Enantioselective synthesis of α,α-difluoro-β-lactams using amino alcohol ligands

Article abstract of DOI:10.1039/c4ob01184h

A practical and highly enantioselective Reformatsky reaction of ethyl bromodifluoroacetate with imines using a cheap and commercially available amino alcohol ligand is described. A variety of α,α-difluoro-β- lactams were obtained in up to 74% yield with high enantioselectivity in excess of 99% ee. The use of ethyl bromodifluoroacetate provides for ease of operation because of the inherent chemical stability of this reagent. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob01184h

Organic &
Biomolecular Chemistry
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Enantioselective synthesis of α,α-difluoro-
β-lactams using amino alcohol ligands†
Cite this: Org. Biomol. Chem., 2014,
12, 6484
Atsushi Tarui, Takeshi Ikebata, Kazuyuki Sato, Masaaki Omote and Akira Ando*
A practical and highly enantioselective Reformatsky reaction of ethyl bromodifluoroacetate with imines
using a cheap and commercially available amino alcohol ligand is described. A variety of α,α-difluoro-
β-lactams were obtained in up to 74% yield with high enantioselectivity in excess of 99% ee. The use of
ethyl bromodifluoroacetate provides for ease of operation because of the inherent chemical stability of
this reagent.
Received 9th June 2014,
Accepted 27th June 2014
DOI: 10.1039/c4ob01184h
www.rsc.org/obc
fluoro-β-lactam (3) and α-bromo-α-fluoro-β-lactam (4), using
the Reformatsky reaction of bromodifluoroacetate (1) or di-
Introduction
The incorporation of fluorine atoms into organic molecules bromofluoroacetate (2) with imines (Scheme 1).17,18 Although
can substantially alter the physical and biological properties of fluorinated β-lactams are important in medicinal chemistry,
the molecules, leading to useful biological and pharmacologi- stereoselective syntheses of these molecules remain scarce.
cal effects.1 Organofluorine compounds have been used exten- Stereoselective approaches have been limited to starting from
sively in the medicinal,2 agrochemical,3 and materials science chiral imines, chiral oxazolines, or chiral halodifluoroacetates
fields.4 In particular, fluorine-containing compounds have in a diastereoselective manner.19 α,α-Difluoro-β-amino esters,
been successful as pharmaceutical drugs.5 The β-lactam struc- which are non-cyclized Reformatsky adducts, have also been
ture has been used not only in antibiotics,6 but also in bio- synthesized using the Reformatsky reaction of 1 with chiral
active compounds, including a hypercholesterol therapeutic imines.20 Akiyama et al. have reported an asymmetric Mannich
agent.7 Incorporation of the CF2 group into a β-lactam ring to reaction using difluoroenol silyl ethers with N-Boc imines in
create an α-fluorinated β-lactam is expected to enhance the the presence of a 1,1′-bi-2-naphthol derived chiral phosphoric
antibiotic activity of the parent β-lactam due to the increased acid catalyst, providing α,α-difluoro-β-lactams enantioselec-
electrophilicity and structural strain of an amide bond. In fact, tively from the Mannich-adducts.21 Recently, a high enantio-
fluoro-β-lactams and difluoro-β-lactams have been shown to be selectivity has been achieved through the reaction of ethyl
effective in the inhibition of β-lactamases8 and human leuko- iododifluoroacetate or ethyl iodofluoroacetate with ketones in
cyte elastase.9 Furthermore, it is important that α-fluorinated the presence of a stoichiometric amount of a chiral ligand.22,23
β-lactams have been used as building blocks to introduce Unfortunately, despite giving the desired products in high
α-fluorinated β-amino acid moieties into bioactive com- yield with good enantioselectivity, the poor chemical stability
pounds.10 To date, fluorinated β-lactams have been syn- of the iodoacetate reagents has impaired the convenience of
thesized by various approaches, including cycloaddition of a this approach. Recently, we published an asymmetric imino-
halofluoroacetate with Schiff bases,11 [2 + 2] fluoroketene- Reformatsky reaction of 2 with an imine using a substoichio-
imine condensation,12 Mitsunobu ring closure of 3-hydroxy-
2,2-difluoropropaneamides,10a,b,13 intramolecular hydroamina-
tion of difluoropropargyl amides,14 cycloaddition of a nitrone
to a hexafluoropropene,15 and direct electrophilic fluorination
of β-lactam nuclei.16 The Reformatsky reaction of a halofluoro-
acetate with an imine is the simplest and most direct
approach toward a fluoro-β-lactam. Recently, we reported the
syntheses of several fluorinated β-lactams, including the α,α-di-
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho,
Hirakata, Osaka 573-0101, Japan. E-mail: aando@pharm.setsunan.ac.jp
†Electronic supplementary information (ESI) available: Copies of 1H NMR, 13C
NMR spectra and HPLC chromatograms. See DOI: 10.1039/c4ob01184h
Scheme 1 Imino-Reformatsky reaction of halofluoroacetates 1 and 2.
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metric amount of (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-propan-1- carried out in CH2Cl2 at 0 °C in the presence of 0.75 equiv. of
ol (L1) as a chiral ligand (eqn (1)).24 In this reaction, a variety L1. The reaction provided the desired product (3a) with excel-
of different imines were used to provide the chiral (3S,4R)- lent enantiomeric excess (96%), but the reaction was slow and
α-bromo-α-fluoro-β-lactams (4) in good yields with high the yield of 3a was moderate (63%). To improve the yield of 3a,
enantio- and diastereoselectivities. As part of our ongoing the reaction conditions were optimized. When a stoichiometric
work toward the stereoselective synthesis of fluorinated amount of L1 was used, the yield of 3a was slightly increased
β-lactams, we herein report the asymmetric synthesis of α,α-di- (entry 2). This improvement in yield was also observed when
fluoro-β-lactams by a convenient approach using the chemi- the reaction was carried out at room temperature (entry 3).
cally stable reagent 1 in the presence of a chiral amino alcohol Different chiral ligands were also explored to find the optimal
ligand.
ligand. (1R,2S)-2-(Dimethylamino)-1-phenylpropan-1-ol (L2)
was effective, although the stereoselectivity was slightly
decreased (entry 4). (1R,2S)-2-(Dibutylamino)-1-phenylpropan-
1-ol (L3) was found to be an inferior catalyst with respect to
the chemical yield and enantioselectivity of the product com-
pared with L1 (entry 5). The prolinol ligand (L4) also led to
lower enantioselectivity of the desired product, although the
yield of the product was comparable to that of L1 (entry 6).
Based on these results, the optimal reaction conditions were
determined to be a stoichiometric amount of ligand L1 at
room temperature.
ð1Þ
Scope and limitations of the enantioselective syntheses of
difluoro-β-lactams
With the optimal conditions in hand, we investigated the gen-
erality of our protocol using a variety of differently substituted
aromatic imines. The results of these investigations are listed
in Table 2. In comparison with the reaction of 2, high enantio-
selectivity was observed regardless of the substituents on the
aromatic rings. In particular, imines bearing an electron-with-
drawing substituent on the aromatic ring gave rise to the
corresponding products with high enantioselectivity (3c–3f).
However, the yields of the products were lower than those of
the products in the reaction with 2. These results suggest that
the low yields of 3 were caused by the low reactivity of 1 with
the diethyl zinc. In fact, generation of the Reformatsky reagent
from 1 required the use of heat or an additive, such as diethyl-
aluminum chloride,19,25 whereas the Reformatsky reagent of 2
can be generated below room temperature without the pres-
ence of a promoter.18,24,26,27 In all cases, the decomposition
products of imine were recovered after column chromato-
graphy. The opposite enantiomer was also obtained, using the
(1S,2R)-isomer of the ligand, in 67% yield and 86% ee.
Results and discussion
Optimization of the enantioselective synthesis of difluoro-
β-lactams
Based on our previous research, we envisioned that the imino-
Reformatsky reaction of 1 using a chiral amino alcohol ligand
would proceed enantioselectively to provide a new approach to
enantioenriched α,α-difluoro-β-lactam 3. We initially investi-
gated the enantioselective Reformatsky reaction with the modi-
fied conditions of our previously reported reaction (Table 1,
entry 1). The reaction of 1 with benzylidenebenzylamine was
Table 1 Screening of reaction conditions
Absolute configuration of the products and the proposed
reaction mechanism
The absolute configuration of the product 3a was determined
by comparison of the order of elution by chiral HPLC analysis
and the sign of the optical rotation with (S)-3a obtained from
the reaction of (−)-menthyl bromodifluoroacetate with benzyl-
idenebenzylamine.19d The results indicated that the absolute
configuration of the product obtained through the Refor-
matsky reaction is (R)-3a. Absolute configurations of the other
products were also assigned in the same manner. Considering
these results, we proposed the reaction mechanism as shown
in Scheme 2, which is the same model that we have previously
proposed.24 This transition model is supported by Noyori’s
Temp
(°C)
Yielda
(%)
eeb
(%)
Entry
Ligand (equiv.)
1
2
3
4
5
6
L1
L1
L1
L2
L3
L4
0.75
0
0
r.t.
r.t.
r.t.
r.t.
63
67
72
76
39
73
96
91
91
85
62
21
1
1
1
1
1
a Isolated yields. b Determined by HPLC.
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Table 2 Scope and limitations of asymmetric syntheses of 3
a Isolated yields. b Determined by HPLC. c The values indicate the ee after recrystallization of the products. d The (1S,2R)-isomer of ligand L1 was
used.
rise to chiral α,α-difluoro-β-lactams with excellent enantio-
selectivity in excess of 99% ee under mild conditions at room
temperature.
Experimental
NMR spectra were obtained from a solution in CDCl3 using
600 and 400 MHz for 1H, 150 and 100 MHz for 13C and 564
Scheme 2 Proposed stereoinduction model of the Reformatsky
reaction.
1
and 84 MHz for 19F. Chemical shifts of H NMR and 13C NMR
are reported in ppm from tetramethylsilane (TMS) as an
internal standard. Chemical shifts of 19F NMR are reported in
representative transition model as well as Soai’s model.28
ppm from benzotrifluoride (BTF) as an internal standard. All
However, the exact mechanism of this reaction remains
data are reported as follows: chemical shifts, relative inte-
unclear. Hence, a detailed investigation on the mechanism
gration value, multiplicity (s = singlet, d = doublet, t = triplet,
will be presented in a future paper.
q = quartet, dd = doublet doublet, br = broad, brs = broad-
singlet, m = multiplet), coupling constants (Hz). High-resolu-
tion mass spectroscopy (HRMS) experiments were performed
on a double-focusing mass spectrometer with an ionization
Conclusions
mode of EI. Infrared (IR) spectra were recorded in KBr tablets
We have presented a convenient method for an enantio- or thin films on KBr disks. Melting points measured were
selective imino-Reformatsky reaction of ethyl bromodifluoro- uncorrected. Analytical high performance liquid chromato-
acetate (1) using a stoichiometric amount of (1R,2S)-1-phenyl- graphy (HPLC) was performed on a Shimadzu 10A instrument
2-(1-pyrrolidinyl)-propan-1-ol (L1) as a chiral ligand. This using a Daicel CHIRALPAK AD-H (0.46 cm I.D. × 25 cm).
approach provides for not only convenient experimental oper- Optical rotations were recorded on a JASCO P1020.
ation, as it uses the chemically stable reagent 1, but also easy
All experiments were carried out under an argon atmos-
access to a chiral fluorinated building block. The reaction gave phere in flame-dried glassware using standard inert tech-
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niques for introducing reagents and solvents unless otherwise requires 323.1122). The ee was determined to be 92% by HPLC
noted. Anhydrous THF and diethyl ether (Et2O) were distilled (Daicel CHIRALPAK AD-H, hexane–iPrOH = 95 : 5, 0.7 mL
over benzophenone ketyl sodium just before use. Anhydrous min−1, 254 nm, major 16.2 min and minor 14.8 min).
dichloromethane was distilled over P2O5 just before use. All
(R)-1-Benzyl-3,3-difluoro-4-{4-(trifluoromethyl)phenyl}azeti-
commercially available materials were used as received din-2-one 3c. The title product 3c was obtained as a colorless
without further purification. Diethyl zinc 1.0 M in hexane was solid (162 mg, 47%) after column chromatography (AcOEt–
purchased from Aldrich. All imines were synthesized from hexane = 1 : 9). mp 142.0–143.0 °C; [α]2D5 −77 (c 1.00 in CHCl3);
amines and aldehydes using MgSO4 as a desiccant. The ligand IR (KBr) cm−1 1771; δH (CDCl3, 400 MHz) 3.98 (1H, dd, J 14.9,
(L2) was synthesized following the procedure described in the 2.2 Hz), 4.77 (1H, dd, J 7.3, 1.9 Hz), 4.95 (1H, d, J 14.9 Hz),
literature.29
7.10–7.13 (2H, m), 7.32–7.36 (5H, m), 7.68 (2H, d, J 7.8 Hz); δC
(CDCl3, 100 MHz) 44.6 (m), 67.3 (dd, J 27, 24 Hz), 120.3 (dd, J
293, 290 Hz), 123.4 (q, J 271 Hz), 125.8 (q, J 4 Hz), 128.3, 128.4,
128.5, 129.0, 131.8 (q, J 33 Hz), 132.8, 134.1 (m), 160.4 (m); δF
General procedure for the enantioselective imino-Reformatsky
reaction of ethyl bromodifluoroacetate
Ethyl bromodifluoroacetate (2) (2.0 mmol, 0.26 mL) was added (CDCl3, 90 MHz, hexafluorobenzene) 41.2 (1F, d, J 225 Hz),
to a solution of the corresponding imine (1 mmol) and 48.1 (1F, dd, J 225, 7 Hz), 99.3 (3F, s); m/z (EI) 341.0839 (M+.
(1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-propan-1-ol (L1) (1.0 mmol, C17H12F5NO requires 341.0839). The ee was determined to be
205 mg) in CH2Cl2 (8 mL) at ambient temperature. Then, the 97% by HPLC (Daicel CHIRALPAK AD-H, hexane–EtOH =
mixture was cooled to 0 °C, and 1.0 M Et2Zn in hexane 98 : 2, 1.0 mL min−1, 254 nm, major 10.4 min and minor
(3.5 mmol, 3.5 mL) was slowly added to the mixture at 0 °C. 9.5 min).
The reaction mixture was allowed to warm to ambient tempera-
(R)-1-Benzyl-4-(4-chlorophenyl)-3,3-difluoroazetidin-2-one
ture, and the whole mixture was stirred at the same tempera- 3d. The title product 3d was obtained as a colorless solid
ture for an appropriate time. The mixture was quenched with (226 mg, 74%) after column chromatography (AcOEt–hexane =
saturated aqueous NaHCO3, and was filtered through a Celite 1 : 9). mp 76.5–77.5 °C; [α]2D5 −109 (c 1.04 in CHCl3); IR (KBr)
pad. The filtrate was extracted with AcOEt, and then the extract cm−1 1814; δH (CDCl3, 400 MHz), 3.93 (1H, dd, J 14.7, 2.0 Hz),
was washed with brine and dried over MgSO4. The solvent was 4.68 (1H, dd, J 7.2, 2.2 Hz), 4.92 (1H, d, J 14.7 Hz), 7.10–7.13
removed in vacuo and the residue was purified by column (2H, m), 7.16 (2H, d, J 8.4 Hz), 7.31–7.34 (3H, m), 7.40 (2H, d, J
chromatography (AcOEt–hexane) to afford the corresponding 8.4 Hz); δC (CDCl3, 100 MHz) 44.3 (m), 67.2 (dd, J 26, 24 Hz),
α,α-difluoro-β-lactam 3.
120.2 (dd, J 293, 290 Hz), 128.3, 128.4, 128.9, 129.1, 129.2,
Racemates 3 were synthesized following the procedure 132.9, 135.8, 160.5 (m); δF (CDCl3, 90 MHz) −58.4 (1F, d, J 225
described in the literature.17
Hz), −51.8 (1F, dd, J 225, 7 Hz); m/z (EI) 307.0575 (M+. 100%.
(R)-1-Benzyl-3,3-difluoro-4-phenylazetidin-2-one
3a. The C16H12ClF2NO requires 307.0575), 309.0538 (34). The ee was
title product 3a was obtained as a colorless liquid (192 mg, determined to be 96% by HPLC (Daicel CHIRALPAK AD-H,
72%) after column chromatography (AcOEt–hexane = 1 : 9). hexane–iPrOH = 9 : 1, 0.7 mL min−1, 254 nm, major 11.2 min
[α]2D5 −92.3 (c 1.05 in CHCl3); IR (neat) cm−1 1790; δH (CDCl3, and minor 10.1 min).
600 MHz) 3.93 (1H, dd, J 14.8, 2.0 Hz), 4.72 (1H, dd, J 7.3, 2.1
(R)-1-Benzyl-3,3-difluoro-4-(4-methoxycarbonylphenyl)azeti-
Hz), 4.95 (1H, d, J 14.8 Hz), 7.11–7.13 (2H, m), 7.22–7.23 (2H, din-2-one 3e. The title product 3e was obtained as a colorless
m), 7.31–7.33 (3H, m), 7.42–7.44 (3H, m); δC (CDCl3, 150 MHz) solid (230 mg, 69%) after column chromatography (AcOEt–
44.2 (m), 68.0 (dd, J 26, 24 Hz), 120.5 (dd, J 293, 290 Hz), hexane = 1 : 4). mp 98.0–99.0 °C; [α]2D5 −92 (c 1.00 in CHCl3); IR
128.1, 128.4, 128.6, 129.0, 129.1, 129.8, 130.0, 133.4, 160.9 (m); (KBr) 1812, 1715 cm−1; δH (CDCl3, 600 MHz) 3.94 (3H, s), 3.96
δF NMR (CDCl3, 90 MHz) −58.9 (1F, d, J 224 Hz), −51.8 (1F, dd, (1H, dd, J 14.8, 2.0 Hz), 4.75 (1H, dd, J 7.3, 1.8 Hz), 4.95 (1H, d,
J 224, 7 Hz); m/z (EI) 273.0963 (M+. C16H13F2NO requires J 14.8 Hz), 7.09–7.11 (2H, m), 7.30 (2H, d, J 8.3 Hz), 7.32–7.33
273.0965). The ee was determined to be 91% by HPLC (Daicel (3H, m), 8.08 (2H, d, J 8.3 Hz); δC (CDCl3, 150 MHz) 44.6 (m),
CHIRALPAK AD-H, hexane–iPrOH = 9 : 1, 0.7 mL min−1
,
52.4, 67.6 (dd, J 27, 24 Hz), 120.4 (dd, J 293, 291 Hz), 128.1,
254 nm, major 10.1 min and minor 9.0 min).
128.6, 128.6, 129.2, 130.2, 131.6, 133.1, 135.0, 160.7 (m), 166.3;
(R)-1-Benzyl-3,3-difluoro-4-(naphthalen-2-yl)azetidin-2-one δF (CDCl3, 90 MHz) −58.1 (1F, d, J 224 Hz), −51.5 (1F, dd, J
3b. The title product 3b was obtained as a colorless solid 224, 7 Hz); m/z (EI) 331.1014 (M+. C18H15F2NO3 requires
(143 mg, 46%) after column chromatography (AcOEt–hexane = 331.1020). The ee was determined to be 94% by HPLC (Daicel
1 : 9). mp 94.5–95.0 °C; [α]2D5 −109 (c 1.00 in CHCl3); IR (KBr) CHIRALPAK AD-H, hexane–iPrOH = 4 : 1, 1.0 mL min−1
,
cm−1 1800; δH (CDCl3, 600 MHz) 3.99 (1H, dd, J 14.9, 1.9 Hz), 254 nm, major 9.5 min and minor 7.0 min).
4.89 (1H, dd, J 7.4, 2.0 Hz), 4.98 (1H, d, J 14.9 Hz), 7.12–7.13
(R)-4-(1-Benzyl-3,3-difluoro-4-oxoazetidin-2-yl)benzonitrile
(2H, m), 7.31–7.33 (4H, m), 7.54–7.56 (2H, m), 7.70 (1H, m), 3f. The title product 3f was obtained as a colorless solid
7.83–7.91 (3H, m); δC (CDCl3, 150 MHz) 44.4 (m), 68.3 (dd, (133 mg, 45%) after column chromatography (AcOEt–hexane =
J 27, 24 Hz), 120.7 (dd, J 293, 290 Hz), 124.5, 126.9, 127.1, 27.5, 1 : 4). mp 66.0–67.0 °C; [α]2D5 −154 (c 1.00 in CHCl3); IR (KBr)
127.9, 128.1, 128.4, 128.5, 128.7, 129.0, 129.1, 133.1, 133.5, cm−1 2228, 1811; δH (CDCl3, 400 MHz) 4.01 (1H, dd, J 14.9,
133.9, 161.0 (m); δF (CDCl3, 90 MHz) −58.6 (1F, d, J 225 Hz), 2.0 Hz), 4.76 (1H, dd, J 7.3, 1.9 Hz), 4.92 (1H, d, J 14.9 Hz),
−51.5 (1F, dd, J 225, 7 Hz); m/z (EI) 323.1121 (M+. C20H15F2NO 7.09–7.12 (2H, m), 7.31–7.35 (5H, m), 7.71 (2H, d, J 8.3 Hz);
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δC (CDCl3, 100 MHz) 44.8 (m), 67.3 (dd, J 26, 24 Hz), 113.7, dd, J 14.8, 2.1 Hz), 4.72 (1H, dd, J 7.2, 2.2 Hz), 4.95 (1H, d, J
117.8, 120.2 (dd, J 293, 291 Hz), 128.4, 128.5, 129.0, 132.5, 14.8 Hz), 7.11–7.14 (2H, m), 7.22–7.24 (2H, m), 7.32–7.33 (3H,
132.7, 135.3, 135.3, 160.2 (m); δF (CDCl3, 90 MHz) −57.7 (1F, d, m), 7.41–7.44 (3H, m); δF (CDCl3, 90 MHz) −58.9 (1F, d, J
J 225 Hz), −51.2 (1F, dd, J 225, 7 Hz); m/z (EI) 298.0909 (M+. 224 Hz), −51.8 (1F, dd, J 224, 7 Hz). The ee was determined to
C17H12F2N2O requires 298.0918). The ee was determined to be be 89% by HPLC (Daicel CHIRALPAK AD-H, hexane–iPrOH =
>99% by HPLC (Daicel CHIRALPAK AD-H, hexane–iPrOH = 9 : 1, 0.7 mL min−1, 254 nm, major 9.0 min and minor
4 : 1, 1.0 mL min−1, 254 nm, major 9.3 min and minor 10.2 min).
8.4 min).
(R)-1-Benzyl-3,3-difluoro-4-(p-tolyl)azetidin-2-one
3g. The
Notes and references
title product 3g was obtained as a colorless solid (219 mg,
76%) after column chromatography (AcOEt–hexane = 1 : 9). mp
75–77.0 °C; [α]2D5 −82 (c 1.00 in CHCl3); IR (KBr) cm−1 1770; δH
(CDCl3, 600 MHz) 2.39 (3H, s), 3.90 (1H, dd, J 14.9, 1.9 Hz),
4.68 (1H, dd, J 7.3, 2.1 Hz), 4.94 (1H, d, J 14.9 Hz), 7.11–7.13
(4H, m), 7.23 (2H, d, J 7.8 Hz), 7.32–7.34 (3H, m); δC (CDCl3,
150 MHz) 21.3, 44.1 (m), 67.8 (dd, J 26, 24 Hz), 120.6 (dd,
J 292, 290 Hz), 126.9, 128.0, 128.4, 128.6, 129.0, 129.8, 133.5,
139.9, 161.0 (m); δF (CDCl3, 90 MHz) −58.8 (1F, d, J 224 Hz),
−52.2 (1F, dd, J 224, 7 Hz); m/z (EI) 287.1118 (M+. C17H15F2NO
requires 287.1122). The ee was determined to be 91% by HPLC
(Daicel CHIRALPAK AD-H, hexane–iPrOH = 9 : 1, 1.0 mL
min−1, 254 nm, major 6.8 min and minor 6.2 min).
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(R)-1-Benzyl-3,3-difluoro-4-(4-methoxyphenyl)azetidin-2-one
3h. The title product 3h was obtained as a colorless solid
(208 mg, 68%) after column chromatography (AcOEt–hexane =
1 : 9). mp 120.0–121.0 °C; [α]2D5 −94 (c 1.00 in CHCl3); IR (KBr)
cm−1 1771; δH (CDCl3, 600 MHz) 3.83 (3H, s), 3.90 (1H, dd,
J 14.9, 2.0 Hz), 4.67 (1H, dd, J 7.3, 2.2 Hz), 4.91 (1H, d,
J 14.9 Hz), 6.94 (2H, d, J 8.6 Hz), 7.11–7.13 (2H, m), 7.15 (2H,
d, J 8.6 Hz), 7.32–7.33 (3H, m); δC (CDCl3, 150 MHz) 44.0 (m),
55.4, 67.7 (dd, J 26, 24 Hz), 114.5, 120.6 (dd, J 292, 290 Hz),
121.7, 128.4, 128.6, 129.0, 129.5, 133.5, 160.8, 160.9 (m);
δF (CDCl3, 90 MHz) −59.2 (1F, d, J 224 Hz), −52.1 (1F, dd,
J 224, 7 Hz); m/z (EI) 303.1073 (M+. C17H15F2NO2 requires
303.1071). The ee was determined to be 86% by HPLC (Daicel
CHIRALPAK AD-H, hexane–iPrOH = 9 : 1, 0.7 mL min−1
,
254 nm, major 15.4 min and minor 13.3 min).
Synthesis of the (S)-isomer of difluoro-β-lactam 3a19d
(−)-Menthyl bromodifluoroacetate (1.5 mmol, 403 mg) was
added to a solution of benzylidenebenzylamine (0.5 mmol) 10 (a) S. Thaisrivongs, H. J. Schostarez, D. T. Pals and
and RhCl(PPh3)3 (0.005 mmol, 4.6 mg) in THF (4 mL) at
ambient temperature. Then the mixture was cooled to −10 °C,
and 1.0 M Et2Zn in hexane (1.5 mmol, 1.5 mL) was slowly
added to the mixture at −10 °C. The whole mixture was stirred
at −10 °C for 3 h. The mixture was quenched with saturated
aqueous NaHCO3, and was filtered through a Celite pad. The
filtrate was extracted with AcOEt, and then the extract was
washed with brine and dried over MgSO4. The solvent was
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removed in vacuo and the residue was purified by column 11 (a) T. Taguchi, O. Kitagawa, Y. Suda, S. Ohkawa,
chromatography (AcOEt–hexane) to afford the corresponding
α,α-difluoro-β-lactam 3a.
(S)-1-Benzyl-3,3-difluoro-4-phenylazetidin-2-one 3a. The title
product 3a was obtained as a colorless liquid (66 mg, 48%)
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after column chromatography (AcOEt–hexane
=
1 : 9).
[α]2D5 +65.1 (c 1.09 in CHCl3); δH (CDCl3, 400 MHz) 3.94 (1H,
6488 | Org. Biomol. Chem., 2014, 12, 6484–6489
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