M. E. Bouillon, H. H. Meyer / Tetrahedron 63 (2007) 2712–2723
2719
3H, H3C–C-1), 1.45* (m, 1H, HbC-10), 1.58 (m, 1H, HbC-7),
1.81 (quin, J¼7.1 Hz, 2H, H2C-70), 1.93 (m, 2H, HbC-6 and
HaC-7), 2.16 (m, 1H, HaC-6), 2.28 (m, 1H, HaC-10), 3.19 (t,
J¼7.0 Hz, 2H, H2C-80), 3.51 (dddd, J1¼J2¼3.7 Hz, J3¼
7.7 Hz, J4¼9.1 Hz, 1H, HC-5), 3.73 (ddd, J1¼9.1 Hz,
J2¼8.2 Hz, J3¼6 Hz, 1H, HC-7a), 4.30 (dq, J1¼8 Hz, J2¼
6.2 Hz, 1H, HC-1).
52.32 (OCH3), 56.47 (HC-50), 67.84 (HC-7a0), 78.76 (HC-
10), 156.04 (OC-30), 167.72 (OC-1), 202.91 (OC-3).
IR (Golden Gate ATR) ~n: 2925 (m), 2854 (m), 1742 (vs)
[C]O], 1713 (s) [C]O], 1650 (w), 1437 (m), 1407 (m),
1384 (m), 1361 (m), 1319 (m), 1261 (m), 1221 (m), 1155
(m), 1050 (m), 905 (w), 801 (w), 766 (w), 722 (w), 681
(w), 651 (w) cmꢀ1
.
13C NMR (100 Hz, CDCl3): d¼7.41 (H2C-80), 19.61 (H3C–
C-1), 26.55 (H2C-20), 28.00 (H2C-7), 28.40, 29.27, 29.39,
30.39 (4ꢄCH2, H2C-30–H2C-60), 30.47 (H2C-10), 33.44,
33.46 (H2C-6 and H2C-70), 56.41 (HC-5), 67.77 (HC-7a),
78.72 (HC-1), 156.00 (OC-3).
EI-MS: m/z¼368 ([M+H]+, 6.4%), 367 (M+, 8.8%), 252
(100%). HRMS (EI): calcd for C20H33NO5: 367.235874;
found: 367.235669. HRMS (ESI): calcd for C20H34NO5
[M+H]+: 368.2437; found: 368.2443; calcd for
C20H33NO5Na [M+Na]+: 390.2256; found: 390.2253.
IR (Golden Gate ATR): ~n¼2924 (m), 2853 (m), 1744 (vs)
[C]O], 1458 (m), 1406 (m), 1383 (m), 1361 (m), 1260
(m), 1212 (m), 1044 (s), 916 (m), 764 (m), 722 (w), 681
20
½aꢂD +14.4 (c 1.0, CHCl3).
(w), 649(w) cmꢀ1
.
5.1.10. (D)-(10S,3R,50S,7a0S)-3-Hydroxy-12-(10-methyl-
30-oxo-tetrahydro-pyrrolo[1,2-c]oxazol-50-yl)-dodeca-
noic acid methyl ester 12. [RuCl2(p-cymene)]2 (69.9 mg,
0.11 mmol) and (R)-(+)-BINAP (138.4 mg, 0.22 mmol)
were placed under an atmosphere of nitrogen in the pressure
flask of a hydrogenation apparatus and were dissolved in
5 mL of degassed DMF. After stirring at 110 ꢁC for
20 min the DMF was removed in vacuo to yield a dark
orange solid. Then the solution of the b-oxoester 11 (2.5 g,
6.9 mmol) in 30 mL of degassed methanol was added to
the solid catalyst via flexible needle. The resulting mixture
was treated with hydrogen (5 bar) at 70 ꢁC under stirring
for 24 h. After cooling to room temperature the dark orange
solution was concentrated in vacuo and purified by flash
chromatography (B 2.8 cmꢄ10.7 cm, EtOAc/n-hexane,
1:9 to 1:3) to afford 2.3 g of b-hydroxyester 12
(6.22 mmol, 90.2%) as dark green solid (the product still
contained small traces of the ruthenium complex, which
could not be removed by column chromatography). Since
the NMR spectra showed no trace of the (3S)-epimer the es-
timated was dr >99:1 in favour for the desired (3R)-epimer.
EI-MS: m/z¼380 ([M+H]+, 5.5%), 379 (M+, 15.7%), 96
(100%). HRMS (EI): calcd for C15H26NO2I: 379.100831;
found: 379.100902. HRMS (ESI): calcd for C15H27NO2I
[M+H]+: 380.1087; found: 380.1102.
20
½aꢂD +15.52 (c 0.525, CHCl3).
5.1.9. (D)-(10S,50S,7a0S)-12-(10-Methyl-30-oxo-tetrahy-
dro-pyrrolo[1,2-c]oxazol-50-yl)-3-oxo-dodecanoic acid
methyl ester (11). NaH (2.3 g, 60% in oil dispersion,
55.85 mmol, 1.25 equiv) was stirred in dry THF (100 mL)
under an atmosphere of nitrogen and cooled to ꢀ5 ꢁC. To
this suspension a solution of methyl acetoacetate (5.19 g,
44.7 mmol, 1 equiv) in THF (10 mL) was added dropwise
over 10 min below 0 ꢁC. After additional stirring at ꢀ5 ꢁC
for 10 min, 35 mL of n-BuLi solution (15% solution in n-
hexane, 55.85 mmol, 1.25 equiv) was added dropwise for
25 min below a temperature of +5 ꢁC. The resulting yel-
low-orange mixture was stirred for an additional 5 min at
ꢀ5 ꢁC and then treated with a solution of iodide 10 (5.1 g,
13.4 mmol, 0.3 equiv) in THF (15 mL) for 5 min. The reac-
tion mixture was allowed to warm slowly to 18 ꢁC within 5 h
before being quenched with ice water (70 mL) and 33 mL of
1 M citric acid adjusting to pH 6. Then the THF was
removed by rotary evaporation and the aqueous residue
was extracted with MTB ether (5ꢄ100 mL). The combined
organic layers were dried over Na2SO4 and concentrated in
vacuo. Purification by column chromatography (B 5 cmꢄ
17 cm, EtOAc/n-hexane 1:9–1:3) afforded the b-oxoester
11 (3.18 g, 8.65 mmol, 64.5%) as an yellow oil.
1H NMR (400 MHz, CDCl3): d¼1.20–1.36* (br, 13H, H2C-
5–H2C-10 and HbC-11), 1.36–1.64* (m, 5H, HbC-12, HaC-
11, H2C-4, HbC-70), 1.43* (d, J¼6.1 Hz, 3H, H3C–C-10),
1.93 (m, 2H, HbC-60 and HaC-70), 2.16 (m, 1H, HaC-60),
2.27 (m, 1H, HaC-12), 2.42 (dd, J1¼16.4 Hz, J2¼8.9 Hz,
1H, HaC-2), 2.52 (dd, J1¼16.4 Hz, J2¼3.1 Hz, 1H, HbC-
2), 2.97 (d, J¼3.7 Hz, 1H, OH), 3.51 (dddd, J1¼J2¼3.8 Hz,
J3¼7.8 Hz, J4¼9.2 Hz, 1H, HC-50), 3.71* (s, 3H, OCH3),
3.72* (m, 1H, HC-7a0), 4.00 (apparent o, J¼3.7 Hz, HC-
3), 4.30 (dq, J1¼8.1 Hz, J2¼6.2 Hz, 1H, HC-10).
1H NMR (400 MHz, CDCl3): d¼1.19–1.36 (br, 12H, H2C-
6–H2C-11), 1.42* (m, 1H, HbC-12), 1.43* (d, J¼6.5 Hz,
3H, H3C–C-10), 1.58 (m, 3H, H2C-5 and HbC-70), 1.93 (m,
2H, HbC-60 and HaC-70), 2.16 (m, 1H, HaC-60), 2.27 (m,
1H, HaC-12), 2.53 (t, J¼7.3 Hz, 2H, H2C-4), 3.46 (s,
2H, H2C-2), 3.51 (dddd, J1¼J2¼3.7 Hz, J3¼7.6 Hz,
J4¼9.3 Hz, 1H, HC-50), 3.73* (m, 1H, HC-7a0), 3.74* (s,
3H, OCH3), 4.30 (dq, J1¼8 Hz, J2¼6.3 Hz, 1H, HC-10).
13C NMR (100 Hz, CDCl3): d¼19.62 (H3C–C-10), 23.43
(H2C-5), 26.62 (H2C-11), 28.02 (H2C-70), 28.94, 29.26,
29.30, 29.44, 29.49 (5ꢄCH2, H2C-6–H2C-10), 30.54
(H2C-12), 33.46 (H2C-60), 43.08 (H2C-4), 49.02 (H2C-2),
13C NMR (100 Hz, CDCl3): d¼19.61 (H3C–C-10), 25.44
(H2C-5), 26.62 (H2C-11), 28.01 (H2C-70), 29.43, 29.45,
29.47, 29.49, 29.51 (5ꢄCH2, H2C-6–H2C-10), 30.54
(H2C-12), 33.46 (H2C-60), 36.55 (H2C-4), 41.18 (H2C-2),
51.71 (OCH3), 56.47 (HC-50), 67.83 (HC-7a0), 68.00 (HC-
3), 78.77 (HC-10), 156.05 (OC-30), 173.47 (OC-1).
IR (Golden Gate ATR) ~n¼3517 (m) [O–H], 2924 (m), 2854
(m), 1733 (vs) [C]O], 1469 (m), 1446 (m), 1402 (m), 1390
(m), 1367 (s), 1339 (m), 1323 (m), 1304 (m), 1259 (s), 1221
(m), 1202 (m), 1170 (s), 1151 (s), 1128 (m), 1095 (m), 1056
(s), 1030 (s), 996 (m), 924 (w), 909 (w), 864 (m), 802 (w),
768 (m), 721 (w), 680 (w), 650 (w) cmꢀ1
.