I2-Catalyzed enantioselective ring expansion of β-lactams to γ-lactams through a novel C3-C4 bond cleavage. Direct entry to protected 3,4-dihydroxypyrrolidin-2-one derivatives

Article abstract of DOI:10.1039/b715661h

Molecular iodine (10 mol%) efficiently catalyzes the ring expansion of 4-oxoazetidine-2-carbaldehydes 1 in the presence of tert-butyldimethyl cyanide to afford protected 5-cyano-3,4-dihydroxypyrrolidin-2-ones 2 with good yield and high diastereoselectivity, through a novel C3-C4 bond cleavage of the β-lactam nucleus. The Royal Society of Chemistry.

Full text of DOI:10.1039/b715661h

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I2-Catalyzed enantioselective ring expansion of b-lactams to c-lactams
through a novel C3–C4 bond cleavage. Direct entry to protected
3,4-dihydroxypyrrolidin-2-one derivatives{
Benito Alcaide,*a Pedro Almendros,b Gema Cabreroa and M. Pilar Ruiza
Received (in Cambridge, UK) 10th October 2007, Accepted 8th November 2007
First published as an Advance Article on the web 19th November 2007
DOI: 10.1039/b715661h
reactions of (R)-2,3-O-isopropylideneglyceraldehyde imines with
the appropriate substituted acetyl chloride in the presence of Et3N,
followed by sequential acidic acetonide hydrolysis, and oxidative
cleavage.14
Molecular iodine (10 mol%) efficiently catalyzes the ring
expansion of 4-oxoazetidine-2-carbaldehydes 1 in the presence
of tert-butyldimethyl cyanide to afford protected 5-cyano-3,4-
dihydroxypyrrolidin-2-ones
2 with good yield and high
The use of molecular iodine as a mild catalyst to promote
various transformations is well documented in the literature.15 In
particular, iodine has been found to catalyze efficiently the addi-
tion of trimethylsilyl cyanide (TMSCN) to ketones16 as well as the
three-component condensation of aldehydes or ketones, amines
and TMSCN for the synthesis of a-aminonitriles.17 Our interest
in the use of 4-oxoazetidine-2-carbaldehydes 1 as substrates for
addition reactions,14 prompted us to evaluate their cyanosilylation
reaction with tert-butyldimethylsilyl cyanide (TBSCN) using iodine
as the catalyst. In this context, we began this work by investigating
the reaction of cis-4-formyl-b-lactam 1a with TBSCN catalyzed by
iodine in dry acetonitrile at room temperature. To our surprise, the
reaction provided the 5-cyanopyrrolidin-2-one 2a in a good 78%
isolated yield after 1.5 h, with total diastereoselectivity (Table 1,
entry 1). The expected addition product, 3a, was not detected in
the crude reaction mixture. Optimal conditions were found when
10 mol% of iodine was used as catalyst at room temperature.{
Switching solvents (dichloromethane, THF, methanol) had no
beneficial effects. Encouraged by these results, we decided to
extend the process to a variety of 4-formyl-b-lactams 1a–i, bearing
different substitution patterns both at the lactam nitrogen and in
position C3 (Table 1). The presence of a bulkier R1 group
decreased the rate of ring expansion while resulting in a totally
diastereoselective process (Table 1, entry 2). b-Lactams bearing
aliphatic substituents at nitrogen also give in a totally chemo-
selective process the corresponding expansion products 2 with
good yields, but with decreased diastereoselectivity. To ensure the
success of the reaction, a larger excess (2.5–5 equiv.) of the reagent
was necessary in all these cases (Table 1, entries 5–7).
diastereoselectivity, through a novel C3–C4 bond cleavage of
the b-lactam nucleus.
The pyrrolidine ring is a ubiquitous structural feature of many
natural products and pharmacologically active compounds.1
Enantiopure pyrrolidines are versatile chiral building blocks for
the synthesis of more complex derivatives,1 as well as valuable
organocatalysts, chiral auxiliaries and ligands for asymmetric syn-
theses.2 In recent years, polyhydroxylated pyrrolidines, dihydroxyl-
ated pyrrolidin-2-ones and their synthetic analogues have attracted
a great deal of attention due to the range of biological activities
they exhibit,3 including action as glycosidase inhibitors,4 and anti-
HIV candidates.5 In addition, pyroglutamic acid derivatives are
structural units of widespread chemical importance.6,7 Although
many methods have been reported for the synthesis of function-
alized pyrrolidines, a great challenge is to design more direct
asymmetric methods allowing access to functionalized rings which
can provide complex compounds.8
Besides 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.9 Due
to ring strain, 2-azetidinones are susceptible to ring cleavage
reactions with a broad range of reagents with high or often
complete regio- and stereoselectivity.10 As part of a program aimed
at exploring new reactivity patterns for the b-lactam nucleus
and subsequent synthetic applications,11 we now document the
catalytic, enantioselective synthesis of protected 5-cyano-3,4-
dihydroxypyrrolidin-2-ones 2 from 4-formylazetidin-2-ones 1. In
addition to providing a new method for the stereoselective
preparation of these important compounds from readily available
starting materials, our chemistry unveils a novel iodo-catalyzed
C3–C4 bond breakage of the b-lactam skeleton.12,13
A dramatic effect on the reactivity was observed with formyl-
b-lactams having R1 groups different from alkoxy substituents at
the C3 position, such as p-methoxybenzoyloxy, 1h, and phthal-
imido, 1i. No reaction took place under the reaction conditions
used for compound 1a. However, when 5 equiv. of TBSCN in the
presence of 10 mol% of iodine were used, the corresponding
O-silylated cyanohydrins 3h and 3i were obtained in reasonable
yield as easily separable mixtures of syn–anti-diastereomers
(Table 1, entries 8 and 9). The change in reactivity for compounds
1h and 1i supports the decisive role of the alkoxy groups at C3 in
promoting the rearrangement to compounds 2.
The starting substrates, enantiopure cis-4-oxoazetidine-2-carbal-
dehydes 1a–i, were prepared from the [2 + 2]-cycloaddition
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/b715661h
Next, the response of the iodo-catalyzed ring expansion reaction
to the sterically encumbered 4-oxoazetidine-2-carbaldehydes 4a
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Chem. Commun., 2008, 615–617 | 615

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Table 1 Iodine mediated TBSCN addition to b-lactam aldehydes 1. Catalytic expansion to 5-cyanopyrrolidin-2-ones 2 vs. O-silylated
cyanohydrins 3
Entry
Aldehyde
R1
R2a
TBSCN (equiv.)
t/h
Product
syn : anti ratio
Yield (%)b
1
2
3
4
5
6
7
8
9
a
(+)-1a
(+)-1b
(+)-1c
(+)-1d
(+)-1e
(+)-1f
(+)-1g
(+)-1h
(+)-1i
MeO
BnO
MeO
MeO
MeO
MeO
BnO
PMBzO
Ft
PMP
PMP
Bn
PMB
allyl
propargyl
PMB
PMP
PMP
1.5
2
1.5
1.5
2.5
4
2.5
5
5
1.5
3
1.5
1.5
1.5
1
2.5
1.5
1
(+)-2a
(+)-2b
2c
2d
2e
2f
2g
3h
3i
100 : 0
100 : 0
90 : 10
90 : 10
86 : 14
87 : 13
88 : 12
46 : 54
75 : 25
78
54c
70
80
65
57
62
59
64
b
PMP = 4-MeOC6H4; PMB = 4-MeOC6H4CH2; PMBz = 4-MeOC6H4CO. Combined yield of pure, isolated products 2 or 3 after silica gel
c
chromatography with correct analytical and spectral data. In addition, a further 15% yield of a syn–anti mixture (73 : 27) of O-silylated
cyanohydrin 3b was obtained.
and 4b was explored.18 Gratifyingly, the reaction afforded in
reasonable yields the corresponding 3,3-disubstituted and spiranic
pyrrolidinone derivatives 5a and 5b, although with some lower
selectivity (Scheme 1). Finally, the susceptibility of the process to
the stereochemically different trans-b-lactam aldehyde (epimerized
at C3), epim-1a, was studied.19 However, no reaction was
produced under different reaction conditions, the starting aldehyde
being recovered as the main component and only traces of the
mixture of O-silylated cyanohydrins was detected. From all these
results we can conclude that a cis-alkoxy group at position C3 is a
necessary condition for the ring expansion to occur.
intermediate 6, probably as a six-membered chelate with the
alkoxy group at C3. This coordination should promote the C3–C4
bond breakage to form N-acyliminium intermediate 7 through a
process which would be favoured by both the ring strain, the
enhanced reactivity of the carbonyl carbon atom and the ability of
the nitrogen atom to stabilize the emerging positive charge at C4
(at the former b-lactam). Finally, cyanation of the N-acylpyrro-
lidinium intermediate 8, formed from cation 7 by iodo–silicon
exchange, produces compounds 2 and 5 with concomitant
liberation of the catalyst. According to the proposed reaction
course, the presence of a cis-alkoxy group attached at C3 should
facilitate the ring expansion to give 5-cyanopyrrolidin-2-one
derivatives 2 and 5.
The cyclic structures and the stereochemistry of 5-cyano-lactams
2 and 5 were established by one- and two- dimensional NMR
techniques and NOE experiments. The values for vicinal coupling
constants (see ESI for data{) show unequivocally an anti–syn
orientation for protons H3–H4/H4–H5 in compounds syn-2 and
anti–anti in compounds anti-2, in agreement with that reported in
the literature for related products.7b
Our proposed working catalytic cycle to account for the new
ring expansion is shown in Scheme 2. It involves previous activa-
tion of the carbonyl aldehyde by coordination with iodine to form
Scheme 1 Preparation of sterically hindered pyrrolidin-2-ones 5a and 5b.
Reagents and conditions: (i) TBSCN (5 equiv.), I2 (10 mol%), CH3CN,
RT, 1 h.
Scheme 2 Proposed catalytic cycle for the formation of pyrrolidin-2-one
derivatives 2 and 5 from 4-formyl-b-lactams 1.
616 | Chem. Commun., 2008, 615–617
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4 (a) G. Legler, in Iminosugars as Glycosidase Inhibitors: Nojirimycin and
Beyond, ed. A. E. Stu¨tz, Wiley-VCH, Weinheim, 1999, p. 50; (b)
N. Asano, R. J. Nash, R. J. Molyneux and G. W. J. Fleet, Tetrahedron:
Asymmetry, 2000, 11, 1645.
5 G. W. J. Fleet, A. Karpas, R. A. Dwek, L. E. Fellows, A. S. Tyms,
S. Petursson, S. K. Namgoong, N. G. Ramsden, P. W. Smith, J. C. Son,
F. X. Wilson, D. R. Witty, G. S. Jacob and T. W. Rademacher, FEBS
Lett., 1988, 237, 128.
From the stereochemical point of view two new stereogenic
centers, C4 and C5, are generated sequentially from the starting
4-formyl-b-lactam. Stereocenter C4 is formed first as a result of the
expansion process of the b-lactam nucleus involving cleavage of
the C3–C4 bond. The fact that compounds 2 and 5 have the same
anti-C3–C4 relative stereochemistry points to a concerted mechan-
ism for this process. Intermediate chelate 6 would be responsible
for the observed stereochemistry at C4. Regarding the C5
stereocenter, its generation cannot be accounted for by taking
into consideration steric effects. In agreement with previous reports
on the Lewis acid-promoted syn-addition of tin and silicon
nucleophiles to N-acyliminium ions controlled by an adjacent
OTBS group,20 the stereochemical outcome may be ruled by the
Cieplak-type stereoelectronic effect.21
6 For an excellent review on their use as building blocks for the synthesis
of biologically active compounds, see: C. Na´jera and M. Yus,
Tetrahedron: Asymmetry, 1999, 10, 2245.
7 More specifically, 5-cyano-3,4-dihydroxypyrrolidin-2-ones have been
used as advanced precursors for the synthesis of 3,4-dihydroxyglutamic
acids, a natural glutamic acid derivative isolated from the seeds of
Lepidum sativum and the leaves of Rheum rhaponticum. See, for
example: (a) M. Oba, Sh. Koguchi and K. Nishiyama, Tetrahedron,
2004, 60, 8089; (b) M. Oba, Sh. Koguchi and K. Nishiyama,
Tetrahedron, 2002, 58, 9359; (c) N. Langlois, Tetrahedron Lett., 1999,
40, 8801.
8 For recent references to the asymmetric synthesis of pyrrolidines, see, for
example: (a) J. Carreras, A. Avenoza, J. H. Busto and J. M. Peregrina,
Org. Lett., 2007, 9, 1235; (b) J. Ichikawa, G. Lapointe and Y. Iwai,
Chem. Commun., 2007, 2698; (c) G. Pandey, P. Banerjee and S. R. Gadre,
Chem. Rev., 2006, 106, 4484; (d) J.-L Vasse, A. Joosten, C. Denhez and
J. Szymoniak, Org. Lett., 2005, 7, 4887.
9 For a very recent review, see: B. Alcaide, P. Almendros and
C. Aragoncillo, Chem. Rev., 2007, 107, 4437.
10 For a review on the selective bond cleavage of the b-lactam nucleus, see:
B. Alcaide and P. Almendros, Synlett, 2002, 381.
11 See, for example: B. Alcaide, P. Almendros, G. Cabrero and M. P. Ruiz,
Chem. Commun., 2007, 4788.
12 As far as we know, the only related iodo-catalyzed rearrangement of
monocyclic b-lactams, namely the conversion of 3-(acylamino)-l,4-
diphenyl-2-azetidinones to 3-(acylamino)-l,2-diphenyl-6-imidazoles, was
reported by Bird, while the rearrangement of penicillin to penillonic acid
is known to occur in the bicyclic series. See, for instance: (a) C. W. Bird
and J. D. Twibell, J. Chem. Soc. C, 1971, 3155; (b) C. W. Bird,
Tetrahedron, 1966, 22, 2489.
13 For other acid-catalyzed C3–C4 bond cleavage of the b-lactam nucleus,
see: B. Alcaide, Y. Mart´ın-Cantalejo, J. Rodr´ıguez-Lo´pez and
M. A. Sierra, J. Org. Chem., 1993, 58, 4767.
14 B. Alcaide and P. Almendros, Chem. Soc. Rev., 2001, 30, 226.
15 See, for example: (a) J. Sun, Y. Dong, L. Cao, X. Wang, Sh. Wang and
Y. Hu, J. Org. Chem., 2004, 69, 8932; (b) P. Phukan, J. Org. Chem.,
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16 J. S. Yadav, B. V. S. Reddy, M. Sridhar Reddy and A. R. Prasad,
Tetrahedron Lett., 2002, 43, 9703.
In conclusion, a novel iodo-catalyzed C3–C4 bond breakage of
the b-lactam skeleton in 4-oxoazetidine-2-carbaldehydes 1 has
been uncovered and this relies upon appropriate substitution and
stereochemistry at C3. In addition, a new, direct method for the
diastereoselective preparation of optically pure protected 5-cyano-
3,4-dihydroxypyrrolidin-2-ones 2 and 5 is described. Studies
concerning the scope and generality of this methodology, as well
as mechanistic implications are underway in our laboratory, and
further details will be reported in due course.
Support for this work by the DGI-MEC (Project CTQ2006-
10292) and CAM-UCM (Grant GR69/06) are gratefully acknowl-
edged. G. C. thanks the MEC for a predoctoral grant.
Notes and references
{ Representative experimental procedure for the b-lactam ring expansion
reaction: Synthesis of the pyrrolidin-2-one derivative 2a. A solution of
TBSCN (271 mg, 1.92 mmol) in acetonitrile (4.3 mL) was added dropwise
to a stirred solution of the 4-oxoazetidine-2-carbaldehyde 1a (300 mg,
1.28 mmol) and molecular iodine (32 mg, 0.13 mmol) in acetonitrile
(4.3 mL) at RT and under argon. The reaction mixture was stirred until
disappearance of starting material (TLC). Then, brine was added and the
resulting mixture was extracted with DCM. The organic layer was dried
and the solvent was removed under reduced pressure. Analytically pure
adduct 2a (375 mg, 78%) was obtained after purification by flash
chromatography on silica gel using a hexanes–ethyl acetate (5 : 1) mixture.
17 L. Royer, S. K. De and R. A. Gibbs, Tetrahedron Lett., 2005, 46, 4595.
18 Enantiopure spiranic or 3-substituted 3-alkoxy-b-lactam aldehydes 4a
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Chem. Commun., 2008, 615–617 | 617