PAPER
Ethanovitamin D3 Lactones with Enyne Metathesis
2541
Hz, 1 H), 5.02 (s, 1 H), 5.28 (s, 1 H), 5.94 (s, 1 H), 6.00 (d, J = 11.2
Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
(23S)-25-Dehydro-24,24-ethano-2a-(3-hydroxypropoxyl)-1a-
hydroxyvitamin D3-26,23-Lactone (6c)
According to the General Procedure, a crude product, which was
obtained from 21 (24 mg, 62 mmol), 12c (52 mg, 93 mmol), Et3N
(1.5 mL) and Pd(PPh3)4 (21 mg, 19 mmol) in toluene (1.5 mL) at
110 °C for 1.5 h, was treated with concd HF in MeCN for 2.5 h. Af-
ter the usual work-up, the crude product was purified by preparative
TLC (silica gel; EtOAc) to give 6c.
13C NMR (100 MHz, CDCl3): d = 12.2, 12.6, 14.9, 16.9, 18.4, 22.3,
23.5, 26.5, 27.6, 29.1, 32.6, 39.8, 40.6, 43.5, 44.2, 46.0, 56.4, 57.0,
71.7, 75.3, 79.5, 113.1, 113.6, 117.1, 124.6, 133.2, 141.1, 142.6,
146.5, 169.7.
EI-LRMS: m/z = 466 (M+), 448, 430, 265, 166.
Yield: 21 mg (2 steps, 66%); amorphous solid; [a]D23 +17.2 (c 1.65,
EI-HRMS: m/z calcd for C30H42O4: 466.3083; found: 466.3075.
CHCl3).
(23S)-25-Dehydro-24,24-ethano-2a-(3-hydroxypropyl)-1a-hy-
droxyvitamin D3-26,23-Lactone (6b)
IR (film, CHCl3): 3395, 1759, 1659, 1342, 1059 cm–1.
According to the General Procedure, a crude product, which was
obtained from 21 (29 mg, 74 mmol), 12b (60 mg, 111 mmol), Et3N
(1.5 mL) and Pd(PPh3)4 (26 mg, 22 mmol) in toluene (1.5 mL) at
110 °C for 1.5 h, was treated with concd HF in MeCN for 2.5 h. Af-
ter the usual work-up, the crude product was purified by preparative
TLC (silica gel; EtOAc) to give 6b.
Yield: 23 mg (2 steps 62%); amorphous solid; [a]D24 +20.1 (c 1.78,
CHCl3).
IR (film, CHCl3): 3351, 1759, 1655, 1343, 1198, 1055 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.53 (s, 3 H), 0.84 (ddd, J = 9.9,
7.0, 5.0 Hz, 1 H), 0.95 (ddd, J = 9.9, 7.0, 4.6 Hz, 1 H), 1.01 (ddd,
J = 9.9, 6.4, 4.6 Hz, 1 H), 1.05 (d, J = 6.6 Hz, 3 H), 1.15–1.75 (m,
17 H), 1.85–2.05 (m, 3 H), 2.13 (br s 1 H), 2.24 (dd, J = 13.2, 8.3
Hz, 1 H), 2.60 (br s, 2 H), 2.65 (dd, J = 13.2, 4.3 Hz, 1 H), 2.82 (m,
1 H), 3.60–3.73 (m, 2 H), 3.87 (ddd, J = 8.3, 8.3, 4.3 Hz, 1 H), 4.36
(br d, J = 2.9 Hz, 1 H), 4.49 (dd, J = 8.7, 3.8 Hz, 1 H), 4.98 (d,
J = 2.0 Hz, 1 H), 5.01 (s, 1 H), 5.26 (br s, 1 H), 5.93 (s, 1 H), 5.99
(d, J = 11.2 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
1H NMR (400 MHz, CDCl3): d = 0.54 (s, 3 H), 0.84 (ddd, J = 9.8,
7.1, 4.7 Hz, 1 H), 0.95 (ddd, J = 9.8, 6.7, 4.7 Hz, 1 H), 1.01 (ddd,
J = 9.8, 6.7, 4.7 Hz, 1 H), 1.05 (d, J = 6.6 Hz, 3 H), 1.15–2.05 (m,
17 H), 2.24 (dd, J = 13.5, 8.7 Hz, 1 H), 2.67 (dd, J = 13.5, 4.5 Hz, 1
H), 2.74 (br s, 3 H), 2.82 (m, 1 H), 3.37 (dd, J = 7.6, 3.2 Hz, 1 H),
3.70–3.93 (m, 4 H), 4.05 (ddd, J = 8.7, 7.6, 4.5 Hz, 1 H), 4.44 (d,
J = 3.2 Hz, 1 H), 4.49 (dd, J = 8.7, 3.8 Hz, 1 H), 5.01 (s, 1 H), 5.08
(d, J = 2.0 Hz, 1 H), 5.38 (d, J = 1.0 Hz, 1 H), 5.93 (s, 1 H), 6.00 (d,
J = 11.1 Hz, 1 H), 6.40 (d, J = 11.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 12.0, 14.8, 16.5, 20.0, 22.3, 23.5,
27.1, 27.8, 29.1, 31.9, 34.6, 39.4, 40.3, 41.0, 46.0, 56.1, 56.6, 61.1,
68.3, 68.5, 71.9, 81.6, 84.5, 113.4, 116.1, 117.2, 125.3, 131.7,
141.0, 143.0, 144.1, 169.8.
EI-LRMS: m/z = 526 (M+), 508, 490, 464, 432, 265, 171.
EI-HRMS: m/z calcd for C32H46O6: 526.3295; found: 526.3297.
(23R)-25-Dehydro-24,24-ethano-2a-(3-hydroxypropoxyl)-1a-
hydroxyvitamin D3-26,23-Lactone (7c)
According to the General Procedure, a crude product, which was
obtained from 22 (30 mg, 77 mmol), 12c (64 mg, 115 mmol), Et3N
(1.5 mL) and Pd(PPh3)4 (27 mg, 23 mmol) in toluene (1.5 mL) at
110 °C for 1.5 h, was treated with concd HF in MeCN for 2.5 h. Af-
ter the usual work-up, the crude product was purified by preparative
TLC (silica gel; EtOAc) to give 7c.
13C NMR (100 MHz, CDCl3): d = 12.0, 14.8, 16.5, 20.0, 22.3, 22.8,
23.5, 27.1, 27.8, 29.0, 30.1, 34.6, 39.5, 40.4, 44.1, 46.0, 49.0, 56.1,
56.6, 62.6, 70.2, 73.5, 81.6, 113.4, 113.5, 117.1, 124.5, 133.0,
141.0, 142.7, 146.4, 169.8.
EI-LRMS: m/z = 510 (M+), 492, 474, 415, 327, 309.
23
EI-HRMS: m/z calcd for C32H46O5: 510.3345; found: 510.3342.
Yield: 22 mg (2 steps, 56%); amorphous solid; [a]D +107.1 (c
1.72, CHCl3).
(23R)-25-Dehydro-24,24-ethano-2a-(3-hydroxypropyl)-1a-hy-
droxyvitamin D3-26,23-Lactone (7b)
IR (film, CHCl3): 3382, 1759, 1651, 1628, 1343, 1057 cm–1.
According to the General Procedure, a crude product, which was
obtained from 22 (29 mg, 74 mmol), 12b (60 mg, 111 mmol), Et3N
(1.5 mL) and Pd(PPh3)4 (26 mg, 22 mmol) in toluene (1.5 mL) at
110 °C for 1.5 h, was treated with concd HF in MeCN for 2.5 h. Af-
ter the usual work-up, the crude product was purified by preparative
TLC (silica gel; EtOAc) to give 7b.
Yield: 20 mg (2 steps 54%); amorphous solid; [a]D24 +123.4 (c 1.57,
CHCl3).
IR (film, CHCl3): 3358, 1757, 1651, 1343, 1196, 1051 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.56 (s, 3 H), 0.82–1.05 (m, 4 H),
0.97 (d, J = 6.6 Hz, 3 H), 1.15 (m, 1 H), 1.20–2.05 (m, 18 H), 2.19
(br s, 1 H), 2.24 (dd, J = 13.2, 8.6 Hz, 1 H), 2.60 (br s, 2 H), 2.65
(dd, J = 13.2, 4.3 Hz, 1 H), 2.83 (m, 1 H), 3.60–3.75 (m, 2 H), 3.88
(ddd, J = 8.6, 8.6, 4.3 Hz, 1 H), 4.36 (d, J = 2.7 Hz, 1 H), 4.50 (dd,
J = 11.5, 1.5 Hz, 1 H), 4.97 (d, J = 1.7 Hz, 1 H), 5.02 (s, 1 H), 5.27
(d, J = 1.7 Hz, 1 H), 5.94 (s, 1 H), 6.00 (d, J = 11.4 Hz, 1 H), 6.37
(d, J = 11.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 12.2, 14.9, 16.9, 18.4, 22.3, 22.8,
23.5, 26.4, 27.7, 29.0, 30.1, 32.6, 39.8, 40.6, 44.3, 46.0, 49.0, 56.3,
56.9, 62.6, 70.2, 73.5, 79.5, 113.5, 113.7, 117.2, 124.4, 133.1,
141.1, 142.4, 146.4, 169.8.
1H NMR (400 MHz, CDCl3): d = 0.56 (s, 3 H), 0.82–1.05 (m, 4 H),
0.97 (d, J = 6.4 Hz, 3 H), 1.15 (m, 1 H), 1.20–1.35 (m, 3 H), 1.40–
2.06 (m, 12 H), 2.23 (dd, J = 13.2, 8.7 Hz, 1 H), 2.67 (dd, J = 13.2,
4.5 Hz, 1 H), 2.81 (br s, 3 H), 2.84 (m, 1 H), 3.37 (dd, J = 7.5, 2.9
Hz, 1 H), 3.73–3.92 (m, 4 H), 4.06 (ddd, J = 8.7, 7.5, 4.5 Hz, 1 H),
4.45 (d, J = 2.9 Hz, 1 H), 4.51 (br d, J = 10.7 Hz, 1 H), 5.02 (s, 1
H), 5.08 (s, 1 H), 5.38 (s, 1 H), 5.94 (s, 1 H), 6.01 (d, J = 11.2 Hz, 1
H), 6.40 (d, J = 11.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 12.2, 14.9, 16.9, 18.4, 22.2, 23.5,
26.5, 27.6, 29.0, 31.9, 32.6, 39.8, 40.5, 41.0, 46.0, 56.3, 57.0, 61.0,
68.3, 68.4, 71.8, 79.5, 84.4, 113.7, 116.1, 117.3, 125.2, 131.8,
141.1, 142.8, 144.2, 169.8.
EI-LRMS: m/z = 526 (M+), 508, 490, 464, 432, 265, 171.
EI-HRMS: m/z calcd for C32H46O6: 526.3294; found: 526.3291.
Vitamin D Receptor (VDR) Binding Assay
[26,27-Methyl-3H]-1a,25-dihydroxyvitamin D3 (specific activity
6.623 TBq/mmol, 15,000 dpm, 15.7 pg) and various amounts of
1a,25-dihydroxyvitamin D3 and the analogue to be tested were dis-
solved in absolute EtOH (50 mL) in 12 × 75-mm polypropylene
tubes. The chick intestinal VDR (0.2 mg) and gelatin (1 mg) in aq
phosphate buffer solution (1 mL; 25 nM KH2PO4, 0.1 M KCl, and
1 mM dithiothreitol, pH 7.4) were added to each tube in an ice bath.
The assay tubes were incubated in a shaking water bath for 1 h at
25 °C and then chilled in an ice bath. Polypropylene glycol 6000
EI-LRMS: m/z = 510 (M+), 492, 474, 415, 327, 309.
EI-HRMS: m/z calcd for C32H46O5: 510.3345; found: 510.3344.
Synthesis 2005, No. 15, 2533–2543 © Thieme Stuttgart · New York