Enantioselective carbonyl ylide cycloaddition

Scheme 7.39 Enantioselective carbonyl ylide cycloaddition using a continuous-flow system.

Hashimoto and co-workers (206,207) recently published enantioselectivities of up to 92% ee in carbonyl ylide cycloadditions to acetylenic esters in the presence of a chiral rhodium catalyst (Scheme 11.58). 

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... 

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). 

Intramolecular ylide formation with the lactone carbonyl oxygen (53) in 145 provided a carbonyl ylide 146 that was trapped with Al-phenyl maleimide to give cycloadduct 147. Likewise (54), carbonyl yhde 149, derived from ester 148, suffers intramolecular cycloaddition with the tethered alkene to deliver acetal 150 in 87% yield. An enantioselective version of this process has also been described (Scheme 4.33). 

After completing his initial intramolecular cycloaddition, Hodgson utilized conditions that had been optimized for the intermolecular cycloaddition of DMAD with simple cyclic carbonyl ylides used by Hashimoto and co-workers (139). Hodgson et al. (140) found that the reaction indeed gave excellent overall chemical yield, but the enantioselectivity dropped to 1%, giving essentially a racemic mixture. It appeared that ee ratios were sensitive to the electronic nature of the dipole. Hodgson chose to screen several binaphthol derived rhodium catalysts of the type developed by McKervey and Pirrung, due in part to the reports of... 

Good yields of the bridged tetrahydropyran-3-one 38 are obtained when the a-diazoketones 37 are decomposed by chiral Rh(II)-catalysts in the presence of DMAD. It is proposed that an enantioselective intermolecular 13-dipolar cycloaddition follows the generation of a carbonyl ylide which is bound to the rhodium (Scheme 21) <99JA1417>. 

Hodgson and co-workers have studied the intramolecular cascade carbonyl ylide formation-cycloaddition with chiral Rh(ii) catalysts.After screening a series of chiral Rh(ii) catalysts, high enantioselectivity was achieved in the reaction of 98 by using the Rh(ii) catalyst with binaphthyl phosphate-derived chiral ligands dirhodium(ii) tetrakis[(i )-6,6 -didodecylbinaphtholphosphate] [Rh2(i -DDBNP)4] (Equation (13)). 

Enandoselective tandem carbonyl ylide formation-cycloaddition of a-diazo- -keto esters is achieved in hexane with [Rh2(5-DOSP)4] (1 mol %) at room temperature to give the corresponding cycloadducts with moderate enantioselectivity [73] (Eq. 8A.49). 

The game is certainly not over, very recently catalytic enantioselective intermolecular cycloadditions of 2-diazo-3,6-diketoester of type 68 derived carbonyl ylides with alkene dipolarophiles have been developed [57]. Relying on chiral rhodium(II) clusters I and II, Hodgson et al. obtained very high enantioselectivities (up to 92% ee on 69) with norbornene as a trap, as disclosed in Scheme 31. 

A review about the rearrangement and cycloaddition of carbonyl ylides generated from a-diazo compounds is available <2001CSR50>. Enantioselective intramolecular cyclopropanations of allyl 2-diazo-3-silanyloxybut-3-enoates to yield cyclopropyl 7-butyrolactones have been investigated with a variety of chiral rhodium catalysts. The best results were obtained with Rh2(PTTL)4, where enantioselectivity culminated at 89% ee (Equation 99) <2005TA2007>. 

Tetrakis(l,T-binaphthyl-2,2 -diyl phosphate) complexes (119) are reported to be much more effective catalysts than the more commonly used carboxylate complexes for enantioselective intramolecular, tandem, carbonyl ylide forma-tion/cycloaddition of a-diazo- -keto esters. The ring-opening reactions of epoxides with diphenyl phosphorazidate (120) have been investigated. A wide range of epoxide substrates have been studied and the products, (121) or (122), depend on the substrate structure. The microbial hydroxylation of novel phos-... 

Hashimoto and coworkers [69] have recently begun to explore the use of chiral rhodium catalysts in the intramolecular dipolar cycloadditirai reactions of indoles, and have applied their methodology to the synthesis of the Aspidosperma ring system. Thus, the cycloaddition of the cyclopropyl carbonyl ylides derived from cyclopropyl diazo-5-imido-3-ketoesters 135 upon treatment with dirhodium (11) tetrakis[Af-tetrachlorophthaloyl-(5)-ferf-leucinate] gave cycloadducts 136 along with the spiro[2.3]hexanes 137 in only moderate yields (Scheme 34). Although the reaction proceeds with exclusive endo diastereoselectivity, only moderate enantioselectivities of up to 66% enantiomeric excess (ee) could be obtained. 

Muthusamy S, Gunanathan C et al (2004) Regioselective synthesis of mono- and bis-decahy-drobenzocarbazoles via tandem reactions of a-diazo ketones. Tetrahedron 60 7885-7897 Nambu H, Hikime M et al (2009) Asymmetric approach to the pentacyclic skeleton of aspidosperma alkaloids via enantioselective intramolecular 1,3-dipolar cycloaddition of carbonyl ylides catalyzed by chiral dirhodium(II) carboxylates. Tetrahedron Lett 50 3675-3678... 

Chapter 4 concerns the cycloaddition of carbonyl ylides generated from diazo carbonyl compounds and rhodium or copper catalysts. In this framework chemoselective and enantioselective transformations leading to the formation of various heterocycles such as tetrahydrofurans, oxazolidines, mesoionic and bicyclic compoxmds, alkaloids, and other natural products are described. 

Despite the great synthetic utihty of diazocarbonyl compounds in the generation of carbonyl ylide intermediates, definitive mechanistic studies on the metal-catalyzed cycloaddition of carbonyl yhdes are scarce. Among the various metal catalysts, dirhodium(II) catalysts are the most effective and versatile for diazo decomposition. Because of the rapid catalytic tmnovers of these reactions, structural information about the intermediates is difficult to obtain. A reasonable mechanism can be rationahzed on the basis of product distribution, and especially on the basis of enantioselective outcome of various carbonyl yhde reactions [55-63]. 

Hashimoto and co-workers have shown the enantioselective 1,3-dipolar cycloaddition of the ester-derived carbonyl ylides using chiral dirhodium(II) carboxylates [110]. The ester-derived carbonyl ylide from the a-diazo ketone 98 in the presence (1 mol%) of Rh2(S-PTTL)4 99 as the catalyst afforded the cycloadduct 100 with 93% ee (Scheme 30). 

Another successful catalytic enantioselective 1,3-dipolar cycloaddition of Qf-diazocarbonyl compounds using phthaloyl-derived chiral rhodium(II) catalysts has been demonstrated [ill]. Six-membered ring carbonyl ylide formation from the a-diazo ketone 80 and subsequent 1,3-cycloaddition with DMAD under the influence of 1 mol % of dirhodium(II) tetrakis[M-benzene-fused-phthaloyl-(S)-phenylvaline], Rh2(S-BPTV)4 101 [112], has been explored to obtain the cycloadduct 102 in up to 92% ee (Scheme 31). 

The asymmetric induction on the 1,3-dipolar cycloaddition reaction of carbonyl ylides has also been studied using chiral dipolarophile. The Rh2(OAc)4-catalyzed reactions of o-(methoxycarbonyl)diazoacetophenone 89 with enantiomerically pure vinyl sulfoxides 103 afforded 4,10-epoxybenzo-[4,5]cyclohepta[l,2-c]furan-3,9-dione 105, in good or moderate yield with complete regioselectivity [113]. The endo stereoisomer 105a is favored with respect to the exo isomer 105b and interestingly, high diastereoselectivity and complete enantioselectivity have been achieved (Scheme 32). 

Somfai has described three-component 1,3-dipolar cycloadditions of in situ generated carbonyl ylides to aldimines induced by chiral Rh(II) carboxylate catalysts 202 [65]. The reaction of ethyl diazoacetate 164, benzaldehyde (92a), and benzylidene benzylamine (203) gave rise to the corresponding syn- -amino alcohol 206 in 62% yield and 88% dr with 24% ee. In spite of its low enantioselectivities, this process provided interesting building blocks for the synthesis of natural products and other biologically important products that are syn- -amino alcohols (Scheme 11.44). 

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