Full text of DOI:10.1016/S0040-4039(00)01490-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8577–8580
Conjugate intra- and intermolecular addition mediated by
methoxide anion on polymeric support
Cristiana Fava, Roberta Galeazzi, Eugenia Maria Gonzalez-Rosende† and Mario Orena*
Dipartimento di Scienze dei Materiali e della Terra, Universita` di Ancona, Via Brecce Bianche,
I-60131 Ancona, Italy
Received 29 August 2000; accepted 6 September 2000
Abstract
By treatment with methoxide anion on polymeric support (IRA 900), chiral b-oxo or b-sulphonyl-
amides 2 bearing an a,b-unsaturated ester gave 3,4-disubstituted pyrrolidin-2-ones 3 as easily separable
diastereomeric mixtures in good yield and moderate-to-good stereoselection. The polymeric reagent was
also effective in promoting both intermolecular conjugate addition and alkylation reactions. © 2000
Published by Elsevier Science Ltd.
As part of a program in medicinal chemistry, we recently required several enantiomerically
pure 3,4-trans-disubstituted pyrrolidin-2-ones, useful intermediates for both non-proteinogenic
amino acids and carbapenems,1 and we reported the stereoselective synthesis of these com-
pounds by intramolecular conjugate addition2 requiring anhydrous solvents and air-sensitive
reagents.3–5 However, we considered it important to find more convenient reaction conditions
for this preparation; thus, a new route was devised where the enolate anion leading to the
conjugate addition could be generated by methoxide anion on polymeric support 1 (Scheme
1).6–9
Scheme 1.
The cyclisation reactions were carried out in methanol at 20°C simply by adding the acyclic
amides 2a–d to a suspension of the resin IRA 900 in the methoxide form, 110,11 (Scheme 2).
* Corresponding author. E-mail: orena@popcsi.unian.it
†
On leave from the University of Valencia, Spain.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01490-8

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Scheme 2.
Thereactionwasfastandafter1htheproductswererecoveredsimplybyfilteringoffthepolymeric
reagent and removing the solvent under reduced pressure.10 Firstly, it must be pointed out that
all the alkoxycarbonyl groups were converted into methoxycarbonyl groups, owing to the
transesterificating properties of the polymeric reagent. The choice of the solvent was critical, both
ethanol and propanol not being suitable, probably owing to their decreased acidity which does
not allow the formation of alkoxide ions. In addition, the temperature was also critical, since at
0°C no reaction was observed. Moreover, the cyclisation proceeded with moderate-to-good
stereocontrol, although with a slightly lower stereoselection in comparison with previously reported
conditions,3–5 and the pure diastereomers were isolated by silica gel chromatography. It is worth
noting that 3, the less stable diastereomer, was always the major component of the reaction mixture,
in agreement with a kinetically controlled cyclisation process.5 In a further development, compound
3a was stereoselectively reduced with K-Selectride® to give the corresponding 3-hydroxyethyl
derivative 5, homochiral with 6, the precursor of carbapenems1,10 (Scheme 3).
Scheme 3.
Then, we extended the applicability of methoxide ion on polymeric support 1, by first considering
the intermolecular conjugate addition of stabilised enolate anions to Michael acceptors.12 In fact,
the conjugate addition products 9 were obtained in good yield simply by adding to the polymeric
reagent 1, suspended in methanol, a solution containing 8 together with diethyl malonate or ethyl
cyanoacetate, 7a,b, respectively13 (Scheme 4).
Scheme 4.

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Furthermore, when the enolate anion of dimethyl chloromalonate 10 was generated in the
presence of 8, a tandem conjugate addition–SN2 reaction occurred, leading to the cyclopropyl
derivative 11 in moderate yield. In this case, however, transesterification at the ethoxycarbonyl
groups was not observed, even on increasing the amount of polymeric reagent 113 (Scheme 5).
Scheme 5.
Subsequently, in order to test the usefulness of 1 in promoting the formation of enolate anions
which could undergo alkylation, a methanolic solution of benzyl bromide and diethyl malonate
or ethyl acetoacetate, 12a,b, respectively, was added to the methoxide ion on a polymeric
support, 1, to give the corresponding alkylation products 13 in good yield after filtration,
removal of the solvent and column chromatography of the residue13 (Scheme 6).
Scheme 6.
Finally, a useful application of the polymeric reagent 1 consisted of converting 3,4-epoxy
amides 14 into the corresponding E-4-hydroxy-2-unsaturated amides 15. In fact, simply by
adding 14 to a suspension of 1 in methanol at rt, the E-isomer of 15 was formed exclusively in
good yield with excellent stereoselection (Scheme 7).
Scheme 7.
In summary, methoxide anion on polymeric support 1 resulted in an effective generation of
enolate anions of b-dicarbonyl esters and amides, which were used to give intra- and intermolec-
ular conjugate addition. The novel features of this methodology are general applicability, mild
reaction conditions, avoiding anhydrous solvents and air-sensitive reagents, and simple work-up,
which is reduced to a simple filtration of the polymeric reagent. Therefore, the present method
can result in useful synthetic organic chemistry and further applications are currently being
investigated in our laboratory.

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Acknowledgements
This research was supported by MURST (Rome) within the project ‘Chimica dei Composti
Organici di Interesse Biologico’ (PRIN 97).
References
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10. All new compounds gave satisfactory spectroscopic and high-resolution mass spectra data.
11. Representative experimental procedure for intramolecular conjugate addition: Resin IRA 900 (4.0 g) was added
to a solution containing NaOH (4.0 g, 100 mmol) in H2O (40 ml) at rt. After 30 min, the water was removed and
the resin was washed twice with methanol (30 ml). Fresh methanol (50 ml) was then added, and a solution
containing 2 (10 mmol) in methanol (10 ml) was added in one portion. After 1 h, the resin was filtered off, the
solvent removed under reduced pressure and the residue was purified by flash chromatography (cyclohexane:ethyl
acetate 70:30 as eluant).
12. Bergmann, E. D.; Ginsburg, D.; Pappo, R. Org. React. 1967, 10, 179–555.
13. Representative experimental procedure for intermolecular conjugate addition: To the resin IRA 900 (4.0 g)
prepared in methanol (50 ml) as in Ref. 11, were added in one portion 8 (10 mmol) and compound 10 or 12 (10
mmol) dissolved in methanol (10 ml). After 1 h, the resin was filtered off, the solvent was removed under reduced
pressure and the residue was purified by flash chromatography (cyclohexane:ethyl acetate 70:30 as eluant).
.