Spiro-P- lactams

Sebti S, Foucaud A (1984) Reaction des acyloxy-2 chloro-3 chloromethyl-2 propanamides avec I hydroxyde de potassium ou le fluorure de cesium en milieu heterogene synthese de spiro P-lactames. Tetrahedron 40 3223-3228... 

Scheme 21 Use of Diels-Alder reaction in synthesis of spiro-P-lactams...

Scheme 26 Catalytic enantio- and diastereoselective synthesis of spiro-P-lactam (+)-SCH 58053...

Scheme 28 Preparation of spiro-P-lactams using regiospecific nitrone cycloaddition...

Scheme 29 Synthesis of optically active spiro-P-lactams using a-alkylidene-P-lactams...

Scheme 31 Preparation of A -aryl-suhstituted spiro-P-lactams via Studinger cycloaddition...

Scheme 37 Diastereoselective preparation of spiro-P-lactams using Mukaiyama s reagent...

Barbas et al. [113] have published the asymmetric synthesis of spiro-p-lactams 171 (Scheme 39) using proline-catalyzed Mannich reaction with branched aldehyde donors. The Mannich reactions of a,a-disubstituted aldehydes 168 with... 

Scheme 40 Efficient synthesis of indolenine spiro-P-lactams in Chartelline...

Scheme 41 Synthesis of spiro-P-lactams via cyclization of lithiated pyridine and quinoline carboxamides...

The authors have demonstrated for the first time the use of a,a-disubstituted aldehydes in the Mannich reaction to generate all-carbon quaternary stereocenters. The enantioselective p-formyl a-aminoacid derivatives 170 were further transformed to spiro- p-lactams 171 using oxidation followed by basic hydrolysis and acidification. 

Isobe et al. [114] have revealed the novel synthesis of indolenine spiro-p-lactams 173 (Scheme 40) in Chartelline, which belongs to the family of marine natural products. The starting precursors 172 were submitted to cyclization by employing a variety of bases such as EtMgBr, n-BuLi, t-BuOK, LDA, KHMDS, NaHMDS, and LiHMDS in THF at different reaction temperatures. Out of all these bases, LiHMDS at -78°C was found to be the best which provided the exclusive formation of spiro-p-lactams 173 without /V-methylamide 174 as a side product. 

Scheme 42 Preparation of spiro-P-lactams, synthons for proteasome inhibitors...

Corey et al. [116] have published the synthesis of spiro-p-lactam 180 (Scheme 42), which is a synthetic intermediate for other p-lactams, which are able to inhibit proteasome. Proteasome inhibition helps in the therapy of cancer and has been evaluated for multiple myeloma [104]. 

The alcohol 177 was converted to starting substrates oxazolidinone 178 by acylation followed by reduction of the azide function along with cyclization. Oxazolidinone 178 was protected with f-butylpyrocarbonate-4-(dimethylamino) pyridine (DMAP) and triethylamine, which was further subjected to reductive cleavage of the benzyl ester unit to afford carboxylic acid 179. The treatment of 179 with solution of l-chloro-/V./V,2-trimethyl-1-propenv I airline resulted in the easy formation of the corresponding acid chloride which on reaction with imine in the presence of triethylamine provided the stereoselective formation of spiro-p-lactam 180. 

Meijere et al. [117] group have investigated the direct synthesis of 3-spiro-cyclopropanated p-lactams 184 (Scheme 43) using novel three-component cascade reaction. Earlier, Alberto Brandi and coworkers [118-120] have applied nitrones 181 and bicyclopropylidene 182 to obtain cylcoadducts 183, which were further fragmented under acidic conditions to afford spiro-p-lactams 184. However, this reaction required longer reaction time for the formation of cycloadducts 183. 

Taking this into account, Meijere and Brandi [117] together explored the effect of microwave heating during the 1,3-dipolar cycloaddition of nitrones, generated in situ and bicyclopropylidene 182 for the synthesis of these spiro-p-lactams 184 (Scheme 43). The reaction of Ai-substituted hydroxylamine hydrochlorides 185,... 

Scheme 44 Chirospecific synthesis of spiro-P-lactams serving as efficient P-tum nucleators...

Recently, Bittermann and Gmeiner [49] have provided a novel protocol for the synthesis of enantiomerically pure spiro-p-lactams 190 and characterized them as efficient p-tum nucleators (Scheme 44). 

Scheme 45 Novel synthetic approach to spiro-P-lactams via halogen-mediated intrasulfenyl cyclization...

In connection with these studies, recently, we have reported from our laboratory a novel, operationally simple and efficient approach for the synthesis of spiro-p-lactams 194, 196-198 (Schemes 45 and 46) [121], In our earlier publications, we have demonstrated well the synthetic potential of cationic p-lactam equivalents... 

Scheme 47 Synthesis of spiro-P-lactams using 3-allyl-3-benzylthio-fS-lactams...

Scheme 50 Diastereoselective synthesis of spiro-P-lactams using unsymmetrical bicyclic ketene...

Jarrahpour et al. [135] have described the synthesis of novel mono- and bis-spiro-[S-lactams 231 and 233, respectively, from benzylisatin 229 (Scheme 52). The starting substrate, benzylisatin 229 was prepared by reaction of isatin 228 with benzyl bromide and calcium chloride in DMF. The benzylisatin substituted imines 230 and di-imines 232 were further subjected to Staudinger reaction with ketenes derived from methoxy, phenoxy, and phthaloglycyl chlorides to afford novel mono- and bis-spiro-p-lactams 231 and 233, respectively. The configuration of benzylisatin 229 and monocyclic spiro-p-lactams 231 was established by X-ray crystallographic studies. These spiro-p-lactams will be studied as precursors of modified p-amino acids, (3-peptides and monobactam analogues. 

An efficient synthesis of tetrahydrofuran-derived spiro-p-lactams has been reported to be performed by a Staudinger-type reaction of either 2- or 3-tetra-hydrofuroyl chloride with imines [66]. The reaction was carried out by adding Et3N... 

Scheme 27 Synthesis of 5,4-spiro-P-lactams by Staudinger reaction...

Scheme 33 Synthesis of spiro-P-lactams by [2+2] cycloaddition reaction...

Spiro-p-lactams have been synthesized via [2+2] cycloaddition of cyclic ketenes with imines [100]. Opposite trans or cis diastereoselectivity was obtained using different imines with electron-donating or electron-withdrawing (R1) substituents at the N-atom, (Scheme 33). 

The cyclic ketenes were generated from /V-acy 1-1,3-thiazolidine-2-carboxylic acids by means of Mukaiyama s reagent. The same reaction generated enantio-merically pure 1,3-thiazolidine-derived spiro-p-lactams, using optically active /V-A rt-butoxycarbonyl-1,3-thiazolidine-2-carboxylic acid derivatives as precursors of the asymmetrical chiral cyclic ketenes (7< r/-butoxy carbonyl Boc) [101]. 

Quaternary p-formyl a-amino acid derivatives have been converted into spiro p-lactams in excellent yield, using oxidation followed by simple base and acid treatment (Scheme 107), [234],... 

Using spiro-p-lactams as substrates, Alonso [76] has applied this trick for the synthesis of a,a-cyclic disubstituted p-amino esters 29, Scheme 12, which might be useful units for the design of p-peptides with new folding patterns. 

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