Open-chain and macrocyclic polyethyleneglycol esters of the diterpenoid isosteviol

Article abstract of DOI:10.1007/s10600-014-0987-8

Open-chain and macrocyclic derivatives of the diterpenoid isosteviol (16-oxo-ent-beyeran-19-oic acid) in which two isosteviol molecules were connected by polyethyleneglycol spacers were synthesized for the first time.

Full text of DOI:10.1007/s10600-014-0987-8

Chemistry of Natural Compounds, Vol. 50, No. 3, July, 2014 [Russian original No. 3, May–June, 2014]
OPEN-CHAIN AND MACROCYCLIC POLYETHYLENEGLYCOL
ESTERS OF THE DITERPENOID ISOSTEVIOL
I. Yu. Strobykina, M. G. Belenok, B. F. Garifullin,
*
V. M. Babaev, and V. E. Kataev
Open-chain and macrocyclic derivatives of the diterpenoid isosteviol (16-oxo-ent-beyeran-19-oic acid) in
which two isosteviol molecules were connected by polyethyleneglycol spacers were synthesized for the first
time.
Keywords: isosteviol, diterpenes, diterpenoids, beyerane, macrocycles, macrocyclic derivatives, polyethyleneglycol.
The number of publications on chemical transformations of the ent-beyerane diterpenoid isosteviol (1, 16-oxo-ent-
beyeran-19-oic acid), which is obtained by acid hydrolysis of Stevia rebaudiana glycosides, has risen dramatically during the
last five years [1]. Greater than 150 isosteviol derivatives have been reported [2]. We previously synthesized open-chain
dinuclear isosteviol derivatives in which two ent-beyerane moieties were connected by polymethylene spacers with terminal
esters via the reactions of isosteviol chloride with diols and of 16-dihydroisosteviol (8) with dibasic carboxylic acid chlorides
[3, 4]. Recently, two of these dinuclear derivatives, i.e., diacids 11 and 12, were transformed into dinuclear macrocycles in
which two isosteviol ent-beyerane moieties were connected by diester spacers of different polymethylene chain lengths via
reactions with diol ditosylates [5].
OTs
O
O
O
1
20
10
17
O
O
n
2 - 4
11
TsO
O
O
3
ii
13
9
5
O
16
H
i
n
19
7
O
HO
HO
O
OH
18
15
O
8
1
O
O
Cl
iii
Cl
m
9, 10
O
O
5 - 7
O
O
HO
O
O
O
O
O
2
i
O
O
O
O
O
m
m
O
O
OH
O
O
11, 12
13, 14
2, 5: n = 1; 3, 6: n = 2; 4, 7: n = 3
9, 11, 13: m = 1; 10, 12, 14: m = 3
i. CH CN, K CO ; ii. NaBH , CH OH; iii. CH Cl , DMAP, Py
3
2
3
4
3
2
2
Scheme 1
A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences,
420088, Kazan, Ul. Arbuzova, 8, e-mail: kataev@iopc.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 3, May–June,
2014, pp. 400–402. Original article submitted January 28, 2014.
©
462
0009-3130/14/5003-0462 2014 Springer Science+Business Media New York

Herein we report the synthesis of analogs of the aforementioned isosteviol derivatives in which the polymethylene
spacers were replaced by polyethyleneglycol (PEG) spacers. Open-chain dinuclear derivatives 5–7 were obtained by reacting
1 with polyethyleneglycol ditosylates 2–4 in refluxing MeCN in the presence of K CO under an inert atmosphere (Scheme 1).
2
3
Macrocyclic dinuclear derivatives 13 and 14 were synthesized by reacting triethyleneglycol ditosylate (2) with diacids 11 and
12, which were prepared by reacting 16-dihydroisosteviol (8) with suberic (9) and sebacic (10) acid chlorides using the
literature methods [4, 6]. Compound 8 was prepared by selective reduction of the oxo-group of 1 by NaBH in MeOH as
4
before [7].
The literature describes only a few derivatives of natural products that were functionalized by PEG chains. These
were derivatives of estradiol [8], cholesterol [9], betulinic acid [10], and the diterpenoid phorbol [11]. They all exhibited one
type of biological activity or another. The properties of isosteviol PEG esters 5–7, 13, and 14 will be reported separately.
EXPERIMENTAL
PMR spectra were recorded on a Bruker Avance-400 instrument. MALDI mass spectra were obtained on an UltraFlex
III TOF/TOF time-of-flight mass spectrometer (Bruker Daltonik GmbH, Germany). Data were processed using the flexAnalysis
3.0 programs (Bruker Daltonik GmbH, Germany). The matrix was p-nitroaniline. Melting points were determined on a
Boetius melting-point apparatus. The course of reactions was monitored by TLC on Silufol UV254 plates (Kavalier,
Czechoslovakia). Compounds were detected using I vapor. Flash chromatography was performed over a dry column of
2
KSKG silica gel (fraction <0.063 mm, Khromlab Ltd.).
Isosteviol (1) was obtained from the sweetener Sweta (Stevian Biotechnology Corp., Malaysia) by the literature
method [12] (mp 233°C, lit. [1] mp 231–233°C). We used commercial triethyleneglycol (grade A, Vekton) and
tetraethyleneglycol (99%, abcr GmbH & Co.). PEG ditosylates 2–4 were prepared by the literature method [13]
{triethyleneglycol ditosylate (2), mp 80°C, lit. [13] mp 80–81°C; tetraethyleneglycol ditosylate (3), oil, m/z 502 (theor. m/z
502.13); pentaethyleneglycol ditosylate (4), oil, m/z 546 (theor. m/z 546.16)}. Diacid 11 was synthesized analogously as
before [4], mp 111°C (lit. [4] mp 108–112°C); diacid 12, also as before [6], mp 109°C (lit. [4] mp 105–110°C).
General Method for Preparing 5–7. Isosteviol (1, 1 mmol) and PEG ditosylate (0.5 mmol) were dissolved with
heating in MeCN (30 mL) under a stream of Ar, treated with K CO (0.5 mmol), and refluxed for 15 h. The precipitate was
2
3
filtered off. The solvent was evaporated at reduced pressure. The residue was chromatographed over silica gel (petroleum
ether–EtOAc eluent, 5:1–1:1).
20
3,6-Dioxaoctane-1,8-diyl-bis(16-oxo-ent-beyeran-19-oate) (5). Yield 77%, mp 127–129ꢀÑ, [ꢁ] –76ꢀ (c 0.19;
D
1
MeOH + CH Cl ). Í NMR spectrum (400 MHz, CDCl , ꢂ, ppm, J/Hz): 0.71 (6Í, s, H -20, 20ꢃ), 0.97 (6Í, s, H -17, 17ꢃ),
2
2
3
3
3
1.19 (6Í, s, H -18, 18ꢃ), 0.87–1.93 (36Í, m, ent-beyerane skeleton), 2.19 (2Í, d, J = 13.3, Í -3, 3ꢃ), 2.62 (2Í, dd, J = 18.6,
3
eq
3.7, Í -15, 15ꢃ), 3.59–3.62 (4Í, br.s, spacer -OCH CH O-), 3.65–3.70 (4Í, m, 19-(Î)ÎÑÍ ÑÍ , 19ꢃ-(Î)ÎÑÍ ÑÍ ), 4.14–
ꢁ
2
2
2
2
2
2
+
4.22 (4Í, m, 19-(Î)ÎÑÍ , 19ꢃ-(Î)ÎÑÍ ). Mass spectrum (MALDI-TOF): m/z (exp) 773.66 [M + Na] , m/z (theor) 773.50
[M + Na] ; m/z (exp) 789.62 [M + K] , m/z (theor) 789.47 [M + K] . C H O .
2
2
+
+
+
46 70
8
20
D
3,6,9-Trioxaundecane-1,11-diyl-bis(16-oxo-ent-beyeran-19-oate) (6). Yield 68%, mp 85–88ꢀÑ, [ꢁ]
–78.3ꢀ
1
(ñ 0.69; CH Cl ). Í NMR spectrum (400 MHz, CDCl , ꢂ, ppm, J/Hz): 0.71 (6Í, s, H -20, 20ꢃ), 0.97 (6Í, s, H -17, 17ꢃ), 1.20
2
2
3
3
3
(6Í, s, H -18, 18ꢃ), 0.85–1.92 (36Í, m, ent-beyerane skeleton), 2.19 (2Í, d, J = 13.5, Í -3, 3ꢃ), 2.62 (2Í, dd, J = 18.6, 3.7,
3
eq
Í -15, 15ꢃ), 3.59–3.65 (8Í, m, spacers 2(-OCH CH O-)), 3.66–3.70 (4Í, m, 19-(Î)ÎÑÍ ÑÍ , 19ꢃ-(Î)ÎÑÍ ÑÍ ), 4.14–4.22
ꢁ
2
2
2
2
2
2
+
(4Í, m, 19-(Î)ÎÑÍ , 9ꢃ-(Î)ÎÑÍ ). Mass spectrum (MALDI-TOF): m/z (exp) 817.52 [M + Na] , m/z (theor) 817.52
[M + Na] . C H O .
2
2
+
48 74
9
20
D
3,6,9,12-Tetraoxatetradecane-1,14-diyl-bis(16-oxo-ent-beyeran-19-oate) (7). Yield 72%, oil, [ꢁ]
–75.5ꢀ
1
(ñ 0.64; CH Cl ). Í NMR spectrum (400 MHz, CDCl , ꢂ, ppm, J/Hz): 0.70 (6Í, s, H -20, 20ꢃ), 0.95 (6Í, s, H -17, 17ꢃ), 1.18
2
2
3
3
3
(6Í, s, H -18, 18ꢃ), 0.86–1.90 (36Í, m, ent-beyerane skeleton), 2.17 (2Í, d, J = 13.3, Í -3, 3ꢃ), 2.60 (2Í, dd, J = 18.6, 3.7,
3
eq
Í -15, 15ꢃ), 3.60–3.62 (8Í, m, spacers 2(-OCH CH O-)), 3.62–3.64 (4Í, m, spacer -OCH CH O-), 3.64–3.68 (4Í, m,
ꢁ
2
2
2
2
19-(Î)ÎÑÍ ÑÍ , 9ꢃ-(Î)ÎÑÍ ÑÍ ), 4.14–4.21 (4Í, m, 19-(Î)ÎÑÍ , 19ꢃ-(Î)ÎÑÍ ). Mass spectrum (MALDI-TOF): m/z (exp)
2
2
2
2
2
2
+
+
861.50 [M + Na] , m/z (theor) 861.55 [M + Na] . C H O .
50 78 10
Method for Preparing 13 and 14. Diacid 11 or 12 (0.26 mmol) and 2 (0.26 mmol) were dissolved with heating in
MeCN (50 mL) under a stream of Ar, treated with K CO (0.52 mmol), and refluxed for 25 h. The precipitate was filtered off.
2
3
463

The solvent was evaporated at reduced pressure. The residue was chromatographed over silica gel (petroleum ether–EtOAc
eluent, 15:1–1:1).
2,11,14,17,20,23-Hexaoxa-1,12(16,4ꢁ)di(19-nor-ent-beyerane)tetracosaphane-3,10,13,24-tetraone (13). Yield
20
1
72%, mp 144–145ꢀÑ, [ꢁ] –102.5ꢀ (ñ 0.60; CH Cl ). Í NMR spectrum (400 MHz, CDCl , ꢂ, ppm, J/Hz): 0.72 (6Í, s,
D
2
2
3
H -20, 20ꢃ), 0.90 (6Í, s, H -17, 17ꢃ), 1.16 (6Í, s, H -18, 18ꢃ), 1.17–1.92 (46Í, m, ent-beyerane skeleton, spacer (ÑÍ ) ), 2.16
3
3
3
2 4
(2Í, d, J = 13.1, Í -3, 3ꢃ), 2.28 (4Í, t, J = 7.1, 16-ÎÑ(Î)ÑÍ , 16ꢃ-ÎÑ(Î)ÑÍ ), 3.49–3.62 (4Í, m, spacer -ÎÑÍ ÑÍ Î-),
eq
2
2
2
2
3.63–3.76 (4Í, m, 19-(Î)ÎÑÍ ÑÍ , 19ꢃ-(Î)ÎÑÍ ÑÍ ), 4.02–4.08 (2Í, m, 19-(Î)ÎÑÍ , 9ꢃ-(Î)ÎÑÍ ), 4.34–4.40 (2Í, m,
2
2
2
2
A
A
19-(Î)ÎÑÍ , 19ꢃ-(Î)ÎÑÍ ), 4.66 (2Í, dd, J = 10.6, 4.1, Í-16, 16ꢃ). Mass spectrum (MALDI-TOF): m/z (exp) 915.56
B
B
+
+
[M + Na] , m/z (theor) 915.60 [M + Na] . C H O .
54 84 10
2,13,16,19,22,25-Hexaoxa-1,14(16,4ꢁ)di(19-nor-ent-beyerane)hexacosaphane-3,12,15,26-tetraone (14). Yield
20
1
11%, mp 181–183ꢀÑ, [ꢁ] –38.8ꢀ (ñ 1.17; CH Cl ). Í NMR spectrum (400 MHz, CDCl , ꢂ, ppm, J/Hz): 0.72–1.92 (50H, m,
D
2
2
3
ent-beyerane skeleton, spacer (CH ) ), 0.72 (6Í, s, H -20, 20ꢃ), 0.91 (6Í, s, H -17, 17ꢃ), 1.17 (6Í, s, H -18, 18ꢃ), 2.17 (2Í, d,
2 6
3
3
3
J = 13.7, Í -3, 3ꢃ), 2.26–2.32 (4Í, m, 16-OÑ(O)ÑÍ , 16ꢃ-OÑ(O)ÑÍ ), 3.53–3.62 (4Í, m, spacer -ÎCH CH O-), 3.65–3.76 (4H,
eq
2
2
2
2
m, 19-(Î)ÎÑÍ ÑÍ , 19ꢃ-(Î)ÎÑÍ ÑÍ ), 4.04–4.11 (2H, m, 19-(Î)ÎÑÍ , 19ꢃ-(Î)ÎÑÍ ), 4.25–4.32 (2H, m, 19-(Î)ÎÑÍ ,
2
2
2
2
A
A
B
+
19ꢃ-(Î)ÎÑÍ ), 4.68 (2Í, dd, J = 10.6, 4.4, Í-16, 16ꢃ). Mass spectrum (MALDI-TOF): m/z (exp) 943.64 [M + Na] , m/z (theor)
B
+
943.63 [M + Na] . C H O .
56 88 10
ACKNOWLEDGMENTS
The work was supported financially by the RFBR (Grant 13-03-00054) and Div. Chem. Mater. Sci., Russ. Acad. Sci.,
Program No. 6.
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