Syntheses of SGLT2 inhibitors by Ni- And Pd-catalyzed fukuyama coupling reactions

Article abstract of DOI:10.1021/acs.joc.0c01635

Nickel- and palladium-catalyzed Fukuyama coupling reactions of a D-gluconolactone-derived thioester with arylzinc reagents at ambient temperature provided the corresponding multifunctional aryl ketones in high yield. Ligand screening for the nickel-catalyzed Fukuyama coupling reactions indicated that 1,2- bis(dicyclohexylphosphino)ethane (dCype) served as a superior supporting ligand to improve the product yield. In addition, Pd/C was a practical alternative that enabled ligand-free Fukuyama coupling reactions and was efficiently applied to the key C-C bond-forming step to prepare canagliflozin and dapagliflozin, which are diabetic SGLT2 inhibitors of current interest.

Full text of DOI:10.1021/acs.joc.0c01635

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Article
Syntheses of SGLT2 Inhibitors by Ni- and Pd-
Catalyzed Fukuyama Coupling Reactions
Jalindar Talode, Daiki Kato, Haruki Nagae, Hayato Tsurugi, Masahiko Seki, and Kazushi Mashima
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01635 • Publication Date (Web): 10 Sep 2020
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Syntheses of SGLT2 Inhibitors by Ni- and Pd-Catalyzed Fukuyama
Coupling Reactions
Jalindar Talode,a Daiki Kato,a Haruki Nagae,a Hayato Tsurugi,a,* Masahiko Seki,b,* and
Kazushi Mashimaa,*
a Department of Chemistry, Graduate School of Engineering Science, Osaka University, Toyonaka, Osaka 560-8531, Japan
E-mail: tsurugi@chem.es.osaka-u.ac.jp, mashima@chem.es.osaka-u.ac.jp
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b MA Group, Tokuyama Corporation, Tsukuba, Ibaraki 300-4247, Japan
E-mail: ma-seki@tokuyama.co.jp
ABSTRACT: Nickel- and palladium-catalyzed Fukuyama coupling reactions of a D-gluconolactone-derived thioester with arylzinc
reagents at ambient temperature provided the corresponding multi-
functional aryl ketones in high yield. Ligand screening for the nickel-
catalyzed Fukuyama coupling reactions indicated that 1,2-
bis(dicyclohexylphosphino)ethane (dCype) served as a superior supporting
ligand to improve the product yield. In addition, Pd/C was a practical al-
ternative that enabled ligand-free Fukuyama coupling reactions and was
efficiently applied to the key C-C bond-forming step to prepare Canagli-
flozin and Dapagliflozin, which are diabetic SGLT2 inhibitors of current
interest.
INTRODUCTION
The target -aryl-C-glycosides, such as Canagliflozin, are
obtained as the major isomer by combining with stereoselec-
tive reductive dehydroxylation using R3SiH and BF3·OEt2.
The drawbacks of the synthetic strategy are poor functional
group compatibility and inevitable cryogenic conditions for
the initial arylation step because of the high reactivity of aryl-
lithium and aryl Grignard reagents.6-7 The second approach is
arylation of glycosyl donors with arylmetal reagents or aryl
halides, which has been conducted under mild reaction condi-
tions in combination with or without transition metal catalysts
(Scheme 1(b)).8-11 Cross-coupling reactions of glycosyl bro-
mides with arylzinc (Negishi coupling) or aryl Grignard (Ku-
mada-Tamao coupling) as well as aryl halides (reductive cou-
pling) have been extensively explored in the last 15 years,
though the stereoselectivity of the anomeric position,  and ,
is highly dependent on the sugar motif, protecting groups, aryl
substituents, and stereochemistry of the original glycosyl do-
nors.8-11 In this context, stereoselective -C-glycosylation
reaction is recently reported using -isomers of glycosyl bro-
mides and arylzinc reagents.10b Pd-catalyzed -selective C-
arylation with aryl halides is accomplished utilizing glycosyl
stannane (Stille coupling), though prior synthesis of -isomers
of glycosyl stannanes is required.12
Sodium-glucose cotransporter-2 (SGLT2) inhibitors, a class of
anti-hyperglycemic agents, have attracted much attention in
recent years due to their effective control and regulation of
type-2 diabetes in a safe and well-tolerated manner.1 SGLT2
inhibitors function through a unique non-insulin dependent
mechanism to reduce renal tubular glucose reabsorption,
which consequently reduces blood glucose levels and contrib-
utes to control blood pressure and weight.2 Accordingly, the
FDA has approved SGLT2 inhibitors, such as Canagliflozin
(Invokana®), Dapagliflozin (Farxiga®), and Empagliflozin
(Jardiance®), as drugs for type-2 diabetes, all of which contain
aryl-C-glycoside is the key structural motif, as shown in (Fig-
ure 1).3
In this context, we envisioned the use of the catalytic C-
arylation of protected gluconolactone-derived thioesters with
arylmetal reagents, and we used the Fukuyama coupling reac-
tion13 as the most suitable approach for synthesizing SGLT2
inhibitors in industrial scale in terms of not only avoiding hal-
ogenation-dehalogenation sequences but also removing cryo-
genic conditions. Starting from benzyl-protected gluconolac-
tone 1, synthetically useful thioester 2 should be easily acces-
sible by AlMe3-mediated thioesterification via opening of the
lactone ring, and a subsequent Fukuyama coupling reaction is
a key step for preparing ketone 3 followed by deacylation to
Figure 1. SGLT2 Inhibitors (aryl-C-glycosides)
Carbon-carbon bond formation for synthesizing an aryl-C-
glycoside skeleton is well investigated, and two strategies are
usually applied to install aryl groups.4-10 The first approach is
C-arylation of readily available O-protected gluconolactone
with aryllithium or arylmagnesium reagents (Scheme 1(a)).6-7
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give aryl-C-glycoside 4 (Scheme 1(c)). Herein, we report our
palladium complexes under ligand-free conditions are shown
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search for a practical synthesis of the SGLT2 inhibitors
Canagliflozin and Dapagliflozin via nickel- and palladium-
catalyzed Fukuyama coupling reactions for the formation of -
C-arylglycosides.
in Table 1. In the presence of 5 mol% of NiCl2(thf)2, cross-
coupling product 3a was obtained in 46% yield, and unreacted
2 was recovered from the reaction mixture (entry 1). Other
nickel(II) sources, such as Ni(OAc)2 and Ni(acac)2, resulted in
a lower yield (entries 2 and 3). In sharp contrast, cobalt(II)
and iron(II) chlorides were inactive for the Fukuyama cou-
pling reaction (entries 4 and 5). We also tested palladium
sources for this coupling reaction: Pd(OAc)2 is typically used
for various coupling reactions, but the yield of 3a was almost
the same as NiCl2(thf)2, and the typically used Pd(0) source,
Pd2(dba)3, was less active under the ligand-free condition. In
sharp contrast, 10 wt% Pd/C (2 mol% catalyst loading)
showed excellent catalytic activity to give 3a in 70% yield
after 48 h at 40 °C. Moderate yield of corresponding coupling
product 3a was also observed in the presence of a typical Fu-
kuyama coupling catalyst PdCl2(PPh3)2 at room temperature
and at 40 °C (entries 9 and 10). We further conducted reaction
of thioester 2 with 3 equiv of PhZnBr and 10 wt% Pd/C as a
catalyst under Fukuyama coupling conditions at 40 °C for 48 h,
showing slightly better yield of product 3a (entry 11), though
the amount of the byproduct, biphenyl, was increased. Without
any catalyst, unreacted starting thioester 2 was recovered, in-
dicating the requirement of Ni and Pd catalysts for the Fuku-
yama coupling reaction (entry 12). Although sugar-derived
thioesters possess many ether moieties within the molecules
and are less reactive (vide infra), these Ni- and Pd-catalyzed
systems overcame the limitations and represent the first exam-
ple of a Fukuyama coupling reaction employing a thioester
with a sugar linkage.15 In fact, under the optimized reaction
conditions with the 10 wt% Pd/C catalyst, we conducted a
competitive experiment using 2 and simple thioester 2’ as
substrates, and ketone 3’ was obtained in better yield (eq 2).
Scheme 1. Formation of Aryl-C-Glycosides from Glyco-
side Donors and Gluconolactone
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RESULTS AND DISCUSSION
We started by preparing the thioester 2 from benzyl-protected
D-gluconolactone 1. Reaction of 1 with a mixture of decan-
ethiol and AlMe3 (both in 1.0 equiv) at 0 °C in CH2Cl2 for 2
h14 followed by hydrolysis and in situ acylation by acetic an-
hydride/4-dimethylaminopyridine (DMAP) afforded 2 in 90%
yield (eq 1). In this reaction, thioester A having a hydroxyl
group at the  position was initially formed by hydrolysis of
the reaction mixture, and it was necessary to treat A under the
acylation condition at 0 °C; otherwise, lactonization of 2 easily
occurred to regenerate the original compound 1. The isolated
thioester 2 was stable toward hydrolysis and lactonization, and
used for further Fukuyama coupling reactions.
Table 1. Catalyst Screening for Fukuyama Coupling Reac-
tion Using Sugar-derived Thioester 2
3a
3a
entry
cat.
entry
cat.
(%)b
(%)b
1
2
3
4
5
6
NiCl2(thf)2
Ni(acac)2
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30
7
8c
9
Pd2(dba)3
Pd/C
<5
70
Ni(OAc)2
CoCl2(thf)2
FeCl2(thf)2
Pd(OAc)2
38
PdCl2(PPh3)2
52
trace
trace
43
10d PdCl2(PPh3)2
11e
12f
64
Pd/C
-
81
n.d.
a Reaction conditions: 2 (0.25 mmol, 1.0 equiv), PhZnBr·LiCl (0.5 mmol,
2.0 equiv, prepared from ZnBr2·LiCl and PhMgBr), catalyst (5 mol%), RT,
d
THF, 6 h. b Isolated yield. c 10 wt% Pd/C (2 mol%), 40 °C, THF, 48 h.
40 °C, THF, 48 h. e PhZnBr·LiCl (0.75 mmol, 3.0 equiv), 10 wt% Pd/C (2
mol%), 40 °C, THF, 48 h. f Without catalyst. n.d. = not detected.
Reaction of the thioester 2 with 2 equiv of PhZnBr was se-
lected as a model reaction for the Fukuyama coupling reaction,
and results of the catalyst screening of nickel, cobalt, iron, and
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ortho, meta, and para-substitutents, and the results were
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shown in Table 3. Coupling reactions with a series of para-
substituted arylzinc reagents gave the corresponding ketones
(3b-f) in good yields, while a dimethylamino group was not
applicable probably due to the coordination of the tert-amine
moiety. Interestingly, para-halo substituted aryl zinc reagents
were tolerant under the reaction conditions without participa-
tion of the reactive halo terminus for Fukuyama coupling reac-
tion. Meta-methyl, methoxy, phenyl, dimethyl, and dimethoxy
substituents on the aryl ring were applicable to afford the cor-
responding ketones (3h-l) in 60-78% yields, respectively.
Further study of ortho-substituted arylzinc reagents with thi-
oester 2 gave the corresponding coupling products (3m-n) in
good yields, whereas ortho-phenyl and bulky ortho-dimethyl-
substituted ones were inactive for this coupling reaction. 6-
Methoxy-2-naphthyl zinc reagent also afforded the corre-
sponding cross-coupling product 3o in excellent yield. In ad-
dition to the phenyl and naphtyl rings, heteroarylation with 2-
thienyl and benzo[b]thiophen-5-yl zinc reagents afforded 3r
and 3s in good yields, respectively.
We next screened for the best supporting ligand for
NiCl2(thf)2, and the results are summarized in Table 2. Mono-
dentate phosphine ligands resulted in moderate yields of 3a.
Reaction with bidentate ligands having a C2-C4 carbon link-
age afforded 3a in 47%-56% yield, while the use of dppf gave
3a in the same yield (56%) as observed for dppe. Other biden-
tate phosphine ligands, such as DPEphos and Xantphos, af-
forded 3a in 34% and 20% yields (entries 8 and 9), although a
Xantphos-ligated nickel complex showed high catalytic activi-
ty for thioesters with a simple aliphatic chain.13d On the other
hand, the ligand dCype showed better catalytic activity, giving
3a in 65% yield (entry 10). In addition, we checked the effect
of chelating ligands dppe and dCype, for palladium-catalyzed
reactions, but those catalysts were less effective compared
with the ligand-free Pd/C catalyst (entries 11 and 12). Ac-
cordingly, we selected Pd/C as the best catalyst to promote the
practical applicability of our strategy using a Fukuyama cou-
pling reaction for preparing various sugar-derived ketones and
biologically active -aryl-C-glycosides, such as Canagliflozin
and Dapagliflozin.
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Table 3. Substrate Scope and Limitations of Arylzinc Rea-
gents in Pd/C-catalyzed Fukuyama Coupling Reactiona
Table 2. Ligand Screening for Fukuyama Coupling Reac-
tion Using Sugar-derived Thioester 2a
3a
entry
ligand
entry
ligand
3a (%)b
(%)b
52
1
2
3
4
5
6
PPh3
PCy3
7
8
dppf
DPEphos
Xantphos
dCype
56
34
20
65
36
12
60
P(2-furyl)3
dppe
24
9
56
10
11c
12c
aReaction conditions: 2 (0.25 mmol, 1.0 equiv), ArZnBr·LiCl (0.5 mmol,
2.0 equiv, prepared from ZnBr2·LiCl and ArMgBr), 10 wt% Pd/C (2
mol%), 40 °C, THF, 48 h. Isolated yield. n.d. = not detected.
dppp
53
dppe
dppb
47
dCype
aReaction conditions: 2 (0.25 mmol, 1.0 equiv), PhZnBr·LiCl (0.5 mmol,
2.0 equiv, prepared from ZnBr2·LiCl and PhMgBr), NiCl2(thf)2 (5 mol%),
ligand (10 mol% for monodentate phosphine and 5 mol% for bidentate
This Fukuyama coupling reaction is also viable with other
sugar precursors. For example, benzyl-protected D- galac-
tonolactone epi-1, was subjected to thioesterification under the
same reaction conditions as 1, giving thioester epi-2 in 87%
yield (eq. 3). Further Fukuyama coupling with arylzinc rea-
gents produced the cross-coupling products epi-3a and epi-3f
in 76% and 82% yields respectively (eq. 4).
c
phosphine), RT, THF, 6 h. b Isolated yield. PdCl2 (5 mol%) was used
instead of NiCl2(thf)2.
Having developed an efficient synthetic protocol for a Fu-
kuyama coupling reaction of sugar derivatives, we examined
substrate scope and limitations of arylzinc reagents including
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ing a typical de-benzylation method. The presence of a thio-
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phene moiety in 5t impaired hydrogenolysis using Pd/C, and
we accordingly applied Me3SiI as a Lewis acid for 5t at 0 °C,
affording the de-benzylated product 6t in 92% yield. In con-
trast, hydrogenolysis of the benzylether was compatible with
5u upon using 5 mol% of Pd/C in EtOAc under a H2 atmos-
phere (1 MPa): de-benzylated product 6u was obtained in 97%
yield without contamination of the -isomer. Notably, even in
the presence of an aryl chloride moiety within 5u, no hy-
drodehalogenation was observed under the reaction conditions.
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Scheme 2. Preparation of Canagliflozin and Dapagliflozin
Compatibility of various aromatic substituents on the aryl-
zinc reagents enabled us to apply this Fukuyama coupling
reaction to the synthesis of anti-diabetic SGLT2 inhibitors.
The required arylzinc reagents were prepared by treating
ZnBr2 with the corresponding aryl Grignard reagents.16 Thi-
oester 2 and 10 wt% Pd/C (2 mol% on Pd cat.) were mixed
with in situ-prepared ArZnBr·LiCl in THF at 40 °C for 48 h,
giving 3t in 71% yield. No catalyst deactivation was observed
even in the presence of a thiophene moiety in the arylzinc
motif (eq 5). In a similar manner, ketone 3u was isolated in
74% yield without any dechlorination of the aryl chloride
moiety.
SUMMARY
We report a new practical strategy for synthesizing pharma-
ceutically important aryl-C-glycosides without cryogenic con-
ditions. Nickel- and palladium-catalyzed Fukuyama coupling
reactions of D-gluconolactone derived thioester 2 with aryl-
zinc reagents provided ketones 3t and 3u as important synthet-
ic intermediates, and subsequent cyclization, reductive dehy-
droxylation, and removal of the benzyl groups gave Canagli-
flozin and Dapagliflozin, respectively. Further synthetic ap-
plications of the present approach to other SGLT2 inhibitors
are under current investigation in our laboratories and will be
disclosed in due course.
We examined further transformations of 3t and 3u to -
aryl-C-glycosides via cyclic acetal formation and reductive
dehydroxylation (Scheme 2). Initially, treatment of 3t and 3u
with NaOMe in MeOH at room temperature afforded hemiace-
tals 4t and 4u in high yields,17a where intramolecular cycliza-
tion of the deacetylated intermediates effectively proceeded.
i
EXPERIMENTAL SECTION
Further treatment of 4t and 4u with Pr3SiH and BF3·OEt2
(both in 3 equiv) in CH2Cl2/CH3CN at 0 °C resulted in exclu-
sive formation of -isomers, 5t (88%) and 5u (94%).17a-d,18
The high β-selectivity is ascribed to the steric bulkiness
around the silicon center: in fact, using Et3SiH instead of
iPr3SiH under the similar reaction conditions resulted in lower
stereoselectivity (α/β = 1/3~1/4), and lower reaction tempera-
ture was necessary to improve the β-selectivity.18 Finally,
benzyl deprotection of the 5t and 5u was achieved by follow-
GENERAL EXPERIMENTAL DETAILS. All reactions
were performed under argon atmosphere using the standard
Schlenk technique and argon-filled glove box. Aryl zinc rea-
gents were prepared by following the literature procedures.16
Anhydrous solvents were purchased from Kanto Chemical and
further purified by passing through activated alumina under
positive argon pressure using Grubbs column (Glass Counter
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Solvent Dispending System, Nikko Hansen & Co., Ltd.).
A solution of 2,3,4,6-tetra-O-benzyl-D-galactopyranose (5.0 g,
9.24 mmol) in DMSO (25 mL) was stirred at RT for 30 min
under an argon atmosphere. Acetic anhydride (15 mL) was
added slowly within 5 min at RT. After the complete addition,
the reaction mixture was stirred at RT for 20 h. The reaction
progress was monitored by TLC analysis, and then the reac-
tion mixture was diluted with toluene (100 mL). 1 N HCl aq
(120 mL) was slowly added to quench the excess acetic anhy-
dride. The reaction mixture was stirred at RT for 20 min.
After the phase separation, the organic layer was washed with
a 1 M aqueous NaHCO3 (3 x 50 mL). Finally, Organic phase
was washed with water (15 mL) and brine (15 mL), and then
dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. The crude material was purified by column chroma-
tography on silica gel (ethyl acetate/hexane = 2/20 ~ 3/20) to
afford 2,3,4,6-tetra-O-benzyl-D-galactonolactone (epi-1, 4.34
g, 87%) as a colorless oil.19b 1H NMR (400 MHz, CDCl3, 30
ºC) δ 7.42 – 7.39 (m, 2H), 7.36 – 7.21 (m, 18H), 5.17 (d, J =
11.0 Hz, 1H), 4.92 (d, J = 11.3 Hz, 1H), 4.81 – 4.71 (m, 2H),
4.68 (d, J = 11.9 Hz, 1H), 4.60 (d, J = 11.3 Hz, 1H), 4.50 (d, J
= 11.7 Hz, 1H), 4.48 – 4.40 (m, 2H), 4.33 (ddd, J = 7.6, 5.5,
1.6 Hz, 1H), 4.15 (t, J = 1.9 Hz, 1H), 3.87 (dd, J = 9.5, 2.2 Hz,
1H), 3.74 – 3.62 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3,
30 ºC) δ 170.1, 137.9, 137.7, 137.6, 128.6, 128.62, 128.6,
128.5, 128.14, 128.12, 128.1, 128.03, 128.0, 127.96, 127.7, 80.3,
77.4 (2 C), 75.4, 74.9, 73.8, 72.9, 72.7, 67.7; IR (KBr): 3063,
2920, 2872, 1751, 1455, 1206, 1172, 1105, 737, 698 cm-1;
HRMS: [M + H]+ calcd for C34H35O6 539.2428; found
539.2432.
iPrMgCl (2.0 M in THF) and AlMe3 (2.0 M in toluene) were
purchased and used as received. Other chemicals and solvents
were used as received. 1H NMR spectra were measured on a
Bruker AV400M (400 MHz) spectrometer at 303 K in 5 mm
NMR tubes. Data were reported as follows: chemical shifts in
ppm () from tetramethylsilane or the residual solvent as an
internal standard in CHCl3 at DMSO at and
MeOH at , integration multiplicity (s = singlet, d = dou-
blet, t = triplet, dd = doublet of doublets, m = multiplet, dt =
doublet of triplets, and ddd = doublet of doublet of doublets),
coupling constants (Hz), and integration. 13C{1H} NMR spec-
tra were measured on a Bruker AV400M (100 MHz) spec-
trometer at 303 K with complete proton decoupling. All 13C
NMR chemical shifts were reported in ppm () relative to car-
bon resonances in CDCl3 at / DMSO-d6 at 39.5. High
resolution mass spectra were obtained on JEOL JMS 700.
Flash column chromatography was performed by using silica
gel 60 (0.040–0.0663 nm, 230–400 mesh ASTM).
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Preparation of PhZnBr·LiCl 16
An oven-dried 30 mL Schlenk-tube containing a magnetic stir
bar was charged in a glove box with anhydrous ZnBr2 (450 mg,
2.0 mmol, 1 equiv.) and anhydrous LiCl (85 mg, 2.0 mmol, 1
equiv.), which was then dried in oil bath (100 °C) under vacu-
um. After flushing the Schlenk-tube with argon, THF (6 mL)
was added and stirred for 5-10 min. Phenylmagnesium bro-
mide (1 M in THF) (2 mL, 2.0 mmol, 1.0 equiv.) was added.
The reaction mixture was stirred at RT for 1 h and diluted with
THF to make approx. 0.25 M concentration as determined by
titration with I2/LiCl, which was used immediately for cou-
pling reactions.
Synthesis of thioester 2
Step I: To a solution of decanethiol (1.61 g, 9.3 mmol) in
anhydrous CH2Cl2 (30 mL) cooled at 0 °C was added Me3Al
(9.3 mL, 9.3 mmol, 1 M in toluene) dropwise over 15 min and
the mixture was stirred for another 30 min. A solution of
compound 1 (5.0 g, 9.3 mmol) in anhydrous CH2Cl2 (20 mL)
was added slowly over a period of 20 min. After 2 h the reac-
tion mixture was diluted with CH2Cl2 (20 mL) and poured
slowly into a 250 mL beaker containing ice cooled water (100
mL) with stirring. 1 N HCl aq (30 mL) was added, and organ-
ic layer was quickly separated. The aqueous layer was further
extracted with cold CH2Cl2 (3 x 100 mL). The combined or-
ganic layers were washed with water, brine, dried over Na2SO4,
and filtration with pad of silica (4 cm) using CH2Cl2 as eluent,
giving crude A. The crude A was subsequently used for the
next step without purification.
Step II: Under an argon atmosphere, to a solution of crude A
in anhydrous CH2Cl2 (100 mL) cooled at 0 °C was added
Ac2O (2.6 mL, 27 mmol) followed by DMAP (23 mg, 2
mol%). After 5 minutes Et3N (3.8 mL, 27 mmol) was added
slowly and the mixture was then stirred under argon at RT for
12 h. The reaction mixture was quenched with water (50 mL),
and the organic product was extracted with dichloromethane
(3 x 50 mL). The combined organic phase was washed with
water (50 mL) and brine (50 mL), and dried over anhydrous
Na2SO4. After decantation, the mixture was concentrated.
The crude material was purified by silica gel column chroma-
tography (ethyl acetate/hexane = 1/20 ~ 2/20) to afford thioe-
ster 2 (6.32 g, 90% from 1) as a colorless liquid. 1H NMR
(400 MHz, CDCl3, 30 ºC) δ 7.40 (d, J = 6.5 Hz, 2H), 7.36-7.15
Synthesis of compound 1
A solution of 2,3,4,6-tetra-O-benzyl-D-glucopyranose (5.0 g,
9.24 mmol) in DMSO (25 mL) was stirred at RT for 30 min
under an argon atmosphere. Acetic anhydride (15 mL) was
added slowly within 5 min at RT. After the complete addition,
the reaction mixture was stirred at RT for 20 h. The reaction
progress was monitored by TLC analysis, and then the reac-
tion mixture was diluted with toluene (100 mL). 1 N HClaq
(120 mL) was slowly added to quench the excess acetic anhy-
dride. The reaction mixture was stirred at RT for 20 min.
After the phase separation, the organic layer was washed with
a 1 M aqueous NaHCO3 (3 x 50 mL). Finally, Organic phase
was washed with water (15 mL) and brine (15 mL), and then
dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. The crude material was purified by column chroma-
tography on silica gel (ethyl acetate/hexane = 2/20 ~ 3/20) to
afford 2,3,4,6-tetra-O-benzyl-D-gluconolactone (1, 4.8 g,
96%) as a colorless oil.19a 1H NMR (400 MHz, CDCl3, 30 ºC)
δ 7.39-7.16 (m, 20H), 4.97 (d, J = 11.4 Hz, 1H), 4.73-4.44 (m,
8H), 4.12 (d, J = 6.4 Hz, 1H), 3.96-3.89 (m, 2H), 3.73-3.64 (m,
2H); 13C{1H} NMR (100 MHz, CDCl3, 30 ºC) δ 169.4, 137.7,
137.6, 137.6, 137.1, 128.6, 128.53, 128.48, 128.2, 128.09,
128.07, 128.0, 127.9, 81.1, 78.3, 77.5, 76.2, 74.0, 73.8, 73.78,
73.7, 68.4; IR (KBr): 3031, 2921, 2867, 1758, 1457, 1172,
1098, 734, 697 cm-1; HRMS: [M
C34H35O6 539.2428; found 539.2420.
Synthesis of compound epi-1
+
H]+ calcd for
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(m, 18H), 5.15 (q, J = 4.3 Hz, 1H), 4.79 (d, J = 10.8 Hz, 1H),
General procedure for ligand-free Fukuyama coupling
reaction (Tables 1)
4.71 (d, J = 11.4 Hz, 1H), 4.65-4.39 (m, 6H), 4.25 (d, J = 4.3
Hz, 1H), 4.01-3.95 (m, 2H), 3.82 (dd, J = 10.6, 4.1 Hz, 1H),
3.65 (dd, J = 10.6, 5.7 Hz, 1H), 2.84 (t, J = 7.4 Hz, 2H), 1.96
(s, 3H), 1.55 (m, 2H), 1.41-1.18 (m, 14H), 0.88 (t, J = 6.7 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3, 30 ºC) δ 201.9, 170.0,
138.5, 138.1, 138.0, 137.1, 128.7, 128.4, 128.4, 128.36, 128.3,
128.2, 128.04, 128.0, 127.8, 127.7, 127.6, 127.5, 85.3, 80.3,
78.5, 75.7, 74.7, 74.5, 73.2, 72.9, 68.1, 31.9, 29.6, 29.6, 29.4,
29.2, 29.1, 28.4, 22.7, 21.1, 14.2; IR (KBr): 3065, 3031, 2924,
2855, 1743, 1678, 1455, 1371, 1238, 1172, 1026, 738, 699 cm-
1; HRMS: [M + H]+ calcd for C46H59O7S 755.3981; found
755.3976.
An oven dried Schlenk tube was charged with catalyst (0.0125
mmol, 0.05 equiv.) and THF (1 mL) under argon atmosphere.
Thioester 2 (0.25 mmol, 190 mg) in THF (2 mL) was added to
the reaction mixture followed by addition of PhZnBr·LiCl
(0.50 mmol, 2 mL) in THF (0.25 M) by syringe. The reaction
mixture was stirred at RT for 6 h. The reaction mixture was
quenched with water, and extracted with ethyl acetate (3 x 30
mL). The organic extract was washed with brine, dried over
anhydrous Na2SO4, and concentrated after filtration. The
crude mixture was purified by silica gel column chromatog-
raphy (ethyl acetate/hexane = 1/20 ~ 2/20) to afford the de-
sired compound 3a.
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Synthesis of thioester epi-2
Step I: To a solution of decanethiol (0.872 g, 5 mmol) in an-
hydrous CH2Cl2 (30 mL) cooled at 0 °C was added Me3Al (5
mL, 5 mmol, 1 M in toluene) dropwise over 15 min and the
mixture was stirred for another 30 min. A solution of com-
pound epi-1 (2.7 g, 5 mmol) in anhydrous CH2Cl2 (20 mL)
was added slowly over a period of 20 min. After 2 h the reac-
tion mixture was diluted with CH2Cl2 (20 mL) and poured
slowly into a 250 mL beaker containing ice cooled water (100
mL) with stirring. 1 N HCl aq (30 mL) was added, and organ-
ic layer was quickly separated. The aqueous layer was further
extracted with cold CH2Cl2 (3 x 100 mL). The combined or-
ganic layers were washed with water, brine, dried over Na2SO4,
and filtration with pad of silica (4 cm) using CH2Cl2 as eluent,
giving crude compound B. The crude compound B was sub-
sequently used for the next step without purification.
Step II: Under an argon atmosphere, to a solution of crude
compound B in anhydrous CH2Cl2 (70 mL) cooled at 0 °C was
added Ac2O (1.5 mL, 15 mmol) followed by DMAP (13 mg, 2
mol%). After 5 minutes Et3N (2.1 mL, 15 mmol) was added
slowly and the mixture was then stirred under argon at RT for
12 h. The reaction mixture was quenched with water (50 mL),
and the organic product was extracted with dichloromethane
(3 x 50 mL). The combined organic phase was washed with
water (50 mL) and brine (50 mL), and dried over anhydrous
Na2SO4. After decantation, the mixture was concentrated.
The crude material was purified by silica gel column chroma-
tography (ethyl acetate/hexane = 1/20 ~ 2/20) to afford thioe-
ster epi-2 (3.3 g, 87% from epi-1) as a colorless liquid. 1H
NMR (400 MHz, CDCl3, 30 ºC) δ 7.40 – 7.35 (m, 2H), 7.35 –
7.17 (m, 18H), 5.43 – 5.39 (m, 1H), 4.83 (d, J = 11.2 Hz, 1H),
4.56 (dd, J = 11.2, 5.5 Hz, 2H), 4.47 – 4.29 (m, 6H), 4.07 (dd,
J = 7.7, 2.8 Hz, 1H), 3.95 (dd, J = 7.8, 2.9 Hz, 1H), 3.66 (dd, J
= 10.1, 6.3 Hz, 1H), 3.59 (dd, J = 10.1, 6.0 Hz, 1H), 2.87 (t, J
= 7.4 Hz, 2H), 2.00 (s, 3H), 1.60 – 1.52 (m, 2H), 1.38 – 1.16
(m, 14H), 0.87 (t, J = 6.7 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3, 30 ºC) δ 203.4, 170.6, 138.3, 138.0, 137.8, 137.3,
128.5, 128.44, 128.43, 128.4, 128.3, 128.2, 128.0, 127.8, 127.78,
127.73, 127.6, 127.3, 84.8, 80.2, 77.4, 76.1, 74.7, 74.1, 73.7,
73.1, 71.4, 68.4, 32.0, 29.64, 29.6, 29.4, 29.2, 29.1, 28.5, 22.8,
21.2, 14.2; IR (KBr): 3064, 3031, 2925, 2855, 1744, 1675,
1498, 1457, 1373, 1236, 1172, 1089, 1026, 734, 697 cm-1;
HRMS: [M + H]+ calcd for C46H59O7S 755.3981; found
755.4001.
Pd/C-catalyzed Fukuyama coupling reaction (Table 1, en-
try 8)
An oven dried Schlenk tube was cooled under argon atmos-
phere and charged with thioester 2 (0.25 mmol, 190 mg) fol-
lowed by addition of 10 wt% Pd/C (0.0005 mmol, 5.4 mg) and
THF (2 mL). PhZnBr·LiCl solution (0.25 M in THF) (0.50
mmol, 2 mL) was added in dropwise manner to the reaction
mixture by syringe. The reaction mixture was further stirred
at 40 °C for 48 h. Allowed the reaction to cool to RT, and
then the reaction mixture was quenched with water (1 mL).
The reaction mixture was filtered through pad of celite with
ethyl acetate (3 x 30 mL). The filtrate was washed with water
and brine, and dried over anhydrous Na2SO4. After decanta-
tion and evaporation, the residue was purified by silica gel
column chromatography (ethyl acetate/hexane = 1/20 ~ 2/20)
to afford compound 3a (115 mg, 0.175 mmol, 70%) as a color-
less oil. Unreacted starting thioester 2 (53 mg, 27%) was re-
covered, and biphenyl (14 mg, 36%) obtained as a side prod-
uct.
1
Characterization data of compound 3a. H NMR (400 MHz,
CDCl3, 30 ºC) δ 7.92 (d, J = 7.8 Hz, 2H), 7.47 (t, J = 7.4 Hz,
1H), 7.37-7.22 (m, 15H), 7.21-7.11 (m, 5H), 7.06-7.00 (m,
2H), 5.27 (q, J = 5.2 Hz, 1H), 4.89 (d, J = 4.2 Hz, 1H), 4.73-
4.55 (m, 4H), 4.53-4.46 (m, 3H), 4.31 (d, J = 10.8 Hz, 1H),
4.21 (dd, J = 6.8, 4.3 Hz, 1H), 4.07 (dd, J = 6.8, 3.4 Hz, 1H),
3.87 (dd, J = 10.2, 5.4 Hz, 1H), 3.63 (dd, J = 10.2, 5.5 Hz, 1H),
1.98 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 30 ºC) δ 199.0,
169.9, 138.4, 137.9, 137.8, 137.1, 136.05, 133.1, 129.0, 128.8,
128.5, 128.4, 128.3, 128.26, 128.19, 128.0, 127.9, 127.8, 127.73,
127.7, 127.5, 127.45, 82.7, 80.4, 79.6, 75.3, 74.6, 73.2, 73.1,
72.6, 67.9, 21.1; IR (KBr): 3065, 3028, 2925, 2868, 1748,
1684, 1557, 1538, 1449, 1369, 1236, 1090, 1027, 738, 696 cm-
1; HRMS: [M + H]+ calcd for C42H43O7 659.3009; found
659.3004.
Large Scale Fukuyama coupling reaction of 2 and
PhZnBr·LiCl catalyzed by Pd/C
An oven dried Schlenk tube was cooled under argon atmos-
phere and charged with thioester 2 (1.0 mmol, 755 mg) fol-
lowed by addition of 10 wt% Pd/C (0.020 mmol, 21.6 mg) and
THF (6 mL). PhZnBr·LiCl solution (0.25 M in THF) (2.0
mmol, 8 mL) was added in dropwise manner to the reaction
mixture by syringe. The reaction mixture was further stirred
at 40 °C for 48 h. Allowed the reaction to cool to RT, and
then the reaction mixture was quenched with water (1 mL).
The reaction mixture was filtered through pad of celite with
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ethyl acetate (3 x 50 mL). The filtrate was washed with water
column chromatography (ethyl acetate/hexane = 1/20 ~ 3/20)
to afford compound 3
and brine, and dried over anhydrous Na2SO4. After decanta-
tion and evaporation, the residue was purified by silica gel
column chromatography (ethyl acetate/hexane = 1/20 ~ 2/20)
to afford compound 3a as a colorless oil (468 mg, 0.71 mmol,
71%). Unreacted starting thioester 2 (181 mg, 24%) was re-
covered.
Characterization data of compound 3b. Purified by silica gel
column chromatography (ethyl acetate/hexane = 1/20 ~ 3/20)
1
as a colorless oil (112 mg, 66% yield); H NMR (400 MHz,
CDCl3, 30 ºC) δ 7.96 (dd, J = 8.8, 5.6 Hz, 2H), 7.36 – 7.12 (m,
18H), 7.00 (dd, J = 7.5, 2.1 Hz, 2H), 6.88 (t, J = 8.7 Hz, 2H),
5.28 – 5.25 (m, 1H), 4.77 (d, J = 4.0 Hz, 1H), 4.68 – 4.47 (m,
7H), 4.31 (d, J = 10.8 Hz, 1H), 4.17 (dd, J = 7.0, 4.1 Hz, 1H),
4.08 (dd, J = 7.0, 3.4 Hz, 1H), 3.89 (dd, J = 10.2, 5.4 Hz, 1H),
3.65 (dd, J = 10.2, 5.5 Hz, 1H), 1.99 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3, 30 ºC) δ 197.9, 170.1, 165.8 (d, J = 256.0
Hz), 138.5, 138.0, 137.8, 137.0, 132.4 (d, J = 3.0 Hz), 132.1,
132.0, 128.9, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 127.9,
127.85, 127.6 (d, J = 7.1 Hz), 115.4 (d, J = 21.2 Hz), 83.4,
80.6, 79.7, 75.5, 74.8, 73.4, 73.3, 72.7, 68.1, 21.2; IR (KBr):
3066, 3031, 2925, 2862, 1742, 1700, 1600, 1509, 1454, 1369,
1242, 1155, 1025, 744, 700 cm-1; HRMS: [M + H]+ calcd. for
C42H42FO7 677.2915; found 677.2914.
General procedure for Ni-catalyzed Fukuyama coupling
reaction (Tables 2)
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An oven dried Schlenk tube was charged with NiCl2(thf)2
(0.0125 mmol, 0.05 equiv.), ligand (10 mol% for monodentate
phosphine and 5 mol% for bidentate phosphine), and THF (1
mL) under argon atmosphere. Thioester 2 (0.25 mmol, 190
mg) in THF (2 mL) was added to the reaction mixture, fol-
lowed by addition of PhZnBr·LiCl (0.50 mmol, 2 mL) in THF
(0.25 M) by syringe. The reaction mixture was stirred at RT
for 6 h. The reaction mixture was quenched with water and
extracted with ethyl acetate (3 x 30 mL). The organic extract
was washed with brine, dried over anhydrous Na2SO4, and
then the mixture was concentrated after filtration. The crude
mixture was purified by silica gel column chromatography
(ethyl acetate/hexane = 1/20 ~ 2/20) to afford the desired
compound 3a.
Characterization data of compound 3c. Purified by silica gel
column chromatography (ethyl acetate/hexane = 1/20 ~ 3/20)
1
as a colorless oil (118 mg, 68% yield); H NMR (400 MHz,
CDCl3, 30 ºC) δ 7.84 (d, J = 8.6 Hz, 2H), 7.33 – 7.21 (m, 15H),
7.20 – 7.12 (m, 5H), 7.00 (dd, J = 7.8, 1.5 Hz, 2H), 5.24 – 5.27
(m, 1H), 4.77 (d, J = 4.0 Hz, 1H), 4.69 – 4.53 (m, 4H), 4.53 –
4.46 (m, 3H), 4.30 (d, J = 10.9 Hz, 1H), 4.16 (dd, J = 7.0, 4.1
Hz, 1H), 4.08 (dd, J = 7.0, 3.4 Hz, 1H), 3.89 (dd, J = 10.2, 5.5
Hz, 1H), 3.64 (dd, J = 10.2, 5.4 Hz, 1H), 1.99 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3, 30 ºC) δ 198.3, 170.1, 139.6, 138.5,
138.0, 137.7, 137.0, 134.4, 130.8, 128.9, 128.63, 128.61, 128.5,
128.43, 128.4, 128.22, 128.2, 127.93, 127.9, 127.7, 127.6, 83.3,
80.6, 79.7, 75.5, 74.8, 73.5, 73.4, 72.7, 68.1, 21.2; IR (KBr):
3062, 3032, 2951, 2869, 1737, 1686, 1589, 1495, 1453, 1373,
1235, 1096, 1025, 745, 697 cm-1; HRMS: [M + H]+ calcd. for
C42H42ClO7 693.2619; found 693.2610.
Competitive experiment using Pd/C catalyst
An oven dried Schlenk tube was cooled under argon atmos-
phere and charged with thioester 2 (0.25 mmol, 190 mg), thi-
oester 2’ (0.25 mmol, 77 mg), 10 wt% Pd/C (0.005 mmol, 5.4
mg), and THF (2 mL). PhZnBr·LiCl (0.25 M in THF) (1.0
mmol, 4 mL) was added to the reaction mixture by syringe.
The reaction mixture was stirred at 40 °C for 24 h. Allowed
the reaction to cool to RT, and then reaction was quenched
with water (1 mL). Reaction mixture filtered through pad of
celite and washed with ethyl acetate (3 x 30 mL). The filtrate
was washed with water and brine, and dried over anhydrous
Na2SO4. After decantation and evaporation, the residue was
purified by silica gel column chromatography (ethyl ace-
tate/hexane = 1/20 ~ 2/20) to afford 3a (89 mg, 0.135 mmol,
54%) and 3’ (40 mg, 0.19 mmol, 76%).
Characterization data of compound 3d. Purified by silica gel
column chromatography (ethyl acetate/hexane = 1/20 ~ 3/20)
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as a colorless oil (125 mg, 74% yield); H NMR (400 MHz,
1
Characterization data of compound 3′20. H NMR (400 MHz,
CDCl3, 30 ºC) δ 7.85 (d, J = 8.2 Hz, 2H), 7.33 – 7.22 (m, 13H),
7.20 – 7.14 (m, 5H), 7.07 – 7.04 (m, 4H), 5.29 – 5.25 (m, 1H),
4.89 (d, J = 4.3 Hz, 1H), 4.69 – 4.56 (m, 4H), 4.54 – 4.45 (m,
3H), 4.33 (d, J = 10.8 Hz, 1H), 4.21 (dd, J = 6.8, 4.3 Hz, 1H),
4.05 (dd, J = 6.8, 3.5 Hz, 1H), 3.87 (dd, J = 10.3, 5.4 Hz, 1H),
3.63 (dd, J = 10.2, 5.5 Hz, 1H), 2.36 (s, 3H), 1.98 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3, 30 ºC) δ 198.3, 170.1, 144.1,
138.6, 138.1, 138.0, 137.4, 133.7, 129.21, 129.2, 128.9, 128.6,
128.43, 128.41, 128.3, 128.2, 128.0, 127.9, 127.8, 127.6, 127.5,
82.7, 80.6, 79.8, 75.4, 74.7, 73.3, 73.1, 72.7, 68.0, 21.8, 21.2;
IR (KBr): 3064, 3030, 2921, 2866, 1738, 1685, 1606, 1497,
1453, 1370, 1238, 1096, 1024, 742, 698 cm-1; HRMS: [M +
H]+ calcd. for C43H45O7 673.3165; found 673.3174.
CDCl3, 30 ºC) δ 7.95 (d, J = 7.3 Hz, 2H), 7.55 (t, J = 7.4 Hz,
1H), 7.45 (t, J = 7.6 Hz, 2H), 7.32 – 7.23 (m, 4H), 7.20 (t, J =
7.0 Hz, 1H), 3.30 (t, J = 7.7 Hz, 2H), 3.07 (t, J = 7.7 Hz, 2H).
13C{1H} NMR (100 MHz, CDCl3, 30 ºC) δ 199.3, 141.5, 137.1,
133.2, 128.74, 128.7, 128.6, 128.2, 126.3, 40.6, 30.3.
General procedure for Pd/C-catalyzed Fukuyama coupling
reaction (Table 3, for compounds 3b-3s; epi-3a and epi-3f)
An oven dried Schlenk tube was cooled under argon atmos-
phere and charged with thioester 2 (0.25 mmol, 190 mg) fol-
lowed by addition of 10 wt% Pd/C (0.005 mmol, 5.4 mg) and
THF (2 mL). ArZnBr·LiCl solution (0.25 M in THF) (0.50
mmol, 2 mL) was added in dropwise manner to the reaction
mixture by syringe. The reaction mixture was further stirred
at 40 °C for 48 h. Allowed the reaction to cool to RT, and
then the reaction mixture was quenched with water (1 mL).
The reaction mixture was filtered through pad of celite with
ethyl acetate (3 x 30 mL). The filtrate was washed with water
and brine, and dried over anhydrous Na2SO4. After decanta-
tion and evaporation, the residue was purified by silica gel
Characterization data of compound 3e. Purified by silica gel
column chromatography (ethyl acetate/hexane = 1/20 ~ 3/20)
1
as a colorless oil (122 mg, 68% yield); H NMR (400 MHz,
CDCl3, 30 ºC) δ 7.86 (d, J = 8.6 Hz, 2H), 7.39 – 7.23 (m, 16H),
7.18 – 7.13 (m, 4H), 7.05 – 7.02 (m, 2H), 5.30 – 5.26 (m, 1H),
4.90 (d, J = 4.3 Hz, 1H), 4.69 – 4.46 (m, 7H), 4.32 (d, J = 10.8
Hz, 1H), 4.20 (dd, J = 6.8, 4.3 Hz, 1H), 4.07 (dd, J = 6.9, 3.5
Hz, 1H), 3.89 (dd, J = 10.2, 5.4 Hz, 1H), 3.64 (dd, J = 10.3,
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5.5 Hz, 1H), 1.98 (s, 3H), 1.30 (s, 9H). 13C{1H} NMR (100
MHz, CDCl3, 30 ºC) δ 198.2, 170.1, 157.0, 138.6, 138.1, 138.0,
137.4, 133.5, 129.0, 128.9, 128.6, 128.5, 128.4, 128.3, 128.2,
128.0, 127.9, 127.8, 127.6, 127.55, 125.5, 82.5, 80.6, 79.9,
75.4, 74.8, 73.4, 73.0, 72.8, 68.1, 35.2, 31.2, 21.2; IR (KBr):
3062, 3031, 2962, 2867, 1737, 1672, 1604, 1497, 1455, 1365,
1236, 1100, 1026, 734, 697 cm-1; HRMS: [M + H]+ calcd. for
C46H51O7 715.3629; found 715.3632.
as a colorless oil (127 mg, 69% yield); H NMR (400 MHz,
CDCl3, 30 ºC) δ 8.19 (t, J = 1.7 Hz, 1H), 7.87 (dt, J = 7.8, 1.3
Hz, 1H), 7.72 – 7.70 (m, 1H), 7.45 – 7.26 (m, 16H), 7.25 –
7.21 (m, 4H), 7.18 – 7.16 (m, 2H), 7.12 – 7.09 (m, 2H), 7.05 –
7.02 (m, 2H), 5.31 – 5.27 (m, 1H), 4.89 (d, J = 4.3 Hz, 1H),
4.65 – 4.35 (m, 8H), 4.23 (dd, J = 6.8, 4.3 Hz, 1H), 4.09 (dd, J
= 6.8, 3.6 Hz, 1H), 3.86 (dd, J = 10.3, 5.1 Hz, 1H), 3.64 (dd, J
= 10.3, 5.6 Hz, 1H), 1.97 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3, 30 ºC) δ 199.5, 170.1, 141.6, 140.3, 138.5, 138.0,
137.9, 137.2, 136.8, 131.8, 128.9, 128.86, 128.7, 128.6, 128.5,
128.45, 128.3, 128.2, 128.1, 128.0, 127.95, 127.9, 127.8, 127.77,
127.6, 127.3, 127.1, 83.2, 80.6, 79.6, 75.4, 74.7, 73.3, 72.8,
68.0, 65.6, 21.2; IR (KBr): 3064, 3030, 2918, 2860, 1736,
1670, 1584, 1454, 1397, 1235, 1108, 1028, 736, 696 cm-1;
HRMS: [M]+ calcd. for C48H47O7 735.3322; found 735.3318.
Characterization data of compound 3k. Purified by silica gel
column chromatography (ethyl acetate/hexane = 1/20 ~ 3/20)
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Characterization data of compound 3f. Purified by silica gel
column chromatography (ethyl acetate/hexane = 1/20 ~ 3/20)
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as a colorless oil (135 mg, 78% yield); H NMR (400 MHz,
CDCl3, 30 ºC) δ 7.96 (d, J = 8.9 Hz, 2H), 7.35 – 7.22 (m, 13H),
7.20 – 7.15 (m, 5H), 7.06 – 7.03 (m, 2H), 6.72 (d, J = 8.9 Hz,
2H), 5.30 – 5.28 (m, 1H), 4.85 (d, J = 4.3 Hz, 1H), 4.68 – 4.54
(m, 4H), 4.50 – 4.45 (m, 3H), 4.35 (d, J = 10.8 Hz, 1H), 4.19
(dd, J = 6.7, 4.4 Hz, 1H), 4.05 (dd, J = 6.8, 3.5 Hz, 1H), 3.89
(dd, J = 10.3, 5.3 Hz, 1H), 3.80 (s, 3H), 3.64 (dd, J = 10.3, 5.5
Hz, 1H), 1.98 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 30
ºC) δ 197.2, 170.1, 163.7, 138.6, 138.1, 138.0, 137.3, 131.6,
129.1, 128.9, 128.5, 128.43, 128.41, 128.3, 128.1, 128.0, 127.9,
127.8, 127.6, 127.5, 113.7, 82.9, 80.7, 79.8, 75.5, 74.7, 73.3,
73.0, 72.7, 68.1, 55.5, 21.2; IR (KBr): 3063, 3031, 2911, 2867,
1739, 1671, 1600, 1510, 1453, 1368, 1238, 1098, 1026, 736,
698 cm-1; HRMS: [M + H]+ calcd. for C43H45O8 689.3114;
found 689.3115.
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as a colorless oil (134 mg, 78% yield); H NMR (400 MHz,
CDCl3, 30 ºC) δ 7.54 (s, 2H), 7.34 – 7.27 (m, 4H), 7.27 – 7.21
(m, 10H), 7.19 – 7.07 (m, 7H), 5.31 – 5.27 (m, 1H), 4.88 (d, J
= 4.4 Hz, 1H), 4.63 – 4.60 (m, 3H), 4.53 – 4.40 (m, 5H), 4.19
(dd, J = 6.5, 4.5 Hz, 1H), 4.02 (dd, J = 6.5, 3.8 Hz, 1H), 3.85
(dd, J = 10.6, 4.8 Hz, 1H), 3.64 (dd, J = 10.6, 5.8 Hz, 1H),
2.22 (s, 6H), 1.98 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3,
30 ºC) δ 199.8, 170.1, 138.6, 138.1, 137.4, 136.5, 135.0, 128.8,
128.5, 128.48, 128.4, 128.37, 128.3, 128.2, 128.0, 127.9, 127.8,
127.7, 127.6, 127.5, 126.9, 82.6, 80.7, 79.5, 75.4, 74.5, 73.2,
73.1, 72.8, 68.1, 21.3, 21.2; IR (KBr): 3063, 3028, 2917, 2849,
1738, 1665, 1598, 1496, 1454, 1395, 1237, 1107, 1028, 735,
696 cm-1; HRMS: [M]+ calcd. for C44H47O7 687.3322; found
687.3326.
Characterization data of compound 3h. Purified by silica gel
column chromatography (ethyl acetate/hexane = 1/20 ~ 3/20)
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as a colorless oil (101 mg, 60% yield); H NMR (400 MHz,
CDCl3, 30 ºC) δ 7.73 – 7.70 (m, 2H), 7.37 – 7.27 (m, 8H),
7.25 – 7.13 (m, 12H), 7.07 – 7.05 (m, 2H), 5.30 – 5.26 (m,
1H), 4.88 (d, J = 4.3 Hz, 1H), 4.65 – 4.45 (m, 7H), 4.35 (d, J =
10.8 Hz, 1H), 4.20 (dd, J = 6.7, 4.4 Hz, 1H), 4.05 (dd, J = 6.7,
3.6 Hz, 1H), 3.86 (dd, J = 10.4, 5.2 Hz, 1H), 3.64 (dd, J = 10.4,
5.6 Hz, 1H), 2.26 (s, 3H), 1.98 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3, 30 ºC) δ 199.4, 170.1, 138.6, 138.3, 138.1, 138.0,
137.3, 136.3, 134.0, 129.7, 128.9, 128.6, 128.4, 128.39, 128.3,
128.2, 128.0, 127.9, 127.82,127.8, 127.59, 127.57, 126.3, 82.7,
80.6, 79.7, 75.4, 74.7, 73.3, 73.1, 72.8, 68.1, 21.4, 21.2; IR
(KBr): 3063, 3030, 2917, 2866, 1737, 1676, 1602, 1496, 1455,
1370, 1237, 1094, 1027, 737, 697 cm-1; HRMS: [M]+ calcd.
for C43H45O7 673.3165; found 673.3163.
Characterization data of compound 3l. Purified by silica gel
column chromatography (ethyl acetate/hexane = 1/20 ~ 3/20)
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as a colorless oil (130 mg, 72% yield); H NMR (400 MHz,
CDCl3, 30 ºC) δ 7.33 – 7.21 (m, 13H), 7.18 – 7.16 (m, 5H),
7.12 (d, J = 2.3 Hz, 2H), 7.07 (dd, J = 6.5, 2.9 Hz, 2H), 6.60 (t,
J = 2.3 Hz, 1H), 5.29 – 5.25 (m, 1H), 4.89 (d, J = 4.2 Hz, 1H),
4.68 – 4.47 (m, 7H), 4.35 (d, J = 10.9 Hz, 1H), 4.23 (dd, J =
6.8, 4.2 Hz, 1H), 4.05 (dd, J = 6.8, 3.6 Hz, 1H), 3.84 (dd, J =
10.3, 5.3 Hz, 1H), 3.66 (s, 6H), 3.61 (dd, J = 10.3, 5.6 Hz, 1H),
1.98 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 30 ºC) δ 198.7,
170.1, 160.8, 138.5, 138.1, 138.0, 137.3, 128.8, 128.5, 128.4,
128.37, 128.31, 128.2, 128.0, 127.93, 127.9, 127.8, 127.6, 127.6,
106.8, 105.9, 82.8, 80.8, 79.6, 75.4, 74.6, 73.2, 72.8, 67.8,
55.6, 21.2; IR (KBr): 3064, 3032, 2923, 2865, 1738, 1701,
1592, 1456, 1239, 1206, 1157, 1098, 1071, 735, 699 cm-1;
HRMS: [M + H]+ calcd. for C44H47O9 719.3220; found
719.3229.
Characterization data of compound 3i. Purified by silica gel
column chromatography (ethyl acetate/hexane = 1/20 ~ 3/20)
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as a colorless oil (128 mg, 74% yield); H NMR (400 MHz,
CDCl3, 30 ºC) δ 7.51 – 7.47 (m, 2H), 7.33 – 7.21 (m, 13H),
7.19 – 7.12 (m, 6H), 7.08 – 7.02 (m, 3H), 5.29 – 5.26 (m, 1H),
4.89 (d, J = 4.2 Hz, 1H), 4.67 – 4.46 (m, 7H), 4.31 (d, J = 10.9
Hz, 1H), 4.22 (dd, J = 6.8, 4.2 Hz, 1H), 4.07 (dd, J = 6.8, 3.5
Hz, 1H), 3.86 (dd, J = 10.3, 5.4 Hz, 1H), 3.67 (s, 3H), 3.63 (dd,
J = 10.2, 5.5 Hz, 1H), 1.98 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3, 30 ºC) δ 198.7, 170.1, 159.7, 138.5, 138.03, 138.0,
137.5, 137.3, 129.4, 128.9, 128.6, 128.4, 128.3, 128.3, 128.2,
128.0, 127.91, 127.9, 127.8, 127.6, 127.57, 121.6, 120.1, 113.1,
82.8, 80.7, 79.7, 75.4, 74.7, 73.3, 73.2, 72.7, 68.0, 55.4, 21.2;
IR (KBr): 3064, 3032, 2929, 2867, 1737, 1672, 1623, 1484,
1456, 1270, 1240, 1029, 741, 699 cm-1; HRMS: [M + H]+
calcd. for C43H45O8 689.3114; found 689.3118.
Characterization data of compound 3m. Purified by silica gel
column chromatography (ethyl acetate/hexane = 1/20 ~ 2/20)
1
as a colorless oil (133 mg, 79% yield); H NMR (400 MHz,
CDCl3, 30 ºC) δ 7.68 (dd, J = 7.8, 1.4 Hz, 1H), 7.37 – 7.22 (m,
13H), 7.21 – 7.16 (m, 7H), 7.13 – 7.09 (m, 2H), 7.02 (td, J =
7.6, 1.3 Hz, 1H), 5.27 – 5.24 (m, 1H), 4.75 (d, J = 4.2 Hz, 1H),
4.69 – 4.45 (m, 7H), 4.33 (d, J = 10.8 Hz, 1H), 4.18 (dd, J =
7.1, 4.2 Hz, 1H), 4.08 (dd, J = 7.0, 3.5 Hz, 1H), 3.86 (dd, J =
10.3, 5.1 Hz, 1H), 3.66 (dd, J = 10.3, 5.7 Hz, 1H), 2.38 (s, 3H),
1.98 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 30 ºC) δ 202.8,
170.1, 138.6, 138.58, 138.2, 138.1, 137.3, 136.4, 131.9, 131.4,
Characterization data of compound 3j. Purified by silica gel
column chromatography (ethyl acetate/hexane = 1/20 ~ 3/20)
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129.9, 129.4, 129.2, 128.9, 128.6, 128.4, 128.3, 128.19, 128.18,
Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 5.4 Hz, 1H),
7.31 – 7.20 (m, 14H), 7.15 (dd, J = 6.7, 2.8 Hz, 2H), 7.13 –
7.08 (m, 3H), 7.01 (dd, J = 7.5, 1.9 Hz, 2H), 5.31 (q, J = 5.3
Hz, 1H), 4.95 (d, J = 4.3 Hz, 1H), 4.67 – 4.45 (m, 7H), 4.37 (d,
J = 10.8 Hz, 1H), 4.25 (dd, J = 6.7, 4.3 Hz, 1H), 4.08 (dd, J =
6.7, 3.6 Hz, 1H), 3.88 (dd, J = 10.4, 5.2 Hz, 1H), 3.65 (dd, J =
10.3, 5.6 Hz, 1H), 1.98 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3, 30 ºC) δ 199.0, 170.1, 144.5, 139.3, 138.5, 138.0,
137.9, 137.2, 132.7, 128.9, 128.6, 128.4, 128.3, 128.13, 128.1,
127.9, 127.83, 127.8, 127.6, 127.56, 125.53, 124.9, 124.3, 122.4,
83.0, 80.7, 79.7, 75.5, 74.7, 73.3, 73.2, 72.7, 68.1, 21.2; IR
(KBr): 3066, 3030, 2923, 2864, 1739, 1674, 1595, 1497, 1454,
1369, 1238, 1095, 1027, 738, 697 cm-1; HRMS: [M + H]+
calcd. for C44H43O7S 715.2729; found 715.2732.
128.0, 127.96, 127.9, 127.6, 127.55, 125.3, 83.7, 80.4, 79.7,
75.4, 74.8, 73.5, 73.4, 73.0, 68.0, 21.2, 20.9; IR (KBr): 3062,
3030, 2918, 2867, 1736, 1699, 1599, 1496, 1454, 1370, 1237,
1097, 1027, 735, 697 cm-1; HRMS: [M]+ calcd. for C43H45O7
673.3165; found 673.3165.
Characterization data of compound 3n. Purified by silica gel
column chromatography (ethyl acetate/hexane = 1/20 ~ 3/20)
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as a colorless oil (133 mg, 77% yield); H NMR (400 MHz,
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CDCl3, 30 ºC) δ 7.50 (s, 1H), 7.32 – 7.27 (m, 6H), 7.24 – 7.11
(m, 16H), 5.29 – 5.25 (m, 1H), 4.72 (d, J = 4.4 Hz, 1H), 4.67
(d, J = 10.8 Hz, 1H), 4.62 (d, J = 11.4 Hz, 1H), 4.53 – 4.40 (m,
6H), 4.17 (dd, J = 6.8, 4.4 Hz, 1H), 4.05 (dd, J = 6.8, 3.6 Hz,
1H), 3.86 (dd, J = 10.5, 4.7 Hz, 1H), 3.68 (dd, J = 10.5, 5.9 Hz,
1H), 2.35 (s, 3H), 2.12 (s, 3H), 1.98 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3, 30 ºC) δ 203.6, 170.1, 138.6, 138.3, 138.1,
137.4, 136.6, 135.2, 134.9, 132.1, 131.6, 130.0, 128.8, 128.5,
128.4, 128.3, 128.2, 128.17, 128.0, 127.9, 127.8, 127.79, 127.6,
127.5, 83.8, 80.6, 79.7, 75.5, 74.6, 73.4, 73.3, 73.0, 68.1, 21.2,
20.8, 20.3; IR (KBr): 3063, 3030, 2919, 2865, 1736, 1685,
1496, 1454, 1370, 1237, 1096, 1027, 735, 697 cm-1; HRMS:
[M]+ calcd. for C44H47O7 687.3322; found 687.3318.
Characterization data of compound epi-3a. Purified by silica
gel column chromatography (ethyl acetate/hexane = 1/20 ~
1
3/20) as a colorless oil (125 mg, 76% yield); H NMR (400
MHz, CDCl3, 30 ºC) δ 8.08 (d, J = 8.3 Hz, 2H), 7.53 (t, J = 7.4
Hz, 1H), 7.37 (t, J = 7.6 Hz, 2H), 7.39 – 7.21 (m, 16H), 7.16 –
7.11 (m, 4H), 5.44 – 5.41 (m, 1H), 4.92 – 4.91 (m, 1H), 4.61
(d, J = 11.3 Hz, 1H), 4.54 (d, J = 11.7 Hz, 1H), 4.47 – 4.29 (m,
6H), 4.17 (dd, J = 8.2, 3.1 Hz, 1H), 4.05 (dd, J = 8.9, 1.9 Hz,
1H), 3.70 – 3.63 (m, 1H), 3.59 (dd, J = 10.2, 6.8 Hz, 1H), 1.96
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 30 ºC) δ 200.5,
170.6, 138.2, 138.1, 137.45, 137.4, 136.0, 133.5, 129.4, 128.6,
128.5, 128.4, 128.38, 128.3, 128.0, 127.9, 127.8, 127.78, 127.7,
127.5, 83.4, 80.4, 76.4, 74.6, 74.1, 73.2, 72.7, 71.5, 68.4, 21.2;
IR (KBr): 3064, 3032, 2927, 2870, 1742, 1688, 1561, 1541,
1456, 1371, 1236, 1099, 1071, 741, 693 cm-1; HRMS: [M +
H]+ calcd for C42H43O7 659.3009; found 659.3006.
Characterization data of compound 3o. Purified by silica gel
column chromatography (ethyl acetate/hexane = 1/20 ~ 3/20)
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as a colorless oil (150 mg, 81% yield); H NMR (400 MHz,
CDCl3, 30 ºC) δ 8.46 (d, J = 1.7 Hz, 1H), 7.97 (dd, J = 8.6, 1.7
Hz, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 8.6 Hz, 1H),
7.57 (d, J = 9.5 Hz, 1H), 7.32 – 7.19 (m, 14H), 7.16 – 7.08 (m,
6H), 7.03 (dd, J = 7.4, 2.1 Hz, 2H), 5.34 – 5.31 (m, 1H), 4.99
(d, J = 4.4 Hz, 1H), 4.69 – 4.40 (m, 8H), 4.26 (dd, J = 6.6, 4.4
Hz, 1H), 4.07 (dd, J = 6.6, 3.7 Hz, 1H), 3.94 (s, 3H), 3.87 (dd,
J = 10.5, 4.9 Hz, 1H), 3.66 (dd, J = 10.5, 5.7 Hz, 1H), 1.98 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3, 30 ºC) δ 198.7, 170.1,
160.0, 138.5, 138.0, 137.9, 137.4, 137.3, 131.55, 131.52, 131.2,
128.8, 128.5, 128.4, 128.38, 128.2, 128.1, 128.0, 127.8, 127.76,
127.5, 127.5, 127.0, 125.4, 119.5, 105.8, 82.8, 80.7, 79.5, 75.4,
74.5, 73.2, 73.1, 72.7, 68.1, 55.5, 21.2; IR (KBr): 3061, 3032,
2934, 2865, 1737, 1671, 1624, 1480, 1456, 1369, 1271, 1237,
1100, 1026, 738, 697 cm-1; HRMS: [M + H]+ calcd. for
C47H47O8 739.3271; found 739.3270.
Characterization data of compound epi-3f. Purified by silica
gel column chromatography (ethyl acetate/hexane = 1/20 ~
1
3/20) as a colorless oil (141 mg, 82% yield); H NMR (400
MHz, CDCl3, 30 ºC) δ 8.13 (d, J = 8.9 Hz, 2H), 7.37 – 7.06 (m,
21H), 6.84 (d, J = 8.6 Hz, 2H), 5.48 – 5.43 (m, 1H), 4.87 (d, J
= 3.0 Hz, 1H), 4.62 (d, J = 11.3 Hz, 1H), 4.54 (d, J = 11.6 Hz,
1H), 4.47 – 4.25 (m, 6H), 4.14 (dd, J = 7.6, 2.5 Hz, 1H), 4.04
(dd, J = 8.2, 2.5 Hz, 1H), 3.84 (s, 3H), 3.67 (dd, J = 9.7, 6.4
Hz, 1H), 3.59 (dd, J = 9.9, 6.4 Hz, 1H), 1.98 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3, 30 ºC) 198.9, 170.7, 163.9, 138.3,
138.1, 137.5, 131.9, 129.1, 128.7, 128.5, 128.4, 128.3, 128.2,
128.0, 127.81, 127.8, 127.7, 127.5, 113.8, 83.6, 80.5, 76.4,
74.7, 74.1, 73.1, 72.6, 71.5, 68.4, 55.6, 21.3; IR (KBr): 3061,
3030, 2929, 2871, 1736, 1685, 1598, 1509, 1457, 1374, 1257,
1086, 1027, 737, 698 cm-1; HRMS: [M + H]+ calcd. for
C43H45O8 689.3114; found 689.3122.
Characterization data of compound 3r. Purified by silica gel
column chromatography (ethyl acetate/hexane = 1/20 ~ 3/20)
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as a colorless oil (97 mg, 58% yield); H NMR (400 MHz,
CDCl3, 30 ºC) δ 7.89 (d, J = 3.7 Hz, 1H), 7.60 (d, J = 4.8 Hz,
1H), 7.33 – 7.14 (m, 18H), 7.02 – 7.00 (m, 2H), 6.94 (t, J =
4.0 Hz, 1H), 5.27 – 5.23 (m, 1H), 4.70 – 4.43 (m, 9H), 4.15
(dd, J = 6.6, 4.5 Hz, 1H), 4.04 (dd, J = 6.5, 3.9 Hz, 1H), 3.86
(dd, J = 10.4, 4.9 Hz, 1H), 3.66 (dd, J = 10.4, 5.6 Hz, 1H),
1.97 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 30 ºC) δ 192.2,
170.1, 142.0, 138.6, 138.0, 137.9, 137.1, 134.5, 134.3, 128.7,
128.5, 128.47, 128.3, 128.2, 128.13, 128.1, 128.0, 127.9, 127.8,
127.64, 127.6, 84.4, 80.7, 79.3, 75.7, 74.8, 73.5, 73.4, 72.8,
68.1, 21.2; IR (KBr): 3065, 3032, 2918, 2868, 1736, 1656,
1497, 1454, 1412, 1235, 1094, 1027, 735, 696 cm-1; HRMS:
[M + H]+ calcd. for C40H41O7S 665.2573; found 665.2572.
Characterization data of compound 3s. Purified by silica gel
column chromatography (ethyl acetate/hexane = 1/20 ~ 3/20)
Synthesis of compound 3t
Step I: Under an argon atmosphere, to a solution of anhydrous
lithium chloride (56 mg, 1.324 mmol, 1.02 equiv.) in THF (2
i
mL) was added PrMgCl in THF (2 M, 0.70 mL, 1.4 mmol,
1.06 equiv.) at 0 °C. Solution of 2-(5-iodo-2-methylbenzyl)-5-
(4-fluorophenyl)thiophene (540 mg, 1.324 mmol, 1 equiv.) in
THF (5 mL) was added dropwise to the reaction mixture at
0 °C, and the reaction mixture was stirred at RT for 1 h. The
reaction mixture was transferred to a solution of ZnBr2 (300
mg, 1.324 mmol, 1 equiv.) in THF (5 mL) at RT. The mixture
was stirred at RT for further 1 h, and used for the next step.
Step II: Freshly prepared arylzinc bromide solution was added
dropwise to a Schlenk tube containing thioester 2 (500 mg,
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as a colorless oil (141 mg, 79% yield); H NMR (400 MHz,
CDCl3, 30 ºC) δ 8.45 (d, J = 1.6 Hz, 1H), 7.91 (dd, J = 8.5, 1.7
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0.66 mmol, 0.5 equiv.) and 10 wt% Pd/C (15 mg, 0.013 mmol)
starting material, aqueous solution of NaHCO3 (20 mL) was
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in THF (5 mL). The reaction mixture was stirred at 40 °C for
48 h, and then reaction was quenched with water (1 mL). The
reaction mixture was filtered through celite with ethyl acetate
(3 x 100 mL). The filtrate was washed with water and brine,
and dried over anhydrous Na2SO4. After decantation and
evaporation, the residue was purified by silica gel column
chromatography (ethyl acetate/hexane = 1/20 ~ 3/20) to afford
slowly added to the reaction mixture at 0 °C, and allowed the
reaction mixture to room temperature. Then reaction mixture
was extracted with dichloromethane (3 × 40 mL). After the
phase separation, the organic layer was washed with brine and
then dried over anhydrous Na2SO4. Filtration and concentra-
tion under reduced pressure gave crude oil which was purified
by flash silica gel column chromatography (ethyl ace-
tate/hexane = 1/10 ~ 3/10) to afford compound 5t21 as a color-
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compound 3t as a colorless oil (406 mg, 0.47 mmol, 71%). H
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NMR (400 MHz, CDCl3, 30 ºC) δ 7.50 (d, J = 1.3 Hz, 1H),
7.43 (dd, J = 7.8, 1.6 Hz, 1H), 7.41 – 7.14 (m, 21H), 7.07 –
7.04 (m, 2H), 7.00 – 6.93 (m, 3H), 6.60 (d, J = 3.5 Hz, 1H),
4.95 – 4.84 (m, 3H), 4.70 – 4.59 (m, 3H), 4.42 (d, J = 10.4 Hz,
1H), 4.19 – 4.14 (m, 2H), 4.04 (d, J = 16.0 Hz, 1H), 3.91 (d, J
= 10.4 Hz, 1H), 3.89 – 3.74 (m, 4H), 3.40 (d, J = 9.6 Hz, 1H),
3.16 (s, 3H), 2.34 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3,
30 ºC) δ 198.5, 170.1, 162.2 (d, J = 245.3 Hz), 142.7, 142.6,
141.8, 138.6, 138.55, 138.1, 138.0, 137.4, 134.5, 130.8 (d, J =
3.4 Hz), 130.7, 130.3, 128.8, 128.5, 128.42, 128.4, 128.3,
128.2, 128.0, 127.91, 127.9, 127.8, 127.58, 127.55, 127.2 (d, J
= 8.0 Hz), 126.2, 122.8, 115.8 (d, J = 21.8 Hz), 82.9, 80.7,
79.5, 75.5, 74.6, 73.3, 73.1, 72.7, 68.1, 34.1, 21.2, 19.9; IR
(KBr): 3062, 3031, 2918, 2864, 1737, 1675, 1605, 1509, 1455,
1371, 1236, 1094, 1027, 808, 736, 699 cm-1; HRMS: [M +
Na]+ calcd. for C54H51FO7SNa 885.3237; found 885.3229.
Synthesis of compound 4t
An oven dried Schlenk tube was cooled to room temperature
and charged with compound 3t (370 mg, 0.423 mmol) in
MeOH (10 mL) at room temperature. To that solution, Na-
OMe (23 mg, 0.423 mmol) was added under argon atmosphere,
and the reaction mixture was stirred at RT for 6 h. The reac-
tion mixture was neutralized with 1N HCl aq (2 mL). All the
solvent was evaporated, and the crude product was purified by
silica gel column chromatography (ethyl acetate/hexane = 1/10
~ 4/10) to afford compound 4t21 (320 mg, 0.39 mmol, 92%) as
a yellowish solid. 1H NMR (400 MHz, CDCl3, 30 ºC) δ 7.52
(s, 1H), 7.47 – 7.43 (m, 1H), 7.39 – 7.09 (m, 21H), 7.03 – 6.89
(m, 5H), 6.61 (d, J = 3.5 Hz, 1H), 4.89 – 4.86 (m, 3H), 4.68 –
4.62 (m, 2H), 4.53 (d, J = 12.3 Hz, 1H), 4.38 (d, J = 10.6 Hz,
1H), 4.19 – 4.03 (m, 4H), 3.94 (d, J = 10.5 Hz, 1H), 3.87 –
3.82 (m, 2H), 3.71 (d, J = 11.1 Hz, 1H), 3.60 (d, J = 9.3 Hz,
1H), 3.08 (s, 1H), 2.33 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3, 30 ºC) δ 162.2 (d, J = 246.6 Hz), 143.6, 141.6, 140.6,
138.9, 138.8, 138.5, 138.1, 137.8, 136.9, 130.9 (d, J = 3.3 Hz),
130.6, 128.52, 128.50, 128.44, 128.38, 128.3, 128.1, 127.9,
127.8, 127.73, 127.7, 127.6, 127.2 (d, J = 8.0 Hz), 125.9, 125.0,
122.8, 115.8 (d, J = 21.6 Hz), 98.0, 85.5, 83.6, 78.5, 75.8, 75.7,
75.2 73.5, 72.4, 69.1, 34.5, 19.4; IR (KBr): 3500, 3064, 3028,
2917, 2864, 1602, 1545, 1508, 1470, 1453, 1354, 1229, 1100,
1027, 835, 798, 729, 697 cm-1; HRMS: [M + Na]+ calcd. for
C52H49FO6SNa 843.3132; found 843.3123.
less gum (216 mg, 0.268 mmol, 88%). The H NMR meas-
urement indicated formation of the β-isomer. 1H NMR (400
MHz, CDCl3, 30 ºC) δ 7.37 – 7.24 (m, 17H), 7.22 – 7.14 (m,
6H), 6.98 – 6.93 (m, 5H), 6.63 (d, J = 3.6 Hz, 1H), 4.93 – 4.85
(m, 3H), 4.66 – 4.62 (m, 2H), 4.54 (d, J = 12.3 Hz, 1H), 4.36
(d, J = 10.4 Hz, 1H), 4.22 (d, J = 9.5 Hz, 1H), 4.17 – 4.08 (m,
2H), 3.89 (d, J = 10.4 Hz, 1H), 3.81 – 3.74 (m, 4H), 3.60 –
3.53 (m, 2H), 2.33 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3,
30 ºC) δ 162.2 (d, J = 247.4 Hz), 143.7, 141.6, 138.9, 138.6,
138.4, 138.3, 138.1, 137.4, 136.6, 131.0 (d, J = 3 Hz), 130.7,
129.1, 128.6, 128.53, 128.5, 128.33, 128.3, 128.1, 127.9, 127.8,
127.7, 127.6, 127.2 (d, J = 8.1 Hz), 126.6, 126.0, 122.8, 115.8
(d, J = 21.2 Hz), 86.8, 84.7, 81.8, 79.6, 78.6, 75.8, 75.2, 75.1,
73.6, 69.3, 34.4, 19.4; IR (KBr): 3064, 3030, 2917, 2857, 1598,
1508, 1498, 1453, 1362, 1232, 1096, 1068, 833, 735, 698 cm-
1; HRMS: [M + Na]+ calcd. for C52H49FO5SNa 827.3182;
found 827.3176.
Compound 5t was also synthesized using Et3SiH, but cooling
to -40 °C was necessary for the high -selectivity: To a solu-
tion of compound 4t (450 mg, 0.548 mmol) in acetoni-
trile/dichloromethane (3:2) (10 mL) under argon atmosphere
was added Et3SiH (0.27 mL, 1.65 mmol), and the reaction
mixture cooled to - 40 °C. BF3·Et2O (0.21 mL, 1.65 mmol)
was added dropwise to the reaction mixture at - 40 °C over a
period of 30 minute. After complete addition, the reaction
mixture was stirred at - 40 °C for 6 h. After consumption of
the starting material, aqueous solution of NaHCO3 (20 mL)
was slowly added to the reaction mixture at -10 °C, and al-
lowed the reaction mixture to room temperature. Then reac-
tion mixture was extracted with dichloromethane (3 × 40 mL).
After the phase separation, the organic layer was washed with
brine and then dried over anhydrous Na2SO4. Filtration and
concentration under reduced pressure gave crude oil which
was purified by flash silica gel column chromatography (ethyl
acetate/hexane = 1/10 ~ 3/10) to afford compound 5t (-
isomer) as a colorless gum (401 mg, 0.498 mmol, 91%).
Synthesis of compound 6t
To a solution of compound 5t (200 mg, 0.248 mmol) in di-
chloromethane (15 mL) under argon atmosphere, trimethylsi-
lyl iodide (0.35 mL, 1.49 mmol) was added dropwise at 0 °C.
After complete addition, the reaction mixture was allowed to
warm to RT and stirred for 8 h. The reaction mixture was
evaporated to dryness. The crude material was purified by
column chromatography on silica gel (MeOH/DCM = 1/30 ~
Synthesis of compound 5t
To a solution of compound 4t (250 mg, 0.304 mmol) in ace-
tonitrile/dichloromethane (3:2) (10 mL) under argon atmos-
phere was added iPr3SiH (0.19 mL, 0.913 mmol), and the reac-
tion mixture cooled to 0 °C. BF3·Et2O (0.13 mL, 0.913 mmol)
was added dropwise to the reaction mixture at 0 °C over a
period of 20 minute. After complete addition, the reaction
mixture was stirred at 0 °C for 6 h. After consumption of the
1/20)
to
afford
(2S,3R,4R,5S,6R)-2-(3-((5-(4-
fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
(Canagli-
flozin) (6t, 102 mg, 92%).9 1H NMR (400 MHz, DMSO-d6,
30 ºC) δ 7.61 – 7.57 (m, 2H), 7.27 (d, J = 4.4 Hz, 1H), 7.22 –
7.10 (m, 5H), 6.79 (d, J = 3.6 Hz, 1H), 4.99 (br, 2H, OH), 4.79
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7
8
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(br, 1H, OH), 4.45 (br, 1H, OH), 4.15 (d, J = 16 Hz, 1H), 4.09
the solvent was evaporated to afford the crude product, and
further purification by silica gel column chromatography
(ethyl acetate/hexane = 1/10 ~ 4/10) to afforded compound
4u22 (442 mg, 0.563 mmol, 93%) as a colorless solid. 1H
NMR (400 MHz, CDCl3, 30 ºC) δ 7.44 (d, J = 1.9 Hz, 1H),
7.37 (dd, J = 8.3, 2.0 Hz, 1H), 7.32 – 7.12 (m, 19H), 7.01 (d, J
= 8.5 Hz, 2H), 6.91 (d, J = 6.7 Hz, 2H), 6.71 (d, J = 8.6 Hz,
2H), 4.86 (s, 2H), 4.85 (d, J = 10.1 Hz, 1H), 4.63 (d, J = 10.9
Hz, 1H), 4.58 (d, J = 12.3 Hz, 1H), 4.49 (d, J = 12.3 Hz, 1H),
4.42 (d, J = 10.7 Hz, 1H), 4.14 – 3.85 (m, 7H), 3.83 – 3.74 (m,
2H), 3.68-3.65 (m, 1H), 3.48 (d, J = 9.3 Hz, 1H), 3.12 (s, 1H),
1.35 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, 30
ºC) δ 157.5, 141.4, 138.9, 138.7, 138.6, 138.4, 137.4, 134.5,
131.4, 129.8, 129.4, 129.0, 128.5, 128.5, 128.3, 128.1, 127.9,
127.84, 127.8, 127.72, 127.7, 127.6, 125.7, 114.6, 97.8, 84.9,
83.7, 78.5, 75.8, 75.6, 75.2, 73.5, 72.4, 69.0, 63.4, 38.6, 15.0;
IR (KBr): 3396, 3063, 3030, 2925, 2866, 1609, 1582, 1509,
1453, 1361, 1242, 1099, 1027, 827, 732, 698 cm-1; HRMS: [M
+ Na]+ calcd. for C49H49ClO7Na 807.3065; found 807.3060.
Synthesis of compound 5u
To a solution of compound 4u (239 mg, 0.304 mmol) in ace-
tonitrile/dichloromethane (3:2) (10 mL) under argon atmos-
phere was added iPr3SiH (0.19 mL, 0.913 mmol), and the reac-
tion mixture cooled to 0 °C. BF3·Et2O (0.13 mL, 0.913 mmol)
was added dropwise to the reaction mixture at 0 °C over a
period of 20 minute. After complete addition, the reaction
mixture was stirred at 0 °C for 6 h. After consumption of the
starting material, aqueous solution of NaHCO3 (20 mL) was
slowly added to the reaction mixture at 0 °C, and allowed the
reaction mixture to room temperature. After extraction with
dichloromethane (3 x 40 mL), the organic layer was washed
with brine and dried over anhydrous Na2SO4. Filtration and
concentration under reduced pressure gave the crude oil. Fur-
ther purification by flash silica gel column chromatography
(d, J = 16 Hz, 1H), 3.96 (d, J = 9.6 Hz, 1H), 3.69 (d, J = 11.2
Hz, 1H), 3.46 – 3.41 (m, 1H), 3.29 – 3.14 (m, 4H), 2.26 (s,
3H). 13C{1H} NMR (100 MHz, DMSO-d6, 30 ºC) δ 161.4 (d, J
= 243 Hz), 143.6, 140.2, 138.2, 137.3, 134.9, 130.5 (d, J = 3.1
Hz), 129.6, 129.0, 126.9 (d, J = 8 Hz), 126.3, 126.2, 123.4,
115.9 (d, J = 21.6 Hz), 81.3, 81.2, 78.5, 74.7, 70.4, 61.4, 33.4,
18.8; IR (KBr): 3588, 3398, 2978, 2925, 1645, 1611, 1509,
1477, 1438, 1395, 1300, 1243, 1133, 1087, 1047, 920, 826,
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11
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17
18
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21
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23
24
25
26
27
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29
30
31
32
33
34
35
36
37
38
39
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
798, 703, 628 cm-1; HRMS: [M
+
Na]+ calcd for
C24H25FO5SNa 467.1304; found 467.1299.
Synthesis of compound 3u
Step I: An oven dried Schlenk tube was cooled under argon
atmosphere and charged with 4-bromo-1-chloro-2-(4-
ethoxybenzyl)benzene (0.163 g, 0.50 mmol) and magnesium
turnings (0.10 g, 4.1 mmol), followed by addition of THF (5
mL) and 1,2-dibromoethane (0.05 mL). The reaction mixture
was heated to reflux to initiate the reaction. After the reaction
initiated,
additional
4-bromo-1-chloro-2-(4-
ethoxybenzyl)benzene (0.49 g, 1.5 mmol) in THF (10 mL)
was added dropwise to the reaction mixture, and allowed the
reaction mixture to reflux for 3 h. Then, the reaction mixture
was cooled to room temperature. The freshly prepared Gri-
gnard reagent was added to a solution of ZnBr2 (450 mg, 2
mmol, 1 equiv.) and LiCl (85 mg, 2 mmol, 1 equiv.) in dry
THF at RT and stirred for 1 h.
Step II: Freshly prepared arylzinc bromide was added drop-
wise to a Schlenk tube containing thioester 2 (756 mg, 1
mmol) and 10 wt% Pd/C (22 mg, 0.020 mmol) in THF (5 mL).
The reaction mixture was stirred at 40 °C for 48 h, and then
reaction was quenched with water (1 mL). The reaction mix-
ture was filtered through celite with ethyl acetate (3 x 100 mL).
The filtrate was washed with water and brine, and dried over
anhydrous Na2SO4. The mixture was decanted and evaporated.
The residue was purified by silica gel column chromatography
(ethyl acetate/hexane = 1/20 ~ 3/20) to afford compound 3u
(ethyl acetate/hexane
=
1/20
~
3/10) afforded
(2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-
6-(4-chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H-pyran
(5u)22 as a colorless gum (220 mg, 0.286 mmol, 94%). The 1H
NMR indicated formation of the β-isomer. 1H NMR (400
MHz, CDCl3, 30 ºC) δ 7.35 (d, J = 8.1 Hz, 1H), 7.32 – 7.16 (m,
20H), 7.03 (d, J = 8.6 Hz, 2H), 6.91 – 6.88 (m, 2H), 6.73 (d, J
= 8.6 Hz, 2H), 4.93 – 4.84 (m, 3H), 4.65 – 4.59 (m, 2H), 4.53
(d, J = 12.3 Hz, 1H), 4.39 (d, J = 10.5 Hz, 1H), 4.15 (d, J = 9.5
Hz, 1H), 4.06 (d, J = 15.4 Hz, 1H), 3.97 – 3.92 (m, 3H), 3.83
(d, J = 10.5 Hz, 1H), 3.79 – 3.71 (m, 4H), 3.57 – 3.54 (m, 1H),
3.45 – 3.40 (m, 1H), 1.37 (t, J = 7.0 Hz, 3H). 13C{1H} NMR
(100 MHz, CDCl3, 30 ºC) δ 157.6, 139.1, 138.8, 138.5, 138.34,
138.3, 137.8, 134.0, 131.4, 130.6, 129.9, 129.6, 128.6, 128.5,
128.4, 128.1, 127.9, 127.86, 127.83, 127.8, 127.76, 127.7, 126.8,
114.6, 86.9, 84.3, 81.1, 79.6, 78.5, 75.8, 75.3, 75.1, 73.6, 69.2,
63.5, 38.5, 15.0; IR (KBr): 3062, 3031, 2932, 2868, 1610,
1584, 1511, 1454, 1392, 1244, 1209, 1099, 1044, 1027, 832,
733, 696 cm-1; HRMS: [M + Na]+ calcd. for C49H49ClO6Na
791.3115; found 791.3109.
1
(613 mg, 0.74 mmol, 74%) as a colorless gum. H NMR (400
MHz, CDCl3, 30 ºC) δ 7.82 (d, J = 1.3 Hz, 1H), 7.68 (dd, J =
8.3, 1.6 Hz, 1H), 7.33 – 7.12 (m, 19H), 6.99 (d, J = 6.8 Hz,
2H), 6.95 (d, J = 8.5 Hz, 2H), 6.71 (d, J = 8.5 Hz, 2H), 5.24 (q,
J = 4.9 Hz, 1H), 4.73 (d, J = 4.5 Hz, 1H), 4.62 – 4.42 (m, 7H),
4.31 (d, J = 10.8 Hz, 1H), 4.13 – 4.09 (m, 1H), 4.02 – 3.99 (m,
1H), 3.94 – 3.88 (m, 4H), 3.84 (dd, J = 10.4, 5.0 Hz, 1H), 3.63
(dd, J = 10.4, 5.5 Hz, 1H), 1.97 (s, 3H), 1.34 (t, J = 7.0 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3, 30 ºC) δ 198.6, 170.1,
157.7, 139.5, 138.4, 138.0, 137.8, 137.1, 134.8, 131.8, 130.7,
130.0, 129.6, 128.7, 128.6, 128.45, 128.4, 128.38, 128.3, 128.2,
128.1, 127.93, 127.9, 127.8, 127.7, 127.6, 114.6, 83.6, 80.6,
79.2, 77.4, 75.5 74.6, 73.3, 72.7, 68.1, 63.5, 38.4, 21.2, 15.0;
IR (KBr): 3064, 3032, 2929, 2866, 1734, 1686, 1605, 1511,
1454, 1370, 1244, 1046, 1027, 824, 738, 697 cm-1; HRMS: [M
+ Na]+ calcd. for C51H51ClO8Na 849.3170; found 849.3165.
Synthesis of compound 4u
An oven dried Schlenk tube was cooled to room temperature
and charged with compound 3u (500 mg, 0.604 mmol) in
MeOH (30 mL) at room temperature. To that solution, Na-
OMe (33 mg, 0.604 mmol) was added under argon atmosphere,
and the reaction mixture was stirred at RT for 6 h. Then, the
reaction mixture was neutralized with 1N HClaq (4 mL). All
Compound 5u was also synthesized using Et3SiH, but cooling
to -40 °C was necessary for the high -selectivity: To a solu-
tion of compound 4u (426 mg, 0.54 mmol) in acetoni-
trile/dichloromethane (3:2) (10 mL) under argon atmosphere
was added Et3SiH (0.27 mL, 1.65 mmol), and then the reaction
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mixture was cooled to - 40 °C. BF3·Et2O (0.21 mL, 1.65
E-mail: tsurugi@chem.es.osaka-u.ac.jp
3
4
5
6
7
8
9
mmol) was added dropwise to the reaction mixture at - 40 °C
over a period of 30 minute. After complete addition, the reac-
tion mixture was stirred at - 40 °C for 6 h. After consumption
of the starting material, aqueous solution of NaHCO3 (20 mL)
was slowly added to the reaction mixture at - 10 °C, and al-
lowed the reaction mixture to room temperature. After extrac-
tion with dichloromethane (3 x 40 mL), the organic layer was
washed with brine and dried over anhydrous Na2SO4. Filtra-
tion and concentration under reduced pressure gave the crude
oil. Further purification by flash silica gel column chromatog-
Masahiko Seki – MA Group, Tokuyama Corporation, Tsuku-
ba, Ibaraki 300-4247, Japan
E-mail: ma-seki@tokuyama.co.jp
Authors
Jalindar Talode – Department of Chemistry, Graduate
School of Engineering Science, Osaka University, Toyonaka,
Osaka 560-8531, Japan
Daiki Kato – Department of Chemistry, Graduate School of
Engineering Science, Osaka University, Toyonaka, Osaka
560-8531, Japan
Haruki Nagae – Department of Chemistry, Graduate School
of Engineering Science, Osaka University, Toyonaka, Osaka
560-8531, Japan
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raphy (ethyl acetate/hexane
= 1/20 ~ 3/10) afforded
(2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-
6-(4-chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H-pyran
(5u) as a colorless gum (402 mg, 0.522 mmol, 96%). The H
1
NMR indicated formation of the β-isomer.
Synthesis of compound 6u
To a solution of 5u (100 mg, 0.13 mmol) in EtOAc (5 mL)
was added 5 wt% Pd/C (14 mg, 6.5 µmol, 5 mol% on metal
basis) in autoclave under argon. The atmosphere was replaced
to dihydrogen, and the mixture was stirred at RT for 24 h. The
reaction mixture was filtered through celite with EtOAc (3 x
40 mL), and all the volatiles of the filtrate was evaporated to
give crude compound. The mixture was purified by column
chromatography (MeOH/CH2Cl2 (1/30-1/20) to afford
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-
REFERENCES
1) (a) Chao, E. C.; Henry, R. R. SGLT2 inhibition — a
novel strategy for diabetes treatment. Nat. Rev. Drug
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Rahuja, N.; Srivastava, D. S. L.; Kumar, A.; Maurya, R.
Synthesis and antihyperglycemic activity of phenolic C-
glycosides. Bioorg. Med. Chem. Lett. 2011, 21, 228-233.
(c) Nomura, S.; Sakamaki, S.; Hongu, M.; Kawanishi,
E.; Koga, Y.; Sakamoto, T.; Yamamoto, Y.; Ueta, K.;
Kimata, H.; Nakayama, K.; Tsuda-Tsukimoto, M. Dis-
covery of canagliflozin, a novel C-glucoside with thio-
phene ring, as sodium-dependent glucose cotransporter 2
inhibitor for the treatment of type 2 diabetes mellitus. J.
Med. Chem. 2010, 53, 6355-6360. (d) Meng, W.; Ells-
worth, B. A.; Nirschl, A. A.; McCann, P. J.; Patel, M.;
Girotra, R. N.; Wu, G.; Sher, P. M.; Morrison, E. P.;
Biller, S. A.; Zahler, R.; Deshpande, P. P.; Pullockaran,
A.; Hagan, D. L.; Morgan, N.; Talyor, J. R.; Obermeier,
M. T.; Humphreys, W. G.; Khanna, A.; Disenza, L.;
Robertson, J. G.; Wang, A.; Han, S.; Wetterau, J. R.; Ja-
novitz, E. B.; Flint, O. P.; Whaley, J. M.; Washburn, W.
N. Discovery of dapagliflozin: a potent, selective renal
sodium-dependent glucose cotransporter 2 (SGLT2) in-
hibitor for the treatment of type 2 diabetes. J. Med. Chem.
2008, 51, 1145-1149. (e) Hasan, F. M.; Alsahli, M.;
Gerich, J. E. SGLT2 inhibitors in the treatment of type 2
diabetes. Diabetes Res. Clin. Pract. 2014, 104 (3), 297-
322.
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
(Dapagli-
flozin) (6u, 52 mg, 97%).22 1H NMR (400 MHz, CD3OD, 30
ºC) δ 7.35 – 7.31 (m, 2H), 7.28 – 7.26 (m, 1H), 7.09 (d, J = 8.4
Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 4.08 (d, J = 9.5 Hz, 1H),
4.03 – 3.96 (m, 3H), 3.89 – 3.85 (m, 1H), 3.71 – 3.66 (m, 1H),
3.47 – 3.26 (m, 5H), 1.35 (t, J = 7.0 Hz, 3H). 13C{1H} NMR
(100 MHz, CD3OD, 30 ºC) δ 158.9, 140.0, 139.9, 134.5, 132.9,
131.9, 130.8, 130.1, 128.2, 115.5, 82.9, 82.2, 79.8, 76.5, 71.9,
64.5, 63.1, 39.2, 15.2; IR (KBr): 3568, 3386, 3032, 2958, 2924,
2855, 1611, 1508, 1451, 1439, 1269, 1243, 1177, 1047, 825,
797, 735, 699 cm-1; HRMS: [M
+
Na]+ calcd. for
C21H25ClO6Na 431.1237; found 431.1231.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
1H and 13C{1H} NMR of starting materials and products (PDF).
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AUTHOR INFORMATION
Corresponding Authors
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Azevedo, H. ́ F. Z.; Guimaraes, C. R. W.; Miranda, L. S.
Kazushi Mashima – Department of Chemistry, Graduate
School of Engineering Science, Osaka University, Toyonaka,
Osaka 560-8531, Japan;
M.; de Souza, R. O. M. A. Synthetic strategies toward
SGLT2 inhibitors. Org. Process Res. Dev. 2018, 22, 467-
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E-mail: mashima@chem.es.osaka-u.ac.jp
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Hayato Tsurugi – Department of Chemistry, Graduate School
of Engineering Science, Osaka University, Toyonaka, Osaka
560-8531, Japan;
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