Reinvigorating the Chiral Pool: Chemoenzymatic Approaches to Complex Peptides and Terpenoids

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: Biocatalytic transformations that leverage the selectivity and efficiency of enzymes represent powerful tools for the construction of complex natural products. Enabled by innovations in genome mining, bioinformatics, and enzyme engineering, synthetic chemists are now more than ever able to develop and employ enzymes to solve outstanding chemical problems, one of which is the reliable and facile generation of stereochemistry within natural product scaffolds. In recognition of this unmet need, our group has sought to advance novel chemoenzymatic strategies to both expand and reinvigorate the chiral pool. Broadly defined, the chiral pool comprises cheap, enantiopure feedstock chemicals that serve as popular foundations for asymmetric total synthesis. Among these building blocks, amino acids and enantiopure terpenes, whose core structures can be mapped onto several classes of structurally and pharmaceutically intriguing natural products, are of particular interest to the synthetic community.In this Account, we summarize recent efforts from our group in leveraging biocatalytic transformations to expand the chiral pool, as well as efforts toward the efficient application of these transformations in natural products total synthesis, the ultimate testing ground for any novel methodology. First, we describe several examples of enzymatic generation of noncanonical amino acids as means to simplify the synthesis of peptide natural products. By extracting amino acid hydroxylases from native biosynthetic pathways, we obtain efficient access to hydroxylated variants of proline, lysine, arginine, and their derivatives. The newly installed hydroxyl moiety then becomes a chemical handle that can facilitate additional complexity generation, thereby expanding the pool of amino acidderived building blocks available for peptide synthesis. Next, we present our efforts in enzymatic C−H oxidations of diverse terpene scaffolds, in which traditional chemistry can be combined with strategic applications of biocatalysis to selectively and efficiently derivatize several commercial terpenoid skeletons. The synergistic logic of this approach enables a small handful of synthetic intermediates to provide access to a plethora of terpenoid natural product families. Taken together, these findings demonstrate the advantages of applying enzymes in total synthesis in conjunction with established methodologies, as well as toward the expansion of the chiral pool to enable facile incorporation of stereochemistry during synthetic campaigns.

Assignment-free chirality detection in unknown samples via microwave three-wave mixing

“…In Figure 4, we show the three-wave mixing spectrum for a mixture of terpenes. Terpenes are naturally occurring chiral building blocks that have been used for decades as starting materials for the synthesis of natural products and active ingredients in pharmaceuticals, due to their abundance and low cost [34][35][36]. All transitions in Figure 4 belong to enantiopure (-)-β-pinene, (R)-fenchone, and (R)-carvone.…”

The role of biocatalysis in the asymmetric synthesis of alkaloids – an update

“… 34 Alternatively, biocatalytic transformations can be used to prepare a wide range of chiral building blocks, which can often be tailored more closely to the desired target structure than the compounds available in nature. 35 This strategy is frequently employed in alkaloid synthesis, and lipases and esterases as well as toluene dioxygenase remain the most important enzymes in this context.…”

Biocatalytic synthesis of peptidic natural products and related analogues

“…In this review, we will discuss the recent development of biocatalyst-based approaches to synthesize structurally diverse PNPs, including NRPs and RiPPs, using selected examples. Of note, this review does not cover the biocatalytic synthesis of amino acid building blocks for the synthesis of complex products, which has recently been reviewed elsewhere ( Stout and Renata, 2021 ).…”