Herein we report a concise protocol for the diastereoselective synthesis of novel bridged bicyclic lactams from commercially available components by the sequence of Ugi, ring-closing metathesis (RCM), and Heck reactions. X-ray diffraction studies revealed that the bicyclic products contain varying degrees of pyramidalization of the bridgehead nitrogen atom.

The influence of attractive, nonbonded interactions on the reactions of 1,2- and 1,3-hydroxyalkyl azides with ketones has been investigated through experimental and computational means. A series of 1,3-hydroxyalkyl azides bearing electronically tuned aromatic groups at the 2 position were prepared and reacted along with several derivatives designed to conformationally restrict the rotational orientation of the aromatic substituent. These studies showed that a cation-pi interaction between an aryl moiety and an N2(+) leaving group plays a role in determining the stereoselectivity of these reactions. A series of ab initio calculations supported this hypothesis. A computational and experimental analysis suggested a primarily steric model for the analogous reactions of substituted 2-azido-1-ethanol analogues.

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...

A concise and asymmetric total synthesis of the title compound is described. The key ring system was constructed using an intramolecular Schmidt reaction on a norbornenone derivative, which was subsequently subjected to ring-opening metathesis followed by reduction. An unusual isomerization of the C-6 ethyl group afforded the desired stereochemistry of the natural product. The synthesis is readily adaptable to analogue production.

A procedure for the conversion of a symmetrical ketone to an enantiomerically pure lactam is described. The technique described here involves a ring-expansion reaction of a 4-substituted cyclohexanone accomplished with a chiral 1,3-azidopropanol derivative. The procedure entails first a one-step preparation of (R)-1-phenyl-3-azidopropanol from a commercially available halide precursor, which is then reacted with the ketone using BF(3) x OEt(2) as a Lewis acid promoter. The resulting lactam is subsequently converted into a chiral lactam of high enantiopurity via the two-stage removal of the chiral nitrogen substituent. The present protocol carries out the diastereoselective ring-expansion reaction with higher selectivity than competing processes and is generally useful for the preparation of 5-substituted caprolactams.