Synthesis of a chiral dendrimer based on polyfunctional amino acids

Article abstract of DOI:10.1039/a809195a

A chiral, nonracemic dendrimer of generation two based on aromatic bis- and tris-amino acids has been synthesised.

Full text of DOI:10.1039/a809195a

Synthesis of a chiral dendrimer based on polyfunctional amino acids
Andreas Ritzén and Torbjörn Frejd*
Organic Chemistry 1, Department of Chemistry, Lund University, PO Box 124, SE-221 00, Lund, Sweden.
E-mail: torbjorn.frejd@orgk1.lu.se
Received (in Liverpool UK) 24th November 1998, Accepted 10th December 1998
NH2
NH2
A chiral, nonracemic dendrimer of generation two based on
aromatic bis- and tris-amino acids has been synthesised.
I
I
I
I
i
ii
The design and synthesis of functional dendrimers has been the
focus of much research during the last ten years.1,2 Chiral,
nonracemic dendrimers with well-defined stereochemistry are a
particularly interesting subclass, with potential applications in
asymmetric catalysis and chiral molecular recognition.3 For
biological applications, polyionic, water-soluble dendrimers
will be of interest.4 Here we report the synthesis of a chiral,
nonracemic dendrimer 14 (see Scheme 2) based on synthetic,
di- and tri-functional amino acids.
The dendrimer 14 is assembled from nine units of the bis-
amino acid 7 and one unit of protected phenyltrisalanine 12.5
The synthesis of 7 is described in Scheme 1, and is based on a
Heck coupling–hydrogenation protocol which has been used in
our laboratory before.5–7 Starting from 4-aminophenylacetic
acid 1, iodination with ICl gave 2.8 Removal of the amino group
via stepwise diazotization and reduction proved difficult, and in
situ generation of the diazonium salt in refluxing EtOH was the
only satisfactory method found. Under these conditions, the
diazonium salt was immediately reduced by EtOH giving 3 as
CO2H
CO2H
CO2R
3
4
5
R = Et
R = H
R = Bn
iii
iv
1
2
v
CO2Me
CO2Me
BocHN
BnO2C
BocHN
BnO2C
vi
BocHN
CO2Me
BocHN
CO2Me
7
6
Scheme 1 Reagents and conditions: i, ICl (2.0 equiv.), HCl (1 m), room
temp. 18 h, 65%; ii, H2SO4, NaNO2 (3.0 equiv.), EtOH (99.5%), reflux, 1
h, 55%; iii, NaOH (2 m), reflux, 3 h, then HCl, 92%; iv, KHCO3 (1.1 equiv.),
BnBr (1.1 equiv.), DMF, 60 °C, 2 h, 58%; v, H2CNC(NHBoc)CO2Me (2.0
equiv.), Pd(OAc)2 (0.10 equiv.), NaHCO3 (5.0 equiv.), Bu4N+Cl2 (2.0
equiv.), DMF, 60 °C, 8 h, 43%; vi, {Rh(COD)[(S,S)-Et-DuPHOS]}+OTf2
(0.009 equiv.), H2 (40 psi), MeOH, room temp., 6 h, > 99%, > 98%, ee dr
> 99:1.
7
ii
i
HCl . H2N
BocHN
CO2Me
MeO2C
CO2Me
MeO2C
H2N . HCl
NHBoc
BnO2C
BocHN
9
8
CO2H
BocHN
CO2Me
MeO2C
NHBoc
iii
CO2Me
MeO2C
BocHN
CO2Me
NHBoc
BocHN
O
MeO2C
HN
MeO2C
O
NHBoc
CO2Me
MeO2C
BocHN
MeO2C
MeO2C
BocHN
O
O
HN
NHBoc
NH
MeO2C
O
MeO2C
CO2Me
NH
MeO2C
O
O
CO2Me
NH
NH
RO2C
iv
MeO2C
10 R = Bn
11 R = H
NH
vi
O
HN
BocHN
MeO2C
MeO2C
BocHN
O
CO2Me
CO2Me
MeO2C
NH
NH
O
MeO2C
MeO2C
NHR
HN
NHBoc
O
MeO2C
CO2Me
BocHN
RHN
CO2Me
CO2Me
RHN
NHBoc
MeO2C
CO2Me
12 R = Z
13 R = H
v
14
BocHN
Scheme 2 Reagents and conditions: i, Pd/C (5%), EtOH (99.5%), H2 (1 atm), room temp., 3 h; ii, 3 m HCl in EtOAc, 30 min, room temp.; iii, 8 (2.0 equiv.),
TFFH (2.4 equiv.), DIEA (4.8 equiv.), DMF, room temp., 5 min, then 9 (1.0 equiv.), room temp., 1 h, then repeat acylation with 8 (1.0 equiv.), TFFH (1.2
equiv.), Pri2NEt (2.4 equiv.), 57% overall from 7; iv, Pd/C (5%), EtOH (99.5%), H2 (1 atm), room temp., 3 h; v, Pd/C (5%), EtOH (99.5%), H2 (1 atm), room
temp., 6 h; vi, 11 (4.0 equiv.), TFFH (4.4 equiv.), Pri2NEt (8.8 equiv.), DMF, room temp., 5 min, then 13 (1.0 equiv.), room temp., 1 h, 87% overall from
12.
Chem. Commun., 1999, 207–208
207

the ethyl ester, which had to be replaced by a benzyl ester to give
5. Unfortunately, reduction of the diazonium salt of 2 with
benzyl alcohol failed. Heck coupling with methyl 2-[(tert-
butoxycarbonyl)amino]acrylate7 gave the unsaturated deriva-
tive 6, which was hydrogenated with a chiral RhI-Et-DuPHOS†
catalyst9 to give 7.
The convergent synthesis of dendrimer 14 from 7 and 12 is
shown in Scheme 2. Since 14 is a polyamide related to a peptide,
but possibly more sterically congested, an efficient peptide
coupling reagent with minimum steric bulk and high reactivity
was desired for the formation of the amide bonds. Based on
these considerations, we chose to use TFFH10† for the amide
bond formations. To this end, hydrogenolysis of 7 yielded 8,
while acidolysis of 7 with HCl in EtOAc (generated from AcCl
and EtOH) gave 9. Acylation of 9 with 2 equiv. of 8 using TFFH
proved difficult, and a substantial amount of monoacylated
material was recovered. To achieve satisfactory results, 9 had to
be acylated twice, first with 2 equiv. of 8 and then with 1 equiv.,
in two consecutive operations. With this procedure, the
dendritic wedge 10 was formed in 57% yield from 7.
Hydrogenolysis of 10 yielded the free acid 11, and similar
treatment of 12 yielded triamine 13. Acylation of 13 with 4
equiv. of 11 using TFFH finally yielded dendrimer 14 in 87%
yield after a single acylation. This coupling thus proceeded with
higher efficiency than that leading to the dendritic wedge 10
above. The reason for this counterintuitive outcome is unclear at
present. The identity of 14 was confirmed by NMR and MALDI
MS analyses (calc. 4488.9 [M + Na], found 4488.7).
polyionic compound with potentially interesting properties.
Studies in this direction are in progress in our laboratory.
We thank the Swedish Natural Science Research Council, the
Crafoord Foundation, the Knut and Alice Wallenberg Founda-
tion, and the Royal Physiographic Society in Lund for financial
support, and Mr Hasse Karlsson, Department of Medical
Biochemistry, Göteborg University, for recording the MALDI
mass spectrum.
Notes and references
† List of abbreviations: (S,S)-Et-DuPHOS = 1,2-bis[(2S,5S)-2,5-diethyl-
phospholano]benzene, TFFH = N,N,NA,NA-tetramethyl-2-fluoroformami-
dinium hexafluorophosphate.
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While 14 was synthesised in fully protected form, deprotec-
tion of the methyl esters, the Boc groups, or both, will yield a
Communication 8/09195A
208
Chem. Commun., 1999, 207–208