Merging chemoenzymatic and radical-based retrosynthetic logic for rapid and modular synthesis of oxidized meroterpenoids

Abstract

Meroterpenoids are natural products of hybrid biosynthetic origins-derived from both terpenoid and polyketide pathways-with a wealth of biological activities. Given their therapeutic potential, a general strategy to access these natural products in a concise and divergent fashion is highly desirable. Here, we report a modular synthesis of a suite of oxidized meroterpenoids using a hybrid synthetic strategy that is designed to harness the power of both biocatalytic and radicalbased retrosynthetic logic. This strategy enables direct introduction of key hydroxyl groups and rapid construction of key bonds and stereocenters, facilitating the development of a concise route (7-12 steps from commercial materials) to eight oxidized meroterpenoids from two common molecular scaffolds. This work lays the foundation for rapid access to a wide range of oxidized meroterpenoids through the use of similar hybrid strategy that combines two synthetic approaches. Multistep chemical synthesis relies almost exclusively on the use of retrosynthetic analysis. 1 Using this conceptual framework, a target molecule is disconnected through a series of reverse reactions to arrive finally at greatly simplified or commercial starting materials. As each disconnection needs to be sensible in the forward synthetic direction, the choice of bond(s) to disconnect is highly dependent on the contemporary synthetic transformations available at the practitioner's disposal. Throughout the history of organic chemistry, polar disconnections, due to their perceived robustness, permeate much of the discourse in the field. More recently, the emergence of new technologies in chemical synthesis has led to the formulation of alternative retrosynthetic strategies. Biocatalytic retrosynthesis 2 has flourished into a highly powerful principle for multistep syntheses due to the unparalleled selectivity of enzymatic transformations and the ever-growing tools of protein engineering and directed evolution. 3 Similarly, radical-based retrosynthetic disconnections 4,5 have become increasingly popular, owing to the unique chemoselectivity and chemofidelity 6 of Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

A Promiscuous Bacterial P450: The Unparalleled Diversity of BM3 in Pharmaceutical Metabolism

“…The production of the anti-cancer and antimicrobial meroterpenoids was achieved via the design of modular retrosynthetic pathways. The addition of molecular handle hydroxyl groups was achieved by variants related to 1857 (V78A/A82G/F87V/P142S/T175I/A184V/F205C/S226R/H236Q/E252G/R255S/A290V/L353V) [ 103 , 104 ]. The selective 3-hydroxylation of sclareolide, an antifungal precursor to arisugacin F and phenylpyropene C, gave an 80–90% conversion and a 60–70% yield for 1857/V328A.…”

“…The selective 3-hydroxylation of sclareolide, an antifungal precursor to arisugacin F and phenylpyropene C, gave an 80–90% conversion and a 60–70% yield for 1857/V328A. A 62% yield was achieved by 1857/V328A/L75A for the oxidation of a tricyclic intermediate at the C3 position, forming a key intermediate for further chemical modification, ultimately yielding either chevalone or stypodiol [ 104 ].…”

Recent Chemical Methodology Advances in the Total Synthesis of Meroterpenoids

“…In early 2020, Renata's group accessed eight natural products from α-pyrone and diterpene meroterpenoids subsets in a concise, high-yielding and modular fashion. 25 While some of them [arisugacin F (160) 26 , pyripyropene E (161) 27 , taondiol (162) 28,29 , and stypodiol (163) 30 ] have been subjects of multiple synthetic studies, others [phenylpyropenes C (164) and F (165), decaturin E (166) and chevalone A (167)] were synthesized for the first time. Instead of using more conventional Wieland-Mischer ketone, sclareolide (168) and sclareol (169) were The remaining four diterpene meroterpenoids were constructed from butenolide 177, which itself was forged from sclareol (169) via peracryloylation, ring-closing metathesis with Grubbs second-generation catalyst and NaH-CO 3 mediated elimination (Scheme 18).…”

Molecular insights into the unusually promiscuous and catalytically versatile Fe(II)/α-ketoglutarate-dependent oxygenase SptF

“…Furthermore, these enzymes exhibit high catalytic efficiencies, and typically have large turnover numbers 11 , 14 , 37 , 38 . These features of Fe/αKG oxygenases, along with their catalytic versatility, have attracted considerable attention as a source of biocatalysts 36 , 39 .…”