General Papers
ARKIVOC 2014 (vi) 206-212
Conclusions An enantioselective synthesis of homoharringtonine ester side chain and its deoxy-derivative have been completed in six steps with 24.5% and 23.5% overall yields, respectively. The key tactical elements of this synthesis include the use of chiral malic acid as starting material and the cross metathesis with available methylbut-3-en-2-ol. These enabled an efficient access to the protected intermediate 5, which can be converted easily into methyl ester of the side chain. This strategy can be considered as a potential pathway to the semi-synthesis of homoharringtonine and its derivatives by the coupling of cephalotaxine and the ester side chain. Studies directed towards the esterification of the α-hydroxy acid with cephalotaxin to produce enantiopure HHT are currently under investigation.
Experimental Section General. All the reactions were carried out under a nitrogen atmosphere. Unless otherwise noted, all the reagents obtained from commercial sources were used without further purification. All solvents were dried by standard methods. THF were dried with sodium and benzophenone and used immediately after distillation. DCM was dried with diphosphorus pentoxide (P2O5). Pentane was distilled and then dried with sodium. Analytical thin-layer chromatography (TLC) was performed on 0.25 mm Merck precoated silica gel plates (60-F254). Column chromatography was carried out with silica gel (60-F254). The TLC plates were visualized with a UV lamp (254 nm and 366 nm) and/or with TLC visualizing solutions activated with heat, including: p-anisaldehyde solution and potassium permanganate solution. Mass spectral analyses were performed with a VARIAN 920-MS at VAST. The specific optical rotation data were measured with a JASCO P-2000 Polarimeter instrument (wavelength of the light used was 589 nm). 1H NMR and 13C NMR were recorded on BRUKER 300 and 500 MHz instruments using TMS as the internal standard and CDCl3 as the solvent. 2-((2R, 4R)-2-tert-Butyl-5-oxo-1,3-dioxolan-4-yl)acetic acid (2). To a suspension of D-(+)malic acid (10 g, 74.58 mmol) and pivalaldehyde (13.2 mL, 116.1 mmol) in pentane (150 mL), PTSA (1.1 g, 6.39 mmol) and concentrated H2SO4 (2 drops) were added. The mixture was heated under reflux for 40 h with azeotropic removal of water. The resulting suspension was filtered. The solid cake was dissolved in CH2Cl2, and washed with 8% aqueous H3PO4 (2×40 mL). The combined organic phases were dried with Na2SO4. The solvent was removed under vacuum, giving 9.554 g of the product as a white solid (yield 64%). [α]D24 +2.20 (c 1.00, MeOH). 1H NMR (300 MHz, CDCl3): δH 5.33 (m, 1H), 4.77 – 4.54 (m, 1H), 3.08 – 2.77 (m, 2H), 0.98 (s, 9H). 13C NMR (75 MHz, CDCl3): δc 1745.0, 172.4, 111.4, 71.4, 35.9, 35.4, 23.4. 2-((2R,4R)-2-tert-butyl-4-allyl-5-oxo-1,3-dioxolan-4-yl)acetc acid (3). To a stirred solution of dioxolanone 2 (1.78 g, 8.83 mmol) in THF (110 mL) a solution of LiHMDS (0.5 M in THF,
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