Piperidinones chiral

The a-arylation of carbonyl compounds (sometimes in enantioselective version) such as ketones,107-115 amides,114 115 lactones,116 azlactones,117 malonates,118 piperidinones,119,120 cyanoesters,121,122 nitriles,125,124 sul-fones, trimethylsilyl enolates, nitroalkanes, esters, amino acids, or acids has been reported using palladium catalysis. The asymmetric vinylation of ketone enolates has been developed with palladium complexes bearing electron-rich chiral monodentate ligands.155... 

Bicyclic alkaloids. Nagao et al. have developed a general synthesis of chiral bicyclic alkaloids with a nitrogen atom at the ring juncture, such as pyrrolizidines [5.5], quinolizidines [6.6], and indolizidines [6.5], based on a highly diastereose-lective alkylation of 3-a>-chloroacyl-(4S)-isopropyl-l,3-thiazolidine-2-thiones (1, m = 1,2) with 5-acetoxy-2-pyrrolidinone (2, n = 1) or 6-acetoxy-2-piperidinone (2, n = 2). Thus the tin enolate of 1 (m = 1), prepared with Sn(OTf) and N-... 

In 2006, Akiyama and coworkers established an asymmetric Brpnsted acid-catalyzed aza-Diels-Alder reaction (Scheme 36) [59]. Chiral BINOL phosphate (R)-3o (5 mol%, R = 2,4,6- Pr3-CgH2) bearing 2,4,6-triisopropylphenyl groups mediated the cycloaddition of aldimines 94 derived from 2-amino-4-methylphenol with Danishefsky s diene 95 in the presence of 1.2 equivalents of acetic acid. Piperidinones 96 were obtained in good yields (72 to >99%) and enantioselectivi-ties (76-91% ee). While the addition of acetic acid (pK= 4.8) improved both the reactivity and the selectivity, the use of benzenesulfonic acid (pK= -6.5) as an additive increased the yield, but decreased the enantioselectivity. A strong achiral Brpnsted acid apparently competes with chiral phosphoric acid 3o for the activation of imine 94 and catalyzes a nonasymmetric hetero-Diels-Alder reaction. The role of acetic acid remains unclear. 

The same group expanded the scope of the aza-Diels-Alder reaction of electron-rich dienes to Brassard s diene 97 (Scheme 37) [60]. In contrast to Danishefsky s diene, it is more reactive, but less stable. Akiyama et al. found chiral BINOL phosphate (R)-3m (3 mol%, R = 9-anthryl) with 9-anthryl substituents to promote the [4 + 2] cycloaddition of A-arylated aldimines 94 and Brassard s diene 97. Subsequent treatment with benzoic acid led to the formation of piperidinones 98. Interestingly, the use of its pyridinium salt (3 mol%) resulted in a higher yield (87% instead of 72%) along with a comparable enantioselectivity (94% ee instead of 92% ee). This method furnished cycloadducts 98 derived from aromatic, heteroaromatic, a,P-unsaturated, and aliphatic precursors 94 in satisfactory yields (63-91%) and excellent enantioselectivities (92-99% ee). NMR studies revealed that Brassard s diene 97 is labile in the presence of phosphoric acid 3m (88% decomposition after 1 h), but comparatively stable in the presence of its pyridinium salt (25% decomposition after 1 h). This observation can be explained by the fact that the pyridinium salt is a weak Brpnsted acid compared to BINOL phosphate 3m. 

Enantiocontrol with 21-23 is lower than that achieved with chiral copper catalysts for reactions of diazoacetates with styrene and a few other alkenes examined thus far [68], but the carboxamidates display far greater stereocontrol than do the dirhodium(II) carboxylates for the same reactions [69]. However, Hashimoto has reported the use of chiral piperidinonate 24 and found exceptional enantiocontrol in the cyclopropanation of styrene and both mono- and... 

Tacamonine, an indole alkaloid of the Iboga type, isolated from Tabermemontana eglandulosa, the root of which is used to treat snake bites in Zaire, bears structural similarity to the Hunteria alkaloids, eburnamonines, which possess vasodilator and hypotensive activities. Its synthesis in racemic and homochiral form was accomplished by incorporating a classic 6-exo-trig radical cyclization in the key step of the synthesis (Scheme 6)71. The radical precursor 6 was constructed in a 7-step synthesis by starting from racemic or chiral propane-1,3-diol. The radical cyclization of 6 produced the piperidinone in 72% yield as a diastereomeric mixture, which was then transformed into tacamonine. 

The chiral piperidinones 46 formed by the reaction between Danishefsky s diene and the glycosyl imines are valuable synthons for the synthesis of higher substituted piperidine derivatives. 2,6-Disubstituted piperidinones 49 are obtained by addition of organocuprates complexes with boron trifluoride [53]. The reaction pathway is illustrated in Scheme 30. 

A new convenient procedure for the chiral alkylation of 5-acetoxy-2-pyrrolidinone (91) and 6-acetoxy-2-piperidinone (92) has been developed. This procedure should be useful for an extremely short chiral synthesis of the bicyclic alkaloids involving pyrrolizidine, indolizidine, and quinolizidine skeletons (88JA289). 

SCHEME 10.65 Lewis acids can facilitate the addition of organocuprates to chiral 2-substituted piperidinone derivatives prepared as previously described. 

A more economical use of 40, in terms of carbon atoms and chiral centers, was devised to produce the heteroyohimbine alkaloid ajmalicine and its 19-epimer [54]. As shown in Scheme 11.13, deoxygenation of 40 at C6 followed by oxidative cleavage of the vinyl group gave the corresponding aldehyde 43, which was equilibrated to the equatorial isomer 44. Subsequent reaction with tryptamine gave the piperidinone 45. Bisher-Napieralsky cyclization provided the alkaloid skeleton, which was elaborated to ajmalicine 46. 

The cyclopropanation with diazo compounds via decomposition is amenable to asymmetric induction using chiral metal chelates. Rhodium complexes of 3(S)-phthalimido-2-piperidinone and Al-(arenesulfonyl)proline 44 are typical. The latter catalyst is suitable for generating alkenylcarbenoids. For intramolecular reactions, the cognate complex 45 and the semicorrin-copper 46 are effective. 

Chiral hydrazones derived from SAMP or RAMP are used in the asymmetric synthesis of 4,5,6-trisubstituted and 6-substituted piperidinones <97LA1115>. Chiral 2-substituted piperidines are prepared by the addition of Grignard reagents to chiral imines followed by oxidation of the terminal double bond and reductive cyclization <97JOC746>. 

Chiral 2-amino-l,3-butadienes derived from 2-(methoxymethyl)pyrrolidine and a-oxo enamines undergo cycloadditions with jV-silylimines in the presence of ZnCl2 to yield 4-piperidinones stereoselectively upon subsequent hydrolysis with aqueous NaHCOs. 

Rhodium(II)-MEPY and rhodium(II)-MACIM (methyl 1-acetylimidazolidin-2-one-4-carboxylate) complexes are efficient chiral catalysts for intramolecular carbon-hydrogen insertion reactions of diazoacetates (224) and metal carbene transformations (225). Dirhodium(II) carboxylates of similar structure (eg, piperidinonate complexes of the Rh2(ligand)4 type) have been found efficient catalysts for asymmetric cyclopropanation of olefins (226). 

Diels-Alder reactions (Scheme 16.16). Recently, they reported that [Rh2(S-BPTPI)4] (56), a new dirhodium(II) carboxamidate complex, that incorporates (S)-3-(benzene-fused-phthalimido)-2-piperidinonate as chiral bridging ligands, is an exceptionally effective Lewis acid catalyst and a more general and highly efficient catalyst for endo- and enantioselective hetero Diels-Alder reactions [17] The catalyst is readily synthesized, air-stable, and easily handled. The present [Rh2(S-BPTPI)4]... 

In addition to protonation, a postdoc in the lab, Jan Streuff, explored the use of our catalytically generated enolate in the context of conjugate additions [31]. While the scope of Michael acceptors reactive enough to be intercepted by our chiral enolate complex was limited, we were able to demonstrate a highly diastereo- and enantioselective S3mthesis of vicinal quaternary and tertiary stereocenters with a number of allyl p-ketoesters. In particular, the most enantio- and diastereoselective reactions of this type were observed with 4-piperidinone-derived pronucleophiles (Scheme 10). 

One of the potential problems associated with 148 lies in its strong acidity, in particular when applied to labile substrates. Akiyama and coworkers have found that its pyridinium salt 150 also exhibits efficient catalytic activity as a chiral Bron-sted acid catalyst that is compatible with labile substrates such as Brassard s diene 113 [68]. Accordingly, an efficient inverse-electron-demand aza-hetero-Diels-Alder reaction of aldimines 146 with Brassard s diene 113 catalyzed by 150 was accomplished to afford piperidinone derivatives 151 in high yields with excellent enan-tioselectivities (Scheme 38.45). 

For example, formal synthesis of the antidepressive drug (-)-paroxetine 31 was achieved based on the iminium-ion-catalyzed conjugate/cyclization cascade reaction (Scheme 3.4) [20]. In the presence of catalyst 29, the reaction of amidomalonate 27 with a,P-unsaturated aldehyde 28 afforded the chiral piperidinone 30 with good results (84% yield, 90% ee, 5 1 dr). After further transformation, formal synthesis of the blockbuster antidepressive drug (-)-paroxetine 31 was achieved. 

Akiyama et al. reported on the chiral Br0nsted-acid-cat-alyzed aza-Diels-Alder reaction of aldimines 237 with Brassard s diene 238. After the C N alkylative cyclization, piperidinone derivatives 239 were formed with high yield and excellent enantioselectivity. " They used pyridinium salt of chiral phosphoric acid as the chiral Br0nsted acid (Scheme 40.52). 

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