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We report a range of highly regioselective openings of [1.1.1]propellane with various allylic zinc halides, as well as zinc enolates of ketones, esters and nitriles. The resulting zincated bicyclopentanes (BCPs) were trapped with a range of electrophiles including acyl chlorides, sulfonothioates, hydroxylamino benzoates, tosyl cyanide as well as aryl and allyl halides, generating highly functionalized BCP‐derivatives. The unusually high regioselectivity of these reactions has been rationalized using DFT calculations. A bioisostere of the synthetic opioid pethidine was prepared in 95 % yield in one step using this method., A wide range of allylic zinc reagents as well as zinc enolates open [1.1.1]propellane to generate zincated bicyclopentanes (BCPs) in a highly regioselective manner. These intermediate zinc reagents are trapped with various electrophiles, giving access to fully functionalized BCPs including a BCP‐analogue of the synthetic opioid pethidine.

Chiral N-(tert-butyl)sulfinyl aldimines easily prepared from commercially available compounds have been used as starting materials for the following processes: (i) hydrogen transfer, (ii) addition of zincates, (iii) In-promoted allylation, and (iv) addition of zinc enolates. In all cases, the final desulfinylation to yield the expected chiral α-substituted primary amines was easily performed with hydrochloric acid in an organic solvent. This methodology has been successfully applied to the preparation of chiral natural products such as alkaloids and amino acids. We thank the continuous financial support from the Ministry of Science and Innovation (Ministerio de Ciencia e Innovación (MICINN), Projects CTQ2007-62771/BQU, CTQ2010-20387, CONSOLIDER INGENIO 2010-CDS2007-00006, CTQ2011-24151, and CTQ20122-24165), the Ministry of Economy and Competitiveness (Ministerio de Economía y Competitividad (MINECO), Projects CTQ2013-43446-P, CTQ2014-51912-REDC, and CTQ2014-53695-P), the Fondo Europeo de Desarrollo Regional (FEDER), the Government of the region of Valencia (Generalitat Valenciana, Project PROME-TEOII/2014/017), and the University of Alicante.

An α-alkylidation of cyclopentanone was achieved in two reaction steps in an overall yield of 20 to 79% via a zinc chloride-catalyzed thioalkylation of the zinc enolate of methyl 2-oxocyclopentanecarboxylate (3) and subsequent saponification/desulfurization of the β-(phenylthio) ketone intermediates 5. For the saponificatioddesuiurization step DABCO proved to be the reagent of choice and superior to the use of alkali or magnesium halides.

An α-alkylation of the 2-methylcycloalkanones 1 and 4 at the higher substituted carbon can be achieved by thioalkylation of the corresponding zinc enolates with the α-chlorosulfides 3. The desulfurization can be carried out with either Raney nickel or lithium in diethylamine for compounds which contain double or triple bonds.