Remote B-Ring Oxidation of Sclareol with an Engineered P450 Facilitates Divergent Access to Complex Terpenoids

Li, Fuzhuo; Deng, Heping; Renata, Hans

doi:10.1021/jacs.2c02958

Cited by 31 publications

(19 citation statements)

References 50 publications

(38 reference statements)

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“…In close agreement with our experimental results, docking studies using homology models of MERO1 L437A and MERO1 M177A with 11 suggest that the requisite binding pose for C3 oxidation is energetically much more favored by the L437A variant and that for enone epoxidation is favored by the M177A variant. Although virtual docking was used to rationalize empirical observations after the fact in this work and related studies, its general agreement with experimental results points to the possibility of using virtual prescreening of substrate candidates in future chemoenzymatic route developments.…”

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confidence: 61%

Concise Chemoenzymatic Synthesis of Gedunin

Chen

Renata

2022

J. Am. Chem. Soc.

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The limonoids have attracted significant attention from the synthetic community owing to their striking structural complexity and medicinal potential. Recent efforts notwithstanding, synthetic access to many intact or ring D-seco limonoids still remains elusive. Here, we report the first de novo synthesis of gedunin, a ring D-seco limonoid with HSP90 inhibitory activity, that proceeds in 13 steps. Two enabling features in our strategy are the application of modern catalytic transformations to set the key quaternary centers in the carbocyclic core and the use of biocatalytic oxidation at C3 to establish a chemical handle to access the A-ring enone motif. The strategy presented herein may provide an entry point to a wider range of oxidized limonoids.

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confidence: 61%

Concise Chemoenzymatic Synthesis of Gedunin

Chen

Renata

2022

J. Am. Chem. Soc.

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“…BM3 variant LG-23 was similarly found to enable hydroxylation of C-6 of sclareol. , This enzyme was further improved through two rounds of directed evolution . The final variant contained two additional mutations and allowed for the gram-scale production of the 6-hydroxylated compound 401 coupled to oxidative chemistry.…”

Section: Applications Of Site-selective Enzyme Catalysismentioning

confidence: 99%

Non-Native Site-Selective Enzyme Catalysis

Mondal,

Snodgrass,

Gomez

et al. 2023

Chem. Rev.

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The ability to site-selectively modify equivalent functional groups in a molecule has the potential to streamline syntheses and increase product yields by lowering step counts. Enzymes catalyze site-selective transformations throughout primary and secondary metabolism, but leveraging this capability for non-native substrates and reactions requires a detailed understanding of the potential and limitations of enzyme catalysis and how these bounds can be extended by protein engineering. In this review, we discuss representative examples of site-selective enzyme catalysis involving functional group manipulation and C–H bond functionalization. We include illustrative examples of native catalysis, but our focus is on cases involving non-native substrates and reactions often using engineered enzymes. We then discuss the use of these enzymes for chemoenzymatic transformations and target-oriented synthesis and conclude with a survey of tools and techniques that could expand the scope of non-native site-selective enzyme catalysis.

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“…210,214 This enzyme was further improved through two rounds of directed evolution. 415 The final variant contained two additional mutations and allowed for the gram-scale production of the 6hydroxylated compound 401 coupled to oxidative chemistry. Using the complementary hydroxylase BM3 MERO then afforded product 402 (Scheme 62 B).…”

Section: Target-oriented Synthesismentioning

confidence: 99%

Non-Native Site-Selective Enzyme Catalysis

Mondal

Snodgrass

Gomez

et al. 2023

Preprint

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The ability to a site-selectively modify equivalent functional groups in a molecule has the potential to streamline syntheses and increase product yields by lowering step counts. Enzymes catalyze site-selective transformations throughout primary and secondary metabolism, but leveraging this capability for non-native substrates and reactions requires a detailed understanding of the potential and limitations of enzyme catalysis and how these bounds can be extended by protein engineering. In this review, we discuss representative examples of site-selective enzyme catalysis involving functional group manipulation and C-H bond functionalization. We include illustrative examples of native catalysis, but our focus is on cases involving non-native substrates and reactions often using engineered enzymes. We then discuss the use of these enzymes for chemoenzymatic transformations and target-oriented synthesis and conclude with a survey of tools and techniques that could expand the scope of non-native site-selective enzyme catalysis.

show abstract

Remote B-Ring Oxidation of Sclareol with an Engineered P450 Facilitates Divergent Access to Complex Terpenoids

Cited by 31 publications

References 50 publications

Concise Chemoenzymatic Synthesis of Gedunin

Concise Chemoenzymatic Synthesis of Gedunin

Non-Native Site-Selective Enzyme Catalysis

Non-Native Site-Selective Enzyme Catalysis

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