Total Synthesis of Dictyodendrins A–F by the Gold-Catalyzed Cascade Cyclization of Conjugated Diyne with Pyrrole

Article abstract of DOI:10.1002/chem.202001950

The total synthesis of dictyodendrins A–F was achieved by using the gold(I)-catalyzed annulation of a conjugated diyne with N-Boc-pyrrole for direct construction of the pyrrolo[2,3-c]carbazole scaffold. Late-stage functionalization of the resulting pyrrolo[2,3-c]carbazole to introduce various substituents provided divergent access to dictyodendrins. Some dictyodendrin analogues exhibited inhibitory activities toward CDK2/CycA2 and GSK3.

Full text of DOI:10.1002/chem.202001950

Accepted Article
Accepted Article
Title: Total Synthesis of Dictyodendrins A–F by the Gold-Catalyzed
Cascade Cyclization of Conjugated Diyne with Pyrrole
Authors: Junpei Matsuoka, Shinsuke Inuki, Yuka Matsuda, Yoichi
Miyamoto, Mayumi Otani, Masahiro Oka, Shinya Oishi, and
Hiroaki Ohno
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To be cited as: Chem. Eur. J. 10.1002/chem.202001950
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01/2020

10.1002/chem.202001950
Chemistry - A European Journal
FULL PAPER
Total Synthesis of Dictyodendrins A–F by the Gold-Catalyzed
Cascade Cyclization of Conjugated Diyne with Pyrrole
Junpei Matsuoka,[a] Shinsuke Inuki,[a] Yuka Matsuda,[a] Yoichi Miyamoto,[b] Mayumi Otani,[b] Masahiro
Oka,[b] Shinya Oishi,[a] and Hiroaki Ohno*[a]
Abstract: The total synthesis of dictyodendrins A–F was achieved
using the gold(I)-catalyzed annulation of a conjugated diyne with N-
Boc-pyrrole for direct construction of the pyrrolo[2,3-c]carbazole
scaffold. Late-stage functionalization of the resulting pyrrolo[2,3-
c]carbazole to introduce various substituents provided divergent
access to dictyodendrins. Some dictyodendrin analogues exhibited
inhibitory activities toward CDK2/CycA2 and GSK3.
designed stepwise construction of the fused carbazole core
(Scheme 1).[6,7] Subsequently, several total syntheses of
dictyodendrins have been established by the research groups of
Ishibashi (dictyodendrin B),[8,9] Tokuyama (A–E),[10,11] Jia (B, C,
and E),[12,13] Guant (B),[14] Yamaguchi/Itami/Davies (A and F),[15]
Ready (F, H, and I),[3] and He (F, G, H, and I).[16] Most reported
syntheses used strategies based on introducing the requisite
substituents prior to construction of the pyrrolo[2,3-c]carbazole
core. The important exception is Fürstner’s synthesis of
dictyodendrins B and E, in which pyrrolo[2,3-c]carbazole 14 was
converted to 15 via bromination, lithiation, and acylation at the C2
position (Scheme 2).[7] We envisaged that early-stage
construction of the core structure followed by regioselective
introduction of the substituents could facilitate a diversity-oriented
synthetic route of a series of dictyodendrins. This would further
expand the medicinal applications of dictyodendrin derivatives.
Introduction
Dictyodendrins (Figure 1), a family of marine indole alkaloids
with important bioactivities, were first isolated by Fusetani and co-
workers from Japanese marine sponge Dictyodendrilla
verongiformis in 2003.[1] Capon and co-workers isolated new
dictyodendrins (F–I) in 2012 from the southern Australian marine
sponge Ianthella sp.[2] The Fusetani group reported that
dictyodendrins A–E have inhibitory activity against telomerase,
making them potential lead compounds as anticancer agents. In
a recent report, Ready showed that dictyodendrins F, H, and I
display cytotoxicity against several human cancer cell lines.[3]
Interestingly, the DNA cleavage activity of dictyodendrin
derivatives is highly dependent on the methylation level of the
phenol moieties, as reported by Fürstner and co-workers.[4] As
dictyodendrins F, H, and I exhibit inhibitory activity towards -site
amyloid-cleaving enzyme 1 (BACE1), they are also recognized as
potential lead compounds for the treatment of Alzheimer’s
disease.[2]
HO
HO
OSO3Na
NH
OR1
NH
O
X
O
N
N
OH
HO
OH
OH
HO
R2O
1
3
dictyodendrin A ( ): X = (CO2Me, H)
dictyodendrin B (2): X = O
dictyodendrin C ( ): R1 = SO3Na, R2 = H
dictyodendrin D (4): R1 = R2 = SO3Na
dictyodendrin F ( ): R1 = R2 = H
5
6
dictyodendrin G ( ): R1 = Me, R2 = H
The highly substituted pyrrolo[2,3-c]carbazole core of
dictyodendrins has attracted much interest from the synthetic
community.[5] In 2005, the Fürstner group disclosed the first total
syntheses of dictyodendrins B, C, E, and F through a carefully
HO
HO
OSO3Na
OH
NH
NH
O
N
N
O
O
HO
[a]
[b]
Dr. J. Matsuoka, Dr. S. Inuki, Y. Matsuda, Prof. Dr. S. Oishi, Prof.
Dr. H. Ohno
Graduate School of Pharmaceutical Sciences
Kyoto University
Sakyo-ku, Kyoto 606-8501 (Japan)
E-mail: hohno@pharm.kyoto-u.ac.jp
Dr. T. Miyamoto, M. Otani, Prof. Dr. M. Oka
National Institutes of Biomedical Innovation, Health and Nutrition
(NIBIOHN)
X
OH
OH
HO
HO
7
8
dictyodendrin E ( )
dictyodendrin H ( ): X = Br
dictyodendrin I (9): X = I
Figure 1. Structures of dictyodendrins A–I.
7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085 (Japan)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.202001950
Chemistry - A European Journal
FULL PAPER
OR2
OR2
Ar
NBoc
[Au+]
R7
R6
Ar
R3
Ar
Ar
Ar
Ar
N
PG
Ar
R4
R5
Ar
N
N
N3
MeO
R1
Ar
R4
H
H
R1
Ar
20
[Au+]
22
23
R3
10
21
N
OR2
NH
N
2
2
11
Jia, He
Fürstner, Ishibashi, Davis
Ar
R1
[Au+]
cyclization
OR2
21
N
OMe
OR2
N
R
N
R
N3
Ar
Ar
H
N
O
18'
19'
O
R1
OMe
dictyodendrins
N
N
MeO
OMe
Scheme 4. Our previous work on construction of the pyrrolo[2,3-c]carbazole
Ar
2
Ar
Ar
2
Ar
12
core structure.
13
Tokuyama, Gaunt
Ready
Scheme 1. Reported total syntheses of dictyodendrins.
Herein, we describe total/formal syntheses of dictyodendrins
A–F based on the gold-catalyzed annulation of azido-diynes and
N-Boc pyrrole for construction of the pyrrolo[2,3-c]carbazole
core.[27] Biological evaluation of the dictyodendrin derivatives is
also presented.
OiPr
NH
OMe
OiPr
Ar
Ar
2
NH
(1) NBS
HO
Ar
dictyodendrins
B (2), E (7)
(2) MeLi, nBuLi
N
N
OMe
ArCHO
Ar
2
Ar
14
Ar
2
Ar
Results and Discussion
: Ar = C6H4(4-OMe)
15
Retrosynthesis: Our retrosynthetic analysis of dictyodendrins
based on the gold-catalyzed annulation is shown in Scheme 5.
Dictyodendrin A (1) could be synthesized from 24 by installation
of a sulfate group and removal of the methyl groups, according to
Tokuyama’s protocol.[11] Ester 24 could be prepared from
pyrrolocarbazole 26 through, for example, a Friedel–Crafts
reaction. Pyrrolocarbazole 26, known as the precursor of
dictyodendrins C (3), D (4), and F (5), could be obtained by
bromination of 27 followed by an Ullmann coupling with
NaOMe.[14] Compound 27 would be prepared by consecutive
functionalization of 28 at the C1 and N3 positions[28] after
bromination, when necessary. We also envisaged that ketone 25,
a known synthetic intermediate of dictyodendrins B (2) and E (7),
would be constructed from 27 via a sequence of bromination,
metalation, and addition to p-anisaldehyde at the C2 position.[7]
As described above, the gold-catalyzed annulation of conjugated
diyne 29 with pyrrole 21a would produce pyrrolo[2,3-c]carbazole
28 bearing an oxygen functional group (OR group). Cyclization
precursor 29 could be readily prepared by the Cadiot–
Chodkiewicz coupling reaction between terminal and brominated
alkynes 30 and 31, respectively.[29,30]
Scheme 2. Acyl group installation at the C2 position by Fürstner.
Currently, gold carbenoids[17,18] have emerged as versatile
intermediates for the construction of heterocyclic compounds.[19–
Gagosz[22] and Zhang[23] reported pioneering works on gold-
21]
catalyzed indole synthesis based on intramolecular acetylenic
Schmidt reactions using ethynylbenzene 16 (Scheme 3). This
reaction proceeds through the formation of gold carbenoid
species 18 by gold-catalyzed nucleophilic attack of the azide
moiety on the activated alkyne followed by nitrogen elimination.
Subsequent nucleophilic trapping of gold carbenoid species 18
produces indole 19 bearing an electron-donating substituent at
the C3 position. Recently, we disclosed that the gold-catalyzed
annulation of azido-diynes 20 with arene 21 leads to the formation
of various aryl-annulated [c]carbazoles 22 (Scheme 4).[24] This
reaction constructs three bonds and two rings through the initial
formation of alkyne-substituted gold carbenoid 18’, intermolecular
arylation with arene 21, and 6-endo-dig hydroarylation.[25] Notably,
the reaction using N-Boc-pyrrole as arene component 21 afforded
pyrrolo[2,3-c]carbazole derivative 23 regioselectively, reflecting
the dictyodendrin core structure. Therefore, if the late-stage
introduction of substituents was successful, we expected that this
annulation could be applied to the diversity-oriented total
synthesis of dictyodendrins.[26]
R
[Au+]
R
Nu
[Au]
[Au+]
NuH
R
R
N
N
N
N3
16
H
N2
17
18
19
(Nu = alkoxy or aryl)
R = alkyl or aryl
Scheme 3. Gold-catalyzed intramolecular acetylenic Schmidt reaction reported
by Gagosz and Zhang.
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10.1002/chem.202001950
Chemistry - A European Journal
FULL PAPER
MeO
TMS
MeO
O
OtBu
Ar
Br
[Pd(PPh3)2Cl2]
CuI, Et3N
31
(Ar = p-anisyl)
OtBu
OtBu
OtBu
NH
F
NHBoc
ꞏ
CuCl, NH2OH HCl
n-BuNH2, EtOH
THF
(96%)
NH
NHBoc
MeO2C
NO2
I
2
7
B (
E (
)
)
(91%)
1
R
A (
)
32
33
N
N
OMe
(69%, 4 steps)
OMe
34
30
: R = TMS
: R = H
K2CO3, MeOH
(quant)
MeO
MeO
OtBu
OtBu
OtBu
OMe
OMe
N3
NHBoc
NH2
24
MeO
MeO
MeO
25
TMSOTf
tBuONO
2,6-lutidine
TMSN3
installation of
(aryloxy)acetate
addition to aldehyde
and Ullmann coupling
CH2Cl2
(99%)
MeCN
(97%)
MeO
Ar
Ar
Ar
36a
OR
NH
OR
NH
29a
35a
BCl3, C6H5Me
CH2Cl2 (83%)
H
H
2
5
3
4
C (
D (
)
)
N
N
OH
OR
OR
N3
OMe
H
OR
F (5)
Ullmann
coupling
NHBoc
MsCl, NEt3
NH2
NHBoc
tBuONO
CH2Cl2
TMSN3
OMe
26
OMe
TFA
CH2Cl2
R'O
R'O
or
27
MeCN
BnBr, K2CO3
acetone
Suzuki coupling
and N-alkylation
Ar
Ar
Ar
Ar
OtBu
37
35b
35c
36b
36c
29b
29c
OR
: R = Ms (quant)
: R = Bn (98%)
: R = Ms (99%)
: R = Bn (quant)
: R = Ms (87%)
: R = Bn (83%)
OR
NH
NHBoc
N3
H
1
[Au+]
Scheme 6. Synthesis of azido-diynes 29a–c.
Br
30
N
Boc
Cadiot-
Chodkiewicz
N
Boc
coupling
21a
OMe
28
OMe
OMe
31
29
Table 1. Optimization of gold-catalyzed annulation of 1,3-diyne and pyrrole.[a]
R2
Scheme 5. Retrosynthetic analysis of dictyodendrins.
R2
R2
N3
N
Boc
N
NH
+
NH
Boc
21a
OMe
Preparation and gold-catalyzed annulation of conjugated
diynes. We prepared conjugated diynes 29a–c bearing an
oxygen functional group as shown in Scheme 6. According to the
reported protocol,[11] 1-fluoro-2-nitrobenzene (32) was converted
to the protected 2-amino-3-iodophenol 33 in four steps. The
N
[BrettPhosAu(MeCN)SbF6]
(5 mol %)[b]
Boc
MeO
iPr
PCy2
iPr
DCE, 80 °C
R1
23 28
R1
23' 28'
iPr
BrettPhos
R1
20 29
/
/
/
subsequent
Sonogashira
coupling
of
33
with
trimethylsilylacetylene, followed by desilylation of the coupling
product with K2CO3 and methanol, afforded corresponding
terminal alkyne 30 in quantitative yield.[31,32] Cadiot–Chodkiewicz
coupling[29] of 30 with bromoalkyne 31[33] and deprotection of
resulting conjugated diyne 35a with TMSOTf and 2,6-lutidine
gave the corresponding diyne (36a) bearing a free amino
group.[34] Finally, azidation of 36a using tBuONO and TMSN3
afforded substrate 29a with a tBu protecting group.[35] Other
conjugated diynes 29b (R = OMs) and 29c (R = OBn) were
prepared from 35a in a similar manner through protecting group
modifications and azidation, as shown in Scheme 6.
entry
1[24]
2
20/29
R1
R2
yield[b]
58%
79%
83%
68%
ratio[c]
20a
29a
29b
29c
H
H
95 : 5 (23a/23’a)
84 : 16 (28a/28’a)
75 : 25 (28b/28’b)
81 : 19 (28c/28’c)
OMe
OMe
OMe
OtBu
OMs
OBn
3
4
[a] Reaction conditions: 20/29 (1 equiv.), 21a (5 equiv.),
[BrettPhosAu(MeCN)SbF6] (5 mol%), 1,2-dichloroethane (DCE), 80 C. [b]
Combined isolated yields. [c] Determined by 1H NMR.
We then explored appropriate oxygen functional groups for the
gold-catalyzed annulation (Table 1). We recently showed that
treatment of diyne 20a and N-Boc-pyrrole 21a with
[BrettPhosAuSbF6][36] (5 mol%) in dichloroethane (DCE) at 80 C
proceeded with high regioselectivity to afford the desired
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10.1002/chem.202001950
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pyrrolo[2,3-c]carbazole (58% yield, 23a/23’a = 95:5).[24] Therefore, brominated product 39 (Table 2). The screening of reaction
these optimized conditions for 20a were applied to conjugated
diynes 29a–c bearing an oxygen functional group. The reaction of
29a bearing methoxy (R1 = OMe) and tert-butoxy groups (R2 =
OtBu) showed slightly decreased regioselectivity (28a/28’a =
84:16) with an improved combined yield (79%). In contrast, 29b
(R2 = OMs) and 29c (R2 = OBn) gave the annulation products with
conditions, including different electrophiles, bases, solvents, and
reaction temperatures (entries 1–5) showed that treating 39 with
bromide 42a in the presence of NaOH in THF afforded the desired
N3-alkylated product 43 in 26% yield (entry 5). Addition of 18-
crown-6 (3 equiv.) using THF/H2O (10:1) significantly improved
the yield of 43 to 82%. Notably, the gram-scale bromination to
prepare 39 was unsuccessful, presumably owing to a rapid
‘bromine dance’[7] during evaporation of the reaction solvent.
Therefore, a one-pot C1-bromination/N3-alkylation protocol was
employed for the total synthesis.
relatively low regioselectivities (28/28’
=
75:25–81:19).
Unfortunately, the reaction with 3-bromo-N-Boc-pyrrole was
unsuccessful, leading to the formation of a complex mixture of
unidentified products. Considering the facile deprotection of tert-
butyl group and slightly better regioselectivity in the annulation
reaction, we selected 29a as the suitable building block for the
total synthesis of dictyodendrins. Notably, the gram-scale reaction
of 29a (2.76 g) with 21a (6.69 g) in the presence of a decreased
amount of [BrettPhosAu(MeCN)SbF6] (162 mg, 2 mol%) afforded
28a (2.27 g) in 58% isolated yield.
Table 2. Investigation of N-alkylation.[a]
OtBu
NH
OtBu
NH
Br
Br
X
MeO
N
N
H
Total syntheses of dictyodendrins C, D, and F. With
pyrrolo[2,3-c]carbazole 28a in hand, the total syntheses of
dictyodendrins C and F bearing a 2,5-dioxo moiety on the core
structure were investigated. Our first attempt at direct C–H
arylation of 28a at the C1 position[28] failed, resulting in starting
material recovery. Therefore, the Boc group was removed to
increase the reactivity of the pyrrole ring in 28a (Scheme 7).
Although the C–H arylation of resulting unprotected pyrrolo[2,3-
c]carbazole 38 using a palladium catalyst was also unsuccessful,
C1 bromination with N-bromosuccinimide (NBS; 1.05 equiv.)
proceeded smoothly to give desired product 39. The Suzuki–
Miyaura coupling of 39 with anisylboronic acid (40) afforded C1-
arylated product 41. Unfortunately, N-alkylation with 42a led only
to the formation of a complex mixture without producing desired
product 27a.
solvent (0.05 M)
42a:
42b:
42c:
X = Br
X = OTs
X = OTf
OMe
OMe
MeO
39
43
42
base
temp
additive
[equiv]
yield
[%]
entry
solvent
[equiv.]
42a [3]
42b [3]
42c [3]
42a [1.2]
42a [2]
[equiv.]
K2CO3 [10]
Cs2CO3 [10]
K2CO3 [10]
NaH [2.5]
[C]
80
rt
1
2
3
4
5
DMF
DMF
DMF
DMF
THF
-
-
-
-
-
trace
0
80
80
50
0
0
NaOH [10]
26
THF/H2O
(1 : 1)
18-C-6
[3]
OtBu
NH
OtBu
OtBu
NH
6
7
42a [10]
42a [10]
NaOH [15]
NaOH [15]
rt
rt
0
Br
1
NH
40
, K3PO4
K2CO3
THF/H2O
(10 : 1)
18-C-6
[3]
[Pd(tBu3P)2]
NaOMe
NBS
2
82
5
N
H
N
N
3
dioxane
(74%)
THF
(92%)
Boc
H
dioxane/H2O
(quant)
[a] Reaction conditions: Substrate 39 (1 equiv.), 42, base (X equiv.), solvent
(0.05 M), additive (3 equiv. where applicable). 18-C-6 = 18-crown 6-ether.
OMe
OMe
OMe
28a
38
39
MeO
We next proceeded to synthesize dictyodendrins C and F
(Scheme 8). One-pot bromination of 38 with NBS (1.05 equiv.)
and N-alkylation with 42a under the optimized conditions (Table
2, entry 7), followed by Suzuki–Miyaura coupling with
anisylboronic acid (40), afforded 27a bearing newly-introduced
substituents at the C1 and N3 positions. Introducing an oxygen
functional group at the C5 position proved to be difficult. After
several unsuccessful attempts, such as direct C–H borylation[37]
or lithiation,[38] we finally succeeded in forming mono-bromide 45
through dibromination of 27a with NBS (2.05 equiv.) at the C2 and
C5 positions, followed by C2-selective mono-debromination of 44
with NaBH4 in the presence of [PdCl2(dppf)].[39] The Ullmann
coupling of 45 with NaOMe in the presence of CuI gave 26a
quantitatively, which has been reported as a precursor of
dictyodendrin C by Tokuyama.[11] We completed the total
synthesis of dictyodendrin F through deprotection of 26a with BBr3
and aerobic oxidation.[7]
MeO
OMe
OtBu
NH
OtBu
NH
42a
(HO)2B
Br
N
N
H
40
OMe
OMe
MeO
42a
MeO
41
27a
Scheme 7. Attempted synthesis of 27a.
As the strategy to introduce the C1-aryl group at the first stage
had failed, we optimized the order of substituent introduction. As
the first N-alkylation was found to significantly decrease the
reactivity for C1 bromination, we focused on the N-alkylation of
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10.1002/chem.202001950
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MeO
followed by methyl esterification led to the formation of keto-ester
46 in 87% yield. Unfortunately, subsequent addition of a Grignard
reagent to introduce an anisyl group into 46 resulted in the
formation of a complex mixture, affording only 9% of the desired
ester 24 after Pd(OH)2/C-mediated hydrogenation to remove the
hydroxy group. To prevent side reactions derived from the methyl
ester moiety of 46, we prepared tert-butyl ester 47 by reacting 46
with tBuOLi. The Grignard reaction of 47 showed clean
conversion to -hydroxyester 48, as expected. However, the
subsequent conversion to methyl ester 24 was unsuccessful.
Therefore, we conducted the Grignard reaction after hydrolysis of
46. Pleasingly, the carboxylic acid derived from 46 reacted with
anisylmagnesium bromide more efficiently, affording ester 24
after esterification with TMS diazomethane and hydrogenation
(33% yield, four steps). In this conversion, rapid esterification of
49 without purification was essential to prevent conversion to aryl
ketone 25 (vide infra, Scheme 12). Removal of the methyl and
tert-butyl groups in 24 would complete the total synthesis of
dictyodendrin A.[11]
OtBu
NH
OtBu
1) NBS (1.05 eq),
THF
NH
42a
, NaOH
NBS
2)
(2.05 eq)
(C2H4O)6, H2O
N
N
H
40
3) , [Pd(tBu3P)2]
K3PO4
THF
(54%)
dioxane/H2O
(42%, 3 steps)
OMe
27a
OMe
MeO
38
MeO
MeO
OtBu
OtBu
NH
dictyodendrin
C (3)
NH
ref 11
CuI
NaOMe
2
X
5
BBr3
dictyodendrin
N
N
Br
OMe
DMF
cyclohexene
CH2Cl2
(42%)
5
F ( )
(quant)
Br
OMe
OMe
26a
OMe
MeO
MeO
[PdCl2(dppf)], NaBH4
TMEDA, THF
(55%)
44
: X = Br
45
: X = H
(HO)2B
MeO
MeO
MeO
40
42a
OtBu
NH
OtBu
NH
Scheme 8. Formal and total syntheses of dictyodendrins C and F.
tBuO2C
N
N
X
OMe
OMe
Formal synthesis of dictyodendrin D (4) was achieved in a
similar manner (Scheme 9). As dictyodendrin D has a sulfate
moiety on the N-alkyl group, benzyl-protected bromide 42d was
employed for the N-alkylation according to Tokuyama’s
synthesis.[11] Therefore, key intermediate 27b was obtained from
38 through a sequence of reactions, including C1-bromination,
N3-alkylation with 42d, and a Suzuki–Miyaura coupling reaction.
The formal total synthesis of dictyodendrin D was accomplished
by introducing a methoxy group into 27b, affording known
precursor 26b.[11]
OMe
OMe
MeO
(COCl)2
then MeOH
THF
MeO
26a
tBuOLi, THF
(61%)
ArMgBr
THF
(84%)
47: X = O
48
: X = [C6H4(4-OMe), OH]
(87%)
MeO
MeO
OtBu
NH
OtBu
NH
MeO2C
MeO2C
1) ArMgBr, THF
N
Ar
N
2) H2, Pd(OH)2/C
iPrOH
O
OMe
OMe
MeO
MeO
(9%, 2 steps)
OtBu
1) NBS (2.05 eq)
THF
2) NaBH4, TMEDA
[PdCl2(dppf)], THF
OtBu
NH
Ar = C6H4(4-OMe)
1) NBS (1.05 eq)
THF
OMe
OMe
NH
3) TMSCHN2
THF/MeOH
4) Pd(OH)2/C
MeO
42d
, NaOH,
(C2H4O)6, H2O
2)
MeO
46
24
1) NaOH aq
THF
2) ArMgBr
THF
N
N
38
OMe
H2, iPrOH
ref 11
3) CuI, NaOMe
DMF
(14%, 3 steps)
3) 40
, [Pd(tBu3P)2]
K3PO4
1,4-dioxane/H2O
(49%, 3 steps)
(33%, 4 steps)
MeO
HO
OMe
27b
OMe
26b
BnO
BnO
OtBu
OSO3NH4
NH
NH
MeO2C
ref 11
HO2C
Ar
BnO
Br
N
42d
N
OH
OMe
OH
4
dictyodendrin D (
)
HO
Scheme 9. Formal total synthesis of dictyodendrin D.
OMe
OH
MeO
HO
dictyodendrin A (1)
49
Total synthesis of dictyodendrin A. We next focused on the
total synthesis of dictyodendrins A (Scheme 10), which required
introduction of a (4-hydroxyphenyl)acetate moiety at the C2
position. Our initial attempts at introducing the C2 substituent on
26a, including C–H insertion and Friedel–Crafts reactions under
various reaction conditions, resulted in decomposition of the
starting material. In contrast, acylation of 26a with oxalyl chloride
Scheme 10. Formal total synthesis of dictyodendrin A.
Total syntheses of dictyodendrins B and E. Dictyodendrins B
and E possess acyl and benzylidene groups at the C2 position,
respectively (Figure 1). We selected the C2 acylation strategy
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10.1002/chem.202001950
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reported by Fürstner (Scheme 2),[7] in which a sequence of
reactions involving bromine–lithium exchange and addition to p-
anisaldehyde afforded C2-substituted pyrrolo[2,3-c]carbazole 15.
Accordingly, regioselective mono-bromination of 27a with NBS
(1.05 equiv.) gave 50 in moderate yield (52%) (Scheme 11).
Subsequent bromine–lithium exchange with MeLi (1.1 equiv.) and
nBuLi (1.1 equiv.), followed by addition to p-anisaldehyde,
afforded corresponding C2-substituted product 51 in 74% yield.
Methyl ether 25 was obtained through selective mono-
bromination of 51 at the C5 position, Ley–Griffith oxidation of the
resulting bromide 52, and Ullmann coupling with NaOMe. We
accomplished the total synthesis of dictyodendrin B (2) through
selective removal of the tert-butyl group using BCl3 at 78 C,
sulfate formation, and deprotection using BCl3 (0 C→rt) and Zn
dust as reported.[11] Tokuyama and co-workers reported that 25
can be transformed to dictyodendrin E by reduction of the
carbonyl group, demethylation, sulfate moiety construction, and
oxidation with DDQ.[11]
MeO
MeO
OtBu
OtBu
NH
NH
O
1) NaOH aq HO2C
THF
3) CHCl3
46
Ar
N
N
Ar
OMe
OH
OMe
2) ArMgBr
THF
(71%, 3 steps)
OMe
25
OMe
MeO
MeO
49
Scheme 12. Alternative route to 25.
As summarized in Scheme 13, our dictyodendrin synthesis was
highly diversity-oriented. Pyrrolocarbazole 38, obtained by the
gold-catalyzed annulation of diyne 29a with N-Boc-pyrrole
followed by removal of the Boc group, was the common
intermediate for all dictyodendrins synthesized in this study.
Therefore, this strategy has potential applications in the synthesis
of various dictyodendrin analogues for medicinal applications.
MeO
MeO
OtBu
OtBu
NH
1) cat. [Au+]
NH
X
2) NaOMe
HO
pyrrolocarbazole
MeLi, nBuLi
32
29a
Br
38
(
)
p-anisaldehyde
NBS
58%, 9 steps
53%, 2 steps
42%, 3 steps
16%, 5 steps
N
N
5
27a
THF
THF
49%, 3 steps
(74%)
(52%)
dictyodendrin
24%, 4 steps
2
B ( )
MeO
25
27a
3 steps, 30%
26a
27b
OMe
OMe
dictyodendrin
ref 11
46
via
7
E ( )
14%, 3 steps
26b
ref 11
dictyodendrin
MeO
MeO
NBS
THF
(50%)
62%, 4 steps
50
51
: X = H
52
: X = Br
dictyodendrin
MeO
24
1
A ( )
ref 11
29%, 5 steps
ref 11
OtBu
1 step, 42%
dictyodendrin
1) BCl3, C6HMe5,
CH2Cl2
2) CCl3CH2OSO2Cl
DABCO, CH2Cl2
NH
dictyodendrin
O
[TPAP]
NMO
3
5
4
C (
)
F (
)
D ( )
2
dictyodendrin B ( )
N
X
3) BCl3, n-BuNI,
CH2Cl2
CH2Cl2
(quant)
Scheme 13. Summary of our dictyodendrin synthesis.
4) Zn dust, HCO2NH4
MeO
MeOH
(24%, 4 steps)
OMe
MeO
Biological evaluation. The biological activities of the
synthesized dictyodendrin analogues were evaluated. As
dictyodendrin F has previously been reported to show cytotoxicity
against human colon cancer HCT116 cells (IC50 = 27.0 M),[3] we
assessed the cytotoxicity of newly synthesized dictyodendrin
analogues toward HCT116 cells at 30 M using the colorimetric
MTS assay (Figure 2). Among the pyrrolo[2,3-c]carbazole
derivatives investigated, 28a and 38 with no substituents at the
C1 and C2 positions exhibited relatively high cytotoxicity against
HCT116 cells (44%–64% cell viability), comparable to that of
dictyodendrin E (7)
ref 11
CuI, NaOMe
DMF, (81%)
53
25
: X = Br
: X = OMe
Scheme 11. Formal and total syntheses of dictyodendrins B and E.
As an alternative route, dictyodendrins B and E can be
accessed from advanced intermediate 46 from the synthesis of
dictyodendrin A. As described in the Grignard reaction of acid 49
(Scheme 10), we unexpectedly found that 49 was gradually
converted into ketone 25 when standing in CDCl3 (Scheme 12).
This oxidative decarboxylation reaction would proceed through
anionic[40] or radical pathways.[41] After complete consumption of
49 in CHCl3, ketone 25 was obtained in 71% yield in three steps
from 46. Therefore, 46 (obtained from 26a) can be considered as
a common intermediate for dictyodendrins A, B, and E. Spectral
data of all the synthetic natural products and the known
intermediates were in good accordance with those of reported in
the literature.[11]
dictyodendrin
F (55%). Interestingly, pyrrolo[3,2-c]carbazole
derivative 28’b, the unnatural regioisomer with no substituents at
C2 and C3, showed the highest activity (19%). In contrast, no
cytotoxicity against HCT116 cells was observed for C1- and C2-
substituted pyrrolocarbazoles 25, 26a, 27a, and 50–52, even at
30 M.
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10.1002/chem.202001950
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FULL PAPER
HO
O
dictyodendrin analogues examined, and that pyrrolo[2,3-
c]carbazole derivative 54 and its [3,2-c] congener 55 are
promising templates for kinase inhibitors.
OH
OtBu
OMs
NH
O
Boc
1
NH
NH
N
2
2
N
N
R
3
Conclusions
OH
We have accomplished total and formal syntheses of
dictyodendrins A–F. The gold-catalyzed annulation of diynes
bearing a tert-butoxy group proceeded efficiently to provide the
pyrrolo[2,3-c]carbazole required for dictyodendrin synthesis. The
late-stage functionalization of pyrrolo[2,3-c]carbazole 38,
including C1 arylation, C2 acylation, N3 alkylation, and C5
OMe
28a (R = Boc) 64%
OMe
HO
28'b
5
) 55%
19%
dictyodendrin F (
MeO
38
44%
(R = H)
MeO
OMs
OtBu
OtBu
NH
NH
R2
NH
R2
X
oxidation, served as
a
diversity-oriented synthesis of
R1
dictyodendrins. Resulting dictyodendrin analogues 54 and 55
exhibited inhibitory activity against CDK2/CycA2 and GSK3.
This strategy enables the comprehensive synthesis of
dictyodendrin derivatives and facilitates a new approach toward
biologically active pyrrolocarbazole-type compounds.
N
N
N
Boc
MeO
OMe
28b
OMe
OMe
MeO
MeO
99%
26a (R1 = H, R2 = OMe) 89%
25 (X = O, R2 = OMe) 86%
51 (X = OH, H, R2 = H) 97%
52 (X = OH, H, R2 = Br) 98%
27a (R1 = H, R2 = H) 121%
50 (R1 = Br, R2 = H)
92%
Acknowledgements
Figure 2. Cytotoxicity of dictyodendrin derivatives (% values of cell viability at
30 M are shown).
We thank Prof. Kenichiro Itami (Nagoya University) for valuable
discussion regarding the C–H activation of pyrrolo[2,3-
c]carbazole derivatives. This work was supported by the JSPS
KAKENHI (JP17H03971, JP18H04408, and JP18J12107), Basis
for Supporting Innovative Drug Discovery and Life Science
Research (BINDS, JP19am0101092j0001) from AMED, Japan,
and Tokyo Biochemical Research Foundation (TBRF). J.M. is
grateful for the JSPS Research Fellowships for Young Scientists.
Several fused carbazoles are known to exhibit inhibitory
activities against protein kinases. For example, PD407824
(Figure 3), containing a pyrrolo[3,4-c]carbazole scaffold, has been
reported to inhibit protein kinases (Wee1, Chk1, PKC, and CDK4)
at nM levels. To examine the potential of pyrrolo[2,3-c]- and
pyrrolo[3,2-c]carbazoles as templates for kinase inhibitors, we
next screened unsubstituted derivatives 54 and 55[42] at 10 M
against 32 protein kinases. As shown in Figure 3, these
carbazoles showed inhibitory activity against CDK2/CycA2[43,44]
[IC50: 0.78 M (54) and 2.6 M (55)] and GSK3[45] [IC50: 3.1 M
(54) and 1.8 M (55)]. Furthermore, as some CDK2 inhibitors
have been found to inhibit core protein nucleolar formation, we
evaluated the inhibitory activity of the dictyodendrin analogues
against nucleolar localization of the flavivirus core protein.[46]
However, these carbazoles did not exhibit antiviral activity like that
of the known CDK2/9 inhibitor (see Supporting information).
Keywords: cascade reaction • conjugated diyne • dictyodendrin
• gold catalyst • pyrrolocarbazole
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Chemistry - A European Journal
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10.1002/chem.202001950
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents
FULL PAPER
OR
N3
OR
Total syntheses of dictyodendrins A–F
Junpei Matsuoka, Shinsuke Inuki, Yuka
Matsuda, Yoichi Miyamoto, Mayumi
Otani, Masahiro Oka, Shinya Oishi, and
Hiroaki Ohno*
N
NH
were achieved based on
a
gold-
Boc
gold(I) catalyst
catalyzed cascade reaction for
construction of the pyrrolo[2,3-
c]carbazole scaffold. This synthetic
strategy features functionalization of
the pyrrolo[2,3-c]carbazole scaffold at
C1 (arylation), C2 (acylation), N3
(alkylation), and C5 (oxidation)
positions. This synthetic method could
be used for the diversity-oriented
synthesis of dictyodendrin derivatives
for medicinal applications.
N
Boc
direct
construction
late-stage
functionalization
OMe
Page No. – Page No.
OMe
HO
HO
HO
O
Total Synthesis of Dictyodendrins A–
F by the Gold-Catalyzed Cascade
Cyclization of Conjugated Diyne with
Pyrrole
OR
NH
OR
NH
O
N
N
R
OH
( )2
( )2
HO
R'O
OH
OH
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