The total synthesis of (+)-tedanolide - A macrocyclic polyketide from marine sponge tedania ignis

Article abstract of DOI:10.1002/chem.200701529

Tedanolide, which was isolated by Schmitz in 1984 from the marine sponge Tedania ignis, is a highly cytotoxic macrolide leading to strong growth inhibition of P338 tumor cells in bioassays. A unique structural feature of the known tedanolides is the prima

Full text of DOI:10.1002/chem.200701529

DOI: 10.1002/chem.200701529
The Total Synthesis of (+)-Tedanolide—A Macrocyclic Polyketide from
Marine Sponge Tedania ignis
Gunnar Ehrlich, Jorma Hassfeld, Ulrike Eggert, and Markus Kalesse*[a]
Abstract: Tedanolide, which was isolat-
ed by Schmitz in 1984 from the marine
sponge Tedania ignis, is a highly cyto-
toxic macrolide leading to strong
growth inhibition of P338 tumor cells
in bioassays. A unique structural fea-
ture of the known tedanolides is the
primary hydroxyl group incorporated
in the macrolactone. This unusual
motif for macrolactones originated
from PKSbiosynthesis might arise
through lactonizations others than
those derived by the thioesterase reac-
tion. First experimental data that sup-
port this hypothesis and reflect the in-
herent preference of PKS-induced
macrolactonization
were
obtained
during this synthesis. The inherent
preference for the formation of a 14-
membered macrocyclization is dis-
cussed together with the pivotal steps
in the synthesis.
Keywords:
aldol reactions
·
macrolactone · natural products ·
tedanolide
Introduction
Currently five members of tedanolides are known, tedano-
lide (1), 13-deoxytedanolide (2), tedanolide C (3) and candi-
daspongiolides (4, 5). Tedanolide (1) was isolated by
Schmitz et al.[1] in 1984 from the Caribbean sponge Tedania
ignis and the structure as well as the absolute configuration
was unambiguously assigned by X-ray analysis. It attracted
very much attention due to its high cytotoxicity against
tumor cell lines and was shown to arrest the growth of P338
cells in the S-phase.[1] In 1991 the isolation of a structural re-
lated compound, 13-deoxytedanolide (2) from the sponge
Mycale adhaerens, exhibiting a deoxygenated position at
C13, was reported by Fusetani et al.[2] Even though only lim-
ited studies on the biological profile have been performed
so far, first data indicate a similar biological profile com-
pared with tedanolide (1).[3] These biological tests unraveled
a strong binding to the 60Ssubunit of ribosomes leading to
an efficient inhibition of peptide elongation in eukaryotic
cells.[4] As a matter of fact, 13-deoxytedanolide (2) is the
first known macrolide binding efficiently to eukaryotic ribo-
somes, whereas other macrolide antibiotics such as erythro-
mycin or carbomycin exclusively bind to procaryontic ribo-
somes. A third member of this family, tedanolide C (3) was
isolated in 2005 by Ireland et al.[5] from the marine sponge
Ircinia sp. collected near Papua New Guinea. Very recently,
the group of candidaspongiolides (4, 5) was isolated by
McKee et al. from the sponge of the genus Candidaspongi.[6]
A unique structural element of all these natural products is
a primary alcohol which is incorporated in the macrolac-
tone. The chemical stability of tedanolides 1 and 2 is limited
by the highly acid sensitive b-hydroxy ketone moieties and
the epoxide in the side chain which is prone to acid-cata-
lyzed opening. Since its first publication by the Schmitz
[a] Dr. G. Ehrlich, Dr. J. Hassfeld, U. Eggert, Prof. Dr. M. Kalesse
Institut für Organische Chemie
Gottfried Wilhelm Leibniz Universität Hannover
Schneiderberg 1B, 30167 Hannover (Germany)
Fax : (+49)0511-7623011
E-mail: Markus.Kalesse@oci.uni-hannover.de
Supporting information for this article is available on the WWW
under http://www.chemistry.org or from the author.
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FULL PAPER
group in 1984 a large variety of synthetic efforts have been
put forward, leading to advanced fragment syntheses.[7] In
the course of these synthetic endeavors the first total synthe-
sis of 13-deoxytedanolide (2) was presented by Smith et al.
in 2003,[8] aiming to provide synthetic access to compounds
1, 2 through a unified approach. Very recently, their concept
resulted in a total synthesis for tedanolide (1) as well.[9]
Short after the first synthesis of 13-deoxytedanolide (2) had
been completed a second total synthesis of 2 by the Roush
group was published.[10] Here we describe the synthetic de-
tails that led to our total synthesis of tedanolide (1).[11] The
key features are an aldol coupling to set up the carbon back-
bone and a final stage epoxidation. Additionally, it turned
out that correct choice of the configuration at C15 was pivo-
tal for the successful synthesis.
Results and Discussion
Scheme 1. Retrosynthesis of tedanolide (1).
Retrosynthetic analysis: As a consequence of the labile ep-
oxide moiety in tedanolide (1) we decided to introduce this
functional group as the last step of the synthesis. The stereo-
selective epoxidation of the D18-allylic alcohol moiety using
mCPBA has already been demonstrated in the Smith syn-
thesis of 13-deoxytedanolide (2).[8] Nevertheless, in their
synthesis the second D8-allylic alcohol was blocked through
protection as the TIPSether. Since both segments represent
a pseudo-enantiomeric relationship we envisioned to use the
Sharpless asymmetric epoxidation as a fall-back position in
order to discriminate between both allylic alcohols as it has
been successfully applied by Mulzer et al.[12] in their laulima-
lide synthesis. Consequently, we envisioned to perform the
epoxidation after global TBSdeprotection of macrolactone
6. This triketo lactone 6 in turn is generated by a macrolac-
tonization of hydroxy acid 7 followed by stepwise deprotec-
tion and oxidation at C5 and C15. To achieve a convergent
synthesis of C1–C23 hydroxy acid 7 we decided to perform
an aldol coupling of methyl ketone 8, previously synthesized
in our group,[7y] and aldehyde 9 (Scheme 1).
Another essential issue was the appropriate choice of or-
thogonal protecting groups for the C29 hydroxy group and
the carboxylate. After substantial variations we found the
monomethoxytrityl group (MMTr) to be ideal as a protect-
ing group for C29 hydroxyl since its installation and chemi-
cal stability was compatible with the operations employed.
Additionally, the very mild conditions for its removal,
namely treatment with hexafluoroisopropanol[13] allow re-
moval even in the presence of unprotected b-hydroxy ke-
tones.
Scheme 2. First-generation synthesis of 13.
more convergent aldol coupling between C16 and C17 that
parallels the fragment synthesis presented by Loh and co-
workers.[7t] The synthesis starts with known trityl protected
Roche aldehyde 14.[14] Subsequent olefination with ethyli-
dene triphenylphosphorane yielded alkene 15 with high Z
selectivity (92:8). The acid-catalyzed cleavage of trityl ether
15 in methanol/CH2Cl2 turned out to be the optimal proce-
dure and separation of the so-obtained alcohol 16 by
column chromatography required careful evaporation of sol-
vents in order to prevent significant loss of volatile 16. On
larger scale the isolation of alcohol 16 first required removal
of the solvents by fractionated distillation over a Vigreux
column. Then the residue was heated to 1008C at a pressure
of 1 mbar, while 16 was collected in a cooling trap at
À1908C together with some residual CH2Cl2. For the subse-
quent transformation it was not necessary to obtain 16 in
pure form. Thus the solution of 16 in CH2Cl2 was used in
the subsequent Swern oxidation[15] to generate aldehyde 17
which was directly subjected to Wittig olefination providing
unsaturated ester 18. Conversion of ester 18 to aldehyde 10
was achieved in a stepwise sequence using DIBAL-H reduc-
tion and subsequent oxidation with manganese dioxide
(Scheme 3).
Synthesis of aldehyde 9: In 2005 we reported a first-genera-
tion synthesis of C13–C23 aldehyde 13[7z] using an anti selec-
tive aldol coupling between C15 and C16 (Scheme 2).
This route had its drawbacks due to a relatively long
number of 18 linear steps and occasionally uncontrolled mi-
gration of protecting groups. These disadvantages led to an
improved synthesis to the C13–C23 aldehyde 9, using a
Ketone 24 was synthesized in four steps according to the
route described by Loh.[7t] Therefore PMB-protected alde-
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M. Kalesse et al.
axial position for these hydrogens. The 13C NMR analysis
unraveled two characteristic signals at d 19.9 and 30.0 ppm
indicative of axial and equatorial methyl groups in acetonide
27. After removing the TBSgroup in 26 with TBAF triol 28
was obtained. This could be used for introducing the re-
quired protecting groups selectively. We focused particularly
on identifying a suitable protecting group for the primary
C29 alcohol which would allow selective removal prior to
macrolactonization. After substantial screening of protecting
groups we decided to use the monomethoxytrityl (MMTr)
group,[19] which can be removed under very mild acidic con-
ditions, required for this sensitive intermediate. The intro-
duction of this protecting group is known to be highly selec-
tive for primary hydroxy groups and diol 29 was obtained in
acceptable yield. Next, the allylic hydroxy group was pro-
tected as the TBSether 30 and the PMB group was put on
to the secondary alcohol using the sequence of oxidation
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)[20]
and reductive opening of the intermediate PMP acetal[21]
with DIBAL-H. Overall, a shift of the PMB group was ach-
ieved to furnish alcohol 32. Oxidation of 32 with TPAP/
NMO[22] proceeded smoothly and provided aldehyde 9
(Scheme 4).
Scheme 3. Synthesis of fragments 10 and 24: a) EtPPh3+BrÀ, nBuLi,
85%, Z/E 92:8; b) p-TsOH, MeOH; c) Swern oxidation; d) EtO2CC-
ACHTREUNG(CH3)=PPh3, 43% from 15; e) DIBAL-H, 87%; f) MnO2, 90%; g) LDA,
CH3CO2Et, 88%; h) LiAlH4, 95%; i) TBSCl, imidazole, 93%; k) Swern
oxidation, 98%.
hyde 20 was subjected to an unselective acetate aldol reac-
tion to generate hydroxy ester 21 as a 1:1 mixture of diaste-
reomers. Reduction of 21 yielded 1,3-diol 22 and the pri-
mary hydroxy group was selectively TBS-protected. In the
last step alcohol 23 was oxidized to give ketone 24 and pro-
viding enantiomerically pure material again.
In order to set the desired anti-relationship between the
C17 hydroxy and the C16 hydroxymethyl group we envi-
sioned using an anti-selective aldol addition between com-
pounds 10 and 24. When ketone 24 was enolized with dicy-
clohexylboron chloride the (E)-enolate was formed predom-
inately and the absolute configuration of both new formed
stereocenters was induced by the chiral ketone 24.[7t,16] Al-
though the aldol addition succeeded with an acceptable
yield of 68%, the diastereomeric ratio was only 2:1 in favor
of the desired isomer 25. Subsequently, hydroxy ketone 25
was reduced to avoid retro aldol reaction. In principal, both
configurations at C15 can be used in the synthesis since this
hydroxy group will be oxidized to the ketone during the
endgame of the synthesis. Nevertheless, in fragments exhib-
iting an anti-orientation both centers would be Felkin en-
forcing, thus potentially enhancing the selectivity of the
aldol step. Based on this analysis Roush’s synthesis used the
(15R)-configuration for the synthesis of 13-deoxytedanolide
(2).[10] Unfortunately, the R configuration in combination
with the presence of a carbonyl group at C5 led to the for-
mation of a stable hemiketal that inhibited oxidation of the
hydroxyl group. Based on experiences in our synthesis of
callystatin[17] we realized that the inherent stereochemistry
of methyl ketone 8 would be a substitute for a chiral auxili-
ary that would override the stereochemical preferences of
the aldehyde 9. Consequently, we decided to apply a syn-re-
duction of 25 to generate the (15S)-configured 1,3-syn-diol
26. For this reduction the use of DIBAL-H provided exclu-
sively syn-diol 26 (dr> 95:5) in good yields. In order to
assign the configuration of diol 26 applying Rychnovskyꢁs
acetonide method[18] 26 was transformed into acetonide 27
Scheme 4. Synthesis of 9: a) Cy2BCl, Et3N, then 10, 68%, dr 2:1; b)
DIBAL-H, 76%, dr >95:5; c) (MeO)2CCAHTRE(UNG CH3)2, PPTS, quant.; d) TBAF,
91%; e) MMTrCl, Et3N, 69%; f) TBSCl, imidazole, 92%; g) DDQ, 85%;
h) DIBAL-H, 81%; i) TPAP, NMO, 90%.
Aldol reaction: For the pivotal aldol coupling of methyl
ketone 8 and aldehyde 9 careful screening of different bases
for the enolization of 8 identified KHMDSto provide the
1
using 2,2-dimethoxy propane. H NMR analysis showed for
all three indicative hydrogen atoms (H15, H16, H17) large
coupling constants of approximately 10 Hz suggesting an
highest selectivities for obtaining Felkin product 33.[7y]
A
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Natural Products
FULL PAPER
preparative separation of 33 from its complex mixture of
diastereomers using chromatography was not successful, but
an analytically pure sample of 33 could be isolated using
HPLC.[23] Next, we analyzed compound 33 for its potential
to undergo macrolactonization. Based on Smith’s synthesis
of 13-deoxytedanolide (2)[8] in which an unprotected triol
was successfully subjected to
NMR methods (HMBC, NOE) did not indicate any NMR
contact between the carboxylic carbon C1 and the two pos-
sible hydrogens at H13 or H29. One argument in favor of
the 14-membered lactone 36 was the chemical shift of
nearly 6 ppm for H13, indicating acylation at the secondary
C13 alcohol (Scheme 5).
macrolactonization we conclud-
ed that in our case the primary
hydroxy group at C29 should
be subjected more readily to
ring closure compared with the
sterically hindered secondary
C13 alcohol. So we continued
the synthesis with liberating the
C29 alcohol. For this conversion
a very mild acid-catalyzed de-
protection of monomethoxytri-
tyl ethers using hexafluoroiso-
propanol had been described by
Leonard and Neelima.[13] In our
case hexafluoroisopropanol did
cleave only the MMTr ether
while all other protecting
groups remained unchanged
and no retro aldol products
were detected. Addition of a
small amount of methanol was
necessary to trap the trityl
cation. Gratifyingly, with the di-
hydroxy compound 34 it was
possible to separate the minor
diastereomers resulting from
the aldol coupling by simple
column chromatography. Next,
the transformation of 34 to free
carboxylic acid 35 was per-
formed by palladium(0)-cata-
Scheme 5. Aldol coupling and lactonization: a) KHMDS, then 9, 59%; b) (CF3)2CHOH, MeOH, 85%; c) [Pd-
(PPh3)2Cl2], Bu3SnH; d) 2,4,6-Cl3C6H2COCl, DMAP, iPr2NEt, 34% over 2 steps.
lyzed cleavage of the allyl ester
and reduction of the p-allyl pal-
ladium species with Bu3SnH.[24]
AHCTREUNG
The subsequent screening of different conditions for macro-
lactonization started with the Mitsunobu protocol,[25] thus
taking advantage of the carboxylate as the nucleophile and
displacement of the primary C29 hydroxy group. Unfortu-
nately the Mitsunobu method proved to be unsuitable for
substrate 35 leading only to complex mixtures of side prod-
ucts. Other lactonization strategies such as Keck–Boden
protocol[26] or Trost–Kita method[27] were also unsuccessful.
On the other hand the Yamaguchi protocol[28] which was al-
ready employed in both syntheses of 13-deoxytedanolide (2)
provided under high dilution conditions between 10–35% of
a macrolactone and best results were obtained when freshly
prepared dihydroxy acid 35 was used immediately. Even
though it was expected that the desired macrolactone 37
had been formed, assignment of the alcohol incorporated in
the lactone was difficult to perform. Investigations via 2D-
As a consequence of the unknown ring size of the macro-
lactone we decided to carry on with the planned synthesis
and hoped to elucidate the ring size at an advanced inter-
mediate. NMR analysis at a later stage then clearly identi-
fied the prepared lactone to be the undesired 14-membered
lactone 36.
This result obtruded the question about the biosynthetic
origin of the unusual primary lactone of the tedanolides.
Since the primary alcohols in polyketides are originated
after PKSbiosynthesis, it is feasible to assume that the lac-
tone of the tedanolides is preformed afterwards either from
the open chain form or through transesterification from a
different lactone. The formation of 14-membered lactone 36
may serve as a first chemical indication that transient lac-
tones may be formed in the course of tedanolides biosynthe-
ses. Protection of the remaining primary alcohol at C29 was
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M. Kalesse et al.
achieved with TBSCl and imidazole yielding completely
protected macrolactone 38. The next transformations re-
quired a subsequent deprotection and oxidation of the C15
and C5 hydroxy groups to install ketones at these positions.
Deprotection of the PMB ether was achieved using DDQ,
followed by Dess–Martin oxidation[29] to generate ketone 40.
For cleavage of the C5 TESether in the presence of four
TBSgroups we decided to apply mild acidic conditions in
contrast to fluoride-based desilylations. A mixture of acetic
acid in water/THF (3.5:1:3.5) proved suitable for a selective
removal of the TESether. Since compound 40 shows low
solubility in this very polar solvent mixture a significant
amount of starting material 40 (50%) could be re-isolated
after 4 d. Deprotection was followed by Dess–Martin oxida-
tion to give lactone 42. At this stage we were able to assign
the connectivity of the macrolactone ring based on an un-
ambiguously strong HMBC contact between carboxylic
carbon C1 and H13 (Scheme 6).
Scheme 6. a) TBSCl, imidazole, 79%; b) DDQ, 83%; c) Dess–Martin ox-
idation, 82%; d) HOAc/THF/H2O, 40% (95% BORSM); e) Dess–
Martin oxidation, 87%.
Lactonization of monohydroxy acid 7: When attempting the
lactonization of dihydroxy acid 35 instead of the 18-mem-
bered lactone 37 exclusively the 14-membered isomer 36
was formed and unfortunately we were not able to change
the selectivity of this lactonization. To avoid the undesired
lactonization the secondary alcohol at C13 was protected
with TBStriflate and 2,6-lutidine. The moderate yield of
55% in the conversion of 33 to 43 could be attributed to
considerable retro aldol processes of 33. Additionally, the
MMTr-protecting group was not completely stable under
these conditions as indicated by the appearance of an inten-
sive yellow color caused by the trityl cation. Again, it was
possible to start with the diastereomeric mixture of aldol
products 33. The separation of undesired isomers was ach-
ieved by simple column chromatography after acid-catalyzed
removal of the MMTr ether to hydroxy ester 44. After
cleavage of the allyl ester, free carboxylic acid 7 was subject-
ed to different lactonization
cantly lower compared to compound 38. The maximum
yield of 68% for alcohol 46 was reached when DDQ was
added in small portions over a period of 4 h. The oxidation
conditions for transforming the C15 hydroxy group into
ketone 47 also required careful optimization. Only with high
excess (10 equiv) of Dess–Martin reagent oxidation proceed-
ed slowly in moderate yield. For the deprotection of the
TESether the use of pyridinium p-toluenesulfonate (PPTS)
in methanol[3] was superior (16 h, 75%) to other reagents
such as trifluoroacetic acid or acetic acid in THF/water. The
concluding oxidation of C5 alcohol 48 to triketo lactone 6
was matched with Dess–Martin reagent in very good yield.
The global deprotection of all TBSethers was supposed to
be a delicate transformation because the partially formed b-
hydroxy ketone moieties were prone to retro aldol reactions.
methods. Interestingly, careful
investigations of the Yamaguchi
reaction showed that the mixed
anhydride had been formed but
no further lactonization was ob-
served, consistent with the fail-
ure of generating the desired
lactone 37 from compound 35
under these conditions. Gratify-
ingly, now the Mitsunobu pro-
tocol led to the desired macro-
lactone 45 in good yields
(Scheme 7).
In the endgame of the syn-
thesis the introduction of the
carbonyl groups at C5 and C15
followed the line described for
the
14-membered
lactone,
albeit the yields for the PMB
Scheme 7. Cyclization of hydroxy acid 7: a) TBSOTf, lutidine 60%; b) (CF3)2CHOH, MeOH, 85%; c) [Pd-
deprotection of 45 were signifi-
ACHTREU(GN PPh3)2Cl2], Bu3SnH; d) PPh3, DEAD, 68% over 2 steps.
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Natural Products
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For this conversion we followed the protocol established by
Roush for the synthesis of 13-deoxytedanolide (2).[10]
3HF·Et3N was described to be only slightly acidic and a
combination of this reagent and additional triethylamine
proved suitable for deprotection of lactone 6. The deprotec-
tion followed a statistical loss of TBSgroups and after 4 d
one defined compound with only one remaining TBSgroup
was isolated together with 32% of completely deprotected
lactone 49. The removal of the last remaining TBSgroup
proceeded very slowly and when the partially TBSprotected
compound was re-subjected to same deprotection conditions
only half conversion to 49 was observed after 4 d, accompa-
nied by side products (Scheme 8).
Scheme 9. Concluding epoxidation to 1: mCPBA, À458C, 3 d, 28 %.
mental results it materialized that subtle changes in configu-
rations and hybridizations are reflected by dramatic changes
in reactivity. It can be expected that these changes will be
transmitted to the biological ac-
tivity of derivatives and that
cellular tests can answer the
questions in connection with
the prerequisites of fine-tuning
the pharmacophoric parame-
ters.
The fact that compound 35
readily generated the 14-mem-
bered macrolactone 36 is
a
strong indication that indeed
the observed macrolactone of
tedanolide (1) is generated at a
later stage, most likely through
a transesterification from a dif-
ferent lacton originated through
catalysis by the polyketide’s thi-
oesterase. Further studies on
the biological activity of ana-
logues and the function of the
epoxide moiety will be reported
in due course.
Scheme 8. Synthesis of tetrahydroxy lactone 49: a) DDQ, 68%; b) Dess–Martin oxidation, 64%; c) PPTS,
MeOH, 67%; d) Dess–Martin oxidation, 91%; e) 3HF·Et3N, CH3CN/Et3N, 32%.
For the final epoxidation we intended to use unprotected
lactone 49. When 49 was treated with substoichiometric
amounts of mCPBA at À458C preferentially the D18 allylic
alcohol was epoxidized to give tedanolide (1).[31] Unfortu-
Experimental Section
nately a separation of 49 and epoxide 1 via column chroma-
tography was not successful, even when RP-18 silica gel was
used. The only way to achieve higher purity of 1 was to in-
crease conversion of 49 by adding three equivalents of
mCPBA. With this excess of mCPBA consumption of 49
was nearly completed but competitively further epoxidation
of 1 proceeded, explaining the low yield of isolated 1. Final-
ly a separation of 1 and over-oxidized products via simple
column chromatography was possible (Scheme 9). Compari-
son of the NMR data of synthetic tedanolide (1) was identi-
cal in all respect to the data published by Schmitz.[1]
General methods: NMR spectra were recorded with Bruker AVS-500,
AVS-400 or AM-200 spectrometers. Corresponding solvent signal served
as an internal standard: for 1H NMR spectra in CDCl3—the singlet of
CHCl3 at d 7.26 ppm, in C6D6—the singlet of C6D5H at d 7.16 ppm; for
13C NMR spectra in CDCl3—the triplet at d 77.00 ppm, in C6D6—the
triplet at d 128.40 ppm. Values of the coupling constant, J, are given in
Hertz (Hz). High-resolution electrospray-mass spectra (HRMS-ESI)
were recorded with Waters Micromass LCT spectrometer with a Lock-
Spray unit. All air- and moisture sensitive reactions were performed
under argon in heat gun-dried glassware. All experiments were moni-
tored by thin layer chromatography (TLC) performed on Merck 60 F-254
(0.2 mm thick) silica gel aluminium supported plates. Spots were visual-
ized by exposure to ultraviolet light (254 nm) or by staining with vanillin
reagent (85 mL MeOH, 5 mL H2SO4, 10 mL AcOH, 0.5 g vanillin, cer re-
Conclusions
agent (10 g CeACHTERU(NG SO4)2, 25 g phosphomolybdenic acid, 80 mL H2SO4, H2O
to 1 L), followed by heating. Tetrahydrofuran (THF) was distilled under
argon from sodium/benzophenone. Dichloromethane was distilled from
calcium hydride under argon. Commercially available reagents were used
as supplied. Flash chromatography was performed with J. T. Baker brand
silica gel (40–60 mm, 60 Š pores). Eluents used for flash chromatography
were distilled prior to use. Additional experimental procedures, 1H and
We have presented a convergent total synthesis of tedano-
lide (1) that provides substantial material which enables a
detailed analysis of SAR data in particular probing the role
of the epoxide moiety. Additionally, concluding the experi-
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M. Kalesse et al.
13C NMR spectra and Ortep plot of 13 are available in the Supporting In-
formation.
yellow filtrate was concentrated again under reduced pressure to dryness
and subjected to column chromatography (hexane/ethyl acetate 10:1).
Ester 18 (5.38 g, 29.5 mmol, 43% over 3 steps) was isolated as a colorless
ACHTREUNG(4S,2Z)-4-Methyl-5-trityloxypent-2-ene (15): Ethyltriphenylphosphonium
1
liquid. [a]2D5 =+138.2 (c=1.08, CHCl3); H NMR (400 MHz, CDCl3): d =
bromide (48.5 g, 131 mmol, 1.6 equiv) was suspended in THF (150 mL)
and cooled to À788C. Then nBuLi solution (49.0 mL, 123 mmol;
1.5 equiv 2.5m in hexane) was added slowly. The orange colored suspen-
sion was warmed up and stirred for 30 min at RT while the most part of
the white solids became dissolved. Then the dark red solution was cooled
6.61 (dd, J=9.7, 1.3 Hz, 1H), 5.44 (dq, J=10.8, 6.7 Hz, 1H), 5.29 (ddq,
J=10.7, 9.1, 1.6 Hz, 1H), 4.19 (q, J=7.2 Hz, 2H), 3.49 (m, 1H), 1.89 (d,
J=1.3 Hz, 3H), 1.65 (dd, J=6.7, 1.6 Hz, 3H), 1.30 (t, J=7.1 Hz, 3H),
1.09 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d = 168.4
(s), 145.6 (d), 133.2 (d), 125.8 (d), 60.4 (t), 31.5 (d), 14.3 (q), 13.0 (q),
12.4 ppm (q); IR (ATR): n˜ = 3012 (m), 2967 (s), 2929 (s), 2871 (m),
1708 (ss), 1647 (m), 1449 (m), 1390 (w), 1367 (m), 1291 (s), 1261 (s), 1229
(ss), 1146 (s), 1098 (s), 1034 (s), 989 (m), 951 (m), 750 (s), 719 cmÀ1 (s);
HRMS(EI): m/z: calcd for C11H18O2: 182.1307 [M]+, found 182.1306.
again to À788C and
a solution of aldehyde 14 (27.0 g, 81.7 mmol,
1.0 equiv) in THF (150 mL) was added rapidly. After complete addition
the reaction was allowed to warm up und stirring was continued for 3 h
at RT. Then water was added and the organic layer was separated. The
aqueous layer was extracted with ethyl acetate and the combined organic
layers were dried over MgSO4 and filtered. The solvent was removed
under vacuum to give a brownish residue. Purification was performed by
column chromatography (hexane/ethyl acetate 10:1 + 1% Et3N) to yield
alkene 15 (23.8 g, 69.5 mmol, 85%) as a highly viscous oil. [a]2D5 =+37.9
(c=0.99, CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.49 (d, J=7.5 Hz,
6H), 7.32 (t, J=7.7 Hz, 6H), 7.25 (t, J=7.3 Hz, 3H), 5.51 (dq, J=10.9,
6.7 Hz, 1H), 5.25 (ddq, J=10.7, 9.4, 1.5 Hz, 1H), 3.02 (dd, 1H, J=8.4,
6.5 Hz, H-6), 2.94 (dd, J=8.3, 7.0 Hz, 1H), 2.83 (m, 1H), 1.69 (dd, J=
6.8, 1.5 Hz, 3H), 1.05 ppm (d, J=6.7 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d = 144.5 (s, 3C), 133.9 (d), 128.8 (d, 6C), 127.6 (d, 6C), 126.8
(d, 3C), 123.9 (d), 86.2 (s), 68.1 (t), 32.4 (d), 17.9 (q), 13.1 ppm (q); IR
(ATR): n˜ = 3059 (m), 3021 (m), 2059 (m), 2917 (m), 2864 (m), 1597 (w),
1491 (s), 1448 (s), 1405 (w), 1317 (w), 1221 (w), 1182 (w), 1154 (w), 1066
(s), 1033 (m), 986 (w), 896 (w), 774 (s), 763 (s), 746 (s), 705 cmÀ1 (ss);
HRMS(EI): m/z: calcd for C25H26O: 342.1984 [M]+, found 342.1987.
AHCTRE(GNU 4S,2E,5Z)-2,4-Dimethylhepta-2,5-diene-1-ol (19): A solution of ester 18
(5.20 g, 28.5 mmol, 1.0 equiv) in THF (100 mL) was cooled to À788C and
DIBAL-H solution (47.5 mL, 71.3 mmol, 2.5 equiv, 1.5m in toluene) was
added. After 1 h the temperature was raised to RT and sat. K/Na tartrate
solution was added slowly under intensive stirring. When gas evolution
ceased the reaction mixture turned gelatinous. Addition of sat. K/Na tar-
trate solution was continued under intensive stirring until the aluminium
hydroxide gels were resolved. The reaction mixture was diluted with
ethyl acetate and the organic layer was separated. The aqueous layer was
extracted with ethyl acetate and the combined organic layers were dried
over MgSO4, filtered and concentrated under reduced pressure
(20 mbar). Purification by column chromatography (hexane/ethyl acetate
4:1) provided allyl alcohol 19 (3.48 g, 24.8 mmol, 87%) as a colorless
liquid. [a]2D5 =+74.2 (c=1.12, CHCl3); 1H NMR (400 MHz, CDCl3): d =
5.37 (dq, J=11.1, 6.6 Hz, 1H), 5.27 (dd, J=8.9, 1.1 Hz, 1H), 5.24 (ddq,
J=10.6, 9.1, 1.6 Hz, 1H), 3.96 (s, 2H), 3.40 (m, 1H), 1.71 (d, J=1.0 Hz,
3H), 1.66 (dd, J=6.7, 1.6 Hz, 3H), 1.60 (brs), 1.02 ppm (d, J=6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3): d = 135.1 (d), 1329 (s), 130.8 (d),
121.9 (d), 68.8 (t), 30.4 (d), 21.4 (q), 13.7 (q), 12.9 ppm (q); IR (ATR): n˜
= 3299 (br, ss), 3010 (m), 2963 (s), 2921 (s), 2867 (s), 1653 (w), 1451 (s),
1402 (m), 1371 (m), 1258 (w), 1224 (w), 1068 (m), 1008 (ss), 951 (s), 855
(m), 814 (w), 719 cmÀ1 (ss); HRMS(EI): m/z: calcd for C9H15O: 139.1123
[MÀH]+, found 139.1118.
ACHTREUNG(2S,3Z)-2-Methylpent-3-ene-1-ol (16): p-Toluene sulfonic acid (1.0 g) was
added to a solution of alkene 15 (23.5 g, 68.6 mmol) in CH2Cl2/methanol
2:1 (150 mL) and the yellow solution was stirred at RT for 24 h. Then
sat. NaHCO3 solution was added to wash out methanol and to neutralize
p-toluene sulfonic acid, and the organic layer was separated. The aqueous
layer was extracted with CH2Cl2 and the combined organic layers were
dried over MgSO4 and the solvent was removed for the most part by dis-
tillation over a Vigreux column at normal pressure yielding a brownish
residue. Then a cooling trap (cooled with liquid nitrogen) was connected
and at a pressure of 1 mbar the residue was slowly heated to 1008C. Al-
cohol 16 was collected in a cooling trap together with remaining CH2Cl2.
The obtained solution of 16 in CH2Cl2 was directly used for oxidation.
An analytically pure sample was prepared by column chromatography
(pentane/Et2O 2:1). [a]D25 =À26.6 (c=1.10, CHCl3); 1H NMR (400 MHz,
AHCTRE(GNU 4S,2E,5Z)-2,4-Dimethylhepta-2,5-diene-1-al (10): Manganese(IV)oxide
(16.5 g, 190 mmol, 20 equiv) was added to a solution of alcohol 19
(1.33 g, 9.46 mmol, 1.0 equiv) in Et2O (25 mL) and the suspension was
stirred intensively for 4 h. Then the suspension was filtered over celite.
The residue was washed with ethyl acetate and the combined filtrates
were concentrated under reduced pressure (20 mbar). The obtained alde-
hyde 10 (1.18 g, 8.52 mmol, 90%) was used without further purification.
An analytically pure sample was prepared by column chromatography
(hexane/ethyl acetate 6:1). [a]2D5 =+120.8 (c=0.96, CHCl3); 1H NMR
(400 MHz, CDCl3): d = 9.36 (s, 1H), 6.31 (dd, J=9.5, 1.1 Hz, 1H), 5.49
(dq, J=10.8, 6.8 Hz, 1H), 5.31 (ddq, J=10.6, 9.0, 1.6 Hz, 1H), 3.67 (m,
1H), 1.79 (d, J=1.1 Hz, 3H), 1.65 (dd, J=6.8, 1.7 Hz, 3H), 1.14 ppm (d,
J=6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): d = 195.5 (d), 157.8 (d),
137.0 (s), 132.2 (d), 124.6 (d), 31.7 (d), 20.4 (q), 13.0 (q), 9.2 ppm (q); IR
(ATR): n˜ = 3013 (m), 2967 (m), 2926 (m), 2871 (m), 2710 (w), 1686 (ss),
1638 (s), 1453 (m), 1403 (m), 1376 (m), 1355 (m), 1279 (m), 1209 (m),
1014 (s), 956 (w), 878 (w), 830 (w), 722 cmÀ1 (s); HRMS(EI): m/z: calcd
for C9H13O: 137.0966 [MÀH]+, found 137.0951.
CDCl3): d
= 5.61 (dq, J=11.0, 6.7 Hz, 1H), 5.17 (ddq, J=10.9, 9.5,
1.5 Hz, 1H), 3.50 (dd, J=10.4, 5.9 Hz, 1H), 3.35 (dd, J=10.4, 8.1 Hz,
1H), 2.72 (m, 1H), 1.67 (dd, J=6.6, 1.8 Hz, 3H), 0.96 ppm (d, J=6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3): d = 133.0 (d), 126.1 (d), 67.6 (t), 34.3
(d), 16.7 (q), 13.1 ppm (q); IR (ATR): n˜ = 3328 (br, ss), 3010 (m), 2958
(s), 2922 (s), 2872 (s), 1453 (m), 1405 (m), 1374 (m), 1260 (w), 1222 (w),
1030 (ss), 984 (m), 947 (m), 715 cmÀ1 (ss).
ACHTREUNG(2S,3Z)-2-Methylpent-3-ene-1-al (17): DMSO (10.7 g, 138 mmol,
2.0 equiv) was added at À788C to a stirred solution of oxalyl chloride
(13.1 g, 103 mmol, 1.5 equiv, calc. based on alkene 15) in CH2Cl2
(100 mL). After 30 min a solution of alcohol 16 in CH2Cl2 (volume ca.
20 mL) was added and the reaction mixture was kept at À788C for 1 h.
Then triethylamine (34.7 g, 343 mmol, 5.0 equiv) was added and the tem-
perature was raised to RT, leading to precipitation of white solids. Water
was added until solids became dissolved. The organic layer was separated
and the aqueous layer was washed with CH2Cl2. The combined organic
layers were dried over MgSO4 and filtered. Due to the highly volatile al-
dehyde 17 the filtrate was used directly without concentration under re-
duced pressure.
AHCTRE(GNU 2R,3R/S)-Ethyl 3-hydroxy-1-(p-methoxybenzyloxy)-2-methylpentanoate
(21): Diisopropylamine (8.72 g, 86.4 mmol, 1.4 equiv) was dissolved in
THF (200 mL) and cooled to À788C. Then under stirring a solution of
nBuLi (32.0 mL, 80.0 mmol, 1.3 equiv, 2.5m in hexane) was slowly added
and the reaction was allowed to warm up. After stirring for additional
30 min at RT the temperature was lowered to À788C and ethyl acetate
(8.15 g, 92.5 mmol, 1.5 equiv) was added. After 30 min a solution of alde-
hyde 20 (12.8 g, 61.7 mmol, 1.0 equiv) in THF (20 mL) was added. The
reaction was quenched after 30 min by addition of sat. NH4Cl solution
and allowed to warm up to RT. Small amounts of solids were dissolved
by addition of water. The organic layer was separated and the aqueous
layer was extracted with ethyl acetate. The combined organic layers were
dried over MgSO4, filtered and concentrated under vacuum. Purification
by column chromatography (hexane/ethyl acetate 1:1) yielded hydroxy
ACHTREUNG(4S,2E,5Z)-Ethyl 2,4-dimethylhepta-2,5-dienoate (18): EtO2CCACHTRE(UGN CH3)=
[32]
PPh3 (74.6 g, 206 mmol, 3.0 equiv, calcd for olefin 15) was added to the
solution of crude aldehyde 17 in CH2Cl2 (ca. 300 mL) and the yellow so-
lution was stirred at RT for 24 h. Then the reaction mixture was carefully
concentrated under reduced pressure. The precipitated solids were
washed several times with MTB ether whereby triphenylphosphine oxide
and ylide remained as solids and the ester 18 remained in solution. The
2238
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 2232 – 2247

Natural Products
FULL PAPER
ester 21 (16.1 g, 54.3 mmol, 88%, dr 1:1) as a slightly yellow oil. [a]D25
=
reaction was stirred at À788C for 1 h and then triethylamine (2.52 g,
22.3 mmol, 5.0 equiv) was rapidly added, leading to precipitation of white
salts. The suspension was allowed to warm up and water was added until
all salts were resolved. The organic layer was separated and the aqueous
layer was washed with CH2Cl2. The combined organic layers were dried
over MgSO4, filtered and concentrated under vacuum to give ketone 24
(1.52 g, 4.14 mmol, 98%) as a slightly yellow oil, which was used without
further purification. [a]D25 =À8.1 (c=1.15, CHCl3); 1H NMR (400 MHz,
CDCl3): d = 7.21 (d, J=8.5 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.43 (d,
J=11.6 Hz, 1H), 4.39 (d, J=11.6 Hz, 1H), 3.89 (dd, J=6.5, 2.4 Hz, 1H),
3.87 (dd, J=6.3, 2.2 Hz, 1H), 3.79 (s, 3H), 3.60 (dd, J=8.9, 7.5 Hz, 1H),
3.43 (dd, J=9.0, 5.6 Hz, 1H), 2.87 (m, 1H), 2.72 (dd, J=6.5, 3.8 Hz, 1H),
2.68 (dd, J=6.1, 3.8 Hz, 1H), 1.07 (d, J=6.8 Hz, 3H), 0.87 (s, 9H),
0.04 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d = 211.7 (s), 159.2 (s),
130.2 (s), 129.1 (d, 2C), 113.7 (d, 2C), 72.8 (t), 71.7 (t), 58.1 (t), 55.2 (q),
47.0 (d), 44.8 (t), 25.8 (q, 3C), 18.1 (s), 13.1 (q), À5.5 ppm (q, 2C); IR
(ATR): n˜ = 2954 (s), 2930 (s), 2856 (s), 1713 (ss), 1613 (m), 1587 (w),
1515 (ss), 1463 (m), 1361 (m), 1302 (w), 1247 (ss), 1211 (s), 1173 (m),
1089 (ss), 1036 (ss), 1005 (s), 917 (w), 829 (ss), 776 (ss), 664 cmÀ1 (w);
À2.5 (c=0.98, CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.27, 7.26 (d,
J=8.5 Hz, 2H), 6.90, 6.89 (d, J=8.5 Hz, 2H), 4.46 (s, 2H), 4.23 (m,
0.5H), 4.19, 4.18 (q, J=7.2 Hz, 2H), 4.01 (m, 0.5H), 3.82 (s, 3H), 3.57–
3.47 (m, 2H), 2.57–2.40 (m, 2H), 1.93 (m, 1H), 1.29 (t, J=7.2 Hz, 3H),
0.97, 0.95 ppm (d, J=7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): d
=
172.9, 172.7, (s), 159.2 (s), 130.2, 130.0 (s), 129.2 (d, 2C), 113.8 (d, 2C),
73.4, 73.3, 73.0, 73.0, 71.8, 69.9, 60.6 (t), 55.3 (q), 39.6, 39.0, 38.3, 37.9,
14.2 (q), 13.7, 11.2 ppm (q); IR (ATR): n˜ = 3436 (br, ss), 2964 (s), 2924
(s), 2869 (m), 1734 (ss), 1718 (ss), 1448 (m), 1406 (m), 1370 (m), 1328
(m), 1270 (s), 1243 (s), 1158 (ss), 1014 (ss), 954 (m), 872 (m), 721 cmÀ1
(s); HRMS(LC-MS):
found 319.1524.
m/z: calcd for C15H22O5Na: 319.1521 [M+Na]+,
ACHTREUNG(2R,3R/S)-1-(p-Methoxybenzyloxy)-2-methylpentane-3,5-diol (22): A so-
lution of hydroxy ester 21 (16.1 g, 54.1 mmol, 1.0 equiv) in THF (100 mL)
was added dropwise at RT over a period of 30 min to a stirred suspension
of lithium aluminum hydride (2.05 g, 54.0 mmol, 1.0 equiv) in THF
(50 mL). After completion of addition the suspension was warmed to
408C and kept at this temperature for 2 h. Then the suspension was
cooled to RT and under intensive stirring sat. Na2SO4 solution was added
dropwise until hydrogen evolution ceased. Addition of Na2SO4 solution
was continued until precipitated aluminium hydroxides became aggregat-
ed. The organic layer was separated and the white residue was washed
with ethyl acetate. The combined organic layers were directly concentrat-
ed under vacuum. After purification via column chromatography
(hexane/ethyl acetate 2:1) diol 22 (13.1 g, 51.4 mmol, 95%) was obtained
as a colorless oil. [a]2D5 =À4.2 (c=1.06, CHCl3); 1H NMR (400 MHz,
CDCl3): d = 7.23 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 4.46 (d,
J=11.6 Hz, 1H), 4.42 (d, J=11.6 Hz, 1H), 3.97 (m, 0.5H), 3.85–3.81 (m,
2H), 3.80 (s, 3H), 3.79–3.73 (m, 0.5H), 3.59 (dd, J=9.1, 4.1 Hz, 0.5H),
3.51 (dd, J=9.1, 4.7 Hz, 0.5H), 3.48 (dd, J=9.0, 6.5 Hz, 0.5H), 3.42 (dd,
J=9.2, 8.0 Hz, 0.5H), 1.89 (m, 1H), 1.81–1.49 (m, 2H), 0.92, 0.85 ppm (d,
J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d = 159.3 (s), 129.9 (s),
129.6, 129.3 (d, 2C), 113.9, 113.8 (d, 2C), 75.1, 74.1, 73.2, 73.1, 62.2, 61.7
HRMS(LC-M)S:
found 389.2143.
m/z: calcd for C20H34O4NaSi: 389.2124 [M+Na]+,
(2R,4R,5S,6E,8S,9Z)-4-(tert-Butyldimethylsilyloxymethyl)-5-hydroxy-1-
(p-methoxybenzyloxy)-2,6,8-trimethylundeca-6,9-diene-3-one (25): Dicy-
clohexylboron chloride solution (15.0 mL, 15.0 mmol, 1.9 equiv, 1.0m in
CH2Cl2) was diluted with Et2O (30 mL) and cooled to À788C. Under stir-
ring triethylamine (1.72 g, 17.0 mmol, 2.1 equiv) was added. After 15 min
a solution of ketone 24 (3.66 g, 10.0 mmol, 1.3 equiv) in Et2O (15 mL)
was slowly added. The reaction mixture was stirred for further 30 min at
À788C and then stored over night in a fridge at À58C, leading to precipi-
tation of white salts. Then the suspension was cooled again to À788C and
a solution of aldehyde 10 (1.10 g, 8.0 mmol, 1.0 equiv) in Et2O (5 mL)
was slowly added. The reaction mixture was stirred at À788C for further
30 min and quenched at this temperature by addition of cold methanol
(10 mL), then pH 7 buffer (5 mL) and hydrogen peroxide (30%, 5 mL)
were added. The mixture was allowed to warm up and intensively stirred
at RT for 1 h. The organic layer was separated and the aqueous layer was
extracted with ethyl acetate. The combined organic layers were dried
over MgSO4, filtered and concentrated under vacuum. The crude prod-
ucts were purified via column chromatography (hexane/ethyl acetate 4:1)
to give a diastereomeric mixture of aldol product 25 (2.77 g, 5.50 mmol,
68%, dr 2:1) as a colorless oil. Both diastereomers of 25 were separated
by a further chromatography (hexane/ethyl acetate 6:1). Major diastereo-
mer (25a): [a]2D5 =+38.5 (c=1.01, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 7.22 (d, J=8.5 Hz, 2H), 6.86 (d, J=6.7 Hz, 2H), 5.32 (ddq, J=10.6,
6.8, 0.6 Hz, 1H), 5.24 (d, J=9.0 Hz, 1H), 5.19 (ddq, J=10.7, 9.2, 1.6 Hz,
1H), 4.47 (d, J=11.7 Hz, 1H), 4.42 (d, J=11.8 Hz, 1H), 4.20 (d, J=
8.0 Hz, 1H), 3.80 (s, 3H), 3.72 (dd, J=9.0, 7.2 Hz, 1H), 3.70 (dd, J=10.2,
8.5 Hz, 1H), 3.52 (dd, J=10.1, 5.1 Hz, 1H), 3.37 (m, 1H), 3.35 (dd, J=
9.0, 6.4 Hz, 1H), 3.11 (dd, J=8.2, 5.1 Hz, 1H), 3.07–2.98 (m, 2H), 1.66
(d, J=1.3 Hz, 3H), 1.63 (dd, J=6.7, 1.7 Hz, 3H), 1.08 (d, J=7.0 Hz, 3H),
1.00 (d, J=6.8 Hz, 3H), 0.84 (s, 9H), À0.02 (s, 3H), À0.03 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d = 215.8 (s), 159.2 (s), 134.8 (d), 132.8
(d), 132.7 (s), 129.8 (s), 129.3 (d, 2C), 121.8 (d), 113.8 (d, 2C), 75.8 (d),
72.9 (t), 71.4 (t), 62.4 (t), 57.2 (d), 55.2 (q), 46.5 (d), 30.3 (d), 25.8 (q,
3C), 21.2 (q), 18.2 (s), 13.4 (q), 12.9 (q), 11.6 (q), À5.7 (q), À5.70 ppm
(q); IR (ATR): n˜ = 3448 (br, m), 3054 (w), 3007 (w), 2956 (s), 2932 (s),
2858 (m), 1710 (s), 1613 (m), 1514 (s), 1464 (m), 1363 (m), 1302 (m),
1266 (s), 1250 (s), 1174 (m), 1092 (s), 1037 (m), 837 (ss), 778 (m), 741
(t), 55.2 (q), 38.5, 38.3, 36.0, 35.0, 13.6, 11.4 ppm (q); IR (ATR): n˜
=
3313 (br, ss), 2957 (ss), 2923 (ss), 2868 (ss), 1450 (s), 1402 (s), 1370 (m),
1316 (m), 1286 (m), 1051 (ss), 987 (s), 860 (m), 720 cmÀ1 (ss); HRMS
(LC-MS): m/z: calcd for C14H22O4Na: 277.1416 [M+Na]+, found
277.1426.
ACHTREUNG(2R,3R/S)-5-(tert-Butyldimethylsilyloxy)-1-(p-methoxybenzyloxy)-2-
methylpentane-3-ol (23): Imidazole (5.25 g, 77.1 mmol, 1.5 equiv) and
TBSchloride (8.52 g, 56.5 mmol, 1.1 equiv) were added in small portions
to a stirred solution of diol 22 (13.1 g, 51.4 mmol, 1.0 equiv) in CH2Cl2
(100 mL). The suspension was stirred for 1 h at RT and sat. NaHCO3 so-
lution was added. Stirring was continued for 5 min until the precipitate
was resolved. The organic layer was separated and the aqueous layer was
washed with CH2Cl2. The combined organic layers were dried over
MgSO4, filtered and concentrated under vacuum. After purification via
column chromatography (hexane/ethyl acetate 4:1) TBS-protected alco-
hol 23 (17.7 g, 47.9 mmol, 93%) was obtained as a colorless oil. [a]D25
=
À1.5 (c=1.14, CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.27 (d, J=
9.2 Hz, 2H), 6.89 (d, J=8.7 Hz, 2H), 4.46 (s, 2H), 3.91–3.83 (m), 3.82 (s,
3H), 3.76–3.70 (m, 1H), 3.56–3.48 (m, 1H), 3.52 (dd, J=5.5, 4.4 Hz, 1H),
3.44 (dd, J=9.0, 5.4 Hz, 1H), 1.89 (m, 1H), 1.78–1.54 (m, 2H), 0.96, 0.95
(d, J=7.2 Hz, 3H), 0.92 (s, 9H), 0.09 ppm (s, 6H); 13C NMR (100 MHz,
CDCl3): d = 159.1 (s), 130.4, 130.3 (s), 129.2 (d, 2C), 113.7 (d, 2C), 74.2,
72.6 (d), 73.5 (t), 72.9 (t), 62.4, 62.1 (t), 55.2 (q), 38.9, 38.7 (d), 36.3, 36.1
(t), 25.9 (q, 3C), 18.2 (s), 13.8, 11.3 (q), À5.5 ppm (q, 2C); IR (ATR): n˜
= 3493 (br, s), 2954 (ss), 2930 (ss), 2857 (ss), 1613 (m), 1513 (ss), 1464
(s), 1388 (w), 1361 (m), 1302 (w), 1248 (ss), 1173 (m), 1083 (ss), 1037 (s),
938 (w), 832 (ss), 776 (ss), 739 cmÀ1 (m); HRMS(LC-MS): m/z: calcd for
C20H36O4NaSi: 391.2281 [M+Na]+, found 391.2293.
(ss), 706 cmÀ1 (w); HRMS(LC-M)S:
m/z: calcd for C29H48O5NaSi:
527.3169 [M+Na]+, found 527.3159; minor isomer 25a: [a]2D5 =À6.7 (c=
1
1.05); H NMR (400 MHz, CDCl3): d = 7.24 (d, J=8.5 Hz, 2H), 6.88 (d,
J=8.5 Hz, 2H), 5.35 (dq, J=11.1, 6.7 Hz, 1H), 5.27 (d, J=9.9 Hz, 1H),
5.23 (ddq, J=10.9, 9.2, 1.6 Hz, 1H), 4.46 (d, J=11.7 Hz, 1H), 4.41 (d, J=
11.7 Hz, 1H), 4.21 (d, J=6.7 Hz, 1H), 3.79 (s, 3H), 3.75 (dd, J=10.1,
8.2 Hz, 1H), 3.70 (dd, J=9.2, 7.0 Hz, 1H), 3.60 (dd, J=9.9, 5.3 Hz, 1H),
3.39 (m, 1H), 3.36 (dd, J=9.1, 6.5 Hz, 1H), 3.17 (dt, J=7.8, 5.4 Hz, 1H),
3.02 (m, 2H), 1.69 (d, J=1.1 Hz, 3H), 1.64 (dd, J=6.8, 1.6 Hz, 3H), 1.08
(d, J=6.9 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H), 0.85 (s, 9H), 0.00 (s, 3H),
À0.01 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d = 215.8 (s), 159.2
(2R)-5-(tert-Butyldimethylsilyloxy)-1-(p-methoxybenzyloxy)-2-methyl-
pentane-3-one (24): Oxalyl chloride (0.85 g, 6.71 mmol, 1.5 equiv) was
dissolved in CH2Cl2 (15 mL) and cooled to À788C. Under stirring DMSO
(0.70 g, 8.94 mmol, 1.7 equiv) was slowly added. The slightly turbid solu-
tion was stirred for further 15 min and then a solution of alcohol 23
(1.64 g, 4.47 mmol, 1.0 equiv) in CH2Cl2 (10 mL) was slowly added. The
Chem. Eur. J. 2008, 14, 2232 – 2247
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2239

M. Kalesse et al.
(s), 134.8 (d), 132.8 (s), 132.4 (d), 129.9 (s), 129.3 (d, 2C), 121.9 (d), 113.7
(d, 2C), 75.6 (d), 72.8 (t), 71.3 (t), 62.4 (t), 56.7 (d), 55.2 (q), 47.0 (d),
30.4 (d), 25.6 (q, 3C), 21.4 (q), 18.1 (s), 13.1 (q), 12.9 (q), 11.9 (q), À5.7
(q), À5.7 ppm (q); IR (ATR): n˜ = 3452 (br, m), 3054 (w), 3007 (w), 2956
(s), 2932 (s), 2858 (m), 1710 (s), 1613 (m), 1515 (s), 1464 (m), 1362 (m),
1302 (m), 1266 (s), 1250 (s), 1174 (m), 1092 (s), 1037 (m), 837 (ss), 778
2.2 mmol, 1.2 equiv, 1.0m in THF) was added dropwise to a stirred solu-
tion of diol 26 (0.93 g, 1.83 mmol, 1.0 equiv) in THF (10 mL). The color
of the solution turned to yellow. After 30 min the reaction was quenched
by addition of sat NaHCO3 solution. The organic layer was separated
and the aqueous layer was extracted with ethyl acetate. The combined or-
ganic layers were dried over MgSO4, filtered and concentrated under
vacuum. Purification via column chromatography (hexane/ethyl acetate
(m), 741 (ss), 706 cmÀ1 (w); HRMS(LC-M):S
m/z: calcd for
1:2) yielded triol 28 (0.67 g, 1.67 mmol, 91%) as a colorless oil. [a]D25
=
C29H48O5NaSi: 527.3169 [M+Na]+, found 527.3162.
+40.4 (c=1.13, CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.28 (d, J=
8.5 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 5.39–5.29 (m, 2H), 5.19 (ddq, J=
10.8, 9.2, 1.7 Hz, 1H), 4.46 (d, J=11.6 Hz, 1H), 4.42 (d, J=11.6 Hz, 1H),
4.27 (d, J=8.9 Hz, 1H), 4.16 (dd, J=9.0, 2.2 Hz, 1H), 3.79 (s, 3H), 3.59
(dd, J=9.0, 4.0 Hz, 1H), 3.52 (dd, J=9.0, 5.0 Hz, 1H), 3.46 (dd, J=11.8,
3.8 Hz, 1H), 3.42 (dd, J=11.6, 3.1 Hz, 1H), 3.43–3.38 (m, 1H), 2.05 (m,
1H), 1.77 (m, 1H), 1.68 (d, J=1.3 Hz, 3H), 1.64 (dd, J=6.8, 1.6 Hz, 3H),
1.03 (d, J=6.8 Hz, 3H), 1.00 ppm (d, J=7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d = 159.2 (s), 134.7 (s), 134.7 (d), 132.9 (d), 129.8 (s),
129.3 (d, 2C), 122.1 (d), 113.8 (d, 2C), 80.1 (d), 75.7 (d), 75.2 (t), 73.1 (t),
61.1 (t), 55.2 (q), 45.3 (d), 35.4 (d), 30.3 (d), 21.1 (q), 12.9 (q), 11.4 (q),
10.4 ppm (q); IR (ATR): n˜ = 3360 (br, ss), 2960 (s), 2919 (s), 2867 (s),
1612 (m), 1586 (m), 1513 (ss), 1454 (s), 1363 (m), 1302 (m), 1265 (s), 1247
(ss), 1174 (m), 1076 (s), 1035 (ss), 978 (m), 821 (m), 738 cmÀ1 (ss);
HRMS(LC-MS): m/z: calcd for C23H36O5Na: 415.2460 [M+Na]+, found
415.2472.
(2R,3S,4S,5S,6E,8S,9Z)-4-(tert-Butyldimethylsilyloxymethyl)-1-(p-me-
thoxybenzyloxy)-2,6,8-trimethylundeca-6,9-diene-3,5-diol (26): A stirred
solution of hydroxy ketone 25 (1.23 g, 2.42 mmol, 1.0 equiv) in THF
(25 mL) was cooled to À788C and DIBAL-H solution (4.1 mL,
6.06 mmol, 2.5 equiv 1.5m in toluene) was added. After stirring for 2 h at
this temperature sat. K/Na tartrate solution was added and the reaction
mixture was warmed to RT. When reaching RT the reaction mixture
became solid due to precipitated aluminum hydroxides. By addition of
sat. K/Na tartrate solution under intensive stirring the precipitated gels
were dissolved and the organic layer was separated. The aqueous layer
was extracted with ethyl acetate and the combined organic layers were
dried over MgSO4, filtered and concentrated under vacuum. Purification
was performed via column chromatography (hexane/ethyl acetate 5:1) to
give diol 26 (0.94 g, 1.85 mmol, 76%, dr >95:5) as a colorless oil. [a]D25
=
+25.0 (c=1.16, CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.26 (d, J=
8.7 Hz, 2H), 6.90 (d, J=8.6 Hz, 2H), 5.35–5.26 (m, 2H), 5.22 (ddq, J=
10.7, 9.3, 1.5 Hz, 1H), 4.49 (d, J=11.7 Hz, 1H), 4.44 (d, J=11.7 Hz, 1H),
4.31 (d, J=9.3 Hz, 1H), 4.25 (d, J=7.0 Hz, 1H), 3.80 (s, 3H), 3.60 (dd,
J=9.0, 4.2 Hz, 1H), 3.54 (dd, J=9.0, 4.6 Hz, 1H), 3.50 (dd, J=10.4,
2.9 Hz, 1H), 3.42 (m, 1H), 3.39 (dd, J=10.4, 3.4 Hz, 1H), 2.07 (m, 1H),
1.75 (m, 1H), 1.65–1.61 (m, 6H), 1.04 (d, J=6.7 Hz, 6H), 0.85 (s, 9H),
À0.04 (s, 3H), À0.05 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d =
159.2 (s), 135.2 (d), 134.0 (s), 133.2 (d), 130.0 (s), 129.1 (d, 2C), 121.4 (d),
113.8 (d, 2C), 79.8 (d), 76.3 (d), 75.5 (t), 73.0 (t), 61.8 (t), 55.2 (q), 44.5
(d), 35.3 (d), 30.3 (d), 25.7 (q, 3C), 21.3 (q), 18.0 (s), 12.9 (q), 11.1 (q),
10.5 (q), À5.6 (q), À5.9 ppm (q); IR (ATR): n˜ = 3380 (br, s), 2955 (s),
2928 (s), 2857 (s), 1613 (w), 1514 (s), 1463 (m), 1361 (w), 1302 (w), 1248
(ss), 1173 (w), 1100 (ss), 1038 (m), 1006 (w), 961 (m), 834 (ss), 777 (s),
725 cmÀ1 (m); HRMS(LC-MS): m/z: calcd for C29H50O5NaSi: 529.3325
[M+Na]+, found 529.3323.
(2R,3S,4S,5S,6E,8S,9Z)-1-(p-Methoxybenzyloxy)-4-[(p-methoxyphenyl)-
diphenyl-methoxymethyl]-2,6,8-trimethylundeca-6,9-diene-3,5-diol (29):
Triol 28 (0.67 g, 1.67 mmol, 1.0 equiv) was dissolved in CH2Cl2 (10 mL)
and the solution was cooled to 08C. Then MMTr-chloride (0.57 g,
1.84 mmol, 1.1 equiv) and triethylamine (0.25 g, 2.51 mmol, 1.5 equiv)
were added under stirring. After 5 min the solution was allowed to warm
up to RT and the brownish solution was stirred for 2 h. Then sat.
NaHCO3 solution was added and the mixture was vigorously stirred for
5 min. The organic layer was separated and the aqueous layer was
washed with CH2Cl2. The combined organic layers were dried over
MgSO4, filtered and concentrated under vacuum. Column chromatogra-
phy (hexane/ethyl acetate 2:1 + 1% Et3N) yielded MMTr protected diol
29 (0.77 g, 1.15 mmol, 69%) as a slightly yellow oil. [a]2D5 =+37.0 (c=
1.28, CHCl3); 1H NMR (400 MHz, C6D6): d = 7.55 (d, J=7.5 Hz, 4H),
7.39 (d, J=8.8 Hz, 2H), 7.15–7.12 (m, 6H), 7.03 (t, J=7.5 Hz, 3H), 6.77
(d, J=8.5 Hz, 2H), 6.72 (d, J=8.8 Hz, 2H), 5.35 (d, J=8.9 Hz, 1H), 5.26
(dq, J=10.7, 6.4 Hz, 1H), 5.19 (ddq, J=10.9, 9.5, 1.0 Hz, 1H), 4.49 (d,
J=8.4 Hz, 1H), 4.43 (dd, J=7.8, 2.1 Hz, 1H), 4.24 (s, 2H), 3.43–3.32 (m,
1H), 3.43 (dd, J=8.8, 5.4 Hz, 1H), 3.38 (dd, J=8.9, 4.5 Hz, 1H), 3.30 (s,
6H), 3.29 (dd, J=9.7, 3.6 Hz, 1H), 3.12 (dd, J=9.7, 5.6 Hz, 1H), 2.24 (m,
1H), 1.92 (m, 1H), 1.73 (s, 3H), 1.47 (dd, J=6.4, 0.8 Hz, 3H), 1.07 (d,
J=6.9 Hz, 3H), 1.02 ppm (d, J=6.7 Hz, 3H); 13C NMR (100 MHz,
C6D6): d = 159.8 (s), 159.2 (s), 145.2 (s), 145.1 (s), 136.0 (s), 135.9 (s),
135.8 (d), 132.6 (d), 131.1 (d, 2C), 130.8 (s), 129.5 (d, 2C), 129.2 (d, 4C),
128.4 (d), 128.2 (d, 4C), 127.2 (d), 121.6 (d), 114.2 (d, 2C), 113.5 (d, 2C),
87.3 (s), 79.5 (d), 75.7 (d), 75.4 (t), 73.3 (t), 63.5 (t), 54.8 (q, 2C), 44.8 (d),
36.3 (d), 30.8 (d), 21.7 (q), 13.0 (q), 12.1 (q), 11.1 ppm (q); IR (ATR): n˜
= 3395 (br, m), 3007 (w), 2960 (m), 2931 (m), 2868 (m), 1610 (m), 1511
(s), 1447 (m), 1301 (m), 1249 (ss), 1217 (m), 1179 (m), 1076 (m), 1035 (s),
(1’E,2’’R,3’S,4S,4’Z,5S,6S)-5-(tert-Butyldimethylsilyloxymethyl)-4-(1’,3’-
dimethylhexa-1’,4’-dienyl)-6-[2’’-(p-methoxybenzyloxy)-1’-methylethyl]-
2,2-dimethyl-[1,3]dioxane (27): 2,2-Dimethoxy propane (0.2 mL) and
PPTS(5 mg) were added to a stirred solution of diol 26 (31 mg, 61 mmol)
in acetone (1.5 mL). After 30 min the reaction was stopped by addition
of sat NaHCO3 solution. The organic layer was diluted with ethyl acetate
and separated. The aqueous layer was washed with ethyl acetate and the
combined organic layers were dried over MgSO4 and filtered. The filtrate
was concentrated under vacuum and purified via column chromatography
(hexane/ethyl acetate 12:1). Acetonide 27 (30 mg, 55 mmol, 90%) was ob-
tained as
a
colorless oil. [a]D25 =+31.8 (c=0.83, CHCl3); 1H NMR
(400 MHz, CDCl3): d = 7.27 (d, J=7.9 Hz, 2H), 6.89 (d, J=8.5 Hz, 2H),
5.38–5.28 (m, 2H), 5.20 (ddq, J=10.7, 9.4, 1.5 Hz, 1H), 4.47 (d, J=
11.7 Hz, 1H), 4.42 (d, J=11.6 Hz, 1H), 4.36 (d, J=10.5 Hz, 1H), 4.25
(dd, J=10.5, 1.6 Hz, 1H), 3.82 (s, 3H), 3.51 (dd, J=10.5, 2.4 Hz, 1H),
3.50–3.39 (m, 1H), 3.46 (dd, J=8.8, 7.8 Hz, 1H), 3.39 (dd, J=10.4,
3.1 Hz, 1H), 3.32 (dd, J=8.9, 6.8 Hz, 1H), 2.17 (m, 1H), 1.69–1.63 (m,
6H), 1.58 (m, 1H), 1.45 (s, 3H), 1.36 (s, 3H), 1.05 (d, J=6.7 Hz, 3H),
0.92–0.86 (m, 3H), 0.89 (s, 9H), 0.00 ppm (s, 6H); 13C NMR (100 MHz,
CDCl3): d = 158.9 (s), 135.1 (d), 134.8 (d), 131.6 (s), 131.1 (s), 129.0 (d,
2C), 121.5 (d), 113.6 (d, 2C), 97.6 (s), 76.9 (d), 73.0 (t), 72.5 (t), 68.6 (d),
59.0 (t), 55.3 (q), 38.6 (d), 34.0 (d), 30.4 (d), 30.0 (q), 25.8 (q, 3C), 21.2
(q), 19.9 (q), 18.0 (s), 12.9 (q), 11.2 (q), 9.9 (q), À5.6 (q), À5.8 ppm (q);
IR (ATR): n˜ = 2954 (ss), 2929 (ss), 2856 (ss), 1728 (w), 1614 (w), 1513
(m), 1463 (m), 1379 (m), 1362 (m), 1249 (ss), 1201 (m), 1172 (m), 1138
(w), 1102 (ss), 1040 (s), 1007 (m), 834 (ss), 776 (s), 741 cmÀ1 (m); HRMS
(LC-MS): m/z: calcd for C32H54O5NaSi: 569.3638 [M+Na]+, found
569.3631.
830 (m), 757 (ss), 708 cmÀ1 (m); HRMS(LC-M)S:
m/z: calcd for
C43H52O6Na: 687.3662 [M+Na]+, found 687.3663.
(2R,3S,4S,5S,6E,8S,9Z)-5-(tert-Butyldimethylsilyloxy)-1-(p-methoxyben-
zyloxy)-4-[(p-methoxyphenyl)diphenylmethoxymethyl]-2,6,8-trimethylun-
deca-6,9-diene-3-ol (30): Imidazole (0.31 g, 4.60 mmol, 4.0 equiv) and
TBSchloride (0.43 g, 2.88 mmol, 2.5 equiv) were added to a stirred solu-
tion of diol 29 (0.77 g, 1.15 mmol, 1.0 equiv) in CH2Cl2 (8 mL). After 16 h
stirring at RT sat. NaHCO3 solution was added. Then the organic layer
was separated and the aqueous layer was washed with CH2Cl2. The com-
bined organic layers were dried over MgSO4, filtered and concentrated
under vacuum. After purification via column chromatography (hexane/
ethyl acetate 4:1 + 1% Et3N) TBS-protected diol 30 (0.83 g, 1.06 mmol,
92%) was isolated as a colorless foam. [a]2D5 =+12.8 (c=1.12, CHCl3);
1H NMR (400 MHz, C6D6): d = 7.62 (d, J=8.3 Hz, 4H), 7.44 (d, J=
8.8 Hz, 2H), 7.28 (d, J=8.5 Hz, 2H), 7.19–7.14 (m, 4H), 7.04 (t, J=
7.2 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 6.74 (d, J=8.9 Hz, 2H), 5.30 (dq,
(2R,3S,4S,5S,6E,8S,9Z)-4-Hydroxymethyl-1-(p-methoxybenzyloxy)-2,6,8-
trimethylundeca-6,9-diene-3,5-diol (28): TBAF solution (2.2 mL,
2240
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Chem. Eur. J. 2008, 14, 2232 – 2247

Natural Products
FULL PAPER
J=10.7, 6.5 Hz, 1H), 5.18 (ddq, J=10.7, 9.2, 1.5 Hz, 1H), 5.04 (d, J=
8.9 Hz, 1H), 4.59 (d, J=7.4 Hz, 1H), 4.54 (dt, J=8.0, 2.4 Hz, 1H), 4.56
(d, J=11.7 Hz, 1H), 4.52 (d, J=11.7 Hz, 1H), 3.88 (d, J=2.1 Hz, 1H),
3.81 (dd, J=8.5, 7.5 Hz, 1H), 3.51 (dd, J=8.6, 5.8 Hz, 1H), 3.37 (dd, J=
9.5, 4.0 Hz, 1H), 3.32 (s, 3H), 3.31 (s, 3H), 3.15 (dd, J=9.6, 4.5 Hz, 1H),
2.38 (m, 1H), 2.32 (m, 1H), 1.65 (d, J=0.8 Hz, 3H), 1.46 (dd, J=6.7,
1.6 Hz, 3H), 1.11 (d, J=6.9 Hz, 3H), 1.02 (s, 9H), 1.03–0.98 (m, 3H),
0.20 (s, 3H), 0.09 ppm (s, 3H); 13C NMR (100 MHz, C6D6): d = 159.6
(s), 159.2 (s), 145.3 (s), 145.1 (s), 136.0 (s), 135.4 (d), 135.1 (s, C-7), 132.6
(d), 131.8 (s), 131.2 (d, 2C), 129.3 (d, 2C), 129.3 (d, 2C), 129.1 (d, 2C),
128.4 (d, 2C), 128.2 (d, 2C), 128.1 (d, 2C), 127.2 (d, 2C), 122.0 (d), 114.1
(d, 2C), 113.5 (d, 2C), 87.2 (s), 80.2 (d), 74.5 (t), 73.1 (t), 71.2 (d), 62.3
(t), 54.8 (q, 2C), 46.4 (d), 36.1 (d), 30.8 (d), 26.2 (q, 3C), 21.2 (q), 18.5
(s), 13.0 (q), 11.9 (q), 11.1 (q), À3.9 (q), À4.6 ppm (q); IR (ATR): n˜ =
3502 (br, m), 3058 (w), 3003 (w), 2955 (s), 2929 (s), 2856 (m), 1611 (m),
1511 (s), 1463 (m), 1448 (m), 1362 (w), 1301 (w), 1249 (ss), 1179 (m),
1074 (s), 1036 (ss), 1003 (s), 879 (m), 834 (ss), 775 (s), 708 cmÀ1 (m);
7.48 (d, J=8.8 Hz, 2H), 7.21–7.14 (m, 6H), 7.05 (t, J=7.2 Hz, 1H), 7.05
(t, J=7.0 Hz, 1H), 6.81 (d, J=8.5 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 5.26
(dq, J=10.7, 6.7 Hz, 1H), 5.15 (ddq, J=10.7, 9.4, 1.4 Hz, 1H), 4.98 (d,
J=9.2 Hz, 1H), 4.51 (d, J=11.0 Hz, 1H), 4.44 (d, J=11.0 Hz, 1H), 4.36
(d, J=8.2 Hz, 1H), 4.18 (dd, J=7.3, 1.2 Hz, 1H), 3.76 (dd, J=10.6,
4.3 Hz, 1H), 3.69 (dd, J=10.4, 6.3 Hz, 1H), 3.32–3.24 (m, 2H), 3.30 (s,
6H), 3.13 (t, J=9.2 Hz, 1H), 2.86 (m, 1H), 2.52 (m, 1H), 2.04–1.95 (brs,
1H), 1.71 (d, J=0.5 Hz, 3H), 1.36 (dd, J=6.7, 1.5 Hz, 3H), 1.17 (d, J=
6.9 Hz, 3H), 0.99 (s, 9H), 0.94 (d, J=6.7 Hz, 3H), 0.13 (s, 3H), 0.05 ppm
(s, 3H); 13C NMR (100 MHz, C6D6): d = 159.6 (s), 159.3 (s), 145.7 (s),
145.3 (s), 136.4 (s), 135.2 (d), 134.5 (s), 132.1 (d), 132.0 (s), 131.0 (d, 2C),
129.5 (d, 2C), 129.2 (d, 2C), 129.0 (d, 2C), 128.2 (d), 128.1 (d, 2C), 127.2
(d, 2C), 127.1 (d, 2C), 121.8 (d), 114.0 (d, 2C), 113.5 (d, 2C), 87.2 (s),
80.4 (d), 78.1 (d), 74.5 (t), 66.9 (t), 63.0 (t), 54.8 (q, 2C), 44.8 (d), 39.8
(d), 30.6 (d), 26.4 (q, 3C), 21.0 (q), 18.6 (s), 15.1 (q), 12.9 (q), 12.0 (q),
À3.8 (q), À4.3 ppm (q); IR (ATR): n˜ = 3458 (br, m), 3057 (w), 2954 (s),
2927 (s), 2856 (s), 1717 (w), 1611 (m), 1586 (w), 1511 (s), 1463 (m), 1447
(m), 1300 (m), 1248 (ss), 1177 (m), 1034 (ss), 880 (m), 834 (ss), 774 (s),
HRMS(LC-M)S:
found 801.4554.
m/z: calcd for C49H66O6NaSi: 801.4526 [M+Na]+,
740 (ss), 707 cmÀ1 (s); HRMS(LC-MS):
m/z: calcd for C49H66O6NaSi:
801.4526, found 801.4551 [M+Na]+.
(2S,3S,4E,4’S,5’R,6S,7Z)-3-(tert-Butyldimethylsilyloxy)-1-[(p-methoxy-
phenyl)-diphenylmethoxy]-2-[2’-(p-methoxyphenyl)-5’-methyl-
(2S,3R,4S,5S,6E,8S,9Z)-5-(tert-Butyldimethylsilyloxy)-3-(p-methoxyben-
zyloxy)-4-[(p-methoxyphenyl)diphenylmethoxymethyl]-2,6,8-trimethylun-
deca-6,9-diene-1-al (9): Powdered molecular sieves (4 Š, 0.40 g) and
NMO (0.165 g, 1.41 mmol, 2.5 equiv) were added to a solution of alcohol
32 (0.44 g, 0.57 mmol, 1.0 equiv) in CH2Cl2 (8 mL) and the suspension
was stirred for 20 min at RT. Then TPAP (5 mg, 14 mmol) was added and
the color turned dark green. After 30 min the suspension was directly fil-
tered over silica gel. After concentration of the solution under vacuum,
aldehyde 7 was used without further purification. For analysis purifica-
tion via column chromatography (hexane/ethyl acetate 8:1 + 1% Et3N)
yielded aldehyde 9 (0.40 g, 0.51 mmol, 90%) as a white foam. [a]2D5 =+
[1,3]dioxan-4’-yl]-4,6-dimethylnona-4,7-diene (31): Powdered molecular
sieve (4 Š) (0.10 g) was added to a stirred solution of PMB-ether 30
(0.83 g, 1.06 mmol, 1.0 equiv) in CH2Cl2 (8 mL) and the suspension was
stirred at RT for 30 min. Then the temperature was decreased to 08C
and DDQ (0.29 g, 1.27 mmol, 1.2 equiv) was added in small portions. The
color of the suspension changed from green to brown and stirring was
continued for 2 h. Then sat. NaHCO3 solution and Na2S2O5 (50 mg) were
added. After stirring for 5 min the organic layer was separated and the
aqueous suspension was extracted with CH2Cl2. The combined organic
layers were dried over MgSO4, filtered and concentrated under vacuum.
Purification via column chromatography (hexane/ethyl acetate 6:1 + 1%
Et3N) yielded PMP acetal 31 (0.70 g, 0.90 mmol, 85%) as a colorless
foam. [a]2D5 =+28.2 (c=1.04, CHCl3); 1H NMR (400 MHz, C6D6): d =
7.67 (d, J=8.9 Hz, 2H), 7.64 (d, J=7.7 Hz, 4H), 7.48 (d, J=8.9 Hz, 2H),
7.22–7.15 (m, 6H), 7.06 (t, J=7.3 Hz, 1H), 7.05 (t, J=7.3 Hz, 1H), 6.95
(d, J=8.7 Hz, 2H), 6.87 (d, J=8.9 Hz, 2H), 5.50 (s, 1H), 5.38 (d, J=
8.5 Hz, 2H), 5.35–5.28 (m, 2H), 4.89 (d, J=4.1 Hz, 1H), 3.88–3.80 (m,
2H), 3.77–3.71 (m, 2H), 3.32 (m, 1H), 3.31 (s, 3H), 3.25 (s, 3H), 3.00
(dd, J=9.1, 7.6 Hz, 1H), 2.81 (m, 1H), 1.72 (m, 1H), 1.59–1.55 (m, 6H),
1.47 (d, J=5.0 Hz, 3H), 1.01 (s, 9H), 0.95 (d, J=6.7 Hz, 3H), 0.11 (s,
3H), 0.10 ppm (s, 3H); 13C NMR (100 MHz, C6D6): d = 160.4 (s), 159.2
(s), 145.7 (s), 145.3 (s), 136.5 (s), 135.9 (d), 133.3 (s), 132.6 (s), 132.2 (d),
130.9 (d, 2C), 129.2 (d, 2C), 129.1 (d, 2C), 128.2 (d, 2C), 128.1 (d, 2C),
127.9 (d, 2C), 127.2 (d), 127.1 (d), 122.4 (d), 113.9 (d, 2C), 113.5 (d, 2C),
102.3 (d), 87.8 (s), 81.2 (d), 75.1 (d), 74.3 (t), 62.7 (t), 54.8 (q), 54.7 (q),
48.4 (d), 31.9 (d), 30.8 (d), 26.4 (q, 3C), 21.3 (q), 18.7 (s), 13.4 (q), 13.3
(q), 12.9 (q), À4.4 (q), À4.7 ppm (q); IR (ATR): n˜ = 3060 (w), 3003 (w),
2955 (s), 2928 (s), 2855 (m), 1960 (w), 1878 (w), 1614 (m), 1510 (s), 1463
(m), 1447 (m), 1301 (m), 1249 (ss), 1179 (m), 1159 (m), 1113 (s), 1035
1
8.1 (c=1.03, CHCl3); H NMR (400 MHz, C6D6): d = 9.72 (d, J=0.8 Hz,
1H), 7.66 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.7 Hz, 2H), 7.47 (d, J=8.8 Hz,
2H), 7.20–7.14 (m, 6H), 7.04 (t, J=7.4 Hz, 2H), 6.80 (d, J=8.7 Hz, 2H),
6.75 (d, J=8.9 Hz, 2H), 5.29 (dq, J=10.9, 6.5 Hz, 1H), 5.19 (ddq, J=
10.6, 9.3, 1.4 Hz, 1H), 5.09 (d, J=9.2 Hz, 1H), 4.49 (dd, J=5.2, 3.2 Hz,
1H), 4.41–4.36 (m, 3H), 3.37 (dd, J=9.3, 6.0 Hz, 1H), 3.32–3.26 (m, 1H),
3.30 (s, 6H), 3.24–3.17 (m, 2H), 2.70 (m, 1H), 1.64 (d, J=0.6 Hz, 3H),
1.40 (dd, J=6.7, 1.5 Hz, 3H), 1.20 (d, J=7.2 Hz, 3H), 0.97–0.93 (m, 3H),
0.95 (s, 9H), 0.05 (s, 3H), 0.03 ppm (s, 3H); 13C NMR (100 MHz, C6D6):
d = 203.4 (d), 159.8 (s), 159.3 (s), 145.6 (s), 145.2 (s), 136.3 (s), 135.2 (d),
133.9 (s), 132.1 (d), 131.3 (s), 130.9 (d, 2C), 129.6 (d, 2C), 129.2 (d, 2C),
129.0 (d, 2C), 128.2 (d, 2C), 127.2 (d), 127.2 (d), 122.1 (d), 114.0 (d, 2C),
113.6 (d, 2C), 87.4 (s), 77.2 (d), 76.1 (d), 73.3 (t), 62.5 (t), 54.8 (q, 2C),
50.3 (d), 46.1 (d), 30.7 (d), 26.3 (q, 3C), 21.2 (q), 18.5 (s), 13.0 (q), 12.6
(q), 10.4 (q), À3.9 (q), À4.6 ppm (q); IR (ATR): n˜ = 3058 (w), 2954 (s),
2929 (s), 2857 (s), 2709 (w), 1724 (s), 1611 (m), 1511 (ss), 1462 (m), 1448
(m), 1300 (m), 1249 (ss), 1178 (m), 1114 (w), 1036 (ss), 834 (ss), 775 (s),
740 (ss), 707 cmÀ1 (s); HRMS(LC-MS):
m/z: calcd for C49H64O6NaSi:
799.4370 [M+Na]+, found 799.4388.
(ss), 1003 (s), 832 (s), 774 (m), 707 cmÀ1 (m); HRMS(LC-MS):
m/z:
(2R,3S,4R,5R,6S,7R,8E,10S,13S,14R,15S,16S,17S,18E,20S,21Z)-Allyl-
2,7,17-tris-(tert-butyldimethylsilyloxy)-13-hydroxy-3-methoxy-15-(p-me-
thoxybenzyloxy)-16-[(p-methoxyphenyl)-diphenylmethoxymethyl]-
4,6,8,10,14,18,20-heptamethyl-11-oxo-5-triethylsilyloxytricosa-8,18,21-tri-
enoate (33): A solution of KHMDS(1.40 mL, 0.69 mmol, 1.45 equiv,
0.5m in toluene) was slowly added at À788C to a stirred solution of
ketone 8 (388 mg, 0.53 mmol, 1.1 equiv) in THF (14 mL). After 1 h a so-
lution of aldehyde 9 (0.33 g, 0.43 mmol, 1.0 equiv) in THF (4 mL) was
slowly added. Then the reaction was stirred for further 30 min at À788C
and was quenched by addition of sat. NH4Cl solution and warmed up to
RT. To dissolve precipitated NH4Cl a small amount of water was added,
and the organic layer was separated. The aqueous layer was extracted
with ethyl acetate. The combined organic layers were dried over MgSO4,
filtered and concentrated under vacuum. The crude product was purified
by two consecutive column chromatography. After the first chromatogra-
phy (hexane/ethyl acetate 20:1 + 1% Et3N) ketone 8 (57 mg, 78 mmol)
was reisolated. The other fractions were purified again (hexane/ethyl ace-
tate 8:1 + 1% Et3N) to give a diastereomeric mixture of aldol product
33 (384 mg, 0.26 mmol, 59%) as a colorless oil. An analytical sample of
calcd for C49H64O6NaSi: 799.4370 [M+Na]+, found 799.4390.
(2R,3S,4S,5S,6E,8S,9Z)-5-(tert-Butyldimethylsilyloxy)-3-(p-methoxyben-
zyloxy)-4-[(p-methoxyphenyl)diphenylmethoxymethyl]-2,6,8-trimethylun-
deca-6,9-diene-1-ol (32): PMP-acetal 31 (0.70 g, 0.90 mmol, 1.0 equiv)
was dissolved in toluene (8 mL) and cooled under stirring to 08C. Then a
solution of DIBAL-H (1.50 mL, 2.25 mmol, 2.5 equiv, 1.5m in toluene)
was added followed after 1 h by an additional amount of DIBAL-H solu-
tion (0.50 mL, 0.75 mmol, 0.83 equiv). The reaction was kept at 08C for
3 h and then sat. NaHCO3 solution was added and the suspension was al-
lowed to warm up. After reaching RT the reaction mixture became solid
due to precipitated alumina gels. By addition of sat. K/Na tartrate solu-
tion and intensive stirring the precipitate was dissolved and the organic
layer was separated. The aqueous layer was extracted with ethyl acetate
and the combined organic layers were dried over MgSO4 and filtered.
After concentration the filtrate under vacuum chromatography (hexane/
ethyl acetate 5:1 + 1% Et3N) yielded alcohol 32 (0.57 g, 0.73 mmol,
81%) as a colorless foam. [a]2D5 =+14.1 (c=1.10, CHCl3); 1H NMR
(400 MHz, C6D6): d = 7.66 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.8 Hz, 2H),
Chem. Eur. J. 2008, 14, 2232 – 2247
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2241

M. Kalesse et al.
diastereomerically pure 33 was obtained after semipreparative HPLC
(eluent MeOH 100%, Merck licrospher100 RP-18 column, detection via
UV absorption at 250 nm). [a]2D5 =+21.1 (c=1.10, CHCl3); 1H NMR
(400 MHz, C6D6): d = 7.72 (d, J=7.4 Hz, 2H), 7.68 (d, J=7.4 Hz, 2H),
7.52 (d, J=8.8 Hz, 2H), 7.25–7.19 (m, 6H), 7.07 (t, J=7.3 Hz, 1H), 7.06
(t, J=7.3 Hz, 1H), 6.83 (d, J=8.7 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 5.78
(ddt, J=16.9, 10.6, 6.1 Hz, 1H), 5.70 (d, J=9.0 Hz, 1H), 5.27 (dq, J=
10.7, 6.6 Hz, 1H), 5.20–5.11 (m, 1H), 5.14 (dd, J=17.1, 1.4 Hz, 1H),
5.06–4.99 (m, 1H), 5.01 (dd, J=10.4, 1.3 Hz, 1H), 4.71 (d, J=9.3 Hz,
1H), 4.57 (d, J=10.5 Hz, 1H), 4.55 (d, J=6.8 Hz, 1H), 4.49–4.39 (m,
5H), 4.12 (d, J=10.0 Hz, 1H), 3.79 (d, J=8.3 Hz, 1H), 3.66 (dd, J=7.0,
0.9 Hz, 1H), 3.63 (s, 3H), 3.51–3.48 (s, 1H), 3.38 (dd, J=9.2, 7.0 Hz, 1H),
3.35–3.26 (m, 2H), 3.33 (s, 3H), 3.32 (s, 3H), 3.13 (t, J=9.2 Hz, 1H),
2.93–2.84 (m, 2H), 2.61 (dd, J=16.9, 2.9 Hz, 1H), 2.53 (m, 1H), 2.11 (m,
1H), 2.00 (m, 1H), 1.75 (d, J=0.2 Hz, 3H), 1.71 (d, J=0.2 Hz, 3H), 1.38
(dd, J=6.7, 1.5 Hz, 3H), 1.29 (d, J=7.0 Hz, 3H), 1.26 (d, J=6.9 Hz, 6H),
1.15 (t, J=7.9 Hz, 9H), 1.15 (d, J=6.9 Hz, 3H), 1.03 (s, 18H), 1.02 (s,
9H), 0.97 (d, J=6.7 Hz, 3H), 0.87–0.79 (m, 6H), 0.21 (s, 3H), 0.18 (s,
3H), 0.16 (s, 6H), 0.11 (s, 3H), 0.07 ppm (s, 3H); 13C NMR (100 MHz,
C6D6): d = 211.6 (s), 171.6 (s), 159.7 (s), 159.3 (s), 145.8 (s), 145.3 (s),
139.3 (s), 136.4 (s), 135.2 (d), 134.6 (s), 132.3 (d), 132.2 (d), 131.8 (s),
131.1 (d, 2C), 129.7 (d, 2C), 129.2 (d, 2C), 129.1 (d, 2C), 128.4 (d, 2C),
128.3 (d), 128.2 (d, 2C), 127.2 (d, 2C), 121.8 (d), 119.0 (t), 114.0 (d, 2C),
113.5 (d, 2C), 87.2 (s), 83.1 (d), 81.4 (d), 80.5 (d), 78.2 (d), 76.6 (d), 74.6
(t), 74.4 (d), 69.7 (d), 65.6 (t), 63.0 (t), 61.1 (q), 54.8 (q, 2C), 46.8 (t), 46.5
(d), 44.5 (d), 41.8 (d), 40.3 (d, 2C), 30.7 (d), 26.5 (q), 26.2 (q), 26.1 (q),
21.0 (q), 18.6 (s, 3C), 17.0 (q), 12.9 (q), 12.1 (q), 12.0 (q), 11.7 (q), 10.7
(q), 10.6 (q), 7.7 (q), 6.6 (t, 3C), À3.8 (q), À3.9 (q), À4.2 (q), À4.5 (q),
À4.7 (q), À4.8 ppm (q); IR (ATR): n˜ = 2954 (s), 2930 (s), 2881 (m),
2857 (m), 1740 (m), 1715 (m), 1611 (w), 1511 (m), 1462 (m), 1361 (w),
1300 (w), 1249 (ss), 1106 (s), 1036 (ss), 1005 (s), 834 (ss), 774 (ss), 726
(q, 3C), 6.6 (t, 3C), À3.9 (s), À4.0 (s), À4.5 (s), À4.7 (s), À4.7 (s),
À4.8 ppm (s); IR (ATR): n˜ = 3494 (br, m), 2954 (ss), 2929 (ss), 2884 (s),
2857 (s), 1738 (m), 1716 (m), 1613 (w), 1514 (m), 1462 (m), 1361 (w),
1250 (ss), 1173 (w), 1108 (s), 1038 (ss), 1006 (s), 836 (ss), 776 (ss),
738 cmÀ1 (ss); HRMS(LC-M)S:
m/z: calcd for C67H124O12NaSi4:
1255.8068 [M+Na]+, found 1255.8048.
(1’R,2’S,3R,3’S,4S,4’S,5S,5’E,6R,7S,7’S,8R,8’Z,9E,11S,14S)-3,8-Bis-(tert-
butyldimethylsilyloxy)-14-[4’-(tert-butyldimethylsilyloxy)-3’-hydroxymeth-
yl-2’-(p-methoxybenzyloxy)-1’,5’,7’-trimethyldeca-5,8-dienyl]-4-methoxy-
5,7,9,11-tetramethyl-6-triethylsilyloxy-oxacyclotetradec-9-ene-2,12-dione
(36)
a) Cleavage of allyl ester 34: [PdACTHER(UNG PPh3)2Cl2] (5 mg, 7 mmol) and tri-n-bu-
tyltin hydride (0.24 mL, 0.91 mmol, 6.0 equiv) were added to a solution
of allyl ester 34 (188 mg, 0.15 mmol, 1.0 equiv) in CH2Cl2 (10 mL). The
color of the solution rapidly changed to dark red and gas evolution oc-
curred. After 20 min sat. NaHCO3 solution was added. The aqueous
layer was separated and the organic layer was washed with brine and sat.
NH4Cl solution. The combined aqueous layers were washed again with
CH2Cl2. The combined organic layers were dried over MgSO4 and fil-
tered. The brownish filtrate of 35 was carefully concentrated under
vacuum at 208C and used immediately without further purification.
b) Yamaguchi lactonization: Crude dihydroxy acid 35 was diluted with
CH2Cl2 (50 mL) and diisopropylamine (1.2 mL, solution in CH2Cl2, c=
0.5m, 0.60 mmol, 4.0 equiv), DMAP (1.5 mL, solution in CH2Cl2, c=
0.1m, 0.15 mmol, 1.0 equiv) and 2,4,6-trichlorobenzoyl chloride (1.5 mL,
solution in CH2Cl2, c=0.2m, 0.30 mmol, 2.0 equiv) were added. The reac-
tion mixture was stirred for 3 h at RT and then sat. NaHCO3 solution was
added. The organic layer was separated and the aqueous layer was
washed with CH2Cl2. The combined organic layers were dried over
MgSO4, filtered and concentrated under vacuum. After purification via
column chromatography (hexane/ethyl acetate 15:1) macrolactone 36
(61 mg, 52 mmol, 34% over 2 steps) was obtained as a colorless oil.
[a]2D5 =+66.8 (c=0.84, CHCl3); 1H NMR (400 MHz, C6D6): d = 7.44 (d,
J=8.5 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 5.71 (m, 1H), 5.57 (d, J=9.6 Hz,
1H), 5.38 (dq, J=10.8, 6.4 Hz, 1H), 5.33–5.28 (m, 2H), 4.78 (d, J=
10.9 Hz, 1H), 4.74 (d, J=10.6 Hz, 1H), 4.46 (d, J=4.8 Hz, 1H), 4.42 (d,
J=6.8 Hz, 1H), 4.06 (d, J=7.9 Hz, 1H), 3.98 (dd, J=5.5, 2.0 Hz, 1H),
3.82 (t, J=4.3 Hz, 1H), 3.75 (dd, J=10.6, 7.2 Hz, 1H), 3.69–3.65 (m,
2H), 3.59 (s, 3H), 3.39 (m, 1H), 3.31 (s, 3H), 3.21 (m, 1H), 2.97 (dd, J=
17.1, 6.5 Hz, 1H), 2.72 (m, 1H), 2.52–2.45 (m, 2H), 2.08 (m, 1H), 1.92
(m, 1H), 1.75 (s, 3H), 1.69 (s, 3H), 1.56 (dd, J=6.5, 1.0 Hz, 3H), 1.36 (d,
J=6.8 Hz, 3H), 1.33 (d, J=7.2 Hz, 3H), 1.29 (d, J=6.8 Hz, 3H), 1.22 (d,
J=6.8 Hz, 3H), 1.12 (t, J=8.0 Hz, 9H), 1.08–1.03 (m, 3H), 1.06 (s, 9H),
1.04 (s, 9H), 1.01 (s, 9H), 0.81 (q, J=8.0 Hz, 6H), 0.26 (s, 3H), 0.20 (s,
3H), 0.17 (s, 3H), 0.17 (s, 3H), 0.10 (s, 3H), 0.07 ppm (s, 3H); 13C NMR
(100 MHz, C6D6): d = 207.1 (s), 172.8 (s), 159.8 (s), 141.4 (s), 135.2 (d),
135.0 (s), 132.1 (d), 131.6 (s), 129.8 (d, 2C), 127.9 (d), 122.5 (d), 114.2 (d,
2C), 84.9 (d), 81.3 (d), 79.0 (d), 77.9 (d), 77.7 (d), 75.9 (d), 74.4 (d), 73.9
(t), 62.1 (t), 59.9 (q), 54.8 (q), 46.6 (t), 46.6 (d), 46.5 (d), 45.0 (d), 43.2
(d), 42.3 (d), 30.8 (d), 26.5 (q, 3C), 26.2 (q, 3C), 26.2 (q, 3C), 21.3 (q),
18.6 (s, 3C), 15.6 (q), 15.2 (q), 13.2 (q), 12.7 (q), 11.7 (q), 11.5 (q), 10.7
(q), 7.6 (q, 3C), 6.0 (t, 3C), À3.9 (q), À4.0 (q), À4.0 (q), À4.4 (q), À4.5
(q), À4.6 ppm (q); IR (ATR): n˜ = 3520 (w), 2954 (s), 2928 (s), 2856 (s),
1740 (m), 1721 (m), 1514 (w), 1462 (m), 1386 (w), 1302 (w), 1249 (s),
1151 (m), 1111 (s), 1039 (ss), 1005 (s), 835 (ss), 775 (ss), 724 (m),
(m), 708 cmÀ1 (m); HRMS(LC-M)S:
m/z: calcd for C87H140O13NaSi4:
1527.9269 [M+Na]+, found 1527.9273.
(2R,3S,4R,5R,6S,7R,8E,10S,13S,14R,15S,16S,17S,18E,20S,21Z)-Allyl-
2,7,17-tris-(tert-butyldimethylsilyloxy)-13-hydroxy-16-hydroxymethyl-3-
methoxy-15-(p-methoxybenzyloxy)-4,6,8,10,14,-18,20-heptamethyl-11-
oxo-5-triethylsilyloxytricosa-8,18,21-trienoate (34): The diastereomeric
mixture of aldol products 33 (384 mg, 0.26 mmol) was dissolved in
CH2Cl2 (2 mL) and hexafluoroisopropanol (3 mL) was added. After stir-
ring for a few min an intensive orange color appeared. After 10 min
methanol was added dropwise until a slight yellow color remained and
stirring was continued for 16 h at RT. Then sat. NaHCO3 solution was
added and the organic layer was diluted with CH2Cl2 and separated. The
aqueous layer was extracted with CH2Cl2 and the combined organic
layers were dried over MgSO4 and filtered. After removing the solvent
under vacuum the diastereomeric mixture of diols could be easily sepa-
rated via column chromatography (hexane/ethyl acetate 10:1
+ 1%
Et3N) to yield major diastereomer 34 (213 mg, 0.17 mmol, 68%) as a col-
orless oil. [a]2D5 =+29.1 (c=0.66, CHCl3); 1H NMR (400 MHz, C6D6): d
= 7.30 (d, J=8.5 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 5.77 (ddt, J=17.0,
10.6 Hz, 6.1 Hz, 1H), 5.71 (d, J=9.7 Hz, 1H), 5.37 (dq, J=10.3, 6.7 Hz,
1H), 5.32–5.26 (m, 2H), 5.15 (dd, J=17.2, 1.4 Hz, 1H), 5.01 (dd, J=10.3,
1.0 Hz, 1H), 4.65 (d, J=11.0 Hz, 1H), 4.54 (d, J=6.9 Hz, 1H), 4.51–4.41
(m, 3H), 4.50 (d, J=10.8 Hz, 1H), 4.24–4.18 (m, 2H), 4.11 (d, J=9.9 Hz,
1H), 3.85–3.75 (m, 1H), 3.77 (d, J=8.5 Hz, 1H), 3.68–3.62 (m, 1H), 3.65
(d, J=6.9 Hz, 1H), 3.59 (s, 3H), 3.44–3.35 (m, 2H), 3.32 (s, 3H), 2.76
(dd, J=16.7, 8.9 Hz, 1H), 2.58–2.49 (m, 1H), 2.50 (dd, J=16.8, 3.2 Hz,
1H), 2.27 (m, 1H), 2.10 (m, 1H), 2.00 (m, 1H), 1.73 (s, 3H), 1.69 (s, 3H),
1.56 (dd, J=6.4, 1.1 Hz, 1H), 1.26 (d, J=6.8 Hz, 3H), 1.24 (d, J=7.3 Hz,
3H), 1.23 (d, J=6.9 Hz, 3H), 1.18–1.12 (m, 3H), 1.15 (t, J=7.8 Hz, 9H),
1.08 (d, J=6.8 Hz, 3H), 1.05 (s, 9H), 1.03 (s, 9H), 1.02 (s, 9H), 0.83 (q,
J=7.7 Hz, 6H), 0.21 (s, 3H), 0.19 (s, 3H), 0.17 (s, 3H), 0.15 (s, 3H), 0.11
(s, 3H), 0.09 ppm (s, 3H); 13C NMR (100 MHz, C6D6): d = 211.1 (s),
171.6 (s), 159.9 (s), 139.3 (s), 135.1 (d), 134.8 (s), 132.4 (d), 132.2 (d),
130.9 (s), 128.7 (d, 2C), 128.2 (d), 122.6 (d), 119.0 (t), 114.3 (d, 2C), 83.1
(d), 81.6 (d), 81.4 (d), 78.0 (d), 76.5 (d), 74.4 (d), 72.4 (t), 71.4 (d), 65.6
(t), 61.7 (t), 61.1 (q), 54.8 (q), 46.6 (d), 46.6 (t), 46.5 (d), 40.3 (d, 2C),
39.9 (d), 30.8 (d), 26.4 (q, 3C), 26.2 (q, 3C), 26.1 (q, 3C), 21.2 (q), 18.6
(s, 3C), 17.1 (q), 13.2 (q), 12.4 (q), 12.0 (q), 11.7 (q), 10.6 (q), 9.5 (q), 7.7
672 cmÀ1 (w); HRMS(LC-M)S:
m/z: calcd for C64H118O11NaSi4:
1197.7649 [M+Na]+, found 1197.7607.
(1’R,2’S,3R,3’S,4S,4’S,5S,5’E,6R,7S,7’S,8R,8’Z,9E,11S,14S)-3,8-Bis-(tert-
butyldimethylsilyloxy)-14-[4’-(tert-butyldimethylsilyloxy)-3’-(tert-butyldi-
methylsilyloxymethyl)-2’-(p-methoxybenzyloxy)-1’,5’,7’-trimethyldeca-5,8-
dienyl]-4-methoxy-5,7,9,11-tetramethyl-6-triethylsilyloxyoxacyclotetradec-
9-ene-2,12-dione (38): Imidazole (45 mg, 0.66 mmol, 30 equiv) and TBS-
chloride (30 mg, 0.20 mmol, 9.0 equiv) were added to a solution of hy-
droxy macrolactone 36 (25.7 mg, 21.9 mmol, 1.0 equiv) in CH2Cl2 (1 mL).
After 1 h sat. NaHCO3 solution was added. The organic layer was diluted
with CH2Cl2 and separated, the aqueous layer was washed with CH2Cl2.
The combined organic layers were dried over MgSO4, filtered and con-
centrated under vacuum. After purification via column chromatography
2242
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 2232 – 2247

Natural Products
FULL PAPER
(hexane/ethyl acetate 50:1) TBS-protected macrolactone 38 (22.3 mg,
17.3 mmol, 79%) was obtained as a colorless oil. [a]2D5 =+46.1 (c=0.90,
CHCl3); 1H NMR (400 MHz, C6D6): d = 7.52 (d, J=8.5 Hz, 2H), 6.86
(d, J=8.5 Hz, 2H), 5.65 (d, J=9.2 Hz, 1H), 5.59 (ddd, J=7.7, 6.1, 1.7 Hz,
1H), 5.52 (d, J=8.9 Hz, 1H), 5.46–5.38, (m, 2H), 4.84 (d, J=10.6 Hz,
1H), 4.74 (d, J=10.9 Hz, 1H), 4.67 (d, J=3.4 Hz, 1H), 4.50 (d, J=
5.5 Hz, 1H), 4.12–4.07 (m, 1H), 4.11 (d, J=7.5 Hz, 1H), 3.97–3.92 (m,
2H), 3.83 (t, J=4.6 Hz, 1H), 3.73 (dd, J=5.5, 3.4 Hz, 1H), 3.61 (s, 3H),
3.48 (m, 1H), 3.35 (m, 1H), 3.31 (s, 3H), 3.02 (dd, J=17.4, 5.8 Hz, 1H),
2.79–2.71 (m, 2H), 2.40 (m, 1H), 2.13 (m, 1H), 2.02 (m, 1H), 1.81 (s,
3H), 1.71 (s, 3H), 1.60 (d, J=5.1 Hz, 3H), 1.35 (d, J=7.5 Hz, 3H), 1.32
(d, J=6.8 Hz, 1H), 1.31 (d, J=7.2 Hz, 3H), 1.29 (d, J=6.5 Hz, 3H), 1.14
(d, J=6.8 Hz, 3H), 1.12 (t, J=7.9 Hz, 9H), 1.06 (s, 9H), 1.03 (s, 18H),
1.00 (s, 9H), 0.81 (q, J=8.0 Hz, 6H), 0.22 (s, 3H), 0.19 (s, 3H), 0.17 (s,
3H), 0.15 (s, 3H), 0.14 (s, 6H), 0.13 (s, 3H), 0.06 ppm (s, 3H); 13C NMR
(100 MHz, C6D6): d = 207.4 (s), 172.1 (s), 159.8 (s), 141.6 (s), 135.6 (d),
134.8 (s), 131.7 (s), 131.1 (d), 129.8 (d, 2C), 127.9 (d), 122.2 (d), 114.2 (d,
2C), 85.3 (d), 81.3 (d), 78.2 (d), 77.0 (d), 76.4 (d), 75.5 (d, 2C), 72.7 (t),
60.9 (t), 60.2 (q), 54.8 (q), 47.9 (d), 46.9 (d), 46.8 (t), 45.3 (d), 42.1 (d),
41.8 (d), 30.9 (d), 26.5 (q, 3C), 26.3 (q, 3C), 26.2 (q, 3C), 26.2 (q, 3C),
21.8 (q), 18.7 (s), 18.6 (s, 2C), 18.5 (s), 16.0 (q), 14.9 (q), 14.1 (q), 13.2
(q), 12.2 (q), 11.6 (q), 11.0 (q), 7.7 (q, 3C), 6.0 (t, 3C), 5.1 (q), À3.8 (q),
À4.1 (q), À4.2 (q), À4.6 (q), À4.6 (q), À4.7 (q), À5.0 ppm (q); IR (ATR):
n˜ = 2954 (s), 2929 (s), 2884 (s), 2857 (s), 1742 (m), 1721 (m), 1614 (w),
1514 (m), 1463 (m), 1250 (s), 1152 (m), 1111 (s), 1041 (s), 1005 (s), 836
(ss), 776 (ss), 724 (m), 671 cmÀ1 (w); HRMS(LC-MS): m/z: calcd for
C70H136NO11Si5: 1306.8960 [M+NH4]+, found 1306.8948.
and the turbid solution was stirred for 1 h at RT. Then sat. NaHCO3 solu-
tion and Na2S2O3 (30 mg) were added. Intensive stirring was continued
until the organic layer became clear. The organic layer was diluted with
CH2Cl2 and separated. The aqueous layer was washed with CH2Cl2 and
the combined organic layers were dried over MgSO4 and filtered. After
removing the solvent under vacuum the residue was purified via column
chromatography (hexane/ethyl acetate 50:1) to give diketo lactone 40
(7.0 mg, 6.0 mmol, 82%) as a colorless oil. [a]2D5 =+87.1 (c=1.61, CHCl3);
1H NMR (400 MHz, C6D6): d = 6.00 (dt, J=7.6, 2.1 Hz, 1H), 5.53 (dd,
J=9.5, 0.7 Hz, 1H), 5.35 (dq, J=10.8, 6.8 Hz, 1H), 5.20 (ddq, J=10.8,
9.3, 1.5 Hz, 1H), 5.08 (d, J=8.9 Hz, 1H), 4.39 (d, J=8.9 Hz, 1H), 4.34 (d,
J=5.0 Hz, 1H), 4.05 (d, J=8.2 Hz, 1H), 3.79 (t, J=3.7 Hz, 1H), 3.68
(dd, J=16.1, 9.4 Hz, 1H), 3.66 (t, J=4.3 Hz, 1H), 3.57 (s, 3H), 3.51 (dd,
J=9.9, 5.0 Hz, 1H), 3.38–3.25 (m, 3H), 3.21 (qui, J=7.3 Hz, 1H), 3.01
(dd, J=17.3, 7.8 Hz, 1H), 2.73 (dd, J=17.2, 2.3 Hz, 1H), 2.00 (m, 1H),
1.85–1.79 (m, 1H), 1.81 (d, J=0.8 Hz, 3H), 1.67 (d, J=0.9 Hz, 1H), 1.57
(dd, J=6.7, 1.7 Hz, 3H), 1.44 (d, J=7.4 Hz, 3H), 1.30 (d, J=7.0 Hz, 3H),
1.26 (d, J=7.0 Hz, 3H), 1.16 (d, J=7.7 Hz, 3H), 1.13 (t, J=8.0 Hz, 9H),
1.08 (s, 9H), 1.01 (s, 9H), 1.00–0.97 (m), 0.98 (s), 0.95 (s, 9H), 0.82 (q,
J=7.9 Hz, 6H), 0.33 (s, 3H), 0.25 (s, 3H), 0.17 (s, 3H), 0.13 (s, 3H), 0.12
(s, 3H), 0.12 (s, 3H), 0.07 (s, 3H), 0.06 ppm (s, 3H); 13C NMR (100 MHz,
C6D6): d = 211.4 (s), 206.5 (s), 172.1 (s), 140.8 (s), 135.2 (d), 133.4 (s),
133.3 (d), 128.1 (d), 122.1 (d), 84.4 (d), 81.4 (d), 77.6 (d), 76.7 (d), 76.1
(d), 72.7 (d), 64.4 (t), 59.9 (q), 56.6 (d), 52.9 (d), 46.4 (d), 46.1 (t), 45.1
(d), 44.3 (d), 30.7 (d), 26.3 (q, 3C), 26.3 (q, 3C), 26.2 (q, 3C), 26.2 (q,
3C), 21.0 (q), 18.7 (s), 18.7 (s), 18.6 (s), 18.5 (s), 15.7 (q), 14.4 (q), 13.2
(q), 12.3 (q), 11.9 (q), 11.3 (q), 10.6 (q), 7.7 (q, 3C), 6.1 (t, 3C), À3.9 (q),
À3.9 (q), À4.3 (q), À4.4 (q), À4.4 (q), À4.6 (q), À5.2 (q), À5.3 ppm (q);
IR (ATR): n˜ = 2955 (s), 2929 (ss), 2885 (m), 2857 (s), 1747 (m), 1720
(m), 1471 (m), 1463 (m), 1387 (w), 1362 (w), 1253 (s), 1146 (m), 1105
(m), 1048 (s), 1006 (m), 836 (ss), 777 (ss), 725 cmÀ1 (m); HRMS(LC-
MS): m/z: calcd for C62H126NO10Si5: 1184.8228 [M+NH4]+, found
1184.8191.
(1’S,2’S,3R,3’S,4S,4’S,5S,5’E,6R,7S,7’S,8R,8’Z,9E,11S,14S)-3,8-Bis-(tert-
butyldimethylsilyloxy)-14-[4’-(tert-butyldimethylsilyloxy)-3’-(tert-butyldi-
methylsilyloxymethyl)-2’-hydroxy-1’,5’,7’-trimethyldeca-5,8-dienyl]-4-me-
thoxy-5,7,9,11-tetramethyl-6-triethylsilyloxy-oxacyclotetradec-9-ene-2,12-
dione (39): Water (0.1 mL) was added to a solution of PMB ether 38
(11.2 mg, 8.7 mmol, 1.0 equiv) in CH2Cl2 (1 mL) and under intensive stir-
ring at 08C DDQ (2.5 mg, 10.5 mmol, 1.2 equiv) was added. Stirring was
continued for 2 h and sat NaHCO3 solution and Na2S2O5 (5 mg) were
added. The organic layer was diluted with CH2Cl2 and separated, while
the aqueous layer was washed with CH2Cl2. The combined organic layers
were dried over MgSO4, filtered and concentrated under vacuum. After
chromatography (hexane/ethyl acetate 50:1) alcohol 39 (8.5 mg, 7.3 mmol,
83%) was obtained as a colorless oil. [a]2D5 =+45.2 (c=0.85, CHCl3);
1H NMR (400 MHz, C6D6): d = 5.76 (dt, J=7.1, 2.8 Hz, 1H), 5.60 (d, J=
9.3 Hz, 1H), 5.42–5.29 (m, 3H), 4.56 (d, J=8.2 Hz, 1H), 4.37 (d, J=
5.0 Hz, 1H), 4.24 (d, J=7.9 Hz, 1H), 4.14 (s, 1H), 4.08 (d, J=8.2 Hz,
1H), 3.82 (t, J=3.8 Hz, 1H), 3.71 (t, J=4.5 Hz, 1H), 3.60 (s, 3H), 3.57
(dd, J=6.8, 3.7 Hz, 1H), 3.46 (dd, J=10.3, 3.7 Hz, 1H), 3.39 (m, 1H),
3.29 (m, 1H), 3.18 (dd, J=17.1, 7.2 Hz, 1H), 2.92 (dd, J=17.2, 2.8 Hz,
1H), 2.49 (m, 1H), 2.04 (m, 1H), 1.98 (m, 1H), 1.88 (m, 1H), 1.80 (s,
3H), 1.65 (s, 3H), 1.56 (d, J=5.3 Hz, 3H), 1.32 (d, J=7.2 Hz, 3H), 1.30
(d, J=6.8 Hz, 3H), 1.29 (d, J=7.0 Hz, 3H), 1.21 (d, J=6.8 Hz, 3H), 1.13
(t, J=8.0 Hz, 9H), 1.08 (s, 9H), 1.05 (d, J=6.8 Hz, 3H), 1.01 (s, 27H),
0.82 (q, J=7.9 Hz, 6H), 0.28 (s, 3H), 0.22 (s, 3H), 0.21 (s, 3H), 0.18 (s,
3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.07 ppm (s, 3H); 13C NMR
(100 MHz, C6D6): d = 207.8 (s), 172.2 (s), 140.8 (s), 135.2 (d), 134.7 (s),
133.3 (d), 128.1 (d), 122.4 (d), 84.5 (d), 81.4 (d), 80.9 (d), 76.7 (d), 76.2
(d), 75.6 (d), 71.3 (d), 61.5 (t), 60.0 (q), 46.8 (d), 46.6 (d), 45.2 (t), 45.1
(d), 44.1 (d), 39.7 (d), 30.9 (d), 26.3 (q), 26.2 (q, 3C), 21.2 (q), 18.7 (s),
18.6 (s), 18.5 (s), 18.4 (s), 15.7 (q), 14.7 (q), 13.2 (q), 11.8 (q, 2C), 10.8
(q), 10.5 (q), 7.7 (q, 3C), 6.1 (t, 3C), À3.8 (q), À3.9 (q), À4.0 (q), À4.3
(q), À4.6 (q), À4.8 (q), À5.3 ppm (q, 2C); IR (ATR): n˜ = 3498 (w), 2954
(s), 2928 (ss), 2856 (s), 1743 (m), 1721 (m), 1462 (m), 1407 (w), 1387 (w),
1253 (s), 1151 (m), 1100 (s), 1043 (s), 1005 (s), 835 (ss), 776 (ss), 725 (m),
(1’R,2’S,3R,3’S,4S,4’S,5R,5’E,6R,7S,7’S,8R,8’Z,9E,11S,14S)-3,8-Bis-(tert-
butyldimethylsilyloxy)-14-[4’-(tert-butyldimethylsilyloxy)-3’-(tert-butyldi-
methylsilyloxymethyl)-2’-oxo-1’,5’,7’-trimethyldeca-5,8-dienyl]-6-hydroxy-
4-methoxy-5,7,9,11-tetramethyloxacyclotetradec-9-ene-2,12-dione
(41):
TESether 40 (19.3 mg, 16.5 mmol) was dissolved in a mixture of HOAc/
THF/H2O (3.5:3.5:1, 3 mL) and some drops of CH2Cl2 were added to im-
prove solubility of the TESether. The solution was stirred for 5 d at RT
and then sat NaHCO3 solution was added carefully. After the gas evolu-
tion ceased, the organic layer was diluted with ethyl acetate and separat-
ed. The aqueous layer was extracted with ethyl acetate and the combined
organic layers were dried over MgSO4, filtered and concentrated under
vacuum. After column chromatography (hexane/ethyl acetate 25:1) alco-
hol 41 (7.0 mg, 6.6 mmol, 40%, 95% borsm) was obtained as a white
solid as well as reisolated TESether 40 (10.8 mg, 9.2 mmol, 56%). [a]D25
=
+127.3 (c=0.62, CHCl3); 1H NMR (400 MHz, C6D6): d = 5.97 (q, J=
4.8 Hz, 1H), 5.36 (dq, J=10.9, 6.7 Hz, 1H), 5.28–5.20 (m, 2H), 5.15 (d,
J=9.2 Hz, 1H), 4.58 (d, J=5.9 Hz, 1H), 4.44 (d, J=8.4 Hz, 1H), 4.13 (d,
J=9.9 Hz, 1H), 3.76–3.71 (m, 2H), 3.59 (dd, J=9.9, 5.3 Hz, 1H), 3.41–
3.30 (m, 4H), 3.24–3.15 (m, 2H), 3.22 (s, 3H), 3.07 (dd, J=18.8, 4.1 Hz,
1H), 2.54 (dd, J=18.7, 5.5 Hz, 1H), 1.96 (m, 1H), 1.83–1.73 (m), 1.80 (d,
J=0.9 Hz, 3H), 1.75 (d, J=0.8 Hz, 3H), 1.57 (dd, J=6.8, 1.6 Hz, 1H),
1.41 (d, J=6.8 Hz, 3H), 1.39 (d, J=6.4 Hz, 3H), 1.37 (d, J=6.5 Hz, 3H),
1.16 (d, J=6.5 Hz, 3H), 1.02–0.98 (m, 3H), 1.01 (s, 9H), 0.99 (s, 18H),
0.98 (s, 9H), 0.25 (s, 3H), 0.17 (s, 3H), 0.16 (s, 3H), 0.16 (s, 6H), 0.11 (s,
3H), 0.10 (s, 3H), 0.02 ppm (s, 3H); 13C NMR (100 MHz, C6D6): d =
210.7 (s), 205.5 (s), 173.3 (s), 140.0 (s), 135.2 (d), 133.6 (s), 133.1 (d),
128.5 (d), 122.1 (d), 86.9 (d), 82.2 (d), 77.7 (d), 72.8 (d), 70.5 (d), 67.5 (d),
63.8 (t), 58.6 (q), 56.6 (d), 51.7 (d), 46.3 (d), 44.4 (t), 44.4 (d), 43.1 (d),
30.8 (d), 26.4 (q, 3C), 26.3 (q, 3C), 26.2 (q, 3C), 26.0 (q, 3C), 21.1 (q),
18.7 (s), 18.6 (s), 18.5 (s), 18.5 (s), 15.0 (q), 13.2 (q), 12.4 (q), 11.6 (q,
2C), 11.6 (q), 10.5 (q), À4.1 (q), À4.3 (q), À4.4 (q), À4.6 (q), À4.7 (q),
À5.5 (q), À5.3 (q), À5.4 ppm (q); IR (ATR): n˜ = 3521 (w), 2955 (s),
2929 (s), 2857 (s), 1722 (s), 1463 (m), 1408 (w), 1388 (w), 1361 (w), 1252
(s), 1205 (w), 1127 (m), 1098 (m), 1050 (s), 1005 (m), 835 (ss), 776 cmÀ1
672 cmÀ1 (w); HRMS(LC-M)S:
m/z: calcd for C62H124O10NaSi5:
1193.8097 [M+Na]+, found 1193.7958.
(1’R,3R,3’R,4S,4’S,5S,5’E,6R,7S,7’S,8R,8’Z,9E,11S,14S)-3,8-Bis-(tert-bu-
tyldimethylsilyloxy)-14-[4’-(tert-butyldimethylsilyloxy)-3’-(tert-butyldime-
thylsilyloxymethyl)-2’-oxo-1’,5’,7’-trimethyldeca-5,8-dienyl]-4-methoxy-
5,7,9,11-tetramethyl-6-triethylsilyloxyoxacyclotetradec-9-ene-2,12-dione
(40): A sat. solution of Dess–Martin reagent in CH2Cl2 (0.1 mL) was
added to a solution of alcohol 39 (8.5 mg, 7.3 mmol) in CH2Cl2 (1 mL),
(ss); HRMS(LC-M)S:
m/z: calcd for C56H108O10NaSi4: 1075.6917
[M+Na]+, found 1075.6917.
Chem. Eur. J. 2008, 14, 2232 – 2247
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2243

M. Kalesse et al.
(1’R,2’S,3R,3’S,4S,4’S,5S,5’E,7R,7’S,8R,8’Z,9E,11S,14S)-3,8-Bis-(tert-bu-
tyldimethylsilyloxy)-14-[4’-(tert-butyldimethylsilyloxy)-3’-(tert-butyldime-
thylsilyloxymethyl)-2’oxo-1’,5’,7’-trimethyldeca-5,8-dienyl]-4-methoxy-
5,7,9,11-tetramethyloxacyclotetradec-9-ene-2,6,12-trione (42): Alcohol 41
(6.1 mg, 5.8 mmol) was dissolved in CH2Cl2 (1 mL) and a sat. solution of
Dess–Martin-periodinane in CH2Cl2 (0.1 mL) was added. The turbid solu-
tion was stirred for 6 h at RT and sat. NaHCO3 solution and Na2S2O3
(30 mg) were added. Stirring was kept on until the organic layer became
clear. The organic layer was diluted with CH2Cl2 and separated, the aque-
ous layer was washed with CH2Cl2. The combined organic layers were
dried over MgSO4, filtered and concentrated under vacuum. Purification
via column chromatography (hexane/ethyl acetate 25:1) yielded triketone
42 (5.3 mg, 5.0 mmol, 87%) as a white solid. [a]2D5 =+108.8 (c=0.51,
CHCl3); 1H NMR (400 MHz, C6D6): d = 6.14 (dt, J=9.0, 1.0 Hz, 1H),
5.35 (dq, J=10.5, 6.5 Hz, 1H), 5.19 (ddq, J=10.7, 9.2, 1.8 Hz, 1H), 5.11
(d, J=9.8 Hz, 1H), 5.06 (d, J=9.2 Hz, 1H), 4.39 (d, J=9.2 Hz, 1H), 4.35
(d, J=9.3 Hz, 1H), 4.26 (d, J=9.5 Hz, 2H), 3.68 (t, J=9.8 Hz, 1H), 3.63
(s, 3H), 3.49 (dd, J=9.9, 4.8 Hz, 1H), 3.40 (m, 1H), 3.34–3.22 (m, 3H),
3.17–3.08 (m, 1H), 3.16 (dd, J=19.2, 9.3 Hz, 1H), 2.97 (dd, J=19.1,
1.5 Hz, 1H), 2.37 (dq, J=7.5, 0.8 Hz, 1H), 1.84 (d, J=1.0 Hz, 3H), 1.66
(d, J=0.9 Hz, 3H), 1.57 (dd, J=6.8, 1.6 Hz, 3H), 1.47 (d, J=7.4 Hz, 3H),
1.31 (d, J=7.4 Hz, 3H), 1.20 (d, J=6.7 Hz, 3H), 1.08 (s, 9H), 0.99–0.94
(m, 6H), 0.98 (s, 9H), 0.95 (s, 18H), 0.26 (s, 3H), 0.22 (s, 3H), 0.14 (s,
3H), 0.11 (s, 6H), 0.06 (s, 6H), À0.05 ppm (s, 3H); 13C NMR (100 MHz,
C6D6): d = 212.1 (s), 211.9 (s), 104.8 (s), 171.3 (s), 137.9 (s), 135.2 (d),
133.4 (d), 133.4 (s), 128.4 (d), 122.0 (d), 80.9 (d), 78.6 (d), 77.6 (d), 75.5
(d), 71.7 (d), 64.7 (t), 61.7 (q), 56.4 (d), 51.8 (d), 50.4 (d), 47.4 (d), 46.5
(t), 45.2 (d), 30.7 (d), 26.3 (q, 3C), 26.2 (q, 3C), 26.2 (q, 3C), 26.1 (q,
3C), 21.0 (q), 18.7 (s), 18.7 (s), 18.6 (s), 18.4 (s), 16.4 (q), 15.5 (q), 13.2
(q), 13.0 (q), 11.2 (q), 11.1 (q), 9.7 (q), À4.4 (q), À4.5 (q), À4.5 (q), À4.6
(q), À4.7 (q), À4.9 (q), À5.2 (q), À5.3 ppm (q); IR (ATR): n˜ = 2955 (m),
2929 (s), 2857 (m), 1766 (w), 1727 (m), 1713 (m), 1462 (m), 1388 (w),
1362 (w), 1254 (s), 1145 (m), 1114 (m), 1082 (s), 1053 (s), 989 (m), 878
(d), 127.2 (d), 127.1 (d), 121.9 (d), 119.1 (t), 113.8 (d), 113.5 (d), 87.5 (s),
83.0 (d), 81.3 (d), 79.5 (d), 76.9 (d), 76.6 (d), 74.8 (t), 74.7 (d), 70.7 (d),
65.6 (t), 62.9 (t), 61.0 (q), 54.8 (q, 2C), 48.3 (d), 47.8 (d), 47.1 (d), 42.1
(d), 40.4 (d), 40.1 (d), 30.7 (d), 26.6 (q, 3C), 26.5 (q, 3C), 26.3 (q, 3C),
26.2 (q, 3C), 21.4 (q), 18.7 (s), 18.6 (s, 2C), 18.5 (s), 17.3 (q), 13.5 (q),
13.0 (q), 12.1 (q), 11.7 (q), 10.9 (q), 10.6 (q), 7.8 (q, 3C), 6.7 (t, 3C), À3.4
(q), À3.5 (q), À3.8 (q), À3.9 (q), À4.1 (q), À4.5 (q), À4.6 (q), À4.8 ppm
(q); IR (ATR): n˜ = 2955 (s), 2930 (s), 2881 (m), 2857 (m), 1740 (m),
1715 (m), 1611 (w), 1511 (m), 1461 (m), 1361 (w), 1300 (w), 1248 (ss),
1106 (s), 1034 (ss), 1008 (s), 834 (ss), 776 (ss), 726 (m), 709 cmÀ1 (m);
HRMS(LC-MS): m/z: calcd for C93H158NO13Si5: 1637.0580 [M+NH4]+,
found 1637.0571
(2R,3S,4S,5R,6S,7R,8E,10S,13S,14S,15S,16S,17S,18E,20S,21Z)-Allyl-
2,7,13,17-tetrakis-(tert-butyldimethylsilyloxy)-16-hydroxymethyl-3-me-
thoxy-15-(p-methoxybenzyloxy)-4,6,8,10,14,18,20-heptamethyl-11-oxo-5-
triethylsilyloxytricosa-8–18–21-trienoate (44): MMTr ether 43 (28.0 mg,
17.3 mmol) was dissolved in a mixture of CH2Cl2 (0.5 mL) and hexafluor-
oisopropanol (0.5 mL). After a short period the stirred solution changed
from colorless to an intensive orange color. After 10 min methanol was
added dropwise until a slight yellow color remained, and the solution was
stirred for 16 h at RT. Subsequently sat. NaHCO3 solution was added,
then the organic layer was diluted with CH2Cl2 and separated. The aque-
ous layer was extracted with CH2Cl2 and the combined organic layers
were dried over MgSO4 and filtered. After removing the solvent under
vacuum column chromatography (hexane/ethyl acetate 25:1 + 1% Et3N)
provided alcohol 44 (20.0 mg, 14.8 mmol, 85%) as a colorless oil. [a]2D5 =+
51.0 (c=1.01, CHCl3); 1H NMR (400 MHz, C6D6): d
= 7.38 (d, J=
8.5 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 5.77 (ddt, J=17.0, 10.5, 6.0 Hz,
1H), 5.72 (d, J=8.3 Hz, 1H), 5.37 (dq, J=10.8, 6.7 Hz, 1H), 5.31–5.24
(m, 2H), 5.15 (dd, J=17.2, 1.4 Hz, 1H), 5.01 (dd, J=10.4, 1.1 Hz, 1H),
4.69 (d, J=10.7 Hz, 1H), 4.65 (d, J=10.8 Hz, 1H), 4.60–4.55 (m, 1H),
4.56 (d, J=6.9 Hz, 1H), 4.52–4.40 (m, 3H), 4.13 (d, J=9.7 Hz, 1H), 3.86
(dd, J=8.2, 1.3 Hz, 1H), 3.77–3.68 (m, 1H), 3.76 (d, J=7.5 Hz, 1H), 3.70
(dd, J=7.0, 0.9 Hz, 1H), 3.60–3.57 (m, 1H), 3.64 (s, 3H), 3.41 (m, 1H),
3.36 (m, 1H), 3.31 (s, 3H), 3.04 (dd, J=16.5, 8.7 Hz, 1H), 2.56 (dd, J=
16.4, 4.1 Hz, 1H), 2.45–2.36 (m, 2H), 2.13 (m, 1H), 1.99 (m, 1H), 1.88 (d,
J=0.6 Hz, 3H), 1.76 (d, J=0.6 Hz, 3H), 1.57 (dd, J=6.7, 1.5 Hz, 3H),
1.34 (d, J=6.9 Hz, 3H), 1.26 (d, J=6.7 Hz, 3H), 1.25 (d, J=6.8 Hz, 3H),
1.24 (d, J=6.7 Hz, 3H), 1.16 (t, J=8.1 Hz, 9H), 1.08 (s, 9H), 1.05–1.02
(m, 3H), 1.04 (s, 9H), 1.04 (s, 18H), 0.83 (q, J=8.0 Hz, 6H), 0.31 (s,
3H), 0.26 (s, 3H), 0.22 (s, 3H), 0.21 (s, 3H), 0.19 (s, 3H), 0.17 (s, 3H),
0.14 (s, 3H), 0.15 ppm (s, 3H); 13C NMR (100 MHz, C6D6): d = 208.5
(s), 171.6 (s), 159.8 (s), 139.4 (s), 136.1 (s), 135.3 (d), 132.5 (d), 132.1 (d),
131.9 (s), 129.8 (d, 2C), 128.0 (d), 122.4 (d), 119.1 (t), 114.1 (d, 2C), 83.0
(d), 81.4 (d), 81.3 (d), 78.9 (d), 76.6 (d), 74.9 (t), 74.6 (d), 69.8 (d), 65.6
(t), 63.7 (t), 61.0 (q), 54.8 (q), 48.4 (d), 47.7 (d), 47.0 (d), 43.1 (d), 40.3
(d), 40.1 (d), 30.8 (d), 26.5 (q, 3C), 26.4 (q, 3C), 26.2 (q, 3C), 26.1 (q),
21.1 (q), 18.7 (s), 18.6 (s), 18.6 (s), 18.5 (s), 17.2 (q), 13.2 (q), 12.5 (q),
12.1 (q), 11.7 (q), 10.6 (q), 9.8 (q), 7.7 (q, 3C), 6.6 (t, 3C), À3.6 (q), À3.8
(q), À4.0 (q), À4.1 (q), À4.2 (q), À4.5 (q), À4.6 (q), À4.8 ppm (q); IR
(ATR): n˜ = 3502 (br, w), 2954 (s), 2930 (s), 2884 (m), 2857 (m), 1741
(w), 1741 (w), 1614 (w), 1514 (w), 1462 (m), 1361 (w), 1249 (s), 1105 (m),
1037 (ss), 1005 (s), 938 (w), 869 (m), 835 (ss), 775 (ss), 727 cmÀ1 (m);
HRMS(LC-MS): m/z: calcd for C73H138O12NaSi5: 1369.8932 [M+Na]+,
found 1369.8929.
(w), 835 (ss), 777 cmÀ1 (ss); HRMS(LC-M):S
m/z: calcd for
C56H106O10NaSi4: 1073.6761 [M+Na]+, found 1073.6743.
(2R,3S,4R,5R,6S,7R,8E,10S,13S,14S,15S,16S,17S,18E,20S,21Z)-Allyl-
2,7,13,17-tetrakis-(tert-butyldimethylsilyloxy)-3-methoxy-15-(p-methoxy-
benzyloxy)-16-[(p-methoxyphenyl)-diphenylmethoxymethyl]-
4,6,8,10,14,18,20-heptamethyl-11-oxo-5-triethylsilyloxytricosa-8,18,21-tri-
enoate (43): 2,6-Lutidine (48 mL, 0.41 mmol, 10 equiv) und TBStriflate
(47 mL, 0.21 mmol, 5.0 equiv) were added at 08C to a solution of aldol
product 33 (62 mg, 41 mmol, 1.0 equiv) in CH2Cl2 (5 mL). During the ad-
dition of TBStriflate the solution rapidly turned to intensive orange
color. After stirring for 4 h sat. NaHCO3 solution was added and the so-
lution turned colorless. The organic layer was separated and the aqueous
layer was washed with CH2Cl2. The combined organic layers were dried
over MgSO4 and filtered. The solvent was removed under vacuum and
purification via column chromatography (hexane/ethyl acetate 20:1
1% Et3N) yielded TBSprotected aldol product 43 (37 mg, 23 mmol,
55%) as
colorless oil. [a]D25 =+29.08 (c=1.38, CHCl3); 1H NMR
+
a
(400 MHz, C6D6): d = 7.71 (d, J=7.3 Hz, 2H), 7.69 (d, J=7.0 Hz, 2H),
7.51 (d, J=8.8 Hz, 2H), 7.26–7.20 (m, 4H), 7.17–7.12 (m, 2H), 7.09 (t,
J=7.3 Hz, 1H), 7.08 (t, J=7.3 Hz, 1H), 6.82 (d, J=8.7 Hz, 2H), 6.77 (d,
J=8.9 Hz, 2H), 5.83–5.72 (m, 2H), 5.33–5.16 (m, 3H), 5.15 (dd, J=17.1,
1.4 Hz, 1H), 5.01 (dd, J=10.4, 1.2 Hz, 1H), 4.73 (m, 1H), 4.77 (d, J=
10.5 Hz, 1H), 4.72 (d, J=10.5 Hz, 1H), 4.56 (d, J=6.9 Hz, 1H), 4.54 (d,
J=6.5 Hz, 1H), 5.33–5.16 (m, 2H), 4.20 (dd, J=7.5, 2.6 Hz, 1H), 4.13 (d,
J=9.5 Hz, 1H), 3.82–3.74 (m, 1H), 3.76 (d, J=8.4 Hz, 1H), 3.71 (dd, J=
6.9, 1.0 Hz, 1H), 3.60 (s, 3H), 3.40–3.26 (m, 3H), 3.34 (s, 6H), 3.09 (dd,
J=16.3, 8.1 Hz, 1H), 2.90 (m, 1H), 2.67 (dd, J=16.3, 4.5 Hz, 1H), 2.33
(m, 1H), 2.13 (m, 1H), 1.99 (m, 1H), 1.75 (s, 3H), 1.73 (s, 3H), 1.44 (dd,
J=6.8, 0.8 Hz, 3H), 1.33 (d, J=6.8 Hz, 3H), 1.26 (d, J=6.4 Hz, 3H), 1.25
(d, J=6.9 Hz, 3H), 1.21 (d, J=7.0 Hz, 3H), 1.16 (t, J=7.8 Hz, 9H), 1.13
(s, 9H), 1.05 (s, 9H), 1.04 (s, 18H), 0.98 (d, J=6.8 Hz, 3H), 0.83 (q, J=
8.0 Hz, 6H), 0.38 (s, 3H), 0.34 (s, 3H), 0.28 (s, 3H), 0.21 (s, 3H), 0.20 (s,
3H), 0.19 (s, 3H), 0.17 (s, 3H), 0.13 ppm (s, 3H); 13C NMR (100 MHz,
C6D6): d = 208.9 (s), 171.6 (s), 159.5 (s), 159.3 (s), 245.9 (s), 145.3 (s),
139.3 (s), 136.4 (s), 135.6 (s), 135.5 (d), 132.1 (d, 2C), 131.3 (d, 2C), 129.5
(d, 2C), 129.4 (d, 2C), 129.3 (d, 2C), 128.2 (d, 2C), 128.1 (d, 2C), 127.7
(1’S,2’E,3R,4S,4’S,5S,5’Z,6R,7S,8R,9E,11S,14S,15S,16S,17S)-3,8,14-Tris-
(tert-butyldimethylsilyloxy)-17-[1’-(tert-butyldimethylsilyloxy)-2’,4’-dime-
thylhepta-2’,5’-dienyl]-4-methoxy-16-[p-methoxybenzyloxy)-5,7,9,11,15-
pentamethyl-6-triethylsilyloxy-oxacyclooctadec-9-ene-2,12-dione (45)
a) Cleavage of allyl ester 44: [PdCAHTRE(UNG PPh3)2Cl2] (3.0 mg, 4 mmol) and
Bu3SnH (68 mL, 0.26 mmol, 6.0 equiv) were added to a stirred solution of
hydroxy allylester 44 (58 mg, 43 mmol, 1.0 equiv) in CH2Cl2 (6 mL). The
color of the solution rapidly changed from yellow to dark red and gas
evolution occurred. After 15 min the reaction mixture was diluted with
CH2Cl2 and transferred into sat. NaHCO3 solution. The organic layer was
separated and washed with sat. NH4Cl solution and brine. The combined
aqueous layers were additionally extracted with CH2Cl2. The combined
organic layers were dried over MgSO4 and filtered. After concentration
2244
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 2232 – 2247

Natural Products
FULL PAPER
under vacuum the crude hydroxy acid 7 was obtained as a grey residue
which was used without further purification.
(s), 18.3 (s), 16.7 (q), 13.2 (q), 12.2 (q), 11.4 (q), 11.3 (q, 2C), 8.9 (q), 7.7
(q, 3C), 6.5 (t, 3C), À3.5 (q), À3.6 (q), À3.9 (q), À4.1 (q), À4.1 (q), À4.5
(q), À4.6 (q), À4.9 ppm (q); IR (ATR): n˜ = 3491 (br, w), 2955 (s), 2930
(s), 2884 (m), 2858 (s), 1753 (m), 1718 (m), 1463 (m), 1409 (w), 1383 (m),
1362 (m), 1252 (s), 1104 (s), 1042 (s), 1005 (s), 938 (w), 836 (ss), 776 (ss),
726 (m), 673 cmÀ1 (w); HRMS(LC-MS): m/z: calcd for C64H124O10NaSi5:
1191.7939 [M+Na]+, found 1191.7937.
b) Mitsunobu lactonization: PPh3 (0.113 g, 0.43 mmol, 10 equiv) and
DEAD (67 mL, 0.43 mmol 10 equiv) were dissolved in toluene (5 mL).
After stirring for 30 min a slight yellow color remained. The crude hy-
droxy acid 7 was dissolved in toluene (3 mL) and slowly added to the so-
lution. After 5 h the reaction was quenched by adding water. The organic
layer was separated and the aqueous layer was extracted with ethyl ace-
tate. After drying the combined organic layers with MgSO4 and filtration
the solvents were evaporated under vacuum to give a brown oil. A mix-
ture of hexane/ethyl acetate (50:1, 1 mL) was added and under continu-
ous stirring CuCl was added in portions leading to precipitation of
Ph3PO and complexation of PPh3. After 30 min the resulting clear solu-
tion was directly subjected to column chromatography (hexane/ethyl ace-
tate 50:1). Macrolactone 45 (38 mg, 29 mmol, 68%) was obtained as a col-
orless oil. [a]2D5 =+41.0 (c=0.83, CHCl3); 1H NMR (400 MHz, C6D6): d
= 7.47 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 5.47 (d, J=8.9 Hz,
1H), 5.36 (dq, J=10.8, 6.5 Hz, 1H), 5.30–5.22 (m, 2H), 4.78 (d, J=
10.9 Hz, 1H), 4.65 (d, J=10.9 Hz, 1H), 4.64 (d, J=7.5 Hz, 1H), 4.55–4.50
(m, 3H), 4.23 (t, J=10.8 Hz, 1H), 4.00 (d, J=10.2 Hz, 1H), 3.75 (d, J=
2.0 Hz, 1H), 3.69 (t, J=4.8 Hz, 1H), 3.63 (dd, J=7.9, 2.4 Hz, 1H), 3.45
(s, 3H), 3.44–3.34 (m, 2H), 3.32 (s, 3H), 2.89–2.83 (m, 2H’), 2.64 (m,
1H), 2.45 (m, 1H), 2.17 (m, 1H), 2.06 (m, 1H), 1.80 (s, 3H), 1.78 (s, 3H),
1.59 (dd, J=6.7, 1.6 Hz, 3H), 1.32 (d, J=7.2 Hz, 3H), 1.28 (d, J=6.8 Hz,
3H), 1.24 (d, J=6.8 Hz, 6H), 1.14 (t, J=7.7 Hz, 9H), 1.13 (s, 9H), 1.05
(s, 9H), 1.02 (s, 9H), 1.01–0.98 (m, 1H), 1.00 (s, 9H), 0.79 (d, 6H), 0.40
(s, 3H), 0.36 (s, 3H), 0.28 (s, 3H), 0.22 (s, 3H), 0.19 (s, 3H), 0.18 (s, 3H),
0.10 (s, 3H), 0.08 ppm (s, 3H); 13C NMR (100 MHz, C6D6): d = 208.3
(s), 172.7 (s), 159.9 (s), 141.5 (s), 135.2 (d), 134.5 (s), 133.9 (d), 131.4 (s),
129.5 (d, 2C), 127.7 (d), 122.4 (d), 114.3 (d, 2C), 84.4 (d), 82.1 (d), 79.8
(d), 77.7 (d), 74.9 (t), 74.6 (d), 72.4 (d), 72.0 (d), 65.5 (t), 60.3 (q), 54.8
(q), 48.5 (d), 47.4 (d), 46.6 (t), 44.8 (d), 43.2 (d), 43.1 (d), 30.8 (d), 26.7
(q, 2C), 26.4 (q), 26.1 (q), 21.1 (q), 19.3 (s), 18.7 (s), 18.6 (s), 18.5 (s),
16.4 (q), 13.2 (q), 12.4 (q, 2C), 12.1 (q, 2C), 10.6 (q), 7.7 (q, 3C), 6.5 (t,
3C), À2.8 (q), À3.6 (q, 3C), À3.9 (q), À4.1 (q), À4.2 (q), À4.6 ppm (q);
IR (ATR): n˜ = 2955 (s), 2930 (s), 2883 (m), 2857 (m), 1758 (m), 1715
(m), 1614 (w), 1514 (m), 1462 (m), 1388 (w), 1361 (w), 1249 (ss), 1153
(m), 1099 (s), 1042 (ss), 1006 (s), 955 (w), 880 (w), 835 (ss), 776 (ss),
(1’S,2’E,3R,4S,4’S,5S,5’Z,6R,7S,8R,9E,11S,14S,15R,17R)-3,8,14-Tris-(tert-
butyldimethylsilyloxy)-17-[1’-(tert-butyldimethylsilyloxy)-2’,4’-dimethyl-
hepta-2’,5’-dienyl]-4-methoxy-5,7,9,11,15-pentamethyl-6-triethylsilyloxy-
oxacyclooctadec-9-ene-2,12,16-trione (47): Dess–Martin-periodinane
(40 mg, 94 mmol, 5 equiv) was added to a stirred solution of alcohol 46
(22.0 mg, 18.8 mmol) in CH2Cl2 (2 mL). After 2 h an additional portion of
Dess–Martin-periodinane (40 mg, 94 mmol, 5 equiv) was added and stir-
ring of the suspension was continued for 4 h. If the reaction showed no
complete conversion the reaction time could be prolonged. The reaction
was quenched by addition of sat. NaHCO3 solution and Na2S2O3 (0.10 g)
and stirring was continued until the turbid organic layer became clear.
The organic layer was diluted with CH2Cl2 and separated. The aqueous
layer was extracted with CH2Cl2. The combined organic layers were
dried over MgSO4, filtered and concentrated under vacuum. After purifi-
cation via column chromatography (hexane/CH2Cl2 2:1) diketone 47 was
obtained as a colorless oil (14.1 mg, 12.1 mmol, 64%). [a]2D5 =+48.7 (c=
0.86, CHCl3); 1H NMR (400 MHz, C6D6): d = 5.43–5.34 (m, 2H), 5.22
(ddq, J=10.4, 9.0, 1.5 Hz, 1H), 5.09 (d, J=9.2 Hz, 1H), 4.79 (dd, J=10.2,
5.5 Hz, 1H), 4.55 (d, J=4.4 Hz, 1H), 4.37 (d, J=9.6 Hz, 1H), 4.34 (dd,
J=11.1, 3.9 Hz, 1H), 4.08 (t, J=10.9 Hz, 1H), 3.97 (d, J=9.9 Hz, 1H),
3.77 (d, J=2.4 Hz, 1H), 3.63–3.55 (m, 2H), 3.50–3.41 (m, 1H), 3.44 (s,
3H), 3.34 (m, 1H), 3.19 (m, 1H), 2.86 (dd, J=16.2, 4.3 Hz, 1H), 2.71 (dd,
J=16.2, 6.0 Hz, 1H), 1.94 (m, 1H), 1.87 (m, 1H), 1.76 (s, 3H), 1.72 (s,
3H), 1.60 (dd, J=6.8, 1.7 Hz, 3H), 1.45 (d, J=7.5 Hz, 3H), 1.25–1.20 (m,
9H), 1.11 (t, J=7.9 Hz, 9H), 1.06 (s, 9H), 1.06 (s, 9H), 1.01 (s, 9H), 0.97
(d, J=6.8 Hz, 3H), 0.96 (s, 9H), 0.78 (q, J=8.0 Hz, 6H), 0.36 (s, 3H),
0.30 (s, 3H), 0.25 (s, 3H), 0.17 (s, 6H), 0.13 (s, 3H), 0.07 (s, 3H),
0.06 ppm (s, 3H); 13C NMR (100 MHz, C6D6): d = 213.2 (s), 208.0 (s),
172.0 (s), 141.3 (s), 134.7 (d), 134.6 (d), 132.8 (s), 128.0 (d), 123.1 (d), 84.5
(d), 82.0 (d), 78.8 (d), 75.4 (d), 73.4 (d), 69.2 (d), 65.5 (t), 60.6 (q), 55.3
(d), 53.6 (d), 47.9 (d), 46.7 (d), 43.9 (d), 43.1 (d), 30.7 (d), 26.6 (q, 3C),
26.4 (q, 3C), 26.3 (q, 3C), 26.2 (q, 3C), 20.7 (q), 18.9 (s), 18.7 (s), 18.6
(s), 18.5 (s), 16.2 (q, C-14), 13.3 (q), 12.4 (q), 12.1 (q), 11.9 (q), 10.9 (q),
10.1 (q), 7.7 (q, 3C), 6.5 (t, 3C), À3.6 (q), À3.8 (q), À3.9 (q), À4.0 (q),
À4.2 (q), À4.3 (q), À4.4 (q), À4.6 ppm (q); IR (ATR): n˜ = 2955 (s), 2930
(s), 2884 (m), 2858 (m), 1742 (w), 1716 (m), 1462 (m), 1388 (w), 1361
(w), 1252 (s), 1147 (m), 1099 (s), 1062 (s), 1005 (s), 836 (ss), 776 (ss),
725 cmÀ1 (m); HRMS(LC-M)S:
m/z: calcd for C70H132O11NaSi5:
1311.8514 [M+Na]+, found 1311.8518.
(1’S,2’E,3R,4S,4’S,5S,5’Z,6R,7S,8R,9E,11S,14S,15S,16S,17S)-3,8,14-Tris-
(tert-butyldimethylsilyloxy)-17-[1’-(tert-butyldimethylsilyloxy)-2’,4’-dime-
thylhepta-2’,5’-dienyl]-16-hydroxy-4-methoxy-5,7,9,11,15-pentamethyl-6-
triethylsilyloxyoxacyclooctadec-9-ene-2,12-dione (46): Water (0.4 mL)
was added to a solution of PMB-ether 45 (38.0 mg, 29.5 mmol, 1.0 equiv)
in CH2Cl2 (4 mL). After cooling to 08C DDQ (8.0 mg, 35.3 mmol,
1.2 equiv) was added and the solution was stirred vigorously. After 2 h an
additional portion of DDQ (0.7 mg, 3.1 mmol, 0.5 equiv) was added.
After 4 h the reaction was stopped by addition of sat. NaHCO3 solution
and Na2S2O5 (10 mg). The organic layer was diluted with CH2Cl2 and sep-
arated. The aqueous layer was extracted with CH2Cl2. The combined or-
ganic layers were dried over MgSO4 and filtered. After removing the sol-
vents under vacuum purification via column chromatography (hexane/
CH2Cl2 2:1) provided alcohol 46 as a colorless oil (23.5 mg, 20.1 mmol,
68%). [a]2D5 =+25.4 (c=0.65, CHCl3); 1H NMR (400 MHz, C6D6): d =
5.45–5.33 (m, 4H), 4.74 (m, 1H), 4.61 (d, J=9.3 Hz, 1H), 4.54 (d, J=
5.1 Hz, 1H), 4.41 (s, 1H), 4.22–4.16 (m, 2H), 4.10 (dd, J=11.9, 1.5 Hz,
1H), 4.02 (d, J=10.3 Hz, 1H), 3.89 (d, J=6.1 Hz, 1H), 3.82 (t, J=4.3 Hz,
1H), 3.52 (s, 3H), 3.37 (m, 2H), 2.95 (dd, J=17.4, 6.7 Hz, 1H), 2.85 (dd,
J=17.3, 3.0 Hz, 1H), 2.12–1.93 (m, 4H), 1.93 (s, 3H), 1.58–1.56 (m, 6H),
1.29 (d, J=6.8 Hz, 3H), 1.25 (d, J=7.0 Hz, 3H), 1.20 (d, J=6.8 Hz, 3H),
1.17 (t, J=8.1 Hz, 9H), 1.07 (d, J=6.5 Hz, 3H), 1.08–1.06 (m, 3H), 1.07
(s, 9H), 1.05 (s, 9H), 1.03 (s, 9H), 0.97 (s, 9H), 0.79 (q, J=8.0 Hz, 6H),
0.40 (s, 3H), 0.31 (s, 3H), 0.27 (s, 3H), 0.20 (s, 9H), 0.10 (s, 3H),
0.07 ppm (s, 3H); 13C NMR (100 MHz, C6D6): d = 207.5 (s), 172.3 (s),
141.6 (s), 135.0 (d), 134.5 (d), 133.6 (s), 128.1 (d), 123.1 (d), 83.1 (d), 81.8
(d), 81.6 (d), 74.7 (d), 74.3 (d), 73.7 (d), 72.1 (d), 63.3 (t), 59.8 (q), 47.2
(d), 46.8 (t), 44.8 (d), 41.6 (d), 41.3 (d), 40.8 (d), 30.9 (d), 26.8 (q, 3C),
26.3 (q, 3C), 26.2 (q, 3C), 26.0 (q, 3C), 21.1 (q), 18.8 (s), 18.8 (s), 18.6
730 cmÀ1 (m); HRMS(LC-M)S:
m/z: calcd for C62H122O10NaSi5:
1189.7782 [M+Na]+, found 1189.7788.
(1’S,2’E,3R,4S,4’S,5R,5’Z,6R,7S,8R,9E,11S,14S,15R,17R)-3,8,14-Tris-(tert-
butyldimethylsilyloxy)-17-[1’-(tert-butyldimethylsilyloxy)-2’,4’-dimethyl-
hepta-2’,5’-dienyl]-6-hydroxy-4-methoxy-5,7,9,11,15-pentamethyloxacy-
clooctadec-9-ene-2,12,16-trione (48): TESether 47 (14.1 mg, 12.1 mmol)
was dissolved in a mixture of MeOH (1.5 mL) and CH2Cl2 (0.3 mL).
Then PPTS(5 mg) was added and the clear solution was stirred at RT for
16 h. Under continued stirring sat. NaHCO3 solution was carefully added
and the organic layer was diluted with CH2Cl2 and separated. The aque-
ous layer was washed with CH2Cl2 and the combined organic layers were
dried over MgSO4 and filtered. After concentration under vacuum purifi-
cation was performed via column chromatography (hexane/ethyl acetate
25:1) to provide alcohol 48 (8.4 mg, 8.0 mmol, 67%) as a colorless oil.
[a]2D5 =+111.6 (c=0.58, CHCl3); 1H NMR (400 MHz, C6D6): d = 5.43
(dq, J=10.4, 6.8 Hz, 1H), 5.25 (ddq, J=10.7, 9.0, 1.7 Hz, 1H), 5.15 (d,
J=10.2 Hz, 1H), 5.13 (d, J=9.0 Hz, 1H), 4.76 (ddd, J=7.6, 5.2, 3.9 Hz,
1H), 4.46 (dd, J=10.6, 3.6 Hz, 1H), 4.44 (d, J=6.0 Hz, 1H), 4.36 (d, J=
9.5 Hz, 1H), 4.00 (t, J=11.1 Hz, 1H), 3.91 (d, J=9.8 Hz, 1H), 3.74 (t, J=
1.6 Hz, 1H), 3.62 (t, J=5.5 Hz, 1H), 3.56 (ddd, J=11.0, 9.9, 3.6 Hz, 1H),
3.49–3.42 (m, 1H), 3.44 (s, 3H), 3.39–3.25 (m, 2H), 2.88 (dd, J=16.0,
3.8 Hz, 1H), 2.61 (dd, J=16.0, 5.5 Hz, 1H), 2.12 (d, J=3.8 Hz, 1H),
1.76–1.69 (m, 2H), 1.72 (d, J=0.9 Hz, 3H), 1.65–1.61 (m, 6H), 1.41 (d,
J=7.3 Hz, 3H), 1.24 (d, J=6.8 Hz, 3H), 1.22 (d, J=6.7 Hz, 3H), 1.15 (d,
J=7.0 Hz, 3H), 1.03 (s, 18H), 0.99–0.96 (m, 3H), 0.98 (s, 9H), 0.94 (s,
Chem. Eur. J. 2008, 14, 2232 – 2247
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2245

M. Kalesse et al.
9H), 0.31 (s, 3H), 0.28 (s, 3H), 0.24 (s, 3H), 0.18 (s, 3H), 0.09 (s, 3H),
0.06 (s, 3H), 0.03 (s, 3H), À0.03 ppm (s, 3H); 13C NMR (100 MHz,
C6D6): d = 213.5 (s), 207.8 (s), 171.1 (s), 140.5 (s), 134.9 (d), 134.5 (d),
132.6 (s), 128.2 (d), 123.4 (d), 87.6 (d), 83.1 (d), 78.5 (d), 75.9 (d), 72.5
(d), 71.2 (d), 64.9 (t), 61.0 (q), 56.3 (d), 54.0 (d), 49.4 (t), 46.6 (d), 43.6
(d), 40.9 (d), 30.7 (d), 26.5 (q, 3C), 26.2 (q, 3C), 26.1 (q, 6C), 20.8 (q),
18.7 (s), 18.6 (s), 18.5 (s), 18.4 (s), 15.2 (q), 14.2 (q), 13.3 (q), 11.5 (q),
11.3 (q), 10.8 (q), 8.8 (q), À3.6 (q), À4.1 (q), À4.2 (q), À4.2 (q), À4.3 (q),
10.0, 7.0 Hz, 1H), 2.78 (d, J=9.2 Hz, 1H), 2.64 (dd, J=17.4, 9.4 Hz, 1H),
2.94 (dd, J=17.4, 2.6 Hz, 1H), 1.60 (d, J=1.0 Hz, 3H), 1.55 (dd, J=6.8,
1.6 Hz, 3H), 1.49 (d, J=1.1 Hz, 3H), 1.27 (d, J=7.0 Hz, 3H), 1.17 (d, J=
6.9 Hz, 3H), 1.00 (d, J=7.2 Hz, 3H), 0.98 (d, J=7.0 Hz, 3H), 0.95 ppm
(d, J=6.8 Hz, 3H); 13C NMR (125 MHz, C6D6): d = 215.2 (s), 214.4 (s),
212.2 (s), 172.2 (s), 137.3 (s), 134.7 (d), 133.9 (d), 133.3 (s), 129.3 (d),
122.8 (d), 84.0 (d), 79.4 (d), 78.0 (d), 71.6 (d), 69.1 (d), 65.6 (t), 60.3 (q),
54.0 (d), 52.9 (d), 50.1 (d), 48.4 (d), 45.8 (t), 45.6 (d), 30.7 (d), 21.3 (q),
16.6 (q), 15.4 (q), 14.6 (q), 13.2 (q), 11.8 (q), 10.8 (q), 10.2 ppm (q); IR
(ATR): n˜ = 3467 (brs), 2957 (s), 2924 (ss), 2854 (s), 1739 (s), 1707 (ss),
1458 (s), 1376 (m), 1273 (s), 1203 (w), 1123 (m), 1084 (m), 995 (m), 860
À4.5 (q), À4.5 (q), À4.8 ppm (q); IR
ACHTRE(UGN ATR): n˜ = 3548 (br, w), 2956 (s),
2930 (s), 2857 (s), 1747 (w), 1716 (m), 1463 (m), 1389 (w), 1361 (w), 1253
(s), 1150 (m), 1065 (s), 1004 (s), 836 (ss), 777 cmÀ1 (ss); HRMS(LC-MS):
m/z: calcd for C56H108O10NaSi4: 1075.6917 [M+Na]+, found 1075.6929.
(w), 722 cmÀ1 (w); HRMS(LC-M)S:
m/z: calcd for C32H50O10Na:
617.3302 [M+Na]+, found 617.3306.
(1’S,2’E,3R,4S,4’S,5S,5’Z,7R,8R,9E,11S,14S,15R,17R)-(3,8,14-Tris-(tert-
butyldimethylsilyloxy)-17-[1’-(tert-butyldimethylsilyloxy)-2’,4’-dimethyl-
hepta-2’,5’-dienyl]-4-methoxy-5,7,9,11,15-pentamethyloxacyclooctadec-9-
ene-2,6,12,16-tetraone (6): The Dess–Martin-reagent (20 mg, 47 mmol)
was added to a stirred solution of alcohol 48 (6.0 mg, 5.7 mmol) in CH2Cl2
(1.5 mL). After stirring for 30 min at RT the oxidation was completed
and sat. NaHCO3 solution and Na2S2O3 (0.10 g) were added. Stirring was
continued until the organic layer became clear. Then the organic layer
was diluted with CH2Cl2 and separated. The aqueous layer was extracted
with CH2Cl2. The combined organic layers were dried over MgSO4, fil-
tered and concentrated under vacuum. After purification via column
(+)-Tedanolide (1): NaHCO3 (1.0 mg) and mCPBA (0.7 mg, 4.2 mmol)
were added to a cooled solution (À408C) of completely deprotected mac-
rolactone 49 (2.1 mg, 3.5 mmol) in CH2Cl2 (0.4 mL). After 24 h the tem-
perature was raised to À308C and an additional equivalent of mCPBA
(0.6 mg, 3.5 mmol) was added. The reaction progress was monitored by
reversed phase TLC (RP-18 F254S, MeOH/H2O 3:1) and showed complete
consumption of all starting material after 2–3 d. The reaction mixture
was diluted with CH2Cl2 and then transferred into sat. NaHCO3 solution.
The organic layer was separated and the aqueous layer was extracted
with CH2Cl2. After drying over MgSO4 the solution was filtered and con-
centrated under vacuum. Purification via column chromatography
(hexane/ethyl acetate 1:1) gave (+)-tedanolide (1) (0.6 mg, 1.0 mmol,
chromatography (hexane/ethyl acetate 25:1) triketone
6 (5.5 mg,
5.2 mmol, 91%) was obtained as a colorless oil. [a]2D5 =+111.6 (c=0.58,
CHCl3); 1H NMR (400 MHz, C6D6): d = 5.39 (dq, J=10.8, 6.7 Hz, 1H),
5.32 (dd, J=9.7, 0.5 Hz, 1H), 5.21 (ddq, J=10.6, 8.9, 1.7 Hz, 1H), 5.02
(d, J=9.6 Hz, 1H), 4.92 (q, J=5.0 Hz, 1H), 4.50 (t, J=11.1 Hz, 1H), 4.30
(d, J=4.1 Hz, 1H), 4.22–4.17 (m, 2H), 4.04–3.99 (m, 2H), 3.79 (ddd, J=
11.3, 9.9, 3.1 Hz, 1H), 3.47 (s, 3H), 3.37 (dq, J=7.1, 5.5 Hz, 1H), 3.28 (m,
1H), 3.20–3.09 (m, 2H), 2.99 (dq, J=6.8, 6.7 Hz, 1H), 2.76 (dd, J=18.3,
4.3 Hz, 1H), 2.61 (dd, J=18.1, 5.5 Hz, 1H), 1.68 (d, J=1.0 Hz, 3H), 1.59
(d, J=0.7 Hz, 3H), 1.57 (dd, J=6.8, 1.7 Hz, 3H), 1.30 (d, J=6.8 Hz, 3H),
1.28 (d, J=6.8 Hz, 3H), 1.23 (d, J=6.8 Hz, 3H), 1.15 (d, J=6.8 Hz, 3H),
1.12 (s, 9H), 1.11 (s, 9H), 0.96–0.91 (m, 3H), 0.94 (s, 18H), 0.40 (s, 3H),
0.39 (s, 3H), 0.38 (s, 3H), 0.33 (s, 3H), 0.06 (s, 3H), 0.08 (s, 3H), À0.01
(s, 3H), À0.07 ppm (s, 3H); 13C NMR (100 MHz, C6D6): d = 213.7 (s),
213.5 (s), 208.1 (s), 171.3 (s), 138.1 (s), 134.7 (d), 134.5 (d), 132.8 (s),
129.3 (d), 123.1 (d), 82.3 (d), 80.8 (d), 79.3 (d), 75.9 (d), 70.4 (d), 65.2 (t),
60.7 (q), 55.8 (d), 54.1 (d), 50.0 (d), 48.9 (d), 47.8 (t), 46.5 (d), 30.7 (d),
26.7 (q, 3C), 26.5 (q, 3C), 26.1 (q, 3C), 26.0 (q, 3C), 20.7 (q), 19.2 (s),
18.8 (s), 18.4 (s), 18.4 (s), 15.5 (q), 15.3 (q), 13.4 (q), 13.3 (q), 12.9 (q),
11.0 (q), 10.7 (q), À3.3 (q), À3.8 (q), À4.0 (q), À4.2 (q), À4.2 (q), À4.6
(q), À4–6 (q), À5.0 ppm (q); IR (ATR): n˜ = 2956 (s), 2930 (s), 2896 (m),
2857 (s), 1761 (m), 1708 (s), 1462 (m), 1389 (w), 1362 (w), 1253 (s), 1162
(s), 1102 (m), 1068 (ss), 1004 (s), 885 (w), 837 (ss), 777 (ss), 719 cmÀ1 (w);
HRMS(LC-MS): m/z: calcd for C56H106O10NaSi4: 1073.6761 [M+Na]+,
found 1073.6721.
28%) as
a
colorless oil. [a]D25 =+14.0 (c=0.05, CHCl3); 1H NMR
(400 MHz, CDCl3): d = 5.47 (dd, J=8.5, 1.0 Hz, 1H), 5.46 (dq, J=10.8,
6.8 Hz, 1H), 5.23 (ddq, J=10.6, 10.4, 1.7 Hz, 1H), 4.31 (m, 1H), 4.26 (dd,
J=10.6, 4.1 Hz, 1H), 4.12 (t, J=11.1 Hz, 1H), 4.11 (dd, J=7.5, 1.0 Hz,
1H), 3.89 (dd, J=7.9, 0.7 Hz, 1H), 3.68 (dd, J=8.5, 1.4 Hz, 1H), 3.54
(ddd, J=11.6, 9.4, 3.9 Hz, 1H), 3.44–3.37 (m, 1H), 3.30 (s, 3H), 3.24 (dd,
J=9.4, 3.6 Hz, 1H), 3.07–3.00 (m, 3H), 2.76 (d, J=8.5 Hz, 1H), 2.61 (d,
J=9.2 Hz, 1H), 2.57 (dd, J=16.7, 9.2 Hz, 1H), 2.47 (dd, J=17.0, 3.1 Hz,
1H), 2.48–2.40 (m, 1H), 2.14 (d, J=4.1 Hz, 1H), 1.62 (d, J=1.4 Hz, 3H),
1.61 (dd, J=8.2, 1.4 Hz, 3H), 1.39 (s, 3H), 1.28 (d, J=7.2 Hz, 3H), 1.23
(d, J=7.2 Hz, 3H), 1.12 (d, J=6.5 Hz, 3H), 1.11 (d, J=7.2 Hz, 3H),
1.09 ppm (d, J=7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3): d = 215.6
(s), 214.2 (s), 212.8 (s), 171.4 (s), 136.3 (s), 130.0 (d), 129.3 (s), 125.2 (d),
83.0 (d), 79.6 (d), 77.0 (d), 71.2 (d), 68.3 (d), 66.7 (d), 63.9 (t), 62.8 (s),
60.5 (q), 53.3 (d), 52.0 (d), 49.6 (d), 48.3 (d), 45.5 (d), 44.8 (t), 31.1 (d),
18.5 (q), 16.6 (q), 15.3 (q), 14.3 (q), 13.4 (q), 11.4 (q), 10.6 (q), 10.2 ppm
(q); HRMS(LC-MS): m/z: calcd for C32H50O11Na: 633.3251 [M+Na]+,
found 633.3244.
Acknowledgements
(1’S,2’E,3R,4S,4’S,5S,5’Z,7R,8R,9E,11S,14S,15R,17R)-3,8,14-Trihydroxy-
17-(1’-hydroxy-2’,4’-dimethylhepta-2’,5’-dienyl)-4-methoxy-5,7,9,11,15-
This work was supported by the DFG (KA 913/9-1, KA 913/9-2). The au-
thors thank Myriam Roy (Taylor group, University of Notre Dame) for
helpful discussions.
pentamethyloxacyclooctadec-9-ene-2,6,12,16-tetraone
(49):
HF·NEt3
(1.1 mL) was added followed by triethylamine (1.2 mL) to a solution of
triketone 6 (10.8 mg, 10.3 mmol) in dry acetonitrile (2.5 mL) in a Nalgene
vessel. Stirring was continued for 5 d at RT. After this period the reaction
mixture was diluted with ethyl acetate and carefully transferred into sat.
NaHCO3 solution. The organic layer was separated and the aqueous
layer was extracted with ethyl acetate. The combined organic layers were
dried over MgSO4, filtered and concentrated under vacuum. Purification
via column chromatography (CH2Cl2/methanol 20:1) yielded completely
deprotected macrolactone 49 (2.1 mg, 3.5 mmol, 32%) as a colorless oil
and a partially deprotected macrolactone with one remaining TBSgroup
(2.3 mg, 3.2 mmol, 30%). [a]2D5 =+72.3 (c=0.16, CHCl3); 1H NMR
(400 MHz, C6D6): d = 5.52 (dd, J=9.5, 0.9 Hz, 1H), 5.35 (dq, J=10.4,
6.9 Hz, 1H), 5.20 (ddq, J=10.7, 9.0, 1.6 Hz, 1H), 5.02 (d, J=9.2 Hz, 1H),
4.52 (m, 1H), 4.43 (t, J=11.2 Hz, 1H), 4.14 (dd, J=10.5, 4.0 Hz, 1H),
3.97 (dd, J=9.0, 1.4 Hz, 1H), 3.97–3.93 (m, 1H), 3.92 (dd, J=9.3, 3.6 Hz,
1H), 3.75 (dd, J=9.1, 1.4 Hz, 1H), 3.67 (ddd, J=11.7, 9.1, 4.0 Hz, 1H),
3.44 (d, J=3.6 Hz, 1H), 3.28 (m, 1H), 3.16–3.07 (m, 1H), 3.12 (s, 3H),
3.04 (dq, J=9.3, 7.0 Hz, 1H), 2.95 (dq, J=8.8, 7.3 Hz, 1H), 2.92 (dq, J=
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Received: September 27, 2007
Published online: December 28, 2007
Chem. Eur. J. 2008, 14, 2232 – 2247
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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