Nitrones lactams

Beckmann rearrangement of nitrones Lactams from cyclic nitrones Ring expansion... 

Other approaches to (36) make use of (37, R = CH ) and reaction with a tributylstannyl allene (60) or 3-siloxypentadiene (61). A chemicoen2ymatic synthesis for both thienamycia (2) and 1 -methyl analogues starts from the chiral monoester (38), derived by enzymatic hydrolysis of the dimethyl ester, and proceeding by way of the P-lactam (39, R = H or CH ) (62,63). (3)-Methyl-3-hydroxy-2-methylpropanoate [80657-57-4] (40), C H qO, has also been used as starting material for (36) (64), whereas 1,3-dipolar cycloaddition of a chiral nitrone with a crotonate ester affords the oxa2ohdine (41) which again can be converted to a suitable P-lactam precursor (65). 

Reports on total synthesis of naniral products using nitrones papers are as follows marine alkaloid lepadiformine fRef 92 and fi-lactam antibiotics fRef 93, ... 

A somewhat unusual sequence to generate azepanones 80 involved the intramolecular addition of hydroxylamines to alkynes 76 to form cyclic nitrones 77. A vinyl magnesium bromide addition at low temperatures and a reduction with TiCls followed by N-Boc protection led to the azepane 78. Double bond bromination and subsequent RUO4 oxidation gave the lactam 79. Several further steps allowed the generation of the lactam structure 80 proposed for d,/-aca-cialactam, but the spectral data of the synthetic material differed from that of the natural product (Scheme 16)] [23 a, b]. 

The chemistry of a-haloketones, a-haloaldehydes and a-haloimines Nitrones, nitronates and nitroxides Crown ethers and analogs Cyclopropane derived reactive intermediates Synthesis of carboxylic acids, esters and their derivatives The silicon-heteroatom bond Syntheses of lactones and lactams The syntheses of sulphones, sulphoxides and cyclic sulphides... 

Spirocyclopropane isoxazolidines 75, obtained from alkylidenecyclopropane nitrones, underwent thermally induced selective rearrangement to pyrrolo[3,4-A]pyridinones 76 <00TA897>. The same adducts 75 in the presence of a protic acid afforded exclusively p-lactams 77 (57-60% yield) accompanied by ethylene extrusion <00JA8075>. 

Dimethyl-3-methylenepyrrolidine-2-thione, which reacts with nitrones regio- and stereoselectively at its exocyclic C=C bond to give only spirocy-cloadducts 116, behaves more complicatedly with nitrile oxides. The latter undergo 1,3-dipolar cycloaddition both to the exocyclic C=C and C=S double bonds with subsequent cycloreversion and formation of spiro-lactams 117 (281). 

To illustrate the synthetic use of photochemical rearrangement, the photolysis of nitrones (249) leading to the formation of bicyclic lactams (250) is an example (Scheme 2.88) (459). 

An alternative method in the synthesis of alkaloids, photochemical rearrangement of endocyclic nitrones into bicyclic lactams has drawn special attention. Analyses of photochemical rearrangement and application of modified conditions of the Barton reaction testify to the comparability of results obtained in these approaches (Scheme 2.89) (460). 

Beckman rearrangement of nitrone (262) into amide (263) occurs in the reaction with lithium cyanide. However, this reaction gives lactam (264) instead of the expected 2-cyanopyrrolidine 1-oxide (265) (Scheme 2.96) (473). 

Diastereoselective intramolecular 1,3-dipolar cycloadditions of alkylidene-cyclopropyl nitrones provide spirocyclopropylisoxazolidines. These compounds have been shown to undergo either thermally induced ring expansion to octahydro[l]pyrindin-4-ones or to acid induced ring contraction into fS-lactams with concomitant loss of ethylene (Scheme 2.218) (710-716). Use of chiral auxiliaries, that is (L)-2-acetoxylactate can lead to enantiomerically enriched heterocycles (715). 

A general synthetic route to p-lactam-fused enediynes (Scheme 2.321) has been successfully developed (848). When nitrone (771) was subjected to Kin-ugasa reaction conditions, two p-lactam containing products were obtained the elimination product (772) and the trans fused compound (773). 

Recent research deals with stereoselective 1,3-dipolar cycloadditions of nitrones for the syntheses of alkaloids and aza heterocycles asymmetric synthesis of biologically active compounds such as glycosidase inhibitors, sugar mimetics, /3-lactams, and amino acids synthesis of peptido-mimetics and peptides chemistry of spirocyclopropane heterocycles synthesis of organic materials for molecular recognition and photochemical applications. 

Dideoxyhex-2-enono-1,5-lactone derivatives (penten-5-olides) have been prepared (255-258) and employed as starting compounds in synthesis. Thus, Michael addition of benzylhydroxylamine to racemic 6-0-acetyl-2,3,4-trideoxy-D,L-g/ycerohex-2-enono-1,5-lactone (267) took place ster-eoselectively to give the unstable benzyloxyamino-2-pyrone 268, which was readily converted into the /Mactam derivative 269, a precursor of thienamy-cin (259). / -Lactams were also obtained (260) by 1,3-dipolar cycloaddition of nitrone 270 to the unsaturated 1,5-lactone 267, followed by hydrogenoly-sis and subsequent cyclization to the /Mactam 271, having a polyol side-chain at the C-3 position. 

Photolysis of nitro-steroids 225 yields the aci-nitronate at 254 nm131. This in turn gives various products, among them are ketone 226 and hydroxamic acid 227 (equation 105) which could be formed from the intermediate anions of the Af-hydroxyoxaziridines, with a possible participation of gem-hydroxynitroso transient (or its anion see Scheme 10). For comparison, IV-butyl spiro-oxaziridine 228 in ethanol is photolysed at 254 nm (equation 106) to give 7V-butyl lactam 229 (50%) and the ketone 230 (25%). The former process is a well-known photoprocess of oxaziridine131. 

Over the last years, one of the most studied DCR has been the asymmetric version of the cycloaddition of nitrones with alkenes. This reaction leads to the construction of up to three contiguous asymmetric carbon centers (Scheme 4). The resulting five-membered isoxazolidine derivatives may be converted into amino alcohols, alkaloids, or p-lactams. Several chiral metal complexes have been used as catalysts for this process [13-15, 18-22]. However, the employment of iridium derivatives is very scarce. 

The transformation of endocyclic nitrone 56 (made from N,0-bis-protected hydroxylamine 55) to lactam 20 can be carried out by photochemical activation or by a two-step modification of Barton s protocol, that is, by trapping the nitrone oxygen followed by an alkali-promoted, semi-pinacol-like rearrangement (03JOC8065). 

A dipolar route of heterocyclization of a monocyclic enallenyl nitrone (from precursor 126 by base-catalyzed propargyl-allenyl isomerization) leads to lactam 127 (05EJO2715) that is an analog of astrocasine (8). 

The continued importance of 3-lactam ring systems in medicine has encouraged a number of research groups to investigate their synthesis via a nitrone cycloaddition protocol. Kametani et al. (60-62) reported the preparation of advanced intermediates of penems and carbapenems including (+)-thienamycin (29) and its enantiomer (Scheme 1.7). They prepared the chiral nitrone 30 from (—)-menthyl... 

Cycloaddition to endocyclic unsaturation has been used by many researchers for the preparation of isoxazoUdinyl adducts with y-lactams derived from pyrogluta-minol and is discussed later in this chapter as a synthesis of unusual amino acids (Scheme 1.20, Section 1.6) (79,80). A related a,p-unsaturated lactam has been prepared by a nitrone cycloaddition route in the total synthesis of the fungal metabolite leptosphaerin (81). A report of lactam synthesis from acyclic starting materials is given in the work of Chiacchio et al. (82) who prepared isoxazolidine (47) via an intramolecular nitrone cycloaddition reaction (Scheme 1.11). 

The acyclic precursor is an oc, 3-unsaturated amido aldehyde that was condensed with iV-methylhydroxylamine to generate the nitrone ( )-48, which then underwent a spontaneous cycloaddition with the alkene to afford the 5,5-ring system of the isoxazolidinyl lactam 47. The observed product arises via the ( )-nitrone transition state A [or the (Z)-nitrone equivalent] in which the position of the benzyl group ot to the nitrone effectively controls the two adjacent stereocenters while a third stereocenter is predicted from the alkene geometry. Both transition states maintain the benzyl auxiliary in an equatorial position and thus avoid the unfavorable 1,3-diaxial interaction with the nitrone methyl or oxygen found in transition state B. Semiempirical PM3 calculations confirm the extra stability, predicting exclusive formation of the observed product 47. Related cycloadducts from the intramolecular reaction of nitrones containing ester- rather than amide-tethered alkene functionality are also known (83-85). 

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