A new synthon for the synthesis of aminoinositol derivatives

Article abstract of DOI:10.1016/j.tetlet.2017.05.099

The regio- and stereoselective synthesis of a new synthon, trans-3,8-dioxatricyclo[3.2.1.0^2,4]octane-6,7-diamine, from 7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate is reported. Transformation of the acid functionalities to acyl azides followed by Curtius rearrangement gave the corresponding trans-diisocyanate, which was reacted with HCl to produce a trans-diamino compound that is a potentially important synthon for the versatile synthesis of aminocyclitols.

Full text of DOI:10.1016/j.tetlet.2017.05.099

Accepted Manuscript
A New Synthon for the Synthesis of Aminoinositol Derivatives
Nalan Korkmaz Cokol, Serdal Kaya, Metin Balci
PII:
S0040-4039(17)30710-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.099
TETL 48992
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 March 2017
25 May 2017
31 May 2017
Please cite this article as: Cokol, N.K., Kaya, S., Balci, M., A New Synthon for the Synthesis of Aminoinositol
Derivatives, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.05.099
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Nalan Korkmaz Cokol, Serdal Kaya, Metin Balci

1
Tetrahedron Letters
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A New Synthon for the Synthesis of Aminoinositol Derivatives
Nalan Korkmaz Cokol,a Serdal Kaya,a,b Metin Balci*,a
aDepartment of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
bDepartment of Chemistry, Giresun University, 28200 Giresun, Turkey
ARTICLE INFO
ABSTRACT
Article history:
Received
The
regio- and
stereoselective
synthesis
from
of
a
new
7-oxabicyclo[2.2.1]hept-5-ene-2,3-
synthon,
trans-3,8-
dioxatricyclo[3.2.1.02,4]octane-6,7-diamine,
Received in revised form
Accepted
dicarboxylate is reported. Transformation of the acid functionalities to acyl azides followed by
Curtius rearrangement gave the corresponding trans-diisocyanate, which was reacted with HCl
to produce a trans-diamino compound that is a potentially important synthon for the versatile
synthesis of aminocyclitols.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Oxabicycloheptene
Aminoinositol
Diacylazide
Curtius rearrangement
Neighbouring group participation
Aminocyclitols,1 also known as amino-carbasugars, are an
important class of compounds that have received wide attention
in recent years due to their varied medicinal applications.
Carbasugars,2 formed by replacing the ring-oxygen atom in
monosaccharides with a methylene moiety, are thought to be
more potent drug candidates than natural sugars because of their
enhanced hydrolytic stability. The aminocyclitol moiety has also
been used by medicinal chemists as a versatile scaffold in drug
design. Natural aminocyclitols such as valienamine (1) and
validamine (2) are secondary metabolites which were first
isolated as fragments of the pseudooligosaccharide validamycin.3
Valienamine (1), validamine (2) and their analogues were
reported to show inhibitory activity against certain glycosidases.1
An aminocyclitol, voglibose (3), is primarily used in the
treatment of diabetes mellitus type 2 for establishing greater
glycemic control by preventing the digestion of carbohydrates.
7-Oxabicyclo[2.2.l]heptene
(4),
7-oxabicyclo[2.2.l]-
heptadiene (5) and their derivatives are valuable intermediates in
the total synthesis of natural products and analogues.6 These 7-
oxanorbornane derivatives can be easily synthesized via the
Diels−Alder addition of furans to alkenes and alkynes.
Figure 2. 7-Oxanorbornane derivatives 4-6.
The ring-opening chemistry of oxabicyclic compounds has
undergone significant growth in recent decades with the
oxabicyclic template becoming an increasingly common starting
material for the preparation of both cyclic and acyclic
compounds. Cleavage of the carbon-oxygen bond in these
systems produces functionalized cyclohexenes or cyclohexenols.
The ring-opening reactions can be triggered by acid catalysts,7
bases,8 and metals.9 Our primary goal was the synthesis of 7-
oxabicyclo[2.2.l]hept-5-ene-2,3-diamine (6) and its derivatives
starting from the adduct 7.
The starting material 7 with an exo-configuration, was
synthesized in almost quantitative yield by the addition of maleic
anhydride to furan at room temperature according to the literature
procedure.10,11 It is well established that the Diels–Alder reaction
between furan and maleic anhydride is reversible and the more
thermodynamically stable exo-adduct 7 is formed as the final
product. The reaction of diacyl chlorides with NaN3 has been
reported as an efficient method for the synthesis of acyl azides.
Reaction of the diacid derived from 7 with thionyl chloride
Figure 1. Selected biologically active aminocyclitols
Various aminocyclitol derivatives have been synthesized from
either natural products or commercially available starting
materials.4 The development of regio- and stereoselective
synthetic methodologies leading to aminocyclitol and analogues
is desirable. Recently, we developed different methodologies for
the synthesis of various aminocyclitols.5

2
Tetrahedron
produced the corresponding anhydride. Therefore, we decided
was successfully converted into the desired dihydrazide 13 upon
treatment with hydrazine hydrate in MeOH (Scheme 3).
to first synthesize diester 9. Thus, adduct 7 was dissolved in
MeOH and the half-ester 8 was isolated in 87% yield. Reaction
of half-ester 8 with SOCl2 in MeOH11 provided the desired
diester 9 (Scheme 1).10a,12
O
O
COCl
COCl
COOCH3
COOCH3
0 o
C
+
MeOH, NEt3
O
30 min
10 oC, 30 min,
72%
ClOC
COCl
15
16
m-CPBA
CH2Cl2, 72%
O
O
CONHNH2
CONHNH2
COOCH3
O
O
NH2NH2 H2O
MeOH, rt, 1 d,
91%
COOCH3
13
17
Scheme 3. Synthesis of trans-dihydrazide 13.
The resulting compound 13 was treated with NaNO2 and HCl
at 0 °C to give the corresponding diacylazide 18. Heating 18 at
reflux in benzene gave diisocyanate 19, which was carried onto
the next step without purification. Heating a solution of 19 in
MeOH at reflux temperature afforded diurethane 20 in 98% yield
(Scheme 4).
Scheme 1. Synthesis of diester 9 and its reaction with hydrazine.
Acyl azides can also be prepared by the diazotization of acyl
hydrazines.13 The reaction of diester 9 with hydrazine in MeOH did
−
not provide the desired dihydrazide 10, instead a retro Diels Alder
reaction occurred to give furan and dimethyl maleate (Scheme 1).
To prevent the retro Diels-Alder reaction and to introduce
additional oxygen functionalities into the molecule, diester 9 was
reacted with m-chloroperbenzoic acid in CH2Cl2 to give the exo-
epoxide 11 in 98% yield.14 Exclusive formation of the exo-isomer
can be explained by double bond pyramidalization15 as well as the
directing effect of the bridge oxygen atom (Scheme 2).
Scheme 4. Synthesis of diurethane 20.
The 1H- and 13C-NMR spectra of 20 are in agreement with the
proposed structure. The epoxide protons give rise to an AB-
system with a coupling constant of J = 3.2 Hz which is within the
expected range for epoxide protons. Bridgehead protons appear at
4.25 and 4.73 ppm as singlet and broad singlet peaks,
respectively. The presence of two different NH-proton
resonances at 5.25 and 5.15 ppm supports the trans-configuration
of the urethane groups. Furthermore, the 10 resonance 13C-NMR
is also in agreement with the structure as well as with the trans-
configuration.
Scheme 2. Synthesis of diester 11 and its reaction with hydrazine.
Epoxide 11 was treated with hydrazine monohydrate in
MeOH at room temperature. However, NMR spectroscopy
indicated the presence of three products, with the desired product
14 formed in only 1% yield. The major product was a cyclic
imide 12, formed via formation of the corresponding
monohydrazide and subsequent intramolecular cyclization.
Diacyl hydrazide 13 was also formed in 32% yield, however, the
configuration of the acyl hydrazide functionalities was changed
from cis to trans. It is expected that carbonyl groups having an α-
proton can easily undergo configurational isomerization in the
presence of a base. At this stage we decided to replace the
starting material, cis-diester 11, with the corresponding trans-
diester 16 in which intramolecular cyclization cannot occur.
Next, the ring opening reaction of 20 was studied. Sulfamic
acid17 was used as an efficient catalyst to promote opening of the
epoxide ring as well as the tetrahydrofuran ring. Diurethane 20
was reacted with sulfamic acid in a mixture of acetic anhydride
and acetic acid, however, instead of the expected tetraacetate 21,
the rearranged compound 22 was formed as the isolable product
(Scheme 5).
1
The H NMR spectroscopic studies on 22 clearly indicated
the removal of one of the two methoxy groups and the
incorporation of two acetyl groups into the molecule.
Furthermore, with the help of 2D−NMR, we were able to
determine that the oxygen bridge was intact and did not undergo
a ring-opening reaction. The structure of 22 was confirmed by
single crystal X-ray analysis (Fig. 3). During the conversion of
trans-Diester 16 was prepared via the cycloaddition of
fumaroyl dichloride with furan to give 15,16 followed by reaction
with MeOH in the presence of NEt3 (Scheme 3). To avoid a
retro-Diels−Alder reaction, the double bond in 16 was epoxidized
with m-chloroperbenzoic acid as described above. Epoxide 17
20
to
22,

3
Scheme 5. Sulfamic acid catalyzed ring-opening reaction of 20.
two successive reactions occurred; opening of the epoxide ring
by nucleophilic attack of the carbonyl group of the endo-urethane
moiety, followed by acetylation. Therefore, we decided to first
convert diisocyanate 19 to diamine 24. Diisocyanate 19 was
reacted with 8 M HCl at room temperature to give salt 23 in 95%
yield. The reaction of 23 with a solution of 0.5 M NaOH at 0 °C
gave the desired compound diamine 24 in 23% yield.
Within 24 the epoxide protons resonated as doublets at 3.62
and 3.34 ppm with a coupling constant of J = 3.4 Hz. The bridge
proton resonances appear at 4.07 and 4.70 ppm as a singlet and
doublet (J = 4.7 Hz), respectively. The 6 resonance 13C-NMR
spectrum was also in agreement with the proposed structure.
Figure 3. Crystal structure of 22.
Scheme 6. Synthesis of diamine 24.
−3529. (e) Brennan,
Bujons, J.; Llebaria, A. J. Org. Chem. 2015, 80, 3512
The synthesis of synthons 22 and 24 was achieved from
The
M. B.; Csatayova, K.; Davies, S. G.; Fletcher, A. M.; Green, W. D.; Lee,
J. A.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. J. Org. Chem. 2015,
80, 6609-6618. (f) Ecer, K.; Salamci, E. Tetrahedron 2014, 70, 8389-
8396. (g) Adams, D. R.; van Kempen, J.; Hudlický, J. R.; Hudlický, T.
Heterocycles, 2014, 88, 1255-1274. (h) Griffen, J. A.; White, J. C.;
Kociok-Köhn, G.; Lloyd, M. D.; Wells, A.; Arnot, T. C.; Lewis, S. E.
Tetrahedron, 2013, 69, 5989-5997. (i) Pilgrim, S.; Kociok-Köhn, G.;
Lloyd, M. D.; Lewis, S. E. Chem. Commun. 2011, 47, 4799-4801.
5. (a) Aydin, G.; Ally, K.; Aktas, F.; Sahin, E.; Baran, A.; Balci, M. Eur. J.
Org. Chem. 2014, 4988 –4955. (b) Ekmekçi, Z.; Balci, M. Eur. J. Org.
Chem. 2012, 4988–4955. (c) Kurbanoglu, N. I.; Celik, M.; Kilic, H.; Alp,
C.; Sahin, E.; Balci, M. Tetrahedron 2010, 66, 3485-3489. (d) Kelebekli,
L.; Celik, M.; Sahin, E.; Kara, Y.; Balci, M. Tetrahedron Lett. 2006, 47,
7031-7034.
trans-7-oxabicyclo[2.2.1]-ept-5-ene-2,3-dicarboxylate.
amine functionalities were introduced by Curtius rearrangement
of the corresponding acyl azide while the oxygen functionality
was introduced to the molecule by epoxidation of the double
bond in 16. This methodology opens up a way to synthesize
versatile isomeric aminoinositol derivatives and further reactions
with compounds 22 and 24 are currently in progress.
Acknowledgments
Financial support from the Turkish Academy of Sciences
(TUBA), and Middle East Technical University (METU) is
gratefully acknowledged.
6. For a reviews on 7-oxabicyclo[2.2.1]heptane intermediates, see: Vogel,
P.; Cossy, J.; Plumet, J. Arjona, O. Tetrahedron 1999, 55, 13521-13642.
Chiu, P.; Lautens, M. Top. Curr. Chem. 1997, 190, 1-85.
7. (a) Sawama, Y.; Kawajiri, T.; Asai, S.; Yasukawa, N.; Shishido, Y.;
Monguchi, Y.; Sajiki, H. J. Org. Chem. 2015, 80, 5556–5565. (b) Xue,
Y. P.; J. Org. Chem. 2011, 76, 57–64. (c) Mao, Y.; Lim, K. M. H.;
Ganguly, R.; Mathey, F. Org. Lett. 2012, 14, 4974–4975. (d) Li, W.-D.
Z.; Gao, Z.-H. Org. Lett. 2005, 7, 2917-2920. (e) Baran, A; Kazaz, C;
Secen, H.; Sutbeyaz, Y. Tetrahedron 2004, 59, 3643-3648. (e) Koreeda,
M.; Jung, K.-J.; Hirota, M. J. Am. Chem. Soc. 1990, 7413-7414.
References and notes
1. For recent reviews on aminocyclitols, see: (a) Huang, G. Curr. Org.
Chem. 2012, 16, 115 –120. (b) Diaz, L.; Delgado, A. Curr. Med. Chem.
2010, 17, 2393-2418. (c) Delgado, A. Eur. J. Org. Chem. 2008, 3893-
3906.
2. (a) Roscales, S.; Plumet, J. Int. J. Carbohyd. Chem. 2016, 1-42. (b)
Altun, Y.; Dogan, S. D.; Balci, M. Tetrahedron 2014, 70, 4884-4890. (c)
Baran, A.; Cambul, S.; Nebioglu, M.; Balci, M. J. Org. Chem. 2012, 77,
5086-5097. (d) Kara, Y.; Balci, M. Tetrahedron 2003, 59, 2063-2066
3. Ogawa, S.; Ohmura, M.; Hisamatsu, S. Synthesis 2000, 312-316.
4. (a) Harit, V. K.; Ramesh, N. G. J. Org. Chem. 2016, 81, 11574−11586.
(b) Worawalai, W.; Sompornpisut, P.; Wacharasindhu, S.;
Phuwapraisirisan, P. Carbohyd. Res. 2016, 429, 155–162. (c) Gerstner,
N. C.; Adams C. S.; Grigg R. D.; Tretbar M.; Rigoli J. W.; Schomaker J.
M. Org Lett. 2016, 18, 284-287. (d) Trapero, A.; Egido-Gabas, M.;
8. Lautens, M.; Ma S. Tetrahedron Lett. 1996, 37, 1727-1730.
9. (a) Huang, Y.; Ma, C.; Lee, Y. X.; Huang, R.-Z.; Zhao, Y. Angew. Chem.
Int. Ed. 2015, 36, 13696-13700. (b) Zhou, H.; Li, J.; Yang, H.; Xia, C.;
Jiang, G. Org. Lett. 2015, 17, 4628−4631. (c) Carlson, E.; Haner, J.;
McKee, M.; Tam, W. G. Org. Lett. 2014, 16, 1776-17779. (d) Schindler,
C. S.; Diethelm, S.; Carreira, E. M. Angew. Chem. Int. Ed. 2009, 48,
6296–6299. (e) Nishimura, T.; Kawamoto, T.; Sasaki, K.; Tsurumaki, E.;
Hayashi, T. J. Am. Chem. Soc. 2007, 129, 1492-1493. (f) Padwa, A.;
Wang, Q. J. Org. Chem. 2006, 71, 3210-3220. (g) Lautens, M.; Fagnou,
K.; Hiebert, S. Acc. Chem. Res. 2003, 36, 48-58. (h) Moinet, C.; Fiaud,
J.-C. Tetrahedron Lett. 1995, 36, 2051-2052.

4
Tetrahedron
10.
(a) Balci, M.; Celik, M.; Demir, E.; Ertas, M.; Gultekin, S. M.;
16. Paquette, L. A.; Kravetz, T. M.; Charumilind, P. Tetrahedron 1986, 42,
1789-1795.
Ozturk, N.; Kara, Y.; Horasan-Kishali, N. Frontiers in Natural Product
Chemistry, Edit. By Ur-Rahman, A.; Choudhary, M. I.; Khan, M. I.
Bentham Science Publ. Vol. 1, Page 169, The Netherlands. (b) Chola, J.;
Masesane, I. B. Tetrahedron Lett. 2008, 49, 5680.
17. (a) Baran, A.; Bekarlar, M.; Aydin, G.; Nebioglu, M.; Sahin, E.; Balci,
M. J. Org. Chem. 2012, 77, 1244-1250. (b) Baran, A.; Balci, M. J. Org.
Chem. 2009, 74, 88-95. (c) Wang, B.; Gu, Y. L.; Gong, W. Z.; Kang, Y.;
Yang, L. M.; Suo, J. S. Tetrahedron Lett. 2004, 45, 6599-6602.
11.(a) Manzano, R.; Andres, J. M.; Muruzabal, M.-D.; Pedrosa, R. J. Org.
Chem. 2010, 75, 5417-5420. (b) Manka, J. T.; Douglass, A. G.;
Kaszynski, P.; Friedli, A. C. J. Org. Chem. 2000, 65, 5202-5206.
12. McCluskey, A.; K., Mirella A.; Walkom, C. C.; Bowyer, M. C.; Sim, A.
T. R.; Young, D. J.; Sakoff, J. A. Bioorg. Med. Chem. Lett. 2002, 12,
391-393.
13. (a) Koza, G.; Ozcan, S.; Sahin, E.; Balci, M. Tetrahedron 2009, 65,
5973-5976. (b) Koza, G.; Karahan, E.; Balci, Helv. Chim. Acta 2010, 93,
1698-1704.
Supplementary Material
Supplementary data (1D and 2D NMR spectra and the X-ray
crystal structure of can be found in the online version, at
http://dx.doi.org/........
14. (a) Yilmaz, O.; Kus, N. S.; Tunc, T.; Sahin, E. J. Mol. Struct. 2015, 1098,
72-75. (b) Moss, Gerard P.; Keat, O. C.; Bondar, G. V. Tetrahedron Lett.
1996, 37, 2877-80.
15. (a) Saracoglu, N.; Talaz, O.; Azizoglu, A.; Watson, W. H.; Balci, M. J.
Org. Chem. 2005, 70, 5403-5408. (b) Can, H.; Zahn, D.; Balci, M.;
Brinkman, J. Eur. J. Org. Chem. 2003, 1111-1117. (c) Borden, W. T.
Chem. Rev. 1989, 89, 1095-1109.

5
Highlights
A new synthon for accessing more complex
azacarbasugars was synthesized.
Concise route to unusual, highly oxygenated
small molecules was developed.
A double Curtius rearrangement was applied to
introduce amino functionalities.