Synthesis of 10,11-dihydroleukotriene B(4) metabolites via a nickel-catalyzed coupling reaction of cis-bromides and trans-alkenyl borates.
Synthesis of 10,11-dihydro-, 10,11,14,15-tetrahydro-, and 10, 11-dihydro-12-oxoleukotriene B(4) compounds (2, 4, 5) was accomplished stereoselectively by using the nickel-catalyzed coupling reaction illustrated in Scheme 1. The C(1)-C(7) fragments, TBS ether 10a for 2 and 4 and ethyoxyethyl (EE) ether 10b for 5, were prepared in enantiomerically pure forms (>99% ee) by a modified literature procedure (ref 11a). On the other hand, boronate esters 11a and 11b, which correspond to the C(8)-C(20) parts of 2 and 4, respectively, were synthesized from (R)-epichlorohydrin (18) of 99% ee. Briefly, 18 was converted into acetylenes 24 and 32 through epoxide ring-opening with LiC triple bond CC(5)H(11)/BF(3).OEt(2) or C(7)H(15)MgBr/CuCN. Hydroboration of these acetylenes with (+)-(Ipc)(2)BH followed by reaction with MeCHO afforded the corresponding diethyl boronates, which upon ligand exchange with Me(2)C(CH(2)OH)(2) furnished boronate esters 11a and 11b in 75% and 77% yields, respectively. In a similar manner, racemic boronate ester rac-11a, an intermediate for synthesis of 5, was prepared from racemic epichlorohydrin. For synthesis of 2, borate 25 was generated from 11a (1.5 equiv) and MeLi (1.6 equiv). Without isolation, 25 was submitted to reaction with 10a (1 equiv) in the presence of a Ni(0) species at room temperature overnight to afford 26, which upon treatment with TBAF furnished 2 in 64% yield from 10a. Similarly, 11b and 10a furnished 4 in good yield. To synthesize 5, rac-11a and EE ether 10b were joined by the coupling reaction to produce 39, which was transformed into 40 by desilylation with TBAF. After hydrolysis of 40, oxidation with PDC followed by deprotection of the EE group furnished 5 in 36% yield from 40. In addition, 2 was converted into amide 3 in 92% yield.
Nakayama
Y
Y
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan.
Kumar
G B
GB
Kobayashi
Y
Y
D001881:Borates / Q000737:chemistry*; D001965:Bromides / Q000737:chemistry*; D002384:Catalysis; D007975:Leukotriene B4 / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D009532:Nickel / Q000737:chemistry*; D013055:Spectrophotometry, Infrared
D001881:Borates; D001965:Bromides; C064945:5,12-dihydroxy-6,8,14-eicosatrienoic acid; D007975:Leukotriene B4; D009532:Nickel