Diastereoselective Synthesis of the Nonracemic Methyl syn-(3-Fluoroalkyl)isoserinates

Article abstract of DOI:10.1021/jo971381a

Cycloaddition of the (fluoroalkyl)imines 7a-c with the ketene formed in situ from (benzyloxy)acetyl chloride and triethylamine provided stereoselectively cis-(fluoroalkyl)azetidinones 5a-c in moderate yields. The corresponding N-Boc-isoserinates 11a-c and protected synthons 12a-c have been prepared from these azetidinones 5a-c. Cycloaddition of the chiral imine 18 (R_F = CF₃) with the same ketene led to the diastereoisomeric azetidinones 19 and 20 with a poor diastereoisomeric excess (10-20%) However, the two diastereoisomers could be easily separated by crystallization and provided enantiomerically pure N-Boc-isoserinates 23 (R,R) and 23 (S,S) after ring opening and debenzylation.

Full text of DOI:10.1021/jo971381a

8826
J . Org. Chem. 1997, 62, 8826-8833
Dia ster eoselective Syn th esis of th e Non r a cem ic Meth yl
syn -(3-F lu or oa lk yl)isoser in a tes
Ahmed Abouabdellah, J ean-Pierre Be´gue´,* Danie`le Bonnet-Delpon, and
Truong Thi Thanh Nga
CNRS, URA 1843, Centre d’Etudes Pharmaceutiques, Rue J .B. Cle´ment,
92296 Chaˆtenay-Malabry, France
Received J uly 28, 1997X
Cycloaddition of the (fluoroalkyl)imines 7a -c with the ketene formed in situ from (benzyloxy)acetyl
chloride and triethylamine provided stereoselectively cis-(fluoroalkyl)azetidinones 5a -c in moderate
yields. The corresponding N-Boc-isoserinates 11a -c and protected synthons 12a -c have been
prepared from these azetidinones 5a -c. Cycloaddition of the chiral imine 18 (RF ) CF3) with the
same ketene led to the diastereoisomeric azetidinones 19 and 20 with a poor diastereoisomeric
excess (10-20%). However, the two diastereoisomers could be easily separated by crystallization
and provided enantiomerically pure N-Boc-isoserinates 23 (R,R) and 23 (S,S) after ring opening
and debenzylation.
â-Amino fluoroalkyl alcohols 1 have been used, like
cytotoxicity in vitro toward human tumoral cell lines than
docetaxel.7,8 We report now the detailed preparation of
4a and 5a , the extension to the preparation of other
fluoroalkyl â-lactams 5b and 5c (RF ) CF2H and CF2-
Cl), and the preparation of nonracemic â-lactams and
isoserinates.
their nonfluorinated analogues, as peptidomimetic units,
and when incorporated in peptidic substrates, they often
exhibit active site directed competitive inhibitory proper-
ties toward proteases.1 Conversely, their regioisomers,
the â-hydroxy (fluoroalkyl)amines 2, had never been
described until the recent paper from Seebach et al.2 The
properties of these amino alcohols 2 as peptidomimetic
units have never been explored, although specific features
brought by the fluorinated moiety can be expected: for
example, the presence of the fluoroalkyl group can
increase the stability of the amide bond toward nonspe-
cific proteolysis3 and strongly weakens the basicity of the
amine function, modifying solubility and desolvation
properties.4
Norstatine, statine, and their analogues have been
largely used as peptidomimetic units in peptide-based
inhibitors of aspartyl proteases such as renin and HIV-1
protease.5 Fluorinated analogues of these nonproteogenic
R-hydroxy-â-amino acids could be of great interest, and
access to fluoroalkyl derivatives 3 of isoserine had to be
investigated. We have recently reported the first access
to the important representative hydroxy amine of type
2, the racemic methyl syn-3-(trifluoromethyl)isoserinate
(4a ), through the â-lactam 5a .6 This â-lactam, after
suitable protection and deprotection steps, has been
coupled with baccatin III, providing an analogue of
docetaxel, where the 3′-phenyl group has been replaced
by a CF3 group. This compound presents a higher
The Staudinger reaction of ketenes to aldimines is well-
known to provide cis-â-lactams.9 However, it had never
been studied in the case of (fluoroalkyl)imines. To check
the feasibility of the reaction, we first examined the [2
+ 2] cycloaddition reaction between ketenes generated
from propionyl, butyryl, phenylacetyl, and phenylpropio-
nyl chlorides and the (fluoroalkyl)acetaldimine 7a , pre-
pared by the usual route from the corresponding ethyl
hemiacetal and p-methoxyaniline.10,11 In all cases, no
traces of the corresponding â-lactam was detected. For-
tunately, reaction of the ketene, generated from R-(ben-
zyloxy)acetyl chloride (6) and triethylamine with imine
7a , performed at 45 °C in methylene chloride, provided
the expected cis-azetidinone 5a in a 65% yield (Scheme
3
2). In azetidinone 5a , the J H-3,H-4 coupling constant of 5
Hz indicates the cis relative configuration. Coupling
constants in parent â-lactams have been reported to be
2 Hz for the trans isomer and 5-6 Hz for the cis one.12
Difluoroacetaldimine13 7b and chlorodifluoroacetaldimine
(7) Ojima, I.; Slater, J . C. Pera, P.; Veith, J . M.; Abouabdellah, A.;
Be´gue´, J . P.; Bernacki, R. J . Bioorg. Med. Chem. Lett. 1997, 7, 133-
138.
(8) Ojima, I.; Kuduk, S. D.; Slater, J . C.; Gimi, R. H.; Sun, C. M.;
Chabravarty, S.; Ourevitch, M.; Abouabdellah, A.; Bonnet-Delpon, D.;
Be´gue´, J . P.; Veith, J . M.; Pera, P.; Bernacki, R. J . In Biomedical
Frontiers of Fluorine Chemistry; Ojima, I., McCarthy, J . R., Welch, J .
T., Eds.; American Chemical Society: Washington, D.C., 1996; Chapter
17, pp 228-245.
(9) (a) Georg, G. I.; Ravikumar, V. T. In The Organic Chemistry of
â-Lactams; Georg, G. I., Ed.; VCH Publishers: New York, 1992; pp
295-368 and references therein. (b) Ojima, I. In The Organic
Chemistry of â-Lactams; Georg, G. I., Ed.; VCH Publishers: New York,
1992; pp 197-255.
(10) Guanti, G.; Banfi, L.; Narisano, E; Scolastico, C.; Bosone, E.
Synthesis 1985, 609-611.
(11) It is worth noting that, unlike cyclocondensation with lithium
acetate enolate, cycloaddition with ketene cannot be performed from
the mixture imine and the corresponding amino ester, which always
accompanies the imine 7a in its preparation. In our hands, the
treatment of this mixture with LDA did not provide the pure imine
7a . However, a careful distillation allowed the separation and the pure
imine 7a was obtained in 60% yield.
(12) Browne, M.; Burnett, D. A.; Caplen, M. A.; Chen, L. Y.; Clader,
J . W.; Domalski, M.; Dugar, S.; Pushpavanam, P.; Sher, R.; Vaccaro,
W.; Viziano, M.; Zhao, H. Tetrahedron Lett. 1995, 36, 2555-2558.
X Abstract published in Advance ACS Abstracts, November 15, 1997.
(1) Sham, H. L.; Stein, H.; Rempel, C. A.; Cohen, J .; Plattner, J . J .
FEBS Lett. 1987, 220, 299-301. Patel, D. V.; Rielly-Gauvin, K.; Ryono,
D. E. Tetrahedron Lett. 1988, 29, 4665-4668. Patel, D. V.; Rielly-
Gauvin, K.; Ryono, D. E.; Free, C. A.; Smith, S. A.; Petrillo J r, E. W.
J . Med. Chem. 1993, 36, 2431-2447. Giordano, C.; Gallina, C.;
Consalvi, V.; Scandurra, R. Eur. J . Med. Chem. 1989, 24, 357-362.
Smith, R. A.; Copp, L. J .; Donnelly, S. L.; Spencer, R. W.; Krantz, A.
Biochemistry 1988, 27, 6568-6573.
(2) Marti, R. E.; Heinzer, J .; Seebach, D. Liebigs Ann. 1995, 1193-
1215.
(3) Ojima, I.; Kato, K.; J ameison, F. A.; Conway, J . Bioorg. Med.
Chem. Lett. 1992, 2, 219-222.
(4) Shirlin, D.; Tarnus, C.; Baltzer, S.; Re´my, J . M. Bioorg. Med.
Chem. Lett. 1992, 2, 651-654.
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G. B. Perspect. Drug Dis. Design 1993, 1, 85-108. Gait, M. J .; Karn,
J . TIBTECH 1995, 13, 430-437.
(6) Abouabdellah, A.; Be´gue´, J . P.; Bonnet-Delpon, D. Synlett 1996,
399-400.
S0022-3263(97)01381-9 CCC: $14.00 © 1997 American Chemical Society

Synthesis of Methyl syn-(1-Fluoroalkyl)isoserinates
J . Org. Chem., Vol. 62, No. 25, 1997 8827
Sch em e 1
Sch em e 2
F igu r e 1. ORPEP stereoplot view of the crystal structure of
(R,R)-methyl isoserinate 21.
cyclocondensation has been successfully demonstrated to
give cis-azetidinone in high yields with very high enan-
tiomeric purity,9b,16-19 we rather first chose this approach.
We showed that the ester cyclodensation of enolate of
benzyloxy esters with the trifluoroacetaldimine 7a failed.6
However, we finally succeeded in the preparation of the
cis â-lactam 14 by using the more reactive (triisopropyl-
silyl)oxy esters 15, as reported by Ojima19 (Scheme 4).
â-Lactams obtained in cyclocondensation reactions from
silyloxy or alkoxy esters and aldimines have in most cases
the cis configuration.16a,19 However, the only reported
cyclocondensation reaction involving a trifluoromethyl
aldimine with an ester lithium enolate, a protected
glycine, provided a trans-4-(trifluoromethyl)azetidinone.10
This opposite result is probably due to a different relative
stability of conformations of the enolate, the disubstituted
nitrogen favoring the formation of the Z-enolate leading
to the trans â-lactam.
7c were prepared in 60-65% yields from the correspond-
ing ethyl hemiacetals by heating a toluene solution of
hemiacetal and p-methoxyaniline in a Dean-Stark ap-
paratus. These ethyl hemiacetals were obtained through
the reduction of the corresponding ethyl esters with
LiAlH4.13 Condensation of the aldimine 7b with the
ketene generated from 6 led to the cis-â-lactam 5b in 72%
yield (3J H-3,H-4 ) 5.2 Hz). The â-lactam 5c was obtained
in a satisfatory yield (55%) from aldimine 7c, the
3J H-3,H-4 coupling constant also indicating its cis relative
configuration (Scheme 2).
â-Lactams 5 can be satisfactorily transformed into
isoserinates. The acidic methanolysis of â-lactams 5 was
very slow and often could not be reproduced. So, to
prepare isoserinates 4a -c, the p-methoxyphenyl group
was first removed with ceric ammonium nitrate (CAN)
(65-87%). The reaction has to be carefully monitored
and stopped as soon as azetidinones 5 have reacted
because of the fast degradation of azetidinones 8 in the
presence of excess of CAN. The resulting azetidinones
8a -c were first converted into N-Boc derivatives 9a -
c. In the case of 8c, a low temperature of reaction (-50
°C) was absolutely required to obtain 9c in good yield.
The sodium azide catalyzed ring opening14 by methanol
provided esters 10a -c. Further debenzylation by a
catalytic hydrogenation followed by the Boc cleavage led
to isoserinates 4a -c (Scheme 3).
For the preparation of fluorinated docetaxel ana-
logues,7,8 azetidinones could directly react with protected
baccatin III after suitable deprotection and protection
steps. Azetidinones 9a -c were debenzylated by catalytic
hydrogenation into azetidinones 13a -c and then pro-
tected again by a reaction with ethyl vinyl ether (EVE)
in the presence of p-toluenesulfonic acid to give azetidi-
nones 12a -c (Scheme 3).
To prepare chiral azetidinones, the asymmetric
Staudinger reaction, controlled by a chiral N-substituent
on imines, is seldom diastereoselective, because of the
relatively long distance between the chiral center and the
reaction center.15 Since the lithium ester enolate-imine
The results were disappointing when the reaction was
performed with esters 16 and 17: azetidinone 14 was
not obtained from 16 and was obtained with a very low
yield from 17.
These poor results prompted us to turn back to the [2
+ 2] ketene-imine cycloaddition route to â-lactam. We
investigated the reaction with the chiral imine 18,
prepared from the trifluoroacetaldehyde hemiacetal and
the (S)-phenethylamine by the same procedure as for
aldimines 7. The cycloaddition reaction with the ketene
generated from the acyl chloride 6 and the imine 18 was
efficient, leading to a mixture of cis-azetidinones 19 and
20 (90%) accompanied by only 5-8% of trans-azetidinone.
As expected, the chirality transfer was low since the
diastereoisomeric excess was 15% only. Fortunately,
crystallization of the crude mixture in ethanol allowed a
(15) Hashimoto, Y.; Kai, A.; Saigo, K. Tetrahedron Lett. 1995, 48,
8821-8824. Georg, G. I.; Wu, Z. Tetrahedron Lett. 1994, 47, 381-384.
(16) (a) Ojima, I.; Habus, I. Tetrahedron Lett. 1990, 30, 4289-4292.
(b) Georg, G. I.; Kant, J .; Gill, H. S. J . Am. Chem. Soc. 1987, 109, 1129.
For reviews: (c) Hart, D. J .; Ha, D. C. Chem. Rev. (Washington, D.C.)
1989, 89, 1447. (d) Ojima, I. Acc. Chem. Res 1995, 28, 383-389 and
references cited herein.
(17) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.; Sun, C.
M.; Brigaud, T. Tetrahedron 1992, 48, 6985-7012.
(13) Kaneko, S.; Yamazaki, T.; Kitazume, T. J . Org. Chem. 1993,
58, 2302-2312.
(14) Palomo, C.; Aizpurua, J . M.; Galarza, R.; Mielgo, A. J . Chem.
Soc., Chem. Commun. 1996, 633-634.
(18) Ojima, I.; Habus, I.; Zhao, M.; Georg, G. I.; J ayasinghe, L. R.
J . Org. Chem. 1991, 56, 1681-1683.
(19) Ojima, I.; Park, Y. H.; Sun, C. M.; Brigaud, T.; Zhao, M.
Tetrahedron Lett. 1992, 33, 5737-5740.

8828 J . Org. Chem., Vol. 62, No. 25, 1997
Abouabdellah et al.
Sch em e 3
Sch em e 4
Sch em e 6
Sch em e 5
(Figure 1).20 From isoserinates 21 and 22, a catalytic
debenzylation in the presence of (Boc)2O provided the two
nonracemic N-Boc isoserinates 23 (R,R) and (S,S) (Scheme
6).
Three fluoroalkyl (CF3, CF2H, and CF2Cl) isoserine
derivatives could be prepared in good yields through a
[2+2] ketene-imine cycloaddition. Starting from a chiral
CF3-substituted aldimine, both pure enantiomers of the
methyl syn-3-(trifluoromethyl)isoserinate could be ob-
tained. These peptidomimetic units are currently under
active investigation in the design of protease inhibitors.
Exp er im en ta l Section
NMR spectra were performed with CDCl3 solutions, on a
Varian EM, FH dual probehead, a Bruker AC 200, and an ARX
400 spectrometer (1H: 90, 200, or 400 MHz, 19F: 84, 188, or
376 MHz; and 13C: 50 or 100 MHz). Chemical shifts are
reported in ppm relative to Me4Si and CFCl3 (for 19F NMR) as
internal standards. In the 13C NMR data, reported signal
multiplicities are related to C-F coupling. For the determi-
nation of fine coupling constants an acquisition of 16K data
points, a Lorenz-Gauss transformation of the FID and a zero
filling to 64K were performed in order to obtain a minimum
of resolution of 0.2 Hz/pt (1H) or 0.5 Hz/pt (13C). COSY,
HMQC, HMBC experiments were performed on a multinuclear
fine separation of the two isomers 19 and 20. Stereoi-
somer 19 crystallized and was obtained in an excellent
diastereoselective purity (>99%), and stereoisomer 20
could be isolated in a 95% diastereoselective purity after
SiO2 chromatography and crystallization in pentane
(Scheme 5).
In contrast to N-(p-methoxyphenyl)azetidinones 5 (p-
methoxyphenyl ) PMP), the azetidinone 19 easily un-
derwent an acidic methanolysis leading to the isoserinate
21. The absolute configuration has been determined for
isoserinate 21. The crystal structure of 21 indicated
unambiguously the configuration (2R,3R) for this isomer
(20) The authors have deposited atomic coordinates for this struc-
ture with the Cambridge Crystallographic Data Centre. The coordi-
nates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK.

Synthesis of Methyl syn-(1-Fluoroalkyl)isoserinates
J . Org. Chem., Vol. 62, No. 25, 1997 8829
3
probehead equipped with a Z-gradient coil. GC analyses were
performed on a capillary column SE 30, 10 or 25 m.
2 H, OCHAHBC6H5), 4.98 (d, J ) 5.0 Hz, 1 H, H-3), 7.2 (q, J
) 10 Hz, δA 6.8, δB 7.4, 4 H, C6H4); 13C NMR δ 55.6, 57.8 (q,
2J CF ) 33 Hz, C-4), 73.9, 80.4, 114.6, 119.6, 123.8 (q, J CF
)
1
(2,2,2-Tr iflu or oeth ylid en e)a n isid in e (7a ). A solution of
ethyl trifluoroacetaldehyde hemiacetal (15 g, 0.1 mol), p-
methoxyaniline (10.26 g, 0.083 mol), and p-toluenesulfonic acid
(50 mg) in toluene (120 mL) was refluxed under Ar for 1.5 h
in a Dean-Stark apparatus.11 The solution was washed with
an aqueous solution of sodium hydrogenocarbonate and then
with brine and dried (MgSO4). The solution was evaporated
under reduced pressure, and the residue was distilled (60 °C,
0.5 mmHg), leading to the N-(2,2,2-trifluoroethylidene)anisi-
dine10 (7a ) (10.4 g, 64%): 19F NMR δ -70.7 (d, 3J FH ) 3.7 Hz);
280 Hz, CF3), 128.0, 128.4, 128.7, 129.5, 136.3, 157.4, 163.9.
Anal. Calcd for C18H16F3NO3: C, 61.54; H, 4.59; N, 4.0.
Found: C, 60.77; H, 4.91; N, 3.81.
cis-N -(4-Me t h oxyp h e n yl)-3-(b e n zyloxy)-4-(d iflu or o-
m eth yl)a zetid in -2-on e (5b). A solution of N-(2,2-difluoro-
methylidene)-4-methoxyaniline (7b) (1.8 g, 9.7 mmol) and
R-(benzyloxy)acetyl chloride (6) (3.69 g, 0.02 mol) in freshly
distilled CH2Cl2 (25 mL) was treated slowly with NEt3 (2.95
g, 0.029 mol). The resulting mixture was then stirred 17 h at
45 °C. Workup and purification by crystallization in cold
ethanol afforded 5b as a white solid (2.35 g, 72%): mp 91 °C
1H NMR δ 3.84 (s, 3 H), 7.1 (q, 4 H), 7.8 (q, 3J HF ) 3.7 Hz); 13
C
NMR δ 55.0, 119.5 (q, 1J CF ) 279 Hz, CF3), 114.5, 123.1, 139.8,
2
2
2
144.2 (q, J CF ) 33 Hz, CCF3), 160.0.
(EtOH); 19F NMR δ - 119.0 (ddd, J FF ) 301 Hz, J FH ) 56
Hz, 3J FH ) 7.6 Hz, 1 F), -122.6 (ddd, 2J FF ) 301 Hz, 2J FH ) 54
(2,2-Diflu or oeth ylid en e)a n isid in e (7b). A solution of
ethyl difluoroacetate (5 g, 0.04 mol) in Et2O (8 mL) was treated
at -78 °C with a solution of LiAlH4 (0.95 g, 0.025 mol) in THF
(15 mL). The reaction mixture was stirred at this temperature
for 3 h. EtOH (95%) (2 mL) was then added. The reaction
mixture was stirred for 2 h at rt and then poured into an
aqueous saturated solution of NH4Cl and extracted with Et2O
(two times). The organic phases were dried (MgSO4), evapo-
rated, and distilled under normal pressure. Ethyl difluoro-
acetaldehyde hemiacetal was obtained at 90 °C (2 g, 40%): 19F
Hz, J FH ) 6 Hz, 1 F); 1H NMR δ 3.7 (s, 3 H), 4.32 (dddd, J FH
3
3
3
) 7.6, 6 Hz, J ) 5.2, 5.7 Hz, 1 H, H-4), 4.7 (q, J AB ) 12 Hz,
δA 4.60, δB 4.80, 2 H, OCHAHBC6H5), 4.84 (d, 3J ) 5.2 Hz, 1 H,
2
3
H-3), 6.0 (ddd, J HF ) 56, 54 Hz, J ) 5.7 Hz, 1 H, CHF2), 7.1
(q, J ) 10 Hz, δA 6.85, δB 7.4, 4 H, C6H4), 7.3 (m, 5 H); 13C
NMR δ 55.6, 57.9 (dd, 2J CF ) 20.6, 32 Hz, C-4), 73.8 (d, 5J CF
)
3
1
1.2 Hz), 80.3 (dd, J CF ) 1.1 Hz, C-3), 114.0 (t, J CF ) 243 Hz,
CF2H), 114.5, 119.3, 128.2, 128.5, 128.8, 130.4, 136.4, 157.1,
164.1. Anal. Calcd for C18H17F2NO3: C, 64.86; H, 5.14; N,
4.20. Found: C, 64.71; H, 5.27; N, 4.15.
2
2
3
NMR δ -131.7 (ddd, J FF ) 291 Hz, J FH ) 54.8 Hz, J FH
)
5.7 Hz, 1 F), -137.2 (ddd, 2J FF ) 291 Hz, 2J FH ) 55.3 Hz, 3J FH
) 7.6 Hz, 1 F); 1H NMR δ 1.24 (t, J ) 7 Hz, 3 H), 3.80 (q, J )
cis-N-(4-Met h oxyp h en yl)-3-(b en zyloxy)-4-(ch lor od i-
flu or om eth yl)a zetid in -2-on e (5c). A solution of N-(2,2,2-
chlorodifluoroethylidene)-4-methoxyaniline (7c) (1.9 g, 8.5
mmol) and R-(benzyloxy)acetyl chloride (6) (3.2 g, 17.4 mmol)
in freshly distilled CH2Cl2 (24 mL) was treated slowly with
NEt3 (2.6 g, 25.5 mmol). The resulting mixture was then
stirred for 26 h at 45 °C. The solution was poured into water
(10 mL) and extracted with EtOAc (2 × 30 mL). The organic
phase was washed with brine and dried over MgSO4. After
evaporation of solvent, the crude product was purified by
crystallization in cold ethanol to give 5c as a white solid (1.76
g, 55%): mp 140 °C (EtOH); 19F NMR δ -54.9 (dd, 2J FF ) 173
7 Hz, 2 H), 4.68 (ddd, 3J ) 2.7 Hz, J FH ) 5.7, 7.6 Hz, 1 H),
3
3
2
5.57 (ddd, J ) 2.7 Hz, J FH ) 54.8, 55.3 Hz, 1 H). A solution
of ethyl difluoroacetaldehyde hemiacetal (2 g, 0.015 mol) and
p-methoxyaniline (1.61 g, 0.083 mol) in toluene (25 mL) was
refluxed under Ar for 1.5 h in a Dean-Stark apparatus. After
workup, the residue was distilled (60 °C, 1.5 mmHg) leading
to the N-(2,2-difluoroethylidene)anisidine (7b)13 (1.8 g, 60%):
19F NMR δ -119.2 (dd, 2J FH ) 55 Hz, 3J FH ) 2.5 Hz); 1H NMR
δ 3.78 (s, 3 H), 7.0 (q, J AB ) 8.9 Hz, δA 6.85, δB 7.15, 4 H), 7.1
2
3
(ddd, J FH ) 54.8, 55.3 Hz, J ) 5.4 Hz, 1 H, CF2H), 7.8 (td,
3J FH ) 2.5 Hz, J ) 5.4 Hz, 1 H).
Hz, 3J FH ) 2.4 Hz, 1 F), - 56.4 (ddd, J FF ) 173 Hz, J FH ) 11
3
2
3
Hz, 1 F); 1H NMR δ 3.8 (s, 3 H), 4.75 (ddd, J FH ) 11, 2.4 Hz,
3
(2,2,2-Ch lor od iflu or oeth ylid en e)a n isid in e (7c). A solu-
tion of ethyl chlorodifluoroacetate (5 g, 3.16 mmol) in Et2O (5
mL) was treated at -78 °C with a solution of DIBAL (solution
1 M in CH2Cl2, 38 mL, 0.038 mol) in THF (15 mL). The
reaction mixture was stirred at this temperature for 5 h.
EtOH (95%) (2 mL) was then added, and the reaction mixture
was stirred 2 h at rt and then poured into an aqueous
saturated solution of NH4Cl and extracted with Et2O (two
times). The organic phases were dried (MgSO4) and evapo-
rated under reduced pressure (5 mmHg). Ethyl chlorodifluo-
roacetaldehyde hemiacetal was obtained at 18 °C (1.67 g,
33%): 19F NMR δ -69.0 (dd, 2J FF ) 8.6 Hz, 3J FH ) 3.5 Hz); 1H
3J ) 5 Hz, 1 H, H-4), 4.85 (q, J AB ) 12.2 Hz, δA 4.81, δB 4.89,
3
2 H, OCHAHBC6H5), 4.97 (d, J ) 5 Hz, 1 H, H-3), 7.1 (q, J AB
) 9 Hz, 4 H, C6H4), 7.4 (m, 5 H); 13C NMR δ 55.6, 62.3 (dd,
2J CF ) 28.5, 25.9 Hz, C-4), 74.0, 80.6 (t, 3J CF ) 2 Hz, C-3), 119.9,
1
127.2 (dd, J CF ) 294, 296 Hz, CF2Cl), 127.8, 128.0, 128.5,
128.6, 129.0, 136.0, 157.1, 164.1. Anal. Calcd for C18H16ClF2-
NO3: C, 58.79; H, 4.39; N, 3.81. Found: C, 58.81; H, 4.43; N,
3.85.
cis-3-(Ben zyloxy)-4-(tr iflu or om eth yl)azetidin -2-on e (8a).
A solution of ceric ammonium nitrate (CAN) (39 g, 71 mmol)
in water (180 mL) was added slowly at 0 °C to a solution of
azetidinone 5a (5 g, 14.2 mmol) in acetonitrile (90 mL). The
reaction mixture was stirred until the disappearance of
starting material (TLC) (about 1 h) at 0 °C. Then water and
ethyl acetate were added for extraction (twice). Organic
phases were washed with NaHCO3 5% aqueous solution and
brine and then dried (MgSO4) and concentrated. Purification
on a SiO2 column (pentane/EtOAc 70:30) provided the azeti-
dinone 8a as a yellow solid (2.23 g, 64%): mp 91 °C (EtOAc);
NMR δ 1.28 (t, J ) 7 Hz, 3 H), 2.55 (s, 1 H, OH), 3.83 (dq, J AB
3
) 9.8 Hz, 3J ) 7 Hz, 2 H), 4.79 (t, J FH ) 3.5 Hz, 1 H).
A
solution of ethyl chlorodifluoroacetaldehyde hemiacetal (1.67
g, 10 mmol) and p-methoxyaniline (1.28 g, 0.01 mol) in toluene
(20 mL) was refluxed under Ar for 1.5 h in a Dean-Stark
apparatus. After workup, the residue was distilled (70 °C, 6
mmHg) leading to the N-(2,2,2-chlorodifluoroethylidene)ani-
sidine (7c) (1.9 g, 64%): 19F NMR δ -59.0 (d, 3J FH ) 5 Hz); 1H
NMR δ 3.78 (s, 3 H), 7.1 (q, 4 H), 7.81 (t, J FH ) 5 Hz); 13C
19F NMR d -72.4 (d, J FH ) 6.2 Hz); 1H NMR δ 4.04 (qd, J FH
3
3
3
1
NMR δ 55.0, 111.6 (q, J CF ) 272 Hz, CF2Cl), 114.8, 123.5,
) 6.0 Hz, 3J ) 4.9 Hz, 1 H, H-4), 4.65 (q, J AB ) 12 Hz, δA 4.62,
2
4
138.7, 139.9, 147.8 (q, J CF ) 31 Hz, CCF2Cl), 160.
δB 4.69, 2 H, OCHAHBC6H5), 4.78 (dd, 3J ) 4.9 Hz, J FH ) 2
Hz, 1 H, H-3), 6.57 (s, 1 H, NH), 7.28 (m, 5 H, C6H5); 13C NMR
[2 + 2] Keten e-Im in e Con d en sa tion : cis-N-(4-Meth -
oxyp h en yl)-3-(ben zyloxy)-4-(tr iflu or om eth yl)a zetid in -2-
on e (5a ). A solution of N-(2,2,2-trifluoroethylidene)-4-meth-
oxyaniline (7a ) (6 g, 0.03 mol) and R-(benzyloxy)acetyl chloride
(6) (11.07 g, 0.06 mol) in freshly distilled CH2Cl2 (40 mL) was
treated slowly with NEt3 (9.1 g, 0.09 mol). The resulting
mixture was then stirred for 26 h at 45 °C. The solution was
poured into water (20 mL) and extracted with EtOAc (2 × 50
mL). The organic phase was washed with brine and dried over
MgSO4. After evaporation of solvent, the crude product was
purified by crystallization in cold ethanol to give 5a as a white
solid (6.72 g, 65%): mp 132 °C (EtOH): 19F NMR δ -68.9 (d,
2
1
δ 54.4 (q, J CF ) 37 Hz, C-4), 73.8, 82.3, 124.0 (q, J CF ) 279
Hz, CF3), 128.1, 128.7, 128.8, 136.3, 167.6. Anal. Calcd for
C11H10F3NO2: C, 53.88; H, 4.11; N, 5.71. Found: C, 53.75; H,
4.25; N, 5.63.
cis-3-(Ben zyloxy)-2-(diflu or om eth yl)azetidin -2-on e (8b).
A solution of ceric ammonium nitrate (CAN) (13.2 g, 0.024
mmol) in water (60 mL) was added slowly at 0 °C to a solution
of azetidinone 5b (1.6 g, 4.8 mmol) in acetonitrile (30 mL). The
reaction mixture was stirred until disappearance of the
starting material (about 3 h) at 0 °C. Workup and evaporation
of the solvents provided, after chromatography on SiO2 (pen-
tane/EtOAc 60:40), the azetidinone 8b as a white solid (840
mg, 72%): mp 67 °C (pentane/EtOAc); 19F NMR δ -121.5 (ddd,
3
3J FH ) 5.5 Hz); 1H NMR δ 3.8 (s, 3 H), 4.6 (qd, J FH ) 5.5 Hz,
3J ) 5.0 Hz, 1 H, H-4), 4.83 (q, J AB ) 11.8 Hz, δA 4.80, δB 4.86,

8830 J . Org. Chem., Vol. 62, No. 25, 1997
Abouabdellah et al.
1
3
2J FF ) 301 Hz, 2J FH ) 57 Hz, 3J FH ) 11.5 Hz, 4J FH not observed,
3J FH ) 10.6 Hz, 1 F); H NMR δ 1.43 (s, 9 H), 4.62 (ddd, J HF
2
2
3
1 F), -128 (ddd, J FF ) 301 Hz, J FH ) 53.4 Hz, J FH ) 7.6
) 3.8, 10.6 Hz, 3J HH ) 5.5 Hz, 1 H, H-4), 4.79 (q, J AB ) 12 Hz,
1
3
3
Hz); H NMR δ 3.89 (dddd, J FH ) 11.5, 7.6 Hz, 3J ) 7, 4.8
δ
A 4.74, δB 4.83, 2 H, OCHAHBC6H5), 4.88 (d, J HH ) 5.9, 1 H,
2
Hz, 1 H, H-4), 4.72 (q, J AB ) 11.5 Hz, δA 4.68, δB 4.76, 2 H,
H-3), 7.3 (m, 5 H); 13C NMR δ 27.8, 61.2 (dd, J CF ) 27.3, 29
Hz, C-4), 74.0, 80.4, 84.8, 126.3 (dd, 1J CF ) 294.5, 296 Hz, CF2-
Cl), 127.9, 128.4, 128.6, 135.7, 146.8, 163.6. Anal. Calcd for
OCHAHBC6H5), 4.8 (ddd, 3J ) 4.8 Hz, J FH ) 2, 1.1 Hz, 1 H,
4
2
3
H-3), 5.9 (ddd, J FH ) 57, 54 Hz, J ) 6.5 Hz, 1 H, CF2H), 6.2
(s, 1 H, NH), 7.3 (m, 5 H, C6H5); 13C NMR δ 55.4 (dd, J CF
)
2
C
16H18ClF2NO4: C, 53.12; H, 5.02; N, 3.87. Found: C, 53.07;
34 Hz, C-4), 74.3 (d, J CF ) 1.3 Hz), 83.1 (3J CF ) 6.3 Hz, C-3),
116.2 (t, 1J CF ) 246 Hz, CF2H) 124.0, 128.2, 128.5, 128.7, 136.3,
167.7. Anal. Calcd for C11H11F2NO2: C, 58.16; H, 4.88; N,
6.16. Found: C, 58.11; H, 4.97; N, 6.09.
5
H, 5.13; N, 3.80.
cis-N-(ter t-Bu t oxyca r b on yl)-3-h yd r oxy-4-(t r iflu or o-
m eth yl)a zetid in -2-on e (13a ). A solution of azetidinone 9a
(0.32 g, 0.93 mmol) in EtOAc, freshly distilled on CaH2 (10
mL), was stirred overnight under H2 over 10% Pd/C. The
mixture was filtered through a Celite pad (CH2Cl2) and
evaporated to dryness to give the crude azetidinone 13a (0.21
g, 88%). This compound has not been purified because of its
instability on silica gel: mp 128 °C; 19F NMR δ -69.9 (d, 3J FH
) 6.2 Hz); 1H NMR δ 1.50 (s, 9 H), 3.4 (bs, 1 H,OH), 4.50 (dq,
cis-3-(Ben zyloxy)-4-(ch lor od iflu or om eth yl)a zetid in -2-
on e (8c). A solution of ceric ammonium cerium nitrate (CAN)
(2.3 g, 4.09 mmol) in water (28 mL) was slowly added at 0 °C
to a solution of azetidinone 5c (300 mg, 0.82 mmol) in
acetonitrile (14 mL). The reaction mixture was stirred for 3.5
h at this temperature. The workup and evaporation of the
solvents provided, after SiO2 chromatography (pentane/EtOAc
70:30), the azetidinone 8c (186 mg, 87%): mp 58 °C (pentane/
EtOAc); 19F NMR δ -60.7 (dd, 2J FF ) 167.5 Hz, 3J FH ) 8.5 Hz,
3J FH ) 6.2 Hz, J HH ) 6.0 Hz, 1 H, H-4), 4.80 (d, J HH ) 6 Hz,
3
3
1 H, H-3); 13C NMR δ 27.8, 58.6 (q, J CF ) 32 Hz, C-4), 76.8,
2
86.4, 123.9 (q, 1J CF ) 279 Hz, CF3), 148.7, 167.5. Anal. Calcd
for C9H12F3NO4: C, 42.36; H, 4.74; N, 5.49. Found: C, 42.25;
H, 4.92; N, 5.36.
2
2
4J FH not observed, 1 F), -62.3 (dd, J FF ) 167.5 Hz, J FH ) 9
Hz, 1 F); 1H NMR δ 4.3 (ddd, J FH ) 8.5, 9 Hz, J ) 4.8 Hz, 1
3
3
H, H-4), 4.8 (q, J AB ) 11.8 Hz, δA 4.75, δB 4.82, 2 H,
cis-N -(t er t -Bu t oxyca r b on yl)-3-h yd r oxy-4-(d iflu or o-
m eth yl)a zetid in -2-on e (13b). A solution of azetidinone 9b
(0.200 g, 0.6 mmol) in freshly distilled EtOAc (3 mL) was
stirred under H2 over 10% Pd/C (100 mg) for 23 h. The
mixture was filtered through a Celite pad and evaporated to
dryness to give crude azetidinone 13b (0.118 g, 78%): mp 149
°C (EtOAc-pentane); 19F NMR δ -120.8 (ddd, 2J FF ) 296 Hz,
OCHAHBC6H5), 4.90 (dd J ) 4.8 Hz, 4J FH ) 1.8 Hz, 1 H, H-3),
3
6.3 (s, 1 H, NH), 7.3 (m, 5 H); 13C NMR δ 59.5 (dd, J CF ) 27,
2
3
1
30 Hz, C-4), 73.7, 82.2 (d, J CF ) 1.5 Hz, C-3), 126.8 (dd, J CF
) 294, 296 Hz, CF2Cl), 127.8, 128.2, 128.5, 132.7, 167.8. Anal.
Calcd for C11H10ClF2NO2: C, 50.49; H, 3.85; N, 5.35. Found:
C, 50.38; H, 3.94; N, 5.23.
cis-N-(ter t-Bu t oxyca r b on yl)-3-(b en zyloxy)-4-(t r iflu o-
r om eth yl)a zetid in -2-on e (9a ). Triethylamine (1.6 mL, 11.6
mmol) and 4-(N-dimethylamino)pyridine (DMAP) (100 mg)
were added at -20 °C under Ar to a solution of the azetidinone
8a (1.14 g, 4.65 mmol) and (Boc)2O (1.52 g, 6.97 mmol) in THF
(12 mL). After 2 h, water was added, and the organic phase
was extracted (EtOAc), washed (brine), and dried (MgSO4).
Evaporation of the solvents and filtration on silica gel (pen-
tane-EtOAc) provided the N-Boc derivative 9a as a white solid
(1.205 g, 75%): mp 100 °C (AcOEt/pentane); 19F NMR δ -69.8
2J FH ) 54 Hz, J FH ) 9.7 Hz, 1 F), -125.1 (dddd, J FF ) 296
3
2
Hz, J FH ) 55 Hz, J FH ) 10 Hz, J FH ) 0.6 Hz, 1 F); 1H NMR
2
3
4
3
3
δ 1.42 (s, 9 H), 4.20 (tdd, J HF ) 9.8 Hz, J ) 6.0, 3.8 Hz, 1 H,
3
4
H-4), 5.0 (dd, J ) 6.0 Hz, J ) 0.6 Hz, 1 H, H-3), 5.97 (ddd,
2J FH ) 55, 54 Hz, J ) 3.8 Hz, 1 H, CHF2); 13C NMR δ 28.0,
3
2
3
59.0 (q, J CF ) 28 Hz, C-4), 76.4 (t, J CF ) 3.5 Hz, C-3), 85.0,
1
111.5 (t, J CF ) 295 Hz, CF2H), 149.2, 168.0. Anal. Calcd for
C9H13F2NO4: C, 45.57; H, 5.50; N, 5.90. Found: C, 45.65; H,
5.67; N, 5.80.
3
1
3
cis-N -(t er t -Bu t oxyca r b on yl)-3-h yd r oxy-4-(ch lor od i-
flu or om eth yl)a zetid in -2-on e (13c). A solution of azetidi-
none 9c (0.200 g, 0.55 mmol) in freshly distilled EtOAc (3 mL)
was stirred under H2 over 10% Pd/C (80 mg) for 16 h. The
mixture was filtered through a Celite pad and evaporated to
dryness to give crude azetidinone 13c (0.135 g, 87%): mp 106
°C (EtOAc/pentane); 19F NMR (CD3OD) δ -51.5 (d, 2J FF ) 168
(d, J FH ) 6 Hz); H NMR δ 1.45 (s, 9 H), 4.42 (qd, J FH ) 6.0
Hz, 3J ) 6.0 Hz, 1 H, H-4), 4.7 (q, J AB ) 11 Hz, δA 4.67, δB
4.74, 2 H), 4.80 (d, J ) 6.0 Hz, 1 H, H-3), 7.30 (m, 5 H); 13C
3
NMR δ 27.8, 56.6 (q, 2J CF ) 34 Hz, C-4), 73.9, 80.0, 84.9, 123.1
(q, 1J CF ) 280 Hz, CF3), 128.0, 128.5, 128.7, 135.7, 146.8, 163.4.
Anal. Calcd for C16H18F3NO4: C, 55.65; H, 5.25; N, 4.05.
Found: C, 55.46; H, 5.32; N, 4.01.
2
3
4
Hz, 1 F), -56.7 (dd, J FF ) 168 Hz, J FH ) 13 Hz, J FH not
observed, 1 F); 1H NMR (MeOD) δ 1.50 (s, 9 H), 4.70 (ddd,
cis-N-(ter t-Bu t oxyca r b on yl)-3-(b en zyloxy)-4-(d iflu o-
r om eth yl)a zetid in -2-on e (9b). Triethylamine (1.2 mL, 8.7
mmol) and DMAP (50 mg) were added at -20 °C under Ar to
a solution of the azetidinone 8b (0.79 g, 3.48 mmol) and (Boc)2O
(1.17 g, 5.36 mmol) in THF (8 mL). After 2 h, workup and
filtration on silica gel (pentane/EtOAc 70:30) provided the
N-Boc derivative 9b as a white solid (718 mg, 63%): mp 48
3J FH ) 13 Hz, J ) 6 Hz, J ) 2 Hz, 1 H, H-4), 4.80 (d, J ) 2
3
4
4
Hz, 1 H, OH); 5.23 (dd, J ) 6 Hz, J FH ) 2 Hz, 1 H, H-3); 13
C
3
4
2
NMR (MeOD) δ 28.2, 63.2 (dd, J CF ) 25.2, 26 Hz, C-4), 77.0
3
1
(dd, J CF ) 1.5, 2.5 Hz, C-3), 85.4, 128.1 (dd, J CF ) 294, 295
Hz, CF2Cl), 148.8, 167.9. Anal. Calcd for C9H12F2NO4: C,
39.79; H, 4.45; N, 5.16. Found: C, 39.95; H, 4.67; N, 5.03.
2
°C (EtOAc/pentane); 19F NMR δ -123.3 (ddd, J FF ) 300 Hz,
2J FH ) 54 Hz, 3J FH ) 9.4 Hz, 1 F), -127.1 (ddd, 2J FF ) 300 Hz,
cis-N-(ter t-Bu t oxyca r b on yl)-2-(et h oxyet h ylen oxy)-4-
(tr iflu or om eth yl)a zetid in -2-on e (12a ). Ethyl vinyl ether
(EVE) (78 mg, 1.1 mmol) was added at 0 °C to a solution of
the azetidinone 13a (140, 0.55 mmol) and p-toluenesulfonic
acid (5 mg) in THF (3 mL). The reaction was stirred for 5 h
at 0 °C. Diethyl ether was added, and the solution was washed
with a saturated aqueous solution of NaHCO3 (2 × 15 mL).
The organic layer was dried (MgSO4) and then evaporated.
Chromatography on SiO2 (petroleum ether/EtOAc 75:25) of the
residue led to the diastereoisomeric azetidinones 12a (140 mg,
3
4
1
2J FH ) 54.5 Hz, J FH ) 7.4 Hz, J FH ) 1 Hz, 1 F); H NMR δ
3
3
1.50 (s, 9 H), 4.29 (dddd, J HF ) 9.4, 7.4 Hz, J ) 6.0, 4.8 Hz,
1 H, H-4), 4.79 (q, J AB ) 11.8 Hz, δA 4.76, δB 4.82, 2 H,
3
4
OCHAHBC6H5), 4.83 (dd, J ) 6.0 Hz, J FH ) 1 Hz, 1 H, H-3),
2
3
6.04 (ddd, J FH ) 54, 54.5 Hz, J FH ) 4.8 Hz, 1 H, CHF2), 7.37
(m, 5 H); 13C NMR δ 28.0, 56.8 (dd, 2J CF ) 30.7, 22.9 Hz, C-4),
3
1
73.8, 80.1 (dd, J CF ) 4.4, 1.7 Hz, C-3), 84.7, 113.4 (t, J CF
)
245 Hz, CHF2), 128.0, 128.6, 128.8, 136.0, 151.4, 163.8. Anal.
Calcd for C16H19F2NO4: C, 58.70; H, 5.85; N, 4.28. Found: C,
58.57; H, 5.94; N, 4.22.
80%) as a liquid: 19F NMR δ - 70.2 (d, J FH ) 5.7 Hz) and
3
3
1
3
-70.3 (d, J FH ) 5.7 Hz); H NMR δ 1.17 (t, J ) 7.1 Hz) and
cis-N-(ter t-Bu toxyca r bon yl)-3-(ben zyloxy)-4-(ch lor od i-
flu or om eth yl)a zetid in -2-on e (9c). Triethylamine (0.2 mL,
1.39 mmol) and DMAP (10 mg) were added at -50 °C under
Ar to a solution of azetidinone 8c (243 mg, 0.93 mmol) and
(Boc)2O (304 mg, 1.39 mmol) in THF (3 mL). After 2 h at -50
°C and then 2 h at 0 °C, water was added, and the organic
phase was extracted (EtOAc), washed (brine), and dried
(MgSO4). Evaporation of the solvents and filtration on silica
gel provided the N-Boc-azetidinone 9c as a white solid (247
mg, 74%): mp 120 °C (EtOAc/pentane); 19F NMR δ -55.5 (dd,
1.18 (t, 3J ) 7.1 Hz) (3 H), 1.28 (d, 3J ) 5.3 Hz) and 1.35 (d, 3J
3
) 5.4 Hz) (3 H), 1.45 (s, 9 H), 3.58 (q, J ) 7.1 Hz, δA 3.53, δB
3.63) and 3.67 (q, 3J ) 7.1 Hz, δA 3.47, δB 3.87), (2 H), 4.45 (dq,
3J FH ) 5.7 Hz, J HH ) 6.0 Hz, 1 H, H-4) and 4.50 (dq, J HF
)
3
3
3
3
5.7 Hz, J HH ) 6.0 Hz, H-4), 4.85 (q, J HH ) 5.4 Hz) and 4.92
3
3
(q, J HH ) 5.3 Hz) (1 H), 5.22 (d, J HH ) 6.0 Hz, H-3) and 5.23
(d, J HH ) 6.1 Hz, H-3); 13C NMR δ 14.8 and 15.0, 19.5 and
3
2
2
19.9, 27.8, 56.5 (q, J CF ) 33.6 Hz, C-4) and 56.8 (q, J CF
)
33.4 Hz, C-4), 61.0 and 62.0, 73.3 and 73.4, 83.7, 123.1 (q, 1J CF
) 280 Hz, CF3), 146.7 and 146.8, 167.1 and 164.4. Anal. Calcd
3
2
2J FF ) 171 Hz, J FH ) 3.7 Hz, 1 F), -57.5 (dd, J FF ) 171 Hz,

Synthesis of Methyl syn-(1-Fluoroalkyl)isoserinates
J . Org. Chem., Vol. 62, No. 25, 1997 8831
for C13H20F3NO5: C, 47.66; H, 6.16; N, 4.28. Found: C, 47.50;
H, 6.28; N, 4.22.
) 284 Hz, 2J FH ) 56 Hz, 3J FH ) 10 Hz, 1 F), -128.7 (ddd, 2J FF
) 284 Hz, 2J FH ) 56 Hz, 3J FH ) 10 Hz, 1 F); 1H NMR δ 1.45 (s,
3
9 H), 3.75 (s, 3 H, OCH3), 4.2 (bs, 1 H, H-2), 4.35 (ddd, J FH
)
cis-N-(ter t-Bu t oxyca r b on yl)-2-(et h oxyet h ylen oxy)-4-
(d iflu or om et h yl)a zet id in -2-on e (12b ). Ethyl vinyl ether
(EVE) (58 mg, 0.8 mmol) was added at 0 °C to a solution of
the azetidinone 13b (100, 0.4 mmol) and p-toluenesulfonic acid
(10 mg) in THF (7 mL). The reaction mixture was stirred for
2 h at 0 °C and then 3 h at rt. Diethyl ether was added, and
the solution was washed with a saturated aqueous solution of
NaHCO3 (2 × 15 mL). The organic phases were dried (MgSO4)
and then evaporated. Chromatography of the residue on SiO2
(petroleum ether/EtOAc 75:25) led to the diastereoisomeric
azetidinones 12b (80 mg, 62%) as a liquid: 19F NMR δ -124.8
(ddd, 2J FF ) 245 Hz, 2J FH ) 55.6 Hz, 3J FH ) 6.8 Hz) and -125.1
(ddd, 2J FF ) 245 Hz, 2J FH ) 54 Hz, 3J FH ) 9.8 Hz) (1 F), -122.8
(ddd, 2J FF ) 297 Hz, 2J FH ) 54.2 Hz, 3J FH ) 9.8 Hz) and -127.0
10, 10 Hz, 3J ) 5.3 Hz, 1 H, H-3), 4.62 (q, J AB ) 11 Hz, δA
3
4.43, δB 4.80, 2 H), 5.1 (d, 3J ) 10 Hz, 1 H, NH), 5.75 (ddd,
3J HF ) 56, 56 Hz, J ) 5.3 Hz, 1 H, CF2H), 7.35 (m, 5 H); 13C
3
2
NMR δ 28.0, 53.3, 53.3 (t, J CF ) 26 Hz, C-3), 74.1, 75.6 (dd,
3J CF ) 1.5 Hz, C-2), 81.4, 113.3 (t, 1J CF ) 258 Hz, CF2H), 129.3,
129.4, 137.3, 155.9, 170.7. Anal. Calcd for C17H23F2NO5: C,
56.82; H, 6.45; N, 3.90. Found: 56.68; H, 6.51; N, 3.88.
Meth yl syn -2-(Ben zyloxy)-4-(ch lor o-4,4-diflu or o-3-[(ter t-
bu toxyca r boxyl)a m in o]bu ta n oa te (10c). A solution of the
azetidinone 9c (150 mg, 0.4 mmol) in DMF (1 mL) was stirred
with NaN3 (31 mg, 0.47 mmol) and MeOH (0.8 mL) under Ar
for 16 h at rt. After workup, the crude product was purified
on a silica gel column (pentane/EtOAc, 75:25) to give the ester
10c as a liquid (136 mg, 83%): 19F NMR δ -59.7 (d, 3J FH ) 10
2
2
3
1
(ddd, J FF ) 297 Hz, J FH ) 55 Hz, J FH ) 7.9 Hz) (1 F); H
NMR δ 1.20 (t, 3J ) 7 Hz) and 1.21 (t, 3J ) 7 Hz) (3 H), 1.5 (s,
9 H), 1.32 (d, 3J ) 5.3 Hz) and 1.38 (d, 3J ) 5.4 Hz) (3 H), 3.47
(q, 3J ) 7 Hz) and 3.63 (q, 3J ) 7 Hz) (2 H), 4.29 (m, 1 H, H-4),
1
3
Hz); H NMR δ 1.35 (s, 9 H), 3.70 (s, 3 H, OCH3), 4.48 (d, J
) 0.9 Hz, 1 H, H-2), 4.64 (q, J AB ) 11 Hz, δA 4.43, δB 4.80, 2
H), 4.80 (tdd, 3J FH ) 10 Hz, 3J ) 0.9, 10 Hz, 1 H, H-3), 5.25 (d,
3J ) 10 Hz, 1 H, NH), 7.30 (m, 5 H); 13C NMR δ 28.2, 52.7,
3
3
3
4.92 (q, J ) 5.3 Hz) and 4.97 (q, J ) 5.4 Hz) (1 H), 5.1 (d, J
3
2
2
1
) 6.0 Hz) and 5.2 (d, J ) 6.1 Hz) (1 H, H-3), 6.2 (ddd, J FH
)
58.8 (t, J CF ) 26 Hz, C-3), 73.4, 74.6, 80.9, 127.8 (t, J CF )
55, 54 Hz, J ) 4.4 Hz, 1 H, CHF2); 13C NMR δ 15.9 and 16.0,
293 Hz, CF2Cl), 128.4, 128.5, 128.7, 136.3, 154.8, 169.5. Anal.
Calcd for C17H22ClF2NO5: C, 51.85; H, 5.63; N, 3.56. Found:
51.77; H, 5.72; N, 3.49.
3
2
20.8 and 21.2, 27.8, 57.5 (t, J CF ) 29.8 Hz, C-4) and 57.9 (t,
2J CF ) 29.4 Hz, C-4), 61.6 and 62.9, 74.3 (dd, J CF ) 3.9, 2.4
3
3
Hz, C-3) and 74.6 (dd, J CF ) 4.4, 1.5 Hz, C-3), 84.3 and 84.4,
Meth yl syn -2-Hyd r oxy-4,4,4-tr iflu or o-3-[(ter t-bu toxy-
ca r boxyl)a m in o]bu ta n oa te (11a ). A solution of the amino
ester 10a (250 mg, 0.66 mmol) in anhydrous EtOAc (5 mL)
was stirred under H2 atmosphere in the presence of Pd/C (5%)
(60 mg) for 18 h. After filtration on Celite and evaporation of
the solvent, purification by SiO2 chromatography (pentane-
EtOAc, 60/40) provided the ester 11a (190 mg, 98%): mp 69
1
111.5 (t, J CF ) 300 Hz, CF2H), 165.4. Anal. Calcd for
C13H21F2NO5: C, 50.48; H, 6.84; N, 4.53. Found: C, 50.56; H,
6.89; N, 4.58.
cis-N-(ter t-Bu t oxyca r b on yl)-2-(et h oxyet h ylen oxy)-4-
(d ich lor oflu or om eth yl)a zetid in -2-on e (12c). Ethyl vinyl
ether (EVE) (100 mg, 1.39 mmol) was added at 0 °C to a
solution of the azetidinone 13c (180 mg, 0.66 mmol) and
p-toluenesulfonic acid (5 mg) in THF (6 mL). The reaction was
stirred for 5 h at 0 °C. Diethyl ether was added, and the
solution was washed with a saturated aqueous solution of
NaHCO3 (2 × 15 mL). The organic layer was dried (MgSO4)
and then evaporated. Chromatography of the residue on SiO2
(petroleum ether/EtOAc 75:25) led to the diastereoisomeric
azetidinones 12c (137 mg, 60%) as a liquid: 19F NMR δ -56.5
3
°C (EtOAc); 19F NMR δ -74.0 (d, J FH ) 8 Hz); 1H NMR δ
1.40 (s, 9 H), 3.24 (s, 1 H, OH), 3.82 (s, 3 H), 4.6 (d, 3J ) 1 Hz,
3
1 H, H-2), 4.70 (ddq, J FH) 8 Hz, 3J ) 10, 1 Hz, 1 H, H-3),
5.18 (d, J ) 10 Hz, 1 H, NH); 13C NMR δ 28.1, 53.6, 53.7 (q,
3
2J CF ) 31 Hz, C-3), 67.8 (d, J CF ) 1 Hz, C-2), 81.1, 124.1 (q,
1J CF ) 283 Hz, CF3), 154.5, 171.9. Anal. Calcd for C10H16F3-
NO5: C, 41.81; H, 5.61; N, 4.87. Found: 42.02; H, 5.79; N,
4.76.
3
2
(d, J FH ) 7 Hz, 2 F) and -55.8 (dd, J FF ) 171 Hz, J FH ) 4
Hz, 1 F), -58.2 (dd, 2J FF ) 171 Hz, J FH ) 11 Hz, 1 F); 1H NMR
Meth yl syn -2-Hyd r oxy-4,4-d iflu or o-3-[(ter t-bu toxyca r -
boxy)a m in o]bu ta n oa te (11b). A solution of the amino ester
10b (138 mg, 0.38 mmol) in anhydrous EtOAc (5 mL) was
stirred under H2 atmosphere in the presence of Pd/C (5%) (25
mg) for 18 h. After filtration on Celite and evaporation of the
solvent, purification by SiO2 chromatography (pentane-
EtOAc, 60/40) of the residue provided the ester 11b (100 mg,
97%): mp 69 °C (pentane/EtOAc); 19F NMR δ -126.2 (ddd,
2J FF ) 286 Hz, 2J FH ) 59 Hz, 3J FH ) 11 Hz, 1 F), -128.8 (ddd,
δ 1.17 (t 3J ) 7 Hz, 3 H), 1.29 and 1.34 (d, J ) 5.4 Hz, 3 H),
3
3
1.45 (s, 9 H), 3.51, 3.65 (dq, J ) 9.5, 7.0 Hz) and 3.47, 3.93
3
3
3
(dq, J ) 9.5, 7.0 Hz) [CH2], 4.61 (dt, J FH ) 7.1 Hz, J HH ) 7
3
3
Hz) and 4.62 (ddd, J HF ) 11.0, 4.0 Hz, J HH ) 7 Hz) (1 H,
3
H-4), 4.85 and 4.92 (q, J HH ) 5.4 Hz, 1 H), 5.20 and 5.22 (d,
3J HH ) 7 Hz, H-3); 13C NMR δ 14.8 and 15.0, 19.6 and 19.8,
2
27.8, 61.2 and 63.4, 62.0 (q, J CF ) 27.5 Hz, C-4) and 62.5 (q,
2J CF ) 28 Hz, C-4), 73.6 and 75.2, 84.5 and 84.6, 101.0 and
101.1, 127.4 (q, 1J CF ) 295 Hz, CF2Cl), 146.7 and 146.8, 164.8
and 167.4. Anal. Calcd for C13H20ClF2NO5: C, 45.42; H, 5.86;
N, 4.07. Found: C, 45.55; H, 5.96; N, 4.03.
2
3
1
2J FF ) 286 Hz, J FH ) 56 Hz, J FH ) 11 Hz, 1 F); H NMR δ
1.42 (s, 9 H), 3.6 (s, 1 H, OH), 3.8 (s, 3 H, OCH3), 4.37 (m, 1 H,
H-3), 4.49 (s, 1 H, H-2), 5.22 (d, 2J ) 10 Hz, 1 H, NH), 5.80
(ddd, J FH ) 59 Hz, J FH ) 56 Hz, J ) 5 Hz, 1 H, CF2H); 13C
NMR δ 28.0, 53.1, 54.2 (t, J CF ) 25 Hz, C-3), 68.2 (d, J CF
4.2 Hz, C-2), 80.5, 117.5 (t, J CF ) 286 Hz, CF3), 155.0, 172.5.
Anal. Calcd for C10H17F3NO5: C, 44.61; H, 6.36; N, 5.20.
Found: 44.49; H, 6.47; N, 5.03.
3
3
3
2
3
)
Met h yl syn -2-(Ben zyloxy)-4,4,4-t r iflu or o-3-[(ter t-b u -
toxyca r boxyl)a m in o]bu ta n oa te (10a ). A solution of the
azetidinone 9a (315 mg, 0.912 mmol) in DMF (1.7 mL) was
stirred with NaN3 (67 mg, 1.03 mmol) and MeOH (1 mL) under
Ar for 20 h at rt. After dilution with EtOAc and washing with
brine, the extracts were dried (MgSO4) and concentrated. The
residue was purified on silica gel column (pentane/EtOAc, 75:
25) to give the ester 10a as a liquid (300 mg, 88%): 19F NMR
1
Met h yl syn -2-H yd r oxy-4-ch lor o-4,4-d iflu or o-3-[(ter t-
bu toxyca r boxyl)a m in o]bu ta n oa te (11c). A solution of the
amino ester 10c (136 mg, 0.35 mmol) in anhydrous EtOAc (4
mL) was stirred under H2 atmosphere in the presence of Pd/C
(10%) (65 mg) for 18 h. After filtration on Celite and evapora-
tion of the solvent, the crude product was purified by SiO2
chromatography (pentane-EtOAc, 60/40) and provided the
ester 11c (78 mg, 75%): mp 87 °C (pentane-EtOAc); 19F NMR
3
1
δ -73.5 (d, J FH ) 7.6 Hz); H NMR δ 1.42 (s, 9 H), 3.77 (s, 3
3
H, OCH3) 4.3 (d, J ) 1.5 Hz, 1 H, H-2), 4.65 (q, J AB ) 11 Hz,
3
3
δA 4.48, δB 4.82, 2 H), 4.75 (dq, J HF ) 7.6 Hz, J ) 1.5 Hz, 1
H, H-3), 5.25 (s, 1 H, NH), 7.35 (m, 5 H); 13C NMR δ 27.9,
2
3
3
1
52.5, 53.8 (q, J CF ) 32 Hz, C-3), 73.0, 74.1 (q, J CF ) 1.3 Hz),
80.8, 124.1 (q, 1J CF ) 283 Hz, CF3), 128.2, 128.4, 136.1, 154.6,
169.1. Anal. Calcd for C17H22F3NO5: C, 54.11; H, 5.87; N,
3.71. Found: 54.01; H, 5.86; N, 3.69.
δ -60.3 (d, J FH ) 10.6 Hz); H NMR δ 1.45 (s, 9 H), 3.23 (d,
3J ) 4.1 Hz, 1 H, OH), 3.87 (s, 3 H, OCH3), 4.69 (d, J ) 4.1
3
Hz, 1 H, H-2), 4.78 (dd, J HF ) 10.6 Hz, 3J ) 10.5 Hz, 1 H,
3
H-3), 5.25 (d, J ) 10.5 Hz, 1 H, NH); 13C NMR δ 28.2, 53.4,
3
2
1
58.8 (t, J CF ) 26 Hz, C-3), 68.2, 80.9, 127.8 (t, J CF ) 298 Hz,
CF2Cl), 154.6 172.2. Anal. Calcd for C17H22ClF2NO5: C, 39.55;
H, 5.31; N, 4.61. Found: 39.38; H, 5.52; N, 4.58.
Meth yl syn -2-(Ben zyloxy)-4,4-d iflu or o-3-[(ter t-bu toxy-
ca r boxyl)a m in o]bu ta n oa te (10b). A solution of the azeti-
dinone 9b (180 mg, 0.55 mmol) in DMF (1.5 mL) was stirred
with NaN3 (43 mg, 0.65 mmol) and MeOH (1 mL) under Ar
for 18 h at rt. After workup, the crude product was purified
on a silica gel column (pentane/EtOAc, 75:25) to give the ester
Meth yl syn -2-Hydr oxy-4,4,4-tr iflu or o-3-am in obu tan oate
(4a ). Trifluoroacetic acid (0.16 mL, 2.18 mmol) was added,
under Ar, to a solution of N-Boc-amino ester 11a (150 mg, 0.52
mmol) in CH2Cl2 (3 mL). The reaction mixture was stirred at
2
10b as a liquid (138 mg, 70%): 19F NMR δ -125.9 (ddd, J FF

8832 J . Org. Chem., Vol. 62, No. 25, 1997
Abouabdellah et al.
3
1
rt for 2 h, Et2O was added (5 mL), and N-methylmorpholine
was added until pH 7. After extraction with Et2O, the organic
phase was washed with brine, dried (MgSO4), and evaporated
7.6 (q, J
) 3.5 Hz, 1 H); 13C NMR δ 23.8, 68.6, 118.9 (q, J
FH
2
) 284 Hz, CF3), 126.5, 127.5, 128.6, 142.0, 147.9 (q, J CF ) 38
Hz, C-CF3).
3
to give the amino ester 4a : 19F NMR δ -76.1 (d, J FH ) 7.4
cis-1-(S )-(P h e n yle t h yl)-3-(b e n zyloxy)-4-(t r iflu or o-
m eth yl)a zetid in -2-on es 19 a n d 20. A solution of N-(2,2,2-
trifluoroethylidene)phenethylamine 18 (7.6 g, 0.038 mol) and
R-(benzyloxy)acetyl chloride (12 mL, 75.9 mmol) in freshly
distilled CH2Cl2 (30 mL) was treated with NEt3 (15.3 mL, 0.11
mol). The resulting mixture was then stirred overnight at 40
°C. The solution was poured into water (20 mL) and extracted
with EtOAc (2 × 50 mL). The organic phase was washed with
brine and dried over MgSO4. After evaporation of solvent, the
crude product was purified by crystallization in cold ethanol.
The white solid was crystallized again (Et2O/2-propanol) to
give the pure azetidinone 19 (3.8 g, 29%, 99% of purity). The
filtrate was evaporated, and the residue was purified by
chromatography on a SiO2 column (pentane-EtOAc 75:25) and
by crystallization (pentane) to give the pure isomer 20 (5.5 g,
41%).
Hz); 1H NMR δ 1.7 (s, 2 H, NH2), 3.55 (bs, 1 H, OH), 3.61 (dq,
3J HF ) 7.4 Hz, 3J ) 1.2 Hz, 1 H, H-3), 3.85 (s, 3 H, OCH3),
4.52 (d, 3J ) 1.2 Hz,1 H, H-2); 13C NMR δ 53.5, 55.0 (q, 2J CF
29 Hz, C-3), 68.9 (q, J CF ) 2.0 Hz), 125.5 (q, J CF ) 283 Hz,
CF3), 172.7. Anal. Calcd for C5H9F3NO3: C, 31.90; H, 4.82;
N, 7.44. Found: 31.48; H, 5.07; N, 7.19.
)
3
1
syn -Meth yl 2-Hyd r oxy-4,4-d iflu or o-3-a m in obu ta n oa te
(4b). Trifluoroacetic acid (0.16 mL, 2.18 mmol) was added,
under Ar, to a solution of N-Boc-amino ester 11b (150 mg, 0.52
mmol) in CH2Cl2 (3 mL). The reaction mixture was stirred at
rt for 2 h, Et2O was added (5 mL), and N-methylmorpholine
was added until pH 7. After extraction with Et2O, the organic
phase was washed with brine, dried (MgSO4), and evaporated
to give the amino ester 4b (40 mg, 64%): mp 60 °C (CH2Cl2-
9
2
2
pentane); F NMR δ -124.8 (ddd, J FF ) 286 Hz, J FH ) 56
3
2
2
(S )-1-P h e n yle t h yl-3(R )-(b e n zyloxy)-4(R )-(t r iflu or o-
Hz, J FH ) 7 Hz, 1 F), -139.6 (dddd, J FF ) 286 Hz, J FH
)
57.5 Hz, J FH ) 11 Hz, J FH ) 1.3 Hz, 1 F); 1H NMR δ 2.1 (bs,
3
4
m eth yl)a zetid in -2-on e (19): mp 108 °C (Et2O-2-propanol);
[R]25 -17.0° (c ) 3, EtOAc); 19F NMR δ - 69.2 (d, J FH ) 7
3
3
D
1
3 H, NH2 and OH), 3.83 (s, 3 H, OCH3), 3.3 (dddd, J FH ) 11,
3
3
3
3
4
Hz); H NMR δ 1.57 (d, J ) 7.4 Hz, 3 H, CH3), 3.7 (qd, J HF
7 Hz, J ) 6.3, 2 Hz, 1 H, H-3), 4.39 (m, J ) 2 Hz, J FH ) 1.3
3
3
3
3
3
) 7 Hz, J ) 6.2 Hz, 1 H, H-4), 4.6 (d, J ) 6.2 Hz, 1 H, H-3),
Hz, J ) 1 Hz, 1 H, H-2), 5.72 (ddd, J HF ) 56, 57.5 Hz, J )
6.4 Hz, 1 H, CF2H); 13C NMR δ 53.1, 55.7 (t, J CF ) 23 Hz,
2
4.66 (q, J AB ) 11.8 Hz, 2 H, OCH2C6H5), 5.0 (q, J ) 7.4 Hz, 1
H) 7.3 (m, 10 H, C6H5); 13C NMR δ 18.2, 51.7, 56.7 (q, J CF
)
2
C-3), 69.3 (dd, 3J CF ) 6.7, 2 Hz), 116.2 (t, 1J CF ) 291 Hz, CF3),
173.1. Anal. Calcd for C5H9F2NO3: C, 35.51; H, 5.36; N, 8.28.
Found: 37.34; H, 5.64; N, 7.81.
1
34 Hz, C-4), 73.5, 80.3, 124.7 (q, J CF ) 280 Hz, CF3), 127.3,
127.9, 128.2, 128.3, 128.6, 129.0, 136.3, 138.1, 166.5. Anal.
Calcd for C20H18F3NO3: C, 65.32; H, 5.19; N, 4.00. Found:
65.17; H, 5.27; N, 4.00.
Rea ction of th e N-(2,2,2-Tr iflu or oeth ylid en e)-4-m eth -
oxya n ilin e (6a ) w it h E st er 15-17 E n ola t es: Gen er a l
P r oced u r e. To a solution of LDA in THF, prepared at 0 °C
from diisopropylamine (1.1 mmol) and BuLi (1.1 mol equiv of
a 1.5 M solution in hexanes) in THF (2 mL), was added, after
30 min at -78 °C, the (silyloxy)acetate 15-17 (1.1 mol equiv).
After 2 h, trifluoroacetaldimine 7a (1.1 mole equiv) in solution
in THF (1 mL) was added. The solution was stirred for 3 h at
-78 °C and then allowed to warm to rt overnight. The
resulting reaction mixture was then poured into a saturated
ammonium chloride solution (10 mL) and extracted with
diethyl ether (3 × 25 mL). The combined organic extracts were
washed (brine), dried (MgSO4), and evaporated to give a
residue that was purified by chromatography on silica gel
(pentane-EtOAc, 95:5).
(S)-1-(P h en ylet h yl)-3(S)-(b en zyloxy)-4-(S)-(t r iflu or o-
m eth yl)a zetid in -2-on e (20): mp 44 °C (pentane); [R]25D -3.7°
(c ) 3, EtOAc); 19F NM δ - 69.4 (d, J FH ) 6 Hz); H NMR δ
3
1
3
3
3
1.8 (d, J ) 7.2 Hz, 3 H, CH3), 3.8 (qd, J HF ) 6 Hz, J ) 6.0
3
3
Hz, 1 H, H-4), 4.5 (q, J ) 7.2 Hz, 1 H), 4.67 (d, J ) 6.0 Hz,
1 H, H-3), 4.69 (q, J AB ) 11.8 Hz, δA 4.73, δB 4.66, 2 H,
OCHAHBC6H5), 7.3 (m, 10 H, C6H5); 13C NMR δ 19.6, 55.7, 56.5
2
1
(q, J CF ) 32.8 Hz, C-4), 73.4, 79.9, 124.0 (q, J CF ) 280 Hz,
CF3), 126.6, 127.8, 128.2, 128.5, 129.0, 129.1, 136.3, 140.3,
166.6. Anal. Calcd for C20H18F3NO3: C, 65.32; H, 5.19; N,
4.00. Found: 65.10; H, 5.35; N, 4.15
Meth yl 2-(R)-Ben zyloxy-4,4,4-tr iflu or o-3(R)-[[(S)-p h en -
yleth yl]a m in o]bu ta n oa te (21). Azetidinone 19 (1 g, 3.03
mmol) was stirred in a methanol solution of HCl gas (3 M)
(20 mL) at rt for 24 h. After evaporation of MeOH under
reduced pressure at rt and treatment with N-methylmorpho-
line and extraction (CH2Cl2), the organic phases were washed
with water (2 × 15 mL) and then with brine. After solvent
evaporation, the residue was purified by SiO2 chromatography
and provided the amino ester 21 (910 mg, 84%): mp 68 °C
Rea ction w ith th e Mesityl (Tr iisop r op ylsilyl)oxy Ester
15: cis-N-(4-Meth oxyp h en yl)-3-[(tr iisop r op ylsilyl)oxy]-
4-(tr iflu or om eth yl)a zetid in -2-on e (14). The reaction per-
formed from 15 (500 mg, 1.18 mmol), trifluoroaldimine 7a (240
mg, 1.18 mmol), and LDA (1.3 mmol equiv) afforded, after
workup and purification, the cis-N-(4-methoxyphenyl)-3-[(tri-
isopropylsilyl)oxy]-4-(trifluoromethyl)azetidin-2-one (14) (400
(pentane); [R]25 -18.3° (c ) 3, EtOAc); 19F NMR δ - 72.6 (d,
D
3
mg, 68%): 19F NMR δ -68.8 (d, J FH ) 5.5 Hz); 1H NMR δ
3J FH ) 7.5 Hz); 1H NMR δ 1.1 (d, J ) 6.4 Hz, 3 H, CH3), 2.25
3
0.82 (m, 3 H), 1.1 (bs, 18 H), 3.7 (s, 3 H), 4.5 (m, 1 H, H-4),
3
(bs, 1 H, NH), 3.5 (m, J FH ) 7.5 Hz, 1 H, H-3), 3.73 (s, 3 H),
3
5.13 (d, J ) 5.1 Hz, 1 H, H-3), 7.0 (q, J ) 10 Hz, 4 H, C6H4).
3.85 (q, 3J ) 6.4 Hz, 1 H); 4.2 (d, 3J ) 1.7 Hz, 1 H, H-2); 4.6 (q,
J AB ) 11.2 Hz, δA 4.45, δB 4.8, 2 H), 7.3 (m, 10 H); 13C NMR δ
Anal. Calcd for C18H16F3NO3: C, 61.54; H, 4.59; N, 4.0.
Found: C, 61.17; H, 4.83; N, 3.81.
2
3
24.0, 52.0, 55.2, 58.2 (q, J CF ) 28 Hz, C-3), 73.2, 74.6 (d, J CF
R ea ct ion w it h t h e Men t h yl (Tr iisop r op ylsilyl)oxy
ester 16. The same reaction performed from ester 16 gave
an unidentified mixture. Azetidinone 14 was not detected.
1
) 2 Hz, C-2), 125.2 (q, J CF ) 284 Hz, CF3), 126 to 128, 136.7,
144.3, 171.0. Anal. Calcd for C20H22F3NO3: C, 63.00; H, 5.80;
N, 3.70. Found: 62.96; H, 5.91; N, 3.69.
Rea ction w ith th e 2-P h en ylcycloh exyl (Tr iisop r op yl-
silyl)oxy ester 17. The reaction performed from 17 (355 mg,
1.15 mmol), trifluoroaldimine 7a (230 mg, 1.15 mmol), and
LDA (1.3 mmol equiv) afforded, after workup and purification,
the azetidinone 14 (117 mg, 20%).
Meth yl 2(S)-(Ben zyloxy)-4,4,4-tr iflu or o-3(S)-[[(S)-p h en -
yleth yl]a m in o]bu ta n oa te (22). Following the same proce-
dure, azetidinone 20 led to isoserinate 22: mp 85 °C (pentane);
3
[R]25 -72.7° (c ) 3, EtOEt); 19F NMR δ -69.1 (d, J FH ) 6.5
D
Hz); 1H NMR δ 1.23 (d, J ) 6.5 Hz, 3 H, CH3), 2.15 (bs, 1 H,
3
NH), 3.3 (q, 3J HF ) 7.7 Hz, 1 H, H-3), 3.60 (s, 3 H, OCH3), 3.97
(S)-N-(2,2,2-Tr iflu or oeth ylid en e)p h en eth yla m in e (18).
A solution of ethyl trifluoroacetaldehyde hemiacetal (15 g, 0.1
mol), (S) phenylethylamine (9 g, 0.074 mol), and p-toluene-
sulfonic acid in toluene (150 mL) was refluxed under Ar for
1.5 h in a Dean-Stark apparatus. Et2O (100 mL) was added,
and the solution was washed with an aqueous solution of
sodium hydrogenocarbonate and then with brine and dried
(MgSO4). The solution was evaporated under reduced pres-
sure, and the residue was distilled leading to the (S)-N-(2,2,2-
trifluoroethylidene)phenethylamine (18) (13.6 g, 55%): 19F
3
3
2
(qd, J HF ) 6.5 Hz, J HH ) 1.4 Hz, 1 H, H-3); 4.11 (d, J ) 2.1
Hz, 1 H, H-2), 4.56 (q, J AB ) 11.2 Hz, δA 4.36, δB 4.76, 2 H),
7.3 (m, 10 H); 13C NMR δ 25.0, 51.9, 55.0, 57.9 (q, J CF ) 26.5
2
3
1
Hz, C-3), 73.3, 76.1 (d, J CF ) 2.7 Hz, C-2), 125.9 (q, J CF
)
289 Hz, CF3), 127.2, 127.3, 128.0, 128.2, 128.3 128.4, 136.6,
143.9, 169.6. Anal. Calcd for C20H22F3NO3: C, 63.00; H, 5.80;
N, 3.70. Found: 63.06; H, 5.95; N, 3.68.
Meth yl 2(R)-Hyd r oxy-4,4,4-tr iflu or o-3(R)-[(ter t-bu toxy-
ca r bon yl)a m in o]bu ta n oa te (23). A solution of the amino
ester 21 (930 mg, 2.44 mmol) and (Boc)2O (640 mg, 2.9 mmol)
in anhydrous EtOAc (20 mL) was stirred under H2 atmosphere
3
1
3
NMR δ -71.8 (d, J FH ) 3.5 Hz); H NMR δ 1.56 (d, J ) 6.6
3
Hz, 3 H, CH3), 4.57 (q, J ) 6.6 Hz, 1 H), 7.3 (m, 5 H, C6H5),

Synthesis of Methyl syn-(1-Fluoroalkyl)isoserinates
J . Org. Chem., Vol. 62, No. 25, 1997 8833
in the presence of Pd(OH)2/C (300 mg) for 24 h. After filtration
on Celite and evaporation of the solvent, purification by SiO2
chromatography (pentane-EtOAc, 60:40) provided the ester
Calcd for C16H16F3NO4: C, 41.81; H, 5.61; N, 4.87. Found:
41.87; H, 5.73; N, 4.84.
23 (2R,3R) (526 mg, 75%): mp 96 °C (EtOAc, pentane); [R]25
Ack n ow led gm en t. The authors thank Dr. Masami-
chi Maruta, from Central Glass Company for his gener-
ous gift of starting materials, Miche`le Oure´vitch for
NMR experiments, Mrs. Sabine Halut (Laboratoire des
Me´taux de Transition, Universite´ P. & M. Curie, Paris-
6) for X-ray diffraction structure. We are pleased to
thank Professor Iwao Ojima for fruitful discussions. This
study was partially supported by Biomed 2 EC program
and by Fondation pour la Recherche Me´dicale (SIDAC-
TION). CNRS is gratefully acknowledged for a PhD
grant (N.T.T.T.).
D
-41.2° (c ) 2, EtOAc); 19F NMR δ -74.0 (d, 3J FH ) 7.5 Hz); 1H
3
NMR δ 1.35 (s, 9 H), 3.25 (d, J ) 3.5 Hz, 1 H, H-2), 3.82 (s,
3 H), 4.57 (d, J ) 3.5 Hz, 1 H, OH), 4.73 (dq, 3J FH ) 7.8 Hz, 3J
) 10 Hz, 1 H, H-3); 5.18 (d, J ) 10 Hz, 1 H, NH); 13C NMR δ
2
27.9, 53.5, 53.6 (q, J CF ) 31 Hz, C-3), 67.8, 81.0, 124.1 (q,
1J CF ) 283 Hz, CF3), 155.0, 172.0. Anal. Calcd for C16H16
-
NO4: C, 41.81; H, 5.61; N, 4.87. Found: 41.76; H, 5.74; N,
4.83.
Meth yl 2(S)-Hyd r oxy-4,4,4-tr iflu or o-3(S)-[(ter t-bu toxy-
ca r bon yl)a m in o]bu ta n oa te (23). Following the same pro-
cedure, the compound 22 (930 mg, 2.44 mmol) led after workup
to the ester 23 (2S,3S) (505 mg, 72%): mp 98 °C (EtOAc,
Su p p or tin g In for m a tion Ava ila ble: Crystal data for 21
(3 pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
pentane); [R]25 +42° (c ) 2.5, EtOAc); 19F NMR δ - 73.9 (d,
D
3J FH ) 7.5 Hz); H NMR δ 1.35 (s, 9 H), 3.25 (d, J ) 3.0 Hz,
1
3
1 H, H-2), 3.82 (s, 3 H), 4.57 (d, J ) 3.0 Hz, 1 H, OH), 4.73
3
3
(dq, J HF ) 7.5 Hz, J ) 10 Hz, 1 H, H-3), 5.18 (d, J ) 10 Hz,
1 H, NH); 13C NMR δ 27.9, 53.4, 53.6 (q, J CF ) 31 Hz, C-3),
2
1
67.8, 81.0, 124.1 (q, J CF ) 283 Hz, CF3), 154.6, 172.0. Anal.
J O971381A