Construction of chiral bridged tricyclic benzopyrans: Enantioselective catalytic diels-alder reaction and a one-pot reduction/acid-catalyzed stereoselective cyclization

Article abstract of DOI:10.1002/anie.201402170

An asymmetric two-step approach to chiral bridged tricyclic benzopyrans, core structures featured in various natural products, is described. In the synthesis, an unprecedented enantioselective catalytic decarboxylative Diels-Alder reaction is developed using readily available coumarin-3-carboxylic acids and aldehydes as reactants under mild reaction conditions. Notably, the decarboxylation-assisted release of the catalyst enables the process to proceed efficiently with high enantio- and diastereoselectivity. Furthermore, a one-pot procedure for either a LiAlH₄- or NaBH₄-mediated reduction with subsequent acid-catalyzed intramolecular cyclization of the Diels-Alder adducts was identified for the efficient formation of the chiral bridged tricyclic benzopyrans.

Full text of DOI:10.1002/anie.201402170

Angewandte
Chemie
DOI: 10.1002/anie.201402170
Synthetic Methods
Construction of Chiral Bridged Tricyclic Benzopyrans:
Enantioselective Catalytic Diels–Alder Reaction and a One-Pot
Reduction/Acid-Catalyzed Stereoselective Cyclization**
Aiguo Song, Xishuai Zhang, Xixi Song, Xiaobei Chen, Chenguang Yu, He Huang, Hao Li,* and
Wei Wang*
Abstract: An asymmetric two-step approach to chiral bridged
tricyclic benzopyrans, core structures featured in various
natural products, is described. In the synthesis, an unprece-
dented enantioselective catalytic decarboxylative Diels–Alder
reaction is developed using readily available coumarin-3-
carboxylic acids and aldehydes as reactants under mild
reaction conditions. Notably, the decarboxylation-assisted
release of the catalyst enables the process to proceed efficiently
with high enantio- and diastereoselectivity. Furthermore, a one-
pot procedure for either a LiAlH4- or NaBH4-mediated
reduction with subsequent acid-catalyzed intramolecular cyc-
lization of the Diels–Alder adducts was identified for the
efficient formation of the chiral bridged tricyclic benzopyrans.
Figure 1. The bridged tricyclic benzopyran core unit A found in natural
products.
T
he discovery of powerful simplifying transformations for
rapid access to the core structures featured in natural
products is a central goal of organic synthesis. The bridged
tricyclic benzopyran framework A is present in a fascinating
array of structurally diverse and biologically intriguing
complex natural products such as cannabinoid,[1] oxabicyclo-
nonane, murrayamines D and cyclomahanimbine,[2] and
kuwanol B (Figure 1),[3] sanggenone R,[4a] mulberrofurans I
and S and sorocenol B,[4b] and saustralisin B,[4c] mongol-
icin C,[4d] and isorubraine, etc.[4e] The construction of the
bridged scaffold requires installing two contiguous chiral
centers, including one quaternary center. Typically, this
substructure is built through acid-catalyzed cyclizations of
phenolic alkene precursors.[5] However, asymmetric synthesis
of the scaffolds remains elusive. To the best of our knowledge,
only a single study was reported by Yao and co-workers
describing a binary Pd(OAc)2 and (S)-Trip system to catalyze
an enantioselective annulation process between 2-hydroxy-
styrenes and 2-alkynylbenaldehyes or 1-(2-alkynylphenyl)ke-
tones.[6] To streamline substantial advances in this arena, new
catalytic asymmetric methodologies using simple substances
are more appealing.
Herein, we report an efficient two-step access to the chiral
complex molecular architecture (Scheme 1). A novel catalytic
enantioselective Diels–Alder reaction of readily available
coumarin-3-carboxylic acids (2) with aldehydes (1) is
designed.[7] The carboxylic moiety not only enhances the
reactivitity of coumarins as dienophiles, but also facilitates the
release of the amine catalyst.[8] Different from the reported
studies in aminocatalytic Diels–Alder reactions where the
dienophiles contain a prerequisite a-hydrogen atom, which is
essential for the release of the amine catalyst,[9] a novel
catalyst release mode by decarboxylation was uncovered.
Importantly, the decarboxylation-assisted release of the
catalyst enables the Diels–Alder reaction to proceed effi-
ciently (short reaction times and high yields) under mild
reaction conditions with high enantio- and diastereoselectiv-
ity. Moreover, a new one-pot protocol involving either
a LiAlH4- or NaBH4-mediated reduction and subsequent
acid-catalyzed intramolecular stereoselective cyclization of
the Diels–Alder adducts was identified for the efficient
formation of the chiral bridged tricyclic benzopyran 8. The
cyclization involves an interesting phenolic attack of the diene
moiety driven by dehydration of the allylic alcohol in 6
(Scheme 1).
[*] A.-G. Song, Dr. X.-S. Zhang, X.-X. Song, X.-B. Chen, C.-G. Yu,
H. Huang, Prof. Dr. W. Wang
Department of Chemistry & Chemical Biology
University of New Mexico, Albuquerque, NM 87131 (USA)
E-mail: wwang@unm.edu
Homepage: http://chemistry.unm.edu/faculty_bio/wwang.html
Prof. Dr. H. Li, Prof. Dr. W. Wang
State Key Laboratory of Bioreactor Engineering and
Shanghai Key Laboratory of New Drug Design
East China University of Science & Technology
Shanghai 200237 (China)
E-mail: hli77@ecust.edu.cn
Homepage: http://pharmacy.ecust.edu.cn/s/48/t/73/6f/89/
info28553.htm
[**] Financial support from the NSF (CHE-1057569) and the National
Science Foundation of China (No. 21372073) is gratefully
acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402170.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
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Table 1: Optimization of reaction conditions.[a]
Entry Cat. Additive
Solvent
t [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
none
none
none
none
none
none
none
none
none
none
none
none
none
none
none
none
none
none
PhCO2H
AcOH
DIPEA
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
10
0.5
0.5
1
2/3
3
3
10
10
4
4
4
4
4
6
7
7
7
81
97
94
95
92
87
94
85
96
94
90
91
85
81
80
97
95
79
91
90
81
83
89
19
54
74
81
10
0
10
11
12
13
14
15
16
17
17
17
17
17
17
17
17
17
17
17
17
17
17
17
61
89
92
39
29
40
54
69
76
88
94
87
91
90
86
91
92
9
DCE
toluene
TME
10
11
12
13
14
15
16
17
18
19
20
21
22
23[d]
Scheme 1. Proposed two-step approach to the preparation of bridged
tricyclic benzopyrans involving a catalytic asymmetric Diels–Alder
reaction and a simple reduction/acid-promoted intramolecular cycliza-
tion.
THF
EtOAc
CH3CN
DMSO
CH2Cl2
CHCl3
MeOH
CHCl3
CHCl3
CHCl3
Firstly we focused on the proposed catalytic asymmetric
Diels–Alder reaction (Table 1). A model reaction between 3-
methyl-2-butenal (1a) and coumarin-3-carboxylic acid (2a) in
the presence of the chiral amine 9 in 1,2-dichloroethane
(DCE) at room temperature was carried out. To our delight,
the process took place regioselectively to give the desired
product 3a in 81% yield, but with poor enantioselectivity
(entry 1). The catalyst was facilely released by the designed
decarboxylation and a quick process (10 h) was observed.
Encouraged by the outcomes, we screened other chiral amine
promoters (Table 1). It was found that the catalyst played
significant roles in governing reaction efficiency and enantio-
selectivity. The TMS catalyst 10[10] was more efficient for
promoting the Diels–Alder reaction by affording 97% yield
of 3a within just 30 minutes with a 54% ee (entry 2). More
bulky diarylprolinol silyl catalysts (e.g., 11 and 12; entries 3
and 4) further enhanced the enantioselectivity of the product
formed. Nonetheless, we were surprised to find that ee values
of 3a decreased dramatically when the more hindered
catalysts 13 and 14, bearing CF3 groups on the aromatic
ring, were employed (entries 5 and 6). We speculated that the
decrease in the ee values might be attributed to the strong
electron-withdrawing properties of the CF3 groups. The
assumption was verified by the studies of the catalysts 15
and 16, wherein the CF3 moiety was replaced by a methyl
group (entries 7 and 8). Among the catalysts probed, 17
proved to be the best. In this case, 96% yield of 3a with
92% ee was achieved within 10 hours (entry 9). In addition to
the catalysts, solvents were also critical to the enantioselec-
tivity of the reaction. In general, nonpolar solvents such as
toluene, TME, and THF led to low ee values (entries 10–12),
whereas slightly improved ones were observed with polar
10
10
10
10
24
2,6-lutidine CHCl3
none CHCl3
[a] Reaction conditions: unless specified, see Experimental Section.
[b] Yield of isolated product. [c] Determined by HPLC using a chiral
stationary phase. [d] 08C. TME=tert-butyl methyl ether. DIPEA=diiso-
propylethylamine, DMSO=dimethyl sulfoxide, TBS=tert-butyldi-
methylsilyl, TES=triethylsilyl, THF=tetrahydrofuran, TMS=trimethyl-
silyl.
solvents such as EtOAc, CH3CN, DMSO, and MeOH
(entries 13–15 and 18). The chlorinated solvents CH2Cl2 and
CHCl3 were a good choice for the reaction (entries 16 and 17).
Acidic or basic additives were detrimental (entries 19–22).
Finally, no benefit was gained when the reaction was
conducted at a decreased temperature (entry 23).
With the optimized reaction conditions in hand for this 17-
catalyzed Diels–Alder reaction, we probed the reaction scope
(Table 2). The results reveal that the process can be applied to
both substrates with a broad generality. Uniformly high yields
(81–95%) and high ee values (90–94%) are obtained for all
cases studied. Investigation of the scope by probing 2
indicates that the electronic effect is very limited. The
aromatic ring bearing electron-neutral (entries 1 and 9),
electron-donating (entries 2–4, 8, and 13), and electron-
withdrawing (entries 5–7, 10–12, and 14–19) groups with
different substitution patterns are well tolerated and lead to
the structurally diverse compounds 3. With respect to 1,
significant structural variations were explored. It appears that
in addition to 1a (entries 1–7), linear aldehydes (entries 8 and
2
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Table 2: Scope of the 17-catalyzed Diels–Alder reactions.[a]
1
yield based on H NMR analysis. However, the product was
decomposed on silica gel during purification to give the
coumarin-3-carboxylate ethyl ester starting material through
a retro-Diels–Alder process.
With 3 in hand, we investigated their transformation into
the bridged tricyclic benzopyrans 8 (Scheme 1). As men-
tioned above, acid-triggered cyclization of phenols with
alkenes has been studied in the synthesis of the scaffold.[5]
Inspired by the studies, we conceived a possibility of a new
cyclization between a phenol and a diene in the presence of an
acid (Scheme 1). The required precursor diol 6a could be
obtained by the reduction of the corresponding lactone 3a
(Table 3, entry 1). Surprisingly, after the reduction by LiAlH4,
the chiral bridged tricyclic benzopyran 8a was obtained
Entry
R1, R2
R3, R4
3
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
H, H
H, H
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
95
97
93
89
97
94
92
85
91
89
93
91
87
83
88
81
91
89
90
94
92
90
94
90
93
91
92
94
92
92
90
92
92
94
90
92
90
94
Me, H
H, Me
MeO, H
Br, H
H, Br
H, NO2
MeO, H
H, H
Br, H
Br, H
Br, H
Me, H
Br, H
Br, H
Br, H
9
Ph, H
Ph, H
Table 3: Formation of 8 by one-pot reduction/acid-catalyzed cyclization
of 3.[a]
10
11
12
13
14
15
16[d]
17[e]
18[f]
19[g]
3-MeC6H4, H
4-MeC6H4, H
4-FC6H4, H
3-BrC6H4, H
3,4-Cl2C6H3, H
H, Me
H, Me
H, Et
H, Pr
H, NO2
H, NO2
H, NO2
Entry R1, R2, R3, R4, R5
3
8
Method Yield [%][b] d.r. [%][c]
3s
1
2
3
4
5
6
7
8
9
10
Me, H, H, H, H, H
Me, H, Me, H, Me
Me, H, H, Me, H
3a 8a
3b 8b
3c 8c
A
A
A
A
A
A
A
A
A
B
86
91
93
87
85
84
89
87
83
75
>20:1
>20:1
>20:1
>20:1[d]
5.5:1
>20:1
>20:1
>20:1
12:1
[a] Reaction conditions: unless specified otherwise, see the Experimental
Section. [b] Yield of isolated product. [c] Determined by HPLC using
a chiral stationary phase. [d] 15 h, 15:1 d.r. (determined by H NMR of
crude reaction mixture). [e] 15 h, 14:1 d.r. [f] 15 h, 21:1 d.r. [g] 15 h, 13:1
d.r.
1
Me, H, MeO, H, MeO 3d 8d
Me, H, H, Br, H
H, H, MeO, H, MeO
Ph, H, Br, H, H
3-MeC6H4, H, Br, H, H 3k 8h
H, Me, Br, H, H
H, Me, Br, H, Br
3 f 8e
3h 8 f
3j 8g
3p 8i
3p 8j
16–19) and branched b, b’-disubstituted aldehydes (entries 9–
15) can serve as effective dienes in the Diels–Alder reactions.
In the case of linear enals (entries 16–19), two new stereo-
genetic centers are formed with high enantio- and diastereo-
selectivity.
>20:1
[a] Reaction conditions: unless specified otherwise, see the Experimental
Section. [b] Yield of isolated product. [c] Determined by 1H NMR
spectroscopy. [d] Determined by HPLC using a chiral stationary phase
with 91% ee (see the Supporting Information for HPLC conditions).
The absolute configuration of 3l was determined by X-ray
crystallographic analysis (see Figure S1 in the Supporting
Information).[11] The relative stereochemistry of 3q, having
a trans geometry, was determined by an NOE experiment (see
Figure S2). The proposed configuration in 5 originates from
Re-face attack of the dienamine 4 by 2 in an exo manner
(Scheme 1). This attack occurs because the Si face is blocked
by the bulky side chain of the catalyst and the interaction
between the nitrogen atom of the catalyst and the carboxylic
acid moiety in 2 dictates an exo addition of the dienophile.[9f]
Furthermore, the steric hindrance between the bulky side
chain of the catalyst and the lactone moiety in 5 leads to the
cis configuration of the catalyst and the carboxylic acid. This
geometry enables the facile decarboxylation to release the
catalyst and the products 3 with the observed configuration.
In addition, the carboxylic acid enhances the reactivity of the
coumarins 3 as dienophiles. Indeed, without it, no desired
Diels–Alder adduct was observed between coumarin and 1a
under identical reaction conditions. In a control study, the
carboxylic acid was masked as an ethyl ester, and the Diels–
Alder reaction with 1a in the presence of 100 mol% of 17
occurred, but afforded a catalyst entrapped product in 53%
directly after workup with 10% HCl aqueous solution
without requiring an additional acid treatment. Moreover,
the unexpected one-pot procedure proceeded smoothly in
86% yield and with excellent diastereoselectivity (> 20:1
d.r.). We also extended the protocol to other substrates
(entries 2–9). In general, high yields (83–93%) and good to
excellent d.r. values (5.5:1– > 20:1) were achieved with the
representative structurally diverse molecules 3. Furthermore,
the enantioselectivity was largely maintained in the two-step
transformations, as demonstrated in the case of 8d with
91% ee (entry 4). The absolute configuration was confirmed
by X-ray crystallographic analysis of a single crystal of 8e (see
Figure S3).[12] It is noteworthy that unexpectedly, the debro-
mination concurred with substrates bearing the bromo atom
at position 7 (e.g., R3, entries 7–9), while a Br at the 6-position
is not affected (entry 5). The use of the milder NaBH4 could
overcome this problem (entry 10). Moreover, the synthetic
utility of the reaction products is also demonstrated by photo-
oxidation of 3a to give the conjugated 6H-dibenzo[b,d]pyran-
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6-one product in 83% yield in the presence of air (O2) and the
photosensitizer rose bengal [see Eq. (S1)]. The structure is
widely featured in numerous natural products such as
fasciculiferol,[13] alternariol,[14] and autumnariol and autum-
nariniol.[15] Furthermore, the the Diels–Alder product 3q can
also be oxidized by mCPBA to produce an epoxide [see
Eq. (S2)].
In conclusion, we have developed a two-step route for the
assembly of chiral bridged tricyclic benzopyrans, a core unit
featured in a number of natural products. A novel amine-
catalyzed decarboxylative enantioselective Diels–Alder reac-
tion between aldehydes and readily available coumarin-3-
carboxylic acids, as dienophiles, has been implemented to
construct the chiral precursors. The decarboxylation facili-
tates the release of the catalyst and achieves high reaction
efficiency in terms of reaction time, yield and enantio- and
diastereoselectivity. The Diels–Alder adducts are smoothly
transformed into the targets by a novel but unexpected one-
pot protocol using a LiAlH4- or NaBH4-mediated reduction
and subsequent acid-catalyzed stereoselective cyclization. We
anticipate that the two new synthetic strategies hold great
potential in the exploration of novel organic transformations.
The application of the chiral bridged tricyclic benzopyran
core in the synthesis of natural products and biologically
relevant molecules is also under investigation.
[6] S.-Y. Yu, H. Zhang, Y. Gao, L. Mo, S. Wang, Z.-J. Yao, J. Am.
Chem. Soc. 2013, 135, 11402.
[7] We are not aware of a catalytic enantioselective Diels–Alder
reaction with dienophilic coumarins. For selected examples of
the non-asymmetric reactions: a) D. Amantini, F. Fringuelli, F.
Pizzo, J. Org. Chem. 2002, 67, 7238; b) M. E. Jung, D. A. Allen,
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Experimental Section
General procedure for the Diels–Alder reactions: 1 (0.1 mmol) was
added to a mixture of coumarin-3-carboxylic acid 2 (0.12 mmol) and
the catalyst 17 (9.4 mg, 0.02 mmol) in 0.2 mL of CHCl3. The reaction
was stirred at room temperature until 1 was consumed completely
(7 h). The mixture was placed on a silica gel column directly and
hexane and ethyl acetate (20:1) to give the pure product 3. The
purified compound was used for characterization and chiral HPLC
analysis.
[8] Significant studies have been carried out on catalytic decarbox-
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malonic acid half (thio)esters. However, to the best of our
knowledge, the application in a Diels–Alder reaction has not
been reported. For reviews, see: a) S. Nakamura, Org. Biomol.
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A. Ricci, Org. Biomol. Chem. 2012, 10, 2911; c) Y. Pan, C.-H.
Tan, Synthesis 2011, 2044; d) Z.-L. Wang, Adv. Synth. Catal.
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General procedure for the reduction-cyclization. Method A: A
solution of 3 (0.30 mmol) in 0.5 mL of THF was injected into the
mixture of LiAlH4 (23 mg, 0.60 mmol) in 5 mL of THF at 08C. The
resulting mixture was stirred for 1 h at 08C and then quenched with
10% HCl solution. The mixture was stirred until the reduced product
was consumed completely as monitored by TLC. The product was
extracted with ethyl acetate (3 ꢀ 10 mL). The combined organic layer
was dried with sodium sulfate and evaporated under reduced
pressure. The crude mixture was purified by silica gel column
chromatography, eluting with hexane and ethyl acetate (40:1) to give
the pure product 8. The purified compound was used for character-
ization.
Received: February 6, 2014
Published online: && &&, &&&&
Keywords: cyclization · decarboxylation · heterocycles ·
.
organocatalysis · synthetic methods
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www.angewandte.org
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.
Angewandte
Communications
Communications
Synthetic Methods
A.-G. Song, X.-S. Zhang, X.-X. Song,
X.-B. Chen, C.-G. Yu, H. Huang, H. Li,*
W. Wang*
&&&& — &&&&
Construction of Chiral Bridged Tricyclic
Benzopyrans: Enantioselective Catalytic
Diels–Alder Reaction and a One-Pot
Reduction/Acid-Catalyzed Stereoselective
Cyclization
The old one-two: A two-step synthetic
strategy was developed for the construc-
tion of the bridged benzopyran core
present in many natural products. It
consisted of an efficient asymmetric
catalytic decarboxylative Diels–Alder
reaction between enals and coumarin-3-
carboxylic acids, and a one-pot protocol
for the reduction/acid-catalyzed stereo-
selective cyclization. TBS=tert-butyldi-
methylsilyl.
6
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!