Highly reactive 2-deoxy-2-iodo-d-: Allo and d- gulo pyranosyl sulfoxide donors ensure β-stereoselective glycosylations with steroidal aglycones

Article abstract of DOI:10.1039/c8ra06619a

The preparation of well-defined d-xylo and d-ribo glycosides represents a synthetic challenge due to the limited configurational availability of starting materials and the laborious synthesis of homogeneous 2-deoxy-β-glycosidic linkages, in particular tha

Full text of DOI:10.1039/c8ra06619a

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Highly reactive 2-deoxy-2-iodo-D-allo and D-gulo
pyranosyl sulfoxide donors ensure b-stereoselective
glycosylations with steroidal aglycones†
Cite this: RSC Adv., 2018, 8, 30076
Jordi Mestre, David Collado, David Benito-Alifonso, Miguel A. Rodrıguez,
´
M. Isabel Matheu,
Yolanda Dıaz,
Sergio Castillon
and Omar Boutureira
*
´
´
The preparation of well-defined D-xylo and D-ribo glycosides represents a synthetic challenge due to the
limited configurational availability of starting materials and the laborious synthesis of homogeneous 2-
deoxy-b-glycosidic linkages, in particular that of the sugar-steroid motif, which represents the
Received 6th August 2018
Accepted 11th August 2018
“stereoselective determining step” of the overall synthesis. Herein we describe the use of 2-deoxy-2-iodo-
glycopyranosyl sulfoxides accessible from widely available D-xylose and D-ribose monosaccharides as
privileged glycosyl donors that permit activation at very low temperature. This ensures a precise kinetic
control for a complete 1,2-trans stereoselective glycosylation of particularly challenging steroidal aglycones.
DOI: 10.1039/c8ra06619a
rsc.li/rsc-advances
glycosylation step is kinetically-controlled and the presence of
iodine favours the stereoselective formation of a 1,2-trans glyco-
Introduction
2
-Deoxy- and 2,6-dideoxy-b-glycosides are common architectures side via the least energetic transition state upon preferential
3
present in many biologically active ingredients such as antibi- nucleophilic attack to the oxonium intermediate H
otics, appetite suppressants, and nucleosides. These deoxy- consistent with the Felkin–Anh–Eisenstein 1,2-induction model
4
. This is
1
*
glycosides, and especially cardiac glycosides (e.g., cardenolides N- with stabilizing hyperconjugative interactions between sCÀI and
3
11
1
from Nerium oleander or those from chrysomelid beetles, and
sC–OR (Scheme 1). According to most current models, the ster-
4
helveticoside ), are usually composed of uncommon glycosyl eoselectivity is determined by the interplay between (a) the
moieties including D-ribo and D-xylo-congured pyranoses ground-state conformational preferences of oxocarbenium
4
3
(
Fig. 1). While these glycoconjugates, with the general structure intermediates ( H
3 4
vs. H ) in which electronegative substituents
[
sugar] –aglycone, are nicely produced in nature, most of the such as I and OBn prefer a pseudo-axial disposition due to
n
5
chemical glycosylation approaches for their preparation are stabilizing electrostatic and/or hyperconjugative interactions
mainly focused on the sugar–sugar motif but are still inefficient (e.g., between sC–I and pCÀO) and (b) the relative reactivity of each
for the b-stereoselective synthesis of the sugar-steroid portion. In conformer under the S 1 paradigm, according to a Curtin–
*
N
addition, the b-stereoselectivity is typically better for the Hammett kinetics scenario. In this context, while glycosylations
construction of the sugar–sugar motif (up to only b) compared to of 2-deoxy-2-iodo-1-thioglycosides with sugar acceptors proceed
ꢀ
that of the sugar-steroid fragment (up to 9 : 1 b/a) and thus, the at ca. À40 C and provided reasonably good selectivities (up to
latter glycosylation step represents the overall “stereoselective 16 : 1 b/a), we observed a reduction to 8 : 1 b/a with steroidal
8
determining step” in 2-deoxy and 2,6-dideoxyglycoconjugates aglycones (Scheme 1). We reasoned that prior oxidation of the 1-
5,6
featuring such particular congurations. Our group has devel- thiophenyl donor to a glycosyl sulfoxide (SPh / S(O)Ph) would
7
oped an indirect synthetic approach for the stereoselective enhance its reactivity enabling activation at lower
synthesis of 2-deoxy- and 2,6-dideoxy-2-iodoglycosides that
utilizes 2-deoxy-2-iodo-1-thioglycoside donors, being particularly
effective for the production of b-D-allo and b-D-gulo pyrano-
2,8–10
sides.
The resulting conguration is predened by the start-
ing furanose and thus, D-ribo and D-xylo structures serve as
congurational templates for D-allo and D-gulo pyranosides,
respectively. Our ndings determined the key b-selective
Departament de Qu ´ı mica Anal ´ı tica i Qu ´ı mica Org a` nica, Universitat Rovira i Virgili,
C/Marcel$l ´ı Domingo 1, 43007 Tarragona, Spain. E-mail: omar.boutureira@urv.cat
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c8ra06619a
Fig. 1 Naturally occurring 2-deoxy and 2,6-dideoxy-b-glycosides
with “rare” D-xylo and D-ribo configurations.
1
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Scheme 1 Scope and limitations of the stereoselective synthesis of b-steroidal glycosides of D-ribo and D-xylo configurations – using sulfoxides
to improve key “sugar–aglycone” glycosylation step.
12,13
temperatures.
Hence, iodine control will perform better at thermodynamically more stable a-anomer could not be separated
lower temperatures restoring the kinetic control in challenging from its b-counterpart. Alternatively, oxidation of 1 followed by
ꢀ
glycosylations as those using steroidal aglycones, favouring the activation using the Tf
selective formation of b-glycosides.
2
O/DTBMP system at À80 C afforded the
corresponding glycosides in very short reaction times and good
yields (up to 80%). Glycosylation with primary benzylic 3a and
Results and discussion
a
Table 1 Glycosylation scope (SPh vs. S(O)Ph)
13
3
Preliminary oxidation studies of 1 with mCPBA (in CHCl ) and
14
3
Selectuor™ (in CH CN) revealed the high reactivity of the
resulting sulfoxide 2, which evaded isolation due to decomposi-
tion. The best protocol used mCPBA as the sole oxidant in CH Cl
2
2
ꢀ
ꢀ
from À80 C to À50 C, followed by neutralization of the residual
benzoic acid with NaHCO , removal of the precipitate, and con-
3
ducting the following glycosylation in sequence (Table 1). Thus,
dichloromethane perfectly combines chemical inertness towards
oxidants, good oxidation rate of suldes using peroxy acids at the
15
low temperatures necessitated to avoid decomposition, and
good b-selective properties in the subsequent glycosylation
reaction with sulfoxides (up to 3 : 1 b/a ratio with Bn as pro-
13
tecting groups). To verify the formation of 2, oxidation was
1
monitored by H NMR in CD
5
1
2
Cl
.10 ppm corresponding to the H-1 proton of the predominant
b-anomer was gradually converted to two new doublets at 5.14
2
(Scheme 2). The signal peak at
and 5.02 ppm, tentatively assigned to 2b(S) and 2b(R), respec-
tively with a 88 : 12 dr. Although the signal of 2b(S) was gradually
b
c
Entry
ROH
Conditions
Yield (%)
b/a ratio
ꢀ
shied upeld upon warming from À70 to À15 C, the Dd of ca.
1
2
3
3a
3a
3b
3b
3c
3c
A
B
A
B
A
B
4a (72)
4a (80)
4b (61)
4b (69)
4c (66)
4c (63)
30 : 1
40 : 1
16 : 1
24 : 1
8 : 1
0
.2 ppm between the two stereoisomers was in accordance with
d
16
previously reported diastereomeric sulfoxides.
4
5
The identity of 2 was further conrmed by high-resolution
mass spectrometry analysis (HRMS). Next, glycosylation was
explored comparing the selectivities obtained for the activation of
d
6
21 : 1
a
˚
Conditions A: 1 (1 mmol), ROH 3a–c (2 mmol) and 4 A molecular sieves
1
and 2 (Table 1). Standard glycosylation using 1-thiophenyl
ꢀ
(MS) in CH
2
Cl
2
(4 mL) at À80 C. Then, addition of NIS (3 mmol) and
ꢀ
ꢀ
donor 1 resulted in excellent b-stereoselectivities with primary 4- TfOH (0.2 mmol) at À80 C to À40 C. Conditions B: 1 (1 mmol),
˚
ꢀ
mCPBA (1.1 mmol) and 4 A MS in CH
NaHCO
DTBMP (3 mmol), 4 A MS and Tf
2
Cl
2
(30 mL) at À80 C. Then,
nitro-benzyl alcohol 3a (up to 30 : 1 b/a) and secondary methyl
8
3
(5 mmol), ltration and addition of ROH 3a–c (2 mmol),
glucoside alcohol 3b (16 : 1 b/a) (entries 1 and 3). In contrast,
˚
ꢀ
b
2
O (2 mmol) at À80 C. Isolated
1
employing cholesterol 3c as representative steroidal acceptor
c
yield. Calculated by integration of anomeric protons in the H NMR
d
substantially decreased the selectivity to 8 : 1 b/a ratio and the spectrum of the crude reaction mixture. See ref. 8.
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Scheme 2 VT-NMR monitoring of the oxidation of 1.
secondary sugar acceptors 3b slightly improved the selectivity up
to 40 : 1 b/a (entries 2 and 4). To our delight, glycosylations using
cholesterol 3c reached comparable levels of stereocontrol (up to
Scheme 3 Synthesis of 2-deoxy- and 2,6-dideoxy-2-iodo-b-pyrano-
sides 7, 8 and 11 and deprotection steps to digitoxigenyl 2-deoxy-b-D-
xylo and D-ribo cardiac glycosides 9 and 10. Reagents and conditions: (a)
ꢀ
ꢀ
2
1 : 1 b/a) only when sulfoxide was used as the glycosyl donor mCPBA, 4 A˚ MS, CH Cl2 from À80 C to À40 C, 30 min; (b) 3,6,
2
ꢀ
(
entries 5 and 6). Thus, merging the excellent stereodirecting DTBMP, 4 A˚ MS, Tf
2
O, À80 C, 30 min; (c) Bu
3
SnH, Et
3
B, toluene, rt, 1 h;
ꢀ
8,9
(d) H
2
(1 atm), 10% Pd/C, 1 : 1 EtOAc/MeOH, 0 C, 1–3 h.
group properties of I and the lower reaction temperature
enabled by the reactive sulfoxide ensured excellent kinetic
control with challenging steroidal aglycones.
Finally, the unique combination of oxidation/glycosylation
sequence of this strategy was utilized for the synthesis of 2-
deoxy-2-iodo-b-pyranosides 7 and 8 with high stereoselectivities
Conclusions
In conclusion, the present work upgrades the previous reported
methodology (using 1-thioglycosides) for the stereoselective
synthesis of 2-deoxy-b-glycosides with D-ribo and D-xylo congu-
rations, improving the overall b-control using challenging
steroidal aglycones. The enhanced reactivity of glycosyl sulfoxides
and the presence of an equatorial steering iodine permitted the
precise formation of complex 2-deoxy-b-glycosides aer removal
of the temporary directing element. We expect that the present
protocol will nd broad application in the chemical synthesis of
steroidal glycosides for the medicinal research eld.
(>22 : 1 b/a) and good yields (up to 64%) using the steroidal
acceptor digitoxigenin 6 and D-gulo- and D-allo-1-thiopyranosides 1
and 5a as glycosyl donors (Scheme 3). The stereochemistry of the
C-4 substituent had little effect on the selectivity although the
slight improvement in the D-allo conguration may be explained
by the less entropically disfavored b-transition state resulting from
3
the stabilizing pseudoaxial positioning of OBn in the
H
4
11,17
conformer (Scheme 1).
Elaboration of 7 and 8 under conven-
2
tional deiodination and debenzylation conditions afforded nal 2-
deoxy cardiac glycosides 9 and 10 in excellent yields (up to 95%).
Likewise, cholesterol 3c was subjected to the same oxidation/
glycosylation sequence with the more challenging 2,6-dideoxy
Conflicts of interest
glycosyl donor 5b to afford 2,6-dideoxy-2-iodo-D-allo derivative There are no conicts to declare.
2,9d
11 with good stereoselectivity (20 : 1 b/a)
and moderate
overall yield (52%). Final products 9 and 10 as well as their
4
Acknowledgements
precursors 7, 8 and 11 adopted a C conformation as deter-
1
mined by NOE experiments and the analysis of diagnostic
coupling constants ( J1,2 ꢁ 9 Hz and JC1–H1 ꢁ 163 Hz).
We thank the Spanish Government-MINECO and the national
agency of investigation-AEI (CTQ2017-89750-R and CTQ2017-
3
1
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0088-R), the European Regional Development Fund, and the
Universitat Rovira i Virgili (Mart ´ı Franqu `e s Research Fellowship
Programme to J. M. and D. C.) for nancial support. We also
thank Arnau R. Rubio for preliminary experiments. O. B. is
a Ram ´o n y Cajal Fellow (RYC-2015-17705).
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