Dynamic kinetic resolution of α-chloro β-keto esters and phosphonates: Hemisynthesis of Taxotere through Ru-DIFLUORPHOS asymmetric hydrogenation

Article abstract of DOI:10.1016/j.tetasy.2010.05.017

The dynamic kinetic resolution (DKR) of racemic α-chloro β-ketoesters and α-chloro β-ketophosphonates through ruthenium-mediated asymmetric hydrogenation is reported. The corresponding α-chloro β-hydroxyesters and α-chloro β- hydroxyphosphonates were obtained in good to high enantio- and diastereomeric excesses using, in particular, the atropisomeric ligand DIFLUORPHOS. This methodology allowed an efficient preparation of the anti phenylisoserine side chain of Taxotere which has been used for the hemisynthesis of the cancer therapeutic agent itself. In addition, ¹³C NMR in chiral oriented solvents was used to investigate the DKR effect.

Full text of DOI:10.1016/j.tetasy.2010.05.017

Tetrahedron: Asymmetry 21 (2010) 1436–1446
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Dynamic kinetic resolution of
a
-chloro b-keto esters and phosphonates:
hemisynthesis of TaxotereÒ through Ru-DIFLUORPHOS asymmetric
hydrogenation
Sébastien Prévost a, Sébastien Gauthier a, Maria Cristina Caño de Andrade a, Céline Mordant a,
Ali Rhida Touati b, Philippe Lesot c, Philippe Savignac d, Tahar Ayad a, Phannarath Phansavath a,
a,
Virginie Ratovelomanana-Vidal a, , Jean-Pierre Genêt
*
*
a Laboratoire Charles Friedel UMR CNRS 7223, Chimie ParisTech ENSCP, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
b Faculté des Sciences, Laboratoire de Synthèse Organique et Photochimie, Avenue de l’Environnement, 5000 Monastir, Tunisia
c RMN en Milieu Orienté, ICMMO, UMR CNRS 8182, Université Paris Sud 11, Bât. 410, F-91405 Orsay Cedex, France
d 146 Allée de la Clairière 91190 Gif-sur-Yvette, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The dynamic kinetic resolution (DKR) of racemic
through ruthenium-mediated asymmetric hydrogenation is reported. The corresponding
a
-chloro b-ketoesters and
a
-chloro b-ketophosphonates
-chloro
-chloro b-hydroxyphosphonates were obtained in good to high enantio- and
Received 2 March 2010
Accepted 6 May 2010
Available online 11 June 2010
a
b-hydroxyesters and
a
diastereomeric excesses using, in particular, the atropisomeric ligand DIFLUORPHOS. This methodology
allowed an efficient preparation of the anti phenylisoserine side chain of TaxotereÒ which has been used
for the hemisynthesis of the cancer therapeutic agent itself. In addition, 13C NMR in chiral oriented
solvents was used to investigate the DKR effect.
Dedicated to Professor Henry Kagan on the
occasion of his 80th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
fosfomycin 2,7 a low molecular weight antibiotic of unusual struc-
ture, originally isolated from the fermentation broth of Streptomy-
Dynamic kinetic resolution (DKR) is an efficient method for the
obtention of enantiomerically pure compounds from racemic sub-
strates. Indeed, DKR allows the formation of a single isomer out of
four stereoisomers by combining kinetic resolution with an in situ
equilibration of the configurationally labile stereogenic center.1 By
using this method, enantiomerically pure compounds can be syn-
thesized in a single step with theoretical yields of 100% in a highly
stereocontrolled manner. Ruthenium-mediated hydrogenation has
been widely used in the DKR of b-ketoesters,2 the first examples
being reported by Noyori et al.3 and Genet et al.4 We report herein
ces fradiae or Pseudomonas syringae (Scheme 1).
O
O
OH
OH
OH
H3C
H
P
(EtO)2P
*
R1
*
H
O
X
2
1
: fosfomycin
(X = halogen)
Scheme 1.
Various methods have been reported for the asymmetric syn-
thesis of hydroxyphosphonates.8 In particular, the enantioselective
hydrogenation of b-ketophosphonates into their corresponding
the dynamic kinetic resolution of an
ruthenium-mediated asymmetric hydrogenation and its applica-
tion to the hemisynthesis of TaxotereÒ. The DKR of
-chloro
b-ketophosphonates leading to the corresponding enantioenriched
a-chloro b-ketoester through
a
b-hydroxyphosphonates or
a
-acetamido b-hydroxyphosphonates
has been described.9 However, with regard to
a
-halo b-keto-
a-chloro b-hydroxyphosphonates is described as well.
phosphonates, only one example of dynamic kinetic resolution
through asymmetric hydrogenation has been previously reported
in the literature by Noyori et al.10 In this study, racemic dimethyl
1-bromo-2-oxopropylphosphonate was hydrogenated in methanol
at 25 °C under 4 bar of hydrogen using the [RuCl2{(S)-BIN-
AP}(DMF)n] complex to give dimethyl (1R,2S)-1-bromo-2-hydrox-
ypropylphosphonate in 98% ee with a 90:10 syn/anti selectivity.
This most straightforward method for the preparation of enantio-
Owing to their biological activities as enzyme inhibitors or drug
candidates5, optically active hydroxy phosphonates have attracted
significant attention over the years. In particular, a-halo b-hydrox-
yphosphonates 1 constitute an interesting class of compounds as
precursors of various 1,2-epoxyalkylphosphonates,6 analogous of
* Corresponding authors. Tel.: +33 1 44276742; fax: +33 1 44071062 (V.R.-V);
tel.: +33 1 44276743; fax: +33 1 44071062 (J.-P.G.).
E-mail addresses: virginie-vidal@chimie-paristech.fr (V. Ratovelomanana-Vidal),
jean-pierre-genet@chimie-paristech.fr (J.-P. Genêt).
enriched b-hydroxy
a-bromophosphonates suffers one major
limitation which is the formation in a significant 15% yield of the
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.017

S. Prévost et al. / Tetrahedron: Asymmetry 21 (2010) 1436–1446
1437
related debrominated compound, resulting from the hydrogenoly-
sis of the carbon–bromide bond. We postulated that the replace-
ment of the bromide atom by a chloride atom would lower this
side reaction. Moreover, since the preparation of enantioenriched
O
O
O
nBuLi
(EtO)2P
a-chloro b-hydroxyphosphonates is barely reported in the litera-
(EtO)2P
Cl
R
EtO(CO)R
ture, we were interested in investigating the dynamic kinetic
Cl
resolution of
a-chloro b-ketophosphonates through ruthenium-
3
( )-
6
mediated asymmetric hydrogenation11 as a practical route to pre-
pare these compounds.
3a: R = Me
3b
3c
: R = Et
: R = i-Pr
2. Results and discussion
3d: R = t-Bu
3e
3f
: R = C6H5
R = p-ClC H
:
A series of a-chloro b-ketophosphonates 3a–3f was first conve-
6
4
niently synthesized by acylation of diethyl 1-chloromethylphosph-
onate 6.12 Asymmetric hydrogenation promoted by ruthenium
catalysts containing the atropisomeric ligands MeO-BIPHEP or
SYNPHOS13 and DIFLUORPHOS,14 developed in our group, provided
O
OH
H2, (S)-Ru(II) complex
(EtO)2P
R
MeOH
Cl
the corresponding
a-chloro b-hydroxyphosphonates 4a–4f
(2R,3S)-4
(Scheme 2). As a starting point, we examined the dynamic kinetic
resolution of compound 3a (Scheme 3, Table 1). The hydrogenation
reaction was first conducted in methanol at 25 °C under 70 bar of
hydrogen for 24 h using 1 mol % of the complex [Ru{(S)-SYN-
PHOS}Br2], generated in situ from commercially available [Ru(-
COD)(2-methylallyl)2].15
Scheme 2.
Under these conditions, (1R,2S)-4a was obtained with a moder-
ate 62:38 diastereomeric ratio but with excellent enantioselectivi-
ty (99% ee, entry 1) together with 22% of the dechlorinated starting
material 5a. By lowering the hydrogen pressure to 10 bar, the for-
mation of 5a was limited to 6% at 50 °C, while the diastereomeric
ratio was slightly improved (dr = 68:32, entry 2). Pleasingly, when
the hydrogenation was run under the same conditions but using
with a slight diastereoselectivity this time in favor of the anti iso-
mer (dr = 47:53, entry 6).
The relative configurations of compounds 4 were established on
3
the basis of their coupling constants J1,2 which bear significantly
distinct values for the syn and anti diastereoisomers (Scheme 4).
O
O
the preformed complex [{RuCl((S)-SYNPHOS)}2(l
-Cl)3][NH2Me2],16
P(OR)2
OH
P(OR)2
H2
H2
hydrogenolysis of the carbon–chloride bond was not observed and
only the desired compound 4a was obtained with the same dr as
mentioned above and with excellent enantioselectivity (ee >99%,
entry 3). The hydrogenation reaction was then performed with
HO
Cl
3J1,2 (syn)
Cl
3J1,2 (anti)
H1
H1
R
R
[{RuCl((S)-DIFLUORPHOS)}2(
BIPHEP)}2( -Cl)3][NH2Me2] complexes and afforded slightly lower
dr (entries 4 and 5) than with [{RuCl((S)-SYNPHOS)}2( -Cl)3]
l-Cl)3][NH2Me2] and [{RuCl((S)-MeO-
O
OH
O
OH
l
(1R)
(1R)
(RO)2P
(RO)2P
(2S)
(2R)
l
R
R
[NH2Me2]. It should be noted that when the reaction was con-
Cl
Cl
ducted in dichloromethane at 80 °C and 100 bar of hydrogen, the
Scheme 4.
corresponding
a-chloro b-hydroxyphosphonate 4a was obtained
H
2 (bar)
O
O
O
OH
Me
O
O
Ru catalyst (1 mol%)
(EtO)2P
(EtO)2P
(EtO)2P
Me
Me
MeOH, T ( C), t (h)
°
Cl
( )-3a
Cl
(1R,2S)-4a
5a
Scheme 3.
Table 1
DKR of racemic 3a through ruthenium-assisted hydrogenationa
Entry
Ru catalyst
Conditions
Productsb (%)
drc (%) for (1R,2S)-4a
eec (%) for (1R,2S)-4a
H2 (bar)
T (°C)
t (h)
5a
(1R,2S)-4a
1
2
3
4
[Ru{(S)-SYNPHOS}Br2]
[Ru{(S)-SYNPHOS}Br2]
[{RuCl((S)-SYNPHOS)}2(
[{RuCl((S)-DIFLUORPHOS)}2(
[{RuCl((S)-MeO-BIPHEP)}2(
70
10
10
10
10
25
50
50
50
50
80
24
24
24
24
24
14
22
6
—
—
—
6
78
94
100
100
100
94
62:38
68:32
67:33
62:38
59:41
47:53
>99
>99
>99
>99
>99
>99
l
-Cl)3][NH2Me2]
-Cl)3][NH2Me2]
-Cl)3][NH2Me2]
l
5
l
6d
[Ru{(S)-MeO-BIPHEP}Br2]
100
a
b
c
All reactions were performed on 1 mmol at 0.5 M.
Conversion rates were determined by 1H NMR (300 MHz) of the crude reaction mixture.
The diastereo- and enantiomeric excesses were determined by HPLC on the corresponding benzoyl esters 4a0 (Chiralpak AS-H column).
The reaction was conducted in dichloromethane.
d

1438
S. Prévost et al. / Tetrahedron: Asymmetry 21 (2010) 1436–1446
The vicinal coupling constants 3J1,2 indicate very clearly the rel-
lectivity (dr = 92:8, >95% ee, entry 7) together with a small amount
of the dechlorinated product 7c. Pleasingly, the dynamic kinetic
resolution of compounds 3e and 3f bearing, respectively, phenyl
ative configuration of the coupling protons, their contribution
depending on the dihedral angle u, enclosed by the CH bonds,
according to the Karplus equation.17 Previously reported 1H NMR
and para-chlorophenyl substituents, led to the expected
a-chloro
studies18 of racemic
a
-chloro b-hydroxyphosphonic derivatives
b-hydroxyphosphonates with good diastereomeric ratios and mod-
erate to high enantioselectivities (dr = 85:15–91:9, 42–90% ee, en-
tries 8–13). For this family of compounds, a ligand effect has been
observed since with the (S)-MeO-BIPHEP ligand, moderate ee were
obtained (42–45% ee, entries 8 and 11), while the (S)-SYNPHOS
diphosphine led to higher enantioselectivities (61–70% ee, entries
9 and 12). Pleasingly, the (S)-DIFLUORPHOS ligand afforded high
ee in the DKR of 3e and 3f (84–90%, entries 10 and 13). The
above-mentioned results indicate that the dynamic kinetic resolu-
3
showed the coupling constant J1,2 was low (<2.5 Hz) for the syn
diastereoisomer compared to the higher value (>7 Hz) observed
for the anti isomer. The absolute configuration of the hydroxyl-
bearing C-2 stereocenter is determined by the chirality of the
diphosphine ligand and was attributed on the basis of the general
rule established for the BINAP-assisted hydrogenation,19 and
which can be extended to other atropisomeric ligands.
The formerly established hydrogenation conditions were then
applied to compounds 3b–3f using the complex [{RuCl((S)-
tion of a-chloro b-ketophosphonates through ruthenium-mediated
*
P P)}2(
l
-Cl)3][NH2Me2] containing MeO-BIPHEP, SYNPHOS, or
hydrogenation is substrate dependent both in terms of conversion
and selectivities. In most cases, standard hydrogenation conditions
have been established which allowed the preparation of syn
DIFLUORPHOS as the diphosphines (Scheme 5, Table 2). Thus, the
dynamic kinetic resolution of compound 3b bearing an ethyl sub-
stituent delivered the expected alcohol 4b with comparable dr as
observed in the reaction of 3a, and with no dechlorinated product
(dr = 57:43–59:41, entries 1–3). On the other hand, under the stan-
dard conditions, the hydrogenation of substrate 3d bearing a more
sterically demanding tert-butyl substituent failed to afford the
corresponding alcohol 4d. In this case, only the recovered starting
material and the related dechlorinated product were obtained
(entries 4 and 5). Switching the hydrogenation conditions to
70 bar of hydrogen and 25 °C did not allow any improvement
either (entry 6).
a-chloro b-hydroxyphosphonates with moderate to good diastere-
oselectivities while suppressing the formation of the related
dechlorinated compounds.
In connection with our ongoing program directed toward the
synthesis of biologically relevant active molecules,20 we envisaged
the hemisynthesis of TaxotereÒ,21 an analogue of TaxolÒ,22 both
remarkable broad-spectrum cancer therapeutic agents, through
the dynamic kinetic resolution of an a-chloro b-keto ester. Toward
this end, we were interested in pursuing an efficient preparation of
the C-13 side chain of TaxotereÒ. Since the C-13 side chain of Taxo-
tereÒ is essential for its potent antitumor activity, the development
of an efficient process for its preparation in enantiopure form has
been the focus of many investigations.23,24 Only one example of
Nevertheless, when these latter conditions were applied to the
isopropyl-substituted compound 3c, the expected alcohol 4c was
obtained with a good diastereomeric ratio and excellent enantiose-
H
2 (10 bar)
O
O
O
OH
O
O
O
OH
[{RuCl((S)-P*P)}2(μ-Cl)3][NH2Et2]
(EtO)2P
(EtO)2P
(EtO)2P
(EtO)2P
R
R
R
R
S/C = 100
MeOH, 50 °C, 24 h
Cl
Cl
3
( )-
4
5
7
(1R,2S)-
4b: R = Et
4c
4d
: R = i-Pr
: R = t-Bu
4e: R = C6H5
4f: R = p-ClC6H4
Scheme 5.
Table 2
DKR of racemic 3 through ruthenium-catalyzed hydrogenationa
Entry
Substrate
Ruthenium complex
Productsb
dr (%) for (1R,2S)-4
ee (%) for (1R,2S)-4
3
5
7
(1R,2S)-4
1
2
3
4
3b
3b
3b
3d
3d
3d
3c
3e
3e
3e
3f
[{RuCl((S)-MeO-BIPHEP)}2(
l
-Cl)3][NH2Me2]
—
—
—
46
56
70
4
—
—
—
—
—
—
—
—
—
54
44
30
—
—
—
—
—
—
—
—
—
—
—
—
—
8
—
—
—
—
—
—
100
100
100
—
—
—
57:43c
57:43c
59:41c
—
—
—
>99c
>99c
>99c
—
[{RuCl((S)-SYNPHOS)}2(
[{RuCl((S)-DIFLUORPHOS)}2(
[{RuCl((S)-MeO-BIPHEP)}2( -Cl)3][NH2Me2]
l-Cl)3][NH2Me2]
l
-Cl)3][NH2Me2]
l
5
[{RuCl((S)-SYNPHOS)}2(l-Cl)3][NH2Me2]
—
—
6d
7d
8
[{RuCl((S)-SYNPHOS)}2(l-Cl)3][NH2Me2]
[{RuCl((S)-MeO-BIPHEP)}2(
[{RuCl((S)-MeO-BIPHEP)}2(
l
l
-Cl)3][NH2Me2]
-Cl)3][NH2Me2]
88
92:8e
88:12
91:9
86:14
87:13
89:11
85:15
>95e
42
100
100
100
100
100
100
9
[{RuCl((S)-SYNPHOS)}2(
[{RuCl((S)-DIFLUORPHOS)}2(
[{RuCl((S)-MeO-BIPHEP)}2( -Cl)3][NH2Me2]
[{RuCl((S)-SYNPHOS)}2( -Cl)3][NH2Me2]
[{RuCl((S)-DIFLUORPHOS)}2( -Cl)3][NH2Me2]
l-Cl)3][NH2Me2]
61
84
45
70
10
11
12
13
l
-Cl)3][NH2Me2]
l
3f
3f
l
l
90
a
b
c
All reactions were performed on 1 mmol at 0.5 M.
Conversion rates were determined by 1H NMR (300 MHz) of the crude reaction mixture.
The diastereo- and enantiomeric excesses were determined by HPLC on the corresponding benzoyl esters 4’ (Chiralpak AS-H column).
The hydrogenation was conducted at 25 °C under 70 bar of hydrogen for 100 h.
d
e
The diastereo- and enantiomeric excesses were determined by 31P NMR of the corresponding O-acetyl-( )-lactic ester 400
L

S. Prévost et al. / Tetrahedron: Asymmetry 21 (2010) 1436–1446
1439
the ruthenium-promoted asymmetric hydrogenation of
b-ketoester into the syn -chloro b-hydroxyester, carried out with
ethyl 2-chlorobenzoyl acetate, has been reported so far with a good
level of syn diastereoselectivity in MeOH/
CH2Cl2 (66–90% de).25
We report in this paper the efficient DKR of an -chloro b-keto-
ester into the corresponding anti -chloro b- hydroxyester and the
a
-chloro
The anti phenylisoserine derivative 15 would result from regiose-
lective cleavage of (2S,3R)-3-phenylglycidate 11 by a nitrogen
nucleophile. Compound 11 would in turn be obtained from race-
mic 9 via (2R,3R)-10, by dynamic kinetic resolution through asym-
metric hydrogenation.
a
e
a
a
The synthesis of the target compound 15 began with the crucial
successful application to the hemisynthesis of TaxotereÒ. The cho-
sen strategy was based on the observation by Greene et al.26 that
anti (2S,3S) phenylisoserine side chain derivatives could be
directly used for the crucial esterification step with baccatine III,
since complete epimerization occurred at the C-2 hydroxyl-bearing
stereocenter, leading to the required syn (2R,3S) configuration for
TaxotereÒ. Hence, the retrosynthetic scheme relies on the esterifi-
cation of 15 with a 10-desacetyl baccatin III derivative 16 which
would deliver TaxotereÒ after global deprotection (Scheme 6).
hydrogenation step of a-chloro b-ketoester 9, which was readily
prepared from acetophenone via a two-step sequence in 80% yield
(Scheme 7). The dynamic kinetic resolution of 9 was first carried
out using conditions that were previously established for the re-
lated compound, ethyl 3-phenyl-3-oxopropanoate (Scheme 7,
Table 3).27
Thus, the asymmetric hydrogenation of 9 was conducted in
dichloromethane at 80 °C under 60 bar of hydrogen using
*
0.5 mol % of the [Ru((R)-P P)Br2] complex, generated in situ from
commercially available [Ru(COD)(2-methylallyl)2].15 Under these
conditions, the reaction afforded the corresponding
a-chloro
O
b-hydroxyester (2R,3R)-10 with complete conversion and good
diastereo- and enantioselectivities (69–82% de, 76–90% ee, entries
1–3) using (R)-MeO-BIPHEP, (R)-SYNPHOS, or (R)-BINAP as ligands.
With the (R)-DIFLUORPHOS diphosphine, 80% conversion was at-
tained after 26 h (entry 4) whereas full conversion could be
achieved after a prolonged reaction time of 36 h, albeit a lower dia-
stereomeric excess was observed (61% de, entry 5). In an attempt
to increase the enantio- and diastereoselectivities, the hydrogena-
tion was then performed at a lower temperature and for a longer
reaction time (50 °C, 48 h, entries 6–9). Using these conditions,
moderate to good conversions were obtained while a drop in dia-
stereoselectivity was observed for (R)-SYNPHOS, (R)-MeO-BIPHEP,
and (R)-BINAP (26–67% de, entries 6–8). In sharp contrast, the re-
sults obtained with the (R)-DIFLUORPHOS ligand showed a signif-
icant increase in both the enantio- and diastereoselectivities (96%
de, 92% ee vs 61% de, 82% ee, entries 9 and 5) although a lower
58% conversion was achieved. In order to increase the conversion
rate in the case of the (R)-DIFLUORPHOS diphosphine, a screening
of solvents was carried out. Thus, under the previously established
hydrogenation conditions, various solvents were examined
(Scheme 8, Table 4). Dioxane and chloroform proved inappropriate
since poor conversions were obtained in these solvents (<5% con-
version, entries 1 and 2).
HO
O
H
OH
7
tBuO
Ph
NH
O
10
2
13
3
O
OH
O
HO
OAc
BzO
19: Taxotere ®
RO
O
OR
PMP
H
O
O
tBuO
Ph
N
HO
+
O
OH
H
HO
O
OAc
BzO
15
16: 10-desacetyl baccatin III derivative
(R = CO2CH2CCl3)
OH
O
O
O
O
CO2Me
Ph
OMe
Ph
OMe
Ph
Cl
(2R,3R)-10
Cl
( )-9
11
Scheme 6.
H2 (60 bar)
[Ru{(R)-P*P}Br2] 0.5 mol%
OH
O
O
O
O
1. NaH, (CH3O)2CO, toluene, Δ
2. SO Cl , CH Cl ,
Ph
OMe
Ph
OMe
Ph
Δ
2
CH2Cl2, T (°C), t (h)
2
2
2
Cl
Cl
80% (2 steps)
9
( )-
(2R,3R)-10
8
Scheme 7.
Table 3
Dynamic kinetic resolution of racemic 9a
Entry
Ru catalyst
T (°C)
t (h)
Conversionb (%)
dec ((2R,3R)-10,%)
eec ((2R,3R)-10,%)
1
2
3
4
5
6
7
8
9
[Ru((R)-MeO-BIPHEP)Br2]
[Ru((R)-SYNPHOS)Br2]
[Ru((R)-BINAP)Br2]
[Ru((R)-DIFLUORPHOS)Br2]
[Ru((R)-DIFLUORPHOS)Br2]
[Ru((R)-SYNPHOS)Br2]
[Ru((R)-MeO-BIPHEP)Br2]
[Ru((R)-BINAP)Br2]
80
80
80
80
80
50
50
50
50
26
26
26
26
36
48
48
48
48
100
100
100
80
100
90
89
88
58
69
75
82
87
61
26
57
67
96
87
90
76
82
82
90
nd
73
92
[Ru((R)-DIFLUORPHOS)Br2]
a
b
c
All reactions were performed on 1 mmol at 0.5 M.
Conversion rates were determined by 1H NMR (300 MHz) of the crude reaction mixture.
The diastereo- and enantiomeric excesses were determined by HPLC (Chiralcel OJ column).

1440
S. Prévost et al. / Tetrahedron: Asymmetry 21 (2010) 1436–1446
difference of 13C CSA, leading to two resonances, one for each enan-
tiomer and the other for each equivalent carbon site of the
molecule.
[Ru{(R)-DIFLUORPHOS }Br2]
S/C = 200
O
O
OH
O
Ph
OMe
Ph
OMe
H
2 (60 bar)
As the parameters governing the strength of the 13C CSA mainly
increase with the electronegativity of the substituents and the
Cl
( )-
Cl
solvent, 50 °C, 68 h
9
(2R,3R)-10
hybridization state of the carbons
Dr (sp) > Dr Dr
(sp2) >
(sp3),29–31 we could expect to obtain a significant chiral discrimina-
tion on the benzenic or carbonyl carbons of 9. In practice, the ortho
and meta aromatic sites are the most suitable carbon sites for accu-
rately evaluating the ee for two reasons: (i) 2 equiv carbons
contribute to signal, (ii) the proton-to-carbon NOE transfer exists
for these sites.
Scheme 8.
In toluene or tetrahydrofuran, low conversions were equally
observed (21–25%, entries 3 and 4). The -chloro b-hydroxyester
a
10 was obtained with higher conversions in ether and hexane
(73–75% conversions, entries 5 and 6) although in these solvents
the related dechlorinated compound was also formed. 1,2-Dichlo-
roethane led to results comparable to those obtained with dichlo-
romethane in terms of both enantio- and diastereoselectivities
(94% de, 93% ee) albeit a low conversion was obtained (36% conver-
sion, entry 7). Finally, the most suitable solvent for the hydrogena-
tion reaction appears to be dichloromethane, which offers the best
compromise between conversion and selectivity. Furthermore, the
reaction could be easily scaled up in this solvent on a 20 mmol
scale using (R)-DIFLUORPHOS as a ligand. Thus, under 60 bar of
hydrogen at 50 °C, (2R,3R)-10 was obtained with reproducible con-
version and selectivities working on this larger scale (58% conver-
sion, 55% isolated yield, 96% de, 92% ee).
Figure 1b presents the 13C–{1H} signals of the ortho and meta
aromatic carbons of 9 before the hydrogenation reaction, and
recorded in the PBLG/CHCl3 mesophase at 300 K. Compared to iso-
topic 13C–{1H} spectrum (Fig. 1a), two 13C resonances are observed
for the ortho and meta carbons, thus clearly indicating the enantio-
discrimination of these sites. The chemical shift differences
(
D
d = |dR ꢀ dS|) for ortho and meta carbons are of 0.06 ppm. As ex-
pected, spectral discriminations were also detected on the ipso
and para carbons and carbonyl sites (Figure 1d). Not surprisingly,
the ee of the sample is equal to zero within the experimental error,
and therefore the starting mixture is effectively racemic.
As seen in Figure 1c, the 13C–{1H} 1D spectrum of the
a-chloro
b-keto-ester, not consumed during the hydrogenation reaction, can
At this stage, taking into account the moderate conversion
observed, one may wonder whether a dynamic kinetic resolution
has really been taking place or if only kinetic resolution has occu-
red. In order to establish the DKR effect, it was necessary to mea-
sure the ee of the initial b-keto ester that has not been consumed
during the reaction in order to determine whether the mixture is
still racemic or enantioenriched in S-isomer. Preliminary HPLC
analysis failed to separate the enantiomers of 9. Although the spe-
cific rotation of the mixture prior to and after the hydrogenation
step remains mainly equal to zero, these experimental facts do
not constitute concluding evidence since the absolute value of
rotation of each enantiomer can be very weak.
To definitely answer this question, we turned our attention to
NMR in chiral liquid crystals (CLC) prepared with concentrated or-
ganic solutions (CHCl3 or DMF) of polypeptides (PBLG).28–30 This
efficient method relies on the ability of the CLC to orient in average
differently two optical isomers relative to the magnetic field Bo.
Advantageously, the R/S orientational ordering difference can be
spectrally revealed through any order-sensitive NMR interactions,
such as the shift anisotropy (CSA), or the dipolar (D) and quadrupo-
lar (Q) interactions that are not anymore averaged to zero at the
NMR time scale as in isotopic solvents.28 Another interest of the
method lies in the possibility to observe any magnetically active
nuclei in the molecule, including dilute atoms such as carbon-13
or deuterium at natural abundance level.30 Considering the struc-
ture of 9, 13C NMR in CLC was chosen.32,33 In proton-decoupled
13C NMR (13C–{1H}), the R/S discrimination is detected via a
be fully superimposed on the spectrum corresponding to the sam-
ple of b-keto-a-chloro ester prior to hydrogenation. The integra-
tion of signal surfaces (confirmed also by deconvolution of peaks)
shows that enantiomeric excess is still zero within the experimen-
tal errors, thus confirming unambiguously the results obtained by
the optical method. Conclusively, the solution of a-chloro b-hydro-
xy ester remains racemic all along the reaction, and so the hydro-
genation of precursor is, as initially suspected, under the control of
a dynamic kinetic resolution.
Having in hand the diastereo- and enantiomerically enriched
a
-chloro b-hydroxy ester 10, we next turned our attention to the
hemisynthesis of TaxotereÒ. Thus, compound 10 was converted
into the corresponding epoxide 11 in an excellent 98% yield by
treatment with DBU in dichloromethane (Scheme 9). Refluxing
11 with sodium azide and ammonium chloride in an acetone-
water mixture allowed the regio- and stereoselective cleavage34
of the epoxide to afford
a-hydroxy b-azidoester 12 in 80% yield.
Subsequent hydrogenation of the azide with Pd/C under hydrogen
pressure (1 atm) in the presence of di-tert-butyldicarbonate35
yielded 13, which was converted into oxazolidine 14 by refluxing
with p-(methoxyphenyl)dimethoxymethane and
a
catalytic
amount of PPTS. Hydrolysis of 14 provided the corresponding car-
boxylic acid 15 as the anti protected phenylisoserine side chain of
TaxotereÒ. Esterification of the 7,10-bis-trichloroethoxycarbonyl
derivative of 10-desacetyl baccatin III 16 with 15 using previously
reported conditions26 provided the TaxotereÒ precursor 17 in 60%
yield, and with complete epimerization at the C-2 stereocenter as
Table 4
Solvent effect in the DKR of 9
Entry
Solvent
Conva (%)
Yld (%)
deb (%), (2R,3R)-10
eeb (%), (2R,3R)-10
1
2
3
4
5
6
7
Dioxane
CHCl3
Toluene
THF
Et2O
Hexane
Cl(CH2)2Cl
<5
<5
21
25
73
75
36
nd
nd
21
24
57c
55c
27
nd
nd
83
50
22
10
94
nd
nd
76
86
85
85
93
a
b
c
Conversion rates were determined by 1H NMR (300 MHz) of the crude reaction mixture.
The diastereo- and enantiomeric excesses were determined by HPLC (Chiralcel OJ column).
The dechlorinated hydrogenated product was also isolated.

S. Prévost et al. / Tetrahedron: Asymmetry 21 (2010) 1436–1446
1441
Figure 1. 100 MHz 13C–{1H} spectrum (aromatic region) of 9 in (a) isotopic solvent (CHCl3) and (b) CLC (PBLG/CHCl3) at 300 K. The spectra (b) and (c) correspond to a mixture
prior to and after the hydrogenation step. The small variations of d 13C in (b) and (c) compared to (a) result from the solvent effect (CLC) and 13C CSA as well. For each trace,
1000 scans were added and the recycling delay is around 3 s. The PBLG samples were prepared with 100 mg of 9, 140 mg of PBLG (D.P. = 463) and 350 mg of CHCl3, (see Ref.
27). On Figure 1d are reported the spectral enantiodifferences (in ppm) measured on each carbon site.
expected. Subsequent cleavage of the oxazolidine moiety36 was
performed using APTS in methanol and furnished 18 in 55% yield
(based on recovered starting material). Deprotection of the 2,2,2-
trichloroethoxycarbonyl (Troc) groups has been previously re-
ported in the literature using standard procedure to give
TaxotereÒ.36
chromatography carried out on precoated silica gel plates (E.
Merck Ref. 5554 60 F254) and revealed with either an ultra-violet
lamp (k = 254 nm) or a potassium permanganate solution. The nu-
clear magnetic resonance spectra were recorded on a Bruker AC
200, AC 300, or Avance 400 instrument at 200, 300, or 400 MHz,
respectively, for 1H and 50, 75, or 100 MHz, respectively, for 13C.
The chemical shifts are expressed in parts per million (ppm) refer-
enced to residual chloroform (7.26 ppm for 1H and 77.1 ppm for
13C). Data are reported as follows: chemical shifts (d), multiplicity
(recorded as s, singlet; d, doublet; t, triplet; q, quadruplet; sept,
septuplet; m, multiplet; and br, broad), coupling constants, inte-
gration, and assignment. Mass spectra (MS) were recorded by the
ENSCP Mass Spectroscopy Service on a Hewlett-Packard HP 5989
A spectrometer. Ionization was obtained either by electronic im-
pact (EI, 70 eV) or chemical ionization with ammonia (CI, NH3)
and data are reported as m/z (relative intensity). Melting points
(mp) were determined on a Kofler melting point apparatus or on
a Büchi apparatus and are uncorrected. Optical rotations were
measured on a Perkin–Elmer 241 polarimeter or a Jasco P-1010
polarimeter. High resolution mass spectrometric (HRMS) analyses
were measured on LTQ-Orbitrap (Thermo Fisher Scientific) at
Pierre et Marie Curie University.
3. Conclusion
In summary, we have shown that the dynamic kinetic resolu-
tion of a series of racemic
ruthenium-mediated asymmetric hydrogenation allowed the for-
mation of the corresponding syn -chloro b-hydroxy phospho-
a-chloro b-keto phosphonates through
a
nates. Complete conversions were obtained in methanol,
alongside with excellent enantioselectivities (up to >99% ee) and
good diastereoselectivities were observed for substrates bearing
phenyl or para-chlorophenyl substituents (up to 84% de). More-
over, under the standard established conditions, no dechlorinated
compounds were observed. The dynamic kinetic resolution has
also been extended to the asymmetric hydrogenation of an
a-chloro b-keto ester. In particular, the use of the (R)-DIFLUOR-
PHOS ligand allowed the formation of the anti protected phenyliso-
serine side chain of TaxotereÒ in a highly enantio- and diaste-
reoselective fashion. This enantioenriched compound (95% de,
92% ee) was then successfully used in the hemisynthesis of Taxo-
tereÒ. Finally, we have nicely demonstrated that NMR in CLC was
a powerful tool to solve problems related to chirality,37 thus pro-
viding a unique alternative to usual NMR methods.
4.2. Diethyl 1-chloromethylphosphonate 6
In a 500 mL round-bottomed flask equipped with a mechanical
stirrer were introduced 1-chloromethylphosphoryl dichloride
(50.2 g; 0.3 mol; 1 equiv) and tetrahydrofuran (100 mL). A solution
of triethylamine (67 g; 0.66 mol; 2.2 equiv) in tetrahydrofuran
(100 mL) was added dropwise under vigorous stirring, then the
reaction mixture was cooled with an ice-bath. Ethanol (31 g or
39.29 mL; 0.66 mol; 2.2 equiv) was added dropwise at such a rate
as to maintain the reaction temperature below 30 °C (CAUTION
exothermic reaction). An important precipitate formed during the
addition, and the resulting suspension was stirred at room temper-
ature for 2 h. The reaction mixture was filtered, rinsed with
tetrahydrofuran (2 ꢁ 100 mL), and the combined filtrate was
4. Experimental
4.1. General
All air- and/or water-sensitive reactions were carried out under
an argon atmosphere. Tetrahydrofuran and diethyl ether were dis-
tilled from sodium-benzophenone. Dichloromethane was distilled
from calcium hydride. Reactions were monitored by thin layer

1442
S. Prévost et al. / Tetrahedron: Asymmetry 21 (2010) 1436–1446
(15 mL), ice (15 g), and dichloromethane (50 mL). The layers were
OH
O
NaN3, NH4Cl
acetone/H2O
O
separated and the aqueous phase was further extracted with
dichloromethane (2 ꢁ 50 mL). The combined organic phases were
washed with water (2 ꢁ 50 mL), dried over magnesium sulfate, fil-
tered, and concentrated under reduced pressure. The residue was
purified by chromatography on silica gel.
H
CO2Me
H
DBU
Ph
OMe
Ph
CH2Cl2, 4 h, rt
98%
Cl
10
96% de, 92% ee
5 h, Δ
80%
11
trans/cis : 99/1, 93% ee
4.3.1. Diethyl 1-chloro-2-oxopropylphosphonate 3a
Prepared according to the general procedure, using n-butyl lith-
ium (1.48 M solution in hexane, 37.2 mL, 55 mmol) in THF (35 mL),
BocHN
Ph
O
N3
O
H2 (1 atm), Pd/C, Boc2O
OMe
Ph
OMe
AcOEt, 16 h, rt
83%
OH
13
OH
12
a
solution of diethyl 1-chloromethylphosphonate (9.33 g,
50 mmol) in THF (15 mL), and a solution of ethyl acetate (5.3 g,
60 mmol) in THF (20 mL). After attempted purification by distilla-
tion failed, the recovered product was purified by chromatography
on silica gel (eluent cyclohexane/ethyl acetate 5:5) to give a yellow
syrup (4.6 g; 40% non optimized yield). Bp = 134 °C (1 mm Hg). 1H
NMR (CDCl3, 200 MHz, 24 °C) d 4.5 (d, J = 17.5 Hz, 1H), 4.3–4.15 (m,
4H), 2.45 (s, 3H), 1.4–1.35 (m, 6H). 31C NMR (CDCl3, 50 MHz, 24 °C)
d 197.4, 64.4 (m, J = 7 Hz), 57.3 (d, J = 138.5 Hz), 27.6, 16.2 (m,
J = 5.9 Hz). 31P NMR (CDCl3, 81 MHz, 24 °C) d 14.
PMP
H
PMP
H
O
K2CO3
BocN
Ph
O
BocN
Ph
p-MeOPhCH(OMe)2
MeOH/H2O
OMe
OH
rt, 20 h
89%
PPTS, toluene, Δ
O
O
70%
14
15
PMP
RO
O
H
O
OR
DCC, DMAP,
BocN
Ph
4.3.2. Diethyl 1-chloro-2-oxobutylphosphonate 3b
Prepared according to the general procedure, using n-butyl lith-
ium (1.47 M solution in hexane, 37.4 mL, 55 mmol) in THF (45 mL),
protected 10-DAB 16
O
toluene, 72 °C, 12 h
60%
O
O
H
a
solution of diethyl 1-chloromethylphosphonate (9.33 g,
HO
OAc
BzO
50 mmol) in THF (15 mL), and a solution of ethyl propanoate
(6.12 g, 60 mmol) in THF (15 mL). After attempted purification by
distillation failed, the recovered product was purified by chroma-
tography on silica gel (eluent cyclohexane/ethyl acetate 5:5) to
give a yellow syrup (5.0 g; 41% non optimized yield). 1H NMR
(CDCl3, 200 MHz, 24 °C) d 4.5 (d, J = 17.5 Hz, 1H), 4.3–4.1 (m, 4H),
2.9 (dq, J = 18.8, 7.2 Hz, 1H), 2.65 (dq, J = 18.8, 7.1 Hz, 1H), 1.4–
1.25 (m, 6H), 1.1 (t, J = 7.2 Hz, 3H). 31P NMR (CDCl3, 81 MHz,
24 °C) d 15. 13C NMR (CDCl3, 75 MHz, 24 °C): d 200.4, 64.5 (d,
J = 6.9 Hz), 64.3 (d, J = 6.9 Hz), 56.7 (d, J = 138.6 Hz), 33.7, 16.2,
16.1, 7.6.
17 (R = CO2CH2CCl3)
RO
O
OR
BocHN
Ph
O
APTS, MeOH, rt, 16h
O
55% (based on recovered
starting material)
OH
O
H
HO
OAc
BzO
18
HO
O
OH
BocHN
Ph
O
Zn, AcOH
4.3.3. Diethyl 1-chloro-3-methyl-2-oxobutylphosphonate 3c
Prepared according to the general procedure, using n-butyl lith-
ium (1.3 M solution in hexane; 42.3 mL, 55 mmol) in THF (45 mL),
O
AcOEt, 30 °C
ref. 36
OH
19 Taxotere®
Scheme 9.
O
H
HO
a
solution of diethyl 1-chloromethylphosphonate (9.33 g,
OAc
BzO
50 mmol) in THF (15 mL), and a solution of ethyl iso-butyrate
(6.4 g, 55 mmol) in THF (15 mL). The residue was purified by chro-
matography on silica gel (eluent cyclohexane/ethyl acetate 3:7) to
give a yellow syrup (7.5 g; 59% yield). Bp = 110–120 °C (1 mm Hg).
1H NMR (CDCl3, 200 MHz, 24 °C) d 4.65 (d, J = 17.5 Hz, 1H), 4.35–
4.15 (m, 4H), 3.2 (sept, J = 6.8 Hz, 1H), 1.65–1.3 (m, 6H), 1.15 (d,
J = 6.7 Hz, 6H). 13C NMR (CDCl3, 50 MHz, 24 °C) d 203.6, 64.4,
55.3 (d, J = 139 Hz), 38.8, 18.9, 18.3, 16.2 (d, J = 6 Hz). 31P NMR
(CDCl3, 81 MHz, 24 °C) d 13.0.
concentrated under reduced pressure. The residue was taken up in
diethyl ether (200 mL) and the precipitated triethylamine hydro-
chloride salt was filtered off and rinsed. The filtrate was concen-
trated under reduced pressure to give a yellow liquid which was
distilled under water-pump vacuum to yield a colorless liquid
(50.8 g; 91% yield). Bp = 130 °C (16 mm Hg). 1H NMR (CDCl3,
200 MHz, 24 °C) d 4.3–4.15 (m, 4H), 3.5 (d, J = 10.5 Hz, 2H), 1.35
(t, J = 7.0 Hz, 6H). 31P NMR (CDCl3, 81 MHz, 24 °C) d 19.
4.3.4. Diethyl 1-chloro-3,3-dimethyl-2-oxobutylphosphonate 3d
1H NMR (CDCl3, 300 MHz, 24 °C): d 4.87 (d, J = 12.6, 1H), 4.26
(m, 4H), 1.37 (dt, J = 3.9, 7.1 Hz, 3H), 1.36 (dt, J = 4.0, 7.0 Hz, 3H),
1.24 (s, 9H). 13C NMR (CDCl3, 50 MHz, 24 °C): d 205.4, 64.5 (d,
J = 6.5 Hz), 64.2 (d, J = 7.0 Hz), 46.9 (d, J = 146.9 Hz), 45.8 (d,
J = 3.3 Hz), 26.1, 16.4, 16.3.
4.3. General procedure for the synthesis of
phosphonates 3
a-chloro b-keto
Procedure described with ethyl iso-butyrate: to a ꢀ78 °C solu-
tion of n-butyl lithium (1.3 M solution in hexane; 42.3 mL,
55 mmol) in THF (45 mL) was added dropwise a solution of diethyl
1-chloromethylphosphonate (9.33 g, 50 mmol) in THF (15 mL). The
reaction mixture was stirred at this temperature for 30 min, then a
solution of ethyl iso-butyrate (6.4 g, 55 mmol) in THF (15 mL) was
added dropwise and the resulting mixture was stirred at ꢀ78 °C for
1 h. The reaction mixture was poured onto a mixture of 12 N HCl
4.3.5. Diethyl 1-chloro-2-phenyl-ethyl-phosphonate 3e
1H NMR (CDCl3, 300 MHz, 24 °C): d 8.01 (m, 2H), 7.62 (m, 1H),
7.49 (m, 2H), 5.47 (d, J = 16.3, 1H), 4.23 (m, 4H), 1.33 (t,
J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 50 MHz,
24 °C): d 189.5, 134.7, 134.0, 129.2, 128.5, 64.5 (d, J = 7.4 Hz),
64.4 (d, J = 7.4 Hz), 52.6 (d, J = 143.7 Hz), 16.1 (d, J = 6.5 Hz), 16.1
(d, J = 6.7 Hz).

S. Prévost et al. / Tetrahedron: Asymmetry 21 (2010) 1436–1446
1443
4.3.6. Diethyl 1-chloro-2-(4-chloro-phenyl)-2-oxo-ethyl-
phosphonate 3f
50 MHz, 24 °C) d 74.9, 64.5 (d, J = 6.7 Hz), 63.1 (d, J = 7 Hz), 54.2 (d,
J = 158 Hz), 31.0 (d, J = 11 Hz), 18.8, 18.5, 16.2. 31P NMR (CDCl3,
162 MHz, 24 °C) d 21.4. MS (CI, NH3) m/z 276 (100%, [M+NH4]+),
259 (60%, [M+H]+). MS (EI, 70 eV) m/z 259 (25%, [M+H]+), 215
(65%), 186 (90%), 159 (100%), 130 (40%), 81 (50%). Anti diastere-
isomer 1H NMR (CDCl3, 400 MHz, 24 °C) d 4.35–4.15 (m, 4H),
3.85–3.75 (m, 2H), 2.25–2.15 (m, 1H), 1.4–1.35 (m, 6H), 1.03 (d,
J = 6.9 Hz, 3H), 0.90 (d, J = 6.7 Hz, 3H). 13C NMR (CDCl3, 50 MHz,
24 °C) d 75.0, 64.4 (d, J = 6.9 Hz), 63.5 (d, J = 6.7 Hz), 51.6 (d,
J = 152 Hz), 29.3 (d, J = 10 Hz), 19.6, 16.4, 14.1. 31P NMR (CDCl3,
162 MHz, 24 °C) d 22.1. MS (CI, NH3) m/z 276 (100%, [M+NH4]+),
259 (90%, [M+H]+). MS (EI, 70 eV) m/z 259 (5%, [M+H]+), 215
(50%), 186 (55%), 159 (100%), 130 (30%), 81 (50%).
1H NMR (CDCl3, 300 MHz, 24 °C): d 8.00 (m, 2H), 7.46 (m, 2H),
5.37 (d, J = 16.6, 1H), 4.22 (m, 4H), 1.33 (t, J = 7.1 Hz, 3H), 1.27 (t,
J = 7.1 Hz, 3H). 13C NMR (CDCl3, 50 MHz, 24 °C): d 188.5, 140.8,
133.0, 130.8, 129.0, 64.7 (d, J = 6.9 Hz), 52.9 (d, J = 143.2 Hz), 16.3
(d, J = 4.6 Hz), 16.2 (d, J = 5.1 Hz).
4.4. General procedure for the dynamic kinetic resolution of
a-chloro b-keto phosphonates 3
Compound 3 (1 mmol) and MeOH (2 mL) were introduced in a
10-mL round-bottomed flask equipped with a magnetic stirrer.
The system was connected to a supply of vacuum/argon and the
solution was carefully degassed by three vacuum/argon cycles. So-
4.4.4. Diethyl 1-chloro-2-hydroxy-2-phenyl-ethyl-phosphonate
(1R,2S)-4e and (1S,2S)-4e
lid catalyst [(RuCl{(R)-SYNPHOS})2(l-Cl)3][NH2Me2] was added in
one portion. The orange solution was degassed by another vac-
uum/argon cycle. Under a flow of argon, the solution was intro-
duced via cannula in a 25 mL stainless steel autoclave which was
connected to a 1590,000 TOP INDUSTRIE25 parallel hydrogenation
system equipped with a central mechanical stirrer and a gas con-
sumption control and display system (TOP VIEW software). The
atmosphere of the autoclave was purged three times with argon
(8 bar) and twice with H2 (5 bar). The autoclave was adjusted to
the required temperature and H2 pressure (stirring 200 rpm). The
autoclave was then filled with H2 (required pressure, stirring
200 rpm). The stirring rate was adjusted to 1200 rpm and the H2
uptake was monitored. After total conversion of the substrate
(end of H2 uptake), the autoclave was adjusted to rt and atmo-
spheric pressure and finally purged three times with argon
(8 bar, stirring 200 rpm). The contents were drained off and the
autoclave was rinsed with MeOH (20 mL). The MeOH was distilled
Syn diastereisomer 1H NMR (CDCl3, 300 MHz, 24 °C): d 7.38 (m,
5H), 5.37 (dd, J = 2.5, 5.3, 1H), 4.17 (m, 5H), 1.36 (t, J = 7.1 Hz, 3H),
1.30 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 75 MHz, 24 °C): d 139.4 (d,
J = 11.8 Hz), 128.1, 128.0, 126.3, 71.4, 64.6 (d, J = 6.8 Hz), 63.1 (d,
J = 7.1 Hz), 57.6 (d, J = 153.6 Hz), 16.3 (d, J = 5.4 Hz), 16.2 (d,
J = 5.6 Hz). Anti diastereisomer 1H NMR (CDCl3, 300 MHz, 24 °C):
d 7.38 (m, 5H), 5.00 (dd, J = 8.4, 12.0, 1H), 4.17 (m, 5H), 1.39 (dt,
J = 0.5, 7.1 Hz, 3H), 1.35 (t, J = 0.6, 7.1 Hz, 3H). 13C NMR (CDCl3,
75 MHz, 24 °C): d 139.4 (d, J = 11.8 Hz), 128.5, 128.2, 127.2, 74.3,
64.6 (d, J = 7.1 Hz), 63.6 (d, J = 6.7 Hz), 54.3 (d, J = 150.1 Hz), 16.3
(d, J = 4.5 Hz), 16.2 (d, J = 6.1 Hz). HPLC: Chiralcel AS-H, 98.5:0.5
hexane/iso-propanol, 0.5 mL/min, k = 215 nm, tR 89.2 min for
(1R,2S), 162.2 min for (1S,2R), 98.1 min and 138.3 min for (1R,2R)
and (1S,2S).
4.4.5. Diethyl 1-chloro-2-(4-chloro-phenyl)-2-hydroxy-ethyl-
phosphonate (1R,2S)-4f and (1S,2S)-4f
off in vacuo to give the crude a-chloro b-hydroxyphosphonate.
Syn diastereisomer 1H NMR (CDCl3, 300 MHz, 24 °C): d 7.32 (m,
4H), 5.31 (m, 1H), 4.20 (m, 5H), 4.01 (dd, J = 2.6, 12.8 Hz, 1H), 1.31
(t, J = 7.0 Hz, 6H). 13C NMR (CDCl3, 50 MHz, 24 °C): d 137.9 (d,
J = 12.3 Hz), 133.8, 128.3, 127.8, 70.9, 65.0 (d, J = 6.8 Hz), 63.3 (d,
J = 7.1 Hz), 57.3 (d, J = 153.7 Hz), 16.4 (d, J = 5.1 Hz), 16.3 (d,
J = 5.2 Hz). Anti diastereisomer 1H NMR (CDCl3, 300 MHz, 24 °C):
d 7.32 (m, 4H), 4.96 (m, 1H), 4.80 (d, J = 3.1 Hz, 1H). 4.20 (m, 4H),
3.95 (d, J = 9.4 Hz, 1H), 1.29 (m, 6H). 13C NMR (CDCl3, 50 MHz,
24 °C): d 138.0 (d, J = 11.0 Hz), 134.2, 128.6, 128.3, 73.9, 64.7 (d,
J = 7.1 Hz), 63.8 (d, J = 7.0 Hz), 54.0 (d, J = 150.0 Hz), 16.4 (d,
J = 4.5 Hz), 16.3 (d, J = 5.9 Hz). HPLC: Chiralcel AS-H, 98.5:0.5 hex-
ane/iso-propanol, 0.5 mL/min, k = 215 nm, tR 77.9 min for (1R,2S)
and 146.2 min for (1S,2R), 91.3 min and 122.6 min for (1R,2R)
and (1S,2S).
4.4.1. Diethyl 1-chloro-2-hydroxypropylphosphonate (1R,2S)-4a
and (1S,2S)-4a
Syn diastereomer 1H NMR (CDCl3, 400 MHz, 24 °C) d 4.4–4.15
(m, 5H), 3.85 (dd, J = 12.4, 2.3 Hz, 1H), 3.3 (br s, 1H), 1.4–1.3 (m,
9H). 13C NMR (CDCl3, 50 MHz, 24 °C) d 66.0, 64.5 (d, J = 6.9 Hz),
63.2 (d, J = 7 Hz), 57.2 (d, J = 156 Hz), 20.1 (d, J = 11 Hz), 16.3. 31P
NMR (CDCl3, 162 MHz, 24 °C) d 20.3. Anti diastereomer 1H NMR
(CDCl3, 400 MHz, 24 °C) d idem except 3.89–3.81 (m, 1H). 13C
NMR (CDCl3, 50 MHz, 24 °C) d 67.5, 64.2 (d, J = 7.1 Hz), 63.4 (d,
J = 6.8 Hz), 56.2 (d, J = 152 Hz), 19.8 (d, J = 7.2 Hz), 16.3. 31P NMR
(CDCl3, 162 MHz, 24 °C) d 20.0.
4.4.2. Diethyl 1-chloro-2-hydroxybutylphosphonate (1R,2S)-4b
and (1S,2S)-4b
Syn diastereomer: 1H NMR (CDCl3, 400 MHz, 24 °C) d 4.3–4.15
(m, 4H), 4.1–4.0 (m, 1H), 3.95 (dd, J = 13.2, 1.9 Hz, 1H), 1.65–1.6
(m, 2H), 1.35 (t, J = 7.1 Hz, 6H), 0.95 (t, J = 7.5 Hz, 3H). 13C NMR
4.5. General procedure for the benzoylation of compounds 4
A mixture of 4a (0.22 mmol, 51 mg), 0.5 mL of anhydrous pyri-
(CDCl3, 50 MHz, 24 °C)
d
71.1, 64.4 (d, J = 6.8 Hz), 63.1 (d,
dine, and benzoyl chloride (0.22 mmol, 1 equiv, 27 lL) was stirred
J = 7.1 Hz), 55.3 (d, J = 157 Hz), 26.8 (d, J = 11 Hz), 16.2, 9.8. 31P
NMR (CDCl3, 162 MHz, 24 °C) d 20.9. Anti diastereomer: 1H NMR
(CDCl3, 400 MHz, 24 °C) d idem except 3.95–3.9 (m, 1H), 3.84
(dd, J = 9.9, 7.2 Hz, 1H), 1.77–1.72 (m, 2H). 13C NMR (CDCl3,
50 MHz, 24 °C) d 72.4, 64.3 (d, J = 6.8 Hz), 63.2 (d, J = 7.1 Hz), 54.1
(d, J = 152 Hz), 26.3 (d, J = 8 Hz,), 16.2, 9.0. 31P NMR (CDCl3,
162 MHz, 24 °C) d 20.9.
at room temperature. After 3 h, brine was added and the aqueous
layer was extracted with ethyl acetate. The combined organic lay-
ers were washed with a 1 M solution of hydrochloric acid, satu-
rated aqueous bicarbonate and brine, dried over magnesium
sulfate, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography using cyclohex-
ane/ethyl acetate (6:4) as eluent to give the product (67 mg, 94%
yield) as a colorless oil.
4.4.3. Diethyl 1-chloro-3-methyl-2-hydroxybutylphosphonate
(1R,2S)-4c and (1S,2S)-4c
4.5.1. Benzoyl ester 4a0
Syn diastereomer 1H NMR (CDCl3, 400 MHz, 24 °C) d 4.3–4.1 (m,
4H), 4.05 (dd, J = 14.0, 1.7 Hz, 1H), 3.65 (ddd, J = 8.7, 4.4, 1.6 Hz,
1H), 3.2 (br d, J = 4.4 Hz, 1H), 1.95–1.85 (m, 1H), 1.3 (t, J = 7.1 Hz,
6H), 1.01 (d, J = 6.6 Hz, 3H), 0.84 (d, J = 6.7 Hz, 3H). 13C NMR (CDCl3,
Syn diastereomer 1H NMR (CDCl3, 300 MHz, 24 °C): d 8.10 (m,
2H), 7.56 (m, 1H), 7.45 (m, 2H), 5.70 (dqd, J = 3.6, 6.4, 7.4 Hz,
1H), 4.19 (m, 4H), 4.09 (dd, J = 3.6, 13.6 Hz, 1H), 1.55 (dd, J = 1.1,
6.4 Hz, 3H), 1.29 (dt, J = 0.5, 7.1 Hz, 3H), 1.25 (dt, J = 0.6, 7.1 Hz,

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S. Prévost et al. / Tetrahedron: Asymmetry 21 (2010) 1436–1446
3H). 13C NMR (CDCl3, 50 MHz, 24 °C): d 165.2, 133.1, 129.8, 129.7,
128.3, 68.8, 63.8, 63.7, 55.4 (d, J = 159.5 Hz), 18.1 (d, J = 8.5 Hz),
16.3 (d, J = 5.5 Hz), 16.3 (d, J = 5.9 Hz). Anti diastereisomer 1H
NMR (CDCl3, 300 MHz, 24 °C): d 8.07 (m, 2H), 7.58 (m, 1H), 7.45
(m, 2H), 5.63 (ddq, J = 3.2, 4.3, 6.4 Hz, 1H), 4.39 (dd, J = 3.1,
15.0 Hz, 1H), 4.27 (m, 4H), 1.58 (d, J = 6.4 Hz, 3H), 1.39 (dt,
J = 0.5, 7.1 Hz, 3H), 1.37 (dt, J = 0.6, 7.1 Hz, 3H). 13C NMR (CDCl3,
50 MHz, 24 °C): d 165.5, 133.3, 130.0, 129.8, 128.4, 69.5, 64.2,
64.1, 55.1 (d, J = 154.8 Hz), 18.1 (d, J = 8.5 Hz), 16.3 (d, J = 5.5 Hz),
16.3 (d, J = 5.9 Hz). HPLC: Chiralcel AS-H, 99.5:00.5 hexane/iso-pro-
panol, 0.5 mL/min, k = 215 nm, tR 58.2 min for (1S,2R), 72.6 min for
(1R,2S), 127.7 min and 144.1 min for (1R,2S) and (1S,2R).
using cyclohexane/ethyl acetate (8:2) as eluent to give the b-keto
ester 8 (13.3 g, 90% yield) as a pale yellow oil. 1H NMR (CDCl3,
300 MHz, 24 °C): d 7.94 (m, 2H), 7.78 (m, 1H), 7.58 (m, 1H), 7.45
(m, 2H), 5.68 (s, 1H), 4.01 (s, 2H), 3.80 (s, 3H), 3.75 (s, 3H). 13C
NMR (CDCl3, 50 MHz, 24 °C): d 192.3, 173.4, 171.6, 167.9, 135.9,
133.8, 133.0, 128.9, 128.5, 128.3, 126.2, 87.0, 52.4, 51.4, 45.4. MS
(DCI, NH3): m/z 196 (100%, [M+NH4]+), 179 (68%, [M+H]+).
4.8. Methyl 2-chloro-3-oxo-3-phenyl-propanoate 9
A mixture of methyl 3-oxo-3-phenyl-propanoate (73 mmol,
13.0 g) and sulfuryl chloride (73 mmol, 6.0 mL) in dichloromethane
(150 mL) was stirred for 15 min at room temperature, then heated
at reflux until the gas evolution ceased. The reaction was then
cooled down and the solvent evaporated under reduced pressure.
The residual oil was purified by silica gel column chromatography
4.5.2. Benzoyl ester 4b0
Syn diastereisomer 1H NMR (CDCl3, 300 MHz, 24 °C): d 8.00 (m,
2H), 7.50 (m, 1H), 7.39 (m, 2H), 5.52 (ddd, J = 3.0, 6.8, 13.9 Hz, 4.14
(m, 5H), 1.91 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.4 Hz, 3H).
13C NMR (CDCl3, 50 MHz, 24 °C): d 165.4, 133.1, 130.0, 129.9, 128.3,
72.7 (d, J = 1.7 Hz), 63.9 (d, J = 6.8 Hz), 63.7 (d, J = 7.0 Hz), 53.5 (d,
J = 160.5 Hz), 25.0 (d, J = 8.8 Hz), 16.3 (d, J = 5.4 Hz), 16.3 (d,
J = 5.5 Hz), 9.6. Anti diastereisomer 1H NMR (CDCl3, 300 MHz,
24 °C): d 8.00 (m, 2H), 7.50 (m, 1H), 7.39 (m, 2H), 5.39 (ddd,
J = 3.7, 6.0, 12.5 Hz, 4.31 (dd, J = 3.6, 14.8 Hz, 1H), 4.14 (m, 4H),
1.91 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.28 (t, J = 7.4 Hz, 3H).). 13C
NMR (CDCl3, 50 MHz, 24 °C): d 165.9, 133.2, 129.8, 129.7, 128.4,
74.2 (d, J = 6.1 Hz), 64.2 (d, J = 6.9 Hz), 63.7 (d, J = 7.0 Hz), 54.0 (d,
J = 154.5 Hz), 23.3, 16.3 (d, J = 5.5 Hz), 16.2 (d, J = 6.3 Hz), 9.9. HPLC:
using cyclohexane/ethyl acetate (8:2) as eluent to give the
a-
chloro-b-keto ester 9 (13.9 g, 90% yield) as a slightly yellow oil.
1H NMR (CDCl3, 200 MHz, 24 °C): d 7.99 (m, 2H), 7.62 (m, 1H),
7.51 (m, 2H), 5.64 (s, 1H), 3.83 (s, 3H). 13C NMR (CDCl3, 50 MHz,
24 °C): d 188.1, 165.7, 134.4, 133.3, 129.3, 129.0, 57.7, 53.8. IR
(cmꢀ1):
m 2954, 1764, 1687, 1269, 1169. MS (DCI, NH3): m/z 230
(100%, [M+NH4]+).
4.9. Methyl (2R,3R)-2-chloro-3-hydroxy-3-phenyl-propanoate
(2R,3R)-10
Chiralcel
AS-H,
99:01
hexane/iso-propanol,
0.5 mL/min,
In a 100-mL flask were placed Ru(cod)[g
3-(CH2)2CHCH3]2
k = 215 nm, tR 95.6 min for (1S,2R), 106.9 min for (1R,2S),
124.3 min and 138.8 min for (1R,2S) and (1S,2R).
(0.1 mmol, 32 mg, 0.5 mol %), (R)-DIFLUORPHOSÒ (0.14 mmol,
94 mg, 0.55 mol %), and methyl 2-chloro-3-oxo-3-phenyl-propano-
ate 9 (20 mmol, 4.25 g) and the vessel was purged by a vacuum-ar-
gon cycle. Anhydrous dichloromethane (40 mL) previously
degassed by three vacuum-argon cycles was added at room tem-
perature. The flask was then placed under argon in a 250 mL stain-
less steel autoclave. The argon atmosphere was replaced with
hydrogen by three cycles of pressurizing and the pressure adjusted
to 100 bar. The autoclave was heated at 50 °C and stirring was
maintained for 45 h. After cooling, the reaction mixture was con-
centrated under reduced pressure. 1H NMR analysis revealed a
conversion of 58%. The residue was purified by silica gel column
chromatography using cyclohexane/ethyl acetate (9:1) as eluent
4.6. Ester 4c00
A
solution of the diethyl a-chloro b-keto phosphonate
(0.1 mmol; 1 equiv) in anhydrous ether (1 mL) was cooled at 0 °C
with an ice-bath. Pyridine (0.2 mL), then (S)-2-acetoxypropionyl
chloride (0.125 mL; 1 mmol; 10 equiv) were added dropwise and
the resulting suspension was stirred at 0 °C, then at room temper-
ature for 1–2 h. After addition of ethyl acetate (3 mL) and saturated
sodium carbonate (3 mL) to the reaction mixture, the organic
phase was decanted, washed with brine (3 mL), dried over magne-
sium sulfate, filtered and concentrated under reduced pressure.
The derivatized product was generally obtained as an oil with
quantitative conversion. Direct analysis of this product was per-
formed by 1H and/or 31P NMR, or by GC on chiral column (after fil-
to afford the anti (2R,3R)-a-chloro-b-hydroxy ester 10 as a pale yel-
low oil (2.35 g, 55% yield, 96% de, 93% ee). 1H NMR (CDCl3,
300 MHz, 24 °C): d 7.39 (m, 5H), 5.04 (dd, J = 4.9, 7.9 Hz, 1H),
4.39 (d, J = 7.9 Hz, 1H), 3.80 (s, 3H), 2.98 (d, J = 4.9 Hz, 1H). 13C
NMR (CDCl3, 50 MHz, 24 °C): d 169.1, 138.7, 128.5, 126.9, 126.5,
75.3, 59.0, 53.0. MS (DCI, NH3): m/z 232 (100%, [M+NH4]+).
tration of
a sample on silica gel using ethyl acetate or
dichloromethane as eluent). 1H NMR (CDCl3, 200 MHz, 24 °C) d
5.3–5.0 (m, 2H), 4.35–4.15 (m, 5H), 2.5–2.0 (m, 1H), 2.14 (s, 1H),
1.65–1.5 (m, 3H), 1.5–1.2 (m, 6H), 1.1–0.85 (m, 6H). Major diaste-
reomers 31P NMR (CDCl3, 162 MHz, 24 °C) d 18.1 and 17.9. Minor
diastereomers 31P NMR (CDCl3, 162 MHz, 24 °C) d 18.3 and 18.1.
½
a 2D1
ꢂ
¼ ꢀ43 (c 1.1, CHCl3). HPLC: Chiralcel OJ, 80:20 hexane/iso-
propanol, 1.0 mL/min, k = 215 nm, tR 11.4 min and 15.3 min for
(2R,3R) and (2S,3S) respectively and 17.7 min and 20.6 min for
(2R,3S) and (2S,3R), respectively.
4.7. Methyl 3-oxo-3-phenyl-propanoate 8
4.10. trans-Methyl (2S,3R)-3-phenyl-glycidate (2S,3R)-11
Into a three-necked flask equipped with an argon inlet and a
condenser were placed sodium hydride (60% in mineral oil,
8.15 g, 210 mmol), dimethylcarbonate (17.6 mL, 210 mmol), and
30 mL of toluene. The mixture was stirred at reflux and a solution
of acetophenone (10.0 g, 83 mmol) in toluene (30 mL) was added
dropwise. After 30 min at reflux, the reaction was cooled down
and a solution of acetic acid (5 mL) in water (20 mL) was added.
After decantation, the aqueous layer was extracted twice with
diethyl ether. The combined organic layers were washed with sat-
urated aqueous potassium carbonate, dried over magnesium sul-
fate, and concentrated under reduced pressure to give a yellow
oil. The residue was purified by silica gel column chromatography
To a solution of methyl (2R,3R)-2-chloro-3-hydroxy-3-phenyl-
propanoate 10 (10.66 mmol, 2.28 g) in dichloromethane (20 mL)
was added DBU (1.77 mL, 11.63 mmol). After 4 hours at room tem-
perature, the reaction was quenched with a buffer solution (pH 7).
The aqueous layer was extracted twice with dichloromethane. The
combined organic layers were dried over sodium sulfate and con-
centrated under reduced pressure to give the crude glycidate.
The residue was purified by silica gel column chromatography
using cyclohexane/ethyl acetate (85:15) as eluent (1.86 g, 98%
yield, 93% ee) to afford the trans-(2S,3R)-epoxy ester 11 as pale yel-
low oil. 1H NMR (CDCl3, 400 MHz, 24 °C): d 7.35 (m, 3H), 7.29 (m,
2H), 4.10 (d, J = 1.7 Hz, 1H), 3.83 (s, 3H), 3.52 (d, J = 1.7 Hz, 1H). 13
C

S. Prévost et al. / Tetrahedron: Asymmetry 21 (2010) 1436–1446
1445
NMR (CDCl3, 50 MHz, 24 °C): d 168.6, 143.9, 129.0, 128.7, 125.8,
58.0, 56.6, 52.6. MS (DCI, NH3): m/z 196 (100%, [M+NH4]+).
(DCI, NH3): m/z 431 (40%, [M+NH4]+), 414 (100%, [M+H]+), 375
(19%, [MꢀC4H8+NH4]+), 358 (14%, [MꢀC4H8+H]+).
½
a 2D6
ꢂ
¼ þ162 (c 1.5, CHCl3). HPLC: Chiralcel OD-H, 98:02 hexane/
iso-propanol, 1.0 mL/min, l = 215 nm, tR 16.0 min and 23.1 min
for (2R,3S) and (2S,3R), respectively (tR 9.6 min and 13.2 min for
cis glycidate (2R,3R) and (2S,3S)).
4.14. (4S,5S)-3-(tert-Butoxycarbonyl)-2-(p-methoxyphenyl)-4-
phenyl-1,3-oxazolidine-5-carboxylic acid 15
To a solution of 14 (0.62 mmol, 257 mg) in a mixture of meth-
anol (20 mL) and water (4 mL) was added potassium carbonate
(2.32 mmol, 321 mg). The reaction mixture was stirred for 20 h
at room temperature and concentrated under reduced pressure.
The residue was diluted in water (50 mL), washed with diethyl
ether, and then cooled down to 0 °C. Under vigorous stirring,
dichloromethane (50 mL) was added and the resulting mixture
was acidified until pH 1 with 1 M aqueous hydrochloric acid. After
decantation and extraction with dichloromethane, the combined
organic layers were washed with water, saturated aqueous sodium
chloride, dried over magnesium sulfate, and concentrated under
reduced pressure to give the desired acid 15 (220 mg, 89% yield)
as a 7:3 mixture of C2-isomers. Mp 132 °C. 1H NMR (CDCl3,
400 MHz, 24 °C): d (major isomer) 7.28–7.52 (m, 7H), 6.92 (m,
2H), 6.05 (br s, 1H), 5.28 (br d, J = 7.2 Hz, 1H), 4.99 (d, J = 7.2 Hz,
1H), 3.82 (s, 3H), 1.26 (s, 9H). 13C NMR (CDCl3, 75 MHz, 24 °C): d
(major isomer) 170.4, 160.1, 153.4, 137.6, 129.1, 128.9, 128.1,
127.5, 113.5, 90.7, 81.3, 79.2, 62.1, 55.3, 28.0. MS (DCI, NH3): m/z
417 (33%, [M+NH4]+), 400 (35%, [M+H]+).
4.11. Methyl (2S,3S)-3-azido-2-hydroxy-3-phenyl-propanoate 12
To a solution of methyl (2S,3R)-3-phenyl-glycidate 11 (1.80 g,
10.13 mmol) in an acetone/water mixture (4:1, 25 mL) was added
sodium azide (1.70 g, 26.01 mmol) followed by ammonium chlo-
ride (242 mg, 3.80 mmol). After 5 h at reflux, the reaction mixture
was concentrated under reduced pressure, diluted with dichloro-
methane, then washed with water, dried over magnesium sulfate,
and concentrated under reduced pressure. The residue was puri-
fied by silica gel column chromatography using cyclohexane/ethyl
acetate (8:2) as eluent to afford the desired product 11 (1.79 g, 80%
yield). 1H NMR (CDCl3, 300 MHz, 24 °C): d 7.32–7.39 (m, 5H), 4.88
(d, J = 4.0 Hz, 1H), 4.54 (dd, J = 4.0, 6.6 Hz, 1H), 3.72 (s, 3H), 2.94 (d,
J = 6.6 Hz, 1H). 13C NMR (CDCl3, 75 MHz, 24 °C): d 171.8, 134.4,
128.9, 128.7, 127.7, 73.8, 67.3, 52.7. MS (DCI, NH3): m/z 239
(100%, [M+NH4]+). ½a D26
¼ þ42 (c 0.3, CHCl3).
ꢂ
4.12. Methyl (2S,3S)-2-hydroxy-3-(N-tert-butoxycarbonyla-
mino)-3-phenyl-propanoate 13
4.15. Compound 17
To a solution of methyl (2S,3S)-3-azido-2-hydroxy-3-phenyl-
propanoate 12 (3.75 mmol, 830 mg) and di-tert-butyl dicarbonate
(4.87 mmol, 1.06 g) in ethyl acetate (10 mL) was added Pd/C
(0.78 mmol, 83 mg). The argon atmosphere was then replaced with
hydrogen and stirring was maintained at room temperature for
16 h. The suspension was then filtered on a Celite pad and washed
with ethyl acetate (60 mL) and water (20 mL). The organic layer
was dried over magnesium sulfate and concentrated under re-
duced pressure. The residue was purified by silica gel column chro-
matography using cyclohexane/ethyl acetate (8:2) as eluent to
afford 13 as a white solid (950 mg, 83% yield). Mp 135 °C. 1H
NMR (CDCl3, 300 MHz, 24 °C): d 7.21–7.33 (m, 5H), 5.59 (br d,
J = 7.1 Hz, 1H), 5.11 (br d, J = 1.7, 6.7 Hz, 1H), 4.60 (dd, J = 3.4,
7.0 Hz, 1H), 3.71 (s, 3H), 2.87 (d, J = 7.0 Hz, 1H), 1.42 (s, 9H). 13C
NMR (CDCl3, 75 MHz, 24 °C): d 172.3, 155.0, 136.8, 128.4, 128.1,
127.3, 80.0, 73.3, 56.7, 52.6, 28.3. MS (DCI, NH3): m/z 313 (35%,
[M+NH4]+), 296 (56%, [M+H]+), 257 (100%, [M-C4H8+NH4]+), 240
To a solution of 15 (53 mg, 130
(28 mg, 130 mol) at room temperature. After stirring for 5 min,
DMAP (5 mg, 45 mol) was added followed by baccatin III deriva-
tive 16 (40 mg, 45 mol). The reaction mixture was heated at 72 °C
lmol) in toluene was added DCC
l
l
l
overnight, then diluted with AcOEt, washed with water, saturated
NaHCO3, then brine. The organic phase was dried over magnesium
sulfate and concentrated under reduced pressure. Purification of
the residue by silica gel column chromatography using cyclohex-
ane/ethyl acetate (85:15) as eluent afforded 17 (34 mg, 60% yield)
as a white solid. 1H NMR (CDCl3, 300 MHz, 24 °C): d 8.04 (d,
J = 7.1 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.43 (m, 9H), 6.93 (d,
J = 8.7 Hz, 2H), 6.50 (s, 1H), 6.36 (t, J = 9.0 Hz, 1H), 6.27 (s, 1H),
5.69 (d, J = 7.1 Hz, 1H), 5.58 (dd, J = 7.1, 10.6 Hz, 1H), 5.32 (d,
J = 3.9 Hz, 1H), 4.91 (d, J = 11.8 Hz, 2H), 4.86 (t, J = 3.6 Hz, 1H),
4.79 (s, 2H), 4.61 (d, J = 11.8 Hz, 1H), 4.28 (d, J = 8.5 Hz, 1H), 4.13
(d, J = 8.2 Hz, 1H), 3.92 (d, J = 6.8 Hz, 1H), 3.85 (s, 3H), 2.62 (ddd,
J = 7.2, 9.4, 14.5 Hz, 1H), 2.30 (m, 2H), 2.11 (s, 2H), 2.01 (s, 1H),
1.90 (s, 2H), 1.84 (s, 3H), 1.42 (s, 9H), 1.34 (s, 3H), 1.31 (s, 6H).
MS (ESI): m/z 1291.6 [M+NH4]+. HRMS (ESI) m/z calcd for
(22%, [MꢀC4H8+H]+). ½a D26
¼ þ33 (c 0.5, CHCl3).
ꢂ
4.13. Methyl (4S,5S)-3-(tert-butoxycarbonyl)-2-(p-methoxy-
phenyl)-4-phenyl-1,3-oxazolidine-5-methanoate 14
C57H61O19NCl6Na: 1296.18612, found: 1296.18619.
A solution of methyl (2S,3S)-2-hydroxy-3-(N-tert-butoxycar-
bonylamino)-3-phenylpropanoate 13 (1.36 mmol, 400 mg) and
pyridinium p-toluenesulfonate (0.135 mmol, 34.6 mg) in toluene
(15 mL) was heated at reflux and a solution of (para-methoxy-
phenyl) dimethoxymethane in toluene was added dropwise. The
heating was maintained until completion of the reaction (moni-
tored by TLC). After cooling down, the reaction mixture was con-
centrated under reduced pressure and the residue purified by
silica gel column chromatography using cyclohexane/ethyl acetate
(98:2–9:1) as eluent to afford the oxazolidine 14 as a white solid
(390 mg, 70% yield, 7:3 mixture of C2-isomers). Mp 105 °C. 1H
4.16. Bis-O-(2,2,2-trichloroethoxycarbonyl)docetaxel 18
To a solution of 17 (27 mg, 21
lmol) in MeOH (400 lL) was
added APTS (4.4 mg, 23 mol) and the reaction mixture was stirred
l
at room temperature for 16 h. The mixture was diluted in EtOAc
and washed with water. The organic phase was dried over magne-
sium sulfate and concentrated under reduced pressure. Purification
of the residue by silica gel column chromatography using cyclo-
hexane/ethyl acetate (7:3) as eluent afforded 18 (6 mg, 25%) to-
gether with recovered 17 (15 mg, 55%) as white solids. The
spectroscopic data matched published ones.21 HRMS (ESI) m/z
calcd for C49H55O18Cl6NNa: 1178.14425, found: 1178.14528.
NMR (CDCl3, 400 MHz, 24 °C):
d (major isomer) 7.48 (d,
J = 8.7 Hz, 2H), 7.42 (m, 2H), 7.29 (m, 3H), 6.91 (m, 2H), 6.05 (br
s, 1H), 5.27 (br d, J = 7.0 Hz, 1H), 5.01 (d, J = 7.0 Hz, 1H), 3.82 (s,
3H), 3.37 (s, 3H), 1.43 (s, 9H). 13C NMR (CDCl3, 75 MHz, 24 °C): d
(major isomer) 167.3, 160.2, 153.3, 138.2, 129.6, 129.0, 128.2,
128.1, 127.7, 113.6, 90.9, 81.1, 79.9, 62.6, 55.3, 51.8, 28.1. MS
Acknowledgments
We thank Dr. D. Lavergne for preliminary experiments and Pro-
fessor B. Ben Hassine for interesting discussions. We are grateful to

1446
S. Prévost et al. / Tetrahedron: Asymmetry 21 (2010) 1436–1446
19. (a) Noyori, R. Acta Chem. Scand. 1996, 50, 380; (b) Ratovelomanana-Vidal, V.;
Genet, J.-P. J. Organomet. Chem. 1998, 567, 163.
Hoffmann La Roche for providing samples of (S)- and (R)-MeO-BIP-
HEP and to Dr. A. Commerçon (Sanofi-Aventis) for a gift of pro-
tected 10-DAB.
20. (a) Labeeuw, O.; Phansavath, P.; Genet, J.-P. Tetrahedron: Asymmetry 2004, 15,
1899; (b) Labeeuw, O.; Blanc, D.; Phansavath, P.; Ratovelomanana-Vidal, V.;
Genet, J.-P. Eur. J. Org. Chem. 2004, 2352; (c) Le Roux, R.; Desroy, N.;
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