Synthesis of the C1-C17 macrolactone of tedanolide

Article abstract of DOI:10.1055/s-2005-865302

The vinylogous Mukaiyama aldol reaction is a useful method to build up complex polyketide structures. It is successfully employed in the synthesis of the C1-C17 macrolactone of tedanolide, a highly cytotoxic marine natural product. These studies present a practical approach toward the total synthesis of tedanolide; it is pursued using the appropriate C13-C23 segment that is introduced by a pivotal aldol reaction to join both hemispheres.

Full text of DOI:10.1055/s-2005-865302

FEATURE ARTICLE
1183
Synthesis of the C1–C17 Macrolactone of Tedanolide
Synthesis
o
of the
C
1–C
r
M
acro
m
lactone of
T
edanol
a
ide Hassfeld, Ulrike Eggert, Markus Kalesse*
Universität Hannover, Institut für Organische Chemie, Schneiderberg 1B, 30167 Hannover, Germany
Fax +49(511)7623011; E-mail: Markus.Kalesse@oci.uni-hannover.de
Received 30 November 2004; revised 2 February 2005
polyketide–enzyme complexes and in the laboratory syn-
thesis, tedious functional group transformations and pro-
tecting group shuffling is required. To make synthesis
more efficient, different research groups have developed
Abstract: The vinylogous Mukaiyama aldol reaction is a useful
method to build up complex polyketide structures. It is successfully
employed in the synthesis of the C1–C17 macrolactone of tedano-
lide, a highly cytotoxic marine natural product. These studies
present a practical approach toward the total synthesis of tedano- strategies that allow for the incorporation of larger seg-
lide; it is pursued using the appropriate C13–C23 segment that is in-
ments in the course of the synthesis. Established examples
are the Evans–Metternich5 and Paterson6 aldol reactions
troduced by a pivotal aldol reaction to join both hemispheres.
Key words: aldol reactions, macrocycles, Mitsunobu, tedanolide,
total synthesis
in which dipropionate fragments are employed in a stereo-
selective aldol reaction. Another powerful method is the
dithiane strategy that allows for bidirectional fragment
coupling, in particular with chiral epoxides.7 Marshall et
al.8 used chiral allenes in order to construct polyketides
that generated the corresponding alkynes. In addition to
the widespread allylation and crotylation protocols,9
Panek and co-workers have established their chiral allyl-
silanes as powerful reagents for the introduction of five-
carbon building blocks.10 Among the alternative proce-
dures are such non-traditional approaches as dipolar
cycloadditions11,12 and Lewis acid-induced epoxide rear-
rangements.13
Introduction
Polyketides play a major role among natural products
since they host a great variety of biologically active com-
pounds. Prominent examples are the epothilones,1
discodermolide2 and the leptomycin family.3 These com-
pounds are not only important lead structures for the de-
velopment of promising antitumor drugs or antibiotics,
but they also serve as tools in the identification of new bi-
ological targets and for unravelling biological processes at
the cellular level. As a consequence, a new field – chemi-
cal genomics – has emerged from these findings.4 For
these types of studies, it is tempting to use the isolated nat-
ural products, which are believed in most cases to be syn-
thesized from microorganisms in order to interact with
biological targets; however, their supply is not always
guaranteed. In the case of marine natural products, for ex-
ample, fermentation is generally excluded. In addition,
chemical transformations are needed to identify struc-
ture–activity relationships. This sets the stage for organic
synthesis, which has to provide not only derivatives, but
also de novo chemical syntheses, in order to evaluate the
full potential of active structures and to fine-tune their bi-
ological properties.
The Vinylogous Mukaiyama Aldol Reaction
One strategy uses the vinylogous aldol reaction for the in-
troduction of combined acetate–propionate building
blocks (Figure 1).14
OTBS
OMe
1
aldol or
aldol-type
reaction
Wittig
homologation
PGO
R
O
OH
O
O
R
OMe
R
Figure 1 Synthesis of propionate–acetate subunits.
Synthesis of Polyketide Subunits
Beyond their contributions to Lewis acid activation stud-
ies, Campagne15,16 (Scheme 1) and Denmark17
(Scheme 2) established additions of g-substituted dieno-
lates through enolate activation.18
Despite several significant differences among them, many
laboratory syntheses parallel the biosynthetic pathway in
one aspect: most structures are generated by aldol or al-
dol-related transformations in which only two (acetate) or
three (propionate) carbon atoms are added at a time to the Among other groups,19 we have focused on the Lewis
growing polyketide chain. The biosynthesis requires large acid-mediated vinylogous Mukaiyama aldol reaction dur-
ing our syntheses of different natural products.
In our synthesis of the polyketide ratjadone, it became ob-
vious that the vinylogous Mukaiyama aldol reaction
(VMAR) used for the formation of the C14–C24 fragment
SYNTHESIS 2005, No. 7, pp 1183–1199
Advanced online publication: 23.03.2005
DOI: 10.1055/s-2005-865302; Art ID: T14604SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
5

1184
J. Hassfeld et al.
FEATURE ARTICLE
O
significantly shortened the synthesis and helped to avoid
extensive protecting group manipulations.20 In addition, it
turned out that tris(pentafluorophenyl)borane (TPPB) is
the superior Lewis acid in these cases. The vinylogous
ketene acetal used in this synthesis introduces two acetate
units while protecting the so-generated hydroxyl group in
situ (Scheme 3).
OH
O
O
(S)-Tol-BINAP·CuF
r.t., 85%
O
+
OMe
OTMS
Ph
2
4
5
OMe
syn/anti
1:1; ee< 5%
syn/anti
2:98; 87% ee
3
Scheme 1 Vinylogous aldol reaction through enolate activation.
OTBS
MeO
O
TBSO
OTBS
O
OTBS
8
MeO
TPPB (100 mol%)
CH2Cl2–Et2O 9:1
Me
O
N
P
–78 °C, 85%
7
9
N
(CH2)5
N
Me
Me
Scheme 3 VMAR in the total synthesis of ratjadone.
(R,R)-6
2
We envisioned that this methodology would be even more
powerful if it could be extended to substituted ketene ace-
tals.21 It became clear that not only does the 3,4-double
bond geometry play an important role in the selectivities,
but that two different catalytic processes lead to the prod-
uct, albeit with different selectivities (Scheme 4). Both the
R4 OTBS
OH R4
O
O
SiCl4 + (R,R)-6
R5
+
OR2
R1
OR2
R
CH2Cl2, –78 °C
3–24 h
R3
R5 R3
Scheme 2 Denmark’s vinylogous aldol reaction.
Biographical Sketches
Jorma Hassfeld, born in A. Wender at Stanford Uni- Free University of Berlin
1975, studied chemistry at versity, USA for undergrad- under the supervision of
the University of Hannover. uate research work in 1998– Professor Markus Kalesse
In the course of his studies, 99. Following his diploma with whom he relocated to
he spent one year in degree in 2001, he started the University of Hannover
the group of Professor Paul his doctoral studies at the in 2003.
Ulrike Eggert was born in cal assistant, she joined the Hannover in 1983. Since
1959. After vocational group of H. Martin R. Hoff- 2003, she works in the
training as chemical-techni- mann at the University of group of Markus Kalesse.
Markus Kalesse, born in turning to the University of He was offered the chair in
1961, was awarded the Dr. Hannover, he completed his Organic Chemistry at the
rer. nat. in the group of Die- habilitation with Ekkehard University of Oslo before he
ter Schinzer at the Universi- Winterfeldt as his mentor in accepted a call from the
ty of Hannover in 1991. 1997. He was visiting pro- Free University of Berlin
Between 1991 and 1992, he fessor at the University of (2002). Since July 2003 he
undertook two postdoctoral Wisconsin (Madison) be- holds the chair (C4) of Or-
investigations at the Univer- tween 1998 and 1999 and ganic Chemistry at the Uni-
sity of Wisconsin (Madison) held a temporary chair in versity of Hannover.
with Steven D. Burke and Organic Chemistry at the
Laura L. Kiessling. After re- University of Kiel in 1999.
Synthesis 2005, No. 7, 1183–1199 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of the C1–C17 Macrolactone of Tedanolide
1185
Lewis acid and the R3Si+ species catalyze the aldol reac- The obvious advantages of the VMAR protocol over con-
tion. The catalysis through TPPB (transition state 13) pro- ventional methods also inspired us in our efforts towards
vides the alcohol 11 with greater than 20:1 syn selectivity. the synthesis of tedanolide.26
Catalysis through the antiperiplanar R3Si+ species 14 sim-
ilarly generates the TBS-protected aldol product 12, but
the observed syn selectivity drops to 4.5:1.21
Application in the Total Synthesis of Tedanolide
OR
O
Tedanolide (18) and 13-deoxytedanolide (19), two closely
related polyketides with promising antitumor activity,
were isolated from marine organisms by Schmitz27 and
Fusetani,28 respectively (Figure 2). Their biological activ-
ity, in combination with their challenging structure, has
drawn much attention over the past decade, and a variety
of fragment syntheses as well as important fundamental
studies have been published on these natural products.29
Recently, Smith et al. published the first total synthesis of
13-deoxytedanolide (19),30 while a total synthesis of mac-
rolide 18 has not yet been accomplished.
O
1, TPPB (20 mol%)
OMe
CH2Cl2–Et2O 9:1
–78 °C, 73%
10
rac-11 R= H: 4%
rac-12 R= TBS: 69% syn/anti 4.5:1
syn/anti >20:1
Si
O
(C6F5)3B
O
H
H
TBSO
OMe
TBSO
OMe
13
14
OH
5
O
OH
4
Scheme 4 Initial attempts with g-substituted ketene acetal 1.
1
O
OMe O
17'
17
23
13
11
15
A more thorough investigation of the Lewis acid catalysis
revealed that it is not the tris(pentafluorophenyl)borane it-
self, but rather a hydrated species, present in most com-
mercially available sources, that is the active Lewis acid.22
The uncoordinated anhydrous Lewis acid in fact leads to
decomposition of the substrate. Having realized this sub-
tle difference, we precipitated the monohydrate from a
pentane solution of TPPB23 and used it in the vinylogous
Mukaiyama aldol reaction; we saw significant improve-
ment in the yields. This is also the case for TPPB·OEt2
which is easily employed by dissolving TPPB in Et2O,
cooling to –78 °C and subsequent addition of the alde-
hyde. In order to demonstrate the applicability of our vi-
nylogous Mukaiyama aldol reaction, we synthesized the
C1–C7 segment of oleandolide.24 In our approach, the ad-
dition of the ketene acetal to aldehyde 15 is followed by
reduction and Sharpless epoxidation to generate the allyl-
ic alcohol (Scheme 5). Subsequent cuprate addition yields
the desired stereopentad for the synthesis of oleandolide.
Final oxidative acetalization and Appel reaction furnished
the C1–C7 segment 17, comparable to the one that had
been used in Panek’s approach.25
12
O
OH
O
R
O
18 R = OH tedanolide
19 R = H 13-deoxytedanolide
Figure 2 Tedanolide and 13-deoxytedanolide.
Retrosynthetic Analysis
Our retrosynthetic analysis proposed an aldol coupling
between C12 and C13 (Scheme 6). The connection be-
tween C4 and C5 should be accomplished through a
VMAR with subsequent dihydroxylation of the double
bond. Since we planned to make extensive use of TBS and
TES protecting groups in our synthesis, the question arose
whether a TBS-protected hydroxyl group at C2 would be
too sterically hindered for further transformations. Anoth-
er question was whether the C11 keto group could be tol-
erated in the cyclization step, or if a protecting group
inducing the Thorpe–Ingold effect, as used in the Smith
synthesis of 13-deoxytedanolide (19), would be necessary
for successful macrolactonization.
TPPB, Et2O
i-PrOH,
In the synthetic direction, the C12–C13 coupling could be
performed by an aldol reaction. An elegant analysis of al-
dol reactions of such methyl ketones has been reported by
Roush et al. who demonstrated that the a-methyl group of
the methyl ketone in combination with the a- and b-ste-
reocenters of the aldehyde affect the stereochemical out-
come of the reaction towards the Felkin product.29e,t
Another obvious problem in the total synthesis of 18 and
19 was the fact that the three ketone carbonyl groups in the
natural product are sensitive to retro-aldol processes. We
therefore decided to carry them through the synthesis as
protected alcohols, which could be selectively liberated
and oxidized at a later stage. Selective epoxidation of the
OH
O
TBSO
O
1
OTBS
OMe
TBSO
4
+
OMe
3
5
–78 °C, 76%
15
1
16
4,5 syn-selective
Felkin-control
PMP
TBSO
O
O
steps
I
17
Scheme 5 Synthesis of the C1–C7 segment of oleandolide.
Synthesis 2005, No. 7, 1183–1199 © Thieme Stuttgart · New York

1186
J. Hassfeld et al.
FEATURE ARTICLE
OH
aldol
epoxidationmm
Mitsunobu
5
O
OH
1
O
1
OMe O
5
OTBS
O
OH
O
OTBS
O
OMe O
17'
17
23
HO
17
12
12
OTBS
23
17'
O
OH
20
OH
O
OH O
18
Evans aldol
crotylboration (Brown et al.)
VMAR
TES
OMe
O
OH
O
O
OTBS
O
O
1
OH OTBS
5
OPMB
12
MeO
MeO
12
OTBS
23
Wittig homologation
21
22
Scheme 6 Retrosynthetic analysis of tedanolide (18).
C18/C19 allylic double bond would then be expected to
A
sequence of DIBAL-H reduction and MnO2
afford the final product. With these prerequisites in mind, oxidation generated the corresponding aldehyde 30 which
we generated the C1–C12 segment as the all-syn was converted to the Evans aldol product 32. Transamina-
polyketide in which the C5-ketone was the TES-protected tion and TBS protection was followed by DIBAL-H re-
alcohol.
duction to furnish aldehyde 34 (Scheme 8) and to set the
stage for the vinylogous Mukaiyama aldol reaction
(Scheme 9).
Synthesis of the Eastern Hemisphere
1. DIBAL-H
CH2Cl2, 91%
O
OPMB
O
OPMB
At the outset of our synthesis, we planned to establish a
route that could provide large quantities of tedanolide and
its precursors. Aldehyde 34 can be rapidly accessed
through crotylboration according to the Brown protocol.31
Reaction of acetaldehyde with Brown’s crotylborane 24
provided alcohol 25. Subsequent PMB-protection gave
the protected olefin in 60% yield over two steps
(Scheme 7).32 This protocol was followed by ozonolysis
and in situ Wittig reaction to the a,b-unsaturated ester 29
in only one step and 76% yield. It was also possible to per-
form an in situ dihydroxylation/diol cleavage sequence to
furnish aldehyde 28. Alternatively, olefin 26 could be di-
hydroxylated to diol 27 and then cleaved to the corre-
sponding aldehyde 28 in an additional step which
facilitates purification of multi-gram quantities.33 In the
second and third approaches, the desired ester 29 was also
obtained from 28 after a Wittig reaction.
EtO
O
2. MnO2
CH2Cl2, 97%
29
30
O
O
N
1. H2NMe(OMe)Cl
Me3Al, CH2Cl2
O
O
OH
OPMB
31
Bn
O
N
2. TBSOTf, 2,6-lutidinem
CH2Cl2, 77%
(2 steps)
Bu2BOTf
Et3N, CH2Cl2
Bn
32
94 %
O
OTBS
OPMB
O
OTBS
OPMB
DIBAL-H
N
OMe
THF, –78 °C
88%
33
Scheme 8 Formation of aldehyde 34.
34
For this transformation, aldehyde 34 was stirred in diethyl
ether with TPPB monohydrate, and ketene acetal 1 (in di-
ethyl ether containing 1.1 equivalents of 2-propanol) was
added over two hours. This modified version of
our general VMAR protocol provided 91% of the desired
syn-aldol product 22 (dr >20:1). Next, the alcohol was
TES-protected and a Sharpless asymmetric dihydroxyla-
tion gave 87% of diol 35 together with 4% of the minor
diastereoisomer.29f The hydroxyl group at C2 was selec-
tively protected as the TBS ether and methylation at the
C3 hydroxyl group was accomplished with Me3OBF4 and
proton sponge.34 For successive generation of methyl ke-
tone 21, PMB ether 36 was treated with DDQ to remove
the PMB protecting group, and was subsequently oxidized
with TPAP/NMO.35
O
NaH, DMSO,
PMBCl
OPMB
OH
Ipc
Ipc
B
BF3⋅OEt2
94% ee
60% over
2 steps
24
25
26
c) 1. O3, CH2Cl
PPh3
2. Wittig
(one-pot)
76%
a) AD-mix α
t-BuOH/H2O
quant.
b) OsO4, NaIO4
dioxane/H2O
3:1, 2 h, r.t.
76%
O
OPMB
O
OPMB
Wittig
OH OPMB
NaIO4
HO
EtO
88%
THF/pH 7
buffer, 95%
28
29
27
Scheme 7 Elaboration of ester 29.
Synthesis 2005, No. 7, 1183–1199 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of the C1–C17 Macrolactone of Tedanolide
1187
prising since it is known through work from the Evans38
and Roush29e laboratories that the stereochemistry at C3
would favor the anti-Felkin product.
TPPB·H2O
1, i-PrOH
O
O
OH OTBS
OPMB
OPMB
34
MeO
MeO
Et2O, –78 °C
91%, >90% de
22
Model reactions carried out with aldehyde 39 and methyl
isopropyl
ketone (40)
also supported their
TES
1. TESOTf
2,6-lutidine
CH2Cl2, 97%
findings, giving a 2:1 mixture of aldol products in favor of
the anti-Felkin isomer (Scheme 11). By using the (+)-di-
isopinocampheylboron enolate of the ketone, the selectiv-
ity could be changed to a 4:1 mixture of Felkin/anti-
Felkin isomers by reagent control. Unfortunately, this
method was not transferable to the reaction of 21, since
the increased steric hindrance of the enolate prohibited re-
action with 39 even after prolonged reaction time.
OH
O
OTBS
2. AD-mix α
t-BuOH/H2O
91%, 92% de
OH
35
TES
OTBS
1. TBSCl, imidazole
DMF, 91%
O
OMe O
OPMB
MeO
2. Me3OBF4
proton sponge
CH2Cl2, 82%
After extensive optimization, the use of NaHMDS or
KHMDS as the base was determined to be superior over a
variety of other methods. With the sodium enolate, the de-
sired Felkin product 43 was obtained in 61% yield along
with 4% of the anti-Felkin isomer (Scheme 12). Addition-
ally, 7% of a second Felkin product was isolated, presum-
ably bearing an epi-C10 methyl group which is believed
to result from non-optimal workup conditions of the aldol
reaction. The unexpected stereochemistry at the
newly generated stereocenter was confirmed by analogy39
and through the Mosher ester method.40 We believe that
the inherent stereochemistry of the methyl ketone over-
rides the anti-Felkin preference of the all-syn aldehyde.
TBSO
36
TES
OTBS
1. DDQ
CH2Cl2/H2O, 91%
O
OMe O
O
2. TPAP/NMO
CH2Cl2, 99%
MeO
TBSO
21
Scheme 9 VMAR and subsequent transformations.
Synthesis of a Model C13–C17 Aldehyde
The preceeding transformations established the carbon
skeleton of the C1–C12 backbone of tedanolide. In order
to investigate the macrocyclization of the sterically hin-
dered seco-acid, the aldol coupling of the C1–C12 seg-
ment with an abbreviated western part of tedanolide
(C13–C17¢) had to be investigated. The synthesis of mod-
el aldehyde 39 starts from the known Roche aldehyde 3736
which was subjected to Evans aldol conditions and then
further elaborated along the lines established by Shibasaki
et al.37 (Scheme 10).
O
40
O
O
OH OTES
O
OTES
LiHMDS
OPMB
OPMB
THF, –78 °C
63%
Felkin/anti-Felkin 1:2
39
41
42
40
OH OTES
OPMB
(+)-Ipc2BOTf
Et2NPr, CH2Cl2
–20 °C, 56%
Felkin/anti-Felkin 4:1
1. ent-31, Bu2BOTf
Et3N, CH2Cl2
O
OH OPMB
O
OPMB
Scheme 11 Model reactions of aldehyde 39 with ketone 40.
N
2. H2NMe(OMe)Cl
Me3Al, CH2Cl2
77% (2 steps)
OMe
37
38
Elaboration of the seco-Acid
1. TESOTf, 2,6-lutidine
CH2Cl2, 85%
O
OTES
Having accomplished the aldol coupling, we protected the
C13 hydroxyl group as a TBS ether and then turned our at-
tention to the macrolactonization step. The first problems
occurred when we tried to saponify the methyl ester. In
our hands, none of the known basic, acidic or SN2 proce-
dures to cleave methyl esters worked, paralleling the
problems described by Smith et al. in their synthesis of
13-deoxytedanolide (19).30 In the Smith synthesis of
deoxytedanolide, a less sterically hindered C2 SEM-pro-
tected hydroxyl ester could only be hydrolyzed in 74%
yield based on recovered starting material. In our case, the
more sterically hindered C2 TBS ether gave no acid prod-
uct at all. Basic procedures also led to elimination prod-
ucts, or to racemization of the C10 stereocenter.
OPMB
2. DIBAL-H, THF
–78 °C, 86%
39
Scheme 10 Synthesis of model aldehyde 39.
Aldol Reaction Studies
The thus-generated aldehyde 39 was used in aldol cou-
plings with methyl ketone 21 under various conditions.
By investigating different bases for this coupling, we
found that the use of LiHMDS predominantly provided
the aldol product 43 in 51% yield as a 1:1 mixture of Fel-
kin and anti-Felkin isomers. This result was rather sur-
Synthesis 2005, No. 7, 1183–1199 © Thieme Stuttgart · New York

1188
J. Hassfeld et al.
FEATURE ARTICLE
TES
OTBS
TES
OTBS
O
OMe O
O
OH OSiEt3
O
OMe O
O
O
OTES
NaHMDS
MeO
TBSO
OPMB
+
MeO
TBSO
OPMB
THF, –78 °C
65%
Felkin/anti-Felkin >10:1
21
39
43
OH
1. TBSOTf, CH2Cl2, 87%
2. DIBAL-H, CH2Cl2, 78%
3. TPAP/NMO, CH2Cl2, MS
O
OTBS
TES
OTBS
TBS
OSiEt3
PPh3, DEAD
toluene, r.t.
O
OMe O
O
O
O
OMe O
TES
4. NaH2PO4/NaClO2
2-methyl-2-butene
t-BuOH–H2O, 70% (2 steps)
5. DDQ, CH2Cl2–H2O
HO
OH
43%
(2 steps)
OH
TESO
O
O
44
45
TBS
Scheme 12 Aldol coupling and macrolactonization.
We decided to change tactics, from nucleophilic attack at from 0% to quantitative, strongly depending on the quali-
the carboxyl group to Lewis acid activation, and reduced ty of the TPAP used. In addition, PMB deprotection to the
the ester to the primary alcohol with DIBAL-H. The re- seco-acid was not possible without varying degrees of C2
sulting diol was reoxidized to the corresponding acid with TBS deprotection, while the yield after macrolactoniza-
TPAP/NMO and subsequent oxidation by sodium chlo- tion was much higher with the TBS group in place.
rite.41 At this stage, the TBS protecting group was cleaved
during workup, possibly due to the adjacent carboxylic
acid which facilitates proton delivery. Deprotection with
DDQ removed the PMB group and provided the precursor
for macrolactonization, hydroxy acid 44.
Route Optimization
To circumvent the encountered problems of methyl ester
saponification and the alternative reduction/oxidation
protocol, we decided to change the carboxyl protecting
group (Scheme 13). With ester 36 in hand from our initial
route, treatment with allyl alcohol and a tin oxide Lewis
Macrolactonization
Since we had encountered difficulty in nucleophilic attack acid at high temperature cleanly provided the transesteri-
at the sterically hindered carboxylate, we envisioned that fication product.43 PMB deprotection followed by TPAP
acylative macrolactonizations utilizing such a nucleo- oxidation afforded methyl ketone 46 in 92% yield over
philic attack would not be very likely to succeed. Instead, three steps, with just one chromatographic step. Deproto-
the Mitsunobu reaction42 with the C17¢ primary alcohol of nation with KHMDS and addition of aldehyde 39 gave the
44 was expected to provide the desired macrolactone 45, desired Felkin aldol product 47 in excellent selectivity.
since this would move the steric hindrance one bond away The secondary hydroxyl group was protected with TB-
from the reacting center. Consequently, the Mitsunobu SOTf, while the primary PMB group was removed with
protocol, carried out under high dilution conditions, gen- DDQ. In contrast to the previous approach, the allyl moi-
erated 45 in good yield. These results clearly indicated ety could now be cleanly and rapidly removed using pal-
that macrolactonization occurred rapidly without the need ladium and tributyltin hydride.44 The crude hydroxy acid,
to protect the ketone at C15. Unfortunately, the reaction still containing the C2-OTBS group in proximity to the
yield of the double oxidation step on the way to 44 varied carboxy group, was then directly cyclized by Mitsunobu
TES
OTBS
TES
OTBS
1. allyl alcohol, (n-Bu2ClSn)2O
2. DDQ, CH2Cl2–H2O
O
OMe O
OPMB
O
OMe O
O
KHMDS
MeO
TBSO
O
3. TPAP/NMO
CH2Cl2, 92% (3 steps)
THF, –78 °C,
39, 59%
TBSO
36
46
TBSO
O
OTBS
TES
OTBS
1. TBSOTf, CH2Cl2, 87%
2. DDQ, CH2Cl2–H2O, 86%
O
OMe O
O
OH OSiEt3
O
OMe O
TES
O
OPMB
3. Pd(PPh3)2Cl2, Bu3SnH, CH2Cl2
4. PPh3, DEAD, toluene, r.t.
5 min, 70% (2 steps)
TBSO
TESO
O
O
Felkin/anti-Felkin >10:1
47
48
TBS
Scheme 13 Alternative approach for macrocyclization.
Synthesis 2005, No. 7, 1183–1199 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of the C1–C17 Macrolactone of Tedanolide
1189
25, containing residual THF and pinenol. The crude product was
used directly in the next reaction. Rf = 0.35 (n-hexane–EtOAc, 2:1).
macrolactonization. Macrolactone 48 was the only detect-
able product of this reaction, although proton NMR anal-
ysis revealed two closely related, inseparable isomers 1H NMR (250 MHz, CDCl3): d = 5.85 (ddd, J = 17.6, 9.9, 7.7 Hz, 1
H), 5.04–5.14 (m, 2 H), 3.69 (qui-like, J = 6.0 Hz, 1 H), 2.24 (sext-
(4:1), presumably the result of epimerization at the C2 ste-
like, J = 6.8 Hz, 1 H), 1.51 (br s, 1 H), 1.14 (d, J = 5.9 Hz, 3 H),
reocenter of the seco-acid.
1.02 (d, J = 7.4 Hz, 3 H).
(1S,2S)-1,2-Dimethylbut-3-enyl 4-Methoxybenzoate (26)
Conclusion
Sodium hydride (2.25 g, 60% in mineral oil, 56.2 mmol) was
washed with n-pentane (20 mL). DMSO (60 mL) was added and the
suspension was stirred at r.t. for 1 h. Crude alcohol 25 (3.8 g, still
containing THF and pinenol from the previous reaction) was added
in THF (5 mL) over 2 min. The yellowish mixture was cooled to
0 °C and PMBCl (4.40 mL, 32.4 mmol) was added slowly. The
mixture was warmed to r.t. and stirred overnight. Brine (80 mL)
was added and the mixture was extracted with MTBE (4 × 100 mL).
The combined organic layers were washed with brine, dried over
MgSO4 and evaporated in vacuo. Silica gel chromatography afford-
ed 4.17 g (18.9 mmol, 60% over 2 steps) of PMB-ether 26 as a col-
orless liquid. Rf = 0.54 (n-hexane–EtOAc, 4:1); [a]D23 = +1.4 (c 1.5,
CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.28 (dm, J = 8.8 Hz, 2 H), 6.88
(dm, J = 8.8 Hz, 2 H), 5.83 (ddd, J = 17.4, 10.3, 7.4 Hz, 1 H), 5.01–
5.08 (m, 2 H), 4.52 (d, J = 11.4 Hz, 1 H), 4.42 (d, J = 11.4 Hz, 1 H),
3.80 (s, 3 H), 3.36 (qui-like, J = 12.4, 6.2 Hz, 1 H), 2.34–2.42 (m, 1
H), 1.14 (d, J = 6.3 Hz, 3 H), 1.05 (d, J = 6.9 Hz, 3 H).
In summary, we were able to prove that the vinylogous
Mukaiyama aldol reaction is another useful method to
build up complex polyketide structures. Additionally, it
was shown that seco-acid 44 and its C2-OTBS derivative
can be successfully transformed into the corresponding
macrolactone, while the carbonyl group at C15 is tolerat-
ed in the cyclization step. These results should enable us
to complete the total synthesis of tedanolide by using the
appropriate eastern hemisphere. With such a convergent
and efficient synthesis in hand, structure–activity studies
will be the ultimate goal of our research.
All reactions were carried out in dried glassware under a positive
pressure of Argon, using Schlenk techniques when air-sensitive
compounds were employed. Commercially available materials
were obtained from Aldrich, Fluka, Merck or Acros, and used with-
out purification unless otherwise noted. TPPB was purchased from
Acros and handled under N2 in a glovebox. Tetrahydrofuran (THF)
and diethyl ether were distilled from sodium/benzophenone, dichlo-
romethane, NEt3 and EtNiPr2 were distilled from CaH2 prior to use.
MeOH was distilled from Mg(OMe)2. Acetone, DMF, DMSO and
2-propanol were distilled and stored over 4 Å molecular sieves.
Flash chromatography was performed using Merck silica gel 230–
13C NMR (125 MHz, CDCl3): d = 159.0, 140.8, 131.1, 129.1, 114.4,
113.7, 78.1, 70.3, 55.2, 43.0, 16.6, 15.9.
MS (EI): m/z (%) = 220 (4) [M]+, 176 (1), 134 (2), 122 (9), 121
(100).
HRMS: m/z calcd for C14H20O2: 220.14633; found: 220.14732.
Ethyl (E)-(4S,5S)-5-[(4-Methoxybenzyl)oxy]-2,4-dimethylhex-
2-enoate (29)
1
400 mesh. H NMR and 13C NMR spectra were recorded with a
A stream of O3 in oxygen (50 L/h) was passed through a solution
containing olefin 26 (200 mg, 0.90 mmol) and Sudan Red III (10
mL, sat. soln in EtOH) in CH2Cl2 (5 mL) at –78 °C. After 10 min,
the color of the solution turned from red to gray. Excess O3 was
purged with argon, PPh3 (348 mg, 1.33 mmol) was added and stir-
ring was continued at –78 °C for 1 h. The mixture was warmed to
r.t. and (1-ethoxycarbonylethylidene)triphenylphosphorane (2.2 g,
6.1 mmol) in CH2Cl2 (5 mL) was added. After 15 h, the solvents
were evaporated in vacuo. The residue was filtered through a short
pad of silica gel (n-hexane–EtOAc, 2:1) and the solvent was evap-
orated. Silica gel chromatography (n-hexane–EtOAc, 10:1) afford-
ed 209 mg (0.68 mmol, 76%) of ester 29 as a colorless liquid.
Rf = 0.41 (n-hexane–EtOAc, 4:1); [a]D23 = +7.8 (c 1.2, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.26 (dm, J = 8.8 Hz, 2 H), 6.86
(dm, J = 8.8 Hz, 2 H), 6.61 (dq, J = 10.3, 1.5 Hz, 1 H), 4.53 (d,
J = 11.3 Hz, 1 H), 4.37 (d, J = 11.3 Hz, 1 H), 4.18 (q, J = 7.2 Hz, 2
H), 3.79 (s, 3 H), 3.36 (qui-like, J = 6.4 Hz, 1 H), 2.63 (ddq,
J = 10.3, 6.8, 6.8 Hz, 1 H), 1.84 (d, J = 1.5 Hz, 3 H), 1.29 (t,
J = 7.2 Hz, 3 H), 1.13 (d, J = 6.2 Hz, 3 H), 1.05 (d, J = 6.7 Hz, 3 H).
Bruker AMX 500, AVS 400, AM 250 or Jeol ECP 500 spectrome-
ter, respectively. Data are reported in d (ppm) with the residual un-
deuterated solvent peak (CDCl3 at d = 7.26 ppm, toluene-d8 at
d = 7.00 ppm) as an internal standard. High resolution mass spec-
troscopy (HRMS-EI) was performed using a Varian MAT 711 mass
spectrometer, electrospray mass spectrometry (ESI) with a Waters
Micromass LCT. Optical rotations were determined with a Perkin
Elmer 241 polarimeter at 23 °C and a wavelength of 589.3 nm (so-
dium lamp) using a 1 mL quartz cell.
(2S,3S)-3-Methylpent-4-en-2-ol (25)31
To a stirred suspension (–78 °C) of KO(t-Bu) (14.0 g, 124 mmol,
dried at 60 °C/0.3 mbar overnight) in THF (80 mL) was added cis-
butene (20 mL, 0.22 mol) via double-tipped needle. n-BuLi
(50.0 mL, 2.5 M in hexanes, 124 mmol) was added over 10 min. Af-
ter complete addition, the mixture was warmed to –25 °C for 30 min
and then recooled to –78 °C. A solution of (+)-methoxydiisopi-
nocampheylborane (47.4 g, 150 mmol) in Et2O (100 mL) was add-
ed slowly. After the resulting solution was stirred for 30 min,
BF3·OEt2 (20.0 mL, 0.158 mmol) was added dropwise, followed by
dropwise addition of acetaldehyde (10.0 mL, 177 mmol) in Et2O
(10 mL). After 3 h, the reaction was quenched with 135 mL aque-
ous NaOH (2 M) and 37.5 mL aqueous H2O2 (30%), warmed to r.t.
and then heated to reflux for 1 h. The organic layer was separated
and the aqueous layer was extracted with Et2O (50 mL). The com-
bined organic layers were washed with water (150 mL) and brine
(150 mL), dried over MgSO4 and filtered. After evaporation of a
major amount of solvent in vacuo (500 mbar, 40 °C water bath), the
residual liquid was carefully fractionated to give 13.3 g (bp 50–
72 °C/94 mbar, 82% yield corrected by NMR analysis) of alcohol
13C NMR (125 MHz, CDCl3): d = 168.2, 159.1, 144.0, 130.9, 129.2,
127.6, 113.7, 77.9, 70.6, 60.4, 55.2, 39.5, 17.3, 16.0, 14.3, 12.6.
MS (EI): m/z (%) = 306 (1) [M]+, 262 (1), 233 (1), 217 (1), 189 (1),
170 (20), 136 (4), 121 (100).
HRMS: m/z calcd for C18H26O4: 306.18311; found: 306.18564.
(E)-(4S,5S)-5-[(4-Methoxybenzyl)oxy]-2,4-dimethylhex-2-en-1-
ol
To a stirred solution (–78 °C) of ester 29 (2.51 g, 8.20 mmol) in
CH2Cl2 (60 mL) was added DIBAL-H (24.6 mL, 1 M in n-hexane,
24.6 mmol). After 1 h of stirring, MTBE (60 mL) was added rapidly
Synthesis 2005, No. 7, 1183–1199 © Thieme Stuttgart · New York

1190
J. Hassfeld et al.
FEATURE ARTICLE
and the mixture was warmed to r.t. Dropwise addition of H2O
(2.5 mL) led to the formation of a colorless gel. Upon addition of
aqueous 2 N NaOH (5 mL) and additional H2O (2.5 mL), a white
solid precipitated. The resulting suspension was dried with MgSO4,
then filtered and evaporated in vacuo. Silica gel chromatography (n-
hexane–EtOAc, 2:1) afforded 1.98 g (7.47 mmol, 91%) of the de-
sired alcohol as a colorless liquid. Rf = 0.23 (n-hexane–EtOAc,
2:1); [a]D23 = +11.2 (c 2, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.26 (dm, J = 8.7 Hz, 2 H), 6.87
(dm, J = 8.7 Hz, 2 H), 5.26 (dq, J = 9.8, 1.3 Hz, 1 H), 4.52 (d,
J = 11.4 Hz, 1 H), 4.37 (d, J = 11.4 Hz, 1 H), 3.98 (d, J = 1.0 Hz, 2
H), 3.80 (s, 3 H), 3.29 (dq, J = 6.9, 3.3 Hz, 1 H), 2.55 (ddq, J = 9.8,
6.8, 6.8 Hz, 1 H), 1.67 (d, J = 1.4 Hz, 3 H), 1.13 (d, J = 6.2 Hz, 3 H),
1.00 (d, J = 6.7 Hz, 3 H).
J = 11.3 Hz, 1 H), 4.37 (d, J = 11.3 Hz, 1 H), 4.34 (d, J = 4.1 Hz, 1
H), 4.09–4.14 (m, 2 H), 4.00 (dq, J = 6.9, 4.5 Hz, 1 H), 3.78 (s, 3 H),
3.29 (dq-like, J = 13.3, 6.2 Hz, 1 H), 3.24 (dd, J = 13.5, 3.2 Hz, 1
H), 2.77 (dd, J = 13.5, 9.5 Hz, 1 H), 2.67 (br s, 1 H), 2.56 (ddq,
J = 10.2, 6.8, 6.8 Hz, 1 H), 1.63 (d, J = 1.2 Hz, 3 H), 1.19 (d,
J = 6.9 Hz, 3 H), 1.10 (d, J = 6.2 Hz, 3 H), 1.00 (d, J = 6.7 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 176.6, 159.0, 152.9, 135.1, 133.5,
131.0, 129.5, 129.4, 129.1, 128.9, 127.3, 113.7, 78.9, 75.7, 70.5,
66.0, 55.2 (2C), 40.5, 38.2, 37.7, 17.4, 17.0, 13.4, 11.0.
MS (EI): m/z (%) = 495 (0.1) [M]+, 477 (0.1), 451 (0.1), 433 (0.1),
386 (0.1), 359 (0.1), 342 (0.1), 330 (0.4), 313 (0.3), 233 (15), 121
(100).
HRMS: m/z calcd for C29H37N1O6: 495.26209; found: 495.26465.
13C NMR (125 MHz, CDCl3): d = 159.0, 134.7, 131.1, 129.2, 128.6,
(E)-(2R,3R,6S,7S)-3-Hydroxy-7-[(4-methoxybenzyl)oxy]-N-
methoxy-N,2,4,6-tetramethyloct-4-enamide
113.7, 78.7, 70.5, 68.9, 55.3, 38.1, 17.0 (2C), 14.0.
MS (EI): m/z (%) = 264 (2) [M]+, 233 (1), 220 (2), 137 (6), 121
(100).
To a stirred suspension (0 °C) of N,O-dimethylhydroxylamine hy-
drochloride (1.05 g, 10.8 mmol) in CH2Cl2 (17 mL) was added
Me3Al (5.4 mL, 2 M in heptane, 10.8 mmol) over 5 min. The mix-
ture was warmed to r.t. After 1 h, the clear solution was cooled to
–20 °C and amide 32 (2.55 g, 5.14 mmol) in CH2Cl2 (5 mL) was
added dropwise. The reaction was allowed to warm to r.t. over 5 h
and was stirred overnight. The mixture was transferred via syringe
to a second flask containing a vigorously stirred aq soln of tartaric
acid (1 M, 30 mL) at 0 °C. After 1.5 h, H2O (50 mL) was added and
the aqueous layer was extracted with CH2Cl2 (3 × 80 mL). The or-
ganic layers were washed with brine (50 mL), dried over MgSO4,
filtered and evaporated in vacuo. The crude product can be directly
used in the next reaction, preferrably after crystallization of the
Evans auxiliary from n-hexane–EtOAc (1:1). The amide can be ob-
tained by silica gel chromatography (n-hexane–EtOAc, 2:1) to af-
ford a colorless liquid (1.74 g, 4.57 mmol, 89%). Rf = 0.12 (n-
hexane–EtOAc, 2:1); [a]D23 = +3.7 (c 1.1, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.26 (dm, J = 8.7 Hz, 2 H), 6.85
(dm, J = 8.7 Hz, 2 H), 5.39 (d, J = 9.9 Hz, 1 H), 4.52 (d,
J = 11.3 Hz, 1 H), 4.35 (d, J = 11.3 Hz, 1 H), 4.22–4.25 (m, 1 H),
3.78 (s, 3 H), 3.66 (s, 3 H), 3.66–3.69 (m, 1 H), 3.25 (dq, J = 8.0,
6.2 Hz, 1 H), 3.17 (s, 3 H), 3.07 (br s, 1 H), 2.51 (ddq, J = 10.0, 8.0,
6.7 Hz, 1 H), 1.60 (d, J = 1.4 Hz, 3 H), 1.11 (d, J = 6.2 Hz, 3 H),
1.09 (d, J = 7.0 Hz, 3 H), 1.01 (d, J = 6.7 Hz, 3 H).
HRMS: m/z calcd for C16H24O3: 264.17255; found: 264.17465.
(E)-(4S,5S)-5-[(4-Methoxybenzyl)oxy]-2,4-dimethylhex-2-enal
(30)
Activated manganese dioxide (26.6 g) was suspended in CH2Cl2
(90 mL). (E)-(4S,5S)-5-[(4-Methoxybenzyl)oxy]-2,4-dimethylhex-
2-en-1-ol (1.97 g, 7.44 mmol) was added in CH2Cl2 (10 mL) at r.t.
and the mixture was stirred for 1 h. The mixture was filtered through
a short pad of celite with CH2Cl2 (100 mL) and the solvent was
evaporated in vacuo to afford pure aldehyde 30 (1.90 g, 7.25 mmol,
97%) as a colorless liquid. Rf = 0.40 (n-hexane–EtOAc, 2:1);
[a]D23 = +22.4 (c 1.2, CHCl3).
1H NMR (500 MHz, CDCl3): d = 9.38 (s, 1 H), 7.25 (dm, J = 8.7 Hz,
2 H), 6.87 (dm, J = 8.7 Hz, 2 H), 6.36 (dq, J = 10.1, 1.4 Hz, 1 H),
4.55 (d, J = 11.4 Hz, 1 H), 4.37 (d, J = 11.4 Hz, 1 H), 3.80 (s, 3 H),
3.45 (quin-like, J = 6.3 Hz, 1 H), 2.84 (ddq, J = 10.1, 6.7, 6.6 Hz, 1
H), 1.75 (d, J = 1.4 Hz, 3 H), 1.17 (d, J = 6.3 Hz, 3 H), 1.10 (d,
J = 6.7 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 195.4, 159.2, 156.4, 138.9, 130.6,
129.2, 113.8, 77.2, 70.6, 55.2, 39.4, 16.9, 15.5, 9.5.
MS (EI): m/z (%) = 262 (1) [M]+, 248 (1), 232 (1), 222 (1), 192 (2),
13C NMR (125 MHz, CDCl3): d = 177.7, 159.0, 132.7, 131.1, 129.5,
129.2, 113.6, 79.0, 75.5, 70.6, 61.5, 55.2, 38.8, 36.9, 31.8, 17.5
(2C), 13.7, 10.6.
137 (8), 126 (15), 121 (100).
HRMS: m/z calcd for C16H22O3: 262.15689; found: 262.15533.
MS (EI): m/z (%) = 379 (0.1) [M]+, 361 (1), 348 (1) [M – CH3O]+,
330 (5), 301 (1), 286 (2), 121 (100).
HRMS (ESI): m/z calcd for C21H34N1O5 [M + H]+: 380.2437; found:
380.2447.
(R)-4-Benzyl-3-{(E)-(2R,3R,6S,7S)-3-hydroxy-7-[(4-methoxy-
benzyl)oxy]-2,4,6-(trimethyl)oct-4-enoyl}oxazolidin-2-one (32)
To a stirred solution (–78 °C) of (R)-(–)-4-benzyl-3-propionyl-2-
oxazolidinone (31) (1.73 g, 7.44 mmol) in CH2Cl2 (13 mL) was
added di(n-butyl)boryl(trifluoromethane)sulfonate (8.9 mL, 1 M in
CH2Cl2, 8.9 mmol) and Et3N (1.35 mL, 9.68 mmol). The mixture
was warmed to 0 °C, stirred for 1 h and then cooled to –78 °C again.
A solution of aldehyde 30 (1.89 g, 7.21 mmol) in CH2Cl2 (5 mL)
was added dropwise over 5 min. After 20 min, the reaction was
warmed to 0 °C and stirred for 1 h. The reaction was quenched by
dropwise addition of pH7 phosphate buffer (7.5 mL), MeOH
(22.5 mL) and a mixture of MeOH and 30% aqueous H2O2 (2:1,
22.5 mL) and stirred for 1 h. H2O (20 mL) was added, the organic
layer was separated and the aqueous layer was extracted with
MTBE (4 × 20 mL). The combined organic layers were washed
with brine (30 mL), dried over MgSO4, filtered and evaporated in
vacuo. Silica gel chromatography (n-hexane–EtOAc, 2:1) afforded
aldol 32 (3.36 g, 6.78 mmol, 94%) as a colorless liquid. Rf = 0.40
(n-hexane–EtOAc, 1:1); [a]D23 = –27.7 (c 0.9, CHCl3).
(E)-(2R,3R,6S,7S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-7-[(4-
methoxybenzyl)oxy]-N-methoxy-N,2,4,6-tetramethyloct-4-ena-
mide (33)
To a stirred solution (0 °C) of crude (E)-(2R,3R,6S,7S)-3-hydroxy-
7-[(4-methoxybenzyl)oxy]-N-methoxy-N,2,4,6-tetramethyloct-4-
enamide (2.75 g) in CH2Cl2 (35 mL) was slowly added 2,6-lutidine
(1.47 mL, 12.6 mmol) and TBSOTf (2.16 mL, 9.40 mmol). The
mixture was warmed to r.t. and stirred for 1 h. The reaction was
quenched with MeOH (0.6 mL), diluted with CH2Cl2 (30 mL) and
successively washed with sat. aq NaHCO3 (20 mL), aq NaHSO4 (1
M, 2 × 50mL) and brine (20 mL), dried over MgSO4 and evaporated
in vacuo. The crude product can be directly used in the next reac-
tion. Pure amide 33 can be obtained by silica gel chromatography
(n-hexane–EtOAc, 2:1) to afford 33 (1.95 g, 3.96 mmol, 77% over
2 steps) as a colorless liquid. Rf = 0.53 (n-hexane–EtOAc, 1:1);
[a]D23 = +12.2 (c 0.8, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.30–7.35 (m, 2 H), 7.22–7.29 (m,
3 H), 7.17–7.21 (m, 2 H), 6.85 (dm, J = 8.7 Hz, 2 H), 5.37 (d,
J = 10.0 Hz, 1 H), 4.64 (dq-like, J = 6.5, 3.2 Hz, 1 H), 4.50 (d,
Synthesis 2005, No. 7, 1183–1199 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of the C1–C17 Macrolactone of Tedanolide
1191
1H NMR (500 MHz, CDCl3): d = 7.25 (dm, J = 8.7 Hz, 2 H), 6.87
(dm, J = 8.7 Hz, 2 H), 5.09 (d, J = 10.2 Hz, 1 H), 4.50 (d,
J = 11.1 Hz, 1 H), 4.33 (d, J = 11.1 Hz, 1 H), 4.14 (d, J = 9.3 Hz, 1
H), 3.80 (s, 3 H), 3.62 (s, 3 H), 3.15 (dd, J = 8.3, 6.2 Hz, 1 H), 3.12–
3.19 (m, 1 H), 3.06 (s, 3 H), 2.36–2.45 (m, 1 H), 1.60 (d, J = 1.2 Hz,
3 H), 1.18 (d, J = 6.9 Hz, 3 H), 1.03 (d, J = 6.2 Hz, 3 H), 0.98 (d,
J = 6.6 Hz, 3 H), 0.88 (s, 9 H), 0.06 (s, 3 H), –0.02 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 175.5, 159.0, 135.0, 131.2, 131.1,
129.2 (2C), 113.7, 80.6, 79.3, 70.7, 61.4, 55.3, 39.9, 39.0, 25.8,
18.2, 17.5, 17.1, 15.3, 11.2, –4.5, –5.0.
H), 3.80 (s, 3 H), 3.73 (s, 3 H), 3.32 (quin-like, J = 6.6 Hz, 1 H),
3.28–3.32 (m, 1 H), 2.61 (ddq, J = 9.9, 6.7, 6.7 Hz, 1 H), 2.41
(dddq, J = 9.4, 9.2, 6.7, 0.8 Hz, 1 H), 2.00 (d, J = 5.1 Hz, 1 H),
1.56–1.63 (m, 1 H), 1.54 (d, J = 1.2 Hz, 3 H), 1.11 (d, J = 6.2 Hz, 3
H), 0.99 (d, J = 6.6 Hz, 3 H), 0.96 (d, J = 6.7 Hz, 3 H), 0.87 (s, 9 H),
0.86 (d, J = 6.9 Hz, 3 H), 0.04 (s, 3 H), –0.03 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 166.9, 159.0, 150.8, 136.2, 131.0,
129.7, 129.0, 120.8, 113.7, 82.4, 78.5, 75.2, 70.3, 55.3, 51.5, 41.0,
39.7, 37.7, 25.9, 18.1, 17.1, 16.6, 16.4, 12.0, 8.1, –4.4, –5.0.
MS (EI): m/z (%) = 548 (2) [M]+, 491 (2), 447 (8), 377 (13), 355 (2),
333 (58), 121 (100).
HRMS: m/z calcd for C31H52O6Si1 [M]+: 548.35333; found:
548.35176.
MS (EI): m/z (%) = 493 (0.1) [M]+, 479 (0.3), 478 (0.9) [M – CH3]+,
462 (0.3), 436 (18), 392 (14), 328 (11), 234 (79), 200 (58), 121
(100).
HRMS (ESI): m/z calcd for C27H48N1O5Si1 [M + H]+: 494.3302;
found: 494.3308.
(2E,8E)-(4S,5R,6S,7R,10S,11S)-7-{[tert-Butyl(dimethyl)si-
lyl]oxy}-11-[(4-methoxybenzyl)oxy]-4,6,8,10-tetramethyl-5-
[(triethylsilyl)oxy]dodeca-2,8-dienoic Acid Methyl Ester
To a stirred solution (0 °C) of ester 22 (172 mg, 0.313 mmol) in
CH2Cl2 (3.5 mL) was added 2,6-lutidine (91 mL, 0.78 mmol) and
TESOTf (106 mL, 0.47 mmol) dropwise. After 15 min, the reaction
was quenched by the addition of sat. aq NaHCO3 (2 mL). The or-
ganic layer was separated and the aqueous layer was extracted with
CH2Cl2 (2 × 5 mL) The combined organic layers were washed with
sat. aq NaHCO3 (5 mL), aq NaHSO4 (1 M, 2 × 5 mL) and brine
(5 mL), dried over MgSO4, filtered and evaporated in vacuo. Silica
gel chromatography (n-hexane–EtOAc, 15:1) afforded the ester
(201 mg, 0.303 mmol, 97%) as a colorless liquid. Rf = 0.48 (n-hex-
ane–EtOAc, 4:1); [a]D23 = +7.1 (c 1.1, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.26 (dm, J = 8.7 Hz, 2 H), 6.94
(dd, J = 15.8, 7.7 Hz, 1 H), 6.87 (dm, J = 8.7 Hz, 2 H), 5.76 (dd,
J = 15.8, 1.4 Hz, 1 H), 5.16 (d, J = 9.9 Hz, 1 H), 4.54 (d,
J = 11.3 Hz, 1 H), 4.37 (d, J = 11.3 Hz, 1 H), 3.80 (s, 3 H), 3.76 (d,
J = 8.8 Hz, 1 H), 3.73 (s, 3 H), 3.55 (dd, J = 5.7, 2.5 Hz, 1 H), 3.25
(dq, J = 7.7, 6.2 Hz, 1 H), 2.56 (ddq, J = 9.9, 8.8, 6.7 Hz, 1 H),
2.41–2.49 (m, 1 H), 1.69 (ddq, J = 8.8, 6.7, 2.5 Hz, 1 H), 1.53 (d,
J = 1.4 Hz, 3 H), 1.17 (d, J = 6.2 Hz, 3 H), 1.02 (d, J = 6.7 Hz, 3 H),
0.96 (t, J = 7.9 Hz, 9 H), 0.95 (d, J = 7.0 Hz, 3 H), 0.87 (s, 9 H), 0.85
(d, J = 6.7 Hz, 3 H), 0.60 (q, J = 7.9 Hz, 6 H), 0.02 (s, 3 H), –0.04
(s, 3 H).
(E)-(2R,3R,6S,7S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-7-[(4-
methoxybenzyl)oxy]-2,4,6-trimethyloct-4-enal (34)
To a stirred solution (–78 °C) of amide 33 (1.00 g, 2.03 mmol) in
THF (6 mL) was added DIBAL-H (5.1 mL, 1 M in heptane,
5.1 mmol) over 20 min. Upon complete addition, the reaction was
stirred for further 15 min. Excess DIBAL-H was quenched by the
addition of acetone (0.25 mL). The mixture was transferred via sy-
ringe to a second flask containing a vigorously stirred mixture
(23 °C) of aqueous tartaric acid (1 M, 18 mL) and n-hexane
(15 mL) and stirred for 1 h. The organic layer was separated and the
aqueous layer was extracted with MTBE (3 × 30 mL). The com-
bined organic layers were washed with brine (20 mL), dried over
MgSO4, filtered and evaporated in vacuo. Silica gel chromatogra-
phy (n-hexane–EtOAc, 15:1) afforded aldehyde 34 (0.778 g,
1.79 mmol, 88%) as a colorless liquid. Rf = 0.65 (n-hexane–EtOAc,
2:1); [a]D23 = +14.3 (c 1.8, CHCl3).
1H NMR (500 MHz, CDCl3): d = 9.64 (d, J = 2.2 Hz, 1 H), 7.26
(dm, J = 8.7 Hz, 2 H), 6.87 (dm, J = 8.7 Hz, 2 H), 5.22 (d,
J = 9.9 Hz, 1 H), 4.52 (d, J = 11.3 Hz, 1 H), 4.33 (d, J = 11.3 Hz, 1
H), 4.21 (d, J = 6.6 Hz, 1 H), 3.80 (s, 3 H), 3.22 (dq, J = 7.0, 6.4 Hz,
1 H), 2.54 (dquin-like, J = 6.7, 2.2 Hz, 1 H), 2.49 (ddq, J = 9.9, 6.9,
6.7 Hz, 1 H), 1.60 (d, J = 1.1 Hz, 3 H), 1.09 (d, J = 6.2 Hz, 3 H),
1.04 (d, J = 6.7 Hz, 3 H), 1.00 (d, J = 6.6 Hz, 3 H), 0.88 (s, 9 H),
0.04 (s, 3 H), –0.01 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 167.0, 159.0, 152.3, 136.8, 131.2,
131.0, 129.0, 120.1, 113.7, 80.6, 78.7, 74.9, 70.5, 55.3, 51.4, 42.3,
39.3, 38.8, 25.9, 18.2, 17.4, 16.9, 15.0, 11.9, 10.8, 7.1, 5.7, –4.3,
–4.9.
13C NMR (125 MHz, CDCl3): d = 204.4, 159.0, 134.9, 131.1, 130.8,
129.2, 113.7, 78.6, 78.4, 70.5, 55.3, 51.1, 38.6, 25.7, 18.1, 17.4,
16.7, 12.4, 9.6, –4.4, –5.2.
MS (EI): m/z (%) = 434 (0.1) [M]+, 416 (0.5), 377 (8) [M – C4H9]+,
MS (EI): m/z (%) = 662 (3) [M]+, 561 (2), 389 (3), 378 (15), 333
333 (16), 121 (100).
(76), 257 (30), 241 (29), 213 (13), 185 (27), 121 (100).
HRMS (ESI): m/z calcd for C25H42Na1O4Si1 [M + Na]+: 457.2750;
HRMS: m/z calcd for C37H66O6Si2 [M]+: 662.43982; found:
found: 457.2743.
662.43843.
(2E,8E)-(4S,5R,6S,7R,10S,11S)-7-{[tert-Butyl(dimethyl)si-
lyl]oxy}-5-hydroxy-11-[(4-methoxybenzyl)oxy]-4,6,8,10-tetra-
methyldodeca-2,8-dienoic Acid Methyl Ester (22)
(E)-(2R,3S,4S,5R,6S,7R,10S,11S)-7-{[tert-Butyl(dimethyl)si-
lyl]oxy}-2,3-dihydroxy-11-[(4-methoxybenzyl)oxy]-4,6,8,10-tet-
ramethyl-5-[(triethylsilyl)oxy]dodec-8-enoic Acid Methyl Ester
(35)
To a stirred solution (–78 °C) of aldehyde 34 (163 mg, 0.37 mmol)
in Et2O (5 mL) was added tris(pentafluorophenyl)borane monohy-
drate (230 mg, 0.43 mmol). Ketene acetal 111 (185 mg, 0.81 mmol)
and i-PrOH (25 mg, 0.42 mmol) were diluted with Et2O (0.8 mL)
and added via syringe pump over 2 h. The mixture was allowed to
warm to –50 °C over 30 min and was then evaporated in vacuo at
r.t.. Silica gel chromatography (n-hexane–EtOAc, 4:1) afforded es-
ter 22 (188 mg, 0.34 mmol, 91%) as a colorless liquid. Rf = 0.29 (n-
hexane–EtOAc, 4:1); [a]D23 = +6.7 (c 0.6, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.25 (dm, J = 8.7 Hz, 2 H), 6.87
(dm, J = 8.7 Hz, 2 H), 6.71 (dd, J = 15.7, 9.3 Hz, 1 H), 5.82 (dd,
J = 15.7, 0.8 Hz, 1 H), 5.24 (d, J = 9.9 Hz, 1 H), 4.51 (d,
J = 11.4 Hz, 1 H), 4.36 (d, J = 11.4 Hz, 1 H), 3.90 (d, J = 7.7 Hz, 1
To a stirred solution of AD-mix a (415 mg) in t-BuOH–H2O (1:1,
2.5 mL) was added methanesulfonamide (21.5 mg, 0.226 mmol) at
r.t. The suspension was cooled to 0 °C and (2E,8E)-
(4S,5R,6S,7R,10S,11S)-7-{[tert-butyl(dimethyl)silyl]oxy}-11-[(4-
methoxybenzyl)oxy]-4,6,8,10-tetramethyl-5-[(triethylsilyl)oxy]do-
deca-2,8-dienoic acid methyl ester (148 mg, 0.223 mmol) was add-
ed in t-BuOH (0.6 mL). After 5 d, the reaction was quenched by the
addition of Na2S2O3 (229 mg), warmed to r.t. and stirred for 1 h.
H2O (2 mL) was added, and the mixture was extracted with EtOAc
(4 × 10 mL), dried over MgSO4, filtered and evaporated in vacuo.
Silica gel chromatography (n-hexane–EtOAc, 3:1) afforded diol 35
(147 mg, 0.202 mmol, 91%) as a mixture of diastereomers (d.r.
24:1).
Synthesis 2005, No. 7, 1183–1199 © Thieme Stuttgart · New York

1192
J. Hassfeld et al.
FEATURE ARTICLE
Major Diastereomer (35)
1.62 (m, 1 H), 1.15 (d, J = 6.2 Hz, 3 H), 1.01 (d, J = 6.7 Hz, 3 H),
0.96 (t, J = 8.0 Hz, 9 H), 0.90 (s, 9 H), 0.88 (d, J = 7.0 Hz, 3 H), 0.88
(d, J = 6.6 Hz, 3 H), 0.87 (s, 9 H), 0.57–0.65 (m, 6 H), 0.08 (s, 3 H),
0.06 (s, 3 H), 0.03 (s, 3 H), –0.04 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 172.3, 159.0, 137.4, 131.2, 131.1,
129.0, 113.7, 81.5, 78.6, 75.8, 74.0, 71.6, 70.3, 55.2, 51.8, 40.0,
38.5, 25.8, 25.7, 25.6, 18.3, 18.2, 17.3, 17.0, 11.5, 10.3, 10.2, 7.2,
5.9, –4.3, –5.0 (2C), –5.3.
MS (EI): m/z (%) = 810 (0.5) [M]+, 793 (22) [M – OH]+, 751 (6),
736 (15) [M – C4H9]+, 707 (13), 644 (23), 619 (100), 512 (1), 121
(13).
HRMS (ESI): m/z calcd for C43H83Na1O8Si3 [M + Na + H]+:
834.5294; found: 834.5303.
Rf = 0.31 (n-hexane–EtOAc, 3:1); [a]D23 = –10.9 (c 1.6, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.26 (dm, J = 8.7 Hz, 2 H), 6.87
(dm, J = 8.7 Hz, 2 H), 5.16 (dd-like, J = 9.7, 1.3 Hz, 1 H), 4.51 (d,
J = 11.8 Hz, 1 H), 4.40 (d, J = 11.8 Hz, 1 H), 4.26 (dd, J = 5.6,
3.0 Hz, 1 H), 3.80 (s, 3 H), 3.80–3.84 (m, 1 H), 3.78 (s, 3 H), 3.74
(d, J = 9.2 Hz, 1 H), 3.61 (dd, J = 5.2, 2.2 Hz, 1 H), 3.29 (quin-like,
J = 6.3 Hz, 1 H), 3.12 (dd, J = 5.5, 1.0 Hz, 1 H), 2.62 (dq-like,
J = 9.8, 6.6 Hz, 1 H), 2.61 (d, J = 8.1 Hz, 1 H), 1.74–1.82 (m, 2 H),
1.58 (d, J = 1.4 Hz, 3 H), 1.12 (d, J = 6.2 Hz, 3 H), 0.97 (t,
J = 7.9 Hz, 9 H), 0.97 (d, J = 6.9 Hz, 3 H), 0.94 (d, J = 7.0 Hz, 3 H),
0.92 (d, J = 6.9 Hz, 3 H), 0.88 (s, 9 H), 0.63 (q, J = 7.9 Hz, 6 H),
0.03 (s, 3 H), –0.04 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 174.1, 159.1, 137.5, 130.8, 130.4,
129.1, 113.8, 81.2, 78.5, 73.4, 73.1, 72.1, 70.3, 55.3, 52.6, 42.4,
39.5, 37.8, 25.9, 18.2, 17.1, 16.5, 11.7, 11.2, 10.5, 7.1, 5.7, –4.3,
–5.0.
(E)-(2R,3S,4S,5R,6S,7R,10S,11S)-2,7-Bis{[tert-butyl(dimeth-
yl)silyl]oxy}-3-methoxy-11-[(4-methoxybenzyl)oxy]-4,6,8,10-
tetramethyl-5-[(triethylsilyl)oxy]dodec-8-enoic Acid Methyl Es-
ter (36)
MS (EI): m/z (%) = 696 (0.1) [M]+, 662 (0.2), 639 (0.2) [M –
C4H9]+, 606 (0.6), 461 (2), 377 (20), 333 (73), 185 (23), 121 (100).
To a stirred solution of trimethyloxonium tetrafluoroborate
(815 mg, 5.54 mmol) in CH2Cl2 (10 mL) was added proton sponge
(1.18 g, 5.51 mmol). The mixture was cooled to 0 °C and a solution
of (E)-(2R,3S,4S,5R,6S,7R,10S,11S)-2,7-bis{[tert-butyl(dimeth-
yl)silyl]oxy}-3-hydroxy-11-[(4-methoxybenzyl)oxy]-4,6,8,10-tet-
ramethyl-5-[(triethylsilyl)oxy]dodec-8-enoic acid methyl ester
(285 mg, 0.351 mmol) in CH2Cl2 (2 mL) was added slowly. The re-
action was protected from light and stirred for 24 h. The mixture
was diluted with CH2Cl2 (50 mL), washed with sat. aq NaHCO3
(3 × 30 mL), dried over MgSO4, filtered and evaporated in vacuo.
The residue was filtered through a short pad of silica gel with
EtOAc and evaporated. Silica gel chromatography (n-hexane–MT-
BE, 20:1) afforded ester 36 (238 mg, 0.288 mmol, 82%) as a color-
less liquid. Rf = 0.28 (n-hexane–EtOAc, 10:1); [a]D23 = +4.6 (c 2,
CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.26 (dm, J = 8.7 Hz, 2 H), 6.87
(dm, J = 8.7 Hz, 2 H), 5.17 (dd-like, J = 9.6, 1.3 Hz, 1 H), 4.53 (d,
J = 11.2 Hz, 1 H), 4.34 (d, J = 11.2 Hz, 1 H), 4.28 (d, J = 6.6 Hz, 1
H), 3.80 (s, 3 H), 3.78 (d, J = 10.0 Hz, 1 H), 3.71 (s, 3 H), 3.46 (dd,
J = 8.8, 0.7 Hz, 1 H), 3.41 (s, 3 H), 3.34 (dd, J = 6.6, 1.4 Hz, 1 H),
3.22 (dq, J = 8.0, 6.1 Hz, 1 H), 2.49 (ddq, J = 9.6, 7.9, 6.7 Hz, 1 H),
1.82 (ddq, J = 10.1, 6.7, 0.6 Hz, 1 H), 1.64 (ddq, J = 8.7, 7.3,
1.3 Hz, 1 H), 1.60 (d, J = 1.3 Hz, 3 H), 1.16 (d, J = 6.2 Hz, 3 H),
1.03 (d, J = 6.6 Hz, 3 H), 0.95 (t, J = 8.0 Hz, 9 H), 0.90 (s, 9 H), 0.87
(s, 9 H), 0.85 (d, J = 6.7 Hz, 3 H), 0.83 (d, J = 7.0 Hz, 3 H), 0.55–
0.66 (m, 6 H), 0.08 (s, 3 H), 0.07 (s, 3 H), 0.03 (s, 3 H), –0.04 (s, 3
H).
HRMS (ESI): m/z calcd for C37H68Na1O8Si2 [M + Na]+: 719.4350;
found: 719.4334.
(2S,3R) Isomer (C2,C3-epi-35)
Rf = 0.40 (n-hexane–EtOAc, 3:1); [a]D23 = –12.8 (c 0.8, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.25 (dm, J = 8.6 Hz, 2 H), 6.87
(dm, J = 8.6 Hz, 2 H), 5.17 (d, J = 9.8 Hz, 1 H), 4.52 (d,
J = 11.6 Hz, 1 H), 4.40 (d, J = 11.6 Hz, 1 H), 4.36 (br s, 1 H), 4.10
(d, J = 8.8 Hz, 1 H), 3.91 (ddd, J = 10.2, 3.4, 1.1 Hz, 1 H), 3.84 (dd,
J = 3.0, 2.1 Hz, 1 H), 3.81 (s, 3 H), 3.80 (s, 3 H), 3.69 (d, J = 9.8 Hz,
1 H), 3.29 (quin-like, J = 6.4 Hz, 1 H), 2.90 (d, J = 8.5 Hz, 1 H),
2.62 (dq-like, J = 9.8, 6.7 Hz, 1 H), 1.94 (ddq, J = 10.4, 6.9, 3.6 Hz,
1 H), 1.83 (ddq, J = 9.8, 6.7, 1.8 Hz, 1 H), 1.55 (d, J = 1.2 Hz, 3 H),
1.13 (d, J = 6.4 Hz, 3 H), 1.03 (d, J = 7.0 Hz, 3 H), 0.97 (t,
J = 7.9 Hz, 9 H), 0.97 (d, J = 7.0 Hz, 3 H), 0.88 (s, 9 H), 0.74 (d,
J = 7.0 Hz, 3 H), 0.60–0.66 (m, 6 H), 0.03 (s, 3 H), –0.03 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 174.3, 159.0, 136.9, 131.0, 130.9,
129.0, 113.7, 81.9, 78.4, 75.0, 74.8, 71.6, 70.2, 55.3, 52.5, 40.1,
37.8, 37.2, 29.7, 25.8, 18.2, 16.8, 16.5, 12.4, 11.5, 6.9, 5.1, –4.4,
–5.0.
MS (EI): m/z (%) = 662 (0.1), 639 (0.2) [M – C4H9]+, 461 (5), 377
(21), 333 (70), 121 (100).
HRMS (ESI): m/z calcd for C37H68Na1O8Si2 [M + Na]+: 719.4350;
found: 719.4349.
13C NMR (125 MHz, CDCl3): d = 172.4, 159.0, 136.8, 131.7, 131.2,
129.0, 113.7, 82.5, 81.2, 78.7, 75.3, 74.3, 70.5, 60.4, 55.2, 51.6,
39.3, 39.2, 39.0, 25.9, 25.7, 18.3, 18.2, 17.8, 16.7, 11.6, 11.2, 10.0,
7.2, 6.2, –4.2, –4.9, –5.1, –5.2.
MS (EI): m/z (%) = 809 (0.1) [M – CH3]+, 767 (0.4) [M – C4H9]+,
659 (0.6), 589 (3), 377 (21), 333 (44), 121 (100).
(E)-(2R,3S,4S,5R,6S,7R,10S,11S)-2,7-Bis{[tert-butyl(dimeth-
yl)silyl]oxy}-3-hydroxy-11-[(4-methoxybenzyl)oxy]-4,6,8,10-
tetramethyl-5-[(triethylsilyl)oxy]dodec-8-enoic Acid Methyl Es-
ter
To a stirred solution (0 °C) of diol 35 (161 mg, 0.231 mmol) in
DMF (2 mL) was added imidazole (95 mg, 1.4 mmol) and TBSCl
(105 mg, 70 mmol). After 16 h, the reaction was quenched by the ad-
dition of sat. aq NH4Cl (2 mL) and the mixture was extracted with
n-hexane–EtOAc (5:1, 4 × 5 mL). The combined organic layers
were dried over MgSO4, filtered and evaporated in vacuo. Silica gel
chromatography (n-hexane–EtOAc, 8:1) afforded the desired ester
(187 mg, 0.230 mmol, 99%) as a colorless liquid. Rf = 0.38 (n-hex-
ane–EtOAc, 10:1); [a]D23 = +2.7 (c 1.1, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.27 (dm, J = 8.7 Hz, 2 H), 6.87
(dm, J = 8.7 Hz, 2 H), 5.13 (dd-like, J = 9.8, 1.2 Hz, 1 H), 4.54 (d,
J = 11.5 Hz, 1 H), 4.40 (d, J = 11.5 Hz, 1 H), 4.08 (d, J = 6.9 Hz, 1
H), 3.80–3.83 (m, 1 H), 3.80 (s, 3 H), 3.74 (d, J = 10.0 Hz, 1 H),
3.72 (s, 3 H), 3.54 (d, J = 7.4 Hz, 1 H), 3.24 (dq, J = 7.1, 6.2 Hz, 1
H), 2.57 (dq-like, J = 6.9, 2.8 Hz, 1 H), 2.54 (d, J = 4.5 Hz, 1 H),
1.86 (dq-like, J = 10.0, 6.6 Hz, 1 H), 1.58 (d, J = 1.1 Hz, 3 H), 1.57–
HRMS (ESI): m/z calcd for C44H84Na1O8Si3 [M + Na]+: 847.5372;
found: 847.5371.
(E)-(2R,3S,4S,5R,6S,7R,10S,11S)-2,7-Bis{[tert-butyl(dimeth-
yl)silyl]oxy}-11-hydroxy-3-methoxy-4,6,8,10-tetramethyl-5-
[(triethylsilyl)oxy]dodec-8-enoic Acid Methyl Ester
To a stirred solution (0 °C) of ester 36 (237 mg, 0.287 mmol) in
CH2Cl2–pH7 buffer (10:1, 1 mL) was added DDQ (81.5 mg,
0.359 mmol). After 1.5 h, the reaction was diluted with CH2Cl2
(10 mL) and sat. aq NaHCO3 (10 mL). The organic layer was sepa-
rated and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL).
The combined organic layers were washed with sat. aq NaHCO3
(10 mL), dried over MgSO4, filtered and evaporated in vacuo. Silica
gel chromatography (n-hexane–EtOAc, 5:1) afforded the alcohol
Synthesis 2005, No. 7, 1183–1199 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of the C1–C17 Macrolactone of Tedanolide
1193
(195 mg, 0.277 mmol, 96%) as a colorless liquid. Rf = 0.32 (n-hex-
ane–EtOAc, 4:1); [a]D23 = –8.2 (c 1.3, CHCl3).
ganic layers were washed with brine (30 mL), dried over MgSO4,
filtered and evaporated in vacuo. Silica gel chromatography (n-hex-
ane–EtOAc, 2:1) afforded the desired compound (1.39 g,
3.15 mmol, 78%) as a colorless solid. Rf = 0.32 (n-hexane–EtOAc,
1:1); [a]D23 = +41.7 (c 2.8, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.31–7.36 (m, 2 H), 7.24–7.30 (m,
3 H), 7.19–7.22 (m, 2 H), 6.87 (dm, J = 8.7 Hz, 2 H), 4.67 (dddd,
J = 9.7, 6.8, 3.4, 3.3 Hz, 1 H), 4.43 (s, 2 H), 4.20 (dd, J = 9.0,
7.2 Hz, 1 H), 4.17 (dd, J = 9.0, 3.4 Hz, 1 H), 3.94–4.02 (m, 2 H),
3.80 (s, 3 H), 3.47 (dd, J = 9.3, 4.5 Hz, 1 H), 3.45 (dd, J = 9.3,
5.2 Hz, 1 H), 3.24 (dd, J = 13.5, 3.3 Hz, 1 H), 3.01 (br s, 1 H), 2.77
(dd, J = 13.5, 9.5 Hz, 1 H), 1.85–1.93 (m, 1 H), 1.32 (d, J = 6.6 Hz,
3 H), 1.02 (d, J = 7.0 Hz, 3 H).
1H NMR (500 MHz, CDCl3): d = 5.20 (dd-like, J = 9.6, 1.4 Hz, 1
H), 4.28 (d, J = 6.7 Hz, 1 H), 3.80 (d, J = 10.0 Hz, 1 H), 3.71 (s, 3
H), 3.56–3.62 (m, 1 H), 3.46 (dd, J = 8.7, 0.8 Hz, 1 H), 3.42 (s, 3 H),
3.33 (dd, J = 6.7, 1.3 Hz, 1 H), 2.41 (ddq, J = 9.6, 6.7, 6.7 Hz, 1 H),
1.81 (ddq, J = 6.8, 3.2, 0.8 Hz, 1 H), 1.61–1.68 (m, 1 H), 1.61 (d,
J = 1.2 Hz, 3 H), 1.17 (d, J = 6.3 Hz, 3 H), 1.01 (d, J = 6.7 Hz, 3 H),
0.96 (t, J = 7.9 Hz, 9 H), 0.90 (s, 9 H), 0.87 (s, 9 H), 0.86 (d,
J = 6.7 Hz, 3 H), 0.84 (d, J = 7.0 Hz, 3 H), 0.55–0.67 (m, 6 H), 0.07
(s, 3 H), 0.06 (s, 3 H), 0.03 (s, 3 H), –0.04 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 172.4, 137.5, 131.0, 82.6, 81.1,
75.3, 74.4, 71.7, 60.4, 51.7, 40.0, 39.4, 38.9, 25.8, 25.7, 21.3, 18.3,
18.2, 15.7, 11.7, 11.2, 10.1, 7.2, 6.2, –4.3, –4.9, –5.1, –5.2.
MS (EI): m/z (%) = 675 (0.3) [M – Et]+, 647 (0.5), 589 (0.9), 515
(1), 471 (5), 257 (100), 213 (23), 115 (3).
13C NMR (125 MHz, CDCl3): d = 177.0, 159.1, 152.8, 135.1, 130.3,
129.4, 129.2, 128.9, 127.4, 113.7, 74.0, 73.9, 72.9, 66.0, 55.2, 55.1,
40.6, 37.7, 36.2, 12.8, 12.4.
MS (EI): m/z = 441 (8), 374 (2), 320 (2), 303 (14), 287 (20), 233
(42), 121 (100).
HRMS: m/z calcd for C25H31O6N1 [M]+: 441.21515; found:
HRMS (ESI): m/z calcd for C36H76Na1O7Si3 [M + Na]+: 727.4797;
found: 727.4802.
(E)-(2R,3S,4S,5R,6S,7R,10S)-2,7-Bis{[tert-butyl(dimethyl)si-
lyl]oxy}-3-methoxy-4,6,8,10-tetramethyl-11-oxo-5-[(triethylsi-
lyl)oxy]dodec-8-enoic Acid Methyl Ester (21)
441.21733.
(2S,3R,4S)-3-Hydroxy-N-methoxy-5-[(4-methoxybenzyl)oxy]-
N,2,4-trimethylpentanamide (38)
To a stirred solution (0 °C) of (E)-(2R,3S,4S,5R,6S,7R,10S,11S)-
2,7-bis{[tert-butyl(dimethyl)silyl]oxy}-11-hydroxy-3-methoxy-
4,6,8,10-tetramethyl-5-[(triethylsilyl)oxy]dodec-8-enoic acid me-
thyl ester (124 mg, 0.176 mmol) in CH2Cl2 (3 mL) was added pow-
dered molecular sieves (3 Å, 100 mg) and N-methylmorpholine-N-
oxide (31.0 mg, 0.265 mmol). TPAP (3.1 mg, 8.8 mmol) was added
after 20 min and the reaction was warmed to r.t.. After 4 h, the mix-
ture was filtered through a short pad (5 × 30 mm) of silica gel with
CH2Cl2 (10 mL) and the solvent was evaporated in vacuo. Silica gel
chromatography (n-hexane–EtOAc, 10:1) afforded methyl ketone
21 (123 mg, 0.175 mmol, 99%) as a colorless liquid. Rf = 0.47 (n-
hexane–EtOAc, 4:1); [a]D23 = +69.7 (c 1, CHCl3).
1H NMR (500 MHz, CDCl3): d = 5.25 (dq, J = 9.4, 1.4 Hz, 1 H),
4.28 (d, J = 6.7 Hz, 1 H), 3.82 (d, J = 10.0 Hz, 1 H), 3.71 (s, 3 H),
3.44 (s, 3 H), 3.39–3.45 (m, 2 H), 3.32 (dd, J = 6.7, 1.4 Hz, 1 H),
2.12 (s, 3 H), 1.81 (ddq, J = 10.1, 6.7, 0.9 Hz, 1 H), 1.69 (d,
J = 1.4 Hz, 3 H), 1.62 (ddq, J = 8.6, 7.0, 1.4 Hz, 1 H), 1.15 (d,
J = 6.7 Hz, 3 H), 0.94 (t, J = 7.9 Hz, 9 H), 0.90 (s, 9 H), 0.87 (s, 9
H), 0.86 (d, J = 6.6 Hz, 3 H), 0.83 (d, J = 6.9 Hz, 3 H), 0.51–0.65
(m, 6 H), 0.08 (s, 3 H), 0.07 (s, 3 H), 0.03 (s, 3 H), –0.04 (s, 3 H).
To a stirred solution (0 °C) of N,O-dimethylhydroxylamine hydro-
chloride (0.48 g, 5.0 mmol) in CH2Cl2 (7 mL) was added Me3Al
(2.4 mL, 2 M in heptane, 4.8 mmol) over 5 min. The mixture was
warmed to r.t.. After 1 h, the clear solution was cooled to –20 °C and
(R)-4-benzyl-3-{(2S,3R,4S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-
2,4-dimethylpentanoyl}oxazolidin-2-one (1.00 g, 2.26 mmol) in
CH2Cl2 (3 mL) was added dropwise. The reaction was allowed to
warm to r.t. for 3 h and was stirred overnight. The mixture was
transferred via syringe to a second flask containing a vigorously
stirred aq soln of tartaric acid (1 M, 20 mL) at 0 °C. After 1 h, H2O
(30 mL) was added and the aqueous layer was extracted with
CH2Cl2 (3 × 50 mL). The organic layers were washed with brine
(30 mL), dried over MgSO4, filtered and evaporated in vacuo. Silica
gel chromatography (n-hexane–EtOAc, 1:1) afforded amide 38
(0.730 g, 2.24 mmol, 99%) as a colorless liquid. Rf = 0.08 (n-hex-
ane–EtOAc, 2:1).
1H NMR (500 MHz, CDCl3): d = 7.22 (dm, J = 8.7 Hz, 2 H), 6.85
(dm, J = 8.7 Hz, 2 H), 4.41 (dd-like, J = 22.4, 11.5 Hz, 2 H), 3.86
(dd-like, J = 5.5, 1.8 Hz, 1 H), 3.71 (s, 3 H), 3.62 (s, 3 H), 3.49 (dd,
J = 9.2, 4.1 Hz, 1 H), 3.40 (dd, J = 9.2, 4.5 Hz, 1 H), 3.15 (s, 3 H),
3.13–3.18 (m, 1 H), 1.81–1.89 (m, 1 H), 1.21 (d, J = 7.0 Hz, 3 H),
1.03 (d, J = 6.9 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 177.7, 159.1, 130.2, 129.8, 129.0,
113.7, 74.9, 74.5, 73.0, 61.5, 55.2, 37.5, 35.7, 12.6, 12.3.
MS (EI): m/z = 325 (6) [M]+, 279 (1), 204 (2), 177 (13), 121 (100).
HRMS: m/z calcd for C17H27O5N1 [M]+: 325.18893; found:
13C NMR (125 MHz, CDCl3): d = 208.9, 172.4, 139.9, 127.4, 82.6,
80.7, 75.4, 74.1, 60.5, 51.7, 46.8, 39.6, 39.0, 28.2, 25.8, 25.7, 18.3,
18.2, 16.1, 11.6, 11.2, 9.9, 7.2, 6.1, –4.3, –4.9, –5.1, –5.2.
MS (EI): m/z (%) = 703 (0.02), 688 (0.1), 673 (0.8), 645 (6) [M –
C4H9]+, 589 (1), 387 (9), 354 (7), 255 (100), 212 (10) 72 (12).
HRMS (ESI): m/z calcd for C36H74Na1O7Si3 [M + Na]+: 725.4640;
found: 725.4641.
325.18755.
(R)-4-Benzyl-3-{(2S,3R,4S)-3-hydroxy-5-[(4-methoxybenzyl)-
oxy]-2,4-dimethylpentanoyl}oxazolidin-2-one
(2S,3R,4S)- N-Methoxy-5-[(4-methoxybenzyl)oxy]-N,2,4-tri-
methyl-3-[(triethylsilyl)oxy]pentanamide
To a stirred solution (–78 °C) of (S)-4-benzyl-3-propionyl-2-oxazo-
lidinone (945 mg, 4.05 mmol) in CH2Cl2 was added di-n-butylbo-
ryltrifluoromethanesulfonate (4.45 mL, 1 M in CH2Cl2, 4.45 mmol)
and Et3N (0.78 mL, 5.6 mmol). The mixture was warmed to 0 °C,
stirred for 1 h and then cooled back down to –78 °C. A solution of
aldehyde 3736 (1.04 g, 5.00 mmol) in CH2Cl2 (3 mL) was added
dropwise over 5 min. After 20 min, the reaction was warmed to 0 °C
and stirred for 1 h. The reaction was quenched by dropwise addition
of pH7 phosphate buffer (4.2 mL), MeOH (12.5 mL) and a mixture
of MeOH and 30% aq H2O2 (2:1, 12.5 mL) and stirred for 1 h. H2O
(15 mL) was added, the organic layer was separated and the aque-
ous layer was extracted with MTBE (4 × 15 mL). The combined or-
To a stirred solution (0 °C) of amide 38 (730 mg, 2.24 mmol) in
CH2Cl2 (15 mL) was slowly added 2,6-lutidine (0.46 mL,
4.0 mmol) and TESOTf (0.68 mL, 3.0 mmol). The mixture was
warmed to r.t. and stirred for 1 h. The reaction was quenched with
MeOH (0.12 mL), diluted with CH2Cl2 (15 mL) and successively
washed with sat. aq NaHCO3 (10 mL), NaHSO4 (1 M, 2 × 20 mL)
and brine (10 mL), dried over MgSO4 and evaporated in vacuo. Sil-
ica gel chromatography (n-hexane–EtOAc, 4:1) afforded the prod-
uct amide (847 mg, 1.92 mmol, 85%) as a colorless liquid. Rf = 0.28
(n-hexane–EtOAc, 2:1); [a]D23 = –1.8 (c 1.9, CHCl3).
Synthesis 2005, No. 7, 1183–1199 © Thieme Stuttgart · New York

1194
J. Hassfeld et al.
FEATURE ARTICLE
1H NMR (500 MHz, CDCl3): d = 7.25 (dm, J = 8.7 Hz, 2 H), 6.85
(dm, J = 8.7 Hz, 2 H), 4.40 (s, 2 H), 4.04 (dd, J = 8.8, 2.1 Hz, 1 H),
3.78 (s, 3 H), 3.65 (s, 3 H), 3.40 (dd, J = 9.1, 6.5 Hz, 1 H), 3.22 (dd,
J = 8.9, 7.7 Hz, 1 H), 3.14 (s, 3 H), 3.07 (br s, 1 H), 1.80–1.89 (m,
1 H), 1.16 (d, J = 7.0 Hz, 3 H), 0.94 (t, J = 7.9 Hz, 9 H), 0.88 (d,
J = 6.9 Hz, 3 H), 0.55–0.65 (m, 6 H).
13C NMR (125 MHz, CDCl3): d = 176.6, 159.0, 130.7, 129.3, 113.6,
74.4, 73.1, 72.3, 61.4, 55.2, 39.4, 37.5, 32.1, 15.3, 10.8, 7.0, 5.4.
MS (EI): m/z = 439 (5) [M]+, 410 (34), 383 (1), 251 (9), 121 (100).
HRMS: m/z calcd for C23H41N1O5Si1 [M]+: 439.27539; found:
1H NMR (500 MHz, CDCl3): d = 7.25 (dm, J = 8.7 Hz, 2 H), 6.87
(dm, J = 8.7 Hz, 2 H), 5.34 (dq, J = 9.1, 1.3 Hz, 1 H), 4.44 (d,
J = 11.5 Hz, 1 H), 4.40 (d, J = 11.5 Hz, 1 H), 4.25 (d, J = 6.7 Hz, 1
H), 4.09–4.14 (m, 1 H), 3.85 (dd, J = 6.6, 2.6 Hz, 1 H), 3.82 (d,
J = 9.8 Hz, 1 H), 3.80 (s, 3 H), 3.71 (s, 3 H), 3.42 (s, 3 H), 3.38–3.45
(m, 3 H), 3.33 (dd, J = 6.7, 1.4 Hz, 1 H), 3.23 (dd, J = 8.9, 7.0 Hz,
1 H), 2.78 (d, J = 2.7 Hz, 1 H), 2.58 (dd, J = 17.5, 7.9 Hz, 1 H), 2.54
(dd, J = 17.5, 4.6 Hz, 1 H), 2.08 (dq, J = 6.8, 2.7 Hz, 1 H), 1.78
(ddq, J = 9.8, 6.7, 0.8 Hz, 1 H), 1.64 (d, J = 1.4 Hz, 3 H), 1.58 (ddq,
J = 8.4, 7.0, 1.4 Hz, 1 H), 1.50 (ddq, J = 7.0, 3.2, 0.8 Hz, 1 H), 1.15
(d, J = 7.0 Hz, 3 H), 0.95 (t, J = 7.9 Hz, 9 H), 0.94 (t, J = 7.9 Hz, 9
H), 0.91 (d, J = 7.0 Hz, 3 H), 0.90 (s, 9 H), 0.87 (s, 9 H), 0.87 (d,
J = 6.9 Hz, 3 H), 0.85 (d, J = 6.7 Hz, 3 H), 0.85 (d, J = 7.0 Hz, 3 H),
0.53–0.65 (m, 12 H), 0.08 (s, 3 H), 0.07 (s, 3 H), 0.03 (s, 3 H), –0.05
(s, 3 H).
439.26820.
(2S,3R,4S)-5-[(4-Methoxybenzyl)oxy]-2,4-dimethyl-3-[(trieth-
ylsilyl)oxy]pentanal (39)
13C NMR (100 MHz, CDCl3): d = 212.4, 172.4, 159.1, 139.6, 130.8,
129.2, 126.8, 113.7, 82.5, 80.6, 75.7, 74.9, 73.4, 72.6, 68.1, 60.6,
55.2, 51.7, 46.4, 46.3, 41.4, 39.4, 39.3, 36.8, 29.7, 25.8 (2C), 18.3,
18.2, 16.6, 11.7, 11.5, 11.2, 9.9 (2C), 7.2, 7.1, 6.1, 5.5, –4.3, –4.9,
–5.1 (2C).
To a stirred solution of (–78 °C) of (2S,3R,4S)-N-methoxy-5-[(4-
methoxybenzyl)oxy]-N,2,4-trimethyl-3-[(triethylsilyl)oxy]pentan-
amide (205 mg, 0.467 mmol) in THF (5 mL) was added DIBAL-H
(1.17 mL, 1 M in heptane, 1.17 mmol) over 10 min. Upon complete
addition, the reaction was stirred for 15 min. Excess DIBAL-H was
quenched by the addition of acetone (60 mL). The mixture was
transferred via syringe to second flask containing a vigorously
stirred mixture (23 °C) of aqueous tartaric acid (1 M, 4 mL) and n-
hexane (4 mL) and stirred for 1 h. The organic layer was separated
and the aqueous layer was extracted with MTBE (3 × 15 mL). The
combined organic layers were washed with brine (10 mL), dried
over MgSO4, filtered and evaporated in vacuo. Silica gel chroma-
tography (n-hexane–EtOAc, 10:1) afforded aldehyde 39 (152 mg,
0.40 mmol, 86%) as a colorless liquid. Rf = 0.37 (n-hexane–EtOAc,
4:1); [a]D23 = +43.9 (c 1.0, CHCl3).
1H NMR (500 MHz, CDCl3): d = 9.81 (d, J = 1.2 Hz, 1 H), 7.24
(dm, J = 8.7 Hz, 2 H), 6.88 (dm, J = 8.7 Hz, 2 H), 4.42 (d,
J = 11.5 Hz, 1 H), 4.38 (d, J = 11.5 Hz, 1 H), 4.22 (dd, J = 5.0,
4.2 Hz, 1 H), 3.80 (s, 3 H), 3.37 (dd, J = 9.1, 7.1 Hz, 1 H), 3.24 (dd,
J = 9.1, 5.8 Hz, 1 H), 2.53 (ddq, J = 6.9, 5.2, 1.2 Hz, 1 H), 1.92
(ddq-like, J = 12.7, 6.9, 4.1 Hz, 1 H), 1.06 (d, J = 7.0 Hz, 3 H), 0.95
(t, J = 7.9 Hz, 9 H), 0.88 (d, J = 6.9 Hz, 3 H), 0.60 (q, J = 7.9 Hz, 6
H).
MS (EI): m/z (%) = 921 (10), 613 (2), 482 (9), 460 (13), 308 (100).
HRMS (ESI): m/z calcd for C57H110Na1O11Si4 [M + Na]+:
1105.7023; found: 1105.7030.
(13R) Isomer (C13-epi-43)45
Rf = 0.14 (2 × n-hexane–EtOAc, 8:1).
1H NMR (500 MHz, CDCl3): d = 7.25 (dm, J = 8.7 Hz, 2 H), 6.87
(dm, J = 8.7 Hz, 2 H), 5.23 (dq, J = 9.6, 1.2 Hz, 1 H), 4.42 (dd-like,
J = 11.3, 15.0 Hz, 2 H), 4.26 (d, J = 6.9 Hz, 1 H), 4.15 (dq, J = 9.7,
2.8 Hz, 1 H), 3.86 (dd, J = 6.5, 2.7 Hz, 1 H), 3.80 (s, 3 H), 3.80 (d,
J = 9.9 Hz, 1 H), 3.72 (s, 3 H), 3.43 (s, 3 H), 3.39–3.47 (m, 3 H),
3.26 (dd, J = 6.9, 1.2 Hz, 1 H), 3.23 (dd, J = 8.9, 7.0 Hz, 1 H), 2.78
(d, J = 3.0 Hz, 1 H), 2.67 (dd, J = 17.5, 9.5 Hz, 1 H), 2.50 (dd,
J = 17.5, 2.6 Hz, 1 H), 2.08 (dq-like, J = 6.8, 2.8 Hz, 1 H), 1.77 (dq-
like, J = 7.0, 3.0 Hz, 1 H), 1.20 (d, J = 1.4 Hz, 3 H) 1.58–1.66 (m, 1
H), 1.50–1.55 (m, 1 H), 1.14 (d, J = 6.9 Hz, 3 H), 0.96 (t,
J = 7.9 Hz, 9 H), 0.94 (t, J = 8.0 Hz, 9 H), 0.91 (d, J = 7.1 Hz, 3 H),
0.91 (s, 9 H), 0.86 (s, 9 H), 0.86 (d, J = 7.0 Hz, 3 H), 0.85 (d,
J = 6.6 Hz, 3 H) 0.84 (d, J = 7.0 Hz, 3 H), 0.55–0.68 (m, 12 H), 0.08
(s, 3 H), 0.07 (s, 3 H), 0.02 (s, 3 H), –0.09 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 205.1, 159.2, 130.5, 129.2, 113.7,
72.7 (2C), 72.6, 55.2, 51.3, 37.2, 12.3, 9.3, 6.9, 5.2.
MS (EI): m/z = 380 (0.3) [M]+, 362 (2), 323 (0.4), 291 (0.4), 279
(0.4), 251 (2), 121 (100).
HRMS (ESI): m/z calcd for C57H110Na1O11Si4 [M + Na]+:
1105.7023; found: 1105.7025.
HRMS: m/z calcd for C21H36O4Si1 [M]+: 380.23828; found:
380.23666.
(E)-(2R,3S,4S,5R,6S,7R,10S,13S,14R,15R,16S)-2,7,13-Tris-
{[tert-butyl(dimethyl)silyl]oxy}-3-methoxy-17-[(4-methoxyben-
zyl)oxy]-4,6,8,10,14,16-hexamethyl-11-oxo-5,15-bis[(triethylsi-
lyl)oxy]heptadec-8-enoic Acid Methyl Ester
(E)-(2R,3S,4S,5R,6S,7R,10S,13S,14R,15R,16S)-2,7-Bis{[tert-bu-
tyl(dimethyl)silyl]oxy}-13-hydroxy-3-methoxy-17-[(4-methoxy-
benzyl)oxy]-4,6,8,10,14,16-hexamethyl-11-oxo-5,15-bis[(trieth-
ylsilyl)oxy]heptadec-8-enoic Acid Methyl Ester (43)
To a stirred solution (0 °C) of alcohol 43 (44.0 mg, 40.6 mmol) in
CH2Cl2 (0.9 mL) was added 2,6-lutidine (24.0 mL, 206 mmol) and
TBSOTf (37.0 mL, 161 mmol). After 45 min, the reaction was
quenched by the addition of MeOH (10 mL). Sat. aq NaHCO3
(2 mL) was added and the mixture was extracted with MTBE (4 ×
10 mL). The combined organic layers were washed with sat. aq
NaHSO4 (10 mL), sat. aq NaHCO3 (10 mL) and brine (10 mL),
dried over MgSO4, filtered and evaporated in vacuo. Silica gel chro-
matography (n-hexane–EtOAc, 30:1) afforded the ester (42.4 mg,
35.4 mmol, 87%) as a colorless liquid. Rf = 0.61 (n-hexane–EtOAc,
4:1); [a]D23 = +37.0 (c 1, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.24 (dm, J = 8.7 Hz, 2 H), 6.86
(dm, J = 8.7 Hz, 2 H), 5.33 (dd-like, J = 9.2, 1.2 Hz, 1 H), 4.44 (d,
J = 11.4 Hz, 1 H), 4.37 (d, J = 11.4 Hz, 1 H), 4.25 (d, J = 6.9 Hz, 1
H), 4.19 (ddd, J = 8.5, 4.7, 1.8 Hz, 1 H), 3.81 (d, J = 10.4 Hz, 1 H),
3.80 (s, 3 H), 3.77 (dd, J = 8.8, 1.8 Hz, 1 H), 3.71 (s, 3 H), 3.42 (s,
3 H), 3.32–3.46 (m, 4 H), 3.22 (dd, J = 8.8, 6.9 Hz, 1 H), 2.82 (dd,
J = 16.0, 8.5 Hz, 1 H), 2.38 (dd, J = 16.0, 4.7 Hz, 1 H), 2.09 (ddq,
To a stirred solution of methyl ketone 21 (30 mg, 43 mmol) in THF
(0.8 mL) were added powdered molecular sieves (3 Å, 20 mg) at r.t.
After 1 h, the mixture was cooled to –78 °C and NaHMDS (47 mL,
1M in THF) was added dropwise. Aldehyde 39 (25 mg, 67 mmol)
was dissolved in THF (50 mL) and a small grain of CaH2 was placed
into the flask. After 1 h, the aldehyde solution was rapidly added to
the enolate solution. The reaction was quenched after 1 min by rapid
addition of pH7 buffer (2 mL). MTBE (3 mL) was added, and the
vessel was warmed to r.t.. The mixture was extracted with MTBE
(4 × 10 mL), the combined organic layers were dried over MgSO4,
filtered and evaporated in vacuo. Silica gel chromatography (n-hex-
ane–EtOAc, 15:1) afforded aldol 43 (28 mg, 26 mmol, 61%) as a
colorless liquid.
Major Diasteromer (43)45
Rf = 0.44 (n-hexane–EtOAc, 4:1), Rf = 0.30 (2 × n-hexane–EtOAc,
8:1); [a]D23 = +22.7 (c 0.4, CHCl3).
Synthesis 2005, No. 7, 1183–1199 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of the C1–C17 Macrolactone of Tedanolide
1195
J = 6.9, 6.9, 1.6 Hz, 1 H), 1.75–1.83 (m, 1 H), 1.65 (d, J = 1.2 Hz, 3
H), 1.55–1.61 (m, 1 H), 1.54 (ddq, J = 6.9, 1.9, 1.8 Hz, 1 H), 1.12
(d, J = 7.0 Hz, 3 H), 0.95 (t, J = 8.1 Hz, 9 H), 0.93 (t, J = 8.0 Hz, 9
H), 0.90 (s, 9 H), 0.89 (d, J = 6.5 Hz, 3 H), 0.87 (s, 9 H), 0.85 (d,
J = 6.6 Hz, 3 H), 0.84 (d, J = 6.9 Hz, 3 H), 0.83 (s, 9 H), 0.81 (d,
J = 6.9 Hz, 3 H), 0.52–0.65 (m, 12 H), 0.08 (s, 3 H), 0.07 (s, 3 H),
0.03 (s, 3 H), 0.02 (s, 3 H), –0.01 (s, 3 H), –0.05 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 209.1, 172.4, 159.0, 139.3, 130.8,
129.5, 129.4, 126.8, 113.6, 82.4, 80.6, 75.8, 74.0, 73.7, 73.5, 72.6,
68.8, 60.6, 55.3, 51.7, 47.3, 46.8, 41.0, 39.3 (2C), 36.2, 26.3, 25.9
(2C), 25.8, 25.7, 18.3, 18.2, 17.9, 16.7, 11.7, 11.2, 10.4, 10.1, 9.8,
7.2 (2C), 6.0, 5.6, –4.1, –4.3, –4.7, –4.9, –5.1.
r.t., followed by TPAP (0.3 mg, 0.8 mmol) after 5 min. The reaction
was stirred for 4 h and then filtered through a short pad of silica (5 ×
25 mm) with CH2Cl2 (10 mL). Evaporation of the solvent in vacuo
followed by silica gel chromatography (n-hexane–EtOAc, 20:1) af-
forded the aldehyde (3.9 mg, 3.3 mmol, 70%) as a colorless liquid.
Rf = 0.54 (n-hexane–EtOAc, 10:1); [a]D23 = +30.5 (c 0.4, CHCl3).
1H NMR (500 MHz, CDCl3): d = 9.69 (d, J = 1.6 Hz, 1 H), 7.24
(dm, J = 8.5 Hz, 2 H), 6.86 (dm, J = 8.5 Hz, 2 H), 5.31 (d-like,
J = 9.1 Hz, 1 H), 4.44 (d, J = 11.5 Hz, 1 H), 4.37 (d, J = 11.4 Hz, 1
H), 4.18 (ddd, J = 8.4, 4.9, 1.8 Hz, 1 H), 4.14 (dd, J = 6.0, 1.6 Hz, 1
H), 3.80 (s, 3 H), 3.79 (d, J = 8.5 Hz, 1 H), 3.76 (dd, J = 8.8, 1.8 Hz,
1 H), 3.44 (dd, J = 6.1, 1.4 Hz, 1 H), 3.41 (dd, J = 7.9, 1.3 Hz, 1 H),
3.38 (s, 3 H), 3.32–3.38 (m, 2 H), 3.21 (dd, J = 8.7, 7.0 Hz, 1 H),
2.81 (dd, J = 16.1, 8.4 Hz, 1 H), 2.38 (dd, J = 15.9, 4.9 Hz, 1 H),
2.08 (dq-like, J = 7.0, 1.5 Hz, 1 H), 1.79–1.88 (m, 1 H), 1.77 (dq-
like, J = 6.8, 2.6 Hz, 1 H), 1.62 (d, J = 1.2 Hz, 3 H), 1.48–1.56 (m,
1 H), 1.12 (d, J = 6.9 Hz, 3 H), 0.95 (t, J = 8.1 Hz, 9 H), 0.93 (t,
J = 8.0 Hz, 9 H), 0.92 (s, 9 H), 0.88 (d, J = 6.5 Hz, 3 H), 0.86 (d,
J = 6.7 Hz, 3 H), 0.86 (s, 9 H), 0.82 (s, 9 H), 0.80 (d, J = 6.7 Hz, 3
H), 0.80 (d, J = 7.1 Hz, 3 H), 0.51–0.64 (m, 12 H), 0.08 (s, 3 H),
0.07 (s, 3 H), 0.02 (s, 3 H), 0.01 (s, 3 H), –0.02 (s, 3 H), –0.06 (s, 3
H).
13C NMR (125 MHz, CDCl3): d = 209.2, 202.4, 159.0, 139.2, 130.8,
129.5, 129.4, 126.8, 113.6, 81.7, 80.7, 78.7, 73.9, 73.6, 73.4, 72.6,
68.8, 59.5, 55.3, 47.2, 46.9, 41.0, 39.1, 39.0, 36.2, 29.7, 26.3, 25.8,
18.2 (2C), 17.9, 16.6, 11.7, 11.6, 10.4, 10.2, 10.1, 7.2, 5.9, 5.5, –4.1,
–4.3, –4.6, –4.7, –4.9, –5.0.
HRMS (ESI): m/z calcd for C62H122Na1O10Si5 [M + Na]+:
1189.7782; found: 1189.7765.
HRMS: m/z calcd for C63H124Na1O11Si5 [M + Na]+: 1219.7888;
found: 1219.7916.
(E)-(2R,3S,4S,5R,6S,7R,10S,13S,14R,15R,16S)-2,7,13-Tris-
{[tert-butyl(dimethyl)silyl]oxy}-3-methoxy-17-[(4-methoxyben-
zyl)oxy]-4,6,8,10,14,16-hexamethyl-5,15-bis[(triethylsilyl)oxy]-
heptadec-8-ene-1,11-diol
To a stirred solution (–78 °C) of the above-described ester (9.6 mg,
8.0 mmol) in CH2Cl2 (0.5 mL) was added DIBAL-H (65 mL, 1 M in
heptane, 65 mmol). After 90 min, Et2O (3 mL) was added slowly
and the mixture was warmed to r.t.. H2O (20 mL) was added, fol-
lowed by aq 2 N NaOH (40 mL) after 10 min. A white solid was
formed after additional 10 min of stirring. The mixture was dried
over MgSO4, filtered and evaporated in vacuo. Silica gel chroma-
tography (n-hexane–EtOAc, 15:1) afforded the desired diol
(5.7 mg, 4.9 mmol, 61%, inseparable 6:1 mixture of C11 diastereo-
mers) along with the corresponding hydroxyaldehyde (1.6 mg,
1.4 mmol, 17%) as a colorless liquid. Rf = 0.21 (n-hexane–EtOAc,
10:1); [a]D23 = –11.1 (c 0.5, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.24 (dm, J = 8.7 Hz, 2 H), 6.86
(dm, J = 8.7 Hz, 2 H), 5.44 (dd-like, J = 9.3, 1.3 Hz, 1 H), 4.43 (d,
J = 11.4 Hz, 1 H), 4.38 (d, J = 11.4 Hz, 1 H), 3.82–3.86 (m, 1 H),
3.82 (d, J = 9.8 Hz, 1 H), 3.80 (s, 3 H), 3.78 (dd, J = 7.1, 3.6 Hz, 1
H), 3.70–3.75 (m, 1 H), 3.63 (dd, J = 11.3, 4.4 Hz, 1 H), 3.49–3.53
(m, 1 H), 3.49 (d-like, J = 8.2 Hz, 1 H), 3.41 (dd, J = 8.7, 6.4 Hz, 1
H), 3.35 (d, J = 7.3 Hz, 1 H), 3.33 (s, 3 H), 3.20 (dd, J = 8.7, 7.4 Hz,
1 H), 3.13 (dd, J = 7.3, 1.2 Hz, 1 H), 2.35–2.42 (m, 1 H), 2.12 (br s,
1 H), 2.03 (ddq, J = 13.8, 6.7, 2.6 Hz, 1 H), 1.94 (br s, 1 H), 1.81
(ddq, J = 6.7, 3.0, 1.0 Hz, 1 H), 1.70–1.75 (m, 2 H), 1.60–1.68 (m,
1 H), 1.58 (d, J = 1.2 Hz, 3 H), 1.53–1.58 (m, 1 H), 0.98 (t,
J = 7.9 Hz, 9 H), 0.94 (t, J = 7.9 Hz, 9 H), 0.91 (s, 9 H), 0.90 (d,
J = 6.9 Hz, 3 H), 0.88–0.90 (m, 6 H), 0.88 (s, 9 H), 0.87 (s, 9 H),
0.86 (d, J = 7.0 Hz, 3 H), 0.85 (d, J = 6.7 Hz, 3 H), 0.64 (q-like,
J = 7.7 Hz, 6 H), 0.57 (q-like, J = 7.8 Hz, 6 H), 0.10 (s, 3 H), 0.09
(s, 3 H), 0.07 (s, 3 H), 0.03 (s, 3 H), 0.03 (s, 3 H), –0.04 (s, 3 H).
7,13-Bis{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxy-3-methoxy-
17-[(4-methoxybenzyl)oxy]-4,6,8,10,14,16-hexamethyl-11-oxo-
5,15-bis[(triethylsilyl)oxy]heptadec-8-enoic Acid
To a stirred solution of the heptadec-8-enal (5.0 mg, 4.3 mmol) in t-
BuOH (0.25 mL) was added 2-methyl-2-butene (75 mL, 1.6 mmol),
followed by NaH2PO4 (29.4 mg, 188 mmol) and NaClO2 (4.4 mg,
49 mmol) in H2O (0.2 mL). The mixture was stirred at r.t. for 3 d.
The reaction was quenched by the addition of Na2S2O3 (0.15 mL,
sat. soln in pH7 buffer). EtOAc (20 mL) was added and the solution
was washed with sat. aq NH4Cl, H2O and brine (5 mL each). The
aqueous layers were reextracted with EtOAc (15 mL), the com-
bined organic layers were dried with MgSO4 and evaporated in vac-
uo. Silica gel chromatography (EtOAc; then EtOAc–MeOH, 1:1)
afforded the carboxylic acid (4.6 mg, 4.3 mmol, 99%) as a viscous
liquid. The product was used directly in the next reaction. Rf = 0.41
(CH2Cl2–MeOH, 10:1)
(E)-(2R,3S,4S,5R,6S,7R,10S,13S,14R,15R,16S)-7,13-Bis{[tert-
butyl(dimethyl)silyl]oxy}-17-hydroxy-3-methoxy-4,6,8,10,14,-
16-hexamethyl-11-oxo-5,15-bis[(triethylsilyl)oxy]heptadec-8-
enoic Acid (44)
13C NMR (125 MHz, CDCl3): d = 159.1, 137.3, 130.8, 130.7, 129.3,
113.7, 81.5, 81.0, 77.2, 74.3, 74.0, 73.6, 73.3, 72.7, 71.8, 71.0, 64.2,
60.3, 55.3, 41.0, 39.8, 39.0, 38.7, 38.1, 37.8, 29.7, 26.0 (2C), 25.9,
18.2, 18.1, 18.0, 13.6, 11.7, 11.6, 11.5, 11.3, 10.5, 7.3, 7.1, 6.1, 5.6,
–4.1, –4.2, –4.3, –4.4, –4.7, –4.9.
HRMS (ESI): m/z calcd for C62H126Na1O10Si5 [M + Na]+:
1193.8095; found: 1193.8069.
To a stirred solution of the above-described heptadec-8-enoic acid
(2.0 mg, 1.7 mmol) in CH2Cl2 (1 mL) was added pH7 buffer
(0.1 mL) and DDQ (1.0 mg, 4.4 mmol) in two portions over 15 min
at r.t.. After 2.5 h, the reaction was quenched with sat. aq NaHCO3
(2 mL) and the aqueous layer was extracted with CH2Cl2 (5 ×
5 mL). The organic layers were washed with sat. aq NaHCO3 and
brine (3 mL each). The aqueous phases were treated with sat. aq
NH4Cl (10 mL) and extracted with CH2Cl2 (3 × 10 mL). The com-
bined organic layers were dried over MgSO4 and evaporated in vac-
uo. Silica gel chromatography (CH2Cl2–MeOH, 10:1; then MeOH)
afforded carboxylic acid 44 (0.8 mg, 0.84 mmol, 50%) as a viscous
liquid. The product was used directly in the next reaction. Rf = 0.37
(CH2Cl2–MeOH, 10:1).
(E)-(2R,3S,4S,5R,6S,7R,10S,13S,14R,15R,16S)-2,7,13-Tris-
{[tert-butyl(dimethyl)silyl]oxy}-3-methoxy-17-[(4-methoxyben-
zyl)oxy]-4,6,8,10,14,16-hexamethyl-11-oxo-5,15-bis[(triethylsi-
lyl)oxy]heptadec-8-enal
To a stirred solution of (E)-(2R,3S,4S,5R,6S,7R,10S,13S,14R,-
15R,16S)-2,7,13-tris{[tert-butyl(dimethyl)silyl]oxy}-3-methoxy-
17-[(4-methoxybenzyl)oxy]-4,6,8,10,14,16-hexamethyl-5,15-
bis[(triethylsilyl)oxy]heptadec-8-ene-1,11-diol (5.6 mg, 4.8 mmol)
in CH2Cl2 (0.5 mL) was added powdered molecular sieves (3 Å,
15 mg) and N-methylmorpholine-N-oxide (1.7 mg, 14.5 mmol) at
Synthesis 2005, No. 7, 1183–1199 © Thieme Stuttgart · New York

1196
J. Hassfeld et al.
FEATURE ARTICLE
(E)-(3S,4S,5S,6R,7S,8R,11S,14S,15R,16R,17S)-8,14-Bis{[tert-
butyl(dimethyl)silyl]oxy}-4-methoxy-5,7,9,11,15,17-hexameth-
yl-6,16-bis[(triethylsilyl)oxy]oxacyclooctadec-9-ene-2,12-dione
(45)
To a stirred solution of PPh3 (1.7 mg, 6.5 mmol) in toluene (1.5 mL)
was added DEAD (1.1 mL, 7 mmol). After 20 min, carboxylic acid
44 (0.7 mg, 0.7 mmol, azeotropically dried by 3 × evaporation of
toluene in vacuo) was added in toluene (1.5 mL) and the reaction
was stirred at r.t.. After 24 h, the mixture was evaporated. Silica gel
chromatography (n-hexane–EtOAc, 30:1) afforded lactone 45
(0.6 mg, 0.6 mmol, 86%) as a colorless liquid. Rf = 0.44 (n-hexane–
EtOAc, 10:1).
1H NMR (500 MHz, CDCl3): d = 5.35 (dq, J = 8.6, 1.2 Hz, 1 H),
4.10 (d, J = 6.1 Hz, 1 H), 4.06 (dd, J = 10.0, 5.4 Hz, 1 H), 3.96 (d,
J = 10.2 Hz, 1 H), 3.78 (dd, J = 6.5, 2.5 Hz, 1 H), 3.70 (d,
J = 10.0 Hz, 1 H), 3.48 (dd, J = 2.2, 2.2 Hz, 1 H), 3.41 (dq, J = 8.5,
7.0 Hz, 1 H), 3.32 (s, 3 H), 3.29 (d, J = 10.3 Hz, 1 H), 2.76 (dd,
J = 17.3, 4.3 Hz, 1 H), 2.67 (d, J = 10.2 Hz, 1 H), 2.54 (dd, J = 17.2,
5.2 Hz, 1 H), 2.34–2.43 (m, 1 H), 1.97–2.03 (m, 1 H), 1.73–1.82 (m,
2 H), 1.59 (d, J = 1.2 Hz, 3 H), 1.57–1.62 (m, 1 H), 1.13 (d,
J = 6.9 Hz, 3 H), 0.99 (t, J = 7.9 Hz, 9 H), 0.98 (d, J = 7.1 Hz, 3 H),
0.98 (t, J = 8.0 Hz, 9 H), 0.96 (d, J = 7.2 Hz, 3 H), 0.92 (d,
J = 7.2 Hz, 3 H), 0.87 (s, 9 H), 0.86 (s, 9 H), 0.85 (d, J = 7.1 Hz, 3
H), 0.60–0.66 (m, 12 H), 0.11 (s, 3 H), 0.08 (s, 3 H), 0.03 (s, 3 H),
–0.05 (s, 3 H).
twice with sat. aq NaHCO3, dried over MgSO4 and evaporated. The
crude product was used in the next step without further purification.
Rf = 0.15 (n-hexane–MTBE, 4:1); [a]D23 = –3.8 (c 0.52, CHCl3).
1H NMR (400 MHz, CDCl3): d = 5.92 (ddt, J = 17.2, 10.4, 6.0 Hz,
1 H), 5.36 (ddd, J = 17.2, 2.9, 1.5 Hz, 1 H), 5.26 (ddd, J = 10.4, 2.5,
1.1 Hz, 1 H), 5.20 (dd-like, J = 9.7, 1.0 Hz, 1 H), 4.59 (ddddd,
J = 17.8, 13.0, 6.1, 1.3, 1.1 Hz, 2 H), 4.28 (d, J = 6.8 Hz, 1 H), 3.79
(d, J = 10.2 Hz, 1 H), 3.59 (qui-like, J = 6.4 Hz, 1 H), 3.46 (d,
J = 8.8 Hz, 1 H), 3.42 (s, 3 H), 3.33 (dd, J = 6.7, 1.1 Hz, 1 H), 2.41
(ddq, J = 9.7, 6.7, 6.7 Hz, 1 H), 1.80 (dq-like, J = 10.0, 6.6 Hz, 1 H),
1.58–1.68 (m, 1 H), 1.61 (d, J = 1.3 Hz, 3 H), 1.17 (d, J = 6.3 Hz, 3
H), 1.01 (d, J = 6.8 Hz, 3 H), 0.96 (t, J = 8.0 Hz, 9 H), 0.90 (s, 9 H),
0.87 (s, 9 H), 0.85 (d, J = 6.9 Hz, 6 H), 0.58–0.66 (m, 6 H), 0.07 (s,
3 H), 0.06 (s, 3 H), 0.03 (s, 3 H), –0.04 (s, 3 H), OH proton not vis-
ible.
13C NMR (100 MHz, CDCl3): d = 171.7, 137.5, 131.6, 131.0, 119.2,
82.6, 81.1, 75.6, 74.3, 71.6, 65.6, 60.5, 40.0, 39.5, 39.0, 25.8 (2C),
21.3, 18.2 (2C), 15.6, 11.7, 11.2, 10.1, 7.2, 6.2, –4.3, –4.9, –5.0,
–5.2
HRMS (ESI): m/z calcd for C38H78NaO7Si3 [M + Na]+: 753.4953;
found: 753.4970.
(E)-(2R,3S,4S,5R,6S,7R,10S)-2,7-Bis{[tert-butyl(dimethyl)si-
lyl]oxy}-3-methoxy-4,6,8,10-tetramethyl-11-oxo-5-[(triethylsi-
lyl)oxy]dodec-8-enoic Acid Allyl Ester (46)
HRMS (ESI): m/z calcd for C48H98Na1O9Si4 [M + Na]+: 953.6186;
found: 953.6188.
To a mixture of the above crude product (0.279 mmol), powdered
molecular sieves (4 Å, 140 mg) and NMO (82.0 mg, 0.698 mmol)
in CH2Cl2 (2.8 mL), was added TPAP (2.0 mg, 56 mmol). After 15
min, no starting material was detectable. The solvent was removed
and the crude product was purified by chromatography (n-hexane–
MTBE, 9:1) to afford the methyl ketone 46 (187 mg, 0.257 mmol,
92% over 3 steps) as a colorless oil. Rf = 0.22 (n-hexane–MTBE,
9:1); [a]D23 = +51.3 (c 0.3, CHCl3).
1H NMR (400 MHz, CDCl3): d = 5.91 (ddt, J = 17.1, 10.4, 6.0 Hz,
1 H), 5.36 (ddd, J = 17.1, 2.9, 1.4 Hz, 1 H), 5.23–5.28 (m, 2 H), 4.59
(ddddd, J = 19.0, 12.9, 6.0, 1.3, 1.2 Hz, 2 H), 4.27 (d, J = 6.9 Hz, 1
H), 3.81 (d, J = 9.9 Hz, 1 H), 3.38–3.47 (m, 2 H), 3.43 (s, 3 H), 3.31
(dd, J = 6.8, 1.2 Hz, 1 H), 2.11 (s, 3 H), 1.78 (dq-like, J = 9.7,
6.9 Hz, 1 H), 1.57–1.72 (m, 1 H), 1.68 (d, J = 1.3 Hz, 3 H), 1.14 (d,
J = 6.9 Hz, 3 H), 0.94 (t, J = 8.0 Hz, 9 H), 0.90 (s, 9 H), 0.86 (s, 9
H), 0.85 (d, J = 6.5 Hz, 3 H), 0.84 (d, J = 6.9 Hz, 3 H), 0.49–0.66
(m, 6 H), 0.07 (s, 3 H), 0.06 (s, 3 H), 0.02 (s, 3 H), –0.05 (s, 3 H).
(E)-(2R,3S,4S,5R,6S,7R,10S,11S)-2,7-Bis{[tert-butyl(dimeth-
yl)silyl]oxy}-3-methoxy-11-[(4-methoxybenzyl)oxy]-4,6,8,10-
tetramethyl-5-[(triethylsilyl)oxy]dodec-8-enoic Acid Allyl Ester
A mixture of methyl ester 36 (230 mg, 0.279 mmol), bis[(dibu-
tyl)chlorotin] oxide (77.4 mg, 0.14 mmol) and allyl alcohol (5 mL)
was heated to 160 °C in a sealed tube under argon for 4 d. The ex-
cess allyl alcohol was evaporated and the residue was dissolved in
MTBE and filtered through celite. The solvent was evaporated
again, and the crude product was used in the next step without fur-
ther purification. Rf = 0.16 (n-hexane–MTBE, 19:1).
1H NMR (400 MHz, CDCl3): d = 7.27 (dm, J = 8.7 Hz, 2 H), 6.87
(dm, J = 8.7 Hz, 2 H), 5.92 (ddt, J = 17.0, 10.4, 6.1 Hz, 1 H), 5.36
(ddd, J = 17.0, 2.9, 1.5 Hz, 1 H), 5.26 (ddd, J = 10.4, 2.5, 1.1 Hz, 1
H), 5.18 (dd-like, J = 9.7, 1.0 Hz, 1 H), 4.59 (ddddd, J = 19.6, 13.0,
6.0, 1.3, 1.1 Hz, 2 H), 4.54 (d, J = 11.2 Hz, 1 H), 4.35 (d,
J = 11.2 Hz, 1 H), 4.28 (d, J = 6.7 Hz, 1 H), 3.80 (s, 3 H), 3.76–3.81
(m, 1 H), 3.46 (d, J = 8.8 Hz, 1 H), 3.41 (s, 3 H), 3.33 (dd, J = 6.7,
1.0 Hz, 1 H), 3.23 (dq, J = 7.9, 6.0 Hz, 1 H), 2.43–2.54 (m, 1 H),
1.81 (dq-like, J = 10.1, 6.6 Hz, 1 H), 1.57–1.70 (m, 1 H), 1.60 (d,
J = 1.3 Hz, 3 H), 1.16 (d, J = 6.0 Hz, 3 H), 1.04 (d, J = 6.7 Hz, 3 H),
0.95 (t, J = 8.0 Hz, 9 H), 0.90 (s, 9 H), 0.87 (s, 9 H), 0.85 (d,
J = 6.9 Hz, 6 H), 0.56–0.65 (m, 6 H), 0.08 (s, 3 H), 0.07 (s, 3 H),
0.03 (s, 3 H), –0.03 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 208.9, 171.6, 139.9, 131.5, 127.4,
119.3, 82.6, 80.7, 75.7, 74.1, 65.6, 60.6, 46.7, 39.7, 39.1, 28.2, 25.8,
25.7, 18.2 (2 C), 16.1, 11.6, 11.2, 9.9, 7.2, 6.1, –4.3, –4.9, –5.0, –5.1.
HRMS (ESI): m/z calcd for C38H76NaO7Si3 [M + Na]+: 751.4797;
found: 751.4781.
(E)-(2R,3S,4S,5R,6S,7R,10S,13S,14R,15R,16S)-2,7-Bis{[tert-bu-
tyl(dimethyl)silyl]oxy}-13-hydroxy-3-methoxy-17-[(4-methoxy-
benzyl)oxy]-4,6,8,10,14,16-hexamethyl-11-oxo-5,15-bis[(trieth-
ylsilyl)oxy]heptadec-8-enoic Acid Allyl Ester (47)
13C NMR (100 MHz, CDCl3): d = 171.7, 159.0, 136.8, 131.7, 131.6,
131.2, 129.0, 119.2, 113.7, 82.5, 81.2, 78.7, 75.5, 74.2, 70.5, 65.5,
60.5, 55.3, 39.3 (2C), 39.0, 25.8 (2C), 18.2 (2 C), 17.8, 16.7, 11.6,
11.2, 10.0, 7.2, 6.1, –4.2, –4.9, –5.0, –5.2.
A 25-mL flask was charged with powdered molecular sieves (4 Å,
257 mg) and heated while being evacuated. The flask was flushed
with argon and after cooling to r.t., (E)-(2R,3S,4S,5R,6S,7R,10S)-
2,7-bis{[tert-butyl(dimethyl)silyl]oxy}-3-methoxy-4,6,8,10-tetra-
methyl-11-oxo-5-[(triethylsilyl)oxy]dodec-8-enoic acid allyl ester
(46, 187 mg, 0.257 mmol) in THF (9 mL) was added. The mixture
was cooled to –78 °C and KHMDS (0.36 mmol, 0.72 mL, 0.5 M so-
lution in toluene) was added dropwise. Aldehyde 39 (0.310 mmol,
118 mg) was dissolved in THF (1 mL), dried with a small piece of
CaH2 for 1 h and then added to the reaction mixture. After 5 min,
the reaction was quenched by the addition of pH7 buffer solution
(10 mL). The aqueous layer was extracted with MTBE (3 × 20 mL).
The combined organic phase was washed with brine, dried over
(E)-(2R,3S,4S,5R,6S,7R,10S,11S)-2,7-Bis{[tert-butyl(dimeth-
yl)silyl]oxy}-11-hydroxy-3-methoxy-4,6,8,10-tetramethyl-5-
[(triethylsilyl)oxy]dodec-8-enoic Acid Allyl Ester
To a solution of (E)-(2R,3S,4S,5R,6S,7R,10S,11S)-2,7-bis{[tert-bu-
tyl(dimethyl)silyl]oxy}-3-methoxy-11-[(4-methoxybenzyl)oxy]-
4,6,8,10-tetramethyl-5-[(triethylsilyl)oxy]dodec-8-enoic acid allyl
ester (0.279 mmol; from the previous reaction) in CH2Cl2 (2.8 mL)
was added pH7 buffer soln (0.28 mL) followed by DDQ
(0.698 mmol, 158 mg). The resulting mixture was stirred for 1 h.
Sat. aq NaHCO3 solution was added. The organic layer was washed
Synthesis 2005, No. 7, 1183–1199 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of the C1–C17 Macrolactone of Tedanolide
1197
MgSO4 and evaporated. The crude product was purified by chroma-
tography (n-hexane–MTBE, 85:15) to afford the aldol product 47
(153 mg, 0.151 mmol, 59%) as a colorless oil. Rf = 0.2 (n-hexane–
MTBE, 85:15); [a]D23 = +21.6 (c 0.12, CHCl3).
(E)-(2R,3S,4S,5R,6S,7R,10S,13S,14R,15R,16S)-2,7,13-Tris-
{[tert-butyl(dimethyl)silyl]oxy}-17-hydroxy-3-methoxy-
4,6,8,10,14,16-hexamethyl-11-oxo-5,15-bis[(triethylsilyl)oxy]-
heptadec-8-enoic Acid Allyl Ester
To a solution of the previous PMB ether (118 mg, 96 mmol) in
CH2Cl2 (5 mL) was added pH7 buffer solution (0.5 mL) followed
by DDQ (54 mg, 0.24 mmol). The resulting mixture was stirred for
1 h. Sat. aq NaHCO3 solution (5 mL) was added. The organic layer
was diluted with CH2Cl2 (15 mL) and washed with sat. aq NaHCO3
solution (3 × 10 mL), dried over MgSO4 and evaporated. The crude
product was purified by chromatography (n-hexane–MTBE, 85:15)
to afford the corresponding hydroxyl ester (91 mg, 83 mmol, 86%)
1H NMR (400 MHz, CDCl3): d = 7.25 (dm, J = 8.7 Hz, 2 H), 6.87
(dm, J = 8.7 Hz, 2 H), 5.91 (ddt, J = 17.2, 10.4, 6.1 Hz, 1 H), 5.36
(ddd, J = 17.2, 2.9, 1.5 Hz, 1 H), 5.32–5.37 (dm, J = 1.3 Hz, 1 H),
5.26 (ddd, J = 10.4, 2.5, 1.1 Hz, 1 H), 4.59 (ddddd, J = 18.2, 12.8,
5.9, 1.2, 1.2 Hz, 2 H), 4.39–4.46 (m, 2 H), 4.25 (d, J = 6.8 Hz, 1 H),
4.11 (ddd, J = 7.4, 4.7, 3.1 Hz, 1 H), 3.84 (dd, J = 6.7, 2.5 Hz, 1 H),
3.79–3.83 (m, 1 H), 3.80 (s, 3 H), 3.38–3.44 (m, 3 H), 3.41 (s, 3 H),
3.32 (dd, J = 6.8, 1.3 Hz, 1 H), 3.23 (dd, J = 8.8, 6.9 Hz, 1 H), 2.53–
2.58 (m, 2 H), 2.08 (dq, J = 6.8, 2.5 Hz, 1 H), 1.73–1.79 (m, 1 H),
1.50–1.70 (m, 2 H), 1.64 (d, J = 1.1 Hz, 3 H), 1.15 (d, J = 6.9 Hz, 3
H), 0.95 (t, J = 7.9 Hz, 9 H), 0.94 (t, J = 8.0 Hz, 9 H), 0.90 (s, 9 H),
0.87 (s, 9 H), 0.83–0.91 (m, 12 H), 0.53–0.64 (m, 12 H), 0.07 (s, 3
H), 0.06 (s, 3 H), 0.03 (s, 3 H), –0.05 (s, 3 H), OH proton not visible.
13C NMR (100 MHz, CDCl3): d = 212.4, 171.6, 159.1, 139.6, 131.6,
130.7, 129.2 (2 C), 126.8, 119.3, 113.7, 82.5, 80.5, 77.2, 76.0, 74.9,
74.0, 73.4, 72.7 (2 C), 72.6, 68.1, 65.6, 60.7, 55.2, 46.4, 46.3, 41.4,
39.5, 39.4, 37.2, 36.7, 25.8 (2 C), 18.2 (2 C), 16.7, 11.7, 11.5, 11.2
(2C), 9.9, 9.8, 7.2, 7.1, 6.0, 5.5, –4.3, –4.9, –5.0, –5.1.
HRMS (ESI): m/z calcd for C59H112NaO11Si4 [M + Na]+: 1131.7179;
found: 1131.7181.
as
a
colorless oil. Rf = 0.34 (n-hexane–MTBE, 85:15);
[a]D23 = +51.5 (c 0.65, CHCl3).
1H NMR (400 MHz, CDCl3): d = 5.92 (ddt, J = 17.2, 10.4, 6.0 Hz,
1 H), 5.36 (ddd, J = 17.2, 2.9, 1.5 Hz, 1 H), 5.31 (dd-like, J = 9.5,
1.1 Hz, 1 H), 5.26 (ddd, J = 10.4, 2.5, 1.1 Hz, 1 H), 4.59 (ddddd,
J = 19.6, 12.8, 5.9, 1.3, 1.1 Hz, 2 H), 4.25 (d, J = 6.8 Hz, 1 H), 4.13
(qui-like, J = 3.8 Hz, 1 H), 3.83 (dd, J = 7.0, 3.3 Hz, 1 H), 3.81 (d,
J = 9.5 Hz, 1 H), 3.55 (d, J = 6.7 Hz, 1 H), 3.54 (d, J = 6.1 Hz, 1 H),
3.37–3.48 (m, 3 H), 3.43 (s, 3 H), 3.33 (dd, J = 6.8, 1.3 Hz, 1 H),
2.86 (dd, J = 15.3, 7.8 Hz, 1 H), 2.41 (dd, J = 15.3, 4.2 Hz, 1 H),
1.92 (dq-like, J = 6.5, 3.2 Hz, 1 H), 1.77 (dq-like, J = 9.4, 6.8 Hz, 1
H), 1.55–1.70 (m, 2 H), 1.66 (d, J = 1.1 Hz, 3 H), 1.13 (d,
J = 6.9 Hz, 3 H), 0.97 (t, J = 8.0 Hz, 9 H), 0.95 (t, J = 7.9 Hz, 9 H),
0.81–0.93 (m, 12 H), 0.90 (s, 9 H), 0.88 (s, 9 H), 0.86 (s, 9 H), 0.53–
0.66 (m, 12 H), 0.08 (s, 3 H), 0.07 (s, 6 H), 0.04 (s, 3 H), 0.03 (s, 3
H), –0.05 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 210.1 171.6, 139.4, 131.6, 126.7,
119.3, 82.5, 80.6, 76.0, 74.0, 73.9, 69.7, 66.1, 65.6, 60.7, 47.1, 47.0,
40.5, 39.5, 39.4, 39.1, 25.9, 25.8 (2 C), 18.2 (2 C), 18.0, 16.6, 11.7,
11.2, 11.0, 10.4, 9.8, 7.2, 7.1, 6.1, 5.6, –4.0, –4.2, –4.6, –4.9, –5.0,
–5.1.
HRMS (ESI): m/z calcd for C57H118NaO10Si5 [M + Na]+: 1125.7469;
found: 1125.7487.
(E)-(2R,3S,4S,5R,6S,7R,10S,13S,14R,15R,16S)-2,7,13-Tris-
{[tert-butyl(dimethyl)silyl]oxy}-3-methoxy-17-[(4-methoxyben-
zyl)oxy]-4,6,8,10,14,16-hexamethyl-11-oxo-5,15-bis[(triethylsi-
lyl)oxy]heptadec-8-enoic Acid Allyl Ester
To a solution of 47 (153 mg, 0.138 mmol) in CH2Cl2 (6.9 mL) was
added 2,6-lutidine (0.16 mL, 1.38 mmol) at 0 °C. TBSOTf
(0.16 mL, 0.69 mmol) was added dropwise. The mixture was stirred
for 30 min at 0 °C. The organic phase was washed with 1 M
NaHSO4 solution (3 × 10 mL) and dried over MgSO4. After remov-
al of the solvent, the crude product was purified by chromatography
(n-hexane–MTBE, 19:1) to afford the protected product (147 mg,
0.120 mmol, 87%) as colorless oil. Rf = 0.18 (n-hexane–MTBE,
19:1); [a]D23 = +37.4 (c 0.305, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.24 (dm, J = 8.8 Hz, 2 H), 6.85
(dm, J = 8.8 Hz, 2 H), 5.92 (ddt, J = 17.1, 10.4, 6.1 Hz, 1 H), 5.36
(ddd, J = 17.1, 2.9, 1.4 Hz, 1 H), 5.30–5.36 (dm, J = 1.3 Hz, 1 H),
5.26 (ddd, J = 10.4, 2.4, 1.1 Hz, 1 H), 4.59 (ddddd, J = 20.3, 13.0,
6.1, 1.3, 1.1 Hz, 2 H), 4.44 (d, J = 11.4 Hz, 1 H), 4.36 (d,
J = 11.4 Hz, 1 H), 4.25 (d, J = 6.8 Hz, 1 H), 4.18 (ddd, J = 8.4, 4.6,
1.6 Hz, 1 H), 3.81 (d, J = 9.4 Hz, 1 H), 3.80 (s, 3 H), 3.76 (dd,
J = 8.9, 1.6 Hz, 1 H), 3.29–3.44 (m, 3 H), 3.41 (s, 3 H), 3.21 (dd,
J = 8.5, 7.3 Hz, 1 H), 2.83 (dd, J = 15.9, 8.6 Hz, 1 H), 2.37 (dd,
J = 15.9, 4.6 Hz, 1 H), 2.09 (dq-like, J = 6.9, 1.4 Hz, 1 H), 1.72–
1.81 (m, 1 H), 1.50–1.70 (m, 3 H), 1.65 (d, J = 1.2 Hz, 3 H), 1.12
(d, J = 6.9 Hz, 3 H), 0.95 (t, J = 8.0 Hz, 9 H), 0.93 (t, J = 8.0 Hz, 9
H), 0.79–0.92 (m, 12 H), 0.90 (s, 9 H), 0.87 (s, 9 H), 0.82 (s, 9 H),
0.52–0.63 (m, 12 H), 0.08 (s, 3 H), 0.06 (s, 3 H), 0.03 (s, 3 H), 0.01
(s, 3 H), –0.01 (s, 3 H), –0.05 (s, 3 H).
(E)-(2R,3S,4S,5R,6S,7R,10S,13S,14R,15R,16S)-2,7,13-Tris-
{[tert-butyl(dimethyl)silyl]oxy}-17-hydroxy-3-methoxy-
4,6,8,10,14,16-hexamethyl-11-oxo-5,15-bis[(triethylsilyl)oxy]-
heptadec-8-enoic Acid
To a solution of the previous allyl ester (63.5 mg, 57.5 mmol) and
Pd(PPh3)2Cl2 (4.0 mg, 5.7 mmol) in CH2Cl2 (2.3 mL) was added
Bu3SnH (230 mmol, 62 ml). After 10 min, the reaction was judged
complete by TLC. The solvent was removed and the residue was pu-
rified by chromatography (gradient elution: n-hexane, then n-hex-
ane–MTBE, 2:1) to afford the seco-acid (59.3 mg, 55.8 mmol, 97%)
as a light-yellow foam. Rf = 0.16 (n-hexane–MTBE, 4:1)
1H NMR (400 MHz, CD3OD): d = 5.38 (br d, J = 9.0 Hz, 1 H),
4.21–4.28 (m, 2 H), 3.88 (d, J = 9.8 Hz, 1 H), 3.80 (dd, J = 8.4,
2.0 Hz, 1 H), 3.46–3.57 (m, 4 H), 3.45 (s, 3 H), 3.40 (dd, J = 10.0,
8.2 Hz, 1 H), 2.98 (dd, J = 16.2, 8.3 Hz, 1 H), 2.47 (dd, J = 16.2,
4.5 Hz, 1 H), 1.92–2.00 (m, 1 H), 1.79–1.89 (m, 2 H), 1.71 (br s, 3
H), 1.58–1.69 (m, 2 H), 1.16 (d, J = 6.8 Hz, 3 H), 0.99 (t,
J = 8.0 Hz, 18 H), 0.85–0.97 (m, 12 H), 0.94 (s, 9 H), 0.90 (2 s, 18
H), 0.60–0.69 (m, 12 H), 0.10 (s, 6 H), 0.10 (s, 3 H), 0.04 (s, 3 H),
0.04 (s, 3 H), –0.01 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 209.1, 171.6, 159.1, 139.2, 131.6,
130.8, 129.5, 126.8, 119.3, 113.6, 82.5, 80.6, 76.0, 74.0, 73.7, 73.5,
72.7, 68.8, 65.5, 60.7, 55.3, 47.3, 46.8, 41.0, 39.5, 39.4, 36.2, 25.9,
25.8 (2 C), 18.2 (2 C), 17.9, 16.7, 11.7, 11.2, 10.4, 10.1, 9.8, 7.2, 7.1,
6.0, 5.6, –4.1, –4.2, –4.7, –5.0, –4.9, –5.1.
HRMS (ESI): m/z calcd for C54H113O10Si5 [M – H]– 1061.7180;
found: 1061.7147.
HRMS (ESI): m/z calcd for C65H126NaO11Si5 [M + Na]+: 1245.8044;
found: 1245.8038.
(E)-(3S,4S,5S,6R,7S,8R,11S,14S,15R,16R,17S)-3,8,14-Tris{[tert-
butyl(dimethyl)silyl]oxy}-4-methoxy-5,7,9,11,15,17-hexameth-
yl-6,16-bis[(triethylsilyl)oxy]oxacyclooctadec-9-ene-2,12-dione
(48)
To a solution of PPh3 (109 mg, 0.42 mmol) in toluene (2.1 mL) was
added DEAD (67 mL, 0.42 mmol). The solution was stirred for 20
Synthesis 2005, No. 7, 1183–1199 © Thieme Stuttgart · New York

1198
J. Hassfeld et al.
FEATURE ARTICLE
min and then a solution of the previous seco-acid (45 mg, 42 mmol)
in toluene (2.1 mL) was added. After a few minutes, the clear solu-
tion became turbid and no acid was detectable by TLC. The solvent
was evaporated and the crude product was purified by chromatog-
raphy (n-hexane–MTBE, 19:1) to afford macrolactone 48 (31.7 mg,
30.2 mmol, 72%) as inseparable mixture of two diastereomers (4:1).
Rf = 0.52 (n-hexane–MTBE, 9:1).
1H NMR (400 MHz, toluene-d8, 360 K, major isomer): d = 5.49 (dq,
J = 9.2, 1.3 Hz, 1 H), 4.44 (d, J = 3.4 Hz, 1 H), 4.34 (ddq, J = 7.0,
5.8, 3.9 Hz, 1 H), 4.15 (dd, J = 11.2, 7.5 Hz, 1 H), 4.07 (dd,
J = 11.2, 3.4 Hz, 1 H), 4.01 (d, J = 10.0 Hz, 1 H), 3.88 (t-like,
J = 4.6 Hz, 1 H), 3.80 (dd, J = 4.3, 1.6 Hz, 1 H), 3.67 (dd, J = 6.6,
3.4 Hz, 1 H), 3.47 (s, 3 H), 3.39 (dq, J = 9.1, 6.9 Hz, 1 H), 2.84 (dd,
J = 17.1, 3.9 Hz, 1 H), 2.76 (dd, J = 17.1, 5.8 Hz, 1 H), 2.23 (ddq,
J = 11.0, 7.4, 3.6 Hz, 1 H), 1.99–2.12 (m, 3 H), 1.76 (d-like, J = 1.3
Hz, 3 H), 1.29 (d, J = 6.9 Hz, 3 H), 1.23 (d, J = 6.8 Hz, 3 H), 1.17
(d, J = 7.2 Hz, 3 H), 1.12 (t, J = 8.0 Hz, 9 H), 1.08 (d, J = 6.9 Hz, 3
H), 1.08 (t, J = 8.0 Hz, 9 H), 1.06 (s, 9 H), 1.01 (d, J = 6.7 Hz, 3 H),
1.00 (s, 9 H), 0.99 (s, 9 H), 0.70–0.83 (m, 12 H), 0.30 (s, 3 H), 0.26
(s, 3 H), 0.23 (s, 3 H), 0.21 (s, 3 H), 0.17 (s, 3 H), 0.09 (s, 3 H).
(11) (a) Bode, J. W.; Carreira, E. M. J. Org. Chem. 2001, 66,
6410. (b) Bode, J. W.; Carreira, E. M. Angew. Chem. Int. Ed.
2001, 40, 2082; Angew. Chem. 2001, 113, 2128. (c)Brown,
A. V.; Taylor, R. E. Chemtracts 2003, 16, 254.
(12) Hoffmann, H. M. R.; Hartung, I. V. Angew. Chem. Int. Ed.
2004, 43, 1934; Angew. Chem. 2004, 116, 1968.
(13) Jung, M. E.; Hoffmann, B.; Rausch, B.; Contreras, J.-M.
Org. Lett. 2003, 5, 3159.
(14) First review covering the vinylogous principle: (a) Fuson,
R. C. Chem. Rev. 1935, 16, 1. For excellent reviews
covering the development until 2000, see: (b) Mahrwald, R.
Chem. Rev. 1999, 99, 1095. (c) Casiraghi, G.; Zanardi, F.;
Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929.
(d) Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Chem.
Soc. Rev. 2000, 29, 109. For vinylogous Mannich reactions
see: (e) Arend, M.; Westermann, B.; Risch, N. Angew.
Chem.; 1998, 110, 1096; Angew. Chem. Int. Ed.; 1998, 37:
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For a review covering the vinylogous aldol reaction between
2000 and 2003 see: (g) Kalesse, M. In Topics in Current
Chemistry, Vol. 244; Mulzer, J. H., Ed.; Springer Verlag:
Heidelberg, 2004, 43.
13C NMR (100 MHz, CDCl3): d = 209.1, 172.3, 141.2, 126.5, 83.1,
81.3, 74.7, 73.4, 72.7, 71.4, 67.3, 60.2, 46.8, 46.0, 42.9 (2C), 41.1,
36.9, 26.2, 26.0, 25.8, 18.6, 18.3, 18.2, 15.5, 12.9, 12.8, 11.7, 11.4,
10.7, 7.2, 7.1, 5.8, 5.7, –4.2 (3C), –4.3, –4.9 (2C).
HRMS (ESI): m/z calcd for C54H112NaO9Si5 [M + Na]+: 1067.7055;
found: 1067.7177.
(15) For catalytic asymmetric vinylogous Mukaiyama aldol
reactions via enolate activation, see: (a) Bluet, G.;
Campagne, J.-M. Tetrahedron Lett. 1999, 40, 221.
(b) Bluet, G.; Campagne, J.-M. J. Org. Chem. 2001, 66,
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125, 7800. (b) Denmark, S. E.; Heemstra, J. R. Jr. Synlett
2004, 2411.
Acknowledgment
The Deutsche Forschungsgemeinschaft (DFG) is gratefully ack-
nowledged for financial support.
(18) For pioneering contributions towards the catalytic
asymmetric vinylogous aldol reaction, see: (a) Sato, M.;
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Synthesis 2005, No. 7, 1183–1199 © Thieme Stuttgart · New York

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(43) (a) Baumhof, P.; Mazitschek, R.; Giannis, A. Angew. Chem.
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(44) De la Torre, B. G.; Torres, J. L.; Bardaji, E.; Clapés, P.;
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(l) Matsushima, T.; Nakajima, N.; Zheng, B.-Z.; Yonemitsu,
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(45) The C13 stereochemical assignment is based on analysis of
the C12 1H NMR signals according to Ref. 39.
Synthesis 2005, No. 7, 1183–1199 © Thieme Stuttgart · New York