Stereocontrolled total syntheses of optically active furofuran lignans

Article abstract of DOI:10.1055/s-0034-1378812

Plant products (+)-sesamin, (+)-sesaminol, (+)-methylpiperitol, (+)-aschantin, and (+)-5'-hydroxymethylpiperitol were synthesized in a highly stereocontrolled manner through l-proline-catalyzed bifunctional-urea-accelerated cross-aldol reaction, followed by biomimetic construction of the furofuran lignan skeleton through a quinomethide intermediate.

Full text of DOI:10.1055/s-0034-1378812

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3513–3521
paper
3513
M. Inai et al.
Paper
Synthesis
Stereocontrolled Total Syntheses of Optically Active Furofuran
Lignans
O
Makoto Inai
O
Ryo Ishikawa
O
OTBS
H
H
H
Naoto Yoshida
O
O
O
O
O
O
O
TBSO
Nana Shirakawa
Yusuke Akao
O
R = H: (+)-sesamin
R = OH: (+)-sesaminol
HO
O
R
H
H
+
Yusuke Kawabe
Tomohiro Asakawa
Masahiro Egi
OH
H
OH
O
O
O
O
O
(OR)n
(OR)n
H
H
Yoshitaka Hamashima*
Toshiyuki Kan*
MeO
MeO
R = H: (+)-methylpiperitol
R = OMe: (+)-aschantin
R = OH: (+)-5'-hydroxymethylpiperitol
R
School of Pharmaceutical Sciences, University of Shizuoka,
52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
hamashima@u-shizuoka-ken.ac.jp
kant@u-shizuoka-ken.ac.jp
Received: 25.05.2015
Accepted after revision: 14.06.2015
Published online: 12.08.2015
O
O
O
DOI: 10.1055/s-0034-1378812; Art ID: ss-2015-f0330-op
H
H
R = H: (+)-sesamin (1a)
Abstract Plant products (+)-sesamin, (+)-sesaminol, (+)-methylpiperi-
tol, (+)-aschantin, and (+)-5'-hydroxymethylpiperitol were synthesized
in a highly stereocontrolled manner through L-proline-catalyzed bifunc-
tional-urea-accelerated cross-aldol reaction, followed by biomimetic
construction of the furofuran lignan skeleton through a quinomethide
intermediate.
O
R = OH: (+)-sesaminol (1b)
O
O
R
O
O
O
O
Key words aldol reaction, natural products, organocatalysts, proline,
stereoselective synthesis
H
H
MeO
MeO
R = H: (+)-methylpiperitol (1c)
R = OMe: (+)-aschantin (1d)
R = OH: (+)-5'-hydroxymethylpiperitol (1e)
Furofuran lignans isolated from various vascular plants
have been reported to exhibit antitumor, antioxidant, anti-
viral, and antihypertensive activities, as well as inhibition
of low-density lipoprotein oxidation.1,2 These furofuran lig-
nans and their derivatives are expected to be useful as lead
compounds for drug development. Furthermore, there is a
need for the development of probe molecules not only to
identify their target proteins, but also to clarify the in vivo
kinetics of furofuran lignans.3 There are many reports on
synthetic studies and total synthesis of symmetrical furofu-
ran lignans, such as sesamin (1a) as a representative exam-
ple.4 However, although many unsymmetrical furofuran
compounds are found in nature, their total synthesis has
been less well investigated (Figure 1).5
Herein, we report an efficient and flexible total synthe-
sis of (+)-sesamin (1a), (+)-sesaminol (1b), (+)-meth-
ylpiperitol [(1c) also known as spinescin, demethoxy-
aschantin and kobusin], (+)-aschantin (1d), and (+)-5'-hy-
droxymethylpiperitol (1e). Our syntheses feature an L-
proline-catalyzed asymmetric cross-aldol reaction, fol-
lowed by biomimetic construction of the furofuran lignan
R
Figure 1 Structures of furofuran lignans
skeleton through a quinomethide intermediate. The two ar-
omatic substituents of the furofuran lignans were incorpo-
rated in a stepwise manner through two stereoselective al-
dol reactions, enabling rapid access to these unsymmetri-
cally substituted furofuran lignans.6
Our previous synthetic investigation of polyphenols
showed that the electronic properties of the phenol-pro-
tecting group have a strong influence on the reactivity at
the benzylic position of benzyl alcohols and aromatic car-
bonyl compounds.7 For example, an alkyl-type protecting
group stabilizes the benzylic cation,7c,d whereas an elec-
tron-withdrawing group enhances the reactivity of the car-
bonyl group as well as the stability of the aromatic ring to
oxidation.7d,e We also established an efficient synthetic
method for the construction of dihydrobenzopyrans
through formation of quinomethide intermediates
3
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Synthesis
(Scheme 1).7 Upon treatment of an electron-rich benzyl al-
cohol 2 with a catalytic amount of 10-camphorsulfonic acid
(CSA) in toluene at 60 °C, stereoselective ring-closing reac-
tion proceeded smoothly to provide 4 as a single diastereo-
mer. At the outset of our synthetic study, we envisioned
that reactivity tuning of phenols by modifying the protect-
ing group and acid-promoted ether ring formation would
both be useful for concise construction of the furofuran
skeleton of 1a–e.
tion of the two different aromatic rings into the core skele-
ton could be achieved by means of stepwise aldol reactions:
these key intermediates could be derived from diastereose-
lective aldol reaction of benzaldehyde derivatives 7 with
lactone 6, which would be generated by L-proline-catalyzed
asymmetric aldol reaction of aliphatic aldehyde 8 with
benzaldehyde derivatives 9.
Initially, we selected (+)-sesamin (1a) as a target com-
pound to establish a general synthetic route. Our synthesis
commenced with the preparation of aliphatic aldehyde 8.9
Ester 11 was obtained from 1,1-dimethylallyl alcohol (10)
by Johnson–Claisen rearrangement on heating in trimethyl
orthoacetate in the presence of a catalytic amount of propa-
noic acid, then the double bond was cleaved by ozonolysis,
and treatment with PPh3 afforded aldehyde 8 (Scheme 3).
OBn
OBn
OBn
OBn
OBn
OBn
H
O
CSA
OH
O
OH
O
toluene
60 °C
O
O
Ar
Ar
2
4
O
MeC(OMe)3
HO
propionic acid
O3; Ph3P
H
OBn
H
O
MeO
135 °C
42%
MeO
CH2Cl2–MeOH
86%
OBn
OBn
O
10
O
11
8
O
Scheme 3 Synthesis of aliphatic aldehyde 8
O
Ar
3
In the L-proline-catalyzed cross-aldol reactions of ali-
phatic aldehyde 8 with 3,4-dihydroxybenzaldehyde deriva-
tives 9a–e, the reactivity was increased markedly when the
phenols were protected with an electron-withdrawing
group (Table 1). Reaction of 8 with electron-rich aldehydes
9a (R1, R2 = Me) and 9b (R1, R2 = –CH2–) did not proceed at
all (entries 1 and 2).10 However, the desired condensation
reaction proceeded in good yield when the protecting
groups were changed to either benzoyl (Bz) or 2-nitroben-
zenesulfonyl (Ns),11 under the same reaction conditions
(entries 4 and 5). Comparison of the results presented in
entries 3 and 5 strongly suggests the importance of the
electron-withdrawing groups; reactivity was markedly re-
duced when even one of the two Ns groups was replaced
with a methyl group. Although aldol reaction of 8 with 9d
(R1, R2 = Bz) and 9e (R1, R2 = Ns) gave the desired aldol
adducts, the reaction was accelerated by addition of
McQuade’s bifunctional urea 14.12 Thus, the aldol reaction
of 8 and 9e was completed within only six hours in the
presence of 14, whereas the reaction without 14 required
26 hours to achieve a similar chemical yield. It should be
noted that the enantiomeric excess (ee) was also greatly
improved in the presence of 5 mol% 14 (entries 5 and 6).
The reduction of the reaction time may contribute to the
high enantiomeric excess. Based on McQuade’s interpreta-
tion of the nitroso-aldol reaction, it is considered that urea
14 promotes the backward reaction to afford the produc-
tive enamine intermediate from the unproductive oxazoli-
din-5-one intermediate, which is formed by intramolecular
cyclization of the proline carboxylate of the proline–ali-
Scheme 1 Cyclization via a quinomethide intermediate
The heart of our synthetic plan for furofuran lignans is
illustrated in Scheme 2. Based on our recent total synthesis
of hedyotol A,8 acidic treatment of tetraol 5 was expected to
provide the desired furofuran skeleton of 1a–e. Incorpora-
O
O
O
HO
O
HO
O
7
8
H
H
H
H
8'
7'
OH
O
OH
5
(OR)n
(OR)n
furofuran lignans 1a–e
O
OR1
OR2
OPG
H
H
OR1
OR2
+
O
9
O
H
6
O
+
MeO
H
O
O
8
7
(OR)n
Scheme 2 Retrosynthetic scheme for the formation of furofuran lig-
nans
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Synthesis
phatic aldehyde adduct.12 Without isolation of the relatively
unstable aldol product, chemoselective reduction of the al-
dehyde with NaBH4 and treatment with AcOH provided lac-
tone 13e in 67% yield (two steps) in a highly stereoselective
manner [dr = 10:1, 97% ee (major isomer)].
Upon treatment of 19a with anhydrous HCl in MeOH,
the furofuran core was constructed to afford (+)-sesamin
(1a) in good yield. Given that a single diastereomer was ob-
tained, it is likely that this cyclization reaction occurred
through the biomimetic quinomethide intermediate 20 to
furnish the thermodynamically stable exo-exo furofuran
ring. Addition of trimethoxy orthoformate may serve to
push the reaction forward by trapping water: 1a was ob-
tained in only 29% yield in its absence. All spectral data (1H
NMR, 13C NMR, IR and HRMS) of synthetic 1a were in full
agreement with the reported values (Scheme 4).4
Table 1 Aldol Reaction of 8 with Aromatic Aldehydes 9a–e
O
OR1
H
OR2
OH
9a–e
L-proline (20 mol%)
DMF, 4 °C, 26 h;
OTBS
H
AcOH
toluene
PhSH
Cs2CO3
OR1
OR2
H
TBSCl
imidazole
ONs
ONs
HO
8
13e
O
MeO
70 °C
yield
(2 steps)
MeCN, 0 °C
85%
NaBH4, MeOH
DMF
90%
12a–e
O
O
15
OH
H
OTBS
OTBS
OR1
OR2
H
O
BrCH2Cl
Cs2CO3
H
OH
OH
O
O
N
O
N
N
O
O
O
O
H
H
DMF, 110 °C
68%
14
O
16
13a–e
17
O
Entry
Benzaldehyde
Product
Yield (%)a
OTBS
O
H
H
H
9a (R1, R2 = Me)
9b (R1, R2 = –CH2–)
9c (R1 = Me, R2 = Ns)
9d (R1, R2 = Bz)
13a
13b
13c
13d
13e
13e
no reaction
no reaction
no reaction
43
O
O
1
O
O
7a
LiHMDS
2
NaBH4, CaCl2
EtOH
OH
3
O
THF, –78 °C
62% (dr = 1.3:1)
4
5
9e (R1, R2 = Ns)
63 (74% ee)
67 (97% ee)
O
18a
6b
9e (R1, R2 = Ns)
O
OTBS
H
a Isolated yield (two steps).
O
HO
HO
b The aldol reaction was carried out for 6 h in the presence of 5 mol% urea
14.
AcCl, HC(OMe)3
O
H
OH
CH2Cl2–MeOH
69% (2 steps)
After separation of the epimer, protection of the sec-
ondary alcohol of 13e with a TBS group and subsequent re-
moval of the Ns groups with PhSH/Cs2CO3,11 key intermedi-
ate 17 was obtained by treatment of the resultant catechol
16 with bromochloromethane and Cs2CO3. The second aro-
matic ring was incorporated by means of strong base-medi-
ated aldol reaction of lactone 17 with aldehyde 7a. The re-
action with LiHMDS occurred from the less-hindered β-face
of the lactone ring to afford 18a in 62% yield. Although the
chiral center of newly formed benzylic alcohol was generat-
ed in a 1.3:1 stereoisomeric ratio, both diastereomers were
converted into the same exo-exo furofuran ring (see below).
Our initial attempts to reduce lactone 18a by using stan-
dard reducing reagents (LiAlH4/THF, excess NaBH4/THF–
MeOH13) gave only partially reduced lactols. However, we
found that the use of Ca(BH4)2, generated in situ from
NaBH4 and CaCl2,14 was extremely effective for reducing the
lactone to give 19a.
19a
[Without HC(OMe)3: 29% (2 steps)]
O
O
O
O
OH
H
H
O
O
HO
O
20
O
O
H
H
O
O
O
1a
Scheme 4 Total synthesis of (+)-sesamin (1a)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3513–3521

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Synthesis
Having established an efficient synthetic route to 1a, we
turned our attention to the synthesis of asymmetrical furo-
furan lignans. In contrast to symmetrical 1a, there is no re-
port of the total synthesis of unsymmetrical compounds 1b,
1d, and 1e.15 We considered that enantio- as well as diaste-
reoselective syntheses of these congeners would be possi-
ble, provided that aromatic aldehydes bearing a different
substitution pattern are used in the second aldol reaction.
As shown in Scheme 5, LiHMDS-mediated aldol reaction of
the common lactone 17 with 7b and subsequent reduction
with LiBH4 provided triol 19b. The aldol reaction was not
affected by the presence of ortho-substitution of 7b. Treat-
ment of the resultant diastereomeric mixture of 19b under
acidic conditions afforded 21 without difficulty. Finally, re-
moval of the benzyl group by hydrogenolysis furnished (+)-
sesaminol (1b).16
O
OMe
OMe
H
OTBS
OH
H
H
R
O
O
R = H: 7c
R = OMe: 7d
R = OTBS: 7e
O
17
O
LiHMDS
THF
R = H: 18c
R = OMe: 18d
R = OTBS: 18e
–78 °C
(dr = 1:1)
MeO
R
OMe
OTBS
OH
H
H
O
O
HO
HO
AcCl
MeOH
NaBH4, CaCl2
EtOH
HC(OMe)3
CH2Cl2
O
MeO
R
R = H: 19c
R = OMe: 19d
R = OTBS: 19e
O
O
OTBS
H
H
H
OMe
O
O
O
BnO
O
7b
LiHMDS
LiBH4
THF
OH
OBn
17
O
O
O
O
THF, –78 °C
(dr = 1:1)
H
H
MeO
MeO
O
18b
O
R = H: 1c (47%, 3 steps)
R = OMe: 1d (50%, 3 steps)
R = OH: 1e (52%, 3 steps)
OTBS
H
O
O
R
HO
HO
AcCl
MeOH
Scheme 6 Total syntheses of (+)-methylpiperitol (1c), (+)-aschantin
(1d), and (+)-5'-hydroxymethylpiperitol (1e)
OH
OBn
H
HC(OMe)3
CH2Cl2
O
O
proline-catalyzed cross-aldol reaction of aliphatic and aro-
matic aldehydes, and biomimetic construction of the exo-
exo furofuran skeleton via a quinomethide intermediate.
Considering the mildness of all the reaction conditions and
the convergent nature of the synthetic route, the present
protocol should, in principle, be applicable to the rapid
preparation of a furofuran library, including unnatural ana-
logues. The electron-rich aromatic ring would be favorable
for the incorporation of an electrophilic halogen atom,
which can act as a handle to install a linker group by cross-
coupling reaction. Thus, concise preparation of various
probe molecules should be possible. Further synthetic stud-
ies and biological investigations of other furofuran lignans,
as well as the development of various probe molecules, are
in progress.
O
O
O
19b
O
H
H
O
O
OR
H2, Pd/C, THF–MeOH
35% (4 steps)
R = Bn: 21
R = H: 1b
Scheme 5 Total synthesis of (+)-sesaminol (1b)
The other compounds were synthesized as described
above through LiHMDS-mediated aldol reaction, reduction
with Ca(BH4)2, and furofuran ring formation (Scheme 6) to
afford (+)-methylpiperitol (1c),5d,17 (+)-aschantin (1d),18
and (+)-5'-hydroxymethylpiperitol (1e)19 in good yield
(three steps). In the synthesis of 1e, simultaneous deprotec-
tion of the TBS ether on the phenol occurred during the cy-
clization of 19e. All characterization data (1H NMR, 13C
NMR, IR and HRMS) of the synthetic compounds 1b–e were
in full agreement with reported values.16–19
1H (500 MHz) and 13C NMR (125 MHz) spectra were recorded with a
JEOL ECA-500 instrument. Chemical shifts for 1H NMR data are re-
ported in parts per million downfield from tetramethylsilane (δ) as
the internal standard, and coupling constants are given in hertz (Hz).
The following abbreviations are used for spin multiplicity: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Chemi-
In conclusion, we have established an efficient and flex-
ible synthetic route for the synthesis of furofuran lignans
such as 1a–e. Our stereocontrolled synthesis includes L-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3513–3521

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Synthesis
cal shifts for 13C NMR signals are reported in ppm relative to the cen-
ter line of the triplet at δ = 77.0 ppm for CDCl3. High-resolution mass
spectra (HRMS) were obtained with a Bruker Daltonics micrOTOF
(ESI). IR spectra were recorded with a Shimadzu IRPrestige-21. Opti-
cal rotations were measured with a Jasco P-1030 Polarimeter at r.t.
using the sodium D line. Analytical thin-layer chromatography (TLC)
was performed on Merck precoated analytical plates (0.25 mm thick,
4-Formyl-1,2-phenylene Bis(2-nitrobenzenesulfonate) (9e)
To a solution of 3,4-dihydroxybenzaldehyde (10.0 g, 72.4 mmol) in
MeCN (200 mL) was added Et3N (38.5 mL, 290 mmol) at 0 °C. A solu-
tion of 2-nitrobenzenesulfonyl chloride (NsCl; 35.3 g, 159 mmol) in
MeCN (100 mL) was added dropwise over a period of 1 h at the same
temperature. The resulting mixture was stirred at r.t. for 3 h, then
poured into 1 M HCl and extracted with CH2Cl2. The organic layer was
dried over anhydrous MgSO4, filtered, and evaporated under reduced
pressure. The residue was purified by recrystallization (EtOAc–n-hex-
ane, 75%) to afford 9e (33.0 g, 90%) as a green solid.
silica gel 60
7 × 20 cm plates prepared with a 0.25 mm layer of Merck silica gel 60
254. Compounds were eluted from the adsorbent with 10% MeOH in
F254). Preparative TLC separations were made on
F
chloroform. Column chromatography separations were performed on
Kanto Chemical Silica Gel 60 (spherical) 40–50 μm, Silica Gel 60
(spherical) 63–210 μm or Silica Gel 60 N (spherical, neutral) 63–210
μm. Reagents and solvents were commercial grades and were used as
supplied with the following exceptions. (1) CH2Cl2, THF, and toluene
were dried over 4Å molecular sieves. (2) MeOH and MeCN were dried
over 3Å molecular sieves. All reactions that were sensitive to oxygen
and/or moisture were conducted under an argon atmosphere.
IR (film): 1703, 1387, 1375, 1246 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 9.99 (s, 1 H), 8.22–8.13 (m, 2 H),
8.13–8.06 (m, 2 H), 8.06–7.98 (m, 3 H), 7.97–7.88 (m, 2 H), 7.85 (d, J =
1.7 Hz, 1 H), 7.59 (d, J = 8.5 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 191.0, 164.3, 164.2, 147.60,
147.56, 144.3, 140.8, 137.5, 136.1, 133.5, 133.4, 131.5, 130.4, 126.3,
126.2, 125.63, 125.55, 125.4, 124.4.
HRMS (ESI): m/z [M + Na]+ calcd for C19H12N2O11S2Na: 530.9780;
found: 530.9774.
Methyl 5-Methylhex-4-enoate (11)
To a solution of 1,1-dimethylallyl alcohol (10; 26 mL, 0.25 mol) in
MeC(OMe)3 (64 mL, 0.50 mol) was added propionic acid (0.1 mL, 1.3
mmol) at r.t. The resulting mixture was heated at 135 °C until no
more MeOH was collected in a dropping funnel. The reaction mixture
was then cooled to 80 °C and the MeOH collected in the dropping
funnel was returned to the flask. To the solution, propionic acid (0.1
mL, 1.3 mmol) was injected and the solution was heated again. The
distillation cycle was repeated until no 11 was detected in the distil-
late. H2O (4.5 mL) was added at r.t. and the mixture was stirred for 30
min. The solvent was removed by distillation, and the resulting resi-
due was purified by distillation (110 °C, 150 mmHg) to afford 11 (12.0
g, 42%) as a colorless oil.
4-{(R)-Hydroxy[(R)-5-oxotetrahydrofuran-3-yl]methyl}-1,2-
phenylene bis(2-nitrobenzenesulfonate) (13e)
To a solution of 8 (1.27 g, 2.50 mmol) and urea 14 (10.3 mg, 0.05
mmol) in DMF (1.0 mL) was added L-proline (23 mg, 0.2 mmol) at
4 °C. After 10 min, a solution of 9e (116 mg, 1.00 mmol) in anhydrous
DMF (1.0 mL) was added dropwise over a period of 5 h by using a sy-
ringe pump at the same temperature. After 1 h, a solution of NaBH4
(113 mg, 3.0 mmol) in MeOH (2.0 mL) was added at 0 °C. The result-
ing mixture was stirred at r.t. for 30 min, then the reaction was
quenched with sat. aq NH4Cl and extracted with EtOAc. The organic
layer was washed with brine, dried over anhydrous Na2SO4, and evap-
orated under reduced pressure. The crude material including 12e was
applied to the following reaction without further purification.
IR (film): 1749 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 5.10–5.07 (m, 1 H), 3.67 (s, 3 H), 2.35–
2.29 (m, 4 H), 1.68 (s, 3 H), 1.62 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 173.8, 133.0, 122.3, 51.4, 34.2, 25.6,
23.5, 17.6.
HRMS (ESI): m/z [M + Na]+ calcd for C8H14O2Na: 165.0891; found:
165.0886.
To a solution of the crude material including 12e in toluene (30 mL)
was added AcOH (10 mL) at r.t. The resulting mixture was stirred at
70 °C for 2 h. After cooling, the reaction mixture was evaporated un-
der reduced pressure. The resulting residue was diluted with EtOAc
and washed with sat. aq NaHCO3 and brine. The organic layer was
dried over anhydrous Na2SO4 and evaporated under reduced pressure.
The residue was purified by column chromatography (SiO2; EtOAc–n-
hexane, 75%) to afford 13e [397 mg, 67%, 97% ee (major isomer), dr =
10:1] as a colorless oil. The diastereomer ratio (dr) and enantiomeric
excess value (ee) were determined by 1H NMR spectroscopic and chi-
ral HPLC analyses, respectively.
Methyl 4-Oxobutanoate (8)9
A solution of 11 (12.0 g, 84.3 mmol) in a 5:1 mixture of CH2Cl2 and
MeOH (total 120 mL) was stirred under O3 bubbling for 30 min at
–78 °C. The reaction mixture was then bubbled with argon gas to
purge the unreacted O3, and triphenyl phosphine (26.5 g, 101 mmol)
was added at –78 °C. The resulting mixture was stirred at r.t. for 3 h,
then concentrated by distillation. The resulting residue was purified
by distillation (75 °C, 15 mmHg) to afford 8 (8.46 g, 86%) as a colorless
oil.
HPLC (Daicel Chiralcel OD-H; i-PrOH–n-hexane, 35%; 1.0 mL/min;
24
254 nm): tR = 12.4 (minor), 14.3 (major) min; [α]D +9.16 (c 0.97,
CHCl3, 97% ee).
IR (film): 2924, 1771, 1544, 1391, 1373, 1246 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.06 (d, J = 7.9 Hz, 1 H), 8.03 (d, J =
8.1 Hz, 1 H), 7.87 (d, J = 7.3 Hz, 1 H), 7.85 (d, J = 7.9 Hz, 1 H), 7.80–7.73
(m, 4 H), 7.37–7.32 (m, 3 H), 4.73 (dd, J = 6.8, 2.8 Hz, 1 H), 4.34 (d, J =
6.8 Hz, 2 H), 2.90–2.81 (m, 1 H), 2.48 (dd, J = 17.9, 8.5 Hz, 1 H), 2.42 (d,
J = 2.8 Hz, 1 H), 2.32 (dd, J = 17.9, 7.4 Hz, 1 H).
IR (film): 2957, 1717, 1738 cm–1
1H NMR (500 MHz, CDCl3): δ = 9.81 (s, 1 H), 3.69 (s, 3 H), 2.81 (t, J =
6.9 Hz, 2 H), 2.63 (t, J = 6.9 Hz, 2 H).
.
13C NMR (125 MHz, CDCl3): δ = 199.9, 172.7, 51.9, 38.5, 26.3.
HRMS (ESI): m/z [M + Na]+ calcd for C5H8O3Na: 139.0371; found:
139.0365.
13C NMR (125 MHz, CDCl3): δ = 176.4, 148.4, 143.2, 141.1, 140.5,
136.0, 135.8, 132.51, 132.49, 131.9, 131.8, 128.4, 128.2, 126.0, 124.9,
124.82, 124.80, 122.2, 73.5, 69.5, 42.2, 31.1.
HRMS (ESI): m/z [M + Na]+ calcd for C23H18N2O13S2Na: 617.0148;
found: 617.0142.
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4-{(R)-[(tert-Butyldimethylsilyl)oxy][(R)-5-oxotetrahydrofuran-3-
yl]methyl}-1,2-phenylene Bis(2-nitrobenzenesulfonate) (15)
1H NMR (500 MHz, CDCl3): δ = 6.76 (d, J = 3.4 Hz, 1 H), 6.74 (d, J =
7.9 Hz, 1 H), 6.69 (dd, J = 7.9, 1.1 Hz, 1 H), 5.96 (d, J = 6.0 Hz, 2 H), 4.49
(d, J = 6.8 Hz, 1 H), 4.31 (dd, J = 9.4, 6.8 Hz, 1 H), 4.27 (dd, J = 9.4,
7.4 Hz, 1 H), 2.81–2.71 (m, 1 H), 2.36 (dd, J = 17.8, 8.5 Hz, 1 H), 2.27
(dd, J = 17.8, 7.4 Hz, 1 H), 0.87 (s, 9 H), 0.03 (s, 3 H), –0.21 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 176.7, 147.9, 147.3, 136.2, 119.5,
108.1, 106.3, 101.1, 75.6, 70.1, 44.2, 31.3, 25.7, 18.0, –4.5, –5.2.
To a solution of 13e (371 mg, 0.62 mmol) in DMF (1.0 mL) were added
imidazole (86 mg, 1.26 mmol) and TBSCl (138 mg, 0.92 mmol) at 0 °C.
The resulting mixture was stirred at r.t. for 5 h, then the reaction was
quenched with sat. aq NH4Cl and extracted with EtOAc. The organic
layer was washed with brine, dried over anhydrous Na2SO4, and evap-
orated under reduced pressure. The residue was purified by column
chromatography (SiO2; EtOAc–n-hexane, 40%) to afford 15 (396 mg,
90%) as a colorless oil.
HRMS (ESI): m/z [M + Na]+ calcd for C18H26O5SiNa: 373.1442; found:
373.1444.
[α]D26 +19.2 (c 0.60, CHCl3).
IR (film): 2929, 1808, 1761, 1560, 1356 cm–1
(+)-Sesamin (1a)
.
To a solution of LiHMDS (1.0 M in THF, 1.6 mL, 1.6 mmol) was added a
solution of 17 (223 mg, 0.64 mmol) in THF (1.0 mL) at –78 °C. After 15
min, a solution of 7a (114 mg, 0.76 mmol) in THF (1.0 mL) was added
at –78 °C. The resulting mixture was stirred at the same temperature
for 2 h, then the reaction was quenched with MeOH and sat. aq NH4Cl,
and the mixture was extracted with EtOAc. The organic layer was
dried over anhydrous Na2SO4, filtered, and evaporated under reduced
pressure. The residue was purified by column chromatography (SiO2;
EtOAc–n-hexane, 10%) to afford an inseparable diastereomeric mix-
ture of 18a (198 mg, 62%, dr = 1.3:1) as a colorless oil (HRMS (ESI):
m/z [M + Na]+ calcd for C26H32O8SiNa: 523.1759; found 523.1780).
1H NMR (500 MHz, CDCl3): δ = 8.02 (dd, J = 7.9, 1.1 Hz, 1 H), 8.00 (dd,
J = 7.9, 1.1 Hz, 1 H), 7.87–7.83 (m, 2 H), 7.77–7.72 (m, 4 H), 7.32–7.24
(m, 3 H), 4.66 (d, J = 5.7 Hz, 1 H), 4.30–4.22 (m, 2 H), 2.76–2.82 (m,
1 H), 2.46 (dd, J = 17.6, 8.5 Hz, 1 H), 2.30 (dd, J = 17.6, 7.9 Hz, 1 H),
0.87 (s, 9 H), 0.06 (s, 3 H), –0.20 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 176.1, 148.4, 143.5, 141.0, 140.2,
135.8, 132.4, 132.3, 131.9, 128.4, 128.2, 125.8, 124.8, 122.1, 74.1, 69.1,
43.7, 31.2, 25.6, 18.0, –4.5, –5.2.
HRMS (ESI): m/z [M + Na]+ calcd for C29H32O13S2SiNa: 731.1007;
found: 731.1053.
To a solution of CaCl2 (133 mg, 1.20 mmol) in EtOH (5.0 mL) was add-
ed NaBH4 (91 mg, 2.4 mmol) at r.t. After 15 min, a solution of 18a (198
mg, 0.40 mmol) in EtOH (5.0 mL) was added at 0 °C. The resulting
mixture was stirred at r.t. for 1.5 h, then the reaction was quenched
with MeOH and sat. aq NH4Cl, and the mixture was extracted with
EtOAc. The organic layer was washed with brine, dried over anhy-
drous Na2SO4, and concentrated under reduced pressure. The crude
material including 19a was applied to the following reaction without
further purification.
(R)-4-{(R)-[(tert-Butyldimethylsilyl)oxy](3,4-dihydroxyphe-
nyl)methyl}dihydrofuran-2(3H)-one (16)
To a solution of 15 (1.92 g, 2.71 mmol) in MeCN (40 mL) were added
Cs2CO3 (2.55 g, 7.72 mmol) and PhSH (0.7 mL, 6.8 mmol) at 0 °C. The
resulting mixture was stirred at the same temperature for 1 h, then
the reaction was quenched with sat. aq NH4Cl and extracted with
EtOAc. The organic layer was washed with brine, dried over anhy-
drous Na2SO4, and concentrated under reduced pressure. The residue
was purified by column chromatography (SiO2; EtOAc–n-hexane,
10%) to afford 16 (780 mg, 85%) as a brown oil.
To a solution of the crude material including 19a in CH2Cl2 (1.0 mL)
were added HC(OMe)3 (0.1 mL) and AcCl (8.5 μL, 0.98 mmol) in MeOH
(0.5 mL) at 0 °C. The resulting mixture was stirred at r.t. for 18 h, then
poured into sat. aq NaHCO3 and extracted with EtOAc. The organic
layer was washed with brine, dried over anhydrous Na2SO4, and evap-
orated under reduced pressure. The residue was purified by column
chromatography (SiO2; EtOAc–n-hexane, 30%) to afford (+)-sesamin
(1a; 96.7 mg, 69%, two steps) as a colorless solid.
[α]D23 +31.7 (c 1.00, CHCl3).
IR (film): 3346, 2955, 2859, 1751, 1611, 1518, 1472 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 6.80 (d, J = 7.9 Hz, 1 H), 6.79 (d, J =
1.7 Hz, 1 H), 6.64 (dd, J = 7.9, 1.7 Hz, 1 H), 6.48 (br s, 2 H), 4.46 (d, J =
6.8 Hz, 1 H), 4.35 (dd, J = 9.1, 6.8 Hz, 1 H), 4.26 (dd, J = 9.1, 7.4 Hz,
1 H), 2.82–2.73 (m, 1 H), 2.39 (dd, J = 17.6, 8.5 Hz, 1 H), 2.32 (dd, J =
17.6, 7.9 Hz, 1 H), 0.86 (s, 9 H), 0.01 (s, 3 H), –0.24 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 178.7, 144.0, 143.6, 134.5, 118.3,
115.1, 113.0, 75.3, 70.8, 43.9, 31.6, 25.7, 18.0, –4.50, –4.53, –5.28.
[α]D26 +68.9 (c 1.00, CHCl3).
IR (film): 2884, 1501, 1491, 1248 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 6.85 (d, J = 1.7 Hz, 2 H), 6.80 (dd, J = 7.9,
1.7 Hz, 2 H), 6.78 (d, J = 7.9 Hz, 2 H), 5.95 (s, 4 H), 4.71 (d, J = 4.5 Hz,
2 H), 4.23 (dd, J = 9.4, 7.4 Hz, 2 H), 3.87 (dd, J = 9.4, 4.0 Hz, 2 H), 3.08–
3.01 (m, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C17H26O5SiNa: 361.1442; found:
361.1443.
13C NMR (125 MHz, CDCl3): δ = 147.9, 147.1, 135.0, 119.3, 108.1,
(R)-4-{(R)-Benzo[d][1,3]dioxol-5-yl[(tert-butyldimethylsi-
lyl)oxy]methyl}dihydrofuran-2(3H)-one (17)
106.5, 101.0, 85.8, 71.7, 54.3.
HRMS (ESI): m/z [M + Na]+ calcd for C20H18O6Na: 377.1001; found:
To a solution of 16 (781 mg, 2.31 mmol) in DMF (8.2 mL) were added
Cs2CO3 (1.14 g, 2.99 mmol) and BrCH2Cl (231 mL, 3.45 mmol) at r.t.
The resulting mixture was stirred at 110 °C for 3 h. The reaction was
then quenched with sat. aq NH4Cl and the mixture was extracted
with EtOAc. The organic layer was washed with brine, dried over an-
hydrous Na2SO4, and evaporated under reduced pressure. The residue
was purified by column chromatography (SiO2; EtOAc–n-hexane,
50%) to afford 17 (550 mg, 68%) as a pale-yellow oil.
377.0996.
6-(Benzyloxy)benzo[d][1,3]dioxole-5-carbaldehyde (7b)
To a stirred solution of 6-hydroxypiperonal (269 mg, 1.62 mmol) in
DMF (3.0 mL) were added K2CO3 (336 mg, 2.43 mmol) and benzyl bro-
mide (0.21 mL, 1.8 mmol) at 0 °C. The resulting mixture was stirred at
r.t. for 12 h, then the reaction was quenched with sat. aq NH4Cl and
the mixture was extracted with Et2O. The organic layer was washed
with brine, dried over anhydrous Na2SO4, filtered, and evaporated un-
der reduced pressure. The residue was purified by recrystallization
(EtOAc–n-hexane, 75%) to afford 7b (386 mg, 93%) as a colorless solid.
[α]D27 +44.8 (c 0.85, CHCl3).
IR (film): 2930, 1773, 1491, 1445, 1244 cm–1
.
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IR (film): 1665, 1618, 1263 cm–1
.
IR (film): 3853, 3309, 2883, 1508, 1490, 1442, 1247 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 10.32 (s, 1 H), 7.45–7.30 (m, 5 H), 7.28
(s, 1 H), 6.59 (s, 1 H), 6.00 (s, 2 H), 5.12 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 187.7, 159.3, 154.1, 142.4, 135.8,
128.7, 128.3, 127.3, 119.2, 106.0, 105.9, 102.1, 95.62, 95.60, 71.5.
HRMS (ESI): m/z [M + Na]+ calcd for C15H12O4Na: 279.0628; found:
279.0640.
1H NMR (500 MHz, CDCl3): δ = 7.73 (s, 1 H), 6.81 (s, 2 H), 6.79 (s, 1 H),
6.50 (s, 1 H), 6.44 (s, 1 H), 5.93 (s, 2 H), 5.89 (s, 2 H), 4.78 (s, 2 H),
4.40–4.30 (m, 1 H), 4.18–4.10 (m, 1 H), 3.90–3.80 (m, 2 H), 3.20–3.10
(m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 150.7, 148.1, 148.0, 147.2, 140.9,
134.5, 119.3, 115.0, 108.2, 106.5, 106.1, 101.2, 99.5, 99.4, 86.5, 85.4,
72.4, 70.5, 53.3, 52.9.
HRMS (ESI): m/z [M – H]– calcd for C20H17O7: 369.0974; found:
369.0969.
3-[(tert-Butyldimethylsilyl)oxy]-4,5-dimethoxybenzaldehyde (7c)
To a solution of 5-hydroxyveratraldehyde (500 mg, 2.75 mmol) in
DMF (3.0 mL) were added imidazole (338 mg, 4.95 mmol) and TBSCl
(500 mg, 3.3 mmol) at 0 °C. The resulting mixture was stirred at r.t.
for 1 h, then the reaction was quenched with sat. aq NH4Cl and the
mixture was extracted with Et2O. The organic layer was washed with
brine, dried over anhydrous MgSO4, and evaporated under reduced
pressure. The residue was purified by column chromatography (SiO2;
EtOAc–n-hexane, 5%) to afford 7c (750 mg, 92%) as a colorless solid.
(+)-Methylpiperitol (1c)
In a manner similar to that used to prepare 1a, 17 (87.6 mg, 0.25
mmol)gave (+)-methylpiperitol (1c, 43.5 mg, 47%, three steps) as a
colorless solid.
[α]D26 +11.8 (c 0.45, CHCl3).
IR (film): 2959, 2870, 1609, 1593, 1518, 1508, 1491, 1443 cm–1
.
IR (film): 2955, 2859, 1763, 1491 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 6.90 (d, J = 1.7 Hz, 1 H), 6.87 (dd, J = 8.5,
1.7 Hz, 1 H), 6.86 (d, J = 1.7 Hz, 1 H), 6.85 (d, J = 8.5 Hz, 1 H), 6.81 (dd,
J = 7.9, 1.7 Hz, 1 H), 6.78 (d, J = 7.9 Hz, 1 H), 5.95 (s, 2 H), 4.74 (t, J =
5.1 Hz, 2 H), 4.25 (dt, J = 9.1, 6.8 Hz, 2 H), 3.90 (s, 3 H), 3.88 (s, 3 H),
3.87 (dd, J = 9.1, 4.5 Hz, 2 H), 3.03–3.13 (m, 2 H).
1H NMR (500 MHz, CDCl3): δ = 9.78 (s, 1 H), 7.08 (d, J = 1.7 Hz, 1 H),
6.99 (d, J = 1.7 Hz, 1 H), 3.87 (s, 3 H), 3.83 (s, 3 H), 0.98 (s, 9 H), 0.17 (s,
6 H).
13C NMR (125 MHz, CDCl3): δ = 191.0, 154.2, 149.7, 146.0, 131.7,
117.1, 105.1, 60.4, 56.0, 25.5, 18.2, –4.8.
HRMS (ESI): m/z [M + Na]+ calcd for C15H12O6Na: 279.0633; found:
279.0628.
13C NMR (125 MHz, CDCl3): δ = 149.2, 148.6, 148.0, 147.1, 135.0,
133.4, 119.4, 118.2, 111.0, 109.1, 108.2, 106.5, 101.1, 85.80, 85.75,
71.73, 71.66, 55.93, 55.90, 54.3, 54.1.
HRMS (ESI): m/z [M + Na]+ calcd for C21H22O6Na: 393.1341; found:
393.1309.
(+)-Sesaminol (1b)
To a solution of LiHMDS (1.0 M in THF, 0.7 mL 0.7 mmol) was added a
solution of 17 (82.0 mg, 0.24 mmol) in THF (0.4 mL) at –78 °C. After
30 min, a solution of 7b (72.0 mg, 0.21 mmol) in THF (0.4 mL) was
added at –78 °C. The resulting mixture was stirred at the same tem-
perature for 45 min, then the reaction was quenched with MeOH and
sat. aq NH4Cl, and the mixture was extracted with EtOAc. The organic
layer was dried over anhydrous Na2SO4, filtered, and evaporated un-
der reduced pressure. The residue was passed through a column
(SiO2; EtOAc–n-hexane, 14%) to afford the crude material including
18b, which was applied to the following reaction without further pu-
rification.
(+)-Aschantin (1d)
In a manner similar to that used to prepare 1a, 17 (236 mg, 0.67
mmol) gave (+)-aschantin (1d, 136 mg, 50%, three steps) as a colorless
solid.
[α]D26 +25.9 (c 0.20, CHCl3).
IR (film): 2930, 1591, 1506, 1449, 1420, 1329, 1238 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 6.86 (d, J = 1.5 Hz, 1 H), 6.81 (dd, J = 8.0,
1.5 Hz, 1 H), 6.79 (d, J = 8.0 Hz, 1 H), 5.95 (s, 2 H), 4.74 (d, J = 4.6 Hz,
2 H), 4.73 (d, J = 5.2 Hz, 2 H), 4.30–4.24 (m, 2 H), 3.90–3.85 (m, 2),
3.87 (s, 6 H), 3.83 (s, 3 H), 3.10–3.06 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 153.6, 148.2, 147.3, 137.6, 136.9,
135.2, 119.5, 108.4, 106.7, 103.0, 101.2, 86.2, 85.9, 72.1, 71.9, 61.0,
56.3, 54.6, 54.4.
To a solution of the crude material including 18b in THF (0.7 mL) was
added a solution of LiBH4 (3.0 M in THF, 0.6 mL 1.8 mmol) at 0 °C. The
resulting mixture was stirred at r.t. for 1 h, then poured into sat. aq
NH4Cl and extracted with EtOAc. The organic layer was washed with
brine, dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The crude material including 19b was applied to the follow-
ing reaction without further purification.
HRMS (ESI): m/z [M + H]+ calcd for C22H25O7: 401.1600; found:
401.1595.
To a solution of the crude material including 19b in CH2Cl2 (2.0 mL)
were added HC(OMe)3 (0.1 mL) and a solution of AcCl (14 μL, 0.20
mmol) in MeOH (1.0 mL) at 0 °C. The resulting mixture was stirred at
r.t. for 18 h, then poured into sat. aq NaHCO3 and extracted with
EtOAc. The organic layer was concentrated under reduced pressure.
The crude material including 21 was applied to the following reaction
without further purification.
(+)-5'-Hydroxymethylpiperitol (1e)
In a manner similar to that used to prepare 1a, 17 (167 mg, 0.48
mmol) gave (+)-5'-hydroxymethylpiperitol (1e; 102 mg, 52%, three
steps) as a colorless solid.
[α]D27 +31.7 (c 0.50, CHCl3).
IR (film): 3421, 2934, 1595, 1508, 1431, 1246 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 6.85 (d, J = 1.2 Hz, 1 H), 6.80 (dd, J = 8.0,
1.7 Hz, 1 H), 6.78 (d, J = 8.0 Hz, 1 H), 6.56 (d, J = 1.7 Hz, 1 H), 6.49 (d,
J = 1.7 Hz, 1 H), 5.95 (s, 2 H), 5.82 (s, 1 H), 4.71 (d, J = 2.9 Hz, 1 H), 4.70
(d, J = 3.4 Hz, 1 H), 4.26 (dd, J = 9.0, 6.8 Hz, 1 H), 4.24 (dd, J = 9.0,
6.8 Hz, 1 H), 3.88 (s, 3 H), 3.87 (s, 3 H), 3.90–3.86 (m, 2 H), 3.11–3.00
(m, 2 H).
A mixture of the crude material including 21 and 5% Pd/C (38 mg) in
EtOAc (2.0 mL) was stirred under hydrogen (balloon) at r.t. for 18 h.
The reaction mixture was filtered through a pad of Celite and evapo-
rated under reduced pressure. The residue was purified by column
chromatography (SiO2; EtOAc–n-hexane, 20%) to afford (+)-sesaminol
(1b, 27.2 mg, 35%, four steps) as a colorless solid.
[α]D20 +31.3 (c 0.29, CHCl3).
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13C NMR (125 MHz, CDCl3): δ = 152.6, 149.4, 148.0, 147.2, 137.5,
135.1, 134.9, 119.5, 108.3, 106.6, 105.6, 101.7, 101.2, 85.9, 85.8, 72.0,
71.8, 61.0, 56.0, 54.4, 54.3.
HRMS (ESI): m/z [M + Na]+ calcd for C21H22O7Na: 409.1258; found:
409.1263.
Synthesis 2005, 2913. (d) Kise, N.; Fujimoto, A.; Moriyama, N.;
Ueda, N. Tetrahedron: Asymmetry 2003, 14, 2495. (e) Brown, R.
C. D.; Bataille, C. J. R.; Bruton, G.; Hinks, J. D.; Swain, N. A. J. Org.
Chem. 2001, 66, 6719. (f) Rana, K. K.; Guin, C.; Roy, S. C. Tetrahe-
dron Lett. 2000, 41, 9337. (g) Hull, H. M.; Jones, R. G.; Knight, D.
W. J. Chem. Soc., Perkin Trans. 1 1998, 1779. (h) Samizu, K.;
Ogasawara, K. Chem. Lett. 1995, 543. (i) Suginome, H.; Orito, K.;
Yorita, K.; Ishikawa, M.; Shimoyama, N.; Sasaki, T. J. Org. Chem.
1995, 60, 3052. (j) Orito, K.; Yorita, K.; Suginome, H. Tetrahedron
Lett. 1991, 32, 5999. (k) Takano, S.; Ohkawa, T.; Tamori, S.;
Satoh, S.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1988, 189.
(l) Pelter, A.; Ward, R. S.; Watson, D. J.; Jack, I. R. J. Chem. Soc.,
Perkin Trans. 1 1982, 183. (m) Pelter, A.; Ward, R. S.; Watson, D.
J.; Collins, P.; Kay, I. T. J. Chem. Soc., Perkin Trans. 1 1982, 175.
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(5) (a) Aldous, D. J.; Batsanov, A. S.; Yufit, D. S.; Dalencon, A. J.;
Dutton, W. M.; Steel, P. G. Org. Biomol. Chem. 2006, 4, 2912.
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Acknowledgment
This work was financially supported by the Uehara Memorial Founda-
tion (Y.H.), MEXT/JSPS KAKENHI Grant Numbers 23390007 and
26860013, Grants-in-Aid for Scientific Research on Priority Areas
12045232 and 24105530 from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT) of Japan, and a grant for Plat-
form for Drug Discovery, Informatics, and Structural Life Science from
the Ministry of Education, Culture, Sports, Science and Technology.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378812.
S
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(6) We previously reported a part of this work as a communication,
see: Ishikawa, R.; Yoshida, N.; Akao, Y.; Kawabe, Y.; Inai, M.;
Asakawa, T.; Hamashima, Y.; Kan, T. Chem. Lett. 2014, 43, 1572.
(7) For a short review, see: (a) Asakawa, T.; Hamashima, Y.; Kan, T.
Curr. Pharm. Des. 2013, 19, 6207. See also: (b) Furuta, T.;
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(c) Hirooka, Y.; Nitta, M.; Furuta, T.; Kan, T. Synlett 2008, 3234.
(d) Aihara, Y.; Yoshida, A.; Furuta, T.; Wakimoto, T.; Akizawa, T.;
Konishi, M.; Kan, T. Bioorg. Med. Chem. Lett. 2009, 19, 4171.
(e) Kawabe, Y.; Aihara, Y.; Hirose, Y.; Sakurada, A.; Yoshida, A.;
Inai, M.; Asakawa, T.; Hamashima, Y.; Kan, T. Synlett 2013, 24,
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(8) Kawabe, Y.; Ishikawa, R.; Akao, Y.; Yoshida, A.; Inai, M.;
Asakawa, T.; Hamashima, Y.; Kan, T. Org. Lett. 2014, 16, 1976.
(9) (a) Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804.
(b) Freeman, P. T.; Siggel, L.; Chamberlain, P. H. Tetrahedron
1988, 44, 5051.
(10) Hajra and co-workers reported a similar aldol reaction, but they
noted that reactions with electron-rich benzaldehydes were
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(b) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
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(11) For protection of phenols, see references 7d and 7e. For reviews
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