Synthesis of (+)-Febrifugine and a Formal Synthesis of (+)-Halofuginone Employing an Organocatalytic Direct Vinylogous Aldol Reaction

Abstract

The enantioselective organocatalytic direct vinylogous aldol reaction of γ-crotonolactone and a suitable aldehyde was utilized in the synthesis of a functionalized γ-butenolide. The γ-butenolide (aldol product) was stereoselectively converted into a 5-aminoalkyl butyrolactone, which isomerized to the key 2,3-disubstituted piperidinone, a common intermediate to (+)-febrifugine and (+)-halofuginone.

New Developments of the Principle of Vinylogy as Applied to π-Extended Enolate-Type Donor Systems

“… 309 Dioxolane derivative ent - 442b , instead, served as key intermediate for the synthesis of antimalarial agents (+)-febrifugine and (+)-halofuginone ( Scheme 121 , eq 3). 310 …”

Enantiodivergent Synthesis of Halofuginone by Candida antarctica Lipase B (CAL-B)-Catalyzed Kinetic Resolution in Cyclopentyl Methyl Ether (CPME)

“…Chromatographic separations were performed under pressure on silica gel 60 (Merck, 70-230 mesh) by using flash column techniques; R f values refer to TLC carried out on 0.25 mm silica gel plates (F 254 ) with the same eluent indicated for column chromatography. 1 H NMR (400 and 200 MHz) and 13 C NMR (100.4 MHz) spectra were recorded on Varian Inova (400 MHz) and Mercury (400 and 200 MHz) spectrometers in the specified deuterated solvent at 25 °C. 1 H NMR (600 MHz) and 13 C NMR (150 MHz) spectra were recorded on a Jeol ECZR600 spectrometer.…”

“…8 More recently explored strategies for the enantioselective synthesis of 3a (R = Cbz) were based on the use of starting material from the chiral pool such as D-arabinose, 11 and the installation of new stereocenters by organocatalysis. 12,13 Despite the tremendous efficacy of enzymes in providing enantiopure compounds, to our knowledge only Evans did report on the enantiodivergent asymmetric synthesis of febrifugine, halofuginone and their hemiketals based on the kinetic resolution (KR) of a linear alcohol (4, Scheme 1, a) catalyzed by Candida antarctica lipase B, 14 which, however, required two iterations to provide one of the enantiomers [alcohol (+)-4] with high optical purity (98% ee) but in low (27%) overall yield. Encouraged by our recent results in the lipase-catalyzed KR of 3-hydroxypiperidine derivatives, 15a the report by Yoshimura et al on the efficient lipase-catalyzed KR of 3-hydroxypipecolic acid derivative 6 (Scheme 1, b), structurally similar to compound 3, 16 and in continuation of our studies on the enantioselective synthesis of (poly)hydroxypiperidine alkaloids by enzyme 15b,15c and transition metal catalysis, 15d-j we decided to establish a practical, synthetic protocol for the synthesis of both enantiomers of 3a with high optical purity by lipase-catalyzed KR of the corresponding racemate (Scheme 1, c).…”

“…After filtration and evaporation of the solvent, crude α-brominated intermediate 14 was obtained and used as such in the next step. J = 17.4, 6.0 Hz, 1 H), 2.92-2.85 (m, 1 H), 1.94-1.89 (m, 1 H), 1.83-1.77 (m, 1 H), 1.68-1.59 (m, 1 H), 1.48-1.42 (m, 1 H) ppm 13. C NMR (DMSO-d6, 150 MHz) δ 200.7, 158.7, 149.6, 147.3, 132.5, 131.9, 128.5, 126.9, 121.8, 66.8, 56.2, 54.5, 43.0, 30.6, 20.2 ppm.…”

“…[8][9][10] Figure 1 Structure of febrifugine (1), halofuginone (2), and 3-hydroxypiperidine derivatives 3 More recently, strategies explored for the enantioselective synthesis of 3a (R = Cbz) were based on the use of starting materials from the chiral pool such as D-arabinose 11 and the installation of new stereocenters by organocatalysis. 12,13 Despite the tremendous efficacy of enzymes in providing enantiopure compounds, to our knowledge only Evans has reported on the enantiodivergent asymmetric synthesis of febrifugine, halofuginone, and their hemiketals based on kinetic resolution (KR) of a linear alcohol (4, Scheme 1, a) catalyzed by Candida antarctica lipase B. 14 However, this approach required two iterations to provide one of the enantiomers (alcohol (+)-4) with high optical purity (98% ee) but in low (27%) overall yield.…”