Five-membered lactam

M-Acyliminium cyclizations of optically active mono- and di-oxygenated hydroxylactam derivatives have been used in the synthesis of a number of natural products. In case of a five-membered lactam the oxygen function adjacent to the iminium carbon directs attack of the internal nucleophile from the least hindered side, opposite to the substituent. In the examples given the size of the newly formed ring is determined by the electronic bias of the alkene substituent. 

As a final example in this section, the mechanistically interesting transformation of a, 3-unsaturated aldehydes containing a chloro or bromo atom in the 3-position into five-membered lactams or lactones is mentioned. In this transformation, which was developed by Riick-Braun and coworkers, an intermediate iron compound is formed by reaction with [C5H5(CO)2Fe]Na, which yields the products either by adding a primary amine and TiCl4 or a metalorganic alkane as RMgX or RLi [483],... 

Cyclization of N-allylic a-chloro-a-thioacetamides, catalyzed by Ru complexes, gives rise to five-membered lactams (equation 167). This reaction has been used as a key step in the synthesis of several natural products597. Other similar Ru-catalyzed cyclizations have been used to prepare 2-pyrrolidinones598,599. This methodology is preferable over the equivalent BusSnH-mediated radical cyclization600,601 when a halogen atom is required in the target molecule. 

The work reported by Eaton and coworkers can be summarized as reactions where an allene system in conjugation with a further unsaturated functionality reacts with carbon monoxide in the presence of an iron-carbonyl complex such as Fe(CO)5 under photochemical and thermal conditions when Fe2(CO)9 is used. When diallenes are used (X=R2C=C, Scheme 9.24), five-membered carbocyclic products are obtained [51, 52], whereas when allenyl ketones (X = O) are applied, five-membered lactones are generated [53, 54]. The use of allenylimines (X = NR) leads to five-membered lactams under these conditions [55]. 

Erythrina alkaloids, possessing curare-like activity, are a large class of natural products found in Erythrina plants (Leguminosae). In a study towards construction of the erythrina skeleton, disfavored 5-endo-trig cyclizations were achieved by Ikeda et al. by BusSnH-mediated radical cyclization of an //-vinylic a-chloroacetamide to give five-membered lactams... 

The cyclocarbonylation of a,/ -unsaturated imines 54 also gave five-membered lactams 55 or 56 with or without 57 depending on the substitution patterns of the starting materials (Eq. 26) [40]. Such a useful [4+1] cycloaddition was applied to a cyclic imine 58 conjugated with a cyclohexenyl group to afford an interesting aza-tricycle 59 in 65% yield (Eq. 27). In the presence of an alkene such as ethylene, norbornene, and vinyltrimethylsilane, a similar cyclocarbonylation of a,/l-unsaturated imines 60 gave rise to a-alkylated /5,y-unsaturated lactam 61 in various yields (Eq. 28) [41,42]. Several plausible mechanisms are proposed for the formation of 61, but the elucidation of the entire mechanism calls for further work. 

The recent synthesis of lycorine (8) from the lactam (5) (cf. Vol. 10, p. 136) has now been modified by conversion of the six-membered lactam (5) into the five-membered lactam (6).4 Functionalization of ring C by the epoxidation-diphenyl selenide procedure, as in the earlier synthesis, gave the lactam (7), which was reduced to lycorine (Scheme 1). 

Formation of Lactams Five-membered lactams (7-lactams) and six-membered lactams (S-lactams) often form upon heating or adding a dehydrating agent to the appropriate 7-amino acids and S-amino acids. Lactams containing smaller or larger rings do not form readily under these conditions. 

The vast majority of indole alkaloids contain a tryptamine unit in which Nb is linked to the j9-position of the indole nucleus by an ethylene chain. On biogenetic grounds and also from the mass spectral similarity with aspidospermine (II), it is reasonable to expect this feature in the aspidofractinine-type alkaloids. Furthermore, in kopsine lactam A (CLXXV), in which C-ll is substituted by the C-3 bridge and C-10 has been oxidized (five-membered lactam), the residual hydrogen atom on C-ll shows as a singlet (2.82 S) in the NMR-spectrum and C-12 is therefore quaternary. 

Direct oxidation of pleiocarpine (CXLV-A) with permanganate gave a mixture of two Nb-lactams, the five-membered lactam A (CXLV-D, v, 1712 or 1683 cm-1) and the six-membered lactam B (CXLV-E, v, 1672 cm-1) whose UV-spectra were unaltered and which could be reduced back to a mixture of kopsinyl alcohol (CXLII-F) and its Ar-methyl derivative (CXLVI-F), thus demonstrating that no skeletal change had taken place. The formation of these neutral lactams has been cited (Section III, B, 3, 4) as evidence that Ab lies at the junction of a five-and a six-membered ring (rings E and D, respectively) (95). 

The amides kopsinilam (CXLII-D) and pleiocarpinilam (CXLVI-D) occur together with the more strongly basic pleiocarpine, pleiocarpinine, and kopsinine (Table I). Their weak basicity derives from the dihydroindole nitrogen which, as is shown by the UV-spectra and ceric color reaction (N—CH3, red NH, orange), is not acylated. The IR-spectra (v, C02Me, 1736-1740 cm-1 v, CO—Nb, 1684—1696 cm-1) suggest the presence of an ester function as well as a five-membered lactam. The nonreactivity of pleiocarpinilam toward methyl iodide confirmed that this involved Nb (note that steric hindrance prevents quaternization of Na). 

Both the aforementioned NMR-singlet exhibited by CXCIII and the existence of the five-membered lactam (CXCVIII) support the earlier-cited mass spectral evidence that aspidoalbine has an aspidospermine-type skeleton. Further confirmation of this was obtained by comparison... 

Dimethyl-3-phenyl-4-oxothieno[2,3-d]pyrimidine-2-thione (319) reacts with ethyl a-chlorophenylacetate in the presence of anhydrous potassium carbonate in boiling dimethylformamide (DMF)-acteone for 12 hr to give 6,7-dimethyl-2,9-diphenyl-9a-ethoxy-9-oxothiazolo[3,2-fl]thieno [2,3-d]pyrimidin-3(2//)-one (321) in 90% yield [81IJC(B)538] (Scheme 75). The absorption at 1745 cm (five-membered lactam C=0) in addition to that at 1690 cm (six-membered C=0) in the product supports the cyclic structure 321. The formation of 321 must have been through the initially formed unstable mesoionic compound 320, which adds 1 mol of ethanol, liberated during reaction, to afford 321. 

Amino-4-deoxy-2,3-0-isopropylidene-D-erythronic acid (155), obtainable from the lactone derivative 153 by treatment with sodium azide followed by hydrogenation of the azido acid (154), forms the lactam (156), but only on sublimation at 150°, because the elements of water must be removed thermally. Once formed, the sterically favored, five-membered lactam (156) is stable toward hydrolysis by acid, in contrast to the six-membered D-ribonolactam (151), and the isopropylidene group can be removed with acid, to give free 4-amino-4-deoxy-D-erythronolactam. 

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