Lactams methoxylation

Oxostephasunoline (4) was isolated from the roots of Stephania japonica(4). The UV spectrum of oxostephasunoline (4) showed an absorption maximum at 286 nm, and the IR spectrum depicted bands at 3550,3500, and 1670 cm, indicating the presence of a hydroxyl group and a y-lactam. The mass spectrum (Table VI) exhibited the most abundant ion peak at m/z 258, and the H-NMR spectrum (Table II) revealed the presence of three methoxyl and one N-methyl group. The downfield shift (53.06) of the JV-methyl resonance indicated that oxostephasunoline (4) was a y-lactam, which was further supported by the IR band at 1670 cm 1, significant features of the mass spectrum (Table VI), and the 13C-NMR spectrum (Table III). On exhaustive H-NMR analysis similar to the case of stephasunoline (17), the structure of oxostephasunoline (4) including the stereochemistry was practically proved (4). 

Much of the recent work on the use of anodic amide oxidation reactions has focused on the utility of these reactions for functionalizing amino acids and for synthesizing peptide mimetics [13]. For example, in work related to the cyclization strategy outlined in Scheme 3, the anodic amide oxidation reaction has been used to construct a pair of angiotensin-converting enzyme inhibitors [14]. The retrosynthetic analysis for this route is outlined in Scheme 4. In this work, the anodic oxidation reaction was used to functionalize either a proline or a pipercolic add derivative and then the resulting methoxylated amide used to construct the bicyclic core of the desired inhibitor. A similar approach has recently been utilized to construct 6,5-bicyclic lactam building blocks for... 

Quite important is also the a-methoxylation of A -carbomethoxylated a-amino acid esters and a-amino-p-lactams (Table 4, No. 53-55) a-Methoxylation was... 

A synthetic method of introducing a methoxy group into the alpha position of alpha-amino acid derivatives and a/p/ia-amino-fern-lactams has been exploited by employing an indirect electrooxidation process 23). For example, the electrolysis of the lactam 33a in a MeOH—NaCl—(Pt) system yields the methoxylated lactam 34a in 92% yield. The indirect methoxylation of fern-lactams proreeds successfully without cleavage of the azetidinone ring (Scheme 2-11). 

Debenzylation of Ar-benzyl-6e/a-lactams 41 has been achieved by electrooxidative methoxylation of 41 at the benzylic position followed by hydrolysis with p-toluene-sulfonic acid in acetone 27>. For example, the electrolysis of A-benzyl-3-methylene-6e/fl-lactam 41 (R = OMe) in an MeOH E NClC —fPt) system in an undivided cell forms iV-methoxybenzyl-3-methylene-6efa-lactam 42 (R = MeO) in 54% yield (Scheme 2-14). The debenzylation of 42 is carried out on treatment with p-toluene-sulfonic acid in aqueous acetone to give 3-methylene-6e/a-lactam 43 in 50% yield. 

The possible origins of highly conjugated lactam groups has been discussed above in connection with the biogenesis of dielsiquinone (134). Similar considerations may be applicable to dielsine (137), dielsinol (138), and 2,7(or 6)-dimethoxy-6(or 7)hydroxyonychine (166, 167). In the case of the latter compound, as with dielsiquinone, the methoxyl group at C-2 can be traced back to a hypothetical 4-methoxylated aporphinoid precursor. 

Tetrahydropalmatine and Sinactine. Irradiation of the enamide 133 afforded a mixture of two lactams 162 and 163 in 20 and 8% yields, respectively, as a result of cyclization to the roots of each one of two o-methoxyl... 

The anodic oxidation of A/ -alkyl- and A/ -benzyl-y3-lactams in methanol at Pt anodes in the presence of Et4NBp4 as an electrolyte leads to the methoxylation of both the endo-and exocyclic carbon in a-position to nitrogen. Usually the exocyclic carbon was more easily oxidized than the endocyclic carbon. With a tertiary exocyclic a-carbon, the formation of the endo-oxidation product was increased. A/"-Benzyl-)3-lactams were predominantly oxidized in the exocyclic a-position. In case of 7V-4-methoxybenzyl-)3-lactam exocyclic oxidation occurred with total regioselectivity [227,228]. 

A completely different route devised by Prelog and co-workers (14) not only afforded a new synthesis of the erythrinane skeleton but also achieved a method of introducing an oxygen function at C-3, the site of the aliphatic methoxyl in the alkaloids. The synthesis is outlined in Fig. 5. The dihydroisoquinolinium salt XXXIV was prepared by Bischler-Napieralski ring closure of the lactam XXXIII. Hydrolysis of the vinyl chloride of XXXIV gave the methyl ketone XXXV. When this salt was made alkaline, addition of the carbanion from the acidic methyl to the C=N double bond created the spiro link. Sodium borohydride reduction of XXXVI gave a mixture of epimeric alcohols. One of them had an IR-spectrum identical with that of a transformation product (XXXVII) of erysonine (If) and on resolution w ith tartaric acid its (— )-enantiomer proved to be identical with XXXVII. 

An attempt to correlate delcosine with lycoctonine proved to be a failure (63), but it did show that the C-6 position of delcosine is substituted with a methoxyl group, a fact previously unestablished and assumed only by analogy with lycoctonine. The initial reactions involved an epimerization at C-1 since lycoctonine has a j8-methoxyl at C-1. This was accomplished by first oxidizing A-desethyldelcosine (XCIII) with Sarett s reagent, giving a mixture of the azomethine XCIV and the diketo lactam XCV. Ethylation of the azomethine (XCIV) was followed... 

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