Highly chemoselective reactions on hindered sulfamidates with oxygenated nucleophiles

Article abstract of DOI:10.1016/j.tetasy.2008.01.030

Although the chemoselectivity problems in substitution reactions, which arise from the use of oxygenated nucleophiles in a basic medium by generating anionic species are well-known, we report herein a highly chemoselective ring-opening reaction of hindered cyclic sulfamidates with O-nucleophiles. The reaction occurs with the inversion of configuration at the quaternary centre, allowing the stereoselective synthesis of an important class of β^2,2-amino acids, namely O-substituted α-methylisoserines.

Full text of DOI:10.1016/j.tetasy.2008.01.030

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 443–449
Highly chemoselective reactions on hindered sulfamidates
with oxygenated nucleophiles
*
*
´
´
´
´
Gonzalo Jimenez-Oses, Alberto Avenoza, Jesus H. Busto and Jesus M. Peregrina
Departamento de Quı´mica, Universidad de La Rioja, Grupo de Sı´ntesis Quı´mica de La Rioja, U.A.-C.S.I.C., E-26006 Logron˜o, Spain
Received 16 November 2007; accepted 24 January 2008
Abstract—Although the chemoselectivity problems in substitution reactions, which arise from the use of oxygenated nucleophiles in a
basic medium by generating anionic species are well-known, we report herein a highly chemoselective ring-opening reaction of hindered
cyclic sulfamidates with O-nucleophiles. The reaction occurs with the inversion of configuration at the quaternary centre, allowing
the stereoselective synthesis of an important class of b2,2-amino acids, namely O-substituted a-methylisoserines.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
NH2
X
via S 2
N
HO2C
Me
The important role that five-membered cyclic sulfamidates
play in organic synthesis is due to the fact that most inter-
molecular ring-opening reactions of these systems with
nucleophiles proceed by the SN2 pathway.1 Although the
synthesis and reactivity of these type of sulfamidates have
been described in detail,2,3 little is known about hindered
sulfamidates.4 On this basis, and considering the impor-
tance of chiral compounds with quaternary carbon cen-
tres,5 we have recently reported the behaviour of
sulfamidates (R)-1a,b with several nucleophiles. Taking
into account that within these chiral building blocks, the
quaternary carbon centre is activated for nucleophilic dis-
placement, the SN2 reactivity with several nucleophiles (sul-
fur derivatives, azide, fluoride, benzoate, cyanide) in a basic
medium was explored.6 Further hydrolysis of the ring
opened products allowed us to obtain interesting chiral
a,a-disubstituted b-amino acids, namely b2,2-amino acids6,7
(Fig. 1).
MeO2C
β
2,2-amino acids
(X = F, CN, OH, SR, N3)
N
O
S
COR
O
O
NHCO2Me
Me
R = N(OMe)Me:
)-1a
R = OMe:
)-1b
COR
(
R
α
β
-unsaturated
via E2
-amino acid
(
R
derivatives
Figure 1. Reactions of chiral building blocks (R)-1a,b.
On the other hand, since Seebach and other authors discov-
ered that b-peptides displayed interesting biological proper-
ties, the field of b-amino acids is a matter of continuous
interest.8
Particularly attractive are the chiral b2,2-amino acids,9 since
they bear a quaternary stereocentre at the a-position. In
this context, the isoserine derivatives have received excep-
tional attention due to their implications as peptidomimetic
units10 and as important targets in the synthesis of b-lac-
tams and of TaxolÒ analogues (taxoids).11
Nevertheless, when basic nucleophiles were used, a compet-
itive reaction pathway was observed which corresponded
to the b-elimination process that allows the synthesis of
a-unsaturated b-amino acid derivatives, which could also
be obtained from these sulfamidates using a base in the
absence of a nucleophile6a (Fig. 1).
2. Results and discussion
*
Bearing these facts in mind, we focused our attention on
Corresponding authors. Fax: +34 941 299 621 (J.M.P.); e-mail
addresses: hector.busto@unirioja.es; jesusmanuel.peregrina@unirioja.es
O-substituted a-methylisoserine derivatives. Indeed, one
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.01.030

444
G. Jime´nez-Ose´s et al. / Tetrahedron: Asymmetry 19 (2008) 443–449
of the best methods to obtain these compounds would
involve the ring-opening reaction of the aforementioned
hindered sulfamidates with oxygen nucleophiles (O-nucleo-
philes), although the problems arising from their use in a
basic medium are well-known. It is important to notice that
although we have reported the SN2 reactivity of these
hindered sulfamidates with several nucleophiles, only one
example has been described with O-nucleophiles.6a As a
result of this, we decided to undertake an in-depth study
into the behaviour of five-membered cyclic sulfamidates
(R)-1a,b with several O-nucleophiles under different basic
conditions. (Table 1).
deprotection products (R)-4a–c (Table 1, entries 6–8 and
11–13). Particularly interesting is the selectivity observed
by using 1.1 or 10.0 equiv of LiOH in MeOH/H2O (3:2),
allowing the synthesis of sulfamidates (R)-4a or (R)-4c,
respectively (Table 1, entries 7 and 8). Curiously, mixtures
of elimination and deprotection products 3a/(R)-4a were
observed in the reaction of sulfamidate (R)-1a with bases
t
such as NMe4OH, BuOK or MeONa, when DMF was
used as a solvent (Table 1, entries 5, 9 and 10, respectively).
When we carried out the reaction of sulfamidate (R)-1a
with PhONa, using DMF as a solvent, followed by acid
hydrolysis, we obtained a mixture of the substitution prod-
uct (S)-20a, elimination product 3a and carbamate group
deprotection product (R)-4a (Table 1, entry 14). Fortu-
nately, this problem was solved by changing the amide
group to an ester group in the sulfamidate, therefore when
using sulfamidate (R)-1b instead of (R)-1a, only the substi-
tution product (S)-20b was obtained (Table 1, entry 15).
Therefore, the ester or amide substituent of the sulfamidate
is responsible for the chemoselectivity observed; the ester
group favours the substitution reaction pathway.
Taking into account the good results previously obtained
with sulfamidate (R)-1b and cesium p-nitrobenzoate6a
(Table 1, entry 2), we assayed the same reaction with
sulfamidate (R)-1a. Now, the above-mentioned elimination
was observed, giving a mixture of substitution and elimina-
tion products (S)-2a and 3a, respectively (Table 1, entry 1).
Other O-nucleophiles under similar conditions were tested,
also giving a mixture of products in different proportions.
It is important to note that the elimination products 3a and
3b can be exclusively obtained carrying out the reaction of
sulfamidates (R)-1a,b with DBU at reflux in THF (Table 1,
entries 3 and 4).6a In contrast, when KOH, LiOH, MeONa
or BnONa were used in H2O, MeOH/H2O or THF none of
the above reactions were observed and we only obtained
Taking into account the importance of these types of five-
membered cyclic sulfamidates as chiral building blocks in
the synthesis of interesting organic compounds that bear
quaternary stereocentres,6,7 this study allows easy access
to differently protected and unprotected cyclic sulfamidate
Table 1. Reactions of sulfamidates (R)-1a,b with several O-nucleophiles under basic conditions
CO2Me
HN
MeO2C
CO2Me
HN
O
-nucleophile,
H
N
O
O
N
conditions
O
O
S
(
+
+
S
COR
O
COR
O
ROC
Me
)-2a,b or (S
OR'
Me
COR
R = N(OMe)Me: a
R = OMe: b
Me
R)-1a,b
(
3a,b
R)-4a-c
(
S
)-2'a,b
R = OH: c
Substitution product
Elimination product Deprotection product
Entry
1
Sulfamidate
O-Nucleophile
Conditions
R0O–
Products
Yielda (%)
71/27
(R)-1a
pNO2–BzOH/CsF
(i) pNO2–BzOH/CsF (1.1 equiv), DMF, 50 °C,
(ii) 20% H2SO4/CH2Cl2 (1:1), 25 °C
(i) pNO2–BzOH/CsF (1.1 equiv), DMF, 50 °C,
(ii) 20% H2SO4/CH2Cl2 (1:1), 25 °C
DBU, THF, reflux
DBU, THF, reflux
NMe4OH (1.1 equiv), DMF, 25 °C
KOH (20 equiv), H2O, 50 °C
LiOHꢀH2O (1.1 equiv), MeOH/H2O (3:2), 25 °C
LiOHꢀH2O (10.0 equiv), MeOH/H2O (3:2), 25 °C
tBuOK (1.1 equiv), DMF, 50 °C
MeONa (1.1 equiv), DMF, 25 °C
MeONa (1.1 equiv), MeOH, 25 °C
MeONa (1.1 equiv), MeOH, 25 °C
BnONa (1.1 equiv), THF, 25 °C
(i) PhONa (1.1 equiv), DMF, 50 °C,
(ii) 20% H2SO4/CH2Cl2 (1:1), 25 °C
(i) PhONa (1.1 equiv), DMF, 50 °C,
(ii) 20% H2SO4/CH2Cl2 (1:1), 25 °C
pNO2–BzO–
(S)-2a/3a
2
(R)-1b
pNO2–BzOH/CsF
pNO2–BzO–
(S)-2b
99b
3b
4
5
6
7
8
9
10
11
12
13
14
(R)-1a
(R)-1b
(R)-1a
(R)-1a
(R)-1a
(R)-1a
(R)-1a
(R)-1a
(R)-1a
(R)-1b
(R)-1a
(R)-1a
—
—
—
—
—
—
—
—
—
—
—
—
—
PhO–
3a
3b
88b
80b
38/31
83
98
89c
31/63
38/31
62/38
93
NMe4OH
KOH
LiOH
3a/(R)-4a
(R)-4c
(R)-4a
LiOH
(R)-4c
tBuOK
MeONa
MeONa
MeONa
BnONa
PhONa
3a/(R)-4a
3a/(R)-4a
(R)-4a/(R)-4b
(R)-4b
(R)-4a
(S)-20a/3a/(R)-4a
96
47/25/28
15
(R)-1b
PhONa
PhO–
(S)-20b
94
a Yield determined after column chromatography.
b Yield of product obtained in Ref. 6a.
c Yield of product obtained in Ref. 6c.

G. Jime´nez-Ose´s et al. / Tetrahedron: Asymmetry 19 (2008) 443–449
445
derivatives to design a future regioselective synthesis. To
MeO2C
this end, the carbamate group of sulfamidates (R)-1a,b
could be deprotected with the NH function to give com-
pounds (R)-4a,b, respectively (Table 1, entries 7, 13 and
12). Moreover, the carbamate and amide groups of sulfam-
idate (R)-1a could be deprotected to give the unprotected
cyclic sulfamidate (R)-4c in a different way to that previ-
ously reported6c (Table 1, entries 6 and 8). To complete
the list of sulfamidate derivatives, we have converted the
amide group of (R)-1a into the carboxylic acid function,
without altering the carbamate group, using acid hydroly-
sis with aqueous H2SO4, to afford sulfamidate (R)-1c
(Scheme 1).
N
O
O
O
O
S
OMe
N
Me
Me
(R)-1a
KOH (20 equiv),
H2O, 50 ºC
83%
H
N
O
Ref. 6a
O
S
83%
(3 steps)
O
O
OH
Me
MeO2C
(R)-4c
H
N
Table 1,
entry 12
N
O
O
O
O
O
O
O
S
S
1. NaHCO3, H2O,
25 ºC, 2 h,
O
OMe
OMe
82%
2. 2 M HCl to pH 1,
3. propylene oxide,
EtOH, reflux, 2 h
Me
Me
(
R)-1b
(R)-4b
Ref. 6a
O
NH2
NH2
OH
Table 1,
entries
MeO2C
CO2H
Me
)-5
HO2C
Me
)-5
HO
H
N
7 and 13
N
O
O
O
O
(
R
(
S
O
S
S
(
OMe
OMe
O
RETENTION
PATHWAY
INVERSION
O
PATHWAY
N
N
Me
Me
(
R)-1a
R)-4a
Me
Me
Scheme 2. Stereodivergent synthesis of (S)- and (R)-a-methylisoserine.
Table 1,
entries
6 M H2SO4,
25 ºC, 48 h
94%
example, the required amino acid O-phenyl-a-methyliso-
serine (S)-6 was easily obtained as a hydrochloride salt
6 and 8
MeO2C
H
1. PhONa·3H2O,
N
O
N
MeO2C
CO2Me
HN
O
O
O
O
DMF, 50 ºC,
2. 20% H2SO4,
CH2Cl2,
S
S
N
O
O
O
O
O
O
O
S
OH
Me
OH
O
Me
R)-4c
25 ºC
(
(
R)-1c
OPh
OMe
Me
MeO
Me
94%
(R)-1b
Scheme 1. Chiral building blocks with cyclic sulfamidate skeleton.
(
S)-2'b
To show the synthetic application of the reactions of these
sulfamidates in basic medium and since a-methylisoserine
is an important b2,2-amino acid,12 whose (S)-isomer,
namely (S)-5, was previously obtained from sulfamidate
(R)-1a in three steps6a with an overall yield of 83%, we car-
ried out the hydrolysis of (R)-4c to give the a-methylisoser-
ine (R)-5 with an excellent yield. Therefore, and taking into
account that (R)-4c comes from sulfamidate (R)-1a (Table 1,
entries 6 and 8), we have developed an interesting stereodi-
vergent synthesis of enantiomerically pure (S)- and (R)-a-
methylisoserine starting from sulfamidate (R)-1a with a
methodology that involves the inversion or retention of
configuration at the quaternary stereocentres (Scheme 2).
Cl
12 M HCl,
reflux,
NH3
12 h
HO2C
OPh
94%
Me
(S)-6
Ph
1. AcCl, MeOH, reflux, 10 h,
H
(S)
(S)
2. (S)-N-(tosyl)phenylalanine
TsHN
acid chloride, DIEA,
CH2Cl2, 25 ºC, 14 h
O
HN
MeO2C
Me
91%
OPh
Moreover, in spite of the inconveniences of the basic
medium, the use of some O-nucleophiles was appropriate
to obtain O-substituted a-methylisoserine derivatives. For
7
Scheme 3. Synthesis of (S)-O-phenyl-a-methylisoserine.

446
G. Jime´nez-Ose´s et al. / Tetrahedron: Asymmetry 19 (2008) 443–449
by acid hydrolysis of (S)-20b (Scheme 3). The absolute con-
figuration of this new b2,2-amino acid was unambiguously
determined by their transformation into dipeptide 7, after
previous esterification with acetyl chloride in methanol
(Scheme 3). This chiral derivative 7 has two stereogenic
centres, whose absolute configurations were found to be
(S,S) by X-ray analysis13 of the corresponding monocrys-
tals (Fig. 2). Additionally, the 1H NMR study of 7
(focused on the methyl group of the tosyl substituent)
allowed us to determine the high enantiomeric purity
(ee > 93%) of b2,2-amino acid (S)-6.
4.2. Methyl (R)-5-hydroxycarbonyl-5-methyl-2,2-dioxo-2k6-
[1,2,3]oxathiazolidine-3-carboxylate (R)-1c
Sulfamidate (R)-1a (103 mg, 0.36 mmol) was suspended in
a 6 M aqueous H2SO4 solution (5 mL) and the mixture was
stirred at room temperature for 48 h. Then, H2O (5 mL)
and AcOEt (15 mL) were added and the phases were sepa-
rated. The corresponding aqueous phase was extracted
with AcOEt (3 ꢁ 15 mL). The combined organic phases
were dried over Na2SO4, and evaporated to give compound
(R)-1c (81 mg, 94%), as a colourless oil. Anal. Calcd for
C6H9NO7S: C, 30.13; H, 3.79; N, 5.86; S, 13.40. Found:
25
C, 30.24; H, 3.81; N, 5.88; S, 13.37. ½aꢂD ¼ ꢃ4:3 (c 1.30,
1
MeOH). ESI+ (m/z): 240.2. H NMR (400 MHz, CDCl3)
d
(ppm): 1.79 (s, 3H, CH3), 3.70–4.05 (m, 4H,
CH2N + CO2CH3), 4.51 (d, 1H, J = 10.5 Hz, CH2N),
8.01 (br s, 1H, CO2H). 13C NMR (100 MHz, CDCl3) d
(ppm): 22.7 (CH3), 53.0 (CH2N), 55.0 (CO2CH3), 83.5
(CCH3), 150.2 (NCO), 170.9 (CO2).
4.3. (S)-2-Methoxycarbonylaminomethyl-2-(p-nitrobenzoyl-
oxy)-N-methoxy-N-methylpropanamide (S)-2a
Figure 2. ORTEP3 representation of compound 7.
Sulfamidate (R)-1a (226 mg, 0.80 mmol), CsF (134 mg,
0.88 mmol), and p-nitrobenzoic acid (147 mg, 0.88 mmol)
were dissolved in DMF (5 mL) and the mixture was
heated at 50 °C for approx. 1 h, when the total disap-
pearance of starting material was observed by TLC or
GC–MS. After evaporating the solvent, the residue was
dissolved in a mixture of aqueous 20% H2SO4/CH2Cl2
(1:1, 10 mL) and it was stirred at room temperature for
10 h. Once the phases were separated, the aqueous phase
was extracted with AcOEt (3 ꢁ 15 mL), the combined
organic phases were dried (Na2SO4), and evaporated to give
a residue which was purified by silica gel column chroma-
tography (hexane/AcOEt, 4:6). In this way, compounds
(S)-2a (213 mg, 71%) and 3a (44 mg, 27%) were obtained
as colourless oils. Anal. Calcd for C15H19N3O8: C, 48.78;
3. Conclusions
An in-depth study on the reactions of ester or amide-de-
rived sulfamidates with O-nucleophiles in basic medium
has helped enhance the understanding of the reactivity of
these systems, with it now being possible to direct the
chemoselectivity of the reactions. The most important
conclusion is related to the development of a practical
method for the ring-opening reaction of hindered sulfami-
dates using O-nucleophiles, which occurs with the inversion
of configuration at the quaternary stereocentre, allowing
the synthesis of interesting b2,2-amino acid derivatives with
isoserine skeleton.
H, 5.19; N, 11.38. Found: C, 48.85; H, 5.01; N, 11.29.
25
½aꢂD ¼ ꢃ11:8 (c 0.94, MeOH). ESI+ (m/z): 370.3 + K.
1H NMR (300 MHz, CDCl3) d (ppm): 1.78 (s, 3 H,
CH3), 3.18 (s, 3H, NCH3), 3.62 (s, 6H, NOCH3 +
CO2CH3), 3.72–3.92 (m, 2H, CH2N), 5.38 (br s, 1H,
NH), 8.10–8.37 (m, 4H, Ph). 13C NMR (75 MHz, CDCl3)
d (ppm): 21.2 (CH3), 34.0 (NCH3), 47.1 (CH2N), 52.6
(CO2CH3), 61.2 (NOCH3), 83.4 (CCH3), 123.9, 131.2,
135.6, 150.9 (Ph), 157.7 (NCO), 164.0 (PhCO2), 171.5
(CON).
4. Experimental
4.1. General procedures
Melting points are uncorrected. All manipulations with air-
sensitive reagents were carried out under a dry argon atmo-
sphere using standard Schlenk techniques. Solvents were
purified according to standard procedures. The chemical
reagents were purchased from Aldrich Chemical Co. Ana-
lytical TLC was performed using Polychrom SI F254 plates.
Column chromatography was performed using Kieselgel 60
(230–400 mesh). Organic solutions were dried over anhy-
drous Na2SO4 and, when necessary, concentrated under
reduced pressure using a rotary evaporator. NMR spectra
were recorded at 300 or 400 MHz (1H) and at 75 or
100 MHz (13C) and signals are reported in ppm downfield
from TMS. The value of coupling constants (J) is reported
in Hertz. Mass spectra were obtained by electrospray ion-
ization (ESI). Optical rotations were measured on a polar-
imeter in an 1 dm cell of 1 mL capacity. Microanalyses
were in good agreement with the calculated values.
4.4. (R)-5-Methyl-5-(N-methoxy-N-methylcarbamoyl)-2,2-
dioxo-2k6-[1,2,3]oxathiazolidine (R)-4a
Method 1 (Table 1, entry 7): Sulfamidate (R)-1a (125 mg,
0.44 mmol) and LiOHꢀH2O (19 mg, 0.44 mmol) were dis-
solved in a mixture of MeOH/H2O (3:1, 10 mL). The
resulting solution was stirred at room temperature for
4 h. After evaporating the solvent, the residue was dis-
solved in CH2Cl2 (15 mL), the base was neutralized with
an aqueous 2 M HCl solution (10 mL) and the organic
phase separated. The aqueous phase was extracted with
CH2Cl2 (3 ꢁ 15 mL) and the combined organic phases
were dried over Na2SO4, and evaporated to give compound

G. Jime´nez-Ose´s et al. / Tetrahedron: Asymmetry 19 (2008) 443–449
447
25
(R)-4a (99 mg, 98%), as a colourless oil. Method 2 (Table 1,
entry 13): To a solution of sulfamidate (R)-1a (92 mg,
0.33 mmol) in THF (3 mL), a filtered solution of BnONa
in THF (0.40 M, 2.5 mL, 1.00 mmol) was added [this last
reagent was in situ prepared by reacting BnOH (204 lL,
1.98 mmol) with Na (57 mg, 2.48 mmol) in THF (5 mL)
under an inert atmosphere]. The resulting mixture was stir-
red at room temperature for 24 h. Then, Et2O (15 mL) was
added and the solution was neutralized with an aqueous
2 M HCl solution (10 mL). Once the organic phase was
separated, the aqueous phase was extracted with Et2O
(3 ꢁ 20 mL). The combined organic phases were dried over
Na2SO4, concentrated, and the residue was purified by a
silica gel column chromatography (hexane/AcOEt, 7:3),
to give compound (R)-4a (70 mg, 96%), as a colourless
oil. Anal. Calcd for C6H12N2O5S: C, 32.14; H, 5.39; N,
S, 17.75. ½aꢂD ¼ ꢃ8:0 (c 0.99, MeOH). Analytical data
are according to those described in the literature.6c
4.7. (S)-2-Methoxycarbonylaminomethyl-2-phenyloxy-N-
methoxy-N-methylpropanamide (S)-20a
Sulfamidate (R)-1a (162 mg, 0.57 mmol) and PhONaꢀ3H2O
(107 mg, 0.63 mg) were dissolved in DMF (5 mL) and the
mixture was heated at 50 °C for approx. 1 h, when the total
disappearance of starting material was observed by TLC or
GC–MS. After evaporating the solvent, the residue was
dissolved in a mixture of aqueous 20% H2SO4/CH2Cl2
(1:1, 10 mL) and it was stirred at room temperature for
10 h. Once the phases were separated, the aqueous phase
was extracted with AcOEt (3 ꢁ 15 mL), the combined or-
ganic phases were dried over Na2SO4, and evaporated to
give a residue which was purified by silica gel column chro-
matography (hexane/AcOEt, 6:4). In this way, compounds
(S)-20a (80 mg, 47%), 3a (29 mg, 25%) and (R)-4a (36 mg,
28%) were obtained as colourless oils. Anal. Calcd for
12.49; S, 14.30. Found: C, 32.26; H, 5.41; N, 12.52; S,
25
14.27. ½aꢂD ¼ ꢃ46:3 (c 1.04, CHCl3). ESI+ (m/z): 225.2.
1H NMR (300 MHz, CDCl3) d (ppm): 1.77 (s, 3H, CH3),
3.12–3.42 (m, 4H, CH2N + NCH3), 3.80 (s, 3H, NOCH3),
4.35–4.51 (m, 1H, CH2N), 5.01 (br s, 1H, NH). 13C NMR
(75 MHz, CDCl3) d (ppm): 21.8 (CH3), 33.7 (NCH3), 52.5
(CH2N), 61.7 (NOCH3), 90.7 (CCH3), 167.8 (CON).
C14H20N2O5: C, 56.75; H, 6.80; N, 9.45. Found: C, 56.92;
25
H, 6.82; N, 9.42. ½aꢂD ¼ ꢃ42:8 (c 1.03, CHCl3). ESI+
1
(m/z): 297.3. H NMR (300 MHz, CDCl3) d (ppm): 1.58
(s, 3H, CH3), 3.26–3.32 (m, 3H, NCH3), 3.51–3.89 (m,
8H, CH2N + NOCH3 + CO2CH3), 5.17–5.30 (m, 1H,
NH), 6.80–7.06 (m, 3H, Ph), 7.19–7.32 (m, 2H, Ph). 13C
NMR (75 MHz, CDCl3) d (ppm): 20.4, 20.5 (CH3), 38.3
(NCH3), 46.5 (CH2N), 52.2, 52.3 (CO2CH3), 60.4, 60.8
(NOCH3), 82.0, 82.2 (CCH3), 118.9, 122.5, 129.5, 154.8
(Ph), 157.3 (NCO), 173.7 (CON).
4.5. Methyl (R)-5-methyl-2,2-dioxo-2k6-[1,2,3]oxathiazoli-
dine-5-carboxylate (R)-4b
To a solution of sulfamidate (R)-1a (87 mg, 0.31 mmol) in
MeOH (10 mL), MeONa (33 mg, 0.62 mmol) was added
and the mixture was stirred at room temperature for
24 h. After evaporating the solvent, the residue was dis-
solved in CH2Cl2 (15 mL) and neutralized with an aqueous
2 M HCl solution (10 mL). Once the organic phase was
separated, the aqueous phase was extracted with CH2Cl2
(3 ꢁ 15 mL). The combined organic phases were dried over
Na2SO4, concentrated, and the residue was purified by a
silica gel column chromatography (hexane/AcOEt, 7:3),
to give compound (R)-4b (60 mg, 93%), as a colourless
oil. Anal. Calcd for C5H9NO5S: C, 30.77; H, 4.65; N,
4.8. Methyl (S)-2-methoxycarbonylaminomethyl-2-phenyl-
oxypropanoate (S)-20b
Following the same protocol described for compound (S)-
20a and starting from sulfamidate (R)-1b (114 mg,
0.45 mmol), compound (S)-20b (113 mg, 94%) was ob-
tained, after purification by a silica gel column chromato-
graphy (hexane/AcOEt, 7:3). Anal. Calcd for C13H17NO5:
C, 58.42; H, 6.41; N, 5.24. Found: C, 58.60; H, 6.39; N,
7.18; S, 16.43. Found: C, 30.89; H, 4.63; N, 7.16; S,
25
1
5.26. ½aꢂD ¼ ꢃ6:9 (c 1.88, CHCl3). ESI+ (m/z): 268.3. H
NMR (300 MHz, CDCl3) d (ppm): 1.49 (s, 3H, CH3),
3.53–3.88 (m, 8H, CH2N + CO2CH3 + CO2CH3), 5.30
(br s, 1H, NH), 6.77–6.92 (m, 2H, Ph), 6.93–7.07 (m, 1H,
Ph), 7.19–7.33 (m, 2H, Ph). 13C NMR (75 MHz, CDCl3)
d (ppm): 19.4 (CH3), 48.4 (CH2N), 52.2 (CO2CH3), 52.6
(CO2CH3), 81.0 (CCH3), 119.4, 122.7, 129.2, 154.5 (Ph),
157.2 (NCO), 172.6 (CO2).
25
16.45. ½aꢂD ¼ ꢃ24:4 (c 1.30, CHCl3). ESI+ (m/z): 196.2.
1H NMR (400 MHz, CDCl3) d (ppm): 1.75 (s, 3H, CH3),
3.44–3.58 (m, 1H, CH2N), 3.87 (s, 3H, CO2CH3), 3.94–
4.09 (m, 1H, CH2N), 4.91 (br s, 1H, NH). 13C NMR
(100 MHz, CDCl3) d (ppm): 22.5 (CH3), 52.1 (CH2N),
53.7 (CO2CH3), 88.0 (CCH3), 169.8 (CO2).
4.6. (R)-5-Methyl-2,2-dioxo-2k6-[1,2,3]oxathiazolidine-5-
carboxylic acid (R)-4c
4.9. (R)-2-Aminomethyl-2-hydroxypropanoic acid (R)-5
To a suspension of sulfamidate (R)-1a (87 mg, 0.31 mmol)
in H2O (10 mL), KOH (347 mg, 6.20 mmol) was added and
the mixture was stirred at 50 °C for 2 h. After evaporating
the solvent, the residue was dissolved in CH2Cl2 (15 mL)
and neutralized with an aqueous 2 M HCl solution
(10 mL). Once the organic phase was separated, the aque-
ous phase was extracted with CH2Cl2 (3 ꢁ 15 mL). The
combined organic phases were dried over Na2SO4, and
concentrated to give compound (R)-4c (47 mg, 83%), as a
white solid. Anal. Calcd for C4H7NO5S: C, 26.52; H,
3.89; N, 7.73; S, 17.70. Found: C, 26.69; H, 3.93; N, 7.79;
To a suspension of sulfamidate (R)-4c (106 mg, 0.58 mmol)
in H2O (3 mL), NaHCO3 (122 mg, 1.45 mmol) was added
and the mixture was stirred at room temperature for 2 h.
Then, an aqueous 2 M HCl solution was added until pH
1 and the resulting mixture was evaporated to obtain the
corresponding 2-methylisoserine amino acid as a hydro-
chloride salt. This salt was dissolved in ethanol/propylene
oxide (3:1, 2 mL) and the solution was refluxed for 2 h.
After that, 2-methylisoserine (R)-5 partially precipitated
as a white solid (22 mg), which was filtered and the filtrate
was evaporated, dissolved in H2O (2 mL), and eluted

448
G. Jime´nez-Ose´s et al. / Tetrahedron: Asymmetry 19 (2008) 443–449
through a reverse-phase Sep-pak C18 cartridge to obtain,
after evaporating the H2O, the corresponding amino acid
(R)-5 (35 mg) as a white solid (total amount: 57 mg,
4.11.2. Crystal data for compound 7. Molecular formula:
C27H30N2O6S, Mw = 510.61, colourless prism of 0.55 ꢁ
0.20 ꢁ 0.05 mm, T = 298 K, monoclinic, space group
˚ ˚
P21, Z = 2, a = 9.7005(6) A, b = 10.4209(7) A, c =
82%). Anal. Calcd for C4H9NO3: C, 40.33; H, 7.62; N,
25
3
13.3439(9) A, V = 1291.76(15) A , dcalcd = 1.313 g cmꢃꢃ31
,
,
˚
˚
11.76. Found: C, 40.26; H, 7.63; N, 11.72. ½aꢂD ¼ ꢃ2:6 (c
˚
1.01, H2O). Analytical data are in good agreement with
those described in the literature.6a
F(000) = 528, k = 0.71073 A (Mo Ka), l = 0.316 mm
Nonius kappa CCD diffractometer, h range 1.44–28.03°,
6240 collected reflections, 2993 unique, full-matrix least-
squares (SHELXL97), R1 = 0.0636, wR2 = 0.1861, (R1 =
0.0952, wR2 = 0.2470 all data), goodness of fit = 1.229,
4.10. (S)-2-Aminomethyl-2-phenyloxypropanoic acid hydro-
chloride (S)-6
ꢃ3
˚
residual electron density between 0.753 and ꢃ0.912 e A
.
Absolute structure parameter (Flack) 0.2(2). Hydrogen
atoms were located from mixed methods (electron-density
maps and theoretical positions). Further details on the
crystal structure are available on request from Cambridge
Crystallographic Data Centre, 12 Union Road, Cam-
bridge, UK on quoting the depository number CCDC
667615.
Compound (S)-20b (109 mg, 0.41 mmol) was suspended in
aqueous 12 M HCl (5 mL) and the mixture was refluxed
for 12 h. After that, the solvent was evaporated, and the
residue was dissolved in H2O (2 mL), and eluted through a
reverse-phase Sep-pak C18 cartridge to obtain, after evapo-
rating the H2O, the corresponding compound (S)-6
(89 mg, 94%) as
a white solid. Anal. Calcd for
C10H14ClNO3: C, 51.84; H, 6.09; N, 6.05. Found: C,
25
52.01; H, 6.12; N, 6.03. ½aꢂD ¼ ꢃ16:8 (c 1.38, H2O). ESI+
1
Acknowledgements
(m/z): 196.2. H NMR (300 MHz, D2O) d (ppm): 1.50 (s,
3H, CH3), 3.42–3.50 (m, 2H, CH2N), 6.91–7.04 (m,
2 H, Ph), 7.06–7.20 (m, 1H, Ph), 7.25–7.40 (m, 2H, Ph).
13C NMR (75 MHz, D2O) d (ppm): 21.6 (CH3), 48.2
(CH2N), 81.1 (CCH3), 122.6, 126.5, 132.2, 155.9 (Ph),
176.6 (CO2).
´
We thank the Ministerio de Educacion y Ciencia (project
CTQ2006-05825/BQU and Ramon y Cajal contract for
J.H.B.), and the Universidad de La Rioja (doctoral fellow-
ship of G.J.-O.).
4.11. (S)-N-(Tosyl)phenylalaninyl-(S)-O-phenyl-a-methyl-
isoserine methyl ester 7
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