Lactams hydroxyalkyl

Intermolecular Schmidt reactions of alkyl azides and hydroxyalkyl azides with cycloketones in the presence of a Lewis acid, lead to formation of iV-alkyl lactams and A-hydroxyalkyl lactams respectively in good yield. The synthesis of chiral lactams by an asymmetric Schmidt reaction has also been reported. ... 

A radical approach to asymmetnc iildol synthesis, which is based on the radical addition of a chiral hydroxyalkyl radical equivalent to a tutroalkene, has been reported, as shown in Eq 4 93 The radical precursor is prepared from the corresponding carboxyhc acid by the Barton reaction, which has been used for synthesis of new fi-lactams ... 

Samarium(II) iodide also allows the reductive coupling of sulfur-substituted aromatic lactams such as 7-166 with carbonyl compounds to afford a-hydroxyalkylated lactams 7-167 with a high anti-selectivity [74]. The substituted lactams can easily be prepared from imides 7-165. The reaction is initiated by a reductive desulfuration with samarium(ll) iodide to give a radical, which can be intercepted by the added aldehyde to give the desired products 7-167. Ketones can be used as the carbonyl moiety instead of aldehydes, with good - albeit slightly lower - yields. 

A different approach to enantiotopic group differentiation in bicyclic anhydrides consists of their two-step conversion, first with (/ )-2-amino-2-phcnylethanol to chiral imides 3, then by diastereoselective reduction with sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) to the corresponding chiral hydroxy lactames 4, which may be converted to the corresponding lactones 5 via reduction with sodium borohydride and cyclization of the hydroxyalkyl amides 101 The overall yield is good and the enantioselectivity ranges from moderate to good. Absolute configurations of the lactones are based on chemical correlation. 

The use of tram-configured (3-lactam moieties has led to drugs displaying much higher stability toward resistant bacteria. Examples of such compounds are thienamycin 94 and the recently discovered trinems 95,85 which also contain a hydroxyalkyl substituent at the C-3 position. 

One method for the synthesis of hydroxyalkyl-substituted P-lactams is by the Staudinger reaction, the most frequently used method for the synthesis of P-lactams.86 This method for the preparation of 4-acetoxy- and 4-formyl-substituted P-lactams involves the use of diazoketones prepared from amino acids. These diazoketones are precursors for ketenes, in a diastereoselective, photochemically induced reaction to produce exclusively tram-substituted P-lactams. The use of cinnamaldimines 96, considered as vinylogous benzaldimines, resulted in the formation of styryl-substituted P-lactams. Ozonolysis, followed by reductive workup with dimethyl sulfide, led to the formation of the aldehyde 97, whereas addition of trimethyl orthoformate permitted the production of the dimethyl acetal 98 (Scheme 11.26). 

There are now large numbers of p-lactam antibiotics known and one family has the opposite (trans) stereochemistry around the four-membered ring. The typical member is thienamycin. We will analyse the spectrum in a moment, but first look at the differences—apart from stereochemistry—between this structure and the last. The sulfur atom is now outside the five-membered ring, the acid group is on a double bond in the same ring, and the amino group has gone from the [3-lactam to be replaced by a hydroxyalkyl side chain. 

Tertiary amines form complexes with mercury(II) ion, which then give iminium ions by loss of a piotoa Addition of perchloric acid permits isolation of the iminium ion as the perchlorate salt and generally the more-substituted ion is favored (equation 14). Intramolecular trapping by a hydroxyalkyl group is also possible to form aminals (equation 15). The lactam products result from over-oxidation, which is promoted by heat. Basification on the other hand usually allows the isolation of enamines although hydroxyenamines have been obtained by reaction of enamines with mercury(II) acetate (equation 16), while dihydroaromatic systems undergo aromatization (equation 17). ... 

The halo-lactams are suitable intermediates for further transformations. They are converted to the corresponding azido lactams and hydroxyalkyl lactams by simple nucleophilic substitution130. 

Oxaziridines are converted to ring-expanded lactams under photochemical conditions. A-Tosyl aziridines with an a-hydroxyalkyl substituent give a pinacol rearrangement product in the presence of Lewis acids, such as Sml2> in this case a keto-A-tosyl amide. ... 

Lithiation of l-aryl-17/-imidazoles followed by quenching with electrophiles provided a route to 1,2-diaryl, l-aryl-2-cycloalkyl- and l-aryl-2-heterocycle-substituted imidazoles <05H(65)2721>. Isoprene-catalyzed lithiation of imidazole provided a synthetic route to 2-(hydroxyalkyl)- and 2-(aminoalkyl)imidazoles <05X11148>. 2-Lithiobenzimidazoles were efficiently acylated with esters, lactones and lactams <05TL5081>. 

Stereoselective synthesis of b/S-alkyl-penicillanates, using reductive removal of a 6/3-isocyano substituent with tributyltin hydride, has been described/ Stereocontrol in the formation of 6-hydroxyalkyl /8-lactam antibiotics by trans-metallation between benzyl 6,6-dibromopenicillanate esters and metal alkyls. 

Intramolecular substitution for chloride or fluoride is particularly effective. Oxygen heterocycles with fused benzo rings are obtained from Cr(CO)3 complexes of fluorobenzene with an o-(hydroxyalkyl) side chain [2]. Using a Cr(CO)3 unit to direct a [2-f2] cycloaddition to an imine, a stereoselective synthesis of a lactam was achieved [32]. 

The reaction of butenolides or a,P-unsaturated lactams (35 X = O or NBoc) reacts with ethylene diamine to form the reduced chiral 7-(a-hydroxyalkyl)- and... 

Completion of the formal synthesis of ( + ) carpetimycin A 48 was effected by tributyltin hydride reduction of the bromohydrin 43, to give predominantly the required cis a-hydroxyalkyl P-lactam 46 in 63% yield, together with the... 

Mechanistically, these reactions are related to the oxazoUne synthesis shown in Scheme 7.3. Both involve the initial formation of an oxonium ion followed by the now-intramolecular addition of the appended azide to this cation (Scheme 7.11). In the present case, migration with loss of N2 occurs to afford an iminium ether salt (e.g. 16), which can be isolated by precipitation with cold THE. Treatment of the iminium salt with aqueous NaHCOs then delivers an A-hydroxyalkyl lactam. 

A modular synthesis of a series of y-tum mimics was enabled by the Lewis acid-mediated reactions of enantiopnre hydroxyalkyl azides with piperidinones. This involved the preparation of enantiopnre azides 103, the side chains of which corresponded to those in natnrally occnrring side amino acids. These azides were combined with piperidinones 102 in the presence of BFs-OEta or TfOH, and the resulting imininm ethers hydrolyzed to the corresponding lactams 104 (Table 7.10). 

Alkylation Reaction of Lactams N-a-hydroxyalkylated lactams are the main reaction product obtained in the C-N coupling reaction over basic catalysts. Calvino-Casilda et al. carried out this syntixesis using 2-pyrrolidinone and 1-heptanal over alkali-AC catalysts. The main product N-l-heptenyl-2-pyrrolidinone 39 was obtained by dehydration of the initially formed N-a-hydroxyheptanyl-2-pyrrolidinone (Scheme 26) [114]. The use of alkaline carbons in combination with MW activation can be considered as an ultra-fast methodology for tire syntixesis of compound 39 in 82% of conversion and total selectivity. 

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