Staudinger reaction, cycloaddition

The Staudinger reaction [92], a [2 + 2]-cycloaddition of a ketene and a nucleophilic imine, usually proceeds by an initial imine attack on the ketene thus forming a zwitterionic enolate which subsequently cyclizes. This reaction is an expedient route to p-lactams, the core of numerous antibiotics (e.g., penicillins) and other biologically active molecules [93]. In contrast, for Lewis-base catalyzed asymmetric reactions, nonnucleophilic imines are required (to suppress a noncatalyzed background reaction), bearing, for example, an N-Ts [94] or -Boc-substituent [95]. 

Density functional theory calculations (B3LYP/6-31G level) have provided an explanation for the stereodivergent outcome of the Staudinger reaction between acyl chlorides and imines to form 2-azetidinones (/3-lactams). When ketene is formed prior to cycloaddition, preferential or exclusive formation of ct5-j6-lactam (50) is predicted. If, however, the imine reacts directly with the acid chloride, the step that determines the stereochemical outcome is an intramolecular 5n2 displacement, and preferential or exclusive formation of trans isomer (51) is predicted. These predictions agree well with the experimental evidence regarding the stereochemical outcome for various reactants and reaction conditions. 

Azetidinones on a solid support 49 have been prepared in high yield by Staudinger reaction of a supported imine with an acid chloride in the presence of a base. The liberated p-lactams were of high purity <99TL1249>. Cycloaddition of a ketene intermediate, derived fi"om an azo compound, to an imine having an oxidatively cleavable chiral auxiliary N-substituent was used to obtain p-lactams 50. The trans. cis ratio which varied between 69 31 and 93 7, depended on the nature of the substituents R and R <99S650>. 

Staudinger reaction of imine 8 derived from 7-oxanorbomenone with 2-alkoxy-acetyl chlorides in the presence of Et3N (toluene, RT), afforded (3-lactams 9 (Scheme 3). These were obtained as single diastereomers, and no traces of the corresponding isomeric exo-(3-lactams were detected in the crude reaction products [50]. It is worth mentioning that this stereochemical outcome of (3-lactam formation with acid chlorides under Staudinger reaction conditions was opposite to the one expected from a simple [2+2]-cycloaddition reaction, which should have taken place from the exo face of compound 8. 

In conclusion, the CAI activity of spiro-(3-lactams, their antiviral and antibacterial properties, their potential as efficient (3-tum nucleators and (3-tum mimetics, and their application as synthons for a,a-disubstituted (3-amino acids motivated synthetic and medicinal chemists to design novel spirocyclic (3-lactams. Several approaches to the stereoselective synthesis of spiro-(3-lactams have been described in this review. However, ketene-imine cycloaddition (Staudinger Reaction) shows much versatility for the access to diversely functionalized spiro-(3-lactams. In addition, we have developed a facile route to novel spiro-(3-lactams by using... 

Compared with the single-bond construction approach of (3-lactam synthesis, the ketene-imine cycloaddition, which includes carbenoid insertion and the Staudinger reaction, have been widely used [56, 65]. Due to the ready availability of both imines and ketenes, the Staudinger reaction has provided a useful and economical approach for the synthesis of (3-lactams. In addition, the ketene-imine cycloaddition is efficient, which constructs the (3-lactam four-member ring in just one-step... 

Gallop et al. [80] reported the preparation of p-lactams via a [2+2] cycloaddition reaction of ketenes with resin-bound imines derived from amino acids (Scheme 9). This is another solid-phase adaptation of the Staudinger reaction, which could lead to the synthesis of structurally diverse 3,4-bis-substituted 2-azetidinones [81]. In addition, a novel approach to the synthesis of A-unsubstituted-p-lactams, important building blocks for the preparation of p-lactam antibiotics, and useful precursors of chiral p-amino acids was described [82]. 

Two possible [2+2] cycloadditions can be envisaged for the synthesis of (3-lactams (Scheme 1). Interestingly, the same fragmentations have been observed in the mass spectra of these compounds [10, 11], One possibility consists of the [2+2] cycloaddition between ketenes (2) and imines (3) to yield (3-lactams (1). This reaction has been explored experimentally and it is also known as the Staudinger reaction between ketenes and imines [12-15]. In an alternative approach, the [2+2] cycloaddition between alkenes (5) and isocyanates (4) leads to (3-lactams (1). This reaction has been less extensively used, but it has proven to be useful in the chemical synthesis of interesting compounds [16-19]. 

A perfunctory study of the Staudinger reaction ( rich alkene + ketene — cyclobuta-none)49 can lead us to believe in a failure of FO theory. The alkene, being rich in electrons, will react preferentially by its HOMO and the ketene by its LUMO. Also, as nco is lower than jtcc, the cycloaddition should give a methylene oxetane and not a cyclobutanone. 

Another common method for the synthesis of 2-azetidinones is the cycloaddition of imines with ketenes, which is known as the Staudinger reaction . Although commonly described as a [2 + 2]... 

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. 

CEJ4035>. Diastereospecific synthesis of r-/3-lactams can be effected via cycloaddition reaction of bisimines and the ketene derived from 582 (R = CH2CO2H) (Staudinger reaction) <2000T8555>. Ruthenium-catalyzed [2-1-2] cycloaddition of norbornene and ynamide 582 (R = C=CPh) <2006T3823> was reported. 

The Staudinger ketene cycloaddition was utilized as the key reaction in the synthesis of a number of bakkane natural products in the laboratory of A.E. Greene. Dichloroketene was generated in situ from trichloroacetyl chloride by zinc-copper alloy in the presence of phosphorous oxychloride. The [2+2] cycloaddition between dichloroketene and 1,6-dimethylcyclohexene gave the product in high yield and excellent regio- and diastereoselectivity. The cycloadduct was successfully converted to (+)-bakkenolide A. 

Cossio, F. P., Lecea, B., Cuevas, C., Mielgo, A., Palomo, C. A novel entry for the asymmetric Staudinger reaction experimental and computational studies on the formation of P-lactams through [2+2] cycloaddition reaction of ketenes to imines. An. Quim. 1993, 89, 119-122. 

Venturini, A., Gonzalez, J. A CASPT2 and CASSCF Approach to the Cycloaddition of Ketene and Imine A New Mechanistic Scheme of the Staudinger Reaction. J. Org. Chem. 2002, 67, 9089-9092. 

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]. 

The Staudinger reaction, i.e. the [2+2] ketene-imine cycloaddition, is the most frequently employed procedure of synthesis of the azetidin-2-one nucleus. Base-promoted cyclization of suitable linear substrates is another frequently employed procedure. We wish to report the electrochemical methodologies of synthesis of P-lactams, according to both procedures, and the possible utilization of RTILs (as solvents and/or as parent of intermediates). 

Scheme 16.3 Synthesis of the azetidin-2-one nucleus via the Staudinger reaction the [2+2] ketene-imine cycloaddition...

Subsequently, the ability of enantiomerically pure N-heterocyclic carbenes (NHCs) to catalyse the enantioselective Staudinger reaction has been tested. Different NHCs, obtained via deprotonation by potassium hexamethyldisilazide KHMDS in Et O of the respective parent ionic liquids, are able to promote the cycloaddition of diphenylketene and N-tosylimide giving P-lactams in elevated yields and 55-75% e.e. (Scheme 16.7) [95]. 

---