A versatile route to syn- and anti-α-amino β-hydroxy esters from β-keto esters by dynamic kinetic resolution with Ru-SYNPHOS catalyst

Article abstract of DOI:10.1002/ejoc.200400078

A general and practical synthesis of both syn- and anti-α-amino β-hydroxy esters with high levels of selectivity by the use of Ru-SYNPHOS catalysts is reported. The key transformations include asymmetric hydrogenations of α-N-substituted β-keto esters pro

Full text of DOI:10.1002/ejoc.200400078

FULL PAPER
A Versatile Route to syn- and anti-α-Amino β-Hydroxy Esters from β-Keto
Esters by Dynamic Kinetic Resolution with Ru-SYNPHOS Catalyst
[a]
[a]
[a]
´
Celine Mordant, Pascal Dünkelmann, Virginie Ratovelomanana-Vidal,* and
Jean-Pierre Genet*[a]
Keywords: α-Amino-β-hydroxy esters / Asymmetric hydrogenation / Catalysis / Dynamic kinetic resolution / Ruthenium
A general and practical synthesis of both syn- and anti-α-
amino β-hydroxy esters with high levels of selectivity by the
genation of α-amino β-keto ester hydrochlorides affords the
corresponding anti-α-amino β-hydroxy esters with high dia-
use of Ru-SYNPHOS catalysts is reported. The key trans- stereoselectivities (up to 99%) and enantioselectivities (up to
formations include asymmetric hydrogenations of α-N-sub-
97%) through dynamic kinetic resolution (DKR).
stituted β-keto esters protected as α-amido or α-amino hydro- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
chloride derivatives, respectively. The RuII-catalyzed hydro- Germany, 2004)
Introduction
adjacent stereogenic centers in one single chemical
operation.[9] It was originally reported simultaneously by
Noyori[10] and by our group[11] in the context of the syn-
thesis of threonine. The α-acetamido β-keto ester was
efficiently hydrogenated, under optimized conditions, dis-
playing high syn diastereoselectivity with (R)-BINAP- and
(S,S)-CHIRAPHOS-ruthenium catalyst (Scheme 1). Since
these pioneering works, this syn selection has been more
generally obtained in the hydrogenation of acyclic α-amido
Amino acids and amino alcohols are finding increasing
synthetic utility as intermediates for pharmaceutical and
agricultural drugs.[1,2] As representative examples, chiral α-
amino β-hydroxy acids are important both as constituents
of biologically active peptides[3] and as key structural units
in numerous bioactive natural products. -erythro-Dihydro-
sphingosine or -erythro-sphingosine (inhibitor of protein
kinase C) and their derivatives are involved in many biologi-
cally crucial processes from cell differentiation to signal
transduction, while naturally occurring anti-(2S,3S)-3-
hydroxyleucine is incorporated into the backbones of a
range of peptide antibiotics and cyclopeptide alkaloids such
as polyoxypeptins[4] and papuamides.[5] Chiral α-amino β-
hydroxy acids are also components of glycopeptide anti-
biotics such as vancomycin.[6] The synthesis of such com-
pounds with high levels of selectivity remains a challenge,
though many approaches have already been reported in the
literature. An elegant and efficient pathway to syn-α-amino
β-hydroxy esters through ruthenium-mediated hydroge-
nation of the corresponding α-amino β-keto esters by dy-
namic kinetic resolution (DKR) has been developed since
the end of the 1980s. For access to the anti isomers, many
different strategies such as sequential catalytic asymmetric
hydrogenation and electrophilic amination have been de-
scribed.[7] Until very recently, however, there was no direct
synthesis of these anti isomers by DKR.[8]
DKR in association with Ru-catalyzed hydrogenation
turned out to be a powerful synthetic tool to control two
[a]
`
´
Laboratoire de Synthese Selective Organique et Produits
Naturels (UMR 7573, CNRS),
´
Ecole Nationale Superieure de Chimie de Paris,
11 rue P. et M. Curie, 75231 Paris Cedex 05, France
Fax: (internat.) ϩ33-(0)1-4407-1062
E-mail: genet@ext.jussieu.fr, gvidal@ext.jussieu.fr
Scheme 1
Eur. J. Org. Chem. 2004, 3017Ϫ3026
DOI: 10.1002/ejoc.200400078
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3017

C. Mordant, P. Dünkelmann, V. Ratovelomanana-Vidal, J.-P. Genet
FULL PAPER
from the corresponding β-keto esters 1 in two steps accord-
ing to the general scheme depicted below (Scheme 2).
Figure 1. Representative examples of syn diastereoselectivity by
DKR
β-keto esters. This efficient technology has been successfully
applied to the total or formal synthesis of drugs (Figure 1)
such as -DOPS (an anti-Parkinsonian agent),[10] bipheno-
mycin A (an antibacterial agent),[12] (Ϫ)-balanol (inhibitor
of protein kinase C),[13] and vancomycin-type β-hydroxy-
tyrosine.[14] This dynamic kinetic resolution[10,15] has also
been highlighted in the industrial synthesis of chiral 4-ace-
toxyazetidinone, followed by RuIII-catalyzed oxidative ace-
toxylation,[16] as precursor for β-carbapenem antibiotics.
Two different models to explain the origin of this syn
diastereoselectivity have been suggested. Noyori’s inter-
pretation is based on a FelkinϪAnh transition state, with
reference to chelation of the ketone and the ester carbonyl
function on the metal.[9a,10] Another explanation has been
proposed by our group, and is based on the formation of
a transition chair-like chelate ruthenium amide complex in
which the amide carbonyl group and the ketone are bonded
to the metal (Scheme 1).[11b]
The selectivity of the dynamic kinetic resolution of α-
substituted β-keto esters was then studied, and showed
great dependence upon the reaction conditions and the
nature of the configurationally labile group at the α position.
The Ru-mediated hydrogenation of cyclic α-alkyl[9a,10,17] or
α-chloro β-keto esters[18] gave the anti adducts. During pre-
liminary work on Dolastatine 10, the anti-γ-amino β-
hydroxy α-methyl ester, derived from (S)-proline, was iso-
lated almost exclusively, as its amine hydrochloride salt,
after asymmetric reduction of the corresponding β-keto α-
methyl ester by DKR.[19] On the basis of these previous
studies and in our ongoing research into ruthenium-cata-
lyzed asymmetric hydrogenation,[20] we could reasonably
hope that the outcome of the dynamic kinetic resolution of
β-keto esters α-substituted with a NH2·HX group (HX ϭ
HCl or TsOH), displaying no chelating properties, would
be in favor of the anti adducts.
Scheme 2. Reagents and conditions: (a) for 1a, 1b, 1e, NaNO2,
AcOH/H2O, Ͼ 84%, (b) for 1c, 1d, BuNO2, HCl in Et2O, Et2O, Ͼ
91%, (c) for 1b to 1e, Zn, (PhCO)2O, AcOH, 27 to 60%, (d) for 1a,
H2, Pd/C, APTS, EtOH then PhCOCl, NEt3, CH2Cl2, 81%, (e) for
1a, 1c, 1d, 1e, H2, Pd/C, HCl in RЈOH, quant, (f) for 1b, Zn, Boc2O,
AcOH then HCl in MeOH, MeOH, 82%
The β-keto esters 1 were conveniently transformed into
the oximes 2 by treatment with sodium nitrite in the pres-
ence of acetic acid or n-butyl nitrite in the presence of an
ethereal solution of hydrochloric acid. These oximes 2 were
reduced with zinc in acetic acid in the presence of benzoic
anhydride to afford the desired α-benzamido β-keto esters
3. This protecting group was preferred for its good chelating
properties and for analytical facility (de and ee were deter-
mined by HPLC analysis). Our next concern was to prepare
the requisite α-amino β-keto ester hydrochlorides 4, starting
from the same intermediates 2. Compounds 4 were synthe-
sized by using Pd/C and an alcoholic solution of hydro-
chloric acid under atmospheric pressure of hydrogen in
quantitative yields. Because of the benzyloxy function in the
substrate 1b (R ϭ BnOϪC4H8), the corresponding α-amino
β-keto ester hydrochloride 4b was formed in a two-step pro-
cedure from 2b, which was treated with zinc in the presence
of Boc2O, followed by addition of a methanolic solution of
hydrochloric acid. The α-benzamido β-keto ester 3a (R ϭ
C3H7) followed another synthetic pathway via the tosylate
salt 6a.
As expected, the syn-α-benzamido β-hydroxy esters 5
were synthesized in good yields (up to 92%) by hydrogena-
tion of the corresponding β-keto esters 3 in dichlorometh-
ane. All the catalytic tests were performed with the chiral
catalyst [Ru(diphosphane)Br2] generated in situ, prepared
from [(cod)(2-methylallyl)2Ru], in the presence of the atrop-
isomeric diphosphane ligand and methanolic HBr by our
convenient procedure.[21] Under optimized but drastic con-
ditions, such as 130 bar of hydrogen at 80 °C for 4 days,
with 2 mol % of Ru-SYNPHOS [22] catalyst, good to excel-
lent syn diastereoselectivities (86 to Ͼ 99% de) were ob-
served. Except in the case of the substrate 3a (R ϭ C3H7,
Entries 1 and 6, 75 and 86% ee, respectively), excellent levels
The purpose of this communication is to report a
straightforward synthesis of anti-α-amino β-hydroxy esters
based on the dynamic kinetic resolution (DKR) of β-keto
esters α-N-substituted as amine hydrochloride salts.
Results and Discussion
This study was conducted with a few examples of syn- of enantioselectivity were achieved (97Ϫ99% ee) (Scheme 3
thetic interest. Compounds 3 and 4 were easily prepared and Table 1).
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Eur. J. Org. Chem. 2004, 3017Ϫ3026

A Versatile Route to syn- and anti-α-Amino β-Hydroxy Esters
FULL PAPER
β-keto α-methyl ester derived from (S)-proline as its amine
hydrochloride salt.[19] We were pleased to find that the reac-
tions proceeded smoothly under these mild conditions with
complete conversions and significant levels of anti dia-
stereoselectivity (up to 98% de) but with disappointing ees
(36 to 88% ee), whatever the pressure (12 to 100 bar) and/
or the temperature (50 to 100 °C). The crude hydrogenated
products were treated with benzoic anhydride and triethyl-
amine to afford the corresponding α-benzamido β-hydroxy
esters 5. The configurations of these adducts were deter-
mined by comparison with the previously synthesized syn-
α-benzamido β-hydroxy esters and authentic samples.[23]
According to these preliminary results, we found that di-
chloromethane was the most appropriate solvent to slow
down the reaction rate and favor better discrimination by
the Ru-catalyst. Because of the poor solubility of the α-
amino β-keto ester hydrochlorides 4 in dichloromethane,
the hydrogenations were carried out with 9% of alcoholic
solvent (MeOH or EtOH), allowing better homogeneity of
the reaction medium. After optimization of the conditions,
we found that 2 mol % of catalyst were required to ensure
complete conversion and that the atropisomeric ligand
Scheme 3
Table 1. Hydrogenation of the α-benzamido β-keto esters 3
Entry[a] Substrate
Yield [%] de [%][b]
ee [%][b]
1
2
3
4
5
3a R ϭ C3H7
81
53
77
82
92
88
70
83
92
94
71
93
98
98
99
86
92
95
98
75 (2R,3S)
Ͼ 99 (2R,3S)
99 (2R,3S)
97 (2R,3S)
97 (2R,3S)
86 (2S,3R)
3b R ϭ BnOϪC4H8
3c R ϭ C5H11
3d R ϭ C15H31
3e R ϭ iPr
6[c]
7[c]
8[c]
9[c]
10[c]
3a R ϭ C3H7
3b R ϭ BnOϪC4H8
3c R ϭ C5H11
3d R ϭ C15H31
3e R ϭ iPr
Ͼ 99 (2S,3R) SYNPHOS, recently developed in our group,[22] provided
99 (2S,3R)
97 (2S,3R)
98 (2S,3R)
high selectivities (Scheme 4).
Ͼ 99
[a]Conversion rates were determined by 1H NMR (CDCl3) spec-
troscopy; all reactions were complete. [b] de and ee were determined
[c]
by HPLC analysis. Reactions conducted with (R)-SYNPHOS
ligand.
It is noteworthy that the diastereoisomeric excesses ob-
tained are directly linked to the steric hindrance created by
the side chain; the higher the steric hindrance, the better
the diastereoselectivity of the reaction [for the long chain
3d (R ϭ C15H31) or branched chain 3e (R ϭ iPr) substrates
(Entries 4, 9 and 5, 10)].
Scheme 4
We next examined the hydrogenation of the α-amino β-
keto ester hydrochlorides 4 in alcoholic solvents such as
methanol or ethanol under 12 bar of hydrogen, for 24 h, at
Both anti-(2S,3S) and (2R,3R) configurations of the α-
50 °C with 1 mol % of catalyst under the hydrogenation benzamido β-hydroxy esters 5 were obtained efficiently with
conditions previously applied to the hydrogenation of the equal ease. The results are summarized in Table 2.
Table 2. Hydrogenation of the α-amino β-keto ester hydrochlorides 4 under optimized conditions
Entry[a]
Substrate
SYNPHOS configuration
Yield [%][b]
de anti [%][c]
ee [%][c]
1
2
3
4
5
6
7
8
9
4a R ϭ C3H7
4b R ϭ BnOϪC4H8
4c R ϭ C5H11
4d R ϭ C15H31
4e R ϭ iPr
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
90
90
94
93
85
90
83
85
90
96
86
86
92
93
93
93
96
98
99
97
92 (2S,3S)
93 (2R,3R)
92 (2S,3S)
93 (2R,3R)
91 (2S,3S)
91 (2R,3R)
96 (2S,3S)
96 (2R,3R)
97 (2S,3S)
96 (2R,3R)
10
[a]
Reaction conditions: 0.5 mmol of substrate, S/C 50, 2 mL of CH2Cl2 and 200 µL of RЈOH (MeOH or EtOH), P(H2):12 bar, 50 °C,
1
[b]
24 h. Conversion rates were determined by H NMR (MeOD) spectroscopy before reprotection; all reactions were complete.
over 2 steps. de and ee were determined by HPLC analysis.
Yields
[c]
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C. Mordant, P. Dünkelmann, V. Ratovelomanana-Vidal, J.-P. Genet
FULL PAPER
Finally, high enantioselectivities (from 91 to 97%) and β-keto ester hydrochlorides (high anti selectivity), we postu-
diastereoselectivities, ranging from 86% for 4a (R ϭ C3H7, late that the reaction proceeds through a favored chair-like
Entries 1 and 2) to 99% for 4e (R ϭ iPr, Entry 9), were transition state (a) with the ketone and the ester carbonyl
achieved with this catalytic system. Once again, the de fol- function chelated on the ruthenium and the NH2.HCl
lowed the same tendency as previously observed, according group in an equatorial position rather than a transition
to the nature of the side chain and its hindrance (Scheme 5). state (b) with NH2.HCl in an axial position (Scheme 6).
Scheme 5. Influence of the side chain on the diastereoselectivity of
Scheme 6. Stereochemical model for anti stereoselectivity
the hydrogenation reaction (reaction conducted with Ru-(S)-
SYNPHOS catalyst)
Conclusion
Subsequent reaction optimization studies revealed that
the hydrogenation reaction did not proceed completely un-
der 6 bar of hydrogen even if the reaction time was in-
Dynamic kinetic resolution of configurationally labile α-
NH2·HCl-β-keto esters with Ru-SYNPHOS catalysts un-
der mild conditions[24] provides a direct and efficient route
creased to 36 h. Furthermore, the catalyst derived from
to anti-α-amino β-hydroxy esters with high levels of stereo-
[Ru(p-cymene)Cl2]2 (prepared simply in situ by mixing this
selectivity. In this paper, we disclose an interesting alterna-
ruthenium precursor with the atropisomeric diphosphane)
tive technology to our sequential approach by hydroge-
was less effective in terms of yield. Another counter-anion
nation and electrophilic amination.[7] Thanks to this con-
venient method, asymmetric hydrogenation emerges as an
elegant and powerful tool for the synthesis of both syn and
anti isomers of α-amino β-hydroxy acids, from the same
common readily available intermediate 2-hydroxyimino β-
keto ester. This study may confirm the role played by the
was investigated for the C3-substrate, which gave lower se-
lectivities. With use of the tosylate derivative 6a in the
hydrogenation reaction under these optimized conditions,
the reaction proceeded with des and ees decreasing from
86 to 80% and from 92 to 86%, respectively (Table 3). The
hydrochloride salts seemed to be the most appropriate
chelating amide carbonyl function on the diastereoselec-
derivatives to achieve high selectivities.
tivity of the hydrogenation reaction of α-amido β-keto es-
ters, as reported in our preliminary studies.[11b] The scope
Table 3. Influence of the counter-anion on the selectivities
of this reaction is still under investigation, and its appli-
cation to the synthesis of natural products and their ana-
logues is underway in our laboratory.
Experimental Section
General Remarks: Dichloromethane and dimethylformamide were
distilled from calcium hydride, and diethyl ether from sodium-
benzophenone. Acetone for the catalyst preparation was distilled
from over potassium carbonate. Other solvents were used without
any purification. Triethylamine was distilled from potassium hy-
droxide. All air- and/or water-sensitive reactions were carried out
under an argon atmosphere unless otherwise noted. 1H NMR spec-
tra were recorded with an Avance 300 at 300 MHz or an Avance
400 at 400 MHz. 13C NMR spectra were recorded with an Avance
300 at 75 MHz or an Avance 400 at 100 MHz. Chemical shifts (δ)
[a]
[b]
TsOH ϭ toluene-4-sulfonic acid.
by HPLC analysis.
de and ee were determined
Although we have no clear evidence to explain the stereo-
chemical outcome of the hydrogenation of these α-amino are reported in ppm downfield relative to internal Me4Si. Coupling
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Eur. J. Org. Chem. 2004, 3017Ϫ3026

A Versatile Route to syn- and anti-α-Amino β-Hydroxy Esters
constants (J) are reported in Hz and refer to apparent peak multi-
FULL PAPER
1.29 (m, 4 H), 1.63 (qu, J ϭ 7.4 Hz, 2 H), 2.78 (t, J ϭ 7.4 Hz, 2
plicities (recorded as s, singlet; d, doublet; t, triplet; q, quadruplet; H), 3.89 (s, 3 H), 10.17 (s, 1 H, OH) ppm. 13C NMR (CDCl3,
qu, quintet; o, octet; m, multiplet; and br., broad). Mass spectra
were determined on a Nermag R10Ϫ10C instrument. Ionization
was obtained by chemical ionization with ammonia (DCI/NH3) or
by electrospray (with a API 3000 PE Sciex instrument) for com-
pounds 4 and 6a. Optical rotations were measured with a
PerkinϪElmer 241 polarimeter at 589 nm (sodium lamp). HPLC
analyses of compounds 5 were conducted with Waters 600 system,
using Daicel Chiralcel and Chiralpak chiral stationary phase col-
umns. The β-keto esters 1a and 1e are commercially available.
75 MHz): δ ϭ 13.5, 22.1, 23.2, 31.0, 37.4, 52.6, 150.4, 162.2, 196.6
ppm. MS (DCI, NH3): m/z (%) ϭ 219 (100) [M ϩ NH4]ϩ, 202 (2)
[M ϩ H]ϩ.
Methyl 2-Hydroxyimino-3-oxooctadecanoate (2d):[27] n-Butyl nitrite
(20 mmol, 2 equiv., 2.3 mL) was added to a solution of methyl 3-
oxooctadecanoate (1d)[27] (10 mmol, 3.12 g) in diethyl ether
(40 mL). The resulting mixture was cooled to 0 °C prior to the
dropwise addition of an ethereal solution of hydrochloric acid (4
, 40 mmol, 4 equiv., 10 mL). The stirring was maintained at 0 °C
for one hour and at room temperature for 3 h. Cold water (125 mL)
was then poured into the reaction mixture. The aqueous layer was
decanted and extracted twice with diethyl ether, and the combined
organic layers were dried with magnesium sulfate and condensed
under reduced pressure to give the α-hydroxyimino β-keto ester 2d
quantitatively as a slightly yellow powder, which was used without
purification in the following reactions. M.p. 49 °C. 1H NMR
(CDCl3, 300 MHz): δ ϭ 0.87 (t, J ϭ 6.8 Hz, 3 H), 1.26 (br. s, 24
H), 1.62 (m, 2 H), 2.78 (t, J ϭ 7.4 Hz, 2 H), 3.90 (s, 3 H), 9.0 (br.
s, 1 H, OH) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 14.1, 23.6,
23.7, 29.1, 29.5, 31.9, 37.8, 52.8, 150.6, 162.0, 196.1 ppm. MS (DCI,
NH3): m/z (%) ϭ 359 (100) [M ϩ NH4]ϩ.
Ethyl 2-Hydroxyimino-3-oxohexanoate (2a): A solution of ethyl 3-
oxo-hexanoate (1a, 31 mmol, 4.91 g, 5 mL) in acetic acid (20 mL)
was cooled to 0 °C, and a suspension of sodium nitrite (77.5 mmol,
2.5 equiv., 5.35 g) in water (17 mL) was added dropwise, the tem-
perature of the reaction mixture being kept below 5 °C. After the
evolution of brown fumes had ceased, the stirring was maintained
at 0 °C for 2 h and at room temperature for 2.5 h. The reaction
mixture was then diluted and extracted with diethyl ether (3 ϫ
50 mL); the combined organic layers were washed with saturated
aqueous sodium hydrogen carbonate, dried with magnesium sulfate
and concentrated under reduced pressure to give the α-hydroxy-
imino β-keto ester 2a quantitatively (5.75 g) as a clear oil. 1H NMR
(CDCl3, 300 MHz): δ ϭ 0.95 (t, J ϭ 7.40 Hz, 3 H), 1.35 (t, J ϭ
7.1 Hz, 3 H), 1.70 (m, 2 H), 2.76 (t, J ϭ 7.3 Hz, 2 H), 4.38 (q, J ϭ
7.1 Hz, 2 H), 9.15 (br. s, 1 H, OH) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ 13.6, 14.0, 17.1, 39.7, 62.3, 150.9, 161.4, 195.7 ppm.
MS (DCI, NH3): m/z (%) ϭ 205 (100) [M ϩ NH4]ϩ.
Ethyl 2-Hydroxyimino-4-methyl-3-oxopentanoate (2e): A solution of
ethyl 4-methyl-3-oxo-pentanoate (1e, 28 mmol, 4.42 g) in acetic
acid (20 mL) was cooled to 0 °C, and a suspension of sodium nitrite
(70 mmol, 2.5 equiv., 4.82 g) in water (15 mL) was added dropwise,
the temperature of the reaction mixture being kept below 5 °C.
After the evolution of brown fumes had ceased, the stirring was
maintained at 0 °C for 2 h and at room temperature for 3 h. The
reaction mixture was then diluted and extracted with diethyl ether
(3*50 mL); the combined organic layers were washed with satu-
rated aqueous sodium hydrogen carbonate, dried with magnesium
sulfate, and concentrated under reduced pressure to give the α-
hydroxyimino β-keto ester 2e (4.71 g, 90% yield) as a white syrup,
Methyl 7-Benzyloxy-2-hydroxyimino-3-oxoheptanoate (2b): A solu-
tion of methyl 7-benzyloxy-3-oxo-heptanoate (1b)[25] (17 mmol,
4.50 g) in acetic acid (85 mL) was cooled to 0 °C and a suspension
of sodium nitrite (42.5 mmol, 2.5 equiv., 2.90 g) in water (50 mL)
was added dropwise, the temperature of the reaction mixture being
kept below 5 °C. After the evolution of brown fumes had ceased,
the stirring was maintained at 0 °C for 2 h. The reaction mixture
was then diluted and extracted with diethyl ether (3 ϫ 50 mL);
the combined organic layers were washed with saturated aqueous
sodium hydrogen carbonate, dried with magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography with cyclohexane/ethyl acetate
(7:3) as eluent to give the desired product 2b (4.18 g, 84% yield) as
1
which partially solidified. H NMR (CDCl3, 300 MHz): δ ϭ 1.16
(d, J ϭ 6.9 Hz, 6 H), 1.28 (t, J ϭ 7.2 Hz, 3 H), 3.32 (hept, J ϭ
6.9 Hz, 1 H), 4.30 (q, J ϭ 7.2 Hz, 2 H) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ 13.9, 18.3, 35.5, 62.4, 149.7, 162.0, 201.1 ppm. MS
(DCI, NH3): m/z (%) ϭ 205 (100) [M ϩ NH4]ϩ.
1
Ethyl 2-Amino-3-oxohexanoate Tosylate Salt 6a: p-Toluenesulfonic
acid (10 mmol, 1 equiv., 1.90 g) was added to a solution of ethyl
2-hydroxyimino-3-oxohexanoate (2a, 10 mmol, 1.87 g) in absolute
ethanol (25 mL), followed by Pd/C 10% (3.33 mmol, 0.33 equiv.,
355 mg). The argon was replaced with hydrogen, and the reaction
mixture was stirred at room temperature under atmospheric pres-
sure of hydrogen for 23 h. The suspension was then filtered through
a celite pad and washed with absolute ethanol. The filtrate was
concentrated under reduced pressure to give the tosylate salt 6a as
a white powder in quantitative yield. M.p. 95 °C. 1H NMR (MeOD,
300 MHz): δ ϭ 0.93 (t, J ϭ 7.4 Hz, 3 H), 1.34 (t, J ϭ 7.1 Hz, 3
H), 1.64 (sextuplet, J ϭ 7.3 Hz, 3 H), 2.36 (s, 3 H), 2.72 (dt, J ϭ
7.0, 25.1 Hz, 1 H), 2.86 (dt, J ϭ 7.3, 18.1 Hz, 1 H), 4.35 (q, J ϭ
7.1 Hz, 2 H), 7.22 (d, J ϭ 8.0 Hz, 2 H), 7.70 (d, J ϭ 8.0 Hz, 2 H)
ppm. 13C NMR (MeOD, 100 MHz): δ ϭ 13.7, 14.3, 17.7, 21.3,
43.3, 64.8, 127.0, 129.8, 141.7, 164.7, 199.6. ESI-MS: m/z ϭ 196.3
[M Ϫ C7H8SO3 ϩ Na]ϩ, 174.2 [M Ϫ C7H8SO3 ϩ H]ϩ. HRMS
(DCIϩ): m/z calcd. for C8H16NO3: 174.1130; found 174.1128.
a white solid. M.p. 52 °C. H NMR (CDCl3, 300 MHz): δ ϭ 1.72
(m, 4 H), 2.83 (t, J ϭ 6.9 Hz, 2 H), 3.52 (t, J ϭ 6.0 Hz, 2 H), 3.91
(s, 3 H), 4.54 (s, 2 H), 7.34 (m, 5 H), 9.65 (s, 1 H, OH) ppm. 13C
NMR (CDCl3, 75 MHz): δ?ϭ 20.3, 29.0, 37.4, 52.6, 70.0, 73.0,
127.9, 128.4, 137.4, 150.4, 162.2, 195.6 ppm. MS (DCI, NH3): m/z
(%) ϭ 311 (100) [M ϩ NH4]ϩ, 294 (3) [M ϩ H]ϩ.
Methyl 2-Hydroxyimino-3-oxooctanoate (2c): n-Butyl nitrite
(23.22 mmol, 2 equiv., 2.63 mL) was added to a solution of methyl
3-oxooctanoate (1c)[26] (11.61 mmol, 2.0 g) in diethyl ether (25 mL).
The resulting mixture was cooled to 0 °C prior to the dropwise
addition of an ethereal solution of hydrochloric acid (2.6 ,
46.44 mmol, 4 equiv., 18 mL). The stirring was maintained at 0 °C
for 1 h and at room temperature for 0.5 h. Cold water (100 mL)
was then poured into the reaction mixture. The aqueous layer was
decanted and extracted twice with diethyl ether, and the combined
organic layers were dried with magnesium sulfate and condensed
under reduced pressure to give the α-hydroxyimino β-keto ester as
a slightly brown oil. The residue was purified by silica gel column
chromatography with cyclohexane/ethyl acetate (8:2) as eluent to Ethyl 2-Benzoylamino-3-oxohexanoate (3a): Benzoyl chloride
give the desired product 2c (2.13 g, 91% yield) as a slightly yellow (4.5 mmol, 1.5 equiv., 522 µL) was added to an ice-cooled solution
oil. H NMR (CDCl3, 300 MHz): δ ϭ 0.88 (t, J ϭ 7.0 Hz, 3 H), of ethyl 2-amino-3-oxohexanoate tosylate salt 6a (3 mmol, 1.03 g)
1
Eur. J. Org. Chem. 2004, 3017Ϫ3026
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3021

C. Mordant, P. Dünkelmann, V. Ratovelomanana-Vidal, J.-P. Genet
FULL PAPER
in dichloromethane (10 mL), followed by triethylamine (6 mmol, 2
(46.2 mmol, 3.05 g), as a white powder (1.29 g, 50% yield); purifi-
equiv., 836 µL). The stirring was maintained at 0 °C for 2 h before cation by silica gel column chromatography (cyclohexane/ethyl
1
quenching with saturated aqueous ammonium chloride. The aque-
acetate, 8:2). M.p. 53 °C. H NMR (CDCl3, 300 MHz): δ ϭ 0.87
ous layer was decanted and extracted (3*) with dichloromethane. (t, J ϭ 6.3 Hz, 3 H), 1.26 (br. s, 24 H), 1.52 (m, 2 H), 2.78 (dt, J ϭ
The combined organic layers were dried with magnesium sulfate
and concentrated under reduced pressure to give a slightly yellow
oil. The residue was purified by silica gel column chromatography
with cyclohexane/ethyl acetate (9:1) as eluent to give 3a (680 mg,
3.4, 7.3 Hz, 2 H), 3.85 (s, 3 H), 5.44 (d, J ϭ 6.5 Hz, 1 H), 7.32 (br.
d, J ϭ 6.5 Hz, 1 H, NH), 7.49 (m, 3 H), 7.84 (m, 2 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ ϭ 14.1, 22.6, 23.4, 28.9, 29.4, 29.6, 31.9,
40.9, 53.3, 62.8, 127.3, 128.6, 132.1, 133.6, 166.8, 201.3 ppm. MS
81% yield) as a white powder. M.p. 48 °C. 1H NMR (CDCl3, (DCI, NH3): m/z (%) ϭ 449 (27) [M ϩ NH4]ϩ, 432 (100) [M ϩ
300 MHz): δ ϭ 0.95 (t, J ϭ 7.4 Hz, 3 H), 1.33 (t, J ϭ 7.2 Hz, 3 H]ϩ) ppm. HRMS (DCIϩ): m/z calcd. for C26H42NO4: 432.3114;
H), 1.68 (sextuplet, J ϭ 7.3 Hz, 2 H), 2.78 (m, 2 H), 4.30 (q, J ϭ
7.2 Hz, 2 H), 5.41 (d, J ϭ 6.4 Hz, 1 H), 7.30 (br. d, 1 H, NH), 7.48
(m, 3 H), 7.84 (m, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ
13.5, 14.0, 17.0, 42.7, 62.6, 62.9, 127.2, 128.6, 132.0, 133.1, 166.3,
166.8, 201.1 S (DCI, NH3): m/z (%) ϭ 295 (28) [M ϩ NH4]ϩ, 278
(100) [M ϩ H]ϩ. C15H19NO4: calcd. C 64.97, H 6.91, N 5.05; found
C 64.94, H 6.81, N 4.96.
found 432.3109.
Ethyl 2-Benzoylamino-4-methyl-3-oxopentanoate (3e): This com-
pound was obtained from 2e (6 mmol, 1.12 g) by the General Pro-
cedure, by treatment with benzoic anhydride (13.2 mmol, 2.99 g)
and zinc (46.2 mmol, 3.05 g), as a white powder (1.0 g, 60% yield);
purification by silica gel column chromatography (cyclohexane/
1
ethyl acetate, 8:2). M.p. 73 °C. H NMR (CDCl3, 300 MHz): δ ϭ
1.14 (d, J ϭ 6.6 Hz, 3 H), 1.26 (d, J ϭ 6.8 Hz, 3 H), 1.35 (t, J ϭ
7.1 Hz, 3 H), 3.17 (heptuplet, J ϭ 6.8 Hz, 1 H), 4.30 (q, J ϭ 7.1 Hz,
2 H), 5.60 (d, J ϭ 6.7 Hz, 1 H), 7.30 (br. d, 1 H, NH), 7.48 (m, 3
H), 7.84 (m, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 14.0,
17.6, 18.9, 38.9, 61.2, 62.6, 127.2, 128.6, 132.0, 133.1, 166.4, 166.7,
205.2 ppm. MS (DCI, NH3): m/z (%) ϭ 295 (18) [M ϩ NH4]ϩ, 278
(100) [M ϩ H]ϩ ppm. HRMS (DCIϩ): m/z calcd. for C15H20NO4:
278.1392; found 278.1388.
General Procedure for the Synthesis of the α-Benzamido-β-keto Es-
ters 3 (except for 3a): Benzoic anhydride (2.2 equiv.) was added to
a solution of 2-hydroxyimino β-keto ester 2 in acetic acid (2 mL/
mmol), followed by zinc dust (7.7 equiv.) in small portions. The
stirring was maintained at room temperature until completion of
the reaction, as monitored by TLC. Water (10 mL/mmol) was then
poured into the reaction mixture. The resulting mixture was filtered
through a celite pad, and the zinc cake was washed with dichloro-
methane. The aqueous layer was decanted and extracted twice with
dichloromethane. The combined organic layers were washed with
saturated aqueous sodium hydrogen carbonate, dried with mag-
nesium sulfate, and concentrated under reduced pressure. The
crude product was purified by silica gel column chromatography.
General Procedure for the Synthesis of the α-Amino β-Keto Ester
Hydrochlorides 4 (except for 4b): Pd/C (10%, 0.33 equiv.) was added
to a solution of 2-hydroxyimino β-keto ester 2 (5 mmol) in alcohol
(RЈOH) (3 mL/mmol). Alcoholic (RЈOH) hydrochloric acid (3 , 3
equiv.) was added dropwise to the resulting mixture, and the argon
atmosphere was replaced with hydrogen. The reaction mixture was
stirred at room temperature under atmospheric pressure of hydro-
gen for 24 h (reaction monitored by TLC). The suspension was
then filtered through a celite pad and washed with RЈOH. The
filtrate was concentrated under reduced pressure to give the β-keto
ester hydrochloride 4.
Methyl 2-Benzoylamino-7-benzyloxy-3-oxoheptanoate (3b): This
compound was obtained from 2b (6 mmol, 1.76 g) by the General
Procedure, by treatment with benzoic anhydride (13.2 mmol,
2.99 g) and zinc (46.2 mmol, 3.05 g), as a clear yellow oil (1.27 g,
54% yield); purification by silica gel column chromatography
1
(cyclohexane/ethyl acetate, 8:2). H NMR (CDCl3, 300 MHz): δ ϭ
1.63 (m, 2 H), 1.74 (m, 2 H), 2.81 (m, 2 H), 3.46 (t, J ϭ 6.1 Hz, 2
H), 3.78 (s, 3 H), 4.47 (s, 2 H), 5.44 (d, J ϭ 6.5 Hz, 1 H), 7.29 (m,
5 H), 7.42 (t, J ϭ 7.5 Hz, 2 H), 7.51 (t, J ϭ 7.3 Hz, 1 H), 7.95 (d,
J ϭ 8.3 Hz, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 20.2,
28.7, 40.4, 53.1, 62.6, 69.7, 72.7, 127.1, 127.4, 127.5, 128.2, 128.5,
131.9, 132.9, 138.3, 166.7, 200.8 ppm. MS (DCI, NH3): m/z (%) ϭ
401 (50) [M ϩ NH4]ϩ, 384 (100) [M ϩ H]ϩ ppm. HRMS (DCIϩ):
m/z calcd. for C22H26NO5: 384.1811; found 384.1806.
Ethyl 2-Amino-3-oxohexanoate Hydrochloride (4a): This compound
was obtained quantitatively from 2a (5 mmol, 935 mg) by the Gen-
eral Procedure, by treatment with Pd/C (1.67 mmol, 178 mg) and
ethanolic HCl (3 , 15 mmol, 5 mL), as a slightly yellow powder.
M.p. 121 °C. 1H NMR (MeOD, 300 MHz): δ ϭ 0.93 (t, J ϭ 7.4 Hz,
3 H), 1.34 (t, J ϭ 7.1 Hz, 3 H), 1.66 (sextuplet, J ϭ 7.3 Hz, 2 H),
2.81 (qt, J ϭ 7.1, 18.1 Hz, 2 H), 4.35 (q, J ϭ 7.1 Hz, 2 H) ppm.
13C NMR (MeOD, 75 MHz): δ ϭ 13.3, 13.9, 17.3, 43.0, 64.4, 164.3,
199.1. ESI-MS: m/z ϭ 196.3 [M Ϫ HCl ϩ Na]ϩ, 174.4 [M Ϫ HCl
ϩ H]ϩ. HRMS (DCIϩ): m/z calcd. for C8H16NO3: 174.1130;
found 174.1129.
Methyl 2-Benzoylamino-3-oxooctanoate (3c): This compound was
obtained from 2c (8.4 mmol, 1.69 g) by the General Procedure, by
treatment with benzoic anhydride (18.5 mmol, 4.18 g) and zinc
(64.7 mmol, 4.26 g), as a yellow oil (663 mg, 27% yield); purifi-
cation by silica gel column chromatography (cyclohexane/ethyl
acetate, 9:1). 1H NMR (CDCl3, 300 MHz): δ ϭ 0.88 (t, J ϭ 6.9 Hz,
3 H), 1.30 (m, 4 H), 1.64 (qu, J ϭ 7.2 Hz, 2 H), 2.76 (o, J ϭ 7.2 Hz,
2 H), 3.81 (s, 3 H), 5.44 (d, J ϭ 6.3 Hz, 1 H), 7.33 (br. d, J ϭ
4.8 Hz, 1 H, NH), 7.44 (m, 2 H), 7.52 (t, J ϭ 7.5 Hz, 1 H), 7.84
(d, J ϭ 6.9 Hz, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 13.8,
22.3, 23.3, 31.0, 40.8, 53.3, 62.8, 127.3, 128.6, 132.1, 132.9, 166.9,
201.2 ppm. MS (DCI, NH3): m/z (%) ϭ 309 (48) [M ϩ NH4]ϩ, 292
(100) [M ϩ H]ϩ. C16H21NO4: calcd. C 65.96, H 7.27, N 4.81; found
C 66.04, H 7.24, N 4.76.
Methyl 2-Amino-3-oxooctanoate Hydrochloride (4c): This com-
pound was obtained quantitatively from 2c (5 mmol, 1.0 g) by the
General Procedure, by treatment with Pd/C (1.67 mmol, 178 mg)
and methanolic HCl (3 , 15 mmol, 5 mL), as a white powder. M.p.
76 °C. 1H NMR (MeOD, 300 MHz): δ ϭ 0.93 (t, J ϭ 6.9 Hz, 3
H), 1.34 (m, 4 H), 1.65 (qu, J ϭ 7.1 Hz, 2 H), 2.86 (qt, J ϭ 7.1,
19.4 Hz, 2 H), 3.93 (s, 3 H) ppm. 13C NMR (MeOD, 75 MHz):
δ?ϭ 14.2, 23.4, 23.9, 32.1, 41.4, 54.6, 62.3, 165.3, 199.5. ESI-MS:
m/z ϭ 210 [M Ϫ HCl ϩ Na]ϩ, 188 [M Ϫ HCl ϩ H]ϩ. HRMS
(DCIϩ): m/z calcd. for C9H18NO3: 188.1287; found 188.1289.
Methyl 2-Amino-3-oxooctadecanoate Hydrochloride (4d): This com-
pound was obtained quantitatively from 2d (4 mmol, 1.36 g) by the
Methyl 2-Benzoylamino-3-oxooctadecanoate (3d): This compound
was obtained from 2d (6 mmol, 2.05 g) by the General Procedure, General Procedure, by treatment with Pd/C (1.33 mmol, 142 mg)
by treatment with benzoic anhydride (13.2 mmol, 2.99 g) and zinc and methanolic HCl (3 , 12 mmol, 4 mL), as a slightly yellow
3022
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 3017Ϫ3026

A Versatile Route to syn- and anti-α-Amino β-Hydroxy Esters
powder. dec. 200 °C. 1H NMR (MeOD, 400 MHz): δ ϭ 0.85 (d,
FULL PAPER
solution prepared by addition of 48% aqueous HBr into degassed
J ϭ 6.8 Hz, 3 H), 1.25 (s, 24 H), 1.59 (m, 2 H), 2.74 (dt, J ϭ 6.8 Hz, methanol) and the suspension was stirred at room temperature for
1 H), 2.85 (dt, J ϭ 7.2 Hz, 1 H), 3.87 (s, 3 H) ppm. 13C NMR 30 min. The suspension immediately turned yellow, and an orange
(MeOD, 100 MHz): δ ϭ 13.1, 22.3, 22.9, 28.6, 29.1, 29.2, 29.4,
precipitate then appeared. The solvent was thoroughly evaporated
31.7, 40.0, 53.2, 117.6, 163.9, 198.1. ESI-MS: m/z ϭ 350.3 [M Ϫ under vacuum to give the catalyst as an orange-brown solid, which
HCl ϩ Na]ϩ, 328.6 [M Ϫ HCl ϩ H]ϩ. HRMS (DCIϩ): m/z calcd. was used directly.
for C19H38NO3: 328.2852; found 328.2862.
General Procedure for the Synthesis of the syn-α-Amino β-Hydroxy
Esters 5: The α-benzamido β-keto ester 3 (0.5 mmol) was added to
the catalyst [Ru(S)- or (R)-SYNPHOSBr2] (0.01 mmol, 2 mol %,
prepared according to the General Procedure), followed by pre-
viously degassed anhydrous dichloromethane (2 mL). The Schlenk
vessel was degassed by three vacuum-argon cycles and then placed
under argon in a 250 mL stainless steel autoclave. The argon at-
mosphere was replaced with hydrogen by three cycles of pressuriz-
ing and the pressure was adjusted to 130 bar. The autoclave was
heated at 80 °C and stirring was maintained for 4 days. After cool-
ing, the reaction mixture was concentrated under reduced pressure
to afford the crude α-benzamido β-hydroxy ester 5. 1H NMR spec-
troscopy showed a complete conversion.
Ethyl 2-Amino-4-methyl-3-oxopentanoate Hydrochloride (4e): This
compound was obtained quantitatively from 2e (7 mmol, 1.31 g) by
the General Procedure, by treatment with Pd/C (2.33 mmol,
248 mg) and ethanolic HCl (3 , 21 mmol, 7 mL), as a slightly
green powder. M.p. 115 °C. 1H NMR (MeOD, 300 MHz): δ ϭ 1.12
(d, J ϭ 6.6 Hz, 3 H), 1.23 (d, J ϭ 7.1 Hz, 3 H), 1.35 (t, J ϭ 7.1 Hz,
3 H), 3.25 (q, J ϭ 6.8 Hz, 1 H), 4.37 (q, J ϭ 7.1 Hz, 2 H) ppm.
13C NMR (MeOD, 100 MHz): δ ϭ 14.2, 17.7, 19.1, 39.8, 64.8,
164.7, 203.8. ESI-MS: m/z ϭ 369.3 [2(M Ϫ HCl) ϩ Na]ϩ, 347.3
[2(M Ϫ HCl) ϩ H]ϩ, 196.0 [M Ϫ HCl ϩ Na]ϩ, 173.9 [M Ϫ HCl
ϩ H]ϩ. HRMS (DCIϩ): m/z calcd. for C8H16NO3: 174.1130;
found 174.1134.
Ethyl (2R,3S)-2-Benzoylamino-3-hydroxyhexanoate [(2R,3S)-5a]:
This compound was obtained from 3a (0.5 mmol, 139 mg) by the
General Procedure, by treatment with [Ru(S)-SYNPHOSBr2], as
a yellow powder (113 mg, 81% yield); purification by silica gel col-
umn chromatography (cyclohexane/ethyl acetate, 7:3). Physical data
identical to those of (2S,3R)-5a. [α]2D1 ϭ Ϫ21 (c ϭ 1.0, CHCl3).
HPLC: Chiralcel OD-H, hexane/2-propanol (85:15), 0.5 mL/min,
λ ϭ 254 nm, tR 11.84 min.
Methyl 2-Amino-7-benzyloxy-3-oxoheptanoate Hydrochloride (4b):
tert-Butoxycarbonyl anhydride (87 mmol, 11.6 equiv., 20 mL) was
added to an ice-cooled solution of 2-hydroxyimino β-keto ester 2b
(7.50 mmol, 2.20 g) in acetic acid (35 mL), followed by zinc dust
(75 mmol, 10 equiv., 4.26 g) in small portions. The reaction mixture
was then heated at 50 °C for 1 h. After it had cooled down, water
(85 mL) was added, the resulting mixture was filtered through a
celite pad, and the zinc cake was washed with dichloromethane.
The aqueous layer was decanted and extracted twice with diethyl
ether. The combined organic layers were washed with saturated
aqueous sodium hydrogen carbonate, dried with magnesium sul-
fate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography with cyclohexane/
ethyl acetate (95:5 Ǟ 80:20) as eluent to give the desired product
(2.49 g, 87% yield) as a colorless oil. 1H NMR (CDCl3, 300 MHz):
δ ϭ 1.43 (s, 9 H), 1.64 (m, 4 H), 2.65 (m, 2 H), 3.45 (t, J ϭ 6.0 Hz,
2 H), 3.76 (s, 3 H), 4.47 (s, 2 H), 5.02 (d, J ϭ 7.1 Hz, 1 H), 5.73
(d, J ϭ 7.1 Hz, 1 H, NH), 7.30 (m, 5 H) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ 20.2, 28.2, 28.8, 40.2, 53.0, 63.4, 69.7, 72.8, 80.5,
127.5, 127.6, 128.3, 138.4, 154.8, 167.1, 201.1 ppm. MS (DCI,
NH3): m/z (%) ϭ 397 (100) [M ϩ NH4]ϩ, 380 (13) [M ϩ H]ϩ, 341
(35) [M Ϫ C4H8 ϩ NH4]ϩ. A solution of this α-NHBoc-β-keto
ester (4 mmol, 1.50 g) in methanolic hydrochloric acid (3 ,
20 mmol, 5 equiv., 6.70 mL) was stirred at room temperature for
16 h. Methanolic hydrochloric acid (3 , 20 mmol, 5 equiv.,
6.70 mL) was added once more, and the stirring was maintained
for an additional 6 h. Afterwards the solvent was removed under
reduced pressure. The product 4b was obtained as a white powder
(1.19 g, 94% yield). M.p. 88 °C. 1H NMR (MeOD, 300 MHz): δ ϭ
1.68 (m, 4 H), 2.88 (m, 2 H), 3.51 (t, J ϭ 6.0 Hz, 2 H), 3.89 (s, 3
H), 4.49 (s, 2 H), 7.30 (m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ ϭ 21.2, 29.8, 41.1, 54.6, 71.0, 73.9, 128.7, 128.9, 129.4, 139.8,
165.2, 199.4. ESI-MS: m/z ϭ 302.5 [M Ϫ HCl ϩ Na]ϩ, 280.2 [M
Ϫ HCl ϩ H]ϩ. HRMS (DCIϩ): m/z calcd. for C15H22NO4:
280.1549; found 280.1552.
Ethyl (2S,3R)-2-Benzoylamino-3-hydroxyhexanoate [(2S,3R)-5a]:
This compound was obtained from 3a (0.5 mmol, 139 mg) by the
General Procedure, by treatment with [Ru(R)-SYNPHOSBr2], as
a yellow powder (123 mg, 88% yield); purification by silica gel col-
umn chromatography (cyclohexane/ethyl acetate, 7:3). M.p. 70 °C.
1H NMR (CDCl3, 300 MHz): δ ϭ 0.92 (t, J ϭ 7.0 Hz, 3 H), 1.31
(t, J ϭ 7.2 Hz, 3 H), 1.40Ϫ1.56 (m, 4 H), 4.24 (m, 1 H, CHOH),
4.26 (m, 2 H), 4.85 (dd, J ϭ 3.1, 7.0 Hz, 1 H, CHNH), 6.94 (br. d,
J ϭ 8.9 Hz, 1 H, NH), 7.45 (m, 3 H), 7.83 (m, 2 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ ϭ 13.9, 14.1, 18.8, 36.0, 56.5, 61.7, 72.0,
127.2, 128.6, 131.8, 133.9, 167.8, 171.4 ppm. MS (DCI, NH3): m/z
(%) ϭ 297 (19) [M ϩ NH4]ϩ, 280 (100) [M ϩ H]ϩ. C15H21NO4:
calcd. C 64.50, H 7.58, N 5.01; found C 64.61, H 7.53, N 5.06.
[α]2D1 ϭ ϩ21 (c ϭ 1.0, CHCl3). HPLC: Chiralcel OD-H, hexane/2-
propanol (85:15), 0.5 mL/min, λ ϭ 254 nm, tR 16.24 min.
Methyl (2R,3S)-2-Benzoylamino-7-benzyloxy-3-hydroxyheptanoate
[(2R,3S)-5b]: This compound was obtained from 3b (0.5 mmol,
191 mg) by the General Procedure, by treatment with [Ru(S)-SYN-
PHOSBr2], as a slightly yellow oil (102 mg, 53% yield); purifi-
cation by silica gel column chromatography (cyclohexane/ethyl
acetate, 6:4). Physical data identical to (2S,3R)-5b. [α]2D1 ϭ Ϫ18 (c ϭ
0.9, CHCl3). HPLC: Chiralcel OD-H, 95:5 hexane/2-propanol,
1 mL/min, λ ϭ 254 nm, tR 37.59 min.
Methyl (2S,3R)-2-Benzoylamino-7-benzyloxy-3-hydroxyheptanoate
[(2S,3R)-5b]: This compound was obtained from 3b (0.5 mmol,
191 mg) by the General Procedure, by treatment with [Ru(R)-SYN-
PHOSBr2], as a slightly yellow oil (135 mg, 70% yield); purifi-
General Procedure for the in situ Preparation of the [Ru(SYN-
PHOS)Br2] Catalyst: (S)- or (R)-SYNPHOS (0.011 mmol, 1.1 cation by silica gel column chromatography (cyclohexane/ethyl
equiv., 7.1 mg) and Ru(cyclooctadiene)[η3-(CH2)2CHCH3]2
(0.01 mmol, 3.2 mg) were placed in a 15 mL Schlenk tube and the
vessel was purged with argon. Anhydrous acetone (1 mL), pre-
viously degassed by three vacuum-argon cycles, was added at room
acetate, 6:4). 1H NMR (CDCl3, 300 MHz): δ ϭ 1.59 (m, 6 H), 3.02
(s, 1 H, OH), 3.48 (t, J ϭ 6.0 Hz, 2 H), 3.77 (s, 3 H), 4.24 (m, 1 H,
CHOH), 4.49 (s, 2 H), 4.88 (dd, J ϭ 2.1, 9.0 Hz, 1 H, CHNH),
7.05 (d, J ϭ 9.0 Hz, 1 H, NH), 7.28 (m, 5 H), 7.43 (t, J ϭ 7.4 Hz,
temperature. To this suspension was added, dropwise, methanolic 2 H), 7.51 (t, J ϭ 7.0 Hz, 1 H), 7.85 (d, J ϭ 8.0 Hz, 2 H) ppm. 13
hydrobromic acid (0.022 mmol, 2.2 equiv., 141 µL of a 0.156  NMR (CDCl3, 75 MHz): δ ϭ 22.4, 29.2, 33.5, 52.5, 56.6, 70.1, 71.9,
C
Eur. J. Org. Chem. 2004, 3017Ϫ3026
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3023

C. Mordant, P. Dünkelmann, V. Ratovelomanana-Vidal, J.-P. Genet
72.9, 127.2, 127.5, 127.6, 128.3, 128.5, 131.8, 133.7, 138.3, 167.8, Ethyl (2S,3R)-2-Benzoylamino-3-hydroxy-4-methylpentanoate
FULL PAPER
171.7 ppm. MS (DCI, NH3): m/z (%) ϭ 403 (4) [M ϩ NH4]ϩ, 386 [(2S,3R)-5e]: This compound was obtained from 3e (0.5 mmol,
(100) [M ϩ H]ϩ ppm. HRMS (DCIϩ): m/z calcd. for C22H28NO5:
386.1967; found 386.1965. [α]2D1 ϭ ϩ18 (c ϭ 0.9, CHCl3). HPLC:
Chiralcel OD-H, hexane/2-propanol (95:5), 1 mL/min, λ ϭ 254 nm,
tR 64.85 min.
139 mg) by the General Procedure, by treatment with [Ru(R)-SYN-
PHOSBr2], as a yellow oil (131 mg, 94% yield); purification by
silica gel column chromatography (cyclohexane/ethyl acetate, 8:2).
1H NMR (CDCl3, 300 MHz): δ ϭ 0.98 (d, J ϭ 6.8 Hz, 3 H), 1.03
(d, J ϭ 6.8 Hz, 3 H), 1.29 (t, J ϭ 7.1 Hz, 3 H), 1.75 (m, 1 H), 3.82
(dd, J ϭ 1.9, 8.9 Hz, 1 H, CHOH), 4.24 (q, J ϭ 7.1 Hz, 2 H), 5.01
(dd, J ϭ 1.9, 9.1 Hz, 1 H, CHNH), 6.91 (br. d, J ϭ 9.1 Hz, 1 H,
NH), 7.47 (m, 3 H), 7.83 (m, 2 H) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ 14.1, 18.9, 19.0, 31.1, 54.7, 61.7, 77.6, 127.2, 128.6,
131.8, 133.9, 167.8, 171.9 ppm. MS (DCI, NH3): m/z (%) ϭ 280
(100) [M ϩ H]ϩ. C15H21NO4: calcd. C 64.50, H 7.58, N 5.01; found
C 64.65, H 7.83, N 4.77. [α]2D1 ϭ ϩ28 (c ϭ 0.8, CHCl3). HPLC:
Chiralcel OJ, hexane/2-propanol (96:4), 1.0 mL/min, λ ϭ 254 nm,
tR 13.25 min.
Methyl (2R,3S)-2-Benzoylamino-3-hydroxyoctanoate [(2R,3S)-5c]:
This compound was obtained from 3c (0.5 mmol, 146 mg) by the
General Procedure, by treatment with [Ru(S)-SYNPHOSBr2], as
a slightly yellow oil (113 mg, 77% yield); purification by silica gel
column chromatography (cyclohexane/ethyl acetate, 7:3). Physical
data identical to those of (2S,3R)-5c. [α]2D1 ϭ Ϫ18 (c ϭ 1.0, CHCl3).
HPLC: Chiralpak AS-H, hexane/2-propanol (98:2), 1.0 mL/min,
λ ϭ 254 nm, tR 46.76 min.
Methyl (2S,3R)-2-Benzoylamino-3-hydroxyoctanoate [(2S,3R)-5c]:
This compound was obtained from 3c (0.5 mmol, 146 mg) by the
General Procedure, by treatment with [Ru(R)-SYNPHOSBr2], as
a slightly yellow oil (122 mg, 83% yield); purification by silica gel
column chromatography (cyclohexane/ethyl acetate, 7:3). 1H NMR
(CDCl3, 300 MHz): δ ϭ 0.89 (t, J ϭ 6.7 Hz, 3 H), 1.27Ϫ1.59 (m,
8 H), 3.77 (s, 3 H), 4.23 (m, 1 H, CHOH), 4.88 (dd, J ϭ 2.0, 8.9 Hz,
1 H, CHNH), 7.04 (br. d, J ϭ 8.9 Hz, 1 H, NH), 7.42 (t, J ϭ
7.5 Hz, 1 H), 7.51 (t, J ϭ 7.5 Hz, 1 H), 7.84 (d, J ϭ 7.5 Hz, 2 H)
ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 14.0, 22.5, 25.3, 31.5, 33.8,
52.6, 56.5, 72.1, 127.2, 128.6, 131.9, 133.7, 167.8, 171.9 ppm. MS
(DCI, NH3): m/z ϭ 311 (4%, [M ϩ NH4]ϩ), 294 (100%, [M ϩ
H]ϩ). C16H23NO4: calcd. C 65.51, H 7.90, N 4.77; found C 65.50,
H 7.95, N 4.68. [α]2D1 ϭ ϩ16 (c ϭ 1.0, CHCl3). HPLC: Chiralpak
AS-H, 98:2 hexane/2-propanol, 1.0 mL/min, λ ϭ 254 nm, tR
59.45 min.
General Procedure for the Synthesis of the anti-α-Amino β-Hydroxy
Esters 5: The α-amino β-keto ester hydrochloride 4 (0.5 mmol) was
added to the catalyst [Ru(S)- or (R)-SYNPHOSBr2] (0.01 mmol,
2 mol%, prepared according to the general procedure), followed by
previously degassed anhydrous dichloromethane (2 mL) and de-
gassed alcoholic solvent RЈOH (200 µL). The Schlenk vessel was
degassed by three vacuum-argon cycles and then placed under ar-
gon in a 250 mL stainless steel autoclave. The argon was replaced
with hydrogen by three cycles of pressurizing and the pressure was
adjusted to 12 bar. The autoclave was heated at 50 °C and stirring
was maintained for 24 h. After cooling, the reaction mixture was
concentrated under reduced pressure to afford the crude β-hydroxy
ester. 1H NMR (MeOD) spectroscopy showed complete conver-
sion.
Benzoic anhydride (0.55 mmol, 1.1 equiv., 122 mg) was added to
an ice-cooled solution of the crude α-amino β-hydroxy ester hydro-
chloride (0.5 mmol) in anhydrous dichloromethane (5 mL), fol-
lowed by triethylamine (0.6 mmol, 1.2 equiv., 84 µL). After the mix-
ture had been kept for 15 min at 0 °C, the stirring was maintained
at room temperature for 20 h. The mixture was then concentrated
under reduced pressure. Tetrahydrofuran (10 mL) was added to the
residue and the mixture was stirred for 15 minutes. The resulting
precipitate was removed by filtration through a celite pad and
washed with tetrahydrofuran. The filtrate was concentrated under
reduced pressure and the crude product was purified by silica gel
column chromatography.
Methyl (2R,3S)-2-Benzoylamino-3-hydroxyoctadecanoate [(2R,3S)-
5d]: This compound was obtained from 3d (0.5 mmol, 215 mg) by
the General Procedure, by treatment with [Ru(S)-SYNPHOSBr2],
as a white solid (178 mg, 82% yield); purification by silica gel col-
umn chromatography (cyclohexane/ethyl acetate 8:2). Physical data
identical to those of (2S,3R)-5d. [α]2D1 ϭ Ϫ7 (c ϭ 1.0, CHCl3).
HPLC: Chiralpak AS-H, 98:2 hexane/2-propanol, 1.0 mL/min, λ ϭ
254 nm, tR 24.13 min.
Methyl (2S,3R)-2-Benzoylamino-3-hydroxyoctadecanoate [(2S,3R)-
5d]: This compound was obtained from 3d (0.5 mmol, 215 mg) by
the General Procedure, by treatment with [Ru(R)-SYNPHOSBr2],
as a white solid (199 mg, 92% yield); purification by silica gel col-
umn chromatography (cyclohexane/ethyl acetate, 8:2). M.p. 72 °C.
1H NMR (CDCl3, 300 MHz): δ ϭ 0.88 (t, J ϭ 6.6 Hz, 3 H), 1.26
(br. s, 26 H), 1.50 (m, 2 H), 3.79 (s, 3 H), 4.24 (m, J ϭ 2.0, 6.8 Hz,
1 H, CHOH), 4.88 (dd, J ϭ 2.0, 8.9 Hz, 1 H, CHNH), 7.02 (br. d,
J ϭ 8.9 Hz, 1 H, NH), 7.48 (m, 3 H), 7.84 (m, 2 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ ϭ 14.1, 22.7, 25.7, 29.7, 31.9, 33.9, 52.6,
56.4, 72.1, 127.2, 128.6, 131.8, 133.8, 167.7, 171.9 ppm. MS (DCI,
NH3): m/z (%) ϭ 434 (100) [M ϩ H]ϩ. C26H43NO4: calcd. C 72.02,
H 10.00, N 3.23; found C 72.03, H 10.03, N 3.28. [α]2D1 ϭ ϩ6 (c ϭ
1.0, CHCl3). HPLC: Chiralpak AS-H, hexane/2-propanol (98:2),
1.0 mL/min, λ ϭ 254 nm, tR 29.59 min.
Ethyl (2S,3S)-2-Benzoylamino-3-hydroxyhexanoate [(2S,3S)-5a]:
This compound was obtained from 4a (0.5 mmol, 105 mg) by the
General Procedure, by treatment with [Ru(S)-SYNPHOSBr2], as
a slightly yellow powder (125 mg, 90% yield over two steps); purifi-
cation by silica gel column chromatography (cyclohexane/ethyl
1
acetate, 7:3). M.p. 45 °C. H NMR (CDCl3, 300 MHz): δ ϭ 0.92
(t, J ϭ 7.0 Hz, 3 H), 1.31 (t, J ϭ 7.2 Hz, 3 H), 1.26Ϫ1.56 (m, 4
H), 4.08 (m, 1 H, CHOH), 4.26 (m, 2 H), 4.85 (dd, J ϭ 3.1, 7.0 Hz,
1 H, CHNH), 7.23 (br. d, J ϭ 7.0 Hz, 1 H, NH), 7.45 (m, 3 H),
7.83 (m, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 13.9, 14.1,
18.9, 35.4, 58.2, 62.0, 73.0, 127.2, 128.6, 132.0, 133.4, 168.0, 170.5
ppm. MS (DCI, NH3): m/z (%) ϭ 297 (4) [M ϩ NH4]ϩ, 280 (100),
[M ϩ H]ϩ ppm. HRMS (DCIϩ): m/z calcd. for C15H22NO4:
280.1549; found 280.1552. [α]2D1 ϭ ϩ32 (c ϭ 1.0, CHCl3). HPLC:
Chiralcel OD-H, hexane/2-propanol (85:15), 0.5 mL/min, λ ϭ
254 nm, tR 14.99 min.
Ethyl
(2R,3S)-2-Benzoylamino-3-hydroxy-4-methylpentanoate
[(2R,3S)-5e]: This compound was obtained from 3e (0.5 mmol,
139 mg) by the General Procedure, by treatment with [Ru(S)-SYN-
PHOSBr2], as a yellow oil (128 mg, 92% yield); purification by
silica gel column chromatography (cyclohexane/ethyl acetate, 8:2).
Physical data identical to those of (2S,3R)-5e. [α]2D1 ϭ Ϫ27 (c ϭ
Ethyl (2R,3R)-2-Benzoylamino-3-hydroxyhexanoate [(2R,3R)-5a]:
0.8, CHCl3). HPLC: Chiralcel OJ, hexane/2-propanol (96:4), This compound was obtained from 4a (0.5 mmol, 105 mg) by the
1.0 mL/min, λ ϭ 254 nm, tR 17.57 min.
General Procedure, by treatment with [Ru(R)-SYNPHOSBr2], as
3024
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3017Ϫ3026

A Versatile Route to syn- and anti-α-Amino β-Hydroxy Esters
FULL PAPER
a slightly yellow powder (125 mg, 90% yield over two steps); purifi-
ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 14.1, 22.7, 25.7, 29.7, 31.9,
cation by silica gel column chromatography (cyclohexane/ethyl 33.4, 52.7, 58.1, 73.3, 127.2, 128.7, 130.1, 132.1, 167.9, 171.0 ppm.
acetate, 7:3). Physical data identical to those of (2S,3S)-5a. [α]D21
Ϫ32 (c ϭ 1.0, CHCl3). HPLC: Chiralcel OD-H, hexane/2-propanol
(85:15), 0.5 mL/min, λ ϭ 254 nm, tR 12.59 min.
ϭ
MS (DCI, NH3): m/z (%) ϭ 434 (100) [M ϩ H]ϩ ppm. HRMS
(DCIϩ): m/z calcd. for C26H44NO4: 434.3270; found 434.3264.
[α]2D1 ϭ ϩ19 (c ϭ 0.8, CHCl3). HPLC: Chiralpak AS-H, hexane/2-
propanol (98:2), 1.0 mL/min, λ ϭ 254 nm, tR 32.31 min.
Methyl (2S,3S)-2-Benzoylamino-7-benzyloxy-3-hydroxyheptanoate
[(2S,3S)-5b]: This compound was obtained from 4b (0.5 mmol,
158 mg) by the General Procedure, by treatment with [Ru(S)-SYN-
PHOSBr2], as a brown solid (182 mg, 94% yield over two steps);
purification by silica gel column chromatography (cyclohexane/
ethyl acetate, 6:4). Physical data identical to those of (2R,3R)-5b.
[α]2D1 ϭ ϩ26 (c ϭ 1.0, CHCl3). HPLC Chiralcel OD-H, hexane/2-
propanol (95:5), 1 mL/min, λ ϭ 254 nm, tR 75.68 min.
Methyl (2R,3R)-2-Benzoylamino-3-hydroxyoctadecanoate [(2R,3R)-
5d]: This compound was obtained from 4d (0.5 mmol, 182 mg) by
the General Procedure, by treatment with [Ru(R)-SYNPHOSBr2],
as a slightly brown solid (185 mg, 85% yield over two steps); purifi-
cation by silica gel column chromatography (cyclohexane/ethyl
acetate, 8:2). Physical data identical to those of (2S,3S)-5d. [α]D21
ϭ
Ϫ22 (c ϭ 0.8, CHCl3). HPLC: Chiralpak AS-H, hexane/2-propa-
nol, (98:2), 1.0 mL/min, λ ϭ 254 nm, tR ϭ 26.37 min.
Methyl (2R,3R)-2-Benzoylamino-7-benzyloxy-3-hydroxyheptanoate
[(2R,3R)-5b]: This compound was obtained from 4b (0.5 mmol,
158 mg) by the General Procedure, by treatment with [Ru(R)-SYN-
PHOSBr2], as a brown solid (179 mg, 93% yield over two steps);
purification by silica gel column chromatography (cyclohexane/
Ethyl
(2S,3S)-2-Benzoylamino-3-hydroxy-4-methylpentanoate
[(2S,3S)-5e]: This compound was obtained from 4e (0.5 mmol,
105 mg) by the General Procedure, by treatment with [Ru(S)-SYN-
PHOSBr2], as a brown solid (125 mg, 90% yield over two steps);
purification by silica gel column chromatography (cyclohexane/
ethyl acetate, 8:2). Physical data identical to those of (2R,3R)-5e.
[α]2D1 ϭ ϩ33 (c ϭ 1.0, CHCl3). HPLC: Chiralcel OJ, hexane/2-pro-
panol (96:04), 1.0 mL/min, λ ϭ 254 nm, tR 19.31 min.
1
ethyl acetate, 6:4). M.p. 42 °C. H NMR (CDCl3, 300 MHz): δ ϭ
1.57 (m, 6 H), 3.46 (t, J ϭ 6.1 Hz, 2 H), 3.77 (s, 3 H), 4.04 (m, 1
H, CHOH), 4.48 (s, 2 H), 4.87 (dd, J ϭ 3.2, 7.3 Hz, 1 H, CHNH),
7.28 (m, 5 H), 7.42 (t, J ϭ 7.0 Hz, 2 H), 7.51 (t, J ϭ 7.2 Hz, 1 H),
7.82 (d, J ϭ 7.0 Hz, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ
22.5, 29.4, 33.1, 52.6, 58.0, 70.1, 72.8, 3.0, 127.2, 127.5, 127.6,
128.3, 128.6, 131.9, 133.3, 138.4, 167.8, 170.9 ppm. MS (DCI,
NH3): m/z (%) ϭ 386 (100) [M ϩ H]ϩ ppm. HRMS (DCIϩ): m/z
calcd. for C22H28NO5: 386.1967; found 386.1971. [α]2D1 ϭ Ϫ28 (c ϭ
1.0, CHCl3). HPLC Chiralcel OD-H, hexane/2-propanol (95:5),
1 mL/min, λ ϭ 254 nm, tR 50.89 min.
Ethyl
(2R,3R)-2-Benzoylamino-3-hydroxy-4-methylpentanoate
[(2R,3R)-5e]: This compound was obtained from 4e (0.5 mmol,
105 mg) by the General Procedure, by treatment with [Ru(R)-SYN-
PHOSBr2], as a brown solid (135 mg, 96% yield over two steps);
purification by silica gel column chromatography (cyclohexane/
1
ethyl acetate, 8:2). M.p. 86 °C. H NMR (CDCl3, 300 MHz): δ ϭ
1.03 (d, J ϭ 6.6 Hz, 3 H), 1.06 (d, J ϭ 6.6 Hz, 3 H), 1.34 (t, J ϭ
7.2 Hz, 3 H), 1.79 (m, 1 H), 3.63 (dd, J ϭ 3.2, 8.7 Hz, 1 H, CHOH),
4.28 (dq, J ϭ 1.9, 7.2 Hz, 2 H), 4.93 (dd, J ϭ 3.1, 7.2 Hz, 1 H,
CHNH), 7.20 (br. d, J ϭ 7.2 Hz, 1 H, NH), 7.47 (m, 3 H), 7.82
(m, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 14.1, 19.0, 31.6,
56.2, 61.9, 78.9, 127.1, 128.6, 131.9, 133.5, 167.5, 171.0 ppm. MS
(DCI, NH3): m/z (%) ϭ 280 (100) [M ϩ H]ϩ ppm. HRMS (DCIϩ):
m/z calcd. for C15H22NO4: 280.1549; found 280.1551. [α]2D1 ϭ Ϫ36
(c ϭ 1.0, CHCl3). HPLC: Chiralcel OJ, hexane/2-propanol (96:4),
1.0 mL/min, λ ϭ 254 nm, tR 15.82 min.
Methyl (2S,3S)-2-Benzoylamino-3-hydroxyoctanoate [(2S,3S)-5c]:
This compound was obtained from 4c (0.5 mmol, 112 mg) by the
General Procedure, by treatment with [Ru(S)-SYNPHOSBr2], as
a brown solid (124 mg, 85% yield over two steps); purification by
silica gel column chromatography (cyclohexane/ethyl acetate, 7:3).
Physical data identical to those of (2R,3R)-5c. [α]2D1 ϭ ϩ26 (c ϭ
1.0, CHCl3). HPLC: Chiralpak AS-H, hexane/2-propanol (98:2),
1.0 mL/min, λ ϭ 254 nm, tR 66.29 min.
Methyl (2R,3R)-2-Benzoylamino-3-hydroxyoctanoate [(2R,3R)-5c]:
This compound was obtained from 4c (0.5 mmol, 112 mg) by the
General Procedure, by treatment with [Ru(R)-SYNPHOSBr2], as
a brown solid (132 mg, 90% yield over two steps); purification by
silica gel column chromatography (cyclohexane/ethyl acetate, 7:3).
M.p. 60 °C. 1H NMR (CDCl3, 300 MHz): δ ϭ 0.87 (t, J ϭ 6.7 Hz,
3 H), 1.28 (m, 4 H), 1.49 (m, 4 H), 3.80 (s, 3 H), 4.04 (m, 1 H,
CHOH), 4.88 (dd, J ϭ 3.2, 7.3 Hz, 1 H, CHNH), 7.24 (br. d, J ϭ
7.3 Hz, 1 H, NH), 7.46 (m, 3 H), 7.82 (d, J ϭ 6.4 Hz, 2 H) ppm.
13C NMR (CDCl3, 75 MHz): δ ϭ 14.0, 22.5, 25.3, 31.5, 33.4, 52.7,
58.0, 73.2, 127.2, 128.6, 131.9, 133.3, 167.9, 171.0 ppm. MS (DCI,
NH3): m/z (%) ϭ 311 (2) [M ϩ NH4]ϩ, 294 (100) [M ϩ H]ϩ ppm.
HRMS (DCIϩ): m/z calcd. for C16H24NO4: 294.1705; found
294.1711. [α]2D1 ϭ Ϫ27 (c ϭ 1.0, CHCl3). HPLC: Chiralpak AS-H,
hexane/2-propanol (98:2), 1.0 mL/min, λ ϭ 254 nm, tR 50.83 min.
Acknowledgments
A
fellowship from the C.N.R.S./D.G.A. (C.M.) is gratefully
acknowledged. We also thank Dr. P. Dellis and Dr. N. Champion
(SYNKEM S. A. S.) for financial support.
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Eur. J. Org. Chem. 2004, 3017Ϫ3026
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3025

C. Mordant, P. Dünkelmann, V. Ratovelomanana-Vidal, J.-P. Genet
FULL PAPER
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SYNPHOS
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Received February 8, 2004
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Eur. J. Org. Chem. 2004, 3017Ϫ3026