Enantioselective synthesis of α,α-difluoro-β-amino acid and 3,3- difluoroazetidin-2-one via the reformatsky-type reaction of ethyl bromodifluoroacetate with chiral 1,3-oxazolidines

Article abstract of DOI:10.1021/jo990868b

Chiral oxazolidines 2a-e can be diastereoselectively alkylated with BrCF₂CO₂Et to furnish 3,3-difluoroazetidin-2-ones 3a-e with up to 99% de. Selective cleavage of the chiral appendage provided the corresponding unsubstituted azetidinones. Formation of optically pure α,α-difluoro-β- amino acids 5a-c can be achieved by acidic hydrolysis of N-vinyl-azetidin-2- ones.

Full text of DOI:10.1021/jo990868b

J . Org. Chem. 1999, 64, 8461-8464
8461
En a n tioselective Syn th esis of r,r-Diflu or o-â-a m in o Acid a n d
3,3-Diflu or oa zetid in -2-on e via th e Refor m a tsk y-Typ e Rea ction of
Eth yl Br om od iflu or oa ceta te w ith Ch ir a l 1,3-Oxa zolid in es
Ste´phane Marcotte, Xavier Pannecoucke, Christian Feasson, and J ean-Charles Quirion*
Laboratoire d’He´te´rochimie Organique associe´ au CNRS, IRCOF, INSA et Universite´ de Rouen,
Pl. E. Blondel, BP 08, 76131 Mont-Saint-Aignan Cedex, France
Received May 27, 1999
Chiral oxazolidines 2a -e can be diastereoselectively alkylated with BrCF2CO2Et to furnish 3,3-
difluoroazetidin-2-ones 3a -e with up to 99% de. Selective cleavage of the chiral appendage provided
the corresponding unsubstituted azetidinones. Formation of optically pure R,R-difluoro-â-amino
acids 5a -c can be achieved by acidic hydrolysis of N-vinyl-azetidin-2-ones.
In tr od u ction
taining â-amino acids is of particular interest. To the best
of our knowledge, only two examples of such a strategy
have been reported. Soloshonok9 described the synthesis
of optically pure â-(fluoroalkyl) â-amino acids via enan-
tioselective biomimetic transamination of â-keto carboxy-
lic acid derivatives. Kobayashi10 used the asymmetric
aldol addition of difluoroketenesilylacetal to aldehydes.
However, this method suffered from a low yield for the
preparation of the salt-free starting reagent from ethyl
bromodifluoroacetate.
In recent years, fluoro compounds have received a great
deal interest. The presence of a fluorine atom introduces
modifications to the physiological activity of bioactive
compounds.1 Indeed, fluorine’s small van der Waals
radius and its high electronegativity have important
effects on the physical and chemical properties of the
molecule. This led to the discovery of potent medicinal
agents and development of original methods of prepara-
tion, especially in the asymmetric series.2 Among them,
gem-difluoro amino acids and derivatives have been the
subject of an important area of research as the CF2/CH2
transposition has been recognized as a valuable tool in
the blockage of metabolic processes. Replacement of
various functional groups by a gem-difluoromethylene
group has generated potent transition-state-type inhibi-
tors.3 Moreover, difluoroazetidin-2-ones have shown spe-
cific properties as an inhibitor of human leucocite elastase.4
The importance of organofluorine compounds is reflected
in the ever-increasing research activity in the field of
their stereoselective synthesis.5 Additionally, â-amino
acids are now recognized as valuable tools for the
generation of new derivatives6 such as â-peptides7 as well
as building blocks for â-lactam antibiotics.8
The aim of this study is the investigation of a new
enantioselective route to R,R-difluoro-â-amino acids.
Resu lts a n d Discu ssion
We first decided to evaluate the potentiality of ethyl-
bromodifluoroacetate 1 in a Reformatsky-type reaction
with aldimines as previously described by Kobayashi.12
Only moderate diastereoselectivity (de <50%) was re-
ported using R-methylbenzylamine as the source of
chirality. We decided to perform the reaction with chiral
1,3-oxazolidines derived from chiral amino alcohols
(Scheme 1). These stable equivalents of imines are known
to furnish highly diastereoselective reactions with several
organometallic reagents.13 Oxazolidines 2a -e were easily
prepared in good yields by condensation of the corre-
sponding amino alcohols and aldehydes and were then
used without any purification. (R)-Phenylglycinol or the
cheaper (R)-aminobutanol was used as the chiral auxil-
iary. Although these 1,3-oxazolidines were in equilibrium
with the corresponding imino alcohol, reaction with ethyl
bromodifluoroacetate (3.5 equiv) in the presence of
activated Zn dust furnished 3,3-difluoroazetidin-2-ones
3a -e as the major products (Scheme 1, Table 1). Even
though we were unable to detect the intermediate
â-amino acids, these results were encouraging as they
allowed the synthesis of the corresponding azetidinones.
In this context, the development of new synthetic
methodology for preparing optically pure fluorine-con-
* To whom correspondence should be addressed. Phone: 33 (0)2 35
52 29 20. Fax: 33 (0)2 35 52 29 59. E-mail address: quirion@ircof.insa-
rouen.fr.
(1) (a) Ojima, I.; McCarthy, J . R.; Welch, J . T. Biomedical Frontiers
of Fluorine Chemistry; ACS Symposium Series 639; American Chemical
Society: Washington, DC, 1996.
(2) (a) For a review on catalytic asymmetric synthesis of fluoro-
containing coupounds, see: Iseki, K. Tetrahedron 1998, 54, 13887. (b)
For a review on the synthesis of gem-difluoro-containing coupounds,
see: Tozer, M. J .; Herpin, T. F. Tetrahedron 1996, 52, 8619. (c) For a
review on fluorinated amino acid, see: Welch, J . T. Tetrahedron 1987,
43, 3123.
(3) Schirlin, D.; Baltzer, S.; Altenburger, J . M.; Tarnus, C.; Remy,
J . M. Tetrahedron 1996, 52, 305.
(4) Doucet, C.; Vergely, I.; Reboud-Ravaux, M.; Guilhem, J .; Kobait-
er, R.; J oyeau, R.; Wakselman, M. Tetrahedron: Asymmetry 1997, 8,
739 and references therein.
(5) Bravo, P.; Resnati, G. Tetrahedron: Asymmetry 1990, 1, 661.
(6) Enantioselective Synthesis of â-Amino Acids; J uaristi, E., Ed.;
VCH-Wiley: New York, 1997.
(7) Matthews, J . L.; Overhand, M.; Ku¨hnle, F. N. M.; Ciceri, P. E.;
Seebach, D. Liebigs Ann./ Recueil 1997, 1371.
(9) Soloshonok, V. A.; Ono, T.; Soloshonok, I. V. J . Org. Chem. 1997,
62, 7538.
(10) Iseki, K.; Kuroki, Y.; Asada, D.; Takahashi, M.; Kishimoto, S.;
Kobayashi, Y. Tetrahedron 1997, 53, 10271.
(11) Hallinan, E. A.; Fried, J . Tetrahedron Lett. 1984, 47.
(12) Taguchi, T.; Kitagawa, O.; Suda, Y.; Ohkawa, S.; Hashimoto,
A.; Iitaka, Y.; Kobayashi, Y., Tetrahedron Lett. 1988, 29, 5291.
(13) (a) Wu, M. J .; Pridgen, L. N. J . Org. Chem. 1991, 56, 1340 and
references therein. (b) Mokhallalati, M. K.; Wu, M. J .; Pridgen, L. N.
Tetrahedron Lett. 1993, 34, 47.
(8) For general reviews, see: (a) Hart, D. J .; Ha, D.-C. Chem. Rev.
1989, 89, 1447. (b) van der Steen, F. H.; van Koten, G. Tetrahedron
1991, 47, 7503.
10.1021/jo990868b CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/12/1999

8462 J . Org. Chem., Vol. 64, No. 23, 1999
Marcotte et al.
Sch em e 1a
Sch em e 2a
a
(a) BrCF2CO2Et (2 eq.), Zn, THF, 77%; (b) CAN, CH3CN, H2O,
83%.
Synthesis of R,R-difluoro-â-amino acids from azetidi-
nones required removal of the chiral auxiliary and ring
opening of the â-lactam. This was achieved in a two-step
process from phenylglycinol derivative (-)-3a . Acidic
treatment gave the amino acid (-)-4a without any trace
of epimerization. Hydrogenolysis of the nitrogen append-
age cleaved the phenylglycinol part of the molecule
selectively, leading to 3-amino-2,2-difluoro-3-phenyl-pro-
panoic acid 5a as the S enantiomer having a dextrorotary
sign ([R]D +7.1).
a
(a) BrCF2CO2Et (3.5 eq), Zn, THF; (b) HCl, 6N, 71%; (c) H2,
Pd/C, MeOH, 90%; (d) (i) Tf2O, pyridine, (ii) for 6a : DBU, 78%,
for 5b.c: t-BuOK, 71 and 69%; (e) 30 N H2SO4, Et2O, 7a : 53%,
7b: 56%. 7c: 61%; (f) 6 N HCl, 93-96%.
Ta ble 1. Dia ster eoselective F or m a tion of
F lu or oa zetid on es 3a -e
Most of our results were obtained in the ethyl series
(R1 ) Et) for which this strategy cannot be used. We then
turned our attention to the deprotection method devel-
oped by Villieras,15 who prepared an enamide that was
then hydrolyzed with sulfuric acid. Application of this
method to our compounds did not yield the corresponding
azetidinones. Finally, we solved this problem by trans-
forming the alcohol functionality to triflate, which was
smoothly eliminated (DBU or t-BuOK) providing enam-
ides 6a -c (Scheme 1).16 Acidic treatment (30 N sulfuric
acid) furnished optically pure azetidinones 7a -c in 53,
56, and 61% yield, respectively. When enamides 6a -c
were treated at reflux with 6 N aqueous hydrochloric
acid, R,R-difluoro-â-amino acids 5a -c were obtained in
nearly quantitative yield as hydrochloric salts.
yielda selectivity
entry substrate R1
R2
product
(%)
(de, %)
1
2
3
4
5
2a
2b
2c
2d
2e
Ph Ph
Et Ph
Et n-C5H11
Et 2-Furyl
Et trans-CHd
CHCH3
3a
3b
3c
3d
3e
65
69d
35
62
32
>99b
96b
90c
85b
96c
a
b
Isolated yields. Diastereomeric excess was determined by
HPLC-Mass spectrometry. c Diastereomeric excess were deter-
mined by 19F NMR spectroscopy. In this case 5% of the non-
d
cyclized coumpound was observed.
To establish the enantiomeric purity of the obtained
compounds, we prepared racemic azetidinone 7a . We
used p-methoxybenzylamine in order to have a substitu-
ent on the nitrogen which could be cleaved under mild
conditions. Compound 8 was reacted with 1 (2 equiv) in
the presence of Zn dust (Scheme 2). The difluoroaze-
tidin-2-one 9 was the only isolated product. Deprotection
was realized by classical treatment with CAN, furnishing
rac-7a in 83% yield. Chiral VPC analysis showed that
7a was of very high (>99%) enantiomeric purity. Since
the enantiomeric purity of 7a was excellent, the other
derivatives prepared in the same manner are expected
to be of comparable purity. Furthermore, if any loss of
stereochemical purity was to occur, the phenyl derivative
would have been the most likely to epimerize.
In conclusion, we performed a diastereoselective route
to the N-protected 3,3-difluoroazetidin-2-one with high
diastereoselectivity using the Reformatsky-type reaction
of ethyl bromodifluoroacetate with chiral 1,3-oxazolidines.
These compounds furnished access to the corresponding
R,R,difluoro-â-amino acid or 3,3-difluoroazetidinone after
two or three steps.
F igu r e 1.
The formation of the noncyclized product in small amounts
(5%) was only observed during the preparation of com-
pound 3b (R1 ) ethyl, R2 ) phenyl). We can notice that
the yields from nonaromatic imines (entries 3 and 5) are
lower, in agreement with Kobayashi’s results. But, in all
cases, we were pleased to observe a very high diastereo-
meric excess, usually more than 90% except when R2 is
a furfuryl moiety (entry 4).
This high asymmetric induction, even at a quite high
temperature (60 °C), can best be explained by the
strongly rigid intermediate proposed by Pridgen13 (Figure
1). In this model, the zinc of the alcoholate is chelated
by the nitrogen atom, and the nucleophile attack occurs
on the less hindered side opposite to the phenyl or ethyl
group of the chiral auxiliary. As the stereochemistry of
the imine is known to be E, this model led us to postulate
the S absolute configuration for the newly created center
as indicated in Figure 1. This hypothesis was confirmed
by an X-ray analysis of â-amino acid 4a (vide infra).14
(15) Nyzam, V.; Belaud, C.; Zammattio, F.; Villieras, J . Tetrahe-
dron: Asymmetry 1996, 7, 1835.
(16) During the course of the preparation of this manuscript, a
similar method applied to N-dealkylation of tertiary amines has been
described: Agami, C.; Couty, F.; Evano, G.; Tetrahedron Lett. 1999,
40, 3709.
(14) Toupet, L. Laboratoire de Chimie Cristalline, Faculte´ des
Sciences, Rennes, France. Complete X-ray data will be published
separately.

Synthesis of R,R-Difluoro-â-amino acid and3,3-Difluoroazetidin-2-one
J . Org. Chem., Vol. 64, No. 23, 1999 8463
(dd, 1H, J ) 1.7, 3.3), 6.52 (d, 1H, J ) 3.3), 7.46 (d, 1H, J )
1.7); 13C NMR (CDCl3) δ 9.6, 20.3, 57.3, 60.9 (dd, J ) 23.3,
27.6), 62.0, 110.2, 111.3, 118.7 (dd, J ) 286, 293), 143.4, 144.0,
160.6 (t, J ) 31.6), 19F NMR (CDCl3) δ -114.7 (dd, J ) 7.0,
225.2), -120.4 (d, J ) 225.2); HRMS (CI) calcd for (M + 1)+
C11H14 F2NO2 246.0942, found 246.0946. Anal. Calcd for C11H13
F2NO2: C, 53.88; H, 5.34; N, 5.71. Found: C, 53.61; H, 5.62;
N, 5.68.
Exp er im en ta l Section
All commercial solvents were distilled before using. Tet-
rahydrofuran (THF) was distilled from sodium benzophenone
ketyl under nitrogen atmosphere. Flash column chromatog-
raphy purifications were carried out using silica gel (70-230
mesh). 1H NMR, 13C NMR and 19F NMR (CFCl3 as external
reference) were recorded at 300.13, 75.47, and 282.40 MHz,
respectively. Coupling constants (J ) are reported in Hz.
HPLC-Mass spectroscopy was done on a C18 HYPERSIL 5
µm column using CH3CN/H2O as solvent. Chiral VPC were
performed on â-DEX 120 (10 m, 0.25 mm, ef 0.25 µm) with He
as GV (30 mL s-1).
(4S)-3,3-Diflu or o-1-((1R)-1-h yd r oxym et h ylp r op yl)-4-
p r op en yla zetid in -2-on e (3e). Flash chromatography (30%
EtOAc in cyclohexane) yielded a colorless oil: 32%; [R]25
D
+12.9° (c 1, CHCl3); IR (neat) 3452 (OH), 1654 (CdC), 1773
1
cm-1 (CdO); H NMR (CDCl3) δ 1.8 (m, 3H), 0.95 (t, 3H, J )
Sta r tin g Ma ter ia ls. All substrate oxazolidines were readily
synthesized by condensation of the appropriate aldehyde with
the prerequiste chiral amino alcohol. They were used without
purification but were dried before use by azeotropic distillation
with toluene. The zinc was freshly activated and dried.
Moisture-sensitive reactions were carried out in predried
glassware and under argon atmosphere.
7.4), 1.65 (m, 2H), 1.8 (m, 3H), 2.1 (br,1H), 3.4 (m, 1H), 4.35
(m, 1H), 5.4 (m, 1H), 6.0 (m, 1H); 13C NMR (CDCl3) δ 9.7, 17.1,
20.6, 57.2, 62.1, 67.1 (dd, J ) 22.6, 26.4), 118.9 (dd, J ) 286,
301), 121.6, 135.7, 160.5 (t, J ) 32.3); 19F NMR (CDCl3) δ
-118.3 (dd, J ) 6.8, 222.0), -126.3 (d, J ) 222.0); HRMS (CI)
calcd for (M + 1)+ C10H16 F2NO2 220.1149, found 220.1147.
Anal. Calcd for C10H15 F2NO2: C, 54.79; H, 6.90; N, 6.39.
Found: C, 54.52; H, 6.58; N, 6.68.
Gen er a l P r oced u r e for 3a -e. (4S)-3,3-Diflu or o-1-((1R)-
2-h yd r oxy-1-p h en ylet h yl)-4-p h en yla zet id in -2-on e (3a ).
To a refluxing suspension of freshly activated Zn dust (2.3 g,
35.4 mmol) in dry THF (10 mL) was added a solution of 2a
(1.66 g, 7.38 mmol) and ethyl bromodifluoroacetate (5.24 g,
25.83 mmol) in THF (1.5 mL) at a rate so as to maintain
vigorous reflux. After 1 h, the reaction mixture was cooled and
quenched by addition of a saturated NH4Cl solution (20 mL).
After filtration, the aqueous layer was extrated with CH2Cl2
(2 × 20 mL). The organic layers were combined, dried over
MgSO4, and concentrated under vacuum. The residue was then
purified by flash column chromatography using 10% ethyl
acetate in cyclohexane, affording 3a as a colorless oil (1.45 g,
(3S)-2,2 Diflu or o-3-((1R)-2-h yd r oxy-1-p h en yleth yla m i-
n o)-3-p h en ylp r op a n oic Acid (4a ). A solution of 3a (43 mg,
0.14 mmol) in HClaq (6 N, 6 mL) was heated at reflux for 5 h.
The resulting mixture was concentrated in vacuo to dryness
to obtain a white residue. After being triturated in ether, the
solid was filtered and then washed with 2 × 5 mL of cold water
and 5 mL of ether. It was recrystallized in MeOH to give 4a
as colorless prisms (32 mg, 0.1 mmol, 71%): mp 189-191 °C
dec; [R]25 -6.4° (c 1, MeOH); IR (KBr) 3368 (OH), 1642 cm-1
D
1
(CdO); H NMR (CD3OD) δ 3.90 (m, 2H), 4.51 (m, 1H), 4.95
(masked by CD3OH), 7-7.3 (m, 10H); 13C NMR (DMSO) δ 62.2
(dd, J ) 23.5, 29.2), 63.2, 64.0, 117.1 (dd, J ) 286, 298), 128.9,
128.8, 129.0, 129.1, 129.7, 130.1, 134.9, 135.0, 163.0 (t, J )
30.4); 19F NMR (DMSO) δ -107.0 (dd, J ) 11.3, 245.1), -112.4
(dd, J ) 14.1, 245.1). Anal. Calcd for C17H17 F2NO3: C, 63.55;
H, 5.33; N, 4.36. Found: C, 63.22; H, 5.24; N, 4.06.
4.79 mmol, 65%): [R]25 -15.4° (c 1, CHCl3); IR (neat) 3436
D
(OH), 1778 cm-1(CdO); 1H NMR (CDCl3) δ 2.71 (br, 1H), 3.74
(dd, 1H, J ) 5.0, 11.5), 4.03 (dd, 1H, J ) 9.1, 11.5), 4.64 (dd,
1H, J ) 5.0, 9.1), 4.77 (dd, 1H, J ) 2.2, 8.1), 7-7.5 (m, 10Η);
13C NMR (CDCl3) δ 64.0, 65.4, 72.6 (dd, J ) 23.5, 29.2), 121.7
(dd, J ) 292 Hz, 298 Hz),130.3, 130.7, 130.8, 130.9, 131.0,
132.0, 133.2, 137.1, 164.5 (dd, J ) 30.7, 32.1); 19F NMR (CDCl3)
δ -114.9 (dd, J ) 8.1, J ) 217.2), -121.8 (d, J ) 217.2); HRMS
(CI) calcd for (M + 1)+ C17H16 F2NO2 304.1149, found 304.1144.
Anal. Calcd for C17H15F2NO2: C, 67.32; H, 4.98; N, 4.62. Found:
C, 67.11; H, 4.96; N, 4.42.
(3S)-3-Am in o-2,2-diflu or o-3-ph en ylpr opan oic Acid (5a).
A solution of 4a (69 mg, 0.216 mmol) in MeOH (10 mL) was
hydrogenated (H2, 1 bar) in the presence of 10% Pd/C. After
filtration and concentration under vacuum, the crude material
was washed with ether to remove phenylethanol. â-Amino acid
5a was obtained as a white solid (39 mg, 0.194 mmol, 90%):
mp 160-165 °C dec; [R]25 +7.1° (c 1, MeOH); IR (KBr) 1652
D
cm-1 (CdO); 1H NMR (CD3OD) δ 4.95 (masked by CD3OH),
7.3-7.5 (m, 5H); 13C NMR (CD3OD) δ 58.6 (dd, J ) 28.6, 29.7),
112.6 (t, J ) 293), 129.9, 130.1, 131.1, 131.5, 166.9; 19F NMR
(CDCl3) δ -110.8 (d, J ) 258.4), -113.9 (d, J ) 258.4). Anal.
Calcd for C9H9 F2NO2: C, 53.73; H, 4.51; N, 6.96. Found: C,
53.61; H, 4.45; N, 6.72.
(4S)-3,3-Diflu or o-1-((1R)-1-h yd r oxym et h ylp r op yl)-4-
p h en yla zetid in -2-on e (3b). Flash chromatography (10%
EtOAc in cyclohexane) yielded a colorless oil: 69%; [R]25
D
+16.9° (c 1, CHCl3); IR (neat) 3417 (OH), 1769 cm-1 (CdO);
1H NMR (CDCl3) δ 0.90 (t, 3H, J ) 7.38), 1.58 (m, 2H), 2.50
(br,1H), 3.33-3.47 (m, 3H), 4.91 (dd, 1H, J ) 2.1, 8.0), 7.2-
7.4 (m, 5H); 13C NMR (CDCl3) δ 9.9, 20.7, 57.4, 62.2, 68.2 (dd,
J ) 21.2, 23.0), 118.7 (dd, J ) 287, 292),127.4, 127.9, 129.0,
130.5, 161.5 (dd, J ) 30.4, 32); 19F NMR (CDCl3) δ -114.7 (dd,
J ) 8.0, 222.3), -122.0 (d, J ) 222.3); HRMS (CI) calcd for (M
+ 1)+ C13H16F2NO2 256.1149 found 256.1145. Anal. Calcd for
(4S)-3,3-Diflu or o-4-p h en yl-1-(1-p h en ylvin yl)a zet id in -
2-on e (6a ). To CH2Cl2 (15 mL) and pyridine (0.311 mL, 3.84
mmol) at -10 °C was slowly added trifluoromethanesulfonic
anhydride (0.354 mL, 2.10 mmol). A thick white precipitate
began to form during the addition. After addition was com-
plete, the suspension was allowed to stir for an additional 10
min. Then 3a (320 mg, 1.05 mmol) in CH2Cl2 (7.5 mL) was
added dropwise, and stirring was continued for 2 h. The
reaction mixture was poured into ice-water (60 mL), the
layers were separated, and the aqueous layer was extracted
with CH2Cl2 (2 × 20 mL). The combined extracts were dried
over magnesium sulfate, and the solvent was removed in
vacuo. Flash chromatography (AcOEt/cyclohexane 10%) gave
a colorless oil. The triflate was dissolved in CH2Cl2 (10 mL) at
-10 °C, and DBU (188 µL, 1.26 mmol) was added. After 1 h,
the mixture was poured into HClaq (2 N, 10 mL). The aqueous
layer was extracted with CH2Cl2 (2 × 10 mL). The combined
organic layers were dried over magnesium sulfate and con-
centrated. The residue was purified on silica gel flash chro-
matography (ethyl acetate/cyclohexane 10%) to give 6a as a
C
13H15F2NO2: C, 61.17; H, 5.92; N, 5.49. Found: C, 61.33; H,
5.95; N, 5.28.
(4S)-3,3-Diflu or o-1-((1R)-1-h yd r oxym et h ylp r op yl)-4-
pen tylazetidin -2-on e (3c). Flash chromatography (10% EtOAc
in cyclohexane) yielded a yellow oil 35%: [R]25 +27.3° (c 1,
D
CHCl3); IR (neat) 3404 (OH), 1773 cm-1 (CdO); 1H NMR
(CDCl3) δ 1.0 (m, 6H), 1.4 (m, 6H), 1.7 (m, 4H), 3.4 (m,1H),
3.5 (br, 1H), 3.8 (m, 2H), 4.4 (m, 1H); 13C NMR (CDCl3) δ 9.7,
12.8, 20.6, 21.3, 24.0, 27.4, 30.5, 57.4, 62.4, 65.5 (dd, J ) 24.2,
29.3), 119.2 (dd, J ) 277, 290), 160.4 (t, J ) 31.5); 19F NMR
(CDCl3) δ -115.5 (dd, J ) 8.1, 222.5), -128.1 (d, J ) 222.5);
HRMS (CI) calcd for (M + 1)+ C12H21F2NO2 250.1619, found
250.1622. Anal. Calcd for C12H21F2NO2: C, 57.81; H, 8.49; N,
5.62. Found: C, 57.61; H, 8.41; N, 5.43.
(4S)-3,3-Diflu or o-1-((1R)-1-h yd r oxym eth ylp r op yl)-4-fu -
r yla zetid in -2-on e (3d ). Flash chromatography (20% EtOAc
white solid (235 mg, 0.82 mmol, 78%): mp ) 56 °C; [R]25
D
in cyclohexane) yielded a yellow oil: 62%; [R]25 +14.6° (c 1,
+55.7° (c 1, CHCl3); IR (neat) 1773 (CdO), 1626 cm-1 (CdC);
1H NMR (CDCl3) δ 4.91 (s,1H), 5.10 (s, 1H), 5.17 (dd, 1H, J )
2.0, 8.2), 7.1-7.3 (m, 10H); 13C NMR (CDCl3) δ 68.3 (dd, J )
24.4, 26.5), 104.7, 118.5 (dd, J ) 286, 274), 126.2, 126.5, 127.3,
D
CHCl3); IR (neat) 3309 (OH), 1785 cm-1 (CdO); 1H NMR
(CDCl3) δ 0.85 (t, 3H, J ) 7.3), 1.52 (m, 2H), 3.09 (br, 1H),
3.43 (m, 1H), 3.50 (m, 2H), 4.96 (dd, 1H, J ) 2.4, 7.0), 6.39

8464 J . Org. Chem., Vol. 64, No. 23, 1999
Marcotte et al.
127.9, 128.3, 128.6, 129.3, 132.7, 139.3, 157.1 (t, J ) 31.7);
19F NMR (CDCl3) δ -113.7 (dd, J ) 8.2, 226.1), -121.0 (d, J
) 226.1). Anal. Calcd for C17H13 F2NO: C, 71.72; H, 4.62; N,
4.98. Found: C, 71.57; H, 4.59; N, 4.91.
11.3, 220.2). Anal. Calcd for C7H5F2NO2: C, 48.57; H, 2.91; N,
8.09. Found: C, 48.72; H, 3.02; N, 8.51.
(3S)-3-Am in o-2,2-diflu or o-3-ph en ylpr opan oic Acid, HCl
Sa lt (5a ). A solution of 6a (56 mg, 0.196 mmol) in HClaq (6 N,
5 mL) was refluxed for 2 h. Water was removed under vacuum,
and the resulting white solid was recrystallized from methanol-
ether leading to 5a HCl salt (45 mg, 0.19 mmol, 96%): mp
(4S)-3,3-Diflu or o-1-(1-et h ylvin yl)-4-p en t yla zet id in -2-
on e (6b). Same procedure as above but the elimination
reaction was carried out as follows. To a solution of the triflate
(450 mg, 1.18 mmol) in THF (40 mL) at -10 °C was added
potassium tert-butylate (158 mg, 1.4 mmol). After 10 min, the
mixture was poured into HClaq (2 N, 50 mL). Then, the same
procedure furnished 6b as of a colorless oil (194 mg, 0.840
159 °C dec; [R]20 +3.3° (c 0.84, MeOH); IR (KBr) 3130 (NH,
D
OH), 1657 cm-1 (COOH); H NMR (CD3OD) δ 5.05 (dd, J )
1
7.5, 19.7, 1H), 7.4 (m,5H); 13C NMR (CD3OD) δ 58.3 (t,J )
24.4), 114.9 (t, J ) 260), 130.5, 130.9, 132.2, 132.4, 163.9 (t, J
) 28.8); 19F NMR (CD3OD) δ -120.2 (dd, J ) 19.7, 249.4),
-110.5 (dd, J ) 7.5, 249.4). Anal. Calcd for C9H10ClF2NO2:
C, 45.49; H, 4.24; N, 5.89. Found: C, 45.32; H, 4.31; N, 5.93
(3S)-3-Am in o-2,2-d iflu or o-3-octa n oic Acid , HCl Sa lt
(5b). A solution of 7b (94 mg, 0.53 mmol) in HClaq (6 N, 8 mL)
was refluxed for 2 h. Water was removed under vacuum, and
the white solid was recrystallized from methanol-ether,
furnishing 5b (116 mg, 0.50 mmol, 95%): mp)190-194 °C;
[R]20D-9.2° (c 0.25, MeOH); IR (KBr) 3152 (NH, OH), 1655
mmol, 71%): [R]25 +20.2° (c 1, CHCl3); IR (neat) 1789 (CdO),
D
1636 cm-1(CdC); 1H NMR (CDCl3) δ 0.83 (m, 3H), 1.05 (t, J )
7.3, 3H), 1.1-1.9 (m, 8H), 2.48 (q, J ) 7.3, 2H), 4.04 (m, 1H),
4.42 (s, 1H), 4.47 (s,1H); 13C NMR (CDCl3) δ 11.0, 12.8, 21.7,
23.6, 24.7, 24.8, 30.5, 64.4 (dd, J ) 23.6, 24.2), 95.6, 118.9 (dd,
J ) 281.5, 287.4), 143.1, 156.0 (t, J ) 31.6); 19F NMR (CDCl3)
δ -115.7 (dd, J ) 11.2, 231.3), -126.4 (d, 231.3). Anal. Calcd
for C12H19 F2NO: C, 62.32; H, 8.28; N, 6.06. Found: C, 62.53;
H, 8.32; N, 6.11.
1
(4S)-3,3-Diflu or o-1-(1-e t h ylvin yl)-4-fu r yla ze t id in -2-
on e (6c). Same procedure as 6b afforded 6c as a colorless oil
(69%): [R]25D +46.0° (c 1, CHCl3); IR (neat) 17881 (CdO), 1635
cm-1 (COO); H NMR (CDCl3) δ 0.75 (m, 3H), 1.15-1.63 (m,
8H), 3.80 (m, masked by CD3OH); 13C NMR (CDCl3) δ 14.7,
23.5, 25.9, 28.4, 32.6, 54.7 (t, J ) 23.7), 115.0 (t, J ) 255);
163.6 (t, J ) 31.2); 19F NMR (CDCl3) δ -119.4 (dd, J ) 16.9,
265.4), -110.5 (dd, J ) 8.4, 265.4). Anal. Calcd for C8H16ClF2-
NO2: C, 41.48; H, 6.96; N, 6.05. Found: C, 41.22; H, 7.05; N,
6.22.
1
cm-1 (CdC); H NMR (CDCl3) δ 1.05 (t, J ) 7.3, 3H), 2.45 (q,
J ) 7.3, 2H), 4.29 (s, 1H), 4.33 (s, 1H), 5.13 (dd, J ) 1.77, 6.7),
6.38 (s, 1H), 6.46 (s, 1H), 7.54 (s, 1H); 13C NMR (CDCl3) δ 11.0,
24.56, 61.4 (dd, J ) 24.1, 28.2), 96.4, 109.9, 110.8, 118.1 (dd,
J ) 282.1, 286.4), 142.8, 143.0, 143.2, 156.0 (t, J ) 30.9); 19F
NMR (CDCl3) δ -114.9 (dd, J ) 6.5, 225.9), -126.4 (d, 225.9).
Anal. Calcd for C11H11 F2NO2: C, 58.15; H, 4.88; N, 6.16.
Found: C, 58.37; H, 4.91; N, 6.13.
(3S)-3-Am in o-2,2-d iflu or o-3-fu r ylp r op a n oic a cid , HCl
sa lt (5c): white solid; mp 185-188 °C dec; [R]20D -19.8° (c 0.6,
MeOH); IR (KBr) 31001 (NH, OH), 1659 cm-1 (COOH); 1H
NMR (CD3OD) δ 5.43 (dd, J ) 6.96, 17.46, 1H), 6.61 (dd, J )
1.3, 3.1), 6.79 (d, J ) 3.1, 1H), 7.74 (d, J ) 1.3, 1H); 13C NMR
(CD3OD) δ_52.3 (t, J ) 27.92), 112.73, 114.48, 114.8 (t, J )
261), 143.7, 146.8, 164.57 (t, J ) 29); 19F NMR (CD3OD) δ
-109.7 (dd, J ) 6.9, 262), -117.6 (dd, J ) 17.4, 262). Anal.
Calcd for C7H8ClF2NO3: C, 36.94; H, 3.54; N, 6.15. Found: C,
37.12; H, 3.62; N, 6.23
r a c-3,3-Diflu or o-1-(4-m eth oxyben zyl)-4-ph en ylazetidin -
2-on e (9). The synthesis of 9 was performed using the usual
procedure with 2 equiv of ethyl bromodifluoroacetate. Silica
gel flash chromatography, eluent 10% EtOAc in cyclohexane,
provided a colorless oil (77%): IR (neat) 1790 cm-1 (CdO); 1H
NMR (CDCl3) δ 3.68 (s, 3H), 3.81 (d, J ) 15.3, 1H), 4.61 (dd,
J ) 1.8, 8.4, 1H), 4.77 (d, J ) 15.3, 1H), 6.72 (m, 2H), 6.94 (m,
2H), 7.06 (m, 2H), 7.32 (m, 3H); 13C NMR (CDCl3) δ 44.1, 55.7,
68.2 (t, J ) 24.1), 114.8, 120.9 (dd, J ) 291, 295), 125.7, 128.5,
129.1, 130.2, 130.4, 130.5, 160.0, 161.2 (t, J ) 30.9); 19F NMR
(CDCl3) δ -114.8 (dd, J ) 8.4, 211.2), -121.9 (d, J ) 211.2).
Anal. Calcd for C17H15F2NO2: C, 67.32; H, 4.98; N, 4.62. Found:
C, 67.12; H, 5.12; N, 4.83
(4S)-3,3-Diflu or o-4-p h en yla zetid in -2-on e (7a ). A solu-
tion of the enamide 6a (65 mg, 0.228 mmol) in ether (20 mL)
containing H2SO4 (30 N, 5 mL) was refluxed until no more
starting material appeared on TLC monitoring. After the
reaction was completed, the solution was neutralized with a
saturated solution of NaHCO3 (30 mL) and then addition of
solid NaHCO3. The aqueous layer was extracted with ethyl
acetate (2 × 20 mL). The combined organic layers were dried
over MgSO4. After concentration, the residue was flash chro-
matographed on silica gel with 15% ethyl acetate in cyclohex-
ane. 7a was obtained as a white solid (22 mg, 0.120 mmol,
53%): mp 64 °C; [R]25 +38.3° (c 1.01, CHCl3); IR (neat) 3271
D
(OH), 1790 cm-1 (CdO); 1H NMR (CDCl3) δ 4.98 (dd, J ) 2.4,
6.5, 1H), 6.94 (br, 1H), 7.1-7.4 (m, 5H); 13C NMR (CDCl3) δ
64.2 (dd, J ) 24.6, 26.4), 120.4 (dd, J ) 279, 290), 126.1, 127.8,
128.6, 130.9, 160.5 (t, J ) 31.5); 19F NMR (CDCl3) δ -114.0
(ddd, J ) 6.5, 12.7, 224.1), -120.1 (ddd, J ) 2.4, 11.2, 224.1).
Anal. Calcd for C9H7 F2NO: C, 59.02; H, 3.85; N, 7.65. Found:
C, 59.11; H, 3.63; N, 7.68
(4S)-3,3-Diflu or o-4-pen tylazetidin -2-on e (7b). Flash chro-
matography (20% EtOAc in cyclohexane) yielded a colorless
r a c-(4S)-3,3-Diflu or o-4-p h en yla zetid in -2on e (7a ). To 9
(53 mg, 0.23 mmol) in a mixture of CH3CN/H2O (9:1, 7 mL) at
0 °C was added CAN (385 mg, 0.70 mmol) in small portions.
After 20 min at 0 °C and 6 h at room temperature, the mixture
was poured on water (50 mL). The aqueous layer was extracted
with EtOAc (2 × 20 mL). The combined organic layers were
washed with 5% NaHCO3 (10 mL), 10% Na2SO3 (10 mL), 5%
NaHCO3 (10 mL), and finally brine (10 mL). After concentra-
tion and flash column chromatography with 15% ethyl acetate
in cyclohexane, the desired racemic product 7a was obtained
in 83% yield (36 mg, 0.19 mmol) (IR, MS, and NMR identical
to previously synthesized (+)-7a ).
oil: 56%;. [R]20 -4.65° (c 0.36, CHCl3); IR (neat) 3271 (NH),
D
1
1789 cm-1 (CdO); H NMR (CDCl3) δ 0.85 (m, 3H), 1.27 (m,
6H), 1.62 (m, 2H), 3.88 (m, 1H), 6.85 (br, 1H); 13C NMR (CDCl3)
δ 12.8, 21.3, 24.0, 25.9, 30.3, 61.6 (t, J ) 24.2), 120.7 (dd, J )
289, 293), 160.2 (t, J ) 30.8); 19F NMR (CDCl3) δ -115.9 (ddd,
J ) 8.4, 14.1, 217.4), -120.1 (dd, J ) 11.3, 217.4). Anal. Calcd
for C8H13F2NO: C, 54.23; H, 7.39; N, 7.90. Found: C, 54.53;
H, 7.56; N, 7.77.
(4S)-3,3-Diflu or o-4-fu r yla zetid in -2-on e (7c). Flash chro-
matography (30% EtOAc in cyclohexane) yielded a colorless
oil: 61%; [R]20 -10.2° (c 0.5, CHCl3); IR (neat) 3256 cm-1
D
(NH), 1802 cm-1 (CdO); 1H NMR (CDCl3) δ 4.98 (dd, J ) 2.25,
5.62, 1H), 6.36 (s, 1H), 6.43 (s, 1H), 6.96 (br, 1H), 7.61 (s, 1H);
13C NMR (CDCl3) δ 58.0 (dd, J ) 24.1, 28.7), 109.8, 109.9, 120.2
(dd, J ) 287, 294), 143.22, 144.63, 160.5 (t, J ) 31.2); 19F NMR
(CDCl3) δ -114.5 (ddd, J ) 5.6, 11.3, 220.2), -119.3 (dd, J )
Ack n ow led gm en t. We thank E. Bourgeaux for
providing HPLC-Mass analysis and Dr. L. Toupet for
providing X-ray analysis of compound 4a .
J O990868B