Bioinspired total synthesis of katsumadain A by organocatalytic enantioselective 1,4-conjugate addition

Article abstract of DOI:10.3762/bjoc.9.182

Katsumadain A, a naturally occurring influenza virus neuraminidase (NA) inhibitor, was synthesized by using a bioinspired, organocatalytic enantioselective 1,4-conjugate addition of styryl-2-pyranone with cinnamaldehyde, followed by a tandem Horner-Wadsworth-Emmons/oxa Michael addition.

Full text of DOI:10.3762/bjoc.9.182

Bioinspired total synthesis of katsumadain A
by organocatalytic enantioselective
1,4-conjugate addition
Yongguang Wang, Ruiyang Bao, Shengdian Huang and Yefeng Tang*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1601–1606.
The Comprehensive AIDS Research Center, Department of
Pharmacology & Pharmaceutical Sciences, School of Medicine,
Tsinghua University, Beijing, 100084, China
doi:10.3762/bjoc.9.182
Received: 30 May 2013
Accepted: 16 July 2013
Published: 06 August 2013
Email:
Yefeng Tang* - yefengtang@tsinghua.edu.cn
This article is part of the Thematic Series "Transition-metal and
organocatalysis in natural product synthesis".
* Corresponding author
Keywords:
Guest Editors: D. Y.-K. Chen and D. Ma
bioinspired synthesis; catalysis; katsumadain A; natural product;
organocatalytic 1,4-conjugate addition
© 2013 Wang et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Katsumadain A, a naturally occurring influenza virus neuraminidase (NA) inhibitor, was synthesized by using a bioinspired,
organocatalytic enantioselective 1,4-conjugate addition of styryl-2-pyranone with cinnamaldehyde, followed by a tandem
Horner–Wadsworth–Emmons/oxa Michael addition.
Introduction
2-Pyranone is a privilege structure that is often present in human influenza virus A/PR/8/34 of the subtype H1N1 (IC50
natural products and pharmaceuticals, many of which exhibit 1.05–0.42 μM) by targeting the enzyme neuraminidase (NA)
diverse molecular architectures and biological profiles [1,2]. [4,5]. Moreover, it also inhibited the NA of four H1N1 swine
For example, katsumadain A (1) and B (2), which were isolated influenza viruses with IC50 values between 0.59 and 1.64 μM.
from Alpinia katsumadai Hayata (Zingiberaceae), a chinese Therefore, katsumadain A represents an attractive lead struc-
herbal drug used as an anti-emetic and stomachic agent, are two ture for the anti-flu drug discovery [6].
natural products bearing a diarylheptanoid scaffold that is incor-
porated into the styryl-2-pyranone moiety [3]. Preliminary bio- We recently reported the biomimetic total synthesis of
logical evaluations showed that 1 and 2 feature anti-emetic katsumadain C [7], a natural product isolated from the same
activities on copper sulfate-induced emesis in young chicks. resource as katsumadain A and B [8]. As part of our continuous
More recently, Rollinger et al. disclosed that katsumadain A (1) interest in the synthesis of bioactive 2-pyranone-derived natural
exhibited prominent in vitro inhibitory activity against the products, we launched a project aiming to develop a highly effi-
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Beilstein J. Org. Chem. 2013, 9, 1601–1606.
cient route for the synthesis of katasumadain A as well as its designed as a fallback, in which katsumadain A could be
analogues, which would pave the way for their application in accessed from the lactol 5a and phosphonate 6 via a tandem
further biomedical investigations.
Horner–Wadsworth–Emmons (HWE)/oxa-Michael addition
reaction [16]. In turn, 5a could be derived from 3 and
Biosynthetically, katsumadain A is assumed to be derived from cinnamaldehyde (7) by an organocatalytic enantioselective 1,4-
styryl-2-pyranone 3 and alnustone (4) [9] through a 1,6-conju- conjugate addition followed by the hemiketal formation.
gate addition/oxa-Michael addition cascade reaction (path a,
Scheme 1). Indeed, both 3 and 4 are known natural substances. Results and Discussion
Apparently, the biosynthetic pathway represents the most Our investigation was initiated by an investigation of the condi-
straightforward and convergent approach to synthesize tions that could effect the proposed biomimetic approach
katsumadain A. However, its efficiency might be limited to towards katsumadain A and katsumadain B. Both styryl-2-pyra-
some extent, given that α,β,γ,δ-unsaturated ketone 4 could none 3 [17] and alnustone (4) [18] were synthesized according
undergo a competitive 1,4-conjugate addition to provide the to the literature methods. First of all, the 1,6-conjugate addition
other natural product katsumadain B (path b, Scheme 1). Actu- of 3 towards 4 was attempted by employing various conditions,
ally, the regioselectivity of a conjugate addition with α,β,γ,δ- including different basic conditions (NaH, DBU, KHMDS) by
unsaturated Michael acceptors remains a considerable chal- activation of the nucleophile 3 or acidic conditions (AcOH,
lenge, as it is heavily dependent on the steric and electronic TMSOTf, Sc(OTf)3 and In(OTf)3) by activation of the elec-
nature of the substrates [10,11]. Moreover, the enantioselective trophile 4. However, all of these reactions failed to provide
1,6-conjugate addition to acyclic dienones or dienoates mono- satisfactory results and only lead to the recovery or the substan-
substituted at the β- and δ-position has rarely been investigated tial decomposition of the starting material. We then turned our
[12-15], thus leaving open the question of whether or not a attention to the organocatalytic conjugated addition reaction.
biomimetic approach towards katsumadain A might succeed. Among the various documented conditions [19-23], the
Keeping these concerns in mind, an alternative strategy was 9-amino-9-deoxyepicinchona alkaloid-promoted Michael addi-
Scheme 1: Proposed biosynthetic pathway and strategic analysis for synthesis of katsumadain A.
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Beilstein J. Org. Chem. 2013, 9, 1601–1606.
tion is particularly attractive, mainly due to the availability of
the catalyst and its superior reactivity towards the activation of
the unsaturated ketone substrates through formation of the
corresponding iminium intermediate [22]. To our delight, when
we tried the standard conditions (30% catalyst A, 60% TFA,
DCM, 96 h) in our case, we isolated a product in 25% isolated
yield, which was proved to be the 1,4-adduct katsumadain B
(2). Encouraged by this result, we further optimized the reac-
tion by screening different solvents (CH3CN, THF, DMSO and
MeOH) and additives (HCl, TFA and DMAP), aiming to
improve the efficiency and selectivity (1,4- or 1,6-adduct) of the
reaction. In most of the cases the 1,4-conjugate addition
proceeded dominantly, while no or only trace amounts of the
1,6-adduct katsumadain A (1) was observed. The best result
was obtained when the reaction was performed with a substoi-
chiometric amount of catalyst A with MeOH as a solvent, in
which katsumadain A and B were isolated in a 5:6 ratio with a
combined yield of 33% (Scheme 2).
Scheme 2: Preliminary results of the biomimetic synthesis of
katsumadain A.
selectivity issues, which we have struggled with in the afore-
mentioned studies. To validate this hypothesis, we performed a
With limited success regarding the the biomimetic synthesis of systematic investigation of the organocatalytic 1,4-conjugate
katsumadain A, we then moved towards the alternative ap- addition by examining various reaction parameters, including
proach as described in Scheme 1. We envisioned that in this organocatalyst, acid additive, solvent temperature, and reaction
scenario an organocatalytic 1,4-conjugate addition [24-27] temperature (Table 1). The first reaction was performed by stir-
between 3 and 7 would circumvent both the reactivity and ring a mixture of 3 and 7 in DCM at room temperature for 12 h
Table 1: Condition screening of organocatalytic 1,4-conjugate addition/hemiketalization of styryl-2-pyranone with α,β-unsaturated aldehydes.
Entrya
Catalyst
Additive
Solvent
T (°C)
Yield (%)
ee (%)b
1
B
B
C
D
B
B
B
B
B
B
B
B
none
BA
DCM
23
23
23
23
23
23
23
23
23
0
41
78
41
10
94
80
78
79
66
78
82
45
78
91
−81
nd
80
91
75
93
91
92
92
93
2
DCM
3
BA
DCM
4
BA
DCM
5
PNBA
BA
DCM
6
MeOH
CH3CN
DMSO
Toluene
MeOH
DCM
7
BA
8
BA
9
BA
10
11
12
BA
BA
0
BA
DCM
−20
aEach reaction was run with 3 (0.5 mmol) and 7 (0.6 mmol) in 2.0 mL solvent as shown above. bThe ee value was measured with the corresponding
lactone product of 5a using chiral HPLC.
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Beilstein J. Org. Chem. 2013, 9, 1601–1606.
in the presence of Hayashi catalyst B [28]. It was found that the To evaluate the substrate scope of the reaction, we then exam-
desired product 5a was obtained, albeit in moderate yield and ined different substituted styryl-2-pyranone and cinnamalde-
enantioselectivity (Table 1, entry 1). To our delight, the usage hyde derivatives as Michael addtion donors and acceptors
of benzoic acid (BA) as an additive could dramatically improve (Table 2). When styryl-2-pyranone 3a remained unchanged, a
the reaction by affording 5a in a good yield (78%) and a good variety of cinnamaldehyde derivatives (7a–f) bearing either
ee value (91%, Table 1, entry 2). Besides the catalyst B, both electron-withdrawing groups (4-Cl, 4-CF3 and 4-NO2, Table 2,
Jørgensen catalyst C [29] and MacMillan catalyst D [30] were entries 2-4) or electron-donating groups (4-MeO or 3,5-MeO,
also tested in this reaction, but gave inferior results (Table 1, Table 2, entries 5 and 6) on the phenyl ring proved to be suit-
entries 3 and 4). As to the acid additive, p-nitrobenzoic acid able substrates, affording the corresponding products (5b–f) in
(PNBA) was found to afford 5a in an excellent yield, but with a good yields and enantioselectivities. Besides 3a, the Michael
decreased ee value (80%). Furthermore, the solvent effect was addition donors could also be extended to other substituted
also examined. Among the several solvents examined, both styryl-2-pyranone derivatives (e.g., 3b and 3c, Table 2, entries
MeOH and DMSO proved to be suitable solvent systems 7–11), all of which gave acceptable results. As proof-of-concept
(Table 1, entries 6 and 8) by furnishing comparable results with cases, the above outcomes indicate that the developed
DCM, while MeCN and toluene led to modest results (Table 1, organocatalytic enantioselective 1,4-conjugate addition could be
entry 7 and 9). Finally, we found that the reaction temperature potentially applied to the synthesis of various bicyclic com-
has some influence on the outcomes, with a slightly improved pounds bearing different aromatic moieties (Ar1 and Ar2),
enantioselectivity (92% ee) obtained at 0 °C (Table 1, entry 10 which paves the way to access katsumadain A and its analogues
and 11). Although the best ee value (93%) was achieved at for further biomedical studies.
−20 °C, the reaction became sluggish and the yield dropped to
45% (Table 1, entry 12). It is noteworthy that 5a was isolated as Having achieved the bicyclic core of katsumadain A in
a mixture of C-5 diastereoisomers (β-isomer/α-isomer = 5:1 to an efficient and enantioselective manner, we then moved
7:1) in all of the above cases. For convenience, the ee value of towards its total synthesis through the proposed tandem
5a was determined with the corresponding lactone derivative. Horner–Wadsworth–Emmons/oxa-Michael addition. As
Furthermore, the absolute stereochemistry of 5a (β-isomer) was expected, deprotonation of 6 [31] with KHMDS at −40 °C for
assigned as (7S,5R) by using the Mosher ester method (see 0.5 h followed by the addition of the lactol 5a led to the forma-
Supporting Information File 1 for details).
tion of katsumadain A as the only diastereoisomer in 52% yield,
Table 2: Substrate scope of organocatalytic 1,4-conjugate addition/hemiketalization of styryl-2-pyranones with α,β-unsaturated aldehydes.
Entrya
Substrate (3 and 7)
Yield of 5 (%)b
ee value of 5 (%)c
1
3a: Ar1 = Ph; 7a: Ar2 = Ph
82 (5a)
59 (5b)
77 (5c)
79 (5d)
78 (5e)
70 (5f)
84 (5g)
88 (5h)
76 (5i)
75 (5j)
79 (5k)
92
83
82
88
87
92
82
84
91
80
90
2
3a: Ar1 = Ph; 7b: Ar2 = 4-Cl-Ph
3a: Ar1 = Ph; 7c: Ar2 = 4-CF3-Ph
3a: Ar1 = Ph; 7d: Ar2 = 4-NO2-Ph
3a: Ar1 = Ph; 7e: Ar2 = 4-MeO-Ph
3a: Ar1 = Ph; 7f: Ar2 = 3,5-MeO-Ph
3b: Ar1 = 4-MeO-Ph; 7a: Ar2 = Ph
3c: Ar1 = Furan; 7b: Ar2 = 4-Cl-Ph
3c: Ar1 = Furan; 7d: Ar2 = 4-NO2-Ph
3c: Ar1 = Furan; 7e: Ar2 = 4-MeO-Ph
3c: Ar1 = Furan; 7g: Ar2 = Naphthyl
3
4
5
6
7
8
9
10
11
aEach reaction was run with 3 (0.5 mmol) and 7 (0.6 mmol) in 2.0 mL solvent as shown above. bEach of 5a–k was obtained as a mixture of C-5 dia-
stereoisomers (the ratio of α-isomer:β-isomer varied from 1:5 to 1:7. cThe ee value of 5a–k was measured with the corresponding lactone product
using chiral HPLC.
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apparently via the in situ generated intermediate 8. The spectro- Experimental
scopic data of the synthetic katsumadain A were in accordance Representative procedure for the organocatalytic 1,4-conju-
with those of the natural one [32]. However, we found that its gate addition: To a mixture of 3a (214 mg, 1.0 mmol) and 7a
optical rotation ([a]D25 = −75.4, c 0.40, EtOH) was quite (163 mg, 1.2 mmol) in dry CH2Cl2 (5 mL) at 0 °C was added
different from the reported one ([a]D25 +3.7, c 0.40, EtOH), PhCOOH (24 mg, 0.2 mmol) and catatalyst B (50 mg,
indicating that the naturally occurring 1 might exist as a racemic 0.2 equiv). The mixture was stirred at 0 °C for 10 h before
substance. Given that the two enantiomers of katsumadain A being quenched by saturated aqueous NH4Cl. The mixture was
might show different behaviors in the biological studies from extracted with DCM (3 × 10 mL), and the organic layers were
each other as well as from the racemic compounds, we also washed with brine and dried over MgSO4. The organic solvent
synthesized (+)-katsumadain A in a similar way by simply was removed under vacuum, and the residue was purified by
replacing the catatalyst B with its enantiomer in the organocat- column chromatography (CH2Cl2:ethyl acetate = 20:1) to give
alytic 1,4-conjugate addition (Scheme 3).
5a (284 mg, 82% yield) as a light yellow solid.
Supporting Information
Supporting Information File 1
Experimental procedures and characterization data for
synthetic 1, 3a–c, 5a–k and 9a–k.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-182-S1.pdf]
Acknowledgements
This work was financially supported by the National Science
Foundation of China (21102081, 21272133), the Beijing
Natural Science Foundation (2132037), the New Teachers' Fund
for Doctor Stations (20110002120011), the Scientific Research
Foundation for the Returned Overseas Chinese Scholars, and
the Ministry of Education.
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