Biomedical Engineering Reference
In-Depth Information
O
HO
O
O
O
N
O
N
N
N
N
N
N
H
H
i -Bu
N
N
O
O
O
N
H
N
N
H
HO
N
Me
Ph
H
Me
H
O
Benzomalvin A
(-)-Asperlicin
Sclerotigenin
Circumdatin C
NH 2
O
R 2
R 1
OMe
CO 2 H
OMe
. HCl
3
NH 2
NH 2
O
F-TMB
CHO
NaBH(OAc) 3
EDCI, NMP
R 1
HN
R 2
OMe
N
CO 2 Me
DIPEA, AcOH
F-SPE
63-95%
F-SPE
50-70%
C 8 F 17
O
OMe
O
R 1
F-TMB
1
4
2
R 2
N 3
O
H
N
O
Me
n -BuLi, THF
-78 to 25°C
PhN
N
R 1
R 3
R 2
O
Ph 3 P
OLi
O
N
N
THF, reflux, 1 h
F-SPE
42-88%
N 3
F-SPE
F-TMB
F-TMB
O
R 3
R 1
COCl
5
7
6
R 2
R 2
O
OMe
O
TFA/DMS/H 2 O
(90:5:5)
N
N
R 3
O
R 3
O
C 8 F 17
N
N
HN
N
O
OMe
F-SPE
HPLC
50-70% from 7
F-TMB
R 1
R 1
F-TMB
8
9 (144 analogues)
SCHEME 10.2 Fluorous TMB-facilitated synthesis of sclerotigenin analogues.
indolylborons with dichloro- or dibromo-substituted heterocyclic compounds
(Scheme 10.3) [22].
The fluorous sulfonyl linker was introduced to 3-iodoindole under basic
conditions, followed by a Pd-catalyzed borylation to give fluorous boronate 3 .Pd-
catalyzed cross-coupling of 10 with dibromo-substituted central ring 11 using Tl 2 CO 3
as a base afforded the mono-coupling product 12 . The latter was then subjected to a
second cross-coupling with TIPS-protected indolylboron 13 followed by the cleavage
of the TIPS to give 14 . Methylation and sequential Mg-promoted fluorous tag
cleavage afforded bis-indole 15 . The fluorous intermediates in the multistep synthesis
were finally purified by F-SPE. This protocol was used to make symmetrical and
nonsymmetrical bis-indolyl-substituted heterocyclic scaffolds by double cross-
coupling reactions of indolylborons with a variety of dihalo central rings.
As the fluorous sulfonyl linker has no acidic protons to eliminate “HF”, it is
stable under lithiation conditions. Kondo and coworkers applied this strategy in the
synthesis of yuehchukene, a dimeric indole alkaloid natural product that possesses
antifertility and estrogenic activities [23]. Fluorous sulfonyl linker attached indole 16
was thus treated with mesityllithium and then reacted with monoterpenoid aldehyde
to afford alcohol
17
(Scheme 10.4)
[24]. Oxidization of
the latter with
2-iodoxybenzoic acid (IBX) followed by a BF 3
OEt 2 -catalyzed cyclization gave
 
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