Asymmetric reactions tetrahydropyridines

The [2 + 2] cycloaddition reaction of A -benzyl-l,4-dihydropyridine 34b with acrylonitrile, followed by catalytic reduction gave two pairs of diastereoisomeric amides 36 and 37 with a low diastereomeric excess, probably due to the large distance between the asymmetric center and the site of acrylonitrile attack. Compounds 36 and 37 were resolved into the four individual diastereoisomers (ca 5% for compound 36 and 15% for 37) [97JCR(M)321], Irradiation of 1,4-dibenzyl-1,4,5,6-tetrahydropyridine 38 in the presence of 29 gave two stereoisomers. 

These results indicate that the sulfinyl group seems to be much more efficient in the control of the stereoselectivity of 1,3-dipolar cycloadditions (endo or exo adducts are exclusively obtained in de> 80%) than in Diels-Alder processes (mixtures of all four possible adducts were formed). Additionally, complete control of the regioselectivity of the reaction was observed. Despite these clearly excellent results, the following paper concerning asymmetric cycloaddition of cyclic nitrones and optically pure vinyl sulfoxides was reported nine years later [154]. (Meanwhile, only one paper [155], related to the synthesis of /1-nicotyri-nes, described the use of reaction of nitrones with racemic vinyl sulfoxides, but these substrates were merely used as a masked equivalent of acetylene dipolaro-phile). In 1991, Koizumi et al. described the reaction of one of the best dipolarophiles, the sulfinyl maleimide 109, with 3,4,5,6-tetrahydropyridine 1-oxide 194 [154]. It proceeded in CH2C12 at -78 °C to afford a 60 20 10 6 mixture of four products in ca. 90 % yield (Scheme 92). 

Asymmetric Michael reactions have heen conducted with assistance of C2-symmetric malonamides derived from (5)-ptohne esters/ 2-Methyl-3,4,5,6-tetrahydropyridine and 2-cyclopentenone are condensed to afford a tricyclic alcohol. The reaction starts from Michael reaction of the endocychc enamine isomer and as the double bond shifts to the exo-cychc position an intramolecular aldol reaction follows. If the imine is hthiated, the initial Michael reaction (CuBr-catalyzed) then involves the exocyclic carbon. ... 

A review of formal aza-Diels-Alder reactions of imines with e-rich dienes and enones, in the presence of Lewis acids/Brpnsted acids/organocatalysts, has been presented. Bifunctional A-acyl aminophosphine catalysts (75) are effective asymmetric organocatalysts in the hetero-4- -2-cycloaddition of a-substituted allenoates with tosylaldimines to produce optically active tetrahydropyridines. The Brpnsted acid-catalysed aza-Diels-Alder reactions of cyclopentadiene with iminoacetates possessing two chiral auxiliaries yielded 2-azabicyclo[2.2.1]hept-5-ene cycloadducts with high exo-selectivities. ... 

X. Li, Y. Zhao, H. Qu, Z. Mao, X. Lin, Chem. Commun. 2013,49, 1401-1403. Organocatalytic asymmetric multicomponent reactions of aromatic aldehydes and anilines with P-ketoesters facile and atom-economical access to chiral tetrahydropyridines. 

In this context. Rueping s group envisioned the asymmetric organocatalytic multiple-reaction cascade version of the abovementioned process in which a six-step sequence was catalyzed by the chiral Brpnsted acid catalyst 21 providing direct access to a broad scope of valuable tetrahydropyridines 26 and azadecalinones 35 with high enantioselectivities (Scheme 11) [99]. 

A catalytic asymmetric intramolecular hydroamination of aminoallenes has been carried out in the presence of titanium complexes prepared by the in situ reaction of Ti(NMe3)4 with chiral amino alcohols [319]. The ring-closing reaction of hepta-4,5-dienylamine at 110 °C with 5 mol% catalyst gives a mixture of 6-ethyl-2,3,4,5-tetrahydropyridine (14-33%) and both Z- and T-2-propenylpyrroli-dine (67-86%), whereas the same reaction with 6-methylhepta-4,5-dienylamine under similar conditions gives exclusively 2-(2-methylpropenyl)pyrrolidine with modest enantiomeric excess values (<16%) (Scheme 14.139). 

The catalytic asymmetric /-selective Diels-Alder annulation of a, -unsaturated /-butyrolactams with enones provided a synthesis of, y-functionalized bridged bi-or tri-cyclic dihydropyranopyrrolidin-2-ones in one step (up to 98% yield, >20 1 dr, and 99% ee) The inverse-electron-demand aza-Diels-Alder cycloaddition 0 of A-aryl-a,/0-unsaturated ketimines with enecarbamates in the presence of chiral bifunctional phosphoric acids produced 4,5,6-trisubstituted 1,4,5,6-tetrahydropyridines having three contiguous stereogenic centres in up to 84% yield, 95 5 dr, and 95% 5-Alkenylthiazoles react as in-out dienes with e-poor dienophiles in polar 44-2- 0 cycloaddition reactions. The cycloadditions are site selective. The mechanism is thought to lie between a concerted but highly asynchronous process and a stepwise process. 

Very recently. Barber et al. reported a tandem reaction combining bifunctional urea and Au(I) salt for the asymmetric synthesis of valuable tetrahydropyridine derivatives [80]. This reaction consisted of a urea-promoted nitro-Mannich reaction of an alkyne-tethered secondary nitroalkane to N-Boc-protected imines and an Au(I) complex-catalyzed intramolecular hydroamination and isomerization (Scheme 9.75). Notably, since the inherent Lewis basic tertiary amine-tethered urea would deactivate the Au catalyst, the reaction system was acidified by additional DPP before addition of an Au catalyst to ensure the success of the overall process. 

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