Electrostatic control of leaving group stereochemistry leads to superior diastereoselectivity in an asymmetric ring expansion reaction.Keywords ring expansion; non-bonded interactions; azides; Schmidt reaction; stereoselectivity † Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. CDCD Correspondence to: Jennifer L. Poutsma; Jeffrey Aubé. NIH Public Access Author ManuscriptAngew Chem Int Ed Engl. Author manuscript; available in PMC 2012 November 29. Most stereoselective reactions are ruled by steric effects. In particular, kinetically controlled asymmetric transformations utilizing chiral reagent, auxiliaries, or catalysts succeed due to energy differences in transition states that most often arise by the minimization of repulsive, non-bonded interactions. Stereoelectronic considerations, which arise when the alignment of particular orbitals are necessary for a successful reaction, can also play a role. [1] An iconic stereoelectronic effect in organic chemistry is the anomeric effect. [2] Reactions controlled by the anomeric effect, such as glycosidations, largely depend on the relative orientation of the non-bonding or n electrons of a nearby alkoxy group. In recent years, alkoxy group control of stereoselective reactions via electrostatic interactions has received renewed scrutiny, led by the Woerpel group. [3] In this communication, we report an alternative and highly effective approach to stereocontrol through the maximization of attractive non-bonded interactions between an alkoxy or alkylthio group and a positively charged leaving group.The Lewis acid-promoted reaction of a symmetrically substituted cyclic ketone with a chiral hydroxyalkyl azide provides a stereoselective route to lactams (Scheme 1). [4] In this reaction, initial formation of a spirocyclic intermediate sets up the selective migration of one of the alkyl groups originally adjacent to the ketone carbonyl. Migration of a C-C bond antiperiplanar to the N 2 + leaving group (only possible when the latter is in an axial position as shown) affords an iminium ether that is converted into lactam by workup with aqueous base. For 1-or 3-substituted azidopropanols (not shown), 10:1 selectivities are obtained, corresponding to preferential reaction through the most stable chairlike heterocyclic ring (A or B) resulting from equatorial addition of azide relative to the tert-butyl group.Intermediates A and B can interconvert through conformational reorganization or by reversion to the initially formed oxonium ion followed by reclosure. In this scenario, selectivity is attained by stabilization of A over B due to traditional minimization of 1,3-diaxial interactions by placement of the R 1 or R 3 into equatorial positions in the former.2-Substituted 1,3-azidopropanols present a special case that is unusually susceptible to stereoelectronic control due to three factors: (1) the methylene groups near the spiro linkage are locally isoelectronic, so the reaction cannot be controlled by "m...
Im Griff: Eine anziehende elektrostatische Kraft stabilisiert die Konformation einer Zwischenstufe (siehe Schema; n=nichtgebundenes Elektron) und legt so die Konfiguration der Abgangsgruppe fest, was in einer asymmetrischen Ringerweiterungsreaktion zu einer außergewöhnlich hohen Diastereoselektivität führt.
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