Substrate-Controlled, One-Pot Synthesis: Access to Chiral Chroman-2-one and Polycyclic Derivatives

Article abstract of DOI:10.1021/acs.orglett.6b00160

Based on the appropriate choice of electrophiles, one-pot, multicomponent, enantioselective domino reactions have been realized which contain a five-step sequence and provide highly efficient access to potentially bioactive chroman-2-one derivatives as a single diastereoisomer with excellent enantioselectivities and in high yields. This new strategy could significantly improve the previous protocol by directly starting from commercial 2-hydroxybenzaldehydes rather than preformed lactols, which have to be synthesized in several additional steps. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.6b00160

Letter
pubs.acs.org/OrgLett
Substrate-Controlled, One-Pot Synthesis: Access to Chiral Chroman-
2-one and Polycyclic Derivatives
Xue-Li Sun,† Ying-Han Chen,† Dan-Yang Zhu,† Yan Zhang,‡ and Yan-Kai Liu*,†
†Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China,
Qingdao 266003, P. R. China
‡Hubei Key Laboratory for Processing and Application of Catalytic Materials, Huanggang Normal University, Huanggang 438000, P.
R. China
S
* Supporting Information
ABSTRACT: Based on the appropriate choice of electro-
philes, one-pot, multicomponent, enantioselective domino
reactions have been realized which contain a five-step
sequence and provide highly efficient access to potentially
bioactive chroman-2-one derivatives as a single diaster-
eoisomer with excellent enantioselectivities and in high yields.
This new strategy could significantly improve the previous
protocol by directly starting from commercial 2-hydroxyben-
zaldehydes rather than preformed lactols, which have to be
synthesized in several additional steps.
he use of lactols or cyclic hemiaminals as nucleophiles in
complex molecular architectures.4 Although considerable efforts
Tenamine catalysis represents an important expansion of have been devoted to the development of such methodology, a
more powerful domino process, which could maximize the
elimination of time-consuming and costly purification proce-
dures, is still highly desirable. Additionally, with the appropriate
choice of substrates, the development of a substrate-controlled
alternative to an existed cascade catalysis process is possible but
challenging, since the newly selected substrate must control
both the reactivity and selectivity to lead to diversity-oriented
synthesis. With this in mind, we argued that the implementa-
tion of domino process into the chemistry of lactols or cyclic
hemiaminals should be beneficial to provide increasingly rapid
access to the synthesis of substituted chiral lactones or lactams.
Encouraged by the well-established iminium organocatalytic
conjugate reduction,5 we hypothesized the preformed chroman-
2-ol 4a in our previous work, the enamine-catalyzed Michael
addition between chroman-2-ol 4a and trans-β-nitrostyrene 2,1a
could be generated by the conjugate reduction of 2-
hydroxycinnamaldehyde 1a, and once the conjugate reductions
occurred, we believe that the inherent hydroxy group of 1a
would then trigger the cyclization to form the required
intermediate chroman-2-ol 4a in situ, which then followed by
the same catalyst directed asymmetric conjugate addition and
subsequent oxidation to generate the designed chiral chroman-
2-one derivatives 5 (Scheme 1, desired path C). However,
several challenges have to be encountered in this straightfor-
ward process: (1) the Michael addition between 2-hydrox-
ycinnamaldehyde 1a and trans-β-nitrostyrene 2 must be
rigorously avoided (Scheme 1, undesired path A);6 and (2)
normal aldehydes in asymmetric synthesis since they could
provide facile access to a large variety of lactones, lactams, and
even more complex heterocyclic frameworks with potential
bioactivity.
Recently, we and others independently reported research on
the utility of lactols or cyclic hemiaminals in enamine catalysis.1
Generally, lactols or cyclic hemiaminals were preformed from
the reduction of corresponding lactones or lactams with
diisobutylaluminum hydride (DIBAL-H). However, even
though we could directly use the in situ generated lactols or
cyclic hemiaminals in the enamine catalytic process and realize
a truly, complete one-pot procedure for this transformation,
there are still several drawbacks: (1) not all the lactones or
lactams are commercially available, and some are even needed
to be synthesized in several additional steps; (2) low-
temperature (generally, −78 °C) and anhydrous solvents are
required for the DIBAL-H induced reduction step; and (3)
moreover, a slightly complex workup is applied to quench the
reduction reaction. Undoubtedly, all of the above-mentioned
disadvantages would decrease the efficiency of the overall
process. On the other hand, since the desired substituted chiral
lactones2 or lactams3 are ubiquitous structural components
presented in natural products and biologically active com-
pounds, the quest for efficient methods to overcome the above-
mentioned drawbacks is extremely appealing and in high
demand.
In recent years, owing to the efficiently formation of multiple
stereocenters and chemical bonds in a single operation, one-
pot, multicomponent, enantioselective domino reactions are
regarded as particularly attractive for accessing of chiral
Received: January 17, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00160
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Letter
a
Scheme 1. Designed Competing Pathways To Synthesize
Substituted Chiral Lactones
Table 1. Selected Optimization Studies
b
c
entry
solvent
acid
yield (%)
ee (%)
1
2
3
4
5
toluene
toluene
toluene
toluene
CH3CN
CH3CN
CH2Cl2
Et2O
A1
A2
A3
A4
A1
A1
A1
A1
A1
85
84
72
87
57
65
84
88
33
>99
99
99
99
99
d
in order to have a full reduction of 2-hydroxycinnamaldehyde
1a with Hantzsch ester 3 based on iminium activation, the
potential H-bonding interaction between the acidic additives
and trans-β-nitrostyrene 2 must be blocked, which may cause
the reduction of trans-β-nitrostyrene 2 and then consume the
only hydride donor, Hantzsch ester 3 (Scheme 1, undesired
path B).7 Taking these considerations into account, it is clear
that central to the success of our hypothetical domino process
is to find a suitable Michael acceptor, which could greatly
balance the chemically selectivity and reactivity to take out the
elucidated challenges. We communicate herein our preliminary
results on this one-pot, multicomponent, organocatalytic
enantioselective domino reaction, which involved a multistep
sequence, iminium/enamine/lactolization/oxidation, leading to
substituted chiral chroman-2-one 5 with excellent diastereo-
and enantioselectivities in good yields and with control of two
adjacent stereogenic centers. It should be noted that the single
commercial catalyst could enable both iminium and enamine
activation in the designed domino process.
Initially, we investigated this domino process with 2-
hydroxycinnamaldehyde 1a and trans-benzoylacrylic ester 6a
in the presence of commercial catalyst 7 and Hantzsch ester 3
as the hydride donor in toluene solvent at room temperature. It
should be pointed out that, in contrast to trans-β-nitrostyrene 2,
the trans-benzoylacrylic ester 6a is a good electrophile but weak
H-bond acceptor,8 which could avoid the H-bonding
interaction induced reduction, and thus, it was selected as the
suitable Michael acceptor. After the completion of the iminium-
reduction/enamine−Michael addition sequence, the original
solvent was replaced with DCM, and the pyridine chlorochro-
mate (PCC)-directed oxidation proved successful leading to the
final chroman-2-one 5a. Pleasingly, the one-pot, multi-
component, enantioselective domino process proceeded
extremely well, and the desired product 5a was isolated as a
single diastereoisomer in 85% yield with excellent enantiose-
lectivity (ee >99%) when PhCOOH was employed as the acidic
additive (Table 1, entry 1). Stimulated by these results, we
further investigated the effects of different reaction media and
acidic additives on the reactivity. Surprisingly, this reaction is
not limited by these screened conditions, and almost no
erosion of the yield or stereoselectivity was observed except for
THF as the solvent, which gave consistently excellent diastereo-
and enantioselectivity but slightly lower yields (Table 1, entries
2−9). Undoubtedly, these results indicated the powerful
synthetic applicability of our domino strategy under a variety
6
>99
99
7
8
9
>99
>99
THF
a
See the Supporting Information for experimental details. Diastereo-
b
meric ratios were determined by chiral HPLC analysis. Isolated yields
for two steps of product 5a. Determined by HPLC analysis over chiral
stationary phases of 5a. 10% (v/v) H2O was added. PCC = pyridine
chlorochromate, TMS = trimethylsilyl, THF = tetrahydrofuran, MTBE
c
d
= methyl tert-butyl ether.
of reaction conditions. However, it is clear that only DCM,
which could be used in the whole domino process without any
unnecessary workup, stands out as the best solvent (Table 1,
entry 7).
As summarized in Scheme 2, with the optimized conditions
(Table 1, entry 7), the substrate generality of this domino
reaction was investigated with respect to both electrophiles and
nucleophiles. Concerning the scope of electrophile 6, both
substituent positions and electronic properties changed in the
aryl moiety were shown to be well tolerated, and excellent
stereoselectivities were obtained in all examined cases (5a−j).
Heteroaromatic groups, such as furan, thiophene, and indole,
could also be employed as the substituent of the electrophile
leading to the desired product with excellent enantioselectivity
(5k−m). Additionally, the ester moiety has no effect on the
reaction outcomes (5n and 5o). Moreover, trans-1,2-dibenzoyl-
ethylene could also be applied in this elegant domino process
(5p). Furthermore, various nucleophiles, regardless of the
substituents on the aromatic groups, proved to have high
reactivity in this reaction (5q−u). It should be noted that when
the nucleophile having a TosNH group instead of an OH group
was used, the efficiency of this domino process was maintained
and thus led to the formation of chiral 3,4-dihydroquinolin-2-
one derivative (5v).
With the successful application of the above reaction
protocol for the construction of highly functionalized chiral
chroman-2-one and 3,4-dihydroquinolin-2-one structures, we
then turned our attention to the preparation of more complex
heterocyclic frameworks. A iminium/enamine/lactolization/
transesterification sequence was designed to further illustrate
the potential of this novel strategy. Surprisingly, catalyzed by p-
TsOH of the last step, this one-pot, multistep sequence
proceeded smoothly to give the fused heterocycle derivatives
with high molecular complexity (Scheme 3). Different
B
DOI: 10.1021/acs.orglett.6b00160
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Organic Letters
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a
substituents in the structures of both 1 and 6 were well-
tolerated, regardless of their positions and electronic properties.
Notably, the corresponding tricyclic γ-lactones, which are
frequently found as privileged intermediates in the synthesis of
numerous natural products and medicines,9 were obtained in
good yield and very high levels of stereocontrol (dr up to 6:1,
ee = 96 to >99%).
Scheme 2. Substrate Scope
As indicated by the retrosynthetic analysis, both 2-
hydroxycinnamaldehyde 1 and trans-benzoylacrylic ester 6
could be easily derivatized from the Wittig reaction. We then
tried to set up this domino reaction via a five-step sequence in
one pot (Scheme 4).10 The overall process started from the in
Scheme 4. Five-Step, One-Pot Synthesis of Substituted
Chiral Chroman-2-one and Tricyclic γ-Lactone
a
See the Supporting Information for experimental details. The isolated
yield is reported. The ee values are determined by HPLC analysis of 5
on chiral stationary phases. Tos = p-methylbenzenesulfonyl. Bs =
benzenesulfonyl.
a
Scheme 3. Synthesis of Tricyclic γ-Lactones
situ generated 1a from the Wittig reaction of 2-hydroxyben-
zaldehyde and ylide 10,11 followed by iminium reduction to
give the chroman-2-ol 4a. It should be highlighted that the
crude reaction mixture of 6 from the Wittig reaction of ethyl 2-
oxoacetate and ylide 1112 could be directly used in the Michael
reaction with 4a under the optimized conditions, and the
subsequent lactolization yielded substituted chroman-2-ol 8,
which delivered the chroman-2-one 5a after PCC-directed
oxidation reaction in good yield (37% for five steps) and
excellent enantioselectivities (ee = 99%) as a single isomer. To
further demonstrate the synthetic utility of this method, the
reaction could be performed on gram scale, and 5a was
obtained in 67% yield (1.2 g) with excellent diastereo- and
enantioselectivity. Moreover, the one-pot, five-step preparation
of 9b could also be realized, affording the enantiomerically
enriched tricyclic γ-lactone with good results (23% for five
steps, ee = 99%, dr = 6:1). The absolute configuration of 9b
was unambiguously determined by X-ray crystallography, and
the absolute configurations of other products were assigned by
analogy.13
a
See the Supporting Information for experimental details. 9f/9f′ and
9g/9g′ are the isolable corresponding epimers, respectively. p-TsOH =
p-toluenesulfonic acid.
In conclusion, we have developed one-pot, multicomponent,
enantioselective domino reactions that contain a five-step
C
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Organic Letters
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(e) Enders, D.; Grondal, C.; Huttl, R. M. M. Angew. Chem., Int. Ed.
̈
sequence and lead to substituted chiral chroman-2-one
derivatives in good isolated yields and excellent diastereo-
and enantioselectivities with control of two adjacent stereogenic
centers. The choice of appropriate electrophiles is the key to
successfully realizing this competitive domino process. It should
be noted that this simplified and atom-economic strategy
significantly improved our previous protocol by directly starting
from commercial 2-hydroxybenzaldehydes rather than pre-
formed lactols, which have to be synthesized individually in
several separate steps. The potentially bioactive chroman-2-ol
derivatives could be easily transformed into polycyclic building
blocks that are difficult to access from traditional methods.
Further applications of this highly efficient method are in
progress.
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00160.
Detailed optimization, experimental procedures, and
spectroscopic data for all new compounds (PDF)
X-ray data for 9b (CIF)
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AUTHOR INFORMATION
Corresponding Author
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*E-mail: liuyankai@ouc.edu.cn.
Notes
The authors declare no competing financial interest.
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64, 3212−3216.
ACKNOWLEDGMENTS
■
We thank the National Nature Science Foundation of China
(No. 21302156), NSFC−Shandong Joint Fund for Marine
Science Research Centers (No. U1406402), the Open Project
Program of Hubei Key Laboratory for Processing and
Application of Catalytic Materials (No. ch201411), and
Ocean University of China (OUC) for generous financial
support.
(10) See the Supporting Information for experimental details.
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(13) CCDC 1438377 (9b) contains the supplementary crystallo-
graphic data for this compound. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
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DOI: 10.1021/acs.orglett.6b00160
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