Synthesis of 10,11-Dihydroleukotriene B₄ Metabolites via a Nickel-Catalyzed Coupling Reaction of cis-Bromides and trans-Alkenyl Borates

Abstract

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.

Total Synthesis of Korormicin

“…Recently, we reported a nickel‐catalyzed coupling reaction between bulky alkenyl halides 2 and alkenyl borates 3 [Equation (1 )],4 and the reaction was applied to the construction of the key intermediates in the synthesis of 10,11‐dihydroleukotriene B 4 and related compounds 5. The reactivity and the almost neutral character of the borates are synthetic advantages of this reaction 6,7.…”

Stereoselective syntheses and biological activities of E-series resolvins

“…The first total synthesis of RvE1 to be published in a peer reviewed scientific journal was that of Ogawa and Kobayashi in 2009. 35 In this convergent synthesis, one key fragment was the previously reported borane 16 36,37 prepared in 10 steps from the acid 17 as outlined in Scheme 4. Acid 17 was first converted into acid chloride 18 using thionyl chloride.…”

Concise Enantiospecific Synthesis of (+)-Calvine

“…Its conversion to pentyl oxirane 6 was done by copper-catalyzed oxirane opening with n-butyl magnesium chloride followed by oxirane formation in basic conditions. 9 Successive oxirane opening with vinyl magnesium bromide gave the homoallylalcohol 5 in 84% yield. 10, 11 Copper cyanide works as well as CuCl(COD) in catalyzing the reaction.…”