Lactam acetals elimination

A study of ketene A, O-acetals has shown that such compounds derived from lactam acetals may be used in the preparation of larger heterocyclic systems via reaction with a 1,3-dipolar species, the initial cycloadducts stabilizing their structures by aromatization. Pyrrolo[2,3-i/]-l,2,3-triazole derivatives, however, do not undergo such elimination reactions and stable cycloadducts may be obtained. Thus, the lactam acetals (133) give the ketene A,0-acetals (134), which on reaction with p-nitrophenyl azide yield substituted pyrrolo[2,3-d]-l,2,3-triazole derivatives (135) <86CB359l>. 

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 cyclohexene 121, which was readily accessible from the Diels-Alder reaction of methyl hexa-3,5-dienoate and 3,4-methylenedioxy-(3-nitrostyrene (108), served as the starting point for another formal total synthesis of ( )-lycorine (1) (Scheme 11) (113). In the event dissolving metal reduction of 121 with zinc followed by reduction of the intermediate cyclic hydroxamic acid with lithium diethoxyaluminum hydride provided the secondary amine 122. Transformation of 122 to the tetracyclic lactam 123 was achieved by sequential treatment with ethyl chloroformate and Bischler-Napieralski cyclization of the resulting carbamate with phosphorus oxychloride. Since attempts to effect cleanly the direct allylic oxidation of 123 to provide an intermediate suitable for subsequent elaboration to ( )-lycorine (1) were unsuccessful, a stepwise protocol was devised. Namely, addition of phenylselenyl bromide to 123 in acetic acid followed by hydrolysis of the intermediate acetates gave a mixture of two hydroxy se-lenides. Oxidative elimination of phenylselenous acid from the minor product afforded the allylic alcohol 124, whereas the major hydroxy selenide was resistant to oxidation and elimination. When 124 was treated with a small amount of acetic anhydride and sulfuric acid in acetic acid, the main product was the rearranged acetate 67, which had been previously converted to ( )-lycorine (108). 

Similarly, urea TV, 0-acetal 64 undergoes condensation reaction with weak carbon acids to afford acyclic 1,1-enediamines with the elimination of alcohol and amine42,95. A number of active methyl compounds such as an aliphatic ketone, acetophenone, imino ester and thioacetoamide has been successfully converted to 1,1-enediamines. Lactones, lactams and thiolactams condense with 64 to give enediamines 65 in moderate yields (equation 24). Very weakly activated methyl groups are also reactive towards urea A, 0-acetal 64, and 1,1-enediamines 66-71 are prepared from the corresponding reactants42,95. 

The rhodium(II) acetate decomposition of ketodiazoamides 296 in the presence dimethyl acetylenedicarboxylate generates intermediate bicyclic lactams 297, which eliminate methyl (or phenyl) isocyanate with the formation of furan derivatives (82-86%) 298 (89TL4077 91JOC820). Using the same route, substituted furans 299 have been obtained by the rhodium-... 

The spectrum of the free acid showed no molecular ion. Ions of highest mass, m/e 30 + and 292, probably arose from the free acid by the hydrolytic elimination of acetic acid and sulfur, and acetic acid and carbon dioxide respectively. An intense peak at m/e + + (CO ) supported this conclusion. Peaks at m/e 216 and 215, expected from the fission across the p-lactam ring, were not observed. Three peaks which may be assigned to the side chain and part of the p-lactam ring were m/e 97 (CsD -CH +), m/e 12 + ( -CH-C=0+), and m/e l8l ( -CH -C0-NH-CH=G=0+). Occolowitz concluded that the spectrum arose by ionization of hydrolysis products of the free acid. 

Homochiral unsaturated seven-membered lactams were prepared by 2,4 rearrangement of vinyl-substituted ketene (V,0-acetals, which are generated in situ by selenoxide elimination of the (V.O-acetal precursors338-339. 

Aldol reaction of the enolate of lactam 119 and 4-(3-methyl-but-2-enyloxy)-benzaldehyde [70] provided a mixture of two separable alcohols 127. Subsequent elimination of the mesylate of both aldol adducts afforded 128. Finally, reduction of the amide using A1H3 [71] and acid hydrolysis of the acetal provides racemic TAN1251A. 

Oxyberberine (XVIII) is the first product of the oxidation of berberine. It may be reduced to tetrahydroberberiiie at a lead cathode in alcoholic sulfuric acid (215). Its synthesis is therefore a synthesis of berberine. The general procedure for the synthesis of this type of compound is described in connection with the synthesis of cryptopine, and oxyberberine itself was prepared by this procedure. Another synthesis of oxyberberine was achieved by Perkin, Ray, and Robinson (216). The 8-piperonyl-ethylimide of meconinecarboxylic acid (XX) was heated with phosphoryl chloride to yield an uncharacterized isoquinoline derivative, presumably XXI, which when reduced with zinc in acetic acid suffered reduction of the doubl bond, opening of the lactone ring, lactam formation, and dehydration to yield oxyberberine. This ready elimination of water was later observed in ophiocarpine (6). 

Muxfeldt reported one of the first apphcations of the reaction in the course of a total synthesis of the alkaloid crinine (Scheme 7.24) [48]. In its key step, cydohex-enol 62 was heated with dimethylacetamide dimethyl acetal (4) to yield amide 63 in 45% yield together with substantial amounts of an elimination product (not shown). Intramolecular transamidation under forcing conditions yielded lactam 64, which was subsequentiy converted into the natural product... 

The first synthesis 104, 105) of racemic thienamycin by the Merck group made use of the azetidinone (113) derived from acetoxybutadiene and chlorosulphonyl isocyanate (CSI). Reduction, hydrolysis and condensation with acetone gave the 1,3-tetrahydrooxazine (114). Introduction of the hydroxyethyl side chain by way of an aldol condensation produced predominantly the thermodynamically more stable tra s-P-lactam (115) as a mixture of R)- and (5)-isomers in the side chain. On removal of the acetone residue a proportion of the unwanted (5)-isomer crystallised from the mixture. The synthesis was continued with the mixture by way of the aldehyde (116) and the thio-acetal (117). Bromination, elimination and introduction of the iV(l) malonate residue gave (119) ready for an intramolecular alkylation reaction. 

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