Azomethine ylides chiral dipolarophiles

In an analogous approach, the chiral stabilized azomethine ylide 165, generated in situ via Lewis acid-catalyzed condensation of (53 )-5-phenylmorpholin-2-one 164 with 2,2-dimethoxypropane, was trapped diastereoselectively with singly and doubly activated dipolarophiles such as the acrylate (Scheme 24). The cycloadduct 84 was then employed to furnish enantiomerically pure 5,5-dimethylproline derivatives (see Section 11.11.6.3), <2001SL1836>. 

A series of analogous py rrolo[ 2,1 -c [ 1,4]oxazine-8-carboxy latcs 188 and 189 (Scheme 28) were obtained by cycloaddition of azomethine ylide 187 with dipolarophiles. The ylide was formed by /(-toluene sulfonic acid-mediated reaction of the benzotriazolyl chiral morpholinone 186, which can be considered as a stable crystalline azomethine ylide precursor <2001SL1841>. This procedure was applied also to morpholinone 190 that generated ylide 191 by reaction with... 

The azomethine ylide was generated by treatment of A -benzyl-Af-(methoxy-methyl)-trimethylsilylmethylamine (155) with TFA and underwent the required cycloaddition step with chiral dipolarophile 156, stereocontrol being induced by Evan s auxiliary. The ot, p-unsaturated acid dipolarophile was tethered to a chiral oxazoladine in two easy, high-yielding steps. The auxiliary served three purposes to give asymmetric control to the reaction, to allow for separation of the reaction products by generating column separable diastereoisomers, and hnally to activate the olefin in the cycloaddition step (Scheme 3.45). 

In synthetic efforts toward the DNA reactive alkaloid naphthyridinomycin (164), Gamer and Ho (41) reported a series of studies into the constmction of the diazobicyclo[3.2.1]octane section. Constmction of the five-membered ring, by the photolytic conversion of an aziridine to an azomethine ylide and subsequent alkene 1,3-dipolar cycloaddition, was deemed the best synthetic tactic. Initial studies with menthol- and isonorborneol- tethered chiral dipolarophiles gave no facial selectivity in the adducts formed (42). However, utilizing Oppolzer s sultam as the chiral controlling unit led to a dramatic improvement. Treatment of ylide precursor 165 with the chiral dipolarophile 166 under photochemical conditions led to formation of the desired cycloadducts (Scheme 3.47). The reaction proceeded with an exo/endo ratio of only 2.4 1 however, the facial selectivity was good at >25 1 in favor of the desired re products. The products derived from si attack of the ylide... 

The chiral dipolarophiles of Garners and Dogan, which were derived from Oppolzer s sultam, have been previously discussed in Section 3.2.1 and, in an extension to these results, the sultam moiety was used as the stereodirecting unit in enantiopure azomethine ylides (56). The ylides were generated either by thermo-lytic opening of N-substituted aziridines or by the condensation of the amine functionality with benzaldehyde followed by tautomerism. These precursors were derived from the known (+)-A-propenoylbornane-2,10-sultam. Subsequent trapping of the ylides with A-phenylmaleimide furnished the cycloaddition products shown in Schemes 3.60 and 3.61. 

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... 

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. 

A new dipolarophile bearing a chirality-controlling heterocyclic auxiliary at the p-position is readily accessible from (5)-A -benzylvalinol and methyl ( )-4-oxo-2-propenoate. However, the dipolarophile is available only as an 86 14 equilibrium mixture of trans and cis stereoisomers (Scheme 11.20) (84). When this is used without separation in the reaction with the Al-hthiated azomethine ylide derived from methyl (benzylideneamino)acetate in THE at 78 °C for 3.5 h, a mixture of two diastereomeric cycloadducts (75 25) was obtained in 82% yield. These two cycloadducts are derived from the trans and cis isomers of acceptor, indicating that both cycloadditions were highly diastereoselective. 

Azomethine ylides are very important 1,3-dipoles, and they are usually used to react with alkenes leading to the formation of the highly substituted pyrrolidine derivatives [17]. A novel and practical process for the 1,3-dipolar cycloaddition of azomethine ylides with alkenes had been reported by j0rgensen and coworkers [18]. They proposed that a dipol-chiral base ion pair would be generated between a-imino ester-metal complex and a cinchona alkaloid, and subsequent cycloaddition with dipolarophile would take place in a stereoselective manner (Scheme 10.13). 

Better diastereoselectivities were achieved with dipolarophiles such as unsaturated esters that bear a chiral auxiliary297-298. For instance, cycloaddition of the EVE-azomethine ylide, generated from the following imine by metalation, with the chiral alkene (27 )-2-(2-methoxycar-bonylethenyl)-3-phenyl-l,3-diazabicyclo[3.3.0]octane affords the pyrrolidine derivative as a single regio- and stereoisomer297. 

A combination of lithium bromide (LiBr) and DBU (1) catalyses regio- and stereospe-cific cycloaddition [54]. Imines of aminopyradazino[l,2-a][l,2]diazepine react with a range of achiral and chiral dipolarophiles in the presence of LiBr and DBU (1) in MeCN to afford enantiopure spiro-cycloadducts in excellent yield via lithio azomethine ylides [54b] (Scheme 3.34). 

Besides the dipolarophiles discussed above, chiral unsaturated (R)s-p-tolyl vinylsulfoxides A have been studied, too. In addition, chiral unsaturated bicyclic lactams B have been applied successfully by Meyers et al. as dipolarophiles in cycloadditions with azomethine ylides. ... 

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