Amines 2-azetidinones

Two equivalents of the tertiary amine base are required, and a significant improvement in the diastereoselectivity was observed with TMEDA over DIPEA. Purification and further enrichment of the desired RRR isomer to >98% ee was achieved by crystallization. Oxidative removal of the chiral auxiliary followed by carbodiimide mediated amide formation provides (3-keto carboxamide 14 in good yield. Activation of the benzylic hydroxyl via PPha/DEAD, acylation, or phosphorylation, effects 2-azetidinone ring-closure with inversion of stereochemistry at the C4 position. Unfortunately, final purification could not be effected by crystallization and the side products and or residual reagents could only be removed by careful chromatography on silica. 

Based on the early racemic synthesis of 4 (cis series), it had already been demonstrated that 2-azetidinone ring closure could be achieved via nucleophilic attack of a lithium amine anion on a (3-ester. Cyclization could be accomplished with other strong bases, but sodium bistrimethylsilylamide was found to effect efficient cyclization without significant racemization at C3. During the search for experimentally convenient bases, it was noted that Noyori (Nakamura et al., 1983) reported that tetrabutylammonium fluoride (TBAF) as well as LiF, KF, and CsF could serve as the base in Aldol reactions. Treatment of 17a or 17b with TBAF trihydrate in THF did not affect cyclization. After much experimentation it was found that addition of A,0-bistrimethylacetamide (BSA) to 19 followed by TBAF addition, effected 2-azetidinone ring closure. Further optimization found that use of catalytic TBAF (< 1%) in methylene chloride afforded near quantitative cyclization. 

In 2000, the group of Banik et al. reported the enantiospecific synthesis of 3-hydroxy-2-azetidinones by microwave assisted Staudinger reaction [51]. Chiral imines, derived from chiral aldehydes and achiral amines, reacted with methoxy- or acet-oxy-acetyl chloride to afford a single, optically pure c/s-p-lactam, (Scheme 7). 

A new and efficient one-pot approach towards chiral 2-azetidinones has been reported to start from (25)-chloro-l-propanol. The treatment of this latter with 5 equivalents of pyridinium chlorochromate in dichloromethane at room temperature afforded the (2S)-chloropropanal which treated with 1 equivalent of amine and 1.5 equivalents of MgSC>4 yielded the (S)-N-(2-chloropropvIiclene)amines. Finally,... 

In an effort to cleave the silyl group (see Section VI.B.2), 4-trimethylsilyl azetidinone was treated with tetrabutylammonium fluoride, TBAF, in the presence of acetaldehyde. The corresponding aminal was obtained instead in 65% yield.223... 

Amino-3-phenylazetidine is obtained in high yield in three steps from Al-benzhydryl-3-azetidinone by using dibenzylamine as an amine equivalent in a modified Strecker reaction (95SC803). 

Oxidative methanolysis of azetidinone 176 followed by hydrogenolysis of compound 177 afforded /3-lactam 178, which was protected to obtain the protected amine 179. The best conditions for rearrangement of 179 were found using TFA. Conversion of compound 180 to carbacephem 183 was accomplished by ketone reduction, alcohol protection, and elimination of methanol. Synthesis of carbacephem derivative 186 has been performed by rhodium(n)-catalyzed cycliza-tion of iodonium ylide 185 <1997TL6981> (Scheme 33). The iodonium ylide 185 was easily prepared from the corresponding /3-keto ester 184 and [(diacetoxy)iodo]benzene in good yield. 

Dehydrohalogenation of substituted acetyl chlorides via tertiary organic bases and the stereoselective construction of an azetidinone ring from an imine (the Staudinger reaction) has played an important part in the development of azetidinone chemistry, which has been reviewed <1993MI637>. The use of bicarbonates in the presence of a crown ether at — 10°C has been suggested as an economical alternative to tertiary amines <2003SL1937>. 

Indium-mediated allylation of 4-acetoxy-2-azetidinones affords 4-allyl-substituted azetidinones with retention of the stereochemistry (Equation (82)).320 An aminoalkoxy titanium complex is readily allylated with allylindium reagents to give homoallylic amines (Scheme 86).321... 

The smino acids used hy Blicke and Gould -were all secondary amines obtained by the addition of benzylamiue or alkyl amines to atropic acid or other substituted acrylic acids. The acid chloride salts v ore prepared by treatment with thionyl chloride, and after removing by-products the crude products were r cxed in bensene solution with excess dimethylaniline. The 1.8- and 1,4-disuhstituted azetidinones were isolated in yields of 40 80%, The benefioial influenoe of substitution was observed with the l-benzyl-S-methyl 4-phenyl- and l-benxyl-.S,3-dim thyl-4 phenyl-2-azetidinones, both of which were obtained in 90% yield. In an unsbooeasfu) attempt to prepare -aminodiasoketonea several of the acid chloride hydrochlorides were treated with diaxo-methane this reaction also fumishes the /9-laotams, although in rather low yield. 

The importance of j -lactams in the penicillins , cephalosporins , thienamycin and the recent discovery of antibiotic activity among monocyclic j -lactams such as norcardicins or the )5-lactamase inhibitor clavulanic acid have recently intensified research toward the synthesis of this system . Among the different procedures that have been developed for incorporating a 2-azetidinone unit , the ring expansion of cyclopropanol amines provides a simple and convenient route to these attractive small ring compounds. 

Several substituted fi-lactams and benzyl amine derivatives participated in this coupling reaction, though the ring expansion was slower when /V-substituted benzyl amines were used. Exposure of the intermediate /V-aryl lactam to AcOH in THF, however, overcame the sluggish transamidation. In some examples, the addition of N,N -dimethylethylene-diamine facilitated the reaction, though it was not required in all cases. Phenethyl amine 672 reacted with azetidinone 670 to give 673 in 78% yield. 

In a new approach to the well known versatile (3-lactam building blocks, an enzymatic deprotection of an acylated methylol amide was applied with advantages (Fig. 18-6)[70j. Thus, the dibenzoate 15 was regioselectively saponified by cholesterol esterase at pH 7 giving rise to a monoacylated aminal. After Jones oxidation and subsequent loss of formaldehyde, the azetidinone 16 was obtained, which can be transformed into various enantiomerically pure penem and carbapenem building blocks. 

Allyl-2-azetidinones are synthesized by displacement of the corresponding acetoxy derivatives, A preparation of homoallylic amines can take advantage of the reactivity of allylindium reagents on iminium species that are formed in situ. ... 

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