Chemoselective Switch in the Asymmetric Organocatalysis of 5H‐Oxazol‐4‐ones and N‐Itaconimides: Addition–Protonation or [4+2] Cycloaddition

Abstract

We report a synthetic strategy for a chemoselective switch and a diastereo-divergent approach for the asymmetric reaction of 5H-oxazol-4-ones and N-itaconimides catalyzed by l-tert-leucine-derived tertiary amine-urea compounds. The reaction was modulated to harness either tandem conjugate addition-protonation or [4+2] cycloaddition as major product with excellent enantio- and diastereoselectivities. Subjecting the enantio-enriched cycloaddition products to a basic silica gel reagent yields the diastereomer vis-à-vis the product directly obtained under conditions for addition-protonation, thus opening a diastereo-divergent route for creating 1,3-tertiary-hetero-quaternary stereocenters. Quantum chemical studies further provide stereochemical analysis for the [4+2] process and a plausible mechanism for this chemoselective switch is proposed.

Highly chemo-, enantio-, and diastereoselective [4 + 2] cycloaddition of 5H-thiazol-4-ones with N-itaconimides

“…A significant amount of conjugate addition adduct led to the unsatisfactory chemoselectivity and thus the moderate yield. When the H-bond donor was changed from thiourea to urea (catalyst II ), it did not provide better results (Table 1, entry 2) [17,19]. In the [4 + 2] annulation of 5 H -thiazol-4-ones with nitroalkenes, dipeptide-based thiourea−amide−tertiary amine III (DP-TAA) was devised and demonstrated as a competent catalyst to furnish excellent chemo- and stereoselectivity [10].…”

Asymmetric Assembly of All‐Carbon Tertiary/Quaternary Nonadjacent Stereocenters through Organocatalytic Conjugate Addition of α‐Cyanoacetates to a Methacrylate Equivalent

“…If so, a shortcut to the challenging construction of acyclic carbonyl adducts with nonadjacent stereocenters would be provided. Specifically, it is predicted that the evolved enolate from step 1 would preferentially adopt a Z configuration because of unfavorable A 1,3 strain in the chelated E form (Figure b), thus overcoming the problem of ill‐defined enolate geometry in asymmetric α‐protonations . Eventually, the prevalence of such dynamic hydrogen‐bond networks may also help during proton transfer (shuttle).…”

Anion–π Catalysis of Diels–Alder Reactions

“…[6][7][8][9][10][11][12][13][14][15][16][17] Theu sual mechanism of Diels-Alder reactions involves activation of the dienophile with Lewis acids. [6] However,b ase-catalyzed Diels-Alder reactions [7] have been realized by activation of dienes such as 5Hoxazol-4-ones, [8,9] 5H-thiazol-4-ones, [10] and 3-hydroxy-2pyrones. [11,12] Several organocatalysts,o ften tertiary amines derived from cinchona alkaloids,h ave been applied to all three diene classes in combination with several dienophiles to yield the corresponding cycloaddition products,o ften with excellent endo selectivity and high enantioselectivity.…”

“…Moving on from coupled cascade cyclizations [3] to concerted cycloadditions,t he Diels-Alder reaction stands out as the grand old classic. [6][7][8][9][10][11][12][13][14][15][16][17] Theu sual mechanism of Diels-Alder reactions involves activation of the dienophile with Lewis acids. [6] However,b ase-catalyzed Diels-Alder reactions [7] have been realized by activation of dienes such as 5Hoxazol-4-ones, [8,9] 5H-thiazol-4-ones, [10] and 3-hydroxy-2pyrones.…”

“…[11,12] Several organocatalysts,o ften tertiary amines derived from cinchona alkaloids,h ave been applied to all three diene classes in combination with several dienophiles to yield the corresponding cycloaddition products,o ften with excellent endo selectivity and high enantioselectivity. [7][8][9][10][11][12] Theselective acceleration of the formation of the usually disfavored exo product of Diels-Alder reactions [13] is an intriguing challenge that has attracted much attention. For example, exo selectivity has been achieved with catalytic antibodies raised against stable analogues of the exo transition state.…”