Carbon-Hydrogen Insertion Reactions of Steroidal Diazoacetates
J . Org. Chem., Vol. 66, No. 24, 2001 8117
3.5 Hz, 1H), 1.69-1.44 (comp, 4H), 1.40-1.20 (comp, 8H),
1.18-0.80 (comp, 11H), 0.90 (d, J ) 6.5 Hz, 3H), 0.87 (d, J )
6.6 Hz, 3H), 0.86 (d, J ) 6.6 Hz, 3H), 0.85 (s, 3H), 0.65 (s,
3H), 0.63 (ddd, J ) 12.3, 10.7, 4.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 168.5, 79.3, 56.4, 56.2, 54.1, 47.6, 44.6, 42.6, 39.9,
39.5, 38.4, 36.3, 36.1, 35.8, 35.4, 35.3, 32.0, 31.9, 28.5, 28.2,
28.0, 24.2, 23.8, 22.8, 22.5, 21.3, 18.6, 12.1, 11.8; IR (film) 1836
(CdO) cm-1; HRMS (FAB+) calcd for C29H49O2 429.3733, found
429.3731 (M+1).
4-(3â-Hyd r oxy-5R-ch olesta n -4R-yl)a cetic a cid la cton e
(15a ): mp 117-119 °C; [R]30D ) +0.8 (c 0.57, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 3.77 (ddd, J ) 11.8, 10.2, 4.2 Hz, 1H),
2.43 (dd, J ) 15.6, 6.0 Hz, 1H, lactone R-Heq), 2.09 (t, J ) 15.6
Hz, 1H, lactone R-Hax), 2.22-1.37 (comp, 10H), 1.36-1.20
(comp, 8H), 1.25 (s, 3H), 1.19-0.92 (comp, 9H), 0.91-0.80
(comp, 2H), 0.89 (d, J ) 5.6 Hz, 3H), 0.87 (d, J ) 6.6 Hz, 3H),
0.86 (d, J ) 6.6 Hz, 3H), 0.71 (dt, J ) 11.0, 4.2 Hz, 1H), 0.66
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.0, 85.9, 56.4, 56.2,
54.2, 49.0, 43.9, 42.5, 39.8, 39.5, 36.4, 36.1, 35.8, 35.1, 34.5,
31.5, 29.7, 28.2, 28.0, 26.2, 25.4, 24.2, 23.8, 22.8, 22.6, 21.2,
18.6, 13.5, 12.1; IR (film) 1789 (CdO) cm-1; HRMS (FAB+)
calcd for C29H49O2 429.3733, found 429.3731 (M+1).
5R-An d r osta n -17-on e-3â-yl d ia zoa ceta te (12b) was pre-
pared as described for 12a . To a stirred solution of 5R-
androstan-17-on-3â-ol (3.00 g, 10.3 mmol) and triethylamine
(15.7 mg, 0.155 mmol) in dry THF (50 mL) at 0 °C was added
diketene (1.30 mg, 15.5 mmol). Triethylamine (1.57 mL, 15.5
mmol) and methanesulfonyl azide (1.88 g, 15.5 mmol) were
added. Flash column chromatography on silica gel (25% ethyl
acetate in hexanes) afforded the diazoacetoacetate in 88%
overall yield (3.62 g, 9.03 mmol) as a yellow oil. 5R-An -
d r ost a n -17-on -3â-yl d ia zoa cet oa cet a t e: 1H NMR (300
MHz, CDCl3) δ 4.89-4.77 (m, 1H), 2.46 (s, 3H), 2.42 (dd, J )
18.9, 9.0 Hz, 1H), 2.05 (dd, J ) 19.0, 9.0 Hz, 1H), 2.00-0.95
(comp, 19H), 0.88 (s, 3H), 0.86 (s, 3H), 0.75 (dt, J ) 11.7, 3.6
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 220.4, 189.7, 160.5, 76.0,
74.6, 53.8, 50.9, 47.3, 44.3, 36.2, 35.4, 35.2, 34.6, 33.7, 31.1,
30.4, 27.9, 27.2, 21.4, 20.1, 13.4, 11.9.
procedure, the Rh2(4S-MEAZ)4-catalyzed reaction of diazoac-
etate 12b afforded 35 mg of 13b and 15b (5:95 ratio respec-
tively, 38% yield) and 26 mg of 14b (38% yield). The Rh2(4S-
MEOX)4-catalyzed reaction of diazoacetate 12b afforded 18 mg
of 13b and 15b (13:87 ratio respectively, 20% yield) and 42
mg of 14b (46% yield).
2-(3â-Hydr oxy-5R-an dr ostan -17-on -2R-yl)acetic acid lac-
ton e (13b): mp 208-210 °C; [R]29 ) +86.8 (c 1.74, CHCl3);
D
1H NMR (300 MHz, CDCl3) δ 3.79 (dt, J ) 10.9, 3.9 Hz, 1H),
2.47 (dd, J ) 14.7, 4.6 Hz, 1H, lactone R-Heq), 2.42 (d, J ) 9.4
Hz, 1H), 2.18 (t, J ) 14.7 Hz, 1H, lactone R-Hax), 2.25-1.76
(comp, 7H), 1.72-1.15 (comp, 11H), 1.01 (t, J ) 12.2 Hz, 1H),
0.94 (s, 3H), 0.87 (s, 3H), 0.90-0.75 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 220.9, 176.6, 85.3, 54.4, 51.2, 47.7, 45.7, 40.4,
40.1, 38.0, 36.1, 35.8, 34.9, 32.7, 31.4, 30.8, 28.2, 21.7, 20.6,
14.1, 13.8; IR (film) 1777 (CdO), 1732 (CdO) cm-1; HRMS
(FAB+) calcd for C21H31O3 331.2273, found 331.2278 (M+1).
3-(3â-Hydr oxy-5R-an dr ostan -17-on -3R-yl)acetic acid lac-
ton e (14b): mp 145-147 °C; [R]30 ) +72.4 (c 1.59, CHCl3);
D
1H NMR (300 MHz, CDCl3) δ 3.08 (s, 2H, lactone R-H), 2.46
(dd, J ) 19.2, 8.9 Hz, 1H), 2.16-1.72 (comp, 7H), 1.71-1.43
(comp, 4H), 1.42-1.18 (comp, 5H), 0.89 (s, 3H), 0.87 (s, 3H),
1.17-0.79 (comp, 4H), 0.72 (dt, J ) 12.0, 8.1 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 221.0, 168.3, 79.0, 54.1, 51.3, 47.7, 47.6,
44.6, 38.3, 36.2, 35.6, 34.9, 31.9, 31.4, 30.7, 29.7, 28.2, 21.8,
20.5, 13.8, 11.8; IR (film) 1824 (CdO), 1738 (CdO) cm-1
;
HRMS (FAB+) calcd for C21H31O3 331.2273, found 331.2277
(M+1).
4-(3â-Hydr oxy-5R-an dr ostan -17-on -4R-yl)acetic acid lac-
ton e (15b): mp 136-138 °C; [R]30 ) +31.3 (c 0.98, CHCl3);
D
1H NMR (300 MHz, CDCl3) δ 3.79 (ddd, J ) 11.8, 10.2, 4.2
Hz, 1H), 2.47 (dd, J ) 16.0, 6.5 Hz, 1H, lactone R-Heq), 2.53-
2.44 (comp, 1H), 2.16 (t, J ) 15.8 Hz, 1H, lactone R-Hax), 2.17-
0.90 (comp, 19H), 0.93 (s, 3H), 0.87 (s, 3H), 0.81 (dt, J ) 12.0,
4.2, 1H); 13C NMR (75 MHz, CDCl3) δ 220.9, 176.7, 85.7, 54.2,
51.3, 48.9, 47.7, 43.8, 37.4, 36.3, 35.7, 34.6, 34.4, 31.4, 30.3,
26.2, 25.1, 21.7, 20.5, 13.8, 13.6; IR (film) 1786 (CdO), 1734
(CdO) cm-1; HRMS (FAB+) calcd for C21H31O3 331.2273, found
331.2269 (M+1).
Acetyl cleavage of 5R-androstan-17-on-3â-diazoacetoacetate
was performed as previously described by the addition of LiOH
monohydrate (0.566 g, 13.5 mmol) to a biphasic solution of the
diazoacetoacetate (3.60 g, 8.99 mmol) in THF (30 mL) and
distilled water (30 mL). Flash column chromatography on
silica gel (25% ethyl acetate in hexanes) afforded 5R-androstan-
17-on-3â-yl diazoacetate (12b) in 77% yield (2.51 g, 6.97 mmol)
as a pale yellow solid: mp 163-165 °C; [R]34D ) +16.6 (c 2.53,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.82-4.70 (m, 1H), 4.69
(bs, 1H), 2.42 (dd, J ) 19.2, 9.0 Hz, 1H), 2.03 (dd, J ) 19.2,
9.0 Hz, 1H), 1.97-1.12 (comp, 17H), 1.05-0.89 (comp, 2H),
0.84 (s, 6H), 0.75 (dt, J ) 11.4, 4.2 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 221.2, 166.4, 74.1, 54.2, 51.3, 47.7, 46.2, 44.6, 36.6,
35.8, 35.6, 35.0, 34.1, 31.5, 30.7, 28.2, 27.6, 21.7, 20.4, 13.8,
5R-Ch olesta n -6-on -3â-yl Dia zoa ceta te (16). To a stirred
solution of 5R-cholestan-6-on-3â-ol (1.00 g, 2.48 mmol) and
triethylamine (2.5 mg, 0.25 mmol) in dry THF (10 mL) at 0
°C was added diketene (0.313 g, 3.72 mmol). Triethylamine
(0.377 g, 3.72 mmol) and methanesulfonyl azide (0.451 g, 3.72
mmol) were added. Flash column chromatography on silica gel
(25% ethyl acetate in hexanes) afforded diazoacetoacetate in
59% overall yield (0.755 g, 1.47 mmol) as a yellow solid. 5R-
Ch olesta n -6-on -3â-yl d ia zoa ceta toa ceta te: 1H NMR (300
MHz, CDCl3) δ 4.89-4.76 (m, 1H), 2.47 (s, 3H), 2.39-2.25
(comp, 2H), 2.10-0.96 (comp, 27H), 0.91 (d, J ) 6.3 Hz, 3H),
0.87 (d, J ) 6.6 Hz, 3H), 0.86 (d, J ) 6.6 Hz, 3H), 0.79 (s, 3H),
0.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 209.9, 189.8, 160.6,
74.2, 56.4, 56.1, 55.8, 53.4, 46.3, 42.7, 42.6, 40.6, 39.2, 39.1,
37.6, 36.0, 35.8, 35.4, 28.0, 27.8, 27.7, 26.8, 26.1, 23.7, 23.5,
22.6, 22.3, 21.2, 18.4, 12.8, 11.7.
12.2; IR (film) 2142 (CdN2), 1720 (CdO), 1657 (CdO) cm-1
.
Anal. Calcd for C21H30N2O3: C, 70.36; H, 8.44; N, 7.81.
Found: C, 70.48; H, 8.55; N, 7.61.
Dia zo Decom p osition of 5R-An d r osta n -17-on -3â-yl Dia -
zoa ceta te. To a stirred solution of Rh2(5R-MEPY)4 (2.4 mg,
0.0028 mmol) in dry CH2Cl2 (5 mL) heated at reflux under a
nitrogen atmosphere was added diazoacetate 12b (100 mg,
0.278 mmol) in dry CH2Cl2 (3 mL) over 5 h via syringe pump.
The reaction mixture was heated at reflux for an additional
0.5 h to complete the reaction. After being cooled to room
temperature, the reaction mixture was filtered through a short
silica plug, which was subsequently washed with 10 mL of 30%
ethyl acetate in hexanes. The solvent was removed under
reduced pressure to afford 84 mg of product (91% yield)
consisting of γ-lactone 13b [2-(3â-hydroxy-5R-androstan-17-
on-2R-yl)acetic acid lactone], â-lactone 14b [3-(3â-hydroxy-5R-
androstan-17-on-3R-yl)acetic acid lactone], and γ-lactone 15b
[4-(3â-hydroxy-5R-androstan-17-on-4R-yl)acetic acid lactone].
The relative ratio of products in the crude reaction mixture
was determined by 1H NMR spectroscopy. Column chroma-
tography on silica gel (2% ethyl acetate in CH2Cl2) afforded
56 mg of a mixture of 13b and 15b (95:5 ratio respectively,
61% yield) and 14 mg of 14b (15% yield). Using the same
Acetyl cleavage of 5R-cholestan-6-on-3â-yl diazoacetoacetate
was performed as previously described by the addition of LiOH
monohydrate (0.141 g, 2.93 mmol) to a biphasic solution of the
diazoacetoacetate (0.752 g, 1.47 mmol) in THF (8 mL) and
distilled water (8 mL). Flash column chromatography on silica
gel, (25% ethyl acetate in hexanes) afforded 5R-cholestan-6-
on-3â-yl diazoacetate (16) in 80% yield (0.546 g, 1.17 mmol)
as a pale crystalline yellow solid: mp 166-168 °C; [R]25D ) -4.6
1
(c 0.34, CHCl3); H NMR (300 MHz, CDCl3) δ 4.83-4.66 (m,
1H), 4.71 (bs, 1H), 2.38-2.22 (comp, 2H), 2.10-0.96 (comp,
27H), 0.91 (d, J ) 6.3 Hz, 3H), 0.87 (d, J ) 6.6 Hz, 3H), 0.86
(d, J ) 6.6 Hz, 3H), 0.77 (s, 3H), 0.66 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 210.3, 166.3, 73.4, 56.6, 56.4, 56.0, 53.7, 46.6,
46.3, 42.9, 40.9, 39.4, 39.5, 37.9, 36.3, 36.0, 35.6, 28.0, 27.9,
27.0, 26.3, 23.9, 23.7, 22.8, 22.5, 21.4, 18.6, 13.0, 11.9; IR (film)
2109 (CdN2), 1709 (CdO), 1689 (CdO) cm-1. Anal. Calcd for
C
29H46N2O3: C, 74.00; H, 9.85; N, 5.95. Found: C, 73.80; H,
9.83; N, 5.69.
Dia zo Decom p osition of 5R-Ch olesta n -6-on -3â-yl Dia -
zoa ceta te (16). To a stirred solution of Rh2(5R-MEPY)4 (0.9