Asymmetric Synthesis of Atorvastatin Calcium through Intramolecular Oxidative Oxygen-Nucleophilic Bromocyclization

Article abstract of DOI:10.1002/ejoc.201700387

The stereocontrolled synthesis of atorvastatin calcium starting from commercially available d-aspartic acid using an intramolecular oxidative oxygen-nucleophilic bromocyclization of a homoallylic tert-butyl carbonate is described. This strategy allows the formation of the chiral syn-1,3-diol moiety with the desired stereochemistry, and provides a functionalized bromomethyl group for the construction of the atorvastatin side-chain with high regio- and diastereoselectivity. This route is attractive as it represents an efficient and environmentally sensitive approach to the large-scale synthesis of statins and their analogues.

Full text of DOI:10.1002/ejoc.201700387

A Journal of
Accepted Article
Title: Asymmetric Synthesis of Atorvastatin Calcium via Intramolecular
Oxidative Oxygen-nucleophilic Bromocyclization
Authors: Yan Wu, Min-Jie Liu, Hai-Qing Huang, Guan-Xin Huang,
Fang-Jun Xiong, and Fener Chen
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700387
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700387
Supported by

10.1002/ejoc.201700387
European Journal of Organic Chemistry
FULL PAPER
Asymmetric Synthesis of Atorvastatin Calcium via Intramolecular
Oxidative Oxygen-nucleophilic Bromocyclization
Yan Wu[a], Min-Jie Liu[a], Hai-Qing Huang[a], Guan-Xin Huang[a], Fang-Jun Xiong[a]*, and Fen-Er Chen[a]*
Abstract: The stereocontrolled synthesis of atorvastatin calcium from
commercially available d-aspartic acid using intramolecular oxidative
oxygen-nucleophilic bromocyclization of homoallylic tert-butyl
carbonate is described. This strategy allows formation of the chiral
syn-1,3-diol moiety in the desired stereochemistry and provides a
functionalized bromomethyl group for construction of the atorvastatin
side chain with high regio- and diastereoselectivity. This route is
attractive as an efficient environmentally sensitive approach to large-
scale synthesis of statins and their analogues.
Hence, it is no surprise that synthetic chemists have developed a
full array of methods to construct this key structural motif in a fully
reliable way. The overwhelming majority of existing approaches
toward the syn-1,3-diol framework of this statin rely heavily on
stereocontrolled variants of the classical Narasaka-Prasad syn-
diasteroselective reduction [3] of chiral β-hydroxy-ketoester from
chiral epichlorohydrin. However, industrial applications of these
approaches are stoichiometrically expensive, use hazardous
diethylmethylborane as complexing agent, and require cryogenic
conditions for high stereocontrol. Many chemoenzymatic
approaches for statin side chain have been developed【1c, 4 , but
】
expensive enzyme or coenzyme made such processes
diseconomy. Therefore, the development of a mild and practical
method to install such vital substructure in statin molecules
remains of great importance.
Introduction
Over the past two decades, there has been considerable interest
in the asymmetric synthesis of bestselling atorvastatin calcium
(Lipitor®, 1), a HMG-CoA reductase inhibitor, in organic synthesis
[1]
because of its high efficacy in low-density lipoprotein
[2]
cholesterol reduction and its established safety profile.
The
most prominent structural feature of 1 (Figure 1) is the syn-1,3-
diol moiety, which itself presents significant synthetic challenges.
Access to this diol serves as a proving ground for new
methodologies for efficient synthetic approaches to this important
statin molecule.
Figure 2. Synthetic strategies for syn-1,3-diol scaffold in statin synthesis
Recently, our own studies on stereoselective construction of chiral
statin side chains suggested that the asymmetric synthesis of statin
molecules such as rosuvastatin (2) and pitavastatin (3) could be
markedly simplified by means of haloiodine-induced intramolecular
iodocyclization of homoallylic tert-butyl carbonate5 (Figure 2). Our
alternative approach toward elaborating the syn-1,3-diol scaffold was
developed through a Br2-induced intramolecular bromocyclization of
homoallylic carbonate.6 The most significant improvement is the
avoidance of expensive IBr or ICl in the syn-1,3-diol building block for
pitavastatin synthesis, which is unacceptable in industrial application.
However, this bromocyclization was not well explored, with
unsatisfactory yield (up to ca. 50%) contaminated with ca. 40% vicinal
dibrominated adduct of homoallylic tert-butyl carbonate. Moreover,
this procedure highlighted that the use of hazardous toxic and
corrosive molecular bromine and the production of stoichiometric
amounts of waste were unavoidable. Clearly, each of the above
methods fails to fulfil the criteria for industrial application. Therefore,
Figure 1. Structures of atorvastatin calcium (1), rosuvastatin calcium (2) and
pitavastatin calcium (3)
[a]
Engineering Center of Catalysis and Synthesis for Chiral Molecules,
Department of Chemistry,Fudan University
Shanghai 200433, P. R. China
E-mail: rfchen@fudan.edu.cn ( F. E. Chen.);
xiongfangjun@fudan.edu.cn ( F. J. Xiong)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700387
European Journal of Organic Chemistry
FULL PAPER
the development of a practical, low-waste method to install such vital
substructure in statin molecules remains of great importance.
In our continuing effort toward the synthesis of statins and their
Scheme 1. Thus, d-aspartic acid was converted to the desired
succinic acid 9 in 73% yield by treatment with NaNO2 in
concentrated hydrochloric acid under mild conditions. Reduction
of the two carboxyl groups in 9 was carried out with NaBH4 in the
presence of BF3·Et2O at room temperature in anhydrous THF to
afford the corresponding 2-chloro diol 10 in 90% yield. In a one-
pot reaction, diol 10 was treated with anhydrous K2CO3 under
TBAB catalysis in CH2Cl2 to give epoxide 11, which was
subsequently benzylated using 60% NaH and benzyl bromide
under TBAB catalysis to give benzyl ether 12 in 46% yield over
the two steps. Ether 12 underwent regioselective ring-opening
with vinylmagnesium chloride in the presence of a catalytic
amount of CuCl in anhydrous THF to afford homoallylic alcohol
13 in 94% yield. Previously, Xia and co-workers [9] showed that
alcohols can undergo esterification with tert-butyl chloroformate
in pyridine to produce O-Boc alcohols in 87% yield. However,
treatment of 13 with tert-butyl chloroformate in pyridine at room
temperature for 2 days showed no reaction. In contrast, treatment
with Boc2O in the presence of Zn(OAc)2 under Bartoli’s conditions
analogues, we are developing new strategies for the preparation
4-7]
of statins,[1e,
and exploring new methodologies for the
preparation of analogue compounds and derivatives for
evaluation of their HMG-CoA reductase inhibition properties.
Herein, we report the outcome of a study that has established a
novel method for construction of the syn-1,3-diol subunit using
intramolecular oxidative oxygen-nucleophilic bromocyclization.
This method has been successfully used for the asymmetrical
synthesis of 1.
Results and Discussion
[10]
(CH2Cl2, reflux) produced the desired homoallylic tert-butyl
carbonate 8 in 73% yield.
Scheme 1. Synthesis of chiral homoallylic tert-butyl carbonate 8.
Figure 3. Retrosynthetic analysis for atorvastatin calcium (1)
With the homoallylic tert-butyl carbonate
8 in hand, we
Our approach toward atorvastatin calcium (1) is outlined in a
retrosynthetic format in Figure 3. We reasoned that the late-stage
intermediate 4 could be converted into 1 via debenzylation,
oxidation, deprotection, and salt formation. The required
atorvastatin precursor 4 would be synthesized using the Paal-
Knorr reaction between the known fully substituted diketone 5 and
the chiral C7-amino benzylether 6. The advanced synthetic
building block 6 could be accessed from chiral syn-1,3-carbonate
7 through a series of simple functional group transformations. The
syn-1,3-diol motif of 7 could be diastereoselectively constructed
investigated the critical intramolecular oxidative oxygen-
nucleophilic bromocyclization using alkali metal reagents and
oxidants for the rapid construction of the syn-1,3-diol core in 6, as
illustrated in Table 1.Our initial attempts using H2O2 or K2S2O8 as
oxidant with KBr as the bromide source failed to give desired
products, despite the use of different solvents (acetonitrile, ethyl
acetate, or dichloromethane; Table 1, entries 1–6). However, the
use of Oxone[11] or m-CPBA in various solvents gave the desired
product 7 in good yield with excellent diastereoselectivity (up to
99.5:0.5 dr). A small amount of vicinal dibromide 14, which is a
by-product generated by electrophilic bromination of terminal
double bonds in 8 with molecular bromide, was also observed
(Table 1, entries 7–15). To improve the selectivity of the reaction,
alkali metal bromides NaBr, NH4Br, and LiBr were used as
alternative bromide sources to promote the bromocyclization
(Table 1, entries 16–18). The temperature of the reaction was also
examined, and it was found that the formation of by-product 14
via
an
intermolecular
oxidative
oxygen-nucleophilic
bromocyclization of carbonate 8. Compound 8 would be prepared
in a chiral pool manner starting from commercially available d-
aspartic acid.
The synthesis of chiral homoallylic tert-butyl carbonate 8 began
with the preparation of (S)-(+)-2-chlorosuccinic acid [(S)-(+)-9]
[8]
using a reported procedure modified by us
as outlined in
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700387
European Journal of Organic Chemistry
FULL PAPER
could be suppressed at lower temperature, but with remarkable
reduced isolated yield (Table 1, entry 21). Overall, we found that
reaction with Oxone and KBr in acetonitrile at 0°C gave the
highest yield with excellent selectivity (88% yield, 99:1 dr, Table
1, entry 11).
crucial. Attempts to achieve the SN2 displacement of the
mesylate group in 18a by treatment with NaCN in DMSO at room
temperature failed, leading only to extensive decomposition. As a
result, we were unable to separate or purify it for further
characterization and elaboration. Moderate yields of nitrile 19
were obtained with benzenesulfonate and tosylate leaving groups,
but the best yields of 19 (85%) were achieved using 4-
chlorobenzenesulfonate as the leaving group. All our attempts to
effect catalytic regioselective hydrogenation of the benzyl ether
group in 19 using Raney Ni under different reaction conditions
were unsuccessful, presumably because of competing
hydrogenolysis of the benzyl C–O bond. Interestingly, we were
able to utilize the reaction conditions and reagents (Raney Ni,
KBH4, ethanol, 55°C, 1 h) reported by Yu and coworkers [13] for
selective reduction of the cyano group in 19 to furnish the desired
C7-amino benzyl ether 6 in 70% yield.
Table 1. Intramolecular oxidative oxygen-nucleophilic bromocyclization of 8[a]
Entry MBr Oxidant
Solvent
Temp. Time Selectivity[b] Yield[c] dr[d]
(oC) (h)
7:14 (%)
(%)
KBr 30%H2O2 MeCN
KBr 30%H2O2 DCM
KBr 30%H2O2 EA
0
48
48
48
48
48
48
30
30
12
6
N. R.
1
0
N. R.
N. R.
N. R.
N. R.
N. R.
47
2
0
3
KBr K2S2O8
KBr K2S2O8
KBr K2S2O8
MeCN
DCM
EA
0
4
0
5
0
6
KBr m-CPBA MeCN
KBr m-CPBA DCM
KBr m-CPBA EA
0
99.4:0.6
99.6:0.4
98.5:1.5
97.5:2.5
99.2:0.8
98.1:1.9
97.9:2.1
98.2:1.8
94.5:5.5
98.0:2.0
99.1:0.9
99.2:0.8
93.5:6.5
98.6:1.4
99.5:0.5
99.6:0.6
99.7:0.3
96.0:4.0
98.6:1.4
99.0:1.0
99.5:0.5
98.0:2.0
99.0:1.0
98.1:1.9
99.6:0.4
99.1:0.9
99.2:0.8
99.5:0.5
98.9:1.0
99.8:0.2
7
0
28
8
0
56
9
KBr m-CPBA EA/AcOH
0
79
10
11
12
13
14
15
16
17
18
19
20
21
KBr Oxone
KBr Oxone
KBr Oxone
KBr Oxone
KBr Oxone
NaBr Oxone
NH4Br Oxone
LiBr Oxone
KBr Oxone
KBr Oxone
MeCN
DCM
0
20
20
20
20
6
89
0
57
EA
0
51
MeNO2
EA/AcOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
0
57
0
74
0
20
20
20
5
74
0
81
0
83
25
15
-15
27
8
20
KBr
Oxone
36
57
[a] All of these reactions were carried out with 8 (0.5 g, 16.3 mmol), MBr (2.5
mmol) and oxidant (2 mmol) in solvent (5 mL). [b] The selectivity was determined
by GC-MS. [c]Isolated yield of 7. [d]The diastereoselectivity was determined byy
GC-MS of acetonide 15.
Scheme 2. Synthesis of chiral C7-amino benzylether 6
With access to the desired carbonate 7, we focused on its
conversion to the amine 6 along the projected pathway (Scheme
2). Carbonate 7 was smoothly converted to acetonide 15 by the
known acetonidation conditions[12] (p-TsOH, acetone, r.t., 20 h) in
81% yield. The absolute stereochemistry of 15 (4S, 6R) was
confirmed through NOESY experiments (see supporting
information for NOESY spectrum of 15). A trial of direct
cyanidation of 15 with NaCN into 19 was failed (16% conversion
of 15 in 48 h at r.t., or decomposition at elevated temperature). So
acetonide 15 was subjected to nucleophilic substitution with
sodium acetate at 135°C in anhydrous DMF to give acetate 16 in
84% yield. Hydrolysis of the acetate ester of 16 to the alcohol
moiety by treatment with K2CO3 in methanol under mild conditions
gave 17 in 88% yield. Alcohol 17 was then transformed into the
corresponding sulfonate 18a–d by reaction with different alkyl or
aryl sulfonyl chloride in the presence of Et3N in CH2Cl2., which
was used in next cyanidation step without further purification. The
choice of leaving group for the cyanidation of sulfonate 18 was
At this juncture, the synthesis of atorvastatin calcium (1) was at
hand according to route outlined in Scheme 3. The Paal-Knorr
condensation of 6 with commercially available fully substituted
diketone 5 was performed in the presence of pivalic acid in a
mixed solvent of THF/toluene/heptane at reflux temperature for
50 h to afford the desired pyrrole 20 in 70% isolated yield.
Transformation of the benzyl ether functionality in 20 into the
desired primary alcohol 21 was achieved in 88% yield via
selective hydrogenation using 5% Pd/C in methanol under mild
reaction conditions.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700387
European Journal of Organic Chemistry
FULL PAPER
Experimental Section
Experimental Details All reagents and solvent were obtained from
commercial sources and used without further purification. 1H (400 MHz)
and 13C (100 MHz) NMR were recorded on a Bruker Avance 400
spectrometer using TMS or CDCl3 as internal standards, IR spectra were
recorded on a Nicolet iS10 FT-IR spectrometer, Optical rotations were
measured by a Rudolph autopol I automatic polarimeter. EI-MS were
recorded on an Agilent 6890N/5975 spectrometer and ESI-MS were
recorded on aWaters Micromass Quattro Micro spectrometer. HRMS were
recorded on a Bruker micrOTOF spectrometer.
(R)-2-chlorosuccinic acid (9) To a stirred solution of D-aspartic acid (100
g, 0.75 mol) and KBr (7.6 g, 64 mmol) in conc. HCl (37%, 500mL) was
added NaNO2 (77.6 g, 1.12 mol) solution in water (180 mL) dropwise
slowly at 0~5oC, stirring was continued for 4h, then urea (22.5 g, 0.38 mol)
was added and stirred for 10 min. EtOAc (500 mL) was added to the
reaction mixture and stirred for few minutes before filtration. The filtrate
was extracted with EtOAc (300mL × 3), dried with Na2SO4 and evaporated
to afford 9 (109 g, 95%) as white powder. mp 187-189oC, (Lit.[8b] 172-174
oC ) ,[]D20 = +51.6 (c 1, DMSO); 1H NMR (400 MHz, DMSO) δ 4.62 (t, J =
6.9 Hz, 1H), 2.99 (dd, J = 16.9, 7.2 Hz, 1H), 2.83 (dd, J = 16.9, 6.7 Hz,
1H); 13C NMR (100 MHz, DMSO) δ 170.65, 169.67, 52.67, 39.34. FT-IR
(ATR): υ 3015, 2915, 1708 cm-1
Scheme 3. Synthesis of atorvastatin 1.
(R)-2-chlorobutane-1,4-diol (10) To a stirred suspension of 9 (80 g, 0.52
mol) and NaBH4 (46.1 g, 1.21 mol) in THF (800 mL) was added 47%
BF3.OEt2 (86.5 g) dropwise at 0~5oC, the reaction was stirred for 24h and
quenched by added water (400 mL) dropwise. The organic solvent was
evaporated and the residue was extracted with EtOAc (500 mL × 3). The
combined organic layer was evaporated, filtered and washed with
petroleum ether (100 mL × 2). The residue was dried under vacumm to
afford 10 (74.9 g, 90%) as colorless oil. []D19 = +45.6 (c 1.2, MeOH) (Lit.[8c]
[]D21=+36.7, (c 1.2, MeOH)); 1H NMR (400 MHz, DMSO) δ 5.8 – 4.2 (br,
2H), 4.13 – 4.03 (m, 1H), 3.67 – 3.41 (m, 4H), 1.98 (dddd, J = 14.5, 8.1,
6.6, 3.8 Hz, 1H), 1.66 (qd, J = 9.8, 5.1 Hz, 1H).; 13C NMR (100 MHz,
DMSO) δ 65.76, 61.59, 57.53, 37.35.FT-IR (ATR): υ 3335, 2956, 2887,
1046 cm-1
Oxidation of primary alcohol 21 to carboxylic acid 22 is the
essential step in the preparation of target molecule 1. Maier and
coworkers [14] accomplished this transformation in two steps with
excellent yield, but this sequence mandated the use of the
expensive Dess-Martin reagent (1,1,1-triacetoxy-1,1-dihydro-1,2-
benziodoxol-3(1H)-one). As an alternative, we considered a one-
pot conversion by the TEMPO/NaOCl-catalyzed NaClO2 alcohol
oxidation developed by Zhao and co-workers (Merck method)[15]
.
Thus, 21 was treated with 3 equivalents of NaClO2 in the presence
of 5% NaOCl and 5% TEMPO in a biphasic mixture of
toluene/phosphate buffer (pH 6.8) at room temperature for 14 h to
afford the carboxylic acid 22 without any ee loss in 85% yield. The
final conversion to obtain 1 was achieved by deprotection of the
acetonide in 22 by treatment with 1.0 M aq. HCl in ethanol,
followed by alkaline hydrolysis with 1.0 M aq. KOH in ethanol, and
calcium salt formation with 5% aq. CaCl2. Atorvastatin calcium 1
was obtained in 90% yield over the three steps.
(S)-2-(oxiran-2-yl)ethan-1-ol (11) To a stirred solution of 10 (68.0 g, 0.55
mol) in DCM (680 mL) was added K2CO3 (151 g, 1.09 mol) and TBAB(1.76
g, 5.5 mmol) at 0 oC, then stirred for 16h at r.t.. The reaction mixture was
filtered, dried over Na2SO4 and evaporated to afford 11 (31.6 g, 66%) as
light yellow oil. []D30 = -26.6 (c 1, DCM) (Lit.[16] []D20 = -30.7 (c 1, DCM)).
1H NMR (400 MHz, CDCl3) δ 3.75 (q, J = 5.6 Hz, 2H), 3.06 (td, J = 6.8, 3.5
Hz, 1H), 2.77 (t, J = 4.4 Hz, 1H), 2.55 (dd, J = 4.4, 2.9 Hz, 1H), 2.41 (s,
1H), 1.92 (ddd, J = 11.9, 11.0, 6.1 Hz, 1H), 1.66 (dq, J = 11.9, 5.9 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 59.79, 50.51, 46.74, 34.85. FT-IR (ATR): υ
3411, 2926, 1056 cm-1
Conclusions
(S)-2-(2-(benzyloxy)ethyl)oxirane (12) To
a stirred suspension of
In summary, we have developed an efficient asymmetric
synthesis of atorvastatin calcium starting from commercially
available d-aspartic acid. The key feature of this approach is the
highly diastereoselective intramolecular oxidative oxygen-
nucleophilic bromocyclization of homoallylic tert-butyl carbonate
to construct the important syn-1,3-diol motif found in atorvastatin
molecule. This new synthetic strategy also serves to provide
access to other statin drugs and their analogues as well as natural
products with a chiral syn-1,3-diol moiety.
60%NaH (0.54 g, 13.5 mmol) in DCM (10 mL) was added a solution of 11
(1.0 g, 11.4 mmol) in DCM (2 mL) dropwise at 0oC, the mixture was stirred
for 10 min, then a solution of BnBr (2.33 g, 13.6 mmol) in DCM (2 mL) was
added dropwise at the same temperature. After completion of the addition,
TBAB (90 mg) was added in one portion and stirred at r.t. for 15h. The
reaction was quenched by water (15 mL) and extracted with DCM (20 mL
× 3), dried with Na2SO4 and evaporated. The residue was purified by
20
column chromatography to afford 12 (1.42 g, 70%) as colorless oil. []D
25
= -14.8 (c 1, CHCl3) (Lit.[17] []D = -16.2 (c 3, CHCl3)). 1H (400 MHz,
CDCl3) δ 7.38 – 7.27 (m, 5H), 4.53 (s, 2H), 3.69 – 3.58 (m, 2H), 3.14 –
3.03 (m, 1H), 2.82 – 2.75 (m, 1H), 2.53 (dd, J = 5.0, 2.7 Hz, 1H), 1.98 –
1.86 (m, 1H), 1.79 (dq, J = 14.3, 5.9 Hz, 1H). 13C NMR (100 MHz, CDCl3)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700387
European Journal of Organic Chemistry
FULL PAPER
δ 138.43, 128.55, 127.77, 73.25, 67.19, 50.23, 47.25, 33.11. FT-IR (ATR):
υ 2922, 2859, 1104, 738, 698 cm-1. MS (ESI): m/z = 201 [M+Na]+. HRMS
(ESI) calcd for C11H14O2Na [M + Na]+ 201.0886, found 201.0899
was neutralized with sat. NaHCO3 solution and acetone was evaporated.
Extracted with DCM (50mL × 3) and washed with brine, dried (Na2SO4)
and evaporated, the residue was purified by column chromatography to
afford 15 (3.32 g, 81%) as light yellow oil. []D20 = -9.7 (c 0.8, CHCl3). 1H
NMR (400 MHz, CDCl3) δ 7.39 – 7.28 (m, 5H), 4.56 – 4.45 (m, 2H), 4.14 –
3.96 (m, 2H), 3.66 – 3.50 (m, 2H), 3.35 (dd, J = 10.2, 5.7 Hz, 1H), 3.24 (dd,
J = 10.2, 6.1 Hz, 1H), 1.86 – 1.69 (m, 3H), 1.44 (s, 3H), 1.40 (s, 3H), 1.19
(dd, J = 24.2, 11.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 138.60, 128.51,
127.79, 127.72, 99.35, 73.16, 69.28, 66.16, 66.00, 36.58, 35.59, 35.55,
30.09, 19.99. FT-IR (ATR): υ 2992, 2942, 2918, 2861, 1380, 1200, 1099
cm-1. MS (ESI): m/z = 365 [M+Na]+. HRMS (ESI) calcd for C16H23BrO3
[M+Na]+ 365.0723, found 365.0727
(R)-1-(benzyloxy)hex-5-en-3-ol (13) To
a
stirred mixture of
vinylmagnesium chloride (96 mL, 2.0 M solution in THF) and CuI (1.1 g,
5.8 mmol) was added a solution of 12 (20 g, 112 mmol) in THF (50 mL) at
-15oC in N2 atmosphere. Stirring was continued for 2h before quenched
with 2N HCl solution (170 mL) with controlling the temperature below 20
oC. Extracted with EtOAc (200 ml × 3), washed subsequently with sat.
NH4Cl, water and brine, dried with Na2SO4 and evaporated to afford 13 (22
g, 94%) as light yellow oil. []D20 = +4.3 (c 1, CHCl3) (Lit.[17] []D25 = +1.55
(c 1.1, CHCl3)). 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.26 (m, 5H), 5.84
(ddt, J = 17.4, 10.3, 7.1 Hz, 1H), 5.12 (ddd, J = 10.1, 6.3, 4.9 Hz, 2H), 4.53
(s, 2H), 3.94 – 3.83 (m, 1H), 3.76 – 3.59 (m, 2H), 2.85 (d, J = 3.0 Hz, 1H),
2.29 – 2.18 (m, 2H), 1.77 (ddd, J = 7.4, 5.9, 4.6 Hz, 2H). 13C NMR (100
MHz, CDCl3) δ 138.10, 134.99, 128.58, 127.86, 127.79, 117.69, 73.44,
70.46, 69.04, 42.05, 36.02. FT-IR (ATR): υ 3432, 2919, 2861,1097 cm-1.
MS (ESI): m/z = 229 [M+Na]+. HRMS (ESI) calcd for C13H18O5Na [M+Na]+
229.1199, found 229.1192
((4S,6S)-6-(2-(benzyloxy)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)methyl
acetate (16) A mixture of 15 (4.8 g, 14 mmol) and AcONa (3.4 g, 42 mmol)
in DMF (40 mL) was heat to 135oC and stirred for 9h. After completion of
the reaction, water (150 mL) and DCM (100 mL) was added and extracted
with DCM (50mL × 2) the combined organic phase was washed with water
and brine, dried over Na2SO4, evaporated to dryness and purified by
20
column chromatography to afford 16 (3.79 g, 84%) as light yellow oil. []D
= -3.4 (c 0.8, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.26 (m, 5H),
4.56 – 4.42 (m, 2H), 4.20 – 3.93 (m, 4H), 3.66 – 3.48 (m, 2H), 2.07 (s, 3H),
1.76 (pd, J = 14.0, 6.8 Hz, 2H), 1.47 (dt, J = 13.0, 2.3 Hz, 1H), 1.44 (s, 3H),
1.39 (s, 3H), 1.28 – 1.18 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 171.10,
138.61, 128.50, 127.77, 127.71, 98.92, 73.14, 67.47, 67.34, 66.15, 65.77,
36.66, 33.25, 30.18, 21.04, 19.89. FT-IR (ATR): υ 2992, 2944, 2864, 1740,
1239 cm-1. MS (ESI): m/z = 345 [M+Na]+. HRMS (ESI) calcd for
C18H26O5Na [M + Na]+ 345.1672, found 345.1672
(R)-1-(benzyloxy)hex-5-en-3-yl tert-butyl carbonate (8) A mixture of 13
( 33.0 g, 0.16 mol), Boc2O (41.9 g, 0.19 mol), Zn(OAc)2 ( 2.93 g, 16 mmol)
and DCM (170 mL) was stirred under reflux for 36h. The reaction mixture
was filtered and evaporated. The residue was purified by column
chromatography to afford 8 (35.7 g, 73%) as light yellow oil. []D20 = -30.7
25
(c 0.6, CHCl3) (Lit.[17] []D = 33.3 (c 0.6, CHCl3)). 1H NMR (400 MHz,
CDCl3) δ 7.37 – 7.26 (m, 5H), 5.79 (ddt, J = 17.2, 10.2, 7.1 Hz, 1H), 5.15
– 5.01 (m, 2H), 4.89 (p, J = 6.2 Hz, 1H), 4.49 (s, 2H), 3.53 (td, J = 6.4, 1.8
Hz, 2H), 2.38 (t, J = 6.4 Hz, 2H), 1.90 (dd, J = 12.8, 6.4 Hz, 2H), 1.47 (s,
9H). 13C NMR (100 MHz, CDCl3) δ 153.36, 138.49, 133.51, 128.50, 127.80,
127.69, 118.12, 81.89, 74.04, 73.25, 66.66, 39.08, 34.01, 27.94. FT-IR
(ATR): υ 2979, 2932, 2862, 1738,1278 cm-1. MS (ESI): m/z = 329
[M+Na]+.HRMS (ESI) calcd for C18H26O4Na [M+Na]+ 329.1723, found
329.1722
((4S,6S)-6-(2-(benzyloxy)ethyl)-2,2-dimethyl-1,3-dioxan-4-
yl)methanol (17) A mixture of 16 (2.5 g, 7.8 mmol). K2CO3 (3.4 g, 24.6
mmol) in MeOH (30 mL) was stirred at r.t. for 3h. the reaction mixture was
filtered. The filtrate was evaporated, water (60 ml) was added to the
residue and extracted with EtOAc ( 40mL × 3) . The combined organic
phase was washed with water and brine, dried over Na2SO4, evaporated
to dryness to afford 17 (1.9 g, 88%) as light yellow oil. []D20 = -13.7 (c 0.85,
CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.27 (m, 5H), 4.50 (t, J = 2.0
Hz, 2H), 4.14 - 4.03 (m, 1H), 4.02 – 3.93 (m, 1H), 3.72 - 3.41 (m, 4H), 2.02
(t, J = 6.4 Hz, 1H), 1.84 - 1.68 (m, 2H), 1.45 (s, 3H), 1.39 (m, 4H), 1.34 –
1.25 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 138.63, 128.51, 127.81,
127.73, 98.90, 73.17, 69.80, 66.25, 66.22, 65.73, 36.72, 32.51, 30.22,
20.09. FT-IR (ATR): υ 3446, 2991, 2942, 2919,2868, 1380, 1200, 1167,
1100 cm-1. MS (ESI): m/z = 303 [M+Na]+. HRMS (ESI) calcd for
C16H24O4Na [M+Na]+ 303.1567, found 303.1574
(4S,6S)-4-(2-(benzyloxy)ethyl)-6-(bromomethyl)-1,3-dioxan-2-one (7)
To a stirred suspension of 8 (500 mg, 1.63mmol) and KBr (290 mg, 2.48
mmol) in MeCN (5 mL) at 0oC was added 5 drops of water and Oxone (1.2
g, 1.95 mmol). The stirring was continued for 20h and filtered. To the filtrate
5% aq. NaHSO3 solution (40mL) was added. Extracted with EA (20mL× 2),
washed with brine, dried with Na2SO4, evaporated to dryness and purified
by column chromatography to afford 7 (470 mg, 89%) as light yellow oil.
[]D20 = -31.9 (c 0.82, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.68 – 7.20 (m,
5H), 4.71 – 4.55 (m, 2H), 4.48 (q, J = 11.8 Hz, 2H), 3.74 – 3.63 (m, 1H),
3.62 – 3.54 (m, 1H), 3.47 (qd, J = 11.0, 5.2 Hz, 2H), 2.24 (dt, J = 14.1, 2.9
Hz, 1H), 1.95 (ddd, J = 13.5, 10.4, 5.3 Hz, 2H), 1.87 – 1.72 (m, 1H). 13C
NMR (100 MHz, CDCl3) δ 148.35, 138.01, 128.59, 127.87, 76.90, 75.89,
73.38, 65.04, 35.45, 32.62, 31.83..FT-IR (ATR): υ 2925, 2865, 1749,1104
cm-1. MS (ESI): m/z = 329 [M+H]+. HRMS (ESI) calcd for C14H18BrO4
[M+H]+ 329.0383, found 329.0382
((4S,6S)-6-(2-(benzyloxy)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)methyl 4-
chlorobenzenesulfonate (18d) To a stirred solution of 17 (3.9 g, 13.9
mmol) and Et3N (2.11 g, 20.9 mmol) in DCM (40 mL) at 0oC was added a
solution of 4-chlorobenzenesulfonyl chloride (3.52 g, 16.7 mmol) in DCM
(20 mL) dropwise. After completion of the addition, the reaction mixture
was allowed to r.t. and stirred for 4h. Water (100 mL) was added and the
organic phase was separated, the water phase was extracted with DCM
(30 mL). the combined organic phase was washed with sat. NH4Cl (100
mL), sat. NaHCO3 (100 mL) and brine (100 mL) successively. Dried with
Na2SO4 and evaporated to dryness to afford 18d (6.5 g) as yellowish syrup,
which was used in next step without further purification. An analytic sample
1-(benzyloxy)-5,6-dibromohexan-3-ol (14) light yellow oil. 1H NMR (400
MHz, CDCl3) δ 7.47 – 7.27 (m, J = 7.1, 5H), 4.62 – 4.50 (m, 2H), 4.52 –
4.27 (m, 1H), 4.19 – 3.86 (m, 2H), 3.86 – 3.59 (m, 3H), 3.27 – 3.10 (m, 1H),
2.32 – 2.18 (m, 1H), 2.20 – 1.82 (m, 1H), 1.82 – 1.71 (m, 2H). 13C NMR
(100 MHz, CDCl3) δ 137.81, 137.75, 128.67, 128.05, 128.01, 127.89,
127.87, 73.65, 73.61, 69.91, 69.35, 69.28, 69.17, 50.15, 49.35, 44.27,
43.40, 37.44, 37.42, 36.58, 35.84. HRMS (ESI) calcd for C13H18O2Br2Na
[M+Na]+ 386.9566, found 386.9557.
20
was achieved by column chromatography. []D = -5.4 (c 1, CHCl3). 1H
NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H),
7.39 – 7.27 (m, 5H), 4.54 – 4.42 (m, 2H), 4.16 – 3.92 (m, 4H), 3.62 – 3.44
(m, 2H), 1.80 – 1.64 (m, 2H), 1.46 (dt, J = 12.7, 2.3 Hz, 1H), 1.35 (s, 3H),
1.28 (s, 3H), 1.15 (dd, J = 24.1, 11.9 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ 140.56, 138.54, 134.68, 129.61, 129.56, 128.51, 127.79, 127.75, 99.01,
73.15, 72.93, 67.09, 65.99, 65.56, 36.55, 32.72, 29.93, 19.75. FT-IR
(ATR): υ 2992, 2943, 2866, 1366, 1187, 1097 cm-1. MS (SEI): m/z = 477
(4S,6S)-4-(2-(benzyloxy)ethyl)-6-(bromomethyl)-2,2-dimethyl-1,3-
dioxane (15) A mixture of 7 (3.95 g, 12 mmol) and TsOH.•H2O (1.14 g, 6
mmol) in Acetone (40 mL) was stirred at r.t. for 20h. The reaction mixture
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700387
European Journal of Organic Chemistry
FULL PAPER
[M+Na]+.HRMS (ESI) calcd for C22H28ClO6S [M + H]+ 455.1290, found
455.1297
reaction mixture was filtered. The filtrate was evaporated and purified by
column chromatography to afford 21 (1.6 g, 88%) as while solid. mp 72-
73oC (Lit.[14] mp 75-85 oC), []D20 = -5.0 (c 1.3, CHCl3) (Lit.[10] []D20 = -6.0
(c 1, CHCl3)). 1H NMR (400 MHz, CDCl3) δ 7.23 – 7.11 (m, 9H), 7.10 –
7.05 (m , 2H), 7.03 – 6.95 (m, 3H), 6.86 (s, 1H), 4.17 – 3.95 (m, 2H), 3.89
– 3.79 (m, 1H), 3.77 – 3.64 (m, 3H), 3.58 (dt, J = 14.7, 7.3 Hz, 1H), 1.73 –
1.61 (m, 4H), 1.53 (d, J = 6.9 Hz, 6H), 1.37 (s, 3H), 1.32 (s, 3H), 1.30 –
1.07 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 164.93, 163.64, 161.17,
141.64, 138.52, 134.76, 133.36, 133.28, 130.62, 128.90, 128.80, 128.48,
126.70, 123.65, 121.93, 119.71, 115.59, 115.49, 115.37, 98.77, 68.95,
66.64, 60.75, 40.97, 38.15, 36.27, 30.18, 26.23, 21.89, 21.72, 19.92. FT-
IR (ATR): υ 3406, 2942, 2873,1660, 1527, 1509, 1437, 1314, 1157, 754,
733cm-1. MS (ESI): m/z = 585 [M+H]+. HRMS (ESI) calcd for C36H42FN2O4
[M+H]+ 585.3123, found 585.3139
2-((4R,6S)-6-(2-(benzyloxy)ethyl)-2,2-dimethyl-1,3-dioxan-4-
yl)acetonitrile (19) A solution of crude 18d (6.5 g) and NaCN (0.83 g, 16.9
mmol) in DMSO (30 mL) was stirred at 30oC for 40h. water (100 mL) was
added and then extracted with EtOAc (100mL × 3), washed with brine (50
× 3), dried with Na2SO4 and evaporated to dryness, the residue was
purified by column chromatography to afford 19 (3.4 g, 85%) as colourless
oil. []D20 = -18.3 (c 1, DCM). 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.28 (m,
5H), 4.55 – 4.45 (m, 2H), 4.16 – 4.02 (m, 2H), 3.65 – 3.49 (m, 2H), 2.57 –
2.42 (m, 2H), 1.86 – 1.69 (m, 2H), 1.65 (dt, J = 12.4, 2.4 Hz, 1H), 1.43 (s,
3H), 1.39 (s, 3H), 1.28 (q, J = 11.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ
138.54, 128.53, 127.81, 127.76, 117.02, 99.43, 73.19, 65.99, 65.72, 65.37,
36.46, 36.15, 29.99, 25.14, 19.87. FT-IR (ATR): υ 2993, 2044. 2919, 2867,
2252, 1382, 1201, 1166, 1123, 1102 cm-1. MS (SEI): m/z = 290
[M+H]+.HRMS (ESI) calcd for C17H24NO [M + H]+ 290.1751, found
290.1761
2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-
(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-
yl)acetic acid (22) To a stirred solution of 21 (1.5 g, 2.6 mmol) and
TEMPO (20 mg) in toluene (15 mL) at r.t. was added 1M phosphate buffer
solution (9 mL, pH 6.8) and sodium chlorite (1.16 g, 12.8 mmol) in one
portion, then 11% sodium hypochlorite solution (0.33 g) was added
dropwise within 0.5h. The stirring was continued for 14h. The reaction
mixture was adjusted to pH 4~5 by sodium dihydrogen phosphate solution,
extracted with EtOAc, washed with brine, dried with Na2SO4, evaporated
and purified by column chromatography to afford 22 (1.31 g, 85%) as while
solid. mp 174-176oC, []D20 = +2.7 (c 0.5, CHCl3) (Lit.[14] []D20 = +5.0 (c 1,
CHCl3)). 1H NMR (400 MHz, CDCl3) δ 7.23 – 6.95 (m, 14H), 6.87 (s, 1H),
4.26 – 4.16 (m, 1H), 4.14 – 4.03 (m, 1H), 3.92 – 3.78 (m, 1H), 3.76 – 3.65
(m, 1H), 3.63 – 3.50 (m, 1H), 2.54 (dd, J = 15.9, 6.6 Hz, 1H), 2.39 (dd, J =
15.9, 5.5 Hz, 1H), 1.75 – 1.61 (m, 2H), 1.53 (d, J = 6.9 Hz, 6H), 1.39 – 1.24
(m, 7H), 1.07 (q, J = 12.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 174.93,
165.07, 163.65, 161.19, 141.58, 138.45, 134.70, 133.34, 133.26, 130.62,
128.93, 128.82, 128.49, 126.72, 123.74, 122.00, 119.79, 115.64, 115.43,
99.17, 66.51, 65.60, 40.99, 40.94, 37.99, 35.85, 30.00, 26.25, 21.92, 21.76,
19.79. FT-IR (ATR): υ 3391, 2992, 2953, 1707, 1657, 1524, 1510, 1438,
1313, 1152 cm-1. MS (ESI): m/z = 599 [M+H]+. HRMS (ESI) calcd for
C36H40FN2O5 [M+H]+ 599.2916, found 599.2929
2-((4R,6S)-6-(2-(benzyloxy)ethyl)-2,2-dimethyl-1,3-dioxan-4-
yl)ethanamine (6) A mixture of 19 (700 mg, 2.4 mmol), W-2 Raney Ni (426
mg, 7.3 mmol) and KBH4 (653 mg, 12.1 mmol) in EtOH (35 mL) was stirred
at 55oC under N2 atmosphere for 1h. The reaction mixture was cooled to
r.t. and filtered. The filtrate was evaporated and to the residue was added
DCM (60 mL) and water (100 mL), the organic phase was separated and
the water phase was extracted with DCM (40mL × 2). The combined
organic phase was washed with brine, dried with Na2SO4 and evaporated
to dryness. the residue was purified by column chromatography to afford
20
6 (500 mg, 70%) as colourless oil. []D20 = -9.2 (c 0.5, DCM) (Lit.[14] []D
= -10 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.27 (m, 5H), 4.54
– 4.45 (m, 2H), 4.07-4.00 (m, 1H), 3.98 – 3.90 (m, 1H), 3.63 – 3.48 (m,
2H), 2.80 (t, J = 6.8 Hz, 2H), 1.77 (s, 2H), 1.76 – 1.51 (m, 4H), 1.48 – 1.43
(m, 1H), 1.42 (s, 3H), 1.36 (s, 3H), 1.19 (dd, J = 24.2, 11.7 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ 138.67, 128.48, 127.77, 127.68, 98.62, 73.12,
67.75, 66.32, 66.20, 39.89, 38.65, 37.25, 36.70, 30.39, 20.02. FT-IR
(ATR): υ 3375, 2940, 2861, 1379,1199,1101, cm-1. MS (ESI): m/z = 294
[M+H]+. HRMS (ESI) calcd for C17H28NO3 [M+H]+ 294.2064, found
294.2077
Atorvastatin Calcium (1) A solution of 22 (0.9 g, 1.5 mmol) in 1M HCl
(5mL) and EtOH (40 mL) was stirred at r.t. for 5h. after completion of the
hydrolysis, the reaction mixture was adjust to pH 7 by sat. NaHCO3,
extracted with EtOAc (30mL × 2), evaporated to dryness. To the residue
was added EtOH (20 mL) and cooled to 0oC under stirring, a 1.0 M KOH
solution (5.5 mL) was added dropwise and stirring was continued for 1h,
then 5% CaCl2 solution (2.5 mL) was added dropwise, a white precipitate
was apparent. Stirring was continued for 1h. EtOH was removed under
vacuum. Filtered.and the filter cake was dried to afford 1 (0.81 g, 90%) as
1-(2-((4R,6S)-6-(2-(benzyloxy)ethyl)-2,2-dimethyl-1,3-dioxan-4-
yl)ethyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-
carboxamide (20) A mixture of 5 (2.45 g, 5.9 mmol), 6 (2.07 g, 7.1 mmol),
pivalic acid ( 0.6 g, 5.9 mmol), THF (11 mL), toluene (11 mL) and heptane
(63 mL) was stirred under reflux in N2 atmosphere for 50h. the reaction
mixture was cooled to r.t. and washed with sat. NaHCO3 (100 mL) and
brine (100 mL) successively, dried with Na2SO4 and evaporated to dryness.
the residue was purified by column chromatography to afford 20 (2.78 g,
70%) as light yellow syrup. []D20 = -0.3 (c 1, CHCl3) (Lit.[14] []D20 = -1.5 (c
1, CHCl3)). 1H NMR (400 MHz, CDCl3) δ 7.39 - 7.27 (m, 5H), 7.23 - 7.12
(m, 9H), 7.11 - 7.04 (m, 2H), 6.98 (t, J = 8.0 Hz, 3H), 6.86 (s, 1H), 4.48 (m,
2H), 4.13 – 4.01 (m, 1H), 4.00 - 3.90 (m, 1H), 3.89 - 3.76 (m, 1H), 3.71 –
3.45 (m, 4H), 1.79 – 1.60 (m, 4H), 1.54 (d, J = 6.9 Hz, 6H), 1.34 (s, 3H),
1.30 (s, 3H), 1.27 – 1.20 (m, 2H), 1.02 (q, J = 12.0 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ 164.95, 163.64, 161.18, 141.70, 138.65, 138.57, 134.83,
133.39, 133.31, 130.66, 128.93, 128.81, 128.50, 127.78, 127.72, 126.69,
123.63, 121.90, 119.71, 115.58, 115.45, 115.37, 98.65, 73.11, 66.72,
66.17, 65.90, 41.05, 38.31, 36.63, 36.59, 30.20, 26.24, 21.89, 21.72, 19.95.
20
while solid. mp 186-188oC (Lit.[1e] mp 173-175oC), []D = -4.4 (c 1,
20
DMSO) (Lit.1d []D = -6.9 (c 1, DMSO)). 1H NMR (400 MHz, DMSO) δ
9.81 (s, 1H), 7.56 – 7.47 (m, 2H), 7.27 – 7.14 (m, 6H), 7.10 – 7.04 (m, 4H),
7.01 – 6.93 (m, 2H), 4.02 – 3.89 (m, 1H), 3.83 – 3.70 (m, 2H), 3.61 – 3.52
(m, 1H), 3.30 – 3.16 (m, 2H), 2.06 (d, J = 14.8 Hz, 1H), 1.89 (dd, J = 14.9,
8.0 Hz, 1H), 1.63 – 1.51 (m, 2H), 1.37 (d, J = 6.6 Hz, 6H), 1.26 – 1.15 (m,
1H).13C NMR (100 MHz, DMSO) δ 177.21, 166.23, 162.83, 160.39, 139.49,
136.00, 134.97, 133.44, 133.36, 129.19, 128.78, 128.75, 128.56, 128.45,
127.64, 127.34, 125.37, 122.98, 120.60, 119.45, 117.50, 115.49, 115.28,
66.39, 66.30, 43.86, 40.89, 25.68, 24.61, 22.32..
FT-IR (ATR): υ 3408, 2991, 2957, 2868, 1667, 1527, 1509, 1435,753 cm-
1
Keywords: Atorvastatin Calcium • Asymmetric Synthesis • chiral
syn-1,3-diol • Intramolecular Oxidative Oxygen-nucleophilic
Bromocyclization • HMG-CoA reductase inhibitor
5-(4-fluorophenyl)-1-(2-((4R,6S)-6-(2-hydroxyethyl)-2,2-dimethyl-1,3-
dioxan-4-yl)ethyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-
carboxamide (21) A mixture of 20 (2.1 g, 3.1 mmol) and 5% Pd/C (0.42
g) in MeOH (25 mL) was stirred under H2 atmosphere at r.t. for 65h. The
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700387
European Journal of Organic Chemistry
FULL PAPER
[1]
For representative reviews, see: a) Z. Casar. Curr. Org. Chem. 2010, 14,
816-845. b) Y. Wu, F. J. Xiong, F. J. F. E. Chen. Tetrahedron 2015, 71,
8487-8510. c) M. Mueller. Angew. Chem. Int.Ed., 2005, 44, 362-365. For
recent papers, see: d) J. M. Lopchuk, G. W. Gribble. Tetrahedron Lett.
2015, 56, 3208-3211. e) H. F. Wang; L. J. Yan, F. J. Xiong, Y. Wu; F. E.
Chen. RSC Advances, 2016, 6, 75470-75477. f) L. C. Dias, A. S. Vieira,
E. J. Barreiro Org. Biomol. Chem. 2016, 14, 2291-2296.
70, 5794-5799. d) F. J. Xiong, J. Li, X. F. Chen, W. X. Chen, F. E. Chen.
Tetrahedron: Asymmetry, 2014, 25, 1205-1208. e) L. M. Hu, F. J. Xiong,
X. F. Chen, W. X. Chen, Q. Q. He, F. E. Chen. Tetrahedron: Asymmetry,
2013, 24, 207–211
[8]
[9]
a) J. A. Frick, J. B. Klassen, A. Bathe, J. M. Abramson, H. Rapoport.
Synthesis, 1992, 621-623. b) E. K. Kunec, D. J. Robins. J. Chem. Soc.
Perkin Trans. 1, 1987, 1089-1093. c) J. M. Spaniol, K. A. Wheeler. RSC
Advances, 2016, 6, 64921-64929.
[2]
a) E. S. Istvan, J. Deisenhofer. Science, 2001, 292, 1160-1164. b) P. H.
Chong, J. D. Seeger. Pharmacotherapy, 1997, 17, 1157-1177. c) J. A.
Tobert. Nat. Rev. Drug Discovery, 2003, 2, 517-526. d) K. H. Han, S. W.
Rha, H. J. Kang, J. W. Bae, B. J. Choi, S. Y. Choi, H. C. Gwon, J. H. Bae,
B. K. Hong, D. H. Choi, K. R. Han, J. Clin. Lipidol. 2012, 6, 340-351.
(a) K. Narasaka, F. C. Pai. Tetrahedron, 1984, 40, 2233-2238. (b) K. M.
Chen, G. E. Hardtmann, K. Prasad, O. Repic, M. Shapiro. Tetrahedron
Lett., 1987, 28, 155-158. (c) S. E. Bode, M. Wolberg, M. Muller.
Synthesis, 2006, 557-588.
J. Xia, J. F. Song, L. Zhen, X. L. Zhang, X. T. Lei, L. N. Zheng, Q. J.
Wang, H. B. Sun. Bioorg. Med. Chem. Lett., 2011, 21, 3894-3897.
[10] G. Bartoli, M. Bosco, A. Carlonr, R. Dalpozzo, M. Locatelli, P. Melchiorre,
P. Palazzi, L. Sambri. Synlett, 2006, 2104-2108.
[3]
[4]
[11] a) K. Moriyama, Y. Izumisawa, H. Togo. J. Org. Chem., 2011, 76, 7249-
7255. b) Y. He, Y. Pu, B. Shao, J. Yan. J. Heterocycl. Chem., 2011, 48,
695-698. c) K. Moriyama, T. Sugiue, C. Nishinohara, H. Togo. J. Org.
Chem. 2015, 80, 9132−9140.
a) S. Tartaggia,S. Fogal, R. Motterle, C. Ferrari, M. Pontini, R. Aureli,O.
De Lucchi. Eur. J. Org. Chem., 2016, 3162-3165. b) M. Oslaj, J. Cluzeau,
D. Orkic, G. Kopitar, P. Mrak, Z. Casar, PLoS One, 2013, 8, e62250; c)
M. Wolberg, M. Villela Filho, S. Bode, P. Geilenkirchen, R. Feldmann, A.
Liese,W. Hummel, M. Mueller. Bioprocess Biosyst.ems Eng., 2008, 31,
183-191.
[12] a) D. L. J. Clive, K. S. K. Murthy, A. G. H. Wee, J. S. Prasad, G. V. J. Da
Silva, M. Majewski, P. C. Anderson, C. F. Evans, R. D. Haugen, L. D.
Heerze, J. R. Barrie. J. Am. Chem. Soc., 1990, 112, 3018-3028. b) S.
Radl, J. Stach, J. Hajicek. Tetrahedron Lett., 2002, 43, 2087-2090. (c) P.
Walleser, R. Brueckner. Eur. J. Org. Chem., 2014, 3210-3224.
[13] B. Wu, J. Zhang, M. Yang, Y. Yue, L. J. Ma, X. Q. Yu. ARKIVOC, 2008,
(12), 95-102.
[5]
[6]
[7]
F. J. Xiong, H. F. Wang, L. J. Yan, S. Han, Y. Tao, Y. Wu, F. E. Chen.
Org. Biomol. Chem., 2016, 14, 1363-1369.
[14] P. Sawant, M. E. Maier. Tetrahedron, 2010, 66, 9738-9744.
[15] M. Zhao, J. Li, E. Mano, Z. Song, D. M. Tschaen, E. J. J. Grabowski, P.
J. Reider. J. Org. Chem. 1999, 64, 2564-2566.
W. Q. Chen, F. J. Xiong, Q. Liu, L. J. Xu, Y. Wu, F. E. Chen. Tetrahedron,
2015, 71, 4730-4737.
a) F. J. Xiong, H. F. Wang, L. J. Yan, L. J. Xu, Y. Tao, Y. Wu, F. E. Chen.
Org. Biomol. Chem., 2015, 13, 9813-9819. b) X. F. Chen, F. J. Xiong, W.
X. Chen, Q. Q. He, F. E. Chen. J. Org. Chem., 2014, 79, 2723-2728. c)
X. F. Chen, F. J. Xiong, C. Zheng, J. Li, F. E. Chen. Tetrahedron, 2014,
[16] B. L. Feringa, B. De Lange. Tetrahedron, 1988, 44, 7213-7222.
[17] S. George, A. Sudalai. Tetrahedron: Asymmetry, 2007, 18, 975-981.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700387
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
intramolecular oxidative oxygen-
nucleophilic bromocyclization *
Yan Wu[a], Min-Jie Liu[a], Hai-Qing
Huang[a], Guan-Xin Huang[a], Fang-Jun
Xiong[a]*, and Fen-Er Chen[a]*
Page No. – Page No.
High regio- and diastereo- selective intramolecular oxidative oxygen-nucleophilic
bromocyclization for construction of syn-1,3-diol moiety along with a novel synthesis
of atorvastatin.
Asymmetric Synthesis of Atorvastatin
Calcium via Intramolecular Oxidative
Oxygen-nucleophilic
Bromocyclization
*one or two words that highlight the emphasis of the paper or the field of the study
This article is protected by copyright. All rights reserved.