Stereoselectivity ketene cycloaddition reactions

Ketenes are especially reactive in [2 + 2] cycloadditions and an important reason is that they offer a low degree of steric interaction in the TS. Another reason is the electrophilic character of the ketene LUMO. As discussed in Section 10.4 of Part A, there is a large net charge transfer from the alkene to the ketene, with bond formation at the ketene sp carbon mnning ahead of that at the sp2 carbon. The stereoselectivity of ketene cycloadditions is the result of steric effects in the TS. Minimization of interaction between the substituents R and R leads to a cyclobutanone in which these substituents are cis, which is the stereochemistry usually observed in these reactions. 

Allene ketene cycloadditions are of greater synthetic utility than cither mixed allene dimerization or mixed ketene dimerization. In this class of reaction the ketene is the more reactive species and homodimerization of ketene can be minimized by use of excess allene. Such cycloadditions always result in 2-alkylidenecyclobutanones with the sp carbons of both moieties forming the initial bond. In substituted allenes and ketenes, mixtures of stereoisomers of 2-alkylidenecyclobutanones are obtained with very little stereoselectivity, the stereoisomers arise from cisUrcins isomerism in the cyclobutane ring and EjZ isomerism of the exocyclic double bond. In unsymmetrically substituted allenes some regiochemical preference for ketene cycloaddition is observed. Examples of dimethylketene allene cycloadditions are summarized in Table 1,2... 

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... 

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). 

As mentioned in Section 7.2, when the electron transfer reaction between electron-rich alkenes and excited carbonyl compounds is energetically favorable, the RI pair becomes an important intermediate in photochemical [2 + 2] cycloaddition reactions (Scheme 7.5). The regioselectivity of these reactions may differ from that observed for the PB reaction involving 1,4-triplet biradical intermediates. Typical examples of PB reactions with very electron-rich alkenes, ketene silyl acetals (Eox = 0.9 V vs SCE), have been reported (Scheme 7.11) [27]. Thus, 2-alkoxyoxetanes were selectively formed as a result of the PB reaction with benzaldehyde or benzophenone derivatives, whereas a selective formation of 3-alkoxyoxetanes was observed in less electron-rich alkenes (see Scheme 7.9). When p-methoxybenzalde-hyde was used in the photochemical reaction, the regioselectivity was less than that observed in the case of benzaldehyde. This dramatic decrease in regioselectivity provided evidence that the selective formation of 2-alkoxyoxetanes occurred via RI pair intermediates. It should be noted that the stereoselectivity is also completely different from that associated with triplet 1,4-biradicals (vide infra). 

A recent study provides comments on the mechanism and origin of stereoselectivity in the Lewis acid catalyzed [2+2] cycloaddition reaction between ketenes and aldehydes to give P-lactones. The observations made in this study highlight the broad range of factors which must be pondered in order to understand and control stereoselectivity in a multistep reaction <02AG(E)1572>. 

Enantiomerically enriched or pure benzaldehydeimine complexes react with nucleophiles such as Grignard see Grignard Reagents) and organozinc reagents, and they participate in a number of cycloaddition reactions. Enantiopure tricyclic /3-lactams can be obtained from stereoselective [2 - - 2]cycloaddition between a complexed chiral benzaldehyde imine and a ketene (Scheme 85). For example, reaction of (44) with acetoxyketene gives (45). 

A new methylseleno-promoted ketene-imine cycloaddition reaction between 151 and 152 (86JOC4737) gave the bicyclic product 153 in an extremely high stereoselective fashion and in fairly good yield (36-92%) (Scheme 27). 

Lopez, R., Suarez, D., Ruiz-Lopez, M. F., Gonzalez, J., Sordo, J. A., Sordo, T. L. Solvent effects on the stereoselectivity of ketene-imine cycloaddition reactions. J. Chem. Soc., Chem. Common. 1995,1677-1678. 

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]. 

Therefore, some conclusions have been generally accepted and have been summarized as follows the cycloaddition reaction is a stepwise reaction rather than a concerted one the reaction is initiated by nucleophihc attack of an imine to a ketene, giving rise to a zwitterionic intermediate a conrotatory eleclrocyclic ring-closure of the zwitterionic intermediate produces the final 2-azetidone product [85], As the stereochemistry of the structure of the P-lactams strongly affects their biological activity, the stereoselectivity of the process must be carefully considered. Uncatalysed as well as catalysed processes have been reported organometallic and organic catalysts have been utilized in procedures oriented to the syntheses of enantiopure P-lactams [90-92],... 

Chiral oxazaborolidines 20 derived from various amino alcohols have been used as catalysts in asymmetric 1,3-dipolar cycloaddition reaction of nitrones with ketene acetals to give substituted isoxazoles in high yield and stereoselectivity but in moderate enantioselectivity (upto 62% ee). This method has also been used for the synthesis of 0-aminoesters... 

Cycloaddition reactions of the chiral exocyclic methylene compounds A and B derived from menthone and of related chiral 1-oxa-l,3-dienes (C) with alkenes as dienophiles, e.g. ketene acetals, proceed smoothly and are highly stereoselective. ... 

Deuteration at C2, which bonds to the carbonyl C-atom of the ketene, accelerates the reaction (fcn/ D 0.91 per D-atom) and deuteration at Ci retards it (fen/ D 1.23), suggesting a stepwise mechanism via a biradical or zwitterion, but the negligible solvent effect and the known stereoselectivity of ketene cycloadditions was taken as presumptive evidence that the reaction nevertheless occurs in a single step Closure of the two bonds was adjudged to be concerted but non-synchronous. 

Triphosgene activation has been used for the construction of ) -lactams through ketene-imine cycloaddition reactions (Staudinger reaction) [1030]. In all the studied cases, the cydoaddition reaction was found to be stereoselective and only cis- 8-lactams 1362 were formed. 

---