Efficient enantioselective synthesis of 2-substituted thiomorpholin-3-ones

Article abstract of DOI:10.1016/j.tetasy.2003.09.010

The synthesis of enantiomerically pure 4-(2-hydroxy-(1R)-phenylethyl)- thiomorpholin-3-one 2 from (R)-phenylglycine methyl ester, S-benzylthioglycolic acid and bromoacetic acid is reported. Stereoselective C-2 alkylation of 2, performed using various elec

Full text of DOI:10.1016/j.tetasy.2003.09.010

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3401–3405
Efficient enantioselective synthesis of 2-substituted
thiomorpholin-3-ones
Nicolas Franceschini, Sophie Da Nascimento, Pascal Sonnet and Dominique Guillaume*
Laboratoire de Chimie The´rapeutique, EA 2629, 1 rue des Louvels, 80000 Amiens, France
Received 18 July 2003; accepted 9 September 2003
Abstract—The synthesis of enantiomerically pure 4-(2-hydroxy-(1R)-phenylethyl)-thiomorpholin-3-one 2 from (R)-phenylglycine
methyl ester, S-benzylthioglycolic acid and bromoacetic acid is reported. Stereoselective C-2 alkylation of 2, performed using
various electrophiles, leads to enantiomerically pure 2-substituted thiomorpholin-3-ones after N-deprotection.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
to obtain different kinds of enantiomerically pure sub-
stituted heterocycles,20–23 we consequently considered
the novel thialactam 2 as a key intermediate for our
synthesis.
2-Substituted thiomorpholin-3-one (2-STMO) 1 is a
pharmacophore of great interest and derivatives con-
taining such a sub-unit have already been prepared and
evaluated in various biological fields.1,2 Compounds
accessible by taking advantage of the chemical potential
of 2-STMOs have also been reported as pharmacologi-
cally relevant3–5 or as chemically peculiar.6 However the
proliferation of 2-STMOs in medicinal chemistry is
undoubtedly hampered by the small number of enan-
tioselective methods available. Indeed, whereas several
racemic syntheses of 2-STMO derivatives have been
described in the liquid1–15 or solid phase16 only two
methods affording enantiomerically pure 2-STMOs
have been reported so far.17,18 However, in both cases,
the diversity for the C2-substituting chain is severely
limited by the availability of the corresponding enan-
tiomerically pure starting material (aminoacid,17 or
alkylglycidic ester18) and in one case,18 the enantiomeric
purity is unsatisfactory. Consequently, although chemi-
cally efficient, these methodologies can hardly be con-
sidered as general. Facing a recent crucial need to have
access to a synthetic method that would quickly afford
a large variety of enantiomerically pure 2-STMOs we
have studied different approaches and finally designed a
strategy leading to the required derivatives with a very
high enantioselectivity. Since 1,2-amino alcohols are
chiral auxiliaries often used in asymmetric synthesis19
and phenylglycinol has already been successfully used
Herein we describe the first, efficient synthesis of 2 in
an enantiomerically pure form together with its
stereoselective C-2 alkylation. N-Deprotection of the
alkylated adducts finally opens the field to a large
diversity of 2-STMOs.
2. Results and discussion
2.1. Preparation of 4-(2-hydroxy-(1R)-phenylethyl)-
thiomorpholin-3-one 2
While morpholin-3-ones, piperazin-2-ones, and d-lac-
tams having a nitrogen atom substituted with a chiral
appendage are known,20–23 the corresponding
thiomorpholin-3-ones have not been described to date.
We prepared 2 from (S)-phenylglycine methyl ester 3.
Condensation between 3 and S-benzylthioglycolic acid
in the presence of 1,3-dicyclohexylcarbodiimide (DCC)
afforded 4 in quantitative yield. Simultaneous reduction
* Corresponding author. Tel.: (33) 322 827 785; fax: (33) 322 827 469;
e-mail: dominique.guillaume@sa.u-picardie.fr
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.09.010

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N. Franceschini et al. / Tetrahedron: Asymmetry 14 (2003) 3401–3405
sation reasonably occured through the sulfonium inter-
mediate 6 that underwent spontaneous debenzylation in
the presence of bromide ions. Deprotection of 7
(Bu4NF) led to the key synthon 2 in 80% yield (Scheme
1).
2.2. Reaction of compound 2 with various electrophiles
and synthesis of 2-substituted-thiomorpholines
Being able to prepare 2 in satisfactory yields and enan-
tiomerically pure, we then studied its C2-substitution.
Stereoselective alkylation of 2 was achieved in THF in
the presence of HMPA (a co-solvent generally permit-
ting the alkylation step to proceed in better yields22),
using LDA as a strong base and methyl iodide, benzyl
bromide, and allyl bromide as model electrophiles
(Scheme 2). Chemical yields were between 91 and 96%
and only one diastereomer was observed on the 1H
NMR spectrum (500 MHz) of the alkylation products
demonstrating their high diastereomeric purity (above
96%) (Table 1). We also prepared an equimolar mixture
of 8b and its C2-epimer by alkylating 7 (LDA/HMPA,
PhCH2Br) which shared no asymmetric induction fol-
lowed by the O-deprotection step. Having in hands the
necessary isomers in pure form and as a racemic mix-
ture, we finally performed a HPLC analysis that
demonstrated the enantiomeric purity of 8b to be above
99% (only one diastereomer was detected).
Scheme 1. Reagents and conditions: (i) DCC, NMM,
PhCH2SCH2COOH; (ii) LAH, Et2O, 30 h; (iii) t-BDMSCl,
imidazole, 0°C; (iv) DCC, NMM, BrCH2COOH; (v) KBr; (vi)
Bu4NF, 0°C.
Unfortunately none of the alkylated compounds 8
afforded crystals suitable for X-ray analysis precluding
the unambiguous determination of the C2-configuration
in this series. Hence, we decided to demonstrate the
C2-configuration in the N-deprotected series and chose
1b as an example. Whereas hydrogenolysis has always
been the method of choice to remove the chiral
appendage in the previously studied series,20–23 8b
remained unreactive in the presence of hydrogen and
various Pt- or Pd-derived catalysts. However, debenzyl-
ation of 8b was successfully achieved using lithium in
ammonia/THF (−78°C, 10 min)24 and 1b was isolated
of the ester and amide function of 4 was achieved using
a suspension of LiAlH4 in ether as a reducting agent,
affording 5 in 95% yield. Protection of the primary
alcohol of 5 was achieved in 95% yield using tert-butyl-
dimethylsilyl chloride (t-BDMSCl) in the presence of
imidazole and condensation of the resulting adduct
with bromoacetic acid in the presence of DCC and
4-methylmorpholine (NMM) allowed the simultaneous
amide bond formation and cyclisation, leading, to the
thiomorpholin-3-one 7 in 85% yield (two steps). Cycli-
Scheme 2. Reagents and conditions: (i) LDA, HMPA, RX, −78°C; (ii) NH3, Li, −78°C, 10 min.
Table 1. Chemical yield and diastereomeric purity of the compounds obtained by enantioselective alkylation of 2
Electrophile used
Chemical yield (%)
De (method)
Isolated adduct ([h]D18
)
CH3I
PhCH2Br
CH2CHCH2Br
93
96
91
>96% (NMR)
>99% (NMR, HPLC)
>96% (NMR)
8a [−97 (c 0.1, EtOH)]
8b [−99 (c 0.1, EtOH)]
8c [−97 (c 0.1, EtOH)]

N. Franceschini et al. / Tetrahedron: Asymmetry 14 (2003) 3401–3405
3403
in 92% yield. Dimer 9 was isolated as a minor adduct
(5%) but longer debenzylation time led to its exclusive
obtention.
column chromatography. Diastereomeric excesses (de)
were determined by NMR and HPLC using a chirobi-
otic 18 mm column eluted with an isopropanol/cyclo-
hexane system. Optical rotations were taken at 18°C
with a Perkin Elmer 241 polarimeter.
To study the configuration of the created stereogenic
center, we also prepared 1b according to the previously
known aminoacid route.17 We separately used
-phenylalanine as starting material in order to obtain,
L
- and
4.2. (2R)-(2-Benzylsulfanylacetylamino)-phenylacetic
acid methyl ester, 4
D
individually, 1b and its enantiomer 1b(S) and, as
expected 1b and 1b(S) displayed specific rotations of
identical absolute value but opposite sign (+34.8, c 0.05,
EtOH, −32.9, c 0.05, EtOH; respectively). Optical rota-
tion observed for 1b obtained by our alkylation route
was found to be +33.9 (c 0.05, EtOH) demonstrating
the anticipated (R)-configuration of C2 and evidencing
the lack of racemization during the debenzylation step
and consequently the high enantiomeric purity of 1b.
A solution of S-benzylthioglycolic acid (5 g, 26.25
mmol) and DCC (6.1 g, 29.61 mmol) in CH2Cl2 (80
mL) was stirred at rt for 1 h. An ice-cooled solution of
3 (5.54 g, 29.61 mmol) and N-methylmorpholine (6 mL,
53.81 mmol) in CH2Cl2 (80 mL) was added. The reac-
tion was stirred overnight at rt. The precipitate was
filtered and washed with CH2Cl2. The filtrate was dried
over MgSO4, evaporated and compound
4 was
obtained as a white solid in quantitative yield after
The origin of the diastereoselectivity during the alkyla-
tion reaction of lactams has been previously
investigated25 and it is very likely that the high
diastereoselectivity observed in our study follows the
suggested models.
silica gel chromatography (EtOAc, C6H12): mp 86°C;
1
[h]1D8=−86 (c 0.1, EtOH); H NMR l (CDCl3) 7.81 (d,
1H, J=7.3 Hz), 7.6–7.3 (m, 10H), 5.72 (d, 1H, J=7.3
Hz), 3.78 (s, 3H), 3.75 (s, 2H), 3.20 (d, 1H, J=16.4 Hz),
3.14 (d, 1H, J=16.4 Hz); 13C NMR l (CDCl3) 171.5,
168.5, 137.2, 136.6, 129.5, 129.4, 129.1, 129.0, 127.8,
127.7, 57.0, 53.2, 37.2, 35.3; IR (cm−1) 3348, 1737, 1666,
1516, 1325, 1172, 711.
3. Conclusion
In summary, we have been able to prepare synthon 2
following a short and efficient route and have demon-
strated that its stereoselective C2-alkylation by various
electrophiles is possible. This shows that the sulfur
atom lone pairs do not modify the chemistry and
stereoselectivity of the alkylation reaction observed in
other series. Our strategy will permit the preparation of
thiomorpholin-3-ones stereoselectively substituted at
their 2-position by non proteogenic side-chains. The
allyl side chain will permit an entry to a variety of
derivatives design to mimic Asn, Gln, Glu, and Arg
side chains and since the phenyl group is not specifi-
cally necessary for the asymmetric induction26 various
4-substituted-2-STMOs can be easily reached. Biologi-
cal properties of selected derivatives obtained from 8
are currently being investigated.
4.3. (2R)-(2-Benzylsulfanylethylamino)-phenylethanol, 5
To an ice-cooled solution of 4 (5.57 g, 16.93 mmol) in
dry Et2O (90 mL) was added LiAlH4 (0.64 g, 16.93
mmol). The mixture was stirred for 1 h at rt, and then
additional LiAlH4 (1.93 g, 50.8 mmol) was added to the
reaction. Stirring was continued for 30 h, and then a
15% aqueous solution of NaOH (0.8 mL) was added
dropwise to the reaction cooled at −10°C. After one
hour, water (2 mL) was added, and the suspension was
stirred overnight at rt. The precipitate was filtered and
then washed with CH2Cl2. The filtrate was dried over
MgSO4, evaporated and a yellow solid was obtained in
95% yield after silica gel chromatography (EtOAc,
1
C6H12): mp 84°C; [h]D18=−50 (c 0.1, EtOH); H NMR l
(CDCl3) 7.2–7.5 (m, 10H), 3.7–3.8 (m, 2H), 3.65 (s,
2H), 3.61–3.59 (m, 1H), 2.89 (broad s, 1H), 2.6–2.8 (m,
2H), 2.6–2.65 (m, 2H); 13C NMR l (CDCl3) 140.9,
138.7, 130.1, 129.3, 128.9, 128.1, 127.7, 127.5, 67.2,
64.8, 45.9, 35.7, 32.1; IR (cm−1) 3252, 1658, 1570, 1043,
769, 698.
4. Experimental
4.1. General
Infrared spectra were recorded on a Nicolet 210 spec-
4.4. 4-[(2R)-[1-(tert-Butyldimethylsilanyloxy)]-phenyl-
ethyl]thiomorpholin-3-one, 7
1
trometer using film KBr pellet techniques. H and 13C
NMR spectra were recorded at 500 and 125 MHz;
respectively, residual solvent traces being used as inter-
nal standard. Mass spectra were obtained in chemical
ionization mode by direct insertion (ionizing gas NH3).
Diisopropylamine was dried over CaH2 and distilled
prior to use. Et2O and THF were dried over sodium/
benzophenone before distillation. Alkylation reactions
were carried out under nitrogen atmosphere condition.
Thin layer chromatography was performed on pre-
coated silica gel plates (60-F254, 0.2 mm) and revealed
by spraying with phosphomolybdic acid the heating.
Silica gel (grade 60, 230–400 mesh) was used for
To an ice-cooled solution of 5 (3.98 g, 13.86 mmol)
were added imidazole (1.89 g, 27.72 mmol) in CH2Cl2
(7 mL) and tert-butyldimethylsilyl chloride (2.7 g, 18.02
mmol). The solution was stirred for 6 h at rt. The
reaction was quenched by addition of H2O (25 mL) and
then made alkaline by addition of a saturated aqueous
solution of Na2CO3 (100 mL). The aqueous phase was
extracted with Et2O (2×150 mL), which was further
washed with H2O (3×75 mL), dried over MgSO4, and
concentrated. An oil was obtained in 95% yield. A
solution of bromoacetic acid (8.3 g, 59.51 mmol) and

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N. Franceschini et al. / Tetrahedron: Asymmetry 14 (2003) 3401–3405
DCC (6 g, 29.02 mmol) in CH2Cl2 (50 mL) was stirred
at rt for 1 h. The white precipitate was removed and
the filtrate poured into a solution of the previously
obtained oil (5.5 g, 13.7 mmol) and N-methylmorpho-
line (4.25 mL, 39.63 mmol) in CH2Cl2 (25 mL) cooled
at 0°C. The reaction was stirred overnight at rt. The
precipitate was filtered and then washed with CH2Cl2.
The filtrate was dried over MgSO4, evaporated and an
oil was obtained in 85% yield after silica gel chro-
matography (EtOAc, C6H12): [h]1D8=−56 (c 0.1, EtOH);
1H NMR l (CDCl3) 7.2–7.4 (m, 5H), 5.85 (t, 1H,
J=5.5 Hz), 4.12 (d, 2H, J=5.5 Hz), 3.5–3.6 (m, 1H),
3.4–3.45 (m, 1H), 3.35 (s, 2H), 2.82–2.78 (m, 1H),
2.55–2.65 (m, 1H), 0.90 (s, 9H), 0.00 (s, 6H); 13C NMR
l (CDCl3) 168.5, 138.1, 129.4, 128.9, 128.1, 77.5, 62.7,
57.3, 44.4, 30.1, 27.2, 26.5, 0.00; IR (cm−1) 3364, 2957,
2862, 1616, 1475, 1259, 1064, 844, 777.
5H), 5.82 (dd, 1H, J=8.8, 5.2 Hz), 4.10 (dd, 1H,
J=11.4, 8.8 Hz), 3.95 (dd, 1H, J=11.4, 5.2 Hz), 3.6–
3.7 (m, 2H), 3.4–3.3 (m, 2H), 2.6–2.7 (m, 1H), 2.2–2.3
(m, 1H), 2.13 (broad s, 1H), 1.19 (s, 3H); 13C NMR l
(CDCl3) 173.5, 137.4, 129.6, 129.2, 128.3, 62.1, 58.5,
42.8, 36.0, 27.8, 15.6; IR (cm−1) 3425, 1659, 1501, 423;
HRMS (ESI+) (MH+): calcd for C13H18NO2S:
252.1058. Found: 252.1046. HPLC analysis: rt=44.4
min.
4.6.2.
(2R)-Benzyl-4-(2-hydroxy-(1%R)-phenylethyl)-
thiomorpholin-3-one, 8b. Following the general proce-
dure, 8b was prepared in 96% yield: [h]1D8=−99 (c 0.1,
EtOH); 1H NMR l (CDCl3) 7.4–7.6 (m, 10H), 6.13
(dd, 1H, J=8.2, 5.5 Hz), 4.01 (dd, 1H, J=11.5, 8.2
Hz), 3.91 (dd, 1H, J=11.5, 5.5 Hz), 3.74 (dd, 1H,
J=9.2, 4.6 Hz), 3.41 (dd, 1H, J=14.3, 4.6 Hz), 3.4–
3.45 (m, 2H), 3.08 (dd, 1H, J=14.3, 9.2 Hz), 2.5–2.55
(m, 1H), 2.42 (broad s, 1H), 2.1–2.2 (m, 1H); 13C
NMR l (CDCl3) 172.3, 138.9, 137.2, 129.7, 129.2,
128.8, 128.5, 128.3, 127.1, 62.3, 58.6, 43.6, 43.0, 36.9,
27.6; IR (cm−1) 3413, 2930, 1655, 1627, 1465, 704;
HRMS (ESI+) (MH)+: calcd for C19H22NO2S:
328.1371. Found: 328.1375. HPLC analysis: rt=39.1
min.
4.5. 4-(2-Hydroxy-(1R)-phenylethyl)-thiomorpholin-3-
one, 2
To an ice-cooled solution of 7 (3.53 g, 10.06 mmol) in
THF (130 mL) was added 20 mL of a 1.0 M solution
of Bu4NF in THF. The reaction was stirred for 2 h at
rt, and then H2O (190 mL) was added. The two phases
were separated, and the aqueous phase was extracted
with CH2Cl2 (2×250 mL). The combined organic
phases were washed with H2O (4×250 mL), dried, and
concentrated, affording a white solid after silica gel
chromatography (EtOAc, C6H12) in 80% yield: mp
4.6.3.
(2R)-Allyl-4-(2-hydroxy-(1%R)-phenylethyl)-
thiomorpholin-3-one, 8c. Following the general proce-
dure, 8c was prepared in 91% yield: [h]1D8=−97 (c 0.1,
EtOH); H NMR l (CDCl3) 7.4–7.2 (m, 5H), 5.82 (dd,
1
88°C; [h]1D8=−102 (c 1, EtOH); H NMR l (CDCl3)
1
7.4–7.6 (m, 5H), 5.85 (dd, 1H, J=8.2, 5.5 Hz), 4.35
(dd, 1H, J=8.2, 6.6 Hz), 4.29 (dd, 1H, J=6.6, 5.5 Hz),
3.6–3.7 (m, 2H), 3.57 (s, 2H), 3.0–3.1 (m, 1H), 2.8–2.85
(m, 1H), 2.80 (broad s, 1H); 13C NMR l (CDCl3)
168.4, 138.5, 129.3, 128.5, 128.2, 62.5, 59.3, 44.5, 30.4,
27.2; IR (cm−1) 3426, 1637, 1450, 1064, 703.
1H, J=9.6, 4.8 Hz), 5.81 (m, 1H), 5.1 (d, 1H, J=17.0
Hz), 5.0 (d, 1H, J=10.1 Hz), 4.10 (dd, 1H, J=11.3,
4.8 Hz), 3.96 (dd, 1H, J=11.3, 9.8 Hz), 3.5–3.6 (m,
1H), 3.3–3.43 (m, 2H), 3.19 (broad s, 1H), 2.75–2.8 (m,
1H), 2.6–2.7 (m, 1H), 2.3–2.4 (m, 1H), 2.25–2.3 (m,
1H); 13C NMR l (CDCl3) 172.2, 137.4, 135.3, 129.2,
128.5, 128.3, 117.9, 62.2, 58.5, 42.9, 41.4, 35.1, 27.5; IR
(cm−1) 3401, 2974, 1651, 1437, 712; HRMS (ESI+)
(MH+): calcd for C15H20NO2S: 278.1215. Found:
278.1211. HPLC analysis: rt=38.3 min.
4.6. Alkylated compounds 8a–c, general procedure
A solution of diisopropylamine (1 mL, 7.35 mmol) in
dry THF (20 mL) was cooled at −78°C under nitrogen
atmosphere. A 1.6 M hexane solution of n-BuLi (4
mL, 6.40 mmol) was carefully added and the reaction
stirred at −78°C for 15 min. A solution of 2 (0.50 g,
2.13 mmol) and HMPA (1.12 mL, 6.3 mmol) in dry
THF (5 mL) was added and the reaction stirred at
−78°C for 15 min. A solution of electrophile (6.3
mmol) in dry THF (5 mL) was added and the reaction
stirred at −78°C for 45 min, and then at −50°C for 3–5
h, and finally at −15°C for 15 min. At the end of this
period, the reaction was quenched by addition of a
saturated aqueous solution of ammonium chloride (100
mL). The two phases were separated and the aqueous
phase was extracted with CH2Cl2 (3×60 mL). The com-
bined organic phases were dried, and concentrated,
affording after silica gel chromatography (EtOAc,
C6H12) the alkylated compound.
4.7. (2R)-Benzylthiomorpholin-3-one, 1b
Anhydrous ammonia (20 mL) was condensed at −78°C
under a nitrogen atmosphere. Lithium (3 equiv.) was
added. A solution of alkylated compound 8b (32.7 mg,
1 mmol) in THF (10 mL) was added slowly. The
solution was stirred at −78°C for 10 min under nitro-
gen atmosphere. Then the reaction was quenched by
addition of water (0.1 mL) and the mixture stirred at rt
for 3 h. The solution was filtered and concentrated
under reduced pressure. Purification was achieved by
silica gel chromatography (EtOAc, C6H12) affording 1b
1
in 92% yield: [h]1D9=+33.9 (c 0.05, EtOH); H NMR l
(CDCl3) 7.2–7.3 (m, 5H), 7.05–7.15 (m, 1H), 3.62 (dd,
1H, J=10.8, 5.5 Hz), 3.5–3.55 (m, 1H), 3.4–3.5 (m,
2H), 2.86 (dd, 1H, J=13.1, 10.8 Hz), 2.65–2.7 (m, 2H);
13C NMR l (CDCl3) 171.2, 138.6, 129.4, 128.8, 127.3,
44.1, 43.7, 37.7, 26.3; IR (cm−1) 3460, 3190, 1741, 1662,
1458, 1346, 711; HRMS (ESI+) (MH)+: calcd for
C11H14NOS: 208.0796. Found: 208.0804.
4.6.1.
(2R)-Methyl-4-(2-hydroxy-(1%R)-phenylethyl)-
thiomorpholin-3-one, 8a. Following the general proce-
dure, 8a was prepared in 93% yield: mp 68°C; [h]1D8=
−97 (c 0.1, EtOH); H NMR l (CDCl3) 7.2–7.4 (m,
1

N. Franceschini et al. / Tetrahedron: Asymmetry 14 (2003) 3401–3405
3405
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