Synthesis of 8-azaprotosappanin A derivatives via intramolecular palladium-catalyzed ortho C-H activation/C-C cyclization and their antibacterial activity

Article abstract of DOI:10.1039/c6ob02707e

A novel synthetic protocol for the construction of eight-membered heterocycles by intramolecular palladium-catalyzed ortho C-H activation/C-C cyclization was proposed. With protosappanin A as the lead compound, 25 derivatives of 8-azaprotosappanin A were prepared in good yields by this protocol. Besides, a plausible reaction mechanism of the intramolecular cyclization was proposed. This strategy could be widely used in the synthesis of some natural products and drugs with large heterocycles due to the fast reaction rate and the mild conditions. In vitro antimicrobial activities of the synthesized compounds were assessed against the strains of Gram-positive bacteria and linezolid and ciprofloxacin were selected as the standard drugs. Some of the synthesized compounds were found to have excellent antibacterial activities.

Full text of DOI:10.1039/c6ob02707e

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Synthesis of 8-azaprotosappanin A derivatives via intramolecular
palladium-catalyzed ortho C–H activation/C–C cyclization and
antibacterial activity
Received 00th January 20xx,
Accepted 00th January 20xx
Xuan Zhou, Wanyong Fu, Hongshuo Jiang, Chenglong Wang, Chao Ju, Wenyi Chu*and Zhizhong
Sun*
DOI: 10.1039/C6CC01149G
www.rsc.org/
A novel synthetic protocol for the construction of eight-numbered which is widely found in natural products and important
heterocycle by intramolecular Palladium-catalyzed ortho C-H intermediates in organic synthesis and drug synthesis. The
activation/C-C cyclization was proposed. With protosappanin A as dibenzoxazinone structure analogues have potential
the lead compoundm, 25 derivatives of 8-azaprotosappanin A antibacterial,11 histone deacetylase inhibition,12 HIV-1 reverse
were prepared in good yields by this protocol. Besides, a plausible transcriptase inhibition13 and other activities.
reaction mechanism of the intramolecular cyclization was
OH
proposed. This strategy could be widely used in the synthesis of
2
11
R'
1
12
R"
10
9
HO
some natural products and drugs with large heterocycle due to the
fast reaction rate and the mild condition. In vitro antimicrobial
activities of the synthesized compounds were assessed against
strains of Gram-positive bacteria and select the linezolid and
ciprofloxcin as standard drugs. Some of the synthesized
compounds were found to have excellent antibacterial activities.
OH
3
4
O
5
8
O
NH
7
6
O
O
8-azaprotosappanin A derivatives
Protosappanin A
Scheme 1 Design of 8-azaprotosappanin A derivatives with Protosappanin A as
lead compound.
Benzoheterocyclic fragment is a key structural motif in some
natural products,1 which are often used as lead compounds in
drug designing and screening due to their good biological
activities.2 Protosappanin A, as a natural product containing
dibenzoheterocyclic fragment, was found in the extraction of
Caesalpinia in 19863 and first total synthesized by our research
group in 2016.4 Some studies of biological activities indicated
that Protosappanin A has anti-bacterial,5 inhibition of xanthine
The biaryl skeleton of 8-azaprotosappanin A derivatives is
often constructed by C−C bond cross coupling reaction. For the
synthesis of 8-azaprotosappanin A derivatives, one of the most
important steps is the construction of dibenzoxazinone via
intramolecular cyclization.14 However, the previous cyclization
methods were mainly used to synthesize five, six or seven-
membered rings.15 The 8-azaprotosappanin
A derivatives
oxidase,6
anti-inflammation,7
anti-HIV-1,8
organ
containing an eight-membered ring were not easy to be
obtained by intramolecular cyclization. The present methods
to synthesize this complex dibenzoheterocyclic fragment
always need complicated reaction process, harsh reaction
conditions and get low product yields.
transplantation immunosuppressive,9 vasorelaxant activity10
and so on. In view of the great value of Protosappanin A, more
extensive exploration on its derivatives would be interesting
and meaningful.
The dibenzoheterocyclic fragment in Protosappanin A
belongs to a biaryl skeleton (Scheme 1). We attempted to
transform the heterocyclic fragment of Protosappanin A to
design its derivatives. An imino group (-NH-) was introduced to
replace the methylene group (C-8) of the heterocyclic
fragment to get 8-azaprotosappanin A (Scheme 1). The 8-
azaprotosappanin A contains a dibenzoxazinone fragment
In recent years, the transition-metal-catalyzed C−H coupling
has emerged as a powerful and ideal method for the
construction of carbon-carbon skeleton.16 Transition-metal-
catalyzed C(sp2)−H coupling17 is an improved method
preceding traditional cross-couplings18 and direct arylations.19
This method makes it possible to synthesize some large ring
compounds directly, which attracts more interests in organic
synthesis.
In this manuscript, a Pd-catalyzed ortho C−H activation/C−C
cyclization for intramolecular C–H arylation strategy, as an
economical, green and efficient approach for the synthesis of
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large ring compounds, was applied to synthesize a serial of 8- yield was 51% and 84% (Table 1, entries 3 and 23). When the
reaction temperature reached to 140 oC, the yield was 65%
(Table 1, entry 24). Obviously, there was no product detected
azaprotosappanin A derivatives.
In order to obtain 8-azaprotosappanin A derivatives, the
steps of this strategy was detailed in Scheme 2. Firstly, α-(2- when the reaction temperature increased to reflux
o
1 were obtained in good yields temperature 166 C (Table 1, entry 25), because high reaction
iodoaryloxy)-N-arylacetamides
by the continuous reactions in N, N-dimethylacetamide (DMAC) temperature was helpful for iodine removal reaction and not
in the presence of K2CO3 including acylation of arylamines with conducive to the cyclization reaction.
chloroacetyl chloride at 0 oC20 and etherification of using 2-
Table 1 Optimization of reaction conditionsa
o
iodo-phenols at 80 C.21 Then, compounds
1 were used as the
key intermediate to synthesize 8-azaprotosappanin
A
derivatives 2 through intramolecular cyclization of Pd-
catalyzed ortho C−H activation/C−C cyclization.
Entry Catalyst
Oxidant Solvent Temp(°C) Yield(%)b
1
2
Pd(PPh3)4
Pd(OAc)2
Pd(TFA)2
AgTFA
AgTFA
AgTFA
DMAC
DMAC
DMAC
120
120
120
63
71
Scheme 2 Synthesis of 8-azaprotosappanin A derivatives.
13
84, 74 c, 84d
α-(2-Iodophenoxy)-N-phenylacetamide 1u was chosen as
the model substrate to investigate the reaction conditions of
ortho C−H activation/C−C cyclization. The reaction conditions
such as catalyst, oxidant, solvent and temperature were
4
Pd(PPh)3Cl2
RuCl3
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgOAc
AgF
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMF
120
120
66
61
50
-
5
6
Ru(PPh3)3
Cu(TFA)2
Cu(OAc)2
-
120
7
120
screened. The experimental results were shown in Table 1
.
For the ortho C-H activation, the catalyst plays a crucial role.
Firstly, different catalysts such as Pd(0), Pd(II), Ru(III), Ru(0)
and Cu(II) salts were screened respectively. The results showed
8
120
-
9
120
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
120
74
62
68
47
43
-
that Pd(TFA)2
Pd(OAc)2, Pd(PPh)3Cl2 and Pd(PPh3)4
While RuCl3 and Ru(PPh3)3 as catalysts exhibited low catalytic
activity with the yields of 61% and 50%, respectively (Table 1
(
Table 1, 84% for entry 3) was superior to
120
(
Table 1, entries 1-4).
Ag2O
120
,
Cu(OAc)2
K2S2O8
DDQ
120
entries 5-6). Also, Cu(TFA)2 and Cu(OAc)2 as catalyst or without
catalyst, no desired product was obtained (Table 1, entries 7-
9).
120
120
-
120
-
For the ortho C−H activation, the oxidant is also an
important factor. The effect of different silver compounds such
as AgTFA, AgOAc, Ag2O and AgF was examined. AgTFA gave a
good yield of 84%, while AgOAc, Ag2O and AgF gave 74%, 68%
and 62%, respectively (Table 1, entries 3 and 10-12). Cu(OAc)2
and K2S2O8 produced an inferior result (Table 1, entries 13-14).
DDQ as the oxidant or without oxidant, the reaction didn’t
occur (Table 1, entries 15-16).
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
120
73
70
65
58
37
trace
51,
65
-
NMP
120
DMSO
CH3CN
dioxane
THF
120
reflux
reflux
reflux
100
DMAC
DMAC
DMAC
Different solvents such as N,N-Dimethylformamide (DMF),
1,4-dioxane, acetonitrile (CH3CN), N-Methylpyrolidone (NMP),
N,N-Dimethylacetamide (DMAC), Dimethylsulfoxide (DMSO)
140
reflux
and Tetrahydrofuran (THF) were also investigated (Table 1
,
a
Reaction conditions: (0.4 mmol), catalyst (15 mol%), oxidant (2eq) and additive K2CO3
b
entries 3 and 17-22). For the amide solvents, DMF, DMAC and
NMP were better than DMSO (Table 1, entries 3 and 17-19).
The low-boiling point solvents gave the reaction a low yield
(2 eq) in solvent (6 mL) for 10 hours. Isolated yields after silica gel column
chromatography. c For 8 h. d For 12 h.
Based on the above research, the optimized condition for
C–H activation/C–C cyclization reaction was 15 mol% Pd(TFA)2
as the catalyst, 2 equiv of AgTFA as the oxidant and 2 equiv of
K2CO3 as the additive in DMAC at 120 oC for 10 hours.
(
Table 1, entries 20-22). The results showed that DMAC was
efficient for the synthesis of 2u in excellent yields (Table 1
entry 3).
Simultaneously, the reaction time and temperature were
investigated. When the reaction time was 8, 10 and 12 hours,
,
The scope of substrates was further investigated by above
optimized synthetic process. A series of 8-azaprotosappanin A
derivatives were successfully synthesized by this method and
the yield was 74%, 84% and 84%，respectively (Table 1, entry
3). When the reaction temperature was 100 oC and 120 oC, the
2 | J. Name., 2012, 00, 1-3
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shown in Table 2. The substrates 1a-y were prepared by the donating groups, the electron-withdrawing group -F at the
continuous reactions through arylamines and 2-iodo-phenols.
Under the optimized conditions, α-(2-iodoaryloxy)-N-
arylacetamides with different electron-donating and electron-
withdrawing groups were catalyzed to undergo intramolecular
meta position showed obviously low reaction activity and yield
Table 2 entry 2z).
(
,
cyclization
smoothly
to
afford
corresponding
8-
azaprotosappanin A derivatives
2
in excellent yields.
Table 2 Synthesis of variously substituted
2
R'
R"
R'
R"
I
Pd(TFA) (15 mol%)
2
AgTFA(2eq)
o
K
CO (2eq)
2
3
DMAC 120 C, 10h
O
Scheme 3 Synthesis of 8-azaprotosappanin A
O
NH
HN
O
O
1a-1y
2a-2y
In order to get 8-azaprotosappanin A (2t’), the methyl
protecting group of compound 2t was removed by
demethylation (Scheme 3). Finally, 8-azaprotosappanin A was
achieved through the cleavage of 2t with 40% HBr in AcOH at
110 oC in 80% yield.
R
1
O
R
1
R
2
R
2
O
NH
O
NH
O
O
CF3COOH
I
O
2a R =H, R =H, 85%
1
2
2f R =H, R =H, 86%
1
2
NH
HOCCF3
2b
R
=H, R =Me,87%
1 2
2g
2h
2i
R
=H, R =Me, 88%
1
2
O
I
2c R =H, R =OMe, 89%
1
2
R =H, R =OMe, 92%
1 2
O
Pd
O
1u
2d R =H, R =Ph, 73%
1
2
R =H, R =Ph, 77%
1 2
2e
R =OMe, R =OMe, 91%
1 2
O
2j
R
1
=OMe, R =OMe, 92%
2
NH
Pd(II)
A
R
1
F
R
1
R
1
Pd(CF3COO)2
R
2
R
2
O
R
2
Ag(1)
Oxidative
addition
O
NH
O
NH
O
NH
O
O
O
Reductive
elimination
2u
2v
R =H,R =H, 84%
1 2
2p
R =H, R =H,86%
1
2
2k R =H, R =H, 79%
1
2
O
NH
R
=H,R =Me, 85%
2
1
Ag(0)
2q
2r
R =H, R =Me,89%
1 2
2l
R =H,R =Me, 81%
1 2
2w R =H, R =OMe, 88%
1
2
R
1
=H, R =OMe, 90%
2
O
I
2m
R =H, R =OMe, 84%
2x R =H,R =Ph, 74%
1 2
1
2
2u
2s
Pd
R
1
=H,R =Ph, 79%
2y R =OMe, R =OMe, 90%
2n
2o
R
=H, R =Ph, 62%
2
1
2
1
2
K2CO3
2t R =OMe, R =OMe, 94%
R =OMe, R =OMe, 86%
1
2z
R
=H,R =F, trace
2
1
2
1
2
NH
O
CF3COOH
O
Pd(IV)
B
The group R’ on the aryl ring with iodo-group could be
electron-donating groups, electron-withdrawing group -F and -
H. When the electron-donating groups such as -OMe and -Me
were at the para position, the cyclization showed high reaction
activities and afforded good yields of 73-92% (Table 2, entries
Scheme 4 Proposed mechanism for compound 2u
.
A
feasible mechanism for intramolecular ortho C–H
activation/C–C cyclization is proposed and shown in Scheme 4
α-(2-Iodophenoxy)-N-phenylacetamide 1u undergoes
cyclopalladation to generate intermediate Then the
is oxidized by AgTFA to give Pd(IV)
containing five-membered and six-
.
a
2a-2j). Compared with the electron-donating groups, the
A
.
electron-withdrawing group -F at the para position showed
intermediate
intermediate
A
B
slightly low reaction activities and the yields of 62-86% (Table
a
a
2
, entries 2k
was at the para or meta position, the reaction activities and
the yields had little effect (Table 2, 77%-92% for entries 2f 2j
and 79%-94% for entries 2p 2t).
-2o). When the electron-donating group -OMe
membered palladacycle22 via oxidative addition. At last, the
intermediate
B is reduced to obtain the compound 2u by the
-
reductive elimination in the present of CF3COOH and K2CO3.
Then a catalytic reaction cycle is completed and the Pd(II) salt
will continue to participate next reaction cycle.
-
Another group R” on the aryl ring with amino-group could
be -Me, -OMe, -Ph, -H and so on. When the electron-donating
groups such as -OMe and -Me were at the meta position, the
cyclization showed highly reaction activities and afforded good
Biological activity
yields of 81-92% (Table 2, entries 2b, 2c, 2g, 2h, 2l, 2m, 2q, 2r,
In vitro antibacterial activities of compounds 2a-2y and
protosappanin A (PA) were studied against a panel of Gram-
positive bacteria. The antibacterial activities of the compounds
were examined against a panel of susceptible and resistant
2v and 2w). The group -Ph was at meta position, the reaction
activities and the yields slightly decreased to 62%-79% (Table 2
,
entries 2d, 2i, 2n, 2s and 2x). Compared with the electron-
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strains of Gram-positive bacteria, including Staphylococcus
According to the obtained anti-bacterial data (Table 3), most of
aureus (ATCC 25923), methicillin-resistant Staphylococcus the tested compounds were appropriate active against Gram-
aureus (MRSA, clinical isolate), Staphylococcus epidermidis positive bacteria. Among the tested compounds for antibacterial
(ATCC 12228) and Enterococcus faecalis (ATCC 29212). E. coli activity against Staphylococcus aureus
,
2c
inhibitory concentration (MIC) of 2 (μg/mL); 2e
MIC of 4 (μg/mL) were found. The compounds 2m
exhibited significant activity against methicillin-resistant
Staphylococcus aureus, the compounds 2c 2j 2m 2o 2t and 2t’
showed excellent activity against Staphylococcus epidermidis and
compounds 2e 2o and 2t’ exhibited significant activity against
,
2o and 2t’ showed low
2h 2r 2t, and 2y
2t, and 2t’
(ATCC 25922) was also used as a Gram-negative bacteria.
,
,
,
,
Table 3 Antibacterial activities (MIC, μg/mL）of 8-azaprotosappanin A derivatives
.
,
,
,
,
,
enterococcus faecalis. In particular, 8-azaprotosappanin A (2t’) had
better activities against Gram-positive bacteria than linezolid
against Staphylococcus aureus and Ciprofloxacin against
Enterococcus faecalis; and 8-azaprotosappanin A (2t’) had higher
active aganist methicillin-resistant Staphylococcus aureus and
methicillin-resistant Staphylococcus aureus than Protosappanin A.
Therefore, it is meaningful work that an imino group (-NH-) was
introduced to replace the methylene group (C-8) of the
Entry
1
Compound
SA MRSA SE
EF EC
2a
16
16
2
16
32
8
32
16
4
32
32
16
>32
>32
>32
2
2b
3
2c
heterocyclic fragment to get 8-azaprotosappanin
A (2t’).
4
2d
32
4
>32
8
>32 >32 >32
Unfortunately, all tested compounds did not show any inhibitive
activity against E. coli. The experimental results indicated that the
5
2e
16
>32
8
4
>32
>32
>32
>32
6
2f
32
16
4
32
16
16
>32
16
16
8
32
16
16
compounds 2c
, 2e, 2m, 2o, 2t and 2t’ showed good antibacterial
7
2g
activities, especially the compound 2t’
.
8
2h
32
Notably, the substituent of the aryl ring had a certain influence
on the anti-bacterial activities of the compounds. The compound
2u without substituent on the aryl ring showed no activities against
9
2i
32
8
>32 >32 >32
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
2j
4
16
8
16
8
>32
>32
>32
>32
2k
8
Gram-positive bacteria. The compounds 2k
substitution on aromatic ring exhibited higher anti-microbial
activity than that with -H (2u 2v and 2w), -Me (2a 2b and 2c) and -
OMe (2f 2g 2h 2p 2q and 2r). The compounds 2e 2j 2o 2t and
2y with double -OMe substitution on aromatic ring had higher
anti-microbial activity, whereas the compounds 2d 2i 2n, 2s and 2x
, 2l and 2m with -F
2l
16
8
16
8
A
2m
2
2
,
,
2n
32
2
>32
8
32
4
>32 >32
2o
2
32
16
8
>32
>32
>32
>32
>32
>32
,
,
,
,
,
,
,
2p
32
16
4
16
16
8
32
8
B
2q
,
,
2r
16
>32
2
with -Ph substitution showed no anti-microbial activity. However,
the compound 2t’ with three -OH substitutions exhibited the most
significant anti-bacterial activity because of the presence of -OH
group to improve the bioavailability of the molecule. The results
indicated that -F and -OH groups on aryl rings of the compounds
were helpful to the antibacterial activity.
2s
>32
4
32
2
32
8
2t
2u
>32
32
16
>32
4
>32
32
16
>32
16
1
>32 >32 >32
2v
32
32
32
16
>32
>32
2w
2x
2y
>32 >32 >32
8
4
4
4
1
16
1
>32
>32
>32
>32
1
2t’
2
Conclusion
PA
4
8
4
A novel synthetic protocol for the construction of eight-
numbered heterocycle by intramolecular Pd-catalyzed ortho
C–H Activation/C–C cyclization was proposed. A series of 8-
azaprotosappanin A derivatives were obtained in good yields.
This protocol could be used in the synthesis of central skeleton
of some natural products and drugs due to its fast reaction
rate and naturally benign condition. Most of the synthesized
compounds showed promising activities against Gram-positive
Linezolid
Ciprofloxacin
4
2
2
-
-
2
aMRSA
= methicillin-resistant Staphylococcus aureus (clinical isolate); SA =
Staphylococcus aureus (ATCC 25923); SE = Staphylococcus epidermidis (ATCC 12228 );
EF = Enterococcus faecalis (ATCC 29212); EC = E. coli (ATCC 25922); PA = protosappanin
A
bBold indicating for significant antibacterial activity.
Linezolid and Ciprofloxacin were used as a positive control in
the experiments. The minimum inhibitory concentration (MIC)
is defined as the lowest concentration of a drug that inhibits
bacteria, wherein the compounds 2c
showed good antibacterial activities,
azaprotosappanin A (2t’ Further research on other biological
,
2e
,
2m
,
2o
,
2t and 2t’
o
especially
8-
the visible bacterial growth after incubation at 37 C for 24 h.
)
.
MICs were determined by agar dilution method as outlined as
following (the clinical and laboratory standards institute). The
experiment results of in vitro evaluation were summarized in
activities and structure-activity relationship of these
compounds is going on. Some other natural products
containing the framework will be synthesized through our
synthetic approach in the future.
Table 3
.
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Klunder, K, D. Hargrave, M. West, E. Cullen, K. M. Pal, L.
S. Behnke, R, D. Kapadia, W. J. McNeil, C. Wu and G.
C.Chow, J. Med. Chem., 1992, 35, 1887–1897.
Acknowledgements
This work was supported by Fund of Natural Science
Foundation of Heilongjiang Province of China (No. 201207 and
No. 201208), for which we are thankful.
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