Functionalized Cis- and Trans-Fused Bicyclic α-Amino Acids via Stereoselective Double Annulation and Dequaternization Reactions

Abstract

Fused bicyclic alpha-amino acids can be prepared by a double Michael reaction of p-anisyl ethynyl ketone and a tethered diacid, cyclization via hydrogenation or hydration of a CN group, and oxidation of the p-anisyl group. The substitution level of the alpha-amino acids can be adjusted by decyanation or decarboethoxylation of the intermediates. Bicyclic alpha-amino acids prepared in this way include cis- and trans-perhydroisoquinoline-3-carboxylic acids and cis-perhydro-2-pyrindine-3-carboxylic acids of various substitutions and oxidation levels. The bicyclic alpha-amino acids may be regarded as functionalized and conformationally restricted analogues of proline, pipecolic acid, 2-aminoadipic acid, or glutamic acid.

Synthesis of Pyroglutamic Acid Derivatives via Double Michael Reactions of Alkynones

“…Over the past few years, Grossman and co-workers have described a range of reactions where compounds containing two acidic carbon atoms undergo double Michael reactions with electron-deficient alkynes (mostly 3-butyn-2-one) to provide highly functionalized cyclic products. , Generating two new carbon−carbon bonds and up to three new stereogenic centers with often high levels of diastereoselectivity, this reaction has been effectively utilized in the preparation of a range of five- and six-membered carbocycles . In comparison, application of this methodology to heterocycle construction has been limited, with just one report of a [5 + 1] annulation route to piperidines having been described …”

“…Our preliminary investigations began with the double Michael reaction of amide-tethered diacid 7a with aromatic alkynone 3a (Table ). In all previous examples of double Michael reactions reported by Grossman and co-workers, , a mandatory requirement for success is the presence of at least one nitrile substituent in the tethered diacid, which ends up in a pseudoaxial position in the product 4i. It is proposed that the small size of the nitrile group reduces the magnitude of unfavorable 1,3-diaxial interactions between acidifying groups in the transition state for cyclization, which would otherwise inhibit ring closure 4i.…”

Diversity-Oriented Synthesis toward Fused and Bridged Benzobicyclic Piperidin(on)es

“…This failure prompted us to transform benzomorphanones 1 into benzomorphanothiones 2 using Lawesson’s reagent and to treat them with NaBH 4 in the presence of NiCl 2 ·6H 2 O in THF/MeOH (1:1) solution. We chose this reducing system because it has gained some appreciation in the reductive desulfurization of thioamides and thiolactams since it was invented . In addition, some literature reports indicated high reducing power of this system because other than sulfur-containing functional groups like alkenyl or alkynyl can be successfully reduced by this method …”

The reductive decyanation reaction: an overview and recent developments

“…Later, they made a full study and successfully reduced to mononitriles a variety of mono- and dialkylated malononitriles but under these conditions, the reduction of cyanoacetates failed [ 115 ]. Synthetic applications of this methodology were later described [ 116 – 118 ]. Chiba et al have developed a concise and stereoselective methodology for the preparation of highly substituted carbocycles [ 119 – 120 ].…”