Synthesis of the First Macrocyclic Glycoterpenoid Based on Trehalose and the Diterpenoid Isosteviol

Article abstract of DOI:10.1007/s10600-015-1440-3

A macrocyclic glycoterpenoid containing the diterpenoid dihydroisosteviol (16-hydroxy-ent-beyeran-19- oic acid) and α,α′-trehalose linked by an ester spacer was synthesized.

Full text of DOI:10.1007/s10600-015-1440-3

DOI 10.1007/s10600-015-1440-3
Chemistry of Natural Compounds, Vol. 51, No. 5, September, 2015
SYNTHESIS OF THE FIRST MACROCYCLIC GLYCOTERPENOID
BASED ON TREHALOSE AND THE DITERPENOID ISOSTEVIOL
B. F. Garifullin, R. R. Sharipova, I. Yu. Strobykina,
*
O. V. Andreeva, and V. E. Kataev
A macrocyclic glycoterpenoid containing the diterpenoid dihydroisosteviol (16-hydroxy-ent-beyeran-19-
oic acid) and ꢀ,ꢀꢁ-trehalose linked by an ester spacer was synthesized.
Keywords: isosteviol, trehalose, diterpenoids, macrocycles, macrocyclic glycoterpenoids.
We recently reported the synthesis of a series of macrocyclic terpenoids constructed from one, two, and four molecules
of the diterpenoid dihydroisosteviol 2 (16-hydroxy-ent-beyeran-19-oic acid) linked through polymethylene spacers containing
esters, hydrazides, and hydrazonohydrazides [1, 2]. The present article is a continuation of our last publications on the
synthesis of macrocyclic dihydroisosteviol derivatives [3, 4] and reports the synthesis of macrocycle 11 in which one of the
spacers linking the diterpenoid 2 into the macrocyclic structure contains ꢀ,ꢀꢁ-trehalose 7. We called it a macrocyclic
glycoterpenoid in analogy with the literature [5] because it contained a carbohydrate moiety in addition to the terpenoid
fragments.
O
OH
O
O
O
O
17
6
16
6
O
O
13
O
O
15
1
1
i
ii
iii, iv
9
7
20
1
5
18
3
19
O
O
HO
O
O
O
HO
O
OH
HO
O
O
1
2
3
4
- 6
R
R
OH
OR
1
OH
OR
1
v
vi
4
5
6
O
O
O
O
vii
HO
O
OH
R
2
O
O
OR
2
HO
OH
HO
OH
R
2
O
OR
2
R
2
O
OR
2
8
- 10
viii
ix
8
9
10
4: R = CH OH; 5: R = COOH; 6: R = C(O)Cl
2
8
: R = Tr, R = H; 9: R = Tr, R = Ac; R = H, R = Ac
1
2
1
2
1
2
i. NaBH , CH OH; ii. ClC(O)(CH ) C(O)Cl, DMAP, Py, CH Cl ; iii. SOCl , 50ꢂC; iv. HO(CH ) OH, CH Cl , yield 60%; v. CrO , H SO ,
4
3
2 6
2
2
2
2 4
2
2
3
2
4
H O, Me CO, yield 88%; vi. SOCl , CH Cl , reflux; vii. Ph CCl, Py; viii. (CH CO) O, Py; ix. FeCl 46H O, CH Cl , H O, yield 60%
2
2
2
2
2
3
3
2
3
2
2
2
2
A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences,
20088, Kazan, Ul. Arbuzova, 8, fax: (843) 273 22 53, e-mail: kataev@iopc.ru. Ttranslated from Khimiya Prirodnykh Soedinenii,
No. 5, September–October, 2015, pp. 760–763. Original article submitted March 18, 2015.
4
8
86
0009-3130/15/5105-0886 ©2015 Springer Science+Business Media New York

The macrocycle was prepared by a convergent synthesis consisting of two branches, the terpene one leading to
difunctionalized dihydroisosteviol derivative 6 (terpene precursor) and the carbohydrate one leading to hexaacetylated trehalose
1
0 (carbohydrate precursor). Covalent binding of precursors 6 and 10 in the last step afforded target macrocyclic glycoterpenoid 11.
17
16
O
O
1
3
1
6
1
1
O
O
20
9
15
7
8
1
5
1
3
i
9
O
6
+
10
O
O
O
O
O
O
O
6'
5
'
O
O
AcO
O
OAc
OAc
3'
1'
AcO
OAc AcO
1
1
i. Et N, CH Cl , yield 7%
3
2
2
Precursor 6 was synthesized in six steps. First, the oxo group of the natural diterpenoid isosteviol 1 (16-oxo-ent-beyeran-
9-oic acid) was reduced selectively and stereospecifically by a known method [6] into dihydroisosteviol 2 (100% de), two
1
molecules of which were then bound covalently via a reaction with suberic acid dichloride as before [7]. The resulting diacid
3
was converted into the dichloride, which was then reacted in situ with a 30-fold excess of 1,4-butanediol. Then, diol 4 was
isolated by column chromatography in 60% yield and oxidized by Jones reagent [8]. The order of addition of the reagents was
atypical for this reaction [9], namely, slow addition of a dilute solution of 4 in Me CO to a solution of chromic acid. The
2
constant deficiency of starting 4 in the reaction mixture avoided forming side macrocyclic products [9] and; therefore, column
chromatography for working up the products. Diacid 5 was obtained in 88% yield. The dichloride 6 was used further as
the terpene precursor.
2
,2ꢁ,3,3ꢁ,4,4ꢁ-Hexa-O-acetyl-ꢀ,ꢀꢁ-trehalose (10) was synthesized by the known method [10]. First, the primary
hydroxyls of trehalose (7) were protected with trityl groups. Then, the secondary hydroxyls of disaccharide 8 were acylated,
after which the protecting groups were removed.
The last step of the convergent synthesis involved refluxing dichloride 6 and hexaacetylated trehalose 10 in CH Cl
2
2
–
4
at high dilution (10 M) in the presence of Et N. Macrocyclic glycoterpenoid 11 was isolated from the reaction mixture in 7%
3
yield by column chromatography.
Only four natural macrocyclic glycoterpenoids (isolated from the sea hare Syphonota geographica) have been described
in the literature [5, 11]. Synthetic macrocyclic glycoterpenoids had not been reported before our first publication [4] appeared.
EXPERIMENTAL
PMR spectra were recorded on an Avance-400 spectrometer (400 MHz, Bruker, Germany). MALDI mass spectra
were obtained in linear mode using a Nd:YAG laser at 355 nm on an UltraFlex III TOF/TOF time-of-flight mass spectrometer
(
Bruker Daltonik GmbH, Bremen, Germany). Data were processed using the FlexAnalysis 3.0 program (Bruker Daltonik
GmbH, Bremen, Germany). Masses were measured in the range m/z 200–6000 in positive-ion mode. The matrix was
–
3
2
,5-dihydroxybenzoic acid (DHB) and p-nitroaniline (p-NA). Samples were dissolved in CH Cl (10 M). The matrix
2 2
solution in MeCN had a concentration of 10 mg/mL. Samples were deposited by the dried-drop method. Matrix solution
0.5 ꢃL) was pipetted onto an Anchor Chip target (Bruker Daltonik GmbH, Bremen, Germany). After the solvent evaporated,
(
–
1
the target was treated with analyte solution (0.5 ꢃL). IR spectra were recorded in the range 400–4000 cm on a Vector 22
Fourier-spectrometer (Bruker). Samples were studied as films. The course of reactions and purity of products were monitored
by TLC on Sorbfil plates (OOO Imid, Krasnodar, Russia). Compounds were detected by treatment with H SO solution (5%)
2
4
887

followed by heating to 120°C. Specific rotation was measured on a Model 341 polarimeter (PerkinElmer Inc., Waltham, USA)
at wavelength 589 nm in a cell thermostatted at 20°C. Melting points were measured on a Boetius apparatus.
Isosteviol (1) was prepared by the literature method [12] from the sweetener Sweta (Stevian Biotechnology Corp.),
mp 235°C (lit. 234–235°C [12], 231–234°C [13]). Its spectral data agreed with the literature [12]. Dihydroisosteviol (2) was
synthesized by the literature method [6] from 1, mp 199°C (lit. 198–200°C [6]). Diacid 3 was prepared from 2 by the literature
method [7], mp 110°C (lit. 108–112°C [7]). 2,2ꢁ,3,3ꢁ,4,4ꢁ-Hexa-O-acetyl-ꢀ,ꢀꢁ-trehalose (10) was synthesized by the literature
method [10], mp 95°C (lit. 102°C [10], 93–96°C [14]). Its spectral data agreed with the literature [10].
Bis[19-nor-4ꢀ(ꢄ-hydroxybutyloxycarbonyl)-ent-beyeran-16-yl]-1,6-hexanedicarboxylate (4). Diacid 3 (1.3 g,
1
.67 mmol) was treated with SOCl (5 mL) and heated at 50°C for 2 h under Ar. The excess of SOCl was vacuum distilled.
2
2
The residue was treated with anhydrous CH Cl and stirred. The solvent was distilled off. The residue was dried in vacuo.
2
2
–
1
Yield 1.36 g (100%). IR spectrum (KBr, ꢅ, cm ): 1732, 1796 (C=O).
A solution of 1,4-butanediol (4.5 g, 49.9 mmol) in anhydrous CH Cl (10 mL) at 50°C under Ar was treated dropwise
2
2
with a solution of freshly prepared 3 (1.36 g, 1.67 mmol) in anhydrous CH Cl (50 mL), and refluxed for 4 h. The CH Cl
2
2
2
2
layer was separated, washed with H O (3 ꢆ 10 mL), and dried over CaCl . The solvent was removed. The residue was
2
2
chromatographed over a dry column (petroleum ether–EtOAc eluent, 4:1, then 1:2) to afford diol 4 as a transparent oil. Yield
2
0
0
.93 g (60%), [ꢀ] –54.0° (c 0.91, MeOH). PMR spectrum (400 MHz, CDCl , ꢇ, ppm, J/Hz): 0.70 (6H, s, 2 ꢆ H -20); 0.90
D
3
3
(
6H, s, 2 ꢆ H -17); 1.16 (6H, s, 2 ꢆ H -18); 0.83–1.90 [56H, m, ent-beyerane skeleton, (CH ) spacer, and two central (CH )
3 3 2 4 2 2
fragments of two 19-(O)O(CH ) OH groups]; 2.16 (2H, d, J = 13.0, 2 ꢆ H -3); 2.30 [4H, t, J = 7.4, 2 ꢆ 16-OC(O)CH ]; 3.67
2
4
eq
2
(
4H, t, J = 6.2, 2 ꢆ CH OH); 3.95–4.04 [2H, m, 2 ꢆ 19-(O)OCH ]; 4.06–4.13 [2H, m, 2 ꢆ 19-(O)OCH ]; 4.71 (2H, dd,
2 A B
+
+
+
+
J = 10.5, 4.5, 2 ꢆ H-16). Mass spectrum: m/z 945.5 [M + Na] , 961.5 [M + K] ; calcd 945.6 [M + Na] , 961.6 [M + K] .
C H O .
5
6 90 10
Bis[19-nor-4ꢀ(ꢄ-carboxypropyloxycarbonyl)-ent-beyeran-16-yl]-1,6-hexanedicarboxylate (5). Asolution of CrO3
0.5 g, 5 mmol) in H SO (38%, 5 mL) was cooled to 3°C and treated slowly dropwise with a solution of 4 (1.16 g, 1.26 mmol)
(
2
4
in Me CO (50 mL) over 20 h. The precipitate was filtered off. The filtrate was concentrated in vacuo to 10 mL, poured into
2
H O (100 mL), and extracted with Et O (5 ꢆ 20 mL). The Et O extract was washed with acidified H O (3 ꢆ 20 mL) and H O
2
2
2
2
2
2
0
(
(
3 ꢆ 20 mL) and dried over CaCl . The solvent was removed to afford diacid 5. Yield 1.05 g (88%), mp 56–57°C, [ꢀ] –45°
c 0.24, MeOH). PMR spectrum (400 MHz, CDCl , ꢇ, ppm, J/Hz): 0.69 (6H, s, 2 ꢆ H -20), 0.89 (6H, s, 2 ꢆ H -17); 1.16 (6H,
2
D
3
3
3
s, 2 ꢆ H -18); 0.80–1.90 [48H, m, ent-beyerane skeleton, (CH ) spacer]; 1.94–2.01 (4H, m, 2 ꢆ 19-(O)OCH CH ]; 2.15 (2H,
3
2 4
2
2
d, J = 14.4, 2 ꢆ H -3); 2.25–2.36 [4H, m, 2 ꢆ 16-OC(O)CH ]; 2.40–2.53 [4H, m, 2 ꢆ 19-(O)OCH CH CH ]; 3.99–4.06 [2H,
eq
2
2
2
2
m, 2 ꢆ 19-(O)OCH ]; 4.09–4.15 [2H, m, 2 ꢆ 19-(O)OCH ]; 4.73 (2H, dd, J = 10.5, 4.2, 2 ꢆ H-16). Mass spectrum: m/z 973.6
A
B
+
+
+
+
[
M + Na] , 989.6 [M + K] ; calcd 973.6 [M + Na] , 989.6 [M + K] . C H O .
56 86 12
2
,11,14,19,22,25,30-Heptaoxa-1,12(16,4ꢀ)di(19-nor-ent-beyerane)-21,23(2,6)di(3,4,5-tri-O-
acetyltetrahydropyran)cyclohentriacontaphane-3,10,13,18,26,31-hexaone (11). A solution of 5 (0.34 g, 0.36 mmol) in
CH Cl (8 mL) was treated with SOCl (1 mL) and refluxed under Ar for 5 h. The excess of SOCl was vacuum distilled.
2
2
2
2
The residue was treated with CH Cl and stirred. The solvent was distilled off. The residue was dried in vacuo to afford 6
2
2
–
1
(
0.35 g, 100%). IR spectrum (KBr, ꢅ, cm ): 1727, 1801 (C=O).
A solution of 10 (0.21 g, 0.36 mmol) in CH Cl (250 mL) was treated with Et N (0.073 g, 0.72 mmol), refluxed under
2
2
3
Ar, treated dropwise with a solution of freshly prepared 6 (0.35 g, 0.36 mmol) in CH Cl (80 mL) over 4 h, refluxed for 10 h,
2
2
washed with H O (3 ꢆ 60 mL), and dried over CaCl . The solvent was removed. The residue was chromatographed over silica
2
2
2
0
gel (100/160) using CH Cl –MeOH (100:0.3 and 100:1). Yield 0.04 g (7.4%), mp 103–104°C, [ꢀ] 16.8° (c 0.78, CH Cl ).
2
2
D
2
2
PMR spectrum (400 MHz, CDCl , ꢇ, ppm, J/Hz): 0.70 (6H, s, 2 ꢆ H -20), 0.90 (6H, s, 2 ꢆ H -17), 1.16 (6H, s, 2 ꢆ H -18),
3
3
3
3
0
2
2
4
2
.80–1.90 [48H, m, ent-beyerane skeleton, (CH ) spacer], 1.95–2.00 [4H, m, 2 ꢆ 19-(O)OCH CH ], 2.03 [6H, s, 2 ꢆ CH C(O)],
.04 6H, s, 2 ꢆ CH C(O)], 2.08 [6H, s, 2 ꢆ CH C(O)], 2.15(2H, d, J = 14.5, 2 ꢆ H -3), 2.27–2.34 [4H, m, 2 ꢆ 16-OC(O)CH ],
.44 [4H, t, J = 7.5, 2 ꢆ 19-(O)OCH CH CH ], 3.91–4.11 [8H, m, 2 ꢆ 19-(O)OCH , 4 ꢆ H-6ꢁ], 4.21–4.30 (2H, m, 2 ꢆ H-5ꢁ),
.75 (2H, dd, J = 10.5, 3.8, 2 ꢆH-16), 5.0–5.05 (4H, m, 2 ꢆ H-2ꢁ, 2 ꢆH-4ꢁ), 5.32 (2H, d, J = 3.8, 2 ꢆ H-1ꢁ), 5.50 (2H, t, J = 9.7,
2 4 2 2 3
3
3
eq
2
2
2
2
2
+
+
+
+
ꢆ H-3ꢁ). Mass spectrum: m/z 1531.9 [M + Na] , 1547.8 [M + K] ; calcd 1531.8 [M + Na] , 1547.7 [M + K] . C H O .
8
0 116 27
ACKNOWLEDGMENT
The work was sponsored by the Russian Science Foundation (Grant No. 14-50-00014).
888

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