(R)-[(2-oxo-4-thiazolidinyl)methyl]triphenylphosphonium iodide: A wittig reagent for the synthesis of cysteine-derived alkenes

Article abstract of DOI:10.1055/s-0031-1289583

(R)-[(2-Oxo-4-thiazolidinyl)methyl]triphenylphosphonium iodide (1), readily prepared in five steps from l-cysteine ethyl ester (39% overall on a 500 g scale), is a useful Wittig reagent for the synthesis of cysteine-derived alkenes such as those found in

Full text of DOI:10.1055/s-0031-1289583

PAPER
3859
(R)-[(2-Oxo-4-thiazolidinyl)methyl]triphenylphosphonium Iodide:
A Wittig Reagent for the Synthesis of Cysteine-Derived Alkenes
Christina J. Shaffer, RuLin Fan,1 Michael D. Lewis, James J. Kowalczyk*
Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA
E-mail: jkowalczyk@alum.mit.edu
Received 27 April 2011; revised 6 September 2011
modifications. We found triphosgene5 to be more conve-
nient and safer to handle and to give more reproducible
yields than phosgene for the thiazolidinone formation, and
cysteine ethyl ester gave consistently higher yields than
Abstract: (R)-[(2-Oxo-4-thiazolidinyl)methyl]triphenylphospho-
nium iodide (1), readily prepared in five steps from L-cysteine ethyl
ester (39% overall on a 500 g scale), is a useful Wittig reagent for
the synthesis of cysteine-derived alkenes such as those found in
dipeptide isosteres and peptidomimetics. Preparation of 1 and its cysteine methyl ester.6 Careful control of the temperature
use in Wittig olefination reactions with aldehydes is described. The
resulting thiazolidinone compounds are readily unmasked to pro-
in the borohydride reduction of ester 4 (both during the re-
action and the quench) gave improved yields of alcohol
vide the corresponding thiol, symmetrical disulfide, or S-trityl de-
5.7 Notably, the sequence was optimized to require no
rivatives.
chromatography, and the final step required only a small
Key words: Wittig reaction, aldehydes, alkenes, peptidomimetics,
thiazolidinones
excess of triphenylphosphine. This sequence has been
used routinely to prepare 1 on a 500–1000 g scale.8 Com-
pound 1 is stored as a powder in a desiccator at room tem-
perature and is routinely dried under vacuum with
In the course of preparing a series of tetrapeptide isosteres
warming prior to use.
of the CA1A2X motif2 (C = cysteine, A = an aliphatic ami-
no acid, and X = methionine, serine, or glutamine) as far-
triphosgene
NaHCO3
nesyltransferase inhibitors,3 the need arose for a Wittig
phosphonium reagent such as compound 1 (Figure 1).
This paper describes the preparation of 1 and its use in
Wittig olefination reactions with aldehydes and some ke-
tones. The analogous serine-derived compound 2 has been
described by Sibi and co-workers.4 Initially we examined
the use of compound 2 for the preparation of cysteine
dipeptide isosteres, but extra steps (with low to modest
yields) subsequent to the carbon–carbon bond forming re-
action were required to convert the hydroxy into a thiol
(via conversion to the mesylate, displacement with iodide,
followed by trityl mercaptan, and deprotection of the trityl
group). Use of compound 1 resulted in much more con-
vergent syntheses and higher overall yields. Furthermore,
in cases in which a thiazolidinone is the desired final com-
pound, use of 1 versus 2 is much more expedient.
HS
S
O
K2CO3
THF–H2O
5–10 °C
90%
N
H
CO2Et
CO2Et
HCl•H2N
4
3
NaBH4
EtOH
5–10 °C
73%
TsCl
pyridine
S
S
O
O
OTs
81%
OH
N
H
N
H
6
5
NaI, MEK
reflux
91%
Ph3P
DMF
S
S
I–
S
O
Ph
P
I–
I–
O
O
Ph
Ph
Ph
Ph
O
O
I
125 °C
81%
N
H
Ph
Ph
Ph
Ph
N
H
P
P
N
H
N
H
+
+
7
1
1
2
Scheme 1 Preparation of phosphonium reagent 1
Figure 1 Wittig phosphonium reagents 1 and 2 derived from cys-
teine and serine, respectively
The Wittig reaction of 1 with benzaldehyde was opti-
mized with regard to base, solvent, and temperature.
When a suspension of 1 in THF or DME is treated with n-
BuLi, a homogeneous orange-red solution results. In
Et2O, 1 remains undissolved even after the addition of the
n-BuLi. The reaction is best carried out below –35 °C, but
may be quenched at 0 °C. Optimal conditions were found
to be 2 equivalents of n-BuLi in THF at ca. –46 °C
(Table 1).9
Phosphonium salt 1 is prepared from L-cysteine ethyl es-
ter hydrochloride (3) in five steps in good overall yield as
shown in Scheme 1. This sequence is analogous to that
published for the preparation of 2, with some important
SYNTHESIS 2011, No. 23, pp 3859–3865
x
x.
x
x
.
2
0
1
1
Advanced online publication: 07.11.2011
DOI: 10.1055/s-0031-1289583; Art ID: M44811SS
© Georg Thieme Verlag Stuttgart · New York

3860
C. J. Shaffer et al.
PAPER
Table 1 Use of Wittig Reagent 1 in Olefination Reactions under Various Conditions
Entry
1
Aldehyde or ketone
PhCHO
Base
Solvent
THF
THF
THF
THF
THF
THF
DME
toluene
Et2O
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Temp (°C) Product
Yield (%)a Ratiob trans/cis
n-BuLi (1 equiv)
n-BuLi (2 equiv)
n-BuLi (3 equiv)
LiHMDS (2 equiv)
NaHMDS (2 equiv)
KHMDS (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
n-BuLi (2 equiv)
–46
13
13
13
13
13
13
13
13
13
13
13
13
14
14
14
14
15
20
21
22
23
24
25
26
31
32
33
34
29
89
36
58
45
0
6:1
13:1
3:1
5:1
1:1
–
2
PhCHO
–46
3
PhCHO
–46
4
PhCHO
–46
5
PhCHO
–46
6
PhCHO
–46
7
PhCHO
–46
74
1
6:1
4:1
–
8
PhCHO
–46
9
PhCHO
–46
N.R.
58
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
PhCHO
–78
4:1
–
PhCHO
0
PhCHO
–78 → 0
–78
67
50
0
>97:3c
1:1
–
Ph(CH2)2CHO
Ph(CH2)2CHO
Ph(CH2)2CHO
Ph(CH2)2CHO
methyl 4-formylbenzoate
thiophene-2-carboxaldehyde
1,4-benzodioxane-6-carboxaldehyde
PhCH2CHO
0
–78 → 0
–46
62
65
62
71
70
52
69
69
72
5
1:1
1:1
5.5:1
5.4:1
7:1
1.2:1
1:1
1.4:1
1.3:1
N/A
N/A
n.d.
–
–46
–46
–46
–46
n-octanal
–46
n-propanal
–46
cyclohexane carboxaldehyde
cyclopentanone
cyclohexanone
butan-2-one
–46
–46
–46
25
2
–46
MeC(O)CH2OSi (t-Bu)Ph2
MeC(O)CH2OSi (t-Bu)Ph2
–46
N.R.
N.R.
–46 → 20
–
a Yields are of purified, isolated material. N.R. = no reaction.
b Ratios were determined by 1H NMR spectroscopy on the crude reaction mixtures by integration of the olefinic proton signals.
N/A = Not applicable. n.d. = not determined.
c To the limits of detection by 500 MHz 1H NMR, no cis-isomer was detected.
For example, in Table 1 see entries 2 and 10, or 13 and 16, temperature, the amount of trans-alkene is decreased, and
to compare yields at –46 °C versus –78 °C. By compari- if quenched at zero, the amount of trans-isomer is in-
son, the published optimal temperature for reactions with creased (Table 1, entries 2, 10, and 12). No such tempera-
compound 2 is –78 °C.4c The Wittig reaction produces ture dependence was observed with an aliphatic aldehyde
mostly the trans-alkene with aromatic aldehydes, but (entry 15). In most cases the cis- and trans-alkenes are
gives approximately one-to-one mixtures of cis- and separable by chromatography on silica gel. Several ke-
trans-alkenes with aliphatic aldehydes. Furthermore, if tones were examined as substrates in the reaction (entries
the reaction with aromatic aldehydes is quenched at low 24–28), but only cyclohexanone gave any significant
Synthesis 2011, No. 23, 3859–3865 © Thieme Stuttgart · New York

PAPER
(R)-[(2-Oxo-4-thiazolidinyl)methyl]triphenylphosphonium Iodide
3861
amount of the olefin product. Hence, this reagent is most
suitable for Wittig olefination reactions of aldehydes and
some electrophilic ketones (Scheme 2).
OHC
CO2Et
27
(Boc)2O
1. n-BuLi (2 equiv)
THF, -46 °C
I–
S
S
cat. DMAP
65%
Ph
1
O
O
Ph
n-BuLi (2 equiv)
THF, –46 °C
P
THF or
MeCN
2. RCHO
N
H
1.4:1
trans/cis
N
H
+
Ph
R
51–89%
1
9
8
85–95%
Cs2CO3
EtOH
S
HS
S
N
O
O
N
H
CO2Et
65–85%
BocHN
R
R
28
Boc
10
(Boc)2O
88%
overall
Ph3COH
BF3•OEt2
Et2O
cat. DMAP, THF
(flash chromatographic
separation of isomers)
I2
EtOH
47–80%
30–80%
S
N
O
Ph3CS
S
CO2Et
2
O
trans-29, cis-29
O
BocHN
BocHN
R
R
11
12
1. Cs2CO3, EtOH
2. I2
47%
S
generic compound 8 corresponds to:
R = Ph (13), R = CH2CH2Ph (14), R = 4-MeO2CC6H4 (15),
R = 2-thienyl (20), R = 1,4-benzodioxan-6-yl (21), R = Bn (22),
R = (CH2)7Me (23), R = Et (24), R = cyclohexyl (25)
2
O
Scheme 2 Use of reagent 1 to prepare cysteine-derived alkenes
O
N
CO2Et
H
Similar to the analogous serine-derived phosphonium salt
2,4c no racemization of 1 was observed during ylide for-
mation or Wittig reaction.2
30
Scheme 3
After the Wittig reaction, hydrolysis of the free thiazolid-
inone 8 requires harsh conditions (e.g., refluxing aq
KOH), but the thiazolidinone 8 is readily converted to the
Boc derivative 9, which is readily hydrolyzed at room
temperature using Cs2CO3 in EtOH under inert atmo-
sphere to give the corresponding free thiol 10. The hydrol-
ysis is complete in a few hours in EtOH, but is much
slower in MeOH, requiring days at room temperature (un-
like the corresponding Boc-oxazolidinones, which are
cleaved by Cs2CO3/MeOH in a few hours). Note that for
substrates containing a carboxylic ester, transesterifica-
tion can be a side reaction during the thiazolidinone hy-
drolysis (e.g., reaction sequence 15 to 16 to 17 or 18 in the
experimental section), and thus it is best to begin with eth-
yl esters when possible. The thiol 10 can be isolated or ox-
idized to the symmetrical disulfide 12 in one-pot by the
addition of iodine (e.g., compound 17), or can be protect-
ed as the trityl derivative 11 using triphenylmethanol and
boron trifluoride etherate9 (e.g., compound 19 in the ex-
in which sulfur is desired. This reagent has proven very
useful for the preparation of cysteine-derived dipeptide
isosteres and peptidomimetics.
Melting points are uncorrected. NMR spectra were recorded on a
Varian INOVA-400 or a Varian INOVA-500 spectrometer. 1H
NMR chemical shifts were relative to internal TMS or CHD2OD;
13C NMR chemical shifts were relative to CDCl3 or CD3OD; 31P
NMR chemical shifts were relative to H3PO4 internal standard. All
starting materials, reagents, and solvents were commercially avail-
able and were used as received.
Ethyl (R)-(–)-2-Oxo-4-thiazolidinecarboxylate (4)
A solution of L-cysteine ethyl ester hydrochloride (3; 504 g, 2.70
mol) in H2O (3.6 L) was cooled to 5–15 °C, and NaHCO3 (246 g,
2.93 mol) was added with efficient stirring over ca. 30 min. The so-
lution was stirred for an additional 15 min, and K2CO3 (400 g, 2.89
mol) was added. The reaction solution was cooled to 5 °C (if neces-
sary). A solution of triphosgene (402 g, 1.35 mol) in THF (anhyd, 1
L, Aldrich) was then added dropwise over 3–4 h while maintaining
perimental section) (Scheme 2). For a specific example of a reaction temperature of 5–10 °C. Stirring was continued for 1 h at
which time TLC (eluent: 15% MeOH–CHCl3) indicated the reac-
the sequence, see Scheme 3.
tion was complete. The reaction solution was kept at 10 °C while N2
was bubbled through to chase out excess phosgene. The THF was
In conclusion, we have developed a thiazolidinone-based
phosphonium reagent 1 which can be used in the Wittig
olefination of a variety of aldehydes. This reagent com-
plements the analogous oxazolidinone-based reagent 2
derived from serine, and offers advantages over 2 in cases
then removed by rotary evaporation to leave an aqueous phase and
a sticky organic layer. These phases were separated, and the aque-
ous phase was extracted with CH2Cl2 (3 × 0.7 L). The CH2Cl2 ex-
tracts were combined with the original organic layer, and the
resulting solution was washed with brine (0.5 L). The brine washing
Synthesis 2011, No. 23, 3859–3865 © Thieme Stuttgart · New York

3862
C. J. Shaffer et al.
PAPER
was back-extracted once with CH2Cl2 (0.5 L). All the organic phas-
es were combined, dried (Na2SO4), filtered, and evaporated to give
429 g (90%) of 4 as a light yellow liquid. This liquid would some-
times solidify on standing at low temperature, and furthermore
could be precipitated from EtOAc–hexane to give 4 as a white pow-
der; mp 167–168 °C.5
1H NMR (CDCl3): d = 1.34 (t, J = 7.1 Hz, 3 H), 3.63 (dd, J = 5.2,
11.2 Hz, 1 H), 3.71 (dd, J = 8.1, 11.2 Hz, 1 H), 4.27 (q, J = 7.1 Hz,
2 H), 4.45 (dd, J = 5.3, 7.8 Hz, 1 H), 6.36 (br s, 1 H).
ther evaporation of the solvent gave a second crop of product of
slightly lower purity (53 g, 15%). Overall yield of 7 as a white pow-
der: 319.2 g (91%); mp 97.5–98 °C; [a]D24 –11.4 (c = 1.47,
CH2Cl2).
1H NMR (CDCl3): d = 3.24–3.37 (m, 3 H), 3.61 (dd, J = 7.5, 11.4
Hz, 1 H), 4.05–4.10 (m, 1 H), 6.51 (br s, 1 H).
1H NMR (CD3OD): d = 3.28 (dd, J = 5.6, 11.5 Hz, 1 H), 3.34 (dd,
J = 4.4, 10.3 Hz, 1 H), 3.42 (dd, J = 7.1, 10.5 Hz, 1 H), 3.60 (dd,
J = 7.7, 11.5 Hz, 1 H), 3.96 (m, 1 H).
Anal. Calcd for C4H6INOS: C, 19.77; H, 2.49; I, 52.21; N, 5.76; S,
13.19. Found: C, 19.84; H, 2.44; I, 52.10; N, 5.68; S, 13.11.
(R)-(–)-2-Oxothiazolidine-4-methanol (5)
Ester 4 (428 g, 2.44 mol) was dissolved in anhyd EtOH (5 L) at 5–
10 °C. NaBH4 (6.0938 g, 161.08 mmol) was added portionwise
over 3–5 h to the turbid solution with stirring. Stirring was contin-
ued for 1 h, and then the solution was cooled to 0 °C. The reaction
was quenched by the addition of aq HCl (4 N, 490 mL), keeping the
temperature at 0 °C. Stirring was discontinued, and the mixture was
allowed to stand overnight during which time a white solid precipi-
tated. The mixture was filtered, and the solid was rinsed with EtOH
(ca. 100 mL). The combined filtrates were evaporated to give a
white, crystalline powder (318 g). These crystals were suspended in
MeOH (180 mL) at r.t. and cooled in a refrigerator (ca. 5–10 °C)
overnight. The crystals were collected by filtration, washed with
cold MeOH (ca. 100 mL), and dried under vacuum at r.t. overnight
to give 211 g (65%) of desired product. The combined filtrate and
washings (ca. 280 mL in total) were combined with Et2O (40 mL)
and allowed to stand at r.t. overnight to afford a second crop of crys-
tals: 26.1 g; total yield: 237.1 g of 5 (73%); mp 101–102 °C.6
(R)-(+)-4-(Triphenylphosphonylmethyl)thiazolidin-2-one Io-
dide (1)
Iodide 7 (318 g, 1.31 mol), Ph3P (370 g, 1.41 mol), and DMF (320
mL) were combined and heated to 125 °C for 5–6 h. The DMF was
removed under vacuum (60–80 °C) to leave a solid residue. This
residue was washed with Et2O (2 × 600 mL) to remove Ph3P. The
resulting yellow solid was pulverized with acetone (300 mL), and
Et2O (300 mL) was added, and the slurry filtered. This was repeated
twice, and finally the solid was washed with ice-cold acetone (300
mL). The white powder was dried under vacuum at 40 °C to give
536 g (81%) of 1; mp 245–246 °C; [a]D24 +18.39 (c = 0.0255,
MeOH).
Alternatively, crude 1 may be purified by flash chromatography on
SiO2 (eluting with MeOH–CHCl3) to give a white solid. It may also
be purified by dissolving in a minimum amount of MeOH and very
slowly adding this solution to rapidly stirring Et2O at r.t.; the prod-
uct precipitates as a white solid.
1H NMR (CD3OD): d = 3.28 (dd, J = 5.7, 11.1 Hz, 1 H), 3.61 (dd,
J = 6.1, 11.1 Hz, 1 H), 3.52 (m, 2 H), 3.91 (m, 1 H).
1H NMR (CD3OD): d = 2.97 (m, 1 H), 3.51 (ddd, J = 1.6, 7.2, 11.5
Hz, 1 H), 3.86–4.06 (m, 2 H), 4.34 (m, 1 H), 4.81 (br s, 1 H), 7.75–
8.00 (m, 15 H).
MS (C.I., ammonia): m/z calcd for C4H11N2O2S [M + NH4] +: 151;
found 151 (relative abundance 100%).
13C NMR (CD3OD–D2O): d = 28.7 (d, J = 52.1 Hz), 37.9 (d, J = 7.3
Hz), 52.0 (s), 119.4 (d, J = 86.9 Hz), 132.5 (d, J = 12.7 Hz), 135.4
(d, J = 10.2 Hz), 137.5 (s), 178.3 (s).
31P NMR (CD3OD–D2O): d = 24.0 (s).
(R)-4-(p-Toluenesulfonyloxymethyl)thiazolidin-2-one (6)
Alcohol 5 (236 g, 1.73 mol) was dissolved in anhyd pyridine (730
mL), and p-TsCl (381 g, 2.0 mol) was added portionwise with stir-
ring while maintaining the reaction temperature below 30 °C. The
resulting solution was stirred at 25–30 °C for 2 h, and then at 40–
50 °C for 4 h (until completion by TLC, eluent: 15% MeOH–
CHCl3). The solution was allowed to cool to r.t. and was poured into
rapidly stirring H2O (10 L). The white solid precipitate was collect-
ed by filtration and was washed thoroughly with H2O. The white
powder was dried under vacuum at 40 °C for 40 h to give 414 g
(81%) of 6.
Anal. Calcd for C22H21INOPS: C, 52.29; H, 4.19; I, 25.11; N, 2.77;
S, 6.34. Found: C, 52.41; H, 4.17; I, 24.99; N, 2.70; S, 6.42.
(R)-4-Styrylthiazolidin-2-one (13)
Compound 1 (430.1 mg, 0.8511 mmol) was dried in a flask under
vacuum using a heat gun. After the flask had cooled, it was
equipped with a stir bar, septum, and N2 line, and THF (4 mL) was
added via a syringe. The suspension was cooled to – 46 °C. n-BuLi
(2.42 M, 0.70 mL, 1.694 mmol) was added, and the solution was
stirred at –46 °C for 20 min (the reaction solution was homogeneous
and red-orange-brown in color). Benzaldehyde (0.085 mL, 0.8362
mmol) was then added via a syringe. The color of the solution faded
to yellow. Stirring was continued at –46 °C for 30 min. The reaction
was quenched with sat. aq NH4Cl (a few mL) at –46 °C. The solu-
tion became colorless and a white precipitate formed. The solution
was diluted with EtOAc (30 mL) and H2O (15 mL), and the phases
were separated. The EtOAc phase was washed with pH 7.2 phos-
phate buffer (15 mL), H2O (15 mL), and brine (15 mL), dried
(MgSO4), filtered, and concentrated to give an oil. Purification by
flash chromatography (FC) on silica gel (EtOAc–hexanes) fur-
nished the cis- (9.9 mg, 6%) and trans-isomers (142.1 mg, 83%) of
13 as oils.
1H NMR (CDCl3): d = 3.13 (dd, J = 4.1, 11.3 Hz, 1 H), 3.54 (dd,
J = 7.3, 11.3 Hz, 1 H), 4.12 (m, 2 H), 4.02 (m, 1 H), 6.04 (br s, 1 H),
7.36 (d, J = 8.0 Hz, 2 H), 7.77 (d, J = 8.1 Hz, 2 H).
Anal. Calcd for C11H13NO4S2: C, 45.98; H, 4.56; N, 4.87; S, 22.31.
Found: C, 46.08; H, 4.54; N, 4.91; S, 22.22.
(S)-(–)-4-(Iodomethyl)thiazolidin-2-one (7)
Tosylate 6 (413 g, 1.44 mol), NaI (263 g, 1.75 mol), and NaHCO3
(5 g, 0.059 mol) were combined in butan-2-one (ca. 5 L). The result-
ing solution was heated at reflux under N2 for 8–10 h (until comple-
tion by TLC, eluent: 50% EtOAc–hexanes). The solution was
cooled to r.t. and filtered. The filtrate was evaporated to give a dark
yellow oil (460 g), which was dissolved in EtOAc (2 L) and the
EtOAc layer was washed with sat. aq Na2SO3 (2 × 100 mL) and
brine (2 × 100 mL). The combined aqueous phases were back-ex-
tracted with EtOAc (2 × 100 mL), and these EtOAc extracts were
combined and washed with brine (50 mL). The combined EtOAc
phases were dried (Na2SO4), filtered, and evaporated. During evap-
oration a white precipitate formed, and when ca. 75% of the solvent
had been removed, the solid was collected by filtration to give a
white powder, which was dried under vacuum (266.2 g, 76%). Fur-
cis-13
1H NMR (CDCl3): d = 3.32 (dd, J = 8.2, 11.0 Hz, 1 H), 3.52 (dd,
J = 7.3, 11.0 Hz, 1 H), 4.85 (q, J = 8.2 Hz, 1 H), 5.53 (br s, 1 H),
5.77 (dd, J = 9.2, 11.4 Hz, 1 H), 6.71 (d, J = 11.4 Hz, 1 H), 7.17 (d,
J = 7.3 Hz, 2 H), 7.31–7.40 (m, 3 H).
Synthesis 2011, No. 23, 3859–3865 © Thieme Stuttgart · New York

PAPER
(R)-[(2-Oxo-4-thiazolidinyl)methyl]triphenylphosphonium Iodide
3863
trans-13
Diethyl 4,4¢-((1E,1¢E,3R,3¢R)-Disulfanediylbis{3-[(tert-butoxy-
carbonyl)amino]but-1-ene-4,1-diyl})dibenzoate (17)
1H NMR (CDCl3): d = 3.29 (dd, J = 7.3, 11.0 Hz, 1 H), 3.57 (dd,
J = 7.3, 11.0 Hz, 1 H), 4.56 (q, J = 7.6 Hz, 1 H), 5.62 (br s, 1 H),
6.22 (dd, J = 7.8, 16.0 Hz, 1 H), 6.64 (d, J = 15.6 Hz, 1 H), 7.28–
7.40 (m, 5 H).
Compound 16 (70 mg, 0.1926 mmol) was dissolved in EtOH (2.0
mL) in a flask equipped with a stir bar, septum, and N2 line. Cs2CO3
(70 mg, 0.2143 mmol) was added, and the solution was stirred at r.t.
overnight. I2 (13.1 mg, 0.1032 mmol) was added, and the mixture
was stirred at r.t. 10 min. The solution was diluted with EtOAc (20
mL) and H2O (10 mL), and the phases were separated. The EtOAc
phase was washed with aq 0.25 N Na2S2O3 (10 mL) H2O (10 mL),
and brine (10 mL), dried (MgSO4), filtered, and concentrated. Puri-
fication by FC (EtOAc–hexanes) furnished the desired disulfide 17
(39 mg, 58%), and the free thiol 18 (15 mg, 23%). (Note that the me-
thyl ester was converted to the ethyl ester under the reaction condi-
tions. Only trans-isomers were isolated.)
(R)-4-(4-Phenylbut-1-en-1-yl)thiazolidin-2-one (14)
Compound 1 (365.4 mg, 0.7231 mmol), THF (4 mL), n-BuLi (2.42
M, 0.6 mL, 1.452 mmol), and hydrocinnamaldehyde (0.095 mL,
0.7215 mmol) furnished 104.1 mg (62%) of 14 (oil) as a 1:1 trans/
cis mixture after FC purification. The ratio was determined by inte-
gration of the olefinic protons at 5.63 ppm (trans) and 5.77 ppm
(cis) in the 1H NMR spectrum.
1H NMR (CDCl3): d = 2.40 (t, J = 6.6 Hz, 2 H), 2.36–2.46 (m, 2 H),
2.63–2.68 (m, 1 H), 2.71 (t, J = 7.8 Hz, 2 H), 2.73–2.79 (m, 1 H),
2.90 (dd, J = 8.2, 11.0 Hz, 1 H), 3.02 (dd, J = 6.9, 11.0 Hz, 1 H),
3.11 (dd, J = 7.8, 11.0 Hz, 1 H), 3.41 (dd, J = 6.9, 11.0 Hz, 1 H),
4.28–4.35 (m, 2 H), 4.46 (br s, 1 H), 5.30 (br s, 1 H), 5.40–5.49 (m,
2 H), 5.63 (dt, J = 5.3, 16.5 Hz, 1 H), 5.77 (dt, J = 7.2, 14.4 Hz, 1
H), 7.14–7.33 (m, 10 H).
1H NMR (CDCl3): d = 1.39 (t, J = 7.1 Hz, 6 H), 1.47 (s, 18 H),
3.00–3.91 (m, 4 H), 4.36 (q, J = 7.2 Hz, 4 H), 4.66 (br s, 1 H), 5.04
(br s, 1 H), 6.28 (dd, J = 5.7, 15.8 Hz, 2 H), 6.58 (d, J = 15.6 Hz, 2
H), 7.40 (d, J = 8.7 Hz, 4 H), 7.97 (d, J = 8.2 Hz, 4 H).
18
1H NMR (CDCl3): d = 1.40 (t, J = 6.9 Hz, 3 H), 1.47 (s, 9 H), 2.72–
2.90 (m, 2 H), 4.37 (q, J = 7.2 Hz, 2 H), 4.58–5.01 (br d, 1 H), 6.22
(dd, J = 6.0, 16.0 Hz, 1 H), 6.60 (d, J = 16.0 Hz, 1 H), 7.42 (d,
J = 8.2 Hz, 2 H), 7.99 (d, J = 8.2 Hz, 2 H).
(R)-Methyl 4-[2-(2-Oxothiazolidin-4-yl)vinyl]benzoate (15)
Compound 1 (329.7 mg, 0.6524 mmol), THF (4 mL), n-BuLi (2.42
M, 0.54 mL, 1.31 mmol) and methyl 4-formylbenzoate (103.9 mg,
0.6329 mmol) furnished 103.9 mg (62%) of 15 after FC purification
(5.5:1 mixture of trans/cis isomers); oil.
(R,E)-Ethyl 4-{3-[(tert-Butoxycarbonyl)amino]-4-mercaptobut-
1-en-1-yl}benzoate (18)
cis-15
Compound 16 (145 mg, 0.3990 mmol) was dissolved in EtOH (2.0
mL) in a flask equipped with a stir bar, septum, and N2 line, and
Cs2CO3 (141.4 mg, 0.4347 mmol) was added. The solution was
stirred at r.t. overnight. The reaction solution was diluted with
EtOAc (20 mL) and 0.1 N HCl (10 mL), and the phases were sepa-
rated. The EtOAc phase was washed with H2O (10 mL), and brine
(10 mL), dried (MgSO4), filtered, and concentrated to furnish crude
18, which could be further purified by FC, if desired (see prepara-
tion of 17).
1H NMR (CDCl3): d = 3.32 (dd, J = 7.8, 11.0 Hz, 1 H), 3.52 (dd,
J = 6.9, 11.0 Hz, 1 H), 3.93 (s, 3 H), 4.81 (q, J = 8.4 Hz, 1 H), 5.63
(br s, 1 H), 5.87 (dd, J = 9.6, 11.4 Hz, 1 H), 6.73 (d, J = 11.4 Hz, 1
H), 7.25 (d, J = 8.2 Hz, 2 H), 8.05 (d, J = 7.8 Hz, 2 H).
trans-15
1H NMR (CDCl3): d = 3.30 (dd, J = 7.3, 11.0 Hz, 1 H), 3.61 (dd,
J = 7.3, 11.4 Hz, 1 H), 3.92 (s, 3 H), 4.58 (q, J = 7.3 Hz, 1 H), 5.64
(br s, 1 H), 6.35 (dd, J = 7.6, 15.8 Hz, 1 H), 6.67 (d, J = 16.0 Hz, 1
H), 7.45 (d, J = 8.2 Hz, 2 H), 8.02 (d, J = 8.2 Hz, 2 H).
(R,E)-Ethyl 4-{3-[(tert-Butoxycarbonyl)amino]-4-(trityl-
thio)but-1-en-1-yl}benzoate (19)
(R)-tert-Butyl 4-[4-(Methoxycarbonyl)styryl]-2-oxothiazoli-
dine-3-carboxylate (16)
The crude compound 18 (134.6 mg, 0.3990 mmol) was dissolved in
Et2O (4 mL), and Ph3COH (195.1 mg, 0.7494 mmol) was added.
The solution was cooled to 0 °C, Et2O·BF3 (0.074 mL, 0.8029
mmol) was added, and the resulting solution was stirred at 0 °C for
ca. 1.25 h. The solution was diluted with EtOAc (20 mL) and sat. aq
NaHCO3 (10 mL), and the phases were separated. The EtOAc phase
was washed with H2O (10 mL) and brine (10 mL), dried (MgSO4),
filtered, and concentrated. Purification by FC (EtOAc–hexanes)
furnished 19 (71 mg, 32%), disulfide 17 (50 mg, 23%), and the ethyl
ester of 15 (9.6 mg, 4.2%) (a contaminant in crude 18).
1H NMR (CDCl3): d = 1.39 (t, J = 7.1 Hz, 3 H), 1.44 (s, 9 H), 2.41–
2.52 (m, 2 H), 4.36 (q, J = 7.0 Hz, 2 H), 4.39–4.69 (br d, 1 H), 6.08
(dd, J = 5.9, 15.6 Hz, 1 H), 6.41 (d, J = 15.6 Hz, 1 H), 7.36 (d,
J = 8.2 Hz, 2 H), 7.42–7.20 (m, 15 H), 7.96 (d, J = 8.2 Hz, 2 H).
Compound 15 (109.8 mg, 0.4170 mmol) was dissolved in THF (2
mL) in a flask equipped with a stir bar, septum, and N2 line. (Boc)2O
(111.7 mg, 0.5118 mmol) and DMAP (5.3 mg, 0.04338 mmol) were
added, and the reaction solution was stirred at r.t. for ca. 1 h. The
solution was diluted with EtOAc (20 mL) and H2O (10 mL), and the
phases were separated. The EtOAc phase was washed with H2O (10
mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated.
Purification by FC (EtOAc–hexanes) furnished a cis/trans mixture
of 16 (148.7 mg, 98%).
cis-16
1H NMR (CDCl3): d = 1.52 (s, 9 H), 3.02 (d, J = 11.0 Hz, 1 H), 3.66
(dd, J = 7.3, 11.0 Hz, 1 H), 3.94 (s, 3 H), 5.43 (t, J = 8.0 Hz, 1 H),
6.07 (dd, J = 9.4, 11.7 Hz, 1 H), 6.67 (d, J = 11.9 Hz, 1 H), 7.33 (d,
J = 8.2 Hz, 2 H), 8.05 (d, J = 8.2 Hz, 2 H).
(R)-4-[2-(Thiophen-2-yl)vinyl]thiazolidin-2-one (20)
Compound 1 (405.8 mg, 0.8030 mmol), THF (4 mL), n-BuLi (2.42
M, 0.65 mL, 1.573 mmol), and thiophene-2-carboxaldehyde (0.073
mL, 0.7883 mmol) furnished 117.9 mg (71%) of 20 as a 5.4:1 trans/
cis mixture after FC purification.
1H NMR (CDCl3): d = 3.29 (dd, J = 7.3, 11.0 Hz, 1 H), 3.56 (dd,
J = 7.3, 11.0 Hz, 1H), 3.65 (dd, J = 6.9, 11.0 Hz, 1 H), 4.50 (q,
J = 7.5 Hz, 1 H), 5.16 (q, J = 7.9 Hz, 1 H), 5.50 (br s, 1 H), 5.67 (dd,
J = 9.2, 11.4 Hz, 1 H), 6.04 (dd, J = 7.8, 15.6 Hz, 1 H), 6.70 (d,
J = 11.4 Hz, 1 H), 6.76 (d, J = 15.6 Hz, 1 H), 6.99 (dd, J = 3.7, 5.0
Hz, 1 H), 7.01 (d, J = 2.7 Hz, 1 H), 7.06 (dd, J = 3.7, 5.0 Hz, 1 H),
7.22 (d, J = 5.0 Hz, 1 H), 7.35 (d, J = 5.0 Hz, 1 H).
trans-16
1H NMR (CDCl3): d = 1.50 (s, 9 H), 3.00 (d, J = 11.4 Hz, 1 H), 3.72
(dd, J = 7.6, 11.2 Hz, 1 H), 3.92 (s, 3 H), 5.15 (t, J = 7.3 Hz, 1 H),
6.48 (dd, J = 7.3, 16.0 Hz, 1 H), 6.69 (d, J = 16.0 Hz, 1 H), 7.45 (d,
J = 8.2 Hz, 2 H), 8.01 (d, J = 8.7 Hz, 2 H).
Synthesis 2011, No. 23, 3859–3865 © Thieme Stuttgart · New York

3864
C. J. Shaffer et al.
PAPER
(R)-4-[2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)vinyl]thiazoli-
din-2-one (21)
(t, J = 10.1 Hz, 1 H), 5.41 (br s, 2 H), 5.43 (dd, J = 7.8, 15.1 Hz, 1
H), 5.49 (t, J = 10.3 Hz, 1 H), 5.70 (dd, J = 6.9, 15.6 Hz, 1 H).
Compound 1 (325.6 mg, 0.6443 mmol), THF (4 mL), n-BuLi (2.42
M, 0.53 mL, 1.283 mmol), and 1,4-benzodioxan-6-carboxaldehyde
(104.3 mg, 0.6354 mmol) furnished 116.3 mg (70%) of 21 as a 7:1
trans/cis mixture after FC purification.
(R)-4-(Cyclohexylidenemethyl)thiazolidin-2-one (26)
Compound 1 (437.4 mg, 0.8655 mmol), THF (4 mL), n-BuLi (2.42
M, 0.7 mL, 1.694 mmol), and cyclohexanone (0.088 mL, 0.8491
mmol) furnished 41 mg (25%) of 26 after FC purification.
trans-21
1H NMR (CDCl3): d = 1.55 (m, 6 H), 2.15 (m, 4 H), 3.15 (dd,
J = 8.9, 10.8 Hz, 1 H), 3.35 (dd, J = 6.9, 11.0 Hz, 1 H), 4.69 (q,
J = 8.2 Hz, 1 H), 5.18 (d, J = 9.2 Hz, 1 H), 5.59 (br s, 1 H).
1H NMR (CDCl3): d = 3.26 (dd, J = 7.8, 11.0 Hz, 1 H), 3.53 (dd,
J = 7.3, 11.0 Hz, 1 H), 4.26 (m, 4 H), 4.52 (q, J = 7.6 Hz, 1 H), 5.54
(br s, 1 H), 6.05 (dd, J = 7.8, 15.6 Hz, 1 H), 6.50 (d, J = 16.0 Hz, 1
H), 6.83 (d, J = 8.2 Hz, 1 H), 6.86 (d, J = 1.8 Hz, 1 H), 6.90 (d,
J = 1.8 Hz, 1 H).
(R)-Ethyl 2-Isopropyl-5-[3-(2-oxothiazolidin-4-yl)allyl]ben-
zoate (28)
Compound 1 (52.62 g, 104.1 mmol), THF (500 mL), n-BuLi (2.5
M, 93.6 mL, 1.694 mmol), and compound 2710 (24.18 g, 103.2
mmol) furnished 22.5 g (65%) of 28 as a pale yellow oil after FC
purification (EtOAc–hexanes).
cis-21
1H NMR (CDCl3): d = 3.28 (dd, J = 8.2, 11.0 Hz, 1 H), 3.51 (dd,
J = 8.2, 11.0 Hz, 1 H), 4.26 (m, 4 H), 4.89 (q, J = 8.2 Hz, 1 H), 5.50
(br s, 1 H), 5.66 (dd, J = 9.4, 11.2 Hz, 1 H), 6.56 (d, J = 11.4 Hz, 1
H), 6.65 (d, J = 2.3 Hz, 1 H), 6.67 (d, J = 2.3 Hz, 1 H), 6.69 (d,
J = 1.8 Hz, 1 H).
trans-28
1H NMR (CDCl3): d = 1.24 (d, J = 6.9 Hz, 6 H), 1.39 (t, J = 7.1 Hz,
3 H), 3.19 (dd, J = 7.3, 10.7 Hz, 1 H), 3.37 (d, J = 6.9 Hz, 2 H), 3.47
(dd, J = 7.3, 11.0 Hz, 1 H), 3.63 (sept, J = 6.9 Hz, 1 H), 4.36 (q,
J = 7.1 Hz, 2 H), 5.53 (br s, 1 H), 5.56 (m, 1 H), 5.89 (m, 1 H), 7.24
(dd, J = 2.1, 8.0 Hz, 1 H), 7.34 (d, J = 7.8 Hz, 1 H), 7.47 (d, J = 1.8
Hz, 1 H).
(R)-4-(3-Phenylprop-1-en-1-yl)thiazolidin-2-one (22)
Compound 1 (394.7 mg, 0.7810 mmol), THF (4 mL), n-BuLi (2.42
M, 0.65 mL, 1.573 mmol), and phenylacetaldehyde (0.085 mL,
0.7605 mmol) furnished 86.7 mg (52%) of 22 as a 1.2:1 trans/cis
mixture after FC purification; oil.
1H NMR (CDCl3): d = 3.24–3.17 (m, 2 H), 3.47–3.39 (m, 6 H), 4.36
(q, J = 7.5 Hz, 1 H), 4.84 (q, J = 6.6 Hz, 1 H), 5.40–5.38 (br s, 2 H),
5.56 (dd, J = 7.8, 15.1 Hz, 1 H), 5.63 (dd, J = 9.2, 10.5 Hz, 1 H),
5.86 (dd, J = 5.9, 13.7 Hz, 1 H), 5.93 (dt, J = 8.4, 16.7 Hz, 1 H),
7.42–7.15 (m, 10 H).
cis-28
1H NMR (CDCl3): d = 1.24 (d, J = 6.6 Hz, 6 H), 1.40 (t, J = 7.1 Hz,
3 H), 3.23 (dd, J = 8.7, 11.0 Hz, 1 H), 3.42 (d, J = 7.3 Hz, 2 H), 3.46
(m, 1 H), 3.64 (sept, J = 6.9 Hz, 1 H), 4.36 (q, J = 6.9 Hz, 2 H), 4.82
(q, J = 2.1 Hz, 1 H), 5.45 (br s, 1 H), 5.65 (m, 1 H), 5.83 (m, 1 H),
7.23 (dd, J = 2.1, 8.0 Hz, 1 H), 7.34 (d, J = 8.2 Hz, 1 H), 7.47 (d,
J = 1.8 Hz, 1 H).
(R)-4-(Non-1-en-1-yl)thiazolidin-2-one (23)
Compound 1 (380.0 mg, 0.7520 mmol), THF (4 mL), n-BuLi (2.42
M, 0.62 mL, 1.500 mmol), and octanal (0.114 mL, 0.7299 mmol)
furnished 114.4 mg (69%) of 23 as a 1:1 trans/cis mixture after FC
purification; oil.
1H NMR (CDCl3): d = 0.89 (t, J = 3.4 Hz, 6 H), 1.34 (m, 20 H), 2.09
(m, 4 H), 3.17 (dd, J = 7.8, 11.0 Hz, 1 H), 3.18 (dd, J = 8.9, 10.8
Hz, 1 H), 3.39 (dd, J = 6.9, 11.0 Hz, 1 H), 3.44 (dd, J = 7.3, 11.0
Hz, 1 H), 4.33 (q, J = 7.6 Hz, 1 H), 4.72 (q, J = 8.2 Hz, 1 H), 5.42–
5.30 (br s, 2 H), 5.47 (m, 2 H), 5.64 (dt, J = 5.4, 16.2 Hz, 1 H), 5.75
(dt, J = 7.2, 14.4 Hz, 1 H).
tert-Butyl (R)-4-{3-[3-(Ethoxycarbonyl)-4-isopropylphe-
nyl]prop-1-en-1-yl}-2-oxothiazolidine-3-carboxylate (29)
Compound 28 (9.7345 g, 29.22 mmol) was dissolved in THF (185
mL), and (Boc)2O (11.54 g, 52.88 mmol) and DMAP (513.6 mg,
4.204 mmol) were added. The solution was stirred at r.t. for 2 h. The
solution was diluted with EtOAc (800 mL), washed with H2O
(2 × 400 mL) and brine (400 mL). The EtOAc layer was dried
(Na2SO4), filtered, and concentrated to afford a yellow oil. Purifica-
tion by FC (EtOAc–hexanes) furnished a cis/trans mixture of 29
(11.1329 g, 88%) as a yellow oil (ca. 1.4:1 trans/cis).
(R)-4-(But-1-en-1-yl)thiazolidin-2-one (24)
trans-29
Compound 1 (541.9 mg, 1.072 mmol), THF (4 mL), n-BuLi (2.42
M, 0.88 mL, 2.129 mmol), and propanal (0.075 mL, 1.039 mmol)
furnished 112.2 mg (69%) of 24 as a 1.4:1 trans/cis mixture after FC
purification; oil.
1H NMR (CDCl3): d = 1.00 (t, J = 7.3 Hz, 3 H), 1.01 (t, J = 7.6 Hz,
3 H), 2.11 (m, 4 H), 3.18 (dd, J = 8.5, 10.8 Hz, 2 H), 3.39 (dd,
J = 6.9, 11.0 Hz, 1 H), 3.44 (dd, J = 7.3, 11.0 Hz, 1 H), 4.34 (q,
J = 7.6 Hz, 1 H), 4.73 (q, J = 8.4 Hz, 1 H), 5.44 (t, J = 9.8 Hz, 1 H),
5.49 (t, J = 7.6 Hz, 1 H), 5.5 (br s, 2 H), 5.64 (dt, J = 5.3, 15.1 Hz,
1 H), 5.81 (dt, J = 6.3, 15.3 Hz, 1 H).
1H NMR (CDCl3): d = 1.24 (dd, J = 2.3, 6.9 Hz, 6 H), 1.39 (t,
J = 7.1 Hz, 3 H), 1.40 (s, 9 H), 2.91 (dd, J = 0.9, 11.0 Hz, 1 H), 3.38
(d, J = 6.9 Hz, 2 H), 3.61 (dd, J = 6.6, 13.5 Hz, 1 H), 3.64 (sept,
J = 6.9 Hz, 1 H), 4.36 (q, J = 7.3 Hz, 2 H), 4.93 (t, J = 7.3 Hz, 1 H),
5.75 (m, 1 H), 5.87 (m, 1 H), 7.25 (dd, J = 1.8, 8.2 Hz, 1 H), 7.32
(d, J = 7.8 Hz, 1 H), 7.49 (d, J = 1.8 Hz, 1 H).
cis-29
1H NMR (CDCl3): d = 1.23 (d, J = 6.9 Hz, 6 H), 1.38 (t, J = 7.1 Hz,
3 H), 1.50 (s, 9 H), 2.85 (dd, J = 2.3, 11.0 Hz, 1 H), 3.53 (d, J = 7.3
Hz, 2 H), 3.60 (dd, J = 7.3, 11.0 Hz, 1 H), 3.62 (sept, J = 6.9 Hz, 1
H), 4.35 (q, J = 7.3 Hz, 2 H), 5.53 (m, 1 H), 5.78 (m, 1 H), 5.86 (m,
1 H), 7.27 (dd, J = 1.8, 8.2 Hz, 1 H), 7.30 (d, J = 8.2 Hz, 1 H), 7.50
(d, J = 1.8 Hz, 1 H).
(R)-4-(2-Cyclohexylvinyl)thiazolidin-2-one (25)
Compound 1 (409.8 mg, 0.8109 mmol), THF (4 mL), n-BuLi (2.42
M, 0.67 mL, 1.621 mmol), and cyclohexanecarboxaldehyde (0.084
mL, 0.6964 mmol) furnished 105.2 mg (72%) of 25 as a 1.3:1 trans/
cis mixture after FC purification.
1H NMR (CDCl3): d = 1.14 (m, 6 H), 1.28 (m, 4 H), 1.56 (m, 3 H),
1.68 (m, 7 H), 1.98 (m, 1 H), 2.64 (m, 1 H), 3.18 (dd, J = 8.9, 19.5
Hz, 2 H), 3.37 (dd, J = 6.9, 11.0 Hz, 1 H), 3.44 (dd, J = 6.9 Hz, 11.0
Hz, 1 H), 4.32 (q, J = 7.6 Hz, 1 H), 4.74 (q, J = 8.4 Hz, 1 H), 5.35
Diethyl 5,5¢-((2E,2¢E,4R,4¢R)-Disulfanediylbis{4-[(tert-butoxy-
carbonyl)amino]pent-2-ene-5,1-diyl})bis(2-isopropylbenzoate)
(30)
Compound trans-29 (8.238 g, 19.00 mmol) was dissolved in abso-
lute EtOH (250 mL). Cs2CO3 (6.5120 g, 20.02 mmol) was added,
and the suspension was stirred at r.t. overnight. I2 (1.31 g, 10.32
Synthesis 2011, No. 23, 3859–3865 © Thieme Stuttgart · New York

PAPER
(R)-[(2-Oxo-4-thiazolidinyl)methyl]triphenylphosphonium Iodide
(3) (a) Barbacid, M. Ann. Rev. Biochem. 1987, 56, 779.
3865
mmol) was added to the homogeneous solution. The mixture was
stirred at r.t. until the I2 dissolved (30 min). The solution was diluted
with EtOAc (1000 mL), and the EtOAc layer was washed with H2O
(2 × 500 mL) and brine (500 mL), dried (Na2SO4), filtered, and con-
centrated to give a yellow oil. Purification by FC (EtOAc–hexanes)
furnished 3.6497 g (47%) of 30.
1H NMR (CDCl3): d = 1.23 (d, J = 6.9 Hz, 6 H), 1.39 (t, J = 7.1 Hz,
3 H), 1.42 (s, 9 H), 2.8–3.0 (m, 2 H), 3.36 (d, J = 6.9 Hz, 2 H), 3.63
(sept, J = 6.9 Hz, 1 H), 4.36 (q, J = 7.1 Hz, 2 H), 4.43–4.92 (br d, 1
H), 5.52 (m, 1 H), 5.77 (m, 1 H), 7.25 (d, J = 6.9 Hz, 1 H), 7.32 (d,
J = 7.8 Hz, 1 H), 7.49 (d, J = 1.8 Hz, 1 H).
(b) Khosravi-Far, R.; Der, C. J. Cancer Metastasis Rev.
1994, 13, 67. (c) Sebti, S. M.; Hamilton, A. D. Drug
Discovery Today 1998, 3, 26. (d) Williams, T. M.;
Dinsmore, C. J. Adv. Med. Chem. 1999, 4, 273.
(4) (a) Sibi, M. P.; Renhowe, P. A. Tetrahedron Lett. 1990, 31,
7407. (b) Sibi, M. P.; Rutherford, D.; Sharma, R. J. Chem.
Soc., Perkin Trans. 1 1994, 1675. (c) Sibi, M. P.;
Rutherford, D.; Renhowe, P. A.; Li, B. J. Am. Chem. Soc.
1999, 121, 7509. (d) Sibi, M. P.; Christensen, J. W. J. Org.
Chem. 1999, 64, 6434.
(5) Falb, E.; Nudelman, A.; Hassner, A. Synth. Commun. 1993,
23, 2839.
(6) Ethyl (R)-(–)-2-oxo-4-thiazolidinecarboxylate (4) has
recently become available commercially from Aldrich
Chemical Co.
(7) The enantiomer of 5, prepared from D-cysteine methyl ester,
has been reported (mp 103.5–104.5 °C): Kubodera, N.;
Nagano, H.; Takagi, M.; Matsunaga, I. Heterocycles 1982,
18, 259.
Acknowledgment
We thank Amy E. Christuk for contributions to the preparation of
compound 1.
References
(8) Similarly, the enantiomer of 1 was prepared from D-cysteine
ethyl ester according to Scheme 1.
(9) Hiskey, R. G.; Tucker, W. P. J. Am. Chem. Soc. 1962, 84,
4794.
(10) Compound 27 was prepared in 4 steps from 4-isopropyl-
benzaldehyde (bromination; halogen–metal exchange using
t-BuLi and quench with ethyl chloroformate; Wittig reaction
with (methoxymethyl)triphenylphosphonium chloride +
t-BuOK; enol ether hydrolysis with aq HI in MeCN). See
ref. 2a. Compound 27 may also be prepared in 6 steps from
5-formylsalicylic acid via Stille coupling using tribut-
yl(prop-1-en-2-yl)stannane and a hydrogenation.
(1) Current address: School of Pharmacy, JiangSu University,
Zhenjiang City, Jiang Su Province, ZP 212003, P. R. of
China.
(2) (a) Garcia, A. M.; Kowalczyk, J. J.; Lewis, M. D. US Patent
6486202 B1 20021126, 2002; Chem. Abstr. 2003, 138,
4818. (b) Lewis, M. D.; Kowalczyk, J. J.; Christuk, A. E.;
Fan, R.; Harrington, E. M.; Sheng, X. C.; Yang, H.; Garcia,
A. M.; Hishinuma, I.; Nagasu, T.; Yoshimatsu, K. US Patent
5840918, 1998; Chem. Abstr. 1995, 124, 146855.
(c) Lewis, M. D.; Garcia, A. M.; Kowalczyk, J. J.; Yang, H.;
Schwartz, C. E. PCT Int. Appl. WO 9838162, 1998; Chem.
Abstr. 1998, 129, 231021. (d) Yang, H.; Sheng, X. C.;
Harrington, E. M.; Ackermann, K.; Garcia, A. M.; Lewis, M.
D. J. Org. Chem. 1999, 64, 242. (e) Harrington, E. M.;
Kowalczyk, J. J.; Pinnow, S. L.; Ackermann, K.; Garcia, A.
M.; Lewis, M. D. Bioorg. Med. Chem. Lett. 1994, 4, 2775.
Synthesis 2011, No. 23, 3859–3865 © Thieme Stuttgart · New York