Synthesis and biological evaluation of (-)-dictyostatin and stereoisomers

Article abstract of DOI:10.1016/j.tet.2007.05.033

Total syntheses of (-)-dictyostatin, 6,16-bis-epi-dictyostatin, 6,14,19-tris-epi-dictyostatin, and a number of other isomers and analogs are reported. Three main fragments-top, middle, and bottom-were first assembled and then joined by olefination or anio

Full text of DOI:10.1016/j.tet.2007.05.033

Tetrahedron 63 (2007) 8537–8562
Synthesis and biological evaluation of (L)-dictyostatin
and stereoisomers
a
Youseung Shin, Jean-Hugues Fournier, Arndt Bruckner, Charitha Madiraju,
a
a
b
€
Raghavan Balachandran,b Brianne S. Raccor,a Michael C. Edler,d Ernest Hamel,d
Rachel P. Sikorski,c Andreas Vogt,c Billy W. Daya,b, and Dennis P. Curran
*
a,
*
aDepartment of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
bDepartment of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
cDepartment of Pharmacology, University of Pittsburgh, Pittsburgh, PA 15261, USA
dToxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis,
National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702, USA
Received 2 April 2007; revised 1 May 2007; accepted 2 May 2007
Available online 13 May 2007
Dedicated to Professor Hisashi Yamamoto on his receipt of the Tetrahedron Prize
Abstract—Total syntheses of (ꢀ)-dictyostatin, 6,16-bis-epi-dictyostatin, 6,14,19-tris-epi-dictyostatin, and a number of other isomers and an-
alogs are reported. Three main fragments—top, middle, and bottom—were first assembled and then joined by olefination or anionic addition
reactions. After appending the two dienes at either end of the molecule, macrolactonization and deprotection completed the syntheses. The
work proves both the relative and absolute configurations of (ꢀ)-dictyostatin. The compounds were evaluated by cell-based measurements of
increased microtubule mass and antiproliferative activity, and in vitro tubulin polymerization assays as well as competitive assays with pac-
litaxel for its binding site on microtubules. These assays showed dictyostatin to be the most potent of the agents and further showed that the
structural alterations caused from 20- to >1000-fold decreases in activity.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
26
24
14
OH
OH
16
21
19
HO
Microtubule stabilization by small molecule natural prod-
ucts and analogs1 is a clinically proven chemotherapeutic
approach for the treatment of solid tumors, and microtubule
stabilizers exhibit a diverse assortment of molecular scaf-
folds. Dictyostatin and discodermolide (Fig. 1), the taxanes
paclitaxel and docetaxel, the epothilones, the sarcodictyins
and eleutherobin, and the ketosteroids 2-ethoxy-7-keto-
17b-estradiol and the taccalonolides all bind with varying
affinities to the paclitaxel binding site on b-tubulin within
microtubules.2–7 The tau neuronal protein binds onto
microtubules in the vicinity of the paclitaxel site, and this
site is well-described due to high resolution cryoelectron
microscopic analyses of zinc-induced sheets of tubulin
polymer stabilized by taxanes or epothilones.8,9 Drugs
binding to the site interact with amino acid residues on the
M-loop (for example, Phe270, Thr274, and Arg276) and
the H7 alpha helix (for example, Ala231 and His227) of
b-tubulin.
HO
O
O
O
O
1
9
7
OH NH2
6
1
OH OH
OH
O
O
dictyostatin, 1
discodermolide, 2
confirmed structure, 2004
hypothetical cyclization (see arrow)
gives 22-membered ring
OH
OH
16
19
14
HO
HO
O
O
O
O
6
OH OH
OH
suggested partial structure 4,
1995
a "dictyo/disco" hybrid 3,
2002
C6,14 different from 2
C16,19 unassigned
Keywords: Microtubule; Macrolactone; Paclitaxel; Discodermolide.
* Corresponding authors. Tel.: +1 412 624 8240; fax: +1 412 624 9861
(D.P.C); tel.: +1 412 648 9706; fax: +1 412 383 5298 (B.W.D); e-mail
addresses: bday@pitt.edu; curran@pitt.edu
Figure 1. Structures of dictyostatin 1, discodermolide 2, and related
compounds.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.033

8538
Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
Interest in the dictyostatin family of microtubule-stabilizing
agents has increased significantly over the last several years.
Pettit initially isolated dictyostatin 1 from a marine sponge,
suggested the correct two-dimensional structure (constitu-
tion), and showed that the compound had potent activity
against cancer cells.10 Subsequently, Wright and co-workers
isolated 1 from a different sponge species and showed that the
compound displays potent microtubule-stabilizing actions.11
by this work, and this was used for the detailed biological
characterization of this molecule. The results of these studies
have fully validated the high level of interest in dictyostatin.2
2. Results
2.1. Chemistry
Dictyostatin is a structural cousin of the important microtu-
bule-stabilizing agent discodermolide 2.12 Dictyostatin’s
26-carbon backbone is two carbons longer than discodermo-
lide’s, and it is joined by a 22-membered macrolactone
formed between the carboxyl group on C1 and the alcohol
on C21. (The longer chain length means that carbon numbers
of dictyostatin are two higher than the comparable carbons
of discodermolide.) Dictyostatin also differs from discoder-
molide by possessing a Z/E diene (C2–C5) instead of a g-
lactone, and it lacks a double bond at C15,16 and a methyl
group at C18. Nonetheless, 10 of dictyostatin’s 11 stereo-
centers are also present in the discodermolide structure.
2.1.1. Synthesis of 6,16-bis-epi-dictyostatin 5. Though dif-
fering in relative configuration from Pettit’s structure 4 in the
middle fragment, we initially decided to make compound 5
because a number of key early intermediates were already in
hand. We selected the (R) configuration at C16 arbitrarily,
and though this proved to be wrong, the molecule—6,16-
bis-epi-dictyostatin—ultimately turned out to be structurally
much closer to dictyostatin than we had initially thought.
The strategy for the synthesis of this molecule is summarized
at a high level in Figure 2. Key targeted bonds were C10,11
(Wittig reaction), C17,18 (Horner–Wadsworth–Emmons re-
action), and O21–C1 (macrolactonization). This divided the
molecule into three approximately equal portions, which we
call top, middle, and bottom. The top and bottom fragments
were further subjected to secondary disconnections to excise
the two dienes. The removal of these two potentially sensi-
tive groups reduced the convergency, but it also expanded
The three-dimensional structure (configuration) of dictyos-
tatin was uncertain for almost a decade. As an outgrowth
of our interest in discodermolide analogs,13 we made ‘dic-
tyostatin/discodermolide’ hybrids like 3 in 2002,14 and these
compounds exhibited high biological activities in both tubu-
lin and cell assays. An underlying tenet of this work was that
a hypothetical cyclization of the carbamate nitrogen of dis-
codermolide 2 onto its lactone carbonyl (C1) would provide
a 22-membered ring, the same size as the macrocycle of dic-
tyostatin 1. At this juncture, the lack of knowledge of the
complete structure of dictyostatin and the tiny quantities
available from isolation were serious impediments to further
medicinal chemistry research. With a solid foundation in
place from the synthesis of compound 3 and related mole-
cules, we decided to address the dictyostatin structure and
supply problems by total synthesis.
top
middle
primary disconnections,
in red
OH
16
HO
21
C10,C11, olefination
C17,C18, olefination
O
O
C1,O21, macrolatonization
1
6
10
secondary disconnections,
in black
OH OH
In a 1995 patent, Pettit and co-workers suggested a partial
configuration for dictyostatin,15 and we selected the absolute
configuration depicted for compound 4 because this enantio-
mer is more closely related to discodermolide. In 4, seven
stereocenters have the same configurations as discodermo-
lide, two are different (C6 and C14), and two are not assigned
(C16 and C19). In 2004, Paterson and co-workers suggested
structure 1 for dictyostatin based on detailed NMR studies;16
in addition to assigning the two missing stereocenters, the
configurations of two other centers were inverted. Structure
1 was promptly proved by a pair of total syntheses that ap-
peared in simultaneous communications from Paterson’s
group17 and ours,18 and recently Phillips and Ramachandran
have also reported the total syntheses of 1.19,20
C2,C3; C23,C24, olefinations
bottom
5
6,16-bis-epi-dictyostatin
Top Fragment
PMP
PMP
a
O
O
O
O
O
O
O
OMe
P(OMe)
2
N
7
6
(a) (MeO)2P(O)CH3, BuLi, –78 °C, 85%
Middle Fragment
In this paper, we provide details of our total synthesis of dic-
tyostatin 1. Along the way, we made several stereoisomers of
the natural product as we drew gradually closer to the correct
structure. All of these compounds have been characterized
by a battery of biological assays. These results, combined
with the additional results for new analogs described else-
where21–23 and with the known SAR for discodermolide,
provide for the first time a good outline of the SAR of dic-
tyostatin. Over 5 mg of synthetic dictyostatin was provided
PMP
known compound,
made in 8 steps from
Roche ester
O
O
IPh P
3
8
Figure 2. Strategy for the synthesis of 5 with top and middle fragments.

Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
8539
options for fragment coupling based on alkene chemistry.
Since speed to the target was more important than efficiency
at this stage of the work, we deemed this a worthwhile
trade off.
acetonide protecting group was removed with Dowex-
H+resin,27 and the resulting triol was triply protected with
TBS groups to give 12 in 81% yield. Selective deprotection
of the primary TBS group was achieved in 65% yield with
HF/pyridine, and the resulting alcohol 13 was oxidized with
the Dess–Martin reagent to give aldehyde 14 in 93% yield.
The selected top and middle fragments are also shown in
Figure 2. Like all the work described herein, the early stages
of the synthesis of the top and middle fragments were bor-
rowed liberally from related work in the discodermolide
field. Weinreb amide 6 is readily available in five steps
from (2S)-3-hydroxy-2-methylpropionic acid methyl ester
(Roche ester),24 and this was parlayed into top fragment 7
in 85% yield by reactionwithlithiomethyltrimethylphospho-
nate. This fragment was used for all of the compounds in
this paper. Middle fragment 8 was borrowed from our prior
work13 because it provides reliable results in Wittig olefina-
tions, and it was readily made in eight steps and 33% overall
yield from the Roche ester. These reactions were readily
conducted on multi-gram scale, and the efficiency of the
plan was increased because the first few steps of the synthe-
ses of 7 and 8 were the same.
The fragment couplings and associated steps form the inter-
mediate stage of the synthesis, as summarized in Scheme 2.
Wittig coupling of 14 was conducted at high concentration
(1 M) of the phosphonium salt 8 to give 15 in 75% yield.
The formation of the (Z)-alkene at C10–C11 was confirmed
by the 10.8 Hz coupling constant between the adjacent vinyl
protons. Hydrolysis of the ester functionality in 15 with 1 N
KOH, activated ester formation with ethyl chloroformate,
and in situ NaBH4 reduction gave the allylic alcohol 16 in
61% yield. Alcohol 16 was protected by a trityl group to
give 17 in 99% yield. The PMB acetal in 17 was cleaved
with DIBALH to give the primary alcohol 18 in 74% yield,
which was oxidized with the Dess–Martin reagent and then
subjected to HWE reaction to give ester 19 in 93% yield.28a,b
The a,b-unsaturated alkene in 19 was reduced selectively
with nickel boride to give 20 in 97% yield, and this was sub-
sequently hydrolyzed and coupled with the Evans oxazolidi-
none by forming the activated ester with pivaloyl chloride to
give 21 in 83% yield. Asymmetric methylation gave 22
stereoselectively in 62% yield.28c The optimal conditions
entailed addition of 3 equiv of methyl iodide dropwise over
30 min, and the temperature was kept at ꢀ78 ꢁC for 4 h to
minimize the formation of the a-dimethylated byproduct.
The synthesis of the bottom aldehyde fragment 14 is summa-
rized in Scheme 1. (L)-Malic acid was esterified and selec-
tively reduced with borane dimethylsulfide and NaBH4 in
97% yield to a diol, which was protected as the acetonide
9 with acetone/p-TsOH in 86% yield.25 The ester in 9 was
reduced to an aldehyde with DIBALH in 67% yield, and
this was subjected to an Evans syn-aldol reaction to give
10 in 98% yield as a single diastereomer.26 The aldol product
10 was reduced to an aldehyde by using Red-Al, and this was
homologated by a Horner–Wadsworth–Emmons (HWE) re-
action to the a,b-unsaturated ester 11 in 52% yield. The
Removal of the Evans auxiliary with LiBH4 produced the
primary alcohol 23 in 87% yield (Scheme 2). This was oxi-
dized by the Dess–Martin protocol to the aldehyde, which
was subjected to an HWE reaction with top fragment phos-
phonate 7 to give the coupled product 24 in 90% yield. The
a,b-unsaturated alkene was reduced with nickel boride in
89% yield to give 25 (over-reduction of the C4–C5 alkene
was also observed as a minor side reaction). Because the
configuration of dictyostatin at C19 was unassigned, the
ketone in 25 was reduced unselectively with NaBH4 to
give a 2.8:1 mixture of diastereomers, which were separated
by silica gel column chromatography. The configuration of
the major product 26 was assigned as b by conversion of
a small sample to a cyclic PMP acetal between O19 and
O21, followed by NOE studies.29 The secondary hydroxy
group of the major b diastereomer 26 was then protected
with a TBS group to give 27 in 94% yield.
O
OEt
b
a
OH
O
HO
O
O
OH
O
L-malic acid
9
Bn
O
OEt
N
c
d
O
O
O
OH
O
O
OH
10
O
O
11
OEt
OEt
e
HO
TBSO
The final stages of the synthesis of 5 included elaboration of
the two dienes and macrocyclization, and these are summa-
rized in Scheme 3. The PMB acetal of 27 was opened with
DIBALH to give 28 in 97% yield. Primary alcohol 28 was
oxidized to an aldehyde and then submitted to a Nozaki–
Hiyama reaction30 with 29 to provide an anti b-hydroxy
silane. This crude silane was directly subjected to Peterson-
type syn-elimination with excess NaH (20 equiv) in THF
to install the (Z)-diene moiety, giving 30 in 72% yield. The
trityl group was removed by B-chlorocatecholborane31 to
give 31 in 61% yield. This moderate yield was due to the par-
tial PMB deprotection at C21 and due to the difficulty in
chromatographic purification because the product 31 had
similar retention characteristics to the TrOH byproduct.
TBSO
OTBS
O
TBSO
OTBS
O
12
13
O
OEt
f
H
TBSO
OTBS
O
14
Scheme 1. Synthesis of bottom fragment 14. (a) (i) EtOH, SOCl2, 99%; (ii)
BH3$SMe2, NaBH4, THF, 97%; (iii) acetone, p-TsOH, 86%. (b) (i) DIBAL,
ꢀ78 ꢁC, 67%; (ii) n-Bu2BOTf, DIPEA, Evans oxazolidinone, 98%. (c) (i)
Red-Al, THF; (ii) triethylphosphonoacetate, KO-t-Bu, 52% (two steps).
(d) (i) Dowex-H+; (ii) TBSOTf, 2,6-lutidine, 81% (two steps). (e) HF/pyr-
idine, pyridine, THF, 65%. (f) Dess–Martin, 93%.

8540
Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
PMP
OH
PMP
O
O
O
O
PMBO
a
b
c
d
8
+
14
OR
OTr
CO Et
2
TBSO
OEt
OTBS
15
TBSO
OTBS
TBSO
OTBS
16, R = H
17, R =Tr
18
O
O
O
O
O
O
OEt
O
N
O
N
Bn
Bn
g
e
f
PMBO
PMBO
PMBO
PMBO
OTr
OTr
OTr
OTr
TBSO
OTBS
19
TBSO
OTBS
TBSO
OTBS
TBSO
OTBS
20
21
22
2.8:1
/
OH
O
O
O
O
OR
19
PMBO
PMBO
PMBO
PMBO
j
h
i
k
O
O
O
O
4
PMP
OTr
PMP
OTr
PMP
OTr
TBSO
OTBS
TBSO
OTBS 5
TBSO
OTBS
TBSO
OTBS
OTr
23
24
25
26 R = H
27 R = TBS
Scheme 2. Intermediate stage of 6,16-bis-epi-dictyostatin synthesis. (a) NaHDMS, THF, 75%. (b) (i) KOH, EtOH; (ii) EtOCOCl, Et3N then NaBH4, 61% (two
steps). (c) (i) TrCl, pyridine, DMAP, 99%; (ii) DIBAL–H, 74%. (d) (i) Dess–Martin; (ii) triethylphosphonoacetate, KO-t-Bu, 93% (two steps). (e) NiCl2$H2O,
NaBH4, MeOH, 97%. (f) (i) KOH, EtOH; (ii) PivCl, Et3N, LiCl, Evans oxazolidinone, 83%. (g) NaHDMS, MeI, 62%. (h) LiBH4, MeOH, THF, 87%. (i) (i)
Dess–Martin; (ii) Ba(OH)2, THF/H2O, 7, 90% (two steps). (j) NiCl2, NaBH4, MeOH/CH2Cl2, 89%. (k) (i) NaBH4, MeOH, 96%. (ii) TBSOTf, 2,6-lutidine, 94%.
The resulting allylic alcohol 31 was oxidized with the Dess–
Martin reagent to an aldehyde, which was subjected to
a Still–Gennari reaction32 to give the (E,Z) doubly unsatu-
rated ester 32 in 82% yield. DDQ deprotection of the two
PMB groups at C13 and C21 gave diol 33 in 95% yield.
Use of excess DDQ (more than 3 equiv) resulted in the for-
mation of a Diels–Alder adduct with the C2–C5 diene por-
tion, lowering the yield dramatically. Hydrolysis of the
methyl ester to acid 34 was achieved by using 1 N KOH in
EtOH, setting the stage for the macrocyclization. Finally,
TBS
O
TBS
O
TBS
O
OTBS
PMBO
PMBO
PMBO
PMBO
f
g
h
i
27
PMBO
OH
OTr
PMBO
PMBO
PMBO
Br
CO Me
2
OTr
OH
TMS
29
TBSO
OTBS
TBSO
OTBS
TBSO
OTBS
31
TBSO
OTBS
32
28
30
TBS
O
TBS
O
TBS
O
OH
21
HO
HO
HO
HO
j
k
m
l
O
1
O
HO
HO
O
O
CO Me
CO H
2
2
OH OH
TBSO
OTBS
TBSO
OTBS
TBSO
OTBS
35
33
34
5
Scheme 3. Final stages of the synthesis of 6,16-bis-epi-dictyostatin. (f) DIBAL–H, 97%. (g) (i) Dess–Martin; (ii) CrCl2, THF, 29; (iii) NaH, THF, 72% (three
steps). (h) B-Chlorocatecholborane, CH2Cl2, ꢀ78 ꢁC, 61%. (i) (i) Dess–Martin; (ii) Still–Gennari, 82% (two steps). (j) DDQ, 95%. (k) 1 N KOH, EtOH, 60 ꢁC.
(l) Yamaguchi, 49% (two steps). (m) 3 N HCl/MeOH, 73%.

Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
8541
reaction again caused some isomerization, but this time
both alkene stereoisomers were isolated.
19
OH
O
16
14
9
HO
We initially attempted to couple the middle and bottom frag-
ments by the same strategy that was used to make 5, but the
C14 epimer of Wittig reagent 8 (not shown) was a white
foam that did not well behave in the Wittig reaction. We
thus reformulated a strategy, summarized in Figure 3, that
used the same top fragment 7 as before, but formed the
C9,C10 bond (rather than the C10,C11 bond) in an alkyne
addition. Middle fragment 38 and bottom fragment 39
were selected as key intermediates in this route, and their
syntheses are shown in Schemes 4 and 5, respectively.
O
6
10
OH OH
36, 6,14-bis-epi-dictyostatin, C19-β
37, 6,14,19-tri-epi-dictyostatin, C19-α
OTBS
OMe
N
OTr
PMBO
Me
O
OTBS
Synthesis of the middle fragment started with preparation of
the Evans anti-aldol product 41,35 which was obtained with
13:1 diastereoselectivity in 71% yield (Scheme 4). The aux-
iliary was then cleaved with LiBH4, and the resulting diol was
protected as the PMB acetal using p-anisaldehyde with CSA
to give 42 in 65% yield in two steps. Hydroboration of alkene
42 with dicyclohexylborane (BH3$SMe2, cyclohexene) af-
forded the alcohol 43 with the desired anti,anti configuration
in 76% yield. This alcohol was converted to the iodide 44 in
98% yield. An attempt to alkylate 44 with Evans auxiliary
was unsuccessful; however, Myers asymmetric alkylation36
with 45 gave the alkylated product 46 in 88% yield as a single
isomer. Removal of the Myers auxiliary with BH3$NH3 gave
alcohol 47 in 83% yield. TBS protection of the resulting pri-
mary alcohol gave 48 in 94% yield. DIBALH cleavage of the
PMB acetal gave the product 49 in 84% yield. Oxidation to
the aldehyde followed by Corey–Fuchs reaction37 gave the
alkyne 38 in 86% yield in three steps.
middle fragment, 38
bottom fragment, 39
Figure 3. Strategy for the synthesis of 6,14-bis-epi-dictyostatin.
Yamaguchi lactonization33 gave the macrolactone 35 in 49%
yield. TBS deprotection with 3 N HCl in MeOH/THF gave
the desired product C6,C16-bis-epi-dictyostatin 5 (73%),
whose structure was confirmed by H–1H COSY, HMQC,
1
HMBC, and other NMR experiments. In particular, a key
crosspeak between H21 and C1 in the HMBC spectrum con-
firmed the 22-membered lactone.
2.1.2. Synthesis of 6,14-bis-epi-dictyostatin. We next de-
cided to make compounds 36 and 37 (Fig. 3), which are
two of the four possible diastereomers from the structure
proposed by Pettit. These are related to 5, but have the 14S
(C13,C14 anti) configuration. Based on some simple com-
putational modeling,34 we also decided to adjust the config-
uration at C16 from R (a) to S (b). In the end, the two
inversions were a wash, one moving us closer to dictyostatin
(C16) and the other further away (C14), providing a target 36
that ultimately proved to be 6,14-bis-epi-dictyostatin. Unex-
pectedly, this target was not accessed in pure form due to the
isomerization of the C2,C3 alkene during the macrolactoni-
zation (see below). Also, to get more information about the
configuration of the alcohol at C19, we decided to take the a-
epimer at this center through the synthesis, and this provided
6,14,19-tris-epi-dictyostatin 37. The macrolactonization
To make the bottom fragment 39, 1,3-propanediol was
mono-protected to give 50 (Scheme 5), which was oxidized
and subjected to Evans syn-aldol reaction to give 51 in 65%
yield in two steps. Reduction with LiBH4 gave alcohol 52
(87%), which was oxidized to the aldehyde with the Dess–
Martin reagent. Subsequent treatment of the aldehyde with
triethyl phosphonoacetate gave the Wadsworth–Horner–
Emmons product 53 in 69% in two steps. The ester 53 was
reduced with DIBALH to give allylic alcohol 54 in 97%
yield, and 54 was protected with a trityl group in 94%
yield. The primary TBS group of 55 was deprotected by
PMP
PMP
O
PMP
O
O
O
O
OH
O
O
c
e
b
d
a
O
O
O
O
+
O
O
N
N
N
OH
I
OH
Bn
Bn
40
41
42
43
44
45
PMP
O
PMP
O
OPMB
OH OPMB
O
O
f, g
h
i
O
OTBS
OTBS
N
OR
OH
46
47, R = H
49
38
48, R = TBS
Scheme 4. Synthesis of middle fragment 38. (a) MgCl2, NaSbF6, Et3N, TMSCl, methacrolein, MeOH, TFA, 71%, dr 13:1. (b) (i) LiBH4, MeOH; (ii) p-anis-
aldehyde, CSA, 65% in two steps. (c) BH3$SMe2, cyclohexene then NaOH, H2O2, 76%. (d) PPh3, I2, imidazole, 98%. (e) LDA, LiCl, 36 h, 88%. (f) BH3$NH3,
LDA, 83%. (g) TBSCl, imidazole, DMAP, 94%. (h) DIBAL, 84%. (i) (i) Py$SO3, Et3N, DMSO/CH2Cl2; (ii) PPh3, CBr4, CH2Cl2; (iii) n-BuLi, THF, 86% in
three steps.

8542
Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
Bn
OH
a
c
d
b
OH
OH
O
CO Et
2
N
TBSO
TBSO
OTBS
TBSO
OTBS
TBSO
OTBS
TBSO
OTBS O
51
53
54
52
50
OMe
N
e
f
g
h
OTr
OTr
HO
OTr
OTr
Me
TBSO
OTBS
HO
OTBS
O
OTBS
57
O
OTBS
39
55
56
Scheme 5. Synthesis of the bottom fragment 39. (a) (i) Py$SO3, Et3N, DMSO/CH2Cl2; (ii) n-Bu2OTf, DIPEA, 65% in two steps. (b) LiBH4, MeOH, THF, 87%.
(c) (i) Dess–Martin; (ii) triethyl phosphonoacetate, NaH, 69% in two steps. (d) DIBAL, 97%. (e) TrCl, DMAP, 94%. (f) HF/Py, 82%. (g) (i) Dess–Martin; (ii)
NaClO2, NaH2PO4, isobutene, THF/H2O. (h) MeNH(OMe)$HCl, DCC, CH2Cl2, 81% in three steps.
HF/pyridine in pyridine to give 56 in 82% yield. This was
oxidized to the aldehyde and then to the acid 57. Finally,
coupling with Weinreb’s salt by using DCC38 gave the
bottom fragment 39 in 81% in three steps.
Noyori product 59 was carefully reduced by using the
Lindlar catalyst41 for 1 h to give the cis-alkene 60 in 90%
yield. When the reaction time was extended to 1 day, over-
reduction of all multiple bonds occurred. The C7,C9 anti
configuration of 60 was confirmed by 13C NMR analysis
of the derived acetonide.42
The intermediate stage of this synthesis is shown in Scheme
6. Coupling of the middle fragment 38 and bottom fragment
39 parallels related work of Marshall and Jacobsen.39 The
anion of alkyne 38 was added to bottom fragment 39 to
give alkynyl ketone 58 in 98% yield. When 58 was subjected
to Noyori reduction conditions,40 a single C9a isomer 59
was formed in 87% yield. About 20 mol % of the (S,S)-
Noyori catalyst was required for rapid, clean reaction. The
The C9 hydroxy group in 60 was protected with a TBS group
to give 61 in quantitative yield. The PMB group was then re-
moved with DDQ to give 62 in 84% yield. The resulting sec-
ondary hydroxy group was protected again by a TBS group,
giving 63 in 94% yield. Selective deprotection of the primary
TBS group was accomplished in 66% yield by treatment
OTBS
OTBS
OTBS
OTBS
PMBO
PMBO
PMBO
PMBO
d
c
a
b
38 + 39
9
OTr
OTr
OTr
OTr
O
OTBS
58
OH OTBS
OH OTBS
TBSO
OTBS
59
60
61
OTBS
OTBS
OH
O
O
HO
TBSO
TBSO
TBSO
g
e
h
f
O
OTr
OTr
OTr
PMP
TBSO
OTBS
TBSO
OTBS
TBSO
OTBS
TBSO
OTBS
OTr
62
63
64
65
1.7/1
/
O
O
OTBS
OH
O
19
TBSO
TBSO
TBSO
TBSO
j
i
k
O
O
O
O
PMP
OTr
PMP
PMP
OTr
TBSO
OTBS
66
TBSO
OTBS
68
OTr
OTBS
67
Scheme 6. Intermediate stages of the synthesis of 6,14-bis-epi-dictyostatin. (a) n-BuLi, THF, 98%. (b) Noyori cat. (20 mol %), i-PrOH, 87%. (c) Lindlar cat., H2,
90%. (d) TBSOTf, 2,6-lutidine, 100%. (e) DDQ, 84%. (f) TBSOTf, 94%. (g) HF/pyridine, 0 ꢁC, 2 days, 66%. (h) (i) Dess–Martin; (ii) 7, Ba(OH)2, THF/H2O,
78% (two steps). (i) NiCl2, NaBH4, MeOH/CH2Cl2, 76%. (j) NaBH4, MeOH, 96%. (k) TBSOTf, 2,6-lutidine, 86%.

Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
8543
with HF/pyridine complex in buffered pyridine at 0 ꢁC for
2 days to give 64 along with some unselectively deprotected
byproducts.
was clearly revealed by a 15.5 Hz coupling constant between
H2 and H3 in 75b, whereas the (2,3Z) dictyostatins 1 and 5
have a coupling constant of about 11 Hz. The formation of
this geometric isomer might be due to a reversible Michael
type addition of 4-DMAP to the activated ester during the
lactonization reaction.45 Final global deprotection of the
TBS groups yielded 76 in 25% yield.
To append the top fragment, 64 was oxidized to the alde-
hyde, which was then subjected to an HWE reaction with
the phosphonate 7, providing 65 in 78% yield. The alkene
in a,b-unsaturated ketone 65 was reduced with nickel boride
giving 66 in 76% yield. Some over-reduction of the C4–C5
alkene in the bottom fragment was also observed, but this
minor product was separated by chromatography. The C19
ketone was reduced unselectively by NaBH4 yielding
a 1.7:1 ratio of diastereomers of 67b/a, with the b isomer
as the major (62%), less polar product and the a isomer as
the minor (36%), more polar product. These two diastereo-
mers were separated by silica gel column chromatography
and pure 67b was advanced first. The newly generated
C19 hydroxy group in 67 was protected by a TBS group to
give 68b in 86% yield.
The C19a-epimer was prepared from 67a by using the same
reaction pathways detailed in Schemes 6 and 7 (not shown,
but fully described in Supplementary data). In this case, after
hydrolysis of 73a and Yamaguchi lactonization (Eq. 1), two
inseparable spots were observed on TLC. In the final global
TBS deprotection step, the (2Z,4E)-isomer 37 (less polar,
45%) was isolated along with the isomerized (2E,4E)-iso-
mer 77 (more polar, 15%) in a 3:1 ratio. Coupling constant
measurements again secured the alkene geometries.
TBS
O
1) 1N KOH;
The diene elaboration and final stages of the synthesis are
shown in Scheme 7. The PMB acetal was cleaved with
DIBALH to give the primary alcohol 69b in 97% yield. Ox-
idation to the aldehyde and subsequent Nozaki–Hiyama and
Peterson syn-elimination reactions gave the diene 70b in
85% yield.
2)Yamaguchi,
45% (2 steps)
TBSO
OH
3) 3N HCl
CO Me
2
TBSO
OTBS
73
ð1Þ
Removal of the trityl group in 70b with ZnBr2 in CH2Cl2/
MeOH43 gave 71b in 83% yield, which was oxidized to
the aldehyde and the (E,Z)-diene was installed by Still–
Gennari reaction in 90% yield. The PMB group in 72b
was removed by DDQ to give 73b in 90% yield, and the
resulting methyl ester was hydrolyzed with 1 N aqueous
KOH in EtOH/THF. Although the resulting acid 74b was
exclusively the 2Z,4E-isomer, macrolactonization by the
Yamaguchi method produced mainly the 2E,4E-lactone
75b, which was isolated in 68% yield.44 The isomerization
OH
OH
HO
HO
+
O
O
O
O
(Z)
11.4 Hz
(E)
15.4 Hz
OH OH
37
OH OH
77
TBS
O
TBS
O
TBS
O
OTBS
TBSO
TBSO
TBSO
TBSO
a
b
c
d
68
PMBO
OH
OTr
PMBO
PMBO
PMBO
CO2Me
OTr
OH
TBSO
OTBS
TBSO
OTBS
TBSO
OTBS
TBSO
OTBS
69
70
71
72
TBS
O
TBS
O
TBS
O
OH
O
TBSO
TBSO
HO
TBSO
g
e
f
h
HO
HO
O
CO2H
CO2Me
O
=
O
(E)
J
125,.35 Hz
TBSO
OTBS
74
TBSO
OTBS
73
OH OH
TBSO
OTBS
75
76
(2E)-6,14-bis-epi-dictyostatin
Scheme 7. Final stages of the synthesis of 6,14-bis-epi-dictyostatin. (a) DIBALH, 97%. (b) (i) Dess–Martin; (ii) CrCl2, 29, NaH, 85% (three steps). (c) ZnBr2,
CH2Cl2/MeOH, 83%. (d) (i) Dess–Martin; (ii) Still–Gennari, 90% (two steps). (e) DDQ, 90%. (f) 1 N KOH, EtOH/THF. (g) Yamaguchi, 68% (two steps).
(h) 3 N HCl, 15%.

8544
Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
2.1.3. Synthesis of (L)-dictyostatin. As this work pro-
gressed, we compared spectral data of the intermediates
and products with both dictyostatin 1 and discodermolide
2 and began to draw conclusions about the structure of
dictyostatin. This exercise was greatly assisted by two-
dimensional NMR spectroscopy because it was generally
possible to assign all or nearly all 1H and 13C resonances with
confidence. First, while all of the isomers made to that date
were clearly different from dictyostatin in material respects,
their spectra were related enough for us to conclude that the
two-dimensional structure proposed by Pettit was correct.
Second, the spectra from the series of compounds with the
b-hydroxy group at C19 clearly resembled both dictyostatin
and discodermolide more than the series with the a-hydroxy
group, so we concluded that dictyostatin and discodermolide
had the same configuration at the C19–C22 stereotetrad.
OH
O
HO
O
OH OH
1, (–)-dictyostatin
OTBS
OMe
N
OTr
TBSO
Me
O
OTBS
middle fragment, 78
bottom fragment, 79
The comparisons of resonances in the middle and bottom
portions of the molecules were very revealing. First, the
resonances of compound 5 with the ‘discodermolide-like’
middle fragment closely resembled their counterparts of
dictyostatin 1 and differed from those of the 6,14-bis-epi se-
ries, for example, compound 36. This suggested that dictyo-
statin has the same configurations as discodermolide for the
C12–C14 stereotriad, and not the configuration assigned in
compound 4. Finally, none of the resonances of the spectra
in the bottom fragment region closely resembled dictyosta-
tin, and all exhibited significant differences centered in the
region of H6/C6 and H7/C7. We thus concluded that this
syn configuration as assigned in compound 4 was not correct
for dictyostatin, and now the clear stereochemical analogy
between the top and middle fragments of dictyostatin and
discodermolide suggested that the bottom fragment of dic-
tyostatin probably also had the same configurations as
discodermolide.
Figure 4. Strategy for the synthesis of (ꢀ)-dictyostatin 1.
We found that the indirect process of converting syn 52 to
anti 82 could be shortened by beginning with Brown crotyl-
ation47 of TBS-protected 3-hydroxypropanal 88 with 89,
which directly provided anti-alcohol 90. Protection of the
alcohol with TBSCl, OsO4-catalyzed dihydroxylation, and
diol cleavage with periodate, followed by HWE homologa-
tion intersected the prior route at unsaturated ester 83. This
second generation route reduced the number of steps to 79
from 15 to 11 and improved the overall yield (from 1,3-
propanediol) to 27%.
The middle fragment 78 was also prepared in two ways as
summarized in Scheme 9. The secondary alcohol of known
compound 92,48 prepared in four steps from the (S)-Roche
ester, was TBS-protected and the Evans auxiliary was
removed with LiBH4 to give alcohol 93. Oxidation to the
aldehyde and HWE reaction gave the ester 95. Alkene reduc-
tion with nickel boride to 96, saponification with LiOH to
97, and coupling with the Evans auxiliary gave amide 98.
Asymmetric methylation provided diastereomer 99 exclu-
sively. Removal of the chiral auxiliary by reduction to give
100, TBS protection, and PMB deprotection with DDQ
gave primary alcohol 101. Oxidation to the aldehyde and
Corey–Fuchs reaction gave the alkyne 78. This route from
92 to 78 proceeded in 16% overall yield. An improved route
to 78 involved conversion of 94 to its iodide and asymmetric
alkylation with Myers’ auxiliary 45 to give amide 103. Re-
moval of the auxiliary as usual intersected the prior route
at 100. This second generation approach to 78 from 92
doubled the overall yield to 31%.
The only remaining configuration to assign was the isolated
stereocenter at C16, which has no analogy in discodermo-
lide. The need to select between these two isomers was
preempted by the appearance of the paper by Paterson and
co-workers suggesting that dictyostatin was 1 (C16-b) based
on detailed NMR analysis and modeling.16 We accordingly
decided to focus on making structure 1 as quickly as possible
to finally resolve the stereochemical issues.
The strategy for the synthesis of 1 followed closely from the
prior work and is summarized in Figure 4. The same discon-
nections as for the 6,14-bis-epi series were used, providing
the standard top fragment 7 along with new middle fragment
78 and bottom fragment 79.
Over the course of the work, we developed two routes to bot-
tom fragment 79, and both are summarized in Scheme 8. The
first route was built on the established route to syn alcohol 52
(see Scheme 5). This compound was converted to the anti-
isomer 82 via tosylation to give 80 and elimination to alkene
81. Hydroboration with 9-BBN and subsequent oxidation
provided a 9:1 mixture 82 and 52.46 These were readily sep-
arable, and 82 was isolated isomerically pure in 72% yield.
The remaining sequence of steps to make 79 followed
closely after the analogous sequence described in Scheme
5. The 15 step process starting ultimately from 1,3-propane-
diol provided key intermediate 79 in 9.5% overall yield.
The bottom and middle fragments were then coupled and the
synthesis of dictyostatin was advanced as summarized in
Scheme 10. The Weinreb amide 79 was reacted with 2 equiv
of the anion from alkyne 78 to give the coupling product 104
in high yield. Reduction of 104 with the (S,S)-Noyori cata-
lyst gave one isomer of the alcohol 105, whose alkyne moi-
ety was reduced by Lindlar hydrogenation to alkene 106.
The newly generated secondary hydroxyl group was pro-
tected with TBSOTf to give 107. Selective deprotection of
the primary TBS group with HF/pyridine in buffered pyr-
idine at 0 ꢁC gave 108 in moderate yield. The aldehyde

Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
8545
a
c
b
OH
OTs
OH
TBSO
OTBS
52
TBSO
OTBS
80
TBSO
OTBS
81
TBSO
OTBS
82
OEt
OH
OTr
OTr
e
f
d
g
TBSO
OTBS
O
TBSO
OTBS
TBSO
OTBS
85
83
84
OMe
N
OTr
HO
O
OTr
h
i
OH OTBS
OTBS
O
OTBS
86
87
79
alternative approach to 79
B
2
j
l
k
+
83
TBSO
O
TBSO
OH
90
TBSO
OTBS
91
88
89
Scheme 8. Two routes to the dictyostatin bottom fragment 79. (a) TsCl, pyridine, 90%. (b) NaI, DBU, glyme, 70%. (c) 9-BBN, 72%. (d) (i) Dess–Martin; (ii)
Horner–Wadsworth–Emmons, 59% (two steps). (e) DIBAL–H, CH2Cl2, 97%. (f) TrCl, 4-DMAP, pyridine. (g) HF/pyridine, pyridine, THF, 89% (two steps). (h)
(i) Pyridine/SO3, Et3N, DMSO–CH2Cl2; (ii) NaClO2, NaHPO4, 2-methyl-2-butene, THF/H2O. (i) NH(Me)(OMe)$HCl, DCC, Et3N, DMAP, CH2Cl2, 73%
(three steps). (j) THF, hexane, ꢀ90 ꢁC, 55%, 95% ee. (k) TBSCl, imidazole, DMAP, 95%. (l) OsO4, NMO, THF, H2O, then NaIO4; (ii) Horner–Wads-
worth–Emmons, 83% (two steps).
formed by Dess–Martin oxidation was reacted with the
phosphonate 7 (Fig. 2) under HWE conditions to give the
conjugated ketone 109 in good yield. Selective reduction
with nickel boride gave the ketone 110, which was again re-
duced in a purposefully unselective manner with NaBH4 to
give a 2.4:1 mixture of the isomers of 111, with the b isomer,
necessary for preparation of (–)-dictyostatin, predominating.
The isomers of 111 were readily separated by silica gel chro-
matography. Later, a 5:1 ratio favoring 111 was obtained by
use of the bulkier reducing agent LiAl(O-t-Bu)3H, whereas
a 1:1 ratio of the a and b isomers was obtained when (L)-
Selectride was employed.
O
O
OH
O
TBSO
O
OTBS
OTBS
O
a
b
c
PMBO
N
Bn
O
PMBO
N
O
PMBO
OH
PMBO
O
OEt
Bn
92
93
94
95
OTBS
O
OTBS
O
O
OTBS
d
e
f
g
PMBO
OEt
PMBO
OH
PMBO
N
O
Bn
96
97
98
O
OTBS
OTBS
OTBS
OTBS
O
h
i
j
PMBO
OH
HO
OTBS
OTBS
PMBO
N
Bn
O
99
100
101
78
abbreviated route to 27
OTBS
O
Me
OTBS
O
Me
N
m
k
Ph
l
Ph
100
94
PMBO
I
+
N
PMBO
Me OH
OH
102
45
103
Scheme 9. Two routes to the dictyostatin middle fragment 78. (a) TBSOTf, 2,6-lutidine. (b) LiBH4, MeOH, THF, 90%. (c) (i) Pyridine/SO3, Et3N, DMSO/
CH2Cl2; (ii) Horner–Wadsworth–Emmons, 70%. (d) NiCl2, NaBH4, 97%. (e) 1 N LiOH, acetone. (f) Evans auxiliary, PivCle, Et3N, LiCl, 70% (two steps).
(g) NaHMDS, MeI, 74%. (h) LiBH4, 83%. (i) (i) TBSCl, imidazole; (ii) DDQ, 81% (two steps). (j) (i) Pyridine/SO3, DMSO/CH2Cl2; (ii) PPh3, CBr4; (iii)
n-BuLi, 73% (three steps). (k) PPh3, I2, imidazole, DIPEA; (l) LDA, LiCl, 45, 87% (two steps). (m) BH3$NH3, LDA, 96%.

8546
Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
OTBS
OTBS
OTBS
OTBS
TBSO
TBSO
TBSO
TBSO
c
d
a
b
78 + 79
OTr
OTr
OTr
OTr
O
OTBS
104
OH OTBS
HO
OTBS
106
TBSO
OTBS
105
107
OH
O
O
OH
O
O
O
TBSO
TBSO
TBSO
TBSO
e
f
38
g
h
O
O
PMP
OTr
O
OTr
PMP
OTr
PMP
OTr
TBSO
OTBS
108
TBSO
OTBS
110
TBSO
OTBS
TBSO
OTBS
109
111 /
Scheme 10. Intermediate stages of the synthesis of (ꢀ)-dictyostatin 1. (a) n-BuLi, THF, 93%. (b) (S,S)-Noyori catalyst (20 mol %), i-PrOH, 79%. (c) Lindlar
catalyst, H2 (balloon), toluene, 91%. (d) TBSOTf, 2,6-lutidine, CH2Cl2, 99%. (e) HF/pyridine, pyridine, THF, 0 ꢁC, 1 day, 67%. (f) (i) Dess–Martin oxidation;
(ii) Ba(OH)2, 7, THF/H2O, 80% (two steps). (g) NiCl2, NaBH4, MeOH/THF, 76%. (h) NaBH4, MeOH/THF, 70% (b), 29% (a).
The final stages of the synthesis paralleled the established
steps, as summarized in Scheme 11. Alcohol 111b was pro-
tected with a TBS group to give 112b, whose PMB acetal
was cleaved with DIBALH to give alcohol 113b. Oxidation
to the aldehyde followed by Nozaki–Hiyama addition with
29 and Peterson-type elimination installed the (E,Z)-diene
to give 114b in high yield. The allylic trityl group was re-
moved with ZnBr2 to give alcohol 115b. Dess–Martin oxi-
dation to the aldehyde and Still–Gennari reaction gave the
(E,Z)-conjugated ester 116b. The PMB group was removed
with DDQ to give 117b and saponification with aqueous
KOH in EtOH/THF gave acid 118b in 61% yield after
TBS
O
TBS
O
OTBS
OTBS
TBSO
TBSO
TBSO
TBSO
c
b
a
d
111
PMBO
OH
OTr
O
O
PMBO
PMBO
PMP
OTr
OH
TBSO
OTBS
113
TBSO
OTBS
OTr
TBSO
OTBS
TBSO
OTBS
112
114
115
TBS
O
TBS
O
TBS
O
TBS
O
TBSO
TBSO
TBSO
TBSO
g
h
e
f
PMBO
HO
HO
O
O
CO2Me
CO2Me
CO2H
TBSO
OTBS
116
TBSO
OTBS
117
TBSO
OTBS
TBSO
OTBS
118
119
OH
OH
OH
O
19
HO
HO
HO
i
a-i
i
116
111
O
O
HO
O
36%
CO2Me
HO HO
OH
OH
HO HO
120
1
121
Scheme 11. Final stages of the synthesis of dictyostatin. (a) TBSOTf, 2,6-lutidine, CH2Cl2, 99%. (b) DIBAL–H, CH2Cl2, 88%. (c) (i) Dess–Martin oxidation;
(ii) 29, CrCl2, THF; (iii) NaH, THF, 89% (three steps). (d) ZnBr2, CH2Cl2/MeOH, 77%. (e) (i) Dess–Martin oxidation; (ii) (CF3CH2O)2P(O)CH2CO2Me,
KHMDS, 18-crown-6, THF, 78% (two steps). (f) DDQ, CH2Cl2/H2O, 88%. (g) 1 N KOH, EtOH/THF, 61%. (h) 2,4,6-Trichlorobenzoyl chloride, Et3N,
THF then 4-DMAP (10 equiv), toluene, 78%. (i) 3 N HCl/MeOH, THF, 55%.

Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
8547
purification by flash chromatography. Yamaguchi macrolac-
tonization of the purified acid now gave 119b in 78% yield
after flash chromatographic purification. Global deprotec-
tion with 3 N HCl in MeOH/THF and careful purification
gave w5 mg of (ꢀ)-dictyostatin 1. There were at least two
minor byproducts from the macrolactonization/deprotection
sequence whose yields were estimated to be <15%. Neither
sample was isolated in highly pure form, but based on com-
parison of 1H NMR spectra from the chromatographic frac-
tions with spectra of related pure samples, we deduced that
one of these side products was the C2,C3 E-isomer (believed
to arise during the macrolactonization), while the other was
a trans-lactonized product with the lactone formed between
O19 and C1 with a free O21 hydroxy group (believed to arise
during the deprotection).49
dilutions of test compounds in collagen-coated 384 well
microplates, fixed and immunostained with an anti-a-tubulin
antibody followed by an FITC conjugated secondary anti-
body as previously described.2 Paclitaxel and discodermo-
lide 2 were included as known microtubule-stabilizing
agent controls. Fluorescence images of 1000 individual cells
were acquired on an ArrayScan II (Cellomics, Inc) auto-
mated microscope and analyzed for tubulin staining inten-
sity as described.2,49 Extrapolation of minimum detectable
effective concentrations (MDECs)50 from 10-point concen-
tration-dependence curves revealed that dictyostatin 1
caused microtubule bundling at low nanomolar concentra-
tions, analogs 3, 120b, and 121 at submicromolar concentra-
tions (about 20-fold less potent than the parent compound),
and compounds 5, 76, 37, and 77 to have little effect on
microtubule morphology (Table 1).
The Paterson group completed an independent total synthe-
sis of 1 roughly concurrently with us, and the two synthetic
samples and one natural sample (from Wright) of (ꢀ)-dic-
tyostatin were identical in all respects. The [a]2D5 of our sam-
ple was ꢀ22.6 (c 0.27, MeOH), in satisfactory agreement
with the values of Pettit (ꢀ20, c, 0.12, MeOH), Wright
(ꢀ27.4, c 0.16, MeOH), and Paterson (ꢀ32.7, c 0.22,
MeOH), so both the relative and absolute configurations of
1 are confirmed. An open-chain analog of 1 was prepared
by global desilylation of 116b to give tetraol ester 120b.
Finally, the a-epimer at C-19, 111a, was taken through the
same sequence of steps as shown in Scheme 11 to provide
19-epi-dictyostatin 121 in comparable overall yield to the
b-series (see Supplementary data). Thus, the chapter on
the structural assignment of dictyostatin was closed.
These same analogs were examined for their antiprolifera-
tive activities against cultures of human ovarian carcinoma
1A9 cells and their paclitaxel-resistant mutants, 1A9/Ptx10
and 1A9/Ptx22.51 Each of these resistant lines contains sin-
gle mutations in the major b-tubulin gene that confer to the
cells, which do not express drug efflux pumps, appreciable
tolerance to paclitaxel.52 Paclitaxel had subnanomolar
potency against the parental 1A9 cells, but the mutant cells
showed ca. 90- and 70-fold resistance to the drug (Table
1). The antiproliferative activities, shown as 50% growth
inhibitory concentrations (GI50s), of the agents paralleled
the activities noted in the cellular microtubule assays, but
the GI50 values were typically two- to seven-fold lower
than the MDECs. Although not a potent agent, compound
3 showed an interesting property in that the 1A9/Ptx10 cells,
which express b-tubulin with a Phe270->Val alteration,
were 27-fold resistant to it as compared to the parental
1A9 cells. This suggested that the C6 and/or C16 methyl sub-
stituents in 1 could be in close proximity to Phe270 in the
taxane binding site.
2.2. Biology
The target compounds, 1, 3, 5, 37, 76, 77, 120b, and 121,
were screened for cellular and biochemical activities. The
effects of compounds on cellular microtubules were quanti-
fied by tubulin immunostaining. In this assay, microtubule-
stabilizing agents cause a dramatic increase in tubulin
immunoreactivity due to the formation of bright polymer
bundles with intense staining.13c Human cervical carcinoma
HeLa cells were treated for 21 h with 10 two-fold serial
The abilities of the new compounds to cause tubulin poly-
merization were determined under reaction conditions with
purified bovine brain tubulin (1 mg/mL) in the presence or
absence of microtubule-associated proteins (MAPs,
Table 1. Biological activities of dictyostatin (1) and analogs as compared to discodermolide (2) and paclitaxel
Cellular
In Vitro
Tubulinc polymerized Inhibition of binding
by 50 mM test
agent, % (Nꢃ3)
b
,
MDECa for tubulin
polymer increase,
nMꢂSD (N)
GI50
nM (fold resistance)
(N¼4)
of [3H]paclitaxel to tubulin
polymer, % (Nꢃ3)d
Test agent
1A9
1A9/Ptx10
1A9/Ptx22
1
2
3
5
37
76
77
120b
121
Paclitaxel
5.4ꢂ1.9 (4)
65ꢂ0 (2)
0.69ꢂ0.80
3.2ꢂ2.4 (5)
1.3ꢂ1.0 (2) 99ꢂ4
75ꢂ5 (3)
76ꢂ6 (4)
27ꢂ8 (6)
0ꢂ1 (3)
0ꢂ1 (3)
0ꢂ0 (3)
0ꢂ1 (3)
42ꢂ1 (3)
7ꢂ2 (3)
—
1.7ꢂ1.2
693ꢂ580
6.2ꢂ3.6 (4)
18,400ꢂ2010 (27)
>50,000 (>2)
7.0ꢂ8.4 (4) 98ꢂ5
328ꢂ142 (2)
4375ꢂ625 (2)
>5000 (4)
625ꢂ9
52ꢂ2
2ꢂ2
20,900ꢂ400
11,560ꢂ1180
30,000ꢂ1000
790ꢂ560 (3)
30,000ꢂ1000
85ꢂ2
28,000ꢂ1000 26,000ꢂ500
5ꢂ1
>5000 (4)
>5000 (4)
219ꢂ36 (4)
284ꢂ108 (4)
5.2ꢂ0.4 (4)
310ꢂ40
780ꢂ200 (3)
1ꢂ1
25,000ꢂ2000 25,000ꢂ1000
5ꢂ4
56ꢂ16
21ꢂ14
79ꢂ13
39ꢂ7
30ꢂ2
89ꢂ6
120ꢂ60 (6)
43ꢂ12 (2)
51ꢂ9 (72)
0.71ꢂ0.11
64ꢂ8 (90)
a
Minimum detectable effective concentration of the test agent in HeLa cells after 21 h of continuous exposure.
Fifty percent growth inhibitory concentration after 72 h of continuous exposure to the test agent.
Bovine brain tubulin (10 mM) in 0.2 M monosodium glutamate, 15 min at 20 ꢁC, centrifugation, and Lowry determination of remaining soluble tubulin.
Percent competition at 37 ꢁC by 4 mM test agent with 2 mM [3H]paclitaxel for binding to microtubules formed from 2 mM bovine brain tubulin and 20 mM
dideoxyGTP.
b
c
d

8548
Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
isomers with (E,E) geometry at C2–C5. The biological eval-
uation of the compounds revealed a wide range of activities
resulting from these very small structural changes. The SAR
determined includes the following. The macrolactone is im-
portant but not a full requisite for microtubule stabilization
and antiproliferative actions. The b configuration of the
hydroxyl at C19 is preferred, and the configuration of the
C6 and C14 methyl groups is important. The natural E/Z
geometry of the macrocyclic diene also appears to be crucial.
Finally, either the C6 or C16 methyl appears to interact with
a phenylalanine in the paclitaxel binding site. This SAR
provided a starting point for the preparation of more potent
dictyostatin analogs, as described elsewhere.21,23,53
4. Experimental
4.1. Ethyl (4R,5S,2E)-5,7-bis(tert-butyldimethylsilyl-
oxy)-4-methylhept-2-enoate (83)
Figure 5. Assembly of bovine brain tubulin induced by compound 3 in
comparison to paclitaxel.
From 82: a solution of triethyl phosphonoacetate (3.5 mL,
17.6 mmol) was added to a cooled (0 ꢁC), stirred suspension
of NaH (0.43 g, 17.0 mmol, 95% dispersion in mineral oil)
in THF (46 mL) dropwise over 10 min. The mixture was
brought to room temperature with a water bath (30 min)
and then cooled back to ꢀ78 ꢁC, and the aldehyde (2.73 g,
7.58 mmol) in THF (5 mL) was added. The resulting mix-
ture was stirred for 1 h at 0 ꢁC, and then pHz7 phosphate
buffer solution (10 mL) and Et2O (50 mL) were added.
The mixture was allowed to warm to room temperature,
and the phases were separated. The organic phase was
washed with saturated NH4Cl solution (30 mL) and brine
(30 mL), dried over MgSO4, filtered, and concentrated to
give oily crude product. Purification by flash chromato-
graphy (EtOAc/hexane 1:9) afforded pure ester 83 (2.92 g,
59% in two steps) as a colorless oil: IR (CHCl3) 2956,
2930, 2857, 1724, 1651, 1472, 1463, 1367, 1256, 1180,
0.75 mg/mL) and GTP (100 mM). Test agents were initially
screened at 10 and 40 mM. In these experiments, test agent-
induced assembly of soluble tubulin into polymer, with
respect to the presence and absence of cofactors and at
different temperatures, was monitored by turbidimetry in
temperature-controlled spectrophotometers. The initial tem-
perature was set at 0 or 2.5 ꢁC (depending upon the instru-
ment used) and then rapidly raised to 10, 20, and 30 ꢁC in
succession. This permitted the determination of both the
temperature at which a test agent-induced assembly and
the extent of agent-induced assembly. The temperature in-
creases were followed by a rapid decrease in temperature
back to the initial temperature to determine the cold-stability
of the polymer formed.
As we have recently reported, the effects of dictyostatin 1
and discodermolide 2 were similar, and both molecules
were far more potent than paclitaxel.2 Compounds 3,
120b, and 121 all showed some activity in this assay, while
the remaining agents were inactive. An example of concen-
tration-dependent trace, wherein a single temperature jump
from 2.5 to 30 ꢁC was used, for compound 3 is shown in
Figure 5. All test agents at 50 mM were then incubated
with 10 mM tubulin for 15 min at 20 ꢁC, reaction mixtures
were centrifuged, and the percentage of the remaining solu-
ble tubulin was measured. Again, compound 1 was by far
the most potent, but compounds 3, 120b, and 121 showed
moderate activity (Table 1).
1
1098, 1036, 836, 775 cmꢀ1; H NMR (300 MHz, CDCl3)
d 6.88 (dd, J¼15.8, 7.6 Hz, 1H), 5.74 (d, J¼15.8 Hz, 1H),
4.19 (q, J¼7.1 Hz, 2H), 3.79 (ddd, J¼6.7, 4.7, 4.4 Hz,
1H), 3.59 (m, 2H), 2.43 (m, 1H), 1.53 (m, 2H), 1.22 (t,
J¼7.1 Hz, 3H), 1.01 (d, J¼6.8 Hz, 3H), 0.83 (s, 18H),
0.02 (m, 12H); 13C NMR (75 MHz, CDCl3) d 166.4,
150.9, 121.3, 71.8, 59.9, 59.5, 42.0, 36.8, 25.82, 25.78,
26.1, 18.1, 18.0, 14.4, 14.2, ꢀ4.6, ꢀ4.7, ꢀ5.4; LRMS (EI)
415 (MꢀCH3)+, 373, 303, 147; HRMS (EI) calcd for
C21H44O4Si2 415.2710 (MꢀCH3)+, found 415.2712; [a]2D0
+3.8 (c 0.21, CHCl3).
4.2. (4R,5S,2E)-5,7-Bis(tert-butyldimethylsilyloxy)-4-
methylhept-2-en-1-ol (84)
Finally, all compounds were tested at 4 mM for their ability
to compete with 2 mM [3H]paclitaxel for its binding to 2 mM
preassembled bovine brain microtubules. Compounds 120b,
3, and 121 showed competitive activity in this assay,
although the latter compound did not compete as well as
one might expect based on the results from the other assays.
DIBALH (26.5 mL, 26.5 mmol, 1.0 M solution in hexane)
was added to the ester 83 (3.14 g, 7.30 mmol) in CH2Cl2
(35 mL) at ꢀ78 ꢁC dropwise and stirred for 1 h. The reaction
mixture was quenched by adding EtOAc (5 mL) and satu-
rated sodium potassium tartrate solution (20 mL), followed
by vigorous stirring for 4 h. The aqueous phase was ex-
tracted with CH2Cl2 (3ꢄ30 mL), and the combined organic
layers were washed with brine (10 mL). After drying over
MgSO4 and evaporation under vacuum, flash column chro-
matography (hexane/EtOAc 4:1) provided 2.75 g of alcohol
84 (97%) as a colorless oil: IR (CHCl3) 3349, 2956, 2928,
3. Conclusions
In summary, we have provided here the full details of synthe-
sis of dictyostatin 1, its open-chain methyl ester analog, as-
sorted C6, C16, and C19 epimers, and two macrolactone

Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
8549
1
2857, 1471, 1462, 1255, 1099, 836, 774 cmꢀ1; H NMR
4.5. (3S,4R,5E)-3-(tert-Butyldimethylsilyloxy)-N-meth-
oxy-N-4-dimethyl-7-(trityloxy)hept-5-enamide (79)
(300 MHz, CDCl3) d 5.57 (m, 2H), 4.03 (m, 2H), 3.70
(ddd, J¼9.7, 6.0, 3.8 Hz, 1H), 3.59 (m, 2H), 2.27 (m, 1H),
2.00 (s, 1H), 1.53 (q, J¼6.5 Hz, 2H), 0.96 (d, J¼6.9 Hz,
3H), 0.85 (s, 9H), 0.84 (s, 9H), 0.00 (m, 12H); 13C NMR
(75 MHz, CDCl3) d 134.7, 129.2, 72.4, 63.6, 60.1, 41.8,
36.3, 25.9, 18.2, 18.0, 15.1, 10.7, ꢀ4.6, ꢀ5.4; LRMS (EI)
370 (MꢀH2O)+, 303, 171, 147; HRMS (EI) calcd for
C20H42O2Si2 370.2723 (MꢀH2O)+, found 370.2725; [a]2D0
ꢀ3.0 (c 0.57, CHCl3).
Sulfur trioxide pyridine complex (3.02 g, 19.1 mmol) was
added to a stirred solution of alcohol 86 (3.26 g,
6.31 mmol) and triethylamine (2.6 mL, 19.1 mmol) in anhy-
drous CH2Cl2 (6 mL) and DMSO (12 mL) at 0 ꢁC. The reac-
tion mixture was stirred at ambient temperature for 1 h. The
mixture was diluted with Et2O (100 mL) and washed with
aqueous 0.5 N HCl (50 mL) and brine (10 mL). The sepa-
rated organic layer was dried over MgSO4. Filtration and
concentration, followed by short flash column chromato-
graphy (hexane/EtOAc 4:1), provided the crude aldehyde
as a colorless oil, which was used without further purifica-
tion. A solution of the aldehyde in THF (25 mL) and H2O
(12 mL) was treated with 2-methyl-2-butene in THF (2 M,
18 mL, 9.0 mmol), NaH2PO4$H2O (2.6 g, 18.8 mmol), and
NaClO2 (2.1 g, 18.6 mmol). The reaction mixture was
stirred for 2 h, diluted with 1 N HCl (20 mL), and extracted
with CH2Cl2 (2ꢄ40 mL). The combined organic layers were
dried over MgSO4, concentrated in vacuo, and the crude acid
87 was used for the next reaction without further purifica-
tion. N,O-Dimethylhydroxylamine hydrochloride (0.62 g,
6.36 mmol), Et3N (0.88 mL, 6.31 mmol), and DMAP
(0.63 mmol) were successively added to a solution of the
crude acid in CH2Cl2 (10 mL). The reaction mixture was
cooled to 0 ꢁC and then DCC (1.30 g, 6.30 mmol) was
added. The mixture was stirred at ambient temperature for
15 h and filtered. The filtrate was washed with 0.5 N HCl,
saturated aqueous NaHCO3, and brine, dried over anhydrous
MgSO4, and concentrated. Purification by column chroma-
tography over silica gel (hexane/EtOAc 4:1) gave the Wein-
reb amide 79 (2.65 g, 73% in three steps) as a colorless oil:
IR (CHCl3) 2956, 2929, 2855, 1663, 1448, 1252, 1083,
4.3. ((4R,5S,2E)-5,7-Bis(tert-butyldimethylsilyloxy)-4-
methylhept-2-enyloxy)triphenylmethane (85)
Trityl chloride (4.1 g, 14.7 mmol) and DMAP (1.8 g,
14.7 mmol) were added to a solution of alcohol 84 (2.75 g,
7.1 mmol) in pyridine (71 mL). The mixture was heated to
reflux for 18 h, cooled to ambient temperature, and added
to a solution of saturated CuSO4 (200 mL). The mixture
was extracted with Et2O (2ꢄ20 mL), and the combined or-
ganic extracts were washed saturated CuSO4 (2ꢄ20 mL).
The organic layer was separated, dried (MgSO4), filtered,
and concentrated in vacuo. Flash column chromatography
(EtOAc/hexane 1:19) provided 85 (4.46 g, quantitative) as
a pale yellow oil: IR (CHCl3) 2954, 2856, 1471, 1448,
1254, 1095, 835, 773, 705 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) d 7.56 (m, 6H), 7.32 (m, 9H), 5.79 (dd, J¼15.6,
6.7 Hz, 1H), 5.65 (dd, J¼15.7, 5.0 Hz, 1H), 3.85 (m, 1H),
3.74 (m, 1H), 3.66 (d, J¼4.9 Hz, 1H), 2.43 (m, 1H), 1.70
(q, J¼6.5 Hz, 2H), 1.21 (d, J¼6.9 Hz, 3H), 0.99 (s, 9H),
0.97 (s, 9H), 0.154 (s, 3H), 0.150 (s, 3H), 0.13 (s, 3H),
0.12 (s, 3H); 13C NMR (75 MHz, CDCl3) d 144.4, 134.2,
128.7, 127.7, 126.9, 126.8, 86.8, 72.6, 65.1, 60.2, 42.1,
36.6, 26.0, 18.3, 18.1, 15.3, ꢀ4.4, ꢀ5.3; LRMS (ESI)
653.3 [M+Na]+; HRMS (ESI) calcd for C39H58O3Si2Na
653.3822 [M+Na]+, found 653.3851; [a]2D0 ꢀ1.9 (c 0.42,
CHCl3).
1
1032, 836 cmꢀ1; H NMR (300 MHz, CDCl3) d 7.58 (m,
6H), 7.37 (m, 9H), 5.89 (dd, J¼15.6, 7.6 Hz, 1H), 5.72 (dt,
J¼15.6, 5.2 Hz, 1H), 4.38 (ddd, J¼8.0, 5.0, 3.0 Hz, 1H),
3.74 (s, 3H), 3.70 (d, J¼5.1 Hz, 2H), 3.27 (s, 3H), 2.79
(dd, J¼15.1, 7.4 Hz, 1H), 2.52 (m, 2H), 1.20 (d, J¼6.9 Hz,
3H), 1.02 (s, 9H), 0.22 (s, 3H), 0.16 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 172.6, 144.2, 133.3, 128.5, 127.7,
127.5, 126.8, 86.7, 72.4, 64.8, 61.2, 42.4, 36.3, 31.9, 25.8,
18.0, 15.7, ꢀ4.6, ꢀ5.0; LRMS (ESI) 596.2 [M+Na]+;
HRMS (ESI) calcd for C35H47O4NSiNa 596.3172
[M+Na]+, found 596.3165; [a]D20 ꢀ14.7 (c 0.65, CHCl3).
4.4. (3S,4R,5E)-3-(tert-Butyldimethylsilyloxy)-4-methyl-
7-(trityloxy)hept-5-en-1-ol (86)
HF/pyridine in pyridine (40 mL, prepared by slow addition
of 12 mL pyridine to 3 mL HF/pyridine complex, followed
by dilution with 25 mL THF) was added to a solution of
TBS ether 85 (4.46 g, 7.07 mmol) in THF (10 mL). The mix-
ture was stirred overnight at room temperature and quenched
with saturated NaHCO3 (100 mL). The aqueous layer was
separated and extracted with Et2O (3ꢄ50 mL). The com-
bined organic layers were washed with saturated CuSO4
(3ꢄ50 mL), dried over MgSO4, and concentrated. Flash col-
umn chromatography (EtOAc/hexane 1:4) afforded 3.26 g
(89%) of alcohol 86 as a colorless oil: IR (CHCl3) 3407,
2955, 2928, 2856, 1490, 1471, 1448, 1254, 1058, 1031,
4.6. (3R,4S)-4,6-Bis(tert-butyldimethylsilyloxy)-3-
methylhex-1-ene (91)
A solution of 90 (9.00 g, 36.8 mmol), imidazole (5.06 g,
73.6 mmol), and DMAP (0.45 g, 3.68 mmol) in DMF
(37 mL) was treated with TBDMSCl (7.44 g, 47.9 mmol)
at 0 ꢁC. The mixture was stirred at room temperature for
12 h, and then diluted with ethyl ether and water. The aque-
ous layer was extracted with ethyl ether. The combined
organic layers were washed with water and dried over anhy-
drous MgSO4. The solvent was removed under vacuum to
provide the oil. Then flash chromatography (hexane/EtOAc
19:1) afforded the title compound (12.54 g, 95% yield):
1H NMR (300 MHz, CDCl3) d 5.84 (m, 1H), 5.02 (m,
2H), 3.79 (m, 1H), 3.67 (m, 2H), 2.34 (m, 1H), 1.62
(m, 2H), 1.00 (d, J¼6.6 Hz, 3H), 0.92 (br s, 18H), 0.06
(m, 12H).
836, 773, 705 cmꢀ1; H NMR (300 MHz, CDCl3) d 7.57
1
(m, 6H), 7.37 (m, 9H), 5.78 (dd, J¼15.6, 6.5 Hz, 1H), 5.73
(dt, J¼15.5, 4.8 Hz, 1H), 3.91 (m, 1H), 3.82 (d, J¼5.9 Hz,
2H), 3.69 (d, J¼4.4 Hz, 2H), 2.51 (m, 1H), 2.22 (br, 1H),
1.77 (m, 2H), 1.13 (d, J¼6.8 Hz, 3H), 1.03 (s, 9H), 0.21
(s, 3H), 0.19 (s, 3H); 13C NMR (75 MHz, CDCl3) d 144.2,
134.1, 128.6, 127.7, 127.1, 126.9, 86.8, 74.3, 64.9, 60.4,
42.0, 34.8, 25.9, 18.0, 14.5, ꢀ4.4, ꢀ4.6; LRMS (ESI) 539.2
[M+Na]+; HRMS (ESI) calcd for C33H44O3Si1Na 539.2957
[M+Na]+, found 539.2976; [a]D20 ꢀ2.8 (c 2.0, CHCl3).

8550
Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
4.7. Ethyl (4R,5S,2E)-5,7-bis(tert-butyldimethylsilyl-
oxy)-4-methylhept-2-enoate (83)
solution of 93 (4.79 g, 8.62 mmol) in THF (75 mL) at 0 ꢁC.
The resulting mixture was stirred at 0 ꢁC for 45 min and at
room temperature for 1 h. The solution was cooled to 0 ꢁC
and treated carefully with a 1.0 M aqueous NaOH (50 mL).
The phases were separated, and the aqueous phase was
extracted with CH2Cl2. The combined organic phases were
washed with brine, dried over MgSO4, filtered, and concen-
trated under reduced pressure. The residue was purified by
flash chromatography (hexane/EtOAc 7:3) to give the alco-
hol 94 (2.98 g, 90%) as a colorless oil: IR (film) 3425,
From 91: a mixture of 91 (1.00 g, 2.79 mmol) in acetone
(16 mL) and water (2 mL) was treated with OsO4
(2.5 wt % in tert-BuOH, 1.14 mL, 0.11 mmol) at room tem-
perature. After 10 min, NMO (0.43 g, 3.63 mmol) was
added. The mixture was stirred at room temperature for
20 h, and then NMO (0.23 g) was added. After 3 h, NaIO4
(0.72 g, 3.35 mmol) and water (5 mL) were added. After
4 h, water was added. The aqueous layer was extracted with
ethyl ether. The combined organic layers were washed with
brine and dried over anhydrous MgSO4. The solvent was re-
moved under vacuum to provide the crude aldehyde, which
was used for the next reaction without further purification.
1613, 1513, 1463, 1249, 1091, 1037 cmꢀ1 1H NMR
;
(300 MHz, CDCl3) d 7.26 (d, J¼8.5 Hz, 2H), 6.88 (d,
J¼8.5 Hz, 2H), 4.47 (d, J¼11.7 Hz, 1H), 4.40 (d,
J¼11.7 Hz, 1H), 3.84 (s, 3H), 3.75 (dd, J¼5.7, 2.9 Hz, 1H),
3.52 (m, 3H), 3.28 (dd, J¼9.1, 7.1 Hz, 1H), 2.10 (br, 1H),
2.05 (m, 1H), 1.93–1.81 (m, 1H), 0.97 (d, J¼7.0 Hz, 3H),
0.90 (s, 9H), 0.87 (d, J¼7.1 Hz, 3H), 0.07 (s, 3H), 0.05 (s,
3H); 13C NMR (75 MHz, CDCl3) d 159.2, 130.7, 129.3, 113.8,
74.8, 72.8, 72.7, 66.3, 55.4, 39.0, 37.7, 26.2, 18.4, 15.2,
12.0, ꢀ4.1; HRMS (ESI) calcd for C18H31O3SiNa 323.2042
[M+Na]+, found 323.2035; [a]D20 ꢀ0.76 (c 2.9, CHCl3).
A suspension of NaH (0.28 g, 11.16 mmol) in THF (14 mL)
was treated with triethyl phosphinoacetate (2.80 mL,
13.95 mmol) at ꢀ5 ꢁC. The mixture was stirred at room
temperature for 30 min and cooled to ꢀ5 ꢁC. Then crude
aldehyde in THF (5 mL) was added dropwise. The mixture
was stirred at 0 ꢁC for 2 h, and then quenched with saturated
aqueous NH4Cl. The aqueous layer was extracted with
ethyl ether. The combined organic layers were washed
with brine and dried over anhydrous MgSO4. The solvent
was removed under vacuum to provide the oil. Then flash
chromatography (hexane/EtOAc 19:1) afforded 83 (1.00 g,
83% yield, two steps). See above for spectroscopic data.
4.10. (4S,5R,6S,2E)-Ethyl-7-(4-methoxybenzyloxy)-5-
(tert-butyldimethylsilyloxy)-4,6-dimethylhept-2-
enoate (95)
The procedure for 84 was used with the aldehyde from 94
(17.5 g, 31.6 mmol), with Py$SO3 (15.2 g, 95.5 mmol) and
Et3N (13.3 mL, 95.5 mmol), followed by NaH (0.90 g,
39.7 mmol) and triethyl phosphonoacetate (7.2 mL,
40.3 mmol) to yield 8.96 g (63% in three steps) of the ester
95 by flash column chromatography (EtOAc/hexane 1:9) as
a colorless oil: IR (CHCl3) 2957, 2931, 2856, 1720, 1651,
1613, 1513, 1463, 1366, 1250, 1180, 1093, 1077,
4.8. (R)-3-((2R,3S,4S)-5-(4-Methoxybenzyloxy)-3-(tert-
butyldimethylsilyloxy)-2,4-dimethylpentanoyl)-4-
benzyloxazolidin-2-one (93)
2,6-Lutidine (5.14 mL, 44.2 mmol) and TBSOTf (9.36 mL,
40.8 mmol) were added to a solution of 92 (15.0 g,
33.9 mmol) in CH2Cl2 (340 mL) that was stirred at 0 ꢁC.
The mixture was stirred at 0 ꢁC for 2 h and then quenched
by the addition of saturated aqueous NaHCO3. The phases
were separated and the aqueous layer was extracted with
CH2Cl2. The combined organic phases were washed with
0.5 M aqueous NaHSO4. The organic phase was dried over
Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography (hex-
ane/EtOAc 4:1) to give 93 (17.9 g, 95%) as a colorless oil:
IR (film) 1781, 1696, 1513, 1383, 1248, 1209, 1110,
1
837 cmꢀ1; H NMR (300 MHz, CDCl3) d 7.31–7.27 (m,
2H), 7.03 (dd, J¼15.8, 7.8 Hz, 1H), 6.93–6.91 (m, 2H),
5.83 (dd, J¼15.8, 1.3 Hz, 1H), 4.48–4.40 (m, 2H), 4.23 (q,
J¼7.1 Hz, 2H), 3.84 (s, 3H), 3.67 (m, 1H), 3.52 (m, 1H),
3.30 (dd, J¼9.1, 7.2 Hz, 1H), 2.59 (m, 1H), 2.00 (m, 1H),
1.33 (t, J¼7.1 Hz, 3H), 1.09 (d, J¼6.8 Hz, 3H), 1.01 (d,
J¼7.0 Hz, 3H), 0.94 (s, 9H), 0.08 (m, 6H); 13C NMR
(75 MHz, CDCl3) d 166.5, 159.0, 152.7, 130.6, 129.0,
120.4, 113.6, 76.8, 72.5, 71.8, 60.0, 55.1, 40.2, 38.0, 26.0,
18.2, 14.8, 14.3, 14.2, ꢀ4.0, ꢀ4.2; LRMS (ESI) 473.2
[M+Na]+; HRMS (ESI) calcd for C25H42O5SiNa 473.2699
[M+Na]+, found 473.2716; [a]D20 ꢀ28.3 (c 0.41, CHCl3).
1
1042 cmꢀ1; H NMR (300 MHz, CDCl3) d 7.35–7.28 (m,
7H), 6.85 (d, J¼8.7 Hz, 2H), 4.49 (m, 1H), 4.38 (d,
J¼11.7 Hz, 1H), 4.34 (d, J¼11.7 Hz, 1H), 4.03 (m, 3H),
3.81 (m, 1H), 3.77 (s, 3H), 3.54 (dd, J¼9.2, 5.6 Hz, 1H),
3.22 (dd, J¼13.3, 3.1 Hz, 1H), 3.17 (dd, J¼9.1, 5.9 Hz, 1H),
2.72 (dd, J¼13.3, 9.6 Hz, 1H), 1.97 (m, 1H), 1.25 (d,
J¼6.5 Hz, 3H), 1.02 (d, J¼7.0 Hz, 3H), 0.91 (s, 9H), 0.07
(s, 6H); 13C NMR (75 MHz, CDCl3) d 176.4, 159.4, 153.1,
135.8, 131.1, 129.8, 129.3, 129.2, 127.6, 75.6, 72.9, 72.0,
66.1, 55.8, 55.6, 41.9, 39.3, 38.0, 26.4, 18.7, 15.3, 15.2, ꢀ3.5,
ꢀ3.6; HRMS (ESI) calcd for C31H45NO6SiNa 578.2914
[M+Na]+, found 578.2923; [a]D20 ꢀ8.1 (c 7.6, CHCl3).
4.11. (4S,5R,6S)-Ethyl-7-(4-methoxybenzyloxy)-5-(tert-
butyldimethylsilyloxy)-4,6-dimethylheptanoate (96)
NiCl2$6H2O (2.4 g, 10.1 mmol) and then portionwise
NaBH4 (1.50 g, 39.7 mmol) were added to a stirred solution
of unsaturated ketone 95 (8.96 g, 19.9 mmol) in MeOH
(66 mL) and THF (20 mL) at 0 ꢁC. After 1 h, the solvent
was evaporated and filtered with Celite using Et2O as an
eluant (60 mL). The organic phase was concentrated, and
the residue was purified by flash chromatography (EtOAc/
hexane 1:9) to yield 8.76 g of 96 (97%) as a colorless oil: IR
(CHCl3) 2957, 2856, 1737, 1613, 1513, 1463, 1374, 1249,
4.9. (2S,3R,4S)-5-(4-Methoxybenzyloxy)-3-(tert-butyl-
dimethylsilyloxy)-2,4-dimethylpentan-1-ol (94)
1172, 1091, 1038, 836, 773 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) d 7.40–7.37 (m, 2H), 7.02–6.99 (m, 2H), 4.59–4.50
(m, 2H), 4.25 (q, J¼7.1 Hz, 2H), 3.91 (s, 3H), 3.66–3.62 (m,
2H), 3.40 (dd, J¼8.8, 7.3 Hz, 1H), 2.52–2.33 (m, 2H),
Dry MeOH (1.05 mL, 26.0 mmol) and then LiBH4 (13 mL,
2.0 M solution in THF, 26 mmol) were added to a stirred

Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
8551
2.13–2.02 (m, 1H), 1.90–1.82 (m, 1H), 1.78–1.57 (m, 2H),
1.38 (t, J¼7.1 Hz, 3H), 1.09 (d, J¼6.9 Hz, 3H), 1.03 (s,
9H), 1.00 (d, J¼6.5 Hz, 3H), 0.19 (s, 3H), 0.18 (s, 3H);
13C NMR (75 MHz, CDCl3) d 173.6, 158.9, 130.7, 129.0,
113.5, 76.8, 72.5, 60.0, 55.0, 38.0, 35.6, 32.5, 29.9, 26.0,
18.3, 14.9, 14.1, 13.7, ꢀ3.9, ꢀ4.2; LRMS (ESI) 475.3
[M+Na]+; HRMS (ESI) calcd for C25H44O5SiNa 475.2856
[M+Na]+, found 473.2877; [a]D20 ꢀ6.0 (c 1.9, CHCl3).
15 min of stirring, the resulting cold solution was treated with
MeI (2.53 mL, 40.8 mmol) and stirred at ꢀ78 ꢁC for 3 h be-
fore being warmed to 25 ꢁC overnight (12 h). The reaction
was quenched with H2O (100 mL), and the aqueous layer
was extracted with Et2O (3ꢄ150 mL). The combined organic
extracts were dried (MgSO4), concentrated in vacuo, and
chromatographed (EtOAc/hexane 1:9) to provide 5.97 g
(74%) of 99 as a colorless oil: 1H NMR (300 MHz, CDCl3)
d 7.42–7.26 (m, 7H), 6.95–6.92 (m, 2H), 4.71 (m, 1H),
4.51 (m, 2H), 4.18 (m, 2H), 3.95 (m, 1H), 3.84 (s, 3H),
3.63 (dd, J¼8.9, 3.8 Hz, 1H), 3.57 (dd, J¼6.4, 2.7 Hz, 1H),
3.35 (t, J¼8.5 Hz, 1H), 3.28 (dd, J¼13.3, 3.1 Hz, 1H), 2.83
(dd, J¼13.3, 9.4 Hz, 1H), 2.10–1.95 (m, 2H), 1.68 (m, 1H),
1.38 (ddd, J¼14.1, 9.8, 4.9 Hz, 1H), 1.31 (d, J¼6.8 Hz,
3H), 1.04 (d, J¼6.9 Hz, 3H), 0.98 (s, 9H), 0.95 (d, J¼
6.7 Hz, 3H), 0.14 (s, 3H), 0.13 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 176.8, 158.8, 152.8, 135.1, 130.8, 129.3, 128.9,
128.7, 127.1, 113.5, 77.6, 72.6, 72.4, 65.7, 55.0, 38.9, 38.0,
37.6, 35.3, 33.8, 26.0, 18.8, 18.3, 14.9, 13.8, ꢀ3.8, ꢀ4.2.
4.12. (4S,5R,6S)-7-(4-Methoxybenzyloxy)-5-(tert-butyl-
dimethylsilyloxy)-4,6-dimethylheptanoic acid (97)
Aqueous LiOH (1 N, 193 mL, 0.19 mol) was added to
a THF/H2O solution of 96 (8.76 g, 19.4 mmol). The result-
ing solution was warmed to 60 ꢁC and stirred with heating
for 6 h. Aqueous 1 N HCl was added to give a neutral pH,
and the mixture was extracted with CH2Cl2, dried over
MgSO4, filtered, and evaporated to yield 8.22 g of crude
1
acid 97, which was used without further purification: H
NMR (300 MHz, CDCl3) d 7.24–7.22 (m, 2H), 6.86–6.83
(m, 2H), 4.39 (m, 2H), 3.77 (s, 3H), 3.69 (q, J¼7.0 Hz,
1H), 3.52 (m, 1H), 3.47 (q, J¼7.0 Hz, 1H), 3.19 (t,
J¼8.5 Hz, 1H), 2.16 (m, 1H), 1.90 (m, 1H), 1.65–1.51 (m,
2H), 1.21 (t, J¼7.0 Hz, 2H), 0.92–0.85 (m, 12H), 0.81 (d,
J¼6.3 Hz, 3H), 0.00 (m, 6H); 13C NMR (75 MHz, CDCl3)
d 181.0, 158.9, 130.6, 129.1, 113.6, 72.5, 65.8, 58.0, 55.1,
37.8, 30.6, 26.1, 18.3, 18.1, 15.2, 14.0, ꢀ3.5, ꢀ4.1.
4.15. (2R,4S,5R,6S)-7-(4-Methoxybenzyloxy)-5-(tert-
butyldimethylsilyloxy)-2,4,6-trimethylheptan-1-ol (100)
From 99: Dry methanol (1.22 mL, 30 mmol) then LiBH4
(15.0 mL, 2.0 M solution in THF, 30 mmol) were added to
a solution of 99 (5.97 g, 9.99 mmol) in THF (75 mL) stirred
at 0 ꢁC. The resulting solution was stirred at 0 ꢁC for 45 min
and at room temperature for 1 h. The solution was cooled to
0 ꢁC and treated carefully with a 1.0 M aqueous solution of
NaOH (50 mL). The phases were separated and the aqueous
phase was extracted with CH2Cl2. The combined organic
phases were washed with brine, dried over MgSO4, filtered
and concentrated under reduced pressure. The residuewas pu-
rified by flash chromatography (hexane/EtOAc 7:3) to give
the alcohol 100 (3.52 g, 83 %) as a colorless oil: IR (film)
4.13. (R)-3-((4S,5R,6S)-7-(4-Methoxybenzyloxy)-5-(tert-
butyldimethylsilyloxy)-4,6-dimethylheptanoyl)-4-
benzyloxazolidin-2-one (98)
A solution of acid 97 (8.22 g, 19.4 mmol) and Et3N
(5.40 mL, 38.8 mmol) in 100 mL of dry THF was cooled
to ꢀ78 ꢁC and treated dropwise with pivaloyl chloride
(2.86 g, 23.3 mmol), stirred in the cold condition for 2 h
and warmed to 0 ꢁC prior to the addition of the oxazolidi-
none (3.5 g, 19.8 mmol) and LiCl (2.46 g, 58.8 mmol).
This mixture was stirred overnight at room temperature
and diluted with water (200 mL). The separated aqueous
phase was extracted with ether (100 mL), and the combined
organic layers were dried and evaporated to give a residue
that was chromatographed to yield 7.91 g (70% in two steps)
of imide 98 by flash column chromatography (EtOAc/hex-
3410, 1612, 1513, 1249, 1067, 1038 cmꢀ1 1H NMR
;
(300 MHz, CDCl3) d 7.26 (d, J¼8.6 Hz, 2H), 6.88 (d, J¼
8.6 Hz, 2H), 4.44 (d, J¼11.7 Hz, 1H), 4.39 (d, J¼11.7 Hz,
1H), 3.81 (s, 3H), 3.51 (m, 2H), 3.44 (dd, J¼5.6, 3.4 Hz,
1H), 3.37 (dd, J¼10.6, 6.5 Hz, 1H), 3.22 (dd, J¼9.0,
7.0 Hz, 1H), 2.03–1.95 (m, 1H), 1.78–1.62 (m, 2H), 1.53
(br, 1H), 1.41 (ddd, J¼13.5, 7.5, 5.8 Hz, 1H), 0.95 (d,
J¼6.9 Hz, 3H), 0.94 (d, J¼6.7 Hz, 3H), 0.88 (s, 9H), 0.87
(d, J¼6.9 Hz, 3H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 159.2, 130.9, 129.4, 113.9, 77.5, 72.8,
67.7, 55.4, 38.3, 38.0, 33.6, 33.2, 26.3, 18.6, 18.0, 15.6,
15.5, ꢀ3.5, ꢀ3.8; [a]2D0 ꢀ6.3 (c 1.7, CHCl3).
1
ane 1:4) as a colorless oil: H NMR (300 MHz, CDCl3)
d 7.41–7.23 (m, 7H), 6.94–6.91 (m, 2H), 4.71 (m, 1H),
4.51 (d, J¼11.6 Hz, 1H), 4.46 (d, J¼11.6 Hz, 1H),
4.25–4.16 (m, 2H), 3.84 (s, 3H), 3.63–3.58 (m, 2H), 3.37–
3.31 (m, 2H), 3.14–3.04 (m, 1H), 2.94–2.86 (m, 1H), 2.79
(dd, J¼13.3, 9.7 Hz, 1H), 2.04 (m, 1H), 1.87–1.60 (m,
3H), 1.03 (d, J¼6.9 Hz, 3H), 0.99–0.97 (m, 12H), 0.14 (s,
3H), 0.12 (s, 3H); 13C NMR (75 MHz, CDCl3) d 173.1,
158.8, 153.3, 135.2, 130.7, 129.3, 129.0, 128.8, 127.1,
113.5, 77.1, 72.5, 72.4, 65.9, 55.1, 54.9, 37.9, 37.7, 35.6,
33.7, 29.2, 26.0, 18.3, 14.9, 13.9, ꢀ3.8, ꢀ4.2.
From 103: a solution of diisopropylamine (6.65 mL,
47.4 mmol) in THF (48 mL) stirred at ꢀ78 ꢁC was treated
with n-butyllithium in hexane (2.5 M, 17.6 mL, 44 mmol).
The solution was stirred at ꢀ78 ꢁC for 5 min and warmed
to 0 ꢁC for 15 min. Borane/ammonia complex (90%,
1.55 g, 45.2 mmol) was added and the resulting mixture
was stirred at 0 ꢁC for 15 min, warmed to room temperature
for 15 min, and then cooled to 0 ꢁC. A solution of amide 103
(6.62 g, 11.3 mmol) in THF (35 mL) was added dropwise
and the reaction mixture was stirred at 0 ꢁC for 1 h and at
room temperature for 2 h. The mixture was then cooled to
0 ꢁC and quenched carefully with saturated aqueous
NH4Cl. The mixture was extracted with diethyl ether and
the combined organic extracts were washed with brine, dried
over MgSO4, filtered, and concentrated under reduced
4.14. (R)-3-((2R,4S,5R,6S)-7-(4-Methoxybenzyloxy)-5-
(tert-butyldimethylsilyloxy)-2,4,6-trimethylheptanoyl)-
4-benzyloxazolidin-2-one (99)
NaHMDS (1 M in THF, 14.9 mL, 14.9 mmol) was added
dropwise over a 30 min period to a cooled (ꢀ78 ꢁC) suspen-
sion of imide 98 (7.91 g, 13.6 mmol) in THF (45 mL). After

8552
Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
pressure. The residue was purified by flash chromatography
(hexane/EtOAc 4:1 to 7:3) to afford the alcohol (4.57 g,
96%) as a colorless oil.
the crude aldehyde as a golden oil, which was used directly
in the next reaction without further purification. Carbon tet-
rabromide (7.56 g, 22.8 mmol) was added to a solution of tri-
phenylphosphine (12.3 g, 45.6 mmol) in CH2Cl2 (56 mL) at
0 ꢁC. The resulting dark-red mixture was stirred at 0 ꢁC for
10 min. A solution of the crude aldehyde and 2,6-lutidine
(2.66 mL, 22.8 mmol) in CH2Cl2 (45 mL) was added drop-
wise. The dark-brown mixture was stirred at 0 ꢁC for 1 h
and then quenched with a saturated aqueous NH4Cl. The
layers were separated, and the aqueous phase was extracted
with CH2Cl2. The combined organic extracts were washed
with H2O, dried over MgSO4, filtered, and concentrated un-
der reduced pressure. The residue was purified by short flash
chromatography (hexane 100%) to afford the dibromoolefin
(4.76 g, 73% yield from the alcohol) as a colorless oil that
was used without further purification. A solution of the
dibromoolefin (4.76 g, 8.2 mmol) in THF (40 mL) stirred
at ꢀ78 ꢁC was treated with n-BuLi (1.6 M in hexane,
15.4 mL, 24.6 mmol). The solution was stirred at ꢀ78 ꢁC
for 2 h and then quenched with saturated aqueous NH4Cl.
The mixture was allowed to reach room temperature and
was diluted with Et2O. The aqueous layer was extracted
with Et2O. The combined organic extracts were washed
with brine, dried over MgSO4, filtered, and concentrated un-
der reduced pressure. The residue was purified by flash chro-
matography (hexane/EtOAc 97:3) to afford the pure alkyne
78 (3.26 g, 95%) as a colorless oil: IR (film) 3313, 2100,
4.16. (2S,3R,4S,6R)-3,7-Bis(tert-butyldimethylsilyloxy)-
2,4,6-trimethylheptan-1-ol (101)
TBSCl (4.16 g, 27.6 mmol) was added to a solution of alco-
hol 100 (5.86 g, 13.8 mmol), imidazole (2.89 g, 41.4 mmol),
and DMAP (169 mg, 1.38 mmol) in CH2Cl2 (55 mL). The
resulting white suspension was stirred at room temperature
for 2 h, and the volatiles were removed under reduced pres-
sure. The residue was dissolved in hexane and brine. The
phases were separated, and the organic layer was washed
with brine, dried over MgSO4, filtered, and concentrated un-
der reduced pressure. The residue was purified by flash chro-
matography (hexane/EtOAc 19:1) to afford the TBS-
protected alcohol (7.04 g, 95%) as a colorless oil: IR (film)
1513, 1471, 1463, 1249, 1091, 1039 cmꢀ1 1H NMR
;
(300 MHz, CDCl3) d 7.30 (d, J¼8.6 Hz, 2H), 6.91 (d, J¼
8.6 Hz, 2H), 4.48 (d, J¼11.9 Hz, 1H), 4.44 (d, J¼11.9 Hz,
1H), 3.82 (s, 3H), 3.60–3.49 (m, 3H), 3.39–3.28 (m, 3H),
2.05–1.95 (m, 1H), 1.80–1.66 (m, 2H), 1.49–1.40 (m, 2H),
1.02 (d, J¼6.9 Hz, 3H), 1.0–0.91 (m, 24H), 0.10 (s, 3H),
0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 159.2, 131.1, 129.3, 127.9, 77.3, 73.1, 72.8, 68.4, 55.3,
38.9, 38.5, 33.5, 26.4, 26.2, 18.7, 18.6, 18.1, 15.3, 15.1,
ꢀ3.4, ꢀ3.8, ꢀ5.2; [a]2D0 ꢀ15.9 (c 0.47, CHCl3).
1
1472, 1463, 1252, 1088, 1005 cmꢀ1; H NMR (300 MHz,
CDCl3) d 3.53–3.48 (m, 2H), 3.33 (d, J¼9.7, 6.8 Hz, 1H),
2.62 (ddddd, J¼7.2, 7.2, 7.2, 5.1, 2.5 Hz, 1H), 2.03 (d,
J¼2.5 Hz, 1H), 1.97–1.80 (m, 1H), 1.73–1.6 (m, 1H), 1.47
(m, 1H), 1.21 (d, J¼7.1 Hz, 3H), 0.99–0.91 (m, 25H), 0.13
(s, 3H), 0.11 (s, 3H), 0.08 (s, 6H); 13C NMR (75 MHz,
CDCl3) d 87.9, 77.8, 70.2, 68.5, 39.2, 33.9, 33.7, 32.3,
26.4, 26.3, 18.6, 17.9, 17.5, 15.7, ꢀ3.6, ꢀ5.1; LRMS
(ESI) 435 [M+Na]+; [a]D20 ꢀ8.2 (c 3.1, CHCl3).
A solution of the above TBS-protected alcohol (5.28 g,
9.8 mmol) in CH2Cl2 (332 mL) and pH 7 phosphate buffer
solution (33 mL) was treated with DDQ (3.34 g,
14.7 mmol). The reaction mixture was stirred at room tem-
perature for 1 h and was quenched with saturated aqueous
NaHCO3 solution. The phases were separated and the aque-
ous layer was extracted with CH2Cl2. The combined organic
extracts were washed with water, dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was
purified by flash chromatography (hexane/EtOAc 97:3 to
93:7) to afford 101 (4.01 g, 98%) as a colorless oil: IR
(film) 3353, 1472, 1463, 1388, 1360, 1255, 1091, 1030,
4.18. (2R,4S,5R,6S)-7-(4-Methoxybenzyloxy)-5-(tert-
butyldimethylsilyloxy)-N-((1S,2S)-1-hydroxy-1-phenyl-
propan-2-yl)-N-2,4,6-tetramethylheptanamide (103)
1005 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 3.60 (d,
PPh3 (7.05 g, 26.2 mmol), imidazole (1.78 g, 26.2 mmol),
and diisopropylethylamine (4.6 mL, 26.2 mmol) in benzene
(80 mL), diethyl ether (165 mL), and acetonitrile (33 mL)
were stirred at room temperature and treated with iodine
(6.65 g, 26.2 mmol). The resulting mixture was vigorously
stirred until a beige suspension formed. A solution of alcohol
94 (5.0 g, 13.1 mmol) in Et2O (20 mL) was added dropwise
to the suspension, and the resulting mixture was stirred at
room temperature for 30 min. The reaction was quenched
with saturated aqueous NaHCO3 and diluted with Et2O.
The aqueous phase was extracted with Et2O, and the com-
bined organic extracts were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure.
The residue was triturated with hexane and the triturate
was concentrated under reduced pressure. This procedure
was repeated two more times to afford iodide 102 as a color-
less oil that was used directly in the next reaction. A solution
of n-BuLi in hexane (2.5 M, 21 mL, 52.4 mmol) was added
to a suspension of LiCl (7.05 g, 166.4 mmol) and
diisopropylamine (7.85 mL, 56.3 mmol) in THF (40 mL) at
ꢀ78 ꢁC. The suspension was stirred at ꢀ78 ꢁC for 5 min,
0 ꢁC for 15 min, and then cooled to ꢀ78 ꢁC. A solution of
J¼5.3 Hz, 2H), 3.55–3.45 (m, 2H), 3.32 (dd, J¼9.7,
6.7 Hz, 1H), 2.49 (br, 1H), 1.45 (ddd, J¼13.5, 7.5, 5.3 Hz,
1H), 0.95 (d, J¼7.1 Hz, 3H), 0.92 (s, 9H), 0.89 (s, 9H),
0.93–0.87 (m, 6H), 0.11 (s, 3H), 0.09 (s, 3H), 0.04 (s, 6H);
13C NMR (75 MHz, CDCl3) d 80.9, 68.0, 66.2, 38.4, 37.8,
35.4, 33.5, 26.3, 26.1, 18.5, 18.3, 16.2, 15.7, ꢀ3.6, ꢀ3.9,
ꢀ5.3; [a]2D0 ꢀ16.1 (c 4.4, CHCl3).
4.17. (3S,4R,5S,7R)-4-(tert-Butyldimethylsilyloxy)-7-
((tert-butyldimethylsilyloxy)methyl)-3,5-dimethyloct-
1-yne (78)
Sulfur trioxide pyridine complex (5.44 g, 34.2 mmol) was
added to a solution of 101 (4.78 g, 11.4 mmol) and triethyl-
amine (4.77 mL, 34.2 mmol) in CH2Cl2 (23 mL) and DMSO
(46 mL) at 0 ꢁC. The mixture was stirred at 0 ꢁC for 1 h and
then diluted with Et2O. The organic phase was washed with
cold 0.5 M aqueous NaHSO4 and then with brine. The
organic layer was dried over MgSO4, filtered, and concen-
trated under reduced pressure. The residue was purified by
short flash chromatography (hexane/EtOAc 9:1) to afford

Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
8553
(S,S)-pseudoephedrine propionamide (Myers’ auxiliary, 45)
(6.09 g, 27.5 mmol) in THF (70 mL) was added dropwise.
The resulting mixture was stirred at ꢀ78 ꢁC for 1 h, at
0 ꢁC for 15 min, and at room temperature for 5 min. The sus-
pension was cooled to 0 ꢁC, and the iodide was added as a so-
lution in THF (6 mL followed by a 6 mL rinse). The reaction
mixture was stirred at room temperature for 24 h and
quenched with half-saturated aqueous NH4Cl. The aqueous
layer was extracted with EtOAc, and the combined organic
extracts were dried over Na2SO4, filtered, and concentrated
under reduced pressure to give a residue, which was purified
by flash chromatography (hexane/EtOAc 1:1) to afford the
amide 103 (6.69 g, 87%) as a colorless oil: IR (film) 3387,
1616, 1513, 1463, 1248, 1087, 1037 cmꢀ1; HRMS (ESI)
calcd for C34H56NO5Si 586.3928 [M+H]+, found
586.3940; [a]2D0 +23.2 (c 1.26, CHCl3).
alcohol 105 (4.18 g, 79%) as a pale yellow oil: IR (CHCl3)
3469, 2955, 2856, 1471, 1448, 1252, 1084, 836, 774 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 7.55 (m, 6H), 7.36 (m, 9H),
5.71 (m, 2H), 4.59 (m, 1H), 4.03 (quint, J¼3.9 Hz, 1H),
3.65 (d, J¼3.9 Hz, 2H), 3.58 (dd, J¼4.6, 3.2 Hz, 1H), 3.55
(dd, J¼10.1, 5.1 Hz, 1H), 3.38 (dd, J¼9.7, 6.8 Hz, 1H),
2.71 (m, 1H), 2.50 (m, 1H), 2.32 (d, J¼5.4 Hz, 1H), 1.88
(m, 1H), 1.80 (m, 2H), 1.55 (m, 1H), 1.23 (d, J¼7.1 Hz,
3H), 1.11 (d, J¼6.8 Hz, 3H), 0.98 (m, 34H), 0.20 (s, 3H),
0.17 (s, 3H), 0.16 (s, 3H), 0.14 (s, 3H), 0.12 (s, 6H); 13C
NMR (75 MHz, CDCl3) d 144.3, 134.0, 128.6, 127.8,
127.1, 126.9, 88.1, 86.8, 83.0, 72.6, 68.3, 65.8, 65.1, 59.5,
41.9, 40.3, 38.7, 33.5, 33.2, 32.1, 26.0, 25.9, 18.4, 18.1,
17.7, 17.4, 15.7, 15.3, 14.2, ꢀ3.9, ꢀ4.0, ꢀ4.4, ꢀ4.5, ꢀ5.3;
LRMS (ESI) 949.7 [M+Na]+; HRMS (ESI) calcd for
C56H90O5Si3Na 949.5994 [M+Na]+, found 949.6018; [a]2D0
ꢀ10.0 (c 1.2, CHCl3).
4.19. (4R,5S,10S,11R,12S,14R,2E)-5,11,15-Tris(tert-
butyldimethylsilyloxy)-4,10,12,14-tetramethyl-1-
(trityloxy)pentadec-2-en-8-yn-7-one (104)
4.21. (2E,4R,5S,7S,8Z,10S,11R,12S,14R)-5,11,15-Tris-
(tert-butyldimethylsilyloxy)-4,10,12,14-tetramethyl-
1-(trityloxy)pentadeca-2,8-dien-7-ol (106)
Alkyne 78 (4.12 g, 10.0 mmol) was dissolved in THF
(100 mL), and the mixture was cooled to ꢀ78 ꢁC. n-BuLi
(6.25 mL, 1.6 M hexane solution) was added slowly. After
5 min, the mixture was warmed to 0 ꢁC and stirred for
30 min. The mixture was then cooled to ꢀ78 ꢁC and amide
79 (6.47 g, 11.3 mmol) in THF (5 mL) was added slowly.
After 5 min, the solution was warmed to 0 ꢁC and stirred
for 30 min. The reaction was quenched with saturated aque-
ous NH4Cl, and the mixture was partitioned in a separatory
funnel. The aqueous phase was extracted with Et2O
(3ꢄ20 mL). The combined organic extracts were washed
with brine and dried over MgSO4. Filtration and concentra-
tion under reduced pressure, followed by flash chromato-
graphy on silica gel (hexane/EtOAc 19:1), afforded the
ynone 104 (9.70 g, 93%) as a pale yellow oil: IR (CHCl3)
2955, 2928, 2856, 2209, 1676, 1471, 1462, 1252, 1085,
Lindlar catalyst (ca. 200 mg) was added to a solution of alco-
hol 105 (4.18 g, 4.51 mmol) in toluene (100 mL). The flask
was flushed with H2 via a balloon several times, and then
stirred under an atmosphere of H2 until starting material
was consumed (usually 1 h) as indicated by TLC analysis.
The mixture was filtered through a pad of Celite and concen-
trated under reduced pressure to afford the alkene 106 as
a colorless oil (3.82 g, 91%): IR (CHCl3) 3436, 2954,
1
2926, 2855, 1461, 1378, 1252, 1061, 836, 773 cmꢀ1; H
NMR (300 MHz, CDCl3) d 7.56 (m, 6H), 7.34 (m, 9H),
5.73 (m, 2H), 5.60 (t, J¼10.3 Hz, 1H), 5.43 (dd, J¼10.9,
8.4 Hz, 1H), 4.73 (m, 1H), 3.98 (q, J¼5.0 Hz, 1H), 3.68 (d,
J¼4.1 Hz, 1H), 3.59 (dd, J¼9.7, 4.7 Hz, 1H), 3.48 (m, 1H),
3.36 (dd, J¼9.0, 7.3 Hz, 1H), 2.79 (m, 1H), 2.58 (m, 1H),
2.23 (br, 1H), 1.78 (m, 1H), 1.71 (m, 1H), 1.66 (m, 2H),
1.50 (m, 1H), 1.11 (d, J¼6.8 Hz, 3H), 1.07 (d, J¼6.8 Hz,
3H), 1.00 (m, 34H), 0.22 (s, 3H), 0.18 (s, 3H), 0.14 (s, 6H),
0.13 (s, 6H); 13C NMR (75 MHz, CDCl3) d 144.3, 135.3,
134.6, 131.5, 128.7, 127.7, 127.0, 126.8, 86.8, 79.6, 73.0,
68.2, 65.0, 64.7, 42.0, 39.6, 38.0, 36.4, 34.9, 33.4, 26.2,
26.0, 25.9, 19.9, 18.4, 18.3, 18.1, 18.0, 15.2, 14.5, ꢀ3.4,
ꢀ3.7, ꢀ4.2, ꢀ4.4, ꢀ4.5, ꢀ5.4; LRMS (ESI) 951.7
[M+Na]+; HRMS (ESI) calcd for C56H92O5Si3Na 951.6150
[M+Na]+, found 951.6172; [a]D20 1.0 (c 0.62, CHCl3).
1
836, 774 cmꢀ1; H NMR (300 MHz, CDCl3) d 7.56 (m,
6H), 7.36 (m, 9H), 5.80 (dd, J¼15.6, 7.1 Hz, 1H), 5.69 (dt,
J¼15.7, 4.8 Hz, 1H), 4.37 (m, 1H), 3.69 (d, J¼4.7 Hz,
2H), 3.61 (m, 1H), 3.58 (dd, J¼9.7, 5.0 Hz, 1H), 3.43 (dd,
J¼9.7, 6.5 Hz, 1H), 2.87 (m, 1H), 2.73 (m, 1H), 2.46 (m,
1H), 1.88 (m, 1H), 1.76 (m, 1H), 1.59 (m, 1H), 1.31 (d,
J¼7.1 Hz, 3H), 1.15 (d, J¼6.8 Hz, 3H), 1.05 (m, 1H), 1.00
(m, 34H), 0.194 (s, 3H), 0.190 (s, 3H), 0.17 (s, 3H), 0.15
(s, 3H), 0.14 (s, 6H); 13C NMR (75 MHz, CDCl3) d 186.1,
144.2, 132.9, 128.6, 127.7, 126.9, 96.8, 86.8, 83.1, 71.5,
68.0, 64.9, 50.0, 42.3, 38.1, 34.4, 33.2, 32.1, 26.01, 25.96,
25.85, 18.3, 18.0, 17.9, 17.2, 15.5, 15.4, ꢀ3.8, ꢀ4.1, ꢀ4.6,
ꢀ4.7, ꢀ5.4; LRMS (ESI) 947.5 [M+Na]+; HRMS (ESI)
calcd for C56H88O5Si3Na 947.5837 [M+Na]+, found
947.5875; [a]2D0 ꢀ12.0 (c 0.54, CHCl3).
4.22. ((2E,4R,5S,7S,8Z,10S,11R,12S,14R)-5,7,11,15-
Tetrakis(tert-butyldimethylsilyloxy)-4,10,12,14-tetra-
methylpentadeca-2,8-dienyloxy)triphenylmethane (107)
TBSOTf (2.08 mL, 9.07 mmol) was added to a stirred solu-
tion of alcohol 106 (3.82 g, 4.11 mmol) and 2,6-lutidine
(1.14 mL, 9.85 mmol) in CH2Cl2 (14 mL) at 0 ꢁC. The reac-
tion mixture was stirred for 1 h at 0 ꢁC. The mixture was
quenched by the addition of H2O (25 mL). The reaction
mixture was extracted with CH2Cl2, and the organic phase
was dried over MgSO4, filtered, and concentrated under re-
duced pressure. The residue was purified by short column
chromatography (hexane/EtOAc 19:1) to yield 107 (4.27 g,
99%) as a colorless oil: IR (CHCl3) 2956, 2929, 2856,
4.20. (2E,4R,5S,7S,10S,11R,12S,14R,2E)-5,11,15-Tris-
(tert-butyldimethylsilyloxy)-4,10,12,14-tetramethyl-1-
(trityloxy)pentadec-2-en-8-yn-7-ol (105)
Ynone 104 (5.28 g, 5.71 mmol) was taken up in i-PrOH
(58 mL). The (S,S)-Noyori catalyst (0.77 g, 1.15 mmol,
20 mol %) was added in one portion, and the solution was
stirred overnight. The solvent was removed under vacuum,
and the crude residue was purified by flash chromatography
on silica gel (hexane/EtOAc 97:3), affording propargylic
1471, 1462, 1449, 1255, 1089, 1005, 836, 773, 705 cmꢀ1
1H NMR (300 MHz, CDCl3) d 7.60 (m, 6H), 7.39 (m, 9H),
;

8554
Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
5.77 (m, 2H), 5.56 (t, J¼10.8 Hz, 1H), 5.42 (dd, J¼11.0,
8.2 Hz, 1H), 4.69 (m, 1H), 4.07 (m, 1H), 3.71 (d,
J¼3.8 Hz, 2H), 3.64 (dd, J¼9.8, 4.8 Hz, 1H), 3.53 (m, 1H),
3.40 (dd, J¼9.6, 7.5 Hz, 1H), 2.74 (m, 1H), 2.55 (m, 1H),
1.89 (m, 3H), 1.59 (m, 3H), 1.12 (d, J¼6.2 Hz, 6H), 1.04
(m, 42H), 0.26 (s, 3H), 0.24 (s, 3H), 0.19 (s, 6H), 0.18 (s,
3H), 0.17 (s, 6H), 0.16 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 144.4, 134.5, 132.9, 132.6, 128.7, 127.7, 126.8,
86.8, 79.9, 72.3, 68.3, 66.5, 65.1, 64.1, 42.4, 41.6, 37.9,
36.0, 35.3, 33.6, 26.3, 26.02, 25.97, 25.7, 19.4, 18.5, 18.4,
18.20, 18.15, 18.1, 15.5, 13.3, ꢀ2.9, ꢀ3.5, ꢀ3.7, ꢀ4.1,
ꢀ4.2, ꢀ4.3, ꢀ5.3; LRMS (ESI) 1065.9 [M+Na]+; HRMS
(ESI) calcd for C62H106O5Si4Na 1065.7015 [M+Na]+, found
1065.7026; [a]20 ꢀ10.4 (c 0.53, CHCl3).
A mixture of ketophosphonate 39 (1.06 g, 2.75 mmol) and
Ba(OH)2 (0.38 g, activated by heating to 100 ꢁC for 1–2 h
before use) in THF (40 mL) was stirred at room temperature
for 30 min. A solution of the above aldehyde in wet THF
(4ꢄ1 mL washings, 40:1 THF/H2O) was then added. After
stirring for 12 h, the reaction mixture was diluted with
Et2O (30 mL) and washed with saturated aqueous NaHCO3
(50 mL) and brine (50 mL). The organic solution was dried
(MgSO4), filtered, and concentrated in vacuo. The residue
was chromatographed (hexane/EtOAc 9:1) to yield 109
(2.60 g, 80% in two steps) as a colorless oil: IR (CHCl3)
2956, 2928, 2855, 1688, 1618, 1518, 1471, 1461, 1338,
1251, 1080, 1038, 836, 773 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) d 7.50 (m, 6H), 7.40 (m, 2H), 7.30 (m, 9H), 6.89
(m, 2H), 6.73 (dd, J¼15.6, 8.5 Hz, 1H), 6.29 (d, J¼
15.6 Hz, 1H), 5.66 (m, 2H), 5.46 (t, J¼10.4 Hz, 1H), 5.46
(s, 1H), 5.31 (dd, J¼11.0, 8.4 Hz, 1H), 4.58 (t, J¼8.1 Hz,
1H), 4.12 (dd, J¼11.3, 4.6 Hz, 1H), 3.96 (m, 1H), 3.92 (dd,
J¼10.0, 4.2 Hz, 1H), 3.80 (s, 3H), 3.60 (d, J¼2.8 Hz, 2H),
3.56 (m, 1H), 3.39 (t, J¼3.3 Hz, 1H), 2.93 (m, 1H), 2.64
(m, 1H), 2.45 (m, 1H), 2.37 (m, 1H), 2.01 (m, 1H), 1.61
(m, 1H), 1.54 (m, 2H), 1.50 (m, 1H), 1.44 (m, 1H), 1.27 (d,
J¼7.0 Hz, 3H), 1.06 (d, J¼6.6 Hz, 3H), 1.02 (d, J¼6.5 Hz,
3H), 0.99 (d, J¼6.6 Hz, 3H), 0.95 (s, 9H), 0.94 (s, 9H),
0.88 (d, J¼6.6 Hz, 3H), 0.84 (s, 9H), 0.79 (d, J¼6.7 Hz,
3H), 0.15 (s, 3H), 0.14 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H),
0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 200.7, 159.8, 152.3, 144.3, 134.3, 132.8, 132.1, 131.0,
128.6, 127.7, 127.1, 126.8, 126.6, 113.4, 100.8, 86.7, 82.7,
80.0, 72.8, 72.1, 66.4, 65.0, 55.2, 47.1, 42.4, 41.4, 39.3,
35.8, 34.7, 34.6, 32.2, 26.1, 25.92, 25.86, 20.8, 19.7, 18.3,
18.1, 18.0, 15.0, 13.0, 12.4, 10.8, ꢀ2.9, ꢀ3.7, ꢀ3.8, ꢀ4.18,
ꢀ4.25, ꢀ4.35; LRMS (ESI) 1209.6 [M+Na]+; HRMS (ESI)
calcd for C72H110O8Si3Na 1209.7406 [M+Na]+, found
1209.7474; [a]2D0 ꢀ6.7 (c 0.11, CHCl3).
4.23. (2R,4S,5R,6S,7Z,9S,11S,12R,13E)-5,9,11-Tris(tert-
butyldimethylsilyloxy)-2,4,6,12-tetramethyl-15-(trityl-
oxy)pentadeca-7,13-dien-1-ol (108)
HF/pyridine in pyridine (40 mL, prepared by slow addition
of 12 mL of pyridine to 3 mL of HF/pyridine complex, fol-
lowed by dilution with 25 mL of THF) was slowly added to
a solution of TBS ether 107 (4.27 g, 4.10 mmol) in THF
(5 mL) at 0 ꢁC. The mixture was stirred for 21 h at 0 ꢁC
and quenched with saturated aqueous NaHCO3 (100 mL).
The aqueous layer was separated and extracted with Et2O
(3ꢄ50 mL). The combined organic layers were washed
with saturated aqueous CuSO4 (3ꢄ50 mL), dried over
MgSO4, filtered, and concentrated. Flash column chromato-
graphy (EtOAc/hexane 1:4) afforded 2.55 g (67%) of the al-
cohol 108 as a colorless oil: IR (CHCl3) 3350, 2956, 2928,
1
2856, 1471, 1448, 1254, 1086, 836, 773, 705 cmꢀ1; H
NMR (300 MHz, CDCl3) d 7.52 (m, 6H), 7.32 (m, 9H),
5.68 (m, 2H), 5.50 (t, J¼10.6 Hz, 1H), 5.35 (dd, J¼10.9,
8.5 Hz, 1H), 4.61 (t, J¼8.5 Hz, 1H), 4.00 (t, J¼8.1 Hz,
1H), 3.62 (d, J¼3.2 Hz, 2H), 3.58 (dd, J¼10.6, 4.3 Hz, 1H),
3.45 (m, 1H), 3.36 (dd, J¼9.9, 7.3 Hz, 1H), 2.66 (m, 1H),
2.48 (m, 1H), 1.70 (m, 3H), 1.49 (m, 3H), 1.04 (d,
,J¼6.6 Hz, 6H), 0.97 (s, 18H), 0.93 (m, 6H), 0.87 (s, 9H),
0.18 (s, 3H), 0.16 (s, 3H), 0.11 (s, 6H), 0.10 (s, 3H), 0.08
(s, 3H); 13C NMR (75 MHz, CDCl3) d 144.3, 134.4, 133.0,
132.1, 128.7, 127.7, 126.8, 86.7, 79.8, 72.3, 67.7, 66.5,
65.1, 42.4, 41.5, 37.3, 35.7, 35.5, 33.3, 26.2, 26.0, 25.9,
19.6, 18.4, 18.14, 18.06, 17.98, 15.7, 13.2, ꢀ2.9, ꢀ3.6,
ꢀ3.7, ꢀ4.1, ꢀ4.2, ꢀ4.3; LRMS (ESI) 951.8 [M+Na]+;
HRMS (ESI) calcd for C56H92O5Si3Na 951.6150
[M+Na]+, found 951.6162; [a]D20 ꢀ12.0 (c 0.71, CHCl3).
4.25. (2R,6S,8S,9R,10S,11Z,13S,15S,16R,17E)-9,13,15-
Tris(tert-butyldimethylsilyloxy)-2-((4S,5S)-2-(4-methoxy-
phenyl)-5-methyl-1,3-dioxan-4-yl)-6,8,10,16-tetra-
methyl-19-(trityloxy)nonadeca-11,17-dien-3-one (110)
NiCl2$6H2O (0.26 g, 1.09 mmol) and NaBH4 (0.17 g,
4.49 mmol) in portions were added to a stirred solution of
unsaturated ketone 109 (2.60 g, 2.19 mmol) in 80 mL of
3:2 MeOH/THF at 0 ꢁC. After 1 h, the reaction mixture
was evaporated and filtered through Celite eluting with
Et2O (30 mL). The organic phase was concentrated, and
the residue was purified by flash chromatography (EtOAc/
hexane 1:9) to yield 1.98 g of 110 (76%) as a colorless oil:
IR (CHCl3) 2955, 2927, 2855, 1711, 1614, 1518, 1461,
4.24. (2R,4E,6R,8S,9R,10S,11Z,13S,15S,16R,17E)-
9,13,15-Tris(tert-butyldimethylsilyloxy)-2-((4S,5S)-2-(4-
methoxyphenyl)-5-methyl-1,3-dioxan-4-yl)-6,8,10,16-
tetramethyl-19-(trityloxy)nonadeca-4,11,17-trien-3-one
(109)
1
1251, 1076, 835, 773 cmꢀ1; H NMR (300 MHz, CDCl3)
d 7.46 (m, 6H), 7.27 (m, 11H), 6.85 (m, 2H), 5.60 (m,
2H), 5.43 (s, 1H), 5.40 (m, 1H), 5.27 (m, 1H), 4.52 (m,
1H), 4.11 (dd, J¼11.1, 4.7 Hz, 1H), 3.91 (m, 2H), 3.78 (s,
3H), 3.55 (m 2H), 3.50 (m, 1H), 3.35 (m, 1H), 2.67 (m,
1H), 2.58 (m, 1H), 2.51 (m, 1H), 2.41 (m, 1H), 2.01 (m,
1H), 1.68 (m, 3H), 1.41 (m, 5H), 1.23 (d, J¼7.1 Hz, 3H),
0.96 (d, J¼6.7 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 9H), 0.88
(m, 1H), 0.87 (m, 3H), 0.80 (s, 9H), 0.78 (m, 6H), 0.10 (s,
3H), 0.08 (s, 3H), 0.04 (s, 3H), 0.03 (s, 6H), 0.01 (s, 3H);
13C NMR (75 MHz, CDCl3) d 211.9, 159.8, 144.5, 144.3,
134.4, 132.9, 132.4, 130.9, 128.6, 127.9, 127.8, 127.7,
127.1, 126.8, 113.4, 100.8, 86.7, 83.1, 79.9, 72.8, 72.2,
Alcohol 108 (2.55 g, 2.75 mmol) in CH2Cl2 (30 mL) was
treated with Dess–Martin periodinane (1.74 g, 4.10 mmol).
After 1 h, the mixture was quenched with saturated aqueous
NaHCO3 (30 mL) and Na2S2O3 (30 mL). The aqueous layer
was extracted with Et2O (2ꢄ30 mL), and the combined
extracts were dried over anhydrous MgSO4. Filtration and
concentration followed by short flash column chromato-
graphy (hexane/EtOAc 4:1) provided the crude aldehyde as
a colorless oil, which was used without further purification.

Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
8555
66.4, 65.1, 55.1, 48.3, 42.3, 41.5, 41.2, 38.1, 35.7, 35.0,
4.27. (4S,5S)-4-((2R,3R,6S,8S,9R,10S,11Z,13S,15S,16R,
31.2, 29.8, 29.7, 26.2, 25.92, 25.87, 20.2, 19.4, 18.4, 18.1,
18.0, 15.2, 13.2, 12.1, 9.6, ꢀ3.0, ꢀ3.5, ꢀ3.7, ꢀ4.2, ꢀ4.28,
ꢀ4.34; LRMS (ESI) 1211.9 [M+Na]+; HRMS (ESI) calcd
for C72H112O8Si3Na 1211.7563 [M+Na]+ found 1211.7616;
[a]2D0 +1.6 (c 0.50, CHCl3).
17E)-3,9,13,15-Tetrakis(tert-butyldimethylsilyloxy)-6,8,
10,16-tetramethyl-19-(trityloxy)nonadeca-11,17-dien-2-
yl)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxane (112b)
TBSOTf (0.40 mL, 1.74 mmol) was added to a stirred solu-
tion of alcohol 111b (1.39 g, 1.17 mmol) and 2,6-lutidine
(0.27 mL, 2.33 mmol) in CH2Cl2 (23 mL) at 0 ꢁC. After stir-
ring for 1 h at ambient temperature, the reaction mixture was
quenched by the addition of water (50 mL) and extracted
with CH2Cl2. After drying the organic phases over MgSO4
and concentrated under reduced pressure, the residue was
purified by short column chromatography (hexane/EtOAc
9:1) to yield 112b (1.51 g, 99%) as a colorless oil: IR
(CHCl3) 2955, 2928, 2855, 1615, 1517, 1461, 1250, 1074,
4.26. (2S,3R,6S,8S,9R,10S,11Z,13S,15S,16R,17E)-9,13,
15-Tris(tert-butyldimethylsilyloxy)-2-((4S,5S)-2-(4-meth-
oxyphenyl)-5-methyl-1,3-dioxan-4-yl)-6,8,10,16-tetra-
methyl-19-(trityloxy)nonadeca-11,17-dien-3-ol (111b)
NaBH4 (0.095 g, 2.51 mmol) was added to a solution of
ketone 110 (1.98 g, 1.67 mmol) in MeOH (28 mL) at 0 ꢁC.
After stirring for 2 h at 0 ꢁC, the reaction mixture was evap-
orated and water (30 mL) was added. The reaction mixture
was extracted with ether (2ꢄ40 mL), and the organic phase
was washed with brine (50 mL), dried over MgSO4, and
concentrated in vacuo. The residue was purified by flash
chromatography (EtOAc/hexane 1:9) to yield as major prod-
uct the title compound 111b (1.39 g, 70%, less polar) and as
minor product 111a (0.58 g, 28%, more polar) as colorless
oils. Compound 111b: IR (CHCl3) 3398, 2954, 2926,
1
1039, 835, 773 cmꢀ1; H NMR (300 MHz, CDCl3) d 7.59
(m, 6H), 7.52 (m, 2H), 7.41 (m, 9H), 7.01 (m, 2H),
5.74 (m, 2H), 5.57 (s, 1H), 5.50 (m, 1H), 5.43 (m, 1H), 4.67
(m, 1H), 4.25 (dd, J¼11.3, 4.6 Hz, 1H), 4.04 (m, 1H), 3.94
(s, 3H), 3.78 (m, 1H), 3.70 (m, 3H), 3.49 (m, 1H), 3.16
(m, 1H), 2.72 (m 1H), 2.54 (m, 1H), 2.18 (m, 1H), 2.01
(m, 1H), 1.82 (m, 3H), 1.54 (m, 6H), 1.14 (d, J¼6.9 Hz,
3H), 1.11 (d, J¼6.8 Hz, 3H), 1.10 (d, J¼6.5 Hz, 3H), 1.05
(s, 9H), 1.03 (s, 9H), 1.02 (s, 12H), 0.98 (d, J¼6.3 Hz,
3H), 0.94 (s, 9H), 0.87 (d, J¼6.7 Hz, 3H), 0.24 (s, 3H),
0.22 (s, 3H), 0.17 (m, 18H); 13C NMR (75 MHz, CDCl3)
d 159.6, 144.5, 144.3, 134.4, 133.1, 132.6, 131.5, 128.6,
127.7, 127.6, 127.1, 126.8, 126.7, 113.3, 100.4, 86.7, 81.9,
79.8, 74.9, 73.3, 72.2, 66.4, 65.1, 55.1, 42.3, 41.5, 38.8,
35.9, 34.5, 31.3, 31.2, 30.8, 30.7, 26.3, 25.99, 25.97,
25.91, 22.6, 20.3, 19.2, 18.5, 18.10, 18.05, 15.1, 14.1,
13.1, 12.4, 10.6, ꢀ3.0, ꢀ3.2, ꢀ3.6, ꢀ4.2, ꢀ4.25, ꢀ4.30;
LRMS (ESI) 1327.8 [M+Na]+; HRMS (ESI) calcd for
C78H128O8Si4Na 1327.8584 [M+Na]+, found 1327.8693;
[a]2D0 +7.6 (c 0.17, CHCl3).
2854, 1517, 1460, 1251, 1072, 835 cmꢀ1
;
1H NMR
(300 MHz, CDCl3) d 7.50 (m, 6H), 7.39 (m, 2H), 7.33 (m,
9H), 6.89 (m, 2H), 5.66 (m, 2H), 5.54 (s, 1H), 5.46 (m,
1H), 5.32 (m, 1H), 4.58 (m, 1H), 4.14 (dd, J¼11.3, 4.6 Hz,
1H), 3.95 (m, 1H), 3.87 (m, 1H), 3.80 (s, 3H), 3.72 (d,
J¼9.8 Hz, 1H), 3.61 (m, 2H), 3.55 (m, 1H), 3.41 (m, 1H),
3.24 (br, 1H), 2.64 (m, 1H), 2.46 (m, 1H), 2.16 (m, 1H),
1.82 (m, 1H), 1.71 (m, 2H), 1.53 (m, 5H), 1.35 (m, 2H),
1.06 (d, J¼7.2 Hz, 3H), 1.01 (d, J¼6.6 Hz, 3H), 0.95 (s,
9H), 0.93 (s, 9H), 0.90 (m, 9H), 0.85 (s, 9H), 0.78 (d,
J¼6.6 Hz, 3H), 0.14 (m, 6H), 0.09 (m, 12H); 13C NMR
(75 MHz, CDCl3) d 160.0, 144.5, 144.3, 134.4, 132.9,
132.4, 130.7, 128.7, 127.9, 127.8, 127.7, 127.6, 127.2,
127.1, 126.8, 113.6, 101.2, 89.1, 86.7, 80.0, 76.9, 73.1,
72.2, 66.5, 65.1, 42.3, 41.5, 41.4, 37.0, 36.7, 35.1,
32.5, 32.1, 30.4, 30.3, 26.2, 25.93, 25.87, 20.4, 19.4, 18.4,
18.1, 18.0, 15.4, 13.2, 11.8, 5.4, ꢀ3.0, ꢀ3.5, ꢀ3.7, ꢀ4.2,
ꢀ4.27, ꢀ4.33; LRMS (ESI) 1213.7 [M+Na]+; HRMS
(ESI) calcd for C72H114O8Si3Na 1213.7719 [M+Na]+, found
1213.7861; [a]2D0 +6.5 (c 0.31, CHCl3). Compound 111a: IR
(CHCl3) 3540, 2956, 2929, 2855, 1615, 1518, 1461, 1383,
4.28. (2S,3S,4R,5R,8S,10S,11R,12S,13Z,15S,17S,18R,
19E)-3-(4-Methoxybenzyloxy)-5,11,15,17-tetrakis(tert-
butyldimethylsilyloxy)-2,4,8,10,12,18-hexamethyl-21-
(trityloxy)henicosa-13,19-dien-1-ol (113b)
DIBALH (1.0 M in hexane, 11.7 mL, 11.7 mmol) was added
dropwise to a stirred solution of acetal 112b (1.53 g,
1.17 mmol) in anhydrous CH2Cl2 (2.3 mL) under an atmo-
sphere of N2 at 0 ꢁC. After stirring for additional 30 min at
0 ꢁC, the reaction was quenched by careful addition of satu-
rated aqueous potassium sodium tartrate (30 mL). The re-
sulting mixture was stirred for 3 h at room temperature.
The organic layer was separated, and the aqueous layer
was extracted with CH2Cl2 (20 mL). The combined organic
layers were washed with brine and dried over MgSO4, and
then concentrated under reduced pressure. The residue was
purified by column chromatography (EtOAc/hexane 1:9)
to yield pure 113b (1.35 g, 88%) as a colorless oil: IR
(CHCl3) 3464, 2956, 2929, 2856, 1613, 1514, 1471, 1252,
1
1251, 1074, 835, 773 cmꢀ1; H NMR (300 MHz, CDCl3)
d 7.61 (m, 6H), 7.51 (m, 2H), 7.44–7.32 (m, 9H), 7.00 (m,
2H), 5.77 (m, 2H), 5.61 (s, 1H), 5.55 (m, 1H), 5.45 (m,
1H), 4.71 (m, 1H), 4.24 (dd, J¼11.1, 4.5 Hz, 1H), 4.07 (m,
1H), 4.01 (m, 1H), 3.88 (s, 3H), 3.73–3.60 (m, 4H), 3.54
(m, 1H), 2.76 (m, 1H), 2.56 (m, 1H), 2.49 (m, 1H), 2.24
(m, 1H), 1.94–1.78 (m, 4H), 1.72–1.46 (m, 6H), 1.42–1.31
(m, 2H), 1.22 (d, J¼7.0 Hz, 3H), 1.13 (d, J¼5.9 Hz, 3H),
1.06 (s, 18H), 1.03 (m, 6H), 0.96 (s, 9H), 0.86
(d, J¼6.6 Hz, 3H), 0.27–0.18 (m, 18H); 13C NMR
(75 MHz, CDCl3) d 159.9, 144.4, 144.3, 134.3, 132.9,
132.4, 131.0, 128.6, 127.6, 127.2, 126.8, 113.5, 101.0,
86.7, 82.8, 79.8, 74.8, 73.2, 72.2, 66.4, 65.0, 55.1, 42.3,
41.5, 37.8, 35.9, 34.9, 33.2, 32.4, 30.3, 30.2, 26.2, 25.92,
25.87, 20.4, 19.3, 18.4, 18.1, 18.0, 15.3, 13.2, 11.8, 11.0,
ꢀ3.0, ꢀ3.4, ꢀ3.7, ꢀ3.9, ꢀ4.2, ꢀ4.28, ꢀ4.34; LRMS (ESI)
1213.9 [M+Na]+; HRMS (ESI) calcd for C72H114O8Si3Na
1213.7719 [M+Na]+, found 1213.7760; [a]2D0 +2.3 (c 0.75,
CHCl3).
1
1087, 836, 773 cmꢀ1; H NMR (300 MHz, CDCl3) d 7.46
(m, 6H), 7.28 (m, 11H), 6.88 (m, 2H), 5.61 (m, 2H), 5.39 (m,
1H), 5.28 (m, 1H), 4.57 (m, 1H), 4.53 (s, 2H), 3.92 (m, 2H),
3.83 (m, 1H), 3.80 (s, 3H), 3.60 (m, 2H), 3.56 (m, 2H),
3.46 (dd, J¼6.2, 4.5 Hz, 1H), 3.37 (m, 1H), 3.03 (m, 1H),
2.86 (m 1H), 2.59 (m, 1H), 2.41 (m, 1H), 1.93 (m, 1H),
1.88 (m, 1H), 1.66 (m, 2H), 1.35 (m, 4H), 1.11 (d,
J¼7.0 Hz, 3H), 1.01 (d, J¼6.8 Hz, 3H), 0.97 (d, J¼6.8 Hz,

8556
Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
3H), 0.92 (m, 27H), 0.85 (m, 10H), 0.81 (s, 9H), 0.11 (s, 3H),
0.09 (s, 3H), 0.07 (s, 3H), 0.06 (s, 6H), 0.05 (s, 6H), 0.04 (s,
3H); 13C NMR (75 MHz, CDCl3) d 159.2, 144.4, 144.3,
134.3, 133.0, 132.4, 130.5, 129.1, 128.6, 127.6, 126.7,
113.8, 86.7, 85.4, 79.8, 75.1, 73.8, 72.2, 66.4, 65.0, 55.0,
42.3, 41.6, 41.5, 40.5, 37.1, 35.8, 34.8, 32.0, 31.9, 30.7,
26.2, 25.94, 25.86, 20.3, 19.2, 18.4, 18.1, 18.0, 15.6, 15.2,
13.2, 10.0, ꢀ3.0, ꢀ3.4, ꢀ3.8, ꢀ3.9, ꢀ4.2, ꢀ4.28, ꢀ4.34,
ꢀ4.4; LRMS (ESI) 1329.8 [M+Na]+; HRMS (ESI) calcd
for C78H130O8Si4Na 1329.8741 [M+Na]+, found
1329.8779; [a]2D0 ꢀ8.9 (c 0.46, CHCl3).
13.3, 9.3, ꢀ2.9, ꢀ3.0, ꢀ3.3, ꢀ3.6, ꢀ3.7, ꢀ4.2, ꢀ4.3, ꢀ4.4;
LRMS (ESI) 1351.8 [M+Na]+; HRMS (ESI) calcd for
C81H132O7Si4Na 1351.8948 [M+Na]+, found 1351.9012;
[a]2D0 +1.1 (c 1.7, CHCl3).
4.30. (2E,4R,5S,7S,8Z,10S,11R,12S,14S,17R,18R,19S,
20S,21Z)-19-(4-Methoxybenzyloxy)-5,7,11,17-tetrakis-
(tert-butyldimethylsilyloxy)-4,10,12,14,18,20-hexa-
methyltetracosa-2,8,21,23-tetraen-1-ol (115b)
ZnBr2 (0.41 g) in 1.2 mL of 5:1 CH2Cl2/MeOH was added
dropwise over 30 min to a stirred solution of 114b (0.24 g,
0.18 mmol) in 1.4 mL of 6:1 CH2Cl2/MeOH at 0 ꢁC. After
4 h, the reaction was quenched with saturated aqueous
NaHCO3 (20 mL) and the mixture was extracted with
Et2O (2ꢄ10 mL). The organic phase was separated, dried
over MgSO4, filtered, and concentrated. The residue was pu-
rified by flash chromatography (EtOAc/hexane 1:9) to yield
115b (0.15 g, 77%) as a colorless oil: IR (CHCl3) 3432,
2956, 2856, 1613, 1514, 1471, 1462, 1360, 1250, 1082,
4.29. ((2E,4R,5S,7S,8Z,10S,11R,12S,14S,17R,18R,19S,
20S,21Z)-19-(4-Methoxybenzyloxy)-5,7,11,17-tetrakis-
(tert-butyldimethylsilyloxy)-4,10,12,14,18,20-hexa-
methyltetracosa-2,8,21,23-tetraenyloxy)triphenyl-
methane (114b)
Alcohol 113b (1.35 g, 1.03 mmol) in CH2Cl2 (20 mL) was
treated with Dess–Martin periodinane (0.66 g, 1.56 mmol).
After 1 h, the reaction was quenched with saturated aqueous
NaHCO3 (20 mL) and Na2S2O3 (20 mL). The aqueous layer
was extracted with Et2O (2ꢄ20 mL), and the combined ex-
tracts were dried over anhydrous MgSO4. Filtration and con-
centration followed by short flash column chromatography
(hexane/EtOAc 9:1) provided the crude aldehyde as a color-
less oil, which was used without further purification. CrCl2
(1.06 g, 8.62 mmol) was added to a stirred solution of the
crude aldehyde and 1-bromoallyl trimethylsilane (1.28 g,
5.20 mmol) in anhydrous THF (26 mL) under an atmosphere
of N2 at room temperature. After 14 h at ambient tempera-
ture, the reaction mixture was diluted with hexane followed
by filtration through Celite. The solvent was evaporated un-
der reduced pressure, and the residue was purified by short
silica gel column chromatography using EtOAc/hexane
(1:9) as eluant. This product in THF (40 mL) was cooled
to 0 ꢁC, and NaH (95% w/w, 0.52 g, 20.6 mmol) was added
in one portion. The ice bath was removed after 15 min, and
the mixture was stirred for 2 h at ambient temperature and
then cooled to 0 ꢁC. The reaction was quenched with H2O
(5 mL) and the mixture extracted with Et2O (2ꢄ20 mL).
The combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromato-
graphy (hexane/EtOAc 49:1) to obtain 114b (1.17 g, 85%
in three steps) as a colorless oil: IR (CHCl3) 2956, 2928,
1
835, 773 cmꢀ1; H NMR (300 MHz, CDCl3) d 7.29 (m,
2H), 6.88 (m, 2H), 6.58 (ddd, J¼16.9, 10.6, 10.6 Hz, 1H),
6.00 (t, J¼11.0 Hz, 1H), 5.63 (m, 3H), 5.38 (t, J¼11.0 Hz,
1H), 5.27 (dd, J¼11.2, 8.3 Hz, 1H), 5.17 (d, J¼16.8 Hz,
1H), 5.10 (d, J¼10.3 Hz, 1H), 4.53 (m, 3H), 4.08 (d,
J¼4.4 Hz, 2H), 3.90 (m, 1H), 3.81 (s, 3H), 3.62 (m, 1H),
3.33 (m, 2H), 2.99 (ddd, J¼10.0, 6.8, 3.2 Hz, 1H), 2.57
(m, 1H), 2.39 (m, 1H), 1.63 (m, 3H), 1.42 (m, 3H), 1.28
(m, 5H), 1.11 (d, J¼6.8 Hz, 3H), 0.97 (d, J¼6.8 Hz, 3H),
0.96 (d, J¼6.9 Hz, 3H), 0.93 (s, 9H), 0.91 (s, 18H), 0.89
(m, 3H), 0.88 (s, 9H), 0.81 (d, J¼6.7 Hz, 3H), 0.80 (d,
J¼6.2 Hz, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (s, 6H),
0.06 (s, 3H), 0.05 (s, 6H), 0.03 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 159.0, 146.9, 135.2, 134.6, 133.0,
132.7, 132.3, 131.4, 129.2, 129.1, 128.9, 127.93, 127.90,
127.2, 84.4, 80.0, 75.0, 72.8, 72.2, 66.6, 63.9, 55.2, 42.4,
41.8, 41.7, 40.5, 35.9, 35.2, 34.6, 32.6, 31.6, 30.5, 26.3,
25.99, 25.96, 25.93, 20.2, 19.2, 18.8, 18.5, 18.2, 18.1,
15.1, 13.2, 9.2, ꢀ3.0, ꢀ3.3, ꢀ3.6, ꢀ3.7, ꢀ4.2, ꢀ4.4, ꢀ4.5;
LRMS (ESI) 1109.8 [M+Na]+; HRMS (ESI) calcd for
C62H118O7Si4Na 1109.7852 [M+Na]+, found 1109.7897;
[a]2D0 +1.6 (c 0.94, CHCl3).
4.31. (2Z,4E,6R,7S,9S,10Z,12S,13R,14S,16S,19R,20R,
21S,22S,23Z)-Methyl-21-(4-methoxybenzyloxy)-7,9,13,
19-tetrakis(tert-butyldimethylsilyloxy)-6,12,14,16,20,
22-hexamethylhexacosa-2,4,10,23,25-pentaenoate
(116b)
2856, 1614, 1514, 1471, 1462, 1249, 1088, 836, 772 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 7.46 (m, 6H), 7.27 (m,
11H), 6.86 (m, 2H), 6.58 (ddd, J¼17.0, 10.6, 10.5 Hz,
1H), 6.00 (t, J¼11.0 Hz, 1H), 5.60 (m, 3H), 5.31 (m, 2H),
5.17 (d, J¼16.9 Hz, 1H), 5.09 (d, J¼10.4 Hz, 1H), 4.51
(m, 3H), 3.90 (m, 1H), 3.80 (s, 3H), 3.61 (m, 1H), 3.56 (d,
J¼3.7 Hz, 1H), 3.33 (m, 2H), 3.00 (m, 1H), 2.56 (m, 1H),
2.40 (m, 1H), 2.21 (m, 1H), 1.63 (m, 3H), 1.38–1.21 (5H),
1.10 (d, J¼6.7 Hz, 3H), 0.96 (m, 3H), 0.93 (s, 9H), 0.91
(s, 9H), 0.89 (s, 9H), 0.86 (m, 6H), 0.82 (m, 6H), 0.80 (s,
9H), 0.79 (m, 3H), 0.08 (m, 6H), 0.05 (m, 6H), 0.04 (m,
6H), 0.01 (m, 6H); 13C NMR (75 MHz, CDCl3) d 159.0,
146.2, 144.5, 144.4, 134.6, 134.5, 133.1, 132.7, 132.3,
131.4, 129.0, 128.9, 128.7, 127.7, 126.8, 117.1, 113.7,
86.8, 84.4, 79.9, 75.0, 72.9, 72.3, 66.5, 65.1, 55.2, 42.4,
41.9, 41.6, 40.6, 36.0, 35.6, 35.3, 34.5, 32.5, 31.7, 30.5,
26.3, 26.0, 25.9, 20.2, 19.2, 18.8, 18.5, 18.2, 18.1, 15.1,
Alcohol 115b (127 mg, 0.117 mmol) in CH2Cl2 (4 mL) was
treated with Dess–Martin periodinane (75 mg, 0.18 mmol).
After 1 h, the reaction was quenched with saturated aqueous
NaHCO3 (5 mL) and Na2S2O3 (5 mL). The aqueous layer
was extracted with Et2O (2ꢄ10 mL), and the combined ex-
tracts were dried over anhydrous MgSO4. Filtration and con-
centration followed by short flash column chromatography
(hexane/EtOAc 9:1) provided the crude aldehyde as a color-
less oil, which was used for the next reaction without further
purification. KHMDS (0.28 mL, 0.14 mmol, 0.5 M solution
in toluene) was added dropwise to a stirred solution of
bis(2,2,2-trifluoroethyl)-(methoxycarbonylmethyl) phos-
phate (0.030 mL, 0.14 mmol) and 18-crown-6 (0.15 g,
0.57 mmol) in THF (2.3 mL) at ꢀ78 ꢁC. The aldehyde in

Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
8557
THF (0.5 mL) was added and the solution was stirred for 4 h
at ꢀ78 ꢁC. The reaction was quenched by the addition of sat-
urated aqueous NH4Cl (5 mL) and the mixture was diluted
with Et2O (20 mL). The organic phase was washed with
brine (30 mL), dried with MgSO4, filtered, and concentrated.
The residue was purified by flash chromatography (EtOAc/
hexane 1:19) yielding ester 116b (0.104 g, 86% in two steps)
as a colorless oil: IR (CHCl3) 2955, 2929, 2856, 1722, 1514,
132.6, 132.3, 129.9, 126.8, 117.7, 115.5, 79.9, 77.6, 76.6,
72.1, 66.5, 51.0, 43.5, 42.4, 41.5, 37.7, 36.1, 35.7, 35.0,
32.1, 31.5, 30.6, 26.3, 25.9, 25.9, 20.4, 19.4, 18.5, 18.1,
17.9, 17.7, 15.3, 13.3, 6.9, ꢀ3.0, ꢀ3.4, ꢀ3.7, ꢀ4.1, ꢀ4.2,
ꢀ4.4; LRMS (ESI) 1043.6 [M+Na]+; HRMS (ESI) calcd
for C57H112O7Si4Na 1043.7383 [M+Na]+, found
1043.7417; [a]2D0 ꢀ25.3 (c 0.61, CHCl3).
1
1471, 1462, 1250, 1174, 1085, 1041, 836, 773 cmꢀ1; H
4.33. (2Z,4E,6R,7S,9S,10Z,12S,13R,14S,16S,19R,20R,
21S,22S,23Z)-7,9,13,19-Tetrakis(tert-butyldimethyl-
silyloxy)-21-hydroxy-6,12,14,16,20,22-hexamethyl-
hexacosa-2,4,10,23,25-pentaenoic acid (118b)
NMR (300 MHz, CDCl3) d 7.39 (dd, J¼15.4, 11.3 Hz,
1H), 7.29 (m, 2H), 6.88 (m, 2H), 6.59 (ddd, J¼16.9, 10.8,
10.6 Hz, 1H), 6.55 (t, J¼11.3 Hz, 1H), 6.01 (t, J¼11.0 Hz,
1H), 6.00 (dd, J¼15.7, 7.0 Hz, 1H), 5.60 (d, J¼11.3 Hz,
1H), 5.59 (t, J¼10.4 Hz, 1H), 5.39 (t, J¼10.4 Hz, 1H),
5.27 (dd, J¼11.0, 8.3 Hz, 1H), 5.18 (d, J¼16.8 Hz, 1H),
5.11 (d, J¼10.3 Hz, 1H), 4.54 (m, 3H), 3.96 (m, 1H), 3.81
(s, 3H), 3.74 (s, 3H), 3.63 (m, 1H), 3.34 (m, 2H), 3.00 (m,
1H), 2.57 (m, 2H), 1.64 (m, 3H), 1.55 (m, 1H), 1.46 (t,
J¼5.9 Hz, 2H), 1.26 (m, 5H), 1.11 (d, J¼6.8 Hz, 3H), 1.05
(d, J¼6.7 Hz, 3H), 0.97 (d, J¼6.9 Hz, 3H), 0.96 (d,
J¼7.1 Hz, 3H), 0.94 (s, 9H), 0.92 (s, 9H), 0.91 (s, 9H),
0.87 (s, 9H), 0.83 (d, J¼6.4 Hz, 3H), 0.82 (d, J¼6.0 Hz,
3H), 0.13 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H),
0.06 (s, 3H), 0.05 (s, 6H), 0.04 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 166.8, 159.0, 147.3, 145.5, 134.6,
132.9, 132.8, 132.4, 131.4, 129.0, 128.9, 126.9, 117.1,
115.5, 113.7, 84.4, 80.0, 75.0, 72.9, 72.1, 66.5, 55.2, 50.9,
43.5, 42.5, 41.8, 40.5, 36.0, 35.3, 34.5, 32.5, 31.6, 30.5,
26.3, 25.99, 25.96, 25.91, 20.2, 19.2, 18.8, 18.5, 18.2,
18.1, 15.0, 13.4, 9.2, ꢀ3.0, ꢀ3.2, ꢀ3.3, ꢀ3.6, ꢀ3.7, ꢀ4.1,
ꢀ4.4, ꢀ4.5; LRMS (ESI) 1163.9 [M+Na]+; HRMS (ESI)
calcd for C65H120O8Si4Na 1163.7958 [M+Na]+, found
1163.7985; [a]2D0 ꢀ9.3 (c 1.2, CHCl3).
A stirred solution of alcohol 117b (26 mg, 24 mmol) in
2.4 mL of 12:5 EtOH/THF was treated with 1 N aqueous
KOH (0.24 mL), and the mixture was refluxed gently for
3 h. The ethanolic solution was concentrated and then diluted
with Et2O (4 mL). After the solution was acidified to pH 3
with 1 N aqueous HCl, the organic phase was separated
and the aqueous phase was extracted with Et2O (2ꢄ5 mL).
The combined organic phase was dried over MgSO4, filtered,
and concentrated. The residue was purified by chromato-
graphy (15% EtOAc/hexane) to give 15.7 mg (61%) alcohol:
IR (CHCl3) 2956, 2929, 2857, 1693, 1635, 1600, 1471, 1462,
1
1254, 1088, 836, 773 cmꢀ1; H NMR (300 MHz, CDCl3)
d 7.33 (dd, J¼15.2, 11.3 Hz, 1H), 6.61 (t, J¼11.4 Hz, 1H),
6.61 (m, 1H), 6.07 (t, J¼11.0 Hz, 1H), 6.02 (dd, J¼15.8,
7.2 Hz, 1H), 5.58 (d, J¼11.3 Hz, 1H), 5.39 (m, 2H), 5.23
(dd, J¼11.0, 8.2 Hz, 1H), 5.18 (d, J¼16.8 Hz, 1H), 5.09 (d,
J¼10.2 Hz, 1H), 4.50 (m, 1H), 3.92 (m, 1H), 3.73 (m, 1H),
3.46 (dd, J¼7.3, 2.6 Hz, 1H), 3.34 (m, 1H), 2.78 (m, 1H),
2.54 (m, 2H), 1.66 (m, 4H), 1.42 (m, 4H), 1.24 (m, 3H),
1.01 (d, J¼6.8 Hz, 3H), 0.95 (d, J¼6.7 Hz, 3H), 0.94 (d,
J¼6.7 Hz, 3H), 0.88 (m, 30H), 0.84 (m, 15H), 0.09 (s, 3H),
0.07 (s, 3H), 0.06 (s, 6H), 0.02 (s, 6H), 0.01 (s, 6H);
13C NMR (75 MHz, CDCl3) d 171.2, 148.2, 147.3, 135.2,
133.2, 132.7, 132.3, 123.0, 127.0, 117.7, 115.2, 79.9, 77.6,
76.5, 72.1, 66.4, 43.5, 42.6, 41.6, 37.8, 36.0, 35.8, 34.9,
32.1, 31.5, 30.6, 26.2, 25.93, 25.87, 20.3, 19.4, 18.4, 18.10,
18.05, 17.7, 15.3, 13.6, 6.9, ꢀ3.0, ꢀ3.4, ꢀ3.7, ꢀ4.1,
ꢀ4.19, ꢀ4.24, ꢀ4.4; LRMS (ESI) 1029.7 [M+Na]+;
HRMS (ESI) calcd for C56H110O7Si4Na 1029.7226
[M+Na]+, found 1029.7274; [a]D20 ꢀ25.7 (c 0.54, CHCl3).
4.32. (2Z,4E,6R,7S,9S,10Z,12S,13R,14S,16S,19R,20R,
21S,22S,23Z)-Methyl-7,9,13,19-tetrakis(tert-butyldi-
methylsilyloxy)-21-hydroxy-6,12,14,16,20,22-hexa-
methylhexacosa-2,4,10,23,25-pentaenoate (117b)
Ester 116b (81 mg, 71 mmol) was added to a mixture of
CH2Cl2 (2 mL) and H2O (0.1 mL), and DDQ (20 mg,
88 mmol) was added at 0 ꢁC. After 1 h at 0 ꢁC, the reaction
was quenched by adding saturated aqueous NaHCO3
(5 mL). The organic phase was washed with saturated aque-
ous NaHCO3 (3ꢄ10 mL) and brine, dried over MgSO4, fil-
tered, and concentrated. Purification by flash column
chromatography (EtOAc/hexane 1:9) furnished 117b
(64 mg, 88%) as a colorless oil: IR (CHCl3) 3541, 2956,
2929, 2856, 1722, 1639, 1471, 1462, 1377, 1360, 1254,
4.34. (8S,10S,14R,20R)-Tetrakis(tert-butyldimethylsilyl-
oxy)-(7R,13S,15S,17S,21S)-pentamethyl-(22S)-((1S)-
methylpenta-2,4-dienyl)oxacyclodocosa-3,5,11-
trien-2-one (119b)
1
1175, 1086, 836, 773 cmꢀ1; H NMR (300 MHz, CDCl3)
A solution of 118b (15.7 mg, 15.6 mmol) in THF (2 mL) was
treated at 0 ꢁC with Et3N (0.013 mL, 93 mmol) and 2,4,6-tri-
chlorobenzoyl chloride (0.012 mL, 77 mmol). The reaction
mixture was stirred at 0 ꢁC for 30 min and then added to 4-
DMAP (7.8 mL, 0.02 M solution in toluene) at 25 ꢁC. After
stirring for 12 h, the reaction mixture was concentrated, Et2O
(10 mL) was added, and the mixture was washed with 1 N
HCl (2ꢄ5 mL) and dried over MgSO4. Purification by flash
column chromatography (EtOAc/hexane 1:49) furnished
the macrolactone (12 mg, 78%) as a colorless oil: IR
(CHCl3) 2955, 2929, 2857, 1716, 1642, 1474, 1225, 1043,
d 7.34 (dd, J¼15.4, 11.2 Hz, 1H), 6.61 (ddd, J¼16.8, 10.7,
10.6 Hz, 1H), 6.51 (t, J¼11.3 Hz, 1H), 6.06 (t, J¼11.0 Hz,
1H), 5.96 (dd, J¼15.4, 7.1 Hz, 1H), 5.56 (d, J¼11.3 Hz,
1H), 5.39 (t, J¼10.1 Hz, 1H), 5.38 (t, J¼10.3 Hz, 1H),
5.22 (dd, J¼11.0, 8.5 Hz, 1H), 5.17 (d, J¼18.7 Hz, 1H),
5.09 (d, J¼10.1 Hz, 1H), 4.50 (m, 1H), 3.92 (m, 1H), 3.71
(m, 1H), 3.70 (s, 3H), 3.44 (m, 1H), 3.32 (m, 1H),
2.74 (m, 1H), 2.52 (m, 2H), 2.31 (br, 1H), 1.61 (m, 4H),
1.39 (m, 2H), 1.31 (m, 2H), 1.26 (m, 3H), 1.00 (d,
J¼6.7 Hz, 3H), 0.93 (d, J¼6.9 Hz, 3H), 0.92 (d, J¼6.7 Hz,
3H), 0.86 (m, 27H), 0.84 (m, 6H), 0.82 (m, 12H), 0.05 (s,
9H), 0.02 (s, 3H), 0.01 (s, 6H), 0.00 (s, 6H); 13C NMR
(75 MHz, CDCl3) d 166.8, 147.3, 145.5, 135.3, 132.7,
1
836, 773 cmꢀ1; H NMR (300 MHz, CDCl3) d 6.98 (dd,
J¼14.8, 11.3 Hz, 1H), 6.55 (m, 1H), 6.52 (t, J¼
11.2 Hz, 1H), 6.04 (t, J¼10.5 Hz, 1H), 6.01 (dd, J¼15.4,

8558
Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
6.4 Hz, 1H), 5.59 (d, J¼11.2 Hz, 1H), 5.58 (m, 1H), 5.38 (t,
J¼10.6 Hz, 1H), 5.33 (dd, J¼11.3, 8.1 Hz, 1H), 5.19 (d,
J¼16.6 Hz, 1H), 5.11 (d, J¼10.5 Hz, 1H), 5.06 (dd, J¼
7.6, 3.7 Hz, 1H), 4.52 (m, 1H), 4.01 (m, 1H), 3.63 (m, 1H),
3.19 (d, J¼6.2 Hz, 1H), 3.03 (m, 1H), 2.58 (m, 1H), 2.52
(m, 2H), 1.81 (m, 4H), 1.45 (m, 3H), 1.25 (m, 3H), 1.09
(m, 3H), 1.02 (d, J¼6.8 Hz, 3H), 1.01 (d, J¼7.0 Hz, 3H),
0.97 (d, J¼6.6 Hz, 3H), 0.95 (d, J¼6.4 Hz, 3H), 0.91 (s,
9H), 0.89 (s, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.77 (d,
J¼6.4 Hz, 3H), 0.75 (d, J¼6.5 Hz, 3H), 0.10 (s, 3H), 0.07
(s, 3H), 0.06 (s, 3H), 0.04 (s, 3H), 0.033 (s, 6H), 0.026 (s,
6H); 13C NMR (75 MHz, CDCl3) d 166.5, 143.1, 141.8,
133.9, 132.7, 131.8, 130.2, 129.8, 128.0, 118.4, 118.1,
81.0, 78.0, 70.4, 66.5, 62.5, 43.1, 42.3, 41.4, 39.1, 35.2,
34.8, 34.5, 31.6, 30.3, 29.7, 29.3, 26.2, 26.0, 25.94,
25.85, 20.2, 19.7, 18.5, 18.24, 18.16, 18.08, 16.2, 14.0,
9.9, ꢀ2.7, ꢀ3.4, ꢀ3.5, ꢀ3.8, ꢀ3.9, ꢀ4.2, ꢀ4.3; [a]D20
ꢀ18.1 (c 0.24, CHCl3). A small amount of the impure
2E,4E-isomer was also isolated: 1H NMR (300 MHz,
CDCl3) d 7.35 (dd, J¼11.2, 15.5 Hz, 1H), 6.63 (dt, J¼10.5,
16.8 Hz, 1H), 6.44 (t, J¼11.3 Hz, 1H), 6.01–5.80 (m, 2H),
5.57 (t, J¼10.6 Hz, 1H), 5.50 (d, J¼11.4 Hz, 1H), 5.38 (t,
J¼10.3 Hz, 1H), 5.30 (dd, J¼8.5, 11.0 Hz, 1H), 5.22–5.01
(m, 3H), 4.47 (m, 1H), 3.77 (m, 1H), 3.48 (m, 1H), 3.30
(m, 1H), 2.97 (m, 1H), 2.56 (m, 1H), 2.44 (m, 1H),
1.91 (m, 1H), 1.65 (m, 1H), 1.52–0.71 (m, 63H), 0.12–0.04
(m, 24H).
(150 MHz, CD3OD) d 168.10, 146.42, 144.90, 134.87,
134.54, 133.43, 131.32, 131.27, 128.60, 118.58, 118.04,
80.37, 78.64, 73.73, 70.41, 65.53, 44.07, 42.28,
40.84, 40.65, 35.84, 35.78, 35.33, 32.75, 32.51, 31.23,
21.81, 19.36, 18.08, 15.98, 13.80, 10.41; LRMS (ESI)
555.3 [M+Na]+; HRMS (ESI) calcd for C32H52O6Na
555.3662 [M+Na]+, found 555.3665; [a]2D0 ꢀ22.6 (c 0.27,
MeOH).
4.36. (2Z,4E,6R,7S,9S,10Z,12S,13R,14S,16S,
19R,20S,21S,22S,23Z)-Methyl-7,9,13,19,21-penta-
hydroxy-6,12,14,16,20,22-hexamethylhexacosa-
2,4,10,23,25-pentaenoate (120b)
HCl (3 N, 10 mL, prepared by adding 2.5 mL of concd HCl
to 7.5 mL MeOH) was added to a stirred solution of 116b
(23 mg, 23 mmol) in THF (3 mL) at 0 ꢁC. After 24 h at
room temperature, the reaction mixture was diluted with
EtOAc (4 mL) and H2O (4 mL). The organic phase was re-
tained, and the aqueous phase was extracted with EtOAc
(2ꢄ4 mL). The combined organic phase was washed with
saturated aqueous NaHCO3 (10 mL), dried with MgSO4,
filtered, and concentrated. The residue was purified by flash
chromatography (EtOAc/hexane 3:2) to yield the product
120b (4.5 mg, 36%) as a colorless oil: IR (CHCl3) 3399,
2917, 2849, 1713, 1635, 1600, 1461, 1439, 1197, 1178,
1
970, 757 cmꢀ1; H NMR (600 MHz, CD3OD) d 7.36 (dd,
J¼15.3, 11.2 Hz, 1H), 6.67 (ddd, J¼16.9, 11.1, 10.6 Hz,
1H), 6.63 (dd, J¼11.3, 11.3 Hz, 1H), 6.14 (dd, J¼15.4,
8.3 Hz, 1H), 6.03 (dd, J¼11.0, 11.0 Hz, 1H), 5.59 (d, J¼
11.4 Hz, 1H), 5.43 (dd, J¼10.7, 10.7 Hz, 1H), 5.42 (dd, J¼
10.8, 9.2 Hz, 1H), 5.32 (dd, J¼10.4, 10.4 Hz, 1H), 5.17
(dd, J¼16.8, 2.0 Hz, 1H), 5.08 (d, J¼10.2 Hz, 1H), 4.61
(ddd, J¼12.9, 8.5, 4.6 Hz, 1H), 3.80 (ddd, J¼8.9, 4.4,
4.4 Hz, 1H), 3.69 (s, 3H), 3.63 (m, 1H), 3.46 (t,
J¼5.8 Hz, 1H), 3.13 (dd, J¼8.0, 3.2 Hz, 1H), 2.93 (m,
1H), 2.71 (m, 1H), 2.38 (m, 1H), 1.73 (m, 1H), 1.56–
1.53 (m, 3H), 1.52–1.46 (m, 2H), 1.44–1.36 (m, 3H),
1.09 (d, J¼6.9 Hz, 3H), 0.98 (d, J¼6.8 Hz, 3H), 0.96 (d,
J¼6.6 Hz, 3H), 0.95 (m, 2H), 0.94 (d, J¼6.9 Hz, 3H),
0.87 (d, J¼6.6 Hz, 3H), 0.86 (d, J¼6.8 Hz, 3H); 13C
NMR (150 MHz, CD3OD) d 168.4, 148.5, 146.9, 135.7,
135.4, 133.85, 133.82, 130.6, 128.2, 117.7, 116.2, 79.2,
78.5, 74.8, 72.4, 65.8, 51.5, 45.1, 43.2, 43.0, 41.0, 37.2,
36.5, 34.0, 33.3, 33.1, 31.0, 20.7, 18.6, 18.4, 16.7, 13.8,
7.8; LRMS (ESI) 587.5 [M+Na]+; HRMS (ESI) calcd for
C33H56O7Na 587.3924 [M+Na]+, found 587.3953; [a]2D0
+8.7 (c 0.30, CDCl3).
4.35. (8S,10S,14R,20R)-Tetrahydroxy-(7R,13S,15S,
17S,21S)-pentamethyl-(22S)-((1S)-methylpenta-2,4-
dienyl)oxacyclodocosa-3,5,11-trien-2-one (1)
A stirred solution of macrolactone 119b (18 mg, 18 mmol) in
THF (3 mL) at 0 ꢁC was treated with 3 N HCl (10 mL, pre-
pared by adding 2.5 mL of concd HCl to 7.5 mL MeOH).
After 24 h at room temperature, the reaction mixture was
diluted with EtOAc (4 mL) and H2O (4 mL). The organic
phase was separated, and the aqueous phase was extracted
with EtOAc (2ꢄ4 mL). The combined organic phase was
washed with saturated aqueous NaHCO3 (10 mL), dried
over MgSO4, filtered, and concentrated. The residue was
purified by flash chromatography (EtOAc/hexane 3:2) to
yield 1 as a white solid (5.3 mg, 55%): IR (CHCl3) 3406,
2960, 2924, 2872, 1693, 1637, 1461, 1378, 1274, 1181,
1069, 998, 738 cmꢀ1
;
1H NMR (600 MHz, CD3OD)
d 7.21 (dd, J¼15.6, 11.1 Hz, 1H), 6.71 (ddd, J¼16.9,
11.0, 10.6 Hz, 1H), 6.65 (dd, J¼11.3, 11.3 Hz, 1H),
6.17 (dd, J¼15.6, 6.7 Hz, 1H), 6.06 (dd, J¼11.1, 11.1 Hz,
1H), 5.56 (d, J¼11.3 Hz, 1H), 5.55 (dd, J¼11.0, 11.0 Hz,
1H), 5.41 (dd, J¼11.1, 8.8 Hz, 1H), 5.34 (dd, J¼10.7,
10.6 Hz, 1H), 5.25 (dd, J¼16.8, 1.8 Hz, 1H), 5.15 (d,
J¼10.1 Hz, 1H), 5.14 (dd, J¼7.0, 5.0 Hz, 1H), 4.65 (ddd,
J¼9.5, 9.5, 3.3 Hz, 1H), 4.05 (ddd, J¼10.6, 3.7, 2.8 Hz,
1H), 3.37 (m, 1H), 3.17 (ddq, J¼10.1, 6.8, 6.6 Hz, 1H),
3.10 (dd, J¼8.1, 2.9 Hz, 1H), 2.76 (m, 1H), 2.60 (m, 1H),
1.89 (m, 1H), 1.84 (dddd, J¼12.9, 11.2, 6.4, 5.4 Hz,
1H), 1.60 (m, 1H), 1.58 (m, 1H), 1.54 (m, 1H), 1.50 (ddd,
J¼14.1, 10.7, 3.5 Hz, 1H), 1.42 (ddd, J¼14.0, 10.0,
2.7 Hz, 1H), 1.25 (ddd, J¼13.7, 10.6, 3.6 Hz, 1H), 1.15 (d,
J¼6.9 Hz, 3H), 1.12 (d, J¼7.0 Hz, 3H), 1.10 (m, 1H),
1.07 (d, J¼6.9 Hz, 3H), 1.01 (d, J¼6.8 Hz, 3H), 0.95 (d,
J¼6.5 Hz, 3H), 0.93 (d, J¼6.5 Hz, 3H), 0.90 (m, 1H),
0.71 (dddd, J¼12.9, 12.8, 8.7, 4.9 Hz, 1H); 13C NMR
4.37. (4S,5S)-4-((2R,3S,6S,8S,9R,10S,11Z,13S,15S,16R,
17E)-3,9,13,15-Tetrakis(tert-butyldimethylsilyloxy)-
6,8,10,16-tetramethyl-19-trityloxynonadeca-11,17-dien-
2-yl)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxane (112a)
The procedure for 112b was used with 112a (0.58 g,
0.49 mmol), TBSOTf (0.17 mL, 0.74 mmol), and 2,6-luti-
dine (0.11 mL, 0.97 mmol) to yield 0.62 g (97%) of the
product by flash column chromatography (EtOAc/hexane
1:9) as a colorless oil: IR (CHCl3) 2955, 2856, 1615,
1
1518, 1462, 1385, 1251, 1082, 835, 773, 705 cmꢀ1; H
NMR (300 MHz, CDCl3) d 7.55 (m, 6H), 7.49 (m, 2H),
7.40–7.27 (m, 9H), 6.96 (m, 2H), 5.72 (m, 2H), 5.53 (m,
1H), 5.52 (s, 1H), 5.38 (m, 1H), 4.65 (m, 1H), 4.19 (dd,

Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
8559
J¼11.0, 4.4 Hz, 1H), 4.03 (m, 1H), 3.95 (d, J¼8.7 Hz, 1H),
3.86 (m, 1H), 3.84 (s, 3H), 3.66 (d, J¼3.7 Hz, 2H), 3.56 (t,
J¼11.1 Hz, 1H), 3.50 (m, 1H), 2.71 (m, 1H), 2.52 (m,
1H), 2.12 (m, 1H), 1.90–1.79 (m, 2H), 1.75–1.68 (m, 3H),
1.61–1.37 (m, 6H), 1.08 (d, J¼6.6 Hz, 6H), 1.02–0.91 (m,
45H), 0.81 (d, J¼6.5 Hz, 3H), 0.22–0.13 (m, 24H); 13C
NMR (75 MHz, CDCl3) d 159.7, 144.5, 134.4, 132.8,
132.6, 131.7, 128.7, 127.7, 127.3, 126.8, 113.4, 100.9,
86.7, 81.4, 80.1, 73.4, 72.3, 71.5, 66.5, 65.1, 55.1, 42.4,
41.5, 37.9, 35.5, 35.1, 31.3, 30.8, 30.2, 27.9, 26.3, 26.01,
25.99, 25.93, 25.7, 20.6, 19.5, 18.4, 18.11, 18.07, 15.4,
13.4, 13.3, 12.2, 9.2, ꢀ2.9, ꢀ3.5, ꢀ3.7, ꢀ3.9, ꢀ4.1, ꢀ4.2,
ꢀ4.3, ꢀ4.9; LRMS (ESI) 1328.0 [M+Na]+; HRMS (ESI)
calcd for C78H128O8Si4Na 1327.8584 [M+Na]+, found
1327.8624; [a]2D0 +6.1 (c 0.93, CHCl3).
J¼16.8 Hz, 1H), 5.19 (d, J¼10.2 Hz, 1H), 4.63 (m, 3H),
4.03 (m, 1H), 3.85 (s, 3H), 3.67 (m, 2H), 3.51 (m, 1H), 3.38
(m, 1H), 2.96 (m, 1H), 2.72 (m, 1H), 2.53 (m, 1H), 1.93–1.74
(m, 2H), 1.66–1.37 (m, 7H), 1.31–1.23 (m, 3H), 1.18 (d,
J¼6.8 Hz, 3H), 1.09 (m, 6H), 1.03–0.92 (m, 45H), 0.23–
0.10 (m, 24H); 13C NMR (75 MHz, CDCl3) d 159.1, 144.5,
144.4, 134.7, 134.5, 133.0, 132.6, 132.2, 131.4, 129.1, 129.0,
128.7, 127.7, 126.8, 117.5, 113.7, 86.8, 84.6, 79.9, 74.7,
73.6, 72.3, 66.5, 65.1, 55.2, 42.5, 42.4, 41.6, 36.1, 35.9,
34.8, 32.0, 30.8, 29.8, 26.3, 26.02, 25.96, 20.5, 19.3, 18.6,
18.5, 18.2, 18.1, 15.4, 13.3, 10.5, ꢀ2.9, ꢀ3.4, ꢀ3.7, ꢀ4.1,
ꢀ4.2, ꢀ4.3; LRMS (ESI) 1352.0 [M+Na]+; HRMS (ESI)
calcd for C81H132O7Si4Na 1351.8948 [M+Na]+, found
1351.8987; [a]2D0 ꢀ8.6 (c 1.6, CHCl3).
4.40. (2E,4R,5S,7S,8Z,10S,11R,12S,14S,17S,18R,
19S,20S,21Z)-19-(4-Methoxybenzyloxy)-5,7,11,17-tetra-
kis(tert-butyldimethylsilyloxy)-4,10,12,14,18,20-hexa-
methyltetracosa-2,8,21,23-tetraen-1-ol (115a)
4.38. (2S,3S,4R,5S,8S,10S,11R,12S,13Z,15S,17S,18R,
19E)-3-(4-Methoxybenzyloxy)-5,11,15,17-tetrakis(tert-
butyldimethylsilyloxy)-2,4,8,10,12,18-hexamethyl-21-
trityloxyhenicosa-13,19-dien-1-ol (113a)
The procedure for 115b was used with 114a (0.46 g,
0.35 mmol) and ZnBr2 (0.41 g in 5.8 mL of 24:5 CH2Cl2/
MeOH) to yield 0.21 g (55%) of the product after flash col-
umn chromatography (EtOAc/hexane 1:9) as a colorless oil:
IR (CHCl3) 3410, 2956, 2929, 2856, 1614, 1514, 1471, 1462,
The procedure for 113b was used with 112a (0.62 g,
0.47 mmol) and DIBALH (1.0 M in hexane, 4.7 mL,
4.7 mmol) to yield 0.54 g (87%) of the product after flash
column chromatography (EtOAc/hexane 1:9) as a colorless
oil: IR (CHCl3) 3479, 2955, 2928, 2856, 1613, 1514,
1
1251, 1075, 836, 773 cmꢀ1; H NMR (300 MHz, CDCl3)
1471, 1251, 1084, 835, 773 cmꢀ1
;
1H NMR (300 MHz,
d 7.28 (m, 2H), 6.87 (m, 2H), 6.60 (ddd, J¼16.8, 10.7,
10.6 Hz, 1H), 6.03 (t, J¼11.0 Hz, 1H), 5.67–5.57 (m, 3H),
5.41 (m, 1H), 5.29 (m, 1H), 5.20 (d, J¼18.2 Hz, 1H), 5.11
(d, J¼10.2 Hz, 1H), 4.56 (m, 3H), 4.10 (d, J¼4.4 Hz, 1H),
3.93 (m, 1H), 3.81 (s, 3H), 3.66–3.57 (m, 2H), 3.40 (dd,
J¼4.6, 2.6 Hz, 1H), 3.28 (dd, J¼6.2, 4.2 Hz, 1H), 2.85 (m,
1H), 2.60 (m, 1H), 2.39 (m, 1H), 1.79 (m, 1H), 1.70 (m,
1H), 1.66–1.56 (m, 2H), 1.51–1.19 (m, 8H), 1.09 (d,
J¼6.8 Hz, 3H), 0.98 (d, J¼6.8 Hz, 3H), 0.97 (d, J¼6.9 Hz,
3H), 0.92–0.86 (m, 45H), 0.11–0.00 (m, 24H); 13C NMR
(75 MHz, CDCl3) d 159.0, 135.2, 134.7, 132.8, 132.7,
132.3, 131.4, 129.2, 129.1, 129.0, 117.4, 113.7, 84.6, 80.0,
74.7, 73.6, 72.2, 66.6, 63.9, 63.3, 55.3, 42.4, 41.7, 36.1,
35.8, 34.8, 31.9, 30.8, 29.8, 26.3, 26.0, 25.9, 20.5, 19.4,
19.3, 18.6, 18.5, 18.1, 15.3, 13.3, 10.5, ꢀ3.0, ꢀ3.4, ꢀ3.7,
ꢀ4.2, ꢀ4.3, ꢀ4.5; LRMS (ESI) 1109.9 [M+Na]+; HRMS
(ESI) calcd for C62H118O7Si4Na 1109.7856 [M+Na]+, found
1109.7902; [a]2D0 ꢀ12.0 (c 1.7, CHCl3).
CDCl3) d 7.56–7.52 (m, 6H), 7.38–7.33 (m, 9H), 7.30 (m,
2H), 6.94 (m, 2H), 5.72 (m, 2H), 5.52 (m, 1H), 5.38 (m,
1H), 4.67 (d, J¼10.3 Hz, 1H), 4.65 (m, 1H), 4.60 (d,
J¼10.4 Hz, 1H), 4.03 (m, 1H), 3.83 (s, 3H), 3.70 (m, 3H),
3.65 (d, J¼3.7 Hz, 2H), 3.49 (m, 1H), 3.02 (m, 1H), 2.71
(m 1H), 2.52 (m, 1H), 1.91 (m, 2H), 1.80–1.64 (m, 3H),
1.60–1.34 (m, 8H), 1.09–0.90 (m, 54H), 0.21–0.12 (m,
24H); 13C NMR (75 MHz, CDCl3) d 159.2, 144.5, 144.3,
134.4, 132.8, 132.4, 130.6, 129.0, 128.6, 127.7, 126.8,
113.8, 86.7, 84.7, 80.0, 74.8, 74.5, 72.2, 66.5, 66.2, 65.1,
55.1, 42.3, 41.4, 38.7, 35.5, 35.2, 35.0, 31.5, 30.9, 30.7,
29.8, 26.2, 26.00, 25.95, 25.89, 20.5, 19.4, 18.4, 18.13,
18.08, 18.02, 15.4, 15.2, 13.2, 10.4, ꢀ3.0, ꢀ3.6, ꢀ3.7,
ꢀ3.8, ꢀ4.18, ꢀ4.24, ꢀ4.3, ꢀ4.4; LRMS (ESI) 1329.8
[M+Na]+; HRMS (ESI) calcd for C78H130O8Si4Na
1329.8741 [M+Na]+, found 1329.8782; [a]2D0 ꢀ6.8 (c 0.66,
CHCl3).
4.39. ((2E,4R,5S,7S,8Z,10S,11R,12S,14S,17S,18R,19S,
20S,21Z)-19-(4-Methoxybenzyloxy)-5,7,11,17-tetrakis-
(tert-butyldimethylsilyloxy)-4,10,12,14,18,20-hexa-
methyltetracosa-2,8,21,23-tetraenyloxy)triphenyl-
methane (114a)
4.41. (2Z,4E,6R,7S,9S,10Z,12S,13R,14S,16S,19S,
20R,21S,22S,23Z)-Methyl-21-(4-methoxybenzyloxy)-
7,9,13,19-tetrakis(tert-butyldimethylsilyloxy)-
6,12,14,16,20,22-hexamethylhexacosa-2,4,10,23,25-
pentaenoate (116a)
The procedure for 114b was used with 113a (0.54 g,
0.41 mmol) and Dess–Martin periodinane (0.26 g, 0.61
mmol), 1-bromoallyl trimethylsilane (0.50 g, 2.60 mmol)
and CrCl2 (0.42 g, 3.42 mmol), and NaH (95% w/w,
0.21 g, 8.31 mmol) to yield 0.46 g (83% in three steps) of
the product by flash column chromatography (EtOAc/hex-
ane 1:9) as a colorless oil: IR (CHCl3) 2955, 2928, 2856,
The procedure for 116b was used with 115a (117 mg,
0.108 mmol) and Dess–Martin periodinane (69 mg,
0.16 mmol),
bis(2,2,2-trifluoroethyl)-(methoxycarbonyl-
methyl) phosphate (0.027 mL, 0.13 mmol), 18-crown-6
(0.14 g, 0.53 mmol), and KHMDS (0.26 mL, 0.13 mmol,
0.5 M solution in toluene) to yield 69 mg (56% in two steps)
of the product after flash column chromatography (EtOAc/
hexane 1:19) as a colorless oil: IR (CHCl3) 2956, 2929,
2856, 1722, 1640, 1514, 1471, 1462, 1250, 1174, 1080,
1
1613, 1514, 1462, 1250, 1069, 835, 773, 705 cmꢀ1; H
NMR (300 MHz, CDCl3) d 7.58–7.54 (m, 6H), 7.40–7.35
(m, 9H), 7.33–7.30 (m, 2H), 6.96–6.93 (m, 2H), 6.69 (ddd,
J¼16.8, 10.6, 10.5 Hz, 1H), 6.12 (t, J¼11.0 Hz, 1H), 5.80–
5.67 (m, 3H), 5.52 (t, J¼10.4 Hz, 1H), 5.40 (m, 1H), 5.28 (d,
1
836, 773 cmꢀ1; H NMR (300 MHz, CDCl3) d 7.44 (dd,
J¼15.2, 11.3 Hz, 1H), 7.28 (m, 2H), 6.88 (m, 2H), 6.60
(ddd, J¼16.7, 10.6, 10.5 Hz, 1H), 6.56 (t, J¼11.3 Hz, 1H),

8560
Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
6.04 (dd, J¼15.5, 7.1 Hz, 1H), 6.00 (t, J¼11.0 Hz, 1H), 5.62
(m, 2H), 5.42 (m, 1H), 5.27 (m, 1H), 5.21 (d, J¼16.8 Hz,
1H), 5.11 (d, J¼10.3 Hz, 1H), 4.54 (m, 3H), 3.97 (m, 1H),
3.81 (s, 3H), 3.74 (s, 3H), 3.60 (m, 1H), 3.40 (m, 1H),
3.29 (m, 1H), 2.86 (m, 1H), 2.57 (m, 2H), 1.80–1.67 (m,
3H), 1.55–1.41 (m, 4H), 1.40–1.20 (m, 4H), 1.09 (d,
J¼6.8 Hz, 3H), 1.06 (d, J¼6.8 Hz, 3H), 0.99 (d, J¼6.6 Hz,
3H), 0.98 (d, J¼6.7 Hz, 3H), 0.95–0.85 (m, 42H), 0.13–
0.00 (m, 24H); 13C NMR (75 MHz, CDCl3) d 166.8,
159.0, 147.3, 145.5, 134.7, 132.9, 132.7, 132.3, 131.4,
129.1, 129.0, 126.9, 117.4, 115.5, 113.7, 84.6, 80.0, 74.7,
73.6, 72.1, 66.5, 55.3, 51.0, 43.5, 42.4, 41.6, 36.1, 35.8,
34.8, 31.9, 30.7, 29.8, 26.3, 26.0, 25.9, 20.5, 19.3, 18.6,
18.5, 18.1, 15.3, 13.4, 10.5, ꢀ3.0, ꢀ3.3, ꢀ3.7, ꢀ4.10,
ꢀ4.15, ꢀ4.19, ꢀ4.3, ꢀ4.4; LRMS (ESI) 1163.8 [M+Na]+;
HRMS (ESI) calcd for C65H120O8Si4Na 1163.7958
[M+Na]+, found 1163.8000; [a]D20 ꢀ16.7 (c 0.33, CHCl3).
3.92 (m, 1H), 3.69 (m, 1H), 3.35 (m, 1H), 2.75 (m, 1H),
2.54 (m, 2H), 1.74–1.56 (m, 4H), 1.49–1.20 (m, 8H), 1.02
(d, J¼6.8 Hz, 3H), 0.98 (d, J¼7.2 Hz, 3H), 0.94 (d,
J¼7.0 Hz, 3H), 0.90–0.82 (m, 45H), 0.09–0.01 (m, 24H);
13C NMR (75 MHz, CDCl3) d 171.1, 148.2, 147.4, 136.4,
132.7, 132.6, 129.6, 127.0, 117.4, 115.1, 79.8, 78.4, 74.2,
72.1, 66.5, 43.5, 42.6, 41.5, 36.0, 35.9, 35.8, 35.0, 31.9,
30.8, 29.7, 26.3, 26.0, 25.9, 20.4, 19.3, 18.5, 18.13, 18.08,
17.97, 17.4, 15.4, 13.7, 10.8, ꢀ3.0, ꢀ3.4, ꢀ3.7, ꢀ4.1,
ꢀ4.2, ꢀ4.3, ꢀ4.4, ꢀ4.8; LRMS (ESI) 1029.8 [M+Na]+;
HRMS (ESI) calcd for C56H110O7Si4Na 1029.7226
[M+Na]+, found 1029.7255; [a]D20 ꢀ6.5 (c 0.17, CHCl3).
4.44. (8S,10S,14R,20S)-Tetrakis(tert-butyldimethylsilyl-
oxy)-(7R,13S,15S,17S,21S)-pentamethyl-(22S)-((1S)-
methylpenta-2,4-dienyl)-oxacyclodocosa-3,5,11-trien-
2-one (119a)
4.42. (2Z,4E,6R,7S,9S,10Z,12S,13R,14S,16S,19S,20R,
21S,22S,23Z)-Methyl-7,9,13,19-tetrakis(tert-butyldi-
methylsilyloxy)-21-hydroxy-6,12,14,16,20,22-hexa-
methylhexacosa-2,4,10,23,25-pentaenoate (117a)
The procedure for 119b was used with 118a, Et3N
(0.046 mL, 33 mmol), 2,4,6-trichlorobenzoyl chloride
(0.043 mL, 28 mmol), and 4-DMAP (27 mL, 0.02 M solution
in toluene) to yield 42 mg (78% in two steps) of 119a after
flash column chromatography (EtOAc/hexane 1:49) as a col-
orless oil: IR (CHCl3) 2956, 2929, 2856, 1704, 1638, 1471,
The procedure for 117b was used with 116a (68 mg,
60 mmol) and DDQ (15 mg, 66 mmol) to yield 56 mg (92%)
of the product after flash column chromatography (EtOAc/
hexane 1:9) as a colorless oil: IR (CHCl3) 3499, 2956,
2929, 2856, 1723, 1641, 1471, 1462, 1255, 1175, 1081,
1462, 1378, 1361, 1255, 1086, 1044, 1004, 835, 773 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 6.98 (dd, J¼15.3, 11.3 Hz,
1H), 6.58 (ddd, J¼16.9, 10.6, 10.5 Hz, 1H), 6.42 (t,
J¼11.4 Hz, 1H), 5.94 (t, J¼9.2 Hz, 1H), 5.92 (dd, J¼9.5,
5.2 Hz, 1H), 5.55 (m, 1H), 5.42 (d, J¼11.6 Hz, 1H), 5.33–
5.21 (m, 3H), 5.12 (d, J¼15.1 Hz, 1H), 4.99 (d, J¼9.7 Hz,
1H), 4.54 (m, 1H), 3.99 (m, 1H), 3.44 (m, 1H), 3.17 (m,
1H), 2.99 (m, 1H), 2.54 (m, 1H), 2.19 (m, 1H), 1.99 (m,
1H), 1.61–1.42 (m, 7H), 1.37–1.18 (m, 3H), 1.10 (d,
J¼6.9 Hz, 3H), 1.05 (d, J¼7.1 Hz, 3H), 1.00 (d, J¼6.3 Hz,
3H), 0.98 (d, J¼6.4 Hz, 3H), 0.98–0.82 (m, 36H), 0.79 (d,
J¼6.6 Hz, 3H), 0.66 (d, J¼6.7 Hz, 3H), 0.11–0.01 (m,
24H); 13C NMR (75 MHz, CDCl3) d 166.4, 146.5, 143.9,
134.3, 132.7, 132.2, 130.8, 129.8, 127.9, 117.4, 117.1,
81.6, 78.0, 77.1, 73.0, 66.7, 46.9, 45.7, 41.2, 37.5, 35.8,
35.1, 34.5, 31.1, 29.7, 26.2, 26.1, 26.0, 25.9, 20.5, 19.5,
19.1, 18.5, 18.4, 18.2, 17.9, 17.3, 16.9, 7.9, ꢀ2.6, ꢀ3.4,
ꢀ3.5, ꢀ4.3, ꢀ4.4, ꢀ4.6; LRMS (ESI) 1011.7 [M+Na]+;
HRMS (ESI) calcd for C56H108O6Si4Na 1011.7121
[M+Na]+, found 1011.7164; [a]D20 ꢀ61.6 (c 2.8, CHCl3).
1
836, 773 cmꢀ1; H NMR (300 MHz, CDCl3) d 7.35 (dd,
J¼15.2, 11.3 Hz, 1H), 6.64 (ddd, J¼16.9, 10.6, 10.5 Hz,
1H), 6.52 (t, J¼11.3 Hz, 1H), 6.07 (t, J¼11.0 Hz, 1H), 5.96
(dd, J¼15.5, 7.1 Hz, 1H), 5.56 (d, J¼11.3 Hz, 1H), 5.44–
5.33 (m, 2H), 5.26–5.21 (m, 1H), 5.17 (d, J¼16.7 Hz, 1H),
5.07 (d, J¼10.1 Hz, 1H), 4.49 (m, 1H), 3.92 (m, 1H), 3.73–
3.67 (m, 5H), 3.34 (m, 1H), 3.25 (br, 1H), 2.73 (m, 1H),
2.52 (m, 2H), 1.82–1.50 (m, 4H), 1.44–1.16 (m, 7H), 1.01
(d, J¼6.8 Hz, 3H), 0.97 (d, J¼7.1 Hz, 3H), 0.93 (d,
J¼6.9 Hz, 3H), 0.90 (d, J¼6.9 Hz, 3H), 0.88–0.81 (m,
42H), 0.08–0.00 (m, 24H); 13C NMR (75 MHz, CDCl3)
d 166.8, 147.3, 145.5, 136.5, 132.8, 132.7, 132.6, 129.6,
126.8, 117.3, 115.5, 79.8, 78.4, 74.2, 72.1, 66.5, 51.0, 43.5,
42.5, 41.4, 36.0, 35.9, 35.8, 35.0, 32.4, 31.9, 30.7, 26.3,
26.0, 25.9, 20.4, 19.4, 18.5, 18.12, 18.08, 17.98, 17.4,
15.3, 13.4, 10.8, ꢀ3.0, ꢀ3.4, ꢀ3.7, ꢀ4.1, ꢀ4.2, ꢀ4.3,
ꢀ4.4, ꢀ4.8; LRMS (ESI) 1043.7 [M+Na]+; HRMS (ESI)
calcd for C57H112O7Si4Na 1043.7383 [M+Na]+, found
1043.7435; [a]2D0 ꢀ9.4 (c 0.62, CHCl3).
4.45. (8S,10S,14R,20S)-Tetrahydroxy-
(7R,13S,15S,17S,21S)-pentamethyl-(22S)-((1S)-
methylpenta-2,4-dienyl)-oxacyclodocosa-3,5,11-trien-
2-one (121)
4.43. (2Z,4E,6R,7S,9S,10Z,12S,13R,14S,16S,19S,20R,
21S,22S,23Z)-7,9,13,19-Tetrakis(tert-butyldimethylsilyl-
oxy)-21-hydroxy-6,12,14,16,20,22-hexamethylhexacosa-
2,4,10,23,25-pentaenoic acid (118a)
HCl (3 N, 10 mL, prepared by adding 2.5 mL of concd HCl to
7.5 mL MeOH) was added to a stirred solution of macro-
lactone 119a (42 mg, 42 mmol) in THF (3 mL) at 0 ꢁC. After
24 h at room temperature, the reaction mixture was diluted
with EtOAc (4 mL) and H2O (4 mL). The organic phase
was retained, and the aqueous phase was extracted with
EtOAc (2ꢄ4 mL). The combined organic phase was washed
with saturated aqueous NaHCO3 (10 mL), dried with
MgSO4, filtered, and concentrated. The residue was purified
by flash chromatography (EtOAc/hexane 3:2) to yield 121
(7.9 mg, 35%) as a colorless oil: IR (CHCl3) 3415, 2961,
The procedure for 118b was used with 117a (56 mg,
55 mmol) and 1 N aqueous KOH (0.54 mL) to yield 118a,
which was used without further purification: IR (CHCl3)
2956, 2929, 2857, 1693, 1634, 1471, 1462, 1254, 1082,
1
836, 773 cmꢀ1; H NMR (300 MHz, CDCl3) d 7.34 (dd,
J¼15.1, 11.4 Hz, 1H), 6.64 (ddd, J¼16.5, 10.6, 10.5 Hz,
1H), 6.61 (t, J¼11.2 Hz, 1H), 6.07 (t, J¼11.0 Hz, 1H),
6.01 (dd, J¼15.5, 7.2 Hz, 1H), 5.58 (d, J¼11.3 Hz, 1H),
5.44–5.34 (m, 2H), 5.23 (dd, J¼11.0, 8.2 Hz, 1H), 5.17 (d,
J¼18.0 Hz, 1H), 5.08 (d, J¼10.1 Hz, 1H), 4.50 (m, 1H),
2917, 2849, 1681, 1637, 1461, 1279, 1067, 965, 758 cmꢀ1
;
1H NMR (600 MHz, CD3OD) d 7.05 (dd, J¼15.3, 11.3 Hz,

Y. Shin et al. / Tetrahedron 63 (2007) 8537–8562
8561
6. Hamel, E.; Sackett, D. L.; Vourloumis, D.; Nicolaou, K. C.
Biochemistry 1999, 38, 5490–5498.
1H), 6.65 (ddd, J¼16.9, 10.2, 10.1 Hz, 1H), 6.53 (dd,
J¼11.5, 11.5 Hz, 1H), 5.97 (dd, J¼15.3, 9.5 Hz, 1H), 5.94
(dd, J¼11.0, 11.0 Hz, 1H), 5.60 (dd, J¼10.8, 9.6 Hz, 1H),
5.41 (d, J¼11.5 Hz, 1H), 5.20 (dd, J¼10.5, 10.3 Hz, 1H),
5.11 (dd, J¼16.9, 2.0 Hz, 1H), 5.10 (dd, J¼9.7, 2.1 Hz,
1H), 5.01 (d, J¼10.1 Hz, 1H), 4.60 (ddd, J¼10.1, 9.7,
2.7 Hz, 1H), 3.94 (ddd, J¼11.0, 2.1, 2.0 Hz, 1H), 3.38
(ddd, J¼9.8, 3.0, 2.0 Hz, 1H), 3.09 (ddq, J¼13.0, 7.0,
4.9 Hz, 1H), 3.01 (dd, J¼8.3, 2.7 Hz, 1H), 2.70 (m, 1H),
2.23 (ddd, J¼9.3, 7.0, 2.4 Hz, 1H), 2.07 (ddd, J¼7.0, 2.6,
2.5 Hz, 1H), 1.67 (m, 2H), 1.56 (ddd, J¼14.0, 10.9, 2.9 Hz,
1H), 1.51 (m, 1H), 1.47 (ddd, J¼14.1, 10.5, 1.9 Hz, 1H),
1.17 (d, J¼6.9 Hz, 3H), 1.13 (m, 1H), 1.11 (d, J¼7.1 Hz,
3H), 1.09 (d, J¼7.0 Hz, 3H), 1.02 (d, J¼6.7 Hz, 3H), 1.00
(m, 1H), 0.93 (d, J¼6.4 Hz, 3H), 0.92 (m, 1H), 0.78 (m,
1H), 0.76 (d, J¼6.7 Hz, 3H), 0.74 (m, 1H); 13C NMR
(150 MHz, CD3OD) d 168.3, 147.6, 145.3, 135.4, 134.3,
133.5, 131.3, 131.0, 130.1, 118.1, 81.2, 79.9, 77.6, 72.0,
65.1, 45.9, 44.8, 42.4, 38.7, 36.0, 35.6, 31.8, 29.8, 27.8,
22.2, 19.8, 18.4, 17.6, 16.4, 9.1; LRMS (ESI) 555.3
[M+Na]+; HRMS (ESI) calcd for C32H52O6 555.3662
[M+Na]+, found 555.3655; [a]2D0 ꢀ76.2 (c 0.45, MeOH).
7. (a) Verdier-Pinard, P.; Wang, Z.; Mohanakrishnan, A. K.;
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Acknowledgements
We thank the National Institutes of Health for support
through grant CA078390. We thank Drs. Kenneth Bair and
Fred Kinder for the gift of discodermolide, Prof. Ian Pater-
1
son and Dr. Robert Britton for conducting some of the H
NMR and TLC comparison experiments of the dictyostatin
samples, and Mr. W.-H. Jung for helpful suggestions on
the manuscript.
Supplementary data
Contains detailed descriptions of the synthesis of the dic-
tyostatin epimers and copies of NMR spectra of all
compounds submitted for biological testing (59 pages). Sup-
plementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2007.05.033.
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mixtures of the PMB acetal (less polar) and the overoxidation
product (more polar) were obtained. These were separated by
silica gel column chromatography. The H19, H21, and Ha
(the PMB acetal) protons of the PMB acetal were assigned
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groups. The resulting triol was reacted with excess 2,2-di-
methoxypropane (3.0 equiv) to form the acetal, whose HMQC
(500 MHz) NMR spectrum showed the two methyl groups of
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€
€
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1
by a H–1H COSY NMR (500 MHz) study. A NOESY NMR
(500 MHz) experiment was carried out, and the major isomer
was assigned as b from the crosspeak between Ha–H19 and
Ha–H21.
44. Also isolated was 21% of an impure fraction containing princi-
pally the expected 2Z,4E-isomer according to 1H NMR analy-
sis. Deprotection of this fraction gave an impure sample of
6,14-bis-epi-dictyostatin 36, again as determined by 1H NMR
analysis. Efforts to purify this small sample did not provide
a product of suitable quality for biological assays.
45. (a) Roush, W. R.; Blizzard, T. A. J. Org. Chem. 1984, 49, 4332–
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49. This type of trans-lactonized product has been isolated and
characterized in the C16-epimeric series. See Ref. 23.
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53. New analogs and associated SAR discussion are found in:
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OH
O
PMP
19
19
PMBO
PMBO
O
1) DIBAL
2) TBSCl
O
O
3) DDQ
PMP
OTr
OTBS
OTr
TBSO
OTBS
TBSO
OTBS
26
configuration of PMP acetal
assigned by NOE
30. (a) Paterson, I.; Schlapbach, A. Synlett 1995, 498–499; (b)
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