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An Abnormal Ring Cleavage of 1 2-Epoxy-3-keto Steroids by Hydrogen Fluoride.

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1 7 ~ - A c e t o . ~ y - 4 ~ - ~ i t o r o - 5 ~ - t r n d-en-3-one
An Abnormal Ring Cleavage of la,2a-Epoxy3-keto Steroids by Hydrogen Fluoride
By U. Kerb, G. Schulz, and R. WiechertI*l
2-Chloro- ( 2 a ) and 2-bromo-5a-androst-l-en-3-one
have been obtained by treatment of 17P-acetoxy-la,2aepoxy-5u-androstan-3-one
( I ) [ I ] with hydrogen chloride and
hydrogen bromide, respectively [2,3J.
However, hydrogen fluoride causes rearrangement, yielding,
from (f), 17~-acetoxy-4~-fluoro-5a-androst-l-en-3-one
m.p. 173-174°C (UV: €234 = 10960)[41.
The characteristic signals in the N M R spectrum of this
product ( 3 ) are the doublets of two olefinic protons (6 = 7.33
and 6.00). the double doublet of the proton on C-4 (S = 4.50),
and the signal of the 19-CH3 group (6 = 1.20) which is split
to a doublet [5J by 1,3-diaxial interaction with the 4P-fluorine
The la-chloro-4a-fluoro ketone ( 4 ) (m.p. 173°C with decamp.) was obtained from ( 3 ) by means of hydrogen chloride
in glacial acetic acid, isomerization at C-4 and addition of
HC1 occurring. Hydrogenation o f (3j in presence of Pd,K in
methanol and subsequent epimerization by hydrogen chloride in glacial acetic acid led to the 4a-fluoro ketone ( 5 )
(m.p. 187.5-188 " C ) .In the N M R spectra of ( 4 ) and ( 5 ) the
signal of the 19-CH3 group appears as a singlet, whence it
follows that the fluorine is in the 4a position.
f 1)
(24, x = c1
(2b), X = B r
Compound ( l a ) (1 g) is added portionwise t o a mixture of
a) dimethylformamide (5 ml) and hydrogen fluoride (5 ml) or
b) tetrahydrofuran (40 ml) and hydrogen fluoride (10 ml) and
the mixture is stirred for 22 h or 48 h, respectively, at room
temperature. The reaction mixture is then poured into icewater and neutralized with K2C03; the precipitate is filtered
off and recrystallized from dichloromethane/isopropyl ether
(yield 60%).
Received: September 16, 1968
12 875 IEI
German version: Angew. Chem. 80, 916 (1968)
[*] Dr. U. Kerb, Dr. G. Schulz, and Dr. R. Wiechert
Hauptlaboratorium der Schering AG
1 Berlin 65, Miillerstrasse 170-172 (Germany)
[l] W . M . Hoehn, J. org. Chemistry 23, 929 (1958).
[2] R. Wiechert, E . Kaspar, and M . Schenck, German Pat.
1076127, (August 30, 1958), Schering AG.
[3] R . E. Counsel/ and P . D. Klimstra, J . rned. phannac. Chem.
5, 477 (1962).
[4] The fluoro compound prepared by P. D . Klimstra and R. E.
Counsefl [J. med. pharmac. Chem. 5 , 1216 (1962)l from (2) by
means of hydrogen fluoride in glacial acetic acid is probably not
(2c), but rather also ( 3 ) .
[ 5 ] A. D. Cross and P. W . Landis, J . Amer. chem. SOC.86, 4005
[6] J . Fajkos and F. Sornz, Collect. czechoslov. chem. Commun.
24, 3115 (1959).
[7] C. Djerassi and C. R. Scholz, J. Amer. chem. SOC. 69, 2404
Formation of Adenosine Triphosphate (ATP)
from Adenosine Diphosphate (ADP) and
Phosphate during Oxidation of Mercaptoacetate by
Bromine 111
f 7)
By Th. Wieland and E. Bauerlein[*l
We have converted oxidation energy into the energy of the
"energy-rich" diphosphate bond, e.g., that in ATP, by oxida(21, N-acetylhomotion of S-alkylmonothiohydroquinones
cysteine thiolactone [ 3 1 , thiazolidones 141, monoacetyldurohydroquinone [51, a-tocopherol 161, and S-p-tolyl thioacetate (61
by bromine in pyridine in the presence of A D P and phosphate (P). We have now found that under these conditions
mercaptoacetate also gives ATP from the tetrabutylammonium (TBA) salts of A D P and P, and that yields exceed 30%.
In several batches, 13.33 ml of 0.1 N (TBA).OH solution in
2-propanol/methanol (Merck, Darmstadt) was treated with
0.67 ml of 1 N solution of cu. 90% phosphoric acid in dioxane; 0.107 g of ADPH3.3 H20 ( C . F. Boehringer und
Soehne, Tutzing) was dissolved therein, and then 0.016 ml
of freshly distilled mercaptoacetic acid was added. The solution was evaporated under vacuum, and the residue was dried
over P4O10 for 20 min at 0.1 torr and then dissolved with
stirring in 9 m l of anhydrous pyridine, whereupon a deep
yellow color developed. (A solution o f the TBA salt of
mercaptoacetic acid in anhydrous pyridine is colorless.) The
solution was then treated, by dropwise addition within a few
minutes, with 519 mmole (0.028 ml), 219 mmole (0.011 ml),
or 0.133 mmole (= 1 . 2 ~ 1 1 9mmole) (0.007 ml) of bromine,
each amount in 1 ml of anhydrous pyridine.
For further proof of the structure of ( 3 ) . 17P-acetoxy-2Pfluoro-5a-androstan-3a-ol (m.p. 205-206 "C) was prepared
from the 2a,3u-epoxide (6)
and was oxidized t o the 2Pfluoro ketone (m.p. 158-160 "C) and converted by acid isomerization into the known 2a-fluoro compound (7) 141 (m.p.
189-190.5 "C). The double bond was introduced into (7) by
bromination and then removal of hydrogen bromide. The
(2c) prepared
in this way (m.p. 16O.5-161.S0C; U V : €238 = 10100) gavea
depression of the melting point on admixture with ( 3 ) . The
N M R spectrum of (2c) contains the signal of only one olefinic proton.
This caused a color change from deep yellow through deep
red t o pale yellow; a precipitate was formed after a few
minutes. After 1 h each batch (several repeats) was worked
up for determination of ATP (results in Table 1).
We were unable t o rearrange (2c) to (3) by hydrogen
fluoride under the conditions of epoxide ring fission, in the
way that Djerassi and Scholz "1 observed for the 17.x-benzoyloxy-2-bromo-5a-androst-l-en-3-one
system which was transformed into the 4-bromo isomer. Compound (2c) adds hydrogen bromide, yielding (8) (m.p. 159.5-160.5 "C).
N o more than conjectures can be made at present about the
mechanism of this coupled reaction. It may be that a sulfenyl
bromide is first formed by bromination of the thiol and then
combines with the phosphate ion to give a mixed sulfenic
which is the actual
phosphoric anhydride R-S-O-P03H-,
phosphorylating agent.
Angew. Chem. internat. Edit.
/ Vol. 7 (1968) No. I I
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hydrogen, steroid, cleavage, fluoride, abnormal, keto, ring, epoxy
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