Rhodium(II) carbene-mediated modification of 2-deoxystreptamine surrogates

Article abstract of DOI:10.1016/j.tetlet.2011.04.034

Rhodium(II)-catalyzed decomposition of carbene precursors grafted to the alcohol of diaminocyclopentanols promotes clean formation of a C-N bond via 1,6-insertion into an adjacent carbamate or azide. These modifications of 2-deoxystreptamine surrogates mi

Full text of DOI:10.1016/j.tetlet.2011.04.034

Tetrahedron Letters 52 (2011) 3201–3203
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rhodium(II) carbene-mediated modification of 2-deoxystreptamine surrogates
⇑
⇑
Aurélie Blond, Roba Moumné, Guillaume Bégis, Morgane Pasco, Thomas Lecourt , Laurent Micouin
Laboratoire de Chimie Thérapeutique, UMR 8638 CNRS – Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 avenue de l’Observatoire, 75006 Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Rhodium(II)-catalyzed decomposition of carbene precursors grafted to the alcohol of diaminocyclopent-
anols promotes clean formation of a C–N bond via 1,6-insertion into an adjacent carbamate or azide.
These modifications of 2-deoxystreptamine surrogates might give rise to aminoglycoside mimics where
the two nitrogen atoms will be differentiated.
Received 2 March 2011
Revised 6 April 2011
Accepted 8 April 2011
Available online 15 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Carbene
Insertion
Rhodium catalyst
Fragment-Based Drug Discovery (FBDD) is now a well-recog-
nized alternative strategy toward the discovery of bioactive com-
pounds. Thus, instead of identifying hits from libraries of
2-DOS surrogates. Tethering this reactive species to the alcohol
of DACP might offer the opportunity to differentiate the two nitro-
gen atoms without changing the spatial orientation of the key
functionalities.
1
complex molecules using high-throughput screening, FBDD relies
on identification of weak ligands before their connection into a
more elaborated drug-like structure. However, efficient FBDD re-
quires screening libraries of small molecules covering a large
chemical space. Moreover, fast evolution of fragments represents
a key feature to improve their affinity with the target and to in-
crease their connectivity. We recently reported an NMR-guided
FBDD approach toward aminoglycoside mimics where diaminocy-
We first studied reactivity of carbene tethered to the bicyclic
8
hydrazine 4. Following a recent procedure reported by Fukuyama
0
involving bromoacetylation followed by diazo-transfert with N,N -
9
ditosylhydrazine, diazoacetate 5 was prepared from 4 in 59% yield
2 4
over two steps. Unfortunately, Rh (OAc) -mediated decomposition
of 5 mainly resulted in dimerization of the metal–carbene even un-
der high dilution conditions (Scheme 2).
clopentanol (DACP) 1 serves as surrogate to 2-deoxystreptamine
2
(
2-DOS), the central core of aminoglycoside antibiotics (Fig. 1).
Thus, connecting this polar molecule to aromatic and heterocyclic
2-DOS
3
fragments delivered small RNA binders and inhibitors of an ami-
H N
NH2
O
noglycoside processing enzyme.4
2
NH2
H N
2
OH
OH
Increasing the molecular diversity of this central scaffold would
be highly desirable to further develop our fragment-based ap-
proach toward aminoglycoside mimics. In this context, diethylami-
nosulfur trifluoride (DAST)-promoted cyclization of Boc-protected
DACP 2 gave a straightforward access to 2-DOS analogs where
the two nitrogen atoms are differentiated (Scheme 1).5 However,
O
O
O
H N
HO
DACP
2
OH
HO
NH2
HO
OH
NH
2
1
Kanamycine B
Figure 1. DACP as mimic of 2-deoxystreptamine.
this modification of DACP, based on electrophilic activation of a
6
1
,2-aminoalcohol, delivered the robust oxazolidinone 3 with
non-desirable inversion of configuration. Thus, following our on-
going program on selective modification of highly functionalized
cyclic compounds, we believed that carbene-mediated modifica-
7
H
H
H
H
N
H N
NH2
BocN
NBoc
2
NBoc
tion of DACP might provide a straightforward entry toward new
ref. 3b
DAST
2%
O
HO
HO
O
5
⇑
Corresponding authors. Tel.: + 33 (0)1 53 73 97 51; fax: + 33 (0)1 43 29 14 03
T.L.); tel.: + 33 (0)1 53 73 97 51; fax: + 33 (0)1 43 29 14 03 (L.M.).
(
1
2
3
E-mail addresses: Thomas.Lecourt@parisdescartes.fr (T. Lecourt), Laurent.Mi-
couin@parisdescartes.fr (L. Micouin).
Scheme 1. DAST-promoted cyclization of Boc-protected DACP.
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.034

3
202
A. Blond et al. / Tetrahedron Letters 52 (2011) 3201–3203
O
Table 1
Rh(II)-mediated decomposition of 10
O
NCbz
Entry
Rh
2
L
4
2%
(OAc)
(oct)
(cap)
(acam)
Yield (%)
48a
31
84
82
N
Cbz
1
2
3
4
Rh
Rh
Rh
Rh
2
2
2
2
4
O
O
a
4
HO
O
O
4
NCbz
NCbz
NCbz
i
ii
4
N
N2
N
N
Cbz
Cbz
Cbz
a
Evaluated from 1H NMR analysis of the crude.
4
5
6
2 2 2
Scheme 2. Reagents and conditions: (i) (a) BrCH COBr, CH Cl , pyridine, 0 °C; (b)
TsNHNHTs, DBU, THF, 0 °C, 59% over two steps; (ii) Rh
dichloroethane, reflux.
2
(OAc)
4
2 mol %, 1,2-
N2
N
N3
O
N3
N3
N3
N
Rh2L4
L4Rh2
O
O
O
O
O
H
H
BocN
NBoc
11
H
H
H
Boc
N
BocN
NBoc
NBoc
Scheme 5. Proposed mechanism for reduction of 10.
4
O
i
ii
N
2
iii
HO
O
O
O
2
7
8
the carbene precursor 10 in 88% yield following Fukuyama’s condi-
tions (Scheme 4).
Scheme 3. Reagents and conditions: (i) (a) H
CO , THF/H O, rt, 72% over two steps; (ii) (a) BrCH
b) TsNHNHTs, DBU, THF, 0 °C, 67% over two steps; (iii) Rh
dichloroethane, reflux, 62%.
2
, 10% Pd/C, MeOH, rt; (b) Boc
COBr, CH Cl , pyridine, 0 °C;
(OAc) 2 mol %, 1,2-
2
O,
2 4
Rh (OAc) -mediated decomposition of 10 gave a complex mix-
K
(
2
3
2
2
2
2
ture from which imine 11 was identified (Table 1, entry 1). Inser-
tion of the metal–carbene into the azide was then optimized by
modulating the steric and electronic properties of the catalyst.16
2
4
Thus, bulky Rh
whereas less electrophilic carbene generated under Rh
or Rh (cap) catalysis gave 11 with complete selectivity (entries
and 4).
To explain this formal reduction of the azide, we propose a step-
2
(oct)
4
delivered the imine in low yield (entry 2),
Believing that steric demand of the bicyclic hydrazine 5 might
favor this intermolecular process, we next turned our attention
to carbene grafted on cyclopentyl cores. Thus, hydrogenolysis of
Cbz protecting-groups and reductive cleavage of the N–N bond
was performed under a hydrogen atmosphere over 10% Pd/C. Car-
bamoylation of the resulting diamine 1 delivered Boc-protected
DACP 2 in 72% yield over two steps (Scheme 1). After bromo-acet-
ylation and diazo-transfert, the carbene precursor 7 was finally ob-
tained in 67% yield over two steps. Catalytic decomposition of 7
2
(acam)
4
2
4
3
wise process involving first chelation of the carbene by the proxi-
17
mal nitrogen atom, followed by nitrogen extrusion (Scheme 5).
In conclusion, we showed that carbenes grafted to the alcohol of
DACP promote efficient 1,6-insertions into the adjacent nitrogen
atom of Boc- or azido-protected derivatives. By delivering new 2-
DOS surrogates, this straightforward approach might now give rise
to aminoglycoside mimics where the two nitrogen atoms will be
differentiated.
1
0
resulted in predictable 1,6-insertion into the acidic N–H bond,
thus delivering the trans-fused morpholinone 8 in 62% yield
(Scheme 3).
As copper-catalyzed [3+2] cycloaddition showed great promises
for discovery of new bioactive compounds,11 we next turned our
attention to an azido-protected carbene precursor. Thus, differenti-
ation of the two nitrogen atoms might then either involve quater-
narization by insertion into the strongly activated adjacent C–H
Acknowledgments
Financial support of this work by ANR (PCV 2008, TriggeRNA),
CNRS (Research Fellowship to T.L.) and Université Paris Descartes
1
2
13
bond, or direct reaction with the organic azide. To prepare azi-
do-DACP 9 from the cyclic 1,3-cis diamine 1, we first used a cop-
per-catalyzed diazo-transfert reaction recently reported by
(
MESR grant to M.P.) is gratefully acknowledged.
1
4
Supplementary data
Goddard-Boger. However, this safe procedure relying on imidaz-
ole-1-sulfonyl azide as the diazo-transfert reagent, delivered 9 in a
non-reproducible 41% yield. By using the more hazardous trifluo-
Supplementary data (experimental procedure, characterization
data) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.04.034.
romethanesulfonyl azide which already showed high efficiency
for per-azidation of aminoglycosides,15 diamine 1 was cleanly con-
verted into 9 with a catalytic amount of Cu(II) sulfate. Having in
hands a reliable method to get azido-DACP 9, we next prepared
References and notes
1.
For reviews, see: (a) Chessari, G.; Woodhead, A. J. Drug Discovery Today 2009,
4, 668–675; (b) Hajduk, P. J.; Greer, J. Nat. Rev. Drug. Disc. 2007, 6, 211–219.
1
2
3
.
.
Maurice, F.; Bégis, G.; Micouin, L.; Dardel, F. C.R. Chim. 2006, 9, 413–419.
(a) Chung, F.; Tisné, C.; Lecourt, T.; Dardel, F.; Micouin, L. Angew. Chem., Int. Ed.
N3
N3
N3
HO
N3
N3
N
2007, 46, 4489–4491; (b) Chung, F.; Tisné, C.; Lecourt, T.; Seijo, B.; Dardel, F.;
1
Micouin, L. Chem. Eur. J. 2009, 15, 7109–7116; (c) Moumné, R.; Larue, V.; Seijo,
B.; Lecourt, T.; Micouin, L.; Tisné, C. Org. Biomol. Chem. 2010, 8, 1154–1159; (d)
Moumné, R.; Pasco, M.; Prost, E.; Lecourt, T.; Micouin, L.; Tisné, C. J. Am. Chem.
Soc. 2010, 132, 13111–13113.
Lombès, T.; Bégis, G.; Maurice, F.; Turcaud, S.; Lecourt, T.; Dardel, F.; Micouin, L.
ChemBioChem 2008, 9, 1368–1371.
O
N2
i
ii
iii
O
O
O
9
10
11
4
.
.
Scheme 4. Reagents and conditions: (i) ImSO
CF SO , CuSO , K CO , DCM/MeOH/H O, rt, 72%; (ii) (a) BrCH
pyridine, 0 °C; (b) TsNHNHTs, DBU, THF, 0 °C, 88% over two steps; (iii) Rh
mol %, 1,2-dichloroethane, reflux, Table 1.
2 3 4
N , CuSO , MeOH, rt, 13–41% or
5
Submitted for publication.
3
2
N
3
4
2
3
2
2
COBr, CH
2
Cl
(L)
2
,
6. For a review on rearrangement of b-amino alcohols, see: Cossy, J.; Pardo, D. G.;
Dumas, C.; Mirguet, O.; Déchamps, I.; Métro, T.-X.; Burger, B.; Roudeau, R.;
Appenzeller, J.; Cochi, A. Chirality 2009, 21, 850–856.
2
4
2

A. Blond et al. / Tetrahedron Letters 52 (2011) 3201–3203
3203
7
.
.
Boultadakis-Arapanis, M.; Lemoine, P.; Turcaud, S.; Micouin, L.; Lecourt, T. J.
Am. Chem. Soc. 2010, 132, 15477–15479.
12. Wang, P.; Adams, J. J. Am. Chem. Soc. 1994, 116, 3296–3305.
13. Wee, A. G. H.; Slobodian, J. J. Org. Chem. 1996, 61, 2897–2900.
14. Goddard-Borger, E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797–3800.
15. Nyffeler, P. T.; Liang, C.-H.; Koeller, K. M.; Wong, C.-H. J. Am. Chem. Soc. 2002,
124, 10773–10778.
16. (a) Padwa, A.; Austin, D. J.; Price, A. T.; Semones, M. A.; Doyle, M. P.; Protopova,
M. N.; Winchester, W. R.; Tran, A. J. Am. Chem. Soc. 1993, 115, 8669–8680; (b)
Pirrung, M. C.; Morehead, A. T., Jr. J. Am. Chem. Soc. 1994, 116, 8991–9000; (c)
Vitale, M.; Lecourt, T.; Sheldon, C. G.; Aggarwal, V. K. J. Am. Chem. Soc. 2006,
128, 2524–2525.
8
(a) Pérez Luna, A.; Ceschi, M.-A.; Bonin, M.; Micouin, L.; Husson, H.-P.;
Gougeon, S.; Estenne-Bouhtou, G.; Marabout, B.; Sevrin, M.; George, P. J. Org.
Chem. 2002, 67, 3522–3524; (b) Pérez Luna, A.; Bonin, M.; Micouin, L.; Husson,
H.-P. J. Am. Chem. Soc. 2002, 124, 12098–12099; (c) Bournaud, C.; Chung, F.;
Pérez Luna, A.; Pasco, M.; Errasti, G.; Lecourt, T.; Micouin, L. Synthesis 2009,
8
69–887.
9
.
Toma, T.; Shimokawa, J.; Fukuyama, T. Org. Lett. 2007, 9, 3195–3197.
1
1
0. Shirude, P. V.; Kumar, V. A.; Ganesh, K. N. Tetrahedron 2004, 60, 9485–9491.
1. Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2003, 8, 1128–1137.
17. Szostak, M.; Aubé, J. Org. Biomol. Chem. 2011, 9, 27–35.