Lactam synthesis oxidative addition

Three other groups reported alternative methods for the synthesis of 3-alkenyl-substituted P-lactams. Durst [71] prepared these compounds via a Peterson olefination reaction. Thus, for example, treatment of 3-trimethylsilyl-azetidinone 116 with lithium diisopropyl amide followed by addition of pro-pionaldehyde gave a mixture of 117 and 118 in 66% yield. Tanaka [72] converted allylic stannanes 119 to bromides 120 which were smoothly cyclized to P-lactams 121 in good yield. Ley [73] treated 7i-allyltricarbonyliron complexes with benzylamine in the presence of Lewis acids to afford the corresponding lactam complexes. Oxidation with cerric ammonium nitrate served to liberate the desired P-lactams (Scheme 14). 

Scheme 18). Addition of Grignard reagents to the aldehyde gave a mixture of adducts with stereoselectivity varying from 4 1 to > 100 1. Completion of the P-lactam synthesis followed either of two routes. Oxidative cleavage of the polyol side chain provided hydroxy acid 149 while prior conversion of the alcohol to an azido group followed by oxidation afforded 150. Either substrate could be cyclized by known procedures. 

Regioselective Beckmann rearrangements were used as key steps in the synthesis of phosphonoalkyl azepinones (Scheme 36) [43b] and in a formal total synthesis of the protein kinase C inhibitor balanol (Scheme 37) the optically active azide 197 derived from cyclohexadiene mono-oxide was converted into ketone 198 in several steps. After preparation of the oxime tosylates 199 (2.3 1 mixture), a Lewis acid mediated regioselective Beckmann rearrangement gave the lactams 200 and 201 in 66% and 9% yield, respectively. Lactam 201 underwent a 3-e im-ination to give additional 200, which served as a key intermediate in a balanol precursor synthesis (Scheme 37) [43 cj. 

Highly efficient and stereoselective addition of tertiary amines to electron-deficient alkenes is used by Pete et al. for the synthesis of necine bases [26,27], The photoinduced electron transfer of tertiary amines like Af-methylpyrrolidine to aromatic ketone sensitizers yield regiospecifically only one of the possible radical species which then adds diastereospecifically to (5I )-5-menthyloxy-2-(5//)-furanone as an electron-poor alkene. For the synthesis of pyrrazolidine alkaloids in approximately 30% overall yield, the group uses a second PET step for the oxidative demethylation of the pyrrolidine. The resulting secondary amine react spontaneously to the lactam by intramolecular aminolysis of the lactone (Scheme 20) [26,27]. 

Mahboobi et al. described a novel synthesis of staurosporinone (293) (791). The intermolecular Michael addition of l-(indol-3-yl)-2-nitroethene (1472) to methyl indol-3-ylacetate (1313) provided with high diastereoselectivity methyl 2,3-bis(indol-3-yl)-4-nitrobutanoate (1473). Catalytic hydrogenation and lactamization afforded 2,3-bis(indol-3-yl)-y-butyrolactam (1474) in 87% yield. Oxidative cyclization of the ds-lactam 1474 with DDQ in the presence of catalytic amounts of p-TsOH led to staurosporinone (293) (791) (Scheme 5.249). 

Similarly, the mixed homodetic/heterodetic bicyclic structures containing a disulfide bridge are preferably produced as monocyclic compounds that are then typically oxidized in solution adopting standard procedures as described in Section 6.1.1 (Scheme 23, path Bl). If even disulfide formation is performed on resin by the procedures reported in Section 6.1.2, an additional level of selective protection is required for the cysteine thiol functions. The synthetic paths Bl and B2 are also applicable for the synthesis of type II and III bicyclic peptides, independent of whether only lactam bridges are produced or mixtures of lactam/ disulfide bridges. 

According to Shaipless, two cycles operate in the catalytic reaction (Scheme 39) (88c, 9CF). The first cycle is highly enantioselective, whereas the second is poorly enantioselective. Hydrolysis of the key intermediate formed from B and oxidant is not very fast. The second osmylation of olefinic substrate occurs as the intermediate enters the undesired catalytic cycle. Therefore, slow addition of olefinic substrates to minimize the second cycle is essential for obtaining high ee. Use of potassium hexacyanoferrate(III) as oxidant in a 1 1 tert-butyl alcohol-water two-layer system can suppress the second cycle and lead to high enantioselectivity (91). This procedure allows the convenient synthesis of 3-lactams from 2-octenoate. 

One of the earliest attempts to prepare analogues of FA as potential inhibitors involved the synthesis of 2-amino-4,7-dihydroxypteridine-6-carboxylyl-p-ami-nobenzoic acid (612) (in which the change from the structure of FA itself is exchange of the methylene bridge for a carbonyl group, and oxidation of position 7 to a lactam). This compound, which was a surprisingly effective inhibitor, was prepared from isoxanthopterin carboxylic acid (611) by in situ conversion to its acid chloride with a mixture of phosphorus oxychloride and phosphorus pentachloride, followed by addition of p-aminobenzoylglutamic acid (Scheme 3.132) [115]. 

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). 

Scheme 2 shows Rapoport s synthesis [15]. The cinnamic acid derivative 3 prepared from m-methoxy benzaldehyde [20] was ethylated by diethyl sulfate to give ethyl cinnamate derivative 4, followed by Michael addition with ethyl cyanoacetate to afford compound 5. Compound 5 was converted to lactam 6 by the reduction of the cyano group and subsequent cyclization. Selective reduction of the lactam moiety of 6 was achieved by treatment with trimethy-loxonium fluorob orate followed by sodium borohydride reduction. Amine 8 was obtained by the reductive methylation of amine 7. Amine 8 was converted to compound 9 by methylene lactam rearrangement [21], followed by selenium dioxide oxidation to provide compound 10. Allylic rearrangement of compound 10 and subsequent hydrolysis gave compound 12. The construction of the decahydroisoquinoline structure began with compound 12,... 

The synthesis of various heterocyclic systems via 1,3-dipolar cycloaddition reactions of 1,3-oxazolium-5-oxides (32) with different dipolarophiles was reported. The cycloaddition reactions of mesoionic 5H,7H-thiazolo[3,4-c]oxazolium-l-oxides (32), which were prepared from in situ N-acyl-(/J)-thiazolidine-4-carboxyIic acids and N,N -dicyclohexylcarbodiimide, with imines, such as N-(phenylmethylene)aniline and N-(phenylmethylene)benzenesulfonamide, gave 7-thia-2,5-diazaspiro[3,4]octan-l-one derivatives (33) and lH,3H-imidazo[ 1,5-cJthiazole derivative (35). The nature of substituents on imines and on mesoionic compounds influenced the reaction. A spirocyclic p-lactam (33) may be derived from a two-step addition reaction. Alternatively, an imidazothiazole (35) may be obtained from a typical 1,3-dipolar cycloaddition via a tricyclic adduct (34) which loses carbon dioxide and benzenesulfinic acid. [95T9385]... 

In the studies of the synthesis of the ansamycin antibiotic rifamycin S (13S), Corey and Clark [76] found numerous attempts to effect the lactam closure of the linear precursor 132 to 134 uniformly unsuccessful under a variety of experimental conditions, e.g. via activated ester with imidazole and mixed benzoic anhydride. The crux of the problem was associated with the quinone system which so deactivates the amino group to prevent its attachment to mildly activated carboxylic derivatives. Cyclization was achieved after conversion of the quinone system to the hydroquinone system. Thus, as shown in Scheme 45, treatment of 132 with 10 equiv of isobutyl chloroformate and 1 eqtuv of triethylamine at 23 °C produced the corresponding mixed carbonic anhydride in 95% yield. The quinone C=C bond was reduced by hydrogenation with Lindlar catalyst at low temperature. A cold solution of the hydroquinone was added over 2 h to THF at 50 °C and stirred for an additional 12 h at the same temperature. Oxidation with aqueous potassium ferricyanide afforded the cyclic product 134 in 80% yield. Kishi and coworkers [73] gained a similar result by using mixed ethyl carbonic anhydride. 

D. Zhu et at., Heterocycles, 1982, T7> 345. The structure (125, Ri=R2=oMe) for pontevedrine has been confirmed by synthesis of the alkaloid by photo-catalysed cyclisation and oxidation of the lactam (128) in alkaline solution, followed by y-methy-lation (Castedo et al.. Tetrahedron Letters, 1978, 2179) and norcepharadione-B has been synthesised by a Diels-Alder addition of benzyne to the masked diene 1,6,7-trimethoxy-l-methyl-tetrahydroisoquinol ine-3,4-dione (Castedo et al.. Tetrahedron Letters, 1982, 23, 451). 

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