Diastereoselective synthesis of pitavastatin calcium via bismuth-catalyzed two-component hemiacetal/oxa-Michael addition reaction

Article abstract of DOI:10.1039/c5ob01148e

An efficient and concise asymmetric synthesis of pitavastatin calcium (1) starting from commercially available (S)-epichlorohydrin is described. A convergent C₁ + C₆ route allowed for the assembly of the pitavastatin C₇ side chain via a Wittig reaction between phosphonium salt 2 and the enantiomerically pure C₆-formyl side chain 3. The 1,3-syn-diol acetal motif in 3 was established with excellent stereo control by a diastereoselective bismuth-promoted two-component hemiacetal/oxa-Michael addition reaction of (S)-α,β-unsaturated ketone 4 with acetaldehyde.

Full text of DOI:10.1039/c5ob01148e

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Diastereoselective synthesis of pitavastatin calcium
via bismuth-catalyzed two-component
Cite this: DOI: 10.1039/c5ob01148e
hemiacetal/oxa-Michael addition reaction†
Fangjun Xiong, Haifeng Wang, Lingjie Yan, Lingjun Xu, Yuan Tao, Yan Wu* and
Fener Chen*
An efficient and concise asymmetric synthesis of pitavastatin calcium (1) starting from commercially avail-
able (S)-epichlorohydrin is described. A convergent C1 + C6 route allowed for the assembly of the pitavas-
tatin C7 side chain via a Wittig reaction between phosphonium salt 2 and the enantiomerically pure C6-
formyl side chain 3. The 1,3-syn-diol acetal motif in 3 was established with excellent stereo control by a
diastereoselective bismuth-promoted two-component hemiacetal/oxa-Michael addition reaction of
(S)-α,β-unsaturated ketone 4 with acetaldehyde.
Received 8th June 2015,
Accepted 10th August 2015
DOI: 10.1039/c5ob01148e
www.rsc.org/obc
enhanced efficiency in its synthesis remains a challenge.
We took on the challenge and herein report our success in
Introduction
Over recent decades, the asymmetric synthesis of pitavastatin the development of a concise and efficient asymmetric
calcium (1, Fig. 1), an HMG-CoA reductase inhibitor, has synthesis of 1.
aroused continuing interest.1 As a result of its proven benefits
in both primary and secondary prevention of cardiovascular
events, many new synthetic strategies for the preparation of 1
continue to be developed.2 However, to the best of our knowl-
edge, none of the known synthetic approaches towards this
statin appear to have a commercial advantage over the cur-
rently used process using a chiral C6-formyl side chain with a
syn-1,3-diol subunit developed by Sagami Chemical Research
Center in 1993.3 Although this synthesis continues to provide
1 on an industrial scale, there are still two principal limitations
that involve the diethylmethoxyborane-mediated diastereo-
selective reduction for setting the (3R)-stereochemistry, and
using a large excess of highly toxic cyanide.4 As a consequence,
Results and discussion
The highly diastereoselective bismuth-mediated two-com-
ponent hemiacetal/oxa-Michael addition of chiral δ-hydroxyl-
α,β-unsaturated carbonyl compounds with alkyl aldehydes has
recently been reported.5 This reaction provides direct and con-
venient access to syn-1,3-diol acetals rich in synthetic potential,
as exemplified by Evans’ total synthesis of natural polyene
macrolide RK-397. Applying this strategy to 1 leads to a retro-
synthetic route as illustrated in Fig. 2.
The essential carbon–carbon double bond forming step
would be achieved by Wittig olefination of phosphonium salt 2
with (3R,5S)-C6-formyl derivative 3 for the assembly of the C7-
side chain skeleton of 1. (3R,5S)-Aldehyde 3 should be attain-
able from (S)-α,β-unsaturated ketone 4 using a diastereo-
selective bismuth-mediated two-component hemi-acetal/oxa-
Michael addition reaction. (S)-Epichlorohydrin (5) was chosen
as a readily available starting material for the synthesis of 4.
The desired quinoline phosphonium salt 2 could be provided
via Friedlander condensation of 2-amino-4′-fluorobenzophe-
none (7) with cyclopropyl α,β-unsaturated ketone 6, derived
from 1-cyclopropylethanone (8).
Fig. 1 Structure of pitavastatin calcium (1).
The synthesis of (3R,5S)-C6-formyl side chain 3 began with
commercially available (S)-(−)-epichlorohydrin (5) (Scheme 1).
Following our previously reported procedures,6 (S)-homoallylic
alcohol 9 was prepared in 92% yield by treatment of 5 with
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
People’s Republic of China. E-mail: rfchen@fudan.edu.cn, wywin8@163.com
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob01148e
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Table 1 Bismuth-catalyzed hemiacetal/oxa-Michael addition reaction
of 4a
Entry
Catalyst
Solvent
Time (h)
Yieldb (%)
drc
1
2
3
4
5
6
7
8
Bi(NO3)3
Bi(NO3)3
Bi(NO3)3
Bi(NO3)3
BiCl3
BiI3
Bi2(SO4)3
Bi(OTf)3
DCM
EtOAc
MeCN
THF
DCM
DCM
DCM
DCM
48
120
48
120
120
120
120
120
91
86
90
73
83
61
55
78
99 : 1
5 : 1
50 : 1
3 : 1
4 : 1
6 : 1
3 : 1
30 : 1
a All reactions were performed at r.t. on a 1 mmol scale. b Yield of
isolated product. c Determined by GC analysis of the crude product.
same reaction using other bismuth salt catalysts including
BiCl3, BiI3, Bi2SO4 and Bi(OTf)3, and observed that all these
catalysts gave a moderate yield of 11 and poor diastereo-
selectivity (entries 5–7), except for Bi(OTf)3 (entry 8). These
observations are now understood as the result of the thermo-
dynamic control of this reaction as pointed out by Evans et al.5
The minor diastereoisomer 11′ can be transformed into the
stable syn-1,3-dioxane 11 under the reaction conditions
(Fig. 3).
Fig. 2 Retrosynthesis of pitavastatin calcium (1).
At the outset, we tried to convert the methylketone 11 to
desired chloro-acid 12 using the bromoform reaction (NaOH/
Br2/H2O/dioxane) at 0 °C. Unfortunately, only 10% of the
desired product 12 was formed, along with 10% α-bromo by-
product 13 and 70% decarboxylation by-product 14. Significant
effort was made to optimize the reaction conditions. It was
found that the use of Br2/NaOMe/MeOH instead of NaOH/Br2/
Scheme 1 Synthesis of (S)-α,β-unsaturated ketone 4.
vinylmagnesium chloride under CuI catalysis in anhydrous
THF. The carbon elongation was completed by Horner–Wads-
worth–Emmons olefination of aldehyde 10, obtained by ozono-
lysis of 9 under standard conditions (DCM, −40 °C, 1 h),
with diethyl(2-oxopropyl)phosphonate. The (S)-α,β-unsaturated
ketone 4 was obtained as a single E isomer with an overall
yield of 73% from 9.
The stereocenter at C5 in this statin side chain was installed
by the bismuth-mediated two-component hemiacetal/oxa-
Michael addition5 of 4 and acetaldehyde (Table 1). The
diastereoselectivity of the reaction was determined by analysis
of the crude product 11. Purification by chromatography pro-
vided a 91% yield of pure 11 with a dr of >99 : 1 when using
10% mol Bi(NO3)3 as a catalyst in CH2Cl2 (entry 1). We then
examined the effects of various solvents (EtOAc, MeCN and
THF), and a dramatic decrease in the diastereoselectivity was
observed in all cases (entries 2–4). Next, we investigated the
Fig. 3 Proposed mechanism for diastereoselective Michael addition
between 4 and acetaldehyde.
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H2O/dioxane led to the formation of a 1 : 4 mixture of desired
methyl ester 15 and its α-monobromo by-product 16. No decar-
boxylation by-product 14 was detected. The mixture of 15 and
16 was directly subjected to reductive debromination with zinc
powder in glacial acetic acid at 35 °C to furnish the pure chiral
chloro-ester 15 as a single product in 90% yield over two steps
(Scheme 2).
Heating 15 with sodium benzoate at 160 °C in DMSO led to
displacement of the chloro moiety with a benzoyl group and
diester 17 was isolated in 80% yield. Methanolysis of 17 with
sodium methoxide in methanol at room temperature worked
well to afford the corresponding alcohol 18 in 87% isolated
yield. This then underwent a Parikh–Doering oxidation7 (py-
SO3, NEt3, DMSO, DCM, 0 °C, 3 h) to generate the (3R,5S)-C6-
formyl side chain 3 in 82% yield (Scheme 3).
Scheme 3 Synthesis of (3R,5S)-C6-formyl side chain 3.
Formylation of cyclopropylketone 8 in the presence of pot-
assium tert-butoxide in anhydrous THF at room temperature
proceeded smoothly to obtain the potassium enolate 19 in
quantitative yield, which directly reacted with 2-(chlorotriphe-
nylphosphoranyl) acetonitrile8 in MeOH at room temperature
to afford nitrile 6 (E/Z = 7 : 3, HPLC) in 64% isolated yield.
Under the standard Friedlander condensation conditions9
(MsOH, toluene, reflux, 13 h), the construction of the quino-
line core was realized by the reaction of 6 with 7, affording the
quinoline nitrile 20 in 87% yield. HPLC analysis of the unpuri-
fied reaction mixture indicated an E/Z ratio of 3 : 1 for the
Friedlander condensation. Cleavage of the double bond in 19
with ozone at −78 °C in MeOH/DCM, followed by reductive
workup with NaBH4, provided quinoline alcohol 21 in 74%
yield. Chlorination10 of 21 was carried out with mesyl chloride
in the presence of trimethylamine in DCM to give quinoline
chloride 22 quantitatively. Subsequent treatment with PPh3 in
acetonitrile formed the corresponding phosphonium salt 2 in
95% yield (Scheme 4).
With efficient syntheses of both 2 and 3 secured, the Wittig
coupling of the two building blocks was undertaken. The alde-
hyde 3 and phosphonium salt 2 were treated with anhydrous
K2CO3 in DMSO at 70 °C,11 and crude 23 was obtained as a
mixture of E/Z > 17 : 1, determined by NMR spectroscopy.
Chromatographic separation of the resulting E/Z olefin
Scheme 2 Synthesis of (3R,5S)-chloro-ester 15.
Scheme 4 Synthesis of phosphonium salt 2.
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tion of 10 in THF was added dropwise within 10 min at 0 °C,
stirring was continued for 1 h at r.t. The solvent was evapor-
ated in vacuo and water (20 mL) was added, extracted with
DCM (20 mL × 3), washed with 10% aq. NaHCO3 and sat. aq.
NH4Cl, dried over Na2SO4 and evaporated in vacuo to afford 4
(1.18 g, 73%) as a yellow oil, which could be used in the next
step without further purification. Analytical sample was
achieved by flash chromatography (petroleum ether/EtOAc =
5 : 1). [α]2D9 = −11.3 (c 1, MeOH). FT-IR (ATR): ν 3283, 1713,
1435, 1118, 720, 693 cm−1. 1H NMR (400 MHz, CDCl3): δ = 6.81
(dt, J = 16, 7.2 Hz, 1H), 6.18 (d, J = 16.0 Hz, 1H), 3.99 (s, 1H),
3.63 (dd, J = 11.2, 4 Hz, 1H), 3.52 (dd, J = 11.2, 6.4 Hz, 1H),
2.65–2.34 (m, 3H), 2.26 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
= 198.4, 142.5, 133.8, 70.2, 49.4, 37.2, 27.1 MS (ESI): m/z = 185
[M + Na]+. HRMS (ESI) calcd for C7H12ClO2 [M + H]+ 163.0520,
found 163.0520.
1-((2S,4R,6S)-6-(Chloromethyl)-2-methyl-1,3-dioxan-4-yl)-
propan-2-one (11)
To a suspension of 4 (1.62 g, 10 mmol), bismuth nitrate penta-
hydrate (0.48 g, 1 mmol) in DCM (25 mL) was added freshly
prepared acetaldehyde (2.20 g, 50 mmol) and stirred at r.t. for
48 h. The reaction mixture was filtered through a short
column of silica gel and evaporated in vacuo to afford 11
(1.87 g, 91%) as a clear yellow oil. [α]2D6 = +6.4 (c 1, MeOH).
Scheme 5 Synthesis of pitavastatin calcium (1).
FT-IR (ATR): ν 2871, 1713, 1123, 937 693 cm−1 1H NMR
.
isomers provided (E)-23 in 76% yield with >99% isomeric
purity. Finally, pitavastatin calcium (1) was prepared by de-
protection of 23 in the presence of TFA, basic hydrolysis with
NaOH, and calcium salt formation with CaCl2, in a one-pot
protocol, in an 83% yield over three steps (Scheme 5).
(400 MHz, CDCl3): δ = 4.74 (q, J = 5.2 Hz, 1H), 4.05–4.16 (m,
1H), 3.82–3.90 (m, 1H), 3.55 (dd, J = 11.2, 6.0 Hz, 1H), 3.45 (dd,
J = 11.2, 5.6 Hz, 1H), 2.79 (dd, J = 16.4, 7.2 Hz, 1H), 2.50 (dd,
J = 16.4, 5.6 Hz, 1H), 2.18 (s, 3H), 1.79–1.70 (m, 1H), 1.36–1.24
(m, 4H). 13C NMR (100 MHz, CDCl3): δ = 206.2, 98.8, 75.5,
71.9, 49.3, 46.3, 33.9, 31.1, 20.9. MS (EI): m/z = 205 [M − H]+.
HRMS (ESI) calcd for C9H16ClO3 [M + H]+ 207.0782, found
207.0772.
Experimental
All reagents and solvents 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 iS5 FT-IR spectrometer,
optical rotations were measured by using a JASCO P1020
digital polarimeter. EI-MS were recorded on an Agilent 6890N/
5975 spectrometer and ESI-MS were recorded on a Waters
Micromass Quattro Micro spectrometer. HRMS were recorded
on a Bruker micrOTOF spectrometer.
Methyl 1-((4R,6S)-6-(chloromethyl)-2-methyl-1,3-dioxan-4-yl)-
acetate (15)
To a stirred solution of 11 (2.00 g, 10 mmol), MeONa (5.40 g,
0.1 mol) in MeOH (50 mL) was added Br2 (5.60 g, 35 mmol)
dropwise at −40 °C within 10 min, stirring was continued for
30 min and then poured into sat. aq. NaHSO3 (50 mL), the
reaction mixture was adjusted to pH 6–8 with Na2SO3. MeOH
was removed in vacuo, extracted with EtOAc (25 mL × 3) and
evaporated in vacuo. To the residue was added zinc dust (1.3 g,
20 mmol) and glacial acetic acid (20 mL), the stirring was con-
(S,E)-7-Chloro-6-hydroxyhept-3-en-2-one (4)
To a solution of (S)-1-chloropent-4-en-2-ol (1.20 g, 10 mmol) in tinued for 12 h at 35 °C, then water (20 mL) was added and
DCM (25 mL) was bubbled with O3 (1 ml min−1) at −40 °C for extracted with DCM (20 mL × 3), washed with sat. aq. NaHCO3,
10 min, and purged with O2 for 1 min, then dimethylsulfide dried with Na2SO4 and evaporated in vacuo to afford 15 (1.95 g,
(2 mL) was added under stirring and the reaction mixture was 90%) as a yellow oil. [α]2D5 = +5.6 (c 1, CHCl3). FT-IR (ATR): ν
warmed to r.t., the solvent was removed in vacuo and THF 3248, 2953, 1737, 1123, 1028 cm−1. 1H NMR (400 MHz, CDCl3):
(10 mL) was added. This THF solution of 10 was directly used δ = 4.86–4.70 (m, 1H), 4.25–4.02 (m, 1H), 4.02–3.84 (m, 1H),
in the next step.
3.72 (s, 3H), 3.59 (dd, J = 11.2, 6.0 Hz, 1H), 3.49 (dd, J = 11.2,
To a stirring solution of t-BuOK (1.12 g, 10 mmol) in dry 5.6 Hz, 1H), 2.68 (dd, J = 15.6, 7.2 Hz, 1H), 2.49 (dd, J = 15.6,
THF (20 mL) was added diethyl(2-oxopropyl)phosphonate 6.0 Hz, 1H), 1.81 (d, J = 12.8 Hz, 1H), 1.46–1.26 (m, 4H). 13C
(1.94 g, 10 mmol) at 0 °C and stirred for 30 min, then the solu- NMR (100 MHz, CDCl3): δ = 171.0, 98.9, 75.5, 72.3, 51.8, 46.3,
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40.6, 33.8, 20.9. MS (EI): m/z = 221 [M − H]+. HRMS (ESI) calcd Potassium 3-cyclopropyl-3-oxoprop-1-en-1-olate (19)
for C9H16ClO4 [M + H]+ 223.0732, found 223.0733.
To a solution of 1-cyclopropylethanone (4.2 g, 50 mmol),
t-BuOK (5.6 g, 50 mmol) in dry THF (50 mL) was added ethyl
((4S,6R)-6-(2-Methoxy-2-oxoethyl)-2-methyl-1,3-dioxan-4-yl)-
methyl benzoate (17)
formate (7.4 g, 0.1 mol) dropwise within 5 min, the stirring
was continued for 3 h and evaporated in vacuo to afford 19
(7.5 g, 100%) as a yellow solid.
A mixture of 15 (1.11 g, 5 mmol) and NaOBz (1.44 g, 10 mmol)
in DMSO (10 mL) was stirred at 160 °C for 4 h under a N2
atmosphere. The reaction mixture was cooled to r.t. and water
(50 mL) was added, extracted with EtOAc/petroleum ether
(1 : 1, 40 mL × 3), the combined organic phase was washed
with water, dried with Na2SO4 and purified by using a filter
through a short column of silica gel to afford 17 (1.23 g, 80%)
as a light brown syrup. [α]D20 = +4.7 (c 1, MeOH). FT-IR (ATR):
5-Cyclopropyl-5-oxopent-2-enenitrile (6)
A mixture of 18 (1.5 g, 10 mmol) and (cyanomethyl)triphenyl-
phosphonium chloride (3.37 g, 10 mmol) in MeOH (20 mL)
was stirred at r.t. for 24 h. The solvent was evaporated in vacuo
and purified by silica column chromatography (petroleum
ether/EtOAc = 5 : 1) to afford 6 (0.86 g, 64%) as an orange oil
(E/Z = 7 : 3, HPLC). FT-IR (ATR): ν 3341, 3008, 2225, 1693, 1385,
ν 2950, 1716, 1270, 1111, 710 cm−1 1H NMR (400 MHz,
.
1
1062 cm−1. H NMR (400 MHz, CDCl3): δ = 6.93–6.46 (m, 1H),
CDCl3): δ = 8.06 (d, J = 7.6 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.44
(t, J = 7.6 Hz, 2H), 4.79 (q, J = 5.2 Hz, 1H), 4.44–4.27 (m, 2H),
4.19–4.10 (m, 1H), 4.00–4.10 (m, 1H), 3.70 (s, 3H), 2.66 (dd, J =
15.6, 7.2 Hz, 1H), 2.48 (dd, J = 15.6, 6.0 Hz, 1H), 1.69 (d, J =
12.8 Hz, 1H), 1.47 (q, J = 12 Hz, 1H), 1.35 (d, J = 5.2 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ = 171.1, 166.4, 133.1, 129.9,
129.8, 128.4, 98.8, 73.8, 72.3, 66.8, 51.8, 40.7, 32.6, 21.0. MS
(EI): m/z = 293 [M − CH3]+. HRMS (ESI) calcd for C16H21O6
[M + H]+ 309.1333, found 309.1344.
5.57–5.35 (m, 1H), 3.79–3.26 (m, 2H), 2.22–1.77 (m, 1H),
1.15–0.80 (m, 4H). 13C NMR (100 MHz, CDCl3): δ = 205.4,
205.4, 198.8, 147.4, 146.9, 133.1, 131.7, 116.9, 115.9, 115.7,
103.2, 102.2, 46.6, 45.1, 20.9, 20.8, 20.4, 20.3, 11.9, 11.8, 11.7.
MS (EI): m/z = 135 [M]+. HRMS (ESI) calcd for C8H10N1O1
[M + H]+ 136.0757, found 136.0756.
3-(2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)acrylonitrile (20)
A mixture of 6 (1.60 g, 12 mmol), 2-amino-4′-fluorobenzophe-
none (2.14 g, 10 mmol) and methanesulfonic acid (100 μl) in
toluene (50 mL) was stirred under reflux for 13 h, the solvent
was removed in vacuo and the residue was purified by silica
column chromatography (petroleum ether/EtOAc = 5 : 1) to
afford 20 (2.73 g, 87%) as a yellow crystalline solid. (E/Z = 3 : 1,
HPLC). The analytic samples of E and Z isomers were achieved
by preparative HPLC by using Venusil XBP-C18 column with
the eluent MeOH/H2O = 80 : 20.
Methyl 2-((4R,6S)-6-(hydroxymethyl)-2-methyl-1,3-dioxan-4-yl)-
acetate (18)
A mixture of 17 (310 mg, 1 mmol) and NaOMe (10 mg,
0.2 mmol) in MeOH (5 mL) was stirred at r.t. for 1 h, and then
sat. aq. NH4Cl (1 mL) was added, the solution was washed
with PE (10 mL × 3) and the methanolic phase was evaporated
in vacuo, then water (10 mL) was added and extracted with
DCM (20 mL × 3), dried (Na2SO4) and evaporated in vacuo to
afford 18 (178 mg, 87%) as a colorless oil. [α]2D0 = +11.5 (c 1,
E-Isomer. Almost white powder. mp 169–172 °C (lit.12 mp
145–146 °C). FT-IR (ATR): ν 3072, 3002, 2221, 1512, 1488, 1218,
1
CHCl3). FT-IR (ATR): ν 3464, 2953, 2871, 1731, 1129 cm−1. H
1162, 761, 738 cm−1 1H NMR (400 MHz, CDCl3) δ 7.97 (d,
.
NMR (400 MHz, CDCl3): δ = 4.77 (q, J = 5.2 Hz, 1H), 4.15–4.07
(m, 1H), 3.84–3.77 (m, 1H), 3.69 (s, 3H), 3.65 (dd, J = 11.6, 2.8
Hz, 1H), 3.56 (dd, J = 11.6, 6.4 Hz, 1H), 2.64 (dd, J = 15.6,
7.2 Hz, 1H), 2.45 (dd, J = 15.6, 6.0 Hz, 1H), 1.72 (br, 1H),
1.56–1.50 (m, 1H), 1.41 (dd, J = 24, 11.2 Hz, 1H), 1.33 (d, J = 5.2
Hz, 3H). 13C NMR (100 MHz, CDCl3): δ = 171.1, 105.8, 98.7,
76.3, 72.3, 65.5, 51.8, 40.7, 31.8, 21.0. MS (EI): m/z = 203
[M − H]+. HRMS (ESI) calcd for C9H17O5 [M + H]+ 205.1071,
found 205.1076.
J = 8.4 Hz, 1H), 7.70–7.65 (m, 1H), 7.52 (d, J = 17.0 Hz, 1H),
7.40–7.35 (m, 2H), 7.29–7.18 (m, 5H), 5.58 (d, J = 17.0 Hz, 1H),
2.40–2.17 (m, 1H), 1.49–1.38 (m, 2H), 1.14–1.08 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ 164.2, 161.7, 159.3, 148.1, 147.7,
146.5, 131.8, 131.7, 131.6, 131.5, 130.5, 129.2, 126.5, 126.4,
126.0, 125.7, 117.6, 116.3, 116.1, 104.1, 16.6, 10.6. MS (EI):
m/z = 313 [M − H]+.
Z-Isomer. Almost white powder. mp 127–129 °C. FT-IR
(ATR): ν 3059, 3013, 2871, 2244, 2214, 1489, 1218, 829,
765 cm−1. 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.4 Hz, 1H),
7.67 (t, J = 6.9 Hz, 1H), 7.45–7.27 (m, 5H), 7.20 (t, J = 8.6 Hz,
2H), 5.63 (d, J = 11.5 Hz, 1H), 2.23–2.11 (m, 1H), 1.48–1.33 (m,
2H), 1.13–1.06 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 164.1,
161.6, 159.2, 149.1, 148.1, 145.7, 132.0, 131.8, 131.7, 130.1,
129.2, 126.6, 126.1, 126.1, 125.5, 116.0, 115.8, 115.6, 104.8,
16.1, 10.9. MS (EI): m/z = 313 [M − H]+.
Methyl 2-((4R,6S)-6-formyl-2-methyl-1,3-dioxan-4-yl)acetate (3)
A solution of Py·SO3 (0.5 g, 3 mmol) in DMSO (2 mL) was
stirred at 0 °C for 30 min, and then the solution of 18 (200 mg,
1 mmol) and Et3N (600 mg, 6 mmol) in DCM (2 mL) was
added, the reaction mixture was stirred for an additional 3 h
and water (20 mL) was added, extracted with DCM (20 mL × 3),
washed with brine (10 mL), dried with Na2SO4 and evaporated
in vacuo to give 3 (159 mg, 82%) as a yellow syrup. This
(2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)methanol (21)
instable material should be used immediately in the next step To a stirred solution of 20 (314 mg, 1 mmol) in MeOH (10 mL)
without further purification. (EI): m/z = 201 [M − H]+.
and DCM (10 mL) was bubbled with ozone (0.5 ml min−1) at
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−78 °C. The reaction was carefully monitored by TLC (ca. 1H), 1.04 (dd, J = 8.0, 3.2 Hz, 2H). 13C NMR (100 MHz, CDCl3):
45 min), then NaBH4 (80 mg, 2 mmol) was added and the reac- δ = 171.3, 163.6, 161.2, 160.8, 147.0, 144.5, 137.1, 133.5, 132.2,
tion was allowed to reach r.t. The stirring was continued for 132.1, 131.9, 131.8, 129.3, 129.0, 128.9, 126.6, 126.2, 125.5,
30 min, the solvent was evaporated in vacuo, and the residue 115.5, 115.4, 115.3, 115.3, 98.7, 76.4, 72.4, 51.9, 40.7, 36.2,
was purified by silica column chromatography (petroleum 21.1, 16.1, 10.6, 10.3. MS (ESI): m/z = 462 [M + H]+. HRMS (ESI)
ether/EtOAc = 4 : 1) to afford 21 (214 mg, 73%) as a colorless calcd for C28H29F1N1O4 [M + H]+ 462.2075, found 462.2074.
crystal. mp 131–133 °C (lit.12 mp 132–133 °C). FT-IR (ATR): ν
Pitavastatin calcium (1)
3419, 3065, 3008, 2899, 2738, 1577, 1510, 1494, 1223, 981, 840,
1
771 cm−1. H NMR (400 MHz, CDCl3): δ = 7.97 (d, J = 8.4 Hz,
A mixture of 22 (230 mg, 0.5 mmol), TFA (2 mL) and water
(0.2 mL) was stirred at r.t. for 1 h, the TFA was removed in
vacuo, then THF (2 mL) and 1 M aq. NaOH (0.5 mL) were
added and stirred at r.t. for 2 h, the organic solvent was
removed in vacuo and water (2 mL) was added, 5% aq. CaCl2
(2 mL) was added dropwise and stirring was continued for 1 h,
the precipitant was collected by filtration and dried in vacuo to
afford 1 (183 mg, 83%) as a white solid. mp 214 °C (dec.), [α]D17
= +22.3 (c 1, MeCN/H2O 1 : 1) (lit.2e [α]D20 = +23.1 (c 1, MeCN/
1H), 7.64–7.60 (m, 1H), 7.38–7.21 (m, 6H), 4.75 (s, 2H),
2.64–2.54 (m, 1H), 1.63 (br, 1H), 1.42–1.34 (m, 2H), 1.15–1.06
(m, 2H). MS (EI): m/z = 293 [M]+.
3-(Chloromethyl)-2-cyclopropyl-4-(4-fluorophenyl)quinoline (22)
To a stirred solution of 21 (300 mg, 1 mmol), Et3N (200 mg,
2 mmol) in DCM (5 mL) was added mesyl chloride (228 mg,
2 mmol) at r.t., the stirring was continued for 2 h. Then DCM
(20 mL) was added, washed with water, dried with Na2SO4,
evaporated in vacuo to afford 22 (320 mg, 100%) as a yellow
crystalline solid, mp 126–130 °C. FT-IR (ATR): ν 3014, 1507,
1494, 1221, 839, 762, 742 cm−1. 1H NMR (400 MHz, CDCl3): δ =
7.98 (d, J = 8.4 Hz, 1H), 7.69–7.58 (m, 1H), 7.41–7.23 (m, 6H),
4.69 (s, 2H), 2.66–2.32 (m, 1H), 1.43–1.35 (m, 2H), 1.17–1.10
(m, 2H). 13C NMR (100 MHz, CDCl3): δ = 164.0, 161.7, 161.5,
147.5, 146.9, 131.8, 131.7, 131.3, 131.2, 129.6, 129.0, 127.2,
126.5, 126.1, 125.8, 115.8, 115.6, 41.5, 14.6, 9.8. MS (EI): m/z =
310 [M − H]+. HRMS (ESI) calcd for C19H16ClF1N1 [M + H]+
312.0950, found 312.0946.
1
H2O 1 : 1)). H NMR (400 MHz, DMSO-d6): δ = 7.84 (d, J = 8.0
Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.40–7.22 (m, 6H), 6.48 (d, J =
16.0 Hz, 1H), 5.58 (dd, J = 16.0, 5.2 Hz, 1H), 4.91 (br, 1H), 4.12
(q, J = 5.6 Hz, 1H), 3.75–3.49 (m, 1H), 2.07 (dd, J = 15.2, 3.6 Hz,
1H), 1.91 (dd, J = 15.2, 8.0 Hz, 1H), 1.54–1.30 (m, 1H),
1.25–1.15 (m, 1H), 1.12–1.06 (m, 1H), 1.05–0.97 (m, 2H). 13C
NMR (100 MHz, DMSO-d6): δ = 178.7, 162.8, 160.6, 160.4,
146.0, 143.7, 142.2, 133.1, 132.2, 132.1, 131.9, 131.8, 129.7,
128.8, 128.4, 125.7, 125.7, 125.6, 123.2, 115.4, 115.3, 115.2,
115.1, 68.9, 65.7, 44.2, 43.9, 15.4, 10.8, 10.7.
((2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)methyl)tri-
phenylphosphonium chloride (2)
Conclusions
A mixture of 22 (311 mg, 1 mmol) and triphenylphosphine
(262 mg, 1 mmol) in MeCN (10 mL) was stirred under reflux
for 24 h and evaporated to dryness to afford 2 (544 mg, 95%),
the crude product was used in the next step without further
purification. FT-IR (ATR): ν 3014, 1507, 1494, 1221, 839, 762,
742 cm−1. MS (ESI): m/z = 538 [M − Cl]+. HRMS (ESI) calcd for
C37H31F1N1P [M − Cl]+ 538.2094, found 538.2094.
In summary, we have successfully implemented a stereocon-
trolled preparation of the key chiral C6-formyl building block
with a 1,3-diol pattern starting from commercially available
(S)-epichlorohydrin using a bismuth-catalyzed two-component
hemiacetal/oxa-Michael addition reaction as the key step. This
process constitutes a practical and concise synthesis of pitavas-
tatin calcium (1), and offers a general and economic synthetic
route to the statin-family HMG-CoA reductase inhibitors.
Methyl 2-((4R,6S)-6-((E)-2-(2-cyclopropyl-4-(4-fluorophenyl)-
quinolin-3-yl)vinyl)-2-methyl-1,3-dioxan-4-yl)acetate (23)
A mixture of 3 (159 mg, 0.8 mmol), 2 (460 mg, 0.8 mmol),
anhydrous K2CO3 (220 mg, 1.6 mmol) in DMSO (5 mL) was
stirred at 70 °C for 2 h under a N2 atmosphere, and cooled to
r.t., water (20 mL) was added. The reaction mixture was
extracted with DCM (20 × 3), dried with Na2SO4 and evaporated
in vacuo to dryness. The residue was purified by silica column
chromatography (petroleum ether/EtOAc = 10 : 1) to afford 23
(350 mg, 76%) as a colorless syrup. [α]2D0 = +8.6 (c 0.84, CHCl3).
FT-IR (ATR): ν 3361, 3059, 2974, 1510, 1489, 1432, 1220, 1108,
Notes and references
1 (a) Z. Časar, Curr. Org. Chem., 2010, 14, 816–845;
(b) J. Wang, M. Sanchez-Rosello, J. L. Acena, C. del Pozo,
A. E. Sorochinsky, S. Fustero, V. A. Soloshonok and H. Liu,
Chem. Rev., 2014, 114, 2432–2506.
2 (a) S. Takano, T. Kamikubo, T. Sugihara, M. Suzuki and
K. Ogasawara, Tetrahedron: Asymmetry, 1993, 4, 201–204;
(b) K. Takahashi, T. Minami, Y. Ohara and T. Hiyama, Tetra-
hedron Lett., 1993, 34, 8263–8266; (c) N. Miyachi,
Y. Yanagawa, H. Iwasaki, Y. Ohara and T. Hiyama, Tetra-
hedron Lett., 1993, 34, 8267–8270; (d) T. Hiyama,
T. Minami, Y. Yanagawa and Y. Ohara, WO Pat. 9511898,
1995; Chem. Abst., 1995, 123, 313782; (e) M. Suzuki,
Y. Yanagawa, H. Iwasaki, H. Kanda, K. Yanagihara,
1
744, 687 cm−1. H NMR (400 MHz, CDCl3): δ = 7.95 (d, J = 8.4
Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.38–7.27 (m, 2H), 7.24–7.11
(m, 4H), 6.59 (d, J = 16.4 Hz, 1H), 5.60 (dd, J = 16.4, 6.0 Hz,
1H), 4.75 (q, J = 5.2 Hz, 1H), 4.19–4.10 (m, 1H), 4.10–4.00 (m,
1H), 3.71 (s, 3H), 2.62 (dd, J = 15.6, 6.8 Hz, 1H), 2.40 (dd, J =
15.4, 6.0 Hz, 2H), 1.44–1.23 (m, 7H), 1.11 (dd, J = 24, 11.2 Hz,
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Paper
H. Matsumoto, Y. Ohara, Y. Yazaki and R. Sakoda, Bioorg.
Med. Chem. Lett., 1999, 9, 2977–2982; (f) M. Acemoglu,
A. Brodbeck, A. Garcia, D. Grimier, M. Hassel, B. Riss and
R. Schreiber, Helv. Chim. Acta, 2007, 90, 1069–1081;
(g) J. Fabris, Z. Časar and I. G. Smilović, Synthesis, 2012,
1700–1710; (h) J. Fabris, Z. Časar, I. G. Smilović and
M. Črnugeljb, Synthesis, 2014, 2333–2346.
7 (a) N. S. Joshi, A. S. Khile, Y. B. Kajale and H. H. Kamble,
WO Pat. 2008059519, 2008; Chem. Abstr., 2008, 148, 585906;
(b) J. R. Parikh and W. v. E. Doering, J. Am. Chem. Soc.,
1967, 89, 5505–5507.
8 R. A. Abramovitch and B. W. Cue, J. Org. Chem., 1980, 45,
5316–5319.
9 K. Nagashima, T. Fukumoto, T. Hayashibara and
M. Torihara, WO Pat. 2004041787, 2004; Chem. Abstr., 2004,
140, 423596.
3 T. Hyama, T. Minami, S. Yanagawa and Y. Obara, JP Pat.
05310700, 1993; Chem. Abstr., 1994, 120, 244704.
4 (a) H. I. Shin, B. S. Choi, K. K. Lee, H. Choi, J. H. Chang, 10 Y. M. Zhang, X. D. Fan, S. M. Yang, R. H. Scannevin,
K. W. Lee, D. H. Nam and N. S. Kim, Synthesis, 2004, 2629–
2632; (b) H. Choi and H. Shin, Synlett, 2008, 1523–1525;
S. L. Burke, K. J. Rhodes and P. F. Jackson, Bioorg. Med.
Chem. Lett., 2008, 18, 405–408.
(c) R. Sun, F. Q. Zhang,T. J. Du, L. P. Fang and F. M. Meng, 11 S. R. Manne, K. R. Bairy, K. R. Chepyala, K. K. Muppa,
CN Pat. 102180862, 2011; Chem. Abstr., 2011, 155, 457681.
5 P. A. Evans, A. Grisin and M. J. Lawler, J. Am. Chem. Soc.,
2012, 134, 2856–2859.
6 F. J. Xiong, J. Li, X. F. Chen, W. X. Chen and F. E. Chen,
Tetrahedron: Asymmetry, 2014, 25, 1205–1208.
R. T. Srinivasan, E. Sajja and S. R. Maramreddy,
Orient. J. Chem., 2007, 23, 559–564.
12 M. Suzuki, H. Iwasaki, Y. Fujikawa, M. Kitahara,
M. Sakashita and R. Sakoda, Bioorg. Med. Chem., 2001, 9,
2727–2743.
This journal is © The Royal Society of Chemistry 2015
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