Guided desaturation of unactivated aliphatics

Abstract

The excision of hydrogen from an aliphatic carbon chain to produce an isolated olefin (desaturation) without overoxidation is one of the most impressive and powerful biosynthetic transformations for which there are no simple and mild laboratory substitutes. The versatility of olefins and the range of reactions they undergo are unsurpassed in functional group space. Thus, the conversion of a relatively inert aliphatic system into its unsaturated counterpart could open new possibilities in retrosynthesis. In this article, the invention of a directing group to achieve such a transformation under mild, operationally simple, metal-free conditions is outlined. This 'portable desaturase' (Tz(o)Cl) is a bench-stable, commercial entity (Aldrich, catalogue number L510092) that is facile to install on alcohol and amine functionalities to ultimately effect remote desaturation, while leaving behind a synthetically useful tosyl group.

Figure 1. Pioneering studies for alkane desaturation

A. Protocol for dehydrogenation employing peroxide-derived O-radicals. B. Breslow’s pioneering study of a remote dehydrogenation. C. Application of Ir-based catalysts toward the desaturation of cyclic alkanes. D. Example of a Pd-catalyzed guided desaturation reaction.

Figure 2. Design of a directing group for desaturation

A. Example of a strategic formal desaturation in the total synthesis of eudesmane terpenes. B. Proposed mechanism for the enzymatic desaturation in Nature. C. Description of the concept behind the guided desaturation reaction with a portable desaturase.

Figure 3. Applications of the guided desaturation reaction on complex substrates

A. Desaturation of a sesquiterpene derivative to a mixture of alkene regioisomers. B. Example of an interrupted desaturation reaction and methylene dehydrogenation. C. Application of the desaturation reaction towards diene synthesis in a complex setting. D. Synthesis of a tetrapeptide incorporating a dehydroleucine amino-acid residue. ^aYield based on a mixture of product and reduction byproduct (10:1), see Supplementary Information.

Figure 4. Mechanistic investigations and proposed reaction mechanism

A. Deuterium-labeling study to support a 1,7 abstraction event during desaturation. B. Indirect evidence for the in situ formation of an intermediate aryl radical. C. Example of a desaturation reaction starting from an aniline derivative. D. Initial result supporting a catalytic cycle in TEMPO. E. Proposed sequence of events for the guided desaturation reaction. ^aYields are based on ¹H-NMR integration relative to an internal standard (1,3,5-trimethoxybenzene); ^bIsolated yield; ^cThe reaction resulted in mostly nonspecific decomposition.