Fluorinated P-lactams

Maillard, J.-L. Favreau, C. Vergely, I. Reboud-Ravaux, M. Joyeau, R. Kobaiter, R. Wakselman, M. Protection of vascular basement membrane and microcirculation from elastase-induced damage with a fluorinated P-lactam derivative. Clin. Chim. Acta 1992, 213, 75-86. 

Very recently, a different synthetic approach to fluorinated p-lactams involving catalytic hydrogenolysis of the N-O bond of isoxazohdines appeared in the literature. The method involves the synthesis of isoxazohdines (71) by 1,3-cycloaddition of aromatic nitrones to fluorinated alkenes, followed by N-O bond cleavage by hydrogenolysis using palladium catalyst (Scheme 2.34). ... 

Monofluoro P-lactams are used not only as synthetic intermediates for the preparation of fluorinated P-lactam antibiotics but also as precursors of carbohydrates and amino acids. However, there are a limited number of reports on the synthesis of such compounds and... 

The Staudinger reaction of ketenes to aldimines is well known to provide cw-p-lactams. However, it had never been studied in the case of fluoroalkyl imines. The trifluoroacetaldimine 17a has been prepared by the usual route from the corresponding ethyl trifluoromethyl hemiketal and p-methoxyaniline. " Reaction of the benzyloxyketene, generated from a-benzyloxyacetyl chloride, with imine 17a, performed at 45 °C in CHjClj, provided the expected cis azetidinone 16a in 65 % yield (Scheme 8). In azetidinone 16a, the Vh.3,h-4 coupling constant of 5 Hz indicates the cis relative configuration. Coupling constants in parent non-fluorinated P-lactams have been reported to be 2 Hz for the trans isomer and 5-6 Hz for the cis one. Condensation of the aldimine 17b with the same ketene led to the cis P-lactam 16b in 72 % yield. The cis P-lactam 16c was obtained in a satisfatory yield (55 %) from the aldimine 17c (Scheme 8). 

The quinoline antibiotics are relatively late arrivals on the antibiotic scene. The parent compound of this class of drugs is nalidixic acid. The downside of this molecule is the rapid development of resistance by pathogenic bacteria. A major step forward was the introduction of a single fluorine atom at a key position, to yield new molecules such as ciprofloxacin, ofloxacin, levofloxacin, andmoxifloxacin. Of these, levofloxacin and moxifloxacin have the best combinations of spectrum of action, potency, and pharmacokinetic properties. In time, they are likely to largely replace the current quinoline antibiotic of choice, ciprofloxacin. Since these molecules work by a different mechanism than do the p-lactams, organisms that become resistant to the latter are generally susceptible to the former. 

Much care has been taken in the selection of work to be included but, necessarily, the choice is subjective and the review is in no way comprehensive. P-Lactam chemistry dominates the field in terms of the number of publications. In contrast, studies of heterocycles containing two different heteroatoms appear to be neglected. In general, reviews are mentioned in the appropriate section but mention of a survey of heterocycles bearing fluorine or trifluoromethyl substituents <98MI3SS> is more appropriate here. 

A multistep solid phase synthesis of (3-lactams with imines of benzaldehyde coming out from commercially available fluorinated a-amino acids has been reported in 2003 [77]. Using the Merrifield resin-bound imine [78, 79] in dichlor-omethane, the cycloaddition was carried out between -78°C and rt by addition of benzyloxyacetyl chloride in the presence of triethylamine. The resin cleavage using sodium methylate resulted in the two cis p-lactam derivatives (Scheme 20). 

In 2008, a very mild reductive N-O bond cleavage of fluorinated isoxazolidines was reported to provide a novel and general entry to p-lactams and ester of p-amino acids containing a trifluoromethyl group (Scheme 94), [210]. 

In this chapter, we describe an account of our research on the chemistry and biology of paclitaxel and taxoid anticancer agents (taxoid = taxol-like compound). The topics covered in this chapter include (i) the development of a practical and efficient method for the semisynthesis of paclitaxel and docetaxel using chiral 3-hydroxy-P-lactams as synthetic intermediates, (ii) structure-activity relationship (SAR) studies of various taxoids that led to the discovery of the extremely potent second-generation taxoids, and (iii) biological and conformational studies with the use of fluorine-containing taxoids as probes. ... 

Kuznetsova, L., Ungureanu, I. M., Pepe, A., et al. (2004) Trifluoromethyl- and difluoromethyl-P-lactams as useful building blocks for the synthesis of fluorinated amino acids, dipeptides, and fluoro-taxoids. Journal of Fluorine Chemistry 125, 487-500. 

Quinolone antibiotics such as ofloxacin 200 are totally different from P-lactams, tetracyclines and so on and work in a different way. They offer some hope that resistance may be slow to appear. They all contain the quinolone core a benzene ring fused to a y-pyridone. Most have various amine substituents and ofloxacin has a fluorine atom. Disconnection of the enamine reveals a benzene ring with a series of heteroatom substituents (N, N, O, F) and the one fluorine suggests that a series of nucleophilic substitutions might provide a synthesis. 

The acetoxy group was hydrolyzed using hydrazine to give (46). Nucleophilic substitution of the fluorine atom produced the tricyclic p lactam (47). A diastereoselective aza-Diels-Alder reaction was used in a synthesis of (—)-lasubine (I). Tin tetrachloride-mediated reaction of complex (48) with Danishefsky s diene afford 2,3-dihydro-4-pyridone (49) as a single diastereomer (Scheme 86). Chiral benzaldehyde imines can be allylated with high diastereoselectivity to give optically active homoallylic amines (Scheme 87). 

Reactive ketenes (usually generated in situ by treating an appropriate acyl chloride with a base) undergo the [2 + 2] cycloaddition with fluorinated imine to afford the mixture of stereoisomers of p-lactam 67 (Scheme 2.31). Then the kinetic optical resolution is performed on the product to obtain pure enantiomers. 

Reports of simple ring-fluorinated tetrazoles appear to be limited. In one example, 1-benzyl-5-fluorotetrazole 166 was prepared by the action of KF on the corresponding chloro derivative. This was used to prepare a series of A-(tetrazol-5-yl) azetidi-nones 167 by reaction with A-unsubstituted p-lactams (Fig. 3.97). 

Scheme 9 Synthesis of fluorine substituted spiro P lactams...

Highly regioselective anodic monofluorination of 2-aryl-4-thia-zolidinones 53 can also be promoted by using pulse electrolysis in EtjN-SHF/MeCN as shown in Scheme 41. In this case, benzylic fluorination does not take place and fluorination occurs at the 5-position selectively. The regioselectivity of this process appears also to be controlled kinetically as shown in Scheme 40. The transformation of the sulfones 55 derived from fluorinated products 54 into monofluoro P-lactams 56 is readily performed in excellent yields by thermolysis (Scheme 41). 

Anodic monofluorination of a-phenylthio-P-lactams 60 in EtjN-SHF/MeCN also leads to production of the corresponding a-fluorinated products in good yields and with high current efficiencies as shown in Eq. 111... 

Suda and his co-workers reported anodic fluoro desilylation of P-trimethylsilyl-P-lactams as shown in Scheme 43. In this reaction, the selection of the trimethylsilyl as a good leaving group enables regioselectivity control in the fluorination process. 

Radical cations of triaiylamines are known to be single electron transfer oxidizing agents. Very recently, these substances have been used as efficient mediators for gcm-difluorodesulfurization as shown in Scheme 56. ° Furthermore, triarylamines have recently been shown to be highly effective mediators for monofluorodesulfurization of P-lactams. Severe passivation of the anode takes place during anodic fluorination of P-phenylthio- P-lactams, which is quite different from the case of a-phenylthio-P-lactams 60. However, selective anodic fluorodesulfurization proceeds efficiently without passivation when tris(2,4-dibromophenyl)amine is employed as a mediator as shown in Scheme 57. ... 

Fustero, S., Fernandez, B., BeUo, P, del Pozo, C., Arimitsu, S., Hammond, G. B. (2007). Intramolecular Hydroamination of Difluoropropargyl Amides Regioselective Synthesis of Fluorinated P- and y-Lactams. Organic... 

Exploration ofaziridine- and p-lactam-based hybrids as both bioactive substances and synthetic intermediates in medicinal chemistry 13BMC3643. Fluorine-18 radiolabeled tropanes for imaging use with positron emission tomography 13CTM920. 

Preparation and synthetic applications of azetidines 12H(84)223. Recent developments in the synthesis of fluorine-containing P-amino acids and P-lactams 13CJO2098. 

Selective Electrochemical Fluorination, Scheme 12 Solvent effect on electrochemical Selective Electrochemical Fluorination, fluorination Scheme 10 Electrochemical fluorodesulfurization of P-lactams using triarylamine mediator... 

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