Chiral NHCs lactams

Scheme 12.43 Asymmetric 3-lactam synthesis using chiral NHCs...

You and co-workers have demonstrated a further application of NHCs in the kinetic resolution of formyl p-lactams ( )-265 [103]. Upon treatment with a chiral NHC, the Breslow-type intermediate is formed, followed by ring-opening of the P-lactam moiety, with subsequent trapping of the acylazolium intermediate leading to the enantio-enriched succinimide product 266 and resolved formyl P-lactam (which is reduced to its alcohol 267). The authors note that when R" = H, the products undergo racemisation readily, and this is a possible explanation for the lower levels of enantioselectivity observed in the succinimide products 266 (Scheme 12.60). 

Scheme 61, yielded thiazole 200 as the major product, along with minor amounts of carbinol 201 [152]. On the other hand, treatment of the imine formed from 199 and p-methoxyphenylamine with catalytic tetrabutylammonium cyanide, produced suc-cinimide derivative 202. In both cases, the process is initiated by nucleophilic attack to the carbaldehyde C=0 (or azomethine s C=N) group, which is followed up by an anionic rearrangement. A variation of the above process using as catalysts /V-heterocyclic carbenes (NHC) derived from base treatment of azolium, imidazo-lium, or triazolium salts, has also been developed to access gem-disubstituted succinimides [153, 154]. Unfortunately, an attempt of kinetic resolution of racemic 4-formyl (3-lactams by using chiral NHC resulted in moderate selectivities only [154]. 

In 2007, You and co-workers found the readily available NHC effieiently catalyzes the ring expansion of 4-formyl-o-lactams. This organoeatalytie process affords succinimide derivatives smoothly, featuring ready availability of the catalyst, low catalyst loading, and mild reaction conditions. Subsequently, they carried out a study on the kinetic resolution of raeemie 4-formyl-a-lactams by chiral NHC. With 5 mol% of the optimized ehiral eatalyst, kinetic resolution of racemic 4-formyl-a-lactams gave (+)-sueeinimide derivatives in 26-50% yield with up to 44% ee and alcohols derived from starting materials in 39-49% yield with up to 99% ee (Scheme 7.87). 

In 2008, Ye and coworkers reported that chiral NHCs prepared from l-pyroglutamic acid were efficient catalysts for the enantioselective Staudinger reaction of ketenes with imines. The corresponding c/s-p-lactams 158 were obtained in good yields with good diastereoselectivities and excellent enantioselectivities (up to 99% ee) (Scheme 20.66). In the same year. Smith and coworkers independently reported the NHC-catalysed [2 + 2] cycloaddition of disubstituted ketenes and N-tosylimines. ... 

Ketenes are attractive due to their remarkable reactivity and wide application in the synthesis of cyclic compounds. Ye et al. and Smith et al. have independently demonstrated that NHCs are efficient catalysts for the reactions of ketenes. In 2008, Ye and co-workers reported the synthesis of chiral NHCs 84 derived from l-pyrolutamic acid, which could catalyze the reaction of aryl(alkyl)ketenes with N-Boc imine to give the corresponding p-lactams in good yield with good diastereo- and high enantioselectivities (Scheme 7.69). More importantly, the NHC-catalyzed... 

The same group accomplished the enantioselective silyl transfer to a,p-unsamrated lactams and acyclic amides with the same chiral NHC-copper(I) catalyst that is formed from L12 (Scheme 12, upper) [39]. y-Butyrolactams having... 

A catalytic activation of esters RCH2CH2CO2R by the NHC organocatalysts (314) to generate chiral enolates (Z)-RCH2CH=C(0 )Cat+ has been reported. The latter species then reacted with a,/ -unsaturated N-tosylimines ArCH=CHC(Ar )=NTs, giving rise to lactams (315) with up to >99% ee and >20 1 dr. Note that this transformation can 0 serve as a neat example of replacing the traditional stoichiometric enolate chemistry with chiral auxiliaries. ... 

Extension of this work to the diastereoselective synthesis of y-lactams from N-sulfonyl aldimines [93] and ketimines [94] was subsequently reported. Scheldt and coworkers disclosed an enantioselective version (up to 98% ee) from reactive hydrazones in the initial demonstration of cooperative NHC/Lewis acid catalysis using a bulky, chiral triazolium salt and catalytic Mg(OBu )2 [95]. Rovis and coworkers synthesized y-lactams 109 enantioselectively using a chiral N-C Fs triazolium salt (Scheme 18.19). A weak carboxylate base was sufficient to partially deprotonate the precatalyst 108 in situ, and the carboxylic acid formed could activate the N-Ar imine acceptor 107 via protonation [lib]. In all these cases, a fine balance must exist between sufficient electrophilicity vis-a-vis the competing enal and reversible addition of the carbene to the imine/hydrazone/iminium or to the Lewis acid. 

The use ofNHCs as transesterification catalysts features among their early applications as nucleophilic catalysts and this area has been reviewed previously (8, 118). More recently, the formation of nucleophilic azoHum enolates via attack of NHCs onto ketenes 144 was reported independently by the groups of Ye and Smith in 2008 [119]. In the presence of N-Boc or N-Ts aromatic imines 145, P-lactams 149 were obtained in moderate to high enantioselectivity using chiral N-Ph triazolium salts (Scheme 18.31). 

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