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Stereoselective synthesis of 2'-beta-carbon-substituted 2'-deoxy-4'-thioribonucleosides from 4-thiofuranoid glycal

Kazuhiro Haraguchi1, Noriaki Shiina, Yuichi Yoshimura

  • 1School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.

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Synthesis of α-Substituted Carbonyl Compounds: The Stork Enamine Reaction

α-Substituted ketones or aldehydes can be synthesized from enamines by the Stork enamine reaction, named after its pioneer Gilbert Stork. Enamines are useful synthetic intermediates where the lone pair on nitrogen is in conjugation with the C=C bond. They resemble enolate ions, as the resonance forms of both species have a nucleophilic α carbon.
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Regioselectivity and Stereochemistry of Hydroboration

A significant aspect of hydroboration–oxidation is the regio- and stereochemical outcome of the reaction.
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As depicted in the figure below, the unsymmetrical ketones can form two possible enolates:  less substituted or more substituted enolates. Usually, the thermodynamic enolates are formed from the more substituted α-carbon atom, while the kinetic enolates are formed faster by deprotonation from the less substituted position. The thermodynamic enolates have lower energy, so they are  more stable. But the energy required to form kinetic enolates is less.
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Malonic ester synthesis is a method to obtain α substituted carboxylic acids from ꞵ-diesters such as diethyl malonate and alkyl halides.
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The Knoevenagel condensation is an aldol-type reaction involving the condensation of aldehydes or ketones with active methylene compounds such as β-diesters to produce substituted olefins.
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In addition to the oxymercuration–demercuration method, which converts the alkenes to alcohols with Markovnikov orientation, a complementary hydroboration-oxidation method yields the anti-Markovnikov product. The hydroboration reaction, discovered in 1959 by H.C. Brown, involves the addition of a B–H bond of borane to an alkene giving an organoborane intermediate. The oxidation of this intermediate with basic hydrogen peroxide forms an alcohol.
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