Preparation of 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine

Syntheses of all four stereoisomers which are conformationally constrained 1,4-dioxanyl analogs of the antineoplastic ether lipid ET-18-OCH3

“…The precursor for the intramolecular cyclization was prepared by hydrogenolysis of 17 to give a mixture of the four diastereomeric (4R)-l,3-dioxolanes 18. The cyclization reaction was performed with potassium tert-butoxide under conditions which have been discussed earlier for the synthesis of the racemic parent compound (±)-7 and gave a 1:4 mixture of the high-fL 4-heptadecyl-3,6,8-trioxabicyclo[3.2.1]octane (19) to the low- 6,8trioxabicyclo[3.2.1]octane (20), based on the integration of the C5 acetal protons of the two diastereomers at 5.11 and 5.18, respectively. The two diasteriomeric bicyclic acetals 19 and 20 were isolated chromatographically in 5.7% yield and 25% yield, respectively.…”

“…The two cts-18 diastereomers underwent cyclizations to different extents. While (2S,4J?,l'R)-2-(l'-bromooctadecyl)-4-(hydroxymethyl)-1.3-dioxolane ((2S,4R,l'fi)-18) was inefficiently cyclized to give the (lJZ,4S,5S)-4-heptadecyl -3,6,8-trioxabicyclo-[3.2.1]octane (19) with the endo or equatorial 4-heptadecyl group due to the competing mechanism of HBr elimina- tion, (2S,4R,l'S)-2-(l'-bromooctadecyl)-4-(hydroxymethyl)-l,3-dioxolane ((2S,4fi,l'S)-18) underwent the intramolecular nucleophilic substitution reaction to the extent of about 50% to give the cyclization product (lR,4JZ,5S)-4-heptadecyl -3,6,8-trioxabicyclo[3.2.1]octane (20) with the exo or axial 4-heptadecyl group. Clearly the required intramolecular SN2 transition state conformation of (2S,4fi,l'S)-18, with the bromide in position for leaving during backside attack of the alkoxide oxygen, has less steric interaction between the heptadecyl group and the rest of the molecule relative to the corresponding conformation of (2S,4R,l'fi)-18 with its crowded transition state during the course of this kinetically controlled reaction mechanism.…”

“…The structures of (lR,4S,5S)-4-heptadecyl-3,6,8-trioxabicyclo[3.2.1]octane (19), which has the equatorial 4heptadecyl group, and (lfi,4fi,5S)-4-heptadecyl -3,6,8-trioxabicyclo[3.2.1]octane (20), which has the axial ¿heptadecyl group, were suggested by NMR spectroscopy. The assignments of the proton resonances for both compounds were first made based on the assignments of related 3,6,8-trioxabicydo[3.2.1]octanes38 and were confirmed with magnitude-mode 2D COSY spectroscopy.…”

“…To a stirred gently refluxing mixture of 1.85 g (10.7 mmol) of p-TsOH in 50 mL of isopropenyl acetate at 110 °C (bT) was added a solution of 30.6 g (108 mmol) of 11 in 100 mL of isopropenyl acetate dropwise over 10 min. The reaction mixture was maintained at 110 °C (bT) for 19 h and then cooled, washed with 0.15 M NaHCOg (1 X 150 mL) and H20 (2 X 150 mL), and evaporated. Chromatography (EtgO/pet (2:98) gave 27.0 g (83.2 mmol, 77%) of 12 as a white solid: mp 41 °C (soften) 44-46 °C (melt); TLC (EtjO/pet 5:95) R, 0.36; NMR (trans/cis 9:1) (trans) 6.99 (dt, 1H,J = 6.5,1.5 Hz), 4.86 (dt, 1 H, J = 6.5, 7.5 Hz), 2.15 (s, 3 ), 1.50-1.70 (m, 2 ), 1.26 (br s, 30 ), 0.88 (t, 3 H, J = 6.6 Hz), (cis) 7.06 (dt, 1 H, J = 12.4, 1.5 Hz), 5.41 (dt, 1 H, J = 12.4, 7.5 Hz), 2.11 (s, 3 ), 1.50-1.70 (m, 2 ), 1.26 (br s, 30 ), 0.88 (t, 3H,«7 = 6.6 Hz); mass spectrum m/z 324 (M+), 282,264,236; HRMS caled for C^H^(M+), m/z 324.3028, found m/z 324.3035.…”

“…Caled for C22H4303Br: C, 60.68; H, 9.95. Found: C, 60.81; H, 10.16. (lfi,4S,5S)-and (1 ,4R,5S)-4-Heptadecyl -3,6,8-trioxabicyclo[3.2.1]octanes (19) and (20). The cyclization of 6.45 g (14.8 mmol) of 18 was performed as described for (±)-7, and chromatography (CHClg) first eluted the minor product which was demonstrated to be homogeneous by TLC and analytical HPLC.…”