Regioselective SN2 reactions for rapid syntheses of azido-inositols by one-pot sequence-specific nucleophilysis

Article abstract of DOI:10.1039/c7cc01219e

Triflates of myo-inositol undergo facile solvolysis in DMSO and DMF yielding S_N2 products substituted with O-nucleophiles; DMF showed slower kinetics. Axial O-triflate undergoes faster substitution than equatorial O-triflate. By exploiting this

Full text of DOI:10.1039/c7cc01219e

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: K. M. Sureshan, A.
Ravi, S. Z. Hassan and A. N. Vanikrishna, Chem. Commun., 2017, DOI: 10.1039/C7CC01219E.
This is an Accepted Manuscript, which has been through the
Volume 52 Number
1 4 January 2016 Pages 1–216
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 3
View Article Online
DOI: 10.1039/C7CC01219E
ChemComm
COMMUNICATION
Regioselective SN2 reactions for rapid syntheses of azido-inositols
by one-pot sequence-specific nucleophilyses
Arthi Ravi, Syed Zahid Hassan, A. N. Vanikrishna and Kana M. Sureshan*
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Triflates of myo-inositol undergo facile solvolysis in DMSO and temporally controlled regioselective azidolysis/solvolysis of
DMF giving SN2 products substituted with O-nucleophiles; DMF myo-inositol 2,5-di-sulfonates.
N3
N3
showed slower kinetics. Axial O-triflate undergoes faster
substitution than equatorial O-triflate. By exploiting this
difference in kinetics, solvent-tuning and by sequence-controlled
nucleophilyses, rapid synthesis of three azido-inositols of myo-
configuration from myo-inositol itself have been achieved.
PO
OP
PO
OP
5
2
2
5
OH
N3
equivalent
PO
OP
PO
OP
OTf
N3
OH
OTf
PO
PO
OP
OP
PO
PO
OP
OP
2
5
N3
5
2
OH
OH
OTf
N3
PO
PO
OP
OP
PO
PO
OP
OP
5
2
Nature uses inositol scaffold for making a combinatorial
library of molecules by phosphorylation, glycosylation and
lipidation, for cellular signalling and other vital cellular
processes.1 Azide being a bio-orthogonal functional group,2
azido-inositols are of great interest for metabolic labelling to
understand these complex cellular processes. Some of the
azido-inositols are known to inhibit cellular proliferation3 show
glycosidase inhibition,4a,b etc. Azido-inositols are also
precursors for the synthesis of aminocyclitols,4c which are
essential pharmacophores for many antibiotics5 and other
bioactive natural products.6 Various azido-cyclitols have been
synthesized from various starting materials via multistep
synthetic transformations.4,5,7 The most common method for
azido-inositol synthesis involves the azidolysis of appropriately
protected sulfonates of cheap and abundant myo-inositol.4
However, for the synthesis of mono-azido derivatives of myo-
configuration, by this strategy, it is necessary to start with an
expensive inositol, whose hydroxyl protection-deprotection
strategies are not known.8 As inversion of both C2 and C5
stereocenters of myo-inositol provide a product with myo-
configuration, it is in principle possible to get monoazido-myo-
inositols from protected 2,5-disulfonyl-myo-inositol by
successive inversion (SN2 reaction) with azide and an oxygen
nucleophile. We herein report the synthesis of 2-azido and 5-
azido inositol of myo- configuration by sequentially and
2
5
N3
O
H
e
q
u
i
v
a
le
n
t
N3
OTf
Fig. 1 Stepwise inversion of 2,5-di-O-sulfonyl-myo-inositol derivative with azide and O-
nucleophile giving 2-azido and 5-azido myo-inositol derivatives.
In view of exploiting the difference in reactivities of the
nucleophilysis of axial and equatorial sulfonates, we have
chosen sulfonates of diol 1, whose trans- fused butane-2,3-
diacetal (BDA)-protection locks the inositol ring in the penta-
equatorial-mono-axial disposition of O-substituents. During
the synthesis of neo-azido-inositol
3 from the triflate 2, we
have noticed a time-dependent solvolysis of the triflate
2
when dissolved in DMSO-d6. The nucleophilic action of DMSO
(ESI) gives an oxosulfonium intermediate, which upon
hydrolysis gives the diol
4 of neo-configuration (Fig. 2A). This
suggests that the solvolysis proceeds via SN2 mechanism.
Though solvolytic effect of DMSO on mesylates and triflates9
has been reported, the stereochemical course of the solvolysis
was unclear. Similarly, formolysis of sulfonates in DMF has
been known to occur via an iminium intermediate which on
hydrolysis gives the ester (Fig. 2B).10 We could reproduce the
solvolysis of triflate
(dimethylacetamide) in high yields (ESI).
Interestingly, reaction of triflate in DMSO with excess of
NaN3 yielded a mixture of azide and the diol 4, (Scheme 1)
suggesting that DMSO can compete with highly nucleophilic
azide ion. The azidolysis of the triflate in DMF gave the azide
and the formate (7:2 ratio) suggesting that though DMF
competes with azide, its nucleophilicity is lower than that of
DMSO. The azidolysis of triflate in acetonitrile yielded the
2
by both DMF and DMA
2
3
2
3
6
2
azide
3
as the exclusive product without any competing
This journal is © The Royal Society of Chemistry 20xx
Chem.Commun., 2017, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 3
View Article Online
DOI: 10.1039/C7CC01219E
COMMUNICATION
ChemComm
solvolysis. The mesylate
7 was unaffected in DMSO at room DMF. It is very clear that, DMSO, DMA and DMF preferentially
temperature and its reaction with NaN3 in DMSO yielded azide solvolyze the triflate group at the 2-position than that at 5-
almost quantitatively (ESI). Having established the solvents position. This difference in reactivity could be due to the less
3
that can solvolyse sulfonates (to introduce oxygen nucleophile) hindered approach of the incoming nucleophile at C2 than at
and their relative reactivities, we set out to explore the C5. It is to be noted that triflates 10 and 12 can offer easy
regioselective solvolysis of ditriflate
8.
access to 2-OH mutated myo-inositol analogues via simple
nucleophilic substitution.
OH
OH
Me
Me
Me
Me
MeO
O
O
O
OMe
Me
MeO
MeO
O
O
O
OMe
Me
5
2
Me
O
+
Me
O
MeO
OMe
OMe
OTf
OH
OTf
9 (38%)
(40%)
1
Me
Me
MeO
MeO
O
O
O
OMe
Me
2
5
Me
O
OR
OR
Me
Me
Me
Me
OMe
MeO
MeO
O
O
OMe
Me
MeO
MeO
O
O
OMe
Me
5
2
OTf
Me
O
Me
O
+
8
O
OMe
O
OMe
OTf
OR
R = CHO (58%)
R = Ac (43%)
10
12
R = CHO (36%)
R = Ac (55%)
11
13
Scheme 1 Solvolysis and azidolysis of triflate 2 and mesylate 7. a) Tf2O, pyridine, DCM,
12 h, 2; b) DMSO, rt, 2.5h, 4; c) DMF, rt, 17h, 6; d) DMA, 50 oC, 3h, 5; e) DMSO, NaN3, rt,
2h, 3 (42%) + 4 (51%); f) DMF, NaN3, rt, 3h, 3 (58%) + 6 (15%); g) Acetonitrile, NaN3, 60
oC, 12h, 3 (73%); (h) NaN3, DMSO, rt, 12 h, 3 (90%).
Scheme 2 Solvolyses of ditriflate 8. a) DMF, rt, 22 h, 10 + 11; b) DMA, rt, 15 h, 12 + 13.
Having established the relative reactivities of axial and
equatorial sulfonates towards solvolysis, we set out to explore
the regioselective nucleophilic substitution in ditriflate
8
to
synthesize azides with myo-configuration. Ditriflate
8
on
treatment with one equivalent of NaN3 in DMF or DMA at rt
yielded the azido-scyllo-triflate 14 in very good yields (Table 1,
entries1 & 2). The mixture when heated after the formation of
14 at 60 oC for 8h yielded the formate 15 (in DMF) or the
acetate 16 (in DMA) as exclusive products in good yields (Table
1, entries 3 & 4). Acidic hydrolysis of 15 and 16 yielded the 5-
azido-myo-inositol in 91% and 95% yields respectively. It may
be noted that triflate 14 can be used to access 5-azido myo-
inositol analogs, having 2-OH mutation, via nucleophilic
substitution.
Fig. 2 Solvolysis of triflate: A) in DMSO via oxosulfonium ion intermediate; B) in DMF via
iminium ion intermediate.
The 19F NMR spectrum of ditriflate
8 in DMSO-d6 showed
To obtain the 2-azido-myo-inositol, it was decided to
azidolyse after partial solvolysis of the ditriflate. Thus, a
two distinct signals at -73.76 ppm and -74.47 ppm
corresponding to two triflate groups (ESI). As the time
progressed, the relative intensities of these signals varied with
the concomitant appearance of a new signal at -77.75 ppm
corresponding to the triflate anion.11 By 5.5 h, the signal at -
73.76 ppm completely disappeared, suggesting that one of the
triflates has been cleaved completely. By 17 h, the other signal
also disappeared, suggesting a clear difference in the kinetics
of the solvolysis of two triflates. The solvolytic effect of DMF
solution of ditriflate
8 in DMSO was stirred at rt for 5.5 h and
was then subjected to azidolysis. However, the required
product 17 was obtained only in 30% yield along with the diol
1
(49%) (Table 1, entry 5). Lowering the solvolysis time to 3h
yielded a mixture of azides 17-19 along with diol 1 (Table 1,
entry 6). The formation of 5-azide 18 and diazide 19 suggests
incomplete solvolysis of the 2-O-triflate before the
introduction of NaN3. Direct azidolysis in DMSO yielded diazide
19 and 2-azide 17 suggesting that DMSO competes even with
azide for the 2-O-triflate (Table 1, entry 7). The isolated scyllo-
and DMA on ditriflate
8 was also studied by recording time-
dependent 19F NMR (ESI). In these cases also, one of the
triflates underwent faster solvolysis compared to the other but
the rate of solvolysis was much slower compared to DMSO
(ESI). It took several days for the solvolyses of both the triflates
in DMF (11 days) and DMA (7 days). When a solution of
triflate
azide 17 and diol
the equatorial triflate (Scheme 3).
Azidolysis of in DMF gave a mixture of diazide 19 and
9
upon azidolysis in DMSO also gave a mixture of 2-
1
suggesting that DMSO competes even for
8
ditriflate
triflate
after 17h, yielded diol
to a solution of ditriflate
triflate 10 (58%) and the diformate 11 (36%). Though same
selectivity was observed in the solvolysis of compound in
8
in DMSO was quenched at 5.5 h, a mixture of
and diol (Scheme 2) were obtained. But quenching
in high yield (85%). Addition of water
in DMF after 22 h gave a mixture of
mono-azide 14 (Table 1, entry 8). But prolonged reaction gives
diazide exclusively (Table 1, entry 9). Delayed addition of azide
led to the formation of the azide 20 along with diformate 11
(Table 1, entry 10). Use of DMA as the solvent, gave the azide
21 along with diacetate 13 (Table 1, entry 11). It is to be noted
that the byproducts diformate 11 and diacetate 13 formed
during regioselective synthesis of 2-azido-myo-inositol
9
1
1
8
8
DMA, the yield of diacetate 13 (55%) was more than that of
trilfate 12 (43%), suggesting that DMA is more reactive than
derivatives 20 and 21, can be recycled to the ditriflate
8
2 | Chem.Commun., 2017, 00, 1-3
This journal is © The Royal Society of Chemistry 2017
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 3 of 3
View Article Online
DOI: 10.1039/C7CC01219E
ChemComm
COMMUNICATION
through hydrolysis and sulfonylation. Acidic hydrolysis of the disulfonate in these solvents by modulating the time of
diazide 19 and formate 20 provided 2,5-diazido-myo-inositol addition of azide nucleophile, we could synthesize 2-azido-
and 2-azido-myo-inositol respectively in quantitative yields myo-inositol and 5-azido-myo-inositol which are otherwise
(ESI). Apart from 5-azido-neo-inositol and 2,5-diazido-myo- difficult to synthesise from myo-inositol in one pot. We have
inositol, our methodology gave access to two mono-azido- also synthesized 5-azido-neo-inostiol and 2,5-diazido-myo-
myo-inositols by regioselective nucleophilic substitutions. inositol from myo-inositol-derived triflates. During this study,
Usual selective transformations in sugars and polyols exploit we have also synthesized several intermediates that can be
the nucleophilicity of hydroxyl groups.12 Here we have shown converted into OH-mutated myo-inositol analogs. This study
that difference in electrophilicities of substituted hydroxy on the selectivity between the nucleophilysis of axial-leaving
groups can also be used for selective reactions.
group versus equatorially placed leaving group and the
exploitation of the difference in kinetics to achieve different
regioselectivities would be of general interest.
Notes and references
1
(a) R. H. Michell, Nat. Rev. Mol. Cell. Biol., 2008, 9, 151; (b)
M. P. Thomas, S. J. Mills and B. V. L. Potter, Angew. Chem.
Int. Ed., 2016, 55, 1614.
2
3
E. Saxon and C. R. Bertozzi, Science, 2000, 287, 2007.
G. Brunn, A. H. Fauq, S. Chow, A. P. Kozikowski, A. Gallegos
and G. Powis, Cancer Chemother. Pharmacol., 1994, 35, 71.
(a) K. M. Sureshan, K. Ikeda, N. Asano and Y. Watanabe,
Tetrahedron Lett., 2004, 45, 8367; (b) K. M. Sureshan, K.
4
5
6
7
Ikeda, N. Asano and Y. Watanabe, Tetrahedron, 2008, 64
4072; (c) A. Trapero and A. Llebaria, ACS Med. Chem. Lett.
2011, , 614.
,
2
(a) L. Diaz and A. Delgado, Curr. Med. Chem. 2010, 17, 2393;
(b) A. Delgado, Eur. J. Org. Chem., 2008, 3893; (c) B. P.
Gurale, M. S. Shashidhar and R. G. Gonnade, J. Org. Chem.,
2012, 77, 5801; (d) F. Kudo and T. Eguchi, Chem. Rec. 2016,
16, 4.
(a) Q. R. Li, S. I. Kim, S. J. Park, H. R. Yang, A. R. Baek, I. S. Kim
and Y. H. Jung, Tetrahedron, 2013, 69, 10384; (b) S.
Mondal, A. Prathap, and K. M. Sureshan, J. Org. Chem., 2013,
78, 7690; (c) J. H. Dam and R. Madsen, Eur. J. Org. Chem.,
2009, 4666.
Scheme 3 Nucleophilyses of ditriflate 8. a) DMF, NaN3, rt, 4 h, 14 (83%); b) DMA, NaN3,
rt, 2 h, 14 (80%); c) DMF, NaN3, (10 equiv), 4 h, 14 (42%), 19 (48%); d) DMF, NaN3 (10
equiv), 24 h, 19 (75%); e) DMF, NaN3 (1 equiv), rt 4 h, then 60 oC, 8 h, 15 (85%); f) DMA,
NaN3 (1 equiv), rt, 3 h, then 60 oC, 6 h, 16 (73%); g) DMSO, rt, 5.5 h then, NaN3 (10
equiv), 17 (30%), 1 (49 %); h) DMSO, rt, 3 h, then NaN3 (10 equiv), 17 (26 %), 18 (18 %),
1 (44%), 19 (10%); i) DMSO, NaN3 (10 equiv), 1 h, 19 (65%), 17 (11%); j) DMF, 22 h, then
NaN3 (5 equiv), 2 h, 20 (58%), 11 (36 %); k) DMA, 15 h, then NaN3 (5 equiv), 2 h 21 (49
%), 13 (40%); l) NaN3 (10 equiv), DMSO, 17 (54%), 1 (36%).
(a) M. A. L. Podeschwa, O. Plettenburg and H. J. Altenbach,
Org. Biomol. Chem., 2003, 1, 1919; (b) K. M. Sureshan, T.
Murakami, Y. Watanabe, Synlett, 2005, 769; (c) S. Pasari, S.
M. Ismail, M. R. Wenk and M. J. Lear, Tetrahedron Lett.,
2015, 56, 2597; (d) P. Serrano, A. Llebaria and A. Delgado, J.
Org. Chem., 2005, 70, 7829; (e) R. C. Acurio, R. G. Soengas,
Paz. F. A. A and A. M. S. Silva, Synlett 2014, 2217.
K. M. Sureshan, M. S. Shashidhar, T. Praveen and T. Das,
Chem. Rev., 2003, 103, 4477.
X. Creary and E. A. Burtch, J. Org. Chem., 2004, 69, 1227.
Table 1 One-pot sequence-specific nucleophilyses of ditriflate 8
Entry
Reagent and conditions
DMF, NaN3 (1 equiv), 4 h
Products
14 (83%)
1
2
3
4
5
6
DMA, NaN3 (1 equiv), 3 h
14 (80%)
8
9
DMF, NaN3 (1 equiv), rt 4 h, then 60 oC, 8 h
DMA, NaN3 (1 equiv), rt, 3 h, then 60 oC, 6 h
DMSO, 5.5 h then, NaN3 (10 equiv),
DMSO 3 h, then NaN3 (10 equiv)
15 (85%)
16 (73%)
10 (a) S. C. Suri, S. L. Rodgers, K. V. Radhakrishnan and V. Nair,
Synth. Commun., 1996, 26, 1031; (b) A. M. Riley, D. J. Jenkins
and B. V. L. Potter, Carbohydr. Res., 1998, 314, 277.
11 D. J. Anderson, R. McDonald and M. Cowie, Angew. Chem.
Int. Ed., 2007, 19, 3815.
12 (a) T. Kawabata, W. Muramatsu, T. Nishio, T. Shibata and H.
Schedel, J. Am. Chem. Soc., 2007, 129, 12890; (b) J. Lawandi,
S. Rocheleau and N. Moitessier, Tetrahedron, 2016, 72, 6283;
(c) D. Lee and M. S. Taylor, J. Am. Chem. Soc., 2011, 133, 3724;
(d) W. Muramatsu, J. M. William and O. Onomura, J. Org.
Chem. 2012, 77, 754; (e) M. W. Giuliano and S. J. Miller
17 (30%), 1 (49%)
17 (26%), 18 (18%), 1
(44%), 19 (10%)
7
8
9
DMSO, NaN3 (10 equiv), 1 h
DMF, NaN3 (10 equiv), 4 h
DMF, NaN3 (10 equiv), 24 h
19 (65%), 17 (11%)
19 (48%), 14 (42%)
19 (75%)
10 DMF, 22 h, then NaN3 (5 equiv), 2 h
11 DMA, 15 h, then NaN3 (5 equiv), 2 h
20 (58%), 11 (36%)
21 (49%), 13 (40%)
Top. Curr. Chem. 2016, 372, 15; (f) B. Ren, M. Rahm, X.
In conclusion, we have observed a remarkable selectivity in
nucleophilic substitution of 2,5-di-sulfonates of myo-inositol.
The C2 sulfonate (axial) underwent faster substitution than the
C5 sulfonate (equatorial). The triflate underwent solvolysis in
DMSO and DMF at room temperature, installing an oxygen
nucleophile, the former showing higher reactivity. Azidolysis of
Zhang, Y. Zhou and H. Dong, J. Org. Chem., 2014, 79, 8134;
(g) S. Yamauchi, M. Hayashi and Y. Watanabe, Synlett, 2009,
2287; (h) M. S. Taylor, Acc. Chem. Res., 2015, 48, 295; (i) K.
Yoshida, T. Furuta and T. Kawabata, Angew. Chem. Int. Ed.
2011, 50, 4888.
This journal is © The Royal Society of Chemistry 2017
Chem.Commun., 2017, 00, 1-3 | 3
Please do not adjust margins