One-pot synthesis of a natural product inspired pyrrolocoumarine compound collection by means of an intramolecular 1,3-dipolar cycloaddition as key step

Article abstract of DOI:10.1016/j.tetlet.2015.01.021

A general, sequential and efficient one-pot synthesis of natural product inspired chromeno[3,4-b]pyrrol-4(3H)-ones is described. The one-pot reaction sequence consists of N-Boc deprotection of a N-substituted Boc-glycine O-aryl ester embodying an ortho-al

Full text of DOI:10.1016/j.tetlet.2015.01.021

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
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One-pot synthesis of a natural product inspired pyrrolocoumarine
compound collection by means of an intramolecular 1,3-dipolar
cycloaddition as key step
Srinivasa Rao Vidadala a, Herbert Waldmann a,b,
⇑
a Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
b Technische Universität Dortmund, Fakultät Chemie und Chemische Biologie, Chemische Biologie, Otto-Hahn-Strasse 6, 44221 Dortmund, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A general, sequential and efficient one-pot synthesis of natural product inspired chromeno[3,4-b]pyrrol-
4(3H)-ones is described. The one-pot reaction sequence consists of N-Boc deprotection of a N-substituted
Boc-glycine O-aryl ester embodying an ortho-alkyne substituent, azomethine ylide generation with an
aldehyde, subsequent intramolecular 1,3-dipolar cycloaddition with the alkyne followed by oxidative
aromatization. This synthesis method gives efficient access to a collection of highly substituted diverse
pyrrolocoumarines.
Received 2 December 2014
Revised 17 December 2014
Accepted 2 January 2015
Available online xxxx
Keywords:
Ó 2015 Published by Elsevier Ltd.
Biology oriented synthesis
Pyrrolocoumarine
1,3-Dipolar cycloaddition
One-pot synthesis
Azomethine ylide
HO
OH
N
OSO3H
Natural products enriched in bioactivity are valuable sources
and tools for chemical biology and medicinal chemistry research.1
Molecular scaffolds derived from or inspired by natural products
can be considered as biologically prevalidated starting points for
the design and synthesis of novel bioactive compounds.2 Biological
relevance and prevalidation are key criteria for the selection of
such novel scaffolds and key to the concept of biology-oriented
synthesis (BIOS).3 The synthesis of natural product inspired com-
pound collections demands robust and efficient reaction sequences
which ideally can be carried out in one pot. Therefore, the develop-
ment of such sequential transformations is at the heart of BIOS.4
Cycloaddition reactions are among the most powerful methods
for the synthesis of complex molecular architectures. For instance,
intermolecular 1,3-dipolar cycloaddition reactions with azome-
thine ylides have been explored extensively for the construction
of various five membered heterocycles,5 and, intramolecular
versions of this reaction may yield efficient access to annulated
polycyclic ring systems.6 In the development of intramolecular
1,3-dipolar cycloaddition reaction of azomethine ylides, efforts
were mainly directed towards the generation of dipolarophiles
tethered to aldehydes.7 In contrast, dipolarophile tethering to the
amine, which will allow the use of numerous readily accessible
aldehydes has rarely been explored.6
HO
HO
OMe
OMe
HO
OH
OH
OH
OH
MeO
HO
O
O
HO
HO
O
O
N
N
H
O
O
O
O
Lamellarin D
Ningalin B
Baculiferin O
R1
R1
N
O
1. deprotection
NBoc
R2
R3
O
O
O
2. imine formation
R2-CHO
R3
1
2
3. intramolecular
[1,3] dipolar
R1
O
cycloaddition
N
O
R2
4. aromatization
R3
3
Figure 1. Structures of representative natural products incorporating the chro-
meno[3,4-b]pyrrol-4(3H)-one scaffold and strategy for the sequential one-pot
synthesis.
The chromeno[3,4-b]pyrrol-4(3H)-one scaffold defines the
structural core of various natural products endowed with diverse
bioactivities. For instance, lamellarin D, ningalin B and baculiferin
O are characteristic for three classes of marine natural products
which exhibit important bioactivities including antitumour activ-
ity, HIV-1 integrase inhibition and multidrug resistance (MDR)
reversal activity (Fig. 1).8 Despite this biological significance, only
⇑
Corresponding author. Tel.: +49 (231) 133 2400; fax: +49 (231) 133 2499.
E-mail address: herbert.waldmann@mpi-dortmund.mpg.de (H. Waldmann).
http://dx.doi.org/10.1016/j.tetlet.2015.01.021
0040-4039/Ó 2015 Published by Elsevier Ltd.
Please cite this article in press as: Vidadala, S. R.; Waldmann, H. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.01.021

2
S. R. Vidadala, H. Waldmann / Tetrahedron Letters xxx (2015) xxx–xxx
R1
NBoc
Table 1
O
Boc
Scope of the one-pot intramolecular 1,3-dipolar cycloaddition reactiona
OMOM
CHO
N
OH
R3
HO
R1
ref. 10
O
R1
NBoc
O
R3
DCC, DCM
DMAP, 12h
1. R2-CHO, xylene
TFA, reflux, 3h
O
O
O
O
N R1
R2
1
3
R3
1a
1b
1c
; R = Me, R = CO2Et, 88%
2. DDQ, rt, 2h
One-pot synthesis
R3
1
3
; R = Me, R = CO2Me, 80%
1
3
1
3
; R = Et, R = CO2Et, 81%
1d; R1= Bn, R3= CO2Et, 77%
1e; R1= Bn, R3= CO2Me, 78%
Entry
Product No.
R1
R2
R3
Yieldb (%)
1
2
3
4
5
6
7
8
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
3x
3y
Me
Bn
Me
Et
Bn
Me
Et
Bn
Me
Et
Bn
Et
1-Naphtyl
1-Naphtyl
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-FC6H4
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
72
82
80
88
74
60
76
74
65
62
53
78
85
73
78
82
75
78
74
73
59
82
58
75
86
69
56
75
61
71
72
51
48
71
78
78
55
74
70
74
56
65
63
Scheme 1. Synthesis of substrates.
CH3
NBoc
O
p-FC6H4
p-FC6H4
O
CO2Et
9
3-Furanyl
3-Furanyl
3-Furanyl
Ph
p-NO2C6H4
p-BrC6H4
p-IC6H4
m-FC6H4
2-Furanyl
Ph
1a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
1. Ph-CHO, xylene
TFA, reflux, 3h
Et
Et
Et
O
O
O
O
N
Me
Me
Bn
Bn
Bn
Bn
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
Me
Me
Me
Me
Me
Me
N CH3
CH3
+
CO2Et
CO2Et
CO2Et
CO2Et
EtO2C
4a
EtO2C
4b
o-FC6H4
p-CF3C6H4
3-Thiophenyl
1-Naphtyl
p-MeOC6H4
2-Furanyl
Ph
1-Naphtyl
p-MeOC6H4
p-NO2C6H4
p-FC6H4
p-BrC6H4
p-CF3C6H4
3-Furanyl
3-Thiophenyl
m-FC6H4
o-FC6H4
2. DDQ, rt, 2h
71%
CO2Et
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CONHMe
CO2Me
CONHMe
CO2Me
CONHMe
CONHMe
CONHMe
O
O
N
CH3
3z
EtO2C
3a
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ao
3ap
3aq
3ar
Scheme 2. Establishment of the one-pot intramolecular 1,3-dipolar cycloaddition.
few synthetic methods to access this scaffold have been reported.9
Notably, a general and efficient synthesis method for the synthesis
construction of this natural product scaffold with broad structural
diversity is lacking.
Here we report on the development of such a sequential one-pot
synthesis which involves N-Boc deprotection of a N-substituted
Boc-glycine O-aryl ester embodying an ortho-alkyne substituent,
azomethine ylide formation with an aldehyde, intramolecular
[3+2] cycloaddition and subsequent aromatization. The method
gives straightforward and efficient access to the pyrrolocoumarine
scaffold 3 with fully substituted pyrrole moiety. It was successfully
applied for the synthesis of a compound library with broad struc-
tural scope.
Ph
Ph
p-NO2C6H4
p-NO2C6H4
p-CF3C6H4
p-CF3C6H4
m-MeC6H4
o-BrC6H4
a
Reaction conditions: 1 (0.16 mmol), TFA (0.8 mmol) and aldehyde (0.32 mmol)
were used for the reaction.
b
Isolated yields after column chromatography.
We envisioned to synthesize the pyrrolocoumarine scaffold 3 by
meansof intramolecular1,3-dipolar cycloaddition reactionbetween
azomethine ylides 2, generated in situ from N-Boc-N-alkylated
glycine esters 1 and aromatic aldehydes (Fig. 1). This strategy would
enable the introduction of diverse substituents (R1, R2 and R3) on the
pyrrole moiety.
Our study commenced with the preparation of N-Boc glycinyl
propiolates 1a–1e (Scheme 1). Phenol derived propiolates were
synthesized using a procedure reported by Yamamoto et al.10 Cou-
pling of different phenol derived propiolates and N-substituted Boc
glycines gave the corresponding substrates 1a–1e in good yields
(Scheme 1).
To establish the reaction sequence, initially we attempted
in situ deprotection of Boc-protected glycine O-aryl ester 1a and
subsequent azomethine ylide formation with benzaldehyde
(Scheme 2). Gratifyingly, TFA mediated NBoc deprotection of 1a,
followed by iminium formation and subsequent intramolecular
1,3-dipolar cycloaddition in refluxing toluene gave a mixture of
dihydropyrrolocoumarines 4a and 4b. Treatment of the reaction
mixture with excess MnO2 at room temperature yielded the
desired pyrrolocoumarine 3a11 in moderate yield. To improve the
efficiency of this one-pot reaction sequence, optimization of reac-
tion conditions with respect to solvent (e.g., o-xylene, toluene,
DCE) and oxidizing agents (e.g., MnO2, DDQ, sulfur) was investi-
gated. The use of DDQ in o-xylene as solvent emerged as most
favourable and furnished the desired product in viable yields
(Scheme 2).
With optimized reaction conditions identified, the scope of the
methodology was investigated with various substitutions R1, R2
and R3 (Table 1). Initial experiments indicated that for R1 several
substituents like, Me, Et and Bn are tolerated to yield the cycload-
ducts in appreciable yields (Table 1, entries 1–11). The one-pot
intramolecular cycloaddition strategy was fairly general with
respect to substituents R2 (Table 1, entries 12–21). Irrespective of
electronic factors various aromatic and heteroaromatic aldehydes
could be successfully employed in the transformation. Thus, in
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S. R. Vidadala, H. Waldmann / Tetrahedron Letters xxx (2015) xxx–xxx
3
the presence of an unsubstituted aryl group (Table 1, entries 12
References and notes
and 18), an electron-donating (Table 1, entries 3–5) or -withdraw-
ing substituent (Table 1, entries 13–16, 19 and 20) on the aromatic
ring the reaction proceeds well to yield the desired pyrrolocouma-
rines in good yields. In addition, heteroaromatic aldehydes are well
tolerated to yield the corresponding cycloadducts in moderate to
good yields (Table 1, entries 9–11, 17 and 21). Reactions with ali-
phatic aldehydes did not proceed well to yield the corresponding
cycloadducts. Instead, hydrolysis of the phenolic ester was
observed.
Investigation of the intramolecular 1,3-dipolar cycloaddition
with variation of R3 (Table 1, entries 22–43) revealed a clear influ-
ence of electronic factors. Thus, electron withdrawing groups such
as esters and amides at this position favour the cycloaddition reac-
tion with various aromatic and heteroaromatic aldehydes to yield
the desired cycloadducts in good yields (Table 1, entries 22–36).
Introduction of a phenyl group at R3 did not yield any cycloadduct.
Instead hydrolysis of the phenolic ester was observed. Also, intro-
duction of various electron withdrawing aryl substituents such as
p-NO2C6H4, p-CO2EtC6H4, p-FC6H4 and 3,5-di-FC6H3 at this position
was not fruitful. Finally, replacement of the ester by an amide was
well tolerated to produce the corresponding pyrrolocoumarines in
appreciable yields (Table 1, entries 37, 39, 41–43).
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In conclusion, we have developed a general and efficient
one-pot method for the synthesis of a natural product-inspired
pyrrolocoumarine compound collection. The sequential one-pot
synthetic strategy includes N-Boc deprotection of a N-substituted
Boc-glycine O-aryl ester embodying an ortho-alkyne substituent,
azomethine ylide generation with an aldehyde, subsequent intra-
molecular 1,3-dipolar cycloaddition with the alkyne followed by
oxidative aromatization. The developed methodology was used
for the synthesis of a diverse compound collection based on the
pyrrolocoumarine scaffold.
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11. (a) General procedure for the synthesis of cycloadducts 3a–3ar: To a solution of
N-Boc alkinylamine (0.16 mmol) in o-xylene, aldehyde (0.32 mmol) and TFA
(0.8 mmol) were added and the resulting mixture was heated to reflux using a
Dean–Stark apparatus. After complete conversion of the substrate (monitored
by means of thin layer chromatography (TLC)) approximately in 3 h, the
reaction mixture was cooled down to rt, DDQ (0.20 mmol) was added and the
mixture was stirred for another 2 h at room temperature. The resulting crude
reaction mixture was filtered and purified by means of column
chromatography to yield the desired pyrrolocoumarines.
Acknowledgments
(b) Characterization data for 3a: Yield: 71%; 1H NMR (400 MHz, CDCl3): d = 8.81
(dd, J = 8.1, 0.8 Hz, 1H), 7.53–7.47 (m, 3H), 7.42–7.38 (m, 2H), 7.37–7.33 (m,
2H), 7.31–7.26 (m, 1H), 4.05 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 0.85 (t, J = 7.1 Hz,
3H); 13C NMR (101 MHz, CDCl3): d = 164.8, 155.3, 151.6, 147.9, 131.0, 130.0,
129.5, 128.8, 128.7, 128.5, 126.6, 124.3, 117.6, 117.2, 117.1, 110.8, 60.5, 34.5,
~
S.R.V. is grateful to the Alexander von Humboldt Foundation for
a Fellowship. The authors acknowledge the fruitful collaboration
with AstraZeneca R&D, Discovery Sciences, Chemistry Innovation
Centre, Mereside, Alderley Park, Macclesfield, Cheshire, UK.
13.5; FT-IR:
m
= 2977, 1700, 1503, 1433, 1143, 1053, 751, 698 cmÀ1; HRMS:
calcd for [M+H]+ C21H17NO4: 348.1236 found: 348.12338.
(c) Characterization data for 3s: Yield: 78%; 1H NMR (400 MHz, CDCl3): d = 8.92–
8.78 (dd, J = 8.4, 1.4 Hz, 1H), 7.52–7.39 (m, 5H), 7.34 (ddd, J = 8.4, 6.6, 2.0 Hz, 1H),
7.27–7.18 (m, 5H), 6.86 (t, J = 3.5 Hz, 1H), 6.85 (d, J = 4.5 Hz, 1H), 5.66 (s, 2H), 4.08
(q, J = 7.1 Hz, 2H), 0.86 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3): d = 164.9,
154.9, 151.7, 148.2, 137.2, 130.7, 130.2, 129.5, 129.1, 128.9, 128.6, 128.3, 127.6,
~
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data for all compounds) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2015.01.021.
126.6, 126.5, 124.4, 117.2, 117.1, 117.1, 111.6, 60.6, 49.6, 13.5; FT-IR:
m = 1702,
1502, 1454, 1436, 1276, 1248, 1141, 1108, 1053, 752, 732, 697 cmÀ1; HRMS:
calcd For [M+H]+ C27H22NO4: 424.15433 found: 424.15422.
Please cite this article in press as: Vidadala, S. R.; Waldmann, H. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.01.021