Highly stereoselective hydrogenations-as key-steps in the total synthesis of statins

Article abstract of DOI:10.1002/chir.20782

Statins are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase) and became the standard of care for treatment of hypercholesterolemia because of their efficacy, safety, and long-term benefits. They are administered as diaste

Full text of DOI:10.1002/chir.20782

CHIRALITY 22:534–541 (2010)
Review Article
Highly Stereoselective Hydrogenations—As Key-Steps in the Total
Synthesis of Statins
1
1
2
NATALIA ANDRUSHKO,1 VASYL ANDRUSHKO,1 VITALI TARAROV, ANDREI KOROSTYLEV, GERD KONIG,
¨
*
1,3
¨
*
AND ARMIN BORNER
1Leibniz-Institut fu¨r Katalyse an der Universita¨t Rostock e.V., 18059, Rostock, Germany
2Ratiopharm GmbH, 89070, Ulm, Germany
3Institut fu¨r Chemie der Universita¨t Rostock, 18059, Rostock, Germany
ABSTRACT
Statins are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A
reductase (HMG-CoA reductase) and became the standard of care for treatment of
hypercholesterolemia because of their efficacy, safety, and long-term benefits. They are
administered as diastereo- and enantiomerically pure compounds. We summarize here
two new approaches for the total synthesis of the most important representatives,
atorvastatin, and rosuvastatin, based on highly stereoselective hydrogenations as key-
C
VV
steps. Chirality 22:534–541, 2010.
2009 Wiley-Liss, Inc.
KEY WORDS: drug synthesis; atorvastatin; rosuvastatin; asymmetric hydrogenation;
enantioselectivity; stereoselectivity; statins; asymmetric catalysis
INTRODUCTION
genation of the statin precursor ethyl (5S)-5,6-isopropyli-
denedioxy-3-oxohexanoate33 as a key-step. The retrosyn-
thetic pathway to the enantiopure side chain of atorvastatin
is depicted on Scheme 1. This involves two-carbon elonga-
tion of methyl (S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)acetate
(1) to afford alkyl (S)-4-(2,2-dimethyl-1,3-dioxolan-4-yl)-3-
oxobutanoate (2) followed by catalytic hydrogenation of
the keto group to afford the corresponding hydroxy ester
D. The protection of the HO-group in compound D and
the subsequent cleavage of acetal-moiety gives lactone C,
which may then be used for the preparation of atorvastatin
precursor B.
Statins1–3 are effective inhibitors of the enzyme 3-
hydroxy-3-methyl-glutaryl coenzyme reductase (HMG-CoA
reductase)4 and are a class of hypolipidemic drugs used to
lower level of cholesterol5 in the blood by reducing the
production of cholesterol by the liver in people with or at
risk of cardiovascular disease.6–8 Recently, statins have
become the standard of care for treatment of hypercholes-
terolemia and hyperlipidaemia9–12 due to their efficacy,
safety, and long-term benefits.13 Among the statin class of
drugs, atorvastatin14–21 and rosuvastatin22–30 are the most
powerful lipid-lowering agents (Fig. 1).
Atorvastatin calcium13 was the first totally synthetic
HMG-CoA-reductase inhibitor developed and marketed as a
single enantiomer.17–21 Currently, it ranks at the top of the
drugs best sold in the world (Atorvastatin calcium tablets
are currently marketed by Pfizer under the trade name Lipi-
tor. According to a recent article in Forbes—The World’s Ten
Best-Selling Drugs: ‘‘Pfizer’s cholesterol pill Lipitor remains
the best-selling drug in the world for the fifth year in a row.
Its annual sales were $12.9 billion, more than twice as much
as its closest competitors.’’).31 Rosuvastatin calcium is the
newest among statins and it was approved as the choles-
terol-lowering drug Crestor in August 2003. Rosuvastatin
has been called a super-statin, because it appears to reduce
low-density lipoprotein (LDL) cholesterol to a greater
degree than rivals in its class without additional adverse
effects. A number of new methods for the synthesis of rosu-
vastatin and its precursors has been published recently.26–30
As methyl (S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)acetate
(1) is commercially available at a rather high price, it was
prepared in our lab starting from (S)-malic acid by a
known sequence (Scheme 2). (S)-Malic acid was esterified
with methanol in the presence of dimethyl orthoformate
to obtain dimethyl (S)-malate (3). This material was
regioselectively reduced using Moriwake’s procedure
(sBH33SMe2, THF, cat. NaBH4).34,35 The resulting crude
methyl (S)-3,4-dihydroxybutanoate was directly trans-
formed without purification into the acetonide (S)-133 with
a yield of 74% after distillation. Saponification of ester (S)-1
with aqueous NaOH and subsequent neutralization gave
the corresponding acid (S)-4 in a chemical yield of 71–
Contract grant sponsor: Ratiopharm GmbH (Ulm)
*Correspondence to: Dr. Vasyl Andrushko, Leibniz-Institut fu¨r Katalyse
an der Universita¨t Rostock e.V., Albert-Einstein-Str. 29a, 18059 Rostock,
Germany. E-mail: vasyl.andrushko@catalysis.de or Prof. Dr. Armin
Bo¨rner, Institut fu¨r Chemie der Universita¨t Rostock, Albert-Einstein-Str.
3a, 18059 Rostock, Germany. E-mail: armin.boerner@catalysis.de
Received for publication 14 October 2008; Accepted 4 August 2009
DOI: 10.1002/chir.20782
SYNTHESIS OF ATORVASTATIN
We recently reported a new approach for the total
Published online 6 November 2009 in Wiley InterScience
synthesis of atorvastatin32 via highly stereoselective hydro- (www.interscience.wiley.com).
C
VV
2009 Wiley-Liss, Inc.

HIGHLY STEREOSELECTIVE HYDROGENATIONS
535
Fig. 1. Structures of atorvastatin calcium and rosuvastatin calcium.
78%. Acid (S)-4 was elongated by application of a general 11). Besides the desired (3R,5S)-6 (syn) alcohol, a side
protocol developed for the synthesis of b-keto esters36 via product was formed in MeOH. On the basis of the NMR
intermediate formation of imidazolide (S)-5. After work-up data,33 we assumed that a thermodynamic equilibrium is
keto ester (S)-2 was obtained after distillation in good established between (3R,5S)-6 (syn) and the rearrange-
yield.33
ment product (S,R)-7 during the hydrogenation reaction
To define optimal conditions for the stereoselective hy- (Scheme 4). This assumption was confirmed by O-silyla-
drogenation of b-keto ester (S)-2 into the desired pro- tion of the mixture of alcohols (3R,5S)-6 and (3R,5S)-7 fol-
tected polyol (3R,5S)-6 (Scheme 3), we studied the per- lowed by chromatographic separation of products 8 and 9.
formance of several homogeneous chiral Rh and Ru cata- Structures of both isomers 8 and 9 were confirmed by ele-
lysts.
mental analysis, mass-spectra, and NMR data. It is remark-
The hydrogenations were performed under mild condi- able that 1,3-dioxolane 8 as well as 1,3-dioxane 9 showed
tions (50 bar initial H2 pressure, room temperature). The only one set of signals in the NMR spectrum. This gives
results are listed in Table 1. The syn/anti ratios were clear evidence that the hydrogenation protocol used pro-
determined on the basis of NMR data. Hydrogenation of duced alcohols (3R,5S)-6 and (3R,5S)-7 with excellent dia-
(S)-2 catalyzed with chiral Rh(I) catalysts showed only stereomeric purity. The same rearrangement was also
moderate diastereoselectivities (entries 1–9). Structures of observed with the Ru[(R)-Tol-BINAP]Cl2 catalyst.
chiral ligands are illustrated on Fig 2. Higher activities
It became obvious that these catalysts have acidic prop-
were observed in aprotic solvents (compare, entry 1 and erties and it is thus necessary to neutralize them before
2). The Rh(I) catalyst with (S,S)-Et-DUPHOS or (S,S)-Me- use. For this reason, we tested several nitrogenous bases
DUPHOS as ancillary ligands induced reasonable syn-se- (Et3N, BnNH2, imidazole, piperazine). These bases had an
lectivity. At the same time, with (R,R)-Et-DUPHOS and uniform influence on the activity of the catalysts. In Table
(R,R)-Me-DUPHOS as ligands, completely opposite results 1 only examples with Et3N are listed (entries 12–15). The
were observed.
addition of Et3N completely inhibited the formation of the
Ru(II) catalysts based on diphosphines BINAP and Tol- transacetalization product (S,R)-7. It was shown also that
BINAP gave markedly varying results (entries 10–22). Par- increasing the concentration of Et3N affected the activity
ticularly, it was found that the application of commercial or of the catalyst and at a ratio of Ru/Et3N 5 1/2, there was
in-house prepared37 Ru[(R)-BINAP]Cl2 afforded a complex complete inhibition of hydrogenation. It is interesting to
mixture of products although the conversion of b-keto note that imidazole and piperazine, which possess two ba-
ester 2 was complete (entry 10).
sic centers, behaved similarly to Et3N. The (R)-BINAP
In comparison with the related Rh(I) complex (entries 1 complex induced exclusively (within analytical error) the
and 2), the Ru(II) complex did not work in AcOEt (entry syn-configuration in the product 6. No significant influ-
Scheme 1. Retrosynthetic pathway to the enantiopure side chain of atorvastatin.
Chirality DOI 10.1002/chir

536
ANDRUSHKO ET AL.
Scheme 3. Hydrogenation of b-keto ester (S)-2 under homogeneously
catalyzed conditions.
in the AcONa/Ru ratio and complete inhibition of the hy-
drogenation at a ratio of 2 (runs 19–20). The parent
Ru[(R)-Tol-BINAP]Cl23Et3N complex exhibited similar
activity and syn-selectivity (entry 21, compare with entry
Scheme 2. Synthesis of ethyl (S)-4-(2,2-dimethyl-1,3-dioxolan-4-yl)-3-
oxobutanoate (2) [(a) MeOH, HC(OMe)3, cat. HCl, RT, (93%); (b)
BH3ꢀSMe2, THF, cat. NaBH4 (1 mol %), RT; (c) Me2C(OMe)2, Me2CO, 16). The solubility of this precatalyst in MeOH was better
cat. p-TsOH, RT, (74%); (d) 2N NaOH, RT, and neutralization with 2N
than the analogous BINAP complex.
NaHSO4, (78%); (e) CDI (N,N0-carbonyldiimidazole), THF, RT; (f)
Finally, we found that application of Ru[(R)-Tol-
BINAP]Cl23 AcONa (entry 22) showed results similar to
Ru[(R)-BINAP]Cl2 (dimer) with addition of 1 equiv. of
AcONa (compare with entry 19).
(EtO2CCH2CO2)2Mg, THF, RT, 12h, (90%).]
ence of the chiral backbone of the substrate was observed.
Partial neutralization of Ru[(R)-BINAP]Cl2 (dimer) could
also be achieved by prior treatment with an excess of Et3N
in CH2Cl2 followed by evaporation and drying in vacuum.
The resulted solid, designated as Ru[(R)-BINAP]Cl23
Et3N, was tested in the hydrogenation of b-keto ester (S)-
2. Particularly, it was shown that the activity of this com-
plex is comparable to the activity of the catalytic system
arising after neutralization in solution (compare with
entries 12 and 13).
The activity of the complex is strongly dependent upon
the polarity of the alcohol and follows the order: MeOH >
EtOH >> i-PrOH (compare entries 16–18).
We noticed that all previously studied catalysts were
poorly soluble in the reaction mixture. To overcome this
problem we studied the influence of AcONa on the cata-
lytic performance of Ru[(R)-BINAP]Cl2 (runs 19–20). It is
interesting to note that AcONa acted in the same way as
Et3N, for example, lowering the activity with an increase
To optimize the substrate to catalyst ratio, several Ru(II)
precatalysts, additives, solvents, and conditions (like, tem-
perature and initial H2-pressure) have been tested. Finally,
the best results were achieved with Ru[(R)-Tol-
BINAP]Cl23 AcONa in EtOH at 508C and 100 bar initial
H2-pressure. Under these conditions it was possible to run
the hydrogenation of (S)-2 at a substrate to catalyst ratio
of 1000:1 with complete conversion within 4 h. The prod-
uct (3R,5S)-6 (syn) was obtained with at least 99% de and
ca. 98% chemical purity.
The subsequent transformation of (3R,5S)-6 (syn) into
the atorvastatin precursor 15 was accomplished as shown
in Scheme 5.32 Protection of the HO-group of (3R,5S)-6 fol-
lowed by reduction of the ester-moiety gave aldehyde
(3R,5S)-10 in good yield. Upon subsequent cleavage of the
acetal, the lactol 11 was obtained. Esterification of the pri-
mary hydroxyl group with 4-chlorotoluenesulfonyl chloride,
followed by treatment of the sulfonate obtained with NaCN
TABLE 1. Stereoselective hydrogenation of b-keto ester (S)-2 with chiral Rh(I) and Ru(II) catalysts33
Entry
Precatalyst
Solvent
Time (min)
Conversion (%)
de (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
{Rh[(S)-BINAP](COD)}BF4
{Rh[(S)-BINAP](COD)}BF4
{Rh[(R)-BINAP](COD)}BF4
{Rh[(S,S)-Et-DUPHOS](COD)}BF4
{Rh[(R,R)-Et-DUPHOS](COD)}BF4
{Rh[(S,S)-Me-DUPHOS](COD)}BF4
{Rh[(R,R)-Me-DUPHOS](COD)}BF4
Rh[(R)-Tol-BINAP](COD)]BF4
{Rh[(R,S)-JOSIPHOS](COD)}BF4
Ru[(R)-BINAP]Cl2 (dimer)
MeOH
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
MeOH
AcOEt
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
1000
120
120
70
> 99
> 99
> 99
> 99
> 99
> 99
> 99
> 99
> 99
> 99
< 10
> 99
> 99
0
> 99
> 99
> 99
0
> 99
0
54 (syn)
52 (syn)
50 (anti)
36 (syn)
18 (anti)
40 (syn)
12 (anti)
50 (anti)
40 (syn)
(S,R)-6 (syn) and 9
n.d.
70
120
150
80
50
80
940
100
200
1310
380
120
300
340
140
1000
100
130
Ru[(R)-BINAP]Cl2 (dimer)
Ru[(R)-BINAP]Cl2 (dimer) 1 0.5 Et3N
Ru[(R)-BINAP]Cl2 (dimer) 1 1.0 Et3N
Ru[(R)-BINAP]Cl2 (dimer) 1 2.0 Et3N
Ru[(S)-BINAP]Cl2 (dimer) 1 1.0 Et3N
Ru[(R)-BINAP]Cl23Et3N
Ru[(R)-BINAP]Cl23Et3N
Ru[(R)-BINAP]Cl23Et3N
Ru[(R)-BINAP]Cl2 (dimer) 1 1.0AcONa
Ru[(R)-BINAP]Cl2 (dimer) 1 2.0AcONa
Ru[(R)-Tol-BINAP]Cl23Et3N
> 99 (syn)
98.2 (syn)
–
2.3 (syn)
> 99 (syn)
> 99 (syn)
–
> 99 (syn)
–
> 99 (syn)
> 99 (syn)
i-PrOH
MeOH
MeOH
MeOH
MeOH
> 99
> 99
Ru[(R)-Tol-BINAP]Cl23AcONa
Chirality DOI 10.1002/chir

HIGHLY STEREOSELECTIVE HYDROGENATIONS
537
Fig. 2. Chiral diphosphine ligands applied for stereoselective Rh(I)- and Ru(II)-catalyzed hydrogenation of b-keto ester (S)-2.
gave the nitrile 12. Raney nickel catalyzed hydrogenation of group subsequently removed. Ylide (R)-19 could be pre-
the latter afforded the desired amine 13, which in turn was pared39 starting from methyl 3,3-dimethoxypropanoate
submitted to the Paal–Knorr condensation with the appropri- (16) by two-carbon elongation followed by the enantiose-
ate functionalized diketone 14 to give atorvastatin lactol 15 lective hydrogenation of the prochiral keto group in b-keto
in 71% yield. Oxidation of the acetal and desilylation in order esters 17 to give finally b-hydroxy ester (R)-18. Protec-
to obtain atorvastatin free acid can be conveniently per- tion of the HO-group and transformation of the
formed as recently suggested.38
(MeO)2CH-moiety should accomplish the synthesis of
ylide (R)-19.
b-Keto ester 17, serving as a prochiral substrate for the
enantioselective hydrogenation, was assembled by a two-
carbon chain elongation of 3,3-dimethoxypropionic acid
20 (Scheme 7). The latter was easily available from ester
16 by hydrolysis. A modified two-step Masamune proce-
dure,36 which involved first the activation of acid 20 with
CDI (N,N-carbonyldiimidazole), followed by subsequent
treatment with Mg(O2CCH2CO2Et)2 prepared in situ,
afforded ethyl 5,5-dimethoxy-3-oxopentanoate (17) in 91%
yield.
For the asymmetric hydrogenation of functionalized
b-keto ester 17 (Scheme 8), a number of Rh(I) and Ru(II)
catalysts were tested. Structures of applied chiral ligands
are illustrated on Figs. 2 and 3. Selected results are sum-
marized in Table 2.
SYNTHESIS OF ROSUVASTATIN
Similarly, as shown earlier for the synthesis of atorvasta-
tins we developed a new pathway for the production of
rosuvastatin comprising two highly stereoselective hydro-
genations as key-steps.39,40 The first part covers the asym-
metric hydrogenation of ethyl 5,5-dimethoxy-3-oxopenta-
noate (17) to ethyl 3-hydroxy-5,5-dimethoxypentanoate
(18) (Scheme 6).41 From the retrosynthetic analysis
depicted in Scheme 6 it follows that the chiral side chain
of rosuvastatin acid A can be created by diastereoselective
and chemoselective reduction of the keto group in struc-
ture B. The protected hydroxy ylide (R)-19 was postulated
as a possible building block for the preparation of B, as
long as the Wittig coupling reaction with the correspond-
ing aldehyde could be performed and the HO-protecting
Rh(I) complexes displayed good activities but only poor
enantioselectivities (entries 1–8). Ethyl acetate was found
to be the solvent of choice, since reactions in methanol
and other solvents ran significantly more slowly.
In strong contrast, hydrogenations catalyzed by com-
mercial Ru[(R)-BINAP]Cl2 proceeded smoothly at room
temperature and confirmed the previously reported results
with related bromide based catalyst.42 A route to the
required chiral methyl 3-hydroxy-5,5-dimethoxypentanoate
(18) had been already reported by Geneˆt et al.42 who
hydrogenated the corresponding b-keto ester 17 in the
presence of Ru(BINAP)Br2 (2 mol % catalyst, room tem-
perature, 1 atm H2 pressure) and obtained 18 in 86% yield
and with enantioselectivity >95% ee. According to our
recently published results,39 the hydrogenation of b-keto
ester 17 proceed in MeOH with an initial H2-pressure of
50 bar to give b-hydroxy ester (R)-18 with an enantiose-
Chirality DOI 10.1002/chir
Scheme 4. Transacetalization reaction in acidic medium.

538
ANDRUSHKO ET AL.
Scheme 5. Synthesis of atorvastatin by the lactol pathway [(a) t-BuPh2SiCl, imidazole, DMF, 108C, (94%); (b) DIBALH, Et2O, 2788C, (77%); (c)
HC(OMe)3, MeOH, cat. p-TsOH3Py, 708C, (64%); (d) p-ClC6H4SO2Cl, Py, RT, (96%); (e) NaCN, DMSO, RT, (79%); (f) H2, RaꢁꢁNi, NH3, MeOH, RT,
(>99%); g) THF/toluene, reflux, 30h, (71%).]
Scheme 6. Retrosynthetic pathway to the enantiopure side chain of statins.
Scheme 7. Synthesis of the prochiral b-keto ester 17 [(a) 2N NaOH, RT, and then 2N NaHSO4; (b) CDI (N,N0-carbonyl-diimidazole), THF, RT; (c)
(EtO2CCH2CO2)2Mg, THF, RT, 12 h, (91%).]
Scheme 8. Enantioselective hydrogenation of functionalized b-keto ester 17.
lectivity of 98.7% (entry 11). The reaction was complete
within 3 h at a ratio of S/C 5 500 (entry 11) and within 10
h at a ratio of S/C 5 1000 (entry 12). An increase in the
temperature to 708C made it possible to complete the reac-
tion in 1h with a S/C ratio as high as 10,000 (entry 16),
thus achieving a turnover frequency (TOF) of 10,000 h–1.
Turnover numbers (TONs) of up to 20,000 could be
reached at this temperature, and the reaction was com-
plete within
8 h (entry 17). Enantioselectivities at
increased temperatures were slightly lower, but still above
95% in all trials. After hydrogenation of 17 at 1008C and
100 bar of initial H2-pressure in the presence of Ru[(R)-
Fig. 3. Chiral diphosphine ligands used for the Rh(I)- and Ru(II)-cata-
lyzed enantioselective hydrogenation of b-keto ester 17 [for structures of
other chiral diphosphines, like (R,S)-JOSIPHOS, (S,S)-Me-DUPHOS, and
BINAP]Cl2 (dimer) and a substrate/catalyst ratio 5 20,000, (R)-BINAP, see Figure 2].
Chirality DOI 10.1002/chir

HIGHLY STEREOSELECTIVE HYDROGENATIONS
539
TABLE 2. Enantioselective hydrogenation of b-keto ester 17 using chiral Rh(I) and Ru(II) catalysts39 at 50 bar of
initial H2-pressure (if not otherwise noted)
Entry
Precatalyst
Solvent
S/C
500
1000
500
500
500
500
200
500
200
T (8C)
Time (h)
Conversion (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
{Rh[(R,S)-JOSIPHOS](COD)}BF4
{Rh[(R,S)-JOSIPHOS](COD)}BF4
{Rh[(R,R)-DIOP](COD)}BF4
{Rh[(R)-BINAP](COD)}BF4
{Rh[(S,S)-CHIRAPHOS](COD)}BF4
{Rh[(S,S)-DEGUPHOS](COD)}BF4
{Rh[(S,S)-Me-DUPHOS](COD)}BF4
{Rh[(S,S)-Me-catASiumM](COD)}BF4
Ru[(R)-BINAP]Cl2 (dimer)
Ru[(R)-BINAP]Cl2 (dimer)
Ru[(R)-BINAP]Cl2 (dimer)
Ru[(R)-BINAP]Cl2 (dimer)
Ru[(R)-BINAP]Cl2 (dimer)
Ru[(R)-BINAP]Cl2 (dimer)
Ru[(R)-BINAP]Cl2 (dimer; 10 bar)
Ru[(R)-BINAP]Cl2 (dimer)
Ru[(R)-BINAP]Cl2 (dimer)
Ru[(R)-BINAP]Cl2 (dimer; 100 bar)
Ru[(R)-Tol-BINAP]Cl2 (dimer)
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
CH2Cl2
EtOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
r. t.
r. t.
r. t.
r. t.
r. t.
r. t.
45
r. t.
r. t.
r. t.
r. t.
r. t.
r. t.
50
2
20
4
20
20
18
6
10
20
20
3
10
24
1
> 99
88
15.2 (R)
n.d.
7.6 (S)
58.6 (S)
29.4 (S)
n.d.
n.d.
6.4 (S)
n. d.
> 99
> 99
> 99
< 5
78
> 99
46
68
> 99
> 99
35
> 99
> 99
> 99
> 99
73
500
500
n. d.
98.7 (R)
98.7 (R)
n.d.
97.8 (R)
98.4 (R)
97.0 (R)
95.8 (R)
90.0 (R)
98.2 (R)
1000
2000
2000
2000
10,000
20,000
20,000
500
50
70
70
100
r. t.
4
1
8
0.3
3
> 99
Scheme 9. Determination of the enantiomeric excess of alcohol 18 with the assistance of enantiopure phosphite (R)-21.
incomplete conversion and diminished enantioselectivity
(90%) was noted (entry 18).
Alcohol (R)-18 was transformed into ylide (R)-19 by
the route depicted in Scheme 10. Protection of the HO-
Methanol was found to be the solvent of choice, group was performed by treatment with t-BuPh2SiCl in
since the reaction rates dropped dramatically when the DMF in the presence of imidazole as a base. Selective
reaction was performed in CH2Cl2 (entry 9) or ethanol cleavage of the acetal-moiety in (R)-23 and oxidation was
(entry 10).
performed in one-pot by treatment with Jones’ oxidation
In contrast, at low hydrogen pressure (10 bar), b-keto reagent at 08C, proceeding without racemization at the C-3
ester 17 could be successfully reduced without any loss carbon atom.
of enantioselectivity, but the reaction was significantly
slower than under a pressure of 50 bar (compare entries
14 and 15). The use of the related Ru((R)-Tol-BINAP)Cl2
complex improved neither the activity nor the stereoselec-
tivity of the hydrogenation (entry 19). The results were
identical to those obtained with Ru(BINAP)Cl2.
Enantiomeric compositions for b-hydroxy ester 18 were
determined with help of the chlorophosphite chiral deriva-
tizing agent (R)-21 (Scheme 9),39 prepared from PCl3 and
(R)-BINOL. Chlorophosphite (R)-21 reacted quantitatively
and rapidly with alcohol 18 to give phosphites 22a and
22b. The 31P NMR spectrum of the two diastereomeric
compounds 22 is characterized by signals separated to
the base line (dP 151.4 and 154.6 ppm), so it is possible to
determine the enantiomeric composition of the catalytic
hydrogenation product precisely.
Scheme 10. Multistep synthesis of ylide (R)-19 [(a) tBuPh2SiCl, imid-
azole, DMF, 08C to RT, overnight, (90%); (b) Jones’ oxidation: CrO3,
H2SO4, acetone/water, 08C to RT (68%); (c) AlkOC(O)Cl, NEt3, toluene,
08C to RT, 1 h; (d) Ph3P1–CH3Br–, nBuLi, THF, –788C to 08C, then 15,
–788C to 08C, overnight, (45%).]
Chirality DOI 10.1002/chir

540
ANDRUSHKO ET AL.
Scheme 11. Synthesis of rosuvastatin ethyl ester [(a) MeCN, reflux, 14 h, (70%); (b) HF (aq.), MeCN; (c) Et2BOMe, NaBH4, THF/MeOH, –788C,
(85%, over two steps).]
7. Zhou Z, Rahme E, Pilote L, Are statins created equal? Evidence from
randomized trials of pravastatin, simvastatin, and atorvastatin for cardi-
ovascular disease prevention, Am Heart J 2006;151:273–281.
Mixed anhydrides (R)-25a,b [R 5 Me (a) or R 5 Et
(b)], prepared by treatment of (R)-24 with 1.5 equiv. of
corresponding methyl or ethyl chloroformate in toluene in
8. van der Harst P, Voors AA, van Gilst WH, Bo¨hm M, van Veldhuisen
the presence of Et3N, were submitted for the synthesis of
DJ. Statins in the treatment of chronic heart failure: a systematic
ylide (R)-19 without additional purification. Treatment of
(R)-25a or (R)-25b with methyltriphenylphosphonium
bromide and nBuLi furnished the targeted Wittig reagent
(R)-19 in 45% yield.
Wittig coupling of aldehyde 26 and ylide (R)-19 was
performed under reflux in CH3CN over 14 h and gave the
rosuvastatin precursor 27 in a yield of 70% (Scheme 11).41
Removal of the tBuPh2Si protective group by treatment
with aqueous HF in CH3CN and final exclusive diastereo-
selective reduction of the keto group with Et2B(OMe) and
NaBH4 in THF/MeOH at –788C, afforded rosuvastatin
ethyl ester in 85% yield.
We have presented here two new approaches for the
total syntheses of atorvastatin and rosuvastatin, based on
highly stereoselective hydrogenations of intermediate
b-keto esters. Optimized syntheses of substrates and sub-
sequent multistep transformations of the chiral hydrogena-
tion products in the desired drug constituents show clearly
the great value of stereoselective homogeneous catalysis
for the establishment of new and patent-free routes to
drugs.
review. PLoS Med 2006;3:e333–e333; literature cited therein.
9. Kaye JA, Meier CR, Walker AM, Jick H. Statin use, hyperlipidaemia,
and the risk of breast cancer. Brit J Cancer 2002;86:1436–1439.
10. Ray SK, Rege NN. Atorvastatin: in the management of hyperlipidae-
mia. Drug Rev 2000;46:242–243.
11. Wierzbicki AS, Mikhailidis DP, Wray R, Schachter M, Cramb R, Simp-
son WG, Byrne CB. Statin-fibrate combination therapy for hyperlipi-
daemia: a review. Curr Med Res Opin 2003;19:155–168.
12. Rodenburg J, Vissers MN, Wiegman A, van Trotsenburg ASP, van der
Graaf A, de Groot E, Wijburg FA, Kastelein JJP, Hutten BA. Statin
treatment in children with familial hypercholesterolemia. Circulation
2007;116:664–668.
13. Li JJ, Johnson DS, Sliskovic DR, Roth BD, Atorvastatin calcium
(Lipitor1). In: Contemporary drug synthesis. New York: Wiley-Inter-
science; 2004. p 113–124.
14. Maggon K, Best-selling human medicines 2002–2004. Drug Discov
Today 2005;10:739–742.
15. Croom KF, Plosker GL. Atorvastatin: a review of its use in the primary
prevention of cardiovascular events in patients with type 2 diabetes
mellitus. Drugs 2005;65:137–152.
16. Law MR, Rudnicka AR, Statin safety a systematic review. Am J Cardiol
2006;97 (suppl 8A):52C–60C.
17. Brower PL, Butler DE, Deering CF, Le TV, Millar A, Nanninga TN,
Roth BD. The synthesis of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-
2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for the prepara-
tion of CI-981, a highly potent, tissue selective inhibitor of HMG-CoA
reductase. Tetrahedron Lett 1992;33:2279–2282.
LITERATURE CITED
1. Gaw A, Packard CJ, Shepherd J. Statins: the HMG CoA reductase
inhibitors in perspective. London: Taylor & Francis; 2004. 262 p.
18. Baumann KL, Butler DE, Deering CF, Mennen KE, Millar A, Nan-
ninga TN, Palmer CW, Roth BD. The convergent synthesis of CI-981,
an optically active, highly potent, tissue selective inhibitor of HMG-
CoA reductase. Tetrahedron Lett 1992;33:2283–2284.
2. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low
density lipoprotein cholesterol, ischaemic heart disease, and stroke:
systematic review and meta-analysis. BMJ 2003;326:1423–1429.
3. Shepherd J, Hunninghake DB, Barter P, McKenney JM, Hutchinson
HG. Guidelines for lowering lipids to reduce coronary artery disease
risk: a comparison of rosuvastatin with atorvastatin, pravastatin, and
simvastatin for achieving lipid-lowering goals. Am J Cardiol 2003;91
(5A Suppl S):11C–17C.
19. Ra´dl S, Stach J, Hajicek J. An improved synthesis of 1,1-dimethylethyl
6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate
for atorvastatin synthesis. Tetrahedron Lett 2002;43:2087–2090.
20. George S, Sudalai A. An efficient organocatalytic route to the atorvas-
tatin side-chain. Tetrahedron Lett 2007;48:8544–8546.
4. Endo A. The discovery and development of HMG-CoA reductase
inhibitors. J Lipid Res 1992;33:1569–1582.
21. Pandey PS, Rao TS. An efficient synthesis of N3,4-diphenyl-5-(4-
fluorophenyl)-2-isopropyl-1H-3-pyrrolecarboxamide, a key intermedi-
ate for atorvastatin synthesis. Bioorg Med Chem Lett 2004;14:
129–131.
5. Chasman DI, Posada D, Subrahmanyan L, Cook NR, Stanton VP Jr,
Ridker PM. Pharmacogenetic study of statin therapy and cholesterol
reduction. JAMA 2004;291:2821–2827.
22. Culhane NS, Lettieri SL, Skae JR. Rosuvastatin for the treatment of
hypercholesterolemia. Pharmacotherapy 2005;25:990–1000; literature
cited therein.
6. Cummings SR, Bauer DC. Do statins prevent both cardiovascular dis-
ease and fracture? JAMA 2000;283:3255–3257.
Chirality DOI 10.1002/chir

HIGHLY STEREOSELECTIVE HYDROGENATIONS
541
23. Hirsch M, O’Donnell J, Olsson A. Rosuvastatin is cost-effective com-
pared with atorvastatin in reaching cholesterol goals. Int J Cardiol
2005;104:251–256.
lytic sodium tetrahydroborate as
a´-hydroxy esters. Versatile chiral building block from (S)-(2)-malic
acid. Chem Lett 1984;13:1389–1392.
a
selective reducing agent for
24. Hoey S. The therapeutic benefits of rosuvastatin. Brit J Card Nurs
2008;3:482–484.
35. Saito S, Ishikawa T, Kuroda A, Koga K, Moriwake T. A revised
mechanism for chemoselective reduction of esters with borane-
dimethyl sulfide complex and catalytic sodium tetrahydroborate
directed by adjacent hydroxyl group. Tetrahedron 1992;48:4067–
4086.
25. Quirk J, Thornton M, Kirkpatrick P. Rosuvastatin calcium. Nature Rev
Drug Discov 2003;2:769–770; literature cited therein.
26. Pfefferkorn JA. Second-generation HMG-CoA reductase inhibitors.
Synthesis of rosuvastatin. In: Johnson DS, Li JJ, editors. The art of
drug synthesis. New Jersey: John Wiley; 2007. p 174–176; literature
cited therein.
36. Brooks DW, Lu LDL, Masamune S, C-Acylation under Virtu-
ally Neutral Conditions. Angew Chem Int Ed Engl 1979;18:72–
74.
27. Casar Z, Mesar T. Processes for the preparation of statins, particularly
rosuvastatin, and intermediates for the preparation thereof. EP1978020
A1, 2008.
37. Kitamura M, Tokunaga M, Ohkuma M, Noyori R. Convenient
preparation of binap-ruthenium(II) complexes catalyzing asymmetric
hydrogenation of functionalized ketones. Tetrahedron Lett 1991;32:
4163–4166.
28. Balanov A, Shenkar N, Niddam-Hildesheim V. Preparation of rosuvas-
tatin. US Pat Appl, US2007167625 A1, 2007.
38. Tararov V, Korostylev A, Bo¨rner A, Boba´l P, Frantisek J, Stohandl J,
Denike K, Jeker N. Process for preparing C5 products and their use
for atorvastatin synthesis. EP1705175 A1, 2006.
29. Radl S, Stach J, Klvana R, Jirman J. A method for the production of
the hemi-calcium salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl
(methylsulfonyl)amino]pyrimidine-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic
acid. PCT Int Appl, WO 2007000121 A1, 2007.
39. Korostylev A, Andrushko V, Andrushko N, Tararov VI, Ko¨nig G,
Bo¨rner A. Highly enantioselective hydrogenation of ethyl 5,5-di-
methoxy-3-oxopentanoate and its application for the synthesis of a sta-
tin precursor. Eur J Org Chem 2008:840–846.
30. Patel DJ, Kumar R, Dwivedi SPD. Process for preparing rosuvastatin
calcium. WO2007099561 A1, 2007.
31. Available at: http://www.forbes.com.
40. Andrushko V, Andrushko N, Ko¨nig G, Bo¨rner A. Highly enantioselec-
tive catalytic hydrogenation of a 5-amino-3,5-dioxopentanoic ester. Tet-
rahedron Lett 2008;49:4836–4839.
32. Tararov VI, Andrushko N, Andrushko V, Ko¨nig G, Spannenberg A,
Bo¨rner A. Synthesis of the chiral side chain of statins—lactone versus
lactol pathway. Eur J Org Chem 2006:5543–5550.
41. Andrushko N, Andrushko V, Ko¨nig G, Spannenberg A, Bo¨rner A. A
new approach to the total synthesis of rosuvastatin. Eur J Org Chem
2008:847–853.
33. Tararov VI, Ko¨nig G, Bo¨rner A. Synthesis and highly stereoselective
hydrogenation of the statin precursor ethyl (5S)-5,6-isopropylidene-
dioxy-3-oxohexanoate. Adv Synth Catal 2006b;348:2633–2644.
42. Poupardin O, Greck C, Geneˆt J-P. Rapid asymmetric synthesis of
highly functionalized C5 chiral synthons. Practical preparation of
trans-3-hydroxy-D-proline. Synlett 1998;11:1279–1281.
34. Saito S, Hasegawa T, Inaba M, Nishida R, Fujii T, Nomizu S, Mori-
wake T. Combination of borane-dimethyl sulfide complex with cata-
Chirality DOI 10.1002/chir