Periodic Reporting for period 1 - DeraceMWalk (Remote functionalization by a “deracemizing” metal walk – An innovative approach to define stereochemistry)
Période du rapport: 2021-05-11 au 2023-05-10
This project seeks to investigate a completely different approach in the field of remote functionalization. We are now proposing to create stereocenters during the metal-walk by “deracemization” of branched substituents, a process that yet remains an unknown terrain. Although this is a high-risk project, we believe that the expertise acquired in this field should allow the design of a proper system that would combine a triggering event at the initiation site followed by a “deracemizing” metal-walk process along the hydrocarbon chain through the induction of a metal/chiral ligand system. This corrective metal walk should induce specific stereochemistry of (multiple) sp3 carbon centers along a branched alkyl chain. Subsequently, functionalization at the terminal position will be addressed. This approach will consist of three major events: (i) a functionalization at the initiation site distal from the remote site; (ii) a “deracemization” metal-walk processes that should determine the stereochemistry of the branched stereocenters and (iii) a termination step at the remote site. This technology will lead to the foundation of new developments in one of the most vibrant areas of expertise when building up molecular complexity and open new vistas in chain-walking scenarios, and in particular within the context of remote functionalization. In this respect, the proposed project aims to merge the fundamentals of a remote functionalization, namely a remote metal-catalyzed hydroboration reaction and a novel “deracemizing” metal-walk that will control the stereochemistry while passing branched alkyl chains. Thus, besides a careful choice of a suitable metal source, catalyst design will be crucial and might involve design and evaluation of novel ligands. This approach offers then an entry to a diastereo- and enantioselective synthesis of complex acyclic architectures including (multiple) stereocenters that otherwise might not be accessible.
Original Project: The manipulation of organic molecules mostly relies on the direct transformation of the chemically more reactive functionalities. This type of interconversion of reactive functional groups has matured over the last few decades to a situation where synthetic transformations become available to all practitioners. However, approaches to address less reactive and unobvious positions remain a long-standing challenge in organic chemistry and are still under extensive exploration. In this respect, remote functionalization has gained increased momentum over the last few years as it provides innovative and original synthetic transformations that were not available before. Remote functionalization by “metal-walk” events are desirable due to their efficiency, their ability to “walk” over alkyl chains of various lengths, are usually synthetically easy to perform and very practical (one-pot) and are often mediated by catalytic amounts of metal/ligand species. Along these lines remote functionalization mediated by Pd, Ni, Rh, Ru, Zr, Ir, Fe and others have been successfully probed. Herein, we report on a chain-walk based on a Cobalt complex as catalytic species. The Co-catalyzed process relies on merging a chain-walking process with a carbon-carbon bond cleavage to yield acyclic architectures of a well-defined stereochemistry. Therefore, we first synthesized a set of stereodefined polysubstituted cyclopropanes via an efficient stereoselective carbometallation of 1,1-disubstituted cyclopropenes. Further investigations lead an optimized transition metal based-catalytic system that proceeds in the following way: (1) hydride addition at the initiating disubstituted double bond, (2) chain-walk towards the direction of the cyclopropyl unit, (3) selective carbon-carbon bond cleavage, (4) the primary Co-alkyl species get transmetallated with pinacolborane to release sophisticated stereoenriched acyclic scaffolds bearing a boronic ester as common platform for further transformations.
Additional Project: Creating stereocenters within acyclic systems by C-C bond cleavage of highly decorated cyclopropanes has matured over the last decade to a situation where synthetic transformations become available to all practitioners. However, while a plethora of stereoselective variants exists, providing a broad range of highly substituted and functionalized cyclopropanes, the stereoselective ring-opening remains a significant challenge in organic synthesis and are still under extensive exploration. In this respect, the host group reported a regio- and stereoselective nucleophilic substitution at the quaternary carbon center of various cyclopropyl carbinols employing TMSBr, TMSCl and HBF4 as nucleophilic source. Whereas recent studies showed the nucleophilic substitution of polysubstituted cyclopropyl methyl phosphates using organoaluminium species. Herein, we present the formation of acyclic frameworks bearing two consecutive stereocenters of either tertiary or quaternary nature starting from easily accessible cyclopropenyl esters. The approach involves a regio- and diastereoselective hydro- and carboborylation of the latter one yielding borylated cyclopropanes. Further treatment with various organolithium reagents results in the formation of boronate complexes, that subsequently undergo 1,2-metallate rearrangement to obtain valuable acyclic fragment as single diastereomer, that otherwise might be difficult to access. These results have been published (A. U. Augustin, S. Di Silvio, I. Marek J. Am. Chem. Soc. 2022, 144, 16298-16302).
Additional Project: Creating stereocenters within acyclic systems by C-C bond cleavage of highly decorated cyclopropanes has matured over the last decade to a situation where synthetic transformations become available to all practitioners. However, while a plethora of stereoselective variants exists, providing a broad range of highly substituted and functionalized cyclopropanes, the stereoselective ring-opening remains a significant challenge in organic synthesis and are still under extensive exploration. In this respect, the host group reported a regio- and stereoselective nucleophilic substitution at the quaternary carbon center of various cyclopropyl carbinols employing TMSBr, TMSCl and HBF4 as nucleophilic source. Whereas recent studies showed the nucleophilic substitution of polysubstituted cyclopropyl methyl phosphates using organoaluminium species. Herein, we present the formation of acyclic frameworks bearing two consecutive stereocenters of either tertiary or quaternary nature starting from easily accessible cyclopropenyl esters. The approach involves a regio- and diastereoselective hydro- and carboborylation of the latter one yielding borylated cyclopropanes. Further treatment with various organolithium reagents results in the formation of boronate complexes, that subsequently undergo 1,2-metallate rearrangement to obtain valuable acyclic fragment as single diastereomer, that otherwise might be difficult to access. These results have been published (A. U. Augustin, S. Di Silvio, I. Marek J. Am. Chem. Soc. 2022, 144, 16298-16302).
Both projects report on stereoselective strategies to access sophisticated acyclic fragments that otherwise might not be accessible, thereby contributing significantly to the toolbox of stereoselective methods for organic practioners. It should be emphasized, that boronic esters are common functionalities and/or intermediates in organic synthesis and have found applications in a vast spectrum of transformation. That being said, the here prepared acyclic fragments might serve as an interesting platform for further investigations in the field of natural product synthesis, material sciences and medicinal chemistry.