Catalytic, enantio- and diastereoselective synthesis of γ-butyrolactones incorporating quaternary stereocentres

Article abstract of DOI:10.1039/c2cc32147e

A new, highly enantio- and diastereoselective catalytic asymmetric formal cycloaddition of aryl succinic anhydrides and aldehydes which generates paraconic acid (γ-butyrolactone) derivatives is reported.

Full text of DOI:10.1039/c2cc32147e

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COMMUNICATION
Catalytic, enantio- and diastereoselective synthesis of c-butyrolactones
incorporating quaternary stereocentreswz
Francesco Manoni, Claudio Cornaggia, James Murray, Sean Tallon and Stephen J. Connon*
Received 23rd March 2012, Accepted 1st May 2012
DOI: 10.1039/c2cc32147e
A new, highly enantio- and diastereoselective catalytic asym-
metric formal cycloaddition of aryl succinic anhydrides and
aldehydes which generates paraconic acid (c-butyrolactone)
derivatives is reported.
dihydroisocoumarin core (a unit–highlighted in blue–present
in a wide range of natural products and other molecules of
medicinal/pharmaceutical interest10) with excellent yield and
enantio/diastereocontrol under convenient conditions.
While the scope of the process with respect to the aldehyde
component was quite broad, an obvious limitation in terms of
synthetic utility is the requirement for the enol-stabilising
benzo-fused anhydride, which restricts the potential scope
considerably.
It has been known for over 140 years that enolisable
anhydrides can participate in aldol-like coupling chemistry
with aldehyde electrophiles to furnish a,b-unsaturated acid
products in the presence of carboxylate bases.1 Later it was
realised that–in a related process–cyclic (e.g. succinic/glutaric)
anhydrides 1 can react with aldehydes (in the presence of
stoichiometric base/Lewis acid) to form lactone products 2
(Scheme 1A).2–5
Accordingly, we became interested in exploring the possibility
of utilising other anhydrides. As a starting point, we targeted the
use of simple succinic anhydrides, which would potentially
allow one-pot access to g-butyrolactones (a highly abundant
feature of natural product structures,11 and in particular, the
carboxylic acid group-bearing paraconic acid class of anti-
tumour, antifungal and antibiotic natural products).12,13
In preliminary experiments, we attempted the catalytic
formal cycloaddition of succinic anhydride (9) with benzalde-
hyde (7) in the presence of catalyst 10 (Scheme 2). Under
conditions previously found to be conducive to the formal
cycloaddition of 7 and homophthalic anhydride 6, succinic
anhydride proved completely unreactive. Elevation of the
reaction temperature also failed to furnish the paraconic acid
natural product (11).
These reactions generate synthetically malleable products
with (in most instances) the creation of two new stereocentres.
Current thinking regarding the mechanism involves initial
enolisation of the anhydride, followed by its addition to the
aldehyde electrophile to generate the tetrahedral intermediate 3,
which then rapidly lactonises.5 This hypothesis is supported by
(inter alia) the observation that homophthalic anhydrides of
general type 4—the enol form of which (i.e. 5) are stabilised by
conjugation with the aromatic ring—are considerably more
reactive substrates than simpler, non-benzo fused analogues
(which usually6 react at elevated temperatures in the presence
of either a stoichiometric Lewis acid4,7 or carboxylate base2a–d,8
)
It appeared likely that the failure of 9 to serve as an effective
substrate was due to ineffective catalysis of the tautomeric
equilibrium under these mild conditions, leading to impracti-
cally low concentrations of the enol 12 in solution. If this
hypothesis was correct, then the installation of an enol-
stabilising group (i.e. 13, Scheme 2) would (if appropriately
chosen) circumvent the problem. We were encouraged by an
earlier observation by Cushman et al.14 in the corresponding
uncatalysed imine-based reaction (which is not thought to
proceed via the same mechanism, but which involves a likely
and can be converted to dihydroisocoumarins under mild
conditions, often in the absence of a catalyst.5
Recently, we disclosed the first examples of an enantio-
selective variant of this process (Scheme 1B).9 The methodology
exploits the aforementioned relative acidity of homophthalic
anhydrides such as 6 in conjunction with an ad hoc-designed
bifunctional organocatalyst, which we suggested was capable
of promoting both enol formation and face-selective addition
to the aldehyde electrophile. The process generates
bicyclic lactone products such as 8 which incorporate the
School of Chemistry, Centre for Synthesis and Chemical Biology,
Trinity Biomedical Sciences Institute, University of Dublin,
Trinity College, Dublin 2, Ireland. E-mail: connons@tcd.ie;
Fax: +35316712826
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures and characterisation data. CCDC 872935. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c2cc32147e
Scheme 1 The formal cycloaddition of anhydrides and aldehydes.
c
6502 Chem. Commun., 2012, 48, 6502–6504
This journal is The Royal Society of Chemistry 2012

to the performance of 10 in this reaction is highlighted by the
clear inferiority of the unsubstituted variant 15 (entry 3). The
thiourea-based catalyst 16 proved comparable to 10 in terms
of activity and product diastereoselectivity but not enantio-
selectivity (entry 4). At reduced temperature, 10 can mediate
the formal cycloaddition with excellent diastereocontrol and
good enantio- and diastereoselectivity (favouring the trans-
diastereomer), at the expense of a synthetically useful product
yield (entries 5 and 6).
Scheme 2 Attempted one-step synthesis of paraconic acid.
It was therefore decided to attempt to further influence the
susceptibility of the keto-enol tautomeric equilibrium to
catalysis by 10 through the variation of the electronic charac-
teristics of the aromatic substituent. Replacement of a the
rate-determining distinct enolisation step5) that phenylsuccinic
anhydride reacted under milder conditions than succinic
anhydride itself.15
The idea of employing aryl succinic anhydrides was there-
fore appealing: it affords the opportunity to tune the keto-enol
equilibrium through the variation of the electronic character-
istics of the aromatic substituent, while rendering one of the
two new stereocentres formed in the C–C bond forming event
quaternary.16
phenyl unit with a 3,5-bromophenyl analogue (ꢀBr sm
=
0.37) resulted in faster, more efficient formation of 17b.
Diastereoselectivity and enantioselectivity diminished marginally
(entry 7). As expected, use of an enol-destabilising electron rich
aryl unit (ꢀOMe sp = ꢀ0.28) almost shut down the catalytic
cycle (entry 8). With the principle of electronic control over
activity established, we were cognisant of the importance of
choosing a powerful enol-stabilising unit which could serve as
a useful functional group for further product elaboration, but
which could be removed if required. We therefore evaluated the
p-nitro substituted variant 14d (ꢀNO2 sp = 0.81). Gratifyingly,
excellent product yield and diastereocontrol were now possible
with an attendant increase in product ee to 86% (entry 9).
With an optimal catalyst and substrate in hand, the sub-
strate scope with respect to the aldehyde component was
investigated (Table 2). Under identical conditions to those
outlined in Table 1 entry 9, we found that electron-neutral
(entry 1), activated (entries 2–3) and deactivated aldehydes
(entry 4) could be reacted with 14d to give the isolated trans-
butyrolactones 17d and 18–20 with product yields and levels of
enantio/diastereocontrol in line with that expected from the
results of our preliminary studies outlined in Table 1. Use of
hindered (entry 5) and p-excessive heterocyclic (entries 6–7)
aldehydes resulted in a sharp increase in enantioselectivity,
which allowed the isolation of trans-21–23 with excellent
product ee (490%) without diastereoselectivity being com-
promised. Aliphatic aldehydes are also tolerated by the catalyst.
The reaction described in Scheme 2 was now repeated at
room temperature using phenylsuccinic anhydride (14a). In our
previous study concerning homophthalic anhydrides, we found
that thiourea-based cinchona alkaloids possessed similar
activity and selectivity profiles to the marginally superior squar-
amide analogues. Therefore, in the current study, in addition to
the previous benchmark catalyst 10, we evaluated the squar-
amide variant devoid of the C–2 phenyl substituent (i.e. 15) and
the corresponding thiourea-based catalyst 16 (Table 1).
In the absence of catalyst, no reaction occurs (entry 1). In
the presence of 10 however, phenylsuccinic anhydride (14a)
underwent conversion to the corresponding phenyl paraconic
acid product 17a (which was esterified to facilitate CSP-HPLC
analysis) at ambient temperature in 44% yield with good
diastereocontrol and moderate enantioselectivity (entry 2).
The importance of the presence of a C–2 phenyl substituent
Table 1 The evaluation of arylsuccinic anhydrides
Table 2 Investigation of substrate scope (aldehyde component)
Entry Prod.
t (h) Yield (%)a drb trans:cis ee (%)c
Entry Cat. Prod. T/1C t (h) yield (%)a dra trans:cis ee (%)b
1
2
3
17d R = C6H5
18 R = 4-Cl-C6H4
19 R = 4-Br-C6H4
99
100 93
97 92
92
97 : 3
95 : 5
94 : 6
92 : 8
95 : 5
99 : 1
98 : 2
72 : 28
88 : 12
86
82
77
73
91
99
91
95
95
1
2
3
4
5
6
7
8
9
—
10
15
16
10
10
10
10
10
17a
17a
17a
17a
17a
17a
17b
17c
17d
rt
rt
rt
rt
24
24
24
24
0
—
—
68
35
34
83
83
76
n.d.
86
44
21
41
90 : 10
80 : 20
88 : 12
97 : 3
499 : 1
94 : 6
n.d.
4
20 R = 4-OMe-C6H4 164 71
21 R = 2-CH3-C6H4 161 63
22 R = 2-furanyl
23 R = 2-thiophenyl 161 90
24 R = (CH2)2-C6H5 100 98
25 R = c-C5H11
5
6d
7
98
95
ꢀ15 110 34
ꢀ30 110 17
8d
9e
ꢀ15 97
ꢀ15 93
ꢀ15 99
76
7
96
98
56
97 : 3
a
b
Isolated (trans-isomer). Determined by 1H NMR spectroscopy using
a
c
either styrene/p-iodoanisole as a standard. Trans-isomer. Determined
d
by CSP-HPLC. Diastereomers inseparable. 20 mol% catalyst.
Determined by 1H NMR spectroscopy using either styrene/p-iodoanisole
b
as an internal standard. Of the trans-isomer. Determined by CSP-HPLC.
e
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6502–6504 6503

3 For seminal work on the (mechanistically distinct) imine-based
reaction: (a) N. Castagnoli, J. Org. Chem., 1969, 34, 3187;
(b) M. Cushman, J. Gentry and F. W. Dekow, J. Org. Chem.,
1977, 42, 1111; (c) M. A. Haimova, N. M. Mollov, S. C. Ivanova,
A. I. Dimitrova and V. I. Ognyanov, Tetrahedron, 1977, 33, 331.
4 Lewis acid catalysis: (a) J. M. Lawlor and M. B. McNamee,
Tetrahedron Lett., 1983, 24, 2211; (b) N. Yu, R. Poulain,
A. Tartar and J.-C. Gesquiere, Tetrahedron, 1999, 55, 13735.
5 For a review of both the aldehyde and the imine based reactions
Scheme 3 The use of the dibromoanhydride 14b.
Either a-unbranched (entry 8) or more hindered branched-
aldehydes (entry 9) could be converted to trans-24–25 using
this protocol. Diastereocontrol is less efficient in these processes
however facial control is excellent (95% ee).
see: M. Gonzalez-Lopez and J. T. Shaw, Chem. Rev., 2009,
´ ´
109, 164.
6 An uncatalysed variant involving clean deprotonation of the
anhydride by a strong base such as Na-, K- or LiHMDS is
possible: (a) S.-I. Yoshida, T. Ogiku, H. Ohmizu and T. Iwasaki,
Tetrahedron Lett., 1995, 36, 1455; (b) S.-I. Yoshida, T. Ogiku,
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The dibromoarylsuccinic anhydride 14b is also a viable
substrate under optimised conditions: the trans-lactone 26
(which offers the practitioner the option of either dehalogena-
tion to the corresponding phenylsuccinic anhydride-derived
lactone or elaboration via Pd(0)-mediated coupling chemistry)
can be readily prepared with high enantioselectivity (Scheme 3).
In summary, it has been shown that succinic anhydride is
unreactive in the organocatalytic asymmetric formal cyclo-
addition of cyclic anhydrides and aldehydes—a reaction
which has previously only been possible using homophthalic
anhydride substrates. It was speculated that this inactivity is
related to poor enolisability in the presence of the catalyst; a
hypothesis which was supported by the finding that the more
hindered (yet presumably more enolisable) phenylsuccinic
anhydride participated in the reaction–albeit with unsatisfac-
tory yield and product ee. After modification of the a-aryl
substituent to incorporate electron withdrawing functionality,
a significant increase in reactivity was observed, which allowed
the optimisation of the protocol and the identification of the
p-nitro analogue 14d as a superior substrate which could react
with benzaldehyde to furnish the aryl paraconic acid derivative
17d in excellent yield and stereocontrol. This is the first
example of such a catalytic, asymmetric reaction using a
succinic anhydride derivative. Further investigation revealed
that while simple aromatic aldehydes behave in a similar
manner to benzaldehyde in the process; hindered, heterocyclic
and aliphatic analogues undergo reaction with excellent levels
of enantiocontrol.
9 C. Cornaggia, F. Manoni, E. Torrente, S. Tallon and S. J. Connon,
Org. Lett., 2012, 14, 1850.
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This process provides one-pot access to highly synthetically
malleable g-butyrolactone materials (which are simple
derivatives of a class of natural products of considerable
pharmacological activity) with the formation of two new
stereocentres–one of which is quaternary–under mild condi-
tions with good-excellent stereocontrol. Investigations aimed
at further broadening the scope of this promising methodo-
logy are underway.
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¨
(e) R. B. Chhor, B. Nosse, S. Sorgel, C. Bohm, M. Seitz and
¨ ¨
O. Reiser, Chem.–Eur. J., 2003, 9, 260; (f) M. T. Barros,
C. D. Maycock and M. R. Ventura, Org. Lett., 2003, 5, 4097;
We are grateful to the European Research Council and
to Trinity College Dublin for financial support and to
Dr T. McCabe for X-ray crystal diffraction analysis.
(g) S. Braukmuller and R. Bruckner, Eur. J. Org. Chem., 2006,
2110.
¨
¨
Notes and references
14 M. Cushman and E. J. Madaj, J. Org. Chem., 1987, 52, 907.
15 More recently, Shaw and Wei demonstrated that the removable
(but less tuneable) thioether moiety can be used in a similar fashion
at the a-carbon: J. Wei and J. T. Shaw, Org. Lett., 2007, 9, 4077.
16 Paraconic acid derivatives with quaternary stereocentres have
recently been evaluated as antitumour agents - one of which
possessed sub-micromolar activity against multiple cancer cell
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c
6504 Chem. Commun., 2012, 48, 6502–6504
This journal is The Royal Society of Chemistry 2012