An efficient hemisynthesis of 20- and 21-[13C]-labeled cortexolone: A model for the study of skin sensitization to corticosteroids

Article abstract of DOI:10.1055/s-0029-1216986

A method is described for the synthesis of isotopomers of cortexolone from the commercially available andros-4-ene-3, 17dione. The strategy is based on the use of K¹³CN for labeling at position 20 and of ¹³CH ₃Mgl, generated in situ, for labeling at position 21. Because of the early introduction of the [¹³C] labeling, our efforts aimed at reproducible experimental procedures giving high yields with respect to the isotope containing precursors. During the development of this hemisynthesis, we noted that judicious choice of protective groups was essential as this could lead not only to mixtures or unstable intermediates but also influence considerably the output of reactions.

Full text of DOI:10.1055/s-0029-1216986

PAPER
3391
An Efficient Hemisynthesis of 20- and 21-[13C]-Labeled Cortexolone: A Model
for the Study of Skin Sensitization to Corticosteroids
Efficient
H
emismynthesis of 20- and 1
i
21-[
C
3 l]-Labe
i
le
d
Cor
e
texolone Claudel, Cécile Arbez-Gindre, Valérie Berl, Jean-Pierre Lepoittevin*
Institut de Chimie, Laboratoire de Dermatochimie, UMR 7177, CNRS et Université de Strasbourg, 4, rue Blaise Pascal, 67070 Strasbourg,
France
Fax +33(3)68851527; E-mail: jplepoit@unistra.fr
Received 15 May 2009
OH
O
Abstract: A method is described for the synthesis of isotopomers
O
21
O
of cortexolone from the commercially available andros-4-ene-3,17-
dione. The strategy is based on the use of K13CN for labeling at po-
sition 20 and of 13CH3MgI, generated in situ, for labeling at position
21. Because of the early introduction of the [13C] labeling, our ef-
forts aimed at reproducible experimental procedures giving high
yields with respect to the isotope containing precursors. During the
development of this hemisynthesis, we noted that judicious choice
of protective groups was essential as this could lead not only to mix-
tures or unstable intermediates but also influence considerably the
output of reactions.
H
OH
OH
HO
alcohol
HO
dehydrogenase
O
O
hydrocortisone
(prohapten)
21-dehydrocortisone
(hapten)
protein
Key words: steroids, medicinal chemistry, isotope labeled, aller-
gen synthesis, protecting groups
antigenic complex
Scheme 1 Potential skin metabolism of corticosteroids
Steroids continue to attract much attention because of
their special biological activities and strong anti-inflam-
matory and immunosuppressive properties. These have
led to their extensive use in rheumatology, traumatology,
and dermatology.1 Nevertheless, despite many beneficial
effects, corticosteroids have also been associated with al-
lergic contact dermatitis (ACD) reactions when applied
topically.2 The frequency of positive ACD reactions to
corticosteroid in eczematous patients has thus been esti-
mated between 3–5.9% in northern European countries
where the use of topical corticosteroids is high.3
hapten-protein coupling by nuclear magnetic resonance,
we were interested in the synthesis of the 20-[13C]- and
21-[13C]-labeled cortexolone. The use of 13C-labeled mol-
ecules in association with NMR techniques is a powerful
tool for the investigation of hapten-protein interactions
and best results are obtained when labeling the reactive
sites of the molecule.8 In the case of corticosteroids, the
labeling sites should be either on position 20 or 21 of the
side chain (Scheme 1).
The literature about the synthesis of corticosteroids is
abundant, but to the best of our knowledge, there had been
no report on the synthesis of labeled molecules at these
two positions. Since the works of Sarett,9 compounds of
the androstan-17-one group seem to be good precursors
for the synthesis of the side chain. Different synthetic ap-
proaches have thus been developed essentially based on
two strategies: the direct introduction of a two carbons
unit10 or the introduction of the two carbons one by
one.10b,11 Unfortunately, even if these strategies could lead
to the corticosteroids structure, they could not be applied
for the preparation of labeled derivatives as labeled re-
agents were not available, their preparations led to mix-
tures of labeled products, or yields after insertion of
labeled unit were low.
From a molecular point of view, ACD is a common dis-
ease induced by the chemical modification of skin pro-
teins by low molecular weight molecules or haptens.4
These modified proteins recognized as foreign by the skin
immune system,5 result from the reaction of an electro-
philic function of the hapten with nucleophilic residues
present on the proteins. Even if several mechanisms have
been identified for the formation of hapten-protein bonds,
in the case of corticosteroids they are still hypothetical. In
many reports, it has been suggested that these drugs are
indeed prohaptens needing a skin metabolic step to form
reactive intermediates.6 Thus, corticosteroids such as hy-
drocortisone, could be oxidized into 21-dehydro deriva-
tives, which are highly reactive a-keto aldehydes toward
nucleophilic amino acids such as arginine (Scheme 1).7
In this article, we report an efficient hemisynthesis of 20-
and 21-[13C]-labeled cortexolones (Figure 1) from the
commercially available andros-4-ene-3,17-dione.
In order to investigate the molecular mechanism of ACD
to corticosteroids and better characterize the nature of
The preparation of [13C]-labeled molecules very often
means the development of new syntheses due to the use of
a restricted number of available precursors and the very
SYNTHESIS 2009, No. 20, pp 3391–3398
Advanced online publication: 03.09.2009
DOI: 10.1055/s-0029-1216986; Art ID: P07109SS
x
x.
x
x
.
2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

3392
E. Claudel et al.
PAPER
OH
efforts were aimed at reproducible experimental proce-
dures giving high-yield products with respect to the iso-
tope-containing precursors.
O
21
OH
The hemisynthesis started by a regio- and stereoselective
cyanation of the commercially available diketone 2 as pre-
viously described.11h The b-cyanosteroid 3 was obtained
in almost quantitative yield, but the use of an excess of
KCN (4.2 equiv) was necessary for a good stereoselectiv-
ity. Before the introduction of the second carbon unit, the
enone function was blocked by a thioketal group and the
hydroxy at position 17 was protected by a silyl group to
form 5 in very high yield. In this sequence leading to the
formation of 4 it is interesting to note that the steps could
be reversed. Thus, a regioselective protection of the A-
ring enone followed by a regio- and stereoselective cyana-
tion afforded 4 with an overall yield of 95%. In this case,
we also tried a direct conversion of 2 into the 3-cyclic ket-
20-[13C]-cortexolone (1a)
21-[13C]-cortexolone (1b)
O
Figure 1 Structure of cortexolones 1a and 1b
high cost of starting material that requires optimized reac-
tions.
Our approach to the synthesis of the labeled cortexolones
is described in Scheme 2. The strategy is based on the
used of K13CN for labeling at position 20 and the used of
13CH3MgI, generated in situ, for labeling at position 21.
Because of the early introduction of the [13C] labeling, our
CN
CN
CN
O
OH
OTMS
OH
b
c
a
S
S
O
O
S
S
2
3
quant
4
quant
5
quant
20-[13C]-3a 85%
20-[13C]-4a 99%
20-[13C]-5a quant
O
O
O
OTMS
OH
OH
d, e
g
+
S
S
O
S
S
8
quant
6
71%
7
26%
20-[13C]-8a 93%
21-[13C]-8b 98%
20-[13C]-6a 41%
21-[13C]-6b 56%
20-[13C]-7a 53%
21-[13C]-7b 23%
f
quant.
Br
Br
O
O
OH
h, i
j
OH
Cl
N
O
9
98 %
10 76%
21-[13C]-10b 74%
20-[13C]-9a 77%
21-[13C]-9b 79%
k
l
1
70%
1
57%
20-[13C]-1a 54%
21-[13C]-1b 31%
Scheme 2 Reagents and conditions: (a) KCN or K13CN, AcOH, MeOH, r.t., 2 h; (b) HS(CH2)2SH, BF3·OEt2, MeOH, r.t., 2 h; (c) TMSCl,
DMF, imidazole, r.t., 19 h; (d) MeMgBr or 13CH3MgI, toluene–Et2O (4:1), 60 °C, 26 h; (e) aq 10% HCl THF–acetone (50:50), r.t., 20 h; (f)
from 6a or 6b: TBAF, THF, r.t., 19 h; (g) MeI, CaCO3, EtOH, H2O, D, 20 h; (h) pyrrolidine, MeOH, D, 2 h; (i) Br2, HCl, EtOH, r.t., 4 h; (j)
K2CO3, EtOH–H2O (87:17), r.t., 1 h; (k) K2CO3, acetone–H2O (60:40), r.t., 0.5 h; (l) K2CO3, acetone–H2O (60:40), r.t., 3 d.
Synthesis 2009, No. 20, 3391–3398 © Thieme Stuttgart · New York

PAPER
Efficient Hemisynthesis of 20- and 21-[13C]-Labeled Cortexolone
3393
Figure 2 1H NMR spectrum of 21-[13-C]-6b: 21-methyl and OTMS parts
al derivative (instead of a 3-thioketal derivative) via liter- [PhI(OAc)2]15 or o-iodosylbenzoic acid (HOOCPhIO),16
ature procedures,12 but only a mixture of the expected 3- but we obtained only a mixture of starting material 8 and
ketal together with the 3,17-bis-ketal could be obtained.
degradation products.
Introduction of the second carbon was achieved by the ad-
dition of an organometallic compound on the protected
cyanhydrin 5. The addition of a Grignard reagent to cy-
anohydrin O-silyl ethers is indeed a very efficient method
for the synthesis a-hydroxy ketones,13 and the labeling on
position 21 could be done using [13C]-methylmagnesium
iodide (99 atom% 13C), formed in situ. Then, addition of
2.5 equivalents of MeMgI to 5 in toluene–Et2O (4:1) at
60 °C for 26 hours, followed by acidic hydrolysis, gave a
mixture of 6 and 7 (Scheme 2) with a combined yield of
94% for 20-[13C]-labeled compounds and of 79% for 21-
[13C]-labeled compounds. However, as we have previous-
ly reported,14 1H NMR (Figure 2) and MS analysis of the
21-[13C]-6b and -7b mixture clearly indicated that the 21-
methyl position was only partially labeled (60 5 atom%
13C) and that methyl groups on silicon were also partially
labeled (30 atom% 13C). This reaction is very interesting
from a mechanistic point of view, however, induced a de-
crease in the expected 13C content.
I
O
O
OH
a
OH
O
O
8
11 0 to 90%
OAc
OH
O
b
c
1 50 to 85%
O
12 97%
Scheme 3 Reagents and conditions: (a) I2, CaO, AIBN (cat.), ‘aged’
THF–MeOH (50:50), r.t. 5 h; (b) AcOH, Et3N, acetone, D, 5 h; (c)
K2CO3, MeOH, H2O, r.t., 3 h.
Then, treatment of 6 with TBAF, followed by deprotec-
tion of the thioketal group led to the expected methyl ke-
tone 8 in almost quantitative yields. To convert this
methyl ketone into cortexolone (1), an additional hydroxy
group had to be introduced at position 21. Three methods
were investigated: a direct hydroxylation, a Stork’s iodi-
nation procedure (Scheme 3) or a bromination after an
iminium protection (Scheme 2). Various direct hydroxy-
lations of methyl ketones exist in the literature, but few of
them have been used on corticosteroids and more particu-
larly on derived pregnenes. We have thus tested a number
of direct hydroxylation on the methyl ketone 8 using orga-
nohypervalent iodine like phenyliodoso diacetate
The iodination procedure of 20-ketopregnene by reaction
with iodine and calcium oxide,17 followed by the reaction
of the 21-iodo intermediate with triethylammonium
acetate18 is the most reported synthetic methods for the
formation of the a-keto functionalized side chain in corti-
costeroids. The iodination is generally carried out with a
large excess of iodine, in a mixture of methanol and
‘aged’ tetrahydrofuran,19 containing a certain amount of
calcium oxide. The mechanism of this reaction is not com-
Synthesis 2009, No. 20, 3391–3398 © Thieme Stuttgart · New York

3394
E. Claudel et al.
PAPER
pletely elucidated and discussions are still open between a od, which could be applied to other substrates like precur-
radical process17 and an ionic one.20 The Stork’s iodina- sors of hydrocortisone, is of particular interest.
tion was performed on the methyl ketone 8 under a range
of conditions and the reaction proved to be somewhat ca-
All air- or moisture-sensitive reactions were conducted in flame-
pricious. Indeed, treatment of 8 with a large excess of io-
dine (5 equiv) and calcium oxide (22 equiv) gave the best
results. As previously descibed,17c the introduction of
small amounts of a radical initiator (AIBN) is important to
accelerate the reaction and then to prevent the slower and
spontaneous deiodination in solution. Thus, no reaction
occurred in freshly distilled THF and a concentration of
peroxide of 5.4 × 10–2 M had been calculated in ‘aged’
THF. But in every case, we were not able to obtain repro-
ducible outputs (Scheme 3) even when iodine uptake
seemed to occur rapidly. Thus, yields ranging from 0 to
90% were obtained without explanation. Conversion of
the 21-iodo derivative 11 into the 21-acetate under
Moreland’s procedure,18 followed by the acetate hydroly-
sis to give cortexolone (1) proceeded readily, but with a
low overall yield from 8.
dried glassware under an atmosphere of dry argon. All solvents used
were of reagent grade. Anhyd solvents were freshly distilled before
use. THF and Et2O were distilled from sodium/benzophenone.
CH2Cl2 was dried over P2O5 before distillation. Petroleum ether
(PE) used refers to the fraction boiling in the range 35–60 °C. Un-
less otherwise noted, reactions were magnetically stirred and mon-
itored by TLC with 0.25 mm Merck precoated silica gel plates.
Flash chromatography was performed with silica gel 60 (particle
size 0.040–0.063 mm) supplied by Merck, Geduran. Yields refer to
chromatographically and spectroscopically pure compounds, unless
1
otherwise stated. H and 13C NMR spectra were recorded on a
Bruker AC300 spectrometer in CDCl3 unless otherwise specified.
Chemical shifts are reported in ppm (d) and CHCl3 was used as in-
ternal standard (d = 7.26). IR spectra were obtained on a Perkin-
Elmer FT-IR 1600 spectrometer; peaks are reported in cm–1. Melt-
ing points were determined on a Büchi Tottoli 510 apparatus and are
uncorrected. Elemental analyses were collected at the Service de
microanalyse of the University of Strasbourg (France).
Caution! Skin contact with cortexolone derivatives must be avoid-
ed. As potential sensitizing substances, these compounds must be
handled with care.
In contrast to the iodination process, the conversion of the
methyl ketone 8 into the bromo derivative 9 proceeded in
good and reproducible yields according to literature pro-
cedure.21 This sequence involves the selective protection
of the enone as its eniminium salt, which is inert in neutral
or acid conditions towards a broad panel of electrophilic
reagents. Thus, pregnene 8 was converted into its pyrro-
lidinyl dienamine, and the crude material was protonated
and brominated in situ to give the dienamine salt, which
in turn gave bromide 9 in almost quantitative yield. Then,
the free a,b-unsaturated ketone group was regenerated by
treatment with potassium carbonate (2.8 equiv) in a mix-
ture of ethanol and water to give the 21-[13C]-bromide 10b
in good yields.21a Finally, the replacement of the bromine
by a hydroxy group could be achieved by treatment with
potassium carbonate (1 equiv) in a mixture of acetone and
water to obtain 1b with a moderate yield.22 In these two
last steps, it is interesting to note that the reaction condi-
tions are very similar and differ only by the amount of po-
tassium carbonate added and the nature of the solvent
used. Thus, in order to reduce the number of steps, we
tried to combine them by treatment of 9 with an excess of
potassium carbonate (3.8 equiv) in a mixture of acetone
and water. This reaction needed three days to reach com-
pletion, but the 20-[13C]-cortexolone (1a) was easily ob-
tained in a yield of 54% from 9a. In this case, the use of
acetone instead of ethanol as co-solvent increased the
yield of the reaction.
17b-Cyano-cyclic-3-(1,2-ethanediylmercapto)-17a-hydroxyan-
drost-4-ene (4)
To a suspension of cyanohydrin 3 (4.36 g, 13.91 mmol) in MeOH
(133 mL) were added ethane dithiol (1.8 mL, 20.87 mmol, 1.5
equiv) and BF3·OEt2 (2.1 mL, 16.69 mmol, 1.2 equiv). The reaction
mixture was stirred at r.t. for 2 h and solvents were removed under
reduced pressure. The white residue was taken up in hot EtOAc (75
mL) and the resulting organic layer was washed with aq sat.
NaHCO3 (3 × 100 mL), H2O (100 mL), dried (MgSO4), and concen-
trated under vacuum to give 4 (5.42 g, 13.91 mmol, quant) as a
white solid; mp 204–205 °C; [a]D20 +139 (c 2.0, CHCl3).
IR (CHCl3): 3586 (OH), 2360 cm–1 (C≡N).
1H NMR (300 MHz, CDCl3): d = 0.67–0.99 (m, 2 H), 0.93 (s, 3 H,
H-18), 1.01 (s, 3 H, H-19), 1.14–2.24 (m, 16 H), 2.38 (ddd, J1 = 2.9
Hz, J2 = 11.5 Hz, JAB = 14.6 Hz, 1 H, H-16b), 2.83 (br s, 1 H, OH-
17), 3.16–3.39 (m, 4 H, SCH2CH2S), 5.48 (s, 1 H, H-4).
13C NMR (75 MHz, CDCl3): d = 16.2 (C-18), 18.5 (C-19), 20.6 (C-
11), 23.9 (C-15), 29.5, 31.8, 32.6, 36.1 (C-8), 36.5 (C-10), 37.3,
37.9, 38.1, 39.5, 40.0, 47.7 (C-14), 49.2 (C-13), 53.4 (C-9), 65.6 (C-
3), 77.9 (C-17), 121.0 (C-20), 124.5 (C-4), 145.7 (C-5).
Anal. Calcd for C22H31NOS2 (389.61): C, 66.76; H, 8.02; N 3,59.
Found: C, 66.53; H, 8.26; N 3.57.
[20-13C]-17b-Cyano-cyclic-3-(1,2-ethanediylmercapto)-17a-hy-
droxyandrost-4-ene (4a)
Starting from 3a (4.44 g, 14.12 mmol) and using the same proce-
dure as for the synthesis of 4 gave 4a (5.45 g, 13.95 mmol, 99%) as
In summary, the synthesis of 20- and 21-[13C]-labeled 21- a white solid; mp 198–199 °C; [a]D20 +142 (c 2.1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.76–0.99 (m, 2 H), 0.93 (s, 3 H,
H-18), 1.01 (s, 3 H, H-19), 1.22–1.85 (m, 11 H), 1.91–2.22 (m, 5 H),
2.39 [dddd, 3J (13C,H) = 3.3 Hz, J1 = 3.3 Hz, J2 = 11.5 Hz,
JAB = 14.6 Hz, 1H, H-16b], 2.50 (br s, 1 H, OH-17), 3.17–3.39 (m,
4 H, SCH2CH2S), 5.48 (s, 1 H, H-4).
cortexolones (1a and 1b), representing an important inter-
mediate for the preparation of the potent allergenic agent
21-dehydrocortexolone, has been completed from the
commercially available andros-4-ene-3,17-dione. Gener-
ally, we noted, during the development of this hemisyn-
thesis that the correct choice of the protective groups is
essential as this can lead not only to mixture or unstable
intermediates but also influences considerably the output
of reactions. Then, the development of this general meth-
13C NMR (75 MHz, CDCl3): d = 16.3 (C-18), 18.5 (C-19), 20.6 (C-
11), 23.9 [d, 3J (13C,C) = 3.1 Hz, C-15], 29.5, 31.8, 32.6, 36.1 (C-8),
3
36.5 (C-10), 37.3, 37.9, 38.1, 39.5, 40.0, 47.7 [d, J (13C,C) = 3.1
Hz, C-14], 49.2 (C-13), 53.4 (C-9), 65.6 (C-3), 77.9 [d, 1J
(13C,C) = 62.9 Hz, C-17], 121.0 (13C-20), 124.5 (C-4), 145.7 (C-5).
Synthesis 2009, No. 20, 3391–3398 © Thieme Stuttgart · New York

PAPER
Efficient Hemisynthesis of 20- and 21-[13C]-Labeled Cortexolone
3395
17b-Cyano-cyclic-3-(1,2-ethanediylmercapto)-17a-trimethyl-
silyloxyandrost-4-ene (5)14
6
Mp 170–171 °C; [a]D20 +119 (c 2.0, CHCl3).
To a suspension of 4 (3.22 g, 8.26 mmol) in DMF (45 mL) and an-
hyd MgSO4 (~2 g) were added imidazole (2.70 g, 39.69 mmol, 4.8
equiv) and TMSCl (3.0 mL, 23.47 mmol, 2.8 equiv). The reaction
mixture was stirred at r.t. for 22 h, hydrolyzed by aq sat. NaHCO3
(200 mL), and extracted with Et2O (3 × 150 mL). The combined or-
ganic layers were washed with H2O (3 × 150 mL), brine (150 mL),
dried (MgSO4), and concentrated under reduced pressure to give 5
(3.81 g, 8.26 mmol, quant) as a white solid; mp 162–163 °C; [a]D
+119 (c 2.0, CHCl3).
IR (CHCl3): 2360 (C≡N), 858 cm–1 (C–Si).
1H NMR (300 MHz, CDCl3): d = 0.22 [s, 9 H, Si(CH3)3], 0.74–1.00
(m, 2 H), 0.89 (s, 3 H, H-18), 1.01 (s, 3 H, H-19), 1.17–2.24 (m, 16
H), 2.32 (ddd, J1 = 3.1 Hz, J2 = 11.5 Hz, JAB = 14.6 Hz, 1 H, H-
16b), 3.18–3.56 (m, 4 H, SCH2CH2S), 5.48 (s, 1 H, H-4).
13C NMR (75 MHz, CDCl3): d = 0.7 [Si(CH3)3], 16.0 (C-18), 18.5
(C-19), 20.6 (C-11), 24.0 (C-15), 29.7, 31.9, 32.7, 36.2 (C-8), 36.6
(C-10), 37.3, 38.0, 38.7, 39.5, 40.0, 47.7 (C-14), 50.1 (C-13), 53.4
(C-9), 65.7 (C-3), 78.7 (C-17), 121.0 (C-20), 124.4 (C-4), 146.0 (C-
5).
IR (CHCl3): 1702 (C=O), 852 cm–1 (C–Si).
1H NMR (300 MHz, CDCl3): d = 0.10 [s, 9 H, Si(CH3)3], 0.54 (s, 3
H, H-18), 0.76–1.02 (m, 2 H), 1.00 (s, 3 H, H-19), 1.15–1.90 (m, 12
H), 1.97–2.32 (m, 4 H), 2.11 (s, 3 H, H-21), 2.69–2.79 (m, 1 H, H-
16b), 3.17–3.40 (m, 4 H, SCH2CH2S), 5.47 (s, 1 H, H-4).
13C NMR (75 MHz, CDCl3): d = 1.2 [Si(CH3)3], 14.5 (C-18), 18.5
(C-19), 21.0 (C-11), 23.4 (C-15), 26.6 (C-21), 30.9, 31.0, 32.0, 32.7,
35.9 (C-8), 36.6 (C-10), 37.3, 38.0, 39.5, 40.0, 47.8 (C-13), 50.4 (C-
14), 53.6 (C-9), 65.8 (C-3), 93.3 (C-17), 124.2 (C-4), 146.3 (C-5),
210.7 (C-20).
20
Anal. Calcd for C26H42O2S2Si (478.84): C, 65.21; H, 8.80. Found:
C, 65.13; H, 8.95.
7
Mp 164–165 °C; [a]D20 +114 (c 1.7, CHCl3).
IR (CHCl3): 3685 (OH), 1697 cm–1 (C=O).
1H NMR (300 MHz, CDCl3): d = 0.70 (s, 3 H, H-18), 0.77–1.04 (m,
2 H), 1.00 (s, 3 H, H-19), 1.21–1.83 (m, 12 H), 1.98–2.18 (m, 4 H),
2.24 (s, 3 H, H-21), 2.59–2.69 (m, 1 H, H-16b), 2.69 (s, 1 H, OH-
17), 3.16–3.39 (m, 4 H, SCH2CH2S), 5.48 (s, 1 H, H-4).
Anal. Calcd for C25H39NOS2Si (461.79): C, 65.02; H, 8.51. Found:
C, 65.24; H, 8.50.
13C NMR (75 MHz, CDCl3): d = 15.4 (C-18), 18.5 (C-19), 20.7 (C-
11), 23.9 (C-15), 27.9 (C-21), 30.1, 32.0, 32.7, 33.5, 35.6 (C-8),
36.6 (C-10), 37.3, 38.0, 39.5, 40.0, 48.3 (C-13), 50.1 (C-14), 53.6
(C-9), 65.7 (C-3), 90.0 (C-17), 124.3 (C-4), 146.1 (C-5), 211.7 (C-
20).
[20-13C]-17b-Cyano-cyclic-3-(1,2-ethanediylmercapto)-17a-tri-
methylsilyloxyandrost-4-ene (5a)
Starting from 4a (5.45 g, 13.95 mmol) and using the same proce-
dure as for the synthesis of 5 gave 5a (6.45 g, 13.94 mmol, quant)
as a white solid; mp 154–155 °C; [a]D20 +110 (c 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.22 [s, 9 H, Si(CH3)3], 0.74–0.99
(m, 2 H), 0.89 (s, 3 H, H-18), 1.01 (s, 3 H, H-19), 1.22–1.81 (m, 11
H), 1.90–2.23 (m, 5 H), 2.32 [dddd, 3J (13C,H) = 3.3 Hz, J1 = 3.3 Hz,
J2 = 11.5 Hz, JAB = 14.6 Hz, 1 H, H-16b], 3.18–3.39 (m, 4 H,
SCH2CH2S), 5.48 (s, 1 H, H-4).
13C NMR (75 MHz, CDCl3): d = 0.7 [Si(CH3)3], 16.0 (C-18), 18.5
(C-19), 20.6 (C-11), 24.0 [d, 3J (13C,C) = 3.7 Hz, C-15], 29.7, 31.9,
32.7, 36.2 (C-8), 36.6 (C-10), 37.3, 38.0, 38.8, 39.5, 40.0, 47.7 [d,
3J (13C,C) = 3.1 Hz, C-14], 50.1 (C-13), 53.4 (C-9), 65.7 (C-3), 78.6
[d, 1J (13C,C) = 62.3 Hz, C-17], 121.0 (13C-20), 124.4 (C-4), 146.0
(C-5).
Anal. Calcd for C23H34O2S2 (406.66): C, 67.97; H, 8.43. Found: C,
68.06; H, 8.57.
[20-13C]-Cyclic-3-(1,2-ethanediylmercapto)-17a-trimethyl-
silyloxypregn-4-en-20-one (6a) and [20-13C]-Cyclic-3-(1,2-
ethanediylmercapto)-17a-hydroxypregn-4-en-20-one (7a)
Starting from 5a (2.00 g, 4.32 mmol) and MeI (0.67 mL, 10.76
mmol, 2.49 equiv) and using the same procedure as for the synthesis
of 6 and 7 gave 6a (844 mg, 1.76 mmol, 41%) and 7a (934 mg, 2.29
mmol, 53%). Then, 6a was converted into 7a (716 mg, 1.76 mmol,
quant) as in Step B above.
6a
[a]D20 +119 (c 2.0, CHCl3).
Cyclic-3-(1,2-ethanediylmercapto)-17a-trimethylsilyloxy-
pregn-4-en-20-one (6) and Cyclic-3-(1,2-ethanediylmercapto)-
17a-hydroxypregn-4-en-20-one (7)
1H NMR (300 MHz, CDCl3): d = 0.10 [s, 9 H, Si(CH3)3], 0.54 (s, 3
H, H-18), 0.76–1.02 (m, 2 H), 1.00 (s, 3 H, H-19), 1.18–2.20 (m, 16
H), 2.11 [d, 2J (13C,H) = 3.0 Hz, 3 H, H-21], 2.69–2.79 (m, 1 H, H-
16b), 3.17–3.40 (m, 4 H, SCH2CH2S), 5.47 (s, 1 H, H-4).
13C NMR (75 MHz, CDCl3): d = 1.2 [Si(CH3)3], 14.5 (C-18), 18.5
(C-19), 21.0 (C-11), 23.4 (C-15), 26.6 [d, 1J (13C,C) = 50.0 Hz, C-
21], 30.9, 31.0, 32.0, 32.7, 35.9 (C-8), 36.6 (C-10), 37.3, 38.0, 39.5,
40.0, 47.8 (C-13), 50.4 (C-14), 53.6 (C-9), 65.8 (C-3), 93.3 [d,
1J (13C,C) = 50.0 Hz, C-17], 124.2 (C-4), 146.3 (C-5), 210.7 (13C-
20).
Step A: To a suspension of Mg turnings (0.11 g, 4.5 mmol, 2.37
equiv) in anhyd Et2O (2 mL) was added MeI (0.32 mL, 5.14 mmol,
2.48 equiv). After complete consumption of Mg, cyanohydrin 5
(0.957 g, 2.07 mmol) in toluene (6 mL) was added. The flask was
sealed with a septum and heated at 59–61 °C for 26 h, cooled down,
and hydrolyzed with aq 10% HCl (50 mL). THF (25 mL) and ace-
tone (25 mL) were added, the solution stirred for 14 h and extracted
with CH2Cl2 (3 × 100 mL). The combined organic layers were
washed with aq sat. NaHCO3 (150 mL), H2O (2 × 100 mL), and
dried (MgSO4). Solvents were concentrated under reduced pressure
and the residue purified by column chromatography over silica gel
(PE, EtOAc 5%, then PE, EtOAc 15%) to give 6 (704 mg, 1.47
mmol, 71%) and 7 (215 mg, 0.53 mmol, 26%).
7a
Mp 164–165 °C; [a]D20 +112 (c 2, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.69 (s, 3 H, H-18), 0.76–1.03 (m,
2 H), 0.99 (s, 3 H, H-19), 1.18–1.82 (m, 12 H), 1.97–2.19 (m, 3 H),
Step B: To a solution of 6 (704 mg, 1.47 mmol) in THF (10 mL)
cooled at 0 °C was added a 1 M solution of TBAF in THF (2.35 mL,
2.35 mmol, 1.6 equiv). The solution was stirred at r.t. for 20 h, fil-
tered over silica gel, which was washed with CH2Cl2 (100 mL) and
Et2O (100 mL). The combined organic solvents were concentrated
under reduced pressure and the residue purified by column chroma-
tography over silica gel (PE, EtOAc 10%, then PE, EtOAc 20%) to
give 7 (598 mg, 1.47 mmol, quant) as a white solid.
2
2.23 [d, J (13C,H)= 5.9 Hz, 3 H, H-21], 2.44–2.49 (m, 1 H), 2.64
[dddd, 3J (13C,H) = 2.9 Hz, J1 = 2.9 Hz, J2 = 11.5 Hz, JAB = 14.8 Hz,
1 H, H-16b], 2.74 (s, 1 H, OH-17), 3.15–3.38 (m, 4 H, SCH2CH2S),
5.47 (s, 1 H, H-4).
13C NMR (75 MHz, CDCl3): d = 15.4 (C-18), 18.5 (C-19), 20.7 (C-
1
11), 23.9 (C-15), 27.8 [d, J (13C,C) = 40.7 Hz, C-21], 30.2, 32.0,
32.7, 33.5, 35.6 (C-8), 36.5 (C-10), 37.3, 38.0, 39.5, 40.0, 48.2 (C-
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3396
E. Claudel et al.
PAPER
13), 50.1 (C-14), 53.6 (C-9), 65.7 (C-3), 89.9 [d, 1J (13C,C) = 44.4
8), 35.6, 38.5 (C-10), 48.0 (C-13), 49.9 (C-14), 53.3 (C-9), 89.8 [d,
2J (13C,C) = 11.1 Hz, C-17], 123.8 (C-4), 171.2 (C-5), 199.6 (C-3),
211.6 [d, 1J (13C,C) = 40.1 Hz, C-20].
Hz, C-17], 124.3 (C-4), 146.1 (C-5), 211.7 (13C-20).
[21-13C]-Cyclic-3-(1,2-ethanediylmercapto)-17a-trimethylsilyl-
oxypregn-4-en-20-one (6b) and [21-13C]-Cyclic-3-(1,2-
ethanediylmercapto)-17a-hydroxypregn-4-en-20-one (7b)
Starting from 5 (0.957 g, 2.07 mmol) and [13C]-MeI (0.35 mL, 5.58
mmol, 2.70 equiv), and using the same procedure as for the synthe-
sis of 6 and 7 gave 6b (555 mg, 1.16 mmol, 56%) and 7b (192 mg,
0.47 mmol, 23%). Then, 6b was converted into 7b (473 mg, 1.16
mmol, quant) as in step B above.
[20-13C]-21-Bromo-17a-hydroxy-3-(1-pyrrolidinium-1-
ylidene)pregn-5-en-20-one Chloride (9a)
Starting from 8a (520 mg, 1.57 mmol) and using the same proce-
dure as for the synthesis of 9 gave 9a (603 mg, 1.21 mmol, 77%) as
a yellow solid (cf. Supporting Information).
1H NMR (300 MHz, CDCl3–DMSO-d6): d = 0.49 (s, 3 H, H-18),
0.92–2.14 (m, 18 H), 1.06 (s, 3 H, H-19), 2.41–2.44 (m, 2 H), 2.47–
2.59 (m, 1 H, H-16b), 2.67–2.87 (m, 2 H), 3.71–3.95 (m, 5 H, 2 ×
H-1¢, 2 × H-4¢, and OH-17), 4.07 [A part of an AB system,
JAB = 15.1 Hz, 2J (13C,C) = 4.2 Hz, 1 H, H-21], 4.36 [B part of an
AB system, JAB = 15.1 Hz, 2J (13C,H) = 4.2 Hz, 1 H, H-21], 6.19 (s,
1 H, H-4).
6b14
1H NMR (300 MHz, CDCl3): d = 0.10 (s, 9 H, Si(CH3)3], 0.54 (s, 3
H, H-18), 0.76–0.97 (m, 2 H), 1.00 (s, 3 H, H-19), 1.15–1.92 (m, 12
H), 1.97–2.37 (m, 4 H), 2.11 [d, 1J (13C,H) = 127.8 Hz, 3 H, H-21],
2.70–2.80 (m, 1 H, H-16b), 2.99–3.40 (m, 4 H, SCH2CH2S), 5.49
(s, 1 H, H-4).
[21-13C]-21-Bromo-17a-hydroxy-3-(1-pyrrolidinium-1-
ylidene)pregn-5-en-20-one Chloride (9b)
Starting from 8b (769 mg, 2.32 mmol) and using the same proce-
dure as for the synthesis of 9 gave 9b (916 mg, 1.83 mmol, 79%) as
a yellow solid (cf. Supporting Information).
1H NMR (300 MHz, DMSO-d6): d = 0.55 (s, 3 H, H-18), 0.92–2.68
(m, 21 H), 1.11 (s, 3 H, H-19), 2.73–2.96 (m, 2 H), 3.70–4.05 (m, 4
H, 2 × H-1¢, 2 × H-4¢), 4.35 [A part of an AB system, JAB = 15.0 Hz,
1J (13C,H) = 150.3 Hz, 1 H, H-21], 4.36 [B part of an AB system,
JAB = 15.0 Hz, 1J (13C,H) = 150.3 Hz, 1 H, H-21], 5.60 (br s, 1 H,
OH-17), 6.50 (s, 1 H, H-4).
13C NMR (75 MHz, CDCl3): d = 1.2 [Si(CH3)3], 14.5 (C-18), 18.5
(C-19), 21.0 (C-11), 23.4 (C-15), 26.7 (13C-21), 30.9, 31.0, 32.0,
32.7, 35.9 (C-8), 36.6 (C-10), 37.3, 38.0, 39.5, 40.0, 47.8 (C-13),
50.4 (C-14), 53.6 (C-9), 65.8 (C-3), 93.3 [d, 2J (13C,C) = 11.3 Hz,
C-17], 124.2 (C-4), 146.3 (C-5), 210.7 [d, 1J (13C,C) = 39.8 Hz, C-
20].
7b14
Mp 161–162 °C; [a]D20 +108 (c 2, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.71 (s, 3 H, H-18), 0.78–1.05 (m,
2 H), 1.01 (s, 3 H, H-19), 1.19–1.84 (m, 12 H), 1.98–2.23 (m, 4 H),
2.24 [d, 1J (13C,H) = 127.8 Hz, 3 H, H-21], 2.60–2.70 (m, 2 H, H-
16b, and OH-17), 3.17–3.39 (m, 4 H, SCH2CH2S), 5.48 (s, 1 H, H-
4).
13C NMR (75 MHz, CDCl3): d = 15.4 (C-18), 18.6 (C-19), 20.7 (C-
11), 24.0 (C-15), 27.9 (13C-21), 30.2, 32.0, 32.7, 33.5, 35.7 (C-8),
36.6 (C-10), 37.3, 38.0, 39.5, 40.0, 48.3 (C-13), 50.1 (C-14), 53.6
(C-9), 65.7 (C-3), 90.0 [d, 2J (13C,C) = 11.1 Hz, C-17], 124.3 (C-4),
146.1 (C-5), 211.7 [d, 1J (13C,C) = 40.1 Hz, C-20].
13C NMR (75 MHz, DMSO-d6): d = 14.6 (C-18), 16.8 (C-19), 20.3
(C-11), 23.1 (C-15), 23.9 (C-2¢ or C-3¢), 24.1 (C-2¢ or C-3¢), 26.1,
30.0, 31.7, 32.8, 33.1 (2 C), 34.8 (C-8), 36.2 (13C-21), 40.3 (C-10),
46.8 (C-13), 48.6 (C-9 or C-14), 52.1 (C-9 or C-14), 52.2 (C-1¢ or
2
C-4¢), 52.5 (C-1¢ or C-4¢), 89.2 [d, J (13C,C) = 14.2 Hz, C-17],
115.6 (C-4), 171.4 (C-3 or C-5), 180.0 (C-3 or C-5), 203.5 [d,
1J (13C,C) = 38.3 Hz, C-20].
[21-13C]-21-Bromo-17a-hydroxypregn-4-ene-3,20-dione (10b)
Starting from 9b (876 mg, 1.75 mmol) and using the same proce-
dure as for the synthesis of 10 gave 10b (533 mg, 1.30 mmol, 74%)
as a white solid (cf. Supporting Information).
1H NMR (300 MHz, DMSO-d6): d = 0.72 (s, 3 H, H-18), 0.74–2.18
(m, 14 H), 1.18 (s, 3 H, H-19), 2.33–2.49 (m, 4 H), 2.64–2.84 (m, 2
H, H-16b and OH-17), 4.16 [A part of an AB system, JAB = 14.9 Hz,
1J (13C,H) = 150.0 Hz, 1 H, H-21], 4.39 [B part of an AB system,
JAB = 14.9 Hz, 1J (13C,H) = 150.0 Hz, 1H, H-21], 5.73 (s, 1 H, H-4).
13C NMR (75 MHz, DMSO-d6): d = 14,8 (C-18), 17.1 (C-19), 20.4
(C-11), 23.3 (C-15), 30.2, 31.7, 32.5, 33.6, 33.9, 35.3, 35.4 (C-8),
35.6 (13C-21), 38.3 (C-10), 47.3 (C-13), 49.8 (C-14), 52.9 (C-9),
89.8 [d, 2J (13C,C)= 14.1 Hz, C-17], 123.5 (C-4), 171.1 (C-5), 199.3
(C-3), 203.6 [d, 1J (13C,C) = 38.0 Hz, C-20].
[20-13C]-17a-Hydroxypregn-4-ene-3,20-dione (8a)
Starting from 7a (2.42 g, 5.94 mmol) and using the same procedure
as for the synthesis of 8 gave 8a (1.83 g, 5.52 mmol, 93%) as a white
20
solid (cf. Supporting Information); mp 208–209 °C; [a]D +70 (c
2.0, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.72 (s, 3 H, H-18), 0.74–1.89 (m,
14 H), 1.16 (s, 3 H, H-19), 2.24 [d, 2J (13C,H) = 5.9 Hz, 3 H, H-21],
3
3
2.26–2.46 (m, 4 H), 2.67 [dddd, J (13C,H) = 2.9 Hz, J = 2.9 Hz,
3J = 11.5 Hz, J = 14.7 Hz, 1 H, H-16b], 3.00 (br s, 1 H, OH-17),
2
5.71 (s, 1 H, H-4).
13C NMR (75 MHz, CDCl3): d = 15.3 (C-18), 17.3 (C-19), 20.5 (C-
1
11), 23.9 (C-15), 27.8 [d, J (13C,C) = 40.1 Hz, C-21], 30.0, 32.0,
32.8, 33.4, 33.9, 35.4 (C-8), 35.7, 38.5 (C-10), 48.0 (C-13), 50.0 (C-
1
14), 53.3 (C-9), 89.8 [d, J (13C,C) = 44.4 Hz, C-17], 123.9 (C-4),
17a,21-Dihydroxypregn-4-ene-3,20-dione (1)
171.1 (C-5), 199.6 (C-3), 211.6 (13C-20).
From 9: To a solution of 9 (185 mg, 0.37 mmol) in acetone and H2O
(60:40, 100 mL) was added K2CO3 (195 mg, 1.41 mmol, 3.8 equiv).
The reaction mixture was stirred at r.t. for 3 days and acetone was
evaporated under reduced pressure. The aqueous phase was extract-
ed with CH2Cl2 (3 × 20 mL). The combined organic layers were
washed with aq 10% HCl (30 mL), brine (2 × 30 mL), dried
(MgSO4), and concentrated under reduced pressure to give 1 (90
mg, 0.26 mmol, 70%) as a white solid.
[21-13C]-17a-Hydroxypregn-4-ene-3,20-dione (8b)
Starting from 7b (1.44 g, 3.54 mmol) and using the same procedure
as for the synthesis of 8 gave 8b (1.15 g, 3.47 mmol, 98%) as a
20
white solid (cf. Supporting Information); mp 207–208 °C; [a]D
+87 (c 2.5, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.72 (s, 3 H, H-18), 0.87–2.04 (m,
14 H), 1.16 (s, 3 H, H-19), 2.22–2.44 (m, 4 H), 2.24 [d, 1J (13C,H) =
127.8 Hz, 3 H, H-21], 2.66 (m, 1 H, H-16b), 3.01 (s, 1 H, OH-17),
5.70 (d, J = 1.5 Hz, 1 H, H-4).
From 10: Product 1 was obtained in 57% yield according to the pro-
cedure described by Numazawa and Nagaoka.22
Mp 201–202 °C [Lit.22,23 mp 196–199 °C (acetone) or 207–208 °C
13C NMR (75 MHz, CDCl3): d = 15.3 (C-18), 17.3 (C-19), 20.5 (C-
(acetone)]; [a]D +123 (c 1.0, CHCl3) {Lit.24 [a]D +126 (c 1.0,
20
20
11), 23.8 (C-15), 28.0 (13C-21), 30.0, 32.0, 32.8, 33.4, 33.9, 35.4 (C-
CHCl3)}.
Synthesis 2009, No. 20, 3391–3398 © Thieme Stuttgart · New York

PAPER
Efficient Hemisynthesis of 20- and 21-[13C]-Labeled Cortexolone
3397
IR (KBr): 3509 (OH), 3461 (OH), 1711 (C=O), 1664 cm–1 (C=O).
(2) (a) Wilkinson, S. M.; Cartwright, P. H.; English, J. S. C.
Lancet 1991, 337, 761. (b) Lauerma, A. I. Contact
Dermatitis 1991, 24, 123. (c) Dooms-Goossens, A.;
Morren, M. Contact Dermatitis 1992, 26, 182. (d) Matura,
M.; Goossens, A. Allergy 2000, 55, 698. (e) Hennge, U. R.;
Ruzicka, T.; Schwartz, R. A.; Cork, M. J. J. Am. Acad.
Dermatol. 2006, 54, 1.
1H NMR (300 MHz, CDCl3): d = 0.68 (s, 3 H, H-18), 0.74–2.05 (m,
14 H), 1.16 (s, 3 H, H-19), 2.19–2.46 (m, 4 H), 2.62–2.71 (m, 1 H,
H-16b), 2.84 (br s, 2 H, OH-17 and OH-21), 4.28 (A part of an AB
system, JAB = 19.8 Hz, 1 H, H-21), 4.66 (B part of an AB system,
JAB = 19.8 Hz, 1 H, H-21), 5.71 (s, 1 H, H-4).
13C NMR (75 MHz, CDCl3): d = 15.0 (C-18), 17.3 (C-19), 20.5 (C-
11), 23.7 (C-15), 30.1, 32.0, 32.8, 33.9, 34.5, 35.6 (C-8), 35.7, 38.6
(C-10), 48.5 (C-13), 50.3 (C-14), 53.3 (C-9), 67.4 (C-21), 89.0 (C-
17), 123.9 (C-4), 171.3 (C-5), 199.8 (C-3), 212.5 (C-20).
(3) (a) Lepoittevin, J.-P.; Drieghes, J.; Goossens, A. Arch
Dermatol. 1995, 131, 31. (b) Bircher, A. J.; Thürlimann,
W.; Hunziker, T. h.; Pasche-Koo, F.; Hunziker, N.;
Perrenoud, D.; Elsner, P.; Schultheiss, R. Dermatology
1995, 191, 109; the author list also includes members of the
Swiss contact dermatitis research group. (c) Isaksson, M.;
Andersen, K. E.; Brandão, F. M.; Bruynzeel, D. P.; Bruze,
M.; Camarasa, J. G.; Diepgen, T.; Ducombs, G.; Frosch, P.
J.; Goossens, A.; Lahti, A.; Menné, T.; Rycroft, R. J. G.;
Seidenari, S.; Shaw, S.; Tosti, A.; Wahlberg, J. E.; White, I.
R.; Wilkinson, J. D. Contact Dermatitis 2000, 42, 27.
(4) Rustemeyer, T.; van Hoogstraten, I. M. W.; von Blomberg,
B. M. E.; Scheper, R. J. In Textbook of Contact Dermatitis;
Rycroft, R. J. G.; Menné, T.; Frosch, P. J.; Lepoittevin, J.-P.,
Eds.; Springer-Verlag: Berlin, 2001, 13–58.
[20-13C]-17a,21-Dihydroxypregn-4-ene-3,20-dione (1a)
Starting from 9a (370 mg, 0.74 mmol) and using the same proce-
dure as for the synthesis of 1 gave 1a (140 mg, 0.40 mmol, 54%) as
a white solid.
1H NMR (300 MHz, CDCl3): d = 0.68 (s, 3 H, H-18), 0.90–2.05 (m,
14 H), 1.17 (s, 3 H, H-19), 2.24–2.47 (m, 4 H), 2.63–2.71 (m, 1 H,
H-16b), 2.84 (br s, 2 H, OH-17 and OH-21), 4.28 [A part of an AB
system, JAB = 19.8 Hz, 2J (13C,H) = 3.9 Hz, 1 H, H-21], 4.66 [B part
2
of an AB system, JAB = 19.8 Hz, J (13C,H) = 3.9 Hz, 1 H, H-21],
5.71 (s, 1 H, H-4).
(5) Lepoittevin, J.-P. In Textbook of Contact Dermatitis;
Rycroft, R. J. G.; Menné, T.; Frosch, P. J.; Lepoittevin, J.-P.,
Eds.; Springer-Verlag: Berlin, 2001, 59–89.
(6) (a) Bundgaard, H. Arch. Pharm. Chem., Sci. Ed. 1980, 8, 83.
(b) Matura, M.; Lepoittevin, J.-P.; Arbez-Gindre, C.;
Goossens, A. Contact Dermatitis 1998, 38, 106.
13C NMR (75 MHz, CDCl3): d = 15.0 (C-18), 17.4 (C-19), 20.5 (C-
11), 23.7 (C-15), 30.1, 32.0, 32.8, 33.9, 34.6, 35.6 (C-8), 35.7, 38.6
(C-10), 48.6 (C-13), 50.3 (C-14), 53.3 (C-9), 67.4 [d, 1J (13C,H) =
1
37.5 Hz, C-21], 89.0 [d, J (13C,C) = 46.5 Hz, C-17], 124.0 (C-4),
170.9 (C-5), 199.6 (C-3), 212.3 (13C-20).
(7) (a) Demoulin, J. D.; Armbruster, A.-M.; Pullman, B.
J. Quantum Chem. 1979, 16, 631. (b) Lo, T. W. C.;
Westwood, M. E.; McLellan, A. C.; Selwood, T.;
Thornalley, P. J. J. Biol. Chem. 1994, 269, 32299.
(c) Wilkinson, S. M.; Jones, M. F. Br. J. Dermatol. 1996,
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Washington, 2002, 278–293.
[21-13C]-17a,21-Dihydroxypregn-4-ene-3,20-dione (1b)
Starting from 10b (533 mg, 1.30 mmol) and using the same proce-
dure as for the synthesis of 1 according to the procedure described
by Numazawa and Nagaoka22 and gave 1b (139 mg, 0.40 mmol,
31%) as a white solid.
1H NMR (300 MHz, CDCl3): d = 0.67 (s, 3 H, H-18), 0.87–2.03 (m,
14 H), 1.16 (s, 3 H, H-19), 2.23–2.46 (m, 4 H), 2.61–2.70 (m, 1 H,
H-16b), 3.00 (br s, 2 H, OH-17 and OH-21), 4.24 [A part of an AB
system, JAB = 19.8 Hz, 1J (13C,H) = 147.0 Hz, 1 H, H-21], 4.68 [B
part of an AB system, JAB = 19.8 Hz, 2J (13C,H) = 147.0 Hz, 1 H, H-
21], 5.70 (s, 1 H, H-4).
(10) (a) Andrews, D. R.; Giusto, R. A.; Sudhakar, A. R.
Tetrahedron Lett. 1996, 37, 3417. (b) Batist, J. N. M.; Marx,
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Wojciechowska, W. Synthesis 1984, 132. (e) Murahashi, S.-
I.; Saito, T. S.; Hanaoka, H.; Murakami, Y.; Naota, T.;
Kumobayashi, H.; Akutagawa, S. J. Org. Chem. 1993, 58,
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13C NMR (75 MHz, CDCl3): d = 14.9 (C-18), 17.3 (C-19), 20.5 (C-
11), 23.7 (C-15), 30.1, 32.0, 32.8, 33.8, 34.5, 35.6 (C-8), 35.7, 38.6
(C-10), 48.5 (C-13), 50.3 (C-14), 53.3 (C-9), 67.4 (13C-21), 89.0 [d,
2J (13C,C) = 10.4 Hz, C-17], 123.8 (C-4), 171.4 (C-5), 199.8 (C-3),
212.4 [d, 1J (13C,C) = 37.0 Hz, C-20].
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are: experimental procedures and characterization details for the in-
termediates 3, 3a, 8, 9, 10, and NMR spectra for compounds 1a and
1b.
Acknowledgment
The authors thank the French Ministère de l’Education Nationale,
de la Recherche et de la Technologie for a fellowship to C.A.G.
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Synthesis 2009, No. 20, 3391–3398 © Thieme Stuttgart · New York