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. 2018 Nov 26;81(11):2419-2428.
doi: 10.1021/acs.jnatprod.8b00439. Epub 2018 Oct 26.

Stereoselective Synthesis of the Isomers of Notoincisol A: Assigment of the Absolute Configuration of this Natural Product and Biological Evaluation

Lukas Rycek  1 , Vincenzo Ticli  1 , Jakob Pyszkowski  2 , Simone Latkolik  3 , Xin Liu  4 , Atanas G Atanasov  3   5 , Theresa Steinacher  6 , Rudolf Bauer  4 , Daniela Schuster  6   7 , Verena M Dirsch  3 , Michael Schnürch  1 , Margot Ernst  2 , Marko D Mihovilovic  1
Affiliations

Stereoselective Synthesis of the Isomers of Notoincisol A: Assigment of the Absolute Configuration of this Natural Product and Biological Evaluation

Lukas Rycek et al. J Nat Prod. .

Abstract

The total syntheses of all stereoisomers of notoincisol A, a recently isolated natural product with potential anti-inflammatory activity, are reported. The asymmetric synthesis was conducted employing a lipase-mediated kinetic resolution, which enables easy access to all required chiral building blocks with the aim of establishing the absolute configuration of the naturally occurring isomer. This was achieved by comparison of optical properties of the isolated compound with the synthetic derivatives obtained. Moreover, an assessment of the biological activity on PPARγ (peroxisome proliferator-activated receptor gamma) as a prominent receptor related to inflammation is reported. Only the natural isomer was found to activate the PPARγ receptor, and this phenomenon could be explained based on molecular docking studies. In addition, the pharmacological profiles of the isomers were determined using the GABAA (gamma-aminobutyric acid A) ion channel receptor as a representative target for allosteric modulation related to diverse CNS activities. These compounds were found to be weak allosteric modulators of the α1β3 and α1β2γ2 receptor subtypes.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Notoincisol A (1) and related natural products (2–4) from the polyeneyne class.
Scheme 1
Scheme 1. Retrosynthetic Analysis of Notoincisol A (1)
Scheme 2
Scheme 2. Strategy for Facile Access to All Necessary Enantiomerically Enriched Synthons
Scheme 3
Scheme 3. Kinetic Resolution of Alcohol rac-6 and the Method for the Control of Optical Purity
Reaction conditions: (a) n-BuLi, TMS-acetylene, THF, 0 °C to rt, 4 h, 89%; (b) Ac2O, DMAP, Et3N, CH2Cl2, rt, 15 min; (c) Amano lipase PS, MTBE, vinyl acetate, rt, 4 h, 48% for R-7, 33% for S-6.
Scheme 4
Scheme 4. Synthesis of Enantioenriched Alkynes R-10 and S-10
Reaction conditions: (a) K2CO3, MeOH, rt, 2 h, 82% yield for R-8, 78% yield for S-10; (b) TBSCl, imidazole, CH2Cl2, rt, 91% yield for R-10, 93% yield for S-9.
Scheme 5
Scheme 5. Synthesis of Enantioenriched Alkynes R-14 and S-15
Reaction conditions: (a) Ni(OAc)2·4H2O, NaBH4, (CH2NH2)2, MeOH, rt, 3 h; (b) IBX, DMSO/CH2Cl2, rt, 2 h; (c) TMS acetylene, n-BuLi, THF, −78 °C to rt, 2.5 h, 60% over three steps; (d) amano lipase PS, MTBE, vinyl acetate, rt, 36 h, 48%, ee > 99% for R-14, 45%, ee > 99% for S-15.
Scheme 6
Scheme 6. Synthesis of Enantioenriched Alkyne Bromides R-17 and S-17
(a) K2CO3, MeOH, rt, 2 h, 85% for R-16, 81% for S-16; (b) AgNO3, NBS, acetone, 2 h, rt, 81% for R-17, 77% for S-17.
Scheme 7
Scheme 7. Key Cadiot–Chodkiewitz Coupling of Enantioenriched Building Blocks and Esterification with TBS-Ferulic Acid
Reaction conditions: (a) TBSCl, imidazole, DMF, rt, 67%; (b) (i) TBSCl, imidazole, CH2Cl2, rt, (ii) THF/MeOH, H2O, K2CO3, 89%, yield after two steps; (c) NH2OH·HCl, EtNH2, CuCl, H2O/MeOH, 0 °C to rt, 2 h; (d) TBS-ferulic acid, EDCI, DMAP.
Scheme 8
Scheme 8. Deprotection of TBS Groups
Reaction conditions: (a) HF·pyridine, THF, 0 °C to rt.
Figure 2
Figure 2
Predicted binding pose of compound 3R,8S-1 in the ligand binding site of PPARγ. The molecule is anchored via a bifurcated hydrogen bond with Tyr327 and Ser289 and forms numerous hydrophobic contacts with the adjacent amino acids (yellow). Red and green arrows represent hydrogen bond acceptors and donors, respectively. The binding site surface is colored by aggregated hydrophobicity (gray) and hydrophilicity (blue).
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