Cycloadditions Staudinger

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... 

Asymmetric synthesis of 3-amino (3-lactams via Staudinger ketene-imine cycloaddition reaction 98KGS1448. 

Staudinger observed that the cycloaddition of ketenes with 1,3-dienes afforded cyclobutanones from a formal [2+2] cycloaddition [52] prior to the discovery of the Diels-Alder reaction. The 2+2 cycloadditions were classified into the symmetry-allowed 2+2 cycloaddition reactions [6, 7], It was quite momentous when Machiguchi and Yamabe reported that [4+2] cycloadducts are initial products in the reactions of diphenylketene with cyclic dienes such as cyclopentadiene (Scheme 11) [53, 54], The cyclobutanones arise by a [3, 3]-sigmatropic (Claisen) rearrangement of the initial products. 

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]. 

These building blocks can be obtained either by the Miller cyclization of (5-hydroxy-ct-amino acids or by the Staudinger reaction7 ([2+2] ketene-imine cycloaddition). The procedure reported here follows the second route and has the advantages of being diastereospecific and to proceed in high yield. For a large scale preparation, the harmful and toxic N-methylhydrazine can be replaced by N,N-dlmethyl-1,3-propanediamine. Further transformations of the key intermediate have been reported elsewhere.7 9... 

Figure 9 (a) Protein modification with PEG through a copper-catalyzed cycloaddition reaction, (b) Protein modification with fluorescein through Staudinger ligation. 

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. 

Deshmukh et al. [134] have investigated the use of D-(+)-glucose derived chiral ketenes in the stereoselective synthesis of spiro-(3-lactams 226-227. The D-(+)-glucose acid chloride 224, serving as a ketene precursor, in the Staudinger cycloaddition reaction with appropriate imines 225 afforded the diastereomeric mixture of spirocyclic-(3-lactams 226-227 in 70 30 ratio, respectively. This reaction has cleanly produced only two diastereoisomers instead of theoretically possible four... 

V./V-Dialkylhydraz()nes as the imine component in the Staudinger-like [2+2] cycloaddition to benzyloxyketene have been reported [71, 72]. The reaction led to the desired (3-lactams in excellent yields (84—98%), moderate to good selectivities (3R,45 > 35,4/ ), and only traces of trans isomers (3/ , 4/ ) were detected in some cases. 

The Staudinger [2+2] cycloaddition of chiral carbohydrate Schiff base with phthalimidoacetyl chloride has yielded the sugar-based monocyclic (3-lactam as a single isomer [88]. This latter could be transformed in several (3-lactams variously functionalized through ozonolysis, reduction, hydrolysis, and acetylation reactions, (Scheme 26). 

Scheme 26 Synthesis of sugar-based monocyclic [S-lactams by Staudinger [2+2] cycloaddition reaction...

The synthesis of 1,3-disubstituted-4-trichloromethyl azetidin-2-ones by the Staudinger cycloaddition of ketenes with imines derived from chloral has been described to occur with high stereoselectivity [91], The civ-isomer was obtained almost always as the major or the single product. 

Reaction of D-phenylalanine ethyl ester with cinnamaldehyde has been reported to give a chiral Schiff base, that underwent an asymmetric Staudinger [2+2] cycloaddition reaction with phthalimidoacetyl chloride to give the monocyclic... 

A combined theoretical and experimental study has been reported for the formation of silylated (3-lactams, via Staudinger [2+2] cycloaddition reaction from silylketenes and imines, in the presence or in the absence of a Lewis acid... 

A benzothiazepine-fused (3-lactam library has been reported to be obtained [106] via Staudinger cycloaddition of 2,3- dihydro-1,5-benzothiazepines and various acyl chlorides such as phthalimidoacetyl chloride (path a, Scheme 35), chloroacetyl chloride (path b, Scheme 35), dichloroacetyl chloride (path c, Scheme 35), and phenoxyacetyl chloride (path d, Scheme 35). 

Y/ .v-(3-Lactains have been reported to be regioselectively synthesized by [2+2] Staudinger cycloaddition reactions of imine such as (3,4-dimethoxybenzylidene)-(4-methoxyphenyl)-amine and ketenes derived from different acyl chlorides and triethylamine [110]. 

A stereocontrolled Staudinger cycloaddition reaction has been reported to be performed on vinylketenes, possessing a y-heteroatom, and imines to produce frans-vinyl-(3-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). 

A new protocol for the stereoselective synthesis of (i-lactams [213] has been reported to be performed by a conrotatory ring closure of l-halo-3-aza-4-alkyl-l, 3-dienes, previously prepared by Staudinger methodology, (for the synthesis and chemistry of /V-silyl imines see [214] for [2+2] cycloaddition of /V-silyl imines and ketenes see [215]) in refluxing toluene (Scheme 96). 

A procedure based on Ru-catalyzed metathesis sequences with oxanorbomene precursors (I, Fig. 20), obtained by the Staudinger [2+2] cycloaddition of related imines, has been reported to lead to spiro-(3-lactams tethered to tetrahydrofuran rings (II, Fig. 20), [292],... 

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... 

Between the above two methods for the synthesis of (3-lactam derivatives, the venerable Staudinger [2+2] imine-ketene cycloaddition [36] is by far the most versatile and simplest entry to the lactam fragment. Application of Staudinger... 

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