Synthesis of chiral n,n+1-diamino acids and their application to the construction of dendrimers

Article abstract of DOI:10.1055/s-2002-33117

Efficient methods for the synthesis of chiral n,n+1-diamino acids starting from L-glutamic acid were developed. A second generation prototype amino acid based dendrimer, containing 1,3-propanediamine as the core and 4,5-diaminopentanoic acid as the branching unit, was synthesised following the divergent approach. Diaminobutane poly(propyleneimine) dendrimers modified at the periphery with n,n+1-diamino acids were synthesized and characterized.

Full text of DOI:10.1055/s-2002-33117

PAPER
1359
Synthesis of Chiral n,n+1-Diamino Acids and their Application to the
Construction of Dendrimers
S
E
ynthesis of
D
ia
v
mino Acids
a
a
nd Dendr
g
imers elos Bellis, Theodoros Markidis, George Kokotos*
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece
Fax +30(10)7274761; E-mail: gkokotos@cc.uoa.gr
Received 28 January 2002; revised 29 April 2002
class of amino acid based dendrimers, and (b) the func-
tionalization of already existing dendrimers.
Abstract: Efficient methods for the synthesis of chiral n,n+1-di-
amino acids starting from L-glutamic acid were developed. A sec-
ond generation prototype amino acid based dendrimer, containing The building block for our applications should meet three
1
,3-propanediamine as the core and 4,5-diaminopentanoic acid as
requirements: (1) presence of two amino groups and one
carboxylic group, (2) chirality, and (3) easy accessibility.
The 1,2-diamine functionality was decided to be present
in the building block, because compounds incorporating
this functionality exhibit pharmacological activity and
find applications in stereoselective organic synthesis.7
the branching unit, was synthesised following the divergent ap-
proach. Diaminobutane poly(propyleneimine) dendrimers modified
at the periphery with n,n+1-diamino acids were synthesized and
characterized.
Key words: amides, amino acids, azides, coupling, dendrimers
The inexpensive L-glutamic acid has been chosen as the
chiral starting material. -Methyl N-(tert-butoxycarbon-
Dendrimers are highly branched macromolecules, synthe-
sized stepwise from a central core and leading to a well-
defined number of generations and end groups. They have
three architectural regions: a core, an interior, and a highly
functionalized surface, and they are generally described as
structures that are spherical possessing a high degree of
8,9
yl)glutaminol, obtained from the suitable glutamate,
was converted to the azide 1 as recently described by us10
Scheme 1). Reduction of the azido group of 1 by NaBH
(
4
11
in the presence of 10% Pd/C afforded exclusively the cy-
clic derivative 2, due to spontaneous lactamization. Even
when the reduction was performed in the presence of di-
tert-butyl dicarbonate lactamization could not be avoided;
a mixture of the desired product 3 (47%) and the lactam 2
1
symmetry. These versatile molecules with controllable
sizes are some of the most powerful synthetic building
blocks available today for the construction of giant mac-
romolecules and supramolecular systems with a complete
architecture, precise shape, and functionality. Molecular
architectures of nanoscopic dimensions may create new
materials with promising catalytic, electronic or magnetic
properties. For example, dendrimers that are functional-
ized with transition metals in the core potentially can
mimic the properties of enzymes, their efficient natural
counterparts, whereas the surface functionalized systems
have been proposed to fill the gap between homogeneous
(
31%) was obtained. (4S)-4,5-Di[(tert-butoxycarbon-
yl)amino]pentanoic acid [5, Boc-DAP(Boc)-OH] was
prepared from 1 by saponification, followed by reduction
of the azido group in the presence of (Boc) O (Scheme 1).
2
O
O
a, b
MeO
OH
NHBoc
MeO
N3
NHBoc
1
2
and heterogeneous catalysis.
c
The number, size and function of peripheral groups of
dendrimers determine many of the dendrimer properties,
such as dense-shell packing, overall shape, solubility,
physical state (semicrystalline, glass, liquid crystalline,
d
98%
O
3
liquid). Furthermore, specific interactions of guest mole-
BocHN
O
HO
N3
NH
(31%)
cules with the dendritic hosts rely on both the core and the
NHBoc
4
shell of the dendrimer. Chiral, enantiomerically enriched
2
4
dendrimers are of special relevance, because they would
potentially allow enantioselective catalysis and molecular
+
c
63%
5
recognition. Although a number of chiral structures have
6
been reported, to date much less work has been devoted
O
O
to chiral dendrimers than to their achiral counterparts. The
aim of this work was to synthesize chiral diamino acids,
which were applied for (a) the construction of a novel
MeO
NHBoc
HO
NHBoc
NHBoc
(47%)
NHBoc
3
5
Synthesis 2002, No. 10, Print: 30 07 2002.
Art Id.1437-210X,E;2002,0,10,1359,1364,ftx,en;T01302SS.pdf.
Scheme 1 Reagents and Conditions: a) MsCl, Et N, CH Cl , 0 °C,
3
2
2
3
1
0 min, r.t. 30 min; b) NaN , DMF, 60 °C, 6 h; c) (Boc) O, NaBH ,
0% Pd/C, MeOH, THF, r.t., 20 min; d) 1 N NaOH, MeOH, r.t., 2 h
3
2
4
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1
360
E. Bellis et al.
PAPER
Compound 1 was converted into the aldehyde 6 after in-
O
troduction of a second Boc group and reduction of the me-
a, b
c
1
1
0
H
N3
N(Boc)2
thyl ester by DIBAL
(Scheme 2). The Horner–
8
1%
Wadsworth–Emmons olefination reaction of this alde-
hyde with the phosphonate anion generated from triethyl-
6
O
4
-phosphonocrotonate by treatment with LiOH12 pro-
d
EtO
N3
N(Boc)2
duced compound 7. Catalytic hydrogenation of the unsat-
95%
urated azide 7 in the presence of (Boc) O led to the
2
7
saturated diamino ester 8 in high yield. (8S)-8,9-Di[(tert-
O
butoxycarbonyl)amino]nonanoic
acid
[9,
Boc-
e, f
DAN(Boc)-OH] was obtained from 8 by treatment with
EtO
HO
NHBoc
N(Boc)2
Mg(ClO ) followed by alkaline hydrolysis.
91%
4
2
8
Boc-protected diamino acids 5 and 9 may be used for the
construction of prototype amino acid based chiral den-
drimers or for end-group modification of dendrimers con-
taining amino groups at the periphery. As an example, the
divergent approach was applied to prepare the second
generation dendrimer 12 {[Boc-DAP(Boc)] -(DAP) -
O
NHBoc
NHBoc
9
4
2
Scheme 2 Reagents and Conditions: a) (Boc) O, DMAP, MeCN,
5 °C, 7 h, r.t., 16 h; b) DIBALH, Et O, -78 °C, 5 min; c) EtOOC-
PDA} using 1,3-propanediamine (10, PDA) as the core
and compound 5 as the branching unit (Scheme 3). PDA
was coupled with compound 5 using 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride (EDC)13 as a
condensing agent in the presence of 1-hydroxybenzotria-
2
5
2
CH=CHCH P(=O)(OEt) , LiOH, THF, 55 °C, 4 h; d) H , 10% Pd/C,
2
2
2
(
Boc) O, MeOH, r.t., 16 h; e) Mg(ClO ) , MeCN, r.t., 1 h, 60 °C, 4 h;
2
4
2
f) 1 N NaOH, MeOH, r.t., 3 h
zole (HOBt). Compound 11 {[Boc-DAP(Boc)] -PDA}
2
was deprotected by treatment with HCl/Et O and coupled
again with the branching unit 5 to produce the second gen-
eration dendrimer 12.
2
amino groups, was coupled with compounds 5 and 9 using
the EDC/HOBt method, as described above, to produce
dendrimers 14 {[Boc-DAP(Boc)] -DAB(AM) } and 15
16
16
Poly(propyleneimine) dendrimers modified at the periph- {[Boc-DAN(Boc)] -DAB(AM) } respectively. Den-
1
6
16
1
4
ery are able to encapsulate guest molecules and may be drimers 14 and 15 were deprotected by treatment with
used in liquid-liquid extractions. The commercially HCl/MeOH and were obtained as free amines after pas-
available diaminobutane poly(propyleneimine) dendrimer sage over Amberlite IRA 900 (OH ) resin followed by
1
5
–
1
3 [DAB(AM) ] (Scheme 4) containing 16 peripheral lyophilization.
16
H N
2
NH2
10
a
68%
O
O
BocHN
N
N
H
NHBoc
NHBoc
H
NHBoc
11
b,a 61%
O
O
O
O
BocHN
N
H
N
H
N
H
N
NHBoc
NHBoc
H
NHBoc
NH
HN
O
O
12
NHBoc
BocHN
BocHN
NHBoc
Scheme 3 Reagents and Conditions: a) 5, EDC, HOBt, Et N, CH Cl , 0 °C, 1 h, r.t., 16 h (40 h for 12); b) HCl/Et O, r.t., 2 h
3
2
2
2
Synthesis 2002, No. 10, 1359–1364 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Diamino Acids and Dendrimers
1361
DAB(AM)16
13
a
NHX
NHX
NHX
NHX
XHN
NHX
)n
O
O
NHX
O
HN
N
HN
N
(
)n
(
XHN
NHX
)n
HN
HN
NHX
O
O
NHX
NHX
(
(
)n
HN
HN
XHN
XHN
O
O
H
N
(
)n HN
N
N
N
N
N
(
)
n
NHX
O
NHX
XHN
XHN
O
HN
N
N
N
N
N
N
NH
(
)
n
NHX
O
O
NHX
HN
NH
XHN
XHN
N
( )n
O
O
HN
NH
XHN
NHX
XHN
(
)n
NH
)n
NH
O
O
O
XHN
XHN
NHX
(
XHN
XHN
XHN
XHN
1
1
4, n=2, X=Boc (84%)
6, n=2, X=H (90%)
15, n=6, X=Boc (69%)
17, n=6, X=H (85%)
b,c
b,c
Scheme 4 Reagents and Conditions: a) 5 or 9, EDC, HOBt, Et N, CH Cl , 0 °C, 1 h, r.t., 40 h; b) 4 N HCl–MeOH, 2 h, r.t.; c) Amberlite IRA
3
2
2
–
9
00 (OH )
The structures of dendrimers and all the intermediates respectively. All dendrimers showed a signal in the range
were established by NMR spectroscopy, MS spectrometry 36–37 ppm, which was attributed to the CH NHCO car-
2
and elemental analyses. Despite the large molecular size bons. It should be noted that in the spectra of 14,15 no sig-
of dendrimers, their symmetrical architecture simplified nal was observed at 40 ppm, where the terminal CH NH2
2
1
the peak assignment of their NMR spectra. In the H NMR carbons of the parent dendrimer 13 resonate, indicating
spectra of dendrimers 11,12,14,15, the CH and CH CO that all the peripheral amino groups of 13 were fully acy-
2
protons gave signals at 3.5–3.6 ppm and 2.1–2.3 ppm re- lated.
spectively. The CH NH protons of all dendrimers resonat-
ed at 2.9–3.4 ppm. In the spectra of 14,15 a multiplet
2
In conclusion, we have developed an efficient strategy for
the synthesis of chiral unnatural diamino acids and den-
appeared at 2.3–3.0 ppm, which was attributed to the me-
drimers based on them. Dendrimers consisting of n,n+1-
thylene protons adjacent to the tertiary nitrogen atoms.
diamino acids, as well as poly(propyleneimine) dendrim-
The signals of the carbamate protons of dendrimers 11,12
ers modified at the periphery with the 1,2-diamine func-
tionality, may find applications in the field of catalysis
and molecular recognition.
appeared in the range 3.9–4.7 ppm, while in the spectra of
dendrimers 14,15 these signals were shifted downfield to
1
3
5
1
1
1
.1–5.6 ppm. In the C NMR spectra of dendrimers
1,12,14,15, the amide carbon atoms gave signals at 173–
75 ppm, while the carbamate carbon atoms resonated at
56–158 ppm. The tertiary and primary carbons of the
Melting points were determined on a melting point apparatus and
are uncorrected. Specific rotations were measured on a polarimeter
using a 10 cm cell. NMR spectra were recorded on a 200 MHz spec-
trometer. Where applicable, structural assignments were based on
COSY experiments. Analytical TLC plates (silica gel 60 F254) and
Boc groups resonated at 79–80 ppm and 28 ppm, respec-
1
3
tively. The C signals of CH and CH N of the n,n+1-di-
2
amino acid residue appeared at 51 ppm and 44–45 ppm, silica gel 60 (70–230 or 230–400 mesh) for column chromatogra-
phy were purchased from Merck. Visualization of spots was effect-
Synthesis 2002, No. 10, 1359–1364 ISSN 0039-7881 © Thieme Stuttgart · New York

1
362
E. Bellis et al.
PAPER
ed with UV light and/or phosphomolybdic acid and/or ninhydrin,
both in ethanol stain. THF was passed through a column of alumi-
by recrystallization (EtOAc–petroleum ether) to give 5 as a white
1
7
25
solid (1.01 g, 63%); mp 125–127 °C (Lit. mp 126–128 °C); [ ]D
1
7
23
num oxide, distilled over CaH and stored over molecular sieves.
–11.7 (c = 2, EtOH) {Lit. [ ]D –12.0 (c = 2, EtOH)}.
2
Et O was treated with CaCl and stored over Na. All other solvents
1
2
2
H NMR (200 MHz, CDCl ): = 1.45 [br s, 18 H, 2 C(CH3)3],
3
and chemicals were of reagent grade and used without further puri-
fication. Petroleum ether used had bp 40–60 °C.The samples for el-
emental analyses were dried over P O under high vacuum for 48 h.
1
3
2
.55–1.93 (m, 2 H, CH CH CO), 2.45 (t, 2 H, J = 7.4 Hz, CH CO),
2
2
2
.05–3.32 (m, 2 H, CH N), 3.55–3.80 (m, 1 H, CH), 4.80–5.10 (m,
2
2
5
H, 2 NH).
1
3
C NMR (50 MHz, CDCl ): = 27.8, 28.3, 30.6, 44.5, 51.1, 79.6,
Reduction of Methyl (4S)-5-Azido-4-[(tert-butoxycarbonyl)ami-
no]pentanoate (1); Typical Procedure
3
1
57.1, 177.3.
To a stirred mixture of the azide 1 (545 mg, 2.00 mmol) and 10%
Anal. Calcd for C H N O (332.40): C, 54.20; H, 8.49; N, 8.43.
Found: C, 54.36; H, 8.22; N, 8.70.
1
5
28
2
6
Pd/C (80 mg) in THF (10 mL), through which N had been passed
2
for 5 min, were added (Boc) O (655 mg, 3.00 mmol) and NaBH
2
4
(
227 mg, 6.00 mmol) followed by dropwise addition of MeOH (20
Ethyl (2E,4E,8S)-9-Azido-8-[bis(tert-butoxycarbonyl)ami-
no]nona-2,4-dienoate (7)
A suspension of the aldehyde 6 (1.00 g, 2.92 mmol), triethyl-4-
mL). After stirring for 20 min at r.t., the catalyst was filtered, the so-
lution was neutralized with aq 1 M KHSO and the organic solvents
were removed. The aqueous phase was extracted with EtOAc (2
3
solvent was removed. The products 2 and 3 were separated by col-
umn chromatography using a mixture of EtOAc–petroleum ether
(
4
phosphonocrotonate (1.09 g, 4.35 mmol), LiOH H O (183 mg, 4.35
2
0 mL), the combined organic layers were dried (Na SO ) and the
2 4
mmol) and activated 4Å molecular sieves (beads, 4–8 mesh, 4.5 g)
in anhyd THF (30 mL) was heated at 55 °C for 4 h under N . The
2
crude reaction mixture was filtered through Celite, eluting with
2:4) as eluent.
Et O. The solvent was evaporated under reduced pressure and the
2
residue was purified by column chromatography using a mixture of
(
5S)-5-[(tert-Butoxycarbonyl)amino]piperidin-2-one (2)
EtOAc–petroleum ether (2:8) as eluent to give 7 as a colorless oil
1
6
White solid (133 mg, 31%); mp 127–128 °C (Lit. mp 128–129
°
CHCl )}.
25
(
1.04 g, 81%); [ ]D –16.6 (c = 0.5, CHCl3).
C); [ ]D25 –36.8 (c = 0.5, CHCl ) {Lit. [ ]D –37 (c = 0.72,
16
3
1H NMR (200 MHz, CDCl3): = 1.27 (t, 3 H, J = 7.0 Hz, CH3),
.49 [br s, 18 H, 2 C(CH ) ], 1.57–1.72 (m, 1 H, CH CHHCHN),
3
1
3
3
2
1
H NMR (200 MHz, CDCl3): = 1.48 [br s, 9 H, C(CH ) ], 1.73–
3 3
1.86–2.08 (m, 1 H, CH CHHCHN), 2.13–2.29 (m, 2 H,
2
1
(
(
.90 (m, 1 H, CHHCH CO), 1.91–2.10 (m, 1 H, CHHCH CO), 2.44
2
2
CH CH=CH), 3.28 (dd, 1 H, J = 12.2, 5.6 Hz, CHHN ), 3.75 (dd, 1
2
3
t, 2 H, J = 7.5 Hz, CH CO), 3.05–3.21 (m, 1 H, CHHN), 3.47–3.60
2
H, J = 12.2, 9.2 Hz, CHHN ), 4.11–4.38 (m, 3 H, CH CH , CHN),
3
2
3
m, 1 H, CHHN), 3.82–4.02 (m, 1 H, CH), 4.65–4.86 (m, 1 H, NH-
5
.76 (d, 1 H, J = 15.6 Hz, CHCO), 5.98–6.26 (m, 2 H,
Boc), 6.11 (br s, 1 H, NHCO).
CH=CHCH=CHCO), 7.22 (dd,
1 H, J = 15.6, 10.2 Hz,
+
CH=CHCO).
MS (FAB): m/z (%) = 237 (M + Na, 100), 181 (21), 159 (13), 136
7).
(
13
C NMR (50 MHz, CDCl ): = 14.2, 28.0, 29.1, 29.6, 53.4, 56.3,
3
6
0.2, 82.7, 119.8, 129.1, 142.4, 144.6, 153.1, 167.1.
Methyl (4S)-4,5-Di[(tert-butoxycarbonyl)amino]pentanoate (3)
White solid (326 mg, 47%); mp 113–115 °C; [ ]D25 –20.0 (c = 0.5,
CHCl3).
+
MS (FAB): m/z (%) = 461 (M + Na, 41), 361 (24).
Anal. Calcd for C21H N O (438.52): C, 57.52; H, 7.82; N, 12.78.
34 4 6
1H NMR (200 MHz, CDCl3): = 1.49 [br s, 18 H, 2 C(CH3)3],
Found: C, 57.77; H, 7.91; N, 12.53.
1
3
4
.57–1.91 (m, 2 H, CH CH CO), 2.39 (t, 2 H, J = 7.5 Hz, CH CO),
2
2
2
Ethyl (8S)-8-[Bis(tert-butoxycarbonyl)amino]-9-[(tert-butoxy-
carbonyl)amino]nonanoate (8)
To a stirred solution of 7 (0.95 g, 2.17 mmol) in MeOH (22 mL)
.03–3.25 (m, 2 H, CH N), 3.51–3.73 (m, 4 H, CH, OCH ), 4.59–
2
3
.91 (m, 2 H, 2 NH).
Anal. Calcd for C H N O (346.42): C, 55.47; H, 8.73; N, 8.09.
Found: C, 55.56; H, 8.50; N, 7.86.
16
30
2
6
were added 10% Pd/C (88 mg) and (Boc) O (615 mg, 2.82 mmol).
2
The reaction mixture was stirred under H for 16 h at r.t. After fil-
2
tration through a pad of Celite, the solvent was removed and the res-
idue was purified by column chromatography using a mixture of
(
4S)-5-Azido-4-[(tert-butoxycarbonyl)amino]pentanoic Acid (4)
To a stirred solution of the ester 1 (1.50 g, 5.50 mmol) in MeOH (11
mL) was added a solution of aq 1 N NaOH (7.15 mL, 7.15 mmol).
After stirring for 2 h at r.t., the organic solvent was removed under
reduced pressure and the residue was acidified with a 10% aq solu-
tion of citric acid. The aqueous phase was extracted with EtOAc (3
EtOAc–petroleum ether (1:4) as eluent to give 8 as a colorless oil
25
(
1.07 g, 95%); [ ]D +29.4 (c = 0.5, CHCl3).
1
H NMR (200 MHz, CDCl ): = 1.20–1.78 [m, 40 H, CH , 3
3
3
C(CH ) , (CH ) ], 2.27 (t, 2 H, J = 7.4 Hz, CH CO), 3.28–3.42 (m,
3
3
2 5
2
2
H, CH N), 4.11 (q, 2 H, J = 7.2 Hz, CH CH ), 4.17–4.31 (m, 1 H,
2
2
3
4
0 mL), the combined organic layers were dried (Na SO ) and the
2 4
CH), 4.82–4.93 (m, 1 H, NH).
solvent was removed. The residue was purified by column chroma-
tography using a mixture of CHCl –MeOH (9:1) as eluent to give 4
as a colorless oil (1.39 g, 98%); [ ]D –26.0 (c = 0.5, CHCl3).
1H NMR (200 MHz, CDCl3): = 1.45 [br s, 9 H, C(CH ) ], 1.65–
13C NMR (50 MHz, CDCl
): = 14.2, 24.8, 26.1, 27.3, 28.0, 28.3,
3
3
2
5
28.4, 28.9, 29.9, 34.3, 43.3, 57.2, 60.1, 79.1, 82.2, 153.5, 155.8,
173.8.
3 3
2
.05 (m, 2 H, CH CH CO), 2.45 (t, 2 H, J = 7.1 Hz, CH CO), 3.25–
Anal. Calcd for C26
H N O (516.68): C, 60.44; H, 9.36; N, 5.42.
48 2 8
2
2
2
3
.55 (m, 2 H, CH N ), 3.70–3.90 (m, 1 H, CH), 4.72 (d, 1 H, J = 8.9
Found: C, 60.71; H, 9.42; N, 5.30.
2 3
Hz, NH).
(
8S)-8,9-Di[(tert-butoxycarbonyl)amino]nonanoic Acid (9)
Anal. Calcd for C H N O (258.28): C, 46.50; H, 7.02; N, 21.69.
Found: C, 46.81; H, 7.26; N, 21.44.
10
18
4
4
To a stirred solution of 8 (950 mg, 1.84 mmol) in MeCN (4.6 mL)
was added Mg(ClO ) (80 mg, 0.36 mmol). The solution was stirred
4
2
for 1 h at r.t. and for 4 h at 60 °C. After evaporation, a 5% aq solu-
tion of citric acid (10 mL) and EtOAc (10 mL) were added and the
aqueous layer was extracted with EtOAc (2 15 mL). The com-
bined organic layers were washed with brine and dried (Na SO ).
(
4S)-4,5-Di[(tert-butoxycarbonyl)amino]pentanoic Acid (5)
The procedure used to prepare compounds 2,3 was applied to the
azide 4 (1.25 g, 4.84 mmol). After filtration of the catalyst, the so-
lution was acidified with aq 1 M KHSO . The product was purified
2
4
4
Synthesis 2002, No. 10, 1359–1364 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Diamino Acids and Dendrimers
1363
The solvent was removed under reduced pressure and the residue
was purified by column chromatography using a mixture of EtOAc–
petroleum ether (3:7) as eluent. The product (721 mg, 1.73 mmol)
was dissolved in MeOH (3.5 mL), a solution of aq 1 N NaOH (2.25
mL, 2.25 mmol) was added and the mixture was stirred for 3 h at r.t.
The solvent was removed under reduced pressure and the residue
was acidified with a 10% aq solution of citric acid. The aqueous
phase was extracted with EtOAc (3 15 mL), the combined organic
layers were dried (Na SO ) and the solvent was removed. The resi-
CH CO), 2.91–3.25 (m, 16 H, 6 CHCH N, NCH CH CH N), 3.60
(m, 6 H, 6 CH), 3.92 and 4.12 (m, 8 H, 8 NH).
2
2
2
2
2
13
C NMR (50 MHz, CD OD): = 28.8, 28.9, 29.6, 33.6, 37.9, 45.4,
3
5
1.8, 80.1, 158.3, 175.2.
+
MS (MALDI-TOF): m/z = 1582.0 (M + Na).
Anal. Calcd for C H N O H O (1577.97): C, 55.57; H, 8.69; N,
7
3
134 14 22
2
1
2.43. Found: C, 55.63; H, 8.71; N, 12.08.
2
4
due was purified by column chromatography using a mixture of
CHCl –MeOH (9:1) as eluent to give 9 as a white solid (651 mg,
Coupling of DAB(AM)16 with 1,2-Diamino Acids; General Pro-
cedure
To a mixture containing DAB(AM)16 (101 mg, 0.06 mmol) in
3
9
1%); mp 71–73 °C;
]D25 –18.4 (c = 0.5, CHCl3).
CH Cl (4 mL) and Et N (0.20 mL, 1.44 mmol) were added com-
[
2 2 3
pound 5 or 9 (1.44 mmol), EDC (276 mg, 1.44 mmol) and HOBt
195 mg, 1.44 mmol). The reaction mixture was stirred for 1 h at 0
C and for 40 h at r.t. The solvent was removed and the product was
1H NMR (200 MHz, CDCl3): = 1.20–1.40 [m, 26 H, 2 C(CH3)3,
CH ) ], 1.55 (m, 2 H, CH CH CO), 2.30 (t, 2 H, J = 7.4 Hz,
(
°
(
2
4
2
2
CH CO), 3.12 (m, 2 H, CH N), 3.58 (m, 1 H, CH), 4.74 (d, J = 8.6
Hz) and 5.78 (br, 1 H, CHNH), 5.02 (br) and 6.02 (br, 1 H, CH NH).
2
2
extracted with EtOAc (2 5 mL). The combined organic layers
were washed consecutively with brine (2 7 mL), 5% aq NaHCO3
(5 7 mL), and brine (2 7 mL) and dried (Na SO ). The solvent
2
1
3
C NMR (50 MHz, CDCl ): = 24.5, 25.5, 28.3, 28.8, 28.9, 32.7,
3
2
4
3
3.9, 44.8, 51.2, 79.3, 156.4, 178.6.
was evaporated and the product was purified by recrystallization
from EtOAc–petroleum ether.
+
+
MS (FAB): m/z (%) = 411 (M + Na, 5), 389 (M + 1, 45), 333 (22),
89 (37).
2
[
Boc-DAP(Boc)] -DAB(AM) (14)
16 16
Anal. Calcd for C H N O (388.50): C, 58.74; H, 9.34; N, 7.21.
Found: C, 58.86; H, 9.54; N, 7.19.
25
19
36
2
6
Light yellow solid (336 mg, 84%); mp 66–68 °C; [ ]D –15.7 (c =
0
.5, CHCl3).
1
H NMR (200 MHz, CDCl ): = 1.45 [br s, 288 H, 32 C(CH3)3],
3
[
Boc-DAP(Boc)] -PDA (11)
2
1
.58–2.00 (m, 92 H, 16 CH CH CH, 30 CH CH N), 2.30 (m, 32
2 2 2 2
To a stirred solution of 5 (598 mg, 1.80 mmol) in CH Cl (16 mL)
were added H N(CH ) NH (67 mg, 0.90 mmol), EDC (380 mg,
1
mmol). The reaction mixture was stirred for 1 h at 0 °C and for 16
h at r.t. The solvent was removed and the product was extracted with
EtOAc (2 25 mL). The combined organic layers were washed con-
secutively with aq 1 M KHSO , H O, 5% aq NaHCO , H O, and
dried (Na SO ). The solvent was evaporated to give 11 as white sol-
id (429 mg, 68%); mp 134–135 °C; [ ]D –9.4 (c = 0.5, MeOH).
2
2
H, 16 CH CO), 2.42–2.98 (m, 84 H, 42 CH N), 3.00–3.39 (m,
6
5
2
2
2
2 3
2
4 H, 16 CH NHCO, 16 CH NHBoc), 3.60 (m, 16 H, 16 CH),
2
2
.98 mmol), HOBt (243 mg, 1.80 mmol) and Et N (0.28 mL, 1.98
3
.62 (br, 32 H, 32 NHBoc), 7.68 (br, 16 H, 16 NHCO).
1
3
C NMR (50 MHz, CDCl ): = 28.5, 29.2, 29.7, 33.0, 37.5, 44.5,
3
51.3, 79.2, 156.7, 157.0, 173.7.
4
2
3
2
+
MS (MALDI-TOF): m/z = 6713.9 (M + 1).
2
4
2
5
Anal. Calcd for C328H624N O 2H O (6752.86): C, 58.34; H, 9.37;
N, 12.86. Found: C, 58.56; H, 9.48; N, 12.66.
62 80
2
1
H NMR (200 MHz, CD OD): = 1.45 [br s, 36 H, 4 C(CH3)3],
3
1
.55–1.80 (m, 6 H, 2 CH CH CH, CH CH N), 2.25 (t, 4 H, J = 7.3
2 2 2 2
[
Boc-DAN(Boc)] -DAB(AM) (15)
1
6
16
Hz, 2 CH CO), 2.92–3.12 (m, 4 H, 2 CHCH N), 3.14–3.26 (m,
4
25
2
2
Light yellow solid (305 mg, 69%); [ ]D –13.0 (c = 0.5, CHCl3).
H, NCH CH CH N), 3.56 (m, 2 H, 2 CH), 4.60–4.73 (m, 4 H, 4
2 2 2
1
H NMR (200 MHz, CDCl3):
= 0.92–1.78 [m, 508 H, 32
NH).
C(CH ) , 16 (CH ) CH, 30 CH CH N], 2.17 (m, 32 H, 16
CH CO), 2.32–2.72 (m, 84 H, 42 CH N), 2.95–3.30 (m, 64 H, 16
1
3
3 3
2 5
2
2
C NMR (50 MHz, CD OD): = 28.8, 29.6, 30.1, 33.7, 37.8, 45.3,
3
2
2
5
1.9, 80.1, 158.3, 175.6.
CH NHCO, 16 CH NHBoc), 3.59 (m, 16 H, 16 CH), 5.10 (br,
2
2
+
+
MS (FAB): m/z (%) = 725 (M + Na, 10), 703 (M + 1, 4), 603 (20),
03 (3), 303 (5).
16 H, 16 CHNHBoc), 5.28 (br, 16 H, 16 CH NHBoc), 7.41 (br,
16 H, 16 CONH).
2
4
1
3
Anal. Calcd for C H N O H O (720.91): C, 54.98; H, 8.95; N,
C NMR (50 MHz, CDCl ): = 25.8, 26.6, 28.4, 28.5, 29.3, 30.7,
3
33
62
6
10
2
1
1.66. Found: C, 55.16; H, 9.02; N, 11.39.
32.9, 36.4, 45.0, 51.2, 79.1, 156.4, 156.7, 173.8.
Anal. Calcd for C392H752N O 4H O (7686.74): C, 61.25; H, 9.97;
N, 11.30. Found: C, 61.50; H, 9.83; N, 11.51.
62
80
2
[
Boc-DAP(Boc)] -(DAP) -PDA (12)
4
2
The tert-butoxycarbonyl groups of 11 (200 mg, 0.28 mmol) were
removed by treatment with 4 N HCl in Et O (8.3 mL) for 2 h at r.t.
2
Removal of Boc Groups from Dendrimers 14 and 15; General
Procedure
After evaporation, Et O was added and the product was filtered and
2
recrystallized from MeOH–Et O. The product was dissolved in
2
The tert-butoxycarbonyl groups of 14 and 15 (0.05 mmol) were re-
moved by treatment with 4 N HCl in MeOH (10 mL) for 2 h at r.t.
After evaporation, the residue was converted into free amine by pas-
CH Cl (14 mL) and to the solution were added 5 (462 mg, 1.39
2
2
mmol), EDC (293 mg, 1.53 mmol), HOBt (188 mg, 1.39 mmol) and
Et N (0.42 mL, 2.92 mmol). The reaction mixture was stirred for 1
–
3
sage over Amberlite IRA 900 (OH ) resin followed by lyophiliza-
h at 0 °C and for 40 h at r.t. The solvent was removed and the prod-
uct was extracted with EtOAc (2 25 mL). The combined organic
layers were washed consecutively with aq 1 M KHSO , H O, 5% aq
tion.
4
2
(
DAP) -DAB(AM) (16)
16 16
NaHCO , and H O, and dried (Na SO ). The solvent was evaporat-
25
3
2
2
4
Colourless oil (158 mg, 90%); [ ]D –7.4 (c = 0.5, H O).
2
ed and the product was purified by recrystallization (EtOAc–petro-
1
H NMR (200 MHz, D O): = 1.17–1.68 [m, 92 H, 16
leum ether) to give 12 as a white solid (265 mg, 61%); mp 176–178
2
C; [ ]D25 –13.0 (c = 0.5, MeOH).
CH CH CH, 30 CH CH N], 1.95–2.17 (m, 32 H, 16 CH CO),
°
2
2
2
2
2
2
.17–2.39 (m, 84H, 42
CH N), 2.39–2.66 (m, 32H, 16
1
2
H NMR (200 MHz, CD OD): = 1.30–2.00 [m, 86 H, 8
3
CH NH ), 2.85–3.10 (m, 48H, 16 CH, 16 CH NHCO).
2
2
2
C(CH ) , 6
CH CH CHN, CH CH N], 2.28 (m, 12 H, 6
3
3
2 2 2 2
Synthesis 2002, No. 10, 1359–1364 ISSN 0039-7881 © Thieme Stuttgart · New York

1
364
E. Bellis et al.
PAPER
1
3
C NMR (50 MHz, D O): = 25.3, 30.4, 32.6, 37.8, 46.3, 50.6,
(4) (a) Zeng, F.; Zimmerman, S. C. Chem. Rev. 1997, 97, 1681;
and references cited therein. (b) Narayanan, V. V.;
2
5
1.6, 176.2.
Newkome, G. R. Top. Curr. Chem. 1998, 197, 19.
(
DAN) -DAB(AM) (17)
(c) Valerio, C.; Alonso, E.; Ruiz, J.; Blais, J. C.; Astruc, D.
Angew. Chem. Int. Ed. 1999, 38, 1747. (d) Baars, M. W. P.
L.; Meijer, E. W. Top. Curr. Chem. 2000, 210, 131.
1
6
16
2
5
Colorless oil (187 mg, 85%); [ ]D –11.2 (c = 0.25, H O).
2
1
H NMR (200 MHz, D O): = 0.92–1.22 [m, 128 H, 16
2
(
(
(
5) Peerlings, H. W.; Meijer, E. W. Chem.–Eur. J. 1997, 3,
563.
(
1
CH ) CH], 1.27–1.60 [m, 92 H, 16 CH CH CO, 30 CH CH N],
2 4 2 2 2 2
1
.92–2.08 (m, 32 H, 16 CH CO), 2.10–2.55 (m, 116 H, 42
2
6) Seebach, D.; Rheiner, P. B.; Greiveldinger, G.; Butz, T.;
Sellner, H. Top. Curr. Chem. 1998, 197, 125.
7) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem. Int.
Ed. 1998, 37, 2580.
CH N, 16
CH NHCO).
CH NH ), 2.86–3.06 (m, 48H, 16
CH, 16
2
2
2
2
1
3
C NMR (50 MHz, D O): = 25.1, 26.0, 28.0, 28.4, 30.1, 32.0,
2
3
6.9, 46.9, 50.7, 51.8, 176.2.
(
8) Kokotos, G. Synthesis 1990, 299.
(9) Kokotos, G.; Noula, C. J. Org. Chem. 1996, 61, 6994.
(
(
10) Markidis, T.; Kokotos, G. J. Org. Chem. 2001, 66, 1919.
11) (a) Kokotos, G.; Constantinou-Kokotou, V. J. Chem. Res.
Acknowledgement
(
S) 1992, 391. (b) Kokotos, G.; Constantinou-Kokotou, V.
This work was partially supported by the Greek Secretariat for Re-
J. Chem. Res. (M) 1992, 3117.
search and Technology (PENED 99
173) and the Special Ac-
(
(
(
12) Takacs, J. M.; Jaber, M. R.; Clement, F.; Walters, C. J. Org.
Chem. 1998, 63, 6757.
13) Sheehan, J. C.; Cruickshank, P. A.; Boshart, G. L. J. Org.
Chem. 1961, 26, 2525.
count for Research Grants (University of Athens).
References
14) (a) Jansen, J. F. G. A.; Meijer, E. W. J. Am. Chem. Soc. 1995,
(
(
(
1) Newkome, G. R.; Moorefield, C. N.; Vögtle, F. Dendritic
Molecules: Concepts, Syntheses, Perspectives; VCH:
Weinheim, 1996.
2) Oosterom, G. E.; Reek, J. N. H.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M. Angew. Chem. Int. Ed. 2001, 40,
1
17, 4417. (b) Stevelmans, S.; van Hest, J. C. M.; Jansen, J.
F. G. A.; van Boxtel, D. A. F. J.; de Brabander-van den Berg,
E. M. M.; Meijer, E. W. J. Am. Chem. Soc. 1996, 118, 7398.
15) Baars, M. W. P. L.; Froehling, P. E.; Meijer, E. W. Chem.
Commun. 1997, 1959.
(
(
(
1828; and references cited therein.
16) Panday, S. K.; Langlois, N. Tetrahedron Lett. 1995, 36,
3) (a) Tomalia, D. A.; Naylor, A.; Goddard, W. A. III Angew.
Chem., Int. Ed. Engl. 1990, 29, 138. (b) Bosman, A. W.;
Janssen, H. M.; Meijer, E. W. Chem. Rev. 1999, 99, 1665;
and references cited therein.
8
205.
17) Altman, J.; Ben-Ishai, D. Tetrahedron: Asymmetry 1994, 5,
87.
8
Synthesis 2002, No. 10, 1359–1364 ISSN 0039-7881 © Thieme Stuttgart · New York