Evolution of Biocatalytic and Chemocatalytic C–H Functionalization Strategy in the Synthesis of Manzacidin C

Abstract

Because of their unique molecular architecture, the manzacidins have been the subject of intense synthetic efforts in the past two decades. Here, we describe two synthetic approaches toward manzacidin C that center on the enzymatic hydroxylation of unprotected l-leucine. This study also resulted in the discovery of novel synthetic methodologies, including a photocatalytic C-H azidation of unprotected amino acids. Additionally, we describe the use of hydroxylated l-leucine in the preparation of various densely substituted pyrrolidines.

Biocatalyst-Initiated Ortho-Quinone Methide Formation and Derivatization

“…Due to the less electron-rich character of these dienophiles, these reactions required a higher temperature of 65 °C to undergo a productive reaction. The major products of these IEDDA reactions resulted from reaction with the o-QM formed at the C3 hydroxyl group (28), while the minor isomers were formed from reaction with the C1 o-QM species (27). Upon the observation that o-QM generation occurs at reduced temperatures, we hypothesized that these reactions likely proceed through low barrier processes.…”

“…We anticipated that an α-ketoglutarate-dependent (α-KG) non-heme iron oxygenase could be employed for the selective oxidation of primary benzylic C-H bonds. This well-studied family of enzymes has precedent for both scalability 28 and substrate scope tunability through protein engineering. 29 By coupling the activation of molecular oxygen to the decarboxylation of inexpensive αoxoacid co-substrates, these enzymes generate an iron(IV)-oxo species (17) capable of H-atom abstraction (Fig.…”

The Hitchhiker's guide to biocatalysis: recent advances in the use of enzymes in organic synthesis

“…[197][198][199] Chemoenzymatic approaches have also proved useful in the synthesis of natural products. [200][201][202][203] A recent important publication by Lipshutz and coworkers has shown that the formation of micelles in the reaction medium can facilitate the combination of chemo-and bio-catalysis in a single reactor as the substrates, products and catalysts partition into the different compartments. 204 For an extensive review of the recent literature on biocatalytic cascade reactions see Kroutil and coworkers.…”

Exploration of Iron- and α-Ketoglutarate-Dependent Dioxygenases as Practical Biocatalysts in Natural Product Synthesis

“…38 This approach led to our first-generation formal synthesis of manzacidin C, which required nine steps overall. 39 Despite this success, we reasoned that a direct C-H amination route at C4 would offer a more-direct approach to manzacidin C. On the basis of previous structure-activity relationship studies, we hypothesized that GriE might accept as substrate a leucine derivative containing an aminogroup surrogate at C4. A report on photocatalytic C-H fluorination of leucine by Britton and co-workers 40 inspired us to develop a similar C-H azidation protocol employing tetrabutylammonium decatungstate (TBADT) as a photocatalyst and 2,5-bis(trifluoromethyl)benzenesulfonyl azide as the azide source.…”