Stereoselective synthesis of highly functionalised tricyclic β-lactams via intramolecular nitrilimine cycloaddition

Article abstract of DOI:10.1016/j.tetasy.2006.04.029

The novel azeto[2′,1′:1,2]pyrrolo[3,4-c]pyrazole skeleton has been obtained in both racemic and enantiopure forms by means of intramolecular cycloaddition of nitrilimines 6. Fully stereoselective cycloadditions were obtained, giving tricyclic β-lactams 7

Full text of DOI:10.1016/j.tetasy.2006.04.029

Tetrahedron: Asymmetry 17 (2006) 1319–1321
Stereoselective synthesis of highly functionalised tricyclic
b-lactams via intramolecular nitrilimine cycloaddition
Paola Del Buttero* and Giorgio Molteni
`
Universita degli Studi di Milano, Dipartimento di Chimica Organica e Industriale, via Golgi 19, 20133 Milano, Italy
Received 4 April 2006; accepted 27 April 2006
Available online 24 May 2006
Abstract—The novel azeto[20,10:1,2]pyrrolo[3,4-c]pyrazole skeleton has been obtained in both racemic and enantiopure forms by means
of intramolecular cycloaddition of nitrilimines 6. Fully stereoselective cycloadditions were obtained, giving tricyclic b-lactams 7 as single
diastereoisomers with good overall yields.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
glycine methylester or L-alanine methylester, respectively,
with cinnamaldehyde. Subsequent [2+2] Staudinger cyclo-
addition between the C@N double bond of 1 and phen-
oxyketene generated in situ from phenoxyacetyl chloride
gave b-lactams 2,10 which, as expected, were cis substituted
at the 3- and 4-position of the four-membered ring.1 In the
case of homochiral imine 1b, however, the corresponding
2b was obtained as the major isomer (67:33) of a mixture
of the two possible diastereoisomeric b-lactams. Chro-
matographic treatment of the latter mixture gave enantio-
pure 2b, which was used further. Acyl hydrazines 4a and
b were obtained from 2a and b through ester hydrolysis,
carboxyl activation with oxalyl chloride and subsequent
treatment with phenylhydrazine. Hydrazonoyl chlorides
5a and b were synthesised from the corresponding acyl
hydrazines via treatment with triphenylphosphine and
carbon tetrachloride, according to the method originally
proposed by Wolkoff.11 The in situ generation of labile
intermediates 6a and b was accomplished by heating
at 50 °C the corresponding hydrazonoyl chlorides 5 in
dry dioxane in the presence of silver carbonate as the
basic agent.12 After 24 h, racemic cycloadduct 7a and
enantiopure 7b were obtained in 65% and 76% yield,
respectively.
Due to their widespread application in the treatment of a
number of infective diseases, the relevance of b-lactam
derivatives in the field of medicinal chemistry is well docu-
mented.1 As a consequence, several strategies devoted to
the synthesis of new b-lactam antibiotics have been devel-
oped,2 giving rise to a large number of compounds featur-
ing enhanced antibacterial activity3 or better resistance
towards b-lactamases.4 Within this developing picture,
the approach to tricyclic b-lactams involving a 1,3-dipolar
cycloaddition as the key step has been exploited in recent
times.5 As an example, the intramolecular nitrone-olefin
cycloaddition allowed the synthesis of tricyclic b-lactams,
which display an astonishing array of latent functional-
ities.6 Much less work has been carried out with other types
of 1,3-dipoles, namely, nitrilium betaines.7 In line with our
recent reports on the synthesis of tricyclic b-lactams,8 we
herein report a straightforward procedure for preparing
racemic and enantiopure azeto[20,10:1,2]pyrrolo[3,4-c]pyra-
zole skeletons by exploiting the intramolecular 1,3-dipolar
cycloaddition of suitably functionalised nitrilimines.
2. Results and discussion
Formulae 7a and b rely upon analytical and spectral data.13
In particular, the scalar couplings between the two hydro-
gens at the 3- and 4-position of the b-lactam ring (HA and
HB, J = 4.0 Hz) reflect their cis arrangement,14 while the
value of 9.1–9.3 Hz, which refers to the two hydrogens in
the 4- and 5-position of the 4,5-dihydropyrazole ring
(HC, HD) agrees with their trans relationship.15 These
Our synthetic sequence is depicted in Scheme 1. a,b-Unsat-
urated imines 1a9 and 1b were readily obtained by reacting
*
Corresponding author. Tel.: +39 02 50314141; fax: +39 02 50314139;
e-mail addresses: paola.delbuttero@unimi.it; giorgio.molteni@unimi.it
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.04.029

1320
P. Del Buttero, G. Molteni / Tetrahedron: Asymmetry 17 (2006) 1319–1321
Ph
Ph
Ph
PhO
O
PhO
O
PhOCH2COCl
Et3N
NaOH
N
N
aq. THF
N
COOMe
COOH
COOMe
a: 67%
b: 60%
a: 96%
b: 96%
R
R
R
1
2
3
Ph
Ph
PhO
PhO
Ag2CO3
dioxane
1) (COCl)2
CCl4
O
Cl
N
N
O
N
2) PhNHNH2
Ph3P
O
a: 58%
b: 68%
a: 91%
b: 86%
NH NHPh
NHPh
R
R
4
5
Ph
H
Ph
Ph
H
N
N
PhO
O
PhO
N
N
O
a: 65%, b: 76%
N
Ph
N
R
R
6
7
a: R = H, b: R = Me
Scheme 1.
findings are consistent with the following statements:
(i) b-lactam ring stereochemistry is retained through dipo-
lar cycloaddition, and (ii) 4,5-dihydropyrazole ring stereo-
chemistry is dictated from the stereoselectivity typical of
concerted dipolar cycloadditions.
the observed mutual NOE enhancements. As far as cyclo-
addition diastereoselectivity is concerned, we were pleased
to find that both 7a and 7b were obtained as single diaste-
reoisomers. This favourable stereochemical outcome may
be accounted for by considering the steric crowding of
the Si face of the ethylenic dipolarophile.
From these considerations, it follows that the relative con-
figurations of the two stereocentres placed on the tetrahy-
dropyrrole ring of both racemic 7a and enantiopure 7b
(HB, HC) can be safely deduced from the observed NOE
enhancements between HB and HD (Fig. 1).16 Furthermore,
the absolute configurations of the newly formed stereocen-
tres of enantiopure (3S,5S,5aR,6aS,6S)-7b were unambigu-
ously determined from the NOE enhancements between HB
and the average position of HE. It is apparent that these
NOE effects can only be operative in the case of the stereo-
chemical arrangement depicted. In order to further sub-
stantiate these NOE effects, the distances HB–HD and
HB–HE were calculated with the AM 117 semi-empirical
3. Conclusion
In conclusion, we demonstrated the feasibility of intramo-
lecular cycloaddition between nitrilimines and the ethylenic
dipolarophile, which are tethered by the b-lactam ring.
Highly functionalised tricyclic b-lactams were obtained
with good overall yields and complete diastereoselectivity.
Acknowledgements
˚
˚
method. Values of 2.25 A for 7a and 2.27 A (HB–HD)
Thanks are due to MURST (COFIN) for financial support.
We are grateful to Dr. Lara De Benassuti, University of
Milan, for NOESY experiments.
18
˚
and 2.89 A (HB–HE) for 7b were found, thus justifying
HD
HC
HD
HC
References
Ph
Ph
Ph
Ph
HB
HB
6
6a
N1
N2
N
N
PhO
HA
PhO
HA
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5
4
2a
3
N
N
3a
O
O
HE
HE
HE
7b
7a
Figure 1.

P. Del Buttero, G. Molteni / Tetrahedron: Asymmetry 17 (2006) 1319–1321
1321
´
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´
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´
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to 50 °C in the dark under a nitrogen atmosphere for 24 h.
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silica gel column with ethyl acetate–hexane 3:7 to give 7.
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irradiation time (for each signal) 1.8 s.
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