Substrate stereocontrol in bromine-induced intermolecular cyclization: Asymmetric synthesis of pitavastatin calcium

Article abstract of DOI:10.1016/j.tet.2015.05.053

A novel approach to synthesize pitavastatin calcium (1), an effective HMG-CoA reductase inhibitor, based on readily available and attractively functionalized (R)-3-chloro-1,2-propanediol is reported. This work highlights an intermolecular diastereoselective bromine-induced cyclization of homoallylic carbonate to meet stereochemical challenges in the synthesis of statins. An efficient route to a new triphenylphosphonium tetrafluoroborate salt of a quinoline core is also presented.

Full text of DOI:10.1016/j.tet.2015.05.053

Accepted Manuscript
Substrate Stereocontrol in Bromine-Induced Intermolecular Cyclization: Asymmetric
Synthesis of Pitavastatin Calcium
Weiqi Chen, Fangjun Xiong, Qian Liu, Lingjun Xu, Yan Wu, Fener Chen
PII:
S0040-4020(15)00724-3
10.1016/j.tet.2015.05.053
TET 26771
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 April 2015
Revised Date: 13 May 2015
Accepted Date: 18 May 2015
Please cite this article as: Chen W, Xiong F, Liu Q, Xu L, Wu Y, Chen F, Substrate Stereocontrol in
Bromine-Induced Intermolecular Cyclization: Asymmetric Synthesis of Pitavastatin Calcium, Tetrahedron
(2015), doi: 10.1016/j.tet.2015.05.053.
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Substrate Stereocontrol in Bromine-Induced
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Synthesis of Pitavastatin Calcium
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Weiqi Chen,a, bFangjun Xiong,a Qian Liu,aLingjun Xu,a Yan Wu,*, a and Fener Chen*, a, b
a Department of Chemistry and b Institutes of Biomedical Science, Fudan University, 220 Handan Road,
Shanghai, 200433, People’s Republic of China

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Tetrahedron
journal homepage: www.elsevier.com
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Substrate Stereocontrol in Bromine-Induced Intermolecular Cyclization: Asymmetric
Synthesis of Pitavastatin Calcium
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Weiqi Chen,a, b Fangjun Xiong,a Qian Liu,a Lingjun Xu,a Yan Wu,a, * and Fener Chena, b, 
aDepartment of Chemistry, Fudan University, 220 Handan Road, Shanghai, 200433, People’s Republic of China
bInstitutes of Biomedical Science, Fudan University, 220 Handan Road, Shanghai, 200433, People’s Republic of China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel approach to synthesize pitavastatin calcium (1), an effective HMG-CoA reductase
inhibitor, based on readily available and attractively functionalized (R)-3-chloro-1,2-propanediol
is reported. This work highlights an intermolecular diastereoselective bromine-induced
cyclization of homoallylic carbonate to meet stereochemical challenges in the synthesis of
statins. An efficient route to a new triphenylphosphonium tetrafluoroborate salt of a quinoline
core is also presented.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Pitavastatin calcium
HMG-reductase inhibitor
Bromocyclization
Substrate Stereocontrol
Asymmetric synthesis
1. Introduction
this synthesis is that the use of cryogenic diastereoselective
borohydride reduction of a boron chelate intermediate derived
Cardiovascular disease is the leading cause of death
worldwide. More than 17 million people die annually from
coronary heart disease (CHD) and stroke.1 Epidemiological
from the chiral β-hydroxy-3-ketoester and diethylmethoxyborane
as a complex agent to form the second stereogenic center (3R)
with very high stereocontrol.7 This drawback of the existing
method prompted us to pursue an alternative practical approach
to synthesize important statin 1. Herein, we describe our recently
developed novel strategy that allows the concise asymmetric
37 evidence indicates that there is a strong correlation between
38
hypercholesterolemia and the risk of CHD.2 HMG-CoA
reductase inhibitors, commonly referred to as statins, have been
successfully used in the clinical setting to decrease the
occurrence of coronary events by lowering total plasma
cholesterol and the level of LDL-C.3 Pitavastatin calcium (1) is
an effective HMG-CoA reductase inhibitor and the active
ingredient in Livalo, which is in clinical use to treat
hypercholesterolemia.4
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synthesis of
1
and features
a
unique intermolecular
diastereoselective bromine-induced cyclization reaction.
Given the promise of 1 as a HMG-CoA reductase inhibitor,
not surprisingly, a large amount of research has been conducted
toward the asymmetric synthesis of this important statin.5 Among
these endeavors, the highly convergent C1 + C6 Wittig-type
olefination strategy using enantiomerically pure C6-formyl side
chain 26 with a syn-1,3-diol subunit and triphenylphosphonium
bromide 3 as important building blocks is considered one of the
most expedient and practical approaches to develop an industrial-
scale synthesis of 1 (Figure 1).5 However, the asymmetric
construction of statin side chain 2 remains challenging. The
efficient chiral route to obtain this framework of statins from
readily available (-)-epichlorohydrin is reliable for large-scale
Figure 1. Structures of pitavastatin calcium (1), chiral C6-formyl side chain 2
and triphenylphosphonium bromide 3
synthesis of 1 and other statins. However, a major problem of
———
 Corresponding author. Tel.: +86 21 65643809; fax: +86 21 65643811; e-mail: wywin8@163.com and rfchen@fudan.edu.cn

2
Tetrahedron
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2. Results/Discussion
Our retrosynthetic analysis of 1 is depicted in Figure 2. Statin
1 can be disconnected into two components: chiral C6-formyl
side chain 2 containing a syn-1,3-diol structural unit and
triphenylphosphonium tetrafluoroborate salt 4 with a quinoline
core, which served as our initial targets. We anticipated that the
six-carbon side chain 2 could be appended onto the quinoline
core of 4 using an improved Wittig coupling reaction that would
facilitate stereoselective construction of the statin side chain in
the target molecule. We envisaged that aldehyde 2 could be
produced from six-membered cyclic bromocarbonate 5, which
could be accessed from stereodefined homoallylic carbonate 6
via an intermolecular diastereoselective bromine-induced
cyclization that would generate the 3R stereogenic center. The
ultimate disconnection identified (R)-3-chloro-1,2-propanediol 7
as the starting material for the proposed route to 2.
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Scheme 1.Synthesis of homoallylic tert-butyl carbonate 6
Having accomplished efficient preparation of the desired
homoallylic carbonates 6a-c, their conversion to the required syn-
bromocarbonate 5 was investigated. First, we reacted homoallylic
carbonate 6a with 1.5 equiv of bromine and 1.5 equiv of
anhydrous K2CO3 as a base in MeCN at -20 °C for 1 h, which
gave bromocarbonate 5a in 27% yield as a single diastereomer
(Table 1, entry 1). Varying the solvent indicated that CH2Cl2 was
the most effective for this transformation (Table 1, entries 1–3).
A study of the effect of temperature (Table 1, entries 3–6)
indicated that the yield of 5a increased when the reaction
temperature was decreased from -20 to -40 °C, but there was
slight decrease in yield when the temperature was further
lowered to -80 °C. The optimized conditions, 1.5 equiv of
bromine and 1.5 equiv of anhydrous K2CO3 in CH2Cl2 at -40 °C
for 1 h, generated exclusively the desired bromocarbonate 5a in
an isolated yield of 55% (Table 1, entry 5). It is worth noting that
the choice of protecting group on the oxygen atom of C1
markedly affected the reactivity of the substrate in the bromine-
induced intermolecular cyclization reaction. No desired product
was detected when a benzyl protecting group was used, while the
use of p-chloro benzyl as a protecting group afforded the
bromocyclization product 5c in a low yield of 18% albeit with
clean conversion (Table 1, entries 7 and 8).
Triphenylphosphonium tetrafluoroborate salt
4
could be
15 synthesized from commercially available cyclopropyl methyl
ketone 9 as a starting material via acetal 8 according to a series of
simple functional transformations.
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Table 1 Bromine-induced intermolecular cyclization of homoallylic tert-
butyl carbonate 6.a
Entry
X
Solvent
MeCN
PhMe
Temp(oC)
-20
Yield(%)
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Br
Br
H
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48
-
-20
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
-20
Figure 2. Retrosynthetic analysis of pitavastatin calcium (1)
-40
Our synthesis began by epoxidation of 7 under basic
conditions (Scheme 1).8 Protection of the primary hydroxyl group
by treatment of 10 with p-bromobenzyl bromide, benzyl bromide,
and p-chlorobenzyl chloride afforded the corresponding benzyl
-60
-80
-40
esters 11a,
b
and c, respectively, in 88%–90% yield.9
Cl
-40
18
Regioselective ring opening of 11a-c with vinylmagnesium
chloride in THF at -10 °C under copper catalysis gave
homoallylic alcohols 12a-c in almost quantitative yield,10 which
were then converted to the corresponding homoallylic tert-butyl
carbonates 6a-c by treatment with Boc2O in the presence of
Zn(OAc)2 in CH2Cl2 under reflux.11
aAll reactions were carried out in the presence of Br2 (1.5 equiv), K2CO3 (1.5
equiv) and 6a-c (2.7 mmol).
bIsolated yields
A simple rationale is presented in the mechanism scheme
given in Figure 3.12 The highly diastereoselectivity of this

3
bromine-induced cyclization is proposed to proceed through
transition state Ⅱ(favored chair conformation), leading to the
syn-bromocarbonate 5a as a sole product.
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Figure 3. Proposed mechanism for the bromine-induced cyclization
Basic methanolysis of bromocarbonate 5a efficiently provided
syn-epoxy alcohol 13 in 84% yield (Scheme 2).12e Epoxide ring
opening of 13 with NaCN in H2O proceeded cleanly under mild
conditions, and pure syn-diol nitrile 14 was isolated in 70% yield.
Nitrile 14 was subjected to a Pinner reaction by treatment with a
saturated solution of hydrogen chloride in MeOH at 0 °C
followed by protection with 2,2-dimethoxypropane (DMP)
through p-toluene sulfonic acid (PTSA) catalysis to provide
exclusively syn-acetonide ester 15 (77% over two steps).
Scheme 2. Synthesis of C6-formly side chain 2
Removal of the 4-bromobenzyl group under hydrogenolysis
conditions provided the corresponding alcohol 16 in 90% yield.
Alcohol 16 was then converted into C6-formyl side chain 2 in
68% yield under oxidizing conditions (NaClO, TEMPO, KBr,
NaHCO3).13
H-9
H-3
H-5
Scheme 3. Synthesis of triphenylphosphonium tetrafluoroborate 4
The synthesis of new triphenylphosphonium tetrafluoroborate
salt 4 began with the formation of the quinoline from cyclopropyl
methyl ketone (9) according to an improved Nagashima protocol,
as shown in Scheme 3.14 Transformation of 9 into the derived
sodium enolate 17 was achieved in 88% yield with ethyl formate
in the presence of 60% NaH in THF. Salt 17 was treated
immediately with neopentyl glycol (NPG) in MeOH using conc.
H2SO4 as catalyst at room temperature to give acetal 18 in 93%
yield. The Friedländer condensation of 18 and 2-amino-4’-fluoro
benzophenone in the presence of PTSA in toluene afforded
quinoline derivative 8 in 63% yield. Deprotection of the acetal
group of 8 under acidic conditions gave quinoline aldehyde 19 in
95% yield, which was reduced with borohydride anion exchange
resin (BER)15 in EtOH to the quinoline alcohol 20 quantitatively.
Alcohol 20 was converted to the corresponding
triphenylphosphonium tetrafluoroborate salt 4 in 96% yield by
treatment with hydrogen triphenylphosphonium tetrafluoroborate
in boiling MeCN.16,17
Figure 4. The NOE correlations of syn-acetonide 15
The NOESY study of 15 revealed that strong NOE
correlations between H-3/H-5, H-3/H-9 and H-5/H-9, which
indicated H-3, H-5 and H-9 were on the same side of the
molecule, and comfirmed the stereochemical assignment of 15.
(Figure 4).6j

4
Tetrahedron
dispersion in mineral oil, (2.88 g, 72 mmol) in anhydrous DMF
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(30 mL) at 0 C. The resultant white suspension was stirred until
effervescence ceased, then benzyl bromide, p-chlorobenzyl
chloride or p-bromobenzyl bromide (72 mmol) and TBAI (2.22 g,
6 mmol) were added sequentially. The reaction mixture was then
allowed to warm to ambient temperature over 18 h, poured into
water, and extracted with EtOAc (3 × 50 mL). The combined
organic phase was then washed with water and brine, dried
(anhydrous Na2SO4), filtered and concentrated in vacuo. The
residue was purified by column chromatography (silica gel,
EtOAc/PE, 1:20) to afford 11
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4.2.1. (S)-2-(((4-bromobenzyl)oxy)methyl)oxirane
(11a)1 2 e
10
11
12
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15
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17
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19
20
21
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25
Obtained (12.92 g, 89% over two steps) as a colorless oil. [α]D25
+5.36 (c 0.5, CHCl3), 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J =
8.0 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 4.54 (d, J = 12.4 Hz, 1H),
4.49 (d, J = 12.4 Hz, 1H), 3.76 (dd, J = 2.8, 11.2 Hz, 1H), 3.39
(dd, J = 5.6, 11.2 Hz, 1H), 3.16-3.20 (m, 1H), 2.79 (t, J = 4.4 Hz,
1H), 2.60 (dd, J = 2.8, 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 136.9, 131.5, 129.3, 121.6, 72.5, 70.9, 50.8, 44.1; IR (thin film,
cm-1) 2996, 2857, 1591, 1486, 1403, 1092, 836; MS (ESI): m/z
265 (M + Na+).
Scheme 4. Synthesis of pitavastatin calcium (1)
With C6-formyl side chain 2 and triphenylphosphonium
tetrafluoroborates salt 4 in hand, our attention was next turned to
their coupling via a Wittig-type olefination reaction to synthesize
1 as outlined in Scheme 4. As expected, stereoselective Wittig
olefination of 2 and 4 proceeded smoothly under mild reaction
conditions (K2CO3, DMSO, 70 °C) to furnish the (E)-olefin 21 as
a single isomer in 72% yield. Removal of the ketal group from
4.2.2. (S)-2-((benzyloxy)methyl)oxirane (11b)9 b
Obtained (8.89 g, 90% over two steps) as a colorless oil [α]D20
-
2.76 (c 0.8, CHCl3); lit.9b [α]D25 -3.0 (c 0.37, CHCl3); H NMR
(400 MHz, CDCl3) δ 7.29-7.36 (m, 5H), 4.60 (d, J = 11.6 Hz,
1H), 4.55 (d, J = 11.6 Hz, 1H), 3.75 (dd, J = 2.8, 11.6 Hz, 1H),
3.42 (dd, J = 6.0, 11.6 Hz, 1H), 3.17-3.21 (m, 1H), 2.80 (t, J =
4.8 Hz, 1H), 2.61 (dd, J = 2.8, 5.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 137.8, 128.4, 127.7, 73.3, 70.7, 50.8, 44.2; MS (ESI):
m/z 187 (M + Na+).
1
26 the resulting (E)-olefin followed by hydrolysis and calcium salt
formation completed the synthesis of 1 with an overall yield of
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85% over three steps.5c-h
3. Conclusion
4.2.3. (S)-2-(((4-chlorobenzyl)oxy)methyl)oxir ane
(11c)9 c
In summary, we have demonstrated a new synthetic sequence
that is robust and highly stereo-and regioselective to prepare a
syn-1,3-diol substructure, which we applied herein to the efficient
asymmetric synthesis of pitavastatin calcium (1). This synthetic
procedure should be applicable to the synthesis of other HMG-
CoA reductase inhibitors and natural products bearing similar
syn-1,3-diol substructures.
Obtained (10.45 g, 88% over two steps) as a colorless oil. [α]D20
+1.66 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J =
8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 4.56 (d, J = 12.4 Hz, 1H),
4.51 (d, J = 12.4 Hz, 1H), 3.78 (dd, J = 2.8, 11.2 Hz, 1H), 3.40
(dd, J = 6.0, 11.6 Hz, 1H), 3.18-3.21 (m, 1H), 2.82 (t, J = 4.8 Hz,
1H), 2.62 (dd, J = 2.4, 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 136.9, 131.4, 129.2, 121.5, 72.4, 70.8, 50.7, 44.1; MS (ESI):
m/z 221 (M + Na+).
4. Experimental Section
4.3. Genneral Procedure for the synthesis of homoallylic alcohol
12
4.1. General
All reagents were obtained from commercial sources and used
43 without further purification. H (400MHz) and 13C (100MHz)
1
To a solution of vinyl magnesium chloride (2.0 M in THF, 15
mL, 30 mmol) was added copper (I) iodide (190 mg, 1 mmol)
NMR were recorded on a Bruker Avance 400 spectrometer using
TMS or CDCl3 as internal standards, IR spectra were recorded on
a JASCO FT/IR-4200 spectrometer, Optical rotations were
measured by a JASCO P1020 digital polarimeter. EI-MS were
recorded on an Agilent 6890N/5975 spectrometer and ESI-MS
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and the mixture was cooled to -10 C. A solution of 11 (20.66
mmol) in THF (17 mL) was then added dropwise over 1 h and
o
the reaction mixture was allowed to stir at -10 C for 10 h. The
reaction was quenched with 2 M HCl and stirred for 30 min.
After separation, the organic phase was washed with brine, dried
(anhydrous Na2SO4), filtered and concentrated in vacuo. The
residue was purified by column chromatography (silica gel,
EtOAc/PE, 1:20) to afford 12.
were
recorded
on
a
Waters
Micromass
Quattro
Microspectrometer. HRMS were recorded on a Bruker micro
TOF spectrometer.
4.2. Genneral Procedure for the synthesis of benzy ester 11
4.3.1. (S)-1-((4-bromobenzyl)oxy)pent-4-en-2-ol
(12a)1 2 e
To a solution of (R)-3-bromo-1,2-propanediol (6.60 g, 60
mmol) in CH2Cl2 (75 mL) was added anhydrous K2CO3 (20.73 g,
150 mol). The reaction mixture was stirred at room temperature
for 24 h. The resulting mixture was vacuum filtered through
Celite and concentrated in vacuo to give crude (R)-glycidol 10,
which was used without further purification.
Obtained (5.5 g, 99%) as a colorless oil. [α]2D5 +1.62 (c 1.1,
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.4 Hz, 2H),
7.19 (d, J = 8.0 Hz, 2H), 5.77-5.87 (m, 1H), 5.09-5.14 (m, 2H),
4.50 (s, 2H), 3.85-3.90 (m, 1H), 3.48 (dd, J = 3.6, 9.6 Hz, 1H),
3.35 (dd, J = 7.2, 9.6 Hz, 1H), 2.33 (br s, 1H), 2.26 (t, J = 6.0 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 136.9, 134.0, 131.5, 129.3,
121.6, 117.8, 73.9, 72.6, 69.7, 37.9; IR (thin film, cm-1) 3469,
Then, the solution of 10 in anhydrous DMF (10 mL) was
slowly dropped into the stirred suspension of NaH (60%

5
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2927, 2863, 1643, 1488, 1099, 1068, 992; MS (ESI): m/z 293 (M
+ Na+).
To a solution of 6 (2.7 mmol) in CH Cl (25 mL) at -40 C
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2 2
was added a solution of bromine (0.65 g, 4.05 mmol) in CH2Cl2
(4.05 mL) and K2CO3 (0.56 g, 4.05 mmol) sequentially. The
reaction was maintained at -40 C for 1 h before warmed up to
ambient temperature. The reaction was quenched with saturated
aqueous Na2SO3/NaHCO3 (1:1, 10 mL) and EtOAc (50 mL).
After separation, the organic phase was washed with saturated
aqueous Na2SO3/NaHCO3 and brine, dried (anhydrous Na2SO4),
filtered and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, EtOAc/PE, 1:5) to afford 5.
4.3.2. (S)-1-(benzyloxy)pent-4-en-2-ol (12b)1 0
Obtained (3.93 g, 99%) as a colorless oil. [α]2D0 +3.2 (c 1.0,
o
1
2
3
4
5
1
CHCl3), lit.10: [α]D20 +3.3 (c 1.0, CHCl3); H NMR (400 MHz,
CDCl3) δ7.28-7.38 (m, 5H), 5.78-5.88 (m, 1H), 5.08-5.14 (m,
2H), 4.56 (s, 2H), 3.86-3.92 (m, 1H), 3.50 (dd, J = 3.2, 9.6 Hz,
1H),3.36 (dd, J = 7.2, 9.2 Hz, 1H), 2.27 (br s, 1H), 2.27 (t, J = 6.8
Hz, 2H); MS (EI): m/z 192 (1), 91 (100).
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7
8
9
4.3.3. (S)-1-((4-chlorobenzyl)oxy)pent-4-en-2-ol
4.5.1. (4S,6R)-4-(((4-bromobenzyl)oxy)methyl)-6-
(12c)
(bromomethyl)-1,3-dioxan-2-one (5a)
Obtained (4.7 g, quant.) as a colorless oil. [α]2D5 +1.20 (c 0.6,
Obtained (0.58 g, 55%) as a colorless oil. [α]2D5 +10.5 (c 0.8,
10
11
12
13
14
15
16
17
18
1
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.4 Hz, 2H),
CHCl3); H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.0 Hz, 2H),
7.27 (d, J = 8.4 Hz, 2H), 5.79-5.89 (m, 1H), 5.11-5.16 (m, 2H),
4.50 (s, 2H), 3.88-3.92 (m, 1H), 3.50 (dd, J = 3.6, 9.2 Hz, 1H),
3.37 (dd, J = 7.2, 9.6 Hz, 1H), 2.40 (br s, 1H), 2.28 (t, J = 6.4 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 136.4, 134.1, 133.5, 129.0,
128.6, 117.8, 73.9, 72.5, 69.6, 37.9; HRMS (ESI-TOF) m/z calcd
for C12H16ClO2 (M + H+) 227.0839, found 227.0833.
7.18 (d, J = 7.6 Hz, 2H), 4.59-4.67 (m, 2H), 4.52 (s, 2H), 3.65 (m,
2H), 3.54-3.58 (m, 1H), 3.44 (dd, J = 6.8, 10.8 Hz, 1H), 2.30 (m,
1H), 1.95 (dt, J = 12.0, 13.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 147.9, 136.3, 131.6, 129.3, 121.9, 76.5, 72.9, 70.6, 32.2,
28.3; IR (thin film, cm-1) 2930, 1747, 1485, 1396, 1246, 1203,
1139, 1111, 1019, 806, 760, 670; HRMS (ESI-TOF) m/z calcd
+
for C13H18Br2NO4 (M + NH4 ) 409.9603, found 409.9593.
4.4. Genneral Procedure for the synthesis of homoallylictert-
19 butyl carbonate 6
4.5.2. (4R,6S)-4-(bromomethyl)-6-(((4-
20
chlorobenzyl)oxy)methyl)-1,3-dioxan-2-one (5c)
To the solution of 12 (18.5 mmol) in anhydrous CH2Cl2 (10
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
Obtained (0.17 g, 18%) as a colorless oil). [α]1D5 +8.3 (c 0.7,
mL) was added anhydrous Zn(OAc)2 (0.35 g, 1.9 mmol) and di-
tert-butyl dicarbonate (4.44 g, 20.4 mmol) sequentially at room
temperature, and the resultant mixure was refluxed for 12 h. The
mixture was vacuum filtered through Celite and the filtrate was
washed with water and brine, dried (anhydrous Na2SO4), filtered
and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, EtOAc/PE, 1:100) to afford 6.
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.4 Hz, 2H),
7.25 (d, J = 8.4 Hz, 2H), 4.59-4.68 (m, 2H), 4.55 (d, J = 2.0 Hz,
2H), 3.66 (d, J = 4.0 Hz, 2H), 3.56 (dd, J = 4.4, 10.8 Hz, 1H),
3.43 (dd, J = 7.2, 10.8 Hz, 1H), 2.34 (dt, J = 2.8, 14.4 Hz, 1H),
1.99 (dt, J = 12.0, 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
147.8, 135.7, 133.8, 129.1, 128.7, 76.6, 73.0, 70.6, 32.1, 28.4;
HRMS (ESI-TOF) m/z calcd for C13H15BrClO4 (M + H+)
348.9842, found 348.9838.
4.4.1. (S)-1-((4-bromobenzyl)oxy)pent-4-en-2-yl
tert-butyl carbonate (6a)1 2 e
Obtained (6.7 g, 98%) as a colorless oil. [α]2D5 +3.02 (c 1.0,
4.6. (S)-1-((4-bromobenzyl)oxy)-3-((R)-oxiran-2-yl)propan-2-ol
1
(13)12e
CHCl3); H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.4 Hz, 2H),
7.19 (d, J = 8.0 Hz, 2H), 5.72-5.82 (m, 1 H), 5.07-5.14 (m, 2H),
4.86-4.91 (m, 1H), 4.50 (d, J = 12.4 Hz, 1H), 4.44 (d, J = 12.0 Hz,
1H), 3.54 (d, J = 5.2 Hz, 2H), 2.35-2.46 (m, 2H), 1.47 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 153.2, 137.1, 132.9, 131.4, 129.2,
121.4, 118.2, 82.1, 74.7, 72.4, 70.8, 35.4, 27.8; IR (thin film, cm-1)
2980, 2935, 2862, 1743, 1487, 1368, 1276, 1161, 1095, 1001,
918, 847, 783; MS (ESI): m/z 393 (M + Na+).
To a solution of 5 (0.5 g, 1.28 mmol) in anhydrous MeOH (5
mL) was added K2CO3 (0.44 g, 3.2 mmol). The reaction mixture
was stirred at ambient temperature for 1 h before diluted with
EtOAc (50 mL) and water (10 mL). After separation, the aqueous
phase was extracted with EtOAc (2 x 50 mL). The combined
organic phase was washed with water and brine, dried
(anhydrous Na2SO4), filtered and concentrated in vacuo. The
residue was purified by column chromatography (silica gel,
EtOAc/PE, 1:5) to afford 13 (0.31 g, 84%) as a colorless oil. [α]D25
+4.68 (c 1.0, CHCl3), 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J =
8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 4.50 (s, 2H), 4.03 (br s,
1H), 3.48 (dd, J = 3.6, 9.6 1H), 3.43 (dd, J = 7.2, 9.2 Hz, 1H),
3.08-3.10 (m, 1H), 2.77 (t, J = 4.8 Hz, 1H), 2.63 (s, 1H), 2.49-
2.51 (m, 1H), 1.81 (dt, J = 4.4, 14.8 Hz, 1H).1.59-1.66 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 136.8, 131.5, 129.3, 121.6, 74.0,
72.6, 68.6, 49.5, 46.6, 35.9.; IR (thin film, cm-1) 3426, 2917,
1651, 1414, 1097, 802, 714, 623; MS (ESI): m/z 309 (M + Na+).
4.4.2. (S)-1-(benzyloxy)pent-4-en-2-yl tert-butyl
carbonate (6b)1 2 f
Obtained (5.1 g, 95%) as a colorless oil. [α]2D5 +3.45 (c 1.0,
CHCl3), lit.12f [α]D25 +4.0 (c 1.0, CHCl3); H NMR (400 MHz,
1
CDCl3) δ 7.29-7.36 (m, 5H), 5.72-5.82 (m, 1H), 5.06-5.14 (m,
2H), 4.86-4.92 (m, 1H), 4.56 (d, J = 12.0 Hz, 1H), 4.50 (d, J =
12.0 Hz, 1H), 3.55 (d, J = 5.2 Hz, 2H), 2.35-2.46 (m, 2H), 1.48 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 153.2, 138.0, 133.0, 128.3,
127.6, 118.1, 82.0, 74.8, 73.1, 70.6, 35.5, 27.8; MS (ESI): m/z
315 (M + Na+).
4.7. (3S,5S)-6-((4-bromobenzyl)oxy)-3,5-
dihydroxyhexanenitrile(14)
4.4.3. (S)-tert-butyl (1-((4-chlorobenzyl) oxy) pent
-4-en-2-yl) carbonate (6c)
Obtained (5.8 g, 97%) as a colorless oil. [α]2D5 +5.14 (c 1.0,
To a stirred solution of 13 (2.86 g, 10 mmol) in water (5 mL)
1
o
CHCl3); H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.4 Hz, 2H),
at 0 C was added dropwise a solution of sodium cyanide (0.734
7.24 (d, J = 8.4 Hz, 2H), 5.71-5.82 (m, 1H), 5.06-5.13 (m, 2H),
4.85-4.91 (m, 1H), 4.51 (d, J = 12.0 Hz, 1H), 4.45 (d, J = 12.4 Hz,
1H), 3.54 (d, J = 5.2 Hz, 2H), 2.38-2.43 (m, 2H), 1.47 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 153.1, 136.6, 133.3, 132.9, 128.8,
128.5, 118.2, 82.0, 74.7, 72.3, 70.8, 35.4, 27.7; HRMS (ESI-TOF)
m/z calcd for C17H24ClO4 (M + H+) 327.1363, found 327.1358.
g, 15 mmol) in water (3 mL). The reaction mixture was stirred at
room temperature for 48 h and the aqueous layer was extracted
with EtOAc (5 × 50 mL). The combined organic phase was
washed with water and brine, dried (anhydrous Na2SO4), filtered
and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, EtOAc/PE, 1:2) to afford 14 (2.19 g,
1
70%) as a pale yellow oil. [α]2D5 +4.63 (c 0.9, CHCl3); H NMR
4.5. Genneral Procedure for the synthesis of bromo–carbonate 5

6
Tetrahedron
(400 MHz, CDCl ) δ 7.48 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.0
Na SO ), filtered and concentrated in vacuo. The residue was
ACCEPTED MANUSCRIPT
3
2 4
Hz, 2H), 4.50 (s, 2H), 4.16-4.22 (m, 1H), 4.07-4.14 (m, 2H), 3.46
(dd, J = 3.2, 9.6 Hz, 1H), 3.34 (dd, J = 7.6, 9.2 Hz, 1H), 2.98 (br
s, 1H), 2.53 (d, J = 5.6 Hz, 2H), 1.71 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 136.4, 131.7, 129.4, 121.9, 117.4, 74.0, 72.7,
70.6, 67.5, 37.9, 25.9; IR (thin film, cm-1) 3443, 2920, 2862,
2356, 1411, 1072, 875, 641; HRMS (ESI-TOF) m/z calcd for
C13H16BrNO3Na (M + Na+) 336.0211, found 336.0214.
purified by column chromatography (silica gel, EtOAc/PE, 1:5)
to afford 2 (0.06 g, 62%) as a yellow oil. [α]2D5 -15.24 (c 1.0,
CHCl3), lit.6j [α]D25 -14.9 (c 1.0, CHCl3); H NMR (400 MHz,
1
1
2
3
CDCl3) δ 9.59 (s, 1H), 4.31-4.42 (m, 2H), 3.70 (s, 3H), 2.56 (dd,
J = 6.8, 15.6 Hz, 1H), 2.41 (dd, J = 6.0, 15.6 Hz, 1H), 1.83 (dt, J
= 2.4, 13.2 Hz, 1H), 1.50 (s, 3H), 1.46 (s, 3H), 1.32-1.37 (m,
1H); MS (ESI): m/z 201 (M – CH3)+.
4
5
6
4.8. Methyl2-((4R,6S)-6-(((4-bromobenzyl)oxy)methyl)-2,2-
4.11. Sodium (Z)-3-cyclopropyl-3-oxoprop-1-en-1-olate(17)18
7
8
9
dimethyl-1,3-dioxan-4-yl)acetate (15)
A solution of cyclopropylmethyl ketone (5 g, 59.5 mmol) in
anhydrous THF (10 mL) was dropped into the stirred suspension
of NaH (60% dispersion in mineral oil, 2.38 g, 59.5 mmol) in
(a)A solution of 14 (3.13 g, 10 mmol) in anhydrous methanol
o
(20 mL) was cooled to 0 C and saturated with gaseous HCl. The
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
reaction mixture was stirred at 0 oC for 8 h before being
quenched by saturated NaHCO3 solution. The solvent was
evaporated under reduced pressure and the aqueous layer was
extracted with EtOAc (3 × 50 mL). The combined organic phase
was dried (anhydrous Na2SO4), filtered and concentrated in
vacuo to give a yellow oil.
o
anhydrous THF (50 mL) at 0 C. The resultant white suspension
was stirred for 1 h, then ethyl formate (4.85 g, 65.5 mmol) were
o
added at 0 C and the reaction mixture was warmed to ambient
temperature and stirred overnight. The mixture was evacuated
and the contents were filtered through a paper filter with a
Büchner funnel. The crude yellow solid was rinsed with MTBE
(10 mL) followed by hexane (20 mL). The solid was allowed to
dry overnight under vacuum to afford 17 (7.0 g, 88%) as a yellow
(b) To a solution of the resulting yellow oil in acetone (25
mL) was added a solution of 2,2-dimethoxypropane (5.20 g, 50
mmol) in acetone (50 mL) and PTSA (190 mg, 1 mmol)
sequentially at room temperature. The reaction mixture was
stirred at room temperature for 24 h before being quenched by
triethylamine (150 mg, 1.5 mmol) and removed solvent under
reduced pressure. The residue was purified by column
chromatography (silica gel, EtOAc/PE, 1:5) to afford 15 (2.97 g,
77% over two steps) as a pale yellow oil. [α]2D5 +1.57 (c 0.8,
1
solid. H NMR (400 MHz, D2O) δ 9.01 (br s, 1H), 1.81-2.37 (m,
1H), 0.80-0.89 (m, 4H).
4.12. 1-Cyclopropyl-2-(5,5-dimethyl-1,3-dioxan-2-yl)ethanone
(18)
A solution of 17 (5 g, 37.3mmol) in MeOH (25 mL) was
dropped into the stirred suspension of 2,2-dimethyl-1,3-
propanediol (7.77 g, 74.6 mmol) and H2SO4 (4 g, 41 mmol) at
room temperature under N2 atmosphere. After stirring for 1 h, the
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.4 Hz, 2H),
7.19 (d, J = 8.4 Hz, 2H), 4.52 (d, J = 12.4 Hz, 1H), 4.47 (d, J =
12.4 Hz, 1H), 4.30-4.36 (m, 1H), 4.08-4.14 (m, 1H), 3.68 (s, 3H),
3.46 (dd, J = 5.6, 10.0 Hz, 1H), 3.35 (dd, J = 4.8, 10.0 Hz, 1H),
2.53 (dd, J = 7.2, 15.2 Hz, 1H), 2.37 (dd, J = 6.0, 15.2 Hz, 1H),
1.60-1.63 (m, 1H), 1.47 (s, 3H), 1.39 (s, 3H), 1.24-1.27 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 171.3, 137.2, 131.4, 129.3, 121.4,
98.9, 73.5, 72.6, 68.3, 65.6, 51.6, 41.2, 33.1, 29.9, 19.6; IR (thin
film, cm-1) 2927, 1736, 1381, 1267, 1112, 1010, 806; HRMS
(ESI-TOF) m/z calcd for C17H23BrNO5Na (M + Na+) 409.0627,
found 409.0621.
o
reaction mixture was heated to 60 C and then held for 8 h. The
reaction was quenched with saturated aqueous NaHCO3, and
EtOAc (100 mL). After separation, the organic phase was
washed with saturated aqueous NaHCO3 and water (3 × 50 mL),
brine, dried (anhydrous Na2SO4), filtered and concentrated in
vacuo to afford 18 (6.87 g, 93%) as a yellow oil. The material
1
was carried on without further purification. H NMR (400 MHz,
CDCl3) δ 4.89 (t, J = 4.8 Hz, 1H), 3.59 (d, J = 10.4 Hz, 2H), 3.45
(d, J = 10.8 Hz, 2H), 2.88 (d, J = 4.8 Hz, 2H), 1.96-2.02 (m, 1H),
1.19 (s, 3H), 1.05-1.07 (m, 2H), 0.87-0.90 (m, 2H), 0.72 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 207.1, 98.8, 48.4, 30.0, 23.0,
21.8, 21.3, 11.0; HRMS (ESI-TOF) m/z calcd for
C13H17BrNO3 (M + H+) 199.1334, found 199.1324.
4.9. Methyl2-((4R,6S)-6-(((4-bromobenzyl)oxy)methyl)-2,2-
dimethyl-1,3-dioxan-4-yl)acetate (16)6d
A solution of 15 (1.93 g, 5 mmol) containing 20% Pd/C
(0.386 g) in MeOH (10 mL) was stirred under hydrogen for 24 h.
The reaction mixture was filtered through Celite and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, EtOAc/PE, 1:5) to afford 16 (0.98 g,
90%) as a pale yellow oil. [α]2D5 +11.01 (c 0.9, CHCl3), lit.6d [α]2D5
+9.7 (c 1.9, CHCl3); 1H NMR (400 MHz, CDCl3) δ 4.31-4.38 (m,
1H), 3.99-4.05 (m, 1H), 3.69 (s, 3H), 3.59 (dd, J = 2.8, 11.6 Hz,
1H), 3.48 (dd, J = 6.0, 11.2 Hz), 2.54 (dd, J = 7.2, 15.6 Hz, 1H),
2.37 (dd, J = 6.0, 15.6 Hz, 1H), 1.49 (dt, J = 2.4, 12.4 Hz, 1H),
1.47 (s, 3H), 1.39 (s, 3H), 1.32 (d, J = 12.4 Hz, 1H); MS (ESI):
m/z 241 (M + Na+).
4.13. 2-Cyclopropyl-3-(5,5-dimethyl-1,3-dioxan-2-yl)-4-(4-
fluorophenyl) quinoline (8)
To a solution of 18 (2 g, 10.1 mmol) in toluene (10 mL) was
added 2-amino-4’-fluorobenzophenone (1.97 g, 9.2 mmol) and p-
toluenesulfonic acid monohydrate (0.57 g, 3 mmol) sequentially.
The reaction was stirred at 120 oC for 24 h. During the period, the
water by produced with the progress of the reaction was
azeotropically removed using a Dean-Stark trap. The reaction
was quenched with saturated aqueous NaHCO3 and EtOAc (50
mL). After separation, the organic phase was washed with
saturated aqueous NaHCO3, brine, dried (anhydrous Na2SO4),
filtered and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, EtOAc/PE, 1:100) to afford 8
4.10. Methyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-
yl)acetate (2)6j
o
1
(2.4 g, 63%) as a white solid. m. p 143-144 C; H NMR (400
MHz, CDCl3) δ 7.91 (d, J = 8.4 Hz, 1H), 7.58-7.62 (m, 1H),
7.28-7.31 (m, 3H), 7.20-7.24 (m, 3H), 5.33 (s, 1H), 3.72 (d, J =
11.6 Hz, 2H), 3.35-3.40 (m, 1H), 3.31 (d, J = 10.8 Hz, 2H), 1.39-
1.43 (m, 2H), 1.27 (s, 3H), 1.05-1.09 (m, 2H), 0.71 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 161.9, 147.5, 146.3, 132.5 (d, J = 3.6
Hz), 131.5, 131.4, 129.4, 128.8, 126.7, 126.4, 125.6, 125.2,
115.4, 115.2, 102.6, 78.5, 30.3, 24.0, 22.1, 15.4, 11.1; HRMS
To a solution of 16 (0.1 g, 0.46 mmol) in CH2Cl2 (10 mL) was
added TEMPO (0.72 mg, 0.0046mmol), KBr (5.5 mg,
0.046mmol) and NaHCO3 (0.4 g, 4.6 mmol) sequentially at 0 C.
A 0.5 M aqueous solution of NaClO (4.6 mL) was then added
dropwise and the reaction mixture was allowed to stir at 0 oC for
15 h. The reaction was quenched with saturated aqueous Na2SO3
and CH2Cl2 (50 mL). After separation, the organic phase was
washed with saturated aqueous Na2SO3, brine, dried (anhydrous
o

7
(ESI-TOF) m/z calcd for C24H25FNO2 (M + H+) 378.1869,
found 378.1862.
(400 MHz, CDCl ) δ 7.93 (d, J = 8.4 Hz, 2H), 7.57 (m, 1H),
3
ACCEPTED MANUSCRIPT
7.28-7.36 (m, 2H), 7.12-7.23 (m, 4H), 6.53 (d, J = 16.4 Hz, 1H),
5.54 (dd, J = 6.0, 16.4 Hz, 1H), 4.26-4.38 (m, 2H), 3.71 (s, 3H),
2.51 (dd, J = 6.8, 15.6 Hz, 1H), 2.40-2.45 (m, 1H), 2.32 (dd, J =
6.4, 15.6 Hz, 1H), 1.46 (s, 3H), 1.35-1.38 (m, 4H), 1.25 (s, 2H),
1.03 (dd, J = 3.2, 8.4 Hz, 2H); MS (ESI): m/z 476 (M + H+).
4.14. 2-Cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde
(19)6d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
To a solution of 8 (1 g, 2.65 mmol) in THF (10 mL) was
added 2 M HCl (50 mL). The reaction mixture was stirred at 60
oC for 10 h. The reaction was quenched with saturated aqueous
NaHCO3, and EtOAc (50 mL). After separation, the organic
phase was washed with saturated aqueous NaHCO3, brine, dried
(anhydrous Na2SO4), filtered and concentrated in vacuo. The
residue was purified by column chromatography (silica gel,
EtOAc/PE, 1:100) to afford 19 (0.73 g, 95%) as a white solid. m.
4.18. Pitavastatin Calcium (1)5j
To a solution of 21 (0.24 g, 0.5 mmol) in acetonitrile (5 mL)
o
at 40 C was added 4 M HCl (0.15 mL, 0.6 mmol). The reaction
mixture was stirred for 2 h and cooled to 0 oC, followed by
addition of 4 M NaOH until PH = 12.0. Then the mixture was
o
stirred at 0 C for 30 min before addition of 2 M HCl until PH =
o
o
1
p 156-157 C, lit.6d m. p 144-144.3 C; H NMR (400 MHz,
CDCl3) δ 10.06 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.23-7.76 (m,
1H), 7.44 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 6.8 Hz, 1H), 7.33-7.37
(m, 2H), 7.28 (s, 1H), 7.24 (s, 1H), 3.19-3.25 (m, 1H), 1.37-1.41
(m, 2H), 1.09-1.12 (m, 2H); MS (ESI): m/z 292 (M + H+).
9. The acetonitrile was evaporated under reduced pressure and
the residue was dissolved in H2O (2 mL). To the clear solution
was added a solution of 5% CaCl2. 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 1 (0.18 g, 85%) as a white
o
powder. m. p 205-210 C (decomposition); [α]2D5 +23.0 (c 0.7,
16 4.15. (2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)methanol
CH3CN:H2O = 1:1), lit.5j m. p 225-235 C (decomposition); [α]2D0
o
(20)5e
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
+23.2 (c 1.0, CH3CN:H2O = 1:1); 1H NMR (400 MHz, DMSO) δ
7.83 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.23-7.38 (m,
6H), 6.46 (d, J = 16.0 Hz, 1H), 5.55 (dd, J = 5.2, 16.0 Hz, 1H),
4.91 (br s, 1H), 4.10 (q, J = 5.6 Hz, 1H), 3.60-3.63 (m, 1H), 2.52
(m, 1H), 2.04 (dd, J = 3.6, 15.6 Hz, 1H), 1.88 (dd, J = 8.0, 15.2
Hz, 1H), 1.36-1.44 (m, 1H), 1.15-1.23 (m, 2H), 1.06-1.12 (m,
1H), 1.00-1.03 (m, 2H); 13C NMR (100 MHz, DMSO): δ 177.7,
160.9, 160.6, 147.2(d, J = 9.0 Hz,), 146.1, 143.9, 142.3, 133.2,
132.4, 132.3, 132.1, 132.0, 129.8, 129.2, 128.5, 125.9, 125.8,
125.0, 123.5, 115.6 (d, J = 4.5 Hz), 115.4 (d, J = 3.8 Hz), 79.3,
69.0, 67.6, 65.7, 44.6, 43.9, 15.6, 14.6, 14.4, 10.9 (d, J = 8.9 Hz).
To a solution of 19 (0.5 g, 1.7 mmol) in EtOH (10 mL) was
added borohydride anion exchange resin (BER). The reaction
mixture was stirred at room temperature for 3 h. The mixture was
filtered through Celite and concentrated in vacuo to afford 20
(0.5 g, quant.) as a white solid. The material was carried on
o
without further purification. mp 129-130 C, lit.5e m. p 133.3-
134.7 oC; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.4 Hz, 2H),
7.60-7.64 (m, 1H), 7.29-7.38 (m, 4H), 7.21 (t, J = 8.8 Hz, 2H),
4.75 (s, 2H), 2.56-2.62 (m, 1H), 1.63 (br s, 1H), 1.36-1.40 (m,
2H), 1.08-1.12 (m, 2H); MS (ESI): m/z 294 (M + H+).
4.16. Triphenylphosphoniumtetrafluoroborate salt (4)
References and notes
To a solution of 20 (0.5 g, 1.7 mmol) in MeCN (10 mL) was
added hydrogen triphenylphosphonium tetrafluoroborate (0.6 g,
1.7 mmol). The reaction mixture was refluxed for 15 h. The
mixture was concentrated in vacuo. The residue was
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33
34
recrystallized from CH2Cl2/MTBE to yield 4 (0.81 g, 76%) as a
o
1
35
36
37
38
39
40
41
42
43
44
45
yellow solid. m. p: 248-250 C; H NMR(400 MHz, DMSO) δ
7.85-7.88 (m, 5H), 7.72 (t, J = 7.6 Hz, 1H), 7.60 (m, 7H), 7.40 (t,
J = 7.6 Hz, 1H), 7.19-7.24 (m, 9H), 7.04 (d, J = 8.0 Hz, 1H), 5.13
(d, J = 10.4 Hz, 2H), 2.00-2.04 (m, 1H), 0.85 (m, 2H), 0.50 (m,
2H). 13C NMR (100 MHz, DMSO) δ 163.3, 160.8, 160.8, 148.0,
147.9, 146.5(d, J = 2.7 Hz), 135.1(d, J = 2.7 Hz), 133.8, 133.7,
131.4, 131.3, 131.0, 130.2, 130.1, 128.5, 128.5, 126.4, 125.8,
125.3, 125.3, 119.7, 119.6, 117.6, 116.7, 116.2, 116.0, 54.9, 25.7,
15.8, 11.3. 19F NMR (376 MHz, DMSO) δ -112.85--112.78 (m), -
148.18, -148.23; 31P NMR (162 MHz, DMSO) 20.36; HRMS
(ESI-TOF) m/z calcd for C37H30FNP+ (M+) 538.2100, found
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4.17. Methyl2-((4R,6S)-6-((E)-2-(2-cyclopropyl-4-(4-
48
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52
53
54
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56
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58
59
60
61
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63
64
65
fluorophenyl)quinolin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-
yl)acetate (21)6c
To a solution of 2 (0.2 g, 0.93 mmol) in DMSO (5 mL) was
added 4 (0.53 g, 0.85 mmol) and K2CO3 (0.23 g, 1.7 mmol)
sequentially. The reaction mixture was stirred at 70 C for 3 h.
o
The mixture was diluted with toluene (50 mL) and water (10
mL). After separation, the aqueous phase was extracted with
toluene (2 × 50 mL). The combined organic phase was washed
with water and brine, dried (anhydrous Na2SO4), filtered and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, EtOAc/PE, 1:20) to afford 21 (0.29g,
72%) as a white solid. m. p: 128-130oC; [α]D25 +18.09 (c 0.5,
CHCl3); lit.6c m. p 133 C; [α]D25 +19.2 (c 0.96, CHCl3); H NMR
o
1

8
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Table(s)
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Table 1 Bromine-induced intermolecular cyclization of homo allylic tert-butyl carbonate 6.a
Entry
X
Solvent
MeCN
PhMe
Temp(oC)
-20
Yield(%)
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Br
Br
H
27
26
33
55
52
48
-
-20
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
-20
-40
-60
-80
-40
Cl
-40
18
a All reactions were carried out in the presence of Br2 (1.5 equiv), K2CO3 (1.5 equiv) and 6a-c (2.7 mmol).
b Isolated yields

Figure(s)
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Figure 1. Structures of pitavastatin calcium (1), chiral C6-formyl side chain 2 and triphenylphosphonium bromide 3
Figure 2. Retrosynthetic analysis of pitavastatin calcium (1)

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Figure 3. Proposed mechanism for the bromine-induced cyclization
H-9
H-5
H-3
Figure 4. The NOE correlations of syn-acetonide 15

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SUPPORTING INFORMATION
Substrate Stereocontrol in Bromine-Induced Intermolecular
Cyclization: Asymmetric Synthesis of Pitavastatin Calcium
Weiqi Chen,a, b Fangjun Xiong,a Qian Liu,a Lingjun Xu,a Yan Wu,*, a and Fener Chen*,
a, b
a Department of Chemistry Fudan University, 220 Handan Road, Shanghai, 200433, People’s Republic of China
b Institutes of Biomedical Science, Fudan University, 220 Handan Road, Shanghai, 200433, People’s Republic of China
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p-BrBnO
O
O
CH3
9
MeO2C
5
H
3
H
CH3
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