Regioselective rearrangement of 7-azabicyclo[2.2.1]hept-2-aminyl radicals: First synthesis of 2,8-diazabicyclo[3.2.1]oct-2-enes and their conversion into 5-(2-aminoethyl)-2,3,4-trihydroxypyrrolidines, new inhibitors of α-mannosidases

Article abstract of DOI:10.1016/S0040-4039(03)01141-9

Enantiomerically pure 2,8-diazabicyclo[3.2.1]oct-2-ene derivatives (+)-5 and (-)-5 have been obtained from 2-azido-3-tosyl-7-azabicyclo[2.2.1]heptanes (+)-1 and (-)-2 and their enantiomers, by ring expansion under radical conditions. Compounds (+)-5 and (

Full text of DOI:10.1016/S0040-4039(03)01141-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5069–5073
Regioselective rearrangement of 7-azabicyclo[2.2.1]hept-2-aminyl
radicals: first synthesis of 2,8-diazabicyclo[3.2.1]oct-2-enes
and their conversion into
5-(2-aminoethyl)-2,3,4-trihydroxypyrrolidines, new inhibitors
of a-mannosidases
Antonio J. Moreno-Vargas and Pierre Vogel*
Institut de Chimie Mole´culaire et Biologique de l’Ecole Polytechnique Fe´de´rale de Lausanne, EPFL-BCH,
CH-1015 Lausanne-Dorigny, Switzerland
Received 28 April 2003; revised 30 April 2003; accepted 3 May 2003
Abstract—Enantiomerically pure 2,8-diazabicyclo[3.2.1]oct-2-ene derivatives (+)-5 and (−)-5 have been obtained from 2-azido-3-
tosyl-7-azabicyclo[2.2.1]heptanes (+)-1 and (−)-2 and their enantiomers, by ring expansion under radical conditions. Compounds
(+)-5 and (−)-5 were transformed into hemiaminals 9 ((3S,4R,5R)- and 10 ((3R,4S,5S)-5-(2-aminoethyl)-2,3,4-trihydroxypyrro-
lidine) that are good inhibitors of a-mannosidases. © 2003 Published by Elsevier Science Ltd.
The 7-azabicyclo[2.2.1]heptane ring system is an attrac-
tive target for synthetic chemists since the discovery in
1992 of (−)-epibatidine,1 a new alkaloid with interesting
biological properties (Fig. 1). The [4+2] cycloaddition
reaction between N-acyl pyrroles and dienophiles has
been shown to be a general method for the synthesis of
the 7-azabicyclo[2.2.1]hepta-2,5-diene and 7-azabicy-
clo[2.2.1]hept-2-ene derivatives.2 In recent years, a num-
ber of successful [4+2] cycloadditions have employed
acetylene equivalents as dienophiles. Ethynyl p-tolyl
sulfone derivatives have been found to be one of the
most synthetically useful acetylene equivalents2–4
because of its high reactivity toward dienes and ease of
removal of the p-toluenesulfonyl moiety under reduc-
tive conditions. Desulfonylation reactions5 have been
widely studied, specially in the case of alkyl sulfones,6
b-keto sulfones7 and vinyl sulfones8 derivatives of 7-
azabicyclo[2.2.1]heptane.
As part of our search for new 1,2-diamines as leads for
glycosidase inhibitors9 we have reported10 the synthesis
of enantiomerically pure 7-azabicyclo[2.2.1]heptanes-2-
yl amines (−)-3 and (−)-4 (and their enantiomers) that
were derived from b-azidosulfones (+)-1 and (−)-2,
respectively, via catalytic hydrogenation of the azido
group, followed by desulfonylation of the correspond-
ing b-amino sulfone with sodium amalgam (Scheme 1).
With the hope to find a better route to these amines
avoiding the use of large amounts of sodium amalgam
(10 equiv.) we explored the possibility to apply a radical
induced desulfonylation. We report here our results
with the reactions of b-azido sulfones (+)-1 and (−)-2
upon treatment with tributyltin hydride (Bu3SnH)5,11 in
the presence of catalytic amounts of azoisobutyrocar-
bonitrile (AIBN) and shall show that a highly regiose-
lective radical rearrangement generating a bicyclic
imine of a new type (2,8-diazabicyclo[3.2.1]oct-2-ene)
has been uncovered. The latter compound has allowed
one to prepare the hemiaminal salt (3S,4S,5R)-5-(2-
ammonioethyl)-2,3,4-trihydroxy-pyrrolidinium dichlo-
ride and its enantiomer that are found to be potent and
selective a-mannosidase inhibitors.
Figure 1. (−)-Epibatidine.
Desulfonylation of (+)-1 upon heating with Bu3SnH
and AIBN in toluene at 110°C (3 h) gave the 2,8-diaz-
abicyclo[3.2.1]oct-2-ene derivative (+)-512 as major com-
* Corresponding author. Fax: +41216939375; e-mail: pierre.vogel@
epfl.ch
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4039(03)01141-9

5070
A. J. Moreno-Vargas, P. Vogel / Tetrahedron Letters 44 (2003) 5069–5073
matography on silica gel). When pure amines 7 and 8
were treated with Bu3SnH/AIBN as above, no trace of
product of rearrangement could be detected. After 3 h
at 110°C, and in the presence of an excess of Bu3SnH/
AIBN, 7 and 8 were recovered unchanged almost quan-
titatively. This indicates that reductions of azides into
the primary amines compete with the radical rearrange-
ment transforming (+)-1 and (−)-2 into imine (+)-5.
After heating (+)-1 and (−)-2 (toluene and xylene at
reflux) in the absence of Bu3SnH/AIBN, all the starting
materials were recovered, while heating of (+)-1 in the
presence of Bu3SnH (without AIBN) only produced
amine 7.
The presence of Bu3SnH/AIBN was absolutely neces-
sary to induce the rearrangement, suggesting that
aminyl radicals of type A (Scheme 3) are probably
involved in the mechanism. It is known that alkyl
azides generate aminyl radicals14 by loss of N2 in the
presence of Bu3SnH/AIBN. Radicals
A undergo
Scheme 1. See Ref. 10.
regiospecific 1,2-shift of the s (C(1)ꢀC(2)) bond form-
ing intermediate radicals B that finally afford rear-
pound isolated by column chromatography on silica gel
(40% yield) (Scheme 2). Primary amine 7 resulting from
the reduction of azide (+)-1 without skeletal rearrange-
ment was isolated as minor compound (14%), together
with secondary amine (+)-613 (13%) resulting from the
reduction of imine (+)-5. Hydrogenation of imine (+)-5
in MeOH in the presence of a catalytical amount of
10% Pd on charcoal provided pure (+)-6 in 97% yield.
Treatment of the diastereoisomeric b-azido sulfone (−)-
2 with Bu3SnH/AIBN as above gave the same intra-
cyclic imine (+)-5 in 56% yield, together with primary
amine 8 (12%) and (+)-6 (10%, after column chro-
’
ranged imines after Bu3Sn elimination. The radical
desulfonylation takes place after the rearrangement
because the C-4 centered radical contiguous to a CꢁN
bond (radical D, Scheme 3) is more stable than other
secondary alkyl radicals, explaining that only desul-
fonylated products were isolated for rearranged species.
Interestingly, the same high regioselectivity is observed
for both the endo-aminyl radical (arising from (+)-1)
and the exo-aminyl radical (arising from (−)-2) in their
rearrangement into (+)-5. The greater migratory apti-
tude of the s (C(1)ꢀC(2)) in radicals of type A com-
pared with that of the s (C(2)-H) or s (C(3)ꢀC(2))
Scheme 2. Ring expansion in the reductive desulfonylation of b-azido sulfones (+)-1 and (−)-2.

A. J. Moreno-Vargas, P. Vogel / Tetrahedron Letters 44 (2003) 5069–5073
5071
Scheme 3. Rearrangement through aminyl radical intermediates.
Boc groups are rapidly cleaved to give the correspond-
ing unstable isopropylidene aminals, which are immedi-
ately hydrolyzed17 to give hemiaminals 918,19 and 10, as
a mixture of anomers, in quantitative yields.
bond is noteworthy. It demonstrates the favorable
effect of the BocN substituent on the 1,2-shift activa-
tion barrier. The 6-exo-oxy substitution may also play
a favorable role.
We have assayed20 hemiaminals 9 and 10 for their
inhibitory activities toward 25 commercially available
glycosidases. The data are summarized in Table 1 for
two a-galactosidases, three b-galactosidases, two b-glu-
cosidases, two a-mannosidases, one b-xylosidase and
one a-N-acetylgalactosaminidase. These compounds
did not show any inhibitory activity at 1 mM concen-
tration toward the following enzymes: a-galactosidase
from Escherichia coli, b-galactosidases from Aspergillus
To our knowledge there is no previous report on the
synthesis of 2,8-diazabicyclo[3.2.1]oct-2-enes, although
the synthesis of 2,8-diazabicyclo[3.2.1]octanes15 and
related structures16 have been reported. Starting from
the enantiomer b-azido sulfones (−)-1 and (+)-2, the
corresponding enantiomerically pure derivatives (−)-5
and (−)-6 were synthesized following the procedure
described above. Compound (+)-6 and (−)-6 were
deprotected under aqueous acidic conditions (HCl 1
M-THF, 1:1) (Scheme 4). Under these conditions the
niger and from Aspergillus orizae, a-L-fucosidase from
bovine epididymis, a-glucosidases from yeast, from rice
and from baker yeasts, amyloglucosidases from
almonds and from Caldocellum saccharolyticum, b-
mannosidases from Helix pomatia and b-N-acetylglu-
cosaminidase from jack beans, from bovine epididymis
A and B.
Hemiaminals (3S,4S,5R)-5-(2-ammonioethyl)-2,3,4-tri-
hydroxypyrrolidinium dichloride 9 (HCl)2 and its enan-
tiomer 10 (HCl)2 resulted to be good inhibitors of
a-mannosidases from jack beans, with Ki=2.5 and 0.94
mM, respectively, and from almonds, with Ki=1.9 and
1.2 mM, respectively. Both enantiomers present similar
inhibitory properties (Table 1). However, the mode of
inhibition depends on the enzyme and on the absolute
configuration of the 2,3,4-trihydroxypyrrolidine. Under
the pH conditions20 used for the inhibition tests, these
hemiaminals can equilibrate with the corresponding
imines through water elimination. Related imines of
this kind have been reported21 to be inhibitors of
a-mannosidases.
In summary, we have described the first case of radical
ring expansion in 2-azido-3-tosyl-7-azabicyclo[2.2.1]-
heptane systems that gives access to a new kind of
bicyclic structures related with the epibatidine, the
enantiomerically pure 2,8-diazabicyclo[3.2.1]oct-2-enes
(+)- and (−)-5. These compounds were transformed in
two steps into hydroxylated hemiaminals 9 and 10, that
are good and relatively selective a-mannosidase
inhibitors.
Scheme
clo[3.2.1]octanes.
4. Acidic
deprotection
of
2,8-diazabicy-

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A. J. Moreno-Vargas, P. Vogel / Tetrahedron Letters 44 (2003) 5069–5073
Table 1. Inhibitory activities of (3S,4S,5R)-5-(2-ammo-
nioethyl)-2,3,4-trihydroxypyrrolidinium dichloride 9 (HCl)2
and its enantiomer 10 (HCl)2. Percentage of inhibition at
1 mM concentration (%), IC50 and Ki in mM, when mea-
sured. Optimal pH, 35°Ca,b
5. For a review about desulfonylation reactions, see: Najera,
C.; Yus, M. Tetrahedron 1998, 55, 10547–10658.
6. Giblin, G. M. P.; Jones, C. D.; Simpkins, N. S. Synlett
1997, 589–590.
7. (a) Wei, Z.-L.; George, C.; Kozikowski, A. P. Tetra-
hedron Lett. 2003, 44, 3847–3850; (b) Wei, Z.-L.;
Petukhov, P. A.; Xiao, Y.; Tu¨ckmantel, W.; George, C.;
Kellar, K. J.; Kozikowski, A. P. J. Med. Chem. 2003, 46,
921–924; (c) Pandey, G.; Tiwari, S. K.; Singh, R. S.;
Mali, R. S. Tetrahedron Lett. 2001, 42, 3947–3949; (d)
Pavri, N. P.; Trudell, M. L. Tetrahedron Lett. 1997, 39,
7993–7996.
8. (a) Clayton, S. C.; Regan, A. C. Tetrahedron Lett. 1993,
34, 7493–7496; (b) Liang, F.; Navarro, H. A.; Abraham,
P.; Kotian, P.; Ding, Y.-S.; Fowler, J.; Volkow, N.;
Kuhar, M. J.; Carroll, F. I. J. Med. Chem. 1997, 40,
2293–2295; (c) Brieaddy, L. E.; Liang, F.; Abraham, P.;
Lee, J. R.; Carroll, F. I. Tetrahedron Lett. 1998, 38,
5321–5322.
9. (a) Popowycz, F.; Gerber-Lemaire, S.; Demange, R.;
Rodr´ıguez-Garc´ıa, E.; Carmona-Asenjo, A. T.; Robina,
I.; Vogel, P. Bioorg. Med. Chem. Lett. 2001, 11, 2489–
2493; (b) Gerber-Lemaire, S.; Popowycz, F.; Rodr´ıguez-
Garc´ıa, E.; Carmona-Asenjo, A. T.; Robina, I.; Vogel, P.
ChemBiochem 2002, 466–470.
Enzyme/inhibitor
9
10
a-Galactosidase
Coffee beans
ni
55%
84%
ni
Aspergillus niger
b-Galactosidase
Escherichia coli
30%
23%
34%
ni
Bovine liver
44%
59%
82%
71%
Jack beans
b-Glucosidase
Almonds
59%
38%
Caldocellum saccharolyticum
a-Mannosidase
Jack beans
97%
97%
IC50=4.8
Ki=2.5 (N)
IC50=4.5
Ki=0.94 (M)
Almonds
98%
98%
IC50=4.9
Ki=1.9 (C)
IC50=4.4
Ki=1.2 (M)
10. Moreno-Vargas, A. J.; Schu¨tz, C.; Scopelliti, R.; Vogel,
P. J. Org. Chem., in press.
11. For examples of reductive elimination using Bu3SnH/
AIBN, see: Padwa, A.; Muller, C. L.; Rodr´ıguez, A.;
Watterson, S. H. Tetrahedron 1998, 54, 9651–9666.
12. Data for (+)-5: [h]D +7 (c 1, CHCl3); 1H NMR (400
MHz, CDCl3, 323 K, l ppm, J Hz) l 7.58 (br. s, 1H,
H-3), 5.61 (br. s, 1H, H-1), 4.59 (d, 1H, J6,7=5.5, H-6),
4.43 (d, 1H, H-7), 4.30 (br. s, 1H, H-5), 2.86 (dd, 1H,
b-Xylosidase
Aspergillus niger
a-N-Acetylgalacto-saminidase
Chicken liver
33%
ni
37%
54%
a For the conditions of measurements, see Ref. 20.
b (C), competitive; (M), mixed type; (N), non-competitive inhibition;
ni, no inhibition at 1 mM concentration.
J4a,4b=18.9, J4a,5=4.4, H-4a), 2.04 (dd, 1H, J3,4b=2.2,
H-4b), 1.48 (s, 9H, (CH3)3C), 1.43, 1.28 (s each, 3H each,
(CH3)2C); 13C NMR (100.4 MHz, CDCl3, l ppm) l 161.7
(C-3), 153.6 (CO), 112.2 ((CH3)2C), 84.2, 83.2 (C-6, C-7),
80.3 ((CH3)3C), 73.9 (C-1), 56.1 (C-5), 34.3 (C-4), 28.3
((CH3)3C), 26.2, 24.7 ((CH3)2C); CIMS 283 (75% [M+
H]+).
Acknowledgements
We are grateful to the Swiss National Science Fonda-
tion (Grant No. 20.63667.00), the ‘Office Fe´de´ral de
l’Education et de la Science’ (Bern, COST D13/0001/
99) and the Direccio´n General de Investigacio´n Cien-
t´ıfica y Te´cnica of Spain (Grant No. BQU-2001-3779)
for generous support. We thank also Miss C. Schu¨tz for
the enzymatic measurements.
1
13. Data for (+)-6: [h]D +50 (c 0.45, CHCl3); H NMR (400
MHz, CDCl3, 298 K, l ppm, J Hz, mixture of two
rotamers) l 5.00, 4.91 (s each, 1H, H-1), 4.73 (d, 1H,
J6,7=5.6, H-6), 4.63 (br. d, 1H, H-7), 4.38, 4.22 (br. s
each, 1H, H-5), 2.93 (dd, 1H, J3a,4a=6.23, J3a,3b=14.7,
H-3a), 2.79 (m, 1H, H-3b), 1.94 (m, 1H, H-4a), 1.50 (s,
9H, (CH3)3C), 1.48 (m, 1H, H-4b), 1.44, 1.35 (s each, 3H
each, (CH3)2C); 13C NMR (100.4 MHz, CDCl3, l ppm,
mixture of two rotamers) l 154.1, 153.6 (CO), 111.3
((CH3)2C), 83.1, 82.5, 82.2, 81.8 (C-6, C-7), 79.9, 79.8
((CH3)3C), 73.4, 72.5 (C-1), 59.5, 58.3 (C-5), 39.1, 39.0
(C-3), 29.3, 29.0 (C-4), 28.4 ((CH3)3C), 26.0 ((CH3)2C),
24.4, 24.3 ((CH3)2C); CIMS 285 (38% [M+H]+).
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