P. Klimko et al. / Bioorg. Med. Chem. 12 (2004) 3451–3469
3461
(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-prost-
enoic acid isopropyl ester (50 mg) in 18% yield in four
steps from 14.
71.92 (CH2), 69.60 (CH), 52.50 (CH), 43.57 (CH), 37.74
(CH2), 36.23 (CH2), 30.72 (CH2), 29.24 (CH2). HRMS,
m=z calcd for C24H26O6Na [(M+Na)þ], 433.162978;
found, 433.16296.
Analogous to the deprotection of THP ether 8 to the
diols 9 and 10, the above THP ether (50 mg) was con-
verted to 17 (29 mg) in 67% yield. 13C NMR (50 MHz): d
173.4 (C), 158.4 (C), 129.8 (CH), 129.5 (CH), 129.1
(CH), 121.2 (CH), 114.6 (CH), 91.7 (d, J ¼ 175 Hz,
CH), 78.9 (CH), 74.7 (CH), 69.6 (d, J ¼ 20 Hz, CH2),
67.6 (CH), 52.7 (CH), 51.7 (CH), 42.6 (CH2), 34.0
(CH2), 30.4 (CH2), 28.8 (d, J ¼ 5 Hz, CH2), 26.8 (d,
J ¼ 15 Hz, CH2), 24.9 (CH2), 21.8 (CH3). HRMS, m=z
calcd for C25H38O5F [(M+H)þ], 437.270528; found,
437.27053.
Analogous to the conversion of the b-alcohol
[3aR,4R(3S),5R,6aS]-5-benzoyloxy-4-(3-hydroxy-4-phen-
oxybutyl)-hexahydro-2H-cyclopenta[b]furan-2-one to
the a-fluoride 13, the above a-alcohol (1.39 g) was con-
verted to a 4:1 molar of 15 and an HF elimination by-
product (1.01 g total, 72% calculated as the fluoride). 13C
NMR line listing for 15: (150 MHz): d 176.54 (C), 166.04
(C), 158.33 (C), 133.29 (CH), 129.64 (CH), 129.54 (CH),
128.52 (CH), 121.39 (CH), 114.62 (CH), 91.45 (d,
J ¼ 171 Hz, CH), 84.30 (CH), 80.18 (CH), 69.28 (d,
J ¼ 26 Hz, CH2), 52.75 (CH), 43.47 (CH), 37.81 (CH2),
36.23 (CH2), 29.88 (d, J ¼ 21 Hz, CH2), 28.86 (CH2).
HRMS, m=z calcd for C24H25O5FNa [(M+Na)þ],
435.158817; found, 435.15881.
4.1.12. (5Z)-(9S,11R,15R)-9,11-Dihydroxy-15-fluoro-16-
phenoxy-17,18,19,20-tetranor-5-prostenoic acid (19).
Analogous to the saponification of ester 9 to acid 11,
17 (8 mg) was converted to 19 (7 mg) in 93% yield. 13C
NMR (67.5 MHz): d 158.5 (C), 129.3 (CH), 129.2 (CH),
129.0 (CH), 120.7 (CH), 114.3 (CH), 91.8 (d,
J ¼ 169 Hz, CH), 77.0 (CH), 72.3 (CH), 69.6 (d,
J ¼ 20 Hz, CH2), 50.6 (CH), 50.1 (CH), 42.6 (CH2), 33.1
(CH2), 29.1 (CH2), 26.2 (d, J ¼ 20 Hz, CH2), 24.8
(CH2). HRMS, m=z calcd for C22H31O5F (Mþ),
394.215436; found, 394.21542.
4.1.15. [3aR,4R(3S),5R,6aS]-4-(3-Fluoro-4-phenoxybutyl)-
5-hydroxy-hexahydro-2H-cyclopenta[b]furan-2-one (16).
Analogous to the debenzoylation of 4 to alcohol 6, the
above 15/HF elimination by-product mixture (982 mg
calculated as the fluoride) was converted to a mixture of
alcohol 16 and an HF elimination by-product (591 mg
combined) in 80% yield (calculated as the fluoride). 13C
NMR line listing for 16: (50 MHz): d 177.43 (C), 158.33
(C), 129.53 (CH), 121.34 (CH), 114.58 (CH), 91.66 (d,
J ¼ 171 Hz, CH), 83.93 (CH), 77.57 (CH), 69.33 (d,
J ¼ 24 Hz, CH2), 53.94 (CH), 43.00 (CH), 40.56 (CH2),
36.02 (CH2), 29.81 (d, J ¼ 21 Hz, CH2), 28.38 (d,
J ¼ 4 Hz, CH2). HRMS, m=z calcd for C17H22O4F
[(M+H)þ], 309.150295; found, 309.15029.
4.1.13. [3aR,4R(1E,3R),5R,6aS]-5-Benzoyloxy-4-(3-hy-
droxy-4-phenoxybutenyl)-hexahydro-2H-cyclopenta[b]-
furan-2-one (3). Analogous to the reduction of enone 1
to b-alcohol 2 with (+)-DIP chloride, enone 1 (3.29 g)
was converted to a-alcohol 3 (1.64 g) in 50% yield using
())-DIP chloride. 1H NMR (600 MHz): d 7.99 (d,
J ¼ 7 Hz, 2H), 7.54 (t, J ¼ 7 Hz, 1H), 7.43 (t, J ¼ 8 Hz,
2H), 7.26 (t, J ¼ 8 Hz, 2H), 6.96 (t, J ¼ 7 Hz, 1H), 6.85
(d, J ¼ 8 Hz, 2H), 5.82 (dd, J ¼ 16 Hz, 7 Hz, 1H), 5.73
(dd, J ¼ 16 Hz, 5 Hz, 1H), 5.28 (q, J ¼ 6 Hz, 1H), 5.05 (t
of d, J ¼ 5 Hz, 2 Hz, 1H), 4.52–4.50 (br m, 1H), 3.94
(dd, J ¼ 9 Hz, 4 Hz, 1H), 3.82 (dd, J ¼ 9 Hz, 7 Hz, 1H),
2.86–2.78 (m, 3 H), 2.61–2.55 (m, 1H), 2.51 (d,
J ¼ 16 Hz, 1H), 2.43 (br s, 1H), 2.28 (dd, J ¼ 16 Hz,
4 Hz, 1H). 13C DEPT NMR (150 MHz): d 133.33 (CH),
131.06 (CH), 130.70 (CH), 129.65 (CH), 129.55 (CH),
128.52 (CH), 121.36 (CH), 114.63 (CH), 83.30 (CH),
79.08 (CH), 71.58 (CH2), 70.19 (CH), 54.18 (CH), 42.67
(CH), 37.59 (CH2), 34.94 (CH2). HRMS, m=z calcd for
C24H24O6Na [(M+Na)], 431.146911; found, 431.14691.
4.1.16. (5Z)-(9S,11R,15S)-9,11-Dihydroxy-15-fluoro-16-
phenoxy-17,18,19,20-tetranor-5-prostenoic acid isopropyl
ester (18). Analogous to the protection of alcohol 6 as its
THP ether 7, the above 16/HF elimination by-product
mixture (542 mg) was converted to a mixture of its THP
ether [3aR,4R(3S),5R(2RS),6aS]-4-(3-fluoro-4-pheno-
xybutyl)-5-(2-tetrahydropyran-2-yloxy)-hexahydro-2H-
cyclopenta[b]furan-2-one and the corresponding HF
elimination by-product (652 mg) in 94% yield (calculated
as the fluoride). HRMS, m=z calcd for C22H30O5F
[(M+H)þ], 393.207942; found, 393.20794.
Analogous to the reduction of lactone 7 to the corre-
sponding lactol, the above THP ether lactone/HF
elimination by-product mixture (641 mg) was converted
to the lactol [2RS,3aR,4R(3S),5R,6aS]-4-(3-fluoro-4-
phenoxybutyl)-5-(tetrahydropyran-2-yloxy)-hexahydro-
2H-cyclopenta[b]furan-2-ol and the corresponding HF
elimination by-product (652 mg) in 100% yield (calcu-
lated as the fluoride). HRMS, m=z calcd for C22H32O5F
[(M+H)þ], 395.223390; found, 395.22339.
4.1.14. [3aR,4R(3S),5R,6aS]-5-Benzoyloxy-4-(3-fluoro-4-
phenoxybutyl)-hexahydro-2H-cyclopenta[b]furan-2-one
(15). Analogous to the hydrogenation of olefin 2 to
[3aR,4R(3S),5R,6aS]-5-benzoyloxy-4-(3-hydroxy-4-phen-
oxybutyl)-hexahydro-2H-cyclopenta[b]furan-2-one,
3
(1.59 g) was reduced to [3aR,4R(3R),5R,6aS]-5-ben-
zoyloxy-4-(3-hydroxy-4-phenoxybutyl)-hexahydro-2H-
cyclopenta[b]furan-2-one (1.60 g) in 100% yield. 13C
NMR (50 MHz): d 176.81 (C), 166.02 (C), 158.40 (C),
133.23 (CH), 129.59 (CH), 129.51 (CH), 128.47 (CH),
121.22 (CH), 114.52 (CH), 84.81 (CH), 80.04 (CH),
Analogous to the conversion of the lactol [3aR,4-
R(1E,3RS),5R,6aS]-4-(3-fluoro-4-phenoxybutenyl)-5-hy-
droxy-hexahydro-2H-cyclopenta[b]furan-2-ol to the
Wittig+esterification product 8, the above lactol