Singapore – SwiSS ConneCtionS
CHIMIA 2015, 69, No. 3 143
Scheme 1. Concept
for small molecule
macrocycles.
and 2). RCM is ineffective with molecules
having basic centres as the catalyst proba-
bly co-ordinates with the basic nitrogens
rendering it inactive.[14] We reasoned that
neutralisation of the basic centre could
free the catalyst, hence an attempt to close
the macrocycle was made with HCl as an
additive. We were delighted to find that
the desired product had formed with good
trans:cis ratios albeit in low yield with the
1st generation catalyst (entry 3). An im-
provement was quickly realised with the
2nd generation catalyst affording a mod-
R
1
R
1
Z
A
R
2
R
2
Cyclize R and R via Z
1
2
through R M
C
N
N
B
N
C
N
H
A
N
N
H
B
RCM was attempted on 11 as described
generation
catalysts failed to afford any product un-
Results and Discussions
in Table 1. Grubbs 1st and 2nd
erate yield (entry 4). However, with TFA
as an additive the RCM proceeded most
Small Molecule Macrocycle SB1317
Kinase inhibitors which inhibit more
than one kinase have yielded better clinical
results than selective compounds as they
block more than one pathway critical for
tumour growth.[4] SB1317 not only inhib-
its key Cyclin-dependent kinases (CDKs)
but other kinases such as Janus kinase 2
(JAK2) and Fms-like tyrosine kinase 3
der normal conditions (Table 1, entries 1
smoothly, full conversion occurred in just
Scheme 2. Synthesis
Synthesis of LHS fragment of SB1317
of key intermediates
of SB1317.
OR
OR
Cl
Pd(PPh )
3 4
N
+
N
o
B(OH)
(FLT-3) that are implicated in the patho-
2
DME, 80 C
N
Cl
genesis of hematological malignancies.
While most of the CDK, JAK2 and Flt3
inhibitors in clinical trials have open chain
structures,[5] SB1317 is unusual in being
a macrocyclic compound exhibiting the
above spectrum of activities combined in
a single molecule.[6]
N
Cl
1
2a R= Bn
2b R= H
3a R= Bn 80%
3b R= H88%
Synthesis of RHS fragment of SB1317
Synthesis
N
CHO
The synthesis (Scheme 2) was initiated
Na(OAc) BH
3
from 2,4-dichloropyrimidine (1). Suzuki
N
H
+
coupling with boronic acid 2a afforded the
CH2Cl2,RT
95%
left-hand fragment, biaryl 3a in 80% yield.[7]
O N
O N
2
2
5
4
6
The right-hand half of SB1317 was con-
structed from 3-nitrobenzadehyde (4) and
N-methyl allylamine (5) via reductive am-
N
ination which proceeded smoothly afford-
ing allyl-benzylamine 6 in good yield.[8]
Aniline 7 was obtained in quantative yield
under SnCl2 reduction conditions.[9]
SnCl2
MeOH/CH2Cl2 (1:1), RT
H N
2
98%
Coupling of 3a with 7 was accom-
plished in the presence of HCl in n-butanol
(Scheme 3).[10] De-benzylation of 8 was at-
tempted under various standard conditions
but without much success.[11]Finally, it was
7
OBn
1N HCl
achieved in 50% yield using TMSI under
N
TMSI
normal reported conditions.[12] Alkylation
of the resulting phenol with homoallyl bro-
mide 10 proceeded efficiently in the pres-
ence of cesium carbonate to furnish RCM
precursor diene 11.[13]
3a
+ 7
o
n-BuOH, 100 C
MeCN, RT
30%
N
77%
N
N
H
8
To circumvent low yields associated
with the benzyl protecting group and to aid
scale-up activities, an atom-efficient syn-
thesis of 11, without the use of a protect-
ing group, was attempted. Suzuki coupling
of 1 with phenol 2b proceeded pleasing-
ly well (Scheme 2) to furnish 3b in 88%
yield. Alkylation of 3b with bromide 10
OH
O
N
N
Cs C 3
O
+
Br
N
10
N
o
D
MF,40 C
N
N
N
N
79%
H
H
afforded 13 in good yield (Scheme 4). The
9
11
coupling of the two halves 13 and 7 pro-
ceeded efficiently in the presence of HCl to
afford 11 in a much improved overall yield.
Scheme 3. Synthesis of key intermediate for RCM.
William, Anthony D.
