Stereocontrolled synthesis of all eight stereoisomers of the putative anti-androgen cyoctol

Article abstract of DOI:10.1016/j.tet.2004.06.143

All eight stereoisomers (1-4 and enantiomers) of the putative anti-androgen cyoctol have been synthesized along stereochemically unambiguous routes. The biological tests of all isomers indicated that cyoctol is not an anti-androgen, contrary to the patent literature. All eight stereoisomers of the putative anti-androgen cyoctol have been prepared and tested biologically.

Full text of DOI:10.1016/j.tet.2004.06.143

Tetrahedron 60 (2004) 9599–9614
Stereocontrolled synthesis of all eight stereoisomers of the
putative anti-androgen cyoctol
*
Johann Mulzer, Ulrich Kaselow, Klaus-Dieter Graske, Holger Kuhne, Andreas Sieg
¨
and Harry J. Martin
¨
¨
¨
Institut fur Organische Chemie der Universitat Wien, Wahringer Strasse 38, A-1090 Wien, Austria
Received 28 April 2004; revised 7 June 2004; accepted 9 June 2004
Available online 21 August 2004
Abstract—All eight stereoisomers (1-4 and enantiomers) of the putative anti-androgen cyoctol have been synthesized along
stereochemically unambiguous routes. The biological tests of all isomers indicated that cyoctol is not an anti-androgen, contrary to the
patent literature.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction and biological background
13-cis-retinoic acid does not function as an anti-androgen,
whereas cyoctol does.3 Because cyoctol has in vitro efficacy
and very low toxicity in experimental animals, investi-
gations as to its clinical use as a topical anti-androgen for the
treatment of acne and other diseases of localized androgen
excess are indicated.4 Fibroblast cultures were established
from both frontal and occipital skin from patients with
clinical diagnosis of androgenic alopecia undergoing hair
transplantation. The DHT receptor activity from fibroblasts
from the frontal region was 19.9 compared to 4.5 fmol per
mg tissue protein in the occipital region. Cyoctol blocked a
mean of 80% of the DHT binding in the fibroblasts derived
from the frontal region and only 22% of that from the
occipital region.5 Anti-androgens, like cyoctol, may help in
prevention and treatment of keloid and abnormal scar
formation.6 Cyoctol may have a role in anti-fungal therapy.7
Intra-abdominal adhesions are the most common post-
infective and postoperative complications. Cyoctol may be
clinically useful in this problem.8 Skin preparations for
aging prevention contain cyoctol and at least one blood-
circulation promoter selected from the group comprising
g-aminobutyric acid, vitamin E orotate, diisopropylamine
dichloroacetate, hyaluronic acid, elastin, water-soluble
collagen, Swertia japonica extract, and ginseng extract.
The preparations stimulate skin functions, prevent dryness,
and show anti-wrinkling effects in a short period of time.9 A
hair tonic was formulated containing Swertia extract 10.0,
cyoctol 0.01, EtOH 60.0, polyoxyethylene hydrogenated
castor oil 0.5 glycerin 5.0, perfume 0.1, and water to 100%
by weight. The preparation significantly promoted the hair
growth in mice and humans.10 Cyoctol was effective in vitro
as an anti-androgen without effect on either the estrogen or
the progesterone receptors in carcinomas of the breast,
The carbacyclin derivative cyoctol has been described as an
androgen receptor blocker which induces a wide variety of
interesting biological effects.
For instance, various forms of alopecia or male pattern
baldness are treated by concomitant administration of
potassium channel openers and cyoctol.l Another interesting
phenomenon was that cyoctol was completely metabolized
when passing through the skin as no unchanged cyoctol
could be detected in ipsilateral plasma samples. This may
eliminate the occurrence of adverse systemic effects after
dermal application.2 The effects of cyoctol or 13-cis-retinoic
acid on binding of 3H-labeled dihydrotestosterone (DHT) by
human facial skin fibroblasts in culture were studied at final
ratios of either cyoctol or 13-cis-retinoic acid to DHT
between 0:1 and 104:1. 13-cis-Retinoic acid did not
inhibit DHT binding even at ratios at 104:1. By contrast,
cyoctol inhibited 78–93% of the DHT binding. Apparently,
Keywords: Putative anti-androgen cyoctol; 13-cis-Retinoic; Cyoctol.
* Corresponding author. Tel.: C431427752190; fax: C431427752189;
e-mail: johann.mulzer@univie.ac.at
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.143

9600
J. Mulzer et al. / Tetrahedron 60 (2004) 9599–9614
ovary, and prostate as well as in malignant melanomas. In a
clonogenic assay, cyoctol was more effective against
carcinomas of the breast, the kidney, the ovary, and the
prostate than conventional anti-neoplastic agents in the
majority of tumors tested.11
cyoctol and to subject these to conclusive biological testing
in order to discriminate the influence of chirality on the
biological activity.
1.1. Total synthesis
All our approaches are convergent. The carbacyclin core
and an appropriately functionalized sidechain were prepared
separately with defined stereochemistry and then united by
efficient CC-connecting reactions.
In the first synthesis we made use of an intramolecular
Pauson–Khand cyclization13a to prepare the carbacyclin
core to which the sidechain was attached via a Wittig
olefination. Specifically (Scheme 1) known enyne 513b was
converted with Co2(CO)8 into the bicyclic enone 6 under
forced Pauson Khand conditions (n-octane, 30 bar CO,
105 8C, 5d).13b Catalytic hydrogenation under controlled
conditions removed the OBn protecting group without
touching the endocyclic double bond to deliver alcohol 7
which was oxidized under Swern conditions to aldehyde 8.
Wittig reaction with phosphonium chloride 9 (prepared
along the straightforward route shown in Scheme 2) gave
low yields, until silver(I)chloride was added in substoichio-
metric amounts. With this additive the yield rose to 90%
obviously due to a catalytic effect of the silver salt which
may act as a mild Lewis acid and facilitate the formation
of the oxaphosphetane intermediate. Olefin 10 was formed
Z-selectively and was converted into hydroxy cyoctol 11 in
two steps. Reductive removal of the hydroxyl function via
Intrigued by the manifold applicability of cyoctol we were
puzzled by the fact that all biological data had been gained
from a racemic mixture of diastereomers.12 So it was
unclear whether all stereoisomers or only a limited number
thereof was responsible for the biological profile. Thus we
decided to develop stereocontrolled approaches to all
possible eight stereoisomers (1-4 and enantiomers) of
Scheme 1.

J. Mulzer et al. / Tetrahedron 60 (2004) 9599–9614
9601
Scheme 2.
the Barton–McCombie protocol14 furnished cyoctol 1 in
stereochemically pure form (HPLC, 1H and 13C NMR)
(Scheme 3).
ester 24 was reduced with sodium borohydride to give
hydroxyester 31 stereoselectively. Again the reagent attack
occurred exclusively from the exo-face. Saponification of
the ester led to hydroxy acid 32 which was treated with
DEAD and triphenylphosphine to form olefin 33 via a
dehydrative decarboxylation19 Catalytic hydrogenation
generated the endo-cyoctol derivative 34 stereoselectively,
again via an exo-attack of the reagent. After ketal hydrolysis
cyoctol 3 and 4 were obtained in stereochemically pure form
(Scheme 6).
An alternative access to the bicyclic carbacyclin core
(Scheme 4) was efficiently provided by the Weiss-reaction
of dimethyl acetone dicarboxylate and glyoxal which, after
enzymatic kinetic resolution and further transformation led
to hydroxyester 22 in diastereo- and enantiopure form. Both
enantiomers of 22 were thus available in multigram
quantities.15 Swern oxidation of 22 led to the keto-enol
ester 23 which was subjected to a Trost–Tsuji allylation16
with acetates 18 and 21, respectively. Acetate 18 was
prepared from alcohol 16 as shown in Scheme 3; Mitsunobu
inversion17 of alcohol 15 gave 19 which was transformed
into allyl acetate 21 as shown. The allylation exclusively
occurred from the less hindered exo face to furnish keto-
ester 24 in diastereomerically pure form. Catalytic hydro-
genation followed by Taber’s decarbomethoxylation18
generated ketones 26 and 27 in a 3:1—ratio, which means
that the kinetic protonation of the corresponding enolate is
not selective. After longer treatment with base, however, the
ratio was shifted to 16:1 most likely due to thermodynamic
control. After chromatographic separation diastereomer 26
was converted into cyoctol 1 via Barton–McCombie
dehydroxylation and ketal hydrolysis.
Instead of using the Trost–Tsuji reaction for attaching the
cyoctol sidechain a stereocontrolled alternative route was
developed (Scheme 7). Hydroxy ester 22 was reduced to the
mono alcohol 40 via the mesylate. Alcohol 40 was then
converted into the sulfone 41 which was deprotonated and
alkylated with bromides (R)- or (S)-39 to furnish 42.
Desulfonation with sodium amalgam led to a mixture of 43
and minor amounts of olefin 44, which were transformed
into cyoctols 1 and 2. Alternatively (Scheme 8) 22 was
dehydrated to the enoate 46. This transformation involves a
syn elimination of water which was not possible via the
mesylate or tosylate. Instead, a Mitsunobu reaction was used
to create bromide 45 under inversion of configuration,20
which immediately underwent an anti-1,2-elimination of
hydrogen bromide to form 46. DIBALH-reduction gener-
ated the allylic alcohol 47 which was hydrogenated from the
exo face to form the endo diastereomer 48. Further
To gain access to the endo-cyoctol series (Scheme 5) keto
Scheme 3.

9602
J. Mulzer et al. / Tetrahedron 60 (2004) 9599–9614

J. Mulzer et al. / Tetrahedron 60 (2004) 9599–9614
9603
manipulation as in the exo series led to cyoctol 4 in
stereochemically pure form. The requisite bromide 39 were
prepared via an enantioselective catalytic addition of diethyl
zinc to aldehyde 36 (Scheme 6). According to a known
protocol21 diamine triflate (R,R)-37 was treated with
Ti(OiPr)4 to form a titanium complex which was used for
activating the diethylzinc. Alcohol 38 was formed with
high yield and ee and was then transformed into the
bromide (R)-38 by routine operations. Analogously, (S)-39
was prepared using (S,S)-37 as the source of chirality.
In conclusion by combining the enantiomers of the exo- and
endo-carbacyclin core with both enantiomers of the side-
chain all eight stereoisomers of cyoctol have been prepared
via totally stereocontrolled routes in quantities of ca. 1 g per
stereoisomer. Catalysis has played a central role in all
syntheses. The absolute and relative configurations of the
products unambiguously follow from the individual syn-
thetic routes. It can be seen that the 1H NMR spectra of the
exo (1)- and the endo (3)-cyoctols are significantly different
(Figs. 1 and 2); however, the configuration of the sidechain
is not reflected in the spectra. For further support, the crystal
structure of sulfone 50 was elucidated via a single crystal
diffraction.22 (Fig. 3).
1.2. Biological tests
All eight stereoisomers of cyoctol were subjected individu-
ally to two different biological tests:
1. a receptor binding test should provide information about
the affinity of the compounds to the binding site of the
cytosolic androgen receptor of rat prostate
2. the effect of cyoctol as a topical anti-androgen was tested
with the aid of the lipogenesis at the gold hamster ear
Ad 1. Androgen receptors was procured from rat prostate
cytosol. 3H-Methyltrienolone was used as a reference for
the binding affinity in presence of the test compound and the
release of radioactivity would indicate a competitive
binding of the cyoctol to the receptor. None of the eight
stereoisomers showed any significant effect.
Ad 2. A 1% acetone solution of the test compound was
applied to one ear of a castrated male Syrian gold hamster
and as a reference, acetone was applied to the second ear.
After 21 days the animals were killed and from each ear a
segment of 8 mm diameter was removed and incubated with
14C labelled acetate for 4 h. Then the tissue was digested
proteolytically and the solutions were tested for their
radioactivity. The higher the radioactivity the more lipids
have been produced, and, hence, the higher the anti-
androgenic effect of the substance. Again, none of the
cyoctol stereoisomers had any significant effect on the
lipogenesis.
These results were very confusing in the light of the patent
literatur cited in the introduction. A possible explanation
may be seen in the different sources of the androgen
receptors applied, so that cyoctol may have a selectivity for
certain kinds of receptors. Regarding the lipogenesis test the
failure may be due to this particular kind of a biological test

9604
J. Mulzer et al. / Tetrahedron 60 (2004) 9599–9614
Scheme 6.
and human skin cells may be different. All in all a
discrepancy exists between our results and the patent
literature, and it appears that additional biological tests
will be needed to clarify the situation.
are reported in d, using CDCl3 as an internal standard
(77.0 ppm). Mass spectra were obtained under electron
impact (EI).
Commercially available chemicals were used without
further purification. Where appropriate, reactions were
performed in flame-dried glassware under an argon
atmosphere.
2. Experimental
2.1. General
Ether (Et2O), tetrahydrofuran (THF) and toluene were
freshly distilled from sodium benzophenone ketyl under an
argon atmosphere. Dichloromethane (DCM), diisopropyl-
amine (iPr2NH), triethylamine (Et3N), and dimethyl sulf-
oxide (DMSO) were distilled from calcium hydride.
Hexanes and ethyl acetate (EtOAc) were distilled to remove
higher boiling fractions.
Fourier transform infrared spectra were calibrated on an
internal standard and are reported in wavenumbers
(cmK1). 1H and 13C NMR spectra were taken on 250,
400 and 600 MHz NMR machines. Proton chemical
shifts are reported in d, using the residual CHCl3 as
internal reference (7.26 ppm). Carbon chemical shifts
Scheme 7.

J. Mulzer et al. / Tetrahedron 60 (2004) 9599–9614
9605
Scheme 8.
Silica gel 60 (230–400 mesh) was used for column
chromatography. Precoated aluminium sheets 60 were
used for analytical thin layer chromatography (TLC).
Compounds were visualised with UV light, p-anisaldehyde
stain, or phosphomolybdic acid in EtOH.
in dichloromethane (25 mL) was treated with DMSO
(1.7 mL, 25 mmol) at K78 8C. The mixture was stirred
for 15 min at K78 8C, then the alcohol (10 mmol) in
dichlorometane (10 mL) was added and the mixture was
stirred at K78 8C for 1 h. NEt3 (5.5 mL, 40 mmol) was
added and the cooling was removed. The completeness of
the reaction was checked via TLC. Water (25 mL) was
added, the organic layer was separated, washed with
brine, dried over magnesium sulfate and concentrated
2.2. Typical procedures (TPs)
TP 1. Swern oxidation. Oxalyl chloride (1 mL, 11 mmol)

9606
J. Mulzer et al. / Tetrahedron 60 (2004) 9599–9614
Figure 1. 1H NMR spectrum of 1 (500 MHz).
Figure 2. 1H NMR Spectrum of 3 (500 MHz).

J. Mulzer et al. / Tetrahedron 60 (2004) 9599–9614
9607
Figure 3. Crystal structure of sulfone 50.

9608
J. Mulzer et al. / Tetrahedron 60 (2004) 9599–9614
under reduced pressure. The residue was purified by
chromatography.
(CDCl3): d [ppm]ZK4.98, K4.44, K1.23, 9.43, 17.99,
25.79, 25.96, 26.85, 30.76, 40.06, 42.98, 50.23, 51.10,
56.56, 75.04, 81.95, 126.67, 129.36, 135.84, 195.66, 213.83.
IR (KBr): nZ2926, 1690, 1606, 835, 774 cmK1. [a]DZ34.1
(cZ1.1, CHCl3). Anal. Calcd for C25H46O3Si2: C, 66.61; H
10.29. Found: C, 66.50, H, 10.21.
TP 2. DIBALH reduction of esters. The ester (10 mmol) in
diethylether (25 mL) was cooled to K90 8C and treated
dropwise with a 1.2 M solution (10 mL, 12 mmol) DIBAL-H
in toluene at a temperature of below K85 8C. The mixture
was stirred for 2 h at K90 8C. A satd. aqueous solution of
tartaric acid (10 mL) was added, the organic layer was
separated, washed with brine, dried over magnesium sulfate
and concentrated under reduced pressure. The residue was
purified by chromatography.
2.2.4. Catalytic hydrogenation of 10. To 10 (2.34 g,
5.19 mmol) in acetic acid (50 mL) was added Pd/C (10%,
120 mg) and the mixture was hydrogenated at 3 bar for 6 h.
The mixture was filtered, 5 mL of water was added and the
solution was heated to 50 8C for 15 h, concentrated under
reduced pressure, diluted with ether, dried (MgSO4) and
chromatographed (ethyl acetetae/hexanes 1:10) to give 11
(1.17 g, 84%) as a colorless oil. 1H NMR (CDCl3): d
[ppm]Z0.89 (t, JZ7.5 Hz, 1H), 1.26–1.65 (m, 13H), 1.97
(ddd, JZ19.5, 6.5, 1.5 Hz, 1H), 2.02–2.24 (m, 2H), 2.48–
2.65 (m, 3H), 2.97 (m, 1H), 3.10 (quint, JZ5.5 Hz, 1H),
3.33 (s, 3H), 4.30 (br, 1H). 13C NMR (CDCl3): d [ppm]Z
9.26, 25.50, 25.63, 28.28, 28.49, 32.74, 36.33, 42.87, 43.21,
43.35, 44.98, 52.65, 56.23, 74.74, 81.93, 220.60. IR (KBr):
nZ2930, 1735, 1090. cmK1. [a]DZK27.5 (cZ1.1,
CHCl3). Anal. Calcd for C16H28O3: C, 71.60; H 10.52.
Found: C, 71.25, H, 10.52.
2.2.1. Synthesis of 1 by Pauson–Khand-cyclization.
Compound 6 (22.94 g, 50.0 mmol) in ethyl acetate
(150 mL) was added dropwise to a suuspension of Pd/
BaSO4 (10%, 1.50 g) in ethyl acetate (60 mL) and stirred
under a hydrogen atmosphere (1 bar) at 0 8C until no more
hydrogen was absorbed. The mixture was filtered over silica
gel, concentrated under reduced pressure and chromato-
graphed (ethyl acetate/hexanes 1:2) to furnish 7 (16.98 g,
92%) as a colorless oil which crystallized in long needles of
1
mp 77 8C. H NMR (CDCl3): d [ppm]Z0.08, 0.09 (two s,
6H), 0.17 (s, 9H), 0.90 (s, 9H), 1.48–1.61 (m, 1H), 1.67 (br.
1H), 1.79 (dq, JZ14, 7 Hz, 1H), 1.92 (dq, JZ14, 7 Hz, 1H),
2.06 (dd, JZ18, 4.5 Hz, 1H), 2.54–2.63 (m, 2H), 2.91 (dd,
JZ19, 4.5 Hz, 1H), 2.96–3.07 (m, 1H), 3.72 (mc, 2H),
4.42 (t, JZ4.5 Hz, 1H) ppm. 13C NMR (CDCl3): d
[ppm]ZK5.04, K4.47, K1.29, 17.92, 25.74, 31.63,
40.01, 42.58, 47.05, 49.97, 60.77, 75.02, 135.69, 196.23,
214.14 ppm. IR (KBr): nZ2955, 2928, 1691, 1608, 840,
777 cmK1. [a]DZ65.6 (cZ1.4, CHCl3). Anal. Calcd for
C19H36O3Si2: C, 61.90; H 9.84. Found: C, 62.06, H, 9.86.
2.2.5. Barton–McCombie-dehydroxylation of 11 to give
1. Compound 11 (700 mg, 2.61 mmol), pyridine (619 mg,
7.83 mmol), and phenoxy-chlorothioformate (585 mg,
3.89 mmol) in methylene chloride (5 mL) were stirred at
rt for 16 h. Workup with water and ether furnished after
chromatography (ethyl acetate/hexanes 1:10) 12 (953 mg,
1
90%) as a yellow oil. H NMR (CDCl3): d [ppm]Z0.89 (t,
JZ7.5 Hz, 1H), 1.26–1.56 (m, 10H), 1.69–1.86 (m, 2H),
2.00 (ddd, JZ19, 7, 1.5 Hz, 1H), 2.09–2.22 (m, 1H), 2.47–
2.68 (m, 4H), 2.96 (mc, 1H), 3.09 (quint, JZ5.5 Hz, 1H),
3.33 (s, 3H), 5.75 (t, JZ4 Hz, 1H), 7.12, 7.31, 7.44 (three
mc, 3H). 13C NMR (CDCl3): d [ppm]Z9.21, 25.36, 25.64,
28.05, 28.38, 32.73, 36.24, 40.03, 43.13, 43.90, 44.72,
51.13, 56.27, 74.74, 81.70, 88.82, 121.72, 126.37, 129.34,
153.10, 194.09, 219.15. IR (KBr): nZ2936, 1737, 1276,
692 cmK1. [a]DZK29.8 (cZ1.6, CHCl3). Anal. Calcd for
C23H32O4S: C, 68.28; H 7.97. Found: C, 68.27, H, 7.93.
2.2.2. Swern-oxidation. Swern-oxidation of 7 (8.40 g,
22.8 mmol) was performed according to TP1. Aldehyde 8
(8.02 g, 96%) was obtained as colorless needles of mp
67 8C. 1H NMR (CDCl3): d [ppm]Z0.03, 0.07 (two s, 6H),
0.18 (s, 9H), 0.89 (s, 9H), 1.83–1.95 (m, 1H), 2.01 (dd, JZ
17, 4.5 Hz, 1H), 2.52 (dd, JZ17, 7 Hz, 1H), 2.57 (d, JZ
19.5 Hz, 1H), 2.62 (dd, JZ18, 5 Hz, 1H), 2.85–3.05
(m, 3H), 4.55 (t, JZ5 Hz, 1H). 13C NMR (CDCl3): d
[ppm]ZK5.09, K4.54, K1.30, 17.86, 25.72, 39.75, 41.79,
43.04, 44.49, 49.48, 74.26, 136.40, 193.95, 201.02, 212.88.
IR (KBr): nZ2935, 1716, 1685, 1602, 840 cmK1. [a]DZ
53.8 (cZ1.4, CHCl3). Anal. Calcd for C19H34O3Si2: C,
62.24; H 9.35. Found: C, 61.91, H, 9.44.
Compound 12 (750 mg, 1.85 mmol) and tributyltin hydride
(646 mg, 2.22 mmol) and AIBN (5 mg) in toluene (10 mL)
were heated to 90 8C for 2 h. Additional tributyl tinhydride
(110 mg, 0.38 mmol) was added and the heating was
continued for another 30 min. The mixture was concen-
trated under reduced pressure and chromatographed (ethyl
acetate/hexanes 1:10). The eluate was treated with NaOH
(7% in water, 10 mL), washed with water, dried (MgSO4)
and chromatographed (ethyl acetate/hexanes 1:10) to give 1
(416 mg, 89%) as a colorless oil. 1H NMR (CDCl3): d
[ppm]Z0.89 (t, JZ7.5 Hz, 1H), 1.18–1.61 (m, 13H), 1.69–
1.86 (m, 2H), 1.89–2.13 (m, 4H), 2.16–2.28 (m, 1H), 2.40–
2.53 (m, 2H), 2.72 (mc, 1H), 3.08 (quint, JZ5.5 Hz, 1H),
3.33 (s, 3H. 13C NMR (CDCl3): d [ppm]Z9.19, 25.43,
25.67, 28.61, 32.87, 35.4, 39.19, 43.85, 44.72, 46.16, 47.19,
2.2.3. Wittig reaction of 8 with 9 to form 10. Phosphonium
salt 9 (8.0 g, 18.5 mmol) and AgCl (0.85 g, 5.9 mmol) in
THF (80 mL) was treated dropwise with n-butyllithium
(1.6 M in hexane, 14.4 mL) at 26 8C. The mixture was
cooled to K78 8C and 8 (2.70 g, 7.36 mmol) in THF
(15 mL) was added dropwise and the mixture was stirred for
15 more min. Workup with water and hexanes furnished
after chromatography (ethyl acetate/hexanes 1:10) olefin 10
(2.99 g, 90%) as a colorless oil. 1H NMR (CDCl3): d
[ppm]Z0.08 (s, 6H), 0.17 (s, 9H), 0.89 (t, JZ7.5 Hz, 1H),
0.90 (s, 9H), 1.36–1.56 (m, 1H), 2.02 (dd, JZ17.5, 4.5 Hz,
1H), 2.17–2.44 (m, 1H), 2.55 (dd, JZ17.5, 6.5 Hz, 1H),
2.58 (d, JZ19.5 Hz, 1H), 2.91 (dd, JZ19.5, 4.5 Hz, 1H),
2.96–3.04 (m, 1H), 3.13 (quint, JZ6 Hz, 1H), 3.35 (s, 3H),
4.41 (t, JZ4.5 Hz, 1H), 5.40–5.56 (m, 2H). 13C NMR
56.21, 81.83, 220.64. IR (KBr): nZ2858, 1736, 1093 cmK1
.
[a]DZK14.8 (cZ1.6, CHCl3). MS (80 eV, 40 8C): m/zZ
252, 223, 73. Anal. Calcd for C16H28O2: C, 76.14; H 11.18.
Found: C, 76.06, H, 11.15.

J. Mulzer et al. / Tetrahedron 60 (2004) 9599–9614
9609
2.3. Trost–Tsuji-reaction for attaching the sidechain.
Synthesis of 1, 2, 3, and 4
2.3.4. Decarboxymethylation of 25b to 26b. Compound
25b (2.18 g, 5.30 mmol) in o-xylene (10 mL) and water
(0.9 mL) was treated with DABCO (6.00 g, 53 mmol) and
refluxed for 16 h. The mixture solidified on cooling and was
dissolved in toluene and chromatographed to give a 3:1
mixture of 26b and 27b (1.27 g, 67%) which was treated
with NaOMe (0.077 mmol) in MeOH/THF (1:1, 4 mL) for
17 h at room temperature. The mixture was concentrated
under reduced pressure, diluted with ether, extracted with
satd. aq. ammonium chloride (10 mL), dried (MgSO4) and
purified by HPLC (hexane/i-PrOH 99:1) to give 26b (1.16 g,
62%) and 27b (70 mg, 4%) as colorless oils.
2.3.1. Synthesis of 23. Enantiomerically (O99% ee) pure
carbacyclin 22 (40.45 g, 142 mmol) was oxidized under
Swern oxidation (TP) to give, after chromatography (ethyl
acetate/hexanes 1:3) ester 23 (60:40 keto-enol mixture)
(32.21 g, 87%) as a yellowish oil which solidified to give
waxy crystals of mp 60–63 8C. 1H NMR (CDCl3): d
[ppm]Z0.94, 0.99 and 0.96, 0.97 (all s, 6H), 1.59–3.0 (m,
8H), 3.28 (m, 0.6H), 3.45, 3.49, 3.51 (all s, 4H), 3.76, 3.80
(all s, 3H), 10.26 (0.4H). 13C NMR (CDCl3): d [ppm]Z
22.34, 22.39, 22.50, 30.04, 33.53, 35.01, 37.68, 38.72,
38.89, 40.59, 41.00, 42.11, 44.63, 50.92, 52.38, 60.62,
71.63, 71.80, 72.29, 72.52, 101.07, 108.69, 109.15, 170.18.
IR (KBr): nZ2960, 1665, 1615, 1440, 1325, 1275, 1250,
1110 cmK1. Anal. Calcd for C15H22O5: C, 63.81; H 7.85.
Found: C, 62.98, H, 7.62.
1
Compound 26b. H NMR (CDCl3): d [ppm]Z0.88 (t, JZ
7.5 Hz, 1H), 0.92, 0.98 (two s, 6H), 1.18–1.58 (m, 9H),
1.60–1.80 (m, 2H), 1.90 (dd, JZ13.5, 4.0 Hz, 1H), 2.02–
2.15 (m, 1H), 2.16–2.54 (m, 5H), 2.66–2.84 (m 1H), 3.00–
3.14 (m, 1H), 3.32 (s, 3H), 3.44, 3.48 (two s, 4H.). 13C NMR
(CDCl3): d [ppm]Z9.30, 22.39, 25.37, 25.80, 27.41, 30.01,
30.77, 32.80, 34.78, 41.11, 41.20, 43.64, 43.82, 54.34,
56.31, 71.93, 72.25, 81.94, 109.67, 221.13. IR (film): nZ
2940, 2860, 1730,1150, 1095 cmK1. [a]DZ27.4 (cZ0.9,
CHCl3). Anal. Calcd for C21H36O4: C, 71.55; H 10.29.
Found: C, 71.40, H, 10.34.
2.3.2. Synthesis of 24b. Ester 23 (8.00 g, 28.1 mmol) in
THF (50 mL) was added dropwise to a suspension of NaH
(60% in mineral oil) (1.24 g, 31 mmol) in THF (50 mL) at
room temperature. The mixture was refluxed for 5 min and
then added to a mixture of Pd(PPh3)4 (3.28 g, 2.80 mmol),
triphenylphophine (15.2 g, 56.2 mmol) and allylacetate 21
(5.50 g, 29.5 mmol) which had previously been stirred at
room temperature for 1 h. The new mixture was stirred at
70 8C for 4 h, concentrated under reduced pressure, diluted
with DCM, chromatographed (ethyl acetate/hexanes 1:4)
and purified by HPLC (i-PrOH/n-hexane 2:98) to obtain 24b
(6.90 g, 60%) as a colorless oil. 1H NMR (CDCl3): d
[ppm]Z0.87 (t, JZ7.5 Hz, 1H), 0.95, 0.97 (two s, 6H),
1.36–1.56 (m, 2H), 1.66–1.72 (m, 1H), 1.78 (dd, JZ13.8,
4.5 Hz, 1H), 2.18 (t, JZ7.5 Hz, 2H), 2.30 (t, JZ7.5 Hz,
1H), 2.28–2.34 (m, 2H), 2.50–2.74 (m, 2H), 2.55 (t, 2H),
2.57–2.90 (m, 1H), 3.09 (m, 1H), 3.44, 3.48 (two s, 4H),
3.71 (s, 3H), 5.27–5.42 (m, 1H), 5.43–5.80 (m, 1H). 13C
NMR (CDCl3): d [ppm]Z9.28, 22.21, 22.29, 25.73, 29.95,
33.51, 35.95, 36.65, 38.38, 40.80, 44.79, 46.82, 56,.41,
63.41, 71.28, 72.68, 81.62, 108.79, 125.87, 131.65, 171.30,
214.26. IR (film): nZ2960, 1765, 1735, 1330, 1240, 1210,
1120, 1100, 1010 cmK1. [a]DZK33.4 (cZ1.4, CHCl3).
MS(EI, 80 eV, 40 8C): m/zZ408, 393, 377, 349, 335, 128,
73, 41. HRMS Calcd for C23H36O6: m/zZ408.2512. Found:
408.2532.
Compound b 1H NMR (CDCl3): d [ppm]Z0.88 (t, JZ
7.5 Hz, 1H), 0.96, 0.98 (two s, 6H), 1.10–1.58 (m, 10H),
1.72–1.96 (m, 2H),2.04 (dd, JZ18, 7 Hz, 1H); 2.24–2.41
(m, 2H), 2.50–2.77 (m, 2H), 2.80–2.96 (m, 1H), 3.07 (quint.,
1H), 3.32 (s, 3H), 3.43 and 3.50 (two s, 4H): 2.24–2.48,
2.58–2.82 (2m, 6H), 2.96–3.10 (m, 1H), 3.30 (m, 3H), 3.44,
3.48 (two s, 4H), 3.72 (s, 3H).
2.3.5. Synthesis of 28b. LiAlH4 (63 mg, 1.7 mmol) in THF
(5 mL) at 0 8C was treated dropwise with 26b (580 mg,
1.65 mmol) in THF (5 mL) for 15 min. The mixture was
warmed to room temperature and stirred for additional 2 h.
Workup with water and NaOH delivered after chromato-
graphy (ethyl acetate/hexanes 1:1) 28b (581 mg, 99%) as a
colorless oil. 1H NMR (CDCl3): d [ppm]Z0.88 (t, JZ
7.5 Hz, 1H), 0.95, 0.98 (two s, 6H), 1.10–1.88 (m, 15H),
1.96–2.28 (m, 4H), 2.30–2.50 (m, 1H), 3.08 (quint, 1H)),
3.32 (s, 3H), 3.46, 3.47 (two s, 4H.). 13C NMR (CDCl3): d
[ppm]Z9.32, 22.47, 22.50, 25.75, 28.14, 30.04, 32.86,
33.61, 36.12, 40.17, 40.75, 41.77, 44.38, 54.38, 56.28,
71.28, 72.25, 79.73, 82.01, 110.40. IR (film): nZ3430,
29940, 1460, 1325, 1110, 1040, 1015 cmK1. Anal. Calcd for
C21H38O4: C, 71.15; H 10.80. Found: C, 71.30, H, 10.95.
2.3.3. Hydrogenation to 25b. Pd/C (10%, 258 mg) in ethyl
acetate (30 mL) was treated with 24b (2.58 g, 6.32 mmol)
and then hydrogenated under normal pressure for 15 h.
After filtration over celite the mixture was chromatographed
(ethyl acetate/hexanes 1:3) to give 25b (2.25 g, 87%) as a
colorless oil. 1H NMR (CDCl3): d [ppm]Z0.86 (t, JZ
7.5 Hz, 1H), 0.95, 0.97 (two s, 6H), 1.08–1.56 (m, 8H),
1.54–1.96 (m, 4H), 2.24–2.48,2.58–2.82 (2m, 6H), 2.96–
3.10 (m, 1H), 3.30 (m, 3H), 3.44, 3.48 (two s, 4H), 3.72 (s,
3H). 13C NMR (CDCl3): d [ppm]Z9.15, 22.13, 22.19,
24.43, 25.41, 25.60, 29.87, 32.48, 33.56, 36.69, 40.78,
44.51, 48.22, 51.71, 52.20, 63.29, 71.25, 72.53, 81.62,
108.69, 171.32, 213.97. IR (film): nZ2960, 1745, 1730,
1330, 1240, 1205, 1120, 1095, 1010 cmK1. [a]DZK36.1
(cZ1.0, CHCl3). Anal. Calcd for C23H38O6: C, 67.29; H
9.33. Found: C, 67.09, H, 9.36.
2.3.6. Synthesis of 29b. Compound 28b (579 mg,
1.6 mmol) in DCM (5 mL) were treated at 0 8C with
pyridine (0.4 g, 7.49 mmol) and O-phenylchlorothioformate
(0.42 g, 2.42 mmol) in DCM (2 mL) at 0 8C. The mixture
was stirred at room temp. for 3 h and then subjected to
aqueous workup to give, after chromatography (ethyl
acetate/hexanes 1:6) 29b (748 mg, 94%) of a slightly
yellow oil.
1H NMR (CDCl3): d [ppm]Z0.91 (t, JZ7.5 Hz, 1H), 0.98,
1.00 (two s, 6H), 1.20–1.90 (m, 13H), 1.98–2.36 (m, 4H),
2.40–2.62 (m, 2H), 3.08 (quint, 1H)), 3.32 (s, 3H), 3.48 (s,
4H.), 5.10–5.28 (m, 1H), 7.00–7.16, 7.22–7.32, 7.34–7.48
(m, 5H). 13C NMR (CDCl3): d [ppm]Z9.33, 22.48, 22.50,

9610
J. Mulzer et al. / Tetrahedron 60 (2004) 9599–9614
25.62, 25.80, 27.90, 30.08, 32.92, 33.28, 36.54, 36.70,
39.93, 40.40, 43.76, 50.55, 56.37, 71.78, 72.40, 81.99,
91.16, 109.94, 121.97, 126.38, 129.42, 153.37, 194.73.
10.8 mmol) was added dropwise at 50 8C, until no more
carbon dioxide was evolved. The solvent was removed
under reduced pressure and the residue was dissolved in
ether (170 mL) and pentane (30 mL). The crystalline
residue of hydrazo ester and phophine oxide was removed
by filtration and the filtrate was chromatographed (hexanes/
ethyl acetate) to give olefin 33a (2.37 g, 61%) as a colorless
IR (film): nZ2940, 1490, 1470, 1460, 1300, 1100,
1015 cmK1. HRMS Calcd for C21H37O3 (MKC7H5O2S):
m/zZ337.27427. Found: 337.274160.
1
oil. H NMR (CDCl3): d [ppm]Z0.88 (t, JZ7.5 Hz, 1H),
2.3.7. Synthesis of 2. Compound 28b (1.29 g, 2.63 mmol)
was reduced with tributyltin hydide as described for 12 to
give 30b (685 mg, 77%) as a colorless oil. 1H NMR
(CDCl3): d [ppm]Z0.88 (t, JZ7.5 Hz, 1H), 0.95, 0.96 (two
s, 6H), 1.06–1.68 (m, 15H), 1.76–1.94 (m, 2H), 1.95–2.09
(m, 1H), 2.22 (dd, JZ13.5, 8.8 Hz, 2H), 2.36–2.58 (m, 1H),
3.08 (quint, 1H)), 3.32 (s, 3H), 3.44, 3.48 (two s, 4H.). 13C
NMR (CDCl3): d [ppm]Z9.32, 22.51, 25.83, 28.77, 30.05,
33.00, 33.84, 35.37, 40.08, 40.27, 47.47, 56.29, 71.63,
72.40, 82.07, 110.56. IR (film): nZ2940, 1460, 1115, 1040,
1015 cmK1. [a]DZK18.9 (cZ1.3, CHCl3). Anal. Calcd for
C21H38O3: C, 74.51; H 11.31. Found: C, 74.69, H, 11.25.
30b (650 mg, 1.92 mmol) in water/acetone (v/v 5:95,
130 mL) was stirred with p-TsOH (183 mg) at room
temperature for 16 h and then neutralized with solid
NaHCO3, concentrated under reduced pressure, diluted
with water, and extracted with ether. The ether phase was
washed with water, dried (MgSO4) and chromatographed
(hexanes/ethyl acetate 1:10) to furnish 2 (484 mg, 99%) as a
colorless oil. [a]DZK14.4 (cZ1.1, CHCl3). The spectral
data are within the limits of detection identical with those
of 1.
0.96 (s, 6H), 1.28–1.62 (m, 10H), 1.84–2.18 (m, 3H), 2.25–
2.42 (m, 2H), 2.48–2.58 (m, 1H), 2.66–2.80 (m, 1H)), 2.92–
3.16 (m, 2H), 3.32 (s, 3H), 3.46, 3.51 (2s, 4H., 5.16 (s, 1H).
13C NMR (CDCl3): d [ppm]Z9.27, 22.45, 25.24, 25.80,
27.78, 29.38, 30.03, 32.86, 37.66, 38.04, 38.26, 41.04,
48.97, 56.27, 71.42, 72.49, 81.93, 109.49, 121.16, 146.60.
IR (film): nZ3940, 3860, 1115, 1095 cmK1. MS (EI, 80 eV,
40 8C): m/zZ336, 218, 189, 176, 160, 147, 128, 105, 91, 79,
69, 55, 41. [a]DZK8.24 (cZ1.5, CHCl3). Anal. Calcd for
C21H36O3: C, 74.96; H 10.78. Found: C, 74.75, H, 10.87.
2.3.10. Synthesis of 34a. Olefin 33a (2.25 g, 6.69 mmol) in
ethanol (100 mL) was hydrogenated with Rh/C (5%)
(113 mg) at 0 8C under normal pressure for 8 h. The mixture
was filtered over celite and evaporated under reduced
pressure and chromatographed (hexanes/ethyl acetate 10:1)
1
to furnish 34a (1.69 g, 75%) as a colorless oil. H NMR
(CDCl3): d [ppm]Z0.89 (t, JZ7.5 Hz, 1H), 0.94 and 0.98
(two s, 6H), 1.12–1.66 (m, 16H), 1.67–1.84 (m, 1H), 2.04
(m, 1H), 2.36–2.60 (m, 3H), 3.07 (m, 1H), 3.32 (s, 3H),
3.46, 3.49 (2s, 4H. 13C NMR (CDCl3): d [ppm]Z9.30,
22.48, 25.70, 25.84, 29.14, 29.54, 30.09, 30.83, 32.26,
33.04, 34.13, 39.05, 40.88, 42.59, 43.37, 56.33, 71.26,
73.06, 82.08, 109.15. IR (film): nZ2940, 1435, 1110,
1095 cmK1. MS (EI, 80 eV, 40 8C): m/zZ338, 323, 309,
265, 241, 223, 209, 181, 167, 141, 128, 95, 81, 73, 55, 41.
[a]DZK35.2 (cZ1.5, CHCl3). Anal. Calcd for C21H38O3:
C, 74.51; H 11.31. Found: C, 74.19, H, 11.36.
2.3.8. Synthesis of 31a. Keto ester 24a (4.90 g,
12.00 mmol) in methanol (80 mL) was treated in portions
at K40 8C with solid sodium borohydride (240 mg,
6.2 mmol) and stirred for 2 h. after additional 1 h at room
temperature the mixture was concentrated under reduced
pressure and diluted with ether (200 mL), washed with
water, dried (MgSO4) and chromatographed (hexanes/ethyl
1
acetate 1:1 to give 31a (4.48 g, 91%) as a colorless oil. H
2.3.11. Synthesis of 3. Compound 34a (1.55 g, 4.58 mmol)
in acetone/water (20:1, 250 mL) was treated with p-TsOH
(220 mg, 1.15 mmol) for 20 h at room temperature. The
mixture was neutralized with NaHCO3, concentated under
reduced pressure and extracted with ether. The ether phase
was washed with brine, dried (MgSO4) and chromato-
graphed (hexanes/ethyl acetate (5:1) to give 3 (1.12 g, 97%)
as a slightly yellow oil. 1H NMR (CDCl3): d [ppm]Z0.89 (t,
JZ7.5 Hz, 1H), 1.12–1.66 (m, 16H), 1.24–1.55 (m, 12H),
1.78–1.87 (m, 1H), 1.91–2.23 (m, 5H), 2.44 (ddd, JZ19, 8,
2 Hz, 1H), 2.6–2.84 (m, 2H), 3.07 (m, 1H),3.32 (s, 3H). 13C
NMR (CDCl3): d [ppm]Z9.19, 25.46, 25.72, 28.97, 30.07,
31.60, 31.48, 32.92, 37.68, 39.40, 43.48, 43.58, 45.46,
56.24, 81.90, 220.38. IR (film): nZ2930, 2850, 1740, 1465,
1400, 1200, 1155, 1090 cmK1. MS (EI, 80 eV, 40 8C):
m/zZ252, 223, 191, 173, 133, 95, 81, 73, 67, 55, 41.
[a]DZK113.4 (cZ1.0, CHCl3). Anal. Calcd for C16H28O2:
C, 76.14; H 11.18. Found: C, 76.13, H, 11.24.
NMR (CDCl3): d [ppm]Z0.87 (t, JZ7.5 Hz, 1H), 0.91,
1.00 (two s, 6H), 1.08–1.95 (m, 14H), 2.04–2.18 (m, 1H),
2.23–2.33 (m, 1H), 2.44–2.65(m, 3H), 2.99–3.08 (m, 1H)),
3.30 (s, 3H), 3.44, 3.45, 3.48, 3.50 (4s, 4H.). 13C NMR
(CDCl3): d [ppm]Z9.24, 22.35,22.49, 25.37, 25.67, 25.71,
30.60, 32.73, 37.59, 37.93, 38.15, 38.83, 40.04, 48.85,
51.38, 56.34, 61.45, 71.15, 72.89, 79.32, 81.82, 109.06,
176.35. IR (film): nZ2940, 1710, 1115, 1095, 1015 cmK1
.
MS (EI, 80 eV, 80 8C): m/zZ412, 397, 351, 335, 295, 284,
265, 181, 168, 128, 95, 69, 41. [a]DZ7.7 (cZ1.3, CHCl3).
Anal. Calcd for C23H40O6: C, 66.96; H 9.77. Found: C,
66.67, H, 7.75.
2.3.9. Synthesis of 33a. Compound 31a (4.80 g,
11.63 mmol) in methanol/water (v/v 2:1, 75 mL)) was
treated with KOH (4.0 g, 7.13 mmol) in water (10 mL) and
the mixture was stirred at 100 8C for 20 h, concentrated
under reduced pressure and extracted with ether. The
aqueous phase was acidified with 2 N HCl to pH 3 and
extracted with ether. The ether phase was washed with
water, dried (MgSO4) and evaporated to dryness to give 32a
(4.30 g, 95%) as a colorless foam, which was dissolved in
THF (250 mL) and treated with triphenylphosphane (2.83 g,
10.8 mmol). Diethyl azodicarboxylate (DEAD, 1.88 g,
2.3.12. Synthesis of 4. The title compound was performed
analogously from 24b. The spectra were indistinguishable
from those of 3. [a]DZK105.4 (cZ1.0, CHCl3). Anal.
Calcd for C16H28O2: C, 76.14; H 11.18. Found: C, 75.92, H,
10.99.

J. Mulzer et al. / Tetrahedron 60 (2004) 9599–9614
9611
2.4. Synthesis of 1, 2 and 4 via sulfone-alkylation
dried (MgSO4) and evaporated to dryness. The residue was
diluted with pentane, filtered and distilled (85–90 8C,
12 mbar) to give (S)-39 (520 mg, 71%) as a colorless oil.
1H NMR (CDCl3): d [ppm]Z0.90(t, JZ7.6 Hz, 1H), 1.40–
1.72 (m, 4H), 1.79–2.07 (m, 2H), 3.13 (quint, JZ6 Hz, 1H),
3.32 (s, 3H), 3.44 (t, JZ7 Hz, 2H). 13C NMR (CDCl3): d
[ppm]Z9.30, 25.73, 28.62, 31.49, 34.20, 56.38, 81.14. IR
(film): nZ2984, 2934, 2877, 1092 cmK1. MS (EI, 80 eV,
40 8C): m/zZ195, 193, 167, 165, 109, 107, 85, 73, 55, 45.
[a]DZ4.7 (cZ3.03, CHCl3). HRMS Calcd for C7H15OBr:
193.02281. Found: C, 193.02278.
2.4.1. Synthesis of 39. Butane-1,4-diol (443 mL, 5.00 mol)
was treated with KOH (132.0 g, 2.00 mol). Water was
removed under reduced pressure at 110 8C. Benzyl chloride
(230 mL, 2.0 mol) was added dropwise, so that the
temperature was above 90 8C. The mixture was stirred at
130 8C for 2 h, cooled to room temperature and diluted with
water (1 L), extracted with ether. The ether phase was dried
(MgSO4), the solvent was removed under reduced pressure
and the residue was distilled at 0.5 mbar to give the
monobenzyl ether (238 g, 66%) as a colorless oil, of which
18.00 g (99.9 mmol) were oxidized under Swern conditions
(TP) to give aldehyde 36 (17.18 g, 97%) as a colorless oil.
1H NMR (CDCl3): d [ppm]Z0.92 (t, JZ7.8 Hz, 1H), 1.36–
1.52 (m, 3H), 1.53–1.81(m, 3H), 2.63 (s, 1H), 3.49 (t, JZ
6 Hz, 2H), 3.49 (m, 1H), 4.50 (s, 2H), 7.30 (m, 5H). 13C
NMR (CDCl3): d [ppm]Z9.89, 26.02, 30.04, 33.89, 70.42,
72.69, 72.82, 127.45, 128.24, 138.12.
2.5. Synthesis of 1 and 2
2.5.1. Synthesis of 40. Ester 22 (15.20 g, 53.4 mmol) in
pyridine (60 mL) was treated with DMAP (100 mg) and
then MsCl (8.3 mL, 107 mmol) was added dropwise. The
mixture was stirred overnight at room temperature, water
(50 mL) and ether (50 mL) were added. The phases were
separated and the ethereal phase was washed with brine,
dried (MgSO4) and evaporated to give the mesylate as a
colorless solid (18.09 g, 49.9 mmol) of mp 84–85 8C.
2.4.2. Synthesis of (S)-38. Ditriflate (R,R-37) (927 mg,
2.45 mmol) in toluene (30 mL) was treated with Ti(OiPr)4
(21.9 mL, 73.6 mmol) and the mixture was stirred at 40 8C
for 1 h. The mixture was cooled to K78 8C and diethylzinc
(1 M in hexane, 135 mL) was added dropwise. A dark red
solution was obtained which was treated dropwise with
aldehyde 36 (10.93 g, 61.3 mmol) in toluene (10 mL) and
the mixture was stirred at K30 8C for 5 h. The reaction was
quenched with 2 N HCl (120 mL) and the ether phase was
washed with brine, dried (MgSO4) and chromatographed
(hexanes/ethyl acetate 5:1) to furnish (S)-38 (11.87 g, 93%)
as a yellowish oil. 1H NMR (CDCl3): d [ppm]Z0.92(t, JZ
7.8 Hz, 1H), 1.36–1.52 (m, 3H), 1.53–1.81 (m, 3H), 2.63 (s,
1H), 3.49 (t, JZ6 Hz, 2H), 3.49 (m, 1H), 4.50 (s, 2H), 7.30
(m, 5H). 13C NMR (CDCl3): d [ppm]Z9.89, 26.02, 30.04,
3.89, 70.42, 72.69, 72.82, 127.45, 128.24, 138.12. IR (film):
nZ3415, 2934, 2858, 1495, 1453, 1362, 1099, 994,
962 cmK1. MS (EI, 80 eV, 40 8C): m/zZ208, 190, 179,
161, 147, 117, 107, 91, 71, 41. [a]DZ7.1 (cZ1.92, CHCl3).
Anal. Calcd for C13H20O2: C, 74.96; H 9.68. Found: C,
74.22, H, 9.48.
The mesylate (9.00 g, 24.8 mmol) in ether (150 mL) and
treated dropwise at K20 8C with LiALH4 (1.6 M in THF,
31.3 mL) for 15 min. The mixture was warmed to room
temperature and stirred for another 90 min and quenched
with iPrOH and then water. MgSO4 and silicagel were
added and the mixture was stirred overnight, filtered and
chromatographed to furnish alcohol 40 (4.33 g, 73%) as a
colorless oil. 1H NMR (CDCl3): d [ppm]Z0.94 (s, 3H), 1.36
(m, 2H), 1.63 (m, 3H), 1.87 (m, 3H), 2.21 (m, 3H), 2.51 (m,
1H), 3.46 (s, 2H), 3.50 (m, 1H). 13C NMR (CDCl3): d
[ppm]Z22.46, 29.97, 30.04, 32.29, 39.60, 40.20, 40.28,
49.72, 66.31, 71.69, 72.34, 110.23. IR (film): nZ3428,
2949, 2866, 1109 cmK1. MS (EI, 80 eV, 40 8C): m/zZ240,
225, 209, 197, 181, 167, 155, 141, 128, 95, 81,69, 55.
[a]DZ22.6 (cZ1.0, CHCl3). Anal. Calcd for C14H24O2: C,
69.96; H 10.07. Found: C, 70.22, H, 9.88. For the
preparation of the tosylate, alcohol 40 (9.13 g, 38.0 mmol)
in pyridine (45 mL) was treated with DMAP (300 mg) and
tosyl chloride (10.9 g, 57 mmol) was added in portions at
0 8C and the mixture was stirred for 16 h at room
temperature. The reaction was quenched with water and
the mixture was extracted with ether. The organic phase was
washed with 2 N HCl, water, NaHCO3 and brine, dried
(MgSO4) and chromatographed (hexanes/ethyl acetate 2:1)
2.4.3. Synthesis of (S)-39. Compound (S)-38 (17.85 g,
85.7 mmol) in DMF (400 mL) was deprotonated with NaH
(80%, 6.0 g, 214 mmol) at 0 8C.The mixture was stirred at
room temperature for 1 h, cooled to 0 8C and treated
dropwise with methyl iodide (21.3 mL, 343 mmol) in DMF
(50 mL). The mixture was stirred overnight, quenched with
water. The product was extracted with ether and the ether
phase was dried (MgSO4) and chromatographed (hexanes/
ethyl acetate 5:1) to give the methyl ether (18.72 g, 98%) as
a colorless oil. For debenzylation the methyl ether (18.72 g,
84 mmol) in MeOH (300 mL) was hydrogenated over Pd/C
(5%, 400 mg) at normal pressure. After filtration the solvent
was removed under reduced pressure and the residue was
chromatographed (hexanes/ethyl acetate 1:1) to give the
mono alcohol (11.13 g, 100%) as a colorless oil. To prepare
the bromide (S)-39, the alcohol (500 mg, 3.78 mmol) in
DCM (8 mL) was added dropwise to mixture of triphenyl
phosphine (2.78 mg, 10.58 mmol) and NBS (2.02 g,
11.34 mmol) in DCM (24 mL) and stirred overnight. The
mixture was diluted with aqueous NaHCO3 and extracted
with ether. The ethereal extract was washed with brine,
1
to give the tosylate (14.66 g, 98%) as a colorless oil. H
NMR (CDCl3): d [ppm]Z0.94 (s, 3H), 1.16–1.43 (m, 2H),
1.60 (m, 2H), 1.80 (m, 2H), 1.95–2.18 (m, 4H), 2.45 (s, 3H),
2.47 (m, 1H), 3.43 (s, 2H), 3.44 (s, 2H), 3.90 (d, JZ7 Hz,
2H), 7.34 (d, JZ9 Hz, 2H), 7.78 (d, JZ9 Hz, 2H). 13C
NMR (CDCl3): d [ppm]Z21.62, 22.46, 30.08, 32.19, 38.97,
40.12, 40.25, 43.56, 46.06, 71.83, 72.20, 73.38, 109.96,
127.84, 129.78, 144.60. IR (film): nZ2952, 2867, 1362,
1109 cmK1. MS (EI, 80 eV, 40 8C): m/zZ394, 239, 223,
209, 167, 137, 91, 69, 41. [a]DZ28.7 (cZ1.4, CHCl3).
Anal. Calcd for C21H30O5S: C, 63.93; H 7.66. Found: C,
63.76, H, 7.45. To prepare the iodide, the tosylate (13.05 g,
33.1 mmol) in acetonitrile (130 mL) was treated with
sodium iodide (10.91 g, 72.8 mmol) and the mixture was
refluxed for 3 h. After cooling to room temperature water
and ether were added and the ether phase was washed with

9612
J. Mulzer et al. / Tetrahedron 60 (2004) 9599–9614
water, sodium thiosulfate and brine, dried (MgSO4), and
evaporated to give the iodide (11.58 g, 100%) as a slightly
yellow oil ([a]DZK20.1 (cZ1.21, CHCl3)) which was
used for the next step without purification. Sodium
phenylsulfinate (8.15 g, 49.7 mmol) in DMF (200 mL)
was added and the mixture was stirred at 110 8C overnight,
cooled to room temperature, quenched with NaHCO3 and
extracted with ether. The ether phase was washed with
brine, dried (MgSO4) and chromatographed (hexanes/ethyl
acetate 2:1) to give sulfone 41 (9.49 g, 79%) along with the
sulfinate (1.99 g, 17%).
110.07, 128.55, 129.08, 133.36, 139.03. IR (film): nZ2952,
2869, 1462, 1109, 1086 cmK1. MS (EI, 80 eV, 40 8C):
m/zZ364, 279, 223, 209, 167, 137, 109, 95, 69, 55, 41.
Anal. Calcd for C27H42O5S: C, 67.75; H 8.84. Found: C,
67.51, H, 7.83.
2.5.3. Synthesis of 43a. The diastereomeric mixture of
sulfones 42a (1.54 g, 3.22 mmol) in methanol (35 mL) was
treated at K20 8C with di-sodiumhydrogenphosphate
(1.83 g, 12.88 mmol) and sodium amalgam (10 g, 6%) and
stirred for 3 h. Water was added and the mixture was stirred
for 30 min. The mercury was removed by decantation and
the aqueous phase was extracted with ether. The ethereal
phase was washed with brine, dried (MgSO4), and
chromatographed (hexanes/ethyl acetate 10:1) to give 43a
(910 mg, 84%) as a colorless oil. 1H NMR (CDCl3): d
[ppm]Z0.89 (t, JZ7.6 Hz, 3H), 0.95 (s, 3H), 0.97 (s,
3H),1.09–1.63 (m, 15H), 1.84 (m, 2H), 2.01 (m, 1H), 2.23
(dd, JZ9.0, 13.0 Hz, 2H) 2.47 (m, 1H), 3.07 (quint, JZ
5.6 Hz, 1H), 3.32 (s, 3H), 3.46 (s, 2H), 3.49 (s, 2H). 13C
NMR (CDCl3): d [ppm]Z9.34, 22.53, 25.64, 25.80, 30.08,
32.67, 32.98, 33.82, 35.38, 40.05, 40.25, 40.30, 47.07,
47.49, 56.35, 71.64, 72.42, 82.04, 110.55. IR (film): nZ
2934, 2854, 1462, 1111 cmK1. MS (EI, 80 eV, 40 8C): m/
zZ338, 323, 309, 265, 241, 223, 209, 181, 167, 141, 128,
73, 69, 55. [a]DZK19.3 (cZ2.01, CHCl3). Anal. Calcd for
C21H38O3: C, 74.51; H 11.31. Found: C, 74.33, H, 10.75.
Compound 41. Solid with mp 60–61 8C: 1H NMR (CDCl3):
d [ppm]Z0.89 (s, 3H), 1.20–1.44 (m, 2H), 1.55–1.74 (m,
2H), 1.88 (m, 1H), 2.02 (m, 1H), 2.07–2.25 (m, 4H), 2.49
(m, 1H), AB-part of an ABX system: dA 3.05, dB 3.17, (JZ
14, 7, 5.8 Hz, 2H), 3.41 (d, JZ11 Hz, 1H), 3.46 (d, JZ
11 Hz, 1H), 7.60 (m, 3H), 7.92 (m, 2H). 13C NMR (CDCl3):
d [ppm]Z22.40, 22.58, 30.00, 32.58, 33.91, 39.55, 40.99,
47.29, 61.26, 71.86, 72.06, 109.84, 127.86, 129.22, 133.49,
140.06. IR (film): nZ2952, 2868, 1462, 1109, 1086 cmK1
.
MS (EI, 80 eV, 40 8C): m/zZ364, 279, 223, 209, 167, 137,
109, 95, 69, 55, 41. [a]DZK30.2 (cZ2.28, CHCl3). Anal.
Calcd for C20H28O4S: C, 65.90; H 7.74. Found: C, 65.62, H,
7.51.
Sulfinate. 1H NMR (CDCl3): d [ppm]Z0.95 (s, 3H), 0.96 (s,
3H), 1.13–1.43 (m, 2H), 1.60 (m, 2H), 1.81 (m, 2H), 1.92–
2.21 (m, 4H), 2.46 (m, 1H), 3.42 (s, 2H), 3.44 (s, 2H), 3.45
(m, 1H), 3.92 (m, 1H), 7.54 (m, 3H), 7.70 (m, 2H). 13C
NMR (CDCl3): d [ppm]Z22.50, 30.04, 30.33, 32.33, 39.24,
40.15, 43.79, 46.77, 46.85, 67.31, 71.79, 72.25, 110.06,
125.24, 128.98, 131.99. IR (film): nZ2867, 1444, 1132,
1108, 944 cmK1. MS (EI, 80 eV, 40 8C): m/zZ364, 279,
239, 223, 209, 208, 167, 137, 125, 95, 81, 69, 55.
2.5.4. Synthesis of 1. Compound 43a (2.66 g, 7.86 mmol)
in acetone (450 mL) and water (22 mL) was treated with
p-TsOH (373 mg, 1.96 mmol) and stirred at room tempera-
ture for 20 h. The mixture was neutralized with NaHCO3
and concentrated under reduced pressure. The residue was
extracted with ether, and the ether phase was washed with
brine, dried (MgSO4), and chromatographed (hexanes/ethyl
acetate 10:1) to give 1 (1.90 g, 96%) as a colorless oil. All
analytical data were fully in agreement with those reported
above.
2.5.2. Alkylation of sulfone 41. Preparation of 42a.
Sulfone 41 (2.00 g, 5.49 mmol) in THF (8 mL) was treated
dropwise with nBuLi (1.6 M in hexane, 3.95 mL,
6.31 mmol) at K20 8C. The mixture was slowly warmed
to room temperature, then cooled to K20 8C and HMPA
(3.82 mL) was added dropwise and the mixture was stirred
at room temperature for 30 min. Then the mixture was
cooled to K30 8C and treated dropwise with bromide (S)-39
(1.29 g, 6.59 mmol) in THF (1 mL). Workup with water and
ether furnished after HPLC (hexane/iPrOH 99.2:1) 42a
(1.58 g, 60%) as a diastereomeric mixture. First diastereomer:
1H NMR (CDCl3): d [ppm]Z0.80 (t, JZ7.6 Hz, 3H), 0.90
(s, 3H), 1.01 (s, 3H),1.19–1.69 (m, 10H), 1.70–1.99 (m, 4H),
2.39 (m, 1H), 2.43 (m, 4H), 2.96 (m, 2H), 3.22 (s, 3H), AB-
system: dA 3.42, dB 3.53, (JZ11.6 Hz, 2H), 7.60 (m, 3H),
7.90 (m, 2H). 13C NMR (CDCl3): d [ppm]Z9.25, 22.36,
22.63, 24.37, 25.54, 26.54, 30.04, 32.61, 33.06, 34.18,
39.19, 40.89, 41.24, 42.60, 45.31, 56.29, 67.47, 71.70,
72.31, 81.20, 110.33, 128.45, 129.08, 133.33, 139.42.
2.5.5. Synthesis of alcohol 48. Hydroxy ester 22 (5.00 g,
17.59 mmol) in THF was treated with triphenyl phosphane
(4.73 g, 18.0 mmol), DEAD (3.13 g, 18.0 mmol) and
lithium bromide (3.34 g, 18.0 mmol) at 0 8C for 5 h. The
solvent was removed under reduced pressure and the residue
was treated with ether to crystallize the hydrazo ester and
the phosphine oxide. The mixture was filtered and the
filtrate was chromatographed (hexanes/ethyl acetate 3:1) to
give ester 46 (4.07 g, 85%) as a colorless oil, which was
reduced with DIBALH (1.6 M in toluene, 12 mL) at K30 8C
for 1 h (TP 2) to give, after aqueous workup allylic alcohol
47 (3.86 g, 92%), which was hydrogenated in ethyl acetate
(700 mL) over Rh/C (5%, 1 g) at K30 8C for 6 h under
normal pressure. The mixture was filtered and evaporated to
dryness. The residue was chromatographed (hexanes/ethyl
acetate 2:1) to give 48 (2.84 g, 74%) as a colorless solid of
1
1
Second diastereomer: H NMR (CDCl3): d [ppm]Z0.84
mp 58–59 8C. H NMR (CDCl3): d [ppm]Z0.95 (s, 3H),
(t, JZ7.6 Hz, 3H), 0.86 (s, 3H), 0.96 (s, 3H),1.21–1.50 (m,
8H), 1.53–1.74(m, 3H), 1.83–2.27 (m, 7H), 2.42 (m, 1H),
3.00 (m, 2H), AB-system: dA 3.20, dB 3.27, (JZ11.4 Hz,
2H), 3.27 (s, 3H), 3.40 (s, 2H), 7.60 (m, 3H), 7.90 (m, 2H).
13C NMR (CDCl3): d [ppm]Z9.18, 22.42, 22.55, 24.97,
25.16, 25.72, 29.35, 29.93, 32.92, 33.23, 37.40, 39.40,
40.63, 44.93, 45.40, 56.48, 66.63, 71.66, 72.05, 81.56,
0.97 (s, 3H),1.22–1.49 (m, 4H), 1.56 (s, 1H), 1.60–1.77 (m,
2H), 1.98–2.23 (m, 2H), 2.41 (m, 1H), 2.58 (m, 2H), 3.47 (s,
2H), 3.49 (s, 2H), AB-part of an ABX system: dA 3.60, dB
3.65, (JZ10, 8, 7.6 Hz, 2H). 13C NMR (CDCl3): d [ppm]Z
22.41, 22.49, 26.63, 30.11, 32.14, 33.37, 39.18, 41.14,
41.22, 45.87, 64.04, 71.28, 73.06, 109.20. IR (film): nZ
3459, 2936, 2862, 1110, 1033, 999, 977 cmK1. MS (EI,

J. Mulzer et al. / Tetrahedron 60 (2004) 9599–9614
9613
80 eV, 40 8C): m/zZ240, 225, 209, 197, 181, 167, 155, 141,
128, 95, 81, 69, 55. [a]DZK28.6 (cZ1.05, CHCl3). Anal.
Calcd for C14H24O3: C, 69.96; H 10.06. Found: C, 69.79, H,
9.88.
of mp 88 8C, 1.76 g, 58%) and 51 (colorless oil, 0.47 g,
15%).
1
Compound 50. H NMR (CDCl3): d [ppm]Z0.84 (t, JZ
7.6 Hz, 3H), 0.89 (s, 3H), 1.02 (s, 3H), 1.10–1.83 (m, 14H),
2.31 (m, 3H), 2.55 (m, 1H), 2.79 (m, 1H), 2.98 (m, 2H), 3.27
(s, 3H), 3.44 (m, 4H), 7.60 (m, 3H), 7.92 (m, 2H). 13C NMR
(CDCl3): d [ppm]Z9.18, 22.28, 22.60, 22.92, 25.62, 27.57,
29.43, 30.08, 31.25, 33.04, 33.72, 38.46, 42.30, 42.99,
56.35, 65.83, 71.20, 73.11, 81.37, 108.30, 128.69, 129.06,
133.45, 138.96. IR (KBr): nZ2963, 2924, 2862, 1445, 1297,
1145 1114, 1087 cmK1. MS (EI, 80 eV, 40 8C): m/zZ478,
463, 449, 393, 377, 361, 337, 219, 128, 95, 69. Anal. Calcd
for C27H42O5S: C, 67.75; H 8.84. Found: C, 67.38, H, 8.52.
2.5.6. Synthesis of sulfone 49. Alcohol 48 (4.82 g,
20.0 mmol) in pyridine (25 mL) was treated with DMAP
(300 mg) and tosyl chloride (5.72 g, 30.0 mmol). The
mixture was stirred at room temperature overnight and
then quenched with water. The mixture was extracted with
DCM and the DCM phase was washed with brine, dried
(MgSO4) and the tosylate was crystallized by addition of
hexane. 7.23 g (92%) was obtained as colorless crystals of
mp 131–132 8C. 1H NMR (CDCl3): d [ppm]Z0.92 (s, 3H),
0.96 (s, 3H),1.08–1.30 (m, 3H), 1.38 (m, 1H), 1.62 (m, 2H),
1.97 (m, 1H), 2.17 (m, 1H), 2.35 (m, 1H), 2.45 (s, 3H), 2.53
(m, 2H), AB-system dAZ3.37, dBZ3.42 (JZ11 Hz, 2H),
3.44 (s, 2H), ABX-system: dAZ3.94, dBZ4.02 (JZ9.0, 9.0,
7.0 Hz, 2H), 7.34 (d, JZ9.7 Hz, 2H), 7.82 (d, JZ9.7 Hz,
2H). 13C NMR (CDCl3): d [ppm]Z21.67, 22.52, 26.56,
30.15, 31.99, 33.12, 39.16, 41.27, 41.41, 42.17, 71.35,
71.68, 72.06, 108.93, 127.95, 129.86. IR (film): nZ2966,
2868, 1175, 1110, 951, 811 cmK1. MS (EI, 80 eV, 40 8C):
m/zZ394, 309, 239, 223, 209, 167, 137, 91, 69. [a]DZK13.4
(cZ1.04, CHCl3). Anal. Calcd for C21H30O5S: C, 63.93; H
7.66. Found: C, 63.77, H, 7.43.
1
Compound 51. H NMR (CDCl3): d [ppm]Z0.82 (t, JZ
7.6 Hz, 3H), 0.88 (s, 3H), 1.02 (s, 3H), 1.10–1.81 (m, 13H),
1.94–2.14 (m, 2H), 2.25 (m, 1H), 2.50 (m, 2H), 2.63 (m,
1H), 2.96 (m, 2H), 3.26(s, 3H), 3.42 (d, JZ11.0 Hz, 1H),
3.47 (d, JZ11.0 Hz, 1H), 3.42 (d, JZ11.0 Hz, 1H), 3.53 (d,
JZ11.0 Hz, 1H), 7.60 (m, 3H), 7.88 (m, 2H). 13C NMR
(CDCl3): d [ppm]Z9.27, 22.10, 22.26, 22.50, 25.67, 27.85,
29.25, 30.07, 32.51, 33.20, 36.21, 37.78, 39.52, 42.08,
42.76, 56.37, 66.87, 71.31, 73.04, 81.51, 108.55, 128.29,
129.03, 133.27, 139.96.
2.5.7. Synthesis of 52. The mixture of 50/51 (2.23 g,
4.66 mmol) in methanol (50 mL) was desulfonated as
described for 43a to furnish 52 (1.27 g, 81%) as a colorless
For the synthesis of the iodide, the tosylate (7.18 g,
18.2 mmol) and sodium iodide (6.00 g, 40 mmol) in
acetonitrile (70 mL) was refluxed for 20 h. After cooling
to room temperature water was added and the product was
extracted with ether. The organic phase was washed with
brine (MgSO4) and chromatographed (hexanes/ethyl acetate
7:1) to give the iodide (5.62 g, 88%) as a slightly brown oil.
1H NMR (CDCl3): d [ppm]Z0.97 (s, 6H), 1.18–1.54 (m,
4H), 1.64–1.83 (m, 2H), 2.26 (m, 2H), 2.43 (m, 1H), 2.59
(m, 2H), ABX-system: dAZ3.07, dBZ3.24 (JZ9.8, 9.8,
7.0 Hz, 2H), 3.47 (s, 2H), 3.50 (s, 2H). 13C NMR (CDCl3): d
[ppm]Z7.29, 22.42, 30.08, 30.16, 32.47, 32.88, 39.12,
41.37, 43.35, 46.93, 71.28, 73.05, 108.65. MS (EI, 80 eV,
40 8C): m/zZ350, 265, 223, 167, 137, 109, 95, 69, 55.
[a]DZK72.7 (cZ1.81, CHCl3). HRMS m/z Calcd for
C14H23O2: 350.07416. Found 350.07414.
1
oil. H NMR (CDCl3): d [ppm]Z0.89 (t, JZ7.6 Hz, 3H),
0.95 (s, 3H), 0.99 (s, 3H), 1.17–1.66 (m, 16H), 1.74 (m, 1H),
2.04 (m, 1H), 2.47 (m, 3H), 3.07 (quint, JZ5.8 Hz, 1H),
3.32 (s, 3H), 3.47 (s, 2H), 3.50 (s, 2H). 13C NMR (CDCl3): d
[ppm]Z9.30, 22.46, 25.64, 25.78, 29.14, 29.49, 30.10,
30.79, 32.25, 33.00, 34.07, 38.95, 40.82, 42.29, 43.34,
56.35, 71.24, 73.06, 82.03, 109.10. IR (KBr): nZ2935,
2856, 1463, 1329, 1114, cmK1. MS (EI, 80 eV, 40 8C):
m/zZ338, 323, 309, 295, 265, 241, 223, 209, 181, 167, 141,
128, 95, 81, 73, 69, 55. [a]DZK26.7 (cZ2.35, CHCl3).
HRMS: m/z Calcd for C16H28O2: 252.20893. Found
252.20889.
2.5.8. Synthesis of 4. Compound 52 (1.20 g, 3.55 mmol)
in acetone (190 mL) and water (9 mL) was treated with
p-TsOH (170 mg) at room temperature overnight. Workup
was performed as described for the synthesis of 1 and the
crude product was hydrogenated in ethyl acetate with Pd/C
at room temperature and normal pressure. Chromatography
(hexane/ethyl acetate 10:1) furnished 4 (820 mg, 92%) as a
colorless oil. [a]DZK112.6 (cZ1.33, CHCl3). The ana-
lytical data were identical with those described above.
The iodide (5.60 g, 16.0 mmol) was converted into sulfone
49 (2.49 g, 43%) as described for 41. Colorless solid of mp
144 8C. H NMR (CDCl3): d [ppm]Z0.91 (s, 3H), 0.98 (s,
1
3H), 1.12–1.47 (m, 4H), 1.62 (m, 1H), 1.75 (m, 1H), 2.20–
2.42 (m, 2H), 2.56 (m, 2H), AB-part of an ABX-system:
dAZ3.12, dBZ3.19 (JZ14.0, 6.6, 7.0 Hz, 2H), 3.43 (s, 4H),
7.64 (m, 3H), 7.95 (m, 2H). 13C NMR (CDCl3): d [ppm]Z
22.33, 22.48, 29.41, 30.06, 31.80, 33.78, 37.04, 38.52,
41.86, 42.82, 57.98, 71.23, 73.05, 108.42, 127.90, 129.25,
133.58, 139.88. IR (film): nZ2953, 2865, 1444, 1290, 1148,
1109, 1012, 997 cmK1. MS (EI, 80 eV, 40 8C): m/zZ364,
279, 223, 167, 137, 109, 95, 69, 55. [a]DZK37.1 (cZ2.45,
CHCl3). Anal. Calcd for C20H28O4S: C, 65.90; H 7.74.
Found: C, 65.52, H, 7.59.
Acknowledgements
¨
We thank Professor Topert from the Schering AG, Berlin
for performing the biological tests, Dr. J. Buschmann and
Professor Dr. P. Luger, Institut fu¨r Kristallographie und
¨
Mineralogie der Freien Universitat Berlin, for determining
the crystal structure of 50.
The sulfone 49 (2.33 g, 6.39 mmol) in THF (8 mL) was
alkylated with bromide S-39 as described for 42a to give
after HPLC (hexane/iPrOH 98:2) diastereomers 50 (crystals

9614
J. Mulzer et al. / Tetrahedron 60 (2004) 9599–9614
10. Miyamoto, T.; Abe, T.; Nishijima, Y. Japan Kokai Tokkyo
References and notes
Koho, CODEN: JKXXAF JP 61056118 A2 19860320 Showa,
Kanebo, Ltd.: Japan, 1986, p 8.
1. Schostarez, H. J.; Diani, A. R. PCT Int. Appl., CODEN:
PIXXD2 WO 9209259 A1 19920611, Upjohn Co.: USA, 1992.
2. Wiechers, J. W.; Herder, R. E.; Drenth, B. F. H.; De Zeeuw,
R. A. Int. J. Pharm. 1990, 65(1–2), 77–84.
11. Ford, L. C.; Kasha, W.; Chang, C.; DeLange, R. J. Chemo-
therapy, (Basel) 1985, 31(5), 362–365.
12. Kasha, US Patent 4689, 345, 4689, 349, 1987
13. (a) Pauson, P. L. Tetrahedron 1985, 41, 5855. Magnus, P.;
Principe, L. M.; Slater, J. J. Org. Chem. 1987, 52, 1483.
Magnus, P.; Becker, D. P. J. Am. Chem. Soc. 1987, 109, 7495.
(b) Mulzer, J.; Graske, K.-D.; Kirste, B. Liebigs Ann. Chem.
1988, 891.
3. King, D.; Newcomer, V.; Burnison, C.; Reisner, R.; Mickus,
K.; Suzuki-Chavez, F.; Ford, L. C. Recent Advances in
Chemotherapy, Proceedings of the 14th International Congress
Chemotherapy, Antimicrobial Sect. 1; Ishigami, J., Ed.;
University of Tokyo Press, Tokyo: Japan, 1985; pp 269–270.
4. King, D.; Newcomer, V.; Reisner, R.; Ford, L. C. Recent
Advances in Chemotherapy, Proceedings of the 14th Inter-
national Congress Chemotherapy, Antimicrobial Sect. 1;
Ishigami, J., Ed.; University of Tokyo Press, Tokyo: Japan,
1985; pp 267–268.
14. Barton, D. H.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574.
15. Petzoldt, K.; Dahl, H.; Skuballa, W.; Gottwald, M. Liebigs
Ann. Chem. 1990, 1087.
16. Trost, B. M. Acc. Chem. Res. 1980, 11, 385.
17. Mitsunobu, O. Synthesis 1980, 1.
5. Ford, L. C.; King, D.; Goldman, P.; Reisner, R.; Newcomer, V.
Recent Advances in Chemotherapy, Proceedings of the 14th
International Congress Chemotherapy, Antimicrobial Sect. 1;
Ishigami, J., Ed.; University of Tokyo Press, Tokyo: Japan,
1985; pp 261–262.
18. Taber, D. F.; Anedio, J. C.; Gulino, F. J. Org. Chem. 1989, 54,
3474.
19. Mulzer, J.; Lammer, O. Angew. Chem. 1983, 95, 629.
20. Loibner, H.; Zbiral, E. Helv. Chim. Acta 1976, 59, 2100.
Manna, S.; Flack, J. R. Synth. Commun. 1985, 15, 663.
21. Knochel, P.; Rozema, M. J.; Sidduri, A. J. Org. Chem. 1992,
57, 1956.
6. King, D. F.; Burnison, C.; Newcomer, V.; Mickus, K.; Suzuki-
Chavez, F.; Ford, L. C. Recent Advances in Chemotherapy,
Proceedings of the 14th International Congress Chemotherapy,
Antimicrobial Sect. 1; Ishigami, J., Ed.; University of Tokyo
Press: Tokyo, Japan, 1985; pp 259–260
22. Formula C27H42O5S, molecular weight 478.70 g/mol, crystal
system monoclinic space group P21, lattice constants: aZ
7. Hammill, H. A.; Mickus, K.; Suzuki-Chavez, F.; Andeshak, J.;
Andres, D.; Ford, L. C.; Burnison, C. Recent Advances in
Chemotherapy, Proceedings of the 14th International Congress
Chemotherapy, Antimicrobial Sect. 1; Ishigami, J., Ed.;
University of Tokyo Press: Tokyo, Japan, 1985; pp 263–264.
8. Ford, L. C.; Hammill, H. A.; Mickus, K.; Suzuki-Chavez, F.;
Lebherz, T. B.; Burnison, C. S. Recent Advances in
Chemotherapy, Proceedings of the 14th International Congress
Chemotherapy, Antimicrobial Sect. 1; Ishigami, J., Ed.;
University of Tokyo Press: Tokyo, Japan, 1985; pp 265–266.
9. Ogawa, Tadatake; Miyamoto, Tatsu; Sada, Masahiro; Abe,
Takashi; Nishijima, Yasushi. (Kanebo, Ltd., Japan), Jpn.
Kokai Tokkyo Koho, 1986, 7.
˚
˚
˚
11.056(1) A bZ5.941(1) A cZ20.677(4) A; aZ98.71(1)8,
3
3
˚
cell volume 1342.5(7) A , ZZ2, density (Calcd) 1.184 g/cm ,
crystal size 0.03!0.08!1.2 mm, radiation Cu Ka, linear
absorption coefficient 13.0 cmK1, number of reflexes 4770,
number of independent reflexes 2817, Reflexes with IO0 2803,
R-value 0.042, wR 0.051, S-value 2.35. Crystallographic data
(excluding structure factors) for the structure have been
deposited with the Cambridge Crystallographic Centre as
supplementary publication number CCDC 237229. Copies of
the data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax: C44-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk).