Convenient general asymmetric synthesis of roche ester derivatives through catalytic asymmetric hydrogenation: Steric and electronic effects of ligands

Article abstract of DOI:10.1002/adsc.200800504

An efficient and concise asymmetric hydrogenation of acrylate esters promoted by the cationic ruthenium monohydride complex [Ru(H) (hη⁶-cot)SYNPHOS]⁺BF4₄^- is reported. A full investigation of the effects of catalyst precursors, solvents, temperature, hydrogen pressure, substrates as well as steric and electronic properties of ligands was carried out. The corresponding valuable Roche ester derivatives were obtained in good to excellent isolated yields and high enantioselectivities under mild conditions. The robustness and practicability of this highly enantioselective hydrogenation was demonstrated by the synthesis of the 3-hydroxy-2-methylpropanoic acid tert-butyl ester on a multigram scale, resulting in excellent yield and ee up to 94%.

Full text of DOI:10.1002/adsc.200800504

FULL PAPERS
DOI: 10.1002/adsc.200800504
Convenient General Asymmetric Synthesis of Roche Ester
Derivatives through Catalytic Asymmetric Hydrogenation:
Steric and Electronic Effects of Ligands
Cyrielle Pautigny,a Sꢀverine Jeulin,a Tahar Ayad,a Zhaoguo Zhang,b,c
Jean-Pierre GenÞt,a and Virginie Ratovelomanana-Vidala,*
a
Laboratoire de Synthꢁse Sꢀlective Organique et Produits Naturels, Ecole Nationale Supꢀrieure de Chimie de Paris, UMR
7573 CNRS, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
Fax: (33)-1-4407-1062; phone: (+33)-1-4427-6742; e-mail: virginie-vidal@enscp.fr
School of Chemistry and Chemical Technology, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai 200240,
b
Peopleꢂs Republic of China
Shanghai Institute of Organic Chemistry, 354 Fenglin Road, Shanghai 200032, Peopleꢂs Republic of China
c
Received: August 12, 2008; Published online: November 4, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800504.
Abstract: An efficient and concise asymmetric hy- yields and high enantioselectivities under mild condi-
drogenation of acrylate esters promoted by the cat- tions. The robustness and practicability of this highly
ionic ruthenium moÀnohydride complex [Ru(H)
(h6- enantioselective hydrogenation was demonstrated by
ACHTUNGTRENNUNG
cot)SYNPHOS]+BF4 is reported. A full investiga- the synthesis of the 3-hydroxy-2-methylpropanoic
tion of the effects of catalyst precursors, solvents, acid tert-butyl ester on a multigram scale, resulting in
temperature, hydrogen pressure, substrates as well as excellent yield and ee up to 94%.
steric and electronic properties of ligands was carried
out. The corresponding valuable Roche ester deriva- Keywords: asymmetric catalysis; hydrogenation;
tives were obtained in good to excellent isolated Roche ester; ruthenium
Introduction
such as the use of stoichiometric amounts of chiral
auxiliaries, long reaction sequences and multiple tedi-
Transition metal-catalyzed reactions and specifically ous purification steps. As none of these procedures
homogeneous catalysis have had considerable provides an atom-economical route to the Roche
a
impact on a wide variety of chemical processes rang- ester compound, we envisaged a one-step stereoselec-
ing from fine organic synthesis to the large-scale in- tive catalytic hydrogenation of the respective unsatu-
dustrial area.[1] Among them, the asymmetric hydro- rated compounds 2 to be a very attractive and direct
genation of unsaturated prochiral substrates using in- method to produce this important building block. Sur-
expensive, clean molecular hydrogen and small prisingly, the synthesis of Roche ester derivatives of
amounts of a chiral catalyst is considered as one of type 1 (Figure 1) through asymmetric hydrogenation
the most efficient and atom-economic ways to pro- has been scarcely described.[8–11] Saito and co-workers
duce a wide range of enantio-enriched compounds in reported enantiomeric excess (ee) ranging from 7 to
large quantities without forming any waste.[2]
90% using Rh-DuPHOS or Rh-BeePHOS catalysts[8]
3-Hydroxy-2-methylpropionic acid methyl ester
(1a) commonly named as Roche ester is a compound
of significant synthetic interest.[3] Besides the current-
ly used industrial enzymatic processes,[4] classical
pathways to synthesize synthon 1a enantioselectively
rely on oxidative degradation of a chiral homoallylic
acetate,[5] diastereoselective addition of chiral alcohols
to arylketenes,[6] or aldol chemistry.[7] However, there
are some drawbacks associated with these methods Figure 1. Roche ester-type derivatives 1.
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Cyrielle Pautigny et al.
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Scheme 1. Synthesis of substrates 2a–g.
whereas Reek and co-workers recently reported ees
We started our investigation by searching for the
ranging from 35 to 98% using an Rh catalyst bearing most appropriate catalyst system to perform asym-
their bidentate phosphine-phosphoramidite INDOL- metric hydrogenation of methyl acrylate ester 2a,
PHOS ligands.[9] To the best of our knowledge, no which resulted in 3-hydroxy-2-methylpropionic acid
report of an efficient Ru-catalyzed hydrogenation re- methyl ester 1a. Toward this end, several catalyst sys-
action has been described except for one example tems (C1–C9), generally prepared in situ by mixing a
using an Ru-BINAP complex in a patent applica- solution of a metal precursor and (R)- or (S)-SYN-
tion.[10] In a previous communication[11] and in connec- PHOS[13] as ligands were screened. Initial hydrogena-
tion with our ongoing program on the use of rutheni- tion experiments were first performed at 20 bar of hy-
um-mediated asymmetric hydrogenation,[12] we have drogen pressure and 508C in methanol for 23 h using
reported the Ru-SYNPHOS[13]-catalyzed synthesis of 1 mol% of catalyst. As outlined in Table 1, we ob-
Roche ester derivatives. In this paper, we wish to served that the stereochemical outcome of the reac-
report the full details of this study regarding both tion was highly dependent on the nature of the com-
steric and electronic effects of a wide range of chiral plexes used. Indeed, the neutral dimeric gold(I) com-
ligands and transition metal complexes.
plex [(AuCl)2((R)-SYNPHOS)] C1 which was in situ
generated by reacting our diphosphine with two
equivalents of [(AuCl)ACTHNUTRGNE(NUG tht)] (tht=tetrahydrothio-
Results and Discussion
phene) using the procedure recently described by the
group of Corma and Echavarren[17] showed no catalyt-
Compounds 2a–c and 2e required for our study were ic activity for the hydrogenation of 2a (Table 1,
readily prepared on a large scale by using the Morita– entry 1). Only 10% conversion was reached when
Bayllis–Hillman[14] reaction between aqueous formal- using either the Ir-SYNPHOS complexes C2 or C3
dehyde and the corresponding commercially available (Table 1, entries 2 and 3). The Pd-SYNPHOS com-
acrylate esters in the presence of DABCO plex C4[18] and the preformed [Rh
(cod)
E
À
(Scheme 1). Concerning the synthesis of compounds BF4 catalyst C5 possess similar catalytic profiles and
2d, 2f and 2g, the Morita–Bayllis–Hillman[14] reaction gave rise to full conversion with, respectively, 62%
failed and only traces of the desired product were de- and 51% yield but with very disappointing enantio-
tected which was probably due to the very high ten- meric excesses, not exceeding 7% (Table 1, entries 4
dency of these substrates to polymerize during the re- and 5). Finally, we found that a dramatic enhance-
action. Instead, these compounds were finally ob- ment of the catalytic activity in terms of both yield
tained via a two-step reaction sequence involving and enantioselectivity was obtained when chiral Ru-
DCC-mediated esterification of diethylphosphonoace- SYNPHOS complexes[19] were used.
tic acid[15] followed by a Wittig–Horner reaction of
the resulting diethylphosphonoester with aqueous yield with a promising ee of 72% using the cationic
formaldehyde[16] (Scheme 1). It should be noted that [Ru((R)-SYNPHOS)(p-cymene)Cl]+ClÀ catalyst C6
For example, compound 1a was isolated in 71%
AHCTUNGTRENNUNG
the entire sequence can be conducted in one-pot, (Table 1, entry 6). This result was far superior to
without isolation of the diethylphosphonoester inter- those obtained with Rh-, Ir-, Au- and Pd-SYNPHOS
mediates.
complexes (entries 1 to 5). An even better selectivity
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Convenient General Asymmetric Synthesis of Roche Ester Derivatives
FULL PAPERS
Table 1. Optimization of reaction conditions for asymmetric hydrogenation of methyl acrylate ester 2a catalyzed by a metal/
SYNPHOS (L1) complex.[a]
Entry
Catalyst
T [8C]
Conv.[b] (Yield)[c]
ee[d]
1
2
3
4
5
6
7
8
C1, AuCl
G
50
50
50
50
50
50
50
50
50
30
20
20
15
10
5
0% (N/D)[e]
N/D[e]
C2, [Ir
C3, [Ir
U
<10% (N/D)[e]
<10% (N/D)[e]
100% (62%)
100% (51%)
100% (71%)
100% (74%)
100% (76%)
100% (68%)
100% (71%)
100% (69%)
100% (83%)
100% (92%)[f]
100% (82%)
100% (85%)
N/D[e]
N/D[e]
C4, Pd
N
5% (S)
7% (S)
72% (S)
77% (S)
79% (S)
86% (S)
86% (R)
86% (R)
87% (R)
86% (R)
88% (R)
88% (R)
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
9
10
11
12
13
14
15
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[a]
Conditions: all reactions were performed using 1 mmol of substrate 2 in methanol for 23 h, catalyst loading, 1 mol%.
Conversion determined by H NMR of crude product.
Isolated yield after flash chromatography.
The ee values were measured by HPLC on a Chiralcel OD-H column. The configuration was determined by comparison
[b]
[c]
[d]
1
with commercially available Roche ester 1a.
Not determined.
0.5 mol% of benzoquinone was used.
[e]
[f]
was obtained when the {(RuCl[(R)-SYNPHOS]
2ACHTUNGTERN(NUNG m- 15). By raising the amount of HBF4 from 1 to 2
Cl)3}À[NH2Me2]+ C7 was used (Table 1, entry 7, 74% mol%, similar enantiomeric excess were still obtained
ACHTUNGTRENNUNG
yield, 77% ee). Further improvement of the enantio- but the yield of the desired hydrogenated compound
selectivity was achieved using the in situ generated 1a was significantly enhanced (Table 1, entries 11 vs.
Ru-SYNPHOS complex C8 prepared according to 12, 69% and 83% yields, respectively). It was worth
ACTHNUTRGNEUNG
our convenient procedure[20] by mixing Ru(cod)(h3- noting that the use of 0.5 mol% of benzoquinone as
methylallyl)2 with the diphosphine in the presence of stabilizer to prevent polymerization of the substrate
methanolic hydrobromic acid (Table 1, entry 8, 76% during the course of the reaction further improved
yield, 79% ee). Finally, the cationic monohydride the yield to 92% without eroding the asymmetric in-
À
ruthenium complex [Ru(H)
(h6-cot)SYNPHOS]+BF4
duction (Table 1, entry 13, 86% ee).
C9[21], which was successfully used with JOSIPHOS
The absolute configuration of the hydrogenated
ligand for the synthesis of (+)-cis-methyldihydrojasm- product was determined by comparison with commer-
onate (paradisoneꢄ) in an industrial enantioselective cially available 3-hydroxy-2-methylpropionic acid
hydrogenation process on a multi t/year scale,[22] dis- methyl ester 1a also known as the Roche ester. In all
played the best catalytic activity in the hydrogenation cases, the Ru catalyst containing the ligand with the
of methyl acrylate ester 2a (Table 1, entry 9, 68% (S)-configuration gave rise to the corresponding (R)-
yield, 86% À ee). Since the [Ru(H)
PHOS]]+BF4 catalytic system prepared by the addi- uration produced the (S)-enantiomer.
tion of 1 equiv. of HBF4 to a mixture of Ru The selectivity observed for the asymmetric hydro-
(cod)(h3-
(h6-cot)SYN- 1a compound whereas the ligand with the (R)-config-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
methylallyl)2 and SYNPHOS in dichloromethane genation of methyl ester 2a could be explained
proved to be the more efficient catalyst, we further through the use of quadrant rules[23] as shown in
decided to study the effect of the temperature and Figure 2. We postulated that the prochiral allylic alco-
the catalytic amount of HBF4 with this system. It was hol coordinates to the Ru catalyst in a bidentate
clearly visible from the data presented in Table 1 that manner by the alkene and the alcohol functions, pro-
lowering the temperature from 508C to 58C had only viding two diastereomeric complexes (re- or si-face).
minimal effects on the stereoselectivity, independently Due to steric hindrance of the ligand towards the sub-
of the amount of HBF4 (compare entries 9 vs. 10 to strate, one of the diastereomeric complexes was ener-
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Figure 2. Transition state model to rationalize the enantioselectivity for Ru-(S)-SYNPHOS-catalyzed asymmetric hydrogena-
tion of methyl ester 2a.
getically favored. The transition state (TS-2) suffers attention to the hydrogenation of the even more hin-
from steric repulsion between the ester group of the dered substrates such as 3-methyldiisopropyl ester
substrate and the phenyl group of the considered li- 2f[24] and 3-methylpentyl ester (Mpe) 2g[25] hoping to
gands in a pseudo equatorial position whereas the further increase the selectivity of the reaction. How-
transition state 1 (TS-1) avoids this steric repulsion, ever, comparable results to the tert-butyl ester 2e in
allowing the reaction to proceed, yielding the (R)- terms of both yield and enantioselectivity were ob-
isomer as the major product. From a theoretical point tained (Table 2, entries 12 and 13). The data in
of view, the allylic alcohol 2a can also coordinate to
the metal center through another bidentate coordina-
tion mode which involves the alkene and the carbonyl
functions, affording also the (R)-isomer as the major
product. However, this possibility was ruled out by
the result obtained for the asymmetric hydrogenation
of the silylated derivative of allylic alcohol 2a (TBS
protection). Indeed, only 10% conversion was
reached when the reaction was carried out at 20 bar
Table 2. Ru-(S)-SYNPHOS-catalyzed asymmetric hydroge-
nation of substrates 2a–g.[a]
Entry
R
P [bar] Yield [%][b] ee[c]
of hydrogen pressure and 508C in methanol for 23 h
using 1 mol% of [Ru(H)ACTHNUTRGNEUNG
(h6-cot)SYNPHOS]+BF4
À
1
2
3
4
5
6
7
8
2a: R=Me
2b: R=Et
2c: R=Bn
2d: R=c-Hex
2e: R=t-Bu
20
20
20
20
20
80
50
5
5
5
5
5
83
82
91
96
87 (R)-1a
83 (R)-1b
87 (R)-1c
90 (R)-1d
94 (R)-1e
94 (R)-1e
94 (R)-1e
94 (R)-1e
94 (R)-1e
94 (S)-1e
86 (R)-1e
93 (R)-1f
94 (R)-1g
catalyst C9.}
Based on the previous model depicted in Figure 2,
we anticipated that the enantioselectivity of the reac-
tion should increase if the steric interactions between
the bottom left quadrant of the ligand and the sub-
strate increase. Several substrates bearing more steri-
cally demanding ester groups were then prepared.
Ethyl ester 2b led to a slight drop in enantioselectivity
compared to the methyl ester 2a (Table 2, entries 1
and 2, 87% and 83% ee), while substrate 2c with a
benzyl substituent, gave similar results to the methyl
ester 2a (Table 2, entry 3, 87% ee). The cyclohexyl-
substituted derivative 2d resulted in an enantiomeric
excess of 90%, which was a slightly better value than
for the methyl-substituted substrate 2a (Table 2,
entry 4). As expected, an increase of the steric
demand of the ester moiety by using the bulky tert-
butyl group 2e led to a drastic increase of the enantio-
selectivity. Thus the corresponding adduct 1e was ob-
tained in high isolated yield (91 to 98%) with up to
94% ee (Table 2, entries 5 to 10). We next turned our
94
93[d]
95[d]
94[e,d]
98[e]
95[e,f]
91[g]
96
9
10
11
12
13
2f: R=CH
2g: R=C(Me)Et2
(i-Pr)2
5
95
[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 Informa-
tion).
[b]
[c]
[d]
[e]
[f]
0.5 mol% of benzoquinone was used.
Hydrogenation carried out on a 5-gram scale.
(R)-SYNPHOS was used instead of (S)-SYNPHOS.
0.5 mol% of catalyst was used.
[g]
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Convenient General Asymmetric Synthesis of Roche Ester Derivatives
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Table 3. Solvent screening for asymmetric hydrogenation of
tert-butyl acrylate ester 2e.[a]
With optimal catalyst and solvent conditions estab-
lished, we decided to study other factors that might
improve the selectivity. Toward this end, several com-
mercially available chiral ligands were screened. The
results, which are summarized in Table 4, indicated
that both the reactivity and the enantioselectivity
were highly affected by the electronic and steric prop-
erties of the ligand considered. From this screening,
we found that atropisomeric diphosphines were in
general excellent ligands providing compound 1e in
high isolated yields with good to excellent enantiose-
lectivities (Table 4, entries 1 to 9, 90–98% yields and
80–94% ee), except in the cases of the electron-rich
isopropyl L10 and cyclohexyl L11 MeOBIPHEP de-
rivatives[26] for which 30% conversion was obtained
(Table 4, entries 10 and 11). The use of L4 (SEG-
PHOS)[27] and L9 (MeOBIPHEP)[26] ligands resulted
in a comparable high enantiodiscrimination to that
reached by L1 (SYNPHOS)[13] (Table 4, compare en-
tries 1 vs. 4 and 9) whereas the same reaction cata-
lyzed by the complex containing BINAP L3[28] led to
a clear drop in selectivity (Table 4, compare entries 1
vs. 3). A decrease in enantioselectivity was also ob-
served when the complex containing the electron-
poor DIFLUORPHOS ligand L2[13a-c,29] was used
(Table 4, entry 2, 82% ee).
Entry
Solvent
Conv. [%][b]
Yield [%][c]
ee[d]
1
2
3
4
5
6
7
8
9
MeTHF
Et2O
100
100
55
100
100
100
100
100
100
100
97
66 (R)
70 (R)
N/D[e]
85 (R)
82 (R)
78 (R)
89 (R)
94 (R)
93 (R)
93 (R)
88
Toluene
CH2Cl2
t-BuOH
i-PrOH
EtOH
MeOH
EtOAc
Acetone
N/D[e]
98
96
96
95
98
93
92
10
[a]
Conditions: all reactions were performed using 1 mmol
of substrate 2, catalyst loading, 1 mol%.
Conversion determined by H NMR of crude product.
Isolated yield after flash chromatography.
Measured by HPLC analysis on Chiralcel OD-H column.
Not determined.
[b]
[c]
[d]
[e]
1
Table 2 also illustrate that the hydrogen pressure has
The data in Table 4 also illustrate that the steric
no impact on the selectivity for the hydrogenation of properties of the diphosphine, in particular the sub-
the tert-butyl-substituted substrate 2e. Finally, at- stituents at the phosphorus atom, mainly influence
tempts to decrease the catalyst loading from 1 to 0.5 the stereochemical outcome of the reaction. This
mol% gave rise to the hydrogenated compound 1e steric effect was revealed by comparison of the selec-
with lower 86% ee (Table 2, entry 11).
tivity of the reaction conducted with catalysts bearing
With these results in hand, we set out to determine the SUNPHOS[30] family of ligands (Table 4, en-
the optimal solvent for the asymmetric hydrogenation tries 5–8). In all cases, full conversions were obtained
of compound 2e. The cationic monohydride rutheni- and compound 1e was isolated in high yields ranging
(h6-cot)SYNPHOS]+BF4 C9 from 90–95%. The unsubstituted diphenyl SUNPHOS
À
um complex [Ru(H)
which proved to be the more efficient catalyst system L5 and the corresponding 4-Me-C6H4 substituted di-
was chosen. All hydrogenations were performed phosphine L6 gave comparable selectivities with, re-
under a hydrogen pressure of 5 bar at room tempera- spectively, 91 and 89% ee (Table 4, entries 5 and 6)
ture for 23 h. In all cases, except for the reaction run while ligands L7 and L8 having bulky substituents led
in toluene, complete conversions were reached and to a significant drop in enantioselectivity (Table 4, en-
compound 1e was obtained in good to excellent yields tries 7 and 8, 84 and 80% ee). Finally, this ligand
ranging from 88 to 98%. The results from these ex- screening also revealed that non-atropisomeric di-
periments are presented in Table 3. It was found that phosphines such as CHIRAPHOS L13[31] or JOSI-
this reaction was strongly solvent-dependent. The best PHOS L14[32] provided the hydrogenated compound
results were obtained in polar solvent with up to 94% 1e in high isolated yields but in moderate to low ee
ee when the reaction was carried out in methanol values (Table 4, entries 13 and 14, 78 and 39% ee)
whereas all other alcoholic solvents tested gave lower whereas almost no catalytic activity was observed
enantioselectivities (Table 3, entries 5–7, 78 to 89% with the phosphoramidite PipPHOS monodentate
ee). The use of acetone and ethyl acetate resulted in ligand L12[33] (Table 4, entry 12).
similar selectivity (Table 3, entries 9 and 10, 93% ee).
As mentioned before, toluene was by far the worst
solvent for this reaction with only 55% conversion Conclusions
whereas the use of other aprotic apolar solvents such
as methyltetrahydrofuran, ether and dichloromethane In conclusion, using the cationic monohydride ruthe-
(h6-cot)SYNPHOS]+BF4 we
À
led to lower selectivities (Table 3, entries 1–4, 66 to nium complex [Ru(H)
85% ee).
have developed an efficient homogeneous asymmetric
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Cyrielle Pautigny et al.
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Table 4. Ligand effects for Ru-catalyzed asymmetric hydro-
genation of tert-butyl acrylate ester 2e.[a]
hydrogenation of acrylate ester compounds 2 which
provides a direct access to synthetically valuable
Roche ester derivatives in high yields and selectivities.
The robustness and practicability of this highly enan-
tioselective hydrogenation were demonstrated by the
synthesis of the 3-hydroxy-2-methylpropanoic acid
tert-butyl ester 1e on a multigram scale, starting with
30 mmol of 2e, and resulting in nearly quantitative
yield and ee up to 94%. As far as the Ru-catalyzed
asymmetric hydrogenation reaction is concerned, we
have demonstrated that the yield and enantioselectivi-
ty depend on both steric and electronic profiling of li-
gands L1–L11 and the bulkiness of the ester function
of substrates 2. As an important complement of our
previous study,[11] and among a wide range of chiral li-
gands and transition metal complexes, we targeted
and identified preferred ligand/substrate correspond-
ences leading to the best yield and enantioselectivity
and confirmed that atropisomeric ligands and particu-
larly SYNPHOS together with hindered Roche ester
derivatives were the most suitable for this reaction.
Experimental Section
Typical Procedure for Asymmetric Hydrogenation of
Acrylate Esters 2
Chiral ligand (0.011 mmol) and (1,5-cyclooctadiene)Ru(h3-
methylallyl)2 (3.2 mg, 0.010 mmol, commercially available
from Acros), were placed in a round-bottomed tube, de-
gassed by three vacuum/argon cycles at room temperature,
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, 0.17N). The reaction mixture was stirred at
room temperature for 30 min and a resulting orange suspen-
sion was observed. After evaporation of the solvent under
vacuum, a solution of the desired substrate 2 (1 mmol) in
3 mL of MeOH was added to the ruthenium catalyst. The
resulting mixture was placed under the desired hydrogen
pressure and temperature for 23 h. After removal of the sol-
vent, the residue was purified by flash chromatography on
silica gel to afford the hydrogenated product 1.
Entry
Ligand
Conv.
[%][b]
Yield
[%][c]
ee[d]
1
2
3
4
5
6
7
8
L1, (S)-SYNPHOS
L2
L3
L4
L5
L6
L7
L8
100
100
100
100
100
100
100
100
100
30
98
91
93
95
92
93
90
91
94 (R)-1e
82 (R)-1e
88 (R)-1e
94 (S)-1e
91 (R)-1e
89 (S)-1e
84 (S)-1e
80 (R)-1e
93 (R)-1e
N/D[e]
9
L9
95
10
11
12
13
14
L10
L11
L12
L13
L14
N/D[e]
N/D[e]
N/D[e]
94
30
10
100
100
N/D[e]
N/D[e]
78 (R)-1e
39 (S)-1e
94
Acknowledgements
[a]
Conditions: all reactions were performed using 1 mmol
of substrate 2e in methanol for 24 h, catalyst loading, 1
mol%.
Conversion determined by NMR analysis of crude prod-
uct.
We thank Synkem S.A.S for a grant to S.J. We also thank R.
Schmidt and M. Scalone for a generous gift of MeOBIPHEP
ligands.
[b]
1
[c]
[d]
Isolated yield after flash chromatography.
Measured by HPLC analysis (see Supporting Informa-
tion).
Not determined.
[e]
References
[1] H.-U. Blaser, B. Pugin, F. Spindler, in: Applied Homo-
geneous Catalysis with Organometallic Compounds, 2nd
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