Generation of carbonyl ylide dipoles from the Rh(II)-catalyzed cyclization of α -diazo- β -keto-1,5-diesters ‡

The Rh(II)-catalyzed reaction of ethyl 2-diazo-3-[1-(ethoxycarbonyl)cyclopropyl]-3-oxo- propanecarboxylate with various dipolarophiles afforded dipolar cycloadducts in good yield. The reaction involves the formation of a rhodium carbenoid and subsequent transannular cyclization of the electrophilic carbon onto the remote ester carbonyl group to generate a five-membered cyclic carbonyl ylide which undergoes a subsequent dipolar cycloaddition reaction. In the absence of a trapping agent, a head to tail coupling of the 1,3-dipole intermediate occurs to give a dimer. Heating a benzene solution of the dimer at 80 ºC in the presence of various dipolarophiles gave the same cycloadducts as was obtained from the Rh(II)-catalyzed reaction.


Introduction
In recent studies, 1 we have described the formation of cyclic carbonyl ylide dipoles by a process involving cyclization of an electrophilic metallo carbenoid onto an adjacent carbonyl group. 2 The general reaction investigated is illustrated below; variations in chain length (n = 0, 1, 2) and nature of the activating group (G) were explored. 1,2With limited exceptions, 3 alkyl and aryl ketones were employed, and dipole 2 was generated by the rhodium(II)-catalyzed decomposition of diazoalkane-dione 1 in benzene at 80 ºC (Scheme 1). 4

Scheme 2
Similar approaches have been independently reported by Kinder 12 and McMorris. 13The illudins and certain derivatives have been evaluated for antitumor activity at the NCI and show selective toxicity for human myelocytic leukemia and other carcinoma cells of various species of origin. 146][17] The spirocyclopropane and α,β-unsaturated ketone moieties present in the illudin skeleton constitute a bis-electrophile that is undoubtedly responsible for the DNA damage. 18me simpler illudin analogs such as the dehydroilludins M (12) as well as isodehydroilludin M (13) have recently been shown to possess high efficacy against a number of adenocarcinomas. 17,18In an effort to increase the versatility of the cascade reaction of diazo ketoesters and also to prepare additional illudin analogs for biological testing, we have undertaken a study of the effect of an interacting ester group on the efficiency of dipole formation.Details of these cyclizations are the subject of this paper.

Results and Discussion
In order to apply the tandem cyclization-cycloaddition sequence to the eventual synthesis of ester analogs of the illudin family, we decided to first establish the viability of the dipolar cycloaddition using the cyclopropanated diazo ketoester 14 with a variety of acyclic and cyclic dipolarophiles.

Scheme 3
Reaction with N-phenylmaleimide and maleic anhydride resulted in the formation of cycloadducts 16 and 17 in comparable yield.Earlier studies in our laboratory demonstrated that the bimolecular cycloaddition of cyclic carbonyl ylides with phenyl-sulfonyl-substituted alkenes was a remarkably efficient process. 20MO calculations using the AM1 Hamiltonian reveal a small energy gap between the HOMO of the dipole and the LUMO of the phenylsulfonyl-substituted alkene.This led us to examine the reaction between 14 and 2-(4-methylphenyl)sulfonyl-5,5-dimethylcyclopentenone11 which afforded the exo-cycloadduct 18 as the major diastereomer in 60% yield.The Rh(II)-catalyzed reaction of 14 with 1,1-diethoxyethylene was also studied and was found to produce cycloadduct 19 in 68% yield.This regiochemical selectivity is readily understandable on the basis of perturbation theory 19 and is also analogous to previous findings encountered in our laboratory. 20

Scheme 4
All of the above results can be accommodated by a mechanism involving formation of a fivemembered ring carbonyl ylide (i.e.20) derived by interaction of the initially formed rhodium carbenoid with a pair of electrons on the neighboring ester carbonyl group.In the absence of any added trapping agent, ylide 20 (Scheme 4) undergoes dimerization to produce the novel head to tail dimer 21 as a crystalline solid, mp 190-191 ºC, in 68% yield.The structure of 21 was unequivocally established by an X-ray crystal structure analysis 21 (Figure 1).A space group of P21/c, Z = 4 and density of 1.35 was found.The oxabicyclo portions of the dimer rest in an envelope conformation as expected from the sp 2 -hybridization of the keto carbonyl groups at the 3 and 7-positions and the sp 2 -like hybridization at the induced planarity of cyclopropane carbons.The packing diagram showed the absence of any strong intermolecular associations.The antirelationship of the bridged ethers is understandable in terms of minimization of unfavorable dipole interactions in the transition state.More than likely, the push-pull nature of the alkoxy substituted carbonyl ylide enhances its stability thereby allowing the relatively rare dimerization reaction of the dipole to occur. 22lacement of a tethered π-bond on the diazo ester side chain was also examined.Thus, the Rh(II)-catalyzed decomposition of diazo ketodiester 22 in benzene at 80 ºC for 5 h furnished the expected intramolecular cycloadduct 24 as the exclusive product (60%).When the reaction was stopped after 1 h, however, a 1:1-mixture of cycloadduct 24 and dimer 25 was obtained in 84% yield.Further heating of the mixture at 80 ºC afforded additional quantities of cycloadduct 24 (Scheme 5).This transformation presumably involves C-C bond cleavage of the dimer followed by intramolecular trapping of the resultant carbonyl ylide intermediate 23.Additional support for the involvement of dipole 23 comes from heating the 1:1-mixture of 24 and 25 in the presence of N-phenylmaleimide.Under these conditions, the bimolecular cycloadduct 26 was isolated in 38% yield.

Scheme 5
In conclusion, the Rh(II)-catalyzed cyclization/cycloaddition cascade of cyclopropylsubstituted diazo ketoesters bearing a neighboring alkoxycarbonyl group affords 1,3-dipolar cycloadducts in good yield.The regiochemical results encountered can be rationalized on the basis of FMO considerations.In the absence of any trapping agent, the initially formed dipole undergoes bimolecular coupling to produce a novel head to tail dimer.We are currently investigating further applications of the method outlined here as an approach to alkoxycarbonylsubstituted illudin derivatives.

Experimental Section
General Procedures.Melting points are uncorrected.Mass spectra were determined at an ionizing voltage of 70 eV.Unless otherwise noted, all reactions were performed in flame-dried glassware under an atmosphere of dry argon.Solutions were evaporated under reduced pressure with a rotary evaporator and the residue was chromatographed on a silica gel column using an ethyl acetate/hexane mixture as the eluent unless specified otherwise.All solids were recrystallized from ethyl acetate/hexane for analytical data.