Organocatalytic ring expansion of β-lactams to γ-lactams through a novel N1-C4 bond cleavage. Direct synthesis of enantiopure succinimide derivatives

Article abstract of DOI:10.1021/ol051504a

(Chemical Equation Presented) Tetrabutylammonium cyanide (20 mol %) catalyzes ring expansion of 4-(arylimino)methylazetidin-2-ones 2 to 5-aryliminopyrrolidin-2-ones 3 through a novel N1-C4 bond cleavage of the β-lactam nucleus. New, efficient one-pot prot

Full text of DOI:10.1021/ol051504a

ORGANIC
LETTERS
2005
Vol. 7, No. 18
3981-3984
Organocatalytic Ring Expansion of
-Lactams to -Lactams through a
Novel N1 C4 Bond Cleavage. Direct
â
γ
−
Synthesis of Enantiopure Succinimide
Derivatives
Benito Alcaide,*,† Pedro Almendros,‡ Gema Cabrero,† and M. Pilar Ruiz†
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, UniVersidad Complutense
de Madrid, 28040 Madrid, Spain, and Instituto de Qu´ımica Orga´nica General, CSIC,
Juan de la CierVa 3, 28006 Madrid, Spain
alcaideb@quim.ucm.es
Received June 28, 2005
ABSTRACT
Tetrabutylammonium cyanide (20 mol %) catalyzes ring expansion of 4-(arylimino)methylazetidin-2-ones 2 to 5-aryliminopyrrolidin-2-ones 3
through a novel N1 C4 bond cleavage of the -lactam nucleus. New, efficient one-pot protocols to enantiopure succinimide derivatives 3 and
4 from -lactam aldehydes 1 have also been developed.
−
â
â
Due to ring strain, azetidin-2-ones are susceptible to ring-
cleavage reactions. We and others have successfully exploited
this property, demonstrating the usefulness of â-lactams as
building blocks in the stereocontrolled synthesis of a wide
variety of compounds.1 Opening of the â-lactam ring can
occur through cleavage of one or more of its bonds.2
Cleavage of the amide bond by nucleophilic attack at the
N1-C2 bond is the most common and has been the subject
of many investigations to give â-amino acids,1d taxoids,3
pyrrolizidines and indolizidines,4 macrocyclic alkaloids,5 and
complex natural products. N-Carboxy anhydrides, R-amino
acids, and peptides have been obtained by breakage of the
C2-C3 bond.6 Pyrazines, oxazines, and eight-membered
lactams can be prepared through cleavage of the C3-C4
bond on the â-lactam nucleus.7 Cleavage of the N1-C4 bond
of 4-arylazetidin-2-ones by hydrogenolysis is a very well-
known methodology developed by Ojima for the synthesis
of R-amino acids and peptidomimetics.8 Furthermore, Mc-
Murray et al. have reported the N1-C4 ring opening of 4-(4′-
hydroxyphenyl)-2-azetidinones, leading to 4-hydroxyhydro-
(4) (a) Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly, M. F. Chem.
Eur. J. 2003, 9, 3415. (b) Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly,
M. F. J. Org. Chem. 2001, 66, 1351.
(5) Wassermann, H. H.; Matsuyama, H. J. Am. Chem. Soc. 1981, 103,
462.
(6) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Amino Acids
1999, 16, 321.
(7) Alcaide, B.; Rodr´ıguez-Ranera, C.; Rodr´ıguez-Vicente, A. Tetrahe-
dron Lett. 2001, 42, 3081.
† Universidad Complutense de Madrid.
‡ Instituto de Qu´ımica Orga´nica General.
(1) For selected reviews, see: (a) Alcaide, B.; Almendros, P. Chem. Soc.
ReV. 2001, 30, 226. (b) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide,
M. Synlett 2001, 1813. (b) Manhas, M. S.; Wagle, D. R.; Chiang, J.; Bose,
A. K. Heterocycles 1988, 27, 1755. (d) Palomo, C.; Aizpurua, J. M.; Ganboa,
I. In EnantioselectiVe Synthesis of â-Amino Acids; Juaristi, E., Ed.; Wiley-
VCH: New York, 1997; p 279.
(2) For a review on the selective bond cleavage of the â-lactam nucleus,
(8) For reviews, see: (a) Ojima, I.; Delaloge, F. Chem. Soc. ReV. 1997,
26, 377. (b) Ojima, I. AdV. Asym. Synth. 1995, 1, 95. (c) Ojima, I. Acc.
Chem. Res. 1995, 28, 383. (d) Ojima, I. In The Organic Chemistry of
â-Lactams; George, G., Ed.; VCH: New York, 1993; p 197.
see: Alcaide, B.; Almendros, P. Synlett 2002, 381.
(3) Boge, T. C.; George, G. In EnantioselectiVe Synthesis of â-Amino
Acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1997; p 1.
10.1021/ol051504a CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/06/2005

cinnamides or glutarimides, after treatment with base;
“tyrosyl” peptidomimetics were also obtained under acidic
conditions.9 Also, we recently described the synthesis of
R-alkoxy-γ-keto acid derivatives via N1-C4 bond cleavage
when we reacted 2-(trimethylsilyl)thiazole with azetidin-2-
ones lacking an aryl moiety at C4.10
Table 1. Catalytic Expansion of
4-Oxoazetidine-2-carbaldehydes 1 and 4-Imino-â-lactams 2 into
5-Iminopyrrolidin-2-ones 3
As part of a program aimed at exploring new reactivity
patterns for the â-lactam nucleus and subsequent synthetic
applications,11 we now document the catalytic synthesis of
enantiopure 5-aryliminopyrrolidin-2-ones 3 as well as pyr-
rolidine-2,5-diones (succinimides) 4 from 4-(arylimino)-
methylazetidin-2-ones 2. In addition to providing a new
method for the preparation of these important compounds
from readily available starting materials, our chemistry
unveils the first organocatalytic N1-C4 bond breakage of
the â-lactam skeleton.
Succinimides are an important class of heterocyclic
compounds with numerous pharmacological applications in
different fields12 such as irreversible protease inhibitors.13
Succinimide-based pseudopeptides have been shown to
stabilize â-turn conformations.14 Also, succinimides have
been used as valuable reagents and intermediates in the
synthesis of natural and unnatural compounds.15 Due to the
many uses of 3-heterosubstituted succinimides and related
pyrrolidin-2-one derivatives in organic and medicinal chem-
istry, the development of new synthetic routes to these
versatile compounds is an important endeavor.16
Our enantiopure cis-disubstituted 4-oxoazetidinecarbalde-
hyde starting substrates 1a-d were prepared from the [2 +
2]-cycloaddition reactions of (R)-2,3-O-isopropylidene-glyc-
eraldehyde imines with methoxy- or benzyloxyacetyl chloride
in the presence of Et3N, followed by sequential acidic
acetonide hydrolysis and oxidative cleavage.4,17 Treatment
of aldehydes 1 with aromatic amines in the presence of
molecular sieves (4 Å), in refluxing benzene for 4-6 h,
provided the corresponding imines 2 (Table 1) in nearly
quantitative yields, which were used without further purifica-
tion.
compd
(+)-2a MeO PMP PMP
(+)-2b MeO Bn PMP
(+)-2c MeO allyl PMP
(+)-2d MeO PMP p-MeC6H4
(+)-2e MeO PMP p-ClC6H4
R1
R2 a
R3
t (h) product yieldb (%)
2
(+)-3a
(+)-3b
(+)-3c
(+)-3d
(+)-3e
(+)-3fc
(+)-3ad
(+)-3cd
(+)-3gd
64
45
44
63
44
53
70
50
67
1.5
1.5
2.5
2
(+)-2f MeO PMP p-Me2NC6H4 24
(+)-1a MeO PMP PMP
(+)-1c MeO allyl PMP
(+)-1d BnO PMP PMP
6
5.5
24
a PMP ) 4-MeOC6H4. b Yields are from aldehydes 1, for pure isolated
products with correct analytical and spectroscopic data. c 50 mol % of
TBACN was used in this case. d One-pot synthesis in acetonitrile; t is overall
time.
trialkylsilyl cyanides has been scarcely studied,18 and as far
as we know its use is unprecedented for the Strecker reaction
of imino derivatives. However, other applications of this
reagent both as nucleophile or base have been reported.19 In
this context, we began this work by investigating the
cyanosilylation of cis-4-imino-â-lactam (+)-2a with tert-
butyldimethylsilyl cyanide (1.2 equiv) catalyzed by TBACN
(20 mol %) in dry acetonitrile at room temperature. The
reaction provided the enantiomerically pure 5-aryliminopy-
rrolidin-2-one (+)-3a in a reasonable 48% isolated yield after
24 h. The expected R-amino nitrile was not detected in the
crude reaction mixture.
Importantly, we were pleased to find that use of catalytic
amounts (from 50 to 10 mol %) of TBACN efficiently
promoted ring expansion to pyrrolidine-2,5-dione (+)-3a
without tert-butyldimethylsilyl cyanide being necessary for
the reaction to occur. Optimal conditions were found when
20 mol % of TBACN was used as catalyst. Encouraged by
these results, we decided to extend the process to a variety
of imino-â-lactams 2b-f, bearing benzyl, allyl, or p-
methoxyphenyl substituents at the lactam nitrogen (Table 1,
entries 2-6). The influence of the nature of different R3
groups bonded to the imine nitrogen was studied next. This
revealed that introducing one methyl group at the 4-position
of the aromatic ring was not detrimental, although the NMe2
and chlorine substituents were (Table 1, entries 4-6). To
The use of tetrabutylammonium cyanide (TBACN) as
catalyst for the cyanosilylation of carbonyl compounds with
(9) (a) Mandal, P. K.; Cabell, L. A.; McMurray, J. S. Tetrahedron Lett.
2005, 46, 3715. (b) Cabell, L. A.; McMurray, J. S. Tetrahedron Lett. 2002,
43, 2491.
(10) Alcaide, B.; Almendros, P.; Redondo, M. C. Org. Lett. 2004, 6,
1765.
(11) See, for instance: (a) Alcaide, B.; Almendros, P.; Alonso, J. M. J.
Org. Chem. 2004, 69, 993. (b) Alcaide, B.; Almendros, P.; Aragoncillo,
C.; Rodr´ıguez-Acebes, R. J. Org. Chem. 2004, 69, 826. (c) Alcaide, B.;
Almendros, P.; Alonso, J. M. Chem. Eur. J. 2003, 9, 5793. (d) Alcaide, B.;
Almendros, P.; Aragoncillo, C. Org. Lett. 2003, 5, 3795.
(12) Hargreaves, M. K.; Pritchard, J. G.; Dave, H. R. Chem. ReV. 1970,
70, 439.
(13) Abell, A. D.; Oldham, M. D. J. Org. Chem. 1997, 62, 1509.
(14) Obrecht, D.; Abrecht, C.; Altorfer, M.; Bohdal, U.; Grieder, A.;
Kleber, M.; Pfyffer, P.; Mu¨ller, K. HelV. Chim. Acta 1996, 79, 1315.
(15) (a) Brie`re, J.-F.; Charpentier, P.; Dupas, G.; Que`guiner, G.;
Bourguignon, J. Tetrahedron 1997, 53, 2075. (b) Reddy, P. Y.; Kondo, S.;
Toru, T.; Ueno, Y. J. Org. Chem. 1997, 62, 2652.
(16) See, for example: (a) Vo-Hoang, Y.; Gasse, C.; Vidal, M.; Garbay,
Ch.; Galons, H. Tetrahedron Lett. 2004, 45, 3603. (b) Ibnusaud, I.; Thomas,
G. Tetrahedron Lett. 2003, 44, 1247. (c) Alvarez-Gutierrez, J. M.; Nefzi,
A.; Houghten, R. A. Tetrahedron Lett. 2000, 41, 609.
(17) (a) Wagle, D. R.; Garai, C.; Chiang, J.; Monteleone, M. G.; Kurys,
B. E.; Strohmeyer, T. W.; Hedge, V. R.; Manhas, M. S.; Bose, A. K. J.
Org. Chem. 1988, 53, 4227.
(18) (a) Amurrio, I.; Co´rdoba, R.; Csa´ky¨, A. G.; Plumet, J. Tetrahedron
2004, 60, 10521.
(19) See, for example: (a) Vidya, R.; Eggen, M. J.; Nair, S. K.; Georg,
G. I.; Himes, R. H. J. Org. Chem. 2003, 68, 9687. (b) Bhat, A. S.; Gervay-
Hague, J. Org. Lett. 2001, 3, 2081. (c) Godskesen, M.; Lundt, I.; Sotofte,
I. Tetrahedron: Asymmetry 2000, 11, 567. (d) Romo, D.; Rzasa, R. M.;
Shea, H. A.; Park, K.; Langenhan, J. M.; Sun, L.; Akhiezer, A.; Liu, J. O.
J. Am. Chem. Soc. 1998, 120, 12237.
3982
Org. Lett., Vol. 7, No. 18, 2005

develop a more simple and convenient experimental proce-
dure, we decided to explore a one-pot procedure for accessing
3 from aldehyde 1, without imine 2 isolation. In this regard,
a solution of compound (+)-1a, or (+)-1c, in acetonitrile
was treated with p-anisidine and heated at reflux for 4 h in
the presence of molecular sieves (4 Å). After the reaction
mixture was cooled, a catalytic (20 mol %) amount of
TBACN was added to the resulting imine solution, and the
reactants were maintained at room temperature for 2 h.
Formation of compounds (+)-3a or (+)-3c took place
smoothly (Table 1, entries 7 and 8). The procedure was
extended to a direct synthesis of 5-iminopyrrolidine-2-one
(+)-3g from aldehyde (+)-1d (Table 1, entry 9). The
presence of a bulkier R1 group decreased the rate of ring
expansion. A dramatic effect on the reactivity was observed
with imines derived from aliphatic amines, as exemplified
by the N-benzylimine (+)-2h (Scheme 1). Its reaction with
Scheme 2. Proposed Catalytic Cycle for the Formation of
Succinimide Derivatives 3 from Imino-â-lactams 2
Scheme 1. Synthesis of R-Amino Nitrile 5 from
N-Benzylimino-â-lactam (+)-2h
4.5 h, to give pure succinimide (+)-4a in 64% yield. As a
consequence, we decided to explore a new one-pot procedure
for obtaining (+)-4a from aldehyde (+)-1a. Thus, the
reaction mixture obtained by sequential treatment of com-
pound (+)-1a with p-anisidine and a catalytic (20 mol %)
amount of TBACN in acetonitrile was hydrolyzed in situ
with aqueous HCl. The overall reaction yield for the one-
pot method (55%) was improved when compared to the step-
by-step procedure (41%). This yield represents a one-pot,
three step process involving imine formation, catalytic ring
expansion and selective imine hydrolysis (Scheme 3).
TBACN under the above experimental conditions was
troublesome.20 R-Amino nitrile 5 was obtained as an easily
separable mixture of diastereomers (74/26), by using 1.2
equiv of TBDMSCN in the presence of 10 mol % of
TBACN, after 4.5 h (Scheme 2). From these results, we have
concluded that an aromatic group bonded to the imine
nitrogen is needed for an effective ring expansion to occur.
We propose the catalytic cycle shown in Scheme 2 to
account for our new ring expansion. Under the reaction
conditions, nucleophilic addition of cyanide to the imino
group will form species 6 which will evolve into the
corresponding R-cyano carbanion 7. Intermediate 7 is then
converted into the imino nitrile amide 9 via the corresponding
enamino nitrile 8 formed by N1-C4 â-lactam bond breakage.
This process should be favored for aromatic R3 groups.
Finally, anionic cyclization on the imino group with concur-
rent cyanide elimination should afford the iminopyrrolidin-
2-one 3.
Scheme 3. One-Pot Synthesis of Succinimides 4 from
â-Lactam Aldehydes 1
We have also investigated hydrolysis of the imino group
of compounds 3 to provide enantiopure pyrrolidin-2,5-diones
4.21 Thus, iminopyrrolidin-2-one (+)-3a was treated with
aqueous 20% HCl in acetonitrile at room temperature for
Analogous results were observed in the preparation of
succinimide (+)-4b (50%) from aldehyde (+)-1d
(Scheme 3).
In conclusion, the first organocatalytic N1-C4 bond
breakage of the â-lactam skeleton has been uncovered, and
this relies upon appropriate substitution at C4. In addition,
a new, direct method for the preparation of enantiopure
5-aryliminopyrrolidin-2-ones 3 as well as pyrrolidin-2,5-
diones (succinimides) 4 from 4-(arylimino)methylazetidin-
2-ones 2 is described. Studies concerning the scope and
generality of this methodology as well as mechanistic
(20) No conversion was observed under catalytic conditions (20 mol %
of TBACN, 142 h). A complex reaction mixture containing R-amino nitrile
5 was obtained when an equimolar amount of the reagent was used after
prolonged reaction time (2 days).
(21) The overall transformation occurs without loss of the stereochemical
integrity of the starting material. The optical purity was checked by 1H
NMR using tris[3-heptafluoropropylhydroxymethylene)-d-camphorate]-
europium(III), Eu(hfc)3, as the chiral shift reagent, both in the racemic and
optically pure compounds.
Org. Lett., Vol. 7, No. 18, 2005
3983

implications are underway in our laboratory, and further
details will be reported in due course.
Supporting Information Available: General experimen-
tal procedures as well as spectroscopic and analytical data
for compounds 2b,d-h, 3a-g, 4a,b, and 5. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Support for this work by the DGI-
MCYT (Project No. BQU2003-07793-C02-01) is gratefully
acknowledged. G.C.G. thanks the MEC for a predoctoral
grant.
OL051504A
3984
Org. Lett., Vol. 7, No. 18, 2005