FULL PAPER An Asymmetric Domino Three-Component Synthesis of β-Lactams Claudio Palomo* a , Jesu ´s M. Aizpurua* a , Jose ´ Javier Gracenea a , Santiago Garcı ´a-Granda b[ ] , and Pilar Pertierra b Departamento de Quı ´mica Orga ´nica, Facultad de Quı ´mica, Universidad del Paı ´s Vasco a , Paseo Manuel Lardizabal-3, E-20009 San Sebastia ´n, Spain Fax: (internat.) + 34-943212236 E-mail: qoppanic@sc.ehu.es Departamento de Quı ´mica Fı ´sica y Analı ´tica, Universidad de Oviedo b , E-33071-Oviedo, Spain Fax: (internat.) + 34-985103125 E-mail: sgg@sauron.quimica.uniovi.es Received March 6, 1998 Keywords: Antibiotics / Asymmetric synthesis / β-Lactams / Michael additions / Multicomponent reactions Lithium dialkylcuprates react either in a sequential one-pot methylidene)(4-methoxyphenyl)amine 9 to afford the corresponding cis -3-alkyl-4-methoxycarbonyl-1-(4-methoxy- or in a domino “three-component” fashion with chiral Michael acceptors, like Oppolzer’s N -enoyl-2,10- phenyl)azetidin-2-ones 10, 14–15 in overall yields of 40–67% and enantiomeric excesses of 91–99 %. camphorsultams 7 and 11 or Evans’ N -enoyl-4-phenyl-1,3- oxazolidin-2-ones 8 and 13, and N -(methoxycarbonyl- Introduction starting materials and the high levels of asymmetric induc- tion often attained through the use of either chiral car- The development of new approaches to the stereocon- boxylic acid esters or chiral imines. [7] trolled synthesis of β-lactams continues to be of crucial im- portance within the context of the most widely employed Figure 1. Representative families of β-lactam antibiotics and elas- class of antimicrobial agents, the β-lactam antibiotics. [1] tase inhibitors characterized by the presence of aliphatic chains at The majority of these compounds are characterized by a the C-α position of the β-lactam carbonyl group; for the nature of R 1 , X and R 2 substituents and configurations in 1, see ref. [1] bicyclic structural framework of type 1. Amongst them, the trinems of Glaxo Wellcome laboratories, particularly the methoxy derivative 2, which is under phase-II clinical trial, exemplify the degree of evolution of this area. [2][3] As a consequence of this current interest, several strategies for the construction of bicyclic β-lactam antibiotics have been developed and the topic has been widely documented and reviewed several times. [4] The most commonly used strategy to access these systems lies in the prior construction of a monocyclic non-racemic β-lactam such as 3, followed by chemical manipulations at N-1 and C-4 positions of the az- etidinone nucleus and ring closure at a later stage of the synthesis. Besides this significance, 3-alkyl-4-alkoxycarbon- ylazetidin-2-ones 4-6 have also been found to be important We wish to report here a conceptually different but in inhibitors of the human leukocyte elastase (HLE), which is practice equivalent strategy of accessing β-lactams based on believed to be at the origin of the enzymolytic degradation a ternary combination of components, namely, the conju- of a variety of proteins, including the structural proteins, gate addition of carbon nucleophiles, i.e. organocuprate re- fibronectin, collagen, and elastin. [5] Therefore, the high agents, to α,β-unsaturated carboxylic acid derivatives and number of methods currently available for the stereoselec- subsequent condensation of the resulting enolates with an tive preparation of monocyclic β-lactams is not surpris- imine. This strategy (Figure 2), distinguished by the discon- ing. [6] With few exceptions, the majority of these methods nection of two carbon-carbon bonds, involves an efficient involve a combination of two reactants that provide the re- combination of three reactants either in a sequential or in quired β-lactam framework in a single step. Special atten- a one-pot domino process. As a result, several parameters tion has been put on the use of the metal ester enolate-im- must be carefully controlled, vide infra, and particularly the ine condensation because of the easy availability of the reactivity of the in situ generated copper enolates which have essentially been ignored within the context of β-lac- [ ] X-ray crystal structure analysis. tam synthesis. [7][8] Eur. J. Org. Chem. 1998, 2201-2207  WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998 1434 -193X/98/1010-2201 $ 17.50+.50/0 2201