Methyl 1,2-shift rearrangement on c-ring and decarboxylation at C28 of oleanolic acid derivatives

Article abstract of DOI:10.1002/cjoc.201300758

A new oleanolic acid derivative with A-ring lactone, C-ring rearrangement and decarboxylation at C28 was synthesized, which was confirmed by HRMS, NMR and X-ray crystal structure. It is the first report about the methyl rearrangement on C-ring of oleanoli

Full text of DOI:10.1002/cjoc.201300758

FULL PAPER
DOI: 10.1002/cjoc.201300758
Methyl 1,2-Shift Rearrangement on C-ring and Decarboxylation
at C28 of Oleanolic Acid Derivatives
Jun Hu, Jindan Wu, and Yong Ju*
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Ministry of Education,
Department of Chemistry, Tsinghua University, Beijing 100084, China
A new oleanolic acid derivative with A-ring lactone, C-ring rearrangement and decarboxylation at C28 was
synthesized, which was confirmed by HRMS, NMR and X-ray crystal structure. It is the first report about the
methyl rearrangement on C-ring of oleanolic phenylmethyl ester, and the possible mechanism was proposed as the
1
,2-methyl shift.
Keywords 1,2-methyl shift, trifluoroacetic acid, oleanolic acid
Introduction
2
9
30
The molecular diversity which arises from research
into natural products represents a valuable tool for driv-
19
13
21
[
1-4]
E
ing drug discovery.
Pentacyclic triterpenoids are
1
1
17
2
5
O
28
currently regarded as one of the most important scaf-
folds for the drug development due to their biological
and pharmacological activities, such as antitumor, anti-
viral, antiinflammatory, hepatoprotective, gastroprotec-
tive, antimicrobial, antidiabetic, and hemolytic proper-
C
1
H
9
26
H
CO H
2
OH
N
A 5
15
3
H
H
27
HO
7
H N
N
2
H
3 24
H
2
[5-11]
ties.
As one of their representatives, oleanolic acid
(a) Oleanolic acid, OA
(b) OA-pyrimidine
(OA, Figure 1a), widely present in natural plants in the
form of free acids or aglycones, has been noted for its
therapeutic effect on human liver disorders and antitu-
mor-promotion.
[
12-14]
H
CO H
2
N
Our previous work showed that OA-heterocyclic
O
H
conjugates have obvious antitumor effects through
N
[
7,15]
H
apoptosis and inhibiting the cell growth,
such as
OA-pyrimidine and OA-oxadiazole (Figures 1b and 1c).
Although lots of work has been done about its modifica-
tion, there is no report about the methyl shift rear-
rangement on C-ring of OA. Herein, a new straightfor-
ward procedure was proposed to convert OA into A-ring
lactone and C-ring rearrangement derivative with elimi-
nation 28-carboxylic benzyl ester by using trifluoroace-
tic acid. This is the first report about the double methyl
(c) OA-oxadiazole
Figure 1 Structures of OA, OA-pyrimidine, and OA-oxadi-
azole.
product 7 is shown in Scheme 1. First, OA was oxidized
to 2 by Jones’ reagent after the protection of 28-car-
boxylic acid. Following treatment with n-butyl nitrite
under strong basic condition, compound 3 was obtained
as well as its reductive product 4 after reacting with so-
dium borohydride. Under the condition of p-toluene-
sulfonyl chloride, ring-opened derivatives 5 and its re-
ductive product 6 were produced. Finally, with treat-
ment of trifluoroacetic acid in autoclave, rearrangement
product 7 was afforded in yield 56% (details see ex-
perimental part).
1
,2-shifts on C-ring, and a possible shift mechanism was
proposed according to analyzing the crystal structure
and reaction condition.
Results and Discussion
The synthetic route of the new ring-opened com-
pounds 5 and 6, as well as the methyl-rearrangement
*
E-mail: juyong@tsinghua.edu.cn; Tel.: 0086-010-62792795; Fax: 0086-010-62781695
Received October 8, 2013; accepted November 21, 2013; published online November 28, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201300758 or from the author.
Chin. J. Chem. 2014, 32, 133—136
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
133

Hu, Wu & Ju
FULL PAPER
Scheme 1
H
CO Bn
H
CO Bn
2
2
HON
O
a
b
OA (1)
H
H
O
H
H
2
3
c
H
CO Bn
H
CO Bn
2
2
d
HON
HO
NC
H
H
OHC
H
H
5
4
e
H
CO Bn
O
H
H
2
f
NC
H
O
HOH C
2
H
H
6
7
Reagents and conditions: (a) i: Jones’ reagent, ii: BnBr, K
2
CO
3
, 96%; (b) n-BuONO, t-BuOK, 76%; (c) NaBH
4
, 94%; (d) p-toluenesulfonyl
chloride, 67%; (e) NaBH , 86%; (f) trifluoroacetic acid (3 equiv.), THF, 56%.
4
At the beginning, our original plan is to synthesize
pressure, followed by cleaving the benzyl alcohol and
the ring-opened compounds 5, 6 and A-ring lactone de-
rivative of OA. However, H NMR spectrum of 7 indi-
carbon dioxide moieties to afford the decarboxylation
1
[17-21]
product.
However, for the rearrangements of two
cated that there was no proton signal for C＝CH on
methyl groups and C＝C double bonds in C-ring, it is
believed that a shift reaction occurred. Through analyz-
ing the crystal structure and the reaction condition, a
possible rearrangement mechanism on C-ring was pro-
C-ring and the 28-carboxylic phenylmethyl ester, which
1
3
was further confirmed by C NMR spectrum. Mean-
while, through comparing its molecular weight (m/z 426,
deduced by ESI-MS (＋) spectrum which gave the sig-
[
22-26]
posed in Figure 3.
Under the acidic condition, the
＋
＋
tertiary carbocation (I) formed on C13, and by twice
methyl 1,2-shifts, the other tertiary carbocation (II) was
produced. Finally, the C＝C double bond between C9
and C10 formed after leaving hydrogen-10. Moreover,
when oleanolic acid was used under the same condition,
no rearrangement product was obtained. In order to ex-
plain the difference, we have tried to get the intermedi-
ate structure, but it did not succeed so far. It is still not
clear what induced the difference and what kinds of role
the benzyl ester group played during this process.
nals of 427 [M＋H] and 449 [M＋Na] ), it indicated
that the product 7 was different from the one we
planned to synthesize, and it is believed that an unex-
pected reaction occurred. In order to figure out its
structure, the crystal was grown in a mixed solvents of
ethyl acetate and hexane (1∶4, V/V) (Figure 2). The
X-ray crystallography showed that: (1) the A-ring lac-
tone formed as expected; (2) the 28-carboxylic benzyl
ester was eliminated; (3) the C＝C double bond shifted
from C12－C13 to C8－C9 in C-ring (bond length of
C8－C9 is 1.33 Å which is shorter than the other C－C
[
15,16]
Conclusions
bonds as shown in Figure 2);
(4) two methyl
groups on C8 and C14 shifted to C14 and C13 with
keeping their stereo configuration respectively. For the
formation of A-ring lactone, it can be easily understood
since the cyano group can be converted to carboxylic
acid under the acid condition, and then reacted with hy-
droxyl group to produce the lactone in A-ring; the
A procedure to convert oleanolic acid into A-ring
lactone and C-ring rearrangement derivative without
2
8-carboxyl acid was reported, and it is the first time to
realize the shifts of methyl groups and C＝C double
bond on C-ring of oleanolic acid benzyl ester. Accord-
ing to analyzing the crystal structure of final product
and the reaction condition, a possible mechanism of
double methyl 1,2-shifts was proposed.
2
8-carboxylic phenylmethyl ester group was protonated
under the acidic condition with the high temperature and
134
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Chin. J. Chem. 2014, 32, 133—136

Methyl 1,2-Shift Rearrangement on C-ring and Decarboxylation at C28 of Oleanolic Acid Derivatives
dissolved in 10 mL anhydrous pyridine, and the mixture
was stirred for 7 h at r.t. Then the mixture was poured
into water, and the precipitate was filtered. The crude
product was purified by flash chromatography (DCM∶
Methanol＝40∶1) to afford 5 as a white solid (149 mg,
＋
6
7%). ESI-MS (＋) m/z: 580.7 [M＋Na] , 1138.5
＋
−
[
2M ＋ Na] ; ESI-MS (−) m/z: 573.2 [M ＋ OH] ;
HRMS-ESI (＋): calcd for C37 : 580.3761; found
H51NO
3
1
5
80.3758. m.p. 78－79 ℃; H NMR (300 MHz, CDCl
3
)
δ: 9.69 (s, 1H, CHO-3), 7.32 (br s, 5H, CH
s, 1H, H-12), 5.08 (d, J＝12.3 Hz, 1H, CH
J＝12.3 Hz, 1H, CH Ph), 2.90 (d, J＝13.2 Hz, 1H,
H-14), 1.20 (s, 3H, CH ), 1.16 (s, 3H, CH ), 1.10 (s, 3H,
), 0.92 (s, 3H, CH ), 0.90 (s, 3H,
); C NMR (75 MHz, CDCl ) δ:
2
Ph), 5.29 (br
2
Ph), 5.03 (d,
2
3
3
CH
CH
3
), 0.95 (s, 3H, CH
), 0.59 (s, 3H, CH
3
3
13
3
3
3
Figure 2 ORTEP drawing of C29
probability ellipsoids (left) and a packing view along a direction
right).
H
46
O
2
(compound 7) with 35%
206.3 (CHO-3), 177.4 (C-28), 144.0 (C-13), 136.4,
128.5, 128.1, 128.0 (CH Ph), 121.4 (C-12), 118.1 (C-2),
2
(
66.0 (CH Ph), 50.8, 49.5, 46.8, 45.7, 42.4, 42.1, 41.7,
2
4
1.5, 39.3, 33.9, 33.1, 32.3, 31.9, 30.8, 29.7, 27.7, 25.4,
23.7, 23.6, 23.5, 20.2, 19.6, 18.2, 16.7.
-Cyano-3-hydroxyl-12-en-oleanolic phenylmeth-
H+
2
-
+
CF CO
3
2
yl ester (6) Sodium borohydride (120 mg, 3.15 mmol)
was added slowly to a solution of 5 (172 mg, 0.31 mmol)
in 5 mL methanol, and then the mixture was stirred for 3
h at r.t. The reaction solution was treated with diluted
hydrochloric acid (1 mol/L), and extracted with ethyl
acetate. The combined organic layer was washed with
H
+
I
II
SM
1,2-shift
water, brine, dried by MgSO and evaporated. Purifica-
4
tion by flash chromatography (DCM∶Methanol＝30∶
1
) afforded 6 as a white solid (149 mg, 86%). ESI-MS
＋ ＋
(
＋
＋): m/z: 561.0 [M＋H] , 582.6 [M＋Na] , 598.4 [M
Product
＋
3
K] ; HRMS-ESI (＋) calcd for C37H53NO : 582.3918
＋
1
Figure 3 A possible mechanism of double methyl 1,2-shifts on
[M＋Na] ; found 582.3913. m.p. 109－110 ℃; H
NMR (300 MHz, CDCl ) δ: 7.33 (br s, 5H, CH Ph),
5
C-ring.
3
2
2
.31 (br s, 1H, H-12), 5.09 (d, J＝12.3 Hz, 1H, CH
Ph),
Experimental
2
5.06 (d, J＝12.3 Hz, 1H, CH Ph), 3.55 (d, J＝9.9 Hz,
1
1
H, H-3), 3.32 (d, J＝9.9 Hz, 1H, H-3), 2.91 (d, J＝
3.2 Hz, 1H, H-14), 2.78 (d, J＝17.7 Hz, 1H, H-1), 2.46
General procedure
1
13
H NMR and C NMR spectra were obtained with a
(d, J＝17.7 Hz, 1H, H-1), 1.18 (s, 3H, CH ), 1.11 (s, 3H,
3
JEOL JNM-ECA 300/400 instrument. Electrospray
ionization mass spectrometry (ESI-MS) was measured
on Bruker ESQUIRE-LC spectrometer in positive/
negative mode; IR spectra were recorded on Spectrum
GX FT-IR spectrophotometer with KBr pellets; melting
point data were obtained by X-4 micro melting point
analyzer. The room temperature (294±1 K) single-
crystal X-ray experiments were performed on a Bruker
P4 diffractometer equipped with graphite monochroma-
tized Mo Kα radiation. Chromatographic purifications
were conducted by column chromatography with the
use of 0.06－0.20 mm silica gel. TLC analysis was fa-
cilitated by the use of UV light (254 nm) with fluores-
cent-indicating plates. Chemicals and solvents were ei-
ther purchased from commercial suppliers or purified by
standard techniques.
CH ), 1.03 (s, 3H, CH ), 0.95 (s, 3H, CH ), 0.92 (s, 3H,
3
3
3
1
3
CH ), 0.90 (s, 3H, CH ), 0.62 (s, 3H, CH ); C NMR
3
3
3
(75 MHz, CDCl ) δ: 177.6 (C-28), 143.8 (C-13), 136.5,
3
128.5, 128.1, 128.0 (CH Ph), 121.8 (C-12), 119.2 (C-2),
2
72.1 (C-3), 66.0 (CH Ph), 48.3, 47.0, 45.9, 42.5, 42.2,
2
41.6, 40.4, 39.5, 34.0, 33.1, 32.6, 32.3, 30.8, 29.7, 27.9,
25.3, 24.6, 24.4, 23.7, 23.2, 21.7, 17.8, 16.9.
1,2-Methyl shift rearrangement derivative of
oleanolic acid (7) Compound 6 (120 mg, 0.21 mmol)
was dissolved in 1 mL THF in autoclave with a PTFE
container inside, and trifluoroacetic acid (0.25 mmol)
was added. After that, the reaction solution was left in
the oven at 100 ℃ for 10 h. After transferring the
autoclave to the room temperature and evaporating the
solvent, the crude product was purified by flash chro-
matography (Hexane∶EtOAc＝3∶1) to afford 7 as a
white powder (50 mg, 56%). ESI-MS (＋) m/z: 427.0
2-Cyano-3-aldehyde-12-en-oleanolic phenylmethyl
＋
＋
ester (5) Compound 4 (230 mg, 0.40 mmol) and
p-toluenesulfonyl chloride (126 mg, 0.66 mmol) were
[M＋H] , 449.5 [M＋Na] ; HRMS-ESI (＋) calcd for
＋
C H O : 449.3390 [M＋Na] ; found 449.3392; m.p.
29
46
2
Chin. J. Chem. 2014, 32, 133—136
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www.cjc.wiley-vch.de
135

Hu, Wu & Ju
FULL PAPER
1
2
67－268 ℃; H NMR (300 MHz, CDCl
3
) δ: 4.11 (d,
CH ), 3.77 (d, J＝12.72 Hz, 1H,
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CO CH ), 0.77 (s, 3H, CH
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) δ: 175.2 (CO CH ), 137.6 (9-C), 131.2 (8-C),
7.58 (OCOCH ), 42.5, 41.9, 40.3, 39.9, 39.2, 37.9,
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The project was supported by NSFC (No. 21172130)
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Chin. J. Chem. 2014, 32, 133—136