Synthesis and theoretical study of azido and amino inositol derivatives from L-quebrachitol

Article abstract of DOI:10.1016/S0040-4039(01)00326-4

Some azido and amino inositol derivatives were synthesised from L-quebrachitol. The reaction between the mesylated compound and sodium azide was studied experimentally. Ab initio quantum mechanical calculations were carried out for this process to better

Full text of DOI:10.1016/S0040-4039(01)00326-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2767–2769
Synthesis and theoretical study of azido and amino inositol
derivatives from -quebrachitol
L
Mauro V. De Almeida,a Renata M. Figueiredo,a He´lio F. Dos Santos,a Adilson D. Da Silvaa and
Wagner B. De Almeidab,*
aDepartamento de Qu´ımica, ICE, Universidade Federal de Juiz de Fora, Juiz de Fora, MG, Brazil
bLaborato´rio de Qu´ımica Computacional e Modelagem Molecular, Departamento de Qu´ımica, ICEx,
Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil
Received 7 December 2000; revised 6 February 2001; accepted 23 February 2001
Abstract—Some azido and amino inositol derivatives were synthesised from L-quebrachitol. The reaction between the mesylated
compound and sodium azide was studied experimentally. Ab initio quantum mechanical calculations were carried out for this
process to better understand the reaction mechanism. © 2001 Elsevier Science Ltd. All rights reserved.
The chemotherapeutic success of the aminocyclitol
antibiotics has stimulated research into the chemistry of
their amino sugar components.1,2 The structure 5-O-
methyl-myo-inosamine 1 was first assigned to the cycli-
tol moiety of antibiotic KA-3093, related to
hygromycin A, which contains an inosamine unit 3.3,4
Later, methoxyhygromycin was isolated5 from the fer-
mentation broth of Streptomyces sp. N° 207, and acid
hydrolysis gave 5-O-methyl-neo-inosamine 2. The
antibiotic minosaminomycin, the product of Strepto-
compounds 8, 11, 12, 15, 19 and 21, COSY 1H–1H
correlations were performed.
As starting material we have used quebrachitol 6 (1-O-
methyl-chiro-inositol; Scheme 1) isolated from waste
rubber solids by extraction with EtOH. Compound 6
was converted to a mixture of 7, 8 and 9 in a 2/2/5 ratio
(90% yield) using 3.3 equiv. of benzoyl chloride in
pyridine at 0°C.13 The reaction of 6 using 4.4 equiv. of
benzoyl chloride in pyridine, at 0°C, furnished 9, 10
and 11 in a 2/2/4 ratio (80% yield).14
myces N° MA 514-A1, contains 1-D-1-amino-1-deoxy-
myo-inositol 4 as an aminocyclitol moiety.6,7 Also, the
aminosugars are components of several compounds of
biological interest such as pancrastitatin.8 Furthermore,
Kozikowski and co-workers have found that azidoinos-
itols such as the 3-azido-3-deoxy-myo-inositol 5 are
selective inhibitors of the growth of v-sis-transformed
NIH 3T3 cells.9–11
Treatment of the diol 9 and alcohol 11 with methane-
sulfonyl chloride in pyridine gave 2,3-di-O-methanesul-
fonyl 12 and 3-O-methanesulfonyl 16 in 90 and 95%
yield, respectively. Cleavage of the benzoyl groups of
compounds 12 and 16 with sodium metoxide in
methanol/THF afforded the triol 13 and the tetrol 17 in
85 and 88% yield, respectively. Reaction of compounds
13 and 17 with sodium azide in DMF followed by
acetylation gave the diazide 15 and the azide 19, respec-
tively, in 25 and 70% overall yield. In the azidation
reaction of 13 we observed the formation of three
others azido compounds that were not isolated. Finally,
In this article we detail an expedient route to prepare
2,3-diazido-2,3-dideoxy-1-O-methyl-scyllo-inositol 14,
1L-3-azido-3-deoxy-1-O-methyl-chiro-inositol 18 and 3-
amino-3-deoxy-1-O-methyl-chiro-inositol 20. The struc-
tures of all new compounds were unequivocally
established by 1H and 13C NMR.12 In the case of
* Corresponding author. E-mail: wagner@netuno.qui.ufmg.br
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00326-4

2768
M. V. De Almeida et al. / Tetrahedron Letters 42 (2001) 2767–2769
Scheme 1.
hydrogenation in the presence of palladium allowed the
reduction of the azido compound 18 into the corre-
sponding amine derivative 20, additionally purified as
its penta-acetate 21 (90% overall yield from 18). The
reaction between the mesylated compound 17 and
sodium azide in DMF at 140°C for 16 h (70% yield;
Scheme 1) rests upon surprising total retention of the
configuration, and the only product 18 was assigned by
analysis of NMR spectra.
The experimentally observed axial product can be
justified based on the thermodynamic aspects of the
process. On the basis of the theoretical results the axial
product 18 was found to be present in DMF in a
relative concentration of 86%. However, aiming at a
complete description of the process investigated, a sys-
tematic analysis was developed with regard to the reac-
tion mechanism. The axial product can be obtained
either via the carbocation formation or from the epox-
ide. The synchronised mechanism (SN2) involving the
direct attack leads exclusively to the formation of the
equatorial product. Considering the carbocation forma-
tion, both products can be obtained depending on the
Theoretical investigation of this process was carried out
to better understand the reaction mechanism. The cal-
culations were performed at the Hartree–Fock (HF)
level of theory using the split valence 6-31+G* basis-set
for the energy calculations considering the HF/3-21+G*
fully optimised geometries (HF/6-31+G*//3-21+G*).
Three distinct mechanisms involving a carbocation, an
epoxide intermediates and a transition state (TS) struc-
−
attack position of the reagent N3 . This mechanism
might be used to understand the experimental finding
considering that the axial product is thermodynamically
more favourable. However, comparing the relative sta-
bility of the carbocation and epoxide intermediates, it
was observed that the reaction pathway involving the
epoxide is favoured. From the theoretical calculations
including solvent effects it was found that the epoxide
intermediate was 30 kcal/mol more stable than the
carbocation one. The calculated activation free energy
(TSepoxide) for the epoxide opening was found to be 47.1
kcal/mol in DMF solution at 140°C. Therefore, the
reaction pathway can be traced considering the process
through two stages. Firstly, the reaction passes through
−
ture for a direct attack of the N3 species were investi-
gated. The solvent (DMF, m=36.7) effect was assessed
at the HF level using the PCM (polarisable continuum
model) approach.15 The reaction Gibbs free energy in
solution (DGDMF) was evaluated using the well-known
thermodynamical cycle according to the equation
DGDMF=DGg+(DGPsolv−DGRsolv),16 where DGg is the gas
solv
phase reaction Gibbs free energy and DGP
and
solv
DGR
are the solvation free energies of products and
reagents, respectively.

M. V. De Almeida et al. / Tetrahedron Letters 42 (2001) 2767–2769
2769
the epoxide intermediate and then ring epoxide opening
takes place leading to the formation of the axial
product.
C2, C3, C4, C5, C6); (found: C, 62.93; H, 5.46. C21H22O8
requires C, 62.68; H, 5.51%); 9: oil; H NMR (400 MHz,
1
CDCl3) l: 6.09 (t, 1H, H5, J5–4=J5–6=10), 5.90 (dd, 1H,
H6, J6–1=9.6), 5.76 (dd, 1H, H4, J4–3=3), 4.58 (t, 1H,
H3, J3–2=3), 4.42 (t, 1H, H2, J2–1=3), 3.94 (dd, 1H, H1);
13C NMR (100 MHz, CDCl3) l: 58.8 (OCH3), 68.7, 69.5,
70.2, 71.9, 72.8, 79.5 (C1, C2, C3, C4, C5, C6); 11: mp
Acknowledgements
1
162–164°C; H NMR (400 MHz, CDCl3) l: 6.20 (t, 1H,
This work was partially supported by CNPq. W.B.D.A.
would like to thank the members of the Departamento
de Qu´ımica, Universidade Federal de Juiz de Fora
(UFJF) for the very pleasant stay during the time that
this work was carried out, and the Pro´-Reitoria de
Po´s-Graduac¸a˜o e Pesquisa (PROPP–UFJF) for a Visit-
ing Professor Fellowship. The authors also thank the
CENAPAD-MG/CO-NAR-UFJF for providing com-
putational facilities.
H6, J6–5=J6–1=10), 5.99 (t, 1H, H5, J5–4=10), 5.94 (dd,
1H, H2, J2–3=J2–1=4), 5.72 (dd, 1H, H4, J4–3=4), 4.60
(q, 1H, H3, J3–OH=4), 4.15 (dd, 1H, H1); 13C NMR (100
MHz, CDCl3) l: 58.8 (OCH3), 68.3, 68.9, 70.2, 71.8, 72.9,
77.6 (C1, C2, C3, C4, C5, C6); (found: C, 68.68; H, 4.66.
C35H30O10 requires C, 68.85; H, 4.95%); 12: mp 167–
1
170°C; H NMR (400 MHz, CDCl3) l: 5.97 (t, 1H, H5,
J
5–6=J5–4=10), 5.85 (t, 1H, H6, J6–1=10), 5.78 (dd, 1H,
H4, J4–5=10, J4–3=3.8), 5.47 (dd, 1H, H3, J3–2=3.5),
5.42 (dd, 1H, H2 J2–1=4), 4.05 (dd, 1H, H1); 13C NMR
(100 MHz, CDCl3) l: 38.5, 39.1 (CH3S), 59.5 (OCH3),
69.3, 69.4, 70.5, 74.3, 74.9 (C1, C2, C3, C4, C5, C6);
(found: C, 54.41; H, 4.83. C30H30O13S2 requires C, 54.37;
H, 4.56%); 15: oil; 1H NMR (400 MHz, CDCl3) l:
5.11–4.97 (3t, 3H, H6, H5, H4,), 2.70–2.58 (3t, 3H, H1,
H2, H3); 13C NMR (100 MHz, CDCl3) l: 60.4 (OCH3),
62.6, 63.6, 71.1, 71.2, 72.2, 81.4 (C1, C2, C3, C4, C5, C6);
19: mp 69–72°C; 1H NMR (400 MHz, CDCl3) l: 5.43
References
1. Da Silva, E. T.; Le Hyaric, M.; Machado, A. S.; De
Almeida, M. V. Tetrahedron Lett. 1998, 39, 6659.
2. (a) Ogawa, S.; Isaka, A. Carbohydr. Res. 1991, 210, 105;
(b) Arjona, O.; De Rios, A.; Plumet, J.; Saez, B. Tetra-
hedron Lett. 1995, 8, 6659.
3. Pittenger, R. C.; Wolfe, R. N.; Hochn, M. M.; Marks, P.
N.; Daily, W. A.; McGuire, J. M. Antibiot. Chemother.
1953, 3, 6659.
(dd, 1H, H2, J2–1=3.2, J2–3=4), 5.41 (t, 1H, H5, J5–4
=
J5–6=10), 5.30 (dd, 1H, H4, J4–3=4, J4–5=10), 5.25 (t,
1H, H6, J1–6=10), 4.12 (t, 1H, H3), 3.55 (dd, 1H, H1);
13C NMR (100 MHz, CDCl3) l: 58.5 (OCH3), 59.5, 66.8,
69.9, 70.9, 71.2, 76.3 (C1, C2, C3, C4, C5, C6); 21: oil; 1H
NMR (400 MHz, CDCl3) l: 5.65 (dd, 1H, H2, J2–1=4.8,
4. Mann, R. L.; Gale, R. M.; Van Abeele, F. R. Antibiot.
Chemother. 1953, 3, 1279.
5. Chida, N.; Nakazawa, K.; Ohtsuka, M.; Suzuki, M.;
Ogawa, S. Chem. Lett. 1990, 423.
J2–3=3), 5.41–5.22 (m, 3H, H4, H5, H6), 4.60 (dd, 1H,
6. Olesker, A.; Mercier, D.; Gero, S. D.; Pearce, C. J.;
H3, J3–4=4, J3–2=3), 3.58 (dd, 1H, H1, J1–6=8, J1–2
=
Barnett, J. E. G. J. Antibiot. 1975, 28, 491.
4.8); 13C NMR (100 MHz, CDCl3) l: 48.3 (C3), 58.3
(OCH3), 66.7, 69.0, 69.8, 70.8, 77.0 (C1, C2, C4, C5, C6).
13. To a solution of powered quebrachitol (3.88 g; 20 mmol)
in dry pyridine (100 mL) benzoyl chloride (7.7 mL; 66
mmol) was slowly added over 10 h at 0°C. After the
addition, the solution was stirred for 6 h at 0–10°C and
for 6 h at room temperature. The mixture was extracted
with CH2Cl2, the organic layer was dried in MgSO4 and
concentrated under reduced pressure. The residue was
chromatographed on silica gel 70–230 mesh (AcOEt/hex-
ane) to give compounds 7 (1.6 g; 20%), 8 (1.6 g; 20%) and
9 (5.0 g; 50%).
7. Hamada, M.; Kondo, S.; Yokoyama, T.; Miura, K.;
Iimura, K.; Yamamoto, H.; Maeda, K.; Takeuchi, T.;
Umezawa, H. J. Antibiot. 1974, 27, 81.
8. (a) Acen˜a, J. L.; Arjona, O.; Iradier, F.; Plumet, J.
Tetrahedron Lett. 1996, 37, 105; (b) Pettit, G. R.; Gad-
damidi, V.; Gragg, G. M.; Herald, D. L.; Sagawa, Y. J.
Chem. Soc., Chem. Commun. 1984, 1693.
9. Kozikowski, A. P.; Fauq, A. H.; Powis, G.; Kurian, P.;
Crews, F. T. J. Chem. Soc., Chem. Commun. 1992, 362.
10. Kozikowski, A. P.; Fauq, A. H.; Powis, G.; Melder, D.
C. J. Am. Chem. Soc. 1990, 112, 4528.
11. Brunn, G.; Fauq, A. H.; Chow, S.; Kozikowski, A. P.;
Gallegos, A.; Powis, G. Cancer Chemother. Pharmacol.
1994, 35, 71.
14. Compounds 9, 10 and 11 were obtained by the same
experimental procedure described above for the prepara-
tion of 7, 8 and 9 from quebrachitol (3.88 g; 20 mmol)
using 10.3 mL (88 mmol) of benzoyl chloride. Purifica-
tion by chromatography on silica gel 70–230 mesh
(CH2Cl2; then AcOEt/hexane) afforded compounds 9 (2.0
g; 20%), 10 (2.8 g; 20%) and 11 (4.8 g; 40%).
15. (a) Cossi, M.; Barone, V.; Camimi, R.; Tomasi, J. Chem.
Phys. Lett. 1996, 255, 327; (b) Barone, V.; Cossi, M.;
Tomasi, J. J. Chem. Phys. 1997, 107, 3210.
12. 7: mp 170–172°C; 1H NMR (400 MHz, acetone-d6) l:
5.67 (t, 1H, H6, J6–1=J6–5=9.8), 5.49 (dd, 1H, H4,
J4–3=3; J4–5=10), 4.85 (d, 1H, OH, J=4.3), 4.60 (d, 1H,
OH, J=5.6), 4.38 (m, 4H, H2, H3, H5, OH), 3.80 (dd,
1H, H1, J1–2=2.8); 8: mp 171–173°C; 1H NMR (400
MHz, acetone-d6) l: 5.87 (t, 1H, H5, J5–4=J5–6=10),
5.58 (dd, 1H, H4, J4–5=10), 4.40 (t, 1H, H3, J3–4=J3–2
=
3), 4.32 (t, 1H, H2, J2–1=3), 4.15 (t, 1H, H6, J6–1=10),
3.60 (dd, 1H, H1); 13C NMR (100 MHz, acetone-d6) l:
57.8 (OCH3), 68.2, 68.9, 70.1, 71.0, 73.6, 73.9, 81.8 (C1,
16. De Almeida, W. B.; Dos Santos, H. F.; Zerner, M. C. J.
Pharm. Sci. 1998, 87, 1101.
.