One-pot conversion of serine and α-methylserine derivatives to the corresponding cysteines and selenocystines by using chalcogenophosphate reagents

Article abstract of DOI:10.1080/10426507.2010.485155

The one-pot reactions of N-acetylserine methyl ester and N-acetyl - methylserine methyl ester with Lawesson's or Woollins' reagent directly produced the corresponding cysteine or selenocysteine derivatives in moderate yields. The transformation would be initiated by phosphorylation of the hydroxy group, rather than chalcogenation of the amide group, and involve the oxazoline as a key intermediate. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.485155

This article was downloaded by: [Ondokuz Mayis Universitesine]
On: 10 November 2014, At: 13:06
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the
Related Elements
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/gpss20
One-Pot Conversion of Serine
and α-Methylserine Derivatives
to the Corresponding Cysteines
and Selenocystines by Using
Chalcogenophosphate Reagents
Akira Makiyama a , Itsuki Komatsu a , Michio Iwaoka a & Masanobu
Yatagai b
a Department of Chemistry, School of Science , Tokai University ,
Kanagawa, Japan
b AminoScience Laboratories , Ajinomoto Co., Inc. , Kanagawa,
Japan
Published online: 13 Jan 2011.
To cite this article: Akira Makiyama , Itsuki Komatsu , Michio Iwaoka & Masanobu Yatagai (2010)
One-Pot Conversion of Serine and α-Methylserine Derivatives to the Corresponding Cysteines and
Selenocystines by Using Chalcogenophosphate Reagents, Phosphorus, Sulfur, and Silicon and the
Related Elements, 186:1, 125-133, DOI: 10.1080/10426507.2010.485155
To link to this article: http://dx.doi.org/10.1080/10426507.2010.485155
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,

systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Phosphorus, Sulfur, and Silicon, 186:125–133, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.485155
ONE-POT CONVERSION OF SERINE AND
α-METHYLSERINE DERIVATIVES TO THE
CORRESPONDING CYSTEINES AND SELENOCYSTINES
BY USING CHALCOGENOPHOSPHATE REAGENTS
Akira Makiyama,1 Itsuki Komatsu,1 Michio Iwaoka,1
and Masanobu Yatagai2
1Department of Chemistry, School of Science, Tokai University, Kanagawa, Japan
2AminoScience Laboratories, Ajinomoto Co., Inc., Kanagawa, Japan
GRAPHICAL ABSTRACT
AcHN
HS
R
N
R
or
S
CO2Me
CO2Me
L. R.
(R = Me)
(R = H)
AcHN
HO
R
CO2Me
W. R.
AcHN
R
Se
CO2Me
2
(R = H, Me)
Abstract The one-pot reactions of N-acetylserine methyl ester and N-acetyl-α-methylserine
methyl ester with Lawesson’s or Woollins’ reagent directly produced the corresponding cysteine
or selenocysteine derivatives in moderate yields. The transformation would be initiated by
phosphorylation of the hydroxy group, rather than chalcogenation of the amide group, and
involve the oxazoline as a key intermediate.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Alcohols; amino acids; selenium; sulfur; thiols
Received 1 March 2010; accepted 7 April 2010.
We thank K. Izawa for valuable suggestions and discussion and K. Ebato for assistance in the synthesis of
Ser derivatives.
Address correspondence to Michio Iwaoka, Department of Chemistry, School of Science, Tokai University,
Kitakaname, Hiratsuka-shi, Kanagawa 259-1292, Japan. E-mail: miwaoka@tokai.ac.jp and Masanobu Yatagai,
AminoScience Laboratories, Ajinomoto Co., Inc., 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-
8681, Japan. E-mail: masanobu yatagai@ajinomoto.com
125

126
A. MAKIYAMA ET AL.
INTRODUCTION
Chalcogenophosphate reagents, Lawesson’s reagent (1)1 and Woollins’ reagent (2)2
(Chart 1), are unique organic reagents with the structure of (ArPX2)2 (1, Ar = p-MeOC6H4
and X = S; 2, Ar = Ph and X = Se), which specifically convert various carbonyl com-
pounds to the corresponding thiocarbonyl3 and selenocarbonyl4 compounds, respectively.
The reagents are also useful for the syntheses of thiols,5 sulfides,6 and selenophenes.7 These
synthetic utilities make the reagents very fascinating because the syntheses are sometimes
difficult when other reaction conditions are employed. In this article, we report another
useful application of 1 and 2 to a convenient one-pot transformation of N-acetylserine
methyl ester (3a) to cysteine (Cys) and selenocysteine (Sec) derivatives. The reaction con-
ditions were further extended to the synthesis of novel α-methylcysteine (MeCys) and
α-methylselenocysteine (MeSec) derivatives.
RESULTS AND DISCUSSION
L-Cys derivatives are usually prepared by chemical synthesis from L-serine (L-Ser)
by substitution of the β-hydroxy group with a sulfhydryl group through the activated inter-
mediates, such as O-sulfonates,8 β-halogenated alanines,9 and β-lactones,10 while in living
organisms L-Cys is derived from L-Ser by the O-acetylation and subsequent thiolation
with a sulfide anion (S2−) or by the sulfur-exchange reaction with L-methionine.11 On the
other hand, L-Sec, the 21st proteinogenic amino acid,12 is biologically synthesized from
L-Ser, which is bound to the Sec-tRNA, either by the direct selenolation with selenophos-
phate (HPO3Se2−) or by the sequential phosphorylation and selenolation.13 In organic
synthesis, L-Sec derivatives can be obtained from L-Ser in a few steps through the acti-
vation to halides, tosylates, β-lactones, oxazolines, or aziridines.14 Alternative strategies
starting from other natural amino acids have also been developed.15
In our research on the derivatization of Ser and the α-methyl alternate (MeSer),
which is a promising chiral building block16 and has been efficiently obtained by enzymatic
synthesis from alanine,17 we encountered a unique reaction between 3a and Lawesson’s
reagent (1) (Table 1).
When L-3a18 was reacted with an equimolar amount of 1 in refluxed dioxane for
16 h, N-acetyl cysteine methyl ester (4a) was directly obtained in up to 51% yield. The
yield was decreased by using a small amount of 1 with respect to 3a. In the reaction
mixture, only one major product, which must be converted to 4a in the workup process,
was observed other than the decomposed products of 1 when the reaction was monitored
by NMR in deuterated dioxane.
Product 4a was also obtained by using toluene as a solvent, although the yield was
decreased. In the meantime, complete racemization of 4a was detected, as confirmed by 1H
S
P
S
Se
MeO
S
P
S
P Se
Se P
OMe
Se
1
2
Chart 1

ONE-POT CONVERSION WITH CHALCOGENOPHOSPHATE REAGENTS
127
Table 1 One-pot conversion of serine derivatives 3a and 3b to the corresponding cysteine derivatives by using
Lawesson’s reagent (1)
N
AcHN
HO
R
AcHN
HS
R
1
R
+
S
solvent
CO2Me
CO2Me
CO2Me
3a R=H
3b R=Me
4a R=H
4b R=Me
5a R=H
5b R=Me
Reactant
1 (eq.)
Solvent
Conditions
4 (%)a
5 (%)a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
6a
6b
1.0
1.0
0.75
0.5
1.0
1.0
0.75
0.75
0.5
1.0
0.9
0.9
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
Dioxane
Dioxane
Reflux, 16 h
Reflux, 1.5 h
Reflux, 16 h
Reflux, 16 h
Reflux, 16 h
Reflux, 16 h
Reflux, 16 h
Reflux, 22 h
Reflux, 16 h
Reflux, 24 h
Reflux, 16 h
Reflux, 16 h
51
49
41
Trace
33
0
0
0
0
0
0
0
0
0
0
29
23
45
9
38
0
54
0
31
aIsolated yields.
NMR for the oxidized disulfide compound, probably due to the high reaction temperature
as well as the long reaction time. Product 4a could be quantitatively led to unprotected Cys
by the treatment in refluxed conc. HCl for 6 h.
Similar reaction conditions were subsequently applied for N-acetyl-α-methylserine
methyl ester (3b).19 In this case, however, N-acetyl-α-methylcysteine methyl ester (4b) was
not obtained. Instead, a thiazoline derivative 5b was obtained in up to 45% yield. Product
5b was deprotected to MeCys in good yields (∼80%) by reflux in conc. HCl for 16 h.
When the reaction conditions were further applied for O-acetylserine methyl esters
6a20 and 6b (Chart 2), 4a, and 5b were obtained, respectively. The reaction would go through
3a or 3b as an initial intermediate because the O-acetyl group of 6b easily migrated to
the amino group by the treatment with a base, such as NaHCO3, to produce 3b in 73%
yield.21
We subsequently employed Woollins’ reagent (2) for one-pot synthesis of Sec deriva-
tives from 3a and 3b (Table 2). L-3a was treated with an equimolar amount of 2 in refluxed
benzene for 16 h to give N,Nꢀ-diacetylselenocystine dimethyl ester (7a) in 25% yield. The
HCl
H2N
R
AcO
CO2Me
6a R=H
6b R=Me
Chart 2

128
A. MAKIYAMA ET AL.
yield was increased up to 36% when 0.75 mol equivalent of 2 was employed. In this re-
action, the primary product would be a selenol (-SeH) but oxidized to the diselenide (7a)
during the workup process. Partial racemization of 7a was again observed in the 1H NMR
spectrum, which indicated that the diastereomeric excess (d.e.) of 7a was 24%. Dioxane
was also a good solvent. When 3b was used instead of 3a, diselenide 7b was obtained in
45% yield with a small amount of selenazoline 8b (3%). The yield of 8b was increased to
12% in refluxed toluene, while the yield of 7b was decreased to 40%. Major products 7a
and 7b could be quantitatively hydrolyzed to unprotected Sec22 and MeSec, respectively,
in refluxed conc. HCl for 1–2 h.
As to the mechanism for the conversion of 3 to a cysteine derivative 4 and a se-
lenocystine derivative 7 by chalcogenophosphate reagents 1 and 2, it should be noted that
4a and 7a were not obtained from 3a when the acetyl group was replaced by Z, Boc, or
Fmoc group. This suggested that the N-acetyl group is essential for the conversion. Fur-
thermore, oxazolines 9a23 (R = H) and 9b (R = Me), which correspond to the dehydrated
products of 3a and 3b, also produced 4a (43%) but not 5a (0%), and 5b (37%) but not 4b
(0%), respectively, by the treatment with 1 under the similar reaction conditions to Table 1
(Scheme 1). The transformation reaction from oxazolines to Sec derivatives by using a
selenolate reagent was reported previously.24
N
N
1
AcHN
HS
R
R
R
+
O
S
dioxane
CO2Me
CO2Me
CO2Me
4a R=H (43%)
4b R=Me (0%)
5a R=H (0%)
5b R=Me (37%)
9a R=H
9b R=Me
Scheme 1 The reaction of oxazolines 9a and 9b with Lawesson’s reagent (1).
Considering these observations, we proposed the reaction mechanism for the reaction
of 3 with 1 (Scheme 2). First, the hydroxy group of 3 reacts with ArPS2, one-half of Lawes-
son’s reagent (1), to form a phosphorylated product (A).25 Second, intermediate A cyclizes
to oxazoline 9 when R = H or react with another ArPS2 to produce the corresponding
thioamide and then thiazoline 5b when R = Me.26 Third, oxazoline 9 reacts with ArPS2
to yield adduct B, which is finally hydrolyzed in the workup process to a Cys derivative.
When R = Me, B would be converted to thiazoline 5b via a thioamide derivative. A similar
mechanism can be drawn for the reaction of 3 with Woollins’ reagent (2), but the paths to
selenazoline 8 must be significantly narrow.
The alternative path, in which the chalcogenophosphate reagents first react with
the amide group of 3 to give thio- or selenoamide and the subsequent cyclization takes
place to form thiazoline or selenazoline as an intermediate, may be possible. However, as
Lawesson’s reagent (1) is more reactive toward a hydroxy group than toward a carbonyl
group,27 the path through A and B would be more feasible.
The transformation of Ser derivatives to the Cys or Sec derivatives by using 1 or 2
reported here has several implications. First, the transformation would be the first example
of convenient one-pot organic synthesis of Cys and Sec derivatives from Ser derivatives.
Second, the reaction can be considered as an analog to the Cys and Sec biosyntheses.11,13 It
must be possible that a dehydrated intermediate such as oxazoline 9 also intervene in their
biological schemes.28 Third, artificial transformation of the Ser residue at the active site of

ONE-POT CONVERSION WITH CHALCOGENOPHOSPHATE REAGENTS
129
S
Ar
S
Ar
P
S
Ar
P
S
HS
P
S
OH
O
O
R
R
R
O
O
(R=H)
MeO2C
MeO2C
MeO2C
N
N
N
H
Me
H
Me
Me
9
3
A
ArPS2
H+
(R=Me)
Ar
(P)
(P)
HS
ArPS2
P
S
S
S
R
R
(R=Me)
O
S
O
R
MeO2C
MeO2C
S
N
N
MeO2C
N
H
Me
H
Me
H
Me
B
H2O
SH
R
R
S
O
MeO2C
MeO2C
N
N
Me
H
Me
5
4
Scheme 2 A plausible mechanism for the reaction between 3 and Lawesson’s reagent (1).
serine protease subtilisin to Cys and Sec was previously reported.29 In this transformation,
the hydroxy group was initially activated to the sulfonate. The present study suggested that
the activation to phosphates is another possibility to obtain such artificial enzymes. Fourth,
the MeCys and MeSec derivatives obtained are of interest in the applications to molecular
design of antitumor and anti-HIV agents.30
CONCLUSION
Lawesson’s and Woollins’ reagents (1 and 2) have been successfully applied to one-
pot conversion of Ser and MeSer derivatives to the corresponding Cys and Sec derivatives
in moderate yields (Tables 1 and 2). However, since the reaction was carried out under
rigorous conditions, racemization at the α-carbon atom was detected in the case of the Ser
derivative. It was further suggested that the transformation likely goes through the oxazoline
intermediate as shown in Scheme 2. Milder reaction conditions, which would suppress the
racemization, are now being sought in our laboratories.

130
A. MAKIYAMA ET AL.
Table 2 One-pot conversion of serine derivatives 3a and 3b to the corresponding selenocysteine derivatives by
using Woollins’ reagent (2)
N
AcHN
HO
R
AcHN
Se
R
2
R
+
Se
solvent
2
CO2Me
CO2Me
CO2Me
3a R=H
3b R=Me
7a R=H
7b R=Me
8a R=H
8b R=Me
7 (%)a
Reactant
2 (eq.)
Solvent
Conditions
8 (%)a
3a
3a
3a
3a
3b
3b
3b
1.0
0.75
0.5
Benzene
Benzene
Benzene
Dioxane
Benzene
Dioxane
Toluene
Reflux, 16 h
Reflux, 16 h
Reflux, 16 h
Reflux, 16 h
Reflux, 24 h
Reflux, 24 h
Reflux, 24 h
25
36
29
26
45
36
40
0
0
0
0
3
0.5
0.75
0.75
0.75
1
12
aIsolated yields.
EXPERIMENTAL
Commercially available organic and inorganic reagents were used without further
purification. L-Serine was purchased from Wako Pure Chemical Industries, Ltd. DL-
α-methylserine, Lawesson’s reagent, and Woollins’ reagent were obtained from Sigma-
1
Aldrich, Inc. H (500 MHz), 13C (125.8 MHz), and 77Se (95.4 MHz) NMR spectra were
measured at 298 K on a Bruker AV500 NMR spectrometer. Gel permeation chromatog-
raphy was performed on a JAI LC-918 HPLC system. High resolution mass spectra were
recorded on a JEOL JMS-T100LP mass spectrometer.
Synthesis of N-Acetylcysteine Methyl Ester (4a)31
L-3a18 (20.5 mg, 0.13 mmol) and Lawesson’s reagent 1 (52 mg, 0.13 mmol) were
added in 1,4-dioxane (1.5 mL). After refluxing for 16 h under nitrogen, the mixture was
diluted with water and extracted with EtOAc. The organic extract was washed with brine,
dried over MgSO4, and concentrated under vacuum. The residue was purified by gel
permeation chromatography (CHCl3) to give a racemic mixture of 4a as a white solid (11.5
mg, 51%).
1H NMR (500 MHz, CDCl3) δ 1.33 (t, J = 9.0 Hz, 1H), 2.07 (s, 3H), 3.02 (m, 2H),
3.80 (s, 3H), 4.89 (m, 1H), 6.36 (s, 1H); 13C NMR (125.8 MHz, CDCl3) δ 23.2, 26.9, 52.9,
53.5, 169.8, 170.6.
Synthesis of 2,4-Dimethyl-4-methoxycarbonylthiazoline (5b)
A racemic mixture of 3b19 (21.0 mg, 0.12 mmol) and 1 (37 mg, 0.09 mmol) were
added in 1,4-dioxane (1.5 mL). After refluxing for 22 h under nitrogen, the mixture was
diluted with water and extracted with EtOAc. The organic extract was washed with brine,
dried over MgSO4, and concentrated under vacuum. The residue was purified by gel

ONE-POT CONVERSION WITH CHALCOGENOPHOSPHATE REAGENTS
131
permeation chromatography (CHCl3) to give a racemic mixture of 5b as a colorless oil
(9.3 mg, 45%).
1H NMR (500 MHz, CDCl3) δ 1.53 (s, 3H), 2.24 (s, 3H), 3.18 (d, J = 11.4 Hz, 1H),
3.79 (s, 3H), 3.82 (d, J = 11.4 Hz, 1H); 13C NMR (125.8 MHz, CDCl3) δ 20.4, 24.1, 42.6,
52.9, 84.3, 167.5, 173.9; HRMS (APCI-TOF) m/z: calcd for C7H12NO2S 174.0589 [M +
1], found 174.0604 [M + 1].
Synthesis of O-Acethyl-α-methylserine Methyl Ester Hydrochloride (6b)
To a solution of racemic α-methylserine methyl ester hydrochloride32 (0.150 g, 0.88
mmol) in AcOH (3 mL), Ac2O (0.35 mL, 3.7 mmol) was added. After stirring at r.t. for
24 h, the solvent was evaporated under vacuum to give a racemic mixture of 6b as a white
solid (0.185 g, 98%).
Mp: 127–131◦C; 1H NMR (500 MHz, CDCl3) δ 1.74 (s, 3H), 2.15 (s, 3H), 3.84 (s,
3H), 4.43 (d, J = 11.8 Hz, 1H), 4.50 (d, J = 11.8 Hz, 1H), 9.19 (s, 3H); 13C NMR (125.8
MHz, CDCl3) δ 18.8, 20.8, 53.8, 59.9, 65.6, 169.2, 170.2; HRMS (APCI-TOF) m/z: calcd
for C7H14NO4 176.0923 [M + 1], found 176.0910 [M + 1].
Synthesis of N,N ꢁ-Diacetylselenocystine Dimethyl Ester (7a)
L-3a18 (19.3 mg, 0.12 mmol) and Woollins’ reagent 2 (47 mg, 0.09 mmol) were
added in benzene (2 mL). After refluxing for 16 h under nitrogen, the mixture was diluted
with water and extracted with EtOAc. The organic extract was washed with brine, dried
over MgSO4, and concentrated under vacuum. The residue was purified by gel permeation
chromatography (CHCl3) to give a diastereomeric mixture of 7a as a yellow oil (9.5 mg,
36%).
1H NMR (500 MHz, CDCl3) δ 2.06 (s, 3H), 2.07 (s, 3H), 3.43 (m, 4H), 3.77 (s, 6H),
4.91 (m, 2H), 6.49 (d, J = 7.0 Hz, 1H), 6.55 (d, J = 6.7 Hz, 1H); 13C NMR (125.8 MHz,
CDCl3) δ 23.2, 31.7, 31.8, 52.6, 52.8, 170.0, 170.2, 171.0, 171.1; 77Se NMR (95.4 MHz,
CDCl3) δ 292.9, 295.0; HRMS (APCI-TOF) m/z: calcd for C12H21N2O680Se2 448.9730
[M + 1], found 448.9792 [M + 1].
Reaction of 3b with 2
A racemic mixture of 3b19 (23.4 mg, 0.13 mmol) and 2 (53 mg, 0.10 mmol) were
added in toluene (1.5 mL). After refluxing for 24 h under nitrogen, the mixture was diluted
with water and extracted with EtOAc. The organic extract was washed with brine, dried
over MgSO4, and concentrated under vacuum. The residue was purified by gel permeation
chromatography (CHCl3) to give a diastereomeric mixture of 7b as a slightly yellow solid
(12.6 mg, 40%) and a racemic mixture of 8b as a slightly yellow oil (3.4 mg, 12%).
N,N ꢁ-Diacetyl-α,αꢁ-dimethylselenocystine dimethyl ester (7b). Mp:
1
184–185◦C; H NMR (500 MHz, CDCl3) δ 1.63 (s, 3H), 1.63 (s, 3H), 2.02 (s, 3H), 2.02
(s, 3H), 3.48 (d, J = 13.1 Hz, 1H), 3.52 (d, J = 13.0 Hz, 1H), 3.77 (s, 6H), 3.88 (d, J =
13.0 Hz, 1H), 3.94 (d, J = 13.0 Hz, 1H), 6.57 (s, 1H), 6.60 (s, 1H); 13C NMR (125.8 MHz,
CDCl3) δ 23.7, 23.8, 23.9, 23.9, 36.5, 53.0, 60.8, 60.8, 170.0, 170.1, 173.3, 173.3; 77Se
NMR (95.4 MHz, CDCl3) δ 293.7; HRMS (APCI-TOF) m/z: calcd for C14H25N2O680Se2
477.0046 [M + 1], found 477.0095 [M + 1].

132
A. MAKIYAMA ET AL.
1
2,4-Dimethyl-4-methoxycarbonylselenazoline (8b). H NMR (500 MHz,
CDCl3) δ 1.55 (s, 3H), 2.33 (s, 3H), 3.38 (d, J = 10.6 Hz, 1H), 3.79 (s, 3H), 3.98 (d, J =
10.6 Hz, 1H); 13C NMR (125.8 MHz, CDCl3) δ 23.6, 24.0, 39.1, 52.9, 86.4, 164.7, 173.7;
77Se NMR (95.4 MHz, CDCl3) δ 494.8; HRMS (APCI-TOF) m/z: calcd for C7H12NO280Se
222.0033 [M + 1], found 222.0056 [M + 1].
Synthesis of α,αꢁ-Dimethylselenocystine Dihydrochloride
A diastereomeric mixture of 7b (18.1 mg, 0.04 mmol) was dissolved in concentrated
HCl (1.5 mL). After refluxing for 2 h, the mixture was lyophilized to give a diastereomeric
mixture of α,αꢀ-dimethylselenocystine dihydrochloride as a yellow solid (16.7 mg, quant.).
1H NMR (500 MHz, 1M HCl-D2O) δ 1.33 (s, 6H), 3.15 (d, J = 14.3 Hz, 1H), 3.20
(d, J = 14.3 Hz, 1H), 3.37 (d, J = 14.4 Hz, 1H), 3.41 (d, J = 14.4 Hz, 1H); 13C NMR
(125.8 MHz, 1M HCl-D2O) δ 22.1, 35.2, 60.5, 172.1; 77Se NMR (95.4 MHz, 1M HCl-D2O)
δ 302.9, 304.1; HRMS (APCI-TOF) m/z: calcd for C8H17N2O480Se2 364.9521 [M + 1],
found 364.9592 [M + 1].
Synthesis of 2,4-Dimethyl-4-methoxycarbonyloxazoline (9b)
To a suspension of racemic α-methylserine methyl ester hydrochloride (60.0 mg,
0.35 mmol) and Et3N (75 µL, 0.54 mmol) in CH2Cl2 (5 mL), methyl acetimidate hy-
drochloride (94 mg, 0.86 mmol) were added at 0◦C. After refluxing for 19.5 h, the mixture
was diluted with water and extracted with CH2Cl2. The organic extract was washed with
brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by gel
permeation chromatography (CHCl3) to give a racemic mixture of 9b as a colorless oil
(41.5 mg, 75%).
1H NMR (500 MHz, CDCl3) δ 1.49 (s, 3H), 2.00 (s, 3H), 3.76 (s, 3H), 3.97 (d, J =
8.7 Hz, 1H), 4.61 (d, J = 8.8 Hz, 1H); 13C NMR (125.8 MHz, CDCl3) δ 14.0, 25.3, 52.7,
74.0, 75.9, 166.1, 173.9; HRMS (APCI-TOF) m/z: calcd for C7H12NO3 158.0817 [M + 1],
found 158.0796 [M + 1].
REFERENCES
1. Pedersen, B. S.; Scheibye, S.; Nilsson, N. H.; Lawesson, S. O. Bull. Soc. Chim. Belg. 1978, 87,
223.
2. (a) Wood, P. T.; Woollins, J. D. J. Chem. Soc., Chem. Commun. 1988, 1190; (b) Gray, I. P.;
Bhattacharyya, P.; Slawin, A. M. Z.; Woollins, J. D. Chem. Eur. J. 2005, 11, 6221; (c) Hua, G.;
Woollins, J. D. Angew. Chem. Int. Ed. 2009, 48, 1368.
3. Ozturk, T.; Ertas, E.; Mert, O. Chem. Rev. 2007, 107, 5210, and the references cited therein.
4. (a) Bhattacharyya, P.; Woollins, J. D.; Tetrahedron Lett. 2001, 42, 5949; (b) Baxter, I.; Hill,
A. F.; Malget, J. M.; White, A. J. P.; Williams, D. J. Chem. Commun. 1997, 2049.
5. (a) Nishio, T. J. Chem. Soc., Chem. Commun. 1989, 205; (b) Nishio, T. J. Chem. Soc., Perkin
Trans. 1 1993, 1113; (c) Nishio, T. Tetrahedron Lett. 1995, 36, 6113; (d) Nishio, T. J. Org.
Chem. 1997, 62, 1106.
6. (a) Bartsch, H.; Erker, T. Tetrahedron Lett. 1992, 33, 199; (b) Tewari, N.; Kumar, Y.; Thaper,
R. K.; Khanna, J. M. Synth. Commun. 1996, 26, 1169; (c) Bates, D. K.; Li, X.; Jog, P. V. J. Org.
Chem. 2004, 69, 2750.
7. Mohanakrishnan, A. K.; Amaladass, P. Tetrahedron Lett. 2005, 46, 7201.
8. Bhatia, S. K.; Hajdu, J. Tetrahedron Lett. 1988, 29, 31.

ONE-POT CONVERSION WITH CHALCOGENOPHOSPHATE REAGENTS
133
9. (a) Kedrowski, B. L.; Heathcock, C. H. Heterocycles 2002, 58, 601; (b) Nagasawa, T.; Hosono,
H.; Yamano, H.; Ohkishi, H.; Tani, Y.; Yamada, H. Agric. Biol. Chem. 1983, 47, 861.
10. Arnold, L. D.; May, R. G.; Vederas, J. C. J. Am. Chem. Soc. 1988, 110, 2237.
11. Nelson, D. L.; Cox, M. M. Lehninger Principles of Biochemistry, 4th ed.; W. H. Freeman and
Company: New York, 2005; Chap. 22.
12. Bo¨ck, A.; Forchhammer, K.; Heider, J.; Leinfelder, W.; Sawers, G.; Veprek, B.; Zinoni, F. Mol.
Microbiol. 1991, 5, 515.
13. (a) Yuan, J.; Palioura, S.; Salazar, J. C.; Su, D.; O’Donoghue, P.; Hohn, M. J.; Cardoso, A. M.;
Whitman, W. B.; So¨ll, D. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 18923; (b) Itoh, Y.; Sekine,
S.; Matsumoto, E.; Akasaka, R.; Takemoto, C.; Shirouzu, M.; Yokoyama, S. J. Mol. Biol. 2009,
385, 1456.
14. Iwaoka, M.; Ooka, R.; Nakazato, T.; Yoshida, S.; Oishi, S. Chem. Biodivers. 2008, 5, 359.
15. (a) Barton, D. H. R.; Bridon, D.; Herve, Y.; Potier, P.; Thierry, J.; Zard, S. Z. Tetrahedron 1986,
42, 4983; (b) Reich, H. J.; Jasperse, C. P.; Renga, J. M. J. Org. Chem. 1986, 51, 2981; (c) Iwaoka,
M.; Haraki, C.; Ooka, R.; Miyamoto, M.; Sugiyama, A.; Kohara, Y.; Isozumi, N. Tetrahedron
Lett. 2006, 47, 3861.
16. (a) Avdillo, C.; Jime´nez-Ose´s, G.; Busto, J. H.; Peregrina, J. M.; Zurbano, M. M.; Avenoza, A.
Chem. Eur. J. 2007, 13, 4840; (b) Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetrahedron: Asymmetry
2007, 18, 569; (c) Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005, 24, 5127.
17. (a) Nozaki, H.; Kuroda, S.; Watanabe, K.; Yokozeki, K. J. Mol. Cat. B: Enzym. 2009, 59, 237;
(b) Nozaki, H.; Kuroda, S.; Watanabe, K.; Yokozeki, K. J. Mol. Cat. B: Enzym. 2009, 56, 221;
(c) Nozaki, H.; Kuroda, S.; Watanabe, K.; Yokozeki, K. Appl. Environ. Microbiol. 2008, 74,
7596; (d) Nozaki, H.; Kuroda, S.; Watanabe, K.; Yokozeki, K. Biosci. Biotech. Biochem. 2008,
72, 3002; (e) Nozaki, H.; Kuroda, S.; Watanabe, K.; Yokozeki, K. Biosci. Biotech. Biochem.
2008, 72, 2580; (f) Yatagai, M.; Hamada, T.; Nozaki, H.; Kuroda, S.; Yokozeki, K.; Izawa,
K. In Asymmetric Synthesis and Application of α-Amino Acids; ACS Symposium Series 1009;
American Chemical Society: Washington, DC, 2009; Chap. 24, pp. 394.
18. Cardillo, G.; Gentilucci, L.; Gianotti, M.; Tolomelli, A. Tetrahedron 2001, 57, 2807.
19. Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J. M.; Sucunza, D.; Zurbano, M. M. Tetrahe-
dron: Asymmetry 2001, 12, 949.
20. Myers, M. C.; Wang, J. L.; Iera, J. A.; Bang, J.; Hara, T.; Saito, S.; Zambetti, G. P.; Appella, D.
H. J. Am. Chem. Soc. 2005, 127, 6152.
21. Similar reactions were reported by Kiso’s group: Sohma, Y.; Sasaki, M.; Hayashi, Y.; Kimura,
T.; Kiso, Y. Chem. Commun. 2004, 124.
22. Mishra, B.; Kumbhare, B. L.; Jain, K. V.; Priyadarsini, I. K. J. Phys. Chem. B 2008, 112, 4441.
23. Lafontaine, J. A.; Provencal, D. P.; Gardelli, C.; Leahy, J. W. J. Org. Chem. 2003, 68, 4215.
24. Braga, A. L.; Vargas, F.; Sehnem, J. A.; Braga, R. C. J. Org. Chem. 2005, 70, 9021.
25. Shabana, R.; Osman, F. H.; Atrees, S. S. Tetrahedron 1993, 49, 1271.
26. (a) Similar cyclization was reported previously: (a)Nishio, T.; Konno, Y.; Ori, M.; Sakamoto, M.
Eur. J. Org. Chem. 2001, 3553; (b) Kodama, Y.; Ori, M.; Nishio, T. Helv. Chim. Acta 2005, 88,
187.
27. Ori, M.; Nishio, T. Heterocycles 2000, 52, 111.
28. In humans, intervention of a dehydroalanine intermediate is proposed in the transformation from
Ser to Sec on the Sec-tRNA: Palioura, S.; Sherrer, R. L.; Steitz, T. A.; So¨ll, D.; Simonovic´, M.
Science 2009, 325, 321.
29. Wu, P. Z.; Hilvert, D. J. Am. Chem. Soc. 1989, 111, 4513.
30. (a) Pattenden, G.; Thom, S. M.; Jones, M. F. Tetrahedron 1993, 49, 2131; (b) Bergeron, R. J.;
Wiegand, J.; McManis, J. S.; Bharti, N. J. Med. Chem. 2006, 49, 7032.
31. Lin, Y. A.; Chalker, J. M.; Floyd, N.; Bernardes, G. J.; Davis, B. G. J. Am. Chem. Soc. 2008,
130, 9642.
32. Easton, C. J.; Ivory, A. J.; Smith, C. A. J. Chem. Soc., Perkin Trans. 2 1997, 503.