Synthesis of a small library of estradiol-based glycosteroid mimics containing a modified D-ring

Article abstract of DOI:10.1002/ejoc.201001342

Glycosylated steroids, such as cardenolides and saponins, are widely distributed in nature and have been shown to possess various types of biological activities. In the present study, carbohydrate donors were evaluated for the glycosylation of steroids; t

Full text of DOI:10.1002/ejoc.201001342

FULL PAPER
DOI: 10.1002/ejoc.201001342
Synthesis of a Small Library of Estradiol-Based Glycosteroid Mimics
Containing a Modified D-Ring
Filip S. Ekholm,[a] Gyula Schneider,[b] János Wölfling,*[b] and Reko Leino*[a]
Keywords: Natural products / Carbohydrates / Steroids / Glycosylation
Glycosylated steroids, such as cardenolides and saponins, are
widely distributed in nature and have been shown to possess
various types of biological activities. In the present study,
carbohydrate donors were evaluated for the glycosylation of
steroids; the results show that benzoylated imidate donors
were superior in terms of efficiency and operational sim-
plicity. These donors were then applied to the synthesis of a
limited library of estradiol-based glycosteroid mimics con-
taining a modified D-ring. The deprotected molecules con-
tained three types of variations in the steroid backbone and
four types of variations in the sugar moiety. The synthesized
structures will be screened for biological activity and for their
potential use in drug delivery systems.
Our interest in glycosteroids stems from the discoveries
that these molecules enhance the transport of polar mole-
cules across membranes, which can be considered as a step
towards drug delivery systems. Here, we describe the syn-
thesis and characterization of a small library of amphiphilic
glycosteroids containing modifications in both the carbo-
hydrate moieties and the steroid skeleton. The method pro-
vides the possibility of synthesizing glycosides of synthetic
cardenolides and related 17β-exo-heterocyclic compounds,
the synthesis of which have both been reported previously.[8]
Glycosylation of steroids is generally considered to be de-
manding because of the low reactivity of secondary
alcohols.[9] Thus, a detailed glycosylation study was first
performed to identify carbohydrate donors that could pro-
vide sufficiently high selectivities and efficiencies under mild
reaction conditions. Due to the challenges associated with
interpretation of the NMR spectra of glycosteroids, com-
plete NMR spectroscopic characterization of all the pre-
pared compounds is also presented here in detail.
Introduction
Glycosteroids are a class of naturally occurring com-
pounds that consist of a lipophilic steroid part and a hydro-
philic carbohydrate moiety. These amphiphilic molecules
are widely distributed in nature and have been isolated from
both plant and animal sources.[1] Recent advances in glyco-
biology have revealed that such glycoconjugates play impor-
tant biological roles ranging from prevention of bacterial
infections to manipulation of immune responses.[2] The
more traditional roles of glycosteroids are exemplified by
the cardenolides and saponins, which are well-known for
their physiological and pharmacological activities.[3] The
discovery that amphiphilic glycosteroids may enhance the
transport of polar molecules across cellular membranes fur-
ther extends their applicability.[4] Accordingly, progress
towards effective drug delivery systems has been made in
recent years as exemplified by the reports on a Gentamycin
delivery system.[5] It is well-known that the biological inter-
actions displayed by biomolecules largely depend on both
their aglycon and glycone structures, as also exemplified by
the complete lack of activity of the erythromycine and dau-
nomycin antitumor agents when the carbohydrate part is
modified or removed.[6] Due to their wide occurrence and
biological activities, much effort has been focused on the
synthesis of naturally occurring glycosteroids.[7]
Results and Discussion
Synthesis of Glycosteroids
The most important part of this delivery system is the
steroid backbone. In humans, estradiol is one of the most
abundant estrogens, and is most associated with the repro-
ductive system. In the present study, an estradiol-inspired
steroid skeleton was selected as the initial target for glycos-
idation studies. In addition to the role of estrogens in hu-
man reproduction, several other biological roles have been
reported for these molecules,[10] ranging in location from
the lungs and brain to the bones.[11] Accordingly, estrogens
can be considered to be versatile transport molecules with
the possibility of enhancing the delivery of drugs to specific
[a] Laboratory of Organic Chemistry Åbo Akademi University,
20500 Åbo, Finland
Fax: +358-2-2154866
E-mail: reko.leino@abo.fi
[b] Department of Organic Chemistry, University of Szeged,
Dóm tér 8, 6720 Szeged, Hungary
Fax: +36-62-544200
E-mail: wolfling@chem.u-szeged.hu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001342.
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Estradiol-Based Glycosteroid Mimics
locations. To diminish or remove the apparent side effects hindered primary hydroxyl group, in contrast to the second-
caused by estradiol itself in such transport applications, ary hydroxyl groups in acceptors 2 and 3, and was accord-
modifications to the steroid backbone are desirable. It is ingly selected as the model substrate for initial glycosylation
widely known that the hydroxyl group at C-3 is important screening (Figure 1).
for the pharmacological activity of steroids.[12] Therefore,
this functionality should be permanently blocked. It should
also be mentioned that glycosylation of this hydroxyl group
cannot be considered as permanent protection because it is
normally cleaved under physiological conditions. The ste-
roid acceptors 1–3, used in the present study, were con-
structed from the common precursor 16,17-seco-3-methox-
yestra-1,3,5(10),16-tetraene-13α-carbaldehyde. This precur-
sor can be prepared from estrone 3-methyl ether in four
steps by using Grob fragmentation as the key transforma-
tion, as reported previously by Schneider et al.[13] Conve-
niently, this procedure allows protection of the hydroxyl
group at C-3 as a methyl ether in the early stages of the
Figure 1. Chemical structure of steroid acceptors 1–3.
synthesis. Steroid acceptor 1 was synthesized from this pre-
cursor by reduction with NaBH4 in ethanol in almost quan-
Several glycosyl donors have been investigated earlier for
titative yield.[14] Compounds 2 and 3 can be synthesized as glycosylation of steroids.[9] Because we have previously uti-
a separable mixture from the common precursor by either lized thio-donors for the preparation of β-1,2-linked oligo-
Grignard addition or by employing metal-mediated al- mannosides,[19] we therefore also selected these compounds
lylation.[15] Because together the ABC-rings form the rigid as a starting point for the present investigation. Given that
backbone of the steroid, we decided to focus on modifica- all the acceptors 1–3 contain alkene functionalities, the
tions of the D-ring instead. In several previous reports, commonly employed NIS/TfOH promoter system was not
large variations in the steroid D-ring have been found to be feasible for activation of the thio-donors.[20] Instead, we
tolerated with regards to retaining the biological activity.[16] turned to the BSP/TTBP/Tf2O activation protocol devel-
Consequently, we were interested in evaluating the effects of oped by Crich and co-workers,[21] and also utilized earlier
acyclic versus cyclic D-rings. Furthermore, D-ring glycos- in our laboratory, for activation of the glycosyl donors 4
ides, for example the shark-repelling pavoninins, have been and 5. In both cases, however, only moderate yields
shown to be active in several biological studies.[17] There- (ca. 50%) were observed. Furthermore, in glycosylation
fore, in the present study, the D-ring hydroxyl group in ste- with 5, the selectivity was fairly low (β/α, 4:1). In addition
roids 1–3 was subjected to modifications by glycosylation. to the moderate efficiency and poor selectivity obtained by
Moreover, modification by glycosylation should affect the applying this protocol, the major drawback of this ap-
solubility of the molecules and the overall selectivity of the proach is the need for a four-fold molar excess of the pro-
system. As mentioned previously, glycosylation of steroids moter over the substrate. Consequently, this led us to aban-
is demanding because of the low reactivity of secondary don thio-donors and to search for a different glycosylation
alcohols.[9a] Consequently, several earlier reported pro- strategy.
cedures on steroid glycosylation suffer from moderate
Another class of frequently utilized glycosyl donors are
yields.[18] In the present study, the methyl group (C-18) close based on imidates, commonly trichloracetimidates
to the glycosylation center further increases the steric hin- (TCA).[22] In several previous studies, acetylated TCA-do-
drance, thereby making highly selective and efficient glycos- nors have been used for the glycosylation of steroids.[9a] In
ylation reactions an even greater challenge. Of the steroid previous work by us, BF3·OEt2 was found to be the best
acceptors investigated here, compound 1 contains the least promoter for TCA-donors in glycosylation of cyclohex-
Figure 2. Chemical structure of carbohydrate donors 4–10.
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Table 1. A summary of the glycosylations and deprotections performed. Reaction conditions: (i) TMSOTf, donor, –20 °C, CH2Cl2; (ii)
NaOMe, MeOH/THF, 1:1.
[a] Isolated yields. [b] Because of purification difficulties, the deprotection was carried out on a mixture of product and starting material.
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Estradiol-Based Glycosteroid Mimics
anol.[19] With steroids sharing the lipophilic features of cyclo- acetylated acceptor (33%), and a mixture of partially dea-
hexanol, we initially screened this promoter in the glycos- cetylated glycosteroids (33%).[24] Similar results have been
ylation of 1 by using 6 as a donor. Unfortunately, in the reported previously with a cyclohexanol acceptor.[19] How-
case of 1, the use of BF3·OEt2 resulted in decomposition of ever, in that case, deprotection of the cyclohexyl glycoside
starting materials and failed to provide the target molecule. and the mixture of partially deacetylated cyclohexyl glyco-
We next turned to trimethylsilyl trifluoromethanesulfonate sides did not yield identical NMR spectra.
(TMSOTf), which was successfully used in glycosylation re-
To circumvent the problems outlined above, we decided
actions with imidate donors previously,[9,23] for screening to change from acetyl protecting groups to the slightly bulk-
glycosylations of 1 with 6. Under these conditions, with ier benzoyl groups, while at the same time retaining the ben-
TMSOTf as a promoter, the glycosylation gave a mixture eficial properties of neighboring group participation dis-
of three components, which were identified by NMR spec- played by ester groups at C-2. Under unoptimized reaction
troscopic analysis as the target compound (33% yield), the conditions with 0.2 equiv. of TMSOTf promoter at –20 °C
Table 2. A summary of the ring-closing reactions and deprotections. Reaction conditions: (i) Grubbs’ 2nd generation catalyst (10 mol-%),
reflux, 6 h, then room temp. overnight, CH2Cl2; (ii) NaOMe, MeOH/THF, 1:1.
[a] Isolated yields.
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in dichloromethane, the reaction between 1 and 7 proceeded heated to reflux in CH2Cl2 for six hours and allowed to
in 91% yield. Application of similar reaction conditions to stand overnight. These conditions proved to be successful
the sterically more demanding acceptor 3 did not result in and the products were isolated in up to 97% yields
any significant reduction in yield. In comparison to the acti- (Table 2).
vation strategy utilized with thio-donors (4 equiv. of pro-
For the manno- and rhamnosylated steroids, the yields
moters), this glycosylation protocol can be considered to be were nearly quantitative, however, for the gluco- and galac-
much more benign, while at the same time being more ef- tosteroids, yields were slightly lower (ca. 77%). The differ-
ficient. After this successful first reaction, donors 8–10 were ence in yields is possibly due to the equatorial benzoyl
prepared according to slightly modified literature pro- group at C-2 in the latter two substrates, which increases
cedures (Figure 2).[25] The glycosylation reactions were then the steric bulk near the reacting center. As a logical next
preformed by applying the same protocol; the results are step, we evaluated whether the RCM could be followed by
summarized in Table 1.
a subsequent glycosylation. Unfortunately, glycosylation of
Interestingly, use of donors 9 and 10 gave slightly lower the more sterically hindered ring-closed products decreased
yields than use of donors 7 and 8. This is most likely due the yield significantly and, thus, this approach was aban-
to the less intrusive arrangement of the substituents at C-1 doned in further studies. Furthermore, although RCM
and C-2 which, in the case of 7 and 8, are in an axial– could, in principal, be performed on the deprotected sub-
axial conformation. Furthermore, glycosylation of the more strates, due to the amphiphilicity and poor solubility of
sterically hindered acceptors 2 and 3 with 9 and 10 resulted these compounds in organic solvents this would require a
in a decreased yield, probably due to the equatorially substi- non-conventional metathesis catalyst instead of the com-
tuted C-2 position, which apparently adds an additional mercially available Grubbs catalysts. Deprotection of the
factor of steric hindrance. Bearing only ester protective ring-closed products proceeded smoothly under conditions
groups, the glycosteroids could easily be deprotected under described previously, thereby providing the glycosteroids 26,
Zemplén conditions with NaOMe in MeOH/THF.[26] Tetra- 28, 30, and 32.
hydrofuran was required as co-solvent because the mole-
Glycosteroids commonly give rise to very complex NMR
cules are lipophilic in the protected state. All deprotection spectra and, accordingly, only a few reports on complete
reactions proceeded in good yields (77–99%). Because the spectroscopic characterization of this class of compound
final products are amphiphilic (Rf values 0.4–0.7 in MeOH/ exist. In addition to providing reference data, accurate
CH2Cl2, 1:5), they were also amenable to purification by NMR spectroscopic characterization often provides valu-
column chromatography, thus enabling a simple method for able structural information. For these reasons, the complete
removing the methyl benzoate formed during the final de- characterization of the glycosteroids prepared here by
protection step.
NMR spectroscopy is discussed in detail.
With the glycosteroids 13, 17, 20, and 23, each possessing
two terminal double bonds, in hand, we next investigated
their application in ring-closing olefin metathesis
(RCM).[27] RCM is an excellent method for creating me-
dium-sized rings, as exemplified by the large number of pa-
Characterization by NMR Spectroscopy
A discussion of the NMR spectral features of the synthe-
pers dealing with this subject.[28] Because the reaction pro- sized glycosteroids will be exemplified here by the charac-
duces two molecules (substrate and ethylene) from one, and terization of glycosteroid 21. Spectral characterization of all
is driven by an increase in entropy, we performed the initial the other compounds was performed similarly. The well-
reactions at room temperature using Grubbs 2nd generation resolved H NMR signal from H-1 in 21 (d, δ = 7.17 ppm)
1
catalyst. However, at this temperature the reaction failed to was selected as a starting point for the characterization
yield the desired product and, therefore, the mixture was (Figure 3).
Figure 3. Spectral simulation of the 1H NMR spectrum of 21 using PERCH NMR software; (top) simulated spectrum; (bottom) observed
spectrum.
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Estradiol-Based Glycosteroid Mimics
From this signal, HMBC correlations to C-3 (δ = NMR spectrum of 21 is shown in Figure 3.[30] Standard
140.2 ppm), C-5 (δ = 139.0 ppm), and C-9 (δ = 44.2 ppm) NMR spectroscopic techniques (1H, 13C, 1D-TOCSY,
were clearly visible. The H-2 (dd at δ = 6.65 ppm) proton COSY, HSQC, HMBC, and NOESY), in combination with
was easily identified by COSY, and H-4 (d, δ = 6.57 ppm) the simulation software, thus enabled complete assignation
was located in a similar fashion. The corresponding carbon of all the glycosteroids synthesized in this study. Such an
and proton atoms were identified from the HSQC spec- approach should also be applicable to the characterization
trum. By use of HMBC, the entire A-ring was solved and of other types of molecules.
attention shifted to the signals arising from the B-ring. A
correlation between H-4 and C-6 was observed from the
Conclusions
HMBC spectra. The H-6 protons (δ = 2.78 and 2.77 ppm)
were subsequently identified from HSQC analysis with cor-
relations between H-6 and H-7 clearly visible in the COSY
spectrum. The correlation between H-6 and C-8 was ob-
tained from HMBC, which enabled the identification of all
signals from the B-ring. For elucidating the C-ring structure
and the remaining parts of the molecule, the signal from
the methyl group at C-18 (s, δ = 0.87 ppm) was selected as
a starting point. Correlations between H-18 and C-12 (δ =
33.2 ppm), C-14 (δ = 43.3 ppm), and C-1Ј (δ = 86.0 ppm)
were observed in the HMBC spectrum. By use of HSQC,
COSY, and HMBC the entire steroid skeleton could be as-
signed. The position of the sugar moiety was verified by
HMBC correlation between the anomeric proton (d, δ =
4.41 ppm) and C-1Ј. Assignment of the steroid dia-
stereomers 2 and 3, prepared by allylation of the corre-
sponding aldehyde and discussed in detail elsewhere by
us,[15c] proved extremely difficult after the allylation reac-
tion. Both compounds 2 and 3 display NOESY correlations
between H-1Ј and H-18, probably due to the rotational free-
dom of the allyl group. Likewise, significant differences in
the NOESY spectra were not observed even after the glycos-
ylation reaction. Fortunately, the benzoylated ring-closed
products 25, 27, 29, and 31 displayed significant differences
in their NOESY spectra, which allowed the stereochemical
assignment of these four compounds; this was applied fur-
ther in the stereochemical assignment of their precursors
13, 17, 20, and 23, and finally to compounds 2 and 3. In
We have here investigated a range of strategies for the
glycosylation of steroids. Of the methods assessed, the use
of benzoylated TCA-donors proved to be superior. These
donors were applied to the synthesis of a small library of
glycosteroids containing three types of variations in the
steroid backbone, and four types of variations in the carbo-
hydrate moiety. The aim of the study was to synthesize am-
phiphilic steroids that are capable of drug transport in bio-
logical systems. The overall specificity of such transport
molecules should be connected to the structural features of
both the steroid part and the carbohydrate moiety. A poten-
tial benefit with the set of compounds prepared here are the
multiple sites available for active component attachment. In
more detail, drug candidates could be either connected to
the free hydroxyl groups of the carbohydrate or linked to
the alkene functionalities of the steroid. Furthermore, it
may prove interesting to compare the steroids containing
cyclic versus acyclic D-rings and the influence of the carbo-
hydrate moieties. Such results should provide valuable infor-
mation on the structural elements required in these trans-
port systems. The elementary structures synthesized in this
paper will, in future work, be modified with drug-like mole-
cules for biological screening.
Experimental Section
the NOESY spectrum of the protected galactosteroid 31, a General Remarks: Reaction solvents were dried and distilled prior
to use when necessary. All reactions containing moisture- or air-
sensitive reagents were carried out under an argon atmosphere.
NMR spectra were recorded with a Bruker Avance spectrometer
operating at 600.13 MHz (1H: 600.13 MHz, 13C: 150.90 MHz); the
probe temperature during the experiments was kept at 25 °C. All
strong correlation between H-18 and H-17b was observed,
indicating that these two protons are located on the same
side of the ring system.
The corresponding correlation was absent in the NOESY
spectra of 25, 27, and 29, which supports the diastereomeric
assignment proposed here. In the deprotected glycosteroids,
spectral correlations were observed for all compounds,
however they were strongest in the case of the galactos-
teroid 32; this is considered here as final proof for the
1
products were fully characterized by use of 1D H and 13C NMR
spectroscopy in combination with DQF-COSY, NOESY, HSQC
and HMBC 2D NMR techniques with pulse sequences provided
by the instrument manufacturer. Chemical shifts are expressed on
the δ scale (in ppm) using TMS (tetramethylsilane), residual chloro-
stereochemical assignment. Whereas such fundamental NMR form, acetone, HOD or methanol as internal standards. Coupling
constants are given in Hz and provided only once when first en-
countered. Coupling patterns are given as: s = singlet, d = doublet,
t = triplet etc. The following indexes are used to clarify between
protons on the same carbon: eq = equatorial, ax = axial, t = trans
and c = cis. The computational analysis of the 1H NMR spectra
of all compounds was performed by the use of PERCH NMR soft-
ware with starting values and spectral parameters obtained from
the various NMR techniques used. Figure 4 indicates the number-
ing system used. HRMS were recorded with a Bruker Micro Q-
TOF with ESI (electrospray ionization) operated in the positive
spectroscopic characterization and signal assignments can
be considered straightforward, determination of the cou-
pling constants in these systems is extremely difficult. This
is mainly due to the severe overlap of signals in the steroid
region. We have, in previous work, described the complete
assignation of a β-1,2-linked mannotetraose by use of the
NMR simulation software PERCH.[29] In the present work
this program was again utilized to completely assign the
proton spectra of the compounds prepared; an example of
the calculated and observed high-field region of the 1H mode. Optical rotations were measured at 23 °C with a Perkin–
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Elmer 241 polarimeter equipped with an Na-lamp (589 nm). TLC
was performed on aluminum sheets precoated with silica gel 60
F254 (Merck). Flash chromatography was carried out with silica gel
60 (0.040–0.060 mm, Merck). Spots were visualized by UV irradia-
tion, followed by charring with H2SO4/MeOH (1:10) and heating.
2ЈЈ-H), 5.10 (dddd, J17t,17c = –1.4, J17t,15b = –1.6, J17t,15a = –1.9 Hz,
1 H, 17t-H), 5.09 (d, 1 H, 1Ј-H), 5.02 (dddd, J17c,15a = –1.6, J17c,15b
= –1.9 Hz, 1 H, 17c-H), 4.71 (dd, J6ЈЈa,5ЈЈ = 2.6, J6ЈЈa,6ЈЈb = –12.2 Hz,
1 H, 6ЈЈa-H), 4.50 (dd, J6ЈЈb,5ЈЈ = 5.0 Hz, 1 H, 6ЈЈb-H), 4.44 (ddd,
1 H, 5ЈЈ-H), 3.78 (s, 3 H, 3-OCH3), 3.76 and 3.25 (each d, J =
–9.4 Hz, each 1 H, 1Ј-H), 2.87 (ddd, J6a,7eq = 2.7, J6a,7ax = 5.5,
J6a,6b = –13.6 Hz, 1 H, 6a-H), 2.85 (ddd, J6b,7eq = 5.8, J6b,7ax
12.4 Hz, 1 H, 6b-H), 2.36 (ddd, J9,11eq = 3.4, J9,8 = 10.4, J9,11ax
=
=
12.2 Hz, 1 H, 9-H), 2.35 (dddd, J11eq,12eq = 2.9, J11eq,12ax = 3.8,
J11eq,11ax = –12.7 Hz, 1 H, 11eq-H), 2.32 (ddddd, J15a,14 = 3.0,
J15a,15b = –16.6 Hz, 1 H, 15a-H), 2.16 (dddd, J7eq,8 = 2.5, J7eq,7ax
= –12.8 Hz, 1 H, 7-Heq), 2.08 (ddddd, J15b,14 = 5.6 Hz, 1 H, 15b-
H), 1.81 (ddd, J12ax,12eq = –12.8, J12ax,11ax = 13.9 Hz, 1 H, 12-Hax),
1.76 (ddd, J12eq,11ax = 3.3 Hz, 1 H, 12-Heq), 1.53 (ddd, J14,8
11.1 Hz, 1 H, 14-H), 1.46 (dddd, 1 H, 11-Hax), 1.43 (dddd, J8,7ax
=
=
11.9 Hz, 1 H, 8-H), 1.38 (dddd, 1 H, 7-Hax), 0.91 (s, 3 H, 18-
H) ppm. 13C NMR (150.9 MHz, CDCl3): δ = 166.1 (6ЈЈ-OCOPh),
165.5 (3ЈЈ-OCOPh, 4ЈЈ-OCOPh, 2ЈЈ-OCOPh), 157.5 (C-3), 140.0
(C-16), 137.9 (C-5), 133.5–128.3 (arom. C), 132.7 (C-10), 126.6 (C-
1), 114.5 (C-17), 113.4 (C-4), 111.7 (C-2), 98.4 (C-1ЈЈ), 77.4 (C-1Ј),
70.5 (C-2ЈЈ), 70.2 (C-3ЈЈ), 69.0 (C-5ЈЈ), 67.0 (C-4ЈЈ), 63.0 (C-6ЈЈ),
55.2 (3-OCH3), 44.6 (C-14), 43.3 (C-9), 41.6 (C-8), 38.2 (C-13), 36.6
(C-12), 32.7 (C-15), 30.6 (C-6), 27.5 (C-7), 26.4 (C-11), 16.2 (C-
18) ppm. HRMS: calcd. for C54H54O11Na [M + Na]+ 901.3564;
found 901.3546.
Figure 4. Numbering of the steroid backbones.
General Procedure for Glycosylation: To a solution containing the
corresponding acceptor (1 equiv.) and pre-activated 4 Å MS in an-
hydrous CH2Cl2 (1.6 mL/0.1 mmol substrate), was added TMSOTf
(0.2 equiv.) at –20 °C. The reaction mixture was stirred for 10 min,
then the corresponding donor (1.4 equiv.) dissolved in anhydrous
CH2Cl2 (1.7 mL/0.1 mmol substrate) was added dropwise. The re-
sulting mixture was stirred for 1.5–2 h, brought to room temp.,
diluted with CH2Cl2 (20 mL) and washed with sat. NaHCO3 solu-
tion (20 mL). The organic phase was dried with Na2SO4, filtered
and concentrated. The crude product was purified by column
chromatography (hexane/EtOAc, 4:1) to give the corresponding
glycosteroid.
13,17-seco-3-Methoxy-13α-methyl-1Ј-(α-D-mannopyranosyloxy)-
estra-1,3,5(10),16-tetraene (12): Synthesized from 11 (128 mg,
0.145 mmol) according to the general procedure for deprotection,
providing 12 as a white solid (60 mg, 90%). Rf = 0.48 (MeOH/
CH2Cl2, 1:5). [α]D = +115.6 (c = 0.1, MeOH). 1 H NMR
(600.13 MHz, CD3OD): δ = 7.17 (d, J1,2 = 8.6 Hz, 1 H, 1-H), 6.66
(dd, J2,4 = 2.7 Hz, 1 H, 2-H), 6.58 (d, 1 H, 4-H), 5.90 (dddd, J16,15a
= 6.1, J16,15b = 7.1, J16,17c = 10.2, J16,17t = 17.1 Hz, 1 H, 16-H),
5.04 (dddd, J17t,17c = –1.5, J17t,15b = –1.7, J17t,15a = –2.1 Hz, 1 H,
17t-H), 4.94 (dddd, J17c,15b = –1.6, J17c,15a = –1.7 Hz, 1 H, 17c-H),
4.72 (d, J1ЈЈ,2ЈЈ = 1.7 Hz, 1 H, 1ЈЈ-H), 3.84 (dd, J2ЈЈ,3ЈЈ = 3.3 Hz, 1
H, 2ЈЈ-H), 3.82 (dd, J6ЈЈa,5ЈЈ = 2.4, J6ЈЈa,6ЈЈb = –11.6 Hz, 1 H, 6ЈЈa-
H), 3.73 (s, 3 H, 3-OCH3), 3.72 (dd, J6ЈЈb,5ЈЈ = 5.5 Hz, 1 H, 6ЈЈb-
H), 3.71 (dd, J3ЈЈ,4ЈЈ = 9.4 Hz, 1 H, 3ЈЈ-H), 3.71 and 3.11 (each d,
J = –9.5 Hz, each 1 H, 1Ј-H), 3.63 (dd, J4ЈЈ,5ЈЈ = 9.9 Hz, 1 H, 4ЈЈ-
H), 3.57 (ddd, 1 H, 5ЈЈ-H), 2.80 (ddd, J6a,7eq = 2.3, J6a,7ax = 6.3,
General Procedure for Deprotection: To a solution containing the
protected glycosteroid (1 equiv.) in anhydrous MeOH or anhydrous
MeOH/THF mixture (2:1) (6.3 mL/0.1 mmol substrate) was added
NaOMe (2 equiv.) and the resulting mixture was stirred for 3–20 h
at room temp., neutralized with DOWEX 50 H+-form, filtered and
concentrated. The crude product was purified by column
chromatography (CH2Cl2 ǞCH2Cl2/MeOH, 5:1 for all compounds
except for 16, 18, 28, which were purified with EtOAc) to give the
deprotected glycosteroid.
J6a,6b = –12.2 Hz, 1 H, 6a-H), 2.79 (ddd, J6b,7eq = 5.9, J6b,7ax
11.5 Hz, 1 H, 6b-H), 2.39 (ddddd, J15a,14 = 3.2, J15a,15b = –16.2 Hz,
1 H, 15a-H), 2.28 (dddd, J11eq,12eq = 3.0, J11eq,9 = 3.6, J11eq,12ax
3.9, J11eq,11ax = –13.1 Hz, 1 H, 11-Heq), 2.24 (ddd, J9,8 = 10.6,
J9,11ax = 12.1 Hz, 1 H, 9-H), 2.19 (dddd, J7eq,8 = 2.5, J7eq,7ax
=
=
General Procedure for Ring-Closing Metathesis: To a solution con-
taining the corresponding glycosteroid (1 equiv.) in anhydrous
CH2Cl2 (1.7 mL/0.1 mmol substrate) was added Grubbs 2nd gener-
ation catalyst (10 mol-%) and the resulting mixture was heated to
reflux for 6 h at 40 °C, brought to room temp., stirred overnight,
and concentrated. The crude product was purified by column
chromatography (hexane/EtOAc, 4:1) to give the corresponding
ring-closed glycosteroid.
=
–13.1 Hz, 1 H, 7-Heq), 2.08 (ddddd, J15b,14 = 5.4 Hz, 1 H, 15b-H),
1.73 (ddd, J12ax,12eq = –13.2, J12ax,11ax = 13.9 Hz, 1 H, 12-Hax), 1.62
(ddd, J12eq,11ax = 3.4 Hz, 1 H, 12-Heq), 1.47 (ddd, J14,8 = 11.2 Hz,
1 H, 14-H), 1.38 (dddd, J8,7ax = 11.6 Hz, 1 H, 8-H), 1.37 (dddd, 1
H, 11-Hax), 1.25 (dddd, 1 H, 7-Hax), 0.88 (s, 3 H, 18-H) ppm. 13C
NMR (150.9 MHz, CD3OD): δ = 158.9 (C-3), 141.4 (C-16), 138.9
(C-5), 133.8 (C-10), 127.4 (C-1), 114.9 (C-17), 114.2 (C-4), 112.6
(C-2), 102.5 (C-1ЈЈ), 78.0 (C-1Ј), 74.7 (C-5ЈЈ), 72.8 (C-3ЈЈ), 72.2 (C-
2ЈЈ), 68.5 (C-4ЈЈ), 62.9 (C-6ЈЈ), 55.5 (3-OCH3), 46.4 (C-14), 45.0 (C-
9), 43.0 (C-8), 39.3 (C-13), 37.9 (C-12), 33.9 (C-15), 31.5 (C-6), 28.9
(C-7), 27.7 (C-11), 17.0 (C-18) ppm. HRMS: calcd. for
C26H38O7Na [M + Na]+ 485.2503; found 485.2503. Calcd. for
C26H42O7N [M + NH4]+ 480.2961; found 480.2952.
13,17-seco-3-Methoxy-13α-methyl-1Ј-(2ЈЈ,3ЈЈ,4ЈЈ,6ЈЈ-tetra-O-benz-
oyl-α-D-mannopyranosyloxy)estra-1,3,5(10),16-tetraene (11): Syn-
thesized from 1 (51 mg, 0.17 mmol) and 7 (176 mg, 0.24 mmol) ac-
cording to the general procedure for glycosylation, providing 11 as
a white foam (135 mg, 91%). Rf = 0.65 (hexane/EtOAc, 1:1). [α]D
= –11.3 (c = 0.3, CHCl3). 1H NMR (600.13 MHz, CDCl3): δ =
8.12–7.25 (m, 20 H, arom. H), 7.26 (d, J1,2 = 8.6 Hz, 1 H, 1-H),
6.75 (dd, J2,4 = 2.8 Hz, 1 H, 2-H), 6.64 (d, 1 H, 4-H), 6.08 (dd,
(1ЈS)-13,17-seco-13α-[But-3Ј-en-1Ј-(2ЈЈ,3ЈЈ,4ЈЈ,6ЈЈ-tetra-O-benzoyl-
J4ЈЈ,3ЈЈ = 10.1, J4ЈЈ,5ЈЈ = 10.2 Hz, 1 H, 4ЈЈ-H), 5.93 (dddd, J16,15a
=
α-D-mannopyranosyloxy)-1Ј-yl]-3-methoxyestra-1,3,5(10),16-
6.2, J16,15b = 6.4, J16,17c = 10.3, J16,17t = 17.2 Hz, 1 H, 16-H), 5.92 tetraene (13): Synthesized from 3 (87 mg, 0.255 mmol) and 7
(dd, J3ЈЈ,2ЈЈ = 3.4 Hz, 1 H, 3ЈЈ-H), 5.77 (dd, J2ЈЈ,1ЈЈ = 1.8 Hz, 1 H, (265 mg, 0.358 mmol) according to the general procedure for glyco-
1070
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Eur. J. Org. Chem. 2011, 1064–1077

Estradiol-Based Glycosteroid Mimics
sylation, providing 13 as a white foam (211 mg, 90%). Rf = 0.83
15b-H), 1.77 (ddd, J12ax,12eq = –13.2, J12ax,11ax = 13.8 Hz, 1 H, 12-
(hexane/EtOAc, 1:1). [α]D = –19.1 (c = 0.5, CHCl3). 1H NMR Hax), 1.72 (ddd, J14,8 = 10.9 Hz, 1 H, 14-H), 1.51 (ddd, J12eq,11ax
=
(600.13 MHz, CDCl3): δ = 8.10–7.25 (m, 20 H, arom. H), 7.26 (d,
J1,2 = 8.6 Hz, 1 H, 1-H), 6.75 (dd, J2,4 = 2.7 Hz, 1 H, 2-H), 6.63
(d, 1 H, 4-H), 6.18 (dd, J4ЈЈ,5ЈЈ = 10.0, J4ЈЈ,3ЈЈ = 10.2 Hz, 1 H, 4ЈЈ-
3.1 Hz, 1 H, 12-Heq), 1.40 (dddd, J8,7ax = 11.4 Hz, 1 H, 8-H), 1.32
(dddd, 1 H, 11-Hax), 1.25 (dddd, 1 H, 7ax), 0.93 (s, 3 H, 18-H) ppm.
13C NMR (150.9 MHz, CD3OD): δ = 158.9 (C-3), 141.3 (C-16),
139.0 (C-5), 138.7 (C-3Ј), 133.7 (C-10), 127.4 (C-1), 117.3 (C-4Ј),
115.1 (C-17), 114.2 (C-4), 112.6 (C-2), 102.8 (C-1ЈЈ), 87.5 (C-1Ј),
75.2 (C-5ЈЈ), 72.7 (C-2ЈЈ, C-3ЈЈ), 68.1 (C-4ЈЈ), 62.5 (C-6Ј), 55.5 (3-
OCH3), 44.7 (C-9), 44.5 (C-14), 43.2 (C-13), 43.1 (C-8), 37.0 (C-
15), 34.8 (C-12), 34.4 (C-2Ј), 31.5 (C-6), 28.9 (C-7), 27.6 (C-11),
19.2 (C-18) ppm. HRMS: calcd. for C29H42O7Na [M + Na]+
525.2828; found 525.2813. Calcd. for C29H46O7N [M + NH4]+
520.3274; found 520.3272.
H), 6.01 (dddd, J16,15a = 6.4, J16,15b = 6.9, J16,17c = 10.2, J16,17t
17.1 Hz, 1 H, 16-H), 5.99 (dddd, J3Ј,2Јa = 5.7, J3Ј,2Јb = 8.4, J3Ј,4Јc
=
=
10.1, J3Ј,4Јt = 17.0 Hz, 1 H, 3Ј-H), 5.92 (dd, J3ЈЈ,2ЈЈ = 3.1 Hz, 1 H,
3ЈЈ-H), 5.81 (dd, J2ЈЈ,1ЈЈ = 1.9 Hz, 1 H, 2ЈЈ-H), 5.27 (dddd, J4Јt,2Јb
=
–1.1, J4Јt,2Јa = –1.4, J4Јt,4Јc = –1.8 Hz, 1 H, 4Јt-H), 5.22 (d, 1 H, 1ЈЈ-
H), 5.16 (dddd, J17t,17c = –1.4, J17t,15b = –1.6, J17t,15a = –2.1 Hz, 1
H, 17t-H), 5.14 (dddd, J4Јc,2Јb = –0.7, J4Јc,2Јa = –1.3 Hz, 1 H, 4Јc-
H), 5.02 (dddd, J17c,15b = –1.2, J17c,15a = –2.1 Hz, 1 H, 17c-H), 4.72
(dd, J6ЈЈa,5ЈЈ = 2.5, J6ЈЈa,6ЈЈb = –12.1 Hz, 1 H, 6ЈЈa-H), 4.55 (ddd,
J5ЈЈ,6ЈЈb = 3.6 Hz, 1 H, 5ЈЈ-H), 4.44 (dd, 1 H, 6ЈЈb-H), 3.81 (dd,
J1Ј,2Јa = 2.5, J1Ј,2Јb = 8.2 Hz, 1 H, 1Ј-H), 3.79 (s, 3 H, 3-OCH3),
2.85 (ddd, J6a,7eq = 2.3, J6a,7ax = 7.4, J6a,6b = –12.3 Hz, 1 H, 6a-H),
2.85 (ddd, J6b,7eq = 5.4, J6b,7ax = 9.6 Hz, 1 H, 6b-H), 2.59 (ddddd,
J15a,14 = 2.8, J15a,15b = –16.4 Hz, 1 H, 15a-H), 2.55 (ddddd, J2Јa,2Јb
= –15.0 Hz, 1 H, 2Јa-H), 2.45 (ddddd, 1 H, 2Јb-H), 2.36 (dddd,
J11eq,9 = 3.3, J11eq,12ax = 3.3, J11eq,12eq = 4.7, J11eq,11ax = –13.0 Hz,
1 H, 11-Heq), 2.32 (ddd, J9,8 = 10.7, J9,11ax = 12.3 Hz, 1 H, 9-H),
2.27 (ddddd, J15b,14 = 4.3 Hz, 1 H, 15b-H), 2.25 (dddd, J7eq,8 = 2.1,
J7eq,7ax = –12.9 Hz, 1 H, 7-Heq), 1.86 (ddd, J12ax,12eq = –11.4,
J12ax,11ax = 13.9 Hz, 1 H, 12-Hax), 1.77 (ddd, J12eq,11ax = 3.3 Hz, 1
H, 12-Heq), 1.61 (ddd, J14,8 = 12.5 Hz, 1 H, 14-H), 1.51 (dddd,
J8,7ax = 11.1 Hz, 1 H, 8-H), 1.43 (dddd, 1 H, 11-Hax), 1.34 (dddd,
1 H, 7ax), 0.99 (s, 3 H, 18-H) ppm. 13C NMR (150.9 MHz, CDCl3):
δ = 166.1 (6ЈЈ-OCOPh), 165.5 (3ЈЈ-OCOPh, 4ЈЈ-OCOPh), 165.3
(2ЈЈ-OCOPh), 157.5 (C-3), 139.2 (C-16), 138.0 (C-5), 136.3 (C-3Ј),
133.4–128.3 (arom. C), 132.5 (C-10), 126.6 (C-1), 118.2 (C-4Ј),
115.3 (C-17), 113.4 (C-4), 111.7 (C-2), 98.7 (C-1ЈЈ), 87.7 (C-1Ј), 71.0
(C-2ЈЈ), 70.1 (C-3ЈЈ), 69.9 (C-5ЈЈ), 66.8 (C-4ЈЈ), 62.7 (C-6Ј), 55.2 (3-
OCH3), 43.6 (C-14), 43.4 (C-9), 42.1 (C-13), 41.3 (C-8), 35.6 (C-
2Ј), 33.6 (C-12), 33.0 (C-15), 30.5 (C-6), 27.7 (C-7), 26.3 (C-11),
18.5 (C-18) ppm. HRMS: calcd. for C57H58O11Na [M + Na]+
941.3877; found 941.3864.
13,17-seco-3-Methoxy-13α-methyl-1Ј-(2ЈЈ,3ЈЈ,4ЈЈ-tri-O-benzoyl-α-L-
rhamnopyranosyloxy)estra-1,3,5(10),16-tetraene (15): Synthesized
from 1 (72 mg, 0.24 mmol) and 8 (208 mg, 0.34 mmol) according
to the general procedure for glycosylation, providing 15 as a white
foam (168 mg, 92%). Rf = 0.75 (hexane/EtOAc, 1:1). [α]D = +96.7
1
(c = 0.12, CHCl3). H NMR (600.13 MHz, CDCl3): δ = 8.13–7.23
(m, 15 H, arom. H), 7.26 (d, J1,2 = 8.5 Hz, 1 H, 1-H), 6.74 (dd, J2,4
= 2.8 Hz, 1 H, 2-H), 6.65 (d, 1 H, 4-H), 5.94 (dddd, J16,15a = 6.3,
J16,15b = 6.9, J16,17c = 10.1, J16,17t = 17.1 Hz, 1 H, 16-H), 5.85 (dd,
J3ЈЈ,2ЈЈ = 3.5, J3ЈЈ,4ЈЈ = 10.1 Hz, 1 H, 3ЈЈ-H), 5.70 (dd, J2ЈЈ,1ЈЈ = 1.8 Hz,
1 H, 2ЈЈ-H), 5.70 (dd, J4ЈЈ,5ЈЈ = 9.7 Hz, 1 H, 4ЈЈ-H), 5.08 (dddd,
J17t,17c = –1.6, J17t,15a = –1.7, J17t,15b = –1.8 Hz, 1 H, 17t-H), 5.00
(dddd, J17c,15a = –1.5, J17c,15b = –1.5 Hz, 1 H, 17c-H), 4.97 (d, 1 H,
1ЈЈ-H), 4.20 (dq, J5ЈЈ,6ЈЈ = 6.3 Hz, 1 H, 5ЈЈ-H), 3.78 (s, 3 H, 3-
OCH3), 3.56 and 3.41 (each d, J = –9.5 Hz, each 1 H, 1Ј-H), 2.88
(ddd, J6a,7eq = 2.5, J6a,7ax = 5.0, J6a,6b = –17.3 Hz, 1 H, 6a-H), 2.86
(ddd, J6b,7eq = 5.9, J6b,7ax = 13.0 Hz, 1 H, 6b-H), 2.41 (ddd, J9,11eq
= 4.2, J9,11ax = 11.6, J9,8 = 11.9 Hz, 1 H, 9-H), 2.36 (dddd, J11eq,12eq
= 3.1, J11eq,12ax = 3.7, J11eq,11ax = –12.9 Hz, 1 H, 11-Heq), 2.31
(ddddd, J15b,14 = 3.7, J15b,15a = –15.6 Hz, 1 H, 15b-H), 2.19 (dddd,
J7eq,8 = 3.6, J7eq,7ax = –14.4 Hz, 1 H, 7-Heq), 2.12 (ddddd, J15a,14
4.6 Hz, 1 H, 15a-H), 1.90 (ddd, J12ax,12eq = –13.1, J12ax,11ax
=
=
13.7 Hz, 1 H, 12-Hax), 1.70 (ddd, J12eq,11ax = 3.3 Hz, 1 H, 12-Heq),
1.62 (ddd, J14,8 = 11.0 Hz, 1 H, 14-H), 1.49 (dddd, 1 H, 11-Hax),
1.44 (dddd, J8,7ax = 12.6 Hz, 1 H, 8-H), 1.42 (dddd, 1 H, 7-Hax),
1.40 (d, 3 H, 6ЈЈ-H), 0.92 (s, 3 H, 18-H) ppm. 13 C NMR
(150.9 MHz, CDCl3): δ = 165.8 (4ЈЈ-OCOPh), 165.5 (2ЈЈ-OCOPh,
3ЈЈ-OCOPh), 157.5 (C-3), 140.0 (C-16), 138.0 (C-5), 133.4–128.3
(arom. C), 132.9 (C-10), 126.4 (C-1), 114.4 (C-17), 113.4 (C-4),
111.6 (C-2), 98.1 (C-1ЈЈ), 76.8 (C-1Ј), 71.9 (C-4ЈЈ), 70.8 (C-2ЈЈ), 70.2
(C-3ЈЈ), 66.8 (C-5ЈЈ), 55.2 (3-OCH3), 44.5 (C-14), 43.3 (C-9), 41.4
(C-8), 38.3 (C-13), 36.5 (C-12), 32.8 (C-15), 30.5 (C-6), 27.5 (C-
7), 26.3 (C-11), 17.7 (C-6ЈЈ), 16.6 (C-18) ppm. HRMS: calcd. for
C47H50O9Na [M + Na]+ 781.3352; found 781.3336. Calcd. for
C47H54O9N [M + NH4]+ 776.3799; found 776.3777.
(1ЈS)-13,17-seco-13α-[But-3Ј-en-1Ј-(α-D-mannopyranosyloxy)-1Ј-yl]-
3-methoxyestra-1,3,5(10),16-tetraene (14): Synthesized from 13
(59 mg, 0.064 mmol) according to the general procedure for depro-
tection, providing 14 as a white solid (33 mg, quant.). Rf = 0.52
(MeOH/CH2Cl2, 1:5). [α]D = +71.5 (c = 0.2, MeOH). 1H NMR
(600.13 MHz, CD3OD): δ = 7.16 (d, J1,2 = 8.6 Hz, 1 H, 1-H), 6.65
(dd, J2,4 = 2.7 Hz, 1 H, 2-H), 6.58 (d, 1 H, 4-H), 6.02 (dddd, J16,15a
= 6.3, J16,15b = 7.3, J16,17c = 10.2, J16,17t = 17.1 Hz, 1 H, 16-H),
5.95 (dddd, J3Ј,2Јa = 5.7, J3Ј,2Јb = 8.3, J3Ј,4Јc = 10.2, J3Ј,4Јt = 17.1 Hz,
1 H, 3Ј-H), 5.14 (dddd, J4Јt,2Јa = –1.3, J4Јt,2Јb = –1.5, J4Јt,4Јc
–1.6 Hz, 1 H, 4Јt-H), 5.08 (dddd, J4Јc,2Јb = –0.2, J4Јc,2Јa = –1.9 Hz,
1 H, 4Јc-H), 5.05 (dddd, J17t,17c = –1.4, J17t,15b = –1.6, J17t,15a
–2.1 Hz, 1 H, 17t-H), 4.95 (dddd, J17c,15b = –1.4, J17c,15a = –1.9 Hz,
=
=
13,17-seco-3-Methoxy-13α-methyl-1Ј-(α-
L-rhamnopyranosyloxy)-
estra-1,3,5(10),16-tetraene (16): Synthesized from 15 (164 mg,
1 H, 17c-H), 4.89 (d, J1ЈЈ,2ЈЈ = 1.9 Hz, 1 H, 1ЈЈ-H), 3.93 (dd, J2ЈЈ,3ЈЈ 0.216 mmol) according to the general procedure for deprotection,
= 3.3 Hz, 1 H, 2ЈЈ-H), 3.78 (dd, J6ЈЈb,5ЈЈ = 4.2, J6ЈЈb,6ЈЈa = –14.0 Hz, providing 16 as a white solid (85 mg, 88%). Rf = 0.21 (EtOAc).
1
1 H, 6ЈЈb-H), 3.77 (dd, J6ЈЈa,5ЈЈ = 2.2 Hz, 1 H, 6ЈЈa-H), 3.74 (dd,
J4ЈЈ,5ЈЈ = 9.7, J4ЈЈ,3ЈЈ = 9.9 Hz, 1 H, 4ЈЈ-H), 3.72 (s, 3 H, 3-OCH3),
[α]D = +13.8 (c = 0.10, CHCl3). H NMR (600.13 MHz, CDCl3):
δ = 7.18 (d, J1,2 = 8.7 Hz, 1 H, 1-H), 6.70 (dd, J2,4 = 2.7 Hz, 1 H,
3.72 (dd, J1Ј,2Јa = 2.0, J1Ј,2Јb = 7.9 Hz, 1 H, 1Ј-H), 3.71 (dd, 1 H, 2-H), 6.60 (d, 1 H, 4-H), 5.82 (dddd, J16,15b = 6.5, J16,15a = 6.7,
3ЈЈ-H), 3.71 (ddd, 1 H, 5ЈЈ-H), 2.78 (ddd, J6a,7eq = 1.9, J6a,7ax = 6.2, J16,17c = 10.2, J16,17t = 17.1 Hz, 1 H, 16-H), 4.99 (dddd, J17t,17c
J6a,6b = –12.3 Hz, 1 H, 6a-H), 2.78 (ddd, J6b,7eq = 6.2, J6b,7ax –1.5, J17t,15b = –1.5, J17t,15a = –2.0 Hz, 1 H, 17t-H), 4.93 (dddd,
J17c,15b = –1.2, J17c,15a = –1.9 Hz, 1 H, 17c-H), 4.70 (d, J1ЈЈ,2ЈЈ
1.6 Hz, 1 H, 1ЈЈ-H), 3.94 (dd, J2ЈЈ,3ЈЈ = 3.3 Hz, 1 H, 2ЈЈ-H), 3.79
=
=
11.5 Hz, 1 H, 6b-H), 2.57 (ddddd, J15a,14 = 3.7, J15a,15b = –16.0 Hz,
1 H, 15a-H), 2.55 (ddddd, J2Јa,2Јb = –14.8 Hz, 1 H, 2Јa-H), 2.27
=
(ddddd, 1 H, 2Јb-H), 2.27 (dddd, J11eq,12eq = 3.1, J11eq,9 = 3.7, (dd, J3ЈЈ,4ЈЈ = 9.3 Hz, 1 H, 3ЈЈ-H), 3.76 (s, 3 H, 3-OCH3), 3.66 (dq,
J11eq,12ax = 3.9, J11eq,11ax = –13.2 Hz, 1 H, 11-Heq), 2.24 (dddd, J5ЈЈ,6ЈЈ = 6.2, J5ЈЈ,4ЈЈ = 9.4 Hz, 1 H, 5ЈЈ-H), 3.51 (dd, 1 H, 4ЈЈ-H),
J7eq,8 = 2.4, J7eq,7ax = –12.7 Hz, 1 H, 7-Heq), 2.20 (ddd, J9,8 = 10.7,
J9,11ax = 12.1 Hz, 1 H, 9-H), 2.18 (ddddd, J15b,14 = 4.8 Hz, 1 H,
3.37 and 3.24 (each d, J = –9.5 Hz, each 1 H, 1Ј-H), 2.82 (ddd,
J6a,7eq = 2.3, J6a,7ax = 5.2, J6a,6b = –17.1 Hz, 1 H, 6a-H), 2.80 (ddd,
Eur. J. Org. Chem. 2011, 1064–1077
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1071

J. Wölfling, R. Leino et al.
FULL PAPER
J6b,7eq = 6.4, J6b,7ax = 12.2 Hz, 1 H, 6b-H), 2.25 (ddd, J9,11eq = 4.2, CHCl3): δ = 7.18 (d, J1,2 = 8.7 Hz, 1 H, H-1), 6.70 (dd, J2,4
=
J9,11ax = 10.9, J9,8 = 12.0 Hz, 1 H, 9-H), 2.23 (dddd, J11eq,12eq 2.7 Hz, 1 H, H-2), 6.60 (d, 1 H, H-4), 6.00 (dddd, J3Ј,2Јa = 6.7,
=
2.7, J11eq,12ax = 3.9, J11eq,11ax = –11.8 Hz, 1 H, 11-Heq), 2.20
(ddddd, J15a,14 = 5.1, J15a,15b = –15.8 Hz, 1 H, 15a-H), 2.12 (dddd,
J3Ј,2Јb = 6.8, J3Ј,4Јc = 10.2, J3Ј,4Јt = 17.2 Hz, 1 H, H-3Ј), 5.83 (dddd,
J16,15b = 5.8, J16,15a = 7.0, J16,17c = 10.2, J16,17t = 17.0 Hz, 1 H, H-
16), 5.05 (dddd, J4Јt,4Јc = –1.6, J4Јt,2Јa = –1.7, J4Јt,2Јb = –1.7 Hz, 1
J7eq,8 = 2.4, J7eq,7ax = –12.8 Hz, 1 H, 7-Heq), 2.00 (ddddd, J15b,14
3.4 Hz, 1 H, 15a-H), 1.73 (ddd, J12ax,12eq = –12.6, J12ax,11ax
=
=
H, H-4Јt), 5.02 (dddd, J17t,17c = –1.4, J17t,15a = –1.9, J17t,15b
–2.0 Hz, 1 H, H-17t), 5.00 (dddd, 1 H, J4Јc,2Јb = –1.1 Hz, J4Јc,2Јa
=
=
14.1 Hz, 1 H, 12-Hax), 1.49 (ddd, J12eq,11ax = 3.4 Hz, 1 H, 12-Heq),
1.46 (ddd, J14,8 = 10.7 Hz, 1 H, 14-H), 1.39 (dddd, 1 H, 11-Hax),
1.35 (dddd, J8,7ax = 11.1 Hz, 1 H, 8-H), 1.34 (d, 3 H, 6ЈЈ-H), 1.29
(dddd, 1 H, 7-Ha x ), 0.77 (s, 3 H, 18-H) ppm. 1 3 C NMR
–1.9, H-4Јc), 4.98 (dddd, 1 H, J17c,15b = –1.7, J17c,15a = –1.7 Hz, H-
17c), 4.76 (d, 1 H, J1ЈЈ,2ЈЈ = 1.7 Hz, H-1ЈЈ), 3.98 (dd, 1 H, J2ЈЈ,3ЈЈ
3.3 Hz, H-2ЈЈ), 3.79 (dq, 1 H, J5ЈЈ,6ЈЈ = 6.2, J5ЈЈ,4ЈЈ = 9.4 Hz, H-5ЈЈ),
=
(150.9 MHz, CDCl3): δ = 157.4 (C-3), 140.2 (C-16), 137.9 (C-5), 3.76 (s, 3 H, 3-OCH3), 3.74 (dd, 1 H, J3ЈЈ,4ЈЈ = 9.3 Hz, H-3ЈЈ), 3.50
132.8 (C-10), 126.4 (C-1), 114.1 (C-17), 113.4 (C-4), 111.6 (C-2), (dd, 1 H, J1Ј,2Јa = 3.4, J1Ј,2Јb = 6.7 Hz, H-1Ј), 3.47 (dd, 1 H, H-4ЈЈ),
99.9 (C-1ЈЈ), 75.8 (C-1Ј), 73.0 (C-4ЈЈ), 72.1 (C-3ЈЈ), 71.1 (C-2ЈЈ), 68.0 2.81 (ddd, 1 H, J6a,7eq = 1.5, J6a,7ax = 5.4, J6a,6b = –13.9 Hz, H-6a),
(C-5ЈЈ), 55.2 (3-OCH3), 44.2 (C-14), 43.4 (C-9), 41.3 (C-8), 38.1 (C- 2.80 (ddd, 1 H, J6b,7eq = 6.5, J6b,7ax = 12.3 Hz, H-6b), 2.45 (ddddd,
13), 36.5 (C-12), 32.7 (C-15), 30.5 (C-6), 27.6 (C-7), 26.2 (C-11), 1 H, J2Јa,2Јb = –15.4 Hz, H-2Јa), 2.35 (ddddd, 1 H, J15a,14 = 2.7,
17.6 (C-6ЈЈ), 16.5 (C-18) ppm. HRMS: calcd. for C26H38O6Na [M
J15a,15b = –16.4 Hz, H-15a), 2.28 (ddddd, 1 H, H-2Јb), 2.23 (dddd,
1 H, J11eq,12eq = 2.9, J11eq,9 = 3.7, J11eq,12ax = 3.9, J11eq,11ax
+ Na]+ 496.2566; found 496.2546.
=
–13.1 Hz, H-11eq), 2.21 (ddd, 1 H, J9,8 = 10.2, J9,11ax = 12.1 Hz,
H-9), 2.13 (dddd, 1 H, J7eq,8 = 2.7, J7eq,7ax = –12.8 Hz, H-7eq), 1.99
(1ЈS)-13,17-seco-13α-[But-3Ј-en-1Ј-(2ЈЈ,3ЈЈ,4ЈЈ-tri-O-benzoyl-α-L-
rhamnopyranosyloxy)-1Ј-yl]-3-methoxyestra-1,3,5(10),16-tetraene
(17): Synthesized from 3 (122 mg, 0.358 mmol) and 8 (311 mg,
0.508 mmol) according to the general procedure for glycosylation,
providing 17 as a white foam (251 mg, 88%). Rf = 0.83 (hexane/
EtOAc, 1:1). [α]D = +116.3 (c = 0.16, CHCl3). 1 H NMR
(600.13 MHz, CDCl3): δ = 8.10–7.22 (m, 15 H, arom. H), 7.26 (d,
J1,2 = 8.5 Hz, 1 H, 1-H), 6.73 (dd, J2,4 = 2.7 Hz, 1 H, 2-H), 6.63
(d, 1 H, 4-H), 6.07 (dddd, J3Ј,2Јa = 6.4, J3Ј,2Јb = 7.2, J3Ј,4Јc = 10.2,
J3Ј,4Јt = 17.1 Hz, 1 H, 3Ј-H), 5.93 (dddd, J16,15b = 5.5, J16,15a = 7.5,
J16,17c = 10.1, J16,17t = 16.8 Hz, 1 H, 16-H), 5.83 (dd, J3ЈЈ,2ЈЈ = 3.2,
J3ЈЈ,4ЈЈ = 10.1 Hz, 1 H, 3ЈЈ-H), 5.75 (dd, J2ЈЈ,1ЈЈ = 1.8 Hz, 1 H, 2ЈЈ-
H), 5.68 (dd, J4ЈЈ,5ЈЈ = 9.8 Hz, 1 H, 4ЈЈ-H), 5.15 (dddd, J4Јt,2Јa = –1.4,
(ddddd, 1 H, J15b,14 = 6.2 Hz, H-15b), 1.66 (ddd, 1 H, J12ax,12eq
–12.8, J12ax,11ax = 14.1 Hz, H-12ax), 1.50 (ddd, 1 H, J12eq,11ax
=
=
3.3 Hz, H-12eq), 1.50 (ddd, 1 H, J14,8 = 11.0 Hz, H-14), 1.37 (dddd,
1 H, J8,7ax = 12.3 Hz, H-8), 1.33 (dddd, 1 H, H-11ax), 1.29 (dddd,
1 H, 7ax), 1.27 (d, 3 H, H-6ЈЈ), 0.82 (s, 3 H, H-18) ppm. 13C NMR
(150.9 MHz, CHCl3): δ = 157.4 (C-3), 139.9 (C-16), 137.9 (C-5),
137.5 (C-3Ј), 132.5 (C-10), 126.6 (C-1), 115.7 (C-4Ј), 114.8 (C-17),
113.3 (C-4), 111.7 (C-2), 102.2 (C-1ЈЈ), 87.9 (C-1Ј), 73.3 (C-4ЈЈ),
72.0 (C-3ЈЈ), 71.1 (C-2ЈЈ), 68.2 (C-5ЈЈ), 55.2 (3-OCH3), 43.7 (C-14),
43.1 (C-9), 42.5 (C-13), 42.3 (C-8), 35.7 (C-2Ј), 32.9 (C-15), 32.6
(C-12), 30.6 (C-6), 27.7 (C-7), 26.4 (C-11), 17.4 (C-6ЈЈ), 17.3 (C-
18) ppm. HRMS: calcd. for C29H42O6Na [M + Na]+ 509.2879;
found 509.2855.
J4Јt,2Јb = –1.5, J4Јt,4Јc = –2.0 Hz, 1 H, 4Јt-H), 5.08 (dddd, J4Јc,2Јb
=
–1.0, J4Јc,2Јa = –1.4 Hz, 1 H, 4Јc-H), 5.06 (d, 1 H, 1ЈЈ-H), 5.05
(dddd, J17t,17c = –1.4, J17t,15a = –1.8, J17t,15b = –2.1 Hz, 1 H, 17t-
H), 4.85 (dddd, J17c,15a = –1.7, J17c,15b = –1.8 Hz, 1 H, 17c-H), 4.34
(dq, J5ЈЈ,6ЈЈ = 6.2 Hz, 1 H, 5ЈЈ-H), 3.78 (s, 3 H, 3-OCH3), 3.69 (dd,
J1Ј,2Јa = 2.8, J1Ј,2Јb = 7.5 Hz, 1 H, 1Ј-H), 2.88 (ddd, J6a,7eq = 1.0,
J6a,7ax = 5.0, J6a,6b = –16.5 Hz, 1 H, 6a-H), 2.85 (ddd, J6b,7eq = 6.3,
J6b,7ax = 13.8 Hz, 1 H, 6b-H), 2.55 (ddddd, J2Јa,2Јb = –15.7 Hz, 1
H, 2Јa-H), 2.48 (ddddd, J15a,14 = 2.8, J15a,15b = –16.5 Hz, 1 H, 15a-
H), 2.43 (ddddd, 1 H, 2Јb-H), 2.42 (ddd, J11eq,9 = 3.6, J9,8 = 11.3,
J9,11ax = 11.8 Hz, 1 H, 9-H), 2.36 (dddd, J11eq,12eq = 3.1, J11eq,12ax
= 3.8, J11eq,11ax = –12.9 Hz, 1 H, 11-Heq), 2.19 (dddd, J7eq,8 = 2.7,
J7eq,7ax = –12.3 Hz, 1 H, 7-Heq), 2.13 (ddddd, J15b,14 = 5.5 Hz, 1
H, 15b-H), 1.91 (ddd, J12ax,12eq = –13.2, J12ax,11ax = 13.8 Hz, 1 H,
12-Hax), 1.73 (ddd, J14,8 = 10.5 Hz, 1 H, 14-H), 1.63 (ddd, J12eq,11ax
= 3.8 Hz, 1 H, 12-Heq), 1.51 (dddd, J7ax,8 = 10.8 Hz, 1 H, 7ax), 1.46
(dddd, 1 H, 8-H), 1.42 (dddd, 1 H, 11-Hax), 1.35 (d, 1 H, 6ЈЈ-H),
0.95 (s, 3 H, 18-H) ppm. 13C NMR (150.9 MHz, CDCl3): δ = 166.0
(4ЈЈ-OCOPh), 165.7 (3ЈЈ-OCOPh), 165.6 (2ЈЈ-OCOPh), 157.6 (C-3),
140.0 (C-16), 138.2 (C-5), 137.5 (C-3Ј), 133.5–128.4 (arom. C),
132.9 (C-10), 126.7 (C-1), 116.2 (C-4Ј), 115.1 (C-17), 113.5 (C-4),
111.8 (C-2), 100.1 (C-1ЈЈ), 88.7 (C-1Ј), 72.1 (C-4ЈЈ), 71.0 (C-2ЈЈ),
70.3 (C-3ЈЈ), 67.3 (C-5ЈЈ), 55.4 (3-OCH3), 43.7 (C-14), 43.2 (C-9),
42.7 (C-13), 42.4 (C-8), 35.8 (C-2Ј), 33.2 (C-15), 32.9 (C-12), 30.7
(C-6), 27.7 (C-7), 26.5 (C-11), 18.0 (C-18), 17.8 (C-6ЈЈ) ppm.
HRMS: calcd. for C50H54O9Na [M + Na]+ 821.3666; found
821.3644. HRMS: calcd. for C50H58O9N [M + NH4]+ 816.4112;
found 816.4092.
13,17-seco-3-Methoxy-13α-methyl-1Ј-(β-D-glucopyranosyloxy)estra-
1,3,5(10),16-tetraene (19): Synthesized from 1 (44 mg, 0.146 mmol)
and 9 (152 mg, 0.205 mmol) according to the general procedure
for glycosylation, providing an impure mixture (126 mg, 97%). The
deprotection step was performed according to the general pro-
cedure for deprotection starting with the mixture (85 mg,
0.096 mmol) to provide 19 as a white solid (39 mg, 88%). Rf = 0.62
(MeOH/CH2Cl2, 1:5). [α]D = +29.4 (c = 2.5, MeOH). 1H NMR
(600.13 MHz, CD3OD): δ = 7.16 (d, J1,2 = 8.6 Hz, 1 H, 1-H), 6.65
(dd, J2,4 = 2.7 Hz, 1 H, 2-H), 6.57 (d, 1 H, 4-H), 5.97 (dddd, J16,15a
= 6.3, J16,15b = 7.2, J16,17c = 10.3, J16,17t = 17.1 Hz, 1 H, 16-H),
5.04 (dddd, J17t,17c = –1.5, J17t,15b = –2.0, J17t,15a = –2.2 Hz, 1 H,
17t-H), 4.92 (dddd, J17c,15b = –1.6, J17c,15a = –1.8 Hz, 1 H, 17c-H),
4.24 (d, J1ЈЈ,2ЈЈ = 7.8 Hz, 1 H, 1ЈЈ-H), 3.88 (dd, J6ЈЈa,5ЈЈ = 2.2, J6ЈЈa,6ЈЈb
= –12.0 Hz, 1 H, 6ЈЈa-H), 3.72 (s, 3 H, 3-OCH3), 3.70 and 3.40
(each d, J = –9.6 Hz, each 1 H, 1Ј-H), 3.69 (dd, J6ЈЈb,5ЈЈ = 5.6 Hz,
1 H, 6ЈЈb-H), 3.36 (dd, J3ЈЈ,4ЈЈ = 9.0, J3ЈЈ,2ЈЈ = 9.2 Hz, 1 H, 3ЈЈ-H),
3.30 (dd, J4ЈЈ,5ЈЈ = 9.6 Hz, 1 H, 4ЈЈ-H), 3.26 (ddd, 1 H, 5ЈЈ-H), 3.22
(dd, 1 H, 2ЈЈ-H), 2.78 (ddd, J6a,7eq = 1.9, J6a,7ax = 6.1, J6a,6b
=
–11.9 Hz, 1 H, 6a-H), 2.78 (ddd, J6b,7eq = 6.6, J6b,7ax = 11.5 Hz, 1
H, 6b-H), 2.35 (ddddd, J15a,14 = 3.3, J15a,15b = –16.0 Hz, 1 H, 15a-
H), 2.26 (dddd, J11eq,12eq = 3.8, J11eq,9 = 3.8, J11eq,12ax = 3.9,
J11eq,11ax = –13.3 Hz, 1 H, 11-Heq), 2.25 (ddd, J9,8 = 10.7, J9,11ax
=
12.0 Hz, 1 H, 9-H), 2.19 (dddd, J7eq,8 = 2.2, J7eq,7ax = –13.0 Hz, 1
H, 7-Heq), 2.05 (ddddd, J15b,14 = 5.6 Hz, 1 H, 15b-H), 1.85 (ddd,
J12ax,11ax = 13.3, J12ax,12eq = –13.6 Hz, 1 H, 12-Hax), 1.63 (ddd, J14,8
= 11.5 Hz, 1 H, 14-H), 1.60 (ddd, J12eq,11ax = 3.4 Hz, 1 H, 12-Heq),
1.36 (dddd, J8,7ax = 11.2 Hz, 1 H, 8-H), 1.35 (dddd, 1 H, 11-Hax),
1.25 (dddd, 1 H, 7-Hax), 0.84 (s, 3 H, 18-H) ppm. 13C NMR
(150.9 MHz, CD3OD): δ = 158.9 (C-3), 142.0 (C-16), 139.0 (C-5),
134.0 (C-10), 127.4 (C-1), 114.6 (C-17), 114.3 (C-4), 112.6 (C-2),
(1ЈS)-13,17-seco-13α-[But-3Ј-en-1Ј-(α-L-rhamnopyranosyloxy)-1Ј-
yl]-3-methoxyestra-1,3,5(10),16-tetraene (18): Synthesized from 17
(59 mg, 0.064 mmol) according to the general procedure for depro-
tection, providing 18 as a white solid (33 mg, quant.). Rf = 0.4
1
(EtOAc). [α]D = +20.5 (c = 0.07, CHCl3). H NMR (600.13 MHz,
1072
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1064–1077

Estradiol-Based Glycosteroid Mimics
104.9 (C-1ЈЈ), 78.9 (C-1Ј), 78.2 (C-3ЈЈ), 77.9 (C-5ЈЈ), 75.3 (C-2ЈЈ), = 5.6 Hz, 1 H, 6ЈЈb-H), 3.33 (dd, J3ЈЈ,4ЈЈ = 9.3, J3ЈЈ,2ЈЈ = 9.5 Hz, 1
71.7 (C-4ЈЈ), 62.8 (C-6ЈЈ), 55.5 (3-OCH3), 45.4 (C-14), 44.9 (C-9), H, 3ЈЈ-H), 3.30 (dd, J4ЈЈ,5ЈЈ = 9.1 Hz, 1 H, 4ЈЈ-H), 3.22 (dd, 1 H,
43.2 (C-8), 39.5 (C-13), 37.6 (C-12), 34.2 (C-15), 31.5 (C-6), 28.9 2ЈЈ-H), 3.20 (ddd, 1 H, 5ЈЈ-H), 2.78 (ddd, J6a,7eq = 1.8, J6a,7ax = 5.9,
(C-7), 27.7 (C-11), 17.0 (C-18) ppm. HRMS: calcd. for
J6a,6b = –13.2 Hz, 1 H, 6a-H), 2.77 (ddd, J6b,7eq = 6.3, J6b,7ax =
11.5 Hz, 1 H, 6b-H), 2.47 (ddddd, J15a,14 = 2.1, J15a,15b = –16.7 Hz,
1 H, 15a-H), 2.46 (ddddd, J20a,20b = –14.6 Hz, 1 H, 2Јa-H), 2.40
C26H38O7Na [M + Na]+ 485.2515; found 485.2500.
(1ЈS)-13,17-seco-13α-[But-3Ј-en-1Ј-(2ЈЈ,3ЈЈ,4ЈЈ,6ЈЈ-tetra-O-benzoyl-
β-D-glucopyranosyloxy)-1Ј-yl]-3-methoxyestra-1,3,5(10),16-tetraene
(ddddd, 1 H, 2Јb-H), 2.29 (ddd, J9,11eq = 3.5, J9,8 = 11.2, J9,11ax
=
11.5 Hz, 1 H, 9-H), 2.27 (dddd, J11eq,12eq = 3.5, J11eq,12ax = 3.8,
J11eq,11ax = –12.7 Hz, 1 H, 11-Heq), 2.18 (dddd, J7eq,8 = 2.5, J7eq,7ax
= –12.6 Hz, 1 H, 7-Heq), 2.05 (ddddd, J15b,14 = 6.2 Hz, 1 H, 15b-
(20): Synthesized from 3 (75 mg, 0.220 mmol) and 9 (228 mg,
0.308 mmol) according to the general procedure for glycosylation,
providing 20 as a white foam (153 mg, 77%). Rf = 0.70 (hexane/
EtOAc, 1:1). [α]D = +28.0 (c = 0.2, CHCl3 ). 1 H NMR
(600.13 MHz, CDCl3): δ = 8.06–7.15 (m, 20 H, arom. H), 7.00 (d,
J1,2 = 8.7 Hz, 1 H, 1-H), 6.64 (dd, J2,4 = 2.7 Hz, 1 H, 2-H), 6.50
(d, 1 H, 4-H), 6.06 (dddd, J3Ј,2Јa = 5.2, J3Ј,2Јb = 8.4, J3Ј,4Јc = 10.1,
J3Ј,4Јt = 17.0 Hz, 1 H, 3Ј-H), 5.90 (dd, J3ЈЈ,4ЈЈ = 9.5, J3ЈЈ,2ЈЈ = 9.9 Hz,
1 H, 3ЈЈ-H), 5.86 (dddd, J16,15b = 5.4, J16,15a = 7.4, J16,17c = 10.2,
J16,17t = 17.1 Hz, 1 H, 16-H), 5.67 (dd, J4ЈЈ,5ЈЈ = 9.9 Hz, 1 H, 4ЈЈ-
H), 2.02 (ddd, J14,8 = 10.6 Hz, 1 H, 14-H), 1.96 (ddd, J12ax,12eq
–13.3, J12ax,11ax = 13.4 Hz, 1 H, 12-Hax), 1.55 (ddd, J12eq,11ax
=
=
3.3 Hz, 1 H, 12-Heq), 1.36 (dddd, J8,7ax = 11.1 Hz, 1 H, 8-H), 1.30
(dddd, 1 H, 7ax), 1.29 (dddd, 1 H, 11-Hax), 0.87 (s, 3 H, 18-H) ppm.
13C NMR (150.9 MHz, CD3OD): δ = 158.9 (C-3), 142.0 (C-16),
140.2 (C-3Ј), 139.0 (C-5), 134.0 (C-10), 127.6 (C-1), 115.2 (C-17),
114.8 (C-4Ј), 114.2 (C-4), 112.6 (C-2), 105.2 (C-1ЈЈ), 86.0 (C-1Ј),
78.3 (C-3ЈЈ), 77.6 (C-5ЈЈ), 75.8 (C-2ЈЈ), 71.9 (C-4ЈЈ), 63.0 (C-6ЈЈ),
55.5 (3-OCH3), 44.2 (C-9, C-8), 43.6 (C-13), 43.3 (C-14), 42.9 (C-
13), 37.3 (C-2Ј), 34.5 (C-15), 33.2 (C-12), 31.7 (C-6), 29.1 (C-7),
27.9 (C-11), 18.2 (C-18) ppm. HRMS: calcd. for C29H42O7Na [M
+ Na]+ 525.2828; found 525.2821.
H), 5.60 (dd, J2ЈЈ,1ЈЈ = 7.8 Hz, 1 H, 2ЈЈ-H), 5.13 (dddd, J17c,15b
=
–1.5, J17c,17t = –1.6, J17c,15a = –1.9 Hz, 1 H, 17c-H), 5.08 (dddd,
J17t,15a = –1.7, J17c,15b = –2.2 Hz, 1 H, 17t-H), 4.96 (d, 1 H, 1ЈЈ-H),
4.95 (dddd, J4Јt,2Јa = –1.3, J4Јt,4Јc = –2.0, J4Јt,2Јb = –2.2 Hz, 1 H, 4Јt-
H), 4.84 (dddd, J4Јc,2Јb = –1.3, J4Јc,2Јa = –1.3 Hz, 1 H, 4Јc-H), 4.68
(dd, J6ЈЈa,5ЈЈ = 3.1, J6ЈЈa,6ЈЈb = –12.0 Hz, 1 H, 6ЈЈa-H), 4.47 (dd, 13,17-seco-3-Methoxy-13α-methyl-1Ј-(β-
J6ЈЈb,5ЈЈ = 5.2 Hz, 1 H, 6ЈЈb-H), 4.08 (ddd, 1 H, 5ЈЈ-H), 3.75 (s, 3 H, estra-1,3,5(10),16-tetraene (22): Synthesized from 1 (19 mg,
3-OCH3), 3.63 (dd, J1Ј,2Јa = 2.8, J1Ј,2Јb = 7.4 Hz, 1 H, 1Ј-H), 2.59 0.063 mmol) and 10 (65 mg, 0.088 mmol) according to the general
(ddd, J6b,7eq = 6.0, J6b,7ax = 11.9, J6a,6b = –16.5 Hz, 1 H, 6b-H), procedure for glycosylation. A pure product was, however, not ob-
D-galactopyranosyloxy)-
2.51 (ddd, J6a,7eq = 1.8, J6a,7ax = 5.4 Hz, 1 H, 6a-H), 2.41 (ddddd, tained and thus the deprotection step was carried out according to
J2Јa,2Јb = –15.5 Hz, 1 H, 2Јa-H), 2.40 (ddddd, 1 H, 2Јb-H), 2.22 the general procedure for deprotection, providing 22 as a white
(ddddd, J15a,14 = 2.3, J15a,15b = –16.6 Hz, 1 H, 15a-H), 2.02 (dddd,
J11eq,9 = 3.3, J11eq,12eq = 3.4, J11eq,12ax = 3.9, J11eq,11ax = –12.8 Hz, [α]D = +38.0 (c = 0.87, MeOH). 1H NMR (600.13 MHz, CD3OD):
1 H, 11-Heq), 1.87 (ddddd, J15b,14 = 6.1 Hz, 1 H, 15b-H), 1.75 δ = 7.17 (d, J1,2 = 8.6 Hz, 1 H, 1-H), 6.66 (dd, J2,4 = 2.6 Hz, 1 H,
(dddd, J7eq,8 = 2.5, J7eq,7ax = –12.9 Hz, 1 H, 7-Heq), 1.60 (ddd, 2-H), 6.58 (d, 1 H, 4-H), 5.98 (dddd, J16,15a = 6.0, J16,15b = 7.4,
J12ax,12eq = –13.3, J12ax,11ax = 13.5 Hz, 1 H, 12-Hax), 1.48 (ddd, J16,17c = 10.2, J16,17t = 17.1 Hz, 1 H, 16-H), 5.03 (dddd, J17t,17c
J12eq,11ax = 3.2 Hz, 1 H, 12-Heq), 1.38 (ddd, J9,8 = 10.5, J9,11ax –1.2, J17t,15b = –1.5, J17t,15a = –2.3 Hz, 1 H, 17t-H), 4.91 (dddd,
J17c,15b = –1.5, J17c,15a = –1.9 Hz, 1 H, 17c-H), 4.19 (d, J1ЈЈ,2ЈЈ
7.7 Hz, 1 H, 1ЈЈ-H), 3.63 (dd, J4ЈЈ,5ЈЈ = 1.3, J4ЈЈ,3ЈЈ = 3.5 Hz, 1 H,
solid (30 mg, 85% over two steps). Rf = 0.58 (MeOH/CH2Cl2, 1:5).
=
=
12.1 Hz, 1 H, 9-H), 1.33 (ddd, J14,8 = 10.7 Hz, 1 H, 14-H), 1.13
(dddd, 1 H, 11-Hax), 1.11 (dddd, J8,7ax = 11.8 Hz, 1 H, 8-H), 0.73
=
(s, 3 H, 18-H), 0.44 (dddd, 1 H, 7ax) ppm. 13C NMR (150.9 MHz, 4ЈЈ-H), 3.79 (dd, J6ЈЈa,5ЈЈ = 6.0, J6ЈЈa,6ЈЈb = –11.6 Hz, 1 H, 6ЈЈa-H),
CDCl3): δ = 166.1 (6ЈЈ-OCOPh), 165.9 (3ЈЈ-OCOPh), 165.2 (4ЈЈ-
3.73 (dd, J6ЈЈb,5ЈЈ = 4.8 Hz, 1 H, 6ЈЈb-H), 3.73 (s, 3 H, 3-OCH3),
OCOPh), 165.0 (2ЈЈ-OCOPh), 157.1 (C-3), 140.4 (C-16), 137.7 (C- 3.69 and 3.42 (each d, J = –9.5 Hz, each 1 H, 1Ј-H), 3.55 (dd, J2ЈЈ,3ЈЈ
3Ј), 137.5 (C-5), 133.4–128.3 (arom. C), 132.4 (C-10), 126.6 (C-1), = 9.8 Hz, 1 H, 2ЈЈ-H), 3.49 (ddd, 1 H, 5ЈЈ-H), 3.46 (dd, 1 H, 3ЈЈ-
115.0 (C-17, C-4Ј), 113.0 (C-4), 111.3 (C-2), 101.7 (C-1ЈЈ), 84.9 (C- H), 2.79 (ddd, J6a,7eq = 1.8, J6a,7ax = 5.6, J6a,6b = –11.5 Hz, 1 H,
1Ј), 72.9 (C-3ЈЈ), 72.3 (C-2ЈЈ), 71.9 (C-5ЈЈ), 69.9 (C-4ЈЈ), 63.1 (C-
6ЈЈ), 55.1 (3-OCH3), 42.6 (C-14), 42.3 (C-13), 42.1 (C-8, C-9), 35.9
6a-H), 2.79 (ddd, J6b,7eq = 6.5, J6b,7ax = 12.1 Hz, 1 H, 6b-H), 2.35
(ddddd, J15a,14 = 3.4, J15a,15b = –16.0 Hz, 1 H, 15a-H), 2.27 (dddd,
(C-2Ј), 33.3 (C-15), 31.5 (C-12), 30.2 (C-6), 26.7 (C-7), 26.1 (C- J11eq,12eq = 3.3, J11eq,9 = 3.7, J11eq,12ax = 3.9, J11eq,11ax = –13.0 Hz,
11), 17.3 (C-18) ppm. HRMS: calcd. for C57H58O11Na [M + Na]+
941.3871; found 941.3866. HRMS: calcd. for C57H58O11K [M +
K]+ 957.3611; found 957.3595.
1 H, 11-Heq), 2.26 (ddd, J9,8 = 10.9, J9,11ax = 11.9 Hz, 1 H, 9-H),
2.21 (dddd, J7eq,8 = 2.3, J7eq,7ax = –13.0 Hz, 1 H, 7-Heq), 2.06
(ddddd, J15b,14 = 5.2 Hz, 1 H, 15b-H), 1.87 (ddd, J12ax,12eq = –13.3,
J12ax,11ax = 13.7 Hz, 1 H, 12-Hax), 1.65 (ddd, J14,8 = 11.3 Hz, 1 H,
14-H), 1.60 (ddd, J12eq,11ax = 3.4 Hz, 1 H, 12-Heq), 1.37 (dddd,
J8,7ax = 10.8 Hz, 1 H, 8-H), 1.36 (dddd, 1 H, 11-Hax), 1.27 (dddd,
1 H, 7-Hax), 0.84 (s, 3 H, 18-H) ppm. 13C NMR (150.9 MHz,
CD3OD): δ = 158.9 (C-3), 142.1 (C-16), 139.0 (C-5), 134.0 (C-10),
127.4 (C-1), 114.5 (C-17), 114.3 (C-4), 112.6 (C-2), 105.5 (C-1ЈЈ),
78.9 (C-1Ј), 76.6 (C-5ЈЈ), 75.1 (C-3ЈЈ), 72.7 (C-2ЈЈ), 70.4 (C-4ЈЈ), 62.5
(C-6ЈЈ), 55.5 (3-OCH3), 45.3 (C-14), 44.9 (C-9), 43.2 (C-8), 39.5 (C-
13), 37.7 (C-12), 34.2 (C-15), 31.6 (C-6), 29.0 (C-7), 27.8 (C-11),
17.1 (C-18) ppm. HRMS: calcd. for C26H38O7Na [M + Na]+
485.2515; found 485.2497.
(1ЈS)-13,17-seco-13α-[But-3Ј-en-1Ј-(β-D-glucopyranosyloxy)-1Ј-yl]-
3-methoxyestra-1,3,5(10),16-tetraene (21): Synthesized from 20
(60 mg, 0.065 mmol) according to the general procedure for depro-
tection, providing 21 as a white solid (25 mg, 77 %). Rf = 0.43
1
(MeOH/CH2Cl2, 1:5). [α]D = +24.0 (c = 1.67, MeOH). H NMR
(600.13 MHz, CD3OD): δ = 7.17 (d, J1,2 = 8.6 Hz, 1 H, 1-H), 6.65
(dd, J2,4 = 2.7 Hz, 1 H, 2-H), 6.57 (d, 1 H, 4-H), 6.18 (dddd, J3Ј,2Јb
= 6.2, J3Ј,2Јa = 7.6, J3Ј,4Јc = 10.1, J3Ј,4Јt = 17.2 Hz, 1 H, 3Ј-H), 6.05
(dddd, J16,15b = 6.1, J16,15a = 6.5, J16,17c = 10.2, J16,17t = 17.2 Hz,
1 H, 16-H), 5.09 (dddd, J17t,17c = –1.6, J17t,15b = –1.8, J17t,15a
–2.1 Hz, 1 H, 17t-H), 5.00 (dddd, J4Јt,2Јb = –1.4, J4Јt,2Јa = –1.5,
J4Јt,4Јc = –2.3 Hz, 1 H, 4Јt-H), 4.98 (dddd, J17c,15b = –1.4, J17c,15a
–2.1 Hz, 1 H, 17c-H), 4.93 (dddd, J4Јc,2Јb = –0.9, J4Јc,2Јa = –1.2 Hz,
=
=
(1ЈR)-13,17-seco-13α-[But-3Ј-en-1Ј-(2ЈЈ,3ЈЈ,4ЈЈ,6ЈЈ-tetra-O-benzoyl-
β-D-galactopyranosyloxy)-1Ј-yl]-3-methoxyestra-1,3,5(10),16-
1 H, 4Јc-H), 4.41 (d, J1ЈЈ,2ЈЈ = 8.0 Hz, 1 H, 1ЈЈ-H), 3.85 (dd, J6ЈЈa,5ЈЈ tetraene (23): Synthesized from 2 (81 mg, 0.237 mmol) and 10
= 2.5, J6ЈЈa,6ЈЈb = –11.7 Hz, 1 H, 6ЈЈa-H), 3.72 (s, 3 H, 3-OCH3), (246 mg, 0.330 mmol) according to the general procedure for glyco-
3.69 (dd, J1Ј,2Јa = 3.7, J1Ј,2Јb = 6.5 Hz, 1 H, 1Ј-H), 3.68 (dd, J6Јb,5ЈЈ
sylation, providing 23 as a white foam (173 mg, 79%). Rf = 0.18
Eur. J. Org. Chem. 2011, 1064–1077
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1073

J. Wölfling, R. Leino et al.
1.57 (ddd, J12ax,11ax = 13.0 Hz, 1 H, 12-Hax), 1.41 (dddd, J8,14
FULL PAPER
(hexane/EtOAc, 4:1). [α]D = +69.3 (c = 0.4, CHCl3). 1H NMR
(600.13 MHz, CDCl3): δ = 8.09–7.23 (m, 20 H, arom. H), 7.20 (d,
J1,2 = 8.6 Hz, 1 H, 1-H), 6.72 (dd, J2,4 = 2.7 Hz, 1 H, 2-H), 6.61
=
11.0, J8,7ax = 11.7 Hz, 1 H, 8-H), 1.40 (ddd, 1 H, 14-H), 1.30 (dddd,
1 H, 11-Hax), 1.26 (dddd, 1 H, 7ax), 1.04 (s, 3 H, 18-H) ppm. 13C
(d, 1 H, 4-H), 5.95 (dd, J4ЈЈ,5ЈЈ = 1.1, J4ЈЈ,3ЈЈ = 3.6 Hz, 1 H, 4ЈЈ-H), NMR (150.9 MHz, CD3OD): δ = 158.9 (C-3), 141.5 (C-16), 139.1
5.88 (dddd, J3Ј,2Јa = 6.3, J3Ј,2Јb = 8.0, J3Ј,4Јc = 10.0, J3Ј,4Јt = 17.4 Hz,
1 H, 3Ј-H), 5.80 (dddd, J16,15b = 6.1, J16,15a = 7.3, J16,17c = 10.0,
(C-3Ј), 138.9 (C-5), 133.9 (C-10), 127.4 (C-1), 116.5 (C-4Ј), 115.0
(C-17), 114.3 (C-4), 112.6 (C-2), 104.1 (C-1ЈЈ), 84.8 (C-1Ј), 76.4 (C-
5ЈЈ), 75.2 (C-3ЈЈ), 73.2 (C-2ЈЈ), 70.2 (C-4ЈЈ), 62.3 (C-6ЈЈ), 55.5 (3-
J16,17t = 16.8 Hz, 1 H, 16-H), 5.76 (dd, J2ЈЈ,1ЈЈ = 7.8, J2ЈЈ,3ЈЈ
=
10.4 Hz, 1 H, 2ЈЈ-H), 5.60 (dd, 1 H, 3ЈЈ-H), 5.04 (d, 1 H, 1ЈЈ-H),4.95 OCH3), 46.7 (C-14), 45.0 (C-9), 43.9 (C-8), 42.9 (C-13), 35.9 (C-
(dddd, J4Јc,2Јb = –0.6, J4Јc,2Јa = –0.8, J4Јc,4Јt = –1.0 Hz, 1 H, 4Јc-H), 2Ј), 34.0 (C-15), 32.6 (C-12), 31.5 (C-6), 29.1 (C-7), 27.4 (C-11),
4.94 (dddd, J4Јt,2Јb = –1.1, J4Јt,2Јa = –1.8 Hz, 1 H, 4Јt-H), 4.94 18.6 (C-18) ppm. HRMS: calcd. for C29H42O7Na [M + Na]+
(dddd, J17t,15a = –0.8, J17t,17c = –1.6, J17t,15b = –2.3 Hz, 1 H, 17t-
H), 4.91 (dddd, J17c,15a = –0.7, J17c,15b = –1.0 Hz, 1 H, 17c-H), 4.64
(dd, J6ЈЈa,5ЈЈ = 7.0, J6ЈЈa,6ЈЈb = –11.4 Hz, 1 H, 6ЈЈa-H), 4.43 (dd,
J6ЈЈb,5ЈЈ = 6.0 Hz, 1 H, 6ЈЈb-H), 4.26 (ddd, 1 H, 5ЈЈ-H), 3.91 (dd,
J1Ј,2Јa = 2.3, J1Ј,2Јb = 8.7 Hz, 1 H, 1Ј-H), 3.78 (s, 3 H, 3-OCH3),
2.82 (ddd, J6a,7eq = 2.1, J6a,7ax = 7.6, J6a,6b = –12.1 Hz, 1 H, 6a-H),
2.82 (ddd, J6b,7eq = 5.6, J6b,7ax = 9.5 Hz, 1 H, 6b-H), 2.41 (ddddd,
J2Јa,2Јb = –14.5 Hz, 1 H, 2Јa-H), 2.21 (dddd, J11eq,12eq = 2.4,
J11eq,12ax = 4.0, J11eq,9 = 5.8, J11eq,11ax = –13.4 Hz, 1 H, 11-Heq),
2.20 (ddddd, J15a,14 = 3.1, J15a,15b = –15.8 Hz, 1 H, 15a-H), 2.17
(ddd, J9,11ax = 11.4, J9,8 = 11.5 Hz, 1 H, 9-H), 2.14 (ddddd, 1 H,
2Јb-H), 2.12 (dddd, J7eq,8 = 2.2, J7eq,7ax = –12.2 Hz, 1 H, 7-Heq),
525.2828; found 525.2828.
3-Methoxy- -dihomo-estra-17bβ-(2Ј,3Ј,4Ј,6Ј-tetra-O-benzoyl-α-D-
D
mannopyranosyloxy)-1,3,5(10),16-tetraene (25): Synthesized from
13 (132 mg, 0.143 mmol) according to the general procedure for
ring-closing metathesis, providing 25 as a yellowish foam (124 mg,
97 %). Rf = 0.33 (hexane/EtOAc 4:1). [α]D = –30.0 (c = 0.15,
1
CHCl3). H NMR (600.13 MHz, CDCl3): δ = 8.12–7.26 (m, 20 H,
arom. H), 7.16 (d, J1,2 = 8.6 Hz, 1 H, 1-H), 6.73 (dd, J2,4 = 2.7 Hz,
1 H, 2-H), 6.65 (d, 1 H, 4-H), 6.08 (dd, J4Ј,5Ј = 10.1, J4Ј,3Ј = 10.2 Hz,
1 H, 4Ј-H), 5.91 (dddd, J16,17a2 = –1.9, J16,15b = 4.2, J16,15a = 8.5,
J16,17 = 10.0 Hz, 1 H, 16-H), 5.91 (dd, J3Ј,2Ј = 3.2 Hz, 1 H, 3Ј-H),
5.63 (dddd, J17,17a1 = 3.1, J17,15a = –5.8, J17,17a2 = 7.5 Hz, 1 H, 17-
H), 5.59 (dd, J2Ј,1Ј = 1.6 Hz, 1 H, 2Ј-H), 4.75 (dd, J6Јa,5Ј = 2.2,
J6Јa,6Јb = –12.0 Hz, 1 H, 6Јa-H), 4.61 (ddd, J5Ј,6Јb = 5.6 Hz, 1 H,
5Ј-H), 4.49 (dd, 1 H, 6Јb-H), 3.78 (s, 3 H, 3-OCH3), 3.45 (dd,
J17b,17a2 = 2.1, J17b,17a1 = 10.2 Hz, 1 H, 17b-H), 2.84 (ddd, J6a,7eq
= 2.9, J6a,7ax = 4.1, J6a,6b = –15.4 Hz, 1 H, 6a-H), 2.83 (ddd, J6b,7eq
= 7.3, J6b,7ax = 12.3 Hz, 1 H, 6b-H), 2.68 (dddd, J17a1,15b = 2.5,
J17a1,17a2 = –15.8 Hz, 1 H, 17a1-H), 2.33 (dddd, 1 H, 17a2-H), 2.26
(dddd, J11eq,12ax = 3.2, J11eq,9 = 3.7, J11eq,12eq = 3.7, J11eq,11ax
–13.7 Hz, 1 H, 11-Heq), 2.25 (ddd, J12eq,11ax = 3.3, J12eq,12ax
–12.1 Hz, 1 H, 12-Heq), 2.25 (dddd, J15a,14 = 1.0, J15a,15b
–16.0 Hz, 1 H, 15a-H), 2.21 (dddd, J7eq,8 = 2.5, J7eq,7ax = –13.8 Hz,
1 H, 7-Heq), 2.10 (ddd, J9,8 = 11.0, J9,11ax = 11.7 Hz, 1 H, 9-H),
1.91 (ddddd, J15b,14 = 5.2 Hz, 1 H, 15b-H), 1.79 (ddd, J12eq,11ax
=
3.8, J12eq,12ax = –13.2 Hz, 1 H, 12-Heq), 1.43 (dddd, J8,14 = 9.8,
J8,7ax = 11.5 Hz, 1 H, 8-H), 1.37 (dddd, J11ax,12ax = 13.0 Hz, 1 H,
11-Hax), 1.36 (ddd, 1 H, 12-Hax), 1.29 (ddd, 1 H, 14-H), 1.26 (dddd,
1 H, 7ax), 1.06 (s, 3 H, 18-H) ppm. 13C NMR (150.9 MHz, CDCl3):
δ = 166.1 (6ЈЈ-OCOPh), 165.7 (3ЈЈ-OCOPh), 165.6 (4ЈЈ-OCOPh),
165.1 (2ЈЈ-OCOPh), 157.4 (C-3), 139.9 (C-16), 137.9 (C-5), 136.6
(C-3Ј), 133.5–128.3 (arom. C), 132.8 (C-10), 126.5 (C-1), 116.7 (C-
4Ј), 114.6 (C-17), 113.4 (C-4), 111.6 (C-2), 100.3 (C-1ЈЈ), 83.4 (C-
1Ј), 71.8 (C-3ЈЈ), 71.1 (C-5ЈЈ), 70.3 (C-2ЈЈ), 68.4 (C-4ЈЈ), 62.3 (C-
6ЈЈ), 55.2 (3-OCH3), 45.5 (C-14), 43.6 (C-9), 42.2 (C-8), 41.6 (C-
13), 34.5 (C-2Ј), 32.8 (C-15), 31.0 (C-12), 30.5 (C-6), 27.7 (C-7),
25.9 (C-11), 17.6 (C-18) ppm. HRMS: calcd. for C57H58O11Na [M
+ Na]+ 941.3877; found 941.3872.
=
=
=
2.09 (dddd, J15b,14 = 10.4 Hz, 1 H, 15b-H), 1.53 (dddd, J11ax,12ax
=
13.8 Hz, 1 H, 11-Hax), 1.42 (ddd, 1 H, 12-Hax), 1.26 (dddd, J7ax,8
= 9.0 Hz, 1 H, 7-Hax), 1.25 (dddd, J8,14 = 9.0 Hz, 1 H, 8-H), 1.22
(ddd, 1 H, 14-H), 1.18 (s, 3 H, 18-H) ppm. 13C NMR (150.9 MHz,
CDCl3): δ = 166.1 (6Ј-OCOPh), 166.0 (4Ј-OCOPh), 165.6 (3Ј-OC-
OPh, 2Ј-OCOPh), 157.5 (C-3), 138.1 (C-5), 134.6 (C-16), 133.5–
128.3 (arom. C), 133.2 (C-10), 126.1 (C-1), 125.8 (C-17), 113.2 (C-
4), 111.4 (C-2), 95.2 (C-1Ј), 85.1 (C-17b), 71.7 (C-2Ј), 70.2 (C-5Ј),
70.1 (C-3Ј), 67.0 (C-4Ј), 63.4 (C-6Ј), 55.2 (3-OCH3), 49.0 (C-14),
43.1 (C-9), 42.7 (C-13), 39.3 (C-8), 38.5 (C-12), 30.2 (C-6), 28.1 (C-
17a), 27.8 (C-7), 26.1 (C-11), 25.9 (C-15), 12.8 (C-18) ppm. HRMS:
calcd. for C55H54O11Na [M + Na]+ 913.3564; found 913.3550.
(1ЈR)-13,17-seco-13α-[But-3Ј-en-1Ј-(β-D-galactopyranosyloxy)-1Ј-
yl]-3-methoxyestra-1,3,5(10),16-tetraene (24): Synthesized from 23
(40 mg, 0.044 mmol) according to the general procedure for depro-
tection, providing 24 as a colorless oil (20 mg, 91%). Rf = 0.66
(MeOH/CH2Cl2, 1:5). [α]D = +41.8 (c = 1.3, MeOH). 1H NMR
(600.13 MHz, CD3OD): δ = 7.16 (d, J1,2 = 8.6 Hz, 1 H, 1-H), 6.65
(dd, J2,4 = 2.5 Hz, 1 H, 2-H), 6.57 (d, 1 H, 4-H), 6.17 (dddd, J3Ј,2Јb
= 7.0, J3Ј,2Јa = 7.1, J3Ј,4Јc = 10.2, J3Ј,4Јt = 17.0 Hz, 1 H, 3Ј-H), 5.90
(dddd, J16,15b = 6.3, J16,15a = 7.0, J16,17c = 10.1, J16,17t = 17.0 Hz,
1 H, 16-H), 5.09 (dddd, J4Јt,2Јa = –1.5, J4Јt,2Јb = –1.5, J4Јt,4Јc
–2.1 Hz, 1 H, 4Јt-H), 5.03 (dddd, J17t,15b = –1.7, J17t,17c = –1.8,
J17t,15a = –1.8 Hz, 1 H, 17t-H), 5.00 (dddd, J4Јc,2Јb = –0.9, J4Јc,2Јa
–0.9 Hz, 1 H, 4Јc-H), 4.96 (dddd, J17c,15b = –1.6, J17c,15a = –1.6 Hz,
=
3-Methoxy-D-dihomo-estra-17bβ-(α-D-mannopyranosyloxy)-
1,3,5(10),16-tetraene (26): Synthesized from 25 (119 mg,
0.134 mmol) according to the general procedure for deprotection,
=
1 H, 17c-H), 4.42 (d, J1ЈЈ,2ЈЈ = 7.6 Hz, 1 H, 1ЈЈ-H), 3.91 (dd, J1Ј,2Јa providing 26 as a white solid (53 mg, 98%). Rf = 0.52 (MeOH/
1
= 2.8, J1Ј,2Јb = 8.2 Hz, 1 H, 1Ј-H), 3.83 (dd, J4ЈЈ,5ЈЈ = 1.1, J4ЈЈ,3ЈЈ
=
CH2Cl2, 1:5). H NMR (600.13 MHz, CD3OD): δ = 7.17 (d, J1,2 =
3.5 Hz, 1 H, 4ЈЈ-H), 3.74 (dd, J6ЈЈa,5ЈЈ = 6.6, J6ЈЈa,6ЈЈb = –11.1 Hz, 1 8.6 Hz, 1 H, 1-H), 6.68 (dd, J2,4 = 2.6 Hz, 1 H, 2-H), 6.60 (d, 1 H,
H, 6ЈЈa-H), 3.72 (s, 3 H, 3-OCH3), 3.71 (dd, J6ЈЈb,5ЈЈ = 5.8 Hz, 1 H,
6ЈЈb-H), 3.50 (dd, J2ЈЈ,3ЈЈ = 9.7 Hz, 1 H, 2ЈЈ-H), 3.45 (dd, 1 H, 3ЈЈ-
H), 3.41 (ddd, 1 H, 5ЈЈ-H), 2.80 (ddd, J6a,7eq = 2.6, J6a,7ax = 5.2,
4-H), 5.89 (dddd, J16,17a2 = –2.1, J16,15b = 4.2, J16,15a = 8.3, J16,17
= 9.8 Hz, 1 H, 16-H), 5.60 (dddd, J17,15a = –2.7, J17,17a1 = 5.1,
J17,17a2 = 7.7 Hz, 1 H, 17-H), 4.87 (d, J1Ј,2Ј = 1.6 Hz, 1 H, 1Ј-H),
3.83 (dd, J6Јa,5Ј = 2.4, J6Јa,6Јb = –12.0 Hz, 1 H, 6Јa-H), 3.75 (dd,
J6a,6b = –13.9 Hz, 1 H, 6a-H), 2.78 (ddd, J6b,7eq = 6.3, J6b,7ax
=
11.5 Hz, 1 H, 6b-H), 2.51 (ddddd, J2Јa,2Јb = –14.7 Hz, 1 H, 2Јa-H), J6Јb,5Ј = 5.1 Hz, 1 H, 6Јb-H), 3.75 (s, 3 H, 3-OCH3), 3.74 (dd, J2Ј,3Ј
2.41 (ddddd, 1 H, 2Јb-H), 2.34 (ddddd, J15a,14 = 2.7, J15a,15b
–16.2 Hz, 1 H, 15a-H), 2.23 (dddd, J11eq,12eq = 3.1, J11eq,12ax = 3.8,
J11eq,9 = 4.6, J11eq,11ax = –12.8 Hz, 1 H, 11-Heq), 2.19 (ddd, J9,8
=
= 3.3 Hz, 1 H, 2Ј-H), 3.73 (ddd, J5Ј,4Ј = 9.8 Hz, 1 H, 5Ј-H), 3.72
(dd, J3Ј,4Ј = 9.4 Hz, 1 H, 3Ј-H), 3.68 (dd, 1 H, 4Ј-H), 3.37 (dd,
J17b,17a2 = 1.9, J17b,17a1 = 9.9 Hz, 1 H, 17b-H), 2.83 (ddd, J6a,7eq =
=
10.6, J9,11ax = 14.7 Hz, 1 H, 9-H), 2.18 (dddd, J7eq,8 = 2.4, J7eq,7ax
= –15.4 Hz, 1 H, 7-Heq), 2.00 (ddddd, J15b,14 = 5.0 Hz, 1 H, 15b-
3.1, J6a,7ax = 5.6, J6a,6b = –16.4 Hz, 1 H, 6a-H), 2.80 (ddd, J6b,7eq
= 6.0, J6b,7ax = 11.7 Hz, 1 H, 6b-H), 2.53 (dddd, J17a1,15b = 2.8,
H), 1.82 (ddd, J12eq,11ax = 3.4, J12eq,12ax = –13.4 Hz, 1 H, 12-Heq), J17a1,17a2 = –15.7 Hz, 1 H, 17a1-H), 2.30 (dddd, J11eq,12eq = 2.8,
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Eur. J. Org. Chem. 2011, 1064–1077

Estradiol-Based Glycosteroid Mimics
J11eq,12ax = 3.5, J11eq,9 = 3.6, J11eq,11ax = –15.1 Hz, 1 H, 11-Heq), J17b,17a2 = 3.0, J17b,17a1 = 10.4 Hz, 1 H, 17b-H), 2.81 (ddd, J6a,7eq
2.28 (dddd, 1 H, 17a2-H), 2.23 (dddd, J15a,14 = 1.3, J15a,15b
=
= 4.5, J6a,7ax = 5.6, J6a,6b = –16.4 Hz, 1 H, 6a-H), 2.78 (ddd, J6b,7eq
–15.5 Hz, 1 H, 15a-H), 2.12 (dddd, J7eq,8 = 2.7, J7eq,7ax = –13.3 Hz, = 6.5, J6b,7ax = 12.8 Hz, 1 H, 6b-H), 2.60 (ddddd, J17a1,17a2
=
1 H, 7-Heq), 2.06 (ddd, J15a,14 = 10.5 Hz, 1 H, 15b-H), 1.45 (dddd, –15.3 Hz, 1 H, 17a1-H), 2.38 (ddd, 1 H, 17a2-H), 2.22 (dddd,
J11ax,12ax = 13.8 Hz, 1 H, 11-Hax), 1.43 (ddd, 1 H, 12-Hax), 1.30 J11eq,12ax = 3.2, J11eq,12eq = 4.3, J11eq,9 = 4.3, J11eq,11ax = –12.6 Hz,
(ddd, J14,8 = 10.3 Hz, 1 H, 14-H), 1.27 (dddd, J7ax,8 = 9.7 Hz, 1 H,
1 H, 11-Heq), 2.21 (ddd, J9,8 = 8.7, J9,11ax = 14.0 Hz, 1 H, 9-H),
7-Hax), 1.22 (dddd, 1 H, 8-H), 1.05 (s, 3 H, 18-H) ppm. 13C NMR 2.19 (ddd, J15a,14 = 1.0, J15a,15b = –15.6 Hz, 1 H, 15a-H), 2.16
(150.9 MHz, CD3OD): δ = 158.7 (C-3), 138.9 (C-5), 135.3 (C-16), (dddd, J7eq,8 = 1.8, J7eq,7ax = –11.7 Hz, 1 H, 7-Heq), 2.00 (ddd,
134.3 (C-10), 126.8 (C-17), 126.7 (C-1), 113.9 (C-4), 112.3 (C-2),
J12eq,11ax = 3.8, J12eq,12ax = –12.9 Hz, 1 H, 12-Heq), 1.95 (ddddd,
98.2 (C-1Ј), 83.7 (C-17b), 75.2 (C-2Ј), 72.8 (C-5Ј), 72.5 (C-3Ј), 68.2 J15b,14 = 8.5 Hz, 1 H, 15b-H), 1.43 (dddd, J11ax,12ax = 11.3 Hz, 1
(C-4Ј), 62.7 (C-6Ј), 55.5 (3-OCH3), 50.2 (C-14), 44.4 (C-9), 43.6 (C-
H, 11-Hax), 1.34 (d, 1 H, 6Ј-H), 1.32 (ddd, 1 H, 12-Hax), 1.26 (dddd,
J7ax,8 = 11.3 Hz, 1 H, 7-Hax), 1.18 (ddd, J14,8 = 10.0 Hz, 1 H, 14-
13), 40.6 (C-8), 39.6 (C-12), 31.1 (C-6), 28.8 (C-7), 28.2 (C-17a),
27.0 (C-11), 26.7 (C-15), 13.3 (C-18) ppm. HRMS: calcd. for H), 1.18 (dddd, 1 H, 8-H), 0.96 (s, 3 H, 18-H) ppm. 13C NMR
C
27H38O7Na [M + Na]+ 498.2515; found 498.2504. Calcd. for (150.9 MHz, CDCl3): δ = 157.5 (C-3), 138.1 (C-5), 133.6 (C-16),
C27H38O7K [M + K]+ 513.2255; found 513.2238.
133.3 (C-10), 126.3 (C-17), 125.9 (C-1), 113.2 (C-4), 111.4 (C-2),
102.8 (C-1Ј), 89.8 (C-17b), 73.1 (C-4Ј), 72.0 (C-3Ј), 71.2 (C-2Ј), 68.4
(C-5Ј), 55.2 (3-OCH3), 48.8 (C-14), 43.4 (C-13), 43.2 (C-9), 39.6
(C-8), 38.1 (C-12), 31.4 (C-17a), 30.2 (C-6), 27.9 (C-7), 26.2 (C-
15), 25.9 (C-11), 17.5 (C-6Ј), 12.6 (C-18) ppm. HRMS: calcd. for
C27H38O6Na [M + Na]+ 481.2566; found 481.2552.
3-Methoxy- -dihomo-estra-17bβ-(2Ј,3Ј,4Ј-tri-O-benzoyl-α-L-rhamno-
D
pyranosyloxy)-1,3,5(10),16-tetraene (27): Synthesized from 17
(164 mg, 0.205 mmol) according to the general procedure for ring-
closing metathesis, providing 27 as a white foam (159 mg, quant.).
Rf = 0.29 (hexane/EtOAc, 4:1). [α]D = +76.3 (c = 0.15, CHCl3). 1H
NMR (600.13 MHz, CDCl3): δ = 8.13–7.23 (m, 15 H, arom. H), 3-Methoxy-D-dihomo-estra-17bβ-(2Ј,3Ј,4Ј,6Ј-tetra-O-benzoyl-β-D-glu-
7.24 (d, J1,2 = 8.4 Hz, 1 H, 1-H), 6.74 (dd, J2,4 = 2.6 Hz, 1 H, 2-
H), 6.64 (d, 1 H, 4-H), 5.91 (dddd, J16,17a1 = –1.9, J16,15b = 4.4,
copyranosyloxy)-1,3,5(10),16-tetraene (29): Synthesized from 20
(98 mg, 0.107 mmol) according to the general procedure for ring-
J16,15a = 8.2, J16,17 = 10.5 Hz, 1 H, 16-H), 5.83 (dd, J3Ј,2Ј = 3.5, closing metathesis, providing 29 as a white foam (69 mg, 72%). Rf
J3Ј,4Ј = 10.0 Hz, 1 H, 3Ј-H), 5.72 (dd, J4Ј,5Ј = 10.0 Hz, 1 H, 4Ј-H),
5.68 (dd, J2Ј,1Ј = 1.6 Hz, 1 H, 2Ј-H), 5.63 (dddd, J17,17a1 = 3.0,
= 0.29 (hexane/EtOAc, 4:1). [α]D = +8.5 (c = 0.15, CHCl3). 1H
NMR (600.13 MHz, CDCl3): δ = 8.05–7.28 (m, 20 H, arom. H),
J17,15b = –4.7, J17,17a2 = 7.7 Hz, 1 H, 17-H), 5.12 (d, 1 H, 1Ј-H), 6.87 (d, J1,2 = 8.6 Hz, 1 H, 1-H), 6.67 (dd, J2,4 = 2.7 Hz, 1 H, 2-
4.33 (dq, J5Ј,6Ј = 6.3 Hz, 1 H, 5Ј-H), 3.77 (s, 3 H, 3-OCH3), 3.35
(dd, J17b,17a2 = 2.7, J17b,17a1 = 10.6 Hz, 1 H, 17b-H), 2.86 (ddd,
H), 6.58 (d, 1 H, 4-H), 5.92 (dd, J3Ј,4Ј = 9.5, J3Ј,2Ј = 9.9 Hz, 1 H,
3Ј-H), 5.79 (dddd, J16,17a1 = –2.5, J16,15b = 4.5, J16,15a = 8.9, J16,17
J6a,7eq = 3.5, J6a,7ax = 5.0, J6a,6b = –16.1 Hz, 1 H, 6a-H), 2.83 (ddd, = 9.9 Hz, 1 H, 16-H), 5.61 (dd, J4Ј,5Ј = 9.9 Hz, 1 H, 4Ј-H), 5.59
J6b,7eq = 6.6, J6b,7ax = 12.1 Hz, 1 H, 6b-H), 2.77 (dddddd, J17a1,15a (dd, J2Ј,1Ј = 7.9 Hz, 1 H, 2Ј-H), 5.31 (dddd, J17,15b = –2.6, J17,17a1
= 0.9, J17a1,15b = 5.3, J17a1,17a2 = –15.6 Hz, 1 H, 17a1-H), 2.47 (ddd, = 3.8, J17,17a2 = 8.4 Hz, 1 H, 17-H), 4.92 (d, 1 H, 1Ј-H), 4.66 (dd,
1 H, 17a2-H), 2.37 (dddd, J11eq,12eq = 3.0, J11eq,12ax = 3.8, J11eq,9 J6Јa,5Ј = 3.1, J6Јa,6Јb = –12.0 Hz, 1 H, 6Јa-H), 4.50 (dd, J6Јb,5Ј
4.2, J11eq,11ax = –13.1 Hz, 1 H, 11-Heq), 2.29 (ddd, J9,8 = 8.8, J9,11ax
= 12.9 Hz, 1 H, 9-H), 2.27 (ddd, J12eq,11ax = 3.4, J12eq,12ax
=
=
–6.5 Hz, 1 H, 6Јb-H), 4.16 (ddd, 1 H, 5Ј-H), 3.75 (s, 3 H, 3-OCH3),
3.63 (dd, J17b,17a2 = 2.8, J17b,17a1 = 11.1 Hz, 1 H, 17b-H), 2.78 (ddd,
=
–13.0 Hz, 1 H, 12-Heq), 2.28 (ddd, J15a,14 = 1.0, J15a,15b = –16.0 Hz, J6a,7eq = 3.3, J6a,7ax = 5.7, J6a,6b = –16.9 Hz, 1 H, 6a-H), 2.74 (ddd,
1 H, 15a-H), 2.23 (dddd, J7eq,8 = 1.8, J7eq,7ax = –12.7 Hz, 1 H, 7- J6b,7eq = 6.2, J6b,7ax = 10.9 Hz, 1 H, 6b-H), 2.67 (ddddd, J17a1,15b
Heq), 2.08 (ddddd, J15b,14 = 5.6 Hz, 1 H, 15b-H), 1.54 (dddd,
J11ax,12ax = 13.2 Hz, 1 H, 11-Hax), 1.47 (ddd, 1 H, 12-Hax), 1.37 (d,
1 H, 6Ј-H), 1.32 (dddd, J7ax,8 = 14.1 Hz, 1 H, 7-Hax), 1.28 (dddd,
J8,14 = 12.3 Hz, 1 H, 8-H), 1.26 (ddd, 1 H, 14-H), 1.16 (s, 3 H, 18-
H) ppm. 13C NMR (150.9 MHz, CDCl3): δ = 165.8 (4Ј-OCOPh),
= 2.5, J17a1,17a2 = –15.7 Hz, 1 H, 17a1-H), 2.56 (ddd, 1 H, 17a2-
H), 2.13 (dddd, J7eq,8 = 3.2, J7eq,7ax = –13.2 Hz, 1 H, 7-Heq), 2.13
(ddd, J15a,14 = 0.1, J15a,15b = –15.7 Hz, 1 H, 15a-H), 2.02 (ddd,
J9,11eq = 4.1, J9,8 = 10.6, J9,11ax = 11.5 Hz, 1 H, 9-H), 1.91 (ddddd,
J15b,14 = 10.1 Hz, 1 H, 15b-H), 1.90 (ddd, J12eq,11eq = 3.3, J12eq,11ax
165.7 (2Ј-OCOPh), 165.6 (3Ј-OCOPh), 157.5 (C-3), 138.1 (C-5), = 3.3, J12ax,12eq = –13.4 Hz, 1 H, 12-Heq), 1.50 (dddd, J11eq,12ax
134.0 (C-16), 134.0–128.3 (arom. C), 133.2 (C-10), 126.1 (C-1, C- 4.0, J11eq,11ax = –13.9 Hz, 1 H, 11-Heq), 1.22 (dddd, J7a,8 = 10.5 Hz,
17), 113.3 (C-4), 111.4 (C-2), 100.2 (C-1Ј), 90.6 (C-17b), 71.9 (C- 1 H, 7ax), 1.06 (ddd, J14,8 = 11.1 Hz, 1 H, 14-H), 1.06 (dddd, 1 H,
4Ј), 71.1 (C-2Ј), 70.2 (C-3Ј), 67.1 (C-5Ј), 55.2 (3-OCH3), 48.8 (C- 8-H), 1.05 (ddd, J12ax,11ax = 13.3 Hz, 1 H, 12-Hax), 0.90 (dddd, 1 H,
14), 43.4 (C-9), 43.2 (C-13), 39.6 (C-8), 37.9 (C-12), 31.5 (C-17a),
11-Hax), 0.82 (s, 3 H, 18-H) ppm. 13C NMR (150.9 MHz, CDCl3): δ
=
30.3 (C-6), 27.9 (C-7), 26.3 (C-15), 26.0 (C-11), 17.6 (C-6Ј), 12.7 = 166.1 (6Ј-OCOPh), 165.9 (3Ј-OCOPh), 165.3 (4Ј-OCOPh), 165.1
(C-18) ppm. HRMS: calcd. for C48H50O9Na [M + Na]+ 793.3353;
found 793.3331. Calcd. for C48H54O9N [M + NH4]+ 788.3799;
found 788.3768.
(2Ј-OCOPh), 157.5 (C-3), 138.1 (C-5), 133.8 (C-16), 133.5–128.3
(arom. C), 133.3 (C-10), 126.8 (C-17), 125.7 (C-1), 113.1 (C-4),
111.4 (C-2), 103.6 (C-1Ј), 90.5 (C-17b), 72.9 (C-3Ј), 72.2 (C-2Ј),
72.1 (C-5Ј), 70.1 (C-4Ј), 63.4 (C-6Ј), 55.2 (3-OCH3), 48.8 (C-14),
43.5 (C-13), 43.0 (C-9), 39.4 (C-8), 37.8 (C-12), 31.9 (C-17a), 30.2
(C-6), 27.9 (C-7), 25.9 (C-15), 25.0 (C-11), 12.0 (C-18) ppm.
HRMS: calcd. for C55H54O11Na [M + Na]+ 913.3558; found
913.3545. Calcd. for C55H54O11K [M + K]+ 929.3298; found
929.3284.
3-Methoxy-D-dihomo-estra-17bβ-(α-L-rhamnopyranosyloxy)-
1,3,5(10),16-tetraene (28): Synthesized from 27 (155 mg,
0.200 mmol) according to the general procedure for deprotection,
providing 28 as a white solid (71 mg, quant.). Rf = 0.17 (EtOAc).
[α]D = –32.5 (c = 0.08, CHCl3). 1H NMR (600.13 MHz, CDCl3): δ
= 7.15 (d, J1,2 = 8.6 Hz, 1 H, 1-H), 6.68 (dd, J2,4 = 2.4 Hz, 1 H, 2-
H), 6.61 (d, 1 H, 4-H), 5.83 (dddd, J16,17a1 = –2.1, J16,15b = 4.3, 3-Methoxy-D-dihomo-estra-17bβ-(β-D-glucopyranosyloxy)-
J16,15a = 8.3, J16,17 = 10.4 Hz, 1 H, 16-H), 5.58 (dddd, J17,17a1
2.6, J17,15b = –4.4, J17,17a2 = 7.7 Hz, 1 H, 17-H), 4.84 (d, J1Ј,2Ј
=
=
1,3,5(10),16-tetraene (30): Synthesized from 29 (66 mg,
0.075 mmol) according to the general procedure for deprotection,
1.6 Hz, 1 H, 1Ј-H), 4.00 (dd, J2Ј,3Ј = 3.3 Hz, 1 H, 2Ј-H), 3.81 (dq,
J5Ј,6Ј = 6.3, J5Ј,4Ј = 9.0 Hz, 1 H, 5Ј-H), 3.78 (dd, J3Ј,4Ј = 9.6 Hz, 1
providing 30 as a white solid (29 mg, 82%). Rf = 0.66 (MeOH/
1
CH2Cl2, 1:5). H NMR (600.13 MHz, CD3OD): δ = 7.15 (d, J1,2
=
H, 3Ј-H), 3.75 (s, 3 H, 3-OCH3), 3.52 (dd, 1 H, 4Ј-H), 3.21 (dd, 8.6 Hz, 1 H, 1-H), 6.66 (dd, J2,4 = 2.7 Hz, 1 H, 2-H), 6.59 (d, 1 H,
Eur. J. Org. Chem. 2011, 1064–1077
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1075

J. Wölfling, R. Leino et al.
FULL PAPER
4-H), 5.84 (dddd, J16,17a1 = –4.6, J16,15b = 2.8, J16,15a = 8.7, J16,17
= 10.3 Hz, 1 H, 16-H), 5.66 (dddd, J17,17a1 = 2.2, J17,15b = –4.5,
J17,17a2 = 8.6 Hz, 1 H, 17-H), 4.36 (d, J1Ј,2Ј = 7.7 Hz, 1 H, 1Ј-H),
3.85 (dd, J6Јa,5Ј = 2.4, J6Јa,6Јb = –11.8 Hz, 1 H, 6Јa-H), 3.73 (s, 3 H,
3-Methoxy-
D
-dihomo-estra-17bα-(β-
D
-galactopyranosyloxy)-1,3,
5(10),16-tetraene (32): Synthesized from 31 (63 mg, 0.071 mmol)
according to the general procedure for deprotection, providing 32
as a white solid (27 mg, 90%). Rf = 0.33 (hexane/EtOAc, 4:1). [α]D
1
3-OCH3), 3.69 (dd, J6Јb,5Ј = 5.5 Hz, 1 H, 6Јb-H), 3.34 (dd, J3Ј,4Ј
=
= +27.0 (c = 0.10, MeOH). H NMR (600.13 MHz, CD3OD): δ =
8.5, J3Ј,2Ј = 9.5 Hz, 1 H, 3Ј-H), 3.30 (dd, J4Ј,5Ј = 10.0 Hz, 1 H, 4Ј- 7.16 (d, J1,2 = 8.6 Hz, 1 H, 1-H), 6.66 (dd, J2,4 = 2.7 Hz, 1 H, 2-
H), 3.25 (dd, J17b,17a2 = 2.7, J17b,17a1 = 11.0 Hz, 1 H, 17b-H), 3.25
(ddd, 1 H, 5Ј-H), 3.20 (dd, 1 H, 2Ј-H), 2.82 (ddd, J6a,7eq = 2.1,
J6a,7ax = 5.8, J6a,6b = –16.2 Hz, 1 H, 6a-H), 2.78 (ddd, J6b,7eq = 5.6, –3.1, J17,17a1 = 3.8, J17,17a2 = 6.6 Hz, 1 H, 17-H), 4.21 (d, J1Ј,2Ј
H), 6.58 (d, 1 H, 4-H), 5.73 (dddd, J16,17a2 = –1.3, J16,15b = 2.9,
J16,15a = 7.9, J16,17 = 10.8 Hz, 1 H, 16-H), 5.59 (dddd, J17,15b
=
=
J6b,7ax = 11.3 Hz, 1 H, 6b-H), 2.63 (ddddd, J17a1,15b = 2.3, J17a1,17a2
= –15.4 Hz, 1 H, 17a1-H), 2.59 (ddd, 1 H, 17a2-H), 2.50 (ddd,
7.7 Hz, 1 H, 1Ј-H), 3.85 (dd, J4Ј,5Ј = 1.0, J4Ј,3Ј = 3.4 Hz, 1 H, 4Ј-
H), 3.75 (dd, J6Јa,5Ј = 6.1, J6Јa,6Јb = –11.2 Hz, 1 H, 6Јa-H), 3.73 (s,
J12eq,11eq = 2.6, J12eq,11ax = 4.3, J12eq,12ax = –13.7 Hz, 1 H, 12-Heq), 3 H, 3-OCH3), 3.72 (dd, J6Јb,5Ј = 6.4 Hz, 1 H, 6Јb-H), 3.64 (dd,
2.25 (dddd, J11eq,12ax = 3.6, J11eq,9 = 3.7, J11eq,11ax = –12.8 Hz, 1 H,
11-Heq), 2.22 (dddd, J7eq,8 = 3.2, J7eq,7ax = –13.0 Hz, 1 H, 7-Heq),
2.22 (ddd, J9,8 = 11.6, J9,11ax = 12.5 Hz, 1 H, 9-H), 2.21 (ddd, J15a,14
J17b,17a2 = 1.6, J17b,17a1 = 9.1 Hz, 1 H, 17b-H), 3.50 (dd, J2Ј,3Ј =
9.7 Hz, 1 H, 2Ј-H), 3.47 (dd, 1 H, 3Ј-H), 3.46 (ddd, 1 H, 5Ј-H),
2.81 (ddd, J6a,7eq = 4.6, J6a,7ax = 5.0, J6a,6b = –16.3 Hz, 1 H, 6a-H),
2.78 (ddd, J6b,7eq = 5.7, J6b,7ax = 13.1 Hz, 1 H, 6b-H), 2.61 (dddd,
J17a1,15b = 3.1, J17a1,17a2 = –17.1 Hz, 1 H, 17a1-H), 2.31 (ddd, J15a,14
= 1.1, J15a,15b = –16.5 Hz, 1 H, 15a-H), 2.29 (dddd, J11eq,12eq = 3.4,
J11eq,9 = 3.7, J11eq,12ax = 3.8, J11eq,11ax = –12.8 Hz, 1 H, 11-Heq),
= 0.6, J15a,15b = –15.7 Hz, 1 H, 15a-H), 2.03 (ddddd, J15a,14
=
10.2 Hz, 1 H, 15b-H), 1.38 (dddd, J11ax,12ax = 12.5 Hz, 1 H, 11-
Hax), 1.33 (ddd, 1 H, 12-Hax), 1.27 (dddd, J7ax,8 = 9.6 Hz, 1 H,
7ax), 1.16 (ddd, J14,8 = 10.9 Hz, 1 H, 14-H), 1.16 (dddd, 1 H, 8-H),
1.06 (s, 3 H, 18-H) ppm. 13C NMR (150.9 MHz, CDCl3): δ = 159.0
(C-3), 139.1 (C-5), 134.7 (C-16), 134.6 (–10), 128.6 (C-17), 126.8
2.26 (ddddd, J17a1,15b = 2.3 Hz, 1 H, 17a2-H), 2.22 (ddd, J9,8
=
10.1, J9,11ax = 12.1 Hz, 1 H, 9-H), 2.17 (dddd, J7eq,8 = 2.9, J7eq,7ax
(C-1), 114.1 (C-4), 112.4 (C-2), 106.7 (C-1Ј), 89.9 (C-17b), 78.3 (C- = –12.8 Hz, 1 H, 7-Heq), 1.96 (ddddd, 1 H, 15b-H), 1.86 (ddd,
3Ј), 77.7 (C-5Ј), 75.9 (C-2Ј), 71.7 (C-4Ј), 62.8 (C-6Ј), 55.5 (3-OCH3), J12ax,11ax = 13.5, J12ax,12eq = –13.5 Hz, 1 H, 12-Hax), 1.68 (ddd,
50.5 (C-14), 44.9 (C-13), 44.7 (C-9), 39.0 (C-8), 33.2 (C-17a), 31.3 J12eq,11ax = 3.5 Hz, 1 H, 12-Heq), 1.66 (ddd, J14,8 = 12.0 Hz, 1 H,
(C-6), 29.3 (C-7), 29.3 (C-7), 27.0 (C-11, C-15), 12.7 (C-18) ppm. 14-H), 1.44 (dddd, 1 H, 11-Hax), 1.26 (dddd, J8,7a = 9.6 Hz, 1 H,
HRMS: calcd. for C27H38O7Na [M + Na]+ 497.2515; found
497.2500.
8-H), 1.22 (dddd, 1 H, 7ax), 1.04 (s, 3 H, 18-H) ppm. 13C NMR
(150.9 MHz, CDCl3): δ = 159.0 (C-3), 139.0 (C-5), 134.6 (C-10),
133.0 (C-16), 128.2 (C-17), 127.0 (C-1), 114.1 (C-4), 112.5 (C-2),
103.1 (C-1Ј), 86.2 (C-17b), 76.5 (C-5Ј), 75.2 (C-3Ј), 72.6 (C-2Ј), 70.3
(C-4Ј), 62.3 (C-6Ј), 55.6 (3-OCH3), 46.5 (C-14), 45.1 (C-9), 41.7 (C-
13), 40.6 (C-8), 34.0 (C-12), 31.3 (C-6), 29.5 (C-17a), 28.6 (C-7),
27.4 (C-11), 27.3 (C-15), 17.7 (C-18) ppm. HRMS: calcd. for
C27H38O7Na [M + Na]+ 497.2515; found 497.2510.
3-Methoxy-D-dihomo-estra-17bα-(2Ј,3Ј,4Ј,6Ј-tetra-O-benzoyl-β-D-ga-
lactopyranosyloxy)-1,3,5(10),16-tetraene (31): Synthesized from 23
(89 mg, 0.097 mmol) according to the general procedure for ring-
closing metathesis, providing 31 as a colorless oil (65 mg, 75%). Rf
= 0.33 (hexane/EtOAc, 4:1). [α]D = +32.2 (c = 0.27, CHCl3). 1H
NMR (600.13 MHz, CDCl3): δ = 8.11–7.20 (m, 20 H, arom. H),
7.21 (d, J1,2 = 8.6 Hz, 1 H, 1-H), 6.72 (dd, J2,4 = 2.7 Hz, 1 H, 2-
H), 6.62 (d, 1 H, 4-H), 5.99 (dd, J4Ј,5Ј = 1.2, J4Ј,3Ј = 3.6 Hz, 1 H,
4Ј-H), 5.79 (dd, J2Ј,1Ј = 7.9, J2Ј,3Ј = 10.4 Hz, 1 H, 2Ј-H), 5.64 (dd,
1 H, 3Ј-H), 5.50 (dddd, J16,17a2 = –1.3, J16,15b = 2.3, J16,15a = 8.0,
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of all new compounds.
J16,17 = 10.8 Hz, 1 H, 16-H), 5.31 (dddd, J17,15a = –2.5, J17,17a1
5.2, J17,17a2 = 5.8 Hz, 1 H, 17-H), 4.81 (d, 1 H, 1Ј-H), 4.68 (dd,
J6Јa,5Ј = 6.8, J6Јa,6Јb = –11.3 Hz, 1 H, 6Јa-H), 4.43 (dd, J6Јb,5Ј
–6.6 Hz, 1 H, 6Јb-H), 4.29 (ddd, 1 H, 5Ј-H), 3.77 (s, 3 H, 3-OCH3),
3.63 (dd, J17b,17a2 = 1.6, J17b,17a1 = 8.5 Hz, 1 H, 17b-H), 2.80 (ddd,
J6a,7eq = 3.6, J6a,7ax = 5.7, J6a,6b = –11.3 Hz, 1 H, 6a-H), 2.77 (ddd,
=
Acknowledgments
=
Financial support from the Academy of Finland (projects 121334
and 121335), the Hungarian Scientific Research Dunf (OTKA
K7309) and the New Hungary Development Plan (TÁMOP 4.2.2-
08/01-2008-0002) is gratefully acknowledged. The authors thank
Monika Poláková (Slovak Academy of Science) and Chinmoy
Mukherjee (Åbo Akademi University) for fruitful discussions, Jari
Sinkkonen (University of Turku) for help with the NMR charac-
terization of the compounds, Tiina Saloranta (Åbo Akademi Uni-
versity) for providing acceptors 2 and 3, and Markku Reunanen
(Åbo Akademi University) for HRMS analyses.
J6b,7eq = 6.2, J6b,7ax = 12.4 Hz, 1 H, 6b-H), 2.40 (dddd, J17a1,15b
3.4, J17a1,17a2 = –17.9 Hz, 1 H, 17a1-H), 2.27 (dddd, J11eq,12eq
=
=
2.9, J11eq,12ax = 3.9, J11eq,9 = 4.0, J11eq,11ax = –13.0 Hz, 1 H, 11-Heq),
2.23 (ddd, J9,8 = 10.5, J9,11ax = 12.4 Hz, 1 H, 9-H), 2.17 (dddd, 1
H, 17a2-H), 2.15 (dddd, J15a,14 = 0.2, J15a,15b = –17.5 Hz, 1 H, 15a-
H), 2.03 (dddd, J7eq,8 = 2.8, J7eq,7ax = –12.2 Hz, 1 H, 7-Heq), 1.83
(ddd, J12ax,11ax = 13.8, J12ax,12eq = –13.3 Hz, 1 H, 12-Hax), 1.79
(dddd, 1 H, 15b-H), 1.82 (ddd, J12eq,11ax = 3.7 Hz, 1 H, 12-Heq),
1.53 (ddd, J14,8 = 11.1 Hz, 1 H, 14-H), 1.47 (dddd, 1 H, 11-Hax),
1.22 (dddd, J8,7a = 10.4 Hz, 1 H, 8-H), 1.15 (dddd, 1 H, 7ax), 0.97
(s, 3 H, 18-H) ppm. 13C NMR (150.9 MHz, CDCl3): δ = 166.0 (6Ј-
OCOPh), 165.7 (4Ј-OCOPh), 165.6 (3Ј-OCOPh), 165.1 (2Ј-OC-
OPh), 157.4 (C-3), 138.1 (C-5), 133.6 (C-10), 133.5–128.3 (arom.
C), 132.3 (C-16), 126.5 (C-1), 125.8 (C-17), 113.2 (C-4), 111.4 (C-
2), 99.3 (C-1Ј), 84.7 (C-17b), 71.8 (C-3Ј), 71.3 (C-5Ј), 69.9 (C-2Ј),
68.3 (C-4Ј), 62.0 (C-6Ј), 55.2 (3-OCH3), 44.0 (C-14), 43.3 (C-9),
40.7 (C-13), 39.0 (C-8), 33.2 (C-12), 30.2 (C-6), 27.8 (C-17a), 27.1
(C-7), 26.3 (C-15), 26.0 (C-11), 17.0 (C-18) ppm. HRMS: calcd.
for C55H54O11Na [M + Na]+ 913.3564; found 913.3552. Calcd. for
C55H54O11K [M + K]+ 929.3303; found 929.3301.
[1] See, for example: a) R. Higuchi, M. Fujita, S. Matsumoto, K.
Yamada, T. Miyamoto, T. Sasaki, Liebigs Ann. 1996, 837; b)
S. Kubo, Y. Mimaki, M. Terao, Y. Sashida, T. Nikaido, T.
Ohmoto, Phytochemistry 1992, 31, 3969; c) K. Tashibana, M.
Sakaitani, K. Nakanishi, Science 1984, 226, 703; d) C.-R.
Yang, O. Tanaka, in: Studies of Plant Science; Advances in
Plant Glycosides, Chemistry and Biology, Elsevier, Amsterdam,
1999, vol. 6.
[2] See, for example: a) J. Dornand, J. Favero, J. C. Bonnafous,
J. C. Mani, Cell Immunol. 1984, 83, 351; b) D. Daniel, C. Süsal,
B. Kopp, G. Opelz, P. Terness, Int. Immunopharmcol. 2003, 3,
1791; c) P. Avato, R. Bucci, A. Tava, C. Vitali, A. Rosato, Z.
Bialy, M. Jurzysta, Phytoter. Res.2006, 20, 454; d) R. Kukhetpi-
1076
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1064–1077

Estradiol-Based Glycosteroid Mimics
takwong, C. Hahnvajanawong, P. Homchampa, V. Leelavatch-
aramas, J. Satra, W. Khunkitti, Int. Immunopharmcol. 2006, 6,
1729.
[16]
See, for example: a) M. M. D. S. Cepa, E. J. T. da Silva, G. Cor-
reia-da-Silva, F. M. F. Roleira, N. A. A. Teixeira, J. Med.
Chem. 2005, 48, 6379; b) D. S. Fischer, S. K. Chander, L. W.
Lawrence Woo, J. C. Fenton, A. Purohit, M. J. Reed, B. V. L.
Potter, J. Steroid Biochem. Mol. Biol. 2003, 84, 343; c) B.
Green, K. Sheu, Steroids 1994, 59, 479.
[3] See, for example: a) M. López-Lázaro, N. Pastor, S. S. Azrak,
M. J. Ayuso, C. A. Austin, F. Cortéz, J. Nat. Prod. 2005, 68,
1642; b) T. Godfraind, J. Cardiovasc. Pharmacol. 1989, 14, 1; c)
M.-A. Lacaille-Dubois, A.-C. Mitaine Offer, Phytochem. Rev.
2005, 4, 139.
[4] B. Davis, J. Chem. Soc. Perkin Trans. 1 1999, 3215.
[5] a) H. R. Axelrod, J. S. Kim, C. B. Longley, E. Lipka, G. L.
Amidon, R. Kakarla, Y. W. Hui, S. J. Weber, S. Choe, M. J.
Sofia, Pharm. Res. 1998, 15, 1876; b) B. P. Ross, S. E. DeCruz,
T. B. Lynch, K. Davies-Goff, I. Toth, J. Med. Chem. 2004, 47,
1251.
[6] a) P. Chandra, D. Gericke, F. Zunino, B. C. G. Kornhuber,
Pharmacol. Res. Commun. 1972, 4, 269; b) W. E. Steinmetz,
B. L. Shapiro, J. J. Roberts, J. Med. Chem. 2002, 45, 4899.
[7] See, for example: a) P. Tang, B. Yu, Eur. J. Org. Chem. 2009,
259; b) W. Yu, Z. Jin, J. Am. Chem. Soc. 2002, 124, 6576; c)
J. R. Williams, H. Gong, N. Hoff, O. I. Olubodun, J. Org.
Chem. 2005, 70, 10732.
[8] a) G. Schneider, J. Wölfling, Curr. Org. Chem. 2004, 8, 1381;
b) J. Wölfling, L. Hackler, E. Mernyák, G. Schneider, I. Tóth,
M. Szécsi, J. Julesz, P. Sohár, A. Csámpai, Steroids 2004, 69,
451; c) J. Wölfling, É. A. Oravecz, D. Ondré, E. Mernyák, G.
Schneider, I. Tóth, M. Szécsi, J. Julesz, Steroids 2006, 71, 809;
d) D. Ondré, J. Wölfling, I. Tóth, M. Szécsi, J. Julesz, G.
Schneider, Steroids 2009, 74, 520; Z. Iványi, J. Wölfling, T.
Görbe, M. Szécsi, T. Wittmann, G. Schneider, Steroids 2010,
75, 450.
[9] For a review, see: a) H. Pellissier, Tetrahedron 2004, 60, 5123;
b) B. Yu, Y. Zhang, P. Tang, Eur. J. Org. Chem. 2007, 5145.
[10] See, for example: a) T. Fotsis, Y. Zhang, M. S. Pepper, H. Ad-
lercreutz, Nature 1994, 368, 237; b) V. Raymond, M. Beaulieu,
F. Labrie, J. Boissier, Science 1978, 200, 1173; c) E. Vegeto, S.
Belcredito, S. Etteri, S. Ghisletti, A. Brusadelli, C. Meda, A.
Krust, S. Dupont, P. Ciana, P. Chambon, A. Maggi, Proc. Natl.
Acad. Sci. USA 2003, 100, 9614.
[11] See, for example: a) C. B. Guzmán, S. Deighton-Collins, A.
Martinez, M. Kleerkoper, C. Zhao, J. A. Benjamins, D. F.
Skafar, Neuro. Endocrinol. Lett.2005, 5, 526; b) E. Vegeto, S.
Cuzzocrea, C. Crisafulli, E. Mazzon, A. Sala, A. Krust, A.
Maggi, Endocrinology 2010, 1, 174; c) R. L. Cruess, K. C.
Hong, Calcif. Tiss. Res.1976, 20, 317.
[17]
[18]
J. R. Williams, H. Gong, Lipids 2007, 42, 77.
See, for example: a) H. Hosoda, K. Osanai, T. Nambara,
Chem. Pharm. Bull. 1991, 39, 3283; b) J. R. Ferguson, J. R.
Harding, K. W. Lumbard, F. Scheinmann, A. W. Stachulski,
Tetrahedron Lett. 2000, 41, 389; c) M. Liu, B. Yu, Y. Hui, Tetra-
hedron Lett. 1998, 39, 415.
a) M. Poláková, M. U. Roslund, F. S. Ekholm, T. Saloranta,
R. Leino, Eur. J. Org. Chem. 2009, 870; b) F. S. Ekholm, M.
Poláková, A. J. Pawłowicz, R. Leino, Synthesis 2009, 567.
See, for example: a) G. H. Veeneman, J. H. van Boom, Tetrahe-
dron Lett. 1990, 31, 275; b) P. Konradsson, U. E. Udodong, B.
Fraser-Reid, Tetrahedron Lett. 1990, 31, 4313.
See, for example: a) D. Crich, H. Li, Q. Yao, D. J. Wink, D. R.
Sommer, A. L. Rheingold, J. Am. Chem. Soc. 2001, 123, 5826;
b) D. Crich, S. Chandrasekera, Angew. Chem. Int. Ed. 2004,
43, 5386.
See, for example: a) R. R. Schmidt, Angew. Chem. Int. Ed.
Engl. 1986, 25, 212; b) A. J. Fairbanks, C. M. P. Seward, in:
Carbohydrates (Ed.: H. Osborn), Academic Press, Oxford,
2003, p. 147–165; c) R. V. Stick, Carbohydrates: the Sweet Mo-
lecules of Life, Academic Press, London, 2001, p. 133–137.
See, for example: S. Deng, B. Yu, J. Xie, Y. Hui, J. Org. Chem.
1999, 64, 7265.
[19]
[20]
[21]
[22]
[23]
[24] Similar effects have been observed previously. See, for example:
a) R. U. Lemieux, Chem. Can. 1964, 16, 14; b) P. J. Garegg, T.
Norberg, Acta Chem. Scand. 1979, 33, 116; c) N. I. Uvarova,
G. I. Oshitok, B. Elyakov, Carbohydr. Res. 1973, 27, 79.
[25] M. A. Brimble, R. Kowalczyk, P. W. R. Harris, P. R. Dunbar,
V. J. Muir, Org. Biomol. Chem. 2008, 6, 112.
[26] a) G. Zemplén, Á. Gerecs, I. Hadácsy, Ber. Dtsch. Chem. Ges.
1936, 69, 1827; b) J. Robertson, P. M. Stafford, in: Carbo-
hydrates (Ed.: H. Osborn), Academic Press, Oxford, 2003, p.
22–67.
[27] S.-Y. Han, S. Chang, in: Handbook of Metathesis, vol. 2 (Ed.:
R. H. Grubbs), Wiley-WCH, Weinheim, 2003, p. 5–119.
[28] See, for example: a) M. Jörgensen, P. Hadwiger, R. Madsen,
A. E. Stütz, T. M. Wrodnigg, Curr. Org. Chem. 2000, 4, 565; b)
A. Fürstner, Top. Catal. 1997, 4, 285; c) M. Delgado, J. D.
Martín, Tetrahedron Lett. 1997, 38, 6299.
[12] P. J. Bentley, in: Endocrine Pharmacology, Cambridge Univer-
sity Press, New York, 1980, p. 267–286.
[13] G. Schneider, S. Bottka, L. Hackler, J. Wölfling, P. Sohár, Lie-
bigs Ann. Chem. 1989, 263.
[14] See, for example: a) S. W. Chaikin, W. G. Brown, J. Am. Chem.
Soc. 1949, 71, 122; b) D. E. Ward, C. K. Rhee, Can. J. Chem.
1989, 67, 1206.
[15] See, for example: a) P. Barbier, Compt. Rendus 1898, 128, 110;
b) V. Grignard, Compt. Rendus 1900, 130, 1322; c) The synthe-
sis and characterization of compounds 2 and 3 will be dis-
cussed in detail separately in a forthcoming paper.
[29] F. S. Ekholm, J. Sinkkonen, R. Leino, New J. Chem. 2010, 34,
667.
[30] a) R. Laatikainen, M. Niemitz, U. Weber, J. Sundelin, T. Has-
sinen, J. Vepsäläinen, J. Magn. Reson., Ser. A 1996, 120, 1; b)
For detailed information on the software see: http://
www.perchsolutions.com.
Received: September 27, 2010
Published Online: December 28, 2010
Eur. J. Org. Chem. 2011, 1064–1077
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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