Synthesis of α-hydroxy-β-triflamido carboxylic esters through ring-opening of alkoxycarbonyl oxiranes

Article abstract of DOI:10.1055/s-2005-865285

The oxirane ring of 3-alkyl- and 3-arylglycidic esters has been opened with trifluoromethanesulfonamide (TfNH₂) under solid-liquid heterogeneous conditions. The corresponding α-hydroxy-β-triflamido sters were produced in good yields, in a regio- and stereoselective fashion. Several reaction parameters, such as the nature of the base, the presence of a phase transfer catalyst and/or a solvent have been examined. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-865285

PAPER
1675
Synthesis of a-Hydroxy-b-triflamido Carboxylic Esters through Ring-Opening
of Alkoxycarbonyl Oxiranes
S
a
ynthesis of
a-Hy
i
b
t
-
triflam
t
ido Ca
o
rboxylic
E
st
r
ers ia Lupi,*a Domenico Albanese,a Dario Landini,a Davide Scaletti,a Michele Penso*b
Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, via Venezian 21, 20133 Milano, Italy
Fax +39(02)50314159; E-mail: vittoria.lupi@unimi.it
b
CNR- Istituto di Scienze e Tecnologie Molecolari (ISTM), via Golgi 19, 20133 Milano, Italy
E-mail: michele.penso@istm.cnr.it
Received 7 December 2004; revised 27 January 2005
In preceding papers we have reported the ring-opening of
alkyl- or aryl-substituted oxiranes by trifluoroacetamide7
and sulfonamides,8 under solid-liquid phase transfer catal-
ysis (SL-PTC) conditions, using catalytic amounts of an-
Abstract: The oxirane ring of 3-alkyl- and 3-arylglycidic esters has
been opened with trifluoromethanesulfonamide (TfNH2) under sol-
id-liquid heterogeneous conditions. The corresponding a-hydroxy-
b-triflamido esters were produced in good yields, in a regio- and ste-
reoselective fashion. Several reaction parameters, such as the nature hydrous potassium carbonate as a base. The results of this
of the base, the presence of a phase transfer catalyst and/or a solvent
have been examined.
research were the starting point for performing a series of
nucleophilic ring-opening reactions of glycidic esters by
Key words: regioselectivity, stereoselectivity, ring-opening, ep-
oxides, amino acids
TfNH2 (Table 1).
COOMe
OH
a
O
Tf-NH
Me
COOMe
Me
OH
b-Amino-a-hydroxy acids show interesting pharmacolog-
ical properties and are also important intermediates in the
synthesis of biologically active molecules,1 e.g. the well
known anti-tumor agent taxol2 (containing a 2R,3S-3-phe-
nylisoserine unit); bestatin3 (a derivative of 3-benzyliso-
serine), which is a potent suppressor of Pseudomonas
aeruginosa infection and of tumorigenesis in esophageal
adenocarcinoma; amastatin4 (derived from 3-isopropyli-
soserine), like bestatin, has been used to improve the ac-
tion of some bioactive peptides by inhibiting their
degradation by aminopeptidases; or kynostatin 272,5
which is one of the more promising new drugs for the
treatment of AIDS.
1a
3a
R1
a
O
R1
+
+
4
syn
COOR2
Tf-NH
COOR2
1
3
anti
Ph
a
O
OH
3b
anti
COOEt
Tf-NH
2
COOEt
4b
syn
Ph
a) Tf-NH2, base.
1,3,4
R1
Ph
R2 1,3,4
R1
R2
Et
The protocols commonly used for the preparation of b-
amino-a-hydroxy acid derivatives, i.e. the ring-opening
reactions of glycidic esters by a source of nucleophilic ni-
trogen,6 like ammonia, amines or azides, often lack regio-
selectivity and hence large amounts of the by-product a-
amino-b-hydroxy ester derivatives accompany the target
compounds. Furthermore, even if the SN2 antiperiplanar
opening is favored and hence the anti-b-amino-a-hydroxy
esters are the main or the sole products, several proce-
dures suffer from a low degree of stereoselectivity and
both anti- and syn-isomers are produced.
b
c
Et
Et
Et
f
C5H11
g
h
c-C6H11-CH2 Et
4-NO2-C6H4 t-Bu
4-NO2-C6H4
d
e
4-Cl-C6H4
4-MeO-C6H4 Et
Scheme 1
It is interesting to note that the reaction in dioxane at
90 °C, with excess TfNH2 in the presence of catalytic
amounts (0.1 mol equiv) of triethylbenzylammonium
chloride (TEBA) as phase transfer agent, and potassium
carbonate gave the anti-a-hydroxy-b-triflamido ester 3b
in 53% yield (entry 2), whereas the use of a stoichiometric
amount of K2CO3 (entry 3) resulted in decomposition of
the starting material. The epoxy ester 1a (entry 1), which
is the unique example of a C-3 unsubstituted starting ma-
terial, gave almost complete conversion under the above
PTC conditions to the corresponding b-amino-a-hydroxy
ester. The reaction of 4-nitro-phenyl glycidates 1c and 1h
(entries 4 and 5) required very long reaction times for the
This report summarizes the results that we obtained by in-
vestigating the reactivity, under different conditions, of a
set of glycidic esters 1a–h, 2 (Scheme 1) by nucleophilic
ring-opening with trifluoromethanesulfonamide (TfNH2)
to give the corresponding N-trifluoromethanesulfonyl-a-
amino-b-hydroxy esters.
SYNTHESIS 2005, No. 10, pp 1675–1681
x
x.
x
x
.
2
0
0
5
Advanced online publication: 07.04.2005
DOI: 10.1055/s-2005-865285; Art ID: Z23104SS
© Georg Thieme Verlag Stuttgart · New York

1676
V. Lupi et al.
PAPER
Table 1 Ring-Opening of Alkyl Glycidates 1 by TfNH2 under SL-PTC Conditionsa
Entry
Substrate
Time (h)
Product
3a
Yield (%)b
Product
-
Yield (%)b
1
2
3
4
5
6
1a
1b
1b
1c
1h
1f
7
46
95
53
24
40
38
33
-
2
3b
4b
25c
120
120
7
3b
4b
-
3c
4c
6
3h
4h
29
33
3f
4f
a Glycidate 1 (1 mol), TfNH2 (2 mol), K2CO3 (0.1 mol), TEBA (0.1 mol), dioxane, 90 °C.
b Isolated yield.
c Using an increased amount of K2CO3 (1 mol).
Table 2 Ring-Opening of 1b by TfNH2 under SL-PTC Conditionsa
reaction to reach completion. In addition, the epoxy ring
of the t-butyl ester 1h (entry 5), owing to the higher steric
hindrance close to the reaction center, was opened with a
lower stereoselectivity (3h/4h, 1.3:1) than that found in
the ring-opening of the corresponding ethyl ester 1c (3c/
4c, 6.7:1, entry 4). Finally, complete loss of stereoselec-
tivity was found in the opening of the 3-pentyl derivative
1f (entry 6).
Entry
Base
Time (h)
3b (%)b
53
4b (%)b
1
2
3
4
5
6
7
K2CO3
Cs2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
KHCO3
46
33
30
48
7
2
2
3
-
3
7
-
58
56
18c
75d
80e
12f
Encouraged by these preliminary results, in order to opti-
mize the reaction conditions, we modified several pa-
rameters for the ring-opening reaction using ethyl trans-3-
phenylglycidate (1b) as a model substrate (Table 2). No
improvements were observed when cesium carbonate was
utilized as the base (entry 2), instead of K2CO3. Changing
the base for lyophilized sodium carbonate (entry 3) pro-
duced comparable yields of 3b in shorter reaction times.
An analogous reaction, carried out without TEBA (entry
4) showed a very low reaction rate. In contrast, good re-
sults were obtained by operating in the absence of solvent
(entry 5) and the product 3b was isolated in 75% yield.
Moreover, in the absence of solvent, the PTC did not ef-
fect the reaction rate and in fact, it promoted the formation
7
89
a Glycidate 1b (1 mol), TfNH2 (2 mol), base (0.1 mol), TEBA (0.1
mol), dioxane, 90 °C.
b Isolated yield.
c Without TEBA.
d Without solvent.
e Without TEBA and solvent.
f Together with 1b (81%).
Table 3 Ring-Opening of Glycidic Ester 1b under Heterogeneous
of by-products, as highlighted by the higher yield of 3b Conditions without a Solvent: Effect of the Inorganic Basea
obtained in the non-catalyzed ring-opening reaction (en-
try 6).
Entry
Base
Time (h)
3b (%)b
80
4b (%)b
1
2
3
4
5
6
7
8
Na2CO3
K2CO3
Cs2CO3
CaCO3
NaOAc
KFd
7
20
21
23
21
8
7
5
6
6
–
–
–
–
These results were partially reported in a preceding com-
munication,9 which indicated that the ring-opening of gly-
cidic esters is more efficient if carried out in the presence
of a catalytic amount of base, without any solvent. Fol-
lowing this rule, 1b was subjected to ring-opening with
TfNH2 with a range of different inorganic, anhydrous
bases and salts (Table 3) as well as several organic bases
(Table 4).
69
67
71
63c
62
Carbonates of alkaline and alkaline-earth metals (Table 3,
entries 1–4) are the most efficient bases (Na >> K = Cs =
Ca). Sodium acetate itself (entry 5) acted in part as a nu-
cleophile and opened the oxirane ring. Potassium and ce-
sium fluoride must be used in stoichiometric quantities, as
the formation of hydrogen fluoride, during the reaction,
produced the corresponding alkali metal hydrogendifluo-
CsFd
15
15
45
LiIe
51
a Glycidate 1b (1 mol), TfNH2 (2 mol), base (0.1 mol), 90 °C.
b Isolated yield.
c Togetherwith ethyl anti-3-acetoxy-2-hydroxy-3-phenyl-propionate
(10%).
ride M+HF2 (Scheme 2), a non-basic species.
–
d Using an increased amount of base (1 mol).
e Using an increased amount of base (0.2 mol).
Synthesis 2005, No. 10, 1675–1681 © Thieme Stuttgart · New York

PAPER
Synthesis of a-Hydroxy-b-triflamido Carboxylic Esters
1677
TfNH–M+ + MHCO3
Table 4 Ring-Opening of Glycidic Ester 1b Using Organic Bases,
TfNH2 + M2CO3 (cat)
TfNH2 + 2 M+F–
without Solventa
TfNH–M+ + M+HF2
–
Entry
Base
Time (h)
16
3b (%)b
64
4b (%)b
M = Na, K, Cs; Tf = CF3SO2
1
2
3
4
5
6
DBU
6
TfNH–M+
O
R1
i-Pr2NEt
i-Pr2NH
Et3N
22
65
-
9
COOR2
1
22
64
O–M+
R1
12
48
-
-
7
COOR2
Pyridine
DMAP
21
46
Tf-NH
TfNH2
15
55
TfNH–M+
a Glycidate 1b (1 mol), TfNH2 (2 mol), organic base (0.2 mol), 90 °C.
b Isolated yield.
OH
R1
COOR2
tron withdrawing group (EWG), proceeded with lower
selectivity than those found for the reactions of the sub-
strates 1b, 1d, and 1e, possessing a weaker EWG (H, Cl,
or OMe, respectively). Actually, while complete conver-
Tf-NH
3
Scheme 2
Among the ring-opening reactions carried out with an or- sion of 1c is achieved in four hours, anti-3c was isolated
ganic base (Table 4), the best results were obtained with in less than 56% yield, even after prolonged reaction times
DBU (entry 1). Analogous yields, in slightly longer reac- (Table 5, entry 4). Furthermore, as found under PTC con-
tion times, were obtained with hindered amines, such as ditions, the presence of the large t-Bu group in 1h leads to
Hunig’s base (entry 2) and diisopropylamine (entry 3), a reduction in stereoselectivity and 4h was isolated in
whereas widely used pyridine (entry 5) and 4-dimethyl- 19% yield. In contrast, 1b, 1d, and 1e gave satisfactory
aminopyridine (entry 6) were less efficient.
yields (74–80%) in reasonable reaction times (entries 2, 5,
and 6). The ring-opening of ethyl 3-pentyl-glycidate (1f)
and ethyl 3-cyclohexylmethyl-glycidate (1g) at 90 °C re-
quired longer reaction times (entries 7 and 8) in order to
attain good yields of the corresponding a-hydroxy-b-trifl-
amido esters. However, such operating temperatures were
required because the stereoselectivity of the nucleophilic
attack on these esters decreased dramatically when the
temperature was increased to 120 °C. Finally, the ester 1a
(entry 1) was also found to be very reactive under these
The optimal reaction conditions were applied to glycidic
esters bearing an aromatic ring (1c–e,h and 2) or an alkyl
group (1f,g) in the C-3 position (Scheme 1). All these sub-
strates underwent reaction with an excess of TfNH2 (2 mol
equiv) in the presence of a catalytic amount of lyophilized
sodium carbonate (0.1 mol equiv), at 90 or 120 °C, de-
pending on the melting point of the starting glycidate and
its reactivity (Table 5). The ring-opening of trans-3-(4-ni-
trophenyl) derivatives 1c and 1h, carrying a strong elec-
Table 5 Preparation of b-Triflamido-a-hydroxy Esters 3 and 4 (General Procedure)a
Entry
Substrate
T (°C)
90
Time (h)
Product
3a
Yield (%)b
Product
-
Yield (%)b
1
2
3
4
5
6
7
8
9
1a
1b
2c
0.5
7
98
80
5
-
8
90
3b
4b
120
120
90
4
3b
4b
77
4
1c
1d
1e
1f
4
3c
56d
80
74
64
50
51
4c
15
0.5
31
30
10
3d
4d
5
90
3e
4e
3
90
3f
4f
6
1g
1h
90
3g
4g
12
19
90
3h
4h
a Glycidate 1, 2 (1 mol), TfNH2 (2 mol), lyophilized Na2CO3 (0.1 mol).
b Isolated yield.
c See ref.9
d After 16 h, 3c was isolated in only 43% yield.
Synthesis 2005, No. 10, 1675–1681 © Thieme Stuttgart · New York

1678
V. Lupi et al.
PAPER
Glycidates 1a and 1b are commercially available, whereas ethyl
3-(4-nitrophenyl)oxirane-2-carboxylate (1c),12 ethyl 3-(4-chlorophe-
nyl)oxirane-2-carboxylate (1d),13 ethyl 3-(4-methoxyphenyl)oxi-
rane-2-carboxylate (1e),14 ethyl 3-pentyloxirane-2-carboxylate
(1f)15 and tert-butyl 3-(4-nitrophenyl)oxirane-2-carboxylate (1h)16
were prepared, according to the literature, from the corresponding
aldehyde through the Darzens reaction with the appropriate 2-bro-
mo- or 2-chloroacetate. Ethyl 3-cyclohexylmethyloxirane-2-car-
boxylate (1g) was prepared by MCPBA epoxidation, in the
presence of catalytic amounts of bis(3-tert-butyl-4-hydroxy-5-
methylphenyl) sulfide,6f ethyl (E)-4-cyclohexyl-but-2-enoate17
which was prepared by the Horner–Emmons reaction of cyclohex-
yl-acetaldehyde18 with (EtO)2P(O)CH2CO2Et. cis-3-Phenyl-oxi-
rane-2-carboxylate 2 was prepared by a multistep protocol from
benzoyl acetate.19 The anti-isomer 3b was prepared by an indepen-
dent literature procedure.6g The regioisomer (R,S)-syn-3-hydroxy-
conditions, giving 2-hydroxy-2-methyl-3-triflamidopro-
pionate (3a) in almost quantitative yield.
The results as a whole indicate that, under the solid-liquid
heterogeneous conditions employed, the ring-opening re-
action of glycidates proceeds principally through the SN2
antiperiplanar mechanism: trans-epoxy esters 1 produces
the corresponding anti-a-hydroxy-b-triflamido esters 3
and only minor amounts of the syn-isomers 4 (e.g., 3b/4b,
10:1), which are derived from the SN1 reaction. Analo-
gously, by the SN2 mechanism the cis-glycidate 2 gave
predominantly ester 4b (4b/3b, 15:1). The carbocation
formed in the monomolecular reaction is attacked by the
nucleophile (TfNH–Na+) from the less crowded side, gen-
erating the syn-stereoisomer. This mechanism was con-
firmed also by the ring-opening of the highly hindered
substrates 1g and 1h, which gave significant amounts of
syn-isomers 4g and 4h. The monomolecular pathway is
promoted by the acidity of triflamide (pKa 9.7 in DMSO,10
pKa 6.3 in water11). In fact, when a stoichiometric amount
of TfNH2 was used, 1b gave anti-3b (78%) as the sole
product, even with a prolonged reaction time.9 Further-
more, the ring-opening reactions show good regioselec-
tivities. In fact, only the regioisomers 3 and 4 which result
from nucleophilic attack on C-b were isolated and, by 1H
3-phenyl-N-(trifluoromethanesulfonyl)-2-aminopropionate
(6b)
was prepared from commercial (R,S)-syn-3-phenylserine as de-
scribed below. The relative configuration of the ester 4b and of the
regioisomer (R,S)-anti-3-hydroxy-3-phenyl-N-(trifluoromethane-
sulfonyl)-2-aminopropionate (5b) were assigned by comparative 1H
NMR analysis of the corresponding proton signals. In addition,
comparison of the chemical shifts and coupling constants of the new
compounds with those of 3b and 4b, permitted assignment of the
identity of 3c–h and 4c–h.
Trifluoromethanesulfonamide
Following a literature method,20 a mixture of trifluoromethane-
NMR spectroscopic analysis of the crude reaction mix- sulfonic anhydride (12 g, 42.5 mmol) and aq NH3 (30%; 300 mL)
was stirred at 0 °C for 30 min and then left at –10 °C for 24 h. After
ture, very small quantities (≤1%) of the regioisomeric b-
hydroxy-a-triflamido esters 5 and 6 were detected.
the work-up described in the literature, triflamide was purified by
sublimation under vacuum (0.02 mmHg) and isolated (5.51 g, 87%)
In conclusion, substituted glycidates underwent ring-
opening by triflamide under solid-liquid heterogeneous
conditions, without a solvent in the presence of catalytic
amounts of lyophilized sodium carbonate as a base. The
corresponding a-hydroxy-b-triflamido esters were syn-
thesized in good stereoselectivity. This simple procedure
is environmentally friendly since it does not require any
organic solvent. Moreover, only catalytic amounts of a
cheap and safe base are needed as the necessary nucleo-
phile (TfNH–M+) is regenerated during the catalytic cycle
(Scheme 2). In order to find the appropriate conditions for
promoting the reversed stereochemical reaction pathway,
i.e. the formation of the syn-isomers from the more avail-
able trans-glycidates, we are currently studying the ring-
opening reaction of several t-butyl glycidates, both under
heterogeneous and homogeneous conditions.
as a white solid.
Mp 117–119 °C (lit.20 117–118 °C).
IR (nujol): 3390, 3279 (NH), 1377 (SO2) cm–1.
19F NMR (CDCl3): d = –79.39 (s).
Ethyl (2RS,3SR)-3-Cyclohexylmethyloxirane-2-carboxylate
(1g)
To a soln of ethyl (E)-4-cyclohexylbut-2-enoate (400 mg, 2.04
mmol) and bis(3-tert-butyl-4-hydroxy-5-methylphenyl)sulfide (72
mg, 0.2 mmol) in DCE (4.5 mL), MCPBA (70%, 754 mg, 3.06
mmol) was added. The reaction mixture was stirred under reflux for
4 h, then a further portion of MCPBA (137 mg, 0.56 mmol) was
added, and stirring and heating were continued for 20 h (TLC anal-
ysis). After cooling to r.t., the crude mixture was filtered, the solvent
was removed under vacuum and the residue was diluted with Et2O
(3 mL), washed with a soln of Na2SO3 (1.5 M; 3 mL), and then with
a sat. soln of NaHCO3 (3 mL). The organic layer was dried over
MgSO4, filtered, the solvent was removed under vacuum, and the
residue purified by flash chromatography on silica gel (Et2O–PE,
1:15). Ester 1g was isolated (313 mg, 72%) as a colorless oil.
Melting points were determined on a Büchi 535 apparatus and are
corrected. IR spectra were measured with a Perkin Elmer FT-IR
spectrometer 1725X. 1H and 19F NMR spectra were recorded on a
Bruker AC 300 spectrometer operating at 300.133 (1H) or 282.407
(19F) MHz; TMS (1H) and CDCl3 (19F) were used as external refer-
ences and d are in ppm. Missing signals of several syn-stereoiso-
mers 4 are hidden by signals of the corresponding anti-
stereoisomers 3, or they could not be unambiguously identified due
to their low intensity. Reagent-grade commercially available re-
agents and solvents were used and dried, when required, before use.
Petroleum ether (PE, 40–60 °C) was used for chromatography on
silica gel (230–400 mesh). Alkaline metal carbonates were dried by
heating at 140 °C under vacuum (0.05 mmHg) for 6 h. Analytical
TLC was performed using Merck pre-coated silica gel F254 plates.
IR (film): 1731 (C=O), 1288 and 848 (COC) cm–1.
1H NMR (CDCl3): d = 1.29 (t, 3 H, J = 7.3 Hz, OCH2CH3), 1.45–
1.79 (m, 13 H, c-C6H11CH2), 3.10–3.21 (m, 2 H, H-2, H-3), 4.22 (q,
2 H, J = 7.3 Hz, OCH2CH3).
Anal. Calcd for C12H20O3 (212.1): C, 67.89; H, 9.50. Found: C,
67.74; H, 9.48.
a-Hydroxy-b-triflamido Esters 3; General Procedure
In a dried flask, a heterogeneous mixture of the glycidate 1 (1
mmol), lyophilized Na2CO3 (11 mg, 0.1 mmol), and trifluo-
romethanesulfonamide (298 mg, 2 mmol) was stirred at 90–120 °C
until the starting material was no longer detectable (TLC analysis).
After cooling to r.t., the crude product was diluted with CH2Cl2 (5
Synthesis 2005, No. 10, 1675–1681 © Thieme Stuttgart · New York

PAPER
Synthesis of a-Hydroxy-b-triflamido Carboxylic Esters
1679
mL), filtered through celite (0.5 g), CH2Cl2 was removed under vac-
uum, and the residue purified by flash chromatography on silica gel.
19F NMR (CDCl3): d = –78.15 (s).
Ethyl (R,S)-anti-2-Hydroxy-3-(4-nitrophenyl)-N-(trifluo-
Methyl 2-Hydroxy-2-methyl-N-(trifluoromethanesulfonyl)-3-
aminopropionate (3a)
Methyl 2-methyloxirane-2-carboxylate (1a; 116 mg) was subjected
to the procedure described above at a temperature of 90 °C for 0.5
h. Flash chromatography (EtOAc–PE, 1:3) gave 3a (260 mg, 98%)
as a white solid.
romethanesulfonyl)-3-aminopropionate (3c) and Ethyl (R,S)-
syn-2-Hydroxy-3-(4-nitrophenyl)-N-(trifluoromethanesulfo-
nyl)-3-aminopropionate (4c)
Ethyl (2RS,3SR)-3-(4-nitrophenyl)-oxirane-2-carboxylate (1c; 237
mg), was subjected to the procedure described above at a tempera-
ture of 120 °C for 4 h. Flash chromatography (EtOAc–PE, 1:2) gave
an inseparable mixture of 3c and 4c (232 mg, 60%; 97:3) as a yellow
solid.
Mp 70–71 °C.
IR (nujol): 3315 (NH), 1750 (C=O), 1372 (SO2) cm–1.
1H NMR (CDCl3): d = 1.44 (s, 3 H, CH3-2), 3.36 (dd, 1 H, J = 13.2,
8.0 Hz, H-3), 3.50 (br s, 1 H, OH), 3.63 (dd, 1 H, J = 13.2, 3.9 Hz,
H-3), 3.85 (s, 3 H, OCH3), 5.51 (dd, 1 H, J = 8.0, 3.9 Hz, NH).
19F NMR (CDCl3): d = –77.70 (s).
IR (nujol): 3340 (NH), 1740 (C=O), 1515, 1333 (NO2), 1352 (SO2)
cm–1.
Anal. Calcd for C12H13F3N2O7S (386.0): C, 37.31; H, 3.39; N, 7.25.
Found: C, 36.92; H, 3.31; N, 7.36.
3c
Anal. Calcd for C6H10F3NO5S (265.0): C, 27.17; H, 3.80; N, 5.28.
Found: C, 27.10; H, 3.69; N, 5.41.
1H NMR (CDCl3): d = 1.25 (t, 3 H, J = 7.1 Hz, OCH2CH3), 3.34 (br
s, 1 H, OH), 4.08–4.23 (m, 2 H, OCH2CH3), 4.69 (d, 1 H, J = 3.5
Hz, H-2), 5.11 (d, 1 H, J = 3.5 Hz, H-3), 6.50 (br s, 1 H, NH), 7.48
(d, 2 H, J = 8.7 Hz, Ar), 8.19 (d, 2 H, J = 8.7 Hz, Ar).
Ethyl (R,S)-anti-2-Hydroxy-3-phenyl-N-(trifluoromethane-
sulfonyl)-3-aminopropionate (3b) and Ethyl (R,S)-syn-2-Hy-
droxy-3-phenyl-N-(trifluoromethanesulfonyl)-3-amino-
propionate (4b)
19F NMR (CDCl3): d = –78.08 (s).
Ethyl (2RS,3SR)-3-phenyl-oxirane-2-carboxylate (1b; 192 mg) was
subjected to the procedure described above at a temperature of
90 °C for 7 h. Flash chromatography (EtOAc–PE, 1:3) gave 3b (273
mg, 80%) as a white solid and 4b (27 mg, 8%) as a white solid.9
4c
1H NMR (CDCl3): d = 1.19 (t, 3 H, J = 7.1 Hz, OCH2CH3), 4.50 (d,
1 H, J = 3.6 Hz, H-2), 5.31 (d, 1 H, J = 3.6 Hz, H-3), 7.53 (d, 2 H,
J = 8.7 Hz, Ar), 8.22 (d, 2 H, J = 8.7 Hz, Ar); NH, OH and
OCH2CH3 protons are hidden.
3b
19F NMR (CDCl3): d = –77.65 (s).
Mp 91–92 °C.
IR (nujol): 3321 (NH), 1747 (C=O), 1358 (SO2) cm–1.
Ethyl (R,S)-anti-2-Hydroxy-3-(4-chlorophenyl)-N-(trifluo-
romethanesulfonyl)-3-aminopropionate (3d) and Ethyl (R,S)-
syn-2-Hydroxy-3-(4-chlorophenyl)-N-(trifluoromethanesulfo-
nyl)-3-aminopropionate (4d)
Ethyl (2RS,3SR)-3-(4-chlorophenyl)-oxirane-2-carboxylate (1d;
227 mg) was subjected to the procedure described above at a tem-
perature of 90 °C for 15 h. Flash chromatography (EtOAc–PE, 1:3)
gave an inseparable mixture of 3d and 4d (319 mg, 85%; 94:6) as a
white solid.
1H NMR (CDCl3): d = 1.23 (t, 3 H, J = 7.2 Hz, OCH2CH3), 3.15 (d,
1 H, J = 5.6 Hz, OH), 4.05–4.21 (m, 2 H, OCH2CH3), 4.63 (dd, 1 H,
J = 5.6, 3.5 Hz, H-2), 4.99 (dd, 1 H, J = 9.6, 3.5 Hz, H-3), 6.21 (d,
1 H, J = 9.6 Hz, NH), 7.24–7.34 (m, 5 H, Ar).
19F NMR (CDCl3): d = –78.18 (s).
Anal. Calcd for C12H14F3NO5S (341.1): C, 42.23; H, 4.13; N, 4.10.
Found: C, 42.08; H, 4.05; N, 4.20.
IR (nujol): 3320 (NH), 1738 (C=O), 1343 (SO2) cm–1.
4b
Anal. Calcd for C12H13ClF3NO5S (375.0): C, 38.36; H, 3.49; N,
3.73. Found: C, 37.99; H, 3.44; N, 3.79.
Mp 85–86 °C.
IR (nujol): 3318 (NH), 1750 (C=O), 1361 (SO2) cm–1.
1H NMR (CDCl3): d = 1.37 (t, 3 H, J = 7.2 Hz, OCH2CH3), 3.28 (d,
1 H, J = 2.9 Hz, OH), 4.28–4.41 (m, 2 H, OCH2CH3), 4.43 (dd, 1 H,
J = 2.9, 1.9 Hz, H-2), 5.07 (dd, 1 H, J = 9.8, 1.9 Hz, H-3), 5.91 (d,
1 H, J = 9.8 Hz, NH), 7.32–7.39 (m, 5 H).
3d
1H NMR (CDCl3): d = 1.24 (t, 3 H, J = 7.1 Hz, OCH2CH3), 3.17 (d,
1 H, J = 5.4 Hz, OH), 4.09–4.20 (m, 2 H, OCH2CH3), 4.62 (dd, 1 H,
J = 5.4, 3.5 Hz, H-2), 4.97 (dd, 1 H, J = 9.3, 3.5 Hz, H-3), 6.21 (d,
1 H, J = 9.3 Hz, NH), 7.20 (d, 2 H, J = 8.5 Hz, Ar), 7.31 (d, 2 H,
J = 8.5 Hz, Ar).
19F NMR (CDCl3): d = –78.06 (s).
Anal. Calcd for C12H14F3NO5S (341.1): C, 42.23; H, 4.13; N, 4.10.
Found: C, 42.12; H, 4.05; N, 4.15.
19F NMR (CDCl3): d = –78.12 (s).
4d
(R,S)-anti-3-Hydroxy-3-phenyl-N-(trifluoromethanesulfonyl)-
2-aminopropionate (5b)
1H NMR (CDCl3): d = 1.37 (t, 3 H, J = 7.1 Hz, OCH2CH3), 3.37 (d,
1 H, J = 5.4 Hz, OH), 4.35 (dd, 2 H, J = 7.2, 1.5 Hz, OCH2CH3),
4.38 (d, 1 H, J = 1.9 Hz, H-2), 5.03 (d, 1 H, J = 1.9 Hz, H-3); NH
and Ar protons are hidden.
(1H NMR and 19F NMR analyses of the crude product)
1H NMR (CDCl3): d = 4.48 (dd, 1 H, J = 9.5, 3.9 Hz, H-2), 5.20 (d,
1 H, J = 3.9 Hz, H-3).
19F NMR (CDCl3): d = –77.80 (s).
19F NMR (CDCl3): d = –78.07 (s).
Ethyl (R,S)-anti-2-Hydroxy-3-(4-methoxyphenyl)-N-(trifluo-
romethane-sulfonyl)-3-aminopropionate (3e) and Ethyl (R,S)-
syn-2-Hydroxy-3-(4-methoxyphenyl)-N-(trifluoromethane-
sulfonyl)-3-aminopropionate (4e)
Ethyl (2RS,3SR)-3-(4-methoxyphenyl)-oxirane-2-carboxylate (1e;
222 mg) was subjected to the procedure described above at a tem-
(R,S)-syn-3-Hydroxy-3-phenyl-N-(trifluoromethanesulfonyl)-2-
aminopropionate (6b)
(1H NMR and 19F NMR analyses of the crude product)
1H NMR (CDCl3): d = 4.24 (d, 1 H, J = 2.7 Hz, H-2), 5.32 (d, 1 H,
J = 2.7 Hz, H-3).
Synthesis 2005, No. 10, 1675–1681 © Thieme Stuttgart · New York

1680
V. Lupi et al.
PAPER
perature of 90 °C for 0.5 h. Flash chromatography (EtOAc–PE, 2:5)
gave an inseparable mixture of 3e and 4e, (286 mg, 77%; 96:4) as a
white solid.
IR (nujol): 3344 (NH), 1753 (C=O), 1350 (SO2) cm–1.
Hz, H-3), 4.22–4.36 (m, 2 H, OCH2CH3), 4.39 (d, 1 H, J = 2.9 Hz,
H-2), 5.51 (br s, 1 H, NH).
19F NMR (CDCl3): d = –78.10 (s).
4g
Anal. Calcd for C13H16F3NO6S (371.1): C, 42.05; H, 4.34; N, 3.77.
Found: C, 42.85; H, 4.44; N, 3.85.
1H NMR (CDCl3): d = 1.29 (t, 3 H, J = 7.1 Hz, OCH2CH3), 4.17 (d,
1 H, J = 3.5 Hz, H-3); the other protons are hidden.
3e
19F NMR (CDCl3): d = –77.74 (s).
1H NMR (CDCl3): d = 1.36 (t, 3 H, J = 7.2 Hz, OCH2CH3), 3.45 (d,
1 H, J = 3.5 Hz, OH), 3.81 (s, 3 H, OCH3), 4.34 (q, 2 H, J = 7.2 Hz,
OCH2CH3), 4.39–4.41 (m, 1 H, H-2), 5.01 (dd, 1 H, J = 9.6, 1.8 Hz,
H-3), 6.24 (d, 1 H, J = 9.6 Hz, NH), 6.89 (d, 2 H, J = 8.7 Hz, Ar),
7.30 (d, 2 H, J = 8.7 Hz, Ar).
Ring-Opening under SL-PTC Conditions; Typical Procedure
t-Butyl (R,S)-anti-2-Hydroxy-3-(4-nitrophenyl)-N-(trifluo-
romethanesulfonyl)-3-aminopropionate (3h) and t-Butyl (R,S)-
syn-2-Hydroxy-3-(4-nitrophenyl)-N-(trifluoromethanesulfo-
nyl)-3-aminopropionate (4h)
19F NMR (CDCl3): d = –78.06 (s).
To a dried flask containing a dioxane solution (2 mL) of t-butyl
(2RS,3SR)-3-(4-nitrophenyl)-oxirane-2-carboxylate (1h) (265 mg,
1 mmol), TfNH2 (298 mg, 2 mmol) and TEBA (23 mg, 0.1 mmol)
was added anhyd K2CO3 (14 mg, 0.1 mmol). The reaction mixture
was stirred at 90 °C for 120 h (TLC analysis). After cooling to r.t.,
the crude mixture was diluted with CH2Cl2 (5 mL), filtered through
celite (0.5 g), the solvent was removed under vacuum, and the resi-
due was purified by flash chromatography on silica gel (EtOAc–PE,
1:4) to give an inseparable mixture of 3h and 4h (261 mg, 67%;
55:45) as a yellow solid.
4e
1H NMR (CDCl3): d = 1.24 (t, 3 H, J = 7.2 Hz, OCH2CH3), 3.22 (d,
1 H, J = 6.0 Hz, OH), 3.78 (s, 3 H, OCH3), 4.08–4.18 (m, 2 H,
OCH2CH3), 4.61 (dd, 1 H, J = 6.0, 3.4 Hz, H-2), 4.94 (dd, 1 H,
J = 9.6, 3.4 Hz, H-3), 6.30 (d, 1 H, J = 9.6 Hz, NH), 6.83 (d, 2 H,
J = 6.6 Hz, Ar), 7.17 (d, 2 H, J = 6.6 Hz, Ar).
19F NMR (CDCl3): d = –78.10 (s).
Ethyl (R,S)-anti-2-Hydroxy-N-(trifluoromethanesulfonyl)-3-
aminooctanoate (3f) and Ethyl (R,S)-syn-2-Hydroxy-N-(trifluo-
romethanesulfonyl)-3-aminooctanoate (4f)
IR (nujol): 3352 (NH), 1735 (C=O), 1506, 1339 (NO2), 1360 (SO2)
cm–1.
Ethyl (2RS,3SR)-3-pentyl-oxirane-2-carboxylate (1f; 186 mg) was
subjected to the procedure described above at a temperature of
90 °C for 31 h. Flash chromatography (Et2O–PE, 2:5) gave an in-
separable mixture of 3f and 4f (235 mg, 70%; 91:9) as a white solid.
Anal. Calcd for C14H17F3N2O7S (414.1): C, 40.58; H, 4.14; N, 6.76.
Found: C, 40.43; H, 4.20; N, 6.88.
3h
1H NMR (CDCl3): d = 1.36 (s, 9 H, t-BuO), 4.58 (d, 1 H, J = 3.6 Hz,
H-2), 5.03 (d, 1 H, J = 3.6 Hz, H-3), 7.53 (d, 2 H, J = 8.7 Hz, Ar),
8.21 (d, 2 H, J = 8.7 Hz, Ar); NH and OH protons are hidden.
IR (nujol): 3326 (NH), 1742 (C=O), 1339 (SO2) cm–1.
Anal. Calcd for C11H20F3NO5S (335.1): C, 39.40; H, 6.01; N, 4.18.
Found: C, 39.85; H, 6.32; N, 4.07.
19F NMR (CDCl3): d = –78.06 (s).
3f
1H NMR (CDCl3): d = 0.86 (t, 3 H, J = 6.9 Hz, H-8), 1.19–1.33 (m,
6 H, H-5, H-6, H-7), 1.28 (t, 3 H, J = 6.9 Hz, OCH2CH3), 1.43–1.62
(m, 2 H, H-4), 3.51 (br s, 1 H, OH), 3.86 (dt, 1 H, J = 10.3, 3.1 Hz,
H-3), 4.23–4.34 (m, 2 H, OCH2CH3), 4.40 (d, 1 H, J = 3.1 Hz, H-2),
5.95 (br s, 1 H, NH).
4h
1H NMR (CDCl3): d = 1.27 (s, 9 H, t-BuO), 3.30 (br s, 1 H, OH),
4.40 (d, 1 H, J = 3.4 Hz, H-2), 5.28 (d, 1 H, J = 3.4 Hz, H-3), 6.40
(br s, 1 H, NH), 7.58 (d, 2 H, J = 8.7 Hz, Ar), 8.25 (d, 2 H, J = 8.7
Hz, Ar).
19F NMR (CDCl3): d = –77.57 (s).
19F NMR (CDCl3): d = –78.20 (s).
Ring-Opening in the Presence of an Organic Base; Typical Pro-
cedure
4f
1H NMR (CDCl3): d = 4.17 (d, 1 H, J = 3.3 Hz, H-3); the other pro-
In a dried flask, a mixture of ethyl (2RS,3SR)-3-phenyl-oxirane-2-
carboxylate (1b) (192 mg, 1 mmol), DBU (30 mg, 0.2 mmol), and
trifluoromethanesulfonamide (298 mg, 2 mmol) was stirred at
90 °C for 16 h (TLC analysis). After cooling to r.t., the crude mix-
ture was diluted with CH2Cl2 (5 mL) and washed with acidic water
(2 × 3 mL). The organic phase was dried over sodium sulfate, evap-
orated to dryness under vacuum and purified by flash chromatogra-
phy on silica gel (EtOAc–PE, 1:3). An inseparable mixture of 3b
and 4b was isolated (239 mg, 70%; 91:9) as a white solid.
tons are hidden.
19F NMR (CDCl3): d = –77.97 (s).
Ethyl (R,S)-anti-2-Hydroxy-4-cyclohexyl-N-(trifluoromethane-
sulfonyl)-3-aminobutanoate (3g) and Ethyl (R,S)-syn-2-Hy-
droxy-4-cyclohexyl-N-(trifluoromethanesulfonyl)-3-amino-
butanoate (4g)
Ethyl (2RS,3SR)-3-cyclohexylmethyl-oxirane-2-carboxylate (1g,
212 mg) was subjected to the procedure described above at a tem-
perature of 90 °C for 30 h. Flash chromatography (Et2O–PE, 2:5)
gave an inseparable mixture of 3g and 4g, (224 mg, 62%; 81:19) as
a colorless oil.
Ethyl (R,S)-anti-2-Hydroxy-3-phenyl-N-(trifluoromethane-
sulfonyl)-3-aminopropionate (3b)
In a dried flask, a solution of ethyl (R,S)-anti-2-hydroxy-3-phenyl-
3-aminopropionate (209 mg, 1.0 mmol), which was prepared by re-
duction of ethyl (R,S)-anti-3-azido-2-hydroxy-3-phenylpropi-
onate,6g triethylamine (101 mg, 1.0 mmol), and trifluoro-
methanesulfonic anhydride (282 mg, 1.0 mmol) in CH2Cl2 (3 mL)
was stirred at 0 °C for 1 h (TLC analysis, EtOAc–PE, 1:3). The
crude product was washed with water (2 × 2 mL) and the organic
layer was dried over MgSO4, filtered, and the solvent was evaporat-
IR (film): 3332 (NH), 1751 (C=O), 1337 (SO2) cm–1.
Anal. Calcd for C13H22F3NO5S (361.1): C, 43.21; H, 6.14; N, 3.88.
Found: C, 43.15; H, 6.06; N, 3.98.
3g
H NMR (CDCl3): d = 0.60–1.01 (m, 2 H, H-cyclo), 1.16–1.50 (m, 8
H, H-cyclo), 1.31 (t, 3 H, J = 7.1 Hz, OCH2CH3), 1.63–1.72 (m, 3
H, H-4, CH-cyclo), 3.20 (br s, 1 H, OH), 4.00 (dt, 1 H, J = 10.8, 2.9
Synthesis 2005, No. 10, 1675–1681 © Thieme Stuttgart · New York

PAPER
Synthesis of a-Hydroxy-b-triflamido Carboxylic Esters
1681
ed under vacuum. Ester 3b was isolated (276 mg, 81%) as a white
solid.
(2) (a) Shigemori, H.; Kobayashi, J. J. Nat. Prod. 2004, 67, 245.
(b) Kingston, D. G. I.; Jagtap, P. G.; Yuan, H.; Samala, L.
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Waldmann, H. Biol. Chem. 2003, 384, 1265. (c) DuBois, R.
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1. (b) de Godoy, M. A. F.; Dunn, S.; Rattan, S.
Gastroenterology 2004, 127, 127. (c) Ben-Sasson, S. A.;
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141, 162351.
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Newcomb, F. M.; Moskovitz, J.; Yarchoan, R. Antimicrob.
Agents Chemother. 2002, 46, 402.
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(b) Bhatia, B.; Jain, S.; De, A.; Bagchi, I.; Iqbal, J.
Tetrahedron Lett. 1996, 37, 7311. (c) Alcaide, B.; Biurrun,
C.; Martínez, A.; Plumet, J. Tetrahedron Lett. 1995, 36,
5417. (d) Hashiyama, T.; Inoue, H.; Takeda, M.; Murata, S.;
Nagao, T. Chem. Pharm. Bull. 1985, 33, 2348.
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Pays-Bas 1992, 111, 1. (g) Legters, J.; van Dienst, E.; Thijs,
L.; Zwanenburg, B. Recl. Trav. Chim. Pays-Bas 1992, 111,
69.
Mp 91–92 °C.
1H NMR and 19F NMR spectra match those of 3b prepared by the
previous method.
(R,S)-syn-3-Hydroxy-3-phenyl-N-(trifluoromethanesulfonyl)-2-
aminopropionate (6b)
Hydrogen chloride was bubbled into a solution of commercially
available (R,S)-syn-3-phenylserine trihydrate (3.60 g, 15.3 mmol) in
anhyd EtOH (36 mL). The solution was stirred under reflux for 1 h
(TLC analysis, MeOH–CH2Cl2, 1:9). After cooling to r.t., the crude
mixture was concentrated under vacuum, Et2O (20 mL) was added,
and (R,S)-syn-3-hydroxy-3-phenyl-2-aminopropionate hydrochlo-
ride was crystallized as a white solid, which was isolated by filtra-
tion (2.10 g, 56%).
Mp 184–185 °C (dec.) [lit.21 186 °C (dec.)].
In a dried flask, a mixture of (R,S)-syn-3-hydroxy-3-phenyl-2-ami-
nopropionate hydrochloride (1.95 g, 8.0 mmol) and Et3N (1.74 g,
16.0 mmol) in CH2Cl2 (20 mL) was stirred at 0 °C for 1 h, then tri-
fluoromethanesulfonic anhydride (4.51 g, 16.0 mmol) was added
and the mixture was stirred for a further 1 h (TLC analysis, EtOAc–
PE, 1:3). The crude mixture was washed with water (2 × 10 mL) and
the organic layer was dried over MgSO4, filtered, and the solvent
evaporated under vacuum. Ester 6b was isolated (2.14 g, 78%) as a
white solid.
(7) Albanese, D.; Landini, D.; Penso, M. Tetrahedron 1997, 53,
4787.
Mp 89–90 °C.
(8) Albanese, D.; Landini, D.; Penso, M.; Petricci, S.
Tetrahedron 1999, 55, 6387.
(9) Penso, M.; Albanese, D.; Landini, D.; Lupi, V. Chem. Lett.
IR (nujol): 3320 (NH), 1746 (C=O), 1358 (SO2) cm–1.
1H NMR (CDCl3): d = 1.23 (t, 3 H, J = 7.1 Hz, OCH2CH3), 3.14 (br
s, 1 H, OH), 4.24 (d, 1 H, J = 2.7 Hz, H-2), 4.28 (d, 2 H, OCH2CH3),
5.32 (d, 1 H, J = 2.7 Hz, H-3), 6.22 (br s, 1 H, NH), 7.34–7.44 (m,
5 H, Ar).
2001, 400.
(10) Bordwell, F. G.; Branca, J. C.; Hughes, D. L.; Olmstead, W.
N. J. Org. Chem. 1980, 45, 3305.
(11) Trepka, R. D.; Harrington, J. K.; Belisle, J. W. J. Org. Chem.
1974, 39, 1094.
(12) Martynov, V. F.; Ol’man, G. Zh. Obshch. Khim. 1958, 28,
592.
19F NMR (CDCl3): d = –78.15 (s).
Anal. Calcd for C12H14F3NO5S (341.1): C, 42.23; H, 4.13; N, 4.10.
Found: C, 42.06; H, 4.08; N, 4.14.
(13) Ayi, A. I.; Remli, M.; Condom, R.; Guedj, R. J. Fluorine
Chem. 1981, 17, 565.
(14) Martynov, V. F.; Ol’man, G. Zh. Obshch. Khim. 1957, 27,
Acknowledgment
Financial support from the Ministero dell’Istruzione dell’Università
e della Ricerca (MIUR), Consiglio Nazionale delle Ricerche (CNR)
and Fondo per gli Investimenti della Ricerca di Base (FIRB) are
gratefully acknowledged.
1881.
(15) Della Pergola, R.; Di Battista, P. Synth. Commun. 1984, 14,
121.
(16) Bachelor, F. W.; Bansal, R. K. J. Org. Chem. 1969, 34, 3600.
(17) Righi, G.; Rumboldt, G.; Bonini, C. J. Org. Chem. 1996, 61,
3557.
(18) Stratakis, M.; Nencka, R.; Rabalakos, C. J. Org. Chem.
2002, 67, 8758.
(19) Hoffmann, R. V.; Kim, H.-O. J. Org. Chem. 1991, 56, 6759.
(20) Burdon, J.; Farazmand, I.; Stacey, M.; Tatlow, J. C. J. Chem.
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Synthesis 2005, No. 10, 1675–1681 © Thieme Stuttgart · New York