Azetidin 2,3-dione

Metal-mediated carbonyl allylation, allenylation, and propargylation of optically pure azetidine-2,3-diones were investigated in aqueous environments.208 Different metal promoters showed varied regioselec-tivities on the product formation during allenylation/propargylation reactions of the kcto-fi-lactams. The stereochemistry of the new C3-substituted C3-hydroxy quaternary center was controlled by placing a chiral substituent at C4. The process led to a convenient entry to densely functionalized hydroxy-ji-lactams (Eq. 8.82). 

Hydroxyazetidin-2-ones can be oxidised efficiently to azetidine-2,3-diones by P205 in DMSO <00JPR585>, and then the 3-carbonyl group can be alkylated stereoselectively by application of the Baylis-Hillman reaction <99TL7537> or by use of substituted propargyl bromides to provide densely functionalized 3-hydroxy-P-lactams . 

Indium mediated allylation of 4-acetoxy-2-azetidinones gave the products 57 in high yield <99SL447> and similar reactions with azetidin-2,3-diones gave 3-substituted 3-hydroxy-P-lactams 58 <98H97>. 

In 2002, the asymmetric synthesis of 3-substituted 3-hydroxy-p-lactams has been reported to be realized by metal-mediated l,3-butadien-2-ylation reactions between 1,4-dibromo-2-butyne and optically pure azetidine-2,3-diones [64]. This latter starting material was prepared via Staudinger reaction followed by sequential transesterification and Swem oxidation (Scheme 15), [65]. 

In 2000, the metal-mediated carbonyl propargylation or allenylation of enantio-merically pure azetidine-2,3-diones [211] has been reported to afford stereoselec-tively functionalized 3-substituted 3-hydroxy-(3-lactams (Scheme 95), [212],... 

Scheme 95 Metal-mediated carbonyl propargylation or allenylation of pure azetidine-2,3-diones...

The Bayhs-Hillman reaction of optically pure azetidine-2,3-diones [235, 236] with methyl vinyl ketone in the presence of l,4-diazabicyclo[2.2.2]octane (DABCO) in acetonitrile at -20°C for 1 h have been reported to give functionalized allylic alcohols, having the p-lactam scaffold, in good yields (80%) and complete diastereoselectivity [237]. In terms of achieving good yields with a reasonable rate of reaction, 50 mol% of DABCO seemed to be the catalyst amount of choice for this reaction. No significant solvent effect was observed in the overall yield (Scheme 108). 

More recently, the direct reaction of amines and amino esters with azetidin-2,3-diones 128 at 90°C, Scheme 43, leading to peptides 130, has also been reported. The reaction is believed to occur through formation of an aziridine intermediate 129 which then rearranges to the amino amide with coextrusion [119, 120]. 

The nucleophilic reaction of Grignard reagents with azetidin-2,3-dione 270 yielded mainly fA-3-hydroxyazetidin-2-ones 271 (Equation 76) <2006S115>. A regio- and stereoselective reaction of azetidine-2,3-dione 272 with an organoindium compound led to the formation of azetidin-2-one-tethered homoallylic alcohol 273 (Equation 77), which has been used as precursor of spirocyclic azetidin-2-ones <2004TL6429>. 

For azetidine-2,3-diones, a-allenic alcohols are obtained as essentially regio- and diastereoisomerically pure products (Scheme ll).115... 

Indium-promoted reaction of l,4-dibromo-2-butyne with carbonyl compounds gives 1,3-butadiene derivatives via the allenic indium intermediates (Scheme 56).220 Similar indium-mediated l,3-butadien-2-ylation reactions of optically pure azetidine-2,3-diones have been investigated in aqueous media, offering a convenient asymmetric entry to the 3-substituted 3-hydroxy-/ -lactam moiety (Equation (40)). The diastereoselectivity of the addition reaction is controlled by the bulky chiral auxiliary at Q4 221 222... 

Recent progress in the synthesis and reactivity of azetidine-2,3-diones 01OPP315. 

Different regioselectivities for the addition to azetidine-2,3-diones by organometallic reagents prepared from propargyhc bromides and Zn or In are observed. " Allenyl derivatives are produced exclusively with In in a mixture of THF and saturated NH4CI. 

Several groups have shown that azetidine-2,3-diones are useful synthetic targets for the construction of p-lactams with the cephamycin [48], aspareno-mycin [49] and nocardicin [50] type side chains. Azetidine-2,3-diones like 93, have been utilized by us (Scheme 14), for the preparation of appropriately substituted P-lactam intermediates in carbapenem synthesis. 

Our first approach [51] to azetidine-2,3-diones relies on the silatropic rearrangement of trimethylsilyl a-hydroxyacetates 87 into the thermodynamically more stable a-trimethylsilyloxyacetic acids 88. The [2 H- 2] cycloaddition step was carried out by means of phenyl dichlorophosphate reagent in yields being in the range 40-65%. Under these conditions, the P-lactam 91 was produced in 45% yield as the single cis isomer. To transform 91 into 93 dimethylbromosulphonium bromide-triethylamine system [52] furnished the desired a-keto P-lactam in 90% yield. 

An alternative route [53] that provided the azetidine-2,3-dione 93 in better yield was the cycloaddition reaction between 90 and the Schiff base. 75 promoted by phenyl dichlorophosphate reagent followed by oxidative hydrolysis of the in situ generated p-lactam 92. In this way the P-lactam 93 was obtained in 90% overall yield from 90. Conversion of 93 into the 3-acetyl-P-lactam 97 was achieved in three steps according to our procedure [54]. Namely, the a-keto-P-lactam 93 was treated with nitroethane in the presence of base. 

Compared with chiral nonracemic a-amino carbonyl compounds - which are not suitable substrates for MBH reaction, mainly due to their racemization under normal conditions after prolonged exposure times to catalyst or due to poor diastereoselectivity " a-keto lactams, enantiopure 3-oxo-azetidin-2-ones 168, readily react with various activated vinyl systems promoted by DABCO to afford the corresponding optically pure MBH adducts 169 without detectable epimerization (Scheme 1.69). " However, the Lewis acid-mediated reaction of electron-deficient alkynes with azetidine-2,3-diones 168 as an entry to p-halo MBH adduets was not very sueeessful the coupling product 170 was achieved with concomitant acetonide cleavage as a single ( )-isomer in low yield, in the presence of trimethylsilyl iodide under BF3 OEt2-induced catalysis (Scheme 1.69). 

Other similar Rh-catalyzed 1,2-addition of oxonium ylides to aldehydes or imines have been described [163]. Moreover, this methodology has been applied to the 1,2-addition of oxonium ylides to isatins [164a], p,y-unsaturated a-ketoesters [164b], and azetidine-2,3-diones [164c]. 

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