An efficient method to synthesize novel 5-O-(6′-modified)-mycaminose 14-membered ketolides

Article abstract of DOI:10.1016/j.tet.2015.11.029

A new and facile procedure was developed to synthesize novel 5-O-(6′-modified)-mycaminose 14-membered ketolides by adopting different protective strategies and comparing various glycosylation conditions. Seven trichloroacetimidate donors which had different types of substituent groups at C-6 position were synthesized to couple with the erythronolide. Nine novel 5-O-(6′-modified)-mycaminose 14-membered ketolides were obtained to verify the utility of the method.

Full text of DOI:10.1016/j.tet.2015.11.029

Accepted Manuscript
An efficient method to synthesize novel 5-O-(6′-modified)-mycaminose 14-membered
ketolides
A-Peng Wang, Chao Liu, Shuang Yang, Zhehui Zhao, Pingsheng Lei
PII:
S0040-4020(15)30214-3
10.1016/j.tet.2015.11.029
TET 27286
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 8 September 2015
Revised Date: 7 November 2015
Accepted Date: 16 November 2015
Please cite this article as: Wang A-P, Liu C, Yang S, Zhao Z, Lei P, An efficient method to synthesize
novel 5-O-(6′-modified)-mycaminose 14-membered ketolides, Tetrahedron (2015), doi: 10.1016/
j.tet.2015.11.029.
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An efficient method to synthesize novel 5-O-(6′-modified)-
mycaminose 14-membered ketolides
Leave this area blank for abstract info.
A-Peng Wang, Chao Liu, Shuang Yang, Zhehui Zhao ,
Pingsheng Lei
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

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
An efficient method to synthesize novel 5-O-(6′-modified)-mycaminose 14-
membered ketolides
A-Peng Wang, Chao Liu, Shuang Yang, Zhehui Zhao , Pingsheng Lei
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
ARTICLE INFO
ABSTRACT
A new and facile procedure was developed to synthesize novel 5-O-(6′-modified)-mycaminose
14-membered ketolides by adopting different protective strategies and comparing various
glycosylation conditions. Seven trichloroacetimidate donors which had different types of
substituent groups at C-6 position were synthesized to couple with the erythronolide. Nine novel
5-O-(6′-modified)-mycaminose 14-membered ketolides were obtained to verify the utility of the
method.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Ketolides
.
desosamine mimetics
mycaminose
glycosylation
modification
1. Introduction
5-O-desosamine of macrolide antibiotics is the most important
pharmacophore which provides the major binding energy with
the target bacterial ribosome.1 Direct modification of 5-O-
desosamine was focused on 2′-OH group and 3′- NMe2 group
which showed no activities or weak activities.2 Modification of
other positions was rarely reported due to the complexity of the
macrolide structure and synthetic difficulty.3 A strategy about the
study of other positions of 5-O-desosamine was to synthesize
new desosamine-mimetics to replace the desosamine. A series of
5-O-(4′-modified)-desosamine 14-membered ketolides were
synthesized in our lab, in which 5-O-mycaminose ketolide
showed obviously improved activity against certain sensitive
pathogens compared to Clarithromycin.4 For 6′-modified
desosamine ketolide, the study on its synthesis and SARs was
hardly reported previously. Liang et al had synthesized several
different 5-O-desosamine modified ketolides, in which 5-O-(6′-
OBz)-desosamine ketolide showed excellent activity against
several erythromycin-resistant pathogens. However, only benzoyl
group was studied for C-6 of desosamine. The method for C-6
modified desosamine and 5-O-(6′-modified)-desosamine ketolide
was not published in detail.5,6 It would be meaningful to develop
this synthetic method to study the 5-O-(6′-modified)-desosamine
ketolides further. Herein we reported a facile procedure of
modifying C-6 of desosamine-mimetics and synthesizing a series
of novel 5-O-(6′-modified)-desosamine-mimetics 14-membered
ketolides which would provide an opportunity for the design of a
new class of ketolides .
Scheme 1. Retrosynthesis of Targets
2. Results and discussion
The retrosynthetic analysis (Scheme 1) of targets adopted the
strategy of replacement 5-O-desosamine with a modified
desosamine mimetic. Erythronolide was obtained via 9 steps
from Clarithromycin as the way Y, Xu et al reported in our lab.4
6-modified desosamine-mimetics were needed to be synthesized
to couple with erythronolide. 5-O-(6′-modified)-desosamine
5,6
ketolide was reported by Liang et al.
4-Methylphenyl-thio
glycosides were used as the donors in glycosidation and 3′-NMe2
group was converted from 3′-NHFmoc group. The neighboring
group participation effect of 2-OBz group in the donors
determined the glycosylation product of β-configuration. Based
on that, the synthetic route for compound 15 was designed
(Scheme 2). Commercial available compound 1 was chosen as
the starting material, compound 3 was obtained by two
consecutive steps in a yield of 80% through oxidation with Dess -
Martin periodinane and then reduction with NaBH4.7 Conversion
of 3-OH group to 3-OTf group with Tf2O formed compound 4 in
95% yield. 3-OTf group was a good leaving group which could
be replaced by azide group to form compound 5 in 99% yield, 3-
N3 group was vital to be converted into 3-NH2 group and 3-

2
Tetrahedron
NHFmoc group.8,9 After that, opening the five-memberd furan
showed low reactivity, the donor 15 with bulky substituent group
ACCEPTED MANUSCRIPT
cyclic compound 5 with TFA and acylation with Ac2O formed
compound 7, the yield of two steps was 80%.10 The 1-OAc group
could selectively react with 4-methylthiophenol to produce
compound 8 in a yield of 87%.11 4-Methylphenyl-thio glycoside
could not only be used as the glucosinolate but also be
transformed to trichloroacetimidate. Adding MeONa to
compound 8 in MeOH produced compound 9 in 95% yield.12 By
using TBDPSCl, 6-OH group could be selectively protected
compared to 2-OH group and 4-OH group, the different protected
groups assigned for the primary alcohol and secondary alcohol
made the modification of C-6 possible. 6-OH group was
selectively protected with TBDPSCl in pyridine to form
compound 10 in a yield of 92%. Staudinger reduction of 3-N3
group formed compound 11 in 80% yield.13 After that, protection
of 3-NH2 group with FmocCl in the mixture of CH2Cl2 and
NaHCO3 aqueous solution produced compound 12 in 78% yield.
Then, protection of 2-OH group and 4-OH group with BzCl
yielded compound 13. This manipulation was adopted based on
that 3-N3 group was hard to reduce under the existent of 2- and 4-
O-benzoyl groups.14 6-OTBDPS group was selectively removed
by adding hydrochloric acid to compound 13 in MeOH to form
compound 14 in a yield of 79%.15 The 6-OH group of compound
14 could be modified with suitable substituents. Compound 15
was synthesized with BzCl via 14 steps in a total yield of 15%.
at C-3 might be not favourite for the acceptor erythronolide.
When the benzyl group was tried to modify the 6-OH group of
compound 14 by using Ag2O and BnBr, no product was
obtained.16 The Fmoc group of 14 was destroyed when NaH was
used as the alkali (Scheme 3). The failure of glycosidation with
15 and modification of 14 forced us to revise our previous
procedure.
Scheme 3. Reagents and conditions: a) NIS, AgOTf, CH2Cl2; b)
Ag2O or NaH, BnBr, DMF.
The synthetic route was adjusted as shown in Scheme 4.
Replacement the 3-NHFmoc group with 3-NMe2 group of the
donor was considered because of its relatively less steric
hindrance. At the same time, trichloroacetimidate donor was also
preferred because of its higher reactivity. Using this strategy, the
target compound could be obtained directly after glycosylation.
The synthetic route was adjusted from compound 10, protection
with BzCl formed compound 19 in a yield of 86%. Then, 6-
OTBDPS group was selectively removed to form compound 20
which could be modified properly at 6-OH group. Benzoyl group
was chosen as well and introduced with BzCl to obtain
compound 21. After that, hydrolysis of thioglycoside 21 with
NBS formed compound 22 in acetone and H2O in 85% yield.17
The condition of Zn and acetic acid was adopted to reduce 3-N3
group of compound 22 and methylation of 3-NH2 with CH3I was
ongoing in a consecutive reaction in a yield of 49% for two
steps.18 The donor 24 was produced by the reaction of compound
23 with CCl3CN and DBU in 91% yield.19
Scheme 2. Reagents and conditions: a) Dess-Martin, CH2Cl2; b)
NaBH4, EtOH, ice-Bath, two steps, 80%; c) Tf2O, pyridine, 95%;
d) NaN3, DMF, 99%; e) TFA, H2O; f) Ac2O, pyridine, two steps,
80%; g) 4-methylthiophenol, BF Et O, CH Cl , 87%; h) MeONa,
·
3
2
2
2
MeOH, 95%. i) TBDPSCl, DMAP, pyridine, 92%; j) PhP3, THF,
H2O, 80%; k) FmocCl, aq. NaHCO3, CH2Cl2, 78%; l) BzCl,
pyridine, 81%; m) HCl, MeOH, 79%; n) BzCl, pyridine, 80%.
Scheme 4. Reagents and conditions: a) BzCl, pyridine, 86%; b)
HCl, MeOH, 90%; c) BzCl, pyridine, 90%; d) NBS, acetone,
H2O, 85%; e) Zn, CH3COOH, then, CH3I, Na2CO3, DMF, two
steps, 49%; f) CCl3CN, DBU, CH2Cl2, 91%.
With the donor 15 in hand, the acceptor erythronolide and
donor 15 were coupled using NIS and AgOTf in dry CH2Cl2 at
-78 ℃ . However, the glycosidation failed even though the
reaction time was prolonged to 24 hours. Glycosylation product
16 was not found (Scheme 3). By using different reaction
conditions such as adjustment of reaction temperature and / or
reactants ratio, the desired product 16 was not found. According
to the work Y, Xu et al reported,4 the 5-OH of erythronolide
With the donor 24 obtained, glycosidation was tried again.
TMSOTf was used as a promoter to couple the donor 24 with the
acceptor erythronolide (Scheme 5). The molar ratio of TMSOTf

3
was 1.1 eq to the acceptor because of 3-NMe2 group which acted
ACCEPTED MANUSCRIPT
as an acid-capturer.4 It was also disappointed that the
glycosidation was not successful. The donor 24 was much too
unstable to form compound 23 in the presence of excess
TMSOTf, while we reduced the molar ratio of TMSOTf to 0.1eq,
no compound 25 was found. The main products were unreacted
erythronolide and compound 23 when the reaction time extended
to 24 hours. Compound 26 was also detected with HRMS
[M+H]+ 648.3150, [M+Na]+ 670.2996. Considering the effect of
the basicity of 3-NMe2 group on the glycosidation, the ratio of
TMSOTf was hard to control to balance the contradictory of
reactivity and stability of the donor in the presence of 3-NMe2
group.
Scheme 6. Reagents and conditions: a) CCl3CN, DBU, CH2Cl2
86%; b) TMSOTf, CH2Cl2, 31%; c) Lindlar catalyst, H2, MeOH;
d) CH3I, Na2CO3, DMF, two steps yield 50%; e) MeOH, reflux,
70%.
In order to estimate the practicability of the synthetic
method aboved, different types of substituted groups for C-6′
were tried. Alkyl ester group (acetyl group) and ether group
(benzyl group and methyl group) were explored to be introduced
to C6′-modified ketolides which have never been reported before
(Scheme 7). Acetyl group was introduced as a similar method for
compound 21, protection of compound 20 with Ac2O in pyridine
formed compound 31a in a yield of 87%. Benzyl group was
introduced with Ag2O and BnBr from compound 20 in a yield of
73%.16 Methyl group was introduced with Ag2O and MeI as the
method for compound 31b in a yield of 70%. Then the donors
33a, 33b and 33c were obtained as the method for donor 27 via
two steps. Similarly, TMSOTf was used as a promoter to couple
donor 33a, 33b or 33c with the acceptor erythronolide
respectively to develop the compound 34a, 34b and 34c, the
yield was 58% for 34a, 46% for 34b and 68% for 34c. The
different yields of glycosidation showed that C6-alkly group
modified donors 31a and 31c might be favored compared to the
donors 27, 31b with aryl group modified at C-6 and donors 31b
and 31c with electron-donating group at C-6 might also be
beneficial compared to donors 27, 31a with electron-withdrawing
groups. Compounds 35a, 35b and 35c were formed via two steps
through reduction of 3′-N3 group and followed by methylation of
newly generated 3′-NH2 group later. Deprotection of 2′-OBz
group and 4′-OBz group in MeOH at 70℃ produced the target
compounds 36a, 36b and 36c. Fortunately, 6′-deacetyl compound
37a and 37c were also separated. The structures of all
compounds were confirmed by by 1HNMR, 13CNMR and HRMS
spectra. Herein, ester groups (aryl group: benzoyl group and
alkyl group: acetyl group) and ether groups (aryl group: benzyl
group and alkyl group: methyl group) were successfully
introduced to C-6’ ketolides with the procedure for compound
30.
Scheme 5. Reagents and conditions: a) TMSOTf, CH2Cl2.
Aiming at avoiding the adverse influence of 3-NMe2 group for
glycosidation, 3-N3 group was taken as the protective group
which could be converted into 3-NMe2 group by reduction and
methlylation. The synthetic route was revised as followed
(Scheme 6). Compound 22 was directly reacted with CCl3CN and
DBU to form donor 27 in 86% yield. Erythronolide was
successfully glycosylated with donor 27 to afford the
glycosylated product 28 in a yield of 31% using TMSOTf as a
1
promoter, the structure was confirmed by H NMR, 13C NMR
and HRMS spectra (H-1′ : 4.83 ppm, J = 7.6 Hz, β-configuration;
C-1′ : 100.7 ppm; HRMS [M+H]+ 1075.4110 ). Compound 29
was obtained with a consecutive reaction through reduction of 3′-
N3 group of compound 28 and followed by methylation of newly
generated 3′-NH2 group later in 50% yield for two steps, 3′-NMe2
1
group was proved by the HNMR signals (2.36 ppm, s, 6H). 2′-
and 4′-OBz groups of compound 29 were removed in MeOH
under reflux condition to obtain the target compound 30 in a
1
yield of 70%, the HNMR signals for H-2′ (5.30 ppm) and H-4′
(5.35 ppm) of compound 29 disappeared and shifted upfield,
Which showed 2′-OBz group and 4′-OBz group were removed.
This result was consistent with the work as Liang et al and Y, Xu
et al reported, transesterification was easier to take place for 2′-
OBz group and 4′-OBz group compared with 6′-OBz group and
9-N=OBz group. Up to now, with the adjustment of protective
strategies and conditions of glycosidation, a new procedure was
developed to obtain the target 30 designed via 18 steps in a total
yield of 4%.

4
Tetrahedron
Two novel ketolides 50a and 50b were obtained in methanol
ACCEPTED MANUSCRIPT
under refluxing condition in a yield of 55% and 69%. With this,
Nine novel ketolides have been successfully synthesized which
included several types of substituent groups at the C6′ of 5-O-
desosamine mimetics. At the same time, the synthetic way was
proved to have excellent practicability.
Scheme 8. Reagents and conditions: a) 4-methylbenzenesulfonic
acid, PhCH(OMe)2, DMF, 71%; b) BzCl, pyridine, 71%; c) NIS,
CH2Cl2, H2O, TFA, 55%; d) CCl3CN, DBU, CH2Cl2, 96%; e)
TMSOTf, CH2Cl2, 60%; f) Lindlar catalyst, H2, MeOH; g) CH3I,
Na2CO3, DMF, two steps yield 60%; h) MeOH, reflux, 65%.
Scheme 7. Reagents and conditions: a) Ac2O, Pyridine for 31a,
87%; Ag2O, BnBr, DMF for 31b 73%; Ag2O, MeI, DMF for 31c,
70%; b) NBS, acetone, H2O; c) CCl3CN, DBU, CH2Cl2 58% -
63% for two steps ; d) TMSOTf, CH2Cl2, 58% for 34a, 46% for
34b, 68% for 34c; e) Lindlar catalyst, H2, MeOH; f) CH3I,
Na2CO3, DMF, two steps yield 70% for 35a, 50% for 35b, 71%
for 35c; g) MeOH, reflux,44% for 36a, 62% for 36b, 35% for
36c, 40% for 37a, 40% for 37c.
C4′, C6′- benzal substituted ketolide was also synthesized here
as a similar procedure (Scheme 8). C4, C6- hydroxyl groups were
protected by benzal group with 4-methylbenzenesulfonic acid
and PhCH(OMe)2 in a yield of 71%.20 Then protection of 2-OH
group with BzCl formed compound 39 in 71% yield. It was
different that hydrolysis of thioglycoside 39 was proceeded under
the condition of NIS/ CH2Cl2 / TFA / H2O to produce compound
40 in a yield of 55%, while the condition of NBS / acetone / H2O
didn’t work.21,22 Compound 41 was obtained from compound 40
by the reaction with CCl3CN and DBU in a yield of 96%. After
that, according to the same procedure, the donor 41 was coupled
with erythronolide in a yield of 60%. Then, 3′-N3 group of
compound 42 was converted to 3′-NMe2 group in a consecutive
reaction, the yield of two steps was 60%. C4′, C6′- benzal
substituted ketolide 44 was obtained successfully from
compound 43 in methanol under refluxing condition. C4′, C6′-
dibenzyl substituted ketolide 50a and C4′-methyl -C6′-benzyl
substituted ketolide 50b were also synthesized as a similar
procedure (Scheme 9) here. Selective cleavage of the benzylidene
group formed compound 45 in a yield of 56%.23 The 4-OH group
was modified with BnBr or MeI under the condition of NaH /
DMF formed compound 46a, 46b respectively. The donors 47a
and 47b were obtained via two steps same as the donor 41.
Similarly, the donors 47a, 47b were coupled with erythronolide
respectively, the yield was 70% for 48a, 62% for 48b. Then, 3’-
N3 group was converted to 3′-NMe2 group in a consecutive
reaction, the yield of two steps was 70% for 49a, 65% for 49b.
Scheme 9. Reagents and conditions: a) Et3SiH, TFA, CH2Cl2,
56%; b) NaH, DMF, BnBr for 46a, 99%; MeI for 46b, 99%; c)
NIS, CH2Cl2, H2O, TFA, then CCl3CN, DBU, CH2Cl2, two steps,
53% for 47a, 31% for 47b; e) TMSOTf, CH2Cl2, 70% for 48a,
62% for 48b; f) Lindlar catalyst, H2, MeOH; g) CH3I, Na2CO3,
DMF, two steps yield 70% for 49a, 65% for 49b; h) MeOH,
reflux, 55% for 50a, 69% for 50b.

5
3. Conclusion
In conclusion, an efficient procedure was developed by
3H). 13C NMR(CDCl3, 75MHz): δ118.6,114.4, 110.3, 104.1,
ACCEPTED MANUSCRIPT
82.3, 77.8, 77.7, 75.2, 66.3, 26.8, 26.5, 26.2, 24.8. ESI-MS: calcd
for C13H20F3O8S [M+H]+ 393.0753, found: 393.0807.
adjustment of protective strategies and glycosylation conditions.
A series of novel ketolides were successfully synthesized which
had different types of substituent groups at C-6′ of desosamine-
mimetics. This work should offer us an opportunity to design
more novel 5-O-(6′-modified)-desosamine-mimetics ketolides
which could be contributed to a better understanding the SARs of
desosamine
4.4. Synthesis of 1,2: 5,6-di-O-isopropylidene-3-azido-3-deoxy-α-
D-allofuranose 5
NaN3 (3.3 g, 0.05 mol) was added to a solution of compound 4
in 24.0 mL DMF. After stirring for 6 hours at 50℃, the reaction
solution was diluted with CH2Cl2, washed with saturated
NaHCO3 and brine, dried over Na2SO4. The concentrate was
purified by column chromatography (PE : EtOAc = 12 : 1) to
1
give compound 5 (12.6 g, 99% ). H NMR(CDCl3, 400 MHz):
4. Experimental section
δ5.85 (d, J1,2 = 3.6 Hz, 1H, H-1), 4.61 (d, J1,2 = 3.6 Hz, 1H, H-2),
4.24 (m, 1H), 4.08-4.16 (m, 3H), 4.00 (dd, J5,6a = 4.8 Hz, J5,6b
=
4.1. General
8.8 Hz, 1H, H-5), 1.51, 1.43, 1.37, 1.32 (4 × s, 4 × 3H). 13C
NMR(CDCl3, 100MHz): δ112.2, 109.5, 110.3, 105.0, 80.4, 72.9,
67.6, 66.2, 26.8, 26.5, 26.3, 25.1. ESI-MS: calcd for C12H20N3O5
[M+H]+ 286.1325, found: 286.1380.
All solvents and reagents were obtained from commercial
sources and used without further purification unless otherwise
noted. All NMR spectra were recorded on Mercury-300, 400, 500
or 600 MHz spectrometers in CDCl3 and CD3OD. HRMS
experiments were done with an Aglient 1100series LC/MSD
TOF and MS with an Thermo-Finnigan LCQ Advantage.
Analytical thin chromatography (TLC) was carried out on TLC
plates silica gel HSGF254 percolated by Branch of Qingdao
Haiyang Chemical Plant. Chromatography was performed with
silica gel H (HG/T2354-92).
4.5. Synthesis of 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy-α,β-D-
glucopyranose 7
Compound 5 (3.1 g, 0.01 mol) was dissolved in a mixture
solution of 20 mL TFA and 3 mL H2O. After stirring for 2 hours
at room temperature, the reaction solution was concentrated and
dissolved with 60 mL pyridine. Added Ac2O (49.7 g, 0.49 mol)
and kept stirring for 20 hours. The reaction solution was
concentrated and diluted with CH2Cl2, washed with saturated
NaHCO3 and brine, dried over Na2SO4. The concentrate was
purified by column chromatography (PE : EtOAc = 5 : 1) to give
4.2. Synthesis of 1,2: 5,6 -di-O-isopropylidene-α-D-allofuranose
3
Compound 1 (13.0 g, 0.05 mol) in 80 mL CH2Cl2 was stirred
at 0℃, Dess-Martin oxidant (35.0 g, 0.08 mol) was added in
batches. After stirring for 2 hours at 0℃, the reaction solution
was warmed up to room temperature and kept stirring for 20
hours. Then 80 mL saturated NaHCO3 and 9.6 g Na2S2O3 were
added and stirred intensely. Organic phase was concentrated and
dissolved in 100 mL ethanol. NaBH4 (1.9 g, 0.05 mol) was
dissolved in the mixture solution of ethanol / H2O (20 mL / 20
mL) and dropped slowly to the reaction solution at 0℃. After
that, kept stirring for 4 hours at room temperature, saturated
NH4Cl was added to quench the reaction and ethyl acetate was
used to extracte. The organic phase was washed with brine, dried
over anhydrous Na2SO4. The concentrate was purified by column
chromatography (PE : EtOAc = 5 : 1) to give compound 3 (10.4
1
compound 7 (9.4 g, 80%, α / β = 1 : 0.4 ). H NMR(CDCl3, 300
MHz, α / β = 1 : 0.4): δ6.29 (d, J1,2 = 3.6 Hz, 1H, H-1α), 5.67 (d,
J1,2 = 8.5 Hz, 0.4H, H-1β), 4.98-5.05 (m, 1.8H), 4.95 (dd, J1 = 3.6
Hz, J2,1 = 10.8 Hz, 1H), 4.18-4.26 (m, 1.4H), 4.02-4.12 (m,
2.4H), 3.96 (t, J = 10.5Hz, 1H), 3.75-3.80 (m, 0.4H), 3.68 (t, J =
10.5 Hz, 0.4H), 2.18, 2.13 (2× s, 2 × 3H), 2.12, 2.11, 2.10 (3 × s,
3 × 3H ), 2.08 (s, 7.17H). ESI-MS: calcd for C14H24N4O10
+
391.1121, found: 391.1478 [M + NH4 ].
4.6. Synthesis of p-methylphenyl-2,4,6-tri-O-acetyl-3-azido-3-de-
oxy-1-thio-β-D-glucopyranoside 8
4-Methylthiophenol (1.3 g, 1.00 mmol) was added to a
solution of compound 7 (3.5 g, 9.30 mmol) dissolved in 10 mL
1
g), the yield of two steps is 80%. H NMR(CDCl3, 400 MHz):
δ5.78 (d, J1,2 = 3.6 Hz, 1H, H-1), 4.58 (dd, J2,1 = 4.0 Hz, J2,3 = 5.2
Hz, 1H, H-2), 4.29 (ddd, J5,6a = 4.8 Hz, J5,6b = 6.4 Hz, J5,4 = 6.4
anhydrous CH Cl Then 3.5 mL BF Et O was dropped slowly.
·
2
2.
3
2
After stirring for 12 hours at 40℃, the reaction solution was
diluted with CH2Cl2, washed with saturated NaHCO3 and brine,
dried over Na2SO4. The concentrate was purified by column
chromatography (PE : EtOAc = 7 : 1) to give compound 8 (3.6 g,
Hz, 1H, H-5), 3.97-4.08 (m, 3H, H-3, H-4, H-6a), 3.80 (dd, J6b,5
=
4.5 Hz, J6b,6a = 8.4 Hz, 1H, H-6b), 2.58 (br, 1H, 3-OH), 1.55,
1.44, 1.36, 1.34 (4 × s, 4 × 3H,). 13C NMR(CDCl3, 100MHz): δ
112.7, 109.7, 103.8, 79.6, 78.8, 75.5, 72.4, 65.7, 26.5, 26.4, 26.2,
25.2. ESI-MS: calcd for C12H20NaO6 [M+Na]+ 283.1260, found:
283.1169
1
β, 87%). H NMR(CDCl3, 400 MHz): δ7.39 (d, J = 8.0Hz, 2H),
7.12 (d, J = 8.0Hz, 2H), 4.91 (t, J = 10.0 Hz, 1H, H-2), 4.87 (t, J
= 10.0 Hz, 1H, H-4), 4.59 (d, J = 9.6 Hz, 1H, H-1), 4.16-4.17 (m,
2H, H-6b, H-6a), 3.62-3.76 (m, 2H, H-5, H-3), 2.29 (s, 3H), 2.18,
2.11, 2.08 (3× s, 3× 3H). 13C NMR(CDCl3, 100 MHz): δ170.8,
169.4, 169.3, 139.0, 133.8, 129.9, 128.1,86.6, 76.6, 70.2, 68.5,
66.0, 62.4, 21.4, 21.1, 21.0, 20.9. ESI-MS: calcd for
4.3. Synthesis of 1,2: 5,6-di-O-isopropylidene-3-O-triflyl-α-D-al-
lofuranose 4
+
A solution of compound 3 (20.0 g, 0.08 mol) in 24 mL
pyridine under argon was cooled to 0℃. Tf2O (20.3 mL, 0.12
mol) was added in. After stirring 3.5 hours at room temperature,
the reaction mixture was diluted with CH2Cl2, washed with
saturated NaHCO3 and brine, dried over Na2SO4. The concentrate
was purified by column chromatography (PE : CH2Cl2 = 1 : 1) to
give compound 4 (28.6g) with a yield of 95%. H NMR(CDCl3,
300 MHz): δ5.83 (d, J1,2 = 3.6 Hz, 1H, H-1), 4.90 (dd, J3,4 = 6.3
Hz, J3,2 = 5.7 Hz, 1H, H-3), 4.76 (dd, J2,3 = 4.8 Hz, J2,1 = 4.2 Hz,
C19H28N4O8S 455.1257, found: 455.1568 [M + NH4 ].
4.7. Synthesis of p-methylphenyl-3-azido-3-deoxy-1-thio-β-D-ma-
nnopyranoside 9
Compound 8 (1.8 g, 4.11 mmol) was dissolved in 20 mL
methanol and added MeONa (0.2 g, 4.00 mmol) under argon.
After stirring for 4 hours at room temperature, the reaction
solution was neutralized with AMBERLYST(R) 15 and filtered.
The concentrate was purified by column chromatography (MeOH
1
1H, H-2), 4.08-4.20 (m, 3H, H-6b, H-4, H-6a), 3.90 (dd, J5,6a
4.5 Hz, J5,6b = 8.7 Hz, 1H, H-5), 1.58, 1.44, 1.38, 1.34 (4 × s, 4 ×
=
1
: CH2Cl2 = 60 : 1) to give compound 9 (1.2 g, 95% ). H

6
Tetrahedron
NMR(CD3OD, 400 MHz): δ7.44 (d, J = 8.0Hz, 2H), 7.10 (d, J =
l-diphenylsilyl-3-fluorenylmethoxycarbonyamino-3-deoxy-1-thi-
ACCEPTED MANUSCRIPT
8.0Hz, 2H), 4.53 (d, J = 9.6 Hz, 1H, H-1), 3.84 (dd, J6a, 6b = 12.0
Hz, J6a, 5 = 2.0 Hz, 1H, H-6a), 3.65 (dd, J6a, 6b = 12.0 Hz, J6b, 5
o-β-D-glucopyranoside 13
=
BzCl (139.0 mg, 0.66 mmol) was added to a solution of
compound 12 (246.0 mg, 0.30 mmol) in 5 mL pyridine under
argon condition. After stirring for 5 hours at room temperature,
the reaction solution was concentrated and diluted with CH2Cl2,
the diluent was washed with saturated NaHCO3 and brine, dried
over Na2SO4. The concentrate was purified by column
chromatography (PE : EtOAc = 10 : 1) to give compound 13
(254.0 mg, 81% ). 1H NMR (CDCl3, 400 MHz) δ 8.07 (d, J = 7.6
Hz, 2H), 7.96 (d, J = 7.6 Hz, 2H), 7.76 (d, J = 7.6 Hz, 2H), 7.65
(d, J = 7.6 Hz, 2H), 7.56 (d, J = 7.6 Hz, 2H), 7.51 (d, J = 7.2 Hz
2H), 7.47 (d, J = 7.2 Hz, 2H), 7.38 (m, 7H), 7.30 (m, 5H), 7.14
(m, 4H), 7.07 (d, J = 7.2 Hz, 2H), 5.45 (t, J = 9.6 Hz, 1H), 5.21
(d, J =10.0 Hz, 1H), 5.15 (t, J =10.0 Hz, 1H), 4.95 (d, J = 9.6 Hz,
1H), 4.50 (t, J = 10.0 Hz, 1H), 3.87-3.94 (m, 5H), 3.72 (t, J = 9.6
Hz, 1H), 2.35 (s, 3H), 1.06 (s, 9H). 13C-NMR (100 MHz, CDCl3)
166.0, 166.0, 156.4, 143.9, 143.9, 141.2, 138.8, 135.9, 135.7,
134.4, 133.6, 133.5, 133.0, 131.1, 130.3, 130.2, 129.9, 129.8,
129.6, 129.4, 129.1, 128.6, 128.6, 127.9, 127.8, 127.6, 127.1,
125.3, 119.9, 86.6, 80.2, 71.3, 68.9, 67.4, 62.7, 58.1, 47.0, 26.8,
21.4, 19.4. ESI-MS: calcd for C58H56NO8SSi[M+H]+ 954.3418,
found: 954.3406.
5.2 Hz, 1H, H-6b), 3.32 (m, 2H, H-2, H-5), 3.25 (t, J = 9.6Hz,
1H, H-4), 3.17 (t, J = 9.6Hz, 1H, H-3), 2.30 (s, 3H). 13C
NMR(CD3OD, 100 MHz): δ137.8, 132.5, 129.6, 129.4,88.7, 81.2,
71.8, 71.5, 68.8, 61.4, 19.9. ESI-MS: calcd for C13H17N3NaO4S
[M+Na]+ 334.0940, found: 344.0799.
4.8. Synthesis of p-methylphenyl-3-azido-3-deoxy-6-O-tertbutyl-
diphenylsilyl-1-thio-β-D-glucopyranoside 10
Compound 9 (2.8 g, 9.11 mmol) was dissolved in 10 mL
pyridine. TBDPSCl (2.9 g, 10.60 mmol) and DMAP (300.0 mg)
were added. After stirring for 5 hours at room temperature, the
reaction solution was concentrated and diluted with CH2Cl2,
washed with saturated NaHCO3 and brine, dried over Na2SO4.
The concentrate was purified by column chromatography (PE :
EtOAc = 5 : 1) to give compound 10 (4.6 g, 92% ). 1H
NMR(CDCl3, 400 MHz): δ 7.69-7.72 (m, 4H), 7.40-7.49 (m,
8H), 7.09 (d, J = 8.0Hz, 2H), 4.45 (d, J = 9.6 Hz, 1H, H-1), 3.94
(m, 2H, H-6a, H-6b), 3.58 (dd, J1 = 2.4 Hz, J2 = 9.2 Hz, 1H, H-
2), 3.50 (m, 2H, H-3, H-5), 3.31 (dd, J1 = 2.4 Hz, J2 = 9.6 Hz,
1H, H-4), 2.91, 2.55 (2 × OH, d, J = 2.4 Hz), 2.33 (s, 3H),
1.07(s, 9H, (CH3)3C). 13C NMR(CDCl3, 100 MHz): δ 138.8,
135.6, 135.5, 133.7, 132.6, 132.5, 130.0, 129.9, 129.8, 127.9,
127.8, 126.7, 88.3, 79.0, 70.8, 70.6, 69.5, 64.3, 26.6, 21.1, 19.1.
ESI-MS: calcd for C29H35N3NaO4SSi [M+Na]+ 572.2118, found:
572.2008.
4.12. Synthesis of p-methylphenyl-2,4-di-O-benzoyl-3-fluorenyl
methoxycarbonyamino-3-deoxy-1-thio-β-D-glucopyranoside 14
Compound 13 (32.0 mg, 0.03 mmol) dissolving in 1 mL
MeOH was added 0.1 mL concentrated hydrochloric acid. After
stirring for 12 hours at room temperature. The reaction solution
was washed with NaHCO3 and brine, dried over Na2SO4. The
concentrate was purified by column chromatography (PE :
EtOAc = 20 : 1) to give compound 14 (19.0 mg, 79% ). 1H-NMR
(400 MHz, CDCl3) δ 8.04 (d, J = 7.6 Hz, 2H), 7.99 (d, J = 7.6
Hz, 2H), 7.62 (d, J = 7.6 Hz, 2H), 7.45 (m, 3H), 7.34 (m, 7H),
7.13 (m, 2H), 7.12 (d, J = 7.2 Hz, 2H), 7.08 (d, J = 7.6 Hz, 2H),
5.24 (t, J = 9.6 Hz, 1H), 5.10 (t, J = 10.0 Hz, 1H), 4.96 (d, J = 9.6
Hz, 1H), 4.50 (q, J = 10.4 Hz, 1H), 4.30 (t, J = 6.8 Hz, 1H), 3.94
(m, 1H), 3.83 (m, 2H), 3.72 (m, 2H), 2.36 (s, 3H). 13C NMR
(CDCl3, 100 MHz) δ 166.6, 166.1, 156.4, 143.8, 141.6, 139.1,
134.2, 133.9, 133.7, 131.1, 130.3, 130.0, 129.4, 129.1, 128.9,
128.7, 128.6, 127.7, 127.1, 125.2, 119.9, 86.7, 79.7, 71.1, 69.6,
67.5, 61.9, 57.5, 46.9, 21.4, 19.4. ESI-MS: calcd for C42H38NO8S
[M+H]+ 716.2240, found: 716.2401.
4.9. Synthesis of p-methylphenyl-3-amino-3-deoxy-6-O-tertbutyl-
diphenylsilyl-1-thio-β-D-glucopyranoside 11
PPh3 (665.0 mg, 2.50 mmol) and H2O (220.0 mg, 12.20
mmol) were added to a solution of compound 10 dissolved in 5
mL THF under argon. After stirring for 24 hours under refluxing
condition. The reaction solution was concentrated and purified by
column chromatography (PE : EtOAc = 3 : 1) to give compound
1
11 (417.0 mg, 80% ). H NMR (CDCl3, 400 MHz) δ 7.70 (m,
4H), 7.40(m, 8H), 7.00 (d, J = 7.6 Hz, 2H), 4.45 (d, J = 9.6
Hz,1H, H-1) , 4.10 (dd, J1 = 12.0 Hz, J2 = 7.6 Hz, 1H, H-6), 3.93
(m, 2H), 3.42 (m, 2H), 3.12 (dd, J1 = 9.6 Hz, J2 = 9.2 Hz, 1H),
2.66 (br, 2H), 2.31 (s, 3H), 1.07 (s, 9H). ESI-MS: calcd for
C29H38NO4SSi [M+H]+ 524.2213, found: 524.2445.
4.13. Synthesis of p-methylphenyl-2,4,6-tri--O-benzoyl-3-fluo-
renylmethoxycarbony amino-3-deoxy- 1-thio-β-D-glucopyrano-
side 15
4.10. Synthesis of p-methylphenyl-6-O-tertbutyldiphenylsilyl-3-
fluorenylmethoxy-carbony-amino-3-deoxy-1-thio-β-D-glucopyr-
anoside 12
Compound 11 (102.0 mg, 0.20 mmol) was dissolved in 3 mL
CH2Cl2 with 0.6 mL saturated NaHCO3 solution. Then FmocCl
(76.0 mg. 0.30 mmol) was added. After stirring for 3 hours at
room temperature, the reaction solution was washed with brine,
concentrated and purified by column chromatography (PE :
EtOAc = 5 : 1) to give compound 12 (112.0 mg, 78% ). 1H NMR
(CDCl3, 400 MHz) δ 7.73 (m, 6H), 7.58 (d, J = 7.6 Hz, 2H), 7.41
(m,10H), 7.28 (d, J = 7.2 Hz, 2H), 7.05 (d, J = 7.2 Hz, 2H), 4.49
(d, J = 9.4 Hz, 1H) , 4.43 (d, J = 6.8 Hz, 2H), 4.21 (m, 1H), 3.95
(m, 2H), 2.35 (s, 3H), 1.07 (s, 9H). 13C NMR (CDCl3, 100 MHz)
δ 143.9, 141.5, 138.5, 135.8, 135.8, 133.6, 133.2, 130.0, 129.9,
128.0, 127.9, 127.3, 125.2, 120.2, 88.9, 80.7, 70.5, 67.5, 64.4,
61.4, 47.3, 27.0, 21.3, 19.4. ESI-MS: calcd for C44H48NO6SSi
[M+H]+ 746.2893, found: 746.3051.
BzCl (40 mg, 0.30mol) was added to a solution of compound
14 dissolved in 2 mL pyridine under argon condition. After
stirring for 5 hours , the reaction solution was concentrated and
diluted with CH2Cl2. The diluent was washed with saturated
NaHCO3 and brine, dried over Na2SO4. The concentrate was
purified by column chromatography (PE : EtOAc = 12: 1) to give
1
compound 15 (116.0 mg, 80%). H NMR (CDCl3, 400 MHz) δ
8.06 (m, 4H), 7.98 (d, J = 7.6 Hz, 2H), 7.62 (d, J = 7.6 Hz, 2H),
7.60 (t, J = 7.2 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.2
Hz, 3H), 7.26-7.41 (m, 10H), 7.11 (m, 2H), 6.95 (d, J = 8.0 Hz,
2H), 5.34 (dd, J1, J2 = 10.0 Hz , 1H, H-2), 5.14 (dd, J1, J2 = 9.6
Hz, 1H, H-4), 5.09 (m, 1H, H-5), 4.98 (d, J = 9.6 Hz, 1H, H-1),
4.70 (d, J = 11.6 Hz, 1H, H-6a), 4.51 (dd, J1, J2 = 10.0 Hz , 1H,
H-3), 4.44 (m, 1H, H-6b), 4.17 (br, 1H), 3.93 (d, J = 7.6 Hz, 2H),
3.68 (t, J = 7.2 Hz, 1H), 2.28 (s, 3H). 13C NMR (CDCl3, 100
MHz) δ 166.2, 166.1, 156.4, 134.6, 133.4, 130.3, 130.2, 130.1,
129.8, 128.6, 127.7, 127.1, 125.2, 119.9, 110.0, 86.5, 77.2, 70.8,
4.11. Synthesis of p-methylphenyl-2,4-di-O-benzoyl-6-O-tertbuty-

7
69.6, 67.5, 63.2, 57.8, 46.9, 21.4. ESI-MS: calcd for C49H4 NO9S
pyranoside 22
ACCEPTED MANUSCRIPT
2
[M+H]+ 820.2502, found: 820.2541.
Compound 21 (89.0 mg, 0.14 mmol) was dissolved in a
mixture solution of 5 mL acetone and 0.5 mL H2O. Then NBS
(76.0 mg, 0.43 mmol) was added. After stirring overnight, the
solution was diluted with CH2Cl2 and washed with saturated
NaHCO3 , brine, dried over Na2SO4. The concentrate was purified
by column chromatography (PE : EtOAc = 10: 1) to give
compound 22 (64.0 mg, 85%). 1H NMR(CDCl3, 400 MHz) δ 8.09
(t, J = 7.6 Hz, 4H), 8.01 (t, J = 7.6 Hz, 2H), 7.60 (t, J = 7.6 Hz,
2H), 7.53 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 7.6 Hz, 4H), 7.38 (t, J =
7.6 Hz, 2H), 5.68 (1H, dd, J1 = 4.0 Hz, J2 = 3.6 Hz ,H-1), 5.40 (t,
J = 10.0 Hz, 1H, H-4), 5.05 (dd, J1 = 10.4 Hz, J2 = 4.0 Hz, 1H,
H-2), 4.53-4.62 (m, 2H, H-6a, H-5), 4.44 (t, J = 10.4 Hz, H-3),
4.36 (dd, J1 = 4.0 Hz, J2 = 12.4, H-6b), 3.43 (d, J = 3.6, 1H, 1-
OH). 13C NMR(CDCl3, 100MHz) δ 166.5, 165.8, 165.2, 133.9,
133.4, 130.2, 130.0, 129.7, 129.1, 129.1, 128.8, 128.6, 90.0, 72.9,
69.65, 67.9, 63.0, 61.5. ESI-MS: calcd for C27H23N3NaO8[M +
Na]+ 540.1485. found: 540.1377.
4.14. Synthesis of p-methylphenyl-3-azido-3-deoxy-2,4-di-O-be-
nzoyl-6-O-tert-butyldiphenylsilyl-1-thio-β-D-gluco-pyranoside
19
To a solution of compound 10 (206.0 mg, 0.40 mmol ) in 3
mL pyridine under argon was added BzCl (160.0 mg, 1.10
mmol). After stirring for 6 hours. The solution was concentrated
and diluted with CH2Cl2. The diluent was washed with saturated
NaHCO3 and brine, dried over Na2SO4. The concentrate was
purified by column chromatography (PE : EtOAc = 10 : 1) to
1
give compound 19 (244.2 mg, 86%). H NMR (CDCl3, 400
MHz) δ 8.12 (d, J = 8.0Hz, 2H), 7.99 (d, J = 7.6 Hz, 2H), 7.70 (d,
J = 8.0 Hz, 2H), 7.61 (m, 4H), 7.48 (m, 6H), 7.37 (t, J = 7.2 Hz,
1H), 7.31 (t, J = 7.2 Hz, 3H), 7.19 (t, J = 7.2 Hz, 2H), 7.05 (d, J =
8.0 Hz, 1H), 5.37(dd, J1, J2 = 10.0 Hz, 9.6 Hz, 1H, H-2), 5.22
(dd, J1, J2 = 10.0 Hz, 9.6 Hz , 1H, H-4), 4.89 (d, J = 9.6 Hz, 1H,
H-1), 3.98 (dd, J1, J2 = 10.0 Hz, 9.6 Hz, 1H, H-5), 3.80 (m, 3H,
H-6a, H-6b, H-3), 2.32 (s, 3H), 1.04 (s, 9H). 13C NMR (CDCl3,
100 MHz) δ 165.1, 164.9, 138.7, 133.8, 133.7, 133.1, 133.1,
130.2, 130.1, 129.9, 129.8, 129.6, 129.3, 128.7, 128.5, 127.9,
127.8, 127.8, 86.9, 80.0, 71.1, 69.1, 66.7, 63.0, 26.9, 21.4, 19.4.
4.18. Synthesis of 2,4,6-tri-O-benzoyl- 3-dimethylamino-3-deoxy-
D-glucopyranoside 23
Compound 22 (200.0 mg, 0.40 mmol) was dissolved in 10 mL
acetic acid. Excessive Zn powder was added in batches. After
stirring for 2 hours, the reaction solution was filtered and the
filtrate was diluted with CH2Cl2 , washed with saturated NaHCO3
and brine, dried over Na2SO4. The concentrate was dissolved in 2
mL DMF with anhydrous sodium carbonate (43.0 mg, 0.40
mmol). Then, 0.5 mL CH3I was added. After stirring overnight,
the solution was washed with H2O and extracted with CH2Cl2,
organic layer was dried over Na2SO4. The concentrate was
purified by column chromatography (PE : EtOAc = 6 : 1 ) to give
ESI-MS: calcd for C43H44N3O6SSi [M+H]+
found:758.2619.
758.2642,
4.15. Synthesis of p-methylphenyl-3-azido-3-deoxy-2,4-di-O-be-
nzoyl-1-thio-β-D-glucopyranoside 20
0.2 mL concentrated hydrochloric acid was added to a
solution of compound 19 (120.0 mg, 0.16 mmol) in 1 mL MeOH.
After stirring for 10 hours, the solution was washe with saturated
NaHCO3 and brine, dried over Na2SO4. The concentrate was
purified by column chromatography (PE : EtOAc = 10 : 1) to
1
compound 23 (97 mg, 49%). H NMR(CDCl3, 400 MHz) δ 8.09
(t, J = 7.2 Hz, 2H), 8.03 (t, J = 7.2 Hz, 4H), 7.51-7.60 (m, 3H),
7.37-7.47 (m, 6H), 5.57 (1H, H-1), 5.42 (t, J = 9.6 Hz, 1H, H-4),
5.28 (1H, H-2), 4.53-4.62 (m, 2H, H-6a, H-5), 4.38 (dd, J1 = 4.0
Hz, J2 = 11.6, H-6b), 3.59 (t, J = 10.4 Hz, H-3), 3.35(1H, 1-OH),
2.40 (s, 6H, NMe2). 13C NMR(CDCl3, 100MHz) δ 166.6, 165.8,
165.6, 133.6, 133.3, 133.2, 130.2, 130.1, 130.1, 123.0, 129.9,
128.7, 128.6, 128.5, 90.7, 70.4, 68.6, 67.8, 63.8, 62.5, 41.5. ESI-
MS: calcd for C29H30NO8 [M + H]+ 520.1893, found: 520.1962.
1
give compound 20 (74.0 mg, 90%). H NMR (CDCl3, 400 MHz)
δ 8.10 (d, J = 7.2 Hz, 2H), 8.03 (d, J = 7.8 Hz, 2H), 7.62 (m, 2H),
7.49 ( m, 4H), 7.37 (d, J = 7.8 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H),
5.19 (d, J1 = 9.1 Hz, J2 = 8.7 Hz, 1H), 5.17 (d, J1 = 9.1 Hz, J2 =
8.7 Hz, 1H), 4.86 (d, J = 9.9 Hz, 1H, H-1), 4.05 (dd, J1, J2 = 9.9
Hz, 9.8 Hz, 1H), 3.79 (dd, J1, J2 = 9.9 Hz, 9.4 Hz, 1H), 3.70 (m,
2H), 2.34 (s, 3H). ESI-MS: calcd for C27H26N3O6S [M+H]+
520.1464, found: 520.1478.
4.19. Synthesis of 2,4,6-tri-O-benzoyl- 3-dimethylamino-3-deoxy-
D-glucopyranoside trichloroacetimidate 24
4.16. Synthesis of p-methylphenyl-3-azido-3-deoxy-2,4,6-tri-O-
benzoyl-1-thio-β-D-glucopyranoside 21
Compound 23 (98.0 mg, 0.19 mmol) was dissolved in 2 mL
anhydrous CH2Cl2 under argon at -10℃. Then CCl3CN (274.3
mg, 1.90 mmol) was injected in. After stirring for 20 minutes,
DBU (3.0 mg, 0.02 mmol) was injected in. Then reaction
solution was warmed to room temperature and stirred for 5 hours.
The reaction mixture was purified by column chromatography on
silica gel (deactivated by 15% Et3N/ PE) (PE : EtOAc = 20 : 1 )
Compound 20 (49.0 mg, 0.10 mmol) was dissolved in 1 mL
pyridine, then BzCl (20.0 mg, 0.14 mmol) was added. After
stirring for 1 hour, the solution was concentrated and diluted with
CH2Cl2. The diluent was washed with saturated NaHCO3 and
brine, dried over Na2SO4. The concentrate was purified by
column chromatography (PE : EtOAc = 20 : 1) to give compound
21(53.0 mg, 90%). 1H NMR (CDCl3, 400 MHz) δ 8.12 (d, J = 8.0
Hz, 2H), 8.02 (t, J = 7.2 Hz, 4H), 7.62 (t, J = 7.2 Hz, 1H),7.56 (t,
J = 7.6 Hz, 2H), 7.50 (t, J = 7.6 Hz, 2H), 7.43 (m, 4H), 7.36 (t, J
= 8.0 Hz, 2H), 6.91 (t, J = 8.0 Hz, 2H), 5.34 (dd, J1, J2 = 10.0 Hz,
1H, H-2), 5.20 (dd, J1, J2 = 10.0 Hz, 9.6 Hz, 1H, H-4), 4.88 (d, J1
= 10.0 Hz, 1H, H-1), 4.63 (m, 1H, H-6a), 4.34 (dd, J1, J2 = 12.0
Hz, 6.0 Hz,1H, H-6b), 4.05 (m, 2H), 2.25 (s, 3H). 13C NMR
(CDCl3, 100 MHz) δ 166.3, 165.1, 165.1, 138.9, 134.0, 133.8,
133.4, 130.2, 130.2, 130.1, 129.8, 129.4, 128.9, 128.8, 128.8,
128.6, 127.8, 86.7, 76.8, 70.9, 69.7, 66.5, 63.3, 21.4. ESI-MS:
calcd for C34H30N3O7S [M+H]+ 624.1726, found: 624.1780.
1
to give compound 24 (114.0 mg. 91%). H NMR(CDCl3, 400
MHz) δ 8.55 (s,1H,C=NH),8.05 (t, J = 7.6 Hz, 4H), 8.00 (t, J =
8.4 Hz, 2H), 7.58 (t, J = 7.6 Hz, 2H), 7.53 (d, J = 7.2 Hz, 1H),
7.44 (m, 6H), 6.67 (d, J = 3.6 Hz, 1H, H-1), 5.56 (dd, J1 = 3.6
Hz, J2 = 10.4, H-2), 5.51 (t, J = 10.4 Hz, 1H, H-4), 4.57 (1H, H-
6a), 4.51 (m, 1H, H-5), 4.40 (dd, J1 = 5.6 Hz, J2 = 12.0, H-6b),
3.62 (t, J = 10.4 Hz, H-3), 2.42 (s, 6H, NMe2).
4.20. Synthesis of 3-azido-3-deoxy-2,4,6-tri-O-benzoyl-D-gluco-
pyranoside trichloroacetimidate 27
Compound 22 (1.7 g, 3.40 mmol) was dissolved in 20 mL
anhydrous CH2Cl2 under argon at 0℃, CCl3CN (4.9 g, 0.03 mol)
was injected in. After stirring for 10 minuts, DBU (0.1 g, 0.7
mmol) was injected in. After stirring for 5 hours, the reaction
4.17. Synthesis of 3-azido-3-deoxy-2,4,6-tri-O-benzoyl-D-gluco-

8
Tetrahedron
ACCEPTED MANUSCRIPT
solution was purified by column chromatography on silica gel
129.6, 128.9, 128.8, 128.7, 128.6, 101.3, 77.1, 73.6, 70.7, 68.1,
(deactivated by 15% Et3N/ PE) (PE : EtOAc = 40 :1 ) to give
compound 27 (1.9 g, 86%). 1H NMR(CDCl3, 400 MHz) δ 8.65 (s,
1H), 8.08 (d, J = 8.0 Hz, 2H), 8.04 (d, J = 8.0 Hz, 2H), 8.01 (d, J
= 8.0 Hz, 2H), 7.38-7.61 (m, 9H), 6.73 (d, J = 3.6 Hz, 1H, H-1),
5.50 (dd, J1 = 10.4 Hz, J2 = 10.0 Hz, H-4), 5.37 (dd, J1 = 10.4 Hz,
J2 = 3.6 Hz, H-2), 4.58 (dd, J1 = 12.4 Hz, J2 = 2.4 Hz, H-6b), 4.51
(m, 1H, H-5), 4.44 (dd, J1 = 10.4 Hz, J2 = 10.0 Hz, H-3), 4.39
(dd, J1 = 10.4 Hz, J2 = 4.8 Hz, H-6a),
76.9, 63.7, 51.3, 49.7, 41.5, 38.2, 29.9, 28.6, 22.8, 20.1, 14.4,
13.6, 10.5. HRMS (ESI) [M+H]+ 1077.4586, calcd for
C59H69N2O17, 1077.4518
4.23. (E)-5-(6-O- benzoyl- 3-dimethylamino-3-deoxy
mycaminosy)
-3-O-descladinosyl-6-O-methyl-3-oxo-erythronolide A 9-O(benz-
oyl) oxime 11,12-cyclic carbonate 30
4.21. (E)-5-(3-azido-3-deoxy-2,4,6-tri-O-benzoyl-mycaminosy)-
3-O-descladinosyl-6-O-methyl-3-oxo-erythronolide A 9-O-(be-
Compound 29 (20.0 mg, 0.02 mmol) was dissolved in 2 mL
methanol under refluxing condition for two days. The reaction
solution was concentrated and purified by column
chromatography on silica gel (CHCl3 : MeOH = 200 : 1 ) to give
nzoyl) oxime 11,12-cyclic carbonate 28
1
the compound 30 (10.7 mg, 70%). H NMR(CDCl3, 400 MHz) δ
Compound 27 (515.0 mg, 0.78 mmol) and compound
erythronolide (193.0 mg, 0.34 mmol) were dissolved in 5 mL
anhydrous CH2Cl2 under argon at -20℃，TMSOTf (15.0 mg,
0.07 mmol) was injected in. Then the reaction solution was
warmed to room temperature and kept stirring for 12 hours.
Trimethylamine (6.8 mg, 0.07 mmol) was added in and stirred
for 20 minutes. Followed by filtration and purification by column
chromatography (PE : EtOAc = 5 : 1 ) to give compound 28
8.01 (d, J = 8.0 Hz, 2H), 7.97(d, J = 8.0 Hz, 2H), 7.59(t, J = 7.2
Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.2 Hz, 2H), 7.34 (t,
J = 7.2 Hz, 2H), 5.06 (d, J = 8.4 Hz, 1H, H-13), 4.83 (s, 1H, H-
11), 4.66 (dd, J1 = 12.0 Hz, J2 = 6.4 Hz, H-6a′), 4.57 (d, J = 11.6
Hz, H-6b′), 4.46 (d, J = 7.2 Hz, 1H, H-1′), 4.23(m, 1H),3.84 (m,
1H), 3.69 (m, 1H), 2.63 (s, 6H, 3′-NMe2), 2.51 (s, 3H, 6-OMe),
1.40 (t, J = 6.4 Hz, 6H), 1.35 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 7.2
Hz, 6H). 13C NMR(CDCl3, 100 MHz) δ 204.0, 175.5, 165.9,
165.0, 163.5, 153.6, 133.5, 130.0, 129.8, 129.7, 128.8, 128.7,
128.7, 103.3, 84.8, 77.4, 76.6, 75.0, 70.7, 66.9, 64.3, 51.3, 49.9,
47.2, 41.9, 38.4, 29.9, 22.6, 20.0, 18.9, 15.6, 14.6, 13.6, 10.6,
10.5. HRMS (ESI) [M+H]+ m/z 869.3999, calcd for C45H60N2O15,
869.3994.
1
(110.0 mg, 31%). H NMR(CDCl3, 400 MHz) δ 8.26 (d, J = 8.0
Hz, 2H), 8.05 (m, 5H), 7.60 (m, 3H), 7.46 (m, 10H), 5.37 (dd, J1
= 10.0 Hz, J2 = 9.6 Hz, 1H, H-4′), 5.30 (dd, J1 = 10.0 Hz, J2 = 8.0
Hz, 1H, H-2′), 5.02 (d, J = 9.6 Hz, 1H, H-13), 4.83 (d, J = 7.6
Hz, 1H, H-1′), 4.79 (s, 1H, H-11), 4.65 (d, J = 7.6 Hz, 1H, H-5),
4.40 (dd, J1 = 12.0 Hz, J2 = 6.8 Hz, H-6b), 4.20 (d, J = 7.6 Hz,
1H, H-2), 4.09 (m, 1H), 3.97 (dd, J1 = 10.0 Hz, J2 = 10.0 Hz, H-
3′), 3.69 (m, 1H), 2.51 (s, 3H, 6-OMe), 1.43(s, 3H), 1.38 (d, J =
6.8 Hz, 3H), 1.32 (d, J = 6.8 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H),
0.99 (d, J = 7.6 Hz, 3H), 0.84 (t, J = 7.6 Hz, 3H). 13C
NMR(CDCl3, 100MHz) δ 203.6, 168.9, 166.1, 165.1, 164.6,
164.6, 153.8, 134.0, 133.8, 133.4, 133.4, 130.5, 130.1, 130.0,
129.9, 129.5, 129.2, 128.8, 128.7, 128.7, 128.6, 100.7, 85.4, 81.2,
79.6, 78.4, 77.4, 76.7, 73.1, 72.2, 69.8, 65.2, 62.9, 51.4, 49.2,
46.9, 38.0, 35.7, 33.8, 22.8, 19.5, 19.1, 15.5, 14.2, 13.9, 11.6,
10.5. HRMS (ESI) [M+H]+ 1075.4188, calcd for C57H63N4O17,
1075.4110.
4.24. Synthesis of p-methylphenyl-6-O-acetyl-3-azido-3-deoxy-
2,4-di-O-benzoyl-1-thio-β-D-glucopyranoside 31a
Compound 31a (912.9mg, 87%) was obtained from compound
20 (971.0 mg, 1.87 mmol) with Ac2O (385.0mg, 3.74 mmol) in
pyridine as the method for 21 via column chromatography on
1
silica gel (PE : EtOAc =50 : 1). H NMR(CDCl3, 400 MHz): δ
8.10 (d, J = 7.6 Hz, 2H), 8.03 (d, J = 7.6 Hz, 2H), 7.52 (m, 2H),
7.48 (m, 4H), 7.38 (d, J1 = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H),
5.26 (t, J = 10.0 Hz, 1H, H-4), 5.19 (dd, J1 = 10.0 Hz, J2 = 9.6
Hz, 1H, H-2), 4.84 (d, J = 9.6 Hz, 1H, H-1), 4.25 (m, 2H, H-6a,
H-6b), 4.00 (dd, J1 = 10.0 Hz, J2 = 9.6 Hz, H-3), 3.91 (m, 1H, H-
5), 2.35 (s, 3H,1-STol), 2.03 (s, 3H, 6-OAc). 13C NMR (CDCl3,
100 MHz) δ 170.8, 165.1, 165.1, 139.0, 134.0, 133.8, 130.2,
130.1, 129.9, 129.4, 128.9, 128.8, 128.8, 128.1, 86.9, 76.7, 70.9,
69.5, 66.4, 62.9, 21.4, 20.9. ESI-MS: calcd for C29H28N3O7S[M +
H]+ 562.1570, found: 562.1688.
4.22. (E)-5-(2,4,6-tri-O-benzoyl- 3-dimethylamino-3-deoxy myc-
aminosy)-3-O-descladinosyl-6-O-methyl-3-oxo-erythronolide A
9-O-(benzoyl) oxime 11,12-cyclic carbonate 29
Compound 28 (60.0 mg, 0.06 mmol) was dissolved in 2 mL
methanol, Lindlar catalyst (100 mg) was added in for
hydrogenation under atmospheric pressure. After compound 28
was reacted completely, the catalyst was filtered and the filtrate
was concentrated. Then concentrate was dissolved in 2 mL DMF
with Na2CO3 (10.0 mg, 0.09 mmol). After stirring for 10 minutes,
0.5 mL CH3I was added in and kept stirring for 10 hours. The
reaction solution was diluted with CH2Cl2 and washed with H2O,
the organic phase was concentrated and purified by column
chromatography on silica gel(CHCl3 : PE : MeOH = 500 : 500 : 1
4.25. Synthesis of p-methylphenyl-3-azido-3-deoxy-2,4-di-O-ben-
zoyl-6-O-benzyl-1-thio-β-D-glucopyranoside 31b
Ag2O (1.3 g, 5.54 mmol) was added in a solution of
compound 20 (957.0 mg, 1.84 mmol) in 7 mL DMF. Then BnBr
(946.0 mg, 5.54 mmol) was added in and kept stirring for 10
hours. The reaction solution was filtered and filtrate was diluted
with CH2Cl2, the diluent was washed with H2O and the organic
layer was concentrated and purified by column chromatography
on silica gel(PE : EtOAc = 20 : 1) to give the compound 31b
1
) to give the compound 29 (32.0 mg, 50%). H NMR(CDCl3, 400
MHz) δ 7.95-8.04 (m, 8H), 7.60 (m, 3H), 7.46 (m, 7H), 7.32 (t, J
= 7.6 Hz, 2H), 5.35 (dd, J1 = 9.6 Hz, J2 = 9.6 Hz, 1H, H-4′), 5.30
(dd, J1 = 9.6 Hz, J2 = 8.0 Hz, 1H, H-2′), 5.06 (dd, J = 10.0 Hz,
2.4 Hz, 1H, H-13), 4.84 (s, 1H, H-11), 4.80 (d, J = 8.0 Hz, 1H,
H-1′), 4.49 (m, 2H), 4.24 (d, J = 7.6 Hz, 1H, H-2), 4.08 (m, 1H),
3.72 (m, 1H), 3.22 (dd, J1 = 10.0 Hz, J2 = 10.0 Hz, H-3′), 2.44 (s,
3H, 6-OMe), 2.36 (s, 6H, 3′-NMe2), 1.39 (d, J = 6.8 Hz, 3H),
1.32 (d, J = 6.8 Hz, 3H), 1.30 (s, 3H), 1.10 (d, J = 6.8 Hz, 3H),
0.96 (d, J = 7.8 Hz, 3H), 0.84 (t, J = 7.2 Hz, 3H). 13C
NMR(CDCl3, 100 MHz) δ 175.2, 169.2, 166.2, 165.4, 164.8,
163.7, 153.8, 133.6, 133.4, 133.5, 130.2, 130.0, 129.9, 129.8,
1
(818.0 mg, 73%). H NMR(CDCl3, 400 MHz) δ 8.11 (d, J = 8.0
Hz, 2H), 8.01 (d, J = 8.0 Hz, 2H), 7.63 (t, J = 7.2 Hz, 2H), 7.50
(m, 4H), 7.33 (m, 7H), 6.90 (d, J = 7.6 Hz, 2H), 5.07 (dd, J1 =
10.0 Hz, J2 = 9.6 Hz, H-4), 4.86 (d, J = 10.4 Hz, 1H, 6-OCH2Ph),
4.73 (dd, J1 = 10.4 Hz, J2 = 9.2 Hz, H-2), 4.70 (d, J = 10.4 Hz,
1H, H-1), 4.64 (d, J = 10.4 Hz, 1H, 6-OCH2Ph), 4.42 (dd, J1 =
12.0 Hz, J2 = 4.8 Hz, H-6a), 3.84 (dd, J1 = 9.6 Hz, J2 = 9.2 Hz,
1H), 3.74 (m, 1H), 3.60 (dd, J1 = 10.0 Hz, J2 = 9.2 Hz, 1H), 2.25
(s, 3H). 13C NMR(CDCl3, 100 MHz) δ 166.2, 165.3, 138.7, 136.9,
134.2, 133.8, 133.5, 130.2, 130.0, 129.8, 128.8, 128.8, 128.7,

9
128.7, 128.6, 127.8, 86.3, 77.9, 76.4, 75.5, 70.9, 69.0, 63.3, 21.4.
ACCEPTED MANUSCRIPT
ESI-MS: calcd for C34H32N3O6S [M+H]+ 610.1934, found:
610.2010.
4.30. (E)-5-(6-O-acetyl-3-azido-3-deoxy-2,4-di-O-benzoyl-
mycaminosy)-3-O-descladinosyl-6-O-methyl-3-oxo-erythronolide
4.26. Synthesis of p-methylphenyl -3-azido-3-deoxy-2,4-di-O-
benzoyl-6-O-methyl 1-thio-β-D-glucopyranoside 31c
A 9-O-(benzoyl) oxime 11,12-cyclic carbonate 34a
Compound 34a (193.7 mg, 58%) was coupled by the donor
33a (400.0 mg, 0.69 mmol) and the acceptor erythronolide (192.0
mg，0.33 mmol) with the promoter TMSOTf (22.3 mg，0.10
mmol) as the procedure for compound 28. The crude product was
purified by column chromatography on silica gel (CHCl3 : PE :
Compound 31c (727.8 mg, 70%) was obtained from compound
20 (1.0 g, 1.95 mmol) with MeI (830.7 mg， 5.85 mmol) and
Ag2O (1.4 g， 5.85 mmol) as the method for compound 31b via
1
column chromatography on silica gel (PE : EtOAc = 50 : 1). H
1
NMR(CDCl3, 400 MHz) δ 8.10 (d, J = 7.6 Hz, 2H), 8.06 (d, J =
7.6 Hz, 2H), 7.62 (m, 2H), 7.50 (t, J = 7.6 Hz, 4H), 7.32 (d, J =
7.6 Hz, 2H), 6.91 (d, J = 7.6 Hz, 2H), 5.02 (t, J = 10.0 Hz, 1H,
H-4), 4.75 (dd, J1 = 11.2 Hz, J2 = 10.0 Hz, 1H, H-2), 4.72 (d, J =
10.0 Hz, 1H, H-1), 4.50 (dd, J1 = 12.0 Hz, J2 = 5.6 Hz, 1H, H-
6a), 3.75 (m, 2H), 3.59 (s, 3H, 6-OMe), 3.31 (dd, J1 = 10.0 Hz, J2
= 9.2 Hz, 1H, H-3), 2.25 (s, 3H,1-STol). 13C NMR(CDCl3, 100
MHz) δ 166.4, 165.3, 138.7, 134.1, 133.7, 133.5, 130.2, 130.0,
129.9, 129.8, 129.6, 128.8, 128.7, 127.8, 86.4, 79.0, 78.0, 77.6,
77.3, 76.9, 70.7, 68.5, 63.4, 61.1, 29.9, 21.4. ESI-MS: calcd for
C28H28N3O6S [M+H]+ 534.1621, found: 534.1731.
MeOH = 250 : 250 : 1). H NMR(CDCl3, 400 MHz) δ 8.03 (m,
6H), 7.61 (t, J = 7.6 Hz, 3H), 7.47 (m, 6H), 5.24 (t, J = 10.0 Hz,
2H, H-4′, H-2′), 5.08 (d, J = 9.2 Hz, 1H, H-13), 4.87 (s, 1H, H-
11), 4.81 (d, J = 8.0 Hz, 1H, H-1′), 4.25 (m, 2H, H-6′), 4.21 (d, J
= 5.2 Hz, 1H, H-2), 3.93 (m, 2H, H-3′, H-5′), 3.75 (m, 1H), 2.74
(s, 3H, 6-OMe), 1.94 (s, 3H, 6′-OAc), 1.33 (d, J = 6.4 Hz, 3H),
0.97 (d, J = 7.2 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H). 13C
NMR(CDCl3, 100 MHz) δ 170.6, 169.2, 165.2, 164.6, 163.8,
153.8, 134.1, 133.9, 133.4, 130.1, 130.0, 129.7, 129.5, 129.2,
128.9, 128.9, 128.8, 100.4, 77.5, 77.2, 72.9, 72.2, 69.8, 65.1,
62.6, 51.4, 50.1, 38.3, 28.6, 27.1, 22.8, 20.8, 19.9, 14.4, 13.6,
10.5. HRMS (ESI) [M+H]+ 1013.3992, calcd for C52H61N4O17,
1013.3954.
4.27. Synthesis of 6-acetyl-3-azido-3-deoxy-2,4-di-O-benzoyl-D-
glucopyranoside trichloroacetimidate 33a
4.31. (E)-5-(3-azido-3-deoxy-2,4-di- O-benzoyl-6- O-benzyl myc-
aminosy)-3-O-descladinosyl-6-O-methyl-3-oxo-erythronolide A
9-O-(benzoyl) oxime 11,12-cyclic carbonate 34b
Compound 33a was obtained as the method for compound 27 in
a yield of 58% for two steps. H NMR(CDCl3, 400 MHz) δ 8.68
1
(s, 1H, -NH), 8.08 (d, J = 7.6 Hz, 2H), 8.03 (d, J = 7.6 Hz,
2H),7.61 (m, 2H), 7.46 (m, 4H), 6.71 (d, J = 3.2 Hz, 1H, H-1),
5.41 (t, J = 10.0 Hz, 1H, H-4), 5.34 (dd, J1 = 10.8 Hz, J2 = 2.8
Hz, 1H, H-2), 4.39 (t, J = 10.0 Hz, 1H, H-3), 4.36 (m, 1H, H-5),
4.23 (m, 2H), 2.03 (s, 3H, 6-OAc). 13C NMR (100 MHz, CDCl3)
δ 170.8, 165.4, 165.1, 160.5, 134.1, 134.1, 130.2, 130.2, 130.1,
128.9, 128.8, 128.7, 92.8, 71.3, 70.5, 68.6, 62.1, 61.8.
Compound 34b (82.9 mg, 46%) was coupled by the donor 33
(217.0 mg, 0.33 mmol) and the acceptor erythronolide (96.0 mg,
0.17 mmol) with the promoter TMSOTf (7.5 mg, 0.03 mmol) as
the procedure for compound 28. The crude product was purified
by column chromatography on silica gel (CHCl3 : PE : MeOH =
1
500 : 500 : 1). H NMR(CDCl3, 400 MHz) δ 8.01 (d, J = 7.7 Hz,
2H), 7.97 (d, J = 6.7 Hz, 4H), 7.50 (m, 7H), 7.30 (m, 7H), 5.11
(dd, J1 = 9.2 Hz, J2 = 9.0 Hz, H-2′), 5.04 (dd, J1 = 10.1 Hz, J2 =
2.8 Hz, H-13), 4.90 (d, J = 10.8 Hz, 1H, H-6′-OCH2Ph), 4.81 (s,
1H, H-11), 4.71 (d, J = 8.0 Hz, H-1′), 4.66 (d, J = 10.8 Hz, 1H,
H-6′-OCH2Ph), 4.62 (d, J = 11.4 Hz, 1H, H-6′), 4.47 (dd, J1 =
11.4 Hz, J2 = 6.3 Hz, H-6′), 4.18 (d, J = 6.2 Hz, 1H, H-2), 3.84
(m, 1H), 3.80 (dd, J1 = 9.8 Hz, J2 = 9.2 Hz, 1H), 3.72 (m, 1H),
3.54 (dd, J1 = 9.5 Hz, J2 = 9.4 Hz, 1H), 2.93 (t, J = 7.2 Hz, 1H),
2.47 (s, 3H, H-6-OMe), 1.37 (d, J = 6.8 Hz, 3H), 1.31 (d, J = 6.8
Hz, 3H), 1.23 (s, 3H), 1.06 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 7.6
Hz, 3H), 0.85 (t, J = 7.6 Hz, 3H). 13C NMR(CDCl3, 100 MHz) δ
204.5, 169.2, 166.2, 164.9, 163.7, 153.8, 150.0, 136.9, 136.2,
133.8, 133.6, 133.3, 130.0, 129.8, 129.6, 129.3, 128.9, 128.8,
128.8, 128.7, 128.7, 124.0, 100.2, 78.0, 77.5, 77.0, 75.4, 74.2,
72.4, 67.6, 63.0, 51.3, 49.8, 38.1, 29.9, 28.6, 22.7, 19.9, 15.7,
14.4, 13.6, 10.5. HRMS (ESI) [M+H]+ 1061.4366, calcd for
C57H65N4O16, 1061.4317.
4.28. Synthesis of 3-azido-3-deoxy-2,4-di- O-benzoyl-6-O-benzyl-
β-D-Glucopyranoside trichloroacetimidate 33b
Compound 32 (400.0 mg, 82%) was obtained from compound
31 (594.0 mg, 0.97 mmol) as the procedure for compound 22 via
column chromatography on silica gel(PE : EtOAc =10 : 1) and
was for next step directly. Compound 33 (350.0 mg, 77%) was
formed from compound 32 (350.0 mg, 0.70 mmol) following the
way for compound 27. The crude product was purified by
column chromatography on silica gel (Ethyl acetate : PE =1 : 20).
1H NMR(CDCl3, 400 MHz): δ 8.60 (s, 1H, C = NH), 8.07 (d, J =
8.0 Hz, 2H), 8.04 (d, J = 8.0 Hz, 2H), 7.60 (t, J = 7.2 Hz, 2H),
7.48 (m, 4H), 7.37 (m, 4H), 7.28 ( d, J = 7.2 Hz, 1H), 6.65 (d, J =
3.6 Hz, 1H, H-1), 5.27 (dd, J1 = 10.0 Hz, J2 = 3.6 Hz, H-2), 4.93
(d, J = 10.5 Hz, 1H, 6-OCH2Ph), 4.68 (d, J = 10.5 Hz, 1H, 6-
OCH2Ph), 4.58 (m, 2H), 4.31 (m, 2H), 3.74 (dd, J1 = 9.8 Hz, J2 =
9.8 Hz, 1H, H-3). 13C NMR(CDCl3, 100 MHz) δ 166.2, 165.6,
160.8, 136.8, 134.0, 133.5, 130.2, 130.0, 129.9, 128.9, 128.8,
128.7, 93.0, 75.8, 75.8, 71.8, 71.4, 64.3, 62.7.
4.32. (E)-5-(3-azido-3-deoxy-2,4-di-O-benzoyl-6-O-methylmy-
caminosy)-3-O-descladinosyl-6-O-methyl-3-oxo-erythronolide A
9-O-(benzoyl) oxime 11,12-cyclic carbonate 34c
4.29. Synthesis of 3-azido-3-deoxy-2,4-di-O-benzoyl-6-O-methyl-
Compound 34c (254.3 mg, 68%) was coupled by the donor
33c (452.0 mg， 0.75 mmol) and the acceptor erythronolide
(227.0 mg， 0.38 mmol) with the promoter TMSOTf (16.7 mg，
0.07 mmol) as the procedure for compound 28. The crude
product was purified by column chromatography on silica gel
D-glucopyranoside trichloroacetimidate 33c
Compound 33c was obtained as the method for compound 27
in a yield of 60% for two steps. 1H NMR(CDCl3, 400 MHz) δ
8.06 (s, 1H, -NH), 8.07 (d, J = 7.6 Hz, 4H), 7.59 (t, J = 7.6 Hz,
2H), 7.47 (m, 4H), 6.10 (d, J = 3.2 Hz, 1H, H-1), 5.20 (dd, J1 =
10.8 Hz, J2 = 3.2 Hz, 1H, H-2), 4.62 (t, J = 11.2 Hz, 1H, H-4),
4.55 (m, 1H, H-6a), 4.20 (m, 2H), 3.64 (s, 3H, 6-OMe), 3.45 (t, J
= 9.6 Hz, 1H, H-3). 13C NMR(CDCl3, 100 MHz) δ 166.3, 165.5,
160.6, 133.9, 133.5, 130.2, 130.1, 129.9, 129.8, 128.9, 128.9,
128.8, 128.7, 93.0, 78.4, 77.6, 77.3, 77.0, 71.8, 71.1, 63.8, 62.8,
61.3, 27.1.
1
(CHCl3 : PE : Methanol = 250 : 250 : 1). H NMR(CDCl3, 400
MHz): δ 8.00 (m, 6H), 7.61 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 7.6
Hz, 2H), 7.46 (m, 4H), 7.38 (t, J = 7.6 Hz, 2H), 5.06 (dd, J1 =
10.0 Hz, J2 = 8.8 Hz, 2H, H-2′, H-13), 4.82 (s, 1H, H-11), 4.70
(d, J = 7.6 Hz, 1H, H-1′), 4.68 (t, J = 10.0 Hz, 1H, H-4′), 4.54
(dd, J1 = 12.0 Hz, J2 = 6.8 Hz, 1H, H-6a′), 4.20 (d, J = 6.0 Hz,

10
Tetrahedron
4.36. (E)-5-(6-O- acetyl- 3-dimethylamino-3-deoxy mycaminosy)-
1H, H-2), 3.79 (m, 1H), 3.71 (m, 2H), 3.62 (s, 3H, 6′-OMe),
ACCEPTED MANUSCRIPT
3-O-descladinosyl-6-O-methyl-3-oxo-erythronolide A 9-O-(ben-
zoyl) oxime 11,12-cyclic carbonate 36a
3.28 (t, J1 = 9.6 Hz, 1H, H-3′), 2.94(m, 1H), 2.48 (s, 3H, 6-OMe),
1.38 (d, J = 6.4 Hz, 3H), 1.33 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 7.6
Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H). HRMS (ESI) [M+H]+
985.4044, calcd for C51H61N4O16, 985.4004.
Compound 36a was obtained as the method for compound 30
in a yield of 44%. H NMR(CDCl3, 400 MHz) δ 8.04 (d, J = 8.0
1
4.33. (E)-5-(6-O-acetyl-2,4-di-O-benzoyl- 3-dimethylamino-3-
deoxy mycaminosy)-3-O-descladinosyl-6-O-methyl-3-oxo-ery-
Hz, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 5.11 (d,
J = 8.8 Hz, 1H, H-13), 4.86 (s, 1H, H-11), 4.37 (d, J = 7.6 Hz, 1H,
H-1′), 4.32 (m, 2H, H-6′), 4.25 (d, J = 6.8 Hz, 1H, H-2), 3.84 (m,
1H), 3.46 (m, 1H), 3.39 (m, 1H), 3.32 (t, J = 9.6 Hz, 1H), 3.06 (t,
J = 10.0 Hz, 1H), 2.75 (s, 3H, 6-OMe), 2.51 (s, 6H, 3′-NMe2),
2.03 (s, 3H, 6′-OAc), 1.44 (d, J = 6.8 Hz, 3H), 1.36 (d, J = 8.0 Hz,
3H), 1.35 (s, 3H), 0.90 (t, J = 7.6 Hz, 3H). 13C NMR(CDCl3, 100
MHz) δ 203.9, 175.3, 171.4, 169.0, 163.6, 153.6, 133.2, 129.5,
129.3, 128.6, 103.3, 75.4, 70.5, 70.2, 66.1, 63.5, 51.2, 41.7, 38.5,
29.7, 28.6, 22.7, 20.8, 19.7, 14.5, 13.4, 10.4. HRMS (ESI)
[M+H]+ 807.3827, calcd for C40H59N2O15, 807.3837.
thronolide A 9-O-(benzoyl) oxime 11,12-cyclic carbonate 35a.
Compound 35a was obtained as the method for compound 29
in a yield of 70% for two steps.1H NMR(CDCl3, 400 MHz) δ 8.03
(m, 6H), 7.58 (t, J = 7.2 Hz, 3H), 7.51 (t, J = 7.2 Hz, 1H), 7.46
(m, 5H), 5.28 (t, J = 9.2 Hz, 2H, H-4′, H-2′), 5.08 (d, J = 8.8 Hz,
1H, H-13), 4.87 (s, 1H, H-11), 4.74 (d, J = 7.6 Hz, 1H, H-1′),
4.25 (d, J = 6.4 Hz, 1H, H-2), 4.21 (m, 2H, H-6′), 3.86 (m, 1H),
3.74 (m, 1H), 3.17 (t, J = 10.0 Hz, 1H, H-3′), 2.74 (s, 3H, 6-
OMe), 2.34 (s, 6H, 3′-NMe2), 1.94 (s, 3H, 6′-OAc), 1.33 (d, J =
6.4 Hz, 3H), 0.94 (d, J = 7.2 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H).
HRMS (ESI) [M+H]+ 1015.4381, calcd for C54H67N2O17,
1015.4361.
4.37. (E)-5-(6- O-benzyl- 3-dimethylamino-3-deoxy mycamino-
sy)-3-O-descladinosyl-6-O-methyl-3-oxo-erythronolide A 9-O-
(benzoyl) oxime 11,12-cyclic carbonate 36b
Compound 36b (15.6 mg, 62%) was yielded from the
compound 35 (30.0 mg, 0.03 mmol) in methanol under refluxing
condition. The crude product was purified by column
4.34. (E)-5-(2,4- O-di-benzoyl-6- O-benzyl- 3-dimethylamino-3-
deoxy mycaminosy)-3-O-descladinosyl-6-O-methyl-3-oxo-eryt-
1
chromatography on silica gel (CHCl3 : MeOH = 100 : 3). H
hronolide A 9-O-(benzoyl) oxime 11,12-cyclic carbonate 35b
NMR(CDCl3, 600 MHz) δ 8.11 (dd, J1 = 8.2 Hz, J2 = 1.3 Hz,
2H), 7.59 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.9 Hz, 2H), 7.36 (m,
5H), 5.07 (dd, J1 = 10.2 Hz, J2 = 2.7 Hz, H-13), 4.80 (s, 1H, H-
11), 4.79 (d, J = 11.1 Hz, 1H, H-6′-OCH2Ph), 4.70 (d, J = 11.8
Hz, 1H, H-6′), 4.62 (d, J = 11.1 Hz, 1H, H-6′-OCH2Ph), 4.52 (dd,
J1 = 11.7 Hz, J2 = 6.8 Hz, H-6′), 4.47 (d, J = 7.4 Hz, 1H, H-1′),
3.85 (m, 1H), 3.78 (m, 1H), 3.07 (t, J = 7.7 Hz, 1H), 2.60 (s, 6H,
H-3′- NMe2), 2.52 (s, 3H, H-6-OMe), 1.39 (d, J = 6.8 Hz, 3H),
1.25 (d, J = 6.9 Hz, 3H), 1.00 (d, J = 7.0 Hz, 3H), 0.92 (t, J = 7.4
Hz, 6H). 13C NMR(CDCl3, 150 MHz) δ 203.9, 169.1, 166.2,
165.5, 154.0, 133.3, 129.8, 129.7, 128.6, 128.5, 128.1, 127.8,
103.1, 84.6, 82.9, 79.1, 78.1, 76.4, 75.0, 74.6, 73.4, 69.5, 63.5,
51.1, 49.6, 47.3, 38.1, 29.7, 25.2, 22.7, 22.4, 19.7, 18.7, 15.5,
15.4, 14.2, 14.1, 13.2, 10.3. HRMS (ESI) [M+H]+ 855.4219,
calcd for C45H63N2O14, 855.4201.
Compound 35b (36.8 mg, 50%) was obtained from compound
34 (80.0 mg, 0.07 mmol) as the method for compound 29 via
column chromatography on silica gel (CHCl3 : PE : MeOH= 500
: 500 : 1). 1H NMR(CDCl3, 400 MHz) δ 8.03(m, 6H), 7.59 (dd, J1
= 8.0 Hz, J2 = 7.6 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.44 (dd, J1 =
8.0 Hz, J2 = 7.6 Hz, 4H), 7.32 (m, 7H), 5.25 (dd, J1 = 8.1 Hz, J2 =
7.6 Hz, H-2’), 5.03 (dd, J1 = 10.2 Hz, J2 = 2.9 Hz, H-13), 4.92 (d,
J = 10.7 Hz, 1H, H-6′-OCH2Ph), 4.82 (s, 1H, H-11), 4.59-4.64
(m, 3H, H-1′, H-6′-OCH2Ph, H-6′), 4.51 (dd, J1 = 11.1 Hz, J2 =
7.1 Hz, H-6′), 4.17 (d, J = 6.4 Hz, 1H, H-2), 3.82 (dd, J1 = 8.7
Hz, J2 = 7.5 Hz, 1H), 3.70 (dd, J1 = 7.4 Hz, J2 = 7.4 Hz, 2H), 3.48
(dd, J1 = 9.6 Hz, J2 = 9.5 Hz, 1H), 3.12 (dd, J1 = 10.0 Hz, J2 =
10.0 Hz, 1H), 2.90 (t, J = 7.3 Hz, 1H), 2.47 (s, 6H, H-3′- NMe2),
2.39 (s, 3H, H-6-OMe), 1.37 (d, J = 6.7 Hz, 3H), 1.30 (d, J = 6.8
Hz, 3H), 1.23 (s, 3H). 13C NMR(CDCl3, 100 MHz) δ 204.3,
169.2, 166.4, 164.9, 163.8, 153.9, 149.7, 138.1, 133.4, 133.3,
129.9, 129.7, 129.6, 128.8, 128.7, 128.7, 128.3, 128.2, 101.3,
82.2, 78.1, 77.4, 74.7, 74.6, 74.3, 70.9, 69.9, 64.0, 51.3, 49.7,
46.4, 41.7, 38.1, 31.8, 28.6, 27.1, 22.9, 20.0, 19.0, 15.7, 14.3,
13.5, 10.5. HRMS (ESI) [M+H]+ 1063.4768, calcd for
C59H71N2O16, 1063.4725.
4.38. (E)-5-(3-dimethylamino-3-deoxy-6- O-methylmycaminosy)-
3-O-descladinosyl-6-O-methyl-3-oxo-erythronolide A 9-O-(ben-
zoyl) oxime 11,12-cyclic carbonate 36c
Compound 36c was obtained as the method for compound 30
1
in a yield of 35%. H NMR(CDCl3 , 400 MHz) δ 7.80 (m, 4H),
7.55 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6
Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 5.07 (d, J = 9.2 Hz, 1H, H-13),
4.82 (s, 1H, H-11), 4.58 (d, J = 11.6 Hz, 1H, H-6b′), 4.51 (t, J =
11.2 Hz, 1H, H-4′), 4.43 (d, J = 7.2 Hz, 1H, H-1′), 4.20 (d, J =
6.0 Hz, 1H, H-2), 3.83 (m, 1H), 3.68 (m, 1H), 3.49 (s, 3H, 6′-
OMe), 3.32 (t, J = 9.6 Hz, 1H), 3.20 (t, J = 8.4 Hz, 1H), 3.04(m,
1H), 2.52 (s, 6H, 3′-NMe2), 2.44 (s, 3H, 6-OMe), 1.40 (d, J = 7.6
Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H), 1.28 (d, J = 7.6 Hz, 3H), 1.08
(d, J = 6.0 Hz, 3H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR(CDCl3,
100 MHz) δ 204.3, 175.4, 169.3, 166.4, 163.8, 153.9, 133.5,
133.3, 129.9, 129.7, 129.7, 129.5, 128.8, 128.7, 103.2, 82.1, 78.1,
75.2, 70.5, 69.6, 63.6, 59.2, 51.4, 49.9, 47.1, 41.8, 38.6, 29.9,
28.7, 22.8, 20.1, 19.1, 15.7, 14.4, 13.6, 10.6. HRMS (ESI)
[M+H]+ 779.3890, calcd for C39H59N2O14, 779.3888.
4.35. (E)-5-(2,4-di-O-benzoyl-3-dimethylamino-3-deoxy-6-O-
methyl mycaminosy)-3-O-descladinosyl-6-O-methyl-3-oxoery-
thronolide A 9-O-(benzoyl) oxime 11,12-cyclic carbonate 35c
Compound 35c was obtained as the method for compound 29
in a yield of 71% for two steps. 1H NMR(CDCl3, 400 MHz): δ
8.00 (t, J1 = 7.6 Hz, 6H), 7.57 (m, 2H), 7.46 (m, 5H), 7.37 (t, J1 =
7.6 Hz, 2H), 5.18 (dd, J1 = 9.6 Hz, J2 = 8.8 Hz, 1H, H-2′), 5.04 (d,
J = 9.6 Hz, 1H, H-13), 4.82 (s, 1H, H-11), 4.64 (m, 2H, H-4′, H-
6b′), 4.57 (d, J = 7.2 Hz, 1H, H-1′), 4.19 (d, J = 6.0 Hz, 1H, H-2),
4.11 (dd, J1 = 12.0 Hz, J2 = 6.8 Hz, 1H, H-6a′),3.71 (m, 2H), 3.54
(s, 3H, 6′-OMe), 3.23 (t, J = 9.6 Hz, 1H, H-3′), 2.93(m, 2H), 2.44
(s, 6H, 3′-NMe2), 2.42 (s, 3H, 6-OMe), 1.39 (d, J = 6.8 Hz, 3H),
1.32 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 7.6 Hz, 3H), 0.86 (t, J = 7.2
Hz, 3H). HRMS (ESI) [M+H]+ 987.4437, calcd for C53H67N2O16,
987.4412.
4.39. (E)-5-(3-dimethylamino-3-deoxy mycaminosy)-3-O-descla-

11
dinosyl-6-O-methyl-3-oxo-erythronolide A 9-O-(benzoyl) oxime
11,12-cyclic carbonate 37a
saturated NaHCO3. The organic phase was concentrated and
ACCEPTED MANUSCRIPT
purified by column chromatography on silica gel (PE : EtOAc =
40 : 1) to form compound 39 (1.3 g, 71%). H NMR(CDCl3, 400
1
Compound 37a was obtained as the method for compound 30
in a yield of 40%.1H NMR(CDCl3, 400 MHz) δ 8.04 (d, J1 = 8.0
Hz, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 5.11 (d,
J = 8.8 Hz, 1H, H-13), 4.86 (s, 1H, H-11), 4.46 (d, J = 7.2 Hz, 1H,
H-1′), 4.25 (d, J = 6.8 Hz, 1H, H-2), 3.86 (m, 2H, H-6′), 3.60 (t, J
= 9.6 Hz, 1H), 3.40 (m, 2H), 3.07 (m, 1H), 2.76 (s, 3H, 6-OMe),
2.59 (s, 6H, 3′-NMe2), 1.42 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 7.6
Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H). 13C NMR(CDCl3, 150 MHz) δ
175.3, 169.0, 163.6, 153.6, 133.2, 129.5, 129.2, 128.6, 103.2,
76.5, 70.5, 66.4, 62.8, 51.2, 50.2, 41.8, 31.9, 29.4, 22.7, 19.9,
14.5, 14.1, 13.4, 10.4. HRMS (ESI) [M+H]+ 765.3730, calcd for
C38H57N2O14, 765.3732.
MHz) δ 8.10 (d, J = 7.9 Hz, 2H), 7.63 (t, J = 7.5 Hz, 1H), 7.50
(m, 4H), 7.37 (m, 5H), 7.11 (d, J = 7.9 Hz, 2H), 5.61 (s, 1H),
5.12 (dd, J1 = 9.7 Hz, J2 = 9.7 Hz, 1H, H-2), 4.83 (d, J = 9.9 Hz,
1H, H-1), 4.44 (dd, J1 = 10.7 Hz, J2 = 4.8 Hz, 1H, H-6), 3.95 (dd,
J1 = 9.6 Hz, J2 = 9.6 Hz, 1H, H-4), 3.83 (dd, J1 = 10.2 Hz, J2 =
10.1 Hz, 1H, H-6), 3.68 (dd, J1 = 9.6 Hz, J2 = 9.3 Hz, 1H, H-3),
3.60 (m, 1H, H-5), 2.34 (s, 3H). 13C NMR(CDCl3, 100 MHz) δ
165.1, 139.0, 136.8, 134.0, 133.8, 130.2, 130.0, 129.5, 129.4,
128.8, 128.6, 128.0, 126.2, 101.7, 87.6, 79.5, 71.6, 71.1, 68.8,
65.0, 21.4. ESI-MS: calcd for C27H26N3O5S [M+H]+ 504.1515,
found: 504.1589.
4.43. Synthesis of 3-azido-3-deoxy-2-O-benzoyl-4,6-O-benzyl-
4.40. (E)-5-(4-O-benzyol-3-dimethylamino-3-deoxy-6- O-meth-
ylmycaminosy)-3-O-descladinosyl-6-O-methyl-3-oxo-erythron-
olide A 9-O-(benzoyl) oxime 11,12-cyclic carbonate 37c
idene-α-D-glucopyranoside trichloroacetimidate 41
Compound 39 (0.2 g, 0.42 mmol) was dissolved in a mixture
solution of 3 mL CH2Cl2 and 0.3 mL H2O and NIS (98.0 mg,
0.42 mmol) was added in. After stirring for 10 minutes, TFA
(45.0 mg, 0.42 mmol) was added in and kept stirring for 5 hours.
The reaction solution was washed with saturated NaHCO3
solution and Na2S2O3 solution. The organic layer was
concentrated and purified by column chromatography on silica
gel(PE : EtOAc = 20 : 1) to form compound 40 (90.0 mg, 55%).
Compound 41 (262.0 mg, 96%) was obtained from compound 40
(200.0 g, 0.50 mmol) as the procedure for compound 27. The
crude product was purified by column chromatography on silica
gel (PE : EtOAc = 40 : 1) to form compound 41 (262.0 mg,
Compound 37c was obtained as the method for compound 30
in a yield of 40%. 1H NMR(CDCl3, 500 MHz) δ 8.11 (d, J1 = 7.5
Hz, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H), 5.04 (d,
J = 10.5 Hz, 1H, H-13), 4.79 (s, 1H, H-11), 4.67 (d, J = 11.5 Hz,
1H, H-6b′), 4.45 (dd, J1 = 11.5 Hz, J2 = 7.0 Hz, 1H, H-6a′), 4.43
(d, J = 8.0 Hz, 1H, H-1′), 4.24 (d, J = 8.0 Hz, 1H, H-2), 3.85 (m,
1H), 3.68 (m, 1H), 3.52 (s, 3H, 6’-OMe), 3.38 (t, J = 10.0 Hz,
1H), 3.25 (dd, J1 = 10.5 Hz, J2 = 7.5 Hz, 1H), 3.05(t, J = 7.5 Hz,
1H), 2.55 (s, 6H, 3′-NMe2), 2.51 (s, 3H, 6-OMe), 1.38 (d, J = 6.5
Hz, 3H), 1.35 (s, 3H), 1.25 (d, J = 6.5 Hz, 3H), 0.98 (d, J = 7.0
Hz, 3H), 0.89 (t, J = 7.5 Hz, 3H). 13C NMR(CDCl3, 125 MHz) δ
203.9, 169.1, 166.3, 165.3, 154.0, 133.3, 129.8, 129.7, 128.5,
103.1, 84.6, 82.9, 79.1, 78.1, 76.6, 76.3, 75.0, 70.3, 69.4, 63.6,
59.0, 51.1, 49.6, 47.3, 41.6, 38.1, 29.7, 22.4, 19.7, 18.7, 15.6,
15.4, 14.2, 13.1, 10.3. HRMS (ESI) [M+H]+ 793.4017, calcd for
C40H61N2O14, 793.4045.
1
96%). H NMR(CDCl3, 400 MHz) δ 8.61 (s, 1H, C = NH), 8.05
(d, J = 7.8 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.52 (d, J = 6.8 Hz,
1H), 7.44 (t, J = 7.6 Hz, 2H), 7.38 (d, J = 6.6 Hz, 3H), 6.62 (d, J
= 3.7 Hz, 1H, H-1), 5.66 (s, 1H), 5.22 (dd, J1 = 10.3 Hz, J2 = 3.7
Hz, 1H, H-2), 4.41 (dd, J1 = 10.6 Hz, J2 = 4.9 Hz, 1H, H-6), 4.36
(dd, J1 = 10.2 Hz, J2 = 9.0 Hz, 1H), 3.83 (dd, J1 = 10.6 Hz, J2 =
10.4 Hz, 3H).
4.41. Synthesis of p-methylphenyl-3-azido-3-deoxy-4,6-O-benzyl-
4.44. (E)-5-(3-azido-3-deoxy-2- O-benzoyl-4,6-O-benzylidenemy-
idene-1-thio-β-D-glucopyranoside 38
caminosy)-3-O-descladinosyl-6-O-methyl-3-oxo-erythronolide A
9-O-(benzoyl) oxime 11,12-cyclic carbonate 42
To a solution of compound 9 (1.5 g, 4.85 mmol) in 15 mL
DMF were added in PhCH(OMe)2 (1.5 g, 9.70 mmol) and PTSA
(0.2 g, 0.73 mmol) at 50 ℃. After stirring for 5 hours, the
reaction solution was added in Et3N to neutralize and diluted with
CH2Cl2, the diluent was washed with H2O and saturated
NaHCO3. The organic phase was concentrated and purified by
column chromatography on silica gel(PE : EtOAc = 20 : 1) to
Compound 42 (140.0 mg, 60%) was coupled by the donor 41
(270.0 mg, 0.50 mmol) and the acceptor erythronolide (140.0 mg,
0.25 mmol) with the promoter TMSOTf (13.9 mg, 0.06 mmol) as
the procedure for compound 28. The crude product was purified
by column chromatography on silica gel (CHCl3 : PE : MeOH=
1
1
500 : 500 : 1). H NMR(CDCl3, 400 MHz) δ 8.03 (m, 4H), 7.61
form compound 38 (1.3 g, 71%). H NMR(CDCl3, 400 MHz) δ
(t, J = 7.4 Hz, 2H), 7.49 (m, 6H), 7.38 (m, 3H), 5.61 (s, 1H), 5.12
(dd, J1 = 8.8 Hz, J2 = 8.9 Hz, 1H, H-2′), 5.08 (dd, J1 = 10.1 Hz, J2
= 2.7 Hz, 1H, H-13), 4.86 (s, 1H, H-11), 4.79 (d, J = 7.9 Hz, 1H,
H-1′), 4.43 (dd, J1 = 10.6 Hz, J2 = 4.8 Hz, 1H, H-6′), 4.24 (d, J =
6.5 Hz, 1H, H-2), 3.90 (dd, J1 = 9.8 Hz, J2 = 9.7 Hz, 1H), 3.79
(dd, J1 = 10.2 Hz, J2 = 10.1 Hz, 1H), 3.68 (dd, J1 = 9.6 Hz, J2 =
8.8 Hz, 1H), 3.61 (m, 1H, H-5′), 2.97 ( t, J = 7.2 Hz, 1H ), 2.74
(s, 3H, 6-OMe), 1.14 ( d, J = 6.8 Hz, 3H), 0.94 (d, J = 7.7 Hz,
3H), 0.86 (t, J = 7.6 Hz, 6H). 13C NMR(CDCl3, 100 MHz) δ
204.5, 175.3, 169.2, 164.8, 163.7, 153.9, 136.8, 133.9, 133.4,
130.1, 129.7, 129.4, 129.2, 128.9, 128.8, 128.5, 126.2, 101.8,
100.7, 79.8, 78.1, 77.1, 72.7, 68.7, 76.3, 63.6, 51.3, 50.2, 46.4,
38.2, 29.9, 28.6, 27.4, 22.7, 20.0, 19.0, 15.8, 14.9, 14.4, 13.6,
10.5. HRMS (ESI) [M+H]+ 955.3962, calcd for C50H59N4O15,
955.3899.
7.48 (m, 2H), 7.42 (d, J = 7.8 Hz, 2H), 7.39 (m, 3H), 7.16 (d, J =
7.8 Hz, 2H), 5.55 (s, 1H), 4.55 (d, J = 9.6 Hz, 1H, H-1), 4.38 (dd,
J1 = 10.6 Hz, J2 = 4.6 Hz, 1H, H-6), 3.76 (dd, J1 = 10.6 Hz, J2 =
9.9 Hz, 1H, H-6), 3.71 (dd, J1 = 9.7 Hz, J2 = 9.3 Hz, 1H, H-4),
3.54 (ddd, J1 = 9.4 Hz, J2 = 9.4 Hz, J3 = 4.8 Hz, 1H, H-5), 3.47
(dd, J1 = 9.5 Hz, J2 = 9.4 Hz, 1H, H-3), 3.33 (ddd, J1 = 9.4 Hz, J2
= 9.4 Hz, J3 = 2.4 Hz, 1H, H-2), 2.68 (d, J = 2.4 Hz, 1H, 2-OH),
2.37 (s, 3H). 13C NMR(CDCl3, 100 MHz) δ 139.4, 136.9, 134.1,
130.2, 129.4, 128.6, 126.9, 126.2, 101.7, 89.4, 79.4, 71.8, 71.7,
68.8, 66.1, 21.4. ESI-MS: calcd for C20H22N3O4S[M+H]+
400.1253, found: 400.1268.
4.42. Synthesis of p-methylphenyl-3-azido-3-deoxy-2-O-benzoyl-
4,6-O-ben-zylidene-1-thio-β-D-glucopyranoside 39
Compound 38 (0.8 g, 1.92 mmol) was dissolved in 5 mL
pyridine, and BzCl (0.7 g, 0.14 mmol) was added in. After
stirring for 2 hours, the reaction solution was concentrated and
diluted with CH2Cl2, the diluent was washed with H2O and
4.45. (E)-5-(2-O-benzoyl-4,6-O-benzylidene-3-dimethylamino-3-
deoxy-mycaminosy)-3-O-descladinosyl-6-O-methyl-3-oxo-eryth-

12
Tetrahedron
ronolide A 9-O-(benzoyl) oxime 11,12-cyclic carbonate 43
400 MHz) δ 8.10 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H),
ACCEPTED MANUSCRIPT
7.49 (t, J = 7.6 Hz, 3H), 7.33 (m, 11H), 7.04 (d, J = 8.0 Hz, 2H),
Compound 43 (12.0 mg, 60%) was obtained from compound
5.08 (t, J = 9.6 Hz, 1H, H-2), 4.81, 4.73 (d, J = 11.4 Hz, 2H, 6-
OBn, AB), 4.62 (m, 3H), 3.78 (m, 3H), 3.62 ( t, J = 9.2 Hz, 1H),
3.58 (t, J = 9.2 Hz, 1H), 2.30 (s, 3H, 1-STol).
42 (20.0 mg, 0.02 mmol) as the method for compound 29 via
column chromatography on silica gel (CHCl3 : PE : MeOH= 500
: 500 : 1). 1H NMR(CDCl3, 400 MHz) δ 8.04 (d, J = 7.6 Hz, 2H),
8.00 (d, J = 7.9 Hz, 2H), 7.59 (m, 2H), 7.50 (m, 7H), 7.36 (m,
2H), 5.55 (s, 1H), 5.08 (m, 2H, H-2′, H-13), 4.85 (s, 1H, H-11),
4.75 (d, J = 7.7 Hz, 1H, H-1′), 4.40 (dd, J1 = 10.5 Hz, J2 = 4.7
Hz, 1H, H-6′), 4.24 (d, J = 7.0 Hz, 1H, H-2), 3.71-3.82 (m, 3H),
2.74 (s, 3H, 6-OMe), 2.46 (s, 6H, H-3′-NMe2), 1.36 (s, 3H), 1.32
( d, J = 6.7 Hz, 6H), 0.97 (d, J = 7.9 Hz, 3H). HRMS (ESI)
[M+H]+ 957.4362, calcd for C52H65N2O15, 957.4307.
4.49. Synthesis of p-methylphenyl-3-azido-3-deoxy-2-O-benzoyl-
6-O-benzyl-4-O-methyl-1-thio-β-D-glucopyranoside 46b
Compound 46b (513.0 mg, 99%) was obtained from
compound 45 (500.0mg, 0.99mmol) as the procedure for
compound 46a via column chromatography on silica gel (PE :
EtOAc = 50 : 1). 1H NMR(CDCl3, 400 MHz) δ 8.10 (d, J = 7.6
Hz, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.48 (m, 3H), 7.36 (m, 6H),
7.01 (d, J = 8.0 Hz, 2H), 5.02 (t, J = 10.0 Hz, 1H, H-2), 4.70 (d, J
= 9.6 Hz, 1H, H-1), 4.63 (d, J = 12.8 Hz, 2H, 6-OBn, AB), 3.75
(m, 4H), 3.54 (s, 3H, 4-OMe), 3.33 ( m, 1H), 2.29 (s, 3H, 1-STol).
4.46. (E)-5-(4,6-O-benzylidene-3-dimethylamino-3-deoxymyca-
minosy)-3-O-descladinosyl-6-O-methyl-3-oxo-erythronolide A 9-
O-(benzoyl) oxime 11,12-cyclic carbonate 44
Compound 44 (7.0 mg, 65%) was yielded from the compound
43 (12.0 mg, 0.01 mmol) in methanol at room temperature for 12
4.50. Synthesis of 3-azido-3-deoxy-2-O-benzoyl-4,6-di-O-benzyl-
α-D-glucopyranoside trichloroacetimidate 47a
hours. The crude product was
purified by column
1
chromatography on silica gel (CHCl3 : MeOH = 100 : 3). H
NMR(CDCl3, 400 MHz) δ 8.05 (d, J = 7.7 Hz, 2H), 7.59 (t, J =
7.5 Hz, 1H), 7.48 (m, 4H), 7.37 (m, 3H), 5.51 (s, 1H), 5.09 (d, J
= 10.1 Hz, 1H, H-13), 4.86 (s, 1H, H-11), 4.52 (d, J = 7.4 Hz,
1H, H-1′), 4.33 (dd, J1 = 10.4 Hz, J2 = 4.8 Hz, 1H, H-6′), 4.25 (d,
J = 7.6 Hz, 1H, H-2), 3.86 (m, 1H), 3.72 (dd, J1 = 10.0 Hz, J2 =
9.8 Hz, 2H), 3.47 (m, 1H, H-5′), 3.26 (t, J = 8.8 Hz, 1H), 3.08 (t,
J = 7.6 Hz, 1H), 2.76 (s, 3H, 6-OMe), 2.53 (s, 6H, H-3′-NMe2),
1.43 ( d, J = 7.0 Hz, 6H), 1.37 ( d, J = 6.9 Hz, 6H),1.32 ( d, J =
7.4 Hz, 6H), 1.14 ( d, J = 6.9 Hz, 3H), 0.91 (t, J = 7.9 Hz, 3H).
13C NMR(CDCl3, 100 MHz) δ 204.0, 169.0, 163.6, 163.6, 153.7,
137.2, 133.1, 129.5, 129.4, 129.0, 128.6, 128.3, 125.9, 103.6,
100.9, 69.9, 68.9, 68.2, 67.8, 51.2, 50.2, 41.7, 29.7, 28.6, 19.8,
14.3, 13.4, 10.4. HRMS (ESI) [M+H]+ 853.4089, calcd for
C45H61N2O14, 853.4045.
Compound 47a (113.0 mg, 53%) was formed from compound
46a (130.0 mg， 0.27 mmol) following the way for compound
41. The crude product was purified by column chromatography
on silica gel (PE : EtOAc = 40 : 1). 1H NMR(CDCl3, 400 MHz) δ
8.54 (s, 1H, 1-NH), 8.04 (d, J = 7.6 Hz, 2H), 7.58 (t, J = 7.6 Hz,
1H), 7.46 (t, J = 7.6 Hz, 2H), 7.32 (m, 8H), 6.63 (d, J = 2.8 Hz,
1H, H-1), 5.18 (t, J1 = 10.4 Hz, J2 = 3.2 Hz 1H, H-2), 4.83, 4.54
(d, J = 11.4 Hz, 2H, 6-OBn, AB), 4.66, 4.60 (d, J = 11.6 Hz, 2H,
6-OBn, AB), 4.21 ( t, J = 10.4 Hz, 1H), 4.04 (d, J = 9.6 Hz, 1H),
3.84 (m, 2H), 3.70 (d, J = 10.8 Hz, 1H).
4.51. (E)-5-(3-azido-3-deoxy-2-O-benzoyl-4,6-di-O-benzylmyca-
minosy)-3-O-descladinosyl-6-O-methyl-3-oxo-erythronolide A 9-
O-(benzoyl) oxime 11,12-cyclic carbonate 48a
Compound 48a was obtained as the method for compound 28
1
4.47. Synthesis of p-methylphenyl-3-azido-3-deoxy-2-O-benzoyl-
6-O-benzyl-1-thio-β-D-glucopyranoside 45
in a yield of 70%. H NMR(CDCl3, 400 MHz) δ 8.06 (d, J = 7.6
Hz, 3H), 8.02 (d, J = 7.6 Hz, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.54 (t,
J = 7.6 Hz, 1H), 7.44 (m, 4H), 7.33 (m, 5H), 7.26 (m, 3H), 5.10
(dd, J1 = 11.6 Hz, J2 = 8.0 Hz, 1H, H-2’), 5.05 (d, J = 10.8 Hz,
1H, H-13), 4.86 (s, 1H, H-11), 4.80 (d, J = 11.4 Hz, 1H, 6′-OBn),
4.62 (d, J = 9.2 Hz, 2H, 6′-OBn, H-1′), 4.53 (s, 2H, 4′-OBn), 4.20
(d, J = 6.8 Hz, 1H, H-2), 3.72 (m, 5H), 3.54 (m, 1H), 2.94 (t, J=
7.6 Hz, 1H), 2.68 (s, 3H, 6-OMe), 1.32 (d, J = 6.4 Hz, 3H), 1.14
(d, J = 5.6 Hz, 3H), 0.94 (d, J = 7.2 Hz, 3H), 0.86 (t, J = 6.8 Hz,
1H). HRMS (ESI) [M+H]+ 1047.4564, calcd for C57H67N4O15,
1047.4525.
Compound 39 was dissolved in 20 mL CH2Cl2 at ice-bath.
Then Et3SiH (2.1 g, 1.77 mmol) and TFA（2.0 g， 1.77 mmol）
were added and stirred at room temperature for 10 hours. After
that, the solution was neutralized by saturated NaHCO3 and
washed by brine. Then the organic phase was concentrated and
purified by column chromatography on silica gel (PE : EtOAc =
1
50: 1) to form compound 45 (1.0 g, 56%). H NMR(CDCl3, 400
MHz) δ 8.10 (d, J = 7.6 Hz, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.49 (t,
J = 7.6 Hz, 2H), 7.34 (m, 6H), 7.06 (d, J = 8.0 Hz, 2H), 5.07 (t, J
= 9.2 Hz, 1H, H-2), 4.76 (d, J = 10.0 Hz, 1H, H-1), 4.60, 4.56 (d,
J = 12.0 Hz, 2H, 6-OBn, AB), 3.85 (dd, J1 = 10.0 Hz, J2 = 4.8 Hz,
1H), 3.78 (J1 = 11.2 Hz, J2 = 4.8 Hz, 1H), 3.70 (m, 2H), 3.60 (m,
1H), 2.30 (s, 3H, 1-STol). 13C NMR (CDCl3, 100 MHz) δ 165.3,
138.7, 137.6, 133.7, 130.2, 129.9, 129.6, 128.7, 128.1, 87.0, 78.5,
74.1, 71.6, 70.9, 70.6, 68.6, 21.4. ESI-MS [M+Na]+ 528.1671,
calcd for C27H27N3O5SNa, 528.1562.
4.52. (E)-5-(3-azido-3-deoxy-2-O-benzoyl-6-O-benzyl-4-O-met-
hyl-mycaminosy)-3-O-descladinosyl-6-O-methyl-3-oxo-eryth-
ronolide A 9-O-(benzoyl) oxime 11,12-cyclic carbonate 48b
Compound 48b was obtained as the method for compound 28
in a yield of 62%.1H NMR(CDCl3, 400 MHz) δ 8.05 (d, J1 = 7.6
Hz, 2H), 8.00 (d, J = 7.6 Hz, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.53
(m, 1H), 7.46 (m, 4H), 7.23 (m, 4H), 5.05 (m, 2H, H-2, H-13),
4.86 (s, 1H, H-11), 4.62 (d, J = 8.0 Hz, 1H, H-1′), 4.56 (s, 2H, 6’-
OBn), 4.30 (t, J = 6.8 Hz, 1H), 4.20 (d, J = 6.8 Hz, 1H, H-2),
3.73 (m, 3H), 3.61 (t, J = 9.6 Hz, 2H), 3.56 (s, 3H, 4′-OMe), 3.45
(m, 2H), 2.68 (s, 3H, 6-OMe), 1.32 (d, J = 6.4 Hz, 3H), 0.94 (d, J
= 7.6 Hz, 3H), 0.86 (t, J = 6.8 Hz, 3H). HRMS (ESI) [M+H]+
971.4252 calcd for C51H63N4O15, 971.4212.
4.48. Synthesis of p-methylphenyl-3-azido-3-deoxy-2-O-benzoyl-
4,6-di-O-benzyl -1-thio-β-D-glucopyranoside 46a
Compound 45 (430.0 mg, 0.85 mmol) was dissolved in 5 mL
DMF and NaH (60.0 mg, 1.49 mmol) at ice-bath. After stirring
for 10 minutes, 0.1 mL BnBr was added and kept stirring for 12
hours at room temperature. Then the solution was quenched by
methanol and diluted by CH2Cl2, the diluent was washed by brine
and the organic layer was concentrated. The crude product was
purified by column chromatography on silica gel (PE : EtOAc =
50 : 1) to form compound 46a (500.0mg, 99%). 1H NMR(CDCl3,
4.53. (E)-5-(2-O-benzoyl-4,6-di-O-benzyl-3-dimethylamino-3-
deoxy-mycaminosy)-3-O-descladinosyl-6-O-methyl-3-oxo-ery-

13
thronolide A 9-O-(benzoyl) oxime 11,12-cyclic carbonate 49a
Compound 49a was obtained as the method for compound 29
51.4, 50.3, 47.6, 41.9, 38.7, 29.9, 28.8, 22.7, 20.2, 14.5, 13.6,
ACCEPTED MANUSCRIPT
10.6. HRMS (ESI) [M+H]+ 869.4372 calcd for C46H65N2O14,
869.4358.
1
in a yield of 70%. H NMR(CDCl3, 400 MHz) δ 8.06 (d, J = 7.6
Hz, 3H), 8.00 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.53 (t,
J = 7.6 Hz, 1H), 7.44 (m, 4H), 7.28 (m, 8H), 5.24 (dd, J1 = 9.2
Hz, J2 = 8.8 Hz, 1H, H-2′), 5.05 (d, J = 9.6 Hz, 1H, H-13), 4.86 (s,
1H, H-11), 4.84 (d, J = 11.6 Hz, 1H, 6′-OBn), 4.56 (m, 2H, 6′-
OBn, H-1′), 4.54 (s, 2H, 4′-OBn), 4.18 (d, J = 6.8 Hz, 1H, H-2),
3.70 (m, 4H), 3.49 (m, 1H), 2.68 (s, 3H, 6-OMe), 2.44 (s, 6H, 3′-
NMe2), 1.31 (d, J = 6.8 Hz, 3H), 1.13 (d, J = 6.0 Hz, 3H), 0.91 (d,
J = 7.6 Hz, 3H), 0.86 (t, J = 7.2 Hz, 1H). HRMS (ESI) [M+H]+
1049.4957 calcd for C59H73N2O15, 1049.4933.
Acknowledgements
This work was supported by the National S&T Major
Special Project on Major New Drug innovation (Item Number:
2014ZX09507-009-09 and 2009ZX09301-003) and National
Natural Science Foundation of China (81072524). And we are
grateful to the Department of Instrumental Analysis of our
institute for performing the NMR and mass spectroscopy
measurements.
4.54. (E)-5-(2-O-benzoyl-6-di-O-benzyl-3-dimethylamino-3-deo-
Supplementary date
xy-4-O-methyl-mycaminosy)-3-O-descladinosyl-6-O-methyl-3-o-
xo-erythronolide A 9-O-(benzoyl) oxime 11,12-cyclic carbonate
49b
Supplementary date associated with this article can be found in
the online version.
References and notes
Compound 49b was obtained as the method for compound 29
in a yield of 65%. H NMR(CDCl3, 400 MHz) δ 8.06 (d, J = 8.0
1
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Hz, 2H), 8.00 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.53 (t,
J = 7.6 Hz, 1H), 7.42 (m, 3H), 7.22 (m, 3H), 5.17 (dd, J1 = 9.6
Hz, J2 = 8.8 Hz, 1H, H-2′), 5.05 (d, J = 8.4 Hz, 1H, H-13), 4.86 (s,
1H, H-11), 4.56 (s, 2H, 6′-OBn), 4.54 (d, J = 8.8 Hz, 1H, H-1′),
4.19 (d, J = 7.2 Hz, 1H, H-2), 3.67 (m, 3H), 3.48 (s, 3H, 4′-OMe),
2.67 (s, 3H, 6-OMe), 2.42 (s, 6H, 3′-NMe2), 1.31 (d, J = 6.8 Hz,
3H), 0.90 (d, J = 7.6 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H). HRMS
(ESI) [M+H]+ 973.4632 calcd for C53H69N2O15, 973.4620.
4.55. (E)-5-(4,6-di-O-benzyl-3-dimethylamino-3-deoxy-mycami-
nosy)-3-O-descladinosyl-6-O-methyl-3-oxo-erythronolide A 9-O-
(benzoyl) oxime 11,12-cyclic carbonate 50a
Compound 50a was obtained as the method for compound 30
in a yield of 55%.1H NMR(CDCl3, 400 MHz) δ 8.06 (d, J = 8.0
Hz, 2H), 7.51 (t, J = 7.2 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.31
(m, 3H), 7.23 (m, 7H), 5.08 (d, J = 10.0 Hz, 1H, H-13), 4.86 (s,
1H, H-11), 4.68 (d, J = 11.8 Hz, 1H, 6′-OBn), 4.56 (m, 3H, 6′-
OBn, 4′-OBn), 4.37 (d, J = 7.2 Hz, H-1′), 4.22 (d, J = 8.0 Hz, 1H,
H-2), 3.81 (m, 2H), 3.66 (m, 2H), 3.40 (d, J = 8.8 Hz, 1H), 3.26
(dd, J = 10.0 Hz, J = 7.6 Hz, 1H), 3.06 (t, J = 7.6 Hz, 1H), 2.73 (s,
3H, 6-OMe), 2.51 (s, 6H, 3′-NMe2), 1.35 (d, J = 6.8 Hz, 3H),
1.15 (d, J = 5.6 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H). 13C NMR
(CDCl3, 100 MHz) δ 204.1, 175.6, 169.2, 163.8, 153.9, 138.0,
137.8, 133.3, 129.7, 128.8, 128.7, 128.6, 128.1, 128.1, 128.0,
103.7, 76.9, 76.6, 73.8, 73.5, 73.1, 70.9, 69.7, 68.5, 51.4, 50.3,
41.9, 29.9, 28.8, 22.8, 20.2, 15.8, 15.7, 14.5, 13.6, 10.6. HRMS
(ESI) [M+H]+ m/z 945.4683 calcd for C52H69N2O14, 945.4671.
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Hz, 2H), 7.50 (t, J = 7.2 Hz, 1H), 7.38 (t, J = 7.6 Hz, 2H), 7.24
(m, 5H), 5.10 (d, J = 8.0 Hz, 1H, H-13), 4.86 (s, 1H, H-11), 4.56,
4.52 (d, J = 12.0 Hz, 1H, 6′-OBn), 4.33 (d, J = 7.6 Hz, 1H, H-1′),
4.20 (d, J = 7.6 Hz, 1H, H-2), 3.85 (m, 1H), 3.64 (m, 2H), 3.53 (t,
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