Stereoselective synthesis of (1′S,3R,4R)-4-acetoxy-3-(2′-fluoro-1′-trimethylsilyloxyethyl)-2-azetidinone

Article abstract of DOI:10.1016/j.tetlet.2009.03.111

A stereoselective synthesis of (1′S,3R,4R)-4-acetoxy-3-(2′-fluoro-1′-trimethylsilyloxyethyl)-2-azetidinone as a new fluorine-containing intermediate towards β-lactams, is described. The synthetic key step relies upon the dynamic kinetic resolution (DKR) o

Full text of DOI:10.1016/j.tetlet.2009.03.111

Tetrahedron Letters 50 (2009) 2676–2677
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of (10S,3R,4R)-4-acetoxy-3-(20-fluoro-10-trimethylsilyl-
oxyethyl)-2-azetidinone
Ivan Plantan a, Michel Stephan b, Uroš Urleb a, Barbara Mohar b,
*
a Lek Pharmaceuticals d.d., Verovškova 57, SI-1526 Ljubljana, Slovenia
b Laboratory of Organic and Medicinal Chemistry, National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
stereoselective synthesis of (10S,3R,4R)-4-acetoxy-3-(20-fluoro-10-trimethylsilyloxyethyl)-2-azetidi-
Article history:
A
Received 10 December 2008
Revised 11 March 2009
Accepted 17 March 2009
Available online 21 March 2009
none as a new fluorine-containing intermediate towards b-lactams, is described. The synthetic key step
relies upon the dynamic kinetic resolution (DKR) of ethyl 2-benzamidomethyl-4-fluoro-3-oxo-butanoate
via asymmetric transfer hydrogenation catalyzed by [Ru(
g
6-arene)(S,S)-R2NSO2DPEN].
Ó 2009 Elsevier Ltd. All rights reserved.
The 2-azetidinone moiety is present in a large number of impor-
tant biologically active compounds of which b-lactam antibiotics
are representative. Despite the rapid increase in the resistance of
microorganisms to current antibiotics, b-lactam antibiotics still
represent more than half of available antibacterial agents.1 More-
over, owing to the unique properties attributed to the fluorine
atom, selectively fluorinated organic intermediates constitute
challenging targets which are useful towards the synthesis of bio-
logically active substances with modified properties.2
reactive 4-acetoxy-azetidinones.6 A literature survey revealed only
a few cases of the preparation of such intermediates.7
Herein, we present our synthesis of the new fluoroalkyl acetoxy
azetidinone 2 (Scheme 1) via a modified procedure to that devel-
oped by the Takasago Co. for the synthesis of 1.
Thus, ethyl 2-benzamidomethyl-4-fluoro-3-oxo-butanoate (4),
prepared by alkylation of commercially available ethyl
acetoacetate (3),8 was subjected to asymmetric transfer hydroge-
nation9 6-arene)(S,S)-
using the Mohar–Stephan [Ru(
c-fluoro-
g
The use of asymmetric catalysis has led to several industrial
processes on a multi-ton scale. One of the earliest and most
referred to being the process for the synthesis of the precursor to
carbapenems by the Takasago Co. Relying upon the Ru-(BINAP)-
catalyzed asymmetric hydrogenation of a b-keto ester derivative
via dynamic kinetic resolution (DKR), the optically pure (3R,4R)-
4-acetoxy-3-[(R)-(tert-butyldimethylsilyloxy)ethyl]-2-azetidinone
(1) precursor was prepared.3 In the subsequent step, the acetoxy
group was displaced readily by nucleophiles with high stereocon-
trol aided by the presence of the bulky O-TBDMS protecting group.4
R2NSO2DPEN] catalyst (R2NSO2DPEN = N-sulfamoyl-1,2-diphenyle-
thylenediamine). Asymmetric hydrogenation of 4 using Ru-BINAP
as catalyst gave poorer results than using the latter asymmetric
transfer hydrogenation.10
O
OH
OH
O
a
b
F
CO2Et
F
CO2Et
NHBz
F
CO2Et
NHBz
F
CO2Et
NHBz
+
39%
60%
3
4
syn-5
(96% ee)
anti-5
syn/anti 83:17
g
c
85%
65%
PG-O
HO
H
H
OH
OAc
NH
F
F
CO2Et
F
e
PG-O
H
d
F
CO2H
NH2
OAc
NH
Z
53%
60%
NH
1'
NHBz
3
E-9
O
O
7
6
h
8: PG= H (trans/cis 4:1)
2: PG= TMS
O
86-88%
f
1: Z= H, PG= TBDMS
2: Z= F, PG= TMS
MeO
MeO
57%
CO2
CO2
S
R
H
Ha
H
Ha
Ph
Ph
F
F
Hb
Hb
2'
2'
4
4
Hb
Hb
Ha
Ha
or
NH
NH
O
O
In our ongoing research on trinems (i.e., tricyclic b-lactams) with
improved biological properties,5 we devised a synthetic strategy to-
wards the preparation of highly optically active fluorine-containing
7-O-Me-(R)-mandelate
7-O-Me-(S)-mandelate
Scheme 1. Reagents and conditions: (a) LiH, BzNHCH2Cl, THF, 0 °C?rt; (b)
[Ru(1,3,5-Et3C6H3)(S,S)-Me2NSO2DPEN], HCO2H–Et3N (5:2), DMF, rt; (c) (i) 10% aq
HCl, reflux; (ii) Et3N, MeOH, rt; (d) (2-PyS)2, PPh3, DMSO, 90 °C; (e) RuCl3ꢀxH2O,
NaOAc, AcOOH, PrOAc, ꢁ40 °C?ꢁ10 °C; (f) (i) TMSCN, DMF, rt; (ii) Buffered silica
gel (pH 8), CH2Cl2, rt, (>99% dr, 96% ee); (g) DEAD, PPh3, CH2Cl2, rt; (h) (R)- or (S)-
PhCH(OMe)CO2H, DCC, DMAP, CH2Cl2, rt.
* Corresponding author. Tel.: +386 147 60 250; fax: +386 147 60 300.
E-mail address: barbara.mohar@ki.si (B. Mohar).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.111

I. Plantan et al. / Tetrahedron Letters 50 (2009) 2676–2677
2677
Table 1
[Ru(
ment with trimethylsilyl cyanide in DMF under mild conditions
affording the crude N,O-bis-TMS-protected derivative of 8, which
yielded in turn the desired O-TMS-protected compound 2 via selec-
tive N-desilylation using buffered silica gel (pH 8).14 Column chro-
matography on buffered silica gel (pH 8) with gradient elution
(hexane/CH2Cl2) allowed the isolation of 2 as a single diastereomer
in 57% yield and with high chemical purity.
g
6-arene)(S,S)-R2NSO2DPEN]-catalyzed transfer hydrogenation of 4a
Ligand:
Ph
Ph
NHSO2NR2
NH2
a: R= Me
b: RR= -(CH2)5-
c: RR= -(CH2)2O(CH2)2-
a-c
In summary, (10S,3R,4R)-4-acetoxy-3-(20-fluoro-10-trimethylsi-
lyloxyethyl)-2-azetidinone (2) was prepared in 96% ee relying
upon asymmetric transfer hydrogenation as the key step using
HCO2H–Et3N (5:2) and catalyzed with 0.5% [Ru(1,3,5-
Et3C6H3)(S,S)-Me2NSO2DPEN]. The application of this reactive
intermediate in the synthesis of fluorine-containing trinems is un-
der study and the results will be communicated shortly.
Entry
[RuCl2(
g
6-arene)]2 arene=
Ligand
syn/antib
ee (syn, %)c
1
2
3
4
5
6
7
1,3,5-Triethylbenzene
Hexamethylbenzene
Benzene
a
a
b
b
b
b
c
83:17
71:29
76:24
71:29
75:25
83:17
74:26
96
96
74
93
95
95
94
Mesitylene
1,3,5-Triethylbenzene
Hexamethylbenzene
Hexamethylbenzene
a
HCO2H–Et3N (5:2, 250
g
lL) was added to a mixture of 4 (1 mmol) and preformed
Supplementary data
[RuCl(
6-arene)(S,S)-R2NSO2DPEN] (0.5 mol %) in DMF (1 mL), and the reaction was
stirred at rt for 1 d to attain 100% conversion.
b
Determined by 19F NMR spectroscopy: d(syn) = ꢁ231, d(anti) = ꢁ228.
Supplementary data (experimental procedures and character-
ization data for all new compounds) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2009.03.111.
c
Determined by HPLC analysis on a chiralcel OD column with hexane/2-PrOH/
CF3CO2H 97:3:0.2 (1 mL/min) and UV (k = 222 nm) detection: t(R,R) = 44 min,
t(S,S) = 58 min.
Asymmetric transfer hydrogenation of 4 in the presence of
References and notes
HCO2H–Et3N (5:2) was performed at rt using 0.5% of the in situ
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chromatography eluting with CH2Cl2/Et2O (4:1) and chiral HPLC
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-
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ˇ
Scheme 1, step g) which showed E-geometry, and in the subse-
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mandelates of 7.
ˇ ˇ
ˇ
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D
d
RS = ꢁ0.31 and ꢁ0.36 ppm for Ha-4
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(10S,4S) configuration for azetidinone 7. This corresponds to the (2S,3S)
configuration for syn-5. For a detailed explanation of this method, see: (a)
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