The energetics of cis-trans proline isomerization in small peptide models have been investigated using the hybrid density functional theory method B3LYP with a 6-31+G* basis set. The molecules studied are models for the phospho-Ser/Thr-Pro substrate for Pin-1, a peptidyl-prolyl isomerase (PPIase) involved in cell division. Pin-1 requires phosphorylation of a Ser or Thr residue adjacent to a Pro residue in the substrate and catalyzes cis-trans isomerization about the proline amide bond. The dihedral angle that would correspond to the reaction coordinate for isomerization of the omega peptide bond was investigated for several small models. Relaxed potential energy scans for this dihedral angle in N-methylacetamide, 1, N,N-dimethylacetamide, 2, acetylpyrrolidine, 3 and acetylproline, 4, were carried out in 20 degrees steps using the B3LYP/6-31+G* level of theory. In addition, similar scans were carried out for 1-4 protonated on the acetylamide carbonyl oxygen. Optimized structures for 1-4 protonated on the amide nitrogen were also obtained at B3LYP/6-31+G*. Relative proton affinities were determined for each site at various angles along the reaction coordinate for isomerization. The relative proton affinities were anchored to experimental gas phase proton affinities, which were taken from the literature for 1 and 2, or determined in an electrospray ionization-quadrupole ion trap instrument using the extended kinetic method for 3 and 4. Proton affinities of 925 +/- 10 and 911 +/- 12 kJ/mol were determined for 3 and 4, respectively. These studies suggest that the nitrogen atom in these amides becomes the most basic site in the molecule at a dihedral angle of ca. 130 degrees . In addition, the nitrogen atoms in 2-4 are predicted to attain basicities in the range 920-950 kJ/mol, making them basic enough to be the preferred site for hydrogen bonding in the Pin-1 active site, in support of the proposed mechanism for PPIases.

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...

The Lewis acid-mediated reactions of substituted cyclopropanone acetals with alkyl azides were found to strongly depend on the structure of the ketone component. When cyclopropanone acetal was treated with alkyl azides, N-substituted 2-azetidinones and ethyl carbamate products were obtained, arising from azide addition to the carbonyl, followed by ring expansion or rearrangement, respectively. When 2,2-dimethylcyclopropanone acetals were reacted with azides in the presence of BF 3 •OEt 2 , the products obtained were α-amino-α′-diazomethyl ketones, which arose from C2-C3 bond cleavage of the corresponding cyclopropanone, giving oxyallyl cations, that were captured by azides. Aryl-substituted cyclopropanone acetals, when subjected to these conditions, afforded [1,2,3] oxaborazoles exclusively, which were also the result of C2-C3 bond rupture, azide capture and then loss of nitrogen. In the reactions of n-hexyl-substituted cyclopropanone acetals with alkyl azides, a mixture of 2-azetidinones and regioisomeric [1,2,3]oxaborazoles were obtained. The reasons for the different behavior of the various systems is discussed.Cyclopropanones display unusual properties arising from the incorporation of the carbonyl group into a strained three-membered ring. 1 Initially, cyclopropanones attracted interest due to their role as intermediates in Favorskii rearrangements. 2 Since then, there have been numerous experimental and theoretical studies aimed at understanding the nature of cyclopropanone reactivity. 3 Inherently reactive, cyclopropanones are usually generated in situ from the corresponding hemiketals (or their derivatives), which are readily synthesized and easily handled (Scheme 1). 4 In general, the chemistry of cyclopropanones is dominated by ketone addition or ring-opening to form oxyallyl cations. 5 The latter species can be trapped with a nucleophile 6 or cyclized with a dipolarophile to give bicyclic ketones. 7In the 1970's, Wasserman et al. showed that cyclopropanones react with sodium azide, to afford β-lactams (Scheme 2). 8 This reaction presumably proceeds due to the release of strain upon ring expansion coupled with the generation of nitrogen as the byproduct. Our group has previously studied the intermolecular reaction of alkyl azides with cyclic ketones, which generally leads to ring-expanded lactams in a process reminiscent of the Schmidt reaction. 9 Following Wasserman, we were initially interested in reacting cyclopropanones with alkyl azides under Lewis acidic conditions as a means of synthesizing N-substituted β-lactams. In the course of this study, we discovered that the Lewis acid promoted reactions of azides and cyclopropanones provide a rich array of products that depend on the nature of the cyclopropanone substitution. Previously, we disclosed that the reactions of 2,2-dimethylcyclopropanone equivalents with azides provide α-amino-α2-diazomethyl ketones. 10 Herein, we describe the results of a broader investigation on the reactions of substituted cyclopropanones with alkyl azides. In s...