Enantioselective heterocyclic synthesis of spiro chromanone-thiochroman complexes catalyzed by a bifunctional indane catalyst

Article abstract of DOI:10.1039/c0cc03489d

Novel asymmetric domino reactions of benzylidenechroman-4-ones and 2-mercaptobenzaldehydes for efficient construction of spiro chromanone- thiochroman complexes were accomplished with high yields and excellent selectivities via a novel bifunctional indane

Full text of DOI:10.1039/c0cc03489d

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Enantioselective heterocyclic synthesis of spiro chromanone–thiochroman
complexes catalyzed by a bifunctional indane catalystw
Yaojun Gao, Qiao Ren, Hao Wu, Maoguo Li and Jian Wang*
Received 26th August 2010, Accepted 7th October 2010
DOI: 10.1039/c0cc03489d
Novel asymmetric domino reactions of benzylidenechroman-4-
ones and 2-mercaptobenzaldehydes for efficient construction of
spiro chromanone–thiochroman complexes were accomplished
with high yields and excellent selectivities via a novel bifunctional
indane catalyst.
the novel stereogenic spiro center, poses a great synthetic
challenge. Thereby efficient stereoselective synthesis is highly
desirable. Only a few asymmetric transformations, such as
1,3-diploar cycloaddition reaction, have proven to be suitable
for achieving this challenging goal. However, to the best of our
knowledge, to date there has been no report on catalytic
enantioselective synthesis of spiro chromanone–thiochroman
complexes. Furthermore, thiochroman, as an important
building block, is also frequently observed in natural products
and pharmaceutical drugs with many potential bio-
logical activities.7 Therefore, the combination of chromanone
and thiochroman (spiro structure) may introduce some
unprecedented benefits to drug discovery.
The structural complexity and well-defined three-dimensional
architecture of natural molecules are generally correlated with
specificity of action and potentially useful biological properties.1
This complexity has inspired a generation of synthetic chemists
to design novel enantioselective strategies for assembling
challenging target structures and reproducing the rich struc-
tural diversity inherent in natural molecules.2
Following in the footsteps of asymmetric organocatalysis,8
several closely organocatalytic systems have emerged as
powerful tools to address many various challenging synthetic
problems, and have resulted in the synthesis of complex
molecules via a one-pot process.9 One of the big advantages
of such one-pot domino reactions over classical synthesis is
that at least two reactions are carried out in a single operation
under the same reaction conditions. Furthermore, this avoids
time-consuming, costly protecting-group manipulations as
well as the isolation of reaction intermediates. In this way,
molecular complexity will be achieved quickly, often accompanied
by high levels of stereoselectivity. Inspired by these protocols,
we herein report a one-pot cyclization reaction (Scheme 2) for
efficient synthesis of spiro chromanone–thiochroman hetero-
cycles in excellent enantioselectivity and yield, using bifunctional
indane amine-thiourea catalyst 5 (Fig. 1) which was developed
by our group. The notable features of this protocol include (1)
in this particular reaction, indane catalyst 5 provides an
excellent stereo-control (92–99% ee, up to 57 : 1 d.r.); (2)
a ring-fused spiro chromanone–thiochroman complex with
three contiguous stereogenic centers and one quaternary
carbon is generated in a one-pot manner under mild con-
ditions with high yields (93–98%).
Highly functionalized 4-chromanones have attracted much
attention due to their significant pharmacological properties.3
They are also versatile intermediates for the synthesis of many
natural products such as brazilin, hematoxylin, ripariochromene
and clausenin.4 As the core component, the spirocyclic
4-chromanone is featured in a large number of pharmacologically
active compounds as well as natural products.3b Naturally
occurring compound morellin I (Scheme 1) and complex II
exhibit significant biological and pharmacological properties,
such as antibacterial, antifungal and antitumor activities.3a,b
Compound III5 has the typical nucleus of sesquiterpene-
phenols, marine natural products with potential antimalarial,
antituberculosis, and antiviral properties. Acetyl-CoA carboxylase
(ACC) inhibitor IV6 and its derivatives demonstrate the
potential to favorably affect the multitude of risk factors
associated with metabolic syndrome, obesity and type-2 diabetes.
However, its stereo-controlled synthesis, particularly installing
To probe the feasibility of the proposed asymmetric cycli-
zation reaction, (E)-3-benzylidenechroman-4-one (7a) was
reacted with 2-mercaptobenzaldehyde (6a) in the presence
of Takemoto’s amine-thiourea catalyst 110 (Fig. 1) and
Connon,11 and Soos’s12 cinchona alkaloid amine-thiourea
catalyst 2 (Fig. 1) in CH2Cl2 at room temperature. Catalysts
1 and 2, as two of the most successful bifunctional amine-
thiourea catalysts, have been applied to many asymmetric
transformations. As shown in Table 1, 85 and 86% ee were
achieved with 97 and 91% yields, respectively. However, both
catalysts 1 and 2 only provide moderate diastereoselectivity
(Table 1; 2.3 : 1 and 2.4 : 1 d.r., respectively). To the best of our
knowledge, the dihedral angle between two functional groups
is one of the key issues for stereo-control. We envisioned that a
Scheme 1 Examples of biologically active spiro chromanones.
Department of Chemistry, National University of Singapore,
3 Science Drive 3, Singapore 117543. E-mail: chmwangj@nus.edu.sg;
Fax: (+) 65-6516-1691
w Electronic supplementary information (ESI) available: Experimental
section. CCDC 784884 (compound 12). For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c0cc03489d
c
9232 Chem. Commun., 2010, 46, 9232–9234
This journal is The Royal Society of Chemistry 2010

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angle. For the cinchona alkaloid amine-thiourea catalyst 2,
from a synthetic aspect, the quinuclidine structure (amine
part) is very difficult to modify. To this challenge, we feel that
the introduction of a novel scaffold with C1 symmetry might
change this situation and solve the stereo-control problem.
Inspired by this hypothesis, we were impressed by an ideal
indane scaffold. It has some impressive features: (1) a scaffold
with C1 symmetry; (2) exchange of two functional group
positions will obviously adjust the dihedral angle; (3) commercially
available starting material, chiral indane amino alcohol, from
a synthetic standpoint, will benefit to the functional group
modification in an efficient and concise manner.
To explore the rationality of our proposed rational design,
a series of indane amine-thiourea catalysts 3–5 has been
synthesized (for synthetic details see ESIw). It includes (1)
modifications on the conformation of amine functional group
(catalyst 3a, 3b and 3c); (2) a specific alternation on the relative
orientation of amine and thiourea functional groups (catalysts
3c and 5); (3) adjustment of the relative positions of amine and
thiourea functional groups (catalysts 4 and 5). Eventually, the
novel catalyst 5 was discovered as an ideal promoter to
catalyze this one-pot cyclization process under the same con-
dition as above (Table 1, entry 7). Surprisingly, this reaction
proceeded smoothly to furnish the desired product 8a in 98%
yield and much improved selectivity (entry 7; 93% ee and
5.0 : 1 d.r.). Upon investigating a variety of other reaction
parameters, such as temperature, concentration and solvent,
we found that the desired reaction manifold could be achieved
through an appropriate choice of solvent and temperature.
Therefore, by conducting the one-pot cyclization reaction in
xylenes under optimized temperature (ꢀ30 1C) condition, we
can efficiently generate the spiro complex target, which bears
three contiguous stereocenters.
Scheme 2 Strategy for the synthesis of chiral spiro chromanone–
thiochroman complex.
Fig. 1 Evaluated bifunctional amine-thiourea organocatalysts.
Table 1 Influence of the bifunctional organocatalyst and optimi-
zation of asymmetric cyclization reaction conditionsa
After the optimal conditions had been established, the
generality of this catalytic process was explored. Remarkably,
this enantioselective one-pot cyclization process can serve as
an efficient synthetic route for the preparation of spiro
chromanone–thiochromans (Table 2). Significantly, the new
stereogenic centers were efficiently created in high enantio-
selectivities (92–99% ee) and good to excellent diastereo-
selectivities (1.2: 1 to 57 : 1 d.r.) in a one-pot manner. Moreover,
the process afforded a new spiro center, and also significant
structural variation of (E)-3-alkyl and arylenechroman-4-ones
7 could be tolerated (Table 2, entries 1–16 and 19–25 when
R = aryl; entries 17–18 when R = alkyl). The process also
bore the replacement of O by S and C to introduce different
heterocycles (entries 19 and 20). The experimentation revealed
that the electronic and steric nature had obvious effect on
diastereoselectivity (entries 4, 7, 17 and 18), but minimal
impact on efficiency and enantioselectivity. The 5-promoted
asymmetric cyclization process also took place with a variety
of 2-mercaptobenzaldehyde Michael donors, which possess
neutral (entries 1–22), electron-donating (entries 23 and 24)
and electron-withdrawing groups (entry 25). In each case, the
process proceeded rapidly (8–24 h), in high yields (93–98%),
high to excellent enantiomeric excesses (92–99% ee) and
diastereomeric ratios (1.2 : 1 to 57 : 1 d.r.). The absolute
configuration of the spiro chromanone–thiochroman 8e was
unequivocally determined by single-crystal X-ray diffraction
Entry
Catalyst
Yieldb (%)
d.r.c
ee (%)d
1
2
3
4
5
6
7
1
2
3a
3b
3c
4
5
5
5
5
97
91
97
90
89
93
98
97
97
96
94
2.3 : 1
2.4 : 1
1.6 : 1
1.5 : 1
1.5 : 1
1.5 : 1
5.0 : 1
6.3 : 1
7.0 : 1
8.0 : 1
6.4 : 1
85
ꢀ86
78
67
77
ꢀ82
93
97
8e
9f
10g
11h
97
97
94
5
a
Reaction was conducted on 0.1 mmol scale in DCM (1.0 mL), and
b
c
the ratio of 6a : 7a is 1 : 1.2. Yield of isolated product. Determined
by 1H NMR analysis of the crude mixture. Determined by HPLC
d
e
analysis. Xylenes as solvent. Reaction was performed in xylenes at
f
g
0 1C for 3 h. Reaction was performed in xylenes at ꢀ30 1C for
h
8 h. Reaction was performed in xylenes at ꢀ50 1C for 24 h.
change of the dihedral angle between the functional groups of
the amine and thiourea might introduce an ideal and stable
transition state to assist the generation of excellent stereo-
selectivity. Takemoto’s amine-thiourea catalyst 1 has a cyclo-
hexane scaffold with C2 symmetry. Therefore, the exchange of
two functional group positions will not affect the dihedral
c
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Table 2 Preliminary substrate scope of the asymmetric cyclization
reaction catalyzed by indane amine-thiourea 5a
bifunctional indane amine-thiourea catalyst 5.
A
broad
substrate scope of spiro chromanone–thiochromans were
obtained. Further application of the catalytic system to other
new reactions is currently under investigation.
We gratefully acknowledge the National University of
Singapore for financial support of this work (Academic
Research Grants: R143000408133, R143000408733 and
R143000443112).
Yieldb
(%)
eed
Entry X
Y
Z
R
d.r.c (%)
1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
O
O
O
O
O
O
O
O
O
O
O
O
O
Ph (8a)
96
98
96
97
97
97
95
96
96
98
97
97
98
8.0 : 1 97
8.1 : 1 95
7.6 : 1 97
19 : 1 95
7.7 : 1 97
8.2 : 1 95
20 : 1 97
8.0 : 1 96
8.0 : 1 96
11 : 1 99
10 : 1 98
8.0 : 1 97
17 : 1 98
Notes and references
2
4-ClC6H4 (8b)
3-ClC6H4 (8c)
2-BrC6H4 (8d)
4-NO2C6H4 (8e)
3,4-Cl2C6H3 (8f)
2-F,4-ClC6H3 (8g)
4-MeOC6H4 (8h)
4-AllyloxyC6H4 (8i)
2-AllyloxyC6H4 (8j)
3-PhOC6H4 (8k)
4-iPrC6H4 (8l)
6-Br-benzodioxole
(8m)
3e
4
1 For reviews, see: (a) K. C. Nicolaou and T. Montagnon,
Molecules that Changed the World: A Brief History of the Art
and Science of Synthesis and its Impact on Society, Wiley,
Weinheim, 2008; (b) K. C. Nicolaou and E. J. Sorensen,
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Chem., 2010, 2, 167; (b) K. C. Nicolaou and J. S. Chen, Chem. Soc.
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3 Books and selected examples of applications of chromanone:
(a) F. M. Dean, Naturally Occurring Oxygen Ring Compounds,
Butterworths, London, 1963; (b) G. P. Ellis, Chromans and
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5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
6-
O
O
O
O
O
5-Me-furan (8n)
2-Thiophene (8o)
1-Naphthyl (8p)
Isopropyl (8q)
Cyclohexyl (8r)
96
98
95
96
98
96
97
98
8.4 : 1 96
8.3 : 1 97
4.5 : 1 95
57 : 1 95
24 : 1 96
10 : 1 95
1.2 : 1 96
16 : 1 97
4 B. Chenera, M. L. West, J. A. Finkelstein and G. B. Dreyer, J. Org.
Chem., 1993, 58, 5605.
5 B. S. Crombie, A. D. Redhouse, C. Smith and T. W. Wallace,
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CH2 Ph (8s)
S
O
Ph (8t)
Ph (8u)
6 T. Yamakawa, H. Jona, K. Niiyama, K. Yamada, T. Iino,
M. Ohkubo, H. Imamura, J. Kusunoki and L. Yang, Int. Pat.,
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and R. E. Bambury, J. Med. Chem., 1970, 13, 238; (b) W. Quaglia,
M. Pigini, A. Piergentili, M. Giannella, F. Gentili, G. Marucci,
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CH3
6-Cl
H
22
23
24
H
5-CH3
5-
OMe
5-Cl
O
O
O
Ph (8v)
Ph (8w)
Ph (8x)
97
96
97
11 : 1 98
9.0 : 1 96
15 : 1 95
H
25
H
O
Ph (8y)
93
8.0 : 1 92
a
Unless specified, see the Experimental section for reaction conditions.
c
Yield of isolated product. Determined by H NMR analysis of the
b
1
d
crude mixture. Determined by HPLC analysis. Room temperature.
e
8 For book reviews of asymmetric organocatalysis, see:
(a) A. Berkessel and H. Groger, Asymmetric Organocatalysis,
Wiley, Weinhein, 2005; (b) P. I. Dalko, Enantioselective Organo-
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Bonding in Organic Synthesis, Wiley, Weinhein, 2009.
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T. R. Wagerle and T. Lectka, Org. Lett., 2002, 4, 387;
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analysis of the Ts-derived spiro chromanone–thiochroman 12
(see ESIw).
Because of the potential biological activities exhibited
by the spiro ring system, structural elaboration of the
spiro 4-chromanone core is also extremely important. Spiro
chromanone–thiochromanone complex 9 has been considered
as a useful intermediate and thus we wish to discover an
efficient way to afford it. Surprisingly, the oxidation of 8a via
2-iodoxybenzoic acid (IBX) afforded the desired compound 9
with an excellent reaction yield (93%) but without any loss
of enantiomeric excess (from 97% ee to 97% ee) [eqn (1)].
Meanwhile, the large scale synthesis from 0.5 g of 6a
demonstrated that there was no obvious alteration on the
reaction results (94% yield, 7.9: 1 d.r., and 97% ee).
10 T. Okino, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc., 2003,
125, 12672.
11 S. H. McCooey and S. J. Connon, Angew. Chem., 2005, 117, 6525;
S. H. McCooey and S. J. Connon, Angew. Chem., Int. Ed., 2005,
44, 6367.
ð1Þ
In conclusion, we have developed an efficient asymmetric
cyclization reaction, catalyzed by our developed chiral
12 CCDC 784884 (compound 12) contains supplementary crystallo-
graphic data for this paper.
c
9234 Chem. Commun., 2010, 46, 9232–9234
This journal is The Royal Society of Chemistry 2010