Novel partial synthetic approaches to replace carbons 2,3,4 of steroids. A methodology to label testosterone and progesterone with 13C in the steroid A ring. Part 2

Article abstract of DOI:10.1016/S0040-4020(00)00967-4

Fragmentation of the A ring of the steroid hormone testosterone to yield the 10-formyl-5-oxo-des A intermediate was achieved by lactolization, lactonization, ozonolysis, and oxidation of the resulting methylol group. The reconstruction of the A ring was carried out via a Wittig synthesis with triphenylphosphoranylidene-2-propanone-¹³C₃. Syntheses of the ylide, of the ¹³C₃-testosterone, and of ¹³C₃-progesterone took place in acceptable yields. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00967-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9967±9974
Novel Partial Synthetic Approaches to Replace Carbons 2,3,4 of
Steroids. A Methodology to Label Testosterone and Progesterone
with C in the Steroid A Ring. Part 21
13
Karlheinz Kockert and Friedrich W. Vierhapperp
È È È
Institut fur Organische Chemie der Universitat Wien, Wahringerstrasse 38, A-1090 Wien, Austria
Received 28 July 2000; revised 10 October 2000; accepted 11 October 2000
AbstractÐFragmentation of the A ring of the steroid hormone testosterone to yield the 10-formyl-5-oxo-des A intermediate was achieved
by lactolization, lactonization, ozonolysis, and oxidation of the resulting methylol group. The reconstruction of the A ring was carried out via
a Wittig synthesis with triphenylphosphoranylidene-2-propanone-13C3. Syntheses of the ylide, of the 13C3-testosterone, and of 13C3-proges-
terone took place in acceptable yields. q 2000 Elsevier Science Ltd. All rights reserved.
Use of 13C labeled steroid compounds as tracers in clinical
investigations is superior in comparison to 14C-labeled
analogs because of the absence of ionizing radiation. Detec-
tion, on the other hand, has to rely on mass spectroscopy. In
order to take care for a suf®cient difference in intensity to
heavier ions resulting from natural abundance, at least three
13C atoms should be introduced into the tracer. A larger
number of labels offers no great advantage and will only
raise the cost of the material.
rather large amounts of solvent were necessary to separate 2
from the crown ether and to obtain satisfactory yields of 2,
making scale-up somewhat troublesome. Crucial step in the
synthesis was the ozonolysis of the lactone 3 to the ring-
opened product 4; conditions had to be carefully optimized
for the reaction to take place in acceptable yields within a
reasonable time (see Experimental Section). The procedure
was successful both with 17b-protected (3b, 3c) or with the
17-OH (3a) compounds. In the latter case the secoalcohol 4a
(RˆH) was oxidized in the subsequent oxidation step D to
the oxo-compound 5d, and the following reactions took
place with the keto compound.
In our attempts to prepare 13C labeled steroid hormones, we
therefore decided to partially degrade the A ring of commer-
cially available starting compounds without losing the
con®gurational information, subsequently reconstructing
the ring with a 13C3 synthon. Our aim was to develop a
synthesis which could be used with small changes for a
number of different steroids. Various possibilities of A
ring degradation were investigated; part of this work has
been reported in the preceding paper.1 Here we report an
additional way for A ring fragmentation, and the synthesis
of the 2,3,4-13C3 steroid hormones testosterone, proges-
terone and androstendione.
If progesterone was used as starting material of the reaction
sequence, enolate formation of the C-20 keto group led to
hydroxylation at C-17 via a peroxide so that 10-formyl-5-
oxo-des A progesterone (5e) could not be obtained by this
route. Either the method described in the preceding paper1
was used to prepare 5e, or a stigmastene side chain could be
used initially and be converted to the progesterone side
chain at a later stage.3
A few methods for the reconstruction of the A ring starting
with 1,5-secosteroids were available in the literature.4,5
However, if the aim of the synthesis is the introduction of
three 13C atoms, most of these techniques would use the
labeled component in large molar excess or as a solvent,
thus lowering the yields of the product relative to the expen-
sive labeled starting materials. The most promising method
was reaction with a Wittig reagent5 1-triphenylphosphora-
nylidene-13C3-2-propanone (6), which could be prepared
from commercially available 13C-methyl-triphenylphospho-
nium iodide and 13C2-acetyl chloride in 75% yield. The
synthesis takes place via an intermediate thioester (Scheme
2); the ethane thiol is removed from the reaction mixture by
Results and Discussion
In an alternative to the synthesis of 10-formyl-5-oxo-des A
testosterone described in the preceding paper1 a reaction
sequence depicted in Scheme 1 via lactol 22 and lactone
32 was carried out. Owing to the poor solubility of the lactol
Keywords: steroids; degradation; labeling.
* Corresponding author. Tel.: 143-1-4277-52106; fax: 143-1-4277-9521;
e-mail: friedrich.vierhapper@univie.ac.at
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00967-4

9968
K. Kockert, F. W. Vierhapper / Tetrahedron 56 (2000) 9967±9974
Scheme 1. Reagents and conditions: A: O2, 18-crown-6, t-BuOK, toluene, 2308C, 6 h; RT, 2±3 d. B: NaBH4, CHCl3, H2O/OH2. B1: TBDMSiCl, imidazole,
DMF, 12 h. B2: H3PO4/BF3, CH2C(CH3)2. C: O3, 2788C, EtOAc/CH3OH; H2O; 10% aqu. K2CO3/H2O. D: SO3´pyridine, DMSO, Et3N. D1: CH3COOH, re¯ux,
20 min.
distillation and the starting ylide is regenerated, shifting the
equilibrium towards the desired product.6
in a very minor extent (,5% in 5 h). This is unimportant,
since the protective group has to be cleaved in any case, and
the free 17-OH does not adversely in¯uence the following
aldol reaction. Absence of impurities, however, appears to
be crucial. If hydrogenation is not complete after a few
hours, catalyst and solvent must be replaced with new
reagents, or else side product formation can lead to drastic-
ally diminished yields of 8. Mainly 3-ethoxylated products
were identi®ed among other products in a long time experi-
ment with 7c over a catalyst intentionally poisoned with
dimethyl sul®de.3
Only the more reactive aldehyde group of the secosteroids 5
reacted with the ylide (Scheme 3).5 Heating in xylene gave
compounds 7. No retroaldol reactions3,7 were observed.
Selective hydrogenation of the double bond in the side chain
of 7 was possible with a palladium catalyst at slightly
elevated pressure. No reduction of the keto groups took
place. The protective TBDMSi group of 7b was split off
Scheme 2.

K. Kockert, F. W. Vierhapper / Tetrahedron 56 (2000) 9967±9974
9969
Scheme 3. Reagents and conditions: E: xylene, re¯ux, 7 d. F: H2, Pd(10%)/C, EtOH. G: 10% KOH, CH3OH. G1: CH3COOH, re¯ux, 20 min. G2: CF3COOH,
RT 1 h; LiOH/CH3OH, 30 min. G3: CH3OH, NaBH4, 08C, 6 h.
1
The crude products 8 were cyclized with potassium hydrox-
ide in methanol at room temperature. The protective groups
(TBDMSi in 9b and the tert butyl group in 9c) were
removed to give 9. The 17-keto group of 4-androsten-
3,17-dione (9d) could be selectively reduced to the 17b-
alcohol 9a; less than 5% of the 3b,17b-diol were formed.
Overall yields of the labeled steroid hormones 9a, 9d and 9e
relative to the starting 13C2-acetyl chloride are shown in
Table 1. Yields for testosterone are quite similar inde-
pendent of starting compound 5; slightly better yields in the
Wittig reaction step for 5b and 5c are compensated by the
additional step necessary to remove the protective groups.
melting point microscope and are uncorrected. H and 13C
NMR spectra were recorded at room temperature on a
Bruker AM 400 in CDCl3 unless otherwise indicated;
internal references were (CH3)4Si (d 0.00) and CDCl3 (d
77.00), respectively. Elemental analyses were carried out by
Mikroanalytisches Laboratorium, Institut fuÈr Physikalische
È
Chemie der Universitat Wien. Mass spectra were generally
recorded on a quadrupole mass spectrometer MS 800
(Frisons Instruments) connected to a gas chromatograph
GC 800 series (Carlo Erba Instruments). Column was a
DB-1 fused silica capillary column (15 m£0.32 mm ID),
®lm thickness 0.25 mm. MS-conditions were 70 eV ioni-
sation energy (EI), scan 50±600. The mass spectrum of
the ylide 6 was recorded on a mass spectrometer 8230
(Finnigan, MAT) with direct inlet and 70 eV ionisation
energy (EI).
In summary, the synthetic sequence starting with com-
mercially available testosterone or progesterone to the
2,3,4-13C3-labeled steroids testosterone, adrostendione and
progesterone, respectively, can be carried out in between 9
to 11 steps, only 4 to 5 of which involve the labeled
material. The 13C of the starting material 13C2-acetyl
chloride is recovered in approximately 40% yield in the
labelled steroids, which allows synthesis of the materials
in the gram-amounts needed for clinical investigations
even at the considerable cost of 13C materials.
Preparative chromatography was carried out either by ¯ash
chromatography using Merck silica gel 60 (0.040±
0.063 mm) or by radial chromatography on a Chromatotron
8924 from Harrison Research, using rotors coated with
Merck silica gel 60 PF-254 with calcium sulfate in various
layer thickness (1, 2 or 4 mm). Results were similar with
both techniques; the method selected depended on the
amounts of sample. If more than 2 g had to be separated,
¯ash chromatography was used. Solvent mixtures were
generally ethyl acetate and petroleum ether. The ratios are
reported with the individual steps.
Experimental
General procedures
Ozonolysis was performed by a Welsbach ozonisator using
dry air as oxygen source, producing 10 g ozone/h with dry
air feed.
Melting points were determined using a Reichert Ko¯er
Table 1. Yields of products
Starting 5
CH3COCl!7 a
7!9
Total a
Solvents were puri®ed by standard methodology. Reactions
requiring anhydrous conditions were carried out under
either dry nitrogen or argon atmospheres. Chemicals were
obtained from Aldrich or Sigma and were used without
further puri®cation unless otherwise indicated. 13C2-Acetyl
chloride was purchased from Stable Isotopes, CEA-France.
5a
5b
5c
5d
5e
7a: 58
7b: 60
7c: 64
7d: 54
7e: 50
9a: 72
9a: 68
9a: 66
9a: 42
9a: 41
9a: 42
9d: 77, 9a: 72
9e: 82
9d: 42, 9a: 39
9e: 38
a Percent of theoretical yield, relative to acetyl chloride. Values are
averages of three runs, with 12C-material.
Content of 13C isotope was determined for the labeled end

9970
K. Kockert, F. W. Vierhapper / Tetrahedron 56 (2000) 9967±9974
products 9a, 9d and 9e by integration of the M1 regions of
the mass spectra and by integration of the 13C NMR spectra.
Quantitative evaluation of the mass spectra was achieved by
dividing the abundance of the M121 peak (the 13C2
compounds) by the sum of M1 (i.e. the 13C3) and M121.
Values of 2^0.1% M121 were obtained for the three
steroids.
and the organic layer was washed with 5% aqueous sodium
hydroxide and dried over magnesium sulfate. The solvent
was distilled off. To the aqueous phase another 500 mL
chloroform was added, and the mixture was stirred over
night. The reaction was then quenched by addition of 10%
aqueous hydrochloric acid. The organic layer was worked
up as described above. The uni®ed products 3a were
puri®ed by chromatography (ethyl acetate:petroleum
etherˆ1:3). Yield 855 mg (90 %). Mp 201±2038C (litera-
ture2 mp 201±2028C). Spectroscopic data agreed with the
values in the literature.2
In the 13C NMR spectra of 9, the signals for the 13C enriched
carbons 2, 3 and 4 were split into doublets of doublets by the
coupling with the neighboring 13C atoms through one and
two bonds, respectively. If the regions for 13C-2 and 13C-4
were expanded, additional small doublets could be assigned,
corresponding to the coupling in the 13C2 compounds with
either only 13C-3 or 13C-2 (for 13C-4) and 13C-4 (for 13C-2),
respectively. Integration of these doublets relative to the
total area of the C-2- and C-4-regions, respectively, indi-
cated an abundance of 99^0.5 % for each of the three
positions. This is in satisfactory agreement with the isotopic
enrichment of the commercial 13C starting materials speci-
®ed by the suppliers.
17b-tert-Butyldimethylsilyloxy-2-oxaandrost-4-en-3-one
(3b). A solution of 3a (1 g, 3.45 mmol), tert-butyldimethyl-
chlorosilane (725 mg, 5 mmol) and imidazole (470 mg,
7.9 mmol) in dimethylformamide (10 mL) was stirred at
room temperature for 12 h. The reaction was quenched
with water, and the mixture was extracted with diethyl
ether. The organic layer was washed with 5% aqueous
hydrochloric acid and then with 10% aqueous sodium
chloride. The diethyl ether solution was dried over mag-
nesium sulfate and the solvent was distilled off at
diminished pressure. The crude 3b was puri®ed chroma-
tographically (ethyl acetate:petroleum etherˆ1:6). Yield
1.25 g (88%). Mp 136±1378C. (Found: C, 71.14; H,
10.05. C24H40O3Si requires: C, 71.23; H, 9.96%). dH
(400 MHz, CDCl3/TMS) 5.56 (s, 1H, 4-H), 4.12 (d, 1H,
1-H), 3.88 (d, 1H, 1-H), 3.45 (t, 1H, 17-H), 1.11 (s, 3H,
19-CH3), 0.78 (s, 9H, C(CH3)3), 0.64 (s, 3H, 18-CH3),
20.09 (s, 6H, Si(CH3)2); dC (100.6 MHz, CDCl3/TMS)
167.6 (C-3), 164.3 (C-5), 113.2 (C-4), 81.4 (C-17), 76.7
(C-1), 25.6 (C(CH3)3), 17.8 (C(CH3)3), 16.2 (C-19), 11.0
(C-18), 24.6, 24.9 (Si(CH3)2).
A similar evaluation of the 13C NMR spectrum of 6 was
problematic due to the additional carbon±phosphorus
coupling; the signals of the doublets of doublets due to
one neighboring 13C and one 31P were too small to be
reliably integrated. The mass spectrum of the unlabeled
analogue of 6 gave an M121 peak (m/zˆ317) of rather
similar intensity to the M1-peak (m/zˆ318) (18.9 vs.
24.2%), so these signals could not be used to assess the
extent of the labelling in 6 (m/z 320:321ˆ20.0:21.2).
However, the 13C-content in each position is re¯ected in
the end products 9.
1j,17b-Dihydroxy-2-oxaandrost-4-en-3-one (2).2 A solu-
tion of testosterone (1) (3.64 g, 12.6 mmol) and 18-crown-6
(5.00 g) in 1 L toluene (previously distilled from sodium)
was cooled to 2278C (^38C). Freshly sublimated tert-
BuOK (4.3 g) was added, and the solution was saturated
with oxygen (dried over sulfuric acid, silica gel and potas-
sium hydroxide) for 2 min. Oxygen was then slowly passed
through the solution which was kept at 2278C until TLC
(acetone: petroleum etherˆ1:3) showed complete reaction
of 1 (,3 h). The mixture was brought to room temperature
and stirred while continuously passing through a slow
stream of oxygen. After ,90 h TLC showed only 2. The
mixture was neutralized by addition of 10% aqueous hydro-
chloric acid and 1 L diethyl ether was added. The organic
layer was washed with 10% aqueous sodium hydrogen car-
bonate, the washings were acidi®ed with hydrochloric acid
and extracted with diethyl ether. The organic phases were
united, dried over magnesium sulfate and the solvent was
distilled off. Lactol 2 was recrystallized from ethyl acetate.
Yield 3.48 g (90%). Mp 238±2418C (literature2 mp 2488C).
Spectroscopic data agreed with the values in the literature.2
17b-tert-Butoxy-2-oxaandrost-4-en-3-one (3c). Isobutene
(Aldrich, 99%) (4 mL) was condensed in a vessel cooled
with liquid nitrogen, and was slowly added to a suspension
of 3a (290 mg, 1 mmol) in 4 mL dichloromethane (dried
Ê
over 4 A molecular sieves) at approx. 2308C. A mixture
of boron tri¯uoride diethyl etherate and phosphoric acid
(0.1 mL; ratioˆ1:1) was added, and the mixture was stirred
at room temperature for 20 h in a pressure resistant
stoppered ¯ask (the joint was protected by a te¯on sleeve).
Unreacted isobutene was evaporated, the residue was
purged by a stream of dry nitrogen, and the dichloromethane
solution was washed with 5% aqueous sodium hydrogen
carbonate. The washings were extracted with dichloro-
methane, the organic layers were united, dried over mag-
nesium sulfate and the solvent was distilled off. The crude
3c was puri®ed chromatographically (ethyl acetate:petro-
leum etherˆ1:3).Yield 322 mg (92%). Mp 176±1778C.
(Found: C, 76.17; H, 9.95. C22H34O3 requires: C, 76.26;
H, 9.89%). dH (400 MHz, CDCl3/TMS) 5.56 (s, 1H, 4-H),
4.13 (d, 1H, 1-H), 3.89 (d, 1H, 1-H), 3.28 (t, 1H, 17-H), 1.16
(s, 3H, 19-CH3), 1.07 (s, 9H, C(CH3)3), 0.66 (s, 3H, 18-
CH3); dC (100.6 MHz, CDCl3/ TMS) 168.0 (C-3), 164.8
(C-5), 113.4 (C-4), 80.5 (C-17), 77.0 (C-1), 72.2
(C(CH3)3), 28.7 (C(CH3)3), 16.4 (C-19), 11.5 (C-18).
17b-Hydroxy-2-oxaandrost-4-en-3-one (3a).2 To a solu-
tion of 2 (1.00 g, 3.3 mmol) in 500 mL chloroform a solu-
tion of sodium borohydride (1.00 g, 26.4 mmol) in 140 mL
water and 1 mL 10% aqueous sodium hydroxide was slowly
added. The mixture was stirred vigorously at room tempera-
ture for ,5 h; progress of the reaction was followed by TLC
(acetone:petroleum etherˆ1:2). The phases were separated,
Optimization of ozonolysis reaction 3!4 with 3c. A solu-
tion of 3c (200 mg) in the solvent listed in Table 2 was
cooled to 2788C. Ozone was passed through the solution
until starting material was no longer visible on TLC (ethyl

K. Kockert, F. W. Vierhapper / Tetrahedron 56 (2000) 9967±9974
9971
Table 2.
CDCl3/TMS) 217.5 (C-5), 81.4 (C-17), 65.4 (C-1), 52.8
(C-10), 25.6 (C(CH3)3), 17.8 (C(CH3)3), 15.7 (C-19), 11.3
(C-18), 25.0, 24.7 (Si(CH3)2).
Solvent
R
t (h)
Yield 4c (%)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2/CH3OH
CH2Cl2/CH3OH
CH2Cl2/CH3OH
AcOEt
10 mL 10% aqu. K2CO3
10 mL 1% aqu. KOH
5 mL 5% aqu. H2SO4
10 mL 10% aqu. K2CO3
10 mL 1% aqu. KOH
5 mL 5% aqu. H2SO4
10 mL 10% aqu. K2CO3
10 mL 1% aqu. KOH
10 mL 10% aqu. K2CO3
15
5
5
15
5
5
15
5
15
68
55
28
59
52
24
75
65
93
4c: Chrom. solvent ethyl acetate:petroleum etherˆ1:5.
Yield 93%. Mp 130±1328C (literature5 mp 130±
1318C). Spectroscopic data agreed with the values in the
literature.5
AcOEt
AcOEt/CH3OH
Oxidation of 4a to 10-formyl-des-A-androstan-5,17-
dione (5d), 4b to 17b-tert-butyldimethylsilyloxy-10-
formyl-des-A-androstan-5-one (5b), 4c to 17b-tert-
butoxy-10-formyl-des-A-androstan-5-one (5c). To
a
acetate:dichloromethaneˆ1:5) and a blue color of ozone
persisted. The residual ozone was purged from the solution
by a stream of dry nitrogen, 1 mL of dimethyl sul®de was
added, and the solution was stirred for 3 h at room tempera-
ture. The solvent was distilled off at reduced pressure and
the residue was dissolved in diethyl ether.
stirred solution of secoalcohol 4 (0.91 mmol) and 1.83 g
triethylamine (18.1 mmol) in anhydrous dimethyl sulfoxide
(12 mL) a solution of 920 mg sulfur trioxide/pyridine
(5.8 mmol) in anhydrous dimethyl sulfoxide (8 mL) was
slowly added at room temperature. Stirring was continued
for 1.5 h after addition was complete. After addition of
diethyl ether the layers were separated. The ether layer
was washed with 10% aqueous sodium chloride solution.
To the dimethyl sulfoxide layer a cold 10% aqueous
solution of sodium chloride was carefully added, and the
resulting mixture was extracted with diethyl ether (precipi-
tates were left in the aqueous phase). The combined
washings were extracted with diethyl ether, the combined
ether phases were dried over magnesium sulfate or sodium
sulfate and the diethyl ether was distilled off. Products were
puri®ed by chromatography. As for 5a1 and 5e,1 no trace of
the M1-peak could be detected in the mass spectra. The
peak with the largest mass in each corresponded to the
loss of a fragment with mass 28.
Reagent `R' (Table 2) was added and the mixture was stirred
for several hours. The phases were separated, the aqueous
phase was extracted with diethyl ether, the organic layers
were united, washed with a saturated aqueous solution of
sodium chloride and dried over sodium sulfate. The solvent
was distilled off and the products were separated by
chromatography (ethyl acetate:petroleum etherˆ1:5 to
1:1). Yields of 4c see Table 2.
Ozonolysis reaction 3a!1,17b-dihydroxy-1,5-secoandro-
stan-5-one (4a), 3b!17b-tert-butyldimethylsilyloxy-1-
hydroxy-1,5-secoandrostan-5-one (4b), 3c! 17b-tert-
butoxy-1-hydroxy-1,5-secoandrostan-5-one (4c). The
lactone 3 (3.5 mmol) was dissolved in 100 mL ethyl
acetate:methanolˆ1:1. and ozone was passed through the
solution at 2788C until a blue color persisted (,13 min
with ¯ow 100 L/min; current intensity 0.6 A) and control
by TLC showed no starting 3. Residual ozone was purged
with dry nitrogen, 3 mL dimethyl sul®de was added and the
mixture was stirred at room temperature for 2 h. The solvent
was distilled off at 508C at reduced pressure and the residue
was dissolved in 100 mL diethyl ether. Aqueous 10% potas-
sium carbonate (100 mL) was added and the mixture was
stirred vigorously over night at room temperature. The
aqueous phase was extracted repeatedly with diethyl ether,
the ether phases were united and dried over magnesium
sulfate. The crude products were puri®ed by chroma-
tography.
5d: Chrom. solvent ethyl acetate:petroleum etherˆ1:3.
Yield 88%. Mp 135±1388C. (Found: C, 73.17; H, 8.51.
C16H22O3 requires: C, 73.25; H, 8.45%). MS (EI), m/z
(%)ˆ234 (100) M1228, 190 (28), 136 (39), 121 (55). dH
(400 MHz, CDCl3/TMS) 9.44 (s, 1H, 1-H), 1.21 (s, 3H,
19-CH3), 0.85 (s, 3H, 18-CH3); dC (100.6 MHz, CDCl3/
TMS) 219.1 (C-17), 211.9 (C-5), 201.0 (C-1), 62.1 (C-10),
13.5 (C-18), 12.3 (C-19).
5b: Chrom. solvent ethyl acetate:petroleum etherˆ1:8.
Yield 92%. Mp 122±1248C. (Found: C, 69.70; H, 10.21.
C22H38O3Si requires: C, 69.79; H, 10.12%). MS (EI), m/z
(%)ˆ350 (13) M1228, 321 (81), 217 (57), 75 (100). dH
(400 MHz, CDCl3/TMS) 9.48 (s, 1H, 1-H), 3.56 (t, 1H,
17-H), 1.24 (s, 3H, 19-CH3), 0.84 (s, 9H, C(CH3)3), 0.73
(s, 3H, 18-CH3), 20.03 (s, 6H, Si(CH3)2); dC (100.6 MHz,
CDCl3/ TMS) 212.8 (C-5), 201.5 (C-1), 81.2 (C-17), 62.5
(C-10), 25.7 (C(CH3)3), 17.9 (C(CH3)3), 12.9 (C-19), 11.3
(C-18), 25.1, 24.7 (Si(CH3)2).
4a: Chrom. solvent ethyl acetate:petroleum etherˆ1:3.
Yield 88%. Mp 155±1588C. (Found: C, 72.08; H, 9.95.
C16H26O3 requires: C, 72.14; H, 9.84%). dH (400 MHz,
CDCl3/TMS) 3.72 (d, 1H, 1-H), 3.41 (d, 1H, 1-H), 3.43 (t,
1H, 17-H), 1.02 (s, 3H, 19-CH3), 0.77 (s, 3H, 18-CH3); dC
(100.6 MHz, CDCl3/TMS) 217.9 (C-5), 81.0 (C-17), 64.7
(C-1), 52.5 (C-10), 15.5 (C-19), 10.9 (C-18).
5c: Chrom. solvent ethyl acetate:petroleum etherˆ1:4.
Yield 90%. Mp 148±1508C (literature5 mp 149±150.58C).
1H NMR spectral data agreed with the values in the litera-
ture.5 In the mass spectrum, in contrast,5 the M1-peak could
not be detected. MS (EI), m/z (%)ˆ292 (22.5) M1228, 236
(24.2), 57 (100).
4b: Chrom. solvent ethyl acetate:petroleum etherˆ1:6.
Yield 87%. Mp 141±1448C. (Found: C, 69.50; H, 10.63.
C22H40O3Si requires: C, 69.42; H, 10.59%). dH (400 MHz,
CDCl3/TMS) 3.80 (d, 1H, 1-H), 3.43 (d, 1H, 1-H), 3.54 (t,
1H, 17-H), 1.04 (s, 3H, 19-CH3), 0.85 (s, 9H, C(CH3)3), 0.74
(s, 3H, 18-CH3), 20.02 (s, 6H, Si(CH3)2); dC (100.6 MHz,
Cleavage of TBDMS protecting group of 5b to 10-form-
yl-17b-hydroxy-des-A-androstan-5-one (5a). To a solu-
tion of 5b (455 mg, 1.2 mmol) in tetrahydrofuran (10 mL)

9972
K. Kockert, F. W. Vierhapper / Tetrahedron 56 (2000) 9967±9974
acetic acid (30 mL) and water (10 mL) was added and the
mixture was heated to re¯ux for 1 h. The cooled mixture
was diluted with water (30 mL) and repeatedly extracted
with CHCl3. The chloroform phases were united, the solvent
was distilled off and residual acetic acid was distilled off by
azeotropic distillation with toluene. Compound 5a was
obtained in quantitative yield after puri®cation by chromato-
graphy (ethyl acetate:petroleum etherˆ1:5). Mp 132±1348C
(mp and spectroscopic data were identical with Ref. 1).
6.0 Hz), 1.29 (s, 3H, 19-CH3), 0.78 (s, 3H, 18-CH3); dC
(100.6 MHz, CDCl3/TMS) 212.5 (C-5), 198.0 (C-3, d,
53.0, of d, 42.5), 150.4 (C-1, d, 70.0, of d, 2.5), 131.0
(C-2, d, 53.0, of d, 15), 81.1 (C-17), 54.4 (C-10), 26.6
(C-4, d, 42,5 of d, 15), 15.2 (C-19), 11.0 (C-18).
7b: Reaction time 3 d. Chrom. solvent ethyl acetate:petro-
leum etherˆ1:6. dH (400 MHz, CDCl3/TMS) 6.73 (dd, 1H,
1-H), 5.99 (ddd, 1H, 2-H, J2C±2Hˆ160.0 Hz), 3.48 (t, 1H,
17-CH), 2.61 and 2.32 (dt, ddd respectively, 1H each,
6-CH2), 2.24 (dd, 3H, 4-H, J4C±4Hˆ128.0 Hz, J3C±
Synthesis of 1-triphenylphosphoranylidene-13C3-2-pro-
panone (6). (a) 13C2-Thioacetic acid S-ethyl ester. To a
solution of 13C2-acetyl chloride (1.00 g, 12.4 mmol, isotopic
purity .99% for each position) in benzene (distilled from
sodium) under argon, sodium thioethylate (1.32 g,
16.2 mmol) was added at 68C. The reaction was complete
after 10 min. (b) Methylenetriphenylphosphorane-methyl-
ene-13C. Methyl-triphenylphosphonium-methyl-13C-iodide
(5.20 g, 12.8 mmol, isotopic purity .99%) was suspended
in dry benzene (80 mL). Sodium amide (0.53 g, 13.6 mmol)
was added, and the mixture was heated to re¯ux under argon
for 5 h. A yellow color of the ylide developed after some
time. (c) 1-Triphenylphosphoranylidene-13C3-2-propa-
none (6). The benzene solution of the thioester (a) was trans-
ferred via a syringe to the solution (b), which had been
®ltered through a sintered glass ®lter disk under argon.
Solids were washed with small amounts of benzene and
this was also added. The resulting benzene solution was
heated to re¯ux under argon for 12 h. The solvent was
distilled off, and the remaining white material was used
directly in the syntheses of 7. Yield 2.93 g (75% relative to
13C2-acetyl chloride). Mass and NMR-spectra were recorded
with a small amount puri®ed by column chromatography
ˆ6.0 Hz), 1.25 (s, 3H, 19-CH3), 0.82 (s, 9H, C(CH3)3),
4H
0.71 (s, 3H, 18-CH3), 20.04 (s, 6H, Si(CH3)2); dC
(100.6 MHz, CDCl3/TMS) 212.8 (C-5), 198.1 (C-3, d, 53,
of d, 42.5), 150.6 (C-1, d, 70.0, of d, 2.5), 130.7 (C-2, d,
53.0, of d, 14.7), 81.2 (C-17), 54.5 (C-10), 26.4 (C-4, d, 42.5
of d, 14.7), 25.7 (C(CH3)3), 17.9 (C(CH3)3), 15.3 (C-19),
11.3 (C-18), 25.0, 24.6 (Si(CH3)2).
7c: Reaction time 3 d. Chrom. solvent ethyl acetate:petro-
leum etherˆ1:7. dH (400 MHz, CDCl3/TMS) 6.73 (dd, 1H,
1-H), 5.97 (ddd, 1H, 2-H, J2C±2Hˆ159.0 Hz), 3.32 (t, 1H,
17-CH), 2.62 and 2.32 (dt, ddd respectively, 1H each,
6-CH2), 2.24 (dd, 3H, 4-H, J4C±4Hˆ127.5 Hz, J3C±4H
ˆ
5.9 Hz), 1.24 (s, 3H, 19-CH3), 1.06 (s, 9H, C(CH3)3), 0.71
(s, 3H, 18-CH3); dC (100.6 MHz, CDCl3/TMS) 213.0 (C-5),
198.3 (C-3, d, 53.0, of d, 42.5), 151.1 (C-1, d, 71.0, of d,
2.5), 130.8 (C-2, d, 53, of d, 14.7), 80.3 (C-17), 72.2
(C(CH3)3), 54.5 (C-10), 28.6 (C(CH3)3), 26.8 (C-4, d, 42.5
of d, 14.7), 15.3 (C-19), 11.6 (C-18).
7d: Reaction time 3 d. Chrom. solvent ethyl acetate:petro-
leum etherˆ1:2. dH (400 MHz, CDCl3/TMS) 6.73 (dd, 1H,
1-H), 5.98 (ddd, 1H, 2-H, J2C±2Hˆ158.0 Hz), 2.60 and 2.31
(dt, ddd respectively, 1H each, 6-CH2), 2.25 (dd, 3H, 4-H,
J4C±4Hˆ128.0 Hz, J3C±4Hˆ6.0 Hz), 1.20 (s, 3H, 19-CH3),
0.82 (s, 3H, 18-CH3); dC (100.6 MHz, CDCl3/TMS) 219.2
(C-17), 211.9 (C-5), 198.0 (C-3, d, 53.0, of d, 42.5), 150.2
(C-1, d, 71.0, of d, 2.5), 131.1 (C-2, d, 53.0, of d, 14.7), 54.4
(C-10), 26.9 (C-4, d, 42.5 of d, 15.0), 15.2 (C-19), 14.0
(C-18).
(aluminum oxide 90 (70±230 mesh) with ethyl acetate).
13C3H19PO: MS (EI), m/z (%)ˆ321 (21.2) M1, 320
12
C
18
(20.0), 305 (100) M1213CH3. dH (400 MHz, CDCl3/TMS)
1
7.3±7.8 (m, 15H, C6H5), 3.72 (dd, 1H, vCH±, JC±H
ˆ
2
1
164 Hz, JP±Hˆ32 Hz), 2.12 (3H, CH3; d, JC±Hˆ126 Hz,
of d, Jˆ5 Hz of d, Jˆ2 Hz of d, Jˆ2 Hz). dC (100.6 MHz,
1
1
CDCl3/TMS) 190.9 (CO, ddd, JvCCOˆ64 Hz, JCH3CO
ˆ
2
41 Hz, JPCˆ2 Hz), 133.0 (arom. C-2, d, Jˆ10.1 Hz),
131.9 (arom. C-4, d, Jˆ2.9 Hz), 128.8 (arom. C-3, d, Jˆ
12.3 Hz), 127.2 (arom. C-1, d, Jˆ90.6 Hz), 51.8 (vCH±,
7e: Reaction time 4 d. Chrom. solvent ethyl acetate:petro-
leum etherˆ1:3. dH (400 MHz, CDCl3/ TMS) 6.73 (dd, 1H,
1-H), 5.97 (ddd, 1H, 2-H, J2C±2Hˆ159.0 Hz), 2.58 and 2.29
(dt, ddd respectively, 1H each, 6-CH2), 2.47 (t, 1H, 17-H),
2.23 (dd, 3H, 4-H, J4C±4Hˆ128.0 Hz, J3C±4Hˆ6.0 Hz), 2.04
(s, 3H, 21-CH3), 1.22 (s, 3H, 19-CH3), 0.62 (s, 3H, 18-CH3);
dC (100.6 MHz, CDCl3/TMS) 212.5 (C-5), 208.9 (C-20),
198.3 (C-3, d, 53, of d, 42.5), 150.8 (C-1, d, 71.0, of d,
2.5), 131.0 (C-2, d, 53.0, of d, 14.7), 63.3 (C-17), 54.5
(C-10), 26.9 (C-4, d, 42.5 of d, 14.7), 15.3 (C-19), 13.4
(C-18).
1
1
2
ddd, JPCˆ108 Hz, JvCCOˆ64 Hz, JCH3CHˆ9 Hz), 28.4
(CH3,ddd, 1JCH3COˆ41 Hz, 2JCH3CHˆ19 Hz, 3JPCˆ16 Hz).
Wittig-reaction 5!7. 5a!2,3,4-13C3-17b-Hydroxy-4,5-
seco-1-androsten-3,5-dione (7a), 5b!2,3,4-13C3-17b-
tert-butyldimethylsilyloxy-4,5-seco-1-androsten-3,5-dione
(7b), 5c!2,3,4-13C3-17b-tert-butoxy-4,5-seco-1-andros-
ten-3,5-dione (7c), 5d!2,3,4-13C3-4,5-seco-1-androsten-
3,5,17-trione (7d), 5e1!2,3,4-13C3-4,5-seco-1-pregnen-
3,5,20-trione (7e). A solution of 5 (5 mmol) and of the
crude 6 (1.28 g, 4 mmol) in xylene (30 mL) was heated to
re¯ux for several days. The solvent was distilled off under
diminished pressure, and the residue was chromatographed
to give products 7 as oils. Yields see Table 1.
Reduction of C±C-double bond (7!8). 7a!2,3,4-13C3-
17b-hydroxy-4,5-seco-androstan-3,5-dione (8a), 7b!2,3,
4-13C3-17b-tert-butyldimethylsilyloxy-4,5-seco-andro-
stan-3,5-dione (8b), 7c!2,3,4-13C3-17b-tert-butoxy-4,5-
seco-androstan-3,5-dione (8c), 7d!2,3,4-13C3-4,5-seco-
androstan-3,5,17-trione (8d), 7e!2,3,4-13C3-4,5-seco-
pregnan-3,5,20-trione (8e). To a solution of enone 7
(2.75 mmol) in ethanol (20 mL) catalyst Pd/C (10%,
210 mg) was added and the mixture was shaken under
7a: Reaction time 3 d. Chrom. solvent ethyl acetate:petro-
leum etherˆ1:3. dH (400 MHz, CDCl3/TMS) 6.76 (dd, 1H,
1-H), 6.00 (ddd, 1H, 2-H, J2C±2Hˆ160.0 Hz), 3.64 (t, 1H,
17-CH), 2.62 and 2.33 (dt, ddd respectively, 1H each,
6-CH2), 2.28 (dd, 3H, 4-H, J4C±4Hˆ127.5 Hz, J3C±4H
ˆ

K. Kockert, F. W. Vierhapper / Tetrahedron 56 (2000) 9967±9974
9973
hydrogen (pressure 3 bar) on a Parr low pressure hydroge-
nator for several hours. (If hydrogenation had not taken
place after that time, the catalyst was ®ltered off, the solvent
was evaporated at reduced pressure and solvent and catalyst
were replaced with new reagents.) The catalyst was ®ltered
by passing over a short column with silica gel, and the
solvent was distilled off. Products could be obtained pure
by chromatography (see below) as colorless oils, or else the
crude products were used in the next step (8!9).
tendione (9d), 8e!2,3,4-13C3-progesterone (9e). To a
solution of crude 8 of the above step in 40 mL methanol
4 mL of 10% aqueous potassium hydroxide solution was
added and the mixture was stirred at room temperature for
several hours under a protective atmosphere of argon. After
addition of a small amount of sodium chloride the methanol
was distilled off at reduced pressure and the residue was
extracted with chloroform. The organic layer was washed
with a 5% aqueous solution of sodium chloride, dried over
magnesium sulfate and the solvent was evaporated. The
products were obtained pure by chromatography (see
below).
8a: Hydrogenation time 5 h. Chrom. solvent ethyl acetate:
petroleum etherˆ1:3. Yield 91%. dH (400 MHz, CDCl3/
TMS) 3.59 (t, 1H, 17-CH), 2.01 (dd, 3H, 4-H, J4C±4H
ˆ
128.0 Hz, J3C±4Hˆ5.6 Hz), 1.03 (s, 3H, 19-CH3), 0.72 (s,
3H,18-CH3); dC (100.6 MHz, CDCl3/TMS) 214.3 (C-5),
209.1 (C-3, d, 40.2, of d, 39.8), 81.1 (C-17), 38.7 (C-2, d,
39.8, of d, 14.6), 30.0 (C-4, d, 40.2 of d, 14.6), 20.3 (C-19),
11.0 (C-18).
9a: Reaction time 3 h. Chrom. solvent ethyl acetate:petro-
leum etherˆ1:3. Yield 80%. Mp 153±1548C (mp of
C
13C3H28O2: MS
16
12
commercial testosterone 152±1548C).
(EI), m/z (%)ˆ291 (33) M1, 247 (31), 204 (23), 147 (29),
127 (100). dH (400 MHz, CDCl3/ TMS) 5.66 (d, 1H, 4-H,
J4C±4Hˆ159.0 Hz), 3.55 (t, 1H, 17-CH), 1.11 (s, 3H,
19-CH3), 0.71 (s, 3H,18-CH3); dC (100.6 MHz, CDCl3/
TMS) 199.3 (C-3, d, 52.0, of d, 39.0), 171.3 (C-5), 123.5
(C-4, d, 52,0 of d, 11.8), 81.1 (C-17), 33.6 (C-2, d, 39.0, of d,
11.8), 17.2 (C-19), 10.9 (C-18).
8b: Hydrogenation time 2 h. Chrom. solvent ethyl acetate:
petroleum etherˆ1:7. Yield 84%; , 5% of 8a is formed and
is not separated for the synthesis of 9a. dH (400 MHz,
CDCl3/TMS) 3.49 (t, 1H, 17-CH), 2.01 (dd, 3H, 4-H,
J4C±4Hˆ127.5 Hz, J3C±4Hˆ5.8 Hz), 1.04 (s, 3H, 19-CH3),
0.81 (s, 9H, C(CH3)3), 0.70 (s, 3H, 18-CH3), 20.06 (s,
6H, Si(CH3)2); dC (100.6 MHz, CDCl3/TMS) 214.6 (C-5),
208.6 (C-3, d, 40.3, of d, 39.8), 130.7 (C-2, d, 53.0, of d,
14.7), 81.4 (C-17), 50.3 (C-10), 29.6 (C-4, d, 40.3 of d,
14.7), 25.7 (C(CH3)3), 20.4 (C-19), 17.9 (C(CH3)3), 11.2
(C-18), 25.0, 24.6 (Si(CH3)2).
9b: Reaction time 3 h. Chrom. solvent ethyl acetate:petro-
leum etherˆ1:8. Yield 81%. Mp 122±1258C.
12
C
22
13C3H42O2Si: MS (EI), m/z (%)ˆ405 (,1) M1, 390
(2.2) M12CH3, 348 (100) M12C(CH3)3. dH (400 MHz,
CDCl3/TMS) 5.64 (d, 1H, 4-H, J4C±4Hˆ161.0 Hz), 3.48 (t,
1H, 17-CH), 1.12 (s, 3H, 19-CH3), 0.80 (s, 9H, C(CH3)3),
0.67 (s, 3H, 18-CH3), 20.07 (s, 6H, Si(CH3)2); dC
(100.6 MHz, CDCl3/TMS) 199.2 (C-3, d, 52.0, of d,
40.0), 171.2 (C-5), 123.7 (C-4, d, 52,0 of d, 11.8),
81.4 (C-17), 33.8 (C-2, d, 40.0, of d, 11.8), 25.7
(C(CH3)3), 17.9 (C(CH3)3), 17.3 (C-19), 13.7 (C-18),
25.0, 24.6 (Si(CH3)2).
8c: Hydrogenation time 2 h. Chrom. solvent ethyl acetate:
petroleum etherˆ1:6. Yield 94%. dH (400 MHz, CDCl3/
TMS) 3.32 (t, 1H, 17-CH), 2.05 (dd, 3H, 4-H, J4C±4H
ˆ
128.0 Hz, J3C±4Hˆ5.6 Hz), 1.04 (s, 3H, 19-CH3), 1.03 (s,
9H, C(CH3)3), 0.68 (s, 3H, 18-CH3); dC (100.6 MHz,
CDCl3/ TMS) 214.8 (C-5), 208.9 (C-3, d, 40.3, of d,
39.9), 80.3 (C-17), 72.1 (C(CH3)3), 50.2 (C-10), 38.6
(C-2, d, 39.9, of d, 14.6), 29.6 (C-4, d, 40.3 of d, 14.6),
28.6 (C(CH3)3), 20.4 (C-19), 11.4 (C-18).
9c: Reaction time 2 h. Chrom. solvent ethyl acetate:petro-
leum etherˆ1:4. Yield 85%. Mp 165±1678C (literature5 mp
C
13C3H36O2: MS (EI),
20
12
of 12C-analogue 168.5±1698C).
m/z (%)ˆ347 (3.62) M1, 291 (100), 127 (32.0). dH
8d: Hydrogenation time 4 h. Chrom. solvent ethyl acetate:
petroleum etherˆ1:2. Yield 92%. dH (400 MHz, CDCl3/
(400 MHz, CDCl3/TMS) 5.66 (d, 1H, 4-H, J4C±4H
ˆ
161.0 Hz), 3.35 (t, 1H, 17-CH), 1.12 (s, 3H, 19-CH3), 1.05
(s, 9H, C(CH3)3), 0.69 (s, 3H, 18-CH3); dC (100.6 MHz,
CDCl3/ TMS) 199.3 (C-3, d, 52.0, of d, 40.0), 171.3
(C-5), 123.6 (C-4, d, 52,0 of d, 11.8), 80.5 (C-17), 72.0
(C(CH3)3), 33.8 (C-2, d, 40.0, of d, 12.0), 28.6 (C(CH3)3),
17.3 (C-19), 11.5 (C-18).
TMS) 2.02 (dd, 3H, 4-H, J4C±4Hˆ128.0 Hz, J3C±4H
ˆ
5.5 Hz), 1.01 (s, 3H, 19-CH3), 0.80 (s, 3H, 18-CH3); dC
(100.6 MHz, CDCl3/TMS) 219.6 (C-17), 213.9 (C-5),
208.6 (C-3, d, 40.3, of d, 39.5), 50.1 (C-10), 38.4 (C-2, d,
39.5, of d, 14.5), 29.6 (C-4, d, 40.3 of d, 14.5), 20.2 (C-19),
13.5 (C-18).
9d: Reaction time 1 h. Chrom. solvent ethyl acetate:petro-
leum etherˆ1:8. Yield 87%. Mp 169±1718C (literature8 mp
of 12C-analogue 173±1748C). 12C1613C3H26O2: MS (EI), m/z
(%)ˆ 289 (100) M1, 245 (33), 149 (54), 127 (85). dH
8e: Hydrogenation time 3 h. Chrom. solvent ethyl acetate:
petroleum etherˆ1:4. Yield 93%. dH (400 MHz, CDCl3/
TMS) 2.12 (dd, 3H, 4-H, J4C±4Hˆ128.0 Hz, J3C±4H
ˆ
5.6 Hz), 2.04 (s, 3H, 21-CH3), 1.03 (s, 3H, 19-CH3), 0.63
(s, 3H, 18-CH3); dC (100.6 MHz, CDCl3/TMS) 214.6 (C-5),
208.7 (C-3, d, 53, of d, 42.5), 208.6 (C-20), 63.2 (C-17),
50.3 (C-10), 38.6 (C-2, d, 53.0, of d, 14.7), 31.3 (C-21), 29.7
(C-4, d, 42.5 of d, 14.7), 20.4 (C-19), 13.3 (C-18).
(400 MHz, CDCl3/ TMS) 5.68 (d, 1H, 4-H, J4C±4H
ˆ
161.0 Hz), 1.12 (s, 3H, 19-CH3), 0.83 (s, 3H,18-CH3); dC
(100.6 MHz, CDCl3/TMS) 220.2 (C-17), 199.1 (C-3, d,
52.0, of d, 40.0), 170.2 (C-5), 124.0 (C-4, d, 52,0 of d,
12.0), 33.8 (C-2, d, 40.0, of d, 12.0), 17.3 (C-19), 13.6
(C-18).
Aldol reaction with 8 to steroids 9. 8a!2,3,4-13C3-testos-
terone (9a), 8b!2,3,4-13C3-17b-tert-butyldimethylsilyl-
oxy-4-androsten-3-one (9b), 8c!2,3,4-13C3-17b-tert-
butoxy-4-androsten-3-one (9c), 8d!2,3,4-13C3-andros-
9e: Reaction time 4 h. Chrom. solvent ethyl acetate:petro-
leum etherˆ1:4. Yield 82%. Mp 121±122.58C (literature9
mp of lower melting modi®cation of 12C-analogue 121±1228C).

9974
K. Kockert, F. W. Vierhapper / Tetrahedron 56 (2000) 9967±9974
12
C
13C3H30O2: MS (EI), m/z (%)ˆ317 (31) M1, 273 (35),
layer was dried over sodium sulfate and the solvent was
evaporated. Yield of 9a 182 mg (92%).
18
230 (34), 127 (100). dH (400 MHz, CDCl3/TMS) 5.70 (d,
1H, 4-H, J4C±4Hˆ160.0 Hz), 2.13 (s, 3H, 21-CH3), 1.18 (s,
3H, 19-CH3), 0.68 (s, 3H,18-CH3); dC (100.6 MHz, CDCl3/
TMS) 208.3 (C-20), 198.8 (C-3, d, 51.9, of d, 39.4), 169.7
(C-5), 123.6 (C-4, d, 51,9 of d, 11.9), 63.3 (C-17), 33.8 (C-2,
d, 39.4, of d, 11.9), 17.3 (C-19), 13.2 (C-18).
References
1. de Avellar, I. G. J.; Vierhapper, F. W. Tetrahedron 2000, 56,
9957±9965.
Removal of 17b-tert-butyldimethylsilyl protecting group
(9b!9a). To a solution of 9b (1.2 mmol) in tetrahydrofuran
(10 mL) acetic acid (30 mL) and water (10 mL) were added
and the mixture was heated to re¯ux for 1 h. The mixture
was cooled, water (30 mL) was added, the aqueous phase
was extracted with chloroform, the organic layer was dried
and the solvent evaporated. Remaining acetic acid was
distilled off under reduced pressure with toluene as an
azeotrope. Yield of 9a 95%.
2. Frimer, A. A.; Hameiri-Buch, J.; Ripshtos, S.; Gilinsky-Sharon,
P. Tetrahedron 1986, 42, 5693±5706.
È
3. Kockert, K. PhD Thesis, Naturwissenschaftliche Fakultat der
È
Universitat Wien, 2000.
4. (a) Pesaro, M.; Bozzato, G.; Schudel, P. Chem. Commun. 1968,
1152±1154. (b) Woodward, R. B.; Singh, T. J. Am. Chem. Soc.
1950, 72, 494±500. (c) Wilds, A. L.; Djerassi, C. J. Am. Chem. Soc.
1946, 68, 1715±1719. (d) Dreiding, A. S.; Tomasewski, A. T.
 Â
J. Org. Chem. 1954, 19, 241±254. (e) Nedelec, L.; Torelli, V.;
Costerousse, G. Bull. Soc. Chim. Fr. 1975, 2037±2042. (f)
 Â
Bucourt, R.; Nedelec, L.; Torelli, V.; Gasc, J.-C.; Vignau, M.
 Â
Bull. Soc. Chim. Fr. 1975, 2043±2047. (g) Guillaume, J.; Nedelec,
Removal of 17b-tert-butyl protecting group (9c!9a).
The tert-butyl group was hydrolyzed with tri¯uoro acetic
acid as described in the literature.5 Yield of 9a was 86%.
L. Bull. Soc. Chim. Fr. 1975, 2048±2051.
5. Ihara, M.; Tokunaga, Y.; Taniguchi, N.; Fukumoto, K.
Tetrahedron 1991, 33, 6635±6648.
Reduction of the 17-keto group to the 17b-alcohol
(9d!9a). To a solution of sodium borohydride in methanol
(25 mL) and dichloromethane (20 mL), stirred at room
temperature for 3 min and brought to 2788C 9d (200 mg
dissolved in methanol/dichloromethane) was added. After
6 h the reaction was quenched with acetone, and the solution
was extracted with a 10% aqueous solution of sodium
hydrogen carbonate at room temperature. The organic
6. Bestmann, H. J.; Arnason, B. Chem. Ber. 1962, 95, 1513±1527.
7. Gros, E. G.; Leete, E. J. Amer. Chem. Soc. 1965, 87, 3479±
3484.
8. Ruzicka, L.; Wettstein, A. Helv. Chim. Acta 1935, 18, 986±994.
9. Butenandt Schmidt, A. Ber. Dtsch. Chem. Ges. 1934, 67, 2088±
2091.