Stereoselective synthesis of fluorine-containing analogues of anti-bacterial sanfetrinem and LK-157

Article abstract of DOI:10.1016/j.tet.2010.03.104

The synthesis of (1′S,3R,4R)-4-acetoxy-3-(1′-trimethylsilyloxy-2′,2′,2′-trifluoroethyl)-2-azetidinone (10) precursor of modified carbapenems is described relying upon [Ru(C₆Me₆)(S,S)-(CH₂)₅NSO₂DPEN]-catalyzed asymmetric transfer hydrogenation under dynamic kinetic resolution using HCO₂H-Et₃N. This fluorine-containing precursor yielded the targeted trinems 1 and 2 via a stereoselective key step condensation with lithium (S)-6-methoxy-cyclohexenolate.

Full text of DOI:10.1016/j.tet.2010.03.104

Tetrahedron 66 (2010) 4144–4149
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of fluorine-containing analogues of anti-bacterial
sanfetrinem and LK-157
,
a
b
Barbara Mohar a , Michel Stephan , Uros Urleb
*
ˇ
a Laboratory of Organic & Medicinal Chemistry, National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia
b
ˇ
Lek Pharmaceuticals d.d., Verovskova 57, 1526 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
The synthesis of (10S,3R,4R)-4-acetoxy-3-(10-trimethylsilyloxy-20,20,20-trifluoroethyl)-2-azetidinone (10)
precursor of modified carbapenems is described relying upon [Ru(C6Me6)(S,S)–(CH2)5NSO2DPEN]-cata-
lyzed asymmetric transfer hydrogenation under dynamic kinetic resolution using HCO2H–Et3N. This
fluorine-containing precursor yielded the targeted trinems 1 and 2 via a stereoselective key step con-
densation with lithium (S)-6-methoxy-cyclohexenolate.
Article history:
Received 18 January 2010
Received in revised form 10 March 2010
Accepted 29 March 2010
Available online 2 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
b-Lactam
Asymmetric transfer hydrogenation
Ruthenium
Total synthesis
1. Introduction
diastereomer of (10S,3R,4R)-4-acetoxy-3-(10-hydroxy-20,20,20-trifluoro-
ethyl)-2-azetidinone (8) has been reported by Prati’s group based
b
-Lactam antibiotics encompassing penicillins, cephalosporins,
upon the condensation of the optically enriched ethyl (R)-3-hydroxy-
monobactams, and carbapenems, are the major class of antibacte-
rial agents used in modern health care. Nonetheless, the resistance
to them by some bacterial strains incited the search for further
modified analogues.1 Following the discovery of the highly active
sanfetrinem (a tricyclic carbapenem referred to as trinem) by the
Glaxo Co.,2 several of its derivatives have been prepared and
tested.3 In particular, the (4S,8S,9R)-10E-ethylidene-4-methoxy-
trinem (LK-157) proved to be effective against both gram-positive
and gram-negative bacteria.4 Furthermore, the increased interest
in fluorine-containing antibiotics stems from the potential to
favorably alter the original pharmacological properties,5 and such
fluorine-incorporated compounds are of great value in drug design.
As part of our ongoing research program aimed to studying the
4,4,4-trifluorobutanoate with N-(trimethylsilyl)cinnamylidenimine.8
R
HO
H
H
H
N
8
R
4
10
9
N
OMe
CO2Na
OMe
CO2Na
1
O
O
Sanfetrinem: R= CH3
LK-157: R= CH3
1: R= CF3
2: R= CF3
Hereafter, we describe a stereoselective synthesis of enantiopure
(10S,3R,4R)-4-acetoxy-3-(10-trimethylsilyloxy-20,20,20-trifluoroethyl)-
-2-azetidinone (10) precursor and its transformation into the new
trinems 1 and 2.
structure–activity relationship of
b-lactam antibiotics through
modification of sanfetrinem substituents at C-4 and C-10,6 we de-
vised the synthesis of the new fluorine-containing trinems 1 and 2.
The synthesis of sanfetrinem and LK-157 has been reported re-
lying on a highly stereoselective SnCl4-catalyzed condensation of
2. Results and discussion
enantiomerically
(10R,3R,4R)-4-acetoxy-3-[10-(tert-butyldimethylsilyloxy)ethyl]-2-aze-
tidinone.7 In addition, the synthesis of the related (10R,3R,4R)-
pure
(S)-2-methoxy-cyclohexanone
with
2.1. Synthesis of (10S,3R,4R)-4-acetoxy-3-(10-trimethylsilyloxy-
20,20,20-trifluoroethyl)-2-azetidinone (10)
Among the several synthetic approaches described in the
literature toward (10R,3R,4R)-4-acetoxy-3-[10-(tert-butyldimethyls-
ilyloxy)ethyl]-2-azetidinone, the Takasago Co. synthetic pathway
* Corresponding author. Tel.: þ386 1 4760250; fax: þ386 1 4760300; e-mail
address: barbara.mohar@ki.si (B. Mohar).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.104

B. Mohar et al. / Tetrahedron 66 (2010) 4144–4149
4145
proved to be highly efficient. It relies upon a stereoselective dy-
namic kinetic resolution (DKR) via the [RuCl2(R)-BINAP]2$Et3N-
catalyzed asymmetric hydrogenation at 100 atm of H2 of methyl
2-benzamidomethyl-3-oxobutanoate leading to a dr of 94:6 and
98% ee for the syn-stereoisomer.9,10 Following a similar general
outlined strategy (Scheme 1), we have prepared the ethyl 2-ben-
zamidomethyl-3-oxo-4,4,4-trifluorobutanoate (3) from the com-
mercially available ethyl 4,4,4-trifluoroacetoacetate and subjected
it to asymmetric transfer hydrogenation. The reduction was carried
out at room temperature in DMF using HCO2H–Et3N 5:2 in the
presence of our11 in situ-generated catalyst derived from
[RuCl2(C6Me6)]2 and (1S,2S)-N-(piperidyl-N-sulfonyl)-1,2-diphe-
nylethylenediamine ((S,S)-(CH2)5NSO2DPEN). The reaction param-
eters were varied in order to attain optimum results. During this
Facing these various synthetic challenges,17 we pursued the
synthesis with the unprotected azetidinone 6. Thus, under the ac-
tion of 16% peracetic acid in PrOAc in the presence of RuCl3$3H2O/
NaOAc, the 4-acetoxy-azetidinone 8 was obtained in a dr of 9:1
(trans/cis) accompanied with up to 4% of the product resulting from
the oxidation of the hydroxy group as shown by 1H NMR.18 The pure
stereoisomer trans-8 was isolated in 65% yield after column
chromatography. Treatment of trans-8 with N,O-bis(trimethylsilyl)-
acetamide (BSA, >2 equiv) in CH2Cl2 led to the N,O-bisTMS-pro-
tected azetidinone
9 (94% yield), which by regioselective
deprotection upon treatment with silica gel slurry in MeOH
afforded the O-TMS-protected compound 10. Note that azetidi-
nones 9 and 10 were conveniently purified by distillation under
high vacuum.
study, it turned out that the substrate concentration and the h6
-
arene of the catalyst were detrimental for high diastereoselectivity.
Thus, operating at different concentrations of substrate 3, syn/anti-
4 ratios of 94:6 (>99% ee syn, 52% ee anti) and 83:17 were obtained
for 0.25 M and 1 M solutions, respectively.12 Also, using C6Me6 as
2.2. Determination of the absolute configuration of syn-4
Attempts to esterify alcohol syn-4 with (R)-Mosher’s acid chlo-
ride led to its dehydration into ethyl (E)-2-benzamidomethyl-4,4,4-
trifluorobut-2-enoate as shown by 1H NMR (see Supplementary
data). In parallel, (S)-1-(phenyl)ethyl and (S)-1-(1-naphthyl)ethyl
carbamates of alcohol syn-4 were prepared, but unfortunately we
were unable to obtain suitable crystals for X-ray diffraction analy-
sis. Finally, the esterification of azetidinone 6 to its (S)-Mosher’s
acid ester 6a ((R)-Mosher’s acid chloride used) followed by crys-
tallization was successful and the X-ray analysis19 revealed
a (10S,3S) configuration. This corresponds consequently to a (2S,3S)
configuration for syn-4.
the h
6-arene yielded the best result compared to employing ben-
zene, p-cymene, mesitylene or 1,3,5-triethylbenzene.13 After a sin-
gle recrystallization from i-Pr2O/hexane, pure alcohol syn-4 was
obtained in >99% de. Note that the [RuCl2(R)-BINAP]2$Et3N-cata-
lyzed hydrogenation of 3 under 90 atm of H2 resulted in our hands
in the formation of syn-4 in a dr of 96:4 in 22% ee. Thus, the transfer
hydrogenation methodology using our [Ru(h
6-arene)(CH2)5NSO2
DPEN] catalyst proved to be highly efficient for the preparation of
fluoroalkyl alcohols from the corresponding ketones.14
1. 10% aq HCl,
1. [Ru(C6Me6)(CH2)5NSO2DPEN],
HCO2H-Et3N 5:2, DMF, rt
2. Recrystallization
HO
HO
F3C
HO
F3C
O
reflux, 10 h
2. Et3N, MeCN
CO2Et
NHBz
CO2H
NH2
CO2H
NH2
CO2Et
NHBz
F3C
syn-4
F3C
+
77%
84%
anti-5
3
syn-5
Ligand:
>99% ee (>99% de)
syn/anti 92:8
Ph
NHSO2N
1. (2-PyS)2, PPh3,
MeCN, 60 °C
Ph
NH2
CF3
60%
MeO
Ph
(S,S)-(CH2)5NSO2DPEN
2. Chromatography
(S)
1. RuCl3.3H2O, NaOAc,
HO
TMSO
F3C
HO
O
O
16% AcOOH in PrOAc
H
H
H
H
(S)
F3C
(R)-MTPA-Cl,
OAc
NH
trans-8
OAc
N-R
9: R= TMS
2. Separation of
cis/trans-isomers
Et3N, CH2Cl2
BSA, CH2Cl2, 45 °C
F3C
F3C
(S)
65%
94%
39%
N-R
6: R= H
NH
O
O
O
O
6a
TBDMSCl, Et3N,
DMAP, CH2Cl2
(SiO2)x, MeOH 97%
75%
7: R= TBDMS
10: R= H
Scheme 1.
Subsequent hydrolysis of syn-4 in boiling 10% aq HCl furnished
the hydroxytrifluoroethyl -amino acid 5. A prolonged hydrolysis
2.3. Synthesis of fluorine-containing trinems 1 and 2
b
period (10 h) was necessary for complete conversion, which is the
double of the required time for the hydrolysis of the non-fluorine-
containing analogue methyl (2S,3S)-2-benzamidomethyl-3-
hydroxybutanoate.9 However, a certain degree of epimerization at
Adopting a comparable literature synthetic strategy for building
trinem skeletons from 4-acetoxy-2-azetidinones,20 the introduction
of the (S)-methoxy-cyclohexanone moiety was accomplished by
reacting lithium (S)-6-methoxy-cyclohexenolate (2 equiv) with the
O-TMS-protected azetidinone 10 in THF at ꢀ78 ꢁC (Scheme 2). The
resulting bicyclic O-TMS-protected product was formed in a dr of
82:18 as determined by 1H and 19F NMR analyses. The pure stereo-
isomer (3S,4R)-4-[(1R,3S)-3-methoxy-2-oxo-cyclohexyl]-3-[1-(S)-
trimethylsilyloxy-2,2,2-trifluoroethyl]-2-azetidinone (11) was isolated
in 72% yield after column chromatography. Note, the condensation of
the N,O-bisTMS-protected azetidinone 9 under the same reaction
conditions led to an identical dr, albeit in 50% yield.
the
a-position concomitantly occurred under these conditions,
which was up to 8% after 10 h and 20% after 24 h. Subsequently, the
syn/anti-5 (92:8) mixture was used directly in the following cycli-
zation step. This latter transformation was carried out according to
Ohno’s conditions,15 which call upon 2,20-dipyridyl disulfide and
PPh3. Interestingly, the azetidinone 6 was isolated as a single ste-
reoisomer in 60% combined yield after recrystallization of the crude
and column chromatography of the filtrate. Attempts to O-TBDMS-
protect azetidinone 6 under various conditions16 led to the
N-TBDMS-protected product 7, in contrast to the literature result
for the non-fluorine-containing analogue.9
Progressing toward the synthesis of 1 and 2, intermediate 11
was treated with allyl oxalyl chloride affording product 12 (95%
yield), which was cyclized into trinem 13 with triethyl phosphite/

4146
B. Mohar et al. / Tetrahedron 66 (2010) 4144–4149
TMSO
OMe, THF, 78 °C
TMSO
1.
H
H
H
H
N
OMe
OMe
OLi
ClC(O)CO2CH2CH=CH2,
Et3N, CH2Cl2
2. Chromatography
F C
3
F C
3
10
O
O
72%
95%
NH
O
O
O
11
12
O
O
P(OEt)3, hydroquinone,
140 °C
59%
F C
3
HO
TMSO
PPh3, DEAD,
CH2Cl2
H
H
H
N
O
H
H
Bu4NF, AcOH
F C
F C
3
3
50%
98%
N
N
OMe
OMe
OMe
O
O
O
O
O
O
O
O
15
14
13
Pd(PPh3)4, PPh3,
Na 2-ethylhexanoate,
CH2Cl2, THF
Pd(PPh3)4, PPh3,
Na 2-ethylhexanoate,
CH2Cl2, THF
37%
45%
2
1
Scheme 2.
hydroquinone at 140 ꢁC (59% yield).21 Removal of the TMS-
protecting group of 13 with Bu4NF/AcOH furnished alcohol 14,
which afforded pure sodium salt 1 in 37% yield following Pd-
catalyzed deallylation22 in the presence of sodium 2-ethyl-
hexanoate. The pure sodium salt 2 was obtained from 14 following
dehydration into 15 by PPh3/DEAD treatment (50% yield) and
Pd-catalyzed deallylation (45% yield).
0.43 mol) in Et2O (100 mL) over 30 min. The mixture was stirred at rt
until all sodium had disappeared (~6 h). Subsequently, solid N-
(chloromethyl)benzamide23 (72.8 g, 0.43 mol) was added portion-
wise and the mixture was left to stir at rt. After 30 min, the yellow
colored suspension was diluted with EtOAc (250 mL) and filtered
through a short pad of silica gel (20 g) washing with EtOAc
(2ꢂ100 mL). The concentrated filtrate was recrystallized from cold
(0 ꢁC) toluene (130 mL). The crystals were filtered, rinsed succes-
sively with cold toluene (100 mL), toluene/i-Pr2O (1:1, 100 mL) and
finally with i-Pr2O (100 mL). After drying, 3 (70.99 g) was obtained as
white crystals. An additional crop (18.3 g) was obtained after con-
centration of the filtrate and recrystallization from toluene (50 mL)
(total yield 72%). Mp 85–88 ꢁC; nmax(KBr) 3328, 1772, 1721, 1640,
3. Conclusion
Though the synthesis of (10R,3R,4R)-4-acetoxy-3-[10-(tert-
butyldimethylsilyloxy)ethyl]-2-azetidinone was straightforward,
unexpected synthetic difficulties were encountered in the prepa-
ration of a CF3-containing analogue. Resorting to a different syn-
thetic approach, we have achieved the stereoselective synthesis of
enantiopure (10S,3R,4R)-4-acetoxy-3-(10-trimethylsilyloxy-20,20,20-
trifluoroethyl)-2-azetidinone (10), which proved to be a useful
precursor for the preparation of modified trinems bearing a CF3
group. This new fluorine-containing intermediate was prepared
relying upon an asymmetric transfer hydrogenation key step under
DKR of ethyl 2-benzamidomethyl-3-oxo-4,4,4-trifluorobutanoate
(3) catalyzed by [Ru(C6Me6)(S,S)–(CH2)5NSO2DPEN]. This latter
transformation proceeded effectively as the corresponding alcohol
syn-4 was obtained in 84% yield with >99% ee (>99% de). The in-
termediate (10S,3R,4R)-10 was further efficiently transformed into
the new trinems 1 and 2 following a novel stereocontrolled ap-
proach via its condensation with lithium (S)-6-methoxy-cyclo-
hexenolate. These trinems are under biological testing and the
results will be communicated in due course.
1526, 1294, 1206, 1182, 1155 cmꢀ1
; dH (mixture of rotamers) 1.27 and
1.30 (3H, 2 t, J 7.2 Hz), 3.16 (0.2H, t, J 4.3 Hz), 3.85–4.41 (4.6H, m), 5.19
(0.1H, s), 6.00 (0.1H, s), 6.69 (1H, m), 7.41–7.53 (3H, m), 7.72–7.76 (2H,
m); dC (mixture of rotamers) 13.8, 37.2, 37.8, 46.8, 52.5, 62.4, 62.8,
93.6 (q, J 33 Hz), 115.1 (q, J 293 Hz), 126.9 (q, J 291 Hz), 128.6, 131.9,
133.5,133.6,166.1, 167.9, 168.6, 172.9,186.5 (q, J 38 Hz); dF (mixture of
rotamers) ꢀ66.9 (s), ꢀ78.3 (s), ꢀ85.3 (s). m/z (FAB) 318 (85, MHþ);
HRMS (EI): Mþ, found 317.0877. C14H14F3NO4 requires 317.0875.
4.1.2. Ethyl
(2S,3S)-2-benzamidomethyl-3-hydroxy-4,4,4-tri-
mixture of
fluorobutanoate (syn-4). Catalyst preparation:
A
[RuCl2(C6Me6)]2 (248 mg, 0.37 mmol) and (1S,2S)-N-(piperidyl-N-
sulfonyl)-1,2-diphenylethylenediamine11 (292 mg, 0.81 mmol) in
DMF (50 mL) was heated progressively to 80 ꢁC, stirred at this
temperature for 30 min then cooled to rt. Reduction of 3: to a solu-
tion of 3 (62.77 g, 198 mmol) in DMF (800 mL) was added the above
catalyst solution followed by HCO2H–Et3N 5:2 (50 mL). The mixture
was left to stir at rt for 12 h. H2O (1 L) was added and the product was
extracted with Et2O (5ꢂ250 mL). The combined organic extracts
were washed with H2O (300 mL) and the aqueous layer was reex-
tracted with Et2O (3ꢂ500 mL). The combined Et2O layers were again
washed with H2O (300 mL), dried (Na2SO4), and partially concen-
trated. The precipitated product was filtered and washed with Et2O
affording white crystals. An additional crop was obtained after con-
centration of the filtrate and washing with i-Pr2O (53.1 g, total yield:
84%). 19F NMR analysis revealed a de >99%. Ee (>99%) was
determined by HPLC on Chiralcel OD column eluting with hexane/i-
4. Experimental section
4.1. General considerations
Reactions were carried out under an inert atmosphere using dry
solvents when required. 1H (300 MHz, internal Me4Si), 13C (75 MHz,
internal CDCl3), and 19F NMR (282 MHz, internal CCl3F) were
recorded as solutions in CDCl3 if not stated otherwise.
4.1.1. Ethyl 2-benzamidomethyl-3-oxo-4,4,4-trifluorobutanoate (3). To
powdered sodium (10.0 g, 0.435 atm g) under Et2O (350 mL) was
added at 0 ꢁC a solution of ethyl 4,4,4-trifluoroacetoacetate (63 mL,
PrOH 98:2 at 1 mL/min flow rate and UV (l 227 nm) detection:
t(R,R)¼52 min, t(S,S)¼56 min. Mp 108–110 ꢁC; [Found: C, 52.52; H,

B. Mohar et al. / Tetrahedron 66 (2010) 4144–4149
4147
25
5.11; N, 4.23. C14H16F3NO4 requires C, 52.67; H, 5.05; N, 4.39]; [
a
]
2 mmol) in CH2Cl2 (10 mL) was added Et3N (290
mL, 2.1 mmol),
D
þ33.8 (c 1.0, CHCl3); nmax(KBr) 3417, 3402, 1724, 1651, 1543, 1281,
DMAP (49 mg, 0.4 mmol), and tert-butyldimethylsilyl chloride
(317 mg, 2.1 mmol). After stirring at rt for one day, the reaction
mixture was washed with 1 M HCl (10 mL), H2O (10 mL), brine
(10 mL), dried (Na2SO4), and concentrated. Column chromatogra-
phy of the residue on silica gel eluting first with CH2Cl2 then with
Et2O afforded pure 7 (426 mg, 75%). nmax(KBr) 3294 (br), 2962,
1177, 1131, 1104 cmꢀ1
;
dH 1.28 (3H, t, J 7.1 Hz), 2.96 (1H, dt, J 9.3,
3.7 Hz), 3.56 (1H, dt, J 14.7, 3.4 Hz), 4.11–4.34 (4H, m), 5.56 (1H, br d, J
5.4 Hz), 6.90 (1H, m), 7.42–7.57 (3H, m), 7.76–7.80 (2H, m); dC 14.0,
37.8, 45.9, 61.6, 68.5 (q, J 31 Hz), 124.6 (q, J 281 Hz), 127.1, 128.8,132.3,
133.2, 169.5, 171.6; dF ꢀ77.5 (d, J 7.1 Hz). m/z (FAB) 320 (80, MHþ).
HRMS (EI): Mþ, found 319.1033. C14H16F3NO4 requires 319.1031.
2934, 2862, 1724, 1364, 1272, 1224, 1169, 1123, 1039 cmꢀ1
; dH 0.22
(3H, s), 0.27 (3H, s), 0.96 (9H, s), 3.03, (1H, app. t, J 4.8 Hz), 3.25 (1H,
t, J 6.0 Hz), 3.53 (1H, m), 3.63 (1H, m), 4.47 (1H, m); dC ꢀ6.3, ꢀ6.2,
18.4, 25.8, 37.8, 51.1, 65.7 (q, J 32 Hz), 124.7 (q, J 282 Hz), 172.6; dF
ꢀ78.7 (d, J 7.7 Hz); m/z (FAB) 284 (100, MHþ).
4.1.3. (2S,3S)-2-Aminomethyl-3-hydroxy-4,4,4-trifluorobutanoic acid
(syn-5). A suspension of alcohol syn-4 (85.5 g, 0.268 mol) in 10% aq
HCl (1.7 L) was refluxed under vigorous stirring for 10 h. The re-
action mixture was cooled down on an ice-bath and the precipitate
filtered. The filtrate was washed with CH2Cl2 (3ꢂ200 mL) and the
aqueous phase concentrated to dryness. The syrupy residue was
dissolved in MeCN (150 mL), concentrated, and dried under high
vacuum. The yellowish viscous residue (66.2 g) was redissolved in
MeCN (450 mL) and Et3N (36.5 mL, 0.267 mol) was added. This
mixture was stirred at rt overnight and the precipitate filtered. The
filter cake was suspended in CH2Cl2 (300 mL), refluxed for 0.5 h
then passed hot through a sintered glass filter. This latter treatment
was repeated in order to eliminate the Et3N$HCl. Product syn-5 was
obtained as a white powder accompanied with 8% of anti-(2S,3R)-5
(38.4 g, 76.6%). nmax(KBr) 3138 (br), 1646, 1577, 1372, 1277, 1179,
1160, 1132, 1080 cmꢀ1; m/z (FAB) 188 (100, MHþ). Characteristics of
syn-5: dH (D2O) 2.85 (1H, app. q, J 6.1 Hz), 3.30 (2H, d, J 6.1 Hz), 4.58
(1H, m); dC (D2O) 35.8, 45.5, 70.5 (q, J 31 Hz), 125.4 (q, J 282 Hz),
176.6; dF (D2O) ꢀ77.0 (d, J 7.6 Hz).
4.1.7. (10S,3S)-3-{10-[(S)-
a-Methoxy-a-(trifluoromethyl)phenyl-
acetoxy]-20,20,20-trifluoroethyl}-2-azetidinone (6a). To a solution of
(10S,3S)-6 (17 mg, 0.10 mmol) in CH2Cl2 (1 mL) was added Et3N
(17
m
L, 0.12 mmol), DMAP (a crystal), and (R)-(ꢀ)-
a-methoxy-a-
L, 0.12 mmol). After
(trifluoromethyl)phenylacetyl chloride (22.4
m
stirring for 16 h at rt, the mixture was concentrated, suspended in
CH2Cl2 and washed with diluted HCl then satd aq NaHCO3, dried
(Na2SO4), and concentrated. The residue was purified by column
chromatography on silica gel eluting with CH2Cl2/Et2O 95:5. The
product was recrystallized from CH2Cl2/heptane to obtain colorless
crystals (15 mg, 39%); mp 69–71 ꢁC; dH 3.33 (2H, m), 3.59 (3H, s),
3.73 (1H, m), 5.24 (1H, br s), 5.99 (1H, m), 7.40–7.54 (5H, m); dF
ꢀ72.14 (s), ꢀ75.85 (d, J 6.1 Hz). For its X-ray structure analysis, see
Supplementary data.
4.1.8. (10S,3R,4R)-4-Acetoxy-3-(10-hydroxy-20,20,20-trifluoroethyl)-2-
azetidinone (trans-8). To a cold mixture (ꢀ10 ꢁC) of (10S,3S)-6
(18.09 g, 0.107 mol), AcONa (8.78 g, 0.107 mol), and RuCl3$3H2O
(675 mg, 2.58 mmol) in a mixture of AcOH (110 mL) and PrOAc
(110 mL), a 16% solution of peracetic acid in PrOAc24 (167 g,
0.35 mol) was added dropwise at ꢀ10 to 0 ꢁC within 2 h. The
reaction mixture was poured onto 10% aq Na2SO3 (300 mL) fol-
lowed by addition of Et2O (250 mL). The aqueous phase was
extracted with Et2O (2ꢂ250 mL) and the combined organic ex-
tracts were washed with satd aq NaHCO3 (3ꢂ50 mL), filtered
through a short pad of silica gel surmounted with Na2SO4 and
concentrated. Crude 8 (trans/cis 9:1) was purified by column
chromatography on silica gel eluting with petroleum ether 40–
60/Et2O 3:2. Pure crystalline trans-8 (15.9 g, 65.4%) was obtained
after rinsing the crystals with EtOAc/hexane. [Found: C, 37.29; H,
4.1.4. (10S,3S)-3-(10-Hydroxy-20,20,20-trifluoroethyl)-2-azetidinone
((10S,3S)-6). To product 5 (31.2 g, 0.167 mol; containing 8% of anti-
5) in MeCN (3 L), PPh3 (48.8 g, 0.168 mol) and 2,20-dipyridyl disul-
fide (37.0 g, 0.168 mol) were successively added and the mixture
was heated at 60 ꢁC for 12 h. The clear yellow solution was cooled
down to rt and Cu(OAc)2$H2O (33.5 g, 0.168 mol) was added. The
orange precipitate was filtered off and the filtrate concentrated. The
residue was suspended in toluene (300 mL) and the product was
extracted with H2O (7ꢂ250 mL). The combined aqueous layers
were washed with toluene (100 mL) and NaCl was added till sat-
uration. The product was extracted with EtOAc (4ꢂ1 L), filtered
through a short pad of silica gel surmounted with Na2SO4 and
concentrated. The solid residue (22.9 g) was triturated with Et2O
and the pure crystalline 6 (15.65 g, 55.5%) was collected by filtra-
tion. The filtrate was concentrated and the residue was purified by
column chromatography on silica gel eluting with n-BuOAc to af-
ford an additional amount of 6 (1.38 g, 4.9%; Rf (EtOAc) 0.5). Further
elution with EtOAc afforded the diastereomer (10S,3R)-6 (0.90 g,
3.2%; Rf (EtOAc) 0.3) as a white powder. (10S,3S)-6: mp 166–167 ꢁC;
3.70; N, 5.90. C7H8F3NO4 requires C, 37.01; H, 3.55; N, 6.17]; Rf
25
(Et2O) 0.67; mp 112–114 ꢁC; [
a
]
þ104.0 (c 1.0, CHCl3); nmax(KBr)
D
3366, 3231, 1768, 1732, 1275, 1221, 1190, 1167, 1127, 1047 cmꢀ1
; dH
2.14 (3H, s), 3.56 (1H, app. t, J 1.5 Hz), 4.17 (1H, br s), 4.43 (1H, q, J
6.3 Hz), 6.00 (1H, s), 7.15 (1H, s); dC 20.7, 56.8, 65.2 (q, J 33 Hz),
73.3, 124.1 (q, J 282 Hz), 164.9, 171.5; dF ꢀ78.9 (d, J 6.9 Hz). m/z
(FAB) 228 (60, MHþ); HRMS (ESI): MHþ, found 228.0488.
C7H9F3NO4 requires 228.0484.
[Found: C, 35.51; H, 3.58; N, 8.28. C5H6F3NO2 requires C, 35.65; H,
25
3.68; N, 8.02]; [
a]
ꢀ42.1 (c 1.0, MeOH); nmax(KBr) 3268, 1736,
D
1704, 1264, 1192, 1176, 1148, 1124 cmꢀ1
; dH (CD3OD) 3.29 (1H, app. t,
J 5.5 Hz), 3.50 (1H, m), 3.57 (1H, dt, J 5.5, 2.3 Hz), 3.34 (1H, dq, J 7.6,
2.3 Hz); dC (CD3OD) 36.9, 51.8, 66.6 (q, J 32 Hz), 126.6 (q, J 290 Hz),
170.0; dF (CD3OD) ꢀ76.2 (d, J 7.3 Hz), HRMS (ESI): MHþ, found
170.0430. C5H7F3NO2 requires 170.0429.
4.1.9. (10S,3R,4R)-4-Acetoxy-3-(10-trimethylsilyloxy-20,20,20-tri-
fluoroethyl)-1-(trimethylsilyl)-2-azetidinone (9). To a solution of 8
(11.3 g, 49.7 mmol) in CH2Cl2 (20 mL) was added N,O-bis(-
trimethylsilyl)acetamide (BSA, 30 mL, 122.7 mmol). After stirring at
45 ꢁC for 2 h, the reaction mixture was distilled on a Kugelrohr:
after removal of the first fraction (50 ꢁC/0.1 mbar) containing BSA
and trimethylsilylacetamide, the product 9 distilled at 60 ꢁC/
0.1 mbar as colorless oil (17.37 g, 94%). dH 0.17 (9H, s), 0.29 (9H, s),
2.10 (3H, s), 3.53 (1H, t, J 1.3 Hz), 4.32 (1H, dq, J 7.0, 1.2 Hz), 6.33 (1H,
s); dC 1.2, 1.9, 20.7, 57.6, 66.5 (q, J 33 Hz), 73.5, 124.1 (q, J 283 Hz),
164.1, 171.3; dF ꢀ78.4 (d, J 6.2 Hz); m/z (LC-MS) 372 (30, MHþ).
4.1.5. (10S,3R)-3-(10-Hydroxy-20,20,20-trifluoroethyl)-2-azetidinone
25
((10S,3R)-6). Mp 125.5–127 ꢁC; [
a]
ꢀ19.4 (c 1.0, MeOH); nmax(KBr)
D
3334, 1732, 1716, 1280, 1184, 1161, 1154, 1132 cmꢀ1
; dH (CD3OD) 3.22
(1H, dd, J 5.6, 2.4 Hz), 3.41 (1H, t, J 5.6 Hz), 3.55 (1H, dt, J 5.6, 2.7 Hz),
4.26 (1H, dq, J 7.6, 5.9 Hz); dC (CD3OD) 38.9, 51.9, 69.1 (q, J 33 Hz),
126.4 (q, J 290 Hz),169.1; dF (CD3OD) ꢀ74.5 (d, J 7.3 Hz). HRMS (ESI):
MHþ, found 170.0423. C5H7F3NO2 requires 170.0429.
4.1.6. (10S,3S)-3-(10-Hydroxy-20,20,20-trifluoroethyl)-1-(tert-butyldi-
methylsilyl)-2-azetidinone (7). To a solution of (10S,3S)-6 (338 mg,
4.1.10. (10S,3R,4R)-4-Acetoxy-3-(10-trimethylsilyloxy-20,20,20-tri-
fluoroethyl)-2-azetidinone (10). N,O-bisTMS-protected 9 (3.20 g,

4148
B. Mohar et al. / Tetrahedron 66 (2010) 4144–4149
8.6 mmol) was stirred with silica gel (1 g) in MeOH (20 mL) overnight.
Themixturewasconcentratedandfilteredthroughashortpadofsilica
gel eluting with EtOAc. The residue was distilled on a Kugelrohr at
100 ꢁC/0.1 mbar affording 10 as colorless oil (2.50 g, 97%). [Found: C,
40.38; H, 5.48; N, 4.51. C10H16F3NO4Si requires C, 40.13; H, 5.39; N,
4.68]; dH 0.17 (9H, s), 2.13 (3H, s), 3.52 (1H, t, J 1.4 Hz), 4.37 (1H, qd, J 6.7,
1.4 Hz), 5.94 (1H, s), 6.56 (1H, br s); dF ꢀ78.6 (d, J 7.0 Hz).
hydroquinone (250 mg, 2.27 mmol) in P(OEt)3 (15 mL) was heated
at 140 ꢁC for 2 h. The mixture was cooled to rt and the excess of
P(OEt)3 was distilled off on Kugelrohr (40 ꢁC/0.1 mbar). The residue
was purified by column chromatography on silica gel (hexane/
EtOAc 9:1) affording 13 as yellowish crystals (1.77 g, 58.8%). dH 0.20
(9H, s), 1.22–1.59 (2H, m), 1.63 (1H, m), 1.86 (2H, m), 2.08 (1H, m),
3.25 (1H, m), 3.20–3.62 (4H, m), 4.44 (2H, m), 4.70 (1H, dd, J 12.9,
4.8 Hz,), 4.79 (1H, dd, J 12.6, 4.5 Hz), 4.96 (1H, m), 5.27 (1H, d, J
10.2 Hz), 5.44 (1H, d, J 17.1 Hz), 5.96 (1H, m); dC ꢀ0.3, 20.1, 30.2,
32.6, 43.4, 52.4, 53.3, 56.1, 65.6, 66.9 (q, J 33 Hz), 72.2, 118.3, 124.2
(q, J 282 Hz), 126.0, 131.3, 148.8, 160.6, 172.8; dF ꢀ78.5 (d, J 8.2 Hz);
HRMS (ESI): MHþ, found 448.1760. C20H29F3NO5Si requires
448.1767.
4.1.11. (S)-6-Methoxy-1-(trimethylsilyloxy)cyclohex-1-ene20b. To a cold
(0 ꢁC) solution of i-Pr2NH (62 mL, 0.44 mmol) in THF (400 mL) was
added dropwise t-BuMgCl (2.0 M in Et2O, 210 mL). After stirring at
0 ꢁC for 1 h, a solution of (S)-2-methoxy-cyclohexanone (50 mL,
0.40 mol) was added over 2.5 h. The mixture was left to stir for 1 h
then TMSCl (60 mL, 0.47 mol) was added. The mixture was left to
warm up to rt and stirred for an additional hour. The precipitate was
filtered off, rinsed with Et2O and the filtrate partitioned between Et2O
(500 mL) and H2O (500 mL). The organic layer was washed with H2O
(200 mL), dried (Na2SO4), and concentrated on rotary evaporator at
200 mbar. The residue was distilled at 75–77 ꢁC/12 mbar affording
colorless oil (65.88 g, 82.6%). dH 0.19 (9H, s), 1.47–1.64 (3H, m), 1.87–
2.09 (3H, m), 3.41 (3H, s), 3.50 (1H, t, J 3.0 Hz), 4.98 (1H, t, J 4.2 Hz); m/z
(EI) 200 (55, Mþ).
4.1.15. Allyl (4S,8S,9R,10S)-4-methoxy-10-[1-(S)-hydroxy-2,2,2-tri-
fluoroethyl]-11-oxo-azatricyclo[7.2.0.03,8]undec-2-ene-2-carboxylate
(14). To a solution of 13 (1.63 g, 3.6 mmol) in THF (30 mL) was
added AcOH (830 mL) followed by Bu4NF (1 M in THF, 11 mL). After
stirring at rt for 30 min, the reaction mixture was partitioned be-
tween EtOAc (100 mL) and satd aq NaHCO3 (50 mL). The organic
layer was washed with satd aq NH4Cl (50 mL), dried (Na2SO4), and
concentrated affording 14 as white crystals (1.34 g, 98%); mp 78–
85 ꢁC; dH 1.27–1.51 (2H, m), 1.63–1.90 (3H, m), 2.09 (1H, m), 3.23–
3.32 (4H, m), 3.58 (1H, m), 3.83 (1H, m), 4.51 (1H, m), 4.60 (1H, m),
4.70 (1H, m), 4.82 (1H, m), 4.95 (1H, m), 5.29 (1H, dq, J 10.5, 1.4 Hz,),
5.41 (1H, dq, J 17.1, 1.5 Hz), 5.97 (1H, m); dC 20.0, 30.1, 32.4, 43.5,
52.4, 52.6, 56.0, 65.5 (q, J 32 Hz), 66.0, 72.3,119.0,124.5 (q, J 282 Hz),
125.8, 131.3, 149.0, 160.7, 173.5; dF ꢀ78.8 (d, J 6.7 Hz); m/z (FAB) 376
(75, MHþ).
4.1.12. (3S,4R)-4-[(1R,3S)-3-Methoxy-2-oxo-cyclohexyl]-3-[1-(S)-tri-
methylsilyloxy-2,2,2-trifluoroethyl]-2-azetidinone (11). To
a cold
(ꢀ60 ꢁC) solution of (S)-6-methoxy-1-(trimethylsilyloxy)cyclohex-
1-ene (2.70 g, 13.5 mmol) in THF (30 mL) was added dropwise MeLi
(1.5 M in Et2O, 8.5 mL) over 20 min. After stirring for 30 min at 0 ꢁC,
the lithium enolate was transferred via a cannula to a cold (ꢀ78 ꢁC)
solution of 10 (2.40 g, 8.0 mmol) in THF (15 mL). The reaction
mixture was left to stir at this temperature for 1 h then quenched
with satd aq NH4Cl (15 mL). The mixture was partitioned between
EtOAc (30 mL) and H2O (30 mL), and the organic layer was dried
(Na2SO4) and concentrated. The excess of (S)-2-methoxy-cyclo-
hexanone was distilled off on Kugelrohr (70 ꢁC/0.1 mbar). The
crude containing the diastereomers in a ratio of 82:18 was purified
by column chromatography on silica gel (EtOAc/hexane 1:1)
affording pure product 11 as white crystals (2.12 g, 72%). dH 0.19
(9H, s), 1.53–1.71 (3H, m), 1.97–2.10 (2H, m), 2.25 (1H, m), 3.10 (1H,
m), 3.25 (1H, t, J 2.4 Hz), 3.29 (3H, s), 3.59 (1H, t, J 3.0 Hz), 4.34 (1H,
m), 4.40 (1H, dq, J 7.3, 1.5 Hz), 5.81 (1H, br s); dC ꢀ0.2, 18.9, 27.2,
33.6, 46.6, 46.7, 52.3, 56.9, 67.2 (q, J 33 Hz), 83.9, 124.4 (q, J 283 Hz),
166.0, 213.4; dF ꢀ78.3 (d, J 8.0 Hz); HRMS (ESI): MHþ, found
368.1514. C15H25F3NO4Si requires 368.1505.
4.1.16. Sodium (4S,8S,9R,10S)-4-methoxy-10-[1-(S)-hydroxy-2,2,2-
trifluoroethyl]-11-oxo-azatricyclo[7.2.0.03,8]undec-2-ene-2-carboxyl-
ate (1). To a solution of 14 (940 mg, 2.5 mmol) in THF (8 mL) was
added a solution of Pd(PPh3)4 (72 mg, 0.06 mmol) and PPh3 (65 mg,
0.25 mmol) in THF (8 mL) followed by sodium 2-ethylhexanoate
(0.21 M, 11.9 mL, 2.5 mmol). The reaction mixture was left to stir at
rt for 2 h. The precipitate was filtered using a DuraporeÒ HV filter
(0.22
white powder (410 mg, 37%). nmax(KBr) 3388 (br), 2938, 1768, 1606,
1406, 1273, 1256, 1178, 1162, 1126, 1089 cmꢀ1
dH (DMSO-d6) 1.14–
m) and washed with THF (10 mL) to afford pure 1 as an off
;
1.39 (2H, m), 1.47–1.74 (3H, m), 1.84 (1H, m), 2.89 (1H, m), 3.10 (3H,
s), 3.41 (1H, t, J 3.3 Hz), 4.11 (1H, dd, J 10.3, 3.1 Hz), 4.40 (1H, m), 5.11
(1H, t, J 2.8 Hz), 7.05 (1H, br s); dC (DMSO-d6) 21.2, 30.5, 32.6, 42.8,
52.5, 52.6, 55.7, 66.0 (q, J 30.4 Hz), 72.7, 126.2 (q, J 283 Hz), 135.6,
135.7, 165.0, 173.5; dF (DMSO-d6) ꢀ76.2 (d, J 7.5 Hz). HRMS (ESI):
MHþ, found 358.0854. C14H16F3NNaO5 requires 358.0878.
4.1.13. (3S,4R)-1-Allyl
oxalyl-4-[(1R,3S)-3-methoxy-2-oxo-cyclo-
hexyl]-3-[1-(S)-trimethylsilyloxy-2,2,2-trifluoroethyl]-2-azetidinone
(12). To a cold (0 ꢁC) solution of 11 (1.85 g, 5.08 mmol) in CH2Cl2
(15 mL) was added allyl oxalyl chloride (0.86 mL, 7.1 mmol) fol-
lowed by Et3N (1 mL, 7.6 mmol) over 10 min. The mixture was
stirred at 0–5 ꢁC for 30 min, then partitioned between H2O (50 mL)
and CH2Cl2 (50 mL). The organic layer was washed with satd aq
NaHCO3 (30 mL), brine (30 mL), dried (Na2SO4), and concentrated.
The residue was rapidly purified by column chromatography on
silica gel (hexane/EtOAc 4:1) affording 12 as light yellowish crystals
(2.30 g, 94.6%); mp 44–50 ꢁC; dH 0.16 (9H, s), 1.39 (1H, m), 1.70 (2H,
m), 2.06 (2H, m), 2.23 (1H, m), 3.22 (3H, s), 3.53 (1H, m), 3.86 (1H,
m), 3.97 (1H, dt, J 13.2, 4.4 Hz), 4.48 (2H, m), 4.79 (2H, m), 5.31 (1H,
m), 5.40 (1H, m), 5.95 (1H, m); dC ꢀ0.5, 19.4, 31.0, 33.7, 43.7, 52.1,
53.6, 56.9, 67.1, 67.3 (q, J 33 Hz), 84.1,119.8, 122.9 (q, J 283 Hz),130.3,
155.7, 159.4, 163.1, 212.2; dF ꢀ77.5 (d, J 6.1 Hz). HRMS (ESI): MHþ,
found 480.1657. C20H29F3NO7Si requires 480.1665.
4.1.17. Allyl (4S,8S,9R)-4-methoxy-10-(E)-2,2,2-trifluoroethylidene-
11-oxo-azatricyclo[7.2.0.03,8]undec-2-ene-2-carboxylate
(15). To
a cold (0 ꢁC) solution of 14 (250 mg, 0.67 mmol) in CH2Cl2 (10 mL)
was added PPh3 (175 mg, 0.67 mmol) and diethyl azodicarboxylate
(DEAD, 117 mg, 0.67 mmol). After stirring at rt for 30 min, the re-
action mixture was concentrated and the residue was purified by
column chromatography on silica gel eluting with CH2Cl2 affording
15 as light yellowish oil (120 mg, 50%), which crystallized upon
standing. dH 1.16 (1H, m), 1.39–1.44 (2H, m), 1.84 (2H, m), 2.08 (1H,
m), 3.27 (3H, s), 3.37 (1H, m), 4.72 (1H, m), 4.83 (1H, m), 4.89 (1H,
m), 4.99 (1H, m), 5.29 (1H, m), 5.44 (1H, m), 5.97 (1H, m), 6.35 (1H,
dq, J 7.6, 1.7 Hz); dC 19.9, 30.5, 32.8, 45.4, 56.2, 62.0, 65.9, 72.5, 115.6
(q, J 36 Hz), 119.0, 121.8 (q, J 271 Hz), 126.2, 131.2, 147.7 (q, J 5 Hz),
149.8, 160.3, 166.8; dF ꢀ62.3 (d, J 7.9 Hz); HRMS (ESI): MHþ, found
358.1273. C17H19F3NO4 requires 358.1266.
4.1.14. Allyl
(4S,8S,9R,10S)-4-methoxy-10-[1-(S)-trimethylsilyloxy-
4.1.18. Sodium (4S,8S,9R)-4-methoxy-10-(E)-2,2,2-trifluoroethylidene-
11-oxo-azatricyclo[7.2.0.03,8]undec-2-ene-2-carboxylate(2). To a solu-
tion of 15 (100 mg, 0.28 mmol) in THF (2 mL) was added a solution of
2,2,2-trifluoroethyl]-11-oxo-azatricyclo[7.2.0.03,8]undec-2-ene-2-car-
boxylate (13). A solution of 12 (2.30 g, 4.80 mmol) and

B. Mohar et al. / Tetrahedron 66 (2010) 4144–4149
4149
Synthesis, Application and Future Directions; Ramachandran, P. V., Ed.; American
Chemical Society: Washington, DC, 2000; pp 255–269; (c) Mikami, K.; Itoh, Y.;
Yamanaka, M. Chem. Rev. 2004, 104, 1–16.
Pd(PPh3)4 (8 mg, 0.007 mmol) and PPh3 (7 mg, 0.028 mmol) in
CH2Cl2 (8 mL) followed by sodium 2-ethylhexanoate (46 mg,
0.28 mmol) in THF (1 mL). The reaction mixture was left to stir at rt
for 3 h. The precipitate was filtered using a DuraporeÒ HV filter
ˇ
ˇ
ˇ
6. Plantan, I.; Selic, L.; Mesar, T.; Stefanic Anderluh, P.; Oblak, M.; Prezelj, A.; Hesse, L.;
ˇ ˇ
Andrejasic, M.; Vilar, M.; Turk, D.; Kocijan, A.; Prevec, T.; Vilfan, G.; Kocjan, D.;
ꢀ
ˇ
Copar, A.; Urleb, U.; Solmajer, T. J. Med. Chem. 2007, 50, 4113–4121.
7. Rossi, T.; Marchioro, C.; Paio, A.; Thomas, R. J.; Zarantonello, P. J. Org. Chem. 1997, 62,
1653–1661.
(0.22 m) and recrystallized from THF to afford pure 2 as yellowish
crystals (43 mg, 45%). dH (D2O) 1.16 (1H, m), 1.48–1.69 (3H, m), 1.85
(1H, m), 2.02 (1H, m), 3.25–3.34 (4H, m), 4.96–5.03 (2H, m), 6.58 (1H,
dq, J 7.5, 1.5 Hz); dC (D2O) 22.8, 33.0, 34.8, 47.5, 58.2, 65.0, 76.4, 118.9
(q, J 35 Hz), 125.0 (q, J 266 Hz), 135.0, 143.8, 149.6 (q, J 5 Hz), 170.8,
173.4; dF (DMSO-d6) ꢀ56.1 (d, J 8.2 Hz). HRMS (ESI): MHþ, found
340.0766. C14H14F3NNaO4 requires 340.0773.
8. Antolini, L.; Forni, A.; Davoli, P.; Moretti, I.; Prati, F. Tetrahedron: Asymmetry 1998, 9,
285–292.
9. (a) Sayo, N.; Saito, T.; Okeda, Y.; Nagashima, H.; Kumobayashi, H. EP0369691, 1990.
(b) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.;
Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H. J. Am. Chem. Soc.
1989, 111, 9134–9135.
10. For [Ru(p-cym)(S,S)-C4F9SO2DPEN]-catalyzed asymmetric transfer hydrogenation
of a
b-keto-a-amino ester via DKR, see: Mohar, B.; Valleix, A.; Desmurs, J.-R.; Fe-
Acknowledgements
lemez, M.; Wagner, A.; Mioskowski, C. Chem. Commun. 2001, 2572–2573.
ˇ
11. (a) Sterk, D.; Stephan, M. S.; Mohar, B. Tetrahedron: Asymmetry 2002, 13, 2605–
ˇ
2608; (b) Sterk, D.; Stephan, M. S.; Mohar, B. Org. Lett. 2006, 8, 5935–5938.
ˇ
ˇ
ˇ
We thank Dr. Anton Stimac, Urban Svajger, and Damjan Sterk for
their partial assistance with this work, Prof. Ivan Leban (University of
Ljubljana) for the X-ray structure determination, and Dr. Alenka
12. The syn/anti configurations for 4 were assigned based on the separate transformation
of the stereoisomers into their corresponding (E)- and (Z)-olefins by stereoselective
dehydration under Mitsunobu’s conditions. For this, see Supporting data.
13. A series of [Ru(h
6-arene)(S,S)–(CH2)5NSO2DPEN] was screened with a [substrate
ꢀ
ˇ
Tomazic for discussion. Financial support of Lek Pharmaceuticals d.d.
and of the Ministry of Higher Education, Science, and Technology of
the Republic of Slovenia (Grant No. J1-9806), are kindlyacknowledged.
3]¼1 M leading to the following syn/anti ratios:
h
6-arene¼ benzene (68:32), p-
cymene (43:57), mesitylene (68:32), 1,3,5-Et3C6H3 (74:26). Noteworthy, NaBH4 in
MeOH at 0 ꢁC led to syn/anti ratio of 13:87. For this, see Supporting data.
14. Asymmetric transfer hydrogenation under DKR of ethyl 2-benzamidomethyl-4-
fluoro-3-oxo-butanoate using [Ru(1,3,5-Et3C6H3)(S,S)-Me2NSO2DPEN] afforded the
Supplementary data
corresponding syn-b-hydroxy ester with 96% ee and a dr of 83:17. For this, see: (a)
Plantan, I.; Stephan, M.; Urleb, U.; Mohar, B. Tetrahedron Lett. 2009, 50, 2676–2677;
ꢀ
(b) Plantan, I.; Prezelj, A.; Urleb, U.; Mohar, B.; Stephan, M. EP158454, 2008.
Experimental procedures, 1H, 13C NMR spectra of the new
compounds and X-ray crystallographic data (cif file) are provided.
Supplementary data associated with this article can be found in the
online version, doi:10.1016/j.tet.2010.03.104. These data include
MOL files and InChIKeys of the most important compounds de-
scribed in this article.
15. Kobayashi, S.; Iimori, T.; Izawa, T.; Ohno, M. J. Am. Chem. Soc. 1981, 103, 2406–2408.
16. Greene, T. W.; Wuts, G. M. Protective Groups in Organic Synthesis; John Wiley &
Sons: New York, NY, 1999.
17. We also failed to acetoxylate the new N-TBDMS-protected azetidinone 7 following
standard literature procedures. For adopted conditions, see: (a) Murahashi, S.-I.;
Naota, T.; Kuwabara, T.; Saito, T.; Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc.
1990, 112, 7820–7822; (b) Murahashi, S.-I.; Saito, T.; Naota, T.; Kumobayashi, H.;
Akutagawa, S. Tetrahedron Lett. 1991, 32, 5991–5994.
18. According to literature, the acetoxylation of 3-(1-hydroxyethyl)-2-azetidinone
using AcOOH/OsCl3/AcONa led to the corresponding trans/cis-4-acetoxy-azetidi-
none in a dr of ca. 4:1, while the RuCl3-catalyzed oxidation gave a complex mix-
ture. For this, see: Murahashi, S.-I.; Saito, T.; Naota, T.; Kumobayashi, H.;
Akutagawa, S. Tetrahedron Lett. 1991, 32, 2145–2148.
19. CCDC 751242 contains the supplementary crystallographic data for this pa-
per. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html or from the Cambridge Crystallographic Data Centre (12,
Union Road, Cambridge CB2 1EZ, UK; fax: þ44 1223 336 033, or deposit@
ccdc.cam.ac.uk).
References and notes
1. (a) Bentley, P. H.; Ponsford, R. Recent Advances in the Chemistry of Anti-infective
Agents; The Royal Society of Chemistry: Cambridge, 1992; (b) Massova, I.; Mo-
bashery, S. Acc. Chem. Res. 1997, 30, 162–168; (c) Bonfiglio, G.; Russo, G.; Nicoletti,
G. Expert Opin. Invest. Drugs 2002, 11, 529–544; (d) Deshmukh, A. R. A. S.; Bhawal,
B. M.; Krishnaswamy, D.; Govande, V. V.; Shinkre, B. A.; Jayanthi, A. Curr. Med.
Chem. 2004, 11, 1889–1920; (e) Yoneyama, H.; Katsumata, R. Biosci. Biotechnol.
Biochem. 2006, 70, 1060–1075.
20. The displacement of the acetoxy group from (10R,3R,4R)-4-acetoxy-3-[10-(tert-
butyldimethylsilyloxy)ethyl]-2-azetidinone using O-TMS-enol ether or metal (Mg,
Zn, Zr, Sn) enolates of (S)-2-methoxycyclohexanone has been shown to be a rea-
sonably stereoselective CꢀC coupling reaction. For examples of this, see: (a) Ref. 7;
(b) Matsumoto, T.; Murayama, T.; Mitsuhashi, S.; Miura, T. Tetrahedron Lett. 1999,
40, 5043–5046; (c) Ghiron, C.; Piga, E.; Rossi, T.; Tamburini, B.; Thomas, R. J. Tet-
rahedron Lett. 1996, 37, 3891–3894; (d) Kennedy, G.; Rossi, T.; Tamburini, B. Tet-
rahedron Lett. 1996, 37, 7441–7444; (e) Giacobbe, S. A.; Rossi, T. Tetrahedron:
Asymmetry 1996, 7, 3079–3082.
21. (a) Ernest, I.; Gosteli, J.; Woodward, R. B. J. Am. Chem. Soc. 1979, 101, 6301–6305; (b)
Perrone, E.; Alpegiani, M.; Bedeschi, A.; Giudici, F.; Franceschi, G. Tetrahedron Lett.
1984, 25, 2399–2402; (c) Yoshida, A.; Tajima, Y.; Takeda, N.; Oida, S. Tetrahedron
Lett. 1984, 25, 2793–2796.
2. (a) Andreotti, D.; Rossi, T.; Gaviraghi, G.; Donati, D.; Marchioro, C.; Di Modugno, E.;
Perboni, A. Bioorg.Med. Chem. Lett.1996,6, 491–496;(b)Perboni,A.;Rossi,T.;Gaviraghi,
G.; Ursini, A.; Tarzia, G. WO9203437, 1992. (c) Tamburini, B.; Perboni, A.; Rossi, T.;
Donati, D.; Andreotti, D.; Gaviraghi, G.; Carlesso, R.; Bismara, C. EP0416953, 1991.
3. (a) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Poletti, L.; Raimondi, L.;
Perboni, A. Eur. J. Org. Chem. 1999, 11, 3067–3072; (b) Iso, Y.; Nishitani, Y. Hetero-
cycles 1998, 48, 2287–2308; (c) Biondi, S.; Piga, E.; Rossi, T.; Vigelli, G. Bioorg. Med.
Chem. Lett. 1997, 7, 2061–2066; (d) Hanessian, S.; Griffin, A. M.; Rozema, M. J. Bi-
oorg. Med. Chem. Lett. 1997, 7, 1857–1862; (e) Rossi, T. Soc. Chim. Ital. 1997, 1, 161–
186; (f) Jackson, P. M.; Roberts, S. M.; Davalli, S.; Donati, D.; Marchioro, C.; Perboni,
A.; Proviera, S.; Rossi, D. J. Chem. Soc., Perkin Trans. 1 1996, 2029–2039; (g) Ha-
nessian, R.; Rozema, M. J. J. Am. Chem. Soc. 1996, 118, 9884–9891; (h) Gaviraghi, G.
Eur. J. Med. Chem. 1995, 30, 467–478.
ˇ
22. Jeffrey, P. D.; McCombie, S. W. J. Org. Chem. 1982, 47, 587–590.
23. (a) Bo¨hme, H.; Eiden, F. DE1025883, 1958. (b) Bo¨hme, H.; Broese, R.; Eiden, F. Chem.
Ber. 1959, 92, 1599–1607.
4. Vilar, M.; Galleni, M.; Solmajer, T.; Turk, B.; Frere, J. M.; Matagne, A. Antimicrob.
Agents Chemother. 2001, 45, 2215–2223.
5. (a) Enantiocontrolled Synthesis of Fluoro-organic Compounds; Soloshonok, V. A., Ed.;
Wiley: Chichester, UK, 1999; (b) Mikami, K. In Asymmetric Fluoroorganic Chemistry:
24. Phillips, B.; Starcher, P. S.; Ash, B. D. J. Org. Chem. 1959, 23, 1823–1826.