Stereoselective and regioselective one-pot synthesis of polyhydroxy bicyclic diazenes and hydrazones from methyl 6-deoxy-6-iodo-hexosides

Article abstract of DOI:10.1016/j.tet.2015.05.105

An efficient, stereoselective, and base-controlled procedure for the preparation of polyhydroxy bicyclic diazenes and polyhydroxy bicyclic hydrazones is described, starting from sugar-derived methyl 6-deoxy-6-iodo-hexosides. The one-pot synthesis involves

Full text of DOI:10.1016/j.tet.2015.05.105

Accepted Manuscript
One-pot, Stereoselective and Regioselective Synthesis of Polyhydroxy Bicyclic
Diazenes/Hydrazones from Methyl 6-deoxy-6-iodo-hexosides
Yunfeng Li, Yao Meng, Zhongjun Li, Xiangbao Meng
PII:
S0040-4020(15)00827-3
10.1016/j.tet.2015.05.105
TET 26824
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 March 2015
Revised Date: 25 May 2015
Accepted Date: 28 May 2015
Please cite this article as: Li Y, Meng Y, Li Z, Meng X, One-pot, Stereoselective and Regioselective
Synthesis of Polyhydroxy Bicyclic Diazenes/Hydrazones from Methyl 6-deoxy-6-iodo-hexosides,
Tetrahedron (2015), doi: 10.1016/j.tet.2015.05.105.
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One-pot, Stereoselective and Regioselective Synthesis of
Polyhydroxy Bicyclic Diazenes/Hydrazones from Methyl
6-deoxy-6-iodo-hexosides
Leave this area blank for abstract info.
Yunfeng Li, Yao Meng, Zhongjun Li*, Xiangbao Meng*
State Key Laboratory of Natural and Biomimetic Drugs;
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University,
Beijing 100191, PR China

1
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Tetrahedron
journal homepage: www.elsevier.com
One-pot, Stereoselective and Regioselective Synthesis of Polyhydroxy Bicyclic
Diazenes/Hydrazones from Methyl 6-deoxy-6-iodo-hexosides
Yunfeng Li, Yao Meng, Zhongjun Li and Xiangbao Meng
State Key Laboratory of Natural and Biomimetic Drugs; Department of Chemical Biology, School of Pharmaceutical Sciences,
Peking University, Beijing 100191, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient, base-controlled stereoselective and product-selective preparation of polyhydroxy
bicyclic diazenes and polyhydroxy bicyclic hydrazones starting from sugar-derived methyl 6-
deoxy-6-iodo-hexosides was described. Both bicyclic diazenes and hydrazones, accomplished
by one-pot three-step reaction, including ring-opening, condensation with tosylhydrazine, and
intramolecular cycloaddition with terminal alkene, were very important synthetic precursors.
Available online
2015 Elsevier Ltd. All rights reserved
.
Keywords:
Bicyclic diazene
Bicyclic hydrazones
Stereoselective
Carbohydrate
One-pot reaction
———
Corresponding author. Tel.: +86 10 82801714; fax: +86 10 82805496; e-mail: xbmeng@bjmu.edu.cn or e-mail: zjli@bjmu.edu.cn

2
Tetrahedron
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1. Introduction
consisted of reductive ring-opening, condensation of
aldehyde and tosylhydrazine, and intramolecular [3+2] ring-
closure.
Cyclic diazene structure, especial the bicyclic diazene,
was considered to be a useful conversion intermediate in the
synthesis chemistry or pharmaceutical chemistry. As shown
in Scheme 1, irradiation[1] of the bicylic diazene A could
easily convert it to cyclopropane C, while tautomerization of
the diazene could generate cyclic hydrazone B with base[2] or
acid[3] present, which was another useful transforment.
Hydrogenation of A followed by acylation could lead to the
cyclic hydrazide D [4], and reduction of A with SmI2 could
produce the cyclopentane E[5]. Recently, both A and B were
converted to 1,2-diazabicyclo[3.3.0]octanes F[6] by Lewis
acid catalyzed reaction with donor-acceptor cyclopropanes,
that contained electron-donating and electron-withdrawing
substituents. The bicyclic diazene and bicyclic hydrazone
seemed to be important intermediates to prepare varied aza-
cyclic compounds.
2. Results and discussion
The key intermediate, tosylhydrazone was produced by
the condensation of hex-5-enal, which generated through the
reductive ring-opening reaction of methyl 6-deoxy-6-iodo-
2,3,4-tri-O-benzyl-α-D-glucopyranoside
(1a)[15]
,
with
tosylhydrazine in MeOH at room temperature. After
removing MeOH under reduced pressure, the obtained crude
ω-diazoalkene, was redissolved in toluene without any
purification and refluxed in the presence of K2CO3. The
desired polyhydroxy bicyclic diazene 3a was obtained as the
single isomer through the three-step one-pot reaction[16] in
70% overall yield.
The common method for preparation of this cyclic
diazene was the dipole cycloaddition of intermolecular[7] or
intramolecular[8] diazonium and olefin. Another useful
method was the cycloaddition reaction of alkene with
tosylhydrazone, which was much more stable and more
easily generated from aldehyde or ketone[9]. However, the
latter method, especially the intramolecular cycloaddition of
tosylhydrazone with the intramolecular alkene to prepare
bicyclic diazene had not been developed as a commonly
useful synthetic method[10]. Just recently, Brewer[11] reported
the similar iodium-mediated bicyclic diazenium salt
formation by the addition of intramolecular phenylhydrazone
and olefin. Of course, the stereoselectivity of this ring-
closing reaction had not been well controlled yet.
Scheme 2. One-pot synthesis of polyhydroxy bicyclic
diazene 3a from iodide 1a
We suspect that the stereoselectivity was controlled by
the two chiral centers at the adjacent positions of aldehyde
and olefin just like the results we obtained in our previous
research[10a]. The one-pot reaction of reductive ring-opening,
condensation of aldehyde and tosylhydrazine, [3+2] ring
closure of five methyl 6-deoxy-6-iodo-hexosides (1a-1e)
were carried out to verify this hypothesis (Scheme 3). And
two methyl 2,6-dideoxy-6-iodo-hexosides (1f and 1g)[14b,14c]
were also designed and synthesized to probe the importance
of the functional groups at the adjacent positions of aldehyde.
The bicyclic diazene with the (3aS, 6aR)-cis-
configuration was characterized as the only isomer from the
reactions of 1a, 1b, 1d (Table 1: entry 1, 2 and 4)
respectively, whereas the (3aR, 6aR)-cis-configurational
bicyclic diazenes (table 1: entry 3 and 5) was produced from
the reactions of 1c and 1e respectively. The methyl 2,6-
dideoxy-6-iodo-hexosides 1f which had no 2-substituted
groups gave no stereoselectivity. These results indicated that
the chiral centers next to the aldehyde in the hex-5-enal
intermediates controlled the stereochemistry of the bicyclic
diazene products. And the one-pot reaction of 1g produced
the (3bR, 6aR)-cis-configurational bicyclic diazene 3g as the
single isomer which converse to 3b (Table 1: entry 7),
whereas two isomers were obtained through the reaction of
Scheme 1. Possible synthesis and conversion of cyclic
diazene and cyclic hydrazone
Carbohydrates were used as synthetic chiral auxiliaries or
chiral building blocks in asymmetric transformations
because of their known absolute stereochemistry and
availability[12]. As a continuing interest in this area[13], herein
we report a one-pot stereoselective and regioselective
synthesis of polyhydroxy bicyclic diazenes/hydrazone from
the common sugar synthon methyl 6-deoxy-6-iodo-
hexosides[14]
.
The three-step sequential procedure is

3
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the other 2-deoxy substance 1f, both of which had the same
demonstration of the above-mentioned conclusion,
proportion (table 1: entry 6). These results were the further
Table 1. The one-pot sythesis of bicyclic diazene from
various methyl 6-deoxy-6-iodo-hexosides
Bicyclic diazene
Yielda
7
78%
Entry
Starting material
product
Condition: i) 1 (0.2 mmol), Zn (10 eq, 2.0 mmol), 95% EtOH,
reflux, 2h; ii) TsNHNH2 (1.05 eq, 0.21 mmol, 38 mg), MeOH (2
mL, 0.1M), rt, 12h; iii) K2CO3 (6 eq, 1.2 mmol, 166 mg), toluene,
120°C, 12h. a isolated yield.
1
72%
and they also may indicate that the chiral center next to the
olefin in the hex-5-enal intermediate also influence the
stereoselectivity of the ring-closing reation in the one-pot three
steps reaction. One bicyclic hydrazone product 4e was obtained
in the one-pot reaction of 1e (Table1: entry 5) in 32% yield,
almost as much as the bicyclic diazene product 3e. That will be
discussed in the following text.
2
3
4
68%
65%
64%
1a
H
H
BnO
6
4
BnO
N
δ ꢀ
2
N
δ +
3
BnO
N
δ +
OBn
N
H
BnO
O
O
H
BnO
δ ꢀ
5
1
O
H
H
I
H
hindered conformation
less hindered conformation G
O
OBn
N
O
N
O
3a
BnO
BnO
H
BnO
H
1d
3d
3
4
5
2
N
1
BnO
N
BnO
BnO
N
N
BnO
H
H
6a
BnO
H
6
H
H
3a
N
O
N
H
O
38%
32%
3e
1c
5
BnO
H
H
H
BnO
BnO
BnO
BnO
N
O
N
δ ꢀ
N
N
BnO
H
H
δ +
O
H
N
OBn
4e
H
N
δ ꢀ
δ +
I
less hindered conformation
hindered conformation J
BnO
H
BnO
H
70%
mix.
~1:1
N
BnO
BnO
N
BnO
BnO
N
6
N
H
H
H
3c
H
Scheme 3. Conformational rationale for the transition
state of dipolar cycloaddition for produce 3a, 3c.
A plausible pathway was proposed to explain the specific
stereochemistry of the ring-closing reaction of the diazonium
dipole from hydrazone intermediate in the one-pot reaction
(Scheme 3). Conformation G of the diazonium dipole of 1a with
H-1 and H-2 at anti-positions was preferred for its less steric

4
Tetrahedron
hindrance, and the (3bS, 6aR)-cis product 3a was formed
reaction condition with proton and base present. And
ACCEPTED MANUSCRIPT
predominantly. The C1-C2 staggered conformation
H
is
confirmatory tests were carried out, as shown in Table 2. There
was no significant difference of the ratio of 3b/4b without
protonic reagent or with any protonic reagents.
disfavored because of the steric hindrance from the dipole and 2-
OBn. Despite the different stereochemistry and substitutions at
3-, 4- positions, 1a, 1b, 1d with 2S configuration all formed the
H-6a, H-6 trans dicyclic diazenes. In contrast, the one-pot
reaction of 1c (or 1e) formed (3bR, 6aR)-cis dicyclic diazene 3c
(or 3e). Less hindered conformation I with cis- H-1 and H-2 was
not the preferred, and the final product 3c (or 3e) with cis- H-3a
and H-6a, and trans- H-6a and H-6 from the hindered
conformation J, which may be determined by electronic effect.
1f
H
H
BnO
BnO
BnO
N
Scheme 5. One-pot reaction with Et3N as base
N
δ ꢀ
δ +
N
H
BnO
N
δ ꢀ
H
δ +
Table 2. Influence of proton on the product selectivity
less hindered conformation K
hindered conformation L
Entry
1b
Proton source
-
3b/4b a
H
H
H
36%/41%
33%/42%
25%/41%
29%/31%
36%/20%
45%/26%
BnO
BnO
H
H
BnO
N
2b
1eq CH3COOH
2.5eq MeOH, 1%
2.6 eq iPrOH, 2%
13 eq iPrOH, 10%
4.8 eq nBuOH, 4%
N
BnO
N
N
H
3f-S
H
H
3f-R
H
H
3c
4c
1g
5c
BnO
BnO
BnO
BnO
H
H
N
δ ꢀ
N
δ +
6c
N
δ +
H
N
δ ꢀ
H
Condition: i) 1b (0.2 mmol, 83 mg), Zn, 95% EtOH, reflux,
2h; ii) TsNHNH2 (1.05eq, 0.21 mmol, 38 mg), toluene (2 mL,
hindered conformation N
less hindered conformation M
a
0.1M), rt, 2h; iii) Et3N (10 or 5eq), ROH, 80°C, 2h. isolated
yieldꢀb 10eq Et3N was used. c 5eq Et3N was used.
H
H
H
BnO
BnO
H
BnO
Initial screening of various strength of organic base was
performed through parallel reactions with pyridine, Et3N,
DIPEA, NMM and DBU as base at 60°C for 2h. The TLC results
shown that just only in the DBU present reaction, there were
detected 4b product point, which was about equal to the 3b
product point. As the reaction temperature increasing, the
bicyclic hydrazone ratio in the products raised(Table 3), with
DBU as base, 4b became the only product when the reaction
temperature increased to 120°C, whereas even the ring-closing
reaction temperature raised to the boiling point of Et3N, the major
product was 3b in the one-pot reaction with Et3N as base.
N
N
BnO
N
N
H
H
H
H
H
H
3g
Scheme 4. Conformational rationale for the transition state of
dipolar cycloaddition for produce 3f, 3g.
In the one-pot reaction of 2-deoxy substances, the
stereochemistry of cycloaddition of the diazonium dipoles was
much more complex, which may attribute to both of the
stereospecific blockade and the dipole moment of the dipole
intermediates. For example, both of the conformation of 1f had
the similar steric hindrance and dipole moment, so two isomers
were conformed (Scheme 4). Because of the hindered
conformation of 1g had more suitable dipole moment in the
reaction condition, the only isomer was formed from it, which
was different from 2-OBn galactose derived substance 1b.
Table 3. The one-pot regioselective synthesis of hydrozone.
Entry
Base
T °C
Solvent
3b/4ba
1
2
3
4
5
60
100
120
120b
140
34%/35%
15%/57%
0/70%
As organic base Et3N was used into accelerating the formation
of hydrazone intermediate with hex-5-enal and tosylhydrazine,
we found that Et3N could also catalyst the ring-closing reaction.
To our surprise, two products were produced, bicyclic diazene
and bicyclic hydrazone (Scheme 5).
DBU
5eq
Xylene
0/68%
We also got the bicyclic hydrazone in the one-pot reaction of
1e (table1, entry 5), which may be substance-related product, or
may be condition-related product [2,3]. Initially, a plausible
pathway was suggested that 3e transformed into 4e in the
0/65%

5
3. Structure determination
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6
7
60
80
45%/5%c
Et3N
5eq
The structure and the stereochemistry of all the bicyclic
diazene and bicyclic hydrazone products were determined by
Toluene
1
1
analysis of their H, 13C, H-1H-COSY and NOE NMR spectra.
The absolute configurations of these bicyclic compounds were
determined by establishing the relative stereochemistry of the
two newly formed stereocenters to those already known in the
starting materials. The configurations of the 2,3,4-carbons of
methyl 6-deoxy-6-iodo-hexosides should remain the same during
the ring-opening, condensation and ring-closing three steps
reactions. For more detailed analysis, please see the supporting
information.
58%/10%
Condition: 1b (0.2 mmol, 83 mg), TsNHNH2 (1.05 eq, 0.21
mmol, 38 mg), xylene (2 mL, 0.1 M). isolated yield. b 4.8 eq n-
a
BuOH was added in the third step. c15% hydrazone intermediate.
Finally, we obtained three conditions to prepare polyhydroxy
bicyclic diazenes and polyhydroxy bicyclic hydrazones
respectively through the one-pot reaction of methyl 6-deoxy-6-
iodo-hexosides. As summarized in Table 4, hex-5-enal was
easily formed by Zn powder in refluxing 95% EtOH for 2 hours,
which was directly reacted with tosylhydrazine with Et3N or
DBU catalyst in toluene or without catalyst in MeOH. The
hydrazone intermediate, which generated with Et3N in toluene,
smoothly transformed into bicyclic diazene with reaction
temperature raised to 60°C, whereas, switched to produce
bicyclic hydrazone quickly with DBU in xylene when the
reaction temperature increased to 120°C.
4. Conclusion
We have developed an efficient one-pot three-step,
stereoselective, and regioselective reactions to prepare
polyhydroxy bicyclic diazenes/hydrazones, respectively,
including reductive ring-opening, aldehyde condensation with
tosylhydrazine, and intramolecular [3+2] cycloaddition, from
sugar derived chiral synthon. Both of the products may be used
as versatile precursors in the synthesis of polyhydroxy natural
product like molecules.
Scheme 6. Optimal reaction conditions for the synthesis of bicyclic diazene/hydrazone
Table 4. A summary of preparing polyhydroxy bicyclic diazenes/hydrazones by one-pot reaction.
Step 2 Step 3
solvent
Products
Proc.
A
Step 1
Base
Temp.
time
base
solvent
Temp.
time
3
4
0.1M
MeOH
0.1M
0.1M
toluene
0.1M
no
rt
12h
K2CO3
120°C
12h
√
-
10 eq Zn, 95%
EtOH, reflux,
2h
B
Et3N
DBU
rt
rt
2h
2h
K2CO3
DBU
120°C
120°C
6h
√
-
toluene
0.1M
toluene
0.1M
C
2-4h
-
√
Xylene
Xylene
Proc means procedure; √ Means produced predominately in the reaction; - means not formed in the reaction.
1H and 13C NMR spectra were recorded on a Bruker 400
instrument using TMS as the internal standard. Mass spectra
were obtained on an IBIMDS Sciex QStar mass spectrometer.
Optical rotations were measured at 25ºC using an Optical
5. Experimental
5.1. General procedure

6
Tetrahedron
ACCEPTED MANUSCRIPT
Activity AA10R automatic polarimeter. TLC was performed on
1H), 4.69 (d, J = 11.7 Hz, 1H), 4.62 (d, J = 11.9 Hz, 1H), 4.55 (d,
glass plates coated with Silica Gel GF254 (Merck). Column
chromatography was performed on Silica Gel H60 (Haiyang
Chemical Factory, Qingdao, Shandong, China). Solvents were
purified by standard procedures.
J = 12.2 Hz, 1H), 4.47 (dd, J = 12.1, 4.2 Hz, 2H), 4.32 (dd, J =
3.5, 2.5 Hz, 1H, H-6), 4.26 (ddd, J = 18.0, 9.8, 1.6 Hz, 1H, H-3’),
4.02 (dd, J = 7.0, 3.9 Hz, 1H, H-4), 3.85 (t, J = 3.8 Hz, 1H, H-5),
2.57 (ddd, J = Hz, 1H, H-3a); 13C NMR (101 MHz, CDCl3) δ
138.32, 138.18, 137.88, 128.64, 128.49, 128.43, 128.01, 127.90,
127.75, 127.65, 127.63, 127.52, 96.07, 82.33, 81.35, 79.16,
78.38, 77.55, 77.23, 76.91, 72.62, 72.35, 72.23, 34.61; HRMS
(ES) m/z calcd for C27H29N2O3, [M+H]+: 429.2178, found:
429.2189.
5.2. General procedure for the preparation of polyhydroxy
bicyclic diazene 3a-3g
Procedure Aꢁ
To a solution of iodide (1 mmol) in 95% EtOH (10 mL)
activated Zn (650 mg, 10 mmol) was added and the mixture was
refluxed with vigorous stirring complete disappearance of iodide
(2 h). The mixture was cooled to room temperature, the solids
were filtered off and the solvent was evaporated. Then the
residue was dissolved into DCM, then washed with saturated
aqueous Na2S2O3, dried (Na2SO4), filtered, and concentrated
under reduced pressure to give pure aldehyde.
5.2.3. (3aR,4R,5S,6R,6aS)-4,5,6-tris(benzyloxy)-
3,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrazole 3c
25
1
Syrup. [α]D +32.0 (c 1.00, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.69 – 7.07 (m, 15H), 4.99 (ddt, J = 8.8, 3.3, 1.8 Hz,
1H, H-3), 4.89 (dt, J = 18.6, 3.4 Hz, 1H, H-6a), 4.83 (d, J = 12.0
Hz, 1H), 4.77 (d, J = 12.0 Hz, 1H), 4.60 (d, J = 11.9 Hz, 1H),
4.56 (d, J = 12.1 Hz, 1H), 4.52 (d, J = 12.1 Hz, 1H), 4.47 (d, J =
11.9 Hz, 1H), 4.32 – 4.23 (m, 2H, H-6, H-3’), 4.20 (t, J = 7.9 Hz,
1H, H-4), 3.19 (dd, J = 7.9, 4.4 Hz, 1H, H-5), 2.66 (ddd, J = 12.6,
9.5, 3.6 Hz, 1H, H-3a); 13C NMR (101 MHz, CDCl3) δ 138.22,
138.03, 128.63, 128.57, 128.50, 128.16, 128.03, 127.89, 127.81,
127.73, 94.67, 82.20, 81.34, 77.90, 77.55, 77.23, 76.91, 76.54,
72.72, 72.57, 72.46, 32.87; HRMS (ES) m/z calcd for
C27H29N2O3, [M+H]+: 429.2178, found: 429.2191.
The hex-5-enals 1 (0.5mmol) and tosylhydrazine (1.05 equiv,
0.525 mmol) were stirred in MeOH (2 mL) at rt overnight.
The MeOH was removed under reduced pressure, the crude
hydrazone was redissolved in toluene (2 mL), K2CO3 (6 equiv, 3
mmol) was added and the reaction mixture was heated in a sealed
vial at 120°C (oil bath) for 12 h. After cooling to rt, the reaction
mixture was partitioned between CH2Cl2 and, sequentially, water
and brine. The combined organic extracts were dried (Na2SO4)
and concentrated. The residue was chromatographed to yield 3.
5.2.4. (3aS,4S,5S,6S,6aR)-4,5-O-isopropylidene-6-
benzyloxy-3,3a,4,5,6,6a-
hexahydrocyclopenta[c]pyrazole 3d
25
1
Syrup. [α]D +32.0 (c 1.00, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.74 – 6.96 (m, 5H), 5.18 (d, J = 17.4 Hz, 1H, H-3),
4.81 (d, J = 7.9 Hz, 1H, H-6a), 4.75 (d, J = 15.7 Hz, 3H, H-6, -
CH2Ph), 4.62 (d, J = 5.7 Hz, 1H, H-5), 4.60 – 4.54 (m, 1H, H-4),
4.06 (ddd, J = 17.4, 8.3, 2.7 Hz, 1H, H-3), 2.72 (q, J = 7.5 Hz, 1H,
H-3a), 1.22 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 137.57,
128.93, 128.77, 128.25, 128.14, 128.05, 127.97, 111.44, 100.14,
85.93, 85.79, 83.75, 80.74, 80.58, 77.55, 77.23, 76.91, 72.17,
37.87, 26.23, 24.54; HRMS (ES) m/z calcd for C16H21N2O3,
[M+H]+: 289.1552, found: 289.1559.
Procedure Bꢁ
To a solution of iodide (1 mmol) in 95% EtOH (10 mL)
activated Zn (650 mg, 10 mmol) was added and the mixture was
refluxed with vigorous stirring complete disappearance of iodide
(2 h). The mixture was cooled to room temperature, the solids
were filtered off and the solvent was evaporated. Then the
residue was dissolved into DCM, then washed with saturated
aqueous Na2S2O3, dried (Na2SO4), filtered, and concentrated
under reduced pressure to give pure aldehyde.
Hex-5-enals 1 (0.5mmol) and tosylhydrazine (1.05 equiv,
0.525 mmol) were stirred in toluene with Et3N (5-10 equiv) at rt
for 2h.
5.2.5. (3aR,4R,5S,6R,6aS)-4-benzyloxy-5,6-O-
isopropylidene-3,3a,4,5,6,6a-
hexahydrocyclopenta[c]pyrazole 3e
25
1
Syrup. [α]D +32.0 (c 1.00, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.50 – 7.14 (m, 5H), 5.18 (d, J = 5.3 Hz, 1H, H-6), 4.98
(dt, J = 17.5, 2.0 Hz, 1H, H-3), 4.82 (d, J = 8.2 Hz, 1H, H-6a),
4.60 (d, J = 12.2 Hz, 1H), 4.44 (dd, J = 5.3, 1.7 Hz, 1H, H-5),
4.40 (d, J = 12.2 Hz, 1H), 4.06 (ddd, J = 17.5, 8.4, 2.4 Hz, 1H, H-
3), 3.88 (dd, J = 6.7, 1.8 Hz, 1H, H-4), 2.88 (td, J = 8.4, 1.8 Hz,
1H, H-3a), 1.48 (s, 3H), 1.36 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 137.67, 128.61, 127.93, 127.56, 111.78, 99.32, 83.77,
82.94, 81.39, 77.55, 77.23, 76.91, 72.16, 38.06, 27.48, 25.30;
HRMS (ES) m/z calcd for C16H21N2O3, [M+H]+: 289.1552,
found: 289.1560.
To the reaction mixture, K2CO3 (6 equiv, 3 mmol) was added,
and then was heated in a sealed vial at 120°C (oil bath) for 12 h.
After cooling to room temperature, the reaction mixture was
filtered and concentrated. The residue was chromatographed to
yield 3.
5.2.1. (3aS,4R,5S,6S,6aR)-4,5,6-tris(benzyloxy)-
3,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrazole 3a
White solid. [α]D25 +32.0 (c 1.00, CHCl3) 1H NMR (400 MHz,
CDCl3) δ 7.53 – 7.15 (m, 15H), 5.05 (d, J = 11.8 Hz, 1H), 4.91 –
4.85 (m, 1H, H-6a), 4.85 – 4.49 (m, 6H), 4.45 (dt, J = 18.2, 2.8
Hz, 1H, H-3), 4.36 (ddd, J = 18.2, 8.9, 2.2 Hz, 1H, H-3’), 4.05 (t,
J = 7.5 Hz, 1H, H-5), 3.95 – 3.89 (m, 1H, H-6), 3.26 (t, J = 7.5
Hz, 1H, H-4), 2.43 (ddd, J = 12.6, 10.3, 3.3 Hz, 1H, H-3a); 13C
NMR (101 MHz, CDCl3) δ 138.36, 138.08, 137.81, 128.64,
128.62, 128.50, 128.17, 128.03, 127.99, 127.88, 127.83, 127.77,
127.72, 95.23, 86.58, 86.03, 83.11, 82.39, 77.55, 77.23, 76.91,
72.75, 72.38, 72.30, 36.56; HRMS (ES) m/z calcd for
C27H29N2O3, [M+H]+: 429.2178, found: 429.2191.
5.2.6. (3aS,4R,5S,6R,6aS)-4-benzyloxy-5,6-O-
isopropylidene-1,3a,4,5,6,6a-
hexahydrocyclopenta[c]pyrazole 4e
1
Syrup. H NMR (400 MHz, CDCl3) δ 7.38 – 7.12 (m, 7H),
6.73 (d, J = 1.2 Hz, 1H), 4.66 (d, J = 12.1 Hz, 1H), 4.48 (d, J =
12.1 Hz, 1H), 4.42 (dd, J = 6.0, 4.3 Hz, 1H), 4.32 (d, J = 6.2 Hz,
1H), 4.10 (dd, J = 7.5, 4.2 Hz, 1H), 3.98 (d, J = 9.7 Hz, 1H), 3.71
(ddd, J = 9.4, 1.4, 0.7 Hz, 1H), 1.37 (s, 4H), 1.22 (s, 4H); 13C
NMR (101 MHz, CDCl3) δ 143.45, 137.94, 128.56, 127.93,
127.87, 111.97, 87.40, 85.74, 85.68, 77.55, 77.23, 76.91, 72.14,
66.19, 55.07, 27.49, 25.24. HRMS (ES) m/z calcd for
C16H21N2O3, [M+H]+: 289.1552, found: 289.1560.
5.2.2. (3aS,4R,5S,6S,6aR)-4,5,6-tris(benzyloxy)-
3,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrazole 3b
25
1
Syrup. [α]D +32.0 (c 1.00, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.54 – 7.13 (m, 15H), 4.99 (dt, J = 18.0, 3.3 Hz, 1H, H-
3), 4.92 (dd, J = 9.0, 1.5 Hz, 1H, H-6a), 4.83 (d, J = 11.7 Hz,

7
5.2.7. 4,5-bis(benzyloxy)-3,3a,4,5,6,6a-
hexahydrocyclopenta[c]pyrazole 3f
References
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Mixture. 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.14 (m, 20H),
5.10 (t, J = 8.2 Hz, 1H), 5.00 – 4.81 (m, 2H), 4.71 – 4.42 (m,
9H), 4.39 – 4.22 (m, 2H), 3.94 (s, 1H), 3.86 (t, J = 7.5 Hz, 1H),
3.66 (s, 1H), 3.39 (dd, J = 15.8, 6.8 Hz, 1H), 2.56 (ddd, J = 29.1,
16.0, 5.1 Hz, 4H), 2.36 (ddd, J = 14.5, 9.4, 4.8 Hz, 1H), 2.01 (dt,
J = 13.8, 9.1 Hz, 1H).
1. (a) Rinehart, K. L., Jr.; Van Auken, T. L. J. Am. Chem. Soc. 1960, 82,
5251-5253. (b) Van Auken, T. L.; Rinehart, K. L., Jr. J. Am. Chem. Soc.
1962, 84, 3736-3743.
2. Padwa, A.; Ku, H. J. Org. Chem. 1980, 45, 3756-3766.
3. Brown, D. S.; Elliott, M. C.; Moody, C. J.; Mowlem, T. J.; Marino, J. P.;
Padwa, A. J. Org. Chem. 1994, 59, 2447-2455.
4. Chênevert, R.; Jacques, F. Tetrahedron: Asymmetry 2006, 17, 1017–
1021.
5.2.8. (3aR,4S,5R,6aR)-4,5-bis(benzyloxy)-
5. Shirakawa, S.; Lombardi, P. J.; Leighton, J. L. J. Am. Chem. Soc. 2005,
127, 9974-9975.
6. Tomilov, Y. V.; Novikov, R. A.; Nefedov, O. M. Tetrahedron 2010, 66,
9151-9158.
7. a) Liu, H. Q.; O’Connor, D. J; Sun, C. R. , Wink, R. J.; Lee, D. Org.
Lett, 2013, 15, 2974-2977. b) Sun, H. B.; Wang, X. Y.; Zhan, M.; Liu,
J.; Xie, Y. M. Tetrahedr. Lett. 2013, 54. 3846-3850.
8. Miyashi, T.; Yamakawa, K.; Kamata, M.; Mukai, T. J. Am. Chem.
Soc. 1983, 105, 6342-6343.
9. (a) Strakova, I.; Strakovs, A.; Petrova, M.; Belyakov, S. Chemistry of
Heterocyclic Compounds 2007, 43, 1512-1518; (b) Prokopenko, V. V.;
Okonnishnikova, G. P.; Klimenko, I. P.;. Shulishov E. V.; Tomilov, Y.
V. Russian Chemical Bulletin 2007, 56, 1515-1521.
10. (a) Zimmerman, H. E.; Fleming, S. A. J. Org. Chem. 1985, 50, 2539-
2551; (b) Miyashi, T.; Nishizawa, Y.; Fujii, Y.; Yamakawa, K.; Kamata,
M.; Akao, S.; Mukai, T. J. Am. Chem. Soc. 1986, 108, 1617-1632; (c)
Adam, W.;Sahin, C.; Schneider, M. J. Am. Chem. Soc. 1995, 117, 1695-
1702; (d) Jung, M. E.; Huang, A. Org. Lett. 2000, 2, 2659-2661.
11. Al-Bataineh, N. Q.; Brewer, M. Tetrahedr. Lett. 2012, 53, 5411-5413.
12. Reviews see: (a) Norbert, P.; Gernot, Z.; Bartlomiej, F.; Horst, K.
Organic Chemistry of Sugars; CRC: Boca Raton, London, New York
NY, 2006, pp 427-488; (b) Reissie, H. U. Angew. Chem., Int. Ed. Engl.
1992, 31, 288-290; (c) Boysen, M. M. K. Chem. Eur. J. 2007, 13, 8648-
8659; (d) Kunz, H.; Rueck, K. Angew. Chem., Int. Ed. Engl. 1993, 32,
336-358; (e) Vega-Perez, J. M.; Ignacio, P.; Vega, M.; Iglesias-Guerra,
F. Tetrahedron: Asymmetry 2008, 19, 1720-1729.
13. (a) Li, Y. F.; Meng, Y.; Meng, X. B.; Li, Z. J. Tetrahedron 2011, 67,
4002-4008; (b) Li, B. Y.; Wang, G.; Li, Z. J.; Meng, X. B. Tetrahedr.
Lett. 2011, 52, 3891-3894. (c) Li, Y. P.; Li, Z. J.; Meng, X. B.
Carbohydr. Res. 2011, 346, 1801-1808. (d) Li, B. Y.; Li, Z. J.; Meng, X.
B. Carbohydr. Res. 2010, 345, 1708-1712. (e) Zhong, M.; Meng, X. B.;
Li, Z. J. Carbohydr. Res. 2010, 345, 1099-1106.
3,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrazole 3g
25
1
Syrup. [α]D +32.0 (c 1.00, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.45 – 7.23 (m, 10H), 5.05 (t, J = 8.0 Hz, 1H, H-6a),
4.64 (d, J = 12.0 Hz, 1H), 4.56 (t, J = 9.3 Hz, 2H), 4.50 (d, J =
12.1 Hz, 1H), 4.48 – 4.42 (m, 1H, H-3), 4.35 (dt, J = 18.4, 3.0
Hz, 1H, H-3’), 3.55 (dd, J = 9.8, 6.0 Hz, 1H, H-5), 3.33 (t, J = 4.0
Hz, 1H, H-4), 2.68 – 2.57 (m, 1H, H-3a), 2.57 – 2.47 (m, 1H, H-
6), 2.17 (dt, J = 13.8, 4.5 Hz, 1H, H-6a); 13C NMR (101 MHz,
CDCl3) δ 138.36, 128.65, 128.61, 127.98, 127.90, 127.79, 90.68,
84.37, 81.27, 78.52, 77.55, 77.23, 76.91, 72.12, 71.98, 38.30,
31.55; HRMS (ES) m/z calcd for C20H23N2O2, [M+H]+:
323.1760, found: 323.1756.
5.3. General procedure for the preparation of polyhydroxy
bicyclic hydrazone 4b
Procedure Cꢁ
To a solution of iodide (1 mmol) in 95% EtOH (10 mL)
activated Zn (650 mg, 10 mmol) was added and the mixture was
refluxed with vigorous stirring complete disappearance of iodide
(2 h). The mixture was cooled to room temperature, the solids
were filtered off and the solvent was evaporated. Then the
residue was dissolved into DCM, then washed with saturated
aqueous Na2S2O3, dried (Na2SO4), filtered, and concentrated
under reduced pressure to give pure aldehyde.
Hex-5-enals 1 (0.5 mmol) and tosylhydrazine (1.05 equiv,
0.525 mmol) were stirred in toluene with DBU (1 equiv) at rt for
2h.
14. (a) Jaramillo, C.; Chiara, J. L.; Martln-Lomas, M. J. Org. Chem. 1994,
59, 3135-3141; (b) Geiger, J.; Reddy, B. G.; Winterfeld, G. A.;
Przybylski, R. W. M.; Schmidt, R. R. J. Org. Chem. 2007, 72, 4367-
4377; (c) Fuwa, H.; Okamura, Y.; Natsugari, H. Tetrahedron 2004, 60,
5341–5352; (d) Göllner, C.; Philipp, C.; Dobner, B.; Sippl , W.; Schmidt,
M. Carbohydrate Research 2009, 344, 1628-1631.
Then the reaction mixture was heated in a sealed vial at 120°C
(oil bath) for 2 h. After cooling to room temperature, the reaction
mixture was filtered and concentrated. The residue was
chromatographed to yield 4b.
15. Andersson, K. N. A.; Somfai, P. Eur. J. Org. Chem. 2006, 978–985.
16. Taber, D. F.; Guo, P. F. J. Org. Chem. 2008, 73, 9479–9481.
(3aR,4S,5S,6S,6aR)-4,5,6-tris(benzyloxy)-1,3a,4,5,6,6a-
hexahydrocyclopenta[c]pyrazole 4b
1
Syrup. H NMR (400 MHz, CDCl3) δ 7.37 – 7.25 (m, 15H),
6.51 (d, J = 1.2 Hz, 1H), 4.76 (d, J = 11.8 Hz, 1H), 4.67 – 4.54
(m, 5H), 4.33 (dd, J = 9.0, 6.8 Hz, 1H), 4.09 (dd, J = 10.4, 6.8
Hz, 1H), 3.77 (d, J = 4.3 Hz, 1H), 3.64 (dd, J = 9.1, 4.3 Hz, 1H),
3.50 (d, J = 10.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 142.67,
138.28, 138.21, 138.02, 128.63, 128.51, 128.00, 127.89, 127.81,
127.70, 83.99, 83.75, 77.55, 77.23, 77.15, 76.91, 73.16, 72.81,
72.13, 57.16, 54.09, 53.59; HRMS (ES) m/z calcd for
C27H29N2O3, [M+H]+: 429.2178, found: 429.2189.
Acknowledgements
The authors thank the financial supports from the National
Natural Science Foundation of China (NSFC No. 21072017) and
National Basic Research Program of China (Grant No.
2012CB822100). The authors also thank Prof. Jianjun Zhang at
China Agricultural University for providing grams of 1a (NKT
R&D Program of China, 2015BAK45B01).

ACCEPTED MANUSCRIPT
Spectroscopic data
One-pot, Stereoselective and Regioselective Synthesis of
Polyhydroxy Bicyclic Diazenes/Hydrazones from Methyl
6-deoxy-6-iodo-hexosides
Yunfeng Li, Yao Meng, Zhongjun Li , and Xiangbao Meng
State Key Laboratory of Natural and Biomimetic Drugs;
Department of Chemical Biology, School of Pharmaceutical Sciences,
Peking University, Beijing 100191, PR China
Corresponding author. Tel.: +86 10 82805939; fax: +86 10 82805496; e-mail: zjli@bjmu.edu.cn
Corresponding author. Tel.: +86 10 82801714; e-mail: xbmeng@bjmu.edu.cn

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Spectroscopic data of compound 3a
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