Y 5).[18] Utilizing CKphos, vinylogous amide was obtained in 77 yield and 94 ee. As anticipated with CKphos, item selectivity favored three over four by 19:1.[19] With optimal conditions in hand, the alkyne scope was explored (Table 2). Aryl alkynes with electron donating and electron withdrawing groups take part in the reaction with moderate to high yield and high enantioselectivity (3aj). Substitution at the orthoand meta positions (3fj) is tolerated with out reduce in yield or enantioselectivity. Heteroaromatic alkynes and enynes are also competent substrates inside the reaction, delivering 3k and 3l with higher enantioselectivity. In all situations, solution selectivity is 19:1 favoring vinylogous amide. Alkyl and internal alkynes do not undergo the preferred reaction with oxygenlinked alkenyl isocyanates beneath the regular situations.[20] Excess alkyne (five.0 equivalents) or prolonged reaction times (48 h) don’t result in cycloadduct formation. On the other hand, within the case of 1heptyne, we identified that with slow addition in the isocyanate, 3m could be isolated in modest yield. Interestingly, isocyanates with a NTs linker deliver the preferred items with each aromatic and alkyl alkynes (Table two). Importantly, the reaction also tolerates Cbz and Boc protecting groups on nitrogen (6pr, Table 2). Vinylogous amide merchandise eight containing a tetrasubstituted carbon could possibly be obtained when alkenyl isocyanate 7 was applied within the reaction (Table three).[1c] These reactions proceed in slightly reduce yield and enantioselectivity. A range of alkynes are tolerated, like aryl alkynes with electron donating or withdrawing substituents and enynes. Substrates bearing a homologous tether afford vinylogous amides ten using a six,6bicyclic ring system (Table four).30094-32-7 web We then turned our consideration to cleavage of your tether.702699-84-1 site Sadly, a 1 step cleavage of the tether proved problematic.PMID:23415682 [21] We found that reduction with the vinylogous amide makes it possible for cleavage with the aminal. 5 Palladium on carbon beneath a hydrogen atmosphere affords bicyclic aminals with higher diastereoselectivity (19:1, Table 5).[1b] A screen of a number of situations to cleave the aminal revealed reductive amination as an efficient method to supply the Nmethylpiperidinol merchandise. Hence, treatment with the aminal with sodium cyanoborohydride inside a mixture of methanol and acetic acid (3:1) at ambient temperature offers the preferred product.[22] Utilizing vinylogous amide 3l in this twostepNIHPA Author Manuscript NIHPA Author Manuscript NIHPA Author ManuscriptAngew Chem Int Ed Engl. Author manuscript; obtainable in PMC 2014 May possibly ten.Martin and RovisPageprocedure affords piperidinol 12l with alkyl substitution. This presents a answer towards the incorporation of alkyl alkynes within the reported [222] cycloaddition.NIHPA Author Manuscript NIHPA Author Manuscript NIHPA Author ManuscriptAn Xray crystal structure was obtained of compound 13a. The protons from the 3 tertiary carbons are all on the similar face with the piperidinol ring, confirming the stereochemistry on the reduction of your vinyologous amide with Pd/C.[23] In conclusion, we present a route to access piperidinol scaffolds according to the rhodium (I) catalyzed asymmetric [222] cycloaddition between alkynes and an oxygenlinked alkenyl isocyanate. The cycloaddition proceeds with fantastic yield and high enantioselectivity to get a assortment of substrates. The stereocenter introduced inside a catalytic, asymmetric style is then applied to manage diastereoselectivity in a subsequent hydrogenation to afford diaste.