Lewis base catalyzed [4+2] annulation of electron-deficient chromone-derived heterodienes and acetylenes

Article abstract of DOI:10.1002/chem.201003572

Lewis base catalyzed [4+2] annulation reactions between electron-deficient chromone oxa- and azadienes and acetylene carboxylates provide tricyclic benzopyrones inspired by natural products. An asymmetric synthesis of the tricyclic benzopyrones was developed by using modified cinchona alkaloids as enantiodifferentiating Lewis base catalysts.

Full text of DOI:10.1002/chem.201003572

DOI: 10.1002/chem.201003572
Lewis Base Catalyzed [4+2] Annulation of Electron-Deficient Chromone-
Derived Heterodienes and Acetylenes
Heiko Dꢀckert, Vivek Khedkar, Herbert Waldmann,* and Kamal Kumar*[a]
Abstract: Lewis base catalyzed [4+2] annulation reactions between electron-defi-
cient chromone oxa- and azadienes and acetylene carboxylates provide tricyclic
benzopyrones inspired by natural products. An asymmetric synthesis of the tricy-
clic benzopyrones was developed by using modified cinchona alkaloids as enantio-
differentiating Lewis base catalysts.
Keywords: annulation · benzopyr-
ones · Lewis bases · natural prod-
ucts · organocatalysis
Introduction
stance, (À)-nidulalin,
a dihydroxanthone, isolated from
Emericella nidulans,[3c] is a DNA topoisomerase II inhibitor
and shows immunomodulatory activity.[3e,f] The fungal me-
tabolites SB238569 and SB236049 from C. funicola TCF
6040 are inhibitors of several bacterial metallo-b-lactamas-
es,[4] which makes them potential guiding structures for anti-
biotic research aimed at multidrug-resistant bacteria.[5]
Among other benzopyrones, the commonly occurring fulvic
acid has been widely studied.[6]
Small molecules embodying molecular scaffolds that exist in
natural product structures are rich sources of inspiration for
drug discovery and probes for chemical biology investiga-
tions.[1] While the syntheses of highly complex natural prod-
ucts, as well as analogues thereof, remain challenging, alter-
native strategies aimed at the synthesis of compounds in-
spired by natural products are gaining attention.[2] In a relat-
ed research program, we targeted tricyclic benzopyrone
scaffolds, which occur in numerous natural products display-
ing pronounced biological activities (Scheme 1).[3] For in-
Tricyclic benzopyrones have been synthesized by employ-
ing 3-formylchromones as oxadienes in the hetero-Diels–
Alder reaction with electron-rich olefins (Scheme 2a).[7]
Scheme 2. Reaction of 3-formylchromone with an electron-rich olefin
and a failed attempt to annulate 1 with dimethylacetylenedicarboxylate
(DMAD).
Scheme 1. Natural products embodying the tricyclic benzopyrone scaf-
fold.
However, 3-formylchromones, which are electron-deficient
heterodienes, should not entertain classical uncatalyzed cy-
cloadditions with electron-poor dienophiles.[8] Accordingly,
our attempts to realize the annulation reaction of 3-formyl-
chromone and DMAD under harsh conditions met with fail-
ure (Scheme 2b).
[a] Dipl.-Chem. H. Dꢀckert, Dr. V. Khedkar, Prof. Dr. H. Waldmann,
Dr. K. Kumar
Max-Planck-Institut fꢀr molekulare Physiologie
Abteilung Chemische Biologie, Otto-Hahn-Str. 11
44227 Dortmund (Germany)
The electronic compatibility required for a [4+2] cycload-
dition reaction between electron-poor substrates 1 and 4 is
the major obstacle for this electron-deficient version of a
hetero Diels–Alder reaction. To find a solution to this syn-
thetic challenge, we turned to Lewis base catalysis by using
tertiary phosphines and amines as catalysts.[9] The underly-
ing idea herein is to catalytically transform the electron-
and Technische Universitꢁt Dortmund
Fakultꢁt Chemische Biologie, Otto-Hahn-Str. 6
44227 Dortmund (Germany)
Fax : (+49)231-133-2499
E-mail: herbert.waldmann@mpi-dortmund.mpg.de
kamal.kumar@mpi-dortmund.mpg.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003572.
5130
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 5130 – 5137

FULL PAPER
poor acetylene into a nucleophilic zwitterion,[10] which could
add in a 1,4-addition to the chromone moiety to yield a sta-
bilized oxanion (7, Scheme 3) that further undergoes a 1,4-
addition to an activated olefin and liberates the catalyst to
yield the desired cycloadduct (5, Scheme 3).
Table 1. Results of the phosphine-catalyzed [4+2] annulations.
Entry
5
R1
R2
R3
R4
R5
Yield [%][a]
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5e
5 f
5g
5h
5i
OMe
OMe
OMe
OMe
OMe
OMe
OH
OH
H
H
H
H
H
H
H
H
H
H
H
H
H
À
H
H
H
H
H
H
H
H
CO2Me
CO2Et
CO2tBu
CO2Me
CHO
CO2Me
CO2Et
CO2tBu
H
Ph
Ph
CO2Me
CO2Et
CO2Me
CO2tBu
Ph
82[b]
78[c]
74[c]
42[d]
58[e,g]
17[f]
CHO
CO2Me
CO2Et
CO2Me
CO2tBu
CHO
25[b]
25[b]
60[b]
67[f]
À
9
Ph
10
11
12
13
H
H
H
H
H
H
H
H
5j
5k
5l
78[e]
28[f,h]
CN
CHO
Ph
n-C5H11
[f]
–
[a] Isolated yields. [b] PPh3 (60 mol%) was used as the catalyst. [c] PBu3
(60 mol%) was used as the catalyst. [d] PPh3 (30 mol%) was used as the
catalyst. [e] PPh3 (50 mol%) was used as the catalyst. [f] PBu3 (30 mol%)
was used as the catalyst. [g] 31% of 1c was recovered. [h] 37% of 1c was
recovered.
Scheme 3. Lewis base catalyzed [4+2] annulation of 3-formylchromones
(1) and an alkyne (4).
Indeed, the reaction of the zwitterions 6 (generated by
the addition of triphenylphosphine to DMAD) with 3-for-
mylchromone yielded the desired annulation product 5.
After optimizing the reaction conditions, a variety of substi-
tuted 3-formylchromones and acetylenecarboxylates were
successfully employed in this annulation reaction and a
small collection of novel tricyclic benzopyrones was generat-
ed.[11] Herein, we present a full account of this work and a
deeper exploration of this novel annulation reaction[12] using
diverse chromone-based heterodienes and electron-poor
acetylenes to generate different tricyclic benzopyrones. We
also propose a mechanistic model for the asymmetric annu-
lation reaction catalyzed by cinchona alkaloid derived orga-
nocatalysts.
were completed in 3 h to provide the tricyclic benzopyrones
5a–c in high yields. The bulky di-tert-butylacetylene diester
performed equally well (Table 1, entry 3) to provide 5c in
74% yield. While the reaction of 1c with methyl propiolate
using triphenylphosphine as the catalyst provided only mod-
erate yields of tricyclic benzopyrone 5d (Table 1, entry 4),
phenylpropargyl aldehyde yielded the corresponding alde-
hyde-substituted tricyclic benzopyrone 5e in 58% yield
(Table 1, entry 5). Unexpectedly, the use of more nucleo-
philic tributylphosphine reduced the yield to 17% (Table 1,
entry 6).
The zwitterion 6, generated by the addition of phosphine
to acetylenecarboxylates, could abstract acidic protons, for
instance, from the hydroxyl group.[15] Therefore, we were
pleased to find that 3-formyl-5-hydroxychromone (1c) gave
the desired product in a yield of 25% by using triphenyl-
phosphine catalyst (60 mol%; Table 1, entries 7 and 8). 3-
Formylbenzo[h]chromone (1d) reacted well with DMAD to
provide the corresponding tricyclic benzopyrone 5h in good
yield.
Results and Discussion
ACHTUNGTRENNUNG[4+2] Annulation of 3-formylchromones and electron-poor
acetylenes: Natural products often embody electron-rich
benzopyrone rings, that is, polyhydroxy benzenes originating
from polyketide biosynthetic pathways.[13] To induce this
characteristic feature of natural products in our collection of
tricyclic benzopyrones, 3-formyl-5-hydroxychromone (1c)
and the methyl derivative (1b) were synthesized by the Vils-
meier–Haack reaction of the corresponding hydroxyaceto-
phenones, according to literature procedures (see the Sup-
porting Information).[14] In addition, 3-formylbenzo[h]chro-
mone with a bulky naphthalene ring (1d) was employed in
the annulation reactions with acetylenes.
AHCTUNGTREG[NNNU 4+2] Annulation of 1a with bulky di-tert-butylacetylene-
dicarboxylate led to the isolation of adduct 5i in 67% yield
(Table 1, entry 10). Phenylpropargyl aldehyde and chromone
1a provided adduct 5j in comparatively better yields than
chromone 1b (Table 1, entries 11 and 5). Interestingly, 3-
phenyl-2-propyne-nitrile also undergoes the [4+2] annula-
tion reaction with 3-formylchromone to provide adduct 5k,
albeit in low yields with much of the chromone recovered
unreacted (Table 1, entry 12). To the best of our knowledge,
this is the first report of employing an acetylenic nitrile in
an organocatalyzed zwitterionic annulation reaction. 2-Octy-
nal did not yield any desired product and most of the 3-for-
mylchromone was recovered (Table 1, entry 13).
3-Formyl-5-methoxychromone (1c) reacted well with
three acetylene dicarboxylates under optimized reaction
conditions when using either triphenyl- or tributylphosphine
(up to 30 mol%) catalysts in toluene at 808C. The reactions
Chem. Eur. J. 2011, 17, 5130 – 5137
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5131

H. Waldmann, K. Kumar et al.
These results demonstrate the wide scope of the phos-
phine-catalyzed [4+2] annulation reaction, which tolerates
a variety of electron-rich 3-formylchromones and different
electron-poor acetylenes to yield diversely functionalized tri-
cyclic benzopyrones.
Asymmetric [4+2] annulation reaction of 3-formylchro-
mones and acetylenedicarboxylates: The organocatalyzed
[4+2] annulation reaction of 3-formylchromones and acety-
lenecarboxylates generates tricyclic benzopyrones with one
stereocenter. To develop an enantioselective version of this
annulation reaction, we investigated the suitability of chiral
phosphine catalysts. Chiral phosphines 8–12 were tested in a
[4+2] annulation reaction between 3-formylchromone and
DMAD in toluene under varying reaction conditions, that is,
from room temperature to 708C, with varying equivalents of
DMAD and reaction times. However, these phosphines
proved ineffective and mostly did not catalyze the reaction.
Only in the case of 11 could we observe product formation
(<5%) with an enantiomeric excess of about 36%.
Scheme 4. Enantioselective [4+2] annulation reaction catalyzed by cin-
chona alkaloid based catalysts.
15, differently substituted formylchromones reacted with
acetylene carboxylates at À60 to À708C to provide the de-
sired tricyclic benzopyrones 5 with appreciable to good
yields (up to 91%) and with ee values consistently above
80% and up to 87% (Scheme 4).[11]
These findings indicate that the quinidine ring embedded
in the catalyst and the substituents are important 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).
To rationalize the observed direction of the stereoselec-
tion, we propose that in the case of the isocupreidines with
a substituent at C-6 of the quinoline moiety, the catalyst
adopts a conformation in which steric interactions between
the C-6 substituent and the bicyclic system are minimized
(for catalyst 15, see I in Scheme 5). Upon formation of the
intermediate zwitterion I, the additional undesirable interac-
tions between the phenyl ring of the chromone and the ester
of the allenoate, as well as between the chromone and the
quinuclidine ring, are minimized. In the ensuing arrange-
ment I shown in Scheme 5, the si face of the allenoate is
shielded by the phenyl substituent at C-6 of the quinoline,
which facilitates the re-face attack at the C-2 position of the
formylchromone and thus preferred formation of the S
enantiomer.
We observed that diazabicycloACTHUNTGRNEUNG[2.2.0]octane (DABCO)
was as efficient a catalyst as triphenylphosphine in this an-
nulation reaction. This finding suggested it would be worth-
while to explore chiral tertiary amines in the development
of an enantioselective version of this annulation reaction. To
this end, we investigated several Cinchona alkaloids and de-
rivatives thereof as chiral catalysts. The naturally occurring
alkaloids cinchonidine, cinchonine, and O-methylhydroqui-
nidine did not catalyze the above reaction. Gratifyingly, in
the presence of b-isoquinidine 13[16] (20 mol%), which em-
bodies a cyclic ether between the isoquinuclidine system
and the quinoline-substituted side chain, the transformation
proceeded at À508C in THF to yield the tricyclic benzopyr-
one 5m (R1 =R2 =H, R3 =Me) with around 50% enantio-
meric excess (ee) and preferred the formation of the S enan-
tiomer (Scheme 4).[11]
The demethoxy analogue 14, however, yielded an excess
of the opposite R enantiomer (Scheme 4). Since cinchona al-
kaloids are not generally available in both enantiomeric
forms, this finding is highly advantageous. Catalyst 15, with
a phenyl ring at C-6 of the quinoline moiety, provided excel-
lent yields and enantioselectivity. In the presence of catalyst
Scheme 5. Possible transition states in the enantioselective annulation re-
action.
5132
www.chemeurj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 5130 – 5137

Chromone-Derived Heterodienes and Acetylenes
FULL PAPER
In the absence of a C-6 substituent, conformation II may
be preferred in which the si face of the allenoate is open for
the approach by the chromone. In this arrangement again
undesirable interactions between the phenyl ring of the
chromone, the ester of the allenoate, the quinoline ring of
the catalyst, and the isoquinuclidine system are minimized
by favoring the allenoate addition on the si face of the C-2
position of the formylchromone, thus leading to the R enan-
tiomer as the major product.
nulation reaction for accessing further benzopyrones with a
fused azaheterocycle, 3-formylchromone-derived N-tosyl-
AHCTUNGTREGiNNUN mines were employed in the [4+2] annulation reaction.
Due to their very low solubility in toluene at room tempera-
ture, the reactions of imines 17 were performed at 808C
(Scheme 6). Gratifyingly these transformations also pro-
The proposed selectivity was further supported by experi-
ments performed with catalyst 16 (Table 2) prepared by the
Suzuki coupling of 4-biphenylboronic acid and b-isocincho-
nine-6’-trifluoromethanesulfonate (see the Supporting Infor-
Table 2. Results of the enantioselective [4+2] annulation reaction with
catalyst 16 (20 mol%).
Scheme 6. ACHTUNTRGNEU[GN 4+2] Annulation reaction of N-tosylimines of 3-formylchro-
mones and acetylene carboxylates.
ceeded smoothly with PBu3 as the catalyst. Compared with
the 3-formylchromones, imines 17 displayed significantly
lower reactivity even at elevated temperatures. After chro-
matographic separation, the tricyclic reaction products 18,
which can also be regarded as highly substituted dihydropyr-
idines, were obtained in acceptable yields. However, along
with the desired adduct, pyridines 19 were isolated in vary-
ing yields (Table 3). Product formation did not occur in the
Entry
R1
R2
R3
5
Yield [%][a]
ee[b] [%]
1
2
3
4
5
6
7
8
H
H
H
H
H
Me
H
H
H
H
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
5m
5n
5o
5p
5q
5r
5s
5t
5u
5v
48
32
67
64
53
15
42
31
27
18
84
77
81
81
80
84
77
79
81
82
iPr
Cl
Br
Cl
H
iPr
Cl
Br
Cl
Table 3. Results of the [4+2] annulation reaction of N-tosylimines of 3-
formylchromones and acetylene carboxylates with PBu3 (30 mol%) as
the catalyst.
Entry R1
R2
Me CO2Me 18a
Et CO2Et 18b 57
54
18d 61
R3
18
Yield [%][a] 19
50 19a 41
19b 30
19c 32
Yield [%][a]
9
10
Me
1
2
3
4
5
6
7
8
9
H
H
[a] Isolated yields. [b] The enantiomeric excesses were determined on an
Agilent 1100 series HPLC machine using a Daicel IC column with 25%
Me Me CO2Me 18c
Me Et CO2Et
Me CO2Me 18e
Et CO2Et 18 f
Me CO2Me 18g
ethanol/isohexane at 0.5 mLminÀ1
.
19d 35
19e 31
iPr
iPr
Br
Br
H
58
62
41
19 f
15
19g 25
19h 22
mation). With a p-biphenyl group in the 6’-position of the
catalyst, the same stereoselectivity as that observed for cata-
lyst 15 should be recorded. Indeed, in all of the reactions
performed with catalyst 16 with different 3-formylchro-
mones and acetylenedicarboxylates, the S enantiomers were
formed in preference to the R enantiomers (Table 2), clearly
supporting the proposed transition-state model (Scheme 5).
Also, it was observed that diethylacetylenedicarboxylate was
less reactive than DMAD in these asymmetric reactions.
This again might be due to the proximity of the generated
allenoate and the quinuclidine ring, which would further
avoid the incoming 3-formylchromone for the ensuing reac-
tion.
Et
Me
CO2Et
H
18h 40
18i
–
19i
60[b]
[a] Isolated yields. [b] PPh3 (30 mol%) was used as the catalyst.
absence of the catalyst when the reactions were performed
for longer times. Moreover, the alternative formation of a,b-
unsaturated five-membered lactams[17] was not observed.
Tricyclic dihydropyridines 18 were obtained in moderate
yields in the reactions with DMAD or diethylacetylenedicar-
boxylate along with pyridines 19 (Table 3, entries 1–8).
However, in the triphenylphosphine-catalyzed reaction of
methylpropiolate with 3-formylchromone, the pyridine 19i
was obtained as the major product. The diyhdropyridine 18i
was observed in trace amounts and could not be isolated
(Table 3, entry 9).
ACHTUNGTRENNUNG
Chem. Eur. J. 2011, 17, 5130 – 5137
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5133

H. Waldmann, K. Kumar et al.
In a separate experiment, we could not convert the tricy-
clic dihydropyridine 18a into pyridine 19a, which suggested
different reaction mechanisms for the formation of these
two products. Moreover, unlike the tricyclic benzopyrones 5,
which are very sensitive to acidic conditions and undergo re-
arrangements,[18] the dihydropyridines 18 were stable. This
could be due to the electron-withdrawing N-tosyl functional-
ity, which reduces the push–pull character unlike benzopyr-
one 5. Thus, the chromone ring in 18 does not tend to open
up as in the case of 5.
inspired by natural products with either a substituted dihy-
dropyran or a dihydropyridine ring fused to the benzopyr-
one scaffold. An enantioselective route to tricyclic benzo-
pyrones was established successfully by using modified cin-
chona alkaloids as chiral Lewis base catalysts. Mechanistic
insights suggest that the substitution pattern on the quino-
line ring of the cinchona alkaloid controls the stereoselectiv-
ity of the annulation reaction.
Mechanistically, we assume that the initial attack of the
zwitterion formed by addition of the phosphine catalyst to
the acetylene carboxylates occurs at the C-2 position of the
chromone and generates the intermediate 20 (Scheme 7).
Experimental Section
General: Unless otherwise noted, chemicals were obtained from Aldrich,
Acros, or Alfa and were used without further purification. Reactions
were carried out in standard glassware or in a Radleys Carousel 12 paral-
lel reactor. H and 13C NMR spectroscopic data were recorded on Varian
1
Mercury VX 400 or Varian 500-inova500 spectrometers at RT. NMR
spectra were calibrated to the solvent signals of CDCl3 (d=7.26 and
77.00 ppm). The ee values were determined on an Agilent 1100 series
HPLC using
a Daicel IC column with 25% ethanol/isohexane at
0.5 mLminÀ1. Fast atom bombardment (FAB) MS measurements were re-
corded on a Finnigan MAT MS 70 spectrometer and electrospray ioniza-
tion (ESI) MS were measured by using an Agilent 1100 series binary
pump together with a reversed-phase HPLC column (Macherey–Nagel).
TLC was performed on Merck silica gel 60 F254 aluminum sheets. For
flash chromatography, Baker silica gel (40–70 mm) was used. Medium-
pressure liquid chromatography (MPLC) purifications were carried out
on an ISCO sq16 instrument using silica gel (30 mm) columns by inter-
chim. Melting points were recorded on Bꢀchi Melting points B-540 appa-
ratus and are uncorrected.
Representative example of [4+2] annulation of the substituted 3-formyl-
chromones: Compound 5a:
A solution of 1c (204 mg; 1.00 mmol;
1.0 equiv) and DMAD (284 mg; 2.00 mmol; 2.0 equiv) in toluene
(10 mL) was heated to 808C and degassed by flushing with argon. Triphe-
nylphosphine (157 mg; 0.6 mmol; 0.6 equiv) was added to this solution
and the solution was stirred until 1c was consumed (as determined by
TLC). The reaction mixture was directly subjected to MPLC (12 g silica
gel, cyclohexane (CH)/EtOAc 0:1 to 1:0). The product was isolated as an
off-white solid (284 mg; 0.82 mmol; 82%). Rf =0.22 (CH/EtOAc 2:3);
m.p. 1548C; 1H NMR (400 MHz, CDCl3): d=7.53 (s, 1H), 7.43 (t, J=
8.4 Hz, 1H), 6.59 (t, J=7.8 Hz, 2H), 5.83 (s, 1H), 3.95 (s, 3H), 3.93 (s,
3H), 3.90 ppm (s, 3H); 13C NMR (101 MHz, CDCl3): d=179.7, 164.8,
161.4, 161.0, 160.1, 147.1, 144.6, 136.8, 114.0, 113.2, 110.6, 110.5, 105.2,
66.9, 56.4, 53.6, 53.0 ppm; HRMS: m/z calcd for C17H15O8 [M+H]+:
347.07614; found: 347.07619.
Scheme 7. Proposed mechanism for the formation of tricyclic dihydropyr-
idines 18 and pyridines 19. Ts=tosyl.
This should be a relatively stable zwitterion due to the elec-
tronegative N-tosyl moiety. A direct 1,4-addition of the
tosylACHTUNGTRENNUNGamide to the phospha-substituted olefin would yield the
dihydropyridine 18 after releasing the catalyst. Alternatively,
the phosphine catalyst could also leave 21 to generate a dif-
ferent dipole system, 22, wherein phenoxide would add to
the pyridinium ring to generate tricyclic aminal 23. Water
can easily cleave the tosyl group with concomitant chro-
mone ring opening to provide the pyridines 19. The aromati-
zation of the pyridine ring would also encourage such nucle-
ophilic removal of the tosyl moiety.
Compound 5b: Brown amorphous solid; Rf =0.31 (CH/EtOAc 3:2);
1H NMR (400 MHz, CDCl3): d=7.51 (d, J=1.2 Hz, 1H), 7.40 (t, J=
8.4 Hz, 1H), 6.58 (d, J=8.4 Hz, 1H), 6.55 (dd, J=8.3, 0.9 Hz, 1H), 5.81
(d, J=1.2 Hz, 1H), 4.38–4.32 (m, 4H), 3.93 (s, 3H), 1.40–1.31 ppm (m,
6H); 13C NMR (101 MHz, CDCl3): d=179.8, 164.2, 161.4, 160.9, 160.6,
147.4, 144.7, 136.8, 114.0, 113.3, 110.5, 110.4, 105.2, 67.1, 63.0, 62.0, 56.4,
14.1, 14.0 ppm; HRMS: m/z calcd for C19H19O8 [M+H]+: 375.10744;
found: 375.10741.
Compound 5c: Yellow amorphous solid; Rf =0.46 (CH/EtOAc 1:2);
1H NMR (400 MHz, CDCl3): d=7.50 (d, J=1.2 Hz, 1H), 7.39 (t, J=
8.3 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 6.52 (d, J=8.3 Hz, 1H), 5.75 (d, J=
1.2 Hz, 1H), 3.92 (s, 3H), 1.55 (s, 9H), 1.55 ppm (s, 9H); 13C NMR
(101 MHz, CDCl3): d=180.1, 163.3, 161.4, 161.1, 159.6, 147.3, 145.0,
136.7, 113.9, 113.3, 111.1, 110.4, 105.1, 84.6, 82.9, 67.8, 56.4, 28.2,
27.9 ppm; HRMS: m/z calcd for C23H27O8 [M+H]+: 431.17004; found:
431.16978.
Conclusion
In our endeavors to synthesize compound collections in-
spired by natural products for chemical biology and medici-
nal chemistry research,[19] we have developed a hitherto un-
precedented [4+2] annulation reaction between electron-
deficient chromone oxa- and azadienes and acetylenes. The
strategy provided novel tricyclic benzopyrone ring systems
Compound 5d: Off-white solid; Rf =0.28 (CH/EtOAc 1:2); m.p. 1558C;
1H NMR (400 MHz, CDCl3): d=7.73 (s, 1H), 7.49–7.46 (m, 1H), 7.40 (t,
J=8.4 Hz, 1H), 6.59 (dd, J=8.3, 0.9 Hz, 1H), 6.56 (dd, J=8.4, 0.6 Hz,
1H), 5.73 (d, J=0.4 Hz, 1H), 3.93 (s, 3H), 3.85 ppm (s, 3H); 13C NMR
(101 MHz, CDCl3): d=180.7, 165.1, 161.4, 161.1, 152.1, 144.9, 136.8,
5134
www.chemeurj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 5130 – 5137

Chromone-Derived Heterodienes and Acetylenes
FULL PAPER
115.3, 113.2, 110.7, 108.4, 104.9, 65.5, 56.4, 52.2 ppm; HRMS: m/z calcd
for C15H13O6 [M+H]+: 289.07066; found: 289.07070.
Representative example of [4+2] annulation of tosylimines derived from
3-formylchromones
and
acetylenecarboxylates:
nBu3P
(9.1 mg,
0.045 mmol,0.3 equiv) was added to a solution containing 3-(tosylimino-
methyl)-4-chromen-4-one (50 mg, 0.15 mmol, 1.0 equiv) and dimethylace-
tylenedicarboxylate (43 mg, 0.30 mmol, 2 equiv) at 808C in degassed tolu-
ene (5 mL) and the reaction mixture was stirred for 4 h (other imines
take up to 20 h for full conversion, as monitored by TLC). After evapora-
tion of the solvent, the crude product was purified by column chromatog-
raphy (silica gel, CH/EtOAc 9:1) to yield dihydropyridine 18a and pyri-
dine 19a.
Compound 5e: Brown amorphous solid; Rf =0.30 (CH/EtOAc 1:2);
1H NMR (400 MHz, CDCl3): d=9.76 (s, J=0.5 Hz, 1H), 7.62 (d, J=
0.9 Hz, 1H), 7.61–7.57 (m, 3H), 7.55–7.50 (m, 2H), 7.43 (t, J=8.4 Hz,
1H), 6.64 (dd, J=8.3, 0.9 Hz, 1H), 6.59 (dd, J=8.4, 0.6 Hz, 1H), 5.96–
5.87 (m, 1H), 3.95 ppm (s, 3H); 13C NMR (101 MHz, CDCl3): d=190.2,
180.7, 167.6, 161.4, 144.6, 136.9, 132.1, 130.1, 129.7, 128.9, 115.9, 113.3,
113.0, 110.9, 104.9, 65.2, 56.4 ppm; HRMS: m/z calcd for C20H15O5
[M+H]+: 335.09140; found: 335.09147.
Compound 18a: Off-white solid; Rf =0.17 (CH/EtOAc 7:3); m.p. 1728C;
1H NMR (400 MHz, CDCl3): d=8.07 (s, 1H), 7.74–7.72 (dd, J=8.0,
1.6 Hz, 1H), 7.68–7.64 (ddd, J=8.4, 7.2, 1.6 Hz, 1H), 7.63–7.61 (m, 2H),
7.46–7.44 (dd, J=8.0, 1.0 Hz, 1H), 7.33–7.29 (ddd, J=8.0, 7.2, 0.8 Hz,
1H), 6.88–6.86 (dd, J=8.4, 0.8 Hz, 1H), 5.48 (s, 1H), 4.33 (s, 3H), 3.69 (s,
3H), 2.16 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=175.1, 162.8,
162.0, 156.9, 155.6, 152.9, 144.9, 134.9, 133.7, 129.2, 127.8, 125.3, 125.1,
124.1, 118.0, 116.1, 115.4, 60.0, 56.9, 51.9, 21.4 ppm; HRMS (FAB): m/z
calcd for C23H19NO8S [M+H]+: 470.0910; found: 470.0891.
Compound 19a: Yellow oil; Rf =0.52 (CH/EtOAc 3:2); 1H NMR
(400 MHz, CDCl3): d=11.66 (s, 1H), 9.01 (d, J=2.1 Hz, 1H), 8.47 (d, J=
2.1 Hz, 1H), 7.63–7.56 (m, 1H), 7.48–7.42 (m, 1H), 7.15–7.09 (m, 1H),
6.94 (ddd, J=8.1, 7.2, 1.1 Hz, 1H), 4.05 (s, 3H), 3.97 ppm (s, 3H);
13C NMR (101 MHz, CDCl3): d=197.4, 166.1, 164.8, 163.6, 153.0, 151.5,
138.3, 137.8, 134.7, 132.9, 126.1, 119.6, 119.2, 118.8, 53.5, 53.4 ppm;
HRMS: m/z calcd for C16H14O6N [M+H]+: 316.08156; found: 316.08157.
Compound 5 f: Yield: 82 mg, 0.25 mmol, 25%; yellow amorphous solid;
Rf =0.66 (CH/EtOAc 6:4); 1H NMR (400 MHz, CDCl3): d=11.72 (s,
1H), 7.55 (d, J=1.3 Hz, 1H), 7.37 (t, J=8.3 Hz, 1H), 6.55 (dd, J=8.4,
0.9 Hz, 1H), 6.41 (dd, J=8.2, 0.9 Hz, 1H), 5.86 (d, J=1.3 Hz, 1H), 3.91
(s, 3H), 3.89 ppm (s, 3H); 13C NMR (101 MHz, CDCl3): d=186.3, 164.5,
162.9, 160.7, 158.7, 146.3, 145.3, 139.2, 112.1, 111.4, 110.8, 109.6, 108.1,
66.9, 53.7, 53.1 ppm.
Compound 5g: Yield: 90 mg, 0.25 mmol, 25%; yellow amorphous solid;
Rf =0.77 (CH/EtOAc 6:4); 1H NMR (400 MHz, CDCl3): d=11.73 (s,
1H), 7.55 (d, J=1.3 Hz, 1H), 7.37 (t, J=8.3 Hz, 1H), 6.55 (dd, J=8.4,
0.9 Hz, 1H), 6.39 (dd, J=8.2, 1.0 Hz, 1H), 5.86 (d, J=1.2 Hz, 1H), 4.42–
4.28 (m, 4H), 1.39–1.32 ppm (m, 6H); 13C NMR (101 MHz, CDCl3): d=
186.4, 164.0, 162.8, 160.3, 158.8, 146.4, 145.4, 139.1, 112.0, 111.2, 110.7,
109.5, 108.0, 67.0, 63.2, 62.3, 14.1, 14.0 ppm.
Compound 5h: Light-yellow solid; Rf =0.61 (CH/EtOAc 6:4); 1H NMR
(400 MHz, CDCl3): d=8.13 (dd, J=8.4, 1.2 Hz, 1H), 7.89 (d, J=8.7 Hz,
1H), 7.78 (d, J=8.2 Hz, 1H), 7.62 (ddd, J=8.2, 6.9, 1.3 Hz, 1H), 7.59 (d,
J=1.4 Hz, 1H), 7.51 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.46 (d, J=8.7 Hz,
1H), 6.06 (d, J=1.4 Hz, 1H), 3.97 (s, 3H), 3.94 ppm (s, 3H); 13C NMR
(101 MHz, CDCl3): d=180.7, 164.7, 161.1, 157.3, 147.4, 144.7, 138.0,
130.2, 128.1, 126.8, 125.0, 123.7, 122.4, 122.0, 117.5, 113.0, 110.5, 68.1,
53.7, 53.1 ppm; HRMS: m/z calcd for C20H15O7 [M+H]+: 367.08123;
found: 367.08136.
Compound 18b: White solid; Rf =0.28 (CH/EtOAc 7:3); m.p. 1768C;
1H NMR (400 MHz, CDCl3): d=8.05 (s, 1H), 7.78–7.75 (dd, J=8.0,
1.6 Hz, 1H), 7.68–7.65 (ddd, J=8.4, 7.2, 1.6 Hz, 1H), 7.64–7.63 (m, 2H),
7.46–7.44 (dd, J=8.4, 0.4 Hz, 1H), 7.34–7.30 (ddd, J=8.0, 6.8,
1.0 Hz,1H), 6.91–6.89 (dd, J=8.0, 1H), 5.52 (s, 1H), 4.79–4.65 (m, 2H),
4.20–4.06 (m, 2H), 2.17 (s, 3H), 1.40 (t, J=7.2, 3H), 1.20 ppm (t, J=7.2,
3H); 13C NMR (100 MHz, CDCl3): d=175.0, 163.1, 156.7, 155.6, 152.7,
144.9, 135.0, 133.7, 129.2, 127.9, 125.4, 125.1, 124.1, 118.0, 117.1, 115.8,
68.6, 60.9, 56.8, 21.4, 15.6, 13.9 ppm; HRMS (FAB): m/z calcd for
C25H23NO8S [M+H]+: 498.12172; found: 498.12097.
Compound 5i: Light-brown solid; Rf =0,74 (CH/EtOAc 6:4); m.p. 1458C
;
1H NMR (400 MHz, CDCl3): d=7.95 (dd, J=7.9, 1.8 Hz, 1H), 7.53 (d,
Compound 19b: Yellow oil; Rf =0.66 (CH/EtOAc 3:2); NMR 1H NMR
(400 MHz, CDCl3): d=11.73 (brs, 1H), 9.00 (d, J=2.1 Hz, 1H), 8.48 (d,
J=2.1 Hz, 1H), 7.61–7.55 (m, 1H), 7.50–7.41 (m, 1H), 7.15–7.10 (m,
1H), 6.94 (ddd, J=8.2, 5.4, 1.8 Hz, 1H), 4.51 (q, J=7.2 Hz, 2H), 4.43 (q,
J=7.1 Hz, 2H), 1.45 (t, J=7.2 Hz, 3H), 1.40 ppm (t, J=7.1 Hz, 3H);
13C NMR (101 MHz, CDCl3): d=197.6, 164.4, 163.6, 153.5, 151.4, 138.3,
137.8, 134.5, 132.9, 126.2, 119.6, 119.1, 77.5, 77.2, 76.8, 62.8, 62.7,
14.2 ppm; HRMS: m/z calcd for C18H18O6N [M+H]+: 344.11286; found:
344.11285.
J=1.3 Hz, 1H), 7.53–7.47 (m, 1H), 7.08 (ddd, J=8.2, 7.2, 1.1 Hz, 1H),
6.95–6.88 (m, 1H), 5.86 (d, J=1.3 Hz, 1H), 1.57 (s, 9H), 1.56 ppm (s,
9H); 13C NMR (101 MHz, CDCl3): d=181.4, 163.2, 159.5, 159.4, 146.9,
145.2, 136.7, 127.6, 122.9, 122.4, 118.4, 113.0, 111.7, 84.7, 83.1, 68.1, 28.2,
28.0 ppm; HRMS: m/z calcd for C22H25O7 [M+H]+: 401.15948; found:
401.15939.
Compound 5j: Light-brown solid; Rf =0.64 (CH/EtOAc 6:4); m.p. 1468C
;
1H NMR (500 MHz, CDCl3): d=9.79 (s, 1H), 8.27 (s, 1H), 8.20 (d, J=
7.8 Hz, 1H), 7.94–7.80 (m, 3H), 7.67 (t, J=7.6 Hz, 1H), 7.56 (t, J=
7.3 Hz, 1H), 7.49–7.34 ppm (m, 4H); 13C NMR (126 MHz, CDCl3): d=
195.3, 191.2, 175.1, 157.3, 156.0, 141.5, 140.5, 135.7, 134.7, 134.5, 129.4,
129.1, 126.4, 126.3, 123.6, 118.8, 118.4 ppm; HRMS: m/z calcd for
C19H13O4 [M+H]+:305.08084; found: 305.08087.
Compound 18c: White solid; Rf =0.19 (CH/EtOAc 7:3); m.p. 231–2328C;
1H NMR (400 MHz, CDCl3): d=8.04 (s, 1H), 7.64–7.61 (dt, J=8.4,
2.0 Hz, 2H), 7.52 (d, J=0.8 Hz, 1H), 7.48–7.45 (dd, J=8.4, 2.0 Hz, 1H),
7.36–7.34 (d, J=8.4 Hz, 1H), 6.89–6.87 (d, J=8.4 Hz, 2H), 5.48 (s, 1H),
4.33 (s, 3H), 3.69 (s, 3H), 2.38 (s, 3H), 2.17 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=175.2, 162.9, 162.1, 156.9, 153.9, 152.9, 144.9,
135.3, 135.0, 134.9, 129.2, 127.8, 124.7, 123.8, 117.7, 116.2, 115.1, 60.0,
56.9, 51.9, 21.3, 20.8 ppm; HRMS (ESI): m/z calcd for C24H21NO8S
[M+H]+: 484.10607; found: 484.10526.
Compound 19c: Yellow oil; Rf =0.50(CH/EtOAc 60:40); 1H NMR
(400 MHz, CDCl3): d=11.49 (s, 1H), 8.98 (d, J=2.0 Hz, 1H), 8.47 (d, J=
2.0 Hz, 1H), 7.40 (dd, J=8.5, 1.8 Hz, 1H), 7.19 (d, J=1.0 Hz, 1H), 7.02
(d, J=8.5 Hz, 1H), 4.05 (s, 3H), 3.97 (s, 3H), 2.26 ppm (s, 3H); 13C NMR
(101 MHz, CDCl3): d=197.3, 166.2, 164.9, 161.6, 152.9, 151.4, 139.0,
138.2, 134.9, 132.4, 128.9, 126.2, 118.9, 118.5, 53.5, 53.4, 20.6 ppm; HRMS:
m/z calcd for C17H16O7N [M+H]+: 330.09721; found: 330.09717.
Compound 5k: Yellow amorphous solid; Rf =0.67 (CH/EtOAc 6:4); m.p.
1078C ; 1H NMR (400 MHz, CDCl3): d=7.96 (dt, J=4.0, 2.0 Hz, 1H),
7.89–7.85 (m, 2H), 7.64 (dd, J=2.7, 1.2 Hz, 1H), 7.60–7.46 (m, 5H),
7.15–7.07 (m, 1H), 5.76 ppm (d, J=1.3 Hz, 1H);13C NMR (101 MHz,
CDCl3): d=181.0, 162.6, 159.0, 145.3, 137.2, 132.6, 129.9, 129.1, 128.3,
127.6, 123.0, 122.8, 118.8, 116.4, 112.2, 87.2, 68.0 ppm; HRMS: m/z calcd
for C19H12O3N [M+H]+: 302.08117; found: 302.08132.
General procedure for asymmetric and enantioselective [4+2] annula-
tion reaction:
A
solution of the 3-formylchromone derivative
(0.10 mmol; 1.0 equiv) and 6’-(4-biphenyl)-b-isocinchonine (8.9 mg;
20 mmol; 0.2 equiv) in dry THF (4 mL) was cooled to À708C. Then, di-
alkylacetylenedicarboxylate (0.2 mmol; 2.0 equiv) was added. The solu-
tion was stirred at À708C for 3 d. A saturated aqueous solution of NH4Cl
(10 mL) was added to the solution and it was allowed to warm to RT. The
mixture was filtered, the solvent was removed under reduced pressure,
and the crude product was purified by column chromatography (5 g silica
gel, CH/EtOAc 87:13) to yield the pure products.[11] For HPLC data, see
the Supporting Information.
Compound 18d: White solid; Rf =0.32 (CH/EtOAc 7:3); m.p. 151–
1528C; 1H NMR (400 MHz, CDCl3): d=8.01 (s, 1H), 7.65–7.62 (td, J=
8.4, 2.0 Hz, 2H), 7.55–7.54 (dd, J=1.2, 0.4 Hz, 1H), 7.48–7.45 (ddd, J=
8.4, 2.4, 0.4 Hz, 1H), 7.35–7.33 (d, J=8.4 Hz, 1H), 6.91–6.89 (dd, J=8.4,
0.8 Hz, 2H) 5.51 (s, 1H), 4.79–4.65 (m, 2H), 4.20–4.05 (m, 2H), 2.39 (s,
3H), 2.18 (s, 3H), 1.40 (t, J=7.0 Hz, 3H), 1.20 ppm (t, J=7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=175.1, 163.1, 161.6, 156.6, 153.9, 152.7,
Chem. Eur. J. 2011, 17, 5130 – 5137
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5135

H. Waldmann, K. Kumar et al.
144.8, 135.2, 135.0, 134.9, 129.2, 127.8, 124.7, 123.8, 117.7, 117.2, 115.5,
68.6, 60.9, 56.8, 21.3, 20.8, 15.6, 13.9 ppm; HRMS (ESI): m/z calcd for
C26H25NO8S [M+H]+: 512.13737; found: 512.13656.
1H), 4.80–4.64 (m, 2H), 4.20–4.05 (m, 2H), 2.23 (s, 3H), 1.39 (t, J=
7.0 Hz, 3H), 1.20 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=173.7, 163.0, 161.5, 156.8, 154.3, 152.8, 145.2, 135.0, 134.4, 129.2, 128.0,
127.7, 125.3, 119.9, 118.6, 116.8, 116.0, 68.7, 60.9, 56.6, 21.4, 15.6,
13.9 ppm; HRMS (ESI): m/z calcd for C25H2279BrNO832S [M+H]+:
576.03223; found: 576.03195.
Compound 19h: Brown oil; Rf =0.61 (CH/EtOAc 3:2); 1H NMR
(400 MHz, CDCl3): d=11.59 (s, 1H), 8.99 (d, J=2.1 Hz, 1H), 8.49 (d, J=
2.1 Hz, 1H), 7.66 (dd, J=8.9, 2.4 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 7.04
(d, J=8.9 Hz, 1H), 4.52 (q, J=7.2 Hz, 2H), 4.44 (q, J=7.2 Hz, 2H), 1.46
(t, J=7.2 Hz, 3H), 1.43–1.38 ppm (m, 3H); 13C NMR (101 MHz, CDCl3):
d=196.7, 165.7, 164.2, 162.5, 153.9, 151.2, 140.5, 138.4, 134.6, 133.9, 126.3,
121.2, 120.0, 111.2, 62.9, 62.8, 14.2 ppm; HRMS (ESI): m/z calcd for
C18H17 O6N79Br [M+H]+: 422.02338; found: 422.02310.
Compound 19d: Yellow oil; Rf =0.63 (CH/EtOAc 60:40); NMR
(400 MHz, CDCl3): d=11.51 (s, 1H), 8.98 (d, J=2.0 Hz, 1H), 8.48 (d, J=
2.0 Hz, 1H), 7.39 (dd, J=8.5, 2.1 Hz, 1H), 7.21 (d, J=1.5 Hz, 1H), 7.02
(d, J=8.5 Hz, 1H), 4.52 (q, J=7.2 Hz, 2H), 4.43 (q, J=7.1 Hz, 2H), 2.26
(s, 3H), 1.45 (t, J=7.2 Hz, 3H), 1.40 ppm (t, J=7.1 Hz, 3H); 13C NMR
(101 MHz,): d=197.5, 165.9, 164.4, 161.6, 153.3, 151.3, 139.0, 138.3, 134.7,
132.4, 128.9, 126.2, 118.9, 118.5, 62.8, 62.7, 29.9, 20.6, 14.2 ppm; HRMS:
m/z calcd for C19H20O6N [M+H]+: 358.12851; found: 358.12853.
Compound 18e: Off-white solid; Rf =0.31 (CH/EtOAc 7:3); m.p. 110–
1118C; 1H NMR (400 MHz, CDCl3): d=8.06 (s, 1H), 7.65–7.64 (m, 1H),
7.62–7.60 (m, 2H), 7.55–7.52 (dd, J=8.4, 2.4 Hz, 1H), 7.40–7.38 (d, J=
8.8 Hz, 1H), 6.91–6.89 (d, J=8.4 Hz, 2H), 5.49 (s, 1H), 4.33 (s, 3H), 3.69
(s, 3H), 2.95 (m, 1H), 2.17 (s, 3H), 1.25–1.23 ppm (dd, J=7.2, 1.2 Hz,
6H); 13C NMR (100 MHz, CDCl3): d=175.4, 162.8, 162.0, 156.9, 154.1,
152.9, 146.4, 144.8, 134.9, 132.8, 129.2, 127.8, 123.8, 121.9, 117.8, 116.1,
115.1, 60.0, 57.0, 51.9, 33.7, 23.9, 23.8, 21.4 ppm; HRMS (ESI): m/z calcd
for C26H25NO8S [M+H]+: 512.13737; found: 512.13692.
Compound 19e: Yellow oil; Rf =0.62 (CH/EtOAc 3:2); 1H NMR
(400 MHz, CDCl3): d=11.50 (s, 1H), 9.02 (d, J=2.0 Hz, 1H), 8.53–8.47
(m, 1H), 7.48 (dd, J=8.7, 2.2 Hz, 1H), 7.28–7.24 (m, 1H), 7.07 (d, J=
8.6 Hz, 1H), 4.06 (s, 3H), 3.98 (s, 3H), 2.82 (dd, J=13.9, 6.9 Hz, 1H),
1.19 ppm (d, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3): d=197.3,
161.9, 153.0, 151.6, 140.2, 138.6, 136.5, 134.9, 133.1, 130.0, 128.4, 126.3,
119.1, 118.4, 53.6, 53.5, 33.4, 24.1 ppm; HRMS (ESI): m/z calcd for
C19H20O6N [M+H]+: 358.12851; found: 358.12832.
Compound 19i: Off-white solid; Rf =0.55 (CH/EtOAc 3:2); m.p. 908C;
1H NMR (400 MHz, CDCl3): d=11.75 (d, J=3.9 Hz, 1H), 9.40 (d, J=
1.9 Hz, 1H), 9.06 (d, J=2.0 Hz, 1H), 8.58 (t, J=2.1 Hz, 1H), 7.60–7.55
(m, 1H), 7.48 (dd, J=8.0, 1.6 Hz, 1H), 7.11 (dd, J=8.5, 0.8 Hz, 1H), 6.93
(ddd, J=8.2, 7.2, 1.1 Hz, 1H), 4.00 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=198.3, 164.8, 163.4, 153.2, 153.0, 137.37, 137.35, 132.8, 119.3,
118.9, 77.3, 77.0, 76.7, 52.8 ppm; HRMS: m/z calcd for C13H12O4N
[M+H]+: 258.07608; found: 258.07583.
Acknowledgements
This research work was supported by the Max Planck Gesellschaft. We
thank Evonik Degussa GmbH (formerly Degussa GmbH) for the gift of
chiral phosphines 11 and 12. H.W. holds an Advanced Investigator Grant
of the European Research Council.
Compound 18 f: White solid; Rf =0.43 (CH/EtOAc 7:3); m.p. 113–1148C;
1H NMR (400 MHz, CDCl3): d=8.04 (s, 1H), 7.65–7.64 (m, 1H), 7.63–
7.62 (m, 2H), 7.64–7.63 (m, 2H), 7.54–7.51 (dd, J=8.8, 2.4 Hz, 1H),
7.39–7.37 (d, J=8.8 Hz, 1H), 6.92–6.90 (d, J=8.0 Hz, 2H), 5.51 (s, 1H),
4.76–4.67 (m, 2H), 4.17–4.06 (m, 2H), 2.95 (m, 1H), 2.18 (s, 3H), 1.39 (t,
J=7.0 Hz, 3H), 1.24–1.23 (d, J=6.8 Hz, 6H), 1.19 ppm (t, J=7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=175.3, 163.0, 161.6, 156.7, 154.0,
152.7, 146.3, 144.7, 134.9, 132.7, 129.1, 127.8, 123.8, 122.0, 117.8, 117.1,
115.8, 68.6, 60.8, 56.9, 33.6, 23.9, 23.8, 21.4, 15.6, 13.9 ppm; HRMS (ESI):
m/z calcd for C28H29NO8S [M+H]+: 540.16867; found: 540.16776.
[1] S. V. Frye, Nat. Chem. Biol. 2010, 6, 159–161.
[2] a) K. Kumar, H. Waldmann, Angew. Chem. 2009, 121, 3272–3290;
Angew. Chem. Int. Ed. 2009, 48, 3224–3242; b) J. P. Nandy, M. Pra-
kesch, S. Khadem, P. T. Reddy, U. Sharma, P. Arya, Chem. Rev.
2009, 109, 1999–2060.
Compound 19 f: Brown oil; Rf =0.72 (CH/EtOAc 3:2); 1H NMR
(400 MHz, CDCl3): d=11.52 (s, 1H), 9.02 (d, J=2.1 Hz, 1H), 8.51 (d, J=
2.1 Hz, 1H), 7.48 (dd, J=8.6, 2.3 Hz, 1H), 7.27 (d, J=2.3 Hz, 1H), 7.06
(d, J=8.6 Hz, 1H), 4.52 (dt, J=7.1, 6.2 Hz, 2H), 4.44 (dt, J=13.5, 3.9 Hz,
2H), 2.90–2.78 (m, 1H), 1.46 (t, J=7.2 Hz, 3H), 1.39 (t, J=7.2 Hz, 3H),
1.19 ppm (d, J=6.9 Hz, 9H); 13C NMR (101 MHz,): d=197.2, 165.7,
164.2, 161.7, 153.3, 151.3, 138.4, 136.2, 134.5, 129.8, 128.9, 126.0, 118.8,
118.3, 62.7, 62.5, 33.2, 23.9, 23.9, 14.1 ppm; HRMS: m/z calcd for
C21H24O6N [M+H]+: 386.15981; found: 386.15948.
[3] a) F. M. Dean, Naturally Occurring Oxygen Ring Compounds, 1963,
Butterworths, London; b) J. C. Liermann, H. Kolshorn, T. Opatz, E.
Thines, H. Anke, J. Nat. Prod. 2009, 72, 1905–1907; c) N. Kawahara,
S. Sekita, M. Satake, S.-i. Udagawa, K.-i. Kawai, Chem. Pharm. Bull.
1994, 42, 1720–1723; d) S. Sato, Y. Suga, T. Yoshimura, R. Nakaga-
wa, T. Tsuji, K. Umemura, T. Andoh, Bioorg. Med. Chem. Lett.
1999, 9, 2653–2656; e) H. Fujimoto, T. Asai, Y.-P. Kim, M. Ishibashi,
Chem. Pharm. Bull. 2006, 54, 550–553; f) K. Tatsuta, S. Yoshihara,
N. Hattori, S. Yoshida, S. Hosokawa, J. Antibiot. 2009, 62, 469–470.
[4] D. J. Payne, J. A. Hueso-Rodriguez, H. Boyd, N. O. Concha, C. A.
Janson, M. Gilpin, J. H. Bateson, C. Cheever, N. L. Niconovich, S.
Pearson, S. Rittenhouse, D. Tew, E. Diez, P. Perez, J. de La Fuente,
M. Rees, A. Rivera-Sagredo, Antimicrob. Agents Chemother. 2002,
46, 1880–1886.
[5] S. M. Drawz, R. A. Bonomo, Clin. Microbiol. Rev. 2010, 23, 160–
201.
[6] a) M. Yamauchi, S. Katayama, T. Todoroki, T. Watanable, J. Chem.
Soc., Chem. Commun. 1984, 1565–1566; b) A. E. Oxfordm, H. Rais-
trick, P. Simonart, Biochem. J. 1935, 29, 1102–1103.
[7] a) S. J. Coutts, T. W. Wallace, Tetrahedron 1994, 50, 11755–11780;
b) G. Sabitha, Aldrichimica Acta 1996, 29, 15–29.
[8] a) P. T. Kaye, D. M. Molefe, A. T. Nchinda, L. V. Sabbagh, J. Chem.
Res. Synop. 2004, 303–306; b) D. M. Molefe, M. M. Ganto, K. A.
Lobb, P. T. Kaye, J. Chem. Res. Synop. 2009, 452–456.
Compound 18g: Yellow solid; Rf =0.23 (CH/EtOAc 7:3); m.p. 219–
2208C; 1H NMR (400 MHz, CDCl3): d=8.07 (s, 1H), 7.83 (d, J=2.4,
1H), 7.75–7.72 (dd, J=8.8, 2.4 Hz, 1H), 7.63–7.60 (td, J=8.4, 2.0 Hz,
2H), 7.36–7.34 (d, J=8.8 Hz, 1H), 6.91–6.89 (d, J=8.4 Hz, 1H), 5.46 (s,
1H), 4.33 (s, 3H), 3.69 (s, 3H), 2.23 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=173.8, 162.7, 162.0, 157.0, 154.3, 152.9, 145.3, 136.7, 134.9,
129.2, 128.0, 127.7, 125.3, 119.9, 118.7, 115.8, 115.7, 60.0, 56.7, 52.0,
21.4 ppm; HRMS (ESI): m/z calcd for C23H1879BrNO832S [M+H]+:
548.00093; found: 548.00026.
Compound 19g: Brown oil; Rf =0.53 (CH/EtOAc 3:2); 1H NMR
(400 MHz, CDCl3): d=11.56 (s, 1H), 9.00 (d, J=2.1 Hz, 1H), 8.48 (d, J=
2.1 Hz, 1H), 7.66 (dd, J=8.8, 2.3 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H), 7.03
(d, J=8.9 Hz, 1H), 4.05 (s, 3H), 3.98 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=196.4, 165.8, 164.5, 162.3, 153.3, 151.1, 140.4, 138.1, 134.4,
133.9, 126.1, 121.0, 119.8, 111.1, 53.4, 53.3 ppm; HRMS: m/z calcd for
C16H13 O6N79Br [M+H]+: 393.99208; found: 395.99003.
[9] a) S. Denmark, G. Beutner, Angew. Chem. 2008, 120, 1584–1663;
Angew. Chem. Int. Ed. 2008, 47, 1560–1638; b) X. Lu, C. Zhang, Z.
Xu, Acc. Chem. Res. 2001, 34, 535–544; c) J. L. Methot, W. R.
Roush, Adv. Synth. Catal. Adv. Synth. Cat. 2004, 346, 1035–1050.
[10] V. Nair, R. S. Menon, A. R. Sreekanth, N. Abhilash, A. T. Biju, Acc.
Chem. Res. 2006, 39, 520–530.
Compound 18h: White solid; Rf =0.43 (CH/EtOAc 7:3); m.p. 130–
1318C; 1H NMR (400 MHz, CDCl3): d=8.04 (s, 1H), 7.85 (d, J=2.4 Hz,
1H), 7.74–7.72 (dd, J=8.8, 2.4 Hz, 1H), 7.64–7.60 (td, J=8.4, 2.0 Hz,
2H), 7.36–7.34 (d, J=8.8 Hz, 1H), 6.92–6.90 (d, J=8.0 Hz, 1H), 5.48 (s,
5136
www.chemeurj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 5130 – 5137

Chromone-Derived Heterodienes and Acetylenes
FULL PAPER
[11] H. Waldmann, V. Khedkar, H. Dꢀckert, M. Schꢀrmann, I. M.
Oppel, K. Kumar, Angew. Chem. 2008, 120, 6975–6978; Angew.
Chem. Int. Ed. 2008, 47, 6869–6872.
[18] V. Khedkar, W. Liu, H. Duckert, K. Kumar, Synlett 2010, 403–406
(erratum: V. Khedkar, W. Liu, H. Duckert, K. Kumar, Synlett 2010,
1576).
[19] a) O. Barun, K. Kumar, S. Sommer, A. Langerak, T. U. Mayer, O.
Muller, H. Waldmann, Eur. J. Org. Chem. 2005, 4773–4788; b) O.
Barun, S. Sommer, H. Waldmann, Angew. Chem. 2004, 116, 3258–
3261; Angew. Chem. Int. Ed. 2004, 43, 3195–3199; c) A. Nçren-
Mꢀller, I. Reis-CorrÞa, H. Prinz, C. Rosenbaum, K. Saxena, H. J.
Schwalbe, D. Vestweber, G. Cagna, S. Schunk, O. Schwarz, H.
Schiewe, H. Waldmann, Proc. Natl. Acad. Sci. USA 2006, 103,
10606–10611; d) H. Waldmann, L. Eberhardt, K. Wittstein, K.
Kumar, Chem. Commun. 2010, 46, 4622–4624; e) A. B. Garcia, T.
Lessmann, J. D. Umarye, V. Mamane, S. Sommer, H. Waldmann,
Chem. Commun. 2006, 3868–3870; f) J. D. Umarye, T. Lessmann,
A. B. Garcia, V. Mamane, S. Sommer, H. Waldmann, Chem. Eur. J.
2007, 13, 3305–3319; g) T. Lessmann, M. G. Leuenberger, S. Men-
ninger, M. Lopez-Canet, O. Muller, S. Hummer, J. Bormann, K.
Korn, E. Fava, M. Zerial, T. U. Mayer, H. Waldmann, Chem. Biol.
2007, 14, 443–451; h) A. P. Antonchick, C. Gerding-Reimers, M.
Catarinella, M. Schurmann, H. Preut, S. Ziegler, D. Rauh, H. Wald-
mann, Nat. Chem. 2010, 2, 735–740; i) V. V. Vintonyak, K. Warburg,
H. Kruse, S. Grimme, K. Hubel, D. Rauh, H. Waldmann, Angew.
Chem. 2010, 122, 6038–6041; Angew. Chem. Int. Ed. 2010, 49, 5902–
5905.
[12] a) M. A. Terzidis, E. Dimitriadou, C. A. Tsoleridis, J. Stephanidou-
Stephanatou, Tetrahedron Lett. 2009, 50, 2174–2176; b) X. Yu, Z.
Caoa, J. Zhang, Org. Biomol. Chem. 2010, 8, 5059–5061.
[13] a) W. Zhang, B. I. Wilke, J. Zhan, K. Watanabe, C. N. Boddy, Y.
Tang, J. Am. Chem. Soc. 2007, 129, 9304–0305; b) K. J. Weissman,
ChemBioChem 2010, 11, 485–488; c) C. Khosla, J. Org. Chem. 2009,
74, 6416–6420; d) C. Hertweck, Angew. Chem. 2009, 121, 4782–
4811; Angew. Chem. Int. Ed. 2009, 48, 4688–4716.
[14] a) M. Lacova, D. Loos, M. Furdik, M. Matulova, H. El-Shaaer, Mol-
ecules 1998, 3, 149–158; b) R. Araya-Maturana, J. Heredia-Moya,
H. n. Pessoa-Mahana, B. Weiss-Lꢃpez, Synth. Commun. 2003, 33,
3225–3231.
[15] B. M. Trost, C. J. Li, J. Am. Chem. Soc. 1994, 116, 10819–10820.
[16] a) A. Nakano, S. Kawahara, S. Akamatsu, K. Morokuma, M. Naka-
tani, Y. Iwabuchi, K. Takahashi, J. Ishihara, S. Hatakeyama, Tetrahe-
dron 2006, 62, 381–389; b) M. Bartꢃk, M. Sutyinszki, K. Felfçldi, J.
Catal. 2003, 220, 207–214; c) T. Marcelli, J. H. van Maarseveen, H.
Hiemstra, Angew. Chem. 2006, 118, 7658–7666; Angew. Chem. Int.
Ed. 2006, 45, 7496–7504.
[17] K. Nozaki, N. Sato, K. Ikeda, H. Takaya, J. Org. Chem. 1996, 61,
4516–4519.
Received: December 10, 2010
Published online: March 22, 2011
Chem. Eur. J. 2011, 17, 5130 – 5137
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5137