Dihydropyridones: Catalytic Asymmetric Synthesis, N‐ to C‐Sulfonyl Transfer, and Derivatizations

Abstract

The piperidine and dihydropyridone motifs are a recognized feature of numerous structurally diverse natural products and bioactive pharmaceuticals. [1] Among the synthetic methods developed for the preparation of these derivatives in enantiomerically pure form, [2] the aza-Diels-Alder reaction is an important and versatile route. [3] Since the introduction of uncatalyzed inverse-electron-demand aza-Diels-Alder cycloaddition processes by Boger and Kasper, [4] and Hsung and Berry, [5] few catalytic asymmetric methods for the promotion of this reaction have been developed. [6,7] The state-of-the-art N-heterocyclic carbene promoted [8] organocatalytic methods of Bode and co-workers (using enals and N-sulfonyl-a,bunsaturated aldimines), [9] and those of Ye and co-workers (arylalkylketenes and N-sulfonyl butenoates) [10] furnish dihydropyridones with high diastereo-and enantioselectivity; on the otherhand Chen and co-workers have employed enamine [11] and dienamine [12] catalysis in the transformation of Nsulfonyl-a,b-unsaturated ketimines [13] into pyridinols with high enantioselectivity. To date, processes that utilize enolate equivalents that have been prepared directly from readily available and bench-stable carboxylic acids have not been developed. [14] Within this area, Romo and co-workers, [15] and ourselves [16] have utilized Lewis base catalyzed [17] in situ activation of a carboxylic acid, [18] in combination with chiral isothioureas [19] (introduced as acyl transfer catalysts by Birman et al.), [20] to promote asymmetric aldol-and Michael/lactonization processes, respectively. To date, the only intermolecular process using this strategy requires aketo-b,g-unsaturated esters as the Michael acceptor, with chalcones being unreactive. To build upon this work, we envisaged that the electron-withdrawing N-sulfonyl group within N-tosyl-a,b-unsaturated ketimine derivatives would facilitate intermolecular organocatalytic Michael/lactamization, furnishing directly stereodefined dihydropyridones from arylacetic acids under isothiourea-mediated catalysis. We detail herein our studies toward this goal, as well as a range of derivatization procedures and a new N-to C-sulfonyl photoisomerization process, for the efficient asymmetric synthesis of polysubstituted dihydropyridones, dihydropyridines, piper-Scheme 1. Versatile route to N-and O-heterocyclic building blocks. Ts = p-toluenesulfonyl, LB = Lewis base.

N- to C-sulfonyl photoisomerisation of dihydropyridinones: a synthetic and mechanistic study

“…A range of racemic N-sulfonyl dihydropyridinones was prepared following established isothiourea-catalysed methods 12,16 in 90 : 10 to >95 : 5 dr and subjected to irradiation under the previously optimised conditions (Table 3). In all cases, no change in dr from the N-sulfonyl starting material (90 : 10 to >95 : 5 dr) to C-sulfonyl product (90 : 10 to >95 : 5 dr) was observed upon photoisomerisation, although chromatographic purification gave some products as single diastereoisomers.…”

“…A solution of the appropriate dihydropyridinone in degassed CH 2 Cl 2 (0.1 M) was irradiated with UV light at 365 nm (internal temperature within the UV chamber recorded as 30°C) 15 (1)), 141.1 (C(6)ArC (1)), 147.1 (C (6) (rac)-Ethyl anti-5-((4-nitrophenyl)sulfonyl)-2-oxo-3,6-diphenyl-1,2,3,4-tetrahydropyridine-4-carboxylate (10). Following the general procedure, irradiation of (rac)-ethyl anti-1-((4-nitrophenyl)sulfonyl)-2-oxo-3,6-diphenyl-1,2,3,4-tetrahydropyridine-4-carboxylate (50.7 mg, 0.1 mmol) in CH 2 Cl 2 (1.0 mL) for 18 h gave the crude product in >95 : 5 dr. Purification by column chromatography (CH 2 (3)), 126.9 (ArCH), 128.3 (C(6)ArC (1)), 128.6 (SO 2 ArC (2)), 128.7 (ArCH), 129.4 (ArCH), 131.1 (ArCH), 135.3 (C(3)ArC (1)), 146.6 (SO 2 ArC (1)), 148.3 (C(6)), 149.5 (SO 2 ArC (4) (rac)-Ethyl anti-5-(ethylsulfonyl)-2-oxo-3,6-diphenyl-1,2,3,4-tetrahydropyridine-4-carboxylate (12). Following a modified general procedure, irradiation of (rac)-ethyl anti-1-(ethylsulfonyl)-2-oxo-3,6-diphenyl-1,2,3,4-tetrahydropyridine-4-carboxylate (26 mg, 0.06 mmol) in CDCl 3 (1.0 mL) in an NMR tube for 24 h gave the crude product in 90 : 10 dr. Purification by column chromatography (hexane/EtOAc, 50 : 50) gave the title compound (20 mg (rac)-Ethyl anti-2-oxo-6-phenyl-5-( phenylsulfonyl)-3-(thiophen-3-yl)-1,2,3,4-tetrahydropyridine-4-carboxylate (13).…”

“…12 She and co-workers subsequently reported that related dihydropyridinones such as 4 also undergo N-to C-sulfonyl transfer into 5 in the presence of catalytic N-hydroxyphthalimide and cobalt(II) acetate under an oxygen atmosphere at high temperature (Scheme 1b). 14 However, to date there have been no detailed investigations into the photochemical N-to C-sulfonyl transfer onto the alkene within substituted dihydropyridinone derivatives.…”

Exploring the scope of the isothiourea-mediated synthesis of dihydropyridinones

“…While the reason for this is not immediately clear, enantioselectivity remained excellent. Arylacetic acids containing para-, meta-and orthotolyl substituents were all incorporated in high yields and excellent stereoselectivities (23)(24)(25), demonstrating that orthosubstitution has no detrimental effect on the course of the reaction, unlike in our previous synthesis of dihydropyridinones 9 amongst other examples. 7,12a,12c paraPhenyl as well as 1-and 2-naphthyl substitution gave the desired dihydropyridinones (26-28) in moderate yields, although stereoselectivities remained excellent.…”

“…12 Our previous synthesis of dihydropyridinones reacted isothiouronium enolates generated from carboxylic acids with N-tosyl chalcone-derived ketimines in a Michael addition / lactamisation cascade (Scheme 2a). 9 This afforded a range of dihydropyridinones in high yields and excellent stereoselectivity. In this methodology the N-tosyl substituent was employed exclusively in the ketimine Michael acceptor.…”