Intermolecular carbonylative cycloaddition

Scheme 1.2 Ruthenium-catalyzed intermolecular carbonylative cycloaddition reaction.

Much of the initial synthetically useful carbonyl ylide work originated from the Ibata group. Exploiting simple disubstituted aromatic diazoketo-esters and structurally diverse dipolarophiles, Ibata and co-workers (64—70) prepared several different cycloadducts 167-169 through an intermolecular ylide cycloaddition (Scheme 4.38). 

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%. 

It is generally accepted that a typical carbonyl yhde reaction proceeds as shown in Fig. 2. Interaction of diazo compound 1 with the metal forms diazonium complex 2, which then extrudes nitrogen forming carbenoid intermediate 3. Reaction of 3 with the carbonyl group present in the substrate forms intramolecular carbonyl yhde 4 (or an intermolecular carbonyl yhde) in which the metal catalyst may or may not remain associated with the ylide [13]. Finally, the [3+2]-cycloaddition and regeneration of the active cat-... 

As was mentioned in Section 13.2, the [27t + 27i] photocycloaddition of alkenes is an allowed reaction according to orbital symmetry considerations. Among the most useful reactions in this categoty, from a synthetic point of view, are intramolecular [27t + 2ti] cycloadditions of dienes and intermolecular [2ti + 2ti] cycloadditions of alkenes with cyclic a, -unsaturated carbonyl compounds. These reactions will be discussed in more detail in Section 6.4 of Part B. 

Introduction of an additional methyl group on the donor atom of TMM moiety gives a low 33% yield of the perhydroindans (49, X=H2) and (50, X=H2) with substantial production of the diene by-products [24]. However, it is still remarkable that the reaction works at all since the corresponding intermolecular cycloaddition failed. Incorporation of a carbonyl moiety adjacent to the donor carbon atom doubles the yield of the cycloadducts to 66% (Scheme 2.15). This so-called acyl effect works by making the donor carbon of the TMM unit "softer," thus facilitating the initial step of the conjugate addition, as well as inhibiting base-induced side reactions [22]. 

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. 

Compounds in which a carbonyl or other nucleophilic functional group is close to a carbenoid carbon can react to give ylide intermediate.221 One example is the formation of carbonyl ylides that go on to react by 1,3-dipolar addition. Both intramolecular and intermolecular cycloadditions have been observed. 

An intermolecular 1,3-dipolar cycloaddition of diazocarbonyl compounds with alkynes was developed by using an InCl3-catalyzed cycloaddition in water. The reaction was found to proceed by a domino 1,3-dipolar cycloaddition-hydrogen (alkyl or aryl) migration (Eq. 12.68).146 The reaction is applicable to various a-diazocarbonyl compounds and alkynes with a carbonyl group at the neighboring position, and the success of the reaction was rationalized by decreasing the HOMO-LUMO of the reaction. 

Diastereoselective intermolecular nitrile oxide—olefin cycloaddition has been used in an enantioselective synthesis of the C(7)-C(24) segment 433 of the 24-membered natural lactone, macrolactin A 434 (471, 472). Two (carbonyl)iron moieties are instrumental for the stereoselective preparation of the C(8)-C(ii) E,Z-diene and the C(i5) and C(24) sp3 stereocenters. Also it is important to note that the (carbonyl)iron complexation serves to protect the C(8)-C(ii) and C(i6)-C(i9) diene groups during the reductive hydrolysis of an isoxazoline ring. 

Padwa has reported an approach to the ring system of the ribasine alkaloids 98 [174], using an intramolecular 1,3-dipolar cycloaddition of the a-diazo ketone 99 to produce the pentacyclic skeleton 100 (Scheme 19.17). Wood [175] used an intermolecular 1,3-dipolar cycloaddition of a carbonyl ylide for the total synthesis of ( )-epoxysorbicilli-nol 101 (Scheme 19.18). The key cycloaddition in this approach is the conversion of 102 to the natural product core 103, which sets the substitution pattern around the entire ring system in a single step. 

The ability to produce 1,3-dipoles, through the rhodium-catalyzed decomposition of diazo carbonyl compounds, provides unique opportunities for the accomplishment of a variety of cycloaddition reactions, in both an intra- and intermolecular sense. These transformations are often highly regio- and diastereoselective, making them extremely powerful tools for synthetic chemistry. This is exemplified in the number of applications of this chemistry to the construction of heterocyclic and natural-product ring systems. Future developments are likely to focus on the enantioselective and combinatorial variants of these reactions. 

Closely related to the already mentioned electrocyclizations of N-acyl thione S-imide (see Section 4.14.9.2) are some intermolecular cycloadditions involving this unusual class of 1,3-dipoles. Thus, the thione-S-imide intermediate (233) is probably involved in the formation of spirodithiazoline derivative (234) from the thione (235) and aryl azides <93HCA2147>. Also fluorenone-S-/ -tosylimide affords with carbonyl or thiocarbonyl compounds (R H) the corresponding oxathia- or dithia-zolidine derivatives (236) (Y = O or S) <80BCJ1023> (Scheme 44) (see also Section 4.14.6.1). 

The in situ formation of nitrones from oximes by 1,3-APT or 1,2-prototropy is clearly a powerful synthetic strategy but conventional nitrone generation, in particular hydroxylamine-carbonyl condensation, has been applied to numerous syntheses, in intra- and intermolecular mode (258). Accordingly, the ring systems similar to those synthesized using 1,3-APT/intramolecular nitrone-alkene cycloaddition (INAC) methodology by Heaney (313-315) (see Section 1.11.2) or Padwa and Norman (340) have been made using conventionally prepared nitrones (Scheme 1.67). As with the previous examples, once formed, the nitrones are suitably placed for a spontaneous intramolecular cycloaddition reaction with the... 

Decomposition of diazoketone 113 with rhodium acetate led to the formation of a tethered cyclic carbonyl ylide 114 that was poised to undergo an intramolecular cycloaddition, preparing 115 in 60% yield. Interestingly, if DMAD was added to the reaction mixture, the only product arose from intermolecular cycloaddition. 

Carbonyl ylides derived from nitrogen-substituted carbonyl moieties provided for the synthesis of very stable push-pull dipolar intermediates. Although these compounds are quite stable, they still have sufficient reactivity to engage in cycloaddition and related processes. Carbonyl ylides derived from amides have been trapped in intermolecular cycloadditions to give aminals (Scheme 4.34) (56). 

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... 

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

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>. 

Carbonyl ylides possess versatile reactivities, among which the 1,3-dipolar cycloaddition is the most common and important reaction. The reaction sequence of ylide formation and then 1,3-dipolar cycloaddition can occur in either inter- or intramolecular manner. When the reaction occurs intermolecularly, the overall reaction is a one-pot three-eomponent process leading to oxygen-containing five-membered cyclic compounds, as demonstrated by the example shown in Scheme 8. A mixture of diazo ester 64, benzaldehyde, and dimethyl maleate, upon heating to reflux in CH2CI2 in the presence of 1 mol% rhodium(ii) perfluorobutyrate [Rh2(pfb)4], yields tetrahedrofuran derivative 65 in 49% yield as single diastereomer. " ... 

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