Endo-selective cycloaddition

Also propiogeninic type macrolide moieties should be accessible via this inverse type hetero-Diels-Alder methodology. This was recently exhibited starting from cis-propenylether as heterodienophile (Schmidt, R.R. Haag-Zeino, B. Hoch, M. Liebigs Ann. Chem., in press). In a highly endo-selective cycloaddition reaction and in subsequent diastereoselective transformations of the methyl substituted dihydropyran obtained a 2,4-dimethyl-... 

Methyl (naphthylideneamino)acetate undergoes dimerization to produce a mixture of two diastereomeric imidazolidines when treated with Mg(C104)2 or C0CI2 (89). Other imines can also be used as acceptor molecules (Scheme 11.12). With the exception of azomethine ylides incorporating sodium and titanium ions, other N-metalated ylides undergo highly endo-selective cycloadditions with a,p-unsaturated... 

The use of Lewis acids in order to catalyze hetero Diels-Alder reactions of thia-1,3-butadienes is not widespread, but recent investigations stemming from Saito et al. reveal a remarkable acceleration of these transformations in the presence of A1C13 or EtAlCl2 [428]. In a first study concerning asymmetric hetero Diels-Alder reactions of thia-1,3-butadienes, Saito et al. found Lewis acids to have a beneficial effect on the induced diastereoselectivities. Thus, the thioketone 5-17, generated in situ by thermal cycloreversion from its dimer, underwent a completely endo-selective cycloaddition upon treatment with (-)-dimenthyl... 

The choice of Lewis acid promoter for these reactions can change the sense of asymmetric induction. " For example, tandem [4 + 2]/ [3 + 2] cycloadditions (eq 4) mediated by Ti(0-i-Pr)2Cl2, followed by hydrogenolysis afforded tricyclic (-)-a-hydroxy lactam [(-)-8] in 98% ee. When mediated by methyl-aluminum-bis(2,6-diphenylphenoxide) (MAPh), the same reaction gave (+ )-8 in 93% ee. Importantly, the observed selectivity is not chiral auxiliary dependent. Rather, it is attributed to a highly endo selective cycloaddition in the case of Ti compared to high exo selectivity in the case of MAPh. 

Maleimides and maleic anhydride have been most frequently employed as cyclic cis-olefin dipolarophiles in the stereochemical investigation of 1,3-dipolar cycloadditions, especially on the endo and exo selection of the reaction. They are one of the most reactive dipolarophiles toward many kinds of azomethine ylide 1,3-dipoles. Because of their structural simplicity, the only stereochemical variation possible in cycloadditions is an endo and exo selection. If a strong attractive interaction exists between the extended conjugation of these dipolarophiles and azomethine ylides, an endo-selective cycloaddition results. 

Table VIII summarizes the cycloaddition reactions of azomethine ylides with maleimides and maleic anhydrides. The upper part of the table involves endo-selective cycloadditions and the lower part nonselective reactions. Endo selectivity is closely related to the substitution pattern of the azomethine ylides used. The azomethine ylides that show high endo selectivity to these cyclic olefins bear an ylide-stabilizing substituent of the carbonyl or cyano type (EWG) at one carbon and an aryl, heteroaryl, acyl, or 1-alkenyl substituent (R ) at the other. These key substituents must be present for high endo selectivity, although the substituent (R) on the ylide nitrogen is equally important.

It is interesting to compare the endo selectivities of two closely related types of dipoles. The ylides 47, derived by an imine-azomethine ylide tautomerism of the imines of a-amino esters (Section II,C), are typical dipoles that exhibit high endo selectivity in cycloadditions to cyclic olefins. On the other hand, N-substituted derivatives 79, derived by the deprotonation route (Section II,D) from N-substituted a-amino esters and aldehydes, are very poor in endo selectivity. The N-unsubstituted dipoles 47 are involved in the cycloadditions as ( , )-ylides (or syn-ylides), while the N-substituted dipoles 79 as ( ,Z)-ylidic forms (or anti -ylides). However, the difference in ylide geometry is not the only reason for the lowered endo selectivity of 79, since the anti forms of heteroaromatic N-ylides undergo exclusive endo-selective cycloadditions with cyclic cis-olefins (83H1907 84CL465 85BCJ3137). 

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). 

Silicon-based Lewis acids are also used to activate dienophiles [299-303]. TBSOTf effectively catalyzes the endo-selective cycloaddition of a l,3-bissiloxy-l,3-diene wifh an acrylamide, whereas non-catalyzed thermal reaction or Eu(fod)3-catalyzed reaction is exo-selective (Scheme 10.112) [299]. In the cycloaddition to mefhyl acrylate fhe catalytic activity ofTMSNTf2 is much higher than that ofTMSOTf [301]. Silyl triflates are useful for fhe HDA reaction with imines catalytically or stoichiometrically [302, 303]. 

Although considerable improvements have been made for endo-selective cycloadditions of azomethine imines, methods for exo and enantioselective cycloaddition of azomethine imines were relatively scarce. By employing novel, multifunctional primary amine catalysts 145 derived from cinchona alkaloids in the presence of triisopropylbenzene sulfonic acid (TIPBA) 146 as cocatalyst, Chen and coworkers developed the first organocatalytic, highly exo-selective, and enantioselective 1,3-DC reaction of cyclic enones 142 and azomethine imines 143 in 2007 [53]. The additional and synergistic hydrogen-bonding interaction of catalyst and 1,3-dipole is essential for enantiocontrol, and excellent stereoselectivities were achieved for a broad scope of substrates (dr > 99 1, up to 95% ee) (Scheme 2.37). 

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