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    Tetrahedron 68 (2012) 10640e10664

    Contents lists available

    Tetrahedron

    journal homepage: www.elsevier .com/locate/ tet

    Advances in the chemistry of b-lactam and its medicinal applications

    Anushree Kamath a,b, Iwao Ojima a,b,*a Institute of Chemical Biology & Drug Discovery (ICB&DD), Stony Brook University, Stony Brook, NY 11794-3400, USAbDepartment of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA

    a r t i c l e i n f o

    Article history:Received 11 May 2012Available online 7 August 2012

    Keywords:b-Lactamb-Lactam synthon methodAsymmetric synthesisStaudinger cycloadditionEster enolate cyclocondensationNon-protein amino acidsPaclitaxelTaxoidNitrogen-heterocycles

    * Corresponding author. Tel.: 1 631 632 1339; faaddress: iojima@notes.cc.sunysb.edu (I. Ojima).

    0040-4020/$ e see front matter 2012 Elsevier Ltd.http://dx.doi.org/10.1016/j.tet.2012.07.090

    1. Introduction

    b-Lactam or azetidin-2-one is an important structural motif ofthe penicillin, cephalosporin, carbapenem, and carbecephem clas-ses of antibiotics.1 Naturally occurring as well as synthetic mono-bactams, such as nocardicins and tabtoxin, are also known for theirunique antibacterial activities.2e4 Besides their importance as thekey structural component of b-lactam antibiotics, b-lactams havebeen attracting considerable interest in organic synthesis as ver-satile synthetic intermediates and chiral synthons.5e13 In addition,the b-lactam scaffold has found new pharmaceutical applicationsother than its use as antibiotics, such as LHRH antagonists,14 cho-lesterol absorption inhibitors,15 and anticancer agents.16e19 Thering strain of the b-lactam skeleton facilitates ring-opening re-actions,8,20,21,22 and this unique property has been exploited for thesynthesis of a variety of medicinally active compounds.

    For the last couple of decades, a large number of b-lactam-basedsynthetic methods, collectively termed as b-lactam synthonmethod, has been developed. This method has provided highlyefficient routes to a variety of non-protein amino acids, oligopep-tides, peptidomimetics, and nitrogen-heterocycles, as well as bi-ologically active natural and unnatural products of medicinal

    x: 1 631 632 7942; e-mail

    All rights reserved.

    interest, such as indolizidine alkaloids, paclitaxel, docetaxel, tax-oids, cyptophycins, lankacidins, etc.5,7e13

    In this report, we present an overview of the evolution of themethods for the synthesis of enantiopure b-lactams, and the ap-plications of the b-lactam synthon method for the synthesis ofbiologically active compounds of medicinal interest. Examples ofthe use of the rigid b-lactam scaffold for drug design and discoveryare also described.

    2. Asymmetric synthesis of b-lactams

    The Staudinger keteneeimine [22] cycloaddition and the chi-ral ester enolateeimine cyclocondensation are the two methods,which are most commonly used for the synthesis of b-lactams withexcellent enantiopurity. Thus, these two synthetic methods arediscussed in this section.

    2.1. Staudinger keteneeimine [2D2] cycloaddition

    In 1907, long before the antibacterial activity of penicillin wasdiscovered, Staudinger reported the first synthesis of a b-lactam,1,3,3,4-tetraphenylazetidin-2-one, through the [22] cycloadditionof diphenylketene with a Schiff base derived from aniline andbenzaldehyde.23 Subsequently, the scope of this reaction has beenextended to alkyl-, amino-, halo-, alkoxy-, and siloxy-ketenes, aswell as imino esters. Because of its broad scope in substrate

    Delta:1_given nameDelta:1_given nameDelta:1_surnameDelta:1_given namemailto:iojima@notes.cc.sunysb.eduwww.sciencedirect.com/science/journal/00404020http://www.elsevier.com/locate/tethttp://dx.doi.org/10.1016/j.tet.2012.07.090http://dx.doi.org/10.1016/j.tet.2012.07.090http://dx.doi.org/10.1016/j.tet.2012.07.090http://crossmark.dyndns.org/dialog/?doi=10.1016/j.tet.2012.07.090&domain=pdf

  • A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e10664 10641

    structures and simplicity in experimental procedure, this reactionis regarded as one of the most reliable routes to b-lactams.1 How-ever, in spite of common practice in laboratory synthesis for de-cades, the mechanistic details of this reaction have been disputedand subjected to theoretical investigations since its inception.24,25

    The most widely accepted mechanism is a two-step reaction pro-cess, which involves the nucleophilic attack of the imine nitrogenon the electrophilic central carbon of a ketene, generated in situfrom an acid chloride and a base, to form a zwitterionic in-termediate, followed by conrotatory ring closure to give the four-membered ring system (Fig. 1).24,25

    R1Cl

    O Base

    O

    R1

    NO R3

    R2R1

    NO

    H HR1

    R3

    R2

    NO R3

    R1 R2N

    O

    H HR1

    R3

    R2

    NR3

    R2

    trans

    cis

    H

    H

    HH

    H H

    Fig. 1. Mechanism of Staudinger [22] keteneeimine cycloaddition.

    In the reactionof amonosubstitutedketenewith analdimine, twochiral centers are introduced to the cycloadduct. Thus, the reactionwould give either a single stereoisomer (i.e., cis or trans) of b-lactamor a mixture of cis- and trans-b-lactams, depending on the reactantsand reaction conditions.25,24 As Fig. 1 shows, cis-b-lactam should beformed from the zwitterionic intermediate bearing the (E)-iminemoiety, but if isomerization to the zwitterionic intermediate bearingthe (Z)-imine moiety takes place, the reaction should give trans-b-lactam.26e29 This mechanism also indicates that the reaction witha (Z)-iminewould give the corresponding trans-b-lactam selectively.Theoretical studies on the origin of the stereoselectivity suggest that

    N

    Me

    Ph

    Cl

    ClN

    O

    O

    O

    Et3NN

    N

    O

    OCl

    Me

    PhON

    N

    O

    OCl

    Me

    PhO

    9:11 2 3

    Scheme 1.

    the relative transition-state energy in the rate-determining step isdictated by electronic torque selectivity.30,31

    The stereoselectivity of the reaction is influenced by reactionvariables such as temperature, solvent, base, additives, chiral pen-dant groups, order of addition of reagents, microwave irradiation,

    N

    Ph

    CO2Bn

    OR N3CH2COCl, Et3NCH2Cl2, -40 C

    N

    4a: R = TPS4b: R = TBS4c: R = H

    64% (for 4a)

    Scheme

    etc.32e34 For example, it has been shown that non-polar solventsfavor the formation of cis-b-lactamwhereas polar solvents facilitatetrans-b-lactam formation. The result was explained by the stabili-zation of the zwitterionic intermediate in a polar solvent, promotingisomerization to the energetically more stable intermediate bearingthe (Z)-imine moiety before conrotatory ring closure.32

    Asymmetric keteneeimine [22] cycloaddition can be per-formed using combinations of (i) a chiral imine with an achiralketene, (ii) a chiral ketene with an achiral amine or (iii) a chiralketene with a chiral imine.

    2.1.1. Asymmetric [22] cycloaddition of achiral ketenes and chiralimines. Chiral imines can be prepared either from chiral aminesor from aldehydes. However, the diastereoselectivity of the re-action is lower, in most cases, using a chiral imine from a chiralamine, as compared to that from a chiral aldehyde.35 Neverthe-less, chiral amine sources are widely used for the asymmetricsynthesis of b-lactams.9,36 For example, the reaction of phthali-midoacetyl chloride with chiral imine 1, derived from (R)-1-phenylethylamine, in the presence of triethylamine gave b-lac-tams 2 and 3 in 74% combined yield with high stereoselectivity(2/39:1) (Scheme 1).36

    Commercially available enantiopure esters of a-amino acids arecommon sources of chiral amines. For example, 3-azido-b-lactam5a (RtriphenylsilylTPS) was obtained in 64% yield and 19:1 dr(5a/6a) using imine 4a derived from (R)-O-TPS-threonine benzylester and cinnamaldehyde (Scheme 2).37 The stereoselectivity of

    NO

    H H3

    Ph

    +

    CO2Bn

    ORN

    O

    H HN3

    Ph

    CO2Bn

    OR

    5a

    5b

    5c

    19:19:11:1

    6a

    6b

    6c

    2.

  • A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e1066410642

    this reaction was found to depend critically on the bulkiness of thehydroxyl protecting group. Thus, the reaction of 4b (Rtert-butyl-dimethylsilylTBS) gave 5b with 9:1 dr (5b/6b) and that of 4c(RH) afforded a 1:1 mixture of 5c and 6c.37

    Alternatively, one of the most effective routes for a large-scalesynthesis of b-lactams with high enantiopurity is to use chiralimines derived from chiral aldehydes such as a-oxyaldehydes andsugar-derived aldehydes (Scheme 3).35,38e40 For example, the[22] cycloaddition of various ketenes with chiral imines 9 of D-glyceraldehyde acetonide (8), derived from D-mannitol via 7,afforded cis-b-lactams 10 exclusively in 45e70% yield.41,42 Theacetonide moiety of b-lactams 10 was deprotected to the corre-sponding b-lactam diols, which were oxidized by ruthenium te-troxide, followed by diazomethane esterification, to afford the 4-carbomethoxy-b-lactams.41 The b-lactam diols were also con-verted into the corresponding 4-formyl-b-lactam 11, which areversatile synthetic intermediates for further manipulations.13,42e44

    HOOH

    OH

    OHOH

    OHD-mannitol

    OO

    NR1

    R2CH2COCl, Et3N

    acetone, rt OO

    CH2Cl2, -78 C-rt

    R1NH2, Et3N

    ZnCl2

    9

    CH2Cl2, rt

    R1 = PMP, Bn, CH2CO2Me; R2 = N3, MeO, PhO

    Scheme

    H2N OH

    Me

    CO2H

    H2N OT

    Me

    CO2Me

    NO

    Ox

    OTBS

    OO

    Me

    MeO2C

    (R)-threonine

    O O

    NTBSO

    CO2Me

    Me

    i) 3 N HCl, MeOHreflux, 100%

    ii) TBSCl, imidazoleDMF,