First one-pot organocatalytic synthesis of α-methylene-γ- lactones

Article abstract of DOI:10.1039/c2cc38659c

All in one pot: an organocatalytic highly enantioselective synthesis of α-methylene-γ-lactones has been reported. The reaction between protected 2-hydroxymalonates and MBH carbonates is simply catalysed by chiral Lewis bases affording after acid treatment

Full text of DOI:10.1039/c2cc38659c

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First One-pot organocatalytic synthesis of α-methylene-γ-lactones
Xavier Companyóa, Andrea Mazzantib, Albert Moyanoa, Anna Janeckac, Ramon Riosad*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
All in one pot: An Organocatalytic high enantioselective
In the literature, other organometallic asymmetric procedures
for the synthesis of α-methylene lactones[6] can be found but they
synthesis of α-methylene-γ-lactones has been reported. The
reaction between protected 2-hydroxymalonates and MBH
carbonates is simply catalysed by Chiral Lewis bases
affording after acid treatment the corresponding lactones in
all rely on the use of chiral auxiliaries.
45
In the kingdom of organocatalysis, Jorgensen and coworkers
reported an elegant asymmetric approach to α-methylene-δ-
lactones and δ-lactams in 2008.[7] And only very recently, Liao
and coworkers reported the non-asymmetric synthesis of α-
10 excellent yields and enantioselectivities.
The α-Methylene-γ-lactone motif is a key structural element
found in a vast number of biologically significant natural
products, mainly of the Compositae family. The first α-
methylene-γ-lactones were isolated over 100 years ago and were
15 often used in traditional medicine for the treatment of
inflammatory diseases. In recent years these compounds have
been found to possess a broad spectrum of biological activities
ranging from antimicrobial, antifungal, phytotoxic to
methylene-γ-lactams
via
both
a
tandem
allylic
50 alkylation/amination protocol[8] and a multicomponent tandem
organocatalytic reaction[9]
Remarkably, despite the interest in the synthesis of these
compounds, a general enantioselective catalytic strategy for the
synthesis of α-exo-methylene-γ-lactones remains an unmet
cytotoxic/anti-cancer.[1] These diverse activities are associated 55 challenge in organocatalysis. Here, we report the first
20 with the presence of the highly electrophilic α-exo-methylene-γ-
lactone moiety which can react via the Michael-type addition
with nucleophilic sites on enzyme targets, resulting in the
disruption of some major processes in the cell. For example α-
enantioselective organocatalytic cascade[10] synthesis of α-
methylene-γ-lactones by means of the asymmetric allyllic
alkylation of Morita-Baylis-Hillman (MBH) carbonates with 2-
hydroxy malonate. Based on our previous research in
[11]
methylene-γ-lactones can act as inhibitors of cellular steroids, 60 organocatalysis,
we envisioned an easy protocol for their
nucleophilic addition of 1,3-dicarbonyl
25 blockers of tumour necrosis factor production, DNA polymerase
inhibitors or apoptosis inducers.[2] Due to these inhibitory
properties, α-methylene-γ-lactones have been tested as potential
drug candidates.[3] α-Methylene-γ-lactone skeleton can be found
synthesis via
a
compounds to MBH carbonates (through
a
SN2’-SN2’
mechanism) followed by an intramolecular lactonization (Scheme
1). Notably, the possible intramolecular Michael reaction
in such natural products as arglabin, parthenolide, helenalin or 65 between the hydroxyl with the conjugated double bond is
30 (+)-paeonilactone (Figure 1).[4]
disfavored (5-endo-trig) in comparison to the lactonization (5-
exo-trig).
r
A
e
M
e o
- x - r
5 t i
g
HO
∗
EtOOC
e
e
M
M
O
O
O
O
EtOOC
H
e
M
4
H
H
avoure
d
O
f
e
M
O
H
O
O
e
M
O
oc
OB
O
e
M
OH
O
O
EtOOC
COO
O
Et
OH
e
COOM
2
O
O
O
r
A
O
∗
-exo- r
t i
5
g
r
a
n
l
bi
g
ar erno
e
lid
e ena n
li
aeon ac one
P il
EtO
OE
t
A
P
th
H
l
t
r
A
e
OM
OH
ew s ase
L
i
b
3
1
70
r
e
COO
M
A
-en o- r
t i
5
d
g
∗
EtOOC
5
Figure 1: Structure of natural compounds with α-methylene-γ-
O
EtOOC
s avoure
di
f
d
-en o- r
t i
lactone skeleton.
5
d
g
Scheme 1. Proposed reaction pathway
The main difficulty in the synthesis of compounds with α-
35 methylene-γ-lactone motif is obtaining them in enantiopure form.
The first example of enantioselective synthesis of α-exo-
methylene-γ-lactones was reported recently by Krische and
coworkers based on iridium-catalyzed C-C bond-forming transfer
hydrogenation. In this work, alcohols react with acrylic ester
40 affording the final lactones in excellent yields and
enantioselectivities.[5]
In the initial experiments, we used 2-hydroxy malonate 1 as a
suitable nucleophile for the reaction. Unfortunately, only oxygen
addition was observed in all the conditions tested. For this reason,
75 we studied the use of Boc-protected hydroxyl malonate (6) in
order to avoid O alkylation and obtain the C-addition product. In
addition, Boc group could be easily “in situ” removed under
acidic conditions that also will favour the later cyclization.
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Satisfactorily, when Boc-protected 2-hydroxymalonate (6) and
when bulky substituents such as 2-Naphtyl were used the
MBH carbonate 2 reacts in the presence of DABCO (20 mol%),
the desired C-addition occurs. Moreover, the in situ deprotection
of BOC under acidic conditions renders the α-methylene-γ-
lactone 4.
55 enantiomeric excess (ee) of the reaction decreased by as much as
68% likely due a steric interaction between the MBH carbonate
and the catalyst. As stated previously, the use of (DHQD)2PHAL
gives access to the opposite enantiomers of the final products
with excellent results. Compounds 4a′, 4c′-e′ and 4g′ were
5
After optimization of the reaction conditions (see sup. Inf,) we
found that toluene is the best solvent to carry out the reaction. In
terms of catalysts the best results were obtained when β-
isocupreine was used as catalyst, rendering the final α-
60 obtained
in
good
yields
and
excellent
opposite
enantioselectivities. Again, when bulky substituents, such 2-
napthyl were used, the lactone 4f′ was obtained with only 72%
ee.
10 methylene-γ-lactone 4a in 92% yield and 91% ee. Remarkably,
when (DHQD)2PHAL was used as catalyst the reaction renders
the final product 4a in 94% yield and 91% ee in longer reaction
times enantioselectivities but with enantioselective induction
opposite to that obtained with β-isocupreine. One of the most
15 significant drawbacks in the use of cinchona-derived catalysts is
the impossibility of deriving both enantiomers of the catalyst.
However, we circumvented this drawback by using two different
catalysts that render the products in excellent yields and excellent
and opposite enantioselectivities, giving access to both the
20 enantiomers of the product through a simple choice of the
catalyst.
The synthetic applicability of this methodology was exemplified
65 by the transformation of 4a in different products. For example, 4a
reacts with cyclopentadiene, rendering the Diels Alder adduct
10a in satisfactory yields and total diastereoselectivity. Moreover,
the hydrogenation of the exo-methylene double-bond of 4a
affords product 9a in quantitative yields and a diastereopure form
70 (cis conformation determined by NMR studies) (Scheme 3).
w w
Pd/C 10
/
%
t
,
)
(
a
9
Ph
a m.
H2
A
1
OEt
,
)
(
e
o uene re ux
T l
fl
M
c
r.
t
,
,
,
g
EtOOC
EtOOC
overn
.
i
ht
EtOOC
EtOOC
O
O
EtOOC
EtOOC
O
O
a
10
O
O
e
i ld
y
91%
uan
r>
a
ve
tit ti
75
Q
r>
25 1
:
d
a
4
mo
l
%
-
:
1/ 20
ICPD
d
25 1
β
or
mo
T
20
l
DH D 2PHAL
Q
)
%
r
O
O
(
A
oc
OB
∗
o uene r. .
l
t
,
e
Et
OOC
+
t
OE
COOM
EtO
r
A
2/ TFA CH Cl
one
,
roc2e ure
d2
)
O
oc
OB
EtOOC
O
a
-
2
g
Scheme 3. Derivatization of 4a
o
t
p
6
p
25
30
35
40
(
a-
4
g
r
e
B
F
M
O
The absolute configuration for α-methylene-γ-lactones was
assigned by means of TD-DFT calculations of the electronic
EtOOC
EtOOC
EtOOC
EtOOC
EtOOC
EtOOC
EtOOC
EtOOC
O
O
O
O
O
80 circular dichroism (ECD) spectra.[13] Four different methods
(functionals) and two different basis sets were used to ascertain if
different theoretical levels provided consistent shapes of the
simulated spectra. Simulations were performed using
BH&HLYP, M06-2X, LC-ωB97XD and CAM-B3LYP, together
85 with the 6-311++G(2d,p) or the def2-TZVP basis sets. The
spectra calculated assuming the R configuration match very well
the experimental spectra of 4b (using β-ICPD as catalyst.) The
full conformational analysis and further details can be found in
S.I.
O
O
O
a:
4
:
4b
c:
:
e
ee
e
ee
e
ee
e
ld 93%
,
ee
4
4d
92%
i
y
ld 91%
93%
i
ld 91%
92%
i
ld 85%%
6
7
%
i
y
,
,
,
y
y
Cl
EtOOC
EtOOC
EtOOC
EtOOC
EtOOC
EtOOC
O
O
ee
O
O
O
O
e:
:
:
e
i
y
ee
e
i ld 68%
y
e
i
y
ee
4
7
%
4f
7
9%
4
g
8
ld 86%
,
80%
ld 93%
,
,
e
M
F
O
C
l
90 Due to anticipated anti-cancer activity, lactones 4a-g was tested
against human leukemia HL-60 cell line. Cytotoxic activity of
these compounds (IC50) was expressed as the concentration (μM)
required inhibiting tumor cell proliferation by 50% after 48 h
exposure of the cells to a tested compound. Carboplatin was used
95 as a reference compound. Obtained results are shown in Table 1.
All tested compounds exhibited a consistent cytotoxic activity
with IC50 values in the low micromolar range.
EtOOC
EtOOC
EtOOC
EtOOC
EtOOC
EtOOC
EtOOC
O
O
Et
OOC
O
O
O
O
O
O
a :
4 '
c :
:
e :
4 '
84%
e
i
ee
e
ee
e
ee
e ee
i ld 92%
4
'
4d'
7
94%
ld 91%
88%
i
y
ld 93%%
,
2%
i
y
ld 88%
,
,
,
y
y
EtOOC
EtOOC
O
O
O
EtOOC
O
EtOOC
:
:
e
ee
e
i
y
ee
4f'
7
4
g
'
81%
i
ld 2%
81%
ld 84%
,
,
y
Table 1: Biological activity
45
Scheme 2. Reaction Scope
100
Entry
Compound
Cytotoxicity IC50* (μM) HL-60
0.94 + 0.08
1.4 + 0.15
1
2
3
4
5
6
7
8
4a
With optimized conditions on hand, we proceeded to study the
scope of the reaction. The reaction rendered the α-methylene-γ-
lactones in excellent yields and in good enantioselectivities. For
example, Ph, 4-BrC6H4, 4-OMeC6H4, or 4-FC6H4 or 2-Naphtyl
50 MBH carbonates rendered the final α-methylene-γ-lactones in
excellent yields and enantioselectivities when β-ICPD was used
as catalyst (compounds 4a-d, 4g: Scheme 2). 4-ClC6H4 generates
the final lactone with slightly worse enantioselectivity. Notably,
4b
1.4 + 0.23
4c
1.5 + 0.17
4d
1.6 + 0.13
4e
2.7 + 0.31
4f
4g
1.65 + 0.21
2.9 + 0.05
Carboplatin
2
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* IC50 50% inhibitory concentration represents the mean from
dose-response curves of three independent experiments.
60 Cell viability was determined by the mitocondrial reduction assay (MTT)
as described elswhere.[13]Footnotes should appear here. These might
include comments relevant to but not central to the matter under
discussion, limited experimental and spectral data, and crystallographic
data.
Conclusions
65
In summary, we developed a new enantioselective one-pot
methodology for the synthesis of α-methylene-γ- lactones.
Starting from MBH carbonates, the reaction renders α-
methylene-γ-lactones in satisfactory yields and good
enantioselectivities when commercially available chiral Lewis
bases are used as catalysts. Moreover, we have easy access to
10 both enantiomers of α-methylene-γ-lactones via the
complimentary induction of β-ICPD and (DHQD)2PHAL,
making this methodology highly interesting for the synthesis of
these compounds. Remarkably, this is the first report of the
organocatalytic synthesis of α-exo-methylene-γ-lactones. Finally,
15 the newly synthesized lactones were evaluated for their ability to
inhibit the growth of human leukemia HL-60 cells, showing
remarkable cytotoxicity. These results allow more compounds to
be synthesized and evaluated, which could lead to the discovery
of new drugs.
1
2
A. Janecka, A. Wyrebska, K. Gach, J. Fichna, T.Janecki, Drug
Discovery Today 2012, 17, 561-572
M. I. Konaklieva, B. J. Plotkin, Mini-ReV. Med. Chem. 2005, 5,
73–95
T. Janecki, E. Blaszczyk, K. Studzian, A. Janecka, U. Krajewska,
M. Rozalski, J. Med. Chem. 2005, 48, 3516–3521
T. Naito, Y. Honda, O. Miyata, I. Ninomiya, Chem. Pharm. Bull.
1993, 41, 217.
5
70 3
4
5
75
T. P. Montgomery, A. Hassan, B. Y. Park, M. J. Krische, J. Am.
Chem. Soc. 2012, 134, 11100-11103.
6
(a) I. Chataigner, J. Lebreton, F. Zammattio, J. Villieras,
Tetrahedron Lett. 1997, 38, 3719. (b) J. W. J. Kennedy, D. G. Hall,
J. Am. Chem. Soc. 2002, 124, 898. (c) J. W. J. Kennedy, D.G. Hall,
J. Org. Chem. 2004, 69, 4412. (d) P. V. Ramachandran, D.
Pratihar, D. Biswas, A. Srivastava, M. V. R. Reddy, Org. Lett.
2004, 6, 481. (e) S. Mitra, S. R. Gurrala, R. S. Coleman, J. Org.
Chem. 2007, 72, 8724. (f) R. Csuk, C. Schroder, S. Hutter,
K.Mohr, Tetrahedron: Asymmetry 1997, 8, 1411.
80
7
85
L. Albrecht, B. Richter, H. Krawczyc, K. A. Jorgensen, J. Org.
Chem. 2008, 73, 8337–8343.
20 Acknoledgements
8
F. Pan, J.-M. Chen, T.-Y. Qin, A. X. Zhang, W.-W. Liao, Eur. J.
Org. Chem. 2012, 5324-5334.
F. Pan, J.-M. Chen, Y.-Z. Fang, S. X. Zhang, W.-W. Liao, Org.
Biomol. Chem. 2012, 10, 2214-2217.
R. Rios and A. Moyano thank the Spanish Ministry of Science
and Innovation (MICINN) for financial support (Project
AYA2009-13920-C02-02). X. Companyó is also grateful to
MICINN for his pre-doctoral fellowship. A. Mazzanti thanks the
25 University of Bologna (RFO funds 2008). R. Rios thanks the
University of Southampton for financial support. A. Janecka
thanks the grant from the Medical University of Lodz (No 503/1-
156-02/503-01) for financial support.
9
90 10
Reviews about organocascade reactions: a) A. Moyano, R. Rios,
Chem. Rev. 2011, 111, 4703-4832; b) A.-N. Alba, X. Companyo,
M. Viciano, R. Rios, Curr. Org. Chem. 2009, 13, 1432-1474; c) D.
Enders, C. Grondal, M. R. M. Huettl, Angew. Chem., Int. Ed. 2007,
46, 1570-1581
For a review about the organocatalytic methodologies of MBH
carbonates see: a) R. Rios Catal. Sci. Technol. 2012, 2, 267-278 b)
X. Companyó, G.Valero, V. Ceban, T. Calvet, M. Font-Bardia, A.
Moyano, R. Rios, Org. Biomol. Chem. 2011, 9, 7986-7899; c) B.
Wang, X. Companyo, J. Li, A. Moyano, R. Rios, Tetrahedron Lett.
2012, 53, 4124-4129; d) G. Valero, A.-N. Balaguer, A. Moyano, R.
Rios, Tetrahedron Lett. 2008, 49, 6559-6562; e) X. Companyó, A.-
N. Balaguer, F. Cárdenas, A. Moyano, R. Rios, Eur. J. Org. Chem.
2009, 3075-3080; f) X. Companyó, A. Zea, A.-N. R. Alba, A.
Mazzanti, A. Moyano, R. Rios. Chem. Commun. 2010, 46, 6953-
6955.
Diels−Alder reaction of α-methylene-γ-butyrolactone with cyclic
dienes has been investigated in connection with the synthesis of
natural products and has been reported to produce exo adducts. We
suppose that the addition of the diene took place from the face
opposite to the phenyl substituent at the β-position of the α-
methylene lactone. This is in accordance with previously Diels
Alder reaction of α-methylene lactones bearing a substituent in the
β position, see: S. Bose, M. Ghosch, S. Ghosch, J. Org. Chem.
2012, 77, 6345-6350.
For reviews see: a) G. Bringmann, T. Bruhn, K. Maksimenka, Y.
Hemberger, Eur. J. Org. Chem. 2009, 2717; b) T. D. Crawford, M.
C. Tam, M. L. Abrams, J. Chem. Phys. A 2007, 111, 12057–
12068. c) G. Pescitelli, L. Di Bari, N. Berova, Chem. Soc. Rev.
2011, 40, 4603-4625. d) A. Mazzanti, D. Casarini, WIREs Comput.
Mol. Sci. 2012, 2, 613-641.
95 11
Notes and references
a
30
35
40
X. Companyó, Prof. A. Moyano. Prof. R. Rios Organic Chemistry
University of Barcelona Marti I Franques 1-11 08028 Barcelona, Spain
Prof. Dr. A. Mazzanti Department of Industrial Chemistry “Toso
100
b
Montanari”, School of Science, University of Bologna
Viale
Risorgimento 4, 40136 Bologna (Italy)
c
Prof. A. Janecka Department of Biomolecular Chemistry Medical
University of Łódź Mazowiecka 6/8, 92-215 Łódź, Poland
d
105
Dr. Ramon Rios, Reader in Organic Chemistry,School of Chemistry,
12
University of Southampton, Southampton, SO17 1BJ, UK
E-mail: R.Rios-Torres@southampton.ac.uk
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See 110
DOI: 10.1039/b000000x/
General procedure for the synthesis of α-methylene-γ-lactones: In a
45 vial equipped with a magnetic stirring bar, the corresponding MBH
carbonate (0.2 mmol, 2 equiv.), O-Boc-hydroximalonate (0.1 mmol, 1
equiv.) and catalyst (0.02 mmol, 20 mol%) were added in 1.0 mL of
toluene (C=0.1M), and the reaction was stirred at room temperature over
a period of 1–5 days. After the consumption of the starting material
115 13
1
50 (monitored by H-NMR), the reaction crude was diluted with 1.0 mL of
CH2Cl2;, 0.1 mL of TFA was added in one portion, and the mixture was
stirred overnight. Then, 1.0 mL H2O was added to the reaction crude; the
mixture was neutralized with Na2CO3, and then extracted 3 times with
EtOAc. The combined organic layers were dried with MgSO4 , and the
55 organic solvent was eliminated at reduced pressure. The crude product
that was purified by flash column chromatography to afford the desired α-
methylene-γ-lactone.
120
14
A. Albrecht, L. Albrecht, M. Różalski, U. Krajewska, A. Janecka,
K. Studzian, T. Janecki, New J. Chem.; 2010, 34,750-76
Cytotoxicity assay:Human leucemia promyelocytic HL-60 cells were
cultured in RPMI 1640 medium according with manufacturer’s protocol.
This journal is © The Royal Society of Chemistry [year]
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