Reaction Steps
To a solution of acetic acid (1R,2S,3S,4R,5S)-3,4-diacetoxy-1-acetoxymethyl-5-[4-chloro-3-(4-ethoxy-benzoyl)-phenyl]-6,8-dioxa-bicyclo[3.2.1]oct-2-yl ester (see Example 11 for preparation; 85 mg, 0.14 mmol) in methanol (3 mL) was added sodium borohydride (25 mg, 0.66 mmol) at room temperature. After one hour, the reaction was quenched by the addition of water (20 mL) and the resulting mixture was concentrated under reduced pressure. The resulting aqueous layer was extracted three times with ethyl acetate (15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. To a solution of this crude material in methanol (5 mL) was added sodium methoxide in methanol (25% wt) until pH 12 was obtained and the resulting mixture was stirred at room temperature. After 16 hours, the reaction mixture was neutralized by the addition of Dowex Monosphere 650C (H) cation exchange resin (the resin was washed with methanol 3 times before use) until the pH of the solution was <7. The reaction mixture was filtered and concentrated under reduced pressure. The resulting material was precipitated from ethyl acetate and heptane. The resulting solid was washed with heptane 2 times and dried under reduced pressure to yield the desired product (58.9 mg, 93% yield) as a white solid. MS (LCMS) 497.3 (M+HCOO−, negative mode)1H NMR (400 MHz, METHANOL-d4) delta ppm 1.33 (t, J=6.9 Hz, 6H), 3.56 (d, J=8.0 Hz, 1H), 3.59-3.64 (m, 3H), 3.64-3.69 (m, 2H), 3.68 (d, J=12.5 Hz, 2H), 3.78 (d, J=8.2 Hz, 2H), 3.84 (d, J=12.5 Hz, 2H), 3.98 (q, J=7.0 Hz, 4H), 4.15 (d, J=7.4 Hz, 1H), 4.16 (d, J=7.4 Hz, 1H), 6.04 (s, 1H), 6.05 (s, 1H), 6.80 (d, J=8.4 Hz, 4H), 7.21 (d, J=8.6 Hz, 2H), 7.22 (d, J=8.6 Hz, 2H), 7.29 (d, J=8.2 Hz, 2H), 7.40-7.42 (m, 2H), 7.91 (d, J=2.0 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H). Analytical method: Column: Chiralpak AD-H (4.6 mm×25 cm), Flow rate: 2.5 mL/minute, mobile phase: 65/35 CO2/propanol; UV detection: 210 nm. Peak 1 (Rt=2.80 minutes, 45.5% area), Peak 2 (Rt=5.51 minutes, 54.5% area). As depicted in Scheme 6, Example 9 could also be prepared according to the procedures described in steps 1 to 6 of Scheme 2 using the appropriate organometallic reagent (IX-1) wherein M is Li or Mg, X′ is Cl, Br or I and p is 0-2 (R7 is OPMB, OBn, OTBS, OTMS, OTES, OTIPS, OAllyl, OBOM, OPMBM, ODMBM, OMOM, OMEM, OMTM, OSEM, OM(X′)p or any suitably protected precursor to the claimed compound example 9).
