Multicomponent synthesis of unnatural pyrrolizidines using 1,3-dipolar cycloaddition of proline esters

Article abstract of DOI:10.1039/c3cc47184e

The synthesis of unnatural pyrrolizidines has been studied using a multicomponent-domino process involving proline or 4-hydroxyproline esters, an aldehyde and a dipolarophile. The formation of the iminium salt promotes the 1,3-dipolar cycloaddition affording highly substituted pyrrolizidines under mild conditions and high regio- and diastereoselectivities.

Full text of DOI:10.1039/c3cc47184e

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Multicomponent synthesis of unnatural pyrrolizidines using 1,3-dipolar
cycloadditions of proline esters
Juan Mancebo-Aracil, Carmen Nájera* and José M. Sansano*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
nitrostyrene. Unexpectedly, the decarboxylation occurred at room
temperature affording mixtures of pyrrolizidines 1 in good
chemical yields (78ꢀ90%).12 More recently, it has been described
that the same proline underwent a domino iminium salt formation
45 with β,γꢀunsaturated αꢀketo esters followed by decarboxylation
and cycloaddition with the named keto ester at 80 ºC in DMSO as
solvent.13
In this work we describe the multicomponent 1,3ꢀDC between
proline esters, aldehydes and dipolarophiles. The generation of the
50 reactive azomethine ylide will be achieved through the iminium
salt route7b and the cycloaddition will be surveyed at room
temperature in the presence or in the absence of silver salts as
activating dipolarophile catalysts. The aim of this strategy is to
maintain the original ester functional group of the proline in order
55 to obtain modified pyrrolizidines with diverse functionalization at
the 7a carbon atom of the named fused heterocycle. In this way the
access to unnatural alkaloids with unknown biological properties
would be ensured.14
The synthesis of pyrrolizidines 3 was initially tested at room
60 temperature employing a multicomponent process following the
previous methodology developed by our group.15 On it, proline
methyl ester hydrochloride was allowed to react with
cinnamaldehyde and methyl acrylate using triethylamine (1 equiv).
Despite toluene16 afforded a slower reaction (5 h) with methyl
65 acrylate (96% crude yield of pure 3a), it was selected as solvent
because a higher diastereoselection (99:1) was obtained in this
example (Scheme 2, Table 1). Two different processes run in THF
(1 h) and DCM (1 h) afforded lower diastereoselectivity of
compound 3a (88:12, and 85:15, respectively). Different
70 dipolarophiles such as allyl methacrylate, N-methylmaleimide
(NMM), dimethyl fumarate, βꢀnitrostyrene, and 1,2ꢀ
The synthesis of unnatural pyrrolizidines has been studied
using a multicomponent-domino process involving proline or
4-hydroxyproline esters an aldehyde and a dipolarophile. The
formation of the iminium salt promotes the 1,3-dipolar
10 cycloaddition affording highly substituted pyrrolizidines under
mild conditions and high regio and diastereoselectivities.
Pyrrolizidine alkaloids are a group of naturally occurring alkaloids1
produced by plants as defense mechanism against insect
herbivores. The evolution of pyrrolizidine alkaloid biosynthesis
15 highly conserves the first steps of the pathway whilst the
diversification of secondary derived pyrrolizidine alkaloids
occurs.2 This process ensures the appearance of new families of
pyrrolizidines along time. Many of them are potent hepatotoxic,
mutagenic and tumorigenic agents although some families of
20 pyrrolizidines posses interesting therapeutic and medicinal
applications. The synthesis of these natural frameworks has been
achieved, for example, employing different strategies such as chain
elongation of proline derivatives, followed by cyclization,3
transanular iodoamination,4 using lactams,5 from other natural
25 products,6 etc. However, the most important and straightforward
route is to employ a 1,3ꢀdipolar cycloaddition (1,3ꢀDC)7,8 using
mainly nitrones9 or azomethine ylides.10,11 The characteristic regioꢀ
and diastereoselective control of these cycloadditions contributes
to the enhancement of the importance of this strategy for this
30 purpose. In particular, proline has been used as starting material for
the in situ generation of an azomethyne ylide ready to react with an
electrophilic alkene.
bis(phenylsulfonyl)ethylene
afforded
the
corresponding
pyrrolizidines 3b-3f in good yields and high dr (Table 1, entries 2ꢀ
6). When the 1,3ꢀDC was carried out in the presence of AgOAc (5
75 mol%) compound 3a was obtained after 10 h (Table 1, entry 1).
Under identical reaction conditions AgTFA, AgOTf and Ag2CO3
afforded similar results for compound 3d. For these reasons the
same reactions described above were also performed at rt in the
presence of AgOAc (Table 1, entries 2ꢀ6).
Scheme 1
35
In these examples the generation of the reactive dipole proceeds
80
The reaction in the absence of silver salts is faster than the
analogous silverꢀmediated processes furnishing the same dr (up to
99:1). However, higher diastereoselections were achieved in the
presence of AgOAc when other aldehydes such as crotonaldehyde,
benzaldehyde, isovaleraldehyde and ethyl glyoxylate were used as
after decarboxylation of the proline, which reduces the
funtionalization of the resulting pyrrolizidine. The intermediate
dipole, generated from 2,3ꢀbutanedione or ethyl pyruvate and
40 proline or (2S,4R)ꢀ4ꢀhydroxyproline, has been trapped using βꢀ
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DOI: 10.1039/C3CC47184E
iminium salt precursors (Table 1, entries 7ꢀ10). Moreover, the last
two reactions did not proceed in the absence of silver acetate.
Scheme 2
5
All diastereoisomers were separated by column chromatography
and the relative configuration of these new compounds was
established according to the Xꢀray diffraction analysis of
molecules 3a17 and additional nOe experiments performed for
other compounds.
10 Due to the existence of multiple hydroxy groups as substituents
in natural pyrrolizidine alkaloids we surveyed the effect of a
stereogenic centre at the 4 position of the heterocycle. Thus
(2S,4R)ꢀ4ꢀhydroxyproline and its O-TBDMS protected derivative
were used as starting material in the titled 1,3ꢀDC with acrylates
15 and NMM employing cinnamaldehyde as the iminium salt
precursor (Scheme 3, and Table 2). The OꢀTBDMS protected
proline ester furnished compound 4b in lower diastereoselection
than the corresponding reaction performed with (2S,4R)ꢀ4ꢀ
hydroxyproline methyl ester yielding cycloadduct 4a (Table 2,
20 entries 1 and 2). tert-Butyl acrylate gave product 4c with higher
diastereoselection (98:2) than methyl acrylate, specially in the
presence of silver acetate (Table 2, entry 3). In the case of NMM
products 4d and 4d’ were obtained in a 4:1 diastereomeric ratio
(Table 2, entry 4). All the diastereoisomers could be separated by
25 column chromatography obtaining enantiomerically enriched
compounds 4. Pale yellow needles obtained from molecule 4a
were submitted to Xꢀray diffraction analysis and served for the
determination of it absolute configuration.18 The relative
configuration of the rest of products was assigned according to
30 positive nOe experiments.
CO2Me
toluene rt
X
Z
MeO2C
RO
NH
CHO
· HCl
Ph
Dipolarophile
HO
N
or
CO2Me
NH
Et3N or not
Ph
AgOAc (5 mol%)
toluene, rt
4
TBDMSO
R = H, TBDMS
Scheme 3
We can conclude that a very simple multicomponent 1,3ꢀDC
from proline methyl esters, aldehydes and dipolarophiles is an
35 appropriate methodology to prepare highly substituted unnatural
pyrrolizidine alkaloids. The corresponding enantiomerically pure
1Hꢀpyrrolizidinꢀ2ꢀol skeleton was prepared from natural (2S,4R)ꢀ
4ꢀhydroxyproline methyl ester. The presence of AgOAc was
crucial when aliphatic aldehydes and ethyl glyoxylate were
40 employed because the reaction failed under standard conditions.
This work has been supported by the DGES of the Spanish
Ministerio de Ciencia
e Innovación (MICINN) (Consolider
INGENIO 2010 CSD2007ꢀ00006, CTQ2007ꢀ62771/BQU,
45 CTQ2010ꢀ20387), FEDER Generalitat Valenciana (PROMETEO/
2009/039), and by the University of Alicante.
2
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Table 1. Synthesis of pyrrolizidines 3 employing Lꢀproline and aldehydes with several dipolarophiles.
Without AgOAc
With AgOAc
Entry Aldehyde
Dipolarophile
Product 3
t (h), Yield (%)a dr
t (h), Yield (%)a dr
1
Cinnamaldehyde Methyl
5,
3,
(95) 80
(93) 82
99:1
10, (94) 80 99:1
acrylate
2
Cinnamaldehyde Allyl
methacrylate
99:1
8,
(93) 81 99:1
3
Cinnamaldehyde NMM
2,
(92) 80
85:15
10, (92) 81
85:15
4
5
Cinnamaldehyde Dimethyl fumarate
2,
2,
(96) 83
(95) 79
85:15
85:15
6, (96) 83
10, (94) 78
85:15
85:15
Cinnamaldehyde
βꢀNitrostyrene
6
Cinnamaldehyde Disulfone
3,
(85) 62
62:19:19b 9, (90) 72
72:28
7
8
Crotonaldehyde
Benzaldehyde
Methyl
acrylate
1,
5,
(96) 85
(85) 65
90:10
9, (96) 85
90:10
80:20
Methyl
acrylate
37:37:26b 24, (90) 75
__
__
__
9
Isovaleraldehyde Methyl
acrylate
3,
24, (96) 80
80:20
__
10
Ethyl glyoxylate Methyl
acrylate
6,
24, (88) 59
99:1
a Isolated yields of the mixture of diastereoisomers (in brackets crude pure yield). b The third isomer was not characterized.
Table 2. Synthesis of pyrrolizidines 4 employing (2S,4R)ꢀ4ꢀhydroxyproline and cinnamaldehyde with several dipolarophiles.
Without AgOAc
With AgOAc
Entry
1
R
H
Dipolarophile
Product 4
MeO2C
t (h), Yield (%)a dr
t (h), Yield (%)a dr
CO2Me
CO2Me
MeO2C
HO
Methyl
acrylate
4,
(93) 85
80:20 6, (92) 85
87:13
N
N
HO
4a
4a'
Ph
Ph
2
3
TBDMS
H
Methyl
Acrylate
4,
3,
(91) 80
(92) 80
78:18 6, (92) 79
80:20
tꢀButyl
Acrylate
90:10 6, (92) 82 98:2
75:25 6, (94) 81 75:25
4
H
NMM
3,
(91) 80
a Isolated yields of the mixture of diastereoisomers (in brackets crude pure yield).
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Notes and references
Departamento de Química Orgánica e Instituto de Síntesis Orgánica,
18 CCDC number of molecule 4a: 961570.
Universidad de Alicante, E-03080-Alicante. Fax: +34-965903549; Tel: +34-
965903549; E-mail: cnajera@ua.es; jmsansano@ua.es
5
† Electronic Supplementary Information (ESI) available: [CCDC: 961250 and
961270, and experimental data]. See DOI: 10.1039/b000000x/.
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14 During the submission of this work we were aware of an online ASAP
Chem. Comm. communication: DOI: 10.1039/c3cc45820b (16/SEP/13).
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16 Since the industrial point of view toluene is preferred, rather than DCM,
THF of ether.
17 CCDC number of molecule 3a: 961250.
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