Scope and limitations in the use of N-(PhF)serine-derived cyclic sulfamidates for amino acid synthesis

Article abstract of DOI:10.1139/v00-176

Ring-opening of N-(PhF)serine-derived cyclic sulfamidate 17 was achieved with different nucleophiles (βketo esters, β-keto ketones, dimethyl malonate, nitroethane, sodium azide, imidazole, and potassium thiocyanate) to prepare a variety of amino acid anal

Full text of DOI:10.1139/v00-176

94
Scope and limitations in the use of N-(PhF)serine-
derived cyclic sulfamidates for amino acid
synthesis
Lan Wei and William D. Lubell
Abstract: Ring-opening of N-(PhF)serine-derived cyclic sulfamidate 17 was achieved with different nucleophiles (β-
keto esters, β-keto ketones, dimethyl malonate, nitroethane, sodium azide, imidazole, and potassium thiocyanate) to pre-
pare a variety of amino acid analogs. Two different pathways for ring opening of 17 were elucidated: direct
nucleophilic displacement, as well as β-elimination followed by Michael addition. Furthermore, β-keto ester and β-keto
ketone products 18k, 18m, and 18i were converted to prolines and pyrazole amino acids.
Key words: glutamate, amino acid, cyclic sulfamidate, proline.
Résumé : L’ouverture des sulfamidates cycliques dérivés de la serine a été explorée avec différents nucléophiles (β-céto
esters, 1,3-dicétones, diméthyle de malonate, nitroéthane, azidure de sodium, imidazole et thiocyanate de potassium)
pour préparer une variété d’analogues d’acides aminés. Deux voies différentes ont été proposées pour l’ouverture du
cycle à cinq membres du sulfamidate 17: le déplacement nucléophile et l’élimination β suivie de l’addition de Michael.
De plus, les β-céto ester 18k, 18m et 1,3-dicétone 18i ont été respectivement convertis en prolines et en acides aminés
pyrazoyle.
Mots clés : glutamate, acide aminé, sulfamidate cyclique, proline.
Wei and Lubell 104
Introduction
Sulfamidate 17 reacted with a series of heteroatomic as well
as carbon nucleophiles to provide the desired amino acid
analogs; however, careful examination of the configurational
integrity of these products revealed that racemization oc-
curred during reactions of 17 with carbon nucleophiles (10).
Although enantiopure serine has often been employed as
starting material, to the best of our knowledge, the
enantiomeric purity of the products from ring opening of its
cyclic sulfamidates had been previously reported in only two
examples (2). Pyrazole 7 and piperidine 8 were checked for
racemization after conversion to diastereomeric amides us-
ing, respectively, (R)-α-methoxy-α-trifluoromethylphenylacetyl
chloride and (–)-menthyl chloroformate. A comparison of
the diastereomeric amides with material prepared from
racemic serine using proton nuclear magnetic resonance (1H
NMR) spectroscopy led the authors to conclude that “no ap-
parent racemization occurred in the course of both the ring
opening and the hydrolysis” reactions involved in the prepa-
ration of 7 and 8. This claim contrasted with our discovery
of racemization in the reactions of sulfamidate 17 with car-
bon nucleophiles and provoked a detailed investigation of
the enantiomeric purity of the various products from
nucleophilic ring opening of sulfamidate 17.
Serine-derived cyclic sulfamidates have served in synthe-
ses of a series of amino acid analogs (Fig. 1) (1–3). For ex-
ample, β-substituted alanines 1–11 have been prepared by
ring opening of sulfamidate with oxygen, nitrogen, sulfur,
and fluorine nucleophiles (1–3). Aspartate analogs 12 and 13
have also been prepared by nucleophilic opening of sulfa-
midate with a cyanide ion (1, 3). Moreover, γ-acyl pyroglu-
tamate 14 was furnished on treatment of sulfamidate with
diethyl malonate (1). These examples demonstrate that
serine-derived cyclic sulfamidates are versatile chiral build-
ing blocks with complementary reactivity to related β-
alanine cation equivalents such as serine-derived β-lactones
(4, 5) and aziridines (6, 7).
Interested in harnessing its power to construct peptide
mimics and glutamate receptor ligands, we have explored
the reactivity of cyclic-sulfamidate 17 derived from N-
(PhF)serine methyl ester (Scheme 1), because of the proven
effectiveness of the PhF protecting group for preserving con-
figurational integrity during manipulations of α-amino car-
bonyl compounds (PhF = 9-(9-phenylfluorenyl)) (8, 9).
Received June 30, 2000. Published on the NRC Research
Press Web site on January 24, 2001.
In reactions with different nucleophiles, sulfamidate 17
was found to undergo additions via two different mecha-
nisms. In the case of weakly basic (conjugate acid pKa ≤ 7)
nucleophiles, direct nucleophilic displacement occurred to
provide enantiopure (>97% ee) β-substituted alanines. On
the other hand, carbon nucleophiles, such as the enolates of
1,3-dicarbonyl compounds, added to sulfamidate 17 by a
L. Wei and W.D. Lubell.1 Département de chimie,
Université de Montréal, C.P. 6128, Succursale Centre Ville,
Montréal, QC H3C 3J7, Canada.
1Author to whom correspondence may be addressed.
Telephone: (514) 343-7339. Fax: (514) 343-7586.
e-mail: Lubell@chimie.umontreal.ca
mechanism featuring β-elimination to provide
a
Can. J. Chem. 79: 94–104 (2001)
© 2001 NRC Canada
DOI: 10.1139/cjc-79-1-94

Wei and Lubell
Table 1. H NMR signal assignments of sulfamidites (2R)- and (2S)-16, and sulfamidate 17.
95
1
Position
(2R)-16
(2S)-16
17
δH [int. mult, J (Hz)]
δH [int. mult, J (Hz)]
δH [int. mult, J (Hz)]
4
5β
5α
MeO
PhF
3.51 (1H, dd, 1.4, 7.1)
4.41 (1H, dd, 1.4, 9.4)
4.75 (1H, dd, 7.1, 9.4)
3.42 (3H, s)
3.37 (1H, t, 7.9)
4.32 (1H, t, 7.9)
4.95 (1H, t, 7.9)
3.57 (3H, s)
3.64 (1H, dd, 4.0, 8.1)
4.38 (1H, dd, 4.0, 8.7)
4.02 (1H, dd, 8.1, 8.7)
3.69 (3H, s)
7.17–8.17 (13H, m)
7.19–7.77 (13H, m)
7.19–8.22 (13H, m)
Scheme 1. Synthesis of cyclic sulfamidate 17.
Fig. 1. Representative amino acids prepared by ring-opening of
serine-derived cyclic sulfamidates.
been prepared by oxidation of the corresponding sulfamidites
(1–3, 11–22). Following this protocol, (4S)-methyl 2,2-dioxo-
3-PhF-1,2,3-oxathiazolidine-4-carboxylate (17) was synthesized
initially by treating N-(PhF)serine methyl ester 15 (23) with
thionyl chloride, triethylamine, and imidazole in dichloro-
methane to furnish quantitatively
a 1:2 mixture of
diastereoisomeric sulfamidites 16 (Scheme 1). Cyclic
sulfamidate 17 was then prepared by subsequent oxidation
of sulfamidites 16 with sodium periodate and catalytic ruthe-
nium trichloride in acetonitrile and water at 0°C.
Diastereoisomers (2R)-16 and (2S)-16 could be separated
by chromatography and independently converted into five-
membered sulfamidate 17. The assignment of the configura-
tion at sulfur for the diastereoisomers (2R)-16 and (2S)-16
1
dehydroalanine intermediate that underwent subsequent Mi-
chael addition and afforded racemic product. In addition,
several nucleophiles were found that caused β-elimination,
yet failed to react with the dehydroalanine intermediate in a
conjugate addition. This spectrum of reactivity and the util-
ity of the addition products have been evaluated to better de-
fine the scope and limitations of N-(PhF)serine-derived
sulfamidate 17 as a chiral educt for amino acid synthesis.
was initially attempted by comparisons of their H NMR
spectra with that of their oxidation product sulfamidate 17
(Table 1), as well as with spectral data for other cyclic
sulfamidites (24). Comparing the spectra of 16 and 17, we
concluded that the (2R)-sulfamidite ((2R)-16), would exhibit
similar steric as well as anisotropic effects as sulfamidate 17
(25, 26). For example, in the spectra of (2R)-16 and 17, the
C-4 proton appeared as a doublet of doublets as the result of
steric interactions between the exocyclic oxygen atom on
sulfur and the PhF group, which twisted the five-membered
ring such that significantly different dihedral angles existed
between the C-4 and C-5 protons. In contrast, the C-4 proton
in (2S)-16 appeared as a triplet indicative of a conformation
with similar dihedral angles between the C-4 proton and
each of the C-5 protons. The magnetic anisotropy of the
S—O bond (26) shifted downfield the resonances of proxi-
mal PhF protons as well as the C-4 proton in the spectra of
(2R)-16 and 17 relative to the respective signals in the spec-
trum of (2S)-16.
Results and discussion
Synthesis of cyclic sulfamidate 17
Sulfamidate derivatives of β-amino alcohols permit pro-
tection of the nitrogen moiety and conversion of the
hydroxyl group into a leaving group. The most direct ap-
proach for their construction has been the reaction of the re-
spective β-amino alcohol with sulfuryl chloride; however,
this process has usually led to the corresponding aziridines,
presumably due to ring closure of the corresponding -OSO2Cl
intermediate (11–13). Because of the difficulties encountered
when using sulfuryl chloride, most cyclic sulfamidates have
The configurational assignments for 16, which were made
1
based on the H NMR chemical shift and coupling constant
© 2001 NRC Canada

96
Can. J. Chem. Vol. 79, 2001
Scheme 2. Ring opening of cyclic sulfamidate 17.
starting material as observed by NMR spectral analysis of
the crude product after aqueous work-up.
Fig. 2. ORTEP view of (2R,4S)-methyl 2-oxo-3-(PhF)-1,2,3-
oxathiazolidine-4-carboxylate ((2R)-16).2
Ring opening of sulfamidate 17 was also examined using
C-nucleophiles including β-keto esters, β-keto ketones,
dimethyl malonate, and nitroethane. Treatment of sulfa-
midate 17 with a premixed solution containing 400 mol% of
either β-keto ester, β-keto ketone, or dimethyl malonate and
220 mol% of sodium hydride in DME, followed by heating
at 60°C caused ring opening to form the polar sulfamic acid
intermediate. Hydrolysis of the reaction mixture with 1 M
KH2PO4 furnished the desired amino acid derivatives 18i–o
after chromatography (Table 2). Since β-keto ester 18k and
β-keto ketone 18i were difficult to separate from methyl
acetoacetate and 2,4-pentanedione, respectively, the crude
material was used without purification in the next step to-
wards the preparation of heterocyclic amino acids.
Nitroethane reacted with 17 using similar conditions to pro-
vide γ-nitro-α-amino pentanoate 18o in 52% yield as a 10:1
mixture of diastereomers.
β-Keto esters 18k and 18m were next converted, respec-
tively, to 5-methylproline 23 and δ-keto α-amino ester 20m,
an intermediate in the synthesis of 5-tert-butylproline (29)
(Scheme 3). Their respective δ-oxo-α-N-(PhF)amino acids
were first obtained from hydrolysis and decarboxylation of
β-keto esters 18k and 18m with sodium hydroxide in ethanol
heated at a reflux. Esterification with iodomethane and po-
tassium carbonate in acetonitrile provided methyl 5-oxo-2-
[N-(PhF)amino]hexanoate (20k) and methyl 6,6-dimethyl-5-
oxo-2-[N-(PhF)amino]heptanoate (20m) in 71% and 52%
overall yields, respectively, from 17. Hydrogenation of δ-
oxoheptanoate with palladium-on-carbon and di-tert-butyl
dicarbonate in methanol proceeded by cleavage of the PhF
protection, N-acylation, imine formation, and hydrogenation
of the imine intermediate on the face opposite the methyl es-
ter to furnish N-(BOC)-5-methylproline methyl ester (21) as
the cis-diastereomer. Hydrolysis of methyl ester cis-21 with
potassium trimethylsilanolate in Et2O furnished cis-N-(BOC)-
5-methylproline (cis-22) in 96% yield. In addition, removal
of the BOC protecting group with trifluoroacetic acid in di-
chloromethane provided cis-5-methylproline 23 (30, 31).
values, were confirmed by X-ray crystallographic analysis of
(2R)-16 (Fig. 2). Single-crystal X-ray analysis showed that
the dihedral angle between the C-4 proton and the C-5α pro-
ton was 25.4°, and the dihedral angle between the C-4 pro-
ton and the C-5β proton was 82.6°. The crystal structure of
(2R)-16 exhibits a conformation in which the α-proton and
the α-acid carbonyl are nearly coplanar (159.5°). Since α-
deprotonation from the coplanar geometry is stereo-
electronically less favoured than from an orthogonal geome-
try, this arrangement has been suggested to contribute to the
configurational stability of PhF amino carbonyl compounds
(27, 28).
Ring opening of five-membered cyclic sulfamidate 17
With cyclic sulfamidate 17 in hand, we next examined
nucleophilic ring opening using different nucleophiles
(Scheme 2, Table 2). Cyclic sulfamidate 17 reacted with
heteroatomic nucleophiles to provide products from both
nucleophilic displacement at C-5 and proton abstraction at
C-4. For example, KSCN, NaN3, and imidazole, all opened
regioselectively the sulfamidate ring to afford, respectively,
thioether 18d, azide 18e, and imidazole 18f. Other nucleo-
philes, such as TBAF, MeONa, diethyl amine, and pipe-
ridine, gave mainly dehydroalanine 19 and recovered
The utility of β-keto ketone 18i was illustrated by its con-
version to pyrazole amino acid 26 (Scheme 3). Methyl 2-[N-
(PhF)amino]-3-(3,5-dimethyl-2H-pyrazol-4-yl)propanoate (24)
was initially prepared by treatment of β-keto ketone 18i with
2 The structure of (2R)-16 was solved at l’Université de Montréal X-ray facility using direct methods (SHELXS 96) and refined with
SHELXL 96: C23H19NO4S, Mr = 405.452, orthorhombic, colourless crystal, space group P212121, unit cell dimensions (Å) a = 9.5587(2),
b = 9.7736(2), c = 21.0498(4), volume of unit cell (Å3) 1966.53(7), Z = 4, R1 = 0.0659 for F2 > 2 σ(F2), wR2 = 0.1613 for all data; GOF =
1.048. The author has deposited the atomic coordinates for the structure of (2R)-16 with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, free of charge, on application to the Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, U.K. (Fax: 44-
1223-336033 or e-mail: deposit@ccdc.cam.ac.uk). Supplementary material may be purchased from the Depository of Unpublished Data
Document Delivery, CISTI, National Research Council Canada, Ottawa, ON, K1A OS2, Canada. For information on ordering electronically
(http://www.nrc.ca/cisti/irm/unpub_e.shtml).
© 2001 NRC Canada

Wei and Lubell
97
Table 2. Treatment of cyclic sulfamidate 17 with nucleophiles.
Nucleophilic
source
Time
(h)
Temp
(°C)
18a
(% yield)
19c
(% yield)
[α ]2D0
Entry
Base
Solvent
a
b
TBAF
Et2NH
Et2NH
Et2NH
piperidine
KSCN
KSCN
NaN3
NaN3
NaN3
imidazole
CH3(CH2)2SH
CH3(CH2)2SH
MeONa
MeCOCH2COMe
PhCOCH2COMe
MeCOCH2CO2Me
MeCOCH2CO2Me
MeCOCH2CO2Me
MeCOCH2CO2Me
MeCOCH2CO2Me
MeCOCH2CO2Me
MeCOCH2CO2Me
EtCOCH2CO2Et
t-BuCOCH2CO2Et
MeCO2CH2CO2Me
CH3CH2NO2
DME
DME
MeCN
DMF
MeCN
DME
DMF
DME
MeCN
DMF
DME
DMF
DMF
DME
DME
DME
DMF
THF
THF
DME
THF
DME
DME
DME
DME
DME
DME
18
18
48
18
48
48
36
72
72
1
18
36
36
0.5
18
18
72
72
90
18
6
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
80
rt
rt
—
—
—
—
—
64
72
50
82
90
85
—
—
—
66b
45
—
30b
—
43b
51b
67b
86b
82
63
65b
52
40
<10
50
100
30
—
—
—
—
—
—
—
10
c
d
–287°
–287°
–294°
–294°
–294°
–241°
e
f
g
NaH
h
i
j
rt
100
d
NaH
NaH
60
60
rt
rt
rt
—
k
K2CO3
K2CO3
Cs2CO3
K3PO4
NaH
NaH
NaH
NaH
NaH
100
d
100
d
rt
60
60
60
60
60
60
60
—
—
—
—
—
—
—
4
18
18
18
18
18
l
m
n
o
NaH
NaH
–4.3°
aIsolated yield.
bCalculated yield from an isolated mixture of 18 and β-dicarbonyl starting material.
1
cDetermined by H NMR spectroscopy.
dObserved by TLC.
Scheme 3. Synthesis of 5-alkylproline 23 and amino-3-(3,5-dimethyl-1H-pyrazol-4-yl) propionic acid 26.
© 2001 NRC Canada

98
Can. J. Chem. Vol. 79, 2001
Fig. 3. Evaluation of enantiomeric purity of amino acids 28, 29, and cis-22.
hydrazine hydrate. Hydrolysis of methyl ester 24 with 1 N
NaOH in EtOH then furnished 2-[N-(PhF)amino]-3-(3,5-
dimethyl-1H-pyrazol-4-yl)propionic acid (25) as a solid after
chromatography. Removal of the PhF group was cleanly ac-
complished by heating 25 with trifluoroacetic acid in di-
chloromethane at a reflux for 18 h and furnished 26 in 88%
yield.
methyl ester singlets at 3.71 and 3.76 ppm in CDCl3 by
400 MHz H NMR spectroscopy demonstrated 30 to be of
1
>97% diastereomeric excess. Hence, (2S)-methyl 3-(1-
imidazol)-2-[N-(PhF)amino]propionate (18f) is presumed to
be of >97% enantiomeric purity. We consider, therefore, that
no racemization occurred during nucleophilic substitution on
cyclic sulfamidate 17 with imidazole nor with potassium
thiocyanate nor with azide ion as nucleophiles.
The enantiomeric purity of cis-N-(BOC)-5-methylproline
(cis-22) was studied after conversion to diastereomeric
α-methylbenzylamides 31 by coupling, respectively, to
R- and S-α-methylbenzylamine in MeCN with TBTU fol-
lowed by removal of the BOC group with 10% TFA in
CH2Cl2 (Fig. 3). In the 1H NMR spectra of α-methyl-
benzylamides 31, the diastereomeric methyl doublets were
resolved and came at 1.50 and 1.49 ppm, as well as at 1.46
and 1.42 ppm. Integration of these doublets indicated that 31
was of only 10% diastereomeric excess.
In contrast to the amino acid syntheses using less basic
nucleophiles, racemization had evidently occurred during the
preparation of cis-N-(BOC)-5-methylproline 22. The source
of the loss of configurational integrity was narrowed down to
the ring opening step after measurement of the specific rota-
tion of δ-keto α-amino ester 20m, which showed a consider-
able drop in optical purity ([α]2D0 –1.2° (c 0.8, CHCl3), lit.
(29) [α]2D0 –137.7° (c 1, MeOH)). Because hydrolysis and
decarboxylation of β-keto ester 18m, prepared from a route
featuring acylation of N-(PhF)glutamate γ-methyl ester (32),
produced enantiopure 20m ([α]2D0 –139° (c 0.8, MeOH)), we
considered that racemization occurred prior to or during the
nucleophilic addition to cyclic sulfamidate 17 and not at the
hydrolysis and decarboxylation steps.
Enantiomeric purity
Enantiomeric purity was evaluated for two products by
conversion to diastereomeric derivatives and analysis of the
1
isomeric signals in their H NMR spectra. In the case of
(2S)-N-PhF-S-cyanocysteine methyl ester (18d), conversion
to N-PhF-L-alanine (28) and comparison of its specific rota-
tion with the literature value was used to estimate purity.
Cleavage of the S—C bond with Raney nickel in EtOAc at
reflux for 6 h gave N-PhF-L-alanine methyl ester (27). Hy-
drolysis of N-PhF-L-alanine methyl ester (27) with 1 N
NaOH in ethanol for 1 h gave N-PhF-L-alanine (28) in 74%
overall yield from 18d (Fig. 3). The specific rotation of N-
PhF-L-alanine (28) and comparison with its literature value
(9) ([α]2D0 150° (c 0.2, CHCl3), lit. (9) [[α]2D0 163° (c 1,
CHCl3)) demonstrated that the material from sulfamidate
opening was significantly enriched with one enantiomer.
The enantiomeric purity of (2S)-methyl 3-(1-imidazol)-2-
[N-(PhF)amino]propionate (18f) was determined after con-
version to diastereomeric amides 30, and subsequent spectral
analysis. (2S)-3-(1-Imidazol)-2-[N-(PhF)amino]propionic acid
(29) was first synthesized by ester hydrolysis in 86% yield
using 1 N NaOH in EtOH. Acid 29 was coupled to L- and D-
phenylalanine methyl ester in MeCN with TBTU and DIEA,
respectively, at room temperature. Measurement of the
© 2001 NRC Canada

Wei and Lubell
99
Scheme 4. Michael addition of methyl acetoacetate enolate to dehydroalanine sulfamic acid 33.
Low specific rotation values were also recorded for δ-keto
α-amino ester 20k ([α]D20 –4.8° (c 0.15, CHCl3)), pyrazole
amino acid 25 ([α]2D0 –9.5° (c 0.2, MeOH)), and malonate
18i ([α]2D0–4.3° (c 0.1, CHCl3)). Because of the characteristi-
cally high specific rotations of N-(PhF)-α-amino
carboxylates (9, 23, 27–29, 32, 33), racemization may be in-
ferred to have occurred in these cases.
lation by chromatography. Hence, α-deprotonation triggers
β-elimination prior to reprotonation and racemization of 17.
A mechanism that may explain the cause of racemization
involves the nucleophile acting as base and removing the α-
proton to trigger ring opening with elimination. A second
nucleophile may then attack 32 to furnish β-keto ester by a
Michael addition (Scheme 5). On the other hand, because
(2S)-methyl 4-(1-imidazol)-2-[N-(PhF)amino]propionate (18f)
was shown to be of >97% enantiomeric purity, ring opening
of cyclic sulfamidate 17 with less basic nucleophiles should
involve only nucleophilic displacement.
The formation of N-(PhF)dehydroalanine 19 by β-elimina-
tion on sulfamidate 17 is remarkable in light of a previous
report in which the PhF group was found to completely sup-
press elimination during Mitsunobu reactions on the alcohol
of N-(PhF)serine methyl ester 15 (34). The related β-N-
(PhF)enamino ester has previously been reported; however,
removal of the α-proton was not required for its formation
via base induced rearrangement of dimethyl N-(PhF)-3,4-
didehydroglutamate (33). In the X-ray crystal structure of
cyclic sulfamidite 16, the α-proton and β-hydroxyl group
from serine are constrained in a nearly coplanar geometry
within the five-membered ring. Most likely, sulfamidate 17
adopts a similar geometry that can favour orbital overlap fa-
cilitating β-elimination. Finally, pyroglutamate 14 should also
be considered to be of suspect enantiomeric purity, because
dehydoalanine product was encountered in its synthesis us-
ing sulfamidate derived from N-(Bn)serine tert-butyl ester
(1).
Dehydroalanine 19 was formed on ring opening of cyclic
sulfamidate 17 by β-elimination induced with a variety of
nucleophiles (Table 2). Postulating that the presumed dehy-
droalanine intermediate 32 could serve as a Michael accep-
tor for the formation of racemic β-keto ester, we treated
sulfamidate 17 with 200 mol% of sodium hydride in DME
to induce elimination (Scheme 4). A premixed solution of
methyl acetoacetate (300 mol%) and NaH (400 mol%) in
DME was then added to the reaction mixture which was
heated at 60°C for 18 h. Hydrolysis of the polar sulfamic
acid intermediate with 1 M KH2PO4 furnished (5RS)-methyl
N-PhF-2-methyl-3-(methyloxy)carbonyl-∆2-pyrroline (33) in
87% yield. Previously, pyrroline 33 was encountered in the
direct ring opening of sulfamidate 17 with the preformed
enolate of methyl acetoacetate when the hot reaction mixture
was quenched with 1 M KH2PO4. Its formation can be
avoided by cooling the reaction mixture to room temperature
prior to hydrolysis of the sulfamic acid; however, we elected
to form pyrroline 33 in the present sequence because it was
easier to characterize. Formation of 33 demonstrated that
dehydroalanine 19 could serve as a prochiral intermediate
for the formation of racemized amino acid product. To verify
if sulfamidate racemized prior to ring opening, aliquots were
taken at different time intervals from the reaction mixture
containing 17 and the preformed enolate of methyl aceto-
acetate in DME at 60°C. No loss of configurational integrity
of sulfamidate 17 was detected after 1 and 2 h of reaction as
ascertained by measurement of its specific rotation after iso-
Conclusion
Five-membered cyclic sulfamidate 17 was synthesized from
serine in good yield. Ring opening of five-membered cyclic
sulfamidate was achieved using a variety of nucleophiles
© 2001 NRC Canada

100
Can. J. Chem. Vol. 79, 2001
Scheme 5. Proposed mechanisms for the ring opening of sulfamidate 17.
(2R,4S)-Methyl 2-oxo-3-(PhF)-1,2,3-oxathiazolidine-4-
carboxylate ((2R)-16) and (2S,4S)-methyl 2-oxo-3-(PhF)-
1,2,3-oxathiazolidine-4-carboxylate ((2S)-16)
including β-keto esters, β-keto ketones, dimethyl malonate,
nitroethane, sodium azide, imidazole, and potassium
thiocyanate. A careful analysis of the enantiomeric purity of
the products from ring opening of five-member cyclic
sulfamidate 17 was performed using optical measurements
as well as conversion of particular products to diastereo-
meric derivatives that were analyzed by NMR spectroscopy.
Direct nucleophilic displacement and β-elimination followed
by Michael addition were both found to be favoured mecha-
nisms for the additions of different nucleophiles to 23,
which formed enantiopure and racemic amino acid product,
respectively. Verification of product enantiomeric purity is
thus essential when using serine-derived cyclic sulfamidates
as chiral educts for amino acid synthesis.
A solution of N-PhF-L-serine methyl ester ((S)-15, 3.57 g,
10 mmol, prepared according to ref. 23) in 150 mL of di-
chloromethane was cooled to 0°C, treated with imidazole
(2.7 g, 40 mmol) followed by triethylamine (2.8 mL,
20 mmol), stirred for 10 min, then treated with thionyl chlo-
ride (0.8 mL, 11 mmol). After stirring an additional 45 min,
water (100 mL) was added and the phases were separated.
The aqueous phase was extracted with dichloromethane (3 ×
50 mL) and the combined organic fractions were washed
with water (2 × 50 mL), dried, filtered, and evaporated. The
residue was normally used without purification in the next
reaction. Purification of the residue by chromatography on
silica gel with an eluant of 20–30% EtOAc in hexane pro-
vided 4 g (99%) of a 1:2 mixture of diastereomers ((2R)-16
and (2S)-16). First to elute was (2R)-16: mp 83–84°C. [α]D20
121° (c 0.14, CHCl3). TLC: Rf = 0.54 (30% EtOAc in hex-
1
Supporting information available: H and 13C NMR spec-
tra for key compounds.2
Experimental section
1
anes). H NMR δ: 3.42 (s, 3H), 3.51 (dd, 1H, J = 1.4, 7.1),
General
4.41 (dd, 1H, J = 1.4, 9.4), 4.75 (dd, 1H, J = 7.1, 9.4), 7.17–
8.17 (m, 13H). 13C NMR δ: 52.1, 59.0, 72.2, 75.2, 171.4.
HRMS calcd. for C23H20O4NS (MH+): 406.1113; found:
406.1130. Next to elute was (2S)-16: mp 71–72°C. [α]D20
243° (c 0.38, CHCl3). TLC: Rf = 0.37 (30% EtOAc in hex-
Unless otherwise noted, all reactions were run under ni-
trogen atmosphere and distilled solvents were transferred by
syringe. Tetrahydrofuran (THF) and ether were distilled
from sodium–benzophenone immediately before use;
1,1,1,3,3,3-hexamethyldisilazane (HMDS) and CH2Cl2 were
distilled from CaH2; Et3N was distilled from BaO. Final re-
action mixture solutions were dried over Na2SO4. Chroma-
tography was on 230–400 mesh silica gel; thin layer
chromatography (TLC) on aluminum-backed silica plates.
Melting points are uncorrected. Mass spectral data, HRMS
(EI and FAB), were obtained by the Université de Montréal
1
anes). H NMR δ: 3.37 (t, 1H, J = 7.9), 3.57 (s, 3H), 4.32
(t, 1H, J = 7.9), 4.95 (t, 1H, J = 7.9), 7.19–7.77 (m, 13H).
13C NMR δ: 52.5, 61.3, 73.5, 76.2, 170.3. HRMS calcd. for
C23H19O4NS (M+): 405.1035; found: 405.1046.
(4S)-Methyl 2,2-dioxo-3-PhF-1,2,3-oxathiazolidine-4-
carboxylate (17)
1
Mass Spectroscopy facility. H NMR (300 and 400 MHz)
A solution of 2-oxo-1,2,3-oxathiazolidine 16 (1.25 g,
3.1 mmol) in 100 mL of acetonitrile was cooled to 0°C,
treated with ruthenium(III) chloride monohydrate (10 mg)
followed by sodium periodate (1.28 g, 6 mmol), stirred
10 min, and quenched with water (100 mL). After stirring
for 4 h, the reaction mixture was diluted with ether
and 13C NMR (75 and 100 MHz) spectra were recorded in
CDCl3. Chemical shifts are reported in ppm (δ units)
downfield of internal tetramethylsilane ((CH3)4Si). Coupling
constants are given in Hz. Chemical shifts for aromatic PhF
carbons are not reported.
© 2001 NRC Canada

Wei and Lubell
101
(100 mL) and the phases were separated. The aqueous phase
was extracted with ether (3 × 60 mL). The combined organic
fractions were washed with saturated aqueous sodium bicar-
bonate (100 mL) and brine (50 mL), dried, filtered, and
evaporated to a residue that was purified by chromatography
on silica gel with an eluant of 10–20% EtOAc in hexane.
Evaporation of the collected fractions provided 1.14 g (87%)
(dd, 1H, J = 6.7, 14.0), 7.01–7.72 (m, 16H). 13C NMR δ:
50.8, 52.3, 56.7, 72.9, 119.7, 128.4, 137.5, 173.4.
General procedure for ring opening of cyclic sulfamidate
17 with β-keto esters, β-keto ketones, and dimethyl
malonate
A solution of sodium hydride (prewashed with hexane, 60
wt% in oil, 85 mg, 2.1 mmol) in DME (15 mL) was treated
with the respective β-keto ester, β-keto ketone, or dimethyl
malonate (3.6 mmol), stirred for 10 min, treated with (4S)-
methyl 2,2-dioxo-3-PhF-1,2,3-oxathiazolidine-4-carboxylate
(17, 380 mg, 0.9 mmol), heated at 60°C for 18 h, cooled to
room temperature, and poured into 1 M NaH2PO4 (50 mL).
The mixture was extracted with EtOAc (3 × 50 mL). The
combined organic phases were washed with brine (2 ×
30 mL), dried, filtered, and evaporated to a residue.
1
of 17: mp 155–156°C. [α]2D0 244° (c 0.1, CHCl3). H NMR
δ: 3.64 (dd, 1H, J = 4.0, 8.2), 3.69 (s, 3H), 4.02 (dd, 1H, J =
8.2, 8.7), 4.38 (dd, 1H, J = 4.0, 8.7), 7.19–8.22 (m, 13H).
13C NMR δ: 52.9, 58.8, 66.8, 77.9, 169.2. HRMS calcd. for
C23H19O5NS (M+): 421.0984; found: 421.0997.
(2S)-N-PhF-S-cyanocysteine methyl ester (18d)
A
solution of (4S)-methyl 2,2-dioxo-3-PhF-1,2,3-
oxathiazolidine-4-carboxylate (17, 48 mg, 0.12 mmol) in
5 mL of DMF was treated with potassium thiocynate 35 mg
(0.36 mmol), stirred at room temperature for 36 h, poured
into 1 M KH2PO4 (20 mL), and extracted with EtOAc (3 ×
20 mL). The combined organic phase was washed with brine
(20 mL), dried, filtered, and evaporated to a residue that was
chromatographed on silica gel eluting with a gradient of 15–
20% EtOAc in hexane. Concentration of the collected frac-
tions provided 34.8 mg (72%) of 18d: mp 149–150°C. [α]D20
Methyl 5-oxo-4-(methylcarbonyl)-2-[N-(PhF)amino]hexan-
oate (18i)
Methyl 5-oxo-4-(methylcarbonyl)-2-[N-(PhF)amino]hexa-
noate (18i) was prepared from 2,4-pentanedione and used di-
rectly in next step. HRMS calcd. for C28H28O4N (MH+):
442.2018; found: 442.2033.
1
–287° (c 0.4, CHCl3). H NMR δ: 2.88 (dd, 1H, J = 4.7,
Methyl 5-oxo-4-(phenylcarbonyl)-2-[N-(PhF)amino]hexa-
noate (18j)
12.6,), 3.02 (dd, 1H, J = 4.7, 5.8), 3.13 (dd, 1H, J = 5.8,
12.6), 3.44 (brs, 1H), 3.48 (s, 3H), 7.23–7.75 (m, 13H).
13C NMR δ: 39.5, 52.6, 54.9, 72.8, 112.8, 172.6. HRMS
calcd. for C24H21O2SN2 (MH+): 401.1324; found: 401.1339.
Methyl 5-oxo-4-(phenylcarbonyl)-2-[N-(PhF)amino]hex-
anoate (18j) was prepared from 1-benzoyl acetone and iso-
lated by chromatography on silica gel eluting with a gradient
of 10–20% EtOAc in hexane as a 1.1:1 mixture of
1
(2S)-N-(PhF)-3-azido-alanine methyl ester (18e)
diastereomers in 45% yield. H NMR δ: 2.00 (s, 3H), 2.07
A
solution of (4S)-methyl 2,2-dioxo-3-PhF-1,2,3-
(m, 4H), 2.17 (s, 3H), 2.58 (m, 2H), 3.26 (s, 3H), 3.28 (s,
3H), 4.78 (t, 1H, J = 6.0), 4.83 (dd, 1H, J = 4.8, 7.4), 6.70–
8.26 (m, 36H). 13C NMR δ: 28.0, 28.7, 33.0, 33.2, 51.69,
51.73, 53.8, 54.5, 59.1, 59.3, 72.7, 72.8, 176.0 (2C), 195.0,
196.1, 202.9, 203.6. HRMS calcd. for C33H30O4N (MH+):
504.2175; found: 504.2153.
oxathiazolidine-4-carboxylate (17, 49 mg, 0.12 mmol) in
5 mL of DMF was treated with sodium azide (24 mg,
0.37 mmol), stirred at room temperature for 1 h, poured into
1 M KH2PO4 (20 mL), and extracted with EtOAc (2 ×
10 mL). The combined organic phase was washed with brine
(10 mL), dried, filtered, and evaporated to a residue that was
chromatographed on silica gel eluting with a gradient of 10–
20% EtOAc in hexane. Concentration of the collected frac-
tions provided 40.3 mg (90%) of 18e as a thick clear oil.
[α]2D0 –294° (c 0.12, CHCl3). 1H NMR δ: 2.85 (dd, 1H, J =
4.7, 5.3), 3.07 (dd, 1H, J = 4.7, 12.3), 3.18 (dd, 1H, J = 5.3,
12.3), 3.42 (s, 3H), 7.21–7.73 (m, 13H). 13C NMR δ: 52.2,
54.5, 56.4, 73.0, 173.6. HRMS calcd. for C23H21O2N4
(MH+): 385.1664; found: 385.1677.
Methyl 5-oxo-4-(methyloxycarbonyl)-2-[N-(PhF)amino]hex-
anoate (18k)
Methyl 5-oxo-4-(methyloxycarbonyl)-2-[N-(PhF)amino]hex-
anoate (18k) was prepared from methyl acetoacetate and
used directly in next step. HRMS calcd. for C28H28O5N
(MH+): 458.1968; found: 458.1982.
Methyl 5-oxo-4-(ethyloxycarbonyl)-2-[N-(PhF)amino]hepta-
noate (18l)
(2S)-Methyl 3-(1-imidazol)-2-[N-(PhF)amino]propionate (18f)
Methyl 5-oxo-4-(ethyloxycarbonyl)-2-[N-(PhF)amino]hep-
tanoate (18l) was prepared from ethyl propionylacetate and
isolated as an inseparable 1.1:1 mixture of diastereomers by
chromatography on silica gel eluting with a gradient of 10–
A
solution of (4S)-methyl 2,2-dioxo-3-PhF-1,2,3-
oxathiazolidine-4-carboxylate (17, 100 mg, 0.24 mmol) in
15 mL of DME was treated with imidazole (49 mg,
0.72 mmol), heated at 80°C for 18 h, poured into 1 M
KH2PO4 (30 mL), and extracted with EtOAc (3 × 20 mL).
The combined organic phase was washed with brine
(20 mL), dried, filtered, and evaporated to a residue that was
chromatographed on silica gel eluting with a gradient of 5–
10% MeOH in EtOAc. Concentration of the collected frac-
tions provided 83.2 mg (85%) of 18f: mp 146–147°C. [α]D20
–241° (c 0.1, CHCl3). MS (m/z): 410.2 (M + 1), 307.1,
1
20% EtOAc in hexane in 82% yield. H NMR δ: 0.98 (t, 3H,
J = 7.2), 1.11 (t, 3H, J = 7.2), 1.19 (t, 3H, J = 7.2), 1.28 (t,
3H, J = 7.2), 1.91–1.99 (m, 4H), 2.32–2.39 (m, 2H), 2.52–
2.68 (m, 4H), 3.24 (s, 3H), 3.25 (s, 3H), 3.67 (t, 1H, J =
6.4), 3.89–4.10 (m, 3H), 4.23 (dd, 2H, J = 7.2, 14.1), 7.14–
7.70 (m, 26H). 13C NMR δ: 7.35, 7.59, 13.8, 13.9, 32.5,
32.7, 35.1, 35.3, 51.3, 51.6, 53.6, 54.1, 54.9, 55.6, 61.1,
61.4, 72.6, 72.7, 169.0, 169.7, 175.9, 176.0, 204.6, 205.5.
HRMS calcd. for C30H31O5NNa (M+ + Na): 508.2100;
found: 508.2116.
1
289.1, 257.1, 241.1, 154.1. H NMR δ: 2.85 (m, 1H), 3.16
(brs, 1H), 3.35 (s, 3H), 3.83 (dd, 1H, J = 4.9, 14.0), 3.94
© 2001 NRC Canada

102
Can. J. Chem. Vol. 79, 2001
Methyl 6,6-dimethyl-5-oxo-4-(ethyloxycarbonyl)-2-[N-
(PhF)amino]heptanoate (18m)
perature for 18 h. Brine (50 mL) was added to the reaction
mixture, which was extracted with EtOAc (3 × 30 mL). The
organic phases were combined, washed with 0.65 M sodium
thiosulfate (50 mL) and brine (50 mL), dried, filtered, and
evaporated to a residue that was purified by chromatography
on silica gel using a gradient of 10–20% EtOAc in hexane.
Evaporation of the collected fractions gave 259 mg (71%
Methyl
6,6-dimethyl-5-oxo-4-(ethyloxycarbonyl)-2-[N-
(PhF)amino]heptanoate (18m) was prepared from ethyl
pivaloylacetate and isolated as an 1:1 mixture of
diastereomers by chromatography on silica gel eluting with
1
a gradient of 10–20% EtOAc in hexane in 63% yield. H
1
overall from 17) of 20k. H NMR δ: 1.71 (m, 2H), 2.11 (s,
NMR δ: 1.10 (s, 9H), 1.13 (t, 3H, J = 7.1), 1.27 (t, 3H, J =
7.1), 1.31 (s, 9H), 1.48 (m, 1H), 1.58 (m, 1H), 2.03 (m, 1H),
2.33 (m, 1H), 2.60 (m, 2H), 3.26 (s, 6H), 3.81–3.98 (m, 3H),
4.24 (q, 2H, J = 7.1), 4.45 (dd, 1H, J = 2.4, 10.4), 7.14–7.71
(m, 26H). 13C NMR δ: 13.7, 14.0, 26.0, 26.2, 33.5, 34.4,
45.3, 45.6, 47.9, 49.8, 51.5, 51.7, 53.6, 54.6, 60.8, 61.2,
72.6, 72.8, 168.9, 169.5, 175.4, 176.5, 209.9, 210.5. HRMS
calcd. for C32H35O5NNa (M+ + Na): 536.2413; found:
536.2392.
3H), 2.45–2.61 (m, 3H), 3.29 (s, 3H), 7.18–7.73 (m, 13H).
13C NMR δ: 28.6, 29.8, 39.6, 51.5, 54.6, 72.8, 176.3, 207.8.
HRMS calcd. for C26H26O3N (MH+): 400.1913; found:
400.1905.
cis-N-(BOC)-5-methylproline methyl ester (cis-21)
A solution of methyl 5-oxo-2-[N-(PhF)amino]hexanoate
(20k, 400 mg,
1 mmol) and di-tert-butyldicarbonate
(670 mg, 3 mmol) in MeOH (50 mL) was placed into a hy-
drogenation vessel and treated with palladium-on-carbon (10
wt%, 65 mg). The vessel was filled, vented and filled three
times with hydrogen, and the mixture was stirred under 4
atm of hydrogen for 48 h. The mixture was filtered on
CeliteTM and washed with MeOH (50 mL). The combined
organic phase was evaporated to a residue that was purified
by chromatography on silica gel using a gradient of 10–15%
EtOAc in hexane. Evaporation of the collected fractions
gave 225 mg (92%) of cis-21 as an oil. 1H NMR δ (showed a
mixture of carbamate isomers): 1.24 (d, 6H, J = 6.2), 1.38
(s, 9H), 1.42 (s, 9H), 1.58 (m, 2H), 1.97 (m, 4H), 2.14 (m,
2H), 3.68 (s, 6H), 3.86 (m, 1H), 3.98 (m, 1H), 4.16 (m, 1H),
4.27 (m, 1H). 13C NMR δ (showed a mixture of carbamate
isomers): 19.7, 20.5, 28.3, 28.7, 31.6, 32.4, 51.9, 53.9, 59.7,
60.0, 79.5, 158.2, 159.0, 173.0, 173.9. HRMS calcd. for
C12H22O4N (MH+): 244.1549; found: 244.1556.
4-(Methyloxycarbonyl)-2-[N-(PhF)]glutamate dimethyl
ester (18n)
4-(Methyloxycarbonyl)-2-[N-(PhF)]glutamate
dimethyl
ester (18n) was prepared from dimethyl malonate and iso-
lated as a 1:1 mixture of diastereomers by chromatography
on silica gel eluting with a gradient of 10–20% EtOAc in
1
hexane in 65% yield. H NMR δ: 2.03 (m, 2H), 2.61 (dd,
1H, J = 4.7, 8.9), 3.20 (s, 3H), 3.36 (s, 3H), 3.57 (s, 3H),
3.73 (m, 1H), 7.11–7.67 (m, 13H). 13C NMR δ: 33.3, 48.3,
51.5, 52.3, 52.5, 53.7, 72.6, 166.8, 169.0, 169.8. HRMS
calcd. for C28H27O6NNa (M+ + Na): 496.1736; found:
496.1728.
Methyl 4-nitro-2-[N-(PhF)amino]pentanoate (18o)
A solution of sodium hydride (prewashed with hexane, 60
wt% in oil, 40 mg, 1 mmol) in DME (12 mL) was treated
with nitroethane (0.2 mL, 2.8 mmol), stirred at 60°C for 3 h,
treated with (4S)-methyl 2,2-dioxo-3-PhF-1,2,3-oxathia-
zolidine-4-carboxylate (17, 100 mg, 0.24 mmol), heated at
60°C for 36 h, cooled to room temperature, and poured into
1 M NaH2PO4 (30 mL). The mixture was extracted with
EtOAc (3 × 30 mL), and the combined organic phases were
washed with brine (2 × 30 mL), dried, filtered, and evapo-
rated. Purification of the residue by chromatography on sil-
ica gel with an eluant of 0–20% EtOAc in hexane provided
52 mg (52%) of a 10:1 mixture of diastereomers 18o. The
spectra data for the major isomer was as follows. 1H NMR δ:
1.51 (d, 3H, J = 6.9), 1.73 (ddd, 1H, J = 3.4, 9.4, 14.8), 2.16
(ddd, 1H, J = 4.2, 9.1, 14.8), 2.64 (dd, 1H, J = 3.4, 9.1),
3.25 (s, 3H), 4.92 (m, 1H), 7.15–7.71 (m, 13H). 13C NMR δ:
20.3, 39.1, 51.8, 52.6, 72.6, 79.4, 175.6. HRMS calcd. for
C25H25O4N2 (MH+): 417.1814; found: 417.1826.
cis-N-(BOC)-5-methylproline (cis-22)
Methyl ester 21 (110 mg, 0.45 mmol) was dissolved in
10 mL of Et2O, treated with KOSi(Me)3 (70 mg, 0.55 mmol)
and stirred for 18 h at room temperature. The reaction mix-
ture was extracted with water (5 × 20 mL), and the aqueous
phases were combined, acidified with acetic acid to pH 2,
saturated with NaCl, and extracted with EtOAc (3 × 30 mL).
The organic phases were combined, dried, filtered, and evap-
orated to give 99.4 mg (0.43 mmol, 96%) of cis-22. 1H
NMR (CD3OD) δ (showed a mixture of carbamate isomers):
1.27 (d, 3H, J = 6.2), 1.42 (brs, 9H), 1.65 (m, 1H), 2.02 (m,
2H), 2.23 (m, 1H), 3.96 (m, 1H), 4.18 (m, 1H). 13C NMR
(CD3OD) δ (showed a mixture of carbamate isomers): 20.1,
20.9, 28.6, 28.8, 29.3, 29.8, 32.7, 33.4, 49.6, 49.8, 55.4,
55.7, 61.2, 61.5, 81.2, 81.3, 155.4, 155.8, 176.6, 176.8.
HRMS calcd. for C11H20O4N (MH+): 230.1392; found:
230.1385.
Methyl 5-oxo-2-[N-(PhF)amino]hexanoate (20k)
Crude
methyl
5-oxo-4-(methyloxycarbonyl)-2-[N-
Enantiomeric purity of cis-N-(BOC)-5-methylproline (cis-22)
A room-temperature solution of cis-N-(BOC)-5-methyl-
proline (cis-22, 20 mg, 0.09 mmol) and either (R) or (S)-α-
methylbenzylamine (28 µL, 0.22 mmol) in 1 mL of
acetonitrile was treated with benzotriazol-1-yl-1,1,3,3-
tetramethyluronium tetrafluoroborate (30 mg, 0.09 mmol)
and stirred for 2 h when TLC showed complete disappear-
ance of the starting acid. Brine (2 mL) was added to the re-
action mixture, which was then extracted with EtOAc (2 ×
(PhF)amino]hexanoate (18k) was dissolved in EtOH
(10 mL), treated with 1 N NaOH (10 mL), and heated at a
reflux for 5 h. The mixture was cooled to room temperature
and adjusted to pH 5 using 10% HCl. The solution was ex-
tracted with EtOAc (3 × 30 mL) and the combined organic
phases were washed with brine (30 mL), dried, filtered, and
evaporated to a residue that was dissolved in acetonitrile
(20 mL), treated with K2CO3 (300 mg, 2.2 mmol) and
iodomethane (0.3 mL, 4.8 mmol), and stirred at room tem-
© 2001 NRC Canada

Wei and Lubell
103
3 mL). The combined organic phase was extracted with 2 N
HCl (2 × 2 mL) and NaHCO3 (2 × 2 mL), washed with H2O
(2 × 2 mL) and brine, dried, filtered, and evaporated to a
residue that was dissolved in CH2Cl2 (5 mL), treated with
0.5 mL TFA, and stirred at room temperature for 1 h. The
solution was concentrated, dried, and directly examined by
1H NMR spectroscopy. When (S)- and (R)-α-methylbenzyl-
amine of 99% diastereomeric purity were used, respectively,
the same mixture of diastereomers were obtained. Examina-
tion of the methyl doublets at 1.50, 1.49, 1.46, and 1.42 ppm
CH2Cl2, treated with 2 mL of CF3CO2H, and heated at a re-
flux for 18 h. The volatiles were evaporated, and the residue
was treated with 10 mL of H2O and filtered. The aqueous
solution was washed with hexanes (2 × 20 mL), and then
evaporated to a solid 55 mg (88%) of 26. 1H NMR (CD3OD)
δ: 2.39 (s, 6H), 3.07 (dd, 1H, J = 7.2, 15.3), 3.19 (dd, 1H,
J = 7.2, 15.3), 4.13 (t, 1H, J = 7.2). 13C NMR (CD3OD) δ:
9.7, 24.6, 53.4, 113.2, 146.1, 170.9. HRMS calcd. for
C8H14N3O2 (MH+): 184.1086; found: 184.1090.
1
in the H NMR spectra in CDCl3 demonstrated 31 to be of
1.1:1 mixture of diastereomers. Hence, cis-22 is presumed to
be of 10% enantiomeric excess.
(2S)-N-PhF-Alanine methyl ester (27)
(2S)-N-(PhF)-S-Cyanocysteine methyl ester (18d, 35 mg,
0.09 mmol) was dissolved in EtOAc (10 mL) and treated
with Raney nickel (50% slurry in water, ≈ 200 mg). The
mixture was heated at a reflux for 6 h, cooled to room tem-
perature, and filtered through Celite™ to remove the cata-
lyst. The filtrate was concentrated. The residue was used
5-Methylproline N′-α-methyl-benzylamide trifloroacetate (31)
1H NMR (CD3OD) δ: 1.42 (d, 3H, J = 6.6), 1.46 (d, 3H,
J = 6.6), 1.49 (d, 3H, J = 7.0), 1.50 (d, 3H, J = 7.0), 1.60
(m, 1H), 1.73 (m, 1H), 2.04 (m, 1H), 2.19 (m, 3H), 2.42 (m,
2H), 3.74 (m, 2H), 4.31 (m, 2H), 5.04 (m, 2H), 7.22–7.37
(m, 10H).
1
without purification in the next reaction. H NMR δ: 1.14 (d,
3H, J = 7.0), 2.79 (dd, 1H, J = 7.0, 14.1), 3.31 (s, 3H), 7.17–
7.73 (m, 13H).
Methyl [N-(PhF)amino]-3-(3,5-dimethyl-2H-pyrazol-4-yl)pro-
panoate (24)
(2S)-N-PhF-Alanine (28)
Crude (2S)-N-PhF-alanine methyl ester (27) was dissolved
in ethanol (5 mL), treated with 1 N NaOH (5 mL), and
heated at 75°C for 1 h. The mixture was cooled to room
temperature, poured into 1 M KH2PO4 (20 mL), and ex-
tracted with EtOAc (3 × 20 mL). The combined organic
phase was washed with brine (2 × 10 mL), dried, filtered,
and evaporated to a residue. Purification of the residue by
chromatography on silica gel with an eluant of 60–70%
EtOAc in hexane provided 22 mg (74% overall from 18d) of
28. [α]2D01 150° (c 0.2, CHCl3), lit. (9) [α]2D0 163° (c 1,
CHCl3). H NMR δ: 1.13 (d, 3H, J = 7.2), 2.71 (q, 1H, J =
7.2), 7.18–7.75 (m, 13H). 13C NMR δ: 19.7, 52.2, 73.0,
175.9.
Crude methyl 5-oxo-4-(methylcarbonyl)-2-[N-(PhF)amino]hexa-
noate (18i) was dissolved in dioxane (10 mL), treated with
hydrazine hydrate (60 µL, 1.7 mmol), stirred for 1.5 h, and
poured into 1 M NaH2PO4 (30 mL). The mixture was ex-
tracted with EtOAc (3 × 20 mL), and the combined organic
phase was washed with brine (2 × 30 mL), dried, filtered,
and evaporated. The residue was normally used without pu-
rification in the next reaction. Purification of the residue by
chromatography on silica gel with an eluant of 20–30%
EtOAc in hexane provided 169 mg (43% overall from 17) of
1
24. H NMR δ: 1.99 (s, 6H), 2.50 (m, 2H), 2.58 (m, 1H),
3.22 (s, 3H), 6.73–7.69 (m, 13H). 13C NMR δ: 10.5, 28.8,
51.4, 56.0, 72.9, 111.1, 142.8, 176.6. HRMS calcd. for
C28H28O2N3 (MH+): 438.2181; found: 438.2189.
(2S)-3-(1-Imidazol)-2-[N-(PhF)amino]propionic acid (29)
Ester hydrolysis was performed on 18f (83 mg, 0.2 mmol)
using the same conditions described for the preparation of
28 and provided 69 mg (86%) of 29: mp 156–157°C. [α]D20
2-N-(PhF)Amino-3-(3,5-dimethyl-1H-pyrazol-4-yl)propionic
acid (25)
Crude
methyl
[N-(PhF)amino]-3-(3,5-dimethyl-2H-
1
–149° (c 0.42, CHCl3). H NMR δ: 2.97 (t, 1H, J = 4.1),
pyrazol-4-yl)propanoate (24) was dissolved in EtOH (5 mL),
treated with 1 N NaOH (5 mL), heated at 60°C for 3 h,
cooled to room temperature, and then poured into 1 M
NaH2PO4 (50 mL). The mixture was extracted with EtOAc
(2 × 30 mL). The combined organic phases were extracted
with 1 N NaOH (2 × 30 mL), the aqueous phase was com-
bined, acidified with citric acid to pH 2, and extracted with
EtOAc (2 × 30 mL). The organic phases were combined,
dried, filtered, and evaporated to a residue that was purified
by chromatography on silica gel with a gradient of 10–20%
MeOH in EtOAc as eluant. Evaporation of the collected
3.94 (dd, 1H, J = 4.1, 13.6), 4.23 (dd, 1H, J = 4.1, 13.6),
7.18–7.70 (m, 15H), 8.86 (brs, 1H). 13C NMR δ: 52.7, 56.4,
73.2, 119.4, 122.1, 135.6, 172.7. HRMS calcd. for
C25H21O2N3 (M+): 395.1634; found: 395.1644.
Enantiomeric purity of (2S)-3-(1-imidazol)-2-[N-
(PhF)amino]propionic acid (29)
A solution of 29 (10 mg, 0.025 mmol) in acetonitrile
(1 mL) was treated with D- or L- phenylalanine methyl ester
hydrochloride (11 mg, 0.05 mmol), TBTU (16 mg,
0.05 mmol), and diisopropylethylamine (35 µL, 0.20 mmol)
at room temperature. After stirring for 1 h, the solution was
diluted with ethyl acetate (5 mL), washed with water (2 ×
5 mL) and brine (5 mL), dried, and concentrated in vacuo to
1
fractions gave 143 mg (37% over all from 17) of 25. H
NMR (CD3OD) δ: 1.95 (s, 6H), 2.50–2.54 (m, 3H), 6.61–
7.72 (m, 13H). 13C NMR (CD3OD) δ: 10.5, 29.9, 57.7, 74.3,
112.6, 144.1, 179.1. HRMS calcd. for C27H26N3O2 (MH+):
424.2025; found: 424.2043.
1
a crude oil, which was directly examined by H NMR spec-
troscopy. The limits of detection were determined by mea-
suring the diastereomeric methyl ester singlets at 3.71 and
3.76 ppm in CDCl3 in the 400 MHz 1H NMR spectra. Purifi-
cation by chromatography using a gradient of 5–10%
Amino-3-(3,5-dimethyl-1H-pyrazol-4-yl)propionic acid (26)
2-[N-(PhF)Amino]-3-(3,5-dimethyl-1H-pyrazol-4-yl)propionic
acid (25, 143 mg, 0.34 mmol) was dissolved in 10 mL of
© 2001 NRC Canada

104
Can. J. Chem. Vol. 79, 2001
methanol in EtOAc as eluant gave dipeptides having the fol-
lowing spectra.
References
1. J.E. Baldwin, A.C. Spivey, and C.J. Schofield. Tetrahedron:
Asymmetry, 1, 881 (1990).
2. B.M. Kim and S.M. So. Tetrahedron Lett. 39, 5381 (1998).
3. L.T. Boulton, H.T. Stock, J. Raphy, and D.C. Horwell. J.
Chem. Soc. Perkin Trans. 1, 1421 (1999).
4. S.V. Pansare and J.C. Vederas. J. Org. Chem. 54, 2311 (1989),
and refs. 2a–d cited within.
(2S)-3-(1-Imidazol)-2-[N-(PhF)amino]propionyl-D-
phenylalanine methyl ester (2′R) (30)
1H NMR δ: 2.73 (m, 1H), 2.97 (dd, 1H, J = 8.1, 14.1),
3.16 (dd, 1H, J = 5.3, 14.1), 3.49 (dd, 1H, J = 4.1, 14.6),
3.76 (s, 3H), 4.09 (m, 1H), 4.49 (m, 1H), 7.01–7.68 (m,
21H).
5. S.V. Pansare, G. Huyer, L.D. Arnold, and J.C. Vederas. Org.
Synth. 70, 1 (1992).
6. L. Dubois, A. Mehta, E. Tourette, and R.H. Dodd. J. Org.
Chem. 59, 434 (1994), and refs. 1–13 cited within.
7. B. Hofmann, P. Dauban, J.P. Biron, P. Potier, and R.H. Dodd.
Heterocycles, 46, 473 (1997).
8. B.D. Christie and H. Rapoport. J. Org. Chem. 50, 1239 (1985).
9. W.D. Lubell and H. Rapoport. J. Am. Chem. Soc. 109, 236
(1987).
(2S)-3-(1-Imidazol)-2-[N-(PhF)amino]propionyl-L-
phenylalanine methyl ester (2′S) (30)
1H NMR δ: 2.80 (m, 1H), 2.88 (dd, 1H, J = 6.0, 13.7),
3.11 (dd, 1H, J = 5.3, 13.7), 3.56 (dd, 1H, J = 4.3, 13.9),
3.71 (s, 3H), 4.21 (m, 1H), 4.73 (m, 1H), 6.80–7.72 (m,
21H).
10. L. Wei and W.D. Lubell. Org. Lett. 2, 2595 (2000).
11. D. Alker, K.J. Doyle, L.M. Harwood, and A. McGregor. Tetra-
hedron: Asymmetry, 1, 877 (1990).
12. M. Pilkington and J.D. Wallis. J. Chem. Soc. Chem. Commun.
1857 (1993).
13. H.S.H. Gautun, T. Bergan, and P.H.J. Carlsen. Acta Chim.
Scand. 53, 446 (1999).
14. G.J. White and M.E. Garst. J. Org. Chem. 56, 3178 (1991).
15. H.S.H. Gautun and P.H.J. Carlsen. Tetrahedron: Asymmetry, 6,
1667 (1995).
16. (a) B. Aguilera, A. Fernandez-Mayoralas, and C. Jaramillo.
Tetrahedron, 53, 5863 (1997); (b) B. Aguilera and A.
Fernandez-Mayoralas. J. Org. Chem. 63, 270 (1998).
17. K.K. Andersen and M. Kociolek. J. Org. Chem. 60, 2003
(1995).
18. M.E. Van Dort, Y.W. Jung, P.S. Sherman, M.R. Kilbourn, and
D.M. Wieland. J. Med. Chem. 38, 810 (1995).
19. M. Okuda and K. Tomioka. Tetrahedron Lett. 35, 4585 (1994).
20. D. Ok, M.H. Fisher, M.J. Wyvratt, and P.T. Meinke. Tetrahe-
dron Lett. 40, 3831 (1999).
Methyl 1-N-PhF-2-methyl-3-[(methyloxy)carbonyl]-∆2-
pyrroline (33)
A
solution of (4S)-methyl 2,2-dioxo-3-PhF-1,2,3-
oxathiazolidine-4-carboxylate (17, 60 mg, 0.14 mmol) in
8 mL of DME was treated with NaH (40 mg, 1 mmol),
stirred at room temperature for 30 min. A 0.5 mL aliquot
was taken, poured into 1 M KH2PO4, and extracted with
EtOAc (2 × 10 mL). The combined organic fractions were
1
concentrated, dried on vacuum, and examined directly by H
NMR spectroscopy, which showed complete conversion to
1
dehydroalanine 19. H NMR δ: 3.76 (s, 3H), 4.63 (brs, 1H),
5.62 (brs, 1H), 7.20–7.74 (m, 13H)). In a separate flask, a
solution of methyl acetoacetate (50 µL, 0.46 mmol) in 3 mL
of DME was treated with NaH (25 mg, 0.6 mmol) and
stirred at room temperature for 1 h. The enolate solution was
then added to the remaining solution of dehydroalanine,
stirred at a reflux for 18h, poured into 40 mL of 1 M
KH2PO4, and extracted with EtOAc (3 × 30 mL). The com-
bined organic phases were washed with brine (2 × 30 mL),
dried, filtered, and evaporated to a residue that was
chromatographed on silica gel eluting with a gradient of 10–
15% EtOAc in hexane. Concentrated of the collected frac-
21. B. Aguilera and A. Fernandez-Mayoralas. Chem. Commun.
127 (1996).
22. T.A. Lyle, C.A. Mafill, and S.M. Pizenberger. J. Am. Chem.
Soc. 109, 7890 (1987).
23. W.D. Lubell and H. Rapoport. J. Org. Chem. 54, 3824 (1989).
24. G. Lowe and M.A. Reed. Tetrahedron: Asymmetry, 1, 885
(1990).
1
tions provided 49.6 mg (87%) of 33. H NMR δ: 2.08 (s,
3H), 2.48 (dd, 1H, J = 6.8, 12.8), 2.82 (t, 1H, J = 12.8), 3.47
(dd, 1H, J = 6.8, 12.8), 3.48 (s, 3H), 3.61 (s, 3H), 7.12–7.77
(m, 13H). 13C NMR δ: 13.4, 33.8, 50.8, 52.2, 61.9, 103.5,
161.9, 166.7, 174.7, 174.8. HRMS calcd. for C28H26O4N
(MH+): 440.1862; found: 440.1870.
25. B.B. Lohray. Synthesis, 1035 (1992).
26. J.A. Deyrup and C.L. Moyer. J. Org. Chem. 34, 175 (1969).
27. M. Atfani and W.D. Lubell. J. Org. Chem. 60, 3184 (1995).
28. J.M. Huphrey, R.J. Bridges, J.A. Hart, and A.R. Chamberlin. J.
Org. Chem. 59, 2467 (1994).
29. E. Beausoleil, B. L’Archevêque, L. Bélec, M. Atfani, and W.D.
Lubell. J. Org. Chem. 61, 9447 (1996).
30. H. Li, T. Sakamoto, and Y. Kikugawa. Tetrahedron Lett. 38,
6677 (1997).
31. T.L. Ho, B. Gopalan, J.J. Nestor Jr. J. Org. Chem. 51, 2405
(1986).
32. H.H. Ibrahim and W.D. Lubell. J. Org. Chem. 58, 6438 (1993).
33. M.M. Paz and J. Sardina. J. Org. Chem. 58, 6990 (1993).
34. R.J. Cherney and L. Wang. J. Org. Chem. 61, 2544 (1996).
Acknowledgment
This research was supported in part by the Natural Sci-
ences and Engineering Research Council of Canada
(NSERC) and the Ministère de l’Éducation du Québec. The
crystal structure analysis of compound (2R)-16 was per-
formed by Francine Bélanger-Gariépy at l’Université de
Montréal X-ray crystallography facility.
© 2001 NRC Canada