Access to Diosgenyl Glycoconjugates via Gold(I)-Catalyzed Etherification of Diosgen-3-yl ortho-Hexynylbenzoate

Article abstract of DOI:10.1021/acs.orglett.6b02963

An efficient protocol for the synthesis of diverse diosgen-3-yl glycoconjugates,a class of novel synthetic analogs of natural saponins of biological significance,has been developed. The method relies on gold(I)-catalyzed etherification of diosgen-3-yl ortho-hexynylbenzoate with stoichiometric sugar alcohols to afford the corresponding glycoconjugates in 38%-99% yields. The reaction involves the preferential attack of hydroxyl groups to the C3 position of homoallylic carbocation intermediate and displays a broad substrate scope and a good functional group tolerance.

Full text of DOI:10.1021/acs.orglett.6b02963

Letter
pubs.acs.org/OrgLett
Access to Diosgenyl Glycoconjugates via Gold(I)-Catalyzed
Etherification of Diosgen-3-yl ortho-Hexynylbenzoate
Li Zhang,† Linfeng Li,‡ Shujin Bai,† Xin Zhou,† Peng Wang,*,† and Ming Li*,†
†Key Laboratory of Marine Medicine, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China,
Qingdao, Shandong 266003, P. R. China
‡Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorda Anschutz
Medical Campus, Aurora, Colorado 80045, United States
S
* Supporting Information
ABSTRACT: An efficient protocol for the synthesis of diverse
diosgen-3-yl glycoconjugates, a class of novel synthetic analogs of
natural saponins of biological significance, has been developed. The
method relies on gold(I)-catalyzed etherification of diosgen-3-yl
ortho-hexynylbenzoate with stoichiometric sugar alcohols to afford
the corresponding glycoconjugates in 38%−99% yields. The reaction
involves the preferential attack of hydroxyl groups to the C3 position
of homoallylic carbocation intermediate and displays a broad
substrate scope and a good functional group tolerance.
aponins with diosgenin as a hydrophobic aglycone backbone
Recently, Morzycki and co-workers10 reported the electro-
Sbelong to a subset of spirostan glycosides widely occurring in chemical synthesis of diosgen-3-yl galactoside in mere 37% or
the plant kingdom.1 They possess noteworthy broad-spectrum
30% yield upon treatment of either diosgenyl diphenylphosphate
or i-steroid thioether with galactosyl diacetonide. Consequently,
exploration of new procedures for the efficient and rapid
construction of structurally appealing diosgenyl glycoconjugates
is highly attractive and desirable.
bioactivities including antitumor, antiviral, antifungal, anti-
inflammatory, and immunostimulant activities.2 Isolation of
saponins from natural sources usually is a formidable task due
to the microheterogeneity of saponins in nature. Moreover,
natural saponins are easily subjected to degradation attributable
to enzymatic hydrolysis of O-glycosidic bonds in tissues and
biofluids. To overcome these problems, intensive research efforts
have been devoted to the synthesis of natural saponins including
diosgenyl glycosides.3 Meanwhile, a variety of glycomimics
resistant to enzymatic hydrolysis has been designed and
synthesized.4 These chemical analogs could be used as molecular
probesorenzyme inhibitors.5 Aspartofourresearch ondiosgenyl
glycosides and their congeners,6 we aimed to generate novel
diosgen-3-yl glycoconjugates by replacing the natural acetal-type
glycosidic bond with an ether linkage between diosgenyl and a
certain nonanomeric hydroxyl group of a sugar moiety.
In principle, current protocols for synthesis of diosgen-3-yl
ethers can be grouped into two large classes. The first involves the
treatment of reactive halogenated alkanes or the related species
with nucleophilic diosgenin as seen in the synthesis of benzyl
ether of diosgenin.7 The other class relies on the concept of i-
steroid and retro-i-steroid rearrangements that was introduced by
Winstein.8 Following this method, diosgenyl tosylate has been
converted into methyl,9a 2-azidoethanol,9b and 1,6-hexandiol
ethers9c by capturing the homoallylic carbocation generated from
diosgenylderivativeswithanalcoholasthenucleophile. However,
this procedure is impractical for employing precious or highly
functionalized alcohols because it requires excess alcohol, an
elongated reaction time, and a high reaction temperature to
obtain the desired diosgen-3-yl ethers in satisfactory yields.
Recently, there has been an explosion in the study of gold-
catalyzed activation of alkynes to exploit the low oxophilic
character of gold and the excellent functional group compatibil-
ities these catalysts exhibit.11 Particularly, gold(I)-catalyzed
etherification of alcohols and Friedel−Crafts alkylation of
electron-rich aromatics with alkyl ortho-alkynylbenzoates,12a [4
+ 3]-cycloaddition of phenylsulfanyl-substituted allylic ortho-
alkynylbenzoates with 2,6-disubstituted furans,12b and Yu
glycosylation with glycosyl ortho-alkynylbenzoates as glycosyl
donors13 have proven to be powerful tools for the synthesis of
ethers, alkylated aromatics, bridged cyclic compounds, and
glycosides. Recently, we reported (4-MeOPh)3PAuCl/AgB-
(C6F5)4-catalyzed stereocontrolled synthesis of β-mannosides
using 4,6-O-benzylidene-protected mannosyl ortho-hexynylben-
zoates as glycosyl donors.14 Herein we describe the
(PhO)3PAuCl/AgB(C6F5)4-promoted etherification of diosgen-
3-yl ortho-hexynylbenzoate with stoichiometric sugar alcohols.
The reaction is compatible with protecting groups commonly
used in carbohydrate chemistry, thus providing a facile route to
diverse diosgenyl glycoconjugates as potential analogs of natural
saponins.
The coupling of diosgen-3-yl ortho-hexynylbenzoate 1 with 2a
was selected as a model reaction to optimize the reaction
Received: September 30, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02963
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Letter
Scheme 1. Synthesis of Diosgenyl Glycoconjugates
a
b
c
d
2.0 equiv of nucleophile were used. 1.2 equiv of nucleophile was used. i-Steroid was not isolated. (PhO)3PAuCl (0.3 equiv) and AgB(C6F5)4 (0.3
e
equiv) were used. 28 h.
conditions. After evaluating various reaction parameters (see
Supporting Information), we found that treatment of 1 (1.0
equiv) with 2a (2.0 equiv) in solvent PhCF3 at 80 °C in the
presence of (PhO)3PAuCl (0.1 equiv) and AgB(C6F5)4 (0.1
equiv) provided the expected glycoconjugate 3a in 83% yield
alongwith a17% yield of i-steroid 3a′ within 5 h (Scheme 1). This
combination stood out as the optimal choice of conditions for the
gold-catalyzed etherification of 1, and the result also suggests that
ahomoallylic carbocation isinvolvedinthetransformation. Based
on this observation and literature results,8,10,12,15 a plausible
mechanismisillustrated inScheme2. Coordination ofthegold(I)
catalyst to the triple bond of 1 leads to intermediate A, which
enhances the electrophilicity of the alkyne group, and the
subsequent nucleophilic attack of the carbonyl oxygen to the
Scheme 3. Deprotection of Diosgenyl Glycoconjugates
Scheme 2. Proposed Reaction Mechanism
isocoumarin D with the simultaneous regeneration of the gold
catalyst, thus completing the catalytic cycle.
It is well-known that i-steroids can be rearranged to 3β-
substituted-Δ5-steroids (retro-i-steroid rearrangement) by acid
catalysis.8,10,16 However, in this study, (PhO)3PAuCl/AgB-
(C6F5)4-catalyzed conversion of i-steroid 3a′ to 3a in PhCF3 at
a temperature up to 100 °C hardly occurred, thus indicating that
3a was exclusively produced by the direct attack of alcohol 2a to
the C3 position of homoallylic carbocation B instead of
rearrangement of 3a′.
activated alkyne generates the homoallylic carbocation inter-
mediate B and metallic isocoumarin C. The attack of 2a to the C3
position of carbocation B gives ether 3a as the thermodynamic
product (path a), whereas the nucleophilic attack of 2a to the C6
position affords i-steroid 3a′ as the kinetic product (path b).
Intermediate C is converted by the released proton into
With the optimized conditions in hand, the scope and
limitations of the transformation were systematically examined.
As shown in Scheme 1, ortho-hexynylbenzoate 1 was treated with
various sugar alcohols 2b−2m as competent nucleophiles to
provide the corresponding diosgen-3-yl glycoconjugates as the
major, even the sole, product. Different from 2a, the coupling of
B
DOI: 10.1021/acs.orglett.6b02963
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Scheme 4. Design and Synthesis of Diosgenyl Glycoconjugate 7
benzoyl-protected glucosyl derivative 2b with 1 afforded the
expected glycoconjugate 3b in an excellent 97% yield without the
isolation of the corresponding 6-substituted i-steroid. Mannitol
2c is also a suitable nucleophile and reacted with 1 to supply
adduct 3c in quantitative yield.
Similarly, glucosyl lactol 2p (β/α = 1:3) was exposed to
etherification of 1 under the established conditions to afford
saponins 3pβ and 3pα in 58% yield (β/α = 1.15:1) together with
the corresponding i-steroids 3p′β and 3p′α in 18% yield (β/α =
1.25:1). These outcomes show that the anomeric hydroxy group
is a potential nucleophile for the present etherification, thus
opening up a new way to synthesize natural saponins. Addition-
ally, compared to 2p, the enhanced β/α ratio of 3p and 3p′ is
attributed to the stronger nucleophilicity of the 2pβ-isomer than
the α-isomer and the rapid equilibrium between them.
With diosgen-3-yl glycoconjugates in hand, deprotection was
carriedout(Scheme3). Birchreductionof3aand3a′withlithium
in liquid ammonia cleaved benzyl protecting groups to afford 4
and 4′ in 92% and 96% yields, respectively. Saponification of 3b
was effected using KOH as the base in MeOH/CH2Cl2 to furnish
4 in 98% yield. Diosgenylated manitol 3c readily underwent Birch
reduction to deliver 5 in 48% yield. Transacetalization of 3e with
methanol in the presence of camphor-10-sulfonic acid (CSA)
supplied 6α in 29% yield together with anomeric isomer 6β in
21% yield (Scheme 3).
After establishing the protocol for synthesis of diosgenyl
glycoconjugates, weappliedthemethodtothesynthesisofnatural
saponin analogs of interest. Dioscin is a representative of
diosgenyl saponins and has become an attractive target for drug
development (Scheme 4).21 Studies on its structure−activity
relationship (SAR) demonstrate that α-L-rhamnosyl residue
appended to the C2 position of the glucosyl unit exerts a
pronounced effect on the activities of dioscin.22 Thus, we
attempted to design and synthesize 7 as an analog of dioscin for
further SAR research. Between the aglycone and the rhamnosyl
moiety, 7 possesses a similar distance and identical stereo-
chemistry of chemical bonds compared to dioscin. However,
replacement of α-L-rhamnosyl and β-D-glucosyl linkages with a
C−C bond and an ether bond would render 7 more resistant to
enzymatic hydrolysis than the parent saponin. These properties
might be interesting for medicinal chemistry.
Gold(I)-catalyzed etherification of diosgenyl benzoate 1 was
expanded to the synthesis of 7 (Scheme 4). Primary alcohol 8 was
converted into ether 9 in quantitative yield. Replacement of
benzyl groups in 8 with acetyl groups is deleterious to the
transformation; thus, 11 was obtained from 10 in 38% yield along
with a 55% yield of i-steroid 11′. Birch reduction of 9 gave 7 in
67% yield. Saponification of 11 and 11′ with MeONa in MeOH
proceeded uneventfully to afford 7 and 7′ in 85% and 58% yields,
respectively. To the best of our knowledge, i-steroids 4′ and 7′
represent the first examples of 6β-substituted 3α,5α-cyclosteroid
glycoconjugates.
Amphiphilic cyclodextrins (CDs) with grafted hydrophobic
moieties are a new generation of cyclodextrin derivatives
compatible with biomembranes.16 Noteworthy, primary alcohol
2d, derived from β-cyclodextrin, a cyclic heptamer comprised of
α-(1 →4)-D-glucopyranosyl units, was treated with 1 tosmoothly
furnish ether 3d in 60% yield, thus opening up the prospect for
modification of CDs. Galactosyl diacetonide 2e reacted with 1 to
afford 3e and 3e′ in 85% and 9% yields, respectively, thus
exhibitingsignificantimprovementinyieldcomparedtotheinitial
synthesis.8 Thioglycoside 2f is a challenging nucleophile for the
transformation. Treatment of 2f with 1 led to an unexpected
thioether 3f in 72% yield without the isolation of desired
glycoconjugate, indicating the migration of the thioether unit, a
common side reaction during glycosylation with thioglycosides as
the glycosyl acceptors.18 This unexpected result could be
rationalized by the hypothesis that the thioether moiety
outcompetes the primary hydroxyl group as the nucleophile to
preferentially attack the C3 position of homoallylic carbocation B
(Scheme 2) to yield 3f.
Secondary hydroxyl groups as the nucleophiles were also found
to be suitable for the present etherification. Benzylidene- and
isopropylidene-protected 2g and 2h, respectively, were observed
to be viable substrates for the transformation; thus, 3g and 3h
were obtained in 74% and 59% yields, respectively, with
benzylidene and isopropylidene being unaffected. Axial 4-OH
of galactoside 2i was diosgenylated by 1 to give the desired
product 3i in satisfactory 86% yield; however, equatorial 3-OH of
glucoside 2j underwent etherification with 1 to afford a mixture of
3j and 3j′ in a ratio of 7.8/1 and in an overall 70% yield.
Aliphatic alcohols were also employed for etherification in this
study. Amino alcohol 2k and diosgenin 2l reacted well with 1 to
provide diosgen-3-yl ether 3k and 3l in 75% and 97% yields,
respectively, without the formation of i-steroids. Distinct from
hexanol providing ether 3m in 96% yield, 6-azido-hexanol 2n
afforded 3n in 64% yield and i-steroid 3n′ in 31% yield, which is
ascribed to different dielectric constants of 2m and 2n.19
Glycosylthiol2oasatypicalexampleofsulfur-nucleophileswas
tested in the transformation. When it was exposed to the coupling
reaction with 1, thioglycoside 3o was obtained in 28% yield
accompaniedbytheformationofi-steroid 3o′in59% yield. Given
that 2o usually reacts with chlorotrialkylphosphine gold(I) to
form the complex such as auranofin,20 this result is interesting and
might provide an entry to the synthesis of intriguing thiosaponin
as analogs of natural saponins.
In summary, an efficient protocol for the synthesis of diosgen-
3-yl glycoconjugates has been developed, which relies on gold(I)-
C
DOI: 10.1021/acs.orglett.6b02963
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Experimental details and spectral data for new compounds
(PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: pengw@ouc.edu.cn.
*E-mail: lmsnouc@ouc.edu.cn.
ORCID
Ming Li: 0000-0001-7383-0214
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from National Science
Funding of China (21272220), NSFC-Shandong Joint Fund
(U1406402), and Fundamental Research Funds for the Central
Universities.
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