A new approach to the total synthesis of rosuvastatin

Article abstract of DOI:10.1002/ejoc.200700813

A new multi-step synthesis of the lipid-lowering agent rosuvastatin, involving two homogeneously catalyzed reaction steps, is described. The key building block, N-[4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl]-N- methylmethanesulfonamide (2), was prepared by Pd-catalyzed formylation with CO/H₂ (1:1, 50 bar, phosphane ligand/substrate ratio of 1:10). Several alternative pathways for the preparation of 2 were also tested, but were found to be inferior. Rosuvastatin precursor 1 was assembled by Wittig coupling of aldehyde 2 and ylide (R)-3, derived from a Rucatalyzed asymmetric hydrogenation. The second stereogenic center was finally created by stereoselective reduction with Et₂BOMe and NaBH₄ to afford rosuvastatin ethyl ester. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700813

FULL PAPER
DOI: 10.1002/ejoc.200700813
A New Approach to the Total Synthesis of Rosuvastatin[‡]
Natalia Andrushko,*[a] Vasyl Andrushko,[a] Gerd König,[b] Anke Spannenberg,[a] and
Armin Börner*[a,c]
Keywords: Drug design / Statins / Synthetic methods / Homogeneous catalysis / 2-Aminopyrimidines / Hydroformylation /
Rosuvastatin
A new multi-step synthesis of the lipid-lowering agent rosu-
vastatin, involving two homogeneously catalyzed reaction
steps, is described. The key building block, N-[4-(4-fluoro-
phenyl)-5-formyl-6-isopropylpyrimidin-2-yl]-N-methylmeth-
anesulfonamide (2), was prepared by Pd-catalyzed for-
mylation with CO/H2 (1:1, 50 bar, phosphane ligand/sub-
strate ratio of 1:10). Several alternative pathways for the
preparation of 2 were also tested, but were found to be in-
ferior. Rosuvastatin precursor 1 was assembled by Wittig
coupling of aldehyde 2 and ylide (R)-3, derived from a Ru-
catalyzed asymmetric hydrogenation. The second ste-
reogenic center was finally created by stereoselective re-
duction with Et2BOMe and NaBH4 to afford rosuvastatin
ethyl ester.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Statins such as atorvastatin[1,2] and rosuvastatin[3] are velopment of new and efficient strategies for their synthesis,
very effective inhibitors[4] of the enzyme 3-hydroxy-3-meth- capable of providing the drug in a cheaper and more conve-
ylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) nient manner, is therefore extremely important and rel-
and are the most powerful lipid-lowering agents in use as evant. The newest of the statins, rosuvastatin,[6] has been
pharmaceutical agents for reducing cholesterol levels in called a super-statin, because it appears to reduce low-den-
people with or at risk of cardiovascular disease.[5] The de- sity lipoprotein (LDL) cholesterol to a greater degree than
Scheme 1. Retrosynthetic analysis of rosuvastatin calcium salt [Alk = Et as follows below or other alkyl group could be used; tert-
butyldiphenylsilyl (TBDPS) was considered as protecting group (PG)].
[‡] Part IV of a series dedicated to the synthesis of statins. Part III:
rivals in its class without additional adverse effects. Rosuva-
Ref.[14]
statin is approved for the treatment of elevated LDL choles-
[a] Leibniz-Institut für Katalyse an der Universität Rostock e.V.,
Albert-Einstein-Str. 29a, 18059 Rostock, Germany
E-mail: natalia.andrushko@catalysis.de
[b] Ratiopharm GmbH,
terol (dyslipidemia),[7] total cholesterol (hypercholesterole-
mia),[8] and/or triglycerides (hypertriglyceridemia).[6]
From the retrosynthetic analysis of rosuvastatin calcium
salt depicted in Scheme 1 it follows that the possible precur-
sor 1 with a stereogenic center at C-3 must have the indi-
cated (R) configuration. It is obvious that this chalcone de-
Graf-Arco-Str. 3, 89070 Ulm, Germany
[c] Institut für Chemie der Universität Rostock,
Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax: +49-0381-1281-5202
E-mail: armin.boerner@catalysis.de
Eur. J. Org. Chem. 2008, 847–853
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
847

N. Andrushko, V. Andrushko, G. König, A. Spannenberg, A. Börner
FULL PAPER
rivative might be easily assembled through Wittig coupling diketones (Scheme 3). We synthesized 1,3-diketone 7 by a
of aldehyde 2 and ylide (R)-3. The second stereogenic center Claisen-type acylation of 4-fluoroacetophenone with
at C-5 in rosuvastatin can later be created by diastereoselec- iPrCO2Et in the presence of NaH in Et2O at room tempera-
tive reduction of the oxo group as described in the litera- ture in 70% yield.[17] An alternative approach in dioxane
ture.[9] Protected hydroxy ylides of type 3 were formulated at 80–90 °C for 4 h gave the product only in 51% yield.[18]
as possible building blocks[10] for the preparation of 1 as Acylation of 3-methylbutan-2-one with 4-fluorobenzoyl
soon as Wittig coupling could be performed with the corre- chloride in the presence of NaNH2 as a base in Et2O at
sponding aldehyde 2 without or in the presence of a strong room temperature afforded 1,3-diketone 7 in 35% yield.[19]
base[11] and subsequent cleavage of the HO-protective
group.[12] Nowadays this synthetic pathway is commonly
employed for the preparation of rosuvastatin.[9,13]
In a parallel paper we report on the highly enantioselec-
tive hydrogenation of ethyl 5,5-dimethoxy-3-oxopentanoate
(5) to ethyl (R)-3-hydroxy-5,5-dimethoxypentanoate [(R)-4]
as one of the alternative pathways for the synthesis of a
precursor for the chiral side chain of rosuvastatin.[14] The
transformation of alcohol (R)-4 into ylide (R)-3 is also con-
sidered.
On the other hand, it is known that aldehyde 2 can be
prepared by chemoselective catalytic oxidation of alcohol 9
Scheme 3. Synthesis of 1,3-diketone 7 and enone 11 and their cycli-
with NaOCl as an oxidant in the presence of catalytic
amounts of 2,2,6,6-tetramethylpiperidinyloxy (TEMPO)
free radical (Scheme 2).[13a,15] The required alcohol 9 can be
synthesized by DIBAL reduction of the corresponding ester
8 as reported by Watanabe et al.[9]
zation with guanidinium salts. (a) iPrCO2Et, NaH, Et2O, room
temp., 1.5 h, 70%; (b) iPrCOMe, NaNH2, Et2O, room temp., 1 h,
35%; (c) [NH2C(NH)NH2]2SO4 (1 equiv.), Na (2 equiv.), iPrOH,
51%; (d) MeNHC(NH)NH2·HCl (1 equiv.), Na (1 equiv.), iPrOH,
65%; (e) iPrCOMe, NaOH, 0 °C, MeOH, 85% (conv. 93%); (f)
MeNHC(NH)NH2·HCl (1 equiv.), Na (2 equiv.), iPrOH, O2 (air),
(9%).
The cyclization of guanidine sulfate with 7 in the pres-
ence of 2 equiv. of iPrONa provided 2-aminopyrimidine
10.[20] Unfortunately, the application of the same reaction
conditions (2 equiv. of iPrONa) for the reaction of N-meth-
ylguanidine hydrochloride with 7 failed, and only traces of
the desired heterocycle 6 were observed. Unexpectedly, the
use of 1 equiv. of iPrONa in iPrOH at 82 °C for 11 h proved
much more successful. The thus obtained 2-(methylamino)-
pyrimidine 6 was purified by flash chromatography to give
the material in 65% yield.
Another possibility for the synthesis of 2-(methylamino)-
pyrimidine 6 is the cyclization of N-methylguanidine hydro-
chloride with (E)-1-(4-fluorophenyl)-4-methylpent-1-en-3-
one (11) (Scheme 3). The starting material could easily be
prepared from 4-fluorobenzaldehyde and 3-methylbutan-2-
one under basic conditions.[21] According to Wendelin et
al., alkenones with hydrogen atoms in their β-positions con-
dense with guanidine to afford labile dihydropyrimidines
that easily undergo aromatization to yield the correspond-
ing pyrimidines.[22] In accordance with this protocol, the β-
substituted alkenone 11 was transformed into the substi-
tuted 2-(methylamino)pyrimidine 6 by treatment with
MeNHC(NH)NH2·HCl in the presence of air, but unfortu-
nately the isolated yield was extremely low. Rapid formation
of aminopyrimidine derivative 6 in the reaction between
methylguanidine and 11 may be a consequence of the rela-
tively strong basicity of the unsaturated intermediates. The
application of tBuOK as a base for the cyclization led to
decomposition.
Scheme 2. Synthesis of aldehyde 2 by chemoselective catalytic oxi-
dation of alcohol 9.
Alternatively, aldehyde 2 could be derived from 2-(meth-
ylamino)pyrimidine derivative 6 by introduction of the for-
myl group into the C-5 position of the pyrimidine ring and
subsequent mesylation of the secondary amine function-
ality, as shown in Scheme 1.
Here we report an entirely new and concise strategy for
the synthesis of aldehyde 2, based on the cyclization of
methylguanidine hydrochloride with 1-(4-fluorophenyl)-4-
methylpentane-1,3-dione (7), followed by regioselective iod-
ization of the pyrimidine and final substitution of the halo-
gen atom by a CHO group. For the last of these conversions
the Pd-catalyzed formylation procedure with CO/H2 (1:1),
recently suggested by Beller et al. for a range of (preferen-
tially nonheterocyclic) aromatic compounds,[16] was envis-
aged. The application of aldehyde 2 in the Wittig reaction
with ylide (R)-3 and the final transformation into rosuvas-
tatin is also considered here.
Results and Discussions
One of the shortest routes to substituted 2-aminopyrim-
The monoalkylation of amine 10 was also tested. Unfor-
idines is the cyclocondensation of guanidine salts with 1,3- tunately, the formic acid/formaldehyde methylation proto-
848
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Eur. J. Org. Chem. 2008, 847–853

A New Approach to the Total Synthesis of Rosuvastatin
col[23] led to the formation of a mixture of products that mixture of products, from which the aliphatic aldehyde 18
could not be separated.
was isolated in 10% yield. Treatment of 17 with I2 in
As an alternative pathway the formylation of a suitably DMSO at 135 °C led to the degradation of the isopropyl
halogenated pyridine derivative of 6 was investigated. The group (19) and did not afford the desired iodide 20. The
required iodide 12 was prepared in 31% yield by treatment inertness of compound 17 in the iodination reaction could
of 2-aminopyrimidine 10 with I2 in DMSO (Scheme 4).[24] be explained by the electron-withdrawing nature of the sul-
Compound 12 was converted into formamide 13 by treat- fonamide group.
ment with POCl3 in DMF. However, because of the low
A more promising route for the formation of aldehyde 2
overall yield of this reaction sequence, the further conver- involves the insertion of iodine into the C-5 position of 6
sion of amide 13 into amine 14 by reduction with LiAlH4 in the first step, this reaction then being followed by N-
or NaBH4 was not investigated.
mesylation and a final formylation step. Thus, treatment of
6 with I2 in DMSO at 100 °C led to the formation of iodide
14. After separation from unreacted initial compound 6 by
column chromatography, 14 was obtained as a solid. An
additional recrystallization from CHCl3 gave 14 as yellow-
ish crystals in 33% yield. The structure of iodide 14 was
confirmed by X-ray analysis and is shown in Figure 1.
Scheme 4. Transformations of 2-aminopyrimidine 10. (a) I2,
DMSO, 100 °C, 1 h, then room temp., 3 d, 31%; (b) POCl3, DMF,
100 °C, 1.5 h, 54%; (c) MeSO2Cl, Et3N, room temp., overnight,
55% (compound 15).
Moreover, mesylation of 10 did not lead to the desired
monosulfonamide 16. Under the conditions applied (Me-
SO2Cl, Et3N, CH2Cl2, 0 °C), the bis(sulfonated) compound
15 was formed as a main product. All attempts to introduce
iodine at the C-5 position in pyrimidine 15 either with I2 in
DMSO or with I2/K2CO3 in CHCl3 at reflux were unsuc-
cessful.
Figure 1. Molecular structure of 2-(methylamino)-4-(4-fluo-
rophenyl)-5-iodo-6-isopropylpyrimidine (14). The thermal ellip-
soids correspond to 30% probability.
The mesylation of 2-(methylamino)pyrimidine 6 led to
the formation of sulfonamide 17 (Scheme 5). After purifica-
tion, this compound was obtained in 30% yield as a color-
less solid. As a by-product the corresponding ammonium
methanesulfonate was detected.
Esterification of 14 with MeSO2Cl gave sulfonamide 20
(Scheme 5). This was subjected to Pd-catalyzed formylation
with CO/H2 (1:1) at a pressure of 5 bar in toluene as sug-
gested by Beller et al.[16] The catalyst was prepared in situ
from Pd(OAc)2, and a number of mono- and bidentate
phosphanes were tested. Unfortunately, under these condi-
tions the reaction did not proceed; neither was any reaction
observed when an isolated Pd(dppe)Cl2 complex was used.
A systematic search for appropriate conditions for the
Pd-catalyzed formylation of 14 gave evidence that the na-
ture and the concentration of the phosphane ligand and the
CO/H2 pressure are crucial for the progress of the reaction
and the ratio of the desired carbaldehyde 21 and the dehalo-
genation product 6. The most important results are shown
in Table 1.
With dppe as a ligand in toluene at 100 °C and a sub-
strate/ligand ratio of 10:1, only traces of aldehyde 21 were
detected even at a very high ligand/substrate ratio (Entry 1).
The application of a catalyst prepared in situ from Pd-
(OAc)2 and PPh3 and a substrate/ligand ratio of 100:1 was
more promising (Entry 2). Replacement of the ancillary li-
Scheme 5. Transformations of 2-(methylamino)pyrimidine 6. (a)
MeSO2Cl, Et3N, CH2Cl2, 0 °C to room temp., 5 h, 30%; (b) POCl3
(5 equiv.), DMF, 100 °C, 3 h, 10%; (c) I2, DMSO, 135 °C, 11 h; (d)
I2, DMSO, 100 °C, 3 h, 33%; (e) MeSO2Cl, Et3N, CH2Cl2, 0 °C to
room temp., 1.5 h, 30%.
Attempted selective formylation of pyrimidine 17 with gand Ph3P by Ad2nBuP improved the results in favor of the
POCl3 (1 equiv.) in DMF at 100 °C failed. An increase in formation of desired aldehyde 21 (Entry 3). An increase in
the amount of POCl3 (5 equiv.) led to the formation of a the substrate concentration to 0.5 molL–1 and the applica-
Eur. J. Org. Chem. 2008, 847–853
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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N. Andrushko, V. Andrushko, G. König, A. Spannenberg, A. Börner
FULL PAPER
Scheme 6. Synthesis of rosuvastatin ethyl ester. (a) Method 1: MeSO2Cl, Et3N, CH2Cl2, 0 °C to room temp., 2 h, 30%; Method 2: NaH,
DMF, 0 °C 30 min, then MeSO2Cl at 0 °C, 3 h room temp., 55%; (b) Method 1: MeCN, reflux, 14 h, 70%; Method 2: toluene, reflux,
48 h, 52%; (c) HF (aq.), MeCN; (d) Et2BOMe, NaBH4, THF/MeOH, –78 °C, 85% (over two steps).
Table 1. Pd-catalyzed formylation of iodide 14.
can also be successfully applied for the production of highly
functionalized heterocyclic carbaldehydes, provided that ap-
propriate conditions have been identified. Together with the
chiral ylide (R)-3, which was produced by an Ru-catalyzed
asymmetric hydrogenation[14] the resulting carbaldehyde 2
is a useful building block for the synthesis of the choles-
terol-lowering drug rosuvastatin.
Entry Ligand[a] Ratio Conc.
Conv. [%]
[mol/L] (isol. yield) [%]
Ratio
21/6/14
l/s[b]
Experimental Section
1
2
3
4
5
dppe
Ph3P
Ad2nBuP 1:100
Ad2nBuP 1:10
Ad2nBuP 1:10
1:10
1:100
0.5
0.05
0.05
0.5
traces
22 (n.d.)
14 (n.d.)
61 (46)
–
6:3:16
9:1:40
8:1:3
General: Reactions and manipulations involving air- and moisture-
sensitive compounds were performed under dry argon by standard
Schlenk techniques. Commercial reagents were used without ad-
ditional purification. Solvents were distilled from appropriate dry-
ing agents before use. Chromatographic purification of products
was accomplished by flash column chromatography on Macherey–
Nagel silica gel 60 (230–400 mesh ASTM) and on neutral Al2O3
with various mixtures of solvents as mobile phases. TLC was car-
ried out on Merck plates with aluminium backing and silica gel
60 F254. NMR spectra were recorded with Bruker ARX 400 and/
or ARX 300 spectrometers. Chemical shifts are reported in ppm (δ)
0.5
ca. 99 (70)[c]
84:16:0[c]
[a] dppe = 1,2-bis(diphenylphosphanyl)ethane, Ad = adamantyl. [b]
l/s = ligand/substrate. [c] Reaction time 72 h.
tion of a substrate/ligand ratio of 10:1 further enhanced the
yield of 21 (Entry 4). Prolongation of the reaction time to
72 h under the same conditions led to nearly complete con-
version. After chromatographic purification, aldehyde 21
was obtained in 70% yield (Entry 5).
Mesylation of 21 with MeSO2Cl in the presence of NEt3
as a base in CH2Cl2 at 0 °C afforded aldehyde 2 in 30%
yield (Scheme 6). A significant improvement of the conver-
sion could be achieved in the presence of NaH in DMF.[25]
After purification, the desired aldehyde 2 was obtained in
55% yield.
Wittig coupling of aldehyde 2 and ylide (R)-3 was per-
formed according to the literature procedure.[9] The reac-
tion proceeded at reflux in CH3CN over 14 h and gave the
rosuvastatin precursor 22 in a yield of 70% (Scheme 6).
Other conditions for the Wittig reaction tested did not im-
prove the yield: the reaction in toluene at reflux, for exam-
ple, for 48 h gave only 52% of 22. Removal of the tBuPh2Si
protective group in 22 by treatment with aqueous HF in
CH3CN and final reduction of the carbonyl group with Et2-
B(OMe) and NaBH4 in THF/MeOH at –78 °C[9] afforded
rosuvastatin ethyl ester in 85% yield.
1
and referred to internal TMS for H NMR and to deuterated sol-
vents for 13C NMR spectroscopy. Elemental and mass spectromet-
ric analyses were performed by the analytic laboratory of the Leib-
niz-Institut für Katalyse e.V. at the Universität Rostock. 1-(4-Fluo-
rophenyl)-4-methylpentane-1,3-dione (7) was prepared according
to ref.[17] The synthesis of (E)-1-(4-fluorophenyl)-4-methylpent-1-
en-3-one (11) was carried out according to ref.[21]
2-Amino-4-(4-fluorophenyl)-6-isopropylpyrimidine (10): A detailed
procedure is given in ref.[20] Purification was carried out by column
chromatography (silica gel; n-hexane/EtOAc, 1:1; Rf = 0.38). Yield:
51% (ref.[20] 56%).
4-(4-Fluorophenyl)-6-isopropyl-2-(methylamino)pyrimidine (6): So-
dium (0.21 g, 9 mmol) was added to anhydrous iPrOH (35 mL),
and the suspension was heated at 80 °C until the metal had dis-
solved. The solution was cooled to 70 °C, and 1-methylguanidine
hydrochloride (1 g, 9 mmol) was added. The suspension was heated
at 82 °C for 2.5 h and then cooled again to 70 °C. A solution of
1,3-diketone 7 (1.9 g, 9 mmol) in iPrOH (10 mL) was added, and
the resulting mixture was heated at 82 °C for 11 h. After cooling
to room temp., the reaction mixture was concentrated in vacuo,
and the residue was diluted with saturated aqueous NH4Cl
(20 mL). The crude product was extracted with EtOAc (3ϫ10 mL).
The combined organic phases were dried with MgSO4 and concen-
trated. The residue was purified on a silica gel column with n-hex-
ane/EtOAc (9:1; Rf = 0.16) or n-hexane/EtOAc (1:1; Rf = 0.45) to
afford the product 6 (1.44 g, 65%) as a colorless powder. M.p. 75–
Conclusions
A new and convenient synthetic protocol for the prepara-
tion of pyrimidinecarbaldehyde 2 by iodization of 2-(meth-
ylamino)4-(4-fluorophenyl)-6-isopropylpyrimidine (6) fol-
lowed by Pd-catalyzed formylation with H2/CO has been
developed. For the first time, evidence has been found that
1
76 °C. H NMR (400 MHz, CDCl3): δ = 1.30 (d, J = 6.8 Hz, 6 H,
Me2CH), 2.86 (m, 1 H, Me2CH), 3.08 (d, J = 5.1 Hz, 3 H, MeNH),
5.15 (br. s, 1 H, NH), 6.82 (s, 1 H, CH, pyrimidine), 7.14 (m, 2 H,
this catalytic reaction, recently discovered by Beller et al., CH, Ar), 8.05 (m, 2 H, CH, Ar) ppm. 13C NMR (100 MHz,
850
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Eur. J. Org. Chem. 2008, 847–853

A New Approach to the Total Synthesis of Rosuvastatin
CDCl3): δ = 21.75 (Me2CH), 28.41 (MeNH), 36.16 (Me2CH),
102.92 (CH, pyrimidine), 115.50 (d, JC,F = 21.14 Hz, CH), 128.89
(CH), 128.98 (CH), 134.26 (C), 163.23 (CH), 163.63 (CH), 164.12
(d, JC,F = 249.96 Hz, CF), 177.26 (CCHMe2) ppm. MS (EI): m/z
idine), 8.08 (m, 2 H, CH, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ
= 21.77 (Me2CH), 28.25 (MeN), 36.22 (Me2CH), 42.29 (MeSO2N),
107.86 (CH, pyrimidine), 115.67 (d, JC,F = 23.23 Hz), 129.13 (CH),
129.25 (CH), 129.36 (C), 163.23 (CH), 159.25 (CH), 163.66 (d, JC,F
(%) = 245 (76) [M]+, 230 (100), 217 (83), 201 (14), 173 (11), 146 = 249.96 Hz, CF), 177.49 (Me2CHC) ppm. MS (EI): m/z (%) = 323
(12). C14H16FN3 (245.30): calcd. C 68.55, H 6.57, N 17.13; found
C 69.10, H 6.30, N 16.57.
(8) [M]+, 308 (12), 245 (41), 244 (100), 230 (47), 217 (30), 57 (19).
4-(4-Fluorophenyl)-6-isopropyl-N-methylpyrimidin-2-ylaminium
Methanesulfonate: This compound was additionally isolated by col-
umn chromatography (silica gel; n-hexane/EtOAc, 4:1; Rf = 0.09).
1H NMR (300 MHz, CDCl3): δ = 1.34 (d, J = 6.79 Hz, 6 H,
Me2CH), 3.03 (m, 1 H, Me2CH), 3.29 (s, 3 H, MeH2N+), 3.71 (s,
2-Amino-4-(4-fluorophenyl)-5-iodo-6-isopropylpyrimidine (12):[24]
A
solution of 10 (50 mg, 0.216 mmol) and I2 (110 mg, 0.43 mmol) in
DMSO (0.3 mL) was heated at 100 °C for 1 h and was then left
standing at room temp. for 3 d. The solution was diluted with an
equal amount of H2O, shaken with Na2S2O3 solution (1 ) for
5 min, and washed with saturated NaHCO3. After extraction with
CH2Cl2 (2ϫ2 mL), the organic phase was dried with MgSO4. The
crude product was purified by column chromatography (neutral
Al2O3; n-hexane/EtOAc, 1:1; Rf = 0.56) to afford 12 (24 mg, 31%)
–
3 H, MeSO2 ), 7.18 (m, 2 H, CH, Ar), 7.25 (s, 1 H, pyrimidine),
8.03 (m, 2 H, CH, Ar) ppm.
N-[4-(4-Fluorophenyl)-6-(2-methyl-1-oxoprop-2-yl)pyrimidin-2-yl]-
N-methylmethanesulfonamide (18): A solution of 17 (100 mg,
0.31 mmol) and POCl3 (285 mg, 1.86 mmol) in DMF (5 mL) was
heated at 100 °C for 3 h. After cooling to room temp., the reaction
mixture was poured into ice-cold water, washed with saturated
NaHCO3, and extracted with EtOAc (2ϫ5 mL). The combined
organic layers were dried with MgSO4; after evaporation of the
solvent, the product was purified by column chromatography (silica
1
as a yellowish solid. H NMR (400 MHz, CDCl3): δ = 1.27 (d, J
= 6.75 Hz, 6 H, Me2CH), 3.50 (m, 1 H, Me2CH), 5.37 (br. s, 2 H,
NH2), 7.15 (m, 2 H, CH, Ar), 7.51 (m, 2 H, CH, Ar) ppm. 13C
NMR (100 MHz, CDCl3): δ = 21.06 (Me2CH), 38.48 (Me2CH),
92.87 (CI, pyrimidine), 115.50 (d, JC,F = 21.15 Hz), 128.9 (CH),
129.0 (CH), 130.79 (C), 163.23 (CH), 163.63 (CH), 164.12 (d, JC,F
= 248.5 Hz, CF), 185.82 (Me2CHC) ppm.
1
gel; toluene/EtOAc, 10:1; Rf = 0.62) to give 18 (11 mg, 10%). H
NMR (300 MHz, CDCl3): δ = 1.55 (s, 6 H, CMe2CHO), 3.50 (s, 3
H, MeN), 3.61 (s, 3 H, MeSO2N), 7.20 (m, 2 H, CH, Ar), 7.29 (s,
1 H, pyrimidine), 8.08 (m, 2 H, CH, Ar), 9.77 (s, 1 H, CMe2CHO)
ppm. MS (CI/isobutene): m/z (%) = 353 (14), 352 (100), 340 (57),
324 (15), 302 (14), 274 (8).
N-[4-(4-Fluorophenyl)-5-iodo-6-isopropylpyrimidin-2-yl]formamide
(13): A mixture of 12 (25 mg, 0.07 mmol) and POCl3 (72 mg,
0.47 mmol) in DMF (1 mL) was heated at 100 °C for 1.5 h. After
cooling, the solution was poured into ice-cold water (5 mL). The
crude product was extracted with CH2Cl2 (2ϫ5 mL). The com-
bined organic layers were washed with saturated NaHCO3 and
brine. After drying of the CH2Cl2 solution with MgSO4, the solvent
was evaporated and the residue purified by column chromatog-
raphy (silica gel; Et2O/MeOH, 10:1; Rf = 0.91) to give 13 (14.6 mg,
54%) as yellowish solid. M.p. 163–164 °C. 1H NMR (300 MHz,
CDCl3): δ = 1.29 (d, J = 6.81 Hz, 6 H, Me2CH), 3.58 (m, 1 H,
Me2CH), 7.17 (m, 2 H, CH, Ar), 7.57 (m, 2 H, CH, Ar), 7.8 (br.
s, 1 H, NH), 9.52 (s, 1 H, CHO) ppm.
N-[4-(4-Fluorophenyl)-6-(prop-1-en-2-yl)pyrimidin-2-yl]-N-methyl-
methanesulfonamide (19): A solution of 17 (105 mg, 0.32 mmol) and
I2 (165 mg, 0.65 mmol) in DMSO (2.5 mL) was heated at 135 °C
for 11 h. The reaction mixture was poured into water (3 mL),
shaken with Na2S2O3 solution (1 ) for 5 min, and washed with
saturated NaHCO3. After extraction with CH2Cl2 (2ϫ3 mL), the
organic phase was dried with MgSO4. The solvent was evaporated
and the residue subjected to purification by column chromatog-
raphy (silica gel; n-hexane/EtOAc, 4:1). Besides initial compound
16, the decomposition product 19 was isolated (Rf = 0.33). M.p.
135 °C. 1 H NMR (400 MHz, CDCl3 ): δ = 2.22 (m, 3 H,
MeC=CH2), 3.54 (s, 3 H, MeN), 3.64 (s, 3 H, MeSO2N), 5.52 (m,
N-[4-(4-Fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-(methylsulfon-
yl)methanesulfonamide (15): A solution of MeSO2Cl (50 mg,
0.43 mmol) in dry CH2Cl2 (1 mL) was added at 0 °C to a solution
of amine 10 (100 mg, 0.433 mmol) and NEt3 (48 mg, 0.48 mmol) 1 H, MeC=CHH), 6.18 (m, 1 H, MeC=CHH), 7.19 (m, 2 H, CH,
in dry CH2Cl2 (3 mL). The reaction mixture was warmed to room Ar), 7.46 (s, 1 H, pyrimidine), 8.09 (m, 2 H, CH, Ar) ppm.
temp. and stirred overnight. The solvent was evaporated, and the
4-(4-Fluorophenyl)-5-iodo-6-isopropyl-2-(methylamino)pyrimidine
residue was dried under high vacuum. After column chromatog-
(14): A solution of 6 (1.08 g, 4.4 mmol) and I2 (2.24 g, 8.8 mmol)
raphy (silica; hexane/EtOAc, 1:1; Rf = 0.76), amide 15 (92 mg,
in DMSO (25 mL) was heated at 100 °C for 3 h and left overnight
55%) was obtained as a colorless solid. M.p. 154–155 °C. 1H NMR
at room temp. The reaction mixture was diluted with water (25 mL)
(400 MHz, CDCl3): δ = 1.36 (d, J = 6.84 Hz, 6 H, Me2CH), 3.11
and extracted with EtOAc (3 ϫ15 mL). The combined extracts
(m, 1 H, Me2CH), 3.72 [s, 6 H, (MeSO2)2N], 7.20 (m, 2 H, CH,
were washed successively with Na2S2O3 solution (1 , 2ϫ10 mL),
Ar), 7.5 (s, 1 H, CH, pyrimidine), 8.05 (m, 2 H, CH, Ar) ppm. MS
saturated NaHCO3 (2ϫ10 mL), and brine (2ϫ10 mL) and then
(EI): m/z (%) = 387 (38) [M]+, 372 (25), 359 (13), 308 (25), 294
dried with MgSO4. After evaporation of the solvent, the mixture
(100), 276 (33), 230 (18), 214 (19).
of the crude product and unreacted initial compound was separated
N-[4-(4-Fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethane-
sulfonamide (17): A solution of MeSO2Cl (0.28 g, 2.45 mmol) in
dry CH2Cl2 (5 mL) was added at 0 °C to a solution of amine 6
(0.6 g, 2.45 mmol) and Et3N (0.32 g, 3.2 mmol) in dry CH2Cl2
(20 mL). The reaction mixture was warmed to room temp. and
stirred for an additional 5 h. The solvent was evaporated, and the
residue was dried under high vacuum. Purification by column
chromatography (silica gel; toluene/EtOAc, 10:1; Rf = 0.45 or n-
hexane/EtOAc, 4:1; Rf = 0.22) afforded 17 (237 mg, 30%) as a col-
by column chromatography (silica gel; toluene/EtOAc, 10:1; Rf =
0.54 and/or silica gel; n-hexane/EtOAc, 1:1; Rf = 0.61). Additional
recrystallization from CHCl3 afforded pure 14 (0.461 g, 33%) as
yellowish crystals. M.p. 195–196 °C. 1H NMR (400 MHz, CDCl3):
δ = 1.26 (d, J = 6.69, Hz, 6 H Me2CH), 2.99 (d, J = 4.95 Hz, 3 H,
MeNH) 3.47 (m, 1 H, Me2CH), 5.15 (br. s, 1 H, NH), 7.12 (m, 2
H, CH, Ar), 7.52 (m, 2 H, CH, Ar) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.12 (Me2CH), 28.41 (MeNH), 38.26 (Me2CH), 80.91
(CI, pyrimidine), 114.89 (d, JC,F = 21.93 Hz, CH, Ar), 130.84 (CH),
orless solid. M.p. 138–139 °C. 1H NMR (300 MHz, CDCl3): δ = 130.92 (CH), 138.13 (C), 162.04 (CH), 168.77 (CH), 163.00 (d, JC,F
1.33 (d, J = 6.8 Hz, 6 H, Me2CH), 3.02 (m, 1 H, Me2CH), 3.55 (s, = 248.72 Hz, CF), 177.24 (Me2CHC) ppm. MS (EI): m/z (%) = 371
3 H, MeN), 3.62 (s, 3 H, MeSO2N), 7.18 (m, 3 H, CH, Ar + pyrim-
(87) [M]+, 356 (20), 245 (22), 244 (100), 146 (14).
Eur. J. Org. Chem. 2008, 847–853
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
851

N. Andrushko, V. Andrushko, G. König, A. Spannenberg, A. Börner
FULL PAPER
X-ray Crystallographic Study of Compound 14: Data were collected
with a STOE-IPDS diffractometer by using graphite-monochro-
mated Mo-Kα radiation. The structure was solved by direct meth-
ods (SHELXS-97: G. M. Sheldrick, University of Göttingen, Ger-
many, 1997) and refined by full-matrix, least-squares techniques
0 °C to a solution of aldehyde 21 (60 mg, 0.22 mmol) in dry DMF
(1 mL). The solution was stirred for 30 min, and then a solution of
MeSO2Cl (37.7 mg, 0.336 mmol) in DMF (1 mL) was added. The
mixture was stirred at 0 °C for 30 min and at room temp. for 3 h.
Water (2 mL) was then added to quench the reaction, and the mix-
against F2 (SHELXL-97: G. M. Sheldrick, University of ture was extracted with EtOAc (3ϫ3 mL). The organic layer was
Göttingen, Germany, 1997). XP (Bruker AXS) was used for graphi-
cal representation. Space group P21/n, monoclinic, a = 11.8954(12),
b = 5.5807(4), c = 22.887(2) Å, β = 102.431(7)°, V = 1483.7(2) Å3,
Z = 4, ρcalcd. = 1.662 gcm–3, 18258 reflections measured, 2907 sym-
metry-independent reflections, of which 2305 were observed
[IϾ2σ(I)], R1 = 0.024, wR2 (all data) = 0.063, 175 parameters.
CCDC-659030 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
washed with brine and dried with MgSO4. After evaporation of the
solvent, the product was purified by column chromatography (silica
gel; toluene/EtOAc, 10:1; Rf = 0.52) to give aldehyde 2 (42.4 mg,
1
55%) as a colorless solid. M.p. 147–148 °C. H NMR (300 MHz,
CDCl3): δ = 1.32 (d, J = 6.62 Hz, 6 H, Me2CH), 3.55 (s, 3 H,
MeN), 3.64 (s, 3 H, MeSO2N), 4.03 (m, 1 H, Me2CH), 7.23 (m, 2
H, CH, Ar), 7.63 (m, 2 H, CH, Ar), 9.97 (br. s, 1 H, CHO) ppm.
13C NMR (100 MHz, CDCl3): δ = 21.38 (Me2CH), 28.32 (MeN),
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ 38.26 (Me2CH), 42.29 (MeSO2N), 115.58 (d, JC,F = 23.5 Hz, CH,
data_request/cif.
Ar), 130.35 (CH), 131. 7 (CH), 137.86 (C), 162.05 (CH), 168.41
(CH), 163.00 (d, JC,F = 246.5 Hz, CF), 177.36 (Me2CHC), 190.12
(CHO) ppm. MS (EI): m/z (%) = 351 (22), 273 (18), 272 (100).
N-[4-(4-Fluorophenyl)-5-iodo-6-isopropylpyrimidin-2-yl]-N-methyl-
methanesulfonamide (20): A solution of amine 14 (20 mg,
0.054 mmol) and Et3N (7.1 mg, 0.07 mmol) in dry CH2Cl2 (2 mL)
was cooled to 0 °C, and a solution of MeSO2Cl (6.2 mg,
0.054 mmol) in dry CH2Cl2 (0.5 mL) was added. The reaction mix-
ture was warmed up to room temp. and stirred for 1.5 h. The sol-
vent was evaporated, and the crude product was purified by column
chromatography (silica gel; toluene/EtOAc, 10:1; Rf = 0.40 or n-
hexane/EtOAc, 4:1; Rf = 0.31). Yield of 20: 7.3 mg (30 %). 1H
NMR (300 MHz, CDCl3): δ = 1.30 (d, J = 6.59 Hz, 6 H, Me2CH),
3.02 (m, 1 H, Me2CH), 3.39 (s, 3 H, MeN), 3.47 (s, 3 H, MeSO2N),
7.16 (m, 2 H, CH, Ar + pyrimidine), 8.10 (m, 2 H, CH, Ar) ppm.
Ethyl (3R,6E)-3-(tert-Butyldiphenylsilyloxy)-7-[4-(4-fluorophenyl)-
6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-5-
oxohept-6-enoate (22). Method 1: According to a modified pro-
cedure given in ref.[9] A solution of aldehyde 2 (16 mg, 0.046 mmol)
and ylide (R)-3 (30 mg, 0.046 mmol) in MeCN (1 mL) was heated
at reflux for 14 h. The solvent was removed in vacuo, and the crude
product was purified by column chromatography (silica gel; EtOAc;
Rf = 0.92) to yield 22 (24 mg, 70%) as a viscous oil. Method 2: A
solution of aldehyde 2 (16 mg, 0.046 mmol) and ylide (R)-3 (30 mg,
0.046 mmol) in toluene (1 mL) was heated at reflux for 48 h, and
the solvent was then evaporated. The product was purified by col-
umn chromatography (silica gel; EtOAc; Rf = 0.92) to afford 22
(18 mg, 52 %) as a colorless, viscous oil. 1H NMR (300 MHz,
CDCl3): δ = 1.00 (s, 9 H, Me3C), 1.26 (m, 3 H + 6 H, Me2CH +
CH2Me), 3.52 (s, 3 H, MeN), 3.59 (s, 3 H, MeSO2N), 2.49 (m, 2
H, CH2CO2Et), 2.69 [dd, J = 15.75, J = 5.53 Hz, 1 H, C(O)CHH],
2.83 [dd, J = 15.75, 7.48 Hz, 1 H, C(O)CHH], 3.25 (m, 1 H,
Me2CH), 4.05 (q, J = 7.11 Hz, CH2Me), 4.59 (m, 1 H, CH), 5.95
(d, J = 16.50 Hz, 1 H, CH=CH), 7.07 (m, 2 H, Ar), 7.36 (m, 7 H,
CH, CH=CH + Ar), 7.55 (m, 2 H, CH, Ar), 7.65 (m, 4 H, CH,
Ar) ppm.
4-(4-Fluorophenyl)-6-isopropyl-2-(methylamino)pyrimidine-5-carbal-
dehyde (21):[16] Under argon a 10-mL flask was charged with
Pd(OAc)2 (29.6 mg, 0.132 mmol), Ad2nBuP (14.3 mg, 0.04 mmol),
and toluene (4 mL). The resulting mixture was vigorously stirred at
room temp. for 1–1.5 h, and N,N,NЈ,NЈ-tetramethylethylenediamine
(TMEDA, 34.9 mg, 0.3 mmol) and iodide 14 (148.5 mg, 0.4 mmol)
were added. The solution was placed in a 25-mL autoclave together
with a magnetic stirring bar. The autoclave was flushed 3 times
with syngas (CO/H2, 1:1) and pressurized to 50 bar. The reaction
mixture was stirred at 100 °C for 72 h. After cooling to room temp.
and releasing of the excess of CO/H2, the solvent was evaporated
and the crude product was purified by column chromatography
(silica gel; toluene/EtOAc, 10:1; Rf = 0.44) to give 21 (76.5 mg,
Ethyl (3R,5S,6E)-7-{4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(meth-
ylsulfonyl)amino]pyrimidin-5-yl}-3,5-dihydroxyhept-6-enoate: This
compound was prepared according to the procedure given in ref.[9]
Yield 85%.
1
70%) as a colorless solid. M.p. 131–132 °C. H NMR (400 MHz,
CDCl3): δ = 1.26 (d, J = 6.60 Hz, 6 H, Me2CH), 3.11 (d, J =
5.11 Hz, 3 H, MeNH), 4.03 (m, 1 H, Me2CH), 5.62 (br. s, 1 H,
NH), 7.17 (m, 2 H, CH, Ar), 7.54 (m, 2 H, CH, Ar), 9.82 (s, 1 H,
CHO) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.36 (Me2CH),
28.31 (MeNH), 38.26 (Me2CH), 115.58 (d, JC,F = 23.90 Hz, CH,
Ar), 130.35 (CH), 131.67 (CH), 137.86 (C), 162.05 (CH), 168.41
(CH), 163.00 (d, JC,F = 246.5 Hz, CF), 177.36 (Me2CHC), 190.12
(CHO) ppm. MS (EI): m/z (%) = 273 (100), 256 (33), 244 (20), 230
(63), 217 (77). C15H16FN3O (273.31): calcd. C 65.92, H 5.90; found
C 65.80, H 6.34.
Acknowledgments
The authors are grateful to Ratiopharm GmbH (Ulm) for financial
support of this work. We appreciate skilled technical assistance by
Mrs. K. Mevius.
[1] For the different pathways for the preparation of statins, see:
Contemporary Drug Synthesis (Eds.: J.-J. Li, D. S. Johnson,
D. R. Sliskovic, B. D. Roth), Wiley-Interscience, New York,
2004, pp. 113–123.
[2] For the alternative preparation of the chiral side chain of stat-
ins by the lactol pathway and its application for the synthesis
of atorvastatin, see: a) V. I. Tararov, G. König, A. Börner, Adv.
Synth. Catal. 2006, 348, 2633–2644; b) V. I. Tararov, N. And-
rushko, V. Andrushko, G. König, A. Spannenberg, A. Börner,
Eur. J. Org. Chem. 2006, 5543–5550.
N-[4-(4-Fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl]-N-meth-
ylmethanesulfonamide (2). Method 1: A solution of MeSO2Cl
(18.9 mg, 0.16 mmol) in dry CH2Cl2 (1 mL) was added at 0 °C to
a solution of aldehyde 21 (40 mg, 0.15 mmol) and Et3N (24.9 mg,
0.25 mmol) in dry CH2Cl2 (3 mL). The reaction mixture was
warmed to room temp. and stirred at this temperature for an ad-
ditional 2 h. The solvent was evaporated, and the residue was puri-
fied by column chromatography (silica gel; toluene/EtOAc, 10:1; Rf
= 0.52) to afford aldehyde 2 (15.5 mg 30%) as a colorless solid.
Method 2: Sodium hydride (NaH, 11 mg, 0.46 mmol) was added at
[3] For very recent methods for the synthesis of rosuvastatin, see:
a) A. Balanov, N. Shenkar, V. Niddam-Hildesheim, US Pat.
Appl. 2007, US 2007167625 A1, Chem. Abstr. 2007, 147,
852
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 847–853

A New Approach to the Total Synthesis of Rosuvastatin
166109; b) S. Radl, J. Stach, R. Klvana, J. Jirman, PCT Int.
Appl. 2007, WO 2007000121 A1, Chem. Abstr. 2007, 146,
121983; c) D. J. Patel, R. Kumar, S. P. D. Dwivedi, 2007, WO
2007099561 A1, Chem. Abstr. 2007, 147, 322770.
1995, JP 07118233 A2, Chem. Abstr. 1995, 123, 286068; d) K.
Hirai, T. Ishiba, H. Koike, M. Watanabe, Eur. Pat. Appl. 1993,
EP 521471 A1, Chem. Abstr. 1993, 118, 254949.
A. Korostylev, V. Andrushko, N. Andrushko, V. I. Tararov,
Gerd König, A. Börner, Eur. J. Org. Chem. 2008, 840–846,
preceding article.
S. Gudipati, S. Katkam, R. R. Sagyam, J. S. Kudavalli, U. S.
Pat. Appl. Publ. 2006, US 2006004200, Chem. Abstr. 2006, 144,
108142.
S. Klaus, H. Neumann, A. Zapf, D. Strübing, S. Hübner, J.
Almena, T. Riermeier, P. Groß, M. Sarich, W.-R. Krahnert, K.
Rossen, M. Beller, Angew. Chem. Int. Ed. 2006, 45, 154–158.
a) T. Ruman, Z. Ciunik, S. Wołowiec, Eur. J. Inorg. Chem.
2003, 13, 2475–2485; b) E. Hasegawa, K. Ishiyama, T. Horagu-
chi, T. Shimizu, J. Org. Chem. 1991, 56, 1631–1635.
According to the modified procedure of: D. R. Sliskovic, B. D.
Roth, M. W. Wilson, M. L. Hoefle, R. S. Newton, J. Med.
Chem. 1990, 33, 31–38.
The reaction was performed according to the modified pro-
cedure of: W. M. Muir, P. D. Ritchie, D. J. Lyman, J. Org.
Chem. 1966, 31, 3790–3793.
A. Kucerovy, P. G. Mattner, J. S. Hathaway, O. Repic, Synth.
Commun. 1990, 20, 913–917.
A. Gillmore, C. Lauret, S. M. Roberts, Tetrahedron 2003, 59,
4363–4375.
W. Wendelin, K. Schermanz, J. Heterocycl. Chem. 1984, 21,
65–69.
[14]
[15]
[16]
[17]
[18]
[19]
[4] Statins: The HMG CoA Reductase Inhibitors in Perspective
(Eds.: A. Gaw, C. J. Packard, J. Shepherd), Taylor & Francis,
London, 2004.
[5] For a systematic review of the application of statins in the treat-
ment of chronic heart failure, see: P. van der Harst, A. A.
Voors, W. H. van Gilst, M. Böhm, D. J. van Veldhuisen, PLoS
Med. 2006, 3, e333; and literature cited therein.
[6] Rosuvastatin was approved as the cholesterol-lowering drug
Crestor in August 2003. For the application of rosuvastatin,
see: N. S. Culhane, S. L. Lettieri, J. R. Skae, Pharmacotherapy
2005, 25, 990–1000 and literature cited therein.
[7] J. M. McKenney, Am. J. Health Syst. Pharm. 2005, 62, 1033–
1047.
[8] For the application of statins for treatment of hypercholesterol-
emia and hyperlipidaemia, see: a) W. Insull Jr, Nat. Clin. Pract.
Cardiovasc. Med. 2006, 3, 134–135; b) M. Hirsch, J. O’Donnell,
A. Olsson, Int. J. Cardiol. 2005, 104, 251–256.
[9] M. Watanabe, H. Koike, T. Ishiba, T. Okada, S. Seo, K. Hirai,
Bioorg. Med. Chem. 1997, 5, 437–444.
[10] T. Konoike, Y. Araki, K. Harada, A. Matsushita, Jpn. Kokai
Tokkyo Koho 1994, JP 06135975, Chem. Abstr. 1994, 121,
230347.
[11] V. Niddam-Hildesheim, A. Balanov, N. Shenkar, S. Shabat, D.
Maidan-Nanoch, PCT Int. Appl. 2006, WO 2006091770 A2,
Chem. Abstr. 2006, 145, 299533.
[12] T. Konoike, Y. Araki, J. Org. Chem. 1994, 59, 7849–7854.
[13] a) V. Niddam-Hildesheim, K. Chen, PCT Int. Appl. 2006, WO
2006017357 A1, Chem. Abstr. 2006, 144, 232853; b) Y. Kumar,
S. De, M. Rafeeq, H. N. P. N. Meeran, S. Sathyanarayana, PCT
Int. Appl. 2003, WO 2003097614 A2, Chem. Abstr. 2003, 139,
355947; c) T. Okada, T. Konoike, Jpn. Kokai Tokkyo Koho
[20]
[21]
[22]
[23]
[24]
S. H. Pine, B. L. Sanchez, J. Org. Chem. 1971, 36, 829–832.
The iodination was performed according to the procedure of:
M. V. Javovic, Heterocycles 1984, 22, 1195–1210.
D.-L. Wang, C.-F. Li, Z.-M. Niu, F. Xin, Chin. J. Med. Chem.
2004, 14, 148–149.
[25]
Received: September 2, 2007
Published Online: November 12, 2007
Eur. J. Org. Chem. 2008, 847–853
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
853