Sequential Assembly of Morita-Baylis-Hillman Carbonates and Activated ortho-Vinylbenzaldehydes to Construct Chiral Methanobenzo[7]annulenone Frameworks

Article abstract of DOI:10.1021/acs.orglett.9b01058

The α-regioselective asymmetric [3 + 2] annulation reaction of Morita-Baylis-Hillman carbonates from isatins and activated ortho-vinylbenzaldehyses was developed by the catalysis of a chiral tertiary amine. The sequential N-heterocyclic carbene-mediated intramolecular Stetter reaction was conducted to finally furnish the bridged 5,8-methanobenzo[7]annulen-9-one architectures incorporating a spirooxindole motif with excellent stereoselectivity.

Full text of DOI:10.1021/acs.orglett.9b01058

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Sequential Assembly of Morita−Baylis−Hillman Carbonates and
Activated ortho-Vinylbenzaldehydes To Construct Chiral
Methanobenzo[7]annulenone Frameworks
Bo Jiang,† Ben-Xian Xiao,† Qin Ouyang,‡ Hua-Ping Liang,*,‡ Wei Du,† and Ying-Chun Chen*,†,‡
†Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of Education and Sichuan Research Center for Drug
Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
‡State Key Laboratory of Trauma, Burn and Combined Injury, and College of Pharmacy, Third Military Medical University,
Shapingba, Chongqing 400038, China
S
* Supporting Information
ABSTRACT: The α-regioselective asymmetric [3 + 2]
annulation reaction of Morita−Baylis−Hillman carbonates
from isatins and activated ortho-vinylbenzaldehyses was
developed by the catalysis of a chiral tertiary amine. The
sequential N-heterocyclic carbene-mediated intramolecular
Stetter reaction was conducted to finally furnish the bridged
5,8-methanobenzo[7]annulen-9-one architectures incorporat-
ing a spirooxindole motif with excellent stereoselectivity.
he fused and bridged polyhydro-5,8-methanobenzo[7]
annulen-9-one skeleton represents a unique and complex
framework, which has been widely witnessed in a number of
natural products with diverse biological activities. As exemplified
in Figure 1, ansalactam C is a polyketide isolated from a marine-
is a polyphenol secondary metabolite isolated from the bark of
Hopea exalata.5 Moreover, duclauxin belongs to a family of
dimeric and heptacyclic fungal polyketides and exhibits tumor
suppression by inhibiting RNA synthesis.6 The total syntheses of
such complex compounds have attracted continuing interest in
the field of organic and medicinal chemistry.7 Nevertheless, the
studies on developing stereoselective protocols to efficiently
construct chiral methanobenzo[7]annulen-9-one systems are
still limited to date, as noted in an asymmetric [3 + 2] annulation
reaction with 2-alkyl-3-hydroxynaphthalene-1,4-diones and
alkyl vinyl ketones (Scheme 1a),8a and an intramolecular
reductive Heck desymmetrization reaction of cyclopentenes
(Scheme 1b).8b A few methods to construct the analogous
skeletons also have been presented.8c−f
T
Recently, vinyl heteroarenes have been successfully applied as
electrophilic reagents in diverse reactions.9 The analogous
styrenes with strongly electron-withdrawing groups also
exhibited similar reactivity in some asymmetric Michael addition
and dipolar cycloaddition reactions.10 On the other hand, the in
situ generated allylic ylides from Morita−Baylis−Hillman
(MBH) derivatives have been widely applied as 1,3-dipoles in
a variety of [3 + n] annulation reactions.11 We further
established that the preferable γ-regioselectivity could be
switched to α-regioselective version by utilizing activated olefins
bearing bulky functional groups.12 Consequently, as outlined in
Scheme 1c, we envisaged that the allylic ylides from MBH
carbonates and a Lewis base (LB) catalyst would react with
suitably activated ortho-vinylbenzaldehydes in an α-regioselec-
tive [3 + 2] annulation pattern owing to the crowded substituted
Figure 1. Selected natural products embedding a unique 5,8-
methanobenzo[7]annulen-9-one skeleton.
derived bacterium of the genus Streptomyces, having anti-
bacterial activity.1 The analogous neoansamycin B is a cytotoxic
naphthalenic octaketide discovered via activation of a cryptic
gene cluster.2 Daeschol A is a promising immunosuppressant
produced from the mantis-associated fungus.3 Merochlorin A is
a halogenated meroterpenoid obtained from a marine bacterium
Streptomyces sp. strain CNH-189, showing potent antimicro-
bial activity against several Gram-positive bacteria.4 Hopeanol A
Received: March 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01058
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Asymmetric Strategies To Access Chiral 5,8-
Methanobenzo[7]annulenone Derivatives
Table 1. Screening Conditions of Sequential [3 + 2]
Annulation and Stetter Reaction
a
b
c
d
entry
C
1
solvent
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
C1
C2
C2
C3
C4
C5
C6
C7
C5
C5
C5
C5
C5
C5
C5
C5
C5
C5
1a
1a
1b
1a
1a
1a
1a
1a
1a
1a
1a
1c
1d
1d
1d
1d
1d
1d
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
toluene
THF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
3a, 90
3a, 41
trace
5:1
17:1
−54
trace
3a, 78
3a, 62
3a, 54
3a, 42
3a, 42
3a, 76
16:1
14:1
14:1
13:1
14:1
14:1
60
74
64
66
72
75
aromatic moiety, and the resulting intermediates A would
undergo an intramolecular Stetter reaction to furnish the desired
bridged 5,6,7,8-tetrahydro-9H-5,8-methanobenzo[7]annulen-
9-one architectures mediated by an N-heterocyclic carbene
(NHC).
9
10
11
12
13
14
15
16
17
18
3b, 72
3c, 84
4a, 81
4a, 84
4a, 87
4a, 83
4a, 74
15:1
15:1
87
93
94
94
95
93
93
e
>19:1
>19:1
>19:1
>19:1
>19:1
As the initial exploration between simple MBH carbonate
from benzaldehyde and methyl acrylate and 5-nitro-2-vinyl
benzaldehyde13 2a resulted in no success, we turned our
attention to the more reactive MBH carbonates 1 from isatins.
As summarized in Table 1, it was pleasing that the combination
of 1a (PG = Boc, R = Me) and 2a underwent efficient conversion
by the catalysis of DABCO C1, and the expected α-
regioselective [3 + 2] annulation product 3a was isolated in a
high yield with moderate diastereoselectivity (Table 1, entry 1).
Therefore, a few cinchona-derived tertiary amine catalysts were
evaluated.14 Chiral amine C2 derived from quinidine showed
modest catalytic activity, and excellent diastereoselectivity with
fair enantioselectivity was obtained (entry 2). Almost no
reaction was observed by using N-methyl substrate 1b (entry
3). Next, more chiral catalysts were tested with substrates 1a and
2a. Amine C3 with a free OH group from quinine exhibited no
catalytic activity (entry 4), but the O-methyl one C4 gave better
data (entry 5). In addition, introducing a methyl group at 2′-
position further improved the enantiocontrol (C5, entry 6),15
whereas inferior results were afforded with bulkier catalysts C6
and C7 (entries 7 and 8). Solvent screenings (entries 9−11)
indicated that toluene was the optimal choice (entry 10). We
further modified the substitution pattern of MBH carbonate
partners (1c, PG = Boc, R = Et; 1d, PG = Boc, R = tBu), and
significant improvements were gained, probably owing to steric
effect (entries 12 and 13). Moreover, the sequential intra-
molecular Stetter reaction of product 3c could be efficiently
promoted by directly adding carbene precursor C8 and K2CO3
into the mixture, and the desired methanobenzo[7]annulen-9-
one derivative 4a incorporating a spirooxindole motif was
e f
,
e fg
, ,
e fgh
, ,
,
e fgi
, ,
,
a
Unless noted otherwise, reactions were performed with MBH
carbonate 1 (0.06 mmol), activated styrene 2a (0.05 mmol), and
b
catalyst C (10 mol %) in solvent (0.5 mL) at rt for 8−14 h. Isolated
c
d
yield. Determined by 1H NMR analysis. Determined by HPLC
e
analysis on a chiral stationary phase. After completion of [3 + 2]
annulation, carbene precursor C8 (10 mol %) and K2CO3 (0.025
f
g
mmol) were directly added. 4 Å MS (15.0 mg) was added. [3 + 2]
h
i
annulation was conducted at 0 °C for 20 h. At a 0.1 mmol scale. At a
1.0 mmol scale, for 72 h + 24 h.
isolated as a single diastereomer (entry 14). Slightly better
results were attained by adding 4 Å MS and conducting the [3 +
2] annulation at 0 °C (entries 15 and 16). The sequential
asymmetric reaction still proceeded well at larger scales, though
slightly reduced yields were observed (entries 17 and 18).
With the optimized catalytic conditions in hand, the substrate
scope and limitations of MBH carbonates 1 and activated ortho-
vinylbenzaldehydes 2 were explored. In general, the [3 + 2]
annulations were conducted in toluene at 0 °C under the
catalysis of chiral amine C5. After completion, the sequential
Stetter reaction was carried out by directly adding salt C8 and
K2CO3 at ambient temperature. As summarized in Table 2, an
array of MBH carbonates derived from diversely substituted
isatins and tert-butyl acrylate generally could be well tolerated in
the reactions with activated styrene 2a, and the corresponding
B
DOI: 10.1021/acs.orglett.9b01058
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Substrate Scope and Limitations of Sequential [3 +
2] Annulation and Stetter Reaction
Scheme 2. Construction of Other Bridged Framework and
Synthetic Transformation of 4a
a
b
c
d
entry
R
R1, R2
time (h)
yield (%)
ee (%)
e
1
2
3
4
5
6
7
8
H
NO2, H
NO2, H
NO2, H
NO2, H
NO2, H
NO2, H
NO2, H
NO2, H
NO2, H
NO2, H
NO2, Me
NO2, MeO
NO2, F
24
24
24
30
24
24
24
24
36
24
24
24
14
24
14
30
24
4a, 83
4b, 83
4c, 77
4d, 73
4e, 94
4f, 67
4g, 81
4h, 72
4i, 70
4j, 69
4k, 88
4l, 92
4m, 94
4n, 91
4o, 69
4p, 46
4q, 94
93
5-Me
7-Me
5,7-Me2
5-MeO
6-MeO
5-F
6-Cl
7-Cl
5-Br
H
H
H
H
H
H
H
94
87
97
96
92
93
90
97
95
97
95
91
93
89
98
95
9
a diastereoselective reduction of ketone 4a with NaBH4 could be
realized to afford alcohol 6 with more stereogenic complexity.
In conclusion, we have demonstrated that activated ortho-
vinylbenzaldehydes could be successfully utilized as 2C
acceptors in an α-regioselective [3 + 2] annulation reaction
with Morita−Baylis−Hillman carbonates from isatins under the
catalysis of a cinchona-derived amine. The cycloadducts bearing
aldehyde and activated alkene groups were obtained efficiently,
which underwent highly diastereoselective intramolecular
Stetter reaction mediated by an N-heterocyclic carbene, finally
giving the bridged 5,6,7,8-tetrahydro-9H-5,8-methanobenzo-
[7]annulen-9-one architectures incorporating a spirooxindole
motif with excellent enantiopurity. Moreover, another sequen-
tial reductive amination/aza-Michael addition process was
similarly conducted, thus furnishing valuable polyhydro-3,6-
methanobenzo[c]azocine frameworks. The potential application
of these bridged products is under investigation in this
laboratory.
10
11
12
13
14
15
NO2, Cl
NO2, CF3
H, NO2
CN, F
f
16
17
a
Unless noted otherwise, reactions were performed with MBH
carbonate 1 (0.12 mmol), activated styrene 2 (0.1 mmol), amine C5
(10 mol %), and 4 Å MS (30.0 mg) in toluene (1.0 mL) at 0 °C. After
completion, NHC precursor C8 (10 mol %) and K2CO3 (0.5 equiv)
were directly added and stirred at rt for 18 h. Referring to the [3 + 2]
annulation reaction. Yield of the isolated product. Determined by
HPLC analysis on a chiral stationary phase; dr >19:1 by H NMR
analysis. The absolute configuration of enantiopure 4a was
determined by X-ray analysis. The other products were assigned by
analogy. The [3 + 2] annulation was conducted at 30 °C.
b
c
d
1
e
f
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b01058.
■
5,8-methanobenzo[7]annulen-9-one derivatives 4b−4j were
obtained in moderate to high yields with good to excellent
enantioselectivity and exclusive diastereoselectivity (entries 2−
10). Furthermore, introducing either electron-donating or
withdrawing groups to the 4-position of 5-nitro-2-vinyl-
benzaldehyde scaffold had limited effects on both reactivity
and stereoselectivity (entries 11−14), except for the one with a
CF3 group (entry 15). Nevertheless, 4-nitro-2-vinylbenzalde-
hyde exhibited lower reactivity even at 30 °C, and the product
4p was attained in a fair yield but with remarkable
enantioselectivity (entry 16). Pleasingly, an ortho-vinylbenzal-
dehyde bearing cyano and fluoro groups showed high reactivity
in combination with MBH carbonate 1d, and outstanding data
were afforded for product 4q accordingly (entry 17).16
Apart from the construction of 5,8-methanobenzo[7]
annulen-9-one scaffold, the multifunctional [3 + 2] annulation
intermediates could be utilized for producing other valuable
bridged architectures. As outlined in Scheme 2, after reductive
amination reaction with aldehyde 3c and methylamine, simply
heating the resulting secondary amine intermediate in toluene
effectively delivered a unique 1,2,3,4,5,6-hexahydro-3,6-
methanobenzo[c]azocine framework 5 via a highly diastereose-
lective intramolecular aza-Michael addition reaction, which may
have potential application in medicinal chemistry.17 In addition,
S
Complete experimental procedures and characterization
of new products; NMR spectra and HPLC chromato-
grams (PDF)
Accession Codes
CCDC 1905569 contains the supplementary crystallographic
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 Authors
■
*E-mail: huaping_liang@163.com.
*E-mail: ycchen@scu.edu.cn.
ORCID
Qin Ouyang: 0000-0002-1161-5102
Ying-Chun Chen: 0000-0003-1902-0979
C
DOI: 10.1021/acs.orglett.9b01058
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the NSFC
(21572135) and the Open Project of the State Key Laboratory
of Trauma, Burn and Combined Injury, Third Military Medical
University (SKLKF201601).
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DOI: 10.1021/acs.orglett.9b01058
Org. Lett. XXXX, XXX, XXX−XXX