A new synthetic route for preparation of enantiomers of gossypol and apogossypol from racemic gossypol

Article abstract of DOI:10.14233/ajchem.2019.21580

The paper described the preparation of enantiomers of gossypol and apogossypol from racemic gossypol via a two-step procedure. In the first step, D-tryptophan methyl ester was used as an effective agent to resolve racemic gossypol into (–)-gossypol and (+)-gossypol. Next, the deformylation reaction of the corresponding (–)-gossypol and (+)-gossypol was conducted in sodium hydroxide solution, followed by sulfuric acid neutralization in inert atmosphere and the resulting precipitate was filtered and washed with water to give (–)-apogossypol and (+)-apgossypol, respectively in high yields and in high enantiomeric excesses.

Full text of DOI:10.14233/ajchem.2019.21580

Asian Journal of Chemistry; Vol. 31, No. 1 (2019), 105-108
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.21580
A New Synthetic Route for Preparation of Enantiomers of
Gossypol and Apogossypol from Racemic Gossypol
*
VU DINH TIEN, VU VAN VU and TRAN KHAC VU
School of Chemical Engineering, Hanoi University of Science and Technology, No. 1 Dai Co Viet, Hai Ba Trung, Hanoi, Vietnam
*Corresponding author: E-mail: vu.trankhac@hust.edu.vn
Received: 13 July 2018;
Accepted: 26 August 2018;
Published online: 30 November 2018;
AJC-19166
The paper described the preparation of enantiomers of gossypol and apogossypol from racemic gossypol via a two-step procedure. In the
first step, D-tryptophan methyl ester was used as an effective agent to resolve racemic gossypol into (–)-gossypol and (+)-gossypol. Next,
the deformylation reaction of the corresponding (–)-gossypol and (+)-gossypol was conducted in sodium hydroxide solution, followed by
sulfuric acid neutralization in inert atmosphere and the resulting precipitate was filtered and washed with water to give (–)-apogossypol
and (+)-apgossypol, respectively in high yields and in high enantiomeric excesses.
Keywords: Racemic, (–)-Gossypol, (+)-Gossypol, D-Tryptophan methyl ester, (–)-Apogossypol, (+)-Apogossypol.
cokinetic characteristics of compound 2 in mice indicated that
compound 2 displays superior blood concentrations over time
in comparison with compound 1because it has slower clearance,
indicating that compound 2 could be a promising lead compound
for cancer therapy in the future [14]. Thus, significant attention
has been focused on potential therapeutic value of apogossypol
(2) and apogossypol derivatives as a promising starting point for
the development of antitumor derivatives for medicinal applica-
tions with enhanced bioactivity and reduced side effects [15-18].
To understand the mechanism by which apogossypol
exhibits its broad biological activities, the preparation of the
enantiomer of gossypol and apogossypol in high chemical
yield and enantiomeric purity is highly desirable.
So far, a number of methods for the preparation of optically
active (–)-gossypol and (–)-apogossypol from racemic mixture
have been studied and reported [19]. However, the reported
methods lack its feasibility in practical preparation.As a result,
the development of a practical method for the production of
(–)-gossypol and (–)-apogossypol in large quantities is impor-
tant from both application and scientific view points. Intrigued
by this practice, this paper presents a simple and improved
method for the preparation of (–)-gossypol and (–)-apogo-
ssypol from racemic gossypol.
INTRODUCTION
Gossypol (1) isolated from cotton seed has recently received
the increasing attention because it possesses a wide range of
biological activities, including anticancer [1-4], contraceptive
[5], antiviral [6-8] or antimicrobial activities [9]. Due to
hindered rotation about the 2,2'-binaphthyl bond, gossypol
exhibits two optically active forms, R-or (–)-1 and S-or (+)-1.
Research in both in vitro and in vivo showed that the (–)-
enantiomer is more potent than the (+)-enantiomer and the
racemic mixture (1) [10]. It was also hypothesized the selective
action at low doses of the (–)-gossypol and a nonselective
action from higher doses of either enantiomer [10]. Regarding
the mechanism of action, the (–)-gossypol targets Bcl-2, Bcl-
xL and Mcl-1 proteins with higher affinities than (+)-gossypol.
It is now in clinical trials as an orally administered agent for
the treatment of several types of human cancer [11]. However,
the application of gossypol as a therapeutic agent was limited
because of the presence of the aldehyde group in its structure,
resulting a number of side effects [12].
Apogossypol (2) is a reduced product of gossypol (1).
Preclinical in vivo data show that apogossypol (2) has superior
efficacy and markedly reduced toxicity compared to gossypol
(1) [13]. In addition, the evaluation of the single-dose pharma-
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106 Tien et al.
Asian J. Chem.
mixture of acetic acid and ether (4:1) (50 mL). The reaction
mixture was kept at -5 to 0 °C under nitrogen atmosphere and
concentrated hydrochloric acid (1.5 mL) was then dropped
into for 10 min. The reaction was then stirred at room tempera-
ture for 72 and monitored by TLC. After the completion of
reaction, the resulting D-tryptophan methyl ester was filtered
and washed by an amount of dichloromethane. The filtrate
was concentrated to the dryness and was dissolved in an amount
of 30 mL of mixture of dichloromethane and n-hexane (2:1)
and was kept in fridge for crystallization. S-(+)-gossypol (5)
was obtained by filtering and washing with cold acetone in
85.2 % yield (4.23 g); 94.4 % ee by HPLC. [α]D20 = + 349 (c
0.160, MeOH). 1H NMR (500 MHz, CDCl3): δ 11.14 (s, 2H,
CHO), 7.79 (s, 2H, Ar-H), 6.45 (br, s, 2H, -OH), 5.84 (br, s,
2H, -OH), 3.91 (m, 2H, CH(CH3)2), 2.16 (s, 6H,Ar-CH3), 1.56
(d, J = 6.9 Hz, 12H, CH(CH3)2). 13C NMR (125 MHz, CDCl3):
199.34, 156.21, 150.43, 143.55, 134.10, 133.71, 129.75, 118.18,
115.82, 114.70, 111.85, 27.90, 20.30, 20.22.
EXPERIMENTAL
All products were examined by thin-layer chromatography
(TLC), performed onWhatman 250lm Silica Gel GF Uniplates
and visualized under UV light at 254 nm. Melting points deter-
mined in open capillaries on Electrothermal IA 9200 Shimazu
apparatus and uncorrected. Purification was done by crystalliza-
tion. Optical rotations were recorded on Polarimeter P8000-T
instrument as an average of six determinations. Nuclear magnetic
resonance spectra (1H and 13C NMR) were recorded using tetra-
methylsilane (TMS) as an internal standard on a Bruker 500
MHz spectrometer with DMSO-d6 and CDCl3 as solvents.
Chemical shifts are reported in parts per million (ppm) down-
field from TMS as internal standard and coupling constants
(J) are expressed in hertz (Hz). All reaction were conducted
under inert atmosphere. Reagents and solvents were purchased
fromAldrich or Fluka Chemical Corp. (Milwaukee, WI, USA)
or Merck unless noted otherwise. Solvents were distilled and
dried before use.
Synthesis of gossypol adducts (3, 4): A solution of D-
tryptophan methyl ester hydrochloride (9.824 g, 0.038 mol)
and NaOH (1.52 g, 0.038 mol) in ethanol (60 mL) was stirred
at 45 °C and the racemic gossypol (9.85 g, 0.019 mol) was
added. The mixture was stirred for 2 h. The reaction was moni-
tored by TLC and then allowed to warm to room temperature.
The resulting precipitate from reaction was then filtered,
washed with cold ethanol and dried under reduced pressure to
obtain compound Sg, R-(3) (8.28 g, 95 %): {[α]D20 = + 222° (c
0.160, CHCl3}. 1H NMR (500 MHz, DMSO-d6): δ 13.47 (t, J
= 8.0 Hz, 2H,-NH), 10.91 (s, 2H, indole, NH), 9.77 (d, J =
12.0, 2H), 8.41 (s, 2H, indole), 7.76 (br, s, 2H, -OH), 7.47 (d,
J = 7.5 Hz, 2H, indole), 7.43 (s, 2H), 7.31 (d, J = 8.0 Hz, 2H),
7.13 (s, 2H), 7.02 (t, J = 7.5 Hz, 2H), 6.93 (t, J = 7.5 Hz, 2H),
4.79 (s, 2H,-OH), 4.45 (m, 2H), 3.65 (s, 6H), 3.65-3.76 (m,
2H), 3.59 (dd, J = 14.5, 3.6 Hz, 2H), 3.23 (dd, J = 14.5, 9.5
Hz, 2H), 1.92 (s, 6H), 1.43 (d, J = 6.5 Hz, 6H), 1.42 (d, J = 6.5
Hz, 6H). 13C NMR (125 MHz, DMSO-d6): δ 172.64, 170.84,
161.6, 149.65, 147.0, 146.24, 136.06, 131.51, 127.14, 127.12,
126.92, 124.22, 121.09, 120.22, 118.56, 118.06, 116.67,
115.60, 111.45, 107.76, 103.82, 61.98, 52.52, 30.72, 28.88,
20.31, 20.25, 20.16.
R-(–)-gossypol (6) were obtained by the same procedure
in 85.5 % yield; 95.2 % ee by HPLC. [α]D20 = - 341 (c 0.160,
1
MeOH). H NMR (500 MHz, CDCl3): 11.14 (s, 2H, CHO),
7.79 (s, 2H, Ar-H), 6.45 (br, s, 2H, -OH), 5.84 (br, s, 2H, -
OH), 3.91 (m, 2H, CH(CH3)2), 2.16 (s, 6H, Ar-CH3), 1.56 (d,
J = 6.9 Hz, 12H, CH(CH3)2). 13C NMR (125 MHz, CDCl3): δ
199.34, 156.21, 150.43, 143.55, 134.10, 133.71, 129.75,
118.18, 115.82, 114.70, 111.85, 27.90, 20.30, 20.22.
Synthesis of (–)-apogossypol (7) and (+)-apogossypol
(8):A solution of sodium hydroxide (17.2 g) in distilled water
(30.8 mL) in a two-neck flask was frozen in the refrigerator.
The flask was then evacuated and flushed with argon using a
balloon. The above prepared (–)-gossypol or (+)-gossypol (1.6
g, 3.08 mmol) was next added to the flask so carefully that it
did not stick the wall. The reaction was then stirred at 90 °C
for 1 h and cooled down and put in an ice bath. A solution of
concentrated sulfuric acid (17.6 mL) in distilled water (12.8
mL) was slowly dropped into via a syringe. The resulting
precipitate was filtered, washed with distilled water to remove
the salts and other impurity. The residue was dried in vacuum
and stored in argon atmosphere. Compounds 7 (1.24 g, 86.6
%); 98.2 % ee by HPLC. [α]D20 = -93° (c 0.150, MeOH) and
compound 8 (1.21 g, 84.6 %); 98.4 % ee by HPLC. [α]D20 = +
96° (c 0.160, MeOH). Compounds 7 and 8 have the same 1H
NMR spectra (500 MHz, CDCl3, δ (ppm): 7.65 (s, 2H); 7.51
(s, 2H); 6.05 (s, 2H); 5.20 (s, 2H); 5.11 (s, 2H); 3.86 (m, 2H);
2.19 (s, 6H); 1.56 (d, 12H, J = 5.5 Hz).
The ethanol mother liquor was then concentrated to dryness.
The residue was extracted with dichloromethane and water. The
combined dichloromethane was concentrated under reduced
pressure to obtain Rg, R-(4) (8.67 g, 99.4 %): {[α]D20= -106°
1
(c 0.160, CHCl3}. H NMR (500 MHz, DMSO-d6): δ 13.46
(br, s, 2H,-NH), 10.91(br, s, 2H, indole, NH), 9.66 (br, s, 2H,
2H),8.41 (br, s, 2H, indole), 7.95 (s, 2H, -OH), 7.48 (J = 7.5
Hz, 2H, indole), 7.43 (br, s, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.15
(s, 2H), 7.04 (t, J = 7.5 Hz, 2H), 6.96 (t, J = 7.5 Hz, 2H), 4.79
(s, 2H,-OH), 4.45 (m, 2H), 3.67 (s, 6H), 3.65-3.76 (m, 2H),
3.59 (dd, J = 14.5, 3.6 Hz, 2H), 3.23 (dd, J = 14.5, 9.5 Hz,
2H), 1.92 (s, 6H), 1.43 (d, J = 6.5 Hz, 6H), 1.42 (d, J = 6.5 Hz,
6H). 13C NMR (125 MHz, DMSO-d6): δ 174.5, 170.8, 162.3,
149.7, 146.2, 136.1, 131.5, 128.9, 127.3, 126.9, 123.8, 121.0,
119.7, 118.5, 115.6, 114.2, 111.4, 109.4, 103.8, 62.0, 54.8,
30.8, 28.7, 20.3, 20.2, 20.1.
RESULTS AND DISCUSSION
Racemic gossypol (1) was obtained from cotton seeds
collected inVietnam according to the reported procedure [20].
As mentioned above, the resolution of ( )-gosssypol has been
reported. The most important report was about the use of
commercially available amino acids to form diastereomeric
adducts that could be separated by column chromatography
or crystallization method due to distinctive differences in their
Rf values, followed by their hydrolysis in acid medium to give
(–)-gossypol [19,21]. In order to resolve ( )-gossypol, Jiang
et al. [21] initially used commercially available chiral amino
acids such as L-tryptophan, L-tyrosine and L-phenylalanine.
Synthesis of S-(+)-gossypol (5) and R-(–)-gossypol
(6): Compound 3 (8.808g, 9.59 mmol) was dissolved in a

Vol. 31, No. 1 (2019)
Preparation of Enantiomers of Gossypol and Apogossypol from Racemic Gossypol 107
H
HO
However, the reaction gave a mixture of water soluble diaste-
reomeric adducts leading to the inseparation by recrysta-
llization or flash chromatography. The next reaction surveys
were carried out using amino acid esters including L-trypto-
phan methyl ester, L-tyrosine methyl ester and L-phenylalanine
methyl ester in several solvents including CH2Cl2, ethyl ether
and methanol, respectively. It was concluded that methanol
and L-tryptophan were the ideal choice for the resolution. Xoan
et al. [22] have reported the resolution of (–)-gosssypol using
L-phenylalanine methyl ester. However, the resolution yield
was low and the procedure was unsatisfactory because both
adducts were soluble in methanol.
O
OH
OH
O
HO
N
OH
HO
+
NH2.HCl
R
OMe
i
O
_
(+ ) -Gossypol (1)
D-Trp-OMe (2)
O
R
MeO
O
R
O
HN
NH
R
O
MeO
HO
MeO
OH
NH
HN
NH
NH
OH
HO
O
O
HO
OH
OH
HO
O
NH
NH
R
Based on the literature reported regarding the resolution
of ( )-gossypol, we found the procedure reprorted by Jiang et
al. [21] is most suitable for the resolution of ( )-gossypol at
larger scale since we need a big amount of (–)-gossypol for
further modifications to obtain new derivatives while commer-
cially available (–)-gossypol is very expensive. We used the
procedure at the scale as reported. However, in the second
step, the hydrolysis of the corresponding diastereoisomeric
gossypol adduct by hydrochloric acid (37 %) in ether failed to
give the desired (–)-gossypol. In this condition, TLC showed
low yield and slow rate of the hydrolysis of corresponding
diastereoisomeric gossypol adduct derived from L-tryptophan
methyl ester (L-Trp-OMe). Additionally, the decomposition
of the formed (–)-gossypol could be observed as a possible
result of oxygen containing reaction atmosphere at reflux
temperature. Next, the hydrolysis experiment was carried out
under nitrogen atmosphere at the same scale. After 2 h of
hydrolysis, low conversion to (–)-gossypol was shown by TLC.
The decomposition of formed (–)-gossypol was still observed.
It was possible that ambient temperature is not favourable for
the hydrolysis and may be the reason for the decomposition.
We examined the experiment under nitrogen atmosphere at
ice-water temperature and found no decomposition, but low
hydrolysis for 2 h. In search for new chiral reagents for the
resolution of racemic gossypol, we reasoned that D-tryptophan
methyl ester may be an alternative choice for L-tryptophan
methyl ester to resolve ( )-gossypol. In fact, the reaction of
D-tryptophan methyl ester hydrochloride in ethanol instead
of methanol [17] with the racemic gossypol in the presence of
equimolar NaOH at 45 °C gave diastereoisomeric gossypol
adducts (Scheme-I). The reaction was almost completed in
2 h. The Sg, R-(+)-diastereoisomeric gossypol adduct (3) is
precipitated and separated by filtration. In this step, (+)-dia-
stereoisomeric gossypol adduct (3) derived from D-tryptophan
methyl ester was found to crystallize out first from the reaction
in quantitative yield. The chemical and optical purity were
determined to be up to 98.5 and 99 %, respectively by analysis
on HPLC using reported procedure [23] with optical rotation
{[α]D20= + 222 (c 0.160, CHCl3}. The mother liquor was then
extracted with water and dichloromethane to remove inorganic
substances. The organic phase was then concentrated to obtain
the (–)-diastereoisomeric gossypol adduct which was recrysta-
llized in methylene chloride to give the Rg, R-(–)-diastereo-
isomeric gossypol adduct (4) with chemical and optical high
purity in 98.7 and 99 %, respectively, with optical rotation
{[α]D20= -106 (c 0.160, CHCl3}.
MeO
O
3 (Sg, R)
4 (Rg, R)
ii
ii
O
O
O
H
OH
HO
HO
HO
HO
H
OH
H
OH HO
OH
OH
OH
HO
H
O
6
5
R -(-)-Gossypol
(+)-Gossypol
S-
iii
iii
HO
HO
HO
HO
OH
OH
OH
OH HO
OH
OH
HO
7
8
(+)-Apogossypol
R -(-)-Apogossypol
S-
Scheme-I: Resolution of ( )-gossypol by D-tryptophan methyl ester. HCl:
(i) NaOH, EtOH, 45 °C, 2 h; (ii) acetic acid:ether (4:1), HCl
(37 %), 0 °C-room temperature, 72 h (85 %); (iii) NaOH 40 %,
1 h; H2SO4 (84-86.6 %)
The hydrolytic step to liberate the resolved gossypol
from the diastereoisomerically pure adducts (3) and (4) were
conducted in the mixture of acetic acid and ether under inert
atmosphere. Different ratios of acetic acid and ether were
examined. In our experiment, the ratio of acetic acid and ether
(4:1) was found to be the most suitable for the hydrolysis.
After 72 h of hydrolysis under nitrogen atmosphere, S-(+)-
gossypol (5) and R-(–)-gossypol (6) were obtained by crysta-
llization procedure in the mixture of dichloromethane and n-
hexane. It was also found in this experiment that the ratio (2:1)
of dichloromethane and n-hexane was most suitable for
crystallization to afford high yields of enantiomers.
Apogossypol is formed by the base catalyzed deformyla-
tion of gossypol. Apoggsypol was firstly prepared by Clark
[24] using NaOH as a deformylation agent of gossypol at
the temperature of steam bath in open atmosphere. In this
condition, gossypol was converted to formic acid and apogo-
ssypol with the ratio 2:1. Due to oxidative instability of apogo-
ssypol, Powers and Dorsett [25] modified the procedure to
prepare apogossypol from racemic gossypol in an inert atmos-
phere to obtain apogossypol with improved yields. The key
point of this procedure was the base catalyzed deformylation
of gossypol conducted in inert atmosphere and elevated tempe-

108 Tien et al.
Asian J. Chem.
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scale was small and apogossypols obtained were in the racemic
forms. In this report, (–)-apogossypol or (+)-apogossypol were
prepared from the corresponding (–)-gossypol and (+)-
gossypol in high yields and enantiomeric purity via a simple
and modified procedure. The deformylation reaction of the
corresponding (–)-gossypol and (+)-gossypol was performed
in 40 % NaOH solution at 90 °C for 1 h, followed by H2SO4
neutralization in inert atmosphere.The resulting precipitate was
carefully washed with distilled water and dried in vacuum to
give the corresponding (–)-apogossypol and (+)-apogossypol
in high yields. The HPLC analysis showed the enantiomeric
purity of (–)-apogossypol (7) and (+)-apogossypol (8)
corresponding to 98.2 and 98.4 %, respectively.
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To our best of knowledge, it is the first time D-tryptophan
methyl ester has been used for effectively resolution of racemic
gossypol into (–)-gossypol and (+)-gossypol via a facile two-
step procedure in high enantiomeric excess and yields. These
enantiomers have been then converted to the corresponding
(–)-apogossypol and (+)-apogossypol in high enantiomeric and
yields. This procedure could also be potential for scaling up
to prepare optically gossypol and apogossypol for different
purposes, especially in the pharmaceutical field.
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The authors thankVietnam Ministry of Science and Tech-
nology for financial support via a project: NÐT.08.GER.15.
https://doi.org/10.1021/jm900472s.
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CONFLICT OF INTEREST
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The authors declare that there is no conflict of interests
regarding the publication of this article.
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