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. 2024 Oct 31;15(46):19307-19314.
doi: 10.1039/d4sc06060a. eCollection 2024 Nov 27.

Unified enantiospecific synthesis of drimane meroterpenoids enabled by enzyme catalysis and transition metal catalysis

Yipeng You  1 , Xue-Jie Zhang  2 , Wen Xiao  2 , Thittaya Kunthic  2 , Zheng Xiang  2   3 , Chen Xu  1
Affiliations

Unified enantiospecific synthesis of drimane meroterpenoids enabled by enzyme catalysis and transition metal catalysis

Yipeng You et al. Chem Sci. .

Abstract

Merging the advantages of biocatalysis and chemocatalysis in retrosynthetic analysis can significantly improve the efficiency and selectivity of natural product synthesis. Here, we describe a unified approach for the synthesis of drimane meroterpenoids by combining heterologous biosynthesis, enzymatic hydroxylation, and transition metal catalysis. In phase one, drimenol was produced by engineering a biosynthetic pathway in Escherichia coli. Cytochrome P450BM3 from Bacillus megaterium was engineered to catalyze the C-3 hydroxylation of drimenol. By means of nickel-catalyzed reductive coupling, six drimane meroterpenoids (+)-hongoquercins A and B, (+)-ent-chromazonarol, 8-epi-puupehenol, (-)-pelorol, and (-)-mycoleptodiscin A were synthesized in a concise and enantiospecific manner. This strategy offers facile access to the congeners of the drimane meroterpenoid family and lays the foundation for activity optimization.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Structure and chemical synthesis of drimane meroterpenoids. (A) Structure of hongoquercins A (1) and B (2), (+)-ent-chromazonarol (3), 8-epi-puupehenol (4), (−)-pelorol (5), and (−)-mycoleptodiscin A (6). (B) Synthesis of (−)-chromazonarol (7) was achieved by Yamamoto and co-workers via a biomimetic polyene cyclization catalyzed by a Lewis acid-assisted chiral Brønsted acid. (C) Synthesis of (+)-hongoquercin B (2) was achieved by Barrett and co-workers via a substrate-controlled epoxy-ene cyclization. (D) The chiral pool approach for the synthesis of drimane meroterpenoids by Baran, Lei, Sau, Wu, Li, and Anderson.
Fig. 2
Fig. 2. The synthetic strategy for drimane meroterpenoids.
Fig. 3
Fig. 3. Heterologous biosynthesis of drimenol in E. coli. (A) The BL21(DE3) strain harboring MVA pathway genes, FPPS gene (ERG20), and drimenol synthase gene from 4 species (yellow background); additional copy of EcIDI and mvaA (blue background) and multienzyme assembly containing the AtoB–mvaS–mvaA assembly (T-ab) and ERG20–EcIDI–DrtB assembly (C-ab) (purple background) based on a DrtB overexpressing strain. (B) Comparison of drimenol production between BL21(DE3) and MG1655(DE3) strain which harbored comparative good construct in terms of species of drimenol synthase (DrtB), rate-limiting enzyme of metabolic pathway (EcIDI & mvaA) and multienzyme assembly (T-ab), respectively, and PhDS as control. The data represent the averages ± standard deviations of three independent colonies.
Fig. 4
Fig. 4. C3-hydroxylation of drimenol was catalyzed by P450BM3 variants. (A) Purified P450BM3 (F87A) catalyzed C–H hydroxylation and C–C epoxidation of 1 mM and 2 mM drimenol (yellow background) to produce compounds 12 (blue background) and 13 (purple background). (B) X-ray crystallography of 3-(OH)-drimenol (12). (C) Docking model of drimenol (cyan) in the active site of P450BM3 (F87A) (green). Several residues (dark blue) show hydrophobic interactions (gray line) with drimenol. (D) Heat map of the yield of compound 12 by screening the P450BM3 L75/F87 mutant library. The yield was determined by GC-MS analysis. (E) Whole cell catalysis (yellow background) and cell lysate catalysis (blue background) by P450BM3 (F87A, L75A/F87I, L75G/F87I). (F) The gram-scale oxidation of drimenol with P450BM3 (L75A/F87I).
Scheme 1
Scheme 1. Synthesis of (+)-ent-chromazonarol (3), (+)-8-epi-puupehenol (4), (−)-pelorol (5), and (−)-mycoleptodiscin A (6). Reagents and conditions: (a) CBr4, PPh3, THF, 0 °C, 80%; (b) NiI2 (10 mol%), dtbpy (5 mol%), dppbe (5 mol%), CoII(Pc) (5 mol%), Mn, pyridine, DMPU, 55 °C, 53%; (c) HCl, iPrOH, 55 °C, 95%; (d) Pt-catalyst (3 mol%), AgOTf (6 mol%), DCE, rt, 90%; (e) NiI2 (10 mol%), dtbpy (5 mol%), CoII(Pc) (5 mol%), Mn, pyridine, DMPU, 48%; (f) K2CO3, MeOH, rt, 95%; (g) Pt-catalyst (3 mol%), AgOTf (6 mol%), DCE, rt, 90%; (h) Pd/C, H2, MeOH, rt, 95%. (i) NiI2 (10 mol%), dtbpy (5 mol%), dppbe (5 mol%), CoII(Pc) (5 mol%), Mn, pyridine, DMPU, 55 °C, 57%; (j) TMSOTf, DCM, 0 °C, 73%; (k) NiI2 (10 mol%), dtbpy (5 mol%), dppbe (5 mol%), CoII(Pc) (5 mol%), Mn, pyridine, DMPU, 55 °C, 45%; (l) TMSOTf, DCM, 0 °C, 70%. MOM = methoxymethyl, DCE = 1,2-dichloroethane, TMSOTf = trimethylsilyl triflate.
Scheme 2
Scheme 2. Synthesis of hongoquercins A (1) and B (2). Reagents and conditions: (a) TBSCl, imidazole, DMF, rt, 90%; (b) NaH, BnBr, DMF, rt; (c) TBAF, THF, 60 °C, 85% over 2 steps; (d) CBr4, PPh3, THF, 0 °C, 62%; (e) NiI2 (10 mol%), dtbpy (5 mol%), dppbe (5 mol%), CoII(Pc) (5 mol%), Mn, pyridine, DMPU, 55 °C, 48% for 31, 48% for 32; (f) HCl, iPrOH, 65 °C, 89%; (g) Pt-catalyst (3 mol%), AgOTf (6 mol%), DCE, rt, 80%; (h) LiOH, MeOH/H2O, reflux, 95%; (i) Pd(OAc)2, L, CsOAc, H2O2 (35% aq.), DMA, 60 °C, 65%; (j) Pd/C, H2, MeOH, rt; (k) Ac2O, pyridine, rt, 80% over 2 steps; (l) K2CO3, MeOH, rt, 90%. TBS = tert-butyldimethylsilyl, TBAF = tetrabutylammonium fluoride, DMA = N,N-dimethylacetamide.
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