An architectonic macrolide library based on a C2-symmetric macrodiolide toward pharmaceutical compositions

Article abstract of DOI:10.1016/j.tet.2015.01.030

Abstract A stereodivergent approach to creation of a specific 14-membered macrolide library is described. We designed a new 14-membered macrolide template possessing 10 sterogenic centers, and established a new library of fully-synthesized 14-membered ring compounds. The designed macrodiolides were synthesized through a convergent approach using an Evans aldol reaction, Keck esterification, and Yamaguchi macrolactonization, or Mitsunobu macrolactonization, as key steps. Moreover, introduction of an aminosugar to a macrodiolide aglycone by Schmidt glycosylation also afforded a new macrodiolide. Comparison between the conformation analysis of the macrolides, which we designed, and NMR analysis of the synthetic macrolides, indicated our stereoisomer library has significant diversity.

Full text of DOI:10.1016/j.tet.2015.01.030

Tetrahedron xxx (2015) 1e11
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An architectonic macrolide library based on a C2-symmetric
macrodiolide toward pharmaceutical compositions
,
,
Hayato Nakano a, Akihiro Sugawara a b, Tomoyasu Hirose a b, Hiroaki Gouda c,
d
b,
a,b,
*
ꢀ
*
Shuichi Hirono , Satoshi Omura , Toshiaki Sunazuka
a Graduate School of Infection Control Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo, 108-8641, Japan
b Kitasato Institute for Life Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo, 108-8641, Japan
c School of Pharmacy, Showa University, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan
d School of Phamaceutical Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo, 108-8641, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereodivergent approach to creation of a specific 14-membered macrolide library is described. We
designed a new 14-membered macrolide template possessing 10 sterogenic centers, and established
a new library of fully-synthesized 14-membered ring compounds. The designed macrodiolides were
synthesized through a convergent approach using an Evans aldol reaction, Keck esterification, and Ya-
maguchi macrolactonization, or Mitsunobu macrolactonization, as key steps. Moreover, introduction of
an aminosugar to a macrodiolide aglycone by Schmidt glycosylation also afforded a new macrodiolide.
Comparison between the conformation analysis of the macrolides, which we designed, and NMR analysis
of the synthetic macrolides, indicated our stereoisomer library has significant diversity.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 4 December 2014
Received in revised form 12 January 2015
Accepted 13 January 2015
Available online xxx
Dedicated to Professor Emeritus Dr. Jiro
Tsuji on the occasion of the 2015 Tetrahe-
dron prize
Keywords:
Macrodiolides
Stereochemical diversity
Natural product-inspired compounds
Macrolactonization
Erythromycin A
1. Introduction
attention on structural or stereochemical diversity in library design
and drug development.8 Macrolides are highly complex chiral
Macrolides are a large and attractive class of natural products
due to their prevalence as numerous small molecules having sig-
nificant and diverse biological and medicinal properties.1 They have
a specific structure, a macrocycle core, which bestows conforma-
tional flexibility in three dimensions; for macrocycles with more
than 10 atoms in the ring, multiple low-energy conformations are
often available. Hence, they have a more accessible surface area
compared with ordinary small organic molecules. These charac-
teristic structures allow them to interact with the surface of target
proteins, as well as making them potentially useful compounds for
modulating protein-protein interactions.2e4
molecules, and inversion of stereochemistry at certain carbon
atoms usually changes the macrolide properties, in particular their
biological activity or PK/PD properties. The investigation of the
stereostructure-activity relationships (SSAR) of naturally or non-
naturally occurring macrocycles has been undertaken.9 G. Kragol
et al. reported on the synthesis and evaluation of oleandomycin
derivatives having different stereochemistry at C8 and/or C9 posi-
tions,10 and J. E. Harvey et al. reported the synthesis of di-
astereomeric analogs of aigialomycin D.11 Furthermore, a few
research groups have published on the stereochemical diversity in
library design and drug development.12 H. Fuwa and M. Sasaki et al.
described a stereoisomer library of 8, 9-dehydroneopeltolide using
olefin metathesis,13 D. P. Curran et al. also reported on the stereo-
isomer library of SCH725674 by fluorous mixture synthesis (FMS).14
Moreover, L. A. Marcaurelle et al. completed the synthesis of 16
stereoisomers of the non-natural macrolactams, based on an aldol-
based build/couple/pair (B/C/P) strategy.15 As mentioned above, the
total synthesis and diversity oriented synthesis of natural products
and non-natural macrocycles with stereochemical complexity are
For decades, efforts have been made to synthesize macrocycle
chemical libraries.5,6 An approach utilizing a diversity oriented
synthesis (DOS) strategy, which was proposed by S. L. Schreiber,7
increased use of non-natural macrocycles and stimulated
* Corresponding authors. Tel./fax: þ81 3 5791 6340; e-mail addresses: omuras@
ꢀ
insti.kitasato-u.ac.jp (S. Omura), sunazuka@lisci.kitasato-u.ac.jp (T. Sunazuka).
http://dx.doi.org/10.1016/j.tet.2015.01.030
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Nakano, H.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.01.030

2
H. Nakano et al. / Tetrahedron xxx (2015) 1e11
still very difficult and require considerable effort. Thus, we hy-
pothesized that a means to systematically access the complete
matrix of stereoisomers for a library of chiral, sp3-rich compounds
would be an important factors for the drug discovery process.
Among the macrolides, 14-membered ring compounds are
considered to be the most important in medicinal chemistry, be-
cause a large number of 14-membered macrolides exist that have
been shown to exhibit various useful bioactivity. Some 14-
membered ring natural products are shown in Fig. 1,16 such as
erythromycin A, rustmicin, clonostachydiol, sekothrixide, migras-
tatin, and these compounds possess significant biological activity,
which varieseor is influenced byethe specific structure of each
compound. Consequently, a 14-membered ring macrolide library
covering multiple, varied substituents promising diversity and
complexity would be an attractive and important research tool. We
have been interested in investigating relationships between 14-
membered macrolides and biological activities and have pre-
viously reported the creation of EM 574,17 which exhibits gastro-
intestinal motor-stimulating activity, and EM 900, which possesses
anti-inflammatory and/or immunomodulatory properties without
antibacterial activity.18 Furthermore, to the best of our knowledge,
the relationships between the stereochemistry and biological ac-
tivities of 14-membered macrolides are still very unexplored field.
Herein, we report the design and synthesis of a new macrolide
template, and the creation of a new stereoisomer macrolide library.
A new macrolide containing an aminosugar was also synthesized
via Schmidt glycosylation. In addition, the most stable conforma-
tion was generated for each of the macrolides. The resulting con-
formations emphasized the stereochemical diversity of our
macrolide library, as expected.
carbons19 large surface area, numerous binding sites and drug-like
physicochemical and pharmacokinetic properties. Furthermore, the
characteristics of erythromycin A, plus the eight hydroxyl groups
and two carbonyl groups, would be incorporated into the template.
We designed a new macrolide template shown in Fig. 2. The tem-
plate devised included a C2 symmetrical skeleton, 10 stereogenic
centers and a macrodiolide backbone, having two ester groups in its
own large ring. In addition, the template allows not only an easy
synthetic route, but also derivation of a stereochemically diverse
range of compounds. Macrolides possess some methyl, ethyl or
other alkyl groups driven by propionates in the biosynthetic
pathway, and these groups also affect the macrolide conformation.
Consequently, we arranged six methyl groups and four hydroxy
groups in the new macrolide ring. The template thereby acquires
more flexibility and variable conformations via combinations of the
stereochemistry of the methyl and hydroxy groups, and we ex-
pected that a macrolide so constructed would show significant
bioactivity.
Fig. 2. Designed 14-membered macrolide template.
The synthetic plan of the new macrolide template is depicted in
Scheme 1. To demonstrate the creation of a new macrolide ste-
reoisomer library, we firstly planned to synthesize 32 stereoiso-
mers, among the possible stereoisomers of template (210¼1024). In
order to prove our concept, we envisioned that the stereochemical
diversity would be produced by two time-syn-Evans aldol reaction,
Keck esterification, and Yamaguchi macrolactonization or Mitsu-
nobu macrolactonization. Because of the C2 symmetical macrolide
skeleton, the combination of various stereoisomer half units would
also give 2-fold stereochemical diversity. Accordingly, four di-
astereomers of half units would lead to 32 stereoisomeric macro-
diolide aglycones, and we could thus create the new divergent
macrolide library based on our envisaged template.
The synthesis was started with the chiral lactic acid methyl ester
6. Then, aldehyde 7 was prepared according to the reported pro-
cedure.20 The first diversity was produced by the Evans aldol re-
action21 with (R) or (S)-chiral auxiliaries 8a, 8b afforded aldol
products 9a, 9b20 with high yield and diastereoselectivity. Sub-
sequently, removal of chiral auxiliary and protection of the hy-
droxyl group gave the Weinreb amide 10a, 10b (10a; 76%, 10b; 84%
over two steps). Reduction of the Weinreb amide 10a, 10b afforded
aldehydes 11a, 11b, in 98% and 94% yield, respectively. Then, a sec-
ond diversity was produced by repeating the Evans aldol reaction,
aldehydes 11a, 11b being subjected to the Evans aldol reaction to
afford aldol products 12aed (Scheme 2) in 85e89% yield and high
diastereoselectivity.22
In order to selectively remove key protecting groups at the late
stage for glycosylation, we choose the BOM and TBS groups as the
protecting groups. The protection of these aldol products with
BOMCl and PMB deprotection of the resulting BOM ethers afforded
the alcohols 13aed in 75e96% yield. The deprotection of aldol
products 12aed using HF-pyridine afforded diols, which were
conveniently transformed into carboxylic acids 14aed in 74e82%
yield over two steps (Scheme 3). The esterification of possible
Fig. 1. The 14-membered macrolides.
2. Results and discussion
2.1. Strategy for construction of a stereoisomer library
Our approach was to focus on a 14-membered macrolide skel-
eton, the designed macrolide template being inspired by the nat-
ural product, erythromycin A, which shows various biological
activities1 and possesses five hydroxy groups, one carbonyl group
and an ester group in its own lactone ring. Eight oxygen atoms exist
in the macrolide skeleton. We anticipated that these oxygen atoms
would play a role of hydrogen bond donor or acceptor, and would
affect bioactivities. We envisioned that the 14-membered ring
macrolide template would possess high fraction of sp3-hybridized
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H. Nakano et al. / Tetrahedron xxx (2015) 1e11
3
Scheme 3. The preparation of alcohols 13aed and carboxylic acids 14aed.
retention of a stereocenter at C13 or Mitsunobu condition25 with
the inversion of a stereocenter at C13 (Scheme 4). Many macrolides
syntheses have been performed, and the key macrolactonization
step was often found to be problematic.26 For the stereoisomeric
macrolide library described in this paper, a variety of stereocenters
are present. Thus, some compounds found in the library do not
cyclize efficiently due, presumably, to steric repulsion. The struc-
tures of synthesized macrodiolide aglycones produced by Yama-
guchi macrolactonization are shown in Table 2.
Yamaguchi macrolactonization of the seco-acid 16a under room
temperature proceeded smoothly, to afford macrodiolide aglycone
17a in 70% yield. However, we found that other seco-acids could not
be efficiently cyclized under Yamaguchi macrolactonization at
room temperature, although heating would allow the conformation
change to occur. By some modification, other seco-acids were
cyclized by Yamaguchi macrolactonization at 80 ꢀC. Therefore, we
conducted Yamaguchi macrolactonization of other seco-acids under
80 ꢀC conditions. In addition, partial epimerization at the C2 posi-
tion occurred during Yamaguchi macrolactonization (2,4,6-
trichlorobenzoyl chloride, DMAP, DIPEA, benzene, at 80 ꢀC) of
seco-acids 16b, 16f, 16g, 16j, 16l, 16n, and macrodiolide aglycones
were obtained as diastereo mixtures, which could not be separated
by flash column chromatography and preparative thin layer
chromatography.
Scheme 1. Synthetic plan for construction of a stereoisomer library.
Conversely, Mitsunobu macrolactonization (DEAD, PPh3, tolu-
ene) under room temperature proceeded, to afford macrodiolide
aglycones 18aep in 10e86% yields (Table 3). These results indicated
that the stereochemistry of seco-acids was an important factor, and
macrolactonization of certain seco-acids 16f, 16g, 16l was not effi-
cient and very slowly cyclized under both conditions due to steric
hindrance. Using this methodology, 16 seco-acids 16aep led to 32
macrodiolide aglycones 17aep and 18aep. Each of the stereoiso-
mer macrodiolide aglycones shows 1H and 13C NMR spectra that are
easily distinguishable from the other stereoisomers. These spectra
data indicated that the conformation of synthesized macrodiolides
were different and the library is of great worth with respect to
stereodivergence.
Scheme 2. The synthesis of 4 type of stereisomers 12aed via the Evans aldol reaction.
2.2. Glycosylation of aglycone leading to a new macrolide
combinations of alcohol units 13aed with carboxylic acid units
14aed produced linear units 15aep under Keck condition23
(Table 1). As a result, Keck esterification afforded each of the lin-
ear units 15aep in 74e99% yield. Then, the removal of oxazolidi-
none by hydrolysis and PMB ether by DDQ afforded the
corresponding seco-acids 16aep over two steps (Scheme 4).
The final diversity was produced by Yamaguchi and Mitsunobu
macrolactonizations, leading to 32 stereoisomers. These seco-acids
16aep were cyclized under Yamaguchi condition24 with the
Macrolides with an amimosugar demonstrate more complexity
and compound diversity. Therefore, such macrolides were expected
to show various biological activities, as is the case with erythro-
mycin A and other 14-membered macrolides. In order to examine
the stereochemical diversity of these macrolides, we first per-
formed conformational analysis to generate the most stable con-
former for each one, using the CAMDAS (Conformational Analyzer
with Molecular Dynamics and Sampling) program.27 The procedure
for the CAMDAS calculation was similar to that already described.28
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4
H. Nakano et al. / Tetrahedron xxx (2015) 1e11
OBOM
OBOM
Bn
O
O
N
O
Table 1
The Keck esterification
O
OTBS
OBOM
OPMB
O
15a-p
a) H2O2
LiOH•H2O
THF/H2O
rt, 60-91%
b) DDQ
pH 7 buffer
CH2Cl2, rt
72-98%
OBOM
OBOM
O
HO
1
13
O
O
OTBS
OBOM
OH
Compound; % yield (Alcohols 13-Carboxylic acids 14)
16a-p
2,4,6-trichloro-
benzoylchloride,
DIPEA, benzene, rt;
DMAP, benzene,
80 °C
DEAD, PPh3,
toluene, rt
Method (A)
Yamaguchi
Macrolactonization
Method (B)
Mitsunobu
Macrolactonization
see Table 3
15a; 83%a (13a-14a)b
15i; 97%a (13c-14a)b
15j; 79%a (13c-14b)b
15k; 82%a (13c-14c)b
15l; 94%a (13c-14d)b
15m; 89%a (13d-14a)b
15n; 94%a (13d-14b)b
15o; 89%a (13d-14c)b
15p; 99%a (13d-14d)b
see Table 2
O
O
O
O
9
9
BOMO
BOMO
OTBS
5
OTBS
5
15b; 82%a (13a-14b)b
15c; 74%a (13a-14c)b
15d; 93%a (13a-14d)b
15e; 93%a (13b-14a)b
15f; 75%a (13b-14b)b
15g; 77%a (13b-14c)b
12
12
13
13
BOMO
BOMO
2
2
OBOM
OBOM
O
O
O
O
18a-p
17a-p
Scheme 4. The synthesis of Macrodiolide aglycones 17aep and 18aep. DDQ¼2,3-
dichloro-5,6-dicyano-p-benzoquinone, DEAD¼diethyl azodicarboxylate, DMAP¼4-
dimethylaminopyridine, DIPEA¼N, N-diisopropylethylamine.
The Merck Molecular Force Field (MMFF) was used to evaluate the
potential energy surface of the molecule.29 The CAMDAS calcula-
tion was performed in vacuo, and the electrostatic potential term
was neglected in order to mimic the shield effects of solvent mol-
ecules on electrostatic interactions. The superimposition of the
most stable conformers (provided in the Supplementary data)
suggests that our macrolide library possesses a wide stereochem-
ical diversity.
We attempted to synthesize a new macrolide containing an
aminosugar moiety via Schmidt glycosylation. The strategy of in-
corporating an aminosugar moiety is described in Scheme 5. We
selected an aglycone 17a in the synthesized library as the starting
compound, because it resembled the conformation of Erythromy-
cin A. At first, we tried to remove the TBS group by treatment with
fluorine reagents. The treatment with HF-pyridine afforded the
desired macrodiolide aglycone 19 in 65% yield, while treatment
with TBAF failed to give the target product.30 Schmidt glycosylation
with trichloroacetimidate 2031 afforded the desired macrolide 21 in
48% yield under the reported condition.20a,32 The selectivity of this
reaction was highly b-selectivity together with no a-isomer, de-
termined by 1H NMR spectra (J1,2¼7.5 Hz). Then, the removal of
BOM groups and acetyl group afforded a new macrolide 22 in 93%
yield over two steps (Scheme 5).
We then determined the three-dimensional (3D) solution
structure of 22 in MeOH-d4 solution, by a combination method of
NMR spectroscopy and conformational analysis.18a,33 The structural
constraints derived from NMR experiments are included in the
Supplementary data. The resulting 3D solution structure of 22 is
given in Fig. 3, together with one obtained as the most stable
conformation in the conformational analysis. We could see that
both structures were very similar. These results suggested that the
15h; 74%a (13b-14d)b
b
aIsolated yield. The number of parenthesis indicates alcohols 13
and carboxylic acids 14.
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H. Nakano et al. / Tetrahedron xxx (2015) 1e11
5
3D solution structure of the synthesized macrolide could be pre-
dicted as the most stable conformation obtained in the conforma-
tion analysis. In future, we expect our macrolide library to become
a useful tool for drug discovery.
3. Conclusion
17d; 73%b
17j; 12% (2:1)c
17p; 68%b
In conclusion, we have synthesized a stereoisomer library of 14-
membered ring compounds using a custom-designed macrolide
template. Four diastereomers of half units lead to 32 stereoisomer
macrolides via Evans aldol reaction, Keck esterification and Yama-
guchi macrolactonization or Mitsunobu macrolactonization. We
also demonstrated the synthesis of a new macrolide with an ami-
nosugar, the desosamine. Our ongoing efforts will synthesize non-
natural macrolides and biologically active compounds based on
a customized template, and biological screenings of the synthe-
sized library are now underway.
(2R, 3S, 4S, 5R, 6R, 9R,
10S, 11R, 12S, 13R)
(2S, 3R, 4R, 5S, 6R, 9S,
10R, 11S, 12R, 13R)
(2R, 3S, 4R, 5S, 6R, 9R,
10S, 11R, 12S, 13R)
17e; 47%b
17k; 48%b
4. Experimental section
4.1. General
(2S, 3R, 4S, 5R, 6R, 9R,
10S, 11S, 12R, 13R)
(2S, 3R, 4R, 5S, 6R, 9S,
10R, 11R, 12S, 13R)
Unless otherwise stated, reactions were carried out under a ni-
trogen atmosphere. Dry dichloromethane (CH2Cl2), tetrahy-
drohuran (THF), benzene, toluene and hexane were purchased from
Kanto Chemical Co., Inc. Pre-coated silica gel plates with a fluores-
cent indicator were used for analytical (Merck Millipore, TLC silica
17f; 23% (2:1)c
17l; 38% (1:1)c
Table 2
(2S, 3R, 4S, 5R, 6R, 9S,
10R, 11S, 12R, 13R)
(2S, 3R, 4R, 5S, 6R, 9R,
10S, 11R, 12S, 13R)
Yamaguchi macrolactonization of seco-acids 16aep
Macrodiolide aglycone; % Yield; Stereochemistry
aSeco-acid 16a was cyclized by Yamaguchi macrolactonization
under room temperature, and afforded macrodiolide aglycone
b
c
17a in 70% yield. Isolated yield. Epimerization occurred, and
the diastereomer ratio was calculated by 1H NMR spectra.
Table 3
Mitsunobu macrolactonization of seco-acids 16aep
17a; 70%a, b
17g; 34% (1:1)c
17m; 34%b
Macrodiolide aglycone; % Yielda; Stereochemistry
(2R, 3S, 4S, 5R, 6R, 9R,
10S, 11S, 12R, 13R )
(2S, 3R, 4S, 5R, 6R, 9S,
10R, 11R, 12S, 13R)
(2R, 3S, 4R, 5S, 6R, 9R,
10S, 11S, 12R, 13R)
18a; 70%
18g; 27%
18m; 79%
17b; 85% (5:1)c
17h; 63%b
17n; 13% (2:1)c
(2R, 3S, 4S, 5R, 6R, 9R,
10S, 11S, 12R, 13S)
(2R, 3S, 4S, 5R, 6R, 9S,
10R, 11S, 12R, 13S)
(2R, 3S, 4R, 5S, 6R, 9S,
10R, 11S, 12R, 13S)
(2R, 3S, 4S, 5R, 6R, 9S,
10R, 11S, 12R, 13R)
(2S, 3R, 4S, 5R, 6R, 9R,
10S, 11R, 12S, 13R)
(2R, 3S, 4R, 5S, 6R, 9S,
10R, 11S, 12R, 13R)
18b; 86%
18h; 27%
18n; 66%
17c; 82%b
17i; 29%b
17o; 16%b
(2R, 3S, 4S, 5R, 6R, 9S,
10R, 11S, 12R, 13S)
(2S, 3R, 4R, 5S, 6R, 9S,
10R, 11R, 12S, 13S)
(2S, 3R, 4R, 5S, 6R, 9S,
10R, 11S, 12R, 13S)
(2R, 3S, 4S, 5R, 6R, 9S,
10R, 11R, 12S, 13R)
(2S, 3R, 4R, 5S, 6R, 9R,
10S, 11S, 12R, 13R)
(2R, 3S, 4R, 5S, 6R, 9S,
10R, 11R, 12S, 13R)
(continued on next page)
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6
H. Nakano et al. / Tetrahedron xxx (2015) 1e11
(continued)
18c; 54%
18i; 50%
18o; 64%
(2S, 3R, 4S, 5R, 6R, 9S,
(2R, 3S, 4S, 5R, 6R, 9S,
10R, 11R, 12S, 13S)
(2R, 3S, 4S, 5R, 6R, 9R,
10S, 11S, 12R, 13S)
10R, 11R, 12S, 13S)
18d; 49%
18j; 59%
18p; 49%
(2R, 3S, 4S, 5R, 6R, 9R,
10S, 11R, 12S, 13S)
(2S, 3R, 4R, 5S, 6R, 9R,
10S, 11R, 12S, 13S)
(2R, 3S, 4R, 5S, 6R, 9S,
10R, 11R, 12S, 013S)
Scheme 5. The synthesis of a new macrolide 22.
4.1.1. (R)-4-Benzyl-3-{(20R,30R, 40R)-30-hydroxy-40-[(4-
methoxybenzyl)oxy]-20-methylpentanoyl} oxazolidin-2-one (9a). To
a solution of Et3B in hexane (1.04 M, 105 mL, 109 mmol) was added
TfOH (9.7 mL, 111 mmol) under N2 at 0 ꢀC. After stirring for 1 h at
40 ꢀC, to the solution mixture was added a solution of (R)-(ꢁ)-4-
benzyl-3-propionyloxazolidin-2-one 8a (22.8 g, 97.7 mmol) in
CH2Cl2 (60 mL) and Et3N (29.0 mL, 209 mmol) at 0 ꢀC. Then, the
mixture was cooled to ꢁ78 ꢀC and to this mixture was slowly added
a solution of aldehyde 7 (16.0 g, 82.4 mmol) in CH2Cl2 (65 mL). After
stirring for 30 min, the mixture was warmed to 0 ꢀC and stirred for
1 h. The reaction mixture was quenched with phosphate buffer
solution in water (100 mL, pH¼7.0) and MeOH/30% aq H2O2 solution
in water (v/v, 2/1, 90 mL) at 0 ꢀC. Resulted two layers were separated
and the aqueous phase was extracted with CHCl3 (50 mLꢂ3). The
combined organic layers were washed with water and brine, dried
over Na2SO4, and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (hexanes/EtOAc¼5/1, 3/1
18e; 73%
18k; 10%
(2R, 3S, 4R, 5S, 6R, 9R,
10S, 11S, 12R, 13S)
(2S, 3R, 4R, 5S, 6R, 9R,
10S, 11S, 12R, 13S)
18f; 38%
18l; 22%
(2R, 3S, 4R, 5S, 6R, 9R,
10S, 11R, 12S, 13S)
(2S, 3R, 4S, 5R, 6R, 9R,
10S, 11R, 12S, 13S)
aIsolated yield.
to 2/1) to afford aldol product 9a (33.9 g, 96%) as a colorless oil; ½a D22
ꢃ
gel 60 F254) and preparative thin layer chromatography (Merck
Millipore, PLC silica gel 60 F254, 0.5 mm). Silica gel 60N, spherical
neutral, for flash chromatography (Kanto Chemical Co., Inc., particle
ꢁ48.6 (c 1.00, CHCl3); IR (neat)/cmꢁ1; 3448, 1780, 1692, 1385, 1246,
1211, 1105, 1039, 754; 1H NMR (500 MHz, CDCl3)
d 7.32 (m, 2H), 7.27
(d, J¼6.3 Hz,1H), 7.23 (d, J¼8.6 Hz, 2H), 7.17 (d, J¼8.0 Hz, 2H), 6.84 (d,
J¼8.6 Hz, 2H), 4.58 (d, J¼11.5 Hz,1H), 4.41 (m,1H), 4.30 (d, J¼11.5 Hz,
1H), 4.07 (dd, J¼8.6,1.7 Hz,1H), 3.99 (dd, J¼8.3, 8.3 Hz,1H), 3.89 (dq,
J¼6.9, 6.9 Hz, 1H), 3.79 (m, 1H), 3.75 (s, 3H), 3.53 (m, 1H), 3.20 (dd,
J¼13.2, 2.9 Hz, 1H), 2.70 (dd, J¼13.2, 9.7 Hz, 1H), 2.52 (d, J¼6.9 Hz,
1H),1.29 (d, J¼6.9 Hz, 3H),1.29 (d, J¼6.3 Hz, 3H); 13C NMR (125 MHz,
size 40e50
mm, Cat. No. 37563e84) was used for flash column
chromatography. 1H NMR spectra were recorded on 500 MHz
spectrometers and 13C NMR spectra were recorded on 125 MHz
spectrometers on JEOL ECA-500 (500 MHz). The chemical shifts are
expressed in parts per million downfield from internal solvent
peaks CDCl3 (7.26 ppm, 1H NMR, 77.0 ppm, 13C NMR), CD3OD
(3.31 ppm, 1H NMR, 49.0 ppm, 13C NMR) and coupling constant (J
values) are given in Hertz. The coupling patterns are expressed by s
(singlet), d (doublet), dd (double doublet), ddd (double double
doublet), dt (double triplet), t (triplet), q (quartet), dq (double
quartet), m (multiplet), br (broadened), complex m, app (appear-
ance). The all infrared (IR) spectra were measured on a Horiba FT-
710 spectrometer using a diamond horizontal ATR accessory.
High- and low-resolution mass spectra were measured on JEOL
JMS-700 MStation and JEOL JMS-T100LP. Optical rotations were
measured with a Jasco P-1010 polarmeter.
CDCl3)
d
175.3, 159.0, 152.7, 135.1, 130.1, 129.6 (Cꢂ2), 129.3 (Cꢂ2),
128.7 (Cꢂ2), 127.2, 113.6 (Cꢂ2), 74.9, 74.1, 69.9, 65.8, 55.1, 55.1, 40.2,
37.5, 15.2, 12.8; HRMS-ESI (m/z); [MþNa]þ calcd for C24H29NO6Na,
450.1893; found: 450.1902.
4.1.2. (2R,3R,4R)-3-[(tert-Butyldimethylsilyl)oxy]-N-methoxy-4-[(4-
methoxybenzyl)oxy]-N,2-dimethylpentamide (10a). To a suspension
of N,O-dimethylhydroxylamine hydrochloride (11.7 g, 120 mmol) in
THF (100 mL) was added AlMe3 (1.06 M in hexane, 116 mL,
123 mmol) under N2 at 0 ꢀC. After stirring for 1 h, the reaction
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H. Nakano et al. / Tetrahedron xxx (2015) 1e11
7
was extracted with CH2Cl2 (40 mLꢂ3). The combined organic layers
were washed with water and brine, dried over Na2SO4 and con-
centrated in vacuo. The residue was purified by flash column
chromatography on silica gel (hexanes/EtOAc¼6/1, 4/1 to 3/1) to
afford Weinreb amide 10a (15.5 g, 76%) as a colorless oil; ½a D24
þ24.2
ꢃ
(c 1.00, CHCl3); IR (neat)/cmꢁ1; 2935, 2362, 1658, 1514, 1466, 1383,
1252, 1095, 1043, 835, 777; 1H NMR (500 MHz, CDCl3)
d 7.24 (d,
J¼8.0 Hz, 2H), 6.83 (d, J¼7.5 Hz, 2H), 4.44 (d, J¼11.5 Hz, 1H), 4.32 (d,
J¼11.5 Hz, 1H), 4.20 (dd, J¼8.6, 4.6 Hz, 1H), 3.78 (s, 3H), 3.61 (s, 3H),
3.55 (m, 1H), 3.18 (app br s, 1H), 2.97 (s, 3H), 1.19 (d, J¼6.3 Hz, 3H),
1.15 (d, J¼6.9 Hz, 3H), 0.89 (s, 9H), 0.10 (s, 3H), 0.03 (s, 3H); 13C NMR
(125 MHz, CDCl3)
d
176.8, 158.9, 131.0, 129.3 (Cꢂ2), 113.4 (Cꢂ2),
76.95, 72.7, 70.7, 61.2, 55.2, 35.0, 32.2, 25.8 (Cꢂ3), 18.1, 15.6, 14.0,
ꢁ4.5, ꢁ4.6; HRMS-ESI (m/z); [MþNa]þ calcd for C22H39NO5SiNa,
448.2495; found: 448.2494.
4.1.3. (2R,3R,4R)-3-[(tert-Butyldimethylsilyl)oxy]-4-(4-
methoxybenzyl)oxy-2-methylpentanal (11a). To a solution of Wein-
reb amide 10a (22.1 g, 51.9 mmol) in THF (100 mL) was added
DIBAL-H (1.0 M in hexane, 110 mL, 110 mmol) under N2 at ꢁ78 ꢀC.
After stirring for 1 h, the reaction was quenched with satd aq
Rochelle’s salt (150 mL) and stirred for 1 h at room temperature.
Resulted two layers were separated and the aqueous phase was
extracted with EtOAc (50 mLꢂ3). The combined organic layers were
washed with water and brine, dried over Na2SO4 and concentrated
in vacuo. The residue was purified by flash column chromatography
on silica gel (hexanes/EtOAc¼7/1 to 4/1) to afford aldehyde 11a
(18.6 g, 98%) as a colorless oil; ½a D24
ꢁ26.4 (c 1.00, CHCl3); IR (neat)/
ꢃ
cmꢁ1 2954, 2931, 2885, 2854,1720,1512,1250,1088,1034, 833, 771;
1H NMR (500 MHz, CDCl3)
d
9.72 (d, J¼1.7 Hz, 1H), 7.21 (d, J¼8.6 Hz,
2H), 6.87 (d, J¼8.6 Hz, 2H), 4.46 (d, J¼11.5 Hz,1H), 4.34 (d, J¼11.5 Hz,
1H), 3.98 (dd, J¼5.7, 4.0 Hz, 1H), 3.80 (s, 3H), 3.55 (dq, J¼6.3, 4.0 Hz,
1H), 2.55 (m, 1H), 1.18 (d, J¼6.3 Hz, 3H), 1.05 (d, J¼6.9 Hz, 3H), 0.88
(s, 9H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 203.2,
159.1, 130.2, 129.3 (Cꢂ2), 113.6 (Cꢂ2), 75.2, 74.6, 70.3, 55.2, 48.9,
25.8 (Cꢂ3), 18.0, 14.6, 10.2, ꢁ4.5, ꢁ4.8; HRMS-ESI (m/z); [MþNa]þ
calcd for C20H34O4SiNa, 389.2124; found: 389.2132.
4.1.4. (R)-4-Benzyl-3-{(20R,30S,40S,50R,60R)-5-[(tert-butyldime-
thylsilyl)oxy]-3-hydroxy-6-(4-methoxybenzyloxy)-2, 4-
dimethylheptanoyl} oxazolidin-2-one (12a). To a solution of (R)-
(ꢁ)-4-benzyl-3-propionyloxazolidin-2-one 8a (7.08 g, 30.4 mmol)
in CH2Cl2 (55 mL) was added Et3N (9.0 mL, 64.9 mmol) and nBu2
-
BOTf (1.0 M in CH2Cl2 solution, 40 mL, 40.0 mmol) under N2 at 0 ꢀC.
After stirring for 40 min, the solution was cooled to ꢁ78 ꢀC and
a solution of aldehyde 11a (8.77 g, 23.9 mmol) in CH2Cl2 (45 mL)
was added. The reaction mixture was stirred at ꢁ78 ꢀC for 1 h. Then
the mixture was allowed to warm to 0 ꢀC and stirred for 1 h. The
reaction mixture was quenched with phosphate buffer solution in
water (90 mL, pH¼7.0) and MeOH/30% H2O2 solution in water (v/v,
2/1, 81 mL). After stirring for 1 h, resulted two layers were sepa-
rated and the aqueous phase was extracted with CH2Cl2 (40 mLꢂ3).
The combined organic layers were washed with water and brine,
dried over Na2SO4 and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (hexanes/
EtOAc¼8/1, 6/1 to 3/1) to afford aldol product 12a (12.6 g, 88%) as
Fig. 3. The conformation of macrolide 22. (A) The conformation determined by NMR
analysis of synthesized macrolide 22 (Blue). (B) The most stable conformation of
macrolide 22 calculated by CAMDAS (Green). (C) Superimposition of (A) and (B).
mixture was warmed to room temperature and stirred for 30 min.
The mixture was then cooled to 0 ꢀC and a solution of aldol product
9a (20.5 g, 48.0 mmol) in THF (60 mL) was added. The reaction
mixture was warmed to room temperature, and stirred for 13 h. The
reaction was quenched with aq 1N HCl (80 mL) and resulted two
layers were separated and the aqueous phase was extracted with
CH2Cl2 (40 mLꢂ3). The combined organic layers were washed with
water and brine, dried over Na2SO4 and concentrated in vacuo. The
residue was used in the next reaction without further purification.
To a solution of crude mixture in CH2Cl2 (120 mL) was added
2,6-lutidine (18.0 mL, 155 mmol) under N2. Then the mixture was
cooled to 0 ꢀC and TBSOTf (25.8 mL, 112 mmol) was added. After
stirring for 4 h, the reaction mixture was quenched with aq 1N HCl
(60 mL). Resulted two layers were separated and the aqueous phase
a colorless oil; ½a D26
ꢃ
ꢁ42.3 (c 1.00, CHCl3); IR (neat)/cmꢁ1; 3564,
2939, 2893, 2854, 1774, 1697, 1381, 1242, 1211, 1026, 833, 741; 1H
NMR (500 MHz, CDCl3)
d 7.33 (m, 2H), 7.29e7.25 (complex m, 3H),
7.21 (d, J¼7.5 Hz, 2H), 6.88 (d, J¼8.6 Hz, 2H), 4.68 (m, 1H), 4.61 (d,
J¼11.5 Hz, 1H), 4.40 (d, J¼11.5 Hz, 1H), 4.22 (m, 1H), 4.16 (d,
J¼5.2 Hz, 2H), 3.97 (dq, J¼6.9, 6.9 Hz, 1H), 3.79 (s, 3H), 3.65 (dd,
J¼5.7, 5.2 Hz, 1H), 3.57 (m, 1H), 3.23 (dd, J¼13.2, 3.3 Hz, 1H), 3.21 (d,
J¼3.9 Hz, 1H), 2.78 (dd, J¼13.2, 9.2 Hz, 1H), 1.81 (m, 1H), 1.34 (d,
J¼6.9 Hz, 3H), 1.26 (d, J¼6.3 Hz, 3H), 0.95 (d, J¼6.9 Hz, 3H), 0.85 (s,
9H), 0.01 (s, 3H), e0.05 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 176.7,
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8
H. Nakano et al. / Tetrahedron xxx (2015) 1e11
159.1, 152.6, 135.0, 130.3, 129.4 (Cꢂ2), 129.1 (Cꢂ2), 128.8 (Cꢂ2),
127.3, 113.7 (Cꢂ2), 77.5, 75.9, 71.8, 70.2, 65.8, 55.1, 54.9, 40.1, 37.9,
37.5, 25.8 (Cꢂ3), 18.1, 14.1, 13.4, 10.2, ꢁ4.3, ꢁ5.0; HRMS-ESI (m/z);
[MþNa]þ calcd for C33H49NO7SiNa, 622.3176; found: 622.3181.
1.31 (d, J¼6.3 Hz, 3H), 1.16 (d, J¼6.9 Hz, 3H), 0.99 (d, J¼6.9 Hz, 3H),
0.91 (s, 9H), 0.08 (s, 3H), ꢁ0.01 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
175.4, 152.8, 137.5, 135.0, 129.3 (Cꢂ2), 128.8 (Cꢂ2), 128.3 (Cꢂ2),
127.6, 127.2 (Cꢂ3), 96.5, 80.8, 76.1, 69.9, 68.6, 65.9, 55.2, 41.5, 39.3,
37.5, 26.0 (Cꢂ3), 19.6, 18.2, 14.3, 11.3, ꢁ3.8, ꢁ4.1; HRMS-ESI (m/z);
[MþNa]þ calcd for C33H49NO7Na, 622.3176; found 622.3170.
4.1.5. (R)-4-Benzyl-3-{(20R,30S,40S,50R,60R)-30-[(benzyloxy)methoxy]-
50-[(tert-butyldimethylsilyl)oxy]-60-[(4-methoxybenzyl)oxy]-20,40-di-
methylheptanoyl} oxazolidin-2-one (S1a).
4.1.7. (R)-4-Benzyl-3-{(20R,30S,40S,50R,60R)-30,50-dihydroxy-60-[(4-
methoxybenzyl)oxy]-20,40-dimethylheptanoyl}
oxazolidin-2-one
(S2a).
To a solution of Evans aldol product 12a (3.06 g, 5.10 mmol) in
CH2Cl2 (7.0 mL) was added DMAP (638 mg, 5.22 mmol) and DIPEA
(22.0 mL, 129 mmol) under N2 at room temperature. Then BOMCl
(10.5 mL, 76.4 mmol) was added to the mixture at 0 ꢀC. After stir-
ring for 5 h at room temperature, the reaction was quenched with
H2O (20 mL) at 0 ꢀC. The resulting mixture was diluted with CH2Cl2
(10 mL) and resulted two layers were separated and the aqueous
phase was extracted with CH2Cl2 (15 mLꢂ3). The combined organic
layers were washed with water and brine, dried over Na2SO4 and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (hexanes/EtOAc¼5/1 to 3/1) to afford
To a solution of 70% HF$Pyr (4.00 mL) in THF (15 mL) was
added a solution of aldol product 12a (2.10 g, 3.50 mmol) at 0 ꢀC.
The reaction mixture was warmed to room temperature and
stirred for 36 h. The reaction was diluted with CH2Cl2 (15 mL) and
quenched by the addition of cold satd aq NaHCO3 (40 mL). Then
the mixture was poured into water (20 mL) and resulted two
layers were separated and the aqueous phase was extracted with
CH2Cl2 (20 mLꢂ3). The combined organic layers were washed
with water and brine, dried over Na2SO4 and concentrated in
vacuo. The residue was purified by flash column chromatography
on silica gel (hexanes/EtOAc¼5/1 to 3/1) to afford a diol S2a
S1a (3.42 g, 93%) as a colorless oil; ½a D27
ꢃ
ꢁ33.7 (c 1.00, CHCl3); IR
(1.30 g, 81%) as a colorless oil; ½
aꢃ2D6 ꢁ60.5 (c 1.00, CHCl3); IR
(neat)/cmꢁ1; 3062, 2939, 2893, 2854, 1774, 1697, 1512, 1458, 1381,
(neat)/cmꢁ1; 3533, 3062, 2978, 2939, 2877, 1774, 1689, 1381, 1242,
1242, 1088, 1026, 833, 741; 1H NMR (500 MHz, CDCl3)
d
7.36e7.23
1211, 1034, 748; 1H NMR (500 MHz, CDCl3)
d
7.33 (dd, J¼7.5,
(complex m, 10H), 7.11 (d, J¼6.9 Hz, 2H), 6.84 (d, J¼8.6 Hz, 2H), 4.82
(d, J¼6.9 Hz, 1H), 4.81 (d, J¼6.9 Hz, 1H), 4.69 (d, J¼12.0 Hz, 1H), 4.58
(d, J¼12.0 Hz, 1H), 4.54 (d, J¼11.5 Hz, 1H), 4.47 (d, J¼11.5 Hz, 1H),
4.35 (m, 1H), 4.12e4.05 (complex m, 2H), 4.01 (dd, J¼9.2, 2.3 Hz,
1H), 3.93 (dd, J¼8.0, 8.0 Hz, 1H), 3.88 (dd, J¼5.2, 4.0 Hz, 1H), 3.78 (s,
3H), 3.55 (m, 1H), 3.23 (dd, J¼13.2, 3.4 Hz, 1H), 2.70 (dd, J¼13.2,
9.7 Hz, 1H), 2.02 (m, 1H), 1.28 (d, J¼6.3 Hz, 3H), 1.16 (d, J¼6.3 Hz,
3H), 0.96 (d, J¼6.9 Hz, 3H), 0.86 (s, 9H), 0.03 (s, 3H), ꢁ0.05 (s, 3H);
6.9 Hz, 2H), 7.29 (d, J¼6.9 Hz, 1H), 7.26 (d, J¼8.6 Hz, 2H), 7.21 (d,
J¼6.9 Hz, 2H), 6.89 (d, J¼8.6 Hz, 2H), 4.68 (m, 1H), 4.61 (d,
J¼10.9 Hz, 1H), 4.35 (d, J¼10.9 Hz, 1H), 4.23e4.16 (complex m,
2H), 4.09 (dd, J¼5.2, 4.2 Hz, 1H), 3.98 (dq, J¼6.9, 6.9 Hz, 1H), 3.81
(s, 3H), 3.60 (app d, J¼8.0 Hz, 1H), 3.50 (m, 1H), 3.24 (dd, J¼13.8,
3.4 Hz, 1H), 2.77 (dd, J¼13.8, 9.7 Hz, 1H), 1.70 (m, 1H), 1.33 (d,
J¼6.9 Hz, 3H), 1.15 (d, J¼6.3 Hz, 3H), 0.94 (d, J¼6.9 Hz, 3H); 13C
NMR (125 MHz, CDCl3)
d 176.9, 159.3, 152.7, 135.0, 130.1, 129.4
13C NMR (125 MHz, CDCl3)
d
175.4, 158.8, 153.0, 138.2, 135.3, 131.1,
(Cꢂ2), 129.4 (Cꢂ2), 129.0 (Cꢂ2), 127.4, 113.9 (Cꢂ2), 77.9, 76.8,
75.0, 70.8, 66.0, 55.3, 55.0, 40.3, 37.7, 35.9, 15.1, 13.4, 6.9; HRMS-
ESI (m/z); [MþNa]þ calcd for C27H35NO7Na, 508.2311; found:
508.2298.
129.4 (Cꢂ2), 129.0 (Cꢂ2), 128.8 (Cꢂ2), 128.2 (Cꢂ2), 127.4, 127.3
(Cꢂ2), 127.1, 113.5 (Cꢂ2), 96.7, 81.2, 77.4, 73.1, 70.2, 70.1, 65.8, 55.5,
55.2, 41.5, 37.7, 37.4, 25.9 (Cꢂ3), 18.2, 14.0, 12.5, 11.3, ꢁ4.4, ꢁ4.5;
HRMS-ESI (m/z); [MþNa]þ calcd for C41H57NO8SiNa, 742.3751;
found: 742.3744.
4.1.8. (R)-4-Benzyl-3-{(20R,30S,40S,50R,60R)-30,50-bis[(benzyloxy)me-
thoxy]-60-[(4-methoxybenzyl)oxy]-20,40-dimethylheptanoyl}
ox-
4.1.6. (R)-4-Benzyl-3-{(20R,30S,40S,50R,60R)-30-(benzyloxy)methoxy-
50-[(tert-butyldimethylsilyl)oxy]-60-hydroxy-20,40-dimethylheptanoyl}
oxazolidin-2-one (13a). To a solution of PMB ether S1a (3.26 g,
4.53 mmol) in CH2Cl2/pH 7.0 phosphate buffer solution in water (v/
v, 4/3, 35 mL) was added DDQ (1.94 g, 8.55 mmol) at room tem-
perature. The heterogeneous solution was stirred for 3 h. Then the
reaction was quenched with satd aq NaHCO3 (50 mL). Resulted two
layers were separated and the aqueous phase was extracted with
CH2Cl2 (25 mLꢂ3). The combined organic layers were washed with
water and brine, dried over Na2SO4 and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
(hexanes/EtOAc¼5/1 to 3/1) to afford alcohol 13a (2.03 g, 75%) as
azolidin-2-one (S3a).
To a solution of diol S2a (1.21 g, 2.49 mmol) in CH2Cl2 (12 mL)
was added DMAP (632 mg, 5.17 mmol) and DIPEA (17 mL,100 mmol)
under N2 at room temperature. BOMCl (7.0 mL, 51.0 mmol) was then
added at 0 ꢀC. After stirring for 6 h at room temperature, the reaction
was quenched with H2O (20 mL) at 0 ꢀC. Then, the resulting mixture
was diluted with CH2Cl2 (10 mL) and resulted two layers were
separated and the aqueous phase was extracted with CH2Cl2
(15 mLꢂ3). The combined organic layers were washed with water
and brine, dried over Na2SO4 and concentrated in vacuo. The residue
a colorless oil; ½a D25
ꢃ
ꢁ59.1 (c 1.00, CHCl3); IR (neat)/cmꢁ1; 3548,
3510, 3062, 2931, 2893, 2854, 1782, 1689, 1381, 1211, 1026, 748; 1H
NMR (500 MHz, CDCl3)
d 7.37e7.25 (complex m, 8H), 7.17 (d,
J¼6.9 Hz, 2H), 4.85 (s, 2H), 4.73 (d, J¼12.0 Hz, 1H), 4.64 (d,
J¼12.0 Hz, 1H), 4.60 (m, 1H), 4.19e4.08 (complex m, 4H), 3.93 (dq,
J¼6.9, 2.9 Hz, 1H), 3.60 (dd, J¼8.0, 2.9 Hz, 1H), 3.22 (dd, J¼13.2,
2.3 Hz,1H), 2.75 (dd, J¼13.2, 9.7 Hz,1H), 2.60 (br s, 1H),1.88 (m, 1H),
Please cite this article in press as: Nakano, H.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.01.030

H. Nakano et al. / Tetrahedron xxx (2015) 1e11
9
was purified by flash column chromatography on silica gel (hex-
J¼6.9 Hz, 1H), 4.82 (d, J¼6.9 Hz, 1H), 4.80 (s, 2H), 4.79 (s, 2H),
4.69e4.64 (complex m, 4H), 4.57 (d, J¼12.6 Hz, 1H), 4.57 (d,
J¼12.6 Hz, 1H), 4.49 (d, J¼11.5 Hz, 1H), 4.43 (d, J¼11.5 Hz, 1H), 4.39
(m, 1H), 4.18 (dd, J¼5.2, 5.2 Hz, 1H), 4.05e3.93 (complex m, 4H),
3.83 (dd, J¼4.6, 4.0 Hz, 1H), 3.77 (s, 3H), 3.72 (dq, J¼6.3, 6.3 Hz, 1H),
3.57 (dd, J¼5.2, 5.2 Hz, 1H), 3.18 (dd, J¼13.2, 2.9 Hz, 1H), 2.94 (m,
1H), 2.66 (dd, J¼13.8, 9.7 Hz, 1H), 2.01 (m, 1H), 1.96 (m, 1H), 1.27 (d,
J¼6.9 Hz, 3H), 1.25 (d, J¼7.5 Hz, 3H), 1.17e1.14 (complex m, 6H), 1.07
(d, J¼6.9 Hz, 3H), 0.97 (d, J¼6.9 Hz, 3H), 0.88 (s, 9H), 0.06 (s, 3H),
anes/EtOAc¼5/1 to 3/1) to afford a BOM ether S3a (1.79 g, 99%) as
23
a colorless oil; [
a
]
D
ꢁ42.6 (c 1.00, CHCl3); IR (neat)/cmꢁ1; 3024,
2978, 2939, 2885, 1774, 1697, 1381, 1211, 1026, 741; 1H NMR
(500 MHz, CDCl3)
d
7.36e7.23 (complex m, 15H), 7.07 (d, J¼6.9 Hz,
2H), 6.83 (d, J¼8.6 Hz, 2H), 4.90 (d, J¼7.5 Hz, 1H), 4.88 (d, J¼7.5 Hz,
1H), 4.88 (d, J¼6.9 Hz, 1H), 4.85 (d, J¼6.9 Hz, 1H), 4.69 (d, J¼12.0 Hz,
1H), 4.66 (d, J¼11.5 Hz, 1H), 4.64 (d, J¼12.0 Hz, 1H), 4.60 (d,
J¼11.5 Hz, 1H), 4.56 (d, J¼11.5 Hz, 1H), 4.47 (d, J¼11.3 Hz, 1H),
4.20e4.11 (complex m, 2H), 4.06 (dd, J¼5.2, 5.2 Hz, 1H), 3.91 (dd,
J¼8.9, 2.0 Hz, 1H), 3.80e3.75 (complex m, 4H), 3.73e3.68 (complex
m, 2H), 3.19 (dd, J¼13.4, 3.2 Hz, 1H), 2.66 (dd, J¼13.2, 9.8 Hz, 1H),
2.05 (m, 1H), 1.28 (d, J¼6.9 Hz, 3H), 1.19 (d, J¼6.3 Hz, 3H), 1.08 (d,
0.04 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 175.0, 174.3, 159.0, 153.0,
138.2, 138.0, 138.0, 135.3, 130.8, 129.4 (Cꢂ2), 129.3 (Cꢂ2), 128.8
(Cꢂ2), 128.3 (Cꢂ2), 128.3 (Cꢂ2), 128.2 (Cꢂ2), 127.7 (Cꢂ2), 127.6
(Cꢂ2), 127.5, 127.4, 127.4, 127.3 (Cꢂ2), 127.2, 113.6 (Cꢂ2), 96.5, 96.3,
96.1, 81.5, 80.9, 80.9, 76.9, 73.0, 73.0, 70.9, 70.2, 70.0 (Cꢂ2), 65.9,
55.5, 55.2, 42.7, 41.4, 38.6, 37.4 (Cꢂ2), 25.9 (Cꢂ3), 18.3, 15.9, 15.5,
12.5, 12.0, 11.1, 10.7, ꢁ4.1, ꢁ4.2; HRMS-ESI (m/z); [MþNa]þ calcd for
J¼6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 175.3,158.9,153.1,138.2,
138.1,135.3,131.1,129.3 (Cꢂ2),129.1 (Cꢂ2),128.7 (Cꢂ2),128.3 (Cꢂ2),
128.2 (Cꢂ2),127.7 (Cꢂ2),127.5 (Cꢂ2),127.5 (Cꢂ2),127.1,113.5 (Cꢂ2),
97.4, 96.4, 82.5, 80.7, 76.2, 70.8, 70.4, 70.3, 65.8, 55.4, 55.2, 41.0, 37.8,
37.4, 15.9, 12.4, 10.8; HRMS-ESI (m/z); [MþNa]þ calcd for
C66H89NO14SiNa, 1170.5950; found 1170.5949.
C
43H51NO9Na, 748.3462; found 748.3453.
4 .1.11. ( 2 R , 3 S , 4 S , 5 R , 6 R ) - 3 - [ ( B e n z yl o x y ) m e t h o x y ] - 6 -
({(20R,30S,40S,50R,60R)-30,50-bis[(benzyloxy)methoxy]-60-[(4-
methoxybenzyl)oxy]-20,40-dimethylheptanoyl}oxy)-5-[(tert-butyldi-
methylsilyl)oxy]-2,4-dimethylheptanoic acid (S4a).
4.1.9. (2R,3S,4S,5R,6R)-3,5-Bis[(benzyloxy)methoxy]-6-(4-
methoxybenzyl)oxy-2,4-dimethylheptanoic acid (14a). To a solution
of 30% H2O2 solution in water (25 mL) in H2O (15 mL) was added
LiOH$H2O (489 mg, 11.7 mmol) at 0 ꢀC. After stirring for 15 min,
a solution of BOM ether S3a (1.71 g, 2.36 mmol) in THF (25 mL) was
added at 0 ꢀC. Then the mixture was allowed to warm to room
temperature and stirred for 4 h. The reaction was quenched with
satd aq NaHCO3 (25 mL). Resulted two layers were separated and
the aqueous phase was extracted with CHCl3 (25 mLꢂ3). The com-
bined organic layers were washed with water and brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (hexanes/EtOAc¼4/1 to 3/1) to
To a solution of 30% H2O2 solution in water (6.0 mL) in H2O
(4.0 mL) was added LiOH$H2O (78.8 mg, 1.88 mmol) at 0 ꢀC. After
stirring for 15 min, a solution of linear unit ester 15a (421 mg,
afford carboxylic acid 14a (1.00 g, 75%) as a colorless oil; ½a D25
þ3.1 (c
ꢃ
1.00, CHCl3); IR (neat)/cmꢁ1; 3224e3170 (br), 3062, 2978, 2939,
367 m
mol) in THF (10 mL) was added at 0 ꢀC. Then the mixture was
2885, 1705, 1512, 1458, 1250, 1026, 748; 1H NMR (500 MHz, CDCl3)
allowed to warm to room temperature and stirred for 9 h. The re-
action was quenched with satd aq NaHCO3 (30 mL). Resulted two
layers were separated and the aqueous phase was extracted with
CHCl3 (20 mLꢂ3). The combined organic layers were washed with
water and brine, dried over Na2SO4 and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
(hexanes/EtOAc¼5/1 to 3/1) to afford carboxylic acid S4a (264 mg,
d
7.33e7.25 (complex m, 10H), 7.22 (d, J¼8.6 Hz, 2H), 6.84 (d,
J¼8.6 Hz, 2H), 4.94 (d, J¼6.9 Hz, 1H), 4.84 (d, J¼6.9 Hz, 1H), 4.77 (d,
J¼6.9 Hz, 1H), 4.73 (d, J¼6.9 Hz, 1H), 4.70 (d, J¼12.6 Hz, 1H), 4.61 (d,
J¼12.6 Hz, 1H), 4.60 (d, J¼12.0 Hz, 1H), 4.57 (d, J¼12.0 Hz, 1H), 4.52
(d, J¼11.5 Hz,1H), 4.40 (d, J¼11.5 Hz,1H), 4.08 (dd, J¼7.5, 3.4 Hz,1H),
3.78 (s, 3H), 3.69 (dq, J¼6.3, 6.3 Hz, 1H), 3.50 (dd, J¼6.3, 4.0 Hz, 1H),
2.94 (dq, J¼6.9, 3.4 Hz,1H),1.96 (m,1H),1.16 (d, J¼6.9 Hz, 3H),1.15 (d,
J¼6.3 Hz, 3H), 1.04 (d, J¼6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3)
73%) as a colorless oil; ½a D24
ꢃ
ꢁ11.7 (c 1.00, CHCl3); IR (neat)/cmꢁ1
;
3224e3155 (br), 3062, 3032, 2939, 2885, 2862, 1728, 1458, 1250,
1149, 1026, 833, 741; 1H NMR (500 MHz, CDCl3)
d 7.37e7.24
d
180.0, 159.0, 137.9, 137.8, 130.5, 129.3 (Cꢂ2), 128.3 (Cꢂ4), 127.7
(complex m,17H), 6.84 (d, J¼8.6 Hz, 2H), 5.03 (dq, J¼6.3, 2.3 Hz,1H),
4.90 (d, J¼7.5 Hz, 1H), 4.83e4.78 (complex m, 4H), 4.76 (d,
J¼12.6 Hz, 1H), 4.75 (d, J¼6.9 Hz, 1H), 4.70e4.66 (complex m, 3H),
4.59 (d, J¼12.6 Hz, 1H), 4.56 (d, J¼12.6 Hz, 1H), 4.54 (d, J¼11.5 Hz,
1H), 4.43 (d, J¼11.5 Hz, 1H), 4.06 (dd, J¼6.9, 4.6 Hz, 1H), 3.80e3.76
(complex m, 4H), 3.74e3.68 (complex m, 2H), 3.54 (dd, J¼5.2,
5.2 Hz, 1H), 2.86 (dq, J¼6.9, 4.6 Hz, 1H), 2.71 (dq, J¼7.5, 7.5 Hz, 1H),
1.93 (m, 1H), 1.88 (m, 1H), 1.20 (d, J¼6.9 Hz, 6H), 1.15 (d, J¼6.3 Hz,
3H), 1.13 (d, J¼6.3 Hz, 3H), 1.09 (d, J¼6.9 Hz, 3H), 1.00 (d, J¼6.9 Hz,
3H), 0.91 (s, 9H), 0.08 (s, 3H), ꢁ0.05 (s, 3H); 13C NMR (125 MHz,
(Cꢂ2), 127.7 (Cꢂ2), 127.5 (Cꢂ2), 113.7 (Cꢂ2), 96.3, 96.2, 81.6 (Cꢂ2),
76.8, 71.0, 70.2, 70.1, 55.2, 41.8, 37.2,15.9,10.6,10.4; HRMS-ESI (m/z);
[MþNa]þ calcd for C33H42O8Na, 589.2777; found 589.2782.
4.1.10. (20R,30R,40S,50S,60R)-7-[(R)-400-Benzyl-200-oxazolidin-300-yl]-50-
[(benzyloxy)methoxy]-30-[(tert-butyldimethylsilyl)oxy]-40,60-di-
methyl-70-oxoheptan-20-yl (2R,3S,4S,5R,6R)-3,5-bis[(benzyloxy)me-
thoxy]-6-[(4-methoxybenzyl)oxy]-2,4-dimethylheptanoate (15a). To
a solution of alcohol 13a (335 mg, 558
14a (355 mg, 626 mol) in CH2Cl2 (2.5 mL) was added DMAP
(45.2 mg, 370 mol) and CSA (38.7 mg, 167 mol) under N2. The
mmol) and carboxylic acid
m
CDCl3)
d
176.2, 174.3, 159.0, 137.9, 137.5, 137.3, 130.4, 129.6 (Cꢂ2),
m
m
mixture was cooled to 0 ꢀC and added DCC (310 mg, 1.50 mmol).
After stirring for 21 h at room temperature, the reaction was
quenched with H2O (5.0 mL). Resulted two layers were separated
and the aqueous phase was extracted with CH2Cl2 (10 mLꢂ3). The
combined organic layers were washed with water and brine, dried
over Na2SO4 and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (hexanes/EtOAc¼6/1 to
128.4 (Cꢂ2). 128.3 (Cꢂ2), 128.3 (Cꢂ2), 128.2 (Cꢂ2), 127.7 (Cꢂ2),
127.7, 127.6, 127.5, 127.4 (Cꢂ2), 113.6 (Cꢂ2), 96.7, 96.5, 95.2, 82.7,
81.5, 80.6, 75.9, 74.3, 71.0, 70.6, 70.2, 69.9, 69.6, 55.2, 43.9, 42.3,
38.9, 37.3, 26.0 (Cꢂ3), 18.3, 17.0, 15.8, 13.7, 11.6, 10.7, 10.7, ꢁ3.5, ꢁ3.8;
HRMS-ESI (m/z); [MþNa]þ calcd for C56H80O13SiNa, 1011.5266;
found 1011.5259.
4/1) to afford a 15a (532 mg, 83%) as a colorless oil; ½a D24
ꢁ21.3 (c
ꢃ
4 .1.12 . ( 2 R , 3 S , 4 S , 5 R , 6 R ) - 3 - [ ( B e n z yl o x y ) m e t h o x y ] - 6 -
({(20R,30S,40S,50R,60R)-30,50-bis[(benzyloxy)methoxy]-60-hydroxy-20,40-
dimethylheptanoyl}oxy)-5-[(tert-butyldimethylsilyl)oxy]-2,4-
dimethylheptanoic acid (16a). A solution of PMB ether S4a (193 mg,
1.00, CHCl3); IR (neat)/cmꢁ1; 2954, 2885, 1782, 1712, 1373, 1234,
1026, 748; 1H NMR (500 MHz, CDCl3)
7.08 (d, J¼6.9 Hz, 2H), 6.81 (d, J¼8.6 Hz, 2H), 5.00 (m, 1H), 4.87 (d,
d 7.35e7.21 (complex m, 20H),
Please cite this article in press as: Nakano, H.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.01.030

10
H. Nakano et al. / Tetrahedron xxx (2015) 1e11
195
m
mol) in CH2Cl2 (5.5 mL) and pH 7.0 phosphate buffer solution
30 min at 0 ꢀC. After warming to room temperature, the reaction
mixture was stirred for 21 h. Silica gel (15 cc) was added to the
reaction mixture, which was then concentrated in vacuo. The res-
idue was purified by flash column chromatography on silica gel
(hexanes/EtOAc¼9/1 to 6/1) to afford macrodiolide aglycone 18a
in water (5.0 mL) at room temperature was added to DDQ (130 mg,
573 mol). The heterogeneous solution was stirred for 3 h. Then the
m
reaction was quenched with satd aq NaHCO3 (30 mL). Resulted two
layers were separated and the aqueous phase was extracted with
CHCl3 (15 mLꢂ3). The combined organic layers were washed with
water and brine, dried over Na2SO4 and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
(hexanes/EtOAc¼5/1 to 3/1) to afford seco-acid 16a (134 mg, 79%) as
(54.3 mg, 70%) as a colorless oil; ½a D26
ꢁ2.5 (c 0.50, CHCl3); IR (neat)/
ꢃ
cmꢁ1; 2939, 2885, 2862, 1728, 1458, 1373, 1250, 1026, 841, 733; 1H
NMR (500 MHz, CDCl3) d 7.36e7.26 (complex m, 15H), 5.10 (m, 1H),
4.94 (m, 1H), 4.87e4.76 (complex m, 6H), 4.70e4.67 (complex m,
3H), 4.62 (d, J¼12.0 Hz, 1H), 4.59 (d, J¼12.6 Hz, 2H), 3.97 (d,
J¼9.2 Hz, 1H), 3.94 (dd, J¼8.0, 3.4 Hz, 1H), 3.77 (dd, J¼9.2, 2.3 Hz,
1H), 3.65 (dd, J¼8.6, 2.9 Hz, 1H), 2.85e2.75 (complex m, 2H), 1.91
(m, 1H), 1.87 (m, 1H), 1.30 (d, J¼5.7 Hz, 3H), 1.28 (d, J¼6.9 Hz, 3H),
1.23 (d, J¼6.9 Hz, 3H), 1.11 (d, J¼6.3 Hz, 3H), 1.04 (d, J¼7.5 Hz, 3H),
1.02 (d, J¼7.5 Hz, 3H), 0.91 (s, 9H), 0.06 (s, 3H), ꢁ0.01 (s, 3H); 13C
a colorless oil; ½a D25
ꢃ
ꢁ29.2 (c 1.00, CHCl3); IR (neat)/cmꢁ1; 3448,
3293, 3170 (br), 3062, 3032, 2939, 2893,1728, 1458, 1381,1026, 833,
741; 1H NMR (500 MHz, CDCl3)
d 7.36e7.25 (complex m, 15H), 5.04
(dq, J¼6.3, 1.7 Hz, 1H), 4.86 (d, J¼6.9 Hz, 1H), 4.84 (d, J¼6.9 Hz, 1H),
4.81 (d, J¼6.9 Hz, 1H), 4.80 (d, J¼6.9 Hz, 1H), 4.79 (d, J¼6.9 Hz, 1H),
4.75 (d, J¼6.9 Hz,1H), 4.72 (d, J¼12.0 Hz,1H), 4.71 (d, J¼12.0 Hz,1H),
4.68 (d, J¼12.0 Hz, 1H), 4.65 (d, J¼12.0 Hz, 1H), 4.58 (d, J¼12.0 Hz,
1H), 4.58 (d, J¼12.0 Hz,1H), 4.06 (m,1H), 4.00 (dd, J¼5.7, 4.6 Hz,1H),
3.78 (m, 1H), 3.71 (dd, J¼8.0, 1.7 Hz, 1H), 3.43 (dd, J¼6.9, 4.0 Hz, 1H),
2.76e2.69 (complex m, 2H), 1.86 (m, 1H), 1.82 (m, 1H), 1.24 (d,
J¼6.9 Hz, 3H), 1.20 (d, J¼6.9 Hz, 3H), 1.14 (d, J¼6.3 Hz, 3H), 1.13 (d,
J¼6.3 Hz, 3H), 1.06 (d, J¼7.5 Hz, 3H), 0.99 (d, J¼6.9 Hz, 3H), 0.91 (s,
NMR (125 MHz, CDCl3)
d
174.3, 173.1, 137.9, 137.7, 137.5, 128.4 (Cꢂ4),
128.3 (Cꢂ2), 127.6 (Cꢂ3), 127.6 (Cꢂ3), 127.5, 127.5 (Cꢂ2), 96.9, 96.2,
95.7, 82.5, 81.3, 81.2, 74.1, 72.5, 71.2, 70.4, 70.1 (Cꢂ2), 46.1, 45.9, 39.7,
38.6, 26.0 (Cꢂ3), 18.3, 18.0, 15.5, 14.9, 14.6, 10.9, 9.4, ꢁ3.7, ꢁ4.0;
HRMS-ESI (m/z); [MþNa]þ calcd for C48H70O11SiNa, 873.4585;
found 873.4576.
9H), 0.08 (s, 3H), ꢁ0.04 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 177.1,
174.8,137.5,137.4,137.2,128.4 (Cꢂ2),128.4 (Cꢂ4),127.8 (Cꢂ2),128.8,
127.8 (Cꢂ2),127.7,127.6,127.4 (Cꢂ2), 96.6, 96.4, 96.0, 85.8, 81.5, 79.9,
74.1, 71.5, 70.4, 70.1, 69.9, 67.8, 43.6, 43.2, 38.8, 38.8, 26.0 (Cꢂ3),19.3,
18.3,16.7,13.6,13.0,10.6,10.3, ꢁ3.7, ꢁ3.9; HRMS-ESI (m/z); [MþNa]þ
calcd for C48H72O12SiNa, 891.4691; found 891.4690.
4.1.15. (3R,4S,5S,6R,7R,10R,11S,12S,13R,14R)-3,6,11-Tris[(benzyloxy)
methoxy]-13-hydroxy-3, 5, 7,10,12,14-hexamethyl-1, 8-
dioxacyclotetradecane-2,9-dione (19). To a plastic centrifuge tube
in THF (1.2 mL) solution of substrate 17a (35.4 mg, 41.6
mmol) was
added 70% HF$Pyr. (200
m
L) under N2 at 0 ꢀC. The reaction mixture
was stirred for 28 h at room temperature. The reaction mixture
was diluted with CH2Cl2 (5.0 mL) and quenched by the addition to
cold satd aq NaHCO3 (15 mL). The mixture was then poured into
water (5 mL) and resulted two layers were separated and the
aqueous phase was extracted with CH2Cl2 (10 mLꢂ3). The com-
bined organic layers were washed with water and brine, dried
over Na2SO4 and concentrated in vacuo. The residue was purified
by flash column chromatography on silica gel (hexanes/EtOAc¼4/1
to 2/1) to afford macrodiolide 19 (20.0 mg, 65%) as a colorless oil;
4.1.13. (3R,4S,5S,6R,7R,10R,11S,12S,13R,14R)-4,11,13-Tris[(benzyloxy)
methoxy]-6-[(tert-butyldimethylsilyl)oxy]-3,5,7,10,12,14-hexamethyl-
1,8-dioxacyclotetradecane-2,9-dione (17a). To a solution of seco-
acid 16a (30.3 mg, 34.9
benzene (5.0 mL) was added 2,4,6-trichlorobenzoyl chloride
(90.0 L, 576
mol) dropwise under N2 at 0 ꢀC. Then, the reaction
mmol) and DIPEA (120 mL, 706 mmol) in
m
m
mixture was allowed to warm to room temperature and stirred for
1.5 h. The mixture was diluted with benzene (2.0 mL) and added
dropwise over a period of 2 h to a refluxing solution of DMAP
½
a 2D5
ꢃ
ꢁ49.6 (c 1.00, CHCl3); IR (neat)/cmꢁ1; 3410, 3379, 3062, 3032,
(63.9 mg, 523
stirred for 3 h at 80 ꢀC and quenched with satd aq NH4Cl (3.0 mL) at
ꢀC. Resulted two layers were separated and the aqueous phase
mmol) in benzene (4.5 mL). Then, the mixture was
2970, 2939, 2885, 1728, 1450, 1373, 1165, 1088, 1018, 733; 1H NMR
(500 MHz, CDCl3)
d 7.37e7.24 (complex m, 15H), 5.23e5.15
0
(complex m, 2H), 4.84 (d, J¼6.9 Hz, 1H), 4.83e4.74 (complex m,
6H), 4.71e4.65 (complex m, 3H), 4.53 (d, J¼11.5 Hz, 2H), 3.73 (d,
J¼10.3 Hz, 1H), 3.71 (d, J¼10.3 Hz, 1H), 3.66 (d, J¼9.7 Hz, 1H), 3.51
(m, 1H), 2.81 (m, 1H), 2.75 (m, 1H), 1.62 (m, 1H), 1.44 (m, 1H), 1.19
(d, J¼6.9 Hz, 3H), 1.17 (d, J¼6.9 Hz, 3H), 1.16 (d, J¼6.3 Hz, 3H), 1.13
(d, J¼6.3 Hz, 3H), 1.09 (d, J¼6.9 Hz, 3H), 1.08 (d, J¼6.9 Hz, 3H); 13C
was extracted with EtOAc (10 mLꢂ3). The combined organic layers
were washed with water and brine, dried over Na2SO4 and con-
centrated in vacuo. The residue was purified by flash column
chromatography on silica gel (hexanes/EtOAc¼8/1 to 6/1) to afford
a macrodiolide aglycone 17a (19.8 mg, 67%) as a colorless oil; ½a D24
ꢃ
ꢁ25.6 (c 1.00, CHCl3); IR (neat)/cmꢁ1; 2939, 2893, 2862, 1728, 1458,
NMR (125 MHz, CDCl3) d 174.9, 174.2, 137.9, 137.5, 137.3, 128.5
1373, 1165, 1095, 1026, 741; 1H NMR (500 MHz, CDCl3)
d
7.35e7.25
(Cꢂ2), 128.3 (Cꢂ4), 127.8, 127.8 (Cꢂ2), 127.6, 127.5, 127.5 (Cꢂ2),
127.5 (Cꢂ2), 96.9, 96.8, 96.7, 81.3, 81.0, 80.9, 74.4, 70.7, 70.5, 70.2,
70.1, 70.0, 44.4 (Cꢂ2), 40.2, 39.4, 17.3, 16.8, 14.8, 14.7, 9.9, 9.6;
HRMS-ESI (m/z); [MþNa]þ calcd for C42H56O11Na, 759.3720; found
759.3720.
(complex m, 15H), 5.20 (q, J¼6.3 Hz, 1H), 5.09 (q, J¼6.3 Hz, 1H),
4.84e4.67 (complex m, 9H), 4.65 (d, J¼12.0 Hz, 1H), 4.58 (d,
J¼12.6 Hz, 1H), 4.53 (d, J¼12.0 Hz, 1H), 3.86 (d, J¼9.2 Hz, 1H), 3.75
(d, J¼9.7 Hz, 1H), 3.67 (d, J¼9.2 Hz, 2H), 2.87e2.75 (complex m, 2H),
1.80 (m, 1H), 1.67 (m, 1H), 1.22e1.18 (complex m, 9H), 1.11 (d,
J¼6.3 Hz, 3H), 1.06 (d, J¼7.5 Hz, 3H), 1.01 (d, J¼6.9 Hz, 3H), 0.91 (s,
4.1.16. Protected macrodiolide (21). To
chloroacetimidate 20 (35.3 mg, 97.6 mol), macrodiolide aglycone
19 (29.5 mg, 40.0 mol) and molecular sieves 4 A powder (228 mg)
a
mixture of tri-
9H), 0.06 (s, 3H), ꢁ0.08 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
174.5,
m
ꢁ
174.2, 138.0, 137.6, 137.5, 128.4 (Cꢂ2), 128.3 (Cꢂ2), 128.3 (Cꢂ2),
127.6, 126.6, 127.5 (Cꢂ5), 127.3 (Cꢂ2), 96.8, 96.6, 96.4, 81.6, 81.1,
80.8, 74.4, 70.6, 70.4, 70.2, 70.0, 69.8, 44.6, 44.3, 40.1, 38.8, 26.0
(Cꢂ3), 18.4, 17.1, 17.0, 14.5, 14.3, 10.7, 9.7, ꢁ3.4, ꢁ3.9; HRMS-ESI (m/
z); [MþNa]þ calcd for C48H70O11SiNa, 873.4585; found 873.4589.
m
were dissolved in CH2Cl2 (2.0 mL) and stirred under N2 at room
temperature. After stirring for 1 h, the mixture was cooled to
ꢁ50 ꢀC and then TfOH (13.0
mmL, 147 mmol) was added. The
resulting mixture was stirred for 26 h at ꢁ50 ꢀC. The reaction was
quenched with NaHCO3 (150 mg) at 0 ꢀC. After filtration through
a pad of Celite with CHCl3/MeOH (v/v, 10/1, 10 mLꢂ3), the filtrate
was concentrated in vacuo. The residue was purified by flash col-
umn chromatography on silica gel (EtOAc/MeOH¼20/1 to 15/1) to
4.1.14. (3R,4S,5S,6R,7R,10R,11S,12S,13R,14S)-4,11,13-Tris[(benzyloxy)
methoxy]-6-[(tert-butyldimethylsilyl)oxy]-3,5,7,10,12,14-hexamethyl-
1,8-dioxacyclotetradecane-2,9-dione (18a). To a solution of PPh3
(92.3 mg, 352
toluene (18 mL) was added DEAD (40% in toluene, 0.24 ml,
48.0
mol) under N2 at 0 ꢀC. The reaction mixture was stirred for
mmol) and seco-acid 16a (79.6 mg, 91.6
mmol) in
afford macrodiolide 21 (18.0 mg, 48%) as a yellow oil; ½a D24
ꢁ36.0 (c
ꢃ
0.20, CHCl3); IR (neat)/cmꢁ1; 3062, 2978, 2939, 2885, 1728, 1458,
m
1373, 1165, 1018, 748; 1H NMR (500 MHz, CDCl3)
d 7.36e7.24
Please cite this article in press as: Nakano, H.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.01.030

H. Nakano et al. / Tetrahedron xxx (2015) 1e11
11
6. Beeler, A. B.; Acquilano, D. E.; Su, Q.; Yan, F.; Roth, B. L.; Panek, J. S.; Porco, J. A.,
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S. L. Science 2003, 300, 294e295; (c) Burke, M. D.; Schreiber, S. L. Angew. Chem.,
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(complex m, 15H), 5.19 (q, J¼6.3 Hz, 2H), 4.88e4.82 (complex m,
3H), 4.79e4.70 (complex m, 6H), 4.68 (d, J¼12.0 Hz, 1H), 4.63 (d,
J¼12.0 Hz, 1H), 4.54 (d, J¼12.6 Hz, 1H), 4.52 (d, J¼12.0 Hz, 1H), 4.31
(d, J¼7.5 Hz, 1H), 3.74 (d, J¼9.7 Hz, 1H), 3.70 (d, J¼10.3 Hz, 1H), 3.67
(dd, J¼9.7, 6.3 Hz, 2H), 3.20 (m, 1H), 2.85e2.72 (complex m, 3H),
2.38 (br s, 6H), 2.11 (s, 3H), 1.73e1.64 (complex m, 2H), 1.36e1.24
(complex m, 2H), 1.22 (d, J¼6.3 Hz, 3H) 1.20e1.16 (complex m, 9H),
8. (a) Arya, P.; Joseph, R.; Gan, Z.; Rakic, B. Chem. Biol. 2005, 12, 163e180; (b)
Dockendorff, C.; Nagiec, M. M.; Weiwer, M.; Buhrlage, S.; Ting, A.; Nag, P. P.;
Germain, A.; Kim, H.-J.; Youngsaye, W.; Scherer, C.; Bennion, M.; Xue, L.;
Stanton, B. Z.; Lewis, T. A.; Macpherson, L.; Palmer, M.; Foley, M. A.; Perez, J. R.;
Schreiber, S. L. ACS Med. Chem. Lett. 2012, 3, 808e813; (c) Su, Q.; Beeler, A. B.;
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A.; Sharma, S.; Gupt, M. P.; Bajpai, V.; Hamidullah; Kumar, B.; Kaushik, M. P.;
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1.08e1.04 (complex m, 9H); 13C NMR (125 MHz, CDCl3)
d 174.5,
174.4, 169.8, 137.9, 137.6, 137.6, 128.5 (Cꢂ2), 128.4 (Cꢂ2), 128.3
(Cꢂ2), 127.7, 127.6, 127.5, 127.5 (Cꢂ2), 127.5 (Cꢂ2), 127.3 (Cꢂ2),
101.9, 97.0, 96.9, 96.5, 81.6, 81.3, 80.9, 79.8, 70.4 (Cꢂ2), 70.4, 70.1,
70.0, 69.8, 68.6, 63.4, 44.2, 44.1, 40.5 (Cꢂ2), 39.7, 39.2, 30.6, 21.3,
20.9, 17.3, 17.1, 14.7 (Cꢂ2), 9.4, 9.3; HRMS-ESI (m/z); [MþH]þ calcd
for C52H74NO14, 936.5109; found 936.5100.
€
9. (a) Shin, Y.; Fournier, J.-H.; Bruckner, A.; Madiraju, C.; Balachandran, R.; Raccor,
B. S.; Edler, M. C.; Hamel, E.; Sikorski, R. P.; Vogt, A.; Day, B. W.; Curran, D. P.
Tetrahedron 2007, 63, 8537e8562; (b) Nicolaou, K. C.; Vourloumis, D.; Li, T.;
Pastor, J.; Winssinger, N.; He, Y.; Ninkovic, S.; Sarabia, F.; Vallberg, H.; Ro-
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ꢂ
ꢃ
ꢂ
ꢃ
10. Bauer, J.; Vine, M.; Coric, I.; Bosnar, M.; Pasalic, I.; Turkalj, G.; Lazarevski, G.;
ꢂ
4.1.17. Macrodiolide (22). To a solution of macrolide 21 (15.4 mg,
ꢃ
Culic, O.; Kragol, G. Bioorg. Med. Chem. 2012, 20, 2274e2281.
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12. Recent diversity-oriented synthesis campaigns have demonstrated the impor-
tance of the SSAR of synthetic macrocycles. (a) Heidebrecht, R. W., Jr.; Mul-
rooney, C.; Austin, C. P.; Baker, R. H., Jr.; Beaudoin, J. A.; Cheng, K. C.-C.; Comer,
E.; Dandapani, S.; Dick, J.; Duvall, J. R.; Ekland, E. H.; Fidock, D. A.; Fitzgerald, M.
E.; Foley, M.; Guha, R.; Hinkson, P.; Kramer, M.; Lukens, A. K.; Masi, D.; Mar-
caurelle, L. A.; Su, X.-Z.; Thomas, C. J.; Weïwer, M.; Wiegand, R. C.; Wirth, D.;
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16.5
m
mol) in MeOH (1.0 mL) was added Pearlman’s catalyst 20% on
carbon (wetted with ca. 50% water, 8.0 mg, 5.70
m
mol) at 0 ꢀC. The
mixture was purged with H2 under 1 atm at room temperature.
After stirring for 22 h, the mixture was filtered through a pad of
Celite with CHCl3/MeOH (v/v, 10/1, 10 mLꢂ3) and the filtrate was
concentrated in vacuo. The resulting crude product was used for
subsequent reaction without further purification.
The crude product was dissolved in MeOH (1.5 mL). This mixture
was heated to 50 ꢀC and stirred for 4.5 h. The mixture was con-
centrated in vacuo. The residue was purified by flash column
chromatography on silica gel (CHCl3/MeOH¼8/1, 5/1 to 3/1) to af-
13. Fuwa, H.; Kawakami, M.; Noto, K.; Muto, T.; Suga, Y.; Konoki, K.; Yotsu-Yama-
shita, M.; Sasaki, M. Chem.dEur. J. 2013, 19, 8100e8110.
14. Moretti, J. D.; Wang, X.; Curran, D. P. J. Am. Chem. Soc. 2012, 134, 7963e7970.
15. Marcaurelle, L. A.; Comer, E.; Dandapani, S.; Duvall, J. R.; Gerard, B.; Kesavan, S.;
Lee, M. D., IV; Liu, H.; Lowe, J. T.; Marie, J.-C.; Mulrooney, C. A.; Pandya, B. A.;
Rowley, A.; Ryba, T. D.; Suh, B.-C.; Wei, J.; Young, D. W.; Akella, L. B.; Ross, N. T.;
Zhang, Y.-L.; Fass, D. M.; Reis, S. A.; Zhao, W.-N.; Haggarty, S. J.; Palmer, M.;
Foley, M. A. J. Am. Chem. Soc. 2010, 132, 16962e16976.
ford macrodiolide 22 (8.2 mg, 93%) as a colorless oil; ½a D23
ꢁ4.4 (c
ꢃ
0.21, MeOH); IR (neat)/cmꢁ1; 3417, 2978, 2939, 2877, 1728, 1705,
1458,1373, 1265, 1165, 1026, 756; 1H NMR (500 MHz, CD3OD)
d 5.08
(q, J¼6.3 Hz,1H), 5.05 (m, 1H), 4.32 (d, J¼7.5 Hz,1H), 3.81 (dd, J¼6.9,
2.9 Hz, 1H), 3.57 (m, 1H), 3.55 (d, J¼10.3 Hz, 1H), 3.52 (d, J¼10.3 Hz,
1H), 3.43 (d, J¼9.7 Hz, 1H), 3.35 (dd, J¼10.3, 7.5 Hz, 1H), 2.74e2.66
(complex m, 2H), 2.61 (dq, J¼9.7, 6.9 Hz, 1H), 2.38 (s, 6H), 1.78 (ddd,
J¼12.9, 4.0, 1.7 Hz, 1H), 1.71 (dq, J¼6.9, 6.9 Hz, 1H),1.63 (m, 1H),
1.31e1.27 (complex m, 7H), 1.22 (d, J¼5.7 Hz, 3H), 1.17 (d, J¼6.9 Hz,
3H), 1.17 (d, J¼6.9 Hz, 3H), 1.09 (d, J¼7.5 Hz, 3H), 1.00 (d, J¼6.9 Hz,
16. (a) Rustmicin: Takatsu, T.; Nakayama, H.; Shimazu, A.; Furihata, K.; Ikeda, K.;
Furihata, K.; Seto, H.; Otake, N. J. Antibiot. 1985, 37, 1806e1809; (b) Sekothrix-
ide: Kim, Y. J.; Furihata, K.; Shimazu, A.; Furihata, K.; Seto, H. J. Antibiot. 1991, 44,
1280e1282; (c) Terayama, N.; Yasui, E.; Mizukami, M.; Miyashita, M.; Nagumo,
S. Org. Lett. 2014, 16, 2794e2797; (d) Migrastatin: Takemoto, Y.; Nakae, K.;
Kawatani, M.; Takahashi, Y.; Naganawa, H.; Imoto, M. J. Antibiot. 2001, 54,
1104e1107; (e) Clonostachydiol: Rama Rao, A. V.; Murthy, V. S.; Sharma, G. V.
M. Tetrahedron Lett. 1995, 36, 139e142.
ꢀ
17. (a) Omura, S.; Tsuzuki, K.; Sunazuka, T.; Marui, S.; Toyoda, H.; Inatomi, N.; Itoh,
3H); 13C NMR (125 MHz, CD3OD)
d 177.0, 177.0, 106.0, 82.3, 76.0,
Z. J. Med. Chem. 1987, 30, 1941e1943; (b) Tsuzuki, K.; Sunazuka, T.; Marui, S.;
ꢀ
Toyoda, H.; Omura, S.; Inatomi, N.; Itoh, Z. Chem. Pharm. Bull. 1989, 37,
75.5, 73.6, 73.3, 71.9, 71.5, 70.3, 65.8, 45.4, 45.1, 40.9 (Cꢂ2), 40.7,
40.2, 32.1, 21.4, 17.6, 17.3, 15.3, 14.9, 9.4, 8.7; HRMS-ESI (m/z);
[MþNa]þ calcd for C26H47NO10Na, 556.3098; found 556.3095.
ꢀ
2687e2700; (c) Sunazuka, T.; Tsuzuki, K.; Murai, S.; Toyoda, H.; Omura, S.; In-
atomi, N.; Itoh, Z. Chem. Pharm. Bull. 1989, 37, 2701e2709.
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This work was supported bya Sasakawa Scientific Research Grant
(to H. N.) from the Japan Science Society (25-312), and a grant from
the 21st Century Center of Excellence Program. We thank Dr. Keni-
chiro Nagai and Ms Noriko Sato for various instrumental analyses.
Supplementary data
25. Mitsunobu, O. Synthesis 1981, 1e28.
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Supplementary data (Full details of experimental procedures
and spectra data for new compounds, together with) related to this
article can be found at http://dx.doi.org/10.1016/j.tet.2015.01.030.
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Please cite this article in press as: Nakano, H.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.01.030