A-Metallated azomethine ylides

This attractive protocol for the asymmetric addition of a, p-unsaturated esters to A-metalated azomethine ylides was further developed using C(2) symmetrical imidazoladine stereodirecting units in an extensive study into the effects of reaction conditions and substituent effects on the facial selectivity of the reaction (36). Both... 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

Although very important for understanding the mechanism of the process, these reactions are of limited usefulness as synthetic methods. In the case of cyclic alkenes, c.g., AT-methyl maleinimidcs or maleic anhydride, high endo selectivity is achieved in the reaction with iV-un-substituted or A -metalated azomethine ylides bearing an electron-withdrawing substituent (carbonyl, cyano) at one carbon and an aryl, acyl, or 1-alkenyl group at the other. 

On the other hand, the use of the suitable combination of a metal salt, chiral ligand, and base promotes at low temperature the formation in situ of chiral A-metalated azomethine ylides from the corresponding iminoester and the subsequent selective cycloaddition onto the fullerene cage. Thus, the P,S chiral ligand Fesulphos along with copper(II) acetate directs the addition toward the formation of the stereoisomer (25, 55)-2-alkoxycarbonyl-5-arylpyrrolidino[3,4 l,2][60]fullerene with complete cis diasteroselectivity and enantiomeric excesses up to 93% (Scheme 34.9). 

Figure 34.5 Site- and regioselectivity in C70 1,3-dipolar cycloaddition of A -metalated azomethine ylides.

One of the most appealing aspects of these multicomponent syntheses is the reactivity of the components. Often, the reaction sequence commences without the aid of external catalysts and still preserves selectivity. However, sometimes the reactive center is created in situ, which does require the assistance of an external catalyst. Transition metals, for instance, can be effectively used to induce reactivity, like in the synthesis of another viral protein inhibitor. The work of Garner and coworkers provided a new route to the core of a novel influenza neuramidase inhibitor in one pot [38]. The [C -I- NC -I- CC] coupling reaction proceeds via a metalated azomethine ylide by condensation of the amine 134 and aldehyde 132, which undergoes a [3 -l- 2] cycloaddition with activated dipolarophile 133 (Scheme 14.17). 

N-Metalated azomethine ylides (44) are probably the most synthetically useful of these dipoles, since they can be generated from readily available N-alkylide-neamino esters or nitriles through a simple activation method. The resulting 1,3-dipoles show high reactivity with a,p-unsaturated carbonyl acceptors to provide excellent stereo- and regioselectivities. A variety of asymmetric versions have been reported. 

The use of lithium amides to metalate the a-position of the N-substituent of imines generates 2-azaallyl anions, typically stabilized by two or three aryl groups (Scheme 11.2) (48-62), a process pioneered by Kauffmann in 1970 (49). Although these reactive anionic species may be regarded as N-lithiated azomethine ylides if the lithium metal is covalently bonded to the imine nitrogen, they have consistently been discussed as 2-azaallyl anions. Their cyclization reactions are characterized by their enhanced reactivity toward relatively unactivated alkenes such as ethene, styrenes, stilbenes, acenaphtylene, 1,3-butadienes, diphenylacetylene, and related derivatives. Accordingly, these cycloaddition reactions are called anionic [3+2] cycloadditions. Reactions with the electron-poor alkenes are rare (54,57). Such reactivity makes a striking contrast with that of N-metalated azomethine ylides, which will be discussed below (Section 11.1.4). 

N-Metalated azomethine ylides generated from a-(alkylideneamino) esters can exist as tautomeric forms of the chelated ester enolate (Scheme 11.8). On the basis of the reliable stereochemical and regiochemical selectivities described below, it is clear that the N-metalated tautomeric contributor of these azomethine ylides is important. Simple extension of the above irreversible lithiation method to a-(alkylideneamino) esters is not very effective, and cycloadditions of the resulting lithiated ylides to a,(3-unsaturated carbonyl compounds are not always clean reactions. When the a-(alkylideneamino) esters bear a less bulky methyl ester moiety, or when a,(3-unsaturated carbonyl compounds are sterically less hindered, these species suffer from nucleophihc attack by the organometalhcs, or the metalated cycloadducts undergo further condensation reactions (81-85). 

The above azomethine ylide cycloadditions have been extended to an enantio-selective version involving amino alcohols both as chiral ligands and amine bases. Thus, reactions of the N-metalated azomethine ylides derived from achiral methyl 2-(arylmethyleneamino)acetates, cobalt(II) chloride [or manganese(II) bromide], and chiral amino alcohols, 1 and 2 equiv each, with methyl acrylate as solvent have been performed to provide the enantiomer-enriched pyrrolidine-2,4-dicarboxylates with the enantioselectivities of up to 96% enantiomeric excess (ee) (128,129). However, a large excess of the metal ions and the chiral source (ligand and base) have to be employed. 

Cycloadditions and Related Reactions Understanding Planar Interactions and Establishing Synthetic Potential, A. G. Fallis and Yee-Fung Lu. Substituent and Structural Effects in the Ozonolysis of Cyclic Vinylogous Esters, W. H. Bunnelle. N-Metalated Azomethine Ylides, S. Kanemasa and Otohiko J A... 

While this initial excursion into the chemistry of nitroalkenes was disappointing, it proved possible to turn the tables by the use of a propionate aldol auxiliary attached at the 2 position of the nitroalkenes, namely, compounds 69 (Scheme 2.19).38 These chiral nonracemic nitroalkenes reacted stereospecifically with metalated azomethine ylides to afford the corresponding product 70 in 60-92% yield. Only 10 mol% of silver acetate was required to achieve complete conversion within 5h at room... 

More recently, another route to N-metallated azomethine ylides has been presented. The N-(p-substituted benzylidene) imines of a-amino esters are... 

N-Metallated azomethine ylides 140 of ester-stabilized types are tautomeric to the metal ester enolates (141) of chelate-stabilized types. The only structural difference is which heteroatom between the imine nitrogen and the ester carbonyl oxygen is connected with the metal (M) by a covalent bond. The difference in chemical properties expected for the ylidic forms 140 and enolate forms 141 is not yet clear. 

Stereochemical path of 1,3-dipolar cycloadditions as shown above. As the major secondary orbital interaction works on the substituents of dipoles, the stereochemistry of cycloadditions depends upon the ylide configuration. A more reliable methodology to control the stereochemistry of cycloadditions has been recently developed. In the cycloadditions of N-metallated azomethine ylides with carbonyl-activated olefins, the carbonyl oxygyen chelates the metal to allow the endo approach of olefinic dipolarophiles. 

The N-metallated azomethine ylides having a wider synthetic potential are N-lithiated ylides 141, derived from the imines of a-amino esters, lithium bromide, and triethylamine, and 144 from the imines of a-aminonitriles and LDA (Section II,G). Ester-stabilized ylides 144 undergo regio- and endo-selective cycloadditions, at room temperature, to a wide variety of unsym-metrically substituted olefins bearing a carbonyl-activating substituent, such as methyl acrylate, crotonate, cinnamate, methacrylate, 3-buten-2-one, ( )-3-penten-2-one, ( )-4-phenyl-3-buten-2-one, and ( )-l-(p-tolyl)-3-phenyl-propenone, to give excellent yields of cycloadducts 142 (88JOC1384). 

With acyclic symmetrically substituted alkenes, cycloadditions to ester- orcyano-stabilized iV-unsubstituted or iV-metalated azomethine ylides also show high endo selectivity, e.g., maleate esters undergo more stereoselective addition than their fumarate analogs, with a marked preference for 2,3-rfs-substituted pyrrolidines211 1 227 -221 256. 

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