Asymmetric synthesis of natural product inspired tricyclic benzopyrones by an organocatalyzed annulation reaction

Article abstract of DOI:10.1002/anie.200802413

(Chemical Equation Presented) Going back to nature: Electron-deficient oxadienes and electron-poor acetylene carboxylates react in the presence of an organocatalyst to give natural product inspired tricyclic benzopyrones efficiently (up to 99% yield) and

Full text of DOI:10.1002/anie.200802413

Angewandte
Chemie
DOI: 10.1002/anie.200802413
Asymmetric Synthesis (1)
Asymmetric Synthesis of Natural Product Inspired Tricyclic
Benzopyrones by an Organocatalyzed Annulation Reaction**
Herbert Waldmann,* Vivek Khedkar, Heiko Dückert, Markus Schürmann, Iris M. Oppel, and
Kamal Kumar*
The structural frameworks of natural product classes provide
evolutionary-selected and biologically prevalidated starting
points in vast chemical structure space for compound devel-
opment in chemical biology and medicinal chemistry
research.[1] The synthetic challenges often posed by natural
products and analogues thereof call for the development of
new enantioselective synthesis methods amenable to the
synthesis of compound collections.[1–4] Recently,a group of
natural products with a tricyclic benzopyrone core structure
was reported as a new class of inhibitors for bacterial metallo-
b-lactamases. This promising class of inhibitors was proposed
for a potential combination treatment of clinically relevant
[5]
pathogens,in particular against multidrug-resistant strains.
The pyrano-benzopyrone core also occurs in other natural
[6]
products,for example,in the fungal metabolite fulvic acid.
As a result of this biological relevance and prevalidation in
structural space,and since new antibiotic candidate classes
are in urgent demand,we aimed at the development of a
synthesis method that would give rapid and flexible access to
a collection of compounds with the tricyclic benzopyrone core
structure (2,Scheme 1).
For the development of a catalytic enantioselective
methodology,we envisioned employing a [4 +2] ring annula-
tion reaction of 3-formylchromones with electron-poor ace-
tylenes as the key step (Scheme 1A). While non-asymmetric
Scheme 1. Ring-annulation strategy employing 3-formylchromones and
Schiff bases derived from them (A), and the postulated mechanism for
nucleophilic catalysis (B).
[4+2] cycloadditions between 3-formylchromone and elec-
tron-rich olefins (for example,vinyl ethers) have been
[*] Prof. H. Waldmann, Dr. V. Khedkar,[+] Dipl.-Chem. H. Dückert,[+]
Dr. K. Kumar
described by Coutts and Wallace,[7] the corresponding annu-
lations between this oxa diene and electron-deficient alkynes
are unprecedented.[8,9] We hypothesized that nucleophilic
catalysis by means of phosphines or tertiary amines could
provide an opportunity to catalyze this transformation. In this
approach,one of two electronically similar substrates (for
example,two electrophiles) reacts with the catalyst to form an
intermediate with altered electronic properties which can
then undergo the desired reaction with the now electronically
complementary partner.[10,11] Here we report on the successful
implementation of this strategy and the extension of this new
annulation reaction to the synthesis of dehydropyrans.
Max Planck Institut für molekulare Physiologie
Otto-Hahn Strasse 11, 44227-Dortmund(Germany)
and
Technische Universität Dortmund, Fachbereich Chemie
44221 Dortmund(Germany)
Fax: (+49)231-133-2499
E-mail: herbert.waldmann@mpi-dortmund.mpg.de
kamal.kumar@mpi-dortmund.mpg.de
Dr. M. Schürmann
Technische Universität Dortmund, Anorganische Chemie
44221 Dortmund(Germany)
Priv.-Doz. Dr. I. M. Oppel
Mechanistically,it was envisioned that a nucleophilic
catalyst would add to the alkyne to give rise to intermediate
zwitterions 3 which would then add to the formylchromone 1
by a conjugate addition to yield intermediate 4 (Scheme 1B).
Ring closure,accompanied by liberation of the phosphine,
would lead to the desired annulation product 2. In an initial
attempt,a 1:1 mixture of 3-formylchromone and dimethyl-
acetylene dicarboxylate (DMAD) was heated to 808C in
toluene in the presence of 50 mol% triphenylphosphine,and,
Analytische Chemie, Ruhr-Universität Bochum
44780 Bochum (Germany)
[+] These authors contributedequally to this work.
[**] This work was supportedby the Ministry of Innovation, Science,
Research, andTechnology of North Rhine-Westphalia andthe
Europäischer Fonds für Regionale Entwicklung of the Europäische
Union.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802413.
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Communications
gratifyingly,the expected annulated product 2a was obtained
necessitated their treatment with the zwitterions,generated
by the reaction of the nucleophilic catalyst and the acetylene
carboxylates,immediately after their formation (see the
Supporting information). Thus,a solution of the diene 6 in
toluene was treated with acetylene carboxylates in the
presence of DABCO or PPh3. The reaction of the conjugated
aldehydes proceeded rapidly (1–3 h) in the presence of
DABCO (Table 2,entries 1–6,R 3 = H). However,the inter-
in 92% yield (Table 1,entry 1). Subsequent experimentation
revealed that 30 mol% triphenylphosphine suffices for com-
pletion of the reaction at room temperature within 4–8 h. No
Table 1: Phosphine-catalyzed[4 +2] annulation of acetylene carboxylates
with 3-formylchromones.
Table 2: Organocatalyzedannulation of acetylene carboxylates with
electron-poor acyclic oxadienes.
Entry Prod. R1 R2
R3
R4
R5
PR3
Yield 2 [%]
1
2
3
4
5
6
7
8
9
2a
2a
2b
2c
2d
2e
2 f
2g
2h
2i
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me CO2Me PPh3
Me CO2Me PBu3
Me CO2Me PBu3
92
96
86
99
62
75
60
75
75
60
65
iPr
iPr
H
iPr
H
H
H
H
H
Et
CO2Et
H
H
PBu3
PPh3
PPh3
PPh3
Entry Prod. R1
R2 R3
R4
R5
Yield 7 or 8 [%][a]
Me
Me
tBu
1
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
8 f
7g
7h
7i
Me Bz
Me Ac
H
H
H
H
H
H
Me CO2Me
Me CO2Me
Me CO2Me
Me CO2Me
65[b]
54[b]
61[b]
53[b]
55[b]
54[b]
68[b]
66[b]
56[c]
54[c]
H
OBn[a] Me Me CO2Me PBu3
Et
Et
Et
Bz
Ac
Bz
OBn
OBn
H
Me Et
Me Me
H
CO2Et
H
Ph
PBu3
PPh3
PBu3
10
11
Et
Et
CO2Et
CO2Et
2j
Et
Me Bz
Me Et CO2Me Me CO2Me
[a] Bn=benzyl.
Me Et CO2Me Et
Me Et CO2Me Me
Me Et CO2Me Et
CO2Me
H
H
10
7j
reaction was observed in the absence of phosphine,even at
higher temperatures. The reaction proceeds well in toluene
and benzene but not in more polar solvents such as CH2Cl2 or
THF. Furthermore,it was observed that the reactions proceed
faster if tributylphosphine is used instead of triphenylphos-
phine. Diazabicyclo[2.2.0]octane (DABCO) also serves as a
catalyst for this reaction. The annulation process is slower in
the presence of this tertiary amine,and unlike with phos-
phines,polar solvents such as THF or acetone are preferable
if DABCO is used.
The transformation tolerates variations in the substituents
on the chromone ring and on the acetylene moieties (Table 1).
Thus,unsubstituted as well as alkyl- and alkoxy-substituted
chromones and esters of acetylene dicarboxylic acid,propiolic
acid,and phenylpropiolic acid can be employed successfully.
In general,the pyran-fused chromones are formed in high
yields. They can be obtained from the reaction mixture in
pure form by means of one simple flash chromatographic
separation (see the Supporting information).
Notably,the reactions of alkynes with chromone-derived
aldehydes did not yield a,b-unsaturated lactones,as has been
observed before for related transformations with simple or
activated aldehydes.[10b] The transformations are simple to
carry out and a variety of formylchromones and substituted
alkynes are commercially available. Thus,this reaction
sequence should be readily amenable to the synthesis of
collections of compounds for chemical biology and medicinal
chemistry research.
To further expand the scope of this unprecedented
annulation we investigated the use of acyclic oxadienes 6,
which contain an ester moiety in the a position to the
aldehyde/ketoester.[12] The low stability of the oxadienes 6
[a] Overall yields of isolated product over two steps. [b] DABCO
(50 mol%) was usedas catalyst. [c] PPh (40 mol%) was usedas
3
catalyst. Bz=benzoyl.
mediate [4+2] annulation products 7a–f (detected by means
1
of H NMR spectroscopic investigation of the crude product
mixtures) underwent a subsequent Claisen rearrangement to
yield dehydropyrans 8a–f in 54–65% yield over two steps
(Table 2).[12] The conjugated ketoesters[13] reacted smoothly
with the zwitterions generated from acetylene dicarboxylates
and DABCO by a [4+2] annulation to yield the adducts 7g
and 7h in high overall yields (Table 2,entries 7 and 8).
Furthermore,alkyl propiolates could also successfully
undergo PPh3-catalyzed annulation reactions to yield the
corresponding [4+2] adducts 7i and 7j (Table 2,entries 9 and
10). Thus,this nucleophile-catalyzed annulation reaction
provides a novel route to highly electron-deficient dehydro-
pyrans which could be further explored for the synthesis of
interesting carbohydrates.[14]
A new stereocenter is formed in the ring annulation
reaction of acetylene carboxylates with formylchromones,
and thus an enantioselective [4+2] annulation could be
envisaged. To this end,we initially investigated chiral
phosphines as nucleophilic catalysts. However,disappoint-
ingly,the majority of the chiral phosphines employed did not
catalyze the transformation at all,and only in a single case
was induction of asymmetry observed,albeit with low
stereoselectivity.
Based on the observation that DABCO also catalyzes the
annulation reaction with 3-formylchromones (see above),we
investigated several cinchona alkaloids and derivatives
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Chemie
thereof as chiral catalysts. Cinchonine and cinchonidine did
not lead to preperatively viable results. However,gratifyingly,
20 mol% b-isoquinidine 10,[15] which contains a cyclic ether
between the isoquinuclidine system and the quinoline-sub-
stituted side chain,catalyzed the transformation at À508C in
THF to yield the tricyclic benzopyrone 9a with 54% ee
(Table 3,entry 1). The major enantiomer of compound 9a
yielded the desired products with similar stereoselectivity,but
in slightly lower yields than 13. Therefore, 13 was used in all
subsequent transformations (Table 3).
These findings indicate that the presence of the quinidine
ring in the catalyst and its decoration with substituents are
essential for the steric steering of the annulation reactions. In
addition,the tricyclic catalysts are sufficiently nucleophilic for
catalysis even at low temperatures (analogues lacking an oxa
ring were only sluggish catalysts; data not shown). Substituted
formylchromones react with acetylene carboxylates at À60 to
À708C in the presence of catalyst 13 to provide the desired
tricyclic benzopyrones 9 with moderate to good yields and
with ee values between 80 and 87% (Table 3).
Table 3: Asymmetric [4+2] annulation of acetylene dicarboxylates with
3-formylchromones.
In conclusion,a new enantioselective organocatalyzed
asymmetric [4+2] annulation between electron-deficient het-
erodienes and acetylene derivatives has been developed that
gives rise to natural product inspired tricyclic benzopyrones
and dehydropyrans. To the best of our knowledge,this is the
first report of an asymmetric annulation involving zwitterions
generated from acetylene carboxylates. The synthesis route
developed and described above is efficient and operationally
simple,and thus amenable to the synthesis of collections of
compounds for chemical biology and medicinal chemistry
research.
Entry
Prod.
R1
R2
R3
Cat.
ee [%][a]
Yield 9 [%][b]
1
2
3
4
5
6
7
8
9
9a
9a
9a
9b
9c
9d
9e
9 f
9g
9h
9i
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Et
10
12
13
13
13
13
13
13
13
13
13
54
56
83
82
83
81
81
87
84
85
85
84[c]
66[c]
91[d]
78[d]
70[d]
52[d]
55[e]
52[d]
46[e]
46[e]
67[d]
Received: May 23,2008
Published online: July 25,2008
Cl
Br
iPr
Cl
H
Cl
Br
iPr
Keywords: annulation · asymmetric catalysis ·
.
cinchona alkaloids · natural products · zwitterions
Et
Et
Et
10
11
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was subjected to crystal-structure analysis (see the Supporting
Information) to determine its absolute configuration and the
sense of the stereoinduction; this analysis revealed that in this
case the S isomer was formed preferentially.
Several derivatives of the cinchona catalyst were synthe-
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aryl boronic acids and b-isocupreidine triflate in an attempt to
improve the stereoselectivity (see the Supporting Informa-
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reaction at all,and,surprisingly,when the demethoxy
analogue 12 was employed,product formation occurred,but
the opposite enantiomer was preferred (Table 3,entry 2).
Since cinchona alkaloids are not generally available in both
enantiomeric forms,this finding is highly advantageous.
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carries a phenyl ring at the C6-position of the quinoline
moiety,provided a marked improvement in both the yield and
enantioselectivity of the products. Adding further substitu-
ents to the phenyl ring,for example,in the ortho or para
positions,did not improve the yield or enantioselectivity.
Catalyst 14,with a naphthyl substituent on the quinoline ring,
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Communications
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