Expeditious synthesis of seven-membered iminocyclitols

Article abstract of DOI:10.1016/S0040-4039(01)01587-8

A concise synthesis of an azepanetriol and an octahydropyrrolo[1,2-a]azepinepentol, by nitrone addition to a pent-4-enofuranoside derived from D-ribose, followed by reductive opening of the isoxazolidine ring formed, is reported.

Full text of DOI:10.1016/S0040-4039(01)01587-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7497–7499
Expeditious synthesis of seven-membered iminocyclitols
John K. Gallos,* Soultana C. Demeroudi, Constantina C. Stathopoulou and
Constantinos C. Dellios
Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 540 06, Greece
Received 27 March 2001; revised 10 August 2001; accepted 24 August 2001
Abstract—A concise synthesis of an azepanetriol and an octahydropyrrolo[1,2-a]azepinepentol, by nitrone addition to a
pent-4-enofuranoside derived from -ribose, followed by reductive opening of the isoxazolidine ring formed, is reported. © 2001
D
Elsevier Science Ltd. All rights reserved.
Natural and synthetic iminocyclitols, frequently known
as ‘aza-sugars’ show specific inhibition against glycosi-
dases and glycosyltransferases, being potential thera-
peutic agents for viral, proliferative and metabolic
diseases.1 As a consequence, intensive work has been
focused on their synthesis, usually directed towards the
five- and six-membered iminocyclitols. However, little
attention has been given to the azepane analogues, in
spite of some reports that several tetra- and tri-hydroxy
seven-membered iminocyclitols such as 1 and 2 (Fig. 1)
show significant activity as glycosidase inhibitors.2 In
addition, azepanediol 3 has been used for the synthesis
of balanol, a popular synthetic target with remarkable
inhibitory activity against protein kinase C, which has
an azepane ring in its structure.3 Further to our recent
synthetic approach to hydroxylated pyrrolizidines and
hydroxylated carbocycles from enofurano(pyrano)-
sides,4 we now report a concise method for the synthe-
sis of azepanetriol 4 and octahydropyrrolo[1,2-a]-
azepinepentol 5, in their protected form.
Addition of the nitrone CH2ꢀN(“O)Bn to pent-4-eno-
furanoside 6 (Scheme 1), readily available from
D-
ribose in three steps,5 afforded cycloadduct 7 as a single
Figure 1.
Scheme 1. Reagents and conditions: (i) CH2ꢀN(“O)Bn, toluene, reflux, 72 h, 59% (30% of 6 recovered); (ii) Raney Ni, H2, MeOH,
H3BO3 (20 equiv.), MgSO4, 20°C, 2 h, 56%; (iii) NaBH3CN, AcOH (gl.), 20°C, 24 h, 49%.
* Corresponding author. Fax: +31-997679; e-mail: igallos@chem.auth.gr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01587-8

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J. K. Gallos et al. / Tetrahedron Letters 42 (2001) 7497–7499
Scheme 2. Reagents and conditions: (i) toluene, reflux, 48 h, 96%; (ii) Raney Ni, H2, MeOH, H3BO3 (20 equiv.), MgSO4, 20°C,
24 h, 43% of 12 and 56% of 13 (as a ca. 1:1 mixture of epimers); (iii) NaBH4, EtOH, 20°C, 4 h, 98% (as a ca. 1:1 mixture of
epimers)
diastereomer.6 Although the diastereoselectivity of this
reaction is of no importance, since the spiro carbon
loses its chirality in the next step, the assigned structure
was analogous to the cycloadducts obtained from the
nitrile oxide and nitrosoalkene additions to 6.4 This
diastereoselectivity results from addition of the nitrone
to the less hindered face of the double bond. Raney Ni
hydrogenation of 7 in MeOH at 20°C in the presence of
20 equiv. of H3BO3, led to the formation of compound
8, isolated in good yield. Evidently, NꢁO bond cleavage
by hydrogenolysis was followed by MeOH elimination
to an aminoketoaldehyde, which spontaneously cyclised
to the N,O-acetal-O,O-hemiacetal 8. Treatment of 8
with NaBH3CN in glacial AcOH at 20°C, gave the
protected azepanetriol 9 as a single diastereomer in
good yield,2h resulting from further reduction of the
ketone intermediate. A bicyclic compound analogous to
8 has been previously isolated as a by-product in the
Raney Ni hydrogenation of a nitrile oxide adduct to
6.4c
genation of the CꢀN bond thus generated. In the case
of 8, the presence of NaCNBH3 in AcOH was necessary
to complete the reaction.
With the exception of 12, all new compounds were
characterized on the basis of their spectroscopic and
analytical data, which were consistent with the given
structures.6 Compound 12 was relatively unstable and
could not be isolated in pure form, but the signal at l
203.1 in the 13C NMR spectrum as well as the mea-
sured exact molecular mass leaves little doubt of its
structure. Especially for compounds 9 and 11 (and
therefore 12 and 13), NOE experiments confirmed the
assigned absolute configuration of the newly formed
stereocenters, resulting from the reduction of the car-
bonyl group and the addition of nitrone to 6, respec-
tively. The significant signal enhancements of the 3-H
and 5-H protons when irradiating the 4-H proton of 9
confirms its expected all-cis stereochemistry. In the case
of 11, the strong signal enhancement of 3a-H upon
saturation of 3-Hb and the considerable enhancement
of the 3-Ha signal caused by the saturation of 4-H
confirm the configuration of the newly formed chiral
center in the major epimer of 11. Regarding compound
13, as already mentioned, it is an inseparable mixture of
epimers in ca. 1:1 ratio, the epimers being different in
the absolute configuration of the stereocenter resulting
from reduction of the carbonyl group of 12.
It was apparent that a bicyclic iminocyclitol with an
azepane fused ring could be prepared by using a cyclic
nitrone and applying the above reaction sequence.
Indeed, 3,4-dihydro-2H-pyrrole-1-oxide was smoothly
added to 6, but the diastereoselectivity of the reaction
was poor. A most satisfactory diastereoselection was
achieved by adding the chiral nitrone 107 to the ribose
derivative 6, where cycloadduct 11 was isolated in good
yield, together with the C-3a epimer, in a ratio ca. 8.5:1
(Scheme 2). Further, Raney Ni hydrogenation in
MeOH at 20°C in the presence of 20 equiv. of H3BO3
gave directly the desired protected octahydro-
pyrrolo[1,2-a]azepinepentol 13 (56%), together with its
ketone precursor 12 (43%). The latter was quantita-
tively reduced to 13 with NaBH4. Compound 13 was
isolated as an inseparable mixture of epimers in ca. 1:1
ratio, due to the non-selective reduction of the carbonyl
group of 12 by Raney Ni or NaBH4.
In conclusion, a new method for the synthesis of
hydroxylated azepanes, either monocyclic or fused with
a pyrrolidine ring from readily available pent-4-eno-
furanoside has been developed, utilizing cheap and
easily available reagents, applying simple and conve-
nient methods. Further work in the synthesis of some
other azepanol analogues is in progress.
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intermediate similar to 8 was formed, which then
underwent spontaneous elimination of water after pro-
tonation of the hydroxyl group, followed by hydro-
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2.82 (m, 2H), 3.81 (d, 1H, J=13.3 Hz), 3.96 (d, 1H,
J=13.3 Hz), 3.98 (s br, 1H), 4.32 (d, 1H, J=5.5 Hz), 4.60
(s, 1H), 4.69 (d, 1H, J=5.5 Hz), 7.3 (m, 5H); 13C NMR
(CDCl3): l 25.1, 26.0, 28.7, 43.3, 55.9, 79.6, 82.8, 92.4,
102.0, 112.9, 127.3, 128.4, 128.9, 138.2; HRMS (MALDI-
FTMS) calcd (C16H22NO4) 292.1543 (M+H), found
292.1535, | 2.7 ppm. Compound 9: oil, [h]D −10.7 (c 2.8,
CHCl3); 1H NMR (CDCl3): l 1.33 (s, 3H), 1.43 (s, 3H),
1.83 (m, 2H), 2.40 (m, 2H), 2.50 (s br, 1H), 2.95 (m, 2H),
3.54 (d, 1H, J=13.2 Hz), 3.70 (d, 1H, J=13.2 Hz), 3.85
(ddd, 1H, J=9.6, 7.5, 2.3 Hz), 4.10 (dd, 1H, J=8.7, 7.5
Hz), 4.32 (ddd, 1H, J=10.7, 7.5, 5.4 Hz), 7.3 (m, 5H); 13C
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75.1, 82.9, 108.7, 127.2, 128.3, 128.7, 138.4; HRMS
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found 278.1747, | 1.4 ppm. Compound 11: oil, [h]D +44.6
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1
(c 1.07, CHCl3); H NMR (CDCl3): l 1.32 (s, 3H), 1.45 (s,
3H), 2.62 (dd, 1H, J=13.8, 8.1 Hz), 2.83 (dd, 1H, J=13.8,
6.2 Hz), 3.37 (s, 3H), 3.38 (s, 3H), 3.41 (s, 3H), 3.42 (dd,
1H, J=13.8, 3.2 Hz), 3.56 (dd, 1H, J=13.8, 5.7 Hz), 3.78
(ddd, 1H, J=8.1, 6.2, 3.5 Hz), 4.09 (dd as t, 1H, J=3.5
Hz), 4.23 (ddd as dt, 1H, J=5.7, 3.5 Hz), 4.65 (m, 6H),
4.99 (s, 1H); 13C NMR (CDCl3): l 25.0, 26.2, 41.4, 54.7,
55.4 (two MeO from MOM overlapping), 60.0, 69.2, 83.1,
83.5, 84.5, 87.1, 95.9, 96.0, 107.8, 112.6, 116.4; HRMS
(MALDI-FTMS) calcd (C17H30NO9) 392.1915 (M+H),
found 392.1918, | 0.8 ppm. Compound 12: oil; HRMS
(MALDI-FTMS) calcd (C16H28NO7) 346.186 (M+H),
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1
found 346.1856, | 1.2 ppm. Compound 13: oil; H NMR
6. All new compounds gave spectral and analytical data
consistent with the proposed structures. Compound 7: oil,
[h]D +49.9 (c 4.62, CHCl3); 1H NMR (CDCl3, 50°C): l
1.31 (s, 3H), 1.43 (s, 3H), 2.35 (m, 2H), 2.95 (m, 2H), 3.30
(s, 3H), 4.01 (d, 1H, J=12.2 Hz), 4.05 (d, 1H, J=12.2
Hz), 4.63 (s, 2H), 4.96 (s, 1H), 7.3 (m, 5H); 13C NMR
(CDCl3, 50°C): l 25.3, 26.4, 36.3, 53.7, 54.7, 63.4, 84.1,
84.8, 108.30, 108.31, 112.7, 127.4, 128.3, 129.2, 137.2;
HRMS (MALDI-FTMS) calcd (C17H24NO5) 322.1649
(M+H), found 322.1651, | 0.6 ppm. Compound 8: oil, [h]D
+1.0 (c 0.5, CHCl3); 1H NMR (CDCl3): l 1.37 (s, 3H),
1.47 (m, 1H), 1.51 (s, 3H), 2.23 (dt, 1H, J=6.7, 6.2 Hz),
(CDCl3): l 1.32 (s, 3H), 1.46 (s, 3H), 1.65 (m, 2H), 2.2–3.2
(several m, 5H), 3.34 (s, 3H), 3.35 (s, 3H), 3.42 (m, 1H),
3.73 (m, 1H), 3.98 (m, 1H), 4.18 (m, 1H), 4.6–4.75 (m,
6H); 13C NMR (CDCl3): l 26.4/26.5, 27.2/27.3, 29.6/29.7,
55.55/55.59, 55.63/55.68, 55.70/55.77, 61.1/61.5, 63.9/65.1,
70.5/70.7, 72.1/74.1, 78.3/78.9, 83.0/83.1, 88.0/89.4, 95.2/
95.3, 95.7/95.9, 108.6/109.3; HRMS (MALDI-FTMS)
calcd (C16H30NO7) 348.2017 (M+H), found 348.2023, |
1.7 ppm.
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