Enantioselective total synthesis of the oral contraceptive desogestrel by a double heck reaction

Article abstract of DOI:10.1002/chem.200700182

A novel enantioselective total synthesis of the oral contraceptive desogestrel (2) is described, in which the tetracyclic steroid core is formed by a sequence of two consecutive Heck reactions. Conversion of the known enantiopure diketone 7 led to the chiral bicycle 6 which was used for a diastereoselective intermolecular Heck reaction with vinyliodide 5 to give 15. In the following intramolecular Heck reaction, the tetracyclic ring system was formed to give 4, from which the synthesis of desogestrel (2) was furnished.

Full text of DOI:10.1002/chem.200700182

FULL PAPER
DOI: 10.1002/chem.200700182
Enantioselective Total Synthesis of the Oral Contraceptive Desogestrel by a
Double Heck Reaction
Lutz F. Tietze* and Ilga K. Krimmelbein[a]
Dedicated to Professor Miguel Yus on the occasion of his 60th birthday
Abstract: A novel enantioselective total synthesis of the oral contraceptive deso-
gestrel (2) is described, in which the tetracyclic steroid core is formed by a se-
quence of two consecutive Heck reactions. Conversion of the known enantiopure
diketone 7 led to the chiral bicycle 6 which was used for a diastereoselective inter-
molecular Heck reaction with vinyliodide 5 to give 15. In the following intramolec-
ular Heck reaction, the tetracyclic ring system was formed to give 4, from which
the synthesis of desogestrel (2) was furnished.
Keywords:
contraceptives · Heck reaction ·
palladium · steroids
Birch reduction
·
Introduction
at C-13 to an ethyl group and the removal of the methyl
group at C-10 as well as the introduction of the methylene
group at C-11. In addition, the availability of diosgenin (1)
is not always guaranteed. Therefore a more efficient total
synthesis of desogestrel (2) starting from simple substrates is
highly wanted.
Here, we report a new efficient enantioselective total syn-
thesis of desogestrel (2) using two consecutive Heck reac-
tions[4,5] as key steps. This strategy which has been devel-
oped by us within the total synthesis of estradiol[6] and ho-
mosteroids[7,8] as well as of spinosyn[9] and cephalostatine an-
alogues[10] has now proved to be successful also in the con-
struction of steroid-cores with an angular ethyl group at
C-13. Furthermore, also 3-ketodesogestrel (3) can be synthe-
sized employing this approach. It should be noted that a few
other approaches for the synthesis of desogestrel (2) have
already been published.[11,12]
Progestagen desogestrel (13b-ethyl-11-methylene-18,19-
dinor-17a-pregn-4-en-20-yn-17-ol) (2) is a highly potent
third generation oral contraceptive. Moreover, its active me-
tabolite, 3-ketodesogestrel (3), has been established as an-
other progestagen of increasing importance in the last
years.[1,2]
The industrial synthesis of desogestrel (2) consists of 24
steps using the natural occurring diosgenin (1) as starting
material (Figure 1).[3] The procedure has several critical
steps including the elongation of the angular methyl group
Results and Discussion
Figure 1. Natural occurring diosgenin (1) and the synthetic oral contra-
ceptive desogestrel (2) with its main metabolite 3-ketodesogestrel (3).
Our retrosynthetic analysis of 2 leads to the B/C cis-fused
compound 4 which can be further disassembled to the aro-
matic AB building block 5 and the chiral CD building block
6 (Scheme 1). For the formation of 4 from 5 and 6 a two-
fold Heck reaction was envisaged, whereas the trans-annu-
lated hydrindene 6 could be obtained from the known
ketone 7, which in turn can be prepared in enantiopure
form by the l-proline-catalyzed Hajos–Parrisch–Eder–
Sauer–Wiechert procedure.[13,14]
[a] Prof. Dr. L. F. Tietze, Dr. I. K. Krimmelbein
Institut für Organische und Biomolekulare Chemie
der Georg-August-Universität Gçttingen
Tammannstrasse 2, 37077 Gçttingen (Germany)
Fax : (+49)551-399-476
E-mail: ltietze@gwdg.de
Chem. Eur. J. 2008, 14, 1541 – 1551
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1541

from the less hindered a-face to give the alcohol 12 selec-
tively. Treatment of 12 with N-formylimidazole afforded
allyl formate 13 in excellent yield, which was further trans-
formed into the desired 6 by an enantioselective Pd-cata-
lyzed rearrangement. This type of reaction, first described
by Tsuji et al.,[15] represents a convenient method to achieve
the desired trans-annulation of the CD building block 6. In
this procedure the conjugated 3,5-diene 14 is formed in
small amounts as byproduct. Separation of 6 and 14 by
column chromatography was not possible, however, hydrin-
dene 6, containing up to 6% of 14, could be used without
any problems for the subsequent intermolecular Heck reac-
tion.
Scheme 1. Retrosynthetic analysis of desogestrel (2).
For the first Heck reaction, coupling 5 and 6, the use of
(OAc)2 in the presence of PPh3 and Ag2CO3 in DMF[16]
PdACHTREUNG
was most appropriate (Scheme 4). Under these conditions
the oxidative addition of the palladium catalyst took place
exclusively at the more reactive vinyl iodide moiety in 5.
Moreover, the insertion into the double bond of 6 took
place exclusively from the a-face anti to the angular ethyl
group establishing the stereochemistry as needed for the
synthesis of 2. On the other hand, the regioselectivity is less
pronounced leading to a 7:1-mixture of 15 and 17. In addi-
tion, the E isomer 16 was obtained in a small amount proba-
bly by readdition of the Pd-H species onto 15 and b-hydride
elimination of the formed Pd species. Due to similar polari-
ties of compounds 15, 16 and 17 separation of these isomers
turned out to be difficult on simple silica gel and although
compounds 16 and 17 can not react in an intramolecular
Heck reaction pure 15 should be used for the next transfor-
mation. Fortunately, the purification could be achieved by
column chromatography using silica gel loaded with 10% of
AgNO3 to give 15 in 56% yield. Construction of the tetracy-
clic steroid core from 15 was then successfully performed
using the palladacene 19[17] at 1358C to afford 4 in 94%
yield. The reaction is highly diastereoselective leading only
to the unnatural cis junction of the rings B and C. Com-
pound 4 proved to be sensitive to oxygen which led to the
formation of the aromatic product 18 being obtained, how-
ever, only in very small amounts if the reaction is performed
under an inert atmosphere. Due to the sensitivity of 4 the
crude material was used for the following transformation
without purification; only the catalyst was removed by quick
filtration through silica gel. The less sterically hindered ben-
zylic D6,7-double bond in 4 was selectively hydrogenated in
the presence of PtO2·H2O to afford 20 (Scheme 5). Al-
though 20 was more stable than the precursor 4 it was still
found to be quite sensitive to air. This is presumably a con-
sequence of the unnatural and therefore less stable cis
fusion of the rings B and C. However, the D10,11-double bond
in 20 was isomerized in the next step under basic conditions
with KOtBu in DMSO to obtain the enantiopure literature
known compound 21 in 69% yield.[18] Cleavage of the tert-
butyl group with BF3·Et2O at RT afforded alcohol 22 in ex-
cellent yield. This compound has already been used as an in-
termediate in a synthesis of desogestrel (2);[11c] thus, synthe-
sis of 22 can also be regarded as formal synthesis of 2. How-
The synthesis of the aromatic compound 5 containing the
required functionalities for the two Heck reactions was ac-
complished in two steps starting from the commercially
available
3-methoxybenzaldehyde
(8)
(Scheme 2).
Scheme 2. Synthesis of the AB building block 5. a) 1.14 equiv bromine,
acetic acid, RT, 48 h, 80%; b) 1.25 equiv [Ph3PCH2I]+Iꢀ (10), 1.25 equiv
KHMDS in toluene, THF, RT, 10 min, addition of 9 at ꢀ788C, 30 min.
Bromination of 8 with equimolar amounts of bromine in
acetic acid at room temperature gave aldehyde 9 regioselec-
tively. Wittig transformation with triphenylphosphonium salt
10 yielded 5 with the Z configuration of the iodo vinyl side
chain in 79% with high stereoselectivity. The minor E
isomer was removed by column chromatography.
Starting from compound 11, a literature known derivative
of 7,[13] the novel CD building block 6 was available in three
high yielding steps (Scheme 3). Reduction of the carbonyl
group in 11 was carried out with DIBAL-H in dichlorome-
thane at ꢀ788C with attack of the hydride ion taking place
Scheme 3. Synthesis of the CD building block 6. a) 1.20 equiv DIBALH
in n-hexane, CH2Cl2, ꢀ788C, 1 h, 95%; b) 2.06 equiv N-formylimidazole,
THF, RT, 2 h, 97%; c) 1.27 mol% PdCAHTRE(UNG OAc)2, 5.00 mol% PnBu3, dioxane,
908C, 35 min, 97%, 6/14 94:6.
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Chem. Eur. J. 2008, 14, 1541 – 1551

Oral Contraceptive Desogestrel
FULL PAPER
in liquid ammonia to afford 28
in 55% yield over four steps.
Noteworthy, in this four-step se-
quence the compounds 26 and
27 were used as crude material
since purification by column
chromatography resulted in a
dramatic loss of material.
The following oxidation of
the 11-hydroxy group proceed-
ed smoothly using Dess–Martin
periodinane to obtain 29 in ex-
cellent yield and the formation
of the required 11-exo-methyl-
ene group was then accom-
plished by a two step sequence
(Scheme 7).
Addition
of
Scheme 4. Inter- and intramolecular Heck reaction of the AB building block 5 and the CD building block 6.
LiCH2TMS in THF at ꢀ788C
a) 1.81 mol% PdACHTREUNG(OAc)2, 5.32 mol% PPh3, 1.77 equiv Ag2CO3, DMF, 958C, 4.5 h, 77%, 15/16/17 7:1.7:1 (56%
pure 15); b) 2.03 mol% 19, 2.57 equiv nBu4NOAc, CH3CN/DMF/H2O 5:5:1, 1358C, 5 h, 94%.
afforded at first the tertiary al-
Scheme 5. Synthesis of 23. a) 1.85 mol% PtO2·H2O, H2, ethyl acetate,
39 h, RT, 91%; b) 2.61 equiv KOtBu, DMSO, RT, 2.5 h, 89% (69% after
recrystallization); c) 39.1 equiv BF3·Et2O, CH2Cl2, RT, 15 min, 96%;
d) 4.88 equiv BH3·THF, THF, RT, 3.5 h, then 30% aqueous H2O2, 30%
aqueous NaOH, RT, 70 min and reflux, 2 h, 90% 23 and 7% 24; e) conc.
H2SO4, CH2Cl2, RT, 30 min, 50%.
Scheme 6. Synthesis of 28. a) 9.33 equiv Li, NH3, iPrOH, THF, ꢀ408C,
1.5 h; b) 1n HCl, acetone, MeOH, H2O, RT, 19 h; c) 1.48 equiv 1,2-etha-
nedithiol, 0.594 equiv BF3·Et2O, RT, 3 h, d) 3.73 equiv Li, NH3, THF,
ꢀ408C, 30 min, 55% over 4 steps.
ever, we developed a new pathway for the formation of 2
from 21, which is more efficient.
cohol 31 which was converted by an acid-catalyzed Peterson
olefination to give 32. Both reactions proceeded in high
yields and could also be performed as an one-pot reaction.
Unfortunately, direct olefination methods of the ketone ac-
cording to the Lombardo or Wittig procedure were not suc-
cessful and led to a decomposition or no conversion of the
starting material.
For the cleavage of the tert-butyl group in 31 we used as a
standard procedure the treatment with BF3·Et2O in di-
chloromethane for 10 min at 258C. However, under these
conditions a migration of the D4,5 double bond to the D5,6 po-
sition took place to give the desired 32a and the undesired
32b in a ratio of 1:2.5. Since the deprotection is much faster
than the double bond isomerization, the problem could be
solved by reducing the reaction time to only 15 s to afford
the desired alcohol 32a almost pure in a ratio of 32a/32b
By hydroboration, 21 was converted into the alcohol 23 in
90% yield with the 11-hydroxy group being the basis for the
construction of the 11-exo-methylene group. As byproduct,
the regioisomer 24 was formed in 7% yield. Treatment of 24
with concentrated sulfuric acid in dichloromethane allowed
a transformation back to the starting material 21.
Birch reduction of 23 provided the corresponding 1,4-di-
hydro derivative which was subsequently treated with aque-
ous hydrochloric acid to give the unconjugated ketone 25 at
first but with prolongation of the reaction time the thermo-
dynamically more stable ketone 26 is formed (Scheme 6).
Without purification 26 was converted into the dithioacetal
27 using 1,2-ethanedithiol in the presence of BF3·Et2O,
which was followed by a reductive replacement with lithium
Chem. Eur. J. 2008, 14, 1541 – 1551
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1543

L. F. Tietze and I. K. Krimmelbein
and achieve a double bond migration from the D5,10 to the
thermodynamically more stable D4,5 position. Simultaneous-
ly, the 11-exo-methylene group was also formed by acid cat-
alyzed elimination.
The following deprotection of the tert-butyl group with
BF3·Et2O proceeded quantitatively and due to the 3-keto
group no double bond isomerisation was observed. Oxida-
tion of alcohol 36 with Dess–Martin periodinane afforded
37, a compound that has been successfully converted to 3-
ketodesogestrel (3) by Gao et al.[19] Besides, alcohol 36 is an
intermediate in the enantioselective total synthesis of deso-
gestrel (2) described by Corey et al.[11e]
For the transformation of 36 into 2, 36 was converted into
the dithioacetal 38 employing 1,2-ethanedithiol in the pres-
ence of BF3·Et2O (Scheme 9). Subsequent reductive removal
Scheme 7. Construction of the 11-exo-methylene group. a) 1.57 equiv
Dess–Martin periodinane, CH2Cl2, RT, 1 h, 94%; b) 2.98 equiv
LiCH2TMS in n-pentane, THF, ꢀ788C, 20 min then RT, 30 min, 94%;
c) conc. HCl, acetone, RT, 1 h, 95%; d) 27.3 equiv BF3·Et2O, CH2Cl2, RT,
15 s, quant., 32a/32b 96:4.
96:4, but it was not possible to separate the double bond iso-
mers at this stage by chromatography or recrystallization.
Employment of other reagents for the removal of the tert-
butyl group like TMSI or CF3COOH effected only decom-
position of the starting material. Therefore an alternative
route starting from alcohol 23 was investigated to avoid a
double bond migration in the deprotection step. For this
purpose we oxidized 23 with the Dess–Martin periodinane
to give ketone 33 which proved to be only moderately
stable and was therefore used directly for the introduction
of the 11-exo-methylene group (Scheme 8). The method of
choice was once more the Peterson olefination as the Wittig
and Lombardo olefination were not successful. Reaction of
33 with LiCH2TMS afforded 34 in good yield which was
then subjected to a Birch reduction with lithium in liquid
ammonia. The crude 1,4-dihydro derivative was subsequent-
ly treated with conc. HCl in acetone to cleave the enol ether
Scheme 9. Synthesis of 32a by reductive removal of the dithioacetal.
a) 1.49 equiv 1,2-ethanedithiol, 0.567 equiv BF3·Et2O, MeOH, RT, 2.5 h,
84%; b) 12.7 equiv Li, NH3, THF, ꢀ408C, 30 min, 96%, ratio 32a/32c
92:8.
of the dithioacetal moiety with lithium in liquid ammonia at
ꢀ408C afforded the desired alcohol 32a, but again a double
bond isomer 32c was formed as byproduct. In contrast to
the synthesis of 32a by Lewis-acid catalyzed deprotection of
the tert-butyl group, the migration of the double bond took
place from the D4,5 to the D3,4 position and also in this case
separation by chromatography or recrystallization was not
successful.
Thus, the synthesis had to be continued with a mixture of
isomers and due to the better ratio the mixture of 32a and
32b from the first approach was chosen for the further
transformation. Oxidation of the 17-hydroxy group with
Dess–Martin periodinane afforded the isomers 39a and 39b
in a ratio of 96:4 (Scheme 10). Attempts to purify 39a by re-
Scheme 8. Synthesis of 36 and 37. a) 1.52 equiv Dess–Martin periodinane,
CH2Cl2, RT, 1 h, 97%; b) 2.51 equiv LiCH2TMS in n-pentane, THF,
ꢀ788C, 30 min then RT, 10 min, 79%; c) 10.0 equiv Li, NH3, iPrOH,
THF, ꢀ408C, 1.5 h; d) conc. HCl, acetone, RT, 15 h, 74% over two steps;
e) 43.9 equiv BF3·Et2O, CH2Cl2, RT, 10 min, quant.; f) 1.55 equiv Dess–
Martin periodinane, CH2Cl2, RT, 80 min, 94%.
Scheme 10. Synthesis of desogestrel (2). a) 1.50 equiv Dess–Martin peri-
odinane, CH2Cl2, RT, 30 min, 96%, 39a/39b 96:4; b) 42.0 equiv lithium,
acetylene, ethylenediamine, RT, 2 h, then 39a/39b 96:4, RT, 2 h, recrys-
tallization afforded pure 2 in 83% yield.
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Oral Contraceptive Desogestrel
FULL PAPER
obtained as yellow oil. Rf =0.17 (n-pentane); 1H NMR (300 MHz,
CDCl3): d=3.84 (s, 3H, 4-OCH3), 6.74 (d, J=8.5 Hz, 1H, 2’-H), 6.78 (dd,
J=8.8, 3.0 Hz, 1H, 5-H), 7.24 (d, J=3.0 Hz, 1H, 3-H), 7.31 (d, J=8.5 Hz,
1H, 1’-H), 7.47 ppm (d, J=8.8 Hz, 1H, 6-H); 13C NMR (50.3 MHz,
CDCl3): d=55.54 (4-OCH3), 83.46 (C-2’), 113.9 (C-1), 115.3, 116.1 (C-3,
C-5), 133.4 (C-6), 138.1 (C-2), 139.0 (C-1’), 158.5 ppm (C-4); IR (film):
n˜ =2933, 1589, 1566, 1462, 1294, 1238, 1176, 1114, 1055, 1018, 860, 806,
722, 667 cmꢀ1; UV (CH3CN): lmax (lg e)=200.5 nm (4.3589); MS (70 eV,
EI): m/z (%): 338.0/340.0 (56/56) [M+], 132.1 (100) [M+ꢀBrꢀI].
crystallization were not successful and thus the mixture of
39a and 39b was used for the final step. The introduction of
the 17b-acetylene group was carried out with lithium and
acetylene in ethylendiamine according to a method de-
scribed by Schwarz et al.[11c] The product obtained was puri-
fied by column chromatography and then subjected to re-
crystallization to afford pure desogestrel (2) in 83% yield.
(+)-(1S,5S,7aS)-1-tert-Butoxy-7a-ethyl-7,7a-dihydroindan-5(6H)-ol (12):
Compound 11 (9.00 g, 38.1 mmol) was dissolved in dry dichloromethane
(135 mL) and cooled to ꢀ788C. DIBAL-H (1.00m in n-hexane, 45.6 mL,
45.6 mmol) was slowly added and the resulting mixture was stirred for
40 min at ꢀ788C and 1 h at room temperature. The reaction mixture was
carefully quenched with a saturated solution of Na2SO4 and then filtered
through Celite. The filtrate was dried over Na2SO4 and the solvent was
removed in vacuo. After purification of the residue by column chroma-
tography on silica gel (n-pentane/EtOAc 4:1) 12 (8.62 g, 95%) was ob-
tained as colorless oil, which solidified upon cooling. Rf =0.15 (n-pen-
tane/EtOAc 9:1); m.p. 528C; [a]2D0 =+14.0 (c=1.0 in CHCl3); 1H NM R
(600 MHz, CDCl3): d=0.95 (t, J=7.6 Hz, 3H, 7a-CH2CH3), 1.13 (s, 9H,
Conclusion
In conclusion, a new efficient enantioselective total synthesis
of the oral contraceptive desogestrel (2) has been devel-
oped. Starting from compound 11, the total synthesis of des-
ogestrel (2) requires 18 steps with an overall yield of 9.8%.
Key step for the construction of the steroid backbone was a
two-fold Heck reaction of 5 and 6 that led to the intermedi-
ate 4, which then could be converted into desogestrel (2) by
common methods.
1-OCACHTRE(UGN CH3)3), 1.24 (dt, J=13.4, 3.2 Hz, 1H, 7-Ha), 1.38 (brs, 1H, 5-OH),
1.46 (dq, J=14.5, 7.6 Hz, 1H, 7a-CHaHbCH3), 1.54 (m, 1H, 6-Ha), 1.65
(dq, J=14.5, 7.6 Hz, 1H, 7a-CHaHbCH3), 1.65–1.73 (m, 1H, 2-Ha), 1.85–
1.96 (m, 2H, 2-Hb, 6-Hb), 1.97–2.08 (m, 2H, 3-Ha, 7-Hb), 2.42 (m, 1H, 3-
Hb), 3.43 (t, J=8.7 Hz, 1H, 1-H), 4.24 (m, 1H, 5-H), 5.39 ppm (s, 1H, 4-
H); 13C NMR (75.5 MHz, CDCl3): d=10.41 (7a-CH2CH3), 24.82 (7a-
Experimental Section
CH2CH3), 26.56 (C-3), 28.60 (1-OC
30.47 (C-7), 45.53 (C-7a), 67.94 (C-5), 72.46 (1-OCAHCTREUNG
ACHTREUNG
General: All moisture sensitive reactions were performed under argon in
flame-dried flasks. All solvents were dried and distilled prior to use by
means of usual laboratory methods. All reagents obtained from commer-
cial sources were used without further purification. Thin-layer chroma-
tography (TLC) was performed on precoated silica gel SIL G/UV254
plates (Macherey-Nagel GmbH & Co. KG), and silica gel 60 (0.032–
0.063 mm, Merck) was used for column chromatography. Phosphomolyb-
dic acid dissolved in methanol (PMA) or vanillin dissolved in methanolic
sulfuric acid were used as staining reagents for TLC analysis. UV spectra
were recorded, using CH3CN or MeOH as solvents, on a Perkin–Elmer
Lambda 2 spectrometer. IR spectra were recorded as KBr pellets or as
122.3 (C-4), 149.4 ppm (C-3a); IR (KBr): n˜ =3287, 2970, 1462, 1389,
1362, 1200, 1091, 1046, 1005, 921, 893, 865, 754 cmꢀ1; UV (CH3CN): lmax
(lg e)=202 nm (3.9046); MS (DCI, NH3): m/z (%): 256.3 (2) [M++NH4],
238.3 (64) [M+ꢀH2O+NH4], 221.3 (87) [M+ꢀH2O+H], 182.2 (100) [M+
ꢀC4H9+H]; elemental analysis calcd (%) for C15H26O2 (238.4): C 75.58,
H 10.99; found: C 75.60, H 10.71.
(ꢀ)-(1S,5S,7aS)-1-tert-Butoxy-7a-ethyl-7,7a-dihydroindan-5-yl-formate
(13): Formic acid (2.45 mL, 65.0 mmol) was slowly added at room tem-
perature to a solution of N,N’-carbonyldiimidazole (10.5 g, 64.5 mmol) in
THF (200 mL). The resulting mixture was stirred for 24 h at room tem-
perature. The solvent was removed and the residue was dried for 30 min
in vacuo and then resolved in THF (40 mL). A solution of alcohol 12
(7.46 g, 31.3 mmol) in THF (10 mL) was added at room temperature and
the mixture was stirred for further 3 h. The solvent was removed in
vacuo, the residue then resolved in n-pentane (200 mL) and decanted
from insoluble components. The organic layer was washed with brine and
dried over Na2SO4. Removal of the solvent afforded 13 (8.13 g, 97%) as
colorless oil. Rf =0.66 (n-pentane/EtOAc 4:1); [a]2D0 =ꢀ60.0 (c=1.0 in
CHCl3); 1H NMR (500 MHz, CDCl3): d=0.94 (t, J=7.6 Hz, 3H, 7a-
1
films on a Bruker IFS 25 spectrometer. H and 13C NMR spectra were re-
corded with Mercury-200, VXR-200, Unity-300, Inova-500, Unity-600
(Varian), or AMX 300 (Bruker) spectrometers. Chemical shifts are re-
ported in ppm using residual solvent as internal standard. Multiplicities
of 13C NMR peaks were determined with the attached proton test (APT)
pulse sequence. Mass spectra were measured on a Finnigan MAT 95,
TSQ 7000 or LCQ instrument. Elemental analysis was carried out by
members of the Mikroanalytisches Labor, Institut für Organische und
Biomolekulare Chemie, Georg-August-Universität Gçttingen.
2-Bromo-5-methoxybenzaldehyde (9): Bromine (5.72 mL, 111 mmol) was
added at room temperature to a solution of 3-methoxybenzaldehyde
(11.8 mL, 97.0 mmol). After stirring for 48 h, the mixture was poured
into water (650 mL) and the precipitated product was filtered of and ex-
tensively washed with water. After drying in vacuo aldehyde 9 (16.7 g,
80%) was obtained as white solid. 1H NMR (200 MHz, CDCl3): d=3.85
(s, 3H, 5-OCH3), 7.04 (dd, J=8.8, 3.2 Hz, 1H, 4-H), 7.42 (d, J=3.2 Hz,
1H, 6-H), 7.53 (d, J=8.8 Hz, 1H, 3-H), 10.32 ppm (s, 1H, 1-CHO); MS
(70 eV, EI): m/z (%): 214.1/216.1 (100/87) [M+].
CH2CH3), 1.13 (s, 9H, 1-OCCATHER(UNG CH3)3), 1.32 (dt, J=13.2, 3.5 Hz, 1H, 7-Ha),
1.48 (dq, J=14.8, 7.6 Hz, 1H, 7a-CHaHbCH3), 1.63 (dq, J=14.8, 7.6 Hz,
1H, 7a-CHaHbCH3), 1.66–1.75 (m, 2H, 2-Ha, 6-Ha), 1.85–1.98 (m, 2H, 2-
Hb, 6-Hb), 2.01 (ddd, J=13.2, 5.8, 3.5 Hz, 1H, 7-Hb), 2.08 (m, 1H, 3-Ha),
2.43 (m, 1H, 3-Hb), 3.46 (t, J=8.7 Hz, 1H, 1-H), 5.38–5.45 (m, 2H, 4-H,
5-H), 8.07 ppm (d, J=0.9 Hz, 1H, 5-OCHO); 13C NMR (75.5 MHz,
CDCl3): d=10.12 (7a-CH2CH3), 24.63 (7a CH2CH3), 25.15 (C-6), 26.74
(C-3), 28.59 (1-OC
ACHTREUNG
(C-5), 72.57 (1-OCAHCTREUNG
(Z)-2-(2-Iodethenyl)-4-methoxybrombenzol (5): KHMDS (0.500m in tol-
uene, 70 mL, 35.0 mmol) was added at room temperature to a suspension
of iodmethyltriphenylphosphonium iodide (10) (18.5 g, 34.9 mmol) in dry
THF (200 mL). The mixture was stirred for 10 min at room temperature
and then cooled to ꢀ788C. A solution of aldehyde 9 (6.00 g, 27.9 mmol)
in dry THF (20 mL) was added slowly and stirring was continued for
30 min at ꢀ788C. The solution was then warmed to room temperature
and poured into saturated aqueous NH4Cl (200 mL). The mixture was ex-
tracted with diethyl ether (3”150 mL), the combined organic layers were
washed with saturated aqueous NaCl (100 mL) and dried over Na2SO4.
The solvent was removed in vacuo and the residue was subjected to
column chromatography (n-pentane). Vinyliodide 5 (7.51 g, 79%) was
161.2 ppm (5-OCHO); IR (film): n˜ =2971, 1724, 1462, 1363, 1181, 1083,
919, 871 cmꢀ1; UV (CH3CN): lmax (lg e)=197.5 nm (4.0231); MS (DCI,
NH3): m/z (%): 284.3 (2) [M++NH4], 238.3 (100) [M+ꢀCO2ꢀH2+NH4];
elemental analysis calcd (%) for C16H26O3 (266.4): C 72.14, H 9.84;
found: C 72.06, H 9.66.
(+)-(1S,3aS,7aS)-1-tert-Butoxy-7a-ethyl-3a,6,7,7a-tetrahydroindane (6):
PdACHTRE(UNG OAc)2 (70.1 mg, 317 mmol) and PnBu3 (312 mL, 1.25 mmol) were
added to a degassed solution of 13 (6.63 g, 24.9 mmol) in dry dioxane.
The mixture was stirred for 15 min at room temperature and then heated
to 908C. After gas evolution started (8 to 20 min) the mixture was stirred
for further 30 min at 908C and then immediately cooled in an ice bath.
Chem. Eur. J. 2008, 14, 1541 – 1551
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1545

L. F. Tietze and I. K. Krimmelbein
The solvent was removed in vacuo and the residue was purified by
column chromatography on silica gel (n-pentane). The bicyclic 6 (5.36 g,
97%, 6/14 94:6) was obtained as colorless liquid which contained a small
amount of the diene 14. Rf =0.19 (n-pentane); [a]2D0 =+31.5 (c=1.0 in
CHCl3); 1H NMR (500 MHz, CDCl3): d=1.01 (t, J=7.5 Hz, 3H, 7a-
ties and was used directly in the next step due to its moderate stability.
Rf =0.27 (Et2O/n-pentane 1:99); 1H NMR (500 MHz, CDCl3): d=1.05 (t,
J=7.5 Hz, 3H, 13-CH2CH3), 1.11 (s, 9H, 17-OCACHTREU(GN CH3)3), 1.22–1.33 (m,
1H, 13-CHaHbCH3), 1.34–1.58 (m, 2H, 15-H2, 16-Ha), 1.61–1.77 (m, 2H,
14-H, 13-CHaHbCH3), 1.82–1.91 (m, 1H, 16-Hb), 2.71 (m, 1H, 8-H), 3.51
(dd, J=8.8, 7.0 Hz, 1H, 17-H), 3.66 (m, 1H, 9-H), 3.78 (s, 3H, 3-OCH3),
5.88 (dd, J=9.8, 6.0 Hz, 1H, 7-H), 6.13 (dd, J=10.1, 1.1 Hz, 1H, 12-H),
6.24 (dd, J=10.1, 4.5 Hz, 1H, 11-H), 6.33 (d, J=9.8 Hz, 1H, 6-H), 6.55
(d, J=2.8 Hz, 1H, 4-H), 6.70 (dd, J=8.4, 2.8 Hz, 1H, 2-H), 7.21 ppm (d,
J=8.4 Hz, 1H, 1-H); 13C NMR (50.3 MHz, CDCl3): d=10.67 (13-
CH2CH3), 1.21 (s, 9H, 1-OCCATHER(UNG CH3)3), 1.13–1.21 (m, 1H, 7-Ha), 1.26–1.42
(m, 3H, 3-Ha, 7a-CH2CH3), 1.47–1.61 (m, 2H, 2-Ha, 3-Hb), 1.90–2.00 (m,
1H, 2-Hb), 2.00–2.14 (m, 4H, 3a-H, 6-H2, 7-Hb), 3.49 (t, J=8.1 Hz, 1H, 1-
H), 5.49–5.60 ppm (m, 2H, 4-H, 5-H); 13C NMR (75.5 MHz, CDCl3): d=
10.19 (7a-CH2CH3), 18.00 (7a-CH2CH3), 23.94 (C-3), 24.50 (C-6), 28.54
(1-OC
(1-OCACHTREUNG
A
CH2CH3), 22.19 (C-15), 22.89 (13-CH2CH3), 28.60 (17-OC
(C-16), 33.57 (C-8), 36.94 (C-9), 42.48 (C-14), 45.64 (C-13), 55.18 (3-
OCH3), 72.34 (17-OC(CH3)3), 78.18 (C-17), 112.0 (C-2, C-4), 126.6 (C-6),
126.8 (C-11), 127.7 (C-1), 129.3 (C-10), 131.1 (C-7), 134.0 (C-5, C-12),
157.9 ppm (C-3); MS (70 eV, EI): m/z (%): 352.4 (37) [M+], 295.3 (46)
[M+ꢀC4H9]; EI-HRMS: m/z: calcd for C24H32O2: 352.2402, found:
352.2402.
ACHTRE(UNG CH3)3), 32.12
2972, 1637, 1463, 1389, 1362, 1252, 1195, 1122, 1071, 982, 936, 888,
678 cmꢀ1; UV (CH3CN): lmax (lg e)=237.5 nm (2.9597); MS (70 eV, EI):
m/z (%): 222.2 (2) [M+], 165.2 (40) [M+ꢀC4H9]; EI-HRMS: m/z: calcd
for C15H26O: 222.1984; found: 222.1984.
ACHTREUNG
(ꢀ)-(1S,3aS,4S,7aS)-4-(Z)-(2-Bromo-5-methoxystyryl)-1-tert-butoxy-7a-
ethyl-3a,4,7,7a-tetrahydroindane (15): Pd
(OAc)2 (24.7 mg, 110 mmol,),
(ꢀ)-17b-tert-Butoxy-13b-ethyl-3-methoxy-9b-gona-1,3,5(10),11-tetraene
PPh3 (85.7 mg, 327 mmol) and Ag2CO3 (2.99 g, 10.8 mmol) were added to
a degassed solution of 6 (1.60 g, 7.20 mmol, 6/14 94:6) in dry DMF
(55 mL) with protection from light. The resulting suspension was treated
with a solution of the vinyliodide 5 (1.22 g, 3.60 mmol) in dry and de-
gassed DMF (5 mL). The mixture was warmed to 958C in a preheated oil
bath for 70 min with stirring. Two other portions of the vinyliodide 5
(610 mg, 1.80 mmol) in DMF (2.5 mL) and (305 mg, 0.900 mmol) in DMF
(1.5 mL) were added after 1 h and 2 h, respectively, and the mixture was
stirred for further 60 min at 958C. Finally, another portion of vinyliodide
5 (305 mg, 900 mmol) in DMF (1.5 mL) was added together with Pd-
(20): A mixture of PtO2·H2O (22.6 mg, 63.7 mmol) and 4 (1.22 g,
3.45 mmol) in ethyl acetate (115 mL) was stirred for 39 h under a hydro-
gen atmosphere at room temperature. The solvent was removed in vacuo
and the residue purified by column chromatography on silica gel (n-pen-
tane/CH2Cl2 4:1) to afford steroid 20 (1.12 g, 91%) as colorless oil. Rf =
0.24 (n-pentane/EtOAc 98:2); [a]2D0 =ꢀ151.4 (c=0.50 in CHCl3);
1H NMR (600 MHz, CDCl3): d=1.04 (t, J=7.5 Hz, 3H, 13-CH2CH3),
1.11 (s, 9H, 17-OCACTHER(UNG CH3)3), 1.31 (dq, J=13.5, 7.5 Hz, 1H, 13-CHaHbCH3),
1.36–1.44 (m, 1H, 15-Ha), 1.45–1.52 (m, 1H, 14-H), 1.52–1.71 (m, 4H, 7-
Ha, 15-Hb, 16-Ha, 13-CHaHbCH3), 1.76–1.84 (m, 1H, 7-Hb), 1.90–1.98 (m,
1H, 16-Hb), 2.38 (m, 1H, 8-H), 2.52 (dt, J=15.9, 4.4 Hz, 1H, 6-Ha), 2.73
(m, 1H, 6-Hb), 3.44 (d, J=7.0 Hz, 1H, 9-H), 3.52 (dd, J=8.5, 7.5 Hz, 1H,
17-H), 3.77 (s, 3H, 3-OCH3), 6.05 (s, 2H, 11-H, 12-H), 6.62 (d, J=2.8 Hz,
1H, 4-H), 6.75 (dd, J=8.5, 2.8 Hz, 1H, 2-H), 7.25 ppm (d, J=8.5 Hz, 1H,
1-H); 13C NMR (151 MHz, CDCl3): d=10.80 (13-CH2CH3), 22.40 (C-15),
ACHTREUNG(OAc)2 (4.5 mg, 20.0 mmol), PPh3 (14.8 mg, 56.4 mmol) and Ag2CO3
(543 mg, 1.97 mmol) and stirring was continued for 70 min at 958C.
Water (100 mL) was added to the hot reaction mixture and after cooling
to room temperature the mixture was extracted with Et2O (4”40 mL).
The organic layers were washed with brine (40 mL), dried over Na2SO4
and the solvent was evaporated in vacuo. The residue was then first puri-
fied by column chromatography on silica gel (EtOAc/n-pentane 1:100)
and afterwards by a second column chromatography on silica gel that
was loaded with 10% AgNO3 (EtOAc/n-pentane 1:150). Compound 15
(1.76 g, 4.05 mmol, 56%) was obtained as colorless oil. In addition, ana-
lytical pure samples of the regioisomer 17 and the E isomer 16 were iso-
lated. Rf =0.32 (n-pentane/CH2Cl2 7:3); [a]2D0 =ꢀ61.2 (c=1.0 in CHCl3);
1H NMR (600 MHz, CDCl3): d=0.90 (t, J=7.5 Hz, 7a-CH2CH3), 1.09–
22.79 (13-CH2CH3), 25.45 (C-7), 26.21 (C-6), 28.63 (17-OC
(C-8), 32.18 (C-16), 38.37 (C-9), 43.40 (C-14), 45.69 (C-13), 55.14 (3-
OCH3), 72.30 (17-OC(CH3)3), 78.66 (C-17), 112.1 (C-2), 113.2 (C-4),
ACHTRE(UNG CH3)3), 31.00
AHCTREUNG
129.1 (C-1), 129.8 (C-11), 131.5 (C-10), 133.6 (C-12), 138.7 (C-5),
157.0 ppm (C-3); IR (KBr): n˜ =2932, 1610, 1500, 1466, 1361, 1257, 1197,
1089, 1043, 911, 793 cmꢀ1; UV (CH3CN): lmax (lg e)=200.0 (4.5815),
260.5 nm (3.7309); MS (70 eV, EI): m/z (%): 354.3 (56) [M+], 297.2 (100)
[M+ꢀC4H9]; EI-HRMS: m/z: calcd for C24H34O2: 354.2559, found:
354.2559.
1.15 (m, 1H, 7a-CHaHbCH3), 1.13 (s, 9H, 1-OCACHTREU(GN CH3)3), 1.16–1.24 (m,
1H, 3-Ha), 1.31–1.43 (m, 2H, 3a-H, 7a-CHaHbCH3), 1.47–1.54 (m, 1H, 2-
Ha), 1.60–1.72 (m, 2H, 3-Hb, 7-Ha), 1.83–1.91 (m, 1H, 2-Hb), 2.40 (dd, J=
17.3, 5.7 Hz, 1H, 7-Hb), 3.02–3.08 (m, 1H, 4-H), 3.55 (t, J=8.5 Hz, 1H, 1-
H), 3.78 (s, 3H, 5’’-OCH3), 5.41–5.46 (m, 2H, 1’-H, 5-H), 5.69–5.73 (m,
1H, 6-H), 6.44 (d, J=11.3 Hz, 1H, 2’-H), 6.69 (dd, J=8.8, 3.1 Hz, 1H,
4’’-H), 6.81 (d, J=3.1 Hz, 1H, 6’’-H), 7.44 ppm (d, J=8.8 Hz, 1H, 3’’-H);
13C NMR (126 MHz, CDCl3): d=10.55 (7a-CH2CH3), 18.25 (7a-
(+)-17b-tert-Butoxy-13b-ethyl-3-methoxygona-1,3,5(10),9(11)-tetraene
(21): A solution of steroid 20 (1.19 g, 3.35 mmol) in dry DMSO (90 mL)
was treated with KOtBu (981 mg, 8.76 mmol) with stirring for 2.5 h at
room temperature. Water (100 mL) and brine (50 mL) were added and
the mixture was extracted with MTBE (3”50 mL). The combined organ-
ic layers were washed with brine (50 mL) and dried over Na2SO4. Evapo-
ration of the solvent and filtration through silica gel (n-pentane/EtOAc/
NEt3 95:5:1) afforded a colorless oil, which solidified after standing. The
enantiopure steroid 21 (821 mg, 2.31 mmol, 69%) was obtained after re-
crystallization from ethanol as colorless needles. Rf =0.29 (n-pentane/
EtOAc 98:2); [a]2D0 =+98.5 (c=1.0 in CHCl3), lit.:[18] +97.13 (c=1.0 in
CH2CH3), 24.43 (C-3), 28.60 (1-OC
38.84 (C-4), 42.64 (C-7a), 47.54 (C-3a), 55.44 (5’’-OCH3), 72.23 (1-OC-
ACHTREUNG(CH3)3), 82.68 (C-1), 114.3 (C-4’’), 114.4 (C-2’’), 115.9 (C-6’’), 127.4 (C-6),
ACHTREU(NG CH3)3), 30.73 (C-2), 34.47 (C-7),
129.1 (C-5), 129.3 (C-2’), 133.0 (C-3’’), 136.5 (C-1’), 138.6 (C-1’’),
158.4 ppm (C-5’’); IR (KBr): n˜ =2967, 1591, 1567, 1463, 1413, 1362, 1297,
1236, 1196, 1162, 1126, 1059, 1018, 878, 687 cmꢀ1; UV (CH3CN): lmax (lg
e)=202.5 (4.3905), 214.0 (4.3863), 291.0 nm (3.3289); MS (70 eV, EI):
m/z (%): 432.3/343.3 (4/4) [M+], 279.3 (32) [M+ꢀBrꢀC4H10O]; EI-
HRMS: m/z: calcd for C24H33BrO2: 432.1664, found: 432.1663.
CHCl3); 1H NMR (600 MHz, C6D6): d=1.23 (s, 9H, 17-OC
ACHTRE(UNG CH3)3), 1.24
(t, J=7.5 Hz, 3H, 13-CH2CH3), 1.26–1.37 (m, 3H, 7-Ha, 14-H, 15-Ha),
1.40–1.47 (m, 1H, 13-CHaHbCH3), 1.57–1.65 (m, 2H, 15-Hb, 13-
CHaHbCH3), 1.69–1.76 (m, 1H, 16-Ha), 1.82–1.91 (m, 3H, 7-Hb, 12-Ha,
16-Hb), 2.09–2.15 (m, 1H, 8-H), 2.63 (ddd, J=17.6, 5.9, 1.5 Hz, 12-Hb),
2.68 (ddd, J=16.7, 5.0, 1.6 Hz, 1H, 6-Ha), 2.77 (ddd, J=16.7, 13.0, 5.3 Hz,
1H, 6-Hb), 3.38 (s, 3H, 3-OCH3), 3.42 (t, J=8.6 Hz, 1H, 17-H), 6.14–6.17
(m, 1H, 11-H), 6.64 (d, J=2.7 Hz, 1H, 4-H), 6.77 (dd, J=8.8, 2.7 Hz,
1H, 2-H), 7.56 ppm (d, J=8.8 Hz, 1H, 1-H); 13C NMR (126 MHz, C6D6):
d=11.15 (13-CH2CH3), 19.07 (13-CH2CH3), 24.29 (C-15), 28.79 (17-OC-
(ꢀ)-17b-tert-Butoxy-13b-ethyl-3-methoxy-9b-gona-1,3,5(10),6,11-pen-
taene (4): A solution of 15 (1.59 g, 3.67 mmol) and nBu4NOAc (2.84 g,
9.43 mmol) in CH3CN/DMF/H2O 5:5:1 (60 mL) was carefully degassed.
Herrmann–Beller catalyst[19] 19 (69.7 mg, 74.3 mmol) was added, the re-
sulting mixture was warmed to 1358C with a preheated oil bath and
stirred for 5 h. The hot solution was then treated with water (200 mL),
cooled to room temperature and extracted with Et2O (3”50 mL). The
combined organic layers were washed with brine (50 mL), dried over
Na2SO4 and the solvent was evaporated in vacuo. The residue was then
quickly filtered through silica gel (EtOAc/n-pentane 5:95) to give 4
(1.22 g, 94%) as a slightly yellow oil which contained some minor impuri-
AHCTREUNG
AHCTREUNG
(C-17), 113.0 (C-2), 113.6 (C-4), 118.0 (C-11), 125.8 (C-1), 128.3 (C-10),
136.4, 137.5 (C-5, C-9), 159.1 ppm (C-3); IR (KBr): n˜ =2969, 1606, 1497,
1468, 1388, 1362, 1317, 1279, 1233, 1197, 1133, 1110, 1081, 1049, 908, 869,
841, 812 cmꢀ1; UV (CH3CN): lmax (lg e)=213.5 (4.2925), 263.0 (4.2821),
1546
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 1541 – 1551

Oral Contraceptive Desogestrel
FULL PAPER
298.5 nm (3.4977); MS (70 eV, EI): m/z (%): 354.5 (100) [M+], 297.3 (65)
[M+ꢀC4H9]; EI-HRMS: m/z: calcd for C24H34O2: 354.2559, found:
354.2559.
the color disappeared and the ammonia was distilled off at room temper-
ature. The residue was dissolved in water (30 mL) and MTBE (20 mL),
the layers were separated and the aqueous layer was extracted with
MTBE (2”30 mL). The combined organic extracts were dried over
Na2SO4 and the solvent was removed in vacuo to give a white foam,
which was resolved in acetone/methanol/water 2:5:1 (36 mL). The solu-
tion was treated with 1n HCl (6.75 mL) and stirred for 19 h at room tem-
perature. The mixture was then neutralized with saturated aqueous
NaHCO3 (5 mL) and the solvent removed in vacuo. Water (20 mL) and
MTBE (30 mL) were added to the residue, the layers separated and the
aqueous layer was extracted with MTBE (2”30 mL). The combined or-
ganic extracts were dried over Na2SO4 and the solvent evaporated. Crude
steroid 26 (418 mg 1.16 mmol) was obtained as colorless foam and was
used in the next step without further purification. An analytical pure
sample was obtained after column chromatography on silica gel (n-pen-
tane/EtOAc 65:35). Rf =0.17 (n-pentane/EtOAc 7:3); [a]2D0 =ꢀ28.7 (c=
1.0 in CHCl3); 1H NMR (600 MHz, CDCl3): d=0.91 (t, J=11.5 Hz, 1H,
(+)-13b-Ethyl-3-methoxygona-1,3,5(10),9(11)-tetraene-17b-ol (22):
A
stirred solution of steroid 21 (48.8 mg, 138 mmol) in dichloromethane
(6.8 mL) was treated with BF3·EtO2 (48% in Et2O, 680 mL, 5.39 mmol)
and stirring was continued for 15 min at room temperature. The reaction
was quenched with saturated aqueous NaHCO3 (20 mL) and the layers
were separated. The aqueous layer was extracted with dichloromethane
(3”10 mL), the combined organic layers were dried over Na2SO4 and the
solvent was removed in vacuo. Column chromatography on silica gel (n-
pentane/EtOAc/NEt3 80:20:1) of the residue afforded alcohol 22
(39.4 mg, 96%) as colorless oil, which was crystallized from methanol.
Rf =0.10 (n-pentane/EtOAc 9:1); [a]2D0 = +123.5 (c=1.0 in CHCl3) lit.:[20]
+124, (c=1.0 in CHCl3); 1H NMR (600 MHz, C6D6): d=1.29 (t, J=
7.5 Hz, 3H, 13-CH2CH3), 1.21–1.31 (m, 3H, 7-Ha, 14-H, 15-Ha), 1.37 (dq,
J=14.7, 7.5 Hz, 1H, 13-CHaHbCH3), 1.45 (dq, J=14.7, 7.5 Hz, 1H, 13-
CHaHbCH3), 1.52–1.61 (m, 2H, 15-Hb, 16-Ha), 1.79–1.85 (m, 2H, 7-Hb,
12-Ha), 1.89–1.96 (m, 1H, 16-Hb), 2.03–2.10 (m, 1H, 8-H), 2.59 (ddd, J=
17.8, 5.7, 1.8 Hz, 1H, 12-Hb), 2.64 (ddd, J=16.7, 5.3, 1.8 Hz, 1H, 6-Ha),
2.73 (ddd, J=16.7, 13.1, 5.3 Hz, 1H, 6-Hb), 3.38 (s, 3H, 3-OCH3), 3.62 (t,
J=8.8 Hz, 1H, 17-H), 6.10 (m, 1H, 11-H), 6.62 (d, J=2.7 Hz, 1H, 4-H),
6.76 (dd, J=8.8, 2.7 Hz, 1H, 2-H), 7.53 ppm (d, J=8.8 Hz, 1H, 1-H);
13C NMR (126 MHz, C6D6): d=11.00 (13-CH2CH3), 18.48 (13-CH2CH3),
23.86 (C-15), 28.87 (C-7), 30.40 (C-6), 31.27 (C-16), 35.50 (C-12), 39.24
(C-8), 43.36 (C-13), 48.99 (C-14), 54.74 (3-OCH3), 83.96 (C-17), 113.0 (C-
2), 113.6 (C-4), 117.8 (C-11), 125.8 (C-1), 128.3 (C-10), 136.3, 137.5 (C-5,
C-9), 159.1 ppm (C-3); IR (KBr): n˜ =3405, 2934, 1607, 1497, 1463, 1279,
1233, 1167, 1111, 1047, 909, 879, 810 cmꢀ1; UV (CH3CN): lmax (lg e)=
263.0 (4.2707), 298.0 nm (3.4612); MS (DCI, NH3): m/z (%): 299.2 (100)
[M++H]; EI-HRMS: m/z: calcd for C20H26O2: 298.1933, found: 298.1933.
12-Ha), 1.04 (t, J=7.4 Hz, 3H, 13-CH2CH3), 1.11 (s, 9H, 17-OCACHTREUNG(CH3)3),
1.00–1.25 (m, 5H, 7-Ha, 9-H, 14-H, 15-Ha, 13-CHaHbCH3), 1.40–1.58 (m,
5H, 8-H, 15-Hb, 16a-H, 13-CHaHbCH3, 11-OH), 1.83–1.95 (m, 2H, 7-Hb,
16-Hb), 2.15–2.32 (m, 4H, 1-Ha, 2-Ha, 6-Ha, 10-H), 2.38 (dd, J=12.2,
4.5 Hz, 1H, 12-Hb), 2.38–2.49 (m, 3H, 1-Hb, 2-Hb, 6-Hb), 3.45 (t, J=
8.5 Hz, 1H, 17-H), 3.71 (ddd, J=10.7, 9.5, 4.5 Hz, 1H, 11-H), 5.80 ppm
(t, J=1.5 Hz, 1H, 4-H); 13C NMR (126 MHz, CDCl3): d=9.61 (13-
CH2CH3), 19.18 (13-CH2CH3), 22.87 (C-15), 27.50 (C-1), 28.51 (17-OC-
AHCTREUNG
AHCTREUNG
;
(4.1616), 283.0 (2.3193), 314.0 nm (2.3067); MS (70 eV, EI): m/z (%):
360.3 (22) [M+]; ESI-HRMS: m/z: calcd for [C23H36O3+H+]: 361.27372,
found: 361.27398.
(ꢀ)-17b-tert-Butoxy-13b-ethyl-11a-hydroxy-3-methoxygona-1,3,5(10)-
triene (23): BH3·THF (1.00m in THF, 8.00 mL, 8.00 mmol) was added at
room temperature to a solution of 21 (581 mg, 1.64 mmol) in dry THF
and the resulting mixture was stirred for 3.5 h. Then water (0.55 mL) was
carefully added, followed by the addition of ice-cold 30% aqueous
NaOH (3.0 mL) and ice-cold 30% aqueous H2O2 (3.0 mL). Stirring was
then continued for 70 min at room temperature and 2 h at 608C. Water
(50 mL) was added and the mixture was extracted with Et2O (3”15 mL).
The combined organic layers were washed with saturated aqueous
Na2SO3, dried over Na2SO4 and the solvent was removed in vacuo.
Column chromatography on silica gel (n-pentane/EtOAc 9:1) of the resi-
due afforded alcohol 23 (552 mg, 90%) as white foam. In addition, small
amounts of the regioisomer 24 (42.8 mg, 7%) were obtained. Rf =0.23
(n-pentane/EtOAc 9:1); [a]2D0 =ꢀ75.5 (c=1.0 in CHCl3); 1H NM R
(600 MHz, CDCl3): d=1.03–1.09 (m, 4H, 12-Ha, 13-CH2CH3), 1.09–1.19
(+)-17b-tert-Butoxy-13b-ethyl-3,3-ethylenedithio-11a-hydroxy-gona-4-
ene (27): 1,2-Ethanedithiol (144 mL, 162 mg, 1.72 mmol) and BF3·Et2O
(48% in Et2O, 87.0 mL, 670 mmol) were added at room temperature to a
solution of crude 26 (418 mg, 1.16 mmol) in methanol (40 mL) and the
mixture was stirred for 3 h. Saturated aqueous NaHCO3 (5 mL) and
water (20 mL) were added and methanol was evaporated in vacuo. The
aqueous layer was extracted with MTBE (2”30 mL) and the combined
organic layers were dried over Na2SO4. Evaporation of the solvent af-
forded crude 27 (507 mg, 1.16 mmol) as white foam, which was used in
the next step without further purification. An analytical pure sample was
obtained by column chromatography on silica gel (n-pentane/EtOAc
4:1). Rf =0.33 (n-pentane/EtOAc 9:1); [a]2D0 =+42.3 (c=1.0 in CHCl3);
1H NMR (600 MHz, CDCl3): d=0.80 (q, J=9.9 Hz, 1H, 9-H), 0.86 (t, J=
11.6 Hz, 1H, 12-Ha), 0.90–0.98 (m, 1H, 7-Ha), 1.00–1.06 (m, 1H, 14-H),
(m, 1H, 13-CHaHbCH3), 1.16 (s, 9H, 17-OCACHTRE(UNG CH3)3), 1.20–1.30 (m, 2H,
1.03 (t, J=7.3 Hz, 3H, 13-CH2CH3), 1.11 (s, 9H, 17-OCACTHRE(UNG CH3)3), 1.08–1.32
14-H, 15-Ha), 1.37–1.46 (m, 3H, 7-Ha, 8-H, 13-CHaHbCH3), 1.54–1.63 (m,
3H, 15-Hb, 16-Ha, 11-OH), 1.84–1.90 (m, 1H, 7-Hb), 1.93–2.01 (m, 1H,
16-Hb), 2.11 (t, J=9.9 Hz, 1H, 9-H), 2.53 (dd, J=12.2, 4.7 Hz, 1H, 12-
Hb), 2.77–2.87 (m, 2H, 6-H2), 3.55 (t, J=8.3 Hz, 1H, 17-H), 3.79 (s, 3H,
3-OCH3), 4.08 (ddd, J=10.8, 9.9, 4.7 Hz, 1H, 11-H), 6.66 (d, J=2.8 Hz,
1H, 4-H), 6.73 (dd, J=8.7 ?z, 2.8 Hz, 1H, 2-H), 7.85 ppm (d, J=8.7 Hz,
1H, 1-H); 13C NMR (126 MHz, CDCl3): d=9.49 (13-CH2CH3), 18.94 (13-
(m, 4H, 8-H, 15-Ha, 13-CHaHbCH3, 11-OH), 1.38–1.56 (m, 3H, 15-Hb, 16-
Ha, 13-CHaHbCH3), 1.65–1.70 (m, 1H, 7-Hb), 1.86–2.05 (m, 5H, 1-Ha, 2-
Ha, 6-Ha, 10-H, 16-Hb), 2.20–2.26 (m, 2H, 2-Hb, 6-Hb), 2.32–2.38 (m, 1H,
1-Hb), 2.36 (dd, J=12.4, 4.6 Hz, 1H, 12-Hb), 3.21–3.27 (m, 1H, S-
CHaHbCH2-S), 3.29–3.38 (m, 3H, S-CHaHbCH2-S), 3.44 (t, J=8.3 Hz,
1H, 17-H), 3.64 (ddd, J=11.2, 9.9, 4.6 Hz, 1H, 11-H), 5.60 ppm (d, J=
1.0 Hz, 1H, 4-H); 13C NMR (126 MHz, CDCl3): d=9.61 (13-CH2CH3),
19.14 (13-CH2CH3), 22.90 (C-15), 28.54 (17-OCCAHTREU(GN CH3)3), 29.28 (C-1), 31.17
(C-7), 31.37 (C-16), 35.47 (C-6), 39.64, 39.66, 39.74 (C-8, S-CH2CH2-S),
40.29 (C-2), 42.31 (C-10), 44.07 (C-13), 45.11 (C-12), 50.13 (C-14), 55.23
CH2CH3), 22.80 (C-15), 26.98 (C-7), 28.58 (17-OC
31.44 (C-16), 37.04 (C-8), 44.06 (C-12), 44.67 (C-13), 50.37 (C-9), 50.88
(C-14), 55.15 (3-OCH3), 70.63 (C-11), 72.31 (17-OC(CH3)3), 82.05 (C-17),
ACHTRE(UNG CH3)3), 28.63 (C-6),
AHCTREUNG
110.9 (C-2), 113.7 (C-4), 127.1 (C-1), 132.7 (C-10), 139.1 (C-5), 157.6 ppm
(C-3); IR (KBr): n˜ =3406, 2936, 1609, 1498, 1464, 1389, 1362, 1255, 1196,
1132, 1092, 1059, 868 cmꢀ1; UV (CH3CN): lmax (lg e)=200.0 (4.6396),
218.0 (3.9241), 277.0 nm (3.2455); MS (70 eV, EI): m/z (%): 372.4 (100)
[M+]; EI-HRMS: m/z: calcd for C24H36O3: 372.2664, found: 372.2664.
(C-9), 65.64 (C-3), 72.23 (17-OCACHTREU(NG CH3)3), 72.61 (C-11), 82.10 (C-17), 125.7
(C-4), 142.0 ppm (C-5); IR (KBr): n˜ =3444, 2929, 2873, 1440, 1389, 1361,
1197, 1132, 1073, 912, 861, 757 cmꢀ1; UV (CH3CN): no absorption; MS
(70 eV, EI): m/z (%): 436.3 (100) [M+]; ESI-HRMS: m/z: calcd for
[C25H40O2S2 + H+]: 437.25425, found: 437.25412.
(ꢀ)-17b-tert-Butoxy-13b-ethyl-11a-hydroxy-gona-4-en-3-one (26): A so-
lution of steroid 23 (434 mg, 1.17 mmol) in dry THF (20 mL) was slowly
added at ꢀ408C to a mixture of condensed ammonia (50 mL) and iPrOH
(2.5 mL). Small pieces of lithium (75.8 mg, 10.9 mmol) were added por-
tionwise over a period of 90 min, so that the deep blue color of the mix-
ture maintained over this time. Then solid NH4Cl was slowly added until
(+)-17b-tert-Butoxy-13b-ethyl-11a-hydroxygona-4-ene (28):
A solution
of crude steroid 27 (507 mg, 1.16 mmol) in dry THF (20 mL) was slowly
added at ꢀ408C to condensed ammonia (40 mL). Small pieces of lithium
(30.0 mg, 4.32 mmol) were added portionwise over a period of 30 min, so
that the deep blue color of the mixture maintained over this time. Then
solid NH4Cl was slowly added until the color disappeared and the ammo-
Chem. Eur. J. 2008, 14, 1541 – 1551
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1547

L. F. Tietze and I. K. Krimmelbein
nia was distilled off at room temperature. The residue was dissolved in
water (30 mL) and MTBE (20 mL), the layers were separated and the
aqueous layer was extracted with MTBE (2”30 mL). The combined or-
ganic extracts were dried over Na2SO4, the solvent was removed in vacuo
and the residue was subjected to column chromatography on silica gel
(n-pentane/EtOAc 97:3). Steroid 28 (221 mg, 637 mmol, 55% over four
steps) was obtained as colorless oil. Rf =0.21 (n-pentane/EtOAc 97:3);
(d, J=15.0 Hz, 1H, 11-CHaHbSiAHCTRE(UNG CH3)3), 1.63–1.70 (m, 1H, 2-Hb), 1.72
(dquint., J=12.6, 2.5 Hz, 1H, 7-Hb), 1.83–1.91 (m, 2H, 1-Ha, 16-Hb),
1.93–1.99 (m, 3H, 1-Hb, 3-H2), 1.99–2.07 (m, 1H, 6-Ha), 2.17–2.24 (m,
2H, 6-Hb, 10-H), 2.47 (d, J=14.3 Hz, 1H, 12-Hb), 3.35 (t, J=8.3 Hz, 1H,
17-H), 5.41 ppm (brs, 1H, 4-H); 13C NMR (126 MHz, CDCl3): d=1.06
(11-CH2Si
23.40 (C-15), 25.62 (C-3), 28.66 (17-OC
32.63 (C-7), 36.00 (11-CH2Si(CH3)3), 36.49 (C-6), 39.29 (C-8), 40.59 (C-
10), 43.13 (C-13), 50.62 (C-12), 50.70 (C-14), 56.81 (C-9), 72.17 (17-OC-
(CH3)3, 77.18 (C-11), 84.12 (C-17), 120.0 (C-4), 142.0 ppm (C-5); IR
(film): n˜ =3627, 2928, 1658, 1436, 1389, 1362, 1248, 1197, 1133, 1080,
ACHTREUNG
AHCTREUNG
1
[a]2D0 =+20.5 (c=1.0 in CHCl3); H NMR (600 MHz, CDCl3): d=0.80 (q,
ACHTREUNG
J=9.9 Hz, 1H, 9-H), 0.85–0.94 (m, 2H, 7-Ha, 12-Ha), 1.01–1.07 (m, 1H,
14-H), 1.04 (t, J=7.4 Hz, 3H, 13-CH2CH3), 1.12 (s, 9H, 17-OC
A
ACHTREUNG
1.14–1.23 (m, 2H, 15-Ha, 13-CHaHbCH3), 1.27–1.33 (m, 2H, 2-Ha, 8-H),
1.33–1.46 (m, 2H, 15-Hb, 13-CHaHbCH3), 1.46–1.57 (m, 2H, 16-Ha, 11-
OH), 1.61–1.72 (m, 3H, 1-Ha, 2-Hb, 7-Hb), 1.86–1.98 (m, 3H, 3-H2, 16-
Hb), 1.98–2.06 (m, 2H, 6-Ha, 10-H), 2.17–2.24 (m, 2H, 1-Hb, 6-Hb), 2.37
(dd, J=12.2, 4.7 Hz, 1H, 12-Hb), 3.45 (t, J=8.2 Hz, 1H, 17-H), 3.67 (ddd,
J=11.2, 9.4, 4.7 Hz, 1H, 11-H), 5.43 ppm (d, J=1.9 Hz, 1H, 4-H);
13C NMR (126 MHz, CDCl3): d=9.60 (13-CH2CH3), 19.13 (13-CH2CH3),
21.93 (C-2), 22.96 (C-15), 25.37 (C-3), 28.53 (17-OCACHTREU(GN CH3)3), 30.00 (C-1),
31.39 (C-16), 31.70 (C-7), 36.03 (C-6), 39.97 (C-8), 43.42 (C-10), 44.00 (C-
13), 44.85 (C-12), 50.20 (C-14), 55.73 (C-9), 72.19 (C-11), 72.64 (17-OC-
1028, 911, 838, 760, 688 cmꢀ1
; UV (CH3CN): lmax (lg e)=198.5 nm
(3.7757); MS (70 eV, EI): m/z (%): 432.4 (7) [M+]; ESI-HRMS: m/z:
calcd for [C27H48O2Si + Na+]: 455.33158, found: 455.33193.
(+)-17b-tert-Butoxy-13b-ethyl-11-methylenegona-4-ene (31): A solution
of 30 (201 mg, 464 mmol) in acetone (20 mL) was treated with conc. HCl
(0.37 mL) and stirred for 60 min at room temperature. The mixture was
then neutralized with saturated aqueous NaHCO3 (10 mL) and the ace-
tone was removed in vacuo. The aqueous residue was diluted with water
(20 mL) and extracted with Et2O (4”10 mL). The combined extracts
were washed with saturated aqueous NaCl (10 mL) and dried over
Na2SO4. Evaporation of the solvent and column chromatography on
silica gel (n-pentane/EtOAc 99:1) of the obtained residue afforded ste-
roid 31 (152 mg, 95%) as colorless oil, which solidified on standing. Rf =
0.53 (n-pentane/EtOAc 100:1); [a]2D0 =+112.3 (c=1.0 in CHCl3);
1H NMR (600 MHz, C6D6): d=0.88–1.00 (m, 2H, 7-Ha, 14-H), 1.10 (s,
ACHTREUNG(CH3)3), 82.19 (C-17), 120.9 (C-4), 140.3 ppm (C-5); IR (KBr): n˜ =3423,
2927, 1445, 1389, 1362, 1198, 1132, 1074, 910, 808 cmꢀ1; UV (CH3CN): no
absorption; MS (70 eV, EI): m/z (%): 346.3 (23) [M+]; ESI-HRMS: m/z:
calcd for [C23H38O2 + Na+]: 369.27640, found: 369.27633.
(+)-17b-tert-Butoxy-13b-ethylgona-4-en-11-one (29): A solution of ste-
roid 28 (243 mg, 702 mmol) in dichloromethane (20 mL) was treated with
Dess–Martin periodinane (467 mg, 1.10 mmol) and stirred for 60 min at
room temperature. Saturated aqueous NaHCO3 (3.0 mL) and 10% aque-
ous Na2S2O3 (3.0 mL) were added and the mixture was stirred for further
45 min. The layers were separated and the aqueous layer was extracted
with dichloromethane (3”20 mL). The combined organic extracts were
dried over Na2SO4, the solvent was removed in vacuo and the residue
was filtered through a short column of silica gel (n-pentane/EtOAc 95:5)
to give ketone 29 (227 mg 94%) as colorless oil. Rf =0.51 (n-pentane/
EtOAc 95:5); [a]2D0 = +142.0 (c=1.0 in CHCl3); 1H NMR (600 MHz,
CDCl3): d=0.83–0.90 (m, 1H, 1-Ha), 0.97–1.08 (m, 5H, 7-Ha, 13-
9H, 17-OCACTHER(UGN CH3)3), 1.20 (dq, J=12.3, 6.5 Hz, 1H, 15-Ha), 1.24–1.40 (m,
8H, 1-Ha, 8-H, 9-H, 15-Hb, 13-CH2CH3, 13-CHaHbCH3), 1.44–1.52 (m,
2H, 2-Ha, 13-CHaHbCH3), 1.47 (d, J=12.2 Hz, 1H, 12-Ha), 1.59–1.68 (m,
3H, 2-Hb, 7-Hb, 16-Ha), 1.76–1.84 (m, 1H, 16-Hb), 1.94–2.06 (m, 3H, 3-
H2, 6-Ha), 2.24–2.38 (m, 3H, 1-Hb, 6-Hb, 10-H), 2.85 (d, J=12.2 Hz, 1H,
12-Hb), 3.31 (t, J=8.3 Hz, 1H, 17-H), 4.79 (s, 1H, 11-CHaHb), 5.06 (d, J=
1.1 Hz, 1H, 11-CHaHb), 5.57 ppm (d, J=2.1 Hz, 1H, 4-H); 13C NM R
(151 MHz, C6D6): d=9.44 (13-CH2CH3), 19.70 (13-CH2CH3), 22.44 (C-2),
22.74 (C-15), 26.16 (C-3), 28.71 (17-OC
32.16 (C-7), 36.11 (C-6), 37.06 (C-10), 42.43 (C-8), 45.54 (C-12), 46.29 (C-
13), 52.52 (C-14), 55.63 (C-9), 72.18 (17-OC(CH3)3, 82.38 (C-17), 108.3
ACHTREU(NG CH3)3), 29.69 (C-1), 32.02 (C-16),
CH2CH3, 13-CHaHbCH3), 1.10 (s, 9H, 17-OC
A
ACHTREUNG
6.5 Hz, 1H, 15-Ha), 1.36–1.46 (m, 1H, 2-Ha), 1.46–1.54 (m, 1H, 13-
CHaHbCH3), 1.54–1.66 (m, 5H, 2-Hb, 8-H, 14-H, 15-Hb, 16-Ha), 1.70–1.77
(m, 2H, 7-Hb, 9-H), 1.88–1.96 (m, 3H, 3-H2, 6-Ha), 1.96–2.04 (m, 1H, 16-
Hb), 2.01 (d, J=11.3 Hz, 1H, 12-Ha), 2.16–2.21 (m, 1H, 6-Hb), 2.23–2.31
(m, 2H, 1-Ha, 10-H), 2.77 (d, J=11.3 Hz, 1H, 12-Hb), 3.66 (t, J=8.2 Hz,
1H, 17-H), 5.45 ppm (s, 1H, 4-H); 13C NMR (126 MHz, CDCl3): d=9.18
(13-CH2CH3), 20.12 (13-CH2CH3), 21.76 (C-2), 22.07 (C-15), 25.47 (C-3),
(11-CH2), 121.5 (C-4), 140.2 (C-5), 147.8 ppm (C-11); IR (film): n˜ =2927,
1642, 1437, 1388, 1362, 1197, 1118, 1079, 892, 759 cmꢀ1; UV (CH3CN):
lmax (lg e)=197.0 (4.1979), 248.0 (2.1226), 254.0 (2.1315), 260.0 nm
(2.0541); MS (70 eV, EI): m/z (%): 342.4 (26) [M+]; EI-HRMS: m/z:
calcd for C24H38O: 342.2923, found: 342.2923.
(+)-17b-tert-Butoxy-13b-ethyl-3-methoxygona-1,3,5(10)-trien-11-one
(33): A solution of steroid 23 (309 mg, 828 mmol) in dichloromethane
(15 mL) was treated with Dess–Martin periodinane (533 mg, 1.26 mmol)
and stirred for 60 min at room temperature. Saturated aqueous NaHCO3
(7.2 mL) and 10% aqueous Na2S2O3 (7.2 mL) were added and the mix-
ture was stirred for further 45 min. The layers were separated and the
aqueous layer was extracted with dichloromethane (3”20 mL). The com-
bined organic extracts were dried over Na2SO4, the solvent was removed
in vacuo and the residue was filtered through a short column of silica gel
(n-pentane/EtOAc 9:1) to give the ketone 33 (298 mg, 805 mmol, 97%)
as colorless foam, which was used directly in the next step because of its
low stability. Rf =0.38 (n-pentane/EtOAc 9:1); [a]2D0 =+211.3 (c=1.0 in
CHCl3); 1H NMR (600 MHz, CDCl3): d=1.04 (t, J=7.3 Hz, 3H, 13-
28.43 (17-OC
35.34 (C-10), 41.90 (C-8), 49.32 (C-13), 50.82 (C-12), 51.18 (C-14), 60.96
(C-9), 72.47 (17-OC(CH3)3), 81.40 (C-17), 122.1 (C-4), 138.6 (C-5),
ACHTREUNG(CH3)3), 28.93 (C-1), 31.73 (C-16), 31.91 (C-7), 34.91 (C-6),
ACHTREUNG
212.1 ppm (C-11); IR (film): n˜ =2927, 1708, 1435, 1389, 1362, 1253, 1195,
1128, 1076, 917, 808, 757 cmꢀ1; UV (CH3CN): lmax (lg e)=194.0 nm
(3.8334); MS (70 eV, EI): m/z (%): 344.4 (64) [M+]; ESI-HRMS: m/z:
calcd for [C23H36O2 + H+]: 345.27881, found: 345.27886.
(+)-17b-tert-Butoxy-13b-ethyl-11b-hydroxy-11a-trimethylsilylmethylgo-
na-4-ene (30): LiCH2TMS (1.00m in n-pentane, 880 mL) was added in one
portion at ꢀ788C to a solution of ketone 29 (102 mg, 295 mmol) in dry
THF (12 mL). Stirring was continued at ꢀ788C for 20 min, then the mix-
ture was warmed to room temperature and stirred for further 30 min.
Water (30 mL) was added and the aqueous phase was extracted with
Et2O (3”15 mL). The combined organic layers were washed with saturat-
ed aqueous NaCl (15 mL) and dried over Na2SO4. The solvent was re-
moved in vacuo and the residue was subjected to column chromatogra-
phy on silica gel (n-pentane/EtOAc 95:5) to afford steroid 30 (120 mg,
94%) as colorless foam. Rf =0.69 (n-pentane/EtOAc 95:5); [a]2D0 =+22.3
(c=1.0 in CHCl3); 1H NMR (600 MHz, CDCl3): d=0.10 (s, 9H, 11-
CH2CH3), 1.08–1.15 (m, 1H, 13-CHaHbCH3), 1.15 (s, 9H, 17-OCACHTREUNG(CH3)3),
1.39–1.59 (m, 3H, 7-Ha, 15-Ha, 13-CHaHbCH3), 1.65–1.74 (m, 2H, 15-Hb,
16-Ha), 1.86–1.97 (m, 3H, 7-Hb, 8-H, 14-H), 2.04–2.12 (m, 1H, 16-Hb),
2.19 (d, J=11.5 Hz, 1H, 12-Ha), 2.75–2.89 (m, 2H, 6-H2), 2.94 (d, J=
11.5 Hz, 1H, 12-Hb), 3.42 (d, J=10.2 Hz, 1H, 9-H), 3.75–3.78 (m, 1H, 17-
H), 3.77 (s, 1H, 3-OCH3), 6.61 (d, J=2.7 Hz, 1H, 4-H), 6.75 (dd, J=8.8,
2.7 Hz, 1H, 2-H), 7.29 ppm (d, J=8.8 Hz, 1H, 1-H); 13C NMR (126 MHz,
CDCl3): d=9.29 (13-CH2CH3), 20.21 (13-CH2CH3), 22.03 (C-15), 27.57
CH2Si
6.8 Hz, 1H, 14-H), 1.02 (d, J=14.3 Hz, 1H, 12-Ha), 1.04 (t, J=10.1 Hz,
1H, 9-H), 1.06 (d, J=15.0 Hz, 1H, 11-CHaHbSi(CH3)3), 1.13 (s, 9H, 17-
OC(CH3)3), 1.15 (t, J=7.4 Hz, 3H, 13-CH2CH3), 1.22–1.30 (dq, J=12.1,
6.4 Hz, 1H, 15-Ha), 1.31 (s, 1H, 11-OH), 1.38–1.45 (m, 2H, 2-Ha, 13-
CHaHbCH3), 1.45–1.56 (m, 4H, 8-H, 15-Hb, 16-Ha, 13-CHaHbCH3), 1.54
G
(C-7), 28.47 (17-OC
(C-13), 50.87, 50.91 (C-12, C-14), 55.16 (3-OCH3), 55.46 (C-9), 72.57 (17-
OC(CH3)3), 81.41 (C-17), 111.4 (C-2), 113.7 (C-4), 123.9 (C-10), 131.0 (C-
1), 138.3 (C-5), 157.9 (C-3), 210.0 ppm (C-11); IR (KBr): n˜ =2971, 1712,
1610, 1502, 1464, 1362, 1246, 1195, 1120, 1089, 1039 cmꢀ1; UV (CH3CN):
lmax (lg e)=200.5 (4.6748), 277.0 (3.2073), 284.0 nm (3.1842); MS (ESI,
ACHTRE(UNG CH3)3), 30.03 (C-6), 31.84 (C-16), 40.35 (C-8), 49.68
ACHTREUNG
G
1548
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 1541 – 1551

Oral Contraceptive Desogestrel
FULL PAPER
MeOH/NH4OAc): m/z (%): 371.3 (26) [M++H], 758.5 (100) [2M+
+NH4]; ESI-HRMS: m/z: calcd for [C24H34O3+H+]: 371.25807, found:
371.25791.
146.3 (C-11), 166.8 (C-5), 200.0 ppm (C-3); IR (KBr): n˜ =3080, 2963,
1672, 1614, 1454, 1360, 1257, 1199, 1116, 1078, 897, 747 cmꢀ1
; UV
(CH3CN): lmax (lg e)=196.5 (4.0609), 236.5 (4.2588), 308.0 nm (2.2252);
MS (70 eV, EI): m/z (%): 356.5 (7) [M+], 300.4 (100) [M+ꢀC4H8]; ESI-
HRMS: m/z: calcd for [C24H36O2+H+]: 357.27881, found: 357.27912.
(ꢀ)-17b-tert-Butoxy-13b-ethyl-11b-hydroxy-3-methoxy-11a-trimethylsilyl-
methylgona-1,3,5(10)-triene (34): LiCH2TMS (1.00m in n-pentane,
2.02 mL, 2.02 mmol) was added in one portion at ꢀ788C to a stirred solu-
tion of ketone 33 (298 mg, 805 mmol) in dry THF (60 mL). Stirring was
continued at ꢀ788C for 30 min, then the mixture was warmed to room
temperature and stirred for further 10 min. Water (100 mL) was added
and the aqueous phase was extracted with Et2O (3”30 mL). The com-
bined organic layers were washed with saturated aqueous NaCl (30 mL)
and dried over Na2SO4. The solvent was removed in vacuo and the resi-
due was subjected to column chromatography on silica gel (n-pentane/
EtOAc/NEt3 97:3:1) to afford steroid 34 (291 mg, 79%) as colorless
foam. Rf =0.61 (n-pentane/EtOAc 9:1); [a]2D0 =ꢀ53.3 (c=1.0 in CHCl3);
(+)-13b-Ethyl-17b-hydroxy-11-methylenegona-4-en-3-one (36):
A solu-
tion of steroid 35 (107 mg, 300 mmol) in dichloromethane (17 mL) was
treated with BF3·EtO2 (48% in Et2O, 1.66 mL, 13.2 mmol) and stirred for
10 min at room temperature. The mixture was quenched with saturated
aqueous NaHCO3 (20 mL) and the layers were separated. The aqueous
layer was extracted with dichloromethane (3”10 mL), the combined or-
ganic layers were dried over Na2SO4 and the solvent was removed in
vacuo. Column chromatography on silica gel (n-pentane/EtOAc 1:1) of
the residue afforded alcohol 36 (90.0 mg, quant.) as white solid. Rf =0.36
(n-pentane/EtOAc 1:1); [a]D20 = +187.3 (c=1.0 in CHCl3), +180.0 (c=
0.53 in C6H6), lit.:[11e] +180.6 (c=0.53 in C6H6); 1H NMR (600 MHz,
CDCl3): d=1.00–1.08 (m, 1H, 7-Ha), 1.04 (t, J=7.5 Hz, 3H, 13-CH2CH3),
1.21–1.36 (m, 3H, 14-H, 15-Ha, 13-CHaHbCH3), 1.36–1.52 (m, 4H, 1-Ha,
8-H, 9-H, 13-CHaHbCH3), 1.52–1.64 (m, 3H, 12-Ha, 15-Hb, 16-Ha), 1.77–
1.82 (m, 2H, 7-Hb, 17-OH), 2.08–2.15 (m, 1H, 16-Hb), 2.17–2.24 (m, 1H,
6-Ha), 2.92 (ddd, J=16.7, 13.8, 4.7 Hz, 2-Ha), 2.38 (dt, J=16.7, 4.1 Hz,
1H, 2-Hb), 2.46 (dt, J=14.6, 3.1 Hz, 1H, 6-Hb), 2.50 (dq, J=13.6, 4.4 Hz,
1H, 1-Hb), 2.54–2.59 (m, 1H, 10-H), 2.85 (d, J=12.4 Hz, 1H, 12-Hb), 3.82
(t, J=8.5 Hz, 1H, 17-H), 4.79 (s, 1H, 11-CHaHb), 5.01 (s, 1H, 11-CHaHb),
5.86 ppm (t, J=1.9 Hz, 1H, 4-H); 13C NMR (126 MHz, CDCl3): d=8.87
(13-CH2CH3), 18.55 (13-CH2CH3), 22.07 (C-15), 28.23 (C-1), 30.08 (C-7),
30.90 (C-16), 35.30 (C-6), 36.91 (C-2), 37.56 (C-10), 41.49 (C-8), 44.33 (C-
12), 46.53 (C-13), 52.14 (C-14), 54.05 (C-9), 82.89 (C-17), 108.5 (11-CH2),
125.5 (C-4), 146.0 (C-11), 166.7 (C-5), 200.1 ppm (C-3); IR (KBr): n˜ =
1H NMR (600 MHz, CDCl3): d=0.13 (s, 9H, 11-CH2Si
J=14.2 Hz, 1H, 12-Ha), 1.14 (d, J=15.1 Hz, 1H, 11-CHaHbSi
1.17 (s, 9H, 17-OC(CH3)3), 1.18 (t, J=7.4 Hz, 3H, 13-CH2CH3), 1.23–1.29
ACHTREUNG
AHCTREUNG
ACHTREUNG
(m, 1H, 14-H), 1.32–1.45 (m, 2H, 13-CHaHbCH3, 11-OH), 1.45–1.60 (m,
3H, 7-Ha, 16-Ha, 13-CHaHbCH3), 1.60–1.76 (m, 4H, 7-Hb, 8-H, 15-H2),
1.90 (d, J=15.1 Hz, 1H, 11-CHaHbSiACHTREU(NG CH3)3), 1.91–1.98 (m, 1H, 16-Hb),
2.21 (d, J=11.0 Hz, 1H, 9-H), 2.63–2.69 (m, 2H, 6-H2), 2.65 (d, J=
14.2 Hz, 1H, 12-Hb), 3.45 (t, J=8.0 Hz, 1H, 17-H), 3.79 (s, 3H, 3-OCH3),
6.71 (d, J=2.9 Hz, 1H, 4-H), 6.72 (dd, J=8.6, 2.9 Hz, 1H, 2-H), 7.85 ppm
(d, J=8.6 Hz, 1H, 1-H); 13C NMR (126 MHz, CDCl3): d=0.73 (11-
CH2Si
26.06 (C-7), 28.62 (17-OC
(C-8, 11-CH2Si(CH3)3), 43.75 (C-13), 49.14 (C-12), 52.29 (C-14), 53.20 (C-
9), 55.12 (3-OCH3), 72.25 (17-OC(CH3)3), 76.17 (C-11), 83.83 (C-17),
ACHTREUNG
AHCTREUNG
ACHTREUNG
AHCTREUNG
109.9 (C-2), 113.6 (C-4), 128.3 (C-1), 130.8 (C-10), 142.4 (C-5), 157.1 ppm
(C-3); IR (KBr): n˜ =3629, 2950, 1610, 1578, 1497, 1466, 1389, 1362, 1254,
1133, 1196, 1088, 1049, 928, 841, 689 cmꢀ1; UV (CH3CN): lmax (lg e)=
199.5 (4.5721), 225.5 (3.8272), 276.5 (3.1354), 281.5 nm (3.1066); MS
(70 eV, EI): m/z (%): 458.4 (7) [M+], 73.1 (100) [C3H9Si+]; ESI-HRMS:
m/z: calcd for [C28H46O3Si+Na+]: 481.31084, found: 481.31084.
3487, 2946, 1664, 1613, 1417, 1354, 1261, 1207, 1110, 1067, 904, 880 cmꢀ1
;
UV (CH3CN): lmax (lg e)=200.0 (4.1316), 236.5 (4.1212), 314.5 nm
(2.1443); MS (70 eV, EI): m/z (%): 300.3 (17) [M+], 282.3 (100) [M+
ꢀH2O]; ESI-HRMS: m/z: calcd for [C20H28O2+H+]: 301.21621, found:
301.21633.
(+)-13b-Ethyl-3,3-ethylenedithio-11-methylenegona-4-en-17b-ol (38): 1,2-
Ethanedithiol (28.0 mL, 31.5 mg, 334 mmol) were added at room tempera-
ture to a solution of 36 (67.4 mg, 224 mmol) in methanol (8.0 mL) and
BF3·Et2O (48% in Et2O, 16.5 mL, 127 mmol) and the mixture was stirred
for 2.5 h. Saturated aqueous NaHCO3 (5 mL) was added and methanol
was evaporated in vacuo. The aqueous residue was diluted with water
(20 mL) and extracted with MTBE (3”15 mL). The combined organic
layers were dried over Na2SO4 and the solvent was evaporated in vacuo.
Filtration through silica gel (n-pentane/EtOAc 7:3) afforded steroid 38
(+)-17b-tert-Butoxy-13b-ethyl-11-methylenegona-4-en-3-one (35): A so-
lution of steroid 34 (172 mg, 375 mmol) in dry THF (14 mL) was slowly
added at ꢀ408C to a mixture of condensed ammonia (35 mL) and iPrOH
(1.8 mL). Small pieces of lithium (26.0 mg, 3.75 mol) were added portion-
wise over a period of 90 min, so that the deep blue color of the mixture
maintained. Then solid NH4Cl was slowly added until the color disap-
peared and the ammonia was distilled off at room temperature. The resi-
due was dissolved in water (30 mL) and MTBE (20 mL), the layers were
separated and the aqueous layer was extracted with MTBE (2”30 mL).
The combined organic extracts were dried over Na2SO4 and the solvent
was removed in vacuo to give a white foam, which was resolved in ace-
tone (20 mL). The solution was treated with conc. HCl (0.50 mL) and
stirred for 15 h at room temperature. The mixture was then neutralized
with saturated aqueous NaHCO3 (5 mL) and the acetone was removed in
vacuo. Water (20 mL) and MTBE (20 mL) were added to the residue, the
layers separated and the aqueous layer was extracted with MTBE (2”
20 mL). The combined organic extracts were dried over Na2SO4, the sol-
vent evaporated and the residue subjected to column chromatography on
silica gel (n-pentane/EtOAc 1:1). Compound 35 (99.4 mg, 74%) was ob-
(70.7 mg, 84%) as white solid. Rf =0.54 (n-pentane/EtOAc 7:3); [a]D20
=
+159.5 (c=1.0 in CHCl3), +168.0 (c=0.98 in C6H6), lit.:[11d] +148.0 (c=
1.0 in CHCl3), lit.:[11e] +142.3 (c=0.98 in C6H6); 1H NMR (600 MHz,
CDCl3): d=0.89–0.97 (m, 1H, 7-Ha), 1.03 (t, J=7.5 Hz, 3H, 13-CH2CH3),
1.19–1.43 (m, 7H, 1-Ha, 8H, 9-H, 14-H, 15-Ha, 13-CH2CH3), 1.48 (brs,
1H, 17-OH), 1.50–1.59 (m, 2H, 15-Hb, 16-Ha), 1.61 (d, J=12.3 Hz, 1H,
12-Ha), 1.67 (dq, J=12.6, 3.3 Hz, 1H, 7-Hb), 1.91 (m, 1H, 6-Ha), 2.02–
2.15 (m, 2H, 2-Ha, 16-Hb), 2.16–2.26 (m, 3H, 2-Hb, 6-Hb, 10-H), 2.28–2.34
(m, 1H, 1-Hb), 2.80 (d, J=12.2 Hz, 1H, 12-Hb), 3.21–3.27 (m, 1H, S-
CHaHbCH2-S), 3.33–3.41 (m, 3H, S-CHaHbCH2-S), 3.81 (t, J=8.5 Hz,
1H, 17-H), 4.74 (s, 1H, 11-CHaHb), 4.96 (s, 1H, 11-CHaHb), 5.64 ppm (d,
J=1.3 Hz, 1H, 4-H); 13C NMR (151 MHz, CDCl3): d=8.95 (13-
CH2CH3), 18.50 (13-CH2CH3), 22.09 (C-15), 28.59 (C-1), 31.03 (C-16),
31.09 (C-7), 34.91 (C-6), 35.86 (C-10), 39.59, 39.97 (S-CH2CH2-S), 40.49
(C-2), 41.95 (C-8), 44.40 (C-12), 46.65 (C-13), 52.36, 54.56 (C-9, C-14),
65.76 (C-3), 83.15 (C-17), 108.3 (11-CH2), 126.2 (C-4), 141.6 (C-5),
146.8 ppm (C-11); IR (KBr): n˜ =3516, 3074, 2927, 1636, 1439, 1275, 1132,
1056, 894, 842, 769, 602 cmꢀ1; UV (CH3CN): no absorption; MS (70 eV,
EI): m/z (%): 379.3 (100) [M+]; ESI-HRMS: m/z: calcd for
[C22H32OS2+H+]: 377.19673, found: 377.19672.
tained as colorless crystals. Rf =0.23 (n-pentane/EtOAc 1:1); [a]D20
=
+156.0 (c=1.0 in CHCl3); 1H NMR (600 MHz, CDCl3): d=0.99–1.07
(m, 1H, 7-Ha), 1.02 (t, J=7.4 Hz, 3H, 13-CH2CH3), 1.12 (s, 9H, 17-OC-
ACHTREUNG(CH3)3), 1.17–1.25 (m, 2H, 14-H, CHaHbCH3), 1.25–1.34 (m, 1H, 15-Ha),
1.35–1.53 (m, 5H, 1-Ha, 8-H, 9-H, 15-Hb, 13-CHaHbCH3), 1.53–1.61 (m,
2H, 12-Ha, 16-Ha), 1.77–1.82 (m, 1H, 7-Hb), 1.89–1.97 (m, 1H, 16-Hb),
2.17–2.24 (m, 1H, 6-Ha), 2.29 (ddd, 16.6, 13.9, 4.7 Hz, 1H, 2-Ha), 2.38 (dt,
J=16.6, 4.3 Hz, 1H, 2-Hb), 2.46 (dt, J=14.6, 3.0 Hz, 1H, 6-Hb), 2.51 (dq,
J=13.8, 4.3 Hz, 1H, 1-Hb), 2.54–2.60 (m, 1H, 10-H), 2.79 (d, J=12.2 Hz,
1H, 12-Hb), 3.51 (t, J=8.3 Hz, 1H, 17-H), 4.77 (s, 1H, 11-CHaHb), 5.00
(s, 1H, 11-CHaHb), 5.86 ppm (s, 1H, 4-H); 13C NMR (126 MHz, CDCl3):
d=8.70 (13-CH2CH3), 19.13 (13-CH2CH3), 22.34 (C-15), 28.26 (C-1),
(+)-13b-Ethyl-11-methylenegona-4-en-17b-ol (32a): Method A: BF3·EtO2
(48% in Et2O, 0.760 mL, 6.04 mmol) was added very fast at room tem-
perature to a solution of steroid 31 (75.7 mg, 221 mmol) in dichlorome-
thane (7.6 mL). After 15 s reaction time, the mixture was quenched
under vigorous stirring with saturated aqueous NaHCO3-Lsg (3.0 mL).
28.49 (17-OC
37.59 (C-10), 41.39 (C-8), 44.85 (C-12), 45.73 (C-13), 52.12 (C-14), 54.24
(C-9), 72.32 (17-OC(CH3)3), 81.83 (C-17), 106.1 (11-CH2), 125.5 (C-4),
ACHTREUNG(CH3)3), 30.14 (C-7), 31.49 (C-16), 35.37 (C-6), 36.96 (C-2),
ACHTREUNG
Chem. Eur. J. 2008, 14, 1541 – 1551
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1549

L. F. Tietze and I. K. Krimmelbein
Water (10 mL) was added and the mixture was then extracted with di-
chloromethane (3”5 mL). The combined organic extracts were washed
with saturated aqueous NaCl (5 mL), dried over Na2SO4 and the solvent
was evaporated in vacuo. Column chromatography on silica gel (n-pen-
tane/EtOAc 4:1) of the residue afforded alcohol 32a which contained
traces of the double bond isomer 32b (63.4 mg, quant., 32a/32b=96:4)
as white solid.
solution of ketone 39a (59.6 mg, 210 mmol, 39a/39b 96:4) in dry THF
(3.2 mL) was slowly added. Stirring at room temperature was continued
for 2 h with the acetylene flow being maintained. The reaction mixture
was poured into 2n HCl (50 mL) and extracted with diethyl ether (4”
20 mL). The combined organic extracts were washed with saturated
aqueous NaCl (20 mL), dried over Na2SO4 and the solvent was removed
in vacuo. Purification of the residue by column chromatography on silica
gel (n-pentane/EtOAc 93:7 ! n-pentane/EtOAc 9:1) afforded desoges-
trel (2) (54.1 mg, 83%) as colorless oil, which was crystallized from n-
pentane. Rf =0.33 (n-pentane/EtOAc 9:1); [a]2D0 =+54.5 (c=1.0 in
Method B: A solution of steroid 38 (90.9 mg, 241 mmol.) in dry THF
(2.0 mL) was slowly added at ꢀ408C to condensed ammonia (6.0 mL).
Small pieces of lithium (21.3 mg, 3.07 mmol) were added portionwise
over a period of 30 min, so that the deep blue color of the mixture main-
tained. Then solid NH4Cl was slowly added until the color disappeared
and the ammonia was distilled off at room temperature. The residue was
dissolved in water (15 mL) and MTBE (5 mL), the layers were separated
and the aqueous layer was extracted with MTBE (2”10 mL). The com-
bined organic extracts were dried over Na2SO4, the solvent was removed
in vacuo and the residue was subjected to column chromatography on
silica gel (n-pentane/EtOAc 97:3). Steroid 32a, which contained small
amounts of the double bond isomer 32c (66.2 mg, 96%, 32a/32c 92:8)
1
CHCl3), lit.:[12a] +55 (c=1.0 in CHCl3); H NMR (600 MHz, CDCl3): d=
0.89–0.98 (m, 1H, 7-Ha), 1.04 (t, J=7.4 Hz, 3H, 13-CH2CH3), 1.10–1.18
(m, 1H, 1-Ha), 1.29–1.39 (m, 3H, 2-Ha, 8-H, 9-H), 1.39–1.48 (m, 3H, 2-
Hb, 13-CH2CH3), 1.58–1.69 (m, 3H, 7-Hb, 15-H2), 1.78 (ddd, J=7.6, 10.3,
12.8 Hz, 1H, 14-H), 1.87 (brs, 1H, 17-OH), 1.91–1.98 (m, 3H, 3-H2, 6-
Ha), 2.10 (ddd, J=14.0, 12.0, 3.6 Hz, 1H, 16-Ha), 2.17–2.27 (m, 3H, 1-Hb,
6-Hb, 10-H), 2.27 (d, J=12.3 Hz, 1H, 12-Ha), 2.34 (ddd, J=14.0, 9.7,
6.0 Hz, 1H, 16-Hb), 2.60 (s, 1H, 17-C=CH), 2.61 (d, J=12.3 Hz, 1H, 12-
Hb), 4.78 (s, 1H, 11-CHaHb), 4.98 (s, 1H, 11-CHaHb), 5.46 ppm (s, 1H, 4-
H); 13C NMR (126 MHz, CDCl3): d=9.13 (13-CH2CH3), 19.79 (13-
CH2CH3), 21.88, 21.93 (C-2, C-15), 25.67 (C-3), 29.08 (C-1), 31.69 (C-7),
35.51 (C-6), 36.56 (C-10), 39.77 (C-16), 40.59 (C-12), 42.57 (C-8), 50.39
(C-13), 52.39 (C-14), 54.63 (C-9), 74.05 (C-17), 81.12 (17-C=CH), 87.83
(17-C=CH), 108.5 (11-CH2), 121.3 (C-4), 139.9 (C-5), 147.5 ppm (C-11);
IR (KBr): n˜ =3542, 3286, 3090, 2928, 2872, 1640, 1465, 1337, 1259, 1121,
1033, 898, 808, 675, 631 cmꢀ1; UV (CH3CN): no absorption; MS (70 eV,
EI): m/z (%): 310.1 (53) [M+]; EI-HRMS: m/z: calcd for C22H30O:
310.2297; found: 310.2293.
was obtained as white solid. Rf =0.43 (n-pentane/EtOAc 4:1); [a]D20
=
+140.2 (c=1.0 in CHCl3) lit.:[11d] +138 (c=1.0 in CHCl3); 1H NM R
(600 MHz, CDCl3): d=0.83–0.92 (m, 1H, 7-Ha), 1.04 (t, J=7.5 Hz, 3H,
13-CH2CH3), 1.07–1.15 (m, 1H, 1-Ha), 1.18–1.46 (m, 7H, 2-Ha, 8-H, 9-H,
14-H, 15-Ha, 13-CH2CH3), 1.47–1.68 (m, 6H, 2-Hb, 7-Hb, 12-Ha, 15-Hb,
16-Ha, 17-OH), 1.90–1.98 (m, 3H, 3-H2, 6-Ha), 2.07–2.15 (m, 1H, 16-Hb),
2.16–2.28 (m, 3H, 1-Hb, 6-Hb, 10-H), 2.80 (d, J=12.2 Hz, 1H, 12-Hb),
3.91 (t, J=8.5 Hz, 1H, 17-H), 4.75 (s, 1H, 11-CHaHb), 4.94 (s, 1H, 11-
CHaHb), 5.46 ppm (s, 1H, 4-H); 13C NMR (126 MHz, CDCl3): d=8.99
(13-CH2CH3), 18.54 (13-CH2CH3), 21.93 (C-2), 22.14 (C-15), 25.65 (C-3),
29.12 (C-1), 31.08 (C-16), 31.67 (C-7), 35.51 (C-6), 36.60 (C-10), 42.21 (C-
8), 44.55 (C-12), 46.70 (C-13), 52.57 (C-14), 55.06 (C-9), 83.28 (C-17),
108.2 (11-CH2), 121.3 (C-4), 139.9 (C-5), 147.2 ppm (C-11); IR (KBr): n˜ =
3356, 2933, 1638, 1436, 1298, 1117, 1056, 910, 893, 805 cmꢀ1
; UV
Acknowledgements
(CH3CN): lmax (lg e)=201.5 nm (4.0987); MS (70 eV, EI): m/z (%): 268.3
(69) [M+], 268.3 (100) [M+ꢀH2O]; EI-HRMS: m/z: calcd for C20H30O:
286.2297; found: 286.2300.
The authors are grateful to the Fonds der Chemischen Industrie for sup-
porting this work. We are also indebted to the Organon GmbH, the
BASF AG, the Bayer AG, the Degussa AG and the Wacker-Chemie
GmbH for generous gifts of chemicals.
(+)-13b-Ethyl-11-methylenegona-4-en-17-one (39a): A solution of ste-
roid 32a (86.0 mg, 300 mmol, 32a/32b=96:4) in dichloromethane
(8.5 mL) was treated with Dess–Martin periodinane (192 mg, 451 mmol)
and stirred for 30 min at room temperature. Saturated aqueous NaHCO3
(1.5 mL) and 10% aqueous Na2S2O3 (1.5 mL) were added and the mix-
ture was stirred for further 45 min. The layers were separated and the
aqueous layer was extracted with dichloromethane (3”5 mL). The com-
bined organic extracts were dried over Na2SO4, the solvent was removed
in vacuo and the residue was filtered through a short column of silica gel
(n-pentane/EtOAc 4:1) to give the ketone 39a which contained traces of
the double bond isomer 39b (81.8 mg, 96%, 39a/39b=96:4) as colorless
crystals. Rf =0.57 (n-pentane/EtOAc 9:1); [a]2D0 =+168.2 (c=1.0 in
CHCl3), lit.:[11a] +166 (c=1.0 in CHCl3); 1H NMR (600 MHz, CDCl3): d=
0.73 (t, J=7.5 Hz, 3H, 13-CH2CH3), 0.90–0.98 (m, 1H, 7-Ha), 1.06–1.13
(m, 1H, 1-Ha), 1.21–1.28 (m, 1H, 13-CHaHbCH3), 1.33 (t, J=10.6 Hz,
1H, 9-H), 1.35–1.45 (m, 2H, 2-Ha, 8-H), 1.51–1.66 (m, 4H, 2-Hb, 14-H,
15-Ha, 13-CHaHbCH3), 1.75 (dq, J=12.5, 3.4 Hz, 1H, 7-Hb), 1.80 (d, J=
12.7 Hz, 1H, 12-Ha), 1.84–1.98 (m, 4H, 3-H2, 6-Ha, 15-Hb), 2.08 (dt, J=
19.2, 8.7 Hz, 1H, 16-Ha), 2.14–2.28 (m, 3H, 1-Hb, 6-Hb, 10-H), 2.35–2.41
(m, 1H, 16-Hb), 2.54 (d, J=12.7 Hz, 1H, 12-Hb), 4.80 (s, 1H, 11-CHaHb),
4.89 (d, J=0.9 Hz, 1H, 11-CHaHb), 5.46 ppm (s, 1H, 4-H); 13C NM R
(126 MHz, CDCl3): d=7.16 (13-CH2CH3), 18.04 (13-CH2CH3), 20.78 (C-
15), 21.83 (C-2), 25.60 (C-3), 29.04 (C-1), 30.95 (C-7), 35.26 (C-6), 36.08
(C-16), 36.53 (C-10), 39.59 (C-12), 41.49 (C-8), 52.29 (C-14), 52.94 (C-13),
55.01 (C-9), 110.0 (11-CH2), 121.7 (C-4), 139.4 (C-5), 146.0 (C-11),
218.9 ppm (C-17); IR (KBr): n˜ =2922, 1727, 1635, 1441, 1224, 1082, 1004,
891, 807, 768, 638 cmꢀ1; UV (CH3CN): lmax (lg e)=192.0 nm (4.2561);
MS (70 eV, EI): m/z (%): 284.2 (100) [M+]; EI-HRMS: m/z: calcd for
C20H28O: 284.2140; found: 284.2136.
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[4] Examples for recent reviews on the Heck reaction: a) M. Beller, A.
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[5] Examples for recent reviews on the asymmetric Heck reaction:
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3453–3516; b) M. Shibasaki, E. M. Vogl, O. Takashi, Adv. Synth.
Catal. 2004, 346, 1533–1552; c) A. B. Dounay, L. E. Overman,
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(+)-13b-Ethyl-17a-ethinyl-11-methylenegona-4-en-17b-ol
(desogestrel)
(2): Acetylene was passed at room temperature into a solution of lithium
(61.2 mg, 8.82 mmol) in dry ethylenediamine over a period of 2 h. Then a
1550
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Chem. Eur. J. 2008, 14, 1541 – 1551

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Received: February 2, 2007
Revised: September 20, 2007
Published online: November 23, 2007
Chem. Eur. J. 2008, 14, 1541 – 1551
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1551