Tsuyoshi Shinozuka1. 1. R&D Planning & Management Department, R&D Division, Daiichi Sankyo Company Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Abstract
A synthetic method for benzyl 2-deoxy-C-glycosides has been developed. Palladium-catalyzed benzyl C-glycosylation of TIPS-protected 1-tributylstannyl glycals with a variety of benzyl bromides provided protected benzyl C-glycals. In this reaction, the use of PdCl2(dppe) promoted a clean reaction, whereas the reaction was accelerated by the addition of Na2CO3. The subsequent transformations provided a novel class of benzyl 2-deoxy-C-glycosides.
A synthetic method for benzyl 2-deoxy-C-glycosides has been developed. Palladium-catalyzed benzyl C-glycosylation of TIPS-protected 1-tributylstannyl glycals with a variety of benzyl bromides provided protected benzyl C-glycals. In this reaction, the use of PdCl2(dppe) promoted a clean reaction, whereas the reaction was accelerated by the addition of Na2CO3. The subsequent transformations provided a novel class of benzyl 2-deoxy-C-glycosides.
Oligosaccharides
have been demonstrated to play multiple roles
in biological reactions.[1] As oligosaccharides
are linked by O-glycosidic bonds, they are vulnerable
to acidic hydrolysis or enzymatic digestion, which is one of the major
issues hindering their use as drugs. One plausible solution is the
replacement of the O-glycosidic bond with C-glycoside, the utility of which has been proven by the
development of sodium glucose cotransporter 2 (SGLT2) inhibitors.
Specifically, many C-glycoside-based SGLT2 inhibitors
are stable in human plasma, and these drugs have been introduced globally
for the treatment of diabetes.[2] Although
it is reported that benzyl C-glycosides of the phlorizin
analog showed poor in vitro SGLT2 activity,[3] they are expected to exhibit a variety of biological activities
owing to their more flexible nature than aryl C-glycosides.Although aryl C-glycosides are naturally occurring
compounds and many synthetic methods are available,[4,5] only
limited methods are available for the preparation of benzyl C-glycosides. Several groups reported the preparation of
benzyl C-glycosides under harsh reaction conditions,[6] whereas an alternative method utilizing exomethylene
sugar was reported.[7] The palladium-catalyzed
coupling reaction of 1-tributylstannyl glucal and benzyl bromide or
benzylsulfonyl chloride was reported with limited examples.[8] To investigate the biological roles of benzyl C-glycosides, the elaboration of synthetic methods for these
compounds is needed. In this study, palladium-catalyzed coupling reactions
of 1-tributylstannyl glycals with a variety of benzyl bromides were
conducted, which provided adducts in fair to good yields, and subsequent
manipulations provided a novel class of benzyl 2-deoxy-C-glycosides.[9]
Results and Discussion
Glycals 1 were protected as triisopropylsilyl (TIPS)
ethers because stannylation requires a strong basic condition. TIPS
protection of glycals 2a and 2b was carried
out in the usual manner (Scheme ).[10,11] Because d-galactal 1c and l-fucal 1d could not be fully
protected under this reaction condition, an alternative method was
employed to obtain fully protected d-galactal 1c and l-fucal 1d using TIPSOTf. In this reaction,
the effect of the base was critical because the usage of 2,6-lutidine
led to a trace amount of 2c or 2d. As reported
previously, TIPS-protected glycals 2a–2d were
lithiated and stannylated to afford stannyl glycals 3a–3d.[10]
Scheme 1
Preparation
of Stannyl Glycals 3
aMeONa,
MeOH then
TIPSCl, imidazole, DMF. bt-BuLi, THF,
Bu3SnCl, −78 °C. cMeONa, MeOH then
TIPSOTf, pyridine, CH2Cl2, 0 °C.
Preparation
of Stannyl Glycals 3
aMeONa,
MeOH then
TIPSCl, imidazole, DMF. bt-BuLi, THF,
Bu3SnCl, −78 °C. cMeONa, MeOH then
TIPSOTf, pyridine, CH2Cl2, 0 °C.The coupling reaction conditions with TIPS-protected d-glucal 3a and 4-substituted benzyl bromide 4a were optimized because the usage of Pd(PPh3)4 as a palladium catalyst did not provide satisfactory results,
as
indicated in Table (entry 1). When Pd(PPh3)4 was used, the yield
was poor despite the use of a variety of solvents (entries 1–5).
A slight improvement of the yield was observed when PdCl2(PPh3)2 or Pd(OAc)2(PPh3)2 was used as a palladium catalyst, whereas PdCl2[1,1′-bis(diphenylphosphino)ferrocene (dppf)] did not
improve the yield. When PdCl2[1,2-bis(diphenylphosphino)ethane
(dppe)] or Pd(dppe)2 was employed, the reaction proceeded
clearly. Under both reaction conditions, the reactions were sluggish
with low yields (both 23%), and large amounts of 3a and 4a were recovered even after several days (entries 9 and 10).
Thus, further optimization of the reaction conditions was attempted
using PdCl2(dppe). The use of xylene improved the yield
(entry 14), whereas increasing the amount of the palladium catalyst
did not significantly improve the yield (entry 12). As the additives
were sometimes effective for promoting the Stille coupling reaction,[12] the effect of the additives was examined. Organic
bases such as Et3N prevented the reaction from proceeding
(entry 15) and the addition of CuI gave a messy reaction with a trace
amount of the adduct (entry 16).[13] The
addition of LiCl was effective for the reaction and the yield was
improved to 44% (entry 17).[14] A further
improvement of yield was observed when Na2CO3 was employed (entry 16), and the adduct was isolated in 63%. The
mechanistic aspects of how Na2CO3 promotes this
reaction remain unclear. Because this reaction requires several days
to achieve completion, the utilization of 3 equivalents of bromide
shortened the reaction time to several hours and the yield reached
86% (entry 19).
Table 1
Optimization of the Conditions for
Benzyl C-Glycosylationa
entry
catalyst
solvent
additive (equiv)
yield (%)b
1
Pd(PPh3)4
toluene
none
11
2
Pd(PPh3)4
THF
none
trace
3
Pd(PPh3)4
xylene
none
trace
4
Pd(PPh3)4
DMF
none
trace
5
Pd(PPh3)4
1,4-dioxane
none
7
6
PdCl2(PPh3)2
toluene
none
23
7
Pd(OAc)2(PPh3)2
toluene
none
30
8
PdCl2(dppf)
toluene
none
trace
9
PdCl2(dppe)
toluene
none
23
10
Pd(dppe)2
toluene
none
23
11
Pd[P(o-Tol3)]4
toluene
none
10
12c
PdCl2(dppe)
toluene
none
39
13
PdCl2(dppe)
DMF
none
trace
14
PdCl2(dppe)
xylene
none
54
15
PdCl2(dppe)
toluene
Et3N (2.0)
trace
16
PdCl2(dppe)
toluene
CuI (2.0)
trace
17
PdCl2(dppe)
toluene
LiCl (2.0)
44
18
PdCl2(dppe)
toluene
Na2CO3 (2.0)
63
19d
PdCl2(dppe)
toluene
Na2CO3 (2.0)
86
The reaction was performed using 3a (0.1 mmol), 4a (0.12 mmol), and the Pd catalyst
(0.01 mmol) in the solvent (5 mL) under reflux unless otherwise noted.
Isolated yield.
0.5 equiv of the catalyst were used.
3.0 equiv of 4a were
used.
The reaction was performed using 3a (0.1 mmol), 4a (0.12 mmol), and the Pd catalyst
(0.01 mmol) in the solvent (5 mL) under reflux unless otherwise noted.Isolated yield.0.5 equiv of the catalyst were used.3.0 equiv of 4a were
used.After optimizing the
reaction conditions, the reactions of 1-tributylstannyl d-glucal 3a with several benzyl bromides 4 were performed. The result is summarized in Table . Although 3-substituted adduct 5b was isolated in fair yields, 2-substituted adduct 5c could not be obtained (entries 1 and 2). A variety of functional
groups are tolerated under these reaction conditions, including ketone
(entry 3), nitrile (entry 4), nitro (entry 5), and acetoxy groups
(entry 9). The yield of adduct 5 with an electron-withdrawing
substituent was better than that with an electron-releasing substituent.
Ketone 5d, nitrile 5e, and nitro compound 5f displayed slightly better yields than tolyl analog 5g. The utilization of 3,4-disubstituted benzyl bromide 4j provided adduct 5j at 45% yield.
Table 2
Reaction with Various Benzyl Bromidesa
entry
4 (Y)
5
yield (%)b
1
4b (3-CO2Me)
5b
71
2
4c (2-CO2Me)
5c
0
3
4d (4-COCH3)
5d
65
4
4e (4-CN)
5e
90
5
4f (4-NO2)
5f
69
6
4g (4-Me)
5g
56
7
4h (3-Cl)
5h
67
8
4i (H)
5i
85
9
4j (4-CO2Me, 3-OAc)
5j
45
All reactions were performed using 3a (0.1 mmol), 4 (0.30 mmol), PdCl2(dppe) (0.01 mmol), and Na2CO3 (0.20 mmol)
in refluxing toluene (5 mL).
Isolated yield.
All reactions were performed using 3a (0.1 mmol), 4 (0.30 mmol), PdCl2(dppe) (0.01 mmol), and Na2CO3 (0.20 mmol)
in refluxing toluene (5 mL).Isolated yield.Then, 1-tributylstannyl
glycals 3b–3d were
reacted with benzyl bromides 4a, 4b, 4e, 4i, and 4j, as indicated in Table . When 6-deoxy-1-tributylstannyl-l-glucal 3b was used, the yield of adduct 6 was excellent for all benzyl bromides excluding 4j. The yields of 4-substituted ester 6a, 3-analog 6b, and nitrile 6c approached 90%, whereas the
unsubstituted benzyl analog 6i was obtained quantitatively.
The yield of 3,4-disubstituted compound 6j was better
than that of 5j (Table entry 9), and similarly modest yields were observed
for the 3,4-disubstituted compounds 7j and 8j. When 1-tributylstannyl d-galactal3c was
employed, high yields were also obtained for ester7a and unsubstituted compound 7i. Although a high yield
was expected when sterically less-hindered 1-tributylstannyl l-fucal 3d was utilized, modest yields were confirmed
for 4-substituted ester8a, 3-analog 8b,
and nitrile8e, being lower than that of 3c. As adduct 8i was unstable, this instability may have
affected the yield of 8. In fact, a small amount of adducts 8b, 8e, and 8j was decomposed after
several days, which was confirmed by the 1HNMR spectra
(see Supporting Information). Note that
deprotected benzyl 2-deoxy-C-l-fucose derivatives 20a, 20b, and 20j are stable.
Table 3
Reactions of 3b, 3c, and 3d with 4a
yield
(%)b
4
Y
from 3b
from 3c
from 3d
4a
4-CO2Me
91 (6a)
93 (7a)
73 (8a)
4b
3-CO2Me
86 (6b)
69 (7b)
61 (8b)
4e
4-CN
86 (6e)
77 (7e)
70 (8e)
4i
H
99 (6i)
92 (7i)
-c (8i)
4j
4-CO2Me, 3-OAc
67 (6j)
67 (7j)
62 (8j)
All reactions
were performed using 3 (0.10 mmol), 4 (0.30
mmol), PdCl2(dppe) (0.01 mmol), and Na2CO3 (0.20 mmol)
in refluxing toluene (5 mL).
Isolated yield.
The adduct
was unstable, and it
decomposed after purification.
All reactions
were performed using 3 (0.10 mmol), 4 (0.30
mmol), PdCl2(dppe) (0.01 mmol), and Na2CO3 (0.20 mmol)
in refluxing toluene (5 mL).Isolated yield.The adduct
was unstable, and it
decomposed after purification.As various benzyl C-glycals were obtained, further
transformations were conducted (Scheme ). The TIPS group was easily deprotected under usual
conditions to provide glycals 9a, 12a, 15a, and 18a.[15] These
glycals were subjected to hydrogenation to provide 2-deoxy glycosides 10a, 13a, 16a, and 19a.[8c] Note that the TIPS-protected d-glucal5a was resistant to hydrogenation because of
its steric bulkiness. Final saponification provided benzyl 2-deoxy-C-glycosides11a, 14a, 17a, and 20a.[16] In the same
manner, 2-deoxy-l-fucose analogs 20b and 20j were synthesized (Figure ). The stereochemistry was determined by observing
NOE between hydrogen molecules in the 1, 3, and 5 positions in each
sugar moiety in 21a–24a as indicated in Figure .
Scheme 2
Preparation of Benzyl 2-Deoxy-C-Glycosides 11a, 14a, 17a, and 20a
aTBAF, THF. bH2, Pd/C, THF. cNaOH, MeOH.
Figure 1
Structures of compounds 20b, 20j, and 21a–24a.
Structures of compounds 20b, 20j, and 21a–24a.
Preparation of Benzyl 2-Deoxy-C-Glycosides 11a, 14a, 17a, and 20a
aTBAF, THF. bH2, Pd/C, THF. cNaOH, MeOH.
Conclusions
In conclusion, a synthetic method for benzyl 2-deoxy-C-glycosides has been developed. A palladium-catalyzed coupling reaction
with 1-tributylstannyl glycals and benzyl bromides proceeded clearly
under the optimized conditions [0.1 equiv of PdCl2(dppe)
and 2 equiv of Na2CO3 in refluxing toluene].
3- or 4-Substituted or 3,4-disubstituted benzyl bromide gave the adducts
in fair to good yields, whereas the 2-substituted analog was not obtained.
These adducts were deprotected, hydrogenated, and saponified to provide
a novel class of benzyl 2-deoxy-C-glycosides. This
method is useful for synthesizing novel benzyl C-glycosides,
which are expected to display a variety of biological activities.
Experimental
Section
Starting reagents were purchased from commercial
suppliers and
were used without further purification, unless otherwise specified.
Chromatographic elution was conducted under continuous monitoring
by TLC using silica gel 60F254 (Merck & Co., Inc.) as the stationary
phase and the elution solvent used in column chromatography as the
mobile phase. A UV detector was used for detection. Silica gelSK-85
(230–400 mesh) or silica gelSK-34 (70–230 mesh), both
of which were manufactured by Merck & Co., Inc., was used as the
column-packing silica gel. 1H and 13C NMR spectra
were obtained on Varian Unity 400 MHz spectrometers. Spectra were
recorded in the indicated solvent at ambient temperature and chemical
shifts are reported in ppm (δ) relative to the solvent peak.
Resonance patterns are represented by the following notations: br
(broad signal), s (singlet), d (doublet), t (triplet), q (quartet),
and m (multiplet). HRMS was conducted using an LC–MS system
consisting of a Waters Xevo Quadropole-ToF MS and an Acquity UHPLC
system.
To a solution of 3,4,6-tri-O-acetyl-d-glucal (1a; 10.8 g, 40.0 mmol) in MeOH (80 mL)
was added a solution of MeONa in MeOH (0.2 mL, 1.0 mmol) at room temperature.
After the reaction mixture was stirred at room temperature for 2 h,
the residue was concentrated under reduced pressure. To this residue
was added DMF (80 mL), imidazole (27.2 g, 400 mmol), and TIPSCl (42
mL, 200 mmol), and the reaction mixture was stirred at 100 °C
for 2 days. Water (50 mL) was added to the cooled reaction mixture,
and the mixture was extracted several times with EtOAc. The combined
organic layers were washed with water and dried over anhydrous Na2SO4. After concentrating under reduced pressure,
the residue was purified via silica gel chromatography to obtain 2a as a colorless oil (20.53 g, 83%). [α]D23 = −14.6
(c = 0.7, CHCl3); 1H NMR (400
MHz, CDCl3): δ 6.34 (1H, d, J =
6.6 Hz), 4.82–4.79 (1H, m), 4.25–4.22 (1H, m), 4.09–4.04
(2H, m), 3.96–3.94 (1H, m), 3.82 (1H, dd, J = 4.0, 11.5 Hz), 1.06–1.06 (63H, m); 13C NMR (67.8
MHz, CDCl3): δ 142.9 (CH), 100.4 (CH), 80.8 (CH),
70.3 (CH), 65.1 (CH), 62.1 (CH2), 18.1 (Me), 18.0 (Me),
12.5 (CH), 12.1 (CH); HRMS (FAB) m/z: [M – H]− calcd for C33H59O4Si3, 613.4504; found, 613.4485.
To a solution of
3,4,6-tri-O-acetyl-d-galactal (1c; 12.68 g, 46.6 mmol) in MeOH (80
mL) was added a solution of MeONa in MeOH (0.2 mL, 1.0 mmol) at room
temperature. The reaction mixture was stirred for 2 h at room temperature
and concentrated under reduced pressure. To this residue was added
CH2Cl2 (80 mL), pyridine (30 mL, 372.8 mmol),
and TIPSOTf (50 mL, 186.4 mmol) at 0 °C, and the reaction mixture
was stirred for 3 days at room temperature. Water (50 mL) was added
to the cooled reaction mixture, and the mixture was extracted several
times with CH2Cl2. The combined organic layers
were washed with water and dried over anhydrous Na2SO4. After concentrating under reduced pressure, the residue
was purified via silica gel chromatography to obtain 2c as a colorless oil (21.92 g, 76%). [α]D23 = −21.3 (c = 0.6, CHCl3); 1H NMR (400 MHz, CDCl3): δ 6.22 (1H, d, J = 6.0 Hz), 4.78 (1H, m),
4.20–4.06 (5H, m), 1.10–1.04 (63H, m); 13C NMR (67.8 MHz, CDCl3): δ 142.8 (CH), 102.4 (CH),
80.6 (CH), 70.3 (CH), 64.2 (CH), 60.8 (CH2), 18.3 (Me),
18.2 (Me), 18.0 (Me), 12.7 (CH), 12.1 (CH); HRMS (FAB) m/z: [M – H]− calcd for
C33H59O4Si3, 613.4504;
found, 613.4482.
To a solution
of 2a (20.53 g, 33.4 mmol) in THF (150 mL) was added t-BuLi (81.0 mL, 133.6 mmol) at −78 °C under
N2. After the reaction mixture was stirred at 0 °C
for 1 h, Bu3SnCl (23.0 mL, 83.5 mmol) was added at −78
°C,
and the reaction mixture was stirred at 0 °C for 1 h. The reaction
was quenched with water (50 mL), and the mixture was extracted several
times with EtOAc. The combined organic layers were washed with water
and dried over anhydrous Na2SO4. After concentrating
under reduced pressure, the residue was purified via silica gel chromatography
to obtain 3a as a colorless oil (15.84 g, 52%). [α]D23 = −23.2
(c = 0.8, CHCl3); 1H NMR (400
MHz, CDCl3): δ 4.83 (1H, dd, J =
1.9, 5.1 Hz), 4.11–4.06 (2H, m), 3.96 (1H, dd, J = 6.7, 10.9 Hz), 3.90 (1H, dd, J = 5.1, 10.9 Hz),
3.85–3.83 (1H, m), 1.60–1.27 (12H, m), 1.06–1.06
(63H, m), 0.94–0.85 (15H, m); 13C NMR (67.8 MHz,
CDCl3): δ 162.4 (C), 111.3 (CH), 80.6 (CH), 70.3
(CH), 65.1 (CH), 62.5 (CH2), 29.0 (CH2), 27.4
(CH2), 27.3 (CH2), 18.2 (Me), 18.1 (Me), 13.7
(Me), 12.6 (CH), 12.5 (CH), 12.1 (CH), 9.5 (CH2); HRMS
(FAB) m/z: [M – H]− calcd for 903.5560; found, 903.5577.
In the same manner in which 3a was
prepared, the use of 2d (18.29 g, 41.3 mmol) afforded 3d as a colorless oil (11.5 g, 38%). [α]D23 = 61.0 (c = 0.8, CHCl3); 1H NMR (400 MHz,
CDCl3): δ 4.76 (1H, m), 4.31 (1H, m), 4.10 (1H, m),
4.01 (1H, m), 1.58–1.48 (6H, m), 1.36–1.26 (9H, m),
1.08–1.08 (42H, m), 0.94–0.85 (15H, m); 13C NMR (67.8 MHz, CDCl3): δ 161.7 (C), 113.3 (CH),
74.1 (CH), 71.0 (CH), 66.3 (CH), 31.6 (CH2), 29.0 (CH2), 27.3 (CH2), 18.3 (Me), 14.2 (Me), 13.7 (Me),
13.0 (CH), 12.8 (CH), 9.6 (CH2); HRMS (FAB) m/z: [M – H]− calcd for
C36H75O3Si2Sn, 731.4277;
found, 731.4285.
General Procedure A: Palladium-Catalyzed
Coupling Reactions
A solution of 1-tributylstannyl glycal 3 (0.10 mmol),
benzyl bromide (0.30 mmol), PdCl2(dppe) (6 mg, 0.010 mmol),
and Na2CO3 (21 mg, 0.20 mmol) in toluene (5
mL) was stirred at reflux for several hours under N2. For
example, the reaction took 6 h to complete and result 5a. After the cooled reaction mixture was concentrated under reduced
pressure, the residue was purified by silica gel chromatography to
obtain 5, 6, 7, or 8.
A small amount of the adduct 8j was decomposed after several days, which was confirmed using the 1HNMR spectra (see Supporting Information). [α]D23 = 44.0 (c = 0.8, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.93 (1H, d, J = 8.1 Hz), 7.18 (1H, dd, J = 1.3, 8.1 Hz), 6.99
(1H, d, J = 1.3 Hz), 4.59 (1H, m), 4.38 (1H, m),
4.17 (1H, m), 4.00 (1H, m), 3.86 (3H, s), 3.32 (2H, s), 2.34 (3H,
s), 1.32 (3H, d, J = 6.7 Hz), 1.08–1.06 (42H,
m); 13C NMR (67.8 MHz, CDCl3): δ 169.7
(C), 164.9 (C), 150.9 (C), 150.7 (C), 145.2 (C), 131.6 (CH), 126.6
(CH), 124.1 (CH), 120.9 (C), 100.4 (CH), 74.1 (CH), 70.5 (CH), 67.0
(CH), 52.0 (Me), 40.1 (CH2), 21.0 (Me), 18.3 (Me), 18.2
(Me), 13.6 (Me), 12.8 (CH), 12.7 (CH); HRMS (FAB) m/z: [M – H]− calcd for
C35H59O7Si2, 647.3799;
found, 647.3778.
General Procedure B: Deprotection, Followed
by Hydrogenation–Saponification
The solution of the
coupled products 5, 6, 7, or 8 (0.60 mmol) in THF (5.0 mL) was
added to 1.0 M THF solution of TBAF (5.0 mL, 5.0 mmol), and the reaction
mixture was stirred at room temperature for several hours. The reaction
was quenched with water (10 mL), and the mixture was extracted several
times with EtOAc. The combined organic layers were washed with water,
dried over anhydrous Na2SO4, and concentrated
under reduced pressure to obtain the crude methyl ester 9, 12, 15, or 18. The solution
of 9, 12, 15, or 18 and 10% Pd/C (13 mg) in THF (5 mL) was stirred at room temperature
under H2 for several hours. The catalyst was removed via
filtration, and the filtrate was concentrated under reduced pressure
to obtain crude 10, 13, 16,
or 19. Crude 10, 13, 16, or 19 was dissolved in MeOH (5.0 mL) and
1 M aqueous solution of NaOH (5.0 mL, 5.0 mmol) was added. The resulting
reaction mixture was stirred at room temperature for several hours.
HCl (1 M) was added to the reaction mixture and the mixture was concentrated
under reduced pressure. The residue purified by column chromatography
afforded benzyl 2-deoxy-C-glycoside 11, 14, 17, or 20.
General Procedure C: Deprotection, Followed by Hydrogenation–Acetylation
The solution of the coupled products 5a, 6a, 7a, or 8a (0.44 mmol) in THF (5.0 mL)
was added to a 1.0 M THF solution of TBAF (5.0 mL, 5.0 mmol), and
the reaction mixture was stirred at room temperature for several hours.
The reaction was quenched with water (10 mL), and the mixture was
extracted several times with EtOAc. The combined organic layers were
washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain crude methyl
ester 9a, 12a, 15a, or 18a. The solution of 9a, 12a, 15a, or 18a and 10% Pd/C (13 mg) in THF (5 mL)
was stirred at room temperature under H2 for several hours.
The catalyst was removed via filtration, and the filtrate was concentrated
under reduced pressure to obtain crude 10a, 13a, 16a, or 19a. Crude 10a, 13a, 16a, or 19a in pyridine (1.0
mL) and Ac2O (1.0 mL) was stirred at room temperature for
several hours. The reaction was quenched with water (10 mL), and the
mixture was extracted several times with EtOAc. The combined organic
layers were successively washed with water and 1 M HCl, and dried
over anhydrous Na2SO4. After concentrating under
reduced pressure, the residue was purified via silica gel chromatography
to obtain 21a, 22a, 23a, or 24a.
Scheme 1
Scheme 2
Figure 1