Design and synthesis of (13S)-methyl-substituted arachidonic acid analogues: templates for novel endocannabinoids

Abstract

Two novel methyl-substituted arachidonic acid derivatives were prepared in an enantioselective manner from commercially available chiral building blocks, and were found to be excellent templates for the development of (13S)-methyl-substituted anandamide analogues. One of the compounds synthesized, namely, (13S,5Z,8Z,11Z,14Z)-13-methyl-eicosa-5,8,11,14-tetraenoic acid N-(2-hydroxyethyl)amide, is an endocannabinoid analogue with remarkably high affinity for the CB1 cannabinoid receptor.

Scheme 1

Retrosynthetic analysis of (13S)-methylanandamide 32. TBDPS=tert-butyldiphenylsilyl.

Scheme 2

Synthesis of chiral aldehydes 3 and 11. Reagents and conditions: a) TBDPSCl, imidazole, CH₂Cl₂, 0°C to RT, 1.5 h, 98%; b) DIBAL-H, CH₂Cl₂, −110–−90°C, 20 min, 61% for 3 and 37% for 4; c) Dess–Martin periodinane, 0°C to RT, 45 min, 90%; d) PCC, CH₂Cl₂, 4 Å molecular sieves, RT, 2.5 h, 93%; e) CH₃(CH₂)₅P⁺Ph₃Br⁻, KHMDS, THF, 10°C, 50 min, then 8, −98°C, 1 h, 50%; f) BF₃•CH₃COOH, MeOH, 0°C, 1 h, 84%; g) Pb(OAc)₄, CH₂Cl₂−78°C, 1.5 h, 97%. PCC = pyridinium chlorochromate, KHMDS = potassium bis(trimethylsilyl)amide.

Scheme 3

Synthesis of alkenyl phosphonium salt 20. Reagents and conditions: a) TBDPSCl, imidazole, THF, 0°C, 1.5 h, 99%; b) nBuLi, THF, 0°C, 1.5 h, then (CH₂O)_n −50°C to RT, 1.5 h, 73%; c) CBr₄, Ph₃P, CH₂Cl₂, 0°C to RT, 3 h, 85%; d) CH≡C-(CH₂)₃-COOMe, Cs₂CO₃, NaI, CuI, DMF, RT, 2.5 h, 95%; e) Ni(OAc)₂, NaBH₄, ethylenediamine, H₂, MeOH, RT, 2h, 85%; f) TBAF, THF, 0°C to RT, 1.5 h, 93%; g) CBr₄, Ph₃P, CH₂Cl₂−25−0°C, 1.5 h, 96%; h) Ph₃P, CH₃CN, 72–75°C, 8 days, 95%. TBAF = tetrabutylammonium fluoride.

Scheme 4

Synthesis of alkynyl phosphonium salt 23. Reagents and conditions: a) TBAF, THF, 0°C, 2 h, 84%; b) CBr₄, Ph₃P, CH₂Cl₂ −16°C, 2 h, 98%; c) Ph₃P, CH₃CN, 70–72°C, 7 days, 88%.

Scheme 5

Synthesis of 32. Reagents and conditions: a) KHMDS, THF, −78–−60°C, 20 min, then 3, −115–0°C, 3 h, 61%; b) TBAF, THF, 0°C to RT, 1.5 h, 85%; c) Dess–Martin periodinane, 0°C to RT, 75 min; d) CH₃-(CH₂)₅P⁺Ph₃Br⁻, KHMDS, THF, 0°C, 40 min, then addition of 26, −115–−100°C, 50 min, 65% from alcohol 25; e) KHMDS, THF, −78–−60°C, 20 min, then 11, −98−0°C, 2.5 h, 22%; f) LiOH, THF/H₂O, RT, 24 h, 86%; g) TBDPSCl, imidazole, CH₃CN, 0°C, 30 min, 97%; h) carbonyldiimidazole, THF, RT, 2 h, then 30, RT, 1 h, 91%; i) TBAF, THF, 0°C to RT, 1 h, 88%.

Scheme 6

Synthesis of the conformationally partially extended (13S)-methyl analogue 39. Reagents and conditions: a) KHMDS, THF, −78°C, 50 min, then 3, −98−0°C, 2.5 h, 58%; b) TBAF, CH₃COOH, THF, 0°C to RT, 20 h, 76%; c) Dess–Martin periodinane, 0°C, 2h; d) CH₃(CH₂)₅P⁺ Ph₃Br, KHMDS, THF, 10°C, 40 min, then addition of 35, −98°C, 1 h, 58% from alcohol 34; e) KHMDS, THF, −78°C, 50 min, then 11, −98–0°C, 2.5 h, 21%; f) LiOH, THF/H₂O, RT, 7 h, 82%; g) TBDPSCl, imidazole, CH₃CN, 0°C, 30 min, 91%; h) Carbonyldiimidazole, THF, RT, 2 h, then 30, RT, 1 h, 97%; i) TBAF, CH₃COOH, THF, 0°C to RT, 20 h, 75%.