Terpenes comprise a diverse set of natural products that function as industry-ready products (e.g., essential oils), as chiral auxiliaries (e.g., (α)-pinene), and as chemically interesting starting materials, particularly in the chiral pool (e.g., the citronell-family of terpenes). One focus of the research in our laboratories is the elucidation of detailed mechanisms by which a broad array of sesquiterpenes is synthesized in Nature from the common precursor, farnesyldiphosphate, using computational and chemical methods. The enzymatic syntheses have in common exquisite stereo- and regiocontrol, allowing us to propose a variety of roles for the enzyme in the enzyme-substrate and enzyme-intermediate complexes along the biosynthetic pathway. After loss of diphosphate, the farnesyl cation engages a variety of chemistries, all (except the synthesis of the linear molecules such as the farnesenes, farnesol and nerolidol, and the linear sesquiterpene lactones) involving cyclization of the farnesyl cation or its C2-C3 cis-trans isomer, the nerolidyl cation, to the 6-membered bisabolyl cation, the 10-membered germacryl cation, or the 11-membered humulyl cation. The study presented here details the energy surface for the humulyl cation resulting from C1-C11 cyclization starting with ring-closure from a pre-organized farnesyl cation in the conformation previously modeled for the active site of pentalenene synthase. The humulyl cation and its conformational isomers differ in structure by the relative orientation of two prenyl moieties and three pairs of adjacent saturated carbon centers (ethylene and substituted ethylene). We demonstrate, using quantum chemical calculations in the gas phase, that the humulyl cation may undergo prenyl flips (in which the relative orientation of one of two prenyl groups inverts) and ethylene rotations (in which the –CH2CH2– or –CH2C(CH3)2– groups co-rotate). We propose ground- and transition- state structures as well as the putative pathways connecting them for the humulyl isomers in the absence of enzyme. In addition, we present evidence that the carbenium ion center may be stabilized both proximally by hyperconjugation and distally through C+···π(alkene) and C+···H–C interactions.

Exploring the conformational isomerization of the humulyl cation using computational methods

249th National Meeting (2015)

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