Stephanie R. Hare

Dynamic behavior of rearranging carbocations – implications for terpene biosynthesis

Summary This review describes unexpected dynamical behaviors of rearranging carbocations and the modern computational methods used to elucidate these aspects of reaction mechanisms. Unique potential energy surface topologies associated with these rearrangements have been discovered in recent years that are not only of fundamental interest, but also provide insight into the way Nature manipulates chemical space to accomplish specific chemical transformations. Cautions for analyzing both experimental and theoretical data on carbocation rearrangements are included throughout.

Navigating Past a Fork in the Road: Carbocation−π Interactions Can Manipulate Dynamic Behavior of Reactions Facing Post-Transition-State Bifurcations

Dynamics calculations are described for carbocation rearrangements involving product-forming pathways with post-transition-state bifurcations. We show that noncovalent interactions with associated benzene rings (a simple model of aromatic amino acid side chains) can switch inherent dynamical tendencies for competing modes of disrotation, establishing that meaningful changes in dynamically controlled product selectivity can be achieved with few weak noncovalent interactions.

Post-transition state bifurcations gain momentum – current state of the field

Abstract The existence of post-transition state bifurcations on potential energy surfaces for organic and biological reaction mechanisms has been known for decades, but recently, new reports of bifurcations have been occurring at a much higher rate. Beyond simply discovering bifurcations, computational chemists are developing techniques to understand what aspects of molecular structure and vibrations control the product selectivity in systems containing bifurcations. For example, the distribution of products seen in simulations has been found to be extremely sensitive to the local environment of the reacting system (i.e. the presence of a catalyst, enzyme, or explicit solvent molecules). The outlook for the future of this field is discussed, with an eye towards the application of the principles discussed here by experimental chemists to design a reaction setup to efficiently generate desired products.

Experimental and Computational Mechanistic Investigation of Chlorocarbene Additions to Bridgehead Carbene–Anti-Bredt Systems: Noradamantylcarbene–Adamantene and Adamantylcarbene–Homoadamantene

Cophotolysis of noradamantyldiazirine with the phenanthride precursor of dichlorocarbene or phenylchlorodiazirine in pentane at room temperature produces noradamantylethylenes in 11% yield with slight diastereoselectivity. Cophotolysis of adamantyldiazirine with phenylchlorodiazirine in pentane at room temperature generates adamantylethylenes in 6% yield with no diastereoselectivity. (1)H NMR showed the reaction of noradamantyldiazirine + phenylchlorodiazirine to be independent of solvent, and the rate of noradamantyldiazirine consumption correlated with the rate of ethylene formation. Laser flash photolysis showed that reaction of phenylchlorocarbene + adamantene was independent of adamantene concentration. The reaction of phenylchlorocarbene + homoadamantene produces the ethylene products with k = 9.6 × 10(5) M(-1) s(-1). Calculations at the UB3LYP/6-31+G(d,p) and UM062X/6-31+G(d,p)//UB3LYP/6-31+G(d,p) levels show the formation of exocyclic ethylenes to proceed (a) on the singlet surface via stepwise addition of phenylchlorocarbene (PhCCl) to bridgehead alkenes adamantene and homoadamantene, respectively, producing an intermediate singlet diradical in each case, or (b) via addition of PhCCl to the diazo analogues of noradamantyl- and adamantyldiazirine. Preliminary direct dynamics calculations on adamantene + PhCCl show a high degree of recrossing (68%), indicative of a flat transition state surface. Overall, 9% of the total trajectories formed noradamantylethylene product, each proceeding via the computed singlet diradical.

Rearrangement of Hydroxylated Pinene Derivatives to Fenchone-Type Frameworks: Computational Evidence for Dynamically-Controlled Selectivity

An acid-catalyzed Prins/semipinacol rearrangement cascade reaction of hydroxylated pinene derivatives that leads to tricyclic fenchone-type scaffolds in very high yields and diastereoselectivity has been developed. Quantum chemical analysis of the selectivity-determining step provides support for the existence of an extremely flat potential energy surface around the transition state structure. This transition state structure appears to be ambimodal, i.e., the fenchone-type tricyclic scaffolds are formed in preference to the competing formation of a bornyl (camphor-type) skeleton under dynamic control via a post-transition state bifurcation (PTSB).

Synthesis of Highly Stereodefined Tetrasubstituted Acyclic All-Carbon Olefins via a Syn-Elimination Approach.

An efficient synthesis of stereodefined tetrasubstituted acyclic all-carbon olefins has been developed via a bis(2,6-xylyl)phosphate formation of stereoenriched tertiary alcohols, followed by in situ syn-elimination of the corresponding phosphates under mild conditions. This chemistry tolerates a wide variety of electronically and sterically diverse substrates and generates the desired tetrasubstituted olefins in high yields and stereoselectivities (>95:5) in most cases. This stereocontrolled olefin synthesis has been applied to the synthesis of anticancer drug tamoxifen in three steps from commercially available 1,2-diphenylbutan-1-one in 97:3 stereoselectivity and 78% overall yield.

CCDC 1586657: Experimental Crystal Structure Determination

Related Article: Ngiap-Kie Lim, Patrick Weiss, Beryl X. Li, Christina H. McCulley, Stephanie R. Hare, Bronwyn L. Bensema, Teresa A. Palazzo, Dean J. Tantillo, Haiming Zhang, and Francis Gosselin|2017|Org.Lett.|19|6212|doi:10.1021/acs.orglett.7b03141

CCDC 1586659: Experimental Crystal Structure Determination

Related Article: Ngiap-Kie Lim, Patrick Weiss, Beryl X. Li, Christina H. McCulley, Stephanie R. Hare, Bronwyn L. Bensema, Teresa A. Palazzo, Dean J. Tantillo, Haiming Zhang, and Francis Gosselin|2017|Org.Lett.|19|6212|doi:10.1021/acs.orglett.7b03141

CCDC 1586641: Experimental Crystal Structure Determination

Related Article: Ngiap-Kie Lim, Patrick Weiss, Beryl X. Li, Christina H. McCulley, Stephanie R. Hare, Bronwyn L. Bensema, Teresa A. Palazzo, Dean J. Tantillo, Haiming Zhang, and Francis Gosselin|2017|Org.Lett.|19|6212|doi:10.1021/acs.orglett.7b03141

Correction: Dynamic behavior of rearranging carbocations – implications for terpene biosynthesis

[This corrects the article DOI: 10.3762/bjoc.12.41.].