Asymmetric annulation reaction

Scheme 7.96 NHC-catal)rzed asymmetric annulation reaction of ynals and enols reported by Bode.

NHC-catalysed umpolung of enals appears to be a useful tool for annulation reactions that generally induces molecular complexity from simple starting materials. Enals have thus been reported as appropriate reaction partners for asymmetric annulation reactions with isatins and benzodi(enone)s to yield spirocyclic oxindolo-y-butyrolactones (121), and polycyclic compounds (122), respectively. Both annulation processes have been catalysed by chiral NHCs and accomplished in good yields with high regio- and/or stereo-selectivities. In parallel, the mechanism of the NHC-catalysed annulation reaction of butenal with pentenone has been computationally explored at the B3LYP/6-31+G and M06-2X/6-31G levels of theory. This study has clearly emphasized the key role played by proton-transfer steps in both the rate and the course of the reaction. 

Recently, 13 was reported to catalyze the asymmetric annulation reaction between allenoates and a,P-unsaturated carbonyl compounds to form substituted 2H-pyrans (Scheme 6.15) [37]. This formal [4+2] cycloaddition afforded exclusively the product with the (E) configuration of the exocyclic double bond, in line with calculations that indicated the ( )-isomer to be about 14.2 kj mol lower in energy than the (Z) isomer. The mechanism of the reaction was formulated as an initial attack by the nitrogen atom of the quinuclidine ring at the allenoate with formation of an ionic intermediate that preferentially reacts at the terminal carbon atom with the a,p-unsaturated carbonyl compound prior to elimination of the catalyst with formation of the 2H-pyran derivative (Scheme 6.15). 

Scheme 6.15 Asymmetric annulation reaction catalyzed by 13 (NR3 in the scheme).

Scheme 20.27 Spiro-phosphine-catalyzed asymmetric annulation reactions.

In 1986, Puchot et al.104 studied the nonlinear correlation between the enantiomeric excess of a chiral auxiliary and the optical yield in an asymmetric synthesis, either stoichiometric or catalytic. Negative NLEs [(—)-NLEs] were observed in the asymmetric oxidation of sulfide and in [.S ]-proline-mediated asymmetric Robinson annulation reactions, while a positive NLE [(+)-NLEs]... 

Stack JG, Curran DP, Geib SV, Rebek J, Ballester P (1992) A new chiral auxiliary for asymmetric thermal reactions High stereocontrol in radical addition, allylation, and annulation reactions. J Am Chem Soc 114 7007-7018 Yang NC, Yang DDH (1958) Photochemical reactions of ketones in solution. J Am Chem Soc 80 2913-2914... 

The biphenyl 187 underwent a facile annulation reaction with bis(mesylate) 191 to give the asymmetric desym-metrization product 192 (m.p. 230-231 °C) with exclusive stereoselectivity, which was readily separated from the byproducts 193 (Equation 41) <20000L1319>. 

Studies on asymmetric annulation of the precursor 203 resulted in development of reaction conditions for the construction of the fused indoline system 204 (Equation 64). Similar cyclization of a substrate containing a longer chain gave a corresponding indoline fused to a six-membered ring <2002TA1351>. 

Bui, T., Barbas, C. F. A proline-catalyzed asymmetric Robinson annulation reaction. Tetrahedron Lett. 2000, 41, 6951-6954. 

Davies and co-workers [12, 35] have exploited one particular aspect of the asymmetric cyclopropanation of alkenes with vinyl diazoacetates, namely, application to substrates suitable for subsequent Cope rearrangement. Cyclopropanation of dienes with predominant cfs-1,2-divinyl diastereoselection makes possible subsequent facile [3,3]-sigmatropic rearrangement with entry to 1,4-cycloheptadienes or bicyclic dienes. Two such examples employing cyclopenta-diene and penta-l,3-diene as substrates and the rhodium(II) prolinate catalyst, Rh2(2S-TBSP)4 in Fig. 1, are shown in Eq. (6) and Eq. (7),respectively cfs-l,2-di-vinylcyclopropanes are presumed to be intermediates in these annulation reactions. In contrast, ethyl diazoacetate and styrene with the prolinate catalyst (Fig. 

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. 

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. 

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. 

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. 

Scheme 5.66 Ir-catalyzed asymmetric [3 + 2] annulation reaction reported by...

In 2012, the Chi group demonstrated a diastereoselective NHC-catalyzed access to p-lactam fused spirocyclic oxindoles with an all-carbon quaternary stereogenic center, employing oxindole-derived p,p-disubstituted a,p-unsaturated imines and enals as substrates. The p-lactam products, stable at room temperature, were easily converted to cyclopentenes at 50 °C. An asymmetric example of the annulation reaction was presented with moderate enantioselectivity (89% yield and 51% ee by using the amino indanol derived catalyst), which is probably due to the sterical hindrance of p,p-disubstituted a,p-unsaturated imines (Scheme 7.58). 

In 2006, the Bode group documented NHC-catalyzed highly enantiose-lective 1-oxodiene Diels-Alder reactions of a broad range of enones with racemic a-chloroaldehydes as the dienophile precursors. This process affords a diverse set of highly enantioenriched 3,4,6-trisubstituted dihydro-pyran-2-ones from readily available starting materials under mild conditions (room temperature, 1.5 equiv. of NEtj, 6 h). The use of readily accessible racemic a-chloroaldehydes as enolate precursors greatly expands the scope of enantioselective NHC-catalyzed Diels-Alder reactions. It also makes possible, for the first time, asymmetric annulations with exceptional enantiose-lectivity under reliable eonditions with less than 1 mol% of a chiral NHC catalyst (Scheme 7.77). 

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