Diastereoselective synthesis of syn-3,5-dihydroxyesters via ruthenium-catalyzed asymmetric transfer hydrogenation

Article abstract of DOI:10.1016/S0040-4039(02)00310-6

The asymmetric transfer hydrogenation of chiral 5-hydroxy-3-ketoesters in 2-propanol using chlororuthenium(II)arene/β-amino alcohol in situ catalyst combinations or a pre-synthesized Ru-{β-amino alcohol} true catalyst, provides syn-3,5-dihydroxyesters in

Full text of DOI:10.1016/S0040-4039(02)00310-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2569–2571
Diastereoselective synthesis of syn-3,5-dihydroxyesters via
ruthenium-catalyzed asymmetric transfer hydrogenation
a
a
a
b,
Kathelyne Everaere, Nicolas Franceschini, Andr e´ Mortreux and Jean-Fran c¸ ois Carpentier *
a
Laboratoire de Chimie Organique Appliqu e´ e, ENSCL, BP 108-59652 Villeneuve d’Ascq, France
b
Laboratoire Organom e´ talliques et Catalyse, Universit e´ de Rennes 1, 35042 Rennes Cedex, France
Accepted 13 February 2002
Abstract—The asymmetric transfer hydrogenation of chiral 5-hydroxy-3-ketoesters in 2-propanol using chlororuthenium(II)arene/
b-amino alcohol in situ catalyst combinations or a pre-synthesized Ru-{b-amino alcohol} true catalyst, provides syn-3,5-dihydroxy-
esters in high yields and up to 80% de. © 2002 Elsevier Science Ltd. All rights reserved.
syn-3,5-Dihydroxyesters 2 are advanced building blocks
ketoesters have shown that the anti-diol is the favoured
5,6
for the preparation of mevinic-type HMG-CoA reduc-
stereoisomer in this process. Herein we report that
1
tase inhibitors of industrial interest, such as
the ruthenium-catalyzed asymmetric transfer hydro-
2
3
7–11
compactin and mevinolin. Their current synthesis
implies the syn-diastereoselective reduction of optically
pure aldols, i.e. 5-hydroxy-3-ketoesters 1, with the
genation of 2-propanol
to chiral 5-hydroxy-3-
ketoesters provides an effective entry to syn-3,5-
dihydroxyesters in high yields and promising diastereo-
selectivity (Scheme 1, Table 1).
1,4
NaBH /BEt or NaBH /B(OMe) Et combinations.
4
3
4
2
This method must, however, be performed at low tem-
perature (5−60°C) to reach high stereoselectivity and
uses expensive borane stoichiometric reagents that gen-
erate considerable amounts of waste. It is therefore of
great interest to develop efficient catalytic approaches
toward these key intermediates that proceed under
friendly conditions. Previous efforts in this direction by
Saburi and our group aimed at the ruthenium-catalyzed
tert-Butyl (S)-5-hydroxy-3-oxohexanoate (1a) was cho-
sen as a model substrate for preliminary investigations.
The treatment of 1a with the in situ catalytic combina-
6
11
tion of [RuCl (h -p-cymene)] and ethanolamine (A)
2
2
(1:4) in 2-propanol in the presence of 6 equiv. (versus
Ru) of 2-PrOK at 50°C for 25 h gave diol 2a in high
1
chemoselectivity but poor conversion (entry 1). H and
13
asymmetric one-pot hydrogenation (H ) of 3,5-di-
C NMR analysis of 2a and GLC analysis of the
2
OH
O
OH OH
2
-PrOH, 2-PrOK
t
t
R
CO2 Bu
R
CO2 Bu
NSO2Ar
[
Ru(arene)Cl2 + L2*]
S/Ru = 100
1
1
1
a: R = H
b: R = BnO
c: R = Cl
2a-c
HO HN R'
H2N
HO
NH2
A
(1S,2R)-B (R' = Me)
1S,2R)-C (R' = CH2C6H4(4-C6H5))
(1S,2S)-D
(Ar = 4-CH3C6H4)
(
Scheme 1.
Keywords: asymmetric transfer hydrogenation; syn-diols; chiral Ru catalysts.
*
Corresponding author. Tel.: +33 (0)223 235 950; fax: +33 (0)223 236 939; e-mail: jean-francois.carpentier@univ-rennes1.fr
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00310-6

2
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K. E6eraere et al. / Tetrahedron Letters 43 (2002) 2569–2571
a
Table 1. Ruthenium-catalyzed asymmetric transfer hydrogenation of aldols 1a,b in 2-propanol
Entry
Aldol 1a–c
Precursor Ru
arene
Ligand
Temp. (°C)
Time (min)
Conv. 1
(mol%)
Sel. 2 (mol%)
de 2 (%)
1
2
3
(S)-1a
(S)-1a
(S)-1a
p-Cymene
Benzene
Benzene
A
50
50
50
1500
20
10
29
99
75
100
85
98
87
96
79
100
90
99
78
48
67
95
29
47
86
\98
97
\98
78
\98
\98
\98
97
\98
91
\98
95
\98
\98
\98
94
\98
\98
\98
97
\98
86
12 syn
25 anti
66 syn
46 syn
70 syn
66 syn
44 anti
71 syn
79 syn
73 syn
74 syn
60 syn
72 syn
39 anti
70 syn
65 syn
80 syn
70 syn
75 syn
72 syn
14 anti
10 anti
15 syn
72 syn
68 syn
(1R,2S)-B
(1S,2R)-B
6
0
4
(S)-1a
Benzene
(1S,2R)-B
20
1140
1
560
60
5
6
7
(S)-1a
(S)-1a
(S)-1a
p-Cymene
p-Cymene
p-Cymene
(1R,2S)-B
(1S,2R)-B
(1S,2R)-B
50
50
20
60
1860
3
660
15
8
(S)-1a
p-Cymene
(1S,2R)-B
80
2
0
9
1
1
(S)-1a
(S)-1a
(S)-1a
Anisole
tBu-benzene
Benzene
(1S,2R)-B
(1S,2R)-B
(1S,2R)-C
50
50
50
80
2880
60
0
1
9
0
1
1
1
1
1
2
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(R)-1b
p-Cymene
(1S,2R)-Ru E
p-Cymene
p-Cymene
p-Cymene
(1S,2R)-C
50
20
50
50
60
320
90
1
1
3b
4
4
50
90
98
78
98
\99
50
(1S,2S)-D
(1R,2R)-D
(1S,2R)-B
380
240
120
5
89
\98
86
3
0
6
1440
\98
a
The reaction was carried out using 2.0 mmol of 1 and 0.02 mmol of Ru in a 0.1 M 2-propanol solution. See footnote † for a typical procedure.
Reaction carried out with isolated catalyst; see Ref. 11.
b
10
corresponding acetonide showed a low de in favour of
the syn diastereomer. This indicates a limited induction
of the chiral centre present in the substrate. When the
same reaction was performed with catalytic combina-
tions based on ephedrine derivatives (B, C), a signifi-
cant increase in the reduction rate was observed.
Completion was usually reached within 1 h at 50°C in
the presence of 1 mol% of Ru. Consistent with the
above results, reversing the configuration of the chiral
ligand resulted in opposite diastereoselectivity for the
diols. syn-Diol 2a is formed from (+)-(1S,2R)-ephedrine
type ligands which give the ‘match-pair’, considering
that the de values with these ligands are systematically
higher than those observed from systems based on
sluggishness of the Ru–(tbutyl-benzene) and the
marked reverse in the diastereoselectivity of the
10
reaction from syn to anti with this system compared
to the other Ru–arene catalysts investigated (entry 10).
The latter experiment clearly confirms a catalyst-con-
trol of the stereoselectivity of the reduction. Regarding
the chiral ligand, systems based on Noyori’s TsDPEN
8
(D) proved surprisingly inefficient in terms of stereose-
lectivity, no matter what the ligand configuration
(entries 14 and 15). N-4-(Biphenyl)methyl-norephedrine
(C), that we specifically developed for the asymmetric
transfer hydrogenation of functionalized ketones such
10
as b-keto esters, did not bring in this case a significant
enhancement of the diastereoselectivity compared to
systems based on simple ephedrine (B), but led logically
to decreased reaction rates (entries 3/11, 6/12). All in
all, the best compromise between stereoselectivity and
activity for the reduction of 1a was obtained in the
(
−)-(1R,2S)-ephedrine type ligands (compare entries 2/3
and 5/6). Previous work in the field of ruthenium-cata-
lyzed asymmetric transfer hydrogenation of ketones has
highlighted the importance of both the chiral ligand and
arene ligand on the enantioselectivity and activity of the
6
presence of the [RuCl (h -p-cymene)] /B (1:4) combina-
2
2
8
–11
reaction.
This also proved to be the case in the
tion. With this system, a moderate erosion of the de
values from 79 to 74% but a large increase in the
present application. With respect to the influence of the
arene ligand, the Ru–benzene precursor gave, under the
same reaction conditions, more active but less stereose-
lective catalysts than those based on the commonly
used Ru–(p-cymene) precursor (entries 2/5, 3/6, 4/7,
−
1
catalyst turnover frequency from 2.5 to 360 h was
noticed upon increasing the reaction temperature from
20 to 80°C (entries 6–8). However, results of Table 1
clearly show that overexposure of the products under
the reaction conditions causes a rapid decrease in
chemoselectivity (mainly due to transesterification reac-
tions) but also of the de values; on the other hand, only
limited erosion of the ee (52%) was observed. A possi-
ble reason for this phenomenon may arise from the use
of a slight excess of base to generate the active species
11/12); reduced steric hindrance at the catalytically
active metal center for the Ru-benzene system most
likely accounts for this very general trend. Using the
same arguments, one may reasonably rationalize: (i) the
similar performance of the Ru–anisole and Ru–(p-
cymene) systems (entries 6/9), and (ii) the extreme

K. E6eraere et al. / Tetrahedron Letters 43 (2002) 2569–2571
2571
7
8
from the in situ combination. Recently, we have shown
13). The reduction of tert-butyl (R)-6-benzyloxy-5-
hydroxy-3-oxohexanoate (1b), an adequately substi-
that side-reactions from 2-acylbenzoates could be over-
come upon using the isolated active catalyst (1S,2R)-
Ru E (Chart 1), that allows us to perform selectively
the transfer reduction under neutral conditions. The
application of this technique to the reduction of 1a
showed, as expected, a better resistance toward transes-
terification reactions, but de values still decreased, pos-
sibly because of the reversibility of the reaction (entry
1
tuted molecule for further functionalization, proceeded
1
0
in similar de for the syn-diol but was much faster and
11
†
also more sensitive in terms of chemoselectivity. No
reaction was observed with tert-butyl (R)-6-chloro-5-
hydroxy-3-oxohexanoate (1c), most likely because of
catalyst poisoning by the chloro group as already
1
0
observed with other chloro-containing substrates.
In conclusion, transfer hydrogenation provides a
promising catalytic alternative to traditional borane
reagents for the syn diastereoselective reduction of chi-
ral 5-hydroxy-3-ketoesters. Current investigations in
this field are aimed at improving diastereoselectivities.
New stereoselective catalytic routes toward functional-
ized-3,5-dihydroxyesters will be reported in due course.
Ru
O
N
Acknowledgements
(1S,2R)-Ru cat E
Chart 1.
We thank PPG-SIPSY for a Ph.D. grant to K.E. and
Dr. M. Bulliard for stimulating discussions.
†
6
In a typical experiment (entry 16), a solution of [RuCl (h -p-
2
References
cymene)] (6.2 mg, 0.01 mmol) and (1S,2R)-ephedrine (6.6 mg, 0.04
2
mmol) in dry freshly distilled 2-propanol (5 mL) was heated under
nitrogen at 80°C for 20 min. After cooling the orange solution to
room temperature, a solution of (R)-1b (615 mg, 2.0 mmol; 96% ee;
prepared by aldolization of ethyl (R)-4-benzyloxy-3-hydroxy-
butyrate with AcOtBu-LDA) in dry freshly distilled 2-propanol (14
mL) and 2-PrOK (1.0 mL, 0.12 m in 2-propanol, 0.12 mmol) were
added. The resulting solution was placed in an oil bath at 30°C,
stirred with a magnetic bar and the reaction was monitored by GLC
analysis using a BPX5 capillary column. After evaporation of
volatiles under vacuum the crude product was purified by column
1
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2
yellow oil (370 mg, 61%). Full assignment of NMR resonances was
4
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6
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1
made on the basis of H, H COSY and C, H HETCOR experi-
1
ments; syn-(3S,5R)-2b: H NMR (CDCl , 300 MHz): l 7.31 (m,
3
5
H, aro), 4.56 (s, 2H, PhCH ), 4.34 (m, 1H, CH CHOHCH ), 4.13
2 2 2
(
m, 1H, OCH CHOH), 3.50 and 3.46 (2m, 2×1H, PhCH OCH ),
2
2
2
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.45 and 2.37 (2m, 2×1H, J=6.3 Hz, CH CO ), 2.01 and 1.50 (2m,
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3
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×1H, CHOHCH CHOH), 1.44 (s, 9H, tBu); C NMR (CDCl , 75
2
3
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3
7
3.08 (OCH CH), 72.87 (PhCH2), 69.89 (0CH CH), 67.64
2
2
(
(
CHOHCH CO ), 42.99 (CH CO ), 34.65 (OCH CH), 27.60
2
2
2
2
2
1
CMe ). anti-(3R,5R)-2b H NMR: l 7.33 (m, 5H), 4.56 (s, 2H),
3
4.27 (m, 1H), 4.12 (m, 1H), 3.49 (m, 2H), 2.43 (m, 2H), 1.60 (m,
2
H), 1.46 (s, 9H); 13C NMR: l 171.98, 137.88, 128.27, 127.58,
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1
1
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1
acetonides were analyzed by GLC on a BPX5 column (25 m×0.32
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mm; 200°C, 0.2 bar N ); the retention times for the syn- and anti-
2
J.-F. Tetrahedron Lett. 2001, 42, 1899–1901.
acetonides are t =11.38 and t =10.32 min, respectively.
R
R