A vinylog of Michael addition (1,6-addition) of azlactones to δ-substituted dienyl N-acylpyrroles has been developed with virtually complete 1,6-, diastereo-, and enantioselectivities by means of chiral P-spiro triaminoiminophosphorane as a catalyst. This system has been successfully extended to an unprecedented bis-vinylog of Michael addition (1,8-addition) of azlactones to ζ-substituted trienyl N-acylpyrroles with high levels of regio- and stereocontrol.
A site‐divergent stereoselective Michael reaction system is developed based on the identification of two distinct catalysts. Cinchonidine‐derived thiourea catalyzes the 1,4‐addition of prochiral azlactone enolates to enynyl N‐acyl pyrazoles in a highly diastereo‐ and enantioselective manner to give stereochemically defined alkynes, while P‐spiro chiral triaminoiminophosphorane catalytically controls the stereoselective 1,6‐addition and the consecutive γ‐protonation of the vinylogous enolate intermediate to afford Z,E‐configured conjugated dienes. This 1,6‐adduct serves as a valuable precursor for the synthesis of a 2‐amino‐2‐deoxy sugar.
As ite-divergent stereoselective Michael reaction system is developed based on the identification of two distinct catalysts.C inchonidine-derived thiourea catalyzest he 1,4addition of prochiral azlactone enolates to enynyl N-acyl pyrazoles in ahighly diastereo-and enantioselective manner to give stereochemically defined alkynes,w hile P-spiro chiral triaminoiminophosphorane catalytically controls the stereoselective 1,6-addition and the consecutive g-protonation of the vinylogous enolate intermediate to affordZ ,E-configured conjugated dienes.T his 1,6-adduct serves as av aluable precursor for the synthesis of a2 -amino-2-deoxy sugar.
Catalytic systems that allow selective generation of any diastereomer of a reaction product bearing multiple stereocentres through minimal modification of a single catalyst scaffold remain elusive, particularly for carbon–carbon bond formations requiring simultaneous control of multiple selectivity factors. Here, we report a catalyst-directed pinpoint inversion of diastereochemical preference in the 1,6-addition of azlactones to δ-aryl dienyl carbonyl compounds with full control over other selectivities preserved. This rigorous diastereodivergence is enabled by the slight structural adjustment of a chiral iminophosphorane catalyst, providing access to all the stereoisomers with high regio-, distereo- and enantioselectivity. The utility of this method is demonstrated in the facile stereodivergent preparation of densely functionalized proline derivatives. The experimental and computational elucidation of the origin of the diastereodivergence is also reported.
Chiral P-spiro triaminoiminophosphorane (1) was developed to promote the highly regio-, diastereo-, and enantioselective 1,6- and 1,8-additions of azlactones (2·H) to dienyl and trienyl N-acylpyrroles (3 and 4). DFT calculations enabled us to gain deep insight into the whole reaction mechanism as well as the origin of the high regio- and stereoselectivities. The present reaction consists of three steps: (1) formation of the phosphonium-enolate ion-pair complex by deprotonation of 2·H with 1, (2) C-C bond formation of 2 with 3 and 4, and (3) protonation of the resulting enolate anion. The C-C bond formation is irreversible, and the rate- and stereodetermining step. The C-protonation preferentially proceeds rather than the thermodynamically and kinetically disfavored O- and C-protonation, respectively. The high regio- and enantioselectivities are mainly attributed to the steric and electronic features of 1·H and 3/4. The hydrogen bonds (NH-O and CH-O) and the attractive CH-π interaction between 1·H and 2 and 3 play a key role in achieving high stereocontrol. The high regioselectivity is mainly controlled by the structural distortion of 1·H and the disruption of the π-conjugated system of 3 (1,4-system) and 4 (1,4- and 1,6-systems).
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