Biology-oriented synthesis of benzopyrano[3,4-c]pyrrolidines

Article abstract of DOI:10.1016/j.bmc.2015.02.044

A natural product inspired synthesis of 6,6,5-tricyclic compounds via a silver(I)-catalyzed formal 1,3-dipolar cycloaddition of coumarins with α-iminoesters was developed. The reaction proceeds in a stepwise reaction course under formation of the trans-su

Full text of DOI:10.1016/j.bmc.2015.02.044

Bioorganic & Medicinal Chemistry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Biology-oriented synthesis of benzopyrano[3,4-c]pyrrolidines
Marco Potowski a,b, Christopher Golz , Carsten Strohmann , Andrey P. Antonchick
Herbert Waldmann
a
c
c
a,b,
⇑
,
a,b,
⇑
Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
Chemical Biology, Faculty of Chemistry and Chemical Biology, TU Dortmund, Otto-Hahn-Strasse 6, 44221 Dortmund, Germany
Inorganic Chemistry, Faculty of Chemistry and Chemical Biology, TU Dortmund, Otto-Hahn-Strasse 6, 44221 Dortmund, Germany
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
A natural product inspired synthesis of 6,6,5-tricyclic compounds via a silver(I)-catalyzed formal
,3-dipolar cycloaddition of coumarins with -iminoesters was developed. The reaction proceeds in a
stepwise reaction course under formation of the trans-substituted diastereomer with respect to the
,3-dipole and shows a broad substrate scope.
Received 22 January 2015
Revised 20 February 2015
Accepted 24 February 2015
Available online xxxx
1
a
1
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
[
2+3] cycloaddition
Azomethine ylide
Coumarin
Biology-oriented synthesis (BIOS)
Catalysis
1
. Introduction
The underlying scaffolds of natural products are biologically
as found in some natural compounds, could be synthesized by
,3-dipolar cycloaddition of coumarins 1 with iminoesters 2
(Scheme 1).
1
relevant because they define the areas of chemical space explored
by nature during evolution.1 In biology-oriented synthesis, (BIOS)
biological relevance is employed as key criterion to choose com-
,2
2
. Results and discussion
1
,2
pound classes for the synthesis of focused compound collections.
To establish the proposed 1,3-dipolar cycloaddition, we investi-
Compound libraries based on natural product scaffolds are
commonly structurally complex. Therefore the development of
efficient synthesis methods for such compound collections is
highly important. In this regard, cycloaddition reactions are
remarkable. The [3+2]-cycloaddition of iminoester-derived azome-
thine ylides with alkenes, for example, is a powerful method for
the construction of substituted pyrrolidines, which can be found
gated the reaction of coumarin 1 with the azomethine ylide pre-
cursor -iminoester 2a in the presence of silver(I) salts as
a
catalysts and triethylamine as base. Fortunately, two diastere-
omers 3a and 4a of the desired cycloaddition product could be iso-
lated in a 3:1 ratio with viable yield (Table 1, entry 1). Encouraged
by these results, we optimized the reaction conditions using vari-
ous metal salts as catalysts. In general, the reaction proceeded
either with silver(I) or copper(I) salts (Table 1, entries 1–5).
However, with copper(I) and copper(II) triflate no product forma-
tion was observed (Table 1, entries 6 and 7). The usage of other
copper(I) salts resulted in the desired diastereomers 3a and 4a in
a ratio of 3:1 with yields up to 50% for the major product 3a after
3
–5
in several natural products and biological active compounds.
There are more than 120 reported examples for natural prod-
ucts containing a 6,6,5-tricyclic scaffold with various biological
activities (selected examples are presented in Fig. 1).6
Inspired by these natural products, we wanted to prepare a
focused 6,6,5-tricyclic compound collection. 1,3-Dipolar cycloaddi-
tions with coumarin as dipolarophile have been investigated
2
4 h (Table 1, entries 4 and 5). The silver(I) catalyzed cycloaddi-
tions proceeded faster and resulted in similar diastereoselectivity,
but with slightly higher yields of up to 69% (Table 1, entries 1–3).
Nevertheless, silver(I) trifluoroacetate as catalyst leads to a higher
diastereoselectivity of 5:1 and was therefore used for further
optimization (Table 1, entry 2).
7
before in a few cases. Therefore, we assumed that the 6,6,5-tri-
cyclic scaffold 3 consisting of a fused lactone with a pyrrolidine,
⇑
Corresponding authors.
E-mail addresses: andrey.antonchick@mpi-dortmund.mpg.de (A.P. Antonchick),
Investigation of various solvents revealed that in toluene and
halogenated solvents only traces of the desired products 3a and
herbert.waldmann@mpi-dortmund.mpg.de (H. Waldmann).
http://dx.doi.org/10.1016/j.bmc.2015.02.044
0
968-0896/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Potowski, M.; et al. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.02.044

2
M. Potowski et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
O
HO
H
O
H
HO
CO
OH
2
Et
H
Br
H
O
O
O
OH O
(-)-HamigeranA
HO
(+)-Equilenin
(
-)-Herbertenolide
Eurotirumin
OH
OH
HO
HO
HO
O O
O
N H
H
H
OH
OH
O
H
HO
H
H
O
OH
2
CO Me
O
HO
HO
O
OH
N
H
OH
HO
O
(
+)-Hematoxylin
Gnetuhainin S
(+)-Brazilide A
10-Hydroxyscandine
Figure 1. Selected examples for natural products containing a 6,6,5-tricyclic core structure.
R1
4a were formed (Table 1, entries 8–11). Methanol, ethyl acetate,
acetonitrile and 1,4-dioxane led to product formation, but with
lower diastereoselectivity (up to 3:1), lower yields (up to 57% for
the major product 3a) and with a slower reaction rate compared
to tetrahydrofuran (Table 1, entries 2, 12–15). Next we investi-
gated the influence of the catalyst loading on the 1,3-dipolar
EWG
EWG
NH
EWG
O
R1
2
R
+
N
EWG
O
O
R2
O
3
1
2
cycloaddition of coumarin 1 and a-iminoester 2a (Table 1, entries
Scheme 1. Retrosynthesis of the 6,6,5-tricyclic scaffold containing a fused lactone
with a pyrrolidine.
16–19). The decrease of catalyst loading to 5 mol % had no major
influence on the diastereoselectivity or yield (Table 1, entry 16).
Table 1
a
Screening of reaction conditions
2
CO Me
Br
Br
2
CO Me
N
catalyst
H
N
H
N
MeO
2
C
H
2
MeO C
+
+
O
2
0 mol%base
H
CO Me
CO Me
O
2
2
solvent, rt
O
O
O
O
Br
1
2a
3a
4a
drb
Entry
mol %
Catalyst
Solvent
Base
T (h)
Yieldc (%)
3a
4a
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
AgOAc
AgTFA
AgOTf
THF
THF
THF
THF
THF
THF
THF
Toluene
CH Cl
2 2
CHCl
DCE
MeOH
EtOAc
MeCN
1,4-Dioxane
THF
THF
THF
THF
THF
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
8
4
2
3:1
5:1
3:1
3:1
3:1
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
3:1
3:1
2:1
2:1
5:1
3:1
n.d.
n.d.
4:1
3:1
3:1
n.d.
61
69
53
50
48
20
14
17
15
16
CuPF
CuBF
6
24
24
48
48
48
48
48
48
2
22
22
22
6
20
48
48
6
24
24
48
4
CuOTf
CuOTf
Traces
Traces
Traces
Traces
Traces
Traces
2
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
1
1
1
1
1
1
1
1
1
1
2
2
2
2
3
48
57
46
40
71
59
19
18
19
24
13
20
3
1
0.5
5
5
Traces
Traces
DIPEA
Py
Pyr
61
46
37
15
14
13
THF
THF
THF
5
5
DBU
Traces
n.d. = not determined; CuBF
4
= Cu(CH
3 4 4 6 3 4 6
CN) BF ; CuPF = Cu(CH CN) PF , DCE = dichloroethane.
a
Reaction conditions: catalyst (0.5–10 mol %), base (20 mol %), coumarin 1 (1 equiv, 0.15 mmol) and alanine ester imine 2a (1.5 equiv, 0.225 mmol) in solvent (0.1 M) at
2
0 °C.
b
c
Determined by 1H NMR spectroscopy of crude reaction mixture.
Yield of isolated pure product 3a and 4a after chromatography on silica gel.
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M. Potowski et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
3
Further decrease to 3 mol % reduced the diastereoselectivity to 3:1
and the yield for the major product3a to 59% (Table 1, entry 17).
Lower catalyst loadings resulted in lower conversion and only
traces of the desired diastereomers 3a and 4a (Table 1, entries 18
and 19). Lower diastereoselectivities and yields were also observed
for various bases compared to triethylamine (Table 1, entries
product inspired 6,6,5-tricyclic compounds. The reaction showed a
broad substrate scope with respect to -iminoester 2 and the
trans-substituted diastereomer 3 was obtained as the major pro-
a
duct with diastereoselectivities up to a ratio of 9:1.
4
4
. Experimental section
2
0–23). Thus, the optimal reaction conditions for the 1,3-dipolar
cycloaddition of coumarin 1 and -iminoester 2a are 5 mol % of
AgTFA as catalyst in the presence of Et N as base in THF at 20 °C
Table 1, entry 16). The application of various chiral ligands with
a
.1. General
3
(
Unless otherwise noted, all commercially available compounds
the intention to obtain an asymmetric version of the reaction
resulted in low enantioselectivities of up to 24% (for details see
Supplementary Table S1).
With the optimized reaction conditions in hand, we investi-
gated the scope of the reaction. Therefore, coumarin 1 was reacted
were used as provided without further purifications. Dry solvents
THF, toluene, 1,4-dioxane) were used as commercially available;
CH Cl was purified by the Solvent Purification System M-BRAUN
Glovebox Technology SPS-800. Solvents for chromatography were
technical grade. Analytical thin-layer chromatography (TLC) was
performed on Merck silica gel aluminium plates with F-254 indica-
tor. Compounds were visualized by irradiation with UV light or
potassium permanganate staining. Column chromatography was
performed using silica gel Merck 60 (particle size 0.040–
(
2
2
with various
a-iminoesters 2 under the given conditions (Table 2).
a-Iminoesters 2 based on glycine and alanine were tolerated in the
formal 1,3-dipolar cycloaddition with coumarin 1 and resulted in
equal diastereoselectivities (Table 2, entries 1–4). However, ala-
nine ester imines 2 led to higher yields for the major diastereomer
0
.063 mm). Solvent mixtures are understood as volume/volume.
1
13
3
. Also 1,3-dipoles 2 obtained from various arylaldehydes were
investigated in the 1,3-dipolar cycloaddition with coumarin 1
Table 2, entries 4–17). Regardless of the electronic properties of
the aryl substitutions on -iminoester 2, the reactions proceeded
with diastereoselectivity ratios of up to 9:1. However, unsubsti-
tuted -iminoesters 2 (Table 2, entry 5) and imines having an elec-
tron-donating substituent, such as methyl or methoxy (Table 2,
entries and 10), gave the products with slightly higher
diastereoselectivity and slightly higher yields than -iminoesters
with aryl substituents having electron-withdrawing groups, such
H NMR and C NMR were recorded on a Bruker DRX300
300 MHz), Bruker DRX400 (400 MHz), Bruker DRX500 (500 MHz)
and INOVA500 (500 MHz) using CDCl or (CD SO as solvent.
(
(
3
3 2
)
a
Data are reported in the following order: chemical shift (d)
values are reported in ppm with the solvent resonance as internal
1
13
a
standard (CDCl
3
: d = 7.26 ppm for H, d = 77.16 ppm for
C;
1
13
(
CD SO: d = 2.50 ppm for H, d = 39.52 ppm for C); multiplici-
3 2
)
9
ties are indicated br s (broadened singlet), s (singlet), d (doublet),
t (triplet), q (quartet) m (multiplet); coupling constants (J) are
given in Hertz (Hz). High resolution mass spectra were recorded
on a LTQ Orbitrap mass spectrometer coupled to an Acceka
HPLC-System (HPLC column: Hypersyl GOLD, 50 mm ꢀ 1 mm, parti-
a
2
as fluorine or trifluoromethyl (Table 2, entries 4 and 6). The
diastereoselectivity and the yield also depended on the position
of the aromatic substituents. para-Substituents resulted in higher
yields and diastereoselectivity than meta- or ortho substituents in
cle size 1.9 lm, ionization method: electron spray ionization).
Fourier transform infrared spectroscopy (FT-IR) spectra were
the aromatic ring (Table 2, entries 6–8, 10–12). Further
noesters with one or two substituents were used for the formal
,3-dipolar cycloaddition and led to the desired products 3 in mod-
erate yields and diastereoselectivity of up to 9:1 (Table 2, entries
3–17). Even the usage of -iminoesters 2 containing heteroaryl
a-imi-
obtained with a Bruker Tensor 27 spectrometer (ATR, neat) and
ꢁ1
are reported in terms of frequency of absorption (cm ).
1
4
.2. General procedure for silver-catalysed [3+2]-cycloaddition
1
a
of azomethinylides with coumarins
and alkyl substituents yielded the desired products 3 and 4, but
with lower diastereoselectivity and yield (Table 2, entries 18–20).
To
-iminoester 2 (1.5 equiv, 0.23 mmol) in THF (2 mL) silver(I)-
trifluoroacetate (5 mol %, 7.5 mol) and triethylamine (20 mol %,
mol) were added. The resulting mixture was stirred for
–16 h at 20 °C. Afterwards the solvent was removed under
reduced pressure. The crude mixture was then directly charged
onto silica gel and the product was purified using n-pentane/ethyl
acetate as eluent. Yields, diastereoselectivity and regioselectivity
are given in the tables.
a solution of coumarin 1 (1 equiv, 0.15 mmol) and
a-Iminoester 2, prepared by condensation of aldehyde with valine
a
ester hydrochloride and phenylglycine ester hydrochloride, did not
lead to product formation (Table 2, entries 21 and 22).
The relative configurations of both diastereomers were deter-
mined by NOE experiments (Fig. 2A). The results showed that the
major product is the unexpected trans-substituted diastereomer
l
3
5
0 l
3
a whereas the side product is the exo cycloaddition product 4a.
The configuration of the major product was further confirmed by
crystal structure analysis of compound 3f (Fig. 2B).
Since the W-shape for
a
-iminoester 2 is common under the
4
.2.1. rel-(1S,3R,3aS,9bR)-Dimethyl 3-(4-bromophenyl)-1-
tested reaction conditions, we proposed a stepwise mechanism
methyl-4-oxo-1,2,3,3a,4,9b-hexa-hydrochromeno[3,4-c]
pyrrole-1,3a-dicarboxylate (3a)
for the reaction course (Scheme 2).3
–5
a-Iminoester 2 coordinates
7
1% yield; R
f
= 0.30 (ethyl acetate/cyclohexane = 1:5); 1H NMR
the silver(I) ion. Deprotonation with triethylamine results in the
formation of an azomethine ylide, the active species, which under-
goes nucleophilic attack on the coumarin 1 double bond in b-posi-
tion of the lactone carbonyl group. The following ring closure
results in the trans-substituted diastereomer with respect to the
(
2
1
400 MHz, CDCl
3
) d = 7.53 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz,
H), 7.35–7.27 (m, 2H), 7.14 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 8.2 Hz,
H), 5.50 (s, 1H), 4.06 (s, 1H), 3.50 (s, 3H), 3.15 (s, 3H), 1.79 ppm
1
3
(
1
1
s, 3H); C NMR (101 MHz, CDCl
3
) d = 173.74, 167.42, 165.84,
50.84, 131.14, 129.86, 129.56, 129.01, 124.67, 122.14, 117.46,
17.13, 69.33, 66.35, 63.40, 53.28, 52.98, 52.18, 23.65 ppm; FT-
1
,3-dipole.
3
. Conclusion
IR:
016 cm ; HRMS: calcd for [M+H]
found: 474.05550; calcd for [M+H] C22H21 BrNO = 476.05263,
m
~ = 2924, 2853, 1740, 1619, 1434, 1242, 1153, 1067,
ꢁ1
+
79
1
C
22
H
6
21 BrNO = 474.05468,
+
81
In conclusion, we developed a formal 1,3-dipolar cycloaddition
6
of coumarin 1 with
a-iminoesters 2 for the preparation of natural
found: 476.05243.
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4
M. Potowski et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
Table 2
Scope of the cycloadditiona
1
1
R H
R2
R H
R2
CO
2
Me 5 mol% AgTFA
CO
2
Me
N
N
R1
MeO
2
C
2
MeO C
20 mol% Et N
3
+
N
H
CO
O
2
Me +
H
CO
O
2
Me
O
O
THF, r.t., 5-16h
R2
O
O
1
2
3
4
Entry
Product
3a
R1
R2
drb
Yieldc (%)
71 (13)
37 (17)
46 (15)
64 (21)
72 (9)
1
2
3
4
5
6
Me
H
Br
Br
CF
5.5:1
2:1
3:1
3:1
8:1
4:1
3b
3c
H
3
3d
Me
Me
Me
CF
3
3e
3f
F
67 (16)
7
3g
3h
Me
Me
3:1
2:1
57
F
8
9
50 (34)
F
3i
3j
Me
Me
OMe
9:1
5:1
69
71
1
0
1
1
3k
3l
Me
Me
5:1
4:1
68
52
1
2
CF
3
1
1
3
4
3m
3n
Me
Me
2:1
9:1
65 (28)
68
CF
3
O
O
1
1
1
5
6
7
3o
3p
3q
Me
Me
Me
9:1
3:1
2:1
63
48
43
OBn
OMe
1
8
3r
Me
2:1
53 (31)
O
1
9
0
3s
3t
Me
Me
1:1
48
54
2
1.5:1
2
2
1
2
3u
3v
iPr
Br
Br
n.r.
n.r.
n.d.
n.d.
Ph
n.r. = no reaction.
a
Reaction conditions: AgTFA (5 mol %), Et
Determined by 1H NMR spectroscopy of crude reaction mixture.
Yield of isolated pure major product 3 after chromatography on silica gel, yield for the minor product 4 is given in brackets.
3
N (20 mol %), coumarin1 (1 equiv, 0.15 mmol) and a-iminoester 2 (1.5 equiv, 0.225 mmol) in THF (0.1 M) at 20 °C.
b
c
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M. Potowski et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
5
A
B
O
O
O
O
Br
O
Br
NH
CO
NH
H
H
2
Me
CO
O
2
Me
O
O
3a
4a
3a
Figure 2. (A) Determination of the relative configuration of the diastereomers 3a and 4a by characteristic NOEs. (B) ORTEP plot of 3f with the thermal ellipsoids at 50%
probability.8
4
.2.2. rel-(1R,3R,3aS,9bR)-Dimethyl 3-(4-bromophenyl)-1-
O
methyl-4-oxo-1,2,3,3a,4,9b-hexa-hydrochromeno[3,4-c]
pyrrole-1,3a-dicarboxylate (4a)
O
CO
2
Me
R1
AgTFA
Et
Ag
N
O
R2
= 0.33 (ethyl acetate/cyclohexane = 1:5); 1H NMR
N
1
3% yield; R
400 MHz, CDCl
H), 7.31 (t, J = 7.7 Hz, 2H), 7.15 (t, J = 7.7 Hz, 1H), 7.08 (d,
J = 7.7 Hz, 1H), 5.52 (s, 1H), 4.51 (s, 1H), 3.90 (s, 3H), 3.22 (s, 3H),
f
+
O
O
3
N
(
2
3
) d = 7.48 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz,
O
R
1
1
A
R2
.12 ppm (s, 3H); 1 C NMR (101 MHz, CDCl
50.86, 138.12, 131.51, 130.14, 129.68, 129.32, 125.12, 122.36,
18.01, 117.03, 69.16, 66.90, 63.82, 53.37, 53.13, 50.90,
0.06 ppm; FT-IR:
151,
3
) d = 174.24, 166.38,
1
1
1
2
1
C
C
3
2
Ag
m
~ = 2926, 2848, 1739, 1617, 1488, 1436, 1242,
O
O
O
R2
1
R
2
ꢁ1
+
+
R1
NH
R
1065,
1016 cm
;
HRMS:
calcd
for
[M+H]
O
N
7
9
1
H
O
22
H
H
21 BrNO
6
= 474.05468, found: 474.05550; calcd for [M+H]
= 476.05263, found: 476.05243.
2
CO Me
8
22
21 BrNO
6
2
CO Me
O
O
O
4
.2.3. rel-(1S,3R,3aS,9bR)-Dimethyl 3-(4-bromophenyl)-4-
3a
B
oxo-1,2,3,3a,4,9b-hexahydro-chromeno[3,4-c]pyrrole-1,
a-dicarboxy-late (3b)
7% yield; R
= 0.25 (ethyl acetate/cyclohexane = 1:5); 1H NMR
400 MHz, CDCl ) d = 7.48 (d, J = 8.4 Hz, 2H), 7.31–7.26 (m, 3H),
.11 (d, J = 8.2 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.52 (d, J = 7.6 Hz,
H), 5.10 (s, 1H), 3.95 (d, J = 10.9 Hz, 1H), 3.84–3.71 (m, 4H),
Scheme 2. Proposed reaction course.
3
3
f
(
3
7
1
3
1
1
5
1
C
C
129.74, 129.43, 128.06, 125.79 (q, J = 3.8 Hz), 125.07, 124.14 (q,
J = 272.1 Hz), 118.13, 117.11, 67.74, 64.83, 63.03, 53.99, 53.31,
.66 ppm (s, 3H); 1 C NMR (101 MHz, CDCl
3
) d = 172.26, 166.99,
~
52.98 ppm; FT-IR:
m
= 2926, 2851, 1741, 1619, 1436, 1242, 1152,
3
1067, 1017 cm 1; HRMS: calcd for [M+H]
ꢁ
+
64.57, 150.03, 137.80, 132.04, 129.66, 129.45, 129.37, 125.01,
22.59, 118.10, 117.04, 67.82, 64.83, 62.93, 53.99, 53.45,
22 19 3 6
C H F NO =
450.11590, found: 450.11578.
3.04 ppm; FT-IR:
m
~ = 2925, 2849, 1734, 1489, 1435, 1244, 1153,
ꢁ
1
+
+
073,
1010 cm
;
HRMS:
calcd
for
[M+H]
4.2.6. rel-(1R,3R,3aS,9bR)-Dimethyl 4-oxo-3-(4-(trifluoro-
methyl)phenyl)-1,2,3,3a,4,9b-hexa-hydrochromeno[3,4-c]
pyrrole-1,3a-dicarboxylate (4c)
7
9
21
H19 BrNO
6
= 460.03903, found: 460.04010; calcd for [M+H]
= 462.03698, found: 462.03706.
8
1
21
H19 BrNO
6
1
5% yield; R
= 0.21 (ethyl acetate/cyclohexane = 1:5); 1H NMR
f
4
.2.4. rel-(1R,3R,3aS,9bR)-Dimethyl 3-(4-bromophenyl)-4-
(400 MHz, CDCl ) d = 7.68 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.3 Hz,
2H), 7.36–7.27 (m, 2H), 7.15 (t, J = 7.5 Hz, 1H), 7.09 (d, J = 8.2 Hz,
3
oxo-1,2,3,3a,4,9b-hexahydro-chromeno[3,4-c]pyrrole-1,
a-dicarboxy-late (4b)
7% yield; R
= 0.31 (ethyl acetate/cyclohexane = 1:5); 1H NMR
400 MHz, CDCl ) d = 7.49 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.4 Hz,
H), 7.31 (dd, J = 14.9, 7.3 Hz, 2H), 7.14 (t, J = 7.0 Hz, 1H), 7.08 (d,
J = 8.0 Hz, 1H), 5.55 (s, 1H), 4.26 (d, J = 10.9 Hz, 1H), 3.83 (s, 3H),
.78 (d, J = 10.9 Hz, 1H), 3.29 ppm (s, 3H); 13C NMR (101 MHz,
CDCl ) d = 171.98, 165.34, 165.09, 150.14, 138.75, 131.60, 129.99,
29.81, 129.35, 125.17, 122.49, 118.61, 117.09, 66.69, 64.66,
4.41, 53.35, 52.78, 46.10 ppm; FT-IR:
~ = 2925, 2850, 1738,
488, 1456, 1221, 1145, 1072, 1009 cm ; HRMS: calcd for
3
1H), 5.65 (s, 1H), 4.29 (d, J = 10.9 Hz, 1H), 3.86–3.78 (m, 4H),
13
1
f
3
3.25 ppm (s, 3H); C NMR (101 MHz, CDCl ) d = 171.94, 165.30,
(
2
3
165.05, 150.15, 143.93, 130.71, 129.99, 129.88, 128.09, 126.02,
125.38 (q, J = 3.8 Hz), 125.24, 118.53, 117.13, 117.08, 66.56,
64.82, 64.40, 53.32, 52.79, 46.02 ppm; FT-IR:
1739, 1619, 1491, 1436, 1242, 1151, 1066, 1016 cm ; HRMS:
m
~ = 2924, 2850,
ꢁ1
3
+
19 3 6
calcd for [M+H] C22H F NO = 450.11590, found: 450.11569.
3
1
6
1
m
4.2.7. rel-(1S,3R,3aS,9bR)-Dimethyl 1-methyl-4-oxo-3-(4-(tri-
fluoromethyl)phenyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]
pyrrole-1,3a-dicarboxylate (3d)
ꢁ
1
M+H]+
M+H] C21
C
H
H
19 BrNO
79
= 460.03903, found: 460.04000; calcd for
= 462.03698, found: 462.03695.
[
[
21
6
+
81
= 0.28 (ethyl acetate/cyclohexane = 1:5); 1H NMR
f
19 BrNO
6
64% yield; R
3
500 MHz, CDCl ) d = 7.79 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.2 Hz,
(
4
.2.5. rel-(1S,3R,3aS,9bR)-Dimethyl 4-oxo-3-(4-(trifluoromethyl)
phenyl)-1,2,3,3a,4,9b-hexa-hydrochromeno[3,4-c]pyrrole-1,
a-dicarboxylate (3c)
6% yield; R
= 0.19 (ethyl acetate/cyclohexane = 1:5); 1H NMR
400 MHz, CDCl ) d = 7.61 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.3 Hz,
H), 7.34–7.27 (m, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.01–6.94 (m,
H), 6.50 (d, J = 7.5 Hz, 1H), 5.13 (s, 1H), 4.07 (d, J = 10.8 Hz, 1H),
.83–3.78 (m, 4H), 3.66 ppm (s, 3H); 13C NMR (101 MHz, CDCl
2H), 7.37–3.28 (m, 2H), 7.15 (t, J = 7.0 Hz, 1H), 7.07 (d, J = 8.2 Hz,
1H), 5.61 (s, 1H), 4.08 (s, 1H), 3.51 (s, 3H), 3.10 (s, 3H), 1.81 ppm
1
3
3
3
(s, 3H); C NMR (126 MHz, CDCl ) d = 173.77, 167.36, 165.74,
4
f
150.87, 130.37 (q, J = 32.7 Hz), 129.63, 129.03, 128.57, 128.06,
124.92 (q, J = 3.7 Hz), 124.73, 124.24 (q, J = 272.1 Hz), 117.40,
117.17, 69.43, 66.35, 63.60, 53.18, 53.09, 52.20, 23.70 ppm; FT-
(
3
2
1
3
IR:
1064, 1016 cm
464.13155, found: 464.13170.
m
~ = 2954, 1765, 1724, 1614, 1418, 1355, 1252, 1229, 1112,
ꢁ1
+
3
)
;
HRMS: calcd for [M+H]
22 21 3 6
C H F NO =
d = 172.32, 166.77, 164.52, 150.09, 143.30, 130.75 (q, J = 32.4 Hz),
Please cite this article in press as: Potowski, M.; et al. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.02.044

6
M. Potowski et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
4
.2.8. rel-(1R,3R,3aS,9bR)-Dimethyl 1-methyl-4-oxo-3-
125.09, 118.08, 117.02, 115.31 (d, J = 21.5 Hz), 69.18, 66.99,
63.88, 53.28, 53.13, 50.97, 19.98 ppm; FT-IR:
~ = 2918, 1770,
(
4-(tri-fluoromethyl)phenyl)-1,2,3,3a,4,9b-hexahydrochromeno
m
1
ꢁ
[
3,4-c]pyrrole-1,3a-dicarboxylate (4d)
1728, 1503, 1458, 1246, 1142, 1115, 1003 cm ; HRMS: calcd for
= 0.36 (ethyl acetate/cyclohexane = 1:5); 1H NMR
+
2
1% yield; R
400 MHz, CDCl
t, J = 7.5 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 5.63 (s, 1H), 4.55 (s,
f
[M+H] C22H21FNO = 414.13474, found: 414.13490.
6
(
(
3
) d = 7.67–7.58 (m, 4H), 7.36–7.29 (m, 2H), 7.16
4.2.13. rel-(1S,3R,3aS,9bR)-Dimethyl 3-(3-fluorophenyl)-1-
methyl-4-oxo-1,2,3,3a,4,9b-hexa-hydrochromeno[3,4-c]
pyrrole-1,3a-dicarboxylate (3g)
13
1
H), 3.91 (s, 3H), 3.18 (s, 3H), 1.14 ppm (s, 3H);
) d = 174.16, 166.33, 166.30, 150.85, 143.27,
30.50 (q, J = 32.3 Hz), 130.16, 129.76, 128.04, 125.31 (q,
C NMR
(
101 MHz, CDCl
3
57% yield; R = 0.30 (ethyl acetate/cyclohexane = 1:5); 1H NMR
1
f
J = 3.7 Hz), 125.20, 117.88, 117.07, 69.18, 66.74, 63.94, 53.33,
(500 MHz, CDCl ) d = 7.40 (t, J = 9.8 Hz, 2H), 7.35–7.27 (m, 3H),
3
5
1
3.17, 50.76, 20.15 ppm; FT-IR:
m
~ = 2957, 1738, 1618, 1493, 1434,
323, 1251, 1155, 1106, 1063, 1016 cm ; HRMS: calcd for
7.14 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 7.00–6.92 (m, 1H),
ꢁ1
5.55 (s, 1H), 4.06 (s, 1H), 3.50 (s, 3H), 3.15 (s, 3H), 1.79 ppm (s,
+
13
[
M+H] C22
H
21
F
3
NO
6
= 464.13155, found: 464.13139.
3
3H); C NMR (126 MHz, CDCl ) d = 173.90, 167.37, 165.78, 162.77
(
d, J = 245.7 Hz), 150.89, 142.36 (d, J = 7.0 Hz), 129.54, 129.47 (d,
4
1
.2.9. rel-(1S,3R,3aS,9bR)-Dimethyl 1-methyl-4-oxo-3-phenyl-
,2,3,3a,4,9b-hexahydro-chromeno[3,4-c]pyrrole-1,3a-
J = 8.0 Hz), 129.03, 124.66, 123.72 (d, J = 2.9 Hz), 117.58, 117.11,
115.08 (d, J = 4.0 Hz), 114.90 (d, J = 2.8 Hz), 69.32, 66.29 (d,
dicarboxy-late (3e)
2% yield; R
= 0.28 (ethyl acetate/cyclohexane = 1:5); 1H NMR
400 MHz, CDCl ) d = 7.62 (d, J = 7.4 Hz, 2H), 7.37–7.30 (m, 3H),
.30–7.24 (m, 2H), 7.14 (t, J = 7.4 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H),
.56 (s, 1H), 4.10 (s, 1H), 3.51 (s, 3H), 3.08 (s, 3H), 1.81 ppm (s,
J = 1.9 Hz), 63.62, 53.17, 53.05, 52.12, 23.79 ppm; FT-IR:
m
~ = 2918,
ꢁ1
7
f
1763, 1722, 1487, 1453, 1355, 1231, 1113, 1021 cm ; HRMS: calcd
+
(
3
for [M+H] C22H21FNO = 414.13474, found: 414.134973.
6
7
5
3
1
1
4.2.14. rel-(1S,3S,3aS,9bR)-Dimethyl 3-(2-fluorophenyl)-1-
methyl-4-oxo-1,2,3,3a,4,9b-hexa-hydrochromeno[3,4-
c]pyrrole-1,3a-dicarboxylate (3h)
1
3
H);
3
C NMR (101 MHz, CDCl ) d = 173.80, 167.49, 165.87,
50.88, 139.22, 129.44, 129.01, 128.20, 128.07, 124.58, 117.72,
50% yield; R = 0.22 (ethyl acetate/cyclohexane = 1:5); 1H NMR
17.07, 69.48, 67.27, 63.77, 53.12, 53.08, 52.10, 23.72 ppm; FT-IR:
f
ꢁ
1
m
~ = 2949, 1770, 1722, 1490, 1452, 1238, 1149, 1079, 1029 cm
;
(500 MHz, CDCl
7.32–7.26 (m, 2H), 7.15 (t, J = 7.6 Hz, 2H), 7.07–6.99 (m, 2H), 5.91
s, 1H), 4.13 (s, 1H), 3.48 (s, 3H), 3.16 (s, 3H), 1.79 ppm (s, 3H);
3
) d 7.67 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H),
+
6
HRMS: calcd for [M+H] C22H22NO = 396.14416, found: 396.14317.
(
1
3
4
1
.2.10. rel-(1R,3R,3aS,9bR)-Dimethyl 1-methyl-4-oxo-3-phenyl-
,2,3,3a,4,9b-hexahydro-chromeno[3,4-c]pyrrole-1,3a-
3
C NMR (126 MHz, CDCl ) d = 173.79, 167.09, 164.73, 160.96 (d,
J = 249.0 Hz), 150.84, 130.86 (d, J = 3.7 Hz), 129.99 (d, J = 8.5 Hz),
129.51, 129.11, 126.79 (d, J = 11.4 Hz), 124.70, 124.08 (d,
J = 3.4 Hz), 117.89, 116.99, 115.58 (d, J = 22.2 Hz), 69.98, 64.23,
62.66 (d, J = 2.0 Hz), 53.45, 53.23, 52.14, 24.14 ppm; FT-IR:
dicarboxy-late (4e)
% yield; R
= 0.31 (ethyl acetate/cyclohexane = 1:5); 1H NMR
400 MHz, CDCl ) d = 7.47 (d, J = 7.3 Hz, 2H), 7.38–7.32 (m, 3H),
.32–7.28 (m, 3H), 7.18–7.12 (m, 1H), 7.08 (d, J = 8.3 Hz, 1H),
.56 (s, 1H), 4.51 (s, 1H), 3.91 (s, 3H), 3.15 (s, 3H), 1.12 ppm (s,
9
f
(
3
ꢁ1
7
5
3
1
6
m ;
~ = 2953, 1774, 1739, 1488, 1454, 1241, 1177, 1115, 1001 cm
+
HRMS: calcd for [M+H]
6
C22H21FNO = 414.13474, found:
1
3
H);
3
C NMR (101 MHz, CDCl ) d = 174.43, 166.48, 138.85,
414.13457.
30.13, 129.57, 128.45, 128.42, 127.56, 125.02, 118.27, 116.99,
9.30, 67.89, 64.13, 53.18, 53.11, 51.20, 20.08 ppm; FT-IR:
4.2.15. rel-(1R,3S,3aS,9bR)-Dimethyl 3-(2-fluorophenyl)-1-
methyl-4-oxo-1,2,3,3a,4,9b-hexa-hydrochromeno[3,4-c]
pyrrole-1,3a-dicarboxylate (4h)
ꢁ
1
m
~ = 2951, 1722, 1488, 1454, 1242, 1149, 1081, 1017 cm ; HRMS:
+
calcd for [M+H] C22
6
H22NO = 396.14416, found: 396.14284.
3
4% yield; R
= 0.28 (ethyl acetate/cyclohexane = 1:5); 1H NMR
f
4
.2.11. rel-(1S,3R,3aS,9bR)-Dimethyl 3-(4-fluorophenyl)-1-
(500 MHz, CDCl ) d = 7.57–7.51 (m, 1H), 7.35 (d, J = 7.7 Hz, 1H),
3
methyl-4-oxo-1,2,3,3a,4,9b-hexa-hydrochromeno[3,4-
7.33–7.28 (m, 2H), 7.19–713 (m, 2H), 7.08 (d, J = 7.7 Hz, 1H), 7.06–
c]pyrrole-1,3a-dicarboxylate (3f)
6.99 (m, 1H), 5.90 (s, 1H), 4.59 (s, 1H), 3.96 (s, 1H), 3.89 (s, 3H),
= 0.30 (ethyl acetate/cyclohexane = 1:5); 1H NMR
3.27 (s, 3H), 1.12 ppm (s, 3H);
13
C NMR (126 MHz, CDCl
3
6
7% yield; R
400 MHz, CDCl
H), 7.14 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 7.02 (t,
J = 8.7 Hz, 2H), 5.52 (s, 1H), 4.08 (s, 1H), 3.50 (s, 3H), 3.13 (s, 3H),
f
(
3
) d = 7.62 (dd, J = 8.4, 5.5 Hz, 2H), 7.35–7.27 (m,
d = 174.72, 166.27, 165.90, 160.62 (d, J = 248.1 Hz), 151.09, 149.27,
134.61, 130.29, 130.06 (d, J = 8.5 Hz), 129.94 (d, J = 3.6 Hz), 129.60,
126.61 (d, J = 11.8 Hz), 125.05, 124.42 (d, J = 3.4 Hz), 118.50,
116.94, 115.54 (d, J = 22.2 Hz), 69.02, 63.89, 61.77 (d, J = 3.7 Hz),
2
1
1
1
1
2
1
C
.79 ppm (s, 3H); 1 C NMR (101 MHz, CDCl
3
3
) d = 173.82, 167.50,
65.91, 162.61 (d, J = 246.4 Hz), 150.86, 135.00 (d, J = 3.0 Hz),
29.83 (d, J = 8.1 Hz), 129.49, 129.00, 124.62, 117.59, 117.10,
14.87 (d, J = 21.3 Hz), 69.27, 66.38, 63.44, 53.19, 52.93, 52.13,
53.30, 53.04, 50.44, 21.23 ppm; FT-IR: m
~ = 2918, 1768, 1723, 1486,
1457, 1245, 1114, 1095, 1009 cm ; HRMS: calcd for [M+H]
ꢁ1
+
C22H21FNO = 414.13474, found: 414.13465.
6
3.69 ppm; FT-IR:
140, 1113, 1095, 1015 cm
21FNO = 414.13474, found: 414.13488.
m
~ = 2952, 2849, 1768, 1728, 1507, 1454, 1214,
ꢁ1
+
;
HRMS: calcd for [M+H]
4.2.16. rel-(1S,3R,3aS,9bR)-Dimethyl 3-(4-methoxyphenyl)-1-
methyl-4-oxo-1,2,3,3a,4,9b-hexa-hydrochromeno[3,4-c]
pyrrole-1,3a-dicarboxylate (3i)
22
H
6
4
.2.12. rel-(1R,3R,3aS,9bR)-Dimethyl 3-(4-fluorophenyl)-1-
69% yield; R
3
(400 MHz, CDCl ) d = 7.53 (d, J = 8.7 Hz, 2H), 7.38–7.27 (m, 2H),
= 0.19 (ethyl acetate/cyclohexane = 1:5); 1H NMR
f
methyl-4-oxo-1,2,3,3a,4,9b-hexa-hydrochromeno[3,4-c]
pyrrole-1,3a-dicarboxylate (4f)
7.13 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 8.7 Hz,
1
6% yield; R
400 MHz, CDCl
H), 7.15 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 7.04 (t,
J = 8.5 Hz, 2H), 5.55 (s, 1H), 4.52 (s, 1H), 3.90 (s, 3H), 3.20 (s, 3H),
f
= 0.33 (ethyl acetate/cyclohexane = 1:5); 1H NMR
2H), 5.50 (s, 1H), 4.09 (s, 1H), 3.79 (s, 3H), 3.50 (s, 3H), 3.13 (s,
1
3
(
3
) d = 7.48 (dd, J = 8.5, 5.4 Hz, 2H), 7.35–7.28 (m,
3
3H), 1.80 ppm (s, 3H); C NMR (101 MHz, CDCl ) d = 173.77,
2
167.60, 165.95, 159.47, 150.89, 131.11, 129.39, 129.27, 129.00,
124.54, 117.80, 117.06, 113.37, 69.39, 67.00, 63.61, 55.38, 53.17,
13
1
.59 (s, 1H), 1.12 ppm (s, 3H);
d = 174.30, 166.46, 166.45, 162.67 (d, J = 247.2 Hz), 150.88,
34.74 (d, J = 3.2 Hz), 130.13, 129.65, 129.38 (d, J = 8.1 Hz),
C NMR (101 MHz, CDCl
3
)
53.07, 52.06, 23.71 ppm; FT-IR: m
~ = 2927, 1766, 1730, 1610, 1587,
1454, 1239, 1163, 1113, 1030 cm ; HRMS: calcd for [M+H]+
ꢁ1
1
C23H24NO = 426.15473, found: 426.15489.
7
Please cite this article in press as: Potowski, M.; et al. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.02.044

M. Potowski et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
7
4
.2.17. rel-(1S,3R,3aS,9bR)-Dimethyl 1-methyl-4-oxo-3-(p-
(s, 1H), 4.62 (s, 1H), 3.94 (s, 3H), 3.29 (s, 3H), 1.16 ppm (s, 3H);
C NMR (101 MHz, CDCl ) d = 174.15, 166.02, 165.82, 150.88,
3
1
3
tolyl)-1,2,3,3a,4,9b-hexahydro-chromeno[3,4-c]pyrrole-1,3a-di-
carboxylate (3j)
142.89, 131.64 (q, J = 33.3 Hz), 130.28, 129.90, 127.84 (q,
J = 3.4 Hz), 126.69 (d, J = 272.1 Hz), 125.41, 124.73, 122.05 (q,
J = 4.9 Hz), 117.74, 117.09, 68.82, 65.33, 63.87, 53.48, 53.19,
7
1% yield; R
500 MHz, CDCl
H), 7.31–7.26 (m, 1H), 7.16–7.11 (m, 3H), 7.05 (d, J = 8.2 Hz,
H), 5.52 (s, 1H), 4.08 (s, 1H), 3.50 (s, 3H), 3.10 (s, 3H), 2.32 (s,
H), 1.80 ppm (s, 3H); 13C NMR (126 MHz, CDCl
) d = 173.82,
f
= 0.31 (ethyl acetate/cyclohexane = 1:5); 1H NMR
3
) d = 7.49 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.5 Hz,
(
1
1
3
1
1
5
1
C
49.29, 21.20 ppm; FT-IR:
1226, 1166, 1109, 1013 cm
C24H20F NO = 532.11893, found: 532.11934.
m
~ = 2959, 1734, 1622, 1456, 1360, 1255,
ꢁ1
HRMS: calcd for [M+H]+
;
3
6
6
67.58, 165.88, 150.93, 137.83, 136.23, 129.38, 129.02, 128.75,
27.93, 124.53, 117.88, 117.05, 69.52, 67.27, 63.82, 53.27, 53.05,
4.2.22. rel-(1S,3R,3aS,9bR)-Dimethyl 1-methyl-3-(naphthalen-2-
yl)-4-oxo-1,2,3,3a,4,9b-hexa-hydrochromeno[3,4-c]pyrrole-
1,3a-dicarboxylate (3n)
2.02, 23.79, 21.28 ppm; FT-IR:
350, 1234, 1165, 1115, 1021 cm ; HRMS: calcd for [M+H]
= 410.15981, found: 410.15974.
m
~ = 2925, 1766, 1735, 1492, 1454,
ꢁ
1
+
H24NO
6
68% yield; R
3
400 MHz, CDCl ) d = 8.10 (s, 1H), 7.91–7.84 (m, 1H), 7.84–7.78
= 0.27 (ethyl acetate/cyclohexane = 1:5); 1H NMR
f
23
(
4
.2.18. rel-(1S,3R,3aS,9bR)-Dimethyl 1-methyl-4-oxo-3-(m-
(m, 2H), 7.78–7.73 (m, 1H), 7.51–7.43 (m, 2H), 7.36 (d, J = 7.6 Hz,
1H), 7.33–7.27 (m, 1H), 7.20–7.11 (m, 1H), 7.08 (d, J = 8.2 Hz,
tolyl)-1,2,3,3a,4,9b-hexahydro-chromeno[3,4-c]pyrrole-1,3a-di-
carboxylate (3k)
1H), 5.73 (s, 1H), 4.17 (s, 1H), 3.53 (s, 3H), 2.95 (s, 3H), 1.86 ppm
(s, 3H); C NMR (101 MHz, CDCl ) d = 173.90, 167.50, 166.01,
3
150.89, 136.80, 133.25, 133.08, 129.46, 129.03, 128.30, 127.71,
127.57, 126.99, 126.14, 125.98, 124.60, 117.71, 117.09, 69.47,
= 0.30 (ethyl acetate/cyclohexane = 1:5); 1H NMR
) d = 7.41 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 7.6 Hz,
H), 7.32–7.26 (m, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.16–7.11 (m, 1H),
.10–7.03 (m, 2H), 5.53 (s, 1H), 4.09 (s, 1H), 3.50 (s, 3H), 3.10 (s,
H), 2.36 (s, 3H), 1.81 ppm (s, 3H); 13C NMR (126 MHz, CDCl
13
6
8% yield; R
f
(
500 MHz, CDCl
3
1
7
3
67.24, 63.74, 53.23, 53.10, 52.13, 23.77 ppm; FT-IR: m
~ = 2922,
ꢁ1
3
)
1770, 1723, 1588, 1490, 1454, 1251, 1184, 1117, 1003 cm
HRMS: calcd for [M+H]
446.15994.
;
+
d = 173.78, 167.46, 165.83, 150.93, 139.19, 137.67, 129.42,
6
C26H24NO = 446.15981, found:
1
6
29.02, 128.91, 128.66, 127.99, 125.09, 124.56, 117.83, 117.06,
9.55, 67.34, 63.86, 53.24, 53.02, 52.05, 23.76, 21.54 ppm; FT-IR:
m
~ = 2950, 1764, 1734, 1491, 1454, 1367, 1215, 1197, 1143, 1112,
4.2.23. rel-(1S,3R,3aS,9bR)-Dimethyl 3-(benzo[d][1,3]dioxol-5-
yl)-1-methyl-4-oxo-1,2,3,3a,4,9b-hexahydrochromeno[3,4-
c]pyrrole-1,3a-dicarboxylate (3o)
ꢁ1
+
1
070 cm
;
HRMS: calcd for [M+H]
23 6
C H24NO = 410.15981,
found: 410.15977.
6
3% yield; R
(400 MHz, CDCl
(d, J = 7.5 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 5.94 (s, 2H), 5.48 (s,
1H), 4.06 (s, 1H), 3.49 (s, 3H), 3.22 (s, 3H), 1.78 ppm (s, 3H); 13
NMR (101 MHz, CDCl d = 173.85, 167.44, 165.90, 150.87,
f
= 0.18 (ethyl acetate/cyclohexane = 1:5); 1H NMR
4
.2.19. rel-(1S,3R,3aS,9bR)-Dimethyl 1-methyl-4-oxo-3-(o-
3
) d = 7.35–7-26 (m, 2H), 7.18–7.08 (m, 3H), 7.05
tolyl)-1,2,3,3a,4,9b-hexahydro-chromeno[3,4-c]pyrrole-1,3a-di-
carboxylate (3l)
C
5
2% yield; R
f
= 0.31 (ethyl acetate/cyclohexane = 1:5); 1H NMR
) d = 7.59 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 7.6 Hz,
H), 7.32–7.27 (m, 1H), 7.23–7.18 (m, 1H), 7.18–7.10 (m, 3H),
.03 (d, J = 7.9 Hz, 1H), 5.91 (s, 1H), 4.16 (s, 1H), 3.49 (s, 3H), 3.03
3
)
(
500 MHz, CDCl
3
147.43, 147.31, 133.21, 129.45, 129.03, 124.59, 121.58, 117.70,
117.06, 108.63, 107.81, 101.14, 69.21, 66.82, 63.47, 53.26, 52.91,
1
7
52.10, 23.76 ppm; FT-IR: m
~ = 2926, 1768, 1731, 1611, 1486, 1443,
s, 3H), 2.63 (s, 3H), 1.80 ppm (s, 3H); 13C NMR (126 MHz, CDCl
)
ꢁ1
HRMS: calcd for [M+H]+
(
3
1236, 1152, 1114, 1034 cm
;
d = 174.33, 166.64, 165.13, 150.91, 138.44, 137.63, 130.33,
8
C23H22NO = 440.13399, found: 440.13399.
1
29.45, 129.17, 128.19, 127.99, 125.73, 124.67, 118.10, 116.87,
9.45, 64.43, 63.17, 52.92, 52.86, 52.09, 24.27, 20.09 ppm; FT-IR:
0
6
4.2.24. rel-(1S,3R,3aS,9bR)-Dimethyl 3-([1,1 -biphenyl]-4-yl)-1-
methyl-4-oxo-1,2,3,3a,4,9b-hexa-hydrochromeno[3,4-
c]pyrrole-1,3a-dicarboxylate (3p)
m
~ = 2928, 1764, 1731, 1489, 1452, 1375, 1247, 1213, 1146, 1118,
ꢁ
1
+
1
058 cm
;
HRMS: calcd for [M+H]
23 6
C H24NO = 410.15981,
found: 410.15986.
48% yield; R
3
400 MHz, CDCl ) d = 7.70 (d, J = 8.3 Hz, 2H), 7.65–7.54 (m, 4H),
= 0.27 (ethyl acetate/cyclohexane = 1:5); 1H NMR
f
(
4
.2.20. rel-(1S,3R,3aS,9bR)-Dimethyl 3-(3,5-bis(trifluoro-
7.48–7.41 (m, 2H), 7.36 (d, J = 7.5 Hz, 2H), 7.33–7.27 (m, 1H),
7.21–7.11 (m, 1H), 7.08 (d, J = 8.3 Hz, 1H), 5.61 (s, 1H), 4.13 (s,
methyl)phenyl)-1-methyl-4-oxo-1,2,3,3a,4,9b-
hexahydrochrom-eno[3,4-c]pyrrole-1,3a-dicarboxylate (3m)
13
1H), 3.52 (s, 3H), 3.11 (s, 3H), 1.83 ppm (s, 3H);
C NMR
1
6
5% yield; R
f
= 0.35 (ethyl acetate/cyclohexane = 1:5); H NMR
(101 MHz, CDCl ) d = 173.77, 167.53, 165.88, 150.88, 140.91,
3
(
7
1
400 MHz, CDCl
3
) d = 8.15 (s, 2H), 7.80 (s, 1H), 7.38–7.28 (m, 2H),
.21–7.13 (m, 1H), 7.08 (d, J = 7.9 Hz, 1H), 5.69 (s, 1H), 4.06 (s,
140.74, 138.25, 129.47, 129.02, 128.92, 128.54, 127.51, 127.13,
126.68, 124.61, 117.68, 117.10, 69.51, 67.05, 63.76, 53.18, 53.13,
1
3
H), 3.50 (s, 3H), 3.14 (s, 3H), 1.82 ppm (s, 3H);
C NMR
52.14, 23.71 ppm; FT-IR:
1247, 1228, 1115, 1003 cm
m
~ = 2952, 1766, 1733, 1587, 1487, 1453,
ꢁ1
HRMS: calcd for [M+H]+
(
101 MHz, CDCl
3
) d = 173.87, 167.10, 165.65, 150.75, 142.74,
;
1
1
1
31.34 (q, J = 33.2 Hz), 129.78, 129.08, 128.35 (q, J = 2.7 Hz),
24.88, 123.45 (q, J = 272.9 Hz), 121.90 (q, J = 3.9 Hz), 117.21,
17.08, 69.34, 65.45, 63.40, 53.31, 52.80, 52.34, 23.68 ppm; FT-
C28H26NO = 472.17546, found: 472.17530.
6
4.2.25. rel-(1S,3R,3aS,9bR)-Dimethyl 3-(4-(benzyloxy)-3-
methoxyphenyl)-1-methyl-4-oxo-1,2,3,3a,4,9b-
IR:
014 cm ; HRMS: calcd for [M+H]
found: 532.11851.
m
~ = 2927, 1763, 1739, 1493, 1455, 1350, 1276, 1172, 1121,
ꢁ
1
+
1
C H
24 20
F
6
NO
6
= 532.11893,
hexahydrochrom-eno[3,4-c]pyrrole-1,3a-dicarboxylate (3q)
43% yield; R
3
400 MHz, CDCl ) d = 7.41 (d, J = 7.3 Hz, 2H), 7.36–7.31 (m, 3H),
= 0.12 (ethyl acetate/cyclohexane = 1:5); 1H NMR
f
(
4
.2.21. rel-(1R,3R,3aS,9bR)-Dimethyl 3-(3,5-bis(trifluoro-
7.30–7.25 (m, 2H), 7.20 (d, J = 1.6 Hz, 1H), 7.16–7.11 (m, 1H),
7.11–7.02 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 5.45 (s, 1H), 5.16 (s,
methyl)phenyl)-1-methyl-4-oxo-1,2,3,3a,4,9b-
hexahydrochrom-eno[3,4-c]pyrrole-1,3a-dicarboxylate (4m)
2H), 4.07 (s, 1H), 3.92 (s, 3H), 3.50 (s, 3H), 3.06 (s, 3H), 1.79 ppm
(s, 3H); C NMR (101 MHz, CDCl ) d = 173.69, 167.53, 165.97,
3
150.88, 149.25, 147.67, 137.16, 129.41, 128.97, 128.61, 127.92,
127.40, 124.55, 120.09, 117.71, 117.08, 113.54, 111.85, 70.96,
1
13
2
8% yield; R
400 MHz, CDCl
.36–7.30 (m, 1H), 720–7.14 (m, 1H), 7.10 (d, J = 8.2 Hz, 1H), 5.75
f
= 0.44 (ethyl acetate/cyclohexane = 1:5); H NMR
(
3
) d = 8.01 (s, 2H), 7.81 (s, 1H), 7.41–7.37 (m, 1H),
7
Please cite this article in press as: Potowski, M.; et al. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.02.044

8
M. Potowski et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
6
9.32, 67.06, 63.51, 56.20, 53.17, 52.98, 52.09, 23.64 ppm; FT-IR:
and the European Research Council under the European Union’s
Seventh Framework Programme (FP7/2007-2013) (ERC Grant no.
268309).
m
~ = 2923, 1769, 1734, 1507, 1489, 1453, 1264, 1180, 1115,
ꢁ1
+
1
004 cm
;
HRMS: calcd for [M+H]
30 8
C H30NO = 532.19659,
found: 532.19649.
Supplementary data
4
4
3
.2.26. rel-(1S,3S,3aS,9bR)-Dimethyl 3-(furan-2-yl)-1-methyl-
-oxo-1,2,3,3a,4,9b-hexahydro-chromeno[3,4-c]pyrrole-1,
a-di-carboxylate (3r)
Supplementary data (copies of H NMR- and 13C NMR-spectra)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.bmc.2015.02.044.
1
5
3% yield; R
= 0.12 (ethyl acetate/cyclohexane = 1:5); 1H NMR
f
(
(
(
(
400 MHz, CDCl ) d = 7.42–7.36 (m, 1H), 7.36–7.30 (m, 1H), 7.28
d, J = 7.8 Hz, 1H), 7.18–7.12 (m, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.44
d, J = 3.2 Hz, 1H), 6.35 (dd, J = 3.2, 1.4 Hz, 1H), 5.65 (s, 1H), 4.15
3
References and notes
13
s, 1H), 3.41 (s, 6H), 1.82 ppm (s, 3H); C NMR (101 MHz, CDCl
3
)
1. For reviews on BIOS, see: (a) Rizzo, S.; Waldmann, H. Chem. Rev. 2014, 114, 4621;
(
5
1
b) Lachance, H.; Wetzel, S.; Kumar, K.; Waldmann, H. J. Med. Chem. 2012, 55,
989; (c) Wetzel, S.; Bon, R. S.; Kumar, K.; Waldmann, H. Angew. Chem. 2011,
23, 10990. Angew. Chem., Int. Ed. 2011, 50, 10800; (d) Bon, R. S.; Waldmann, H.
d = 173.32, 166.97, 164.74, 151.82, 150.51, 142.80, 129.55,
129.16, 124.83, 117.75, 117.07, 110.76, 108.88, 70.57, 63.48,
63.13, 54.11, 53.71, 52.18, 24.16 ppm; FT-IR:
~ = 2922, 1771,
1729, 1491, 1439, 1242, 1183, 1114, 1001 cm ; HRMS: calcd for
m
1
Acc. Chem. Res. 2010, 43, 1103; (e) Kumar, K.; Waldmann, H. Angew. Chem. 2009,
121, 3272. Angew. Chem., Int. Ed. 2009, 48, 3224; (f) Kaiser, M.; Wetzel, S.; Kumar,
K.; Waldmann, H. Cell Mol. Life Sci. 2008, 65, 1186.
ꢁ
+
[
7
M+H] C20H20NO = 386.12343, found: 386.12581.
2.
(a) Dakas, P.-Y.; Parga, J. A.; Höing, S.; Schöler, H. R.; Sterneckert, J.; Kumar, K.;
Waldmann, H. Angew. Chem. 2013, 125, 9755. Angew. Chem., Int. Ed. 2013, 52,
9
576; (b) Antonchick, A. P.; López-Tosco, S.; Parga, J.; Sievers, S.; Schürmann, M.;
4
4
3
.2.27. rel-(1R,3S,3aS,9bR)-Dimethyl 3-(furan-2-yl)-1-methyl-
-oxo-1,2,3,3a,4,9b-hexahydro-chromeno[3,4-c]pyrrole-1,
a-di-carboxylate (4r)
Preut, H.; Höing, S.; Schöler, H. R.; Sterneckert, J.; Rauh, D.; Waldmann, H. Chem.
Biol. 2013, 20, 500; (c) Voigt, T.; Gerding-Reimers, C.; Tran, T. T. N.; Bergmann, S.;
Lachance, H.; Schölermann, B.; Brockmeyer, A.; Janning, P.; Ziegler, S.;
Waldmann, H. Angew. Chem. 2013, 125, 428. Angew. Chem., Int. Ed. 2013, 52,
= 0.18 (ethyl acetate/cyclohexane = 1:5); 1H NMR
3
1% yield; R
f
4
10; (d) Zimmermann, T. J.; Roy, S.; Martinez, N. E.; Ziegler, S.; Hedberg, C.;
(
7
1
400 MHz, CDCl
3
) d = 7.56–7.47 (m, 1H), 7.37–7.28 (m, 2H), 7.22–
.15 (m, 1H), 7.07 (d, J = 8.2 Hz, 1H), 6.37–6.24 (m, 2H), 5.47 (s,
H), 4.79 (s, 1H), 3.85 (s, 3H), 3.48 (s, 3H), 3.10 (s, 1H), 1.01 ppm
Waldmann, H. ChemBioChem 2013, 14, 295; (e) Over, B.; Wetzel, S.; Grütter, C.;
Nakai, Y.; Renner, S.; Rauh, D.; Waldmann, H. Nat. Chem. 2013, 5, 21; (f)
Edwankar, C. R.; Edwankar, R. V.; Namjoshi, O. A.; Liao, X.; Cook, J. M. J. Org.
Chem. 2013, 78, 6471; (g) Dückert, H.; Pries, V.; Khedkar, V.; Menninger, S.;
Bruss, H.; Bird, A. W.; Maliga, Z.; Brockmeyer, A.; Janning, P.; Hyman, A.;
Grimme, S.; Schürmann, M.; Preut, H.; Hübel, K.; Ziegler, S.; Kumar, K.;
Waldmann, H. Nat. Chem. Biol. 2012, 8, 179; (h) Baskar, B.; Dakas, P.-Y.;
Kumar, K. Org. Lett. 1988, 2011, 13; (i) Basu, S.; Ellinger, B.; Rizzo, S.; Deraeve, C.;
Schürmann, M.; Preut, H.; Arndt, H.-D.; Waldmann, H. PNAS 2011, 108, 6805; (j)
Nören-Müller, A.; Wilk, W.; Saxena, K.; Schwalbe, H.; Kaiser, M.; Waldmann, H.
Angew. Chem. 2008, 120, 6061. Angew. Chem., Int. Ed. 2008, 47, 5973; (k) Nören-
Müller, A.; Reis-Correa, I.; Prinz, H.; Rosenbaum, C.; Saxena, K.; Schwalbe, H. J.;
Vestweber, D.; Gagna, G.; Schunk, S.; Schwarz, O.; Schiewe, H.; Waldmann, H.
Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 10606.
1
3
(
s, 3H); C NMR (101 MHz, CDCl
3
) d = 176.19, 165.73, 164.94,
52.42, 151.10, 142.79, 130.48, 129.47, 125.23, 119.35, 116.79,
10.59, 108.58, 67.92, 62.79, 61.02, 53.60, 53.08, 47.78,
1
1
2
1
C
4.58 ppm; FT-IR:
161, 1115,
m
~ = 2922, 1769, 1735, 1491, 1459, 1352, 1245,
ꢁ1
+
1012 cm
;
HRMS:
calcd
for
[M+H]
20
H20NO
7
= 386.12343, found: 386.12492.
4
.2.28. rel-(1S,3R,3aS,9bR)-Dimethyl 3-isobutyl-1-methyl-4-
oxo-1,2,3,3a,4,9b-hexahydro-chromeno[3,4-c]pyrrole-1,
a-di-carboxylate (3s)
8% yield; R
= 0.18 (ethyl acetate/cyclohexane = 1:5); 1H NMR
400 MHz, CDCl ) d = 7.31–7.23 (m, 2H), 7.15–7.08 (m, 1H), 7.05
d, J = 8.2 Hz, 1H), 4.39–4.32 (m, 1H), 3.81 (s, 1H), 3.70 (s, 3H),
3. For reviews on 1,3-dipolar cycloadditions of azomethine ylides, see: (a) Adrio, J.;
Carretero, J. C. Chem. Commun. 2014, 12434; (b) Narayan, R.; Potowski, M.; Jia,
Z.-J.; Antonchick, A. P.; Waldmann, H. Acc. Chem. Res. 2014, 47, 1296; (c) Adrio, J.;
Carretero, J. C. Chem. Commun. 2011, 6784; (d) Najera, C.; Sansano, J. M.; Yus, M.
J. Braz. Chem. Soc. 2010, 21, 377; (e) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008,
3
4
f
(
(
3
1
08, 2887; (f) Pellissier, H. Tetrahedron 2007, 63, 3235; (g) Nair, V.; Suja, T. D.
Tetrahedron 2007, 63, 12247; (h) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev.
006, 106, 4484; (i) Najera, C.; Sansano, J. M. Angew. Chem. 2005, 117, 6428.
Angew. Chem., Int. Ed. 2005, 44, 6272; (j) Coldham, I.; Hufton, R. Chem. Rev. 2005,
05, 2765.
For selected recent examples on [3+2] cycloadditions of azomethine ylides, see:
a) Pascual-Escudero, A.; González-Esguevillas, M.; Padilla, S.; Adrio, J.;
3
0
.40 (s, 3H), 1.82–1.73 (m, 1H), 1.70 (s, 3H), 1.51–1.34 (m, 2H),
2
13
.98 ppm (t, J = 6.5 Hz, 6H);
C
3
NMR (101 MHz, CDCl )
1
d = 172.81, 169.20, 166.05, 150.53, 129.33, 128.92, 124.50,
4.
1
2
1
17.85, 117.09, 71.09, 64.26, 62.48, 56.34, 53.58, 52.08, 41.75,
5.65, 24.30, 23.90, 21.64 ppm; FT-IR:
~ = 2954, 2922, 1753,
724, 1490, 1452, 1379, 1227, 1167, 1114, 1009 cm ; HRMS:
(
m
Carretero, J. C. Org. Lett. 2014, 16, 2228; (b) Liu, K.; Teng, H.-L.; Yao, L.; Tao,
H.-Y.; Wang, C.-J. Org. Lett. 2013, 15, 2250; (c) He, Z.-L.; Teng, H.-L.; Wang, C.-J.
Angew. Chem. 2013, 125, 3006. Angew. Chem., Int. Ed. 2013, 52, 2934; (d)
González-Esguevillas, M.; Adrio, J.; Carretero, J. C. Chem. Commun. 2013, 4649;
ꢁ1
+
6
calcd for [M+H] C20H26NO = 376.17546, found: 376.17647.
(
e) Trost, B. M.; Silverman, S. M. J. Am. Chem. Soc. 2012, 134, 4941; (f) Reboredo,
S.; Reyes, E.; Vicario, J. L.; Badía, D.; Carrillo, L.; De Cózar, A.; Cossío, F. P. Chem.
Eur. J. 2012, 18, 7179; (g) Jing, X.; He, C.; Dong, D. P.; Yang, L. L.; Duan, C. Y.
Angew. Chem. 2012, 124, 10274. Angew. Chem., Int. Ed. 2012, 51, 10127; (h)
Hernández-Toribio, J.; Padilla, S.; Adrio, J.; Carretero, J. C. Angew. Chem. 2012,
124, 8984. Angew. Chem., Int. Ed. 2012, 51, 8854; (i) Conde, E.; Bello, D.; de Cózar,
A.; Sánchez, M.; Vázquez, M. A.; Cossío, F. P. Chem. Sci. 2012, 3, 1486; (j)
González-Esguevillas, M.; Adrio, J.; Carretero, J. C. Chem. Commun. 2012, 2149;
4
1
.2.29. rel-(1S,3R,3aS,9bR)-Dimethyl 1-methyl-4-oxo-3-pentyl-
,2,3,3a,4,9b-hexahydro-chromeno[3,4-c]pyrrole-1,3a-
dicarboxy-late (3t)
4% yield; R
= 0.27 (ethyl acetate/cyclohexane = 1:5); 1H NMR
400 MHz, CDCl ) d = 7.29–7.23 (m, 2), 7.15–7.08 (m, 1H), 7.05 (d,
J = 8.2 Hz, 1H), 4.25 (dd, J = 9.3, 4.2 Hz, 1H), 3.81 (s, 1H), 3.70 (s,
5
f
(
3
(
k) Liu, T.-L.; He, Z.-L.; Li, Q.-H.; Tao, H.-Y.; Wang, C.-J. Adv. Synth. Catal. 2011,
3
4
H), 3.40 (s, 3H), 1.70 (s, 3H), 1.64–1.39 (m, 4H), 1.36–1.28 (m,
353, 1713; (l) Yamashita, Y.; Imaizumi, T.; Kobayashi, S. Angew. Chem. 2011, 123,
4995. Angew. Chem., Int. Ed. 2011, 50, 4893; (m) Li, Q.-H.; Tong, M.-C.; Li, J.; Tao,
H.-Y.; Wang, C.-J. Chem. Commun. 2011, 11110; (n) Liu, T.-L.; He, Z.-L.; Wang, C.-
J. Chem. Commun. 2011, 9600; (o) Teng, H.-L.; Huang, H.; Tao, H.-Y.; Wang, C.-J.
Chem. Commun. 2011, 5494; (p) Liu, T.-L.; He, Z.-L.; Tao, H.-Y.; Cai, Y.-P.; Wang,
C.-J. Chem. Commun. 2011, 2616.
For examples from our group, see: (a) Narayan, R.; Bauer, J. O.; Strohmann, C.;
Antonchick, A. P.; Waldmann, H. Angew. Chem. 2013, 125, 13120. Angew. Chem.,
Int. Ed. 2013, 52, 12892; (b) Takayama, H.; Jia, Z.-J.; Kremer, L.; Bauer, J. O.;
Strohmann, C.; Ziegler, S.; Antonchick, A. P.; Waldmann, H. Angew. Chem. 2013,
13
H), 0.89 ppm (t, J = 6.9 Hz, 3H);
3
C NMR (101 MHz, CDCl )
d = 172.83, 169.16, 166.08, 150.55, 129.33, 128.91, 124.50,
117.78, 117.08, 70.93, 66.18, 62.36, 56.20, 53.57, 52.05, 33.15,
31.98, 27.08, 24.20, 22.69, 14.17 ppm; FT-IR:
~ = 2953, 1768,
1729, 1491, 1454, 1226, 1166, 1115, 1032 cm ; HRMS: calcd for
m
1
5.
ꢁ
+
[
M+H] C21
6
H28NO = 390.19111, found: 390.19142.
1
25, 12630. Angew. Chem., Int. Ed. 2013, 52, 12404; (c) Potowski, M.; Antonchick,
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M.P. thanks the Fonds der Chemischen Industrie for
Fellowship. This work was funded by the Max-Planck-Gesellschaft
a
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Please cite this article in press as: Potowski, M.; et al. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.02.044