Daicel, Chiralpak AD-H column (25 cm × 4.6 mm × 5 μm), n-
hexane/isopropanol = 98/2, 1.0 mL/min, 254 nm, 30 °C, tR (minor) =
32.4 min, tR (major) = 36.0 min; recovered yield 81%; [α]27.1D +7.5 (c
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(b) Han, K. H.; Rha, S. W.; Kang, H. J.; Bae, J. W.; Choi, B. J.; Choi, S.
Y.; Gwon, H. C.; Bae, J. H.; Hong, B. K.; Choi, D. H.; Han, K. R. J.
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(3) (a) Roth, B. D.; Mich, A. A. U.S. Patent 4681893, 1987. (b) Roth,
B. D.; Ortwine, D. F.; Hoefle, M. L.; Stratton, C. D.; Sliskovic, D. R.;
Wilson, M. W.; Newton, R. S. J. Med. Chem. 1990, 33, 21. (c) Roth, B.
D.; Mich, A. A. U.S. Patent 5273995, 1991. (d) Endo, A. J. Lipid Res.
1992, 33, 1569. (e) Istvan, E. S.; Deisenhofer, J. Science 2001, 292,
1160. (f) Hajkova, M.; Kratochvil, B.; Radl, S. Chem. Listy 2008, 102,
3.
1
1.0, CHCl3, 99% ee); H NMR (400 MHz, CDCl3) δ 1.24−1.30 (m,
1H), 1.30 (s, 3H), 1.36 (s, 3H), 1.53 (d, J = 7.2 Hz, 6H), 1.67 (m,
3H), 2.32 (dd, J = 6.4, 15.6 Hz, 1H), 2.51 (dd, J = 6.8, 15.6 Hz, 1H),
3.53−3.60 (m, 1H), 3.67 (s, 3H), 3.71 (m, 1H), 3.79−3.86 (m, 1H),
4.04−4.11 (m, 1H), 4.17−4.23 (m, 1H), 6.87 (s, 1H), 6.96−7.01 (m,
3H), 7.07 (d, J = 8.0 Hz, 2H), 7.16−7.19 (m, 9H); 13C NMR (100
MHz, CDCl3) δ 19.6, 21.5, 21.7, 26.1, 29.9, 35.9, 38.0, 40.8, 41.0, 51.6,
65.5, 66.3, 98.8, 115.2, 115.3 (d, JC−F = 3.3 Hz), 115.4, 119.5, 121.8,
123.5, 126.5, 128.3, 128.5 (d, JC−F = 43.2 Hz), 128.6, 130.5, 133.2 (d,
JC−F = 8.3 Hz), 134.6, 138.4, 141.5, 162.2 (d, JC−F = 247.3 Hz), 164.8,
171.2; IR (KBr) 3407, 2955, 1740, 1666, 753, 688 cm−1; HRMS (ESI-
TOF) m/z calcd for C37H42FN2O5 (M + H)+ 613.3072, found
613.3090.
(4) (a) Muller, M. Angew. Chem., Int. Ed. 2005, 44, 362. (b) Liu, J.;
̈
Hsu, C. C.; Wong, C. H. Tetrahedron Lett. 2004, 45, 2439.
(c) Bergeron, S.; Chaplin, D. A.; Edwards, J. H.; Ellis, B. S. W.; Hill,
C. L.; Holt-Tiffin, K.; Knight, J. R.; Mahoney, T.; Osborne, A. P.;
(3R,5R)-Methyl 7-(2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-
4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyhepta-
noate (15). To a stirred solution of 14 (240 mg, 0.4 mmol) in MeOH
(6 mL) at rt was added HCl (1 mL, 1.0 M, 1.0 mmol), which was then
reacted for 6 h before being quenched by 5% NaHCO3. The reaction
mixture was added to 30 mL of brine, extracted with EtOAc (3 × 50
mL), dried over Na2SO4, concentrated, and then purified by column
chromatography (silica gel, PE/EtOAc 3:2) to afford 1515 (220 mg,
94%) as a white powder: mp 92.7−96.3 °C (EtOAc), lit.15 mp 110−
112 °C; [α]27.7D −1.4 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ
1.43−1.49 (m, 1H), 1.54 (d, J = 7.2 Hz, 6H), 1.58−1.74 (m, 2H), 2.41
(d, J = 6.0 Hz, 2H), 3.54−3.61 (m, 1H), 3.70 (s, 3H), 3.74 (m, 2H),
3.90−3.98 (m, 1H), 4.07−4.18 (m, 2H), 6.88 (s, 1H), 6.96−7.01 (m,
3H), 7.06 (d, J = 8.0 Hz, 2H), 7.15−7.19 (m, 9H); 13C NMR (100
MHz, CDCl3) δ 21.6, 21.7, 26.1, 39.0, 41.2, 41.2, 41.7, 51.8, 68.8, 69.5,
115.2, 115.3 (d, JC−F = 3.4 Hz), 115.4, 119.6, 121.8, 123.5, 126.5,
128.3, 128.5 (d, JC−F = 37.6 Hz), 128.6, 130.4, 133.2 (d, JC−F = 8.1
Hz), 134.6, 138.3, 141.4, 162.2 (d, JC−F = 246.3 Hz), 164.8, 172.9; IR
(KBr) 3413, 2952, 1730, 1651, 1601, 838, 753 cm−1; MS (ESI) m/z =
595 (M + Na+).
̈
Ruecroft, G. Org. Process Res. Dev. 2006, 10, 661. (d) Ohrlein, R.;
Baisch, G. Adv. Synth. Catal. 2003, 345, 713. (e) Greenberg, W. A.;
Varvak, A.; Hanson, S. R.; Wong, K.; Huang, H.; Chen, P.; Burk, M. J.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5788. (f) Goldberg, S.; Guo, Z.;
Chen, S.; Goswami, A.; Patel, R. N. Enzyme Microb. Tech. 2008, 43,
544. (g) Wu, X.; Wang, L.; Wang, S.; Chen, Y. Amino Acids 2010, 39,
305. (h) Wu, X.; Jiang, J.; Chen, Y. ACS Catal. 2011, 1, 1661. (i) Sun,
F.; Xu, G.; Wu, J.; Yang, L. Tetrahedron: Asymmetry 2007, 18, 2454.
(j) Ma, S.; Gruber, J.; Davis, C.; Newman, L.; Gray, D.; Wang, A.;
Grate, J.; Huisman, G. W.; Sheldon, R. A. Green Chem. 2010, 12, 81.
(5) (a) Roth, B. D.; Blankley, C. J.; Chucholowski, A. W.; Ferguson,
E.; Hoefle, M. L.; Ortwine, D. F.; Newton, R. S.; Sekerke, C. S.;
Sliskovic, D. R.; Stratton, C. D.; Wilson, M. W. J. Med. Chem. 1991, 34,
357. (b) Jendralla, H.; Baader, E.; Bartmann, W.; Beck, G.; Bergmann,
A.; Granzer, E.; Kerekjarto, B. V.; Kesseler, K.; Krause, R.; Schubert,
W.; Wess, G. J. Med. Chem. 1990, 33, 61. (c) Reddy, M. V. R.; Brown,
H. C.; Ramachandran, P. V. J. Organomet. Chem. 2001, 624, 239.
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Tetrahedron 2011, 67, 6539. (b) Kawato, Y.; Chaudhary, S.; Kumagai,
N.; Shibasaki, M. Chem.Eur. J. 2013, 19, 3802. (c) Andrushko, N.;
Atorvastatin Calcium (1). To a stirred solution of 15 (120 mg,
0.2 mmol) in MeOH (1 mL) at 0 °C was added NaOH (0.5 mL, 1.0
M, 0.5 mmol), which was then reacted at 0 °C for 30 min before a
solution of 5% Ca(OAc)2 was added. The mixture was stirred at 0 °C
for 1 h before the resulting white slurry was filtrated, washed, and dried
in a vacuum to afford 17c (105 mg, 91%) as a white powder: mp
172.9−175.5 °C (water), lit.18 mp 177−182 °C; 99% ee, determined
by HPLC analysis, Daicel, Chiralpak AD-H column (25 cm × 4.6 mm
× 5 μm), n-hexane/EtOH/HOAc = 92/8/0.3, 1.0 mL/min, 244 nm,
30 °C, tR (major) = 26.7 min, tR (minor) = 18.4 min; [α]26.9D −7.9 (c
Andrushko, V.; Tararov, V.; Korostylev, A.; Konig, G.; Borner, A.
̈
̈
Chirality 2010, 22, 534. (d) Sawant, P.; Maier, M. E. Tetrahedron 2010,
66, 9738. (e) Fan, W.; Li, W.; Ma, X.; Tao, X.; Li, X.; Yao, Y.; Xie, X.;
Zhang, Z. J. Org. Chem. 2011, 76, 9444. (f) Hu, L.; Xiong, F.; Chen, X.;
Chen, W.; He, Q.; Chen, F. Tetrahedron: Asymmetry 2013, 24, 207.
(7) (a) Butler, D. E.; Deering, C. F.; Millar, A.; Nanninga, T. N.;
Roth, B. D. PCT Int. Appl. WO 8907598, 1989. (b) Brower, P. L.;
Butler, D. E.; Deering, C. F.; Le, T. V.; Millar, A.; Nanninga, T. N.;
Roth, B. D. Tetrahedron Lett. 1992, 33, 2279. (c) Baumann, K. L.;
Butler, D. E.; Deering, C. F.; Mennen, K. E.; Millar, A.; Nanninga, T.
N.; Palmer, C. W.; Roth, B. D. Tetrahedron Lett. 1992, 33, 2283.
(d) Shin, H.; Choi, B. S.; Lee, K. K.; Choi, H.; Chang, J. H.; Lee, K.
W.; Nam, D. H.; Kim, N. S. Synthesis 2004, 16, 2629. (e) Reddy, P. P.;
Yen, K. F.; Uang, B. J. J. Org. Chem. 2002, 67, 1034. (f) Tararov, V.;
0.7, DMSO), lit.7c [α]D −7.4 (c 1.0, DMSO); H NMR (400 MHz,
1
DMSO-d6) δ 1.19−1.25 (m, 1H), 1.37 (d, J = 6.8 Hz, 6H), 1.49−1.54
(m, 1H), 1.55−1.65 (m, 1H), 1.91 (dd, J = 7.6, 15.2 Hz, 1H), 2.05
(dd, J = 4.0, 15.2 Hz, 1H), 3.19−3.28 (m, 1H), 3.53 (m, 2H), 3.68−
3.80 (m, 2H), 3.91−3.98 (m, 1H), 6.96−7.03 (m, 2H), 7.06−7.08 (m,
4H), 7.16−7.26 (m, 6H), 7.50 (d, J = 8.0 Hz, 2H), 9.80 (s, 1H); IR
(KBr) 3360, 2962, 1656, 842, 810, 745 cm−1; MS (ESI) m/z = 559
(acid, M + H+).
Konig, G.; Borner, A. Adv. Synth. Catal. 2006, 348, 2633.
̈
̈
(8) (a) Rosen, T.; Heathcock, C. H. J. Am. Chem. Soc. 1985, 107,
3731. For reviews on enantioselective desymmetrization of cyclic
anhydrides, see: (b) Spivey, A. C.; Andrews, B. I. Angew. Chem. 2001,
113, 3227; Angew. Chem., Int. Ed. 2001, 40, 3131. (c) Chen, Y.;
McDaid, P.; Deng, L. Chem. Rev. 2003, 103, 2965. (d) Atodiresei, I.;
Schiffers, I.; Bolm, C. Chem. Rev. 2007, 107, 5683. (e) Johnson, J. B.;
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ASSOCIATED CONTENT
* Supporting Information
■
S
Copies of NMR, GC−MS, HPLC, and XRPD spectral data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Gal
́ ́
vez, J. A.; Etayo, P.; Badorrey, R.; Lopez-Ram-de-Víu, P. Chem. Soc.
Rev. 2011, 40, 5564.
(9) (a) Yang, H.; Xiong, F.; Li, J.; Chen, F. Chin. Chem. Lett. 2013,
24, 553. (b) Yang, H.; Xiong, F.; Chen, X.; Chen, F. Eur. J. Org. Chem.
2013, 4495.
AUTHOR INFORMATION
Corresponding Author
*E-mail: rfchen@fudan.edu.cn.
■
́
(10) Pehlivan, L.; Metay, E.; Delbrayelle, D.; Mignani, G.; Lemaire,
M. Eur. J. Org. Chem. 2012, 4689.
Notes
The authors declare no competing financial interest.
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