Iminolactones

Early attempts to produce cephalosporin analogs by varying the 7-acylamino substituent were frustrated because, in contrast to previous experience with penicillins, a good method for producing the necessary 7-amino compound (33a) could not be found. This problem was finally solved when it was discovered that diazotization of the a-aminoadipyl residue produces an iminolactone (33b) which can be hydrolyzed to the free amine in good yield. Subsequently an improved procedure was developed which involves silylation of the carboxyl groups followed by reaction with phosphorus pentachloride to yield iminochloride (33c)... 

There are related procedures involving A -haloamides which lead to lactones via iminolactone intermediates ... 

The 4-pentenoyl group is easily removed from amides by I2 and can be used as a protecting group. The mechanism of cleavage involves iodocyclization and hydrolysis of the resulting iminolactone (see Section 4.2.1).239... 

Part B of Scheme 4.5 gives some examples of cyclizations induced by selenium electrophiles. Entries 9 to 13 are various selenyletherifications. All exhibit anti stereochemistry. Entries 14 and 15 are selenyllactonizations. Entries 17 and 18 involve amido groups as the internal nucleophile. Entry 17 is an 5-exo cyclization in which the amido oxygen is the more reactive nucleophilic site, leading to an iminolactone. Geometric factors favor N-cyclization in the latter case. 

A closely related procedure results in formation of y-lactones. Amides are converted to AHodoamidcs by reaction with iodine and /-butyl hypochlorite. Photolysis of the AHodoamides gives lactones via iminolactone intermediates.372... 

Photolysis of sugar oximes produces iminolactones.178,179 These are the compounds proposed to arise from irradiation of glycosyl azides however, the mechanism leading to formation of iminolactones from these two starting-materials (azides and oximes) must be quite different (see Scheme 30). Photolysis of azides is considered to generate a nitrene, whereas photolysis of oximes produces an iminolactone that... 

With catalysis by tetrakis(triphenylphosphane)palladium(0), the reaction of allenic amides 275 and aryl or vinyl iodides afforded Z-configured iminolactones 277... 

Internal DCR of Nitroaldol Libraries (Scheme 6.10) [5,6] iDCR was demonstrated by using a conceptual nitroaldol library including five benzaldehyde derivatives (24,36, and 47-49) and one nitroalkane (50, DCL-F, Scheme 6.11). The benzaldehydes, all with a unique substitution pattern, were selected in order to make analysis clear and simple. However, one of the henzaldehydes contained a cyano functionality in the 2-position (49), deliberately making it a candidate for subsequent tandem cyclization following nitroalcohol formation. 5-exo-dig type cyclizations of hydrox-ynitriles to the corresponding iminolactones are expected [40,41], albeit unexplored [42 5], intramolecular transformations, which in this case could lead to possible kinetic resolution of the library. 

To initiate the equilibrium, triethylamine was added and the reaction followed frequently by H-NMR. Under these conditions, equilibrium was reached within 3 hours (Fig. 6.15). Following this, the full hbrary (DCL-F) including aldehyde (49) was constructed. This library initially behaved similarly to DCL-G, with several nitroaldoladducts forming competitively. A total of 20 individual (3-nitroalcohol adducts is possible including enantiomers and diastereoisomers. However, within 1 hour, a clear amplification of a single diastereomeric pair, supposedly iminolactone (56), became clearly visible. The amphfication effect then gradually continued until all... 

An interesting observation was made upon isolation and characterization of the amplified product. NMR spectroscopic data together with supporting X-ray diffraction analysis clearly proved the compound not to he iminolactone (56), but rather lactam (57). Further mechanistic studies are yet to he carried out for the proposed rearrangement, hut a few related systems are reported [46 8]. 

Detailed time-dependent NMR studies were also performed in order to evaluate the kinetic profile of the tandem reaction (Fig. 6.17). Experimental data was coherent with a reversibly-irreversihly-coupled model, suggesting the proposed rearrangement step to he faster compared to the iminolactone cycfizafion. The studies also revealed the forward nitroaldol formation to he of comparable rate to tandem cycfizafion, while the reverse nitroaldol reaction was slower and thereby rate determining for the overall DCR process. 

Angelin, M. Vongvilai, R Fischer, A. Ramstrom, O. Tandem driven dynamic combinatorial resolution via Henry-iminolactone rearrangement. Chem. Commun. 2008, 6, 768-770. 

The adduct of benzylamine to the chloro ester 1-fBu (89b-fBu) in a three-step sequence yielded the -lactam 107 and the isomeric iminolactone 108 in approximately equal amounts (Scheme 36) [26]. The mechanism for the formation of 108 remains unknown presumably it was formed from 107 via a 1,3-shift, in fact 107 and 108 are stable in pure form, but would be equilibrating under the reaction conditions. 

Scheme 36. Preparation of )8-lactam 107 and isomeric iminolactone 108 from the )8-amino-a-chloroester 89b-fBu [26]...

Nair V, Vinod AU, Abhilash N et al (2003) Multicomponent reactions involving zwitterionic intermediates for the construction of heterocyclic systems one pot synthesis of aminofurans and iminolactones. Tetrahedron 59(51) 10279-10286... 

Benzylic deprotonation occurs under normal lithiation conditions when both ortho-positions are occupied. Interestingly, Thomas and co-workers were able to deprotonate a benzylic proton in the presence of an ortho proton (Scheme 8.137). Thus, metalation of 2-(2-methylphenyl)oxazoline 424 produced a benzylic lithium species that reacted with a Cbz-protected leucinal 425 to give a modest yield of the iminolactone diastereomers 426 and 427 together with the expected alcohols 428 and 429. The mixture of 426—429 was efficiently hydrolyzed to give the lactones 430 and 431. 

Transformation of both the ester and nitrile derivatives 726 or 727 into pyrano[2,3-t7 pyridazines 728 or 729, respectively, by treatment with dilute HCl at room temperature involved nucleophilic displacement of the morpholine group by the hydroxyl group with an acidic hydrolysis followed by intramolecular iminolactonization and then hydrolysis of the formed imino group to a carbonyl group. Compounds 726 and 727 were prepared by Vilsmeier-Haack formylation of 2-methyl-5-morpholino-3(2/7)-pyridazinone 724 followed by condensation of the resulting product 725 with either ethyl a-cyanoacetate or malononitrile in EtOH (Scheme 34) <1994H(37)171>. 

The key reaction, based on a method for removing glutamate residues in peptides, involves the conversion of the sole primary amine in the molecule to a diazo function. The most expeditious method consists of reacting (18-1) with nitrosyl chloride. The resulting diazo function in the product (18-2) can be displaced formally by oxygen from the enol form of the amide at the 7 position to form the iminolactone (18-3) the reaction may involve a spontaneous loss of nitrogen followed by capture of the resulting carbocation. Hydrolysis of the imine function in the product the leads to one of the key intermediates in this series, 7-ACA (18-4) [22]. 

Cyclization to yield fused ring y-lactones has also been effected using A V-dialkylamide derivatives as the nucleophile, as shown in equation (8).29 39-40 Isolation of the fused ring iminolactone from cyclization of an yV-monoalkylamide derivative with phenylselenenyl chloride has been repotted also.41... 

Chain-extension reactions constitute a more widely used approach. Thus, the cyanohydrin synthesis followed by base-catalyzed cyclization and /1-elimination to iminolactones, which then undergo stepwise hydrolysis, affords 3-deoxy-2-glyculosonic acids.313 The overall yield of this reaction is low. Paerels314 used this method to prepare the first crystalline members of this group, namely 3-deoxy-D-m //iro-hex-2-ulosopyranosonic acid (2-keto-3-deoxy-D-gluconic acid, KDG, 119), and the L isomer, starting from D-ribose and L-arabinose, respectively. The synthesis of 119 is illustrated in Scheme 10. 

Certain exceptions to this general scheme have been noted in which the normal hydrogenation of the nitrile group has not taken place. In these cases, a hydrolytic reaction has occurred, with the formation of an aldonic acid instead of the expected aldose.12 The anomalous reaction occurs when the nitrile exists in the (isomeric) iminolactone form for example, compound I is hydrolyzed directly, before hydrogenation can take place. This isomerism of the aldononitriles was established by Papadakis and Cohen,16 and the cyclic structure I was postulated by Wolfrom and coworkers.108... 

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