Lactam acetals synthesis

Isocyanides have also been used to prepare unsaturated 5(4//)-oxazolones and they are particularly useful for the synthesis of 4-(aminomethylene)-5(4//)-oxazo-lones 374. For instance, cyclization of an unsaturated isocyanide obtained from condensation of alkyl isocyanoacetates and lactam acetals has been reported (Scheme 7.120). ° ... 

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)-... 

Amide and lactam acetals in synthesis of heterocyclic compounds 92KGS762. 

Intramolecular heterocyclization in polyacrylonitrile 86UK62. a-Isocyano acetates, synthesis of N-heterocycles from 85YGK764. Isonitrosotosyl malonates in synthesis of N-heterocycles 80H(14)1581. Lactams, regioselective formation from bridged bicyclic ketones 81T1283. Malononitrile derivatives, synthesis of N-heterocycles condensed from ... 

Synthesis of enamines from carboxylic acid amides via 1-alkoxyazomethi-nium salts and amide acetals—Gyclic enamines via lactam acetals— Easy reaction of amide acetals with nucleophiles, urea acetals s. 16, 785 Enamines from carboxylic acid amides GHg + OG N < G G N <... 

A selection of recent results will be presented on a synthesis of monocyclic 3 lactams, a synthesis based on the Lewis acid promoted reaction between silyl ketene acetals and N-silyl imines. Attention will be focussed on aspects of stereocontrol in the preparation of N-protio 3 lactams possessing a variety of usefully functionalised structures. 

Synthesis of enamines from carboxylic acid amides via 1-alkoxyazomethinium salts and amide acetals Cyclic enamines via lactam acetals... 

There are several examples of intramolecular reactions of monocyclic /3-lactams with carbenes or carbenoids most of these involve formation of olivanic acid or clavulanic acid derivatives. Thus treatment of the diazo compound (106) with rhodium(II) acetate in benzene under reflux gives (107), an intermediate in the synthesis of thienamycin (80H(14)1305, 80TL2783). 

A wide variety of /3-lactams are available by these routes because of the range of substituents possible in either the ketene or its equivalent substituted acetic acid derivative. Considerable diversity in imine structure is also possible. In addition to simple Schiff bases, imino esters and thioethers, amidines, cyclic imines and conjugated imines such as cinnamy-lidineaniline have found wide application in the synthesis of functionalized /3-lactams. A-Acylhydrazones can be used, but phenylhydrazones and O-alkyloximes do not give /3-lactams. These /3-lactam forming reactions give both cis and /raMS-azetidin-2-ones some control over stereochemistry can, however, be exercised by choice of reactants and conditions. 

Schemes 15 and 16 summarize the syntheses of intermediates that represent rings A and D of vitamin Bi2 by the Eschenmoser group. Treatment of lactam/lactone 51, the precursor to B-ring intermediate 8 (whose synthesis has already been described, see Scheme 8), with potassium cyanide in methanol induces cleavage of the y-lac-tone ring and furnishes intermediate 76 after esterification of the newly formed acetic acid chain with diazomethane. Intermediate 76 is produced as a mixture of diastereomers, epimeric at the newly formed stereocenter, in a yield exceeding 95%. Selective conversion of the lactam carbonyl in 76 into the corresponding thiolactam...

Treatment of the 1,2-oxazines 52 with carbon monoxide at 1000 psi in the presence of cobalt carbonyl brings about insertion of carbon monoxide to form the 1,3-oxazepines S3 <96TL2713>. A convenient route to P-lactams fused to oxepines is made available by alkene metathesis. Thus reaction of 4-acetoxyazetidin-2-one with ally alcohol in the presence of zinc acetate, followed by iV-allylation of the nitrogen affords the derivative 54 which cyclises by RCM to form the oxazepinone 55 <96CC2231>. The same communication describes a similar synthesis of 1,3-dioxepines. 

Hepatite Virus NS3/4A having the pyrrolidine-5,5-trans-lactam skeleton [83], starting from (R)- and (S)-methionine, respectively. The key step is the addition of the proper silyl ketene acetal to an iminium ion, e.g., that generated by treatment of the intermediate 177 with boron trifluoride, which provided the adduct 178 with better diastereoselectivity than other Lewis acids. Inhibitors of hepatitis C virus NS3/4A were efficiently prepared by a similar route from (S)-methionine [83]. The addition of indole to a chiral (z-amino iminium ion was a completely diastereoselective step in a reported synthesis of tilivalline, a natural molecule which displays strong cytotoxicity towards mouse leukemia L 1210 [84]. 

The formation of an iminium ion as 2-530 is also proposed by Heaney and coworkers in the synthesis of a tetrahydro- 3-carboline 2-531 (Scheme 2.120) [282]. Herein, heating a solution of tryptamine (2-526) and the acetal 2-527 in the presence of 10 mol% of Sc(OTf)3 gives in the first step the N, O-acetal 2-528, which then leads to the lactam 2-529 and further to the iminium ion 2-530 by elimination of methanol. The last step is a well-known Pictet-Spengler type cyclization to give the final product 2-531 in 91% yield. 

The yields of AEG were between 11 and 79%, at starting concentrations of 10 —10 4 M. AEG cyclizes to the lactam, monoketopiperazine, at neutral pH and around 373 K. The synthesis of the monomeric PNA units was carried out three years later (Nelson et al., 2000a, b). The synthesis of pyrimidine-A -acetic acid can be achieved if the reaction of cyanoacetaldehyde with high concentrations of urea mentioned above is modified slightly, with hydantoic acid replacing urea (Robertson and Miller, 1995). 

The insertion of carbon monoxide into readily available 2-bromo-3-aminopropene derivatives can be effected by catalytic quantities of palladium acetate and triphenylphosphine high CO pressures are not required (Scheme 16).38 The /Mactam products presumably arise by palladation,carbonylation, and cyclization as depicted in Scheme 17.38 An extension of this approach to the synthesis of biologically interesting condensed /(-lactams can be expected. 

Another chiral auxiliary for controlling the absolute stereochemistry in Mukaiyama aldol reactions of chiral silyl ketene acetals has been derived from TV-methyl ephedrine.18 This has been successfully applied to the enantioselec-tive synthesis of various natural products19 such as a-methyl-/ -hydroxy esters (ee 91-94%),18,20 a-methyl-/Miydroxy aldehydes (91% ee),21 a-hydrazino and a-amino acids (78-91% ee),22 a-methyl-d-oxoesters (72-75% ee),20b cis- and trans-l1-lactams (70-96% ee),23 and carbapenem antibiotics.24... 

Related catalytic enantioseiective processes Representative examples of other catalytic asymmetric Mannich additions are depicted in Scheme 6.31. In 1997, Tomioka demonstrated a Li-catalyzed synthesis of functionalized p-lactams that proceeds through a catalytic enantioseiective Mannich reaction (promoted by 103) [95], and a year later Lectka and his team published a series of reports concerning additions of silyl ketene acetals... 

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