Rearrangement of oxazolidinethiones to thiazolidinediones or thiazinanediones and their application for the synthesis of chiral allylic ureas and α-methyl-β-amino acids

Article abstract of DOI:10.1016/j.tet.2009.11.035

A novel rearrangement has been found between oxazolidinethiones and acyl halides under N-acylation reaction conditions to afford N-substituted 2,4-thiazolidinediones and N-substituted 1,3-thiazinane-2,4-diones. These heterocycles were used for the synthesis of chiral allylic ureas and α-methyl-β-amino acids.

Full text of DOI:10.1016/j.tet.2009.11.035

Tetrahedron 66 (2010) 111–120
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Rearrangement of oxazolidinethiones to thiazolidinediones or thiazinanediones
and their application for the synthesis of chiral allylic ureas
and
a-methyl-b-amino acids
a
a
b
a
c
´
´
`
Rocio Sabala , Jacqueline Hernandez , Vladimir Carranza , Rosa L. Meza-Leon , Sylvain Bernes ,
Estibaliz Sansinenea b, Aurelio Ortiz a
,
*
a
´
´
´
Facultad de Ciencias Quımicas, de la Benemerita Universidad Autonoma de Puebla, 72570 Puebla, Pue., Mexico
b Instituto de Ciencias, de la Beneme´rita Universidad Auto´noma de Puebla, 72570 Puebla, Pue., Mexico
c Facultad de Ciencias Qu´ımicas, Universidad Auto´noma de Nuevo Leo´n, Monterrey, N.L. 64570, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel rearrangement has been found between oxazolidinethiones and acyl halides under N-acylation
Received 2 October 2009
Received in revised form
4 November 2009
Accepted 5 November 2009
Available online 10 November 2009
reaction conditions to afford N-substituted 2,4-thiazolidinediones and N-substituted 1,3-thiazinane-2,4-
diones. These heterocycles were used for the synthesis of chiral allylic ureas and
a-methyl-b-amino acids.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Chiral oxazolidinethiones have been widely used as chiral
auxiliaries in the asymmetric synthesis of complex natural prod-
ucts. The preparation and applications of chiral oxazolidinethiones
in asymmetric synthesis have been covered in previous reviews.1 A
new series of reactions have been recently described employing
chiral oxazolidinethiones such as the asymmetric intramolecular
We now report that the reaction described above proved to be
successful for five- and six-membered rings’ formation, giving good
yields of 2,4-thiazolidinediones (2a–d), 1,3-thiazinane-2,4-diones
(3a–d), and 5-methylthiazolidine-2,4-diones (4a–d) and their ap-
plication to yield chiral ureas and
shown in Scheme 1.
a
-methyl-
b
-amino acids, as
sulfur transfer reaction carried out on di-, tri-substituted
saturated N-enoyl oxazolidinethiones, and -disubstituted N-
enoyl oxazolidinethiones to afford chiral -sulfanyl carboxylic acid
-sulfanyl alcohols,2 3-methylthioalcohols,3
-di-
-sulfanyl carboxylic esters, and 1,3-hydroxythiols,4
a,b-un-
S
b,b
b
O
NH
R2
R1
1a R1 = Pr R2 = H
derivatives,
substituted
b
b
b,b
i
with high degrees of stereocontrol. Two tandem Michael-aldol re-
actions were described also, carried out on N-enoyl oxazolidine-
thiones to afford unusual heterotricyclic compounds5 and 3-
sulfanylpropanols6 both with three consecutive chiral centers. Most
significant, N-enoyl oxazolidinethiones can be arranged to N-
substituted 1,3-thiazinane-2,4-diones with one or two new chiral
centers.7
1b R1 = H R2 = Ph
1c R1 = Me R2 = H
1d R1 = Bn R2 = H
O
S
O
O
R2
R1
R2
R1
R2
N
N
S
R1
N
S
We had previously described an interesting reaction observed
during the attempted attachment of oxazolidinethiones to bro-
moacetyl bromide, under N-acyl reaction conditions, to provide
five-membered ring heterocycles of N-substituted 2,4-thiazolidi-
nediones8 type.
O
O
2a-d
O
4a-d
3a-d
Boc
R1
NH
O
O
OH
R1
N
N
H
R2
H
16
5
* Corresponding author. Tel.: þ52 222 2295500x7518; fax: þ52 222 2295584.
E-mail address: jaortizm@siu.buap.mx (A. Ortiz).
Scheme 1. Versatility of the oxazolidinethiones.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.035

112
R. Sabala et al. / Tetrahedron 66 (2010) 111–120
Table 2
Four chiral auxiliaries of oxazolidinethione (1a–d) type were
easily prepared from their corresponding -amino acids through
a series of transformations described by Davies.9 The condensation
of their respective -amino alcohols with CS2 in an aqueous solu-
tion of Na2CO3 furnished compounds (1a–d) in good yields as
shown in Figure 1. Furthermore, the physical and spectroscopic
characterizations for compounds 1a–c were completed. Compound
1d had been previously described.10
Conversion of oxazolidinethiones to 1,3-thiazinane-2,4-diones
a
Entry
Product
R1
R2
Yielda (%)
[a
]
(c)b
25
D
iPr
H
Me
Bn
H
Ph
H
70.0
78.0
23.0
53.0
ꢁ122.0 (1.08)
ꢁ6.0 (0.9)
b
1
2
3
4
3a
3b
3c
3d
ꢁ89.5 (1.41)
ꢁ162.1 (1.7)
H
a
Purified yield.
Determined in CHCl3 at 25 ꢀC.
b
S
S
S
S
O
NH
Bn
O
NH
O
NH
Ph
O
NH
5-Methyl-2,4-thiazolidinethiones (4a–d) were obtained as di-
astereomeric mixtures by reaction of oxazolidinethiones (1a–d)
with an excess of racemic 2-bromopropionyl bromide under N-acyl
reaction conditions. The diastereomeric mixture was formed be-
cause the structure of compounds (4a–d) has an asymmetric center
at the C-5 position in the thiazolidine ring. We were however un-
able to separate these diastereomeric mixtures by column chro-
matography. A rapid analysis of the 1H NMR spectra showed signals
for a single diastereomer only, however, an analysis by HPLC
showed that the diastereomeric ratios for compounds 4a–d were
50/50 (Scheme 4, Table 3).
1a
1b
1c
1d
a-amino acids.
Figure 1. Oxazolidinethione derivatives from
Oxazolidinethiones (1a–d) were treated with NaH in CH2Cl2
followed by dropwise addition of bromoacetyl bromide at 0 ꢀC to
afford the N-substituted 2,4-thiazolidinediones (2a–d) in moderate
yields (40–67%). In all cases, the thiazolidinediones (2a–d) were
dense liquids. The presence of disubstituted terminal olefins was
confirmed by 1H and 13C NMR spectroscopy. Further, the presence
of isopropyl group in oxazolidinethione 1a has a significant in-
fluence on the reaction outcome. The thiazolidinedione 2a was
achieved with the best yield and it was easily purified, as shown in
Scheme 2 and Table 1.
S
O
O
i
R2
R1
R2
R1
O
NH
R2
N
S
+
N
S
O
R1
O
1a-d
4a-d
S
O
Scheme 4. (i) NaH, 0 ꢀC, CH2Cl2, BrCOCH3CHBr.
i
R2
R1
O
NH
R2
N
S
R1
O
Table 3
Conversion of oxazolidinethiones to 5-methyl-2,4-thiazolidinediones
2a-d
1a-d
Scheme 2. (i) NaH, 0 ꢀC, CH2Cl2, BrCOCH2Br.
Entry
1
Product
R1
iPr
R2
H
Yielda (%)
70.0
[
a
]
(c)b
25
D
4a
ꢁ33.4 (3.86)
ꢁ33.1 (1.84)
ꢁ33.9 (1.7)
ꢁ81.0 (1.2)
ꢁ153.1 (2.0)
2
3
4
4b
4c
4d
H
Me
Bn
Ph
H
H
60.0
50.0
67.0
Table 1
Conversion of oxazolidinethiones to 2,4-thiazolidinediones
Entry
Product
R1
R2
Yielda (%)
[a]
25 (c)b
D
a
Purified yield.
1
2
3
4
2a
2b
2c
2d
iPr
H
Me
Bn
H
Ph
H
67.0
60.0
40.0
48.0
ꢁ45.9 (2.00)
ꢁ14.8 (2.05)
þ1.52 (1.42)
b
Determined in CHCl3 at 25 ꢀC, value corresponding to mixture of diastereomers.
H
ꢁ151.6 (0.96)
a
The reaction of oxazolidinethione 1a with (S)-2-bromopro-
Purified yield.
Determined in CHCl3 at 25 ꢀC.
b
pionyl bromide was explored under the same reaction conditions,
which afforded compound 4a again as a diastereomeric mixture.
This result can be explained on the basis of an in situ racemization,
because of basic reaction conditions employed. Interestingly, thia-
zolidinedione heterocycles have been the subject of extensive re-
searches due to their important antidiabetic activity. These contain
a stereogenic center at the C-5 position in the 2,4-thiazolidine-
thione ring and this stereogenic center has been claimed to un-
dergo rapid racemization under physiological conditions.11 In order
to further characterize this peculiar behavior, compound 4a was
exposed under reaction conditions for isotopic exchange; first, 4a
was treated with a 40% solution of D2O/NaOD in CH3OD, this
The methodology described above was successful for the
achievement of the six-membered rings of 1,3-thiazinane-2,4-
diones type too. Their synthesis was achieved through the reaction
of oxazolidinethiones (1a–d) with NaH in CH2Cl2 followed by
dropwise addition of 3-bromopropionyl chloride at 0 ꢀC to afford
the 1,3-thiazinane-2,4-diones (3a–d) in moderate yields (23–78%),
Scheme 3. The oxazolidinethiones 1a and 1b gave the best results to
produce five- and six-membered rings, as shown in Tables 1 and 2.
mixture provided a rapid exchange of a-hydrogen by deuterium at
S
O
C-5: after 10 min, isotopic exchange was completed, giving 4a0. In
a second experiment, 4a was treated with DCl in C6D5CD3. By
heating the mixture at 70 ꢀC, completed deuteration was observed.
In general compound 4a showed a slow tautomeric equilibrium
keto–enol, which can be catalyzed in basic or acid media, as shown
in Scheme 5.
i
R2
R1
O
NH
R2
N
S
O
R1
3a-d
1a-d
Scheme 3. (i) NaH, 0 ꢀC, CH2Cl2, BrCH2CH2COCl.

R. Sabala et al. / Tetrahedron 66 (2010) 111–120
113
rapid
MeOD
O
O
NaOD/D2O
2
N3 1S
N
S
5
4
DCl
O
H
O
D
C6D5CD3
70 °C
slow
4a
4a´
Scheme 5. Isotopic exchange reactions on compound 4a.
The obtaining of five- and six-membered rings, in compounds 2,
3, and 4a–d can be explained by previous formation of the a,b-
bromoamide I or S-alkylated compound II, and both could give the
immonium III by an intramolecular nucleophilic substitution re-
action or an N-acylation reaction. The formation of the double
bonds on heterocycles 2, 3, and 4a–d could be presumably due to
the presence of halides; the immonium III could loss an unusual
acid hydrogen atom provoking the opening of bicycle III, as shown
in Scheme 6.
Figure 3. Molecular structure of the bis-allylurea 5d.
X
S
( )1,2
S
O
NNa
O
N
O
S
)
1,2
O
(
N
2a
1a
i
O
N
O
N
S
I
NH2
N
S
X
O
( )1,2
I
X
O
H
SNa
N
2a
II
III
S
i
O
N
O
O
O
N
H
N
H
1a
II
5a
Scheme 6. Possible course of the reaction from 1a to 3a.
Scheme 7. Possible course of the reaction from 2a to 5a. Reagents: (i) KOH, THF, H2O.
Both heterocycle types 2, 3, and 4(a–d) can be transformed to
the unexpected allylic ureas 5(a, b, d) by treatment with KOH in
THF/H2O. The chiral ureas12 5(a, b, d) were synthesized in good
yields (70–80%) as crystalline solids, as shown in Figure 2. The
chiral ureas derived from the heterocycles 2c, 3c or 4c were not
obtained because of their low yield.
mixture of syn- and anti-alcohols.15 Compounds 2a–d exposed to
reaction conditions described above provided the syn-alcohols 6a–
d and anti-alcohols 7a–d in 63–80% yield. Both alcohols 6a–d and
7a–d were separated by column chromatography on silica using
hexane/ethyl acetate (8/2) as eluent and their diastereomeric ratios
were determined by net weight of the diastereoisomers isolated. In
all cases syn-alcohols were formed predominantly as shown in
Scheme 8 and Table 4.
O
O
N
H
N
H
Ph
N
H
N
H
Ph
OH
OH
O
O
5a
5b
R2
+
R1
i
R2
R1
2a-d
N
S
N
S
O
O
7a-d
O
6a-d
Bn
N
H
N
Bn
H
5d
Scheme 8. Reagents: (i) 9-BBN, THF, rt, 24 h, EtOH, buffer of phosphates pH 7,
peroxide, 24 h, Na2SO3.
Figure 2. Chiral ureas bearing disubstituted terminal olefins.
Table 4
The structure of compounds 5(a, b, d) was established by 1H
NMR, 13C NMR, and EM spectroscopy and confirmed by X-ray
analysis13 on compound 5d as shown in Figure 3. This molecule
approximates a C2 symmetry in the solid state.
The obtaining of chiral symmetric ureas can be explained by in
situ previous formation of the amine I, from the basic hydrolysis of
2a, followed by a subsequent nucleophilic addition of I to 2a to
afford the non-detected 2-iminothiazolidin-4-one derivative14 II,
which could lead to urea 5a by subsequent basic hydrolysis, as
shown in Scheme 7.
Hydroboration–oxidation of compounds 2(a–d)
Entry
Starting material
R1
R2
Yielda (%) 6/7
syn/anti 6/7
1
2
3
4
2a
2b
2c
2d
iPr
H
Me
Bn
H
Ph
H
80
72
63
58
60/40
21/79b
73/27
76/24
H
a
Yields of diastereoisomer mixture.
The major diastereoisomer is syn, compound 7b.
b
When the diastereomeric mixtures of compounds 4a–d were
Compounds 2a–d and 4a–d were hydroborated with 9-BBN,
followed by an oxidation with peroxide to yield a diastereomeric
exposed to hydroboration–oxidation conditions, a mixture of syn-
alcohols 8a–d and anti-alcohols 9a–d was obtained in 32–80%

114
R. Sabala et al. / Tetrahedron 66 (2010) 111–120
yields. Both alcohols were isolated easily by column chromatogra-
phy and their diastereomeric ratios were determined by net weight
of the diastereomers. However, each syn- and anti-alcohol has
a mixture of non-separable epimers because of the stereogenic
center at C-5 of thiazolidinone ring, as detected by NMR and HPLC.
Enhanced bulk on thiazolidinodione ring in compounds 4a–d pro-
vided an increase of syn-selectivity in the hydroboration reaction,
as shown in Scheme 9 and Table 5.
OH
OH
O
O
R2
+
R1
i
R2
R1
4a-d
N
S
N
S
O
9a-d
O
8a-d
Scheme 9. Reagents: (i) 9-BBN, THF, rt, 24 h, EtOH, buffer of phosphates pH 7, per-
oxide, 24 h, Na2SO3.
Table 5
Hydroboration–oxidation of compounds 4a–d
Entry
Starting material
R1
R2
Yielda (%) 8/9
syn/anti 8/9
Figure 4. Molecular structure of the 1,3-oxazinones 10a. The asymmetric unit of the
crystal contains two molecules with almost identical conformations.
1
2
3
4
4a
4b
4c
4d
iPr
H
Me
Bn
H
Ph
H
77
80
32
69
80/20
6/94b
80/20
89/11
H
R3
R3
a
R2
O
R2
O
Yields of diastereoisomer mixture.
The major diastereoisomer is syn, compound 9b.
R1
R1
b
i
ii
HN
Boc
N
The alcohols 6 (a, b, d) and 7 (a, d) were exposed under basic
O
10 (a, d)
O
hydrolysis conditions with KOH in THF/H2O to yield the heterocy-
cles 1,3-oxazinones type 10 (a, b, d) and 11 (a, d) in moderate yields
and the bis(carboxymethyl)disulfide A. The alcohols 8 (a, b, d) and 9
(a, d) were treated under the reaction conditions described above
to yield 1,3-oxazinones type 10 (a, b, d) and 11 (a, d) too and the
compound 2,20-dithiobispropanoic acid B, as shown in Scheme 10.
The absolute and relative configurations of the 1,3-oxazinone
10a were confirmed by X-ray analysis,16 where its relative config-
uration is trans and absolute configurations at stereogenic centers
(C-4, C-5) are S as shown in Figure 4. The achievement of the
structure of compound 10a by X-ray analysis allowed the assign-
ment of the configurations for alcohols 6, 7, 8, and 9.
12(a, d)
11 (a´,d´)
13(a´, d´)
Boc
Boc
R1
NH
R3
NH
O
iii
R1
OH
OH
R2
R2
R3
16 (a, d)
17(a´,d´)
14(a,d)
15(a´,d´)
i
a R1 = Pr R2 = H R3 = Me
a´ R1 = Pr R2 = Me R3 = H
d R1 = Bn R2 = H R3 = Me
d´ R1 = Bn R2 = Me R3 = H
i
Scheme 11. Reagents and conditions: (i) n-BuLi, (Boc)2O, THF, ꢁ78 ꢀC, (ii) Cs2CO3,
MeOH, rt, (iii) NaIO4, RuCl3, CCl4/CH3CN/H2O 1.0/1.0/1.2, rt.
OH
O
O
O
Me
S)2
i
In conclusion we have found a new reaction pathway that was
carried out using oxazolidinethiones and acyl halides under N-ac-
ylation reaction conditions to provide N-substituted 2,4-thiazoli-
dinedione and N-substituted 1,3-thiazinane-2,4-dione. This
reaction featured an unexpected elimination reaction: one methyl
group on oxazolidinethione was converted into a terminal olefin.
These heterocycles were exposed to basic hydrolysis conditions to
yield new chiral allylic ureas in good yields. The terminal olefins on
the heterocycles were hydroborated with 9-BBN, followed by an
oxidation with peroxide to yield a diastereomeric mixture of syn-
and anti-alcohols. These alcohols were treated under basic hydro-
lysis conditions to provide 1,3-oxazinones, which were eventually
+
N
S
HO
HO
HN
O
or
S)2
O
R1
O
10 a
A
B
6a R1 = H
8a R1 = CH3
Scheme 10. Reagents: (i) KOH, THF/H2O 3.0/1.0, rt, 4 h.
The
a-alkyl-b-amino acids are constituents of biologically active
natural products, as some peptides.17 The asymmetric synthesis of
a
-methyl-b-amino acids bearing phenyl or methyl groups has been
widely described.18 However, the preparation of the derivates
bearing isopropyl or benzyl group has not been reported to date.
employed for the synthesis of new
allylic ureas.
a-methyl-b-amino acids and
This work was focused on the preparation of these
a-methyl b-
amino acids through N-tert-butoxycarbonyl protection19 of the 1,3-
oxazinones 10 (a, d) and 11 (a0, d0) followed by ring opening with
a catalytic amount of cesium carbonate in methanol at room tem-
perature to give amino alcohols 14 (a, d) and 15 (a0, d0) in 95–97%
yields. Their oxidation with NaIO4 and a catalytic amount of RuCl3
led to N-protected amino acids20 16 (a, d) and 17 (a0, d0) in 92–99%
yields as shown in Scheme 11.
3. Experimental
3.1. General remarks
All 1H and 13C spectra were recorded in CDCl3 using two NMR
spectrometers operating at 400 or 300, and 100 or 75 MHz,

R. Sabala et al. / Tetrahedron 66 (2010) 111–120
115
respectively. Chemical shifts are reported in parts per million (
d
chromatography (2% ethyl acetate in hexane as eluent) to afford 2a
scale), and coupling constants (J values) are listed in hertz (Hz).
(0.41 g, 67% yield) as a colorless liquid.
Tetramethylsilane (TMS) and CHCl3 were used as the internal
standards (
d
¼0 ppm) and (
d
¼77.0 ppm). Infrared spectra were
3.3.1. (S)-3-(2,4-Dimethylpent-1-en-3-yl)thiazolidine-2,4-dione
recorded on a Nicolet 380 FT-IR spectrometer. Melting points were
recorded on a Barnsted Electrothermal apparatus and are un-
corrected. Optical activities were measured at 589 nm using a dig-
ital polarimeter. Mass spectra were recorded on MStation JMS.
(2a). Colorless liquid, 1H NMR (CDCl3, 400 MHz):
d 5.13 (1H, s, d,
J¼0.8 Hz, CH]), 5.02 (1H, dq, J¼1.6, 1.2 Hz, CH]), 4.22 (1H, d,
J¼11.6 Hz, CH–N), 3.91 (2H, s, CH2), 2.85 (1H, m, CH(CH3)2),1.74 (3H,
s, CH3), 0.93 (3H, d, J¼6.4 Hz, CH3), 0.83 (3H, d, J¼6.4 Hz, CH3); 13
C
NMR (CDCl3, 100 MHz):
d 171.6 (2C]O), 140.3 (C]), 117.2 (CH2]),
67.2 (CN), 33.3 (CH2S), 25.4 (CH(CH3)2), 20.8 (CH3) 20.6 (CH3), 19.7
(CH3); IR nmax: 1753.1, 1676.5, 1370.9, 1318.3, 1181.4, 1165.7, 1113.2,
904.8 cmꢁ1. EIMS: calculated for (C10H15NO2S), 213.08; found, 213.0
3.2. General procedure for the condensation reaction
of
b-amino alcohols with CS2
ꢃ
(Mþ ), 96.0 (100%).
To a flask were added (S)-3-amino-2,4-dimethylpentan-2-ol
(1.0 g, 7.62 mmol), aqueous solution of Na2CO3 (100 mL), and CS2
(2.32 g, 30.5 mmol). The mixture was allowed to stir at reflux
temperature for 16 h, and then cooled to room temperature. After
cooling, CS2 (1.16 g, 15.2 mmol) was added and allowed to stir at
reflux temperature for 4 h. The product was extracted with CH2Cl2
(50 mLꢂ4), washed with brine (30 mLꢂ2), and dried over Na2SO4.
The solvent was removed under reduced pressure and the product
was purified by column chromatography (10% ethyl acetate in
hexane as eluent) to afford 1a (1.06 g, 80% yield) as a white solid.
3.3.2. (S)-3-(2-Methyl-1-phenylallyl)thiazolidine-2,4-dione
(2b). Colorless liquid, 1H NMR (CDCl3, 300 MHz):
d
7.44–7.30 (5H,
m, Ph), 5.82 (1H, s, CHN), 5.14 (1H, s, CH]), 4.75 (1H, s, CH]), 3.92
(2H, s, CH2), 1.80 (3H, s, CH3); 13C NMR (CDCl3, 75 MHz):
171.2
d
(2CO),139.6 (C]),135.8 (Ci),129.5 (Cm),128.3 (Co),128.2 (Cp),115.3
(CH2]), 63.0 (CHN), 33.3 (CH2), 21.2 (CH3); IR nmax: 1754.6, 1677.8,
1378.6, 1330.4, 1153.9, 897.3, 724.4, 699.5, 669.5 cmꢁ1. EI-HRMS:
calculated for (C13H13NO2S), 247.0667; found, 247.0662.
3.3.3. (S)-3-(3-Methylbut-3-en-2-yl)thiazolidine-2,4-dione
3.2.1. (S)-4-Isopropyl-5,5-dimethyloxazolidine-2-thione (1a). White
(2c). Colorless liquid, 1H NMR (CDCl3, 400 MHz):
d 5.02 (1H, s,
25
solid, mp¼110–111 ꢀC, 80% yield, [
a
]
ꢁ14.3 (c 2.0, CHCl3); 1H NMR
D
CH]), 4.98 (1H, s, CH]), 4.80 (1H, q, CHN), 3.92 (2H, s, CH2), 1.70
(CDCl3, 400 MHz):
d
8.30 (1H, br s, NH), 3.40 (1H, d, J¼8.0 Hz, CHN),
(3H, s, CH3), 1.56 (3H, d, J¼7.2 Hz, CH3); 13C NMR (CDCl3, 100 MHz):
1.90 (1H, m, CHCH3), 1.60 (3H, s, CH3), 1.50 (3H, s, CH3), 1.00 (3H, d,
d
171.2 (2CO), 141.3 (C]), 113.1 (CH2]), 54.2 (CHN), 33.2 (CH2), 20.4
J¼6.6 Hz, CH3CH), 0.90 (3H, d, J¼6.6 Hz, CH3CH); 13C NMR (CDCl3,
(CH3), 15.2 (CH3); IR nmax: 2919.8, 1753.7, 1674.1, 1377.7, 1332.7,
1144.6, 897.3, 749.4, 700.7 cmꢁ1
EI-HRMS: calculated for
(C8H11NO2S), 185.0511; found, 185.0510.
100 MHz): d 188.1 (C]S), 90.4 (C–O), 71.2 (C–N), 28.2 (CHCH3), 28.0
.
(CH3), 20.9 (CH3), 19.9 (2CH3); IR nmax: 3177.6, 2964.1, 2935.0,
1717.5, 1518.6, 1391.4, 1210.7, 1139.6, 1023.8, 819.0 cmꢁ1. EI-HRMS:
calculated for (C8H15NOS), 173.0874; found, 173.0875.
3.3.4. (S)-3-(3-Methyl-1-phenylbut-3-en-2-yl)thiazolidine-2,4-dione
(2d). Colorless liquid, 1H NMR (CDCl3, 400 MHz):
7.26–7.14 (5H,
d
3.2.2. (R)-5,5-Dimethyl-4-phenyloxazolidine-2-thione (1b). White
m, Ph), 5.12 (1H, s, CH]), 5.10 (1H, s, CH]), 5.00 (1H, dd, J¼11.2,
5.2 Hz, CHN), 3.67 (2H, dd, J¼17.2 Hz, CH2S), 3.51(1H, dd, J¼14.0,
11.2 Hz, CHaHb), 3.23 (1H, dd, J¼14.0, 5.2 Hz, CHbHa), 1.77 (3H, s,
25
solid, mp¼111–113 ꢀC, 70% yield, [
a
]
ꢁ94.7 (c 1.0, CHCl3); 1H
D
NMR (CDCl3, 400 MHz):
d 7.82 (1H, br s, NH). 7.40–7.36 (3H, m,
Ph), 7.24–7.20 (2H, m, Ph), 4.76 (1H, s, CHN), 1.68 (3H, s, CH3), 1.01
CH3); 13C NMR (CDCl3, 100 MHz):
d 171.3 (2CO), 140.6 (C]), 137.3
(3H, s, CH3); 13C NMR (CDCl3, 75 MHz):
d
189.2 (C]S), 135.3 (Ci),
(Ci), 128.8 (Cm), 128.5 (Co), 126.8 (Cp), 114.0 (CH2]), 60.0 (CH–N),
34.4 (CH2), 33.0 (CH2S), 21.0 (CH3); IR nmax: 2919.8, 1753.7, 1674.1,
1455.4, 1377.7, 1332.7, 1144.6, 897.3, 749.4, 700.7 cmꢁ1. EIMS: cal-
129.1 (Cp), 129.0 (Cm), 126.5 (Co), 91.6 (C–O), 69.1 (C–N), 28.0
(CH3), 23.3 (CH3); IR nmax: 3184.2, 2980.8, 1732.5, 1494.5, 1454.7,
1283.4, 1215.3, 1127.9, 746.1, 700.5 cmꢁ1. EI-HRMS: calculated for
(C11H13NOS), 207.0718; found, 207.0715.
ꢃ
culated for (C14H15NO2S), 261.08; found, 261.0 (Mþ ), 144.0 (100%).
3.4. General procedure for the conversion of oxazolidine-
thiones to N-substituted 1,3-thiazinane-2,4-dione (3a)
3.2.3. (S)-4,5,5-Trimethyloxazolidine-2-thione (1c). White solid,
25
mp¼100–101 ꢀC, 65% yield, [
a
]
ꢁ5.83 (c 1.19, CHCl3); 1H NMR
D
(CDCl3, 400 MHz):
d
8.22 (1H, br s, NH), 3.82 (1H, q, J¼6.8 Hz, CH),
To a solution of (S)-4-isopropyl-5,5-dimethyloxazolidine-2-thi-
one 1a (0.3 g, 1.73 mmol) in CH2Cl2 (30 mL) was added NaH
(0.083 g, 3.46 mmol) at 0 ꢀC under an argon atmosphere, followed
by dropwise addition of 3-bromopropionyl chloride (0.44 g,
2.59 mmol). The mixture was stirred at 0 ꢀC for 4 h. The reaction
mixture was quenched with a saturated solution of NH4Cl (15 mL).
The product was extracted with CH2Cl2 (50 mLꢂ2), washed first
with a saturated solution of NaHCO3 (20 mLꢂ3) and then with
brine (30 mLꢂ2), and dried over Na2SO4. The solvent was removed
under reduced pressure and the product was purified by column
chromatography (2% ethyl acetate in hexane as eluent) to afford 3a
(0.27 g, 70% yield) as a colorless liquid.
1.52 (3H, s, CH3), 1.40 (3H, s, CH3), 1.23 (3H, d, J¼7.2 Hz, CH3CH);
13C NMR (CDCl3, 100 MHz):
d
188.0 (C]S), 90.4 (C–O), 60.4 (C–N),
27.0 (CH3), 21.1 (CH3), 15.3 (CH3); IR nmax: 2980.0, 2939.1, 2872.8,
1748.5, 1681.2, 1324.9, 1180.6, 881.9 cmꢁ1. EI-HRMS: calculated for
(C6H11NOS), 145.0561; found, 145.0565.
3.3. General procedure for the conversion of oxazolidine-
thiones to N-substituted 2,4-thiazolidinediones
To a solution of (S)-4-isopropyl-5,5-dimethyloxazolidine-2-thi-
one 1a (0.5 g, 2.88 mmol) in CH2Cl2 (30 mL) was added NaH (0.14 g,
5.76 mmol) at 0 ꢀC under an argon atmosphere, followed by
dropwise addition of bromoacetyl bromide (0.87 g, 4.32 mmol).
The mixture was stirred at 0 ꢀC for 4 h. The reaction mixture was
quenched with a saturated solution of NH4Cl (15 mL). The product
was extracted with CH2Cl2 (50 mLꢂ2), washed first with a satu-
rated solution of NaHCO3 (20 mLꢂ3) and then with brine
(30 mLꢂ2), and dried over Na2SO4. The solvent was removed under
reduced pressure and the product was purified by column
3.4.1. (S)-3-(2,4-Dimethylpent-1-en-3-yl)-1,3-thiazinane-2,4-dione
(3a). Colorless liquid, 1H NMR (CDCl3, 400 MHz):
d 5.10 (1H, s,
CH]), 5.07 (1H, s, CH]), 4.84 (1H, d, J¼11.0 Hz, CHN), 3.05 (4H, m,
2CH2), 2.75 (1H, m, CH(CH3)2), 1.72 (3H, s, CH3), 0.97 (3H, d,
J¼6.8 Hz, CH3), 0.83 (3H, d, J¼6.4 Hz, CH3); 13C NMR (CDCl3,
100 MHz):
d 170.7 (C]O), 169.0 (C]O), 140.5 (C]), 116.0 (CH2]),
65.0 (CHN), 35.1 (CH2S), 26.8 (CH(CH3)2), 22.0 (CH2), 21.7 (CH3), 21.3

116
R. Sabala et al. / Tetrahedron 66 (2010) 111–120
(CH3), 19.3 (CH3); IR nmax: 2967.7, 1711.6, 1644.3, 1334.8, 1284.1,
1219.6, 1156.6, 1112.5 cmꢁ1. EI-HRMS calculated for (C11H17NO2S),
227.0980; found, 227.0984.
(CH3), 19.2 (CH3); IR nmax 2979.7, 1751.5, 1670.1, 1375.4, 1325.1,
1166.3, 740.2, 700.7 cmꢁ1. EI-HRMS: calculated for (C14H15NO2S),
261.0824; found, 261.0830.
3.4.2. (S)-3-(2-Methyl-1-phenylallyl)-1,3-thiazinane-2,4-dione
3.5.3. 3-[(S)-3-Methylbut-3-en-2-yl]-5-methyl thiazolidine-2,4-di-
(3b). Colorless liquid, 1H NMR (400 MHz, CDCl3):
d
7.43–7.41 (2H, m,
one (4c). Liquid, 1H NMR (CDCl3, 400 MHz):
d 5.01 (1H, s, CH]),
Ph), 7.33–7.26 (3H, m, Ph), 6.33 (1H, s, CHN), 5.05 (1H, s, CH]), 4.70
4.96 (1H, s, CH]), 4.80 (1H, q, J¼7.0 Hz, CH–N), 4.10 (1H, q,
(1H, s, CH]), 3.05 (4H, m, 2CH2), 1.80 (3H, s, CH3); 13C NMR (CDCl3,
J¼7.2 Hz, CHS),1.70 (3H, s, CH3),1.67 (3H, d, J¼7.0 Hz, CH3),1.56 (3H,
100 MHz):
d
170.2 (C]O), 168.3 (C]O), 141.2 (C]), 137.2 (Ci), 130.0
d, J¼7.2 Hz, CH3); 13C NMR (CDCl3, 100 MHz):
d 175.2 (C]O), 170.4
(Cm), 128.0 (Co), 127.6 (Cp), 114.0 (CH2]), 62.6 (CHN), 35.0 (CH2–S),
22.0 (CH2), 21.4 (CH3); IR nmax: 2921.4, 1711.7, 1649.6, 1335.3, 1287.3,
1219.7, 1145.6 cmꢁ1. EIMS: calculated for (C14H15NO2S), 261.08;
(C]O), 141.4, 141.3 (C]), 112.8 (CH2), 54.0 (CHN), 43.1, 42.9 (CS),
20.4 (CH3), 19.2, 19.1 (CH3), 15.2, 15.1 (CH3); IR nmax 2979.9, 1748.8,
1667.2, 1448.7, 1376.7, 1328.7, 1180.8, 882.5 cmꢁ1. EI-HRMS: calcu-
lated for (C9H13NO2S), 199.0667; found, 199.0665.
ꢃ
found, 261.0 (Mþ ), 233.0 (100%).
3.4.3. (S)-3-(3-Methylbut-3-en-2-yl)-1,3-thiazinane-2,4-dione
3.5.4. 3-[(S)-3-Methyl-1-phenylbut-3-en-2-yl]-5-methyl thiazolidine-
(3c). Colorless liquid, 1H NMR (CDCl3, 400 MHz):
d
5.32 (1H, q,
2,4-dione (4d). Liquid,1H NMR (CDCl3, 400 MHz):
d 7.27–7.13 (5H, m,
J¼6.4 Hz, CHN), 5.00 (1H, s, CH]), 4.90 (1H, s, CH]), 3.05 (4H, m,
Ph) 5.10 (1H, s, CH]), 5.08 (1H, s, CH]), 5.00 (1H, m, CHN), 3.93 (1H,
q, J¼7.3 Hz, CHS), 3.50 (1H, dd, J¼14.0, 9.6 Hz, CHaHb), 3.21 (1H, dd,
J¼14.0, 5.0 Hz, CHbHa), 1.76 (3H, s, CH3), 1.46 (3H, d, J¼7.2 Hz, CH3),
2CH2), 1.68 (3H, s, CH3), 1.52 (3H, d, J¼6.4 Hz, CH3); 13C NMR (CDCl3,
100 MHz):
d 170.2 (C]O), 168.3 (C]O), 143.1 (C]), 111.3 (CH2]),
54.0 (CHN), 35.0 (CH2), 22.0 (CH2), 20.1 (CH3), 16.1 (CH3); IR nmax
:
1.21 (3H, d, J¼7.2 Hz, CH3); 13C NMR (CDCl3, 100 MHz):
d 175.2
2938.6, 1709.2, 1643.6, 1222.5, 1162.6, 896.3 cmꢁ1. EIMS: calculated
(C]O), 170.8 (C]O), 140.6 (C]), 137.2, 128.9, 128.8, 128.4, 128.3,
126.7,126.6 (Ph),113.6,113.4 (]CH2), 59.4, 59.3 (CHN), 43.0, 42.6 (C–
S), 34.5, 34.3 (CH2), 21.0 (CH3), 19.1 (CH3), 19.0 (CH3); IR nmax: 2931.1,
1705.3, 1673.5, 1449.0, 1329.4, 1147.0, 738.9, 700.1 cmꢁ1. EIMS: cal-
culated for (C15H17NO2S), 275.098; found, 275, 144, 129, 91.
ꢃ
for (C9H13NO2S), 199.07; found, 199.0 (Mþ ), 171.0 (100%).
3.4.4. (S)-3-(3-Methyl-1-phenylbut-3-en-2-yl)-1,3-thiazinane-2,4-
dione (3d). White solid, mp¼78–79 ꢀC; 1H NMR (CDCl3, 400 MHz):
d
7.29–7.15 (5H, m, Ph), 5.62 (1H, m, CHN), 5.00 (2H, s, CH2]), 3.40
(1H, dd, J¼13.4, 11.0 Hz, CHaHb), 3.25 (1H, dd, J¼13.4, 6.0 Hz,
3.6. General procedure for basic hydrolysis of N-substituted
2,4-thiazolidinediones or N-substituted 1,3-thiazinane-2,4-
dione
CHbHa), 2.80–2.50 (4H, m, 2CH2), 1.74 (3H, s, CH3); 13C NMR (CDCl3,
100 MHz): d 170.4 (C]O), 168.6 (C]O), 142.6 (C]), 138.2 (Ci), 129.0
(Cm), 128.3 (Co), 126.5 (Cp), 111.4 (CH2]), 58.5 (CHN), 35.5 (CH2),
34.6 (CH2), 21.7 (CH2), 21.1 (CH3); IR nmax: 2937.6, 1709.5, 1643.1,
1222.7, 1135.2, 884.9, 748.8, 701.1 cmꢁ1. FAB-HRMS: calculated for
(C15H17NO2S) 276.1058 (MþH); found, 276.1067 (MþH).
To a flask were added 3a (0.15 g, 0.66 mmol), THF (9 mL), H2O
(3 mL), and KOH (0.15 g, 2.63 mmol). The mixture was allowed to
stir at room temperature for 4 h. The THF was removed under re-
duced pressure. The product was extracted with CH2Cl2 (40 mLꢂ2),
washed first with a saturated solution of NaHCO3 (20 mLꢂ3) and
then with brine (30 mLꢂ2), and dried over Na2SO4. The solvent was
removed under reduced pressure and the product was recrystal-
lized with ethanol (three drops) in hexane.
3.5. General procedure for the conversion of oxazolidine-
thiones to N-substituted 2,4-thiazolidinediones
To a solution of (S)-4-isopropyl-5,5-dimethyloxazolidine-2-thi-
one 1a (0.4 g, 2.30 mmol) in CH2Cl2 (30 mL) was added NaH (83 mg,
3.46 mmol) at 0 ꢀC under an argon atmosphere, followed by
dropwise addition of 2-bromopropanoyl bromide (0.59 g,
2.77 mmol). The mixture was stirred at 0 ꢀC for 4 h. The reaction
mixture was quenched with a saturated solution of NH4Cl (15 mL).
The product was extracted with CH2Cl2 (50 mLꢂ2), washed first
with a saturated solution of NaHCO3 (20 mLꢂ3) and then with
brine (30 mLꢂ2), and dried over Na2SO4. The solvent was removed
under reduced pressure and the product was purified by column
chromatography (2% ethyl acetate in hexane as eluent) to afford 4a
(0.36 g, 70% yield) as a diastereomeric mixture.
3.6.1. 1,3-Bis((S)-2,4-dimethylpent-1-en-3-yl)urea (5a). Crystalline
25
solid, mp¼224–225 ꢀC, 80% yield, [
a]
þ55.8 (c 0.5, CHCl3); 1H
D
NMR (CDCl3, 400 MHz): d 4.90 (1H, s, CH]), 4.85 (1H, s, CH]), 4.55
(1H, d, J¼6.8 Hz, NH), 3.72 (1H, m, CHN), 1.77 (1H, m, CH(CH3)2),
1.68 (3H, s, CH3), 0.92 (3H, d, J¼6.8 Hz, CH3), 0.90 (3H, d, J¼6.8 Hz,
CH3); 13C NMR (CDCl3, 100 MHz):
d 157.8 (C]O), 142.2 (C]), 112.4
(CH2]), 62.6 (CHN), 29.8 (CH3), 20.1 (CH3), 18.6 (CH), 18.4 (CH3); IR
nmax: 3329.3, 2962.3, 1625.5, 1560.8, 1313.6, 891.4 cmꢁ1. EI-HRMS:
calculated for (C15H28N2O), 252.2202; found, 252.2189.
3.6.2. 1,3-Bis((S)-2-methyl-1-phenylallyl)urea (5b). White solid,
25
3.5.1. 3-[(S)-2,4-Dimethylpent-1-en-3-yl]-5-methylthiazolidine-2,4-
mp¼216–218 ꢀC, 70% yield, [
a
]
ꢁ85.5 (c 0.8, CHCl3); 1H NMR
D
dione (4a). Liquid, 1H NMR (CDCl3, 300 MHz):
d
5.11 (1H, s, HC]),
(300 MHz, CDCl3):
d
7.34–7.20 (5H, m, Ph), 5.18 (1H, d, J¼6.6 Hz,
5.01 (1H, s, HC]), 4.20 (1H, d, J¼11.2 Hz, CHN), 4.12 (1H, dq, J¼5.0,
7.2 Hz, CH–S), 2.84 (1H, m, CH), 1.74 (3H, s, CH3), 1.66 (3H, dd, J¼7.2,
1.6 Hz, CH3), 0.94 (3H, d, J¼6.8 Hz, CH3), 0.82 (3H, dd, J¼6.4, 1.2 Hz,
CHN), 5.01 (1H, s, CH]), 4.90 (1H, s, CH]), 4.81 (1H, d, J¼7.0 Hz,
NH), 1.80 (3H, s, CH3); 13C NMR (CDCl3, 75 MHz):
157.0 (C]O),
145.0 (C]), 140.5 (Ci), 128.6 (Cm), 127.5 (Cp), 127.0 (Co), 119.0
d
CH3); 13C NMR (CDCl3, 75 MHz)
d
ppm: 175.8 (2C]O), 140.5, 140.4
(CH2]), 60.1 (CHN), 19.8 (CH3); IR nmax: 3317.1, 1624.3,
(C]), 117.1, 117.0 (C]), 67.0, 66.8 (CN) 43.0, 42.8 (CS), 25.4, 25.3
(CH3) 20.8, 20.7 (CH3), 20.5 (CH3) 19.5, 19.4 (CH3); IR nmax: 2926.1,
1556.6,1492.6, 1271.6, 901.1, 698.6 cmꢁ1. EI-HRMS: calculated for
(C21H24N2O), 320.1889; found, 320.1897.
1752.2, 1685.6, 1330.5, 1183.0, 1118.86, 911.8 cmꢁ1
.
3.6.3. 1,3-Bis((S)-3-methyl-1-phenylbut-3-en-2-yl)urea (5d). White
25
3.5.2. 3-[((S)-2-Methyl-1-phenylallyl)]-5-methylthiazolidine-2,4-di-
one (4b). Liquid, 1H NMR (CDCl3, 300 MHz):
7.70–7.13 (5H, m, Ph)
solid, mp¼80–81 ꢀC, 71% yield, [
a
]
ꢁ21.3 (c 1.7, CHCl3); 1H NMR
D
d
(CDCl3, 400 MHz): d 7.29–7.10 (5H, m, Ph), 4.80 (1H, s, CH]), 4.65
5.79 (1H, s, CH–N), 5.13 (1H, s, CH]), 4.73 (1H, s, CH]), 4.15 (1H, q,
J¼7.2 Hz, CHS), 1.78 (3H, s, CH3), 1.65 (3H, d, J¼7.2 Hz, CH3); 13C
(1H, s, CH]), 4.51 (1H, d, J¼7.2 Hz, NH), 4.20 (1H, m, CHN), 2.84
(1H, dd, J¼14.0, 6.8 Hz, CHaHb), 2.75 (1H, dd, J¼14.0, 7.4 Hz, CHbHa),
NMR (CDCl3, 100 MHz):
d
175.1 (C]O), 170.5 (C]O), 139.9 (C]),
1.72 (3H, s, CH3); 13C NMR (CDCl3, 100 MHz):
d 157.1 (C]O), 145.1
135.9, 129.4, 128.3 (Ph), 115.2 (CH2), 63.0 (CHN), 43.1 (CS), 21.0
(C]), 137.3 (Ci), 129.1 (Cm), 128.3 (Co), 126.6 (Cp), 112.2 (CH2]),

R. Sabala et al. / Tetrahedron 66 (2010) 111–120
117
57.0 (CHN), 29.6 (CH2), 18.7 (CH3); IR nmax: 3340.8, 2922.3, 2853.2,
1747.2,1682.8,1638.5,1551.3,1328.7,1064.3, 743.1, 699.3 cmꢁ1. FAB-
HRMS: calculated for (C23H28N2O) 349.2280 (MþH); found,
349.2272 (MþH).
CH2S), 3.46 (2H, dd, J¼4.0, 2.4 Hz, CH2O), 2.38 (1H, m, CHCH3), 1.71
(1H, br s, OH),1.47 (3H, d, J¼6.8 Hz, CH3),1.04 (3H, d, J¼6.8 Hz, CH3);
13C NMR (CDCl3, 100 MHz):
d 172.3 (C]O), 65.6 (CH2O), 53.4 (CHN),
37.0 (CH2S), 33.4 (CHCH3), 16.0 (CH3), 14.8 (CH3); IR nmax: 3402.7,
2934.8, 2866.7, 1742.8, 1672.2, 1339.4, 1179.2, 873.0 cmꢁ1. EIMS:
calculated for (C8H13NO3S), 203.06; found, 203 (5%), 173 (39%), 144
(80%), 118 (100%), 116 (40%).
3.6.4. 3-[((2S,3S)-1-Hydroxy-2,4-dimethylpentan-3-yl)thiazolidine-
25
2,4-dione (6a). Liquid, 55% yield, [
(400 MHz, CDCl3)
a
]
D
ꢁ7.0 (c 1, CHCl3); 1H NMR
d
: 4.03 (1H, s, CHS), 4.00 (1H, dd, J¼9.6, 7.2 Hz,
CHN), 3.87 (1H, s, CHS), 3.51 (2H, m, CH2O), 2.52 (2H, m, 2CH), 1.01
3.6.10. 3-[(2S,3S)-4-Hydroxy-3-methyl-1-phenylbutan-2-yl]-
25
(3H, d, J¼6.6 Hz, CH3), 0.96 (3H, d, J¼7.0 Hz, CH3), 0.85 (3H, d,
thiazolidine-2,4-dione (6d). Colorless liquid, 44% yield, [
a]
ꢁ51.5
D
J¼6.6 Hz, CH3); 13C NMR (100 MHz, CDCl3)
d
: 173.6,172.6, 65.0, 64.8,
(c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz):
d 7.30–7.10 (5H, m, Ph),
64.7, 35.3, 35.2, 33.8, 32.2, 29.6, 27.6, 27.4, 20.7, 20.6, 19.8, 19.6, 15.4;
IR nmax: 3415.7, 2965.9, 2934.8, 2876.1, 1750.4, 1667.2, 1387.5,
1331.9, 1187.3, 1108.0, 897.9, 802.1 cmꢁ1; EIMS: calculated for
(C10H17NO3S), 231.09; found, 231 (2%), 188 (27%), 172 (36%), 158
(100), 118 (68%), 84 (30%).
4.55 (1H, m, CHN), 3.74 (2H, m, CH2S), 3.68 (1H, dd, J¼11.2, 4.4 Hz,
CHBn), 3.48 (1H, m, CHBn), 3.31(1H, m, CHO), 3.18 (1H, dd, J¼14.0,
5.2 Hz, CHO), 2.50 (1H, m, CHCH3), 0.94 (3H, d, J¼6.8 Hz, CH3); 13
C
NMR (CDCl3,100 MHz): d 172.3,172.0,137.6,128.7,128.4,126.6, 64.7,
59.2, 37.2, 35.0, 34.5, 33.2, 14.4; IR nmax: 3414.1, 2928.4, 1676.0,
1343.6, 1152.7, 1030.6, 710.8 cmꢁ1
.
FABMS: calculated for
3.6.5. 3-[((2R,3S)-1-Hydroxy-2,4-dimethylpentan-3-yl)thiazolidine-
(C14H17NO3S), 279.09; found, 280 (15%), 154 (100), 136 (85%), 91
(55%), 57 (95%) 55 (90%), 43 (72%).
25
2,4-dione (7a). Liquid, 45% yield, [
a
]
ꢁ5.5 (c 1, CHCl3); 1H NMR
D
(400 MHz, CDCl3)
d
: 3.97 (1H, s, CHS), 3.94 (1H, dd, J¼10.0, 5.6 Hz,
CHN), 3.81 (1H, s, CHS), 3.40 (1H, dd, J¼12.0, 4.8 Hz, CHaO), 3.20
(1H, m, CHbO), 2.75 (1H, m, CH), 2.26 (1H, m, CHCH3), 0.93 (3H, d,
J¼6.8 Hz, CH3), 0.81 (3H, d, J¼7.6 Hz, CH3), 0.78 (3H, d, J¼6.8 Hz,
3.6.11. 3-[(2S,3R)-4-Hydroxy-3-methyl-1-phenylbutan-2-yl]-
25
thiazolidine-2,4-dione (7d). Colorless liquid, 14% yield, [
a
]
ꢁ60.2
D
(c 0.8, CHCl3); 1H NMR (CDCl3, 400 MHz):
d
7.30–7.05 (5H, m, Ph),
CH3); 13C NMR (100 MHz, CDCl3)
d: 174.3, 172.6, 65.1, 63.6, 63.4,
4.40 (1H, m CHN), 3.68 (1H, m, CHaO), 3.49 (2H, d, J¼4.0 Hz, CH2S),
3.43 (1H, m, CHbO), 3.31 (1H, m, CHBn), 0.88 (1H, dd, J¼4.8, 14.0 Hz,
CHBn), 2.50 (1H, m, CHCH3), 1.17 (3H, d, J¼6.8 Hz, CH3); 13C NMR
37.0, 36.9, 33.6, 32.4, 29.6, 25.6, 25.4, 20.6, 20.5, 12.4, 12.2; IR nmax
:
3415.5, 2924.7, 1749.2, 1670.7, 1333.1, 1162.4, 703.3 cmꢁ1; EIMS:
calculated for (C10H17NO3S), 231.09; found, 231 (7%), 188 (27%), 172
(35%), 158 (100), 118 (68%), 84 (32%).
(CDCl3, 100 MHz): d 172.3, 172.1, 137.5, 128.7, 128.4, 126.7, 65.5, 59.5,
36.4, 34.8, 33.3, 24.6, 15.1; IR nmax: 3414.1, 2928.4, 1676.0, 1343.6,
1152.7, 1030.6, 710.8 cmꢁ1. FABMS: calculated for (C14H17NO3S),
279.09; found, 280 (15%), 154 (100),136 (85%), 91 (55%), 57 (95%) 55
(90%), 43 (72%).
3.6.6. 3-[(1S,2S)-3-Hydroxy-2-methyl-1-phenylpropyl]thiazolidine-
25
2,4-dione (6b). Colorless liquid, 15% yield, [
a
]
D
ꢁ41.9 (c 1.25,
CHCl3); 1H NMR (CDCl3, 400 MHz):
d
7.55–7.53 (2H, m, Ph), 7.36–
7.30 (3H, m, Ph), 5.16 (1H, d, J¼11.6 Hz, CHN), 3.85 (2H, s, CH2), 3.63
3.6.12. 3-[(2S,3S)-1-Hydroxy-2,4-dimethylpentan-3-yl]-5-methyl-
25
(2H, d, J¼4.4 Hz, CH2OH), 3.26 (1H, m, CH),1.78 (1H, br s, OH), 0.88
thiazolidine-2,4-dione (8a). Liquid, 61.5% yield, [
a
]
ꢁ10.33 (c 1.8,
D
(3H, d, J¼7.2 Hz, CH3); 13C NMR (CDCl3, 100 MHz):
d
172.3 (C]O),
CHCl3); 1H NMR (CDCl3, 400 MHz):
d
4.25 (1H, q, J¼7.2 Hz, CH–S),
172.0 (C]O), 136.8 (Ci), 129.5 (Ci), 128.5 (Co), 128.4 (Cp), 65.6 (C–O),
61.5 (CN), 33.4 (CH), 33.2 (CS), 15.4 (CH3); IR nmax: 3416.0, 2929.1,
1748.9, 1655.5, 1328.8, 1170.7, 700.0 cmꢁ1. EI-HRMS: calculated for
(C13H15NO3S), 265.0773; found, 265.0761.
4.10 (1H, q, J¼7.2, CHS), 3.97 (4H, m, CH2O), 3.48 (2H, m, CHN), 2.57
(2H, m, CH(CH3)2), 2.51 (2H, m, CHCH3), 1.67 (6H, d, J¼6.8 Hz, CH3),
1.00 (6H, d, J¼6.8 Hz, CH3), 0.96 (6H, d, J¼7.2 Hz, CH3), 0.84 (6H, d,
J¼6.4 Hz, CH3); 13C NMR (CDCl3, 100 MHz):
d 177.6, 176.7 (C]O),
172.9, 172.3 (C]O), 65.0, 64.9 (CH2O), 64.7, 64.6, 64.3 (CHN), 43.8
3.6.7. 3-[(1S,2R)-3-Hydroxy-2-methyl-1-phenylpropyl]thiazolidine-
(CH2S), 41.9 (CH), 35.5, 35.3, 35.2 (CH(CH3)2), 27.7, 27.5, 27.3, 27.1
25
2,4-dione (7b). White solid 57% yield, mp¼103 ꢀC, [
a
]
ꢁ22.3 (c
(CH3), 20.7 (CH3),19.8,19.7,19.6,19.5,19.4 (CH3),15.4 (CH3); IR nmax
:
D
1.9, CHCl3); 1H NMR (CDCl3, 400 MHz):
d
7.56–7.54 (2H, m, Ph),
3414.1, 2930.0, 1745.3, 1658.7, 1330.5, 1100.5, 1027.2, 741.0 cmꢁ1
.
7.33–7.31 (3H, m, Ph), 5.20 (1H, d, J¼12.0 Hz, CHN), 3.86 (2H, s,
CH2), 3.53 (1H, dd, J¼10.8, 2.8 Hz, CHaHb), 3.31 (1H, dd, J¼10.4,
5.2 Hz, CHbHa), 3.24 (1H, m, CH), 1.63 (1H, br s, OH), 1.05 (3H, d,
EI-HRMS: calculated for (C11H19NO3S), 245.1086; found, 245.1088.
3.6.13. 3-[(2R,3S)-1-Hydroxy-2,4-dimethylpentan-3-yl]-5-methyl-
25
J¼6.8 Hz, CH3); 13C NMR (CDCl3, 100 MHz):
d
172.0 (C]O), 171.7
thiazolidine-2,4-dione (9a). Liquid, 15.5% yield, [
a
]
ꢁ1.16 (c 1.2,
D
(C]O), 137.1 (Ci), 129.2 (Cm), 128.6 (Co), 128.5 (Cp), 64.6 (C–O), 61.2
(CN), 34.3 (CH), 33.1 (C–S), 14.5 (CH3); IR nmax: 3415.5, 2924.7,
1749.2, 1670.7, 1333.1, 1162.4, 703.3 cmꢁ1. EI-HRMS: calculated for
(C13H15NO3S), 265.0773; found 265.0776.
CHCl3); 1H NMR (CDCl3, 400 MHz):
d 4.27 (1H, m, CHS), 4.09 (1H, m,
CHS), 4.00 (2H, m, CHN), 3.46 (2H, m, CHaO), 3.23 (2H, m, CHbO),
2.81 (2H, m, CH(CH3)2), 2.33 (2H, m, CHCH3), 1.68 (6H, d, J¼7.2 Hz,
CH3), 0.99 (6H, d, J¼6.8 Hz, CH3), 0.88 (6H, d, J¼7.2 Hz, CH3), 0.85
(6H, d, J¼6.4 Hz, CH3); 13C NMR (CDCl3, 100 MHz):
d 178.6, 178.4
3.6.8. 3-[((2S,3S)-4-Hydroxy-3-methylbutan-3-yl)thiazolidine-2,4-
(C]O), 176.6, 176.2 (C]O), 65.0 (CH2O), 63.5, 63.4, 62.7 (CHN), 43.4
(CH2S), 42.1 (CH), 37.1, 37.0, 36.9, 36.8 (CH(CH3)2), 25.7, 25.5, 25.4,
25.2 (CH3), 20.5, 20.2, 20.1, 20.0 (CH3), 19.9, 19.8, 19.5, 19.4 (CH3),
12.2, 12.1, 12.0 (CH3); IR nmax: 3414.1, 2930.0, 1745.3, 1658.7, 1330.5,
1100.5, 1027.2, 741.0 cmꢁ1. EI-HRMS: calculated for (C11H19NO3S),
245.1086; found, 245.1088.
25
dione (6c). Liquid 46% yield, [
a
]
þ6.40 (c 1.6, CHCl3); 1H NMR
D
(CDCl3, 400 MHz):
d
4.39 (1H, dq, J¼7.0, 9.2 Hz, CHN), 3.94 (2H, d,
J¼0.8 Hz, CH2S), 3.62 (2H, d, J¼4.8 Hz, CH2O), 2.40 (1H, m, CHCH3),
1.83 (1H, br s, OH), 1.49 (3H, d, J¼6.8 Hz, CH3), 0.90 (3H, d, J¼6.8 Hz,
CH3); 13C NMR (CDCl3, 100 MHz):
d 172.1 (C]O), 64.8 (CH2O), 53.1
(CHN), 37.8 (CH2S), 33.2 (CH), 15.7 (CH3), 14.1 (CH3); IR nmax: 3402.9,
2934.8, 2866.7, 1742.8, 1672.2, 1339.4, 1179.2, 872.6 cmꢁ1. EIMS:
calculated for (C8H13NO3S), 203.06; found, 203 (5%), 173 (40%), 144
(80%), 118 (100%), 116 (45%).
3.6.14. 3-[(1S,2S)-3-Hydroxy-2-methyl-1-phenylpropyl]-5-methyl-
25
thiazolidine-2,4-dione (8b). Liquid, 5.0% yield, [
a
]
ꢁ44.0 (c, 0.98,
D
CHCl3); 1H NMR (CDCl3, 300 MHz):
d
7.60–7.50 (2H, m, Ph), 7.40–
7.30 (3H, m, Ph), 5.14 (1H, dd, J¼11.7, 6.3 Hz, CHN), 4.08 (1H, dq,
J¼7.2, 2.8 Hz, CHS), 3.62 (2H, d, J¼4.5 Hz, CH2O), 3.23(1H, m,
CHCH3), 1.63 (3H, dd, J¼7.2, 2,1 Hz, CH3), 0.88 (3H, dd, J¼6.9, 6.6 Hz,
3.6.9. 3-[((2S,3R)-4-Hydroxy-3-methylbutan-3-yl)thiazolidine-2,4-
25
dione (7c). Liquid, 17% yield, [
(CDCl3, 400 MHz):
a]
þ3.76 (c 0.9, CHCl3); 1H NMR
D
d
4.26 (1H, dq, J¼10.7, 7.1 Hz, CHN), 3.92 (2H, s,
CH3); 13C NMR (CDCl3, 100 MHz):
d 175.6 (C]O), 171.2 (C]O), 137.1

118
R. Sabala et al. / Tetrahedron 66 (2010) 111–120
(Ci), 129.5 (C, Ph), 128.4 (C, Ph), 65.6 (CH2O), 61.5 (CHN), 43.1 (CHS),
33.5 (CHCH3), 18.9 (CH3), 15.4 (CH3); IR nmax: 3409.2, 2927.1, 1747.4,
. EI-HRMS: calculated for
(C14H17NO3S), 279.0929; found, 279.0931.
(Ci), 129.0 (Ph), 128.5, 128.4 (Ph), 126.7 (Ph), 65.5 (CH2O), 59.0
(CHN), 43.5 (CHS), 36.7, 36.5 (CH2), 35.1 (CHCH3), 19.2 (CH3), 15.0
(CH3); IR nmax: 3415.0, 2967.0, 2935.0, 1750.4, 1671.6, 1340.3, 1154.7,
979.1, 740.3, 703.2 cmꢁ1. EIMS: calculated for (C15H19NO3S), 293.11;
found, 293 (2%), 154 (100%), 136 (70%), 91 (43%), 55 (50%).
1662.8, 1326.9, 1168.9, 701.0 cmꢁ1
3.6.15. 3-[(1S,2R)-3-Hydroxy-2-methyl-1-phenylpropyl]-5-methyl-
25
thiazolidine-2,4-dione (9b). Liquid, 75% yield, [
a]
ꢁ43.0 (c, 1.6,
3.6.20. (4S,5S)-4-Isopropyl-5-methyltetrahydro-2H-1,3-oxazin-2-
D
25
CHCl3); 1H NMR (CDCl3, 400 MHz):
d
7.60–7.50 (2H, m, Ph), 7.38–
one (10a). White crystalline solid, 77% yield, mp¼108–109 ꢀC, [
a]
D
7.30 (3H, m, Ph), 5.16 (1H, dd, J¼11.6, 12.0 Hz, CHN), 4.11 (1H, m,
CHS), 3.54 (1H, ddd, J¼10.4, 5.6, 2.8 Hz, CHaO), 3.34 (1H, ddd,
J¼10.4, 5.6, 2.8 Hz, CHbO), 3.32 (1H, m, CHCH3), 1.63 (3H, dd, J¼7.6,
7.2 Hz, CH3), 1.04 (3H, dd, J¼6.8, 6.9 Hz, CH3); 13C NMR (CDCl3,
ꢁ3.03 (c 1.12, CHCl3); 1H NMR (400 MHz, CDCl3):
d 5.44 (1H, br s,
NH), 4.17 (1H, dd, J¼10.8, 4.0 Hz, CHaHb), 3.88 (1H, dd, J¼11.2,
9.6 Hz, CHbHa), 2.94 (1H, ddd, J¼8.3, 3.7, 1.2 Hz, CHN), 1.98 (1H, m,
CHCH3), 1.90 (1H, m, CH(CH3)2), 1.00 (3H, d, J¼6.6 Hz, CH3), 0.99
(3H, d, J¼6.6 Hz, CH3), 0.91 (3H, d, J¼6.6 Hz, CH3); 13C NMR
100 MHz):
d 175.6 (C]O), 171.2 (C]O), 137.1 (Ci), 129.2 (C, Ph),
128.4 (C, Ph), 64.7 (CH2–O), 61.1 (CHN), 43.1 (CHS), 34.6 (CHCH3),
19.2 (CH3), 14.4 (CH3); IR nmax: 3412.8, 2952.2, 1747.2, 1667.2,
1327.5, 1163.4, 697.2 cmꢁ1. EI-HRMS: calculated for (C14H17NO3S),
279.0929; found, 279.0930.
(100 MHz, CDCl3): d 155.0 (C]O), 70.8 (C–O), 62.4 (C–N), 29.6
(CHN), 28.5 (CH), 19.4 (CH3), 15.3 (CH3), 13.7 (CH3); IR nmax: 3289.1,
2962.3, 2875.7, 1693.3, 1479.0, 1421.0, 1285.8, 1109.6, 1016.6,
766.8 cmꢁ1. EI-HRMS: calculated for (C8H15N1O2), 157.1103; found,
157.1100.
3.6.16. 3-[(2S,3S)-4-Hydroxy-3-methylbutan-2-yl]-5-methyl-
25
thiazolidine-2,4-dione (8c). Liquid 65% yield, [
a
]
þ8.77 (c 1.23,
3.6.21. (4S,5R)-4-Isopropyl-5-methyl tetrahydro-2H-1,3-oxazin-2-one
D
CHCl3); 1H NMR (CDCl3, 400 MHz):
d
4.31 (1H, m, CHN), 4.10 (1H, q,
(11a0). White solid, 79.2% yield, mp¼90–92 ꢀC, [
a]
D
ꢁ1.75 (c 0.4,
25
J¼7.2 Hz, CHS), 3.60 (2H, d, J¼4.8 Hz, CH2O), 2.40 (1H, m, CHCH3),
CHCl3); 1H NMR (400 MHz, CDCl3):
d 5.41 (1H, br s, NH), 4.28 (1H, dd,
2.04 (1H, br s, OH), 1.70 (3H, d, J¼6.8 Hz, CH3), 1.50 (3H, d, J¼7.2 Hz,
J¼11.0, 2.6 Hz, CHaHb), 4.13 (1H, dd, J¼11.0, 2.6 Hz, CHbHa), 3.08 (1H,
dd, J¼10.0, 4.0 Hz, CHN), 2.08 (1H, m, CHCH3), 1.60 (1H, m,
CH(CH3)2), 1.05 (3H, d, J¼6.8 Hz, CH3), 1.01 (3H, d, J¼6.4 Hz, CH3),
CH3), 0.88 (3H, d, J¼6.8 Hz, CH3); 13C NMR (CDCl3,100 MHz):
d 176.0
(C]O), 171.5 (C]O), 64.8 (CH2O), 53.0 (CHN), 43.1, 42.9 (CH2S),
37.9, 37.7 (CHCH3), 19.4, 19.2 (CH3), 15.8, 15.7 (CH3), 14.0 (CH3);
IR nmax: 3410.1, 2931.0, 1746.3, 1653.7, 1329.5, 1108.5, 1027.2,
740.4 cmꢁ1. EIMS: calculated for (C9H15NO3S); 217.08; found, 217
(5%), 199 (15%), 187 (30%), 158 (70%), 132 (100%), 130 (42%).
0.94 (3H, d, J¼6.8 Hz CH3); 13C NMR (100 MHz, CDCl3)
d: 153.7
(C]O), 72.8 (C–O), 61.0 (C–N), 29.3 (CH), 27.4 (CH), 19.0 (CH3), 18.5
(CH3), 9.5 (CH3); IR nmax: 3290.0, 2964.3, 2932.2, 1695.3, 1487.0,
1423.0, 1286.0, 1108.6, 1016.6, 766.2 cmꢁ1. EI-HRMS: calculated for
(C8H15N1O2), 157.1103; found, 157.1100.
3.6.17. 3-[(2S,3R)-4-Hydroxy-3-methylbutan-2-yl]-5-methyl-
25
thiazolidine-2,4-dione (9c). Liquid 6.5% yield, [
a
]
ꢁ0.8 (c 1.6,
3.6.22. (4S,5S)-4-Benzyl-5-methyltetrahydro-2H-1,3-oxazin-2-one
D
25
CHCl3); 1H NMR (CDCl3, 400 MHz):
d
4.21 (1H, m, CHN), 4.16 (1H,
(10d). White solid, 60% yield, mp¼124 ꢀC, [
a
]
D
ꢁ79.3 (c 0.6,
dq, J¼7.2, 1.0 Hz, CHS), 3.43 (2H, dd, J¼4.2, 2.6 Hz, CH2O), 2.40 (1H,
m, CHCH3), 1.69 (3H, dd, J¼7.4, 3.4 Hz, CH3), 1.46 (3H, d, J¼6.8 Hz,
CH3), 1.03 (3H, d, J¼6.8 Hz, CH3); 13C NMR (CDCl3, 100 MHz):
CHCl3); 1H NMR (400 MHz, CDCl3):
d 7.37–7.19 (5H, m, Ph), 5.00
(1H, br s, NH), 4.26 (1H, dd, J¼3.0, 11.0 Hz, CHaHb), 4.14 (1H, dd,
J¼4.6, 11.0 Hz, CHbHa), 3.80 (1H, ddd, J¼10.0, 5.0, 5.1 Hz, CHN), 2.85
(1H, dd, J¼5.2, 13.2 Hz, CHaHbPh), 2.60 (1H, dd, J¼9.6, 13.2 Hz,
CHbHaPh), 2.17 (1H, m, CH), 1.16 (3H, d, J¼6.8 Hz, CH3); 13C NMR
d
176.3, 176.1 (C]O), 171.8, 171.7 (C]O), 65.6, 65.5 (CH2O), 53.4,
53.3 (CHN), 43.2, 43.0 (CH2S), 37.1, 36.9 (CHCH3), 19.1, 19.0 (CH3),
16.0, 15.9 (CH3), 14.8 (CH3); IR nmax: 3412.0, 2931.0, 1746.3,
1653.7, 1329.5, 1108.5, 1027.2, 740.4 cmꢁ1. EIMS: calculated for
(C9H15NO3S); 217.08; found, 217 (3%), 199 (15%), 187 (30%), 158
(70%), 132 (100%), 130 (42%).
(100 MHz, CDCl3): d 153.4 (C]O), 136.2 (Ci), 129.2 (Cm), 129.0 (Co),
127.1 (Cp), 71.5 (CH2–O), 55.3 (CHN), 38.2 (CH2Ph), 28.8 (CH), 10.6
(CH3); IR nmax: 3242.8, 2922.7, 1703.8, 1422.8, 1117.6, 767.5, 731.3,
700.8 cmꢁ1; FAB-HRMS calculated for (C12H16N1O2), 206.1181;
found, 206.1162.
3.6.18. 3-[(2S,3S)-4-Hydroxy-3-methyl-1-phenylbutan-2-yl]-5-
25
methylthiazolidine-2,4-dione (8d). Liquid 62% yield, [
a
]
ꢁ49.1 (c
3.6.23. (4S,5R)-4-Benzyl-5-methyltetrahydro-2H-1,3-oxazin-2-one
D
25
1.0, CHCl3); 1H NMR (CDCl3, 400 MHz):
d
7.27–7.13 (5H, m, Ph), 4.64
(11d0). White solid, 60% yield, mp¼126 ꢀC, [
a
]
D
ꢁ39.6 (c 1.0,
(1H, m, CHN), 3.94 (1H, m, CHS), 3.76 (1H, m, CHaHbO), 3.68 (1H, dd,
J¼11.2, 4.8 Hz, CHbHaO), 3.36 (1H, m, CHaHbPh), 3.17 (1H, dd, J¼13.4,
5.0 Hz, CHbHaPh), 2.49 (1H, m, CHCH3), 2.10 (1H, br s, OH), 1.55 (1H,
d, J¼6.8 Hz, CH3), 1.28 (1H, d, J¼7.2 Hz, CH3), 1.0 (1H, d, J¼7.2 Hz,
CHCl3); 1H NMR (400 MHz, CDCl3):
d 7.36–7.18 (5H, m, Ph), 5.60
(1H, br s, NH), 4.22 (1H, dd, J¼4.0, 11.2 Hz, CHaHb), 3.91 (1H, t,
J¼11.0 Hz, CHbHa), 3.33 (1H, ddd, J¼9.0, 4.0, 3.6 Hz, CHN), 3.09 (1H,
dd, J¼14.0, 3.6 Hz, CHaHbPh), 2.55 (1H, dd, J¼13.6, 9.6 Hz, CHbHaPh),
1.92 (1H, m, CH), 1.09 (3H, d, J¼6.4 Hz, CH3); 13C NMR (100 MHz,
CH3), 0.95 (3H, d, J¼6.4 Hz, CH3); 13C NMR (CDCl3,100 MHz):
d 176.0
(C]O),171.8 (C]O),137.6 (Ci),129.0, 128.9, 128.8 (Ph),128.4,128.35
(Ph), 126.6 (Ph), 64.9 (CH2O), 59.1, 58.9, 57.4 (CHN), 43.4, 43.2, 41.9
(CHS), 37.6, 37.4, 37.1, (CH2), 35.2, 35.1, 34.5 (CHCH3), 19.2 (CH3),
14.5, 14.3 (CH3); IR nmax: 3413.1, 2965.3, 2931.9, 1748.4, 1670.6,
1339.3, 1154.5, 979.2, 740.0, 701.2 cmꢁ1. EIMS: calculated for
(C15H19NO3S), 293.11; found, 293 (3%), 154 (100%), 136 (90%), 91
(60%), 55 (50%).
CDCl3): d 154.5 (C]O), 135.7 (Ci), 129.2 (Cm), 129.0 (Co), 127.3 (Cp),
70.7 (CH2O), 58.0 (CHN), 40.7 (CH2Ph), 31.1 (CH),13.4 (CH3); IR nmax
:
;
3243.8, 2924.6, 1704.8, 1420.8, 1117.6, 768.5, 733.3, 701.8 cmꢁ1
FAB-HRMS calculated for (C12H16N1O2), 206.1181; found, 206.1162.
3.6.24. (4S,5S)-4-Isopropyl-5-methy-3-(tert-butylcarboxylate)-
25
tetrahydro-2H-1,3-oxazin-2-one (12a). Liquid, 80% yield,
[a]
D
þ78.4 (c 1.39 CHCl3); 1H NMR (CDCl3, 400 MHz):
d 4.18 (1H, dd,
3.6.19. 3-[(2S,3R)-4-Hydroxy-3-methyl-1-phenylbutan-2-yl]-5-
J¼10.8, 5.6 Hz, CHaHbO), 3.80 (1H, dd, J¼4.8, 2.4 Hz, CHN), 3.77
(1H, d, J¼10.8 Hz, CHaHbO), 2.27 (1H, m, CHCH3), 2.01 (1H, m, CH),
1.52 (9H, s, 3CH3), 1.10 (3H, d, J¼6.8 Hz, CH3), 0.96 (3H, d,
J¼6.8 Hz, CH3), 0.95 (3H, d, J¼6.8 Hz, CH3); 13C NMR (CDCl3,
25
methylthiazolidine-2,4-dione (9d). Liquid 7.5%, yield, [
a
]
ꢁ79.3 (c,
D
1.4, CHCl3); 1H NMR (CDCl3, 400 MHz):
d
7.27–7.13 (5H, m, Ph), 4.36
(1H, m, CHN), 3.94 (1H, m, CHS), 3.49 (2H, s, CH2O), 3.30 (1H, m,
CHaHbPh), 3.11 (1H, dd, J¼13.6, 4.8 Hz, CHbHaPh), 2.50 (1H, m,
CHCH3), 1.54 (1H, br s, OH), 1.18 (3H, d, J¼6.8 Hz, CH3), 0.99 (3H, d,
100 MHz):
d 152.7 (C]O), 151.9 (C]O), 83.1 (C), 70.4 (CH2O), 64.5
(CHN), 30.0 (CH), 30.1 (CH), 28.0 (3CH3), 19.1 (CH3), 17.7 (CH3); IR
nmax 2966.4, 2928.6, 1762.3, 1720.4, 1366.9, 1298.8, 1156.6,
J¼6.4 Hz, CH3); 13C NMR (CDCl3, 100 MHz):
d
176.3 (C]O), 137.5
:

R. Sabala et al. / Tetrahedron 66 (2010) 111–120
119
854.8 cmꢁ1. EIMS: calculated for (C13H23NO4), 257.16; found, 257
1366.2, 1170.9 cmꢁ1
.
FAB-HRMS calculated for (C12H16N1O3),
(2.0%), 114 (100%), 70 (35%) 57 (55%).
232.1913; found, 232.1923.
3.6.25. (4S,5R)-4-Isopropyl-5-methyl-3-(tert-butylcarboxylate)-
3.6.30. (2S,3S)-2-Methyl-4-phenyl-3-[N-(tert-butoxycarbonyl)amino]-
25
25
tetrahydro-2H-1,3-oxazin-2-one (13a0). Liquid, 60% yield,
[
a
]
butan-1-ol (14d). White solid, mp¼76 ꢀC, 95% yield, [
a]
D
þ3.35 (c
D
þ15.5 (c 0.6 CHCl3); 1H NMR (CDCl3, 400 MHz):
d
4.27 (1H, ddd,
0.92 CHCl3); 1H NMR (CDCl3, 400 MHz):
d 7.32–7.18 (5H, m, Ph), 4.64
J¼11.2, 6.4, 1.2 Hz, CHaHbO), 4.07 (1H, dd, J¼11.28 Hz, CHaHbO), 4.06
(1H, dd, J¼4.4 Hz, CHN), 2.47 (1H, m, CHCH3), 1.98 (1H, m, CH), 1.54
(9H, s, 3CH3), 1.10 (3H, d, J¼6.8 Hz, CH3), 1.05 (3H, d, J¼6.8 Hz, CH3),
(1H, d, J¼9.2 Hz, NH), 3.83 (1H, m, CHN), 3.78 (1H, d, J¼12.0 Hz,
CHaHbO), 3.46 (1H, d, J¼11.6 Hz, CHbHaO), 3.00 (1H, dd, J¼4.8,14.0 Hz,
CHaHb), 2.86 (1H, br s, OH), 2.71 (1H, dd, J¼8.0,14.0, CHbHa), 1.54 (1H,
m, CHCH3), 1.36 (9H, s, 3CH3), 1.15 (3H, d, J¼6.8 Hz, CH3); 13C NMR
0.95 (3H, d, J¼6.8 Hz, CH3); 13C NMR (CDCl3, 100 MHz):
d 152.6
(C]O), 149.01 (C]O), 83.5 (C), 70.3 (CH2O), 61.4 (CHN), 32.0 (CH),
(CDCl3, 100 MHz): d 156.8 (C]O), 138.0 (Ci), 129.1 (Cm), 128.5 (Co),
29.7 (CH), 28.0 (3CH3), 27.4 (CH3), 19.2 (CH3), 13.3 (CH3); IR nmax
:
.
126.4 (Cp), 79.6 (C), 64.6 (CH2O), 53.1 (CHN), 39.0 (CH2), 38.3
(CHCH3), 28.3 (3CH3), 15.1 (CH3); IR nmax: 3365.6, 2974.9, 2930.6,
1685.3, 1506.9, 1365.7, 1250.0, 1169.3, 1042.8 cmꢁ1. EI-HRMS: calcu-
lated for (C16H25N03) [MþꢁOC(CH3)3], 206.1181; found, 206.1178.
2966.4, 2928.6, 1762.3, 1720.4, 1366.9, 1298.8, 1156.6, 854.8 cmꢁ1
EIMS: calculated for (C13H23NO4), 257.16; found, 257 (2.0%), 114
(100%), 70 (35%) 57 (55%).
3.6.26. (4S,5S)-4-Benzyl-5-methy-3-(tert-butylcarboxylate)tetrahy-
3.6.31. (2R,3S)-2-Methyl-4-phenyl-3-[N-(tert-butoxy carbonyl)amino]-
25
25
dro-2H-1,3-oxazin-2-one (12d). Liquid, 97% yield, [
a]
þ27.9 (c 1.36
butan-1-ol (15d0). White solid, mp¼116 ꢀC, 99% yield, [
a
]
ꢁ18.5 (c
D
D
CHCl3); 1H NMR (CDCl3, 400 MHz):
d
7.32–7.20 (5H, m, Ph), 4.28
1.94, CHCl3); 1H NMR (CDCl3, 400 MHz):
d 7.31–7.22 (5H, m, Ph), 6.13
(1H, dd, J¼11.0, 4.6 Hz, CHaHbO), 4.13 (1H, ddd, J¼9.2, 4.6, 4.4 Hz,
CHN), 3.88 (1H, dd, J¼11.2, 6.8 Hz, CHaHbO), 3.15 (1H, dd, J¼13.6,
4.6 Hz, CHaHb), 2.75 (1H, dd, J¼13.6, 9.2 Hz, CHaHb), 2.10 (1H, m,
CHCH3), 1.54 (9H, s, 3CH3), 0.90 (3H, d, J¼6.8 Hz, CH3); 13C NMR
(1H, d, J¼9.2 Hz, NH), 5.36 (1H, d, J¼9.6 Hz, NH), 4.00 (1H, m, CHN),
2.84 (1H, m, CHCH3), 2.68 (2H, m, CH2), 1.40 (9H, s, 3CH3), 1.26 (3H, d,
J¼6.8 Hz, CH3); 13C NMR (CDCl3, 100 MHz):
d 180.7 (C]O), 156.0
(C]O), 137.8 (Ci), 129.3 (Cm), 128.4 (Co), 126.5 (Cp), 79.4 (C), 54.1
(CDCl3, 100 MHz):
d
152.3 (C]O), 150.4 (C]O), 136.5 (Ci), 129.4
(CHN), 40.8 (CHCH3), 40.2 (CH2), 28.3 (3CH3), 15.1 (CH3); IR nmax:
(Cm), 128.7 (Co), 127.0 (Cp), 83.6 (C), 69.6 (CH2O), 61.2 (CHN), 40.9
(CH2), 30.8 (CHCH3), 27.9 (3CH3), 16.3(CH3); IR nmax: 2978.1, 2933.4,
3089.4, 2977.6, 2931.8, 1704.5, 1497.1, 1394.1, 1367.3, 1166.0,
700.1 cmꢁ1. EI-HRMS: calculated for (C16H25N03) [MþꢁOC(CH3)3],
206.1181; found, 206.1178.
1788.8, 1741.1, 1720.1, 1292.9, 1255.3, 1153.0, 1096.3, 701.0 cmꢁ1
.
EIMS: calculated for (C17H18NO4), 305.37; found, 305 (1.0%), 249
(10%), 141 (40%), 114 (100%), 71 (90%) 57 (62%).
3.6.32. (2S,3S)-2,4-Dimethyl-3-[N-(tert-butoxy carbonyl)amino]pen-
25
tanoic acid (16a). White solid, mp¼89 ꢀC, 97% yield, [
a
]
ꢁ29.4 (c
D
3.6.27. (4S,5R)-4-Benzyl-5-methyl-3-(tert-butylcarboxylate)tetrahy-
0.9 CHCl3); 1H NMR (CDCl3, 400 MHz):
d 9.95 (1H, br, OH), 5.82 (1H,
25
dro-2H-1,3-oxazin-2-one (13d0). Liquid, 97% yield, [
a
]
D
ꢁ8.9 (c 1.38
d, J¼10.4 Hz, NH), 5.21 (1H, d, J¼10.4 Hz, NH), 3.40 (1H, m, CHN),
2.82 (1H, m, CHCH3), 1.74 (1H, m, CH(CH3)2), 1.44 (9H, s, 3CH3), 1.26
(3H, d, J¼7.2 Hz, CH3), 0.96 (3H, d, J¼6.8 Hz, CH3), 0.93 (3H, d,
CHCl3); 1H NMR (CDCl3, 400 MHz):
d 7.31–7.20 (5H, m, Ph), 4.55
(1H, ddd, J¼10.9, 6.2, 1.2 Hz, CHaHbO), 4.14 (1H, dd, J¼12.0, 11.2 Hz,
CHaHbO), 2.93 (1H, dd, J¼14.0, 4.8 Hz, CHaHb), 2.73 (1H, dd, J¼14.0,
9.6 Hz, CHaHb), 2.52 (1H, m, CHCH3), 1.26 (9H, s, 3CH3), 1.06 (3H, d,
J¼6.4 Hz, CH3); 13C NMR (CDCl3, 100 MHz):
d 180.3 (C]O), 156.4
(C]O), 79.0 (C), 58.4 (CHN), 40.5 (CHCH3), 32.0 (CH(CH3)2), 28.4
(3CH3), 20.0 (CH3), 19.3 (CH3), 15.6 (CH3); IR nmax: 3313.1, 2964.4,
2926.5, 1709.0, 1392.0, 1367.4, 1169.9 cmꢁ1. FAB-HRMS calculated
for (C12H24N04), 246.1705; found, 246.1690.
J¼7.2 Hz, CH3); 13C NMR (CDCl3, 100 MHz):
d 151.0 (C]O), 148.7
(C]O), 137.1 (Ci), 129.5 (Cm), 128.6 (Co), 126.7 (Cp), 83.4 (C), 70.4
(CH2O), 58.1 (CHN), 34.6 (CH2), 31.4 (CHCH3), 27.6 (3CH3), 13.4
(CH3); IR nmax: 2980.0, 2934.4, 1788.8, 1741.1, 1721.0, 1292.9, 1255.3,
1154.0, 1096.3, 701.0 cmꢁ1
.
EIMS: calculated for (C17H18NO4),
3.6.33. (2R,3S)-2,4-Dimethyl-3-[N-(tert-butoxy carbonyl)amino]pen-
25
305.37; found, 249 (10%), 141 (40%), 114 (100%), 71 (90%) 57 (55%).
tanoic acid (17a0). Liquid, 96% yield, [
a]
þ3.7 (c 0.9 CHCl3); 1H
D
NMR (CDCl3, 400 MHz):
d
9.22 (1H, br, OH), 5.83 (1H, d, J¼10.0 Hz,
3.6.28. (2S,3S)-2,4-Dimethyl-3-[N-(tert-butoxy carbonyl)amino]pen-
NH), 4.50 (1H, d, J¼10.8 Hz, NH), 3.80 (1H, m, CHN), 3.67 (1H, m,
CHCH3), 1.77 (1H, m, CH(CH3)2), 1.43 (9H, s, 3CH3), 1.17 (3H, d,
J¼7.2 Hz, CH3), 0.95 (3H, d, J¼6.4 Hz, CH3), 0.90 (3H, d, J¼6.8 Hz,
25
tan-1-ol (14a). Liquid, 95% yield, [
(CDCl3, 400 MHz):
a
]
ꢁ4.1 (c 0.70 CHCl3); 1H NMR
D
d
4.53 (1H, d, J¼10.0 Hz, NH), 3.73 (1H, dd,
J¼12.0, 3.0 Hz, CHaHbO), 3.44 (1H, dd, J¼12.0, 2.0 Hz, CHbHaO), 3.38
(1H, ddd, J¼10.0, 9.6, 4.0 Hz, CHN), 3.15 (1H, br s, OH), 2.00 (1H, m,
CHCH3), 1.45 (9H, s, 3CH3), 1.43 (1H, m, CH(CH3)2), 1.03 (3H, d,
J¼7.2 Hz, CH3), 0.93 (3H, d, J¼7.2 Hz, CH3), 0.81 (3H, d, J¼6.8 Hz,
CH3); 13C NMR (CDCl3, 100 MHz):
d 180.0 (C]O), 156.0 (C]O), 79.3
(C), 57.1 (CHN), 42.5 (CHCH3), 30.2 (CH(CH3)2), 28.3 (3CH3), 20.2
(CH3), 16.9 (CH3), 12.9 (CH3); IR nmax: 3313.1, 2964.4, 2926.5, 1709.0,
1392.0, 1367.4, 1169.9 cmꢁ1. FAB-HRMS calculated for (C12H24N04),
246.1705; found, 246.1690.
CH3); 13C NMR (CDCl3, 100 MHz):
d 157.7 (C]O), 79.6 (C), 65.0
(CH2O), 56.2 (CHN), 38.0 (CH), 28.3 (3CH3), 27.5 (CH), 20.6 (CH3),
15.1 (CH3), 15.0 (CH3); IR nmax: 3329.9, 2965.9, 2929.6, 1677.4,
1532.6, 1366.2,1170.9 cmꢁ1. FAB-HRMS calculated for (C12H16N1O3),
232.1913; found, 232.1923.
3.6.34. (2S,3S)-2-Methyl-4-phenyl-3-[N-(tert-butoxy carbonyl)amino]-
25
butanoic acid (16d). White solid, mp¼116 ꢀC, 99% yield, [
a
]
ꢁ18.5 (c
D
1.94, CHCl3); 1H NMR (CDCl3, 400 MHz):
d 7.31–7.22 (5H, m, Ph), 6.13
(1H, d, J¼9.2 Hz, NH), 5.36 (1H, d, J¼9.6 Hz, NH), 4.00 (1H, m, CHN),
3.6.29. (2R,3S)-2,4-Dimethyl-3-[N-(tert-butoxy carbonyl)amino]pen-
2.84 (1H, m, CHCH3), 2.68 (2H, m, CH2), 1.40 (9H, s, 3CH3), 1.26 (3H, d,
J¼6.8 Hz, CH3); 13C NMR (CDCl3, 100 MHz):
d 180.7 (C]O), 156.0
(C]O), 137.8 (Ci), 129.3 (Cm), 128.4 (Co), 126.5 (Cp), 79.4 (C), 54.1
25
tan-1-ol (15a0). White solid, mp¼76 ꢀC, 95% yield, [
a
]
ꢁ6.6 (c 0.5
D
CHCl3); 1H NMR (CDCl3, 400 MHz):
d
4.42 (1H, d, J¼8.0 Hz, NH), 4.13
(1H, br, OH), 3.45 (1H, ddd, J¼10.0, 9.8, 2.8 Hz, CHN), 3.41 (1H, dd,
J¼12.4, 4.8 Hz, CHaHbO), 3.21 (1H, dd, J¼11.6, 10.4 Hz, CHbHaO), 2.03
(1H, m, CHCH3), 1.58 (1H, m, CH), 1.45 (9H, s, 3CH3), 1.00 (3H, d,
J¼6.8 Hz, CH3), 0.94 (3H, d, J¼6.4 Hz, CH3), 0.63 (3H, d, J¼7.2 Hz,
(CHN), 40.8 (CHCH3), 40.2 (CH2), 28.3 (3CH3), 15.1 (CH3); IR nmax:
3089.4, 2977.6, 2931.8, 1704.5, 1497.1, 1394.1, 1367.3, 1166.0,
700.1 cmꢁ1. EI-HRMS: calculated for (C16H23N04) [MþꢁOC(CH3)3],
220.0974; found, 220.0970.
CH3); 13C NMR (CDCl3, 100 MHz):
d 157.7 (C]O), 79.8 (C), 65.0
(CH2O), 55.6 (CHN), 36.1 (CH), 30.0 (CH), 28.2 (3CH3), 20.6 (CH3),
19.6 (CH3), 9.0 (CH3); IR nmax: 3329.9, 2965.9, 2929.6, 1677.4, 1532.6,
3.6.35. (2R,3S)-2-Methyl-4-phenyl-3-[N-(tert-butoxy carbonyl)amino]-
25
butanoic acid (17d0). White solid, mp¼156 ꢀC, 92% yield, [
a]
D
ꢁ32.7

120
R. Sabala et al. / Tetrahedron 66 (2010) 111–120
(c 1.88, CHCl3); 1H NMR (CDCl3, 400 MHz):
d
7.92–7.19 (5H, m, Ph),
range 2
q
¼4–50ꢀ, of which 979 are unique (Rint¼0.0386). 124 variables refined:
R1¼0.0608 [601 data with I>2
s
(I)] and wR2¼0.1849 [all data].21 Absolute con-
6.22 (1H, d, J¼8.8 Hz, NH), 4.81 (1H, d, J¼9.2 Hz, NH), 4.12 (1H, m,
figuration was determined assigned as (S,S) from synthetic route, which uses
a commercial chiral starting material, and measured Friedel pairs were merged.
CCDC-745170 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_re-
quest/cif, by emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ,
UK; fax: þ44 1223 336033.
CHN), 2.87 (1H, m, CHCH3), 2.71 (2H, m, CH2), 1.34 (9H, s, 3CH3), 1.26
(3H, s, CH3); 13C NMR (CDCl3, 100 MHz):
d 179.8 (C]O), 155.3 (C]O),
137.7 (Ci), 129.3 (Cm), 128.3 (Co), 126.4 (Cp), 79.4 (C), 53.4 (CHN), 43.1
(CHCH3), 37.8 (CH2), 28.0 (3CH3), 13.3 (CH3); IR nmax: 3316.1, 2977.8,
2931.8, 1704.9,1647.6, 1393.9, 1167.1, 699.6 cmꢁ1. EI-HRMS: calculated
for (C16H23N04) [MþꢁOC(CH3)3], 220.0974; found, 220.0970.
14. (a) Chowdhry, M. M.; Mingos, D. M. P.; White, A. J. P.; Williams, D. J. J. Chem. Soc.,
Perkin Trans. 2 2000, 2265–2268; (b) Saeed, A.; Abbas, N.; Flo¨rke, U. J. Braz.
Chem. Soc. 2007, 18, 559–565; (c) Tetsuro, S.; Yuki, M.; Tetsuo, I.; Teruo, S.;
Kenichi, S. Heterocycles 2007, 71, 1053–1058.
Acknowledgements
15. Burgess, K.; Ohlmeyer, M. J. J. Org. Chem. 1991, 56, 1027–1036.
16. Crystal data for 10a: C8H15NO2, M¼157.21, colorless prism, 0.40ꢂ0.36ꢂ0.
30 mm3, space group P212121, cell parameters a¼8.3878 (14), b¼10.3030 (14),
c¼21.031 (2) Å, Z¼8, Z0¼2, Dc¼1.149 g cmꢁ3. 4043 reflections collected on
We thank VIEP (project) and CONACyT (project) 80915. R.S. and
J.H. acknowledge a grant from CONACyT and VIEP.
a Siemens P4 diffractometer at room temperature, with the Mo Ka radiation
¼4–52.5ꢀ, of which 2112 are unique (Rint¼0.0413).
References and notes
(
l
¼0.71073 Å) in the range 2
q
214 variables refined. R1¼0.0438 [1322 data with I>2 (I)] and wR2¼0.1107 [all
s
data].21 Absolute configuration was assigned as S-C4, S-C5, S-C14, and S-C15
from the synthetic route, and measured Friedel pairs were merged. CCDC-
745171 contains the supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif,
by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: þ44
1223 336033.
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13. Crystal data for 5d: C23H28N2O, M¼348.47, colorless prism, 0.60ꢂ0.40ꢂ0.
38 mm3, space group P64, cell parameters a¼b¼11.737 (3), c¼13.573(8) Å Z¼3,
Z¼1/2, Dc¼1.072 g cmꢁ3. 6350 reflections collected on a Siemens P4 diffrac-
21. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112–122.
´
tometer at room temperature, with the Mo K
a
radiation (l¼0.71073 Å) in the