A stereoselective route towards highly functionalized 4,6-diaminocyclohexene derivatives

Article abstract of DOI:10.1016/S0040-4039(02)01364-3

A flexible synthetic route towards chirally pure 4,6-diaminocyclohexene derivatives based on palladium catalyzed allylic amination of carbohydrate derived cyclohexenes is presented.

Full text of DOI:10.1016/S0040-4039(02)01364-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6451–6455
A stereoselective route towards highly functionalized
4,6-diaminocyclohexene derivatives
Steven H. L. Verhelst,a Wouter Wiedenhof,a Huib Ovaa,a Gijsbert A. van der Marel,a
Herman S. Overkleeft,a Constant A. A. van Boeckelb and Jacques H. van Booma,*
aLeiden Institute of Chemistry, PO Box 9502, 2300 RA Leiden, Netherlands
bN.V. Organon, Lead Discovery Unit, PO Box 20, 5340 BH Oss, Netherlands
Received 11 June 2002; accepted 28 June 2002
Abstract—A flexible synthetic route towards chirally pure 4,6-diaminocyclohexene derivatives based on palladium catalyzed allylic
amination of carbohydrate derived cyclohexenes is presented. © 2002 Elsevier Science Ltd. All rights reserved.
Aminoglycosides, polyamino oligosaccharides often
containing the aminocyclitol 2-deoxystreptamine (Fig.
1), show strong binding with a variety of RNA struc-
tures, including bacterial 16S ribosomal RNA1 and
the HIV transactivating region.2 Based on the RNA
binding properties, aminoglycosides are widely consid-
ered as potential therapeutics in combating bacterial
and viral infections.3 For example, the aminogly-
cosides tobramycin and neomycin B are presently
used as antibiotics in the treatment of some bacterial
infections.4 However, the toxicity of most aminogly-
cosides limits their use as broad-spectrum therapeu-
tics. The latter may be ascribed to the undesired
binding with eukaryotic rRNA.5 It may therefore be
expected that aminoglycoside derivatives with
enhanced selectivity towards bacterial/viral RNA
would find broader application as clinically useful
drugs.
Figure 1.
* Corresponding author. Tel.: +31 71 5274274; fax: +31 71 5274307; e-mail: j.boom@chem.leidenuniv.nl
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01364-3

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S. H. L. Verhelst et al. / Tetrahedron Letters 43 (2002) 6451–6455
The derivatization of aminoglycoside substructures,
such as the pseudo-disaccharide neamine (Fig. 1), is a
burgeoning field of research aimed at the preparation of
novel and more effective aminoglycosides.6 This strat-
egy is certainly attractive for the rapid generation of
new, functionally diverse RNA-binding ligands. How-
ever, the limited stereochemical diversity in this type of
ligands is a drawback, as the spatial positioning of the
amino groups in aminoglycosides may well be critical
for selective recognition of RNA.7
In general, the implementation of stereochemical diver-
sity in aminoglycosides may eventually result in the
discovery of new lead compounds with potential selec-
tive RNA binding properties. It was envisaged that this
objective could be attained by the synthesis of 4,6-
diaminocyclohexene derivatives which are structural
analogs of 2-deoxystreptamine (Fig. 1). In this paper we
report a flexible route towards highly functionalized
4,6-diaminocyclohexene derivatives starting from car-
bohydrate-derived 1,7-dienes.
Scheme 1. Retrosynthetic analysis.
Retrosynthetic analysis (Scheme 1) reveals that Vasella
fragmentation of a readily available methyl-5-deoxy-5-
iodo furanoside in the presence of an alkylamine fol-
lowed by in situ Barbier-type allylation of the resulting
imine affords the required functionalized 1,7-diene.8
Subsequent ring-closing metathesis (RCM) and further
elaboration will give the cyclic carbonate derivative
which is amenable to palladium catalyzed allylic amina-
tion resulting in the target 4,6-diaminocyclohexene.
presence of benzylamine and allyl bromide, led to the
isolation of optically pure 1,7-diene 2. The secondary
amine function in 2 was protected, prior to the ensuing
RCM reaction, with the o-nitrobenzenesulfonyl (Ns)
group, the removal of which can be effected under very
mild conditions.10 RCM of fully protected 3 in the
presence of Grubbs’ catalyst (Cl2(PPh3)2RuꢀCHPh)11
proceeded smoothly to give cyclohexene derivative 4.
Transformation of 4 into the cyclic carbonate 512 was
then followed by a Pd(0) catalyzed allylic amination
using N-benzyl-nosylamide as the nucleophile.13 Several
palladium complexes, generated in situ from
In the first instance, the conversion of methyl-5-deoxy-
5-iodo-2,3-isopropylidene-ribofuranoside
1
into
diaminocyclohexenol 7 was examined (Scheme 2).9
Vasella–Barbier domino reaction8 on 1 using zinc in the
Scheme 2. Reagents and conditions: (i) Zn (excess), allyl bromide (2.2 equiv.), benzylamine (2 equiv.), THF, sonication, 70%.8 (ii)
a. NsCl, DCM/sat. Na2CO3, 90%. (iii) Grubbs’ catalyst (1.5 mol%), 93%. (iv) a. AcOH/H2O 8/2, reflux, b. carbonyldiimidazole,
DMF, 84% (two steps). (v) NsNHBn (1.5 equiv.), Pd2(dba)3·CHCl3 (2.5 mol%), PPh3 (25 mol%), Et3N (3 equiv.), THF, 80%.

S. H. L. Verhelst et al. / Tetrahedron Letters 43 (2002) 6451–6455
6453
(dba)3Pd2·CHCl3 and an excess of the respective
phosphine ligands (PPh3, dppb14 and dppp14), were
tested for their catalytic activity. It turned out that
the triphenylphosphine ligand was superior over the
bidentate ligands dppb and dppp in terms of overall
yield.15 The regio- and stereoselective formation of 7
is ensured by the formation of the p-allyl complex 6
and subsequent substitution with overall retention at
the less hindered carbon atom.
15 in 71% (entry 2). Furthermore, amino acid deriva-
tives 16–18 were isolated, although in lower yields,
using a-Ns-o-Z-lysine methyl ester, a-Ns-glutamic acid
dimethyl ester and a-Ns-phenylalanine methyl ester as
the nucleophiles (entry 3–5). It is also interesting to
note that reaction of scaffold 5 with galactose and
acridine derivatives featuring a terminal nosylated
amine furnished compounds 19 and 20 in satisfactory
yields (entry 6 and 7).
The synthesis of the enantiomeric and similarly pro-
tected 4,6-diaminocyclohexenol 13 (Scheme 3) was
readily accomplished starting from methyl-5-deoxy-5-
iodo-2,3-isopropylidene-lyxofuranoside (8), obtained
The results described in this paper clearly show that
chiral 4,6-diaminocyclohexene derivatives can be
obtained by palladium catalyzed allylic amination of
easily accessible carbocyclic cores 5 and 12 with o-
nitrobenzenesulfonyl amides. The versatility of the
allylic amination was nicely illustrated by the use of
structurally diverse nucleophiles including amino acid
and carbohydrate derived nosyl amides. The authors
firmly believe that the approach presented here gives
access to valuable synthons for the future design and
synthesis of stereochemically diverse aminoglycoside
antibiotics. Further synthetic efforts along these lines
are underway and will be reported in due course.
from
D
-mannose.16 Subjection of 8 to the Vasella–
Barbier tandem reaction provided 1,7-diene 9. Execu-
tion of the sequence of reactions mentioned above for
the conversion of 2 into 7 gave compound 139 in
comparable overall yield (Scheme 3).
At this stage it was gratifying to find that the scope
of the allylic amination of carbocyclic cores 5 or 12 is
not limited to the use of N-benzyl-nosylamide, but
can also be extended to the synthesis of higher func-
tionalized cyclohexenediamines. The results of these
substitution reactions are summarized in Table 1.
Acknowledgements
It can be seen (entry 1) that allylic amination of
cyclic carbonate 5 with Ns-glycine methyl ester pro-
ceeded as expected to give glycine derivative 14 in a
high yield. A similar result was obtained in the case
of o-Ns-a-boc-lysine methyl ester providing compound
The authors thank Fons Lefeber and Cees Erkelens
for recording NMR spectra, Hans van den Elst for
mass spectrometry, and Organon N.V. for financial
support.
Scheme 3. Reagents and conditions: (i) Zn (excess), allyl bromide (2.2 equiv.), benzylamine (2 equiv.), THF, sonication, 66–80%.
(ii) a. NsCl, DCM/sat. Na2CO3, 88%. (iii) Grubbs’ catalyst (1.5 mol%), 91%. (iv) a. AcOH/H2O 8/2, reflux, b. carbonyldiimida-
zole, DMF 84% (two steps). (v) NsNHBn (1.5 equiv.), Pd2(dba)3·CHCl3 (2.5 mol%), PPh3 (25 mol%), Et3N (3 equiv.), THF, 82%.

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S. H. L. Verhelst et al. / Tetrahedron Letters 43 (2002) 6451–6455
Table 1. Transformation of 5 into 4,6-diaminocyclohexene
derivatives
2. (a) Zapp, M. L.; Stern, S.; Green, M. R. Cell 1993, 74,
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1
9. Selected analytical data: 5: H NMR (CDCl3, 600 MHz):
l 7.52–7.47 (m, 2H), 7.40–7.39 (d, 1H, J=8.0 Hz, J=1.4
Hz), 7.27–7.24 (m, 1H), 7.19–7.13 (m, 2H), 7.07–7.04 (m,
3H), 6.04 (ddd, 1H, J=10.2 Hz, J=6.2 Hz, J=1.9 Hz),
5.64–5.61 (m, 1H), 5.25–5.22 (m, 1H), 5.09–5.07 (m, 1H),
4.80(d, 1H, J=15.9Hz), 5.54(d, 1H, J=15.8Hz), 4.55–4.52
(m, 1H), 2.47–2.42 (m, 1H), 2.32–2.28 (m, 1H). 13C NMR
(CDCl3, 150MHz):l154.13, 146.96, 135.73, 134.16, 133.38,
132.66, 131.70, 131.22, 128.30, 128.12, 127.65, 124.01,
121.11, 78.99, 75.09, 54.43, 49.34, 25.20. ESI MS: m/z=
431.2 (M+H)+. [h]D20 −76.4 (c 0.1, CHCl3). 12: [h]2D0 +76.8
(c 0.1, CHCl3). Regio- and stereochemistry of the amination
products were ascertained by HH-COSY and H-NOESY
1
(NOE signals were visible between H-4 and H-6). 7: H
NMR (CDCl3, 600 MHz): l 7.70–7.79 (m, 1H), 7.56–7.51
(m, 5H), 7.43–7.40 (m, 1H), 7.39–7.36 (m, 1H), 7.19–7.04
(m, 10H), 5.80 (ddd, 1H, J=10.0 Hz, J=5.7 Hz, J=2.6
Hz), 5.56–5.54 (m, 1H), 4.69–4.65 (m, 1H), 4.58 (d, 1H,
J=16.4 Hz), 4.50 (d, 1H, J=15.8 Hz), 4.41 (d, 1H, J=16.4
Hz), 4.27 (d, 1H, J=15.8 Hz), 4.14 (bs, 1H), 3.96 (dt, 1H,
J=13.1 Hz, J=2.9), 2.04–1.97 (m, 1H), 1.80–1.74 (m, 1H),
1.53 (bs, 1H). 13C NMR (CDCl3, 150 MHz): l 147.49,
147.46, 137.28, 133.84, 133.78, 133.52, 133.39, 131.68,
131.65, 131.37, 131.32, 130.95, 130.92, 128.51, 128.38,
127.73, 127.68, 127.45, 124.12, 124.08, 66.72, 56.97, 56.75,
49.29, 48.79, 27.44. ESI MS: m/z=701.4 (M+Na)+. [h]D20
−17.8 (c 0.1, CHCl3). 13: [h]2D0 +17.0 (c 0.1, CHCl3).
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dioxide and generates an allylic alcohol which is not
susceptible for further reaction. The corresponding bis-
acetates did not react in palladium catalyzed allylic
aminations.
13. Typical experimental procedure: THF was distilled under
argon prior to use. Cyclic carbonate 5 and the o-nitroben-
zenesulfonyl amide nucleophile (1.5 equiv.) were coevapor-
ated with dioxane and dissolved in THF (final concentra-
tion of 5: 0.1 M). Subsequently triethylamine (3 equiv.),
Pd2(dba)3·CHCl3 (2.5 mol%) and PPh3 (25 mol%) were
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phinopropane.
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respectively. The yield could not be improved by perform-
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