Carbonyl ylides, cycloaddition with

Lycorine is an alkaloid that has attracted attention from both the synthetic community and pharmacologists. Prior synthetic approaches have included inter-and intramolecular Diels-Alder cycloaddition. Based on a similar retrosynthetic disconnection, Padwa and co-workers (106,109) chose to use a push-pull carbonyl ylide cycloaddition with a disubstituted pyrrolidinone core to generate a tricyclic substrate. The major difference for this synthetic smdy was the availability of a labile proton a to the carbonyl moiety (Scheme 4.53). 

The intermolecular version of the above reaction has also been reported (391). In the first example, a rhodium-catalyzed carbonyl ylide cycloaddition with maleimide was studied. However, only enantioselectivities of up to 20% ee were obtained... 

A type of 1,3-dipole that has received considerable recent interest is the carbonyl ylide. One method for its formation makes use of carbenoid chemistry (see Section 4.2). Cyclization of an electrophiUc rhodium carbenoid onto a nearby carbonyl group provides access to the carbonyl ylide. Cycloaddition with an alkyne or alkene dipolarophile then gives the dihydro- or tetrahydrofuran product. For example, the carbonyl ylide 235, formed from the diazo compound 234 and rhodium(II) acetate, reacts with dimethyl acetylenedicarboxylate to give the bridged dihydrofuran 236 (3.148). 

As with any modern review of the chemical Hterature, the subject discussed in this chapter touches upon topics that are the focus of related books and articles. For example, there is a well recognized tome on the 1,3-dipolar cycloaddition reaction that is an excellent introduction to the many varieties of this transformation [1]. More specific reviews involving the use of rhodium(II) in carbonyl ylide cycloadditions [2] and intramolecular 1,3-dipolar cycloaddition reactions have also appeared [3, 4]. The use of rhodium for the creation and reaction of carbenes as electrophilic species [5, 6], their use in intramolecular carbenoid reactions [7], and the formation of ylides via the reaction with heteroatoms have also been described [8]. Reviews of rhodium(II) ligand-based chemoselectivity [9], rhodium(11)-mediated macrocyclizations [10], and asymmetric rho-dium(II)-carbene transformations [11, 12] detail the multiple aspects of control and applications that make this such a powerful chemical transformation. In addition to these reviews, several books have appeared since around 1998 describing the catalytic reactions of diazo compounds [13], cycloaddition reactions in organic synthesis [14], and synthetic applications of the 1,3-dipolar cycloaddition [15]. 

Friedrichsen and co-workers (135), along with Padwa, has utilized the carbonyl ylide cycloaddition to generate reactive furan moieties that can be further used in inter- or intramolecular Diels-Alder reactions to prepare aza- and carbocyclic compounds. Friedrichsen conducted a number of synthetic and theoretical studies on the reactivity, regioselectivity, and stereoselectivity of substituted furan formation and subsequent Diels-Alder reaction (Scheme 4.69). 

Hashimoto and co-workers (139) further looked at an intermolecular carbonyl ylide cycloaddition screening several different chiral rhodium catalysts. The Hashimoto group chose to study phthaloyl amino acid derivatives for enantiocon-trol of the cycloaddition reactions (Fig. 4.8). Using fluorinated or ethereal solvents with the phthaloyl catalysts gave ee ratios of 20-69%. 

Reactions of the same carbonyl ylide intermediate with aldehydes are even more fruitful. The Rh2(OAc)2 catalyzed reaction proceeds at room temperature in the presence of 2 mol% of the catalyst, but the diastereoselectivity is disappointingly low (endo/exo = 49 51, Scheme 11.56). However, when 10 mol% of the cocatalyst Yb(OTf)3 is added, the reaction becomes highly exo-selective (endo/ exo = 3 97) (198). Suga has extended this Lewis acid catalyzed carbonyl ylide cycloaddition reaction to catalyzed asymmetric versions. The chiral cocatalyst employed is ytterbium(III) tris(5)-1,1 -binaphthyl-2,2 -diyl phosphonate, Yb[(S) BNP]3 (10 mol%). In the reaction of methyl o-(diazoacetyl)benzoate with benzyloxyacetaldehyde in the presence of Rh2(OAc)2 (2 mol%) at room temperature with the chiral Yb catalyst, the diastereoselectivity is low (endo/exo = 57 43) and the enantiopurity of the endo-cycloadduct is 52% ee. 

The only other dipolar species that has been added to thiophene is the carbonyl ylide (287). Thus tetracyanoethylene oxide, as the carbonyl ylide, reacts with thiophene to form the adduct (288) in 70% yield (65JA3657, 68T2551). Several monosubstituted thiophenes have been used in this reaction. From competitive experiments it has been shown that the rate of cycloaddition to furan and benzo[6]furan is greater than that to thiophene and benzo[6]thiophene respectively (75ACS(B)441). 

The Rh2(OAc)4-catalysed reactions of ethyl diazoacetate with substituted benzalde-hydes yielded 1,3-dioxolanes via an initially formed carbonyl ylide. Catalyst-dependent diastereo-control was observed only when p-mtxobenzaI dchydc was used as catalyst.104 The intramolecular cycloaddition of carbonyl ylide dipoles with tethered alkenyl 71-bonds is greatly enhanced by placing an sp1 centre on the tethered side-chain.105 The thermal reaction of 3-phenyloxirane-2,2-carbonitrile and 2-phenyl-3-thia-l-azaspiro-[4,4]non-l-ene-4-thione yields cis- and trans-cycloadducts via a regioselective 1,3-dipolar cycloaddition of an intermediate carbonyl ylide.106... 

The tandem carbonyl ylide/cycloaddition reaction is also observed when crotonaldehyde or acetone is used instead of benzaldehyde (dimethyl fumarate as dipolarophile), whereas with cyclohexanone, an enol ether derived from the carbonyl ylide is isolated [19] (Scheme 9). 

The distinction between Pd and Rh catalysts was also verified for diazoketone 190. In this case, the carbonyl ylide was trapped by intramolecular [3-1-2] cycloaddition to the C=C bond Decomposition of bis-diazoketone 191 in the presence of CuCl P(OEt)3 or RhjCOAc) led to the pentacyclic ketone 192 most remarkably, one diazoketone unit reacted by cyclopropanation, the second one by carbonyl ylide formation With [(ri -CjHjlPdClJj, a non-separable mixture containing mostly polymers was obtained, although bis-diazoketones with one or two allyl side chains instead of the butenyl groups underwent successful twofold cyclopropanation... 

Mejia-Oneto JM, Padwa A (2006) Application of the Rh(II) cyclization/cycloadditi(Hi cascade for the total synthesis of (H—)-aspidophytine. Org Lett 8 3275-3278 Mejia-Oneto JM, Padwa A (2008) Total synthesis of the alkaloid (+—)-aspidophytine based on carbonyl ylide cycloaddition chemistry. Helv Chim Acta 91 285-302 Hong X, France S et al (2006) Cycloaddition protocol for the assembly of the hexacyclic framework associated with the kopsifoline alkaloids. Org Lett 8 5141-5144 Hong X, France S et al (2007) A dipolar cycloaddition approach toward the kopsifoline alkaloid framework. Tetrahedron 63 5962-5976... 

An efficient protocol for the synthesis of syn-facially bridged norbornane frameworks has been developed via the tandem cyclization-cycloaddition reactions of the carbonyl ylide 57 with norbornene derivatives. The reaction of the diazo ketone 56 with the dipolarophile 62 in the presence of Rh2(OAc)4 furnished [85] the 5y -facially bridged oxa-norbornane framework 63 in high yield (Scheme 17). 

An enantioselective version of the above reactions has been reported. Lewis acids such as Yb(OTf)3 can profoundly affect the stereochemical outcome of the carbonyl ylide 1,3-dipolar cycloadditions [137]. This provided an indication to effect asymmetric carbonyl ylide cycloaddition using a chiral Lewis acid. The first example of such asymmetric induction using the chiral lanthanide catalysts has been reported [138,139]. For example, the reaction of diazoacetophenone 89 with benzyloxyacetaldehyde, benzyl pyruvate and 3-acryloyl-2-oxazoHdinone in the presence of chiral 2,6-bis(oxazolinyl)pyridine ligands and scandium or ytterbium complexes furnished the corresponding cycloadducts 165-167 with high enantioselectivity (Scheme 53). 

Kusama et al. also developed the PtCl2-catalyzed benzannulation using o-alkynylbenzoates 41 or benzothioates with vinyl ethers 8. The reaction proceeded at room temperature and naphthyl ketones 42 were obtained [28]. They proposed that the reaction proceeded through [3 -I- 2]-cycloaddition of the platinum-containing carbonyl ylides 43 with 8, followed by 1,2-alkyl migration, as shown in Scheme 15.16. 

The rhodium-catalyzed tandem carbonyl ylide formation/l,3-dipolar cycloaddition is an exciting new area that has evolved during the past 3 years and high se-lectivities of >90% ee was obtained for both intra- and intermolecular reactions with low loadings of the chiral catalyst. 

Interaction of a carbonyl group with an electrophilic metal carbene would be expected to lead to a carbonyl ylide. In fact, such compounds have been isolated in recent years 14) the strategy comprises intramolecular generation of a carbonyl ylide whose substituent pattern guarantees efficient stabilization of the dipolar electronic structure. The highly reactive 1,3-dipolar species are usually characterized by [3 + 2] cycloaddition to alkynes and activated alkenes. Furthermore, cycloaddition to ketones and aldehydes has been reported for l-methoxy-2-benzopyrylium-4-olate 286, which was generated by Cu(acac)2-catalyzed decomposition of o-methoxycarbonyl-m-diazoacetophenone 285 2681... 

Diels-Alder reaction of the 1,3,4-oxadiazole with the pendant olefin and loss of N2, the C2-C3 7t bond participates in a subsequent 1,3-dipolar cycloaddition with the carbonyl ylide to generate complex polycycles such as 45 as single diastereomers with up to six new stereocenters. That the cascade reaction is initiated by a Diels-Alder reaction with the alkene rather than with the indole is supported by the lack of reaction even under forcing conditions with substrate 46, in which a Diels-Alder reaction with the indole C2-C3 n bond would be required [26a]. 

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