A ring-closing metathesis route to 7-membered aza-heteroannulated sugars

Article abstract of DOI:10.1016/j.tetlet.2005.02.007

Azepane rings have been constructed diastereoselectively upon a carbohydrate derivative utilising reductive amination and RCM. The stereochemistry of the ring junctions was confirmed by X-ray crystallography and NMR. Diastereoselective dihydroxylation has

Full text of DOI:10.1016/j.tetlet.2005.02.007

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2295–2298
A ring-closing metathesis route to 7-membered
aza-heteroannulated sugars
Dominic M. Laventine, Paul R. Jenkins* and Paul M. Cullis
Department of Chemistry, University of Leicester, Leicester LE1 7RH, UK
Received 10 December 2004; revised 22 January2005; accepted 1 February2005
Abstract—Azepane rings have been constructed diastereoselectivelyupon a carbohydrate derivative utilising reductive amination
and RCM. The stereochemistry of the ring junctions was confirmed by X-ray crystallography and NMR. Diastereoselective dihydr-
oxylation has also been employed to afford a tetrahydroxylated azepane carbohydrate derivative with potential biological activity.
Ó 2005 Elsevier Ltd. All rights reserved.
Polyhydroxylated aza-heterocycles and aminosugars are
of interest because theyshow a wide range of biological
activities.1 This large number of stereocentres confers
great potential stereospecificityin biological interactions
and chemical transformations. Possible therapeutic
applications include treatments for cancer, HIV and
diabetes.1
Few examples of fused N-heteroannulation of carbohy-
drates are to be found. Ring-closing reductive amination
has been employed in the diastereoselective formation of
5-membered rings (3)7 and 6- and 7-membered N-het-
erocycles (4) have been regioselectivelyformed from
N-allyl nitrones.8
Bn
Ring-closing metathesis (RCM) has found extensive
application in the synthesis of nitrogen-containing
heterocycles of various ring configurations2 including
azepanes such as 13 and aza-sugars such as
castanospermine (2).4
O
OMe
H
N
O
O
O
O
Ph
O
N
R
O
H
N
R
4
3
H
N
HO
HO
HO
OH
N
HO
HO
Previous work in this area bythe Jenkins group has in-
cluded the construction of carbocycles by Robinson
annulation;6 carbocycles such as 5 and O-containing
heterocycles including spiro-annulated examples such
as 6 byRCM 9 and photoannulation;10 and N-containing
OH
OH
HO
1
2
7
heterocycles such as 3 bydouble reductive amination.
Our aim was to extend the use of RCM methodology
Metathesis has also been widelyused in carbohydrate
chemistryto achieve the total snytheses of carbo-
hydrate-containing natural products,5 dimerisation of
sugar derivatives5 and annulation of sugars.6
O
OMe
O
O
OMe
H
O
O
( )n
Ph
O
Keywords: Pyrrolidines; Carbohydrate annulation; Amino sugars;
Ring-closing metathesis.
Ph
O
n( )
H
*
Corresponding author. Tel.: +44 0 116 252 2124; e-mail: kin@
le.ac.uk
6
5
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.007

2296
D. M. Laventine et al. / Tetrahedron Letters 46 (2005) 2295–2298
to include the synthesis of N-heteroannulated carbohy-
drates of various ring sizes that prove to be difficult to
access via reductive amination ring closure and to assess
their biological activity.
RCM was initiallyattempted with amine 8, but no reac-
tion took place.2 RCM of dialkene 9 was undertaken
using 0.05 equiv of GrubbsÕ 1st generation catalyst in
refluxing DCM.2 Protected didehydroazepane 10 was
obtained in 68% yield (Scheme 1). The 19F NMR spectra
contained two signals at d À 69.3 and d À 67.1 in a
ratio of 1:4.6 in CDCl3. This duplicityof signals was
mirrored in some of the signals in the 1H NMR spectra,
particularlythose due to the protons of the MeO group
and the proton attached to C-1, and was considered to
be due to restricted rotation of the amide bond.14 Con-
firmation of the identityof compound 10 and the benz-
ylidene group was obtained by X-ray crystallography15
(Fig. 1) after recrystallisation from 1:9 DCM–hexane.
Known compound 76 was converted to the a-amine 811
in 87% yield by reductive amination using an excess of
allylamine with acetic acid and NaCNBH3 in THF at
rt7 (Scheme 1). The stereoselectivityof reduction of
the imine formed at C-2 is due to preferential attack
of the hydride from the direction opposite to the meth-
oxygroup attached to C-1. 12 The stereochemistryat C-2
was indicated bythe coupling constants of H-2 and H-3
in CDCl3. H-2 has a trans diaxial coupling constant of
11.3 Hz and a cis axial–equatorial coupling constant of
3.4 Hz to H-3 and H-1, respectively.11
Removal of the trifluoroacyl protecting group using a
number of literature methods failed. These included
treatment of amide 10 with NH3 in MeOH, heating with
K2CO3 in aq MeOH, and heating with KOH in aq
EtOH. The trifluoroacetyl amide group was finally re-
moved via reductive cleavage byrefluxing with excess
NaBH4 in anhydrous EtOH to give didehydroazepane
compound 11 in 96% yield (Scheme 1).16 Removal of
the benzylidene protecting group of compound 11 to
give 1217 was achieved in 79% yield by heating in 80%
aq AcOH for 2 h (Scheme 1).18
Various methods to protect the 2° amine of compound 8
were attempted. Tosylation and BOC protection failed
to give the desired products and onlystarting material
was isolated; possiblydue to steric hindrance. Protection
of amine 8 was finallyachieved using trifluoroacetic acid
anhydride in DCM and pyridine at rt13 to afford trifluoro-
acetamide compound 9 in 58% yield (Scheme 1). Inter-
pretation of the NMR spectra was complicated bythe
duplication of manyof the signals in the
1H, 13C and 19F NMR spectra. For example, the 19F
NMR spectra in CDCl3 contained two signals at
d À 68.1 and d À 67.1 in a 1:3 ratio. This was attributed
to restricted rotation about the acyl C–N bond, produc-
ing two pseudo-geometric isomers.14 It was found that
even at 343 K (C6D6) the signals in the 1H and 19F
NMR spectra did not coalesce although significant
signal broadening was observed.
A similar procedure to that described above was also
used to synthesise a regioisomeric 7-membered N-con-
taining ring in which the nitrogen is attached at the C-
3 position of the sugar ring (Scheme 2). Known com-
pound 136 was converted to the a-amine 14 in 76% yield
byreductive amination using an excess of alllyamine
with acetic acid and NaCNBH3 in THF at rt (Scheme
2).7 Onlythe axial a-amine was isolated due to reduction
of the imine formed at C-3 from the b face. This follows
the general trend observed for the reduction of ketones
at the analogous position in similar compounds.12
14
6
Ph
Ph
O
11
9
O
O
O
i
4
O
O
5
2
1
13
12
10
3
7
8
NH
Amine 14 was protected byconversion to trifluoroacet-
amide 15 via treatment with TFAA and pyridine in
O
OMe
OMe
7
8
ii
Ph
Ph
O
O
iii
O
O
N
O
O
OMe
O
OMe
O
N
F3C
F3C
10
9
iv
6
Ph
O
HO
4
O
O
O
HO
2
5
1
10
11
3
7
v
OMe
8
NH
NH
9
OMe
12
11
Scheme 1. Reagents and conditions: (i) 8 equiv allylamine, AcOH,
THF, then NaCNBH3, rt, 2 h, 87%; (ii) TFAA, pyridine, DCM, rt,
16 h, 58%; (iii) 0.05 equiv GrubbsÕ cat, DCM, reflux, 16 h, 68%; (iv)
NaBH4, anhyd EtOH, reflux, 1 h, 96%; (v) 80% AcOH aq, reflux, 2 h,
then K2CO3, MeOH, 79%.
Figure 1. X-raycrystal structure of 10.15

D. M. Laventine et al. / Tetrahedron Letters 46 (2005) 2295–2298
Ph
2297
Ph
O
O
O
O
O
O
i
O
OMe
NH
OMe
13
14
ii
Ph
Ph
O
O
iii
O
O
O
O
O
F3C
OMe
N
OMe
N
F3C
O
16
15
iv
Figure 2. X-raycrystal structure of 16.19
OH
Ph
O
O
O
O
HO
cis-Dihydroxylation of didehydroazepane 10 with
v
1
OsO4 and NMO proceeded as expected,22 and H and
OMe
OMe
19F NMR indicated that onlyone product ( 21) was pro-
duced, in 80% yield. Assignment of the stereochemistry
of 21 was not possible due to the presence of two
pseudo-geometric isomers arising from the amide group.
Removal of the amide bythe usual method gave
dihydroxyazepane 22 in 60% yield. 1H and NOE
NMR were used to determine that both the hydroxyl
groups were on the a face of the molecule. H-2 has
NOE interactions with H-8b, H-11b (but not H-8a and
H-11a) and H-10. H-10 also has two cis coupling con-
stants of 2.2 Hz to H-9 and H-11b and a trans coupling
constant of 6.9 Hz to H-11a in MeOD. The benzylidene
group was removed to give the tetrahydroxylated aze-
pane 23 as the acetate salt in 64% yield (see Scheme 3).
HN
HN
17
18
Scheme 2. Reagents and conditions: (i) 8 equiv allylamine, AcOH,
THF, then NaCNBH3, rt, 2 h, 76%; (ii) TFAA, pyridine, DCM, rt,
16 h, 85%; (iii) 0.05 equiv GrubbsÕ cat, DCM, reflux, 16 h, 65%; (iv)
NaBH4, anhyd EtOH, reflux, 24 h, 84%; (v) 80% AcOH aq, reflux, 4 h,
then K2CO3, MeOH, 77%.
DCM at rt13 in 85% yield (Scheme 2). Duplication of
manysignals in the 1H and 13C NMR spectra was ob-
served in a similar wayto compound 9; the 19F NMR
spectra in CDCl3 contained two signals at d À 67.3
and d À 65.1 in a 1:1.7 ratio.
In conclusion, we have developed a versatile and effi-
cient method for the construction of azepane rings on
carbohydrates. Work is in progress to synthesise piperi-
dine and azocane homologues of 12 and 18, and to fur-
ther alter the regio- and stereochemistryof the ring
RCM of dialkene 15 using 0.05 equiv of GrubbsÕ 1st
generation catalyst in refluxing DCM gave the ring-
closed product 16 in 65% yield (Scheme 2).2 Assignment
of the H and 13C NMR spectra was hampered byline
1
broadening due to the presence of pseudo-geometric
stereoisomers and the 19F NMR spectra contained two
signals at d À 68.5 and d À 64.8 in a ratio of 6.9:1 in
CDCl3. X-raycrsytallographyconfirmed the stereo-
chemistryof compound 16 (Fig. 2).19 Removal of the
trifluoroacetyl group to give didehydroazepane 17 in
12
6
Ph
O
Ph
O
O
5
O
R
4
O
O
2
1
11
10
iii
3
7
OMe
O
8
OMe
N
9
N
HO
10
OH
84% yield was achieved by refluxing 16 with NaBH4 in
16
F3C
21, R = COCF3
22, R = H
dryEtOH
byrefluxing in 80% aq AcOH to afford compound 18
and the benzylidine group was removed
iv
i
in 77% yield (Scheme 2).18
v
6
HO
The presence of the double bond in compound 10 allows
facile functionalisation in order to maximise analogue
diversity. Protected didehydroazepane 10 was hydro-
genated bystirring vigorouslywith a suspension of
10% Pd/C under an atmosphere of H2.20 The reduction
of the alkene bond was accompanied bythe removal of
the benzylidene protecting group to afford azepane 19
in 83% yield. The trifluoroacetyl group was removed
in the usual wayto afford azepane 2021 in 82% yield,
which was converted to the acetate salt bytreatment
with acetic acid.
5
O
4
HO
2
1
11
10
HO
3
7
O
HO
8
OMe
9
N
R
OMe
NH
HO
19, R = COCF3
20, R = H
ii
OH
23
Scheme 3. Reagents and conditions: (i) H2, Pd/C, EtOH, rt, 16 h, 83%;
(ii) NaBH4, EtOH, reflux, 3 h, 82%; (iii) 0.04 equiv OsO4, NMO,
acetone, H2O, rt, 48 h, 80%; (iv) NaBH4, EtOH, reflux, 2 h, 60%; (v)
80% AcOH aq, reflux, 4 h, then K2CO3, MeOH, 64%.

2298
D. M. Laventine et al. / Tetrahedron Letters 46 (2005) 2295–2298
14. Lewin, A. H.; Frucht, M.; Chen, K. V. J.; Benedetti, E.; Di
Blasio, B. Tetrahedron 1975, 31, 207.
15. Crystal data for C20H22F3NO5 (10), M = 413.39, ortho-
junction. Evaluation of the glycosidase inhibitory activ-
ityof these compounds is in progress.
rhombic, space group P212121, a = 9.0310(19), b =
3
˚
˚
11.557(2), c = 18.439(4) A, V = 1924.6(7) A , T = 150(2) K,
Z = 4, Dc = 1.427 gcmÀ3, l(Mo-Ka) = 0.121 mmÀ1, Final,
R1 = 0.0326 (for 3094 reflections with I > 2r(I)) and
wR2 = 0.0743 for all data. Crystallographic data for 10
has been deposited with the Cambridge Crystallographic
Data Centre as supplementarypublication number CCDC
257391.
Acknowledgements
Manythanks to J. Fawcett for X-raydata and to G.
Eaton for MS analysis. We would like to acknowledge
the ESPRC and the Universityof Leicester for financial
support of this research.
16. Weygand, F.; Fauendorfer, E. Chem. Ber. 1970, 103, 2437.
17. For compound 12: colourless oil; dH (300 MHz, MeOD)
1.71 (1H, qd, J = 10.6, 1.6, H-3), 1.81 (1H, s, H-N), 1.95
(1H, br t, J = 14.7, H-11a), 2.73 (1H, ddd, J = 15.6, 8.4,
1.4, H-11b), 2.81 (1H, dd, J = 10.9, 3.4, H-2), 3.01 (1H, t,
J = 9.9, H-4), 3.22 (1H, m, H-8a), 3.31 (3H, s, H-14), 3.39–
3.49 (2H, m, H-5, H-8b), 3.57 (1H, dd, J = 11.7, 5.6, H-
6ax), 3.70 (1H, dd, J = 11.7, 2.4, H-6eq), 4.54 (1H, d,
J = 3.4, H-1), 5.80 (1H, dtd, J = 10.6, 5.5, 2.7, H-10), 5.91
(1H, dddd, J = 10.6, 8.5, 3.6, 1.8, H-9). FAB HRMS calcd
for C11H20O4N (M+H)+ 230.13923, found 230.13921.
18. Sakakibara, T.; Shindo, T.; Hirai, H. Carbohydr. Res.
2002, 337, 2061.
References and notes
1. Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R.
J.; Nash, R. J. Phytochemistry 2001, 56(3), 265.
2. Phillips, A. J.; Abell, A. D. Aldrichim. Acta 1999, 32, 75.
3. Li, H.; Chantereau, C.; Mallet, J.; Sollogoub, M.; Zhang,
Y.; Rodriguez-Garcia, E.; Vogel, P.; Jimenez-Barbero, J.;
Sinay, P. Org. Biomol. Chem. 2004, 2, 1492.
4. Overkleeft, H. S.; Bruggeman, P.; Pandit, U. K. Tetrahe-
dron Lett. 1998, 39, 3869.
5. Roy, R.; Das, S. K. Chem. Commun. 2000, 519.
6. Holt, D. J.; Barker, W. D.; Jenkins, P. R. J. Org. Chem.
2000, 65, 482.
7. Laventine, D. M.; Davies, M.; Evinson, E. L.; Jenkins, P.
R.; Cullis, P. M.; Fawcett, J. Tetrahedron Lett. 2005, 46,
307.
8. Majumdar, S.; Bhattacharjya, A.; Patra, A. Tetrahedron
1999, 55, 12157.
9. Wood, A. J.; Holt, D. J.; Dominguez, M.; Jenkins, P. R. J.
Org. Chem. 1998, 63, 8522.
10. Holt, D. J.; Barker, W. D.; Ghosh, S.; Jenkins, P. R. Org.
Biomol. Chem. 2004, 2, 1093.
19. Crystal data for C20H22F3NO5 (16), M = 413.39, ortho-
rhombic, space group P212121, a = 9.460(3), b = 10.230(3),
3
c = 20.101(6) A, V = 1945.2(10) A , T = 150(2) K, Z = 4,
˚
˚
Dc = 1.412 gcmÀ3
,
l(Mo-Ka) = 0.119 mmÀ1
,
Final,
R1 = 0.0282 (for 3275 reflections with I > 2r(I)) and
wR2 = 0.0691 for all data. Crystallographic data for 16
has been deposited with the Cambridge Crystallographic
Data Centre as supplementarypublication number CCDC
257392. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
11. For compound 8: white solid; dH (300 MHz, CDCl3) 1.12
(1H, broad s, H–N), 1.84 (1H, tt, J = 11.0, 3.9, H-3), 2.45
(2H, m, H-11a,b), 2.50 (1H, dd, J = 11.3, 3.4, H-2), 2.99
(1H, dd, J = 13.9, 6.0, H-8a), 3.15 (1H, obs t, J = 10.4, H-
4), 3.20 (4H, s and m, H-14, H-8b), 3.67 (1H, t, J = 10.0,
H-6ax), 3.55 (1H, td, J = 9.6, 4.3, H-5), 4.08 (1H, dd,
J = 9.6, 4.3, H-6eq), 4.57 (1H, d, J = 3.3, H-1), 4.82–5.10
(4H, m, H-13, H-10), 5.29 (1H, s, H-14), 5.73 (2H, m, H-
12, H-9), 7.10–7.40 (5H, m, Ph). FAB HRMS calcd for
C20H28O4N (M + H)+ 346.20183, found 346.20189.
mp = 151–153 °C.
20. Onomura, O.; Kanda, Y.; Nakamura, Y.; Maki, T.;
Matsumura, Y. Tetrahedron Lett. 2002, 43, 3229.
21. For compound 20 acetate salt: dH (300 MHz, MeOD) 1.35
(1H, dddd, J = 21.5, 11.8, 9.6, 1.6, H-11b), 1.54 (1H, m, H-
10a), 1.70–2.02 (7H, m, H-3, H-9a,b, H-10b, H3COÀ2 ), 2.34
(1H, m, H-11a), 3.07 (1H, dd, J = 11.8, H-2), 3.13 (1H, obs
m, H-8a), 3.19 (1H, t, J = 10.0, H-4), 3.23 (1H, obs m, H-
8b), 3.46 (3H, s, H-7), 3.53 (1H, ddd, J = 9.6, 5.5, 2.3, H-
5), 3.69 (1H, dd, J = 11.8, 5.5, H-6ax), 3.83 (1H, dd,
J = 11.8, 2.3, H-6eq), 4.80 (1H, d, J = 3.3, H-1) FAB
HRMS calcd for C11H22O4N (M+H)+ 232.15488, found
232.15491.
12. Yu, K. L.; Handa, S.; Tsang, R.; Fraser-Reid, B.
Tetrahedron 1991, 47, 189.
22. Hu, H.; Jagdmann, G. E., Jr. Tetrahedron Lett. 1995, 36,
3659.
13. Sala, R. F.; MacKinnon, S. L.; Palcic, M. M.; Tanner, M.
E. Carbohydr. Res. 1998, 306, 127.