Synthesis of novel bi- and tricyclic heteroactivated b-lactams by pressure promoted [4+2]/[3+2] tandem cycloadditions of enol ethers and nitrostyrene
G.J.T. Kuster , F. Kalmoua, J.W. Scheeren*
Department of Organic Chemistry, NSR-Center, University of Nijmegen,
Toernooiveld, 6525 ED, Nijmegen, The Netherlands.
E-mail: jsch@ sci.kun.nl
Tandem [4+2]/[3+2] cycloadditions of nitroalkenes with electron-rich and
electron-poor alkenes have been applied by Denmark et. al. in the
synthesis of several natural pyrrolizidine alkaloids as (-) hastanecine, (-)
rosmarinecine and (-) crotanecine 1,2. In these tandem
cycloadditions an electron-rich alkene reacts with a nitroalkene in an inverse
electron demand Diels-Alder reaction under formation of a nitronate
(mono-adduct), which then reacts with a second alkene in a [3+2] cycloaddition,
leading to a nitroso acetal (di-adduct):
At ambient pressure this reaction needs strongly activated nitroalkenes or a
stoichiometric amount of Lewis acid catalyst. Since cycloadditions are
accelerated by high pressure it was tried to eliminate the use of Lewis acid
catalysts or strongly activated nitroalkenes by using high pressure conditions
Recently, we observed a strong accelerating effect of high pressure on the
tandem [4+2]/[3+2] cycloaddition of nitroalkenes with enol ethers
Since nitronates (mono-adducts) react faster with electron-poor alkenes than
with electron-rich alkenes it was possible to perform the tandem cycloaddition
in an one-pot-three-component system containing an electron-rich enol ether,
nitrostyrene and an electron-poor or neutral mono-substituted alkene (ratio
1/1/1). Results of this one-pot-three-component tandem cycloaddition
using different dipolarophiles are shown in the following scheme.
R1= p-MeO-benzyl, R2= H
In all cases the [4+2] cycloaddition was completely regio- and stereoselective,
whereas the [3+2] cycloaddition was regioselective but not completely
stereoselective. Recently we reported the high pressure promoted three
component tandem [4+2]/[3+2] cycloaddition on the solid phase 5.
By using an excess of nitrostyrene the nitroalkene reacted as well in the
Diels-Alder reaction (hetero-diene) as in the 1,3-dipolar cycloaddition
The results are presented in the next scheme.
A mixture of regio-isomers A and B was found.
The main regio-isomer A was easily transformed into a
lactam after a base catalysed intra-molecular rearrangement:
By performing the tandem cycloaddition with a range of enol ethers and
nitrostyrene the synthesis of novel bi- and tri-cyclic [beta]-lactams was
Reduction of some cycloadducts resulted in the formation of pyrrolidine and
pyrrolizidine derivatives containing the rigid aryl-ethyl-amine moiety:
Currently we are investigating how to optimise the reduction and how to
influence the regio-selectivity in the [3+2] cycloaddition.
In conclusion, we have shown that the application of high pressure in this
tandem [4+2]/[3+2] cycloaddition eliminates the use of stoichiometric amounts
of Lewis acid catalysts or strongly activated nitroalkenes, which is necessary
at ambient pressure. By the application of high pressure we were able to extend
the scope of the tandem [4+2]/[3+2] cycloadditions towards the use of higher
substituted nitroalkenes and enol ethers.
The high pressure promoted one-pot-three-component tandem cycloaddition
opens a straightforward route towards a variety of pyrrolidine and
pyrrolizidine derivatives, simply by varying the alkene substituents.
Furthermore, the high pressure promoted synthesis of novel di- and
tri-cyclic [beta]-lactams was performed.
1Denmark S.E. J.Org. Chem. 1997, 62, 435-436 and ref. cited
Denmark S.E. et al, Chem. Rev. (1996) 96, 137.
2 Denmark, S.E.; Schnute, M.E. J. Org. Chem. 1994, 59,
3 By using nitrostyrene as heterodiene, cyclic compounds containing
the aryl-ethyl-amine moiety in a fixed
position could be formed .This aryl-ethyl-amine moiety is occurring in
several neurotransmitters, hormones and
because of this also in CNS active drugs. Our research is focussed on the
synthesis of compounds containing a
rigid aryl-ethyl-amine moiety. This rigidity could express itself in a higher
receptor selectivity, finally resulting
in a more selective drug.
4 Uittenboogaard, R.; Seerden, J.P.G.; Scheeren, J.W.
Tetrahedron 1997, 53, 11929.
5 Kuster, G.J.T.; Scheeren, J.W. Tetrahedron Letters 1998,
6 To be submitted.