Ru-catalyzed asymmetric hydrogenation of 3-oxoglutaric acid derivatives via solvent-assisted pinpoint recognition of carbonyls in close chemical propinquity

Article abstract of DOI:10.1021/ol201406w

Upon comparison of hydrogenation rates of various β-ketocarboxylic acid derivatives, β-ketoamides were found to be hydrogenated slightly faster than β-ketoesters in EtOH in the presence of [RuCl(benzene)(S)- SunPhos]Cl at 70 °C with 20 bar of hydrogen. In THF these differences were so sharpened that β-ketoamides were hydrogenated even faster than in EtOH while the esters were extremely slow. Based on these findings, a series of 3-oxoglutaric acid derived with ester and amide moieties on the two ends were hydrogenated to 3-hydroxyl products with high enantioselectivities.

Full text of DOI:10.1021/ol201406w

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3876–3879
Ru-Catalyzed Asymmetric Hydrogenation
of 3-Oxoglutaric Acid Derivatives via
Solvent-Assisted Pinpoint Recognition of
Carbonyls in Close Chemical Propinquity
Wanfang Li,† Xin Ma,† Weizheng Fan,† Xiaoming Tao,† Xiaoming Li,† Xiaomin Xie,† and
Zhaoguo Zhang*,†,‡
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800
Dongchuan Road, Shanghai 200240, China, and Shanghai Institute of Organic
Chemistry, 345 Lingling Road, Shanghai 200032, China
zhaoguo@sjtu.edu.cn
Received May 24, 2011
ABSTRACT
Upon comparison of hydrogenation rates of various β-ketocarboxylic acid derivatives, β-ketoamides were found to be hydrogenated slightly
faster than β-ketoesters in EtOH in the presence of [RuCl(benzene)(S)-SunPhos]Cl at 70 °C with 20 bar of hydrogen. In THF these differences were
so sharpened that β-ketoamides were hydrogenated even faster than in EtOH while the esters were extremely slow. Based on these findings, a
series of 3-oxoglutaric acid derived with ester and amide moieties on the two ends were hydrogenated to 3-hydroxyl products with high
enantioselectivities.
Asymmetric hydrogenation of carbonyls has become a
routine method for building up chiral alcohol centers in
organic synthesis.1 Both mono- and nonfunctionalized ketones
can be enantioselectively hydrogenated by the delicate cata-
lytic systems developed by Noyori and co-workers.2 Hitherto,
polyfunctionalized ketones have been relatively intractable
substrates. The primary difficulty lies in the emulative coordi-
nations of multiple directing groups with the catalyst.3 When
two carbonyl directing groups C(O)X and C(O)Y are present
in one molecule (Scheme 1), the configurations of the resultant
alcohol are usually antipodal in cases when one overrides
in the emulation.3 High ee’s are expected only if one of
them dominated in the directing effect. More often than
not, both directing groups would comparably participate
in the chelating. The more polyfunctionalized a ketone is,
the more versatile the hydrogenation product will be as a
synthetic block. For example (Figure 1), syn-3,5-dihydrox-
yhept-6-enoic acid is a key substructure in side chains for
statins.4 Epothilone and its congeners contain a common
C1ÀC6 block derived from an enantiopure 3-hydroxyl
glutaric acid structure.5
Our group has been devoted to studying the asymmetric
hydrogenation of various functionalized ketones and its
applications in organic synthesis.6 Herein we report our
recent attempts to realize the pinpoint recognition of two
† Shanghai Jiao Tong University.
‡ Shanghai Institute of Organic Chemistry.
(1) (a) Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856.
(b) Shang, G.; Li, W.; Zhang, X. In Catalytic Asymmetric Synthesis, 3rd
ed.; Ojima, I., Ed.; John Wiley & Sons: Hoboken, NJ, 2010. (c) de Vries, J. G.;
Elsevier, C. J., Eds. The Handbook of Homogeneous Hydrogenation;
Wiley-VCH: Weinheim, 2007.
€
(4) (a) Ohrlein, R.; Baisch, G. Adv. Synth. Catal. 2003, 345, 713.
(2) (a) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40.
(b) Noyori, R.; Sandoval, C. A.; Muniz, K.; Ohkuma, T. Philos. Trans.
(b) Liljeblad, A.; Kallinen, A.; Kanerva, L. T. Curr. Org. Synth. 2009, 6,
362.
~
R. Soc. London, Ser. A 2005, 363, 901.
(3) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994; Chapter 2.
(5) Balog, A.; Meng, D.; Kamenecka, T.; Bertinato, P.; Su, D. S.;
Sorensen, E. J.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1997, 35,
2801.
r
10.1021/ol201406w
Published on Web 07/05/2011
2011 American Chemical Society

substrates with an equivalent molar ratio were performed
with [RuCl(benzene)(rac)-SunPhos]Cl under our conditions:
0.5% mol of catalyst, 20 bar of H2 at 70 °C (Scheme 2).
Conversion analysis with more components in the mixture
faileddue tothefollowing:(1) 1bÀk underwent ethanolysis
on GC to various extents; (2) 1h and 2gÀk were ungasifiable
and unable to produce signals for GC. To obtain a quali-
tative rate order, TLC and NMR methods were employed.
By mixing 1aÀc (0.5 mmol of each, 1% mmol of
Scheme 1. Emulative Coordination Model of Carbonyls with X
and Y
Scheme 2. Competitive Hydrogenation Test of Various β-Keto
Acid Derivatives
catalyst) in EtOH, small residual 1a and 1b were detected
by TLC after 3 h, while 1c was not. This indicated that tert-
butyl acetoacetate undergoes hydrogenation faster than its
ethyl and isopropyl counterparts. The rate difference between
1a and 1d were too subtle for TLC comparison, as they
both remained untouched after 1 h and almost consumed
after 4 h. Other triad mixing tests revealed that the differ-
ence between the esters and amides was not very evident
but the latter were slightly faster. For example, when 1a
and 1j were mixed under the standard conditions for 3 h,
the NMR conversions were 18% and 75% respectively. By
comparing the integration value of the residual CH3(CdO);
group in NMR of the reaction mixtures, we noted that
β-keto primary amides 1j and 1k were slightly slower than
β-keto secondary amides 1h and 1g, respectively.
Figure 1. Polyfunctionalized chiral alcohol blocks in important
pharmaceuticals and natural products.
carbonyls in close chemical propinquity by [RuCl(benzene)-
(S)-SunPhos]Cl demonstrated in Scheme 1.
To this end, we intended toeither select the proper X and
Y, with such enormously different coordinating abilities
that only the 1,3-chelation mode dominates, or introduce
an assistant ligand or solvent whose coordination abilities
are somewhere in between the 1,3- and 3,5-dicarbonyls as
their presence may expel the weaker coordinating carbonyl
away from the metal (Scheme 1) which would probably
impair the minor chelation mode.
€
Bruckner et al. concluded that β-ketocarboxylic acid
Table 1. Asymmetric Hydrogenation of 1 with [RuCl(benzene)-
(S)-SunPhos]Cla
derivatives with more electron-rich C(O)NR2 moieties had
a faster onsethydrogenation rate thanthose withC(dO);
OR by studying their rate differences in alcohols with
[RuCl2(S)-BINAP]2 NEt3 under relatively mild conditions
3
(4 bar of H2, ambient temperature).7 They also mentioned
thatthe conclusion was based ontheir specified conditions.
We felt that the rate difference might be further modulated
to achieve more subtle differentiation. Several competitive
hydrogenation tests in ethanol by mixing as many as six
ee (%)
ee (%)
entry
1
R1
R2
in EtOH
in THF
1
2
3
1f
1i
OMe
Me
N/Ab
N/Ab
98.9
97.2c
99.3
99.4
-(CH2CH2OCH2CH2) -
Ph
(6) (a) Sun, Y.; Wan, X.; Wang, J.; Meng, Q.; Zhang, H.; Jiang, L.;
Zhang, Z. Org. Lett. 2005, 7, 5425. (b) Wan, X.; Sun, Y.; Luo, Y.; Li, D.;
Zhang, Z. J. Org. Chem. 2005, 70, 1070. (c) Wan, X.; Meng, Q.; Zhang,
H.; Sun, Y.; Fan, W.; Zhang, Z. Org. Lett. 2007, 9, 5613. (d) Meng, Q.;
1k
H
a All reactions were carried out with a substrate (1 mmol) concentra-
tion of 0.2 M in EtOH or THF (5 mL) at 70 °C with 20 bar of H2 for 8 h.
Substrate/catalyst = 200. Conversions were 100% and ee’s were deter-
mined by HPLC. The absolute configurations were determined by the
specific rotations (see Supporting Information). b No product was
separated. c 15 h for full conversion.
^
Sun, Y.; Ratovelomanana-Vidal, V.; Genet, J. P.; Zhang, Z. J. Org.
Chem. 2008, 73, 3842. (e) Meng, Q.; Zhu, L.; Zhang, Z. J. Org. Chem.
2008, 73, 7209. (f) Yao, Y.; Fan, W.; Li, W.; Ma, X.; Zhu, L.; Xie, X.;
Zhang, Z. J. Org. Chem. 2011, 76, 2807.
€
(7) (a) Kramer, R.; Bruckner, R. Angew. Chem., Int. Ed. 2007, 46,
€
6537. (b) Kramer, R.; Bruckner, R. Chem.;Eur. J. 2007, 13, 9076.
Org. Lett., Vol. 13, No. 15, 2011
3877

Unexpectedly, when 1f and 1i were involved in the
mixing tests, the substrates became rather inert to the
catalyst and hardly any product was detected. Finally we
found that 1f and 1i were partially ethanolyzed to give 1a
and the freed amines poisoned the catalyst. To solve this
problem, we performed the hydrogenation of 1f and 1i in
nonalcohol solvent. To ourdelight, 2f and 2i were obtained
quantitatively in THF. It is known that solvents played
important roles in the asymmetric hydrogenation of
methyl acetoacetate8 while THF is an infrequently used
solvent9 for the ruthenium catalyzed hydrogenation of
keto esters due to its competitive coordination to metal
with substrates. Such oddities of THF prompted us to
compare the hydrogenation rates of 1aÀk in it. Under the
same conditions, we found more conspicuous differences
in THF: all esters 1aÀd reacted extremely slowly (almostno
conversion after 7 h which was long enough for full conver-
sion in EtOH) while amides reacted very fast. An apparent
order of reaction rate was observed: 1e, 1g, 1h, 1i > 1j >
1k > 1f . 1aÀd.
Table 2. Asymmetric Hydrogenation of 3 with
[RuCl(benzene)(S)-SunPhos]Cla
ee (%)
ee (%)
entry
3
R1
Et
R2
Et
in THF
in EtOH
1
3a
3b
3c
3d
3e
3f
96.5
96.7
95.2
96.4
98.1(R)c
87.3
94.4d
87.1
86.7
93.6
88.2
49.3
93.4
2
-(CH2)4-
-(CH2)5-
-CH2CH2OCH2CH2-
81.7
3
86.5
4
N/Ab
53.3(R)c
N/Ab
91.4d
79.3
5
Ph
Me
Ph
OMe
H
6
7
3g
3h
3i
tBu
8
Bn
H
9
Ph
H
88.4
10
11
12
3j
2,6-DiMe-Ph
p-MeO-Ph
p-CF3-Ph
H
70.1
3k
3l
H
90.2
Having such a qualitative order in hand, we wondered if
β-keto amides can be hydrogenated with good ee’s in THF
as in EtOH.10 Asymmetric reaction versions of 1f, 1i, and
1k with chiral (S)-SunPhos were tested. The exhilarating
results in Table 1 indicated a more direct route to useful
chiral blocks 2f11 and 2i12 for natural products. The
β-keto(N-phenyl)amide 2k also gave a very high ee (98.9%
in EtOH and 99.4% in THF).
H
88.6
a All reactions were carried out in THF or in EtOH with a substrate
(1 mmol) concentration of 0.2 M at 70 °C with 20 bar of H2 for 15 h.
Substrate/catalyst = 200. Conversions were 100% except where indi-
cated. Ee’s were determined on HPLC. b No productwas obtained due to
alcoholysis of the substrate. c The absolute configuration was deter-
mined by X-ray crystallography (see Supporting Information). d Ee of its
4-nitrobenzoate.
Based on the above observations, we assembled a series
of 3-oxoglutaric acid derivatives with ethyl ester on one
end and amides moieties on the other. As expected,
excellent enantioselectivities were obtained for 4aÀd in
THF, and the ee’s range from 95.2% to 96.7% (entries
1À4, Table 2). The N,N-diphenylamide 3e also gave an ee
as high as 98.1% (entry 5, Table 2). As it can be inferred
from the rate order in which the Weinreb amide moiety
sloweddown the hydrogenation ratethatthe eeof 4fwould
be lower than 4aÀd, this was validated by the outcome of
an 87.3% ee of 4f (entry 6, Table 2).
rate order in THF. The benzylamide 3h (entry 8, Table 2)
gave a little higher ee than 3i (entry 9, Table 2). Preferably,
amide moieties were the dominant directing groups when
the hydrogenations were performed in THF. The effect of
the substituents on the N-phenyl rings provided further
evidence: the electron-donating groups such as methyl on
3j (entry 10, Table 2) and methoxyl on 3k (entry 11,
Table 2) improved the ee by 6.9 and 1.5% respectively;
the electron-withdrawing group like trifluoromethyl in 3l
(entry 12, Table 2) drastically impaired the ee from 86.7%
to 49.3%.
For comparison, the reactions in EtOH were also per-
formed. For most substrates, higher ee’s were obtained in
THF than in EtOH, with an increase of ee ranging from 3.0
(entry 7, Table 2) to 44.8% (entry 5, Table 2). For 3i, 3k,
and 3l, an inversed trend was found.The absolute config-
uration of 4e was determined to be R by X-ray crystallo-
graphy, which also proved domination of the amide
carbonyl as the directing group.
The ee’sof 4gand 4i, 94.4% (entry 7, Table2) and 86.7%
(entry 9, Table 2) respectively, were alsoconsistent withthe
(8) Wolfson, A.; Vankelecom, I. F. J.; Geresh, S.; Jacobs, P. A.
J. Mol. Catal. A: Chem. 2003, 198, 39.
(9) (a) Starodubtseva, E. V.; Turova, O. V.; Vinogradov, M. G.;
Gorshkova, L. S.; Ferapontov, V. A. Russ. Chem. Bull. 2007, 56, 552.
(b) Flowers, B. J.; Gautreau-Service, R.; Jessop, P. G. Adv. Synth. Catal.
2008, 350, 2947. (c) Zhu, L.; Meng, Q.; Fan, W.; Xie, X.; Zhang, Z.
J. Org. Chem. 2010, 75, 6027.
(10) (a) Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi,
H.; Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. J. Am. Chem. Soc.
1988, 110, 629. (b) Huang, H. L.; Liu, L. T.; Chen, S. F.; Ku, H.
Tetrahedron: Asymmetry 1998, 9, 1637. (c) Touati, R.; Gmiza, T.; Jeulin,
S.; Deport, C.; Ratovelomanana-Vidal, V.; Ben Hassine, B.; Genet, J. P.
Synlett 2005, 2478. (d) Le Gendre, P.; Offenbecher, M.; Bruneau, C.;
Dixneuf, P. H. Tetrahedron: Asymmetry 1998, 9, 2279.
(11) (a) Denmark, S. E.; Fujimori, S. Org. Lett. 2002, 4, 3477. (b) Wu,
B.; Mallinger, A.; Robertson, J. Org. Lett. 2010, 12, 2818. (c) Cohen, F.;
Overman, L. E. J. Am. Chem. Soc. 2001, 123, 10782. (d) Nelson, S. G.;
Cheung, W. S.; Kassick, A. J.; Hilfiker, M. A. J. Am. Chem. Soc. 2002,
124, 13654. (e) Cohen, F.; Overman, L. E. J. Am. Chem. Soc. 2006, 128,
2594.
These hydrogenation products may provide important
intermediates for statins.13 For extension, several geminal
substituents were introduced onto the methylenes in
hoping that they may influence the competing coordina-
tions between the two pairs of the β-dicarbonyl system to
the catalyst center.
€
€
(13) (a) Andrushko, V.; Andrushko, N.; Konig, G.; Borner, A.
(12) (a) Goodman, S. N.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2002, 41, 4703. (b) Demizu, Y.; Kubo, Y.; Matsumura, Y.; Onomura, O.
Synlett 2008, 433.
Tetrahedron Lett. 2008, 49, 4836. (b) Andrushko, N.; Andrushko, V.;
Tararov, V.; Korostylev, A.; Konig, G.; Borner, A. Chirality 2010, 22,
534.
€
€
3878
Org. Lett., Vol. 13, No. 15, 2011

two independent β-keto acid derivative systems within one
molecule might be recognized by the catalyst. When ethyl
10-morpholino-3,8,10-trioxodecanoate (7) was subjected
to the same conditions (20 bar of H2, 70 °C, 15 h), only the
β-carbonyl to the amide was saturated with 97.7% ee
Table 3. Asymmetric Hydrogenation of Substituted 3-Oxoglu-
taric Acid Derivativesa
13
(Scheme 3, confirmed by 1HÀ C HMBC experiment; see
Supporting Information). This excellent regio- and enan-
tioselectivity is the first example of asymmetric monohy-
drogenation of bis(β-ketocarboxylic acid) derivatives.7,16
ee (%)
ee (%)
entry
5
R1, R2
Me, H
X
in THF
in EtOH
1
2
3
4
5a
5b
5c
5d
NEt2
90.3b
92.4c
NR
44.7
81.6d
98.1e
91.7
Scheme 3. Higly Selective Monohydrogenation of Bis(β-keto-
carboxylic Acid) Derivatives within One Molecule
Me, H
NMeOMe
NMeOMe
NMeOMe
H, Me
H, -(CH2)4-
NR
a All reactions were carried out in EtOH or THF with a substrate
(1 mmol) concentration of 0.2 M at 70 °C with 20 bar of H2 for 15 h.
Substrate/catalyst = 200. Conversions were 100% except where indi-
cated. b 100% conversion for 26 h. c 36% conversion for 20 h. d Less than
10% conversion due to alcoholysis. e 75 °C, 30 bar of H2. NR = no
reaction even under harsher conditions and prolonged reaction times.
In summary, we have discovered that in THF β-keto
amides showed fast hydrogenation rates while esters were
almost inert. A series of 3-oxoglutaric acid derivatives were
hydrogenated to the 3-hydroxyl products with excellent
ee’s. Such serendipity with THF also made it possible to
distinguish β-keto amides from β-keto esters within one
molecule, which had previously remained difficultin asym-
metrichydrogenation. Moreover, ourfindingsmay furnish
new concepts for more challenging recognitions in various
highly functionalized carbonyl substrates.
For 5a and 5b, better enantioselectivities were observed
in THF than in EtOH, with the ee’s increased from 44.7%
to 90.3% (entry 1, Table 3) and from 81.6% to 92.4%
(entry 2, Table 3), respectively. However, the reactions in
THF became sluggish for the 2,2-disubstituted substrates.
Weinreb amides 5c and 5d remained untouched in THF
under even harsher conditions (90 °C, 30 bar of H2, 16 h)
while they underwent smooth hydrogenation in EtOH to
produce 6c and 6d with very good ee’s: 98.1% (entry 3,
Table 3) and 91.7% (entry 4, Table 3), respectively. As
Weinreb amide facilitates diversified transformations in
organic synthesis,14 enantiomerically pure 6c may provide
an important intermediate for a C1ÀC6 chiral block in
Epothilones and congeners.15
Acknowledgment. Dedicated to Prof. Christian Bruneau
on the occasion of his 60th birthday. We thank the
National Natural Science Foundation of China for finan-
cial support. We thank Mr. Chengfeng Zhu in Prof. Yong
Cui’s group for X-ray crystallographic analysis.
The distinct behavior in hydrogenation of β-keto acid
esters and amides in THF enlightened us to envisage that
Supporting Information Available. The experiment de-
tails of substrates synthesis, NMR and/or HPLC data of
1À8, crystallographic data of (R)-4e (cif). This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(b) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15.
(15) (a) Bertinato, P.; Sorensen, E. J.; Meng, D.; Danishefsky, S. J.
J. Org. Chem. 1996, 61, 8000. (b) Yang, Z.; He, Y.; Vourloumis, D.;
Vallberg, H.; Nicolaou, K. C. Angew. Chem., Int. Ed. 1997, 36, 166.
€
(16) Knobloch, E.; Bruckner, R. Synthesis 2008, 2229.
Org. Lett., Vol. 13, No. 15, 2011
3879