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Determination of the Absolute Configuration of β-Chiral Primary Alcohols Using the Competing Enantioselective Conversion Method Heteroatom-Directed Acylation of Secondary Alcohols to Assign Absolute Configuration Total Synthesis of Illisimonin A Osmate Esters are Crystalline Derivatives of Alkenes


The first chapter details the development of a method for determining the absolute configuration of β-chiral primary alcohols that bear a π or heteroatom substituent on the stereocenter. The method relies on the rate differences of acylation using Birman’s homobenzotetramisole acylation catalyst. An empirical relationship between the faster reacting catalyst system and absolute configuration of the substrate was developed. The method is applicable to primary carbinols appended to tertiary stereocenters that bear a directing group; directing groups include arenes, heteroarenes, enones, and halides.

The second chapter details the extension of the competing enantioselective conversion method to assign the absolute configuration of secondary alcohols bearing electron-withdrawing groups such as halides and other heteroatoms. The level of selectivity is modest to good and is sufficient for determining configuration. A mathematical analysis identifies conditions for achieving maximum differences in conversion and, consequently, assigning configuration with greater confidence. The new method is effective for halohydrins and secondary−tertiary 1,2-diols and was used to confirm the configuration of two inoterpene natural products.

The third chapter details the completion of the first synthesis of (±)-illisimonin A. Notable steps in the route include a 1,3-dioxa-2-silacyclohexene templated Diels–Alder cycloaddition and type-3 semipinacol rearrangement to generate the trans-pentalene. The final step is an iron-catalyzed C-H oxidation. The synthetic route is robust, with 94 mg of racemic material prepared in a single pass. Classical resolution of a late stage intermediate enabled the synthesis of natural (–)-illisimonin A. The absolute configuration of (–)-illisimonin A was revised to 1S,4S,5S,6S,7R,9R,10R based on the X-ray structure of an heavy-atom analogue.

The fourth chapter details the use of osmium tetroxide and TMEDA to form stable crystalline adducts with alkenes. Osmate derivatization converted many liquid alkenes into solid crystalline compounds, enabling structure determination through X-ray analysis. Osmium, a heavy atom, facilitates the crystallographic analysis and the determination of the absolute configuration using common Mo X-ray sources. The utility of this method for assigning structures and absolute configurations was demonstrated on a number of unsaturated substrates that include simple alkenes, enones, enol ethers, and silyl enol ethers.

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