Stereoselective Synthesis of Ezetimibe via Cross-Metathesis of Homoallylalcohols and α-Methylidene-β-Lactams

Article abstract of DOI:10.1021/acs.joc.6b01406

Ru-catalyzed cross-metathesis (CM) reaction between β-arylated α-methylidene-β-lactams and terminal olefins was developed. The CM reaction is effectively catalyzed with Hoveyda-Grubbs second-generation catalyst affording corresponding α-alkylidene-β-aryl-

Full text of DOI:10.1021/acs.joc.6b01406

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Article
Stereoselective Synthesis of Ezetimibe via Cross-Metathesis
of Homoallylalcohols and alpha-Methylidene-beta-Lactams
Marek Humpl, Jiri Tauchman, Nikola Topolovcan, Jan Kretschmer,
Filip Hessler, Ivana Cisarova, Martin Kotora, and Jan Vesely
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01406 • Publication Date (Web): 05 Aug 2016
Downloaded from http://pubs.acs.org on August 7, 2016
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Stereoselective Synthesis of Ezetimibe via Cross-Metathesis of Homoallylalcohols and α-Methylidene-
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β-Lactams
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Marek Humpl, a Jiří Tauchman,a Nikola Topolovčan,a Jan Kretschmer, a Filip Hessler, a Ivana Císařová, b
Martin Kotoraa* and Jan Veselý a*
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a
Department of Organic Chemistry, Faculty of Science, Charles University in Prague, Hlavova 2030/8,
12843 Praha 2 (Czech Republic), e-mail: jxvesely@natur.cuni.cz, kotora@natur.cuni.cz
b
Department of Inorganic Chemistry, Faculty of Science, Charles University in Prague, Hlavova 2030/8,
12843 Praha 2 (Czech Republic)
ABSTRACT: Ru-catalyzed cross-metathesis (CM) reaction between β-arylated α-methylidene-β-lactams
and terminal olefins was developed. The CM reaction is effectively catalyzed with Hoveyda-Grubbs 2nd
generation catalyst affording corresponding α-alkylidene-β-aryl-β-lactams in good isolated (41-83%)
yields with exclusive Z-selectivity. The developed protocol was successfully applied for stereoselective
preparation of Ezetimibe, the commercial cholesterol absorption inhibitor.
Keywords: Metathesis, β-lactams, total synthesis, organocatalysis,
Table of Content Graphics:
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INTRODUCTION
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β-Lactam scaffold is the common structural feature of a number of compounds with broad
pharmacological profile.1 In addition to their importance as bioactive compounds, β-lactams also serve
as valuable building blocks in organic synthesis for the preparation of non-proteinogenic β-amino acids,
alkaloids, macrolides, toxoids, etc.2 Ezetimibe – (3R,4S)-4-(4-hydroxyphenyl)-1-(4-fluorophenyl)-3-[(S)-3-
hydroxy-3-(4-fluorophenyl)propyl]azetidine-2-on] – is one example from the family of the β-lactam
derived pharmaceuticals and is marketed as blockbuster drugs Zetia or Ezetrol.3 It is a strong cholesterol
absorption inhibitor reducing LDL concentration. Despite the fact that a number of synthetic approaches
have been developed for its preparation,4 there are still other pathways that have not been explored yet.
In this respect we envisioned that a stereoselective synthesis of Ezetimibe could be based on cross-
metathesis reaction as depicted in retrosynthesis in Scheme 1. The crucial step of the construction of the
Ezetimibe framework was assumed to be based on cross-metathesis (CM) of a α-methylene-β-lactam
building block (1b) with enantiomerically enriched homoallylic alcohols (2o). The former could be
prepared by Kinugasa reaction5 or by asymmetric allylic amination of Baylis-Hillman derivatives followed
by lactamization.4b The latter could come from enantioselective allylation of 4-fluorobenzaldehyde.6
The pioneering work showing that α-methylidene-β-lactams could be used for synthesis of α-
alkylidene-β-lactams by using CM7 was reported by Howell and coworkers in 2009.8 However, only one
example of cross-metathesis of β-substituted α-methylidene-β-lactam was presented. Since then only
one more example of CM of α-methylidene-β-lactams has been reported describing the reaction of β-
phenyl-α-methylidene-β-lactam with 1-hexene giving β-phenyl-α-hexylidene-β-lactam as a mixture of
E/Z isomers.4b Up to date no systematic study regarding reactivity of arylated α-methylidene-β-lactams in
CM has been undertaken despite the fact that such a reaction could provide access to synthetically
interesting intermediates. In view of the aforementioned, we decided to explore the scope of CM
reaction of β-arylated α-methylidene-β-lactams and selected terminal olefins with the aim to develop a
new synthetic approach to Ezetimibe.
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Scheme 1. Retrosynthetic analysis of Ezetimibe.
RESULTS AND DISCUSSION
At the outset we decided to study CM of 3-methylidene-1,4-diphenylazetidin-2-one 1a with
styrene 2a as model substrates in the presence of the ruthenium-based Hoveyda-Grubbs 2nd generation
catalyst9 to assess the best reaction conditions (Table 1). Initially, the reaction was performed with 1a
and 2a in 1:2 ratio under standard conditions at 40 °C either in dichloromethane (for 40 hrs) or in
toluene (for 90 hrs) (Entries 1 and 2). It provided the desired α-alkylidene-β-lactam 3aa in indentical
yields of 29%. Higher yields of 3aa were obtained when the reaction was carried out at 100 °C either in
toluene (48%) or octafluorotoluene10 (59%) (Entries 3 and 4). Further screening of the reaction
conditions showed that a portionwise addition of the catalyst had a beneficial effect on the yield of 3aa
(Entries 5 and 6). The use of CuI as an additive, which has been shown to have a positive effect on the
course of cross-metathesis,11 resulted in the drop of 3aa yield (Entries 7 and 8). Obviously, the use of a
perfluorinated solvent (octafluorotoluene) had a positive effect on the course of the reaction.8 It is also
worth mentioning that in all cases the exclusive formation of the Z-isomer was observed.
During the course of our experiments a paper describing effect of residual water, air, a catalyst
load, etc. on the efficacy of cross-metathesis was published.12 In view of these results, lactam 1a was,
prior to the reaction, evaporated several times with toluene to reduce its amount and styrenes were
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distilled. Thus a reaction of 1a with 2a carried out in toluene provided 3aa in almost double yield of 77%
(Table 1, Entry 9) in comparison with undried substrates (Entry 3). A similar effect albeit not so dramatic
was observed also in octafluorotoluene (Entry 10). These results thus clearly indicated that a reduction
of an amount of residual water in reactants had beneficial effect on the reaction yields. In order to assess
influence of a catalyst, reaction catalyzed by G I (Entries 11 and 12), G II (Entry 13), and H-G I (Entry 14)
were carried out. The reactions in octafuorotoluene were conducted at 80 °C to avoid decomposition of
the catalysts used at higher temperatures. Although the desired product was obtained in all cases, only
in case of G II a reasonable yield of 71% of 3aa was achieved (Entry 13). The use G I and H-G I provided
3aa in 30-40% yields only (Entries 11, 12, and 14). The above mentioned results clearly indicate that
suitable conditions for cross-metathesis of 1a with 2a are as follows: a portion-wise addition of H-G II
and the use octafluorotoluene as the solvent (Entry 10)
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Table 1. Cross-metathesis between 1a and 2a under various conditions.
Entry
Catalyst
Cat. Load
(mol%)
10
Solvent
T (°C).
Yield (%)a
1
2b
3
H-G II
H-G II
H-G II
H-G II
H-G II
H-G II
H-G II
H-G II
H-G II
H-G II
G I
dichloromethane
toluene
toluene
C6F5CF3
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29
29
10
10
100
100
100
100
100
100
100
100
40
48
4
10
51
5
3 × 3c
3 × 3c
10
toluene
C6F5CF3
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83
7c
8d
9
C6F5CF3
48
3 × 3c
3 × 3c
3 × 3c
3 × 3c
3 × 3c
3 × 3c
C6F5CF3
74
toluene
C6F5CF3
77e
88e
40e
30e
71e
10
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13
DCM
G I
C6F5CF3
80
G II
C6F5CF3
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H-G I
3 × 3c
C6F5CF3
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30e
a Isolated yields. b Reaction was stirred at given temperature for 90h. c 3 mol% of the catalyst was added
in 3 portions during course of the reaction. d In the presence of CuI (15 mol%). e 1H NMR yields
(mesitylene was used as the internal standard).
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With the optimized reaction conditions on hand, we proceeded with a study of cross-metathesis
reaction of β-arylated α-methylidene-β-lactams 1a and 1b with selected monosubstituted alkenes 2 in
1:2 ratio (Table 2). Initially, the metatheses of 1a with several substituted styrenes 2b-2f were carried
out. A reaction with 4-nitrostyrene 2b provided the corresponding 3ab in a higher yield in toluene (66%)
than in octafluorotoluene (51%) (Entries 1 and 2). In a similar manner proceeded also reactions with
other 4-cyanostyrene 2c, 4-trifluoromethylstyrene 2d, 4-chlorostyrene 2e, 4-carboxymethylstyrene 2f
and 4-acetoxystyrene 2g furnishing the corresponding lactames 3ac-3ag in good 41-83% isolated yields
(Entries 3-7). Surprisingly, the use of electron-rich styrene 2h gave rise to 4,4’-dimethoxystilbene only
(Entry 8) and an attempt to carry out a reaction with 2-vinylnaphthalene 2i resulted in the formation of a
complex reaction mixture in which the desired product was not detected (Entry 9). A significant drop in
yields of metathesis products was observed in the reactions of 1a with allylbenzene 2j. In both solvents
yields were 43% (Entries 10 and 11). With respect to our goal, the reactivity of 1a towards the
unprotected 2k and protected homoallylic alcohols 2l-2n was also studied. Attempts to carry out CM of
1a with 2k ,2l and 2m did not give rise to the desired CM products (Entries 12-14). Gratifyingly,
employing the TBDMS protected homoallylic alcohol 2n led to the formation of the desired product 3an.
The non-reactivity of 2k,2l and 2m could be speculatively explained by the formation of an internal
interaction between the lone electron pair of the oxygen atom from the corresponding hydroxyl,
acetate, or benzyloxy group with Ru-carbene complex.13 The coordinately saturated complex became
unproductive in further transformation. Notably, lack of reaction of protected homoallylic alcohols in
similar situations has also been reported.14 On the other hand, the bulky TBDMS group in 2n and 2o
(Entries 15-18) prevented the formation of this internally stabilized complex, and this the reactions
proceeded.15 Nevertheless, successful CM of homoallylic alcohols were reported as well,16 and thus the
lack of reactivity of 2k-2m might be a complex issue. In order to compare solvent effect cross-metathesis
of 1a with 2n was carried out in toluene and octafluorotoluene (Entries 15 and 16). Interestingly, as in
the cases of 2b (Entries 1 and 2), a better yield of 3an was obtained in toluene (72%) than in
octafluorotoluene (57%). Although these results may seem rather puzzling, there is not currently any
rational explanation for the observed solvent effect. Finally, CM metathesis of 1b in toluene with (S)-2o,
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prepared either by allylation of 4-fluorobenzaldehyde with allyl boronate (98% ee)6 or by
allyltrichlorosilane (95% ee),17 gave rise to (S)-3bo in a good 67% yield (Entry 17). In all cases Z-
stereoisomers were exclusively formed based on 1H NMR. Formation of the corresponding E-isomers
was not observed and the structures of the Z-isomers were unequivocally confirmed by the X-ray
diffraction analysis of 3aa and 3aj.18 Our results are in agreement with observations described by Howell8
and Ding.23 An increased Z-selectivity in CM of 1 with 2 could be explained by lowered steric hindrance of
bulkier phenyl, benzyl and branched benzyl substituents of 2a-o and aryl moiety (Ph or TBDMSOC6H4) at
C-4 of 1a,b in corresponding CM products 3 with Z-configuration.
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In summary, despite the fact that octafluorotoluene seemed to be the solvent of choice, in some cases
performing reactions in toluene gave better results indicating a complex relationship of influence of
solvent effect on the course of the reaction.
Table 2. Cross metathesis of 1 with various alkenes 2a-2o.
Entry
1
1
2
R3
4-O2NC6H4
4-O2NC6H4
4-NC-C6H4
Solvent
toluene
3
Yield (%)a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
2b
2b
2c
2d
2e
2f
3ab
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
66
51
83
62
41
51
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0b
2
C6F5CF3
3
C6F5CF3
4
4-CF3-C6H4
4-Cl-C6H4
C6F5CF3
5
C6F5CF3
6
4-MeOOC-C6H4
4-AcO-C6H4
4-MeO-C6H4
2-Naphthyl
PhCH2
C6F5CF3
7
2g
2h
2i
C6F5CF3
8
C6F5CF3
c
9
C6F5CF3
-
10
11
12
13
2j
toluene
3aj
43
43
0
2j
PhCH2
C6F5CF3
3aj
2k
2l
rac-PhCH(OH)CH2
rac-PhCH(OAc)CH2
toluene or C6F5CF3
toluene or C6F5CF3
3ak
3al
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1a
1a
1a
1b
2m
2n
2n
rac-PhCH(OBn)CH2
rac-PhCH(OTBDMS)CH2
rac-PhCH(OTBDMS)CH2
toluene or C6F5CF3
3am
3an
0
toluene
C6F5CF3
toluene
toluene
72
57
67
65
16
3an
17
(S)-2o (S)-4-F-C6H4CH(OTBDMS)CH2
(7S)-3bo
(4R,7S)-
18d
(R)-1b (S)-2o (S)-4-F-C6H4CH(OTBDMS)CH2
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3bo
a
b
c
d
Isolated yields. 4,4’-Dimethoxystilbene was formed. A complex reaction mixture. Compound 1b
with 72% ee of (R)- isomer.
With the above described results on hand, we proceeded with the synthesis of Ezetimibe (6,
Scheme 2). Having obtained (7S)-3bo in a good yield (67%) hydrogenation of the trisubstituted double
bond by using Pd/C in MeOH ensued. The hydrogenation proceeded exclusively from the less hindered
side providing the corresponding cis-β-lactam 4 as 1:1 mixture of (3R,4R,7S)- and (3S,4S,7S)-
diastereoisomers in 90% isolated yield. The exclusive preference for the formation of the cis-lactam is
caused by steric hindrance exerted by the β-aryl substituent. Our observation is in agreement with
results of hydrogenation of structurally similar α-alkylidene-β-lactams reported previously.19,20 An
attempt to employ other hydrogenation methods, such as the Stryker's reagent,21 resulted in the
formation of a rather complex reaction mixture out of which only a small amount (~30%) of the cis-
products was isolated. In order to convert the cis-lactam 4 to the desired trans-lactam, epimerization by
using DBN (1,5-diazabicyclo[4.3.0]non-5-ene) in DMSO was applied. During this process occurred not
only epimerization at the position 3, but also deprotection of the phenolic hydroxyl group to the
monosilylated trans-lactam 5 was observed. (3R,4S,7S)-Lactam 5 was easily isolated from the mixture of
trans-diastereoisomers in 42% yield as a single enantiomer. Deprotection of the residual TBDMS group
from the secondary alcohol moiety was accomplished by using Olah reagent (HF/pyridine)22 in a mixture
of THF/pyridine providing Ezetimibe in a high yield of 93% without loss of optical purity (98% ee), which
was the same as that of the starting alcohol (S)-2o (98% ee).
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Scheme 2. Synthesis of Ezetimibe (6) from (S)-3bo.
This approach can be performed even more effectively when enantimerically enriched α-
methylidene-β-lactam 1b would be used. Our attempt to prepare enantimerically pure 1b using
asymmetric amination/lactamization reaction sequence23 starting from the corresponding Morita-Baylis-
Hillman acetate led to formation of (R)-1b in an acceptable yield (41 %) but with 72% ee only. Although
we duly followed the published procedure4b we were not able to achieve the reported enantioselectivity
of 95% ee. Cross-metathesis of (R)-1b with (S)-2o resulted in the formation of (4R,7S)-3bo as a mixture of
diastereoisomers (S,S/S,R = 1:3.5). Subsequent hydrogenation of diastereomerically enriched (4R,7S)-3bo
on Pd/C followed by DBN-based epimerization led to formation of (3R, 4S,7S)-5 in only slightly higher
yield (46% from (4R,7S)-3bo) (Scheme 3). Lower yield of (3R, 4S,7S)-5 is probably caused by opening of
the lactam ring. Based on the reported protocol, Ezetimibe (6) was prepared from the corresponding
homoallylic alcohol and β-lactam in 4 steps and 30% overall yield.
Scheme 3. Synthesis of (3R,4S,7S)-5 from (S,S)-3bo.
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CONCLUSION
In summary, we have explored the Ru-catalyzed cross-metathesis (CM) reaction between β-arylated α-
methylidene-β-lactams and selected olefins. The reaction was efficiently catalyzed by the Hoveyda-
Grubbs 2nd generation catalyst furnishing the corresponding α-alkylidene-β-aryl-β-lactams in good yields
and with the exclusive Z-selectivity. The developed protocol was successfully applied for enantioselective
preparation of Ezetimibe (the commercial cholesterol absorption inhibitor) by using CM, reduction,
epimerization, desilylation reaction sequence in the overall yield of 30%.
EXPERIMENTAL SECTION
General procedure for preparation of (Z)-nitrones: Following the reported procedure,24 to a stirred
solution of a nitrobenzene (100 mmol) in aqueous EtOH (50 mL, 50% aq.) ammonium chloride was added
(6.25 g, 120 mmol). The resulting suspension was cooled to 0 °C by immersion to an ice bath then zinc
dust (15.5 g, 240 mmol) was added in 5 portions, keeping the reaction temperature below 10 °C. The
resulting grey suspension was stirred for 20 minutes and then a solution of a benzaldehyde (70 mmol) in
AcOH (50 mL) was added and the mixture was stirred another 30 minutes. The resulting crystalline mass
was dissolved in toluene (200 mL). The organic phase was separated and washed with water (2×100 mL),
aqueous saturated NaHCO3 solution (100 mL), brine (100 mL), dried over Na2SO4, and concentrated
under reduced pressure to volume of 50 mL. Hexane (120 mL) was added and the precipitated crystals
were collected on a sintered glass funnel, washed with hexane (3×20 mL) and the pure product was dried
under reduced pressure.
C,N-Diphenylnitrone. The reaction was carried out with nitrobenzene (12.50 g, 100 mmol) and
benzaldehyde (7.43 g, 70 mmol). The title compound was obtained as a pale yellow solid (8.12 g, 57 %).
1H and 13C NMR data were in agreement with the previously reported values.25
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C-(4-t-Butyldimethylsilyloxyphenyl)-N-(4-fluorophenyl)nitrone. The reaction was carried out with 4-
fluoronitrobenzene (7.41 g, 53 mmol) and 4-(t-butyldimethylsilyloxy)benzaldehyde (8.61 g, 37 mmol).
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7
1
The title compound was obtained as a pale yellow solid (4.75 g, 38%). Mp 117-119 °C (MeCN). H NMR
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(600 MHz, CDCl3) δ 8.34-8.31 (m, 2H), 7.81-7.75 (m, 3H), 7.16-7.13 (m, 2H), 6.96-6.93 (m, 2H), 1.00 (s,
9H), 0.24 (s, 6H); 13C NMR ( 151 MHz, CDCl3): δ 164.1, 157.9, 144. 8, 133.9, 130.7, 123.2, 119.9, 115.7,
115.4, 25.1, 17.8, - 4.8; 19F NMR (282 MHz, CDCl3) δ -110.96 – (-110.87) (m); IR (KBr): 3120, 3049, 3016,
2959, 2947, 2929, 2890, 2857, 1906, 1691, 1595, 1509, 1497, 1473, 1422, 1320, 1284, 1254, 1236, 1195,
1069, 914, 839, 782 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H25FNO2Si 346.1633; found
346.1632
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General procedure for preparation of 3-methylenelactames (1). Following the reported procedure,5
DMSO (6 mL) was added to (S)-proline (173 mg, 1.5 mmol) under argon, then propargyl alcohol (84 mg,
1.5 mmol) was added and the suspension was stirred 30 min. Then CuI (286 mg, 1.5 mmol) was added in
a stream of argon and the resulting yellow-green suspension was stirred for 5 minutes. After that a
solution of a nitrone (1.5 mmol) in DMSO (6mL) was added in stream of argon and the reaction mixture
was stirred for 18 h. It was then poured into dichloromethane (50 mL) and water (50 mL), vigorously
mixed, then the mixture was filtered through a short column of silica gel (10 g) on a sintered funnel. The
column was washed with dichloromethane (5×10 mL), the biphasic filtrate was transported to a
separating funnel and the organic phase separated. The water phase was extracted with
dichloromethane (3×10 mL), the combined organic phases were washed with water (5×20 mL), dried
(Na2SO4), and concentrated under reduced pressure. Column chromatography of the residue on silica gel
(hexane→5/1 hexane-EtOAc) furnished the title compound.
3-Methylene-1,4-diphenylazetidin-2-one (1a). The reaction was carried out with diphenylnitrone (3.00
g, 15 mmol). Column chromatography furnished 0.677 g (19%) of the title compound as a pale yellow
crystals. 1H and 13C NMR data were in agreement with the reported values.5
4-[4-(t-Butyldimethylsilyloxy]phenyl]-1-(4-fluorophenyl)-3-methyleneazetidin-2-one (1b). The reaction
was carried out with the corresponding nitrone (520 mg, 1.5 mmol). Column chromatography furnished
90 mg (16%) of the title compound as a colorless solid. Mp 112-114 °C (MeOH). 1H NMR (600 MHz,
CDCl3) δ 7.32-7.30 (m, 2H), 7.24-7.23 (m, 2H), 6.96-6.93 (m, 2H), 6.84-6.82 (m, 2H), 5.83 (t, J = 1.8 Hz,
1H), 5.32 (s, 1H), 5.16 (s, 1H), 0.97 (s, 9H), 0.19 (s, 6H); 13C NMR (151 MHz, CDCl3) δ 160.9, 159.9, 158.3,
156.2, 150.0, 133.9, 128.5, 128.0, 120.6, 118.5, 115.9, 115.6, 110.9, 63.5, 25.6, 18.1, -4.4; 19F NMR (282
MHz, CDCl3) δ -117.63- (-117.72) (m); IR (KBr): 3091, 3078, 3062, 3033, 2953, 2931, 2883, 2857, 1739,
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1607, 1509, 1470, 1374, 1266, 1227, 1126, 911, 836, 809 cm-1; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C22H26FNNaO2Si 406.1609; found 406.1609.
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(S)-[1-(4-Fluorophenyl)but-3-en-1-yloxy](t-butyl)dimethylsilane ((S)-2o). Following the reported
procedure,26 t-butyl(dimethyl)silyl chloride (720 mg, 4.79 mmol) was added to a solution of (S)-[1-(4-
fluorophenyl)but-3-en-1-ol6 (551 mg, 3.31 mmol) and imidazole (407 mg, 5.97 mmol) in DMF (6.0 mL),
and the resulting reaction mixture was stirred for 4 h. Then it was poured to a mixture of
dichloromethane (10 mL) and water (10 mL). The phases were separated, the aqueous phase was
extracted with dichloromethane (10 mL) and the combined organic phases were washed with saturated
aqueous NH4Cl solution (10 mL), dried over Na2SO4, and concentrated under reduced pressure. Column
chromatography of the residue on silica gel (hexane, 20 g) furnished 710 mg (75%) of the title compound
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as a colorless oil. H NMR (600 MHz, CDCl3) δ 7.30-7.27 (m, 2H), 7.02-6.99 (m, 2H), 5.80-5.75 (m, 1H),
5.04 (s, 1H), 5.02-5.01 (m, 1H), 4.69 (t, J = 5.4 Hz, 1H) 2.49-2.35 (m, 2H), 0.91 (s, 9H), 0.06 (s, 3H), -0.10 (s,
3H); 13C NMR (151 MHz, CDCl3) δ 162.6, 161.0, 140.9, 134.9, 127.4, 117.1, 114.8, 74.3, 45.5, 25.8, 18.2, -
4.7, -5.0; 19F NMR (282 MHz) δ -116.09 - (-115.99) (m); [α]D = -40.5° (c = 0.237, CHCl3); IR (KBr): 3072,
2959, 2926, 2896, 2857, 1882, 1829, 1760, 1643, 1607, 1509, 1467, 1632, 1251, 1227, 1153, 1081, 1003,
914, 836, 776 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H26FOSi 281.1732; found 281.1736.
General procedure for cross metathesis of lactams 1 with alkenes 2. Method A (catalyst loading in one
portion): In a vial with a PTFE septum (4 mL) was dissolved lactam 1 (0.1 mmol) under argon in a dry
solvent (1 mL), then alkene 2 (0.2 mmol) and the Hoveyda-Grubbs second generation catalyst (6.2 mg,
0.01 mmol) were added and the reaction mixture was stirred at given temperature for given time. Then
the mixture was concentrated under reduced pressure and column chromatography of the residue on
silica gel (toluene) furnished the desired product 3.
General procedure for cross metathesis of lactams 1 with alkenes 2. Method B (gradual catalyst
loading): In a vial with a PTFE septum (4 mL) was dissolved lactam 1 (0.1 mmol) under argon in a dry
solvent (1 mL), then alkene 2 (0.2 mmol) and the Hoveyda-Grubbs second generation catalyst (1.9 mg,
0.003 mmol) were added and the reaction mixture was stirred at 100 °C for 12 h. Then the second
portion of Hoveyda-Grubbs second generation catalyst (1.9 mg, 0.003 mmol) was added and the mixture
was stirred again at 100 °C. After 12 h the final portion of the catalyst (1.9 mg, 0.003 mmol) was added
and the stirring of the reaction mixture at 100 °C continued for 16 h. After cooling to room temperature
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the mixture was concentrated under reduced pressure and column chromatography of the residue on
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silica gel (toluene) furnished the desired product 3.
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(Z)-3-Benzyliden-1,4-diphenylazetidin-2-one (3aa). The reaction was carried out with 1a (23 mg, 0.10
mmol) and 2a (21 mg, 0.20 mmol). Column chromatography furnished 3aa (method A, 16.0 mg, 51%;
method B, 26 mg, 83%) as a colorless crystalline solid. The compound was recrystallized from
methanol/acetone mixture (2/1) for X-ray structure analysis. NMR data were in agreement with the
reported values.27
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(Z)-3-(4-Nitrobenzylidene)-1,4-diphenylazetidin-2-one (3ab). According method B of the general
procedure, the reaction was carried out with 1a (23 mg, 0.10 mmol) and 2b (30 mg, 0.20 mmol). Column
chromatography furnished 23 mg (66%) of the title compound as a yellow needles. NMR data were in
agreement with the reported values.28
(Z)-1,4-Diphenyl-3-(4-cyanobenzylidene)azetidin-2-one (3ac). Following the general procedure (method
B), the reaction was carried out with 1a (23 mg, 0.10 mmol) and 2c (0.026 mL, 0.20 mmol). Column
chromatography (4/1 hexanes/EtOAc) funished 3ac 28 mg (83%) as a yellow solid. Mp. 215-218 °C.1H
NMR (600 MHz, CDCl3) δ 8.12-8.10 (m, 2H), 7.68-7.66 (m, 2H), 7.45-7.38 (m, 7H), 7.31-7.28 (m, 2H), 7.11-
7.08 (m, 1H), 6.28 (s, 1H), 5.44 (d, J = 1.2 Hz, 1H); 13C NMR (151 MHz, CDCl3) δ 159.5, 144.3, 138.0, 137.4,
136.3, 132.4, 130.3, 129.3, 129.2, 129.1, 128.5, 126.7, 124.6, 118.7, 117.2, 112.5, 62.4; IR (KBr): 2926,
2226, 1721, 1709, 1503, 1494, 1377, 1135, 755 cm-1; HRMS (TOF-MS-CI) m/z: [M + H]+ Calcd for
C23H17N2O 337.1335; found 337.1340.
(Z)-1,4-Diphenyl-3-(4-(trifluoromethyl)benzylidene)azetidin-2-one (3ad). Following the general
procedure (method B), the reaction was carried out with 1a (23 mg, 0.10 mmol) and 2d (0.030 mL, 0.20
mmol). Column chromatography (4/1 hexanes/EtOAc) funished 3ad 23.5 mg (62%) as a colorless solid.
Mp 226-227.5 °C.1H NMR (600 MHz, CDCl3) δ 8.12-8.11 (m, 2H), 7.64-7.63 (m, 2H), 7.46-7.38 (m, 7H),
7.31-7.28 (m, 2H), 7.10-7.07 (m, 1H), 6.31 (s, 1H), 5.43 (s, 1H); 13C NMR (151 MHz, CDCl3) δ 159.8, 143.2,
137.6, 137.1, 136.5, 130.90 (q, J = 32.62 Hz), 130.1, 129.3, 129.2, 129.0, 128.9, 126.7, 125.6 (q, J = 3.78
Hz), 124.36, 124.0 (q, J = 272.40 Hz), 117.10, 62.34; 19F NMR (400 MHz, CDCl3) δ - 62.9; IR (KBr) 1724,
1503, 1386, 1326, 1168, 1132, 1123, 1069 cm-1; HRMS (TOF-MS-CI) m/z: [M + H]+ Calcd for C23H17F3NO
380.1250; found 380.1256.
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(Z)-1,4-Diphenyl-3-(4-chlorobenzylidene)azetidin-2-one (3ae). Following the general procedure (method
B), the reaction was carried out with 1a (23 mg, 0.10 mmol) and 2e (0.023 mL, 0.20 mmol). Column
chromatography (4/1 hexanes/EtOAc) funished 3ae 14 mg (41%) as a colorless solid. Mp. 253-255 °C.1H
NMR (600 MHz, CDCl3) δ 7.96-7.94 (m, 2H), 7.45-7.34 (m, 9H), 7.30-7.27 (m, 2H), 7.08-7.05 (m, 1H), 6.23
(s, 1H), 5.40 (s, 1H); 13C NMR (151 MHz, CDCl3) δ 160.1, 141.1, 137.7, 136.8, 135.5, 132.5, 131.3, 129.5,
129.2, 129.1, 128.9, 128.8, 126.7, 124.2, 117.0, 62.3.;IR (KBr) 1715, 1589, 1494, 1452, 1374, 1350, 1132,
839, 749 cm-1; HRMS (TOF-MS-CI) m/z: [M + H]+ Calcd for C22H17ClNO 346.0993; found 346.1000.
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Methyl (Z)-4-((2-oxo-1,4-diphenylazetidin-3-ylidene)methyl)benzoate (3af). Following the general
procedure (method B), the reaction was carried out with 1a (23 mg, 0.10 mmol) and 2f (0.031 g, 0.20
mmol). Column chromatography (4/1 hexanes/EtOAc) funished 3af 18.5 mg (51%) as a colorless solid.
Mp. 188-190 °C.1H NMR (600 MHz, CDCl3) δ 8.07-8.04 (m, 4H), 7.45-7.37 (m, 7H), 7.30-7.27 (m, 2H), 7.09-
7.06 (m, 1H), 6.31 (d, J = 1.2 Hz, 1H), 5.42 (s, 1H), 3.92 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 166.6, 159.8,
143.0, 138.5, 137.6, 136.6, 130.5, 130.1, 129.8 (d, J = 4.08 Hz), 129.5, 129.2 (d, J = 5.29 Hz), 128.9, 126.7,
126.6, 124.3, 117.1, 62.3, 52.2; IR (KBr) 1724, 1595, 1503, 1434, 1377, 1344, 1284, 1105, 908, 752 cm-1;
HRMS (TOF-MS-CI) m/z: [M + H]+ Calcd for C24H20NO3 370.1438; found 370.1436.
(Z)-4-((2-Oxo-1,4-diphenylazetidin-3-ylidene)methyl)phenyl acetate (3ag). Following the general
procedure (method B), the reaction was carried out with 1a (23 mg, 0.10 mmol) and 2g (0.030 mL, 0.20
mmol). Column chromatography (4/1 hexanes/EtOAc) funished 3ag 19 mg (52%) as a colorless solid. Mp.
184-186 °C.1H NMR (600 MHz, CDCl3) δ 8.05-8.03 (m, 2H), 7.45-7.43 (m, 2H), 7.41-7.39 (m, 4H), 7.37-7.34
(m, 1H), 7.29-7.26 (m, 2H), 7.13-7.10 (m, 2H), 7.07-7.05 (m, 1H), 6.26 (s, 1H), 5.40 (s, 1H), 2.30 (s, 3H); 13C
NMR (151 MHz, CDCl3) δ 169.2, 160.3, 151.5, 140.6, 137.8, 136.9, 131.8, 131.3, 129.8, 129.2, 129.1,
128.8, 126.8, 124.1, 121.8, 117.0, 62.2, 21.1;IR (KBr) 3069, 3025, 2361, 2325, 1763, 1715, 1601, 1506,
1497, 1452, 1374, 1210, 1165, 1135, 1009, 917, 851, 752 cm-1; HRMS (TOF-MS-CI) m/z: [M + H]+ Calcd for
C24H20NO3 370.1432; found 370.1430.
(Z)-1,4-Diphenyl-3-(2-phenylethyliden)azetidin-2-one (3aj). Following the general procedure (method
B), the reaction was carried out with 1a (23 mg, 0.10 mmol) and 2j (23.6 mg, 0.20 mmol). Column
chromatography furnished 14 mg (43%) of the title compound as a colorless solid. The compound was
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recrystallized from methanol for X-ray structure analysis. Mp 143-145 °C (MeOH). H NMR (600 MHz,
CDCl3) δ 7.40-7.20 (m, 14 H), 7.07-7.04 (m, 1H), 5.74 (t, J = 6.3 Hz, 1 H), 5.35 (s, 1 H), 4.05-4.01 (m, 1 H),
3.81-3.77 (m, 1H); 13C NMR (151 MHz, CDCl3) δ 161.6, 141.6, 138.9, 137.8, 137.0, 130.1, 129.1, 129.0,
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128.7, 128.6, 128.5, 126.5, 123.8, 116.9, 62.8, 34.9; IR (KBr): 3060, 3028, 2929, 1727, 1589, 1500, 1455,
1374, 1129, 749, 701 cm-1; HRMS (EI-TOF) m/z: [M]+ Calcd for C23H19NO 325.1467; found 325.1463.
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(Z)-3-(3-(t-Butyldimethylsilyloxy)-3-phenylpropyliden-1,4-diphenylazetidin-2-one (3an). According
method B of the general procedure, the reaction was carried out with 1a (23 mg, 0.10 mmol) and 2n (53
mg, 0.20 mmol). Column chromatography furnished 34 mg (72%) of the title compound as 1/1 mixture of
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diastereoisomers as a colorless oil. H NMR (600 MHz, CDCl3) δ 7.36-7.20 (m, 28H), 7.03-7.01 (m, 2H),
5.62 (t, J = 7.5 Hz, 2H), 5.27 (d, J = 3 Hz, 2H), 4.85 (t, J = 6 Hz, 1H), 4.73 (m, 1H), 3.02-2.81 (m, 4H), 0.85 (s,
9H), 0.80 (s, 9H), -0.01 (s, 3H), -0.13 (s, 3H), -0.15 (s, 3H), - 0.20 (s, 3H); 13C NMR (151 MHz, CDCl3) δ
161.5, 144.2, 144.1, 142.7, 142.6, 137.9, 137.0, 129.1, 129.0, 128.9, 128.5, 128.4, 128.1, 128.0, 127.1,
127.0, 126.6, 126.5, 125.8, 125.7, 123.7, 116.9, 74.5, 74.3, 62.8, 39.5, 39.3, 25.8, 25.7, 18.1, -4.8, - 5.0, -
5.3 ppm; IR (KBr): 3084, 3060, 3031, 2956, 2935, 2896, 2854, 1751, 1595, 1500, 1455, 1371, 1254, 1120,
1090, 1066, 937, 839, 779, 755, 698 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C30H36NO2Si 470.2510;
found 470.2502.
3’-(S)-4-(R,S)-(Z)-3-[3’-t-Butyldimethylsilyloxy-3’-(4-fluorophenyl)propylid-1-en]-4-(4-t-
butyldimethylsilyloxy)phenyl-1-(4-fluorophenyl)azetidin-2-one ((7S)-3bo). According method B of the
general procedure, the reaction was carried out with 1b (67 mg, 0.175 mmol) and (S)-2o (98 mg, 0.35
mmol). Column chromatography furnished 75 mg (67%) of the title compound as 1/1 mixture of
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diastereoisomers as a colorless oil. H NMR (600 MHz, CDCl3) δ 7.27-6.78 (m, 24H), 5.58 (t, J = 7.5 Hz,
2H), 5.18 (d, J = 7.7 Hz, 2H), 4.84 (t, J = 6 Hz, 1H), 4.72 (m, 1H), 3.04-2.74 (m, 4H), 0.98 (s, 9H), 0.97 (s,
9H), 0.85 (s, 9H), 0.80 (s, 9H), 0.20 (dd, J = 1.7, 3.2 Hz, 12H), -0.00 (s, 3H), -0.12 (d, J = 4.5 Hz, 6 H), -0.19
(s, 3H); 13C NMR (151 MHz, CDCl3) δ 162.7, 162.6, 161.3, 161.3, 161.1, 161.0, 159.7, 158.1, 156.0, 143.2,
143.1, 140.0, 139.8, 134.2, 129.2, 129.1, 127.9, 127.8, 127.4, 127.3, 127.2, 127.1, 120.5, 120.4, 118.2,
115.9, 115.7, 115.0, 114.9, 114.8, 114.7, 73.9, 73.6, 62.7, 39.5, 39.2, 25.7, 25.7, 25.6, 18.2, 18.1, 18.0, -
4.4, -4.9, -5.0, -5.2; 19F NMR (282 MHz) δ -115.67 – (-115.79) (m, 1F), -115.92 – (-116.10) (m, 1F), -118.12
– (-118.43) (m, 2F); [α]D = 0 (c = 0.096, CHCl3); IR (KBr): 2956, 2935, 2881, 2857, 1751, 1604, 1512, 1473,
1380, 1278, 1263, 1227, 1174, 1135, 917, 839, 782 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C36H48F2NO3Si2 636.3135; found 636.3137.
3’-(S)-4-(R,S)-(Z)-3-[3’-t-Butyldimethylsilyloxy-3’-(4-fluorophenyl)propylid-1-en]-4-(4-t-
butyldimethylsilyloxy)phenyl-1-(4-fluorophenyl)azetidin-2-one ((4R,7S)-3bo). According method B of
the general procedure, the reaction was carried out with (R)-1b (34.7 mg, 0.09 mmol) and (S)-2o (50.7
mg, 0.18 mmol). Column chromatography furnished 37 mg (65%) of the title compound as 1/3.5 mixture
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of diastereoisomers (4R,7S major/4S,7S minor) as a colorless oil. H NMR (600 MHz, CDCl3) δ 7.27-6.79
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(m, 12.33H), 5.58 (t, J = 7.4 Hz, 1H), 5.18 (d, J = 7.8 Hz, 1H), 4.85 (dd, J = 6 Hz, 5.2 Hz, 0.80H, 4R,7S), 4.73
(dd, J = 7.2 Hz, 5.0 Hz, 0.23H, 4S,7S), 3.04-2.95 (m, 0.99H), 2.88-2.84 (m, 0.81H, 4R,7S), 2.79-2.75 (m,
0.22H, 4S,7S), 0.98 (d, 8.50H), 0.85 (s, 7.05H, 4R,7S), 0.80 (s, 1.68H, 4S,7S), 0.20 (dd, J = 4.9, 1.7 Hz,
5.64H), -0.00 (s, 2.37H, 4R,7S), -0.12 (d, J = 4.3 Hz, 2.86 H), -0.18 (s, 0.53H, 4S,7S); 13C NMR (151 MHz,
CDCl3) δ 162.73, 162.65, 161.34, 161.32, 161.11, 161.03, 159.73, 158.12, 156.04, 143.20, 143.13, 140.03,
140.01, 139.82, 139.80, 134.17, 134.15, 129.17, 129.12, 127.95, 127.91, 127.88, 127.86, 127.36, 127.31,
127.25, 127.20, 120.49, 120.43, 118.23, 118.21, 118.18, 118.15, 115.85, 115.70, 115.00, 114.94, 114.86,
114.80, 73.92, 73.60, 62.75, 62.70, 39.50, 39.24, 25.75, 25.68, 25.60, 18.16, 18.14, 18.08, -4.42, -4.85, -
5.01, -5.18.; 19F NMR (376 MHz) δ -115.67 – (-115.75) (m, 0.18F, 4S,7S), -115.90 – (-115.96) (m, 0.78F), -
118.19 – (-118.28) (m, 1F); [α]D = -4.2 (c = 0.176, CHCl3); IR (KBr): 2956, 2935, 2881, 2857, 1751, 1604,
1512, 1473, 1380, 1278, 1263, 1227, 1174, 1135, 917, 839, 782 cm-1; HRMS (ESI-TOF) m/z: HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C36H48F2NO3Si2 636.3135; found 636.3139.
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3’-(S)-4-(R)-3-(R)-[3’-t-Butyldimethylsilyloxy-3’-(4-fluorophenyl)propyl]-4-(4-t-
butyldimethylsilyloxy)phenyl-1-(4-fluorophenyl)azetidin-2-one (3R,4R,7S)-4 and 3’-(S)-4-(S)-3-(S)-[3’-t-
butyldimethylsilyloxy-3’-(4-fluorophenyl)propyl]-4-(4-t-butyldimethylsilyloxy)phenyl-1-(4-
fluorophenyl)azetidin-2-one, (3S,4S,7S)-4. To a solution of 3bo (20 mg, 0.03 mmol) in MeOH (2 mL) Pd/C
(10 %, 10 mg) was added and the flask was flushed with hydrogen. After 24 hours of stirring under
hydrogen atmosphere, the content of the flask was concentrated under reduced pressure and column
chromatography of the residue on silica gel (toluene, 10 g) furnished 18 mg (90%) of 1/1 mixture of
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diastereoisomers as a colorless oil. H NMR (600 MHz, CDCl3) δ 7.26-6.78 (m, 24H), 5.07-5.06 (m, 2H),
4.44-4.42 (m, 1H), 4.33-4.30 (m, 1H), 3.49-3.32 (m, 2H), 1.72-1.59 (m, 2H), 1.45-1.23 (m, 6H), 1.00 (s, 9H),
0.99 (s, 9H), 0.80 (s, 9H), 0.77 (s, 9H), 0.22 (s, 12H), -0.11 (s, 3H), -0.15 (s, 3H), -0.25 (s, 3H), -0.26 (s, 3H);
13C NMR (151 MHz, CDCl3) δ 167.8, 167.6, 162.5, 160.9, 159.6, 158.0, 155.7, 140.8, 133.9, 128.2, 128.1,
127.1, 120.2, 120.1, 118.5, 118.4, 115.8, 115.6, 114.8, 114.7, 74.2, 73.9, 58.0, 54.7, 54.6, 38.2, 38.1, 25.7
(2x), 25.6, 22.0, 18.0, -4.4, -4.8, -5.1, -5.2 ; 19F NMR (282 MHz) δ -116.01 -(-116.11) (m, 1F), -116.19 - (-
116.29) (m, 1F), -118.38 - (-118.51) (m, 2F); [α]D = -13.9 (c = 0.200, CHCl3); IR (KBr): 2956, 2926, 2899,
2857, 1721, 1709, 1559, 1535, 1512, 1263, 1222, 1099, 1087, 917, 836, 779 cm-1; HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C36H49F2NNaO3Si2 660.3111; found 660.3112.
3’-(S)-4-(R)-3-(R)-[3’-t-Butyldimethylsilyloxy-3’-(4-fluorophenyl)propyl]-4-(4-t-
butyldimethylsilyloxy)phenyl-1-(4-fluorophenyl)azetidin-2-one (3R,4R,7S)-5 and 3’-(S)-4-(S)-3-(S)-[3’-t-
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butyldimethylsilyloxy-3’-(4-fluorophenyl)propyl]-4-(4-t-butyldimethylsilyloxy)phenyl-1-(4-
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fluorophenyl)azetidin-2-one, (3S,4S,7S)-5. To a solution of ((4R,7S)-3bo) (18 mg, 0.027 mmol) in MeOH
(2 mL) Pd/C (10 %, 8.5 mg) was added and the flask was flushed with hydrogen. After 30 minutes of
stirring under hydrogen atmosphere, the content of the flask was filtred through celite, washed by (3 x
5mL) of toluene. The procedure furnished 17.7 mg (98%) of 1/3,57 mixture of diastereoisomers (3S,4S,7S
major/3R,4R,7S minor) as a colorless oil. 1H NMR (600 MHz, CDCl3) δ 7.26-6.78 (m, 12.19H), 5.07-5.06 (t,
1H), 4.43 (t, J = 5.6 Hz, 0.23H, 3R,4R,7S), 4.32 (dd, J = 7.5, 5.1 Hz, 0.80H, 3S,4S,7S), 3.49-3.42 (m, 0.98H),
1.73-1.58 (m, 2.51H), 1.45-1.26 (m, 2.61H), 1.13-1.05 (m, 0.90H) 1.00 (s, 8.63H), 0.90-0.84 (m, 0.79H),
0.79 (d, 8.34, 8.44H), 0.22 (s, 5.74H, 3S,4S,7S), -0.13 (d, J = 20.3 Hz, 2.92H), -0.25 (s, 3H), -0.26 (s, 2.80H);
13C NMR (151 MHz, CDCl3) δ 167.76, 167.59, 162.55, 160.93, 159.64, 158.03, 155.78, 140.81, 140.79,
133.93, 133.91, 133.89, 128.25, 128.15, 127.18, 127.13, 127.10, 127.05, 126.83, 120.20, 120.17, 118.49,
118.44, 115.78, 115.63, 114.83, 114.69, 74.19, 73.92, 58.05, 58.03, 54.68, 54.60, 38.25, 38.20, 25.75,
25.72, 25.60, 22.01, 18.16, 18.13, 18.06, -4.40, -4.43, -4.77, -4.80, -5.09, -5. 19F NMR 19F NMR (282 MHz,
cdcl3) δ -116.09 – -116.28 (m, 1F), -118.45 (dq, J = 8.4, 4.7 Hz, 1F); [α]D = -44 (c = 0.187, CHCl3); IR (KBr):
2956, 2926, 2899, 2857, 1721, 1709, 1559, 1535, 1512, 1263, 1222, 1099, 1087, 917, 836, 779 cm-1;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C36H49F2NNaO3Si2 660.3111; found 660.3108.
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3’-(S)-4-(S)-3-(R)-[3’-t-Butyldimethylsilyloxy-3’-(4-fluorophenyl)propyl]-4-(4-hydroxyphenyl-1-(4-
fluorophenyl)azetidin-2-one ((3R,4S,7S)-5). To a solution of (3S,4S,7S)-5/(3R,4R,7S)-5,in ratio 1/1, (75
mg, 0.12 mmol) in DMSO (10 mL) 1,5-diazabicyclo[4.3.0]non-5-ene (17 mg, 0.14 mmol) was added. After
24 hours of stirring, content of the flask was poured to aqueous hydrochloric acid (20 mL, 0.1 M) with
stirring. The mixture was extracted with EtOAc (3×10 mL) and the combined organic phases were washed
with water and dried with Na2SO4. The solution was concentrated under reduced pressure and column
chromatography of the residue on silica gel (toluene-EtOAc 10/1, 25 g) furnished 26 mg (42%) of the title
compound as an colorless oil. Sample for characterization purposes was purified via reverse-phase
preparative TLC. 1H and 13C NMR data were in agreement with the reported values.29 19F NMR (282 MHz)
δ -115.73 - (-115.86) (m, 1F), -118.14 - (-118.29) (m, 1F). [α]D = -20.3 (c = 0.958, CHCl3); LRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C30H35F2NNaO3Si 546.2; found 546.2.
3’-(S)-4-(S)-3-(R)-[3’-t-Butyldimethylsilyloxy-3’-(4-fluorophenyl)propyl]-4-(4-hydroxyphenyl-1-(4-
fluorophenyl)azetidin-2-one ((3R,4S,7S)-5). To a solution of (3S,4S,7S)-5/(3R,4R,7S)-5 in ratio 3.5/1 (30
mg, 0.048 mmol) in DMSO (4 mL) 1,5-diazabicyclo[4.3.0]non-5-ene (7 mg, 0.056 mmol) was added. After
13 hours of stirring, content of the flask was added dropwise to aqueous hydrochloric acid (8 mL, 0.1 M)
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with stirring. The mixture was extracted with EtOAc (3×10 mL) and the combined organic phases were
washed with water and dried with Na2SO4. The solution was concentrated under reduced pressure and
column chromatography of the residue on silica gel (EtOAc-Hexanes 7/1, 10 g), second column
chromatography (EtOAc-Hexanes 10/1, 8 g) furnished 11,5 mg (46%) of the title compound as an
colorless oil. 1H and 13C NMR data were in agreement with the reported values.29 19F NMR (282 MHz) δ -
115.73 - (-115.86) (m, 1F), -118.14 - (-118.29) (m, 1F). [α]D = -20.3 (c = 0.958, CHCl3); LRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C30H35F2NNaO3Si 546.2; found 546.2.
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3’-(S)-4-(S)-3-(R)-[3’-Hydroxy-3’-(4-fluorophenyl)propyl]-4-(4-hydroxyphenyl-1-(4-
fluorophenyl)azetidin-2-one), Ezetimibe (6). To a solution of (S,R,S)-5 (20 mg, 0.04 mmol) in dry THF (1
mL) and anhydrous pyridine (0.5 mL) was added followed by HF·pyridine complex (0.5 mL). After 24
hours of stirring at room temperature, aqueous sodium hydrogencarbonate (5 mL) was added with
stirring. The mixture was extracted with EtOAc (4×5 mL) and the combined organic phases were washed
with water and dried with Na2SO4. The content of the flask was concentrated under reduced pressure
and flash chromatography of the residue on silica gel (chloroform→acetone, 10 g) furnished 15 mg (93%)
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of the title compound as a white solid. H and 13C NMR data were in agreement with the reported
values.29 19F NMR (282 MHz) δ -114.72 - (-115.80) (m, 1F), -117.62 - (-117.73) (m, 1F). [α]D = -29.9 (c =
0.194, MeOH).
ACKNOWLEDGMENT
Authors gratefully acknowledge financial support from the Czech Science Foundation, M.K (13-15915S),
J.V. (16-23597S), Charles University Grant Agency, N.T. (1132/2015), and support from the Ministry of
Education, Youth, and Sports (MSM0021620857). This publication is also a result of the project
implementation: Support of establishment, development and mobility of quality research teams at
Charles University, project number CZ.1.07/2.3.00/30.0022, supported by the Education for
Competitiveness Operational Programme (ECOP) and co-financed by the European Social Fund and the
state budget of the Czech Republic.
ASSOCIATED CONTENT
Supporting Information: 1H NMR spectra of 1a, 1b, 2n, (S)-2o, 3aa, 3ab, 3ac, 3ad, 3ae, 3af, 3ag, 3aj, 3an,
(7S)-3bo, (4R,7S)-3bo, (3R,4R,7S)-4/(3S,4S,7S)-4, (3R,4R,7S)-5, Ezetimibe. 13C NMR spectra of 1a, 1b, (S)-
2o, 3ac, 3ad, 3ae, 3af, 3ag, 3an, (7S)-3bo, (4R,7S)-3bo, (3R,4R,7S)-4/(3S,4S,7S)-4, (3R,4R,7S)-5, Ezetimibe,
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19F NMR spectra of 1b, (S)-2h, 3ad, (7S)-3bo, (4R,7S)-3bo, (3R,4R,7S)-4/(3S,4S,7S)-4, (3R,4R,7S)-5,
Ezetimibe and X-ray crystallographic data for 3aa and 3aj. This material is available free of charge via the
Internet at http://pubs.acs.org/.
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References
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