A Glycal Approach to the Synthesis of Pregnane Glycoside P57

Article abstract of DOI:10.1002/cjoc.201800331

Pregnane glycoside P57 is known as an active component of Hoodia gordonii, which has long been used as a diet with appetite suppressant property. Chemical synthesis of P57 demands installation of β-cymarosyl linkage onto the steroid aglycone. The stereoselective formation of this special 2-deoxy-β-glycosidic linkage has previously been proven to be difficult and thus a limiting step in the synthesis of P57 and its congeners. Herein, we report the glycosylation reactions with glycals as donors and TPHB (triphenylphosphine hydrobromide) as promoter and a convergent synthesis of P57 via a β-selective glycosylation with a trisaccharide glycal donor.

Full text of DOI:10.1002/cjoc.201800331

A glycal approach to the synthesis of pregnane glycoside P57
Chao Liu,a Yuyong Ma,a Chengfeng Pei,a Wei Li,*,a,b and Biao Yu*,a
ABSTRACT Pregnane glycoside P57 is known as an active component of Hoodia gordonii, which has long been used as a diet with appetite suppressant
property. Chemical synthesis of P57 demands installation of a -cymarosyl linkage onto the steroid aglycone. The stereoselective formation of this special
2-deoxy--glycosidic linkage has previously been proven to be difficult and thus a limiting step in the synthesis of P57 and its congeners. Herein we report
the glycosylation reactions with glycals as donors and TPHB (triphenylphosphine hydrobromide) as promoter and a convergent synthesis of P57 via a
-selective glycosylation with a trisaccharide glycal donor.
KEYWORDS glycosylation, pregnane glycoside, glycal, P57, cymarose
strategy was applied, in which the first cymarose unit was
Introduction
installed onto hoodigogenin
A
via
a
gold(I)-catalyzed
glycosylation[15-18] with a cymarosyl o-alkynylbenzoate donor in 75%
yield and a moderate -selectivity (/ = 3.5:1).[14] To improve the
overall efficiency,[19,20] a convergent strategy was applied in the
Obesity is an increasing health risk in the 21st century, causing
serious diseases such as diabetes, cardiovascular diseases, and
dyslipidemia. Apart from the changes of dietary and physical
activity, the use of appetite suppressant is also a practical way for
synthesis of gordonoside
condensation of hoodigogenin
F
(2) employing
a
later stage
body weight control. Hoodia gordonii (Asclepiadaceae),
a
A
with
a tetrasaccharide
well-known natural appetite suppressant, has been used in Africa
for thousands of years.[1] Its extract has been recommended as a
modern remedy for overweight, obesity, and related diseases.[2-6]
Thus, it is of great interest to investigate its active components for
the development of relevant health products and drugs.
o-alkynylbenzoate donor. However, this glycosylation reaction led
to the coupled glycosides without stereoselectivity (/= 1:1).[13]
These poor -selectivities could be attributed to the -favored
anomeric effect as well as the incapable of participation from the
C2 or C3 substituents of the cymarosyl donors.[21-28]
Glycals are capable donors for the synthesis of
2-deoxyglycosides under the action of triphenylphosphine
hydrobromide (TPHB).[29-31] In McDonald and Reddy‘s synthesis of
digitoxin, the glycosylation of the steroid aglycone was achieved
with a trisaccharide glycal in the presence of TPHB (82%, / =
3:2).[25,26] We explored the glycosylation of hoodigogenin A (3)
with glycal donors to construct the -cymaroside linkage, and
gratifyingly, the optimized reaction conditions have led to a
convergent and stereoselective synthesis of P57.
Results and Discussion
The yield and stereoselectivity of the TPHB-catalyzed glycosylation
of glycals have been found to be highly dependent on the
coupling substrates and reaction conditions.[29-31] Thus, we
commenced the present studies with model reactions employing
the easily accessible cymarosyl glycals 5–7 as donors and
dehydroepiandrosterone (8) as acceptor. Glycals 5–7 were
prepared in three steps each from methyl -D-cymaroside (4),
which was conveniently synthesized from methyl -D-glucoside[14]
(Scheme 1). These steps include (1) installation at 4-OH of benzoyl,
benzyl, or TBDPS groups, respectively, (2) removal of the
anomeric methyl group in a heated 80% aqueous AcOH solution,
and (3) subsequent glycal formation in the presence of MsCl and
Et3N.[32,33]
Figure 1 The structure of P57 (1) and gordonoside F (2) and the
glycosylation reactions in the previous synthesis.
Among the complex pregnane glycoside components
occurring in H. gordonii,[7-11] trisaccharide P57 (1, Figure 1) has
been identified as the active component.[1,2,7] It was reported that
injection of P57 into the brain of rats could significantly increase
ATP content in hypothalamus, this might be responsible for its
appetite suppressant activity.[12] Recently, Xie et al. found that
gordonoside F (2)[8], a tetrasaccharide congener of P57, was able
to specifically active GPR119 and consequently reduce the food
intake in mice.[13] Further biological and pharmacological studies
require large amounts of P57, gordonoside F, and congeners.
However, the limited production of H. gordonii and the low
content of the active components make it difficult to produce
these pregnane glycosides in large quantities from the plant. On
the other hand, the previous synthetic approaches toward P57
and gordonoside F suffer low efficiency.[2,13,14] Especially, the
installation of the glycan onto the aglycone was poorly
stereoselective. Thus, in the synthesis of P57, a stepwise assembly
Scheme 1 Prepartion of cymarosyl glycals 5-7
a State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for
Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032 (China)
b Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong
Jia Xiang, Nanjing 210009 (China)
E-mail: byu@sioc.ac.cn; wli@cpu.edu.cn
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/cjoc.201800331
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Table 1 Glycosylation of dehydroepiandrosterone (8) with glycals 5-7 in
the presence of TPHB under varied conditions.
The
coupling
of
glycals
5–7
(1.0
eq)
with
dehydroepiandrosterone (8, 1.5 eq) in the presence of TPHB (0.15
eq) in CHCl3 at rt led to the desired glycosides 9–11 in varied
yields and stereoselectivities (Table 1, entries 1-3). It was evident
that the protecting group at O4 exerted a strong influence on the
reactivity of the glycals. Thus, glycal
5
bearing an
electron-withdrawing benzoyl group at O4 was found to be poorly
reactive; the reaction hardly proceeded and led to the desired
glycoside 9 in only 14% yield (/3.9:1.0) with glycal 5 being
largely recovered (entry 1). Glycal 6 with an electron-donating
benzyl group at O4 was much more reactive upon treatment of
TPHB; the desired glycoside 10 was obtained in 21% yield
(/1:1) and the rest of the glycal underwent Ferrier I reaction
(entry 2). Delightfully, glycal 7 bearing a bulky TBDPS group at O4
turned out to be a better donor, giving the desired glycoside 11 in
47% yield and with a good -selectivity (/4.1:1; entry 3).
Hence, the reaction conditions with glycal 7 as the donor were
further studied.
Scheme 2 Preparation of trisaccharide glycal 19
The solvents were screened for the coupling reactions of 8
and glycal 7 in the presence of TPHB (Table 1, entries 3-7).
High-polar solvents such as CH3CN (entry 4) and THF (entry 5)
dramatically decreased the glycosylation yields with most of the
starting glycal 7 being recovered, even under the promotion of up
to 0.5 eq of TPHB. PhCl turned out to a good solvent for the
present reaction (0.1 eq TPHB, rt), leading to the desired
glycoside 11 in 50% yield with a satisfactory -selectivity (/ =
7.0:1.0; entry 6). Comparable results were obtained when PhCl
was replaced with toluene (entry 7); when 0.2 eq of TPHB was
added in two portions, the coupling yield was increased to 68%
while the -selectivity was slightly decreased (/ = 5.7:1.0).
o
Raising the reaction temperature to 46 C in toluene with 0.1 eq
of TPHB gave similar results (55%, / = 7.6:1.0; entry 8), whereas
a higher temperature (86 oC) led to decomposition of the product
(10%, / = 3.4:1.0; entry 9). Further efforts such as prolongation
of the reaction time failed to offer any better results than that in
PhCl at rt (entry 6) or in toluene at 46 oC (entry 8), due to the
competitive acidolysis of glycal 7 and product 11 as well as the
Ferrier I reaction.
The synthesis of P57 commenced with the preparation of
disaccharide 13 from an already optimized 2,6-di-O-TBDPS-
digitoxosyl o-alkynylbenzoate donor 12 via 5 steps in an overall 82%
yield (Scheme 2).[34,35] The excellent -selectivity of the
glycosylation with 12 as donor can be attributed to the two bulky
TBDPS groups at O3 and O4 which block effectively the  face of
the glycosylation intermediates. Disaccharide diol 13 was then
subjected to regioselective protection. Treatment of 13 with
n-Bu2SnO in refluxing MeOH followed by addition of BnBr and CsF
at rt led to the 4’-O-benzyl derivative 14 in a satisfactory 77%
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yield. The 3-O-acetyl group in 14 was removed with LiOH in MeOH
at rt, subsequent methylation under the conditions of MeI and
NaH in DMF provided the 3,3’-di-O-methyl derivative 15 in 64%
Conclusion
In summary, we have examined the -selective glycosylation
of a model steroid (8) with cymarosyl glycals (5-7) under the
promotion of TPHB. Optimal conditions are obtained and applied
successfully to the synthesis of P57 (1). Thus, the coupling of
trisaccharide glycal (19) and hoodigogenin A (3) can lead to the
desired glycoside (20) in 70% yield with an excellent -selectivity
(/ = 6.0:1.0). This glycosylation step is greatly improved
compared to the previous procedures used in the synthesis of P57
and congeners.[2,13,14] A practical synthetic approach toward this
important type of pregnane glycosides will facilitate the in-depth
studies of their biological and pharmacological activities.
o
yield (based on 14). Hydrogenolysis of 15 over Pd(OH)2 at 50 C
led to cleavage of the terminal benzyl group to give alcohol 16
(93%). During the hydrogenolysis, addition of Et3N was required
to prevent the cleavage of the acid-labile glycosidic linkage.
Disaccharide alcohol 16 was then subjected to glycosylation with
6-deoxy-glucosyl o-alkynylbenzoate donor 17 (4 eq).[14] The
reaction proceeded smoothly under the catalysis of PPh3AuNTf2
(0.07 eq) in toluene to give trisaccharide 18 in 81% yield. The
anomeric p-methoxyphenyl (MP) group was removed with
Ag(DPAH)2 in CH3CN and H2O at rt,[36,37] and subsequent
dehydration of the nascent 1-OH under the action of
Tf2O/i-Pr2NEt afforded the desired trisaccharide glycal 19 in 44%
yield (93%, b.r.s.m.).[38]
Experimental
Preparation of trisaccharide 20
A mixture of trisaccharide glycal 19 (7.7 mg, 0.012 mmol) and
hoodigogenin A (3) (7.6 mg, 0.018 mmol) was azeotropically dried
(3 x toluene) and dissolved in dry PhCl (0.5 mL). TPHB (1.1 mg,
0.0032mmol) and 4 Å MS were added, and the resulting mixture
was allowed to stir at rt for 12 hours. Another portion of TPHB
(5.3 mg, 0.015 mmol) was added and the stirring continued for 6
h. After quenching with saturated aqueous NaHCO3, the mixture
was diluted with CH2Cl2 and filtered through Celite. The organic
layer was washed with saturated aqueous NaHCO3 and brine,
dried over anhydrous Na2SO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography
(petroleum ether/EtOAc = 10:1 to 3:2) to afford 20β (7.6 mg, 60%)
Scheme 3 Glycosylation of hoodigogenin A (3) with trisaccharide glycal 19
and the synthesis of P57 (1).
29
1
and 20α (1.3 mg, 10%): 20β: [α]D = 4.0 (c 1.1, CHCl3); H NMR
(500 MHz, chloroform-d) δ 8.06-8.04 (m, 4H), 7.62–7.53 (m, 2H),
7.48–7.42 (m, 4H), 6.95–6.89 (m, 1H), 5.40–5.37 (m, 1H), 5.32 (dd,
J = 9.6, 7.9 Hz, 1H), 5.17–5.13 (m, 1H), 4.81 (dd, J = 9.6, 2.0 Hz, 1H),
4.71 (dd, J = 9.6, 2.0 Hz, 1H), 4.68 (d, J = 7.9 Hz, 1H), 4.63 (dd, J =
12.0, 4.4 Hz, 1H), 4.25 (s, 1H), 3.84–3.75 (m, 4H), 3.75–3.66 (m,
2H), 3.55–3.46 (m, 1H), 3.47 (s, 3H), 3.37 (s, 3H), 3.34 (s, 3H), 3.20
(dd, J = 9.5, 2.8 Hz, 1H), 3.17–3.10 (m, 2H), 2.38–2.27 (m, 2H),
2.19 (s, 3H), 2.14–2.08 (m, 1H), 2.07–1.91 (m, 5H), 1.88 (s, 3H),
1.83 (d, J = 7.1 Hz, 3H), 1.80–1.72 (m, 3H), 1.67–1.60 (m, 2H),
1.56–1.45 (m, 3H), 1.30 (d, J = 6.2 Hz, 3H), 1.18 (d, J = 6.2 Hz, 3H),
1.09 (dd, J = 13.7, 3.6 Hz, 1H), 1.05 (s, 3H), 0.97 (s, 3H), 0.94 (d, J =
6.2 Hz, 3H); 13C NMR (126 MHz, chloroform-d) δ 217.2, 167.8,
165.4, 164.9, 139.1, 137.9, 133.5, 133.3, 129.9, 129.9, 129.8,
129.8, 128.9, 128.7, 128.6, 122.1, 102.7, 99.7, 96.0, 85.8, 84.2,
82.6, 81.7, 77.6, 76.7, 76.0, 74.6, 73.4, 70.6, 68.6, 68.1, 59.2, 58.7,
57.9, 57.3, 53.9, 43.2, 38.8, 37.4, 37.2, 36.0, 35.8, 35.5, 34.5, 33.3,
29.6, 27.5, 26.2, 24.5, 19.4, 18.3, 18.1, 17.8, 14.6, 12.3, 10.0;
ESI-HRMS calcd for C61H86O17N [M+NH4]+ m/z = 1104.5890, found
1104.5890.
With the optimized TPHB-catalyzed conditions and the
trisaccharide glycal 19 at hand, we conducted the glycosylation of
hoodigogenin A (3, 1.5 eq) to elaborate P57 (Scheme 3). When 0.2
eq of TPHB was used in PhCl at rt, a significant amount of the
glycal 19 still remained after 56 h, and the desired coupled
product 20 was obtained in 40% yield with an / ratio of 2.6:1.0
(entry 1). Raising the amount of TPHB to 0.5 eq could result in full
consumption of glycal 19 in 8 h with a better -selectivity (/ =
7.7:1.0; entry 2). However, several unidentified by-products were
observed presumably due to the cleavage of the acid-labile
glycosidic linkages of the deoxytrisaccharides, with the desired
trisaccharide 20 being isolated in 40% yield. We also found that
the use of 1.0 eq of TPHB increased the yield to 57% with a good
/ selectivity of 6.1:1.0 (entry 3). The most satisfactory results
were attained by the addition of 1.5 eq of TPHB in portion at rt,
leading to a 70% yield and a / ratio of 6.0:1.0 (entry 4). Finally,
selective removal of the two benzoyl groups in the β-anomer 20
was achieved by carefully adding KOH in MeOH into a diluted
solution of substrate 20 in toluene, furnishing P57 (1) in 64%
yield.
29
20α: [α]D = 44.9 (c 0.6, CHCl3); 1H NMR (500 MHz,
chloroform-d) δ 8.07–8.04 (m, 4H), 7.62–7.54 (m, 2H), 7.50–7.40
(m, 4H), 6.96–6.87 (m, 1H), 5.37–5.31 (m, 2H), 5.17–5.13 (m, 1H),
4.85 (d, J = 3.4 Hz, 1H), 4.76 (dd, J = 9.6, 2.0 Hz, 1H), 4.68 (d, J =
7.9 Hz, 1H), 4.63 (dd, J = 11.9, 4.4 Hz, 1H), 4.23 (s, 1H), 4.22–4.16
(m, 1H), 3.83–3.75 (m, 3H), 3.73–3.64 (m, 2H), 3.46 (s, 3H), 3.41–
3.37 (m, 1H), 3.36 (s, 3H), 3.35 (s, 3H), 3.25 (dd, J = 9.2, 3.0 Hz, 1H),
3.22 (dd, J = 9.5, 2.8 Hz, 1H), 3.15–3.10 (m, 1H), 2.35–2.25 (m, 3H),
2.19 (s, 3H), 2.17–2.06 (m, 2H), 2.02–1.93 (m, 3H), 1.89–1.86 (m,
3H), 1.83 (d, J = 7.1, 1.3 Hz, 3H), 1.80–1.73 (m, 4H), 1.70–1.64 (m,
2H), 1.53–1.42 (m, 2H), 1.31 (d, J = 6.2 Hz, 3H), 1.16 (d, J = 6.4 Hz,
3H), 1.06 (s, 3H), 1.03–1.00 (m, 1H), 0.96 (s, 3H), 0.94 (d, J = 6.2 Hz,
3H); 13C NMR (101 MHz, chloroform-d) δ 217.2, 167.8, 165.4,
165.0, 139.6, 137.9, 133.5, 133.3, 130.0, 129.9, 129.8, 129.8,
128.9, 128.7, 128.6, 121.7, 102.7, 99.5, 93.9, 85.9, 84.2, 81.7, 76.6,
76.1, 75.7, 75.6, 74.6, 73.4, 70.6, 68.1, 63.1, 59.2, 58.5, 57.3, 53.9,
43.1, 40.0, 37.3, 37.2, 35.9, 35.7, 34.5, 33.3, 32.8, 27.6, 27.4, 26.2,
24.5, 19.5, 18.0, 17.8, 17.8, 14.7, 12.3, 10.1; ESI-HRMS calcd for
C61H86O17N [M+NH4]+ m/z = 1104.5890, found 1104.5885.
This article is protected by copyright. All rights reserved.

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Preparation of P57 (1)
To a solution of 20β (54.4 mg, 0.050 mmol) in toluene (9 mL)
was added KOH (46.0 mg, 0.82 mmol) in MeOH (4 mL) slowly at
0 °C. The ice-water bath was removed and the reaction was
allowed to stir at rt for 3.5 hours. The resulting mixture was
neutralized with acidic resin, filtered and concentrated in vacuo.
The residue was purified by silica gel column chromatography
(CH2Cl2/MeOH = 50:1 to 30:1) to give P57 (1) (28.1 mg, 64%) as a
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white solid: [α]27 = 6.5 (c 0.5, CHCl3); 1H NMR (500 MHz,
D
chloroform-d) δ 6.95–6.89 (m, 1H), 5.41–5.40 (m, 1H), 4.84 (dd, J
= 9.6, 2.0 Hz, 1H), 4.76 (dd, J = 9.5, 2.0 Hz, 1H), 4.64 (dd, J = 12.0,
4.4 Hz, 1H), 4.30 (d, J = 7.7 Hz, 1H), 4.25 (s, 1H), 3.94–3.88 (m, 1H),
3.87–3.82 (m, 1H), 3.81–3.77 (m, 2H), 3.65 (s, 3H), 3.57–3.48 (m,
2H), 3.44 (s, 3H), 3.43 (s, 3H), 3.40–3.33 (m, 1H), 3.27 (dd, J = 9.5,
3.0 Hz, 1H), 3.23–3.16 (m, 2H), 3.15–3.07 (m, 2H), 2.37–2.30 (m,
4H), 2.19 (s, 3H), 2.17–2.13 (m, 1H), 2.11–2.07 (m, 1H), 2.03–1.90
(m, 4H), 1.88 (s, 3H), 1.84–1.83 (m, 3H), 1.79–1.75 (m, 3H), 1.68–
1.63 (m, 1H), 1.31 (d, J = 6.1 Hz, 3H), 1.21 (d, J = 6.2 Hz, 3H), 1.10
(dd, J = 13.7, 3.8 Hz, 1H), 1.06 (s, 3H), 0.98 (s, 3H); 13C NMR (126
MHz, chloroform-d) δ 217.2, 167.8, 139.1, 137.9, 128.9, 122.1,
104.5, 99.8, 96.0, 85.9, 85.4, 82.9, 82.7, 77.6, 77.1, 76.1, 74.9,
74.8, 71.8, 68.7, 68.4, 60.8, 58.1, 58.1, 57.3, 53.9, 43.2, 38.8, 37.4,
37.2, 35.9, 35.7, 35.3, 34.6, 33.3, 29.6, 27.5, 26.2, 24.5, 19.5, 18.6,
18.4, 18.0, 14.7, 12.3, 10.1; ESI-HRMS calcd for C47H74O15Na
[M+Na]+ m/z = 901.4920, found 901.4916.
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Supporting Information
The experimental details of the model glycosylation reactions
and the preparation of trisaccharide glycal 19 and the NMR
spectra of the new compounds are available on the WWW under
https://doi.org/10.1002/cjoc.2018xxxxx.
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Financial support from the National Natural Science
Foundation of China (21432012, 21621002, and 21672248), the
Strategic Priority Research Program of the CAS (XDB20020000),
the K. C. Wong Education Foundation, and the Mizutani
Foundation for Glycoscience is acknowledged.
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Entry for the Table of Contents
Page No.
A glycal approach to the synthesis of
pregnane glycoside P57
Pregnane glycoside P57 with potent appetite suppressant activity was synthesized via a -selective
TPHB-promoted glycosylation with a trisaccharide glycal as donor.
Chao Liu, Yuyong Ma, Chengfeng Pei, Wei
Li,* Biao Yu*
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