Belani and Rychnovsky
56.0, 45.2, 39.3, 37.2, 35.9, 34.5, 33.7, 29.1, 28.2, 27.0, 23.9, 22.9,
22.7, 18.9, 16.3 IR (film in CDCl3) 2929, 1742, 1463, 1383, 1158
cm-1; HRMS (ESI) m/z calcd for C18H30ONa (M + Na)+ 285.2194,
found 285.2191.
reductive alkylation of enone 12 (Scheme 6). Further elaboration
and modification of ring A provided deutero-ent-cholesterol in
good yields.
Sulfone (14). Enone 1 (1.6 g, 6.15 mmol, 1.0 equiv) was
dissolved in a premixed solution of HOAc (20 mL) and TMEDA
(60 mL), and sodium benzenesulfinic acid (recrystallized from
EtOH, 1.32 g, 8.39 mmol, 1.36 equiv) and paraformaldehyde (0.36
g, 12 mmol, 1.95 equiv) were added. The reaction mixture was
heated to 60 °C for 5 h under inert atmosphere. The reaction was
quenched with H2O (10 mL), and EtOAc (75 mL) was added. The
mixture was then washed with H2O (250 mL), aqueous HCl (10%,
50 mL) and brine (50 mL). The organic layer was dried,
concentrated and passed through a 1-in. silica plug to provide 2.7
g of crude oil. Flash chromatography with 10% EtOAc-hexanes
provided 1.7 g (66%) of desired sulfone 14 as a colorless oil. The
reaction can also be carried out at lower temperature (35 °C);
however reaction times are usually longer (∼36 h) and yields are
very similar. Sulfone 14: [R]24D -67.5, (c ) 2.3, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 7.86 (2 H, d, J ) 7.2 Hz), 7.62 (1 H, t, J )
7.6 Hz), 7.52 (2 H, t, J ) 8 Hz), 4.26 (1 H, d, J ) 13.6 Hz), 4.02
(1 H, d, J ) 13.6 Hz), 2.82 (1 H, dd, J ) 10.1, 20.4 Hz), 2.66 (1
H, m), 2.35 (1 H, m), 2.20 (1 H, m), 2.05 (1 H, m), 1.77 (1 H, td,
J ) 5, 13.9 Hz), 1.40-1.65 (3 H, m), 1.25-1.50 (5 H, m), 1.10-
1.22 (4 H, m), 1.09 (3 H, s), 0.96 (3 H, d, J ) 6.6 Hz), 0.868 (3
H, d, J ) 6.6 Hz), 0.863 (3 H, d, J ) 6.6 Hz); 13C NMR (100
MHz, CDCl3) δ 195.3, 182.5, 139.1, 133.8, 129.0, 128.8, 120.3,
56.0, 53.1, 46.5, 39.6, 36.3, 35.9, 34.2, 32.9, 29.0, 28.2, 27.3, 23.9,
22.9, 22.85, 22.74, 19.0, 16.5, 14.3; IR (film in CDCl3) 2929, 1742,
1463, 1383, 1158 cm-1 HRMS (ESI) m/z calcd for C25H36O3SNa
(M + Na)+ 439.2282, found 439.2289.
trans-Hydrindane (15). Sulfone 14 (0.85 g, 2 mmol) was
dissolved in a mixture of MeOH (14 mL), acetic acid (4 mL), and
aqueous HCl (1 N, 0.2 mL). The 10% Pd/C catalyst (0.80 g) was
added, and the mixture was cooled and stirred at 0 °C under an
atmosphere of hydrogen for 12 h. The mixture was filtered through
Celite to give 0.85 g of crude mixture of two epimers at the ring
junction is a ratio of 8:1 in favor of trans. The ratio of the two
isomers can be easily obtained from GC analysis (column RTX-
1701), cis isomer (16.72 min) and trans isomer (17.44 min).
Recrystallization of the crude mixture provided 0.53 g (62%) of
the desired trans isomer, and this process provided a 1:1 mixture
of isomers in the mother liquor along with variable amounts of
ketone 16. The mother liquor was concentrated and purified by
chromatography to remove ketone 16. The partially purified mixture
was loaded as a solution in 50% IPA-hexanes on a preparative
HPLC system (column 300 × 50 mm, KromaSpher 80, 5 µM silica
column; solvent system 0.5% IPA-hexanes; retention times trans
37.64 min; cis 38.77 min; flow rate 40 mL/min at 41 bar) to provide
77 mg (9%) of desired trans isomer and 93 mg of cis epimer
Conclusion
The total synthesis of ent-cholesterol using C-H insertion
as the key step was achieved in 16 steps with an overall yield
of 2.0%. The route uses commercially available (S)-citronellol
and a diastereoselective C-H insertion reaction to provide the
D-ring synthon with the ent-cholesterol side chain already
attached. Two crystalline intermediates (the CH insertion product
2 and the hydrogenated CD-ring sulfone 15) facilitate purifica-
tion and separation of minor diastereomers. While the reductive
alkylation step must be run at moderate dilution (and thus on a
limited scale), this step occurs near the end of the synthesis
and does not present a practical limitation for material through-
put. Isotopic labels may be introduced late in the synthesis using
labeled methyl iodide, a practical and inexpensive source of
isotopic atoms. This synthetic pathway has a potential to supply
gram quantities of ent-cholesterol for biological studies.
Experimental Section
â-Ketoester (2). To a stirred solution of diazo-â-ketoester 3 (64
g, 0.22 mol) in dry CH2Cl2 (800 mL) cooled in an ice bath was
added Rh2 (R)-(PTV)4 (1.5 g, 0.45 mol%) at 10 °C. Immediate
evolution of N2 gas was observed. Temperature was not allowed
to rise above room temperature. Reaction mixture was stirred until
evolution of the gas ceased (∼2-3 h). Solvent was removed under
vacuum, and the crude material was loaded on a silica plug (∼500
mL) and eluted with 20% ether-hexanes mixture (6 × 1000 mL)
to afford 56.2 g of crude yellow oil that was seeded with 99% ee
crystals to afford 17 g (30%) of the desired diastereomerically pure
CH insertion product 2. Physical and spectroscopic data were
consistent with literature data:8 mp ) 54-55 °C; H NMR (500
1
MHz, CDCl3) δ 5.07 (1H, m), 3.74 (3H, s), 2.96 (1H, d, J ) 11.4
Hz), 2.56 (1H, m), 2.45-2.30 (2H, m), 2.17 (1H, m), 2.05 (1H,
m), 1.92 (1H, m), 1.69 (3H, s), 1.61 (3H, s), 1.59-1.40 (3H, m),
1.15 (1H, m), 0.87 (3H, d, J ) 7.3 Hz); 13C NMR (125 MHz,
CDCl3) δ 212.5, 170.9, 131.9, 124.4, 59.8, 52.6, 47.0, 38.8, 37.0,
34.0, 25.9, 25.5, 25.4, 17.8, 17.1; IR (film in CDCl3) 2956, 1755,
1726, 1435 cm-1 HRMS (ESI) m/z calcd for C15H24O3Na (M +
Na)+ 275.1623, found 275.1623.
Enantiopure CD-Enone (1). To a solution of NaOMe (freshly
prepared from 30 mL MeOH and 0.6 g of Na) was added a solution
of ketone 8 (3.6 g, 17.1 mmol) in MeOH (10 mL) at 0 °C. After
stirring for 5 min at 0 °C, methyl vinyl ketone (5 mL, 61.7 mmol)
was added, and the yellow mixture was stirred at 23 °C for 6 h.
The reaction was quenched with saturated aqueous NH4Cl (20 mL)
and was concentrated. The crude oil was extracted with EtOAc
(3 × 25 mL), concentrated, and then passed through a silica plug
using a mixture of EtOAc, hexanes, and MeOH (10:89:1) to afford
a yellow oil (3.7 g) that was dissolved in toluene (100 mL).
p-Toluenesulfonic acid (250 mg, 1.4 mmol) was added, and the
mixture was heated at reflux temperature for 3 h in a flask attached
to Dean-Stark trap and condenser. The reaction mixture was
washed with saturated NaHCO3, concentrated, and chromatographed
with 10% EtOAc-hexanes to provide 2.45 g (55% over two steps)
of the CD enone 1 as a yellow oil. Physical and spectroscopic data
(10.9%). The combined yield for the trans hydrindane system was
1
71%. trans Isomer: ([R]24 -15.6, c ) 1.45, CHCl3); H NMR
D
(500 MHz, CDCl3) δ 7.90 (2 H, m), 7.62 (1 H, tt, J ) 7.2, 2 Hz),
7.55 (2 H, m), 4.0 (1 H, dd, J ) 6.5, 14.5 Hz), 3.03 (1 H, ddd, J
) 2, 6.5, 11 Hz), 2.87 (1 H, dd, J ) 2.5, 14 Hz), 2.50 (1 H, td, J
) 6.5, 14.5 Hz), 2.30 (1 H, ddd, J ) 14.9, 4.9, 2.0 Hz), 2.17 (1 H,
ddd, J ) 1, 4.5, 11 Hz), 1.94 (1 H, m), 1.65 (2 H, m), 1.30-1.55
(7 H, m), 1.20-1.10 (4 H, m), 1.04 (3 H, s), 0.95 (1 H, m), 0.90
(3 H, J ) 7 Hz), 0.865 (3 H, d, J ) 6.6 Hz), 0.860 (3 H, d, J ) 6.6
Hz); 13C NMR (100 MHz, CDCl3) δ 208.0, 140.1, 133.8, 129.3
(2C), 128.2 (2C), 55.7, 55.1, 53.0, 45.9, 43.5, 39.6, 38.5, 37.5, 35.9,
35.7, 28.8, 25.0, 23.9, 23.0 (2C), 22.7, 18.7, 11.5; IR (film in CDCl3)
2929, 1742, 1463, 1383, 1158 cm-1; HRMS (ESI) m/z calcd for
were consistent with literature data:3 [R]24 -64.3, (c ) 1.0,
D
1
CHCl3); H NMR (500 MHz, CDCl3) δ 5.72 (1 H, s), 2.61 (1 H,
C25H38O3SNa (M + Na)+ 441.2439, found 441.2430. cis Isomer:
1
dd, J ) 10.9, 19.7 Hz), 2.51 (1 H, m), 2.40 (1 H, m), 2.34-2.20
(2 H, m), 2.0 (1 H, m), 1.80 (1 H, td, J ) 4.9, 13.8, 18.6 Hz), 1.53
(3 H, m), 1.30-1.45 (3 H, m), 1.10-1.25 (4 H, m), 1.08 (3 H, s),
0.97 (3 H, d, J ) 6.6 Hz), 0.862 (3 H, d, J ) 6.6 Hz), 0.858 (3 H,
d, J ) 6.6 Hz); 13C NMR (100 MHz, CDCl3) δ 199.5, 180.3, 121.6,
([R]24 +82.6, c ) 0.52, CHCl3); H NMR (500 MHz, CDCl3) δ
D
7.90 (2 H, m), 7.62 (1 H, tt, J ) 7.5, 2 Hz), 7.55 (2 H, m), 4.0 (1
H, dd, J ) 7.4, 14 Hz), 2.98 (1 H, ddd, J ) 1.5, 7.5, 10 Hz), 2.32
(2 H, m), 2.05 (1 H, m), 2.0-1.87 (3 H, m), 1.53-1.26 (9 H, m),
1.17-1.038 (4 H, m), 0.93 (1 H, m), 0.88 (3 H, J ) 6.5 Hz), 0.87
2772 J. Org. Chem., Vol. 73, No. 7, 2008