Direct organocatalytic synthesis of enantiopure succinimides from β-lactam aldehydes through ring expansion promoted by azolium salt precatalysts

Article abstract of DOI:10.1039/b711473g

A single-step catalytic ring expansion approach from 4-oxoazetidine-2- carbaldehydes to enantiopure succinimides has been achieved by the use of a base (DBU) and a thiazolium salt precatalyst. The Royal Society of Chemistry.

Full text of DOI:10.1039/b711473g

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Direct organocatalytic synthesis of enantiopure succinimides from
b-lactam aldehydes through ring expansion promoted by azolium salt
precatalysts{
Benito Alcaide,*a Pedro Almendros,*b Gema Cabreroa and M. Pilar Ruiza
Received (in Cambridge, UK) 26th July 2007, Accepted 22nd August 2007
First published as an Advance Article on the web 4th September 2007
DOI: 10.1039/b711473g
were prepared from (S)-4-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-(4-
methoxyphenyl)azetidine-2,3-dione via metal-mediated Barbier-
type carbonyl–addition reactions in aqueous media followed by
functionalization reactions, as we recently described.9 First, the
general reactivity of 4-oxoazetidine-2-carbaldehydes toward the
ring expansion reaction was tested with substrate 1a by the use of
commercially available imidazolium salt 2 as well as readily
prepared thiazolium chloride 3 (Fig. 1).10 The combination of an
amine base and azolium salts 2 or 3 should produce the necessary
nucleophilic zwitterionic catalyst in situ which promotes the
b-lactam to succinimide conversion.11 At the outset, reaction
of b-lactam aldehyde 1a was studied by using different loadings
(1–10 mol%) of both azolium precatalysts and bases (Table 1).
While Hu¨nig’s base or triethylamine afforded poor (imidazolium
chloride 2) or moderate (thiazolium chloride 3) yields of
succinimide 4a, the chemical yields were good when DBU was
used. The activity of the azolium salt precatalyst was similar in the
presence of DBU, but a superior yield (88% vs. 57%) was obtained
by the use of thiazolium chloride 3 in comparison with
imidazolium salt 2 (Table 1, entries 5 and 10). Optimization of
solvent revealed that acetonitrile was superior to chlorinated or
aromatic solvents. Optimal reactivity was obtained at 80 uC when
5 mol% of thiazolium chloride 3 and 10 mol% of DBU were
employed in boiling acetonitrile. With the best succinimide
formation conditions identified, the scope of this transformation
was examined (Table 2).{ No advantage accrues from changing
the methoxy group at C1 to a benzyloxy (Table 2, entry 1) in the
starting 4-oxoazetidine-2-carbaldehyde 1. Interestingly, nitroge-
nated substituents can be incorporated onto the b-lactam scaffold
to afford good yield of succinimide 4c (Table 2, entry 2).12 Both
placing a less electron-donating substituent in the para position of
the N-aryl ring (Table 2, entry 3) as well as the introduction of one
halogen atom at the 4-position of the aromatic ring (Table 2, entry
4) slightly decreased the efficiency of the process. b-Lactams
bearing a benzyl or an allyl substituent at nitrogen failed to give
the ring expansion; partial epimerization together with some
unreacted aldehyde was observed.
A single-step catalytic ring expansion approach from 4-oxoa-
zetidine-2-carbaldehydes to enantiopure succinimides has been
achieved by the use of a base (DBU) and a thiazolium salt
precatalyst.
Succinimides constitute an important compound class due to their
wide profile of biological activity.1 Besides, the succinimide nucleus
is a useful building block for the synthesis of natural as well as
unnatural products,2 and succinimide-based pseudopeptides have
been shown to stabilize b-turn conformations.3 On the other hand,
in addition to the key role that b-lactams have played in the fight
against pathogenic bacteria, the use of 2-azetidinones as chiral
building blocks in organic synthesis is now well established.4
Although many efforts have been made in these fields, the
preparation of the succinimide ring from the b-lactam nucleus has
remained unexplored, with the only exception being our one-flask
three-step process from b-lactam aldehydes involving imine
formation, TBACN-promoted ring expansion and selective imine
hydrolysis.5 One aspect of the above transformation is the
prerequisite of preparing the imino-b-lactam in a separate step
coupled with the necessity of a final hydrolysis step. Herein, we
present an alternative single-step approach starting directly from
4-oxoazetidine-2-carbaldehydes by the use of a thiazolium salt
precatalyst, thus further enhancing the applicability of this
unconventional transformation. The inspiration comes from our
previous report on the addition reaction of 2-(trimethylsilyl)-
thiazole to 4-oxoazetidine-2-carbaldehydes to give enantiopure
a-alkoxy-c-keto acid derivatives via a novel N1–C4 bond breakage
of the b-lactam nucleus,6 in conjunction with the fact that
thiazolium salts have been reacted with an aziridinylcarbaldehyde
to afford a b-aminoester.7
Precursors for succinimide formation, enantiopure 2-azetidi-
nones 1a–e, were prepared using standard methodology as single
cis-enantiomers from aryl imines of (R)-2,3-O-isopropylidenegly-
ceraldehyde, through Staudinger reaction with the corresponding
acetyl chloride in the presence of Et3N, followed by sequential
acidic acetonide hydrolysis and oxidative cleavage.8 Enantiopure
spiranic or 3-substituted 3-alkoxy-b-lactam aldehydes 1f and 1g
aDepartamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, Universidad
Complutense de Madrid, 28040-Madrid, Spain.
E-mail: alcaideb@quim.ucm.es; Fax: +34 91-3944103
bInstituto de Qu´ımica Orga´nica General, CSIC, Juan de la Cierva 3,
28006-Madrid, Spain. E-mail: iqoa392@iqog.csic.es;
Fax: +34 91-5644853
{ Electronic supplementary information (ESI) available: Compound
characterization data and experimental procedures for all new compounds.
See DOI: 10.1039/b711473g
Fig. 1 Structure of azolium salt precatalysts 2 and 3.
4788 | Chem. Commun., 2007, 4788–4790
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Table 1 Optimization of b-lactam ring expansion reaction
conditionsa
Precatalyst
Entry (mol%)
Yield
(%)b
Base (mol%)
Solvent T/uC t/h
c
d,e
d,f
1
2
3
4
5
6
7
8
9
10
11
12
13
a
2 (10)
2 (10)
2 (10)
2 (10)
2 (5)
2 (1)
2 (1)
3 (5)
3 (5)
3 (5)
3 (5)
3 (2)
3 (1)
(iPr)2EtN (10) CH2Cl2 40
(iPr)2EtN (10) MeCN 80
23
22
22
Et3N (10)
DBU (10)
DBU (10)
DBU (10)
DBU (5)
MeCN 80
MeCN 80
MeCN 80
MeCN 80
MeCN 80
0.75 53
0.33 57
d,g
21
d,h
18
22
21
(iPr)2EtN (10) MeCN 80
54
d,i
Et3N (10)
DBU (10)
DBU (5)
DBU (10)
DBU (10)
b
MeCN 80
MeCN 80
MeCN 80
MeCN 80
MeCN 80
Scheme 1 Preparation of conformationally constrained enantiopure
succinimides 4f and 4g and succinimide enant-4a.
0.33 88
d,j
18
0.33 67
0.33 64
addition of a zwitterionic species 6, generated in situ from the
exposure of the azolium salt 3 to DBU, to a 4-oxoazetidine-2-
carbaldehyde 1. This addition product, alkoxide 7, initiates a
1,2-hydrogen group migration and produces intermediate 8. Due
to ring strain, species 8 would suffer a N1–C4 b-lactam bond
breakage to afford the enolamide intermediate 9 and reforms the
carbonyl to species 10, which produces the succinimide compound
4 with concomitant liberation of the catalyst.
PMP = 4-MeOC6H4. Yields are for pure isolated products with
c
correct analytical and spectroscopic data. A complex mixture of
d
uncharacterized products was obtained. A mixture of compounds
1/4 was obtained as determined by 1H NMR analysis of the crude
reaction mixture before purification. In addition, some epimerization
e
of the starting aldehyde was detected. Ratio 1a : 4a = 79 : 9; 12%
f
epimerization of 1a. Ratio 1a : 4a = 79 : 14; 7% epimerization of
g
1a. Ratio 1a : 4a = 24 : 54; 22% epimerization of 1a. Ratio 1a :
h
i
4a = 36 : 35; 29% epimerization of 1a. Ratio 1a : 4a = 27 : 63; 10%
j
epimerization of 1a. Ratio 1a : 4a = 18 : 76; 6% epimerization of
1a.
In conclusion, this is the first single-step catalytic approach to
the succinimide core via the thiazolium-catalyzed ring expansion
reaction of the b-lactam nucleus. This mild protocol uses a neutral
organic molecule as the catalyst, can install polysubstitution at the
Table 2 Scope of b-lactam ring expansion reactiona
Entry Aldehyde R1
R2
t/h
Product Yield (%)a
1
2
3
4
a
(+)-1b
(+)-1c
(+)-1d
(+)-1e
BnO
Phtc
PMPb
PMP
1
(+)-4b
0.3 (+)-4c
62
87
78
76
MeO PMePd
MeO PCPe
2
2
(+)-4d
(+)-4e
Yields are for pure isolated products with correct analytical and
b
spectroscopic data. PMP = 4-MeOC6H4. Pht = phthalimidoyl.
c
d
e
PMeP = 4-MeC6H4. PCP = 4-ClC6H4.
Gratifyingly, the reaction of sterically encumbered 4-oxoazeti-
dine-2-carbaldehydes 1f and 1g afforded in reasonable yields
enantiopure tertiary and spiranic succinimide derivatives 4f and 4g
(Scheme 1).13 Next, the response of the ring expansion reaction to
the stereochemically different trans-b-lactam aldehyde epim-1a was
explored.14 Happily, the enantiopure succinimide enant-4a was
obtained in good yield (Scheme 1), matching the absolute
configuration of the succinimide product to that of the
corresponding b-lactam aldehyde. Therefore, a synthesis of both
enantiomers of succinimide derivatives could be achieved.
Our proposed working catalytic cycle to account for the new
ring expansion is shown in Scheme 2. It involves the nucleophilic
Scheme 2 Proposed reaction course for the formation of succinimides 4
from 4-oxoazetidine-2-carbaldehydes 1.
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4 For selected recent reviews, see: (a) B. Alcaide, P. Almendros and
succinimide ring, and can provide both enantiomers of the final
product. Studies concerning the scope and generality of this
methodology are underway in our laboratory, and further details
will be reported in due course.
C. Aragoncillo, Chem. Rev., 2007, DOI: 10.1021/cr0307300; (b)
A. R. A. S. Deshmukh, B. M. Bhawal, D. Krishnaswamy,
V. V. Govande, B. A. Shinkre and A. Jayanthi, Curr. Med. Chem.,
2004, 11, 1889; (c) B. Alcaide and P. Almendros, Synlett, 2002, 381; (d)
C. Palomo, J. M. Aizpurua, I. Ganboa and M. Oiarbide, Synlett, 2001,
1813.
Support for this work by the DGI-MEC (Project CTQ2006-
10292) and CAM-UCM (Grant GR69/06) is gratefully acknowl-
edged. G. C. thanks the MEC for a predoctoral grant.
5 B. Alcaide, P. Almendros, G. Cabrero and M. P. Ruiz, Org. Lett., 2005,
7, 3981.
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10 Precatalyst 3 was prepared from 4,5-dimethylthiazole and benzyl
chloride as reported in ref. 7.
11 No succinimides were produced in the absence of the catalyst or in the
presence of azolium salt or base on their own.
12 No loss of enantiomeric purity of succinimides 4 was evident by the 1H
NMR spectra in presence of a chiral shift reagent of europium(III),
except for phthalimidoyl succinimide 4c which was obtained in 50% ee.
It is well known that the structurally related thalidomide may suffer
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13 It was observed that the organocatalyzed reaction of b-lactam aldehyde
1f yielded as main product succinimide 4f, together with maleimide 5
(Scheme 1). The formation of compound 5 involves methanol
elimination under the reaction conditions to relieve the strain.
14 Optically pure trans-4-oxoazetidine-2-carbaldehyde (+)-epim-1a was
prepared as reported, see: D. R. Wagle, C. Garai, J. Chiang,
M. G. Monteleone, B. E. Kurys, T. W. Strohmeyer, V. R. Hedge,
M. S. Manhas and A. K. Bose, J. Org. Chem., 1988, 53, 4227.
Notes and references
{ Representative experimental procedure for the b-lactam ring expansion
reaction: synthesis of succinimides 4. DBU (15 mg, 0.10 mmol, 15 mL) was
added to a stirred solution of thiazolium chloride 3 (12 mg, 0.05 mmol) and
the appropriate 4-oxoazetidine-2-carbaldehyde 1 (1.0 mmol) in acetonitrile
(10 mL). The reaction mixture was heated at 80 uC until complete
disappearance (TLC) of starting material. The reaction mixture was
allowed to cool to room temperature, the solvent was removed under
reduced pressure, and analytically pure adducts 4 were obtained after
purification by flash chromatography on silica gel using hexanes–ethyl
acetate mixtures.
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4790 | Chem. Commun., 2007, 4788–4790
This journal is ß The Royal Society of Chemistry 2007