Azomethine ylides, cycloadditions

The first report on metal-catalyzed asymmetric azomethine ylide cycloaddition reactions appeared some years before this topic was described for other 1,3-dipolar cycloaddition reactions [86]. However, since then the activity in this area has been very limited in spite of the fact that azomethine ylides are often stabilized by metal salts as shown in Scheme 6.40. 

Type Ilbd pyrrole syntheses fall into three general categories (1) Hinsberg-type (2) azomethine ylide cycloadditions and (3) isocyanide-based cyclocondensations. The Hinsberg pyrrole synthesis, the cyclocondensation between iminodiacetates and oxalates, has been further exploited in the total synthesis of the lamellarins <06T594,06TL3755>. 

Azomethine ylide cycloadditions have been utilized to prepare a number of novel fused pyrroles including pyrrolo[2,1 -a isoquinolincs <06CHJC279, 06TL1469> and pyrrolo[l,2-Zdpyridazines <06SL804>. Fused hydroxypyrroles were obtained in cycloaddition reactions with trimethylsilylketenes (TMS ketene) <06TL1469>. 

Scheme 9. Examples of azomethine ylide cycloaddition by (a) Affymax and (b) Bartlett and coworkers.

However, the highly stereoselective nature of the dipole intermediate, which was observed in the preceding cases, did not translate to azomethine ylide cycloadditions of 113 and 114, both of which formed mixtures of products derived from endo... 

This represents an interesting study into the use of a C(2) symmetrical stereocontrolling unit for the azomethine ylide cycloadditions of a, p-unsamrated esters. In particular, consideration of the effect of both N-substiments in the... 

Pyridones, as exemplified by ABT-719 (154, Figure 3.8), represent a new class of DNA gyrase inhibitors possessing a broad spectmm of antibacterial activity and, in studies toward such compounds, it was revealed that the C(8) functionality was an important part of the DNA binding action. Azomethine ylide cycloadditions were employed to give a range of proline-type derivatives in order to study stmcture-activity relationships (39). 

Several syntheses of the hepatatoxic alkaloid (+)-retronecine have been reported although the most succinct has utilized a chiral azomethine ylide cycloaddition to construct the bicychc skeleton. The ylide processor 175, which was obtained in five efficient steps from commercially available tran -(l )-4-hydroxy-L-proline, underwent double desilyation in the presence of AgF (described in detail in Section 3.1.1) and in situ cycloaddition with methyl propiolate, to deliver a 3 1 mixture of cycloadducts in favor of the desired regioisomer. DiisobutyMuminum (DIBAL) reduction of 176 furnished enantiopure (-F)-retronecine (Scheme 3.50). 

Chiral bicyclic lactams have been successfully utilized by Meyers as chiral dipolarophiles in highly diastereoselective azomethine ylide cycloadditions (73). Treatment of the ylide precursor 218 with the unsaturated, non-racemic dipolar-ophile 219 in the presence of a catalytic amount of TFA led to the formation of tricyclic adducts 220 and 221 in excellent yields (85-100%). The diastereofacial preference for the reaction was dependent on the nature of R with a methyl group... 

During the synthetic efforts of Heathcock and co-workers toward the complex marine alkaloid sarain-A (Scheme 3.80), he outlined an elegant intramolecular, azomethine ylide cycloaddition, as one of the key stages in the construction of the central core (76). Of the generation methods known for azomethine ylides, thermolysis of aziridines was selected in this instance. The azomethine ylide... 

However, replacement of LiBr with AgOAc inverted the ratio of exo to endo products. For Ar = 334, the major adduct was isolated in 42% yield with an endo/ exo ratio of 1 1.7, while Ar = 335 gave 333 in 36% yield with an endo/exo ratio of 1 2.3. Note that attempts at the thermal reaction met with low yields of complex reaction mixmres containing all possible regio- and stereoisomers. This smdy exemplifies the value of metal mediation in the stereo- and regiocontrol of azomethine ylide cycloadditions. 

The reaction mechanism proposed for the LiBr/NEta induced azomethine ylide cycloadditions to a,p-unsaturated carbonyl acceptors is illustrated in Scheme 11.10. The ( , )-ylides, reversibly generated from the imine esters, interact with acceptors under frontier orbital control, and the lithium atom of ylides coordinates with the carbonyl oxygen of the acceptors. Either through a direct cycloaddition (path a) or a sequence of Michael addition-intramolecular cyclization (path b), the cycloadducts are produced with endo- and regioselectivity. Path b is more likely, since in some cases Michael adducts are isolated. 

Although the first attempts at asymmetric azomethine ylide cycloadditions were reported by Padwa s group (92), the acyclic azomethine ylides chosen, bearing an a-chiral alkyl substituent on the nitrogen, showed poor diastereoselectivities (93,94). When the chiral center is fixed in a cyclic structure (95) or when chirality is introduced in an intramolecular cycloaddition system (96-98), high selectivities have been accomplished. There are only a few examples known of asymmetric cycloadditions of achiral azomethine ylides to chiral dipolarophiles where cyclic azomethine ylides (99,100) or cyclic chiral dipolarophiles (94) were used. 

The above azomethine ylide cycloadditions have been extended to an enantioselective version involving amino alcohols both as chiral ligands and amine bases. Thus, reactions of the N-metalated azomethine yhdes 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. 

Unactivated dipolarophiles readily participate in intramolecular azomethine ylide cycloadditions with a more reactive azomethine ylide. Thus, flash vacuum pyrolysis of aziridine (113) afforded a 67% yield of the 5,5-fused bicyclic pyrrolidine (Scheme 34).59 A singly stabilized azomethine ylide was the apparent intermediate. Similarly, cyclization of the azomethine ylides derived from (114a-c) gave the corresponding cw-fused 6,6-bicyclic pyrrolidines in 69%, 26% and 16% yield, respectively the original double bond stereochemistry was retained in the latter two cases. 

Intramolecular azomethine ylide cycloaddition to the C—O double bond of an aldehyde was reported in 197369 and cycloaddition to the C—C double bond was first reported in 1975.70 Competition between 1,1- and 1,3-cycloaddition is observed in intramolecular reactions, although intermolecular reactions give only 1,3-cycloaddition. Photolysis of 2//-azirines is one generation method of nitrile ylides applicable to intramolecular cycloaddition.70 Another method involves the base-catalyzed 1,3-elimination of hydrogen halide from alkenyl imidoyl halides. Still other procedures involve thermolytic and photolytic cycloreversions of oxazolinones and dihydrooxazaphospholes. 

A one-pot chroman-4-one synthesis-azomethine ylide cycloaddition can be performed using 2-iodophenol, carbon monoxide, allene and imine 1099 to furnish a mixture of exo- and OTr/o-cycloadducts 1100 (Equation 431) <2000TL7129>. Other nucleophiles are viable alternatives for this process <2000TL7125>. Synthesis of chroman-4-one 1101 is possible using a palladium catalyzed carbonylative cyclization of o-allyloxyliodobenzene (Equation 432) <2001JOC2175>. 

Tsuge. Azomethine Ylide Cycloadditions via 1,2- Prototropy and Metallo-Dipole Formation from Imines, R. Grigg and V. Sridharan. Index. ... 

As a part of a program directed toward the synthesis of the potent topisomerase I inhibitors, the lamellarins (e.g., 153 and 154), Porco has reported the silver triflate-catalyzed tandem cycloisomerization-azomethine ylide cycloaddition of 155 (Scheme 2.42).75 The postulated mechanism of this intriguing and highly efficient process is shown in Scheme 2.43. Silver-catalyzed addition of the imine nitrogen to the alkyne results, on subsequent deprotonation, in the formation of an azomethine ylide 160. This ylide participates in [3+2] cycloaddition with the alkyne component leading to formation of a dehydropyrrole 161. Finally, oxidation by adventitious oxygen leads to formation of the product 162. 

Gamer, P.P., Cox, P.B., Klippenstein, S.J., Youngs, W.J., and McConville, D.B. (1994) Tether-mediated stereocontrol in intramolecular azomethine ylide cycloadditions. Journal of Organic Chemistry, 59, 6510-6511. 

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