Stereoselective Synthesis of the C27-C35 Eribulin Fragment and Its Utilization in Building Structurally Diverse Macrocycles

Article abstract of DOI:10.1055/s-0035-1561431

A practical and scalable stereoselective synthesis of the western substituted tetrahydrofuran ring C27-C35 fragment of eribulin was developed by using (2S,3S)-tartaric acid as a cheap starting material that was converted into an intermediate through a stereoselective vinylation and cross-metathesis as the key steps. A regio-and stero-selective intramolecular oxy-Michael cyclization or an iodocyclization reaction finally provided the required western tetrahydrofuran ring fragment and its related isomeric analogues. These key fragments were further utilized in obtaining several types of macrocyclic derivatives for exploration of their biological properties. The simplicity of our present approach has the potential to be considered for large-scale syntheses of key fragments of eribulin and related analogues.

Full text of DOI:10.1055/s-0035-1561431

SYNTHESIS
0
0
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9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–U
A
special topic
S. Konda et al.
Special Topic
Synthesis
Stereoselective Synthesis of the C27–C35 Eribulin Fragment and
Its Utilization in Building Structurally Diverse Macrocycles
R
1 = CH2SO2Ph, CH2CH2OH
Saidulu Konda
OPG
MeO
32
1
R1
30
PhO2
MeO
S
HO
OH
31
MeO
H
O
Mahender Khatravath
Naveen Kumar Mallurwar
Pallavi Rao
SO2Ph
29
O
O
H
H2
N
32
MeO
H
PGO
30
32 29
O
O
O
30
O
35
31
HO
H
*
27
32
30
29
PGO
32
34
35
H
H
29
O
cross
metathesis
O
eribulin
33
O
O
O
R2
NH
O
O
HO
O
vinylation
27 CHO
O
H
EtOOC
14
O
R2
N
H
O
O
O
OH
31
COOH
HO
32
14-membered ring diversity
Shivashankar Sripelly
Javed Iqbal*
(2S,3S)-tartaric acid
pure cis or trans
29-H and C32-H
HOOC
C
Prabhat Arya*
Dr. Reddy’s Institute of Life Sciences, University of Hyderabad
Campus, Gachibowli, Hyderabad 500 046, India
prabhata@drils.org
prof.javediqbal@gmail.com
www.prabhatarya.org
Received: 10.02.2016
Accepted after revision: 17.03.2016
Published online: 19.04.2016
out affecting the rate of microtubule stretching. In the case
of eribulin-treated human lymphoma and prostate cancer,
several biochemical apoptosis-related studies that included
examinations of cytochrome c release from mitochondria,
activation of caspase-3 and caspase-9, cleavage of po-
ly(ADP-ribose) polymerase, and phosphorylation of Bcl-2
were also undertaken to understand the biological effects
of eribulin.16,23
Shown in Scheme 1 are the three key fragments of
eribulin, according to Kishi:3,24,25 2 (the western tetrahydro-
furan ring), 3, and 4. Over the years, serious efforts have
been made to develop practical and viable approaches for
the large-scale synthesis of these fragments, which eventu-
ally led to a total synthesis of eribulin.
DOI: 10.1055/s-0035-1561431; Art ID: ss-2016-c0084-st
Abstract A practical and scalable stereoselective synthesis of the
western substituted tetrahydrofuran ring C27–C35 fragment of eribulin
was developed by using (2S,3S)-tartaric acid as a cheap starting materi-
al that was converted into an intermediate through a stereoselective
vinylation and cross-metathesis as the key steps. A regio- and stereo-
selective intramolecular oxy-Michael cyclization or an iodocyclization
reaction finally provided the required western tetrahydrofuran ring
fragment and its related isomeric analogues. These key fragments were
further utilized in obtaining several types of macrocyclic derivatives for
exploration of their biological properties. The simplicity of our present
approach has the potential to be considered for large-scale syntheses of
key fragments of eribulin and related analogues.
We previously reported a stereoselective synthesis of
the tetrahydrofuran 5 (Scheme 2), an analogue of the west-
ern tetrahydrofuran ring fragment of eribulin.26 The key re-
actions in our approach were a chiral auxiliary-based syn-
aldol reaction to give vinylic ester 6 from aldehyde 7, and a
regio- and stereoselective oxy-Michael reaction that led to
the required fragment 5. This approach also permitted a
synthesis of the isomeric compound 10 in which a diaste-
reomeric analogue of 7 was used in the syn-aldol reaction
(not shown in the scheme). Aldehyde 7 and its diastereo-
meric derivative were synthesized from D-(+)-xylose. Final-
ly, the furan ring fragment 5 and its isomeric derivative 10
were used in syntheses of the 14-membered macrocycle 9
and the 12-membered macrocycle 11, respectively, with
the aim of exploring the biological properties of these prod-
ucts.
Key words halichondrins, eribulin, medicinal chemistry, macrocycles,
natural products, stereoselective synthesis
The marathon efforts by Kishi and co-workers,1–6
Phillips and co-workers,7–11 and others12,13 toward the syn-
thesis of members of the halichondrin family of marine nat-
ural products led to the development of eribulin (1),12,14–20
a
drug for treating metastatic breast cancer, approved by the
FDA in 2010 and marketed by Eisai Co., Ltd. (Tokyo) as Hala-
ven. Eribulin is a nontaxane microtubule-dynamics inhibi-
tor that functions through novel binding interactions with
tubulin as a target.20–22 Its precise mechanism of action is
still not clear, and several groups are working toward its
elucidation. It appears that the binding site for eribulin in
tubulin differs from that of several known anticancer drugs
such as paclitaxel or the vinca alkaloids.21 Eribulin binds to
an interdimer interface or to a β-tubulin subunit and, in do-
ing so, inhibits the microtubular growth phase of microtu-
bular dynamics instability in interphase cells without any
effect on the shortening of the microtubules.20 Further-
more, it also promotes centromere spindle relaxation with-
In a continuation of our interest in obtaining a series of
various macrocyclic compounds containing the western
tetrahydrofuran ring fragment, we describe our next-gen-
eration synthesis plan and its execution. Our first goal was
to develop a practical and scalable stereoselective synthesis
of several forms of the western furan ring fragment (for ex-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U

B
S. Konda et al.
Special Topic
Synthesis
Kishi fragments
26
I
MsO
PhO2S
MeO
3
2
1
MeO
HO
PGO
14
H
O
O
32
29
O
O
H
HO
PGO
OPiv
35
O
35
O
H
27CHO
27
O
O
O
ER-076349
eribulin (1)
H
1
O
14
H
O
O
O
H
O
4
OTBS
TBSO
OTBS
13
I
Scheme 1 Eribulin (1) and its three key fragments, according to Kishi
Arya approach:
OPG3
OPG1 OPG2
O
OPG1
PG1O
PG1O
O
32
29
34
32
34
29
O
O
O
COOEt
OPG1 OPG2
6
5
syn aldol
PG1O
H
H
10
PG1O
PG1O
D-(+)-xylose
MeO
34
32
(8)
30
29
7
O
32
34
O
COOEt
O
OH
HO
HO
OH HO
H
34
32
30
29
34
32
30
29
O
O
O
O
R
5
O
O
11
9
H
H
O
NH
O
N
H
R
Scheme 2 Arya’s approach to the western furan ring fragment 5, and the synthesis of the 14- and 12-membered macrocyclic compounds 9 and 11
from 5 and 10, respectively
ample, 12, 14, and 16; Scheme 3) by using commercially
available (2S,3S)-tartaric acid as a cheap starting material. If
we could develop a synthetic route to these three ana-
logues, we then planned to obtain various types of macro-
cyclic compounds as follows: (i) synthesis of 14-membered
rings through the ring-closing metathesis approach (see 13
and 15) from the two isomeric starting materials 12 and 14,
and (ii) a modular synthesis of two different 14-membered
ring derivatives 17 and 18 from 16. There is growing inter-
est in developing practical methods for synthesizing vari-
ous natural-product-inspired macrocyclic compounds be-
cause of their attractive features, which include dynamic
preorganization, the ability to interact with several binding
sites, and enhanced cell permeation.26–32
In the past few years, our group has reported the devel-
opment of several methods for synthesizing diverse sets of
macrocyclic compounds.26,34–39 The long-term goal of our
current study is to assemble a macrocyclic chemical toolbox
consisting of compounds originating from substructures of
eribulin to permit the exploration of their biological prop-
erties in several challenging targets related to protein–pro-
tein interactions and deregulated signaling pathways.
Our synthesis plan for obtaining fragment 12 and its
two analogues 14 and 16 from (2S,3S)-tartaric acid is
shown in Scheme 4. As demonstrated in our first ap-
proach,26 ester 19 can be obtained from the vinyl ester 20
through a regio- and stereoselective oxy-Michael reaction.
We envisioned a synthesis of 20 from the dioxolane 21 in
two key steps: cross-metathesis and stereoselective vinyla-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U

C
S. Konda et al.
Special Topic
Synthesis
MeO
O
SO2Ph
MeO
O
SO2Ph
14-membered
SO2Ph
SO2Ph
32 29
MeO
HO
32 29
MeO
HO
30
29
O
O
H
H
H
H
29
32
32
O
R
O
O
O
O
O
12
N
H
O
13
R
N
H
O
14
15
MeO
MeO
H
MeO
OH
30
OPG1
O
R
O
29
32
28
29
29
32
32
O
H
H
O
HO
O
NH
O
R
O
H
PG2O
O
O
16
17
18
O
N
H
O
Scheme 3 Plan to obtain several macrocyclic compounds from three analogues of the western furan ring fragments 12, 14, and 16
tion. The dioxolane 21 can be easily obtained from (2S,3S)-
tartaric acid (22). A key attraction of this approach is its use
of 22 as a cheap chiral starting material.
Information. Tetrahydrofuran 29 was subjected to several
simple reactions to complete the synthesis of the diol 33.
Overall, the current approach is simple and practical in na-
ture; for example, by starting from 100 grams of (2S,3S)-
tartaric acid, we can easily prepare 5 grams of 33 within a
short period. The method therefore has the potential to be
accepted as a process synthesis of 33.
As an alternative to the oxy-Michael approach, we de-
veloped the iodocyclization-based strategy shown in
Scheme 7. The precursor 35 needed for our iodocyclization
strategy was obtained from dioxolane 36 or 37, both of
which can be obtained from (2S,3S)-tartaric acid.
(2S,3S)-tartaric acid based approach:
OPG
SO2Ph
OH
MeO
OH
31
SO2Ph
32
30
29
30
HO
32
HO
34
20
O
COOEt
cross
vinylation
metathesis
oxy-Michael
19
EtOOC
Compound 25 (Scheme 8) was subjected to acetonide
removal and then treated with iodine to give the iodo com-
pounds 38 and 39 as a mixture of two separable diastereo-
mers. Details of the stereochemical assignment are provid-
ed in the Supporting Information. To test the iodocycliza-
tion reaction on 44, we used dioxolane 40 as a starting
material, easily obtained from diol 23 (see the Supporting
Information). Grignard vinylation of 40 gave stereoisomeric
products 41 in a 13:1 ratio; these were then converted into
the corresponding separable lactones 42 (major) and 43
(minor). The vinyl derivative 44 was obtained from the ma-
jor lactone 42 in three steps. Iodocyclization of 44 gave the
tetrahydrofuran 45 as a single diastereomer. At this stage,
the configuration of 45 was thoroughly assigned by one-
and two-dimensional NMR studies (see Supporting Infor-
mation). In addition, iodo compounds 39 and 40 were also
easily converted into the corresponding derivatives 46 and
47, useful as key precursors for completing the synthesis of
several macrocycles.
OH
31
HO
32
O
31
O
32
21
22
COOH
HOOC
BnO
(2S,3S)-tartaric acid
Scheme 4 Plan to obtain 19 from (2S,3S)-tartaric acid (22)
SO2Ph
(2S,3S)-Tartaric acid (22) was converted into the diol 23
in two steps (Scheme 5). Subsequent oxidation of 23 fol-
lowed by two-carbon homologation gave dioxolane 24. Vi-
nylation of 24 gave vinylic derivative 25 as a single diaste-
reomer; the absolute stereochemistry at C-30 was assigned
following cyclization. Cross-metathesis and removal of the
acetonide group gave diol 26 in high yield. Treatment of 26
with NaH in THF at 0 °C resulted in an intramolecular oxy-
Michael reaction to give the two inseparable products 27
and 28 in a 4:1 diastereomeric ratio. Complete stereochem-
ical assignments for these products were made at a later
stage (see compounds 29 and 30).
The 4:1 diastereomeric mixture of 27 and 28 was sub-
jected several simple transformations to give the tetrahy-
drofurans 29 (major) and 30 (minor) as separable com-
pounds (Scheme 6). Details of the stereochemical assign-
ment of 29 and 30 are provided in the Supporting
The syntheses of various 14-membered-ring-based
macrocyclic compounds from tetrahydrofurans 46, 47, and
48 are shown in Scheme 9. A three-step sequence consist-
ing of debenzylation, coupling with various N-allyloxycar-
bonyl-protected amino acids, and ring-closing metathesis
with the Grubbs second-generation catalyst gave macrocy-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U

D
S. Konda et al.
Special Topic
Synthesis
1. Me2C(OMe)2, TsOH
MeOH, 65 °C, 16 h
1. NaH, BnBr, THF, r.t., 12 h
2. IBX, MeCN, 80 °C, 1 h
O
O
31
O
31
O
22
32
32
2. NaBH4, MeOH
r.t., 16 h
85% (2 steps)
3. PhO2SCH2PO(OEt)2
NaH, THF, 0 °C, 3 h
50% (3 steps)
OH
SO2Ph
OBn
24
OH
23
1. ethyl acrylate, G-II
(10 mol%), toluene
110 °C, 16 h, 70%
OBn OH
CH2=CHMgBr, CuI
THF, –78 °C, 1 h
O
32
O
32
SO2Ph
H
30
29
SO2Ph
31
30
BnO
OH
26
–20 °C, 5 h, 75%
2. TsOH, H2O, THF
60 °C, 16 h, 82%
single diastereomer
CO2Et
25
HO
SO2Ph
CO2Et
HO
31
SO2Ph
31
30
NaH, THF, 0 °C
30 min, 70%
30
32
29
29
32
O
O
CO2Et
BnO
BnO
27
28
mixture of inseparable diastereomers, 4:1 ratio
Scheme 5 Furan ring formation; IBX = 2-iodoxybenzoic acid; G-II = Grubbs second-generation catalyst
separable
1. LiAlH4, THF, 0 °C to r.t., 16 h
SO2Ph
O
SO2Ph
O
2. TBDPSCl, imidazole, CH2Cl2
0 °C to r.t., 2 h, 80% (2 steps)
32
32
29
29
27 + 28
+
O
O
OTBDPS
OTBDPS
3. MeI, Ag2O, DMF, 0 °C to r.t.
24 h, 80%
BnO
BnO
29, major
30, minor
PhO2S
MeO
1. Pd/C, H2, EtOAc
16 h, 85%
MgBr
29, major
32
OTBDPS
I
29
2. I2, PPh3, imidazole, CH2Cl2
0 °C to r.t., 6 h, 80%
CuI, HMPA, THF
–30 °C, 3 h, 70%
O
31
PhO2S
PhO2S
MeO
5:1 diastereomeric
MeO
mixture
OsO4
(DHQ)2PYR
HO
HO
OTBDPS
32 29
OTBDPS
32
29
34
O
0 °C, 80%
O
33
32
R2
Hc
MeO
Hd
29
(2S,3S)-tartaric acid (100 g)
33 (5 g)
31
OPG
32
R1
O
Hb
Ha
NOE
Scheme 6 Completion of the synthesis of Kishi’s western furan ring fragment; (DHQ)2PYR = (8a,9R,8′′′a,9′′′R)-9,9′-[(2,5-diphenylpyrimidine-4,6-di-
yl)bis(oxy)]bis(6′-methoxy-10,11-dihydrocinchonan)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U

E
S. Konda et al.
Special Topic
Synthesis
iodocyclization-based approach:
R
OBn
MeO
OH
O
O
29
R
(2S,3S)-tartaric acid
32
32
30
BnO
O
HO
I
BnO
29
iodocyclization
34
35
R
vinylation
R = SO2Ph (36), COOEt (37)
Scheme 7 Our planned iodocyclization approach
SO2Ph
HO
SO2Ph
HO
31
1. 2 M HCl, aq THF
65 °C, 16 h, 85%
31
30
30
29
+
25
2. I2, MeCN, –20 °C
3 h, 70%
32
32
O
O
I
I
BnO
BnO
38, major, 70%
39, minor, 30%
O
O
2 M HCl
THF
H2O, 65 °C
BnO
O
O
BnO
CH2=CHMgBr, CuI
THF, TMSCl
O
O
O
H
O
H
30
+
32 31
H
31
31
COOEt
32
16 h
90%
30
HMPA, –78 °C
7 h, r.t., 12 h
75%
BnO
BnO
OH
OH
(13:1)
42, major
43, minor
41
40
COOEt
He1
He2
R
see
Supporting
Information
OTBDPS
OMe
OBn
I2, MeCN
–20 °C, 3 h
MeO
Hb
Hc
I
32
30
MeO
BnO
31
30
29
31
42
29
32
80%
29
BnO
DCBO
O
Hd
OTBDPS
O
I
Ha
NOE
44
45
see the experimantal section for the synthesis of 46, 47 and 48 from 45, 38 and 39, respectively
MeO
MeO
MeO
OTBDPS
BnO
BnO
BnO
SO2Ph
SO2Ph
32
32
32
29
29
29
O
O
O
48
46
47
Scheme 8 Iodocyclization approach to 45, 46, and 47
cles 49 smoothly from 48. The formation of the 14-mem-
bered macrocyclic ring is independent of the choice of the
amino acid moiety, and it produced a single double-bond
isomer (the trans-olefin). A similar approach led to the syn-
thesis of 14-membered macrocyclic compounds 50 and 51
from 47 and 46, respectively.
To summarize, scalable stereoselective syntheses of the
key western tetrahydrofuran ring fragment-based com-
pounds 45, 46, and 47 were achieved in a manner that per-
mitted their large-scale preparation in a time-efficient way.
The use of (2S,3S)-tartaric acid in the preparation of these
key intermediates is attractive in making our approach ac-
ceptable as a process synthesis. Compounds 45–47 were
also used in syntheses of several 14-membered macrocy-
cles. Biological evaluation of the compounds generated in
this program is in progress, and the results of these studies
will be made available in due course.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U

F
S. Konda et al.
Special Topic
Synthesis
14-membered macrocyclic ring
MeO
SO2Ph
MeO
O
SO2Ph
1. TiCl4, CH2Cl2, 3 h, 75%
2. EDCI, DMAP, CH2Cl2
N-Alloc-AA, r.t., 3 h
75–80%
32 29
32 29
O
O
H
H
H
H
48
47
O
O
O
O
O
3. G-II (10 mol%)
CH2Cl2, 40 °C, 16 h
70–75%
R1
N
H
O
R1
N
H
O
50
49
4 examples each
4 examples
1. TBAF, THF, r.t., 3 h, 85%
2. EDCI, DMAP
N-Alloc-AA, CH2Cl2, r.t.
3 h, 80–90%
MeO
H
O
O
28
46
32
29
R1
NH
HO
O
3. G-II (10 mol%)
CH2Cl2, 40 °C, 16 h
70–75%
H
51
O
O
4. Pd/C, H2, EtOAc, 65–70%
Scheme 9 Syntheses of various macrocycles; N-Alloc-AA = N-allyloxycarbonyl amino acid
All reactions were carried out in flame-dried glassware under N2. TLC
was carried out on aluminum sheets coated with silica gel 60F254
(Merck, 1.05554); spots were visualized by UV irradiation at 254 nm
or by staining with aq basic KMnO4 or ceric ammonium molybdate.
Flash column chromatography was performed on silica gel (Merck,
60A; 230–400 mesh). Commercially available reagents were used as
supplied or were distilled before use. 1H and 13C NMR spectra were
recorded on a Varian 400 MHz spectrometer at the frequencies indi-
cated. Where indicated, NMR peaks were assigned by COSY or NOESY
experiments. All chemical shifts are referenced to residual solvent as
an internal standard. Mass spectra and LC/MS were recorded by using
electron impact, chemical ionization, or electrospray ionization tech-
niques on an Agilent 6430 Triple-Quadrupole spectrometer. HPLC was
carried out on Agilent 1200 series equipment. All reactions were per-
formed in oven-dried glassware. DMF, CH2Cl2, and THF were dried by
standard procedures immediately before use. Acetone was distilled
under an inert atmosphere from K2CO3. DMF and CH2Cl2 were dis-
tilled from CaH2 under N2. THF were distilled over Na under N2. All
solvents were removed by evaporation under reduced pressure.
material was consumed (TLC), then concentrated under reduced pres-
sure and purified by column chromatography (hexanes–EtOAc, 9:1) to
give 22.1 as a colorless liquid.
This was dissolved in MeOH (100 mL), and NaBH4 (2 equiv) was added
in a portionwise manner at 0 °C. After 16 h, the mixture was concen-
trated and extracted with EtOAc (3 × 50 mL). The combined organic
layers were dried (Na2SO4) and concentrated under reduced pressure
to give 23 as a colorless liquid; yield: 92 g (85%). This was used direct-
ly in the next step.
Molecular formula: C7H14O4; Rf = 0.5 (hexanes–EtOAc, 5:5).
1H NMR (400 MHz, CDCl3): δ = 4.05–4.00 (m, 2 H), 3.85–3.80 (m, 2 H),
3.75–3.70 (m, 2 H), 2.35–2.30 (m, 2 H), 1.45 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 142.1, 139.9, 137.4, 133.5, 131.1,
129.3, 128.4, 127.8, 127.7, 127.7, 110.4, 79.0, 73.6, 69.0, 26.8, 26.5.
1. NaH, BnBr, THF, r.t., 12 h
2. IBX, MeCN, 80 °C, 1 h
O
O
O
O
3. PhO2SCH2PO(OEt)2
NaH, THF, 0 °C, 3 h
50% (3 steps)
OH
Synthesis of Fragment 33
SO2Ph
OBn
24
OH
23
Scheme 11
1. Me2C(OMe)2, TsOH
OH
HO
MeOH, 65 °C, 16 h
O
O
2. NaBH4, MeOH
r.t., 16 h
85% (2 steps)
COOH
HOOC
OH
(4R,5R)-4-[(Benzyloxy)methyl]-2,2-dimethyl-5-[(E)-2-(phenylsul-
fonyl)vinyl]-1,3-dioxolane (24)
OH
23
(2S,3S)-tartaric acid
NaH (1 equiv) was added in a portionwise manner to a stirred solu-
tion of diol 23 (92 g) in THF (100 mL) at 0 °C. BnBr (1 equiv) was then
added and, after 12 h, the reaction was quenched with H2O. The mix-
ture was extracted with EtOAc (3 × 50 mL), and the combined organic
layers were dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by column chromatography (hexane–EtOAc,
8:2) to give 23.1 as a colorless liquid; yield: 98 g.
22
Scheme 10
[(4R,5R)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl]dimethanol (23)
To a stirred solution of (2S,3S)-tartaric acid (22; 100 g) in MeOH (20
mL) were added a catalytic amount of TsOH and 2,2-dimethoxypro-
pane (2 equiv). The mixture was refluxed for 16 h until the starting
Compound 23.1 (98 g) was dissolved in MeCN (100 mL) and 2-iodoxy-
benzoic acid (IBX; 2 equiv) was added. The mixture was then refluxed
at 80 °C for 1 h. When all the starting material was consumed (TLC),
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U

G
S. Konda et al.
Special Topic
Synthesis
the mixture was filtered through Celite and concentrated under re-
duced pressure to provide crude 23.2 as a pale-yellow liquid; yield: 98
g. This was used directly in the next step.
O
O
O
O
ethyl acrylate, toluene
G-II (10 mol%)
A solution of the crude 23.2 (98 g) in THF was added to a Wittig ylide,
freshly prepared from PhO2SCH2PO(OEt)2 and NaH at 0 °C, and the
mixture was stirred at 0 °C for 2 h. The reaction was then quenched
with H2O and the mixture was extracted with EtOAc (3 × 50 mL). The
combined organic layers were dried (Na2SO4) and concentrated under
reduced pressure. The residue was purified by column chromatogra-
phy (hexane–EtOAc, 8:2) to give a white solid; yield: 110 g (50%, 3
steps); molecular formula: C21H24O5S; Rf = 0.4 (hexanes–EtOAc, 8:2).
BnO
BnO
110 °C, 16 h, 70%
SO2Ph
SO2Ph
25
25.1
O
OEt
Scheme 13
1H NMR (400 MHz, CDCl3): δ = 7.87–7.83 (m, 2 H), 7.60 (t, J = 7.20 Hz,
1 H), 7.51 (t, J = 7.70 Hz, 2 H), 7.37–7.25 (m, 5 H), 6.96 (dd, J = 14.95,
4.09 Hz, 1 H), 6.61 (dd, J = 14.96, 1.64 Hz, 1 H), 4.61–4.51 (m, 2 H),
4.48 (ddd, J = 8.36, 4.07, 1.64 Hz, 1 H), 3.95–3.89 (m, 1 H), 3.62 (dq,
J = 10.30, 4.88 Hz, 2 H), 1.40 (s, 3 H), 1.36 (s, 3 H).
ture was refluxed for 16 h. When the reaction complete, the mixture
was filtered through Celite and concentrated under reduced pressure.
The residue was purified by column chromatography (hexanes–
EtOAc, 8:2) to give a light-yellow oil; yield: 780 mg (70%); molecular
formula: C26H32O7S; Rf = 0.5 (hexanes–EtOAc, 8:2).
1H NMR (400 MHz, CDCl3): δ = 7.88–7.86 (m, 2 H), 7.65 (t, J = 7.2 Hz, 1
H), 7.55–7.52 (m, 2 H), 7.39–7.29 (m, 5 H), 6.58 (dd, J = 9.60, 15.60 Hz,
1 H), 5.84 (d, J = 15.60 Hz, 1 H), 4.54 (s, 2 H), 4.15 (q, J = 7.40 Hz, 2 H),
3.95–3.85 (m, 2 H), 3.58 (dd, J = 2.80, 15.60 Hz, 1 H), 3.50 (t, J = 4.37
Hz, 2 H), 3.25 (dd, J = 9.60, 14.40 Hz, 1 H), 3.04–2.96 (m, 1 H), 1.37 (s,
3 H), 1.34 (s, 3 H), 1.30–1.28 (m, 3 H).
13C NMR (100 MHz, CDCl3): 165.3, 143.8, 139.3, 137.6, 133.8, 129.3,
128.4, 128.1, 127.7, 127.6, 124.9, 109.9, 78.6, 78.1, 73.5, 70.2, 60.5,
56.3, 40.9, 31.9, 30.0, 29.7, 27.0, 22.7, 14.2.
13C NMR (100 MHz, CDCl3): δ = 142.2, 139.9, 137.5, 133.5, 131.2,
129.3, 128.5, 127.9, 127.7, 110.4, 79.1, 73.7, 69.1, 26.8, 26.6.
MS (ES+): m/z = 389.2 [M + 1].
CH2=CHMgBr, CuI
THF, –78 °C, 40 min
–20 °C, 5 h, 75%
O
O
O
O
H
SO2Ph
H
BnO
BnO
SO2Ph
25
24
Scheme 12
MS (ES+): m/z = 489.2 [M + 1].
OH
O
O
TsOH, THF–H2O (1:1)
65 °C, 16 h, 82%
(4R,5R)-4-[(Benzyloxy)methyl]-2,2-dimethyl-5-{(1S)-1-[(phenyl-
sulfonyl)methyl]prop-2-en-1-yl}-1,3-dioxolane (25)
BnO
SO2Ph
BnO
OH
CH2=CHMgBr (37 mL, 38.1 mmol) was added dropwise to a stirred
solution of CuI (1.8 g, 9.538 mmol) in anhyd THF (10 mL) at –78 °C,
and the mixture was stirred at –78 °C for 10 min. A solution of sulfone
24 (3.7 g, 9.538 mmol) in THF (2 mL) was added dropwise over 20
min, and the mixture was stirred at –78 °C to –20 °C for 40 min and at
–20 °C for 5 h. When the reaction was complete, it was quenched
with a 1:1 aq soln of NH4Cl and NH4OH at –20 °C, and the mixture
was extracted with EtOAc (3 × 50 mL). The combined organic layers
were dried (Na2SO4) and concentrated under reduced pressure. The
residue was purified by column chromatography (hexanes–EtOAc,
9:1) to give a colorless oil; yield: 1.45 g (75%); molecular formula:
SO2Ph
25.1
COOEt
26
O
OEt
Scheme 14
Ethyl (2E,4S,5R,6R)-7-(Benzyloxy)-5,6-dihydroxy-4-[(phenylsulfo-
nyl)methyl]hept-2-enoate (26)
TsOH (281 mg, 1.639 mmol) was added to a stirred solution of dioxol-
ane 25.1 (780 mg, 1.639 mmol) in THF–H2O (1:1; 20 mL), and the
mixture was refluxed for 16 h until all the starting material was con-
sumed (TLC). The mixture was then extracted with EtOAc (3 × 50 mL)
and the combined organic layers were dried (Na2SO4) and concentrat-
ed under reduced pressure. The residue was purified by column chro-
matography (hexanes–EtOAc, 5:5) to give a white solid; yield: 588 mg
(82%); molecular formula: C23H28O7S; Rf = 0.2 (hexanes–EtOAc, 5:5).
C
23H28O5S; Rf = 0.35 (hexanes–EtOAc, 8:2).
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 7.31 Hz, 2 H), 7.67–7.58 (m,
1 H), 7.54 (d, J = 7.70 Hz, 2 H), 7.37–7.26 (m, 4 H), 5.53–5.41 (m, 1 H),
5.14 (s, 1 H), 5.04 (d, J = 11.00 Hz, 1 H), 4.54 (s, 2 H), 3.97–3.91 (m, 1
H), 3.73 (s, 1 H), 3.60–3.50 (m, 2 H), 3.49–3.41 (m, 1 H), 3.20–3.11 (m,
1 H), 2.82–2.72 (m, 1 H), 1.35 (s, 3 H), 1.29 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.88–7.86 (m, 2 H), 7.62 (t, J = 7.41 Hz,
1 H), 7.55–7.52 (m, 2 H), 7.38–7.27 (m, 5 H), 6.58 (dd, J = 15.60, 9.57
Hz, 1 H), 5.85 (d, J = 15.60 Hz, 1 H), 4.52 (s, 2 H), 4.14 (q, J = 7.15 Hz, 2
H), 3.77 (dd, J = 14.16, 2.40 Hz, 1 H), 3.72 (t, J = 4.06 Hz, 1 H), 3.58 (d,
J = 4.83 Hz, 2 H), 3.52 (d, J = 7.94 Hz, 1 H), 3.21 (dd, J = 14.16, 9.20 Hz,
1 H), 3.16–3.08 (m, 1 H), 2.97–2.91 (br s, 1 H), 2.63–2.56 (br s, 1 H),
1.27 (t, J = 7.13 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 139.7, 137.8, 134.8, 133.6, 129.4,
129.2, 128.4, 128.1, 127.7, 127.3, 119.4, 109.5, 79.0, 78.2, 73.3, 70.4,
57.2, 43.5, 27.1, 27.1.
MS (ES+): m/z = 417.1 [M + 1].
Ethyl (2E,4S)-4-{(4R,5R)-5-[(Benzyloxy)methyl]-2,2-dimethyl-1,3-
dioxolan-4-yl}-5-(phenylsulfonyl)pent-2-enoate (25.1)
13C NMR (100 MHz, CDCl3): 165.5, 144.4, 137.1, 133.7, 129.3, 128.6,
128.1, 127.9, 125.2, 110.0, 73.8, 73.0, 72.6, 68.7, 60.5, 56.6, 41.0, 14.2.
To a stirred solution of dioxolane 25 (1 g, 2.403 mmol) in toluene (50
mL) were added the Grubbs second-generation catalyst (G-II; 101 mg,
0.120 mmol) and ethyl acrylate (1.27 mL, 12.015 mmol), and the mix-
MS (ES+): m/z = 449.3 [M + 1].
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U

H
S. Konda et al.
Special Topic
Synthesis
PhO2S
HO
PhO2S
HO
OH
O
O
NaH, THF, 0 °C
30 min, 70%
BnO
SO2Ph
OEt
OEt
OH
BnO
BnO
+
O
O
COOEt
27
28
26
Scheme 15
Ethyl {(2R,3R,4R,5R)- and {(2S,3R,4R,5R)-5-[(Benzyloxy)methyl]-4-
hydroxy-3-[(phenylsulfonyl)methyl]tetrahydrofuran-2-yl}acetate
(27 and 28)
Molecular formula: C21H26O6S; Rf = 0.2 (hexanes–EtOAc, 5:5).
1H NMR (400 MHz, CDCl3): δ = 7.94–7.89 (m, 2 H), 7.70–7.64 (m, 1 H),
7.58–7.54 (m, 2 H), 7.37–7.27 (m, 5 H), 4.59–4.44 (m, 3 H), 4.29 (t,
J = 4.40 Hz, 0.7 H), 4.22 (q, J = 7.14 Hz, 0.3 H), 4.00 (q, J = 5.20 Hz, 0.7
H), 3.80–3.69 (m, 5 H), 3.24–3.12 (m, 2 H), 2.73 (br s, 2 H), 2.67–2.62
(m, 1 H), 2.47–2.41 (m, 2 H), 1.95—1.79 (m, 1.6 H), 1.67–1.51 (m, 0.8
H).
60% NaH (21 mg, 0.892 mmol) was added to a stirred solution of ester
26 (400 mg, 0.892 mmol) in anhyd THF (15 mL) at 0 °C, and the mix-
ture was stirred for 30 min. When the reaction was complete, it was
quenched with H2O and the mixture was extracted with EtOAc (3 ×
20 mL). The combined organic layers were dried (Na2SO4) and con-
centrated under reduced pressure, and the residue was purified by
column chromatography (hexanes–EtOAc, 3:7) to provide an insepa-
rable mixture of the isomers 27 and 28 as a white gummy liquid;
yield: 360 mg (70%); molecular formula: C23H28O7S; Rf = 0.3 (hexanes–
EtOAc, 5:5).
MS (ES+): m/z = 407.3 [M + 1].
PhO2S
HO
TBDPSCl, imidazole
CH2Cl2
PhO2S
HO
0 °C to r.t.
2 h
OH
BnO
OTBDPS
BnO
1H NMR (400 MHz, CDCl3): δ = 7.95–7.88 (m, 2 H), 7.67 (t, J = 7.45 Hz,
1 H), 7.58–7.54 (m, 2 H), 7.38–7.26 (m, 5 H), 4.62–4.48 (m, 2.6 H),
4.24–4.18 (m, 1 H), 4.11 (q, J = 7.14 Hz, 2 H), 4.03 (dd, J = 11.92, 5.52
Hz, 0.68 H), 3.94 (dd, J = 9.59, 4.66 Hz, 0.68 H), 3.79–3.65 (m, 2.2 H),
3.26 (d, J = 6.99 Hz, 1.3 H), 3.23–3.15 (m, 1 H), 2.87–2.76 (m, 1.5 H),
2.71–2.65 (m, 1 H), 2.59–2.50 (m, 0.8 H), 2.48–2.44 (m, 0.5 H), 1.23 (t,
J = 9.6 Hz, 3 H).
O
O
90%
27.2 + 28.2
27.1 + 28.1
Scheme 17
(2R,3R,4R,5R)- and (2R,3R,4R,5S)-2-[(Benzyloxy)methyl]-5-(2-
{[tert-butyl(diphenyl)silyl]oxy}ethyl)-4-[(phenylsulfonyl)meth-
yl]tetrahydrofuran-3-ol (27.2 and 28.2)
MS (ES+): m/z = 449.7 [M + 1].
To a stirred solution of 27.1 + 28.1 (200 mg, 0.492 mmol) in anhyd
CH2Cl2 (10 mL) at 0 °C were added imidazole (100 mg, 1.479 mmol)
and TBDPSCl (0.15mL, 0.5911 mmol), and the mixture was stirred at
r.t. for 3 h. When the reaction was complete it was quenched with
H2O and the mixture was extracted with CH2Cl2 (3 × 10 mL). The com-
bined organic layers were dried (Na2SO4) and concentrated under re-
duced pressure, and the residue was purified by column chromatog-
raphy (hexanes–EtOAc, 7.5:2.5) to give a gummy liquid; yield (27.2 +
28.2): 280 mg (90%); molecular formula: C37H44O6SSi; Rf = 0.5 (hex-
anes–EtOAc, 7:3).
PhO2S
HO
PhO2S
HO
LiAlH4, THF
0 °C to r.t., 3 h
O
OEt
OH
BnO
BnO
85%
O
O
27 + 28
27.1 + 28.1
Scheme 16
(2R,3R,4R,5R)- and (2R,3R,4R,5S)-2-[(Benzyloxy)methyl]-5-(2-hy-
droxyethyl)-4-[(phenylsulfonyl)methyl]tetrahydrofuran-3-ol
(27.1 and 28.1)
1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 8.23 Hz, 2 H), 7.68–7.60 (m,
5 H), 7.56–7.51 (m, 2 H), 7.44–7.27 (m, 11 H), 4.61–4.52 (m, 2 H),
4.51–4.41 (m, 0.7 H), 4.37 (t, J = 4.80 Hz, 1 H), 4.11 (q, J = 4.80 Hz, 0.3
H), 3.97 (q, J = 4.80 Hz, 0.7 H), 3.81–3.66 (m, 5 H), 3.23–3.11 (m, 2 H),
2.60–2.54 (m, 0.7 H), 2.33–2.25 (m, 1 H), 1.91–1.81 (m, 1 H), 1.76–
1.61 (m, 1.3 H), 1.03–1.01 (m, 9 H).
LiAlH4 (43 mg, 1.138 mmol) was added to a stirred solution of 27 + 28
(340 mg, 0.7589 mmol) in anhyd THF (15 mL) at 0 °C and the mixture
was stirred for 3 h. The reaction was quenched with sat. aq NaOH (2
mL), and the mixture was filtered through Celite and concentrated
under reduced pressure to give a colorless liquid; yield (27.1 + 28.1):
260 mg (85%). This was used directly in the next reaction.
MS (ES+): m/z = 645.1 [M + 1].
PhO2S
PhO2S
MeO
PhO2S
MeO
HO
Ag2O, MeI, DMF
dark place, 16 h
+
OTBDPS
OTBDPS
BnO
BnO
OTBDPS
BnO
80%
O
O
O
27.2 + 28.2
29
major 80%
30
minor 20%
Scheme 18
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U

I
S. Konda et al.
Special Topic
Synthesis
(2-{(2R,3S,4R,5R)- and (2-{(2S,3S,4R,5R)-5-[(Benzyloxy)methyl]-4-
methoxy-3-[(phenylsulfonyl)methyl]tetrahydrofuran-2-
yl}ethoxy)(tert-butyl)diphenylsilane5-[(Benzyloxy)methyl]-4-
methoxy-3-[(phenylsulfonyl)methyl]tetrahydrofuran-2-
yl}ethoxy)(tert-butyl)diphenylsilane (29 and 30)
1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 7.83 Hz, 2 H), 7.67–7.63 (m,
5 H), 7.55 (t, J = 7.72 Hz, 2 H), 7.46–7.34 (m, 6 H), 4.11 (br s, 1 H),
3.87–3.70 (m, 6 H), 3.43 (s, 3 H), 3.16–3.11 (m, 2 H), 2.57–2.52 (m, 1
H), 2.20 (br s, 1 H), 1.93 (dt, J = 13.68, 5.80 Hz, 1 H), 1.79 (dt, J = 13.13,
12.77, 5.84 Hz, 1 H), 1.01 (s, 9 H).
13C NMR (100 MHz, CDCl3): 139.5, 135.5, 133.9, 133.7, 133.6, 129.6,
129.4, 127.8, 127.7, 127.6, 86.5, 81.0, 80.5, 61.5, 60.7, 57.9, 57.6, 44.2,
37.7, 26.8, 19.2.
To a stirred solution of 27.2 + 28.2 (120 mg, 0.1863 mmol) in anhyd
DMF (15 mL) at 0 °C were added Ag2O (243 mg, 0.931 mmol) and MeI
(0.12mL, 1.863 mmol), and the mixture was stirred at r.t. for 48 h in
darkness. When the reaction was complete, the mixture was filtered
through Celite and extracted sequentially with EtOAc (20 mL) and
cold water (3 mL). The combined organic layers were dried (Na2SO4)
and concentrated under reduced pressure, and the residue was puri-
fied by column chromatography (hexanes–EtOAc, 8:2) to give 29 as a
colorless liquid (yield: 85 mg), and 30 as a white solid (yield: 10 mg);
combined yield: 90%.
MS (ES+): m/z = 569.2 [M + 1].
PhO2S
MeO
PhO2S
I2, PPh3, imidazole
CH2Cl2
MeO
0 °C to r.t.
16 h
OTBDPS
OTBDPS
HO
I
O
O
80%
29.1
31
29
Scheme 20
Molecular formula: C38H46O6SSi; Rf = 0.6 (hexanes–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 7.78 Hz, 2 H), 7.66–7.63 (m,
5 H), 7.53 (t, J = 7.72 Hz, 2 H), 7.46–7.25 (m, 11 H), 4.57 (dd, J = 41.73,
12.20 Hz, 2 H), 4.01 (d, J = 3.68 Hz, 1 H), 3.96–3.91 (m, 1 H), 3.80–3.64
(m, 5 H), 3.39 (s, 3 H), 3.17–3.06 (m, 2 H), 2.55–2.48 (m, 1 H), 1.97 (dt,
J = 13.61, 6.57 Hz, 1 H), 1.74 (dt, J = 13.61, 6.57 Hz, 1 H), 1.02 (s, 9 H).
13C NMR (100 MHz, CDCl3): 139.5, 138.1, 135.5, 133.9, 133.8, 133.6,
129.6, 129.4, 128.3, 127.8, 127.7, 127.6, 85.5, 80.8, 80.7, 73.4, 68.4,
60.8, 57.8, 43.9, 37.9, 26.8, 19.1.
tert-Butyl(2-{(2S,3S,4R,5S)-5-(iodomethyl)-4-methoxy-3-[(phenyl-
sulfonyl)methyl]tetrahydrofuran-2-yl}ethoxy)diphenylsilane (31)
To a stirred solution of the tetrahydrofuran 29.1 (50 mg, 0.088 mmol)
in anhyd CH2Cl2 (10 mL) at r.t. were added PPh3 (115 mg, 0.440 mmol)
and imidazole (29 mg, 0.440 mmol). The mixture was cooled to 0 °C,
I2 (110 mg, 0.440 mmol) was added, and the mixture was stirred for
16 h until the starting material was consumed (TLC). The reaction
was then quenched with sat. aq Na2S2O3, and the mixture was ex-
tracted with EtOAc (3 × 20 mL). The combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure, and the res-
idue was purified by column chromatography (hexanes–EtOAc,
9.5:0.5) to give a white solid; yield: 45 mg (80%); molecular formula:
MS (ES+): m/z = 659.2 [M + 1]
30
Molecular formula: C38H46O6SSi; Rf = 0.65 (hexanes–EtOAc, 7:3).
C
31H39IO5SSi; Rf = 0.2 (hexanes–EtOAc, 9:1).
1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 7.69 Hz, 2 H), 7.67–7.60 (m,
5 H), 7.55 (t, J = 7.76 Hz, 2 H), 7.44–7.25 (m, 11 H), 4.55 (dd, J = 41.73,
12.20 Hz, 2 H), 4.35–4.24 (m, 3 H), 3.74–3.64 (m, 2 H), 3.62–3.51 (m, 2
H), 3.37 (s, 3 H), 3.15 (dd, J = 14.26, 3.23 Hz, 1 H), 2.85 (dd, J = 14.20,
10.61 Hz, 1 H), 2.72–2.65 (m, 1 H), 1.67–1.58 (m, 2 H), 1.03 (s, 9 H).
13C NMR (100 MHz, CDCl3): 139.7, 138.3, 135.5, 133.9, 133.7, 129.6,
129.4, 128.3, 127.8, 127.7, 127.6, 127.5, 84.5, 78.6, 75.7, 73.3, 68.9,
61.2, 58.0, 53.2, 41.2, 33.2, 26.8, 19.2.
1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 7.98 Hz, 2 H), 7.67–7.63 (m,
5 H), 7.55 (t, J = 7.76 Hz, 2 H), 7.44–7.34 (m, 6 H), 4.05–4.02 (m, 1 H),
4.01–3.98 (m, 1 H), 3.87 (td, J = 8.03, 5.05 Hz, 1 H), 3.79–3.67 (m, 2 H),
3.45 (s, 3 H), 3.32 (t, J = 8.78 Hz, 1 H), 3.21 (dd, J = 9.41, 5.73 Hz, 1 H),
3.12 (d, J = 6.99 Hz, 2 H), 2.61 (dd, J = 12.01, 6.62 Hz, 1 H), 1.91 (td,
J = 13.67, 6.85 Hz, 1 H), 1.76 (td, J = 13.19, 6.15 Hz, 1 H), 1.01 (s, 9 H).
13C NMR (100 MHz, CDCl3): 139.5, 135.5, 133.9, 129.6, 129.5, 127.8,
127.6, 84.9, 82.2, 81.6, 60.6, 58.0, 57.8, 43.7, 38.2, 29.7, 26.8, 19.2.
MS (ES+): m/z = 659.2 [M + 1].
MS (ES+): m/z = 679.1 [M + 1].
Pd/C
H2
EtOAc
16 h
PhO2S
MeO
PhO2S
MeO
PhO2S
MeO
PhO2S
MeO
MgBr
CuI, HMPA
THF
–30 °C
3 h
OTBDPS
OTBDPS
HO
BnO
OTBDPS
OTBDPS
I
85%
O
O
O
O
29
29.1
31
32
70%
Scheme 19
Scheme 21
{(2R,3R,4S,5S)-5-(2-{[tert-Butyl(diphenyl)silyl]oxy}ethyl)-3-meth-
oxy-4-[(phenylsulfonyl)methyl]tetrahydrofuran-2-yl}methanol
(29.1)
(2-{(2S,3S,4R,5R)-5-Allyl-4-methoxy-3-[(phenylsulfonyl)meth-
yl]tetrahydrofuran-2-yl}ethoxy)(tert-butyl)diphenylsilane (32)
To a stirred solution of iodide 31 (25 mg, 0.0368 mmol) in anhyd THF
(2 mL) at 23 °C were added CuI (3 mg, 0.0184 mmol) and HMPA (0.07
mL, 0.368 mmol). The mixture was cooled to –30 °C and CH2=CHMgBr
(1 M in THF; 0.11 mL, 0.11 mmol) was added dropwise. The mixture
was stirred for 3 h at –30 °C and then the reaction was quenched with
sat. aq NH4Cl solution. The mixture was extracted with EtOAc (3 × 20
mL), and the combined organic layers were dried (Na2SO4) and con-
centrated under reduced pressure. The residue was purified by col-
To a stirred solution of tetrahydrofuran 29 (160 mg) in anhyd EtOAc
(15 mL) was added Pd/C (20 mg) and the mixture was stirred for 24 h
under H2 (1 atm). The mixture was then filtered through a Celite pad,
and the filtrate was concentrated under reduced pressure. The residue
was purified by column chromatography (hexanes–EtOAc, 6:4) to give
a colorless gummy liquid; yield: 118 mg (85%); molecular formula:
C
31H40O6SSi; Rf = 0.3 (hexanes–EtOAc, 5:5).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U

J
S. Konda et al.
Special Topic
Synthesis
PhO2S
PhO2S
MeO
OsO4, NMO, THF–H2O (1:1)
r.t., 16 h, 85%
MeO
HO
HO
OTBDPS
OTBDPS
or
O
O
OsO4, (DHQ)2PYR
0 °C, 80%
33
32
Scheme 22
umn chromatography (hexanes–EtOAc, 7:3) to give a colorless oil;
yield: 15 mg (70%); molecular formula: C33H42O5SSi; Rf = 0.2 (hex-
anes–EtOAc, 6:4).
Synthesis of Fragments 38 and 39
(2R,3R,4S)-1-(Benzyloxy)-4-[(phenylsulfonyl)methyl]hex-5-ene-
1H NMR (400 MHz, CDCl3): δ = 7.90–7.87 (m, 2 H), 7.70–7.64 (m, 4 H),
7.62–7.59 (m, 1 H), 7.55–7.49 (m, 2 H), 7.46–7.36 (m, 6 H), 5.58–5.48
(m, 2 H), 5.25–5.16 (m, 3 H), 4.04 (dd, J = 6.11, 3.16 Hz, 1 H), 3.98 (dd,
J = 4.90, 2.53 Hz, 1 H), 3.88–3.80 (m, 2 H), 3.31–3.29 (m, 2 H), 3.22 (s,
3 H), 2.27–2.21 (m, 2 H), 1.77–1.73 (m, 2 H), 1.02 (s, 9 H).
13C NMR (100 MHz, CDCl3): 139.7, 135.6, 135.5, 134.9, 133.6, 133.5,
133.3, 129.7, 129.2, 128.0, 127.8, 127.7, 118.4, 110.0, 81.2, 70.6, 62.2,
56.6, 52.8, 42.7, 37.3, 31.9, 29.7, 29.6, 29.3, 26.9, 26.8, 22.7, 19.1, 14.1.
2,3-diol (25.1)
2 M aq HCl (1 mL) was added to a stirred solution of sulfone 25 (1 g,
2.87 mmol) in THF–H2O (1:1), and the mixture was refluxed for 16 h
until the starting material was consumed (TLC). The mixture was ex-
tracted with EtOAc (3 × 50 mL), and the combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure. The residue
was purified by column chromatography (hexanes–EtOAc, 5:5) to give
a
light-yellow solid; yield: 760 mg (85%); molecular formula:
C
20H24O5S; Rf = 0.4 (hexanes–EtOAc, 5:5).
MS (ES+): m/z = 579.3 [M + 1].
1H NMR (400 MHz, CDCl3): δ = 7.93–7.89 (m, 2 H), 7.66–7.62 (m, 1 H),
7.57–7.53 (m, 2 H), 7.39–7.29 (m, 5 H), 5.65–5.56 (m, 1 H), 5.17–5.11
(m, 2 H), 4.54 (s, 2 H), 3.89–3.84 (m, 1 H), 3.71 (dd, J = 14.31, 2.97 Hz,
1 H), 3.62–3.58 (m, 2 H), 3.50–3.46 (m, 1 H), 3.19 (dd, J = 14.30, 8.94
Hz, 1 H), 2.96 (dq, J = 18.00, 2.80 Hz, 1 H), 2.31–2.16 (br s, 2 H).
(2S)-3-{(2R,3R,4S,5S)-5-(2-{[tert-Butyl(diphenyl)silyl]oxy}ethyl)-
3-methoxy-4-[(phenylsulfonyl)methyl]tetrahydrofuran-2-yl}pro-
pane-1,2-diol (33)
To a stirred solution of vinyl compound 32 (5 mg, 0.086 mmol) in 1:1
THF–H2O (1 mL) at r.t. was added N-methylmorpholine N-oxide
(0.023 mL, 0.198 mmol), OsO4 (0.1 M in t-BuOH; 0.08 mL, 0.00172
mmol), and (DHQ)2PYR (0.07 mg, 1 mol%), and the mixture was
stirred for 16 h. When the starting material was completely con-
sumed, Na2S2O3 (2 mg in 2 mL H2O) was added, and the mixture was
extracted with EtOAc (3 × 20 mL). The combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure, and the res-
idue was purified by column chromatography (hexanes–EtOAc, 5:5)
to give a colorless oil:4 yield: 4 mg (80%); molecular formula:
13C NMR (100 MHz, CDCl3): δ = 139.9, 137.3, 135.8, 133.6, 129.2,
128.6, 128.1, 127.8, 119.4, 73.2, 73.0, 68.4, 57.2, 42.5, 28.1.
MS (ES+): m/z = 393.2 [M + 17].
(2R,3R,4R,5S)- and (2R,3R,4R,5R)-2-[(Benzyloxy)methyl]-5-(io-
domethyl)-4-[(phenylsulfonyl)methyl]tetrahydrofuran-3-ol (38
and 39)
Diol 25.1 (1 g, 2.645 mmol) was dissolved in MeCN (20 mL) in round-
bottomed flask, and a solution of I2 (1 g, 3.968 mmol) in MeCN (2 mL)
was added slowly at –20 °C. The mixture was stirred for 3 h at –20 °C
until the reaction was complete. The reaction was then quenched
with sat. aq Na2S2O3 and the mixture was extracted with EtOAc (3 ×
20 mL). The combined organic layers were dried (Na2SO4) and con-
centrated under reduced pressure. The residue was purified by col-
umn chromatography (hexanes–EtOAc, 8:2) to give 38 as white solid
(yield: 600 mg) and 39 as a colorless liquid (yield: 250 mg); combined
yield: 70%.
C
33H44O7SSi; Rf = 0.2 (hexanes–EtOAc, 5:5).
1H NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 7.91 Hz, 2 H), 7.68–7.65 (m,
5 H), 7.59 (t, J = 7.68 Hz, 2 H), 7.49–7.40 (m, 6 H), 4.08–4.02 (m, 1 H),
3.98–3.75 (m, 5 H), 3.68–3.64 (m, 2 H), 3.49–3.45 (m, 1 H), 3.42 (s, 3
H), 3.14–3.06 (m, 1 H), 2.72–2.65 (m, 1 H), 2.10–1.85 (m, 3 H), 1.82–
1.68 (m, 3 H), 1.06 (s, 9 H).
MS (ES+): m/z = 613.2 [M + 1].
38
2 M HCl, THF–H2O (1:1)
65 °C, 16 h, 85%
OH
Molecular formula: C20H23IO5S; Rf = 0.3 (hexanes–EtOAc, 7:3).
BnO
SO2Ph
25
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 7.56 Hz, 2 H), 7.68 (t,
J = 7.41 Hz, 1 H), 7.58 (t, J = 7.67 Hz, 2 H), 7.39–7.28 (m, 5 H), 4.72 (br
s, 1 H), 4.61–4.50 (m, 3 H), 4.33 (q, J = 5.60 Hz, 1 H), 3.74 (d, J = 4.24
Hz, 2 H), 3.29–3.21 (m, 2 H), 3.19–3.03 (m, 3 H), 2.76–2.68 (m, 1 H).
OH
25.1
Scheme 23
SO2Ph
SO2Ph
HO
HO
OH
I2, MeCN
–20 °C, 3 h
BnO
SO2Ph
+
O
O
70%
I
I
OH
BnO
BnO
25.1
38 major 70%
39 minor 30%
Scheme 24
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U

K
S. Konda et al.
Special Topic
Synthesis
13C NMR (100 MHz, CDCl3): 138.5, 137.2, 134.1, 129.5, 128.5, 128.1,
127.8, 78.4, 78.2, 75.6, 73.9, 69.4, 53.0, 45.3, 3.6.
(2R,3S,4R,5R)-2-Allyl-5-[(benzyloxy)methyl]-4-methoxy-3-[(phe-
nylsulfonyl)methyl]tetrahydrofuran (47)
Ag2O (2 equiv) and MeI (5 equiv) were added to a stirred solution of
sulfone 38.1 (320 mg) in DMF (20 mL) in darkness and the mixture as
stirred for 16 h at r.t. The mixture was then filtered through Celite and
the filtrate was extracted with EtOAc (3 × 20 mL). The combined or-
ganic layers were dried (Na2SO4) and concentrated under reduced
pressure, and the residue was purified by column chromatography
(hexanes–EtOAc, 9:1) to give a white solid; yield: 240 mg (70%); mo-
lecular formula: C23H28O5S; Rf = 0.6 (hexanes–EtOAc, 9:1).
1H NMR (400 MHz, CDCl3): δ = 7.89–7.84 (m, 2 H), 7.63–7.59 (m, 1 H),
7.52 (t, J = 7.59 Hz, 2 H), 7.36–7.27 (m, 5 H), 5.75–5.62 (m, 1 H), 5.13–
5.06 (m, 2 H), 4.51 (s, 2 H), 3.62–3.52 (m, 3 H), 3.44–3.39 (m, 1 H),
3.37–3.36, (m, 6 H), 3.30 (dd, J = 6.52, 3.21 Hz, 1 H), 3.21 (dd, J = 14.28,
10.09 Hz, 1 H), 3.05–2.98 (m, 1 H).
MS (ES+): m/z = 502.8 [M + 1].
39
Molecular formula: C20H23IO5S; Rf = 0.2 (hexanes–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 8.17 Hz, 2 H), 7.70 (t,
J = 7.01 Hz, 1 H), 7.61 (t, J = 7.72 Hz, 2 H), 7.41–7.30 (m, 5 H), 4.60 (s, 2
H), 4.44 (t, J = 4.37 Hz, 1 H), 4.10 (q, J = 4.78 Hz, 1 H), 3.83–3.77 (m, 2
H), 3.77–3.72 (m, 1 H), 3.47 (dd, J = 10.31, 5.73 Hz, 1 H), 3.38 (dd,
J = 10.28, 5.54 Hz, 1 H), 3.32–3.22 (m, 2 H), 2.53–2.45 (m, 2 H).
13C NMR (100 MHz, CDCl3): 138.6, 137.5, 134.2, 129.6, 128.5, 128.2,
127.9, 127.8, 81.7, 79.8, 77.8, 73.8, 68.8, 58.0, 48.2, 29.7, 8.4.
MS (ES+): m/z = 502.8 [M + 1].
13C NMR (100 MHz, CDCl3): 140.0, 137.7, 136.8, 133.4, 129.0, 128.3,
128.0, 127.7, 118.2, 82.6, 80.1, 73.4, 68.4, 60.7, 58.6, 56.8, 41.1, 29.6.
Synthesis of Macrocycles 50a–d
MS (ES+): m/z = 417.2 [M + 1].
SO2Ph
SO2Ph
HO
HO
CH2=CHMgBr
CuI, THF
SO2Ph
SO2Ph
MeO
MeO
TiCl4, CH2Cl2, r.t., 3 h
75%
O
O
I
HMPA, –30 °C
3 h, 75%
BnO
Scheme 25
BnO
O
O
38
38.1
HO
BnO
47.1
47
Scheme 27
(2R,3R,4R,5R)-5-Allyl-2-[(benzyloxy)methyl]-4-[(phenylsulfo-
nyl)methyl]tetrahydrofuran-3-ol (38.1)
{(2R,3R,4S,5R)-5-Allyl-3-methoxy-4-[(phenylsulfonyl)methyl]tet-
To a stirred solution of compound 38 (500 mg, 0.793 mmol) in anhyd
THF (5 mL) were added CuI (75 mg, 0.396 mmol) and HMPA (1.41 mL,
7.93 mmol) at 23 °C. The mixture was cooled to –30 °C and
CH2=CHMgBr (1 M in THF; 2.3 mL, 2.37 mmol) was added dropwise.
The mixture was stirred for 3 h at –30 °C and then the reaction was
quenched with sat. aq NH4Cl. The mixture was extracted with EtOAc
(3 × 20 mL), and the combined organic layers were dried (Na2SO4) and
concentrated under reduced pressure. The residue was purified by
column chromatography (hexanes–EtOAc, 7:3) to give a white solid;
yield: 300 mg (75%); molecular formula: C22H26O5S; Rf = 0.4 (hexanes–
EtOAc, 5:5).
1H NMR (400 MHz, CDCl3): δ = 7.92–7.87 (m, 2 H), 7.64–7.61 (m, 1 H),
7.54 (t, J = 7.60 Hz, 2 H), 7.38–7.27 (m, 5 H), 5.66–5.55 (m, 1 H), 5.16–
5.10 (m, 2 H), 4.53 (d, J = 1.45 Hz, 2 H), 3.86–3.84 (m, 1 H), 3.70 (dd,
J = 14.29, 2.98 Hz, 1 H), 3.62–3.57 (m, 2 H), 3.48 (d, J = 8.72 Hz, 1 H),
3.18 (dd, J = 14.30, 8.84 Hz, 1 H), 2.95 (dq, J = 8.88, 2.89 Hz, 1 H), 2.16–
1.61 (m, 4 H).
rahydrofuran-2-yl}methanol (47.1)
TiCl4 (0.14 mL, 1.329 mmol) was added to a stirred solution of sulfone
47 (250 mg, 0.664 mmol) in CH2Cl2 (100 mL), and the mixture was
stirred for 3 h at r.t. When the starting material was completely con-
sumed, the reaction was quenched with sat. aq NH4Cl and the mix-
ture was extracted with CH2Cl2 (3 × 50 mL). The combined organic
layers were concentrated under reduced pressure and the residue was
purified by column chromatography (hexanes–EtOAc, 5:5) to give a
colorless oil; yield: 150 mg (75%); molecular formula: C16H22O5S;
Rf = 0.35 (hexanes–EtOAc, 5:5).
1H NMR (400 MHz, CDCl3): δ = 7.91–7.87 (m, 3 H), 7.63 (t, J = 7.43 Hz,
1 H), 7.54 (t, J = 7.55 Hz, 2 H), 5.73 (dt, J = 17.16, 8.85 Hz, 1 H), 5.11–
5.06 (m, 2 H), 3.75 (dd, J = 11.52, 5.02 Hz, 1 H), 3.67 (dd, J = 11.53, 4.41
Hz, 1 H), 3.49 (dd, J = 14.40, 2.93 Hz, 1 H), 3.42 (d, J = 7.78 Hz, 6 H),
3.32 (dt, J = 9.56, 9.31, 4.49 Hz, 2 H), 3.22 (dd, J = 14.38, 9.47 Hz, 1 H),
3.04–2.97 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 140.0, 137.0, 133.6, 129.1, 128.0,
118.0, 83.6, 81.5, 60.9, 60.4, 58.5, 56.6, 40.7, 30.9, 29.6.
13C NMR (100 MHz, CDCl3): 140.0, 137.4, 135.8, 133.6, 129.1, 128.5,
128.0, 127.8, 119.3, 73.7, 73.2, 73.0, 68.4, 57.2, 42.4.
MS (ES+): m/z = 327.1 [M + 1].
MS (ES+): m/z = 402.8 [M + 1].
Dienes 47.2–47.5; General Procedure
SO2Ph
SO2Ph
HO
MeO
MeI, Ag2O, DMF
3 h, 70%
To a stirred solution of alcohol 47.1 (30 mg) in CH2Cl2 (20 mL) were
added EDCI (2 equiv), DMAP (2 equiv), and the appropriate N-allyl-
oxycarbonyl amino acid (2 equiv). The mixture was stirred for 3 h at
r.t. until the starting material was completely consumed and then the
reaction was quenched with H2O and the mixture was extracted with
CH2Cl2. The combined organic layers were concentrated under re-
duced pressure and the residue was purified by column chromatogra-
phy (hexanes–EtOAc, 7:3).
O
O
BnO
BnO
38.1
47
Scheme 26
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U

L
S. Konda et al.
Special Topic
Synthesis
13C NMR (100 MHz, CDCl3): δ = 171.5, 155.6, 139.8, 136.0, 133.7,
132.5, 129.2, 128.7, 128.1, 128.0, 127.2, 119.6, 119.0, 117.9, 81.6, 72.3,
69.0, 65.9, 64.4, 60.6, 58.9, 57.5, 56.6, 54.9, 42.5, 41.2, 38.2.
SO2Ph
MeO
SO2Ph
MeO
EDCI, DMAP
CH2Cl2, N-Alloc-AA
r.t., 3 h, 75–80%
O
O
MS (ES+): m/z = 558.2 [M + 1].
O
O
O
HO
47.1
1-Allyl 2-({(2R,3R,4S,5R)-5-allyl-3-methoxy-4-[(phenylsulfo-
nyl)methyl]tetrahydrofuran-2-yl}methyl) (2S)-Piperidine-1,2-di-
carboxylate (47.5)
R1
N
O
H
47.2 R1 = 2-propyl
47.3 R1 = 2-butyl
47.4 R1 = benzyl
Colorless oil; yield: 38.38 mg (80%); molecular formula: C26H35NO8S;
Rf = 0.4 (hexanes–EtOAc, 5:5).
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 7.43 Hz, 2 H), 7.62 (t,
J = 7.34 Hz, 1 H), 7.53 (t, J = 7.57 Hz, 2 H), 5.96–5.81 (m, 1 H), 5.73–
5.61 (m, 1 H), 5.34–5.07 (m, 4 H), 4.95–4.82 (m, 1 H), 4.58–4.56 (m, 2
H), 4.31 (dd, J = 11.36, 5.87 Hz, 1 H), 4.24–4.14 (m, 1 H), 4.13–3.98 (m,
1 H), 3.56–3.43 (m, 2 H), 3.38–3.36 (m, 6 H), 3.26–3.16 (m, 2 H), 3.06–
3.04 (m, 2 H), 2.24–2.14 (m, 1 H), 1.85–1.57 (m, 2 H), 1.50–1.35 (m, 1
H), 1.28–1.20 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 171.3, 156.2, 140.0, 136.4, 133.6,
132.7, 129.1, 128.0, 118.7, 117.4, 82.3, 78.9, 66.2, 63.4, 60.6, 58.9,
56.8, 54.2, 41.8, 41.7, 41.0, 26.6, 24.6, 20.6.
47.5 R1 = pipecolic acid
Scheme 28
{(2R,3R,4S,5R)-5-Allyl-3-methoxy-4-[(phenylsulfonyl)methyl]tet-
rahydrofuran-2-yl}methyl (2S)-2-{[(Allyloxy)carbonyl]amino}-3-
methylbutanoate (47.2)
Colorless oil; yield: 32.78 mg (75%); molecular formula: C25H35NO8S;
Rf = 0.4 (hexanes–EtOAc, 5:5).
1H NMR (400 MHz, CDCl3): δ = 7.89–7.87 (m, 2 H), 7.64–7.60 (m, 1 H),
7.55–7.52 (m, 2 H), 5.94–5.84 (m, 1 H), 5.74–5.63 (m, 1 H), 5.34–5.17
(m, 3 H), 5.10 (dd, J = 13.83, 2.73 Hz, 2 H), 4.55 (d, J = 5.57 Hz, 2 H),
4.29–4.19 (m, 3 H), 3.55–3.45 (m, 2 H), 3.40–3.38 (m, 6 H), 3.25–3.18
(m, 2 H), 3.06–3.01 (m, 1 H), 2.18–2.09 (m, 1 H), 0.97 (d, J = 6.84 Hz, 3
H), 0.89 (d, J = 6.87 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.8, 156.0, 140.0, 136.4, 133.6,
132.5, 129.1, 128.0, 118.6, 117.8, 82.3, 79.0, 65.8, 63.7, 60.5, 59.0,
58.9, 56.7, 40.9, 31.1, 19.0, 17.5.
MS (ES+): m/z = 522.2 [M + 1].
SO2Ph
MeO
MeO
O
SO2Ph
G-II
CH2Cl2
40 °C
16 h
O
O
O
H
O
H
O
O
O
O
70–75%
R1
R1
N
H
N
O
H
MS (ES+): m/z = 510.3 [M + 1].
50a R1 = 2-propyl
50b R1 = 2-butyl
47.2–47.5
50c R1 = benzyl
{(2R,3R,4S,5R)-5-Allyl-3-methoxy-4-[(phenylsulfonyl)methyl]tet-
rahydrofuran-2-yl}methyl 2-{[(Allyloxy)carbonyl]amino}-3-meth-
ylpentanoate (47.3)
50d R1 = pipecolic acid
Scheme 29
Macrocycles 50a–d; General Procedure
Colorless oil; yield: 36.57 mg (76%); molecular formula: C26H37NO8S;
Rf = 0.5 (hexanes–EtOAc, 5:5).
1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 7.69 Hz, 2 H), 7.63 (t,
J = 7.39 Hz, 1 H), 7.54 (t, J = 7.71 Hz, 2 H), 5.95–5.84 (m, 1 H), 5.75–
5.63 (m, 1 H), 5.34–5.18 (m, 3 H), 5.11 (dd, J = 13.59, 2.64 Hz, 2 H),
4.55 (d, J = 5.43 Hz, 2 H), 4.34–4.19 (m, 3 H), 3.56–3.45 (m, 2 H), 3.41–
3.39 (m, 5 H), 3.25–3.17 (m, 2 H), 3.08–3.02 (m, 1 H), 1.83–1.79 (m, 2
H), 1.46–1.35 (m, 1 H), 1.23–1.12 (m, 1 H), 0.94–0.89 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 171.8, 155.9, 140.0, 136.4, 133.6,
132.5, 129.1, 128.0, 118.6, 117.9, 82.3, 79.0, 65.8, 63.7, 60.5, 59.0,
58.3, 56.7, 40.9, 37.8, 30.9, 29.6, 24.9, 15.5, 11.5.
G-II (10 mol%) was added to a stirred solution of the appropriate di-
ene 47.2–47.5 (30 mg) in CH2Cl2 (100 mL), and the mixture was
stirred for 16 h at 40 °C until the starting material was completely
consumed. The mixture was then concentrated under reduced pres-
sure and the residue was purified by column chromatography (hex-
anes–EtOAc, 5:5).
(1R,5S,13R,14S,15R)-5-Isopropyl-15-methoxy-14-[(phenylsulfo-
nyl)methyl]-3,8,16-trioxa-6-azabicyclo[11.2.1]hexadec-10-ene-
4,7-dione (50a)
MS (ES+): m/z = 524.6 [M + 1].
Colorless oil; yield: 20.4 mg (72%); molecular formula: C23H31NO8S;
Rf = 0.2 (hexanes–EtOAc, 5:5).
{(2R,3R,4S,5R)-5-Allyl-3-methoxy-4-[(phenylsulfonyl)methyl]tet-
rahydrofuran-2-yl}methyl (2S)-2-{[(Allyloxy)carbonyl]amino}-3-
phenylpropanoate (47.4)
1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 7.47 Hz, 2 H), 7.67–7.62 (m,
1 H), 7.56 (d, J = 7.72 Hz, 2 H), 5.88–5.82, (m, 1 H), 5.75–5.64 (m, 1 H),
5.30–5.22 (m, 1 H), 5.13–5.09 (m, 2 H), 4.57 (br s, 2 H), 4.33–4.19, (m,
3 H), 3.54–3.48 (m, 1 H), 3.42–3.40 (m, 5 H), 3.25–3.19 (m, 2 H), 3.10–
3.02 (m, 1 H), 2.20–2.10 (m, 1 H), 0.98 (d, J = 6.80 Hz, 3 H), 0.90 (d,
J = 6.56 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.8, 155.9, 140.0, 136.4, 133.6,
129.2, 128.1, 128.0, 118.7, 82.3, 78.9, 64.6, 63.7, 60.5, 59.0, 56.7, 53.4,
40.9, 31.9, 31.1, 29.7, 29.6, 29.3, 22.7.
Colorless oil; yield: 39.98 mg (78%); molecular formula: C29H35NO8S;
Rf = 0.4 (hexanes–EtOAc, 5:5).
1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 7.97 Hz, 2 H), 7.65–7.61 (m,
1 H), 7.54 (t, J = 7.57 Hz, 2 H), 7.32–7.21 (m, 4 H), 7.13 (t, J = 8.01 Hz, 2
H), 5.91–5.81 (m, 1 H), 5.69–5.48 (m, 1 H), 5.31–5.04 (m, 5 H), 4.60–
4.52 (m, 3 H), 4.29–4.06 (m, 2 H), 3.81–3.64 (m, 1 H), 3.57–3.26 (m, 4
H), 3.24–2.93 (m, 5 H), 2.16 (s, 2 H).
MS (ES+): m/z = 482.3 [M + 1].
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U

M
S. Konda et al.
Special Topic
Synthesis
(1R,13R,14S,15R)-5-sec-Butyl-15-methoxy-14-[(phenylsulfo-
nyl)methyl]-3,8,16-trioxa-6-azabicyclo[11.2.1]hexadec-10-ene-
4,7-dione (50b)
under reduced pressure. The residue was purified by column chroma-
tography (hexanes–EtOAc, 7:3) to give a white solid; yield: 300 mg
(75%); molecular formula: C22H26O5S; Rf = 0.5 (hexanes–EtOAc, 5:5).
1H NMR (400 MHz, CDCl3): δ = 7.92–7.87 (m, 2 H), 7.66–7.60 (m, 1 H),
7.53 (dd, J = 10.40, 4.69 Hz, 2 H), 7.38–7.26 (m, 5 H), 5.66–5.55 (m, 1
H), 5.17–5.08 (m, 2 H), 4.53 (d, J = 1.57 Hz, 2 H), 3.87–3.84 (m, 1 H),
3.70 (dd, J = 14.31, 3.01 Hz, 1 H), 3.61–3.55 (m, 2 H), 3.47 (dd, J = 8.72,
1.37 Hz, 1 H), 3.18 (dd, J = 14.32, 8.86 Hz, 1 H), 2.95 (dd, J = 8.91, 2.88
Hz, 1 H), 2.28 (m, 4 H).
Colorless oil; yield: 21 mg (74%); molecular formula: C24H33NO8S;
Rf = 0.25 (hexanes–EtOAc, 5:5).
1H NMR (400 MHz, CDCl3): δ = 7.65–7.61 (m, 1 H), 7.57–7.52 (m, 2 H),
7.38–7.37 (m, 1 H), 7.33–7.30 (m, 1 H), 5.76–5.64 (m, 1 H), 5.37–5.24
(m, 1 H), 5.18–5.10 (m, 2 H), 4.73 (d, J = 6.16 Hz, 1 H), 4.38–4.19 (m, 3
H), 3.55–3.46 (m, 2 H), 3.44–3.38 (m, 5 H), 3.24–3.19 (m, 2 H), 3.11–
3.02 (m, 1 H), 1.94–1.82 (m, 1 H), 1.75–1.70 (m, 2 H), 0.96–0.89 (m, 6
H).
13C NMR (100 MHz, CDCl3): 140.0, 137.4, 135.8, 133.6, 129.1, 128.5,
128.0, 127.8, 119.3, 73.7, 73.2, 73.0, 68.4, 57.2, 42.4.
MS (ES+): m/z = 496.3 [M + 1].
MS (ES+): m/z = 403.3 [M + 1].
SO2Ph
SO2Ph
HO
(1R,5S,13R,14S,15R)-5-Benzyl-15-methoxy-14-[(phenylsulfo-
nyl)methyl]-3,8,16-trioxa-6-azabicyclo[11.2.1]hexadec-10-ene-
4,7-dione (50c)
MeO
MeI, Ag2O, DMF
16 h, r.t.
70%
O
O
Colorless oil; yield: 19.4 mg (70%); molecular formula: C27H31NO8S;
Rf = 0.1 (hexanes–EtOAc, 5:5).
BnO
BnO
48
39.1
1H NMR (400 MHz, CDCl3): δ = 7.92–7.84 (m, 2 H), 7.70–7.60 (m, 1 H),
7.56–7.53 (m, 2 H), 7.34–7.28 (m, 3 H), 7.18–7.17 (m, 2 H), 6.02–5.38
(m, 2 H), 5.05–4.25 (m, 4 H), 3.76–3.38 (m, 5 H), 3.33–2.74 (m, 5 H),
2.35–1.58 (m, 5 H).
Scheme 31
(2S,3S,4R,5R)-2-Allyl-5-[(benzyloxy)methyl]-4-methoxy-3-[(phe-
nylsulfonyl)methyl]tetrahydrofuran (48)
MS (ES+): m/z = 530.6 [M + 1].
To a stirred solution of tetrahydrofuran 39.1 (320 mg) in DMF (20 mL)
were added Ag2O (2 equiv) and MeI (5 equiv) in a dark environment.
The mixture was stirred for 16 h at r.t., then filtered through Celite.
The filtrate was extracted with EtOAc (3 × 20 mL), and the combined
organic layers were dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified by column chromatography (hex-
anes–EtOAc, 9:1) to give a colorless oil; yield: 250 mg (70%); molecu-
lar formula: C23H28O5S; Rf = 0.6 (hexanes–EtOAc, 9:1).
1H NMR (400 MHz, CDCl3): δ = 7.92–7.85 (m, 2 H), 7.64–7.60 (m, 1 H),
7.53 (t, J = 7.56 Hz, 2 H), 7.38–7.27 (m, 5 H), 5.66–5.54 (m, 1 H), 5.14–
5.10 (m, 2 H), 4.54–4.48 (m, 2 H), 3.71 (dd, J = 14.25, 2.66 Hz, 1 H),
3.61 (dq, J = 9.93, 5.15 Hz, 2 H), 3.52–3.35 (m, 6 H), 3.16 (dd, J = 14.24,
9.31 Hz, 2 H), 2.97 (dq, J = 9.08, 2.52 Hz, 1 H), 2.57 (d, J = 7.96 Hz, 1 H).
(4R,5R,6S,7R,18aS)-5-methoxy-6-[(phenylsulfonyl)methyl]-
4,5,6,7,8,11,16,17,18,18a-decahydro-3H-4,7-epoxypyrido[1,2-
c][1,6,3]dioxazacyclopentadecine-1,13(15H)-dione (50d)
Colorless oil; yield: 20.4 mg (72%); molecular formula: C24H31NO8S;
Rf = 0.2 (hexanes–EtOAc, 5:5).
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 7.43 Hz, 2 H), 7.64 (t,
J = 7.43 Hz, 1 H), 7.54 (t, J = 7.61 Hz, 2 H), 5.99–5.53 (m, 2 H), 4.84–
4.55 (m, 1 H), 4.45–3.75 (m, 4 H), 3.52–2.97 (m, 12 H), 2.91–2.75 (m, 1
H), 2.25 (d, J = 13.73 Hz, 1 H), 1.86–1.66 (m, 4 H), 1.45–1.41 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 155.8, 143.4, 133.8, 129.3, 128.0,
128.0, 127.9, 110.0, 102.7, 84.9, 82.3, 62.1, 56.5, 36.8, 31.9, 31.4, 29.7,
25.7, 24.2, 22.7, 20.4, 14.1.
13C NMR (100 MHz, CDCl3): 140.0, 137.8, 136.8, 133.5, 129.1, 129.1,
128.4, 128.1, 128.0, 127.8, 127.7, 118.3, 82.0, 80.0, 73.4, 68.4, 60.8,
58.7, 56.8, 41.2.
MS (ES+): m/z = 494.1 [M + 1].
MS (ES+): m/z = 416.8 [M + 1].
Synthesis of Macrocycles 49a–d
SO2Ph
SO2Ph
SO2Ph
MeO
SO2Ph
MeO
HO
HO
TiCl4, CH2Cl2
r.t., 3 h
CH2=CHMgBr
CuI, THF
75%
O
O
HMPA, –30 °C
3 h, 75%
O
O
I
HO
BnO
BnO
BnO
Scheme 30
39.1
39
48.1
48
Scheme 32
(2R,3R,4R,5S)-5-Allyl-2-[(benzyloxy)methyl]-4-[(phenylsulfo-
{(2R,3R,4S,5S)-5-Allyl-3-methoxy-4-[(phenylsulfonyl)methyl]tet-
nyl)methyl]tetrahydrofuran-3-ol (39.1)
rahydrofuran-2-yl}methanol (48.1)
CuI (75 mg, 0.396 mmol) and HMPA (1.41 mL, 7.93 mmol) were add-
ed to a stirred solution of iodide 39 (500 mg, 0.793 mmol) in anhyd
THF (5 mL) at 23 °C. The mixture was cooled to –30 °C and
CH2=CHMgBr (2.4 mL, 2.4 mmol) was added dropwise. The mixture
was stirred for 3 h at –30 °C and then the reaction was quenched with
sat. aq NH4Cl. The mixture was extracted with EtOAc (3 × 20 mL), and
the combined organic layers were dried (Na2SO4) and concentrated
To a stirred solution of sulfone 48 (250 mg, 0.664 mmol) in CH2Cl2
(100 mL) was added TiCl4 (0.14 mL, 1.329 mmol), and the mixture
was stirred for 3 h at r.t. until all the starting material was consumed.
The reaction was then quenched with sat. aq NH4Cl and the mixture
was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers
were concentrated under reduced pressure and the residue was puri-
fied by column chromatography (hexanes–EtOAc, 5:5) to give a color-
less oil; yield: 150 mg (75%); molecular formula: C16H22O5S; Rf = 0.4
(hexanes–EtOAc, 5:5).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U

N
S. Konda et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.87–7.85 (m, 2 H), 7.64–7.60 (m, 1 H),
7.56–7.51 (m, 2 H), 5.71 (td, J = 17.19, 8.92 Hz, 1 H), 5.10–5.05 (m, 2
H), 3.05–2.95 (m, 1 H), 3.77–3.69 (m, 1 H), 3.69–3.62 (m, 1 H), 3.49
(dd, J = 14.40, 2.90 Hz, 1 H), 3.41–3.38 (m, 5 H), 3.31 (dt, J = 9.41, 4.35
Hz, 2 H), 3.22 (dd, J = 14.39, 3.02–3.95 (m, 1 H), 9.59 Hz, 1 H), 2.17 (br
s, 1 H).
4.28–4.22 (m, 1 H), 4.19–4.09 (m, 1 H), 3.68 (dd, J = 14.24, 2.42 Hz, 1
H), 3.55–3.32 (m, 5 H), 3.26–3.12 (m, 2 H), 3.07–2.94 (m, 1 H), 2.47–
2.42 (m, 1 H), 1.74–1.47 (m, 4 H), 0.92 (dd, J = 6.41, 1.66 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 173.0, 155.9, 140.0, 136.0, 133.6,
132.5, 129.2, 128.0, 119.6, 117.8, 81.7, 72.3, 69.1, 65.9, 64.1, 60.7,
58.9, 57.5, 56.5, 52.5, 42.5, 41.2, 29.7, 24.7, 22.8, 21.7, 14.1.
13C NMR (100 MHz, CDCl3): δ = 139.9, 136.9, 133.6, 129.2, 128.0,
118.1, 83.5, 81.4, 60.9, 60.5, 58.5, 56.6, 40.8, 29.7.
MS (ES+): m/z = 524.6 [M + 1].
MS (ES+): m/z = 327.2 [M + 1].
1-Allyl 2-({(2R,3R,4S,5S)-5-allyl-3-methoxy-4-[(phenylsulfo-
nyl)methyl]tetrahydrofuran-2-yl}methyl) (2R)-Pyrrolidine-1,2-di-
carboxylate (48.4)
SO2Ph
MeO
SO2Ph
MeO
EDCI, DMAP
CH2Cl2, N-Alloc-AA
Colorless oil; yield: 34 mg (73%); molecular formula: C25H33NO8S;
Rf = 0.4 (hexanes–EtOAc, 5:5).
r.t., 3 h, 75–80%
O
O
O
1H NMR (400 MHz, CDCl3): δ = 7.90–7.88 (m, 2 H), 7.63–7.61 (m, 2 H),
7.59–7.51 (m, 2 H), 5.98–5.80 (m, 1 H), 5.63–5.53 (m, 1 H), 5.35–5.05
(m, 4 H), 4.61–4.54 (m, 2 H), 4.41–4.15 (m, 3 H), 3.62–3.35 (m, 7 H),
3.25–3.13 (m, 2 H), 3.06–2.98 (m, 1 H), 2.42–2.13 (m, 2 H), 2.01–1.90
(m, 4 H).
O
O
HO
R1
48.1
N
O
H
48.2 R1 = benzyl
13C NMR (100 MHz, CDCl3): δ = 172.4, 154.7, 136.0, 132.7, 129.1,
128.0, 118.8, 117.4, 81.9, 72.2, 68.9, 66.0, 60.5, 58.8, 56.6, 46.4, 42.6,
41.3, 30.9, 29.7, 24.5, 24.4, 23.5.
48.3 R1 = isobutyl
48.4 R1 = D-proline
48.5 R1 = pipecolic acid
MS (ES+): m/z = 508.1 [M + 1].
Scheme 33
Dienes 48.2–48.5; General Procedure
1-Allyl 2-({(2R,3R,4S,5S)-5-allyl-3-methoxy-4-[(phenylsulfo-
nyl)methyl]tetrahydrofuran-2-yl}methyl) (2S)-Piperidine-1,2-di-
carboxylate (48.5)
To a stirred solution of sulfone 48.1 (30 mg) in CH2Cl2 (20 mL) were
added EDCI (2 equiv), DMAP (2 equiv), and the appropriate N-allyl-
oxycarbonyl amino acid (2 equiv), and the mixture was stirred for 3 h
at r.t. until all the starting material was consumed. The reaction was
quenched with H2O and the mixture was extracted with CH2Cl2 (3 ×
30 mL). The combined organic layers were concentrated under re-
duced pressure, and the residue was purified by column chromatog-
raphy (hexanes–EtOAc, 7:3) to provide give a colorless oil.
Colorless oil; yield: 34 mg (73%); molecular formula: C26H35NO8S;
Rf = 0.3 (hexanes–EtOAc, 5:5).
1H NMR (400 MHz, CDCl3): δ = 7.93–7.88 (m, 2 H), 7.72–7.51 (m, 3 H),
5.99–5.81 (m, 1 H), 5.73–5.49 (m, 1 H), 5.41–5.05 (m, 4 H), 4.95–4.84
(m, 1 H), 4.58–4.57 (m, 2 H), 4.35–4.17 (m, 2 H), 4.10–3.99 (m, 2 H),
3.72–3.31 (m, 4 H), 3.28–2.89 (m, 3 H), 2.26–1.98 (m, 3 H), 1.69–1.66
(m, 3 H), 1.24–1.20 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 140.0, 139.7, 135.9, 132.7, 129.2,
129.1, 128.0, 119.6, 117.4, 110.0, 81.7, 72.3, 66.2, 63.5, 57.4, 56.5,
54.5, 54.3, 53.1, 41.8, 41.2, 29.6, 29.6, 26.6, 24.6, 22.6, 20.6, 20.6, 20.6,
14.1.
{(2R,3R,4S,5S)-5-Allyl-3-methoxy-4-[(phenylsulfonyl)methyl]tet-
rahydrofuran-2-yl}methyl (2S)-2-{[(Allyloxy)carbonyl]amino}-3-
phenylpropanoate (48.2)
Colorless oil; yield: 36.9 mg (72%); molecular formula: C29H35NO8S;
Rf = 0.4 (hexanes–EtOAc, 5:5).
MS (ES+): m/z = 522.2 [M + 1].
1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 7.23 Hz, 2 H), 7.65–7.61 (m,
1 H), 7.56–7.52 (m, 2 H), 7.34–7.21 (m, 4 H), 7.13 (s, 1 H), 5.92–5.82
(m, 1 H), 5.71–5.59 (m, 1 H), 5.31–5.16 (m, 3 H), 5.15–5.08 (m, 2 H),
4.62 (dd, J = 14.26, 6.35 Hz, 1 H), 4.54 (d, J = 5.56 Hz, 3 H), 4.20 (d,
J = 5.91 Hz, 2 H), 3.50 (dd, J = 14.15, 2.50 Hz, 1 H), 3.37–3.35 (m, 3 H),
3.33 (s, 3 H), 3.24–3.01 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 171.4, 155.5, 140.0, 136.4, 135.5,
133.6, 132.5, 129.3, 129.3, 129.2, 128.7, 128.0, 127.3, 118.7, 117.9,
110.0, 82.2, 78.8, 65.9, 64.0, 60.5, 59.0, 56.8, 54.8, 40.9, 38.2, 29.7,
29.6.
SO2Ph
MeO
MeO
O
SO2Ph
G-II, CH2Cl2
40 °C, 16 h
O
O
O
H
O
H
O
O
O
O
70–75%
R1
R1
N
H
N
O
H
48.2–48.5
49a R1 = benzyl
49b R1 = isobutyl
49c R1 = D-proline
49d R1 = pipecolic acid
MS (ES+): m/z = 558.2 [M + 1].
{(2R,3R,4S,5S)-5-Allyl-3-methoxy-4-[(phenylsulfonyl)methyl]tet-
rahydrofuran-2-yl}methyl (2S)-2-{[(Allyloxy)carbonyl]amino}-4-
methylpentanoate (48.3)
Scheme 34
Macrocycles 49a–d; General Procedure
Colorless oil; yield: 34.6 mg (72%); molecular formula: C26H37NO8S;
Rf = 0.4 (hexanes–EtOAc, 5:5).
G-II (10 mol%) was added to a stirred solution of the appropriate di-
ene 48.2–48.5 (30 mg) in CH2Cl2 (100 mL), and the mixture was
stirred for 16 h at 40 °C until the starting material was completely
1H NMR (400 MHz, CDCl3): δ = 7.92–7.86 (m, 2 H), 7.66–7.60 (m, 1 H),
7.55–7.52 (m, 2 H)5.95–5.82 (m, 1 H), 5.74–5.51 (m, 1 H), 5.33–5.24
(m, 1 H), 5.22–5.07 (m, 4 H), 4.54–4.53 (m, 2 H), 4.37–4.28 (m, 1 H),
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U

O
S. Konda et al.
Special Topic
Synthesis
consumed. The mixture was concentrated under reduced pressure
and the residue was purified by column chromatography (hexanes–
EtOAc, 5:5) to provide give a colorless oil.
13C NMR (100 MHz, CDCl3): δ = 156.3, 142.7, 133.6, 129.1, 128.1,
128.1, 128.0, 110.0, 63.2, 57.0, 55.4, 41.3, 31.9, 29.7, 29.6, 29.6, 29.3,
26.0, 24.3, 24.3, 24.3, 24.2, 22.7, 20.4, 14.1.
MS (ES+): m/z = 494.1 [M + 1].
(1R,5S,13S,14S,15R)-5-Benzyl-15-methoxy-14-[(phenylsulfo-
nyl)methyl]-3,8,16-trioxa-6-azabicyclo[11.2.1]hexadec-10-ene-
4,7-dione (49a)
Synthesis of Fragment 46
Colorless oil; yield: 21.9 mg (75%); molecular formula: C27H31NO8S;
Rf = 0.2 (hexanes–EtOAc, 5:5).
O
O
literature
6 steps
1H NMR (400 MHz, CDCl3): δ = 7.89–7.84 (m, 2 H), 7.65–7.61 (m, 1 H),
7.56–7.52 (m, 2 H), 7.34–7.27 (m, 3 H), 7.18 (d, J = 6.73 Hz, 2 H), 5.72–
5.63 (m, 1 H), 5.58–5.49 (m, 1 H), 4.98–4.90 (m, 1 H), 4.76–4.67 (m, 1
H), 4.42–4.27 (m, 1 H), 4.12–4.02 (m, 1 H), 3.73–3.63 (m, 2 H), 3.40–
3.34 (m, 3 H), 3.26–3.10 (m, 4 H), 2.99–2.87 (m, 4 H), 1.61 (br s, 2 H).
22
BnO
COOEt
40
Scheme 35
13C NMR (100 MHz, CDCl3): δ = 170.6, 155.8, 133.6, 129.2, 129.0,
128.9, 128.9, 128.1, 127.5, 114.1, 113.8, 83.3, 59.1, 56.9, 56.4, 36.5,
31.9, 29.7, 22.7, 14.1.
Ethyl (2E)-3-{(4R,5R)-5-[(Benzyloxy)methyl]-2,2-dimethyl-1,3-di-
oxolan-4-yl}acrylate (40)
Triethyl phosphonoacetate (23.6 mL, 119.047 mmol) was added drop-
wise to a stirred solution of 60% NaH (2.85 g, 119.047 mmol) in anhyd
THF over 30 min at 0 °C, and the mixture was stirred at 0 °C for 30
min. Aldehyde 23.2 (10 g, 39.682 mmol) was added slowly and the
mixture was stirred for 2 h at 0 °C until the reaction was complete
(TLC). The reaction was then quenched with H2O, and the mixture
was extracted with EtOAc (3 × 100 mL). The combined organic layers
were dried (Na2SO4) and concentrated under reduced pressure. The
residue was purified by column chromatography (hexane–EtOAc, 9:1)
to give a yellowish liquid; yield: 11.2 g (90%); molecular formula:
MS (ES+): m/z = 530.1 [M + 1].
(1R,5S,13S,14S,15R)-5-Isobutyl-15-methoxy-14-[(phenylsulfo-
nyl)methyl]-3,8,16-trioxa-6-azabicyclo[11.2.1]hexadec-10-ene-
4,7-dione (49b)
Colorless oil; yield: 19.9 mg (75%); molecular formula: C24H33NO8S;
Rf = 0.25 (hexanes–EtOAc, 5:5).
1H NMR (400 MHz, CDCl3): δ = 7.90–7.87 (m, 2 H), 7.65–7.61 (m, 1 H),
7.57–7.53 (m, 2 H), 5.79–5.54 (m, 2 H), 5.20–4.99 (m, 1 H), 4.91 (d,
J = 5.99 Hz, 1 H), 4.86–4.78 (m, 1 H), 4.72 (dd, J = 12.92, 6.22 Hz, 1 H),
4.12–4.06 (m, 1 H), 4.03–3.99 (m, 1 H), 3.82 (dd, J = 14.23, 2.19 Hz, 1
H), 3.61–3.55 (m, 1 H), 3.47 (m, 3 H), 3.23–3.12 (m, 2 H), 2.83–2.73
(m, 1 H), 2.09–2.02 (m, 1 H), 1.76–1.45 (m, 4 H), 0.95–0.90 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 171.2, 155.8, 140.1, 133.6, 133.6,
129.7, 129.2, 128.0, 128.0, 122.0, 114.0, 74.5, 63.3, 58.7, 57.2, 54.4,
40.1, 39.6, 29.7, 24.8, 22.7, 21.6.
C
18H24O5; Rf = 0.5 (hexanes–EtOAc, 9:1).
1H NMR (400 MHz, CDCl3): δ = 7.39–7.28 (m, 5 H), 6.90 (dd, J = 15.63,
5.6 Hz, 1 H), 6.10 (dd, J = 15.64, 1.20 Hz, 1 H), 4.64–4.56 (m, 2 H),
4.45–4.41 (m, 1 H), 4.21 (q, J = 7.2 Hz, 2 H), 3.98–3.94 (m, 1 H), 3.64
(d, J = 4.80 Hz, 2 H), 1.46 (s, 3 H), 1.44 (s, 3 H), 1.30 (t, J = 7.20 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 165.9, 144.0, 137.6, 128.4, 127.7,
127.6, 122.5, 110.1, 79.5, 73.6, 69.2, 60.5, 26.9, 26.6, 14.20.
MS (ES+): m/z = 496.3 [M + 1].
MS (ES+): m/z = 337.1 [M + 17].
(4R,5R,6S,7S,17aS)-5-Methoxy-6-[(phenylsulfonyl)methyl]-
4,5,6,7,8,11,15,16,17,17a-decahydro-1H,3H-4,7-epoxypyrrolo[1,2-
c][1,6,3]dioxazacyclopentadecine-1,13-dione (49c)
CH2=CHMgBr, CuI
THF, TMSCl
O
O
O
O
HMPA, –78 °C
7 h, r.t., 12 h, 75%
H
COOEt
H
Colorless oil; yield: 20.4 mg (72%); molecular formula: C23H29NO8S;
Rf = 0.1 (hexanes–EtOAc, 5:5).
BnO
BnO
COOEt
40
Scheme 36
41
1H NMR (400 MHz, CDCl3): δ = 7.91–7.83 (m, 2 H), 7.66–7.61 (m, 1 H),
7.59–7.51 (m, 2 H), 5.03–4.89 (m, 1 H), 4.79–4.71 (m, 1 H), 4.63–4.40
(m, 1 H), 4.36–4.04 (m, 2 H), 3.70–3.35 (m, 7 H), 3.27–3.13 (m, 1 H),
3.04–2.88 (m, 1 H), 2.78–2.57 (m, 1 H), 2.36–2.19 (m, 1 H), 2.09–1.82
(m, 3 H), 1.77–1.55 (m, 2 H), 6.00–5.78 (m, 1 H), 5.76–5.40 (m, 2 H).
Ethyl (3S)-3-{(4R,5R)-5-[(Benzyloxy)methyl]-2,2-dimethyl-1,3-di-
oxolan-4-yl}pent-4-enoate (41)
MS (ES+): m/z = 480.6 [M + 1].
CH2=CHMgBr (8.1 mL, 8.12 mmol) was added dropwise to a stirred
solution of CuI (77 mg, 4.062 mmol) in anhyd THF (10 mL) at –78 °C,
and the mixture was stirred at –78 °C for 40 min. TMSCl (1 mL, 8.12
mmol) and a solution of ester 40 (1.3 g, 4.062 mmol) in THF (2 mL)
were added dropwise over 20 min, followed by HMPA (2.8 mL, 16.24
mmol). The mixture was stirred at –78 °C for 7 h and then at r.t. for 12
h until the reaction was complete. The reaction was quenched with a
1:1 aq solution of NH4Cl and NH4OH at –78 °C, and the mixture was
extracted with EtOAc (3 × 100 mL). The combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure. The residue
was purified by column chromatography (hexanes–EtOAc, 9:1) to give
a colorless oil; yield: 990 mg (75%); molecular formula: C20H28O5;
Rf = 0.5 (hexanes–EtOAc, 9:1).
(4R,5R,6S,7S,18aS)-5-Methoxy-6-[(phenylsulfonyl)methyl]-
4,5,6,7,8,11,16,17,18,18a-decahydro-3H-4,7-epoxypyrido[1,2-
c][1,6,3]dioxazacyclopentadecine-1,13(15H)-dione (48d)
Colorless oil; yield: 20.6 mg (73%); molecular formula: C24H31NO8S;
Rf = 0.1 (hexanes–EtOAc, 5:5).
1H NMR (400 MHz, CDCl3): δ = 7.87–7.85 (m, 2 H), 7.65–7.61 (m, 1 H),
7.56–7.52 (m, 2 H), 5.85–5.44 (m, 2 H), 5.16–4.62 (m, 3 H), 4.54–4.42
(m, 1 H), 4.23–3.78 (m, 3 H), 3.64 (d, J = 2.11 Hz, 1 H), 3.51–3.35 (m, 5
H), 3.27–3.13 (m, 2 H), 3.00–2.83 (m, 2 H), 2.34–2.07 (m, 1 H), 1.79–
1.60 (m, 4 H), 1.49–1.38 (m, 2 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U

P
S. Konda et al.
Special Topic
Synthesis
O
O
O
O
O
O
2 M HCl, THF
H2O, 65 °C
H
H
H
COOEt
+
BnO
BnO
BnO
16 h, 90%
OH
42 major
OH
43 minor
41
Scheme 37
1H NMR (400 MHz, CDCl3): δ = 7.37–7.26 (m, 5 H), 5.53 (td, J = 17.20,
17.20 Hz, 1 H), 5.14 (d, J = 17.20 Hz, 1 H), 5.03 (dd, J =10.29, 1.19 Hz, 1
H), 4.58 (s, 2 H), 4.14–4.06 (m, 2 H), 4.02–3.96 (m, 1 H), 3.74 (t,
J = 7.66 Hz, 1 H), 3.59 (dd, J = 10.52, 2.98 Hz, 1 H), 3.48 (dd, J = 10.52,
5.95 Hz, 1 H), 2.78–2.68 (m, 2 H), 2.37–2.28 (m, 1 H), 1.40 (s, 6 H),
1.23 (s, 3 H).
13C NMR (100 MHz, CDCl3): 176.0, 137.8, 136.8, 136.6, 132.9, 130.2,
128.4, 128.4, 127.7, 117.3, 83.4, 76.1, 73.6, 69.1, 67.0, 40.6, 34.9.
MS (ES+): m/z = 279.7 [M + 17].
O
O
O
O
13C NMR (100 MHz, CDCl3): 172.2, 138.0, 136.3, 128.3, 127.7, 118.0,
109.2, 79.4, 78.8, 73.3, 70.6, 60.3, 45.1, 36.7, 27.2, 14.2.
H
H
Ag2O, 2,6-Cl2C6H3CH2Cl
DMF, TBAI, 16 h
H
H
BnO
BnO
MS (ES+): m/z = 349.3 [M + 1].
OH
ODCB
42.1
70%
42
(4S,5R)- and (4R,5R)-5-[(1R)-2-(Benzyloxy)-1-hydroxyethyl]-4-vi-
nyldihydrofuran-2(3H)-one (42 and 43)
Scheme 38 DCB = 2,4-dichlorobenzyl
2 M aq HCl (1 mL) was added to a stirred solution of ester 41 (1 g, 2.87
mmol) in 1:1 THF–H2O (20 mL), and the mixture was refluxed for 16 h
until the starting material was consumed (TLC). The mixture was ex-
tracted with EtOAc (3 × 50 mL), and the combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure. The residue
was purified by column chromatography (8:2 hexanes–EtOAc) to give
42 (yield: 650 mg) and 43 (yield: 50 mg) in 13:1 ratio (total yield:
90%).
(4S,5R)-5-{(1R)-2-(Benzyloxy)-1-[(2,6-dichlorobenzyl)oxy]ethyl}-
4-vinyldihydrofuran-2(3H)-one (42.1)
To a stirred solution of alcohol 42 (1.2 g, 4.58 mmol) in anhyd DMF
(10 mL) were added Ag2O (1.8 g, 6.87 mmol), TBAI (3.38 g, 9.16
mmol), and 2,6-dichlorobenzyl chloride (1.78 g, 9.16 mmol) under an
inert atmosphere, and the mixture was stirred for 48 h in darkness.
When the reaction was complete, the mixture was filtered through
Celite and extracted with EtOAc (30 mL) and cool H2O (15 mL). The
combined organic layers were dried (Na2SO4) and concentrated under
reduced pressure, and the residue was purified by column chroma-
tography (hexanes–EtOAc, 9:1) to provide give a colorless oil; yield:
1.35 g (70%); molecular formula: C22H22Cl2O4; Rf = 0.5 (hexanes–
EtOAc, 8:2).
1H NMR (400 MHz, CDCl3): δ = 7.38–7.30 (m, 7 H), 7.21 (dd, J = 8.67,
7.40 Hz, 1 H), 5.71 (dt, J = 17.10, 10.16, 8.37 Hz, 1 H), 5.09–4.95 (m, 2
H), 4.83 (d, J = 10.50 Hz, 1 H), 4.62–4.53 (m, 2 H), 4.40 (dd, J = 6.80,
1.60 Hz, 1 H), 3.88 (dd, J = 8.82, 4.85 Hz, 1 H), 3.75–3.67 (m, 2 H), 3.17
(m, 1 H), 2.77 (dd, J = 17.60, 9.00 Hz, 1 H), 2.37 (dd, J = 17.60, 9.00 Hz,
2 H).
42
Molecular formula: C15H18O4; Rf = 0.3 (hexanes–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): δ = 7.33–7.28 (m, 5 H), 5.79–5.70 (m, 1 H),
5.22–5.14 (m, 2 H), 4.59–4.52 (m, 2 H), 4.23 (dd, J = 7.6, 2.00 Hz, 1 H),
3.91–3.88 (m, 1 H), 3.64–3.56 (m, 2 H), 3.30 (p, 1 H), 2.80 (dd,
J = 17.60, 9.20 Hz, 1 H), 2.42 (dd, J = 17.60, 9.20 Hz, 1 H), 2.32 (d,
J = 6.00 Hz, 1 H).
13C NMR (100 MHz, CDCl3): 175.7, 137.5, 136.0, 128.5, 127.9, 127.8,
118.0, 83.4, 73.5, 71.1, 69.4, 41.0, 34.9.
MS (ES+): m/z = 279.7 [M + 17].
13C NMR (100 MHz, CDCl3): 176.0, 137.8, 136.8, 136.6, 132.9, 130.3,
128.5, 128.4, 127.8, 117.4, 83.4, 76.1, 73.6, 69.1, 67.1, 40.7, 34.9.
43
Molecular formula: C15H18O4; Rf = 0.5 (hexanes–EtOAc, 7:3).
MS (ES+): m/z = 437.6 [M + 17].
1H NMR (400 MHz, CDCl3): δ = 7.36–7.28 (m, 5 H), 5.68–5.59 (m, 1 H),
5.37 (d, J = 3.60 Hz, 1 H), 5.34 (d, J = 2.80 Hz, 1 H), 4.54 (s, 2 H), 4.34
(dd, J = 9.60, 2.40 Hz, 1 H), 3.88 (bt, 1 H) 3.68–3.57 (m, 3 H), 1.90–1.83
(m, 1 H), 1.74–1.67 (m, 1 H), 1.66–1.62 (br s, 1 H).
O
1) LiAlH4, THF, 0 °C to r.t., 16 h
2) TBDPSCl, imidazole, CH2Cl2
0 °C to r.t., 3 h
OMe
O
OTBDPS
H
BnO
H
BnO
3) NaH, MeI, DMF, 0 °C, 1 h
50% (3 steps)
ODCB
44
ODCB
42.1
Scheme 39
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U

Q
S. Konda et al.
Special Topic
Synthesis
(3S,4R,5R)-6-(Benzyloxy)-5-[(2,4-dichlorobenzyl)oxy]-3-vinylhex-
ane-1,4-diol (42.2)
13C NMR (100 MHz, CDCl3): 139.4, 138.2, 137.0, 135.6, 134.1, 134.1,
133.7, 129.8, 129.5, 128.3, 128.3, 127.8, 127.6, 127.5, 116.8, 83.7, 78.6,
73.5, 69.2, 67.0, 62.0, 60.7, 41.9, 32.7, 26.9, 19.2.
LiAlH4 (312 mg, 8.21 mmol) was added in a portionwise manner to a
stirred solution of tetrahydrofuranone 42.1 (2.3 g, 5.476 mmol) in an-
hyd THF (20 mL) at 0 °C. After 16 h, the reaction was quenched with 1
M aq NaOH and the mixture was filtered through Celite. The filtrate
was concentrated under reduced pressure and product 42.2 was used
directly in the next reaction.
MS (ES+): m/z = 677.7 [M + 1].
OTBDPS
OMe
I2, MeCN, –30 °C
OTBDPS
3 h, 80%
BnO
O
I
Molecular formula: C22H26Cl2O4; Rf = 0.4 (hexanes–EtOAc, 8:2).
ODCB
1H NMR (400 MHz, CDCl3): δ = 7.38–7.28 (m, 7 H), 7.22–7.16 (m, 1 H),
5.66–5.57 (m, 1 H), 5.07–4.96 (m, 3 H), 4.83–4.80 (m, 1 H), 4.61–4.53
(m, 2 H), 3.79–3.66 (m, 4 H), 3.60–3.53 (m, 2 H), 2.47 (dq, J = 8.77,
4.41 Hz, 1 H), 2.27 (s, 3 H), 2.01–1.91 (m, 1 H), 1.62–1.53 (m, 1 H).
BnO
O
45
44
Scheme 40
13C NMR (100 MHz, CDCl3): 139.4, 137.8, 136.8, 133.2, 130.0, 128.4,
128.2, 127.7, 127.6, 116.9, 74.2, 73.6, 70.2, 66.5, 60.9, 44.7, 33.9, 30.8
(4 are overlapping signals).
(2R,3R,4R,5R)-2-[(Benzyloxy)methyl]-4-(2-{[tert-butyl(diphe-
nyl)silyl]oxy}ethyl)-5-(iodomethyl)tetrahydrofuran-3-ol (45)
A soln of I2 (1 g, 3.9 mmol) in MeCN (50 mL) was added dropwise to
stirred solution of alkene 44 (1.8 g, 3.3 mmol) in MeCN (50 mL) at
–30 °C. After 3 h, sat. aq Na2S2O3 was added, and the mixture was
extracted with EtOAc (3 × 20 mL). The combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure. The residue
was purified by column chromatography (hexanes–EtOAc, 9:1) to give
a colorless oil; yield: 1.45 g (80%); molecular formula: C32H41IO4Si;
Rf = 0.5 (hexanes–EtOAc, 9.5:0.5).
1H NMR (400 MHz, CDCl3): δ = 7.71–7.68 (m, 4 H), 7.46–7.32 (m, 11
H), 4.58 (dd, J = 43.23, 12.13 Hz, 2 H), 4.10 (td, J = 6.65, 4.58 Hz, 1 H),
3.80 (dt, J = 6.69, 3.73 Hz, 1 H), 3.76–3.69 (m, 3 H), 3.64 (dd, J = 10.05,
6.74 Hz, 1 H), 3.56 (dd, J = 4.00, 1.09 Hz, 1 H), 3.29–3.28 (m, 2 H), 3.24
(s, 3 H), 2.51–2.44 (m, 1 H), 1.70–1.62 (m, 1 H), 1.57–1.50 (m, 1 H),
1.07 (s, 9 H).
MS (ES+): m/z = 425.1 [M + 1].
(2R,3R,4S)-1-(Benzyloxy)-4-(2-{[tert-butyl(diphenyl)silyl]oxy}eth-
yl)-2-[(2,4-dichlorobenzyl)oxy]hex-5-en-3-ol (42.3)
Crude product 42.2 (2.93 g, 6.896 mmol) was dissolved in anhyd
CH2Cl2 (20 mL), and imidazole (1.4 g, 20.688 mmol) and TBDPSCl (2.2
mL, 8.275 mmol) were added at 0 °C. The mixture was then stirred for
3 h until the reaction was complete. The reaction was quenched with
H2O, and the mixture was extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were dried (Na2SO4) and concentrated under
reduced pressure, and the residue was purified by column chroma-
tography (hexanes–EtOAc, 9.6:0.4) to give a colorless oil; yield: 3.42 g
(75%); molecular formula: C38H44Cl2O4Si; Rf = 0.5 (hexanes–EtOAc,
9:1).
1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 6.99 Hz, 4 H), 7.43–7.28 (m,
13 H), 7.21–7.15 (m, 1 H), 5.53 (td, J = 17.39, 9.82 Hz, 1 H), 5.05–4.93
(m, 3 H), 4.86–4.81 (m, 1 H), 4.60–4.54 (m, 2 H), 3.80–3.59 (m, 4 H),
3.53 (t, J = 7.80 Hz, 1 H), 2.61–2.51 (m, 1 H), 2.45 (d, J = 7.71 Hz, 1 H),
2.10–2.02 (m, 1 H), 1.61 (s, 1 H), 1.54–1.43 (m, 1 H), 1.03 (s, 9 H).
13C NMR (100 MHz, CDCl3): 138.2, 135.6, 135.5, 134.8, 133.5, 135.5,
129.8, 129.7, 129.6, 128.3, 127.8, 127.7, 127.6, 86.2, 84.3, 81.2, 73.4,
69.1, 61.6, 57.0, 45.2, 35.2, 29.7, 26.9, 26.5, 19.2, 9.8.
MS (ES+): m/z = 645.1 [M + 1].
OTBDPS
I
OTBDPS
13C NMR (100 MHz, CDCl3): 139.1, 138.1, 136.9, 135.6, 135.2, 134.8,
134.0, 133.9, 133.5, 135.6, 130.0, 129.7, 129.5, 128.4, 127.7, 127.7,
127.6, 127.6, 117.2, 74.1, 73.6, 70.5, 66.8, 61.8, 43.8, 33.0, 26.9, 26.6,
19.2, 19.0.
CH2=CHMgBr, CuI, THF
HMPA, –30 °C, 3 h
75%
O
O
BnO
BnO
MS (ES+): m/z = 663.1 [M + 1].
O
O
46
45
[((3S)-3-{(1R,2R)-3-(Benzyloxy)-2-[(2,4-dichlorobenzyl)oxy]-1-
methoxypropyl}pent-4-en-1-yl)oxy](tert-butyl)diphenylsilane
(44)
Scheme 41
(2-{(2S,3S,4R,5R)-2-Allyl-5-[(benzyloxy)methyl]-4-methoxytetra-
hydrofuran-3-yl}ethoxy)(tert-butyl)diphenylsilane (46)
Alcohol 42.3 (2.5 g, 4.7 mmol) was dissolved in DMF (20 mL), and NaH
(177 mg, 0.177 mmol) was added slowly at 0 °C. MeI was added at 0
°C and, after 1 h, the reaction was quenched with H2O. The mixture
was extracted with EtOAc (3 × 20 mL), and the combined organic lay-
ers were dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by column chromatography (hexanes–
EtOAc, 9.5:0.5) to give a colorless oil; yield: 1.8 g (50%, 3 steps); mo-
lecular formula: C39H46Cl2O4Si; Rf = 0.6 (hexanes–EtOAc, 9:1).
1H NMR (400 MHz, CDCl3): δ = 7.71–7.67 (m, 5 H), 7.45–7.27 (m, 12
H), 7.17–7.11 (m, 1 H), 5.56 (td, J = 17.08, 9.58 Hz, 1 H), 5.00–4.93 (m,
2 H), 4.86 (q, J = 10.21 Hz, 2 H), 4.55 (s, 2 H), 3.75–3.57 (m, 5 H), 3.42
(s, 3 H), 3.25 (dd, J = 7.57, 1.83 Hz, 1 H), 2.68 (dt, J = 10.09, 2.06 Hz, 1
H), 2.04–1.93 (m, 1 H), 1.52–1.41 (m, 1 H), 1.04 (s, 9 H).
To a stirred solution of iodide 45 (500 mg, 0.793 mmol) in anhyd THF
(5 mL) were added CuI (75 mg, 0.396 mmol) and HMPA (1.41 mL, 7.93
mmol) at 23 °C. The mixture was cooled to –30 °C and CH2=CHMgCl
(2.4 mL, 2.4 mmol) was added dropwise. The reaction mixture was
stirred for 3 h at –30 °C, and then the reaction was quenched with sat.
aq NH4Cl. The mixture was extracted with EtOAc (3 × 20 mL), and the
combined organic layers were dried (Na2SO4) and concentrated under
reduced pressure. The residue was purified by column chromatogra-
phy (hexanes–EtOAc, 7:3) to give a colorless oil; yield: 320 mg (75%);
molecular formula: C34H44O4Si; Rf = 0.3 (hexanes–EtOAc, 9.5:0.5).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U

R
S. Konda et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 6.68 Hz, 4 H), 7.43–7.28 (m,
11 H), 5.69–5.57 (m, 1 H), 5.08–5.01 (m, 2 H), 4.55 (s, 2 H), 3.92–3.85
(m, 1 H), 3.77–3.69 (m, 2 H), 3.65 (m, 2 H), 3.57–3.49 (m, 2 H), 3.44 (s,
3 H), 3.17 (dd, J = 6.80, 2.64 Hz, 1 H), 2.68–2.61 (m, 1 H), 2.38–2.35
(m, 1 H), 1.56–1.44 (m, 1 H), 1.98–1.88 (m, 1 H), 1.07 (s, 9 H).
2-{(2S,3S,4R,5R)-2-Allyl-5-[(benzyloxy)methyl]-4-methoxytetra-
hydrofuran-3-yl}ethyl (2S)-2-{[(Allyloxy)carbonyl]amino}-3-
phenylpropanoate (46.2)
Colorless oil; yield: 92 mg (85%); molecular formula: C31H39NO7;
Rf = 0.5 (hexanes–EtOAc, 7:3).
13C NMR (100 MHz, CDCl3): 134.1, 133.3, 130.8, 129.2, 124.8, 123.7,
123.0, 123.0, 122.8, 112.3, 78.5, 68.6, 66.9, 65.4, 57.1, 55.5, 37.5, 28.0,
22.2, 22.1, 14.5.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.23 (m, 8 H), 7.12 (d, J = 6.79 Hz,
2 H), 5.93–5.83 (m, 1 H), 5.59–5.46 (m, 1 H), 5.32–5.03 (m, 6 H), 4.66–
4.50 (m, 6 H), 4.23–4.17 (m, 1 H), 4.08–4.01 (m, 1 H), 3.68 (dd,
J = 9.95, 5.29 Hz, 1 H), 3.60 (dd, J = 9.96, 4.76 Hz, 1 H), 3.46–3.41 (m, 4
H), 3.10 (dq, J = 13.95, 6.01 Hz, 2 H), 2.49 (d, J = 7.42 Hz, 1 H), 2.38 (dq,
J = 10.68, 10.48, 3.09 Hz, 1 H), 2.22–2.11 (m, 1 H), 1.79 (br s, 1 H),
1.56–1.47 (m, 1 H).
MS (ES+): m/z = 544.8 [M + 1].
Synthesis of Macrocycles 46.2.1–46.5.1
13C NMR (100 MHz, CDCl3): δ = 171.5, 155.5, 138.3, 137.9, 135.8,
132.6, 129.3, 128.6, 128.4, 127.8, 127.8, 127.7, 127.1, 118.1, 117.8,
78.6, 74.3, 73.6, 69.9, 65.8, 64.0, 58.4, 54.8, 44.9, 38.2, 29.2.
MeO
MeO
TBAF
THF
r.t., 3 h
OTBDPS
OH
BnO
BnO
O
O
85%
MS (ES+): m/z = 538.1 [M + 1].
46
Scheme 42
46.1
2-{(2S,3S,4R,5R)-2-Allyl-5-[(benzyloxy)methyl]-4-methoxytetra-
hydrofuran-3-yl}ethyl (2S)-2-{[(allyloxy)carbonyl]amino}-4-
methylpentanoate (46.3)
2-{(2S,3S,4R,5R)-2-Allyl-5-[(benzyloxy)methyl]-4-methoxytetra-
hydrofuran-3-yl}ethanol (46.1)
Colorless oil; yield: 57.8 mg (88%); molecular formula: C28H41NO7;
To a stirred solution of silyl ether 46 (500 mg) in THF (50 mL) was
added TBAF (2 equiv), and the mixture was stirred for 3 h at r.t. until
the starting material was completely consumed. The mixture was
concentrated under reduced pressure, and the residue was purified
by column chromatography (hexanes–EtOAc, 5:5) to give a colorless
oil; yield: 245 mg (85%); molecular formula: C18H26O4; Rf = 0.5 (hex-
anes–EtOAc, 5:5).
1H NMR (400 MHz, CDCl3): δ = 7.38–7.27 (m, 5 H), 5.71–5.59 (m, 1 H),
5.10–5.08 (m, 2 H), 4.58–4.49 (m, 2 H), 3.71–3.64 (m, 1 H), 3.64–3.53
(m, 3 H), 3.49–3.43 (m, 4 H), 3.41 (s, 3 H), 3.18 (dd, J = 7.98, 3.05 Hz, 1
H), 2.62–2.53 (m, 1 H), 1.97–1.86 (m, 2 H), 1.57–1.46 (m, 1 H).
Rf = 0.4 (hexanes–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): δ = 7.38–7.27 (m, 5 H), 5.90 (ddd,
J = 22.68, 10.81, 5.61 Hz, 1 H), 5.56 (td, J = 17.13, 9.94 Hz, 1 H), 5.34–
5.25 (m, 1 H), 5.21–5.01 (m, 4 H), 4.58–4.52 (m, 4 H), 4.35 (dt, J = 8.86,
5.33 Hz, 1 H), 4.20–4.15 (m, 1 H), 4.07–3.98 (m, 1 H), 3.66–3.57 (m, 2
H), 3.48–3.41 (m, 4 H), 3.40 (s, 3 H), 3.16 (dd, J = 8.35, 2.50 Hz, 1 H),
2.56 (dt, J = 11.30, 3.00 Hz, 1 H), 2.12–2.02 (m, 1 H), 1.74–1.46 (m, 4
H), 0.94–0.92 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 173.1, 155.8, 138.5, 138.0, 132.6,
128.4, 127.7, 117.7, 117.7, 83.3, 79.8, 73.4, 68.8, 65.7, 63.9, 60.8, 58.8,
52.5, 43.1, 41.9, 28.8, 24.7, 22.8, 21.9.
13C NMR (100 MHz, CDCl3): δ = 139.4, 137.9, 128.4, 127.7, 117.0, 78.9,
74.5, 73.5, 71.5, 70.0, 60.9, 58.4, 45.2, 34.2.
MS (ES+): m/z = 504.3 [M + 1].
MS (ES+): m/z = 307.1 [M + 1].
2-{(2S,3S,4R,5R)-2-Allyl-5-[(benzyloxy)methyl]-4-methoxytetra-
hydrofuran-3-yl}ethyl 2-(2S)-{[(Allyloxy)carbonyl]amino}-3-
methylpentanoate (46.4)
Dienes 46.2–46.5; General Procedure
To a stirred solution of alcohol 46.1 (60 mg, 0.196 mmol, 1 equiv) in
CH2Cl2 (30 mL) were added EDCI (0.392 mmol, 2 equiv), DMAP (0.392
mmol, 2 equiv), and the appropriate N-allyloxycarbonyl amino acid
(0.392 mmol, 2 equiv). The mixture was stirred for 3 h at r.t. until all
the starting material was consumed. The reaction was then quenched
with H2O and the mixture was extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were concentrated under reduced pressure,
and the residue was purified by column chromatography (hexanes–
EtOAc, 7:3).
Colorless oil; yield: 48.4 mg (82%); molecular formula: C28H41NO7;
Rf = 0.45 (hexanes–EtOAc, 7:3).
1H NMR (100 MHz, CDCl3): δ = 7.37–7.26 (m, 5 H), 5.90 (ddd, J =
22.71, 10.88, 5.64 Hz, 1 H), 5.52 (dt, J = 19.80, 6.80 Hz, 1 H), 5.35–5.25
(m, 2 H), 5.24–5.02 (m, 4 H), 4.59–4.51 (m, 5 H), 4.31–427 (m, 1 H),
4.21–4.16 (m, 2 H), 4.10–4.04 (m, 1 H), 3.67 (dd, J = 9.94, 5.29 Hz, 1 H),
R1
MeO
MeO
OH
O
BnO
BnO
NH
EDCI, DMAP, CH2Cl2, N-Alloc-AA
O
O
O
O
O
r.t., 3 h, 80–90%
46.1
46.2 R1 = benzyl
46.3 R1 = isobutyl
46.4 R1 = 2-butyl
46.5 R1 = 2-propyl
Scheme 43
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U

S
S. Konda et al.
Special Topic
Synthesis
R1
O
trans olefin only!
R1
O
MeO
O
O
BnO
G-II, CH2Cl2
40 °C, 16 h
NH
NH
MeO
H
O
O
O
O
32
30
O
70–75%
29
O
H
BnO
46.2–46.5
46.2.1 R1 = benzyl
46.3.1 R1 = isobutyl
46.4.1 R1 = 2-butyl
46.5.1 R1 = 2-propyl
Scheme 44
3.60 (dd, J = 9.94, 4.79 Hz, 1 H), 3.46–3.40 (m, 5 H), 2.47 (d, J = 7.76 Hz,
1 H), 2.44–2.35 (m, 1 H), 2.27–2.16 (m, 1 H), 1.58–1.47 (m, 1 H), 1.44–
1.37 (m, 1 H), 1.21–1.11 (m, 1 H), 0.92–0.88 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 172.0, 155.9, 138.3, 137.9, 132.7,
128.4, 127.8, 127.8, 127.7, 127.6, 118.1, 117.8, 78.6, 74.2, 73.6, 69.9,
65.8, 63.7, 58.4, 44.9, 38.0, 29.2, 24.9, 15.4, 11.6.
13C NMR (100 MHz, CDCl3): δ = 171.5, 155.4, 137.9, 135.7, 129.3,
129.2, 128.7, 128.6, 128.5, 128.4, 128.4, 128.3, 128.1, 127.8, 127.8,
127.7, 127.1, 118.1, 82.8, 73.4, 71.5, 69.9, 64.6, 63.9, 60.8, 54.7, 43.2,
38.3, 29.7, 29.7, 28.8.
MS (ES+): m/z = 510.3 [M + 1].
(2R,3R,3aS,8S)-2-[(Benzyloxy)methyl]-8-isobutyl-3-methoxy-
2,3,3a,4,5,8,9,12,15,15a-decahydrofuro[3,2-i][1,6,3]dioxazacyclo-
tetradecine-7,10-dione (46.3.1)
MS (ES+): m/z = 504.1 [M + 1].
2-{(2S,3S,4R,5R)-2-Allyl-5-[(benzyloxy)methyl]-4-methoxytetra-
hydrofuran-3-yl}ethyl (2S)-2-{[(Allyloxy)carbonyl]amino}-3-
methylbutanoate (46.5)
Colorless oil; yield: 23.1 mg (82%); molecular formula:
C26H37NO7;
Rf = 0.4 (hexanes–EtOAc, 5:5).
Colorless oil; yield: 34.4 mg (86%); molecular formula: C27H39NO7;
Rf = 0.5 (hexanes–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): δ = 7.39–7.28 (m, 5 H), 5.86–5.64 (m, 2 H),
4.90–4.64 (m, 2 H), 4.53 (s, 2 H), 4.25–4.09 (m, 2 H), 3.73–3.54 (m, 4
H), 3.46–3.37 (m, 8 H), 3.17–3.08 (m, 1 H), 2.67–2.54 (m, 1 H), 2.07–
2.00 (m, 1 H), 1.80–1.55 (m, 3 H), 0.95–0.90 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 170.4, 141.5, 137.9, 128.4, 127.8,
127.8, 125.0, 110.0, 82.4, 82.4, 73.5, 68.8, 61.1, 58.9, 54.3, 45.8, 29.7,
24.8.
1H NMR (400 MHz, CDCl3): δ = 7.37–7.25 (m, 5 H), 5.90 (qd, J = 10.79,
5.62 Hz, 1 H), 5.57 (td, J = 17.05, 9.92 Hz, 1 H), 5.33–5.25 (m, 2 H),
5.23–5.17 (m, 1 H), 5.12–5.06 (m, 2 H), 4.59–4.50 (m, 4 H), 4.28–4.16
(m, 2 H), 4.06–4.00 (m, 1 H), 3.85 (dt, J = 6.29, 1.98 Hz, 1 H), 3.54–3.44
(m, 2 H), 3.42 (s, 3 H), 3.12 (dd, J = 7.97, 2.02 Hz, 1 H), 2.51 (dt,
J = 10.99, 3.06 Hz, 1 H), 2.27 (br s, 1 H), 2.19–2.10 (m, 1 H), 2.09–2.00
(m, 2 H), 1.60–1.50 (m, 1 H), 0.95 (d, J = 6.84 Hz, 3 H), 0.87 (d, J = 6.86
Hz, 3 H).
MS (ES+): m/z = 476.3 [M + 1].
(2R,3R,3aS,8S)-2-[(Benzyloxy)methyl]-8-sec-butyl-3-methoxy-
2,3,3a,4,5,8,9,12,15,15a-decahydrofuro[3,2-i][1,6,3]dioxazacyclo-
tetradecine-7,10-dione (46.4.1)
13C NMR (100 MHz, CDCl3): δ = 172.1, 156.1, 137.9, 132.7, 128.4,
127.8, 118.1, 117.8, 82.8, 73.4, 71.5, 69.9, 65.8, 63.6, 60.7, 58.9, 43.2,
31.3, 28.8, 19.0, 17.4.
Colorless oil; yield: 26.4 mg (72%); molecular formula: C26H37NO7;
MS (ES+): m/z = 490.2 [M + 1].
Rf = 0.4 (hexanes–EtOAc, 5:5).
1H NMR (400 MHz, CDCl3): δ = 7.36–7.27 (m, 5 H), 3.67 (dd, J = 9.93,
5.31 Hz, 1 H), 3.61 (dd, J = 9.93, 4.79 Hz, 1 H), 5.84 (br s, 1 H), 5.52 (dt,
J = 17.20, 9.60 Hz, 1 H), 5.29–5.25 (m, 1 H), 5.15–5.04 (m, 2 H), 4.56–
4.53 (m, 4 H), 4.29 (dd, J = 8.81, 4.86 Hz, 1 H), 4.22–4.16 (m, 1 H),
4.13–4.04 (m, 1 H), 3.49–3.40 (m, 3 H), 2.48–2.35 (m, 2 H), 2.27–2.18
(m, 1 H), 1.92–1.82 (m, 1 H), 1.61–1.49 (m, 5 H), 0.93–0.89 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 172.0, 155.8, 137.9, 137.9, 128.4,
128.2, 127.8, 127.8, 118.2, 82.8, 73.4, 71.5, 69.9, 64.6, 63.5, 60.7, 58.3,
43.2, 38.0, 28.8, 24.9, 15.5, 11.6.
Macrocycles 46.2.1–46.5.1; General Procedure
To a stirred solution of the appropriate diene 46.2–46.5 (85 mg) in
CH2Cl2 (100 mL) was added G-II (10 mol%). The mixture was stirred
for 16 h at 40 °C until all the material was consumed. It was then con-
centrated under reduced pressure, and the residue was purified by
column chromatography (hexanes–EtOAc, 5:5).
(2R,3R,3aS,8S)-8-Benzyl-2-[(benzyloxy)methyl]-3-methoxy-
2,3,3a,4,5,8,9,12,15,15a-decahydrofuro[3,2-i][1,6,3]dioxazacyclo-
tetradecine-7,10-dione (46.2.1)
MS (ES+): m/z = 476.1 [M + 1].
Colorless oil; yield: 24.8 mg (75%); molecular formula: C29H35NO7;
Rf = 0.5 (hexanes–EtOAc, 5:5).
(2R,3R,3aS,8S)-2-[(Benzyloxy)methyl]-8-isopropyl-3-methoxy-
2,3,3a,4,5,8,9,12,15,15a-decahydrofuro[3,2-i][1,6,3]dioxazacyclo-
tetradecine-7,10-dione (46.5.1)
1H NMR (400 MHz, CDCl3): δ = 7.38–7.25 (m, 8 H), 7.15–7.10 (m, 2 H),
5.77 (br s, 1 H), 5.57 (dt, J = 17.2, 10.0 Hz, 1 H), 5.28–5.20 (m, 1 H),
5.12–5.06 (m, 2 H), 4.65–4.57 (m, 1 H), 4.54–4.50 (m, 4 H), 4.23–4.15
(m, 1 H), 4.00 (dd, J = 7.75, 2.87 Hz, 1 H), 3.88–3.81 (m, 1 H), 3.54–
3.45 (m, 2 H), 3.42 (s, 3 H), 3.14–3.02 (m, 3 H), 2.51–2.44 (m, 1 H),
2.39–2.24 (m, 1 H), 2.05–1.94 (m, 1 H), 1.57–1.48 (m, 1 H).
Colorless oil; yield: 31.4 mg (74%); molecular formula: C25H35NO7;
Rf = 0.5 (hexanes–EtOAc, 5:5).
1H NMR (400 MHz, CDCl3): δ = 7.37–7.26 (m, 5 H), 5.84 (br s, 1 H),
5.57 (td, J = 17.09, 9.92 Hz, 1 H), 5.28 (d, J = 7.57 Hz, 1 H), 5.15–5.06
(m, 2 H), 4.63–4.49 (m, 4 H), 4.29–4.15 (m, 2 H), 4.04 (td, J = 10.70,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U

T
S. Konda et al.
Special Topic
Synthesis
R1
O
R1
O
O
O
NH
NH
MeO
MeO
H
H
O
Pd/C, H2, EtOAc
65%
O
32
O
O
30
32
30
29
29
O
BnO
O
HO
H
H
46.4.1 - R1 = 2-butyl
51a - R1 = 2-butyl
46.5.1 - R1 = 2-propyl
51b - R1 = 2-propyl
Scheme 45
8.39 Hz, 1 H), 3.88–3.84 (m, 1 H), 3.54–3.45 (m, 2 H), 3.44 (s, 3 H),
3.13 (dd, J = 7.93, 1.74 Hz, 1 H), 2.51 (dt, J = 10.84, 3.05 Hz, 1 H), 2.20–
1.99 (m, 3 H), 1.60–1.50 (m, 1 H), 0.87 (d, J = 6.76 Hz, 3 H), 0.95 (d,
J = 6.82 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 172.0, 156.0, 137.8, 128.4, 127.8,
118.2, 82.8, 73.4, 71.5, 69.9, 64.6, 63.6, 60.8, 59.0, 43.2, 31.3, 29.7,
28.8, 19.0, 17.5.
Fellowships. DRILS analytical facility is thanked for providing excel-
lent technical support.
References
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(2R,3R,3aS)-8-sec-Butyl-2-(hydroxymethyl)-3-methoxydodecahy-
drofuro[3,2-i][1,6,3]dioxazacyclotetradecine-7,10-dione (51a)
Colorless oil; yield: 15.5 mg (65%); molecular formula: C19H33NO7;
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2 H), 4.15–4.04 (m, 3 H), 3.67–3.64 (m, 2 H), 3.57–3.52 (m, 1 H), 3.48
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3.72–3.63 (m, 2 H), 3.59–3.52 (m, 1 H), 3.48 (s, 3 H), 3.19–3.17 (m, 1
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We thank DST India, DBT India, and DRILS for financial support. S.K.,
M.K. and N.K.M. thank UGC, and CSIR for the award of Senior Research
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Special Topic
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–U