Amino−Zinc−Enolate Carbometalation Reactions:  Application to Ring Closure of Terminally Substituted Olefin for the Asymmetric Synthesis of cis- and trans-3-Prolinoleucine

Abstract

The amino-zinc-enolate cyclization reaction is a straightforward route for the synthesis of 3-substituted prolines. As classical intramolecular carbometalation reactions, the applicability of the addition of zinc to a double bond was limited to a substrate in which the terminal alkene carbon was unsubstituted. Being interested in the synthesis of cis- and trans-3-prolinoleucine derivatives for our structure-activity relation (SAR) studies, we focused our effort on the preparation of these compounds by amino-zinc-enolate cyclization of terminally substituted double bonds. Herein we report that the attachment of an activating group such as cyclopropyl to the terminal olefin carbon allows the amino-zinc-enolate cyclization of a terminally substituted alkene. The reaction is stereospecific, leading to a trans-3-substituted proline derivative, whereas a cis stereochemistry was observed with the amino-zinc-enolate cyclization of terminally nonsubstituted olefins. Absolute configurations obtained for the 3-prolinoleucine were established by X-ray analysis, NMR, and optical activity comparison of the cis and trans derivatives obtained by an unambiguous pathway.

Characterization of the bioactive conformation of the C‐terminal tripeptide Gly‐Leu‐Met‐NH2 of substance P using [3‐prolinoleucine10]SP analogues

“…Proline has been widely used as a scaffold and substitutions on the pyrrolidine ring have yielded a large variety of proline analogues [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Such constrained templates have been introduced in peptides to elucidate their bioactive conformation: for instance, 3-methylthiomethylproline (3-prolinomethionine) in substance P (SP) [20], 3-(p-hydroxyphenyl)proline (3-prolinotyrosine) in opioid peptides [21] as well as 3-n-propylproline [22], 3-and 4-alkylthioprolines [23] in cholecystokinin analogues.…”

Proton affinity of diastereoisomers of modified prolines using the kinetic method and density functional theory calculations: role of the cis/trans substituent on the endo/exo ring conformation

“…2) were achieved in a diastereoselective and enantioselective way via the amino–zinca–ene–enolate cyclization 5, 6. As previously reported, the following nomenclature7 is used to name these modified prolines: PAA where C is or T rans defines the relative stereochemistry of the ring substituent and the subscript 3 specifies the substituted position on the proline.…”

Diastereoselective Palladium Catalyzed Carbenylative Amination of ortho‐Vinylanilines with 3‐Diazoindolin‐2‐ones

“…Ylide B could undergo 1,3Pd-shift to provide intermediate C, which in turn would give cyclized zwitterion intermediate D via metallo-ene type cyclization reaction. [18] Finally, In conclusion, an efficient carbenylative amination of alkenes has been accomplished for the synthesis of diverse substituted spirooxindoles. The key feature of the methodology includes in-situ generation and trapping of ammonium ylide, derived from o-vinylaniline derivatives and isatin based diazo compound, with unactivated alkene in the presence of palladium catalyst.…”