Asymmetric syntheses and applications of planar chiral hypervalent iodine(V) reagents with crown ether backbones

Article abstract of DOI:10.1016/j.tet.2019.06.008

Novel optically active hypervalent iodine(V) reagents with planar chiral crown ether backbones were synthesized using the intramolecular Huisgen reaction as a key step and L-methyl lactate as the source of chirality. The relative configurations of these r

Full text of DOI:10.1016/j.tet.2019.06.008

Accepted Manuscript
Asymmetric syntheses and applications of planar chiral hypervalent iodine(V)
reagents with crown ether backbones
Yasushi Yoshida, Yuto Kanashima, Takashi Mino, Masami Sakamoto
PII:
S0040-4020(19)30648-9
https://doi.org/10.1016/j.tet.2019.06.008
TET 30400
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 May 2019
Revised Date: 31 May 2019
Accepted Date: 4 June 2019
Please cite this article as: Yoshida Y, Kanashima Y, Mino T, Sakamoto M, Asymmetric syntheses and
applications of planar chiral hypervalent iodine(V) reagents with crown ether backbones, Tetrahedron
(2019), doi: https://doi.org/10.1016/j.tet.2019.06.008.
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ACCEPTED MANUSCRIPT
Asymmetric syntheses and applications of
Leave this area blank for abstract info.
planar chiral hypervalent iodine(V) reagents
with crown ether backbones
Yasushi Yoshida,* Yuto Kanashima, Takashi Mino, Masami Sakamoto
Molecular Chirality Research Center, Graduate School of Engineering
Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba-shi, Chiba 263-8522 (Japan)

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Asymmetric syntheses and applications of planar chiral hypervalent iodine(V)
reagents with crown ether backbones
Yasushi Yoshida,* Yuto Kanashima, Takashi Mino, Masami Sakamoto
Molecular Chirality Research Center, Graduate School of Engineering
Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba-shi, Chiba 263-8522 (Japan)
ARTICLE INFO
ABSTRACT
Article history:
Received
Novel optically active hypervalent iodine(V) reagents with planar chiral crown ether backbones
were synthesized using the intramolecular Huisgen reaction as a key step and -methyl lactate as
L
Received in revised form
Accepted
Available online
the source of chirality. The relative configurations of these reagents and stabilities of planar
chiralities were determined by DFT calculations. These planar chiral reagents were applied to
the hydroxylative dearomatization/[4+2]-dimerization reactions of phenols to afford bisthymol
and biscarvacrol, a natural product, with moderate enantioselectivities.
Keywords:
2009 Elsevier Ltd. All rights reserved
.
Hypervalent iodine reagent
Planar chirality
Crown ether
Oxidation
DFT calculations
1. Introduction
developed an easy-to-synthesize lactic-acid-derived novel chiral
hypervalent iodine(V) reagent 8, which was applied to the
asymmetric oxidative dearomatization of substituted phenol
derivatives in combination with TFAA to give the dimerized
products in up to 58% ee (Scheme 1).5f Despite the above-
mentioned excellent examples, a new type of hypervalent
iodine(V) reagent that delivers high product enantioselectivity
and shows wide substrate scope needs to be developed.
Chiral hypervalent iodine reagents have been studied because
they can mediate characteristic molecular transformations
enantioselectively (Figure 1).1-3 In 2008, Kita et al. developed a
chiral hypervalent iodine(III) reagent with a spiro skeleton 1,
which oxidatively spirolactonized 1-naphthol derivatives with
enantioselectivities of up to 86% ee.2d In 2010, Ishihara, Uyanik
et al. reported the first highly enantioselective catalytic Kita
Over the past few decades, planar chiral catalyst have been
reported to show high asymmetric inducing abilities (Figure 2).6,7
In 1997, Fu and co-workers developed a nucleophilic catalyst 9
based on a planar chiral ferrocene unit, which was applied to
kinetically resolve secondary alcohols through the formation of
acylated products in up to 99.7% ee (up to s = 52).6a,7a,7b
Following their report, planar chirality has been used in the
design of asymmetric catalysis to the present date. Recently, Lu,
Zheng, and co-workers reported the syntheses and applications
spirolactonization by employing
a lactic-acid-derived C2-
symmetric chiral iodoarene 2b with mCPBA as the
stoichiometric co-oxidant, which provided the corresponding
products in up to 92% ee.3a Following their elegant publication,
the catalytic use of chiral hypervalent iodine(III) reagents was
expanded to include diamination,2g aminofluorination,2h
spirocyclization,3c,3d,3i,3k intramolecular double carbon-carbon
bond
formation,3e fluorination,3f-3h
and
hydroxylative
dearomatization.3m
of the first planar chiral iodoarene 13 bearing
a
Hypervalent iodine(V) reagents are interesting chemical
species because they can mediate characteristic transformations.4
Chiral hypervalent iodine(V) reagent have also been studied;
however, few successful examples have been reported.5 In 2014,
Pouységu, Quideau, and co-workers reported the first highly
enantioselective chiral hypervalent iodine(V)-mediated oxidative
dearomatization/dimerization reactions of substituted phenol
derivatives, which produced ortho-quinol-based [4+2]
cyclodimers in up to 94% ee when a bulky substituent was
present in the ortho position (Scheme 1).5e Subsequently, they
also developed a novel salen-type chiral iodane that was used in
the asymmetric total synthesis of (–)-bacchopetiolone, which
was formed in high yield and up to 82% ee.5g Recently, we
[2.2]paracyclophane unit, which was employed as a hypervalent
iodine(III) precursor in the enantioselective fluorination of β-
ketoesters to form the corresponding products in up to 92% ee
(Scheme 2),7g and planar chiral crown ether units have been used
in the design of chiral metal ligands and chiral-recognition
reagents.8,9 In 1992, Sawamura, Ito, and co-workers reported the
development of a chiral ferrocene ligand with a crown ether
moiety, which was applied to the asymmetric allylations of β-
diketones with enantioselectivities of up to 75% ee.8
Nevertheless, the applications of planar chiral catalyst remain
limited.
* Corresponding author.

2
Tetrahedron
E-mail address: yoshiday@chiba-u.jp
by Ochiai et al.10 and intermolecular hydroxy group of
ACCEPTED MANUSCRIPT
substrate,11 which constructs an efficient asymmetric
environment around the prochiral molecules. The construction of
the macrocycle is achieved through the Huisgen reaction12,13 as a
key step; these reagents were then used in the asymmetric
oxidative dearomatization reactions of phenol derivatives.
2. Results and discussion
The retrosyntheses of the planar chiral hypervalent iodine(V)
reagents are shown in Scheme 4. In this scheme, ester 19 is
enantiospecifically formed from 2-iodoresorcinol (21) and
optically pure (S)-methyl lactate using the Mitsunobu reaction,
after which the long polyether chain is introduced to give 17.
The azide and alkyne moieties are then installed to form the
Huisgen reaction precursor 16, which is cyclized using the
Huisgen reaction to generate the planar chiral iodoarene 15.
After separating both regioisomers of 15 by silica-gel column
purification, they are converted into hypervalent iodine(V)
reagents 14 by oxidation with DMDO.
FIGURE 1 Examples of (a) chiral hypervalent iodine(III)
reagents and their precursors, and (b) chiral hypervalent
iodine(V) reagents.
SCHEME
1
The
asymmetric
hydroxylative
dearomatization/[4+2]-dimerization cascade reactions of phenol
derivatives mediated by chiral hypervalent iodine(V) reagents.
FIGURE 2 Planar chiral catalysts with high asymmetric
inducing abilities.
SCHEME 4 Retrosynthesis of planar chiral hypervalent
iodine(V) reagents bearing crown ether backbones.
Accordingly, a hydroxyl group of 2-iodoresorcinol (21) was
MOM-protected following the reported procedure (Scheme 5).14
Chiral ester 23 was synthesized in 92% yield by the
enantiospecific Mitsunobu reaction of 22 with the lactic-acid-
derived chiral alcohol using DIAD and PPh3. The MOM group
of 23 was then removed in 70% yield by treatment with
trifluoroacetic acid. The long polyether chain was introduced
into 19 using K2CO3 and a dichloroalkyl polyether to form the
corresponding products in 85% and 90% yields, respectively.
The reduction of the methoxycarbonyl group of 17b was next
attempted (Table 1). First, LiAlH4 was employed in THF at 0 °C
to room temperature, but only the deiodinated product was
obtained (Table 1, entry 1); hence the reaction conditions
required optimization. The iodine atom was still lost at lower
reaction temperatures (Table 1, entries 2–3), and the use of
iBu2AlH also did not give any desired product even when
conducted at –78 ºC with warming to room temperature (Table 1,
entries 4–5). The desired iodide 24b was formed in 10% yield
when NaBH4 was used in a mixed THF/MeOH solvent system.
SCHEME
2 Asymmetric fluorinations of β-ketoesters
catalyzed by a planar chiral iodine reagent bearing a
[2.2]paracyclophane unit.
SCHEME 3 Applications of planar chiral hypervalent
iodine(V) reagents with crown ether backbones (this work).
In this report, we describe the synthesis of the first planar
chiral hypervalent iodine(V) reagents with crown ether
backbones (Scheme 3). They are expected to make I(V)⋯O
interactions between intramolecular iodyl moiety early studied

3
When, the Huisgen reaction was carried out in refluxing m-
TABLE 1 Optimizing the conditions for the
A
red
C
uc
C
ti
E
on
P
o
T
f 1
ED MANUSCRIPT
7
b
xylene, the desired planar chiral iodine reagent 15a and 15a’
were obtained in 83% yield with a 3:2 regioisomeric ratio (rr)
(Table 2, entry 10).15 Compound 15b and 15b’, with the shorter
polyether chain, was also prepared in the same manner as 15a
and 15a’ in 79% yield with a 3:2 rr (Scheme 7). The
regioisomers of 15a and 15b failed to separate by column
chromatography or recrystallization; hence the regioisomeric
mixtures of chiral iodoarenes 15 were oxidized into the
corresponding hypervalent iodine(V) reagents (Scheme 8). When
15a was oxidized using dimethyldioxirane (DMDO), the chiral
hypervalent iodine(V) reagents (R)-14a and (R)-14a’ were
isolated in 32% and 23% yields, respectively; (Sp,R)-14b and
(Sp,R)-14b’ were isolated in 4% and 15% yields from 15b,
respectively, using the same method. These low yields are
ascribable to the high polarity of 14b and 14b’, which makes
their recovery from silica gel difficult.
Yield
(%)a
Entry Reductant (eq.)
Solvent (M)
THF (0.1)
Temp.
1
2
3
4
5
6
7
LiAlH4 (5.0)
LiAlH4 (10)
0 ºC to r.t. n.d.
0 ºC to r.t. n.d.
THF (0.1)
LiAlH4 (5.0)
i-Bu2AlH (5.0)
i-Bu2AlH (5.0)
NaBH4 (5.0)
NaBH4 (8.0)
THF (0.1)
−40 ºC
n.d.
n.d.
n.d.
10
−78 ºC to
0 ºC to r.t.
Toluene (0.1)
Toluene (0.1)
−78 ºC
THF/MeOH (1/1)
(0.1)
THF/MeOH (1/2)
(0.07)
0 ºC to r.t.
0 ºC to r.t.
TABLE 2 Optimizing the conditions for the Huisgen
reaction of 16a
68
aYield of isolated product.
Cu salt
(eq.)
Additive
(eq.)
Total yield
(%)a
Entry
Solvent (M)
H2O/tBuOH (1/1)
(0.025)
CuSO4 • 5H2O
(0.5)
1
2
–
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
Trace
83
CuSO4 • 5H2O NaAsc H2O/tBuOH (1/1)
(0.5)
CuSO4 • 5H2O NaAsc H2O/tBuOH (1/1)
(0.5) (0.5) (0.01)
CuSO4 • 5H2O NaAsc H2O/tBuOH (1/1)
(1.0) (1.0) (0.01)
CuSO4 • 5H2O NaAsc H2O/tBuOH (3/2)
(1.0) (1.0) (0.01)
CuSO4 • 5H2O NaAsc H2O/tBuOH/THF
(1.0)
CuSO4 • 5H2O NaAsc
(1.0) (1.0)
CuSO4 • 5H2O NaAsc
(0.5)
(0.025)
SCHEME 5 Synthesis of chiral polyethers 17.
3
4
5
6
(1.0)
(3/2/1) (0.01)
7
DMF (0.01)
8
DMF (0.005)
Toluene (0.01)
m-Xylene (0.01)
(0.2)
(0.4)
SCHEME 6 Syntheses of Huisgen reaction precursors 16.
9b
10b
–
–
The reaction was finally carried out with 8.0 equivalents of 0.07
M NaBH4 in 1:2 THF/MeOH to give 24b in 68% yield (Scheme
6). In the same manner, 24a was synthesized in 71% yield. The
azide group was next introduced into 24 with NaN3 in DMF to
give 25a and 25b in 97% and 96% isolated yields, respectively,
after which they were treated with propargyl bromide under
basic condition in THF to afford the Huisgen reaction precursors
16a and 16b in 91% and 79% yields, respectively.
–
–
aYield of 15a and 15a’ mixture after chromatographic
purification. No isolable amount of diastereomers were
observed.
bThe reaction was carried out under reflux.
With the planar chiral precursors in hand, we used 16a to
optimize the conditions for the intramolecular Huisgen reaction
(Table 2). Typical conditions using a copper salt in a mixed
H2O/tBuOH solvent system were first employed (Table 2, entries
1–8),13a which resulted in full conversion but none of the desired
product, which is due to loss of the iodine atom regardless of the
presence or absence of the sodium L-ascorbate (NaAsc) ligand.
A trace amount of the desired product was detected, but with low
substrate conversion, when the same reaction was conducted in
refluxing toluene in the absence of a catalyst (Table 2, entry 9).

4
Tetrahedron
backbones have enough high epimerization barrier for their
SCHEME 7 Huisgen reactions of 16.
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planar chiralities, although, 15a and 15a’ with larger crown ether
backbones have smaller epimerization barrier. From above
calculations, we concluded 15b and 15b’ can keep their planar
chiralties stably, on the other hand, the planar chirality of 15a
and 15a' is not fixed even at room temperature. Because no
1
changes were observed on H-NMR analyses of recovered 15b
and 15b’ after the oxidation reaction shown in Scheme 10, the
hypervalent iodine(V) reagent 14 are found to have the same
stereochemistry to 15.19
SCHEME 8 Synthesis of chiral hypervalent iodine(V)
reagents 14.
We next investigated the oxidation state of 14 (Figure 3).
According to Katritzky and co-workers, the oxidation state of an
iodine atom can be determined by comparing the 13C-NMR
chemical shift of its aromatic ipso-carbon atom (Cipso-IIII or -IV)
with that prior to oxidation.16 From their report, the 13C-NMR
chemical shift of the ipso-carbon atom of an I(III) species is
shifted by around 15 ppm to lower field compared to that of the
corresponding I(I) compound, and around 50 ppm for an I(V)
compound. In the present case, although the corresponding I(I)
species (R)-15a could not be isolated, the Cipso-I 13C-NMR
chemical shift of (R)-14a is similar to that previously reported
for the I(V) reagent 26, which indicates that the oxidation state
of the iodine in (R)-14a is five.
FIGURE 4 Calculational results for the diastereomers of 15.
Basic structure of (Rp,R)-15a’ Transition structure of 15a’
0 kcal mol-1
+8.9 kcal mol-1
FIGURE 3 Oxidation state determination of 14a.
Attempts to determine the absolute configuration of the chiral
iodine(V) reagents by single-crystal X-ray crystallography failed
because of their low crystallinities. Consequently, we calculated
the total free energies of both diastereomers of 15 to determine
which isomer is preferred. Accordingly, we optimized the
geometries of both diastereomers of 15 by DFT calculation at the
M05-2X/6-31G* level of theory (LANL2DZ17 basis set for the
iodine atom) in toluene using Gaussian 1618 (Figure 4); these
calculations reveal that (Rp,R)-15a is 0.15 kcal mol–1 more stable
than (Sp,R)-15a in total free energy. Therefore, we conclude that
the major diastereomer produced during the stereoselective
Huisgen reaction of 16a is (Rp,R)-15a, with the minor
diastereomer being (Sp,R)-15a. The same DFT method was also
applied to 15a’, 15b, and 15b’, which revealed the different
selectivity to that of 15a. This reason seems to be the decrease of
steric repulsion of methyl group on its asymmetric center with
crown ether moiety compared with highly flexible 15a.
Additionally, we have calculated for the transition state
structures at the epimerization of 15a’ and 15b’ by scanning
their dihedral angles, which results are summarized in Figure 5.
These results suggest 15b and 15b’ with smaller crown ether
Basic structure of (Sp,R)-15b’
Transition structure of 15b’
0 kcal mol-1
+32.7 kcal mol-1
FIGURE 5 Calculational results for the transition structures
of 15’.
With the planar-chiral hypervalent iodine(V) reagents in
hand, we applied them to the asymmetric oxidation-dimerization
reactions of substituted phenol derivatives (Schemes 9 and 10),
with carvacrol (27) employed as the first example (Scheme 9).
The oxidation-dimerization reaction of 27 proceeded to form
dimer 28, a natural product isolated from callitris macleayana,20

5
in 84% yield and 14% ee when (R)-14a (bearing the longer
ACCEPTED MANUSCRIPT
polyether chain) was used with trifluoroacetic anhydride (TFAA)
in dichloromethane at low temperature; 28 was obtained in 53%
yield and 9% ee when (R)-14a’ was used in this reaction. This
result suggests that the 14a with larger crown ether backbone
constructs a more-efficient asymmetric environment than the
14a’.
We next examined the use of the planar chiral hypervalent
iodine(V) reagent 14b, which possesses the smaller ether ring. In
both cases, the yields of 28 were lower with 14b than 14a, which
may be ascribable to the low activity associated with the
sterically bulky ether ring. On the other hand, the ee of 28 was
the highest (35% ee) when (Sp,R)-14b’ was used, which suggests
that the smaller ether ring more efficiently blocks the chiral face
that leads to the formation of the minor enantiomer of 28.
SCHEME 10 Asymmetric hydroxylative
dearomatization/[4+2]-dimerizations of thymol (29).
Finally, we present a plausible reaction mechanism for the
present transformations (Figure 6). First, the hypervalent iodine
moiety is activated by TFAA to form A,21 which is then
nucleophilically attacked by the phenol derivative to form C.
The oxonium moiety of C is deprotonated to form D, which
undergoes intramolecular asymmetric oxidation to form E. The
removal of the iodine reagent then produces ortho-quinol F that
is dimerized through a stereospecific [4+2] cycloaddition
reaction to give the corresponding product 28.4h
SCHEME 9 Asymmetric hydroxylative
dearomatization/[4+2]-dimerizations of carvacrol (27).
Because our chiral reagents were found to promote the
oxidation-dimerization reaction of carvacrol, they were applied
to the oxidation of thymol (29), which is a regioisomer of
carvacrol (Scheme 10). Previously, we applied the chiral-lactic-
acid-derived hypervalent iodine(V) reagent (R,R)-26 to the
present reaction, with no success;5f when (R)-14a was used under
the same conditions to oxidize carvacrol, the desired product was
obtained in 50% yield with 19% ee. This result shows that 14 is
more reactive than the previously reported reagent. Although the
planar chiral hypervalent iodide (Sp,R)-14b with the longer ether
chain provided 30 in 5% ee, both (R)-14a’ and (Sp,R)-14b gave
only low yields of racemic product.
To determine the importance of planar chirality in the
hypervalent iodine(V) reagent 14, we synthesized the non-planar
chiral reagent (R)-14c and compared its reactivity with those of
14a and 14b (Schemes 9 and 10). Accordingly, chiral ester 17b
was oxidized in 49% yield to the hypervalent iodine(V) reagent
(R)-14c by DMDO, which was then used to oxidize carvacrol
(27) and thymol (29). Although, (R)-14c was able to oxidize both
substrates under the optimized condition, biscarvacrol (28) and
bisthymol (30) were obtained in 46% yield with 24% ee, and
15% yield with racemate, respectively. These yields and
enantioselectivities are lower than those mediated by planar
chiral reagents 14a and 14b. On the basis of these observations,
we conclude that the planar chirality of 14 assist its high
reactivity and enantiofacial discriminating ability.
FIGURE 6 Plausible reaction mechanism.
A
plausible mechanism that explains the asymmetric
induction in the present transformation is shown in Figure 7.
When carvacrol (27) was oxidized by our reagent, the highest
enantioselectivity was observed using (Sp,R)-14b’, which
contains a 16-membered ether ring; i.e., the smaller ring-
containing reagent produced the product in higher
enantioselectivity. The smaller crown ether ring appears to
hydrogen bond more efficiently to the intramolecular iodyl
moiety and hydroxy group of the substrate than the larger ring
molecule, which makes the better asymmetric environment

6
Tetrahedron
ACCEPTED MANUSCRIPT
around the prochiral carbon atom.11 On the other hand, for the
To a stirred solution of 2-iodoresorcinol (21) (670 mg, 2.84
asymmetric oxidation of thymol (29), the 22-membered-ring-
containing planar chiral reagent afforded better
mmol, 1.0 equiv) and K2CO3 (510 mg, 3.69 mmol, 1.3 equiv) in
acetone (7 mL) at room temperature was added MOMCl (0.28
mL, 3.41 mmol, 1.2 equiv) and the resulting mixture was stirred
at the same temperature for 24 h. The reaction was quenched by
addition of H2O and extracted with EtOAc, dried over Na2SO4.
After filtration and evaporation of the solvent under reduced
pressure, the residue was purified by flash column
chromatography (silica gel, hexane:EtOAc = 3:1, v/v) to give
phenol 22 (278 mg, 0.994 mmol, 35% yield). The spectral data
was matched with the reported value.23
enantioselectivity, which is ascribable to the larger degree of
steric repulsion between with the bulky isopropyl group at the
ortho-position of thymol and (Sp,R)-14b with the smaller ring
than with (R)-14a; hence, (R)-14a can efficiently transfer its
asymmetric information.
Methyl (R)-2-(2-iodo-3-(methoxymethoxy)phenoxy)propanoate
(23)
To a stirred solution of 22 (4.40 g, 15.7 mmol, 1.0 equiv), Ph3P
(4.93 g, 18.8 mmol, 1.2 equiv), and methyl L-(–)-lactate (1.80 g,
17.2 mmol, 1.1 equiv) in THF (78 mL) at 0 ºC was added DIAD
(1.9 M toluene solution, 10.7 mL, 20.3 mmol, 1.3 equiv) and the
resulting mixture was stirred at the room temperature for 72 h.
After evaporation of the solvent under reduced pressure, the
residue was purified by flash column chromatography (silica gel,
hexane:EtOAc = 3:1, v/v) to give chiral ester 23 (5.29 g, 14.5
mmol, 92% yield).
FIGURE 7 Plausible asymmetric induction mechanism for the
asymmetric oxidation of carvacrol (27).
3. Conclusion
In conclusion, we developed the first planar chiral
hypervalent iodine(V) reagents with crown ether backbones. The
macrocycles were constructed using the Huisgen reaction as a
key step. The stereochemistries of the planar chiral reagents were
determined on the basis of DFT calculation of the Huisgen
adducts, which revealed 14b and 14b’ with smaller crown ether
backbone had planar chirality stably. These reagents were
applied to the asymmetric oxidative dearomatizations of phenol
derivatives, which revealed that the prepared hypervalent iodides
are potential asymmetric induction reagents. Further
investigations into the applications of planar chiral crown ether
skeletons to chiral catalyst are currently underway.
Colorless solid, Mp 45-47ºC; 1H-NMR (400 MHz,
CHLOROFORM-D) δ 7.18 (t, J = 8.3 Hz, 1H), 6.74 (dd, J = 8.3,
1.0 Hz, 1H), 6.39 (dd, J = 8.3, 1.0 Hz, 1H), 5.26 (d, J = 7.0 Hz,
1H), 5.24 (d, J = 7.0 Hz, 1H), 4.78 (q, J = 6.8 Hz, 1H), 3.76 (s,
3H), 3.51 (s, 3H), 1.71 (d, J = 6.8 Hz, 3H); 13C-NMR (101 MHz,
CHLOROFORM-D) δ 172.16, 157.97, 157.66, 129.67, 108.48,
106.94, 94.97, 80.64, 74.22, 56.46, 52.37, 18.61; HRMS (ESI+ in
MeCN) calcd for C12H16O5I (M+H) 367.0037 found 367.0030;
IR (KBr) 3469, 3086, 2957, 2820, 1936, 1737, 1458, 1248, 921,
638 cm-1; [α]D20 = –10.46 (c = 0.43, CHCl3).
4. Experimental section
Methyl (R)-2-(3-hydroxy-2-iodophenoxy)propanoate (19)
Instruments and materials
To a stirred solution of 23 (5.24 g, 14.3 mmol, 1.0 equiv) in
CH2Cl2 (143 mL) at 0 ºC was slowly added TFA (5.47 mL, 71.6
mmol, 5.0 equiv) and the resulting mixture was stirred at the
room temperature for 5 h. The reaction was quenched by
addition of H2O and extracted with CH2Cl2, dried over Na2SO4.
After filtration and evaporation of the solvent under reduced
pressure, the residue was purified by flash column
chromatography (silica gel, hexane:EtOAc = 4:1, v/v) to give
phenol 19 (3.23 g, 10.0 mmol, 70% yield).
1H-, 13C-NMR spectra were recorded with JEOL JMN ECS400
FT NMR, JNM ECA500 FT NMR or Bruker AVANCEIII-400M,
DPR-300 (1H-NMR 300, 400, 500 MHz, 13C-NMR 75, 100 or
1
125 MHz). H-NMR spectra are reported as follows: chemical
shift in ppm (δ) relative to the chemical shift of CHCl3 at 7.26
ppm, integration, multiplicities (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet), and coupling constants (Hz).
13C-NMR spectra reported in ppm (δ) relative to the central line
of triplet for CDCl3 at 77 ppm. ESI-MS spectra were obtained
with Thermo Fisher, Exactive. Optical rotations were measured
with JASCO P-2100 polarimeter. HPLC analyses were
performed on a JASCO HPLC system (JASCO PU-1580 pump
and UV-2075 UV/Vis detector). FT-IR spectra were recorded on
a JASCO FT-IR system (FT/IR-460 Plus). Mp was measured
with AS ONE ATM-02. Column chromatography on SiO2 and
neutral SiO2 was performed with Kanto Silica Gel 60 (40-50 ꢀm).
All reactions were carried out under Ar atmosphere unless
otherwise noted. Commercially available organic and inorganic
compounds were used without further purification. All
dehydrated solvents were purchased from Wako Pure Chemical
Industries, Ltd, and were used without further purification.
DMDO was prepared through the reported procedure.22
Colorless solid, Mp 65-67ºC; 1H-NMR (400 MHz,
CHLOROFORM-D) δ 7.13 (t, J = 8.2 Hz, 1H), 6.68 (dd, J = 8.2,
1.0 Hz, 1H), 6.24 (dd, J = 8.2, 1.0 Hz, 1H), 5.48 (s, 1H), 4.78 (q,
J = 6.8 Hz, 1H), 3.76 (s, 3H), 1.70 (d, J = 6.8 Hz, 3H); 13C-NMR
(101 MHz, CHLOROFORM-D) δ 172.01, 157.09, 156.42,
130.08, 108.64, 104.66, 79.37, 74.00, 52.41, 18.58; HRMS (ESI+
in MeCN) calcd for C10H12O4I (M+H) 322.9775 found 322.9771;
IR (KBr) 3418, 2999, 2949, 2847, 1913, 1727, 1458, 1223, 1061,
773 cm-1; [α]D20 = –24.64 (c = 0.53, CHCl3).
General procedure for the alkylation of 19.
To a stirred solution of 19 (1.0 equiv) in acetone (0.1 M) at room
temperature was added K2CO3 (3.0 equiv) and corresponding
alkyl dichloride (10.0 equiv) and the resulting mixture was
refluxed for 48 h. After filtration and evaporation of the solvent
2-Iodo-3-(methoxymethoxy)phenol (22)

7
under reduced pressure, the residue was purified by flash column
chromatography (silica gel, hexane:EtOAc = 4:1, v/v) to give
chiral ester 17. Spectroscopic data of 17a and 17b are given
below.
C H O ClI (M−H) 487.0390 found 487.0411; IR (NaCl)
17 25 6
ACCEPTED MANUSCRIPT
3453, 2873, 1586, 1461, 1296, 1252, 1092, 1019, 766, 666 cm-1;
[α]D20 = –28.35 (c = 0.58, CHCl3).
Methyl
(R)-2-(3-(2-(2-(2-(2-
(R)-2-(3-(2-(2-chloroethoxy)ethoxy)-2-iodophenoxy)propan-1-ol
(24b)
chloroethoxy)ethoxy)ethoxy)ethoxy)-2-iodophenoxy)propanoate
(17a)
Light yellow oil, 209 mg, 0.523 mmol, 68% yield
Light yellow oil, 1.16 g, 2.24 mmol, 85% yield
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.22 (t, J = 8.3 Hz,
1H), 6.56 (dd, J = 8.3, 1.0 Hz, 1H), 6.50 (dd, J = 8.3, 1.0 Hz,
1H), 4.48-4.55 (m, 1H), 4.19 (dd, J = 5.1, 4.4 Hz, 2H), 3.94-3.98
(m, 4H), 3.75-3.77 (m, 2H), 3.68 (t, J = 5.8 Hz, 2H), 2.15 (s,
1H), 1.35 (d, J = 6.3 Hz, 3H); 13C-NMR (101 MHz,
CHLOROFORM-D) δ 158.92, 157.91, 129.78, 107.62, 105.68,
80.98, 77.33, 71.96, 69.53, 69.38, 66.18, 43.03, 16.06; HRMS
(ESI− in MeCN) calcd for C13H17O4ClI (M−H) 398.9866 found
398.9878; IR (NaCl) 3433, 2931, 1585, 1455, 1377, 1247, 1088,
920, 765, 666 cm-1; [α]D20 = –37.17 (c = 1.24, CHCl3).
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.18 (t, J = 8.3 Hz,
1H), 6.51 (d, J = 8.3 Hz, 1H), 6.36 (d, J = 8.3 Hz, 1H), 4.78 (q, J
= 6.8 Hz, 1H), 4.17 (dd, J = 5.3, 4.8 Hz, 2H), 3.93 (dd, J = 6.0,
4.8 Hz, 2H), 3.82-3.84 (m, 2H), 3.74-3.77 (m, 5H), 3.68-3.71 (m,
6H), 3.62 (t, J = 5.9 Hz, 2H), 1.70 (d, J = 6.8 Hz, 3H); 13C-NMR
(101 MHz, CHLOROFORM-D) δ 172.17, 159.17, 158.04,
129.66, 106.36, 106.19, 79.93, 74.23, 71.34, 71.25, 70.80, 70.67,
70.62, 69.50, 69.37, 52.34, 42.72, 18.60 HRMS (ESI− in MeCN)
calcd for C18H25O7ClI (M−H) 515.0339 found 515.0355; IR
(NaCl) 2872, 1756, 1734, 1587, 1457, 1253, 1134, 1021, 767,
668 cm-1; [α]D20 = –10.51 (c = 1.42, CHCl3).
General procedure for the azidation of 24.
To a stirred solution of 24 (1.0 equiv) in DMF (0.1 M) at room
temperature was added NaN3 (3.0 equiv) and the resulting
mixture was stirred at 70 ºC for 24 h. The reaction was quenched
by addition of H2O and saturated NH4Cl aq. and extracted with
Et2O, dried over Na2SO4. After filtration and evaporation of the
solvent under reduced pressure, the residue was purified by flash
column chromatography (silica gel, hexane:EtOAc = 2:1, v/v) to
give chiral azide 25. Spectroscopic data of 25a and 25b are given
below.
Methyl
(R)-2-(3-(2-(2-chloroethoxy)ethoxy)-2-
iodophenoxy)propanoate (17b)
Light yellow oil, 432 mg, 1.01 mmol, 90% yield
1H-NMR (300 MHz, CHLOROFORM-D) δ 7.19 (t, J = 8.3 Hz,
1H), 6.51 (dd, J = 8.3, 0.9 Hz, 1H), 6.36 (dd, J = 8.3, 0.9 Hz,
1H), 4.78 (q, J = 6.8 Hz, 1H), 4.18 (dd, J = 5.3, 4.2 Hz, 2H),
3.95-3.99 (m, 4H), 3.75 (s, 3H), 3.68 (t, J = 5.7 Hz, 2H), 1.70 (d,
J = 6.8 Hz, 3H); 13C-NMR (101 MHz, CHLOROFORM-D) δ
172.15, 159.06, 158.06, 129.69, 106.44, 106.12, 79.89, 74.22,
71.98, 69.54, 69.45, 52.35, 43.06, 18.60; HRMS (ESI+ in MeCN)
calcd for C14H19O5ClI (M+H) 428.9960 found 428.9952; IR
(NaCl) 2952, 2873, 1755, 1587, 1463, 1252, 1210, 1134, 1021,
766 cm-1; [α]D20 = –12.84 (c = 1.29, CHCl3).
(R)-2-(3-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-
iodophenoxy)propan-1-ol (25a)
Colorless oil, 562 mg, 1.13 mmol, 97% yield
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.21 (t, J = 8.3 Hz,
1H), 6.55 (dd, J = 8.3, 1.0 Hz, 1H), 6.50 (dd, J = 8.3, 1.0 Hz,
1H), 4.48-4.55 (m, 1H), 4.18 (dd, J = 5.4, 4.4 Hz, 2H), 3.93 (dd,
J = 5.4, 4.4 Hz, 2H), 3.81-3.84 (m, 2H), 3.75-3.77 (m, 2H), 3.65-
3.72 (m, 8H), 3.37 (t, J = 5.1 Hz, 2H), 2.19 (s, 1H), 1.34 (d, J =
6.3 Hz, 3H); 13C-NMR (101 MHz, CHLOROFORM-D) δ
158.98, 157.86, 129.71, 107.50, 105.70, 80.99, 77.32, 71.18,
70.76, 70.64, 70.61, 69.97, 69.44, 69.25, 66.13, 50.63, 16.06;
HRMS (APCI+ in MeCN) calcd for C17H26O6N3I (M+) 495.0866
found 495.0864; IR (NaCl) 3446, 2925, 2871, 2108, 1586, 1457,
1252, 1092, 934, 766 cm-1; [α]D20 = –25.49 (c = 0.92, CHCl3).
General procedure for the reduction of 17.
To a stirred solution of 17 (1.0 equiv) in THF/MeOH = 1/2 (0.07
M) at 0 ºC was added NaBH4 (8.0 equiv) and the resulting
mixture was stirred at room temperature for 24 h. The reaction
was quenched by addition of H2O and extracted with EtOAc,
dried over Na2SO4. After filtration and evaporation of the solvent
under reduced pressure, the residue was purified by flash column
chromatography (silica gel, hexane:EtOAc = 3:1, v/v) to give
chiral alcohol 24. Spectroscopic data of 24a and 24b are given
below.
(R)-2-(3-(2-(2-azidoethoxy)ethoxy)-2-iodophenoxy)propan-1-ol
(25b)
(R)-2-(3-(2-(2-(2-(2-chloroethoxy)ethoxy)ethoxy)ethoxy)-2-
iodophenoxy)propan-1-ol (24a)
Colorless oil, 204 mg, 0.501 mmol, 96% yield
Light yellow oil, 673 mg, 1.38 mmol, 71% yield
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.14 (t, J = 8.3 Hz,
1H), 6.48 (dd, J = 8.3, 1.0 Hz, 1H), 6.43 (dd, J = 8.3, 1.0 Hz,
1H), 4.40-4.47 (m, 1H), 4.11 (dd, J = 5.4, 4.1 Hz, 2H), 3.87 (dd,
J = 5.4, 4.1 Hz, 2H), 3.79 (dd, J = 5.6, 4.6 Hz, 2H), 3.67-3.69
(m, 2H), 3.35 (t, J = 5.0 Hz, 2H), 2.30 (s, 1H), 1.27 (d, J = 6.3
Hz, 3H); 13C-NMR (101 MHz, CHLOROFORM-D) δ 158.85,
157.83, 129.75, 107.54, 105.63, 80.91, 77.31, 70.63, 69.46,
69.35, 66.08, 50.82, 16.01; HRMS (APCI+ in MeCN) calcd for
C13H19O4N3I (M+H) 408.0415 found 408.0409; IR (NaCl) 3420,
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.22 (t, J = 8.3 Hz,
1H), 6.55 (dd, J = 8.3, 0.9 Hz, 1H), 6.50 (dd, J = 8.3, 0.9 Hz,
1H), 4.48-4.55 (m, 1H), 4.18 (dd, J = 5.1, 4.6 Hz, 2H), 3.94 (dd,
J = 5.4, 4.6 Hz, 2H), 3.82-3.84 (m, 2H), 3.74-3.77 (m, 4H), 3.68-
3.71 (m, 6H), 3.62 (t, J = 5.9 Hz, 2H), 1.35 (d, J = 6.3 Hz, 3H);
13C-NMR (101 MHz, CHLOROFORM-D) δ 159.04, 157.90,
129.76, 107.54, 105.76, 81.05, 71.34, 71.23, 70.80, 70.67, 70.61,
69.50, 69.31, 66.20, 42.72, 16.09 (One carbon peak is
overlapped with other one); HRMS (ESI− in MeCN) calcd for

8
Tetrahedron
2931, 2871, 2108, 1586, 1457, 1252, 1092, 932, 765 cm-1;
The solution of DMDO (0.010-0.058 M in acetone) was added to
ACCEPTED MANUSCRIPT
[α]D20 = –30.56 (c = 1.30, CHCl3).
the mixture of iodoarenes 15 and 15’, which was stirred for 1 h.
After the evaporation of solvent under reduced pressure, the
residue was purified by preparative TLC (MeCN:MeOH = 3:1-
1:1).
General procedure for the propargylation of 25.
To a stirred solution of NaH (4.0 equiv) in THF (0.01 M) was
added 25 (1.0 equiv) in THF at room temperature and the
resulting mixture was cooled to 0 ºC. The mixture was added
propargyl bromide (3.0 equiv) and the resulting solution was
stirred at room temperature for 4 h. The reaction was quenched
by addition of H2O at 0 ºC and extracted with EtOAc, dried over
Na2SO4. After filtration and evaporation of the solvent under
reduced pressure, the residue was purified by flash column
chromatography (silica gel, hexane:EtOAc = 2:1, v/v) to give
Huisgen precursors 16. Spectroscopic data of 16a and 16b are
given below.
(R)-14a
Colorless oil, 97.4 mg, 0.183 mmol, 32% yield
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.57 (s, 1H), 7.42 (t,
J = 8.3 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 8.3 Hz,
1H), 5.19 (d, J = 13.6 Hz, 1H), 4.90 (d, J = 13.6 Hz, 1H), 4.55-
4.68 (m, 3H), 4.26-4.34 (m, 2H), 3.57-3.90 (m, 14H), 1.44 (d, J
= 6.3 Hz, 3H); 13C-NMR (101 MHz, CHLOROFORM-D) δ
159.06, 158.60, 135.58, 135.52, 132.43, 126.30, 109.25, 107.68,
76.61, 73.97, 70.67, 70.62, 70.52, 70.40, 70.18, 69.01, 68.56,
64.34, 46.63, 15.34
HRMS (APCI+ in MeCN) calcd for C20H29O8N3I (M+H)
566.0994 found 566.0984; IR (NaCl) 3461, 2922, 2871, 1586,
1464, 1360, 1253, 1096, 754, 664 cm-1; [α]D20 = +0.44 (c = 1.27,
CHCl3).
(R)-1-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-iodo-3-
((1-(prop-2-yn-1-yloxy)propan-2-yl)oxy)benzene (16a)
Light brown oil, 519 mg, 0.974 mmol, 91% yield
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.20 (t, J = 8.3 Hz,
1H), 6.56 (d, J = 8.3 Hz, 1H), 6.48 (dd, J = 8.3, 1.0 Hz, 1H),
4.54-4.62 (m, 1H), 4.28 (d, J = 2.4 Hz, 2H), 4.17 (dd, J = 5.4, 4.5
Hz, 2H), 3.93 (dd, J = 5.4, 4.5 Hz, 2H), 3.82-3.84 (m, 2H), 3.78
(dd, J = 10.3, 6.0 Hz, 1H), 3.65-3.72 (m, 9H), 3.38 (t, J = 5.0 Hz,
2H), 2.45 (t, J = 2.4 Hz, 1H), 1.37 (d, J = 6.3 Hz, 3H); 13C-NMR
(101 MHz, CHLOROFORM-D) δ 159.03, 158.25, 129.54,
107.58, 105.53, 80.94, 79.68, 75.31, 74.53, 72.96, 71.20, 70.79,
70.67, 70.64, 69.98, 69.47, 69.27, 58.88, 50.65, 17.11; HRMS
(APCI+ in MeCN) calcd for C20H29O6N3I (M+H) 534.1096 found
534.1094; IR (NaCl) 3284, 2930, 2869, 2109, 1586, 1457, 1251,
1099, 1019, 766 cm-1; [α]D20 = –17.05 (c = 1.38, CHCl3).
(R)-14a’
Colorless oil, 72.1 mg, 0.135 mmol, 23% yield
1H-NMR (400 MHz, CHLOROFORM-D) δ 8.33 (s, 1H), 7.36 (t,
J = 8.3 Hz, 1H), 6.67 (d, J = 8.3 Hz, 2H), 4.89 (d, J = 12.8 Hz,
1H), 4.66 (d, J = 12.8 Hz, 1H), 4.64-4.59 (m, 1H), 4.52-4.56 (m,
2H), 4.23-4.38 (m, 2H), 3.58-3.98 (m, 14H), 1.45 (d, J = 6.5 Hz,
3H); 13C-NMR (101 MHz, CHLOROFORM-D) δ 159.22,
158.14, 143.85, 135.56, 126.74, 125.89, 110.33, 108.42, 77.20,
76.90, 71.29, 70.86, 70.74, 70.34, 69.73, 69.00, 64.62, 49.89,
16.82 (One peaks are overlapped with other one); HRMS (APCI+
in MeCN) calcd for C20H29O8N3I (M+H) 566.0994 found
566.0981; IR (NaCl) 3464, 2920, 2870, 1584, 1470, 1355, 1250,
1090, 941, 774 cm-1; [α]D20 = –27.10 (c = 0.37, CHCl3).
(R)-1-(2-(2-azidoethoxy)ethoxy)-2-iodo-3-((1-(prop-2-yn-1-
yloxy)propan-2-yl)oxy)benzene (16b).
Light brown oil, 173 mg, 0.173 mmol, 79% yield
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.20 (t, J = 8.3 Hz,
1H), 6.56 (d, J = 8.3 Hz, 1H), 6.49 (dd, J = 8.3, 1.0 Hz, 1H),
4.55-4.62 (m, 1H), 4.28 (d, J = 2.4 Hz, 2H), 4.18 (dd, J = 5.1, 4.4
Hz, 2H), 3.95 (dd, J = 5.1, 4.4 Hz, 2H), 3.86-3.88 (m, 2H), 3.68-
3.80 (m, 2H), 3.42 (t, J = 5.1 Hz, 2H), 2.45 (t, J = 2.4 Hz, 1H),
1.37 (d, J = 6.3 Hz, 3H); 13C-NMR (101 MHz, CHLOROFORM-
D) δ 158.92, 158.24, 129.59, 107.64, 105.49, 80.87, 79.66,
75.29, 74.54, 72.93, 70.67, 69.51, 69.40, 58.86, 50.88, 17.09;
HRMS (APCI+ in MeCN) calcd for C16H21O4N3I (M+H)
446.0571 found 446.0572; IR (NaCl) 3288, 2931, 2869, 2109,
(Sp,R)-14b
Colorless oil, 4.94 mg, 0.0111 mmol, 4% yield
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.47 (s, 1H), 7.38 (t,
J = 8.3 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 8.3 Hz,
1H), 4.93 (d, J = 12.0 Hz, 1H), 4.69-4.77 (m, 2H), 4.38-4.43 (m,
3H), 4.27 (td, J = 10.1, 7.4 Hz, 1H), 3.96-4.05 (m, 3H), 3.81-
3.88 (m, 1H), 3.70-3.75 (m, 1H), 3.65 (d, J = 10.1 Hz, 1H), 1.46
(d, J = 6.5 Hz, 3H); 13C-NMR (101 MHz, CHLOROFORM-D) δ
160.57, 158.73, 135.58, 133.61, 133.43, 127.82, 111.39, 111.30,
78.04, 75.24, 70.94, 69.22, 68.09, 60.74, 45.74, 17.16; HRMS
(APCI+ in MeCN) calcd for C16H21O6N3I (M+H) 478.0470 found
478.0461; IR (NaCl) 3450, 2979, 2925, 2871, 1584, 1463, 1228,
1085, 1007, 758 cm-1; [α]D20 = +1.14 (c = 0.53, CHCl3).
20
1586, 1457, 1250, 1099, 1020, 764 cm-1; [α]D = –5.11 (c =
2.61, CHCl3).
General procedure for the Huisgen reaction of 16.
(Sp,R)-14b’
The solution of 16 (1.0 equiv) in m-xylene (0.01 M) was stirred
at 140 ºC for 24 h. After evaporation of the solvent under
reduced pressure, the residue was purified by flash column
chromatography (silica gel, EtOAc:MeOH = 9:1, v/v) to give the
regioisomeric mixture of planar chiral iodoarene 15a, 15a’ and
15b, 15b’ in 83% and 79% total yields, which was used next step
without further purification.
Colorless oil, 18.1 mg, 0.0407 mmol, 15% yield
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.97 (s, 1H), 7.28 (t,
J = 8.3 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 8.3 Hz,
1H), 5.05 (d, J = 12.3 Hz, 1H), 4.70 (ddd, J = 12.9, 9.2, 1.6 Hz,
1H), 4.56-4.63 (m, 1H), 4.37-4.48 (m, 4H), 4.10-4.16 (ddd, J =
12.9, 9.2, 1.6 Hz, 1H), 3.80-3.89 (m, 2H), 3.73-3.77 (m, 1H),
3.53 (dd, J = 10.8, 3.1 Hz, 1H), 3.38 (dd, J = 10.8, 3.1 Hz, 1H),
General procedure for the oxidation of 15.

9
1.50 (d, J = 6.5 Hz, 3H); 13C-NMR (101 MHz, CHLOROFORM-
D) δ 159.67, 157.38, 143.24, 135.02, 126.17, 125.10, 110.28,
108.97, 70.21, 69.67, 68.30, 66.45, 64.75, 53.40, 49.61, 17.42;
HRMS (APCI+ in MeCN) calcd for C16H21O6N3I (M+H)
478.0470 found 478.0462; IR (NaCl) 3459, 3151, 2981, 2869,
1584, 1463, 1231, 1084, 930, 764 cm-1; [α]D20 = –6.69 (c = 1.90,
CHCl3).
N.; Senami, K.; Minamitsuji, Y.; Fujioka, H.; Caemmerer, S.
ACCEPTED MANUSCRIPT
B.; Kita, Y. Angew. Chem. Int. Ed. 2008, 47, 3787–3790; e) Fujita,
M.; Yoshida, Y.; Miyata, K.; Wakisaka, A.; Sugimura, T. Angew.
Chem. Int. Ed. 2010, 49, 7068–7071; f) Fujita, M.; Wakita, M.;
Sugimura, T. Chem. Commun. 2011, 47, 3983-3985; g) Röben,
C.; Souto, J. A.; González, Y.; Lishchynskyi, A.; Muñiz, K.
Angew. Chem. Int. Ed. 2011, 50, 9478–9482; h) Kong, W.; Feige,
P.; de Haro, T.; Nevado, C. Angew. Chem. Int. Ed. 2013, 52,
2469–2473; i) Takesue, T.; Fujita, M.; Sugimura, T.; Akutsu, H.
Org. Lett. 2014, 16, 4634–4637; j) Mizar, P.; Wirth, T. Angew.
Chem. Int. Ed. 2014, 53, 5993–5997; k) Shimogaki, M.; Fujita,
M.; Sugimura, T. Molecules. 2015, 20, 17041–17057; l)
Shimogaki, M.; Fujita, M.; Sugimura, T. Angew. Chem. Int. Ed.
2016, 55, 15797–15801; m) Yoshimura, A.; Nguyen, K. C.;
Rohde, G. T.; Postnikov, P. S.; Yusubov, M. S.; Zhdankin, V. V.
J. Org. Chem. 2017, 82, 11742–11751; n) Shimogaki, M.; Fujita,
M.; Sugimura, T. J. Org. Chem. 2017, 82, 11836–11840; o)
Qurban, J.; Elsherbini, M.; Wirth, T. J. Org. Chem. 2017, 82,
11872–11876.
Methyl
(R)-2-(3-(2-(2-chloroethoxy)ethoxy)-2-
iodylphenoxy)propanoate ((R)-14c)
Colorless oil, 26.7 mg, 0.0581 mmol, 49% yield
1H-NMR (400 MHz, CHLOROFORM-D) δ 7.41 (t, J = 8.3 Hz,
1H), 6.80 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 4.89 (q, J
= 6.9 Hz, 1H), 4.31 (dd, J = 4.9, 4.5 Hz, 2H), 3.98-4.01 (m, 4H),
3.77 (s, 3H), 3.71 (dd, J = 6.1, 4.9 Hz, 2H), 1.71 (d, J = 6.9 Hz,
3H); 13C-NMR (101 MHz, CHLOROFORM-D) δ 171.92,
160.05, 157.67, 135.85, 125.78, 109.60, 108.46, 76.31, 72.00,
70.27, 68.90, 53.05, 43.60, 18.43; HRMS (APCI+ in MeCN)
calcd for C14H19O7ClI (M+H) 460.9859 found 460.9848; IR
(NaCl) 3461, 3073, 2953, 1754, 1575, 1471, 1258, 1078, 765,
659 cm-1; [α]D20 = –41.59 (c = 1.03, CHCl3).
3. Selected examples for chiral hypervalent iodine(III) catalyzed
reactions see; a) Uyanik, M.; Yasui, T.; Ishihara, K. Angew. Chem.
Int. Ed. 2010, 49, 2175–2177; b) Fujita, M.; Mori, K.; Shimogaki,
M.; Sugimura, T. Org. Lett. 2012, 14, 1294–1297; c) Uyanik, M.;
Yasui, T.; Ishihara, K. Angew. Chem. Int. Ed. 2013, 52, 9215–
9218; d) Dohi, T.; Takenaga, N.; Nakae, T.; Toyoda, Y.;
Yamasaki, M.; Shiro, M.; Fujioka, H.; Maruyama, A.; Kita, Y. J.
Am. Chem. Soc. 2013, 135, 4558–4566; e) Wu, H.; He, Y.-P.; Xu,,
L.; Zhang, D.-Y.; Gong, L-Z. Angew. Chem. Int. Ed. 2014, 53,
3466–3469; f) Banik, S. M.; Medley, J. W.; Jacobsen, E. N.
Science. 2016, 353, 51–54; g) Molnár, I. G.; Gilmour, R. J. Am.
Chem. Soc. 2016, 138, 5004–5007; h) Banik, S. M.; Medley, J.
W.; Jacobsen, E. N. J. Am. Chem. Soc. 2016, 138, 5000–5003; i)
Uyanik, M.; Yasui, T.; Ishihara, K. J. Org. Chem. 2017, 82,
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General procedure for asymmetric hydroxylative phenol
dearomatization/[4+2]-dimerization cascade reaction.
To a stirred solution of phenol derivatives (5.0 equiv) in CH2Cl2
(0.025 M) at room temperature was slowly added chiral I(V)
reagent (1.0 equiv) in CH2Cl2 and the resulting mixture was
stirred at –80 ºC for 10 min. TFAA (3.0 equiv) was slowly added
at the same temperature and slowly warm to –40 ºC and stirred
for 24 h. The reaction was quenched by addition of saturated
NaHCO3 aq. and extracted with CH2Cl2, dried over Na2SO4.
After filtration and evaporation of the solvent under reduced
pressure, the yield of product was determined by 1H-NMR using
benzyl phenyl ether as internal standard. Pure HPLC sample was
prepared by preparative TLC purification of residue (silica gel,
hexane:EtOAc = 3:1, v/v). The ee of product was determined by
HPLC analysis under the reported condition.5e The spectroscopic
data was matched with the reported value.5e
Acknowledgments
We are grateful for financial support from the Toyo Gosei
Memorial Foundation, the Meiji Seika Pharma Award in
Synthetic Organic Chemistry, Japan, and the Leading Research
Promotion Program ‘Soft Molecular Activation’ of Chiba
University, Japan.
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Supplementary data associated with this article can be found,
in the online version, at xx.