Synthesis of optically active macrolides bearing di- and triethylene glycol and dicarboxylic acid hydrazide moieties from (-)-α-pinene

Article abstract of DOI:10.1007/s11172-019-2575-3

Six optically active macroheterocycles bearing ester and dihydrazide moieties were synthesized from available natural (-)-α-pinene through the intermediate keto acid, (3¹R,3³R)- 1-hydroxy-3²,3²-dimethyl-1,4-dioxopentaphane, using the [2+1] reaction of this keto acid with di- or triethylene glycols and the [1+1] condensation of the resulting α,ω-diketo diesters with dicarboxylic acid dihydrazides in the key steps.

Full text of DOI:10.1007/s11172-019-2575-3

Russian Chemical Bulletin, International Edition, Vol. 68, No. 7, pp. 1445—1450, July, 2019
1445
Synthesis of optically active macrolides bearing di- and triethylene glycol
and dicarboxylic acid hydrazide moieties from (–)-α-pinene
M. P. Yakovleva, G. R. Mingaleeva, K. S. Denisova, and G. Yu. Ishmuratov
Ufa Institute of Chemistry, Ufa Federal Research Centre, Russian Academy of Sciences,
7
1 prosp. Oktyabrya, 450054 Ufa, Russian Federation.
Tel.: +7 (8347) 235 5801. E-mail: insect@anrb.ru
Six optically active macroheterocycles bearing ester and dihydrazide moieties were synthe-
1
3
sized from available natural (–)--pinene through the intermediate keto acid, (3 R,3 R)-
2
2
1
-hydroxy-3 ,3 -dimethyl-1,4-dioxopentaphane, using the [2+1] reaction of this keto acid with
di- or triethylene glycols and the [1+1] condensation of the resulting ,-diketo diesters with
dicarboxylic acid dihydrazides in the key steps.
Key words: (–)--pinene, macrocyclization, [2+1] and [1+1] condensation, macrolides.
Natural macroheterocycles, in particular macro-
lactones, are characterized by great structural diversity.
They possess various interesting properties, including
perfume properties, phytotoxicity, pheromone and insec-
ticidal activity, and pharmaceutical (antibiotic, cytotoxic,
antitumor, etc.) properties. Hence, the isolation and syn-
and hydrazide moieties, from (–)--pinene through the
1
3
2
2
intermediate keto acid, (3 R,3 R)-1-hydroxy-3 ,3 -di-
methyl-1,4-dioxopentaphane.
Results and Discussion
thesis of such compounds have attracted great atten-
The ozonolysis of (–)--pinene 115 affords isopropyl
keto ester 2 as a 4 : 1 mixture of cis and trans isomers
tion.1
—3
The use of natural monoterpenoids in the
synthesis of macroheterocycles was reported in recent
literature. For instance, (+)-3-carene and (–)--pinene
(
Scheme 1). The formation of this mixture is attributed to
4
5
the fact that the reduction of peroxide ozonolysis products
of (–)--pinene 1 gives a cis-cyclobutane derivative, in
which the keto group -positioned to the four-membered
ring can be partially enolized. The protonation of the enol
double bond for the reverse transformation to the keto
group can occur from two sides, resulting in the starting
ketone in a mixture with its S-isomer. The alkaline hydro-
lysis of isopropyl keto ester 2 affords keto acid 3. The
acylation of di- or triethylene glycols with this keto acid
was performed by three methods giving the target products
in approximately equal yields. The first approach is based
on the reaction of keto acid 3 with di- or triethylene glycol
ditosylates in the presence of K CO in acetonitrile and
were converted into chiral pentadentate macrocyclic
ligands used in the synthesis of stable nickel(II), cobalt(II),
and copper(II) complexes. Highly symmetrical macro-
heterocycles were synthesized from 1R-mirtenal and
6
R-carvone. The latter compound was successfully utilized
7
in the synthesis of germacrane and guaiane sesquiterpenes.
S-Citronellal was used as the starting compound in the
synthesis of palmyrolide A, a new neuroactive macrolide
isolated from marine cyanobacteria of the genera Lepto-
lyngbya and Oscillatoria.8 S-Citronellene was utilized
in the synthesis of the macrocyclic antifungal agent
9
(
–)-PF1163B. The synthesis of terpenophenol—chlorin
2
3
conjugates based on isoborneol and its derivates, which
produced ,-diketones 4 and 5 in 57 and 59% yields,
respectively (see Scheme 1). The second approach involves
the reaction of keto acid 3 with 1,5-dibromo-3-oxapentane
and 1,8-dibromo-3,6-dioxaoctane in the presence of
K CO in DMF (the yields of diketones 4 and 5 were 58
possess membranotropic membrane-protective properties,
was described.1
0,11
Natural (+)-dihydrocarvone was used in
the synthesis of the natural macrocyclic diterpene verticillol,
1S,11S,12S)-(+)-verticilla-3E,7E-dien-12-ol, isolated
from flowering shrubs Bursera suntui. Previously,
(
2
3
1
2
13,14
and 56%, respectively). The third approach is based on
the acylation of di- or triethylene glycols with acid chloride
6 in pyridine. This method produced diketones 4 and 5 in
55 and 54% yields, respectively.
The condensation of diketone 4 with adipic and
2,6-pyridinedicarboxylic acid dihydrazides afforded macro-
cycles 7 and 8 in 65 and 45% yields, respectively. The
condensation of diketone 5 with malonic, adipic, 2,6-pyr-
we have synthesized five macroheterocycles bearing two
ester groups and azine or dihydrazide moieties from (+)-
and (–)--pinenes (1) through the key hydroxy ketone,
1
-[3-(2-hydroxyethyl)-2,2-dimethylcyclobutyl]ethanone.
In this work, we report on the synthesis of macro-
heterocycles containing gem-dimethylcyclobutyl groups,
di- or triethylene glycol moieties, ester and ether groups,
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1445—1450, July, 2019.
066-5285/19/6807-1445 © 2019 Springer Science+Business Media, Inc.
1

1446 Russ. Chem. Bull., Int. Ed., Vol. 68, No. 7, July, 2019
Yakovleva et al.
Scheme 1
n = 1 (4, 8), 2 (5, 11)
n = 1, m = 4 (7); n = 2, m = 1 (9), m = 4 (10)
i
Reagents and conditions: i. O , Pr OH, 0 C, then NH C(O)NHNH •HCl; ii. KOH, MeOH, H O; iii. TsOCH (CH OCH ) CH OTs
3
2
2
2
2
2
2 n
2
(
n = 1, 2), K CO , MeCN; iv. BrCH (CH OCH ) CH Br (n = 1, 2), K CO , DMF; v. SOCl ; vi. HOCH (CH OCH ) CH OH
2 3 2 2 2 n 2 2 3 2 2 2 2 n 2
(
n = 1, 2), CH Cl , DMAP; vii. NH NHC(O)(CH ) C(O)NHNH (m = 1, 4), dioxane, H O; viii.
,
2
2
2
2 m
2
2
dioxane, H O; xi.
, dioxane, H O.
2
2
idinedicarboxylic, and (+)-L-tartaric acid dihydrazides
gave macroheterocycles 9—12 in 62, 67, 47, and 43%
yields, respectively.
malonic acid dihydrazide. In the case of the synthesis of
macrocycle 12 bearing the tartaric acid moiety, the nega-
tive inductive effect of two hydroxy groups decreases the
nucleophilicity of hydrazide moieties.
The NMR spectra of macroheterocycles 7—12 show
two sets of the proton and carbon signals for the cyclo-
butane moiety and the signals of protons in the  position
with respect to this moiety. This is attributed to the fact
that isopropyl keto ester 2, which was used as the starting
compound in the synthesis of products 7—12, was prepared
as a mixture of cis and trans isomers in a ratio of 1 : 4. The
A decrease in the yield of macrocycles 8 and 11 con-
taining the 2,6-pyridinedicarboxylic acid moiety compared
to the yield of macrocycles 7 and 10 bearing the adipic
acid moiety can be attributed to lower nucleophilicity of
amino groups in 2,6-pyridinedicarboxylic acid dihydrazide.
For macrocycle 9 containing the malonic acid moiety,
a decrease in the yield is apparently due to steric factors
caused by the close proximity of the functional groups in


-Pinene-derived macrolides
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 7, July, 2019
1447
same ratio of the cis to trans isomers (4 : 1) was observed
for all its derivatives 3—12.
the Ufa Research Center, Russian Academy of Sciences. The IR
spectra were recorded on a Shimadzu IR-Prestige-21 Fourier-
transform infrared spectrometer in a thin layer. The NMR
spectra were measured on a Bruker AM-500 spectrometer
The IR spectra of reaction products 7—12 show no
–
1
absorption bands at 1700 and 1703 cm characteristic of
1
13
operating at 500.13 ( H) and 126.76 MHz ( C)) in CDCl using
3
keto groups of diketo diesters 4 and 5, respectively. The
chloroform signals as the internal standard (proton signals of the
–
1
presence of absorption bands at 3193—3348 cm (NH)
1
nondeuterated solvent (H 7.27) for H NMR; the carbon signal
–
1
and 1733—1739 cm (CONH) in the IR spectra of com-
pounds 7—12 provides evidence for the formation of
hydrazide groups.
13
of CDCl (C 77.00) for C NMR). The carbon atom number-
3
1
13
ing pattern used for the description of H and C NMR spectra
is shown in relation to compounds 3 (see Scheme 1), 4, 8, 9, and
11 (Fig. 1). The TLC monitoring was performed on silica gel
plates Sorbfil (Russia). Atmospheric-pressure chemical ionization
(APCI) mass spectra were obtained on a Shimadzu LC MS 2010
EV LC/mass spectrometer (infusion of a solution in acetonitrile
using a syringe pump at a flow rate of 100 L min–1) in positive
and negative ion modes; the electron energy was 20 eV; aceto-
nitrile—water (95 : 5) as the liquid mobile phase, the nebulizer
The NMR spectra of compounds 7—12 were compared
with those of the starting diketo diesters 4 and 5 and the
13
corresponding dicarboxylic acid hydrazides. The C NMR
spectra of reaction products 7—12 show no carbon signals
for the carbonyl groups ( ~208) of diketo diesters 4 and 5.
1
In the H NMR spectra, the proton signals of the NHNH
2
group ( ~4.8) are absent. This indicates that compounds
–1
flow rate was 0.10 mL min . The optical rotation was measured
1
3
7
—12 are not linear condensation products. The C NMR
on a Perkin Elmer-141-MC polarimeter. The elemental analysis
data for all compounds were in agreement with the calculated
values. The reactions were performed and the reaction products
were isolated using methanol, isopropyl alcohol, petroleum ether
spectra of compounds 7—12 show the carbon signals of
ester groups ( 172.89 (7), 172.65 (8), 172.86 (9), 172.85
(
(
(
10), 172.90 (11), and 173.14 (12)), NH—C=O groups
 175.40 (7), 172.82 (8), 169.94 (9), 175.68 (10), 172.74
11), and 169.50 (12)), and C=N groups ( 151.37 (7),
54.84 (8), 151.12 (9), 150.54 (10), 159.03 (11), and
59.42 (12)), which confirms the formation of the hydr-
(
PE, b.p. 40—70 C), methyl tert-butyl ether (MTBE), dichlo-
romethane, pyridine, DMF, and acetonitrile, which were purified
1
6
and dried by standard procedures. (–)--Pinene (ee 86%, 97%
chemical purity) was purchased from Acros Organics.
1
1
1
3
2
2
(
3 S,3 S)-3 ,3 ,7-Trimethyl-2,5-dioxo-6-oxa-3(1,3)-cyclo-
azide—hydrazone moiety (CH C=N—NH—C=O). The
butanaoctaphane (2). An ozone—oxygen mixture was bubbled
2
1
H NMR spectra of macrocycles 7—12 have down-field
through a solution of (–)--pinene 1 (1.36 g, 10.0 mmol) in
i
signals ( 8.67 (7), 10.18 (8), 8.60 (9), 8.70 (10), 10.30 (11),
and 9.60 (12)), the chemical shifts and integrated intensi-
ties of which correspond to two protons of NHC=O groups
of macrocycles. The upfield chemical shifts for the carbon
atoms of two methyl groups ( 15.67 (7), 16.49 (8), 15.85 (9),
anhydrous Pr OH (30 mL) at 0 C until 10 mmol of ozone were
consumed. Then the stirred mixture was purged with argon at
0
C, and NH C(O)NHNH •HCl (3.90 g, 35.0 mmol) was
2 2
added. The mixture was stirred at room temperature until the
peroxides disappeared (the iodine starch test). The solvent was
removed by evaporation. The residue was dissolved in CHCl3
1
5.84 (10), 16.50 (11), and 16.46 (12)) correspond to the
(
150 mL), successively washed with brine (4×15 mL) and water,
trans configuration of both MeC=N double bonds of
macrocycles 7—12. The chemical shifts of proton signals
for two methyl groups ( 1.82 (7), 1.91 (8), 1.81 (9), 1.80 (10),
dried with Na SO , and concentrated. The residue was chromato-
2
4
graphed (SiO , PE—MTBE, 4 : 1). Keto ester 2 was obtained in
2
2
0
a yield of 2.25 g (93%); []
–31.6 (c 0.6, CH Cl ). The IR
D
2 2
1
and H NMR spectral parameters are identical to those reported
1
.93 (11), and 1.92 (12)) are indicative of their cis orien-
1
5
previously.
tation and, consequently, the trans configuration of the
double bonds in macrocycles 7—12. Singlets of the carbon
atoms at the C=N double bond attest to the absence of cis
and trans isomerism.
All these spectral data and the mass spectra confirm
the formation of macrocycles 7—12.
1
3
2
2
(
3 R,3 R)-1-Hydroxy-3 ,3 -dimethyl-1,4-dioxopentaphane
(
3). Potassium hydroxide (0.77 g, 13.8 mmol) was added to
a vigorously stirred solution of keto ester 2 (2.00 g, 8.8 mmol) in
MeOH (9 mL) at room temperature. The mixture was kept for
6
h (TLC monitoring), and excess methanol was removed under
reduced pressure. The residue was diluted with water (15 mL),
washed with CH Cl (3×2 mL), acidified with hydrochloric acid
To sum up, we synthesized six optically active macro-
heterocycles bearing ester and dihydrazide moieties. The tar-
get macroheterocycles were synthesized through the inter-
2
2
to pH 5, extracted with CH2Cl2 (2×20 mL), washed with brine
(
3×3 mL), dried with MgSO , and concentrated. The yield of
4
1
1
3
2
2
keto acid 3 was 1.54 g (96%). The IR and H NMR spectral
parameters are identical to those reported previously.15
Reactions of keto acid 3 with di- and triethylene glycols (gen-
eral procedures). Method A. A solution of keto acid 3 (1.00 g,
mediate keto acid, (3 R,3 R)-3 ,3 -dimethyl-1,4-dioxo-
-hydroxypentaphane, using the [2+1] reaction of this acid
1
(
or the corresponding acid chloride) with di- or triethylene
glycols and [1+1] condensation of the resulting ,-diketo
5
.4 mmol) and K CO (0.75 g, 5.4 mmol) in anhydrous aceto-
2 3
diesters with dicarboxylic acid dihydrazides as the key steps.
nitrile (20 mL) was refluxed under argon for 1 h. Then a solution
of appropriate di- or triethylene glycol ditosylate (2.7 mmol) in
acetonitrile (20 mL) was added dropwise with stirring. The reac-
tion mixture was refluxed for 80 h and the solvent was removed.
Experimental
The residue was dissolved in CH Cl (20 mL), washed with brine
2
2
The study was performed using equipment of the Center of
Collective Use "Chemistry" of the Ufa Institute of Chemistry of
(3×5 mL), dried with Na SO , and concentrated. The residue
2 4
was chromatographed (SiO , PE—MTBE, 5 : 1).
2

1448 Russ. Chem. Bull., Int. Ed., Vol. 68, No. 7, July, 2019
Yakovleva et al.
Fig. 1. The carbon atom numbering pattern of compounds 4, 8, 9, and 11 for H and 13C NMR spectra interpretation.
1
Method B. Potassium carbonate (0.75 g, 5.4 mmol) was
added to a solution of keto acid 3 (1.00 g, 5.4 mmol) in anhydrous
DMF (20 mL) under argon. The mixture was stirred for 1 h and
a solution of appropriate di- or triethylene glycol dibromide
(20 mL), and successively washed with 5% HCl (3Ѕ3 mL) and a
cold saturated solution of NaHCO (3Ѕ3 mL) and a cold brine
3
(3×3 mL), dried with Na SO , and concentrated. The residue
2
4
was chromatographed (SiO , PE—MTBE, 5 :1 ).
2
2
2
2
2
(
2.7 mmol) in anhydrous DMF (20 mL) was added dropwise.
3 ,3 ,15 ,15 -Tetramethyl-2,5,13,16-tetraoxo-6,9,12-tri-
oxa-3,15(1,3)-dicyclobutanaheptacosaphane (4). Yields 0.69 g
(58%, by method А), 0.65 g (55%, by method B), 0.68 g (57%,
The mixture was stirred for 3 days (TLC monitoring), diluted
with water (20 mL), and extracted with ethyl acetate (3×50 mL).
The organic layer was washed with brine (3×5 mL), dried with
2
0
–1
by method C). []
–2.6 (c 6.7, CH Cl ). IR (KBr), /cm :
D
2 2
1
Na SO , and concentrated. The residue was chromatographed
1734 (—O—C=O); 1700 (—C=O). H NMR (CDCl ), : 0.86
2
4
3
2
2
(
SiO , PE—MTBE, 5 : 1).
(s, 6 H, cis-Me-C(3 ), cis-Me-C(15 )); 1.03 (s, 6 H, trans-Me-
2
2
2
a
4
a
4
Method C. Thionyl chloride (0.98 g, 0.6 mL, 8.2 mmol) was
C(3 ), trans-Me-C(15 )); 1.55 (2.05)* (dd, 2 H, H(3 ), H(15 ),
J = 9.7 Hz, J = 8.5 Hz); 2.05 (s, 6 H, H(1), H(17)); 2.34—2.37
added to keto acid 3 (1.00 g, 5.4 mmol) at room temperature
1
1
under argon. The mixture was kept for 6 h (TLC monitoring),
(m, 2 H, H(3 ), H(15 )); 2.38—2.50 (m, 2 H, H(4), H(14));
b
4
b
4
and excess SOCl was removed under reduced pressure. The yield
1.93—2.51 (m, 2 H, H(3 ), H(15 )); 2.97 (2.90) (dd, 2 H,
2
-
1
3
3
of acid chloride 6 was 1.10 g (100%). IR (KBr), max/cm : 1804
H(3 ), H(15 ), J = 10.1 Hz, J = 7.5 Hz); 3.68 (t, 4 H, H(8),
H(10), J = 4.7 Hz); 4.21 (t, 4 H, H(7), H(11), J = 4.7 Hz).
(
(
COCl). A solution of appropriate di- or triethylene glycol
2.6 mmol) in a mixture of anhydrous pyridine (0.4 mL, 6.3 mmol)
1
3
2
2
C NMR (CDCl ), : 17.28 (cis-Me-C(3 ), cis-Me-C(15 ));
22.91 (22.49) (C(3 ), C(15 )); 24.63 (trans-Me-C(3 ), trans-Me-
3
4
4
2
and diethyl ether (0.2 mL) was added dropwise to freshly prepared
acid chloride 6 (1.10 g, 5.4 mmol) and DMAP (0.018 g,
0
.15 mmol) at 5 C under argon. The mixture was kept at room
* Hereinafter, the chemical shifts in parentheses correspond to
trans isomers.
temperature for 8 h (TLC monitoring), diluted with diethyl ether


-Pinene-derived macrolides
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 7, July, 2019
1449
2
20
C(15 )); 30.15 (30.78) (C(1), C(17)); 34.96 (35.87) (C(4), C(14));
(8). Yield 0.30 g (45%). []
–57.4 (c 1.3, CH Cl ). IR (KBr),
D 2 2
1
1
2
2
–1
3
5
7.87 (37.57) (C(3 ), C(15 )); 43.19 (41.46) (C(3 ), C(15 ));
/cm : 3348 (NH); 1733 (—C(O)—NH); 1695 (—O—C=O);
3
3
1
4.09 (53.36) (C(3 ), C(15 )); 63.24 (C(7), C(11)); 68.96 (C(8),
1629 (CN); 1591 (Ar). H NMR (CDCl ), : 0.81 (s, 6 H,
3
2
2
2
C(10)); 172.93 (C(5), C(13)); 208.55 (207.45) (C(2), C(16)).
cis-Me-C(6 ), cis- Me-C(18 )); 1.25 (s, 6 H, trans-Me-C(6 ),
MS, m/z (Irel (%)): 439 [M + H]+ (100.00), 456 [M + H O]
+
trans-Me-C(18 )); 1.85—2.07 (m, 4 H, H(6 ), H(18 )); 1.91
2
4
4
2
1
1
(
80.00).
(s, 6 H, Me-C(5), Me-C(19)); 2.13—2.41 (m, 2 H, H(6 ), H(18 ));
2
2
2
2
3
,3 ,18 ,18 -Tetramethyl-2,5,16,19-tetraoxo-6,9,12,15-
2.37 (d, 4 H, H(7), H(17), J = 11.6 Hz); 2.70 (2.64) (dd, 2 H,
3
3
tetraoxa-3,18(1,3)-dicyclobutanaicosaphane (5). Yields 0.73 g
H(6 ), H(18 ), J = 10.0 Hz, J = 7.0 Hz); 3.61 (t, 4 H, H(11),
H(13), J = 4.6 Hz); 4.18 (t, 4 H, H(10), H(14), J = 4.7 Hz); 7.90
(
56%, by method А), 0.70 g (54%, by method B), 0.76 g (59%,
2
0
–1
4
3
5
by method C). []
–10.0 (c 1.10, CH Cl ). IR (KBr), /cm
:
(d, 1 H, H(1 ), J = 7.7 Hz); 8.20 (d, 2 H, H(1 ), H(1 ), J = 7.7 Hz);
D
2
2
1
13
1
(
738 (—O—C=O); 1703 (—C=O). H NMR (CDCl ), : 0.97
10.18 (br.s, 2 H, H(3), H(21). C NMR (CDCl ), : 16.49
3
3
2
2
2
2
s, 6 H, cis-Me-C(3 ), cis-Me-C(18 )); 1.13 (s, 6 H, trans-Me-
(Me-C(5), Me-C(19)); 17.28 (17.35) (cis-Me-C(6 ), cis-Me-(18 ));
2
2
а
4
а
4
4
4
2
C(3 ), trans-Me-C(18 )); 1.83—1.97 (m, 2 H, H(3 ), H(18 ));
22.87 (22.47) (C(6 ), C(18 )); 30.14 (30.32) (trans-Me-C(6 ),
1
1
2
1
.99 (s, 6 H, H(1), H(20)); 2.18—2.40 (m, 4 H, H(3 ), H(18 ),
trans-Me-C(18 )); 34.94 (35.88) (C(7), C(17)); 37.93 (37.55)
b
4
b
4
1
1
2
2
H(3 ), H(18 )); 2.41—2.50 (m, 2 H, H(4), H(17)); 2.83 (2.80)
(C(6 ), C(18 )); 43.21 (41.48) (C(6 ), C(18 )); 54.12 (53.38)
3
3
3
3
(
dd, 2 H, H(3 ), H(18 ), J = 10.0 Hz, J = 7.3 Hz); 3.58 (t, 4 H,
(C(6 ), C(18 )); 63.29 (C(10), C(14)); 68.98 (C(11), C(13));
3
5
2
6
4
H(10), H(11), J = 4.9 Hz); 3.61 (t, 4 H, H(8), H(13), J = 4.95 Hz);
125.80 (C(1 ), C(1 )); 139.26 (C(1 ), C(1 )); 148.84 (C(1 ));
154.84 (C(5), C(19)); 172.65 (C(8), C(16)); 172.82 (C(2), C(22)).
1
3
4
1
2
.12 (t, 4 H, H(7), H(14), J = 4.65 Hz). C NMR (CDCl ), :
3
2
2
4
4
+
+
7.28 (cis-Me-(3 ), cis-Me-(18 )); 22.91 (22.49) (C(3 ), C(18 ));
MS, m/z (Irel (%)): 598 [M + H] (100.00), 616 [M + H + H O]
(100.00); 638 [M + MeCN – H] (30.00).
2
2
2
–
4.63 (trans-Me-(3 ), trans-Me-(18 )); 30.15 (30.78) (C(1),
1
1
1
3
1
3
2
2
2
2
C(20)); 34.96 (C(4), C(17)), 37.87 (37.57) (C(3 ), C(18 )); 43.19
(1 R,1 R,11 R,11 R)-1 ,1 ,2,10,11 ,11 -Hexamethyl-
5,7,13,24-tetraoxo-14,17,20,23-tetraoxa-3,4,9,10-tetraaza-
1,11(1,3)-dicyclobutanacyclopentacosaphane-2,9-diene (9). Yield
2
2
3
3
(
(
41.46) (C(3 ), C(18 )); 54.09 (53.36) (C(3 ), C(18 )); 63.24
C(7), C(14)); 68.96 (C(8), C(10), C(11), C(13)); 172.93 (C(2),
2
0
–1
C(19)); 208.55 (207.45) (C (5), C(16)). MS, m/z (I (%)): 483
0.40 g (62%). []
–6.2 (c 1.1, CH Cl ). IR (KBr), /cm :
rel
D 2 2
+
+
[
M + H] (47); 500 [M + H O] (100.00).
3193 (NH); 1738 (—C(O)—NH); 1733 (—O—C=O); 1652 (CN).
2
1
2
Synthesis of macrocycles 7—12 (general procedure). A solu-
H NMR (CDCl ), : 0.85 (s, 6 H, cis-Me-C(1 ), cis-Me-
3
2
2
2
tion of malonic, adipic, 2,6-pyridinedicarboxylic, or (+)-L-
tartaric acid dihydrazide16 (1.13 mmol) in water (1 mL) was
slowly added to a vigorously stirred solution of diketo diesters 4
or 5 (1.13 mmol) in anhydrous dioxane (9.7 mL). The mixture
was stirred for 48 h (TLC monitoring), dioxane was removed
C(11 )); 1.20 (s, 6 H, trans-Me-C(1 ), trans-Me-C(11 )); 1.77
а
4
а
4
(dd, 2 H, H(1 ), H(11 ), J = 10.0 Hz, J = 8.6 Hz); 1.81 (s, 6 H,
b
4
b
4
Me-C(2), Me-C(10)); 1.90—1.99 (m, 2 H, H(1 ), H(11 ));
2.08 (t, 4 H, H(12), H(25), J = 6.4 Hz); 2.10 (s, 2 H, H(6));
1
1
3
2.23—2.28 (m, 2 H, H(1 ), H(11 )); 2.87 (2.80) (dt, 2 H, H(1 ),
3
under reduced pressure, CH Cl (50 mL) was added to the resi-
H(11 ), J = 9.9 Hz, J = 7.1 Hz); 3.58 (t, 4 H, H(18), H(19),
2
2
due, the mixture was washed with H O (3×5 mL) and dried with
J = 4.0 Hz); 3.67 (t, 4 H, H(16), H(21), J = 4.1 Hz); 4.20 (t, 4 H,
2
Na SO , the solution was concentrated, and the residue was
H(15), H(22), J = 4.1 Hz); 8.60 (br.s, 2 H, H(4), H(8)). 13C NMR
2
4
2
washed with hexane (10 mL) and concentrated.
(CDCl ), : 15.85 (Me-C(2), Me-C(10)); 17.33 (cis-Me-C(1 ),
3
1
3
1
3
2
2
2
2
2
4
4
(
3 R,3 R,14 R,14 R)-1 ,1 ,2,13,14 ,14 -Hexamethyl-
,10,16,24-tetraoxo-17,20,23-trioxa-3,4,11,12-tetraaza-1,14-
1,3)-dicyclobutanacyclopentacosaphane-2,12-diene (7). Yield
cis-Me-C(11 )); 24.49 (24.69) (C(1 ), C(11 )); 30.21 (trans-Me-
2
2
5
C(1 ), trans-Me-C(11 )); 35.00 (35.07) (C(12), C(25)); 37.91
1
1
2
2
(
(37.62) (C(1 ), C(11 )); 43.25 (42.78) (C(1 ), C(11 )); 50.27
2
0
–1
3
3
0
.42 g (65%). []
–19.0 (c 0.1, CH Cl ). IR (KBr), /cm
:
(C(6)); 54.19 (53.45) (C(1 ), C(11 )); 63.59 (C(15), C(22));
69.17 (C(16), C(21)); 70.65 (C(18), C(19)); 151.12 (C(2), C(10));
D
2
2
3
193 (NH); 1738 (—C(O)—NH); 1733 (—O—C=O); 1653 (CN).
1
2
H NMR (CDCl ), : 0.86 (s, 6 H, cis-Me-C(1 ), cis-Me-
169.94 (C(5), C(7)); 172.86 (C(13), C(24)). MS, m/z (I (%)):
579 [M + H] (100.00); 577 [M – H] (100.00), 613 [M + Cl]
(100.00).
(1 R,1 R,14 R,14 R)-1 ,1 ,2,13,14 ,14 -Hexamethyl-
5,10,16,27-tetraoxo-17,20,23,26-tetraoxa-3,4,12,13-tetraaza-
1,14(1,3)-dicyclobutanacyclooctacosaphane-2,12-diene (10).
3
rel
2
2
2
+
–
–
C(14 )); 1.22 (s, 6 H, trans-Me-C(1 ), trans-Me-C(14 ));
а
4
1
.45—1.51 (m, 4 H, H(7), H(8)); 1.73 (2.05) (dd, 2 H, H(1 ),
а
4
1
3
1
3
2
2
2
2
H(14 ), J = 10.0 Hz, J = 8.5 Hz); 1.82 (s, 6 H, Me-C(2),
b
4
b
4
Me-C(13)); 1.89—1.94 (m, 2 H, H(1 ), H(14 )); 2.07 (t, 4 H,
H(15), H(25), J = 6.1 Hz); 2.20 (t, 4 H, H(6), H(9), J = 6.9 Hz);
1
1
3
20
2
.21—2.33 (m, 2 H, H(1 ), H(14 )); 2.89 (2.91) (dt, 2 H, H(1 ),
Yield 0.47 g (67%). []
–61.8 (c 0.5, CH Cl ). IR (KBr),
D 2 2
3
–1
H(14 ), J = 9.8 Hz, J = 7.1 Hz); 3.68 (t, 4 H, H(19), H(21),
J = 4.3 Hz); 4.22 (t, 4 H, H(18), H(22), J = 4.2 Hz), 8.67 (br.s,
/cm : 3213 (NH); 1734 (—C(O)—NH); 1733 (—O—C=O);
1
2
1669 (CN). H NMR (CDCl ), : 0.89 (s, 6 H, cis-Me-C(1 ),
3
1
3
2
2
2
2
H, H(4), H(11)). C NMR (CDCl ), : 15.67 (Me-C(2),
cis-Me-C(14 )); 1.22 (s, 6 H, trans-Me-C(1 ), trans-Me-C(14 ));
3
2
2
а
4
а
4
Me-C(13)); 17.24 (cis-Me-C(1 ), cis-Me-C(14 )); 24.05 (C(7),
1.48—1.50 (m, 4 H, H(7), H(8)); 1.75 (dd, 2 H, H(1 ), H(14 ),
4
4
2
C(8)); 24.46 (24.67) (C(1 ), C(14 )); 30.20 (trans-Me-C(1 ),
J = 10.1 Hz, J = 8.5 Hz); 1.80 (s, 6 H, Me-C(2), Me-C(13));
2
b
4
b
4
trans-Me-C(14 )); 32.61 (C(15), C(25)); 35.05 (C(6), C(9));
1.91—1.97 (m, 2 H, H(1 ), H(14 )); 2.07 (t, 4 H, H(15), H(28),
1
1
2
2
3
5
7.77 (37.58) (C(1 ), C(14 )); 42.79 (42.51) (C(1 ), C(14 ));
J = 6.2 Hz); 2.23 (t, 4 H, H(6), H(9), J = 7.0 Hz); 2.88 (dd, 2 H,
3
3
3
3
3.29 (53.09) (C(1 ), C(14 )); 63.23 (C(18), C(22)); 69.01
H(1 ), H(14 ), J = 9.8 Hz, J = 7.2 Hz); 2.97—3.12 (m, 2 H,
1
1
(
C(19), C(21)); 151.37 (C(2), C(13)); 172.89 (C(16), C(24));
H(1 ), H(14 )); 3.56 (t, 4 H, H(21), H(22), J = 4.1 Hz); 3.68
+
1
5
75.40 (C(5), C(10)). MS, m/z (I (%)): 577 [M + H] (100.00);
(t, 4 H, H(19), H(24), J = 4.1 Hz); 4.22 (t, 4 H, H(18), H(25),
rel
–
–
13
75 [M – H] (100.00); 611 [M + 2 H O – H] (46).
J = 4.1 Hz); 8.70 (br.s, 2 H, H(4), H(11)). C NMR (CDCl ),
2
3
1
3
1
3
2
2
2
2
2
(
6 R,6 R,18 R,18 R)-5,6 ,6 ,18 ,18 ,19-Hexamethyl-
: 15.84 (Me-C(2), Me-C(13)); 17.30 (cis-Me-C(1 ), cis-Me-
1
2
4
4
2
,8,16,22-trioxo-9,12,15-trioxa-1 ,3,4,20,21-pentaaza-1(2,6)-
pyridina-6,18(1,3)-dicyclobutanacyclodocosaphane-4,19-diene
C(14 )); 24.43 (24.65) (C(1 ), C(14 )); 24.60 (C(7), C(8)); 30.07
2
2
(trans-Me-C(1 ), trans-Me-C(14 )); 32.54 (C(6), C(9)); 35.06

1450
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 7, July, 2019
Yakovleva et al.
1
1
(
(
C(15), C(28)); 37.64 (37.58) (C(1 ), C(14 )); 42.87 (42.54)
istry", theme No. 8 "Chemo-, regio, and stereoselective
transformations of terpenoids, steroids, and lipids in the
targeted synthesis of low-molecular-weight bioregulators";
registration number AAAA-A17-117011910023-2).
2
2
3
3
C(1 ), C(14 )); 53.45 (53.19) (C(1 ), C(14 )); 63.10 (C(18),
C(25)); 69.10 (C(19), C(24)); 70.88 (C(21), C(22); 150.54 (C(2),
C(13)); 172.85 (C(16), C(27)); 175.68 (C(5), C(10)). MS, m/z
Irel (%)): 621 [M + H] (100.00); 620 [M – H]– (100.00), 655
+
(
[
–
M + Cl] (100.00).
1
3
1
3
2
2
2
2
(
6 R,6 R,21 R,21 R)-5,6 ,6 ,21 ,21 ,22-Hexamethyl-
,8,19,25-trioxo-9,12,15,18-tetraoxa-1 ,3,4,23,24-pentaaza-
(2,6)-pyridina-6,21(1,3)-dicyclobutanacyclopentacosaphane-
References
1
2
1
4
1
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in Russian).
2
0
,22-diene (11). Yield 0.34 g (47%). []
–44.5 (c 1.0, CH Cl ).
D
2 2
–
1
IR (KBr), /cm : 3245 (NH); 1739 (—C(O)—NH); 1730
(
1
(
(
—O—C=O); 1653 (CN); 1593 (Ar). H NMR (CDCl ), : 0.86
3
2. G. Yu. Ishmuratov, M. P. Yakovleva, V. A. Vydrina, O. O.
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2
2
s, 6 H, cis-Me-C(6 ), cis-Me-C(21 )); 1.23 (s, 6 H, trans-Me-
2
2
C(6 ), trans-Me-C(21 )); 1.93 (s, 6 H, Me-C(5), Me-C(22));
а
4
а
4
1
1
.95—2.10 (m, 2 H, H(6 ), H(21 )); 2.10—2.39 (m, 2 H, H(6 ),
3
. G. Yu. Ishmuratov, M. P. Yakovleva, V. A. Vydrina, M. A.
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Chem., 2007, 52, 42.
1
H(21 )); 2.41 (2.37) (d, 4 H, H(7), H(20), J = 10.9 Hz); 2.75
3
3
b
4
b
4
(
2.70) (dd, 4 H, H(6 ), H(21 ), H(6 ), H(21 ), J = 10.1 Hz,
J = 7.0 Hz); 3.59 (t, 4 H, H(13), H(14), J = 4.9 Hz); 3.67 (t, 4 H,
H(11), H(16), J = 4.9 Hz); 4.18 (t, 4 H, H(10), H(17), J = 4.9 Hz);
4
3
5
4
8
.30 (d, 2 H, H(1 ), H(1 ), J = 7.7 Hz); 8.34 (d, 1 H, H(1 ),
1
3
J = 7.7 Hz); 10.30 (br.s, 2 H, H(3), H(24)). C NMR (CDCl ),
3
5. S. V. Larionov, A. V. Tkachev, L. I. Myachina, S. N. Bizyaev,
2

: 16.50 (Me-C(5), Me-C(22)); 17.41 (17.33) (cis-Me-C(6 ),
L. A. Glinskaya, R. F. Klevtsova, Dokl. Chem., 2006, 411, 206.
2
4
4
cis-Me-C(21 )); 22.98 (22.54) (C(6 ), C(21 )); 30.37 (trans-Me-
6
. M. C. de la Torre, M. Asenjo, P. Ramirez-Lopez, M. A.
2
2
C(6 ), trans-Me-C(21 )); 35.02 (35.96) (C(7), C(20)); 38.01
Sierra, Eur. J. Org. Chem., 2015, 1054.
1
1
2
2
(
(
37.92) (C(6 ), C(21 )); 43.27 (41.51) (C(6 ), C(21 )); 53.51
7
. E. E. Anagnostaki, Z. L. Zografos, Org. Lett., 2013, 15, 152.
3
3
54.20) (C(6 ), C(21 )); 63.44 (C(10), C(17)); 69.19 (C(11),
8
. S. C. Philkhana, B. Seetharamsingh, Y. B. Dangat, K. Vanka,
D. S. Reddy, Chem. Commun., 2013, 49, 3342.
. F. Bouazza, B. Renoux, C. Bachmann, J.-P. Gesson, Org.
Lett., 2003, 5, 4049.
3
5
C(16)); 70.55 (C(13), C(14)); 125.89 (C(1 ), C(1 )); 148.73
4
2
6
(
(
[
(
C(1 )); 158.79 (C(1 ), C(1 )); 159.03 (C(5), C(22)); 172.74
9
C(2), C(25)); 172.90 (C(8), C(19)). MS, m/z (I (%)): 642
rel
+
+
–
M + H] (100.00), 660 [M + H + H O] (100.00); 640 [M – H]
2
10. D. V. Belykh, E. V. Buravlev, I. Yu. Chukicheva, I. S.
Tarabukina, O. G. Shevchenko, S. N. Plyusnina, A. V. Kut-
chin, Russ. J. Bioorg. Chem., 2012, 38, 558.
–
100.00), 676 [M + Cl – H] .
1
3
1
3
2
2
2
2
(
1 R,1 R,6R,7R,12 R,12 R)-6,7-Dihydroxy-1 ,1 ,2,11,12 ,12 -
hexamethyl-5,8,14,25-tetraoxo-15,18,21,24-tetraoxa-2,3,9,10-
tetraaza-1,12(1,3)-dicyclobutanacyclohexacosaphane-2,10-diene
1
1. E. V. Buravlev, I. Yu. Chukicheva, D. V. Belykh, A. V. Kutchin,
Chem. Nat. Compd., 2007, 43, 678.
2
0
(

1
12). Yield 0.30 g (43%). []
–70.4 (c 0.5, CH Cl ). IR (KBr),
D 2 2
12. K. Nakashima, Y. Kondo, K. Yoshimasu, M. Sono, M. Tori,
Nat. Prod. Commun., 2015, 10, 551.
13. G. Y. Ishmuratov, G. R. Mingaleeva, M. P. Yakovleva, O. O.
Shakhanova, R. R. Muslukhov, A. G. Tolstikov, Russ. J. Org.
Chem., 2011, 47, 1416.
–
1
/cm : 3193 (NH); 1739 (—C(O)—NH); 1733 (—O—C=O);
1
2
653 (CN). H NMR (CDCl ), : 0.83 (s, 6 H, cis-Me-C(1 ),
3
2
2
2
cis-Me-C(12 )); 1.20 (s, 6 H, trans-Me-C(1 ), trans-Me-(12 ));
1
1
а
3
а
3
1
2
.70—2.09 (m, 4 H, H(1 ), H(12 ), H(1 ), H(12 )); 1.75 (dd,
b
3
b
3
H, H(1 ), H(12 ), J = 10.1 Hz, J = 8.8 Hz); 1.92 (s, 6 H,
1
4. G. Yu. Ishmuratov, V. A. Vydrina, K. S. Denisova, M. P.
Me-C(2), Me-C(11)); 2.38 (d, 4 H, H(13), H(26), J = 6.8 Hz);
Yakovleva, R. R. Gazetdinov, E. M. Vyrypaev, A. G. Tolstikov,
3
3
2
(
.78 (dd, 2 H, H(1 ), H(12 ), J = 9.8 Hz, J = 7.0 Hz); 3.58
Chem. Nat. Compd., 2017, 53, 63.
t, 4 H, H(19), H(20), J = 4.8 Hz); 3.69 (t, 4 H, H(17), H(22),
1
5. G. Y. Ishmuratov, Yu. V. Legostaeva, L. R. Garifullina, L. P.
Botsman, Z. I. Idrisova, R. R. Muslukhov, N. M. Ishmuratova,
G. A. Tolstikov, Russ. J. Org. Chem., 2013, 49, 1409.
16. Weygand-Hilgetag, Organisch-Chemische Experimentierkunst,
J. A. Barth Verlag, Leipzig, 1964.
J = 4.8 Hz)); 4.19 (t, 4 H, H(16), H(23), J = 4.8 Hz); 5.30 (s, 4 H,
H(6), H(7), C(6)OH, C(7)OH); 9.60 (br.s, 2 H, H(4), H(9)).
1
3
C NMR (CDCl ), : 16.46 (Me-C(2), Me-C(11)); 17.46
3
2
2
4
4
(
cis-Me-C(1 ), cis-Me-C(12 )); 22.96 (22.52) (C(1 ), C(12 ));
2
2
3
3
5
0.17 (trans-Me-C(1 ), trans-Me-C(12 )); 35.14 (C(13), C(26));
1
1
2
2
7.90 (38.11) (C(1 ), C(12 )); 43.23 (42.68) (C(1 ), C(12 ));
3
3
0.32 (50.54) (C(1 ), C(12 )); 63.37 (C(16), C(23)); 69.15
(
(
C(17), C(22)); 70.48 (C(6), C(7)); 70.87 (C(19), C(20)); 159.42
C(2), C(11)); 169.50 (C(5), C(8)); 173.14 (C(14), C(25)). MS,
m/z (Irel (%)): 625 [M + H]+ (100.00); 623 [M – H]– (100.00).
Received January 14, 2019;
in revised form March 14, 2019;
accepted April 13, 2019
This study was financially supported by the Russian
Academy of Sciences (Program "Basic research in chem-