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Link to original content: https://pubmed.ncbi.nlm.nih.gov/36192432
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. 2022 Dec;14(12):1421-1426.
doi: 10.1038/s41557-022-01048-2. Epub 2022 Oct 3.

Practical synthesis of the therapeutic leads tigilanol tiglate and its analogues

Paul A Wender  1   2 , Zachary O Gentry  3 , David J Fanelli  3 , Quang H Luu-Nguyen  3 , Owen D McAteer  3 , Edward Njoo  3
Affiliations

Practical synthesis of the therapeutic leads tigilanol tiglate and its analogues

Paul A Wender et al. Nat Chem. 2022 Dec.

Abstract

Tigilanol tiglate is a natural product diterpenoid in clinical trials for the treatment of a broad range of cancers. Its unprecedented protein kinase C isoform selectivity make it and its analogues exceptional leads for PKC-related clinical indications, which include human immunodeficiency virus and AIDS eradication, antigen-enhanced cancer immunotherapy, Alzheimer's disease and multiple sclerosis. Currently, the only source of tigilanol tiglate is a rain forest tree, Fontainea picrosperma, whose limited number and restricted distribution (northeastern Australia) has prompted consideration of designed tree plantations to address supply needs. Here we report a practical laboratory synthesis of tigilanol tiglate that proceeds in 12 steps (12% overall yield, >80% average yield per step) and can be used to sustainably supply tigilanol tiglate and its analogues, the latter otherwise inaccessible from the natural source. The success of this synthesis is based on a unique strategy for the installation of an oxidation pattern common to many biologically active tiglianes, daphnanes and their analogues.

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Figures

Fig. 1 ∣
Fig. 1 ∣. Structural analysis of tigilanol tiglate (1) and a retrosynthetic analysis of its synthesis from phorbol (2).
Over 10 g of diversifiable intermediate 7 was prepared from phorbol (2), which was isolated in decagram quantities from C. tiglium seeds. The three-dimensional structure of 1 was calculated using Macromodel (Schrödinger Suite 2016) and optimized with density functional theory (M06-2X3).
Fig. 2 ∣
Fig. 2 ∣. Overview of the importance of the B-ring oxidation pattern in tigliane and daphnane natural products and the pharmacophore model.
a, The structures of phorbol 13-acetate and of representative members of the tigliane and daphnane families with a shared B-ring functionality. b, X-ray crystal structure of phorbol 13-acetate bound to the C1 domain of PKC-δ,. c, Predicted binding mode of EBC-46 to the C1 domain of PKC-δ. Dotted lines represent hydrogen bonds.
Fig. 3 ∣
Fig. 3 ∣. Reaction sequence from phorbol (2) to tigilanol tiglate (1).
Reagents and conditions. (1) C20 silylation: tert-butyldimethylsilyl chloride (TBSCl) (7 equiv.), imidazole (15 equiv.), dimethylformamide, 0 °C. (2) C12,C13 acetylation and C20 desilylation: acetic anhydride (Ac2O) (15 equiv.), triethylamine (NEt3) (15 equiv.), 4-dimethylaminopyridine (0.3 equiv.), CH2Cl2; then MeOH, 0 °C to room temperature; then HClO4 (25 equiv.). (3) C7 singlet oxygen ene reaction (cyclic flow, approximately 100 cycles of 5 min, reaction progress tracked by thin-layer chromatography and/or NMR spectroscopy; for more information, see Supplementary pages SI-13 and SI-14.); Rose bengal (1.5 mM), O2, CD3OD, 20 °C; then thiourea (3 equiv.). (4) C5,C6 epoxidation: mCPBA (2 equiv.), 3:1 CH2Cl2:ether, 4 °C. (5) C20 tosylation and reductive epoxide opening: p-toluenesulfonyl chloride (TsCl) (1.2 equiv.), NMI (0.1 equiv.), NEt3 (1.5 equiv.), acetonitrile, 0 °C; then H2O; then sodium iodide (NaI) (3 equiv.), 60 °C. (6) C7,C20 allylic transposition: rhenium(VII) oxide (Re2O7), (0.10 equiv.), THF, 4 °C. (7) C5,C20 acetonide protection: 2,2-dimethoxypropane (300 equiv.), pyridinium p-toluenesulfonate (PPTS) (0.15 equiv.), acetone; then rotovap; then acetone (8) C6,C7 epoxidation: dimethyldioxirane (DMDO) (3 equiv.), acetone. (9) C12,C13 deacetylation: Cs2CO3 in methanol (pH = 11). (10) C13 esterification: (S)-2-methylbutanoic acid (3 equiv.), 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide (EDC) (3.15 equiv.), NEt3 (3.30 equiv.), 4-dimethylaminopyridine (DMAP) (0.2 equiv.), CH2Cl2. (11) C12 esterification: tiglic acid (2.2 equiv.), 2,4,6-trichlorobenzoyl chloride (Yamaguchi reagent) (2 equiv.), NEt3 (4 equiv.), DMAP (2.6 equiv.), toluene. (12) C5,C20 acetonide deprotection: p-toluenesulfonic acid in water (1 M), acetonitrile. b.r.s.m., based on recovered starting material.
Fig. 4 ∣
Fig. 4 ∣. Representative biological data for synthetic EBC-46 and its analogues.
a, Structures of EBC-46 analogues. b, Cell-free PKC binding data for 1, 13, 14 and 15. The unique PKCβ-selective binding mode of 1 is mimicked by 13, whereas 14 exhibits no meaningful PKC binding and 15 binds in a potent and unselective fashion. c, In-vitro PKC-βI-GFP translocation in CHO-K1 cells mediated by 1 and 13 (1,000 nM). Scale bars, 10 μm). Upon exposure to PKC modulators 1 and 13 for 5 min, the GFP-labelled PKC was observed to translocate from the middle of the cells (cytosol) to the periphery (cell membrane).
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