1R,25-Dihydroxyvitamin D3 A-Ring Precursors
J . Org. Chem., Vol. 64, No. 20, 1999 7509
En zym a tic Alk oxyca r bon yla tion of Diol 3c w ith Ace-
t on e O-[(Vin yloxy)ca r b on yl]oxim e (4). Syn t h esis of
(3S,5S)-1-Eth yn yl-3-h yd r oxy-2-m eth yl-5-[(vin yloxy)ca r -
bon yloxy]-1-cycloh exen e (7). The procedure as described for
3b gave, after flash chromatography (silica gel, with gradient
eluent 15-50% EtOAc/hexane), C-5 monovinyloxycarbonyla-
tion product 7 (major or unique product, yields ranged from
87% to 97%), C-5 oximecarbonate 8, and C-3,5 divinyloxycar-
bonylation product 9, depending on conditions. All of these
data are summarized in Table 2. Data for 7: 1H NMR (CDCl3,
400 MHz) δ 1.65 (br s, 1H, OH), 2.06 (s, 3H, H9), 2.09 (ddd,
2.16 (s, 3H, H9), 2.43 (m, 2H, H4eq + H6ax), 2.66 (m, 1H, H6eq),
3
3.68 (s, 1H, H8), 4.37 (apparent t, 1H, H3, J HH ) 6.5 Hz), and
4.97 (m, 1H, H5); 13C NMR (MeOH-d4, 50.3 MHz) δ 18.3 (C9),
37.0 (C6), 38.4 (C4), 68.9 (C5), 69.4 (C3), 82.4 (C8), 84.1 (C7),
114.4 (C1), 145.5 (C2), and 159.5 (C10).
(3R,5R)-5-(Car bam oyloxy)-1-eth yn yl-3-h ydr oxy-2-m eth -
yl-1-cycloh exen e (17a ): same data as for its enantiomer,
compound 16a .
Hyd r a zin olysis Rea ction of Ca r bon a tes 5, 7, a n d 10.
Syn th esis of A-Rin g Ca r ba za te Der iva tives 15b-17b. To
a solution of carbonate 5 (or 7 or 10) (20 mg, 0.091 mmol) in
THF (0.5 mL) was added hydrazine (14.2 µL, 0.453 mmol). The
solution was stirred under nitrogen atmosphere at room
temperature until no starting material remained (3.5 h). Then,
solvent was evaporated under reduced pressure. The residue
was substantially pure without purification steps (yields
ranged from 94% to 97%).
2
3
3
1H, H4eq, J HH ) 14.2, J HH ) 5.7, J HH ) 2.4 Hz), 2.22 (ddd,
1H, H4ax, 2J HH ) 14.2, 3J HH ) 6.5, 3J HH ) 4.2 Hz), 2.52 (m, 2H,
H6), 3.12 (s, 1H, H8), 4.11 (br s, 1H, H3), 4.59 (dd, 1H, H12-cis,
2
3
3J HH ) 6.1, J HH ) 2.0 Hz), 4.91 (dd, 1H, H12-trans, J HH
)
,
2
13.8, J HH ) 2.0 Hz), 5.11 (m, 1H, H5), and 7.06 (dd, 1H, H11
3J HH ) 13.8, J HH ) 6.1 Hz); 13C NMR (CDCl3, 100.6 MHz) δ
18.6 (C9), 34.4 (C6), 34.8 (C4), 67.2 (C3), 72.1 (C5), 81.1 (C8),
82.5 (C7), 98.1 (C12), 112.1 (C1), 142.3 (C11), 143.5 (C2), and
151.5 (C10).
3
(3R,5S)-5-(Ca r ba zoyloxy)-1-eth yn yl-3-h yd r oxy-2-m eth -
yl-1-cycloh exen e (15b): 1H NMR (MeOH-d4, 200 MHz) δ
2
2.14 (m, 2H, H4), 2.17 (s, 3H, H9), 2.36 (dd, 1H, H6ax, J HH
)
)
3
2
3
(3S,5S)-1-Eth yn yl-3-h ydr oxy-2-m eth yl-5-[(aceton oxim e)-
ca r bon yloxy]-1-cycloh exen e (8): 1H NMR (CDCl3, 200
MHz) δ 1.98 (s, 3H, H12), 1.99 (s, 3H, H12), 1.97-2.10 (m, 1H,
17.2, J HH ) 5.7 Hz), 2.77 (ddd, 1H, H6eq, J HH ) 17.2, J HH
4
3.2, J HH ) 1.6 Hz), 3.67 (s, 1H, H8), 4.38 (apparent t, 1H, H3,
3J HH ) 5.0 Hz), and 5.22 (m, 1H, H5); 13C NMR (MeOH-d4,
75.5 MHz) δ 18.9 (C9), 36.8 (C6), 37.9 (C4), 68.9 (C3), 69.2 (C5),
82.3 (C8), 84.1 (C7), 115.1 (C1), 144.5 (C2), and 160.4 (C10).
(3S,5S)-5-(Ca r ba zoyloxy)-1-eth yn yl-3-h yd r oxy-2-m eth -
yl-1-cycloh exen e (16b): 1H NMR (MeOH-d4, 400 MHz) δ
2
3
H4), 2.05 (br s, 3H, H9), 2.24 (dddd, 1H, H4, J HH ) 14.4, J HH
3
4
) 5.9, J HH ) 3.6, J HH ) 1.0 Hz), 2.41-2.67 (m, 2H, H6), 2.70
(br s, 1H, OH), 3.11 (s, 1H, H8), 4.06 (m, 1H, H3), and 5.20 (m,
1H, H5); 13C NMR (CDCl3, 75.5 MHz) δ 16.8 (C12), 18.8 (C9),
21.7 (C12), 34.3 and 34.5 (C4 and C6), 67.0 (C3), 72.0 (C5), 80.9
(C8), 82.7 (C7), 111.8 (C1), 143.6 (C2), 152.7 (C10), and 163.5
(C11).
1.98 (m, 2H, H4ax), 2.17 (s, 3H, H9), 2.37-2.53 (m, 2H, H4eq
+
2
H
6ax), 2.67 (d, 1H, H6eq, J HH ) 17.0 Hz), 3.67 (s, 1H, H8), 4.37
(apparent t, 1H, H3, J HH ) 6.4 Hz), and 5.08 (m, 1H, H5); 13
C
3
En zym a tic Alk oxyca r bon yla tion of Diol 3d w ith Ace-
t on e O-[(Vin yloxy)ca r b on yl]oxim e (4). Syn t h esis of
(3R,5R)-1-Eth yn yl-3-h yd r oxy-2-m eth yl-5-[(vin yloxy)ca r -
bon yloxy]-1-cycloh exen e (10). The procedure as described
for 3c gave C-5 monovinyloxycarbonylation product 10 and/
or C-5 oximecarbonate 11 and/or C-3 monovinyloxycarbony-
lation product 12 and/or C-3,5 divinyloxycarbonylation product
13, depending on conditions. All of these data are summarized
in Table 3. Data for 10: same as for its enantiomer, com-
pound 7.
(3R,5R)-1-Eth yn yl-3-h ydr oxy-2-m eth yl-5-[(aceton oxim e)-
ca r bon yloxy]-1-cycloh exen e (11): same data as for its
enantiomer, compound 8.
(3R,5R)-1-Eth yn yl-2-m eth yl-3,5-bis[(vin yloxy)car bon yl-
oxy]-1-cycloh exen e (13): 1H NMR (CDCl3, 200 MHz) δ 1.97
(s, 3H, H9), 2.29 (m, 2H, H4), 2.56 (m, 2H, H6), 3.19 (s, 1H,
NMR (MeOH-d4, 75.5 MHz) δ 18.3 (C9), 37.0 (C6), 38.4 (C4),
69.3 (C3), 69.5 (C5), 82.4 (C8), 84.1 (C7), 114.4 (C1), 145.5 (C2),
and 160.3 (C10).
(3R,5R)-5-(Ca r ba zoyloxy)-1-eth yn yl-3-h yd r oxy-2-m eth -
yl-1-cycloh exen e (17b): same data as for its enantiomer,
compound 16b.
Am in olysis Rea ction of Ca r bon a tes 5, 7, a n d 10 w ith
P r op a n -1,3-d ia m in e (14c). Syn th esis of A-Rin g N-(a m i-
n oa lk yl)ca r ba m a te Der iva tives 15c-17c. To a solution of
carbonate 5 (or 7 or 10) (20 mg, 0.091 mmol) in THF (5 mL)
was added propan-1,3-diamine (18.9 µL, 0.227 mmol). The
solution was stirred under nitrogen atmosphere at 60 °C until
no starting material remained (28 h). Then, solvent was
evaporated under reduced pressure, and the residue was
subjected to flash chromatography (silica gel, 1% NH3(aq)/
MeOH) (yields ranged from 93% to 95%).
3
2
H8), 4.59 (dd, 1H, H12-cis or H15-cis, J HH ) 6.2, J HH ) 2.1
(3R,5S)-5-[[N-(3-Am in op r op yl)ca r ba m oyl]oxy]-1-eth y-
3
2
Hz), 4.60 (dd, 1H, H12-cis or H15-cis, J HH ) 6.2, J HH ) 1.8
n yl-3-h yd r oxy-2-m eth yl-1-cycloh exen e (15c): 1H NMR
3
2
3
Hz), 4.92 (dd, 1H, H12-trans or H15-trans, J HH ) 13.9, J HH
)
(MeOH-d4, 400 MHz) δ 1.85 (p, 2H, H12, J HH ) 7.0 Hz), 2.12
2.1 Hz), 4.94 (dd, 1H, H12-trans or H15-trans, 3J HH ) 13.9, 2J HH
(m, 2H, H4), 2.17 (s, 3H, H9), 2.34 (dd, 1H, H6ax, J HH ) 17.1,
2
3
2
) 2.1 Hz), 4.97 (m, 1H, H5), 5.34 (t, 1H, H3, J HH ) 6.0 Hz),
3J HH ) 6.0 Hz), 2.75 (d, 1H, H6eq, J HH ) 17.1 Hz), 2.89 (t, 2H,
3
3
3
3
7.06 and 7.08 (2dd, 2H, H11 and H14, J HH ) 13.9, J HH ) 6.1
Hz); 13C NMR (CDCl3, 75.5 MHz) δ 17.9 (C9), 32.1 (C4), 34.5
(C6), 70.2 (C5), 73.8 (C3), 81.8 (C7), 82.3 (C8), 98.1 (C12 and C15),
115.8 (C1), 138.4 (C2), 142.4 and 142.5 (C11 and C14), 151.9 and
152.4 (C10 and C13).
H13, J HH ) 7.0 Hz), 3.35 (t, 2H, H11, J HH ) 6.6 Hz), 3.66 (s,
1H, H8), 4.38 (m, 1H, H3), and 5.18 (m, 1H, H5); 13C NMR
(MeOH-d4, 100.6 MHz) δ 18.9 (C9), 33.5 (C12), 36.9 (C6), 38.0
(C4), 39.2 (C11), 39.8 (C13), 68.7 (C5), 69.0 (C3), 82.2 (C8), 84.2
(C7), 115.2 (C1), 144.6 (C2), and 159.0 (C10).
Am m on olysis Rea ction of Ca r bon a tes 5, 7, a n d 10.
Syn th esis of A-Rin g Ca r ba m a te Der iva tives 15a-17a . To
a solution of carbonate 5 (or 7 or 10) (20 mg, 0.091 mmol) in
THF (15 mL) was bubbled ammonia during 30 min at 0 °C.
The solution was stirred at 30 °C until no starting material
remained (approximately 22 h). Then, solvent was evaporated
under reduced pressure. The residue was substantially pure
without purification steps (yields ranged from 95% to 98%).
(3R,5S)-5-(Car bam oyloxy)-1-eth yn yl-3-h ydr oxy-2-m eth -
yl-1-cycloh exen e (15a ): 1H NMR (MeOH-d4, 400 MHz) δ 2.13
(3S,5S)-5-[[N-(3-Am in op r op yl)ca r ba m oyl]oxy]-1-eth y-
n yl-3-h yd r oxy-2-m eth yl-1-cycloh exen e (16c): 1H NMR
3
(MeOH-d4, 200 MHz) δ 1.85 (p, 2H, H12, J HH ) 6.8 Hz), 1.95
(m, 1H, H4ax), 2.16 (s, 3H, H9), 2.41 (m, 1H, H4eq), 2.46 (m, 1H,
3
H
6ax), 2.65 (m, 1H, H6eq), 2.89 (t, 2H, H11, J HH ) 6.7 Hz), 3.36
3
(t, 2H, H13, J HH ) 6.7 Hz), 3.69 (s, 1H, H8), 4.37 (apparent t,
1H, H3, 3J HH ) 6.0 Hz), and 4.99 (m, 1H, H5); 13C NMR (MeOH-
d4, 100.6 MHz) δ 18.3 (C9), 33.4 (C12), 37.1 (C6), 38.5 (C4), 39.1
(C11), 39.7 (C13), 69.1 (C5), 69.4 (C3), 82.4 (C8), 84.1 (C7), 114.4
(C1), 145.5 (C2), and 158.8 (C10).
2
(m, 2H, H4), 2.17 (s, 3H, H9), 2.35 (dd, 1H, H6, J HH ) 17.0,
(3R,5R)-5-[[N-(3-Am in op r op yl)ca r ba m oyl]oxy]-1-eth y-
n yl-3-h yd r oxy-2-m eth yl-1-cycloh exen e (17c): same data
as for its enantiomer, compound 16c.
2
3J HH ) 6.5 Hz), 2.75 (d, 1H, H6, J HH ) 17.0 Hz), 3.67 (s, 1H,
3
H8), 4.39 (t, 1H, H3, J HH ) 4.7 Hz), and 5.16 (m, 1H, H5); 13
C
NMR (MeOH-d4, 100.6 MHz) δ 18.9 (C9), 36.8 (C6), 37.9 (C4),
68.5 (C5), 69.0 (C3), 82.3 (C8), 84.2 (C7), 115.3 (C1), 144.5 (C2),
and 159.7 (C10).
Am in olysis Rea ction of Ca r bon a tes 5, 7, a n d 10 w ith
Sp er m in e (14d ). Syn th esis of A-Rin g P olya m in o Ca r -
ba m a te Der iva tives 15d -17d . To a solution of carbonate 5
(or 7 or 10) (20 mg, 0.091 mmol) in THF (5 mL) was added
spermine (45.9 mg, 0.227 mmol). The solution was stirred
under nitrogen atmosphere at 40 °C until no starting material
(3S,5S)-5-(Car bam oyloxy)-1-eth yn yl-3-h ydr oxy-2-m eth -
yl-1-cycloh exen e (16a ): 1H NMR (MeOH-d4, 200 MHz) δ
2
3
3
1.95 (ddd, 1H, H4, J HH ) 12.7, J HH ) 9.7, J HH ) 7.5 Hz),