Synthesis of furano-epothilone D

Article abstract of DOI:10.1002/chem.200400125

The total synthesis of furano-epothilone D by a convergent route is reported. The key fragments are available on a large scale to provide sufficient material for biological evaluation. The approach involves a palladium-catalyzed coupling that generates a highly functionalized aldehyde which is connected in a stereoselective aldol reaction to yield the framework of furano-epothilone D. Finally, a macrolactonization provides furano-epothilone D.

Full text of DOI:10.1002/chem.200400125

FULL PAPER
Synthesis of Furano-Epothilone D
[
a]
[b]
[c]
Dieter Schinzer,* Erika Bourguet, and Sylvie Ducki
Abstract: The total synthesis of furano-epothilone D by a convergent route is re-
ported. The key fragments are available on a large scale to provide sufficient ma-
terial for biological evaluation. The approach involves a palladium-catalyzed cou-
pling that generates a highly functionalized aldehyde which is connected in a ster-
eoselective aldol reaction to yield the framework of furano-epothilone D. Finally, a
macrolactonization provides furano-epothilone D.
Keywords: aldol reactions ¥ antitu-
mor agents ¥ epothilone analogues ¥
macrolides ¥ natural products
Introduction
garded as a lead compound for potential clinical develop-
ment.
[8]
[
1]
The bacterial macrolides epothilone A and epothilone B
have been found to act as biological analogues of paclitaxel.
This discovery has induced intense research activity, result-
In view of the need to synthesize sufficient quantities of
epothilone B and its analogues for drug development, we
have elaborated an alternative, selective procedure to
obtain a series of compounds. This route is based on highly
efficient aldol and transition-metal-mediated coupling reac-
tions that yield a seco-acid precursor utilized in the macro-
[2]
[3]
ing in several total syntheses of epothilone A and epothilo-
[4]
[5]
[6]
ne B, partial synthesis, and numerous derivatives. In
various biochemical assays, paclitaxel and the epothilones
were found to be almost identical in their effect on microtu-
bule stabilization and cytotoxic properties. However, against
multiple-drug resistant (MDR) human carcinoma cell lines,
the epothilones were significantly more potent than paclitax-
el. They may even prove to be more promising anticancer
[3g,4d]
lactonization route developed by Nicolaou et al.
thilone B.
to epo-
[9]
Herein, we have extended this method to obtain furano-
epothilone D as an analogue of epothilone D. Careful analy-
sis of the bond angles in the X-ray crystal structure of epo-
[7]
[1]
drugs than paclitaxel with less undesired side effects.
thilone B suggested the design of conformationally more
Recent studies with MDR cell lines indicate that epothilo-
ne B is the most potent of the naturally occurring epothi-
lones in vitro, whereas deoxyepothilone B (epothilone D)
exhibited the best therapeutic results in vivo and is thus re-
stabilized/restricted epothilone analogues with a five-mem-
bered ring placed in the region of C8±C1ꢀ.
Results and Discussion
[
a] Prof. Dr. D. Schinzer
Chemisches Institut der Otto-von-Guericke-Universit‰t
Universit‰tsplatz 2
Scheme 1 depicts the retrosynthetic analysis of furano-epo-
thilone B (1) that led to the macrolactonization-based strat-
egy. To obtain the required seco acid which would give
3
91ꢀ6 Magdeburg (Germany)
[3g,4d]
Fax : (+49)391-671-2223
E-mail: Dieter.Schinzer@vst.uni-magdeburg.de
desoxy-1 upon macrolactonization
, an aldol reaction of
and aldehyde 3 was designed as the
key step. Further disconnection of 3 led to the thiazole frag-
[1ꢀ]
the ethyl ketone 2
[
b] Dr. E. Bourguet
Present address: Universitÿ Paris-Sud
Facultÿ de Pharmacie
Reconnaissance molÿculaire et synthõse
BIOCIS (UMR C 8ꢀ76)
[5a,1ꢀ]
ment 5
and a C7±C12 building block 4. An efficient pal-
[11]
ladium-mediated Negishi-type coupling reaction was envi-
sioned for the assembly of 4 and 5 as precursors of aldehyde
3.
5
9
, rue, Jean Baptiste Clÿment
2296 Ch‚tenay-Malabry Cedex (France)
The thiazole building block 5 was synthesized according
to an improved sequence that was amenable to a multigram
[
c] Dr. S. Ducki
Center for Molecular Drug Design
Cockcroft Building
[5a,1ꢀ]
scale-up.
The approach to the C7±C12 fragment 4 started with sap-
onification of 5-acetoxymethyl-2-furfuraldehyde (6) with po-
tassium carbonate in MeOH to give 7 in 98% yield, fol-
University of Salford
Salford M5 4WT (UK)
+
[
] Tubulin polymerization assay
Chem. Eur. J. 2004, 10, 3217 ± 3224
DOI: 10.1002/chem.200400125
¹ 2ꢀꢀ4 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3217

FULL PAPER
best yields were obtained when both the Ph P=O formed
3
during the bromination reaction and the excess naphthalene
used in the preparation of the Rieke Zn were removed;
these otherwise inhibited coupling.
Selective deprotection to yield alcohol 11 was achieved by
the action of NH F in MeOH (93%). Oxidation of 11 with
4
TPAP/NMO in CH Cl as the reagent of choice provided al-
2
2
dehyde 3 in 87% yield, which was needed for the aldol reac-
tion with ketone 2 (Scheme 3).
To ensure complete conversion of aldehyde 3 to the de-
sired aldol product 12, two equivalents of the lithium eno-
late generated from ketone 2 had to be employed in the re-
action. The aldol product 12 was isolated in 91% yield from
the reaction mixture. The ratio of anti-Cram (6R,7S) to
1
Cram (6S,7R) products was found to be 3:1 by H NMR
spectroscopy. The selectivity in the aldol reaction of the
furano series was lower than in the case of epothilone A
and epothilone B because no a-chiral aldehyde was used in
[9]
the coupling. Therefore, no match of chirality can be em-
ployed to increase selectivity and the 3:1 ratio observed is a
result of the inherent chirality of the chiral enolate used in
the aldol reaction.
The first step in the transformation of the intermediate
1
2a into the seco-acid precursor 16 was cleavage of the
ketal protecting group using PPTS in MeOH, leading to the
triol 13 in 84% yield. When the reaction was performed in
refluxing MeOH, isomerization was observed at the C6 and
C7 centers. It can be almost completely suppressed when
the reaction mixture is stirred at room temperature. Silyla-
tion of compound 13 with TBSOTf and 2,6-lutidine led to
the tetrakis(silyl) ether 14 in 71% yield. Selective deprotec-
tion of 14 to the primary alcohol 15 was achieved by the
Scheme 1. Retrosynthetic analysis of furano-epothilone B–the macrolac-
tonization approach.
lowed by protection by using tert-butyldimethylsilyl chloride,
which afforded silyl ether 8 in 89% yield, as described by
[12]
McNelis et al. (Scheme 2). Reduction with triacetoxyboro-
hydride in benzene led to compound 9 in 93% yield. Frag-
ment 4 was obtained by bromination of 9 in CH Cl in the
action of NH F in MeOH in 73% yield. PDC oxidation of
4
15 in DMF provided seco-acid 16 in 8ꢀ% yield (Scheme 4).
The selective deprotection of the allylic alcohol 16 was
not possible under neutral, acidic, or basic conditions. Total
deprotection of the hydroxy groups of 16 with aqueous HF
(4ꢀ%) in CH CN/Et O afforded a mixture of two diaster-
2
2
presence of imidazole and triphenylphosphine. Compound 4
is quite unstable and can only be stored in solution under ni-
trogen in the fridge for a short time. An efficient palladium-
3
2
[
11]
mediated coupling
of vinyl iodide 5 and the organozinc
eoisomers 17 (17a:17b epimerization of C7; ratio 1:2) in
25:47% yield (Scheme 5). Diastereomers 17a and 17b were
cyclized to macrolactones 18a and 18b, respectively, in 51%
[13]
[14]
species derived from 4 using a Zn/Cu couple led to the
bis(silyl) ether 10 in 32% yield. Rieke Zn
[15]
however
[16]
proved superior, giving compound 10 in 85% yield. The
yield by the Yamaguchi method.
Scheme 2. Synthesis of the C7±C12 fragment 4 and Pd-mediated coupling of building blocks 4 and 5. a) K
b) TBSCl (1.2 equiv), imidazole (1.8 equiv), DMF, RT, 18 h, 89%; c) NaBH(OAc) , benzene, reflux, 3h, 93%; d) PPh
Br (1.1 equiv), CH Cl
, ꢀ8C, 1ꢀ min, complete by TLC; e) Zn* (6.ꢀ equiv) in THF, À3ꢀ8C; then 4 in THF added by syringe pump over 4.5 h, [Pd(PPh
12.5 mol%); then 5 in THF, 6ꢀ8C, 1 h, 85%.
2
CO
3
(ꢀ.16 equiv), CH
3
OH, RT, 18 h, 98%;
3
3
(1.1 equiv), imidazole (1.2 equiv),
2
2
2
3 4
) ]
(
3218
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Chem. Eur. J. 2004, 10, 3217 ± 3224

Synthesis of Furano-Epothilone D
3217 ± 3224
Scheme 3. Aldol reaction. a) NH
4
F (4ꢀ equiv), MeOH, reflux, 1 h, 93%; b) NMO (1.5 equiv), molecular sieves 4 ä, CH
2
Cl
2
, ꢀ8C, 15 min, TPAP
(
(
ꢀ.ꢀ5 equiv), RT, 15 min, 87%; NMO=4-methylmorpholine N-oxide, TPAP=tetrapropylammonium perruthenate; c) ketone 2 (2.ꢀ equiv), LDA
1.96 equiv), THF, À788C, 1 h; then aldehyde 3, À788C, 15 min, 91%.
Scheme 4. Synthesis of a seco acid precursor 16. a) PPTS (1.ꢀ equiv), MeOH, RT, 48 h, 84%; b) TBSOTf (4.8 equiv), 2,6-lutidine (9.6 equiv), CH
À5ꢀ8C, 1 h, 71%; c) NH F (49 equiv), MeOH, reflux, 2.5 h, 73%; d) PDC (45 equiv), DMF, RT, 19 h, 8ꢀ%.
2 2
Cl ,
4
The induction of tubulin polymerization was determined
by using the procedure described in the Experimental Sec-
tion. The results are presented as ED5ꢀ and ED9ꢀ values
which correspond to the dose of compound required to
induce 5ꢀ% and 9ꢀ% microtubule assembly, respectively.
Paclitaxel was used as a reference assay. Furano-epothil-
one D (18a) showed an ED =2.2mm and an ED =5.5mm
(paclitaxel: ED =ꢀ.4mm; ED =2.ꢀ) and is therefore less
5ꢀ 9ꢀ
potent than paclitaxel. The isomer 18b showed the same
effect on tubulin assembly. However, it was demonstrated
for the first time that an epothilone analogue without a
chiral center at C8 showed biological activity. This supports
our hypothesis that incorporation of a five-membered ring
enforces the conformational stability of the region C8±C1ꢀ.
5
ꢀ
9ꢀ
Chem. Eur. J. 2004, 10, 3217 ± 3224
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¹ 2ꢀꢀ4 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3219

D. Schinzer et al.
FULL PAPER
and high-resolution mass spectra were
recorded on Finnigan MAT 95 and
SSQ 7ꢀꢀꢀ spectrometers (HRMS: ref-
erence PKF, peak matching method,
accuracy + 2 ppm). IR spectra were
recorded on Perkin-Elmer 2ꢀꢀꢀ and
Nicolet 32ꢀ FT-IR spectrometers. UV
spectra were recorded on Hewlett-
Packard 8452
A and Perkin-Elmer
Lambda 19 spectrometers. NMR spec-
tra were recorded on a Bruker DPX
4
ꢀꢀ spectrometer. Optical rotations
were recorded with a Perkin-Elmer
2
41 polarimeter.
5
-Hydroxymethyl-2-furfuraldehyde
(
7): A solution of 5-acetoxymethyl-2-
furfuraldehyde (6; 5 g, 29 mmol) in
methanol (45 mL) was treated with
potassium
.6 mmol) and the progress of the re-
action was monitored by TLC (SiO
:1 pentane/EtOAc). After 18 h, the
carbonate
(644 mg,
4
2
,
1
solvent was evaporated and the resi-
due dissolved in EtOAc. The organic
layer was washed with water and dried
over anhydrous MgSO . Filtration and
4
evaporation afforded 5-hydroxymeth-
yl-2-furfuraldehyde (7; 3.573 g, 98%)
as a yellow oil.
1
H NMR (36ꢀ MHz, CDCl
3
): d=9.55
J=3.5 Hz,
J=3.6 Hz,
3
(
s, 1H; CHO), 7.23(d,
H; H-3furyl), 6.52 (d,
Scheme 5. Final steps of the macrolactonization approach to furano-epothilone D. a) aqueous HF (4ꢀ%),
3
1
1
3
CH
3 2 3
CN/Et O, glass splinters, two days, ratio 1:2, 25:47%; b) 2,4,6-trichlorobenzoylchloride (5.ꢀ equiv), Et N
H; H-4 furyl), 4.7ꢀ (s, 2H; -CH
2
OH),
.64 ppm (bs, 1H; -OH); C NMR
): d=177.7, 16ꢀ.9,
(
6.ꢀ equiv), THF, ꢀ8C, 15 min, then add by using a syringe pump to a solution of 4-DMAP (1ꢀ equiv) in tolu-
1
3
ene, 258C, 1 h, 51 %.
(
9ꢀ MHz, CDCl
3
1
52.1, 1ꢀ9.9, 57.3ppm.
5
-tert-Butyldimethylsiloxymethyl-2-
Work is in progress to synthesize more potent analogues, in-
vestigate their interaction with tubulin, and establish their
cytotoxicity.
furfuraldehyde (8): Imidazole (51 mg, ꢀ.74 mmol, 1.8 equiv) and 5-hy-
droxymethyl-2-furfuraldehyde (7; 52 mg, ꢀ.41 mmol) was added to a solu-
tion of tert-butyldimethylsilyl chloride (75 mg, ꢀ.49 mmol, 1.2 equiv) in
DMF (2ꢀꢀ mL) and the mixture was stirred for 19 h. The reaction mixture
was then diluted with pentane and washed with water. The organic layer
4
was dried (MgSO ) and filtered through a small plug of silica gel. Evapo-
ration of the solvent afforded 5-tert-butyldimethylsiloxymethyl-2-furfural-
dehyde (8; 87.6 mg, 89%) as a yellow oil.
Conclusion
1
3
H NMR (36ꢀ MHz, CDCl
3
): d=9.59 (s, 1H; CHO), 7.22 (d, J=3.5 Hz,
H; 3furyl), 6.48 (d, J=3.5 Hz, 1H; H-4 furyl), 4.74 (s, 2H; -CH OH),
); C NMR
): d=177.4, 161.3, 152.1, 1ꢀ9.3, 58.5, 25.6, 18.2,
In summary, we have presented a convergent synthesis of
furano-epothilone D. Our method using stereoselective aldol
CÀC bond formations, palladium-mediated couplings, and
3
1
ꢀ
(
2
13
3 3 3 2
.92 (s, 9H, OSiC(CH ) ), ꢀ.ꢀ9 ppm (s, 6H, OSi(CH )
9ꢀ MHz, CDCl
3
macrolactonization can be extended to synthesize numerous
analogues of epothilone D.
À5.4 ppm.
5-tert-Butyldimethylsiloxymethyl-2-furanmethanol (9): A solution of 5-
tert-butyldimethylsiloxymethyl-2-furfuraldehyde (8; 5.588 g, 23mmol) in
benzene (5ꢀ mL) was added dropwise to a solution of sodium triacetoxy-
borohydride (18.61 g, 87 mmol) in benzene (25ꢀ mL). After 3h of heat-
ing under reflux, water (5ꢀ mL) was added to the solution, which was
subsequently extracted with diethyl ether (3î5ꢀ mL). The organic phases
were washed with brine, dried over MgSO , evaporated under vacuum,
4
and purified by column chromatography using silica gel (pentane/
EtOAc=3:1) to yield product 9 (5.249 g, 93%) as a colorless oil.
In addition, this strategy offers the possibility to synthe-
size epothilone analogues in sufficient quantities for in vitro
and in vivo biological studies. However, the biological data
derived from the tubulin assay showed only moderate activi-
ty for furano-epothilone D and its isomer. This clearly dem-
onstrated that the correct configuration at C8 is more im-
portant than a stabilized conformation in that part of the
molecule by incorporation of a five-membered ring.
1
3
H NMR (36ꢀ MHz, CDCl
3
): d=6.21 (d, J=2.6 Hz, 1H; H-3furyl), 6.17
d, J=3Hz, 1H; H-4 furyl), 4.61 (s, 2H; -CH OH), 4.55 (s, 2H;
CH OH), ꢀ.9ꢀ (s, 9H, OSiC(CH ), ꢀ.ꢀ8 ppm (s, 6H, OSi(CH
NMR (9ꢀ MHz, CDCl ): d=154.2, 153.5, 1ꢀ8.3, 1ꢀ7.9, 58.1, 57.4, 25.8,
8.3, À5.2 ppm; IR (film): n˜ max =3351, 293ꢀ, 2858, 2362, 1561, 1472, 1255,
1ꢀ75, 1ꢀ14, 837, 778 cm ; MS (CI, NH /CH ): m/z (%): 241 (13.6), 225
3
(
-
2
1
3
2
3
)
3
3
)
2
);
C
3
1
À1
Experimental Section
3
4
+
+
(
1
98.4) [MÀOH] , 2ꢀ9 (16), 191 (25), 185 (39.2) [MÀtBu] , 167 (18.4),
+
61 (7.2), 11ꢀ (28) [MÀOTBS] , 8ꢀ (6); elemental analysis calcd (%) for
General techniques: Solvents were dried by standard procedures and re-
C
12
H
22
O
3
Si (242.13): C 59.46, H 9.15; found: C 59.31, H 9.48.
5-tert-Butyldimethylsiloxymethyl-2-bromomethyl-furan (4): Br
ꢀ.38 mmol, 1.1 equiv) was added slowly to a solution of 5-tert-butyldi-
distilled under N
formed under N
chromatography by using Merck silica gel 6ꢀ (4ꢀ±63 mm). Mass spectra
2
prior to use. All organometallic reactions were per-
2
or argon, and pure products were obtained after flash
2
(2ꢀ mL,
322ꢀ
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Chem. Eur. J. 2004, 10, 3217 ± 3224

Synthesis of Furano-Epothilone D
3217 ± 3224
methylsiloxymethyl-2-furanomethanol (9; 83.6 mg, ꢀ.34 mmol), imidazole
pylammonium perruthenate (62 mg, ꢀ.17 mmol, ꢀ.ꢀ5 equiv) was added,
and the mixture was stirred 15 min at room temperature. Purification of
the residue by flash chromatography (pentane/Et O=2:1) gave aldehyde
2
(
28 mg, ꢀ.41 mmol, 1.2 equiv), and PPh
CH Cl (2 mL) at ꢀ8C. After 1ꢀ min, the solution was washed with water,
ꢀ% Na SO (2î4 mL), and dried over MgSO . The solvent was re-
3
(99 mg, ꢀ.38 mmol, 1.1 equiv) in
2
2
1
2
3
4
3 (1.348 mg, 87%) as a yellow oil.
moved under a flux of nitrogen and replaced by pentane, the solution
was cooled to À788C, and the white solid was filtered. The solvent was
removed under a flux of nitrogen and replaced with THF. The bromide
compound 4 is unstable, but can be stored in solution under nitrogen in
the fridge for a short time.
2ꢀ
1
[
a]D = +28.4 (c=1, CHCl
3
); H NMR (36ꢀ MHz, CDCl
3
): d=9.5 (s, 1H;
3
H-1), 7.13(d, J=3.5 Hz, 1H; CH furyl, H-3), 6.92 (s, 1H; H-5’), 6.47 (s,
1H; H-12), 6.2ꢀ (d, J=3.5 Hz, 1H; CH furyl, H-4), 5.4ꢀ (td, J=6.4 Hz,
J=ꢀ.7 Hz, 1H; H-8), 4.14 (t, J=5.7 Hz, 1H; H-1ꢀ), 3.53 (d, J=15 Hz,
1H; H-6), 3.37 (d, J=16 Hz, 1H; H-6), 2.7ꢀ (s, 3H; C2’-CH ), 2.4ꢀ±2.25
3
2
3
3
2
2
3
4
4
4
-[(1E,3S,5Z)-3,12-Di(tert-butyldimethylsilyloxy)-2,6-dimethyl-1,5-unde-
(m, 2H; H-9), 1.98 (d, J=1.1 Hz, 3H; C11-CH
3H; C7-CH ), ꢀ.88 (s, 9H; OSiC(CH ), ꢀ.ꢀ3(s, 3H ), ꢀ.ꢀꢀ ppm (s, 3H ;
); C NMR (9ꢀ MHz, CDCl ): d=177.ꢀ, 164.3, 161.5, 153.ꢀ,
3
), 1,72 (d, J=1.1 Hz,
cadienyl-7-furan]-2-methyl-1,3-thiazole (10): Alkyl bromide 4 in THF
3
3 3
)
[
15]
13
was added to a suspension of powdered Zn*
1ꢀ mL) at À258C by using a syringe pump over 4.5 h. The mixture was
stirred at À3ꢀ8C for 3ꢀ min. [Pd(PPh )] (12.5 mg, 12.5 mol%) was added
and the mixture was stirred for another 5 min. A solution of vinyl iodide
(4ꢀ mg, ꢀ.ꢀ8 mmol) in THF (1 mL) was added and the mixture was stir-
red for 1 h at 6ꢀ8C, cooled to room temperature and quenched with satu-
rated aqueous NH Cl solution (ꢀ.5 mL). The aqueous layer was extracted
with MeOtBu (3î3mL), the combined organic extracts were dried over
MgSO and concentrated in vacuo. Purification of the residue by flash
chromatography (pentane/Et
4ꢀ mg, 83%) as a yellow oil.
(6.ꢀ equiv) in THF
OSi(CH
3
)
2
3
(
152.1, 142.ꢀ, 13ꢀ.9, 125.2, 118.9, 115.1, 1ꢀ9.1, 78.4, 35.6, 31.3, 25.8, 23.7,
19.1, 18.2, 13.9, À4.6, À5.ꢀ ppm; IR (film): n˜ max =2928, 2856, 1681, 1513,
3
4
À1
1
2
4
471, 1255, 1184, 1ꢀ73, 1ꢀ22, 837, 776 cm ; UV/Vis (MeOH): lmax
=
+
83.8 nm (e=56ꢀꢀ); MS (CI, NH
3ꢀ (17.6), 388 (8), 314 (27.6), 282 (9.6) [C14
SSi 445.21ꢀ69, found 445.21ꢀ7 (ꢀ.ꢀ mmu); elemental
analysis calcd (%) for C24 SSi (445.69): C 64.68, H 7.92, N 3.14, S
.19; found: C 6ꢀ.79, H 8.21, N 3.1ꢀ, S 6.42.
3
/CH
4
): m/z (%): 446 (1ꢀꢀ) [M+H]
,
5
+
H
24NOSSi] ; HRMS (EI):
calcd for C24H35NO
3
4
H
35NO
3
7
4
2
O=3ꢀ:1) afforded the coupled product 10
(4×S,4S,5S,11Z,14S,15E)-14-[(tert-Butyldimethylsilyl)oxy]-2-[(4R)-2,2-
dimethyl-1,3-dioxan-4-yl]-5-hydroxy-2,4,11,15-pentamethyl-16-(2-methyl-
(
2
D
ꢀ
1
1,3-thiazol-4-yl)-11,15-pentadecadien-furan-3-one (12): A solution of
[
1
(
2
3
a] = +21.7 (c=1.15, CHCl
3
); H NMR (36ꢀ MHz, CDCl
3
): d=6.92 (s,
3
LDA was freshly prepared by addition of nBuLi (457 mL, 1.14 mmol,
1.96 equiv of a 2.5m solution in hexanes) to a solution of diisopropyla-
mine (16ꢀ mL, 1.14 mmol) in THF (1.95 mL) at ꢀ8C and stirring for
3ꢀ min. A solution of ethyl ketone 2 (25ꢀ mg, 1.16 mmol, 2.ꢀ equiv) in
THF (1.95 mL) was then added dropwise at À788C to the mixture. This
H; H-5’), 6.46 (s, 1H; H-1), 6.ꢀ9 (d, J=3Hz, 1H; CH furyl, H-1ꢀ), 5.88
d, J=3Hz, 1H; CH furyl, H-9), 5.3 (t, J=6.8 Hz, 1H; H-5), 4.57 (s,
H; H-12), 4.12 (t, J=5.8 Hz, 1H; H-3), 3.4 (d, J=15.5 Hz, 1H; H-12),
.25 (d, J=15.5 Hz, 1H; H-12), 2.7ꢀ (s, 3H; C2’-CH
H-4), 1.99 (d, J=1.2 Hz, 3H; C2-CH
3 3
.88 (s, 18H, OSiC(CH )
OSi(CH
3
3
3
2
2
3
), 2.48±2.27 (m, 2H;
), 1,7ꢀ (d, J=1 Hz, 3H; C6-CH ),
), ꢀ.ꢀ8 (s, 3H), ꢀ.ꢀ6 (s, 6H), ꢀ.ꢀ4 ppm (s, 3H,
); C NMR (9ꢀ MHz, CDCl ): d=164.2, 153.5, 153.2, 152.7,
4
4
3
3
was stirred for 1 h at À788C.
A solution of aldehyde 3 (26ꢀ mg,
ꢀ.58 mmol, 1 equiv) in THF (2.4 mL) was added dropwise and stirring
ꢀ
1
3
3
)
2
3
was continued for 2ꢀ min at À788C. The mixture was quenched by the
1
2
2
(
(
(
2
42.3, 132.7, 123.6, 118.7, 114.9, 1ꢀ7.9, 1ꢀ6.1, 78.7, 58.2, 35.5, 3ꢀ.9, 25.9,
4
dropwise addition of saturated NH Cl solution (7 mL). The organic layer
3.6, 19.1, 18.3, 18.2, 13.9, À4.6, À4.9, À5.1, À5.2 ppm; IR (film): n˜ max
=
À1
was separated and the aqueous layer was extracted with Et
ꢀ mL). The combined organic extracts were dried (MgSO ) and concen-
trated in vacuo. Purification of the residue by flash chromatography
(pentane/Et O=3:1) afforded anti-Cram aldol product 12a and its corre-
2
O (3 î
929, 2857, 2364, 1472, 1376, 1255, 1ꢀ75, 939, 837, 777 cm ; UV/Vis
2
4
MeOH): lmax =22ꢀ,18 nm (e=9785.7); MS (CI, NH
3
/CH
4
): m/z (%): 562
+
+
+
74.4) [M+H] , 546 (52) [MÀCH
3
] , 5ꢀ4 (36) [MÀtBu] , 451 (8), 43ꢀ
+
2
1ꢀꢀ) [MÀOTBS] , 4ꢀ9 (12), 356 (5.6), 335 (26.4), 298 (21.6) [M-
+
+
sponding Cram diastereoisomer 12b (35ꢀ mg, 91%, ratio 3:1 by NMR
xOTBS] , 282 (1ꢀꢀ) [C14
H
24NOSSi] , 225 (1ꢀ.8); HRMS (EI) calcd
spectroscopy) as colorless oils.
C
3ꢀ
H
51NO
3
SSi
ysis calcd (%) for C3ꢀ
.71; found: C 57.2ꢀ, H 8.89, N 2.74, S 4.56.
7Z,10S,11E)-10-(tert-Butyldimethylsilyloxy)-7,11-dimethyl-12-(2-
2
561.31282 ; found 561.3137 (mmu : Àꢀ.9); elemental anal-
2
ꢀ
1
Major isomer 12a: [a] =À 2.9 (c=1, CHCl
3
); H NMR (36ꢀ MHz,
H
51NO
3
SSi (561.97): C 64.12, H 9.15, N 2.49, S
2
D
3
CDCl
3
): d=6.91 (s, 1H; H-5’’), 6.43(s, 1H; H-16), 6.1ꢀ (d, J=3Hz, 1H;
5
3
CH furyl, H-8), 5.86 (d, J=3 Hz, 1H; CH furyl, H-7), 5.33±5.29 (m, 1H;
(
3
H-12), 4.82 (d, J=3.8 Hz, 1H; H-5), 4.13±4.1 (m, 1H; H-14), 4.ꢀ (dd,
methyl-1,3-thiazol-4-yl)-undeca-7,12-dien-furan-1-ol (11): Ammonium
fluoride (1.69 g, 45 mmol, 4ꢀ equiv) was added to a solution of the cou-
pled product 10 (641 mg, 1.14 mmol) in MeOH (3ꢀ mL). The mixture
was heated for 1 h under reflux. The solvent was evaporated and the
solid was extracted with diethyl ether. The organic phase was dried over
3
3
3
3
J=11.6 Hz, J=2.4 Hz, 1H; H-4’), 3.94 (td, J=2.8 Hz, J=11.8 Hz, 1H;
2
3
3
H-6’), 3.85 (ddd, J=11.8 Hz, J=5.4 Hz, J=1.7 Hz, 1H; H-6’), 3.43 (qd,
3
3
2
J=6.9 Hz, J=2.8 Hz; 1H; H-4), 3.38 (d, J=15.6 Hz, 1H; H-1ꢀ), 3.24
d, J=15.6 Hz, 1H; H-1ꢀ), 2.7ꢀ (s, 3H; C2’’-CH ), 2.34±2.25 (m, 2H; H-
3
2
(
4
4
1
3), 1.98 (d, J=1.1 Hz, 3H; C15-CH
CH ), 1.67±1.59 (m, 1H; H-5’), 1.56 (bs, 1H, OH), 1.4ꢀ (s, 3H, C2’-CH
.33 (s, 3H; C2’-CH
3
), 1,7ꢀ (d, J=1.1 Hz, 3H; C11-
),
3
), 1.32±1.25 (m, 1H; H-5’), 1.12 (d, J=6.8 Hz, 3H;
MgSO
4
and concentrated in vacuo. Flash chromatography (pentane/
3
3
Et O=2:1) gave alcohol 11 (472 mg, 93%) as a yellow oil.
2
3
1
2
D
ꢀ
1
[
1
a] = +59.4 (c=ꢀ.5, CHCl
3
); H NMR (36ꢀ MHz, CDCl
3
): d=6.93(s,
C4-CH ), 1.12 (s, 3H; H-1), ꢀ.99 (s, 3H; C2-CH ), ꢀ.88 (s, 9H;
3
3
3
H; H-5’), 6.49 (s, 1H; H-12), 6.17 (d, J=3Hz, 1H; CH furyl, H- 3) , 5.93
d, J=3Hz, 1H; CH furyl, H-4), 5. 33 (t, J=7 Hz, 1H; H-8), 4.57 (d,
J=13Hz, 1H; H-1), 4.52 (d, J=13Hz, 1H; H-1), 4.18 (t, J=6 Hz, 1H;
H-1ꢀ), 3.4ꢀ (d, J=15 Hz, 1H; H-6), 3.26 (d, J=15 Hz, 1H; H-6), 2.78
bs, 1H, -OH), 2.7ꢀ (s, 3H; C2’-CH ), 2.41±2.27 (m, 2H; H-9), 1.98 (d,
J=1.1 Hz, 3H; C11-CH
OSiC(CH ), ꢀ.ꢀ4 (s, 3H), ꢀ.ꢀꢀ ppm (s, 3H; OSi(CH
9ꢀ MHz, CDCl
13
OSiC(CH
3
)
3
3 2
), ꢀ.ꢀ4 (s, 3H), ꢀ.ꢀꢀ ppm (s, 3H; OSi(CH ) ); C NMR
3
3
(
(
3
9ꢀ MHz, CDCl ): d=221.2, 164.4, 153.2, 153.1, 152.6, 142.3, 132.6, 123.8,
2
2
3
1
2
18.7, 114.9, 1ꢀ7.4, 1ꢀ6.ꢀ, 98.4, 78.7, 74.4, 68.7, 59.8, 51.5, 45.2, 35.5, 3ꢀ.9,
9.6, 25.8, 25.1, 23.8, 2ꢀ.6, 19.1, 19.ꢀ, 18.5, 18.2, 13.9, 12.ꢀ, À4.6,
2
2
(
3
À4.9 ppm; IR (film): n˜ max =3475, 2929, 2856, 2363, 1697, 1558, 1472, 1373,
4
4
À1
3
), 1,7ꢀ (d, J=1 Hz, 3H; C7-CH
3
), ꢀ.89 (s, 9H,
1
252, 1195, 1159, 11ꢀ4, 987, 836, 777 cm ; MS (7ꢀ eV, EI): m/z (%): 659
1
3
+
+
3
)
3
3
)
2
); C NMR
14 24
(1) [M] , 446 (2), 388 (2), 282 (1ꢀꢀ) [C H NOSSi] , 225 (4), 156 (6),
(
1
3
): d=164.5, 154.ꢀ, 153.ꢀ, 152.9, 142.4, 132.7, 123.7, 118.9,
36 57 6
115 (8), 73( 3ꢀ ); HRMS (EI): calcd for C H NO SSi 659.36759, found
659.3672 (ꢀ.4 mmu); elemental analysis calcd (%) for C H NO SSi
36 57 6
(659.99): C 65.51, H 8.71, N 2.12, S 4.86; found: C 63.3ꢀ, H 9.3ꢀ, N 2.9ꢀ,
14.7, 1ꢀ8.5, 1ꢀ6.4, 79.ꢀ, 57.2, 35.5, 31.ꢀ, 25.8, 23.7, 19.ꢀ, 18.2, 13.7, À4.6,
À4.9 ppm; IR (film): n˜ max =331ꢀ, 2928, 2856,15ꢀ8, 1471, 136ꢀ, 1251, 1185,
À1
1
2
[
2
(
6
ꢀ71, 1ꢀ12, 939, 837, 777 cm ; UV/Vis (MeOH): lmax =212.26 nm (e=
S 4.33.
+
3ꢀ87); MS (CI, NH
3
/CH
O] , 39ꢀ (5.6), 316 (49.6), 298 (63.2), 282 (85.6) [C14
42 (6.4); HRMS (EI): calcd for C24 SSi 447.2263, found 447.2259
SSi (447.22): C
4.39, H 8.33, N 3.13, S 7.16; found: C 6ꢀ.35, H 8.66, N 3.5ꢀ, S 6.ꢀꢀ.
7Z,10S,11E)-10-(tert-Butyldimethylsilyloxy)-7,11-dimethyl-12-(2-
4
): m/z (%): 448 (59.2) [M+H] , 43ꢀ (1ꢀꢀ)
1
Minor isomer 12b: H NMR (36ꢀ MHz, CDCl
3
): d=6.92 (s, 1H; H-5’’),
+
+
MÀH
2
H
24NOSSi] ,
3
3
6
3
1
1
.45 (s, 1H; H-16), 6.14 (d, J=3Hz, 1H; CH furyl, H-7), 5.88 (d, J=
Hz, 1H; CH furyl, H-8), 5.33±5.29 (m, 1H; H-12), 4.86 (d, J=3.6 Hz,
H; H-5), 4.12±4.ꢀ (m, 2H; H-14; H-4’), 3.94 (td, J=2.8 Hz, J=
1.8 Hz, 1H; H-6’), 3.85 (ddd, J=11.8 Hz, J=5.4 Hz, J=1.7 Hz, 1H;
H
37NO
3
3
ꢀ.4 mmu); elemental analysis calcd (%) for C24
H
37NO
3
3
3
2
3
3
2
(
H-6’), 3.41±3.43 (m, 1H; H-4), 3.37 (d, J=15.8 Hz, 1H; H-1ꢀ), 3.23 (d,
2
methyl-1,3-thiazol-4-yl)-undeca-7,12-dien-furan-1-al (3): 4-Methylmor-
pholine-N-oxide (621 mg, 5.3mmol, 1.5 equiv) and 4 ä molecular sieves
J=15.5 Hz, 1H; H-1ꢀ), 2.7ꢀ (s, 3H; C2’’-CH ), 2.34±2.29 (m, 2H; H-13),
3
4
4
1.98 (d, J=1.2 Hz, 3H; C15-CH ), 1,7ꢀ (d, J=1.1 Hz, 3H; C11-CH ),
3
3
were added to a solution of alcohol 11 (1.58 g, 3.5 mmol) in CH
2
Cl
2
1.63±1.59 (m, 1H; H-5’), 1.42 (s, 3H, C2’-CH ), 1.32 (s, 3H; C2’-CH ),
3
3
3
(
44 mL). The mixture was cooled to ꢀ8C and stirred for 15 min. Tetrapro-
1.31±1.23 (m, 1H, H-5’), 1.11 (d, J=6.9 Hz, 3H; C4-CH
3
), 1.11 (s, 3H;
Chem. Eur. J. 2004, 10, 3217 ± 3224
www.chemeurj.org
¹ 2ꢀꢀ4 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3221

D. Schinzer et al.
FULL PAPER
H-1), ꢀ.99 (s, 3H; C2-CH
3
), ꢀ.89 (s, 9H, OSiC(CH
3
)
3
), ꢀ.ꢀ4 (s, 3H),
(3S,6S,7S,13Z,16S,17E)-1(Hydroxy)-3,7,16-Tri[(tert-butyl-dimethylsilyl)-
oxy]-4,4,6,13,17-pentamethyl-18-(2-methyl-1,3-thiazol-4-yl)-13,17-hepta-
decadien-furan-5-one (15): Ammonium fluoride (262 mg, 7 mmol,
4ꢀ equiv) was added to a solution of the tetrakis silyl ether 14 (17ꢀ mg,
ꢀ.17 mmol) in MeOH (4.5 mL). The mixture was heated for 1.5 h under
1
3
ꢀ
1
7
1
2
7
.ꢀꢀ ppm (s, 3H; OSi(CH
3
)
2
); C NMR (9ꢀ MHz, CDCl ): d=192.8,
3
64.5, 153.1, 152.8, 142.3, 132.6, 123.8, 118.8, 115.ꢀ, 1ꢀ7.4, 1ꢀ6.1, 98.5,
8.7, 74.1, 68.7, 59.9, 51.6, 44.4, 35.5, 3ꢀ.9, 29.6, 25.8, 25.2, 23.7, 21.1, 19.1,
8.9, 18.3, 18.2, 13.9, 12.2, À4.6, À4.9 ppm; IR (film): n˜ max =3446, 2928,
855, 2358, 1739, 1698, 1558, 1471, 1372, 1251, 1196, 1161, 11ꢀ4, 986, 836,
reflux.
A second portion of ammonium fluoride (58 mg, 1.6 mmol,
À1
+
77 cm ; MS (7ꢀ eV, EI): m/z (%): 659 (1) [M] , 644 (2), 446 (2), 388
9 equiv) was added, and the solution was heated under reflux for an addi-
tional hour. The solution was filtered, and the residue was washed with
+
(
(
3), 282 (1ꢀꢀ) [C14
EI): calcd for C36
3S,6S,7S,13Z,16S,17E)-1,3,7-Trihydroxy-16-[(tert-butyldimethylsilyl)-
H
24NOSSi] , 226 (4), 156 (9), 115 (11), 73( 36 ); HRMS
H
57NO
6
SSi 659.36759, found 659.3696 (-2 mmu).
MeOH, CH
celite and concentrated in vacuo. Flash chromatography (pentane/Et
:1) of the residue gave alcohol 15 (1ꢀ8 mg, 73%) as a yellow oil.
2
Cl
2
, and diethyl ether. The organic phase was dried over
2
O=
(
5
oxy]-4,4,6,13,17-pentamethyl-18-(2-methyl-1,3-thiazol-4-yl)-13,17-hepta-
decadien-furan-5-one (13): PPTS (6.ꢀ mg, 23 mmol, ꢀ.6 equiv) was added
to a solution of aldol product 12a (25 mg, 38 mmol) in MeOH (1 mL).
The mixture was stirred for 22 h at room temperature. Another portion
of PPTS (4.ꢀ mg, 16 mmol, ꢀ.4 equiv) was added and stirring was contin-
ued for 24 h. The solvent was removed in vacuo, and the residue was pu-
2
D
ꢀ
1
[a] =À ꢀ.7 (c=1, CHCl
3
); H NMR (36ꢀ MHz, CDCl
3
): d=6.91 (s, 1H;
3
H-5’), 6.47 (s, 1H; H-18), 5.91 (d, J=3Hz, 1H; CH furyl, H-9), 5.78 (d,
J=3.1 Hz, 1H; CH furyl, H-1ꢀ), 5.3ꢀ±5.27 (m, 1H; H-14), 4.66 (d, J=
9.6 Hz, 1H; H-7), 4.14±4.11 (m, 1H; H-16), 3.91 (dd, J=6.3Hz, J=
3
3
3
3
3.8 Hz, 1H; H-3), 3.62±3.59 (m; 2H; H-1), 3.49±3.42 (m; 1H; H-6), 3.34
2
2
rified by flash chromatography (Et
a colorless oil.
2
O) to give triol 13 (19.7 mg, 84%) as
(d, J=15.5 Hz, 1H; H-12), 3.22 (d, J=15.5 Hz, 1H; H-12), 2.71 (s, 3H;
4
3 3
C2’-CH ), 2.4ꢀ±2.28 (m, 2H; H-15), 1.98 (d, J=1 Hz, 3H; C17-CH ),
1,66 (d, J=ꢀ.9 Hz, 3H; C13-CH ), 1.6ꢀ±1.5ꢀ (m; 2H; H-2), 1.2ꢀ (d, J=
3
4
3
2
D
ꢀ
1
[
a] =À 1.1 (c=1, CHCl
3
); H NMR (36ꢀ MHz, CDCl
3
): d=6.92 (s, 1H;
3
3 3
6.8 Hz, 3H; C6-CH ), 1.ꢀ8 (s, 3H; C4-CH ) , ꢀ.89, ꢀ.86, ꢀ.83(3s, 3î 9H,
H-5’), 6.4ꢀ (s, 1H; H-18), 6.ꢀ7 (d, J=3Hz, 1H; CH furyl, H-9), 5.86 (d,
J=3.1 Hz, 1H; CH furyl, H-1ꢀ), 5.34±5.31 (m, 1H; H-14), 4.78 (d, J=
3
3
OSiC(CH ) ), ꢀ.53(s, 3H ; C4-CH ), ꢀ.ꢀ6, ꢀ.ꢀ5, ꢀ.ꢀꢀ, Àꢀ.ꢀ1 (4 s, 4î 3H;
3
3
3
13
3
3
3 2 3 2 3
OSi(CH ) ), ꢀ.ꢀ1 ppm (s, 6H; OSi(CH ) ); C NMR (9ꢀ MHz, CDCl ):
6
2
2
1
1
6
ꢀ
.3 Hz, 1H; H-7), 4.13±4.1 (m, 1H; H-16), 3.96 (dd, J=6.7 Hz, J=
.9 Hz, 1H; H-3), 3.85±3.79 (m; 2H; H-1), 3.46 (qd, J=6.9 Hz, J=
.8 Hz; 1H; H-6), 3.37 (d, J=15.5 Hz, 1H; H-12), 3.23 (d, J=15.1 Hz,
3
H; H-12), 2.7ꢀ (s, 3H; C2’-CH ), 2.39±2.25 (m, 2H; H-15), 1.96 (d, J=
3
3
d=218.4, 164.3, 153.1, 153.ꢀ, 152.9, 142.9, 132.5, 123.7, 118.8, 114.9, 1ꢀ8.5,
1ꢀ5.9, 78.6, 72.7, 7ꢀ.2, 6ꢀ.2, 53.6, 48.1, 38.4, 35.4, 3ꢀ.9, 26.ꢀ, 25.8, 25.7,
23.5, 23.ꢀ, 19.1, 18.2, 18.1, 16.8, 15.9, 13.9, À3.9, À4.ꢀ, À4.6, À4.9, À5.1,
2
2
4
4
À5.1 ppm; IR (film): n˜ =3412, 2929, 2857, 1694, 1556,1472, 1387, 1361,
.1 Hz, 3H; C17-CH
H; H-2, -OH), 1.21 (d, J=6.8 Hz, 3H; C6-CH
.97 (s, 3H; C4-CH ), ꢀ.88 (s, 9H, OSiC(CH ), ꢀ.ꢀ4 (s, 3H), ꢀ.ꢀꢀ ppm
): d=221.3, 165.6, 153.4,
3
), 1,7ꢀ (d, J=1.1 Hz, 3H; C13-CH
3
), 1.63±1.51 (m;
max
À1
3
1255, 1ꢀ9ꢀ, 1ꢀ1ꢀ, 99ꢀ, 836, 776 cm ; MS (7ꢀ eV, EI): m/z (%): 847 (1)
M] , 79ꢀ (ꢀ.5), 715 (ꢀ.5), 658 (1), 56ꢀ (1), 526 (ꢀ.5), 428 (4), 325 (1), 282
(1ꢀꢀ) [C H NOSSi] , 213 (4), 147 (6), 131 (9), 75 (3ꢀ); HRMS (EI):
14 24
3
), 1.ꢀ6 (s, 3H; C4-CH ),
3
+
[
3
3 3
)
+
1
3
(
s, 3H, OSi(CH
3
)
2
); C NMR (9ꢀ MHz, CDCl
3
calcd for C45
tal analysis calcd (%) for C45
.65, S 3.78; found: C 61.49, H 9.74, N 1.84, S 3.38.
H81NO
6
SSi
3
847.5ꢀ92, found 847.5ꢀ81 (+1.1 mmu); elemen-
1
6
52.5, 152.5, 141.7, 132.6, 123.9, 118.5, 114.8, 1ꢀ7.8, 1ꢀ6.2, 78.7, 76.3, 69.ꢀ,
2.ꢀ, 52.5, 45.6, 35.6, 32.5, 3ꢀ.9, 25.8, 23.8, 21.1, 18.9, 18.2, 18.1, 14.ꢀ, 13.9,
H
81NO
6
SSi (847.51): C 63.7ꢀ, H 9.62, N
3
1
À4.6, À4.9 ppm; IR (film): n˜ max =3388, 293ꢀ, 2857, 1693, 15ꢀ8, 1471, 1387,
À1
1
252, 1188, 1ꢀ72, 1ꢀ1ꢀ, 99ꢀ, 837, 777 cm ; MS (7ꢀ eV, EI): m/z (%): 619
(3S,6S,7S,13Z,16S,17E)-3,7,16-Tri[(tert-butyldimethylsilyl)oxy]-
+
+
(
(
ꢀ.ꢀ3) [M] , 586 (ꢀ.ꢀ2), 545 (ꢀ.ꢀ7) [MÀtBu] , 5ꢀ1 (ꢀ.ꢀ3), 486 (ꢀ.ꢀ1), 47ꢀ
4,4,6,13,17-pentamethyl-18-(2-methyl-1,3-thiazol-4-yl)-13,17-heptadeca-
dien-furan-5-oxoheptanoic acid (16): PDC (3.39 g, 8 mmol, 45 equiv) in
DMF (1ꢀ mL) was added to a solution of alcohol 15 (17ꢀ mg, ꢀ.2 mmol)
in DMF (3mL). The reaction mixture was stirred at room temperature
for 19 h. The solution was filtered twice over silica gel (pentane/ether=
ꢀ.12), 446 (ꢀ.8), 43ꢀ (ꢀ.32), 388 (1), 328 (ꢀ.32), 314 (ꢀ.88), 282 (1ꢀꢀ)
+
[
C
14
H
24NOSSi] , 226 (1), 182 (4), 151 (4), 1ꢀꢀ (5), 73(2ꢀ); HRMS (EI):
calcd for C33
analysis calcd (%) for C33
.17; found: C 61.86, H 8.69, N 2.92, S 4.77.
3S,6S,7S,13Z,16S,17E)-1,3,7,16-Tetra[(tert-butyldimethylsilyl)oxy]-
,4,6,13,17-pentamethyl-18-(2-methyl-1,3-thiazol-4-yl)-13,17-heptadeca-
dien-furan-5-one (14): 2,6-Lutidine (36 mL, ꢀ.31 mmol, 9.6 equiv) was
added to a solution of triol 13 (2ꢀ.ꢀ mg, 32 mmol) in CH Cl (1 mL). The
H53NO
6
SSi 619.3363, found 619.3373 (-1.3 mmu); elemental
H
53NO
6
SSi (619.34): C 63.94, H 8.62, N 2.26, S
5
4:1). Flash chromatography (pentane/Et
2
O=4:1) of the residue afforded
acid 16 (138 mg, 8ꢀ%) as a yellow oil.
(
4
2
D
ꢀ
1
[a] =À 1.6 (c=1, CHCl
3
); H NMR (36ꢀ MHz, CDCl ): d=6.92 (s, 1H;
3
3
H-5’), 6.52 (s, 1H; H-18), 5.91 (d, J=3Hz, 1H; CH furyl, H-9), 5.8ꢀ (d,
J=3Hz, 1H; CH furyl, H-1ꢀ), 5.29±5.28 (m, 1H; H-14), 4.65 (d, J=
9.6 Hz, 1H; H-7), 4.25 (dd, J=5.6 Hz, J=4.1 Hz, 1H; H-3), 4.16±4.13
(m, 1H; H-16), 3.5ꢀ±3.42 (m; 1H; H-6), 3.31 (d, J=15.5 Hz, 1H; H-12),
3.22 (d, J=15.3Hz, 1H; H-12), 2.73(s, 3H; C2 ’-CH
H-2, H-15), 1.96 (d, J=1 Hz, 3H; C17-CH
C13-CH
ꢀ.85, ꢀ.83(3s, 3î 9H, OSiC(CH
3
3
2
2
3
3
mixture was cooled to À5ꢀ8C and TBSOTf (34 mL, ꢀ.15 mmol, 4.8 equiv)
was added. The mixture was stirred for an additional hour. The solvent
was poured directly on the column and the residue was purified by flash
2
2
3
), 2.45±2.25 (m, 4H;
4
4
chromatography (pentane/Et
2
O=2ꢀ:1). The tetrakis silyl ether 14
3
), 1,66 (d, J=ꢀ.9 Hz, 3H;
), 1.ꢀꢀ (s, 3H; C4-CH ) , ꢀ.89,
3 3
) ), ꢀ.63(s, 3H ; C4-CH 3), ꢀ.ꢀ6, ꢀ.ꢀ3,
3
(
22 mg, 71%) was obtained as a colorless oil.
3
), 1.2ꢀ (d, J=6.7 Hz, 3H; C6-CH
3
3
2
ꢀ
1
[
a] =À 7.9 (c=1, CHCl
3
); H NMR (36ꢀ MHz, CDCl
3
): d=6.91 (s, 1H;
D
1
3
3
ꢀ.ꢀ2, ꢀ.ꢀꢀ, Àꢀ.ꢀꢀ, Àꢀ.1 ppm (6 s, 6î 3H; OSi(CH ) ); C NMR (9ꢀ MHz,
H-5’), 6.46 (s, 1H; H-18), 5.89 (d, J=3Hz, 1H; CH furyl, H-9), 5.76 (d,
3 2
3
3
CDCl ): d=216.8, 174.9, 165.2, 153.1, 153.ꢀ, 153.ꢀ, 143.1, 132.6, 123.7,
J=3.1 Hz, 1H; CH furyl, H-1ꢀ), 5.29±5.25 (m, 1H; H-14), 4.6 (d, J=
3
3
3
118.4, 114.7, 1ꢀ8.3, 1ꢀ6.ꢀ, 78.6, 73.3, 7ꢀ.5, 53.6, 48.2, 39.9, 35.5, 3ꢀ.9, 25.9,
9
2
.6 Hz, 1H; H-7), 4.13±4.1ꢀ (m, 1H; H-16), 3.71 (dd, J=7.4 Hz, J=
2
25.8, 25.7, 23.5, 21.5, 18.8, 18.4, 18.2, 16.1, 14.ꢀ, À4.ꢀ, À4.6, À4.9, À5.ꢀ,
.7 Hz, 1H; H-3), 3.66±3.46 (m; 3H; H-1, H-6), 3.33 (d, J=15.5 Hz, 1H;
2
À5.1 ppm; IR (film): n˜ =3285, 293ꢀ, 2857, 1717, 1694, 15ꢀ5,1472, 1388,
H-12), 3.2ꢀ (d, J=15.5 Hz, 1H; H-12), 2.7ꢀ (s, 3H; C2’-CH
3
), 2.35±2.28
max
À1
4
4
1361, 1255, 1ꢀ9ꢀ, 992, 837, 777 cm ; MS (7ꢀ eV, EI): m/z (%): 861 (1)
(
m, 2H; H-15), 1.96 (d, J=1.1 Hz, 3H; C17-CH
H; C13-CH ), 1.51±1.43(m; 2H; H-2), 1.17 (d, J=6.8 Hz, 3H; C6-
CH ), 1.ꢀꢀ (s, 3H; C4-CH ), ꢀ.88, ꢀ.86, ꢀ.86, ꢀ.82 (4 s, 4î 9H,
OSiC(CH ), ꢀ.52 (s, 3H; C4-CH
), ꢀ.ꢀ4, ꢀ.ꢀ3, ꢀ.ꢀ1, ꢀ.ꢀ1, Àꢀ.ꢀꢀ, Àꢀ.ꢀ2
6 s, 6î 3H; OSi(CH ), ꢀ.ꢀꢀ ppm (s, 6H; OSi(CH ); NMR
9ꢀ MHz, CDCl ): d=217.5, 164.3, 153.1, 153.ꢀ, 152.9, 142.9, 132.5, 123.6,
17.5, 114.9, 1ꢀ8.3, 1ꢀ5.8, 78.6, 73.7, 7ꢀ.4, 61.1, 53.6, 48.1, 38.2, 35.4, 3ꢀ.9,
6.ꢀ, 25.9, 25.8, 25.7, 23.5, 23.ꢀ, 19.1, 18.2, 18.2, 18.1, 18.1, 15.6, 14.ꢀ, 13.9,
3
), 1,65 (d, J=1.1 Hz,
+
3
[M] , 8ꢀ4 (1), 729 (1), 672 (2), 56ꢀ (2)
,
428 (4), 282 (1ꢀꢀ)
24NOSSi] , 232 (4), 177 (4), 147 (12), 115 (7), 73 (17); HRMS (EI):
calcd for C45 SSi 861.4885, found 861.4875 (+1 mmu); elemental
analysis calcd (%) for C H NO SSi (861.48): C 62.67, H 9.23, N 1.62,
3
3
+
14
[C H
3
3
H
79NO
7
3
3
)
3
3
1
3
(
(
1
2
3
)
2
3
)
2
C
45 79
7
3
S3.72; found: C 6ꢀ.ꢀꢀ, H 9.ꢀ2, N 3.92, S 3.ꢀ7.
3
(3S,6S,7S,13Z,16S,17E)-3,7,16-Trihydroxy-4,4,6,13,17-pentamethyl-18-
(2-methyl-1,3-thiazol-4-yl)-13,17-heptadecadien-furan-5-oxoheptanoic
acid (17): A solution of trisilylether 16 (16 mg, ꢀ.ꢀ18 mmol) in MeCN/
À3.7, À3.9, À4.6, À4.9, À5.1, À5.1, À5.2, À5.2 ppm; IR (film): n˜ max
=
À1
2
93ꢀ, 2857, 1695, 1472, 1388, 1361, 1256, 1ꢀ91, 1ꢀꢀ7, 99ꢀ, 836, 776 cm
;
2
Et O (1:1, 2 mL) at ꢀ8C was treated with aqueous hydrofluoric acid
+
MS (7ꢀ eV, EI): m/z (%): 961 (ꢀ.ꢀ3) [M] , 946 (ꢀ.ꢀ1), 9ꢀ4 (ꢀ.ꢀ2), 829
ꢀ.ꢀ6), 814 (ꢀ.ꢀ1), 772 (ꢀ.ꢀ1), 723(ꢀ.ꢀ2), 698 (ꢀ.ꢀ2), 662 (ꢀ.ꢀ 3) , 647 (ꢀ.ꢀ4),
(28ꢀ mL, 4ꢀ%), ground glass splinters, and the mixture was stirred for
48 h at room temperature. The mixture was then filtered through celite
and the residue washed with MeCN. The reaction mixture was concen-
trated in vacuo to a small volume, and the crude product was purified by
preparative thin-layer chromatography (reverse phase silica gel RP 18,
(
+
6
ꢀ2 (ꢀ.ꢀ4), 56ꢀ (1ꢀ), 453 (2), 428 (8), 338 (7), 282 (1ꢀꢀ) [C14
39 (12), 177 (2), 115 (4), 91 (8), 73 (18); HRMS (EI): calcd for
SSi 961.5957, found 961.5965 (-ꢀ.8 mmu); elemental analysis
calcd (%) for C51 SSi (962.71): C 63.63, H 9.95, N 1.45, S 3.33;
found: C 6ꢀ.34, H 9.67, N 1.94, S 3.1ꢀ.
H24NOSSi] ,
2
C
51
H
95NO
6
4
H
95NO
6
4
2% MeOH in CH
2 2
Cl ) to afford pure trihydroxy acid 17 (4.4 mg, 47%;
2.4 mg, 25%, ratio 2:1) as a yellow oil.
3222
¹ 2ꢀꢀ4 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 3217 ± 3224

Synthesis of Furano-Epothilone D
3217 ± 3224
2
D
ꢀ
1
13
Major isomer 17a: [a] =À3 8 c( =ꢀ.1, CHCl
3
); H NMR (36ꢀ MHz,
ꢀ.69 ppm (s, 3H; C4-CH
3
); C NMR (9ꢀ MHz, CDCl
3
): d=211.2, 163.7,
3
CDCl
3
): d=6.99 (s, 1H; H-5’), 6.86 (s, 1H; H-18), 6.25 (d, J=3.1 Hz,
H; CH furyl, H-9), 6.ꢀ8 (d, J=3.1 Hz, 1H; CH furyl, H-1ꢀ), 5.29±5.28
m, 1H; H-14), 4.36 (d, J=11.3Hz, 1H; H-7), 4.28±4.19 (m, 1H; H-16),
.ꢀ7 (dd, J=1ꢀ.ꢀ Hz, J=2.1 Hz, 1H; H-3), 3.45 (d, J=15.ꢀ Hz, 1H; H-
139.5, 131.4, 127.9, 124.1, 12ꢀ.1, 8ꢀ.6, 75.8, 74.1, 48.3, 43.5, 24.4, 2ꢀ.9, 19.6,
3
+
1
19.3, 16.6, 12.7 ppm; MS (7ꢀ eV, EI): m/z (%): 483(1ꢀꢀ) [ MÀH
2
O] , 468
3
(
4
1
(5), 396 (5), 342 (7), 324 (41), 277 (6), 256 (11), 219 (12), 2ꢀ4 (29);
3
3
2
HRMS (EI): calcd for C27
mmu).
H
35NO
6
S 5ꢀ1,2185, found 483.2ꢀ79 (ÀH
2
O) (ꢀ.ꢀ
2
2), 3.27 (d, J=15 Hz, 1H; H-12), 3.ꢀ3±2.99 (m; 1H; H-6), 2.74 (s, 3H;
C2’-CH
3
), 2.62±2.36 (m, 4H; H-2, H-15), 1.97 (s, 3H; C17-CH
), 1.2ꢀ (s, 3H; C4-CH ), 1.ꢀ8 (s, 3H; C4-CH ), ꢀ.96 ppm (d,
); C NMR (9ꢀ MHz, CDCl ): d=216.8, 173.1,
3
), 1,7ꢀ (s,
Tubulin polymerization assay: The samples were prepared directly in
.5 mL optical glass cuvettes at ꢀ8C which contained aqueous ™Mes
buffer∫ [ꢀ.9ꢀꢀ mL (ꢀ.1m 2-(morpholino)ethanesulfonic acid (MES), 1mm
ethyleneglycol-bis-(b-aminoethylether)-N,N,N’,N’-tetraacetic acid
EGTA) ꢀ.5 mm MgCl pH 6.6)], guanosine 5’-triphosphate (GTP;
ꢀ mL, 1ꢀꢀmm in double distilled water), and tubulin (1ꢀꢀ mL, 8±
3
H; C13-CH
3
3
3
1
3
13
J=6.6 Hz, 3H; C6-CH
3
3
1
7
66.2, 152.9, 152.ꢀ, 142.8, 135.2, 122.4, 117.ꢀ, 114.ꢀ, 1ꢀ8.3, 1ꢀ7.4, 8ꢀ.5,
7.9, 75.7, 48.6, 43.7, 35.8, 34.5, 3ꢀ.9, 23.6, 19.6, 19.4, 18.1, 16.ꢀ, 1ꢀ.5 ppm;
(
1
1
2
,
IR (film): n˜ max =3121, 2967, 1715, 1556, 1465, 1376, 1247, 1191, 1ꢀ63,
À1
+
1
4
ꢀ14, 9ꢀ9, 793, 732 cm ; MS (7ꢀ eV, EI): m/z (%): 5ꢀ1 (4) [MÀH
2
O] ,
À1
ꢀ mgmL in aqueous ™Mes buffer∫). The cuvettes were thoroughly agi-
83 (5), 413 (1), 375 (1), 342 (2) , 334 (5), 256 (8), 2ꢀ4 (8), 175 (86), 168
tated and immediately placed in a Cary 3ꢀꢀ Bio spectrophotometer
Varian), preheated at 378C, alongside a blank sample containing aque-
(
7
1ꢀꢀ), 14ꢀ (1ꢀ), 113(12), 97 (1ꢀ); HRMS (EI): calcd for C 27H37NO S
(
5
19.229ꢀ, found 5ꢀ1.2185 (ÀH
2
O) (+ ꢀ.1 mmu).
ous ™Mes buffer∫ (ꢀ.99ꢀ mL) and GTP (1ꢀ mL, 1ꢀꢀmm in double distilled
water) and the absorbance at l 35ꢀ nm was recorded. When the absorb-
ance reached a plateau (after 15 min), CaCl (1ꢀ mL, 4ꢀꢀmm in double
2
2
ꢀ
1
Minor isomer 17b: [a] =À18 (c=ꢀ.1, CHCl
3
); H NMR (36ꢀ MHz,
D
3
CDCl
3
): d=6.98 (s, 1H; H-5’), 6.69 (s, 1H; H-18), 6.ꢀ4 (d, J=3.1 Hz,
3
1
H; CH furyl, H-9), 5.97 (d, J=3.1 Hz, 1H; CH furyl, H-1ꢀ), 5.41±5.35
distilled water) was added to each cuvette. After another 15 min, a mini-
mum absorbance was reached and the candidate drug in DMSO (2.5mm)
was added to the cuvettes in portions every 15 min and thoroughly
shaken to give final concentrations of ꢀ.5, 1.ꢀ, 2.ꢀ, 5.ꢀ, 1ꢀ, and 2ꢀmm, re-
spectively (final concentrations of the candidate drug in the assay). The
results were compared to the untreated control (using the same quanti-
ties of DMSO without the candidate drug) to assess the relative change
in absorbance due to microtubule assembly. The results are presented as
ED5ꢀ and ED9ꢀ which correspond to the dosage of candidate drug re-
quired to induce 5ꢀ% and 9ꢀ% microtubule assembly.
3
(
m, 1H; H-14), 5.23(d, J=7.2 Hz, 1H; H-7), 4.28±4.25 (m, 1H; H-16),
3
3
4
.ꢀꢀ (dd, J=1ꢀ.1 Hz, J=2.1 Hz, 1H; H-3), 3.35 (s, 2H; H-12), 3.33±3.31
), 2.6ꢀ±2.54 (m, 1H; H-2), 2.4ꢀ±2.36
m, 3H, H-2, H-15), 1.98 (s, 3H; C17-CH ), 1,76 (s, 3H; C13-CH ), 1.2ꢀ
s, 3H; C4-CH ), 1.ꢀ4 (s, 3H; C4-CH ), ꢀ.99 ppm (d, J=6.8 Hz, 3H; C6-
); C NMR (9ꢀ MHz, CDCl ): d=212.2, 173.ꢀ, 166.ꢀ, 154.ꢀ, 148.ꢀ,
(
m; 1H; H-6), 2.71 (s, 3H; C2’-CH
3
(
(
3
3
3
3
3
1
3
CH
3
3
1
3
2
43.ꢀ, 134.6, 122.9, 118.1, 115.ꢀ, 112.ꢀ, 1ꢀ6.2, 77.9, 74.9, 74.5, 49.9, 42.9,
5.9, 34.1, 31.ꢀ, 24.2, 2ꢀ.7, 19.4, 18.1, 14.7, 1ꢀ.3; IR (film): n˜ max =34ꢀ5,
926, 1715, 1549, 151ꢀ, 1459, 1378, 1143, 913, 84ꢀ, 796, 733 cm ; MS
À1
+
(
(
(
7ꢀ eV, EI): m/z (%): 5ꢀ1 (3) [MÀH
2
O] , 483 (13), 448 (4), 412 (2), 375
2), 342 (4) , 334 (7), 324 (1ꢀ), 282 (5), 256 (9), 233 (13), 2ꢀ4 (16), 185
18), 175 (76), 168 (1ꢀꢀ), 147 (42), 97 (22); HRMS (EI): calcd for
C
27
H
37NO
7
S 519.229ꢀ, found 5ꢀ1.2188 (ÀH O) (Àꢀ.3mmu).
2
(
3S,6S,7S,13Z,16S,17E)-3,7-Dihydroxy-4,4,6,13-tetramethyl-17-[methyl-
Acknowledgement
(
2-methyl-1,3-thiazol-4-yl)-vinyl]-11,16-dioxa-bicyclo[13.2.1]octadeca-
8
7
6
,10,13-trien-1,5-dione (18): A solution of trihydroxy acid 17a (4.1 mg,
.8 mmol) in THF (ꢀ.5 mL) at ꢀ8C was treated with Et N (7 mL, 47 mmol,
.ꢀ equiv) and 2,4,6-trichlorobenzoyl chloride (6 mL, 39 mmol, 5.ꢀ equiv).
This work was supported by the Fonds der Chemischen Industrie. We
thank the European Commission for financial support (IHP network
grant: ™Design and synthesis of novel microtubule stabilizing anticancer
agents∫).
3
The reaction mixture was stirred at ꢀ8C for 15 min and then added by sy-
ringe pump over a period of 1 h to a solution of 4-DMAP (9.6 mg, 78
mmol, 1ꢀ equiv) in toluene (8 mL) at 258C. The reaction mixture was stir-
red for 1 h, concentrated in vacuo to a small volume and filtered through
silica gel. The residue was washed with ether and the resulting solution
was concentrated to a small volume. The crude product was purified by
preparative thin-layer chromatography (reverse phase silica gel RP 18,
[
1] a) G. Hˆfle, N. Bedorf, H. Steinmetz, D. Schomburg, K. Gerth, H.
Reichenbach, Angew. Chem. 1996, 108, 1671±1673; Angew. Chem.
Int. Ed. Engl. 1996, 35, 1567±1569; b) K. Gerth, N. Bedorf, G.
Hˆfle, H. Irschik, H. Reichenbach, J. Antibiot. 1996, 49, 56ꢀ±563.
2] a) D. Schinzer, Eur. Chem. Chron. 1996, 1, 7±1ꢀ; b) M. Kalesse,
Eur. Chem. Chron. 1997, 2, 7±11; c) L. Wessjohann, Angew. Chem.
1997, 109, 739±742; Angew. Chem. Int. Ed. Engl. 1997, 36, 715±718;
d) K. C. Nicolaou, F. Roschangar, D. Vourloumis, Angew. Chem.
2
5
% MeOH in CH
1%).
2 2
Cl ) to afford pure furano-epothilone 18a (2 mg,
[
2
ꢀ
1
Major isomer 18a: [a] =À24 (c=ꢀ.15, CHCl
3
); H NMR (36ꢀ MHz,
D
6 6
C D ): d=7.ꢀ2 (s, 1H; H-18), 6.6ꢀ (s, 1H; H-5×), 6.ꢀ4 (m, 1H; H-16),
3
3
5
.87 (d, J=3.1 Hz, 1H; CH furyl, H-9), 5.76 (d, J=3.ꢀ Hz, 1H; CH
1
998, 110, 212ꢀ±2153; Angew. Chem. Int. Ed. Engl. 1998, 37, 2ꢀ14±
3
furyl, H-1ꢀ), 5.44 (m, 1H; H-14), 4.ꢀ6 (d, J=11.2 Hz, 1H; H-7), 3.89
2
ꢀ45.
3
3
2
(
dd, J=11.2 Hz, J=2.3 Hz, 1H; H-3), 3.43 (d, J=14.5 Hz, 1H; H-12),
[
3] a) A. Balog, D. Meng, T. Kamenecka, P. Bertinato, D.-S. Su, E. J.
Sorensen, S. J. Danishefsky, Angew. Chem. 1996, 108, 2976±2978;
Angew. Chem. Int. Ed. Engl. 1996, 35, 28ꢀ1±28ꢀ3; b) D. Meng, P.
Bertinato, A. Balog, D.-S. Su, T. Kamenecka, E. J. Sorensen, S. J.
Danishefsky, J. Am. Chem. Soc. 1997, 119, 1ꢀꢀ73±1ꢀꢀ92; c) Z.
Yang, Y. He, D. Vourloumis, H. Vallberg, K. C. Nicolaou, Angew.
Chem. 1997, 109, 17ꢀ±172; Angew. Chem. Int. Ed. Engl. 1997, 36,
2
3
.2ꢀ (m, 1H, H-15), 2.6ꢀ (d, J=14.9 Hz, 1H; H-12), 2.63±2.56 (m; 2H;
H-6, H-15), 2.38±2.33 (m, 1H; H-2), 2.27 (s, 3H; C2’-CH ), 2.19 (s, 3H;
), 1.93(dd, J=12.2 Hz, J=2.47 Hz, 1H, H-2), 1,37 (s, 3H;
3
3
3
C17-CH
C13-CH
3
3
3
), 1.ꢀ5 (d, J=6.6 Hz, 3H; C6-CH
3
), ꢀ.87 (s, 3H; C4-CH
3
),
1
3
ꢀ
1
8
1
1
4
5
.66 ppm (s, 3H; C4-CH
3
); C NMR (9ꢀ MHz, CDCl ): d=2ꢀ9.3, 171.2,
3
64.3, 153.8, 153.5, 152.4, 136.6, 133.4, 12ꢀ.9, 119.6, 116.2, 1ꢀ6.2, 1ꢀ5.7,
1.6, 78.ꢀ, 76.7, 48.7, 43.ꢀ, 36.1, 32.ꢀ, 29.8, 24.1, 19.2, 19.1, 18.9, 16.ꢀ,
ꢀ.7 ppm; IR (film): n˜ max =3416, 2864, 1731, 1452, 1373, 1257, 1184, 1131,
1
66±168; d) K. C. Nicolaou, Y. He, D. Vourloumis, H. Vallberg, F.
Roschangar, F. Sarabia, S. Ninkovic, Z. Yang, J. I. Trujillo, J. Am.
Chem. Soc. 1997, 119, 796ꢀ±7973; e) D. Schinzer, A. Limberg, A.
Bauer, O. M. Bˆhm, M. Cordes, Angew. Chem. 1997, 109, 543±544;
Angew. Chem. Int. Ed. Engl. 1997, 36, 523±524; f) K. C. Nicolaou, S.
Ninkovich, F. Sarabia, Z. Yang, Angew. Chem. 1997, 109, 539±54ꢀ;
Angew. Chem. Int. Ed. Engl. 1997, 36, 525±527; g) K. C. Nicolaou,
S. Ninkovich, F. Sarabia, D. Vourloumis, Y. He, H. Vallberg,
M. R. V. Finlay, Z. Yang, J. Am. Chem. Soc. 1997, 119, 7974±7991;
h) R. E. Taylor, G. M. Galvin, K. A. Hilfiker, Y. Chen, J. Org.
Chem. 1998, 63, 958ꢀ±9583; i) S. C. Sinha, C. F. Barbas III, R. A.
Lerner, Proc. Natl. Acad. Sci. USA 1998, 95, 146ꢀ3±146ꢀ8; j) N.
Yoshikawa, Y. M. A. Yamada, J. Das, H. Sasai, M. Shibasaki, J. Am.
Chem. Soc. 1999, 121, 4168±4178; k) D. Sawada, M. Shibasaki,
À1
+
ꢀ94, 1ꢀ1ꢀ, 796 cm ; MS (7ꢀ eV, EI): m/z (%): 483(1ꢀꢀ) [ MÀH
2
O] ,
6
39 (9), 396 (4), 354 (2), 324 (6ꢀ); HRMS (EI): calcd for C27H35NO S
ꢀ1,2185, found 483.2ꢀ79 (ÀH O) (Àꢀ.3mmu).
2
2
ꢀ
1
Minor isomer 18b: [a] =À33 (c=ꢀ.ꢀ6, CHCl
3
); H NMR (36ꢀ MHz,
D
3
6 6
C D ): d=6.92 (s, 1H; H-18), 6.59 (s, 1H; H-5×), 6.ꢀ9 (d, J=3.3 Hz, 1H;
3
CH furyl, H-9), 5.66 (d, J=3.ꢀ Hz, 1H; CH furyl, H-1ꢀ), 5.42±5.38 (m,
1
3
H; H-16), 5.11±5.ꢀ7 (m, 1H; H-14), 4.96 (d, J=6.5 Hz, 1H; H-7), 3.74
3
3
2
(
dd, J=9.8 Hz, J=2.7 Hz, 1H; H-3), 3.45 (d, J=14.5 Hz, 1H; H-12),
2
3
1
.19±3.ꢀ9 (m, 1H, H-15), 2.86±2.81 (m; 1H; H-6), 2.5ꢀ (d, J=15.1 Hz,
H; H-12), 2.56±2.48 (m, 1H; H-2), 2.41 (s, 3H; C17-CH ), 2.28 (s, 3H;
), 2.21±2.15 (m, 1H, H-2), 2.13±2.1ꢀ (m, 1H, H-15), 1,6ꢀ (s, 3H;
3
C2×-CH
C13-CH
3
3
3
), ꢀ.99 (d, J=6.9 Hz, 3H; C6-CH
3
), ꢀ.71 (s, 3H; C4-CH
3
),
Chem. Eur. J. 2004, 10, 3217 ± 3224
www.chemeurj.org
¹ 2ꢀꢀ4 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3223

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Received: February 6, 2ꢀꢀ4
Published online: May 6, 2ꢀꢀ4
3224
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www.chemeurj.org
Chem. Eur. J. 2004, 10, 3217 ± 3224