Preparation of the key intermediate in the synthesis of GV143253A: The anti-MRSA/E injectable trinem

Article abstract of DOI:10.1021/op020024l

GV143253A is a broad-spectrum injectable β-lactam belonging to the class of trinem antibiotics. A key intermediate (3S,4R)-3-[(1R)-1-(tert-butyldimethyl- silyloxy)ethyl]-4-[-(6′R)-2′-[(E)-(pyrid-4yl)methylene]- 1′-oxocyclohex-6′-yl]azetidin-2-one (10) was identified and synthesized via different enolate coupling approaches, using enol ether, lithium, sodium, magnesium, tin, zinc, zirconium, and titanium enolates. Among these approaches, the synthesis of (3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[-(6′R)- 2′-[(E)-(pyrid-4yl)-methylene]-1′-oxocyclohex-6′-yl] azetidin-2-one (10) via a titanium enolate offered advantages in terms of greater diastereoselectivity, higher yield, robustness, and isolation of intermediates and was superior to the method previously used for preparing large quantities of drug substance for early development studies.

Full text of DOI:10.1021/op020024l

Organic Process Research & Development 2002, 6, 597−605
Preparation of the Key Intermediate in the Synthesis of GV143253A: The
Anti-MRSA/E Injectable Trinem
Paolo Maragni, Mario Mattioli, Roberta Pachera,* Alcide Perboni, and Bruno Tamburini
Synthetic Chemistry Department, GlaxoSmithKline SpA, Via Fleming 4, 37135, Verona, Italy
Abstract:
GV143253A is a broad-spectrum injectable â-lactam belonging
to the class of trinem antibiotics. A key intermediate (3S,4R)-
3-[(1R)-1-(tert-butyldimethyl- silyloxy)ethyl]-4-[-(6′R)-2′-[(E)-
(pyrid-4yl)methylene]-1′-oxocyclohex-6′-yl]azetidin-2-one (10)
was identified and synthesized via different enolate coupling
approaches, using enol ether, lithium, sodium, magnesium, tin,
zinc, zirconium, and titanium enolates. Among these ap-
proaches, the synthesis of (3S,4R)-3-[(1R)-1-(tert-butyldimeth-
Figure 1.
ylsilyloxy)ethyl]-4-[-(6′R)-2′-[(E)-(pyrid-4yl)-methylene]-1′-oxo-
and transformation of a transient phosphorane intermediate
was used to selectively protect the nitrogen of GV97322X
and to perform the subsequent cyclization (Scheme 1).
This synthetic approach was not ideal for further scale-
up, as all of the intermediates possessed physical properties
that were unsuitable for purification using standard crystal-
lisation techniques.
cyclohex-6′-yl]azetidin-2-one (10) via a titanium enolate offered
advantages in terms of greater diastereoselectivity, higher yield,
robustness, and isolation of intermediates and was superior to
the method previously used for preparing large quantities of
drug substance for early development studies.
An alternative convergent route was developed by the
Chemical Development group which identified (3S,4R)-3-
[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[-(6′R)-2′-[(E)-
(pyrid-4yl)methylene]-1′-oxocyclohex-6′-yl]azetidin-2-one,
‘â-enone- azetidinone’ 2 (Figure 2) as a pivotal synthetic
intermediate.
Introduction
In recent years, bacteria have enhanced their mechanism
of resistance against the most common antibacterial drugs.
In particular, methicillin-resistant staphylococci represent one
of the most challenging and threatening diseases globally.
Although confined to hospitals, it represents an important
clinical problem, with up to 30% incidence in some U.S.
hospitals and an average of 13% in Europe. GV143253A 1
(Figure 1) is a broad-spectrum injectable trinem antibiotic
with satisfactory solubility and no nephrotoxic effects. The
spectrum and activity are similar to those of the carbapenems.
Activity against Pseudomonas is lost, but unlike carba-
penems, GV143253A is active against MRSA/E pathogens.
Pockets of resistance to the best treatment for MRSA (the
glycopeptide vancomycin) have recently been reported, and
no alternatives are currently available; hence, GV143253A
represents an opportunity to become a first-line replacement,
allowing the valuable glyclopeptide class held back as
appropriate.
Figure 2.
Much effort was devoted to obtaining this intermediate
in a single step starting from the commercially available
4-acetoxyazetidinone 3 and 2-[(E)-pyrid-4-yl)methylene]-
cyclohexanone, “Pyridylenone” 4 (Scheme 2), thus allowing
a convergent synthetic route.
Background
Results and Discussion
The original synthesis of GV143253A was a linear
process that started with the synthesis of the chiral intermedi-
ate GV97322X. The whole process required a multistep
approach starting from the commercially available 4-ac-
etoxyazetidinone. Introduction of the side-chain on the
cyclohexanone moiety was then carried out, and synthesis
“Pyridylenone” 4 was easily prepared following a litera-
ture procedure1 starting from the commercial pyridine
4-carboxaldehyde 5 and 1-morpholine-1-cyclohexene 6 as
depicted in Scheme 3. The mixture of the two diastereoiso-
mers 7 (syn/anti 15/85) was converted to the desired inter-
mediate and isolated as a salt of trifluoroacetic acid 8.2
* Correspondence author. Roberta Pachera, GlaxoSmithKline, Synthetic
Chemistry Department, Via Fleming 4, 37135 Verona, Italy. Telephone: +39
0459219814. E-mail: rp43009@gsk.com. Fax: +39 0459218117.
(1) Sam, J.; Aparajithan, K. J. Pharm. Sci. 1967, 56, 664.
10.1021/op020024l CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/18/2002
Vol. 6, No. 5, 2002 / Organic Process Research & Development
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597

Scheme 1. Original synthesis
Scheme 2
Scheme 3. “Pyridylenone” synthesis
In a previous study3 it was shown that a general approach
to the synthesis of compounds such as 2 may be adopted by
reacting the commercially available chiral “4-acetoxyazeti-
dinone” 3 with suitably activated ketones. The first coupling
(2) Two minor byproducts were isolated.
approach (Scheme 4) was carried out by activating the
pyridylenone 4 as a trimethylsilyl enol ether derivative 9 and
reacting this with 3 under trimethylsilyl triflate catalysis. In
this case the reaction afforded a mixture of R- and â-isomers
10 (R/â:50/50) in good yield.
(3) Barrett, A. G. M.; Quayle, P. J. Chem. Soc., Chem. Commun. 1981, 1076.
598
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Scheme 4. Initial approach via the silyl enol ether
The two isomers were isolated from the reaction mixture
by precipitating them as the L-(+)-tartaric acid salts (R/â in
a 1/1 ratio), allowing a first purification of the diasteroisomers
11 from the complex reaction mixture.
The whole process (Stage 1), depicted in Scheme 4,
consisted of six steps for the isolation of the â-isomer.
(1) silyl enol ether formation
(2) coupling
A breakthrough in this approach was achieved when it
was found that oxamic acid in IPA was able to selectively
precipitate the R-isomer as oxamate 13, leaving the desired
â-isomer 14 in the mother liquors and allowing its separation
from the diasteromeric mixture 12. The pure â-isomer was
further precipitated as the oxamate from ethyl acetate,
affording the desired compound as a yellow solid 15.
Finally, it was found that the R-oxamate 13 could also
be isomerised into a 60/40 R/â mixture, allowing a potential
recycling of the R-isomer.
(3) isolation of the R/â isomers as a 1/1 mixture of their L-tartrate salts
(4) separation of the R isomer from the R/â mixture
(5) isolation of the pure â isomer as oxamate
(6) isolation of the â-isomer
This nonstereoselective process was scaled up to a 200-L
pilot-plant vessel achieving a 30% yield of the â-isomer 2
from 4-acetoxyazetidinone 3 without recycling.
Although this procedure allowed the preparation of our
target key intermediate in a good yield and within the
deadline to produce the required amount of GV143253A for
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599

Table 1
entry method (equiv) GW395686X (equiv)
base (equiv)
DIPEAf (2.6)
DIPEA (2.9)
DIPEA (2.9)
1-ethylpiperidine (2.4)
1-ethylpiperidine (1.8)
LHMDS (2 + 1 equiv)
LHMDS (1.8)
Lewis acid (°C)
conditions
-20 f 0
-20 f 0 f 20
-20 f 0 f reflux
-20 f 0 f 20
-20 f 0 f 20
-20 f 0 f 20
-5 f 0 f 20
R/â
yield
1
2
3
4
5
6
7
Aa
Bb
Bb
Cc
Bb
Dd
E
2
2
2
2
1.3
2
1.4
SnCl4 (5)
68/32 15%
70/30 20%
SnCl4 (1 + 4)
SnCl4 (1 + 4)
Sn(OTf)2 (2.2)
Sn(OTf)2 (2.3)
ZnBr2 (2)
-
-
-
-
-
-
40/60 10%
60/40 20%
ClZr(O-n-Bu)3(1.8)
a Method A: base added to the mixture of GW395686X, GR91990X (1 equiv), and Lewis acid (5 equiv). b Method B: a mixture of GR91990X (1 equiv) and Lewis
acid (1 equiv) added to a solution of GW395686X (2 equiv) and Lewis acid (4 equiv) and base (2.6-2.9 equiv). c Method C: GR91990X (1 equiv) added to a solution
of GW395686X and Lewis acid and base. d Method D: base (1 equiv) and GR91990X added to the mixture of GW395686X and Lewis acid and base (2 equiv).
e Method E: LHMDS added to GW395686X after transmetalation with ClZr(O-n-Bu)3, GR91990X then added. f DIPEA ) N,N-Diisopropylethylamine.
Scheme 5. Enolates approach
Scheme 6. Tin enolates
toxicology studies, a more streamlined process was inves-
tigated. The metal enolate chemistry of pyridylenone 4 was
studied to find an efficient and stereoselective reaction
(Scheme 5).
reaction; hence, enolates prepared from metal enolates whose
salts are generally used as Lewis acids in enolate coupling
reactions were studied. These metal enolates were generated
following either a Mukaiyama-like procedure or a trans-
metalation protocol from the corresponding lithium enolates.
Tin, zinc, zirconium, and titanium enolates were investigated.
In the tin enolate case, the enolisation of pyridylenone 4 was
carried out in the presence of a tertiary amine and a tin(IV)5
or tin(II)6 Lewis acid (Scheme 6). As clearly indicated in
Table 1, when reaction occurred, the yields were low, and
the R-isomer was generally the preferred one. Different
addition orders were also tried to better activate the 4-acet-
oxyazetidinone, with no significant success (see entries 1-5
in Table 1).
The preparation of the zinc enolate7 (entry 6, Table 1)
was carried out by transmetalation of the lithium enolate with
zinc bromide at 0 °C. Less than a 10% yield was obtained
with a slight preference for the â-isomer. Similar results were
obtained with the tri-n-butoxyzirconium enolate (entry 7,
Table 1) generated by transmetalation from lithium enolates.
However, when we focused our attention on other zirconium
enolates, it was found that zirconium (IV) tert-butoxide8 was
The study of the reactivity of the enolates started with
the evaluation of the reactivity of the acetoxyazetidinone 3
and the lithium and sodium enolates of pyridylenone 4.
Following the generation of the enolates in THF using
LiHMDS, LDA, or solid NaHMDS, 4-acetoxyazetidinone 3
was added. Different equivalents, volumes, and temperatures
were tried, resulting in no more than a 30% yield with an
R/â ratio of approximately 1/1. This was probably due to
the short lifetime of 3 under such basic reaction conditions.
To increase the yields and to prevent degradation of 3, the
reactivity of a softer counterion was investigated. Magnesium
enolates were generated according to two different protocols4
by reacting pyridylenone 4 with either Cl-Mg-N(i-Pr)2 or
Br-Mg-N(i-Pr)2 in THF at +5 °C or by a Mg/Li exchange
with MgBr2 on the lithium enolate formed with LiHMDS in
THF.
Both of these approaches gave very low reaction yields
(10%-15%) with a diastereoselectivity in favour of the
R-isomer (R/â ) 3/1). In addition a large amount of
unreacted pyridylenone 4 was recovered.
Attempts were then aimed at increasing both the reactivity
of acetoxyazetidinone 3 and the â-diasteroselectivity of the
(5) Evans, D. A. J. Am. Chem. Soc. 1991, 113, 1047.
(6) Mukaiyama, T.; Stevens, R. W. Chem. Lett. 1982, 353.
(7) Kennedy, G.; Rossi, T.; Tamburini, B. Tetrahedron Lett. 1996, 37, 7441.
(8) Shibasaki, M.; Kirio, Y.; Sasai, H. J. Org. Chem. 1990, 55, 5306.
(4) Hobayashi, K.; Takabatake, H. Bull. Chem. Soc. Jpn. 1997, 70, 1697.
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Table 2a
entry
Ti-complex
MHMDS
% yield
analytical data (by HPLC)
notes
1
2
3
4
5
A
B
C
C
D
Na
Na
Na
Li
72b
â/R ratio ) 49/51 (44/56 after work-up)
â/R ratio ) 20/80
-
-
-
18c
No react.
No react.
40c
-
-
transmetalation at -25 °C f r.t.
Li
â/R ratio ) 48/52 (after 50 min)
â/R ratio ) 25/75 (after 2.5 h)
â/R ratio ) 42/58
6
7
E
F
Li
Li
45c
45c
â/R ratio ) 62/38 (after 10 min)
â/R ratio ) 57/43 (after 75 min)
-
transmetalation at -25 °C f rt
8
9
G
H
Li
Na
0
n.d.
LiHMDS 1.4 equiv Ti(OMe)4 insoluble
TiCl4‚THF complex very insoluble
â/R ratio ) 55/45 (after 30 min)
a Typical procedure: Lithium enolate was generated at 0 °C; transmetalation and quenching of the titanium enolate with 3 were carried out at rt GR91990X (1
c
equiv), GW395686X (1.4 equiv), Li(Na)HMDS (1.8 equiv), ClTi(OR)2X (1.8 equiv). bYield calculated on the isolated product (by flash chromatography). Yield in
solution estimated by comparing %a/a of HPLC peaks.
Scheme 7
Scheme 8
Scheme 9
a mild basic reagent that could be utilized in aldol reactions.
It was described that treatment of Zr(O-t-Bu)4 with some
carbonyl compounds resulted in the direct formation of zirco-
nium enolates and tert-butyl alcohol. These enolates were
then reacted with aldehydes in cross and intramolecular aldol
reactions. In our work we were attempting to directly gener-
ate the tri-tert-butoxyzirconium enolate on the pyridylenone
4 and to carry out the coupling with 3 as the electrophile.
Contrary to the results obtained with ClZr(O-n-Bu)3, Zr(IV)
tert-butoxide gave the desired compound in medium-to-good
yield but with a prevalence of the R-isomer (Scheme 7).
On the basis of some literature9 findings showing the
titanium enolate of cyclohexanone reacting with aldehydes
syn-selectively, a more in-depth study was carried out on
titanium enolates. After deprotonation of 4 with LiHMDS
and transmetalation with chlorotitanium triisopropoxide10 at
ambient temperature, the azetidinone 3 was added (Scheme
8). The coupling gave both a promising yield (60%) and
â-selectivity (â/R ) 2/1).
was carried out. When not commercially available, the
titanium complexes were prepared11 via ligand exchange.
These complexes (Scheme 9) were then reacted in situ with
the Li/Na enolates of compound 4, giving the desired
titanium enolates which were finally treated with acetoxyaze-
tidinone 3 to afford the desired compound as a mixture of â
+ R isomers.
Results are reported in Table 2.
None of the reported enolates gave an enrichment in the
â-isomer; therefore, a standard procedure with ClTi(i-OPr)3
was developed by optimizing the equivalents of base and
ClTi(i-OPr)3. The resulting reaction protocol was set up,
Further work to increase the â/R stereoselectivity by
reacting 3 with titanium enolates carrying different ligands
(9) Reetz, M. T.; Peter, R. Tetrahedron Lett. 1981, 22, 4691.
(10) Wollmann, T.; Gerlach, U. In Recent AdVances in the Chemistry of Anti-
infectiVe Agents; Bentley, P. H., Ed.; Royal Society of Chemistry:
Cambridge, U.K., 1993; p 50.
(11) (a) Hafner, A.; Duthaler, R. O. J. Am. Chem. Soc. 1992, 114, 2321. (b)
Mikami, K.; Matsukawa, S. J. Am. Chem. Soc. 1994, 116, 4077.
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601

Scheme 10. Stage 1 (Ti enolate approach)
Preparation of ‘Pyridylaldol’, GW401506X, 7. Pyri-
dine-4-carboxaldehyde 5 (48 g, 0.9 equiv, 450 mmol) was
added over 1.5 h to a solution of 1-morpholine-1-cyclohexene
(1 equiv, 84.46 g, 505 mmol) in toluene (85 mL) at 5 °C.
The solution was stirred for 1.5 h, and then 2 M H2SO4 (aq)
(2.2 equiv, 500 mL) was added dropwise in 1 h and the
mixture stirred at 15 °C for 30 min. The organic layer was
run off, and 32% NH3 (aq) was added at 15 °C until pH )
3.5. The mixture was seeded, and then further 32% NH3 (aq)
was added until pH ) 5. The mixture was seeded again,
stirred for 30 min, and then 32% NH3 (aq) was added until
pH ) 7.5. The suspension was stirred at rt for 30 min, then
filtered, washed with water (2 × 400 mL), and dried under
vacuum to give 7 as a white solid: yield 61%. H1 NMR
(CDCl3): 8.57 (2H, d), 7.26 (2H, d), 4.79 (1H, dd), 4.12
(1H, d), 2.59 (1H, m), 2.48 (1H, m), 2.36 (1H, m), 2.12 (1H,
m), 1.84 (1H, m), 1.5-1.8 (3H, m), 1.39 (1H, m).
2-[(E)-(Pyrid-4-yl)methylene]cyclohexanone Trifluoro-
acetic Acid Salt, 8. Triethylamine (3 equiv, 76 g, 753 mmol)
was added to a suspension of 7 (51 g, 251 mmol, 1 equiv)
in THF (200 mL) at reflux (ca. 69 °C), and then a solution
of acetic anhydride (51 mL, 2 equiv, 502 mmol) was added
dropwise in over 30 min.The mixture was stirred at reflux
(ca. 76 °C) for 1 h. The mixture was cooled to 10 °C, and
16% NaOH (aq) (140 mL) was added dropwise in 10 min.
Water (100 mL) and EtOAc (300 mL) were added, and the
resulting mixture was warmed to 25°. The organic layer was
washed with saturated NH4Cl (4 × 200 mL) and brine (200
mL) and then filtered through a silica pad, washing the silica
with EtOAc (2 × 200 mL). The solution obtained was
concentrated under vacuum to 50 mL. TFA (29 g, 251 mmol,
1 equiv) was added dropwise in over 30 min and then
cyclohexane in 30 min. The resulting suspension was stirred
for 1 h at 5 °C, filtered, washed with EtOAc/cyclohexane )
2/1 (2 × 70 mL), and dried under vacuum to give 8 as a
pale yellow solid: yield 64.7%. H1 NMR (CDCl3): 8.80 (2H,
d), 7.62 (2H, d), 7.38 (1H, m), 2.84 (2H, m), 2.62 (2H, t),
2.00 (2H, m), 1.86 (2H, m).
(3S,4R)-3(1′R)-1′-(tert-Butyldimethylsilyloxy)ethyl]4-
[-2′′-{(E)-(pyrid-4yl)methylene-l-oxocyclohex-6′′-yl]-azetidin-
2-one. 12. Triethylamine (6 equiv, 2.13 L, 15 mol) was added
to a suspension of 8 (758 g, 2.51 mol, 1 equiv), in acetonitrile
(6.06 L) at room-temperature resulting in complete dissolu-
tion. Trimethylsilyl chloride (3 equiv, 7.53 mol, 818 g) was
then added over 15 min. The mixture was stirred at 60 °C
for 2.5 h, cooled to 10 °C, and poured into a beaker
containing ethyl acetate (9 L) and NaHCO3 (5%, 3.64 L)
with stirring. The organic layer was washed with cold
saturated NH4Cl (2 × 7.5 L) and brine (2 × 7.5 L). The
organic phase was dried and concentrated at 40 °C in vacuo
to give a solution of 9 in ethyl acetate (1.29 L). This solution
was added to 3 (1 equiv, 2.50 mol, 720 g) dissolved in
acetonitrile (5.87 L); the solution was cooled to 15 °C, and
trimethylsilyl triflate (1 equiv, 2.50 mol, 550 g) was added
over 30 min, keeping the temperature at <-2 °C. Further
trimethylsilyl triflate (1 equiv, 2.50 mol, 550 g) was then
added dropwise over 2 h. The resulting solution was stirred
at 0 °C for l h and then poured into a mixture of cold
whereby pyridylenone 4 (1.3 equiv) was dissolved in dry
tetrahydrofuran (THF, 5 mL/g) and added dropwise over 30
min to potassium hexamethyldisilazide (0.5 M in toluene,
1.69 equiv) at 0-5 °C. The suspension was stirred at 5 °C
for 30 min and then treated with chlorotitaniumtrisisopro-
poxide (1.69 equiv) in THF (5 mL/g) over 2 min at 10-12
°C. The dark brown suspension was held at 15-20 °C for
45 min and then treated with 3 (33.8 g, 1 equiv) in one
portion. The dark solution was then stirred at 20-25 °C for
60 min. (Notes: â/R ratio in the range 2/1 to 3/1; solution
yield in the range 70-83% R + â isomers). The removal of
residual titanium complexes from the crude reaction mixture
and the isolation of the pure â-isomer was facilitated using
acetic acid at low temperature (0-5 °C) which prevented
the formation of an emulsion and allowed the â/R ratio to
remain stable at around 2/1. The final solution was washed
with aqueous 5% w/w NaHSO3. Finally, (R)-(-)-10-cam-
phorsulfonic acid was added to selectively precipitate (from
nBuOAc) the desired â-isomer from the R/â mixture, thus
allowing separation of the two isomers.
Stage 1 was therefore set as shown in Scheme 10,
achieving a 40% overall yield from 4-acetoxyazetidinone.
This process was successfully scaled up to a 5-L reactor.
Conclusions
A thorough investigation into the coupling between
4-acetoxyazetidinone 3 and pyridylenone 4 resulted in a
stereoselective reaction using the Ti enolate where the
maximum â/R ratio achievable was 2/1. The work-up was
optimised with the aim of preventing emulsions and remov-
ing titanium complexes. The desired â-enoneazetidinone was
isolated as the camphorsulfonate salt in a 40% overall yield
which was an improvement of 10% over the original silyl
enol ether approach and involved a much simplified isolation
procedure. The whole method was successfully scaled-up
to a 5-L reactor.
Experimental Section
Reagents were purchased from standard suppliers.
1H NMR spectra were recorded at 300 or 500 MHz in
CDCl3 or d6-DMSO and are reported in parts per million
downfield.
HPLC analyses were conducted using a 5 µ Hypersil BDS
C18 column, solvent system acetonitrile/buffer NH4H2PO4
(0.05 M) 60/40 (v/v), flow rate 1 mL/min and detection at
270 λ. Retention time of R-enoneazetidinone 13 10.1 min.
Retention time of â-enoneazetidinone 14 8.5 min.
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Vol. 6, No. 5, 2002 / Organic Process Research & Development

saturated NaHCO3 (4.9 L) and ethyl acetate (8.6 L). The
organic layer was washed with saturated NaHCO3 (3.8 L),
water (3 × 3.8 L), and brine (2 × 3.8 L). The organic phase
was dried and concentrated at 45 °C in vacuo to 1.97 L.
Isopropyl alcohol (2.58 L) and L-(+)-tartaric acid (0.5 equiv,
1.26 mol, 190 g) were then added to the concentrate. The
resulting solution was warmed to 75 °C, stirred for 1 h, and
then cooled to 2 °C for 1 h. The resulting yellow solid was
filtered and washed with ethyl acetate (1.63 L) to give the
tartrate salt 11 as a pale yellow solid; 711 g yield 90%. A
portion of 11 (0.31 mol, 180 g) was suspended in ethyl
acetate (900 mL), and an aqueous solution of NaHCO3 (5%,
900 mL) was added over 30 min. After stirring for 1 h the
two phases were separated, and the organic layer was washed
with a 5% NaHCO3 solution (450 mL) and water (450 mL),
filtered over Celite, and evaporated to dryness to afford
compound 12: 150 g, yield 93%. H1 NMR(CDCl3) 8.64 (2H,
d + d), 7.23 (2H, m), 6.32 (1H, bs), 5.69 (1H, bs), 4.32
(1H, m), 4.26-4.16 (1H, m), 3.69 (1H, dd), 3.06 (1H, bs),
3.02-2 99 (1H, m), 2.98 (1H, bs), 2.78-2.76 (1H, m), 2.70-
2.50 (1H, m), 2.45 (1H, m) 2.17 (1H, m), 1.99 (1H, m), 1.85
(1H, m), 1.65 (1H, m), 1.25 (3H, d), 0.88 (9H, s), 0.08 (6H,
s). Selectivity: 1:1 â/R.
A solution of oxamic acid (1 equiv, 0.29 mol, 25 g) in
methanol (6 L) was added in 20 min to a solution of 12 (1
equiv, 0.29 mol, 120 g) in IPA (6 L). After the mixture stirred
for 5 min, the methanol was removed under vacuum (T <
25 °C), and the residual suspension was cooled to 0 °C and
stirred for 1 h. The solid was filtered, washed with cold
2-propanol (0.2 L) and cold isopropyl ether (0.2 L) and dried
under vacuum to afford compound 13: 75 g, yield 51%. H1
NMR (DMSO): 8.60 (2H, d), 8.11 (1H, bs), 7.94 (1H, s),
7.38 (2H, d), 7.09 (1H, m), 4.06 (1H, m), 3.58 (1H, d′d),
2.90 (1H, m), 2.87 (1H, dd), 2.68 (1H, m), 2.62 (1H, m),
2.04 (1H, m), 1.82 (1H, m), 1.68-1.60 (1H, m), 1.12 (1H,
d), 0.84 (9H, s), 0.04 (3H, s), 0.02 (3H, s).
(3S,4R)-3-[(1′R)-1′-(tert-Butyldimethylsilyloxy)ethyl]-4-
[(6′′S)-2′′-[(E)-(pyrid-4-yl)methylene]-oxocyclohex-6′′-yl]-
azetidin-2-one oxamate, 13; (3S,4R)-3-[(1′R)-1′-(tert-
Butyldimethylsilyloxy)ethyl]-4-[(6′′R)-2′-[(E)-(pyrid-4-
yl)methylene]-oxocyclohex-6′′-yl]-azetidin-2-one oxamate,
15. The solid 13 was filtered off, and the mother liquors 14
were concentrated, diluted with ethyl acetate and re-
evaporated. Petroleum ether was added and the mixture was
cooled to 5 °C. After stirring for 1 h the solid was filtered,
washed with cold ethyl acetate/petroleum ether mixture (1/
1; 1 L) and dried for 24 h under vacuum at 25 °C to give
compound 15 as yellow/beige solid: 62 g, yield 42%. H1
NMR (DMSO): 13.63 (1H, bs), 8.62 (2H, d), 8.10 (1H, bs),
7.94 (1H, s), 7.79 (1H, bs), 7.40 (2H, d), 7.18 (1H, m), 4.15
(1H, m), 3.98 (1H, dd), 2.94 (1H, dd), 2.90 (1H, m), 2.70
(1H, m), 2.63 (1H, m), 2.08 (1H, m), 1.86 (1H, m), 0.72-
1.65 (2H, m), 1.16 (3H, d), 0.85 (9H, s), 0.06 (3H, s), 0.04
(3H, s).
(2 × 0.5 L) and brine (0.5 L), dried with Na2SO4, and
evaporated to give compound 2: 45 g, yield 91%. H1 NMR
(CD3OD): 8.58 (2H, d), 7.43 (2H, d), 7.27 (1H, m), 4.30
(1H, m), 4.20 (1H, dd), 3.06 (1H, dd), 3.01 (1H, m), 2.75
(1H, m), 2.72 (1H, m), 2.20 (1H, m), 2.00 (1H, m), 1.75-
1.85 (2H, m), 1.26 (3H, d), 0.92 (9H, s), 0.12 (3H, s), 0.11
(3H, s).
Procedure for the Reaction with Lithium and Sodium
Enolates. Lithium or sodium enolates of 2[(E)-(pyrid-4-yl)-
methylene]cyclohexanone were generated by using LiHMDS,
LDA, and NaHMDS.
Example: 2[(E)-(pyrid-4-yl)methylene]cyclohexanone 4
(3 equiv, 6.15 mmol, 1.1 g) was added over 15 min to a
solution of LiHMDS (2.1 equiv, 1 M in hexanes, 4.31 mmol)
in THF (4 mL) at -78 °C. The solution was stirred for 40
min, keeping the temperature under -70 °C. 4-Acetoxy-
azetidinone 3 (1 equiv, 2.05 mmol, 0.58 g) was then added,
and the mixture was stirred at -78 °C over 60 min and then
poured into an aqueous solution of ammonium chloride (5
mL), extracted with THF (2 × 5 mL), and distilled under
reduced pressure to dryness to give the desired product as
an oil: yield 15% a/a by HPLC.
Procedure for the Reaction with Magnesium Enolates.
Example: EtMgBr 1 M in THF (2 equiv, 2.12 mmol, 2.12
mL) was added to a solution of N,N-diisopropylethylamine
(2 equiv, 2.12 mmol, 0.27 g) in dry THF (1 mL) and the
mixture heated to reflux for 1.5 h. The resulting white
suspension was cooled to 0 °C, and 2[(E)-(pyrid-4-yl)-
methylene]cyclohexanone 4 (2 equiv, 2.12 mmol, 0.4 g) was
added. After stirring for 20 min 4-acetoxyazetidinone 3 (1
equiv, 1.06 mmol, 0.3 g) was poured into the mixture and
stirred for 5 min. The crude reaction mixture was quenched
into saturated aqueous NH4Cl and extracted with ethyl
acetate, and the organic layers were dried on Na2SO4.
Removal of the solvent followed by flash chromatography
on silica gel (ethyl acetate) gave the desired compound (0.06
g; yield 10-15%) as a mixture of R + â isomers. Selectiv-
ity: 1:3 â:R
Procedure for the Reaction with Tin (IV) and Tin (II)
Enolates. Example: SnCl4 1 M in CH2Cl2 (5 equiv, 8.7
mmol, 8.7 mL) was added to a solution of 2[(E)-(pyrid-4-
yl)methylene]cyclohexanone 4 (2 equiv, 3.5 mmol, 0.65 g)
and 4-acetoxyazetidinone 3 (1 equiv, 1.74 mmol, 0.5 g) in
CH2Cl2 (15 mL) at -20 °C. After stirring for 10 min at 0
°C, N,N-diisopropylethylamine (2.6 equiv, 4.5 mmol, 0.58
g) in CH2Cl2 (4 mL) was added over 20 min. The mixture
was slowly warmed to room temperature and stirred for 1
h. The solution was quenched by pouring into a mixture of
saturated aqueous potassium sodium tartrate (16 mL),
saturated aqueous sodium bicarbonate (16 mL), and diethyl
ether (54 mL). The mixture was stirred vigorously for 1 h,
and then the two phases were separated, and the organic layer
was dried with Na2SO4. The solvent was evaporated and the
residue purified by flash chromatography to give a mixture
of R + â isomers (0.1 g; yield 14%).
(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-
[(6′R)-2′-[(E)-(pyrid-4yl)methylene]-1′-oxocyclohex-6′-yl]-
azetidin-2-one, 2. 15 (62 g, 0.12 mol) was dissolved in ethyl
acetate (1 L), washed with 5% aqueous bicarbonate solution
Procedure for the Reaction with Zinc Enolates. Ex-
ample: LiHMDS 1 M in hexanes, (2 equiv, 2.08 mmol,2.08
mL) was added to a solution of 2[(E)-(pyrid-4-yl)methylene]-
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cyclohexanone 4 (2 equiv, 2.08 mmol, 0.39 g) in dry THF
(5 mL) at -20 °C. The mixture was stirred 15 min before
heating to 0 °C, and then ZnBr2 (2 equiv, 2.08 mmol, 0.47
g) dissolved in THF (5 mL) was added. After 10 min a
solution of 4-acetoxyazetidinone 3 (1 equiv, 1.04 mmol, 0.3
g) in dry THF (4 mL) was added, the mixture was stirred
for 1 h at 0 °C and then was quenched into a mixture of
ethyl acetate and saturated aqueous NH4Cl. The two phases
were separated, and the organic layer was dried with Na2-
SO4. The solvent was evaporated and the residue purified
by flash chromatography to give a mixture of R + â isomers
(0.05 g, yield 11%).
Procedure for the Reaction with a Zirconium Enolate.
A solution of 4 (1.3 equiv, 1.83 mmol, 0.344 g,) in dry THF
(4 mL) and added dropwise over 5 min to a solution of
zirconium(IV) tert-butoxide (1.06 g, 2.76 mmol, 2.1 equiv)
in dry THF (4 mL) at -10/-5 °C. The mixture was stirred
at -5 °C for 1.5 h and then treated with 4-acetoxyazetidinone
3 (1 equiv, 1.31 mmol, 0.378 g) in one portion. The dark
mixture was held at 20-25 °C for 40 min and then poured
into saturated sodium bicarbonate and ethyl acetate (80 mL).
The biphasic mixture was filtered on Celite through a glass
sinter washing, with ethyl acetate. The phases were separated
and organics were washed with saturated sodium bicarbonate
(30 mL), saturated ammonium chloride (30 mL), and brine
(30 mL) and concentrated to give a mixture of R + â
isomers: 0.25 g, yield 46%.
at 0-5 °C. The brown suspension was allowed to warm to
15 °C over 30 min, and then a solution of chlorotitanium-
trisisopropoxide (1.1 mL) in THF (5 mL) was added over
20 min at 15-23 °C. The dark brown suspension was held
at 20-23 °C for 45 min, and then treated with 4-acetoxyaze-
tidinone 3 (1 equiv, 3.48 mmol, 1 g) in one portion. The
dark mixture was held at 21-23 °C for 45 min and then
poured into saturated sodium bicarbonate/ethyl acetate (1:1,
66 mL). The biphasic mixture was filtered through a glass
sinter, the phases were separated and organics washed with
brine (27 mL), dried, and concentrated to afford a red oil
which was purified by chromatography (ethyl acetate:
cyclohexane, 6:1) to give a mixture of 2 and its R-isomer
(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[-(6′S)-
2′-[(E)-(pyrid- 4-yl)methylene]-1′-oxocyclohex-6′-yl]azeti-
din-2-one as a creamy white foam (1.29 g, yield 90%).
HPLC analysis of the product (Column: Hypersil BDS
C18 (5 µm; 4.6 mm × 200 mm). Mobile phase: NH4H2PO4
0.05 M/CH3CN ) 40/60. Flow ) 1.0 mL/min λ ) 270 nm.
Retention times: â-isomer ) 8.5 min, R-isomer ) 10.1 min)
established that the product of the reaction was a 2.3:1
mixture of the title compound and the corresponding (6′S)
compound (R-isomer): 1.1 g; yield 83%. Selectivity: 2:1
â:R.
(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[-
(6′R)-2′-[(E)-(pyrid-4yl)methylene]-1′-oxocyclohex-6′-yl]-
azetidin-2-one camphorsulfonate. 16. (2-Pyridylmethylene)-
cyclohexanone 4 (13.8 g, 1.3 equiv) in dry THF (75 mL)
was added under nitrogen over 30 min to a solution 0.5 M
of potassium bis(trimethylsilyl)amide in toluene (0.66 M,
176.4 mL, 1.69 equiv) at 0 °C. The mixture was stirred under
nitrogen for 30-45 min at 0 °C, and then chlorotitaniumtri-
isopropoxide (23 g, 1.7 equiv) in dry THF (75 mL) was
added in 10 min. The resulting dark brown mixture was
stirred for 45 min at 20-25 °C, and then solid 3 (15 g, 1
equiv) was added. The mixture was stirred for 1 h from 25
to 30 °C, and then the THF was removed under vacuum in
15 min and the mixture cooled to -10 °C. Glacial acetic
acid (150 mL) was added dropwise, maintaining the tem-
perature between -10 and 0 °C. The resulting mixture was
stirred under nitrogen for 10 min at -5 °C, and then water
(225 mL) and ethyl acetate (225 mL) were added over 20
min. After stirring for 10 min the mixture was separated,
the aqueous layer was re-extracted with ethyl acetate (150
mL) at -5 °C, and the combined organics were washed with
water (150 mL) at -5 °C. Citric acid disodium salt buffer
pH ) 5 0.1 M (150 mL) was added followed by 32% sodium
hydroxide 10.8 M (about 100 mL) with stirring over 30 min
at -5 °C to pH ) 6.5. After stirring for 10 min the phases
were separated, and the organic layer was washed with brine
(150 mL) and then filtered through silica gel (Merck 60, 30
g).
Procedure for the Reaction with Titanium Complex
Enolates. Example: (2-Pyridylmethylene)cyclohexanone 4
(1.39 equiv, 3.37 mmol, 0.63 g) was added dropwise to a
solution of sodium hexamethyldisilazide 1 M in THF (1.8
equiv, 4.35 mmol, 4.35 mL) at 0 °C.
In a separate flask, chlorotitaniumtrisisopropoxide (1.8
equiv, 4.38 mmol, 4.35 mL) in n-hexane (8 mL) was added
to a solution of S-(-)-2-methyl-1-butanol (3.6 equiv, 8.76
mmol, 0.77 g) in toluene (80 mL). The mixture was stirred
at room temperature for 30 min and then the mixture
evaporated by distillation to give an oil which was diluted
in dry THF (7 mL). This solution was then added dropwise
to the preformed sodium enolate of (2-pyridylmethylene)-
cyclohexanone 4 at room temperature and stirred for 1 h,
and 4-acetoxyazetidinone 3 (1 equiv, 2.42 mmol, 8.43 g)
was added. After stirring for 2 h the mixture was quenched
by diluting with ethyl acetate (70 mL) and pouring into a
saturated solution of NaHCO3 (70 mL). The emulsion was
filtered through a Celite pad and washed with ethyl acetate
(2 × 30 mL). The organic layer was dried on Na2SO4 and
concentrated in vacuo to give a dark red oil. The residue
was purified by flash chromatography (ethyl acetate/cyclo-
hexane: 75/35) to give a mixture of the two R + â isomers:
0.7 g, yield 71%. Selectivity: 1:1 â:R.
Procedure for the Reaction via a Simple Titanium
Enolate. (3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)-
ethyl]-4-[-(6′R)-2′-[(E)-(pyrid-4yl)methylene]-1′-oxocyclo-
hex-6′-yl]azetidin-2-one. 2. Example: (2-Pyridylmethylene)-
cyclohexanone 4 (1 equiv, 3.58 mmol, 0.67 g) was dissolved
in THF (6.7 mL) and added dropwise over 30 min to
potassium hexamethyldisilazide 0.5 M in toluene (8.5 mL)
The silica was washed with ethyl acetate (75 mL). The
organic solution was extracted twice with sodium hydro-
gensulfite solution 5% w/w 0.54 M (150 mL) followed by
aqueous sodium bicarbonate 5% 0.615 M (150 mL) and
water (150 mL) to afford a yellow solution which was
concentrated to dryness to give an oil that was dissolved in
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n-butyl acetate (225 mL). The resulting solution was treated
with 1R-(-)-camphorsulfonic acid (7.32 g, 0.6 equiv) and
stirred 1 h at room temperature and 3 h at 0 °C. The resulting
solid was filtered, washed with n-butyl acetate (30 mL), and
dried under vacuum for 14 h at 20 °C to give 16 as a pale
yellow solid: GW415667B, 14 g, yield 42%. 1H NMR (CD3-
OD): 9.03 (2H, d), 7.82 (2H, d), 7.30 (1H, s), 5.93 (1H,
bs), 4.30 (1H, dd), 4.25 (1H, q), 3.36 (1H, d), 3.02 (1H, m),
3.02 (1H, m), 2.94 (1H, d), 2.70 (1H, m), 2.70 (1H, m), 2.6
(1H, m), 2.35 (1H, m), 2.2 (1H, m), 2.1 (1H, m), 1.95 (1H,
m), 1.8 (1H, m), 2.1-1.8 (4H, m), 1.4 (1H, m), 1.26 (3H,
d), 1.09 (3H, s), 0.85 (3H, s), 0.88 (9H, s), 0.098 (3H, s),
0.092 (3H, s).
Acknowledgment
We thank colleagues from the Medicinal Chemistry
Department for their helpful discussions. Dr. C. Marchioro
1
and Dr. D. Papini are acknowledged for carrying out H
NMR and HPLC analyses.
Received for review February 9, 2002.
OP020024L
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