Highly enantioselective hydrogenation of ethyl 5,5-dimethoxy-3- oxopentanoate and its application for the synthesis of a statin precursor

Article abstract of DOI:10.1002/ejoc.200701059

The highly enantioselective hydrogenation of ethyl 5,5-dimethoxy-3- oxopentanoate (3) to ethyl 3-hydroxy-5,5-dimethoxypentanoate (4) - a key intermediate in the synthesis of pharmacologically important statin drugs - has been investigated. The stereochemistry of the catalytic hydrogenation of the β-keto ester in the presence of a number of homogeneous chiral Rh ^I and Ru^II complexes with phosphane ligands has been studied. The highest enantioselectivity for the homogeneous hydrogenation of 3 (up to 98.7%ee) was achieved through an optimized version of Genet's procedure with a Ru[(R)-BINAP]Cl₂ pre-catalyst (substrate/catalyst ratio up to 20000:1, 50 bar H₂, 50°C, in MeOH). The transformation of alcohol R-(4) into ylide R-(6) as an important precursor of the chiral side chain of rosuvastatin is also illustrated. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701059

FULL PAPER
DOI: 10.1002/ejoc.200701059
Highly Enantioselective Hydrogenation of Ethyl 5,5-Dimethoxy-3-
oxopentanoate and its Application for the Synthesis of a Statin Precursor[‡]
Andrei Korostylev,[a] Vasyl Andrushko,*[a] Natalia Andrushko,[a] Vitali I. Tararov,[a]
Gerd König,[b] and Armin Börner*[a,c]
Keywords: Statins / Asymmetric catalysis / Hydrogenation / β-Keto esters / Rhodium / Ruthenium / Stereoselectivity /
Rosuvastatin
The highly enantioselective hydrogenation of ethyl 5,5-di-
methoxy-3-oxopentanoate (3) to ethyl 3-hydroxy-5,5-dimeth-
oxypentanoate (4) – a key intermediate in the synthesis of
pharmacologically important statin drugs – has been investi-
gated. The stereochemistry of the catalytic hydrogenation of
the β-keto ester in the presence of a number of homogeneous
chiral RhI and RuII complexes with phosphane ligands has
geneous hydrogenation of 3 (up to 98.7% ee) was achieved
through an optimized version of Genêt’s procedure with a
Ru[(R)-BINAP]Cl2 pre-catalyst (substrate/catalyst ratio up to
20000:1, 50 bar H2, 50 °C, in MeOH). The transformation of
alcohol R-(4) into ylide R-(6) as an important precursor of the
chiral side chain of rosuvastatin is also illustrated.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
been studied. The highest enantioselectivity for the homo- Germany, 2008)
atoms,[6c,9,12] or double bonds[12c] – in the vicinity of the
keto group.
Introduction
Asymmetric reactions catalyzed by transition metals rep-
resent one of the most powerful tools for the synthesis of
enantiomerically pure compounds.[1] In particular, enantio-
selective hydrogenation can be conducted on a large scale
by use of hydrogen as a cheap reducing agent.[2] Various
β-keto esters have thus been hydrogenated with excellent
enantioselectivities in the presence of Ru-diphosphane cata-
lysts to afford β-hydroxy esters.[3] These compounds can
serve as valuable building blocks for the synthesis of natural
and biologically active compounds.[4] Starting with the pi-
oneering experiments with a Ru catalyst based on the atrop-
Recently we reported on the preparation and highly ster-
eoselective hydrogenation of ethyl (5S)-5,6-isopropylidene-
dioxy-3-oxohexanoate (1)[13] as a key intermediate on the
pathway to the chiral side chain of pharmaceutically impor-
tant atorvastatin (Scheme 1).[14,15]
Systematic investigation of the diastereoselective hydro-
genation of β-keto ester 1 in the presence of a number of
homogeneous achiral and chiral RhI and RuII complexes
with phosphane ligands showed that Ru[(R)-Tol-BINAP]-
Cl2, neutralized with one equivalent of AcONa, afforded
the most efficient catalytic system for the production of op-
tically pure syn-(5S)-3-hydroxy-5,6-(isopropylidenedioxy)-
hexanoate (syn-2). At a preparative substrate/catalyst ratio
of 1000:1, diastereoselectivities of up to Ͼ99% were
achieved.[13] Chiral building block syn-3 was successfully
applied for the synthesis of atorvastatin by the lactol path-
way.[14]
From the retrosynthetic analysis shown in Scheme 2 it
follows that the chiral side chain of statins of general struc-
ture A (R is a hydrophobic heterocyclic or a carbocyclic
moiety) can also be created by diastereoselective and
chemoselective reduction of the carbonyl group in structure
B. Protected hydroxy ylides 6 were postulated as possible
building blocks for preparation of B, as long as the Wittig
coupling reaction with the corresponding aldehyde could
be performed and the HO-protecting groups subsequently
cleaved.[16] This approach would give access to the newest
statin, rosuvastatin,[17] also known as super-statin.[18]
Our strategy for the synthesis of the chiral side chain of
statins is also shown in Scheme 2. It includes two-carbon
isomeric ligand BINAP performed by Noyori et al.,[5]
a
wide variety of other chiral phosphorus ligands have been
developed, including other biaryl diphosphanes,[6] bisphos-
pholanes,[7] P-chiral ligands,[8] monodentate phosphanes,[9]
planar chiral diphosphanes derived from ferrocene,[10] and
paracyclophane.[11] In contrast, the array of substrates in-
vestigated is rather limited, usually restricted to simple β-
alkyl or aryl residues. Only a few investigations have been
dedicated to the use of substrates bearing functional
groups – such as a benzyloxy group,[4a,4b,5a] halogen
[‡] Part III of a series of manuscripts dedicated to the synthesis of
statins. Part II: Ref.[14]
[a] Leibniz-Institut für Katalyse an der Universität Rostock e.V.,
Albert-Einstein-Str. 29a, 18059 Rostock, Germany
E-mail: vasyl.andrushko@catalysis.de
[b] Ratiopharm GmbH,
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
840
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Enantioselective Hydrogenation
Scheme 1. Alternative pathways for the total synthesis of statins such as atorvastatin and rosuvastatin with stereoselective hydrogenations
as key steps.
Scheme 2. Retrosynthetic pathway to the enantiopure side chain of statins [Alk = Et as follows below, or other alkyl group could also
be used; tert-butyldiphenylsilyl (TBDPS) was considered as protecting group (PG)].
elongation of methyl 3,3-dimethoxypropanoate (5) to afford
Results and Discussion
β-keto esters 3, followed by enantioselective hydrogenation
β-Keto ester 3, serving as a prochiral substrate for the
of the prochiral keto group to furnish β-hydroxy esters 4.
subsequent enantioselective hydrogenation, was assembled
by a two-carbon chain elongation of 3,3-dimethoxypropi-
onic acid (7, Scheme 3). The latter compound was easily
available from ester 5 by hydrolysis. A modified two-step
Protection of the HO functionality and transformation of
the (MeO)2CH moiety affords the desired Wittig reagent 6.
A route to the required chiral methyl 3-hydroxy-5,5-di-
methoxypentanoate (4) had been already reported by Genêt
et al., who hydrogenated the corresponding β-keto ester 3
in the presence of Ru(BINAP)Br2 (2 mol-% catalyst, room
temperature, 1 atm H2 pressure) and obtained 4 in 86%
yield and with Ͼ95% ee.[19]
Here we report on our efforts towards the highly enantio-
selective preparation of β-hydroxy ester 4 and its subse-
quent transformation into the Wittig reagent 6. Both chiral
compounds are not only useful for the synthesis of enantio-
pure statins, but can also be applied as versatile chiral build-
ing blocks for the synthesis of other β-substituted carbox-
ylic acid derivatives.[20]
Scheme 3. Synthesis of the prochiral substrate 3.
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V. Andrushko, A. Börner et al.
FULL PAPER
Masamune procedure,[13,21] which first involved the acti- by protection of these hydroxy groups as an acetonide. A
vation of acid 7 with N,NЈ-carbonyldiimidazole, followed similar observation was made by Jendralla et al. in the hy-
by subsequent treatment with Mg(O2CCH2CO2Et)2 pre- drogenation of a 5-benzyloxy-3-oxopentanoate, where no
pared in situ, afforded ethyl 5,5-dimethoxy-3-oxopentano- influence of the protected HO group on the course of the
ate (3) in 91% yield.
hydrogenation was noted.[24] Also in the case of substrate 3
Results of the catalytic enantioselective hydrogenation of considered here, the presence of the acetal group did not
3 are summarized in Table 1. Hydrogenation catalyzed by prevent the achievement of excellent ee values. Moreover,
commercial Ru[(R)-BINAP]Cl2 proceeded smoothly at Noyori et al. found that the highest ee values and shortest
room temp. and confirmed the results of Genêt et al. with reaction times (5 min) with related substrates were obtained
the related bromide-based catalyst.[19] In MeOH with an when the hydrogenations were run at 100 °C and 100 bar
initial H2 pressure of 50 bar, β-hydroxy ester 4 was obtained H2 initial hydrogen pressure.[25] When the hydrogenation of
with an enantioselectivity of 98.7% ee (Entry 3). The reac- 3 was performed under these conditions, incomplete con-
tion was complete within 3 hours at a ratio of S/C = 500 version and diminished enantioselectivity (90% ee) was ob-
(Entry 3) and within 10 hours at a ratio of S/C = 1000 (En- tained (Entry 10). In contrast, at low hydrogen pressure
try 4). An increase in the temperature to 70 °C made it pos- (10 bar), β-keto ester 3 could be successfully reduced with-
sible to complete the reaction in 1 h with a S/C ratio as high out any loss of enantioselectivity, but the reaction was sig-
as 10000 (Entry 8), thus achieving a turnover frequency nificantly slower than under a pressure of 50 bar (compare
(TOF) of 10000 h–1. Turnover numbers (TONs) of up to Entries 6 and 7).
20000 could be reached at this temperature, and the reac-
The use of the related Ru((R)-Tol-BINAP)Cl2 complex
tion was complete within 8 h (Entry 9). Enantioselectivities improved neither the activity nor the stereoselectivity of the
at increased temperatures were slightly lower, but still above hydrogenation (Entry 12). The results were identical to
95% ee in all trials. Methanol was found to be the solvent those obtained with Ru(BINAP)Cl2.
of choice, since the reaction rates dropped dramatically
when the reaction was performed in CH2Cl2 (Entry 1) or metal catalysts able to mediate the hydrogenation of ketones
ethanol (Entry 2). to alcohols. Togni et al. reported the highly enantioselective
Homogeneous ruthenium complexes are not the only
As pointed out by Brown, the presence of additional reduction of β-keto esters (up to 97% ee) catalyzed by a
functional groups may seriously affect the enantioselectivity rhodium complex based on Josiphos as a chiral ligand un-
of hydrogenation, due to competitive ligation to the catalyt- der mild conditions (room temp., 20 bar H2, 15 h).[26]
ically active metal.[23] This rule was confirmed by us in the Therefore, we also screened a set of analogous rhodium
hydrogenation of a related β-keto ester bearing neighboring complexes with several commercially available chiral di-
hydroxy groups.[13] However, this effect could be diminished phosphanes. Ethyl acetate was found to be the solvent of
Table 1. Enantioselective hydrogenation of functionalized β-keto ester 3.[22]
Entry Catalyst
Solvent
S/C
ratio
T
[°C]
Time
[h]
%
%
ee
Conversion
1
2
3
4
5
6
7
8
Ru((R)-BINAP)Cl2
Ru((R)-BINAP)Cl2
Ru((R)-BINAP)Cl2
Ru((R)-BINAP)Cl2
Ru((R)-BINAP)Cl2
Ru((R)-BINAP)Cl2
Ru((R)-BINAP)Cl2 (10 bar)
Ru((R)-BINAP)Cl2
Ru((R)-BINAP)Cl2
CH2Cl2
EtOH
200
500
500
room temp.
room temp.
room temp.
room temp.
room temp.
50
50
70
70
100
20
20
3
10
24
1
4
1
8
0.3
6
46
68
Ͼ99
Ͼ99
35
Ͼ99
Ͼ99
Ͼ99
Ͼ99
73
n.d.
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)
n.d.
98.2 (R)
15.2 (R)
n.d.
7.6 (S)
n.d.
58.6 (S)
29.4 (S)
n.d.
n.d.
6.4 (S)
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
CH2Cl2
MeOH
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
1000
2000
2000
2000
10000
20000
20000
200
500
500
1000
500
1000
500
9
10
11
12
13
14
15
16
17
18
19
20
21
Ru((R)-BINAP)Cl2 (100 bar)
Ru((R)-Tol-BINAP)Cl2
Ru((R)-Tol-BINAP)Cl2
45
82
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
45
3
2
Ͼ99
Ͼ99
88
Ͼ99
64
Ͼ99
Ͼ99
Ͻ5
[Rh((R,S)-Josiphos)COD]BF4
[Rh((R,S)-Josiphos)COD]BF4
[Rh((R,R)-DIOP)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((R,R)-Me-catASiumM)COD]BF4
20
4
20
20
20
18
6
500
500
200
500
78
Ͼ99
room temp.
10
842
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Enantioselective Hydrogenation
choice, since reactions in methanol and other solvents ran product precisely. According to the well established general
significantly more slowly. Even in ethyl acetate, however, trend,[5a,12c] Ru((R)-BINAP)Cl2 produced (R)-4 as the pre-
Rh/Josiphos gave much lower activity than Ru/BINAP and dominant enantiomer.
only a disappointing 15% ee (Entries 13, 14). Other Rh cat-
Alcohol (R)-4 was transformed into ylide (R)-6 by multi-
alysts provided low to moderate enantioselectivities and step synthesis by the route depicted in Scheme 5. Protection
were less active than the Rh/Josiphos complex (Entries 15– of the HO functionality of alcohol (R)-4 was performed
21).
by treatment with tBuPh2SiCl in DMF in the presence of
Interestingly, several trials of the analysis of the alcohol imidazole as a base. The silyl ether (R)-10 was obtained in
4 by gas chromatography on various chiral columns gave a yield of 90%. Selective cleavage of the acetal moiety in
no satisfactory resolution of enantiomers. As a convenient (R)-10 was performed in acetone/H2O in the presence of
alternative, enantiomeric compositions of the product were a catalytic amount of p-toluenesulfonic acid hydrate. After
determined with the help of the chiral derivatizing agent 8 purification, the aldehyde (R)-11 was obtained in 98%
(Scheme 4).
yield. Oxidation was performed by treatment with Jones’
oxidation reagent at 0 °C, proceeding without racemization
at the C-3 carbon atom. It was found that both cleavage of
the acetal moiety and oxidation of the aldehyde group
could be performed in one-pot fashion under Jones’ oxi-
dation conditions in acetone at 0 °C.
Further transformations of (R)-3-(tert-butyldiphenyl-
silyloxy)-5-ethoxy-5-oxopentanoic acid ((R)-12) into ylide
(R)-6 were performed by a modified procedure reported by
Konoike et al.[16] by preparation of mixed anhydrides (R)-
13a or (R)-13b (for 13a: R = Me; for 13b: R = Et). Treat-
ment of (R)-12 with 1.5 equiv. of methyl or ethyl chloro-
formate proceeded in toluene in the presence of Et3N. Com-
pounds (R)-13a or (R)-13b were formed in 91–95% yields.
Mixed anhydrides were obtained with 95–98% purity and
were applied in the next step without additional purifica-
tion. Treatment of (R)-13a or (R)-13b with methyltri-
phenylphosphonium bromide and nBuLi furnished the tar-
geted Wittig reagent (R)-6 in 45% yield.[28] The employ-
ment of ylide (R)-6 for the synthesis of rosuvastatin, as well
as the synthesis of the requisite heterocyclic part, will be
described in a subsequent publication.[29]
Scheme 4. Determination of the enantiomeric excess of alcohol 4
with the assistance of enantiopure phosphite 8.
This chlorophosphite is readily available from (R)-
BINOL in one step[27] and reacted quantitatively and
rapidly with the alcohol 4 to give phosphites 9a and 9b. The
31P NMR spectrum of the two diastereomeric compounds
9 is characterized by signals separated to the base line (δP
Conclusions
The highly enantioselective homogeneous hydrogenation
151.4 and 154.6 ppm), so it is possible to determine the en- of ethyl 5,5-dimethoxy-3-oxopentanoate (3) can be carried
antiomeric composition of the catalytic hydrogenation out in the presence of Ru((R)-BINAP)Cl2 as pre-catalyst at
Scheme 5. Synthetic pathway to rosuvastatin through the Wittig reaction between ylide (R)-6 and the corresponding aldehyde; a) tBuPh2-
SiCl, imidazole, DMF, 0 °C Ǟ room temperature, overnight, 90%; b) pTsOH·H2O, acetone/H2O (5:1), reflux, 2 h, 98%; c) Jones’ oxi-
dation: CrO3, H2SO4, acetone/water, 0 °C Ǟ room temperature, 68%; d) AlkOC(O)Cl, NEt3, toluene, 0 °C Ǟ room temperature, 1 h;
e) Ph3P+–CH3 Br–, nBuLi, THF, –78 °C Ǟ 0 °C, then 15, –78 °C Ǟ 0 °C, overnight, 45%.
Eur. J. Org. Chem. 2008, 840–846
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V. Andrushko, A. Börner et al.
FULL PAPER
Evaporation of the solvent in vacuo gave hydroxy ester 4 as yellow-
ish oil in quantitative yield. 1H NMR (400 MHz, CDCl3): δ = 1.27
(t, J = 7.1 Hz, 3 H, OCH2CH3), 1.75–1.83 [m, 2 H, CH2CH-
(OMe)2], 2.60 (dd, J = 15.96 and 4.35 Hz, 1 H, CHaHbCO2Et),
2.74 (dd, J = 15.96 and 8.26 Hz, 1 H, CHaHbCO2Et), 3.42 [s, 3 H,
CH(OCH3)a(OCH3)b], 3.45 [s, 3 H, CH(OCH3)a(OCH3)b], 3.76
(brs, 1 H, OH), 4.25 (q, J = 7.1 Hz, 2 H, OCH2CH3), 4.59–4.72
(m, 1 H, CHOH), 4.92 [t, J = 5.63 Hz, 1 H, CH(OMe)2] ppm. 13C
NMR (75 MHz, C6D6): δ = 14.15 (OCH2CH3), 39.62 (CH2CO2Et),
41.91 [CH2CH(OMe)2], 52.88 [CH(OCH3)a(OCH3)b], 52.92
room temperature according to an optimized methodology
by Genêt et al., affording the corresponding β-function-
alized β-hydroxy ester (R)-4 in up to 98.7% ee. TONs of up
to 20000 were achieved. An increase in the temperature to
70 °C made it possible to complete the reaction up to ten
times more rapidly, with enantioselectivities slightly lower,
but still above 95% ee. The resulting chiral ethyl (R)-3-hy-
droxy-5,5-dimethoxypentanoate [(R)-4] represents a valu-
able chiral building block for further transformations. For
example the conversion of alcohol R-(4) into ylide R-(6) as [CH(OCH3)a(OCH3)b], 60.35 (CHOH), 65.27 (OCH2Me), 103.13
[CH(OMe)2], 172.23 (CO2Et) ppm.
a versatile building block for the synthesis of the chiral side
chain of statins has been demonstrated.
Determination of the Enantiomeric Composition of Compound 4. Ge-
neral Procedure: A solution of (R)-8[27] (10%, 0.5 mL, 0.14 mmol)
in dry benzene, the alcohol 4 (21 mg, 0.10 mmol), abs. Et3N (20 mg,
0.19 mmol), and dry [D6]benzene (0.1 mL) were mixed together in
a vial. The resultant pale solution was immediately transferred into
an NMR tube under argon, and the 31P NMR spectrum was then
recorded. Two singlet peaks at δP = 151.4 and 154.6 ppm and sepa-
rated down to the baseline correspond to compounds 9a and 9b,
respectively. The enantiomeric excess of the alcohol 4 was calcu-
lated from the integral intensities of the peaks.
Experimental Section
General: MeOH and AcOEt (packed under N2) for hydrogenation
were purchased from Aldrich. CH2Cl2 was distilled from CaH2,
THF and Et2O were distilled from Na·Ph2CO under Ar, and DMF
was dried with 3-Å molecular sieves for 72 h prior to vacuum distil-
lation. Other commercial reagents were used without additional pu-
rification. NMR spectra were recorded with a Bruker ARX 400
spectrometer or a Bruker ARX 300 spectrometer. Chemical shifts
Ethyl (R)-3-(tert-Butyldiphenylsilyloxy)-5,5-dimethoxypentanoate
(10): tert-Butyldiphenylsilyl chloride (4.15 g, 15.09 mmol) was
added dropwise over 30 min at 0 °C to a solution of ethyl (R)-3-
hydroxy-5,5-dimethoxypentanoate [(R)-4, 2.83 g, 13.72 mmol] and
imidazole (2.05 g, 30.18 mmol) in dry DMF (15 mL). The reaction
mixture was stirred for 2 h at room temp. and then diluted with
H2O (100 mL). The crude product was extracted with ethyl acetate
(3ϫ100 mL), and the combined extracts were washed successively
with water, saturated NaHCO3 (2ϫ100 mL), and brine and dried
with Na2SO4. EtOAc was then evaporated. Column chromatog-
raphy purification (silica gel, eluent n-hexane/EtOAc, 5:1) afforded
1
(δ, in ppm) are given relative to TMS as internal standard for H
NMR and relative to the residual CDCl3 peak for 13C NMR (δ =
77.16 ppm) and C6D6 peak for 13C NMR (δ = 128.06 ppm).[30]
Spin–spin coupling constants (J) are given in Hz. The optical rota-
tion was measured on a “gyromat-HP” instrument.
Ethyl 5,5-Dimethoxy-3-oxopentanoate (3): Solid N,NЈ-carbonyl-
diimidazole (Im2CO, 50.02 g, 0.308 mol) was added in portions
over 5–10 min to a solution of acid 7 (41.45 g, 0.288 mol) in dry
THF (200 mL, gas evolution). The mixture was then stirred at
room temp. for 2 h to produce the corresponding imidazolide in
situ.
1
(R)-10 (5.49 g, 90% yield). H NMR (400 MHz, C6D6): δ = 0.9 (t,
J = 7.17 Hz, 3 H, OCH2CH3), 1.17 [s, 9 H, C(CH3)3], 2.01–2.06
[m,
2 H, CH2CH(OMe)2], 2.57 (d, J = 1.16 Hz, 1 H,
In another flask, a mixture of monoethyl malonate (83.5 g,
0.632 mol) and commercial Mg powder of particle size Ͻ0.1 mm
(10.24 g, 0.422 mol) in dry THF (300 mL) was stirred under reflux
for 4 h to form Mg(OOCCH2COOEt)2 in situ; this was cooled
down to room temp. and added to the former solution. The resid-
ual Mg powder was rinsed with THF (100 mL), and the washing
solution was added to the reaction mixture. The mixture was stirred
overnight at room temp. and concentrated in vacuo. The residue
was dissolved in ethyl acetate (300 mL) and acidified with NaHSO4
(620 mL, 2 ) with vigorous stirring. The organic layer was sepa-
rated and washed successively with water, saturated NaHCO3
(3ϫ200 mL), and brine. It was subsequently dried with Na2SO4
and the solvents were removed. Vacuum distillation of the residue
(b.p. 86–92 °C/0.06 mbar) afforded keto ester 3 (53.62 g, 91%
CHaHbCO2Et), 2.59 (d, J = 1.26 Hz, 1 H, CHaHbCO2Et), 2.95 [s,
3 H, CH(OCH3)a(OCH3)b], 2.99 [s, 3 H, CH(OCH3)a(OCH3)b],
3.87 (q, J = 7.17 Hz, 2 H, OCH2CH3), 4.54 [t, J = 5.71 Hz, 1 H,
CH(OCH3)2], 4.60 (quintet, J = 6.11 Hz, 1 H, CHOSi), 7.17–7.21
(m, 6 H, Ar), 7.78–7.86 (m, 4 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.19 (OCH2CH3), 19.21 (CMe3), 26.98 [C(CH3)3],
37.87 (CH2CO2Et), 42.40 [CH2CH(OMe)2], 52.05 [CH(OCH3)a-
(OCH3)b], 52.90 [CH(OCH3)a(OCH3)b], 60.36 (OCH2Me), 67.50
(CHOSi), 101.58 [CH(OMe)2], 133.76 (C, Ar), 133.95 (C, Ar),
134.92 (CH, Ar), 135.49 (C, Ar), 135.60 (CH, Ar), 135.97 (CH,
Ar), 136.04 (CH, Ar), 171.26 (CO2Et) ppm.
Ethyl (R)-3-(tert-Butyldiphenylsilyloxy)-5-oxopentanoate (11): p-
Toluenesulfonic acid hydrate (p-TsOH·H2O, 120 mg, 0.63 mmol)
was added to a solution of (R)-10 (1.2 g, 2.7 mmol) in acetone/H2O
(5:1, 28.8 mL). The reaction mixture was heated at reflux for 2 h
until 100% conversion was achieved (reaction was monitored by
TLC: toluene/EtOAc, 20:1), and the solvent was evaporated under
reduced pressure. The residue was dissolved in EtOAc, and washed
successively with saturated NaHCO3 and brine. The organic layer
was subsequently dried with Na2SO4 and the solvents were evapo-
rated. Purification of the crude product by column chromatography
(silica gel, eluent n-hexane/EtOAc, 10:1) afforded aldehyde (R)-11
1
yield). H NMR (400 MHz, CDCl3): δ = 1.28 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 2.86 [d, J = 5.6 Hz, 2 H, CH2CH(OMe)2], 3.37 [s, 6
H, CH(OCH3)2], 3.49 (s, 2 H, CH2CO2Et), 4.20 (q, J = 7.1 Hz, 2
H, OCH2CH3), 4.78 [t, J = 5.6 Hz, 1 H, CH(OCH3)2] ppm. 13C
NMR (100 MHz, CDCl3):
δ = 14.34 (OCH2CH3), 46.88
[CH2CH(OMe)2], 50.40 (CH2CO2Et), 54.21 [CH(OCH3)2], 61.61
(OCH2Me), 101.59 [CH(OMe)2], 167.21 (CO2Et), 200.08 [C(O)-
CH2CO2Et] ppm.
Catalytic Hydrogenation of 3. General Procedure: Keto ester 3
(2.04 g, 10 mmol) and Ru((R)-BINAP)Cl2 (0.004 g, 0.005 mmol) (1.05 g, 98% yield) as a colorless, viscous oil. 1H NMR (300 MHz,
were placed in an autoclave under argon, followed by addition of
abs. MeOH (8 mL). The mixture was pressurized with hydrogen to
50 bar and stirred at 50 °C until the H2 consumption stopped (1 h).
C6D6): δ = 0.88 (t, J = 7.17 Hz, 3 H, OCH2CH3), 1.11 [s, 9 H,
C(CH3)3], 2.30–2.34 (m, 2 H, CH2CHO), 2.39 (d, J = 6.07 Hz, 1
H, CHaHbCO2Et), 2.46 (d, J = 6.07 Hz, 1 H, CHaHbCO2Et), 3.82
844
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Eur. J. Org. Chem. 2008, 840–846

Enantioselective Hydrogenation
(q, J = 7.17 Hz, 2 H, OCH2CH3), 4.67 (quintet, J = 6.0 Hz, 1 H,
tig reagent 6 (3.7 g, 45%) as a viscous oil. [α]2D2 = –6.5 (c = 1,
CHOSi), 7.17–7.23 (m, 6 H, Ar), 7.67–7.80 (m, 4 H, Ar), 9.24 (t, J CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.01 [s, 9 H, SiC-
= 1.88 Hz, 1 H, CHO) ppm.
(CH3)3], 1.19 (t, J = 7.12 Hz, 3 H, OCH2CH3), 2.33–2.83 (m, 4 H,
CH2COCH=PPh3 and CH2CO2Et), 3.43 (br., 1 H, CH=P), 3.96–
4.13 (m, 2 H, OCH2CH3), 4.57–4.65 (m, 1 H, CHOSi), 7.25–7.33
(m, 6 H, Ar), 7.37–7.44 (m, 6 H, Ar), 7.47–7.55 (m, 9 H, Ar) 7.69–
7.74 (m, 4 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.11
(OCH2CH3), 19.23 (CMe3), 26.83 [C(CH3)3], 42.24 (CH2CO2Et),
(R)-3-(tert-Butyldiphenylsilyloxy)-5-ethoxy-5-oxopentanoic
Acid
(12): Jones’ oxidizing reagent was added dropwise (over ca. 30 min)
at 0 °C to a solution of alcohol (R)-10 (1.2 g, 2.7 mmol) in an ace-
tone/water mixture (5:1, 10.6 mL). The addition was continued un-
til the characteristic orange color of the reagent persisted for about
20 min. The stirrer was removed, and the mixture was decanted.
The residual green salts were rinsed with acetone (2ϫ10 mL). The
washings were added to the main acetone solution and additional
oxidizing agent was added, if necessary, to ensure complete reac-
tion. The stirrer was replaced and propan-2-ol was added dropwise
until excess Jones’ reagent was destroyed. In small portions and
with caution, a solution of NaHCO3 was added and the suspension
was stirred vigorously until the pH of the reaction mixture became
neutral. The suspension was filtered, and the filter cake was washed
with acetone (2ϫ25 mL). The filtrate was concentrated and ad-
ditionally purified by column chromatography (silica gel, eluent n-
hexane/EtOAc, 1:1). Yield of (R)-12: 761 mg (68% yield) as a color-
less oil. 1H NMR (300 MHz, CDCl3): δ = 0.92 [s, 9 H, SiC-
(CH3)3], 1.08 (t, J = 7.17 Hz, 3 H, OCH2CH3), 2.38–2.60 (m, 4 H,
CH2CO2H and CH2CO2Et), 3.92 (q, J = 7.17 Hz, 2 H, OCH2CH3),
4.67 (quintet, J = 6.04 Hz, 1 H, CHOSi), 7.23–7.36 (m, 6 H, Ar),
7.54–7.60 (m, 4 H, Ar), 12.9 (br. 1 H, CO2H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.12 (OCH2CH3), 19.25 (CMe3), 26.83
[C(CH3)3], 41.43 (CH2CO2Et), 41.68 (CH2CO2H), 60.55
(OCH2Me), 66.98 (CHOSi), 127.69 (CH, Ar), 129.89 (CH, Ar),
133.24 (C, Ar), 133.36 (C, Ar), 135.89 (CH, Ar), 170.78 (CO2Et),
176.78 (CO2H) ppm.
49.44 (d, JCP = 14.7 Hz, CH2COCH=PPh3), 53.3 (d, JCP
=
106.5 Hz, HC=PPh3), 59.99 (OCH2Me), 70.55 (CHOSi), 126.27 (C,
Ar), 127.17 (CH, Ar), 127.34 (C, Ar), 127.44 (C, Ar), 127.46 (C,
Ar), 128.51 (C, Ar), 128.62 (CH, Ar), 128.74 (CH, Ar), 129.34 (d,
JCP = 4.55 Hz, CH, Ar), 131.95 (d, JCP = 2.89 Hz, CH, Ar), 132.93
(CH, Ar), 133.03 (CH, Ar), 133.91 (C, Ar), 134.36 (C, Ar), 135.92
(d, JCP
=
1.59 Hz, CH, Ar), 172.21 (CO2Et), 189.58
(COCH=PPh3) ppm. 31P NMR (162 MHz, CDCl3): δ = 15.25 ppm.
Acknowledgments
The authors are grateful to Ratiopharm GmbH (Ulm) for financial
support of this work and appreciate the skillful technical assistance
by Mrs. K. Mevius.
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Carbonic) Anhydride (13b): A solution of acid (R)-12 (4.97 g,
11.99 mmol) and triethylamine (1.81 g, 17.89 mmol) in dry toluene
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warmed to 0 °C and stirred for 1 h. The reaction mixture was then
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dried in high vacuum to give the anhydride (R)-13b (5.54 g, 95%
yield) as a clear, colorless oil. 1H NMR (400 MHz, C6D6): δ = 0.87
(t, J = 7.17 Hz, 3 H, OCH2CH3), 0.90 (t, J = 7.17 Hz, 3 H,
OCH2CH3), 1.14 [s, 9 H, SiC(CH3)3], 2.49–2.72 (m, 4H CH2CO2C-
O2Et and CH2CO2Et), 3.82 (q, J = 7.17 Hz, 2 H, OCH2CH3), 3.89
(q, J = 7.17 Hz, 2 H, OCH2CH3), 4.69 (quintet, J = 6.02 Hz, 1 H,
CHOSi), 7.17–7.26 (m, 6 H, Ar), 7.74–7.85 (m, 4 H, Ar) ppm.
Ethyl (R)-3-(tert-Butyldiphenylsilyloxy)-5-oxo-6-(triphenylphosphor-
anylidene)hexanoate (6): A suspension of methyltriphenylphospho-
nium bromide (8.85 g, 24.77 mmol) in dry THF (40 mL) was co-
oled to –78 °C, and n-BuLi in hexane (1.6 , 15.4 mL, 24.66 mmol)
was added dropwise over 20 min. The mixture was warmed to 0 °C
and kept at this temperature for ca. 10 min (solution became yellow
and the white powder dissolved). The mixture was again cooled to
–78 °C, and
a THF solution of the anhydride 13b (6.0 g,
12.33 mmol) was added over 1 h. The resulting mixture was stirred
overnight at –30 °C, warmed up to room temp., and additionally
stirred for 1 h. The mixture was poured into water and extracted
with EtOAc (2ϫ100 mL). Combined organic layers were washed
with saturated NaHCO3 and brine, and dried with MgSO4. Solvent
was evaporated and residual material was purified by column
chromatography (silica gel, n-hexane/EtOAc, 1:10) to provide Wit-
Eur. J. Org. Chem. 2008, 840–846
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
845

V. Andrushko, A. Börner et al.
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Received: November 9, 2007
Published Online: January 3, 2008
846
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Eur. J. Org. Chem. 2008, 840–846