An investigation of construction of chondroitin sulfate E (CS-E) repeating unit

Article abstract of DOI:10.1016/j.tet.2016.07.042

A series of the derivatives of chondroitin sulfate E (CS-E) disaccharide repeating unit were prepared by postglycosylation–oxidation strategy. The strategy showed excellent performance in glycosylation both on the reactivity and stereoselectivity. Different protecting methodologies were used for the manipulation of disaccharide building blocks. Substitutes at C-4 of glucosyl donors mildly influenced the glycosylation. The current synthesis afforded a feasible approach for the preparation of CS-E repeating unit.

Full text of DOI:10.1016/j.tet.2016.07.042

Tetrahedron 72 (2016) 5659e5670
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An investigation of construction of chondroitin sulfate E (CS-E)
repeating unit
,
Shuang Yang a, A-peng Wang a, Guangyan Zhang a, Xiangjie Di b, Zhehui Zhao a
*
,
Pingsheng Lei a
a State Key Laboratory of Bioactive Substance and Function of National Medicines, Institute of Materia Medica, Peking Union Medical College and
Chinese Academy of Medical Sciences, Beijing 100050, PR China
b Yantai Dongcheng Biochemicals Company Limited, Shandong, 264006, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 May 2016
Received in revised form 11 July 2016
Accepted 12 July 2016
Available online 14 July 2016
A series of the derivatives of chondroitin sulfate E (CS-E) disaccharide repeating unit were prepared by
postglycosylationeoxidation strategy. The strategy showed excellent performance in glycosylation both
on the reactivity and stereoselectivity. Different protecting methodologies were used for the manipu-
lation of disaccharide building blocks. Substitutes at C-4 of glucosyl donors mildly influenced the gly-
cosylation. The current synthesis afforded a feasible approach for the preparation of CS-E repeating unit.
Ó 2016 Published by Elsevier Ltd.
Keywords:
Chondroitin sulfate E
Repeating unit
Reactivity
Stereoselectivity
Postglycosylationeoxidation
1. Introduction
employed for the further preparation of CS-E tetrasaccharides.5 On
the other hand, Hsieh-Wilson and co-workers described the syn-
Chondroitin sulfate (CS) is a linear sulfated polysaccharide
composed of repeating dimeric units GlcA- (1/3)-GalNAc-
(1/4). Variation of sulfation position and number gives rise to
thesis of CS-E tetra- and hexa-saccharides having a GlcAeGalNAc
motif came from 3, which is in a reverse sequence.6 Different with
constructing disaccharide unit from two monosaccharide building
blocks, Jacquinet and co-workers synthesized CS-E oligosaccha-
rides starting from the key disaccharide unit 4, which was obtained
directly by hydrolysis of commercially available CS polymer.7e10
b
b
different subtypes of CS polymer. CS-E is characterized by two sul-
fates at C-4 and C-6 positions of GalNAc residue, and it was reported
to play critical roles in various physiological processes.1 Precise
molecular structure is essential for accurate pharmacological study.
However, the complexity and heterogeneity of CS make it difficult to
obtain structurally defined CS-E oligosaccharides in significant
amounts from natural sources. To addressthe problem, well-defined
synthetic CS-E oligosaccharides are required. Moreover, a further
chemical structural modification of CS-E will give access to the ex-
amination of structureeactivity relationship, providing more un-
derstanding of its biofunction on pharmacological targets.
Several reports of total synthesis of CS-E oligosaccharides have
been published so far (Scheme 1).2e10 Using a GalNAc donor and
GlcA acceptor, Tamura, J. and co-workers successfully obtained di-
saccharide unit 1, which was further elongated to give tetra-, hexa-,
and octa-saccharides.2e4 In the same sequence, repeating unit 2
was developed by Pedro M. Nieto and co-workers and it was
Scheme 1. Structures of key disaccharide used in total synthesis of CS-E oligosac-
* Corresponding author. E-mail address: zhaozh@imm.ac.cn (Z. Zhao).
charides reported.
http://dx.doi.org/10.1016/j.tet.2016.07.042
0040-4020/Ó 2016 Published by Elsevier Ltd.

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S. Yang et al. / Tetrahedron 72 (2016) 5659e5670
Besides, along with the development of total synthesis of CS-E,
some derivatives were prepared and estimated in various bi-
ological activity studies.11e19
2. Results and discussion
Synthesis of eight donors were carried out as shown in Scheme
As illustrated in all these approaches, CS-E was prepared by
‘oligomerization’ of a key disaccharide repeating unit, to which an
easy access was crucial to the efficient synthesis of CS-E oligosac-
charides. According to the structural feature of CS-E, suitable pro-
tection and transformation strategy should be employed in the
construction of the disaccharide repeating unit. However, their
influence on glycosylation was poorly understood, although sub-
stituents may significantly affect yield and stereoselectivity in
glycosylation reactions. In this article, we focused on the con-
struction of CS-E repeating disaccharide unit in GlcAeGalNAc se-
quence, synthesized a small library of monosaccharide building
blocks as donors and acceptors, compared their reactivity in gly-
cosylation, and investigated the suitable strategies used in CS-E
synthesis. At the same time, we explored the feasibility of post-
glycosylationeoxidation strategy20 at the disaccharide stage. In this
approach, the disaccharide is assembled with nonoxidized glucosyl
building block and the carboxylic acid moiety is introduced at the
later stage. Since glucuronic acids are usually considered to be in-
active glycosyl donors due to the presence of the electro-
withdrawing carboxylic acid moiety,20 we envisioned that the
postglycosylationeoxidation strategy would be more effective for
CS-E oligosaccharide glycosylation than the preglycosylatione
oxidation strategy.
2. Compound 16 was prepared from
D-glucose monohydrate
according to the traditional literature protocols for carbohydrates
with select modifications.6 Lev and TBS substitute were installed at
the C-4 position of the glucosyl moiety to afford thioglycosides 5
and 7 in 96% and 66% yield, respectively. p-Methoxybenzyl ether
(PMB) of 7 was subjected to oxidative removal with 2,3-dicyano-
5,6-dichlorobenzoquinone (DDQ) to give alcohol in 96% yield. The
primary alcohol was oxidized by pyridinium dichromate (PDC)
followed by methyl esterification to afford the donor 9 in 77% yield
(two steps). 9 was transformed into 11 through cleavage of the TBS
group with HF$Py followed by levulinoylation in 69% yield (two
steps). Conversion of donors 5, 7, 9, and 11 to glycosyl tri-
chloroacetimidate 6, 8, 10, and 12 by cleavage of the anomeric
thioether with NIS or NBS and subsequent treatment of the lactol
with trichloroacetonitrile and catalytic amount of 1,8-diazabicyclo
[5.4.0]undec-7-ene (DBU) or Cs2CO3 was readily achieved (69%e
81%, two steps).
We initially designed a small library of monosaccharide building
blocks containing eight donors and three acceptors, which pre-
sumably possess different reactivity in glycosylation (Fig. 1). In
particular, to improve the utilization of compound library, all
monosaccharides were enabled to be potentially useful building
blocks for CS-E disaccharide fragments, and the corresponding
basic structural characteristics were taken into account: (1) The b-
stereoselectivity was controlled by the presence of a benzoyl par-
ticipating group in the glucosyl unit. (2) A 4,6-O-benzylidene acetal
was used to give an access to 4,6-sulfation of GalNAc residue in the
future. (3) The anomeric hydroxyl group of galactosamine unit was
masked with OMP, which could be oxidative deprotected by ceric
ammonium nitrate (CAN) allowing further elongation. Apart from
these common features, protection strategies at other positions
were investigated of their influence on glycosylations. Firstly, thi-
oglycoside and trichloroacetimidate were designed as anomeric
group of glucosyl moiety. Secondly, nonoxidized glucosyl building
blocks 5e8 were designed to investigate the difference of reactivity
in glycosylation with their oxidized counterparts 9e12. Thirdly,
with respect to the C-4 position in glucosyl residue, the selectively
removable Lev and TBS groups were chosen as representatives of
orthogonal protecting groups which possess opposite electronic
property. On the other hand, in galactosamine residue, three ac-
ceptor moieties 13e15 were designed differentiated by the amino
types at C-2 position, as representatives of N-protection methods
which were commonly used in CS-E synthesis.
Scheme 2. Reagents and conditions: a. Ac2O, cat. DMAP, 90 ꢀC, 2.5 h, 94%; b. p-Tol-
uenethiol, BF3$Et2O, DCM, 40 ꢀC, 8 h, 71%; c. NaOMe, MeOH, rt, 1 h, 93%; d. p-Me-
thoxybenzaldehyde dimethyl acetal, cat. PTSA, 40 ꢀC, reduced pressure, 6 h, 89%; e.
BzCl, cat. DMAP, Py, rt, overnight, 70%; f. NaBH3CN, TFA, molecular sieve, DMF, rt, 3 d,
93%; g. Levulinic acid, EDCI, cat. DMAP, DCM, rt, 2 h, 96%; h. TBDMSCl, imidazole, DMF,
2 d, 66%; i. NIS,TFA,DCM/H2O, rt, 4 h; j. DBU, CCl3CN, DCM, rt, overnight, 81% for two
steps; k. NBS, acetone, 0 ꢀC, 2 h, 77%; l. DBU, CCl3CN, DCM, 9 h, 88%; m. DDQ, DCM/H2O,
rt, overnight, 96%; n. 1) PDC,DMF, rt, 3 d; 2) CH3I, K2CO3, DMF, rt, 1 h, 77% for two steps;
o. NIS, TfOH, DCM/H2O, rt, 6 h, 98%; p. Cs2CO3, CCl3CN, DCM, overnight, 84%; q. HF$Py,
THF/Py, 18 h; r. Levulinic acid, EDCI, cat. DMAP, DCM, rt, 2 h, 69% for two steps; s. NIS,
Tf2O, DCM/H2O, rt, 20 h, 97%; t. DBU, CCl3CN, DCM, overnight, 80%.
It is worth noting that the four thioglycoside donors, bearing
different substitutes, exhibited different performance in the pro-
cess of hydrolysis of thioglycosides. Hydrolysis of thioglycoside 7
proceeded smoothly under a mild condition (NBS/Acetone, rt, 2 h),
and it came into a mess of products with the presence of acid.
Treated with traditional procedures (NIS/Acid/CH2Cl2, rt, 4e6 h),
thioglycoside 5 and 11 were converted smoothly into correspond-
ing hemiacetals. As for hydrolysis of thioglycoside 9, it didn’t work
with the usual conditions such as NIS/TFA, NIS/trifilic acid or NIS/
AgOTf. At last, the hydrolysis of 9 was conducted with NIS/Tf2O at
room temperature for 20 h.21
Synthesis of three acceptors were carried out as shown in
Scheme 3. Peracetylated derivative of commercially available D-
galactosamine hydrochloride was converted into corresponding
Fig. 1. A small library of monosaccharide building blocks.
OMP glycoside directly with BF3$Et2O in CH2Cl2. Then 4,6-O-

S. Yang et al. / Tetrahedron 72 (2016) 5659e5670
5661
Table 1
benzylidene acetal was installed after de-O-acetylation and ac-
Glycosylations of donor 6 and acceptor 14 at varied reaction conditions
ceptor 13 was obtained. However, 13 suffered from poor solubility
in organic solvents such as dichloromethane, acetonitrile, and tol-
uene. Acceptor 14 was prepared through a similar procedure of
synthesis of 13, accompanying with a
b isomer in an a:b ratio of
about 2:1. The azido derivative 14 was smoothly reduced with
Lindlar catalyst under an H2 atmosphere, followed by N-tri-
chloroacetylation to give acceptor 15.
Entry
Promotor
Condition
Yield
38%
87%e90%
87%
1
2e4
5
TMSOTf
TMSOTf
TESOTf
ꢁ20 ꢀC, 15min
ꢁ40 ꢀC, ꢁ60 ꢀC, ꢁ80 ꢀC, 15min
ꢁ60 ꢀC, 15min
6
BF3$Et2O
ꢁ60 ꢀC to rt, rt for 16 h
73%
aThe reaction was conducted in the identical process: To a mixture of donor 6
(1.2 equiv) and acceptor 14 (1.0 equiv) in dry CH2Cl2 (0.05 M) was added a solution
of promoter (0.12 equiv) in CH2Cl2 (0.1 M). The reaction was monitored by TLC till
a complete consumption of donor. Then the reaction was quenched by Et3N and
purified by column chromatography (petroleum ether/ethyl acetate 4/1).
Coupling acceptor 14 with nonoxidized glucosyl donors 6 and 8
were performed at ꢁ60 ꢀC within 15 min to furnish the desired
disaccharide 17 and 18 in 87% and 96% yield, respectively. In
a similar manner, coupling reaction of acceptor 15 with non-
oxidized glucosyl donors 6 and 8 afforded the expected di-
saccharide 19 and 20 in 79% and 98% yield, respectively. In contrast,
glycosylation with oxidized glucosyl donors were performed in
a very hard way. All of the relating entries were failed except for the
condensation between 15 and 10, affording the expected di-
saccharide 21 in 8% yield accompanied by its orthoester 22 (dH-1
Scheme 3. Reagents and conditions: a. Ac2O, Py, rt, overnight, 75%; b. p-Methox-
yphenol, BF3$Et2O, DCM, rt, overnight; N2H4-HOAc, DMF, rt, 3.5 h, 45%; c. 1) NaN3, Tf2O,
DCM, H2O, 0 ꢀC, 3 h; 2) CuSO4$5H2O, K2CO3, MeOH/DCM/H2O, rt, 24 h; Gly, 24 h; 3)
Ac2O, Py, cat. DMAP, rt, overnight, 81% for three steps; d. p-Methoxyphenol, BF3$Et2O,
DCM, rt, 3 d; N2H4-HOAc, DMF, rt, 1.5 h, 86% (a:b, 2:1); e. NaOMe, MeOH/DCM, rt,
5 min, 86%; f. benzaldehyde dimethyl acetal, cat. PTSA, 40 ꢀC, reduced pressure, 5 h,
70%; g. NaOMe, MeOH/DCM, rt, 30 min; h. benzaldehyde dimethyl acetal, cat. PTSA,
40 ꢀC, reduced pressure, 10 h, 62% with 27%
b isomer; i. Lindlar catalyst, MeOH, rt,
1
overnight; j. TCACl, Et3N,THF, 0 ꢀC, 20 min, 73% for two steps.
6.01 ppm, dC-orthoester 121.08 ppm, JH-1,H-2 5.2 Hz) in 12% yield.
Therefore, the reactivity order of imidate donors in the glycosyla-
tion was inferred as 8>6>10>12. On the other hand, in this study
thioglycoside donors either didn’t work or gave only a trace of
With all these building blocks in hand, we then preliminarily
investigated the reactivity of monosaccharides library. Initially,
condensations of acceptor 13 with thioglycoside 5 were conducted
in the presence of NIS/TMSOTf or NIS/BF3$Et2O, however, no de-
sired product was obtained. Likewise, condensation between 13
and imidate 6 was also proved to be failed. The failures may be
attributed to the poor solubility of acceptor 13, just like a similar
observation described by Susana Maza and co-workers.22 As good
solubility is essential for a reasonable comparison of reactivity,
attention was then turned towards acceptor 13, whose solubility
was significantly improved by azido substitute instead of N-acetyl.
Although glycosylation between acceptor 14 and thioglycoside 5
still didn’t work, trichloroacetimidate 5 was coupled with acceptor
14 in excellent yield. Different reaction conditions was tested, and
the optimal results were obtained with TMSOTf as catalyst and
CH2Cl2 as solvent at temperature in a range of ꢁ80 ꢀC to ꢁ40 ꢀC, the
outcomes were listed in Table 1. In all these TMSOTf or TESOTf-
catalyzed glycosylations, donor 6 was consumed completed in less
than 15 min, and plenty of hydrolysis product of donors were
detected only when reaction was carried out at ꢁ20 ꢀC. Besides,
BF3$Et2O-catalyzed reaction took a relative drastic condition (room
temperature, 16 h) and led to a slightly lower yield (73%). All these
results suggested the good reactivity of imidate 6 and acceptor 14.
Encouraged by the good result, we then proceeded to examine
the influence of protecting groups both on the reactivity and ster-
eoselectivity towards assembling CS-E disaccharide unit. ꢁ60 ꢀC
was chosen as the reaction temperature, and if the reaction didn’t
work at ꢁ60 ꢀC within 1 h, the reaction would be allowed to warm
to room temperature and be stirred for several hours before being
quenched. Then at the identical reaction condition (1.2 equiv donor,
0.12 equiv TMSOTf in dichloromethane), a series of condensations
between acceptors 14e15 and donors 5e12 were carried out. As
shown in Table 2, it is very clear that condensations with non-
oxidized glucosyl donors were performed in a rapid way with ex-
cellent yields (79%e98%) and designed stereoselectivity. No
a
disaccharide (Entry 1) under NIS/TMSOTf reaction condition. This
was, however, not a surprise to us, because thioglycosides were
never reported as an efficient donor in CS-E synthesis before, per-
haps due to its poor reactivity.
Taken together, these results showed that, substitutes at C-5
position strongly influenced the reactivity of donors. Although
glucuronic acid was universally adopted as donor in CS-E synthesis
before, we thought nonoxidized glucosyl as superior. As a matter
of fact, the reactivity of nonoxidized glucosyl donors were much
higher than that of their oxidized counterparts in glycosylation,
demonstrating that postglycosylationeoxidation strategy could
significantly improve glycosylation efficiency in CS-E repeating
disaccharide unit synthesis. The second impact factor on reactivity
is the electronic property of substitutes at C-4 position. An
electron-donating substitute TBS could mildly raise the reactivity
of donors 7 and 10. In contrast, Lev group exhibited a negative
effect on the reactivity of donors 5 and 12 probably resulted from
electron-withdrawing functionality. Except for donors, acceptors
also playing a role in affecting glycosylation, especially when the
donor was poor active. N-Trichloroacetylated acceptor 15 was
proved to be slightly more reactive than azido type acceptor 14 in
condensation with imidate 10. And this may be due to the strong
electron-withdrawing property of azido, which led a loss of the
nucleophilicity of the neighboring hydroxyl group. To verify this
speculation and further explore the extent of capability impact of
increasing electron density of acceptors, we designed and syn-
thesized three more acceptors 23e25, bearing Cbz and 4,6-di-tert-
butylsilylene group as electron-donating substitutes, and coupled
them with trichloroacetimidate 10 at the same reaction condition
used before. The synthesis of acceptors 23e25 was described in
Scheme 4.
Acceptor 23 was prepared from 14 as described for 15. Then 4,6-
di-tert-butylsilylene group was installed after de-protection of 4,6-
O-benzylidene acetal group and acceptor 24 was obtained.
formation of the isomeric
a-linked disaccharide was observed.

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S. Yang et al. / Tetrahedron 72 (2016) 5659e5670
Table 2
Glycosylations of donors 5e12 and acceptors 13e15
Entry
Donor
Acceptor
Promoter
Reaction condition
Product/Yield
1
2
3
4
5e6
7
8
9
5
6
6
8
13
13
14
14
14
15
15
15
NIS/TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
ꢁ40 ꢀC, 30 min
ꢁ40 ꢀC, 30 min
ꢁ60 ꢀC, 15 min
ꢁ60 ꢀC, 15 min
ꢁ60 ꢀC to rt, 16 h
ꢁ60 ꢀC, 15 min
ꢁ60 ꢀC, 15 min
ꢁ60 ꢀC to rt, 16 h
ꢁ60 ꢀC to rt, 16 h
ꢁ60 ꢀC to rt, 16 h
NRa
NRb
17/87%
18/96%
NRc
10, 12
6
8
10
12
5, 7, 9, 11
19/79%
20/98%
21/8%
NRc
22/12%
10
11e18
15
14, 15
NIS/TMSOTf
NRc
a
The donor was completely hydrolyzed. The products were an
No reaction, and the donor was completely hydrolyzed.
No reaction, and the donor could be detected with its hydrolysis product.
a disaccharide (5%) and an orthoester (5%).
b
c
Table 3
Glycosylations between donor 10 and acceptors 23e25
Entry Donor Acceptor Reaction condition
Product/Yield
1
2
3
4
10
10
10
10
23
24
25
15
TMSOTf, ꢁ60 ꢀC to rt, 16 h 26/42%
Scheme 4. Reagents and conditions: a. Lindlar catalyst, H2, MeOH, overnight; b. CbzCl,
DCM, satd NaHCO3, 0 ꢀCdrt, overnight, 68% for two steps; c. MeOH, TsOH$H2O, reflux,
1 h; d. (t-Bu)2Si(OTf)2, Py, 0 ꢀCdrt, 20 min, 29% for two steps; e. (t-Bu)2Si(OTf)2, Py,
27/31%
No reaction
21/8%
22/12%
0
ꢀCdrt, 20 min, 41% with 24%
b isomer.
Similarly, 25 was prepared from a 4,6-dihydroxy intermediate in
the synthesis route of 14.
within 15 min at ꢁ60 ꢀC, thus the glycosidic bond is formed quickly
even for the less active acceptor 15, leading to regioselectivity in
Much to our surprise, only orthoesters 26 and 27 were obtained
without any of expected disaccharide product, at the yield of 42%
for 26 (dH-1 5.86 ppm, dC-orthoester 120.61 ppm, 1JH-1,H-2 5.2 Hz) and
31% for 27 (dH-1 6.03 ppm, dC-orthoester 121.36 ppm, 1JH-1,H-2 4.4 Hz),
respectively (Table 3). Combined with the result of glycosylation
between donor 10 and acceptor 15, it could be concluded that
glucuronic acid donors tends to generate orthoesters as main
products in glycosylations. Studies have found that acetylated tri-
chloroacetimidate donors are known to give orthoesters as in-
termediates, especially when encountered in slow coupling
reactions.23 Thus it was speculated that, in a similar manner, the
low reactivity of benzoylated imidate 10 led a slow reaction rate
(room temperature, 16 h, and donor was not consumed com-
pletely), enabling the reaction to take orthoester pathway with
good selectivity (See Scheme 5). With regard to high reactive imi-
dates 6 and 8, the reactions went very fast and were completed
desired b disaccharide way. As to acceptor 25, the glycosylation
didn’t work. This may be due to the detrimental combination of the
Scheme 5. Formation of the orthoesters 26 and 27.

S. Yang et al. / Tetrahedron 72 (2016) 5659e5670
5663
electro-withdrawing N3 substitute and the large steric hindrance
4,6-di-tert-butylsilylene group.
600 MHz spectrometers in CDCl3, CD3OD and DMSO. HRMS ex-
periments were done with an Aglient 1100 series LC/MSD TOF and
MS with a Thermo-Finnigan LCQ Advantage. Analytical thin chro-
matography (TLC) was carried out on TLC plates silica gel HSGF254
percolated by Branch of Qingdao Haiyang Chemical Plant. Chro-
matography was performed with silica gel H (HG/T2354-92).
Next,
we
explored
the
applicability
of
post-
glycosylationeoxidation strategy in the synthesis of CS-E di-
saccharide repeating unit. Compound 17 was chosen as the
research object whose p-methoxybenzyl ether was easily removed
by DDQ to give 28 (87%). Further oxidation of primary alcohol by
TEMPO/BAIB following methyl esterification afforded C-5 carbox-
ylic acid ester disaccharide derivative 29 in excellent yield (90% for
two steps) (Scheme 6). 29 could be used as CS-E disaccharide unit
for further elongation, as established by previous reports of syn-
thesis of CS-E oligomers.6,8,15 Subsequently, the efficiency of two
glycosylationeoxidation approach was examined. In the applica-
tion of postglycosylationeoxidation strategy, the total yield of
glycosylationeoxidation reactions was 70% of 29 (glycosylation:
90%, oxidation: 87%, 90%), much higher than that of 26 (less than
8%) with employment of preglycosylationeoxidation strategy. We
therefore believed that the former strategy is more favorable in the
synthesis of CS-E disaccharide repeating unit. From this, a new
synthesis approach was proposed that the nonoxidized di-
saccharide repeating unit is straightly elongated, and the carboxylic
acid moiety is introduced at the CS-E oligosaccharide stage. This
approach was expected to exhibit higher efficiency than the existed
way with preglycosylationeoxidation strategy.
4.2. 6-((4-Methoxybenzyloxy)methyl)-5-(4-
oxopentanoyloxy)-2-(p-tolylthio)tetrahydro-2H-pyran-3,4-
diyl dibenzoate, 5
EDCI$HCl (7.70 g, 40.19 mmol), DMAP (589 mg, 4.82 mmol) and
Et3N (5.6 mL, 40.19 mmol) were added into a solution of levulinic
acid (4.67 g, 40.19 mmol) in CH2Cl2 (40 mL), and the solution was
stirred at room temperature for 30 min. Then the resulting mixture
was added to the solution of 16 (10.13 g, 16.07 mmol) in CH2Cl2
(50 mL), and the mixture was stirred at room temperature for 2 h.
The reaction was diluted with CH2Cl2 and was washed by water and
brine. The organic layer was dried over Na2SO4, filtered, and con-
centrated, and purified by column chromatography (1:50 EtOAc/
CH2Cl2) to afford 5 (11.24 g, 96%) as a white solid. 1H NMR(CDCl3,
400 MHz):
d
7.88 (d, J¼7.2 Hz, 2H, ArH-Bz), 7.80 (d, J¼7.6 Hz, 2H,
ArH-Bz), 7.19e7.46 (m, 10H, ArH-Bz, PMB, and SPhMe), 6.96 (d,
J¼7.6 Hz, 2H, ArH-SPhMe), 6.82 (d, J¼8.4 Hz, 2H, ArH-PMB), 5.58 (t,
J¼9.6 Hz, 1H, H-3), 5.29 (t, J¼9.6 Hz, 1H, H-2), 5.19 (t, J¼9.6 Hz, 1H,
H-4), 4.81 (d, J¼10.0 Hz, 1H, H-1), 4.45 (d, J¼11.6 Hz, 1H, CH2-PMB),
4.41 (d, J¼11.6 Hz, 1H, CH2-PMB), 3.74e3.82 (m, 4H, H-5, OCH3-
PMB), 3.57e3.64 (m, 2H, H-6a,b), 2.17e2.54 (m, 7H, H of Lev), 1.94 (s,
3H, CH3-SPhMe); 13C NMR(CDCl3, 100 MHz):
d 205.98 (CO-Lev),
171.24 (CO-Lev), 165.97 (CO-Bz), 165.22 (CO-Bz), 159.44 (ArC-PMB),
138.56 (ArC-SPhMe), 133.60 (2C, ArC-SPhMe), 133.47 (CO-Bz),
133.45 (CO-Bz), 130.39, 130.04 (2C), 130.03 (2C), 129.89 (2C), 129.70
(2C), 129.51, 129.21, 128.55 (4C), 128.47, 113.93 (2C, ArC-PMB), 86.48
(C-1), 77.98 (CH2-PMB), 74.76, 73.43, 70.79, 69.40, 68.96, 55.43
(OCH3-PMB), 37.91 (C-Lev), 29.68 (C-Lev), 28.05 (C-Lev), 21.36
(CH3-SPhMe). HRMS (ESI) m/z: 735.2174 [MþNa]þ. Calcd for
C40H41NaO10S 735.2240.
Scheme 6. Reagents and conditions: 1. DDQ, DCM/H2O, rt, overnight, 87%; 2. 1)
TEMPO, BAIB, rt, 4 h; 2) CH3I, K2CO3, DMF, rt, 2 h, 90% for two steps.
4.3. 6-((4-Methoxybenzyloxy)methyl)-5-(4-
oxopentanoyloxy)-2-(2,2,2-trichloro-1-iminoethoxy)tetrahy-
dro-2H-pyran-3,4-diyl dibenzoate, 6
3. Conclusion
On the basis of the results, the following conclusions can be
drawn: (1) the type of C-6 decisively affected glycosylation both on
reactivity and stereoselectivity. The glucosyl donors performed ex-
To a solution of 5 (512 mg, 0.70 mmol) in CH2Cl2 (6 mL) and
water (400
mL) was added N-iodosuccinimide (237 mg, 1.06 mmol).
Then trifluoroacetic acid (50
m
L, 0.70 mmol) was added dropwise to
the mixture at 0 ꢀC, and the reaction was allowed to warm to room
temperature, and stirred for 4 h. Then the reaction was quenched
with 5 M Na2S2O3 solution. The aqueous layer was extracted with
CH2Cl2 (3ꢂ). The combined organic layer was washed with brine,
dried over Na2SO4, filtered, and concentrated to afford a yellow
syrup containing the corresponding hemiacetal. ESI-MS m/z: 629.13
[MþNa]þ. Calcd for C33H34O11Na 629.20.
cellently in glycosylation with good
b stereoselectivity. In contrast,
the oxidized type derivatives were proved to tend to generate
orthoesters probably due to its poor reactivity. (2) The efficiency of
glycosylation could be mildly improved by the raise of donors’ re-
activity mediated by substitutes at C-4. And the substitutes of ac-
ceptors also had some impact on coupling. (3) A smooth conversion
of disaccharide 17 to 29, demonstrated the feasibility of post-
glycosylationeoxidation strategy in the synthesis of CS-E repeating
unit, which has never been reported before. (4) Compared with
preglycosylationeoxidation approach, postglycosylationeoxidation
strategy was found preferable for the efficient construction of CS-E
repeating disaccharide unit, and it was worthful to be applied in the
synthesis of CS-E oligosaccharides or analogues.
A mixture of the hemiacetal, Cl3CCN (232
mL, 2.31 mmol), and
DBU (28 L, 0.19 mmol) in anhyd CH2Cl2 (3 mL) was stirred over-
m
night at room temperature. Then the resulting mixture was con-
centrated. Column chromatography (1:10/1:5 EtOAc/PEþ0.1%
Et3N) gave imidate 6 (210 mg, 81% for two steps) as a yellow syrup.
1H NMR(CDCl3, 400 MHz):
d 8.59 (s, 1H, NH), 7.95e7.93 (m, 4H,
ArH-Bz), 7.52e7.47 (m, 2H, ArH-Bz), 7.39e7.26 (m, 6H, ArH-Bz,
PMB), 6.87 (d, J¼8.4 Hz, 2H, ArH-PMB), 6.77 (d, J¼3.6 Hz, 1H, H-
1), 6.05 (t, J¼10.0 Hz, 1H, H-3), 5.61 (t, J¼10.0 Hz, 1H, H-4), 5.50 (dd,
J¼10.4, 3.6 Hz, 1H, H-2), 4.53e4.46 (m, 2H, CH2-PMB), 4.35e4.27
(m, 1H, H-5), 3.79 (s, 3H, CH3-PMB), 3.69 (dd, J¼11.2, 2.0 Hz, 1H, H-
6a), 3.63 (dd, J¼11.2, 4.0 Hz, 1H, H-6b), 2.63e2.29 (m, 4H, CH2CH2-
4. Experimental section
4.1. General
All solvents and reagents were obtained from commercial
sources and used without further purification unless otherwise
noted. All NMR spectra were recorded on Mercury-400, 500 or
Lev), 2.02 (s, 3H, CH3-Lev); 13C NMR(CDCl3, 100 MHz):
d
205.92
(CO-Lev), 171.32 (CO-Lev), 165.80 (CO-Bz), 165.43 (CO-Bz), 160.62

5664
S. Yang et al. / Tetrahedron 72 (2016) 5659e5670
(C]NH), 159.35 (ArC-PMB), 133.54 (ArC-Bz), 133.40 (ArC-Bz),
129.97, 129.91, 129.81, 129.20, 128.74, 128.50, 128.48, 128.08, 113.81
(2C, ArC-PMB), 93.44 (C-1), 73.29, 71.76, 70.76, 70.57, 68.24, 67.42,
55.33 (OCH3-PMB), 37.85 (C-Lev), 29.61 (C-Lev), 27.92 (C-Lev). ESI-
MS m/z: 750.12 [MþH]þ, 772.12 [MþNa]þ. Calcd for C35H35Cl3NO11
750.13, C35H34Cl3NO11Na 772.11.
room temperature for 3 days. The resulting mixture was filtered
and concentrated. Column chromatography (1:2 EtOAc/PE) gave
a white foam containing the corresponding carboxylic acid. The
crude acid was dissolved in DMF (56 mL), then K2CO3 (5.76 g,
41.7 mmol) and CH3I (6.9 mL, 111.2 mmol) were added. The reaction
was stirred at room temperature for 1 h, and was quenched with
water. The reaction was diluted with CH2Cl2, washed with brine,
and dried over Na2SO4, filtered, and concentrated. Column chro-
matography (1:10 EtOAc/PE) gave 9 (7.09 g, 77% for two steps) as
4.4. 5-(tert-Butyldimethylsilyloxy)-6-((4-methoxybenzyloxy)
methyl)-2-(p-tolylthio)tetrahydro-2H-pyran-3,4-diyl
dibenzoate, 7
a yellow solid. 1H NMR(CDCl3, 400 MHz):
d 7.90e7.87 (m, 4H, ArH-
Bz), 7.51e7.46 (m, 2H, ArH-Bz), 7.37e7.32 (m, 6H, ArH-Bz, SPhMe),
7.10 (d, J¼8.0 Hz, 2H, ArH of SPhMe), 5.60 (t, J¼9.2 Hz, 1H, H-3), 5.31
(t, J¼9.2 Hz, 1H, H-2), 4.91 (d, J¼10.0 Hz, 1H, H-1), 4.27 (t, J¼9.2 Hz,
1H, H-4), 4.09 (d, J¼9.2 Hz, 1H, H-5), 3.82 (s, 3H, CH3-COOMe), 2.33
(s, 3H, CH3-SPhMe), 0.72 (s, 9H, CH3-TBS), ꢁ0.04 (s, 3H, CH3-TBS),
To a solution of alcohol 16 (23.73 g, 37.66 mmol) and imidazole
(5.46 g, 80.23 mmol) in DMF (130 mL) was added tert-butyldime-
thylsilyl chloride (12.09 g, 80.23 mmol) at 0 ꢀC. The mixture was
stirred at room temperature for 2 days. It was then quenched with
satd NaHCO3 aq and diluted with CH2Cl2. The aqueous layer was
separated and extracted with CH2Cl2 (3ꢂ). The combined organic
layer was washed with brine, dried over Na2SO4, filtered, and
concentrated. Column chromatography (1:10 EtOAc/PE) gave 7
(17.83 g, 66%) as a white foam. 1H NMR(CDCl3, 400 MHz):
ꢁ0.21 (s, 3H, CH3-TBS); 13C NMR(CDCl3, 100 MHz):
d 168.30 (CO-
COOMe), 165.90 (CO-Bz), 165.31 (CO-Bz), 138.77 (ArC-SPhMe),
133.72 (2C, ArC-SPhMe), 133.38 (ArC-Bz), 133.33 (ArC-Bz), 130.02
(2C), 129.96 (4C), 129.75, 129.49, 128.51 (4C), 128.19, 87.22 (C-1),
80.42, 76.63, 70.93, 70.77, 52.79 (CH3-COOMe), 25.62 (3C, CH3-TBS),
21.42 (CH3-SPhMe), 17.96 (C-TBS), ꢁ4.20 (CH3-TBS), ꢁ4.90 (CH3-
TBS). HRMS (ESI) m/z: 637.2272 [MþH]þ, 659.2083 [MþNa]þ. Calcd
for C34H41O8SSi 637.2291, C34H40NaO8SSi 659.2111.
d
7.92e7.87 (m, 4H, ArH-Bz), 7.31e7.50 (m, 10H, ArH-Bz, PMB, and
SPhMe), 7.04 (d, J¼8.0 Hz, 2H, ArH-PMB), 6.93 (d, J¼8.4 Hz, 2H, ArH-
SPhMe), 5.60 (t, J¼8.8 Hz, 1H, H-3), 5.30 (t, J¼9.6 Hz, 1H, H-2), 4.89
(d, J¼10.0 Hz, 1H, H-1), 4.60 (d, J¼11.2 Hz, 1H, CH2-PMB), 4.52 (d,
J¼11.2 Hz, 1H, CH2-PMB), 4.01 (t, J¼8.8 Hz, 1H, H-4), 3.81e3.84 (m,
4H, H-5, OCH3-PMB), 3.65e3.77 (m, 2H, H-6a,b), 2.31 (s, 3H, CH3-
SPhMe), 0.75 (s, 9H, CH3-TBS), 0.03 (s, 3H, CH3-TBS), ꢁ0.21 (s, 3H,
4.7. 5-(tert-Butyldimethylsilyloxy)-6-(methoxycarbonyl)-2-
(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4-diyl
dibenzoate, 10
CH3-TBS); 13C NMR(CDCl3, 100 MHz):
d 166.07 (CO-Bz), 165.49 (CO-
Bz), 159.41 (ArC-PMB), 138.33 (ArC-SPhMe), 133.59 (2C, ArC-
SPhMe), 133.27 (ArC-Bz), 133.18 (ArC-Bz), 130.67, 130.02 (3C),
129.94 (2C), 129.82 (2C), 129.66, 129.46 (2C), 128.74, 128.47 (2C),
128.45 (2C), 113.98 (2C, ArC-PMB), 86.15 (C-1), 81.05, 77.55 (CH2-
PMB), 73.34, 71.35, 69.42, 68.76, 55.51 (OCH3-PMB), 25.84 (3C, CH3-
TBS), 21.41 (CH3-SPhMe), 18.06 (C-TBS), ꢁ4.02 (CH3-TBS), ꢁ4.52
(CH3-TBS). ESI-MS m/z: 746.04 [MþNH4]þ, 1478.92 [2MþNa]þ.
Calcd for C41H52NO8SSi 746.32, C82H96O16S2Si2Na 1479.56.
A mixture of the hemiacetal 80 (see Supplementary data, 151 mg,
0.28 mmol), Cl3CCN (171
mL, 1.71 mmol), and Cs2CO3 (37 mg,
0.11 mmol) in anhyd CH2Cl2 (8 mL) was stirred overnight at room
temperature, then it was concentrated. Column chromatography
(1:10 EtOAc/PEþ0.1% Et3N) gave imidate 7 (161 mg, 84%) as a white
foam. 1H NMR(CDCl3, 400 MHz):
d 8.60 (s, 1H, NH), 7.95e7.87 (m,
4H, ArH-Bz), 7.50e7.26 (m, 6H, ArH-Bz), 6.74 (d, J¼3.6 Hz, 1H, H-1),
5.97 (t, J¼9.6 Hz, 1H, H-3), 5.41 (dd, J¼3.6, 10.4 Hz, 1H, H-2), 4.51 (d,
J¼9.6 Hz, 1H, H-5), 4.39 (t, J¼9.2 Hz, 1H, H-4), 3.79 (s, 3H, CH3-
COOMe), 0.74 (s, 9H, CH3-TBS), ꢁ0.01 (s, 3H, CH3-TBS), ꢁ0.15 (s, 3H,
4.5. 5-(tert-Butyldimethylsilyloxy)-6-((4-methoxybenzyloxy)
methyl)-2-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-
pyran-3,4-diyl dibenzoate, 8
CH3-TBS); 13C NMR(CDCl3, 75 MHz):
d 168.65 (CO of COOMe),
165.71 (CO-Bz), 165.64 (CO-Bz), 160.77 (C]NH), 133.65 (ArC-Bz),
133.46 (ArC-Bz), 130.05 (ArC-Bz), 129.89 (2C, ArC-Bz), 129.74 (ArC-
Bz), 128.72 (ArC-Bz), 128.62 (2C,ArC-Bz), 128.57 (2C,ArC-Bz), 93.38
(C-1), 74.65, 72.46, 70.90, 70.80, 52.91 (OCH3-COOMe), 25.66 (CH3
of TBS), 18.03 (C-TBS), ꢁ4.14 (CH3-TBS), ꢁ4.88 (CH3-TBS). HRMS
(ESI) m/z: 696.0903 [MþNa]þ. Calcd for C29H34Cl3NNaO9Si
673.1068.
A mixture of the hemiacetal 60 (see Supplementary data,177 mg,
0.29 mmol), Cl3CCN (171
mL, 1.71 mmol), and DBU (17 mL,
0.11 mmol) in dry CH2Cl2 (7 mL) was stirred overnight at room
temperature. Then the resulting mixture was concentrated. Column
chromatography (1:10 EtOAc/PEþ0.1% Et3N) gave imidate
8
8.51
(193 mg, 88%) as a white foam. 1H NMR(CDCl3, 400 MHz):
d
(1H, s, NH), 7.95e7.88 (4H, m, ArH of PMB and Bz), 7.49e7.28 (8H,
m, ArH of Bz), 6.91 (2H, d, J¼8.4 Hz, ArH of PMB), 6.73 (1H, d,
J¼3.6 Hz, H-1), 5.98 (1H, t, J¼9.2 Hz, H-3), 5.39 (1H, dd, J¼3.6,
10.4 Hz, H-2), 4.59e4.50 (2H, m, CH2 of PMB), 4.27 (1H, t, J¼9.2 Hz,
H-4), 3.84e3.71 (6H, m, CH3 of PMB, H-5, H-6), 0.76 (9H, s, CH3 of
TBS), 0.06 (3H, s, CH3 of TBS), ꢁ0.14 (3H, s, CH3 of TBS); 13C
4.8. 6-(Methoxycarbonyl)-5-(4-oxopentanoyloxy)-2-(p-
tolylthio)tetrahydro-2H-pyran-3,4-diyl dibenzoate, 11
To a solution of 6 (1 g, 1.50 mmol) in anhyd THF (25 mL) and Py
(25 mL) was added HF$Py (7.8 mL, 1.50 mmol) dropwise at 0 ꢀC. The
reaction was stirred at room temperature for 18 h. The mixture was
washed with 10% CuSO4 solution, and the aqueous layer was
extracted with EtOAc (3ꢂ). The combined organic layers were
washed with brine, dried over Na2SO4, filtered, and concentrated to
afford a white solid containing desired de-protected product. 1H
NMR(CDCl3, 75 MHz): d 165.92 (CO-Bz), 165.78 (CO-Bz), 161.05 (C]
NH), 159.46 (ArC-PMB), 133.52 (ArC-Bz), 133.29 (ArC-Bz), 130.34,
130.07 (2C), 129.88 (2C), 129.53 (2C), 128.97, 128.60, 128.55 (2C),
128.52 (2C), 114.02 (2C, ArC-PMB), 93.82 (C-1), 75.02, 73.36, 73.31,
71.51, 68.76, 67.93, 55.48 (OCH3-PMB), 25.92 (3C, CH3-TBS), 18.19
(C-TBS), ꢁ3.98 (CH3-TBS), ꢁ4.58 (CH3-TBS). HRMS (ESI) m/z:
788.1575 [MþNa]þ. Calcd for C36H42Cl3NNaO9Si 788.1592.
NMR(CDCl3, 400 MHz):
d 7.97e7.95 (m, 4H, ArH-SphMe, Bz),
7.54e7.48 (m, 2H, ArH-Bz), 7.40e7.33 (m, 6H, ArH-Bz), 7.12 (d,
J¼7.6 Hz, 2H, ArH-SPhMe), 5.55 (t, J¼9.2 Hz, 1H, H-3), 5.39 (t,
J¼9.6 Hz,1H, H-2), 4.92 (d, J¼10.0 Hz,1H, H-1), 4.18e4.09 (m, 2H, H-
4, H-5), 3.87 (s, 3H, OCH3-COOMe), 3.39 (s, 1H, COOH), 2.04 (s, 3H,
4.6. 5-(tert-Butyldimethylsilyloxy)-6-(methoxycarbonyl)-2-
(p-tolylthio)tetrahydro-2H-pyran-3,4-diyl dibenzoate, 9
CH3-SphMe); 13C NMR(CDCl3, 75 MHz):
d 169.12 (CO of COOMe),
166.83 (CO-Bz), 165.33 (CO-Bz), 138.97 (ArC-SPhMe), 133.84 (2C,
ArC-SPhMe), 133.63 (ArC-Bz), 133.56 (ArC-Bz), 130.16 (2C), 130.07
(2C), 129.99 (2C), 129.42, 129.18, 128.63 (2C), 128.60 (2C), 128.15,
To a solution of 70 (8.51 g, 13.9 mmol) in DMF (139 mL) was
added PDC (31.38 g, 83.41 mmol), and the mixture was stirred at

S. Yang et al. / Tetrahedron 72 (2016) 5659e5670
5665
87.42 (C-1), 78.34, 76.50, 70.65, 70.03, 53.22 (OCH3-COOMe), 21.43
(CH3-SPhMe). ESI-MS m/z: 544.94 [MþNa]þ. Calcd for C28H26NaO8S
545.12.
(ArC-OMP), 151.40 (ArC-OMP), 138.53 (ArC-benzylidene), 128.66
(ArC-benzylidene), 127.92 (2C, ArC-benzylidene), 126.29 (2C, ArC-
benzylidene), 117.87 (2C, ArC-OMP), 114.47 (2C, ArC-OMP), 100.21
(C-1), 99.74 (CH-benzylidene), 75.18, 69.35, 68.52, 66.10, 55.37
(OCH3-OMP), 51.85 (C-2), 23.13 (CH3-NHAc). HRMS (ESI) m/z:
416.1687 (MþH)þ, 438.1504 [MþNa]þ. Calcd for C22H26NO7
416.1709, C22H25NNaO7 438.1529.
The crude product was added to a solution containing EDCI$HCl
(719 mg, 3.75 mmol), DMAP (55 mg, 0.45 mmol), and levulinic acid
(435 mg, 3.75 mmol). The reaction was stirred at room temperature
for 2 h and poured into cold water. The resulting mixture was
extracted with CH2Cl2 (3ꢂ). The combined organic layers were
washed with brine, dried over Na2SO4, filtered, and concentrated.
Column chromatography (1:20 EtOAc/CH2Cl2) gave 11 (642 mg, 69%
4.11. 7-Azido-6-(4-methoxyphenoxy)-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-8-ol, 14
for two steps) as a white solid. 1H NMR(CDCl3, 400 MHz):
d 7.95 (d,
J¼8.0 Hz, 2H, ArH-Bz), 7.87 (d, J¼7.6 Hz, 2H, ArH-SPhMe), 7.48e7.55
(m, 2H, ArH-Bz), 7.33e7.41 (m, 6H, ArH-Bz), 7.12 (d, J¼7.6 Hz, 2H,
ArH-SPhMe), 5.69 (t, J¼9.6 Hz, 1H, H-3), 5.34e5.42 (m, 2H, H-2, H-
4), 4.90 (d, J¼10.0 Hz, 1H, H-1), 4.20 (d, J¼10.0 Hz, 1H, H-5), 3.80 (s,
3H, COOCH3), 2.38e2.64 (m, 4H, CH2CH2-Lev), 2.35 (s, 3H, CH3-Lev),
To a solution of 150 (see Supplementary data) in DMF (90 mL)
was added benzaldehyde dimethyl acetal (4.8 mL, 31.82 mmol) and
p-toluene sulfonic acid monohydrate (2.75 g, 14.47 mmol). The
mixture was stirred at 40 ꢀC for 10 h at reduced pressure. Then it
was quenched by Et3N, diluted with EtOAc, and washed with brine.
The organic phase was dried over Na2SO4, filtered, concentrated
and purified by column chromatography (1:5 EtOAc/PE) to afford
desired product (9.89 g, 89% for two steps) as white solid which
2.03 (s, 3H, CH3-SPhMe); 13C NMR(CDCl3, 75 MHz):
d 205.95 (CO-
Lev), 171.42 (CO-Lev), 167.17 (CO-COOMe), 165.85 (CO-Bz), 165.10
(CO-Bz), 139.23 (ArC-SPhMe), 134.29 (2C, ArC-SPhMe), 133.66 (ArC-
Bz), 133.62 (ArC-Bz), 130.12 (2C), 130.10 (2C), 130.04 (2C), 129.30,
128.92, 128.65 (2C), 128.63 (2C), 127.45, 86.92 (C-1), 76.54 (C-2),
73.75, 70.14, 69.74, 53.32 (CH3-COOMe), 37.87 (C-Lev), 29.84 (C-
Lev), 27.91 (C-Lev), 21.50 (CH3-SPhMe). ESI-MS m/z: 620.99
contained 14 (6.90 g, 62%) with its
b
isomer (2.99 g, 27%).
a:
1H
NMR(CDCl3, 400 MHz):
d
7.52 (d, J¼4.4 Hz, 2H, ArH-benzylidene),
7.39e7.38 (m, 3H, ArH-benzylidene), 7.06 (d, J¼9.2 Hz, 2H, ArH-
OMP), 6.85 (d, J¼9.2 Hz, 2H, ArH-OMP), 5.58e5.56 (m, 2H, CH, H-
1), 4.37 (dd, J¼10.8, 3.2 Hz,1H, H-3), 4.31 (d, J¼2.8 Hz, 1H, H-4), 4.24
(d, J¼12.4 Hz, 1H, H-6a), 4.03 (d, J¼12.4 Hz, 1H, H-6b), 3.84 (s, 1H, H-
5), 3.77 (s, 3H, OCH3), 3.68 (dd, J¼10.4, 3.2 Hz, 1H, H-2); 13C
[MþH]þ, 643.06 [MþNa]þ. Calcd for C33H33O10
S
621.18,
C
33H32NaO10S 643.16.
4.9. 6-(Methoxycarbonyl)-5-(4-oxopentanoyloxy)-2-(2,2,2-
trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4-diyl di-
benzoate, 11
NMR(CDCl3, 100 MHz): d 155.51 (ArC-OMP), 150, 74 (ArC-OMP),
137.42 (ArC-benzylidene), 129.65 (ArC-benzylidene), 128.59 (2C,
ArC-benzylidene), 126.43 (2C, ArC-benzylidene), 117.79 (2C, ArC-
OMP), 114.96 (2C, ArC-OMP), 101.52 (CH), 98.36 (C-1), 75.58,
69.38, 67.64, 63.60, 60.73 (C-2), 55.90 (OCH3). ESI-HRMS m/z:
400.1494 (MþH)þ, 422.1308 [MþNa]þ. Calcd for C20H22O6N3
A mixture of 90 (see Supplementary data, 152 mg, 0.30 mmol),
Cl3CCN (296 mL, 2.96 mmol), and DBU (13 mL, 0.09 mmol) in anhyd
CH2Cl2 (2 mL) was stirred overnight at room temperature. Then it
was concentrated. Column chromatography (1:5 EtOAc/PEþ0.1%
Et3N) gave imidate 12 (155 mg, 80%) as a yellow syrup. 1H
400.1509, C20H21N3NaO6 422.1328. b:
1H NMR(CDCl3, 400 MHz):
d
7.51 (d, J¼4.4 Hz, 2H, ArH-benzylidene), 7.37e7.36 (m, 3H, ArH-
benzylidene), 7.06 (d, J¼8.8 Hz, 2H, ArH-OMP), 6.82 (d, J¼8.8 Hz,
2H, ArH-OMP), 5.55 (s, 1H, CH), 4.73 (d, J¼8.4 Hz, 1H, H-1), 4.33 (dd,
J¼12.4 Hz, 1H, H-6a), 4.17 (d, J¼3.2 Hz, 1H, H-4), 4.06 (d, J¼12.4 Hz,
1H, H-6b), 3.88 (t, J¼8.4 Hz, 1H, H-2), 3.76e3.74 (m, 4H, H-5, OCH3),
3.59 (dd, J¼10.4, 1.6 Hz, 1H, H-3), 3.49 (s, 1H, OH); 13C NMR(CDCl3,
NMR(CDCl3, 400 MHz) d 8.66 (s,1H, NH), 7.94e7.91 (m, 4H, ArH-Bz),
7.53e7.47 (m, 3H, ArH-Bz), 7.40e7.32 (m, 5H, ArH-Bz), 6.84 (d,
J¼3.2 Hz, 1H, H-1), 6.10 (t, J¼9.6 Hz, 1H, H-4), 5.57e5.52 (m, 2H, H-
3, H-2), 4.64 (d, J¼10.0 Hz, 1H, H-5), 3.78 (s, 3H, CH3-COOMe),
2.63e2.39 (m, 4H, CH2CH2-Lev), 2.03 (s, 3H, CH3-Lev); 13C
100 MHz):
d 155.82 (ArC-OMP), 151.30 (ArC-OMP), 137.52 (ArC-
NMR(CDCl3, 100 MHz):
d
205.75 (CO-Lev), 171.51 (CO-Lev), 167.39
benzylidene), 129.63 (ArC-benzylidene), 128.55 (2C, ArC-
benzylidene), 126.68 (2C, ArC-benzylidene), 119.03 (2C, ArC-
OMP), 114.73 (2C, ArC-OMP), 102.00 (C-1), 101.62 (CH), 74.68,
71.45, 69.10, 66.84, 63.86 (C-2), 55.88 (OCH3). HRMS (ESI) m/z:
400.1485 [MþH]þ, 422.1301 [MþNa]þ, 438.1030 [MþK]þ. Calcd for
(CO-COOMe), 165.72 (CO-Bz), 165.45 (CO-Bz), 160.44 (C]NH),
133.82 (ArC-Bz), 132.71 (ArC-Bz), 130.10 (2C, ArC-Bz), 130.06 (2C,
ArC-Bz), 129.04 (ArC-Bz), 128.69 (2C, ArC-Bz), 128.66 (2C, ArC-Bz),
128.63 (ArC-Bz), 93.01 (C-1), 70.98, 70.39, 69.61, 69.31, 53.41
(CH3-COOMe), 37.83 (C-Lev), 29.76 (CH2-Lev), 27.92 (CH3-Lev).
HRMS (ESI) m/z: 680.0260 [MþNa]þ. Calcd for C28H26Cl3NNaO11
680.0469.
C
20H22O6N3 400.1509, C20H21N3NaO6 422.1328, C20H21KN3O6
438.1067.
4.12. 2,2,2-Trichloro-N-(8-hydroxy-6-(4-methoxyphenoxy)-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)acetamide, 15
4.10. N-(8-Hydroxy-6-(4-methoxyphenoxy)-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)acetamide, 13
To a solution of 160 (see Supplementary data) in anhyd THF
To a solution of 120 (see Supplementary data,1.91 g, 58.47 mmol)
(20 mL) were added Et3N (1.3 mL, 8.99 mmol) and trichloroacetyl
in DMF (25 mL) was added benzaldehyde dimethyl acetal (965
m
L,
chloride (670 m
L, 6.03 mmol) successively at 0 ꢀC. The reaction was
64.31 mmol) and p-toluene sulfonic acid monohydrate (45 mg,
2.34 mmol). The mixture was stirred at 40 ꢀC for 5 h at reduced
pressure. Then it was quenched by Et3N, poured into 200 mL cold
water, and stirred continuously for 2 h. Precipitate was filtered and
washed by water and CH2Cl2 to afford 13 (1.72 g, 70%) as white
stirred at 0 ꢀC for 20 min, and was quenched by satd NaHCO3 aq.
The aqueous layer was extracted with CH2Cl2 (3ꢂ). The combined
organic layer was washed with brine, dried over Na2SO4, filtered,
and concentrated. Column chromatography (2:5 EtOAc/PE) to af-
ford 15 (1.01 g, 73% for two steps) as white solid. 1H NMR(CDCl3,
solid. 1H NMR(DMSO-d6, 400 MHz):
d
7.77 (d, J¼8.8 Hz, 1H, ArH-
400 MHz): d 7.57e7.49 (m, 2H, ArH-benzylidene), 7.44e7.35 (m, 3H,
benzylidene), 7.50 (d, J¼4.8 Hz, 2H, ArH-benzylidene), 7.40e7.38
(m, 3H, ArH-benzylidene, NH), 6.94 (J¼9.2 Hz, 2H, ArH-OMP), 6.86
(J¼8.8 Hz, 2H, ArH-OMP), 5.62 (s,1H, CH), 5.00e4.95 (m, 2H, H-1, H-
3), 4.16 (d, J¼2.8 Hz,1H, H-4), 4.08 (br s, 2H, H-5, OH), 4.00e3.93 (m,
1H, H-2), 3.79e3.70 (m, 5H, H-6a,b, OCH3-OMP), 1.82 (s, 3H, CH3-
ArH-benzylidene), 7.09e7.02 (m, 3H, ArH-OMP, NH), 6.84 (d,
J¼8.8 Hz, 2H, ArH-OMP), 5.65 (d, J¼3.2 Hz,1H, H-1), 5.62 (s,1H, CH),
4.52 (td, J¼9.6, 3.2 Hz, 1H, H-2), 4.36 (d, J¼2.8 Hz, 1H, H-4), 4.29 (d,
J¼12.8 Hz, 1H, H-6a), 4.19 (d, J¼9.2 Hz, 1H, H-3), 4.09 (d, J¼12.4 Hz,
1H, H-6b), 3.90 (s, 1H, H-5), 3.77 (s, 3H, OCH3), 2.73 (s, 1H, OH); 13
C
NHAc); 13C NMR(DMSO-d6, 100 MHz):
d
169.48 (CO-NHAc), 154.49
NMR(CDCl3, 75 MHz): d 162.92 (CO-NH), 155.77 (ArC-OMP), 150.54

5666
S. Yang et al. / Tetrahedron 72 (2016) 5659e5670
(ArC-OMP), 137.38 (ArC-benzylidene), 129.64 (ArC-benzylidene),
128.60 (2C, ArC-benzylidene), 126.47 (2C), 118.02 (2C, ArC-OMP),
115.07 (2C, ArC-OMP), 101.52 (CH), 97.77 (C-1), 75.30, 69.40,
68.32, 63.84, 55.91 (OCH3), 52.83 (C-2). HRMS (ESI) m/z: 518.0513
[MþH]þ, 540.0321 [MþNa]þ. Calcd for C22H23Cl3NO7 518.0540,
150.71 (ArC-OMP), 137.85 (ArC-benzylidene), 133.53 (ArC-Bz),
133.29 (ArC-Bz), 130.16, 130.08 (2C), 130.00 (2C), 129.73 (2C),
129.56, 129.17, 128.98, 128.61 (2C), 128.41 (2C), 128.32 (2C), 126.31
(2C, ArC-benzylidene), 117.81 (2C, ArC-OMP), 114.90 (2C, ArC-OMP),
114.03 (2C, ArC-PMB), 102.46 (CH-benzylidene), 100.68 (CA-1),
98.46 (CB-1), 76.94, 76.22, 75.62, 73.73, 73.58, 71.90, 69.72, 69.54,
69.08 (C-6), 63.85 (C-6), 58.55 (CA-2), 55.55 (OCH3), 55.88 (OCH3),
37.97 (C-Lev), 29.78 (C-Lev), 28.06 (C-Lev). HRMS (ESI) m/z:
988.3555 [MþH]þ, 1010.3317 [MþNa]þ, 1026.3093 [MþK]þ. Calcd
C
22H22Cl3NNaO7 540.0360.
4.13. 5-Hydroxy-6-((4-methoxybenzyloxy)methyl)-2-(p-
tolylthio)tetrahydro-2H-pyran-3,4-diyl dibenzoate, 16
for
C
53H54N3O16
988.3504,
C53H53N3NaO16
1010.3324,
To a solution of 50 (see Supplementary data, 10 g, 48.78 mmol) in
C53H53N3KO16 1026.3063.
ꢀ
dry DMF (100 mL), NaBH3CN (5.1 g, 243.88 mmol) and 4 A MS (10 g)
were added. Trifluoroacetic acid (12.1 mL, 487.76 mmol) was added
dropwise to the system at 0 ꢀC. The mixture was stirred at room
temperature for 3 days. Then it was filtered, diluted with CH2Cl2,
and quenched with satd NaHCO3 aq. The aqueous layer was
extracted with CH2Cl2 (3ꢂ). The combined organic layer was
washed with brine, dried over Na2SO4, filtered, and concentrated,
and purified by column chromatography (1:10 EtOAc/PE) to afford
4.15. 2-(7-Azido-6-(4-methoxyphenoxy)-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yloxy)-5-(tert-
butyldimethylsilyloxy)-6-((4-methoxybenzyloxy)methyl)
tetrahydro-2H-pyran-3,4-diyl dibenzoate, 18
A mixture of donor 8 (122 mg, 0.16 mmol) and acceptor 14
(51 mg, 0.13 mmol) was coevaporated with toluene (3ꢂ5 mL), dried
under vacuum for 30 min the mixture was dissolved in CH2Cl2
16 (11 g, 93%) as white solid. 1H NMR(CDCl3, 400 MHz):
d 7.90e7.85
ꢀ
(m, 4H, ArH-Bz), 7.45e7.18 (m, 10H, ArH-Bz, PMB, and SphMe), 6.98
(d, J¼8.0 Hz, 2H, ArH-SphMe), 6.81 (d, J¼8.8 Hz, 2H, ArH-PMB), 5.37
(t, J¼9.2 Hz, 1H, H-3), 5.30 (t, J¼9.6 Hz, 1H, H-2), 4.78 (d, J¼9.6 Hz,
1H, H-1), 4.46 (s, 2H, CH2-PMB), 3.83 (td, J¼3.2, 9.6 Hz, 1H, H-4),
3.77e3.76 (m, 2H, H-6), 3.73 (s, 3H, OCH3-PMB), 3.64e3.60 (m, 1H,
H-5), 3.17 (d, J¼3.2 Hz, 1H, OH), 2.24 (s, 3H, CH3-SphMe); 13C
(3.2 mL), and activated 4 A powdered molecular sieves were added.
The reaction was stirred at room temperature for 30 min. The re-
action was then cooled to ꢁ60 ꢀC and stirred for an additional
15 min. Trimethylsilyl trifluoromethanesulfonate (0.1 M in CH2Cl2,
159
mL, 0.016 mmol) was added to the reaction dropwise. After
15 min, the reaction was quenched with TEA, and allowed to warm
to room temperature. The reaction was filtered and concentrated to
afford a yellow syrup. The product was purified by column chro-
matography (1:10 EtOAc/PE) to afford 18 (129 mg, 96%) as white
NMR(CDCl3, 100 MHz):
d 167.64 (CO-Bz), 165.48 (CO-Bz), 159.63
(ArC-PMB), 138.71 (ArC-SPhMe), 133.76 (CO-Bz), 133.71 (2C, ArC-
SPhMe), 133.52 (CO-Bz), 130.18 (2C), 130.04 (2C), 129.94 (2C),
129.84, 129.77 (2C), 129.52, 129.08, 128.64 (2C), 128.62 (2C), 128.34,
114.13 (2C, ArC-PMB), 86.52 (C-1), 78.75 (C-5), 77.95 (CH2-PMB),
73.71 (C-3), 71.11 (C-2), 70.33 (C-4), 69.89 (C-6), 55.51 (OCH3-PMB),
21.41 (CH3-SPhMe). ESI-MS m/z: 636.97 [MþNa]þ. Calcd for
foam. 1H NMR(CDCl3, 400 MHz):
d 7.92e7.89 (m, 4H, ArH-Bz),
7.52e7.25 (m, 13H, ArH-Bz, benzylidene, PMB), 7.01 (d, J¼9.2 Hz,
2H, ArH-OMP), 6.85e6.80 (m, 4H, ArH-PMB, OMP), 5.62 (t,
J¼9.2 Hz, 1H, HB-3), 5.52e5.44 (m, 3H, HA-1, HB-2, CH-
benzylidene), 5.10 (d, J¼8.0 Hz, 1H, HB-1), 4.59 (J¼2.8 Hz, 1H, HB-
4), 4.53 (s, 1H, CH2-PMB), 4.51 (s, 1H, CH2-PMB), 4.36 (dd, J¼10.8,
3.2 Hz, 1H, HA-2), 4.14 (d, J¼11.6 Hz, 1H, HA-6a), 4.02 (t, J¼8.8 Hz,
1H, HB-4), 3.87 (dd, J¼10.8, 3.2 Hz, 1H, HA-3), 3.84e3.68 (m, 11H,
HA-6b, HA-5, HB-5, HB-6a,b, CH3-PMB, OMP), 0.76 (s, 9H, t-Bu-TBS),
0.02 (s, 3H, CH3-TBS), ꢁ0.20 (s, 3H, CH3-TBS); 13C NMR(CDCl3,
C
35H34O8SNa 637.19.
4.14. 2-(7-Azido-6-(4-methoxyphenoxy)-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yloxy)-6-((4-
methoxybenzyloxy)methyl)-5-(4-oxopentanoyloxy)tetrahy-
dro-2H-pyran-3,4-diyl dibenzoate, 17
100 MHz):
d 165.90 (CO-Bz), 165.44 (CO-Bz), 159.36 (ArC-PMB),
A mixture of donor 6 (149 mg, 0.20 mmol) and acceptor 14
(63 mg, 0.17 mmol) was coevaporated with toluene (3ꢂ5 mL), dried
under vacuum for 30 min. The mixture was dissolved in CH2Cl2
155.26 (ArC-OMP), 150.54 (ArC-OMP), 137.68 (ArC-benzylidene),
133.07 (ArC-Bz), 132.98 (ArC-Bz), 129.73, 129.82, 129.73, 129.70,
129.63, 129.42, 129.39, 128.89, 128.30, 128.16, 128.14, 126.20 (2C,
ArC-benzylidene), 117.69 (2C, ArC-OMP), 114.70 (2C, ArC-OMP),
113.88 (2C, ArC-OMP), 102.28 (CH-benzylidene), 100.59 (CA-1),
98.36 (CB-1), 76.22, 76.09, 75.95, 75.53, 73.29, 72.27, 69.70, 69.28,
68.93, 63.63, 58.31 (CA-2), 55.64 (OCH3), 55.25 (OCH3), 25.64 (3C,
t-Bu-TBS), 17.85 (C-TBS), ꢁ4.17 (CH3-TBS), ꢁ4.64 (CH3-TBS). HRMS
(ESI) m/z: 1026.3788 [MþNa]þ, 1042.3530 [MþK]þ. Calcd for
ꢀ
(4 mL), and activated 4 A powdered molecular sieves were added.
The reaction was stirred at room temperature for 30 min. The re-
action was then cooled to ꢁ80 ꢀC and stirred for an additional
15 min. Trimethylsilyl trifluoromethanesulfonate (0.1 M in CH2Cl2,
198 mL, 0.020 mmol) was added to the reaction dropwise. After
15 min, the reaction was quenched with TEA, and allowed to warm
to room temperature. The reaction was filtered and concentrated to
afford a yellow syrup. The product was purified by column chro-
matography (1:4 EtOAc/PE) to afford 17 (147 mg, 90%) as white
C54H61N3NaO14Si 1026.3820, C54H61N3KO14Si 1042.3560.
4.16. 6-((4-Methoxybenzyloxy)methyl)-2-(6-(4-
foam. 1H NMR(CDCl3, 400 MHz):
d
7.96 (d, J¼7.6 Hz, 2H, ArH-Bz),
methoxyphenoxy)-2-phenyl-7-(2,2,2-trichloroacetamido)
hexahydropyrano[3,2-d][1,3]dioxin-8-yloxy)-5-(4-
oxopentanoyloxy)tetrahydro-2H-pyran-3,4-diyl dibenzoate, 19
7.90 (d, J¼7.2 Hz, 2H, ArH-Bz), 7.52e7.45 (m, 4H, ArH-Bz, benzyli-
dene), 7.38e7.32 (m, 7H, ArH-Bz, benzylidene), 7.24 (d, J¼8.4 Hz,
2H, ArH-PMB), 7.01 (d, J¼9.2 Hz, 2H, ArH-OMP), 6.84e6.80 (m, 4H,
ArH-PMB, OMP), 5.70 (t, J¼9.6 Hz, 1H, HB-4), 5.57 (dd, J¼9.6, 8.0 Hz,
1H, HB-3), 5.51 (d, J¼3.2 Hz, 1H, HA-1), 5.46 (s, 1H, CH-
benzylidene), 5.29 (t, J¼9.6 Hz, 1H, HB-2), 5.10 (J¼7.6 Hz, 1H, HB-
1), 4.55e4.52 (m, 2H, CH2-PMB, HA-4), 4.43 (d, J¼11.2 Hz, 1H,
CH2-PMB), 4.34 (dd, J¼10.4, 3.2 Hz, 1H, HA-2), 4.13 (dd, J¼12.4,
1.2 Hz,1H, HA-6a), 4.00e3.95 (m,1H, HB-5), 3.87 (dd, J¼10.8, 3.6 Hz,
1H, HA-3), 3.76e3.65 (m, 10H, HA-6b, HA-5, HB-6a,b, CH3-PMB,
OMP), 2.67e2.30 (m, 4H, CH2CH2-Lev), 2.06 (s, 3H, CH3-Lev); 13C
A mixture of donor 6 (129 mg, 0.17 mmol) and acceptor 15
(74 mg, 0.14 mmol) was coevaporated with toluene (3ꢂ5 mL),
dried under vacuum for 30 min. The mixture was dissolved in
ꢀ
CH2Cl2 (3.4 mL), and activated 4 A powdered molecular sieves
were added. The reaction was stirred at room temperature for
30 min the reaction was then cooled to ꢁ60 ꢀC and stirred for an
additional 15 min. Trimethylsilyl trifluoromethanesulfonate (0.1 M
in CH2Cl2, 172 mL, 0.017 mmol) was added to the reaction drop-
NMR(CDCl3, 100 MHz):
d
206.18 (CO-Lev), 171.73 (CO-Lev), 166.02
wise. After 15 min, the reaction was quenched with TEA, and
(CO-Bz), 165.30 (CO-Bz), 159.58 (ArC-PMB), 155.45 (ArC-OMP),
allowed to warm to room temperature. The reaction was filtered

S. Yang et al. / Tetrahedron 72 (2016) 5659e5670
5667
and concentrated to afford a yellow syrup. The product was pu-
4.18. 5-(tert-Butyldimethylsilyloxy)-6-(methoxycarbonyl)-2-
rified by column chromatography (2:5e1:2 EtOAc/PE) to afford 19
(6-(4-methoxyphenoxy)-2-phenyl-7-(2,2,2-
trichloroacetamido)hexahydropyrano[3,2-d][1,3]dioxin-8-
yloxy)tetrahydro-2H-pyran-3,4-diyl dibenzoate, 21
(126 mg, 79%) as white foam. 1H NMR(CDCl3, 400 MHz):
d
7.91e7.88 (m, 4H, ArH-Bz), 7.52e7.46 (m, 4H, ArH-Bz, benzyli-
dene), 7.38e7.23 (m, 7H, ArH-Bz, PMB, benzylidene), 6.96e6.92
(m, 3H, ArH-OMP, NH), 6.83e6.78 (m, 4H, ArH-PMB, OMP), 5.75 (d,
J¼2.0 Hz, 1H, HA-1), 5.63 (t, J¼9.2 Hz, 1H, HB-4), 5.52 (d, J¼8.8 Hz,
1H, HB-3), 5.46 (t, J¼9.2 Hz, 1H, HB-2), 5.32 (s, 1H, CH-
benzylidene), 5.19 (d, J¼7.6 Hz, 1H, HB-1), 4.59e4.41 (m, 4H,
CH2-PMB, HA-4, HA-2), 4.18 (d, J¼12.4 Hz, 1H, HA-6a), 3.95e3.92
(m, 1H, HB-5), 3.86e3.74 (m, 10H, HA-6b, HA-5, HB-6a,b, CH3-PMB,
OMP), 3.66 (dd, J¼10.8, 4.8 Hz, 1H, HA-3), 2.67e2.28 (m, 4H,
CH2CH2-Lev), 2.05 (s, 3H, CH3-Lev); 13C NMR(CDCl3, 100 MHz):
A mixture of donor 10 (170 mg, 0.21 mmol) and acceptor 15
(96 mg, 0.17 mmol) was coevaporated with toluene (3ꢂ5 mL), dried
under vacuum for 30 min the mixture was dissolved in CH2Cl2
ꢀ
(4.5 mL), and activated 4 A powdered molecular sieves were added.
The reaction was stirred at rt for 30 min the reaction was then
cooled to ꢁ60 ꢀC and stirred for an additional 15 min. Trimethylsilyl
trifluoromethanesulfonate (0.1 M in CH2Cl2, 206 mL, 0.021 mmol) at
ꢁ60 ꢀC was added to the reaction dropwise. The temperature was
gradually raised to room temperature over 2 h, and the mixture was
stirred overnight. Then the reaction was quenched with TEA, fil-
tered and concentrated to afford a yellow syrup. The product was
purified by column chromatography (1:10e1:5 EtOAc/PE) to afford
a mixture of product (35 mg, 20%) containing 21 and 22 at a ratio of
d
206.05 (CO-Lev), 171.39 (CO-Lev), 165.80 (CO-Bz), 165.37 (CO-Bz),
161.79 (CO-NH), 159.43 (ArC-PMB), 155.44 (ArC-OMP), 150.65
(ArC-OMP), 137.44 (ArC-benzylidene), 133.54 (ArC-Bz), 133.46
(ArC-Bz), 129.97, 129.89, 129.84, 129.74, 128.91, 128.76, 128.50,
128.48, 128.08, 126.13 (2C, ArC-benzylidene), 118.08 (2C, ArC-
OMP), 114.77 (2C, ArC-OMP), 113.89 (2C, ArC-PMB), 100.75 (CH-
benzylidene), 99.58 (CA-1), 97.28 (CB-1), 74.69, 74.00, 73.58, 73.44,
71.58, 71.18, 69.11, 68.72, 68.27, 63.64, 50.70 (CA-2), 55.69 (OCH3),
55.31 (OCH3), 37.80 (C-Lev), 29.61 (C-Lev), 27.87 (C-Lev). HRMS
(ESI) m/z: 1106.2357 [MþH]þ, 1128.2317 [MþNa]þ, 1144.2084
[MþK]þ. Calcd for C55H55Cl3NO17 1106.2536, C55H55Cl3NNaO17
1128.2355, C55H55Cl3NKO17 1144.2094.
2:3 as colorless syrup. 1H NMR(CDCl3, 400 MHz):
d
7.93 (d, J¼7.2 Hz,
2H, ArH-Bz), 7.88 (d, J¼7.2 Hz, 2H, ArH-Bz), 7.52e7.20 (m, 11H, ArH-
Bz, benzylidene), 7.06e7.02 (m, 3H, NH, ArH-OMP), 6.82 (d,
J¼9.2 Hz, 2H, ArH-OMP), 5.74 (d, J¼2.4 Hz, 1H, HA-1), 5.54 (t,
J¼8.4 Hz, 1H, HB-3), 5.47 (t, J¼8.4 Hz, 1H, HB-2), 5.32 (s, 1H, CH-
benzylidene), 5.27 (d, J¼7.2 Hz, 1H, HB-1), 4.67e4.58 (m, 2H, HA-
3, HA-2), 4.53 (s, 1H, HA-4), 4.43 (t, 1H, J¼8.8 Hz, HB-4), 4.27 (d,
J¼12.8 Hz, 1H, HA-6a), 4.23 (d, J¼9.2 Hz, 1H, HB-5), 4.06 (d,
J¼12.4 Hz, 1H, HA-6b), 3.93 (s, 1H, HA-5), 3.81 (s, 3H, COOCH3), 3.77
(s, 3H, CH3-OMP), 0.74 (s, 9H, t-Bu-TBS), ꢁ0.06 (s, 3H, CH3-TBS),
4.17. 5-(tert-Butyldimethylsilyloxy)-6-((4-methoxybenzyloxy)
methyl)-2-(6-(4-methoxyphenoxy)-2-phenyl-7-(2,2,2-
trichloroacetamido)hexahydropyrano[3,2-d][1,3]dioxin-8-
yloxy)tetrahydro-2H-pyran-3,4-diyl dibenzoate, 20
ꢁ0.20 (s, 3H, CH3-TBS); 13C NMR(CDCl3, 150 MHz):
d 168.47 (CO-
COOMe), 165.58 (CO-Bz), 165.52 (CO-Bz), 161.67 (CO-NH), 155.34
(ArC-OMP), 150.77 (ArC-OMP), 137.18 (ArC-benzylidene), 133.52
(ArC-Bz), 133.28 (ArC-Bz), 129.83, 129.74, 129.29, 128.74, 128.62,
128.43, 128.38, 127.98, 126.03 (2C, ArC-benzylidene), 117.87 (2C,
ArC-OMP), 114.69 (2C, ArC-OMP), 100.87 (CH-benzylidene), 98.59
(CB-1), 97.44 (CA-1), 92.33 (C-Cl3), 76.63, 75.38, 74.56, 71.19, 70.55,
69.90, 69.17, 63.54, 55.63 (OCH3-OMP), 52.65 (OCH3-COOMe), 50.47
(CA-2), 25.32 (3C, t-Bu-TBS), 17.67 (C-TBS), ꢁ4.43 (CH3-TBS), ꢁ5.22
(CH3-TBS). HRMS (ESI) m/z: 1052.2201 [MþNa]þ, 1068.1930
[MþK]þ. Calcd for C49H54Cl3NNaO15Si 1052.2226, C49H54Cl3NKO15Si
1068.1965.
A mixture of donor 8 (170 mg, 0.22 mmol) and acceptor 15
(96 mg, 0.19 mmol) was coevaporated with toluene (3ꢂ5 mL), dried
under vacuum for 30 min the mixture was dissolved in CH2Cl2
ꢀ
(4.5 mL), and activated 4 A powdered molecular sieves were added.
The reaction was stirred at room temperature for 30 min. The re-
action was then cooled to ꢁ60 ꢀC and stirred for an additional
30 min. Trimethylsilyl trifluoromethanesulfonate (0.1 M in CH2Cl2,
222 mL, 0.022 mmol) was added to the reaction dropwise. After
15 min, the reaction was quenched with TEA, and allowed to warm
to room temperature. The reaction was filtered and concentrated to
afford a yellow syrup. The product was purified by column chro-
matography (1:5 EtOAc/PE) to afford 20 (204 mg, 98%) as white
4.19. Methyl 7-(benzoyloxy)-6-(tert-butyldimethylsilyloxy)-
3a-(6-(4-methoxyphenoxy)-2-phenyl-7-(2,2,2-
trichloroacetamido)hexahydropyrano[3,2-d][1,3]dioxin-8-
yloxy)-2-phenyltetrahydro-3aH-[1,3]dioxolo[4,5-b]pyran-5-
carboxylate, 22
foam. 1H NMR(CDCl3, 400 MHz):
d
7.88 (d, J¼7.6 Hz, 2H, ArH-Bz),
7.84 (d, J¼8.0 Hz, 2H, ArH-Bz), 7.49e7.42 (m, 2H, ArH-Bz, benzyli-
dene), 7.36e7.23 (11H, m, ArH-Bz, benzylidene, OMP), 6.98 (d,
J¼4.4 Hz, 1H, NH), 6.94 (d, J¼8.8 Hz, 2H, ArH-OMP), 6.80e6.78 (m,
4H, ArH-PMB, OMP), 5.79 (s, 1H, HA-1), 5.55 (t, J¼8.8 Hz, 1H, HB-3),
5.41 (t, J¼8.8 Hz, 1H, HB-2), 5.31 (s, 1H, CH-benzylidene), 5.17 (d,
J¼8.0 Hz, 1H, HB-1), 4.57e4.46 (m, 5H, HB-4, HA-4, HA-2, CH2-
PMB), 4.19 (d, J¼11.2 Hz, 1H, HA-6a), 3.90e3.75 (m, 12H, HA-6b, HA-
3, HA-5, HB-5, HB-6a,b, CH3-PMB, OMP), 0.75 (s, 9H, t-Bu-TBS), 0.03
(s, 3H, CH3-TBS), ꢁ0.20 (s, 3H, CH3-TBS); 13C NMR (CDCl3,100 MHz):
1H NMR(CDCl3, 400 MHz):
d
7.99 (d, J¼7.2 Hz, 2H, ArH-Bz), 7.81
(d, J¼7.2 Hz, 2H, ArH-Bz), 7.64e7.40 (m, 9H, ArH-Bz, benzylidene),
7.27e7.26 (m, 2H, ArH-Bz, benzylidene), 6.94 (d, J¼8.8 Hz, 2H, ArH-
OMP), 6.80e6.75 (m, 3H, NH, ArH-OMP), 6.01 (d, J¼5.2 Hz, 1H, HB-
1), 5.57 (d, J¼3.6 Hz, 1H, HA-1), 5.47 (t, J¼2.8 Hz, 1H, HB-3), 5.33 (s,
1H, CH-benzyl), 4.76 (t, J¼3.6 Hz, 1H, HB-2), 4.68e4.63 (m, 1H, HA-
2), 4.20e4.14 (m, 2H, HA-6a, HB-4), 4.09 (dd, J¼10.8, 3.2 Hz, 1H, HA-
3), 4.03 (d, J¼8.0 Hz, 1H, HB-5), 3.96 (d, J¼2.8 Hz, 1H, HA-4), 3.89 (d,
J¼12.4 Hz, 1H, HA-6b), 3.75 (s, 3H, CH3-OMP), 3.72e3.66 (m, 4H,
HA-5, CH3-COOMe), 0.81 (s, 9H, t-Bu-TBS), 0.13 (s, 3H, CH3-TBS),
d
166.02 (CO-Bz), 165.82 (CO-Bz), 162.06 (CO-NH), 159.58 (ArC-
PMB), 155.66 (ArC-OMP), 150.80 (ArC-OMP), 137.59 (ArC-benzyli-
dene), 133.55 (ArC-Bz), 133.32 (ArC-Bz), 130.07 (2C), 130.00, 129.93
(2C), 129.81, 129.55 (2C), 129.12, 128.93, 128.56 (2C), 128.52 (2C),
128.22 (2C), 126.33 (2C, ArC-benzylidene), 118.56 (2C, ArC-OMP),
114.92 (2C, ArC-OMP), 114.13 (2C, ArC-PMB), 100.98 (CH-benzyli-
dene), 99.63 (CA-1), 97.54 (CB-1), 77.12, 76.53, 74.81, 73.56, 72.20,
70.95, 69.31, 69.06, 68.74 (C-6), 63.77 (C-6), 55.85 (OCH3), 55.52
(OCH3), 50.92 (CA-2), 25.83 (3C, t-Bu-TBS), 18.08 (CH3-TBS), ꢁ3.97
(CH3-TBS), ꢁ4.56 (CH3-TBS). HRMS (ESI) m/z: 1122.3018 [MþH]þ,
1144.2838 [MþNa]þ, 1160.2581 [MþK]þ. Calcd for C56H63Cl3NO15Si
ꢁ0.02 (s, 3H, CH3-TBS); 13C NMR(CDCl3, 150 MHz):
d 169.71 (CO-
COOMe), 164.79 (CO-Bz), 161.63 (CO-NH), 155.49 (ArC-OMP),150.37
(ArC-OMP),137.24 (ArC-benzylidene),135.05 (ArC-Bz), 133.68 (ArC-
Bz), 130.07, 129.94, 128.98, 128.86, 128.54, 128.42, 128.20, 126.42
(2C, ArC-benzylidene), 125.96, 121.08 [ArC-Bz(orthoester)], 118.03
(2C, ArC-OMP), 114.69 (2C, ArC-OMP), 100.73 (CH-benzylidene),
97.54 (CB-1), 97.44 (CA-1), 92.24 (C-Cl3), 73.56, 73.51, 72.13, 71.79,
69.23, 69.11, 68.92, 63.06, 55.61 (OCH3-OMP), 52.33 (OCH3-
COOMe), 50.21 (CA-2), 25.47 (t-Bu-TBS), 17.74 (C-TBS), ꢁ4.57 (CH3-
1122.3033,
1160.2591.
C56H62Cl3NNaO15Si 1144.2852, C56H62Cl3NKO15Si

5668
S. Yang et al. / Tetrahedron 72 (2016) 5659e5670
TBS), ꢁ5.57 (CH3-TBS). HRMS (ESI) m/z: 1052.2227 [MþNa]þ,
1068.1895 [MþK]þ. Calcd for C49H54Cl3NNaO15Si 1052.2226,
The organic layer was dried over Na2SO4, filtered, and concentrated.
Column chromatography (1:5 EtOAc/PE) afforded desired product
(260 mg, 65%) as yellow syrup which contained 25 (164 mg, 41%)
C
49H54Cl3NKO15Si 1068.1965.
with its
b d 7.04 (d,
isomer (96 mg, 24%). 1H NMR(CDCl3, 100 MHz):
4.20. Benzyl 8-hydroxy-6-(4-methoxyphenoxy)-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-7-ylcarbamate, 23
J¼8.8 Hz, 2H, ArH-OMP), 6.83 (d, J¼9.2 Hz, 2H, ArH-OMP), 5.46 (d,
J¼3.2 Hz, 1H, H-1), 4.53 (d, J¼3.2 Hz, 1H, H-4), 4.53 (dd, J¼12.8,
1.6 Hz, 1H, H-6a), 4.20 (dd, J¼10.8, 2.8 Hz, 1H, H-3), 4.14 (J¼13.2 Hz,
1H, H-6b), 3.92 (s, 1H, H-5), 3.76 (s, 3H, OCH3), 3.61 (s, 1H, OH), 3.56
(dd, J¼10.4, 3.2 Hz, 1H, H-2), 1.07 [s, 9H, (t-Bu)2Si], 1.05 [s, 9H, (t-
160 (see Supplementary data) was prepared from 13 (406 mg,
1.06 mmol) as described for the preparation of 15. This compound
was suitable for the next step without purification. To a solution of
160 in anhyd CH2Cl2 (10 mL) and satd NaHCO3 aq (10 mL) was added
Bu)2Si]; 13C NMR(CDCl3, 100 MHz):
d 155.45 (ArC-OMP), 150.73
(ArC-OMP), 118.05 (2C, ArC-OMP), 114.81 (2C, ArC-OMP), 98.43 (C-
1), 72.88, 68.61, 67.93, 66.84, 60.58 (C-2), 55.76 (OCH3), 27.69
[OCH3-(t-Bu)2Si], 27.35 [OCH3-(t-Bu)2Si], 23.46 [C-(t-Bu)2Si], 20.88
[C-(t-Bu)2Si]. HRMS (ESI) m/z: 452.2197 [MþH]þ, 474.2005
[MþNa]þ. Calcd for C21H34N3O6Si 452.2217, C21H33N3NaO6Si
474.2036.
CbzCl (281 m
L, 1.97 mmol) at 0 ꢀC. The reaction was stirred at room
temperature overnight, poured into water and separated. The
aqueous layer was extracted with CH2Cl2 (3ꢂ). The combined or-
ganic layer was washed with brine, dried over Na2SO4, filtered, and
concentrated. Column chromatography (2:25 EtOAc/CH2Cl2) gave
23 (350 mg, 65% for two steps) as white solid. 1H NMR(CDCl3,
100 MHz):
d
7.53 (m, 2H, ArH-benzylidene), 7.39e7.32 (m, 8H, ArH-
4.23. 2-(7-(Benzyloxycarbonylamino)-6-(4-
benzylidene, Cbz), 7.00 (d, J¼8.8 Hz, 2H, ArH-OMP), 6.83 (d,
J¼8.8 Hz, 2H, ArH-OMP), 5.62 (s, 1H, H-1), 5.60 (s, 1H, CH), 5.17 (d,
J¼9.2 Hz, 1H, NH), 5.11 (s, 2H, CH2), 4.36 (td, J¼10.8, 1.2 Hz, 1H, H-2),
4.30 (s, 1H, H-4), 4.25 (d, J¼12.4 Hz, 1H, H-6a), 4.06e4.03 (m, 2H, H-
6b, H-3), 3.81 (s, 1H, H-5), 3.77 (s, 3H, OCH3); 13C NMR(CDCl3,
methoxyphenoxy)-2-phenylhexahydropyrano[3,2-d][1,3]
dioxin-8-yloxy)-5-(tert-butyldimethylsilyloxy)-6-(methox-
ycarbonyl)tetrahydro-2H-pyran-3,4-diyl dibenzoate, 26
A mixture of donor 10 (116 mg, 0.17 mmol) and acceptor 23
(73 mg, 0.14 mmol) was coevaporated with toluene (3ꢂ5 mL),
dried under vacuum for 30 min the mixture was dissolved in
100 MHz): d 156.95 (CO-NH), 155.28 (ArC-OMP), 150.39 (ArC-OMP),
137.47 (ArH-benzylidene), 136.25 (ArH-Cbz), 129.39 (ArH-benzyli-
dene), 128.68 (ArH-Cbz), 128.43 (ArH-Cbz), 128.36 (ArH-Cbz),
126.42 (ArH-benzylidene), 117.36 (2C, ArC-OMP), 114.85 (2C, ArC-
OMP), 109.89 (ArH-benzylidene), 101.41 (CH), 97.81 (C-1), 75.45,
69.38, 68.96, 67.33 (CH2), 63.66 (C-6), 55.81 (OCH3), 52.32 (C-2).
HRMS (ESI) m/z: 508.1961 [MþH]þ, 530.1776 [MþNa]þ. Calcd for
ꢀ
CH2Cl2 (3.5 mL), and activated 4 A powdered molecular sieves
were added. The reaction was stirred at room temperature for
30 min. The reaction was then cooled to ꢁ60 ꢀC and stirred for an
additional 15 min. Trimethylsilyl trifluoromethanesulfonate (0.1 M
in CH2Cl2, 173 mL, 0.017 mmol) was added to the reaction drop-
C
28H30NO8 508.1971, C28H29NNaO8 530.1791.
wise. The temperature was gradually raised to room temperature
over 2 h, and the mixture was stirred overnight. Then the reaction
was quenched with TEA, filtered and concentrated to afford
a yellow syrup. The product was purified by column chromatog-
raphy (1:5 EtOAc/PE) to afford 22 (61 mg, 42%) as colorless syrup.
4.21. Benzyl 2,2-di-tert-butyl-8-hydroxy-6-(4-
methoxyphenoxy)hexahydropyrano[3,2-d][1,3,2]dioxasilin-7-
ylcarbamate, 24
1H NMR(CDCl3, 400 MHz):
d
7.99 (d, J¼7.6 Hz, 2H, ArH-Bz), 7.77 (d,
To a solution of 170 (see Supplementary data) in Py (25 mL) was
J¼7.2 Hz, 2H, ArH-Bz), 7.63e7.20 (m, 17H, ArH-Bz, benzylidene,
Cbz, and NH), 6.95 (d, J¼8.0 Hz, 2H, ArH-OMP), 6.78 (d, J¼8.8 Hz,
2H, ArH-OMP), 5.86 (d, J¼5.2 Hz, 1H, HB-1), 5.50 (s, 1H, HA-1), 5.43
(s, 1H, HB-3), 5.31 (s, 1H, CH-benzylidene), 4.98e4.90 (m, 2H, CH2-
Cbz), 4.81e4.70 (m, 2H, HB-2, HA-4), 4.49 (td, J¼10.8, 3.2 Hz, 1H,
HA-2), 4.16 (dd, J¼8.0, 0.8 Hz, 1H, HB-4), 4.12 (d, J¼12.4 Hz, 1H,
HA-6a), 4.06 (d, J¼8.4 Hz, 1H, HB-5), 3.95 (dd, J¼10.8, 2.0 Hz, 1H,
HA-3), 3.83 (d, J¼12.0 Hz, 1H, HA-6b), 3.79e3.73 (m, 4H, OCH3-
OMP, HA-5), 3.69 (s, 3H, OCH3-COOMe), 0.81 (s, 9H, t-Bu-TBS), 0.13
(s, 3H, CH3-TBS), ꢁ0.01 (s, 3H, CH3-TBS); 13C NMR(CDCl3,
added Bu2Si(OTf)2 (318 m
L, 0.98 mmol) at 0 ꢀC. The reaction was
stirred at room temperature for 20 min, and was quenched by
MeOH, diluted with EtOAc, washed with 1 M HCl aq, satd NaHCO3
aq, and brine successively. The organic layer was dried over Na2SO4,
filtered, and concentrated. Column chromatography (1:5 EtOAc/PE)
afforded 24 (260 mg, 29% for two steps) as white solid. 1H
NMR(CDCl3, 100 MHz):
d 7.40e7.28 (m, 5H, ArH-Cbz), 6.96 (d,
J¼8.8 Hz, 2H, ArH-OMP), 6.82 (d, J¼8.8 Hz, 2H, ArH-OMP), 5.50 (d,
1H, J¼2.0 Hz, H-1), 5.17e5.10 (m, 3H, NH, CH2-Cbz), 4.50 (d,
J¼0.8 Hz, 1H, H-4), 4.30 (td, J¼9.6, 3.2 Hz, 1H, H-2), 4.25 (d,
J¼13.6 Hz, 1H, H-6a), 4.12 (J¼12.4 Hz, 1H, H-6b), 3.89e3.85 (m, 2H,
H-5, H-3), 3.77 (s, 3H, OCH3), 1.10 [s, 9H, (t-Bu)2Si], 1.07 [s, 9H, (t-
150 MHz):
d 169.68 (CO-COOMe), 165.11 (CO-Bz), 162.49 (CO-Bz),
155.71 (ArC-OMP), 155.06 (CO-NH), 150.44 (ArC-OMP), 137.46
(ArC-benzylidene), 136.26 (ArC-Cbz), 135.26 (CO-Bz), 133.60 (CO-
Bz), 129.93, 129.03, 128.88, 128.81, 128.53, 128.43, 128.20, 128.15,
126.49, 126.07, 120.61 [ArC-Bz(orthoester)], 117.47 (2C, ArC-OMP),
114.57 (2C, ArC-OMP), 100.79 (CH-benzylidene), 98.05 (CB-1),
97.33 (CA-1), 73.87, 73.52, 73.13, 71.64, 69.61, 69.43, 69.19, 66.78
(CH2-Cbz), 63.02, 55.63 (OCH3-OMP), 52.30 (OCH3-COOMe), 49.69
(CA-2), 25.47 (t-Bu-TBS), 17.74 (C-TBS), ꢁ4.55 (CH3-TBS), ꢁ5.51
(CH3-TBS). HRMS (ESI) m/z: 1020.3777 [MþNa]þ, 1042.3621
[MþK]þ. Calcd for C55H62NO16Si 1020.3838, C55H61NNaO16Si
1042.3657.
Bu)2Si]; 13C NMR(CDCl3, 100 MHz):
d 156.98 (ArC-OMP), 155.35
(CO-NH), 150.49 (ArC-OMP), 136.35 (ArC-Cbz), 128.71 (ArH-Cbz),
128.35 (ArH-Cbz), 128.28 (ArH-Cbz), 117.84 (2C, ArC-OMP), 114.84
(2C, ArC-OMP), 98.11 (C-1), 72.88, 70.14, 68.27, 67.04 (C-6), 55.82
(OCH3), 52.01 (C-2), 27.69 [OCH3-(t-Bu)2Si], 27.48 [OCH3-(t-Bu)2Si],
23.53 [C-(t-Bu)2Si], 20.96 [C-(t-Bu)2Si]. HRMS (ESI) m/z: 560.2668
[MþH]þ, 582.2481 [MþNa]þ. Calcd for C21H34N3O6Si 560.2680,
C
21H33N3NaO6Si 582.2499.
4.22. 7-Azido-2,2-di-tert-butyl-6-(4-methoxyphenoxy)
hexahydropyrano[3,2-d][1,3,2]dioxasilin-8-ol, 25
4.24. 2-(7-(Benzyloxycarbonylamino)-2,2-di-tert-butyl-6-(4-
methoxyphenoxy)hexahydropyrano[3,2-d][1,3,2]dioxasilin-8-
yloxy)-5-(tert-butyldimethylsilyloxy)-6-(methoxycarbonyl)
tetrahydro-2H-pyran-3,4-diyl dibenzoate, 27
To
a
solution of 150 (see Supplementary data, 276 mg,
0.89 mmol) in Py (25 mL) was added Bu2Si(OTf)2 (318
mL,
0.98 mmol) at 0 ꢀC. The reaction was stirred at room temperature
for 20 min, and was quenched by MeOH, diluted with EtOAc,
washed with 1 M HCl aq, satd NaHCO3 aq, and brine successively.
A mixture of donor 10 (94 mg, 0.14 mmol) and acceptor 24
(65 mg, 0.12 mmol) was coevaporated with toluene (3ꢂ5 mL), dried

S. Yang et al. / Tetrahedron 72 (2016) 5659e5670
5669
under vacuum for 30 min. The mixture was dissolved in CH2Cl2
(3.0 mL), and activated 4 A powdered molecular sieves were added.
The reaction was stirred at room temperature for 30 min the re-
action was then cooled to ꢁ60 ꢀC and stirred for an additional
15 min. Trimethylsilyl trifluoromethanesulfonate (0.1 M in CH2Cl2,
4.26. 2-(7-Azido-6-(4-methoxyphenoxy)-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yloxy)-6-
(methoxycarbonyl)-5-(4-oxopentanoyloxy)tetrahydro-2H-
pyran-3,4-diyl dibenzoate, 29
ꢀ
140
m
L, 0.017 mmol) was added to the reaction dropwise. The
Glucoside 28 (600 mg, 0.69 mmol) was dissolved in a mixture of
CH2Cl2/buffer (Na2CO3/NaHCO3, PH 9.5) (2/1, 4.5 mL). A CH2Cl2 so-
lution of TEMPO (0.1 M, 1.4 mL, 0.14 mmol) was added, followed by
addition of BAIB (557 mg, 1.73 mmol). The reaction mixture was
stirred at room temperature for 4 h. Then the reactionwas quenched
by addition of satd Na2S2O3 aq followed by separation of the layers.
The aqueous layer was extracted with EtOAc (3ꢂ). The combined
organic layer was washed with brine, dried over Na2SO4, filtered,
and concentrated to afford a yellow syrup. The crude acid was dis-
solved in DMF (9 mL). Then K2CO3 (287 mg, 2.08 mmol) and CH3I
temperature was gradually raised to room temperature over 2 h,
and the mixture was stirred overnight. Then the reaction was
quenched with TEA, filtered and concentrated to afford a yellow
syrup. The product was purified by column chromatography (1:5
EtOAc/PE) to afford 27 (39 mg, 31%) as colorless syrup. 1H
NMR(CDCl3, 400 MHz):
d
8.03 (d, J¼7.2 Hz, 2H, ArH-Bz), 7.75 (d,
J¼6.8 Hz, 2H, ArH-Bz), 7.60 (t, J¼7.2 Hz, 1H, ArH-Bz), 7.47e7.24 (m,
11H, ArH-Bz, Cbz, and NH), 6.88 (d, J¼8.8 Hz, 2H, ArH-OMP), 6.77 (d,
J¼8.4 Hz, 2H, ArH-OMP), 6.03 (d, J¼4.4 Hz, 1H, HB-1), 5.46 (s, 1H,
HA-1), 5.36 (s, 1H, HB-3), 5.00e4.91 (m, 2H, CH2-Cbz), 4.83 (d,
J¼1.2 Hz, 1H, HB-2), 4.59 (d, J¼9.6 Hz, 1H, HB-4), 4.45 (td, J¼10.4,
2.0 Hz, 1H, HA-2), 4.20e4.13 (m, 2H, HA-4, HA-6a), 4.07e3.99 (m,
3H, HB-5, HA-5, HA-6b), 3.85 (dd, J¼9.2, 0.8 Hz, 1H, HA-3), 3.75 (s,
3H, OCH3-OMP), 3.67 (s, 3H, OCH3-COOMe), 1.06 (s, 9H, t-Bu-TBS),
0.98 [s, 12H, t-Bu-(t-Bu)2Si], 0.79 [s, 12H, t-Bu-(t-Bu)2Si], 0.12 (s, 3H,
CH3-TBS), ꢁ0.02 (s, 3H, CH3-TBS); 13C NMR(CDCl3, 150 MHz):
(345 mL, 5.54 mmol) were added. The reaction was stirred at room
temperature for 2 h, and was quenched with water. The reactionwas
diluted with CH2Cl2, washed with brine, and dried over Na2SO4,
filtered, and concentrated. Column chromatography (1:1 EtOAc/PE)
gave 29 (560 mg, 90% for two steps) as a white foam. 1H NMR(CDCl3,
500 MHz):
d
7.97 (d, J¼7.5 Hz, 2H, ArH-Bz), 7.91 (d, J¼8.0 Hz, 2H, ArH-
Bz), 7.54e7.33 (m, 11H, ArH-Bz, benzylidene), 7.03 (d, J¼8.5 Hz, 2H,
ArH-OMP), 6.81 (d, J¼8.5 Hz, 2H, ArH-OMP), 5.75 (t, J¼9.0 Hz, 1H,
HB-4), 5.61e5.53 (m, 4H, HB-3, HB-2, HA-1, CH-benzylidene), 5.24
(d, J¼7.5 Hz, 1H, HB-1), 4.62 (J¼2.0 Hz, 1H, HA-4), 4.39 (dd, J¼10.5,
2.5 Hz, 1H, HA-2), 4.35 (d, J¼10.0 Hz, 1H, HA-5), 4.22 (d, J¼12.5 Hz,
1H, HA-6a), 4.05 (d, J¼12.0 Hz, 1H, HA-6b), 3.93 (dd, J¼10.5, 3.0 Hz,
1H, HA-2), 3.84 (s, 1H, HA-5), 3.76 (s, 3H, CH3-OMP), 3.73 (s, 3H,
OCH3-COOMe), 2.64e2.36 (m, 4H, CH2CH2-Lev), 2.03 (s, 3H, CH3-
d
169.84 (CO-COOMe), 165.12 (CO-Bz), 155.99 (ArC-OMP), 155.30
(CO-NH), 150.73 (ArC-OMP), 136.54 (ArC-Cbz), 135.85 (ArC-Bz),
133.77 (ArC-Bz), 130.10, 129.84, 129.20, 128.66, 128.61, 128.47,
128.23, 126.61, 121.36 [ArC-Bz(orthoester)], 118.29 (2C, ArC-OMP),
114.71 (2C, ArC-OMP), 98.59 (CB-1), 97.45 (CA-1), 73.89, 73.02,
72.28 (CA-4), 72.13, 70.78 (CA-3), 69.37, 68.31 (CA-5), 67.01 (CA-6),
66.82, 55.79 (OCH3-OMP), 52.45 (OCH3-COOMe), 49.31 (CA-2),
27.67 [CH3-(t-Bu)2Si], 27.55 [CH3-(t-Bu)2Si], 25.49 (CH3-TBS), 23.49
[C-(t-Bu)2Si], 20.93 [C-(t-Bu)2Si], 17.88 (C-TBS), ꢁ4.42 (CH3-TBS),
ꢁ5.33 (CH3-TBS). HRMS (ESI) m/z: 1094.4312 [MþNa]þ, 1110.3502
[MþK]þ. Calcd for C56H73NNaO16Si2 1094.4366, C56H73NKO16Si2
1110.4105.
Lev); 13C NMR(CDCl3, 125 MHz):
d 205.63 (CO-Lev), 171.25 (CO-Lev),
167.25 (CO-COOMe), 165.61 (CO-Bz), 164.90 (CO-Bz), 155.33 (ArC-
OMP),150.47 (ArC-OMP),137.65 (ArC-benzylidene),133.43(ArC-Bz),
133.24 (ArC-Bz), 129.89, 129.16, 129.81, 128.76, 128.43, 128.29,
128.06, 126.14 (2C, ArC-Ph), 117.69 (2C, ArC-OMP), 114.72 (2C, ArC-
OMP), 101.77 (CH-benzylidene), 100.53 (CA-1), 98.19 (CB-1), 75.58
(CB-4), 75.42 (CA-4), 72.60 (CB-5), 72.39 (CA-5), 71.53 (CB-2), 69.62
(CB-3), 68.97 (CA-3), 63.68 (CA-6), 58.70 (CA-2), 55.62 (OCH3-OMP),
53.01 (CH3-COOMe), 37.55 (C-Lev), 29.56 (C-Lev), 27.69 (C-Lev).
HRMS (ESI) m/z: 918.2641 [MþNa]þ, 934.2460 [MþK]þ. Calcd for
4.25. 2-(7-Azido-6-(4-methoxyphenoxy)-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yloxy)-6-
(hydroxymethyl)-5-(4-oxopentanoyloxy)tetrahydro-2H-
pyran-3,4-diyl dibenzoate, 28
C46H45N3NaO16 918.2698, C46H45N3KO16 934.2437.
In a flask covered with aluminum foil, 17 (469 mg, 0.48 mmol)
was dissolved in CH2Cl2 (12 mL). Water (640 mL) and DDQ (130 mg,
Acknowledgements
0.57 mmol) were added. The reaction was stirred at room tem-
perature overnight, and quenched with satd NaHCO3 aq. The
aqueous layer was separated and extracted with CH2Cl2 (3ꢂ). The
combined organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated. Column chromatography (1:1 EtOAc/PE)
gave 28 (357 mg, 87%) as a white foam. 1H NMR(CDCl3, 400 MHz):
We are grateful to the Department of Instrumental Analysis of
our institute for performing the NMR and mass spectroscopy
measurements.
Supplementary data
d
7.96 (d, J¼7.2 Hz, 2H, ArH-Bz), 7.91 (d, J¼7.6 Hz, 2H, ArH-Bz),
7.51e7.33 (m, 11H, ArH-Bz, benzylidene), 7.03 (d, J¼8.8 Hz, 2H,
ArH-OMP), 6.82 (d, J¼8.8 Hz, 2H, ArH-OMP), 5.75 (t, J¼10.0 Hz, 1H,
HB-4), 5.59e5.54 (m, 3H, HB-3, HA-1, H-benzylidene), 5.36 (t,
J¼9.6 Hz, 1H, HB-2), 5.21 (J¼7.6 Hz, 1H, HB-1), 4.55 (J¼1.6 Hz, 1H,
HA-4), 4.42 (dd, J¼10.8, 2.4 Hz, 1H, HA-2), 4.21 (d, J¼12.4 Hz, 1H,
HA-6a), 4.04 (d, J¼12.4 Hz, 1H, HA-6b), 3.93e3.76 (m, 8H, HB-5, HB-
Supplementary data (Experimental procedures for in-
termediates and compound characterizations were described) as-
sociated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2016.07.042.
References and notes
6
a,b, HA-3, HA-5, CH3-OMP), 2.74e2.30 (m, 4H, CH2CH2-Lev), 2.08
206.76 (CO-Lev),
(s, 3H, CH3-Lev); 13C NMR(CDCl3, 75 MHz):
d
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Sotogaku, N.; Tully, S. E.; Gama, C. I.; Higashi, H.; Tanaka, M.; Hsieh-Wilson, L.
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Morita, K.; Hidari, K. I.; Suzuki, T. Antiviral Res. 2010, 88, 236e243; (e) Bergefall,
K.; Trybala, E.; Johansson, M.; Uyama, T.; Naito, S.; Yamada, S.; Kitagawa, H.;
172.39 (CO-Lev), 165.85 (CO-Bz), 165.21 (CO-Bz), 155.40 (ArC-OMP),
150.56 (ArC-OMP), 137.55 (ArC-benzylidene), 133.46 (ArC-Bz),
133.25 (ArC-Bz), 129.97, 129.92, 129.85, 129.31, 128.99, 128.95,
128.51, 128.34, 128.19, 126.21 (2C, ArC-benzylidene), 117.79 (2C,
ArC-OMP), 114.80 (2C, ArC-OMP), 101.89 (CH-benzylidene), 100.70
(CA-1), 98.41 (CB-1), 76.84, 75.68, 74.78, 73.11, 71.86, 69.22, 69.05,
63.75 (CA-6), 61.39 (CB-6), 58.71 (CA-2), 55.74 (OCH3-OMP), 37.90
(C-Lev), 29.64 (C-Lev), 28.00 (C-Lev). ESI-MS m/z: 890.28 [MþNa]þ.
Calcd for C45H45N3NaO15 890.27.
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