Amino Zinc Enolate Carbocyclization Reactions. New Access to Polysubstituted Piperidine Derivatives

Abstract

Various N-pent-4-enylglycine methyl esters have been submitted to carbocyclization of their zinc enolates onto the unactivated double bond. The cyclization to substituted pipecolic esters is highly stereoselective. In most cases, substitution of the pent-4-enyl moiety on various sites leads to a single isomer, hence a way to di-, tri-, tetra-, or pentasubstituted piperidines.

Carbozincation Reactions of Carbon–Carbon Multiple Bonds

“…However, the cyclization reaction of a zinc enolate has been successfully applied to the formation of six-membered rings in a new route to substituted piperidine derivatives (Scheme 94). 128 After lithiation in ether and transmetalation with zinc bromide, the corresponding (Z)-α-aminozinc enolate cyclizes at room temperature to afford the metalated piperidines. Protonation, iodinolysis, or allylation of the reaction mixture after a subsequent transmetalation step affords the functionalized piperidines in 66, 81, and 65% yields, respectively.…”

Carbometallation Reactions

“…However, cyclization of the zincaminoenolate has been successfully applied to the formation of sixmembered rings, as a new access to oligosubstituted piperidine derivatives (Scheme 7-144) [176].…”

“…In all cases, only the cis-isomer was detected. The stereoselectivity has been explained by a chair-like transition state in which the electrophilic double bond occupies a pseudo-axial position (the zinc (Z)-a-aminoenolate and the double bond are gauche to each other), as depicted in Scheme 7-144 [176]. Scheme 7-143 Intramolecular carbocyclization of a zincated N,N-dimethylhydrazone and an v-alkenyl ketone [175].…”

“…The study of the stereochemical influence of substituents on the starting linear substrates on the carbocyclization reaction has been performed in detail, and the stereochemical outcome of this carbocyclization has been found to be mainly controlled by the presence or absence of a substituent in the homoallylic position [176].…”

Highly Functionalized and Potent Antiviral Cyclopentane Derivatives Formed by a Tandem Process Consisting of Organometallic, Transition‐Metal‐Catalyzed, and Radical Reaction Steps

“…[12] In contrast, enolates VII are usually unable to undergo inter-or intramolecular additions to unactivated olefins. [13] Here, a switch by a single-electron oxidation to constitutionally identical free radicals, which undergo this type of reaction easily, [14] may provide a solution. The validity of these hypotheses is documented herein.…”