Acid-labile δ-ketal-β-hydroxy esters by asymmetric hydrogenation of corresponding δ-ketal-β-keto esters in the presence of CaCO 3

Article abstract of DOI:10.1039/c2cc31002c

A series of acid-labile, optically pure ε-substituted δ-ketal-β-hydroxy esters were obtained by a Ru-SunPhos catalyzed asymmetric hydrogenation of the corresponding ε-substituted δ-ketal-β-keto esters. CaCO₃ played a dual role in the hydrogenation reaction - removing the acid generated during the formation of the catalyst and maintaining the activity of the catalyst.

Full text of DOI:10.1039/c2cc31002c

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COMMUNICATION
Acid-labile d-ketal-b-hydroxy esters by asymmetric hydrogenation of
corresponding d-ketal-b-keto esters in the presence of CaCO3w
Weizheng Fan,a Wanfang Li,a Xin Ma,a Xiaoming Tao,a Xiaoming Li,a Ying Yao,a
Xiaomin Xiea and Zhaoguo Zhang*ab
Received 11th February 2012, Accepted 28th February 2012
DOI: 10.1039/c2cc31002c
A series of acid-labile, optically pure e-substituted d-ketal-b-hydroxy
esters were obtained by a Ru-SunPhos catalyzed asymmetric hydro-
genation of the corresponding e-substituted d-ketal-b-keto esters.
CaCO3 played a dual role in the hydrogenation reaction—removing
the acid generated during the formation of the catalyst and
maintaining the activity of the catalyst.
Statins are among the most commonly applied lipid regula-
tion drugs world-wide.1 The annual market value has been
approximately 23 billion US$ during the past 10 years (Fig. 1).
Statins, in particular those containing a CQC double bond,
can be efficiently synthesized by olefination of a heteroaryl
aldehyde with a phosphorous or phosphorane side chain
(Scheme 1).2
Scheme 1 The asymmetric hydrogenation protocol for side chains of
superstatins.
Over the last three decades, diverse strategies to construct
this phosphorous or phosphorane side chain possessing one chiral
center have been developed.3 However, almost all approaches
can be readily converted to a side chain through the Arbuzov
reaction4 (Scheme 1), however, no efficient method for preparing
were focused on the construction of the key chiral inter-
compound A has been reported. Therefore, it’s of great value to
mediates, 3-hydroxyglutaric acid derivatives B (Scheme 1). Interest-
devise an efficient method for its synthesis.
ingly, the chiral alkyl 6-chloro-3-hydroxy-5-oxohexanoate A
Reduction of b,d-diketo esters, C, to b-hydroxy-d-oxo
esters with both high regio- and enantioselectivity is the
most straightforward way, but it is difficult to realize. The
ruthenium-catalyzed asymmetric hydrogenation of substrate C
always gave a b,d-dihydroxy ester with moderate diastereo-
selectivity, as it involves moieties of both b-diketones and
b-keto esters in the molecule.5 It is noteworthy that Saburi
et al. reported that a ruthenium-catalyzed asymmetric hydro-
genation of b,d-diketo esters proceeded sequentially at positions
C-3 (b) and C-5 (d) with moderate anti-selectivity and enantio-
selectivity, but the monohydrogenation product was neither
isolated nor identified from the reaction mixture.6 Under
optimized reaction conditions, Carpentier et al. first reported
a regioselective hydrogenation of the C-3 (b) carbonyl group of
methyl 3,5-dioxohexanoate with high yields, but fair enantiomeric
Fig. 1 Structures of some important artificial statins.
excess (78% ee).7
Several investigations have involved b-keto esters bearing
a School of Chemistry and Chemical Engineering,
Shanghai Jiao Tong University, 800 Dongchuan Road,
Shanghai 200240, China
b Shanghai Institute of Organic Chemistry, 345 Lingling Road,
adjacent heteroatoms, such as a benzyloxyl group,8 alkoxyl
group,3g,9 halogen atoms10 or carbonylamino groups,11 in the
vicinity of the keto group. Recently, Borner et al. reported a
¨
Shanghai 200032, China. E-mail: zhaoguo@sjtu.edu.cn
w Electronic supplementary information (ESI) available: Experimental
procedures and full characterization data for all compounds are
provided. See DOI: 10.1039/c2cc31002c
new approach to synthesise chiral 3-hydroxyglutaric acid
derivative B based on the asymmetric hydrogenation of
5,5-dimethoxy-3-oxopentanoate as a key step.3g We envisioned
c
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Chem. Commun., 2012, 48, 4247–4249 4247

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that if the hydrogenation of e-chloro substituted d-ketal-b-keto
esters 1 could be successfully performed to yield enantiomerically
pure e-chloro substituted d-ketal-b-hydroxy esters, it would
provide a short and efficient access to the chiral e-chloro
substituted b-hydroxy-d-oxo esters A by deprotecting the
hydrogenated products. Herein we present an unprecedented
work in the highly enantioselective hydrogenation of e-substituted
d-ketal-b-keto esters.
to establish the hydrogenation conditions under which degradation
of the hydrogenated products can be avoided.
To restrain the deprotection of the hydrogenated product 2a,
we increased the hydrogen pressure to 60 bar, based on initial
hydrogenation conditions, and 1a was completely converted
after 4.5 h. The ratio of 2a to deprotected product 3a was
79/21, and they had the same ee of 99.2% (entry 1, Table 1),
supporting our previous hypothesis that deprotection occurs
after the hydrogenation, and the substrate is more stable
than the product. After careful analysis of the hydrogenation
products, unidentified complex products were found and the
combined yields of 2a and 3a were generally less than 70%.
Therefore, it is not efficient to suppress the degradation of the
hydrogenated product by increasing the hydrogen pressure
to shorten the reaction time, keeping the reaction conditions
neutral during the hydrogenation process is an alternative that
possibly works.
Initially, the evaluation of the hydrogenation of 1a was
carried out at 55 1C with 0.4 mol% of [RuCl(benzene)(S)-
SunPhos]Cl (ref. 12) in EtOH under 20 bar of H2. Although
complete conversion and up to 98.8% ee were observed, the
combined yield of 2a and 3a was only 49%. To our delight,
when the carbonyl protective group was changed to a glycol
ketal, the hydrogenated product 2b was obtained in excellent
enantioselectivity (99.7% ee) and high yield (95%). However,
when 1c was hydrogenated, no expected product was observed
and the 1H NMR spectra of the crude hydrogenation products
showed that the ketal was completely deprotected and a
complicated mixture of byproducts was obtained (Scheme 2).
Because the hydrogenation substrates 1a and 1c are relatively stable
under acidic conditions, we may conclude that the degradation
occurred after the hydrogenation. Comparing these results, we
may infer that it was the strong electron-withdrawing ability of
the chloro atom that restrained the formation of carbocations,
which was crucial during the deprotection of d-ketal.14
Because diethoxy ketal is not as stable as glycol ketal,14 the
deprotection of the hydrogenated product occurred in the
acidic system,5c,13 and the deprotected product was further
converted to a complex of unidentified byproducts. Without
an electron-withdrawing group at the e position, deprotection
of the product would readily occur, and other byproducts
would thereby come up. Unfortunately, no conversion of 2b
was observed when deprotection of the glycol ketal was
conducted under commonly-used conditions, and only a
33% yield of the expected product was obtained when 2b
was treated with 2 M H2SO4 and refluxed in acetone for 14 h.14
Because of the harsh reaction conditions, a complicated
mixture of byproducts was obtained.
To remove the acidity, different alkali additives were tested.
When organic nitrogen bases were used, only imidazole could
give full conversion of 1a, but the deprotection of the hydro-
genated product was not effectively inhibited. The addition of
Et3N and iPr2NEt impaired the activity of the catalyst, which may
be due to the catalyst being poisoned by nitrogen (entries 2–4,
Table 1). Consequently, when other alkali additives that did
not contain nitrogen were tested, such as AcONa, inorganic
carbonates or basic Al2O3, only CaCO3 could not only
completely restrain the deprotection of ketal during the hydro-
genation, but also had no adverse affects on the activity of the
catalyst (entries 5–8, Table 1). Furthermore, on adding more
CaCO3 to the system, the activity of the catalyst was not
impaired and the same results were obtained (entry 7 vs. entry 9,
Table 1).
To our surprise, the additive was also effective for substrates
with 1,3-dioxolane ketals 1c and 1d, affording the corres-
ponding hydrogenated products in high yields and with
excellent ees, 2c (99.3%) and 2d (99.5%) (entries 2 and 3,
Table 2, respectively), while no expected product was observed
when 1c was hydrogenated under the initial hydrogenation
Table 1 Effects of additives on catalytic hydrogenation of 1aa
The low yields after the hydrogenation of 1a and the
deprotection of 2b posed a dilemma for us when developing
a practical asymmetric hydrogenation for a wide scope of
e-substituted d-ketal-b-keto esters and obtaining the key inter-
mediate A for statins. However, when we treated 2a with a
catalytic amount of p-toluenesulfonic acid in a mixed solvent of
acetone and water, the diethoxy ketal was readily deprotected
and a quantitative yield was obtained. Therefore, it is desirable
Entry
Additives
Conv. (%)b
2a/3ac
ee of 2a (%)d
1
2
3
4
none
Et3N
100
86
90
100
92
0
100
100
100
79/21
54/46
2a
28/72
2a
NA
2a
79/21
2a
99.2/99.2d
99.0
98.9
99.3
99.0
NA
99.2
99.0
99.2
iPr2NEt
Imidazole
AcONa
K2CO3
CaCO3
Al2O3
5
6e
7f
8f
9g
CaCO3
a
Reaction conditions: 1a (1.25 mmol), 0.4 mol% of [RuCl(benzene)(S)-
b
SunPhos]Cl, and 0.4 mol% of additive in EtOH (3 mL). Determined
by 1H NMR. The molar ratio of 2a/3a was calculated by the direct
d
integration of appropriate signals. The ee of 2a and 3a was determined
c
via their corresponding 4-chlorobenzenethiol substituted derivatives
e
by HPLC (see ESI). 1.2 mol% of K2CO3. 3.2 mol% of additives.
f
Scheme 2 Asymmetric hydrogenations of e-substituted d-ketal-b-keto
esters.
g
9.6 mol% of CaCO3, 97% isolated yield.
c
4248 Chem. Commun., 2012, 48, 4247–4249
This journal is The Royal Society of Chemistry 2012

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Table 2 The asymmetric hydrogenation of 1 by [RuCl(benzene)(S)-
SunPhos]Cl in the presence of CaCO3
2 Z. Casar, Curr. Org. Chem., 2010, 14, 816.
a
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WO2003087112, 2003; (g) A. Korostylev, V. Andrushko,
Entry
X
R’
R
2
Yield (%)b
ee (%)c
1
2
3
4
Cl
H
Me
Cl
Et
Me
Me
Me
Et
Me
Me
Et
2a
2c
2d
2e
2f
2g
2h
2i
97
79
81
95
91
93
91
95
99.2d
99.3(S)e
99.5e
99.4d
99.2d
99.2h
99.2h
99.6h
N. Andrushko, V. I. Tararov, G. Konig and A. Borner, Eur. J.
¨
¨
–(CH2)2–
–(CH2)2–
Et
Org. Chem., 2008, 840; (h) V. Andrushko, N. Andrushko,
G. Konig and A. Borner, Tetrahedron Lett., 2008, 49, 4836;
¨
¨
5f
6g
7i
8
Cl
Me
(i) N. Andrushko, V. Andrushko, V. Tararov, A. Korostylev,
G. Konig and A. Borner, Chirality, 2010, 22, 534.
¨
¨
BnO
BnO
BnO
–(CH2)2–
–(CH2)2–
–(CH2)2–
4 (a) A. Michaelis and R. Kaehne, Ber., 1898, 31, 1048;
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1991, 32, 7699; (b) L. Shao, H. Kawano, M. Saburi and Y. Uchida,
Tetrahedron, 1993, 49, 1997.
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Chem., 1999, 3421; (b) V. Blandin, J. F. Carpentier and
A. Mortreux, Eur. J. Org. Chem., 1999, 1787; (c) V. Blandin,
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Carpentier, Tetrahedron Lett., 2002, 43, 2569; (e) G. Juszkiewicz
and J. Jurczak, Org. Prep. Proced. Int., 2002, 34, 187.
tBu
a
Reaction conditions: 1 (1.25 mmol), CaCO3 (12 mg) and 0.4% mol
b
[RuCl(benzene)(S)-SunPhos]Cl in EtOH (3 mL). Yield of isolated
c
product. Absolute configuration of 2c was determined by the
comparison of the optical rotation of 3c with literature values, the
configuration of other products can be assigned as S according to
d
the well-established general trend (see ref. 7a and 15). Values of the
ee of the corresponding 4-chlorobenzenethiol substituted derivatives.
e
f
g
Values of the ee of their p-nitrobenzoates. MeOH as solvent. 65 1C.
h
i
The ee values were determined directly by HPLC. 75 1C, 10 h.
conditions. Additionally, the asymmetric hydrogenation of
substrates possessing acyclic ketals, 1e and 1f, gave excellent
ees of 2e (99.4%) and 2f (99.2%) (entries 4 and 5, Table 2,
respectively). However, a higher temperature was needed
for the full conversion of e-benzyloxy substituted substrates
with glycol ketals. Asymmetric hydrogenations of 1g and 1h
were conducted at 65 1C and 75 1C, respectively, and the
same excellent ees of 2g (99.2%) and 2h (99.2%) were
obtained. Substrate 1i (R = tert-butyl) was hydrogenated
successfully to yield 2i with 99.6% ee and 95% yield (entries 6–8,
Table 2).
8 (a) O. Labeeuw, D. Blanc, P. Phansavath, V. Ratovelomanana-Vidal
and J.-P. Genet, Eur. J. Org. Chem., 2004, 11, 2352; (b) M. Kitamura,
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¨
2006, 24, 5543.
¨
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To illustrate the utility of hydrogenated products, 2a, 2c
and 2d can be readily deprotected using a catalytic amount
of tosylic acid in high yields, giving b-hydroxy-d-oxo esters,
which could be used to synthesize key intermediates of chiral
drugs.16,17
11 T. Nishi, M. Kitamura, T. Ohkuma and R. Noyori, Tetrahedron
Lett., 1988, 29, 6327.
In conclusion, we have described an effective method for
Ru-catalyzed asymmetric hydrogenation of e-substituted
d-ketal-b-hydroxy esters in the presence of catalytic amounts
of CaCO3, giving the hydrogenated products with remarkably
high enantioselectivities and high yields. Calcium carbonate
played a key role in removing the acidity and maintaining the
high enantioselectivity during the hydrogenation reaction.
These hydrogenated products can be readily converted into
b-hydroxy-d-oxo esters, which are important chiral building
blocks for many pharmaceutical products.
12 (a) W. Li, X. Ma, W. Fan, X. Tao, X. Li, X. Xie and
Z. Zhang, Org. Lett., 2011, 13, 3876; (b) Y. Yao, W. Fan, W. Li,
X. Ma, L. Zhu, X. Xie and Z. Zhang, J. Org. Chem., 2011,
76, 2807.
¨ ¨
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This work was financially supported by National Natural
Science Foundation of China.
Notes and references
1 (a) M. H. Davidson and J. G. Robinson, Expert Opin. Pharmacother.,
2006, 7, 1701; (b) J. Kidd, Nat. Rev. Drug Discovery, 2006, 5, 813.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4247–4249 4249