Frans-P-Lactams

According to this scheme, the Staudinger reaction between (E)-imines and ketenes should yield preferentially the kinetic c/s-p-lactams. provided that the first step takes place via an exo attack, which leads to a second transition state in which the L substituent occupies the 3-out position (Scheme 8). Using the same argument, (Z)-imines should yield frans-p-lactams as main cycloadducts [26]. 

The stereochemistry of the Staudinger reaction was highlighted [86] using as substrates polyaromatic imines and acetoxy, phenoxy, or phthalimido acid chloride. The stereochemistry of the resulting p-lactams seemed to vary depending on the substituents present in the imines and the acid chlorides. For instance, if the polyaromatic moiety was linked to the iminic nitrogen, the reaction produced frans-p-lactams if the same moiety was linked to the iminic carbon, c T-p-lactams were isolated. 

In 2005, the Kinugasa reaction performed on W-propargyl nucleobases, such as adenine, uracil, and thymine derivatives, with diphenyl nitrone has been reported to produce cis- and frans-p-lactam nucleosides (Scheme 63), [157]. 

A mechanistic rationale for the observed cw-selectivity has been proposed based on preorganisation of the Breslow-type intermediate and imine through hydrogen bonding 253, with an aza-benzoin oxy-Cope process proposed. Reaction via a boat transition state delivers the observed cw-stereochemistry of the product (Scheme 12.57). Related work by Nair and co-workers (using enones 42 in place of a,P-unsaturated sulfonylimines 251, see Section 12.2.2) generates P-lactones 43 with fran -ring substituents, while the P-lactam products 252 possess a cw-stereo-chemical relationship. 

The frans-3-benzylthio-3-chloro-p-lactams 192, the appropriate p-lactam car-bocation equivalents, were prepared by stereospecific chlorination of their corresponding frans-3-benzylthio-(3-lactams 191 using Af-chlorosuccinimide and catalytical amount of AIBN [125]. These (3-lactam carbocation equivalents 192 on treatment with propargyl alcohol or allyl alcohol in the presence of ZnCl2/Si02 were further transformed to suitable substrates, such as, ds-3-benzylthio-3-(prop-2-ynyloxy/enyloxy)- 3-lactams 193 and 195 respectively [126]. 

A stereocontrolled Staudinger cycloaddition reaction has been reported to be performed on vinylketenes, possessing a y-heteroatom, and imines to produce frans-vinyl-p-lactams [112]. The vinyl side chain adopted stereoselectively the (Z) configuration in the transition state, stabilizing the vinyl ketene and leading, exclusively, to the frans-3-vinyl-(3-lactam (Scheme 37). 

The group of Podlech has reported that frans-substituted p-lactams dr 70 30) can be prepared treating an Fmoc-protected leucine-derived diazoketone with a benzylidene-protected glycine ester in a photochemically induced Staudinger-type reaction [173]. Separation of the isomers, deprotection, and attachment of Fmoc-proline using the pentafluorphenyl ester activation protocol yielded the protected peptidomimetic in 93% yield, (Scheme 74). Deprotection and amidation resulted in formation of the frans-substituted p-lactam. 

When R was a stereogenic center, of the four possible stereoisomers only the two frans-3-halo-isomers were obtained. A modification of the so-obtained p-lactams [216] has been also reported consisting in a dehalogenation procedure giving rise to 3-unsubstituted (3-lactams, (Scheme 96). 

Solid-phase preparation of trans 3-alkyl p-lactams was reported by Mata et al. recently (Scheme 14) [103]. The synthetic sequence involved the start from Fmoc-glycine tethered to Wang resin, followed by addition of a controlled excess of 43 (4 equiv) and triethylamine (8 equiv) to the resin bound imine 42 in refluxing toluene. Cleavage form resin surface and esterification afforded the 3-alkyl p-lactams, 45, as a single product with excellent frans-selectivity. 

In a new formal synthesis of (-h)-thienamycin (Scheme 29), the 6-deoxy-glucosamine derivative 142 underwent base-catalysed rearrangement (see Vol. 16, p. 149), followed by oxidation, to give the separable isomers of 143. Both of these could be transformed, by sequences involving base-catalysed epimeriz-ation, into the same all-frans-lactone 144. Formation of a p-lactam and then oxidation by lead tetraacetate gave 145 (original sugar carbons indicated), which is an intermediate in a previous route to thienamycin. ... 

Morken et al. demonstrated that the combination of [Ir(COD)Cl]2 (2.5 mol %) and P(OPh)3 catalyzed the Mannich reaction of aldimine 164 and trifluorophenyl acrylate 165 at 60 °C. Under these conditions, the initially formed Mannich product undergoes cyclization to furnish the corresponding lactam 166 in 80% with high frans-seleclivily > 20 1 (Scheme 42) [73],... 

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