Dendroids: A building block for the synthesis of polymodal dendritic structures

Article abstract of DOI:10.1039/a705304e

Differentially substituted 1,8-naphthalene and 1,2,3-trihydroxybenzene derivatives are synthesised and termed 'dendroids'; these may be differentially derivatised with mimetics of amino acid side chains.

Full text of DOI:10.1039/a705304e

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Dendroids: a building block for the synthesis of polymodal dendritic structures
Joanne V. Allen, David C. Horwell,* Julia A. H. Lainton, Jacqueline A. O’Neill and Giles S. Ratcliffe
Parke-Davis Neuroscience Research Centre, Cambridge University Forvie Site, Robinson Way, Cambridge, UK CB2 2QB
Differentially substituted 1,8-naphthalene and 1,2,3-tri-
hydroxybenzene derivatives are synthesised and termed
‘dendroids’; these may be differentially derivatised with
mimetics of amino acid side chains.
surfaces, such as the constituent amino acid side-chains or the
peptide backbone.
We describe here the synthesis of simple aromatic com-
pounds with low molecular weight ( < 1000 Daltons) which can
serve as a structural motif that is able to display different
functional groups which correspond to the side-chains of amino
acids. Such polymodal ‘dendritic wedges’2 we term ‘dendroids’
(1, Fig. 1). The dendroid motif is anticipated to facilitate
intramolecular self-organisation (cf. intermolecular self-as-
sembly associated with nanostructures6,7) by choice of suitable
spacer groups B and C, which may non-covalently interact with
each other by steric crowding, hydrophobic collapse and
stereoelectronic attractive or repulsive effects. For example,
Dendritic polymers are synthetic polymers that are charac-
terised by a non-linear array of monomeric species. They are
self-organising moieties that have unique physico-chemical
properties with respect to their linear counterparts and have a
range of potentially novel industrial applications.1–5
The topographical features of starburst dendrimers have been
compared with those found in globular proteins.1 However,
proteins display heterogeneous functional moieties on their
OR1
OR2
OR3
OR1
O
D
OR2
B
C
OR4
OR5
E
F
O
A
R4
O
OR3
N
R5
G
O
1
O
OR6
OR7
2 R1–R7 = Me
3 R1–R5 = Me
R1–R7 = (CH2)nX; n = 1–3, X = amino acid side chain
Fig. 1 Dendroid motif 1 exemplified by 1,2,3-trialkoxybenzenes 2 and 1,8-disubstituted naphthalenes 3
OR1
OR2
OH
OH
OH
i
ii
OH
O
O
Br
O
OEt
O
R2O
OR1
O
OEt
iii
OR1
OR1
OR2
OR3
OR2
OR1
O
O
O
O
OR2
OR4
OR5
v
iv
OH
O
O
Br
Br
OH
R3O
OR5
OR6
OR6
OR7
OR6
OR7
OH
OR4
OR7
2
Scheme 1 Reagents and conditions: i, CH(OEt)3, Amberlyst-IR-120(plus), reflux, 28 h, 92%; ii, K2CO3, 18-crown-6, room temp., 18 h, 92%; iii, TsOH, room
temp., 20 h, 90%; iv, K2CO3, 18-crown-6, room temp., 21 h, 32%; v, K2CO3, 18-crown-6, room temp., 21 h, 46%
Chem. Commun., 1997
2121

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R5
the polymodality of part protein structures can be mimicked by
use of the dendroid motif. The elaboration of the dendroid motif
to give protein mimetics of the ‘hot spots’ of key amino acids in
interleukin-Ira,16 interleukin-817 and the conotoxin derivative
SNX-III18 is under investigation in our laboratory.
R4
N
O
R2
HO
R1
R3
+
Footnotes and References
OH
i
* E-mail: david.horwell@camb.wl.com
† Selected data for 2: dH (CDCl3) 3.69 (s, 3 H, OCH3), 3.75 (s, 6 H, 2 3
OCH3), 3.80 (s, 6 H, 2 3 OCH3), 3.85 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3),
5.02 (s, 2 H, CH2), 5.04 (s, 2 H, CH2), 5.06 (s, 2 H, CH2), 6.40 (t, J 2.0, 1
H, ArH), 6.61 (d, J 2.0, 2 H, ArH), 6.65–6.68 (m, 4 H, ArH), 6.75 (d, J 8.4,
1 H, ArH), 6.92–6.97 (m, 2 H, ArH), 7.03 (d, J 1.6, 1 H, ArH). For 3g: dH
(CDCl3) 2.45–2.50 (m, 1 H, CHH), 2.79–2.84 (m, 1 H, CHH), 3.00–3.18
(m, 1 H, CHH), 3.60 and 3.69 (2 3 s, 3 H, OMe), 3.58–3.75 (m, 1 H, CHH),
4.40 (AB q, 1 H, CHH), 4.90 (AB qt, 1 H, CHH), 4.94–4.96 (m, 2 H),
5.01–5.02 (m, 1 H, ArH), 6.51–6.52 (m, 1 H, ArH), 6.67–6.68 (m, 1 H,
ArH), 6.77–6.85 (m, 2 H, ArH), 6.85–7.00 (m, 7 H, ArH), 7.00–7.23 (m, 7
H, ArH), 7.23–7.37 (m, 7 H, ArH), 7.68–7.78 (m, 2 H, ArH), 8.88 (br s, 1
H, NH).
R1
R2
R4
O
R3
N
R5
O
3a R1 = R2 = R3 = OMe, R4 = R5 = Me
b R1 = R3 = H, R2 = OBn, R4 = R5 = Me
c R1 = R3 = H, R2 = OBn, R4 = Pri, R5 = (R,S)CHMe-(indol-3-yl)
d R1 = R3 = H, R2 = OBn, R4 = Bn, R5 = CH2C6H4OMe-p
e R1 = R3 = H, R2 = OBn, R4 = Bn, R5 = CH2CH2-(indol-3-yl)
R1 = R3 = H, R2 = OBn, R4 = CH2C6H4OMe-p, R5 = CH2CH2-(indol-3-yl)
g R1 = R3 = H, R2 = OBn, R4 = CH2CH2C6H4OMe-p, R5 = CH2-(indol-3-yl)
f
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Scheme 2 Reagents and conditions: i, PPh3 (1 equiv.), diisopropyl
azodicarboxylate (1 equiv.), THF, 0 °C to room temp., 4 h
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1,2,3-trisubstituted benzenes8–11 and 1,8-disubstituted naph-
thalenes12–15 have been shown to adopt non-planar arrange-
ments by X-ray, NMR and chemical reactivity analysis. As one
example, the dendroid motif 2† may be synthesised from
1,2,3-trihydroxybenzene (Scheme 1). This type of molecule is
able to achieve a non-planar structure by virtue of the electronic
repulsion between the crowded 1,2,3-aryl ether oxygen atoms,
so that the central 2-aryl ether oxygen substituent is forced out
of plane with respect to the benzene ring.8,9
The 1,8-disubstituted naphthalene dendroids 3a–g are pre-
pared from 8-hydroxy-N,N-dimethylnaphthalenecarboxamide12
(Scheme 2). Such 1,8-naphthalenes have been shown by X-ray
analysis to exhibit a non-planar preference via a truly remark-
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oxygen substituent atom and the 1-substituted carbonyl group of
the amide moiety,12 allowing the attached groups R1–R5 in 3 to
be splayed into a polymodal surface. Examples of where this
dendroid motif has been derivatised to give amino acid side-
chains include the mimetics of phenylalanine 3b,
b-methyltryptophan 3c, tyrosine (as its O-methyl ether) 3d and
tryptophan 3e. The examples 3f and 3g† also mimic tryptophan
and tyrosine side-chains bearing differing methylene spacer
groups.
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In these cases, the synthetic schemes allow separate
functionalisation of the dendroid motif, which can be converted
by further synthesis into separate amino acid side-chains. Hence
Received in Glasgow, UK, 22nd July 1997; 7/05304E
2122
Chem. Commun., 1997