Trienamines Derived from Interrupted Cyclic 2,5‐Dienones: Remote δ,ε‐CC Bond Activation for Asymmetric Inverse‐Electron‐Demand Aza‐Diels–Alder Reaction

Abstract

A special challenge in the field of asymmetric catalysis is the realization of remote stereocontrol.[1] The problem can be extended to remote sites which must be activated to ensure better reactivity. While most early examples of remote asymmetric inductions rely on enzyme catalysis or intramolecular relay of chiral information through the substrate, [2] current studies have demonstrated that chiral catalysts can facilitate enantioselectivity in variety of reactions.[3] In particular, our group and the group of Jørgensen found that the well-established enamine chemistry of saturated carbonyl compounds could be expanded to polyconjugated 2,4-dienals based on the principle of vinylogy, [4] thus leading to the remote e-site activation and still allowing highly stereoselective cycloadditions at b,e-sites of in situ formed linear trienamine intermediates.[5] Moreover, such an activation mode was successfully applied to 2,4-dienone analogues. Unfortunately, it was not possible to utilize 2,4-dienones with an enolizable a'-alkyl substitution because the cross-conjugated trienamine species were preferably generated. [6] In fact, we also found that the cyclic 2,4-dienone 1 would predominantly generate the cross-conjugated trienamine I, catalyzed by a primary amine, and then react with a dienophile by a a',b-regioselective [4+2] annulation pathway (Scheme 1). [7] To overcome the inherent preference for the formation of cross-conjugated trienamines from 2,4-dienones bearing an enolizable a'-alkyl group, we envisaged that an appropriately positioned d,e-C=C bond, as shown for the interrupted 3-allyl cyclohexen-2-one 2 a (Scheme 1), would induce the generation of the desired polyconjugated linear trienamine II, rather than the dienamine [8] III which has a higher energy.[9] Thus, the electron-donating effects of the amine could be transmitted through the conjugated p system, and raise the HOMO energy of the remote d,e-C=C group to participate in asymmetric reactions.Based on the above considerations, we initially investigated the reaction of the 2,5-dienone 2 a and the 1-azadiene 3 a, containing a 1,2-benzoisothiazole-1,1-dioxide moiety, [10] in the presence of 9-amino-9-deoxyepiquinidine (C1) and benzoic acid (A1).[11] To our gratification, the reaction proceeded smoothly in toluene at 35 8C, and the inverse-electrondemand aza-Diels-Alder cycloaddition product 4 a was isolated in 63 % yield with exclusive d,e-regioselectivity.

Diastereodivergent and Enantioselective [4+2] Annulations of γ-Butenolides with Cyclic 1-Azadienes

“…All chemicals including α-angelica lactone 2a were used without purification as commercially available unless otherwise noted, and the other butenolides were prepared according to the literatures [15]. α,β-Unsaturated imines 2 and 7 were prepared according to the literature procedures [16]. The tertiary amines 1b and 1c were also synthesized according to the literature procedures [21,22], and others were commercial available.…”

“…On the other hand, our group recently developed a series of asymmetric reactions involving cyclic 1-azadienes containing a 1,2-benzoisothiazole-1,1-dioxide motif [16][17][18][19]. They are stable materials, and readily available from diverse saccharins and aldehydes.…”

Cross‐conjugated Trienamine Catalysis with α′‐Alkylidene 2‐Cyclohexenones: Application in β,γ‐Regioselective Aza‐Diels–Alder Reaction

“…[4] In addition, the application of interrupted b-allylic cyclic enones could accomplish either d,e-regioselectivei nverse-electron-demand cycloadditions or e-regioselective bisvinylogous additions (Scheme 1b). [5] In contrast, cross-conjugated tri enaminei ntermediates would be preferably generatedw ith cyclic 2,4-dienonem aterialsi nt he presenceo faprimary amine catalyst, and a',b-regioselective formal [4+ +2] cycloadditions would occurw ith electron-deficient dienophiles (Scheme1c). [6] As ar esult, the application of structurally diverse polyunsatura-ted ketones ubstrates mayh ave high potential to uncover new reactionmodes by amine-based catalysis.…”

Asymmetric Allylic Alkylation with Deconjugated Carbonyl Compounds: Direct Vinylogous Umpolung Strategy

“…In addition, only the Michael adduct 3a' ' was obtained in al ow yield by using the conjugated enone 2a' ' (entry 3), indicating that the inducing effect of the previously positioned b,g-C=Cb ond would be crucial for generating the required dienolate intermediate (Scheme 1d). [7] Encouraged by these results, we explored the potential asymmetric version by the cooperative catalysis of Pd(OAc) 2 and chiral PTC. [8] While poor yield and enantioselectivity were obtained with ammonium salt C1 (Table 1, entry 4), it was found that better reaction could be attained by employing the l-amino-acid-derived phosphonium salts C2-C4 (entries 5-7), [9] and agood ee value was gained with C4 at À10 8 8C(entry 8).…”

“…Fort he reactions with 2a,u niformly high to excellent enantioselectivities were obtained by introducing diverse substituents into the oxindole core of the nucleophiles 1 (entries 2-6), whereas slightly lower yields were observed for those with electron-withdrawing groups (entries 4-6). Outstanding enantiocontrol was attained for other 3-aryl-substituted oxindoles (entries [7][8][9]. Notably,a n oxindole bearing a1 -pyrrolyl group could be successfully applied (entry 10), and outstanding ee values were generally afforded by introducing various benzyl (entries [11][12][13] or [b] ee [%] [c] 1 [d] -K OAc Toluene 8--2 [d] TBAB KOAc Toluene 87 9-3 [d,e] TBAB KOAc Toluene 81 [b] ee [%] [c] 1H [e] The absolutec onfiguration of chiral 3n was determined by X-ray analysis of its derivative 12' ' (see the SupportingInformation).…”