Syntheses of Thailandepsin B Pseudo-Natural Products: Access to New Highly Potent HDAC Inhibitors via Late-Stage Modification

Abstract

New Thailandepsin B pseudo-natural products have been prepared. Our synthetic strategy offers the possibility to introduce varying warheads via late stage modification. Additionally, it gives access to the asymmetric branched allylic ester moiety of the natural product in a highly diastereoselective manner applying rhodium-catalyzed hydrooxycarbonylation. The newly developed pseudo-natural products are extremely potent and selective HDAC inhibitors. The non-proteinogenic amino acid d-norleucine was obtained enantioselectively by a recently developed method of rhodium-catalyzed hydroamination.

Keywords: asymmetric catalysis; histone deacetylase inhibitors; rhodium; synthetic methods; thailandepsin.

Figure 1

Thailandepsins A‐F and FK228.

Scheme 1

Reduction of the disulfide in thailandepsins to generate the thiol as zinc binding warhead.

Scheme 2

Thailandepsin B pseudo‐natural product 8 and retrosynthetic approach: Macrocyclic precursor 9 offers the possibility of late stage modification to introduce varying warheads via cross‐metathesis. Disconnection of 8 via macrolactamization.

Scheme 3

Retrosynthetic analysis.

Scheme 4

Synthesis of Fmoc‐protected d‐norleucine via rhodium‐catalyzed hydroamination. a) aq. HCl, Et₂O, r.t., 24 h; b) PGCl, Na₂CO₃, dioxane, 0 °C to r.t., 17 h; c) K₂OsO₂(OH)₄, NMO, acetone, H₂O, THF, 18 h, PG=Fmoc 79 %, PG=Cbz 91 %; d) NaIO₄, THF/H₂O, 2 h; e) NaClO₂, NaH₂PO₄, tBuOH/H₂O, PG=Fmoc 1.5 h 70 %, PG=Cbz 20 h, 82 %. NMO=N‐Methylmorpholine N‐oxide.

Scheme 5

Synthesis of compound 12. a) EDCI*HCl, HOBt, NEt₃, DCM, r.t., 18 h, 76 %; b) TFA, Et₃SiH, DCM, r.t., 18 h, 81 %. EDCI=1‐Ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide, TFA=trifluoroacetic acid.

Scheme 6

Synthesis of macrocyclic precursor 8. a) HNEt₂ (10 %), DMF, r.t., 5 min; b) 12, HATU, HOBt, DIPEA, DCM, r.t., 24 h; c) HF*pyridine (70 %), pyridine, THF, 0 °C to r.t., 2 h, 58 % over 3 steps; d) Jones reagent, acetone, r.t., 55 sec, 60 %; e) piperidine, DCM, r.t., 45 min, 90 %; f) HATU, DIPEA, DCM (1 mm), r.t., 16 h, 51 %. DIPEA=N,N‐Diisopropylethylamine.

Scheme 7

Late stage modification of 9. a) HCl, acetone, r.t., 2.5 h, 66 %; b) Grubbs II catalyst (20 mol %), toluene, 80 °C, 18 h, 69 % brsm; c) HCl, acetone, r.t., 3 h, 78 %; d) potassium thioacetate, acetone, r.t., 3 h, 78 %; e) HCl, acetone, r.t., 3 h, 61 %; f) Grubbs II catalyst (20 mol %), toluene, 80 °C, 18 h, 52 % brsm; g) HCl, acetone, r.t., 2.5 h, 58 %; h) TFA, Et₃SiH, DCM, r.t., 5 min.