Staudinger s ketene-imine

Staudinger s Ketene-imine Reactions This is the most fundamental and versatile... 

The common methods for the S5mthesis of p-lactams are cycloaddition reactions such as the Staudinger s ketene-imine cycloadditions, ester enolate-imine cycloadditions, alkyne-nitrone cycloadditions (Kinugasa reaction), alkene-isocyanate cycloadditions, and Torii s cyclocarbonylation of allyl halides with imines. Several cyclizahon reactions of p-amino esters, p-amino acids, p-hydroxamate esters, and a-diazocarbonyls have been developed for the formation of p-lactam ring. N,N-Disubstituted a-haloamides cyclize by C3-C4 bond formation leading to the formation of P-lactam ring. 

Enantiomerically pure 1,3-thiazolidine-derived spiro /3-lactams 505 and 506 were stereoselectively synthesized by means of a Staudinger ketene-imine reaction in the presence of 2-chloro-l-methylpyridinium iodide (Mukaiyama s reagent) starting from optically active A -BOC-l,3-thiazolidine-2-carboxylic acid derivatives 504 and imines (Scheme 127). The reactions were stereoselective and afforded spiro-/3-lactams with a /ra r -configuration. The spiro-/3-lactams 505 and 506 were transformed into enantiomerically pure chiral monocyclic /3-lactams 507 and 508... 

The j -lactam nucleus can also be assembled efficiently by a ketene-imine cycloaddition known as the Staudinger reaction. The reaction of chiral imine 759 with alkoxyketenes generated tfom benzyloxyacetyl chloride or acetoxyacetyl chloride affords cw-3,4-di-substituted )S-lactams 764a (75% yield) or 764b (61% yield) with diastereoselectivities greater than 95% [218]. 

Solid-phase and combinatorial synthesis of 6-lactams using the Staudinger reaction has widely been studied. Carbohydrates as a chiral pool, however, were not employed except for one report [148]. The polymer supported-imines were employed to prepare several -lactams by enolate/imine condensation and ketene/imine cycloaddition (Scheme 46) [146]. The reactions carried out on the polymer-boimd imines showed a remarkable similarity to those in solution, both in terms of yield and stereoselectivity [54,55]. )S-Lactams were removed from the polymer by CAN oxidation [ 148]. 

Two new glucose-derived oxazolidinones have been prepared, and converted to iV-acyl derivatives of type 204 (R = Me or Piv). The dialkylboron enolates derived from 204 underwent aldol reactions to give syn-products 205, with diastereomeric ratios between 8 1 and 16 1. The same group has also made the oxazolidinone 206 from D-xylose. When this was treated with Mukaiyama s reagent (2-chloro-l-methylpyridinium iodide) in the presence of an imine, a Staudinger ketene-imine cyclization occurred to give a p-lactam such as 207, the structure of which was confirmed by X-ray crystallography, in >98% de. ... 

Zhang YR, He L, Wu X, Shao PL, Ye S (2008) Chiral N-heterocyclic carbene catalyzed Staudinger reaction of ketenes with imines highly enantioselective synthesis of W-Boc P-lactams. Org Lett 10 277-280... 

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. 

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]. 

There are some examples on diastereoslective reactions between ketenes and imines [54-61]. However, the number of computational studies dealing with these reactants is scarce [59, 62-64]. As an example of Staudinger reaction in which the chirality source is at the C4 position of the ring being formed, our group studied the reaction between methoxyketene (38) and imine (S)-(39) derived from (S)-a-alkoxyaldehydes to yield the corresponding cis-(3-lactam (3S,4R)-(40) (Scheme 9). 

Staudinger Reactions. Chiral oxazolidinones have been employed as the chiral control element in the Staudinger reaction as well as the ultimate source of the a-amino group in the formation of p-lactams." Cycloaddition of ketene derived from 4-(S)-phenyloxazolidylacetyl chloride with conjugated imines affords the corresponding p-lactams in 80-90% yields with excellent diastereoselectivity (eq 54). The auxiliary can then be reduced under Birch conditions to reveal the a-amino group. 

The majority of reported solid-phase combinatorial syntheses of the lactam core utilize a [2-i-2] cycloaddition reaction of ketenes with resin-bound imines [33-41]. A further development of the Staudinger reaction was reported by Mata and coworkers using Mukaiyama s reagent [42]. In addition, a stereoselective synthesis of chi-rally pure P-lactams has been performed as a first utilization of polymer-supported oxazolidine aldehydes [43]. Other strategies include an ester enolate-imine condensation [44], an Hg(OCOCF3)2-mediated intramolecular cydization [45], and Miller hydroxamate synthesis [46]. Because of the variability derived from the scaffold synthesis, not many attempts have been made to derivatize the resin-bound lactam template [47]. One of the most detailed descriptions of a versatile (3-lactam synthesis on a resin employed amino acids tethered as esters on Sasrin resin [48]. 

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. ... 

The Staudinger synthesis is catalysed by NHCs (A -heterocyclic carbenes), via Ye s possible ketene-first or imine-first mechanisms. To test these alternatives, four zwitterionic NHC adducts have been prepared two using A -tosyl benzaldimine and two using diphenylketene. All four adducts had 1 1 stoichiometry and have been extensively characterized by H- and C-NMR, X-ray crystallography and catalytic tests. The imine-derived zwitterions proved poor catalysts, whereas those derived from diphenylketene replicated the free carbene catalysts, strongly supporting the ketene-first route. 

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