Synthesis of optically active macrolides with hydrazide fragments from tetrahydropyran and L-(+)-tartaric acid derivatives

Article abstract of DOI:10.1007/s10600-013-0708-8

The synthesis of two potentially useful optically active 23- and 30-membered macrolides containing a 1,2-diol system and dihydrazide fragments was developed starting from tetrahydropyran. It was based on [1+1]-condensation of 7-oxooctyl-7-oxooctanoate and bis(7-oxooctyl)hexanedioate with L-(+)-tartaric acid hydrazide.

Full text of DOI:10.1007/s10600-013-0708-8

Chemistry of Natural Compounds, Vol. 49, No. 4, September, 2013 [Russian original No. 4, July–August, 2013]
SYNTHESIS OF OPTICALLY ACTIVE MACROLIDES WITH
HYDRAZIDE FRAGMENTS FROM TETRAHYDROPYRAN
AND L-(+)-TARTARIC ACID DERIVATIVES
*
G. Yu. Ishmuratov, M. P. Yakovleva, G. R. Mingaleeva,
M. A. Shutova, R. R. Muslukhov, E. M. Vyrypaev,
and A. G. Tolstikov
UDC 547.447+547.442.5+547.811
The synthesis of two potentially useful optically active 23- and 30-membered macrolides containing
a 1,2-diol system and dihydrazide fragments was developed starting from tetrahydropyran. It was based on
[
1+1]-condensation of 7-oxooctyl-7-oxooctanoate and bis(7-oxooctyl)hexanedioate with L-(+)-tartaric acid
hydrazide.
Keywords: tetrahydropyran, 7-oxooctyl-7-oxooctanoate, bis(7-oxooctyl)hexanedioate, macrolide with 1,2-diol and
dihydrazide fragments, [1+1]-condensation, synthesis.
Only a small fraction of the several hundreds of thousands of secondary metabolites that have been isolated from
various natural sources and are now described in the literature are macrocycles. However, compounds with antibiotic
(
antimicrobial, antiviral, antiparasite) and antitumor activity were found among them [1, 2]. This is due to the unwavering
attention of chemists, biochemists, and pharmacologists to this class of natural metabolites and their synthetic derivatives.
We previously proposed the synthesis from tetrahydropyran (1) of ꢀ,ꢁ-diketones 2 and 3 containing one (2) or two
(
3) esters [3, 4]. Their [1+1]-condensation with hydrazine hydrate or dihydrazides of fatty dicarboxylic acids led to
macroheterocycles containing one or two esters and azine or dihydrazide fragments. Macrolide 4 that was synthesized by us
exhibited significant (at the level of erythromycin) antibacterial activity in vitro and in vivo with respect to voucher and field
strains of pathogenic microorganisms (S. aureus, E. coli, and P. aeruginosa) [5]. Reduced solubility of the synthesized
macroheterocycles in H O was noted.
2
Herein we present results for the first reported [1+1]-condensation of aforementioned ꢀ,ꢁ-diketones 2 or 3 with
L-(+)-tartaric acid hydrazide (5) that was prepared by us using the standard method [6] in order to increase the solubility of this
type of N-containing macrolides and to introduce into them an optically active 1,2-diol fragment. The [1+1]-condensation was
carried out in a mixture of solvents at mole ratio (diketone–dioxane–H O 1:100:100) in order to increase the solubility of 5.
2
As a result, optically active macroheterocycles 6 and 7 containing dihydrazide and 1,2-diol fragments and one or two esters
were prepared in good yields.
The structures and compositions of synthesized macroheterocycles 6 and 7 were confirmed by elemental analyses;
IR, PMR, and 13C NMR spectroscopy; and GC/MS. The chemical purity (~95%) was established by HPLC.
–
1
–1
IR spectra of 6 and 7 lacked absorption bands [1718 cm (6) and 1703 cm (7)] characteristic of the ketone groups
–
1
of key diketodiesters 2 and 3. Bands at 1630 cm (C=N), 1664–1671 (CONH), and 3354–3455 (NH) in the IR spectra of 6
and 7 proved that the macrocycles involving the hydrazides had formed.
NMR spectra of 6 and 7 were compared with those of the starting compounds diketodiesters 2 and 3 and tartaric acid
dihydrazide.
13C NMR spectra of 6 and 7 lacked resonances of carbonyl C atoms of starting compounds 2 and 3 (208.86 and
2
08.99 ppm in 6 and 208.66 in 7). Furthermore, a resonance for the hydrazine (NH NH) group (~4.90 ppm) was missing in
2
PMR spectra of 6 and 7. These facts indicated that the obtained compounds were not linear substitution products.
Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, Russian Federation, 450054,
Ufa, Prosp. Oktyabrya, 71, e-mail: insect@anrb.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 4, July–August,
2
013, pp. 592–594. Original article submitted March 21, 2013.
0
009-3130/13/4904-0691 ©2013 Springer Science+Business Media New York
691

O
O
O
O
1
[3]
[4]
O
O
O
O
O
O
O
[5]
N
O
O
N
O
O
HN
NH
O
O
3
2
3
4
1,4-dioxane
5, 1,4-dioxane
O
O
O
O
O
O
N
O
O
N
N
N
O O
O
O
N
H
N
H
H NHN
2
HN
NH
NHNH
2
HO
OH
HO
OH
HO
OH
6
7
5
13C NMR spectra of 6 and 7 showed resonances for ester C atoms (173.42 in 6 and 172.73 ppm in 7) and resonances
for C atoms of NH–C=O that were shifted compared with starting tartaric acid dihydrazide (175.31 ppm vs. 167.55 ppm in 6
and 167.10 in 7) in addition to singlets for C=N (160.11 ppm in 6 and 159.12 in 7) and two quartets for cis-CH groups
3
(
15.55 ppm in 6 and 15.29 in 7), the chemical shifts of which corresponded to C atoms of two magnetically equivalent
CH –C=N groups. The presence of triplets (40.35 ppm in 6 and 40.15 ppm in 7) for C atoms of two CH C=N groups also
3
2
confirmed that the hydrazide (CH C=N–NH–C=O) group had formed. PMR spectra of macrocycles 6 and 7 showed weak-
2
field resonances (9.60 ppm in 6 and 8.80 ppm in 7), the chemical shifts and integrated intensities of which corresponded to two
NHC=O protons of the macrocycles.
All these spectral data indicated that macrocycles 6 and 7 had formed. This was also confirmed by mass spectral data.
Mass spectra of synthesized compounds 5, 6, and 7 were studied using electrospray ionization (ESI) with simultaneous
recording of positive and negative ions at capillary potentials of 4.5 and 3.5 kV, respectively. Very strong peaks for protonated
+
–
+
+
–
MH and deprotonated [M – H] ions in addition to their ionic associates with ions (Na , K , Br ) and molecules (H O and
2
CH CN) were recorded in the mass-spectrometric study of 5, 6, and 7. This could be considered proof of the existence of
3
compounds with the corresponding molecular weights.
EXPERIMENTAL
IR spectra were recorded from thin layers on a Shimadzu IR Prestige-21 instrument. PMR spectra were taken from
DMSO-d or D O solutions with TMC or DSS internal standard, respectively, on a Bruker AM-300 spectrometer (operating
6
2
1
13
frequency 300.13 MHz for H and 75.47 MHz for C). Chromatographic analysis was performed on a Chrom-5 instrument
column length 1.2 m, stationary phase silicone SE-30 (5%) on Chromaton N-AW-DMCS (0.16–0.20 mm), operating temperature
0–300°C] using He carrier gas. Column chromatography used Lancaster SiO (70–230) (England). TLC monitoring used
[
5
2
Sorbfil SiO (Russia). Elemental analyses of all compounds agreed with those calculated. Optical rotation was measured on
2
a PerkinElmer 241-MC polarimeter. Mass spectra were obtained in a Shimadzu 2010 EV LC/MS instrument (syringe input,
sample solution in CH CN at flow rate 60 ꢂL/min) using electrospray ionization (ESI) with simultaneous recording of positive
3
and negative ions at capillary potentials 4.5 and –3.5 kV, respectively. The capillary interface temperature was 230°C; nebulizer
gas (dry N ) flow rate, 1.5 L/min. HPLC analysis was carried out on a Shimadzu LC-20AD liquid chromatograph with an
2
692

SPD-M20A diode-array detector (Shimadzu, Japan) using a Phenomenex column (250 ꢃ 4.6 mm) with Luna C18 sorbent
(
5 ꢂm). The mobile phase was H O:CH CN at flow rate 1 mL/min. The analytical wavelength was 215 nm.
2 3
L-(+)-Tartaric Acid Dihydrazide (5). A mixture of N H 4H O (5.46 g, 171 mmol, 98%) and dimethyl L-(+)-tartrate
2
4
2
(
5.00 g, 28 mmol) was stirred vigorously for 1 h. The resulting white precipitate was filtered off and washed with Et O to
2
2
0
–1
afford 5 (4.90 g, 98%), mp 184ꢄC, [ꢀ] +158.3ꢄ (c 3.09, H O). IR spectrum (cm ): 3319 (NHNH ), 1666 (C(O)NH).
D
2
2
1
13
H NMR spectrum (300 MHz, D Î, ꢅ, ppm): 4.50 (2Í, s, Í-2, Í-3), 4.80 (8Í, s, 2NHNH , 2OH).
Ñ NMR spectrum
2
2
(
(
75 MHz, D Î, ꢅ, ppm): 74.69 (d, Ñ-2, Ñ-3), 175.31(s, C(O)NH). Mass spectrum (ESI), m/z (%), CH CN/H O – 95/5;
2
3
2
+
–
Scan+): [M] 179 (8.6); (Scan–): [M] 177 (22.7). C H N O .
4
10 4 4
Macroheterocycles 6 and 7. General Method. Diketone 2 (0.28 g, 1.0 mmol) or diketone 3 (0.43 g, 1.0 mmol) in
anhydrous dioxane (8.5 mL) was stirred vigorously, treated slowly with dihydrazide 5 (0.18 g, 1.0 mmol) in H O (1.8 mL),
2
and stirred for 120 h (TLC monitoring). The dioxane was evaporated at reduced pressure. The precipitate was dissolved in
CH Cl (20 mL), washed with H O (3 ꢃ 5 mL), dried over MgSO , and evaporated. The resulting residue was treated with
2
2
2
4
stirring with anhydrous CH Cl (1 mL) and hexane (10 mL) and stored until the layers separated. The upper layer was
2
2
decanted. The residue was washed with hexane (5 mL) and evaporated in vacuo.
8E,12R,13R,16E)-12,13-Dihydroxy-8,17-dimethyl-1-oxa-9,10,15,16-tetraazacyclotricosa-8,16-diene-2,11,14-
(
2
0
–1
trione (6). Yield 0.37 g (68%), [ꢀ] –9.0ꢄ (c 0.048, DMSO), mp 154.5ꢄC. IR spectrum (cm ): 3355 (NH), 1731 (COO),
671 (C(O)NH), 1630 (C=N). H NMR spectrum (300 MHz, DMSO-d , ꢅ, ppm): 1.21–1.36 (6Í, m, Í-4, Í-5, Í-6),
D
1
1
6
1
.40–1.58 (8Í, m, Í-19, Í-20, Í-21, H-22), 1.80 (6Í, s, ÑÍ -8, ÑÍ -17), 2.23 (4Í, t, J = 6.8, Í-7, Í-18), 2.25 (2Í, t, J = 6.9,
3
3
1
3
Í-3), 3.96 (2Í, t, J = 6.3, Í-23), 4.30 (2Í, s, Í-12, Í-13), 6.00 (s, 2OH), 9.60 (2Í, s, NH). Ñ NMR spectrum (75 MHz,
DMSO-d , ꢆꢅ, ppm): 15.55 (q, ÑÍ -8, ÑÍ -17), 24.42 (t, Ñ-21), 25.44 (t, Ñ-19), 25.72 (t, Ñ-4), 25.96 (t, Ñ-5), 28.30 (t, Ñ-20),
6
3
3
2
1
[
8.50 (t, Ñ-6), 33.71 (t, Ñ-22), 38.38 (t, Ñ-3), 40.35 (t, Ñ-7, Ñ-18), 64.00 (t, Ñ-23), 72.38 (d, Ñ-12, Ñ-13), 160.11 (s, Ñ-8, Ñ-17),
+
67.55 (s, Ñ-11, Ñ-14), 173.42 (s, Ñ-2). Mass spectrum (ESI), m/z (%), CH CN/H O – 95/5, (Scan+): [M + H] 427 (11),
3
2
+
+
–
–
M + Na] 449 (75), [M + K] 465 (4); (Scan–): [M – H] 425 (100), [M – H + 2H O] 461 (47). C H N O .
2 20 34 4 6
(
15E,19R,20R,23E)-19,20-Dihydroxy-15,24-dimethyl-1,8-dioxa-16,17,22,23-tetraazacyclotriaconta-15,23-diene-
2
0
–1
2
1
,7,18,21-tetraone (7). Yield 0.48 g (89%), [ꢀ]
732 (COO), 1697 (C(O)NH), 1624 (C=N). H NMR spectrum (300 MHz, DMSO-d , ꢅ, ppm): 1.40–1.71 (8Í, m, Í-10, Í-11,
+96.0ꢄ (c 0.048, DMSO), mp 156.5ꢄC. IR spectrum (cm ): 3332 (NH),
D
1
6
Í-28, Í-29), 1.41–1.65 (12Í, m, H-12, H-13, H-26, H-27), 1.82 (6Í, s, ÑÍ -15, ÑÍ -24), 2.32 (4Í, t, J = 6.6, Í-14, Í-25),
3
3
1
3
4
.03 (4Í, t, J = 6.5, Í-9, Í-30), 4.30 (2Í, t, Í-19, Í-20), 5.9 (s, 2OÍ), 9.60 (2Í, s, NH). Ñ NMR spectrum (75 MHz,
DMSO-d , ꢅ, ppm): 15.29 (q, ÑÍ -15, ÑÍ -24), 22.86 (t, Ñ-4, Ñ-5), 25.17 (t, Ñ-11, Ñ-28), 28.02 (t, Ñ-13, Ñ-26), 28.27
6
3
3
(
t, Ñ-12, Ñ-27), 33.12 (t, Ñ-10, Ñ-29), 38.15 (t, Ñ-3, Ñ-6), 40.15 (t, Ñ-14, Ñ-25), 63.67 (t, Ñ-9, Ñ-30), 72.57 (d, Ñ-19, Ñ-20),
1
59.12 (s, Ñ-15, C-24), 167.10 (s, Ñ-18, Ñ-21), 172.73 (s, Ñ-2, Ñ-7). Mass spectrum (ESI), m/z (%), CH CN/H O – 95/5;
3
2
–
+
+
+
–
(
Scan+): [M + H] 541 (39), [M + Na] 563 (100), [M + K] 579 (8); (Scan–): [M – H] 539 (9), [M – H + 2H O] 575 (21),
2
–
–
–
–
[M – H + Br] 619 (100), [M + H + Br] 621 (90), [M + H O + Br – H] 637 (24), [M + H O + Br + H] 639 (19). C H N O .
2
2
26 44
4
8
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1.
2.
3.
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5.
6.
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R. N. Kashipov, and A. G. Tolstikov, Butler. Soobshch., 21 (2009).
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