Oxidative heck reaction of glycals and aryl hydrazines: A palladium-catalyzed C-glycosylation

Article abstract of DOI:10.1021/jo401032r

An efficient Heck-type C-glycosylation of glycals via the C-N bond cleavage of aryl hydrazines has been developed. The flexibility of the reaction was tested by the substrate scope, consisting of glycals from different carbohydrate origins as well as aryl hydrazines with various substituents. Pure α-C-glycosides were obtained when (3R)-glycals were employed, whereas α,β mixtures were observed with (3S)-glycals.

Full text of DOI:10.1021/jo401032r

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Note
Oxidative Heck Reaction of Glycals and Aryl
Hydrazines: A Palladium-Catalyzed C-Glycosylation
Yaguang Bai, Le Mai Hoang Kim, Hongze Liao, and Xue-Wei Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401032r • Publication Date (Web): 13 Aug 2013
Downloaded from http://pubs.acs.org on August 14, 2013
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Oxidative Heck Reaction of Glycals and Aryl
Hydrazines: A Palladium-Catalyzed C-
Glycosylation
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Yaguang Bai, Le Mai Hoang Kim, Hongze Liao and Xue-Wei Liu*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371
xuewei@ntu.edu.sg
α isomers only
Abstract: An efficient Heck type C-glycosylation of glycals via the C-N bond cleavage
of aryl hydrazines has been developed. The flexibility of the reaction was tested by the
substrate scope, consisting of glycals from different carbohydrate origins as well as aryl
hydrazines with various substituents. Pure α-C-glycosides were obtained when 3R glycals
were employed while α, β mixtures were observed with 3S glycals.
Aryl-C-glycosides are a group of compounds possessing aryl groups as the aglycon at the
anomeric carbon position. Many synthetic methods have been discovered since 1980s
towards aryl-C-glycosides due to their frequent presence in natural products1 and their
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important biological functions such as enzyme inhibitors and sugar mimics. 2 Until now,
most of the synthetic methods have focused on the transition metal catalyzed cross
coupling reaction to construct the glycosidic C-C bond. Earlier strategies comprise using
pre-activated reagents either on the glycal parts such as iodinated or stannylated glycals3
or on the aromatic parts such as organometallic reagents.4 Therefore, problems that often
arise from early methods include restricted substrate scopes and high toxicity. In the last
decade, Heck reactions were employed to the syntheses of aryl-C-glycosides by direct
coupling of inactivated glycals and aromatic compounds such as aryl halides,5 aryl
boronic acids6 and benzoic acids.7 Since the reagents in these reactions are moisture
stable and relatively environmental friendly, Heck reaction became one of the most
attractive approach to aryl-C- glycosylation. There are two main classes of products
generated by Heck type aryl-C-glycosylation. One is the 2,3-deoxy-C-glycosides, which
is generated via beta-heteroatom elimination when the glycals are protected by good
leaving groups such as acetyl group. The other is the 2-deoxy-C-glycosides, which will
undergo beta-hydride elimination when the glycals are protected by poor leaving groups
such as silyl or benzyl groups.
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Recently, C-C bond constructions via cleavage of pre-activated C-N bond have attracted
considerable attention.8 Inspired by the versatility of the C-N bond activation, we
envisioned that we could further explore the synthetic methods9 towards aryl-C-glycoside
by coupling glycals with activated anilines. The general approaches to activate aniline C-
N bonds include conversion to diazonium salts or hydrazines. We decided to make
hydrazines as the coupling partners of glycals for two main reasons. Firstly some of the
diazonium salts such as diazonium halides are highly explosive and the stable diazonium
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salts such as diazonium tetrafluoroborates or hexafluorophosphates are prone to
decompose upon heating10 while heating is usually an indispensible condition for
transition metal catalyzed coupling reaction. The other reason accouting for our choice is
that aryl hydrazines are much more commercially available than aryl diazonium salts. As
a result, we herein describe our results for the syntheses of aryl-C-glycosides by a
palladium catalyzed cross coupling reactions of glycals and aryl hydrazines.11
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Table 1. Palladium-catalyzed Ferrier type C-glycosylation with 3,4,6-tri-O-acetyl glucal
and phenyl hydrazine.a
N
N
O
a
H
N
(10 mol %)
AcO
Pd(OAc)2 (5 mol %)
O
NH2
+
AcO
AcO
AcO
O2
HOAc
OAc
1a
1 equiv
2a
2 equiv
3a
entry
ligand
solvent
time (h)
temp
(oC)
yield (%)b
1
2
3
4
-
-
-
-
DCE
DCE
PhCl
PhCl
AcOH/PhCl
AcOH
24
12
12
8
8
6
6
6
6
40
80
80
80
80
80
50
60
65
-
43
40
55
71
82
35
77
90
5c
6
-
a
a
a
a
7
AcOH
8
AcOH
9
AcOH
aUnless otherwise specified, reactions were carried out with 1 equivalent of 1a, 2 equivalents of 2a, 5%
b
catalyst, 10% ligand and 1 atm of oxygen. Isolated yield. c PhCl : AcOH (v/v) = 1:1
Our initial effort was made to achieve the successful coupling of commercially available
3, 4, 6-tri-O-acetyl-D-glucal with phenyl hydrazine. The reaction was carried out by the
o
catalysis of palladium acetate at 40 C under 1 atm oxygen (entry 1, Table 1) in
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dichloroethane. No new compound was detected after 12 hours stirring. Fortunately,
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increasing the reaction temperature to 80 C (entry 2, Table 1) with other factors
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remaining unchanged offered the desired product 3a in 43% yield as pure α isomer.
Several commonly used organic solvent such as chlorobenzene (entry 3-5, Table 1) and
acetic acid (entry 5-6, Table 1) were tested and it was proven that higher yield was
obtained by using acetic acid as solvent. Addition of 1,10-phenanthroline (entry 6, Table
1) as ligand was found to further enhance the yield. Screening the reaction at different
o
temperatures (entry 7-9, Table 1) revealed that 65 C was optimal to give the desired
product in highest yield (90%) as pure α form.
With these optimized conditions in hand, we first explored the substrate scope of glycals
and the results were summarized in Table 2. Glycals with different protecting groups
were tested and the results show that the desired products were found only when the C-3
protecting groups of glycals are acetyl (3a - 3e) or ethoxycarbonyloxyl (3f). Possibly the
acetic acid as solvent restricts the reactivity of glycals with other protecting groups. Other
leaving groups such as benzoyl, pivaloyl or tert-butoxycarbonyloxy were proven to be
inactive under the standard conditions. Subsequently, we moved on to investigate the
reactivities of glycals prepared with different carbohydrate origins. Results revealed that
glycals prepared from galactose (3b), L-6-deoxyglucose (3d) and ribose (3c) also reacted
well with phenyl hydrazine to provide the corresponding C-glycosides in moderate to
high yields.
a, b
Table 2. C-Glycosylation coupling reaction of glycals and phenyl hydrazine.
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N
N
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8
R2
O
H
N
R2
O
(10 mol%)
Pd(OAc)2 (5 mol%)
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NH2
R1O
+
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OR
O2
HOAc
R1O
1
2a
2 equiv
3
1 equiv
entry
glycal
product
yield (%)
90
1
2
3
85
81
4
5
83
72
6
43
aReactions were carried out with 1 equivalent of 1a, 2 equivalents of 2a, 5% catalyst, 10% ligand and 1 atm
of oxygen at 65 oC for 6 hours. b Isolated yield
Next, 3,4,6-tri-O-acetylglucal was treated with various hydrazines of different
substituents on different positions (Table 3). Notably, if phenyl hydrazine was replaced
with the corresponding hydrochloric salt, no desired product was detected after 48 hours.
Among all the hydrazines tested, ortho-substituted aryl hydrazines were found to have
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the worst reactivities. Only o-chlorophenylhydrazine could offer the corresponding aryl-
C-glycoside in moderate yield (3i). Other ortho-substituented aryl hydrazines such as o-
tolylphenylhydrazine or o-bromophenylhydrazine failed to offer any desired product. It is
possible that the more steric hindered bromo or methyl group in ortho position prevents
the aryl-palldium complex from approching the glycal and thus the migratory insertion is
inhibited. 12 Moderate to good yields were obtained from various meta- (3g, 3m) or para-
phenylhydrazines(3h, 3j, 3k, 3l, 3n). No desired product was detected for aryl hydrazines
with strong electron donating groups, such as methoxyl or ethoxyl due to the possible
decomposition of hydrazine substrates under standard conditions such as 1 atm oxygen
and high temperature. All the aryl-C-glycosides were obtained in pure α selectivity.
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Table 3. C-Glycosylation coupling reaction of 3,4,6-tri-O-acetylglucal and various aryl
hydrazines. a, b
entry
R
time (h)
yield (%)
1
2
3-Me-C6H4 (3g)
4-Me-C6H4 (3h)
4
3
80
86
3
4
2-Cl-C6H4 (3i)
4-Br-C6H4 (3j)
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6
43
85
5
6
4-COOMe-C6H4 (3k)
4-I-C6H4 (3l)
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2
51
30
7
8
3, 5-CF3-C6H3 (3m)
4-F-C6H4 (3n)
8
4
64
79
aUnless otherwise specified, reactions were carried out with 1 equiv-alent of 1a, 2 equivalents of 2, 5%
catalyst, 10% ligand and 1 atm of oxygen at 65 C. b Isolated yield
o
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Although all the reported transition metal catalyzed Heck type C-glycosylation methods
showed α selectivity, few reports provided the reason. The stereoselectivity could be
attributed to any of the 3 pre-existing chiral centers on the glycal substrates. In 2009,
Ye’s group deduced that the stereochemistry of C3 on glycal was the main reason for α
selectivity.5bDue to the steric hindrance between the bulky palladium species and the
protecting group on C3, the palladium species can only approach glycals from the side
opposite to the C3 group. Thus, α product was obtained exclusively. To test this
hypothesis and prepare β aryl-C-glycosides, (3S, 4S, 6R)-tri-O-acetylglycal was
synthesized13 and treated with various hydrazines under standard conditions. The results
were summarized in Table 4. Instead of pure α product, a mixture of α and β isomers
were obtained, with ratios ranging from 1:1 to 1:0.6. These results suggest that the
stereochemistry at C-3 is not the only determining factor for the observed α selectivity.
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Table 4. C-Glycosylation coupling reaction of (3S, 4S, 6R)-tri-O-acetylglycal and various
aryl hydrazines. a, b
entry
R
time (h)
yield (h)
α:β
1
2
Ph (3o)
4-F-C6H4(3p)
6
4
79
75
1:1
1:0.81
3
4
4-Br-C6H4 (3q)
3-Me-C6H4(3r)
6
4
83
74
1:0.6
1:0.87
a Unless otherwise specified, reactions were carried out with 1 equivalent of 4, 2 equivalents of 2, 5%
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catalyst, 10% ligand and 1 atm of oxygen at 65 C. b Isolated yield.
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In conclusion, an efficient Heck type C-glycosylation method of glycals and aryl
hydrazines, by the C-N bond cleavage, has been developed. The substrate scope includes
glycals with protecting groups which function as good leaving groups and various aryl
hydrazines. High stereoselectivities were achieved when 3R glycals substrate were used.
On the contrary, α and β mixtures were obtained when 3S glycals were chosen. To the
best of our knowledge, this is the first example for the formation of β aryl- C-glycoside
via Heck type reaction. Since aryl hydrazines could be prepared by short steps from their
corresponding anilines, 14 this protocol presents promising applications to the syntheses
of aryl-C-glycosides containing natural products.
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Experimental Section
General procedure of Pd catalyzed cross-coupling of glycals and aryl hydrazines: To
a round bottom flask containing the solution of glycal (1 equiv), palladium(II) diacetate
(5% mol) and 1, 10-phenantroline (10% mol) in acetic acid (2.5 mL/mmol) at 65 °C,
phenyl hydrazine (1.5 equiv) in acetic acid (5 mL/mmol) was added dropwise. The
mixture was allowed to stir at 65 °C for the indicated time in Scheme 1, Table 2 and
Table 3. Then the mixture was diluted with ethyl acetate (20 mL/mmol), filtered, washed
with water (5 mL/mmol) and brine (5 mL/mmol). The organic layer was evaporated and
the residue was purified by flash column chromatography to afford the product.
((2R,3S,6S)-3-Acetoxy-6-phenyl-3,6-dihydro-2H-pyran-2-yl)methyl acetate (3a).
Following the general procedure, the crude product was purified over a silica gel column
1
using hexane/EtOAc system (6:1 to 4:1) to give a colorless oil, 52 mg, 90% yield: H
NMR (CDCl3, 400 MHz) δ 2.07 (s, 3H), 2.09 (s, 3H), 3.83–3.97 (m, 1H), 4.09 (dd, J =
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3.1, 12.0 Hz, 1H), 4.25 (dd, J = 5.9, 12 Hz, 1H), 5.29–5.33 (m, 2H), 5.97–6.01 (m, 1H),
6.19 (ddd, J = 1.5, 3.0, 10.4 Hz, 1H), 7.32–7.39 (m, 5H);13C NMR (CDCl3, 400 MHz) δ
20.8, 21.1, 62.9, 65.0, 69.3, 73.7, 125.0, 127.9, 128.3, 128.5, 131.5, 138.8, 170.5,
ꢀ ꢂ ꢃꢄ
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170.9; ꢁ
= 13.9 (c 2.00, CHCl3); HRMS (ESI) calcd for C16H18O5Na
ꢅ
[M+Na]+313.1052, found 313.1053.
((2R,3R,6S)-3-Acetoxy-6-phenyl-3,6-dihydro-2H-pyran-2-yl)methyl acetate (3b).
Following the general procedure, the crude product was purified over a silica gel column
using hexane/EtOAc system (6:1 to 4:1) to give a pale yellow oil, 49 mg, 85% yield: 1H
NMR (CDCl3, 400 MHz) δ 1.99 (s, 3H), 2.11 (s, 3H), 3.92–3.95 (m, 1H), 4.14–4.23 (m,
2H), 5.11 (dd, J = 2.6, 5.1 Hz, 1H), 5.39–5.41 (m, 1H), 6.20 (ddd, J = 2.1, 5.2, 10.2 Hz,
1H), 6.41 (ddd, J = 0.5, 3.6, 10.2 Hz, 1H), 7.30–7.35 (m, 5H);13C NMR (CDCl3, 400
MHz) δ 20.7, 20.9, 62.8, 63.8, 68.3, 73.8, 123.5, 127.8, 128.2, 128.5, 133.3, 138.3, 170.6,
ꢀ ꢂ ꢃꢄ
170.6; ꢁ
= -371.1 (c 3.00, CHCl3); HRMS (ESI) calcd for C16H18O5Na
ꢅ
[M+Na]+313.1052, found 313.1060.
(3S,6R)-6-Phenyl-3,6-dihydro-2H-pyran-3-yl acetate (3c). Following the general
procedure, the crude product was purified over a silica gel column using hexane/EtOAc
system (10:1 to 8:1) to give a yellow oil, 35 mg, 81% yield: 1H NMR (CDCl3, 400 MHz)
δ 2.11 (s, 3H), 3.69 (dd, J = 5.2, 11.9 Hz, 1H), 4.04 (dd, J = 4.4, 11.9 Hz, 1H), 5.21 (t, J
= 2.1, 1H), 5.22–5.29 (m, 1H), 6.03–6.07 (m, 1H), 6.16 (ddd, J = 1.2, 2.6, 10.4 Hz, 1H),
7.30–7.39 (m, 5H);13C NMR (CDCl3, 400 MHz) δ 21.1, 64.7, 64.7, 75.1, 124.5, 127.8,
ꢀ ꢂ ꢃꢄ
128.3, 128.6, 133.3, 139.1, 170.7; ꢁ
= 170.0 (c 3.00, CHCl3); HRMS (ESI) calcd for
ꢅ
C13H14O3Na [M+Na]+ 241.0841, found 241.0842.
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(2S,3R,6R)-2-Methyl-6-phenyl-3,6-dihydro-2H-pyran-3-yl acetate (3d). Following the
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general procedure, the crude product was purified over a silica gel column using
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hexane/EtOAc system (8:1) to give a bright yellow oil, 38 mg, 83% yield: H NMR
(CDCl3, 400 MHz) δ 1.25 (d, J = 6.44 Hz, 3H), 2.10 (s, 3H), 3.87 (t, J = 6.3 Hz, 1H),
5.05 (m, 1H), 5.23 (q, J = 2.2 Hz, 1H), 5.95 (ddd, J = 2.1, 3.2, 10.3 Hz, 1H), 6.13 (ddd, J
= 1.4, 2.8, 10.3 Hz, 1H), 7.30 – 7.42 (m, 5H);13C NMR (CDCl3, 400 MHz) δ 17.3, 21.2,
ꢀ ꢂ ꢃꢄ
68.0, 69.8, 72.8, 124.2, 127.9, 128.1, 128.5, 132.2, 139.6, 170.8; ꢁ
= -34.8 (c 1.50,
ꢅ
CHCl3); HRMS (ESI) calcd for C14H16O3Na [M+Na]+ 255.0997, found 255.0989.
(2R,3R,6S)-3-(Benzyloxy)-2-((benzyloxy)methyl)-6-phenyl-3,6-dihydro-2H-pyran
(3e). Following the general procedure, the crude product was purified over a silica gel
column using hexane/EtOAc system (10:1 to 6:1) to give a colorless oil, 56 mg, 72%
yield: 1H NMR (CDCl3, 400 MHz) δ 3.60–3.67 (m, 1H), 3.68–3.72 (m, 2H), 4.18–4.21
(m, 2H), 4.45–4.51 (m, 2H), 4.58–4.64 (m, 2H), 5.32 (d, J = 1.5 Hz, 1H), 6.08–6.16 (m,
2H), 7.25–7.37 (m, 13H), 7.43–7.46 (m, 2H);13C NMR (CDCl3, 400 MHz) δ 69.2, 70.2,
70.7, 71.2, 73.3, 74.1, 77.2, 127.2, 127.6, 127.8, 127.9, 128.0, 128.1, 128.3, 128.4, 128.4,
ꢀ ꢂ ꢃꢄ
129.6, 138.2, 139.6; ꢁ
= 22.8 (c 1.20, CHCl3); HRMS (ESI) calcd for C26H26O3Na
ꢅ
[M+Na]+ 409.1780, found 409.1779.
((2R,3S,6S)-6-Phenyl-2-((ethoxycarbonyloxy)methyl)-3,6-dihydro-2H-pyran-3-
yl)methyl ethyl carbonate (3f). Following the general procedure, the crude product was
purified over a silica gel column using hexane/EtOAc system (4:1 to 3:1) to give a brown
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oil, 30 mg, 43% yield: H NMR (CDCl3, 400 MHz) δ 1.27–1.34 (m, 6H), 3.87–3.91 (m,
1H), 4.15–4.28 (m, 5H), 4.30–4.33 (m, 1H), 5.21 (dd, J = 1.9, 7.6 Hz, 1H), 5.33 (d, J =
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2.4 Hz, 1H), 6.06 (dt, J = 2.2, 10.4 Hz, 1H), 6.20 (ddd, J = 1.6, 3.1, 10.4 Hz, 1H), 7.32–
7.41 (m, 5H);13C NMR (CDCl3, 400 MHz) δ 14.1, 14.1, 64.1, 64.3, 66.0, 68.1, 68.5, 73.7,
ꢀ ꢂ ꢃꢄ
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77.0, 124.4, 127.9, 128.1, 128.3, 128.4, 131.7, 138.3, 154.4, 154.9; ꢁ
= 19.8 (c 0.80,
ꢅ
CHCl3); HRMS (ESI) calcd for C18H22O7Na [M+Na]+ 373.1263, found 373.1263.
((2R,3S,6S)-3-Acetoxy-6-(m-tolyl)-3,6-dihydro-2H-pyran-2-yl)methyl acetate (3g).
Following the general procedure, the crude product was purified over a silica gel column
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using hexane/EtOAc system (6:1 to 4:1) to give a colorless oil, 49 mg, 80% yield: H
NMR (CDCl3, 400 MHz) δ 2.08 (s, 3H), 2.09 (s, 3H), 2.37 (s, 3H), 3.84–3.88 (m, 1H),
4.10 (dd, J = 3.1, 12.0 Hz, 1H), 4.27 (dd, J = 5.9, 12 Hz, 1H), 5.29–5.32 (m, 2H), 5.96–
6.00 (m, 1H), 6.17–6.20 (m, 1H), 7.13–7.25 (m, 4H); 13C NMR (CDCl3, 400 MHz) δ 20.8,
21.1, 21.5, 62.9, 65.0, 69.3, 73.7, 124.9, 124.9, 128.4, 128.6, 129.0, 131.6, 138.2, 138.8,
ꢀ ꢂ ꢃꢄ
170.5, 170.9; ꢁ
= 19.5 (c 1.50, CHCl3); HRMS (ESI) calcd for C17H20O5Na [M+Na]+
ꢅ
327.1208, found 327.1204.
((2R,3S,6S)-3-Acetoxy-6-(p-tolyl)-3,6-dihydro-2H-pyran-2-yl)methyl acetate (3h).
Following the general procedure, the crude product was purified over a silica gel column
1
using hexane/EtOAc system (6:1 to 4:1) to give a pale yellow oil, 52 mg, 86% yield: H
NMR (CDCl3, 400 MHz) δ 2.07 (s, 3H), 2.08 (s, 3H), 2.36 (s, 3H), 3.80–3.84 (m, 1H),
4.08 (dd, J = 3.1, 12.0 Hz, 1H), 4.26 (dd, J = 5.7, 12.0 Hz, 1H), 5.30–5.33 (m, 2H), 5.98
(dt, J = 2.1, 10.3 Hz, 1H), 6.17 (ddd, J = 1.4, 2.9, 10.4 Hz, 1H), 7.18 (m, 2H), 7.28 (m,
2H);13C NMR (CDCl3, 400 MHz) δ 20.8, 21.1, 21.2, 62.9, 65.1, 69.0, 73.7, 125.0, 128.0,
ꢀ ꢂ ꢃꢄ
129.2, 131.6, 135.8, 138.1, 170.5, 170.9; ꢁ
= 5.2 (c 1.50, CHCl3); HRMS (ESI) calcd
ꢅ
for C17H20O5Na [M+Na]+ 327.1208, found 327.1198.
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((2R,3S,6S)-3-Acetoxy-6-(2-chlorophenyl)-3,6-dihydro-2H-pyran-2-yl)methyl acetate
(3i). Following the general procedure, the crude product was purified over a silica gel
column using hexane/EtOAc system (6:1 to 4:1) to give a pale yellow oil, 28 mg, 43%
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yield: H NMR (CDCl3, 400 MHz) δ 2.06 (s, 3H), 2.11 (s, 3H), 3.95–3.99 (m, 1H), 4.10
(dd, J = 3.7, 12.0 Hz, 1H), 4.34 (dd, J = 6.6, 12 Hz, 1H), 5.23–5.26 (m, 1H), 5.71 (dd, J =
2.2, 2.2 Hz, 1H), 6.04 (ddd, J = 2.0, 3.1, 10.4 Hz, 1H), 6.12 (dd, J = 1.2, 2.6, 10.4 Hz,
1H), 7.27–7.30 (m, 2H), 7.30–7.42 (m, 1H), 7.47 (m, 1H); 13C NMR (CDCl3, 400 MHz) δ
20.8, 21.1, 62.5, 64.8, 70.2, 77.2, 124.7, 126.7, 129.3, 129.6, 130.0, 131.4, 134.2, 135.9,
ꢀ ꢂ ꢃꢄ
170.5, 170.9; ꢁ
= 16.8 (c 1.50, CHCl3); HRMS (ESI) calcd for C16H17O5ClNa
ꢅ
[M+Na]+ 347.0662, found 347.0669.
((2R,3S,6S)-3-Acetoxy-6-(4-bromophenyl)-3,6-dihydro-2H-pyran-2-yl)methyl
acetate (3j). Following the general procedure, the crude product was purified over a
silica gel column using hexane/EtOAc system (4:1) to give a colorless oil, 62 mg, 85%
yield: 1H NMR (CDCl3, 400 MHz) δ 2.07 (s, 3H), 2.08 (s, 3H), 3.77–3.81 (m, 1H), 4.08
(dd, J = 3.0, 12.0 Hz, 1H), 4.25 (dd, J = 6.0, 12.0 Hz, 1H), 5.27–5.29 (m, 2H), 5.97–6.00
(m, 1H), 6.12–6.16 (m, 1H), 7.26–7.29 (m, 2H), 7.48–7.51 (m, 2H); 13C NMR (CDCl3,
400 MHz) δ 20.8, 21.1, 62.8, 64.9, 69.4, 73.0, 122.4, 125.5, 129.6, 130.9, 131.7, 137.9,
ꢀ ꢂ ꢃꢄ
170.4, 170.8; ꢁ
= -22.0 (c 3.00, CHCl3); HRMS (ESI) calcd for C16H17O5BrNa
ꢅ
[M+Na]+ 391.0157, found 391.0155.
Methyl-4-((2S,5S,6R)-5-acetoxy-6-(acetoxymethyl)-5,6-dihydro-2H-pyran-2-
yl)benzoate (3k). Following the general procedure, the crude product was purified over a
silica gel column using hexane/EtOAc system (4:1 to 3:1) to give a yellow oil, 35 mg,
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51% yield: 1H NMR (CDCl3, 400 MHz) δ 2.08 (s, 3H), 2.10 (s, 3H), 3.80–3.84 (m, 1H),
3.92 (S, 3H), 4.11 (dd, J = 3.0, 12.0 Hz, 1H), 4.20–4.28 (m, 1H), 5.28–5.30 (m, 1H), 5.36
(s, 1H), 5.98–6.02 (m, 1H), 6.17–6.21 (m, 1H), 7.48 (d, J = 8.2 Hz, 2H), 8.04 (d, J = 8.2
Hz, 2H);13C NMR (CDCl3, 400 MHz) δ 20.8, 21.0, 52.1, 62.7, 64.8, 69.7, 73.1, 125.4,
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127.5, 129.8, 129.9, 130.8, 144.0, 166.7, 170.4, 170.7; ꢁ
= -6.0 (c 2.00, CHCl3);
ꢅ
HRMS (ESI) calcd for C18H20O7Na [M+Na]+ 371.1107, found 371.1111.
((2R,3S,6S)-3-Acetoxy-6-(4-iodophenyl)-3,6-dihydro-2H-pyran-2-yl)methyl acetate
(3l). Following the general procedure, the crude product was purified over a silica gel
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column using hexane/EtOAc system (4:1) to give a dark brown oil, 25 mg, 30% yield: H
NMR (CDCl3, 400 MHz) δ 2.08 (s, 3H), 2.09 (s, 3H), 3.78–3.82 (m, 1H), 4.09 (dd, J =
3.1, 12.0 Hz, 1H), 4.26 (dd, J = 6.0, 12.0 Hz, 1H), 5.26–5.31 (m, 2H), 5.98–6.01 (m, 1H),
13
6.13–6.16 (m, 2H), 7.16 (d, J = 8.2 Hz, 2H), 7.72 (dd, J = 1.8, 6.6 Hz, 2H); C NMR
(CDCl3, 400 MHz) δ 20.9, 21.1, 62.9, 64.9, 69.5, 73.2, 94.1, 125.5, 129.8, 130.9, 137.7,
ꢀ ꢂ ꢃꢄ
138.7, 170.5, 170.9; ꢁ
= 1.4 (c 1.00, CHCl3); HRMS (ESI) calcd for C16H17O5INa
ꢅ
[M+Na]+ 439.0018, found 439.0014.
((2R,3S,6S)-3-Acetoxy-6-(3,5-bis(trifluoromethyl)phenyl)-3,6-dihydro-2H-pyran-2-
yl)methyl acetate (3m). Following the general procedure, the crude product was purified
over a silica gel column using hexane/EtOAc system (6:1 to 4:1) to give a colorless oil,
54 mg, 64% yield: 1H NMR (CDCl3, 400 MHz) δ 2.10 (s, 3H), 2.11 (s, 3H), 3.81–3.86 (m,
1H), 4.16 (dd, J = 2.9, 12.0 Hz, 1H), 4.28 (dd, J = 7.4, 12.0 Hz, 1H), 5.25–5.28 (m, 1H),
5.42 (d, J = 1.84 Hz, 1H), 6.08 (ddd, J = 2.2, 2.8, 10.4 Hz, 1H), 6.26 (ddd, J = 1.5, 3.1,
10.4 Hz, 1H), 7.85 (s, 1H), 7.90 (s, 2H);13C NMR (CDCl3, 400 MHz) δ 20.6, 21.0, 29.9,
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ꢀ ꢂ ꢃꢄ
62.9, 64.7, 70.4, 72.0, 122.0, 126.3, 127.4, 129.9, 131.8, 132.1, 170.4, 170.8; ꢁ
=
ꢅ
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24.4 (c 0.80, CHCl3); HRMS (ESI) calcd for C18H16O5F6Na [M+Na]+ 449.0800, found
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449.0811.
((2R,3S,6S)-3-Acetoxy-6-(4-fluorophenyl)-3,6-dihydro-2H-pyran-2-yl)methyl acetate
(3n). Following the general procedure, the crude product was purified over a silica gel
column using hexane/EtOAc system (6:1 to 4:1) to give a colorless oil, 48 mg, 79% yield
： 1H NMR (CDCl3, 400 MHz) δ 2.06 (s, 3H), 2.09 (s, 3H), 3.79–3.83 (m, 1H), 4.08 (dd,
J = 3.1, 12.0 Hz, 1H), 4.26 (dd, J = 6.0, 12.0 Hz, 1H), 5.28–5.30 (m, 2H), 5.98–6.01 (m,
1H), 6.19 (m,1H), 7.04–7.08 (m, 2H), 7.36–7.40 (m, 2H); 13C NMR (CDCl3, 400 MHz) δ
20.8, 21.1, 62.8, 64.9, 69.3, 73.0, 115.3, 115.5, 125.2, 129.7, 129.8, 131.3, 134.6, 134.7,
ꢀ ꢂ ꢃꢄ
161.4, 163.9, 170.5, 170.8; ꢁ
= 15.8 (c 2.50, CHCl3); HRMS (ESI) calcd for
ꢅ
C16H17O5FNa [M+Na]+ 331.0960, found 331.0958.
((2R,3S,6S)-3-Acetoxy-6-phenyl-3,6-dihydro-2H-pyran-2-yl)methyl acetate and
((2R,3S,6R)-3-acetoxy-6-phenyl-3,6-dihydro-2H-pyran-2-yl)methyl acetate (3o).
Following the general procedure, the crude product was purified over a silica gel column
using hexane/EtOAc system (6:1 to 4:1) to give a yellow oil, 46 mg, 79% yield. 1H NMR
(CDCl3, 400 MHz) δ 2.07–2.09 (m, 9H), 2.11 (s, 3H), 3.83–3.87 (m, 1H), 3.92–3.96 (m,
1H), 4.10 (dd, J = 3.1, 12.0 Hz, 1H), 4.18–4.30 (m, 3H), 5.21–5.22 (m, 1H), 5.30–5.34
(m, 2H), 5.40–5.44 (m, 1H), 5.83 (dt, J = 2.1, 10.3 Hz, 1H), 5.91–6.18 (m, 1H), 7.31–
7.42 (m, 10H);13C NMR (CDCl3, 400 MHz) δ 20.8, 20.9, 21.1, 62.9, 63.8, 65.0, 65.5,
69.3, 73.7, 74.8, 77.2, 77.6, 124.9, 125.0, 127.2, 127.9, 128.3, 128.4, 128.5, 128.7, 131.5,
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132.8, 138.8, 139.8, 170.4, 170.5, 170.9, 171.0; HRMS (ESI) calcd for C 16H18O5Na
[M+Na]+ 313.1052, found 313.1053.
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((2R,3S,6S)-3-Acetoxy-6-(4-fluorophenyl)-3,6-dihydro-2H-pyran-2-yl)methyl acetate
and
((2R,3S,6R)-3-acetoxy-6-(4-fluorophenyl)-3,6-dihydro-2H-pyran-2-yl)methyl
acetate (3p). Following the general procedure, the crude product was purified over a
silica gel column using hexane/EtOAc system (6:1 to 4:1) to give a colorless oil, 46 mg,
1
75% yield: H NMR (CDCl3, 400 MHz) δ 2.07 (s, 3.56H), 2.08 (s, 3.15H), 2.09 (s,
3.63H), 2.11 (s, 2.89H), 3.79–3.83 (m, 1.24H), 3.91–3.95 (m, 1H), 4.08 (dd, J = 3.1, 12.0
Hz, 1.28H), 4.19 (dd, J = 5.9, 12.1 Hz, 1H), 4.24–4.29 (m, 2.27H), 5.20 (s, 1H), 5.20–
5.30 (m, 2.45H), 5.39–5.42 (m, 1H), 5.82–5.90 (m, 2H), 5.98–6.02 (m, 1.24H), 6.13–6.16
(m, 1.25H), 7.02–7.08 (m, 4.47H), 7.29–7.33 (m, 2H), 7.37 – 7.38 (m, 2.45H); 13C NMR
(CDCl3, 400 MHz) δ 20.8, 20.9, 21.1, 62.8, 63.7, 64.9, 65.3, 69.3, 73.0, 74.9, 76.9, 77.2,
115.3, 115.4, 115.5, 115.7, 125.2, 129.0, 129.1, 129.7, 129.8, 131.3, 132.5, 134.7, 134.7,
135.7, 135.7, 161.4, 161.5, 163.9, 163.9, 170.4, 170.5, 170.8, 171.0; HRMS (ESI) calcd
for C16H17O5FNa [M+Na]+ 331.0958, found 331.0956.
((2R,3S,6S)-3-Acetoxy-6-(4-bromophenyl)-3,6-dihydro-2H-pyran-2-yl)methyl
acetate and ((2R,3S,6R)-3-acetoxy-6-(4-bromophenyl)-3,6-dihydro-2H-pyran-2-
yl)methyl acetate (3q). Following the general procedure, the crude product was purified
over a silica gel column using hexane/EtOAc system (4:1 to 3:1) to give a yellow oil, 61
mg, 83% yield: 1H NMR (CDCl3, 400 MHz) δ 2.08 (s, 3H), 2.08 (s, 1.68H), 2.09 (s, 3H),
2.11 (s, 1.77H), 3.78–3.82 (m, 1H), 3.91–3.94 (m, 0.64H), 4.09 (dd, J = 3.1, 12.0 Hz,
1H), 4.17–4.24 (m, 0.67H), 4.25–4.30 (m, 1.66H), 5.18 (s, 0.87H), 5.18 (s, 0.60H), 5.28–
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5.31 (m, 2H), 5.38–5.41 (m, 0.61H), 5.84–5.86 (m, 1.22H), 6.00 (dt, J = 2.1, 10.4 Hz,
1H), 6.13 –6.16 (m, 1H), 7.20–7.24 (m, 1.25H), 7.26–7.30 (m, 2H), 7.47–7.52 (m,
3.2H);13C NMR (CDCl3, 400 MHz) δ 20.8, 20.9, 21.1, 62.8, 63.6, 64.9, 65.3, 69.4, 73.0,
74.8, 76.9, 77.2, 122.3, 122.4, 125.4, 125.5, 128.9, 129.6, 130.9, 131.7, 131.8, 132.0,
132.2, 137.9, 138.8, 170.4, 170.4, 170.8, 171.0; HRMS (ESI) calcd for C16H17O5BrNa
[M+Na]+ 391.0157, found 391.0156.
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((2R,3S,6S)-3-Acetoxy-6-(m-tolyl)-3,6-dihydro-2H-pyran-2-yl)methyl acetate and
((2R,3S,6R)-3-acetoxy-6-(m-tolyl)-3,6-dihydro-2H-pyran-2-yl)methyl acetate (3r).
Following the general procedure, the crude product was purified over a silica gel column
using hexane/EtOAc system (6:1 to 4:1) to give a pale yellow oil, 45 mg, 84% yield. 1H
NMR (CDCl3, 400 MHz) δ 2.08 (s, 5.35H), 2.09 (s, 3H), 2.11 (s, 2.59H), 2.35 (s, 2.62H),
2.37 (s, 3H), 3.84–3.88 (m, 1H), 3.91–3.95 (m, 0.87H), 4.10 (dd, J = 3.1, 12.0 Hz, 1H),
4.20 (dd, J = 6.0, 12.1 Hz, 0.88H), 4.25–4.29 (m, 2H), 5.18 (s, 0.87H), 5.18–5.32 (m, 2H),
5.41–5.44 (m, 0.87H), 5.82 (dt, J = 2.1, 10.3 Hz, 0.87H), 5.93 (dt, J = 1.6, 10.2 Hz, 1H),
6.19 (m, 1H), 7.11–7.23 (m, 6.72H), 7.24–6.29 (m, 0.87H); 13C NMR (CDCl3, 400 MHz)
δ 20.8, 20.9, 21.1, 21.4, 21.5, 62.9, 63.8, 65.1, 65.5, 69.3, 73.7, 74.8, 77.2, 77.7, 124.4,
124.8, 124.9, 124.9, 128.0, 128.4, 128.6, 128.6, 129.0, 129.2, 131.6, 132.9, 138.2, 138.4,
138.8, 139.7, 170.4, 170.5, 170.9, 171.0; HRMS (ESI) calcd for C17H20O5Na [M+Na]+
327.1208, found 327.1204.
Acknowledgement
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We gratefully acknowledge Nanyang Technological University (RG50/08) and the
Ministry of Education, Singapore (MOE 2009-T2-1-030) for the financial support of this
research.
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Supporting Information
General experimental conditions; general synthesis of compound 4; spectral data for all
new compounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
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