Synthesis and antibacterial activity of new 1β-methylcarbapenems having the potential for intramolecular nonbonded S···O interactions

Article abstract of DOI:10.1248/cpb.49.1660

Mercaptoacetyliminothiadiazoline derivatives (19, 20) useful for the pendant moiety of 1β-methylcarbapenem antibiotics were efficiently synthesized. Acetyl derivative (18) of 20 was submitted to X-ray analysis, and a significant nonbonded S···O close cont

Full text of DOI:10.1248/cpb.49.1660

1660
Communications to the Editor
Chem. Pharm. Bull. 49(12) 1660—1661 (2001)
Vol. 49, No. 12
activities of new 1b-methylcarbapenems (5, 6) having the
potential for intramolecular nonbonded interactions in their
molecules, as shown in Chart 1.
Synthesis and Antibacterial Activity of
b
New 1 -Methylcarbapenems Having the
Potential for Intramolecular Nonbonded
S···O Interactions
Commercially available 2-amino-1,3,4-thiadiazole (7) and
its 5-methyl derivative (8) were treated with trifluoroacetic
anhydride in toluene at 0 °C and then room temperature to af-
ford the corresponding 2-trifluoroacetylamino derivatives (9,
10) in 70 and 80% yields. Regioselective methylation of 9
and 10 with MeI and K2CO3 in N,N-dimethylformamide
(DMF) gave their 3-methylthiadiazoline derivatives (11, 12)
as colorless prisms in 78 and 97% yields, respectively. After
hydrolysis of 11 and 12 with 5% aqueous NaOH in tetrahy-
drofuran (THF), the resultant 2-iminothiadiazolines (13, 14)
were allowed to react with bromoacetyl chloride in the pres-
ence of pyridine in CH2Cl2 to obtain the corresponding 2-
bromoacetylimino-3-methylthiadiazolines (15, 16) as pale
yellow prisms in 83% and quatitative yields, as shown in
Chart 2. Treatment of 15 and 16 with potassium thioacetate
in acetone furnished crystalline 2-acetylthioacetylimino de-
rivatives (17, 18),7) which were submitted to alkaline hydrol-
ysis with 4 N NaOH in MeOH to afford the desired thiols (19,
20) in excellent yields, respectively (Chart 2).
Yoshimitsu NAGAO, ,a Hitoshi IIMORI,a
*
b
Ki Hong NAM,a,1) Shigeki SANO,a and Motoo SHIRO
Faculty of Pharmaceutical Sciences, The University of Tokushima,a
Sho-machi, Tokushima 770–8505, Japan and Rigaku Corporation,b
3–9–12 Matsubara-cho, Akishima, Tokyo 196–8666, Japan.
Received September 5, 2001; accepted October 24, 2001
Mercaptoacetyliminothiadiazoline derivatives (19, 20) useful
for the pendant moiety of 1b-methylcarbapenem antibiotics
were efficiently synthesized. Acetyl derivative (18) of 20 was sub-
mitted to X-ray analysis, and a significant nonbonded S···O
close contact was recognized in the crystallographic structure.
New 1b-methylcarbapenems (5, 6) were synthesized by exploit-
ing 19 and 20, and exhibited considerable antibacterial activities
in vitro.
Key words carbapenem antibiotic; thiadiazoline; X-ray analysis; crys-
tallographic structure; close contact
Introduction of the thiols (19, 20) into the 1b-mehtylcar-
bapenem skeleton was performed as follows (Chart 3): Chi-
ral compound 21, prepared according to the asymmetric syn-
thesis which was established by us,3h) was treated with 19
and 20 in the presence of i-Pr2NEt in MeCN to give
thioethers (22, 23) in 79 and 85% yields. Deprotection of the
Since discovery of a non-natural 1b-methylcarbapenem
antibiotic by a Merck Sharp & Dohme research group,2) we
have been extensively studying the development of new 1b-
substituted carbapenems and useful new methods for synthe-
sizing them.3) Nagao and Wyeth Lederle groups disclosed a
unique 1b-methylcarbapenem antibiotic, biapenem (1), bear-
ing a s-symmetric bicyclotriazoliumthio group as the pen-
dant moiety.3h,k) Interestingly, an intramolucular nonbonded
S···O interaction (“close contact”) was recognized in the
crystal structure of 1.3k) Ishiguro et al. reported a significant
relationship between an intramolecular nonbonded S···O in-
teraction in the molecule of penem antibiotic (2) and its an-
tibacterial activities.4) The intramolecular nonbonded interac-
tions such as S···O, S···S, S···N have been observed in a large
amount of organosulfur compounds.5) We also reported the
fascinating intramolecular nonbonded S···O interactions in
the molecules of 2-acylimino-1,3,4-thiadiazolines (e.g., 3),
which exhibited strong angiotensin II receptor antagonistic
activity, and the structural stability of their model compounds
(e.g., 4) involving such a nonbonded interaction on the basis
of the ab initio MO calculations.6) With background de-
scribed above, we now report the synthesis and antibacterial
Chart 1. New 1b-Methylcarbapenems
Chart 2. Synthesis of 2-Mercapotacetylimino-3-methyl-1,3,4-thiadiazo-
line Derivatives (19, 20)
To whom correspondence should be addressed. e-mail: ynagao@ph2.tokushima-u.ac.jp
© 2001 Pharmaceutical Society of Japan

December 2001
1661
molecules of 5 and 6 must be possible (Chart 1).
Finally, in vitro screening of new 1b-methylcarbapenem
antibiotics (5, 6) against several bacteria was performed. The
data are summarized in Table 1. Although these new antibi-
otics did not exhibit remarkable antibacterial activities, this
new synthetic approach based on the intramolecular non-
bonded interaction concept seemes to be an attractive gate-
way toward the development of a new class of 1b-methylcar-
bapenem antibiotics.
Acknowledgements This work was supported by Grants-in-Aid for Sci-
entific Research on Priority Areas (A)(2)(No. 13029085) from the Ministry
of Education, Culture, Sports, Science, and Technology, Japan and for Sci-
entific Research (B)(2)(No. 12470482) from Japan Society for the Promo-
tion of Science.
Chart 3. Synthesis of New 1b-Methylcarbapenems (5, 6)
References and Notes
1) Present address: Central Research Institute, Dong Kook Pharmaceuti-
cal Co., LTD., # 150–3, Hoijuk-Ri, Kwanghyewon-Myun, Jincheon-
Gun, Choongcheongbook-Do, Korea.
2) Shih D. H., Baker F., Cama L., Christensen B. G., Heterocycles, 21,
29—40 (1984).
3) a) Nagao Y., Kumagai T., Takao S., Abe T., Ochiai M., Inoue Y., Taga
T., Fujita E., J. Am. Chem. Soc., 108, 4673—4675 (1986); b) Nagao
Y., Kumagai T., Abe T., Ochiai M., Taga T., Machida K., Inoue Y., J.
Chem. Soc., Chem. Commun., 1987, 602—603; c) Nagao Y., “ Per-
spectives in the Organic Chemistry of Sulfur,” ed. by Zwanenburg B.,
Klunder A. J. H., Elsevier, Amsterdam, 1987, pp. 57—73; d) Nagao
Y., Abe T., Shimizu H., Kumagai T., Inoue Y., J. Chem. Soc., Chem.
Commun., 1989, 821—822; e) Idem, Heterocycles, 33, 523—528
(1992); f ) Nagao Y., Kumagai T., Nagase Y., Tamai S., Inoue Y., Shiro
M., J. Org. Chem., 57, 4232—4237 (1992); g) Nagao Y., Nagase Y.,
Kumagai T., Kuramoto Y., Kobayashi S., Inoue Y., Taga T., Ikeda H.,
ibid., 57, 4238—4242 (1992); h) Nagao Y., Nagase Y., Kumagai T.,
Matsunaga H., Abe T., Shimada O., Hayashi T., Inoue Y., ibid., 57,
4243—4249 (1992); i) Kumagai T., Abe T., Fujimoto Y., Hayashi T.,
Inoue Y., Nagao Y., Heterocycles, 36, 1729—1734 (1993); j) Kumagai
T., Tamai S., Abe T., Nagase Y., Inoue Y., Nagao Y., ibid., 37, 1521—
1527 (1994); k) Kumagai T., Tamai S., Abe T., Matsunaga H., Hayashi
K., Kishi I., Shiro M., Nagao Y., J. Org. Chem., 63, 8145—8149
(1998); l) Nagao Y., Tamai S., Tanigawa N., Sano S., Kumagai T.,
Kishi I., Heterocycles, 48, 617—620 (1998).
Chart 4. Computer-Generated Drawing Derived from the X-Ray Coordi-
nates of Compound 18
Table 1. Antibacterial Activity of Compounds 5 and 6
MIC (mg/ml)a)
Organism
5
6
S. aureus TERAJIMA
S. pyogenes Cook
S. subtilis ATCC 6633
M. luteus ATCC 9341
E. coli NIHJ JC-2
0.25
0.5
0.5
0.5
0.125
0.25
0.25
0.125
32
32
K. pneumoniae PCI-602
S. enteritidis G14
0.25
1.5
0.125
0.5
4) Tanaka R., Oyama Y., Imajo S., Matsuki S., Ishiguro M., Bioorg. Med.
Chem., 5, 1389—1399 (1997).
5) Kucsman A., Kapovits I., “Organic Sulfur Chemistry: Theoretical and
Experimental Advances,” ed. by Bernardi F., Csizmadia I. G., Mangini
A., Elsevier, Amsterdam, 1985, pp. 191—245 and references cited
therein.
S. marcescens IMA 1184
P. rettgeri IFO 3850
P. aeruginosa IFO 3445
128
8
Ͼ128
64
8
Ͼ128
a) Tested by the agar dilution method (inoculum size : 106 cell/ml).
6) Nagao Y., Hirata T., Goto S., Sano S., Kakehi A., Iizuka K., Shiro M.,
J. Am. Chem. Soc., 120, 3104—3110 (1998).
7) 17: mp 78—78.5 °C (CHCl3–n-hexane). H -NMR (200 MHz, CDCl3)
p-nitrobenzyl group of 22 and 23 was done by means of
treatment using excess Zn powder in THF–0.35 M phosphate
buffer (1 : 3) at room temperature,3i) and then the usual work-
up3i,k) of the reaction mixture afforded the desired com-
pounds 5 (33% yield) and 6 (19% yield), respectively.8)
1
d: 2.40 (3H, s), 3.99 (3H, s), 4.01 (2H, s), 8.35 (1H, s). IR (KBr)
cmϪ1: 1656, 1736. Electron impact-mass spectra (EI-MS) m/z:
231.0147 (Calcd for C7H9N3O2S2: 231.0136). Anal. Calcd for
C7H9N3O2S2: C, 36.35; H, 3.92; N, 18.17. Found: C, 36.27; H, 3.88; N,
18.01. 18: mp 84—85 °C (THF–n-hexane). 1H-NMR (200 MHz,
CDCl3) d: 2.39 (3H, s), 2.52 (3H, s), 3.90 (3H, s), 3.99 (2H, s). IR
Because both compounds 5 and 6 were amorphous pow-
der, we attempted recrystallization of crystalline compounds
17 and 18 in a solution of THF and n-hexane. Fortunately,
compound 18 was obtained as an excellent single crystal,
which was submitted to X-ray crystallographic analysis.9)
The computer-generated drawing of the crystal structure of
18 is depicted in Chart 4. In the represented structure of 18,
significant close contact [2.644(3) Å] between S1 and O1
atoms and planarity of the S1–C1–N1–C2–O1 moiety (tor-
sion angles shown in Chart 3) were recognized. The non-
bonded S1···O1 atoms’ distance [2.644(3) Å] is considerably
lesser than the sum (3.32 Å) of the van der Waals radii (S and
O). Thus, it can be suggested from the viewpoints of the struc-
tural data3k) of 18 and 1 and the ab initio MO calculation6) of
4 that intramolecular nonbonded S···O interactions in the
(KBr) cmϪ1
: 1655, 1736. EI-MS m/z: 245.0312 (Calcd for
C8H11N3O2S2: 245.0293). Anal. Calcd for C8H11N3O2S2: C, 39.17; H,
4.52; N, 17.13. Found: C, 38.92; H, 4.53; N, 17.05.
8) 5: Colorless amorphous powder. 1H-NMR (200M Hz, D2O) d: 1.19
(3H, d, Jϭ7.1 Hz), 1.28 (3H, d, Jϭ6.3 Hz), 3.43 (1H, dd, Jϭ6.1, 2.0
Hz), 3.51—3.63 (1H, m), 3.79 (1H, d, Jϭ15.6 Hz), 3.99 (3H, s), 4.01
(1H, d, Jϭ15.2 Hz), 4.16—4.29 (2H, m), 8.82 (1H, s). IR (KBr) cmϪ1
:
1607, 1757. FAB-MS m/z: 421.0584 (Calcd for C15H18N4O5S2ϩNaϩ:
421.0616). [a]D29 ϩ18.1° (cϭ1.0, H2O). 6: Colorless amorphous pow-
1
der. H-NMR (200 MHz, D2O) d : 1.19 (3H, d, Jϭ7.3 Hz), 1.30 (3H,
d, Jϭ6.4 Hz), 2.58 (3H, s), 3.41—3.56 (2H, m), 3.71 (1H, d, Jϭ
15.1 Hz), 3.90 (1H, d, Jϭ14.9 Hz), 3.93 (3H, s), 4.14—4.27 (2H, m).
IR (KBr) cmϪ1: 1549, 1747. FAB-MS m/z: 435.0750 (Calcd for
C16H20N4O5S2ϩNaϩ: 435.0773). [a]D29 Ϫ189.4° (cϭ1.0, H2O).
9) The crystal data of compound 18: Monoclinic, C2/c(#15), aϭ
17.609(2) Å, bϭ13.318(2) Å, cϭ12.851(2) Å, bϭ130.001(6)°, Vϭ
2308.6(6) Å3, zϭ8, Dcalcϭ1.412 g/cm3, Rϭ0.047, Rwϭ0.075.