Thieme chemistry journal awardees-where are they now? A convenient route for introduction of lipophilic side chains in polyamine backbones by solid-phase synthesis

Article abstract of DOI:10.1055/s-0029-1217987

The synthesis of polyamines is often a laborious task that usually requires the use of complex protection schemes in combination with harsh alkylation steps. Here, we report the development of a convenient strategy for the generation of various linear as

Full text of DOI:10.1055/s-0029-1217987

LETTER
2755
Thieme Chemistry Journal Awardees – Where are They Now?
A Convenient Route for Introduction of Lipophilic Side Chains in Polyamine
Backbones by Solid-Phase Synthesis
I
ntroduction o
r
Lipoph
a
ilic
S
ide Ch
n
ains in Polya
k
mine Backbones Hahn,a Ute Schepers*a,b
a
LIMES-Institute Program Unit Membrane Biology and Lipid Biochemistry and Kekulé-Institut für Organische Chemie and Biochemie,
University of Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtzplatz 1,
76344 Eggenstein-Leopoldshafen, Germany
b
Fax +49(7247)823354; E-mail: ute.schepers@itg.fzk.de; E-mail: ute.schepers@kit.edu
Received 22 June 2009
Abstract: The synthesis of polyamines is often a laborious task that
usually requires the use of complex protection schemes in combina-
tion with harsh alkylation steps. Here, we report the development of
a convenient strategy for the generation of various linear as well as
branched lipophilic polyamine structures on solid phase. The se-
quential use of Aloc-, o-nosyl-, and Dde groups for differentiation
between the primary and secondary amines and Fukuyama alkyla-
tion and reductive amination for elongation and modification of the
backbone enabled the synthesis of both, linear as well as branched
polyamines. The mild deprotection conditions facilitated the syn-
thesis of acid- and base-labile conjugates. This strategy was applied
for the synthesis of a range of fluorescently labelled polyamine con-
jugates with varying degrees of lipophilic substitution.
Dr. Ute Schepers was born in Rhede, Germany, in 1966. After her
studies in Chemistry at the University of Bonn, she received her PhD
in 1997 working with Prof. Dr. Konrad Sandhoff. She then moved to
Harvard Medical School for a post-doctorate (1998-2000) with Prof.
Tom Kirchausen at the Department of Cell Biology. In 2000 she re-
turned to the Kekulé-Institut für Organische Chemie und Biochemie
in Bonn to start her independent research and her habilitation. Since
2009 she became an independent group leader at the Institute of To-
xicology and Genetics of the Karlruhe Institute of Technology (KIT)
in Karlsruhe. Her research is focused on combinatorial synthesis for
the development of organ specific drug delivery systems for small
molecules and siRNAs.
Key words: solid-phase synthesis, drug delivery, polyamines,
alkylations, protecting groups, polycations
Polyamines are polycationic molecules, which are abun-
dantly present in mammalian cells in relatively high con-
centrations, giving rise to important cellular functions.1
Their mode of action mostly depends on their highly pos-
itive net charge at physiological pH, which enables them
to tightly interact with negatively charged components
such as DNA, RNA, as well as proteoglycans and phos-
pholipids in the cell membrane. Polyamine conjugates and
derivatives have found an application in DNA recognition
and binding, in naturally occurring and synthetic toxins
and venoms, as an integral part of some antibiotic, bacte-
ricidal, or antiparasitic conjugates, in cancer therapy, and
finally in drug delivery.1b In analogy to cell-penetrating
peptides,2 mimetics like b-peptides3 or peptoids,2
polyamines are promising candidates to act as covalently
coupled transporter moieties in drug delivery. A main fea-
ture shared by all these molecules is their positive net
charge, which is believed to enable interaction with cellu-
lar membranes. However, introduction of lipophilic side
chains are assumed to enhance the amphiphilicity and
therefore the passage through biological membranes.
Here we report on a convenient strategy for the synthesis
of elongated and branched polyamines carrying lipophilic
side chains and their conjugation to potential drugs and
fluorophores on solid phase.
Synthesis of polyamine conjugates faces frequent prob-
lems. It usually requires a target specific protection strat-
egy with multiple conversions to enable differentiation of
the individual amino functionalities and specialised work-
up procedures.1 To minimise efforts, solid-phase synthe-
sis has become the method of choice for polyamine
synthesis and during the last decade, several improve-
ments were made.5 However, polyamine solid-phase syn-
theses are often less flexible in the diversity of their target
molecules, require harsher conditions, and finally produce
lower yields compared to solid-phase syntheses of pep-
tides or peptoids with comparable molecular weight due
to the polarity and symmetry of the polyamine building
blocks. This shows that a strategy for synthetic advance-
ments in polyamine solid-phase synthesis is absolutely re-
quired, which leads to more generally applicable synthetic
schemes.
SYNLETT 2009, No. 17, pp 2755–2760
x
x
.x
x
.2
0
0
9
Recently, we have published a strategy for the synthesis of
linear polyamines on trityl resins, which makes use of the
Advanced online publication: 24.09.2009
DOI: 10.1055/s-0029-1217987; Art ID: S07009ST
© Georg Thieme Verlag Stuttgart · New York

2756
F. Hahn, U. Schepers
LETTER
Aloc group for permanent protection of the secondary
amines during elongation of the backbone.6 In combina-
tion with the use of the o-nosyl group, this strategy al-
lowed for the synthesis of small polyamine conjugates
with similar efficiency to other protection-group combi-
nations, however, under much milder conditions. In a de-
tailed study we could also show that Aloc is compatible
with the conditions of Fukuyama alkylation and that the
secondary amines can be orthogonally liberated for fur-
ther modifications. Herein, we report some advantages of
this strategy and show the application for the solid-phase
synthesis of various polyamine structures, which differ in
their lipophilic substitution pattern.
Table 1 Cargo Molecules Coupled to the Polyamine Moiety
N
N
O
O
N
O
N+
NO2
Cl–
6
7
rhodamine B
NBD
O
O
C11H23
We chose trityl resin 1, a commercially available 2-chlo-
rotrityl resin that was loaded with an asymmetrically sub-
stituted polyamine building block as described
previously,6 as a universal starting point for all syntheses.
It provides a spermine moiety, which is orthogonally pro-
tected at its primary and secondary amines and provides a
direct access for elongation by alkylation or acylation at
one terminus. Following the procedure shown in Scheme
1, several terminally modified spermidine derivatives
with the fluorescent markers 7-nitrobenzo-2-oxa-1,3-di-
azol (NBD, 7) and rhodamine B (6), drugs like in-
domethacin (9), and a lipophilic porphyrin 87 were
generated. Besides the coupling of the drugs, coupling of
the fluorescent labels such as NBD and rhodamine B al-
lows the monitoring of the lipophilic derivatives in living
cells. Resin 1 was o-nosyl-deprotected, a cargo molecule
was coupled, the Aloc groups were removed, and after
cleavage from the resin the products were purified by pre-
parative RP-HPLC in case of compounds 5a–c and simple
washing of the crude cleavage mixture with aqueous solu-
tions of K2CO3 (pH 10) in the case of 5d.8 The pure prod-
ucts were obtained in good to excellent yields.
N
H
MeO
N
N
H
N
N
C11H23
C11H23
O
Cl
8
9
6,11,16-tris-undecanyl-p-
carboxyphenyl porphyrin
indomethacin
Compound R
Yield
(%)a
Purity
(%)a
5a
5b
5c
5d
rhodamine B (6)
NBD (7)
74
84
97
90
51
indomethacin (8)
74
tris-undecanyl-carboxyporphyrin (9) 96
>95
a Yield after purification, purity after cleavage from the resin.
In this synthetic scheme, the cargo molecule is only ex-
posed to the mild conditions of Pd-mediated Aloc depro-
tection and linker cleavage at low acid concentrations
(0.1–1% TFA), which allows the coupling to acid-sensi-
tive moieties such as many biomacromolecules. As the
use of an NBD label showed to be advantageous to the
rhodamine B and to other labels in cellular live imaging
experiments,9 the following conjugates were all prepared
with NBD as the cargo molecule.
Aloc
H
N
N
N
H
N
o-Ns
1
2
Aloc
Aloc
N
a
NH2
N
H
N
Aloc
Aloc
N
The polyamine backbone of 1 was elongated by Fukuya-
ma alkylation with N-Dde-3-aminopropyliodide (Scheme
2). The o-nosyl group of 10 was exchanged against an
Aloc group, the Dde group was removed, and the label
was introduced by reaction with NBDCl in the presence of
DIPEA. After cleavage from the resin and purification by
RP-HPLC the pure product was obtained in 98% yield and
66% purity after cleavage. The exchange of o-nosyl
against Aloc avoids exposure of the cargo molecule to the
harsh conditions of o-nosyl deprotection, which are detri-
mental to the NBD group. Cleavage experiments, in
which each of the protection groups was separately re-
moved, and the crude cleavage product subsequently anal-
b
H
N
3
N
H
N
R
Aloc
+
c
H2
N
H
N
4
5
N
H
N
H2
R
+
+
d
H2
N
H
N
+H3N
N
H2
R
+
Scheme 1 Synthesis of spermidine conjugates. Reagents and condi-
tions: (a) b-mercaptoethanol (10 equiv), DBU (5 equiv), DMF, 1 h,
r.t.; (b) indomethacin (rhodamine B) (5 equiv), DCC (5 equiv), HOBt
(5 equiv), DMF, 16 h, r.t.; or NBDCl (3.3 equiv), K2CO3 (1.7 equiv),
DMF, 16 h, r.t.; (c) N,N¢-dimethylbarbituric acid (10 equiv),
Pd(PPh3)4 (20 mol%), CH2Cl2, 6–8 h, 40 °C; (d) 10% TFA in CH2Cl2,
3 × 1 min, r.t.
1
ysed by H NMR showed full orthogonality of these
protection groups.
Synthesis of polyamines with a larger lipophilic group on
the opposite terminus of NBD, providing the conjugate an
Synlett 2009, No. 17, 2755–2760 © Thieme Stuttgart · New York

LETTER
Introduction of Lipophilic Side Chains in Polyamine Backbones
2757
1
2
a
a
Aloc
H
Aloc
N
o-Ns
N
H
N
14a,b
15a,b
N
N
R
R
N
H
N
N
H
N
Dde
10
Aloc
O
O
Aloc
b, c
Aloc
b
Aloc
N
Aloc
N
H
N
H
N
N
N
H
N
Dde 11
NBD 12
+H3N
N
Aloc
⋅TFA
Aloc
d, e
Aloc
c
Aloc
N
H
N
Aloc
N
N
H
N
N
H
N
16a,b
17a,b
R
R
NBD
N
H
N
Aloc
f, g
Aloc
O
O
d
+
+
H2
N
H2
N
+
H
N
H2
N
H
N
+H3N
N
H2
NBD
13
+
NBD
N
H
N
H2
+
⋅2AcO–
⋅4TFA
Scheme 3 Synthesis of amphiphilic, NBD-labelled polyamine deriva-
tives. Reagents and conditions: (a) 1-adamantyl carboxylic acid or
undecanoic acid (8 equiv), DCC (8 equiv), NHS (5 equiv), DMF–
THF, r.t.; (b) 10% TFA in CH2Cl2; (c) NBDCl (2.9 equiv), K2CO3 (3
equiv), THF, 18 h, r.t.; (d) N,N¢-dimethylbarbituric acid (10 equiv),
Pd(PPh3)4 (10 mol%), CH2Cl2, 2.5 h, 40 °C.
Scheme 2 Synthesis of spermine–NBD conjugate. Reagents and
conditions: (a) N-Dde-3-aminopropyliodide (13 equiv), K2CO3 (13
equiv), DMF, 18 h, 60 °C; (b) b-mercaptoethanol (10 equiv), DBU (5
equiv), DMF, 3 × 30 min, r.t.; (c) allyloxycarbonyl chloride (10
equiv), Et3N (10 equiv), CH2Cl2, 16 h, r.t.; (d) N2H4·H2O (10 equiv),
allyl alcohol (100 equiv), DMF, 3 × 15 min, r.t.; (e) indomethacin (5
equiv), DCC (5 equiv), HOBt (5 equiv), DMF, 16 h, r.t.; or NBDCl (4
equiv), DIPEA (4 equiv), THF, 16 h, r.t.; (f) N,N¢-dimethylbarbituric
acid (10 equiv), Pd(PPh3)4 (20 mol%), CH2Cl2, 6 h, 35 °C; (g) Et3N
(5%)–CH2Cl2.
H
N
H
N
N
H
N
H
o-Ns/Ac
18a,b
R2
H
N
amphiphilic structure, is shown in Scheme 3. Starting
from resin 2, the o-nosyl group was removed and 1-ada-
mantylcarboxylic acid and undecanoic acid were coupled
to the liberated primary amine. The compound was
cleaved from the resin, and the remaining steps were car-
ried out in solution. TFA was removed under high vacu-
um, and NBD was introduced by reaction with NBDCl in
the presence of a base. Compounds 15a,b could be isolat-
ed in high purity for step d by evaporation of THF, disso-
lution in chloroform, and simple washing of the organic
layer with water. Finally, the Aloc groups were removed
with N,N¢-dimethylbarbituric acid and catalytical
Pd(PPh3)4, and the products 17a and 17b were isolated in
66% and 92% yield after flash chromatography over a
short pad of silica gel and transformation into their acetic
acid salts.
N
N
H
N
o-Ns/Ac
19
R = benzyl, adamantyl, or alkyl chain
R2
Scheme 4 Introduction of various side chains by SN2-alkylation, re-
ductive amination, and reduction of amides
ation worked reliably well and enabled introduction of
most moieties without evidence for relevant problems
with steric congestion. Thus, it was selected for the intro-
duction of alkyl side chains to linear polyamines. An ex-
ample for the synthesis of a branched polyamine
conjugate is shown in Scheme 5. Starting from 14a, the
Aloc groups were removed and C6 alkyl chains were in-
troduced by imine formation with capronaldehyde and
subsequent reduction with NBu4BH4.
The substituted polyamine was cleaved from the resin,
NBD-labelled, and 23 was isolated by flash chromatogra-
phy. Finally, 2310,11 was obtained after six steps in 53%
yield related to the loading of resin 1.
For the synthesis of branched polyamine conjugates, the
modification of secondary amines is an important issue.
To identify the most convenient method for this, SN2 alkyl-
ation, reductive amination, and reduction of amides were
evaluated on resins 18a and 18b with several bromides, The possibility to introduce branches on the remote amine
aldehydes and acid chlorides bearing benzylic groups, is demonstrated by the synthesis of an NBD-polyamine
adamantylic groups, and alkyl chains with lengths from with a longer alkyl chain for membrane anchoring on the
C4–C12 (Scheme 4). While reduction of amides suffers
from insufficient formation of tertiary amides and/or slug-
gish borane reduction, SN2 alkylation required tempera-
tures higher than 80 °C for a complete reaction.
more lipophilic head group shown in Scheme 6. Starting
from resin 1, a benzyl group was introduced by Fukuyama
alkylation with benzylbromide.6 The o-nosyl group was
removed, and the amine was reacted with lauroylchloride
in pyridine–dichloromethane, thereby introducing a
branch. Application of the Kaiser test as well as spectro-
scopic analysis of cleaved 25 showed an almost quantita-
However, even in this case, bulkier groups could not be
introduced by this method, indicating that steric con-
straints are the main problem. In contrast, reductive amin-
Synlett 2009, No. 17, 2755–2760 © Thieme Stuttgart · New York

2758
F. Hahn, U. Schepers
LETTER
14a
1
a
a
+
H2
N
H
N
20
21
Aloc
N
N
H
N
b, c
d, e
+
N
N
H2
O
O
N
H
N
o-Ns
b
24
25
C6H13
NH+
Aloc
H
N
H+
N
N
H
Aloc
N
C6H13
C11H23
c
N
H
N
C6H13
NH+
H
N
Aloc
O
O
H+
N
22
23
+H3N
C6H13
d
O
⋅3TFA
C6H13
NH+
f, g
H+
N
N
C11H23
N
H
26
C6H13
H
N
N
NBD
N
N
H
O
N
N
27
NBD
N
H
N
4
Scheme 5 Synthesis of a conjugate with adamantyl group and C6-
side-chain modifications. Reagents and conditions: (a) N,N¢-dime-
thylbarbituric acid (10 equiv), Pd(PPh3)4 (20 mol%), CH2Cl2, 20 h,
35 °C; (b) 40 °C, capronaldehyde (6 equiv), Bu4N(BH4) (6 equiv), 3%
HOAc in DMF, 2 × 30 min 1 × over night, 40 °C; (c) 10% TFA in
CH2Cl2, r.t.; (d) NBDCl (3 equiv), K2CO3 (4 equiv), THF, 17 h, r.t.
O
Scheme 6 Synthesis of a conjugate with expanded lipophilic tail
and side-chain modifications. Reagents and conditions: (a) BnBr (20
equiv), DBU (20 equiv), DMF, 16 h, r.t.; (b) b-mercaptoethanol (10
equiv), DBU (5 equiv), DMF, 3 × 30 min, r.t.; (c) lauroyl chloride (20
equiv), pyridine–CH2Cl2 (1:2), 18 h, r.t.; (d) (10 equiv) N,N¢-dime-
thylbarbituric acid, Pd(PPh3)4 (20 mol%), CH2Cl2, 6 h, 35 °C; (e) ca-
pronaldehyde (6 equiv), 3% AcOH in DMF, 40 °C, 30 min, then
NBu4BH4 (6 equiv), 2 × 30 min, 1 × 16 h; (f) 10% TFA in CH2Cl2; (g)
NBDCl (3 equiv), K2CO3 (4 equiv), THF, 17 h, r.t.
tive reaction. Thus, the steric bulk of the benzyl group is
not detrimental to peptide bond formation if the carboxy-
lic acid is sufficiently activated as its acid chloride. Al-
though it is known that partial cleavage from trityl linkers
can occur in the presence of acyl chlorides, we did not ob-
serve similar problems. Possibly, the length of the lauroyl
chloride avoids its vicinity to the bulky tritylamine an-
chor. After removal of the Aloc groups, the liberated
amines were alkylated, the molecule was cleaved from the
resin, and the liberated primary amine was labelled with
NBDCl. The product of the seven-step synthesis was pu-
rified by flash chromatography and isolated in 91% yield.
This higher yield is in accordance with the lower sterical
demand of the lauroyl group compared to the adamantyl
group in 23, which allows a more exhaustive alkylation of
the secondary amines near the bulky trityl linker (see ex-
ample described in Scheme 5).
yield, which is very good for a nine-step polyamine syn-
thesis. This result amongst others indicates that the ada-
mantyl group does not disturb the alkylation of secondary
amine if it is not bound to the adjacent 3-aminopropyl
group.
Taken together we have shown the advantages of a solid-
phase strategy for polyamine synthesis, which based on
the use of Aloc-, o-nosyl-, and Dde-group for differentia-
tion of the particular amines, Fukuyama alkylation for
backbone elongation and reductive amination for intro-
duction of substituents onto the secondary amines of the
backbone. We showed that the orthogonally protected
amines can individually be customised. Steric congestions
are the main constraint, which can in the case of very
bulky substituents like adamantyl groups hinder a modifi-
cation of adjacent amino functionalities. By sequential o-
nosyl deprotection–amine modification and following ex-
change of Dde against o-nosyl group after each elongation
step or by introducing another orthogonal protection
group for the secondary amines (for example the Teoc
group12), a longer backbone with individual substitution
pattern could be generated. Finally, this mild strategy can
also be applied for the synthesis of polyamines with other
substituents than hydrocarbons if side chains are appropri-
ately protected.
Sequential elongation of the backbone leading to an ex-
tended lipophilic part on the terminus is shown in Scheme
7. After elongation of the spermine backbone, an immobi-
lised pentaamine is obtained, on which all four differently
protected amines can be orthogonally modified. The o-
nosyl group of 10 was exchanged against a lauroyl group
and subsequently, the Dde group against a bulky adaman-
tyl group. Again, the Kaiser test of 29 showed a complete
acylation. If introduced in this order, the high steric de-
mand of the adamantyl group is not detrimental to lauroyl-
isation of the secondary amine. Finally, the Aloc-
protected amines are liberated and alkylated with C6
chains. After cleavage and NBD labelling the product was
isolated by flash chromatography on silica gel in 89%
Synlett 2009, No. 17, 2755–2760 © Thieme Stuttgart · New York

LETTER
Introduction of Lipophilic Side Chains in Polyamine Backbones
2759
10
a,b
O
O
C11H23
Aloc
N
H
N
N
N
N
H
N
Dde
28
29
Aloc
c,d
C11H23
Aloc
N
H
N
N
H
N
Aloc
O
e,f
O
C11H23
C6H13
NH+
H
N
H+
N
N
N
H
30
C6H13
O
⋅2AcO–
g,h
O
4
H
N
N
N
NBD
N
N
H
31
O
Scheme 7 Synthesis of a conjugate with expanded lipophilic tail and side-chain modifications. Reagents and conditions: (a) b-mercaptoetha-
nol (10 equiv), DBU (5 equiv), DMF, 3 × 30 min, r.t.; (b) lauroyl chloride (20 equiv), pyridine–CH2Cl2 (1:2), 18 h, r.t.; (c) N2H4·H2O (10 equiv),
allyl alcohol (100 equiv), DMF, 3 × 15 min, r.t.; (d) 1-adamantyl carboxylic acid (5 equiv), DCC (5 equiv), HOBt (5 equiv), DMF–THF (1:1),
20 h, r.t.; (e) N,N¢-dimethylbarbituric acid (10 equiv), Pd(PPh3)4 (20 mol%), CH2Cl2, 6 h, 35 °C; (f) capronaldehyde (6 equiv), 3% AcOH in
DMF, 40 °C, 3 min, then NBu4BH4 (10 equiv), 2 × 30 min, 1 × 16 h; (g) TFA (5%)–CH2Cl2; (h) NBDCl (4.7 equiv), Et3N (4.7 equiv), THF,
16 h, r.t.
Lett. 2000, 41, 1095. (g) Manku, S.; Laplante, C.; Kopac,
D.; Chan, T.; Hall, D. G. J. Org. Chem. 2001, 66, 874.
(h) Picard, S.; Le Roch, M.; Renault, J.; Uriac, P. Org. Lett.
2004, 6, 4711.
Acknowledgment
We would like to thank the DFG Center for Functional Nanostruc-
tures (CFN), Karlsruhe for financial support, and Prof. Bräse, Karls-
ruhe for fruitful discussions.
(6) Hahn, F.; Schepers, U. J. Comb. Chem. 2008, 10, 267.
(7) Hahn, F.; Schmitz, K.; Balaban, T. S.; Bräse, S.; Schepers,
U. ChemMedChem 2008, 3, 1185.
(8) The highly amphiphilic structure of this molecule avoided
References and Notes
purification either on silica gel or on usual reversed-phase
materials.
(9) The coupling of NBD allows the time lapse monitoring
(up to 24 h) of living cells without much bleaching of the
fluorophore. Unpublished results of our group.
(10) Experimental Procedures
(1) (a) Cohen, S. S. A Guide to the Polyamines; New York:
Oxford University Press, 1998. (b) Hahn, F.; Schepers, U.
In Combinatorial Chemistry on Solid Supports, Vol. 278;
Bräse, S., Ed.; Springer: Berlin/Heidelberg, 2007, 135–208.
(2) (a) Wender, P. A.; Galliher, W. C.; Goun, E. A.; Jones, L. R.;
Pillow, T. H. Adv. Drug Deliv. Rev. 2008, 60, 452.
(b) Lebleu, B.; Moulton, H. M.; Abes, R.; Ivanova, G. D.;
Abes, S.; Stein, D. A.; Iversen, P. L.; Arzumanov, A. A.;
Gait, M. J. Adv. Drug Deliv. Rev. 2008, 60, 517.
(3) (a) Umezawa, N.; Gelman, M. A.; Haigis, M. C.; Raines,
R. T.; Gellman, S. H. J. Am. Chem. Soc. 2002, 124, 368.
(b) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem.
Biodiversity 2004, 1, 1111.
Introduction of Aloc Group
The resin was swollen in CH2Cl2 and after removal of the
solvent a solution of of allylchloroformate (10 equiv) and
Et3N (10 equiv) in CH2Cl2 was added. The suspension was
agitated overnight, the solvent was removed, and the resin
was washed with CH2Cl2–MeOH and CH2Cl2.
Aloc Deprotection
The resin was swollen in CH2Cl2 in a lock-up vial and N,N¢-
dimethylbarbituric acid (8 equiv) and Pd(PPh3)4 (10 mol%)
in CH2Cl2 (1.5 mL) were added. The suspension was
agitated for at least 6 h at 35 °C in the absence of light. The
resin was transferred to a glas frit and washed with a solution
of sodium diethylaminodithiocarbamate in CH2Cl2–MeOH
and CH2Cl2.
(4) (a) Wender, P. A.; Mitchell, D. J.; Pattabiraman, K.; Pelkey,
E. T.; Steinman, L.; Rothbard, J. B. Proc. Natl. Acad. Sci.,
U.S.A. 2000, 97, 13003. (b) Schröder, T.; Schmitz, K.;
Niemeier, N.; Balaban, T. S.; Krug, H. F.; Schepers, U.;
Bräse, S. Bioconjugate Chem. 2007, 18, 342.
(5) (a) Olsen, C. A.; Witt, M.; Hansen, S. H.; Jaroszewski, J. W.;
Franzyk, H. Tetrahedron 2005, 61, 6046. (b) Manov, N.;
Bienz, S. Tetrahedron 2001, 57, 7893. (c) Hahn, F.; Müllen,
K.; Schepers, U. Synlett 2008, 2785. (d) Kan, T.;
o-Nosyl Removal
The resin was swollen in DMF, and after removal of the
solvent a solution of b-mercaptoethanol (10 equiv) and DBU
(5 equiv) in DMF was added. The suspension was agitated
for 1 h. After removal of solvent the resin was washed with
Kobayashi, H.; Fukuyama, T. Synlett 2002, 1338. (e) Hone,
N. D.; Payne, L. J. Tetrahedron Lett. 2000, 41, 6149.
(f) Chhabra, S. R.; Khan, A. N.; Bycroft, B. W. Tetrahedron
Synlett 2009, No. 17, 2755–2760 © Thieme Stuttgart · New York

2760
F. Hahn, U. Schepers
LETTER
DMF until the filtrate was colourless. The procedure was
repeated in steps of 30 min until the supernatant stays
colourless after the reaction. The resin was washed with
DMF.
Compound 5d: 1H NMR (400 MHz, CD3OD): d = 9.64 (s, 4
H), 9.56 (d, J = 4.9 Hz, 2 H), 8.80 (d, J = 4.9 Hz, 2 H), 8.60
(d, J = 8.2 Hz, 2 H), 8.44 (d, J = 8.2 Hz, 2 H), 5.10 (m, 6 H),
3.57 (t, J = 7.1 Hz, 2 H), 3.34 (t, J = 6.4 Hz, 2 H), 3.16 (t,
J = 7.7 Hz, 2 H), 2.97–3.11 (m, 8 H), 2.50–2.60 (m, 6 H),
2.34 (t, J = 6.5 Hz, 2 H), 2.10 (tt, J1 = 9.0 Hz, J2 = 6.4 Hz, 2
H), 1.93 (tt, J1 = 6.9 Hz, J2 = 6.8 Hz, 2 H), 1.73–1.86 (m, 10
H), 1.47–1.58 (m, 8 H), 1.20–1.38 (m, 40 H), 0.87 (t, J = 7.0
Hz, 9 H). 13C NMR (75 MHz, CD3OD): d = 177.3 (Cq), 169.7
(Cq), 146.4, 146.1, 146.1, 145.6, 139.2, 137.1, 128.5, 128.3,
128.2, 121.0, 115.9, 113.6 (Cq, +), 143.4 (Cq), 130.5 (Cq),
124.6, 124.5 (+), 48.3, 48.2 (–), 46.5, 45.9 (–), 41.2 (–), 37.8,
37.0 (–, 3 C), 33.1 (–), 31.4, 31.3 (–), 30.9, 30.8, 30.5, 30.4
(–), 27.9 (–), 26.8 (–), 27.8, 25.4 (–), 24.4, 24.3 (–), 23.8 (–),
14.5 (+). ESI-HRMS: m/z calcd [M + 2 H]2+: 595.9816;
found: 595.9816.
Dde Removal
The resin was swollen in DMF, and after removal of the
solvent a solution of N2H4·H2O (10 equiv, 80% in H2O) and
allyl alcohol (100 equiv) of in DMF was added. The
suspension was agitated (3 × 15 min), and after removal of
the solvent the resin was washed with DMF in each case.
Fukuyama Alkylation
Compound 1 (1 equiv) and K2CO3 (13 equiv) were
suspended in DMF, and after 5 min N-Dde-3-aminopropyl-
iodide (13 equiv) was added. The suspension was agitated at
60 °C for 18 h. The resin was washed with H2O, THF–
MeOH (2:1)/MeOH, and CH2Cl2. Compound 1 (1 equiv)
was swollen in DMF for 5 min, and DBU (20 equiv) and
halide (20 equiv) were added. The suspension was agitated
at r.t. for 16 h. The resin was washed with DMF, THF–
MeOH (2:1)/MeOH, and CH2Cl2.
Compound 13: 1H NMR (400 MHz, CD3OD): d = 8.53 (d,
J = 8.7 Hz, 1 H), 6.40 (d, J = 8.7 Hz, 1 H), 3.75–3.65 (m, 2
H), 3.23–3.03 (m, 14 H), 2.17 (tt, J1 = 8.1 Hz, J2 = 6.9 Hz, 2
H), 2.19–2.11 (m, 2 H), 2.08 (tt, J1 = 7.8 Hz, J2 = 7.8 Hz, 2
H), 1.83–1.77 (m, 4 H). ESI-HRMS: m/z calcd [M + H]+:
423.2827; found: 423.2820.
Reductive Amination
The resin was placed in a frit with a plastic cap and 3%
HOAc in DMF (3 mL) was added. The suspension was
shortly agitated, heated to 40 °C, and capronaldehyde (6
equiv) was added. The suspension was left for 30 min under
occasional stirring, and then NBu4BH4 (6 equiv) was added.
The suspension was again left for 30 min under occasional
stirring or overnight and was then cooled to r.t. The resin was
washed with DMF. The alkylation was twice repeated. The
resin was washed with DMF, THF–MeOH, and CH2Cl2.
Compound 17a: 1H NMR (400 MHz, CD3OD): d = 8.46 (d,
J = 8.8 Hz, 1 H), 6.38 (d, J = 8.8 Hz, 1 H), 3.74–3.63 (m, 2
H), 3.30 (t, J = 6.6 Hz, 2 H), 3.22 (t, J = 7.2 Hz, 2 H), (3.12
(t, J = 7.1 Hz, 2 H), 2.95 (t, J = 7.1 Hz, 2 H), 3.04 (t, J = 6.8
Hz, 2 H), 2.20 (tt, J1 = 7.8 Hz, J2 = 6.8 Hz, 2 H), 2.03–1.98
(m, 3 H), 1.88 (tt, J1 = 7.2 Hz, J2 = 6.6 Hz, 2 H), 1.87–1.67
(m, 16 H). ESI-HRMS: m/z calcd [M + H]+: 528.3293;
found: 528.3304.
(11) Spectroscopic Data
Compound 17b: ESI-HRMS: m/z calcd [M + H]+: 646.5014;
found: 646.4998.
Compound 5a: 1H NMR (400 MHz, CD3OD): d = 8.00–7.95
(m, 1 H), 7.67–7.59 (m, 2 H), 7.52–7.46 (m, 2 H), 7.25–7.11
(m, 3 H), 6.99–6.91 (m, 2 H), 3.64 (q, J = 7.0 Hz, 8 H), 3.35
(t, J = 6.4 Hz, 2 H), 3.15 (t, J = 7.7 Hz, 2 H), 3.12–2.98 (m,
6 H), 2.92 (t, J = 6.5 Hz, 2 H), 2.12 (tt, J1 = 7.7 Hz, J2 = 7.3
Hz, 2 H), 1.88–1.78 (m, 4 H), 1.54 (tt, J1 = 6.8 Hz, J2 = 6.5
Hz, 2 H), 1.30 and 1.16 (t, J = 7.0 Hz, 12 H). ESI-HRMS:
m/z calcd [M + H]+: 627.4381; found: 627.4362.
Compound 23: 1H NMR (400 MHz, CDCl3): d = 8.38–8.30
(m, 1 H), 6.71 (m, 1 H), 3.75–3.62 (m, 2 H), 3.38–3.30 (m,
2 H), 3.27–3.22 (m, 4 H), 3.16–2.94 (m, 8 H), 2.32–2.21 (m,
2 H), 2.04–1.97 (m, 5 H), 1.90–1.86 (m, 4 H), 1.85–1.81 (m,
4 H), 1.76–1.60 (m, 12 H), 1.45–1.22 (m, 12 H), 0.90–0.81
(m, 6 H). ESI-HRMS: m/z calcd [M + H]+: 696.5171; found:
696.5167.
Compound 5b: 1H NMR (400 MHz, CD3OD): d = 7.69 (d,
J = 8.4 Hz, 2 H), 7.55 (d, J = 8.4 Hz, 2 H), 7.02 (d, J = 2.5
Hz, 1 H), 6.94 (d, J = 9.0 Hz, 1 H), 6.69 (dd, J1 = 9.0 Hz,
J2 = 2.5 Hz, 1 H), 3.80 (s, 3 H), 3.65 (s, 2 H), 3.32 (t, J = 6.7
Hz, 2 H), 3.12 (t, J = 7.7 Hz, 2 H), 3.06 (t, J = 7.8 Hz, 2 H),
3.07–3.00 (m, 4 H), 2.95 (t, J = 7.1 Hz, 2 H), 2.32 (s, 3 H),
2.09 (tt, J1 = 7.8 Hz, J2 = 7.7 Hz, 2 H), 1.88 (tt, J1 = 7.1 Hz,
J2 = 6.7 Hz, 2 H), 1.81–1.67 (m, 4 H). 13C NMR (75 MHz,
CD3OD): d = 174.4 (Cq), 170.0 (Cq), 157.6 (Cq), 140.3 (Cq),
137.3 (Cq), 135.6 (Cq), 132.3 (+), 132.1 (Cq), 130.2 (+),
116.0, 114.6, 112.5 (Cq), 102.6 (+), 56.2 (+), 48.2, 48.0 (–),
46.3 (–), 45.8 (–), 37.8, 37.1 (–, 2 C), 32.3 (–), 27.5 (–), 25.3
(–), 24.2 (–, 3 C), 13.6 (+). ESI-HRMS: m/z calcd [M + H]+:
542.2892; found: 542.2890.
Compound 27: 1H NMR (400 MHz, CD3OD): d = 8.42 (d,
J = 8.7 Hz, 1 H, 12 H), 7.40–7.16 (m, 5 H), 6.29 (d, J = 8.7
Hz, 1 H), 4.62 (s, 2 H), 3.68–3.58 (m, 2 H), 3.42 (t, J = 7.0
Hz, 2 H), 3.12–2.84 (m, 12 H), 2.40 (t, J = 7.6 Hz, 2 H, 17-
H), 2.11 (tt, J1 = 7.1 Hz, J2 = 7.1 Hz, 2 H), 1.89 (tt, J1 = 7.3
Hz, J2 = 7.0 Hz, 2 H), 1.77–1.69 (m, 4 H), 1.69–1.52 (m, 6
H), 1.35–1.19 (m, 28 H), 0.91–0.83 (m, 9 H). ESI-HRMS:
m/z calcd [M + H]+: 806.6266; found: 806.6249.
Compound 31: 1H NMR (400 MHz, CDCl3): d = 8.44–8.33
(m, 1 H), 6.31–6.26 (m, 1 H), 6.09–6.01 (m, 1 H), 3.66–3.54
(m, 2 H), 3.42–3.34 (m, 2 H), 3.34–3.22 (m, 4 H), 3.16–2.84
(m, 8 H), 2.78–2.60 (m, 4 H), 2.30 (t, J = 7.1 Hz, 2 H), 2.22–
2.15 (m, 2 H), 2.08–1.96 (m, 7 H), 1.88–1.81 (m, 6 H), 1.72–
1.66 (m, 6 H), 1.66–1.50 (m, 12 H), 1.34–1.16 (m, 28 H),
0.90–0.79 (m, 9 H). ESI-HRMS: m/z calcd [M + H]+:
935,7420; found: 936.7415.
Compound 5c: 1H NMR (400 MHz, CD3OD): d = 8.50 (d,
J = 8.8 Hz, 1 H), 6.39 (d, J = 8.8 Hz, 1 H), 3.74–3.64 (m, 2
H), 3.20 (t, J = 7.9 Hz, 2 H), 3.17–3.03 (m, 8 H), 2.18 (tt,
J1 = 7.8 Hz, J2 = 7.4 Hz, 2 H), 2.08 (tt, J1 = 7.8 Hz, J2 = 7.7
Hz, 2 H), 1.84–1.78 (m, 4 H). ESI-HRMS: m/z calcd [M +
H]+: 366.2248; found: 366.2252.
(12) Olsen, C. A.; Jorgensen, M. R.; Witt, M.; Mellor, I. R.;
Usherwood, P. N. R.; Jaroszewski, J. W.; Franzyk, H. Eur.
J. Org. Chem. 2003, 17, 3288.
Synlett 2009, No. 17, 2755–2760 © Thieme Stuttgart · New York

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