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Diastereoselective synthesis of 3,4-trans-disubstituted pyrrolidin-2-ones via conjugate addition

R.Galeazzi, S.Geremia, G. Mobbili and M.Orena*

Dipartimento di Scienze dei Materiali e della Terra Università degli Studi di Ancona Via Brecce Bianche 60131 Ancona, Italy
The carbapenems are antibiotics obtained by fermentation whose activity is higher than the corresponding penicillins. Their base structure consist of a b-lactam ring condensed with a cyclopentene (1-carbapenem) ring and the sulfur atom is substituted with a carbon atom.

As part of a project [1] aimed at synthesizing enantiomerically pure carbapenem antibiotics, we decided to prepare 3,4-trans-disubstituted pyrrolidin-2-ones which could then be converted by ring contraction into the corresponding 3,4-trans-disubstituted azetidin-2-ones.

The pyrrolidin-2-ones are obtained by cyclisation of the amides 1a-c by using the conjugate addition reaction.

We observed that the d.r. can be reversed, simply by changing the reaction conditions. Thus, by treating 1a with NaH in THF at - 60 C, an easily separable diastereomeric mixture 2a + 2b was obtained in 80% yield and 70:30 d.r. On the other hand, by treating 1a with EtO- in EtOH at - 78 C, a diastereomeric mixture 2a + 2b was recovered in 83% yield and 15:85 d.r. The stereochemical assignment of compounds 2a and 2b was performed by analysis of 1H NMR spectra , supported by Molecular mechanics calculations.

In order to optimize the synthesis of the diastereomer with the correct configuration at the centres 3 and 4, starting from (R)-phenylethylamine, we performed the reaction under conditions giving the best d.r.

In this way the acetacetamide 3 containing the (R)-phenylethylamine moiety underwent conjugate addition with EtO- in EtOH at - 78 C, to give an easily separable diastereomeric mixture 4a + 4b in 81% yield and 84:16 d.r.

The reduction of the keto group in 4a was then performed with high diastereoselectivity (95:5) using KBH4 [2], and the stereochemistry of the newly formed stereogenic centre was assigned as (S)- by X-ray analysis of the corresponding p-iodobenzoate ester.

The conjugate addition performed starting from 1b gave the same results observed for compound 1a. In fact the d.r. inverts on changing the reaction conditions from NaH/THF -60 C to EtO-/EtOH -78 C (d.r.70:30/15:85).

The reaction proceeds with good distereoselection in forming the centres in 3 and 4 (as observed for the cyclisation of compounds 1a), although this does not allow us to control the stereochemistry of the centre in 1". This is not a problem since the conversion of a methyl (in an a:b mixture) into a methylene terminal group has previously been reported [3]. The reaction is performed by using Se derivatives subsequentely transformed into the methylene group by elimination. Catalytic hydrogenation gives the desired 1 b-methyl group.

Starting from 5a-b it is possible to synthesize 1 b-methyl carbapenems that are even more active than thienamycin because of its particularly strained structure. In fact the 1 b-methyl group is endo with respect to the bicyclic system.

It is noteworthy that the reduction performed on 5a-b with KBH4 affords a 95:5 diastereomeric mixture as observed for 4a.

Finally, the reaction, performed starting from 1c, afforded an unseparable mixture of four diastereomers as determined from the peaks of the methyl at C-4 in the 1H NMR spectrum, although the configuration of the single components were not assigned.

In conclusion, a synthesis of 3,4-trans-disubstituted pyrrolidin-2-ones was realized with high stereocontrol at either C-3 and C-4, leading to products having the same configuration of the azetidin-2-one ring of carbapenems. In addition a stereoselective reduction of the keto group in the chain at C-3 has been realized. The ring contraction to b-lactams is currently under investigation and will be reported in due course.


  1. R.Galeazzi, S.Geremia, G.Mobbili, M.Orena, Tetrahedron: Asymmetry, 1996, 7, 79.
  2. For a similar reduction of a methyl ketone proceeding stereoselectively, see: Y.Hirai, T.Terada, T.Yamazaki, T.Momose, J.Chem. Soc., Perkin Trans. 1, 1992, 509.
  3. A.H.Berks, Tetrahedron, 1996, 52, 331.