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Selective Functionalization of Saturated Hydrocarbons

Periodic Reporting for period 1 - BioMet (Selective Functionalization of Saturated Hydrocarbons)

Reporting period: 2018-11-01 to 2020-04-30

Selective functionalization of unreactive C–H bonds represents a significant paradigm shift from the standard logic of organic synthesis, traditionally confined to the orchestration of transformations at the most reactive functional groups. Research efforts in targeting C-H bond functionalization have mainly focused on the use of directing groups, present or pre-installed, or through the undirected activation of particularly reactive C-H bonds. Extending this strategy to undirected C-H bond functionalization requires the discovery of new strategies that would accurately activate and differentiate energetically akin C-H bonds, featured both in the substrate and in the product without cross-activation. This selective functionalization of alkanes, that do not possess directing groups, historically stands as one of the most challenging transformation in chemistry, particularly for undirected functionalization of strong and less electron-rich primary C-H bonds.
Extensive efforts have been fueled by the prospect of rapidly valorizing cheap and readily available unert alkanes, classical organic feedstock representing the major constituents of natural gas and petroleum, in a sustainable manner through selective catalytic processes. Converting these cheap and widely available hydrocarbon feedstocks into added-value intermediates would tremendously affect the field of chemistry. Although few reported examples highlight the remarkable accomplishments of transition-metal based transformations for selective alkane functionalization, an inherent limitation of these strategies was that each transformation led to a single type of functionalization.
A general, high-yielding and fully selective approach to the activation of primary C-H bonds allowing a large number of different terminal functionalization at the exclusive terminus position of alkanes from a single starting material remains elusive. We set out to develop this missing link in this ERC research work by proposing an alternative approach that would first transform a linear alkane into alkene, that would subsequently be engaged in a remote functionalization through a metal-catalyzed hydrometalation/migration sequence into the formation of a primary organometallic species that could react with a large variety of electrophiles to provide the expected functionalized alkanes exclusively at the primary position.
We have initially identified a mutant strain of a bacteria, obtained through random mutagenesis, that could hyperproduce internal alkenes from linear alkanes. Despite the initial rather low yields, this remarkable monodehydrogenation transformation could be achieved under ambient conditions (30 °C, aqueous solution, atmospheric pressure) and conveniently using oxygen as the presumed terminal oxidant. We were then, first interested to implement this original low-yielding transformation as a general approach and evaluate whether synthetically useful yields of alkenes could be obtained. Following a thorough optimization, olefin production could be maximized converting hexadecane (1) into two major cis-hexadecene regioisomers (80% cis-7-hexadecene + 20% cis-8-hexadecene) with a remarkable 61% isolated yield and 83% dehydrogenation efficiency (alkenes/alkane) of aerobic incubation. We observed that the resulting olefins were accumulated over time, indicating that they were not further metabolized by this strain. The biological material could also easily be recovered and re-utilized into another batch of transformation for 4 consecutive runs giving useful yields, further asserting the resiliency of this strain under the set conditions.
The fermentation reaction could be scaled-up to reach multigram scale synthesis, demonstrating the practicality of this procedure. The same protocol somewhat allowed to specifically desaturate linear C14-C20 alkanes, reaching optimal conversions for n-hexadecane and n-heptadecane. In all cases, the olefins produced were exclusively (Z)-isomers. Importantly, this microorganism enabled to mediate the desaturation of aliphatic xenobiotics such as terminally functionalized aliphatic derivatives. Linear -olefins such as 1-hexadecene or 1-octadecene also underwent the biocatalytic desaturation to provide the corresponding unconjugated dienes in decent isolated yields. The reaction similarly proceeded with n-hexadecyl methyl ether, or chloro and fluoro hexa- and octadecane affording -functionalized Z-olefins with somewhat variable yields and dehydrogenation ratios. These last examples strongly contrasts with the relatively low functional group tolerance of synthetic reagents or catalysts capable of activating C-H bonds in alkanes.
We then proceeded by examining the remote and selective terminal functionalization reaction. This strategy capitalizes on the remarkable ability of some transition-metal complexes to promote rapid and long-range migration along linear hydrocarbon chains under specific conditions as was demonstrated in our parallel studies. When taking place, this equilibrium is usually shifted towards the predominant formation of the anti-Markovnikov terminal organometallic intermediate, enabling eventual terminal derivatization either through reductive elimination or subsequent electrophilic functionalization. If successful, an inherent advantage of our strategy is that the chemical outcome is independent of the position of the initial double bond, thus serving as a regioconvergent remote activation of terminal C-H bonds. To this purpose, we prospectively identified several transition-metal based catalysts and reagents capable of affecting such long-range functionalization upon our biodesaturated substrates. As a proof of concept, we successfully engaged the mixture of hexadecenes produced from n-hexadecane during the biocatalytic desaturation process into various metal-mediated remote hydrofunctionalization reactions, thoroughly optimized to reach excellent site-selectivities (>98:2 in all cases).
In parallel to these studies, we have investigated the metal-walk in details (second step of our project) to have a clear and detailed picture of this transformation. For lack of space, I can not detailed the results that have been produced but are summarized in our list of publications.
The goal of this work was to develop a general principle in organic synthesis for the preparation of a wide variety of more complex molecular architectures from saturated hydrocarbons. In our approach, the alkane is first transformed into an alkene that is subsequently engaged in a metal-catalyzed hydrometalation/migration sequence. The first step of the sequence, ideally represented by the removal of two hydrogen atoms, is performed by the use of a mutated strain of a bacteria. The position and geometry of the formed double bond has no effect on the second step of the reaction as the metal-catalyzed hydrometalation/migration isomerizes the double bond along the carbon skeleton to selectively produce the primary organometallic species. Trapping the resulting organometallic derivatives with a large variety of electrophiles provides the desired functionalized alkane. This work lead to the invention of new, selective and efficient processes for the utilization of simple hydrocarbons and valorize the synthetic potential of raw hydrocarbon feedstock for the environmentally benign production of new compounds and new materials.