Synthesis of asymmetrically substituted scyllo-inositol

Article abstract of DOI:10.1016/j.tetlet.2016.06.038

scyllo-Inositol, a rare member of the inositol family, is present in axinelloside A, a marine metabolite with interesting inhibitory activity against human telomerase. Here, we present a concise synthesis of asymmetrically substituted scyllo-inositol star

Full text of DOI:10.1016/j.tetlet.2016.06.038

Tetrahedron Letters 57 (2016) 3281–3283
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Tetrahedron Letters
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Synthesis of asymmetrically substituted scyllo-inositol
⇑
Jacob Rodriguez, Maciej A. Walczak
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
scyllo-Inositol, a rare member of the inositol family, is present in axinelloside A, a marine metabolite with
Received 30 May 2016
Revised 8 June 2016
Accepted 9 June 2016
Available online 15 June 2016
interesting inhibitory activity against human telomerase. Here, we present a concise synthesis of asym-
metrically substituted scyllo-inositol starting from inexpensive D-glucose. Our synthetic approach capital-
izes on Ferrier rearrangement of vinyl acetate and stereoselective reduction of the resultant ketone to
establish the scyllo-inositol core. The protocol provides access to large quantities of scyllo-inositol in 10
steps from commercially available materials.
Keywords:
Ó 2016 Elsevier Ltd. All rights reserved.
scyllo-Inositol
Ferrier rearrangement
Inositols
Introduction
itols have been prepared synthetically.13 Due to the C3 symmetry
of the orthoester derivatives, the hexol scaffold has been used in
Inositols are a class of nine distinct isomers of 1,2,3,4,5,6-cyclo-
hexanehexol in which the configuration of the hydroxyl group is
permutated giving rise to seven meso and two chiral isomers.1
Among the members of this family, myo-inositol (1) and its deriva-
tives are the most studied inositols due to their role as secondary
messengers (in the form of phosphates and pyrophosphates) and
their presence in glycoconjugates (e.g., glycosylphosphatidylinosi-
tol (GPI) anchors).2 However, scyllo-inositol (2), an isomer with all
hydroxyl groups in equatorial configuration, is less explored.1 The
parent compound is found at high concentrations in human brain,3
and has been implicated in certain neurological disorders.1 There
are numerous reports describing the use of scyllo-inositol as a
potential drug targeting Alzheimer’s4 and Parkinson’s diseases,5
and research in this area is a topic of current interest.6 For instance,
orally administered scyllo-inositol inhibited the aggregation of
amyloid-b (Ab)7 and prevented the formation of insoluble amyloid
fibers believed to cause neuronal dysfunction in Alzheimer’s dis-
ease. Derivatives of scyllo-inositol (including fluorinated analogs8)
have been investigated, among which the hexaphosphate has been
identified as a promising drug candidate.
the preparation of glycodendrimers,14 drug delivery compounds,15
siderophore (enterobactin) analogs,16 and hetero-bimetallic
catalysts.17
There is only a small number of examples in which scyllo-inos-
itol is present in an asymmetric form,1 and axinelloside A (5)
stands out due to its intriguing chemical structure and biological
activity.18 This polysulfated oligosaccharide was isolated from a
marine sponge Axinella infundibula, and its structure was proposed
based on 1D and 2D NMR studies. The unique features of this mole-
cule are the presence of ten 1,2-cis glycosidic bonds, four fatty acid
chains, and the eastern part terminated with scyllo-inositol con-
nected through a b-glycosidic bond. Axinelloside A possesses sig-
nificant inhibitory activity (2 lg/mL) against human telomerase
determined in a TRAP assay. Telomerase, an enzyme overexpressed
in over 85% of human tumors, is an attractive target for anticancer
therapy,19 and although a handful of small molecules (dictyoden-
drin A,20 telomestatin21) are known to inhibit telomerase, there
are no drugs utilizing telomerase inhibition as the mechanism of
action. Axinelloside A and related sulfated analogs may provide a
starting point for the development of small molecule candidates
with a therapeutic potential.
Having in mind these considerations, we embarked upon syn-
thesis of scyllo-inositol suitable for further elaboration in the total
synthesis of axinelloside A. The synthetic scheme toward asym-
metrically substituted building block 4 capitalizes on a stereoselec-
tive Ferrier-II carbocyclization22 of a vinyl acetate derived from
From the synthetic standpoint, the conversion of myo-inositol
into scyllo-inositol by Kishi9 is a practical route to prepare large
quantities of symmetrical scyllo-inositol from an inexpensive start-
ing material.10 Other studies by Ikegami11 and Altenbach12 pro-
vided the parent hexols using glucose or p-quinone as the
substrates. Similar to myo-inositol, phosphate esters of scyllo-inos-
D-glucose. The C2, C3, and C4 hydroxyl groups in the glucose
substrate will correspond to three equatorial C2, C3, and C4 sub-
stituents in 4 (Fig. 1). Four orthogonal protective groups, which
⇑
Corresponding author. Tel.: +1 303 492 7670; fax: +1 303 492 5894.
E-mail address: maciej.walczak@colorado.edu (M.A. Walczak).
http://dx.doi.org/10.1016/j.tetlet.2016.06.038
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

3282
J. Rodriguez, M. A. Walczak / Tetrahedron Letters 57 (2016) 3281–3283
Figure 1.
will mask the sulfate monoester, fatty acid, and free hydroxyl
groups in axinelloside A, and the hydroxyl group at C1 will serve
as a handle to attach the galactose residue (Fig. 2).
Results and discussion
Scheme 1. Reagents and conditions: (a) p-anisaldehyde (1.0 equiv), p-TsOH
(0.025 equiv), (MeO)3CH (1.2 equiv), DMF, 50 °C, 82%; (b) BnBr (3.0 equiv), NaH
(10 equiv), KHMDS (0.5 equiv), DMF, rt, 73%; (c) BH3–THF (10 equiv), n-Bu2BOTf
(1.95 equiv), 0 °C, 70%; (d) (COCl)2 (1.2 equiv), DMSO (2.5 equiv), Et3N (3.5 equiv),
CH2Cl2, ꢀ78 to ꢀ40 °C; (e) Ac2O (12 equiv), K2CO3 (8 equiv), MeCN, reflux, 61% (over
2 steps).
The synthesis of partially protected scyllo-inositol 14 begun
with the preparation of
D-glucose derivative 10 from commercially
available methyl -glucopyranoside 6 (Scheme 1). First, the
a-D
hydroxyl functionalities at C4 and C6 were protected as an acetal
by installation of the benzylidene group with p-anisaldehyde in
the presence of catalytic amounts of p-toluenesulfonic acid
(p-TsOH). The subsequent benzylation with BnBr in DMF furnished
fully protected glucose 8. The addition of KHMDS proved benefi-
cial, as this protocol results in higher yields of O-alkylation prod-
ucts when multiple alcohols are simultaneously reacted with an
alkylating agent. To reveal the primary hydroxyl functionality,
acetal 8 was treated with three equivalents of BH3–THF and a
Lewis acid (n-Bu2BOTf) resulting in exclusive formation of 4-O0-
PMB protected glucose 9 in 70% yield. This reaction was also
conducted on a multigram scale without erosion of the yield and
selectivity. Next, we oxidized the resultant alcohol 9 to an alde-
hyde using the Swern conditions23 and the product of this reaction
was converted immediately into an enol acetate 10 in a reaction
with Ac2O and inorganic base (K2CO3). The formation of the enol
ester proceeded in high selectivity giving exclusively the
Z
diastereoisomer 10.
With compound 10 in hand, we explored the feasibility of the
Ferrier rearrangement (Scheme 2). Mercury salts are known as effi-
cient promoters of this reaction,22b and Hg(TFA)2 facilitated the
conversion of 10 into the desired diastereoisomer 11 in 50% yield
(including 7% of C1 epimer). The configuration of the major
product was confirmed by NMR spectroscopy where the
diagnostic coupling constant revealed an axial configuration of
the C1 alcohol (1H NMR: 4.31 ppm, t, 3J = 2.8 Hz). This compound
was stable to chromatographic purifications, and no elimination
Scheme 2. Reagents and conditions: (a) Hg(TFA)2 (1.2 equiv), H2O/AcONa, rt, 50%,
(b) NaBH(OAc)3 (10 equiv), AcOH (16 equiv), MeCN, rt, 82%; (c) TBSOTf (1.5 equiv),
2,6-lutidine (2 equiv), CH2Cl2, rt, 34%; (d) (COCl)2 (1.2 equiv), DMSO (2.5 equiv),
Et3N (3.5 equiv), CH2Cl2, ꢀ78 to ꢀ40 °C; (e) NaBH4 (4.5 equiv), MeOH, rt, 39% (over
2 steps).
At this point, two hydroxyl groups in 12 were distinguished via
selective silyl protection. We found that the yield of this reaction
was critically dependent on the temperature and silylating agent.
When the diol 12 was treated with TBSOTf at a low temperature
(ꢀ78 °C) a mixture of 13 (25%) and doubly protected ether (18%)
was formed. We found that the yield of this reaction could be
to
a,b-unsaturated ketone was observed. The subsequent
reduction of 11 with borohydride afforded 12 (1H NMR:
4.11 ppm, 3J = 9.8 Hz), in which the new stereocenter (C5) was
formed through
nucleophile.
a
hydroxyl directed delivery of
a
hydride
OX
XO
O
O
C13H27
O
C13H27
XO
O
O
Me
Me
XO
O
O
O
XO
HO
O
O
XO
O
Me
OH
C13H27
O
O
XO
O
XO
Me
OH
XO
OX
O
OH
O
O
O
O
HO
O
O
O
XO
O
O
O
O
OX
XO
O
XO
O
XO
XO
OX
OH
O
O
OH
Me
OH
OH
X = SO3Na
OX
HO
OH
XO
C15H31
(5)
Axinelloside A
Figure 2.

J. Rodriguez, M. A. Walczak / Tetrahedron Letters 57 (2016) 3281–3283
3283
a-methyl D-glucoside. The key features of the synthetic scheme
include a rearrangement of vinyl acetate under the Ferrier condi-
tions to establish the cyclohexane ring and a stereoselective reduc-
tion of the ketone group to install the equatorial hydroxyl group.
This protocol provides an entry into the synthesis of axinelloside
A and relevant sulfated analogs containing scyllo-inositol groups.
Studies focused on the synthesis of axinelloside A and its analogs
will be published in due course.
Acknowledgments
This work was supported by the University of Colorado Boulder.
J. R. acknowledges the Bob and Dickie Lacher Fund for the financial
support. Aaron Crossman is thanked for a careful proofreading of
the manuscript.
Figure 3. 29Si–1H HMBC NMR correlation for 13.
improved when 1.5 equiv of the silylating agent was added to 12 at
0 °C in the presence of 2,6-lutidine. Although the silyl ether 13 was
formed in 39% (the remainder of the material being 12), no doubly
protected side product was detected and exclusive selectivity for
the equatorial OH was observed. To confirm the structural assign-
ment of 13, 29Si–1H HMBC experiments,24 which allow for 29Si–1H
shift correlations over two and/or three bonds, were performed
(Fig. 3). This structural method is particularly useful in systems
where the long-range C–H couplings cannot be detected. The 29Si
NMR signal (18.7 ppm) showed three cross peaks—two of the
t-BuMe2 group and a weaker one with a signal at 4.19 ppm (dd,
3J = 9.9, 8.9 Hz) assigned to the axial proton at C5.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.06.
038.
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To complete the synthesis of scyllo-inositol 14, the configura-
tion of the alcohol group at C1 in 13 needed to be corrected to pro-
vide the all-equatorial product. This transformation turned out to
be challenging as the hindered C1 hydroxyl group in the axial con-
figuration was resistant to the Mitsunobu conditions (2,2-bis
(diphenylphosphino)ethane (dppe) or PPh3, diethyl azodicarboxy-
late (DEAD), PhCO2H).25 Although we were able to form the
expected phosphonium salt by mixing DEAD and Ph3P, this inter-
mediate was reluctant to undergo substitution with a nucleophile,
and the only product observed after extended heating was the ben-
zoate ester derived from activation of benzoic acid with a phospho-
nium salt followed by O-acylation. Approaches to convert the
alcohol into a triflate ester under standard conditions (Tf2O, pyri-
dine, CH2Cl2, 0 °C) followed by a substitution with sodium ben-
zoate were equally unsuccessful. However, we found that the
desired configuration of the C1 alcohol could be established in a
two-step oxidation–reduction sequence. Thus, the hydroxyl group
in 13 was oxidized under the Swern conditions and the resultant
ketone was reduced with NaBH(OAc)3/AcOH to provide 14 in 58%
yield (dr 1.5:1.0). A more reactive (and smaller) reducing reagent
(NaBH4) provided scyllo-inositol in an improved yield (62%) and
higher diastereoselectivity (1.7:1.0). The configuration of the pro-
duct was established using 1D and 2D NMR techniques—the diag-
nostic coupling constant of H1 (t, 3J = 9.6 Hz) indicated that the
newly established alcohols was formed in an equatorial configura-
tion. We also isolated protected myo-inositol 13, which can be
recycled and reduced to scyllo-inositol 14 via the sequence of reac-
tions described above. The axial delivery of the hydride to 13 is
contrasting with the previously reported addition of hydride or
Grignard nucleophiles to per-O-benzylated scyllo-inose, in which
the myo-inositol was the major diastereoisomer.26 We rationalize
the reversal of selectivity by a weakly coordinating ability of the
acetate group to direct the delivery of a hydride.
25. Kwon, Y.-U.; Im, J.; Choi, G.; Kim, Y.-S.; Yong Choi, K.; Chung, S. K. Bioorg. Med.
Chem. Lett. 2003, 13, 2981–2984.
Conclusions
26. (a) Jagdhane, R. C.; Patil, M. T.; Krishnaswamy, S.; Shashidhar, M. S. Tetrahedron
2013, 69, 5144–5151; (b) Collet, C.; Chrétien, F.; Chapleur, Y.; Lamandé-Langle,
S. Beilstein J. Org. Chem. 2016, 12, 353–361.
To summarize, we described a practical synthesis of asymmet-
rically protected scyllo-inositol starting from a readily available