A Practical Synthesis of 14-epi-19-nor-1α,25-Dihydroxyvitamin D3 Analogues
FULL PAPER
night at room temp. The solution was quenched with a saturated
solution of NH4Cl and brine, and extracted with Et2O. The com-
bined organic layers were dried, filtered, and concentrated. Puri-
and the 7,8-Z isomer of 50 (ratio 36:2:1; 72% total yield). Com-
pound 50: HPLC retention time: 10.4 min. Ϫ H NMR (500 MHz,
CDCl3): δ ϭ 0.95 (s, 3 H), 1.05 (d, J ϭ 6.2 Hz, 3 H), 1.06 (s, 9 H),
1.30 (m, 3 H), 1.51 (s, 6 H), 1.53Ϫ2.45 (m, 19 H), 3.85 (m, 1 H),
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fication by HPLC (hexane/EtOAc, 9:1) afforded 20b (396 mg, 79%)
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as an oil. Rf ϭ 0.41 (hexane/EtOAc, 8:2). Ϫ H NMR (500 MHz, 4.05 (m, 1 H), 5.71 (d, J ϭ 11.2 Hz,1 H), 6.21 (d, J ϭ 11.2 Hz, 1
CDCl3): δ ϭ 0.30 (t, 4.7 Hz, 1 H), 0.41 (dd, J ϭ 5.3, 8.1 Hz, 1 H), H), 7.39 (m, 4 H), 7.44 (m, 2 H), 7.65 (dd, J ϭ 1, 7 Hz, 2 H), 7.71
0.87 (s, 3 H), 0.87 (m, 2 H), 1.03 (s, 9 H), 1.09 (d, J ϭ 6.2 Hz, 3
H), 1.20 (t, J ϭ 7.2 Hz, 3 H), 1.25 (m, 3 H), 1.31 (d, J ϭ 5.1 Hz,
3 H), 1.51 (s, 3 H), 1.60 (s, 3 H), 1.60Ϫ2.15 (m, 11 H), 2.25 (br. d,
J ϭ 16.0 Hz, 1 H), 3.51 (dq, J ϭ 7.2, 9.1 Hz, 1 H), 3.69 (dq, J ϭ
7.2, 9.1 Hz, 1 H), 3.94 (m, 1 H), 5.31 (dd, J ϭ 16.0 Hz, 1 H), 5.33
(d, J ϭ 16.0 Hz, 1 H), 7.37 (m, 4 H), 7.40 (m, 2 H), 7.65 (m, 4 H).
(dd, J ϭ 1, 7 Hz, 2 H).
Compound 51: HPLC retention time: 12.2 min. Ϫ UV (MeOH):
λmax ϭ 219, 243, 251, 260. Ϫ H NMR (500 MHz, CDCl3): δ ϭ
0.94 (s, 3 H), 1.02 (d, J ϭ 6.3 Hz, 3 H), 1.05 (s, 9 H), 1.30 (m, 3
H), 1.49 (s, 3 H), 1.50 (s, 3 H), 1.52Ϫ2.45 (m, 19 H), 3.84 (m, 1
H), 3.98 (m, 1 H), 6.06 (d, J ϭ 12.0 Hz, 1 H), 6.08 (d, J ϭ 12.0 Hz,
1 H), 7.38 (t, J ϭ 7.0 Hz, 4 H), 7.43 (m, 2 H), 7.67 (m, 4 H).
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Allylic Alcohol 20a: This compound was prepared from 7b and 16a
as described for 20b. Rf ϭ 0.32 (hexane/EtOAc, 9:1). Ϫ IR: ν˜ ϭ
3492, 2932, 2235, 1660, 1470, 1454, 1379, 1256, 1118, 1092, 972,
7,8-Z Epimer of 50: HPLC retention time: 7.8 min. Ϫ 1H NMR
(500 MHz, CDCl3): δ ϭ 0.98 (s, 3 H), 1.06 (s and d, 12 H), 1.30
(m, 3 H), 1.47 (s, 3 H), 1.51 (s, 3 H), 1.52Ϫ2.63 (m, 15 H), 2.64
(m, 2 H), 3.90 (m, 1 H), 4.02 (m, 1 H), 6.05 (d, J ϭ 11.0 Hz, 1 H),
6.17 (d, J ϭ 11.0 Hz, 1 H), 7.41 (m, 4 H), 7.46 (m, 2 H), 7.66 (d,
J ϭ 8.0 Hz, 2 H), 7.72 (d, J ϭ 8.0 Hz, 2 H).
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837 cmϪ1. Ϫ H NMR (500 MHz, CDCl3): δ ϭ 0.02 (s, 3 H), 0.04
(s, 3 H), 0.53 (m, 2 H), 0.86 (s, 9 H), 0.87 (s, 3 H), 1.08 (d, J ϭ
6.4 Hz, 3 H), 1.19 (t, J ϭ 7.0 Hz, 3 H), 1.20Ϫ1.30 (m, 2 H), 1.33
(d, J ϭ 5.3 Hz, 3 H), 1.41 (m, 3 H), 1.44 (s, 3 H), 1.51 (s, 3 H),
1.55Ϫ2.24 (m, 16 H), 3.50 (m, 1 H), 3.69 (m, 1 H), 3.95 (m, 1 H),
5.15 (m, 1 H), 5.33 (s, 2 H).
6-Deuterio-48: This compound was prepared from 38b as described
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for 48 from 38a. H NMR (500 MHz, CDCl3): δ ϭ 0.95 (s, 3 H),
TX 522 (3) from 20b: PTSA (35 mg, 0.3equiv.) in dioxane/H2O
(8 mL, 5:3) was added to a solution of 20b (440 mg, 0.620 mmol)
in dioxane (5 mL) and the mixture was stirred at 55Ϫ60 °C for 2 h.
After dilution with Et2O, the solution was washed with a saturated
aqueous solution of NaHCO3 to pH 7 and then with H2O, dried,
filtered, and concentrated. Purification by HPLC (isooctane/
EtOAc, 85:15) gave 47 (318 mg, 80.4%) as an oil. Rf ϭ 0.24 (isooc-
1.05 (s and d 12 H), 1.57 (s, 6 H), 1.70Ϫ2.20 (m, 17 H),
2.27Ϫ2.40(m, 4 H), 2.46 (m, 1 H), 3.09 (d, J ϭ8.4 Hz, 1 H), 3.85
(br. s, 1 H), 4.05 (br. s, 1 H), 5.72 (s, 1 H), 7.36Ϫ7.48 (m, 6 H),
7.66 (d, J ϭ 7.1 Hz, 2 H), 7.72 (d, J ϭ 7.1 Hz, 2 H).
3,14-Bis-epi-19-nor-23-yn-1α,25-dihydroxy Vitamin D3 (54): This
compound was prepared from 50 as described for 3 from 47. Rf ϭ
0.2 (MeOH/CH2Cl2, 1:20). Ϫ 1H NMR (500 MHz, CDCl3): δ ϭ
0.96 (s, 3 H), 1.02 (d, J ϭ 6.6 Hz, 3 H), 1.30 (m, 5 H), 1.50(s, 6 H),
1.51Ϫ2.20 (m, 16 H), 2.25 (dd, J ϭ 3.8, 16.6 Hz, 1 H), 2.29 (dd,
J ϭ 6.2, 13.4 Hz, 1 H), 2.55 (dd, J ϭ 6.2, 13.6 Hz, 1 H), 3.99 (m,
2 H), 6.07 (d, J ϭ 11.3 Hz, 1 H), 6.27 (d, J ϭ 11.3 Hz, 1 H).
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tane/EtOAc, 7:3). Ϫ H NMR (500 MHz, CDCl3): δ ϭ 0.95 (s, 3
H), 1.05 (d, J ϭ 6.2 Hz, 3 H), 1.06 (s, 9 H), 1.50(s, 6 H), 1.50Ϫ2.40
(m, 19 H), 4.06 (m, 1 H), 4.14 (m, 1 H), 5.63 (d, J ϭ 11.3 Hz, 1
H), 6.11 (d, J ϭ 11.3 Hz, 1 H), 7.33Ϫ7.44 (m, 6 H), 7.61Ϫ7.73 (4
H). A solution of 47 (318 mg, 0.498 mmol) and TBAF (10 mL, 1
in THF) in THF (5 mL) was stirred at room temp. for 2 days.
After dilution with Et2O (50 mL) the solution was washed with
H2O, dried, filtered, and concentrated. HPLC purification (as
above) gave 3 (199 mg, quant.).
7,8-Z Isomer of 54: Rf ϭ 0.2 (MeOH/CH2Cl2, 1:20). Ϫ UV
(MeOH): λmax ϭ 242, 250, 259 nm. Ϫ 1H NMR (500 MHz,
CDCl3): δ ϭ 0.98 (s, 3 H), 1.03 (d, J ϭ 6.5 Hz, 3 H), 1.41 (m, 2
H), 1.51 (s, 6 H), 1.52Ϫ2.45 (m, 18 H), 2.47 (dd, J ϭ 2, 14 Hz, 2
H), 2.55 (m, 1 H), 2.68 (t, J ϭ 10.0 Hz, 1 H), 3.98 (m, 2 H), 6.13
(d, J ϭ 11.1 Hz, 1 H), 6.22 (d, J ϭ 11.4 Hz, 1 H).
Compound 48, Intermediate for 3-epi Analogues: This compound
was prepared from 38a as described for 18a from 14a. The epimers
(ratio circa 1:1) were separated by column chromatography (isooc-
tane/Et2O, 1:12 Ǟ 1:4). C-6 configuration undetermined:
Compound 53, Intermediate for 1-epi Analogues: This compound
was prepared from 35 in 2 steps as described for 50 and 51 from
38a. Ratio 53/52, 7:1. Compound 53, HPLC retention time: 10.8
min. (Et2O/isooctane/MeOH/CH2Cl2, 100:100:1:20). Ϫ 1H NMR
(500 MHz, CDCl3): δ ϭ 0.94 (s, 3 H), 1.04 (s, 9 H), 1.05 (d, J ϭ
6.0 Hz, 3 H), 1.30 (m, 3 H), 1.52 (s, 6 H), 1.78 (m, 1 H), 1.80- 2.30
(m, 17 H), 2.37 (m, 1 H), 2.46 (m, 1 H), 3.85 (m, 1 H); 4.06 (m, 1
H), 5.71 (d, J ϭ 11.3 Hz, 1 H), 6.21 (d, J ϭ 11.3 Hz, 1 H), 7.38
(br. t, J ϭ 7.0 Hz, 4 H), 7.45 (m, 2 H), 7.65 (d, J ϭ 6.8 Hz, 2 H),
7.71 (d, J ϭ 6.81 Hz, 2 H).
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Compound 48: More polar Rf ϭ 0.37 (isooctane/Et2O, 1:1). Ϫ H
NMR (500 MHz, CDCl3): δ ϭ 0.66 (m, 1 H), 0.92 (s, 3 H), 1.02
(d, J ϭ 6.2 Hz, 3 H), 1.03 (s, 9 H), 1.19 (t, J ϭ 6.0 Hz, 3 H), 1.30
(m, 3 H), 1.33 (d, J ϭ 4.8 Hz, 3 H), 1.44 (s, 3 H), 1.50 (s, 3 H),
2.18 (m, 1 H), 2.25 (dd, J ϭ 2, 16 Hz, 1 H), 3.49 (dq, J ϭ 7, 9 Hz,
1 H), 3.69 (dq, J ϭ 7, 9 Hz, 1 H), 4.23 (d, J ϭ 8.4 Hz, 1 H), 4.36
(br. t, J ϭ 6.0 Hz, 1 H), 5.12 (d, J ϭ 8.4 Hz, 1 H), 5.13 (q, J ϭ
4.8 Hz, 1 H), 7.36 (t, J ϭ 7.0 Hz, 4 H), 7.41 (t, J ϭ 7.0 Hz, 2 H),
7.62 (d, J ϭ 7.0 Hz, 4 H).
Compound 48: Less polar: Rf ϭ 0.43 (isooctane/Et2O, 1:1). Ϫ 1H
NMR (500 MHz, CDCl3): δ ϭ 0.66 (m, 1 H), 0.94 (s, 3 H), 1.01
(d, J ϭ 6.7 Hz, 3 H), 1.03 (s, 9 H), 1.18 (t, J ϭ 5.9 Hz, 3 H), 1.30
(m, 3 H), 1.33 (d, 5.2 Hz, 3 H), 1.43 (s, 3 H), 1.50 (s, 3 H),
1.50Ϫ2.20 (m, 17 H), 2.21 (m, 1 H), 2.25 (br. d, J ϭ 16.0 Hz, 1 H),
3.49 (dq, J ϭ 7, 9 Hz, 1 H), 3.68 (dq, J ϭ 7, 9 Hz, 1 H), 4.30 (d,
J ϭ 8.5 Hz, 1 H), 4.31 (br. t, J ϭ 6.0 Hz, 1 H), 5.11 (q, J ϭ 5.2 Hz,
1 H), 5.14 (d, J ϭ 8.5 Hz, 1 H), 7.36 (t, J ϭ 7.0 Hz, 4 H), 7.41 (t,
J ϭ 7.0 Hz, 2 H), 7.62 (d, J ϭ 7.0 Hz, 4 H).
Compound 52: HPLC retention time: 12.8 min. (Et2O/isooctane/
MeOH/CH2Cl2, 100:100:1:20). Ϫ 1H NMR (500 MHz, CDCl3):
δ ϭ 0.97 (s, 3 H), 1.03 (d, J ϭ 6.53 Hz, 3 H), 1.6 (s, 9 H), 1.30 (m,
3 H), 1.49 (s, 6 H), 1.50Ϫ2.20 (m, 16 H), 2.25 (dd, J ϭ 3.4, 16.4 Hz,
1 H), 2.41(m, 2 H), 2.56 (m, 1 H), 3.83 (m, 1 H), 3.98 (m, 1 H),
6.08 (s, 2 H), 7.38 (t, J ϭ 7.0 Hz, 4 H), 7.44 (br. t, J ϭ 7.0 Hz, 2
H), 7.66 (d, J ϭ 6.92 Hz, 2 H), 7.70 (d, J ϭ 7.03 Hz, 2 H).
14-epi-19-nor-23-yn-1β,25-dihydroxy Vitamin D3 (55): This com-
pound was prepared from 53 as described for 3 from 47. Rf ϭ 0.2
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Solvolysis of 48: This was as described for 3 from 18a. HPLC sep-
aration (isooctane/Et2O/MeOH/CH2Cl2, 100:100:1:20) gave 50, 51,
(MeOH/CH2Cl2, 1:20). Ϫ H NMR (500 MHz, CDCl3): δ ϭ 0.95
(s, 3 H), 1.02 (d, J ϭ 6.6 Hz, 3 H), 1.30 (m, 5 H), 1.50(s, 6 H),
Eur. J. Org. Chem. 2001, 3779Ϫ3788
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