Synthesis of 8-HEPE and 10-HDoHE in both (R)- and (S)-Forms via Wittig Reactions with COOH-Ylides

Abstract

Wittig reactions using carboxy (CO2H) ylides derived from a carboxylic phosphonium salt and NaN(TMS)2 (NaHMDS) in a 1:1 ratio were applied to the synthesis of 8-HEPE and 10-HDoHE, which are metabolites of eicosapentaenoic acid and docosahexaenoic acid, respectively. The attempted Wittig reaction of 3-(TBS-oxy)pentadeca-4E,6Z,9Z,12Z-tetraenal with the carboxy ylide (2 equiv) derived from Br– Ph3P+(CH2)4CO2H and NaHMDS (1:1) competed with the elimination of the TBS-oxy group at C3 to give a mixture of the Wittig product and the elimination product in 45–50% and 30–40% yields, respectively. The elimination was suppressed completely by using three equiv of the carboxy ylides in THF/HMPA (7–8:1), and the subsequent desilylation gave 8-HEPE in (R)- and (S)-forms. Similarly, both enantiomers of 10-HDoHE were synthesized.

Total synthesis of resolvin D3

“…1,3-Propanediol ( 19 ) was converted into optically active acetylene alcohol ( R )- 21 in good yield by a five-step reaction. The stereoselectivity of ( R )- 21 10 was determined to be 98% ee by chiral HPLC analysis (see ESI†). TBDPS protection of the hydroxy group in ( R )- 21 and subsequent deprotection of the TMS group afforded 23 .…”

Stereoselective Construction of (E,Z)‐1,3‐Dienes and Its Application in Natural Product Synthesis

“…Lundgren recently developed a Z-selective, Ir-catalysed coupling reaction of α-aryl diazo esters (118) with allyl carbonates (119) to form substituted Z,E-dienoates (120, Scheme 48). [109] Key features of the method are i) remarkable control of the Z-geometry of the newly formed carbon-carbon double bond, ii) higher selectivities than those of traditional olefinations of carbonyl compounds with hindered phosphate derivatives (122!123, Still-Gennari modification of HWE, see section 2.6), and iii) unique reactivity and selectivity stemming from merging Ir-carbene and Ir-allyl species.…”

“…The synthesis of polyunsaturated fatty acid derivatives was also accomplished by taking advantage of Wittig olefinations to install the E,Z-diene moieties that are common in compounds of this type. [114][115][116][117][118] As an example, the synthesis of primary alcohol 136, a key intermediate for preparing (14S,21R)-dihydroxy docosahexaenoic acid (diHDHA), is depicted in Scheme 53. [115] A target that inspired the use of Wittig and related olefination reactions is (À )-callystatin A (Scheme 54).…”

The Hudrlik–Peterson Reaction of Secondary cis-TMS-Epoxy Alcohols and its Application to the Synthesis of the Fatty Acid Intermediates

“…Finally, aldehyde 24 was subjected to the Wittig reaction with the ylide derived from n-Pr phosphonium salt 25 and NaHMDS (NaN(TMS) 2 ). Since the elimination of the TBS-oxy group was expected, HMPA was added according to the previous results, 14 and the protectin D1 intermediate 26 7b was produced in 94% yield. Similarly, the Wittig reaction of 24 with 27/NaHMDS afforded 28, which is the synthetic fragment of maresin 1.…”