Apoptolidinone A: Synthesis of the apoptolidin a aglycone

Article abstract of DOI:10.1002/chem.200600461

An efficient stereocontrolled synthesis of apoptolidinone A, the aglycone of apoptolidin A is described. The synthetic strategy relies on a cross coupling between C11/C12 of a northern half (C1-C11) and a southern part (C12-C28) followed by a ring-size selective macrolactonization. Key steps for the introduction of the southern half stereocenters are a stereoselective aldol reaction, a substrate controlled dihydroxylation and a chelation-controlled Grignard/aldehyde addition. The conjugated triene of the northern half was built up successively by E-selective Wittig reactions. L-Malic acid was chosen as the chiral pool source for the C8/C9 stereocenters. The final cleavage of the silyl ethers and the conversion of the C21 methyl ketal into the hemiketal was achieved by HF-pyridine.

Full text of DOI:10.1002/chem.200600461

DOI: 10.1002/chem.200600461
Apoptolidinone A: Synthesis of the Apoptolidin A Aglycone
[a]
Julia Schuppan,Hermut Wehlan,Sonja Keiper,and Ulrich Koert*
Abstract: An efficient stereocontrolled
synthesis of apoptolidinone A, the
aglycone of apoptolidin A is described.
The synthetic strategy relies on a cross
coupling between C11/C12 of a north-
ern half (C1–C11) and a southern part
(C12–C28) followed by a ring-size se-
lective macrolactonization. Key steps
for the introduction of the southern
half stereocenters are a stereoselective
aldol reaction, a substrate controlled
dihydroxylation and a chelation-con-
trolled Grignard/aldehyde addition.
The conjugated triene of the northern
half was built up successively by E-se-
lective Wittig reactions. l-Malic acid
was chosen as the chiral pool source
for the C8/C9 stereocenters. The final
cleavage of the silyl ethers and the con-
version of the C21 methyl ketal into
the hemiketal was achieved by HF·pyr-
idine.
Keywords: apoptolidin · dihydroxy-
lation · natural products · stereose-
lective synthesis · total synthesis
Introduction
Natural products that selectively induce apoptosis (program-
med cell death) in tumor cells have a considerable potential
for medicinal chemistry.[1] Among the numerous naturally
occurring apoptosis inducers, apoptolidins hold a prominent
position. Apoptolidin A (1) was isolated by Hayakawa et al.
from Nocardiopsis sp. in 1997 (Figure 1).[2] It selectively in-
duces apoptosis in rat glia cells transformed with the E1A
oncogene (IC50 =11 ngmLꢀ1) but not in untransformed cell
lines.[3] Apoptolidin A (1) is a 20-membered macrolactone
with a side chain containing a cyclic six-membered hemike-
tal. 6-Deoxy-4-O-methyl-l-glucose is attached to O9 and a
disaccharide consisting of l-olivomycose and d-oleandrose is
linked to O27. The chemistry and biology of apoptolidin A
(1) was investigated in main part by Khosla[4] and Wender[5]
and its apoptotic activity was correlated with its inhibition
of mitochondrial F0-F1-ATPase. Apoptolidin B (2) and
apoptolidin C (3) differ from 1 by the lack of the C16 hy-
droxyl group and different substituents at C20.[6] The prom-
ising biological properties and the structural challenges of
the apoptolidins evoked synthetic efforts, which culminated
in the total syntheses of apoptolidin A (1) by Nicolaouꢀs
group[7] and our own synthesis.[8] The aglycone of apoptoli-
din A named apoptoldinone A (4) was synthesized besides a
Figure 1. Structures of apoptolidin A (1), apoptolidin B (2), apoptolidin
C (3) and apoptolidinone A (4).
contribution from these laboratories[9] by Sulikowsky,[10]
Crimmins[11] and by Nicolaou.[7] In addition, several valuable
studies on apoptolidins have been published.[12] Here, and in
the following contribution, we report in detail our synthetic
route to the apoptolidins.[13]
[a] Dr. J. Schuppan, Dr. H. Wehlan, Dr. S. Keiper, Prof. Dr. U. Koert
Fachbereich Chemie, Philipps-Universität Marburg
Hans-Meerwein-Strasse, 35032 Marburg (Germany)
Fax : (+49)6421-282-5677
Results and Discussion
Our synthetic plan was first focused on an efficient route to
the aglycone. The retrosynthetic analysis of apoptolidinone
E-mail: koert@chemie.uni-marburg.de
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FULL PAPER
(4) led to two strategic disconnections (Scheme 1): a sp2–sp2
ꢀ
cross-coupling for the C11 C12 bond and a macrolactoniza-
tion to close the 20-membered macrolide. From these con-
siderations resulted a C1–C11 fragment 5 (northern half)
and a C12–C28 fragment 6 (southern half). No protective
group differentiation between the hydroxy groups at C16,
C19 and C20 was chosen, because—based on molecular
model considerations—we expected a ring-size selective
macrolactonization.
Scheme 2. a) [RuCl
TBSCl, imidazole, 288C; ii) DIBAH, CH2Cl2, ꢀ788C; c) Sn
CH2Cl2, ꢀ788C; d) NaBH(OAc)3, HOAc, CH3CN, ꢀ20 ! 258C; e) i)
AlMe3, Me
(MeO)NH·HCl, CH2Cl2, ꢀ108C; ii) TMSCl, imidazole, 08C.
(C6H6)]2, (S)-BINAP, H2, MeOH, DMF, 958C; b) i)
AHCTREUNG
AHCTREUNG
AHCTREUNG
Scheme 1. Retrosynthetic analysis of apoptolidinone A (4).
The starting point of the synthesis of the southern half
was b-ketoester 7 (Scheme 2). Asymmetric hydrogenation
with Ru-(S)-BINAP[14] gave b-hydroxyester 8 with 97% ee
(determined by HPLC). After TBS protection, the ester was
reduced to aldehyde 9. A stannous triflate-mediated syn-
stereoselective Evans aldol reaction[15] of b-ketoimide 10[16]
with aldehyde 9 gave aldol product 11 in excellent yield
with 96:4 diastereoselectivity. The relative configuration of
11 was proven by X-ray structure analysis.[12a] The anti-selec-
tive reduction of b-ketoimide 11 provided b-hydroxy imide
12 with a > 95:5 diastereoselectivity.[17] The use of NaBH-
ACHTREUNG(OAc)3 was superior to Me4NBHACHTRE(UNG OAc)3 with respect to
yield and ease of workup in > 20 mmol scale. Transamida-
tion of 12 to the Weinreb amide[18] and subsequent TMS
protection gave compound 13. The free hydroxy group in 12
is a prerequisite for the successful transamidation due to the
precomplexation of the aluminium reagent.[19]
Scheme 3. a) (E)-1-bromo-1-propene, tBuLi, Et2O, ꢀ788C; b) PPTS,
MeOH, CH2Cl2, 08C; c) AD-mix a, tBuOH/H2O, 0 8C, 16a/16b 3:1; d)
PPTS, MeOH, CH2Cl2, 08C; e) [K2OsO2(OH)4], NMO, THF/H2O/
tBuOH, 208C; f) 2,2-dimethoxypropane, CSA, 08C. PPTS=pyridinium
p-toluenesulfonate, NMO=N-methylmorpholine-N-oxide, CSA=cam-
phorsulfonic acid.
The introduction of the C19–C20 diol was intended by a
dihydroxylation of a corresponding (E)-alkene precursor.
Exploratory studies towards a stereocontrolled dihydroxyla-
tion[20] of this alkene were conducted with an (E)-propenyl
model system first (Scheme 3). For this purpose, Weinreb
amide 13 was allowed to react with (E)-propenyl lithium to
produce a,b-unsaturated ketone 14. The latter could be con-
verted smoothly into cyclic methyl ketal 15 by treatment
with pyridinium p-toluene sulfonate (PPTS) in MeOH. The
reagent controlled dihydroxylation of alkenone 14 with AD-
mix a gave a 3:1 mixture of diols 16a and 16b favouring the
desired diastereomer 16a. The use of AD-mix b resulted in
a 1:8 diastereoselectivity in unfavor of 16a. The diastereo-
meric mixture of diols 16a/16b was transformed into the
cyclic methyl ketals 17a/17b, which could be easily separat-
ed by chromatography. The modest selectivity for the re-
agent-controlled dihydroxylation of 14 led us to investigate
the stereocontrolled dihydroxylation of alkene 15. Com-
pound 15 gave under substrate-controlled conditions
([K2OsO2(OH)4], NMO) a 2:1 mixture of 17a and 17b.
Thus the stereocenters of the THP ring direct the dihydrox-
ylation into the desired direction. Attempts to improve the
stereoselectivity by use of AD-mix a or b were not success-
ful. Diol 17a was converted into acetonide 18. An X-ray
structure of 18[12a] verified the stereochemical assignments of
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7365

U. Koert et al.
the dihydroxylation step and the earlier aldol reaction (9 +
10 ! 11).
dure[25] the corresponding 5-lithio-2,3-dihydrofuran was con-
verted into the cyclic a-alkoxyalkenylcuprate, which upon
dyotropic rearrangement and subsequent methylation gave
alcohol 28. From 28, bromide 29 was obtained. Aldehyde 30
was obtained from 26 by hydrogenolytic benzyl ether cleav-
age followed by Dess–Martin oxidation of the resulting alco-
hol. Bromide 29 could be converted into the corresponding
Grignard reagent, which was allowed to react with aldehyde
30 to yield alcohol 31. The stereoselectivity of this chela-
tion-controlled[26] reaction was determined to be 96:4 by
1HNMR. Noteworthy for the Grignard reaction is the com-
patibility of the stannyl group with the organomagnesium
functionality.
Having collected information about the dihydroxylation
from the model system we turned back on the route towards
apoptolidinone A (Scheme 4). Epoxide 19[21] was opened at
Scheme 4. a) i) LiCCSiMe3, BF3·OEt2, TH F,ꢀ788C; ii) LiHMDS, MeI,
THF, 408C; iii) Bu4NF, THF, 08C; b) [Cp2ZrCl2], LiEt3BH, NIS, THF,
208C; c) 21, tBuLi, Et2O, ꢀ788C, then 13; d) PPTS, MeOH/CH2Cl2 1:1,
08C; e) TBS triflate, 2,6-lutidine, CH2Cl2; f) [K2OsO2(OH)4], NMO,
Scheme 5. a) Dihydrofuran, tBuLi, ꢀ608C; [Bu3Sn(Bu)CuCN]Li2, TH F,
MeI, ꢀ308C; b) i) MsCl, Et3N, CH2Cl2, 08C; ii) LiBr, acetone, 508C; c) i)
H2, Pd(OH)2/C, EtOAc, 208C, 1 h; ii) Dess–Martin periodinane, pyridine,
CH2Cl2; d) 29, Mg, 1,2-dibromoethane, Et2O, 20 8C, then ꢀ788C addition
of 30.
THF/H2O/tBuOH,
LiHMDS=lithium
0
!
108C; g) Ac2O, pyridine, DMAP, 408C.
hexamethyldisilazide, NIS=N-iodosuccinimide,
PPTS=pyridinium p-toluene sulfonate, DMAP=4-N,N-dimethylamino-
pyridine.
the terminal position with lithiated TMS acetylene.[22] A fol-
lowing methyl ether formation and TMS deprotection gave
alkyne 20 in 66% overall yield. A hydrozirconation/iodoly-
sis[23] provided (E)-alkenyl iodide 21. Iodine–lithium ex-
change of 21 followed by acylation with Weinreb amide 13
and treatment of the resulting ketone 22 with PPTS in
MeOHgave methyl ketal 23. After TBS protection to 24
the substrate controlled dihydroxylation gave diol 25 with a
6:1 stereoselectivity, which was converted into diacetate 26.
The low reactivity of the double bond in 24 required a reac-
tion time of several days at 0–108C. The undesired minor
isomer of the dihydroxylation was separated chromato-
graphically at the diacetate stage.
The synthesis of the C1–C11 fragment (northern half) re-
quired the generation of the C8/C9 stereocenters and the as-
sembly of a conjugated all-trisubstituted triene C2–C7
(Scheme 6). l-malic acid was chosen as the chiral pool
source for the C8/C9 part from which b-hydroxy-g-lactone
32 was prepared.[27] The hydroxy group in 32 was TBS pro-
tected to 33. A linear, successive introduction of the three
double bonds was chosen for the synthesis of the conjugated
triene. Reduction of lactone 33 to the corresponding lactol
followed by a Wittig reaction generated the C6/C7 double
bond. The E-stereoisomer 34 which was formed with a 96:4
selectivity was obtained as a pure stereoisomer after chro-
matography. The primary alcohol in 34 was TES protected
to 35, which could be transformed smoothly via the corre-
sponding aldehyde and a subsequent Wittig olefination into
a,b,g,d-unsaturated ester 36. Preliminary experiments with
the introduction of the third conjugated double bond
The last part of the synthesis of the southern half 31 re-
quired the introduction of the missing C12–C15 fragment
(Scheme 5). The stereoselective synthesis of the trisubstitut-
ed alkenyl stannane started from dihydrofuran. Using the
Ardisson/Pancrazi modification[24] of Kocienskisꢀs proce-
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Apoptolidin A Aglycone
FULL PAPER
Scheme 6. a) tBuMe2SiOTf, 2,6-lutidine, CH2Cl2, 08C; b) i) DIBAH,
CH2Cl2, ꢀ788C; ii) Ph3P=CCH3CO2Et, toluene, 1008C; c) Et3SiCl, imida-
zole, CH2Cl2, 08C; d) i) DIBAH, toluene, ꢀ788C; ii) MnO2, CH2Cl2,
408C; iii) Ph3P=CCH3CO2Et, toluene, 1008C; e) camphorsulfonic acid,
MeOH/CH2Cl2, 08C; f) i) Dess–Martin periodinane, pyridine, CH2Cl2,
208C; ii) CrCl2, CH I, cat. hydroquinone, THF, 1,4-dioxane, 208C; g) i)
3
DIBAH, toluene, ꢀ788C; ii) MnO2, CH2Cl2, 208C; iii) Ph3P=
CCH3CO2Et, toluene, 1008C; DIBAH=diisobutylaluminium hydride.
showed that the conjugated triene system is light-sensitive
and can isomerize to a mixture of side products. For this
reason, the introduction of the C2/C3 double bond was post-
poned to a later stage and the synthesis of the C10/C11 al-
kenyl iodide was addressed next. The primary TES ether in
36 could be cleaved chemoselectively with camphorsulfonic
acid at 08C. The resulting alcohol 37 was Dess–Martin oxi-
dized to the corresponding aldehyde, which could be con-
verted into (E)-alkenyl iodide 38 following Takaiꢀs proce-
dure.[28] Attempts to prepare an alkenyl stannane from 36
via Corey–Fuchs reaction[29] of the aldehyde and Pd-mediat-
ed hydrostannylation[30] of the resulting alkyne led to a 4:1
mixture of regioisomeric alkenyl stannanes. This lack of re-
gioselectivity led us to reject the alkenyl stannane option for
the northern half. The final step for the northern half intro-
duced the C2/C3 double bond by another ester/aldehyde/
Wittig sequence (38 ! 39). This reaction and all following
steps were performed in amber colored glassware with ex-
clusion of bright daylight to prevent the triene photoisome-
rization. The photosensitivity was observed only for the acy-
clic intermediates 39, 40, and 41 but not for the ring-closed
macrolides.
Scheme 7. a)
CuI-thiophene-2-carboxylate,
N-methylpyrrolidinone,
ꢀ108C; b) LiOH, THF/MeOH/H2O, 40 8C; c) 2,4,6-trichlorobenzoyl
chloride, Et3N, THF, 258C, then DMAP, toluene, 808C; d) HF·pyridine,
THF, 0 ! 258C.
gave an 81% yield of the desired coupling product 40 under
very mild conditions (ꢀ108C, 1 h). It is instructive to com-
pare this cross-coupling step with the related reaction from
Nicolaouꢀs synthesis.[7] In Nicolaouꢀs case the Pd coupling
worked fine for the combination monosubstituted alkenyl-
stannane/disubstituted alkenyl iodide. In our case a CuI cou-
pling was required for the combination monosubstituted al-
kenyl iodide/disubstituted alkenylstannane.
The following hydrolysis of the ethyl ester and the two
acetates in 40 with LiOH in THF/MeOH/H2O required
longer reaction times (28 h) and elevated temperatures
(408C). Trihydroxy acid 41 was obtained in 87% yield. The
macrolactonization of 41 according to the modified Yamagu-
chi procedure[33] produced 20-membered macrolide 42 in
74% yield. The ring-size selectivity of this step is remarka-
ble. No 21-membered lactone could be identified. Treatment
of 42 with HF·pyridine cleaved all silyl ethers and converted
the C21 methyl ketal into the hemiketal. The target com-
pound apoptolidinone A (4) was obtained in 55% yield.
The aglycone alone exhibited no antitumor activity (IC50
> 10 mm) against several cancer cell lines (A431, MeTu,
Hecat).
The final part of the synthesis focused on the coupling of
the southern and the northern half as well as on the macro-
lactonization (Scheme 7). Several attempts for a Pd0-mediat-
ed Stille coupling[31] between 31 and 39 were disappointing
(yield < 30% at prolonged reaction times and 608C). In
contrast, the use of 2 equiv of CuI-thiophene carboxylate[32]
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U. Koert et al.
satd aq NH4Cl (150 mL). The aqueous layer was extracted with MTBE
(3ꢂ100 mL). The combined organic layers were washed with brine
(150 mL), dried with Na2SO4, concentrated and the residue was purified
by flash chromatography (400 g silica gel, pentane/MTBE 20:1 ! 5:1) to
yield corresponding silyl ether (13.4 g, 50.9 mmol, 93%) as a colorless oil.
This showed the necessity of the sugar residues for the bio-
activity and motivated us to complete the total synthesis of
apoptolidin A (1) itself. The results of these efforts are de-
scribed in the following manuscript.[13]
1
Rf =0.54 (n-hexane/MTBE 5:1); [a]2D3 =+24.0 (c=1.03, CHCl3); HNMR
(200 MHz, CDCl3): d=0.03, 0.05 (2s, 6H, SiCH3), 0.83 (s, 9H, SiC-
AHCTRE(UNG CH3)3), 2.40 (dd, J=14.8, 4.8 Hz, 1H, 2-H), 2.56 (dd, J=14.8, 7.8 Hz,
Conclusion
1H, 2-H), 3.32 (s, 3H, OCH3), 3.25 (dd, J=9.6, 5.3 Hz, 1H, 4-H), 3.48
(dd, J=9.8, 6.9 Hz, 1H, 4-H), 3.64 (s, 3H, CO2CH3), 4.17–4.29 (m, 1H, 3-
H); 13C NMR (75 MHz, CDCl3): d=ꢀ5.3, ꢀ4.7 (Si-CH3), 17.9 (SiC-
The synthesis of apoptolidinone A (4) described here pro-
vides an efficient synthetic access to this molecular frame-
work. It forms the basis for the attachment of the sugar resi-
dues at C9 and C27 and the total synthesis of apoptolidin A
(1). Although the present route is efficient, it leads to a
methyl ketal at C21. The conversion of this methyl ketal
into the hemiketal in the presence of the acid labile O27 di-
saccharide will be a challenge for the total synthesis of the
natural product itself.
ACHRETGNU(CH3)3), 25.6 (SiCCAHTREU(GN CH3)3), 40.0 (C-2), 51.3 (CO2CH3), 58.9 (OCH3), 68.4
(C-3), 76.5 (C-4), 171.8 (C-1); IR (film): n˜ =2955 (s), 2930 (s), 2858 (s),
1744 (s), 1463 (m), 1438 (m), 1254 (m), 1129 (m), 838 (m), 779 cmꢀ1 (m);
elemental analysis calcd (%) for C12H26O4Si (262.42): C 54.92, H9.99;
found C 54.66, H9.86.
DIBAH reduction: The TBS-protected ester (9.90 g, 37.7 mmol) was dis-
solved in CH2Cl2 (250 mL) and cooled to ꢀ788C. DIBAH(45 mL,
45 mmol, 1.0m in PE) was added via dropping funnel within 2 h, so that
the internal temperature was lower than ꢀ748C. After complete addition
the mixture was stirred for 1 h at ꢀ788C and the reaction was quenched
by addition of MeOH(20 mL). The reaction mixture was added to a sol-
ution of Rochelles salt (1.0m, 700 mL). After 3 h stirring the two layers
were separated and the aqueous layer was extracted with CH2Cl2 (3ꢂ
100 mL). The combined organic layers were dried with MgSO4, concen-
trated and the residue was purified by flash chromatography (260 g silica
gel, pentane/MTBE 10:1) to yield aldehyde 9 (8.02 g, 34.5 mmol, 92%)
as a colorless oil. Rf =0.40 (n-hexane/MTBE 5:1); [a]2D3 =+9.7 (c=1.10,
Experimental Section
General methods: All reactions sensitive to air or moisture were con-
ducted in flame-dried glassware under an atmosphere of dry Argon. THF
and Et2O were distilled from sodium/benzophenone. CH2Cl2, toluene,
hexanes, pyridine, and Et3N were distilled from CaH2. All starting mate-
rials and reagents were used as received unless noted otherwise. Thin
layer chromatography was performed on glass-supported Merck silica gel
60 F254 plates. Spots were visualized by UV light and by heat staining
with 2% molybdophosphoric acid in ethanol. Column chromatography
was performed on Merck silica gel 60 (63–200 mm). Melting points were
measured with a Büchi Melting Point Apparatus and are not corrected.
IR Spectra were measured with a Bruker FT-IR spectrometer. 1Hand
13C NMR spectra were recorded with Bruker spectrometers ARX-200,
AC-300, AV-300, AMX-400, DRX-400, DRX-500, DRX-600. CDCl3 was
used as normal solvent. TMS was used as internal standard. Optical rota-
tions: Perkin–Elmer polarimeter 241, cuvette path length 10 cm; CHCl3
for spectroscopy was filtered over basic aluminium oxide before use. Mi-
croanalysis: CHN rapid, Heraeus. HRMS: Finnigan LTQ FT (ESI).
MTBE = tert-butyl methyl ether; PE = petrol ether (b.p. range 40–
608C.
1
CHCl3); HNMR (200 MHz, CDCl 3): d=0.06, 0.07 (2s, 6H, SiCH3), 0.85
(s, 9H, SiCCAHTRE(UGN CH3)3), 2.45–2.68 (m, 2H, 2-H2), 3.28 (dd, J=10.0, 6.3 Hz,
1H, 4-H), 3.33 (s, 3H, OCH3), 3.39 (dd, J=9.5, 5.3 Hz, 1H, 4-H), 4.23–
4.37 (m, 1H, 3-H), 9.78 (t, J=2.4 Hz, 1H, 1-H); 13C NMR (75 MHz,
CDCl3): d=ꢀ5.3, ꢀ4.8 (SiCH3), 17.7 (SiC
ACHRTNUE(G CH3)3), 25.5 (SiCACHTRE(UGN CH3)3), 48.5
(C-2), 58.7 (OCH3), 66.9 (C-3), 76.3 (C-4), 200.6 (C-1); IR (film): n˜ =
2930 (s), 2858 (s), 1733 (s), 1464 (s), 1362 (m), 1254 (s), 1122 (s), 1006
(m), 838 (s), 778 cmꢀ1 (s).
(4R,2’R,4’S,5’R,7’R)-4-Benzyl-3-(7’-tert-butyldimethylsilyloxy-5’-hydroxy-
8’-methoxy-2’,4’-dimethyl-1’,3’-dioxooctyl)-1,3-oxazolidin-2-one (11): Sn-
AHCTREUNG
ACHTREUNG
was suspended in CH2Cl2 (60 mL) and cooled to ꢀ208C. NEt3 (3.1 mL,
22 mmol) was added and the solution was stirred for 5 min at 208C. Oxa-
zolidinone 10 (5.38 g, 18.6 mmol) in CH2Cl2 (23 mL) was added via drop-
ping funnel to the yellow colored solution. After stirring for 45 min at
ꢀ208C the mixture was cooled to ꢀ788C and aldehyde
9 (4.32 g,
(3R)-3-Hydroxy-4-methoxybutyric acid methylester (8): [RuCl2ACHTER(UNG C6H6)]2
18.6 mmol) in CH2Cl2 (23 mL) was added slowly (internal temperature
< ꢀ758C). The mixture was stirred for 1 h at ꢀ788C and then added to
800 mL of an ice cooled 1:1 mixture of CH2Cl2 and aq NaHSO4 (1m).
After 20 min stirring at 208C the two layers were separated and the
aqueous layer was extracted with CH2Cl2 (3ꢂ100 mL). The combined or-
ganic layers were washed with satd aq NaHCO3 (500 mL), dried with
MgSO4, concentrated and the residue was purified by flash chromatogra-
phy (260 g silica gel, pentane/MTBE 3:2) to yield alcohol 11 (8.86 g,
17.0 mmol, 91%) as a colorless oil. Rf =0.50 (n-hexane/MTBE 3:2);
(126 mg, 0.25 mmol) and (S)-BINAP (255 mg, 0.41 mmol) were dissolved
in DMF (5 mL) and stirred for 15 min at 1158C. After cooling the cata-
lyst solution was transferred into an autoclave. Freshly distilled 4-me-
thoxyacetoacetic acid methylester (7) (9.97 g, 68.2 mmol) was dissolved
in MeOH(30 mL), degassed and then transferred into the high pressure
reaction vessel. The autoclave was filled with hydrogen (6 bar) and the
solution was vigorously stirred for 42 h at 908C. After cooling the sol-
vents were removed and the residue was purified by flash chromatogra-
phy (450 silica gel, pentane/MTBE 1:2) to yield alcohol
8 (9.5 g,
64 mmol, 94%) as a light yellow oil. Rf =0.39 (MTBE); HPLC: tR =
15.2 min (Chiracel-OD-H, 6% iPrOHin n-hexane, 1 mLminꢀ1, 238C);
[a]2D3 =+25.4 (c=1.00, CHCl3); 1HNMR (200 MHz, CDCl 3): d=2.51 (d,
J=6.3 Hz, 2H, 2-H2), 2.93 (d, J=4.3 Hz, 1H, OH), 3.29–3.47 (m, 2H, 4-
H2), 3.37 (s, 3H, OCH3), 3.69 (s, 3H, CO2CH3), 4.11–4.27 (m, 1H, 3-H);
13C NMR (75 MHz, CDCl3): d=37.7 (C-2), 51.0 (CO2CH3), 58.3 (OCH3),
66.2 (C-3), 75.3 (C-4), 171.7 (C-1); IR (film): n˜ =3446 (brs), 2926 (s),
1736 (s), 1439 (s), 1004 (m), 967 cmꢀ1 (m); elemental analysis calcd (%)
for C6H12O4 (148.16): C 48.64, H8.16; found C 48.37, H8.12.
HPLC: tR =15.9 min (Superspher-Si60, 3% iPrOHin
n-hexane,
1.0 mLminꢀ1, 398C); [a]D23 =ꢀ29.5 (c=1.10, CHCl3); 1HNMR (300 MHz,
CDCl3): d=0.08 (2s, 6H, SiCH3), 0.88 (s, 9H, SiCACHTERU(NG CH3)3), 1.21 (d, J=
7.1 Hz, 3H, 4’-CH3), 1.47 (d, J=7.3 Hz, 3H, 2’-CH3), 1.41–1.72 (m, 2H,
6’-H2), 2.77 (dd, J=13.2, 9.8 Hz, 1H, CHPh), 2.79–2.91 (m, 1H, 4’-H),
3.25–3.43 (m, 3H, CHPh, 8-H2), 3.34 (s, 3H, OCH3), 3.99–4.21 (m, 2H,
5’-H, 7’-H), 4.18 (dd, J=9.2, 2.8 Hz, 1H, 5-H), 4.25 (dd, J=8.4, 8.2 Hz,
1H, 5-H), 4.68–4.80 (m, 1H, 4-H), 4.89 (q, J=7.2 Hz, 1H, 2’-H), 7.14–
7.39 (m, 5H, Ph); 13C NMR (75.5 MHz, CDCl3): d=ꢀ5.1, ꢀ4.6 (SiCH3),
11.3 (2’-CH3), 12.8 (4’-CH3), 18.0 (SiCACHTRENGU(CH3)3), 25.8 (SiCCAHTRE(UGN CH3)3), 37.8 (C-
(3R)-3-tert-Butyldimethylsilyloxy-4-methoxybutanal (9): TBS protection:
Alcohol 8 (8.15 g, 55.0 mmol) was dissolved in DMF (80 mL) and cooled
to 08C. Imidazole (8.60 g, 127 mmol) and TBSCl (21.6 g, 71.5 mmol, 50%
in toluene) were added. The cooling bath was removed and the mixture
was stirred 14 h at 28C. The mixture was added to MTBE (150 mL) and
6’), 38.0 (CH2Ph), 49.6 (C-4’), 52.1 (C-2’), 55.2 (C-4), 58.9 (OCH3), 66.3
(C-5), 68.5 (C-5’), 69.4 (C-7’), 76.6 (C-8’), 127.3, 128.9, 129.3, 135.0 (Ph),
153.3 (C-2), 170.6 (C-1’), 210.9 (C-3’); IR (film): n˜ =3534 (brs), 2929 (s),
2857 (s), 1782 (s), 1715 (s), 1488 (s), 1361 (s), 1249 (s), 1124 (s), 1005 (s),
7368
www.chemeurj.org
ꢁ 2006 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 7364 – 7377

Apoptolidin A Aglycone
FULL PAPER
838 (s), 778 cmꢀ1 (s); elemental analysis calcd (%) for C27H43NO7Si
(521.72): C 62.16, H8.31, N 2.68; found C 62.39, H8.08, N 2.52.
Si
AHCTREUNG
ACHTRE(UGN CH3)3, SiCH3), 0.83 (d, J=7.0 Hz, 3H, 4-CH3), 0.86 (s, 9H, SiC-
1.84 (m, 2H, 6-H, 4-H), 2.91–3.08 (m, 1H, 2-H), 3.15 (s, 3H, N-CH3),
3.21–3.37 (m, 2H, 8-H2), 3.32 (s, 3H, OCH3), 3.61–3.75 (m, 1H, 7-H),
3.66 (s, 3H, NOCH3), 3.89–3.97 (m, 1H, 5-H), 4.01 (dd, J=7.5, 3.5 Hz,
1H, 3-H); 13C NMR (75.5 MHz, CDCl3): d=ꢀ4.6, ꢀ4.3 (SiCH3, TBS),
(4R,2’R,3’S,4’S,5’R,7’R)-4-Benzyl-3-(7’-tert-butyldimethylsilyloxy-3’,5’-di-
hydroxy-8’-methoxy-2’,4’-dimethyl-1’-oxooctyl)-1,3-oxazolidin-2-one (12):
NaBH4 (7.98 g, 211 mmol) was added in portions at 108C within 45 min
to glacial acetic acid (350 mL). The mixture was stirred for 1 h at 108C
and ketone 11 (11.0 g, 21.1 mmol) in glacial acetic acid (70 mL) was
added within 20 min. The reaction was warmed to 208C and stirred for
30 min. The solvent was removed and satd aq NaHCO3 (600 mL) and
CH2Cl2 (200 mL) were added carefully. After separation of the two
layers the aqueous layer was extracted with CH2Cl2 (2ꢂ100 mL). The
combined organic layers were dried with MgSO4 and the solvent was re-
moved in vacuo. The residue was taken up in MeOH(200 mL) and
AcOH(5 mL) and the solvents were evaporated. The residue was azeo-
troped with MeOH(2ꢂ200 mL), toluene (2ꢂ100 mL) and the product
was dried under high vacuum for 14 h to give diol 12 (10.9 g, 20.8 mmol,
0.8, 1.2 (SiCH3, TMS), 10.5, 10.6 (2-CH3, 4-CH3), 18.2 (SiCACHTRE(UNG CH3)3), 25.9
(SiCACHTRE(UGN CH3)3), 32.3 (N-CH3), 38.8 (C-2), 40.5 (C-6), 41.7 (C-4), 58.9
(OCH3), 60.8 (N-OCH3), 69.5 (C-7), 69.8 (C-5), 74.9 (C-3), 79.8 (C-8),
176.7 (C-1); IR (film): n˜ =2956 (s), 2897 (m), 1673 (s), 1462 (m), 1383
(m), 1251 (s), 1116 (s), 839 (s), 777(m), 752 cmꢀ1 (m); HR-MS (EI): m/z:
calcd for C24H54NO6Si3: 536.3259; found 536.3258 [MꢀCH3]+.
(E,5R,6S,7S,8R,10R)-10-tert-Butyldimethylsilyloxy-8-methoxy-5,7-di-
methyl-6,8-di(trimethylsilyloxy)-undec-2-en-4-one (14): (E)-1-Bromo-1-
propene (29 mL, 0.34 mmol) was added to tBuLi (0.42 mL, 1.48m in pen-
tane, 0.62 mmol) in Et2O (25 mL) at ꢀ788C. The solution was stirred for
10 min at ꢀ788C and then for 10 min at ꢀ408C. After recooling to
ꢀ788C, amide 13 (156 mg, 0.283 mmol) dissolved in Et2O (2.5 mL) was
added dropwise. The reaction mixture was stirred for 4 h at ꢀ788C, when
satd aq NaHSO4 (10 mL) and Et2O (10 mL) were added. The aqueous
layer was extracted with Et2O (3ꢂ10 mL). The combined organic layers
were washed with brine (2ꢂ5 mL) and dried with MgSO4. Purification by
flash chromatography (4 g silica gel, pentane/MTBE 3:2) gave alkenyl
ketone 14 (131 mg, 0.246 mmol, 87%) as a colorless oil. Rf =0.67 (n-
hexane/MTBE 5:1); [a]2D3 =ꢀ38.1 (c=1.34, CHCl3); 1HNMR (300 MHz,
CDCl3): d=0.02, 0.04, 0.05, 0.08 (4s, 24H, Si-CH3), 0.84 (d, J=7.3 Hz,
98%) as a colorless, viscous oil. Rf =0.44 (n-hexane/MTBE 1:3); [a]D21
=
ꢀ7.9 (c=1.00, CHCl3); 1HNMR (300 MHz, CDCl 3): d=0.07, 0.08 (2s,
6H, SiCH3), 0.82–0.90 (m, 12H, SiCACHTREU(NG CH3)3, 4’-CH3), 1.25 (d, J=6.8 Hz,
3H, 2’-CH3), 1.51–1.63 (m, 1H, 6’-H), 1.72–1.91 (m, 2H, 6’-H, 4’-H), 2.75
(dd, J=13.3, 9.6 Hz, 1H, CHPh), 3.27 (dd, J=13.4, 3.2 Hz, 1H, CHPh),
3.33 (s, 3H, OCH3), 3.27–3.43 (m, 2H, 8’-H2), 3.83–4.25 (m, 6H, 2’-H, 3’-
H , ’5-H, 7’-H, 5-H2), 4.62–4.73 (m, 1H, 4-H), 7.12–7.37 (m, 5H, Ph);
13C NMR (75.5 MHz, CDCl3): d=ꢀ5.1, ꢀ4.6 (SiCH3), 9.76 (2’-CH3), 12.0
(4’-CH3), 18.0 (SiCACHTREUNG(CH3)3), 25.8 (SiCAHCTRE(UGN CH3)3), 36.4 (C-6’), 37.7 (CH2Ph),
39.4 (C-4’), 40.1 (C-2’), 55.3 (C-4), 59.0 (OCH3), 66.1 (C-5), 69.9 (C-5’),
71.0 (C-7’), 73.7 (C-3’), 76.3 (C-8’), 127.4, 128.9, 129.4, 135.2 (Ph), 153.0
(C-2), 177.1 (C-1’); IR (film): n˜ = 3483 (brs), 2929 (s), 2858 (s), 1782 (s),
1697 (s), 1458 (s), 1389 (s), 1211 (s), 1112 (s), 910 (s), 734 cmꢀ1 (s); ele-
mental analysis calcd (%) for C27H45NO7Si (523.73): C 61.92, H8.66, N
2.67; found C 61.69, H8.26, N 2.42.
3H, 7-CH3), 0.86 (s, 9H, Si-CCAHTRE(UNG CH3)3), 1.01 (d, J=6.8 Hz, 3H, 5-CH3),
1.49–1.82 (m, 3H, 7-H, 9-H2), 1.86 (dd, J=6.9, 1.6 Hz, 3H, 1-H3), 2.87
(dq, J=6.8, 3.4 Hz, 1H, 5-H), 3.23–3.33 (m, 2H, 11-H2), 3.31 (s, 3H, 11-
OCH3), 3.64–3.72 (m, 1H, 10-H), 3.93 (ddd, J=8.1, 5.9, 2.1 Hz, 1H, 8-H),
4.07 (dd, J=7.3, 3.3 Hz, 1H, 6-H), 6.18 (dq, J=15.6, 1.6 Hz, 1H, 3-H),
6.82 (dq, J=15.6, 6.9 Hz, 1H, 2-H); 13C NMR (75.5 MHz, CDCl3): d=
ꢀ4.6, ꢀ4.3 (Si-CH3,TBS), 0.9, 1.1 (Si-CH3, TMS), 9.9, 10.9 (5-CH3, 7-
(2R,3S,4S,5R,7R)-7-tert-Butyldimethylsilyloxy-N,8-dimethoxy-N,2,4-tri-
methyl-3,5-di(trimethylsilyloxy)octamide (13): Transamidation: (MeO)-
MeNH·HCl (14.3 g, 147 mmol) was dissolved in CH2Cl2 (220 mL) and
cooled to ꢀ108C. AlMe3 (74 mL, 147 mmol, 2m in hexane) was added
and the mixture was stirred at 208C for 1 h. The mixture was cooled to
ꢀ108C and oxazolidinone 12 (10.9 g, 20.8 mmol) in CH2Cl2 (220 mL) was
slowly added. After stirring for 4 h at ꢀ108C the mixture was added via
cannula to a solution of Rochelles salt (1.5 L, 1.0m) at 08C. After 12 h
stirring the two layers were separated and the aqueous layer was extract-
ed with CH2Cl2 (3ꢂ140 mL). The combined organic layers were washed
with brine (200 mL), dried with MgSO4, concentrated and the residue
was purified by flash chromatography (300 g silica gel, pentane/MTBE
1:1!2:3) to yield the corresponding amide (6.90 g, 16.9 mmol, 81%) as a
colorless oil. Rf =0.29 (n-hexane/MTBE 1:4); [a]2D0 =+20.1 (c=1.10,
CH3), 18.1 (C-1), 18.2 (Si-CACTHERUNG(CH3)3), 25.9 (Si-CACHTRE(UGN CH3)3), 40.5 (C-9), 42.0
(C-7), 47.5 (C-5), 58.9 (11-OCH3), 69.5 (C-10), 70.0 (C-8), 74.6 (C-6), 76.8
(C-11), 130.7 (C-3), 142.0 (C-2), 201.8 (C-4); IR (film): n˜ =2956 (s), 2929
(s), 2857 (m), 1699 (m), 1675 (m), 1633 (m), 1463 (m), 1251 (s), 1116 (s),
839 (s), 776 (m), 751 cmꢀ1 (m); HR-MS (EI): m/z: calcd for C26H56O5Si3:
517.3201; found 517.3201 [MꢀCH3]+.
(E,2R,3R,4S,5R,6R,2’R)-6-[2’-tert-Butyldimethylsilyloxy-3’-methoxyprop-
yl]-4-hydroxy-2-methoxy-3,5-dimethyl-2-[1’’-propenyl]-2,3,5,6-tetrahydro-
4H-pyran (15): Enone 14 (75 mg, 0.14 mmol) was dissolved in CH2Cl2
(0.6 mL) and MeOH(0.5 mL) at 0 8C. PPTS (3.5 mg, 0.014 mmol) was
added and the reaction mixture was stirred for 1.5 h at 08C. Satd aq
NaHCO3 (3 mL) and CH2Cl2 (3 mL) were added. The aqueous layer was
extracted with CH2Cl2 (3ꢂ3 mL). The combined organic layers were
washed with brine (10 mL) and dried with MgSO4. Purification by flash
chromatography (3 g silica gel, PE/MTBE 5:1) gave methyl ketal 15
(51 mg, 0.13 mmol, 93%) as a colorless oil. Rf =0.19 (n-hexane/MTBE
5:1); [a]2D3 =+41.8 (c=0.98, CHCl3); 1HNMR (300 MHz, CDCl 3): d=
1
CHCl3); HNMR (300 MHz, CDCl 3): d=0.07, 0.08 (2s, 6H, SiCH3), 0.82
(d, J=6.8 Hz, 3H, 4-CH3), 0.87 (s, 9H, SiCACHTRE(UNG CH3)3), 1.16 (d, J=6.8 Hz,
3H, 2-CH3), 1.41–1.53 (m, 1H, 6-H), 1.68–1.86 (m, 2H, 6-H, 4-H), 2.95–
3.07 (m, 1H, 2-H), 3.17 (s, 3H, N-CH3), 3.33 (s, 3H, OCH3), 3.28–3.40
(m, 2H, 8-H2), 3.68 (s, 3H, NOCH3), 3.71 (brs, 1H, OH), 3.79–3.87 (m,
1H, 3-H), 3.98–4.15 (m, 2H, 7-H, 5-H), 4.37 (s, 1H, OH); 13C NMR
(75.5 MHz, CDCl3): d=ꢀ5.0, ꢀ4.5 (SiCH3), 10.1 (2-CH3), 12.0 (4-CH3),
0.03, 0.04 (2s, 6H, Si-CH3), 0.85 (s, 9H, Si-CCAHTREU(GN CH3)3), 0.86 (d, J=6.6 Hz,
3H, 5-CH3), 0.98 (d, J=6.8 Hz, 3H, 3-CH3), 1.43–1.58 (m, 2H, 1’-H2, 3-
H), 1.69 (dd, J=1.70, 6.6 Hz, 3H, 3’’-H), 1.71–1.84 (m, 2H, 1’-H2, 5-H),
3.06 (s, 3H, 2-OCH3), 3.22–3.38 (m, 2H, 3’-H2), 3.30 (s, 3H, 3’-OCH3),
3.75–3.96 (m, 3H, 2’-H, 6-H, 4-H), 5.38 (dq, J=15.5, 1.6 Hz, 1H, 1’’-H),
5.80 (dq, 1H, J=15.6, 6.6 Hz, 2’’-H); 13C NMR (75.5 MHz, CDCl3): d=
ꢀ4.7, ꢀ3.9 (Si-CH3), 4.9 (5-CH3), 11.2 (3-CH3), 17.6 (C-3’’), 18.2 (Si-C-
18.1 (SiCACHTREUNG(CH3)3), 25.9 (SiCCAHTRE(UGN CH3)3), 32.3 (br, N-CH3), 40.1 (C-2), 40.5 (C-
6), 41.8 (C-4), 58.9 (OCH3), 60.8 (N-OCH3), 69.5 (C-7), 69.8 (C-5), 74.9
(C-3), 76.8 (C-8), 176.7 (C-1); IR (film): n˜ = 3450 (brm), 2929 (s), 2856
(m), 1637 (s), 1462 (m), 1405 (s), 1107 (s), 987 (s), 837 (s), 777 cmꢀ1 (s);
HR-MS (EI): m/z: calcd for C19H41NO6SiH: 408.2781; found 408.2784
[M+H]+.
ACHTRE(GNU CH3)3), 25.9 (Si-CCAHTRE(UGN CH3)3), 38.5 (C-1’), 39.0 (C-5), 40.7 (C-3), 48.8 (2-
OCH3), 58.8 (3’-OCH3), 67.9 (C-6), 70.0 (C-2’), 72.8 (C-4), 77.8 (C-3’),
101.0 (C-2), 128.3 (C-2’’), 130.0 (C-1’’); IR (film): n˜ =3449 (br), 2929 (s),
2888 (s), 2857 (s), 1460 (s), 1386 (m), 1251 (m), 1110 (s), 1062 (s), 974
(m), 835 (m), 776 cmꢀ1 (s); HR-MS (EI): m/z: calcd for C21H42O6Si:
317.2617; found 371.2616 [MꢀOCH3]+.
(2S,3R,5R,6S,7S,8R,10R)-10-tert-Butyldimethylsilyloxy-2,3-dihydroxy-11-
methoxy-5,7-dimethyl-6,8-di(trimethylsilyloxy)-undecan-4-one (16a) and
(2R,3S,5R,6S,7S,8R,10R)-10-tert-butyldimethylsilyloxy-2,3-dihydroxy-11-
TMS protection: The diol (4.40 g, 10.8 mmol) was dissolved in CH2Cl2
(170 mL) and cooled to 08C. Imidazole (5.9 mg, 86 mmol) and TMSCl
(8.2 mL, 65 mmol) were added. After 2 h stirring at 08C the mixture was
quenched with phosphate buffer (120 mL, 1m, pH7). The aqueous layer
was extracted with MTBE (3ꢂ100 mL). The combined organic layers
were washed with brine (120 mL), dried with MgSO4, concentrated and
the residue was purified by flash chromatography (260 g silica gel, pen-
tane/MTBE 3:2) to yield (bis)silyl ether 13 (5.1 g, 9.2 mmol, 86%) as a
colorless oil. Rf =0.67 (n-hexane/MTBE 2:3); [a]2D3 =ꢀ18.6 (c=1.00,
CHCl3); 1HNMR (200 MHz, CDCl 3): d=0.04, 0.05, 0.08, 0.09 (4s, 24H,
methoxy-5,7-dimethyl-6,8-di(trimethylsilyloxy)-undecan-4-one
(16b):
AD-mix a (89 mg) was dissolved in tBuOH(0.2 mL) and H 2O (0.5 mL)
Chem. Eur. J. 2006, 12, 7364 – 7377
ꢁ 2006 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
www.chemeurj.org
7369

U. Koert et al.
at 08C. After addition of enone 14 (34 mg, 0.064 mmol) dissolved in
tBuOH(0.3 mL) the reaction mixture was stirred for 14 h at 0–7 8C.
Na2SO3 (80 mg, 0.64 mmol), H2O (3 mL) and CH2Cl2 (4 mL) were added.
After stirring for 10 min the layers were separated and the aqueous layer
was extracted with CH2Cl2 (3ꢂ5 mL). The combined organic layers were
washed subsequently with NaOH(1 m, 10 mL) and brine (10 mL) and
dried with MgSO4. Purification by flash chromatography (1 g silica gel, n-
hexane/AcOEt 3:1) gave a 3:1 mixture of diols 16a and 16b (26 mg,
0.046 mmol, 72%) as a colorless oil. Rf =0.50 (n-hexane/MTBE 1:1);
1HNMR (300 MHz, CDCl 3): d=0.04, 0.06, 0.07, 0.10 (4s, Si-CH3), 0.78–
(2R,3R,4S,5R,6R,2’R,1’’R,2’’S)-6-(2’-tert-Butyldimethylsilyloxy-3’-me-
thoxypropyl)-2-(1’’,2’’-dihydroxypropyl)-4-hydroxy-2-methoxy-3,5-dimeth-
yl-2,3,5,6-tetrahydro-4H-pyran (17a) by dihydroxylation of alkene 15:
[K2OsO2(OH)4] (1 mg, 3 mmol) and NMO (26 mg, 0.12 mmol) was added
to alkene 15 (26 mg, 0.065 mmol) dissolved in THF/H2O/tBuOH(4:1:4,
3 mL). The reaction mixture was stirred for 8 d at 208C. Na2SO3
(180 mg), H2O (3 mL) and MTBE (3 mL) were added. The layers were
separated and the aqueous layer was extracted with MTBE (3ꢂ3 mL).
The combined organic layers were washed with brine (10 mL) and dried
with MgSO4. Purification by chromatography (2.5 g silica gel, PE/MTBE
1:2) gave a 2:1 mixture of diols 17a/17b (20 mg, 0.046 mmol, 70%). Both
isomers could be separated by a second chromatography (5 g silica gel,
PE/MTBE 1:2) to yield 17a (13 mg, 0.030 mmol, 46%) and 17b (6 mg,
0.014 mmol, 21%). The analytical data for 17a were identical with the
data for the product obtained from 16a.
0.88 (m, 7-CH3, Si-CACHTREUNG(CH3)3), 1.06 (d, J=6.8 Hz, 6H, 5-CH3), 1.12 (d, J=
7.2 Hz, 3H, 5-CH3), 1.31 (d, J=6.4 Hz, 9H, 1-H3), 1.47–1.57 (m, 3H, 7-
H), 1.60–1.89 (m, 6H, 9-H2), 2.97 (dq, J=7.2, 2.6 Hz, 1H, 5-H), 3.06 (dq,
J=6.7, 2.4 Hz, 2H, 5-H), 3.23–3.34 (m, 15H, 11-H2, 11-OCH3), 3.64–3.74
(m, 3H, 10-H), 3.81 (d, J=4.9 Hz, 2H, 2-OH), 3.84 (d, J=5.1 Hz, 1H, 2-
OH), 3.93–4.01 (m, 6H, 6-H, 8-H), 4.07–4.27 (m, 9H, 3-H, 2-H, 3-OH);
13C NMR (75.5 MHz, CDCl3): d=ꢀ4.6, ꢀ4.5, ꢀ4.3, ꢀ4.2 (Si-CH3, TBS),
0.77, 0.82, 1.2, 1.3 (Si-CH3, TMS), 8.8, 10.3, 10.8, 10.9 (5-CH3, 7-CH3),
(2R,3R,4S,5R,6R,2’R,4’’R,5’’S)-6-(2’-tert-Butyldimethylsilyloxy-3’-me-
thoxypropyl)-4-hydroxy-2-methoxy-3,5-dimethyl-2-(2’’,2’’,5’’-trimethyl-
1’’,3’’-dioxolan-4’’-yl)-2,3,5,6-tetrahydro-4H-pyran (18): Triol 17a (10 mg,
0.023 mmol) was dissolved in 2,2-dimethoxypropane (0.5 mL) at 08C.
CSA (1 mg, 4 mmol) was added and the reaction mixture was stirred for
30 min. Et3N (0.2 mL) in toluene (3 mL) was added. After removal of
the solvents in vacuo the residue was purified by chromatography (6 g
18.21, 18.22 (Si-CACHTREUNG(CH3)3), 20.4, 20.5 (C-1), 25.9 (Si-CCAHTRE(UGN CH3)3), 40.3, 40.6
(C-9), 41.9, 42.2 (C-7), 44.6, 45.6 (C-5), 58.95, 58.98 (11-OCH3), 67.8, 68.5
(C-2), 69.3, 69.5 (C-6), 69.7, 69.8 (C-8), 72.4, 74.7 (C-6), 76.8, 76.9 (C-11),
78.1, 78.3 (C-3), 212.1, 213.1 (C-4); IR (film): n˜ =3456 (br), 2956 (s), 2930
(s), 2858 (m), 1711 (m), 1463 (m), 1385 (m), 1252 (s), 1116 (s), 1029 (m),
838 (s), 776 (m), 751 cmꢀ1 (m); HR-MS (EI): m/z: calcd for C25H55O7Si3:
calcd 551.3256; found 551.3264 [MꢀCH3]+.
silica gel, PE/MTBE 5:1
!
1:1) to afford acetonide 18 (9 mg,
0.019 mmol, 84%) as a crystalline solid. Recrystallization from MeOH/
H2O gave crystals suitable for X-ray structure analysis.[12a] M.p. 868C;
Rf =0.80 (n-hexane/MTBE 1:3); [a]2D3 =+64 (c=0.22, CHCl3); 1HNMR
(300 MHz, CDCl3): d=0.04 (s, 6H, Si-CH3), 0.82 (d, J=7.0 Hz, 3H, 5-
Dihydroxylation of enone 14 (30 mg, 0.056 mmol) with AD-mix
b
(78 mg) afforded a 1:8 mixture of diols 16a and 16b (25 mg, 0.044 mmol,
CH3), 0.86 (s, 9H, Si-CACTHERU(NG CH3)3), 1.20 (d, J=6.6 Hz, 3H, 3-CH3), 1.31 (d,
78%).
J=5.8 Hz, 3H, 5’’-CH3), 1.37 (s, 3H, 2’’-CH3), 1.41 (s, 3H, 2’’-CH3), 1.45
(ddd, J=14.2, 7.4, 3.5 Hz, 1H, 1’-H2), 1.68 (ddd, J=14.3, 8.3, 4.3 Hz, 1H,
1’-H2), 1.74–1.86 (m, 2H, 3-H, 5-H), 3.22–3.35 (m, 2H, 3’-H2), 3.27 (s,
3H, 2-OCH3), 3.31 (s, 3H, 3’-OCH3), 3.47 (s, 1H, 4-OH), 3.77 (d, J=
8.3 Hz, 1H, 4’’-H), 3.79 (dd, J=10.2, 5.1 Hz, 1H, 4-H), 3.94–4.00 (m, 2H,
2’-H, 6-H), 4.05 (dq, J=8.3, 5.9 Hz, 1H, 5’’-H); 13C NMR (75.5 MHz,
CDCl3): d=ꢀ4.7, ꢀ3.9 (Si-CH3), 5.0 (5-CH3), 11.6 (3-CH3), 18.2 (Si-C-
(2R,3R,4S,5R,6R,2’R,1’’R,2’’S)-6-[2’-tert-Butyldimethylsilyloxy-3’-me-
thoxypropyl]-2-[1’’,2’’-dihydroxypropyl]-4-hydroxy-2-methoxy-3,5-dimeth-
yl-2,3,5,6-tetrahydro-4H-pyran (17a) from ketone 16a: A mixture of di-
hydroxyketones 16a/16b (89 mg, 0.16 mmol) was dissolved in MeOH
(0.5 mL) and CH2Cl2 (0.5 mL) at 08C. PPTS (4 mg, 0.02 mmol) was
added and the reaction mixture was stirred for 1 h. Satd aq NaHCO3
(3 mL) was added. The layers were separated and the aqueous layer was
extracted with CH2Cl2 (3ꢂ5 mL). The combined organic layers were
washed with brine (10 mL) and dried with MgSO4. Purification by flash
chromatography (5 g silica gel, PE/MTBE 1:2) gave dihydroxy methylke-
tal 17a (7 mg, 0.02 mmol, 12%) as a colorless oil and diastereomeric
methyl ketal 17b (45 mg, 77%) which contained inseparable quantities
of its hemiketal. Rf =0.13 (17a) and 0.31 (17b) (n-hexane/MTBE 1:3).
17a: [a]2D3 =+40 (c=0.06, CHCl3); 1HNMR (300 MHz, CDCl 3): d=0.03,
ACHRTE(UGN CH3)3), 19.1 (5’’-CH3), 25.9 (Si-CACHTREU(GN CH3)3), 26.9, 27.0 (2’’-CH3), 36.0 (C-3),
38.3 (C-1’), 38.6 (C-5), 47.8 (2-OCH3), 58.8 (3’-OCH3), 68.2, 69.8 (C-2’, C-
6), 73.3 (C-4), 73.8 (C-5’’), 77.6 (C-3’), 81.9 (C-4’’), 100.0 (C-2), 108.0 (C-
2’’); IR (film): n˜ =3460 (br), 2931 (s), 2893 (s), 1463 (m), 1380 (m), 1249
(s), 1086 (s), 1017 (s), 933 (m), 836 (s), 777 (s), 734 cmꢀ1 (m); HR-MS
(EI): m/z: calcd for C23H45O7Si: 461.2935; found 461.2933 [MꢀCH3]+.
(2S)-1-O-Benzyl-2-methoxypent-4-in-1-ol (20): Epoxide opening: nBuLi
(52 mL, 2.5m in hexane, 130 mmol) was added at ꢀ408C over 15 min to a
solution of (trimethylsilyl)acetylene (18.0 mL, 130 mmol) in THF
(200 mL). After 10 min, the solution was cooled to ꢀ788C and (R)-ben-
zylglycidol in THF (100 mL) was added dropwise. Then, BF3·OEt2
(9.7 mL, 78 mmol) in THF (50 mL) was added dropwise. After 2 h at
ꢀ788C, Et3N (11 mL, 78 mmol) was added and the reaction mixture was
stirred for 30 min at ꢀ788C. Then, it was transferred via a Teflon cannula
into satd aq NaHCO3 (250 mL) cooled to 08C. MTBE (250 mL) was
added and the layers were separated. The aqueous layer was extracted
with MTBE (3ꢂ50 mL). The combined organic layers were subsequently
washed with NaHSO4 (1m, 100 mL), satd aq NaHCO3 (50 mL), brine
(150 mL) and dried with MgSO4. After removal of the solvents in vacuo,
the corresponding alcohol was obtained. A 50 mg sample of the alcohol
was purified by chromatography (5 g silica gel, pentane/MTBE 3:1) for
analytical purposes: Rf =0.19 (n-hexane/MTBE 3:1); [a]2D3 =+16.9 (c=
1.34, CHCl3); 1HNMR (200 MHz, CDCl 3): d=0.02 (s, 9H, TMS), 2.28–
2.38 (m, 2H, 3-H2), 2.40 (m, 1H, OH), 3.35 (dd, J=9.9, 6.3 Hz, 1H, 1-H),
3.47 (dd, J=9.9, 3.5 Hz, 1H, 1-H), 3.73–3.90 (m, 1H, 2-H), 4.43 (s, 2H,
OCH2Ph), 7.24–7.32 (m, 5H, Ph); 13C NMR (50 MHz, CDCl3): d=0.0
(SiMe3), 24.9 (C-3), 68.8 (C-2), 72.7 (C-1), 73.4 (OCH2Ph), 87.2 (C-4),
102.5 (C-5), 127.7, 127.8, 128.4 (CH, Ph), 137.8 (Cq, Ph); IR (film): n˜ =
3428 (bm), 3058 (m), 2956 (m), 2904 (s), 2858 (w), 2178 (w), 1454 (m),
1248 (s), 1111 (s), 847 (s), 767 (s), 705 cmꢀ1 (m); HR-MS (EI): m/z: calcd
for C15H22O2Si: 262.1389; found 262.1392 [M]+.
0.04 (2s, 6H, Si-CH3), 0.84–0.88 (m, 12H, 5-CH3, Si-CCAHTRE(UNG CH3)3), 1.06 (d,
J=6.6 Hz, 3H, 3-CH3), 1.25 (d, J=6.6 Hz, 3H, 3’’-H3), 1.50 (ddd, J=
14.4, 7.4, 3.9 Hz, 1H, 1’-H2), 1.73 (ddd, J=14.4, 8.2, 4.2 Hz, 1H, 1’-H2),
1.79–1.86 (m, 1H, 5-H), 2.08 (dq, J=10.9, 6.6 Hz, 1H, 3-H), 3.26 (s, 3H,
2-OCH3), 3.25–3.32 (m, 2H, 3’-H2), 3.31 (s, 3H, 3’-OCH3), 3.41–3.44 (m,
1H, 1’’-H), 3.76 (dd, J=10.9, 4.7 Hz, 1H, 4-H), 3.85–3.92 (m, 2H, 6-H, 2’-
H), 4.05 (dq, J=6.4, 2.4 Hz, 1H, 2’’-H); 13C NMR (75.5 MHz, CDCl3):
d=ꢀ4.7, ꢀ3.9 (Si-CH3), 5.0 (5-CH3), 11.4 (3-CH3), 18.2 (Si-C
ACHTRE(UNG CH3)3),
21.0 (C-3’’), 25.9 (Si-C(CH3)3), 35.9 (C-3), 38.5 (C-1’), 38.6 (C-5), 48.7 (2-
ACHTREUNG
OCH3), 58.9 (3’-OCH3), 66.6 (C-2’’), 69.4, 69.6 (C-6, C-2’), 72.6 (C-4),
75.3 (C-1’’), 77.2 (C-3’), 102.6 (C-2); IR (film): n˜ =3443 (br), 2929 (s),
2891 (s), 2857 (s), 1460 (m), 1388 (m), 1252 (m), 1112 (s), 1015 (s), 836
(s), 777 cmꢀ1 (s); HR-MS (EI): m/z: calcd for C18H37O5Si: 361.2410;
found 361.2413 [MꢀC3H7O2]+. 17b containing impurities of its hemike-
1
tal: HNMR (300 MHz, CDCl 3): d=0.040, 0.044, 0.05 (3s, Si-CH3), 0.79–
0.88 (m, 5-CH3, Si-CACHTREUNG(CH3)3), 0.94, 0.96 (2d, J=5.5, 5.5 Hz, 6H, 3-CH3),
1.17, 1.19 (2d, J=6.2, 6.4 Hz, 6H, 3’’-H3), 1.29–1.52 (m, 2H, 1’-H2), 1.64–
1.86 (m, 6H, 3-H, 5-H, 1’-H2), 2.71, 2.85 (2d, J=9.8, 8.9 Hz, 2H, 1’’-OH),
3.14–3.33 (m, 6H, 1’’-H, 3’-H2), 3.26, 3.28 (2s, 6H, 3’-OCH3), 3.37 (s, 3H,
2-OCH3), 3.47–3.53 (m, 2H, 2’’-OH), 3.67–3.92 (m, 6H, 4-H, 4-OH, 2’-
H), 3.94–4.16 (m, 4H, 6-H, 2’’-H); 13C NMR (75.5 MHz, CDCl3): d=
ꢀ4.8, ꢀ4.7, ꢀ4.2, ꢀ4.0 (Si-CH3), 5.0, 5.1 (5-CH3), 11.3, 11.7 (3-CH3), 18.0,
18.1 (Si-CACHTREUNG(CH3)3), 19.6, 20.0 (C-3’’), 25.8, 25.9 (Si-CAHCTRE(UGN CH3)3), 35.5, 36.5 (C-
3), 38.4, 38.7 (C-1’), 38.9, 39.5 (C-5), 51.6 (2-OCH3), 59.0, 59.1 (3’-OCH3),
64.9, 66.8 (C-2’’), 67.6, 68.9, 69.5, 69.6 (C-6, C-2’), 72.36, 72.40 (C-4), 73.9,
76.2 (C-1’’), 77.1, 77.3 (C-3’), 100.5, 101.8 (C-2).
Methylation and subsequent TMS deprotection: A solution of LHMDS in
THF was prepared by addition of nBuLi (80 mL, 2.5m in hexane,
7370
www.chemeurj.org
ꢁ 2006 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 7364 – 7377

Apoptolidin A Aglycone
FULL PAPER
200 mmol) to hexamethyldisilazane (40 mL, 200 mmol) in THF (200 mL)
at ꢀ208C. The solution was stirred for 45 min after the addition. The
LHMDS solution was transferred via a Teflon cannula to a solution of
the alcohol (18 g, 65 mmol) and methyl iodide (28 mL, 460 mmol) in
THF (150 mL) cooled to 08C. After 30 min, the reaction mixture was stir-
red for 16 h at 408C. For workup it was added to an ice-cold NH4Cl/NH3
4:1 buffer solution (300 mL). After stirring for 1 h, the organic solvents
were evaporated in vacuo. The remaining aqueous layer was extracted
with MTBE (3ꢂ150 mL). The combined organic layers were washed with
brine (150 mL) and dried with MgSO4. After removal of the solvent the
remaining TMS-methyl ether was dissolved in THF (150 mL) at 08C. Tet-
rabutylammonium fluoride (21 g, 66 mmol) dissolved in THF (100 mL)
was added and the reaction mixture was stirred for 90 min. Work up was
started by addition of satd aq NH4Cl (200 mL). The organic solvents
were removed in vacuo. The remaining aqueous layer was extracted with
MTBE (3ꢂ150 mL). The combined organic layers were washed with
brine (150 mL) and dried with MgSO4. Purification by chromatography
(500 g silica gel, pentane/MTBE 10:1 ! 7:1) gave alkyne 20 (8.8 g, 66%)
as a light yellow liquid. Rf =0.25 (n-hexane/MTBE 7:1); [a]2D3 =+13.1
(c=1.12, CHCl3); 1HNMR (300 MHz, CDCl 3): d=1.88 (t, J=2.7 Hz,
1H, 5-H), 2.31–2.49 (m, 2H, 3-H2), 3.35 (s, 3H, OCH3), 3.40–3.49 (m,
1H, 2-H), 3.49–3.61 (m, 2H, 1-H2), 4.48 (s, 2H, OCH2Ph), 7.14–7.25 (m,
5H, Ph); 13C NMR (75 MHz, CDCl3): d=20.9 (C-3), 57.7 (OCH3), 69.5
(C-5), 70.6 (C-1), 73.5 (CH2Ph), 78.4 (C-2), 80.6 (C-4), 127.60, 127.64,
128.3 (CH, Ph), 138.1 (C, Ph); IR (film): n˜ =3293 (s), 3060 (m), 3030 (m),
2983 (m), 2913 (s), 2866 (s), 2831 (m), 2120 (w), 1454 (s), 1358 (m), 1202
(m), 1110 (s), 738 (s), 699 cmꢀ1 (s); elemental analysis calcd (%) for
C13H16O2: C 76.44, H7.90; found C 76.61, H8.15.
1:1); [a]2D4 =+53.1 (c=1.03, CHCl3); 1HNMR (300 MHz, CDCl 3): d=
0.03, 0.04 (2s, 6H, SiCH3), 0.83–0.90 (m, 12H, 5-CH3, SiCCAHTRE(UNG CH3)3), 0.95
(d, J=6.8 Hz, 3H, 3-CH3), 1.35 (d, J=5.6 Hz, 1H, OH), 1.43–1.57 (m,
2H, 3-H, 1’’-H), 1.68–1.87 (m, 2H, 5-H, 1’’-H), 2.25–2.36 (m, 2H, 3’-H2),
3.04 (s, 3H, 2-OCH3), 3.25 (dd, J=9.8, 6.1 Hz, 1H, 3’’-H), 3.30 (s, 3H,
OCH3), 3.37–3.48 (m, 3H, 4’-H, 5’-H2), 3.40 (s, 3H, OCH3), 3.74–3.96 (m,
3H, 4-H, 6-H, 2’’-H), 4.50 (d, J=12.2 Hz, 1H, CHPh), 4.55 (d, J=12.2,
1H, CHPh), 5.41 (bd, J=15.6 Hz, 1H, 1’-H), 5.76 (ddd, J=15.5, 7.3,
7.3 Hz, 1H, 2’-H), 7.22–7.36 (m, 5H, Ph); 13C NMR (75.5 MHz, CDCl3):
d=ꢀ4.8, 3.9 (SiCH3), 4.9 (5-CH3), 11.1 (3-CH3), 18.2 (SiC
ACHTRE(UNG CH3)3), 25.9
(Si-C(CH3)3), 34.0 (C-3’), 38.4 (C-1’’), 39.0 (C-5), 40.5 (C-3), 48.8 (2-
AHCTREUNG
OCH3), 57.4, 58.7 (4’-OCH3, 3’’-OCH3), 67.9 (C-6), 69.9 (C-2’’), 71.5 (C-
5’), 72.5 (C-4), 73.3 (CH2Ph), 77.7 (C-3’’), 79.7 (C-4’), 100.9 (C-2), 127.5,
127.6, 128.3, 138.2 (Ph), 128.9 (C-2’), 131.5 (C-1’); IR (film): n˜ =3470
(brs), 2929 (s), 2891 (s), 1462 (m), 1362 (m), 1251 (m), 1108 (s), 985 (s),
833 (s), 735 cmꢀ1 (m); HR-MS (EI): m/z: calcd for C31H54O7Si: 566.3639;
found 566.3645 [M]+.
TBS-protected THP ketal 24: 2,6-Lutidine (0.36 mL, 3.1 mmol) and TBS
triflate (0.66 mL, 2.9 mmol) were added at ꢀ788C to alcohol 23 (1.08 g,
1.91 mmol) dissolved in CH2Cl2 (70 mL). After stirring for 3 h, NaHCO3
(50 mL) was added. The reaction mixture was warmed to 208C and the
layers were separated. The aqueous layer was extracted with MTBE (3ꢂ
50 mL). The combined organic layers were washed with brine (150 mL)
and dried with MgSO4. Chromatography (20 g silica gel, PE/MTBE 10:1)
yielded TBS ether 24 (1.29 g, 1.89 mmol, 99%) as a colorless oil. Rf =
0.64 (n-hexane/MTBE 3:1); [a]2D4 =+57.4 (c=1.01, CHCl3); 1HNMR
(300 MHz, CDCl3): d=0.04, 0.07, 0.08 (3s, 12H, Si-CH3), 0.84–0.94 (m,
24H, 3-CH3, 5-CH3, Si-CACTHERU(NG CH3)3), 1.42–1.61 (m, 2H, 3-H, 1’’-H2), 1.63–
A
1.80 (m, 2H, 5-H, 1’’-H2), 2.28–2.34 (m, 2H, 3’-H2), 3.06 (s, 3H, 2-OCH3),
3.23–3.50 (m, 5H, 4’-H, 5’-H2, 3’’-H2), 3.32, 3.42 (2s, 6H, 4’-OCH3, 3’’-
OCH3), 3.78 (dd, J=10.5, 4.7 Hz, 1H, 4-H), 3.83–3.97 (m, 2H, 6-H, 2’’-
H), 4.49–4.60 (m, 2H, CH2Ph), 5.44 (d, J=15.6 Hz, 1H, 1’-H), 5.70–5.82
(m, 1H, 2’-H), 7.14–7.35 (m, 5H, Ph); 13C NMR (75.5 MHz, CDCl3): d=
ꢀ4.8, ꢀ4.7, ꢀ4.3, ꢀ3.8 (Si-CH3), 5.1 (5-CH3), 11.8 (3-CH3), 18.1, 18.2 (Si-
were carried out with exclusion of sunlight in amber colored glassware.
LiEt3BH(18.1 mL, 1 m in THF, 18.1 mmol) was added at 208C during
20 min to a solution of [Cp2ZrCl2] (5.29 g, 18.1 mmol) in THF (150 mL).
After 1 h, alkyne 20 (1.85 g, 9.05 mmol) in THF (40 mL) was added drop-
wise. At the end of the addition the colorless suspension had turned into
a yellow solution. After 15 min NIS (4.48 g, 19.9 mmol) was added and
the reaction mixture was stirred for additional 10 min. NaHCO3 (60 mL)
and Na2S2O3 (1m, 15 mL) was added. The THF was removed in vacuo
and the remaining aqueous layer was extracted with pentane/MTBE 10:1
(3ꢂ100 mL). The combined organic layers were washed with brine
(100 mL) and dried with MgSO4. Purification by chromatography (100 g
silica gel, pentane/MTBE 10:1) gave alkenyl iodide 21 (2.64 g, 7.94 mmol,
88%) as a colorless liquid. Rf =0.26 (n-hexane/MTBE 7:1); [a]2D3 =+2.3
(c=1.20, CHCl3); 1HNMR (300 MHz, CDCl 3): d=2.22–2.42 (m, 2H, 3-
H2), 3.46–3.43 (m,1H, 2-H), 3.40 (s, 3H, OCH3), 3.44–3.49 (m, 2H, 1-H2),
4.54 (s, 2H, OCH2Ph), 6.06 (d, J=14.5 Hz, 1H, 5-H), 6.51 (dt, J=14.6,
7.3 Hz, 1H, 5-H), 7.25–7.41 (m, 5H, Ph); 13C NMR (75 MHz, CDCl3):
d=37.7 (C-3), 57.6 (OCH3), 70.8 (C-1), 73.4 (CH2Ph), 77.0 (C-5), 78.7
(C-2), 80.6 (C-4), 127.7, 128.4 (CH, Ph), 138.0 (C, Ph), 142.1 (C-4); IR
(film): n˜ =3058 (m), 3030 (m), 2975 (m), 2929 (s), 2900 (s), 2861 (s), 2829
(s), 1494 (m), 1453 (s), 1362 (m), 1190 (m), 1108 (s), 949 (s), 737 (s),
698 cmꢀ1 (s); HR-MS (EI): m/z: calcd for C13H17O2I: 332.0273; found
332.0271 [M]+.
CACHTER(UNG CH3)3), 25.8, 25.9 (Si-CHCARTEU(GN CH3)3), 34.0 (C-3’), 38.7 (C-1’’), 40.0 (C-5),
40.7 (C-3), 48.8 (2-OCH3), 57.4, 58.7 (4’-OCH3, 3’’-OCH3), 67.9 (C-6),
70.2 (C-2’’), 71.5 (C-5’), 73.34 (C-4), 73.35 (CH2Ph), 77.8 (C-3’’), 79.8 (C-
4’), 101.2 (C-2), 127.57, 127.61, 128.2, 138.2 (Ph), 128.7 (C-2’), 131.9 (C-
1’); IR (film): n˜ =2929 (s), 2988 (s), 2857 (s), 1462 (m), 1360 (w), 1252
(m), 1107 (s), 1066 (s), 836 (s), 775 (s), 698 (w), 675 cmꢀ1 (w); HR-MS
(EI): m/z: calcd for C37H68O7Si2: 680.4504; found 680.4501 [M]+.
Diol 25: [K2OsO2(OH)4] (27 mg, 0.074 mmol) and NMO (497 mg,
3.68 mmol) was added to alkene 24 (836 mg, 1.23 mmol) dissolved in
tBuOH(12 mL)/H 2O (6 mL). The reaction mixture was stirred for 9 d at
0–108C. Na2SO3 (458 mg, 1.85 mmol), H2O (15 mL) and MTBE (15 mL)
were added. The layers were separated and the aqueous layer was ex-
tracted with MTBE (3ꢂ10 mL). The combined organic layers were
washed with brine (30 mL) and dried with MgSO4. Purification by chro-
matography (50 g silica gel, PE/MTBE 1:1) gave diol 25 (686 mg,
0.959 mmol, 78%) with a 6:1 diastereomeric ratio. An analytical sample
of diasteromeric pure diol 25 was obtained by a second chromatography.
Rf =0.64 (25), 0.30 (epimer) (n-hexane/MTBE 3:1); [a]2D4 =+48.0 (c=
1.04, CHCl3); 1HNMR (300 MHz, CDCl 3, 6:1 mixture of 25 and its dia-
stereomer (ds)): d=ꢀ0.06, ꢀ0.03, ꢀ0.02 (3s, Si-CH3), 0.76–0.83 (m, 3-
Tetrahydropyran methyl ketal 23: Iodide 21 (2.7 g, 8.2 mmol) was dis-
solved in Et2O (300 mL) and cooled to ꢀ788C. tBuLi (8.9 mL, 1.7m in
pentane, 15 mmol) was added slowly. The mixture was stirred for 1.5 h at
ꢀ788C and then amide 13 (2.0 g, 3.6 mmol) (azeotroped with toluene 3ꢂ
15 mL) in Et2O (180 mL) was added within 1 h. After stirring for 3.5 h at
ꢀ788C the reaction was quenched with iPrOH(7.5 mL) and the cooling
bath was removed. NaHCO3 (200 mL) was added and the two layers
were separated. The aqueous layer was extracted with MTBE (3ꢂ
100 mL). The combined organic layers were washed with brine (140 mL),
dried with MgSO4 and concentrated. The residue was dissolved in
MeOH/CH2Cl2 1:1 (60 mL) and PPTS (90 mg, 0.36 mmol) was added at
08C. After stirring for 30 min at 08C, NaHCO3 (40 mL) was added and
the aqueous layer was extracted with MTBE (3ꢂ50 mL). The combined
organic layers were washed with brine (100 mL), dried with MgSO4, con-
centrated and the residue was purified by flash chromatography (250 g
silica gel, pentane/MTBE 3:1) to yield methyl ketal 23 (1.58 g,
2.80 mmol, 78%, 2 steps) as a colorless oil. Rf =0.35 (n-hexane/MTBE
CH3 (ds), 5-CH3, Si-CACHTRE(UGN CH3)3), 0.91 (d, J=6.6 Hz, 18H, 3-CH3 (25)), 1.33–
1.46 (m, 7H, 1’’-H2), 1.55–1.77 (m, 28H, 5-H, 3’-H2, 1’’-H2), 1.91–2.01 (m,
7H, 3-H), 2.67 (d, J=5.8 Hz, 1H, 1’-OH( ds)), 3.15–3.25 (m, 21H, 2’-OH,
3’’-H2), 3.19 (s, 18H, 2-OCH3 (25)), 3.22 (s, 18H, 3’’-OCH3 (25)), 3.24 (s,
3H, 2-OCH3 (ds)), 3.32, 3.34 (2s, 6H, 4’-OCH3 (25), 3’’-OCH3 (ds)), 3.36
(s, 18H, 4’-OCH3 (25)), 3.39–3.50 (m, 21H, 1’-H, 5’-H2), 3.57–3.69 (m,
15H, 4-H, 4’-H, 2’-H( ds)), 3.75–3.87 (m, 14H, 6-H, 2’’-H), 3.96–4.06 (m,
6H, 2’-H( 25)), 4.41–4.52 (m, 14H, CH2Ph), 7.04–7.27 (m, 35H, Ph);
13C NMR (75.5 MHz, CDCl3): 25: d=ꢀ4.8, ꢀ4.7, ꢀ4.4, ꢀ3.9 (Si-CH3), 5.3
(5-CH3), 12.1 (3-CH3), 18.1, 18.2 (Si-CACHTER(NGU CH3)3), 25.8, 25.9 (Si-CACHTREUNG(CH3)3),
35.9 (C-3), 37.2 (C-3’), 38.7 (C-1’’), 39.7 (C-5), 48.4 (2-OCH3), 57.9, 58.8
(4’-OCH3, 3’’-OCH3), 67.3 (C-2’), 69.0, 69.9 (C-6, C-2’’), 71.8 (C-5’), 73.3
(C-4), 73.4 (CH2Ph), 74.7 (C-1’), 77.5 (C-3’’), 77.6 (C-4’), 102.6 (C-2),
127.59, 127.61, 128.4, 138.1 (Ph); ds: d=ꢀ4.9, ꢀ4.8, ꢀ4.4, ꢀ3.9 (Si-CH3),
5.3 (5-CH3), 11.6 (3-CH3), 18.0, 18.1 (Si-CACHTRE(UNG CH3)3), 25.8, 25.9 (Si-C-
Chem. Eur. J. 2006, 12, 7364 – 7377
ꢁ 2006 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
www.chemeurj.org
7371

U. Koert et al.
A
washed with brine (100 mL) and dried with MgSO4. Chromatography
(350 g silica gel, PE/MTBE 5:1, 0.5% Et3N) gave alcohol 28 (4.62 g,
12.3 mmol, 62%) as pure E isomer and a second fraction of 28 with a >
90:10 E selectivity (2.7 g, 7.2 mmol, 36%). Rf =0.28 (n-hexane/MTBE
3:1); 1HNMR (300 MHz, CDCl 3): d=0.81–0.91 (m, 15H,
SnCH2C2H4CH3), 1.28 (tq, J=7.3, 7.3 Hz, 6H, SnC2H4CH2CH3), 1.40–
1.52 (m, 6H, SnCH2CH2C2H5), 1.76–1.94 (m, 3H, 5-H3), 2.40 (qd, J=6.6,
0.8 Hz, 2H, 2-H2), 3.63 (dt, J=6.0, 5.8 Hz, 2H, 1-H2), 5.33–5.66 (m, 1H,
57.1, 58.8 (4’-OCH3, 3’’-OCH3), 68.1, 69.3, 69.8 (C-6, C-2’, C-2’’), 71.7 (C-
5’), 72.7 (CH2Ph), 73.2 (C-4), 75.1 (C-1’), 77.4 (C-3’’), 77.9 (C-4’), 101.8
(C-2), 127.5, 127.6, 128.3, 138.1 (Ph); IR (film): n˜ =3494 (brs), 2930 (s),
2888 (s), 2857 (s), 1463 (m), 1387 (w), 1361 (w), 1253 (m), 1106 (s), 1069
(s), 835 (s), 776 (m), 698 cmꢀ1 (w); HR-MS (EI): m/z: calcd for
C36H65O7Si2: 665.4269; found 665.4271 [MꢀOCH3ꢀH2O]+.
Diacetate 26: Acetic anhydride (3 mL) and DMAP (3 mg, 0.02 mmol)
was added to diol 25 (436 mg, 0.610 mmol, 6:1 diastereomeric mixture)
dissolved in pyridine (9 mL). The reaction mixture was stirred for 13 h at
408C. After cooling to 208C, pH7 phosphate buffer (15 mL, 1 m) and
MTBE (15 mL) were added. The layers were separated and the aqueous
layer was extracted with MTBE (10 mL). The combined organic layers
were subsequently washed with NaHCO3 (30 mL) and brine (30 mL) and
dried with MgSO4. Chromatography (20 g silica gel, cyclohexane/AcOEt
10:1) gave diacetate 26 (356 mg, 0.445 mmol, 73%) and the diastereo-
meric diacetate (49 mg, 0.061 mmol, 10%). 26: Rf =0.60 (n-hexane/
3-H); 13C NMR (75 MHz, CDCl3): d=9.1 (dt, J
ACHTRE(UNG C,Sn)=157, 165 Hz,
SnCH2C3H7), 13.7 (SnC3H6CH3), 19.3 (C5), 27.3, 29.1 (SnCH2C2H4CH3),
31.7 (C2), 62.2 (C1), 135.7 (C3), 142.4 (C4); IR (film): n˜ =2956 (s), 2924
(s), 2871 (s), 2851 (s), 1458 (s), 1420 (m), 1264 (s), 1204, (s), 1072, (m),
960 (m), 870 cmꢀ1 (m).
(E)-1-Bromo-4-tributylstannyl-pent-3-ene (29): Et3N (1.6 mL, 11 mmol)
and MsCl (0.80 mL, 10 mmol) were added at 08C successively to a solu-
tion of alcohol 28 (3.22 g, 8.58 mmol) in CH2Cl2. After 1 h at 08C, H2O
(50 mL) and MTBE (100 mL) were added. The aqueous layer was ex-
tracted with MTBE (3ꢂ50 mL). The combined organic layers were
washed with brine (50 mL) and dried with Na2SO4. The solvents were re-
moved in vacuo. Toluene (20 mL) was added and subsequently removed
in vacuo. The mesylate thus obtained was dissolved in acetone (30 mL)
at 208C. LiBr (2.6 g, 30 mmol) was added and the reaction mixture was
stirred for 2.5 h at 508C. After cooling to 208C, H2O (100 mL) was
added. The aqueous layer was extracted with PE (3ꢂ100 mL). The com-
bined organic layers were washed with brine (100 mL) and dried with
MgSO4. Chromatography (100 g silica gel, PE/1% Et3N) gave bromide
29 (2.9 g, 6.7 mmol, 78%) as a colorless liquid. Rf =0.66 (n-hexane);
1HNMR (300 MHz, CDCl 3): d=0.74–0.97 (m, 15H, SnCH2C2H4CH3),
1.29 (tq, J=7.3, 7.3 Hz, 6H, SnC2H4CH2CH3), 1.40–1.53 (m, 6H,
SnCH2CH2C2H5), 1.74–1.92 (m, 3H, 5-H3), 2.67 (q, J=7.2 Hz, 2H, 2-H2),
3.36 (t, J=7.4 Hz, 2H, 1-H2), 5.32–5.63 (m, 1H, 3-H); 13C NMR
MTBE 1:1); [a]2D4 =+36.5 (c=1.00, CHCl3); HNMR (300 MHz, CDCl 3):
d=ꢀ0.01, 0.02, 0.03 (3s, 12H, Si-CH3), 0.80–0.88 (m, 21H, 5-CH3, Si-C-
ACHTREUNG(CH3)3), 1.02 (d, J=6.8 Hz, 3H, 3-CH3), 1.43 (ddd, J=14.6, 7.9, 3.3 Hz,
1H, 1’’-H2), 1.59–1.71 (m, 3H, 5-H, 3’-H2, 1’’-H2), 1.79 (dq, J=10.1,
6.7 Hz, 1H, 3-H), 1.91–2.02 (m, 1H, 3’-H2), 1.99, 2.06 (2s, 6H, OAc), 3.08
(s, 3H, 2-OCH3), 3.17–3.30 (m, 3H, 4’-H, 3’’-H2), 3.27, 3.36 (2s, 6H, 4’-
OCH3, 3’’-OCH3), 3.41–3.45 (m, 2H, 5’-H2), 3.70 (dd, J=10.2, 4.7 Hz,
1H, 4-H), 3.82 (ddd, J=7.7, 2.8, 2.8 Hz, 1H, 6-H), 3.85–3.93 (m, 1H, 2’’-
H), 4.46–4.56 (m, 2H, CH2Ph), 5.00 (d, J=5.5 Hz, 1H, 1’-H), 5.41 (ddd,
J=9.1, 3.6, 5.5 Hz, 1H, 2’-H), 7.22–7.32 (m, 5H, Ph); 13C NMR
(75.5 MHz, CDCl3): d=ꢀ4.9, ꢀ4.8, ꢀ4.3, ꢀ3.8 (Si-CH3), 5.1 (5-CH3),
11.2 (3-CH3), 18.1, 18.2 (Si-C
ACHTREUNG(CH3)3), 35.7 (C-3’), 36.5 (C-3), 38.5 (C-1’’), 39.6 (C-5), 47.9 (2-OCH3),
58.1, 58.7 (4’-OCH3, 3’’-OCH3), 69.0, 69.2 (C-6, C-2’), 69.9 (C-2’’), 72.1
(C-5’), 73.0, 73.1 (C-4, C-1’), 73.3 (CH2Ph), 76.5 (C-4’), 77.6 (C-3’’), 100.8
(C-2), 127.5, 128.3, 138.2 (Ph), 169.8, 170.0 (2 OAc); IR (film): n˜ =2954
(s), 2930 (s), 2892 (s), 2857 (s), 1748 (s), 1463 (m), 1370 (m), 1249 (s),
1227 (s), 1104 (s), 1072 (s), 836 (m), 775 cmꢀ1 (m); HR-MS (EI): m/z:
calcd for C40H71O10Si2: 767.4586; found 767.4581 [MꢀOCH3]+. Diastereo-
meric diacetate: Rf =0.41 (n-hexane/MTBE 1:1); 1HNMR (300 MHz,
CDCl3): d=0.00, 0.02, 0.03, 0.04 (4s, 12H, Si-CH3), 0.81 (d, J=7.0 Hz,
(75 MHz, CDCl3): d=9.1 (dt, JCAHTRE(UNG C,Sn)=158, 165 Hz, SnCH2C3H7), 13.7
(SnC3H6CH3), 19.3 (C5), 27.3, 29.1 (SnCH2C2H4CH3), 31.6, 32.5 (C1, C2),
136.2 (C3), 142.4 (C4); elemental analysis calcd (%) for C17H35BrSn
(438.06): C 46.61, H8.05, Br 18.24; found C 46.71, H8.05, Br 18.16.
Aldehyde 30: Benzyl ether cleavage: Pd(OH)2/C (70 mg, 20 wt%) was
added to benzyl ether 26 in AcOEt (30 mL). After hydrogenation
(1 atm) at 208C for 1 h TLC control showed complete turnover. The sol-
vent was evaporated. The residue was taken up in toluene (3 mL) and
purified by chromatography (70 g silica gel, PE/MTBE 5:1) to give the
corresponding alcohol (767 mg, 1.08 mmol, 98%) as a colorless oil. Rf =
0.32 (n-hexane/MTBE 1:2); [a]2D4 =+44.4 (c=1.00, CHCl3); 1HNMR
(300 MHz, CDCl3): d=ꢀ0.02, 0.01, 0.02 (3s, 12H, Si-CH3), 0.78–0.86 (m,
3H, 5-CH3), 0.85, 0.87 (2s, 18H, Si-CCAHTRE(UNG CH3)3), 0.90 (d, J=6.6 Hz, 3H, 3-
CH3), 1.42–1.48 (m, 1H, 1’’-H2), 1.57–1.88 (m, 5H, 3-H, 5-H, 3’-H2, 1’’-
H2), 1.99, 2.06 (2s, 6H, OAc), 3.21–3.37 (m, 2H, 3’’-H2), 3.27, 3.30, 3.33
(3s, 9H, 2-OCH3, 4’-OCH3, 3’’-OCH3), 3.40–3.47 (m, 3H, 4’-H, 5’-H2),
3.63 (dd, J=10.4, 4.7 Hz, 1H, 4-H), 3.73–3.79 (m, 1H, 6-H), 3.85–3.94
(m, 1H, 2’’-H), 4.46–4.55 (m, 2H, CH2Ph), 5.19 (d, J=5.1 Hz, 1H, 1’-H),
5.40 (dt, J=8.1, 5.1 Hz, 1H, 2’-H), 7.22–7.32 (m, 5H, Ph); 13C NMR
(75.5 MHz, CDCl3): d=ꢀ4.9, ꢀ4.7, ꢀ4.3, ꢀ3.8 (Si-CH3), 5.0 (5-CH3),
21H, 5-CH3, Si-CACHTER(UNG CH3)3), 1.01 (d, J=6.6 Hz, 3H, 3-CH3), 1.41 (ddd, J=
14.4, 8.0, 3.1 Hz, 1H, 1’’-H2), 1.51–1.86 (m, 5H, 3-H, 5-H, 3’-H2, 5’-OH,
1’’-H2), 1.98–2.11 (m, 1H, 3’-H2), 2.00, 2.06 (2s, 6H, OAc), 3.07 (s, 3H, 2-
OCH3), 3.18–3.30 (m, 3H, 4’-H, 3’’-H2), 3.30, 3.34 (2s, 6H, 4’-OCH3, 3’’-
OCH3), 3.37–3.47 (m, 1H, 5’-H2), 3.65–3.75 (m, 2H, 4-H, 5’-H2), 3.82
(ddd, J=8.1, 2.6, 2.6 Hz, 1H, 6-H), 3.85–3.93 (m, 1H, 2’’-H), 5.01 (d, J=
5.1 Hz, 1H, 1’-H), 5.30 (ddd, J=8.1, 4.9, 4.9 Hz, 1H, 2’-H); 13C NMR
(75 MHz, CDCl3): d=ꢀ4.9, ꢀ4.7, ꢀ4.3, ꢀ3.7 (Si-CH3), 5.1 (5-CH3), 11.2
11.9 (3-CH3), 18.1, 18.2 (Si-C
ACHTREUNG(CH3)3), 33.9 (C-3’), 38.0 (C-3), 38.5 (C-1’’), 39.5 (C-5), 49.7 (2-OCH3),
57.1, 58.7 (4’-OCH3, 3’’-OCH3), 69.3, 69.4 (C-6, C-2’), 70.1 (C-2’’), 71.1
(C-5’), 73.2 (CH2Ph), 73.8 (C-4), 74.6 (C-1’), 77.5 (C-4’), 77.6 (C-3’’),
101.3 (C-2), 127.5, 127.6, 128.3, 138.2 (Ph), 169.9, 170.0 (2OAc).
(E)-4-Tributylstannylpent-3-en-1-ol (28): Preparation of the mixed cuprate
[Bu3Sn(Bu)CuCN]Li2: nBuLi (16 mL, 2.5m in hexane, 40 mmol) was
added slowly at ꢀ308C to a suspension of CuCN (1.8 g, 20 mmol) in
Et2O (40 mL)/THF (24 mL). The reaction mixture was stirred for 15 min
at ꢀ108C. After cooling to ꢀ308C nBu3SnH(11 mL, 40 mmol) was
added dropwise.
(3-CH3), 18.1, 18.2 (Si-C
ACHTRE(UGN CH3)3), 20.8, 20.9 (2 OAc), 25.8, 25.9 (Si-C-
AHCTRE(UNG CH3)3), 34.6 (C-3’), 36.5 (C-3), 38.6 (C-1’’), 39.6 (C-5), 47.9 (2-OCH3),
57.5, 58.8 (4’-OCH3, 3’’-OCH3), 63.4 (C-5’), 69.0, 69.1 (C-6, C-2’), 69.8 (C-
2’’), 72.5 (C-4), 73.0 (C-1’), 77.5 (C-3’’), 77.9 (C-4’), 100.8 (C-2), 169.9,
170.1 (2OAc); IR (film): n˜ =3472 (br), 2953 (s), 2930 (s), 2891 (s), 2858
(s), 1746 (s), 1463 (m), 1373 (m), 1250 (s), 1228 (s), 1072 (s), 869 (m), 835
(m), 774 cmꢀ1 (m); HR-MS (EI): m/z: calcd for C33H65O10Si2: 677.4116;
found 677.4112 [MꢀOCH3]+.
Dess–Martin oxidation: Dess–Martin periodinane (245 mg, 577 mmol) was
dissolved in CH2Cl2 (5 mL) and pyridine (93 mL, 1.2 mmol) was added at
208C. The alcohol (315 mg, 0.444 mmol) dissolved in CH2Cl2 (3 mL) was
added and the reaction mixture was stirred for 45 min. NaHCO3 (20 mL),
water (3 mL), Na2S2O3 (211 mg, 1.33 mmol), and MTBE (20 mL) were
added and the mixture was stirred for 10 min. The aqueous layer was ex-
tracted with MTBE (3ꢂ10 mL). The combined organic layers were
washed with brine (40 mL), dried with MgSO4, concentrated and the resi-
due was purified by chromatography (25 g silica gel, pentane/MTBE 1:1)
Metallation of dihydrofuran: tBuLi (14 mL, 1.7m in pentane, 24 mmol)
was added at ꢀ608C over 5 min to dihydrofuran (1.7 mL, 20 mmol) in
THF (20 mL). The reaction mixture was stirred at 08C for 50 min.
Reaction of the lithiated dihydrofuran with the mixed cuprate: The solu-
tion of the lithiated dihydrofuran was cooled to ꢀ308C. To this was
added via a transfer needle the solution of the mixed cuprate. The reac-
tion mixture was stirred at 08C for 90 min. Next it was cooled to ꢀ308C
and MeI (8.8 mL, 0.14 mol) was added dropwise. The mixture was then
kept at 208C for 3 h. Satd aq NH4Cl/satd aq NH3 (150 mL, 4:1) was
added for starting the work up. After 30 min, the deep blue mixture was
extracted with MTBE (3ꢂ100 mL). The combined organic layers were
7372
www.chemeurj.org
ꢁ 2006 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 7364 – 7377

Apoptolidin A Aglycone
FULL PAPER
to yield the sensitive aldehyde 30 (289 mg, 0.409 mmol, 92%) as a color-
less oil. Rf =0.36 (MTBE/n-hexane 1:1); HNMR (300 MHz, CDCl 3): d=
analysis calcd (%) for C11H22O3Si (230.38): C 57.35, H9.63; found C
57.48, H9.44.
1
ꢀ0.02, 0.00, 0.01 (3s, 12H, Si-CH3), 0.77–0.86 (m, 21H, 5’-CH3, Si-C-
(2E,4R,5S)-Ethyl
5-tert-butyldimethylsilyloxy-6-hydroxy-2,4-dimethyl-
ACHTREUNG(CH3)3), 1.00 (d, J=6.6 Hz, 3H, 3’-CH3), 1.42 (ddd, J=14.3, 7.9, 3.4 Hz,
hex-2-enoate (34): Lactone 33 (4.40 g, 19.1 mmol) was dissolved in
CH2Cl2 (90 mL) at ꢀ788C and DIBAH(29 mL, 1.0 m in PE, 29 mmol)
was added dropwise. After stirring for 30 min at ꢀ788C, the reaction was
quenched by addition to a cooled (08C) solution of Rochelles salt
(150 mL, 1.0m). After 1.5 h stirring the two layers were separated and
the aqueous layer was extracted with CH2Cl2 (3ꢂ40 mL). The combined
organic layers were dried with MgSO4 and concentrated. The crude lactol
(4.40 g, 18.9 mmol, 99%) was used for the next step without purification.
The lactol was azeotroped with toluene (3ꢂ10 mL) and dissolved in tol-
1H, 1’’-H2), 1.60–1.85 (m, 4H, 3-H2, 3’-H, 5’-H, 1’’-H2), 1.94–2.05 (m, 1H,
3-H2), 1.99, 2.04 (2s, 6H, OAc), 3.06 (s, 3H, 2’-OCH3), 3.21–3.79 (m, 2H,
3’’-H2), 3.27, 3.37 (2s, 6H, 2-OCH3, 3’’-OCH3), 3.35–3.45 (m, 1H, 2-H),
3.68 (dd, J=10.4, 4.7 Hz, 1H, 4’-H), 3.81 (ddd, J=7.8, 2.8, 2.7 Hz, 1H, 6’-
H), 3.84–3.92 (m, 1H, 2’’-H), 4.99 (d, J=5.7 Hz, 1H, 5-H), 5.39 (ddd, J=
9.4, 5.6, 3.0 Hz, 1H, 4-H), 9.57 (d, J=2.1 Hz, 1H, 1-H); 13C NMR
(75 MHz, CDCl3): d=ꢀ4.9, ꢀ4.8, ꢀ4.4, ꢀ3.8 (Si-CH3), 5.0 (5’-CH3), 11.2
(3’-CH3), 18.0, 18.2 (Si-C
ACHTRE(UGN CH3)3), 20.7, 20.8 (2 OAc), 25.8, 25.9 (Si-C-
ACHTREUNG(CH3)3), 33.5 (C-3), 36.5 (C-3’), 38.4 (C-1’’), 39.5 (C-5’), 47.9 (2’-OCH3),
uene (660 mL). Ph3PCACHTRE(UNG CH3)CO2Et (17.1 g, 47.3 mmol) was added and
58.6, 58.7 (2-OCH3, 3’’-OCH3), 68.1 (C-4), 69.2 (C-6’), 69.8 (C-2’’), 72.8,
73.0 (C-4’, C-5), 77.4 (C-3’’), 82.4 (C-2), 100.7 (C-2’), 169.7, 170.0
(2OAc), 203.0 (C-1).
the mixture was heated under reflux for 20 h. The solvent was removed
and the residue was purified by flash chromatography (450 g silica gel,
pentane/MTBE 5:1) to give ester 34 (4.90 g, 15.5 mmol, 82%) as a color-
less oil. Rf =0.52 (n-hexane/MTBE 1:1); [a]2D2 =+25.8 (c=1.31, CHCl3);
1HNMR (200 MHz, CDCl 3): d=0.057, 0.064 (2s, 6H, SiCH3), 0.89 (s,
Alcohol 31: Bromide 29 (2.297 g, 5.244 mmol) and 1,2-dibromoethane
(0.45 mL, 5.2 mmol) in Et2O (5 mL) were added dropwise to magnesium
turnings (254 mg, 10.5 mmol). The rate of bromide addition was adjusted
so that a gentle boiling of the reaction mixture was maintained. Et2O
(5 mL) was added and the solution of the Grignard reagent was cooled
to ꢀ788C. Aldehyde 30 (618 mg, 0.874 mmol) dissolved in Et2O (4 mL)
was added dropwise. After stirring at ꢀ788C for 3.5 h, the reaction was
quenched by addition of iPrOH(4 mL). The reaction mixture was
warmed to 208C and then separated between NaHCO3 (20 mL) and
MTBE (20 mL). The aqueous layer was extracted with MTBE (3ꢂ
10 mL). The combined organic layers were washed with brine (40 mL)
and dried with MgSO4. Chromatography (100 g silica gel, PE/MTBE 5:1)
gave alcohol 31 (542 mg, 0.508 mmol, 58%) as a colorless oil. Rf =0.52
(n-hexane/MTBE 1:1); [a]2D4 =+27.6 (c=1.00, CHCl3); 1HNMR
(600 MHz, CDCl3): d=ꢀ0.01, 0.01, 0.016, 0.020 (4s, 12H, Si-CH3), 0.80–
9H, SiCACTHER(UGN CH3)3), 0.99 (d, J=6.8 Hz, 3H, 4-CH3), 1.26 (t, J=7.1 Hz, 3H,
CO2CH2CH3), 1.78–1.90 (m, 1H, OH), 1.83 (d, J=1.5 Hz, 3H, 2-CH3),
2.65–2.84 (m, 1H, 4-H), 3.37–3.59 (m, 3H, 5-H, 6-H2), 4.15 (q, J=7.1 Hz,
2H, CO CH2CH3), 6.55 (dq, J=10.3, 1.3 Hz, 1H, 3-H); 13C NMR
2
(75 MHz, CDCl3): d=ꢀ4.7, ꢀ4.3 (SiCH3), 12.6 (2-CH3), 14.3
(CH3CH2O), 15.8 (4-CH3), 18.1 (SiCACHTER(UGN CH3)3), 25.7 (SiCCAHTREU(NG CH3)3), 36.2 (C-
4), 60.5 (OCH2CH3), 64.7 (C-6), 75.8 (C-5), 127.9 (C-2), 143.6 (C-3),
168.2 (C-1); IR (film): n˜ =3490 (brs), 2957 (s), 2930 (s), 2885 (s), 2859
(s), 1712 (s), 1369 (s), 1254 (s), 1116 (s), 1049 cmꢀ1 (s); elemental analysis
calcd (%) for C16H32O4Si (316.51): C 60.72, H10.19; found C 60.49, H
10.38.
AHCTRE(UGN 2E,4R,5S)-Ethyl 5-tert-butyldimethylsilyloxy-2,4-dimethyl-6-triethylsilyl-
oxy-hex-2-enoate (35): Imidazole (2.1 g, 31 mmol) and TESCl (3.1 mL,
19 mmol) were added at 08C to alcohol 34 (4.90 g, 15.5 mmol) in CH2Cl2
(90 mL). After stirring for 30 min at 08C, the reaction was quenched with
phosphate buffer solution (50 mL, 1.0m, pH7) and the aqueous layer was
extracted with MTBE (3ꢂ70 mL). The combined organic layers were
washed with brine (80 mL), dried with MgSO4 and the solvents were
evaporated. The crude product was purified by flash chromatography
(500 g silica gel, pentane/MTBE 9:1) to give bis(silylether) 35 (6.20 g,
14.4 mmol, 93%) as a colorless oil. Rf =0.21 (n-hexane/CH2Cl2 5:1);
[a]2D3 =+0.21 (c=0.96, CHCl3); 1HNMR (200 MHz, CDCl 3): d=ꢀ0.03,
ꢀ0.02 (2s, 6H, SiCH3), 0.58 (q, J=7.9 Hz, 6H, SiCH2CH3), 0.87 (s, 9H,
0.87 (m, 36H, Si-CACHTREUNG(CH3)3, Sn-nBu, 5’-CH3), 1.02 (d, J=6.6 Hz, 3H, 3’-
CH3), 1.23–1.31 (m, 6H, Sn-nBu), 1.38–1.50 (m, 7H, Sn-nBu, 1’’-H2),
1.50–1.56 (m, 1H, 5-H2), 1.61–1.72 (m, 3H, 5’-H, 8-H2, 1’’-H2), 1.78–1.86
(m, 1H, 3’-H), 1.81 (s, 3H, 1-H3), 1.99–2.06 (m, 1H, 8-H2), 2.00, 2.05 (2s,
6H, OAc), 2.11 (d, J=5.8 Hz, 1H, 6-OH), 2.12–2.20 (m, 1H, 4-H2), 2.25–
2.32 (m, 1H, 4-H2), 3.03–3.06 (m, 1H, 7-H), 3.08 (s, 3H, 2’-OCH3), 3.23–
3.27 (m, 2H, 3’’-H2), 3.28 (s, 3H, 3’’-OCH3), 3.39 (s, 3H, 7-OCH3), 3.43–
3.50 (m, 1H, 6-H), 3.69 (dd, J=10.0, 4.9 Hz, 1H, 4’-H), 3.80–3.84 (m,
1H, 6’-H), 3.86–3.91 (m, 1H, 2’’-H), 5.01 (d, J=5.7 Hz, 1H, 10-H), 5.33
(ddd, J=8.8, 5.3, 3.7 Hz, 1H, 9-H), 5.47–5.51 (m, 1H, 3-H); 13C NMR
(75 MHz, CDCl3): d=ꢀ4.9, ꢀ4.7, ꢀ4.3, ꢀ3.8 (Si-CH3), 5.1 (C-5’), 9.0 (Sn-
SiCACHTREU(GN CH3)3), 0.93 (t, J=7.9 Hz, 9H, SiCH2CH3), 0.96 (d, J=6.5 Hz, 3H,
nBu), 11.2 (C-3’), 13.7 (Sn-nBu), 18.1, 18.2 (Si-C
ACHTRE(UNG CH3)3), 19.1 (C-1), 20.9
4-CH3), 1.26 (t, J=7.1 Hz, 3H, CO2CH2CH3), 1.82 (d, J=1.5 Hz, 3H, 2-
CH3), 2.65–2.83 (m, 1H, 4-H), 3.42–3.49 (m, 2H, 6-H2), 3.51–3.62 (m,
1H, 5-H), 4.05–4.25 (m, 2H, CO2CH2CH3), 6.71 (dq, J=10.4, 1.2 Hz, 1H,
3-H); 13C NMR (75 MHz, CDCl3): d=ꢀ5.0, ꢀ4.2 (SiCH3), 4.3
(SiCH2CH3), 6.7 (SiCH2CH3), 12.4 (2-CH3), 13.2 (4-CH3), 14.3
(2 OAc), 24.7 (C-4), 25.8, 25.9 (Si-C(CH3)3), 27.3, 29.1 (Sn-nBu), 33.2 (C-
AHCTREUNG
5), 34.9 (C-8), 36.5 (C-3’), 38.6 (C-1’’), 39.6 (C-5’), 47.9 (2’-OCH3), 58.8
(3’’-OCH3), 59.5 (7-OCH3), 69.1 (C-6’), 69.4 (C-9), 69.8 (C-2’’), 72.9, 73.0,
73.1 (C-6, C-10, C-4’), 77.5 (C-3’’), 80.4 (C-7), 100.8 (C-2’), 138.6 (C-2),
140.2 (C-3), 168.8, 170.2 (2 OAc); IR (film): n˜ =3482 (brw), 2956 (s),
2929 (s), 2857 (s), 1748 (s), 1463 (m), 1373 (m), 1249 (s), 1228 (s), 1071
(s), 869 (m), 836 (m), 774 cmꢀ1 (m); HR-MS (EI): m/z: calcd for
(CO2CH2CH3), 18.2 (SiCACHTREU(NG CH3)3), 25.9 (SiCACHTREU(GN CH3)3), 35.4 (C-4), 60.3
(CO2CH2CH3), 64.8 (C-6), 75.6 (C-5), 126.4 (C-2), 145.6 (C-3), 168.4 (C-
1); IR (film): n˜ =2957 (s), 2936 (s), 2878 (s), 1714 (s), 1463 (s), 1367 (s),
1254 (s), 1080 cmꢀ1 (s); elemental analysis calcd (%) for C22H46O4Si2
(430.77): C 61.34, H10.76; found C 61.33, H10.87.
C47H93O11Si2Sn: 1009.5278; found 1009.5280 [MꢀC
(2S,3S)-3-tert-Butyldimethylsilyloxy-2-methyl-g-butanolide (33): Alcohol
(CH3)3]+.
ACHTREUNG
ACHTREUNG
32 (2.52 g, 21.7 mmol) was dissolved in CH2Cl2 (85 mL) and cooled to
08C. 2,6-Lutidine (5.1 mL, 43 mmol) and TBSOTf (6.0 mL, 26 mmol)
were added and the solution was stirred for 4 h at 08C. The reaction was
quenched by addition of NaHCO3 (40 mL) and water (40 mL). The aque-
ous layer was extracted with CH2Cl2 (3ꢂ50 mL). The combined organic
layers were washed with brine (60 mL), dried with Na2SO4, and the sol-
vent was evaporated. The residue was purified by flash chromatography
(180 g silica gel, pentane/MTBE 9:1) to yield silyl ether 33 (4.40 g,
19.1 mmol, 88%) as a colorless oil. Rf =0.47 (n-hexane/MTBE 5:1);
[a]2D2 =ꢀ2.1 (c=1.0, CHCl3); 1HNMR (200 MHz, CDCl 3): d=0.05, 0.06
(2E,4E,6R,7S)-Ethyl
7-tert-butyldimethylsilyloxy-2,4,6-trimethyl-8-tri-
ethylsilyloxyocta-2,4-dienoate (36): DIBAH reduction: Ester 35 (6.20 g,
14.4 mmol) was dissolved in toluene (120 mL) at ꢀ788C and DIBAH
(32 mL, 1.0m in PE, 32 mmol) was added dropwise. After stirring for
30 min at ꢀ788C, the reaction was quenched by addition via cannula to a
cooled (08C) solution of Rochelles salt (450 mL, 1.0m). After 2 h stirring
the two layers were separated and the aqueous layer was extracted with
MTBE (3ꢂ70 mL). The combined organic layers were washed with brine
(80 mL), dried with Na2SO4 and concentrated. The crude allylic alcohol
(5.50 g, 14.1 mmol, 98%) was used for the next step without purification.
Rf =0.47 (n-hexane/MTBE 1:1); [a]2D3 =ꢀ20.2 (c=0.96, CHCl3); 1HNMR
(200 MHz, CDCl3): d=0.01, 0.03 (2s, 6H, SiCH3), 0.57 (q, J=8.1 Hz, 6H,
(2s, 6H, SiCH3), 0.86 (s, 9H, SiCCAHTER(UNG CH3)3), 1.23 (d, J=7.2 Hz, 3H, 2-CH3),
2.47 (dq, J=7.3, 6.9 Hz, 1H, 2-H), 3.90 (ddd, J=8.9, 6.1, 0.3 Hz, 1H, 4-
H), 4.07–4.19 (m, 1H, 3-H), 4.33 (dd, J=9.0, 6.2 Hz, 1H, 4-H); 13C NMR
SiCH2CH3), 0.87 (s, 9H, SiCCATHER(UGN CH3)3), 0.91 (d, J=6.8 Hz, 3H, 4-CH3), 0.93
(75 MHz, CDCl3): d=ꢀ4.8 (2C, SiCH3), 12.7 (2-CH3), 17.9 (SiC
25.6 (SiC(CH3)3), 43.3 (C-2), 72.4 (C-4), 74.7 (C-3), 177.7 (C-1); IR
(film): n˜ =2956 (m), 1784 (s), 1345 (s), 1129 (s), 1001 cmꢀ1 (s); elemental
A
(t, J=7.6 Hz, 9H, SiCH2CH3), 1.20 (t, J=6.0 Hz, 1H, OH), 1.65 (d, J=
1.2 Hz, 3H, 2-CH3), 2.54–2.68 (m, 1H, 4-H), 3.37–3.55 (m, 3H, 5-H, 6-
H2), 3.97 (d, J=5.1 Hz, 2H, 1-H2), 5.33 (dq, J=9.6, 1.1 Hz, 1H, 3-H);
ACHTREUNG
Chem. Eur. J. 2006, 12, 7364 – 7377
ꢁ 2006 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
www.chemeurj.org
7373

U. Koert et al.
13C NMR (75 MHz, CDCl3): d=ꢀ4.8, ꢀ4.1 (SiCH3), 4.4 (SiCH2CH3), 6.8
stirred for 1 h at 208C. The reaction was quenched by addition of
NaHCO3 (30 mL) and Na2S2O3 (3.1 g, 13 mmol). After stirring for
30 min, the layers were separated and the aqueous layer was extracted
with MTBE (3ꢂ40 mL). The combined organic layers were washed with
brine (30 mL), dried with MgSO4 and concentrated. The crude aldehyde
(630 mg, 1.78 mmol) was used for the next step without purification.
(SiCH2CH3), 13.8 (2-CH3), 14.6 (4-CH3), 18.2 (SiCACTHRE(UNG CH3)3), 25.9 (SiC-
ACHTREUNG(CH3)3), 34.4 (C-4), 65.1 (C-6), 69.1 (C-1), 76.8 (C-5), 130.4 (C-3), 144.7
(C-2); IR (film): n˜ =3338 (brs), 2957 (s), 2930 (s), 2878 (s), 2859 (s), 1462
(s), 1252 (s), 1126 cmꢀ1 (s); elemental analysis calcd (%) for C20H44O3Si2
(388.73): C 61.79, H11.41; found C 61.76, H11.52.
MnO2 oxidation: MnO2 (27.5 g, 316 mmol) was added at 208C to the al-
lylic alcohol (5.50 g, 14.1 mmol) dissolved in CH2Cl2 (220 mL). The reac-
tion mixture was heated to 408C for 30 min. After cooling to 208C the
mixture was filtered over a pad of Celite and the residue was washed
with CH2Cl2 (200 mL). The solvent was removed and the aldehyde
(5.40 g, 14.0 mmol, 99%) thus obtained was used directly for the follow-
ing Wittig reaction. Rf =0.78 (n-hexane/MTBE 4:1); 1HNMR (200 MHz,
CDCl3): d=0.01, 0.03 (2s, 6H, SiCH3), 0.58 (q, J=8.0 Hz, 6H,
Takai reaction: CrCl2 (1.46 g, 11.9 mmol) was treated with a degassed
mixture of 1,4-dioxane and THF (5 mL, 4:1). After 10 min a mixture of
the crude aldehyde (630 mg, 1.78 mmol), CHI3 (1.4 g, 3.6 mmol) and hy-
drochinone (5 mg, 0.05 mmol) in a mixture of 1,4-dioxane and THF
(20 mL, 4:1) was added via cannula to the CrCl2 suspension at 208C.
After stirring for 16 h the reaction was quenched by addition of pentane/
MTBE 3:1 (50 mL). The mixture was filtered over a pad of Celite and
washed with pentane/MTBE (3:1, 200 mL). The organic layer was
washed subsequently with aq 1.0m Na2S2O3 (50 mL) and brine (50 mL).
After drying with MgSO4 the solvents were evaporated and the crude
product was purified by chromatography (100 g silica gel, pentane/
CH2Cl2 4:1 ! 2:1) to yield colorless iodide 38 (571 mg, 1.19 mmol, 67%,
2 steps) as a single E isomer. Rf =0.34 (n-hexane/CH2Cl2 1:1); [a]2D3 =+
SiCH2CH3), 0.87 (s, 9H, SiCACHTERU(NG CH3)3), 0.93 (t, J=7.6 Hz, 9H, SiCH2CH3),
1.03 (d, J=6.8 Hz, 3H, 4-CH3), 1.74 (d, J=1.5 Hz, 3H, 2-CH3), 2.86–3.06
(m, 1H, 4-H), 3.44–3.53 (m, 2H, 6-H2), 3.56–3.68 (m, 1H, 5-H), 6.45 (dq,
J=10.2, 1.2 Hz, 1H, 3-H), 9.36 (s, 1H, 1-H).
Wittig olefination: The crude aldehyde was azeotroped with toluene (3ꢂ
20 mL) and dissolved in toluene (700 mL). Ph3PCACHTREU(NG CH3)CO2Et (20.3 g,
1
25.8 (c=0.19, CHCl3); HNMR (300 MHz, CDCl 3): d=ꢀ0.04, ꢀ0.05 (2s,
6H, SiCH3), 0.88 (d, J=6.8 Hz, 3H, 6-CH3),0.90 (s, 9H, SiCCAHTRE(UNG CH3)3), 1.01
56.0 mmol) was added and the mixture was heated under reflux for 14 h.
The solvent was removed and the residue was purified by flash chroma-
tography (550 g silica gel, pentane/CH2Cl2 2:1) to yield dienoate 36
(5.30 g, 11.3 mmol, 81%) as a colorless oil. Starting from this step all re-
actions were carried out under exclusion of sun light (working with
amber colored glassware in a shaded fume hood). Rf =0.44 (n-hexane/
CH2Cl2 1:1); [a]2D3 =+11.8 (c=0.97, CHCl3); 1HNMR (200 MHz,
CDCl3): d=0.01, 0.03 (2s, 6H, SiCH3), 0.57 (q, J=7.8 Hz, 6H,
(t, J=7.1 Hz, 3H, CO2CH2CH3), 1.57 (d, J=1.3 Hz, 3H, 4-CH3), 2.11 (d,
J=1.3 Hz, 3H, 2-CH3), 2.32–2.46 (m, 1H, 6-H), 3.59 (dt, J=6.6, 0.9 Hz,
1H, 7-H), 4.07 (q, J=7.1 Hz, 2H, CO2CH2CH3), 5.25 (d, J=10.0 Hz, 1H,
5-H), 6.00 (dd, J=14.4, 1.0 Hz, 1H, 9-H), 6.42 (dd, J=14.5, 6.8 Hz, 1H,
8-H), 7.38 (s, 1H, 3-H); 13C NMR (75 MHz, CDCl3): d=ꢀ5.0, ꢀ4.4
(SiCH3), 14.1 (2-CH3), 14.3 (CO2CH2CH3), 16.3 (4-CH3), 16.7 (6-CH3),
18.2 (SiCACTHREU(GN CH3)3), 25.8 (SiCAHCTRE(UGN CH3)3), 39.7 (C-6), 60.6 (CO2CH2CH3), 76.7
(C-9), 78.9 (C-7), 126.0 (C-4), 132.4 (C-2), 136.6 (C-5), 142.7 (C-3), 147.6
(C-8), 169.1 (C-1); IR (film): n˜ =2957 (s), 2930 (s), 2897 (s), 2858 (s),
1708 (s), 1460 (s), 1366 (s), 1252 (s), 1034 cmꢀ1 (s); elemental analysis
calcd (%) for C20H35IO3Si (478.48): C 50.20, H7.37; found C 49.98, H
7.31; HR-MS (ESI): m/z: calcd for: 479.1478; found 479.1486 [M+H]+.
SiCH2CH3), 0.86 (s, 9H, SiCCAHTER(UNG CH3)3), 0.88–1.00 (m, 12H, 6-CH3,
SiCH2CH3), 1.28 (t, J=7.0 Hz, 3H, CO2CH2CH3), 1.82 (d, J=1.3 Hz, 3H,
4-CH3), 1.98 (d, J=1.5 Hz, 3H, 2-CH3), 2.60–2.80 (m, 1H, 6-H), 3.39–
3.60 (m, 3H, 7-H, 8-H2), 4.18 (q, J=7.1 Hz, 2H, CO2CH2CH3), 5.52 (d,
J=9.8 Hz, 1H, 5-H), 7.09 (brs, 1H, 3-H); 13C NMR (75 MHz, CDCl3):
d=ꢀ4.8, ꢀ4.0 (SiCH3), 4.3 (SiCH2CH3), 6.8 (SiCH2CH3), 14.0 (2-CH3),
Ethyl (2E,4E,6E,10E,8R,9S)-9-tert-Butyldimethylsilyloxy-11-iodo-2,4,6,8-
tetramethylundecatetra-2,4,6,10-enoate (39): DIBAH reduction: Ester 38
(571 mg, 1.19 mmol) was dissolved in toluene (17 mL) at ꢀ788C and
DIBAH(2.6 mL, 1.0 m in PE, 2.6 mmol) was added via syringe within
10 min. After stirring for 30 min at ꢀ788C, the reaction was quenched by
addition via cannula to a cooled (08C) solution of Rochelles salt (50 mL,
1.0m). After 1 h stirring the two layers were separated and the aqueous
layer was extracted with MTBE (3ꢂ40 mL). The combined organic
layers were washed with brine (30 mL), dried with MgSO4, concentrated
and the residue was purified by flash chromatography (60 g silica gel,
pentane/MTBE 6:1 ! 4:1) to give the corresponding alcohol (510 mg,
1.17 mmol, 98%) as a colorless oil. Rf =0.44 (CHCl3/MeOH100:1);
[a]2D3 =ꢀ22.9 (c=0.19, CHCl3); 1HNMR (200 MHz, CDCl 3): d=ꢀ0.01,
14.3 (CO2CH2CH3), 14.7 (6-CH3), 16.5 (4-CH3), 18.2 (SiCCAHTRE(UNG CH3)3), 25.9
(SiCACHTREUNG(CH3)3), 35.4 (C-6), 60.5 (CO2CH2CH3), 65.2 (C-8), 76.6 (C-7), 125.3
(C-4), 131.1 (C-2), 139.9 (C-5), 143.1 (C-3), 169.2 (C-1); IR (film): n˜ =
2957 (s), 2931 (s), 2859 (s), 1710 (s), 1463 (s), 1367 (s), 1252 (s),
1112 cmꢀ1 (s); elemental analysis calcd (%) for C25H50O4Si2 (470.83): C
63.77, H10.70; found C 63.62, H10.91.
(2E,4E,6R,7S)-Ethyl 7-tert-butyldimethylsilyloxy-8-hydroxy-2,4,6-trimeth-
ylocta-2,4-dienoate (37): TES ether 36 (5.30 g, 11.3 mmol) was dissolved
in CH2Cl2 (60 mL) and MeOH(30 mL) and cooled to 0 8C. CSA (0.21 g,
0.91 mmol) was added in portions. The reaction was monitored by TLC
(n-hexane/CH2Cl2 1:1). The reaction was quenched after 15 min by addi-
tion of phosphate buffer (50 mL, 1.0m, pH7) and MTBE (100 mL). The
layers were separated and the aqueous layer was extracted with MTBE
(3ꢂ50 mL). The combined organic layers were washed with brine
(60 mL), dried with MgSO4, concentrated and the resulting crude oil was
purified by flash chromatography (550 g silica gel, pentane/MTBE 5:1) to
obtain the corresponding alcohol 37 (3.80 g, 10.5 mmol, 93%) as a color-
less oil. Rf =0.45 (n-hexane/MTBE 1:1); [a]2D3 =+0.39 (c=1.04, CHCl3);
1HNMR (200 MHz, CDCl 3): d=0.08 (2s, 6H, SiCH3), 0.90 (s, 9H, SiC-
0.02 (2s, 6H, SiCH3), 0.87 (s, 9H, SiCCAHTRE(UNG CH3)3), 0.96 (d, J=6.8 Hz, 3H, 6-
CH3), 1.71 (d, J=1.0 Hz, 3H, 4-CH3), 1.77 (d, J=1.0 Hz, 3H, 2-CH3),
2.41–2.61 (m, 1H, 6-H), 3.84 (t, J=6.5 Hz, 1H, 7-H), 4.03 (brs, 2H, 2-
H2), 5.06 (d, J=9.8 Hz, 1H, 5-H), 5.84 (s, 1H, 3-H), 6.15 (dd, J=14.3,
1.0 Hz, 1H, 9-H), 6.51 (dd, J=14.4, 6.4 Hz, 1H, 8-H); 13C NMR
(75 MHz, CDCl3): d=ꢀ4.9, ꢀ4.4 (SiCH3), 15.4 (2-CH3), 16.7 (4-CH3),
17.3 (6-CH3), 18.2 (SiCACHTER(NGU CH3)3), 25.8 (SiCACHTRE(UGN CH3)3), 39.6 (C-6), 69.3 (C-1),
76.3 (C-7), 79.2 (C-9), 129.3 (C-3), 131.7 (C-5), 133.1 (C-2), 134.7 (C-4),
148.0 (C-8); IR (film): n˜ =3332 (brs), 2957 (s), 2929 (s), 2858 (s), 1463
(s), 1361 (s), 1257 (s), 1165 (s), 1068 (s), 1006 cmꢀ1 (s); HR-MS (ESI):
m/z: calcd for C18H33IO2SiNa: 459.1192; found 459.1198 [M+Na]+.
ACHTREUNG(CH3)3), 1.00 (d, J=6.8 Hz, 3H, 6-CH3), 1.28 (t, J=7.1 Hz, 3H,
CO2CH2CH3), 1.85 (d, J=1.3 Hz, 3H, 4-CH3), 1.97 (d, J=1.3 Hz, 3H, 2-
CH3), 2.65–2.85 (m, 1H, 6-H), 3.39–3.60 (m, 3H, 7-H, 8-H2), 4.18 (q, J=
7.2 Hz, 2H, CO2CH2CH3), 5.36 (d, J=10.0 Hz, 1H, 5-H), 7.07 (s, 1H, 3-
H); 13C NMR (75 MHz, CDCl3): d=ꢀ4.6, ꢀ4.3 (SiCH3), 14.0 (2-CH3),
MnO2 oxidation: To the allylic alcohol (605 mg, 1.39 mmol) in CH2Cl2
(15 mL) was added MnO2 (4.24 g, 48.8 mmol). After 2 h at 208C, the mix-
ture was filtered over a pad of Celite and the residue was washed with
CH2Cl2 (100 mL). The solvent was removed and the crude aldehyde was
used directly for the following Wittig reaction. Rf =0.28 (n-hexane/
MTBE 1:1); 1HNMR (200 MHz, CDCl 3): d=ꢀ0.00, 0.02 (2s, 6H, Si-
14.3 (CO2CH2CH3), 16.6 (4-CH3), 17.1 (6-CH3), 18.1 (SiCCAHTRE(UNG CH3)3), 25.9
(SiCACHTREUNG(CH3)3), 36.0 (C-6), 60.6 (CO2CH2CH3), 64.6 (C-8), 76.4 (C-7), 125.8
(C-4), 132.6 (C-2), 137.9 (C-5), 142.7 (C-3), 169.1 (C-1); IR (film): n˜ =
3495 (brs), 2957 (s), 2884 (s), 1708 (s), 1460 (s), 1368 (s), 1253 (s), 1047
(s), 1034 cmꢀ1 (s); elemental analysis calcd (%) for C19H36O4Si (356.57):
C 64.00, H10.18; found C 63.72, H10.16.
CH3), 0.87 (s, 9H, Si-CACTHERU(NG CH3)3), 1.01 (d, J=6.8 Hz, 3H, 6-CH3), 1.92 (s,
(2E,4E,8E,6R,7S)-Ethyl 7-tert-butylsilyloxy-9-iodo-2,4,6-trimethylnona-
2,4,8-trienoate (38): Dess–Martin oxidation: Alcohol 37 (633 mg,
1.78 mmol) was dissolved in CH2Cl2 (10 mL) at 08C. Pyridine (0.35 mL,
4.4 mmol) and DMP (925 mg, 2.18 mmol) were added. The mixture was
3H, 4-CH3), 1.93 (s, 3H, 2-CH3), 2.55–2.71 (m, 1H, 6-H), 3.93 (t, J=
5.7 Hz, 1H, 7-H), 5.61 (d, J=9.8 Hz, 1H, 5-H), 6.21 (dd, J=14.3, 0.8 Hz,
1H, 9-H), 6.50 (dd, J=14.5, 6.2 Hz, 1H, 8-H), 6.68 (s, 1H, 3-H), 9.37 (s,
1H, 1-H); 13C NMR (75 MHz, CDCl3): d=ꢀ5.0, ꢀ4.4 (Si-CH3), 10.8 (2-
7374
www.chemeurj.org
ꢁ 2006 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 7364 – 7377

Apoptolidin A Aglycone
FULL PAPER
CH3), 15.9 (4-CH3), 16.5 (6-CH3), 18.2 (Si-C
39.7 (C-6), 76.9 (C-9), 78.6 (C-7), 133.1 (C-2), 141.3 (C-5), 147.2 (C-8),
154.6 (C-3), 196.1 (C-1).
A
(CH3)3),
(2E,4E,6E,10E,12E,8R,9R,16S,17S,19S,20R,2’R,3’R,4’S,5’R,6’R,2’’R)-9-
tert-Butyldimethylsilyloxy-[4’-tert-butyldimethylsilyloxy-6’-[[2’’-tert-butyl-
dimethylsilyloxy-3’’-methoxypropyl]]-2’-methoxy-3’,5’-dimethyl-2’,3’,5’,6’-
tetrahydro-4H-pyran-2’-yl]-10,19,20-trihydroxy-17-methoxy-2,4,6,8,12-
pentamethyl-2,4,6,10,12-eicosapentaenoic acid (41): Ethyl ester 40
(112 mg, 0.096 mmol) and LiOH(24 mg, 0.58 mmol) were stirred in
THF/MeOH/H2O 2:1:1 (4 mL) for 28 h at 408C. The reaction mixture
was partitioned between water (10 mL) and AcOEt (10 mL). The aque-
ous layer was extracted with AcOEt (2ꢂ10 mL). The combined organic
layers were washed with brine (20 mL) and dried with MgSO4. Chroma-
tography (10 g silica gel, CH2Cl2/MeOH20:1) gave trihydroxy carboxylic
acid 41 (88 mg, 0.083 mmol, 87%) as a colorless oil. Rf =0.30 (CH2Cl2/
MeOH20:1); [ a]2D3 =+81 (c=0.90, CHCl3); 1HNMR (600 MHz, C 6D6):
d=ꢀ0.08, ꢀ0.05, ꢀ0.04, ꢀ0.02, ꢀ0.01 (5s, 18H, Si-CH3), 0.80, 0.81, 0.82
Wittig olefination: The crude aldehyde was azeotroped with toluene (3ꢂ
10 mL) and dissolved in toluene (60 mL). Ph3PCACHTREU(NG CH3)CO2Et (3.03 g,
8.32 mmol) was added and the mixture was heated under reflux for 26 h.
The solvent was removed and the residue was purified by chromatogra-
phy (25 g silica gel, PE/MTBE 30:1, 0.1% Et3N) to yield tetraenoate 39
(418 mg, 0.806 mmol, 58%) as a colorless oil. Rf =0.41 (n-hexane/CH2Cl2
1:1); [a]2D3 =+13.7 (c=0.49, CHCl3); 1HNMR (300 MHz, CDCl 3): d=
ꢀ0.01, 0.02 (2s, 6H, Si-CH3), 0.87 (s, 9H, Si-C
3H, 8-CH3), 1.29 (t, J=7.0 Hz, 3H, CO2CH2CH3), 1.74 (d, J=1.1 Hz,
3H, 6-CH3), 1.96 (d, J=1.1 Hz, 3H, 4-CH3), 2.01 (d, J=1.1 Hz, 3H, 2-
CH3), 2.48–2.61 (m, 1H, 8-H), 3.88 (t, J=5.8 Hz, 1H, 9-H), 4.19 (q, J=
7.2 Hz, 2H, CO2CH2CH3), 5.17 (d, J=9.8 Hz, 1H, 7-H), 5.98 (s, 1H, 5-
H), 6.17 (dd, J=14.5, 0.9 Hz, 1H, 11-H), 6.51 (dd, J=14.3, 6.4 Hz, 1H,
10-H), 7.13 (s, 1H, 3-H); 13C NMR (75 MHz, CDCl3): d=ꢀ5.0, ꢀ4.4 (Si-
CH3), 14.1 (2-CH3), 14.3 (CO2CH2CH3), 16.3 (8-CH3), 17.2 (6-CH3), 18.2
(3s, 27H, Si-CCAHTRE(UGN CH3)3), 0.78–0.83 (m, 3H, 24-CH3), 0.92 (d, J=6.8 Hz,
3H, 8-CH3), 0.96 (d, J=6.6 Hz, 3H, 22-CH3), 1.30–1.41 (m, 2H, 15-H2,
26-H2), 1.43–1.52 (m, 1H, 15-H2), 1.53–1.68 (m, 4H, 18-H2, 24-H, 26-H2),
1.66 (s, 6H, 6-CH3, 12-CH3), 1.86 (d, J=0.9 Hz, 3H, 4-CH3), 1.89 (d, J=
1.1 Hz, 3H, 2-CH3), 1.91–2.02 (m, 1H, 22-H), 2.06–2.30 (m, 2H, 14-H2),
2.44–2.58 (m, 1H, 8-H), 3.17 (s, 3H, 21-OCH3), 3.20–3.32 (m, 3H, 17-H,
28-H2), 3.22, 3.36 (2s, 6H, 17-OCH3, 28-OCH3), 3.42 (d, J=2.8 Hz, 1H,
20-H), 3.48–3.56 (m, 1H, 16-H), 3.70 (dd, J=10.6, 4.7 Hz, 1H, 23-H),
3.78–3.89 (m, 3H, 19-H, 25-H, 27-H), 3.95 (dd, J=6.6, 6.6 Hz, 1H, 9-H),
5.17 (d, J=9.6 Hz, 1H, 7-H), 5.37 (dd, J=7.9, 7.4 Hz, 1H, 13-H), 5.44
(dd, J=15.6, 7.2 Hz, 1H, 10-H), 5.89 (s, 1H, 5-H), 6.07 (d, J=15.8 Hz,
1H, 11-H), 7.06 (s, 1H, 3-H); 13C NMR (75.5 MHz, CDCl3): d=ꢀ4.54,
ꢀ4.50, ꢀ4.4, ꢀ4.0, ꢀ3.6, ꢀ3.4 (Si-CH3), 6.1 (C-24), 12.72, 12.74 (C-12, C-
22), 14.4 (2-CH3), 17.0 (8-CH3), 17.6 (6-CH3), 18.7 (4-CH3), 19.0, 19.1,
(Si-CACHTREUN(G CH3)3), 18.4 (4-CH3), 25.8 (Si-CACHTREU(NG CH3)3), 39.6 (C-8), 60.6
(CO2CH2CH3), 76.4 (C-9), 79.0 (C-11), 125.9 (C-2), 131.8 (C-6), 132.6 (C-
4), 133.6 (C-7), 138.8 (C-5), 143.6 (C-3), 147.8 (C-10), 169.1 (C-1); IR
(film): n˜ =2957 (s), 2929 (s), 2857 (s), 1706 (s), 1463 (ms), 1366 (m), 1251
(s), 1112 (m), 1068 (m), 1033 (m), 949 (m), 836 (s), 776 cmꢀ1 (s); HR-MS
(EI): m/z: calcd for C23H40IO3Si: 519.1791; found 519.1799 [M+H]+.
Ethyl
(2E,4E,6E,10E,12E,8R,9R,16S,17S,19S,20R,2’R,3’R,4’S,5’R,6’R,
2’’R)-19,20-Diacetoxy-9-tert-butyldimethylsilyloxy-[4’-tert-butyldimethyl-
silyloxy-6’-[[2’’-tert-butyldimethylsilyloxy-3’’-methoxypropyl]]-2’-me-
thoxy-3’,5’-dimethyl-2’,3’,5’,6’-tetrahydro-4H-pyran-2’-yl]-16-hydroxy-17-
methoxy-2,4,6,8,12-pentamethyl-2,4,6,10,12-eicosapentaenoate (40): Al-
kenyl stannane 31 (150 mg, 0.141 mmol) and alkenyl iodide 39 (89 mg,
0.17 mmol) were dissolved in degassed N-methyl pyrrolidone (5 mL).
CuI-thiophene-2-carboxylate (66 mg, 0.36 mmol) was added at ꢀ108C
and the brown colored reaction mixture was stirred at ꢀ108C for 90 min.
MTBE (2 mL) was added and the mixture was filtered over neutral alu-
minium oxide (7 g). The aluminium oxide was washed with MTBE
(20 mL). The combined filtrates were subsequently washed with water
(5 mL) and brine (20 mL) and dried with MgSO4. Chromatography (25 g
silica gel, cyclohexane/AcOEt 5:1, 0.25% Et3N) gave the coupling prod-
uct 40 (133 mg, 0.114 mmol, 81%) as a colorless oil. Rf =0.66 (n-hexane/
19.2 (Si-CACTHERNG(U CH3)3), 25.8 (C-14), 26.4, 26.5, 26.6 (Si-CAHCRTE(UGN CH3)3), 33.2 (C-15),
37.3 (C-22), 37.7 (C-18), 39.9 (C-26), 41.3 (C-24), 41.7 (C-8), 48.2 (21-
OCH3), 59.2, 59.4 (17-OCH3, 28-OCH3), 68.3, 69.8, 71.5 (C-19, C-25, C-
27), 72.8 (C-16), 75.1 (C-23), 75.6 (C-20), 78.9 (C-28), 79.4 (C-9), 82.5 (C-
17), 103.2 (C-21), 129.6 (C-10), 132.88, 132.94, 134.6 (C-2, C-4, C-6),
133.2 (C-13), 136.0 (C-7), 136.8 (C-11), 140.1 (C-5), 145.1 (C-3), 172.6 (C-
1); IR (film): n˜ =3434 (s), 2953 (s), 2930 (s), 2892 (s), 2857 (s), 1681 (s),
1462 (s), 1362 (s), 1257 (s), 1069 (s), 835 (s), 776 cmꢀ1 (s); HR-MS
(FAB): m/z: calcd for C56H106O12Si3Na: 1077.6890; found 1077.6876
[M+Na]+.
9,23,27-Tri-O-(tert-butyldimethylsilyl)-21-O-methylapoptolidinone
A
(42): Et3N (0.12 mL, 0.83 mmol) was added at 208C to trihydroxy carbox-
ylic acid 41 (88 mg, 83 mmol) in THF (5 mL). After 5 min 2,4,6-trichloro-
benzoic acid chloride (0.13 mL, 0.83 mmol) was added. The reaction mix-
ture was stirred at 208C for 18 h. It was diluted with toluene (25 mL),
transferred into an addition funnel and added dropwise over 6 h to a sol-
ution of DMAP (102 mg, 0.834 mmol) in toluene (50 mL) at 808C. After
cooling to 208C, phosphate buffer (70 mL, 1m, pH7) was added. The
aqueous layer was extracted with MTBE (3ꢂ50 mL). The combined or-
ganic layers were washed with brine (100 mL) and dried with MgSO4.
Chromatography (30 g silica gel, PE/MTBE 4:1) gave macrolide 42
(64 mg, 62 mmol, 74%) as a colorless oil. Rf =0.57 (n-hexane/MTBE
1:1); [a]2D3 =+46 (c=0.60, CHCl3); 1HNMR (600 MHz, C 6D6): d=0.07,
0.15, 0.16, 0.17, 0.18 (5s, 18H, Si-CH3), 0.99, 1.02, 1.05 (3s, 27H, Si-C-
1
MTBE 1:2); [a]2D3 =+64.7 (c=1.02, CHCl3); HNMR (300 MHz, CDCl 3):
d=0.08, 0.10, 0.126, 0.129, 0.134, 0.161 (6s, 18H, Si-CH3), 0.98, 1.01, 1.04
(3s, 27H, Si-CACHTREUNG(CH3)3), 1.00–1.05 (m, 3H, OCH2CH3), 1.14 (d, J=6.7 Hz,
3H, 8-CH3), 1.20 (d, J=7.0 Hz, 3H, 24-CH3), 1.51 (d, J=6.6 Hz, 3H, 22-
CH3), 1.50–1.58 (m, 2H, 15-H2), 1.63 (ddd, J=14.4, 8.1, 3.1 Hz, 1H, 26-
H2), 1.67 (d, J=1.0 Hz, 3H, 6-CH3), 1.75 (s, 3H, 12-CH3), 1.79, 1.80 (2s,
6H, OAc), 1.87–1.95 (m, 3H, 18-H2, 24-H, 26-H2), 1.92 (d, J=1.1 Hz,
3H, 4-CH3), 2.14 (d, J=1.4 Hz, 3H, 2-CH3), 2.20–2.27 (m, 1H, 14-H2),
2.27–2.33 (m, 2H, 18-H2, 22-H), 2.36–2.43 (m, 1H, 14-H2), 2.65–2.72 (m,
1H, 8-H), 3.11–3.16 (m, 1H, 17-H), 3.12 (s, 3H, 28-OCH3), 3.22–3.24 (m,
2H, 28-H2), 3.30, 3.34 (2s, 6H, 17-OCH3, 21-OCH3), 3.48–3.53 (m, 1H,
16-H), 4.05–4.15 (m, 5H, 9-H, 23-H, 27-H, OCH2CH3), 4.18 (ddd, J=8.1,
2.7, 2.7 Hz, 1H, 25-H), 5.40 (d, J=9.9 Hz, 1H, 7-H), 5.47 (d, J=5.3 Hz,
1H, 20-H), 5.52–5.56 (m, 1H, 13-H), 5.66 (dd, J=15.7, 7.2 Hz, 1H, 10-
H), 5.79–5.83 (m, 1H, 19-H), 6.03 (s, 1H, 5-H), 6.29 (d, J=15.7 Hz, 1H,
11-H), 7.48 (s, 1H, 3-H); 13C NMR (75 MHz, CDCl3): d=ꢀ4.7, ꢀ4.6,
ꢀ4.5, ꢀ4.2, ꢀ3.7, ꢀ3.4 (Si-CH3), 5.6 (24-CH3), 11.9 (22-CH3), 12.6 (12-
CH3), 14.39, 14.42 (2-CH3, CO2CH2CH3), 16.8 (8-CH3), 17.3 (6-CH3),
AHCTRE(GNU CH3)3), 1.19 (d, J=6.7 Hz, 3H, 8-CH3), 1.27 (d, J=6.9 Hz, 3H, 24-CH3),
1.41–1.48 (m, 2H, 15-H2), 1.50 (d, J=6.7 Hz, 3H, 22-CH3), 1.55 (s, 3H,
12-CH3), 1.62–1.66 (m, 1H, 26-H2), 1.67 (d, J=1.0 Hz, 3H, 6-CH3), 1.84
(s, 3H, 4-CH3), 1.88–1.95 (m, 2H, 24-H, 26-H2), 2.05–2.10 (m, 1H, 14-
H2), 2.14 (s, 3H, 2-CH3), 2.16 (brs, 1H, 16-OH), 2.22–2.32 (m, 3H, 18-H2,
22-H), 2.39–2.42 (m, 1H, 20-OH), 2.47–2.54 (m, 1H, 14-H2), 2.55–2.61
(m, 1H, 8-H), 3.02–3.06 (m, 1H, 17-H), 3.06 (s, 3H, 28-OCH3), 3.16–3.22
(m, 2H, 28-H2), 3.28 (s, 3H, 21-OCH3), 3.38 (s, 3H, 17-OCH3), 3.48–3.53
(m, 1H, 16-H), 3.81 (dd, J=8.5, 8.3 Hz, 1H, 9-H), 3.89 (dd, J=4.9,
4.6 Hz, 1H, 20-H), 4.10–4.15 (m, 2H, 23-H, 27-H), 4.18–4.21 (m, 1H, 25-
H), 5.05 (d, J=9.8 Hz, 1H, 7-H), 5.35 (dd, J=15.6, 8.6 Hz, 1H, 10-H),
5.53 (dd, J=10.0, 5.8 Hz, 1H, 13-H), 5.92–5.95 (m, 1H, 19-H), 5.95 (d,
J=15.8 Hz, 1H, 11-H), 6.20 (s, 1H, 5H), 7.55 (s, 1H, 3-H); 13C NMR
(75.5 MHz, CDCl3): d=ꢀ4.7, ꢀ4.6, ꢀ4.5, ꢀ4.2, ꢀ3.5, ꢀ3.4 (Si-CH3), 5.8
(24-CH3), 11.8, 11.9 (12-CH3, 22-CH3), 14.2 (2-CH3), 16.2 (6-CH3), 17.4
18.36 (Si-C
A
(OAc), 25.4 (C-14), 26.1, 26.15, 26.23 (Si-CAHCTREUNG
18), 37.3 (C-22), 39.2 (C-26), 40.5 (C-24), 41.0 (C-8), 48.2 (21-OCH3),
58.5 (28-OCH3), 59.2 (17-OCH3), 60.5 (CO2CH2CH3), 69.6 (C-19, C-25),
70.4 (C-27), 72.5 (C-16), 73.3 (C-20), 73.8 (C-23), 78.0 (C-28), 78.5 (C-9),
81.1 (C-17), 101.5 (C-21), 126.4 (C-6), 127.9 (C-12), 129.0 (C-10), 132.0
(C-4), 132.6 (C-13), 133.7 (C-2), 135.2 (C-7), 135.8 (C-11), 139.3 (C-5),
143.8 (C-3), 168.5, 169.4, 169.8 (C-1, OAc); IR (film): n˜ =2954 (s), 2930
(s), 2894 (s), 2858 (s), 1748 (s), 1706 (m), 1463 (m), 1371 (m), 1251 (s),
1109 (m), 1071 (m), 1030 (m), 835 (s), 775 cmꢀ1 (m); HR-MS (FAB): m/
z: calcd for C62H114O14Si3: 1166.7516; found 1166.7524 [M]+.
(4-CH3), 18.1 (8-CH3), 18.3, 18.4, 18.6 (Si-C
ACHTRE(UNG CH3)3), 25.0 (C-14), 26.1,
26.2, 26.3 (Si-C(CH3)3), 34.9 (C-15), 37.1 (C-22), 38.3 (C-18), 39.2 (C-26),
AHCTREUNG
Chem. Eur. J. 2006, 12, 7364 – 7377
ꢁ 2006 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
www.chemeurj.org
7375

U. Koert et al.
40.6, 40.8 (C-8, C-24), 47.9 (21-OCH3), 58.5 (28-OCH3), 60.3 (17-OCH3),
69.5 (C-25), 70.7, 73.5 (C-23, C-27), 72.0 (C-19), 74.2 (C-16), 75.9 (C-20),
78.0 (C-28), 81.3 (C-9), 82.3 (C-17), 102.1 (C-21), 124.1, 131.9, 132.1,
133.4 (C-2, C-4, C-6, C-12), 129.1 (C-10), 132.8 (C-13), 136.7 (C-11),
141.5 (C-7), 145.0 (C-5), 145.9 (C-3), 169.7 (C-1); IR (film): n˜ =3103 (s),
2929 (s), 2856 (s), 1699 (m), 1401 (s), 1257 (m), 1074 (m), 835 (m), 776
(m), 741 cmꢀ1 (s); HR-MS (FAB): m/z: calcd for C56H104O11Si3:
1036.6887; found 1036.6910 [M]+.
Chem. Int. Ed. 2001, 40, 3849–3854; b) K. C. Nicolaou, Y. Li, K. C.
Fylaktakidou, H. J. Mitchell, K. Sugita, Angew. Chem. 2001, 113,
3972–3976; Angew. Chem. Int. Ed. 2001, 40, 3854–3857; c) K. C.
Nicolaou, K. C. Fylaktakidou, H. Monenschein, Y. Li, B. Weyer-
shausen, H. J. Mitchell, H. X. Wei, P. Guntupalli, D. Hepworth, K.
Sugita, J. Am. Chem. Soc. 2003, 125, 15433–15442; d) K. C. Nico-
laou, Y. Li, K. Sugita, H. Monenschein, P. Guntupalli, H. J. Mitchell,
K. C. Fylaktakidou, D. Vourloumis, P. Giannakakou, A. OꢀBrate, J.
Am. Chem. Soc. 2003, 125, 15443–15454.
Apoptolidinone A (4): Trisilyl ether 42 (11 mg, 11 mmol) was dissolved at
08C in THF (0.6 mL) in a polypropylene flask. HF·py (60 mL, 2.1 mmol)
was added and the reaction mixture was stirred for 8 h at 08C. Further
HF·py (60 mL, 2.1 mmol) was added and the reaction mixture was stirred
at 208C for 15 h. After cooling to 08C, HF·py (80 mL, 2.8 mmol) was
added and the reaction mixture was stirred for 9 h. NaHCO3 (3 mL) and
AcOEt (3 mL) were added. The aqueous layer was extracted with
AcOEt (3ꢂ3 mL). The combined organic layers were washed with brine
(8 mL) and dried with MgSO4. Chromatography (2 g silica gel, CH2Cl2/
MeOH15:1) gave apoptolidinone A ( 4) (4 mg, 6 mmol, 55%) as a color-
less solid. Rf =0.09 (CH2Cl2/MeOH15:1); [ a]2D3 =+70 (c=0.3, MeOH);
1HNMR (600 MHz, CD 3OD): d=0.88 (d, J=6.7 Hz, 3H, 24-CH3), 1.02
(d, J=6.7 Hz, 3H, 22-CH3), 1.13 (d, J=6.3 Hz, 3H, 8-CH3), 1.26–1.32 (m,
1H, 26-H2), 1.37–1.44 (m, 1H, 15-H2), 1.51–1.60 (m, 2H, 15-H2, 26-H2),
1.67 (s, 3H, 12-CH3), 1.72–1.78 (m, 2H, 18-H2, 24-H), 1.92 (s, 3H, 6-
CH3), 2.02–2.09 (m, 2H, 14-H2, 22-H), 2.11 (s, 3H, 2-CH3), 2.13–2.18 (m,
1H, 18-H2), 2.19 (s, 3H, 4-CH3), 2.41–2.52 (m, 2H, 8-H, 14-H2), 2.73 (dd,
J=9.9, 4.4 Hz, 1H, 17-H), 3.15–3.23 (m, 2H, 28-H2), 3.30 (s, 3H, 28-
OCH3), 3.36 (s, 3H, 17-OCH3), 3.42–3.45 (m, 1H, 16-H), 3.53–3.58 (m,
2H, 20-H, 27-H), 3.73–3.79 (m, 2H, 9-H, 23-H), 4.09 (ddd, J=8.5, 2.8,
2.5 Hz, 1H, 25-H), 5.22 (d, J=10.2 Hz, 1H, 7-H), 5.29–5.32 (m, 1H, 19-
H), 5.33 (dd, J=15.4, 8.8 Hz, 1H, 10-H), 5.64 (dd, J=9.3, 6.9 Hz, 1H, 13-
H), 6.10 (d, J=15.7 Hz, 1H, 11-H), 6.19 (s, 1H, 5-H), 7.37 (s, 1H, 3-H);
13C NMR (75.5 MHz, CDCl3): d=5.3 (24-CH3), 12.1, 12.2 (12-CH3, 22-
CH3), 14.0 (2-CH3), 16.4 (6-CH3), 17.7, 17.8 (4-CH3, 8-CH3), 24.5 (C-14),
36.4 (C-22), 36.6 (C-15), 38.4 (C-26), 38.6 (C-18), 40.8, 41.0 (C-8, C-24),
59.4 (28-OCH3), 61.4 (17-OCH3), 68.1 (C-27), 69.2 (C-25), 72.3 (C-19),
73.7 (C-23), 74.6 (C-16), 75.5 (C-20), 78.6 (C-28), 80.6 (C-9), 83.8 (C-17),
101.3 (C-21), 123.8, 133.0, 133.1, 134.9 (C-2, C-4, C-6, C-12), 129.6 (C-10),
132.6 (C-13), 137.7 (C-11), 143.6 (C-7), 147.3 (C-5), 149.1 (C-3), 172.6 (C-
1); IR (film): n˜ =3414 (s), 2927 (s), 1667 (s), 1458 (m), 1256 (s), 1092 (s),
1020 (s), 732 (s), 669 cmꢀ1 (s); HR-MS (FAB): m/z: calcd for
C37H60O11Na: 703.4033; found 703.4029 [M+Na]+.
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Support by Schering AG Berlin and the Fonds der Chemischen Industrie
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