Organocatalytic Asymmetric Synthesis of Spiro-Bridged and Spiro-Fused Heterocyclic Compounds Containing Chromane, Indole, and Oxindole Moieties

Article abstract of DOI:10.1021/acs.orglett.8b02731

Following the reactivity inversion strategy, two different two-step sequences were designed and successfully applied to the asymmetric synthesis of spiro-bridged and spiro-fused heterocyclic compounds, which combined chromane, indole, and oxindole, three

Full text of DOI:10.1021/acs.orglett.8b02731

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Organocatalytic Asymmetric Synthesis of Spiro-Bridged and Spiro-
Fused Heterocyclic Compounds Containing Chromane, Indole, and
Oxindole Moieties
Zhi-Hao You,† Ying-Han Chen,† Yu Tang,†,‡ and Yan-Kai Liu*,†,‡
†Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China,
Qingdao 266003, China
‡Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao
266003, China
S
* Supporting Information
ABSTRACT: Following the reactivity inversion strategy, two different two-step sequences were designed and successfully
applied to the asymmetric synthesis of spiro-bridged and spiro-fused heterocyclic compounds, which combined chromane,
indole, and oxindole, three potential pharmacophores, in one molecule. The power of these two organocatalytic pathways is
underscored by mild reaction conditions and high efficiency in the production of synthetically challenging, but biologically
important heterocyclic products, which could be transformed into more biologically interesting heterocyclic structures.
hiral spiro-bridged and spiro-fused heterocyclic frame-
Cworks are widely encountered in numerous natural
products and biologically active compounds.1 However, the
asymmetric construction of these spirocyclic structural motifs
is quite challenging due to their molecular complexity with
multiple stereogenic centers.2 New transformations that could
provide rapid access to the aforementioned heterocyclic
frameworks in an asymmetric catalytic manner are thus
particularly appealing.
The combinatorial pharmacophore strategy has played a
central role in the search of leading compounds for new drug
development.3 Chromane,4 indole,5 and oxindole6 fragments
are three well-known heterocyclic pharmacophores and are
found in various natural and bioactive molecules. Despite
extensive efforts that have been devoted to the asymmetric
Figure 1. Selected compounds containing chromane, indole, and
oxindole moieties.
construction of molecules containing such three potential
applied as pharmaceutical agents. Therefore, it is highly
desirable to develop enantioselective catalytic procedures for
the synthesis of spiro-fused and spiro-bridged heterocyclic
compounds containing these three potential pharmacophores.
pharmacophores, all the established protocols furnished the
chiral products containing only two of these three potential
pharmacophores in spiro-fused heterocyclic systems (Figure
1),7 and to the best of our knowledge, there have been no
reports on a catalytic enantioselective construction of
compounds combining all of them in one spiro-bridged or
spiro-fused heterocyclic molecule,8 which may be potentially
Received: August 26, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02731
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Reactivity inversion turned out to be useful as a heuristic
principle in the design of synthetic strategy for the synthesis of
structurally diverse products.9 3-Indolyl-substituted oxindoles
2a have emerged as valuable nucleophiles (3-position of
oxindole moiety) for the synthesis of natural products and
biologically active compounds,10 but the application of 2a to
construct chiral spiro-bridged heterocycles has not been
reported until now.11 By introduction of a leaving group,
such as a hydroxy or alkyloxy group, an inversion of the general
nucleophilic nature of 3-position of 2a will be observed
(Scheme 1). Thus, 3-indolyl-substituted oxindoles 7a could be
hand, by inversing the reactivity of 1a and 2a, respectively, to
give chroman-2-ol 6a and 3-methoxy-3-indolyl-disubstituted
oxindole 7a, 6a reacts with 7a via the enamine-catalyzed C−C
bond formation, resulting in the production of intermediate 8
bearing a lactol moiety, followed by treatment with acid
furnishing the target spiro-fused heterocyclic products 9
(Scheme 1, path B). Therefore, both of the spiro-fused and
spiro-bridged heterocyclic molecules containing three potential
pharmacophores, such as chromane, indole, and oxindole
fragments, in one molecule have been constructed in a highly
stereocontrolled manner by a two-step sequence using simple
and easily available starting materials.
To prove the viability of our envisioned design, we initially
investigated the asymmetric catalytic two-step sequence of
reactions between 1a and 2a in the presence of aminocatalyst 3
and o-fluorobenzoic acid (o-FBA). As shown in Scheme 2
Scheme 1. Design of Synthetic Strategies
Scheme 2. Synthesis of Spiro-Bridged Heterocyclic Products
5a and 5′a
potentially used as electrophiles to construct spiro-fused
oxindole derivatives.12 It is noteworthy that the indole moiety
in both 2a and 7a could serve as potential nucleophilic partners
to react with an oxocarbenium ion for further trans-
formations,13 which allows the possibility of creating
structurally complex enantioenriched fused and bridged
heterocycles. Meanwhile, under conditions of asymmetric
aminocatalysis, 2-hydroxy cinnamaldehyde 1a is generally
employed as an electrophile (β-position).14 In contrast, we
have recently found that the simple chroman-2-ol 6a, which
was easily obtained by reduction of 2-hydroxy cinnamaldehyde
1a and thus showed inverse reactivity, could be directly used as
a nucleophile (α-position) in the synthesis of structurally
diverse polycyclic compounds via lactol intermediates,15 which
are the precursors of an oxocarbenium ion under acidic
conditions.16 Herein, for the first time we report two different
two-step sequences for the asymmetric construction of spiro-
bridged and spiro-fused heterocyclic compounds, containing
chromane, indole, and oxindole moieties in one molecule.
Based on these considerations and also as a continuation of
our interest in the application of 2-hydroxy cinnamaldehyde
1a,15b,c chroman-2-ol 6a,15 and 3-substituted oxindole17 as
useful starting materials to construct complex heterocyclic
compounds, we sought to further extend the concept of
reactivity inversion in the construction of spiro-fused and
spiro-bridged heterocyclic frameworks. Our design plan is
illustrated in Scheme 1; the asymmetric Michael addition
between 1a and 2a leads to a lactol intermediate 4 via iminium
catalysis, which subsequently undergoes acid-catalyzed intra-
molecular Friedel−Crafts alkylation by the nucleophilic attack
of the indole moiety to an oxocarbenium ion, providing the
desired spiro-bridged heterocyclic products 5 that bear one
tetrasubstituted spiro stereogenic carbon center and two chiral
bridgehead carbon centers (Scheme 1, path A). On the other
(TBS = tert-butyldimethylsilyl; optimization studies are
detailed in Table S1 of the Supporting Information, SI), the
first Michael addition step proceeded smoothly in tetrahy-
drofuran (THF) at −20 °C, producing the corresponding
lactol intermediates 4a and 4′a as two separable diastereomers,
which were efficiently transformed into the desired spiro-
bridged heterocycles 5a and 5′a, respectively, in good isolated
yields (5a, 22%; 5′a, 61%; over two steps based on 2a) with
excellent enantioselectivities (>99% for each diastereomer)
through the BF3·Et2O catalyzed intramolecular Friedel−Crafts
alkylation at 0 °C in CH2Cl2 within 10 min.
Next, the substrate scope of the designed asymmetric two-
step sequence was studied with respect to both 1 and 2 under
the optimized conditions, and the results are given in Scheme
3. Generally, the reactions furnished the expected spiro-
bridged products 5a−l and 5′a−l in moderate to good yields
and with good to excellent enantioselectivities (most >99%),
regardless of the electronic and steric properties of the
substituents on the aromatic rings of chromane, indole, and
oxindole moieties that are contained in the two reaction
partners 1 and 2. Note that the corresponding N-benzyl-
protected or N-unprotected substrates 2 could also be applied
to this transformation (5m−n and 5′m−n).
Inspired by the success of the preparation of spiro-bridged
heterocyclic compounds consisting of chromane, indole, and
oxindole moieties, we further attempted to install three such
potential pharmacophores in spiro-fused heterocyclic systems
based on the inversion strategy. However, to our surprise, the
initial Michael addition between chroman-2-ol 6a and 3-
methoxy-3-indolyl-disubstituted oxindoles 7a did not take
place under the optimized conditions for the synthesis of spiro-
bridged products 5 and 5′. This may be presumably attributed
B
DOI: 10.1021/acs.orglett.8b02731
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Letter
Scheme 3. Substrate Scope of Spiro-Bridged Heterocyclic
Products
Scheme 5. Substrate Scope of Spiro-Fused Heterocyclic
Products
step sequence tolerates both electron-donating and -with-
drawing substituents at different positions on the aromatic ring
of both 6 and 7, thus furnishing the spiro-fused heterocyclic
products in moderate to good yields and with excellent
enantioselectivities (9a−i and 9′a−i). The starting lactol
containing a naphthalene ring can also be applied in this
sequential reaction (9j and 9′j). To our surprise, N-
unprotected substrate 7k delivered only one spiro-fused
isomer 9′k with excellent enantioselectivity, while 9k was
extensively decomposed under the current conditions.
to the fact that 7a did not produce the required carbocation
intermediate in the absence of acid.18 Therefore, we proposed
that the MacMillan imidazolidinone catalysts in conjunction
with different protonic acids might be the proper choice for the
initial Michael addition, since the acids might serve as the
promoter resulting in the departure of the methoxy group to
give the required carbocation intermediate. Pleasingly, as
shown in Scheme 4, after screening several MacMillan
The absolute configurations of product 5′i (CCDC
1863213) and 9′c (CCDC 1863212) were unequivocally
determined by X-ray crystallographic analysis (see Scheme 3
for 5′i and Scheme 5 for 9′c; the H atoms are omitted for
clarity), and all other products were assigned by analogy.
To further expand the concept and also to investigate the
synthetic utility of both spiro-bridged and spiro-fused products,
several transformations were carried out (Scheme 6). With the
exception of 3-indolyl-substituted oxindoles, the reaction of 3-
pyrrolyl-oxindole 10 and 1a could also be achieved under the
optimal conditions, leading to the generation of two separable
epimers 11 and 11′ in a spiro-bridged heterocyclic system and
each with excellent enantioselectivity. Spiro-bridged 5′a was
treated with LiAlH4 to afford the hemiaminal intermediate 12,
which subsequently underwent a p-TsOH promoted ring-
expansion reaction, yielding the bridged seven-membered
heterocyclic scaffold 13 containing two adjacent indole
moieties. Additionally, the hemiaminal intermediate 14 was
obtained by treatment of spiro-fused 9′a with LiAlH4, followed
by an unexpected ring cleavage reaction to afford indolo[3,2-
a]carbazole derivative 15 in high isolated yield (90% over two
steps), which might exhibit potential biological activity.19
Finally, the lactol intermediate 8′a could also be reduced by
LiAlH4 to provide an unstable hemiaminal intermediate 16,
which was stabilized by methylation protection to give 17 in
54% yield (two steps) with excellent diastereoselectivity (dr
>20:1).
Scheme 4. Synthesis of Spiro-Bridged Heterocyclic Products
9a and 9′a
imidazolidinone catalysts in aqueous media (MeCN/H2O, v/
v = 5/1) at 25 °C (see Table S2 in the SI for full optimization
studies),18a we found that the Michael adducts 8a and 8′a
could be obtained as two separable diastereomers, when using
3′ as the aminocatalyst, and the subsequent p-Toluenesulfonic
acid (p-TsOH) catalyzed intramolecular Friedel−Crafts
alkylation between the indole and lactol moieties afforded
the desired spiro-fused heterocyclic product 9a and 9′a in
good yield (9a, 30%; 9′a, 42%; over two steps based on 7a)
and with excellent enantioselectivities (98% and 99% for two
diastereomers, respectively).
Next, the substrate scope with respect to 6 and 7 was
initially explored. As shown in Scheme 5, the designed two-
In conclusion, based on the reactivity inversion strategy, we
developed two different two-step sequences to synthesize
C
DOI: 10.1021/acs.orglett.8b02731
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Scheme 6. Useful Transformations
ACKNOWLEDGMENTS
■
This work was supported by the NSFC-Shandong Joint Fund
for Marine Science Research Centers (No. U1606403), the
Scientific and Technological Innovation Project Financially
Supported by Qingdao National Laboratory for Marine
Science and Technology (No. 2015ASKJ02-06), and the
National Natural Science of China (No. 81561148012).
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02731.
Detailed optimization, experimental procedures, spectro-
scopic data for all new compounds, X-ray data, and
proposed reaction mechanism of the two different two-
step sequences (PDF)
Accession Codes
CCDC 1863212−1863213 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: liuyankai@ouc.edu.cn.
ORCID
Yu Tang: 0000-0001-8224-4639
Yan-Kai Liu: 0000-0002-6559-2348
Notes
The authors declare no competing financial interest.
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