Lactams from ketene

Chiral fi-lactams. The synthesis of /5-lactams from ketene silyl acetals and Schiff bases (8, 484-485) results in asymmetric induction at C4 in the range 44 78% when optically active Schiff bases are used. An example is shown in equation (l)-... 

Three-component coupling reaction of a-enones, silyl enolates, and aldehydes by successive Mukaiyama-Michael and aldol reactions is a powerful method for stereoselective construction of highly functionahzed molecules valuable as synthetic intermediates of natural compounds [231c]. Kobayashi et al. recently reported the synthesis of y-acyl-d-lactams from ketene silyl thioacetals, a,/l-urisalu-rated thioesters, and imines via successive SbCl5-Sn(OTf)2-catalyzed Mukaiyama-Michael and Sc(OTf)3-catalyzed Mannich-type reactions (Scheme 10.87) [241]. 

In [2+2] cycloaddition reactions of carbon cumulenes, often only one four-membered ring compound is obtained. This reaction is of considerable importance in the synthesis of 8-lactams from ketenes and C=N double bond containing substrates. The j8-lactam structure is present in a variety of antibiotics. Also, j8-thiolactams are obtained from thioketenes and imines. 

The first catalytic, asymmetric synthesis of /3-lactams from ketenes and imines with useful selectivity was reported by Lectka, who used cinchona alkaloids [99]. The underlying principle in the development of such processes is the recognition that the optically active amine catalyst undergoes addition to the ketene to provide a chiral enolate, which then adds to the imine. The intermediate chiral zwitterion undergoes ring-closure, producing the /3-lac-tam. The cinchona alkaloid 111 has served admirably as a nucleophilic amine catalyst, furnishing adducts such as 112 with excellent enantio- and diastereoselectivity (99 1 dr, 99% ee, Equation 8) [31, 32, 99, 100]. 

An interesting bifunctional system with a combination of In(OTf)3 and benzoyl-quinine 65 was developed in p-lactam formation reaction from ketenes and an imino ester by Lectka [Eq. (13.40)]. High diastrereo- and enantioselectivity as well as high chemical yield were produced with the bifunctional catalysis. In the absence of the Lewis acid, polymerization of the acid chloride and imino ester occurred, and product yield was moderate. It was proposed that quinine activates ketenes (generated from acyl chloride in the presence of proton sponge) as a nucleophile to generate an enolate, while indium activates the imino ester, which favors the desired addition reaction (66) ... 

Scheme 90 Synthesis of a-alkilidene-P-lactams from a-acyl, a-carbamoyl ketene-S,S-acetals...

Cyclization of halogenoaryl-substituted /3-lactams can be mediated by palladium(n) derivatives. The formation of the lactam from a ketene-imine addition and subsequent cyclization of the product can be carried out as a one-pot process. As an example, in situ generation of the ketene from the acid chloride and formation of the /3-lactam followed by addition of palladium(ll) acetate, triphenylphosphine, and thalium carbonate gave 495 in 54% yield (Equation 79) <1995TL9053>. 

Significant progress has been made in the development of asymmetric syntheses of the biologically important 3-amino-p-lactams from homochiral ketene precursors.High levels of diastereoselection have been observed with chiral 1,3-oxazolidinones. Thus (4/ )-phenyloxazolidylacetyl chloride, readily prepared from (S)-phenylglycine, reacts with N-benzylaldimines in the presence of tri-ethylamine to yield die cis 3-lactams in high diastereoisomeric excesses (Scheme IS). ... 

Borer, B C, Balogh, D W, An asymmetric synthesis of a 3-hydroxy-(3-lactam by ketene-imine cycloaddition utilization of chiral ketenes from carbohydrates. Tetrahedron Lett., 32, 1039-1040, 1991. 

Photodecomposition of the diazo group containing acetals (472 Scheme 87) furnishes lactam acetals (473) similar compounds are accessible from ketenes and azidoformates. From 1,3-dioxolanes and azidoformate the aminodioxolanes (474) were prepared. " ... 

Lactams The ketene derived from (S)-phenyloxazolidylacetyl chloride (1), prepared from (S)-phenylglycine, undergoes cycloaddition with N-benzyl al-dimines to give two cw-azetidinones with high stereochemical control (equation I). The chiral auxiliary and the benzyl group are cleaved by Birch reduction to provide enantiomerically pure azetidinones (3). 

Condensation reactions of simple carboxylic acids with imines are of intense interest because of their applications to 3-lactam synthesis. Activation of the carboxylic acid derivative is accomplished by preforming the enolate in situ or by using a silyl ketene acetal derivative with Lewis acid catalysis. The first example of an enolate-imine condensation of this type can be attributed to Gillman and Speeter, who in 1943 reported the synthesis of 3-lactams from Reformatsky reagents and Schiff bases. Subsequently, other workers have investigated the mechanism and syn-anti selectivity of this reaction. A review of these studies by Evans et al. covering work through 1980 has appeared in their review, Stereoselective Aldol Condensations . ... 

An efficient and selective solid-phase synthesis of trans 3-alkyl-4-aryl-P-lactams from nonactivated acid chlorides has been accomplished <04TL4085>. The [2+2] cycloaddition between an aldehyde-derived resin-bound imine and a solution-generated ketene has been used to generate a variety of stereochemically pure cw-P-lactams <04JOC5439>. A new polymer-supported reagent has been used for the preparation of P-... 

SCHEME 2.7 A more general kinetic scheme for the formation of cis- and trawi -P-lactams from monosubstituted ketenes and ( )-imines. 

The existence of the zwitterionic intermediates has been inferred from the results of trapping experiments and by direct observation of zwitterionic intermediates that are unable to complete the cyclization to a P-lactam. Generation of the zwitterion 7 from ketene 5 and imine 6, followed by in situ trapping with sulfur dioxide, afforded the thiazolidine-4-one 1,1-dioxide 87 Similarly, reaction of the formamidate 10 with ketene 9 generated in situ by pyrolysis of the acylal afforded the formamide diethylacetal 12 upon trapping with ethanol, which suggests the intermediacy of the zwitterion 11 in this reaction pathway ... 

In a preliminary report, Bose et had described an efficient and rapid synthesis of number of P-lactams under microwave irradiation (MWI). Further in closed Teflon vessels using KF and phase transfer catalyst (PTC), P-lactams have been synthesized in few minutes from ketene silyl acetal and aldimines (Scheme 53). ... 

Scheme 4.29 Stereochemistry of p-lactam formation from ketene-imine cycioaddition.

The bis(acyl chloride) from adipic acid reacts with imines generated in situ from 2-aminobenzothiazole and aryl aldehydes in the presence of zeohtes as acid catalysts resulting in formation of bis(p-lactams) (Scheme 4.31). The reactions were found to be enhanced by the use of ultrasound, and while the reactions were presumably largely stepwise bisketenes can be formed under these conditions. The preparation of bis- and poly(p-lactams) by ketene cycloadditions has been reviewed. 

The formation of j8-lactams from aliphatic acid chlorides and imines has been reviewed. The reaction is assumed to proceed through in situ formation of a ketene, followed by interaction with the imine to form a zwitterionic intermediate, which undergoes an electrocyclic conrotatory ring closure to give the jS-lactam ring (Scheme 8). The stereoselectivity of the reaction is sensitive to both the electronic and steric effects of the substituents on the ( )- or (Z)-imine, and the former manifest themselves in the electronic torquoselectivity that occurs during the conrotating cyclization of a zwitterionic intermediate [shown for ( )-imine in Scheme 8]. ... 

The synthesis of fused-ring j8-lactams from azomethines and ketenes is well known. Manhas et al have now described an in situ synthesis of ketenes from carboxylic acids, carbon tetrabromide, triphenylphosphine and triethylamine at —78 °C the use of carbon tetrachloride gives much lower yields (Scheme 57). An alternative is to treat an acid with diethylphosphonochloridate and triethylamine, thereby generating a mixed anhydride in situ, which reacts with an imine to yield... 

In addition to the range of asymmetric routes toward 13-lactone and (3-lactam scaffolds, Lewis bases have been used to access a variety of other important four-membered heterocyclic classes via formal [2+2] cycloadditions. In this section, the use of tertiary amines or NHCs to generate ammonium or azolium enolates, respectively from ketenes and their subsequent application toward the formation of other synthetically interesting heterocycles, will be discussed. A series of reports concerning the use of sulfenes, the sulfonyl equivalents of ketenes, in Lewis base-catalyzed asymmetric [2+2] cycloadditions will also be detailed. 

Asymmetric synthesis of trans- -lactams from disubstituted ketenes and N-tosyl arylimines has been catalysed by (R)-BINAPHANE with up to 98% ee and (ir> 90 10. " However, the Staudinger cycloaddition method can be unsuitable if the reactants (ketones -I- imines) bear electron-withdrawing substituents as 0-lactams undergo base-induced isomerization to the azacyclobutene followed by electrocyclic ring opening to the corresponding a, 0-unsaturated alkenamide. ... 

A variety of a-spirolactones and lactams from 2-diazo-l,3-dicarbonyl compounds, (homo)allylic alcohols or amines and acrylic derivatives, in a single synthetic operation by a Wolff rearrangement/a-oxo ketene trapping/cross metathesis/ intramolecular Michael addition sequence has been obtained by Boddaert et al. (2011). 

Allylic phosphates are used for carbonylation in the presence of amines under pressure. Carbonylation of diethyl neryl phosphate (389) affords ethyl homonerate (390), maintaining the geometric integrity of the double bond[244]. The carbonylation of allyl phosphate in the presence of the imine 392 affords the /3-lactam 393. The reaction may be explained by the formation of the ketene 391 from the acyl phosphate, and its stereoselective (2 + 2] cycloaddition to the imine 392 to give the /3-lactam 393(247],... 

---