Regioselective and stereoselective nucleophilic ring opening of trifluoromethylated cyclic sulfates: Asymmetric synthesis of both enantiomers of syn-(3-trifluoromethyl)isoserine

Article abstract of DOI:10.1021/jo0497611

A novel and efficient enantioselective synthesis of both enantiomers of syn-(3-trifluoromethyl)isoserine was achieved. Ring opening of trifluoromethylated cyclic sulfates 3, derived from enantiopure trifluoromethylated vicinal diols 2, with various nucleo

Full text of DOI:10.1021/jo0497611

author for investigation on the bioactive conformations
of taxiods by 19F NMR. The first synthesis of racemic
methyl syn-(3-trifluoromethyl)isoserine by ring opening
of the trifluoromethyl-substituted â-lactam was published
in 1996 by Begue et al.5 Uneyama et al.6a and Burger et
al.6b prepared racemic anti-(3-trifluoromethyl)isoserine
via intramolecular rearrangement of trifluoromethylated
imino ether starting from N-acyl-1-chloro-2,2,2-trifluoro-
ethylamine, respectively. However, the synthesis of
enantiomerically pure syn/ anti-(3-trifluoromethyl)iso-
serine required the resolution of racemic aziridines7 and
the separation of diastereoisomeric azetidinones.8 There-
fore, it is of great importance to develop new routes to
enantiomerically pure (3-trifluoromethyl)isoserine. Herein,
we report a novel and efficient enantioselective synthesis
of both enantiomers of syn-(3-trifluoromethyl)isoserine
based upon regioselective and stereoselective nucleophilic
ring opening of trifluoromethylated cyclic sulfates.
Recently, we have reported that the Sharpless asym-
metric dihydroxylation (AD) of 1 provided both enantio-
mers of 1-benzyloxy-4,4,4-trifluoro-2,3-butanediol 2a and
2b in good yield and high enantioselectivity, and the
resulting diols 2a and 2b were converted to sulfates 3a
and 3b in excellent yield, respectively (Scheme 1).9
However, the Sharpless AD reaction of 1 proceeded quite
slowly (3-4 days) under standard AD conditions due to
the strong electron-withdrawing effect of the trifluorom-
ethyl group (Table 1, entries 1 and 2). We were pleased
to find that a dramatic increase of the reaction rate can
be achieved by doubling the amount of both OsO4 and
ligand (Table 1, entries 3 and 4).10 Both isomers of high
enantiomerically pure 1-benzyloxy-4,4,4-trifluoro-2,3-bu-
tanediol 2a and 2b can be prepared on a 10 g scale
through Sharpless AD reaction of 1.
Regioselective a n d Ster eoselective
Nu cleop h ilic Rin g Op en in g of
Tr iflu or om eth yla ted Cyclic Su lfa tes:
Asym m etr ic Syn th esis of Both En a n tiom er s
of syn -(3-Tr iflu or om eth yl)isoser in e
Zhong-Xing J iang† and Feng-Ling Qing*,†,‡
Key Laboratory of Organofluorine Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Science,
354 Fenglin Lu, Shanghai 200032, China, and College of
Chemistry and Chemistry Engineering, Donghua University,
1882 West Yanan Lu, Shanghai 200051, China
flq@mail.sioc.ac.cn
Received February 11, 2004
Abstr a ct: A novel and efficient enantioselective synthesis
of both enantiomers of syn-(3-trifluoromethyl)isoserine was
achieved. Ring opening of trifluoromethylated cyclic sulfates
3, derived from enantiopure trifluoromethylated vicinal diols
2, with various nucleophiles occurred exclusively at C2 with
inversion of chirality. Treatment of 4c and 4d , obtained by
nucleophilic opening of 3a and 3b with PhCO2NH4, with
(CF3SO2)2O followed by substitution with sodium azide,
J ones oxidation, and hydrogenolysis furnished (2S,3S)-(N-
benzoyl)-3-(trifluoromethyl)isoserine 9a and (2R,3R)-(N-
benzoyl)-3-(trifluoromethyl)isoserine 9b, respectively.
â-Amino acids and their derivatives are valuable
intermediates in the synthesis of â-lactams, Taxol semi-
synthetic analogues, and peptidomimetic units.1 Because
of the importance of fluorine-containing molecules in
chemical and pharmaceutical research,2 fluorinated ana-
logues of nonproteinogenic â-amino acids have attracted
a great deal of attention in the past few years.3 Among
these fluorine-containing amino acids, a special interest
has been put to (3-trifluoromethyl)isoserine. One notable
example is that Ojima synthesized a class of novel taxoids
with a syn-(3-trifluoromethyl)isoserine side chain which
exhibited greatly enhanced activities against several
different human cancer cell lines as compared to those
of paclitaxel and docetaxel, in particular against a drug-
resistant breast cancer cell line, MCF 7-R.4 These trif-
luoromethylated taxoids were also used by the same
In our previous study, it was found that the nucleo-
philic ring opening of trifluoromethylated cyclic sulfates
3a and 3b with NaN3 occurred exclusively at C2 with
clean inversion of C2 followed by acidic hydrolysis to
provide 4a and 4b respectively (Table 2, entries 1 and
2).9 These results prompted us to investigate the reaction
of 3 with other nucleophiles. As shown in Table 2,
nucleophilic ring opening of trifluoromethylated cyclic
-
sulfates 3 in an SN2 fashion with PhCO2 (PhCO2NH4),
PhthN- (potassium phthalimide), and H- (NaBH4) were
generally carried out for 4 h at 80 °C and followed by
acidic hydrolysis to provide 4 in excellent yield except
for 4e and 4f, which may be due to steric effects of the
bulky nucleophile. In every case, nucleophilic substitution
* To whom correspondence should be addressed. Fax: 86-21-
64166128.
† Shanghai Institute of Organic Chemistry.
‡ Donghua University.
(4) (a) Ojima, I.; Slater, J . C. Chirality 1997, 9, 487-494. (b) Ojima,
I.; Slater, J . C.; Perea, P.; Vieth, J . M.; Abouabdellah, A.; Be´gue´, J . P.;
Bernacki, R. J . Bioorg. Med. Chem. Lett. 1997, 7, 133-138.
(5) Abouabdellah, A.; Begue, J . P.; Bonnet-Delpon, D. Synlett 1996,
399-400.
(1) (a) Cardilllo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 25, 117-
128 and references therein. (b) Ojima, I.; Delaloge, F. Chem. Soc. Rev.
1997, 26, 377-386.
(2) (a) Fluorine-containing Amino Acids, Synthesis and Properties;
Kukhar, V. P., Soloshonok, V. A., Eds.; J . Wiley and Sons: New York;
1995. (b) Biomedical Aspect of Fluorine Chemistry; Filler, R., Koba-
yashi, Y., Eds.; Kodansha Ltd.: Tokyo; Elsevier Biomedical: Amster-
dam, 1982. (c) Asymmetric Fluoroorganic Chemistry, Synthesis, Ap-
plication and Future Directions; Ramachandran, P. V., Eds.; American
Chemical Society: Washington, DC; 2000. (d) Organofluorine Com-
pounds in Medicinal Chemistry and Biochemical Applications; Filler,
R., Kobayashi, Y., Yagupolskii, L. M., Eds.; Elsenvier: Amsterdam,
1993.
(6) (a) Uneyama, K.; Hao, J .; Amii, H. Tetrahedron. Lett. 1998, 39,
4079-4082. (b) Setgeeva, N. N.; Golubev, A. S.; Hennig, L.; Burger,
K. Synthesis 2002, 2579-2584.
(7) Davoli, P.; Forni, A.; Franciosi, C.; Moretti, I.; Prati, F. Tetra-
hedron: Asymmetry 1999, 10, 2361-2371.
(8) Abouabdellah, A.; Begue, J . P.; Bonnet-Delpon, D.; Nga, T. T. T.
J . Org. Chem. 1997, 62, 8826-8833.
(9) J iang, Z. X.; Qin, Y. Y.; Qing, F. L. J . Org. Chem. 2003, 68, 7544-
7547.
(3) Brovo, P.; Crucianelli, M.; Ono, T.; Zanda, M. J . Fluorine Chem.
1999, 97, 27-49 and references therein.
(10) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483-2547.
10.1021/jo0497611 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/03/2004
5486
J . Org. Chem. 2004, 69, 5486-5489

SCHEME 1
TABLE 1. Sh a r p less Asym m etr ic Dih yd r oxyla tion of
Olefin 1
TABLE 2. Nu cleop h ilic Op en in g of Cyclic Su lfa tes 3
time eeb
yield
entry
reaction conditionsa
AD-mix-â
(h) (%) config product (%)
1
2
3
72 93
96 93
2S,3R 2a
2R,3S 2b
95
94
96
AD-mix-R
(DHQD)PHAL (2% equiv), 48 99.4 2S,3R 2a
OsO4 (0.8% equiv),
K3Fe(CN)6 (3 equiv),
K2CO3 (3 equiv)
4
(DHQ)PHAL (2% equiv),
OsO4 (0.8%, equiv),
K3Fe(CN)6 (3 equiv),
K2CO3 (3 equiv)
48 97.5 2R,3S 2b
93
a
All reactions were carried out in the presence of MeSO2NH2
t
b
(1 equiv) in H2O- BuOH at room temperature. Determined by
HPLC on Chiralcel OD column.
occurred exclusively at C2 with clean inversion at C2,
as only one peak appeared in the 19F NMR of the reaction
mixture after acidic hydrolysis. The high regioselectivity
is attributed to the strong electron-withdrawing effect of
the trifluoromethyl group which destabilizes the transi-
tion state for C3 substitution. The structure of 4 was
confirmed in many ways. First, it was confirmed by the
19F NMR spectroscopy of 4g: A doublet peak appeared
at -79.80 ppm (J ) 8.1 Hz), indicating that the trifluoro-
methyl group of 4g is adjacent to a methine group (CH),
and not a methylene group (CH2). Second, we had
prepared (2S)-2-(tert-butoxycarbonyl) amino-4,4,4-tri-
fluorobutanoic acid from 4a using the radical-based
dehydroxylation as the key step.9 A triplet peak appeared
at -65.09 (J ) 12.4 Hz) in the 19F NMR spectrum of (2S)-
2-(tert-butoxycarbonyl) amino-4,4,4-trifluorobutanioc acid,
which further showed that the trifluoromethyl group of
4 was adjacent to methine group (CH). Furthermore, the
absolute configuration of 2 and 4 was determined by
comparison the optical rotation data of (2S)-2-(tert-
butoxycarbonyl) amino-4,4,4-trifluorobutanioc acid and
(2S,3R)-4,4,4-trifluorothreonine derived from 4a with
that reported.9
With 4c and 4d in hand, we sought to apply them to
the synthesis of (3-trifluoromethyl)isoserine. The syn-
thesis of (2S,3S)-N-benzoyl-3-(trifluoromethyl)isoserine
9a commenced with alcohol 4c (Scheme 2). Alcohol 4c
was treated with trifluoromethanesulfonic anhydride and
pyridine at -40 °C to afford trifluoromethanesulfate 5a
in quantitative yield. Exposure of trifluoromethane-
sulfonate 5a to sodium azide in dimethyl sulfoxide at 40
°C gave azide 6a in 94% yield. Removal of the benzyl
group with boron trichloride at -78 °C generated primary
alcohol 7a in quantitative yield, which was then oxidized
with J ones reagent to give the acid 8a in good yield. To
complete the synthesis of (2S,3S)-N-benzoyl-3-(trifluoro-
methyl)isoserine 9a , the azido group had to be reduced
to an amino group and the benzoyl group needed to
a
DMAC was used as solvent, at 60 °C.
migrate to the amino group. It was anticipated that a
migration of the benzoyl group from the oxygen atom to
the nitrogen atom would readily occur.11 As expected,
(11) (a) Bessodes, M.; Abushanab, E.; Antonakis, K. Tetrahedron
Lett. 1984, 25, 5899-5902. (b) Denis, J . N.; Greene, A. E.; Serra, A.
A.; Luche, M. J . J . Org. Chem. 1986, 51, 46-50. (c) Gou, D. M.; Liu, Y.
C.; Chen, C. S. J . Org. Chem. 1993, 58, 1287-1289. (d) Bonini, C.;
Righi, G. J . Chem. Soc. Chem. Commun. 1994, 2767-2768. (e) Soucy,
F.; Grenier, L.; Behnke, M. L.; Destree, A. T.; McCormack, T. A.;
Adams, J .; Plamondon, L. J . Am. Chem. Soc. 1999, 121, 9967-9976.
(f) Hamamoto, H.; Mamedov, V. A.; Kitamoto, M.; Hayashi, N.; Tsuboi,
S. Tetrahedron: Asymmetry 2000, 11, 4485-4498.
J . Org. Chem, Vol. 69, No. 16, 2004 5487

SCHEME 2
Rep r esen ta tive P r oced u r e for th e Nu cleop h ilic Rin g
Open in g of Tr iflu or om eth ylated Cyclic Su lfates 3. (2R,3R)-
1-Ben zyloxy-2-a zid o-4,4,4-tr iflu or obu ta n -3-ol (4a ). A solu-
tion of cyclic sulfate 3a (1.80 g, 5.77 mmol) and sodium azide
(0.75 g, 11.54 mmol) in DMF (20 mL) was stirred for 4 h at 80
°C. The solvent was carefully removed by distillation under
reduced pressure. THF (20 mL), water (54 µL), and sulfuric acid
(150 µL) were added, and the resulting suspension was stirred
for 1 h. Then NaHSO3 was added. The reaction mixture was
stirred for 20 min and filtered on silica gel. The filtrate was
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate )
8:1) to give 4a (1.53 g, 96%): 1H NMR (300 MHz, CDCl3) δ 7.33-
7.42 (m, 5H), 4.62 (s, 2H), 4.18-4.26 (m, 1H), 3.98 (dd, J ) 4.2
Hz, 10.2 Hz, 1H), 3.90 (dd, J ) 3.3 Hz, 10.2 Hz, 1H), 3.64-3.69
(m, 1H); 19F NMR (282 MHz, CDCl3) δ -76.90 (d, J ) 6.6 Hz).
(2S,3S)-1-Ben zyloxy-2-azido-4,4,4-tr iflu or obu tan -3-ol (4b).
This compound was prepared from 3b in 100% yield by using
the same procedure as described for 4a : 1H NMR (300 MHz,
CDCl3) δ 7.29-7.39 (m, 5H), 4.58 (s, 2H), 4.10-4.20 (m, 1H),
3.93 (dd, J ) 4.9 Hz, 9.4 Hz, 1H), 3.90 (dd, J ) 3.1 Hz, 9.4 Hz,
1H), 3.61-3.65 (m, 1H); 19F NMR (282 MHz, CDCl3) δ -76.53
(d, J ) 6.6 Hz).
SCHEME 3
both the reduction and the migration of the benzoyl group
proceeded smoothly under normal palladium catalyzed
hydrogenation conditions to give amino acid 9a in 98%
yield from 8a . The migration of the benzoyl group was
confirmed by IR spectroscopy of 9a : A strong absorption
at 1655 cm-1 was observed, which is the typical absorp-
tion of the amide groups.
The same procedure as described above can smoothly
convert 4d to (2R,3R)-N-benzoyl-3-(trifluoromethyl)iso-
serine 9b (Scheme 3).
In summary, we have described an efficient procedure
for construction of both enantiomers of trifluorometh-
ylated cyclic sulfates 3. Nucleophilic ring opening of
trifluoromethylated cyclic sulfates 3 with various nucleo-
philes took place exclusively at C2 with clean inversion
of chirality. Both enantiomers of (3-trifluoromethyl)-
isoserine were successfully synthesized from the nucleo-
philic substitution products 4c and 4d .
(2R,3R)-Ben zoic Acid 1-Ben zyloxym eth yl-3,3,3-tr iflu or o-
2-h yd r oxyp r op yl Ester (4c). This compound was prepared
from 3a in 100% yield by using the same procedure as described
for 4a : [R]20 ) -5.14 (c 3.315, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 8.08-8.12 (m, 2H), 7.60-7.65 (m, 1H), 7.47-7.52 (m,
2H), 7.33-7.35 (m, 5H), 5.40-5.44 (m, 1H), 4.61 (s, 2H), 4.46-
4.50 (m, 1H), 4.06 (dd, J ) 3.3 Hz, 10.8 Hz, 1H), 3.92 (dd, J )
3.3 Hz, 11.4 Hz, 1H); 19F NMR (282 MHz, CDCl3) δ -76.73 (d,
J ) 8.5 Hz); IR (thin film) νmax 3448, 3035, 1719, 1603, 1585,
1497, 1453, 1264, 1145 cm-1. MS (EI) m/z 354 (M+, 2), 107 (15),
105 (100), 91 (89), 77 (52), 69 (1). Anal. Calcd for C18H17O4F3:
C, 61.02; H, 4.83. Found: C, 61.47; H, 4.94.
Exp er im en ta l Section
(2S,3R)-1-Ben zyloxy-4,4,4-tr iflu or o-2,3-bu ta n ed iol (2a ).
To a stirred mixture of tert-butyl alcohol (250 mL) and water
(250 mL) were added (DHQD)2PHAL (0.78 g, 2.0 mol %), K3Fe-
(CN)6 (49.50 g, 150 mmol), K2CO3 (21.00 g, 150 mmol), and OsO4
(4.00 mL of a 0.1 M solution in toluene, 0.8 mol %) at room
temperature. After the solid was dissolved, MeSO2NH2 (4.75 g,
50 mmol) was added. Then the mixture was cooled to 0 °C. Olefin
19 (10.80 g, 50 mmol) was added at once, and the heterogeneous
slurry was stirred vigorously at room temperature for 48 h. Na2-
SO3 was added, and the mixture was stirred for 30 min and then
extracted with ethyl acetate. The combined organic layer was
washed with 2 N KOH and brine, dried over anhydrous MgSO4,
and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (petroleum ether/ethyl acetate )
5:1) to give 2a (12.01 g, 96% yield, 99.4% ee): 1H NMR (300
MHz, CDCl3) δ 7.31-7.42 (m, 5H), 4.59 (s, 2H), 4.16 (dt, J ) 2.1
Hz, 6.0 Hz, 1H), 3.97 (dq, J ) 2.1 Hz, 9.0 Hz, 1H), 3.63 (d, J )
6.0 Hz, 2H); 19F NMR (282 MHz, CDCl3) δ -77.45 (d, J ) 9.0
Hz).
(2S,3S)-Ben zoic Acid 1-Ben zyloxym eth yl-3,3,3-tr iflu or o-
2-h yd r oxyp r op yl Ester (4d ). This compound was prepared
from 3b in 97% yield by using the same procedure as described
for 4a : [R]20 ) +5.20 (c 0.63, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 8.07-8.11 (m, 2H), 7.60-7.65 (m, 1H), 7.46-7.52 (m,
2H), 7.31-7.35 (m, 5H), 5.39-5.43 (m, 1H), 4.61 (s, 2H), 4.46-
4.50 (m, 1H), 4.06 (dd, J ) 3.3 Hz, 10.8 Hz, 1H), 3.92 (dd, J )
3.3 Hz, 11.1 Hz, 1H); 19F NMR (282 MHz, CDCl3) δ -76.73 (d,
J ) 8.5 Hz); IR (thin film) νmax 3442, 3035, 1725, 1603, 1586,
1490, 1454, 1279, 1141 cm-1; MS (EI) m/z 354 (M+, 1), 107 (14),
105 (100), 91 (87), 77 (48), 69 (1). Anal. Calcd for C18H17O4F3:
C, 61.02; H, 4.83. Found: C, 61.33; H, 4.80.
(2R,3R)-2-(1-Ben zyloxym eth yl-3,3,3-tr iflu or o-2-h yd r oxy-
p r op yl)isoin d ole-1,3-d ion e (4e). This compound was prepared
from 3a in 70% yield by using the same procedure as described
for 4a : [R]20 ) -27.2 (c 0.750 CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 7.84-7.90 (m, 2H), 7.76-7.80 (m, 2H), 7.18-7.26 (m,
5H), 4.89 (qd, J ) 6.9 Hz, 2.7 Hz, 1H), 4.63-4.71 (m, 1H), 4.60
(d, J ) 12 Hz, 1H), 4.45 (d, J ) 12 Hz, 1H), 3.98-4.09 (m, 2H);
19F NMR (282 MHz, CDCl3) δ -77.49 (d, J ) 6.9 Hz); IR (thin
film) νmax 3473, 2885, 1778, 1716, 1614, 1498, 1470, 1456, 1390,
1178 cm-1; MS (EI) m/z 380 (M + 1, <1), 379 (M+, 1), 174 (100),
146 (2), 107 (7), 91 (94), 77 (11), 69 (1). Anal. Calcd for
(2R, 3S)-1-Ben zyloxy-4,4,4-tr iflu or o-2,3-bu ta n ed iol (2b).
This compound was prepared from 1 in 93% yield by using the
same procedure as described for 2a : 1H NMR (300 MHz, CDCl3)
δ 7.30-39 (m, 5H), 4.57 (s, 2H), 4.14 (dt, J ) 1.8 Hz, 5.7 Hz,
1H), 3.95 (dq, J ) 1.8 Hz, 7.5 Hz, 1H), 3.60 (d, J ) 5.7 Hz, 2H);
19F NMR (282 MHz, CDCl3) δ -77.45 (d, J ) 7.5 Hz).
5488 J . Org. Chem., Vol. 69, No. 16, 2004

C19H16O4F3N: C, 60.16; H, 4.25; N, 3.69. Found: C, 59.79; H,
4.45; N, 3.53.
(thin film) νmax 2119, 1731, 1602, 1587, 1496, 1454, 1266, 1108
cm-1; MS (EI) m/z 380 (M+, 1), 216 (22), 107 (3), 105 (100), 91
(70), 77 (24), 69 (2). Anal. Calcd for C18H6O3F3N3: C, 56.99; H,
4.25; N, 11.08. Found: C, 56.91; H, 4.21; N, 10.86.
(2S,3S)-Ben zoic Acid 2-Azid o-3,3,3-tr iflu or o-1-h yd r oxy-
m eth ylp r op yl Ester (7a ). To a stirred solution of 6a (1.20 mg,
3.15 mmol) in anhydrous methylene chloride (60 mL) at -78 °C
was added dropwise boron trichloride (6.30 mL of 1 M solution
in methylene chloride, 6.30 mmol). The reaction mixture was
stirred for 2 h at -78 °C, and then methanol (8 mL) was added.
The solution was washed with saturated aqueous sodium
bicarbonate and brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by flash chromatography on
(2S,3S)-2-(1-Ben zyloxym eth yl-3,3,3-tr iflu or o-2-h yd r oxy-
p r op yl)isoin d ole-1,3-d ion e (4f). This compound was prepared
from 3b in 74% yield by using the same procedure as described
for 4a : [R]20 ) +26.4 (c 1.100 CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 7.84-7.90 (m, 2H), 7.75-7.80 (m, 2H), 7.17-7.27 (m,
5H), 4.89 (qd, J ) 6.9 Hz, 2.7 Hz, 1H), 4.65-4.70 (m, 1H), 4.59
(d, J ) 12 Hz, 1H), 4.44 (d, J ) 12 Hz, 1H), 3.98-4.09 (m, 2H);
19F NMR (282 MHz, CDCl3) δ -77.49 (d, J ) 6.9 Hz); IR (thin
film) νmax 3464, 2885, 1777, 1716, 1609, 1498, 1470, 1456, 1389,
1179 cm-1; MS (EI) m/z 380 (M + 1, 3), 379 (M+, 2), 174 (95),
147 (60), 107 (7), 91 (100), 77 (17), 69 (1). Anal. Calcd for
C19H16O4F3N: C, 60.16; H, 4.25; N, 3.69. Found: C, 60.49; H,
4.10; N, 4.07.
silica gel (petroleum ether/ethyl acetate ) 6:1) to give 7a (910
1
mg, 100%): [R]20 ) +6.5 (c 0.25, CHCl3); H NMR (300 MHz,
D
(3R)-4-Ben zyloxy-1,1,1-tr iflu or obu ta n -2-ol (4g). This com-
pound was prepared from 3a in 95% yield by using the same
procedure as described for 4a (DMAC was used as solvent, at
CDCl3) δ 8.04-8.07 (m, 2H), 7.59-7.65 (m, 1H), 7.45-7.51 (m,
2H), 5.56-5.61 (m, 1H), 4.26 (qd, J ) 6.9 Hz, 3.0 Hz, 1H), 4.00
(dd, J ) 11.4 Hz, 2.7 Hz, 1H), 3.90 (dd, J ) 11.4 Hz, 7.2 Hz,
1H); 19F NMR (282 MHz, CDCl3) δ -71.72 (d, J ) 6.9 Hz); IR
60 °C): [R]20 ) -14.4 (c 0.825 CHCl3); 1H NMR (300 MHz,
D
(thin film) νmax 3456, 2121, 1727, 1603, 1454, 1272, 1143 cm-1
;
CDCl3) δ 7.29-7.41 (m, 5H), 4.56 (s, 2H), 4.18-4.24 (m, 1H),
3.79-3.86 (m, 1H), 3.68-3.75 (m, 1H), 1.91-2.09 (m, 2H); 19F
NMR (282 MHz, CDCl3) δ -79.80 (d, J ) 8.1 Hz); IR (thin film)
νmax 3413, 2874, 1497, 1456, 1278, 1170 cm-1; MS (EI) m/z 234
(M+, 7), 107 (65), 91 (100), 69 (2). Anal. Calcd for C11H13O2F3:
C, 56.41; H, 5.60. Found: C, 56.83; H, 5.98.
MS (EI) m/z 290 (M + 1, 4), 272 (8), 123 (11), 105 (100), 77 (23),
69 (2). Anal. Calcd for C11H0O3F3N3: C, 45.68; H, 3.49; N, 14.53.
Found: C, 45.56; H, 3.58; N, 14.53.
(2S,3S)-Ben zoic Acid 2-Azid o-1-ca r boxy-3,3,3-tr iflu or o-
p r op yl Ester (8a ). To a mixture of 7a (549 mg, 1.9 mmol) in
acetone (60 mL) at 0 °C was added J ones reagent (1 M, 15 mL,
15 mmol). The mixture was stirred for 20 min at 0 °C under
nitrogen. The reaction was quenched with isopropyl alcohol (7
mL) and then diluted with water (60 mL) and ethyl acetate (60
mL). The aqueous layer was extracted with ethyl acetate. The
combined organic layers were dried, filtered, and concentrated
in vacuo. The residue was purified by column chromatography
(3S)-4-Ben zyloxy-1,1,1-tr iflu or obu ta n -2-ol (4h ). This com-
pound was prepared from 3b in 98% yield by using the same
procedure as described for 4a (DMAC was used as solvent, at
60 °C): [R]20 ) +14.5 (c 1.030 CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 7.27-7.41 (m, 5H), 4.55 (s, 2H), 4.17-4.23 (m, 1H),
3.78-3.85 (m, 1H), 3.67-3.74 (m, 1H), 1.90-2.07 (m, 2H); 19F
NMR (282 MHz, CDCl3) δ -80.09 (d, J ) 8.1 Hz); IR (thin film)
νmax 3413, 2874, 1497, 1456, 1278, 1170 cm-1; MS (EI) m/z 234
(M+, 17), 107 (28), 91 (100), 69 (1); HRMS (EI) calcd for
on silica gel (petroleum ether/ethyl acetate ) 1:1) to give 8a (495
1
mg, 86%): [R]20 ) -22.9 (c 0.45, CHCl3); H NMR (300 MHz,
D
C
11H13O2F3 234.08677, found 234.08804.
CDCl3) δ 8.09-8.12 (m, 2H), 7.62-7.68 (m, 1H), 7.48-7.53 (m,
2H), 5.91 (d, J ) 2.4 Hz, 1H), 4.40 (qd, J ) 7.2 Hz, 2.1 Hz, 1H);
19F NMR (282 MHz, CDCl3) δ -71.62 (d, J ) 7.2 Hz); IR (thin
film) νmax 3300, 2120, 1729, 1603, 1454, 1266, 1145 cm-1; MS
(EI) m/z 303 (M+, 1), 284 (1), 105 (100), 77 (28) 69 (3); HRMS
(EI) calcd for C11H8O4F3N3 303.04669, found 303.04698.
(2R,3R)-Ben zoic Acid 1-Ben zyloxym eth yl-3,3,3-tr iflu or o-
2-tr iflu or om eth an esu lfin yloxypr opyl Ester (5a). To a stirred
solution of 4c (1.42 g, 4 mmol) and pyridine (0.63 g, 8 mmol) in
methylene chloride (25 mL) at -40 °C was added dropwise
trifluoromethanesulfonic anhydride (1.24 g, 4.4 mmol) in me-
thylene chloride (5 mL). The reaction mixture was stirred for 1
h at -40 °C. The solution was then washed with brine. After
the layers were separated, the organic phase was dried over Na2-
SO4 and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (petroleum ether/ethyl acetate )
(2S,3S)-3-Ben zoyla m in o-4,4,4-tr iflu or o-2-h yd r oxybu tyr -
ic Acid (9a ). A mixture of 10% palladium on charcoal (73 mg)
and 8a (364 mg, 1.2 mmol) in THF (15 mL) was stirred under
hydrogen at room temperature for 16 h. Filtration and removal
of the solvent gave the crude product, which was purified by
column chromatography on silica gel (petroleum ether/ethyl
25:1) to give 5a (1.95 g, 100%): [R]20 ) +13.4 (c 1.11, CHCl3);
D
1H NMR (300 MHz, CDCl3) δ 8.05-8.09 (m, 2H), 7.62-7.67 (m,
1H), 7.47-7.52 (m, 2H), 7.32-7.33 (m, 5H), 5.75 (q, J ) 4.9 Hz,
1H), 5.57 (qd, J ) 4.9 Hz, 6.0 Hz, 1H), 4.64 (d, J ) 11.7 Hz, 1H),
4.55 (d, J ) 11.7 Hz, 1H) 3.87 (d, J ) 4.7 Hz, 2H); 19F NMR
(282 MHz, CDCl3) δ -73.09 (m, 3F), -74.16 (m, 3F); IR (thin
film) νmax 3036, 1734, 1604, 1587, 1497, 1454, 1263, 1199, 1139
cm-1; MS (EI) m/z 486 (M+, 6), 379 (49), 107 (29), 105 (100), 91
(86), 77 (36), 69 (7). Anal. Calcd for C19H16O6F6S: C, 46.92; H,
3.32. Found: C, 46.96; H, 3.30.
acetate ) 1:1) to give 9a (326 mg, 98%): [R]20 ) -14.9 (c 0.12,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.02-8.05 (m, 2H), 7.57-
7.61 (m, 1H), 7.45-7.50 (m, 2H), 5.19-5.20 (m, 1H), 4.98-5.02
(m, 1H); 19F NMR (282 MHz, CDCl3) δ -76.53 (d, J ) 5.0 Hz);
IR (thin film) νmax 3350, 1734, 1655, 1603,1523, 1491,1454, 1268,
1135 cm-1; MS (EI) m/z 277 (M+, 1), 259 (7), 239 (26), 202 (5),
105 (100), 77 (47) 69 (5); HRMS (ESI) calcd for C11H10O4F3NNa
300.04541, found 300.04516.
(2S,3S)-Ben zoic Acid 2-Azid o-1-ben zyloxym eth yl-3,3,3-
tr iflu or op r op yl Ester (6a ). A solution of 5a (1.70 g, 3.5 mmol)
and sodium azide (455 mg, 7.0 mmol) in DMSO (15 mL) was
stirred for 6 h at 40 °C. The resulting suspension was washed
with brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate ) 50:1) to give 6a (1.25 g, 94%):
Ack n ow led gm en t. We thank the National Natural
Science Foundation of China, Ministry of Education of
China, and Shanghai Municipal Scientific Committee
for funding this work.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for 5b, 6b, 7b, 8b, and 9b.
This material is available free of charge via the Internet at
http://pubs.acs.org.
[R]20 ) +12.5 (c 1.15, CHCl3); 1H NMR (300 MHz, CDCl3) δ
D
8.03-8.07 (m, 2H), 7.58-7.64 (m, 1H), 7.42-7.50 (m, 2H), 7.31-
7.34 (m, 5H), 5.71 (qd, J ) 5.4 Hz, 2.7 Hz, 1H), 4.57-4.66 (m,
2H), 4.26 (ddd, J ) 3.0 Hz, 7.2 Hz, 14.7 Hz, 1H), 3.72-3.81 (m,
2H); 19F NMR (282 MHz, CDCl3) δ -71.77 (d, J ) 5.4 Hz); IR
J O0497611
J . Org. Chem, Vol. 69, No. 16, 2004 5489