A formal synthesis of ezetimibe via cycloaddition/rearrangement cascade reaction

Article abstract of DOI:10.1021/jo2010846

A formal synthesis of a powerful cholesterol inhibitor, ezetymibe 1, is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from acetonide of l-glyceraldehyde and suitable C,N-diarylnitrone. The adduct with (3R,4S) configuration at the azetidinone ring, obtained with high stereoselectivity, was subsequently subjected to deprotection of the diol side chain followed by glycolic cleavage and base-induced isomerization at the C3 carbon atom to afford the (3S,4S) aldehyde, which has been already transformed into ezetimibe by the Schering-Plough group.

Full text of DOI:10.1021/jo2010846

NOTE
pubs.acs.org/joc
A Formal Synthesis of Ezetimibe via Cycloaddition/Rearrangement
Cascade Reaction†
Michaz Michalak, Maciej Stodulski, Sebastian Stecko, Adam Mames, Irma Panfil, Magdalena Soluch,
Bartzomiej Furman, and Marek Chmielewski*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
S Supporting Information
b
ABSTRACT:
A formal synthesis of a powerful cholesterol inhibitor, ezetymibe 1, is described. The crucial step of the synthesis is based on Cu(I)-
mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from acetonide of
L-glyceraldehyde and suitable C,N-diarylnitrone. The adduct with (3R,4S) configuration at the azetidinone ring, obtained with
high stereoselectivity, was subsequently subjected to deprotection of the diol side chain followed by glycolic cleavage and base-
induced isomerization at the C3 carbon atom to afford the (3S,4S) aldehyde, which has been already transformed into ezetimibe by
the ScheringꢀPlough group.
zetimibe (1) is a strong cholesterol absorption inhibitor that
proceeds in the presence of base (known as Kinugasa reaction14)
has received increased attention during the past decade.15,16
Recently, we have demonstrated that the reaction of cyclic
aliphatic nitrones with terminal acetylenes, both achiral or
enantiomerically defined, led to the formation of β-lactam ring
with a high cis-stereoselectivity (Scheme 2).16 The yield of
desired products varies from poor (for aliphatic acetylenes) to
moderate and good for aryl acetylenes. Interestingly, somewhat
better results have been observed for certain aliphatic acetylenes
bearing oxygen atoms.16a The acetylene derived from the acet-
onide of glyceraldehyde has been found to be a particularly
attractive substrate for Kinugasa reaction (Scheme 2).16a
Encouraging results for the glyceraldehyde-derived acetylene
2/2ent prompted further studies on the potential of this com-
pound as a precursor for ezetimibe (1) following the proposed
synthetic reaction sequence (Scheme 3). Consequently, we
focused our attention on the Kinugasa reactions involving readily
available C,N-diarylnitrone 3a.
E
reduces plasma low-density lipoprotein fraction (LDL-C).1
Owing to the clinical attractiveness of ezetimibe (1), its synthesis
became a target for many academic and industrial laboratories.
To date, several synthetic routes for the preparation of ezetimibe
have been described, mainly over past few years.2ꢀ11 The
reported methodologies are usually based on the construction
of the β-lactam ring via a cyclocondensation between diaryl imine
and ester or amide enolate (Scheme 1). The essential factor of
the reported syntheses is the formation of three stereogenic
centers present in 1 with the correct absolute configuration. The
configuration of the chiral center in the side chain is usually
accomplished either at the beginning or at the end of the reaction
sequence, by the enantioselective reduction of phenone carbonyl
group (for instance via CBS method10b or by treatment with
(ꢀ)-DIP chloride7a). The control over configuration of the
remaining two stereogenic centers in the β-lactam ring is usually
achieved by the use of R1 (Scheme 1) as a chiral auxiliary, except
for instances when the (S)-β-hydroxy-γ-butyrolactone10b or the
(S)-6-(4-fluorophenyl)tetrahydro-2H-pyran-2-one11 was used as
the ester component. In the latter case, however, the stereo-
chemical pathway of the reaction has not been discussed and no
information on the diastereomeric excess of the desired product
has been provided.11
We considered the synthesis of ezetimibe (1) via Scheringꢀ
Plough intermediate 5, for which the transformation leading to
the target molecule 1 has been reported.10b The key features of
the retrosynthetic analysis are shown in Scheme 3. The aldehyde
5 with trans configuration at carbon atoms C3 and C4 would be
prepared by the deprotection of 1,2-diol fragment of 4, followed
Among numerous direct methodologies leading to the chiral
β-lactams,12,13 the Cu(I)-mediated cycloaddition/rearrange-
ment cascade process of nitrones with terminal alkynes that
Received: June 3, 2011
Published: July 11, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
NOTE
Scheme 1
Scheme 2
The configuration of the major product 4 was assigned by 1H
NMR (J3,4 = 5.8 Hz, and J3,1 = 9.4 Hz) and was also unequi-
0
vocally confirmed by the X-ray structure analysis. The second cis
isomer 7 did not formed crystals suitable for X-ray measurement,
but analysis of 1H NMR coupling constants provided unambig-
uous evidence of its absolute configuration (J3,4 = 6.1 Hz and
0
J3,1 = 6.6 Hz). Isolation of the trans isomer 6 in a pure form was
difficult because its polarity is close to that of the major reaction
product. An analytical sample was obtained via repeated pre-
parative HPLC (the sample with 93% diasteroisomeric purity
was obtained). The trans substitution of the β-lactam ring in 6
was assigned following analysis of its 1H NMR spectrum where a
small J3,4 = 2.4 Hz coupling constant was observed. The absolute
configuration of stereogenic centers in 6 was substantiated by
comparison of the CD spectra of compounds 4, 6, 7, and 4ent
(see Supporting Information). Under the initial reaction condi-
tions, the presence of a fourth possible isomer (8) was not
detected. During subsequent optimization of the Kinugasa reac-
tion conditions, compound 8 was found in certain cases; how-
ever, the attempts to isolate it failed. Nevertheless, the careful
analysis of NMR spectra of crude postreaction mixtures led to
identification of the well-separated diagnostic signals of H3 and
by a glycolic cleavage and epimerization at the C3 stereogenic
center in the cis aldehyde by treatment with a weak base.
Considering our previous observations that acetylene derived
from D-glyceraldehyde 2ent reacted with nonchiral 1,2-pyrroline-
N-oxide to produce corresponding carbapenam with the (5S)
configuration (Scheme 2),16a we expected that 2ent with nitrone
3a should yield the cis substituted adduct (4ent) also with (4S)
configuration, opposite to that present in ezetimibe (1). Indeed,
appropriate experiment returned the predicted stereochemistry.
Consequently, as the substrate of the synthesis we selected the
readily available isopropylidene L-glyceraldehyde, which was
transformed into corresponding acetylene 2 by treatment with
BestmanꢀOhira reagent according to the known procedure.16a
The second component of the Kinugasa reaction, the nitrone 3a,
was obtained in 60% yield by the standard procedure using
p-benzyloxybenzaldehyde and p-fluorophenylhydroxylamine
(prepared from 4-fluoro-1-nitrobenzene).17
0
H4 protons (J3,4 = 2.5 Hz and J3,1 = 6.0 Hz) that were indicative
of the existence of alternative trans adduct 8.
Due to lower than expected16a stereoselectivity of the Kinugasa
reaction, further optimization of this process was performed by
varying copper(I) source, base type, solvent, and other reaction
conditions. Selected results are collected in Table 1.
The Kinugasa cycloaddition/rearrangement cascade between
nitrone 3a and acetylene 2 under our standard conditions
(2 equiv of nitrone with respect to acetylene, 1 equiv of CuI, 4
equiv of Et3N in MeCN) provided the desired cis-azetidinone 4
along with two other isomers: trans isomer 6 and alternative cis
product 7 in a ratio of 50:25:25, respectively (Scheme 4).
The choice of solvents for the reaction is restricted to the polar
aprotic ones. The surprisingly low solubility of nitrone 3a in
organic solvents (even in alcohols) was found to be the main
Scheme 3
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NOTE
Scheme 4
Table 1. Kinugasa Reaction of Nitrone 3a and L-Glyceraldehyde-Derived Acetylene 2a
entry
copper salt (equiv)
baseb (equiv)
nitrone 3 (eqiuv)
(4:6):(7:8)c
yield 4 (4 + 6)
overall
1
2
3
4
5
6
7
8
9
CuI (1.0)
Et3N (4)
1.6
1.6
1.1
1.1
1.1
1.2
1.1
1.2
1.2
(59:23):(1:17)
(68:19):(7:7)
(62:22):(8:8)
(57:25):(9:9)
(48:30):(20:2)
(61:21):(14:4)
(40:32):(25:3)
(65:20):(8:7)
(54:11):(21:14)
28 (32)
41 (53)
37 (50)
37 (54)
28 (45)
30 (40)
19 (35)
44 (58)
25 (30)
39
61
60
66
58
49
48
67
45
CuI (1.0)
TMG (2)
Et3N (4)
CuI (1.0)
Cu(Et3N)I (1.0) d
Cu(MeCN)4PF6 (1.0)
CuI (1.0)
TMG (2)
Et3N (4)
(i-Pr)2NEt (4)
Et3N (4)
CuI (0.1)
CuI (0.1)
Cu(Et3N)4I (1.0)d
TMG (2)
TMG (2)
a Reactions performed in MeCN at room temperature. b TMG = N,N,N0,N0-tetramethylguanidine. c Determined by 1H NMR and HPLC. d Prepared in situ.
problem of the reaction. Acetonitrile is the solvent of choice that
provided the optimal combination of solubility and an acceptable
reaction rate. The higher solubility of the nitrone was observed
when a mixture of MeCN with HMPA in ratio 1:1 was used;
however, its use did not improve the overall yield.
and O-silyl ether 3d were ineffective substrates for the reaction.
Moreover, the nitrone 3d underwent desilylation under reaction
conditions. Only the O-tosylated compound 3e reacted well,
providing corresponding β-lactams, but no improvement of the
selectivity and yield was observed.
Replacement of CuI by other copper(I) salts, such as CuCl,
CuBr, CuOAc, or CuSO4/sodium ascorbate, resulted in reduc-
tion of yield of desired products. Moreover, the copper-mediated
deoxygenation of the nitrone 3a to the corresponding imine
constituted a significant side process and necessitated the use
1.2ꢀ2 equiv excess of the nitrone with respect to the acetylene.
An exchange of Et3N by other bases, for instance, i-Pr2NEt or
c-Hex2NMe or DABCO, decreased the efficiency of the reaction.
Only the N,N,N0,N0-tetramethylguanidine offered a higher yield
of desired products 4 and 6. However, in contrast to reactions
performed in the presence of triethylamine, the formation of the
second trans isomer 8 was observed. N,N,N0,N0-Tetramethylgua-
nidine afforded also the best diastereoselectivity: dr = 68:19:7:7
for 4, 6, 7, and 8, respectively.
The surprisingly low stereoselectivity of the reaction of 3a
with 2 suggested that such result might be triggered by the
electronic properties of the nitrone itself. When acetylene 2 was
subjected to the reaction with diphenylnitrone 9, the azetidinone
10 was isolated as a single product in a good yield (Scheme 5).
Bearing in mind that the electronic properties of nitrone 3a
might affect the course of the Kinugasa reaction, we explored the
use of nitrones 3bꢀe with alternative O-protection of the phenol
group. The nonsubstituted phenol 3b, its O-acetyl derivative 3c,
Recently, we have shown that 4-(p-methoxy-aryl)-substituted
azetidin-2-ones are particularly sensitive to the nucleophilic
reagents in the presence of acid catalysts and undergo addition of
the nucleophile to the C4 carbon atom with opening of the four-
membered β-lactam ring.18 Henceforth, the assessment of rea-
sons for lower than expected yield and selectivity of the Kinugasa
reaction involving 3aꢀe should take into account observation
that substitution in both aryls in adducts 4 and 6ꢀ8 can promote
a similar reactivity. Better results found for the nitrone 9 support
such an assumption.
The transformation of 4 into ezetimibe (1) precursor 5 is
shown in Scheme 6. It should be noted that the trans isomer 6 has
the same configuration at C4 of the azetidin-2-one ring as
ezetimibe 1, so from the synthetic point of view both stereo-
isomers 4 and 6 are precursors for the target molecule and can be
used for the next steps without separation.
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NOTE
Scheme 5
Scheme 6a
a Reagents and conditions: (a) CF3COOH, THF/H2O; (b) 2.4 equiv of NaIO4 (on silica), CH2Cl2, 2 h, 0 °C; (c) 20 equiv of NaHCO3, CH2Cl2, 3 h,
0 °C, 82ꢀ86% (after 2 steps, cis (12):trans (5) = 1:6.2ꢀ8.8).
Deprotection of 4 proceeded smoothly in THF/H2O (2:1) in
the presence of 10 equiv of trifluoroacetic acid to give diol 11 in
76% yield. The rate of hydrolysis can be accelerated in the
presence of microwave irradiation (200 W, 3 min) affording diol
11 in 70%.
the first example of an application of the Kinugasa reaction in a
target-oriented synthesis. Taking into account the inexpensive
starting materials and simple steps that do not require special
preparative procedures, our methodology leading to 5 offers
certain advantages over ScheringꢀPlough’s synthesis.10b More-
over, Kinugasa reaction involving diaryl nitrones offers an
attractive approach to the recently reported family of new
anticancer β-lactams.20
Initial attempts to cleave the 1,2-diol moiety were performed
according to the ScheringꢀPlough procedure.10b However,
when diol 11 was treated with NaIO4 in MeCN/H2O solution
followed by the standard work up to afford 12, the desired
aldehyde was accompanied by decomposition products. This
may be caused by a reactive β-dicarbonyl fragment present in 12.
Moreover, probable formation of the hydrate by 12 could have
made the isolation product more difficult, consequently leading
to a low yield of the overall transformation. To overcome these
difficulties, we turned our attention to the method reported by
Shrig et al.19 This alternative protocol, applying silica gel-
supported NaIO4 in anhydrous dichloromethane, should exclude
formation of a hydrate. Indeed, glycolic cleavage with above
method, followed by the epimerization of initially formed cis
aldehyde with solid sodium bicarbonate (20 equiv), directly after
the oxidation step, yielded crude aldehyde products (82ꢀ85%)
as a mixture of C-3 epimers cis 12 and trans 5 in a ratio of about
1:8.5, respectively. Due to instability of 5 this compound should
be used directly in further steps leading to ezetimibe (1).
Transformation of compound 5 into ezetimibe (1) has already
been reported by the ScheringꢀPlough group.10b This sequence
involved Mukayiama reaction of 5 with silyl enol ether of
p-fluoro-acetophenone to afford an enone, which was hydro-
genated followed by a stereoselective reduction of the carbonyl
group in the presence of a chiral ligand (R)-2-methyl-CBS-
oxaborolidine.10b
’ EXPERIMENTAL SECTION
Syntheses of Nitrones 3aꢀe
General Method,17 Step 1. To a suspension of p-fluoronitroben-
zene (300 mmol, 31.8 mL) in a solution of NH4Cl (390 mmol, 20.9 g) in
water (600 mL) at 60 °C was added zinc powder in 1.0ꢀ1.5 g portions
(39.2 g, 600 mmol), keeping the temperature of the reaction mixture in
the range of 60ꢀ65 °C. When zinc addition was completed, the mixture
was stirred for an additional 15 min at 60 °C. Then zinc oxide was filtered
(with the use of a Schott funnel, porosity G3) and washed with water
(3 ꢁ 50 mL, water temp 70 °C), to the resulting solution was added solid
NaCl (205 g), and the solution was cooled to 0 °C. After 30 min the
yellow precipitate was filtered, washed with cold water (∼0 °C, 2 ꢁ
40 mL), and dried in vacuo (2.5 mbar) for 1 h. The crude 4-fluorophe-
nylhydroxylamine was used directly in the next step without further
purification.
Step 2. To a solution of crude 4-fluorophenylhydroxylamine
(10 mmol) in acetone (10 mL) were added p-benzyloxybenzaldehyde
(10 mmol) and catalytic amount of CH3SO3H (10 mol %) at room
temperature. After 2 h, the resulting precipitate was filtered, washed with
acetone, and dried in vacuo.
N-(4-Fluorophenyl)-R-(4-benzyloxyphenyl)nitrone (3a).
Off-white solid; yield 60%. Mp 193ꢀ195 °C (acetone); 1H NMR
(500 MHz, DMSO-d6) δ 8.49ꢀ8.47 (m, 2H), 8.42 (s, 1H), 7.99ꢀ
7.95 (m, 2H), 7.50ꢀ7.45 (m, 2H), 7.44ꢀ7.32 (m, 5H), 7.13 (d, J =
5.0 Hz, 2H), 5.20 (s, 2H); 13C NMR (125 MHz, DMSO-d6) δ 162.2 (d,
JCF = 245.6 Hz), 159.9, 144.8 (d, JCF = 2.4 Hz), 136.6, 133.0,
130.9, 128.4, 127.9, 127.8, 124.1, 123.6 (d, JCF = 9.3 Hz), 115.7 (d,
In summary, we have described a novel approach for synthesis
of β-lactamic cholesterol absorption inhibitors, particularly eze-
timibe 1. The key step of the newly presented synthesis is the
formation of N,4-diaryl-substituted azetidin-2-one ring via copper-
(I)-catalyzed Kinugasa reaction. The presented methodology is
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NOTE
JCF = 22.9 Hz), 114.7, 69.4; HR MS (ESI) m/z calcd for C20H16NO2F-
Na [M + Na+] 344.1057, found 344.1055. Anal. Calcd for C20H16FNO2:
C, 74.75; H, 5.02; F, 5.91; N, 4.36. Found: C, 74.76; H, 5.08; F, 6.03;
N, 4.40.
Azetidinone 4. Mp 150ꢀ152 °C (EtOH); [R]25 ꢀ74 (c 0.6,
D
CH2Cl2); 1H NMR (500 MHz, C6D6) δ 7.20 (2H, m), 7.12 (2H, m),
7.06 (2H, m), 7.01 (m,1H), 7.86 (2H d J = 14 Hz), 6.69 (2H d J =
14 Hz), 6.61 (2H, m), 4.55 (2H, m), 4.45 (1H,d J = 5.8 Hz),4.13 (1H, dd
J = 8.5, 6.5 Hz), 3.94 (1H, dd J = 8.5, 6.1 Hz), 3.81 (1H, dt J = 9.4, 6.1
Hz), 3.33 (1H, dd J = 9.4, 5.8 Hz), 1.30 (3H, s), 0.93 (3H, s); 13C NMR
(125 MHz, C6D6) δ 162.9, 159.7, 158.8 (d, JCF = 241.5 Hz), 158.1,
N-(4-Fluorophenyl)-R-(4-hydroxyphenyl)nitrone (3b).
Light pink solid; yield 61%. Mp 216ꢀ217 °C (acetone); IR (film)
3186 cmꢀ1 1H NMR (600 MHz, DMSO-d6) δ 10.23 (s, 1H),
;
136.9, 134.2 (d, JCF = 2.6 Hz), 128.3, 128.0, 126.3, 118.4 (d, JCF
=
8.39ꢀ8.35 (m, 2H), 8.33 (s, 1H), 7.97ꢀ7.92 (m, 2H), 7.38ꢀ7.32
(m, 2H), 6.91ꢀ6.86 (m, 2H); 13C NMR (125 MHz, DMSO-d6) δ 162.0
(d, JCF = 204.4 Hz), 159.8, 144.8 (d, JCF = 2.0 Hz), 133.4, 131.2, 123.5
(d, JCF = 7.4 Hz), 122.5, 115.7 (d, JCF = 19.1 Hz), 115.3; HRMS (EI)
m/z calcd for C13H10O2NF: 231.0696, found 231.0688. Anal. Calcd for
C13H10FNO2: C, 67.53; H, 4.36; N, 6.06. Found: C, 67.50; H, 4.37;
N, 6.04.
7.6 Hz), 115.6 (d, JCF = 22.5 Hz), 115.3, 114.8, 108.5, 71.0, 69.6, 67.3,
58.7, 57.0, 26.8, 25.1; IR (film) 1748, 1510 cmꢀ1; HRMS (ESI) m/z
calcd for C27H26NO4FNa [M + Na]+ 470.1738, found 470.1754. Anal.
Calcd for C27H26NO4F: C, 72.47; H, 5.86; N, 3.13, F 4.25. Found: C,
72.39; H, 5.78; N, 3.15, F 4.32.
Azetidinone 6. A sample (12 mg) with 93% diasteroisomeric purity
was obtained by repetitive preparative HPLC (optical rotation not
recorded). 1H NMR (600 MHz, C6D6) δ 7.42ꢀ7.336 (4H, m);
7.28ꢀ7.22 (5H, m), 6.98ꢀ6.90 (4H, m), 4.90 (1H, d, J = 2.4 Hz),
4.52ꢀ4.47 (1H, m), 4.12ꢀ4.06 (2H, m), 3.30 (1H, dd, J = 3.9, 2.4 Hz),
4.42 (3H, s), 1.39 (3H, s); 13C NMR (150 MHz, CDCl3) δ 164.2, 159.1,
159.0 (d, JCF = 244 Hz), 136.7, 133.7 (d, JCF = 2.4 Hz), 129.3, 128.6,
128.1, 127.5, 127.3, 118.5 (d, JCF = 7.9 Hz), 115.8 (d, JCF = 22.6 Hz),
115.8, 110.0, 72.5, 70.1, 66.2, 61.7, 57.3, 26.4, 25.7; IR (film) 1749,
1511 cmꢀ1; HRMS (ESI) m/z calcd for C27H26O4NFNa [M + Na+]
470.1738, found 470.1741.
N-(4-Fluorophenyl)-R-(4-acyloxyphenyl)nitrone (3c). Light
yellow solid; yield 57%. Mp 166ꢀ169 °C (acetone); IR (film)
1756 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.43ꢀ8.39 (m, 2H), 7.86
(s, 1H), 7.76ꢀ7.71 (m, 2H), 7.21ꢀ7.16 (m, 2H), 7.15ꢀ7.09 (m, 2H),
2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.9, 162.9 (d, JCF
=
246.4 Hz), 152.1, 145.0 (d, JCF = 3.2 Hz), 133.4, 130.3, 128.1, 123.5 (d,
JCF = 8.7 Hz), 121.8, 115.9 (d, JCF = 23.2 Hz), 114.7, 21.1; HRMS (ESI)
m/z calcd for C15H12FNO3Na [M + Na]+ 296.0693, found 296.0690.
Anal. Calcd for C15H12FNO3: C, 65.93; H, 4.43; N, 5.13. Found: C,
65.91; H, 4.40; N, 5.08.
Azetidinone 7. Mp 104ꢀ107 °C; [R]25 = +74.8 (c 0.51,
N-(4-Fluorophenyl)-R-(4-tert-butyldiphenylsilyloxyphenyl)-
D
1
CH2Cl2); IR (film): 1748, 1510, 1372 cmꢀ1; H NMR (600 MHz,
1
nitrone (3d). Yellowish solid; yield 45%. Mp 109ꢀ112 °C; H NMR
C6D6) δ 7.31ꢀ7.27 (m, 2H), 7.21ꢀ7.17 (m, 2H), 7.14ꢀ7.10 (m, 2H),
7.09ꢀ7.04 (m, 1H), 6.86ꢀ6.82 (m, 2H), 6.73ꢀ6.69 (m, 2H), 6.69ꢀ
6.63 (m, 2H), 4.61 (s, 2H), 4.28 (d, J = = 6.0 Hz, 1H), 3.87ꢀ3.81 (1H,
dt, J = 7.7, 6.6, 6.0 Hz), 3.48 (1H, pseudo dd, J = 8.1, 7.9 Hz), 3.29 (dd,
J = 8.1, 6.0 Hz, 1H), 3.14 (pseudo dd, J = = 6.6, 6.1 Hz, 1H), 1.49 (s,
3H), 1.16 (s, 3H); 13C NMR (150 MHz, C6D6) δ 163.8, 159.3, 158.7 (d,
JCF = 201.1 Hz), 137.2, 134.8 (d, JCF = 2.3 Hz), 128.9, 128.8, 128.4,
(CDCl3, 400 MHz) δ 8.17 (2H, m), 7.74ꢀ7.70 (5H, m), 7.40ꢀ7.24 (7H,
m), 7.14 (2H, m), 6.85 (2H, m), 1.11 (9H, s); 13C NMR (CDCl3, 100
MHz) δ 190,8, 164,0 (d, JCF = 250 Hz), 158,5, 144,7, 136,2, 132,9, 132,1,
130,9, 128,7, 124,3, (d, JCF = 9 Hz), 120,9, 116,4 (d, JCF = 23 Hz), 114,3,
26,4. HRMS (ESI) m/z calcd for C29H28NO2FSiNa [M + Na]+ 492.1756,
found 492.1754. Anal. Calcd for C29H28FNO2Si: C, 74.17; H, 6.01; N, 2.98.
Found: C, 74.15; H, 5.98; N, 3.00.
128.1, 128.0, 127.7, 126.6, 118.7 (d, JCF = 6.4 Hz), 116.1, 115.9 (d, JCF
=
N-(4-Fluorophenyl)-R-(4-tosyloxyphenyl)nitrone (3e).
White solid; yield 67%. Mp 172ꢀ174 °C (acetone); 1H NMR
(600 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.48ꢀ8.44 (m, 2H), 7.98ꢀ
7.94 (m, 2H), 7.77ꢀ7.74 (m, 2H), 7.49ꢀ7.46 (m, 2H), 7.42ꢀ7.36
(m, 2H), 7.18ꢀ7.14 (m, 2H), 2.42 (s, 3H); 13C NMR (150 MHz,
22.4 Hz), 109.9, 72.5, 70.1, 68.2, 58.0, 56.9, 26.9, 26.1; HRMS (ESI) m/z
calcd for C27H26O4NFNa [M + Na]+ 470.1738, found 470.1756. Anal.
Calcd for C27H26NO4F: C, 72.47; H, 5.86; N, 3.13, F 4.25. Found: C,
72.41; H, 5.86; N, 3.09, F 4.29.
DMSO-d6) δ 162.4 (d, JCF = 205.0 Hz), 149.6, 146.0, 144.7 (d, JCF
2.4 Hz), 132.5, 131.2, 130.4, 130.3, 130.1, 128.3, 123.8 (d, JCF
=
=
Azetidinone 10. To a suspension of CuI (190 mg, 1.0 mmol) in
anhydrous CH3CN (10 mL) were added Et3N (0.56 mL, 4.0 mmol) and
acetylene 2 (126 mg, 1.0 mmol) at 0 °C. After 15 min nitrone 920 was
added (395 mg, 2.0 mmol, 2.0 eqiuv) as a solid, and the mixture was
stirred for 16 h at rt. Then solvent was evaporated, and the residue was
chromatographed on silica gel (60 mL, 10% EtOAc/hexanes) to give an
7.5 Hz), 122.1, 115.9 (d, JCF = 19.3 Hz), 21.2; HRMS (ESI) m/z
calcd for C20H16NO4FSNa [M + Na]+ 408.0682, found 408.0679.
Anal. Calcd for C20H16FNO4S: C, 62.33; H, 4.18; F, 4.93; N, 3.63.
Found: C, 61.93; H, 4.32; F, 5.13; N, 3.52.
off-white solid (218 mg, 68%). Mp 153ꢀ155 °C (EtOH);[R]25
=
Synthesis of 2-Azetidinone 4. A Schlenk flask was charged with
copper(I) iodide (4.53 g, 23.8 mmol) and purged with argon, and
degassed MeCN (120 mL)and N,N,N0,N0-tetramethylguanidine
(47.6 mmol, 5.48 g, 6 mL) were added. After cooling to 0 °C, acetylene
2 (23.8 mmol, 3.0 g) was added, and the yellow mixture was stirred for 15
min. A second Schlenk flask was charged with nitrone 3a (28.56 mmol,
9.18 g) and purged with argon, and degassed MeCN was added
(120 mL). Subsequently, a solution of copper acetylide was cannulated
into the suspension of nitrone 3a. After stirring for 16 h at room temper-
ature under argon atmosphere, the reaction mixture was diluted with
AcOEt (100 mL) and H2O (100 mL). The aqueous phase was separated
and washed with AcOEt (2 ꢁ 50 mL). The combined organic phases
were washed with brine, dried (anhydr Na2SO4), and concentrated. The
diasteroisomer ratio of crude products mixture was assigned by HPLC
(hexane/MTBE, 7:3 v/v, 1 mL/min, det 223 nm; tR = 11.7 min for 4,
13.2 min for 6, 14.5 min for 8 and 42.3 min for 7), and the ratio was
68:19:7:7 for 4, 6, 7, and 8, respectively. The product was isolated by
column chromatography on silica gel (hexane/AcOEt 6:1) to afford
adduct 4 (4.37 g, 41%) accompanied by 6 (1.28 g, 12%), and 7 (0.47 g,
5%). The second trans isomer was not isolated.
D
ꢀ125.1 (c 0.57, CHCl3); IR (film) 1749, 1599 cmꢀ1
;
1H NMR
(400 MHz, CDCl3) δ 7.36ꢀ7.19 (m, 9H), 7.06ꢀ6.98 (m, 1H), 5.29
(d, J = 5.2 Hz, 1H), 3.97ꢀ3.87 (m, 2H), 3.83ꢀ3.71 (m, 2H), 1.31 (s,
3H), 0.97 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.7, 137.4, 134.1,
129.1, 128.5, 128.3, 127.2, 124.1, 117.1, 108.6, 70.9, 67.3, 57.9, 57.4, 26.8,
25.3; HRMS (EI) m/z calcd for C20H21O3N 323.1521, found 323.1536.
Diol 11. To a solution of acetonide 4 (933 mg, 2.1 mmol) in a
mixture of THF (20 mL) and water (10 mL) was added CF3CO2H
(1.60 mL), and the mixture was kept at 50 °C for 6 h (TLC analysis
showed complete consumption of substrate, 50% EtOAc/hexanes).
Then the organic solvents were evaporated, and a white solid was
formed. After filtration, the crude diol was recrystallized from EtOH to
give a product as a white, thin neeedles (702 mg, 76%). Mp 210ꢀ212 °C
(EtOH); [R]25 ꢀ52.1 (c 0.7, acetone); IR (film) 3369, 1726,
D
1
1512 cmꢀ1; H NMR (500 MHz, CDCl3/CD3OD) δ 7.42ꢀ7.27 (m,
5H), 7.25ꢀ7.19 (m, 4H), 6.98ꢀ6.88 (m, 2H), 5.25 (d, J = 5.5 Hz, 1H),
5.01 (s, 2H), 3.81ꢀ3.74 (m, 1H), 3.71ꢀ3.65 (m, 1H), 3.62ꢀ3.54 (m,
2H); 13C NMR (125 MHz, CDCl3/CD3OD) δ 164.7, 158.9 (d, JCF
=
242.5 Hz), 158.7, 136.4, 133.1 (d, JCF = 2.5 Hz), 128.3, 128.2, 127.7,
6935
dx.doi.org/10.1021/jo2010846 |J. Org. Chem. 2011, 76, 6931–6936

The Journal of Organic Chemistry
NOTE
127.2, 125.8, 118.5 (d, JCF = 7.5 Hz), 115.5 (d, JCF = 22.5 Hz), 69.8, 67.3,
64.6, 57.4, 57.1; HRMS (ESI) m/z calcd for C24H22O4FNNa [M + Na+]
430.1425, found 430.1416. Anal. Calcd for C24H22FNO4: C, 70.75; H,
5.44; F, 4.66; N, 3.44. Found: C, 70.74, H, 5.45; F, 4.88, N, 3.42.
Aldehyde 5. To a vigorously stirred suspension of diol 11 (330 mg,
0.81 mol) in anhydrous CH2Cl2 (15 mL), cooled to 0 °C, was added
silica gel-supported NaIO4 reagent (1.78 g, 2.13 mmol), and the mixture
was stirred for 2 h at this temperature. Then silica was filtered and
washed with anhydrous CH2Cl2 (2 ꢁ 5 mL), and the solvent was
evaporated to give a white solid (285 mg). 1H NMR indicated the ratio
of diastereisomers as trans:cis (12:5) = 7.8:1 (based on integration of
aldehyde hydrogen atom). Selected diagnostic signals for 12: 1H NMR
(400 MHz, CDCl3) δ 9.30 (d, J = 2.4 Hz, CHO), 5.36 (d, J = 6.0 Hz,
H-4); 3.40 (dd, J = 6.0, 2.4 Hz, H-3); HRMS (ESI) m/z calcd for
C23H18FNO3Na [M + Na]+ 398.1168, found 398.1172. To the crude
mixture of aldehydes in anhydrous CH2Cl2 (15 mL) was added
NaHCO3 (1.36 g, 16.2 mmol, 20.0 eqiuv) at 0 °C, and the mixture
was stirred for 3 h at this temp. The solid was filtered, and the solvent was
evaporated to give a mixture of trans:cis diastereoisomers in a ratio of
(4) Thiruvengadam, T. K.; Sudhakar, A. R.; Wu, G. In Process
Chemistry in the Pharmaceutical Industry; Gadamasetti, K. G., Ed.; Marcel
Dekker: New York, 1999, 221ꢀ242 and references therein.
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Appl. WO 2008032338, 2008; Chem. Abstr. 2008. (b) Additional
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Information.
(8) Sasikala, C. H. V. A.; Padi, P. R.; Sunkara, V.; Ramayya, P.;
Dubey, P. K.; Uppala, V. B. R.; Praveen, C. Org. Process Res. Dev. 2009,
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Tetrahedron 2000, 56, 5735.
(10) (a) Rosenblum, S. B.; Huynh, T.; Afonso, A.; Davis, H. R.;
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Appl. WO 2004099132A2, 2004. (b) Alley, J.; Martinez, E.; Zimmer, D.;
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(12) (a) Bruggink, A. Synthesis of β-Lactam Antibiotics; Kluwer:
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(13) (a) Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., Scriven, E. F., Eds.; Pergamon: New York, 1996; Chapters
1.18ꢀ1.20. (b) Furman, B.; Borsuk, K.; Kazuz_a, Z.; yysek, R.;
Chmielewski, M. Curr. Org. Chem. 2004, 8, 463. (c) Furman, B.; Kazuz_a,
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p 101.
1
8.5:1 (based on integration of aldehyde hydrogen atom). Selected H
NMR data for aldehyde 5: 1H NMR (400 MHz, CDCl3) δ 9.90 (d, J =
1.2 Hz, CHO), 5.40 (d, J = 2.4 Hz, H-4), 4.23 (dd, J = 2.4, 1.2 Hz, H-3);
the spectral data are in agreement with those reported.10b The aldehyde
5 is unstable and was used directly in next steps of the synthesis
according to the ScheringꢀPlough protocol.10b
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra; CD
S
b
spectra of 4, 4ent, 6, and 7; CIF file of compound 4.21 This
material is available free of charge via the Internet at http://pubs.
acs.org.
(14) Kinugasa, M.; Hashimoto, S. J. J. Chem. Soc., Chem. Commun.
1972, 466.
(15) (a) Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org. Chem.
1995, 60, 4999. (b) Lo, M.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 4572.
(c) Shintani, R.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 4082. (d)
Tang, Y.; Ye, M.-C.; Zhou, J. J. Org. Chem. 2006, 71, 3576. For more
references concerning Kinugasa reaction, see Supporting Information.
(16) (a) Mames, A.; Stecko, S.; Mikozajczyk, P.; Soluch, M.; Furman,
B.; Chmielewski, M. J. Org. Chem. 2010, 75, 7580. (b) Stecko, S.; Mames,
A.; Furman, B.; Chmielewski, M. J. Org. Chem. 2009, 74, 3094. (c)
Stecko, S.; Mames, A.; Furman, B.; Chmielewski, M. J. Org. Chem. 2008,
73, 7402.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: chmiel@icho.edu.pl.
’ ACKNOWLEDGMENT
We are grateful for Prof. Jadwiga Frelek from Institute of
Organic Chemistry PAS (Warsaw) for assistance in CD spec-
troscopy. Financial support for this work was provided through
the National Center of Research and Development INITECH
Project No. ZPB/51/64927/IT/10. Authors are also grateful for
ADAMED Ltd. for financial support.
(17) Jiao, P.; Nakashima, D.; Yamamoto, H. Angew. Chem., Int. Ed.
2008, 47, 2411.
(18) Zabmronꢀ, B.; Masnyk, M.; Furman, B.; Chmielewski, M.
Tetrahedron 2009, 65, 4440.
(19) Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622.
(20) Meegan, M. J.; Carr, M.; Knox, A. J. S.; Zisiters, D. M.; Lloyd,
D. G. J. Enzyme Inhib. Med. Chem. 2008, 23, 668.
(21) Crystallographic data for the structure 4 reported in this paper
have been deposited with the Cambridge Crystallographic Data Center,
Cambridge, U.K., as supplementary publications no. CCDC 827106.
’ DEDICATION
†Dedicated to Professor Janusz Jurczak in the year of his 70th
birthday.
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dx.doi.org/10.1021/jo2010846 |J. Org. Chem. 2011, 76, 6931–6936