Tandem cyclization–cycloaddition reactions of .Tandem cyclization–cycloaddition reactions of

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  • Tandem cyclizationcycloaddition reactions of rhodiumgenerated carbenoids from a-diazo carbonyl compounds

    Goverdhan Mehtaa,* and Sengodagounder Muthusamyb,*,

    aDepartment of Organic Chemistry, Indian Institute of Science, Bangalore 500 012, IndiabCentral Salt and Marine Chemicals Research Institute, Bhavnagar 364 002, India


    1. Introduction 94771.1. Scope and organization of the review 9478

    2. Intramolecular five-membered ring carbonyl ylides 94782.1. With keto carbonyl groups 94792.2. With ester carbonyl groups 94842.3. With amide carbonyl groups (isomunchnones) 9485

    2.3.1. Intermolecular isomunchnone cycloadditions 94852.3.1.1. Applications in asymmetric synthesis 9487

    2.3.2. Intramolecular isomunchnone cycloadditions 94893. Intramolecular six-membered ring carbonyl ylides 9492

    3.1. With keto carbonyl groups 94923.1.1. Applications in asymmetric synthesis 9495

    3.2. With ester carbonyl groups 94963.2.1. Applications in asymmetric synthesis 9497

    3.3. With amide carbonyl groups 94984. Intramolecular seven-membered ring carbonyl ylides 9498

    4.1. With keto carbonyl groups 94984.2. With amide carbonyl groups 9499

    5. Intermolecular carbonyl ylides 94996. Concluding remarks 9500

    1. Introduction

    The rapid generation of molecular complexity, in acontrolled and predictable manner, is a contemporarytheme in the practice of modern organic synthesis andfinds application in accessing newer entities for thepharmaceutical industry. Efficiency, atom economy, regio-,stereo- and enantiocontrol, ready availability of startingmaterials and environmentally benign processing are someof the common concerns in any synthetic endeavor.Synthetic brevity is, however, central to the generation ofmolecular complexity in a resource-effective manner and, in

    order to attain that objective, two strategic options havebeen generally explored in recent years, one involvingmulticomponent reactions and the other involving reactionsleading to multiple carbon-carbon bond formation throughtandem processes. The latter approach involves recourse toreactions like multiple cycloadditions or cyclizationcycloaddition sequences in which many bonds areformed in a single mode operation and these cascadeprocesses have an inherent advantage in expeditiouslyassembling polycyclic structures with proper stereo-chemical control.

    Tandem processes1 7 of a diverse nature, promoted throughthermal or photochemical activation or catalysts, havealready proven their utility in organic synthesis and foundmany applications in the acquisition of complexity in theform of functionalized carbo- and heteropolycyclic struc-tures. Cascade reactions involving transition-metal catalysts Tel.: 91-278-567-760; fax: 91-278-567-572.

    * Corresponding authors. Tel.: 91-80-360-2367; fax: 91-80-360-0936;e-mail: gm@orgchem.iisc.ernet.in; salt@csir.res.in

    Keywords: carbonyl ylides; cyclization; cycloaddition; diazo carbonylcompounds; polycyclic systems; rhodium(II) acetate.

  • in particular have gained significant importance in recentyears.8 11 Among these, the tandem cyclizationcyclo-addition reaction of carbenoids derived from a-diazocarbonyl compounds using rhodium(II) catalysts has beenon the ascendancy and attracted the attention of manychemists for diverse synthetic applications and forms thesubject matter of this report.12,13

    Historically, carbenoids derived from a-diazo carbonylcompounds using copper catalysts were mainly employedfor cyclopropanation and CH and XH insertion reac-tions. The formation of carbonyl ylides (1,3-dipolesobtained through carbenoid insertion into a carbonylgroup) under these conditions was not very efficient andefforts to trap them received only limited attention. Theadvent of rhodium-based14 catalysts for generatingcarbenoids from a-diazo carbonyl compounds was a turningpoint, however, as it provided efficient access to carbonylylides that could be trapped through 1,3-dipolar cyclo-addition.15,16 It is the selectivity and preparative efficiencyof the rhodium(II) mediated carbonyl ylide formation froma-diazo carbonyl compounds that has paved the way formany interesting synthetic applications through cascadeprocesses.12,13 Many methods like thermolysis or photolysisof epoxides (D) having electron-withdrawing substituents,17

    the thermal extrusion of nitrogen from 1,3,4-oxadiazolines(G),18 extrusion of carbon dioxide from 1,3-dioxolan-4-ones (F)19 and the photolysis of diazo carbonyl compoundsin noble gas matrixes (E)20 are known for the generation ofcarbonyl ylides (Fig. 1). The easiest route to carbonyl ylides,however, is through the addition of a metallo-carbenoid12,13

    derived from a diazo precursor onto the oxygen atom of acarbonyl group (A) (Fig. 1). The carbonyl ylides (B)generated can be readily trapped inter- or intramolecularlywith p-bonds via a range of 1,3-dipolar cycloadditionreactions21 to afford oxygen-containing polycyclic systems(C), which are amenable to further diverse transformations.This aspect of carbonyl ylide chemistry, particularly whenexecuted in an intramolecular mode, leading to complexoxacyclic systems, has gained importance because highlysubstituted oxacyclic moieties are conspicuous22,23 struc-tural units in naturally occurring bioactive molecules likeionophores,24 macrocyclic antibiotics25 and a range ofmarine toxins.26 In addition, complex oxapolycyclics can be

    readily maneuvered to furnish carbocyclic compounds andcarbonyl ylide cycloadditions have therefore found appli-cation in the synthesis of both heterocyclic and carbocyclicsystems.

    1.1. Scope and organization of the review

    As indicated above, access to practical methods forgenerating carbonyl ylides has resulted in a plethora ofactivity directed towards the acquisition of complexheterocyclic frameworks and diverse natural products. Thegeneration and trapping of an intramolecular carbonyl ylidemethodology were initially demonstrated by Ibata andco-workers27 and this has culminated in the development ofa very versatile methodology for the construction ofcomplex and highly functionalized organic compounds.This review will cover aspects related to the carbonyl ylidesderived from the Rh(II)-catalyzed reactions of a-diazocarbonyl compounds and provide an overview of theexisting literature with appropriate emphasis on recentexamples. For convenient dissemination of the literature,the examples are schematically presented. The fertile area ofcascade reactions emanating from carbonyl ylides has beenreviewed in 199112 and updated13 in part in 1996 by Padwa,whose group has made pioneering contributions to the field.It is hoped that the present review covering the period of1991 to mid-2002 will provide a useful reference for thoseactive in this area and stimulate further efforts in this spherewhich has much more potential for varied syntheticapplications.

    This report is organized on the basis of the intramoleculargeneration of carbonyl ylide intermediates of various ringsizes, namely five, six and seven-membered rings, and theirsynthetic applications are delineated in the respectivesections. Each of these ring sizes is further sub-classifiedbased on the nature of the carbonyl group, e.g. ketone, esterand amide, primarily involved in the generation of thecarbonyl ylide intermediate from the rhodium(II) carbenoidprecursor. In general, ketone and amide carbonyl groups aremuch more reactive towards the formation of carbonyl ylidethan the ester carbonyl group. From the synthetic andmechanistic point of view, five- and six-memberedintramolecular carbonyl ylide intermediates and theirsubsequent [32]-cycloaddition reactions have receivedgreater attention. Only a very few examples of the formationof seven-membered ring carbonyl ylides have surfaced sofar. In Section 5, the intermolecular generation of carbonylylides is discussed and these have not yet received as muchattention as their intramolecular counterparts.

    2. Intramolecular five-membered ring carbonyl ylides

    When a diazo functionality located at the g-position to acarbonyl group of a substrate is exposed to an appropriatetransition metal catalyst, an intramolecular five-memberedring carbonyl ylide is formed as a transient species throughtransannular cyclization onto the neighboring keto carbonyloxygen. The formation of less strained five-membered ringylides is generally favored compared to other ring sizes.28

    The generation of intramolecular five-membered ringcarbonyl ylide intermediates in the presence of metalFigure 1.

  • catalyst can be achieved with a variety of carbonyl-bearingprecursors such as ketones, esters and amides. Thesuccessful trapping of such five-membered ring carbonylylides depends on the substrate structure and the absence ofcompetition from alternative intramolecular reaction path-

    ways. As an example, the rhodium(II)-catalyzed reaction ofsubstituted a-diazo ketones 1 generates initially therhodium-carbenoids 2, followed by the five-memberedring carbonyl ylides 3, which can be trapped regio- andstereoselectively using a dipolarophile AB to form theoxabicyclic compounds 4 (Scheme 1). If R1 is a hydrogenatom (see Scheme 1), the formation of the correspondinghydrogen migrated product 5 through an intramolecularproton transfer, which is faster than intermolecular 1,3-dipolar cycloaddition, is observed. From a syntheticperspective and to gain efficient access to the cycloadditionproducts 4, it is important that competitive reactions likeproton transfer and CH insertion are avoided through aproper choice of the substrate 1.

    2.1. With keto carbonyl groups

    Among the early examples of the successful generation andtrapping of the five-membered ring carbonyl ylidesemanating from the pioneering efforts of Padwa are thereactions of the readily accessible diazo carbonyl com-pounds 6 and 8 with rhodium(II) acet