Simple synthesis of 17α20β-dihydroxypregn-4-en-3-one

Article abstract of DOI:10.1023/A:1017602526723

Reduction of 17α-hydroxyprogesterone (1) with NaBH₄ produces 17α,20β-dihydroxypregn-4-en-3-one (2) and pregn-4-en-3β,17α,20β-triol (3).

Full text of DOI:10.1023/A:1017602526723

Chemistry of Natural Compounds, Vol. 37, No. 1, 2001
SIMPLE SYNTHESIS OF 17
,20 -DIHYDROXYPREGN-4-EN-3-ONE
N. V. Kovganko, Zh. N. Kashkan, and V. M. Shkumatov
UDC 547.92
Reduction of 17 -hydroxyprogesterone (1) with NaBH produces 17 ,20 -dihydroxypregn-4-en-3-one (2)
4
and pregn-4-en-3 ,17 ,20 -triol (3).
Key words: 17 -hydroxyprogesterone, 17 ,20 -dihydroxypregn-4-en-3-one, pregn-4-en-3 ,17 ,20 -triol.
The steroid 17 ,20 -dihydroxypregn-4-en-3-one (2) is a common natural derivative of 17 -hydroxyprogesterone (1).
It has been isolated several times from various natural sources [1-3]. Scientific interest in this compound has recently increased
significantly because, primarily, it acts as a fish sex pheromone [4, 5]. Convenient methods of synthesizing 2 from available
steroids, for example, 1, are necessary for broad research of its biological functions. A key step in the synthesis of 2 in the
literature [6, 7] is the reduction of the corresponding pregnan-20-ones by LiAlH . Naturally, the 3-ketone is also reduced. This
4
makes it necessary to protect the 3-ketone, which increases significantly the number of synthetic steps and reduces the overall
yield of the desired product. Furthermore, reduction of 17 -hydroxy-20-ketosteroids with LiAlH or LiAl(t-OBu) H produces
4
3
the usual 17 ,20 -diols and their 20 -isomers [7, 10]. This also decreases the yield of the desired compounds.
Me
Me
H
H
HO
HO
O
OH
OH
OH
+
O
O
HO
1
2
3
We developed a new method for synthesizing 17 ,20 -dihydroxypregn-4-en-3-one (2) that is based on reduction of
1 by NaBH , which is less reactive and more selective than LiAlH . It was found that reduction of 1 by NaBH in methanol
4
4
4
gives 2 in ~30% yield. The second product is 3 ,17 ,20 -triol 3 in 70% yield.
1
The structure of 2 was proved using H NMR spectra. The spectrum contains a signal for the methine proton H-20
geminal to the hydroxyl. The presence of the 20-hydroxyl was confirmed by the fact that the signal for the 21-methyl protons
appears as a doublet with splitting constant J = 6 Hz, which is due to vicinyl coupling with H-20. Furthermore, the characteristic
shift of the signal for the 21-methyl to strong field at 1.18 ppm compared with its position in the spectrum of starting 1
( 2.30 ppm) is interesting. The presence of the 17 -hydroxyl in 2 is inferred from the magnitude of the chemical shift of H-20
( 4.04 ppm). It is known [11] that this signal is observed at 3.72-3.73 ppm in the corresponding 20-hydroxypregnane steroids
that lack the 17 -hydroxyl. The shapes and positions of the signal for vicinyl proton H-4 in spectra of 1 and 2 are identical,
4
suggesting that the -3-ketone is retained in the latter. The 20 -configuration of the newly formed chiral center in 2 was
1
confirmed by the similarity of its H NMR spectrum with that described in the literature [3].
1
The H NMR spectrum of 3 exhibits characteristic signals for the H-20 and H-21 methyl protons, the position and
multiplicity of which agree with analogous signals in the spectrum of 2. Hence, it can be concluded that 3 is a 17 ,20 -diol.
Furthermore, the spectrum of 3 also contains a signal for methine proton H-3 ( 4.15 ppm), which indicates the presence of a
3-hydroxyl. The quasi-equatorial (i.e., ) orientation is consistent with the half-width of the H-3 signal (W/2 = 19 Hz).
Institute of Bioorganic Chemistry, National Academy of Sciences, Belarus, 220141, Belarus, Minsk, ul. Akad.
Kuprevicha, 5/2. Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 51-52, January-February, 2001. Original article
submitted February 6, 2001.
0009-3130/01/3701-0055$25.00 ©2001 Plenum Publishing Corporation
55

In conclusion, it should be noted that although the yield of 2 from reduction of 1 by NaBH is moderate, the simplicity
4
of the method and the lack of 20 -epimers among the products gives this method an advantage over those known previously.
EXPERIMENTAL
1
Melting points were determined on a Kofler block. H NMR spectra of CDCl solutions were obtained on a Bruker
3
AC-200 NMR spectrometer at working frequency 200 MHz. Chemical shifts are given relative to TMS internal standard.
Reduction of 17 -Hydroxyprogesterone (1) by NaBH . A solution of 1 (50 mg) in methanol (7 mL) was treated with
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NaBH (6 mg), stirred with cooling on an ice bath for 1.5 h, treated with acetic acid (0.3 mL), and evaporated under vacuum.
4
The solid was dissolved in CHCl . The solution was filtered through a layer of silica gel and evaporated under vacuum. Yield
3
of products, 64 mg. The mixture was separated by preparative TLC on silica-gel plates with elution by CHCl :CH OH (20:1).
3
3
1
Yield of 2 in fraction 1, 14 mg (28%). H NMR ( , ppm): 0.85 (3H, s, 18-Me), 1.18 (3H, d, J = 6 Hz, 21-Me), 1.19
(3H, s, 19-Me), 4.04 (1H, q, J = 6 Hz, H-20), 5.74 (1H, br. s, H-4).
1
Yield of 3 in fraction 2, 35 mg (70%). H NMR ( , ppm): 0.82 (3H, s, 18-Me), 1.06 (3H, s, 19-Me), 1.17 (3H, d,
J = 6 Hz, 21-Me), 4.02 (1H, q, J = 6 Hz, H-20), 4.15 (1H, m, W/2 = 19 Hz, H-3 ), 5.28 (1H, d, J = 1 Hz, H-4).
REFERENCES
1.
2.
R. Neher and A. Wettstein, Helv. Chim. Acta, 43, 1628 (1960).
W. S. Lynn, Jr., and R. H. Brown, Biol. Chem., 232, 1015 (1958).
3.
4.
5.
6.
S. Nakajin, S. Ohno, M. Takahashi, K. Nishimura, and M. Shioda, Chem. Pharm. Bull., 35, 2490 (1987).
W. Zheng, C. Strobeck, and N. Stacey, J. Exp. Biol., 200, 2833 (1997).
A. P. Scott, R. M. Inbaraj, and E. L. M. Vermeirsen, Gen. Comp. Endocrinol., 105, 62 (1997).
J. Romo, M. Romero, C. Djerassi, and G. Rosenkranz, J. Am. Chem. Soc., 73, 1528 (1951).
R. Neher and A. Wettstein, Helv. Chim. Acta, 43, 1171 (1960).
7.
8.
G. I. Pools, J. Am. Chem. Soc., 77, 4932 (1955).
9.
10.
11.
M. G. Ward, J. C. Orr, and L. L. Engel, J. Org. Chem., 30, 1421 (1965).
H. Hirschmann and F. B. Hirschmann, J. Biol. Chem., 187, 137 (1950).
D. N. Kirk, H. C. Toms, C. Douglas, K. A. White, K. E. Smith, S. Latif, and R. W. P. Hubbard, J. Chem. Soc.,
Perkin Trans. 2, 1567 (1990).
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