Organic Syntheses, CV 9, 564
Submitted by Yoshiaki Horiguchi, Eiichi Nakamura, and Isao Kuwajima
1.
Checked by Ronald W. Regenye, Miguel Pagan, and David L. Coffen.
1. Procedure
CAUTION:
Hexamethylphosphoramide (HMPA) has been identified as a carcinogen. Glove protection is required during the handling in Part A. In addition, the column chromatography in Part B using
chloroform as the eluent should be conducted in a
well-ventilated hood.
A.
(Z)-16α-Methyl-20-trimethylsiloxy-4,17(20)-pregnadien-3-one (2). (All transfers are conducted under dry
nitrogen; reagents are introduced into reaction vessels through rubber septa using a syringe.) An
oven-dried, 300-mL, two-necked, round-bottomed flask equipped with a
magnetic stirring bar,
nitrogen-vacuum inlet, and
rubber septum is charged with
6.25 g (20 mmol) of 16-dehydroprogesterone (1) and
0.20 g (1.0 mmol) of cuprous bromide-dimethyl sulfide complex (Note
1). After the apparatus is flushed with
nitrogen,
100 mL of tetrahydrofuran (THF) and
7.7 mL (44 mmol) of hexamethylphosphoramide are added (Note
1). The resulting clear solution, upon cooling to −78°C, becomes a white slurry to which
5.1 mL (40 mmol) of chlorotrimethylsilane is added dropwise (Note
1). To the resulting yellow solution is added
23.7 mL (22 mmol) of a 0.93 M solution of methylmagnesium bromide in THF (Note
2) over a 30-min period. The resulting yellow slurry is then stirred at

−55 to −60°C (Note
3) for 12 hr followed by addition of
5.6 mL (40 mmol) of triethylamine dropwise (Note
1). The reaction mixture is then poured into a vigorously stirred mixture of
50 mL of saturated aqueous sodium bicarbonate, 50 g of ice, and
200 mL of hexane. After stirring for 15 min, the mixture is transferred to a
1-L separatory funnel, and the organic phase is separated. The remaining aqueous phase is extracted three times with
50-mL portions of hexane. The combined organic phases are washed successively with 50 mL of water and
50 mL of brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure to give
6.84–8.67 g of crude
(Z)-16α-methyl-20-trimethylsiloxy-4,17(20)-pregnadien-3-one (2) as an amorphous white solid. Analysis of crude
2 by
1H NMR indicates a chemical purity of 90–95% and a geometrical ratio of >95% (Z) (Note
4).
B.
16α-Methylcortexolone (3). An
oven-dried, 1-L, three-necked, round-bottomed flask, equipped with a magnetic stirring bar, nitrogen-vacuum inlet,
200-mL addition funnel topped with a
nitrogen inlet, and a rubber septum, is charged with
7.20 g of the crude (Z)-16α-methyl-20-trimethylsiloxy-4,17(20)-pregnadien-3-one (2). The apparatus is flushed with
nitrogen and
200 mL of methylene chloride (CH
2Cl
2) is added (Note
1). Quickly under
nitrogen flow, the rubber septum is removed from the flask and
12.8 g (128 mmol) of finely powdered, dry potassium bicarbonate (Note
5) is added to the solution, and the flask is resealed with the rubber septum. The flask is then immersed in an ice bath. With vigorous stirring of the mixture,
100 mL of a 0.5 M solution (50 mmol) of m-chloroperoxybenzoic acid (MCPBA) in CH
2Cl
2 is added dropwise via the addition funnel over a 2.5-hr period followed by a few mL of CH
2Cl
2to rinse the addition funnel (Note
6). TLC is used to monitor the progress of the reaction (Note
7). After stirring the reaction mixture for an additional 10 min after the addition is complete, the addition funnel, nitrogen-vacuum inlet, and rubber septum are removed and
100 mL of aqueous 0.5 M sodium thiosulfate solution is added, vigorous stirring is maintained at room temperature for 30 min. The mixture is then transferred to a 1-L separatory funnel, and the organic phase is separated. The aqueous phase is extracted three times with 50 mL of CH
2Cl
2. The combined organic extracts are concentrated on a
rotary evaporator. The residue is dissolved in
100 mL of THF, and the solution is acidified to

pH 1 by addition of
10 mL of 1 N hydrochloric acid (HCl) to effect desilylation of the
21-trimethylsilyl ether of 16α-methylcortexolone (6) (Note
8). The homogeneous solution is allowed to stand at room temperature for 30 min and then most of the solvent is removed by rotary evaporation under reduced pressure. The residue is dissolved in 300 mL of CH
2Cl
2, transferred into a 1-L separatory funnel, and the solution washed with
50 mL of saturated aqueous sodium bicarbonate solution. After separation of the organic phase, the aqueous phase is extracted three times with 50-mL portions of CH
2Cl
2. The combined organic extracts are washed with
50 mL of brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure to give
6.0 g of a white solid. Chromatographic purification on
silica gel (300 g) with 30
40% ethyl acetate/chloroform eluent gives
2.92 g (
40.5%, 2 steps) of
16α-methylcortexolone (3) (Note
9).
2. Notes
3. The reaction temperature was controlled by an electric cooling system. A higher reaction temperature would cause undesired methylation of the A-ring enone.
4. Crude
2 is free from HMPA. The spectral properties of
2 were as follows: IR (neat) cm
−1: 1670, 1610, 1265, 1250, 1230;
1H NMR (200 MHz, CDCl
3) δ: 0.19 (s, 9 H), 0.90 (s, 3 H), 0.99 (d, 3 H, J = 7.1), 1.09–2.71 (m including two s at 1.19 and 1.79, 25 H), 5.73 (s (br), 1 H);
13C NMR (50 MHz, CDCl
3) δ: 1.07, 17.1, 17.3, 20.6, 21.3, 22.1, 32.1, 32.9, 33.5, 34.0, 34.2, 34.3, 35.6, 37.3, 38.7, 44.0, 52.1, 54.1, 123.6, 132.5, 139.9, 171.3, 199.2. The geometry was determined based on observed NOEs from 20-methyl to 16β-H and 16α-methyl.
5.
Potassium bicarbonate was purchased from Koso Chemical Co., Ltd., Japan. It was finely powdered and dried under reduced pressure (

0.1 mm) at ambient temperature over P
2O
5.
6.
m-Chloroperoxybenzoic acid (MCPBA) of 85% purity was purchased from Aldrich Chemical Company, Inc. and purified according to Schwartz's procedure
3 to remove any remaining
m-chlorobenzoic acid. Slow addition of MCPBA is required to avoid hydrolysis of the transient, intermediate epoxide
4 by rapid formation of free
m-chlorobenzoic acid.
7. Progress of the double hydroxylation reaction can be monitored by TLC analysis. The R
f values of the products with 30%
ethyl acetate/
hexanes as the eluent are as follows: 0.70 for
2, 0.59 for
5, 0.29 for
6, and 0.18 for
7. Additional MCPBA may be added until the intermediate hydroxy enol
silyl ether 5 has completely reacted.
8. Desilylation of
6 can be monitored by TLC analysis. The R
f values of
3 and
6 are 0.32 and 0.67, respectively, with 50%
ethyl acetate/
hexanes as the eluent.
9. A portion of this compound is recrystallized from 1:1
ethyl acetate/
hexanes to yield white plates with mp
194–197°C (Anal. Calcd for C
22H
32O
4: C, 73.30; H, 8.95. Found: C, 73.24; H, 8.98). The spectral properties were as follows: IR (CDCl
3) cm
−1: 3650–3100, 1705, 1660, 1615;
1H NMR (400 MHz, CDCl
3) δ: 0.79 (s, 3 H), 0.93 (d, 3 H, J = 7.3), 0.97–2.49 (m including s at 1.18), 2.62 (s, 1 H), 2.94–3.14 (m, 1 H), 3.20 (s (br), 1 H), 4.30 (dd, 1 H, J = 20, 4.8), 4.62 (dd, 1 H, J = 20, 4.8), 5.73 (s (br), 1 H);
13C NMR (100 MHz, CDCl
3) δ: 14.8, 15.2, 17.4, 20.5, 30.4, 32.0, 32.5, 32.8, 33.9, 35.6, 35.7, 36.8, 38.6, 49.7, 49.8, 53.3, 67.8, 90.5, 123.8, 170.8, 199.3, 212.4. The stereochemistry of the 16- and 17-positions were determined based on the observed NOEs from the 18-methyl (δ 0.79, s) to both 16β-H (δ 2.94–3.14, m) and 21-H (δ 4.63, dd). The submitters obtained an overall yield of 68%
Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The present procedure is an efficient two-step preparation of the
17-dihydroxyacetone side chain with a 16α-methyl substituent from the 16-dehydro-17-acetyl substructure.
4 The D-ring substructure of the product is of pharmaceutical importance as seen in synthetic corticoids such as betamethasone.
5 The two-step conversion consists of 1) conjugate addition of a methyl group into the 16-position and 2) a novel, double hydroxylation of the resultant enol silyl ether.
Although the
chlorotrimethylsilane-accelerated conjugate addition of the catalytic methylcopper reagent
6 proceeds at the sterically less congested D-ring enone in a highly chemoselective manner under the reaction conditions discussed in the procedure, a higher reaction temperature and/or use of excess
methylmagnesium bromide might cause undesired methylation of the A-ring enone.
Since Hassner's initial report in 1975,
7 oxidation of an enol silyl ether with peracid has been a reliable method for the preparation of α-siloxy and α-hydroxy ketones. However, the submitters have found that, if the enol silyl ether possesses certain structural features, the reaction, with more than two equivalents of the oxidant, affords α,α'-dihydroxylated ketones (i.e., introduction of two
oxygen atoms in a single-step) instead of the expected monohydroxylated compounds.
8

Mechanistic investigations carried out in some depth suggested an interesting reaction pathway (
path a, Scheme I), in which rearrangement of the intermediate epoxide
B to the hydroxy enol silyl ether
D (with loss of H
*) represents the crucial step. In the normal Hassner reaction (
path b), rearrangement of epoxide
B to the siloxy ketone
C proceeds through migration of the silyl group from the enol
oxygen to the epoxide
oxygen. The inertness of
C under the reaction conditions indicated that
path a and
path b are independent reactions. The hydroxy enol silyl ether
D has been shown to be the primary product of the reaction by its isolation upon use of only one equivalent of the oxidant, and its subsequent conversion to
E upon addition of another equivalent of the oxidant.
Scheme 1
The major by-product in the double hydroxylation reaction is the α-hydroxy ketone
F which forms presumably by protiodesilylation of the transient, intermediate epoxide
B. In order to exclude free
m-chlorobenzoic acid that might cause this side reaction, MCPBA is purified and added very slowly to the substrate in the presence of excess, finely powdered
potassium bicarbonate. In the case of the example presented above, the mechanism presumably is as follows:
Examples of the double hydroxylation reaction observed for several representative substrates illustrate the scope of this reaction (Table). Path a is generally preferred by the internal olefinic isomer of the enol silyl ether of methyl alkyl ketones (entries 1–4, and 9) among which methyl sec-alkyl ketones (entries 1–3, and 9) overwhelmingly prefer the path a. Choice of the silyl group substantially affects path a vs. path b ratio: path a becomes the favored pathway when the bulky tripropylsilyl group was used in place of the trimethylsilyl group (cf. entries 4 and 5). Thus steric hindrance at the site of the initial oxidation, the nature of the site of the proton removal (i.e., H* in B), and the steric effect of the silyl group all contribute to the relative amounts of the two pathways.
TABLE
DOUBLE HYDROXYLATION OF ENOL SILYL ETHERS
|
Entry |
Substrate |
MCPBA, equiv |
Path a: Path b |
Combined %Yield |
Major product |
|
1 |
|
2.5 |
100:0 |
72 |
|
2 |
|
2.5 |
100:0 |
79a |
|
3 |
|
3.3 |
100:0 |
74a |
|
4 |
|
1.0 |
100:0 |
91 |
|
5 |
|
1.0 |
63:35 |
75 |
|
6 |
|
1.0 |
32:68 |
94 |
|
7 |
|
2.0 |
25:75 |
88 |
|
8 |
|
2.0 |
0:100 |
ndb |
|
9 |
|
2.0 |
0:100 |
ndb |
|
|
aIsolated after acidic workup. bNot determined. A major portion of the initial monooxygenation product was lost by further oxidation with excess MCPBA.
|
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