Synthesis of /1-lactams

The one-pot synthesis of /1-lactams containing the ferrocene moiety 226 (Scheme 9.73) was described by Bonini [124], The reactions were performed under classical heating (3.5-24 h) and/or by using a focused microwave reactor (4—6 min). In this case, the stereochemical outcome of the reaction is the same with both procedures and microwave irradiation does not necessarily improve on the yields obtained by classical heating. 

Since the discovery and clinical introduction of penicillin, considerable industrial and academic effort has been addressed to the design and synthesis of /1-lactam antibiotics. However, among the numerous methods developed for / -lactam synthesis, no single method is compatible with all possible functional groups and/or the chirality needed on the /3-lactamic ring. 

The Synthesis of [1-Lactam Antibiotics in the Presence of Undissolved Substrates... 

Solid phase-transfer reactions.2 A strong base ion-exchange resin (Duolile A-109, Diamond Shamrock) can serve as a solid phase-transfer catalyst for synthesis of /1-lactams (3) from oc-methyl-a./l-dibromopropionyl chloride (I) and an amino acid (2) U / 9, 360). 

A novel method for the synthesis of /1-lactams (35), starting from / -amino acids (34) by means of a PT system, has been recently proposed by Watanabe and Mukaiyama.61 The reaction involves initial esterification of the carboxylic acid, which can later undergo the cyclization. 

Scheme 45 Application of Mitsunobu reaction in solid phase synthesis of [1-lactam...

Chiral fi-lactams. The synthesis of /1-lactams from ketene silyl acetals and Schiff bases (8, 484-485) results in asymmetric induction at C4 in the range 44-78% when optically active Schiff bases are used. An example is shown in equation (I). 

Fig. 37 BTSIL synthesis of /1-lactams using a hydroxyl derived imidazolium dissolved in [bmim]...

Advances in the catalytic, asymmetric synthesis of /1-lactams 04ACR592. y-Imino esters as versatile substrates for the catalytic, asymmetric synthesis of /l-lactams 03ACR10. 

Synthesis of /1-lactams and amino acids by enyne methathesis (enyne bond reorganization) 04CRV1317. 

Induced stereoselectivity can also be obtained with chiral ketenes. Since most studies have been directed toward the synthesis of /1-lactam antibiotics, cycloadditions of protected aminoketenes have been extensively explored to produce intermediates for penicillin and cephalosporin synthesis and cycloadditions of protected hydroxyethylketenes have been used to produce intermediates for carbapenem synthesis. 

Scheme 87 Stereoselective synthesis of [1 lactams from amino acid derivatives...

Scheme 98 Synthesis of [1 lactams from substituted P amino acids...

Scheme 15 Synthesis of [1 lactam using Fmoc Wang resin...

Whereas there are numerous examples of the application of the products from diastereoselective 1,3-dipolar cycloaddition reaction in synthesis [7, 8], there are only very few examples on the application of the products from metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction in the synthesis of potential target molecules. The reason for this may be due to the fact that most metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction have been carried out on model systems that have not been optimized for further derivatization. One exception of this is the synthesis of a / -lactam by Kobayashi and Kawamura [84]. The isoxazoli-dine endo-21h, which was obtained in 96% ee from the Yb(OTf)3-BINOL-catalyzed... 

Treatment of the 1,2-oxazines 52 with carbon monoxide at 1000 psi in the presence of cobalt carbonyl brings about insertion of carbon monoxide to form the 1,3-oxazepines S3 <96TL2713>. A convenient route to P-lactams fused to oxepines is made available by alkene metathesis. Thus reaction of 4-acetoxyazetidin-2-one with ally alcohol in the presence of zinc acetate, followed by iV-allylation of the nitrogen affords the derivative 54 which cyclises by RCM to form the oxazepinone 55 <96CC2231>. The same communication describes a similar synthesis of 1,3-dioxepines. 

The next four procedures describe the preparation of strained ring systems. Preparation of 3-CHLORO-2-(CHLOROMETHYL)-l-PROPENE provides a facile approach to the olefin required for the synthesis of [1.1.1 [PROPELLANE, one of the most strained hydrocarbons prepared to date. The ready availability of this hydrocarbon should prove particularly useful to those interested in the development of the chemistry of this fascinating compound. Preparation of N-BENZYL-2,3-AZETIDINEDIONE provides an efficient approach to the unadorned a-keto-/3-lactam, a potential... 

The different carbosilane dendrimer supports (generation 0, 1 R=H, Me) were then used for the synthesis of the / -lactam (13). As shown in Scheme 7.2, the first step was again an immobilization of a carboxylic acid via ester bond formation. Treatment with LDA and ZnCl2 yielded in situ the corresponding zinc ester enolate (11) which reacts with N-(trimethylsilyl)phenylimine (12) to form the final four membered lactam ring (13). The last reaction step includes several intermediates. The last one is a supported /9-amino ester which undergoes spontaneous... 

Stang etal. (94JA93) have developed another alkynyliodonium salt mediated approach for the synthesis of y-lactams including bicyclic systems containing the pyrrole moiety. This method is based on the formation of 2-cyclopentenones 114 via intramolecular 1,5-carbon-hydrogen insertion reactions of [/3-(p-toluenesulfonyl)alkylidene]carbenes 113 derived from Michael addition of sodium p-toluenesulfinate to /3-ketoethynyl(phenyl) iodonium triflates 112 (Scheme 32). Replacing 112 by j8-amidoethynyl (phenyl)iodonium triflates 115-119 provides various y-lactams as outlined in Eqs. (26)-(30). 

Hanusch-Kompa C, Ugi 1 (1998) Multi-component reactions 13 synthesis of y-lactams as part of a multi-ring system via Ugi-4-centre-3-component reaction. Tetrahedron Lett 39 2725-2728... 

Bicyclic ester 100 forms in analogy to isomeric ester 65 (Section 2.4.1.1) (07JOC5608). /l-Phenylethylamine 101 undergoes palladium-catalyzed direct aromatic carbonylation, thus providing another synthesis of benzo-lactam 78b (06JOC5951). A stereoselective nitro-Mannich/lactamization cascade of y-nitro ester and cyclic imine affords polysubstituted lactam 102 (08OL4267). 

In cell culture, 1 is by far the most active of these three natural products. The challenge in the synthesis of 1 is not closing the (1-lactone, but rather the stereocontrolled assembly of the y-lactam 9. 

Samuel Danishefsky of Columbia University has also described (J. Am. Chem. Soc. 2005, 127, 8298) a total synthesis of 1, starting from the pyroglutamate derivative 10. Conjugate addition followed by alkylation established the lactam framework. Intramolecular cyclization of 12 gave 13, establishing the aminated quaternary center. The oxygenated quaternary center was then constructed by phenylselenyl-mediatcd cyclization of 14. The end game of this synthesis used the already-established cyclohexenyl zinc addition, which worked as well with 16 as it had with 7. 

Si-Lactams. The synthesis of /5-lactams employing organoiron complexes as intermediates (8, 454-455) has been extended to the preparation of bicyclic lactams, in particular to the new carbopenams. A synthesis of 2-methylcarbopenam (1) is shown in equation (I). 

According to Shaipless, two cycles operate in the catalytic reaction (Scheme 39) (88c, 9CF). The first cycle is highly enantioselective, whereas the second is poorly enantioselective. Hydrolysis of the key intermediate formed from B and oxidant is not very fast. The second osmylation of olefinic substrate occurs as the intermediate enters the undesired catalytic cycle. Therefore, slow addition of olefinic substrates to minimize the second cycle is essential for obtaining high ee. Use of potassium hexacyanoferrate(III) as oxidant in a 1 1 tert-butyl alcohol-water two-layer system can suppress the second cycle and lead to high enantioselectivity (91). This procedure allows the convenient synthesis of 3-lactams from 2-octenoate. 

Extrusion of sulfur dioxide from l,3-thiazolidin-4-ones 1,1-dioxides (17) can be used in the synthesis of [3-lactams (83JOC494). 

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