Synthesis of novel chiral macrolides and their antifungal activity

Article abstract of DOI:10.1016/S0040-4039(02)00900-0

Nineteen chiral macrocyclic diamide-diester ligands were synthesized using a three step reaction. The synthesis utilized the condensation of dicarbonyl dichlorides with chiral 2-aminoethanol derivatives. The reaction was catalyzed in a dual catalyst system. Some of the compounds were found to display antifungal activity.

Full text of DOI:10.1016/S0040-4039(02)00900-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5001–5003
Synthesis of novel chiral macrolides and their antifungal activity
Ming Zhang Gao,a,b Jian Gao,a Zun Le Xub and Ralph A. Zingaroa,*
aDepartment of Chemistry, Texas A & M University, College Station, TX 77842-3012, USA
bSchool of Chemistry and Chemical Engineering, ZhongShan University, Guangzhou 510275, PR China
Received 1 April 2002; accepted 7 May 2002
Abstract—Nineteen chiral macrocyclic diamide–diester ligands were synthesized using a three step reaction. The synthesis utilized
the condensation of dicarbonyl dichlorides with chiral 2-aminoethanol derivatives. The reaction was catalyzed in a dual catalyst
system. Some of the compounds were found to display antifungal activity. © 2002 Elsevier Science Ltd. All rights reserved.
Macrocyclic lactones and diamides are widely found in
nature and constitute an extensive range of natural
products with diverse biological activity.1–3 As reported,
macrocyclic lactones and macrolides, such as the ery-
thromycins and cytochalasins, display antibiotic and
antitumor activity.4,5 All of these natural compounds are
complexstructuresduetothepresenceofmulti-functional
groups and their chirality. A number of macrocyclic
compounds containing diamide–diester groups have been
synthesized.6–8 However, relatively little has been done
with respect to the synthesis of chiral macrocyclic
diamide–diester ligands. In this report, the synthesis of
a series of new chiral macrocyclic lactam–lactones and
their antibacterial and antifungal activities are described.
Scheme 1.
* Corresponding author. Tel.: 1-979-845-2731; fax: 1-979-845-4719; e-mail: zingaro@mail.chem.tamu.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00900-0

5002
M. Z. Gao et al. / Tetrahedron Letters 43 (2002) 5001–5003
As shown in Scheme 1, 2,6-isophthalic acid or 2,6-pyri-
dine dicarboxylic acid (1) undergo reaction with SOCl2
to form the corresponding dicarbonyl dichlorides (2).
presence of pyridine and N,N%-dimethyl-4-amino pyri-
dine (DMAP) a high cyclization yield was achieved. In
the synthesis of macrocycle 1, the influence of the
catalyst used on the reaction yield is significant and the
results are listed in Table 2. The yield of 65% was the
highest reached in this type of cyclization. Employing
this new dual catalyst system not only increased the
yield of the product, but also improved the reaction
rate by a factor of three.
Condensation of
2 with the C-substituted chiral
aminoethanols, yields compounds 3.9 In the subsequent
steps, 2,6-isophthalic dicarbonyl dichloride, 2,6-pyri-
dine dicarbonyl dichloride or 2,5-thiophene dicarbonyl
dichloride undergo reaction with 3 to form the
macrolides 4.10 All of the macrocycles synthesized and
some of their properties are listed in Table 1.11
One of the aims of the investigation was to determine
the biological properties of these new chiral macrocy-
cles. As shown in Table 1, the macrocycles synthesized
possess heterocyclic subunits including pyridine and/or
thiophene. This allowed us to determine the influence of
the incorporated heterocyclic groups on biological
In the cyclization procedure, the inorganic base K2CO3
showed no catalytic activity. By adding Et3N or pyri-
dine, the reaction can be improved, but with a relatively
low product yield. An alternate catalyst system was
sought to promote cyclization. It was found that in the
Table 1. Compounds synthesized and their physical properties
Entry
Ar (X)
R
Ar (Y)
Yield (%)
mp (°C)
272–274
239–241
233–235
\300
148–151
\280
245–247
142–144
195–197
[h]2D5
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Py
Py
Py
Py
Py
Py
Py
Py
Py
Et
Et
Et
iso-Pr
iso-Pr
iso-Pr
Ph
Ph
Ph
Ph
Py
Thio
Ph
Py
Thio
Ph
Py
Thio
Ph
Ph
Py
Thio
Ph
Py
Thio
Ph
65
28
36
50
22
37
30
26
29
67
47
42
62
41
44
20
50
28
22
−105.8
+260.2
−61.6
−272.0
−312.4
−85.9
+161.5
+340.9
+255.8
−205.1
+354.6
+260.2
−96.3
−278.6
−342.7
−82.9
Benzyl
Et
Et
\280
219–221
244–246
215–217
258–260
263–265
175–178
239–243
272–275
220–222
Et
iso-Pr
iso-Pr
iso-Pr
Benzyl
Benzyl
Benzyl
−125.8
−188.8
−94.5
Py
Thio
Table 2. Influence of the catalyst on the product yield for macrolide 4a
Catalyst
Yield%
K2CO3
2
Et3N
10
Pyridine
25
DMAP
28
Et3N+DMAP
Pyridine+DMAP
65
58
Table 3. Antibacterial and antifungal activity of the synthesized macrolides (the concentration used in the experiment,
macrolide=0.2 mg/L)
C
Compound
Bacterialsa
Fungalsa
E. coli
B. subtilis
M. tetragenus
S. aureus
S. schenckii
M. gypseum
A. niger
C. globosum
4a
4e
4j
4k
4m
4n
4o
+
++
+
+
−
−
+
+
+
++
+
++
−
+
++
+
+++
+++
+++
+++
+++
+++
+++
+++
++
++
++
+++
+
++
+++
++
++
+++
++
+++
+++
+++
+++
+
+
+
++
++
++
++
++
++
++
++
++
++
+++
+++
+++
+
+++, Bacteria or fungus are totally to be inhibited. ++, Almost to be inhibited. +, Only partially to be inhibited. −, The growth of the bacteria
and fungus was not different from control.
a Culture temperature 25–37°C and times 1–6 days.

M. Z. Gao et al. / Tetrahedron Letters 43 (2002) 5001–5003
5003
Table 4. MIC values of antifungal activity (mg/L)
3. Kuroda, T.; Imashiro, R.; Seki, M. J. Org. Chem. 2000,
65, 4213.
4. Nicolaou, K. C. Tetrahedron 1977, 33, 683.
5. Mansuri, M. M.; Paterson, I. Tetrahedron 1985, 41, 3569.
6. Kumar, S.; Singh, R.; Singh, H. Bioorg. Medicinal Chem.
Lett. 1993, 3, 363.
Compound S. schenckii M.
gypseum
A. niger
C. globosum
4e
4j
4k
4m
0.20
0.10
0.10
0.18
0.25
0.25
0.25
0.20
0.20
0.22
0.22
0.20
0.13
0.22
0.20
0.20
7. Kumar, S.; Hundal, M. S.; Kaur, N.; Singh, R.; Singh,
H. Tetrahedron Lett. 1995, 36, 9543.
8. Kumar, S.; Hundal, M. S.; Hundal, G.; Kaur, N.; Singh,
H. Tetrahedron 1997, 53, 10841.
9. The following procedure was used for the synthesis of
diol 3: 0.01 mol of solid 2 was added to 15 ml CH2Cl2.
After the solution was cooled, it was added dropwise to
60ml of CH2Cl2 solution containing 0.024 mmol chiral (R
or S) 2-aminoethanol derivatives and 30 ml Et3N over a
period of 2 h. The mixture was allowed to react at 0°C
for 4 h and at 25°C for an additional 4 h. The solid
product that separated was washed with 20 ml H2O, and
a mixture of acetone and petroleum ether (7:3) 20 ml. By
re-crystallization from methanol, diol 3 was obtained as
white crystals. (yield ꢀ80%).
10. The following procedure was used for the synthesis of the
macrolide 4: A dry flask was charged with 1.2 mmol of
compound 3 and 40 ml MeCN. On heating the system to
50°C and stirring magnetically, 2 ml Et3N and 20 mg of
DMAP was added. To the above system, 0.5 g compound
2 in 20 ml MeCN was added dropwise over a period of 1
h. The reaction solution was stirred for another 10 h.
White solid, Et3N·HCl formed, and was separated. The
remaining solvent was evaporated under reduced pres-
sure. The residue was purified by chromatography on
silica gel.
activity. The results of the tests are summarized in
Table 3. The minimum inhibitory concentration (MIC)
for the active compounds are listed in Table 4.
It is to be noted that the compounds synthesized are
not active as antibacterial agents. However, a signifi-
cant antifungal effect is demonstrated in some cases. It
can be seen that, of the 19 macrocycles tested, seven
possess antifungal activity. Macrocyclic compounds 4e,
4j, 4k and 4m show the best activity. Correlating the
structure of the macrocycles to their antifungal activity
revealed that the most active compound contains one
pyridine and a thiophene moiety in the macrocycle. The
best compound, 4m, completely inhibited the growth of
Sporothrix schenckii, Microsporum gypseum, Aspergillus
niger as well as Chaetonmium globosum. The enhanced
antifungal activity of this compound was attributed to
the simultaneous presence of N and S heterocyclic
subunits in the chiral macrolide.
Acknowledgements
11. Compound 4m: IRw, 3332, 3279, 3084, 2968, 2932, 2877,
1727, 1656, 1531, 1450, 1367, 1346, 1305, 1124, 1203,
1
1144, 1101, 1028, 997, 962, 842, 744, 664 cm−1. H NMR,
The financial assistance of the Natural Science Founda-
tion of China and the Robert Welch foundation in
support of this research are appreciated.
lH: 0.97–1.03 (6H, t, J=7.0 Hz, CH3), 1.71–1.93 (4H, m,
CH2), 4.12–4.17 (2H, m, CH), 4.35–4.38 (2H, dd, J=4.0,
10.5 Hz, CH2O), 4.58–4.61 (2H, dd, J=5.5, 11.0 Hz,
CH2O), 7.76 (2H, s, thiophene-H), 8.14–8.17 (1H, dd,
J=7.0, 8.0 Hz, Py-H), 8.25 (2H, d, J=7.5 Hz, Py-H),
8.32 (2H, d, J=8.5 Hz, CONH); 13C, NMR, lC: 11.15,
25.53, 52.60, 66.08, 125.47, 133.25, 139.41, 139.62, 151.43,
160.72, 164.55; MS (FAB): 446 (M+1, 100%), 155, 111,
77, 55.
References
1. Roxburgh, C. J. Tetrahedron 1995, 51, 9767.
2. Frensch, V. K.; Vogtle, F. Tetrahedron Lett. 1997, 2573.