Syntheses of new polyamine dendrimer units via a tandem hydroformylation/reductive amination sequences

Article abstract of DOI:10.1016/j.tet.2004.06.129

Rh-catalyzed tandem hydroformylation/reductive amination sequences (hydroaminomethylation) starting from olefins are applied to the synthesis of new polyamine dendrimer units using both convergent and divergent strategies in solution as well as on solid support. Graphical abstract.

Full text of DOI:10.1016/j.tet.2004.06.129

Tetrahedron 60 (2004) 8465–8476
Syntheses of new polyamine dendrimer units via a tandem
hydroformylation/reductive amination sequences
*
Fikret Koc¸ and Peter Eilbracht
¨
Fachbereich Chemie, Organische Chemie I, Universitat Dortmund, Otto-Hahn-Strasse 6, 44221 Dortmund, Germany
Received 27 May 2004; revised 28 June 2004; accepted 30 June 2004
Available online 4 August 2004
Abstract—Rh-catalyzed tandem hydroformylation/reductive amination sequences (hydroaminomethylation) starting from olefins are
applied to the synthesis of new polyamine dendrimer units using both convergent and divergent strategies in solution as well as on solid
support.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
nitrile, which is reduced with CoCl2 and NaBH4 to give the
primary amine.12 As an example using this method Ganesh
and co workers13 synthesized pyrrolidyl polyamines with
dendrimer like structures to stabilize DNA duplexes and
triplexes. Other polyamine dendrimers were constructed
using similar methodologies.14 Alternatively Tomalia et
al.15 started from mesylated or tosylated aziridines to obtain
protected polyethylenimines, which can be deprotected by
acidic hydrolysis to yield the primary amine. Repetition of
this sequence leads to polyethyleneamine dendrimers.
Using these methods, polyamine dendrimers are also
obtained by functionalization of the outer spheres as well
as the core of preformed dendritic structures. The
functionalization of the outer spheres is well examined
and numerous examples are reported using various methods
of amine synthesis.16 Only rare examples, however, are
known for a core functionalization of dendrimers starting
from amphiphilic17 and dendrimer-like13 polyamines.
Putrescine, spermidine and spermine and many other
biogenic polyamines from plants and animals1,2 as polyca-
tions at physiological pH play an important role in various
biological processes such as cell regulation,3,4 or DNA
transfection.5 They interact with nucleic acids, proteins and
phospholipids and therefore affect DNA conformation and
aggregation as well as membrane5 or enzyme activitities.6
The concentration of these polyamines is strictly regulated.
Consequently selective analogues of naturally occurring
polyamines offer a wide range of therapeutic potential, e.g.
in treatment of cancer,7 AIDS8 or neurological diseases.9
Various methods for the synthesis and modification of linear
polyamines are available,10,11 among these alkylations
including standard procedures as well as the Mitsunobu
method, reduction of amides, nitriles, nitro compounds,
azides and Schiff bases, and amine syntheses via conjugate
addition. Polyamine modifications usually involve the
number and type of nitrogen atoms, the chain length
between these and changes in conformational rigidity by
introducing cyclic units. Instead of linear polyamine chains,
branched systems or highly branched systems like those in
dendrimers can be envisaged. Thus dendrimer-like poly-
amines are of high interest due to their structural similarities
with the natural products. A general strategy to synthesize
Recently hydroaminomethylation (Scheme 1), a rhodium-
catalyzed reaction sequence combining hydroformylation of
olefins and reductive amination of the resulting aldehydes
under the same conditions, has been used in the synthesis of
linear and cyclic polyfunctionalized amines including
polyamines and azamacroheterocycles.18 This method
should also be applicable to dendrimer synthesis offering
access to new structural features.
dendrimer like polyamines was developed by Vogtle.12 The
¨
sequence starts with an amine which is reacted with
acrylonitrile in a Michael-type addition to form a saturated
Keywords: Dendrimer units; Polyamines; Hydroformylation; Hydroamino-
methylation; Reductive amination; Rh-Catalysis; Solid support.
* Corresponding author. Tel: C49-231-7553858; fax: C49-231-7555363;
e-mail: peter.eilbracht@udo.edu
Scheme 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.129

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F. Koc¸, P. Eilbracht / Tetrahedron 60 (2004) 8465–8476
2. Results and discussion
principle numerous other linear, branched or cyclic
unsaturated amines can be used. In our model studies the
methallyl system was chosen, since there are no n/iso-
selectivity problems to complicate the initial hydroformyla-
tion step (Scheme 2). This step is followed by a
condensation of the aldehyde with a primary or secondary
amine already present in the reaction mixture to give imine
3 or enamine 30. Finally reduction of the intermediate imine
3 or enamine 30 under hydroformylation conditions forms
We here wish to report first applications of hydroamino-
methylation in the synthesis of dendrimer-type polyamines
both using convergent and divergent strategies. As building
block the easily obtainable methallylphthalimide (1)19 was
used as the olefinic reaction partner bearing a protceted
primary amino group which after deprotection provides the
branching point for the next dendrimer generation. In
Scheme 2.
Scheme 3.

F. Koc¸, P. Eilbracht / Tetrahedron 60 (2004) 8465–8476
8467
Scheme 4.
the saturated secondary or tertiary amine 4 resp. 40. Now
the phthalimides 4 resp. 40 can be deprotected by
hydrazinolysis to give a primary amine 5 which estab-
lishes the branching point for the next generation via
hydroaminomethylation and hydrazinolysis forming the
growing dendrimer.
in an autoclave under rhodium catalysis at 120 8C, 100 bar
(CO/H2; 1/1) in 72 h.
The phthalimide and benzyl protected compound 7 is
debenzylated under reductive conditions with Pd/C under
H2 atmosphere to give 8 in nearly quantitative yield. The
secondary amino group can then be attached to trihalide
cores using general substitution conditions.20 Thus alkyl-
ation with 1,3,5-tris(bromomethyl)benzene (9)21 results in
the polyamine dendrimer unit 10 in good yields (Scheme 3).
Using this method dendrimer units can be prepared by
divergent and convergent strategies. Following a con-
vergent strategy benzylamine (6) is converted under
hydroaminomethylation conditions with 2.0 equiv of
methallylphthalimide (1) to afford the orthogonally pro-
tected triamine 7 in very good yields. This step is performed
As an alternative, if using the p-methoxybenzyl protecting
group, the phenolic function can be deprotected and used for

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F. Koc¸, P. Eilbracht / Tetrahedron 60 (2004) 8465–8476
Scheme 5.
alkylation with a trihalide core 9. For this the PMB
protected triamine 12 is obtained via hydroaminomethyl-
ation of methallylphthalimide (1) in the presence of
p-methoxybenzylamine (11). For demethylation, compound
12 is treated with 1.5 equiv BBr3 at K78 8C.22
step piperazine (19) is converted in an autoclave under
rhodium catalysis at 120 8C, 100 bar (CO/H2; 1/1) in 48 h
with 2.0 equiv methallylphthalimide (1) to the solid diimide
derivative 20 in 95% yield. Free tetraamine 21 is obtained
after treatment of 20 with hydrazine at 50 8C. Interestingly,
piperazine compounds of type 21 are used as heterocyclic
analogues of spermine with pharmaceutical activities as
anticancer agents or N-methyl-D-aspartate (NMDA) recep-
tor modulators.23
Using a standard procedure in polyether dendrimer
synthesis20 the activated polyamine dendron 13 react with
the core 1,3,5-tris-(bromomethyl)benzene (9) in a nearly
quantitative yield to give the dendrimer unit 14 with a
polyamine scaffold around a polyether core (Scheme 4).
The hydroaminomethylation protocol used for compound
21 with 4.1 equiv of methallylphthalimide (1) results in the
tetraphthalimide 22 in 94% yield. Deprotection of 22 gives
the symmetric polyamine 23 in 84% yield. Whereas up to
this point the hydroaminomethylation steps proceeded with
excellent yields, the outcome of further conversions of
polyamine 23 with methallylphthalimide (1) under the usual
conditions of hydroaminomethylation is strongly dependent
on the amounts of catalyst used. With 0.3 mol% product 24
is obtained only in traces. The major product here is the
alcohol formed via reduction of the hydroformylation
product of methallylphthalimide (1). If lowering the catalyst
amount to 0.05 mol% the aldehyde reduction can be
suppressed and after 120 h reaction time the third generation
polyamine product 24 is obtained in 35% yield. Thus
reductive amination of the newly formed aldehyde with the
amine groups here appears to be slower than the aldehyde
reduction. Slowing down the hydroformylation by lowering
the catalyst concentration reverses the relative rates of
Following this strategy benzylamine (6) or p-methoxy-
benzylamine (11) can also be used as starting amine for
larger dendron units such as 17, obtained in an overall
yield of 68% from p-methoxybenzylamine (11). Depro-
tection of 12 with hydrazine nearly quantitatively gives
polyamine 15. The second hydroaminomethylation to
form 16 requires longer reaction times to give yields
higher than 90%. The hydrazinolysis of 16 gives the
second generation polyamine 17 in 81% yield. Whereas
for demethylation of 12 1.5 equiv BBr3 were sufficient,
the deprotection of 16 to give 18 needs 3 equiv BBr3 for
reasonable yields (Scheme 5).
Hydroaminomethylation procedures can also be used to
construct larger polyamine dendrimer units such as 24,
synthesized in five steps following a divergent strategy
starting from piperazine (19) as an diamine core. In the first

F. Koc¸, P. Eilbracht / Tetrahedron 60 (2004) 8465–8476
8469
Scheme 6.
aldehyde reduction and reductive amination to give the
desired product 24 (Scheme 6).
With this modification the yield of 24 can be optimized up to
61% (based on 23).
As an alternative route to achieve better yields of 24 the
stepwise version of hydroaminomethylation can be used.
For this first the aldehyde 25 is prepared in quantitative
yields (Scheme 7). Subsequently this aldehyde 25 is added
portion wise to the polyamine 23 and converted under
reductive amination conditions stepwise to the product 24.
Although in amine and polyamine syntheses on solid
support reductive amination is a widely used method only
few applications of hydroaminomethylation on solid sup-
port are reported.24 For polyamines attached to solid
supports either a preformed polyamine dendron can be
linked to a polymer25 or the dendritic structures are formed

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F. Koc¸, P. Eilbracht / Tetrahedron 60 (2004) 8465–8476
Scheme 7.
directly on the polymer. Here we wish to present a first
example of the latter method using the hydroaminomethyla-
tion/deprotection protocol. For this commercially available
Wang-resin was functionalized with Fmoc-L-proline using
the carbodiimide method and cleavage of the Fmoc group
with piperidine in DMF to give the NH-functionalized resin
29.
the first branching point for a growing dendron unit on
solid support (Scheme 8).
3. Conclusion
The results presented here show that hydroaminomethyla-
tion sequences can be used in solution or on solid support
following divergent or convergent strategies to give
polyamines in very good yields. This is demonstrated by
using phthalimide protected methallylamine building
blocks. According to earlier results, in principle, a variety
of nonbranched, branched or cyclic unsaturated amine units
can be used with high diversity. Similarly in the convergent
strategies various core units can be used. Thus hydro-
aminomethylation allowing higher diversities than other
established procedures is well suited as a new method for
the generation of tertiary amines as branching points in
dendrimer and solid phase synthesis.
The secondary amine function of resin 29 was alkylated
using 5 equiv methallylphthalimide (1) under hydro-
aminomethylation conditions. Mechanical destruction of
the polymer beads was minimized by slow stirring and
use of a glass insert in the autoclave. After workup the
result of hydroaminomethylation to give resin 30 in nearly
quantitative yield was confirmed by hydrolysis of the
linker function of a sample probe [with TFA/DCM/H2O
1
(49/49/2)] and H NMR and MS analysis of the cleavage
product. The NMR investigation revealed no detectable
diastereoselectivity during hydroformylation and forma-
tion of the new stereogenic centers. Resin 30 is
deprotected by hydrazinolysis at room temperature.
Treatment with 3 equiv H2NNH2$H2O in dry ethanol
results in resin 31 bearing a primary amine function in
95% yield. This step again was monitored by hydrolytic
cleavage of a sample probe and NMR and MS
investigation. Similarly a second hydroaminomethylation
sequence was found to proceed in very good yields to give
4. Experimental section
4.1. General remarks
All general chemicals were purchased from commercial
sources. The catalyst precursor [Rh(cod)Cl]2 was prepared
as previously described.26 1H and 13C NMR spectra were

F. Koc¸, P. Eilbracht / Tetrahedron 60 (2004) 8465–8476
8471
Scheme 8.
recorded at room temperature with Bruker DRX 400 and
DRX 500 spectrometers using CDCl3 as solvent and TMS as
an internal standard. The signals were assigned using APT,
HH- and CH-correlation techniques. Infrared spectra were
recorded with a Nicolet Impact 400 D spectrometer using
neat compounds as films between NaCl or KBr plates or
as disks with KBr. FAB-MS were recorded with a JEOL
JMS-SX 102A spectrometer. MALDI-TOF-MS was carried
out with a Voyager-DE Pro BioSpectrometerTM from
PerSeptive Biosystems using a a-Cyano-4-hydroxycin-
namic acid matrix. ESI-MS were recorded with a Finnigan
(LC-Q). Elemental analyses were performed with a Leco
CHNS-932 analyzer. Pressure reactions were carried out in
autoclaves (type A, 250 ml, PTFE insert) from Berghof,
Eningen and in a Parr stainless steel autoclave (250 ml).
After charging the autoclave with the starting material, the
catalyst precursor, the solvent, the reactor was flushed with
argon, subjected to hydrogen and carbon monoxide, and
heated to the required reaction temperature. Following the
reaction, the solvent was removed by rotary evaporation and
the catalyst was filtered off by passage through a small pad
of neutral alumina (activity III). The products were purified
by column chromatography on neutral alumina (activity III)
gel from Merck (Darmstadt) or on silica gel 60 (70–230
mesh ASTM) from Macherey-Nagel GmbH & Co. KG.
was added dropwise to a well-stirred suspension of
phthalimide (44.12 g, 300.00 mmol), anhydrous potassium
carbonate (84.00 g, 608.00 mmol) and methyltrioctyl-
ammoniumchloride (5 ml) in dimethylformamide (160 ml),
while maintaining the temperature at 20 8C in a water bath.
After 20 h stirring, the slurry was poured into water (500 ml),
the resulting precipitate was filtered, dried and crystallized
from ethanol to give pure 1 (59.88 g, 297.58 mmol, 99%),
1
mp 88 8C (lit. 87–88.27) H NMR (400 MHz, CDCl3): d
[ppm]Z1.77 (s, 3H), 4.22 (s, 2H), 4.81 (s, 1H), 4.89 (s, 1H),
7.65–7.90 (m, 4H). 13C NMR (100 MHz, CDCl3): d
[ppm]Z20.4, 43.2, 111.9, 123.3, 132.0, 134.0, 139.3,
168.1. IR (KBr), n~ [cmK1]Z1124, 1188, 1327, 1383,
1393, 1428, 1443, 1467, 1610, 1713, 1769, 2920, 2973,
3095.
4.2.2. Preparation of benzyl-bis[4-(N-phthalimidyl)-3-
methylbutyl]amine (7). Methallylphthalimide (1) (3.75 g,
18.64 mmol), Benzylamine (6) (1.00 g, 9.33 mmol) and
[Rh(cod)Cl]2 (15 mg, 0.33 mol%) were dissolved in 20 ml
of dry toluene and placed in the autoclave. The autoclave
was pressurized with 100 bar CO/H2 (1:1) and heated to
120 8C for 3 days. After cooling the solvent was removed in
a rotary evaporator and the crude mixture was purified by
column chromatography (neutral alumina activity III, ethyl
acetate/hexane 1:5) to give 4.75 g (8.84 mmol, 95%) 7 as a
viscous oil. 1H NMR (400 MHz, CDCl3): d [ppm]Z0.80 (d,
JZ6.5 Hz, 6H), 1.21–1.32 (m, 2H), 1.50–1.61 (m, 2H),
1.96–2.05 (m, 2H), 2.35–2.55 (m, 4H), 3.35–3.60 (m, 6H),
7.11–7.30 (m, 5H), 7.65–7.90 (m, 8H). 13C NMR
4.2. Convergent route
4.2.1. Preparation of N-methallylphthalimide (1).19
Freshly distilled methallylchloride (29.90 g, 330.00 mmol)

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F. Koc¸, P. Eilbracht / Tetrahedron 60 (2004) 8465–8476
(100 MHz, CDCl3): d [ppm]Z17.4, 17.5, 30.8, 31.5, 44.1,
44.1, 51.2, 51.3, 58.6, 123.1, 126.7, 128.1, 128.8, 132.0,
133.8, 139.7, 168.6. IR (Film, NaCl), n~ [cmK1]Z1157,
1171, 1188, 1264, 1318, 1335, 1366, 1380, 1397, 1434,
1453, 1467, 1641, 1705, 1715, 1773, 2856, 2873, 2930,
2960, 3028, 3060. HR-MS (FAB): for C33H35N3O4 calcd:
538.2706 [MCCH]C, found: 538.2680 [MCCH]C.
6.68–6.77 (m, 2H), 7.08–7.17 (m, 2H), 7.61–7.82 (m, 8H).
13C NMR (100 MHz, CDCl3): d [ppm]Z17.3, 17.4, 30.6,
30.6, 31.3, 31.4, 43.9, 44.0, 50.8, 50.9, 55.0, 57.6, 113.2,
113.5, 122.9, 129.8, 131.4 131.8, 133.6, 133.7, 158.4, 168.6.
IR (Film, NaCl), n~ [cmK1]Z1055, 1171, 1251, 1359, 1456,
1513, 1584, 1612, 1712, 1775, 2833, 2967, 3029, 3060,
3467, 3543. HR-MS (FAB): for C34H37N3O5 calcd:
568.2811 [MCCH]C, found: 568.2788 [MCCH]C.
4.2.3. Preparation of bis[4-(N-phthalimidyl)-3-methyl-
butyl]amine (8). A mixture of 7 (240 mg, 0.45 mmol) and
10% palladium on carbon (100 mg with 50 w.-% water) in
ethanol (120 mL) was stirred at room temperature under a
hydrogen atmosphere for 24 h at atmospheric pressure. The
catalyst was then filtered off and the organic phase was
4.2.6. Preparation of p-hydroxybenzyl-bis[4-(N-phthali-
midyl)-3-methylbutyl]amine (13).21 A solution of 12
(2.0 g, 3.52 mmol) in 50 mL of dry dichloromethane was
cooled to K78 8C, and BBr3 (1.32 g, 5.28 mmol in 10 ml
dichloromethane) was added. After the mixture was stirred
for 2 h at this temperature, the mixture was stirred for 18 h
at room temperature. The BBr3 was decomposed by addition
of 10 mL of MeOH. The solvents were removed in vacuo,
and the residue was suspended in water. The suspension was
extracted with ethyl acetate. The crude mixture were
purified by column chromatography (neutral alumina
activity III, ethyl acetate) to give 1.33 g (2.40 mmol, 68%)
1
evaporated to give 195 mg (0.44 mmol, 98%) 8. H NMR
(400 MHz, CDCl3): d [ppm]Z0.89 (d, JZ6.7 Hz, 6H),
1.27–1.37 (m, 2H), 1.45–1.57 (m, 2H), 1.91–2.28 (m, 3H),
2.50–2.75 (m, 4H), 3.40–3.57 (m, 4H), 7.52–7.81 (m, 8H).
13C NMR (100 MHz, CDCl3): d [ppm]Z17.5, 30.8, 34.3,
43.9, 47.4, 123.1, 131.9, 133.8, 168.5. IR (Film, NaCl), n~
[cmK1]Z912, 1054, 1088, 1336, 1362, 1381, 1399, 1435,
1456, 1468, 1684, 1714, 1772, 2253, 2809, 2874, 2932,
3155, 3400, 3466. HR-MS (FAB): for C26H29N3O4 calcd:
448.2236 [MCCH]C, found: 448.2235 [MCCH]C.
1
13 as a viscous brown oil. H NMR (400 MHz, CDCl3): d
[ppm]Z0.75–0.95 (m, 6H), 1.25–1.39 (m, 2H), 1.45–1.65
(m, 2H), 1.90–2.05 (m, 2H), 2.35–2.55 (m, 4H), 3.35–3.65
(m, 6H), 6.65–6.75 (m, 2H), 7.05–7.15 (m, 2H), 7.65–7.90
(m, 8H), (phenolic H is not visible). 13C NMR (100 MHz,
CDCl3): d [ppm]Z17.4, 17.5, 30.9, 31.2, 43.9, 44.0, 50.8,
57.8, 115.0, 123.2, 130.2, 131.9, 133.8, 154.9, 168.6. IR
(Film, NaCl), n~ [cmK1]Z1054, 1362, 1381, 1399, 1711,
1772, 2964, 3463. HR-MS (FAB): for C33H35N3O5 calcd:
554.2655 [MCCH]C, found: 554.2628 [MCCH]C.
4.2.4. Preparation of [3,5-bis({bis-[4-(N-phthalimidyl)-3-
methyl-butyl]amino}methyl)benzyl]-bis[4-(N-phthal-
imidyl)-3-methyl-butyl]amine (10). A mixture of the
1,3,5-tris(bromomethyl)benzene (9) (150 mg, 0.42 mmol),
8 (941 mg, 2.10 mmol), potassium carbonate (1.16 g,
8.41 mmol), and 18-Crown-6 (222 mg, 0.84 mmol) in dry
acetonitrile (100 ml) was refluxed under nitrogen for 3 days
with vigorous stirring. The mixture was then cooled and
evaporated to dryness under reduced pressure. Water
(100 mL) was added to dissolve inorganic salts. After
extraction with ethyl acetate and drying over sodium sulfate
solvents were removed. The crude mixture was purified by
column chromatography (silica gel, ethyl acetate) to give
333 mg (0.23 mmol, 55%) 10. 1H NMR (500 MHz, CDCl3):
d [ppm]Z0.92 (d, JZ6.7 Hz, 18H), 1.37–1.50 (m, 12H),
1.57–1.68 (m, 6H), 2.07–2.17 (m, 6H), 3.49–3.79 (m, 24H),
7.37–7.56 (m, 3H), 7.66–7.82 (m, 24H). 13C NMR
(125 MHz, CDCl3): d [ppm]Z17.6, 29.8, 36.9, 43.9, 53.0,
60.5, 123.1, 123.1, 123.2, 129.4, 132.0, 12.4, 133.9, 168.5,
168.7. IR (Film, NaCl), n~ [cmK1]Z1056, 1361, 1382, 1399,
1436, 1468, 1712, 1772, 2933, 2964. MALDI-TOF-MS: for
C87H93N9O12 calcd: 1456.70 [MCCH]C, found: 1456.29
[MCCH]C.
4.2.7. Preparation of (4-{3,5-bis[4-({bis-[4-(N-phthalimi-
dyl)-3-methyl-butyl]amino}methyl)-phenoxymethyl]
benzyloxy}benzyl)-bis[4-(N-phthalimidyl)-3-methyl-
butyl]amine (14). A mixture of the 1,3,5-tris(bromo-
methyl)benzene (9) (100 mg, 0.28 mmol), 13 (466 mg,
0.84 mmol), potassium carbonate (125 mg, 0.90 mmol),
and 18-crown-6 (23 mg, 0.09 mmol) in dry acetonitrile
(20 ml) was refluxed under nitrogen for 5 days with
vigorous stirring. The mixture was then cooled and
evaporated to dryness under reduced pressure. Water
(20 mL) was added to dissolve inorganic salts. After
extraction with ethyl acetate and drying over sodium sulfate
solvents were removed. The crude mixture was purified by
column chromatography (silica gel, ethyl acetate) to give
489 mg (0.28 mmol, 98%) 14. 1H NMR (400 MHz, CDCl3):
d [ppm]Z0.76–0.83 (m, 18H), 1.24–1.32 (m, 6H), 1.47–1.58
(m, 6H), 1.74–1.88 (m, 6H), 1.96–2.02 (m, 6H), 2.40–2.46
(m, 6H), 3.41–3.54 (m, 18H), 4.92–5.09 (m, 6H), 6.79–6.96
(m, 6H), 7.06–7.24 (m, 6H), 7.29–7.40 (m, 3H), 7.66–7.83
(m, 24H). 13C NMR (100 MHz, CDCl3): d [ppm]Z17.4,
17.5, 30.9, 31.4, 44.0, 44.1, 51.0, 57.7, 69.7, 70.4, 113.4,
114.4, 114.8, 123.1, 129.2, 130.0, 132.0, 133.8, 137.9,
151.3, 168.6. IR (Film, NaCl), n~ [cmK1]Z1053, 1239,
1359, 1381, 1398, 1434, 1467, 1510, 1611, 1712, 1771,
2930, 2959. ESI-MS: for C108H111N9O15 calcd: 1774.828
[MCCH]C, found: 1774.823 [MCCH]C.
4.2.5. Preparation of p-Methoxybenzyl-bis[4-(N-phthali-
midyl)-3-methylbutyl]amine (12). Methallylphthalimide
(1) (7.25 g, 36.00 mmol), p-methoxybenzylamine (11)
(2.47 g, 18.00 mmol) and [Rh(cod)Cl]2 (20 mg, 0.45 mol%)
were dissolved in 80 ml of dry toluene and placed in the
autoclave. The autoclave was pressurized with 100 bar
CO/H2 (1:1) and heated at 120 8C for 2 days. After cooling
the solvent was removed in a rotary evaporator and the
crude mixture was purified by column chromatography
(neutral alumina activity III, ethyl acetate/hexane 1:5) to
give 9.45 g (16.70 mmol, 93%) 12 as a viscous yellow oil.
1H NMR (400 MHz, CDCl3): d [ppm]Z0.77 (d, JZ6.5 Hz,
6H), 1.18–1.32 (m, 2H), 1.41–1.65 (m, 2H), 1.83–2.06 (m,
2H), 2.27–2.52 (m, 4H), 3.34–3.52 (m, 6H), 3.74 (s, 3H),
4.2.8. Preparation of N1-(4-Amino-3-methyl-butyl)-N1-p-
methoxybenzyl-3-methyl-butan-1,4-diamine (15). 12
(5.00 g, 8.80 mmol) and hydrazine hydrate (2.05 g,
40.95 mmol) in 50 ml dry ethanol were heated at 50 8C

F. Koc¸, P. Eilbracht / Tetrahedron 60 (2004) 8465–8476
8473
for 24 h. The suspension was cooled and filtered. The filtrate
was concentrated with a rotary evaporator. The residue was
dissolved in 50 ml 2 N NaOH and extracted 3 times with
100 ml ethyl acetate. The combined organic layers were
dried over MgSO4, filtered and concentrated to give 15
(2.66 g, 8.65 mmol, 98%) as a yellow oil. 1H NMR
(500 MHz, CDCl3): d [ppm]Z0.85 (d, JZ6.7 Hz, 6H),
1.12–1.30 (m, 6H), 1.31–1.60 (m, 4H), 2.28–2.71 (m, 8H),
3.34–3.59 (m, 2H), 3.75 (s, 3H), 6.75–6.96 (m, 2H), 7.15–
7.25 (m, 2H). 13C NMR (125 MHz, CDCl3): d [ppm]Z17.4,
17.5, 31.3, 34.5, 48.3, 48.4, 51.3, 55.0, 57.7, 113.3, 129.8,
131.7, 158.3. IR (Film, NaCl), n~ [cmK1]Z1038, 1170,
1247, 1300, 1376, 1463, 1511, 1611, 1662, 2853, 2923.
HR-MS (FAB): for C18H33N3O calcd: 308.2707 [MCCH]C,
found: 308.2717 [MCCH]C.
C38H77N7O calcd: 648.6268 [MCCH]C, found: 648.6243
[MCCH]C.
4.2.11. Preparation of {[p-hydroxybenzyl-({bis[4-(N-
phthalimidyl)-3-methyl-butyl]amino}methyl-butyl)
amino]methyl-butyl}-bis[(N-phthalimidyl)methyl-butyl]
amine (18).21 A solution of 16 (2.0 g, 1.71 mmol) in 50 mL
of dry dichloromethane was cooled to K78 8C, and BBr3
(1.29 g, 5.15 mmol in 10 ml dichloromethane) was added.
After the mixture was stirred for 2 h at this temperature, the
mixture was stirred for 18 h at room temperature. The BBr3
was decomposed by addition of 10 mL of MeOH. The
solvents were removed in vacuo, and the residue was
suspended in water. The suspension was extracted with
ethyl acetate. The crude mixture were purified by column
chromatography (neutral alumina activity III, first ethyl
acetate then methanol) to give 1.25 g (1.08 mmol, 63%) 18
4.2.9. Preparation of {[p-methoxybenzyl-({bis-[4-(N-
phthalimidyl)-3-methyl-butyl]amino}methyl-butyl)
amino]methyl-butyl}-bis[(N-phthalimidyl)methyl-
butyl]amine (16). Methallylphthalimide (1) (2.72 g,
13.50 mmol), 15 (1.00 g, 3.25 mmol) and [Rh(cod)Cl]2
(10 mg, 0.30 mol%) were dissolved in 30 ml of dry toluene
and placed in the autoclave. The autoclave was pressurized
with 100 bar CO/H2 (1:1) and heated at 130 8C for 3 days.
After cooling the solvent was removed in a rotary
evaporator and the crude mixture was purified by column
chromatography (neutral alumina activity III, ethyl acetate/
hexane 1:1) to give 3.50 g (3.00 mmol, 92%) 16 as a viscous
1
as a viscous brown oil. H NMR (500 MHz, CDCl3): d
[ppm]Z0.68–0.89 (m, 18H), 1.00–1.26 (m, 6H), 1.35–1.60
(m, 8H), 1.80–2.15 (m, 9H), 2.20–2.60 (m, 11H), 3.30–3.55
(m, 10H), 6.67–6.85 (m, 2H), 7.05–7.20 (m, 2H), 7.55–7.85
(m, 16H), (phenolic H is not visible). 13C NMR (125 MHz,
CDCl3): d [ppm]Z17.4, 17.4, 17.5, 17.5, 18.3, 29.8, 30.8,
30.9, 31.4, 31.4, 31.5, 44.0, 44.1, 51.7, 51.8, 56.9, 60.6,
61.6, 115.7, 122.8, 123.1, 131.3, 131.8, 133.8, 148.2, 168.5.
IR (Film, NaCl), n~ [cmK1]Z1053, 1087, 1189, 1359, 1380,
1398, 1434, 1467, 1514, 1614, 1716, 1772, 2804, 2872,
2930, 2958, 3440. HR-MS (FAB): for C69H83N7O9 calcd:
1154.6331 [MCCH]C, found: 1154.6372 [MCCH]C.
1
yellow oil. H NMR (400 MHz, CDCl3): d [ppm]Z0.68–
0.85 (m, 18H), 1.05–1.26 (m, 6H), 1.35–1.60 (m, 8H), 1.85–
2.10 (m, 8H), 2.15–2.45 (m, 12H), 3.30–3.55 (m, 10H), 3.71
(s, 3H), 6.67–6.78 (m, 2H), 7.07–7.16 (m, 2H), 7.56–7.80
(m, 16H). 13C NMR (100 MHz, CDCl3): d [ppm]Z17.4,
17.4, 17.5, 17.6, 18.4, 18.4, 29.6, 29.7, 30.8, 30.9, 31.6,
31.7, 32.0, 43.9, 44.0, 44.1, 44.1, 51.3, 51.3, 51.7, 51.8,
51.9, 55.0, 57.2, 60.3, 61.8, 113.2, 123.0, 129.8, 131.7,
131.9, 133.7, 158.1, 168.4. IR (Film, NaCl), n~ [cmK1]Z
1053, 1087, 1171, 1188, 1246, 1356, 1380, 1398, 1435,
1467, 1510, 1622, 1712, 1773, 2803, 2932. HR-MS (FAB):
for C70H85N7O9 calcd: 1168.6487 [MCCH]C, found:
1168.6488 [MCCH]C.
4.3. Divergent route
4.3.1. Preparation of 4-bis(4-N-phthalimido-3-methyl-
butyl)piperazine (20). Methallylphthalimide (1) (4.03 g,
20.00 mmol), piperazine (19) (862 mg, 10.00 mmol) and
[Rh(cod)Cl]2 (15 mg, 0.61 mol%) were dissolved in 50 ml
of dry toluene and placed in the autoclave. The autoclave
was pressurized with 100 bar CO/H2 (1:1) and heated at
120 8C for 2 days. After cooling the solvent was removed in
a rotary evaporator and the crude mixture was purified by
column chromatography (silica gel, ethyl acetate/hexane
1:5) to give 4.91 g (9.51 mmol, 95%) 20 as a white solid. 1H
NMR (400 MHz, CDCl3): d [ppm]Z0.91 (d, JZ6.7 Hz,
6H), 1.25–1.40 (m, 2H), 1.49–1.61 (m, 2H), 1.90–2.05 (m,
2H), 2.15–2.75 (m, 12H), 3.45–3.65 (m, 4H), 7.65–7.86 (m,
8H). 13C NMR (100 MHz, CDCl3): d [ppm]Z17.6, 31.4,
31.4, 44.1, 53.2, 56.3, 123.2, 132.0, 133.9, 168.6. IR (Film,
NaCl), n~ [cmK1]Z1053, 1161, 1354, 1379, 1399, 1433,
1466, 1610, 1725, 1771, 2688, 2814, 2879, 2937, 3463. EA:
for C30H36N4O4 calcd: CZ69.7%, HZ7.0%, NZ10.8%,
found: CZ69.7%, HZ7.0%, NZ10.5%. HR-MS (FAB):
for C30H36N4O4 calcd: 517.2815 [MCCH]C, found:
517.2782 [MCCH]C.
4.2.10. Preparation of N1-(4-Amino-3-methyl-butyl)-N1-
{4-[{4-[bis(4-amino-3-methyl-butyl)amino]-3-methyl-
butyl}-(4-methoxy-benzyl)amino]-2-methyl-butyl}-3-
methyl-butane-1,4-diamine (17). 16 (560 mg, 0.48 mmol)
and hydrazine hydrate (240 mg, 4.80 mmol) in 50 ml dry
ethanol and 5 ml dry dichloromethane were heated at 50 8C
for 48 h. The suspension was cooled and filtered. The filtrate
was concentrated with a rotary evaporator. The residue was
dissolved in 50 ml 8 N NaOH and extracted 10 times with
250 ml ethyl acetate. The combined organic layers were
dried over MgSO4, filtered and concentrated to give 17
(250 mg, 0.39 mmol, 81%) as a yellow-orange oil. 1H NMR
(400 MHz, CDCl3): d [ppm]Z0.50–0.98 (m, 18H), 0.99–
1.27 (m, 6H), 1.28–1.80 (m, 12H), 1.85–3.00 (m, 31H),
3.29–3.64 (m, 3H), 3.72 (s, 3H), 6.68–6.90 (m, 2H), 7.06–
7.22 (m, 2H). 13C NMR (100 MHz, CDCl3): d [ppm]Z17.4,
17.5, 17.5, 17.6, 18.4, 18.5, 29.7, 29.7, 31.2, 31.3, 31.9,
32.0, 34.4, 47.9, 48.2, 48.3, 48.4, 51.1, 51.3, 52.2, 55.0,
60.3, 61.7, 113.2, 129.8, 129.8, 131.6, 158.2. IR (Film,
NaCl), n~ [cmK1]Z1007, 1029, 1079, 1158, 1272, 1374,
1462, 1668, 2806, 2924, 3296. HR-MS (FAB): for
4.3.2. Preparation of 4-[4-(4-amino-3-methyl-butyl)
piperazin-1-yl]-2-methyl-butylamine (21). 4-Bis(4-N-
phthalimido-3-methyl-butyl)piperazine (20) (4.30 g,
8.32 mmol) and hydrazine hydrate (1.25 g, 24.46 mmol) in
100 ml dry ethanol were heated at 50 8C for 24 h. The sus-
pension was cooled and filtered. The filtrate was concen-
trated with a rotary evaporator. The residue was dissolved in
50 ml 8 N NaOH and extracted 3 times with 100 ml ethyl
acetate. The combined organic layers were dried over

8474
F. Koc¸, P. Eilbracht / Tetrahedron 60 (2004) 8465–8476
MgSO4, filtered and concentrated to give 4-[4-(4-amino-
3-methyl-butyl)-piperazin-1-yl]-2-methyl-butylamine
(21) (2.09 g, 8.15 mmol, 98%) as a yellow oil. H NMR
After cooling, the solvent was removed in a rotary
evaporator and the crude mixture was purified by column
chromatography (neutral alumina activity III, ethyl acetate/
hexane 10:1) to give 119 mg (51.60 mmol, 35%) compound
24 as a yellow wax. 1H NMR (400 MHz, CDCl3): d [ppm]Z
0.68–1.04 (m, 36H), 1.05–1.29 (m, 7H), 1.29–1.48 (m,
10H), 1.49–1.68 (m, 10H), 1.72–2.01 (m, 8H), 2.01–2.19
(m, 8H), 2.21–2.99 (m, 25H), 3.03–4.15 (m, 44H), 7.62–
7.77 (m, 32H). 13C NMR (100 MHz, CDCl3): d [ppm]Z
17.5, 17.9, 27.7, 29.8, 36.8, 36.9, 43.1, 43.8, 48.3, 60.3,
123.1, 131.8, 133.8, 168.6. IR (Film, KBr), n~ [cmK1]Z
1054, 1088, 1171, 1188, 1263, 1334, 1358, 1383, 1398,
1437, 1458, 1468, 1616, 1712, 1772, 2933, 2964, 3467.
ESI-MS: for C138H180N16O16 calcd: 2320.01 [MCCH]C,
found: 2319.40 [MCCH]C.
1
(500 MHz, CDCl3): d [ppm]Z0.75–0.85 (m, 6H), 1.09–
1.29 (m, 6H), 1.33–1.42 (m, 2H), 1.43–1.54 (m, 2H), 2.01–
2.58 (m, 16H). 13C NMR (125 MHz, CDCl3): d [ppm]Z
17.4, 31.2, 34.9, 48.9, 53.1, 56.4. IR (film, KBr), n~ [cmK1]Z
1123, 1160, 1273, 1310, 1336, 1373, 1463, 1558, 1568,
1601, 1667, 2809, 2870, 2949, 3291, 3363. HR-MS (FAB):
for C14H32N4 calcd: 257.2705 [MCCH]C, found: 257.2698
[MCCH]C.
4.3.3. Preparation of {4-[4-(4-{bis[4-(N-phthalimidyl)-3-
methyl-butyl]amino}-3-methyl-butyl)piperazin-1-yl]-2-
methyl-butyl}-bis[4-(N-phthalimidyl)-3-methyl-butyl]
amine (22). Methallylphthalimide (1) (1.75 g, 8.70 mmol),
21 (550 mg, 2.14 mmol) and [Rh(cod)Cl]2 (10 mg,
0.47 mol%) were dissolved in 30 ml of dry toluene and
placed in the autoclave. The autoclave was pressurized with
100 bar CO/H2 (1:1) and heated at 120 8C for 2 days. After
cooling the solvent was removed in a rotary evaporator and
the crude mixture was purified by column chromatography
(neutral alumina activity III, ethyl acetate/hexane 1:1) to
give 2.25 g (2.01 mmol, 94%) 22 as a viscous yellow oil. 1H
NMR (500 MHz, CDCl3): d [ppm]Z0.69–0.96 (m, 18H),
0.99–1.31 (m, 6H), 1.35–1.67 (m, 8H), 1.84–2.15 (m, 9H),
2.16–2.65 (m, 19H), 3.38–3.62 (m, 8H), 7.59–7.84 (m,
16H). 13C NMR (125 MHz, CDCl3): d [ppm]Z17.4, 17.5,
17.5, 17.6, 18.5, 29.8, 30.2, 30.8, 30.9, 31.6, 31.7, 32.1,
32.2, 44.0, 44.1, 44.1, 44.1, 51.9, 52.0, 52.0, 53.2, 56.7,
60.4, 123.1, 123.1, 131.9, 133.7, 133.8, 168.5. IR (Film,
KBr), n~ [cmK1]Z1269, 1356, 1379, 1398, 1414, 1467,
1614, 1716, 1772, 2808, 2873, 2930, 3058, 3467. HR-MS
(FAB): for C66H84N8O8 calcd: 1117.6490 [MCCH]C,
found: 1117.6489 [MCCH]C.
4.3.5.2. Method B. Preparation of phthalimidyl-3-
methyl-butyraldehyde (25). Methallylphthalimide (1)
(5.00 g, 24.85 mmol) and [Rh(cod)Cl]2 (15 mg,
0.24 mol%) were dissolved in 50 ml of dry toluene
and placed in the autoclave. The autoclave was
pressurized with 100 bar CO/H2 (1:1) and heated at
120 8C for 1 day. After cooling, the solvent was
removed in a rotary evaporator and the crude mixture
was purified by column chromatography (neutral
alumina activity III, ethyl acetate) to give 5.73 g
(24.80 mmol, 100%) 25 as a colorless wax. 1H NMR
(500 MHz, CDCl3): d [ppm]Z1.01 (d, JZ6.8 Hz, 3H),
2.21–2.66 (m, 3H), 3.58–3.65 (m, 2H), 7.68–7.88 (m,
4H), 9.72 (s, 1H). 13C NMR (125 MHz, CDCl3): d
[ppm]Z17.8, 30.0, 43.3, 48.5, 123.3, 131.9, 134.0,
168.6, 201.2.
Preparation of compound 24.180 mg (0.74 mmol) 25,
88 mg (0.15 mmol) 23 and [Rh(cod)Cl]2 (5.0 mg,
1.35 mol%) were dissolved in 10 ml of dry toluene placed
in the autoclave and stirred for 1 h at RT under Argon. The
autoclave is then pressurized with 50 bar H2 and 10 bar CO
and heated at 120 8C for 1 day. After cooling and expanding
the gases 180 mg (0.74 mmol) 25 is added and the mixture
is stirred again for 2 h at RT under Argon. At last step the
autoclave is pressurized again with 50 bar H2 and 10 bar CO
and heated at 120 8C for one more day. After cooling, the
solvent was removed in a rotary evaporator and the crude
mixture was purified by column chromatography (neutral
alumina activity III, ethyl acetate/hexane 10:1) to give
208 mg (0.09 mmol, 61%) compound 24 as a yellow wax.
1H NMR (400 MHz, CDCl3): d [ppm]Z0.68–1.04 (m,
36H), 1.05–1.29 (m, 7H), 1.29–1.48 (m, 10H), 1.49–1.68
(m, 10H), 1.72–2.01 (m, 8H), 2.01–2.19 (m, 8H), 2.21–2.99
(m, 25H), 3.03–4.15 (m, 44H), 7.62–7.77 (m, 32H). 13C
NMR (100 MHz, CDCl3): d [ppm]Z17.5, 17.9, 27.7, 29.8,
36.8, 36.9, 43.1, 43.8, 48.3, 60.3, 123.1, 131.8, 133.8, 168.6.
IR (Film, KBr), n~ [cmK1]Z1054, 1088, 1171, 1188, 1263,
1334, 1358, 1383, 1398, 1437, 1458, 1468, 1616, 1712,
1772, 2933, 2964, 3467.ESI-MS: for C138H180N16O16 calcd:
2320.01 [MCCH]C, found: 2319.40 [MCCH]C.
4.3.4. Preparation of N1-(4-amino-3-methyl-butyl)-N1-
[4-(4-{4-[bis(4-amino-3-methyl-butyl)amino]-3-methyl-
butyl}piperazin-1-yl)-2-methyl-butyl]-3-methyl-butane-
1,4-diamine (23). 22 (500 mg, 0.45 mmol) and hydrazine
hydrate (450 mg, 9.00 mmol) in 70 ml dry ethanol were
heated at 50 8C for 48 h. The suspension was cooled and
filtered. The filtrate was concentrated with a rotary
evaporator. The residue was dissolved in 50 ml 8 N NaOH
and extracted 10 times with 250 ml ethyl acetate. The
combined organic layers were dried over MgSO4, filtered
and concentrated to give 23 (224 mg, 0.38 mmol, 84%) as a
viscous yellow oil. 1H NMR (400 MHz, CDCl3): d [ppm]Z
0.68–0.93 (m, 18H), 0.99–1.20 (m, 7H), 1.26–1.80 (m,
23H), 1.91–2.10 (m, 4H), 2.13–2.44 (m, 19H), 2.44–2.67
(m, 5H). 13C NMR (100 MHz, CDCl3): d [ppm]Z17.4,
18.4, 18.9, 30.0, 31.2, 32.0, 34.4, 48.2, 48.3, 48.3, 48.4,
52.1, 53.1, 56.6, 60.2, 61.6. IR (Film, KBr), n~ [cmK1]Z
1007, 1029, 1079, 1158, 1272, 1374, 1462, 1668, 2806,
2923, 3290. HR-MS (FAB): for C34H76N8 calcd: 597.6271
[MCCH]C, found: 597.6287 [MCCH]C.
4.3.5. Preparation of compound 24.
4.4. Solid supported reactions
4.3.5.1. Method A. Methallylphthalimide (1) (0.30 g,
1.49 mmol), 23 (88 mg, 0.15 mmol) and [Rh(cod)Cl]2
(0.2 mg, 0.05 mol%) were dissolved in 10 ml of dry toluene
and placed in the autoclave. The autoclave was pressurized
with 100 bar CO/H2 (1:1) and heated at 100 8C for 5 days.
4.4.1. Preparation of L-proline-Wang-yl-ester (29).
4.4.1.1. Preparation of Fmoc-L-proline-Wang-yl-
ester. A solution of Fmoc-L-proline (556 mg, 1.65 mmol),

F. Koc¸, P. Eilbracht / Tetrahedron 60 (2004) 8465–8476
8475
diisopropylethylamine (DIPEA) (213 mg, 1.65 mmol), 1-
hydroxybenzotriazolehydrate (HOBt$H2O) (253 mg,
1.65 mmol), diisopropylcarbodiimide (DIPCDI) (208 mg,
1.65 mmol) in 5 ml dry DMF was added to Wang resin
(500 mg 0.82 mmol/g). The mixture was shaken at room
temperature for 24 h. The resin was filtered, washed with
DMF (5 times) and CH2Cl2 (5 times) and dried to constant
weight in vacuo.
4.4.6. Preparation of 1-(4-{bis[4-(N-phthalimidyl)-3-
methyl-butyl]amino}-3-methyl-butyl)proline-Wang-yl-
ester (32). Methallylphthalimide (1) (131 mg, 0.65 mmol),
31 (100 mg, 71.29 mmol) and [Rh(cod)Cl]2 (1 mg,
0.62 mol%) were dissolved in 80 ml of dry toluene and
placed with the glass inlet in the Parr autoclave. The
autoclave was pressurized with 100 bar CO/H2 (1:1) and
heated at 100 8C for 3 days. After cooling the resin was
filtered, washed with DMF (5 times), CH2Cl2 (5 times),
DMF (5 times), CH2Cl2 (5 times) and dried to constant
weight in vacuo.
4.4.1.2. Deprotection of Fmoc-L-proline-Wang-yl-
ester on solid support to form 29. A suspension of the
obtained Fmoc-L-proline-Wang-yl-ester (550.0 mg) in
DMF/piperidine (4:1, 6 ml) was shaken at room temperature
for 30 min and filtered, washed with DMF (5 times) and
CH2Cl2 (5 times) and dried to constant weight in vacuo.
4.4.7. Confirmation of the structure of 1-(4-{bis[4-(N-
phthalimid-yl)-3-methyl-butyl]amino}-3-methyl-butyl)-
proline (32). A suspension of 32 (103 mg, 56.20 mmol) in
TFA/CH2Cl2/H2O (49:49:2.5 ml) was shaken at room
temperature for 60 min. The resin was filtered and the
filtrate was evaporated in vacuo to give 1-(4-{bis-[4-(N-
phthalimid-yl)-3-methyl-butyl]amino}-3-methyl-butyl)-
proline (30 mg, 47.56 mmol, 85%) as a diastereomeric
mixture. 1H NMR (400 MHz, CDCl3): d [ppm]Z0.76–1.01
(m, 9H), 1.12–1.30 (m, 2H), 1.41–1.59 (m, 3H), 1.63–1.81
(m, 3H), 1.84–2.10 (m, 6H), 2.65–2.77 (m, 2H), 2.81–2.92
(m, 2H), 2.97–3.14 (m, 4H), 3.19–3.35 (m, 1H), 3.39–3.52
(m, 3H), 3.57–3.65 (m, 1H), 4.20–4.38 (m, 1H), 7.77–8.00
(m, 8H), (hydrogen of carboxyl group is not visible). HR-MS
(FAB): for C36H46N4O6 calcd: 630.3463 [MCCH]C,
found: 630.3417 [MCCH]C.
4.4.2. Preparation of 1-[4-(N-phthalimidyl)-3-methyl-
butyl]proline-Wang-yl-ester (30). Methallylphthalimide
(1) (433 mg, 2.15 mmol), 29 (510 mg, 387.06 mmol) and
[Rh(cod)Cl]2 (2 mg, 0.38 mol%) were dissolved in 80 ml of
dry toluene and placed with the glass inlet in the Parr
autoclave. The autoclave was pressurized with 100 bar
CO/H2 (1:1) and heated at 100 8C for 3 days. After cooling
the resin was filtered, washed with DMF (5 times), CH2Cl2
(5 times), DMF (5 times), CH2Cl2 (5 times) and dried to
constant weight in vacuo.
4.4.3. Confirmation of the structure of 1-[4-(N-phthali-
midyl)-3-methyl-butyl]proline-Wang-yl-ester (30). A sus-
pension of 30 (90 mg, 58.73 mmol) in TFA/CH2Cl2/H2O
(49:49:2.5 ml) was shaken at room temperature for 60 min.
The resin was filtered and the filtrate was evaporated in
vacuo to give a diastereomeric mixture (1:1) of 1-[4-(N-
phthalimidyl)-3-methyl-butyl]proline (19 mg, 57.51 mmol,
References and notes
1
98%). H NMR (400 MHz, CDCl3): d [ppm]Z0.87–1.02
1. Morris, D. R.; Marton, L. J. Polyamines in Biology and
Medicine; Marcel Dekker: New York, 1981.
2. Ganem, B. Acc. Chem. Res. 1982, 15, 290.
(m, 3H), 1.52–1.89 (m, 2H), 1.95–2.21 (m, 3H), 2.25–2.58
(m, 2H), 3.05–3.24 (m, 1H), 3.27–3.63 (m, 4H), 3.92–4.27
(m, 2H), 7.62–7.89 (m, 4H), 9.15 (bs, 1H). HR-MS (FAB):
for C18H22N2O4 calcd: 331.1658 [MCCH]C, found:
331.1673 [MCCH]C.
3. Tabor, C. W.; Tabor, H. Annu. Rev. Biochem. 1984, 53, 749.
4. (a) Pegg, A. E. Cancer Res. 1988, 759. (b) Pegg, A. E.
Biochem. J. 1986, 234, 249. (c) Schuber, F. Biochem. J. 1989,
260, 1.
4.4.4. Preparation of 1-(4-amino-3-methyl-butyl)proline-
Wang-yl-ester (31). A suspension of 30 (500 mg,
326.18 mmol), hydrazine hydrate (76 mg, 1.50 mmol) in
3 ml dry ethanol was shaken at room temperature for 48 h.
The resin was filtered and washed with DMF (5 times),
CH2Cl2 (5 times), DMF (5 times), CH2Cl2 (5 times),
diethylether (5 times), methanol (5 times), diethylether (5
times) and dried to constant weight in vacuo.
5. (a) Henner, W. D.; Kleber, I.; Benzinger, R. J. Virol. 1973, 12,
741. (b) Brissault, B.; Kichler, A.; Guis, C.; Leborgne, C.;
Danos, O.; Cheradame, H. Bioconjugate Chem. 2003, 14, 581.
6. Flink, I.; Pettijohn, D. E. Nature 1975, 253, 62.
7. (a) Martin, L. J.; Pegg, A. E. Annu. Rev. Pharmacol. Toxicol.
1995, 33, 55. (b) Cohen, S. S. A Guide to the Polyamines,
1998, Oxford University Press, Oxford.
8. Bergeron, R. J.; Yao, G. W.; Yao, H.; Weimar, W. R.; Sninsky,
R. B.; Feng, Y.; Wu, Q.; Gao, F. J. Med. Chem. 1996, 39, 2461.
9. (a) Johnson, T. D. Trends Pharmacol. Sci. 1996, 17, 22. (b)
Williams, K. Neurosci. Lett. 1995, 184, 181. (c) Bergeron,
R. J.; Weimar, W. R.; Wu, Q.; Austin, J. K.; McManis, J. S.
J. Med. Chem. 1995, 38, 425.
4.4.5. Confirmation of the structure of 1-(4-amino-3-
methyl-butyl)proline-Wang-yl-ester (31). A suspension of
31 (94 mg, 67.03 mmol) in TFA/CH2Cl2/H2O (49:49:2.5 ml)
was shaken at room temperature for 60 min. The resin was
filtered and the filtrate was evaporated in vacuo to give a
diastereomeric mixture (1:1) of 1-(4-amino-3-methyl-
butyl)proline (13 mg, 64.91 mmol, 97%). 1H NMR
(400 MHz, CDCl3): d [ppm]Z0.80–1.10 (m, 3H), 1.37–
1.63 (m, 2H), 1.63–1.96 (m, 4H), 2.30–2.45 (m, 2H), 2.56–
2.92 (m, 2H), 2.94–3.21 (m, 2H), 3.21–3.41 (m, 1H), 3.44–
3.69 (m, 1H), 4.21–4.40 (m, 1H), (hydrogen of carboxyl
group is not visible). HR-MS (FAB): for C10H20N2O2 calcd:
201.1603 [MCCH]C, found: 201.1596 [MCCH]C.
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