Preparation of (3S,4S)-1-Benzhydryl-3-[(5R)-1′-hydroxyethyl]-4-acyl-2-azetidinones from (2R,3R)-Epoxybutyramide Precursors
Introduction
The pharmaceutical development of carbapenems, an important class of β-lactam antibiotics,1 is connected to the availability of appropriate synthetic precursors, such as the chiral azetidinone 1: (3R,4R)-4-acetoxy-3-[(5R)-1′-(tert-butyldimethylsilyloxy)ethyl]-2-azetidinone.2
Amongst the various strategies explored for the construction of this versatile building block,3 one is based on the C-3/C-4 ring closure via an intramolecular nucleophilic substitution of (2R,3R)-epoxy-butyramide precursors 3 derived from l-threonine (Scheme 1).4., 5., 6., 7., 8., 9., 10., 11. The structures 3 are equipped with an electron-withdrawing group (EWG) able to stabilise a carbanionic intermediate, and with a nitrogen-protecting group (PG) that could be cleaved from the β-lactams 2 by oxidation with ceric ammonium nitrate, i.e. 4-methoxybenzyl-, 2,4-dimethoxybenzyl-, or most usually, 4-methoxyphenyl-(=p-anisyl) groups. This method, starting from a low cost, naturally occurring chiron,12., 13. generates the three chiral centres of the β-lactam precursors 2 in the required absolute configuration.
In our laboratory, we became interested in a modification of the previous strategy making use of a nitrogen-protecting group cleavable by hydrogenolysis. Our previous experience in the related β-lactamiminium derivatives led us to consider the benzhydryl group.14 Accordingly, we prepared the precursors 8 (Scheme 2) and examined their transformation into the corresponding β-lactams. During this work, we found unexpected cyclization- and rearrangement products described in this article.
Section snippets
Results
(2R,3R)-cis-2,3-Epoxybutanoate 4 was prepared from l-threonine according to known procedures,12., 13. adapted for large quantities (100 g scale). The enantiomeric purity of 4 has been established by chiral GC analysis, after derivatization into the corresponding isopropyl ester.13
From the examination of several conditions for direct activation of the salt 4 (SOCl2/THF; SOCl2+pyridine/benzene; (COCl)2+pyridine/THF; 2,3,5-trichlorobenzoyl chloride/DMF; i-butyl chloroformate/DMF or CH3CN; pivaloyl
Discussion
The intramolecular ring-opening of chiral expoxides is a stereochemically controlled SNi process useful for the preparation of various carbocycles16., 17., 18. and heterocycles.19., 20., 21., 22., 23., 24. The epoxide function behaves as an ambident electrophile that can be attacked by nucleophiles on the C-2 or C-3 position of the small ring. In our case, the internal nucleophile is an enolate, thus also an ambident function, that could attack with either its carbon- or oxygen atom, leading
Experimental
The melting points were determined with an Electrothermal microscope and are uncorrected. The specific rotations (±0.5) were determined on a Perkin–Elmer 241 MC polarimeter (concentration in g/100 mL). The IR spectra were taken with a Bio-Rad FTS 135 instrument, and calibrated with polystyrene (1601 cm−1). The 1H and 13C NMR spectra were recorded on Varian Gemini 300 (at 300 MHz for proton and 75 MHz for carbon), or Bruker AM-500 spectrometers (at 500 MHz for proton and 125 MHz for carbon); the
Acknowledgements
We thank Dr B. Tinant for the X-ray diffraction analyses15 and V. Durieu for technical assistance. This work was supported by the Fonds National de la Recherche Scientifique (FNRS, Belgium) and by Tessenderlo Chemie (Belgium).
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Cited by (22)
Recent progress in the synthesis and chemistry of azetidinones
2003, TetrahedronChapter 7 Seven-membered rings
2001, Progress in Heterocyclic ChemistryCitation Excerpt :When the nitrile group was replaced either by a carboxamido or a tetrazolyl group, complex mixtures of products resulted <00TA533>. O-Alkylation of N-(phenacyl)- and N-(pivaloylmethyl)-derivatives of N-(benzhydryl)-(2R,3R)-cis-2,3-epoxybutyramide gave 4,5,6,7-tetrahydro-4-aza-oxepin-5-ones by SNi reactions under basic conditions <00T3209>. A ring enlargement process was used effectively to access the enantiopure pyrrolo [1,2-d][1,4]oxazepine-9a(7H)-carboxylate derivatives 142 and 143 .
Chapter 4 Four-membered ring systems
2001, Progress in Heterocyclic ChemistryCitation Excerpt :The mesylate 69 cyclized in the presence of base to 70 and, after deprotection, the racemic β-lactam was subjected to lipase-mediated resolution to yield 71 (R = Et, ee 99%) and the amino acid 72 (R = Et, ee 98%) <00JOC4919>. Intramolecular attack of the tertiary amide anion 73 on the epoxide yielded a β-lactam <00T3209>. Radical cyclizations of 2-azabutadienes <00OL1077>and enamides in solution to give β-lactams have been reported <00OL401>.
ORGANIC REACTION MECHANISMS Selected Problems and Solutions: Second Edition
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