Chiral phosphoramide-catalyzed enantioselective synthesis of 2,3′-diindolylarylmethanes from indol-2-yl carbinols and indoles

Article abstract of DOI:10.1039/c4cc03605k

We present the first asymmetric reaction of indol-2-yl carbinols with indole derivatives catalyzed by chiral phosphoramides for the enantioselective synthesis of 2,3′-diindolylarylmethanes in excellent yields of over 90% as well as high enantioselectivity

Full text of DOI:10.1039/c4cc03605k

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Chiral phosphoramide-catalyzed enantioselective
synthesis of 2,30-diindolylarylmethanes from
indol-2-yl carbinols and indoles†
Cite this: Chem. Commun., 2014,
50, 8605
Received 13th May 2014,
Accepted 9th June 2014
Shuai Qi,ab Chao-You Liu,ab Jin-Ying Dinga and Fu-She Han*ac
DOI: 10.1039/c4cc03605k
www.rsc.org/chemcomm
We present the first asymmetric reaction of indol-2-yl carbinols with
indole derivatives catalyzed by chiral phosphoramides for the
enantioselective synthesis of 2,30-diindolylarylmethanes in excellent
yields of over 90% as well as high enantioselectivity of up to 96% ee.
Hetero-triarylmethanes are unique structural motifs and have a
broad range of applications in areas such as materials science,
biochemistry, and pharmaceuticals.1 Among which, diindolylar-
ylmethanes represent appealing hetero-triarylmethanes due to
their highly promising therapeutic utility as anticancer agents2
against an array of cancer cell lines such as breast,3a prostate,3b
colon,3c pancreatic,3d acute myelogenous leukemia,3e bladder,3f
and endometrial cancer cell lines.3g Despite these important
advances, the biological properties of the chiral derivatives
Scheme 1 Protocols for the enantioselective synthesis of 3,30-diindolylaryl-
methanes, (a); and 2,30-diindolylarylmethanes, (b).
remain unexplored due to the lack of effective methods for with indoles. Namely, indole C-2 exhibits a much lower nucleophi-
enantioselective synthesis of such compounds. However, numerous licity than that at the C-3 position.7 On the other hand, the formation
studies have witnessed that the biological activity of a molecule, of electrophilic indol-2-yl cation species B from indol-2-yl derivatives
including that of the hetero-triarylmethanes,4 is dramatically is more difficult to compare with that of indol-3-yl cation A.8
influenced by its chirality. It is therefore highly desired to establish
some methods for the enantioselective synthesis of diindolylaryl- initiated a project to investigate the enantioselective synthesis of
methanes for activity evaluation.
2,30-diindolylarylmethanes by using indol-2-yl carbinol deriva-
We took particular interest in these challenging issues and
So far, a few protocols for the enantioselective synthesis of 3,30- tives as the electrophiles (Scheme 1b). Initial evaluation on the
diindolylarylmethanes have been developed via the Friedel–Crafts- feasibility of the protocol through the reaction of 8a and indole
type reaction of indol-3-yl carbinol derivatives (Scheme 1a).5 In 9a for the synthesis of 10a showed that, among an array of
addition, the synthesis of other 3-substituted chiral indole derivatives BINOL-based chiral Brønsted acids such as (thio)phosphora-
using indol-3-yl carbinol analogues has also been frequently mides (11), (thio)phosphoric acids (12), and imidodiphosphoric
reported.6 However, to the best of our knowledge, methods for the acids (13), phosphoramides 119 might be promising catalysts
asymmetric synthesis of 2,30- or 2,20-diindolylarylmethanes as well as (Table 1). The reaction could be completed very rapidly within ca.
the chemistry of indol-2-yl substrates have not been achieved 10 min at room temperature to give 10a in excellent yield of
(Scheme 1b). This is due to the distinctive chemistries associated higher than 90% and moderate enantioselectivity of ca. 40% ee
in several low polarity solvents (see entry 1 in Table 1 for
a Changchun Institute of Applied Chemistry, Chinese Academy of Sciences,
5625 Renmin Street, Changchun, Jilin 130022, China. E-mail: fshan@ciac.ac.cn
b The University of Chinese Academy of Sciences, Beijing 100864, China
c Key Lab of Synthetic Chemistry of Natural Substances,
representative data). In comparison, phosphoric acids 12 and
imidodiphosphoric acids 13, which have been shown to be
powerful catalysts for indol-3-yl carbinol derivatives,5,6 were far
less effective for indol-2-yl carbinol 8a.10 More interestingly,
among a range of catalysts 11 being examined, the simplest
catalyst (R)-11a (R = H, X = O) derived from the unsubstituted
BINOL, exhibited a much better and reversed enantioinducing
Shanghai Institute of Organic Chemistry, CAS, China
† Electronic supplementary information (ESI) available: Detailed experimental
procedures, 1H- and 13C-NMR, and HRMS data, and the copies of 1H- and 13C-NMR
spectra, and HPLC chart. See DOI: 10.1039/c4cc03605k
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Table 1 Optimization of the reaction conditionsa
toluene (entry 3), via chlorobenzene (entry 7) and fluorobenzene
(entry 8) to pentafluorobenzene (entry 9), and was almost lost in
high polar solvents such as acetone and MeCN (entries 11 and 12).
The observation of such a strong solvent effect strongly demon-
strates that the ion-pairing interaction11 between an indole
iminium cation species B (Scheme 1b) or a benzhydryl-type
carbocation12 and a phosphoramide anion should be involved
in the reaction cycle. Finally, considering that a molecule of water
is generated during the reaction, we investigated the effect of
water on the reaction. Only negligible influence was observed
both on yield and enantioselectivity either in the presence of
molecular sieves (entries13and14)orbythe externaladdition ofa
large excess amount of water (entry 15).
Thus, an extensive screening of various reaction parameters
led to the establishment of the optimized conditions for the
asymmetric synthesis of 2,30-diindolylarylmethanes. The reaction
with 10 mol% of (R)-11a in toluene at ꢀ60 1C afforded the product
10a in 92% yield and 91% ee (entry 5). Furthermore, the use of
1 : 1 substrates and the absence of extra additives, as well as the
generation of water as the sole by-product makes this protocol
simple, clean, and atom-economical. In addition, the use of the
most readily available catalyst represents an added bonus.
For a better understanding of the working model of the
asymmetric transformation, we carried out additional control
experiments (Scheme 2). High enantioinduction was achieved
for the reaction of indol-2-yl carbinol 8a with N–H free indole 9a
(91% ee, 10a). In stark contrast, the enantioselectivity dropped
down dramatically to 9% ee for 10b when N–Me protected indole
9b was used as a nucleophile although the yield was not
Entry
T (1C)
Solvent
Additive
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
rt
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
ClC6H5
FC6H5
F5C6H
DCM
Acetone
MeCN
Toluene
Toluene
Toluene
—
—
—
—
—
—
—
—
—
—
—
—
3 Å MS
4 Å MS
H2O
90
92
94
93
92
94
88
90
57
92
74
62
90
90
95
46
75
82
89
91
80
67
50
27
42
13
0
ꢀ30
ꢀ40
ꢀ50
ꢀ60
ꢀ70
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ60
ꢀ60
ꢀ60
9
10
11
12
13
14
15
90d
89d
90e
a
Reaction conditions: indol-2-yl carbinol 8a (0.05 mmol), indole 9a
(0.05 mmol), catalyst (R)-11a (10 mol%) in solvent (2 mL) for 10 min to
b
c
4 h. Yield of isolated product. The ee value was determined by HPLC
on an AD-H column. In the presence of a 60 wt% molecule sieve. In
the presence of 10.0 equiv. of water.
d
e
ability as compared to the 3,30-disubstituted (R a H) catalysts.10 influenced. These results suggested that, in addition to the
Here, although the reasons for such an unusual observation exemplified ion-pairing interaction between the catalyst and
await a detailed clarification, the results imply that the reaction cation species B, the intermolecular H-bonding interaction
mechanism of indol-2-yl carbinol substrates is somewhat differ- between the catalyst and the N–H free indole nucleophile may
ent from other types of reactions catalyzed by BINOL-based also play a crucial role in high enantioselectivity. In fact, the
phosphoric acids or phosphoramides,5,6,9,11 since for most of important role of H-bonding interactions has been frequently
the reported asymmetric transformations, the incorporation of proposed in chiral phosphoric acid or phosphoramide-catalyzed
bulk substituents at the 3,30-position to increase the steric asymmetric reactions.11,13 These results would provide impor-
shielding or p–p interaction was an essential requirement for tant information for the design and development of other new
inducing good enantioselectivity.
asymmetric reactions related with indol-2-yl carbinol substrates.
Next, we investigated the scope and limitation of the protocol.
Thus, owing to the promising asymmetric catalytic ability, and
the indisputable advantage for easy preparation of 11a, we carried First, an array of indol-2-yl carbinols 8 bearing different R1, R2, R3,
out a detailed optimization of the reaction parameters by using and Ar groups was reacted with indole 9a (Table 2). An excellent
this catalyst. The enantioselectivity increased gradually upon low- yield (490%) as well as high to excellent enantioselectivity (up to
ering the temperature and reached up to 91% ee at ꢀ60 1C (entries 96% ee) was obtained for indol-2-yl carbinols modified by a Me
1–5). Somewhat surprisingly, the ee value reduced to 80% when group (R1) at C-4, C-5, and C-6 positions (10a–10g). In addition,
the temperature was further lowered to ꢀ70 1C (entry 6). These various R2 substituents such as Me (10a–10g), Et (10h–10j), and
observations suggest that a boundary reaction temperature exists
for producing the best enantioselectivity although the reasons are
not clear at this stage. Of note, although the enantioselectivity was
considerably influenced by the reaction temperature, the catalytic
activity was less affected by the temperature since all the reactions
could proceed smoothly to afford 10a in excellent yields within
10 min to 4 h at different temperatures in toluene.
We then examined the effect of solvents on this reaction.
The results showed that the enantioselectivity dropped off
Scheme 2 Control experiments.
markedly when the polarity of the solvents was increased from
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Table 2 Enantioselective reaction of various indol-2-yl carbinols 8 with
indole 9aa
in excellent yields (490%) as well as high ee values (86–95%).
These results unambiguously exemplified that the asymmetric
reaction presented herein also displays a broad substrate scope
for indole nucleophiles. Finally, by replacing the catalyst
(R)-11a with (S)-11a, the corresponding enantiomers could also
be synthesized uneventfully in identically high yields and
enantioselectivities as seen from the data of 10u–10w vs.
ent-10u-ent-10w. These results would facilitate a clear investiga-
tion into the effect of chirality on anticancer properties.
In summary, we have developed a novel methodology that
has realized the asymmetric reaction of the inherently challen-
ging indol-2-yl carbinols. The protocol exhibits a broad compat-
ibility for these substrates and can proceed in a very simple,
clean, and atom-economical manner in the presence of the
most readily available BINOL-based phosphoramides as cata-
lysts. The unprecedented chiral 2,30-diindolylarylmethane
compounds synthesized in this work are interesting candidates
for the discovery of new anticancer drugs. In addition, the
established interaction model should be useful for the de novo
design of other types of asymmetric reactions related with
indol-2-yl carbinols. Currently, we are screening the anticancer
activity of the synthesized chiral diindolylarylmethanes and
exploring new conditions for the enantioselective reaction of
indol-2-yl carbinols with other appropriate p-nucleophiles. In
addition, the determination of the absolute configuration of
the products and the clarification of the reasons for why the
unsubstituted catalyst 11a afforded a better and reversed enan-
tioselectivity as compared to the 3,30-disubstituted catalysts are
also the focus of our current studies.
a
Reaction conditions: indol-2-yl carbinols 8 (0.1 mmol), indole 9a
(0.1 mmol), catalyst (R)-11a (10 mol%) in toluene (4 mL) at ꢀ60 1C
for 3–10 h, yield of isolated products; ee % was the average value of two
runs and was determined by HPLC on AD-H, OD-H, or OJ-H column (see
ESI for details); the reaction time was not optimized.
cyclopentyl (10k) were also compatible, although a bulkier R2
group led to a somewhat decreased enantioselectivity. Finally, an
array of R3 groups such as iPr (10a–10j), Me (10k), Bn (10l), and
PMB (10m) was also viable. These results exemplified that the
reaction exhibits a broad substrate scope for indol-2-yl carbinol
electrophiles.
To further demonstrate the broad generality and reliability
of the protocol, we examined the asymmetric reaction by
varying the indole nucleophiles 9. The results are summarized
in Table 3. Typically, indole nucleophiles with a variety of
substituents such as 5-F, Cl, Br, Me, and 4-F reacted smoothly
with 8a to deliver the corresponding diindolylarylmethanes
10n–10r both in good yield and enantioselectivity. Further-
more, a flexible combination of various indol-2-yl carbinols 8
and indole nucleophiles 9 showed that all the combinations
could also proceed very cleanly and efficiently under the
optimized conditions to afford the desired products 10s–10bb
Financial support from NSFC (21272225), and Key Lab of
Synthetic Chemistry of Natural Substances, SIOC, is acknowledged.
Notes and references
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a
Reaction conditions: indol-2-yl carbinols 8 (0.1 mmol), indoles 9
(0.1 mmol), catalyst (R) or (S)-11a (10 mol%) in toluene (4 mL) at
ꢀ60 1C for 3–12 h. Isolated yield; ee % was the average value of two runs
and was determined by HPLC on an AD-H or OD-H column; the
reaction time was not optimized.
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8608 | Chem. Commun., 2014, 50, 8605--8608
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