3.2 Designing for Mainly Dual Activity
67
delocalisation in the phenoxide ion, can then be functionalised further through Oalkylation reactions under basic conditions. O-Arylation reactions however required
a pre-reduction of berberrubine with NaBH 4 to the terahydroderivative which could
then be smoothly O-arylated via a copper-catalysed reaction with aryl iodides. Sudsequent re-oxidation with I 2 /DMSO then gave the substituted quaternary ammonium
iodide salt system in good yields (Teng et al. 2019). Chen and colleagues have also
reported on additional O-alkylation and O-acylation reactions of berberrubine and
tetrahydroberberrubine respectively to access further 9-substituted derivatives (Chen
et al. 2017). O-Propargylation at the 9-hydroxy position also proceeds smoothly and
the alkyne group then provides a useful handle for triazole-based linking of other
moieties, increasing the versatility of this chemistry. For instance, this reaction has
been used to access a range of such triazolyl derivatives substituted with various arylsulfonamide groups which displayed good antiplasmodial activity in vitro against
Plasmodium falciparum (Batra et al. 2018).
The C12 position in berberine is reactive towards electrophilic substitution such
as bromination (Zhou et al. 2017) and nitration (Wang et al. 2020) providing direct
access to groups which can also be elaborated further via selective synthetic methods
either still at the ring quaternary ammonium oxidation level or at the tetrahydroberberine level and then later re-oxidation (Wang et al. 2020). Electrophilic substitution
at C12 on berberrubine to afford a range of Mannich base derivatives in moderate to
good yields has also been described (Li et al. 2014b; Mistry et al. 2017).
Extensive chemistry is also accessible through the C13 position in the dihydroberberine derivative of berberine (Tang et al. 2017), or via 8-substituted dihydroberberines, as illustrated by C13 alkylation of the enamine moiety and subsequent reformation of the berberine quaternary ammonium ion structure (Ball et al. 2006;
Bremner and Kelso 2010; Park et al. 2006; Bhowmik et al. 2014). In one application of this, 8-allyldihydroberberine has been used in the enamine arylalkyation
step followed by a [3,3]-sigmatropic rearrangement then a retro-ene reaction to give
the 13-substituted berberine salt directly in a one pot thermal reaction sequence
(Bremner and Kelso 2010). The enamine moiety in 8-acetonyldihydroberberine can
also be hydroxylated with KMnO 4 and then converted on acid-catalysed elimination
of acetone to 13-hydroxyberberine. The synthesis of 13-substituted derivatives of
berberine, including 13-hydroxyberberine, is described by Tang et al. (2017). 13Hydroxyberberine as the phenolbetaine is amenable to O-alkylation of the 13-oxy
functionality (Samosorn et al. 2009) affording access to potential new derivatives
incorporating other useful functional groups.
For other chemistry associated with 13-substituted berberines and some 8-oxo
analogues, including transformation skeletally to the 7/5 series, see Zhou and Tong
(2016). Other 13-substituted 8,13-dihydroberberines, still with a quaternary iminium
nitrogen present in the ring, can also be readily accessed after enamine alkylation reactions. Fully reduced 13-substituted tetrahydroberberines can also be made
facilely from these precursors by sodium borohydride reduction (Mari et al. 2020).
The products in this case were investigated for their antiproliferative activity in vitro
on NCI-H1975 lung cancer cells.
67
delocalisation in the phenoxide ion, can then be functionalised further through Oalkylation reactions under basic conditions. O-Arylation reactions however required
a pre-reduction of berberrubine with NaBH 4 to the terahydroderivative which could
then be smoothly O-arylated via a copper-catalysed reaction with aryl iodides. Sudsequent re-oxidation with I 2 /DMSO then gave the substituted quaternary ammonium
iodide salt system in good yields (Teng et al. 2019). Chen and colleagues have also
reported on additional O-alkylation and O-acylation reactions of berberrubine and
tetrahydroberberrubine respectively to access further 9-substituted derivatives (Chen
et al. 2017). O-Propargylation at the 9-hydroxy position also proceeds smoothly and
the alkyne group then provides a useful handle for triazole-based linking of other
moieties, increasing the versatility of this chemistry. For instance, this reaction has
been used to access a range of such triazolyl derivatives substituted with various arylsulfonamide groups which displayed good antiplasmodial activity in vitro against
Plasmodium falciparum (Batra et al. 2018).
The C12 position in berberine is reactive towards electrophilic substitution such
as bromination (Zhou et al. 2017) and nitration (Wang et al. 2020) providing direct
access to groups which can also be elaborated further via selective synthetic methods
either still at the ring quaternary ammonium oxidation level or at the tetrahydroberberine level and then later re-oxidation (Wang et al. 2020). Electrophilic substitution
at C12 on berberrubine to afford a range of Mannich base derivatives in moderate to
good yields has also been described (Li et al. 2014b; Mistry et al. 2017).
Extensive chemistry is also accessible through the C13 position in the dihydroberberine derivative of berberine (Tang et al. 2017), or via 8-substituted dihydroberberines, as illustrated by C13 alkylation of the enamine moiety and subsequent reformation of the berberine quaternary ammonium ion structure (Ball et al. 2006;
Bremner and Kelso 2010; Park et al. 2006; Bhowmik et al. 2014). In one application of this, 8-allyldihydroberberine has been used in the enamine arylalkyation
step followed by a [3,3]-sigmatropic rearrangement then a retro-ene reaction to give
the 13-substituted berberine salt directly in a one pot thermal reaction sequence
(Bremner and Kelso 2010). The enamine moiety in 8-acetonyldihydroberberine can
also be hydroxylated with KMnO 4 and then converted on acid-catalysed elimination
of acetone to 13-hydroxyberberine. The synthesis of 13-substituted derivatives of
berberine, including 13-hydroxyberberine, is described by Tang et al. (2017). 13Hydroxyberberine as the phenolbetaine is amenable to O-alkylation of the 13-oxy
functionality (Samosorn et al. 2009) affording access to potential new derivatives
incorporating other useful functional groups.
For other chemistry associated with 13-substituted berberines and some 8-oxo
analogues, including transformation skeletally to the 7/5 series, see Zhou and Tong
(2016). Other 13-substituted 8,13-dihydroberberines, still with a quaternary iminium
nitrogen present in the ring, can also be readily accessed after enamine alkylation reactions. Fully reduced 13-substituted tetrahydroberberines can also be made
facilely from these precursors by sodium borohydride reduction (Mari et al. 2020).
The products in this case were investigated for their antiproliferative activity in vitro
on NCI-H1975 lung cancer cells.