Traceless Solid-Phase Synthesis of Mappicine Ketone Library via Multiple Chemoselective Palladium-Catalyzed Reactions on Benzenesulfonate Linker

Abstract

We report here a solid-phase synthesis of a library of mappicine ketone, a leading antiviral compound with activity against herpes viruses and human cytomegalovirus. The synthesis is based on multiple chemoselective palladium-catalyzed reactions involving a regioselective intramolecular Heck reaction at C-2, substitution of Cl at C-7 by Suzuki-Miyaura cross-coupling reaction and Buchwald-Hartwig amination, and reductive cleavage of the benzenesulfonate linker at C-10.

Key words

mappicine ketone - traceless solid-phase synthesis - benzenesulfonate linker - palladium - chemoselective

References and Notes

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12

One-pot deprotection of tert-butyl ester and formation of acid chloride followed by NaBH₄ reduction turned out to be more effective for the 3-quinolinemethanol preparation than reduction of ethyl esters described in ref. 17.

23

Preparation of 19 (Step a)
To a suspension of JandaJel^TM-OH (2.00 g, 1.0 mmol/g, 2.0 mmol) in anhyd DMF (13 mL) were added 6-heptynoic acid (0.76 mL, 6.0 mmol), pyridine (0.65 mL, 8.0 mmol), and 2,6-dichlorobenzoyl chloride (0.86 mL, 6.0 mmol). The mixture was agitated at r.t. for 12 h. The resin was washed alternately with DMF and H₂O (3×), CHCl₃ and MeOH (3×), and Et₂O, and then dried under vacuum to yield 19 (2.13 g).
Preparation of 20 (Step b)
To a suspension of 19 (2.0 mmol), 4b (2.55 g, 5.0 mmol), PdCl₂(PPh₃)₂ (140 mg, 0.20 mmol), and CuI (76.2 mg, 0.40 mmol) in anhyd DMF (16 mL) was added Et₃N (5.3 mL, 38 mmol) at r.t. under argon. The mixture was agitated at r.t. for 12 h. The resin was washed alternately with DMF and H₂O (3×), CHCl₃ and MeOH (3×), and Et₂O, and then dried under vacuum to yield 20 (2.68 g).
Preparation of 21 (Step c)
To a suspension of 20 (2.0 mmol) in anhyd DMF (22 mL) was added Br₃P (0.95 mL, 10 mmol) at r.t. under argon. The mixture was agitated at r.t. for 6 h. The resin was washed alternately with DMF and H₂O (3×), CHCl₃ and MeOH (3×), and Et₂O, and then dried under vacuum to yield 21 (2.66 g, 0.46 mmol/g calculated by increased resin weight).
General Procedure for N-Alkylation (Step d)
To a solution of 5b-g (3.9 mmol) in DME (5.2 mL) and DMF (1.3 mL) was added t-BuOLi (3.6 mmol) under argon. The mixture was agitated at r.t. for 30 min, after which 21 (0.80 g, 0.37 mmol) was added. The mixture was then agitated at r.t. for 24 h. The resin was washed alternately with DMF and H₂O (3×), CHCl₃ and MeOH (3×), and Et₂O, and then dried under vacuum to yield N-alkylation products.
General Procedure for Heck Reaction (Step e)
To a test tube containing the N-alkylation product (0.045 mmol), Pd(OAc)₂ (0.032 mmol), Ph₃P (0.064 mmol), and KOAc (0.64 mmol) was added benzonitrile (0.8 mL) under argon. The mixture was agitated at 80 ˚C for 12 h. The resin was washed alternately with DMF and H₂O (3×), CHCl₃ and MeOH (3×), and Et₂O, and then dried under vacuum to yield 22.
General Procedure for Methylation of 22 (Step f)
To a test tube containing 22 (0.041 mmol), MeB(OH)₂ (0.45 mmol), Pd(OAc)₂ (0.027 mmol), S-Phos (0.054 mmol), and K₃PO₄×nH₂O (0.45 mmol) was added toluene (0.8 mL) under argon. The mixture was agitated at 100 ˚C for 12 h. The resin was washed alternately with DMF and H₂O (3×), CHCl₃ and MeOH (3×), and Et₂O, and then dried under vacuum.
General Procedure for Arylation of 22 (Step g)
To a test tube containing 22 (0.041 mmol), p-Ac-C₆H₄B(OH)₂ (0.45 mmol), Pd(OAc)₂ (0.027 mmol), S-Phos (0.054 mmol), and K₃PO₄ (0.45 mmol) was added toluene (0.8 mL) under argon. The mixture was agitated at 100 ˚C for 12 h. The resin was washed alternately with DMF and H₂O (3×), CHCl₃ and MeOH (3×), and Et₂O, and then dried under vacuum.
General Procedure for Amination of 22 (Step h)
To a test tube containing 22 (0.041 mmol), BnNH₂ (0.46 mmol), Pd(OAc)₂ (0.066 mmol), XANTPHOS (0.073 mmol), and K₂CO₃ (0.46 mmol) was added 1,4-dioxane (0.8 mL) under argon. The mixture was agitated at 100 ˚C for 12 h. The resin was washed alternately with DMF and H₂O (3×), CHCl₃ and MeOH (3×), and Et₂O, and then dried under vacuum.
General Procedure for NaBH ₄ Reduction of 22 (Step i)
To a suspension of 22 (0.021 mmol) in THF-EtOH (3:1, 0.5 mL) was added NaBH₄ (0.11 mmol) under argon. The mixture was agitated at r.t. for 3 h. The resin was washed alternately with DMF and H₂O (3×), CHCl₃ and MeOH (3×), and Et₂O, and then dried under vacuum to yield 23.
General Procedure for Reductive Cleavage (Step j)
To a test tube containing 23 or 24 (0.021 mmol), Pd(OAc)₂ (0.0084 mmol), and dppp (0.0092 mmol) were added anhyd 1,4-dioxane (0.5 mL), Et₃N (0.63 mmol), and formic acid (0.63 mmol) under argon. The mixture was agitated at
100 ˚C for 12 h. The mixture was filtered and thoroughly washed with CHCl₃. The filtrate was concentrated in vacuo and the residue was purified by PLC eluting with 6% MeOH-CHCl₃ to yield 25 or 26. Spectral data of 25bA agreed with the reported ones. [²b] [d]