A practical synthesis of long-chain iso-fatty acids (iso-C12–C19) and related natural products

Summary A gram-scale synthesis of terminally-branched iso-fatty acids (iso-C12–C19) was developed commencing with methyl undec-10-enoate (methyl undecylenate) (for iso-C12–C14) or the C15 and C16 lactones pentadecanolide (for iso-C15–C17) and hexadecanolide (for iso-C18–C19). Central to the approaches outlined is the two-step construction of the terminal isopropyl group through addition of methylmagnesium bromide to the ester/lactones and selective reduction of the resulting tertiary alcohols. Thus, the C12, C17 and C18 iso-fatty acids were obtained in three steps from commercially-available starting materials, and the remaining C13–C16 and C19 iso-fatty acids were prepared by homologation or recursive dehomologations of these fatty acids or through intercepting appropriate intermediates. Highlighting the synthetic potential of the iso-fatty acids and various intermediates prepared herein, we describe the synthesis of the natural products (S)-2,15-dimethylpalmitic acid, (S)-2-hydroxy-15-methylpalmitic acid, and 2-oxo-14-methylpentadecane.


General experimental methods
Proton nuclear magnetic resonance spectra ( 1 H NMR, 500 MHz) and proton-decoupled carbon nuclear magnetic resonance spectra ( 13 C NMR,125 MHz) were obtained in deuterochloroform, methanol-d 4 (CD 3 OD) and DMSO-d 6 with residual protonated solvent as internal standard.
Abbreviations for multiplicity are s, singlet; d, doublet; t, triplet; q, quartet; p, pentet. Fouriertransform infrared spectra were obtained as neat samples on an attenuated total reflectance instrument using a diamond-coated zinc selenide sample accessory. Flash chromatography was carried out on silica gel 60 according to the procedure of Still et al. [1] Analytical thin layer chromatography (tlc) was conducted on aluminium-backed 2 mm thick silica gel 60 GF 254 and chromatograms were visualized with ceric ammonium molybdate (Hanessian's stain) or potassium permanganate. High resolution mass spectra (HRMS) were obtained by ionizing samples using electrospray ionization (ESI) and a time-of-flight mass analyzer. Dry DMF was obtained by drying over 4 Å molecular sieves. Hexanes refers to petroleum ether, boiling range 40-60 °C.
Dichloromethane and THF were dried over alumina according to the method of Pangborn et al [2].

12-Methyltridecanoic acid (3; iso-C 14 acid)
8 N aq NaOH solution (200 mL) was added to a solution of 14 (11.0 g, 52.5 mmol) in EtOH (200 mL), and the resulting cloudy reaction mixture was stirred at reflux under nitrogen for 48 h.
The resulting bright yellow, biphasic mixture was then cooled to rt and a white precipitate appeared.