Highly enantioselective synthesis of 3-hydroxy-2-methylpropanoic acid esters through ruthenium-SYNPHOS-catalyzed hydrogenation: Useful building blocks for the synthetic community

Article abstract of DOI:10.1002/adsc.200700025

Both enantiomers of 3-hydroxy-2-methylpropanoic acid tert-butyl ester were prepared with high enantioselectivity (up to 94%) through a ruthenium- SYNPHOS-promoted asymmetric hydrogenation reaction using an atom-economic transformation from simple and inexpensive precursors.

Full text of DOI:10.1002/adsc.200700025

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DOI: 10.1002/adsc.200700025
Highly Enantioselective Synthesis of 3-Hydroxy-2-methylpropano-
ic Acid Esters through Ruthenium-SYNPHOSꢀ-Catalyzed
Hydrogenation: Useful Building Blocks for the Synthetic
Community
SØverine Jeulin,a Tahar Ayad,a Virginie Ratovelomanana-Vidal,a,*
and Jean-Pierre GenÞta,*
a
Laboratoire de Synth›se SØlective Organique et Produits Naturels, Ecole Nationale SupØrieure de Chimie de Paris, UMR
7573 CNRS, 11 rue Pierre et Marie Curie, 75231 ParisCedex 05, France
Fax : (+33)-1-4407-1062; e-mail: virginie-vidal@enscp.fr or jean-pierre-genet@enscp.fr
Received: January 16, 2007
Supporting information for thisarticle isavailable on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Both enantiomersof 3-hydroxy-2-methyl-
propanoic acid tert-butyl ester were prepared with
high enantioselectivity (up to 94%) through a
ruthenium-SYNPHOSꢀ-promoted asymmetric hy-
drogenation reaction using an atom-economic trans-
formation from simple and inexpensive precursors.
by Rh-DUPHOS or Rh-BeePHOS catalysts was re-
[6]
ported, with ee valuesranging from 7 to 90%.
To
the best of our knowledge, a method that provides a
reliable and stereocontrolled direct access to the
Roche ester-type derivatives 1 through Ru-catalyzed
asymmetric hydrogenation has not been described,
except for one example in a Japanese patent[7] using a
Ru-BINAP catalyst and stabilizers to prevent poly-
merization. Consequently, the development of an effi-
cient large-scale enantioselective synthesis of the
Roche ester and its derivatives still remains a chal-
lenge and would find significant use in total syntheses.
Our interest in the preparation of biologically rele-
Keywords: asymmetric catalysis; hydrogenation;
Roche ester; ruthenium
3-Hydroxy-2-methylpropionic acid methyl ester vant natural products[8] such as discodermolide and
(Figure 1), known asRoche etser ( 1a), represents a dolabelide A[8b] required large quantitiesof both
major building block in organic synthesis. It is present enantiomersof 3-hydroxy-2-methylpropanoic acid
in a substantial number of both naturally occurring methyl ester (1a). Recently, we succeeded in design-
and synthetic biologically relevant molecules.[1]
ing and developing new chiral SYNPHOS ligands.[9]
However, despite the huge number of papers dem- Our group has focused on expanding the versatile ap-
onstrating its wide potential synthetic value, there are plications of SYNPHOS towards the synthesis of key
surprisingly only few reports on the synthesis of intermediatesand the preparation of target molecules
1a,[2–7] which rely on the oxidative degradation of a of synthetic interest.[8] In thiscontext, we report an ef-
chiral homoallylic acetate,[2] diastereoselective addi- ficient, high-yielding synthesis of both enantiomers of
[3]
tion of chiral alcoholsto arylketene,s
bacterial or Roche ester derivatives 1 using a Ru-SYNPHOS-cata-
microbial oxidation and enzyme-mediated transfor- lyzed asymmetric hydrogenation of readily available
mations[4] or aldol chemistry.[5] Recently one example acrylate esters.
of an asymmetric hydrogenation reaction promoted
The required precursors 2a–f for the hydrogenation
reaction were easily prepared according to published
procedures.[10] Asoutlined in Table 1, initial tsudies
were directed toward the asymmetric hydrogenation
of the methyl ester 2a. A series of chiral Ru-SYN-
PHOS catalysts was examined to perform the hydro-
genation reactions. All the catalytic tests were con-
ducted under 20 bar and 508C in methanol for 23 h
using 1 mol% of Ru-SYNPHOS complexes.
Figure 1. Roche esters type derivatives 1.
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Adv. Synth. Catal. 2007, 349, 1592 – 1596

Enantioselective Synthesis of 3-Hydroxy-2-methylpropanoic Acid Esters
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Table 1. Ru-(R)-SYNPHOS-promoted asymmetric hydrogenation of acrylate ester 2a.
Entry
Ru-catalyst[a]
{Ru[(R)-SYNPHOS]
Conversion[b] (yield)[c]
ee[d]
1
2
3
4
N
100 (71)
100 (74)
100 (76)
100 (68)
72 (S)
77 (S)
79 (S)
86 (S)
G
ACHTREUNG
ACHTREUNG
ACHTREUNG
[a]
1 mol% of Ru-catalyst. (cod=cycloocta-1,5-diene; cot=cycloocta-1,3,5-triene).
Conversion determined by H NMR of crude product.
Isolated yield after flash chromatography.
Measured by HPLC (Chiralcel OD-H). The configuration was determined to be S by comparing with commercially avail-
able Roche ester 1a.
[b]
[c]
[d]
1
Complete conversions were observed for all catalyt-
ic systems examined. However, the ee valuesof the
Upon heating to 808C and 908C, decreased yields
were observed mainly due to the polymerization of
Roche ester 1a were highly dependent on the nature the substrate (Table 2, entries 2 and 3, 64% and 53%
of chiral Ru-SYNPHOS catalysts.[11] The cationic yields), independently of the amount of HBF4 (1 to 2
[Ru((R)-SYNPHOS)
(p-cymene)Cl]+ClÀ catalyst ex- mol%). Anticipating that a lower temperature may
G
hibited moderate activity and selectivity (Table 1, induce better yield and enantiofacial discrimination,
entry 1, 71% yield, 72% ee). An improvement was we performed the hydrogenation of 2a at 208C, 158C
obtained by using {(RuCl[(R)-SYNPHOS])
2(m-Cl)3]À and 58C. The yields and enantioselectivities were sig-
U
[NH2Me2]+ (Table 1, entry 2, 74% yield, 77% ee). Fi- nificantly enhanced (Table 2, entries4–7, 69 to 92%
nally, better results were achieved with the in situ gen- yield, 86 to 88% ee) although a lower yield wasob-
erated Ru-SYNPHOS complex prepared according to tained by using 1 mol% HBF4 under the same condi-
our convenient procedure[12] by mixing Ru(cod)(h3- tions(Table 2, entry 5, 69% yield). Conesquently, all
G
methylallyl)2 with SYNPHOS in the presence of reactionswere conducted with 2 mol% of HBF . Af-
4
methanolic hydrobromic acid (Table 1, entry 3, 76% terwards, hydrogenation of 2a wasrun in the presence
yield, 79% ee). From thisinitial csreening, we were
of 0.5 mol% of benzoquinone at 158C to prevent
polymerization and 3-hydroxy-2-methylpropionic acid
À
pleased to find that [Ru(H)
C
HBF4 to a mixture of Ru
SYNPHOS in dichloromethane gave the best enantio-
selectivity and satisfactory yield (Table 1, entry 4, on ethyl ester 2b. In this case, similar results were
68% yield, 86% ee). Thiscationic Ru-type pre-cata- achieved and 3-hydroxy-2-methylpropanoic acid ethyl
lyst was synthesized for the first time in our group,[14a] ester [(R)-1b] was synthesized in 82% yield albeit
fully characterized with Me-DuPHOS and used for with slight decrease of the enantioselectivity
ACHTREUNG
a
the key diastereoselective step of a paradisone syn- (Table 2, entry 8, 83% ee). Changing the ethyl ester
thesis.[14] In all cases, Ru-(R)-SYNPHOS catalyst pro- group to a benzyl 2c or a cyclohexyl group 2d led to
vided the desired (S)-enantiomer of the product re- the reaction being more effective in termsof both
sulting from the coordination of the Ru-catalyst with yield and selectivity (Table 2, entries 9 and 10). Espe-
the alkene and the alcohol function of substrate 2. cially in the case of the cyclohexyl ester group 2d, the
Thus, anticipating that a bulkier ester function may yield wasincreased to 96% with an ee value of 90%.
induce increased ee, we subsequently investigated the
hydrogenation of compounds 2a–f by using [Ru(H)- come of the reaction isgreatly affected by the nature
(h6-cot)(SYNPHOS)]+BF4À (3) catalyst.
of the ester functionality: due to greater steric hin-
The results are presented in Table 2. Efforts were drance, a higher enantioselectivity was achieved. As
These results suggest that the stereochemical out-
A
ACHTREUNG
preliminary focused on the asymmetric hydrogenation expected, the use of the sterically hindered tert-butyl
of 2a by varying the temperature and the catalytic ester 2e induced both an increase of yield and selec-
amount of HBF4 (1 to 2 mol%). The reactionswere
tivity, with no influence of hydrogen pressure
carried out under 5 to 80 bar of hydrogen pressure in (Table 2, entries11–16, 5 to 80 bar, 94% ee). It should
methanol for 23 h.
be noted that the use of benzoquinone as stabilizer
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SØverine Jeulin et al.
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Table 2. Enantioselective hydrogenation of substrates 2 using Ru-(S)-SYNPHOS catalyst 3.[a]
Entry
Substrate
HBF4·Me2O [mol%]
P [bar]
T [8C]
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
1
1
2
2
1
2
2
20
20
20
20
20
20
20
50
80
90
20
20
15
5
68
64
53
83
69
86 (R)-1a
77 (R)-1a
76 (R)-1a
87 (R)-1a
86 (R)-1a
87 (R)-1a
88 (R)-1a
92[d]
75
8
2
20
20
82
83 (R)-1b
9
2
20
20
91
96
87 (R)-1c
10
2
20
20
90 (R)-1d
11
12
13
14
15
16
2
2
2
2
2
2
20
80
50
5
5
5
20
20
20
20
20
20
94
94 (R)-1e
94 (R)-1e
94 (R)-1e
94 (R)-1e
94 (R)-1e
94 (S)-1e
93[d]
95[d]
94[e,d]
98[e]
95[e,f]
17
2
5
20
95
94 (R)-1f
[a]
Conditions: all reactions were performed using 1 mmol of substrate 2 in methanol for 23 h, catalyst loading, 1 mol%. In
all cases, complete conversions were achieved.
Isolated yield after flash chromatography.
Measured by HPLC analysis (see Supporting Information).
0.5 mol% of benzoquinone isused.
Hydrogenation carried out on a 5-gram scale.
[b]
[c]
[d]
[e]
[f]
(R)-SYNPHOS wasused instead of ( S)-SYNPHOS.
had a positive effect only on substrates with a high the reaction and comparable results to those of the
tendency for polymerization, such as methyl ester 1a. tert-butyl ester 2e were obtained (Table 2, entry 17,
In all other cases, its use did not really change the 95% yield, 94% ee). Finally, we were pleased to find
chemical outcome of the reaction (see Table 2). With that under the optimized reaction conditions(5 bar,
thisencouraging reus lt in hand, and keeping in mind
208C), hydrogenation of substrate 2e with the Ru-
that a bulky ester substituent is essential for obtaining SYNPHOS catalyst 3 afforded the desired (R)-1e
high selectivity, we then turned our attention to the product on a 5-gram scale with excellent isolated
hydrogenation of the even more hindered 3-methyl- yield (98%) and an highly reproducible ee up to
pentyl ester (Mpe)[15] 2f. Disappointingly, the two 94%.
added methyl groupshave no impact on the course of
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Enantioselective Synthesis of 3-Hydroxy-2-methylpropanoic Acid Esters
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In conclusion, highly efficient syntheses of Roche Acknowledgements
ester derivatives were successfully achieved with ex-
We thank Synkem S.A.S for a grant to S. J.
cellent isolated yields and enantioselectivities through
ruthenium catalytic hydrogenation. To the best of our
knowledge, this is one of the first reported uses of a
chiral cationic Ru-catalyst based upon SYNPHOS
ligand to effect thisreaction in a ismple way, with
great atom-efficiency and under very mild conditions.
Moreover, thistransformation can be carried out with
no stabilizers on a multigram scale.
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General Procedure for the Asymmetric
Hydrogenation of Baylis–Hillman Adducts 2a–f
Chiral diphosphine (0.011 mmol) and (1,5-cyclooctadi-
ene)Ru(2-methylallyl)2 (3.2 mg, 0.010 mmol, commercially
available from Acros), were placed in a round-bottomed
tube, degassed by three vacuum/argon cycles at room tem-
perature, and dissolved in degassed dichloromethane
(1 mL). To this suspension was added dropwise at 08C, a
freshly prepared solution of HBF4·Me2O in dichloromethane
(130 mL, 0.022 mmol, 0.17 N). The reaction mixture was
stirred at room temperature for 30 min and a resulting
orange suspension was observed. After evaporation of the
solvent under vacuum, a solution of the desired substrate
2a–f (1 mmol) in 3 mL of MeOH wasadded to the rutheni-
um catalyst. The resulting mixture was placed under the de-
sired hydrogen pressure and temperature for 23 h. After re-
moval of the solvent, the residue was purified by flash chro-
matography on silica gel to afford the hydrogenated product
1a–f.
[10] Compounds 2a, b, c and e were prepared using the
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Synthesis 1982, 39, 924.
Supporting Information
Characterization data for products 1a–f are given in the
Supporting Information.
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[14a]
analogy with our previouswork see ref.
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Adv. Synth. Catal. 2007, 349, 1592 – 1596