Novel synthesis and γ-alkylation reactions of 4-(1-pyrrolidinyl)-2(5H)-thiophenones

Article abstract of DOI:10.1016/S0040-4039(01)01705-1

Four-step synthesis of achiral and chiral 4-(1-pyrrolidinyl)-2(5H)-thiophenones with 61 and 66% overall yields are described. The γ-alkylation reaction studies and synthetic applications toward the thiolactomycin analog are also reported.

Full text of DOI:10.1016/S0040-4039(01)01705-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8011–8013
Novel synthesis and g-alkylation reactions of
4
-(1-pyrrolidinyl)-2(5H)-thiophenones
Yu-Jang Li,* Zen-Ting Liu and Sheng-Chuan Yang
Department of Applied Chemistry, Chaoyang University of Technology, 168 Gifeng E. Rd, Wufeng,
Taichung County, Taiwan 413, ROC
Received 16 February 2001; revised 11 September 2001; accepted 12 September 2001
Abstract—Four-step synthesis of achiral and chiral 4-(1-pyrrolidinyl)-2(5H)-thiophenones with 61 and 66% overall yields are
described. The g-alkylation reaction studies and synthetic applications toward the thiolactomycin analog are also reported.
©
2001 Elsevier Science Ltd. All rights reserved.
8
Substituted thiotetronic acid related compounds such as
6a in 81 and 83% yields, respectively. Deprotonation
1
2
(
3
+)-thiolactomycin 1, thiotetromycin 2, and U-68,204
are a group of compounds with important bioactivi-
of 6 or 6a with LDA, followed by chlorination with
hexachloroethane afforded chlorinated compound 7
and 7a, respectively. Subsequent treatment of the chlo-
rinated compounds 7 or 7a with potassium thioacetate
produced thiolated adducts, which without purification
were treated with sodium methoxide to facilitate
cyclization to produce 2(5H)-thiophenones 8 and 8a in
3
ties. For example, (+)-thiolactomycin 1 is an antibiotic
produced by Nocardia sp. No. 2-200, that is active
against many species of pathogens including Gram-pos-
itive cocci, enteric bacteria, acid-fast bacteria and
anaerobic bacteria. It has been found that the com-
bined use of thiolactomycin and b-lactam antibiotics
produces a synergistic effect against the inducible b-lac-
7
5 and 80% yields (Scheme 1).
4
tamase-producing microorganism. A common impor-
With 8 and 8a in hand, reaction of compound 8 was
studied first under various conditions. Compound 8
was deprotonated with lithium diisopropylamide
LDA) and then treated with alkyl halide to produce
mono-alkylated products 9–13 in moderate yields. A
tant feature in these three compounds is the
g-disubstitution on the thiotetronic acid. Therefore, the
study of the g-alkylation reaction of similar systems
becomes vital to the synthesis of thiotetronic acid
(
5
related antibiotics.
O
S
O
O
H N
2
S
S
O
HO
HO
HO
Thiolactomycin 1
Thiotetromycin 2
U-68,204 3
Herein, we first report on a novel procedure for the
second alkylation of 9 and 12, using LDA or t-BuLi as
a base, provided 14 and 15 in good yields (Scheme 2).
synthesis of achiral and chiral 4-(1-pyrrolidinyl)-2(5H)-
6
thiophenones. Secondly, g-alkylation reactions of the
title compound has been studied and applied in the
Deprotonation and alkylation of 8a under similar con-
ditions afforded 9a–13a in 53–93% yields. Though the
mono-alkylation reaction was successful in compound
7
synthesis of a thiolactomycin analog.
Methyl acetoacetate 4 in benzene was condensed with
compound 5 or 5a to afford vinylogous urethane 6 and
8
a, di-alkylation of 8a turned out to be problematic,
presumably due to the steric hindrance of the bulky
substitution on the pyrrolidine. The only success was
the hydroxymethylation reaction. Deprotonation of 9a
*
0
Corresponding author.
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01705-1

8
012
Y.-J. Li et al. / Tetrahedron Letters 42 (2001) 8011–8013
OMe
O
OMe
O
S
OMe
O
PhH
N
H
R
LDA/C Cl
1) CH COSNa
2
6
O
3
Cl
N
N
N
2) MeONa
O
R=H
5
R=CMe (OMe) 5a
R
2
R
R
7
R=H
8 (75%)
4
R=H
6 (81%)
R=H
R=CMe (OMe) 7a
R=CMe (OMe) 8a (80%)
2
R=CMe (OMe) 6a (83%)
2
2
Scheme 1.
O
O
S
O
t
S
LDA or BuLi/ R X
LDA/R X
2
1
S
N
N
N
R1
R2
R1
8
R1 = Me
9
83%
R1
R1
= Me R2
=
=
Bn 14 57%
Bn 15 69%
Et
10 75%
11 63%
=
Bn R2
Pr
Bn
12 68%
Allyl 13 71%
Scheme 2.
with t-BuLi followed by treatment with formaldehyde
gas at −50°C provided 16 in moderate yield and excel-
lent diastereoselectivity (Scheme 3).
The diastereoselectivities of 9a–13a and 16 were deter-
mined using HPLC and NMR as shown in Scheme 3.
The stereochemistry of the major diastereomer as deter-
mined by single-crystal X-ray analysis of the com-
9
pounds 9a and 16 is shown in Fig. 1.
Figure 1. Molecule structures of 9a and 16.
Our synthetic approach toward the thiolactomycin
analog started from the second alkylation of the com-
pound 9. Deprotonation of the compound 9, followed
by the addition–elimination reaction with a mixture
to synthesize the chiral analog are being continuously
investigated in our laboratory (Scheme 4).
(
E:Z/3:1) of 3-bromo-2-methacrylonitrile provided 17E
10
and 17Z in 81% yield with a 4:1 ratio. Reduction of
7E with diisobutylaluminum hydride (DIBAL-H) at
20°C provided aldehyde 18 in 81% yield. Finally,
1
−
Acknowledgements
reaction of compound 18 with phosphonium ylide gen-
erated by the deprotonation of methyltriphenylphos-
phonium iodide resulted in thiolactomycin analog 19 in
We thank the National Science Council (NSC-87-2113-
M-324-004) and Sinon cooperation for generous finan-
cial support. Partial support of the Mass spectrometer
1
1
7
4% yield. Synthetic efforts using chiral compound 9a
O
O
O
S
S
LDA/R X
S
t-BuLi/ HCHO
1
N
N
o
-
50 C, THF
N
OH
R1
R
R
R
8a
R=C(CH ) OMe
R
1 =
Me 9a 79%, 86%d.e.
3
2
16 55%
Et 10a 72%, 90%d.e.
Pr 11a 53%, 91%d.e.
Bn 12a 85%, 90%d.e.
Allyl 13a 93%, 84%d.e.
Scheme 3.

Y.-J. Li et al. / Tetrahedron Letters 42 (2001) 8011–8013
8013
O
O
O
O
a
S
b
S
c
S
S
N
81%
N
81%
N
74%
CHO
N
CN
17E/Z=4:1
9
18
19
Scheme 4. Reagents and conditions: (a) t-BuLi, THF, 3-bromo-2-methacrylonitrile (E:Z/3:1); (b) diisobutylaluminum hydride,
heptane; (c) LDA, THF, methyltriphenylphosphonium iodide.
Facility provided by National Chung-Hsing University
and the X-ray crystallography facility provided by
National Taiwan University are also acknowledged.
10. For synthesis of 3-bromo-2-methacrylonitrile, see:
Wiemer, D. F.; Han, Q. J. Am. Chem. Soc. 1992, 114,
7692–7697.
1
1. All compounds have been fully characterized. 9: mp
1
8
7–89°C. H NMR (200 MHz, CDCl ) l 4.88 (s, 1H),
3
References
4.30 (q, J=6.96 Hz, 1H), 3.50 (br, 2H), 3.29 (br, 2H),
13
1.85–2.18 (br, 4H), 1.66 (d, J=6.96 Hz, 3H). C NMR
1
2
3
4
5
. Hasaki, H.; Oishi, H.; Hayashi, T.; Matsuura, I.; Ando,
K.; Sawada, M. J. Antibiot. 1982, 35, 396–400.
. Omura, S.; Nakagawa, A.; Iwata, R.; Hatano, A. J.
Antibiot. 1983, 36, 1781–1782.
. Dolak, L. A.; Castle, T. M.; Truesdell, S. E.; Sebek, O.
K. J. Antibiot. 1986, 39, 26–31.
. Noto, T.; Miyakawa, S.; Oishi, H.; Endo, H.; Okazaki,
H. J. Antibiot. 1982, 35, 401–410.
. For g-alkylation reactions of thiotetronic acid system,
see: (a) Wang, J. C.-L.; Salvino, J. M. Tetrahedron Lett.
(50 MHz, CDCl ) l 192.7, 172.9, 96.3, 50.6, 48.4, 43.8,
25.8(2C), 21.4. EIMS: 183 (M , 100), 150(80), 70 (80).
3
+
Anal. calcd for C H NOS: C, 58.98; H, 7.15; N, 7.64.
9
13
2
0
Found: C, 59.04; H, 7.29; N, 7.63. 9a: [h] =−49.6
(c=1, CH Cl ). H NMR (200 MHz, CDCl ) l 5.12 (s,
D
1
2
2
3
1H), 4.26 (q, J=6.87 Hz, 1H), 3.59 (m, 1H), 3.49 (m,
2H), 3.10 (s, 3H), 1.99 (m, 4H), 1.60 (d, J=6.87 Hz, 3H),
13
1.08 (s, 3H), 1.07 (s, 3H); C NMR (50 MHz, CDCl ) l
3
195.0, 175.4, 98.6, 78.7, 69.3, 49.8, 49.1, 44.4, 25.3, 24.3,
22.0(2C), 21.6. EIHRMS: (C H NO S) calcd 255.1293;
13
21
2
1
984, 25, 5243–5246; (b) Stachel, H.-D.; Fendl, A. Arch.
found 255.1295. Anal. calcd for C H NO S: C, 61.14;
13 21 2
Pharm. 1988, 321, 439–440.
H, 8.29; N, 5.49; found C, 61.18; H, 8.26; N, 5.48. 17E:
1
6
. Synthesis and reaction studies of a similar furanone
system has been reported previously by Professor R. H.
Schlessinger in: (a) Schlessinger, R. H.; Iwanowicz, E. J.
Tetrahedron Lett. 1988, 29, 1489; (b) Schlessinger, R. H.;
Mjalli, A. M. M.; Adams, A. D. J. Org. Chem. 1992, 57,
mp 195–196°C. H NMR (200 MHz, CDCl ) l 6.46 (s,
3
1H), 4.84 (s, 1H), 3.35 (br, 4H), 1.98 (br, 4H), 1.93 (s,
13
3H), 1.87 (s, 3H). C NMR (50 MHz, CDCl ) l 190.0,
3
171.2, 145.9, 119.7, 114.3, 96.8, 55.2, 50.5(2C), 29.5,
25.4(2C), 15.3. EIHRMS: (C H N OS) calcd 248.0984;
1
3
16
2
1
2
992.
found 248.0991. 18: H NMR (200 MHz, CDCl ) l 9.36
3
7
8
9
. For synthesis related to thiolactomycin, see: Thomas, E.
J.; Chambers, M. S. J. Chem. Soc., Perkin Trans. 1 1997,
(s, 1H), 6.41 (s, 1H), 4.80 (s, 1H), 3.35 (br, 4H), 1.97 (br,
4H), 1.92 (s, 3H), 1.68 (s, 3H). C NMR (50 MHz,
13
4
17–443 and references cited therein.
CDCl ) l 194.6, 194.2, 171.7, 151.1, 141.1, 97.2, 55.7,
3
. For synthesis of 5a see: Enders, D.; Kipphardt, H.;
Gerdes, P.; Brena-Valle, L. J.; Bhushan, V. Bull. Soc.
Chim. Belg. 1989, 97, 691–704.
. The crystal structure of compounds 9a and 16 have been
deposited at the Cambridge Crystallographic Data Centre
as CCDC 158219 and CCDC 158220. The absolute stere-
ochemistry at the g-position was determined based on the
existing chiral center on the pyrrolidine that originated
from L-proline.
50.8(2C), 29.2, 26.3(2C), 9.1. EIHRMS: (C H NO S)
1
3
17
2
1
calcd 251.0980; found 251.0979. 19: H NMR (200 MHz,
CDCl ) l 6.29 (dd, J=17.58, 10.84 Hz, 1H), 5.56 (d,
3
J=17.58 Hz, 1H), 5.05 (d, J=10.84 Hz, 1H), 4.84 (s,
1H), 3.32 (br, 4H), 1.92 (br, 4H), 1.91 (s, 3H), 1.73 (s,
13
3H). C NMR (50 MHz, CDCl ) l 194.2, 174.7, 155.4,
3
140.51, 130.8, 113.7, 96.8, 56.3, 50.8(2C), 30.9, 26.3(2C),
11.6. EIHRMS: (C H NOS) calcd 249.1187; found
14
19
249.1183.