D. Jo¨nsson, A. Unde´n / Tetrahedron Letters 43 (2002) 3125–3128
3127
ondary amines, leaving the amine mono protected. The
cleavage is easily monitored by the strong yellow color
from the Mmd carbonium ions, which diminishes with
each wash. The reductive alkylation in step iii is a
robust reaction and secondary amines are normally
alkylated fast and in high yields at room temperature.
As a result of the steric hindrance of the Mmd group,
reductive alkylation with Fmoc-protected aminoalde-
hydes had to be performed three times at 40°C for 1 h
each, to ensure completion. The Fmoc group is then
cleaved with 20% piperidine in DMF for 30 min and
the synthetic cycle is repeated.
when branched aldehydes such as isobutyraldehyde
were used (data not shown). Branching of the
polyamine backbone is possible if amino aldehydes,
protected with protecting groups orthogonal to TFA
and piperidine, e.g. Alloc, are used.
Cleavage of the Fmoc group, step vi, yields a primary
amine and steps i–v can be repeated. Cleavage and
characterisation of product 2 was carried out as
described above. RP-HPLC and MALDI-TOF analyses
confirmed the correct product in 39% yield and 76%
purity.21
Synthesis of a selectively branched polyamine (Scheme
3): This strategy consists of a combination of Schemes
1 and 2 with use of either Mmd or Dod as the protect-
ing group depending on whether further derivatisation
of a particular nitrogen is desired. In step viii, where the
introduced Dod group is cleaved in the presence of the
Mmd group, completely selective cleavage of the Dod is
not possible. However, cleavage of the Mmd group can
be held at a low level by using 5% TFA in DCM for 15
min. In 5% TFA in DCM, approximately 0.1% of Mmd
is cleaved per minute, resulting in branching of the
polyamine backbone as a minor side reaction. This
problem should be minimized by using a slightly more
acid-stable protecting group (compared to the Mmd
group). The obtained product 3 was cleaved and char-
acterized as described above. RP-HPLC and MALDI-
TOF analyses confirmed the correct product in 40%
yield and 88% purity.21
Product 1, after final Fmoc deprotection, was incubated
in neat TFA for 2 h at 50°C. These conditions removed
the tertiary Mmd groups and cleaved the ester linkage
to the Merrifield resin. The TFA solution was filtered
and triethylsilane was added to decolorize the solution
by scavenging of the cations. After evaporation, the
products were dissolved in 0.1 M HCl (aq.) and
extracted with EtOAc. RP-HPLC19 (Fig. 2) and
MALDI-TOF20 analyses of the aqueous phase con-
firmed the correct product in high purity and 30%
yield.21
Synthesis of a completely branched polyamine (Scheme
2): Steps i–iii are the same as in the syntheses of
unbranched polyamines with the exception that Dod-Cl
is used instead of Mmd-Cl. The key step to obtain
branched polyamines is step iv, where cleavage of the
Dod group renders the secondary amine susceptible to
reductive alkylation. This cleavage, which is possible
only when the amine is tertiary, can be performed with
5% TFA in DCM for 15 min.
In this communication, we have presented novel proto-
cols for the syntheses of branched or unbranched
polyamines by repetitive synthesis utilizing benzhydryl-
based N-alkyl protective groups for semi-permanent
and temporary protection. The protocols should be
easy to implement in automated syntheses, as the chem-
istry used is robust and straightforward, and contribute
to the collection of methods for syntheses of polyamine
compounds. Further studies will be needed in order to
evaluate the relative merits of these and other strategies
for repetitive solid-phase synthesis of polyamines.
At this point, derivatisation is possible with most
aliphatic aldehydes and no problems were encountered
References
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Figure 2. Analytical RP-HPLC chromatogram of cleaved
product 1.19
8. Stromgaard, K.; Bjornsdottir, I.; Andersen, K.; Brierley,
M. J.; Rizoli, S.; Eldursi, N.; Mellor, I. R.; Usherwood,