Asymmetric aza-annulation reaction

Development in the area of asymmetric aza-annulation reactions paralleled achievements in the analogous area of asymmetric Michael addition reactions with chiral imines.111 Induction of asymmetry has been primarily controlled through substitution at the nitrogen of the imine or enamine that becomes incorporated into the heterocycle. Restricted rotation of this asymmetric substituent led to preferred conformational isomers, which provided stereofacial bias for carbon-carbon bond formation. 

Amino acid derivatives have also been explored as potential chiral auxiliaries in the asymmetric aza-annulation reaction. As reported for the Michael addition to acrylate derivatives, the reaction outcome has also shown sensitivity to the special balance of complementary steric demands of the methyl and phenyl substituents. The degree of diastereoselectivity in carbon-carbon bond... 

Substituted acrylate derivatives have also been employed in the asymmetric aza-annulation reaction (Scheme 40). Aza-annulation of 479b with crotonyl chloride (490) demonstrated several important features of this reaction.115 First, concomitant formation of two stereogenic centers gave 491 with high internal asymmetric induction, while high relative asymmetric induction resulted from the amine substituent. However, the presence of a methyl substituent at the (3-position of the acrylate derivative slowed the reaction significantly, and resulted in a poor yield. 

Hydrogenation of this annulation product resulted in stereoselective formation of 340. In each of these examples, formation of a stereogenic center occurred, and this methodology was used as the ground work for asymmetric induction in the aza-annulation reaction (see Section 8). 

Substrates in this section contain a stereogenic center, which was utilized to selectively generate additional asymmetry. Several important features of the aza-annulation reaction are illustrated in this section. In some examples, asymmetric carbon-carbon bond formation resulted from the aza-annulation process, while other aza-annulation reactions led to a 8-lactam skeleton with an asymmetric substituent attached to the ring, as seen for the synthesis of (-)-pumiliotoxin (eq. 2).5 In this case, asymmetry was not generated through aza-annulation, but rather, peripheral asymmetry directed diastereoselective reduction of the aza-annulation product. 

Asymmetric induction in the aza-annulation reaction through the use of a chiral auxiliary was pioneered by d Angelo and coworkers in their work with 456. Even though annulation was not accomplished with the use of methyl crotonate, crotonyl cyanide produced an equimolar mixture of 458 and 459 in moderate yield (Scheme 36).112 Both 458 and 459 reflect regioselective Michael addition at the most substituted cx-carbon. The vicinal methyl substituents that resulted from aza-annulation were oriented in a cis relationship. 

The acrylic acid derivative 460 was successfully used for asymmetric carbon-carbon bond formation to form 461, and in situ hydrolysis provided 462 with good selectivity.112 This stepwise aza-annulation process was completed by treatment with NH4OH, which led to the formation of 463. In the examples shown in Scheme 36, both reactions resulted in deracemization of the initial racemic ketone substrate through formation of the carbon-carbon bond. 

The angular methyl derivative of 143 was prepared stereoselectively through a related approach (Scheme 38).113 In this reaction sequence, condensation and aza-annulation of the methylated substrate 138 led to diastereoselective formation of 471 through asymmetric carbon-carbon bond formation (25 1). Selective reduction of 471 generated 472 along with the cis isomer (6 1), and 472 was methylated to give 140.113... 

More recently, Enders et al. disclosed a facile access to tetracyclic double annulated indole derivatives 175, which basically relies on the chemistry of the acidic 2-substituted indole and its nitrogen nucleophilicity. Indeed, the employed quadruple cascade is initiated by the asymmetric aza-Michael-type A-alkylation of indole-2-methylene malono-nitrile derivative 174 to o,p-unsaturated aldehydes 95 under iminium activation (Scheme 2.57). The next weU-known enamine-iminium-enamine sequence, which practically is realized with an intramolecular Michael addition followed by a further intermolecular Michael and aldol reactions, gives access to the titled tetracyclic indole scaffold 175 with A-fused 5-membered rings annulated to cyclohexanes in both diastereo- and enantioselectivity [83]. 

The catalytic asymmetric /-selective Diels-Alder annulation of a, -unsaturated /-butyrolactams with enones provided a synthesis of, y-functionalized bridged bi-or tri-cyclic dihydropyranopyrrolidin-2-ones in one step (up to 98% yield, >20 1 dr, and 99% ee) The inverse-electron-demand aza-Diels-Alder cycloaddition 0 of A-aryl-a,/0-unsaturated ketimines with enecarbamates in the presence of chiral bifunctional phosphoric acids produced 4,5,6-trisubstituted 1,4,5,6-tetrahydropyridines having three contiguous stereogenic centres in up to 84% yield, 95 5 dr, and 95% 5-Alkenylthiazoles react as in-out dienes with e-poor dienophiles in polar 44-2- 0 cycloaddition reactions. The cycloadditions are site selective. The mechanism is thought to lie between a concerted but highly asynchronous process and a stepwise process. 

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