A Chiron Approach to Diversity-Oriented Synthesis of Aminocyclitols, (-)-Conduramine F-4 and Polyhydroxyaminoazepanes from a Common Precursor

Article abstract of DOI:10.1021/acs.joc.6b01790

The total syntheses of aminocyclitols, (-)-conduramine F-4, and polyhydroxyaminoazepanes have been achieved from a common precursor derived from tri-O-benzyl-d-glucal through a 'diversity-oriented' approach. Tri-O-benzyl-d-glucal was converted into a protected 1,6-diol through a sequence of steps that include transformation to a 2-tosylamidoglucose derivative, selective deprotection of primary C-6 benzyloxy group, LiAlH₄-mediated one-step reduction of acetate groups, and reductive ring opening of the resulting hemiacetal as the key steps. The 1,6-diol served as a common precursor in our diversity oriented approach toward the target molecules. Mesylation of the diol followed by double nucleophilic substitution reaction with primary amines led to the synthesis of amino-substituted polyhydroxyazepanes. On the other hand, dialdehyde obtained from the oxidation of 1,6-diol was found to be a convenient starting material for the synthesis of aminocyclitols and (-)-conduramine F-4. McMurry coupling of the dialdehyde was successfully employed, for the first time, to construct the carbocyclic framework of aminoyclitols, while bis-Wittig olefination of the dialdehyde followed by Grubb's(II)-catalyzed RCM delivered (-)-conduramine F-4. The stereochemistry of newly created chiral centers in aminocyclitols was established through single crystal X-ray crystallography and detailed NOE studies.

Full text of DOI:10.1021/acs.joc.6b01790

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Article
A Chiron Approach to Diversity-Oriented Synthesis of Aminocyclitols, (-)-
Conduramine F-4 and Polyhydroxyaminoazepanes from a Common Precursor
Vimal Kant Harit, and Namakkal Govind Ramesh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01790 • Publication Date (Web): 02 Nov 2016
Downloaded from http://pubs.acs.org on November 3, 2016
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A Chiron Approach to DiversityꢀOriented Synthesis of Aminocyclitols, (ꢀ)ꢀ
Conduramine Fꢀ4 and Polyhydroxyaminoazepanes from a Common Precursor
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Vimal Kant Harit and Namakkal G Ramesh*
Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi ꢀ
110016, India.
ramesh@chemistry.iitd.ac.in
Graphical Abstract:
ABSTRACT: The total syntheses of aminocyclitols, (˗)ꢀconduramine Fꢀ4 and
polyhydroxyaminoazepanes have been achieved from a common precursor derived from
triꢀOꢀbenzylꢀDꢀglucal through a 'DiversityꢀOriented' approach. TriꢀOꢀbenzylꢀDꢀglucal
was converted into a protected 1,6ꢀdiol through a sequence of steps that include
transformation to 2ꢀtosylamidoglucose derivative, selective deprotection of primary Cꢀ6
benzyloxy group, LiAlH mediated oneꢀstep reduction of acetate groups and reductive
4
ring opening of resulting hemiacetal as the key steps. The 1,6ꢀdiol served as a common
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precursor in our diversity oriented approach towards the target molecules. Mesylation of
the diol followed by double nucleophilic substitution reaction with primary amines led to
the synthesis of aminoꢀsubstituted polyhydroxyazepanes. On the other hand, dialdehyde
obtained from the oxidation of 1,6ꢀdiol, was found to be a convenient starting material for
the synthesis of aminocyclitols and (˗)ꢀconduramine Fꢀ4. McMurry coupling of the
dialdehyde was successfully employed, for the first time, to construct the carbocyclic
framework of aminoyclitols, while bisꢀWittig olefination of the dialdehyde followed by
Grubb's(II) catalyzed RCM delivered (˗)ꢀconduramine Fꢀ4. The stereochemistry of newly
created chiral centres in aminocyclitols were established through single crystal Xꢀray
crystallography and detailed NOE studies.
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INTRODUCTION
Aminocyclitols 1, also regarded as aminoꢀcarbasugars, are important class of
compounds that have received wide attention in recent years due to their varied medicinal
1
applications. They are found as structural motifs in a variety of aminoglycoside
2
3
antibiotics such as hygromycin A 2, minosaminomycin 3 etc. (Figure 1) and also serve
4
as valuable synthons for the synthesis of natural Amaryllidaceae alkaloids.
Aminocyclitol phytoceramides have the capacity to modulate the response arising from
5
Invariant Natural Killer Tꢀcell (INKT) activation. NꢀAlkylaminoꢀmyoꢀinositol
6
derivatives are identified as chemical chaperones for Gaucher's disease. Aminocyclitol
7
8
derivatives are also found to be inhibitors of glycosidases and cell growth. Several
9
,10,11
12
strategies,
including chemoꢀenzymatic approach, SmI mediated pinacol type
2
1
3
14
coupling and intramolecular NHC catalyzed benzoin type condensation are available
for the construction of aminocyclitol framework. Interestingly, McMurry coupling of a
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suitably substituted acyclic dialdehyde, wherein carbocyclization accompanied by
installation of two of the hydroxyl groups of aminocyclitols, has never been investigated.
Conduramines, synthetic aminoꢀanalogues of naturally occurring conduritols, are
known for their selective glycosidase inhibitory activities due to which they have become
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a,15
attractive targets for synthetic organic chemists.
One among them is (+)ꢀconduramine
Fꢀ4 4 whose Nꢀalkyl derivatives are, very recently, identified as potential chemical
chaperones for GM1 gangliosidosis, a rare disease caused by mutation of lysosomal βꢀ
1
6,17
galactosidase.
Only two strategies for the synthesis of conduramine Fꢀ4 are reported
18
16
either through chemoenzymatic approach or starting from (+)ꢀprotoꢀquercitol.
Noticeably, a carbohydrate based approach to either (+)ꢀ or (ꢀ)ꢀconduramine Fꢀ4 is still at
large.
Iminocyclitols, referred to as azasugars, have found wide applications as drugs
1
9
and chaperones for various cellꢀmediated disorders and lysosomal storage diseases.
While extensive research have been carried out on the chemistry and biology of fiveꢀ and
sixꢀ membered iminocyclitols and the molecular basis for their binding with
1
9,20
glycosidases,
such studies on azepanes (sevenꢀmembered iminocyclitols) are in infant
stage though they have also been found to be inhibitors of glycosidases. Unlike their
conformationally rigid fiveꢀ and sixꢀmembered counterparts, polyhydroxyazepanes, such
as 6, due to their flexibility can adopt different conformations and hence they can be
better accommodated within the active site of glycoside hydrolases resulting in enhanced
2
1
inhibition. Studies further reveal that replacement of one or more of the hydroxyl
groups of polyhydroxyazepanes with an amino group further increases their inhibitory
2
2,23
23
activities.
Compound 7 is strong inhibitor of Nꢀacetylglucosaminidases. Molecular
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basis for inhibition with glycoside hydrolases reveals that aminoꢀazepane 7 binds 140
2
1b
times more tightly than the product OꢀGlcNAC itself. The aminoꢀazepane core in the
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fungal metabolite (ꢀ)ꢀbalanol is crucial for its inhibition against protein kinase.
These
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significant findings have prompted a spurt in developing novel methodologies for the
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synthesis of aminoꢀazepanes.
_
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OH
HO
H
O
N
HO
HO
HO
OH
OH
O
H N
2
O
O
O
O
N
N
H
H
N
OH
NH2
OH
HO
HO
HN
O
NH OH
O O
OH
1
2
aminocyclitol
hygromycin A
HO
OH
HO
minosaminomycin
OH
3
OH
OH
HO OH
HO OH
H
HO
HO
HO
HO
R
N
OH
HO
OH
O
N
H
N
H
NH2
NH2
4
5
6
7
(+)-conduramine F-4
(−)-conduramine F-4
polyhydroxylated
azepane
amino-substituted
polyhydroxylated
azepane
Figure 1.
Structures of aminocyclitol antibiotics, conduramine Fꢀ4 and
polyhydroxyazepanes
_
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Synthesis of skeletally and stereochemically diverse biologically active small
molecules and their building blocks, from a common precursor, referred to as “Diversityꢀ
2
7
oriented Synthesis’ (DOS) has proven to be a successful paradigm in organic synthesis
since the last decade. As a part of our research on the use of readily available glycals for
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the synthesis of natural products and their analogues, we conceived and successfully
accomplished a DOS strategy towards the synthesis of aminocyclitols, (ꢀ)ꢀconduramine
F4 and aminoazepanes from a common precursor derived from triꢀOꢀbenzylꢀ
Dꢀglucal
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which we present here.
RESULTS AND DISCUSSION
Our retrosynthesis of target molecules is given in Scheme 1. As depicted, (ꢀ)ꢀ
conduramine Fꢀ4, aminocyclitols and aminoꢀazepanes could be obtained from a common
diol 10. Oxidation of the diol to the dialdehyde 9 and subsequent bisꢀWittig olefination
followed by RCM would deliver (ꢀ)ꢀconduramine Fꢀ4 5. On the other hand, construction
of the cyclohexane ring of aminocyclitols 11 could be achieved through McMurry
coupling of the dialdehyde 9. Dimesylation of the diol 10 and nucleophilic substitution
with amines would result in the formation of aminoꢀazepanes 12. 1,6ꢀDiol 10, in turn,
could be obtained by the reductive ring opening of bisꢀacetate 13, generated through
chemoselective deprotection of Cꢀ6 primary benzyloxy group of hemiacetal 14. TriꢀOꢀ
benzylꢀDꢀglucal 15 could be transformed in to hemiacetal 14 in two steps using a
modified procedure developed in our lab.
Synthesis of the common precursor 10. Our synthesis of glucose derived 1,6ꢀdiol 10
commenced with the conversion of triꢀOꢀbenzylꢀ
Dꢀglucal 15 to 2ꢀdeoxyꢀ2ꢀsulfonamidoꢀ
2
9
Dꢀglucose 14 in two steps following a modified procedure of Danishefsky reported by
28
us earlier. Next, selective debenzylation of the primary benzyloxy group of 14, under
acetolysis condition, was attempted. The debenzylative acetylation reaction proceeded
smoothly with ZnCl in acetic anhydride–acetic acid in a ratio of 5:1. During this process,
2
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Scheme 1. Retrosynthesis of Aminocyclitols, (ꢀ)ꢀConduramine Fꢀ4 and
Polyhydroxyaminoazepanes
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OH
OBn
HO
OH
HO
HO
BnO
BnO
CH2
CH2
RCM
H N
2
OH
deprotection
N
R
NH2
N
Bn
Ts
5
8
12
Dimesylation
Wittig
RNH2
deprotection
OBn
N
OH
OBn
N
BnO
BnO
Bn
O
O
BnO
OH
OH
HO
HO
OH
OH
McMurry
deprotection
BnO
Bn
NH2
Ts
Ts
11
9
10
reductive ring
opening
selective
debenzylation
OBn
OBn
OAc
2
steps
O
O
BnO
BnO
O
BnO
BnO
BnO
BnO
Ref. 28
TsHN
TsHN
OAc
OH
15
14
13
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the anomeric hydroxyl group also got acetylated to give the 1,6ꢀOꢀdiacetate 13. Exposure
of the diacetate to an excess of LiAlH in THF led to the reduction of the acetate groups
4
accompanied by concomitant reductive ring opening of the resulting hemiacetal to afford
the triol 16. Attempts to selectively oxidize the primary hydroxyl groups of 16 to the
corresponding dialdehyde were in vain. Oneꢀpot silylation of all the hydroxyl groups of
1
6 followed by quinolinium fluorochromate (QFC) mediated deprotective oxidation of
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primary hydroxyl groups to get 19, following the procedure of Chandrasekar, was
unsuccessful with our substrate. Efforts to realize this protocol in a stepꢀwise manner
through the synthesis of the trisꢀsilyl ether 18 followed by its exposure to QFC also did
not give the desired result. Hence it was decided to follow protectionꢀdeprotection
strategy to obtain the 1,6ꢀdiol 10. In this direction, the primary hydroxyl groups of triol
10
11
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1
6 were converted as their TBS ethers (17) and the resulting secondary hydroxyl and
amino groups
________________________________________________________________________
Scheme 2. Synthesis of common precursor 10.
OBn
O
OBn
O
OAc
O
ZnCl2
Ac O:AcOH (5:1)
2
steps
2
BnO
BnO
BnO
BnO
BnO
BnO
Ref. 28
2
5 °C, 16 h
TsHN
TsHN
OH
OAc
90%
15
14
13
6
5 °C
LiAlH4
THF
1
6 h
8
6%
OBn
N
OH
TBS chloride
imidazole
CH Cl
OH
BnO
BnO
OTBS NaH, BnBr
DMF
BnO
BnO
OTBS
OTBS
BnO
OH
OH
2
2
OTBS
0 °C 10 °C
0 °C, 1.5 h BnO
88%
2
83%
h
HN
HN
Bn
Ts
Ts
Ts
17
2
0
16
TBS chloride
imidazole
DMF, 32 °C
CSA (20 mol%)
MeOH
25 °C, 12.5 h
2
2 h
86%
9
1%
OBn
OTBS
OTBS
QFC
BnO
BnO
BnO
OH
OH
BnO
BnO
OTBS
O
OTBS
BnO
O
N
HN
HN
Bn
Ts
Ts
Ts
1
0
18
19
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were benzylated to get compound 20. Desilyation of 20 was smoothly accomplished
using a catalytic amount of camphor sulfonic acid to get the 1,6ꢀdiol 10 (Scheme 2).
Synthesis of Aminocyclitols using McMurry coupling. It was envisaged that
dialdehyde 9 obtained by the oxidation of diol 10 would be a suitable substrate for
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investigating McMurry coupling that would lead either to protected aminocyclitols or
conduramine Fꢀ4. Towards this direction, diol 10 was first oxidized to dialdehyde 9
under Swern condition using DMSO and oxalyl chloride. Though the oxidation
proceeded smoothly, the product was found to decompose during purification by column
chromatography over silica gel. Hence, the crude product was taken over to the next step
1
after ascertaining its formation by H NMR spectroscopy. McMurry coupling of
dialdehyde 9 was initially attempted with ZnꢀCu in presence of TiCl . However, the
4
outcome was not promising with no useful products being formed in the reaction (Entry
1
6
, Table 1). Change of metal from zinc to magnesium was equally discouraging (Entry
). Use of LiAlH as a reducing agent did show some positive results with new
4
compounds being formed, but the yields were very low (Entry 5). After several attempts,
zinc along with TiCl and catalytic amount of CuCl in THF at 80 ºC was found to be the
4
most appropriate condition affording a mixture of two compounds that could be readily
separated by column chromatography (Entry 4, Table 1). Careful analysis of their spectral
data (IR, NMR and HRMS) indicated that both of them were aminocyclitols formed in a
ratio of 0.7:1 with a total yield of 63% (for two steps from 10). Interestingly, the reaction
did not proceed further to give the corresponding cyclohexene derivative even after a
prolonged reaction time. The stereochemistry of the newly created chiral centres of more
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Table 1. Reaction optimization conditions for McMurry coupling:
10
11
12
13
14
15
16
17
18
19
20
21
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23
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26
27
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Time Temp. Yield Ratio
entry. Reagents (equiv.)/solvents
o
a
b
( h)
( C)
(%)
0
(21 : 22)
ꢀꢀꢀꢀꢀ
1
2
3
4
5
ZnꢀCu (40); TiCl (20); THF
23
80
78
86
80
95
80
4
Zn (4); TiCl (2); pyridine (20 µL); THF 4.5
56
31
63
10
0
0.5 : 1
0.72 : 1
0.7 : 1
1 : 0.6
ꢀꢀꢀꢀꢀ
4
Zn (50); TiCl (25); CuCl (5); DME
40
4
4
Zn (20); TiCl (10); CuCl (0.2); THF
4
LAH (5); TiCl (10); Et N(6); DME
1.4
10
4
3
6
Mg (10); TiCl (5); HgCl (0.2); THF
4 2
a
b
isolated yields after column chromatography for two steps from 10; ratio based on isolated
yields.
________________________________________________________________________
polar major compound 22, a solid, was identified through single crystal Xꢀray
crystallography (see Supporting Information). Subsequent confirmation also came from
the nonꢀoptical activity of the product 27, being meso, obtained after complete
deprotection of 22 (Scheme 4). The stereochemistry of the less polar minor diastereomer
1
2
1, a viscous liquid, however, could not be arrived at from its H NMR spectrum due to
overlapping of signals of various protons. Hence the free hydroxyl groups of compound
1 were converted in to their pꢀnitrobenzoyl derivatives 23 (Scheme 3). The cis
2
stereochemical relationship between Hꢀ1 and Hꢀ2 in 23 was initially deduced based on
1
the coupling constant values. In its H NMR spectrum, Hꢀ6 resonated at δ 5.47 as a dd
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3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
with J = 11.1 and 10.8 Hz due to its coupling with Hꢀ5 and Hꢀ1. The two large coupling
constants of Hꢀ6 with Hꢀ5 and Hꢀ1 confirmed its diaxial relationship with both of them.
With Hꢀ1 being in axial position, the weak coupling constant observed between Hꢀ1 and
Hꢀ2 and viceꢀversa (~ 3.3 Hz) suggested they are in cis stereochemical relationship to
each other. Subsequently, through detailed 2D NMR studies and NOE correlations, the
relative (cis) and absolute stereochemistries of the newly formed chiral centres were
unambiguously confirmed (Scheme 3).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
________________________________________________________________________
Scheme 3. Synthesis of compound 23 and its NOE correlation.
_
_______________________________________________________________________
A rationale for selective formation of only two stereoisomeric diols 21 and 22,
out of four possible, during McMurry coupling may be explained as follows.
Intramolecular pinacol coupling reaction under McMurry condition has been known to
proceed through coupling of radicals on a titanium particle/surface and that the product
3
1c
stereochemistry is mainly controlled by steric interactions in the newly formed ring. In
the diradical intermediates I and II as well as in their respective cyclized titanoꢀ
pinacolates V and VI, the bulky –NBnTS group poses a severe steric hindrance to the
adjacent axial –O[Ti] and hence are unfavorable. Absence of such an hindrance in titanoꢀ
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pinacolates VII and VIII make them favorable, with a greater preference, amongst them,
for transꢀdiꢀO[Ti] intermediate (VIII) over the cisꢀdiꢀO[Ti] intermediate (VII), leading to
the formation of diol 22 (major) and 21 (minor) respectively (Figure 2).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
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_
_______________________________________________________________________
O
H
O
H
BnO
BnO
BnO
BnO
[Ti]
BnO
BnO
BnO
BnO
BnO
BnO
[Ti]
BnO
H
O
H [Ti]
H
O
BnO
H
[Ti]
O
O
N
N
O
O
N
H
Ts
N
H
Ts
Bn
Bn
Bn
Bn
Ts
Ts
I
II
III
IV
O
N
H
N
BnO
BnO
BnO
BnO
O
[Ti]
H
BnO
BnO
BnO
BnO
BnO
BnO
[Ti]
BnO
H
O
H [Ti]
H
O
O
H
[Ti]
O
BnO
O
O
N
N
Bn
Bn
H
H
Bn
Bn
Ts
Ts
Ts
VII
favorable
Ts
VIII
most favorable
V
VI
not favorable
not favorable
Figure 2. Probable Mechanistic Explanation for Selectivity in McMurry Coupling of
Compound 9.
________________________________________________________________________
In order to complete the synthesis, compounds 21 and 22 were deprotected in a
twoꢀstep process. First Nꢀdetosylation was performed using NaꢀHg in DMF to get the
amines 24 and 25 respectively. Subsequent catalytic hydrogenation in presence of 10%
Pd/C under acidic medium deprotected both Oꢀ and Nꢀbenzyl groups to give the
aminocyclitols 26 and 27. As Nꢀacetyl derivatives of aminocyclitols have been shown to
be better inhibitors of Nꢀacetylhexosaminidases, chemoselective Nꢀacetylation of 26 and
3
2
2
7 have also been carried out to get compounds 28 and 29 (Scheme 4).
Total Synthesis of (ꢀ)ꢀconduramine Fꢀ4. Synthesis of (ꢀ)ꢀconduramine Fꢀ4 was
envisioned through the RCM of diene 8 that could be readily obtained by bisꢀWittig
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
olefination of 9. Thus, exposure of crude 9 to methyltriphenylphosphonium bromide in
presence of BuLi as a base proceeded to give the diene 8 in 60% yield (for two steps from
_
_______________________________________________________________________
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4. Synthesis of Aminocyclitols.
_
_______________________________________________________________________
10). Initial RCM of diene 8 with Grubbs'ꢀI catalyst was not successful. However,
Grubbs'ꢀII catalyst proved effective, albeit slow, and the protected (ꢀ)ꢀconduramine Fꢀ4
3
0 was isolated in 70% yield, in 72 h, along with 20% recovery of unreacted starting
material. NꢀDetosylation of compound 30 was then carried out with NaꢀHg to get the
amino derivative 31. When single step cleavage of both Nꢀ and Oꢀbenzyl groups of 31
was attempted under Birch condition, the reaction was not clean, resulting in the
formation of a complex mixture. In contrast, its Nꢀacetyl derivative 32, underwent a
smooth deprotection when exposed to Na/liq. NH to afford (ꢀ)ꢀconduramine Fꢀ4 5.
3
Advantageously, the intermediate 31 also allowed us to obtain Nꢀbenzylꢀ(ꢀ)ꢀconduramine
33
Fꢀ4 34 through chemoselective Oꢀ debenzylation in presence of Nꢀbenzyl group, by
exposing 31 to BCl . Nꢀbenzylꢀ(ꢀ)ꢀconduramine Fꢀ4 was isolated as its hydrochloride salt
3
33, which when neutralized with saturated NH OH liberated the free amine 34 (Scheme
4
5
).
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Scheme 5. Total Synthesis of (ꢀ)ꢀConduramine Fꢀ4 and its NꢀBenzyl Derivative
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
DMSO
oxalyl chloride
OBn
OBn
Ph PCH Br
3 3
CH
2 Grubb's-II
toluene,
BnO
BnO
BnO
BnO
Et N
3
n-BuLi
1
0
9
78 °C, 4 h
THF
78 °C
72 h
70%
(90% BRSM)
CH2
25 °C
N
N
15 h,
60% (two steps from 10)
Bn
Ts
Bn
Ts
8
30
Na-Hg
DMF 74%
6
5 °C
OH
OBn
OBn
Ac O, DMAP
2
Na/liq. NH3
Et N, CH Cl
HO
HO
BnO
BnO
3
2
2
BnO
BnO
7
0 °C, 5 h
35 °C, 5 h
52%
80%
NH2
N
CH3
NH
Bn
Bn
5
32
O
31
(
-)-conduramine F-4
BCl3
CH Cl 69%
2
2
0
°C, 1 h
OH
OH
HO
HO
sat. NH OH
HO
4
2
5 °C, 10 min.
HO
Bn
77%
NH
NH2
Bn
Cl
34
33
_
_______________________________________________________________________
Synthesis of Polyhydroxyaminoazepanes. Towards the synthesis of aminoꢀsubstituted
polyhydroxyazepanes, diol 10 was first converted to the dimesyl derivative 35. Upon
heating with benzylamine at 100 ºC, dimesylate 35 underwent a facile double
nucleophilic substitution to deliver the azepane 36. The reaction was also successful with
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
butylamine and hydroxyethyl amine, and the corresponding azepanes 37 and 38.
Protected azepanes 36ꢀ38 were taken through a twoꢀstep deprotection sequence to get the
final aminoꢀsubstituted polyhydroxyazepanes 42ꢀ44 in high yields. It has been reported
that polyhroxyazepanes with an acetamido group at 2ꢀposition were found to be strong
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
inhibitors of Nꢀacetylhexosaminidases. Hence it was of our interest to acetylate the C2ꢀ
amino group of compounds 42ꢀ44. The acetamido derivatives 45─47 were obtained in
good yields. However, in the case of compound 42, the reaction afforded diacetate 45
irrespective of the amount of acetic anhydride used in the reaction and efforts to
selectively acetylate the primary amino group at Cꢀ2 position did not succeed (Scheme
6
).
_
_______________________________________________________________________
Scheme 6. Synthesis of Aminoꢀsubstituted Polyhydroxyazepanes
_
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CONCLUSION
10
11
12
13
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16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
33
In summary, we have employed a 'reagentꢀbased diversity' on a triꢀOꢀbenzylꢀ
D
ꢀglucal
derived 'common precursor' for successful synthesis of three structurally different
molecules of biological and medicinal relevance. Moreover, our protocol involving an
earlyꢀstage installation of the amino group, is distinctly different from most of the
existing strategies that rely on its introduction towards the completion of the synthesis.
For the first time, application of McMurry coupling for the construction of the sixꢀ
membered ring of
aminocyclitols has been demonstrated. Total synthesis of (ꢀ)ꢀconduramine Fꢀ4 reported
here represents the first carbohydrate based approach. Extension of the present
methodology for the synthesis of aminoꢀazepanes to other amines would provide access
to a library of Nꢀsubstituted derivatives for structureꢀactivity relationship (SAR) studies.
The strategy presented in the manuscript is flexible to be adopted on other sugars for
obtaining different stereoisomers of these biologically important compounds.
EXPERIMENTAL SECTION
General Experimental Methods. All experiments were performed in oven–dried
apparatus and in dry solvents unless otherwise mentioned. Commercial grade solvents
were distilled and dried as per standard procedures and were stored over 4 Å molecular
sieves wherever applicable. IR spectra were recorded as a KBr pellet or neat (ATR) and
–1
expressed in cm . High resolution mass spectra were recorded on a Q–TOF instrument
1
13
using electrospray ionization (ESI) as the source. H NMR (300 and 400 MHz) and C
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1
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1
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1
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NMR (75 and 100 MHz) spectra were recorded using CDCl , CD OD, C D or D O as a
3
3
6
6
2
solvent. Chemical shifts have been reported in ppm downfield to tetramethylsilane and
coupling constants are expressed in Hertz (Hz). Optical rotations were measured at
indicated temperature and solvents. Commercial TLC plates were used and the spots
were visualized by exposure to the required developing agent/reagent. Column
chromatography was performed over silica gel (230–400 mesh).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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3
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8
9
0
1
2
3
4
5
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7
8
9
0
1,6ꢀDiꢀOꢀacetylꢀ3,4ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀ(pꢀtoluenesulfonamido)ꢀαꢀDꢀgluco
2
8
pyranose (13). Compound 14 (19.2 g, 31.8 mmol) was dissolved in a 5:1 mixture of
acetic anhydride (175 mL) and acetic acid (35 mL). Anhydrous zinc chloride (21.67 g,
1
59 mmol) was added to the reaction mixture portion wise over a period of 10 minutes.
The reaction mixture was then stirred at room temperature under nitrogen atmosphere
After completion of the reaction (16 h, TLC), ethyl acetate (500 mL) was added to the
reaction mixture and it was washed with water (6 x 200 mL) followed by saturated
aqueous sodium bicarbonate solution (4 x 100 mL). Solvent was removed under vacuum
and the resulting crude reaction mixture was purified by column chromatography over
silica gel using ethyl acetate as an eluent to get the diacetate 13 as a pale yellow viscous
liquid. Crystallization of the product in a mixture of ethyl acetate in hexane (1:4) afforded
compound 13 (17.1 g, 90%) as white crystals. Mp 102ꢀ105 °C; TLC: R 0.5 (hexane/ethyl
f
31
acetate, 3:2); [α]D +38.5 (c 0.53, CHCl ); IR (KBr) ν 3246, 3064, 3033, 2984, 2920,
3
max
2
9
8
878, 1771, 1714, 1598, 1495, 1446, 1373, 1337, 1267, 1210, 1162, 1134, 1084, 1051,
ꢀ1 1
32, 899, 849, 813, 739, 696, 667, 613 cm . H NMR (300 MHz, CDCl ) δ 7.73 (d, J =
3
.7 Hz, 2H), 7.30ꢀ7.16 (m, 12H), 5.81 (d, J = 3.9 Hz, 1H), 5.57 (t, J = 9.3 Hz, 1H
exchangeable with D O), 4.83 (d, J = 9.9 Hz, 1H), 4.77 (d, J = 10.8 Hz, 1H), 4.69 (d, J =
2
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0.8 Hz, 1H), 4.49 (d, J = 10.8 Hz, 1H), 4.26ꢀ4.14 (m, 2H), 3.82ꢀ3.77 (m, 1H), 3.72 (m,
13
1
H), 3.60ꢀ3.57 (m, 2H), 2.36 (s, 3H), 2.05 (s, 3H), 2.01 (s, 3H); C NMR (75 MHz,
CDCl ) δ 170.6 (s), 168.9 (s), 143.9 (s), 137.7 (s), 137.37 (s), 137.34 (s), 129.9 (d), 128.5
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
d), 128.3 (d), 128.0 (d), 127.9 (d), 127.8 (d), 126.8 (d), 90.7 (d), 79.9 (d), 77.1 (d), 75.7
+
(t), 75.1 (t), 70.8 (d), 62.3 (t), 56.1 (d), 21.5 (q), 20.8 (2 x q); HRMS (ESI): [M + Na]
calcd for C H NNaO S: 620.1925; found: 620.1909.
3
1
35
9
3,4ꢀDiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀ(pꢀtoluenesulfonamido)ꢀDꢀglucitol (16). Diacetate
13 (5 g, 8.37 mmol) was dissolved in dry THF (50 mL) under nitrogen atmosphere.
°
Reaction mixture was immersed in an ice bath (0 C) and LiAlH (1.11 g, 29.18 mmol)
4
was added to the reaction mixture, in portions, over a period of 20 min. The reaction
o
o
mixture was subsequently refluxed at 65 C for 16 h after which it was cooled to 0 C
(bath temperature) and 10% HCl solution was added dropwise until the effervescence
subsided. Water (100 mL) was then added and extracted with ethyl acetate (3 x 100 mL).
Solvent was evaporated under vacuum to get the crude product as a white solid.
Purification of the product by column chromatography over silica gel using a mixture of
hexane and ethyl acetate (2:3) afforded triol 16 (3.7 g, 86%) as a white solid. Mp 108ꢀ111
19
°
C; TLC: R 0.3 (hexane/ethyl acetate, 1:4); [α]D +5.05 (c 0.97, CH Cl ); IR (KBr) ν
f 2 2 max
3
562, 3490, 3265, 3063, 3032, 2936, 2879, 1598, 1496, 1453, 1319, 1124, 1044, 931,
ꢀ1 1
875, 814, 734, 696, 679, 651 cm . H NMR (300 MHz, CDCl ) δ 7.65 (d, J = 8.1 Hz,
3
2
1
H), 7.27ꢀ7.16 (m, 12H), 5.24 (bm, 1H exchangeable with D O), 4.67 (d, J = 11.4 Hz,
2
H), 4.59 (d, J = 11.4 Hz, 1H), 4.50 (d, J = 11.4 Hz, 1H), 4.43 (d, J = 11.4 Hz, 1H), 3.75
(bs, 1H), 3.61ꢀ3.58 (m, 3H), 3.55ꢀ3.51 (m, 2H), 3.43 (dd, J = 11.4, 4.2 Hz, 1H), 3.23 (dd,
13
J = 11.1, 6.3 Hz, 1H), 2.32 (s, 3H), 2.16 (bm, 3H exchangebale with D O); C NMR (75
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
MHz, CDCl ) δ 142.7 (s), 138.1 (s), 137.9 (s), 129.2 (d), 128.0 (d), 127.8 (d), 127.5 (d),
3
1
27.9 (d), 127.2 (d), 126.6 (d), 78.5 (d), 77.9 (d), 74.4 (t), 73.6 (t), 71.9 (d), 63.0 (t), 61.4
+
(
t), 55.7 (d), 21.1 (q); HRMS (ESI): [M + H] calcd for C H NO S: 516.2050; found:
2
7
34
7
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
16.2050.
3,4ꢀDiꢀOꢀbenzylꢀ1,6ꢀdiꢀOꢀ(tertꢀbutyldimethylsilyl)ꢀ2ꢀdeoxyꢀ2ꢀ(pꢀtoluenesulfon
amido)ꢀ ꢀglucitol (17). A solution of triol 16 (8.1 g, 15.71 mmol) in dry CH Cl (80 mL)
D
2
2
was cooled to 0 °C. Imidazole (2.35 g, 34.56 mmol) and TBSCl (5.21 g, 34.56 mmol)
°
were added successively at 0 C and the reaction mixture was stirred at the same
temperature. After completion (1.5 h, TLC), reaction was stopped and solvent was
evaporated under vacuum. Ethyl acetate (300 mL) was added to the resulting residue and
the organic layer was washed with water (3 x 200 mL) and solvent was evaporated under
vacuum to get the crude product as a white mass. Purification of the product by column
chromatography over silica gel using a mixture of hexane and ethyl acetate (9:1) afforded
the bisꢀsilylated derivative 17 (10.3 g, 88%) as a white solid. Mp 109ꢀ111 °C; TLC: Rf
31
0
.55 (hexane/ethyl acetate, 4:1); [α]D +16.8 (c 0.77, CH Cl ); IR (KBr) ν 3484, 3166,
2
2
max
3031, 2953, 2927, 2881, 2855, 1598, 1460, 1403, 1358, 1336, 1256, 1164, 1096, 1066,
ꢀ1 1
1
049, 933, 836, 814, 773, 732, 675, 701, 666 cm . H NMR (300 MHz, CDCl ) δ 7.66
3
(d, J = 7.8 Hz, 2H), 7.25ꢀ7.16 (m, 12H), 4.98 (d, J = 8.4 Hz, 1H), 4.71 (d, J = 10.8 Hz,
1H), 4.58 (d, J = 11.4 Hz, 1H), 4.46 (m, 2H), 3.91 (dd, J = 6.6, 2.1 Hz, 1H), 3.61ꢀ3.50
(
m, 5H), 3.40ꢀ3.30 (m, 2H), 2.32 (s, 3H), 1.56 (bs, 1H exchangeable with D O), 0.84 (s,
2
1
3
9
H), 0.74 (s, 9H), ꢀ0.001 (s, 3H), ꢀ0.004 (s, 3H), ꢀ0.12 (s, 3H), ꢀ0.13 (s, 3H); C NMR
(
75 MHz, CDCl ) δ 143.2 (s), 138.4 (s), 138.26 (s), 138.24 (s), 129.6 (d), 128.45 (d),
3
1
28.41 (d), 128.0 (d), 127.9 (d), 127.8 (d), 127.6 (d), 127.1 (d), 78.4 (d), 77.5 (d), 75.3
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(
t), 74.3 (t), 72.5 (d), 63.7 (t), 62.1 (t), 55.6 (d), 26.0 (q), 25.9 (q), 21.5 (q), 18.3 (s), 18.1
+
(s), ꢀ5.23 (q), ꢀ5.27 (q), ꢀ5.42 (q),
ꢀ5.49 (q); HRMS (ESI): [M + Na] calcd for
C H NNaO SSi : 766.3602; found: 766.3592.
39
61
7
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3
,4ꢀDiꢀOꢀbenzylꢀ1,5,6ꢀtriꢀOꢀ(tertꢀbutyldimethylsilyl)ꢀ2ꢀdeoxyꢀ2ꢀ(pꢀtoluenesulf
onamido)ꢀ ꢀglucitol (18). To a solution of disilyl compound 17 (0.2 g, 0.27 mmol) in
D
dry DMF (1.5 mL) were added imidazole (0.183 g, 2.69 mmol) and TBSCl (0.121 g, 0.80
o
mmol) at room temperature (32 C). After completion (22 h, TLC), ethyl acetate (50 mL)
was added to the reaction mixture and washed with water (7 x 20 mL). Solvent was
evaporated under vacuum to get the crude product as a pale yellow liquid. Purification of
the product by column chromatography over silica gel using a mixture of hexane and
ethyl acetate (9.5:0.5) afforded the trisꢀsilylated derivative 18 (0.21 g, 91%) as a viscous
30
transparent liquid. TLC:R 0.35 (hexane/ethyl acetate, 9:1); [α]D +8.4 (c 1.2, CHCl ); IR
f
3
(
KBr) νmax 3284, 3032, 2931, 2857, 1465, 1411, 1335, 1254, 1160, 1089, 841, 777, 662
ꢀ1 1
cm . H NMR (400 MHz, CDCl ) δ 7.75 (d, J = 8.4 Hz, 2H), 7.35ꢀ7.23 (m, 12H), 4.94
3
(
d, J = 9.6 Hz, 1H exchangeable with D O), 4.89 (d, J = 11.2 Hz, 1H), 4.75 (d, J = 11.2
2
Hz, 1H), 4.66 (d, J = 11.2 Hz, 1H), 4.47 (d, J = 11.2 Hz, 1H), 4.11ꢀ4.09 (m, 1H), 4.04 (d,
J = 8.0 Hz, 1H), 3.81 (dd, J = 7.6, 2.0 Hz, 1H), 3.75ꢀ3.66 (m, 2H), 3.55ꢀ3.49 (m, 1H),
3
.38 (t, J = 9.6 Hz, 1H), 3.24 (dd, J = 9.6, 4.8 Hz, 1H), 2.42 (s, 3H), 0.96 (s, 9H), 0.95 (s,
9H), 0.83 (s, 9H), 0.19 (s, 3H), 0.18 (s, 3H), 0.12 (s, 3H), 0.11 (s, 3H), ꢀ0.061 (s, 3H), ꢀ
13
0
1
.066 (s, 3H); C NMR (75 MHz, CDCl ) δ 143.1 (s), 139.27 (s), 139.21 (s), 138.6 (s),
3
29.6 (2 x d), 128.3 (2 x d), 128.1 (2 x d), 127.83 (2 x d), 127.80 (2 x d), 127.5 (d), 127.3
(
d), 126.9 (2 x d), 82.3 (d), 75.6 (d), 75.06 (t), 75.03 (d), 74.7 (t), 64.5 (t), 62.1 (t), 56.6
d), 26.2 (3 x q), 26.0 (3 x q), 25.9 (3 x q), 21.4 (q), 18.5 (s), 18.2 (s), 18.1 (s), ꢀ4.2 (q), ꢀ
(
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+
4
.5 (q), ꢀ5.1 (q),
ꢀ5.2 (q), ꢀ5.53 (q), ꢀ5.55 (q); HRMS (ESI): [M + Na] calcd for
C H NNaO SSi : 880.4465; found: 880.4464.
45 75
7
3
3
,4,5ꢀTriꢀOꢀbenzylꢀ1,6ꢀdiꢀOꢀ(tertꢀbutyldimethylsilyl)ꢀ2ꢀdeoxyꢀ2ꢀ(NꢀbenzylꢀNꢀ
0
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8
9
0
pꢀtoluenesulfonyl)aminoꢀ ꢀglucitol (20). A solution of compound 17 (10.2 g, 13.71
D
mmol) in dry DMF (100 mL) was cooled to 0 °C. Sodium hydride (1.64 g in 60%
paraffin oil, 41.12 mmol) was added over a period of 30 min while stirring at 0 °C
followed by benzyl bromide (3.58 mL, 30.16 mmol). The reaction mixture was then
stirred at 10 °C for 2 h, cooled to 0 °C and quenched by dropwise addition of saturated
ammonium chloride solution until the effervesence stopped. An additional 300 mL water
was added to the reaction mixture and it was extracted with ethyl acetate (3 x 100 mL).
The combined organic layer was concentrated under vacuum to get crude product as a
white solid. Purification by column chromatography over silica gel using a mixture of
hexane and ethyl acetate (9:0.5) as an eluent afforded the benzylated derivative 20 (10.5
19
g, 83%) as a colorless viscous liquid. TLC: R 0.4 (hexane/ethyl acetate, 9:1); [α]D +33.1
f
(
c 0.48, CH Cl ); IR (neat) ν 3029, 2953, 2931, 2886, 2857, 1599, 1495, 1457, 1343,
2 2 max
ꢀ1 1
1254, 1161, 1093, 1044, 1004, 842, 777, 698, 675 cm . H NMR (300 MHz, CDCl ) δ
3
7
.61 (d, J = 8.1 Hz, 2H), 7.40ꢀ7.07 (m, 22H), 4.80 (d, J = 11.7 Hz, 1H), 4.69ꢀ4.62 (m,
H), 4.57ꢀ4.50 (m, 2H), 4.40 (d, J = 10.5 Hz, 1H), 4.33 (d, J = 15.9 Hz, 1H), 4.15ꢀ4.07
2
(m, 2H), 4.00 (t, J = 5.4 Hz, 1H), 3.96ꢀ3.83 (m, 4H), 3.79ꢀ3.74 (m, 1H), 3.30 (bm, 1H),
2
3
1
.35 (s, 3H), 0.91 (s, 9H), 0.77 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H), ꢀ0.11 (s, 3H), ꢀ0.13 (s,
1
3
H); C NMR (75 MHz, CDCl ) δ 143.1 (s), 139.4 (s), 139.2 (s), 138.9 (s), 138.5 (s),
3
37.9 (s), 129.5 (d), 129.1 (d), 128.2 (d), 128.0 (d), 127.7 (d), 127.4 (d), 127.3 (d), 127.2
(
d), 127.1 (d), 81.4 (d), 79.9 (d), 78.5 (d), 75.0 (t), 74.1 (t), 72.8 (t), 63.4 (t), 61.5 (d),
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0.7 (t), 50.0 (t), 26.1 (q), 25.9 (q), 21.5 (q), 18.4 (s), 18.1 (s), ꢀ5.10 (q), ꢀ5.12 (q), ꢀ5.4
+
(2xq); HRMS (ESI): [M + Na] calcd for C H NNaO SSi : 946.4538; found: 946.4534.
53 73
7
2
3,4,5ꢀTriꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀ(NꢀbenzylꢀNꢀpꢀtoluenesulfonyl)aminoꢀDꢀ
10
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glucitol (10). Compound 20 (10 g, 10.82 mmol) was taken in a 100 mL round bottomed
flask and dissolved with dry MeOH (100 mL). Camphorꢀ10ꢀsulfonic acid (0.502 g, 20
mol%) was added to it. After 12.5 h (TLC), the reaction was stopped and the solvent was
evaporated under vacuum. The crude reaction mixture was purified by column
chromatography over silica gel using a mixture of hexane and ethyl acetate (7:3) as an
eluent to get 10 (6.5 g, 86%) as a colorless viscous liquid. TLC: R 0.4 (hexane/ethyl
f
25
acetate, 1:1); [α]D +17.1 (c 1.5, CH Cl );IR (neat) ν 3431, 3062, 3029, 2924, 2875,
2
2
max
ꢀ1 1
1598, 1495, 1454, 1335, 1210, 1158, 1091, 858, 815, 734, 697 cm . H NMR (300 MHz,
CDCl ) δ 7.66 (d, J = 8.1 Hz, 2H), 7.39ꢀ7.14 (m, 22H), 4.68 (d, J = 11.4 Hz, 1H), 4.58ꢀ
3
4
2
.50 (m, 4H), 4.44ꢀ4.35 (m, 3H), 4.17ꢀ4.158 (m, 1H), 3.93ꢀ3.87 (m, 3H), 3.81ꢀ3.76 (m,
H), 3.61 (dd, J = 11.7, 5.4 Hz, 1H), 3.38 (dd, J = 11.7, 6.3 Hz, 1H), 2.38 (s, 3H), 2.05
13
(
bm, 2H exchangeable with D O); C NMR (75 MHz, CDCl ) δ 143.3 (s), 138.2 (s),
2
3
138.0 (s), 137.5 (s), 129.5 (d), 128.9 (d), 128.4 (d), 128.39 (d), 128.30 (d), 128.2 (d),
28.0 (d), 127.8 (d), 127.79 (d), 127.71 (d), 127.5 (d), 127.3 (d), 79.7 (d), 78.5 (d), 77.6
1
(d), 74.4 (t), 74.1 (t), 71.9 (t), 61.5 (d), 60.9 (t), 60.7 (t), 50.0 (t), 21.4 (q); HRMS (ESI):
+
[M + Na] calcd for C H NNaO S:718.2809; found: 718.2806.
4
1
45
7
3,4,5ꢀTriꢀOꢀbenzylꢀ2ꢀdeoxyꢀ2ꢀ(NꢀbenzylꢀNꢀpꢀtoluenesulfonyl)aminoꢀDꢀglucoꢀ
hexodialdehyde (9). A solution of oxalyl chloride (1.24 mL, 14.37 mmol) in dry
dichloromethane (40 mL) was cooled to −78 °C. Dry DMSO (1.02 mL, 14.37 mmol) was
added to it dropwise over a period of 10 min under nitrogen atmosphere. The reaction
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mixture was allowed to stir for 20 min at this temperature and then diol 10 (1 g, 1.44
mmol) dissolved in 10 mL of dry dichloromethane was added slowly over a period of 15
min. The reaction mixture was then stirred at −78 °C for 3 h. Triethylamine (4.01 mL,
0
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0
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8.74 mmol) was added to it over a period of 15 min. The reaction vessel was taken away
from the cooling bath and stirred at 25 °C (bath temperature) for 30 min, after which
ethyl acetate (200 mL) was added to it. The organic layer was washed with water (7 x 60
mL) and concentrated under vacuum. The crude dialdehyde 9 was obtained as a pale
yellow viscous liquid (0.99 g, 99.6%). As the dialdehyde was quite unstable, it was taken
1
for subsequent reaction, without purification, after ascertaining its formation through Hꢀ
NMR spectrum.
(1R,2S,3R,4S,5S,6S)ꢀ1,2,3ꢀTriꢀOꢀbenzylꢀ6ꢀ(NꢀbenzylꢀNꢀpꢀtoluesulfonyamino)ꢀ
4
,5ꢀdihydroxycyclohexane (21) and (1R,2S,3R,4R,5S,6S)ꢀ1,2,3ꢀTriꢀOꢀbenzylꢀ6ꢀ(Nꢀ
benzylꢀNꢀpꢀtoluensulfonyl)aminoꢀ4,5ꢀdihydroxycyclohexane (22). In a 100 mL round
bottomed flask, TiCl (1.57 mL, 14.31 mmol) was taken in dry THF (20 mL) and cooled
4
°
to 0 C. Zinc powder (1.87 g, 28.62 mmol) was added to it portion wise, during which the
color of the reaction mixture changed from yellow to violet. Cuprous chloride (0.028 g,
°
0
.29 mmol) was then added to it and refluxed at 80 C for 1 h. Crude dialdehyde 9 (0.99
g, 1.43 mmol) dissolved in dry THF (10 mL) was added dropwise over a period of 30
°
min and refluxing was continued for 4 h. The reaction mixture was cooled to 0 C and
quenched with saturated sodium bicarbonate solution. The resulting mass was filtered
through a Celite bed. The residue was washed with ethyl acetate (3 x 10 mL) and water
(100 mL) was added to the filtrate and the organic layer was separated. The aqueous layer
was further extracted with ethyl acetate (3 x 20 mL). The combined organic layer was
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concentrated under vacuum. Purification of the product was done by column
chromatography over silica gel using a mixture of hexane and ethyl acetate (3:1) as an
eluent to get the cyclic diols 21 (0.25 g, 25%) as a colorless viscous liquid and 22 (0.38 g,
10
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17
18
19
20
21
22
23
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3
8%) as a white solid.
25
Data for compound 21. TLC:R 0.55 (hexane/ethyl acetate, 1:1); [α]D −9.25 (c
f
0
1
.92, CHCl ); IR (KBr) νmax 3481, 3061, 3029, 2920, 1598, 1494, 1452, 1321, 1207,
3
ꢀ
1 1
150, 1092, 927, 868, 812, 732, 696 cm . H NMR (300 MHz, CDCl ) δ 7.68 (d, J = 7.5
3
Hz, 2H), 7.34ꢀ6.93 (m, 22H), 4.74ꢀ4.69 (m, 2H), 4.62ꢀ4.39 (m, 5H), 4.17ꢀ4.10 (m, 1H),
4
.03ꢀ3.87 (m, 4H), 3.67 (d, J = 15.9 Hz, 1H), 3.17 (d, J = 10.5 H, 1H), 3.09 (bs, 1H D O
2
1
exchangeable), 2.52 (bs, 1H D O exchangeable), 2.27 (s, 3H); H NMR (300 MHz,
2
MeOD) δ 7.73 (d, J = 7.5 Hz, 2H), 7.33ꢀ7.04 (m, 22H), 4.65ꢀ4.47 (m, 5H), 4.40ꢀ4.30 (m,
3
1
1
1
H), 4.05 (d, J = 15.6 Hz, 1H), 3.93ꢀ3.88 (m, 3H), 3.72 (t, J = 9.6 Hz, 1H), 3.58 (d, J =
1
3
0.2 Hz, 1H), 2.30 (s, 3H); C NMR (75 MHz, CDCl ) δ 142.9 (s), 138.4 (s), 138.2 (s),
3
37.2 (s), 129.1 (d), 128.6 (d), 128.3 (d), 128.2 (d), 128.0 (d), 127.9 (d), 127.88 (d),
27.82 (d), 127.6 (d), 127.5 (d), 127.4 (d), 127.2 (d), 82.4 (d), 75.3 (d), 73.4 (t), 73.0 (t),
1
3
72.5 (t), 69.0 (d), 67.6 (d), 61.0 (d), 47.5 (t), 21.5 (q); C NMR (75 MHz, MeOD) δ
44.1 (s), 140.1 (s), 139.9 (s), 139.6 (s), 139.4 (s), 138.6 (s), 130.3 (d), 130.1 (d), 129.3
d), 129.2 (d), 129.09 (d), 129.06 (d), 129.02 (d), 128.8 (d), 128.63 (d), 128.61 (d), 128.2
1
(
(d), 83.5 (d), 77.2 (d), 76.1 (d), 74.4 (t), 74.1 (t), 73.4 (t), 70.8 (d), 67.9 (d), 61.9 (d), 48.3
+
(t), 21.5 (q); HRMS (ESI): [M + Na] calcd for C H NNaO S: 716.2652; found:
4
1
43
7
7
16.2652.
Data for compound 22. Mp 102ꢀ105 °C; TLC: R 0.35 (hexane/ethyl acetate,
f
25
1
:1); [α]D
̶ 3.6 (c 0.573, CHCl ); IR (KBr) ν 3577, 3383, 3061, 3030, 2922, 2886,
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598, 1495, 1452, 1403, 1359, 1330, 1259, 1210, 1157, 1114, 1081, 1053, 926, 887, 812,
ꢀ1 1
44, 698, 659 cm . H NMR (300 MHz, CDCl ) δ 7.71 (d, J = 8.1 Hz, 2H), 7.38ꢀ7.03 (m,
3
2H), 4.83 (d, J = 11.4 Hz, 1H), 4.69ꢀ4.53 (m, 4H), 4.48ꢀ4.41 (m, 2H), 3.98ꢀ3.92 (m,
H), 3.73 (d, J = 15.6 Hz, 1H), 3.54ꢀ3.47 (m, 1H), 3.37ꢀ3.33 (m, 1H), 3.28ꢀ3.22 (m, 1H),
0
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0
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3
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0
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4
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8
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0
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3
4
5
6
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8
9
0
2.40 (d, J = 3.6 Hz, 1H, D O exchangeable), 2.30 (s, 3H), 2.25 (d, J = 5.7 Hz 1H, D O
2
2
1
exchangeable); H NMR (300 MHz, MeOD) δ 7.76 (d, J = 8.1 Hz, 2H), 7.35ꢀ7.22 (m,
7H), 7.14ꢀ7.10 (m, 3H), 6.97 (t, J = 7.5 Hz, 2H), 4.79ꢀ4.71 (m, 2H), 4.63 (d, J = 11.4
1
Hz, 1H), 4.56ꢀ4.51 (m, 2H), 4.26ꢀ4.10 (m, 3H), 4.06ꢀ3.99 (m, 2H), 3.77ꢀ3.66 (m, 2H),
13
3
.55 (dd, J = 9.9, 1.2 Hz, 1H), 3.45 (dd, J = 9.0, 1.2 Hz, 1H), 2.34 (s, 3H); C NMR (75
MHz, CDCl ) δ 142.9 (s), 138.8 (s), 138.3 (s), 137.8 (s), 137.7 (s), 137.0 (s), 129.1 (d),
3
128.8 (d), 128.5 (d), 128.4 (d), 128.29 (d), 128.24 (d), 128.1 (d), 127.9 (d), 127.8 (d),
1
27.6 (d), 127.5 (d), 127.4 (d), 83.6 (d), 76.4 (d), 74.6 (t), 73.9 (d), 73.7 (d), 73.5 (t), 72.5
1
3
(t), 69.3 (d), 62.6 (d), 47.3 (t), 21.5 (q); C NMR (75 MHz, MeOD) δ 144.1 (s), 140.5
(s), 140.1 (s), 139.63 (s), 139.60 (s), 138.4 (s), 130.5 (d), 130.0 (d), 129.5 (d), 129.35 (d),
1
29.31 (d), 129.1 (d), 129.0 (d), 128.99 (d), 128.97 (d), 128.6 (d), 128.4 (d), 128.2 (d),
84.7 (d), 78.8 (d), 76.5 (d), 75.8 (t), 74.8 (d), 74.6 (t), 73.3 (t), 69.4 (d), 64.0 (d), 48.1 (t),
+
2
1.4 (q); HRMS (ESI): [M + Na] calcd for C H NNaO S: 716.2652; found: 716.2651.
4
1
43
7
(1S,2R,3S,4S,5R,6R)ꢀ1,2ꢀBisꢀ(4ꢀnitro)benzoyloxyꢀ3,4,5ꢀtriꢀOꢀbenzylꢀ6ꢀ(Nꢀ
benzylꢀNꢀpꢀtoluensulfonyl)aminocyclohexane (23). Diol 21 (0.04 g, 0.057 mmol)
dissolved in dry dichloromethane (0.6 mL)was taken in a 100 mL round bottomed flask.
4
ꢀNitrobenzoyl chloride (0.0267 g, 0.144 mmol), triethyl amine (0.0261 mL, 0.173
mmol) and DMAP (0.0014 g, 0.0115 mmol) were added to it sequentially and it was
o
stirred at 23 C for 5 h. Dichloromethane (30 mL) was added to the reaction mixture,
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washed with water (3 x 10 mL) and the solvent was concentrated under vacuum.
Purification of the product was done through column chromatography over silica gel
using a mixture of hexane and ethyl acetate (9:0.5) as an eluent to get bisꢀ4ꢀnitrobenzoyl
10
11
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derivative 23 (0.052 g, 91%) as a pale yellow low melting solid. TLC: R 0.34
f
27
(hexane/ethyl acetate, 9:1); [α]D −43.57 (c 0.28, CHCl ); IR (KBr) ν 3060, 3030,
3
max
2
8
923, 1735, 1604, 1528, 1496, 1454, 1344, 1277, 1209, 1157, 1097, 1013, 928, 870, 843,
ꢀ1 1
14, 782, 747, 720, 699, 661, 601 cm . H NMR (300 MHz, C D ) δ 8.36 (d, J = 8.4 Hz,
6
6
2H), 7.94 (d, J = 7.8 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 3H), 7.61 (d,
J = 8.4 Hz, 3H), 7.41ꢀ7.34 (m, 5H), 7.27 (t, J = 7.2 Hz, 3H), 7.12ꢀ7.05 (m, 6H), 6.99ꢀ6.94
(m, 3H), 6.61 (d, J = 7.8 Hz, 2H), 6.26 (t, J = 3.3 Hz, 1H), 5.47 (dd, J = 11.1, 10.8 Hz,
1H), 5.04 (d, J = 10.2 Hz, 1H), 4.93 (d, J = 11.4 Hz, 1H), 4.64ꢀ4.39 (m, 8H), 4.15 (d, J =
13
7
.5 Hz, 1H), 3.90 (t, J = 3.0 Hz, 1H), 3.47 (d, J = 15.6 Hz, 1H), 1.85 (s, 3H); C NMR
(
75 MHz, C D ) δ 164.1 (s), 163.9 (s), 151.0 (s), 150.9 (s), 142.8 (s), 138.6 (s), 138.5 (s),
6 6
1
37.9 (s), 137.8 (s), 136.8 (s), 134.9 (s), 134.2 (s), 131.3 (d), 130.7 (d), 129.3 (d), 129.2
(d), 129.1 (d), 128.8 (d), 128.7 (d), 128.6 (d), 128.5 (d), 127.8 (d), 123.8 (d), 123.7 (d),
82.6 (d), 74.2 (t), 73.7 (d), 73.18 (t), 73.18 (d), 72.5 (t), 69.9 (d), 69.1 (d), 58.5 (d), 47.5
+
(
t), 21.1 (q); HRMS (ESI): [M + Na] calcd for C H N NaO S: 1014.2878; found:
5
5
49
3
13
1
014.2863.
General procedure for Nꢀdetosylation reaction: NꢀTosylated derivative (1
equiv.) was dissolved in a solvent mixture of DMF and methanol. Disodium hydrogen
phosphate dihydrate (5 equiv.) was added to the reaction mixture followed by 3% Na–Hg
o
(
20 equiv.). The reaction mixture then stirred at 65 C and after completion (TLC), ethyl
acetate was added to it, washed with water and solvent was concentrated under vacuum.
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Purification of the product was done by column chromatography over silica gel to get the
Nꢀdetosylated derivatives.
(1R,2S,3R,4S,5S,6S)ꢀ1,2,3ꢀTrisꢀbenzyloxyꢀ6ꢀ(Nꢀbenzylamino)ꢀ4,5ꢀ
0
1
2
3
4
5
6
7
8
9
0
1
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4
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7
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9
0
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0
dihydroxycyclohexane (24). Compound 21 (0.8 g, 1.15 mmol) was subjected to Nꢀ
detosylation reaction as per the general procedure described above in DMF (15 mL) and
methanol (5 mL), in presence of Na HPO 2H O (1.03 g, 5.76 mmol) and 3% Na–Hg
2
4.
2
(17.67 g, 23.06 mmol) for 3.5 h. Product was purified by column chromatography using a
mixture of hexane and ethyl acetate (2:3) to get 24 (0.55 g, 88%) as a colorless viscous
18
liquid. TLC: R 0.39 (hexane/ethyl acetate, 1:4); [α]D −8.57 (c 0.21, CHCl ); IR (KBr)
f
3
ꢀ1
νmax 3410, 3063, 3029, 2905, 2869, 1495, 1453, 1367, 1215, 1097, 1061, 750,697 cm .
1
H NMR (300 MHz, CDCl ) δ 7.34ꢀ7.20 (m, 20H), 5.06 (d, J = 11.1 Hz, 1H), 4.80ꢀ4.63
3
(m, 5H), 4.16 (t, J = 3.3 Hz, 1H), 3.99ꢀ3.88 (m, 4H), 3.79 (dd, J = 10.2, 2.7 Hz, 1H), 3.71
1
3
(
d, J = 12.6 Hz, 1H), 2.88 (t, J = 9.3 Hz, 1H), 2.01 (bm, 3H D O exchangeable); C
2
NMR (75 MHz, CDCl ) δ 140.1 (s), 138.7 (s), 138.5 (s), 138.4 (s), 128.5 (d), 128.44 (d),
3
1
28.41 (d), 128.29 (d), 128.25 (d), 128.06 (d), 128.03 (d), 127.76 (d), 127.72 (d), 127.6
(d), 127.1 (d), 81.7 (d), 78.4 (d), 75.8 (d), 74.9 (t), 73.3 (t), 72.6 (t), 68.9 (d), 68.8 (d),
+
5
9.7 (d), 50.0 (t); HRMS (ESI): [M + H] calcd for C H NO : 540.2744; found:
3
4
38
5
5
40.2744.
(1R,2S,3R,4R,5S,6S)ꢀ1,2,3ꢀTrisꢀbenzyloxyꢀ6ꢀ(benzylamino)ꢀ4,5ꢀ
dihydroycyclohexane (25). Compound 22 (0.75 g, 1.08 mmol) was subjected to Nꢀ
detosylation reaction as per the general procedure described above in DMF (15 mL) and
methanol (5 mL), in presence of Na HPO 2H O (0.962 g, 5.4 mmol) and 3% Na–Hg
2
4.
2
(16.57 g, 21.62 mmol) for 4 h. Product was purified by column chromatography using a
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mixture of hexane and ethyl acetate (1:1) to get 25 (0.483 g, 83%) as a white solid. Mp
34
6
8ꢀ71 °C; TLC: R 0.46 (hexane/ethyl acetate, 1:4); [α]D
̶ 2.51 (c 2.31, CHCl ); IR
3
f
(KBr) νmax 3390, 3061, 3029, 2915, 1600, 1492, 1455, 1360, 1212, 1143, 1058, 733, 697,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
35
36
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38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ꢀ1 1
6
03 cm . H NMR (300 MHz, CDCl ) δ 7.36ꢀ7.27 (m, 17H), 7.24ꢀ7.22 (m, 3H),5.05 (dd,
3
J = 11.1, 5.1 Hz 2H), 4.77ꢀ4.66 (m, 4H), 4.08 (t, J = 2.4 Hz, 1H), 4.02ꢀ3.92 (m, 2H), 3.80
(
d, J = 12.9 Hz, 1 H), 3.71 (t, J = 9.9 Hz, 1H), 3.53 (dd, J = 9.6, 2.4 Hz, 1H), 3.41 (dd, J
13
=
9.3, 2.7 Hz, 1H), 2.50 (t, J = 10.2 Hz, 1H), 1.68 (bm, 3H D O exchangeable); C NMR
2
(75 MHz, CDCl ) δ 140.3 (s), 138.8 (s), 138.6 (s), 138.1 (s), 128.59 (d), 128.54 (d), 128.4
3
(
d), 128.3 (d), 128.1 (d), 127.8 (d), 127.7 (d), 127.1 (d), 83.1 (d), 79.2 (d), 77.2 (d), 75.3
+
(
t), 74.9 (t), 73.6 (d), 72.7 (t), 71.6 (d), 62.2 (d), 51.3 (t); HRMS (ESI): [M + H] calcd for
C H NO : 540.2744; found: 540.2739.
34
38
5
(1R,2S,3s,4S,5S,6s)ꢀ6ꢀAminoꢀ1,2,3,4,5ꢀpentahydroxycyclohexane
(26).
Compound 24 (0.15 g, 0.278 mmol) was dissolved in ethanol (3 mL). 10% Palladium on
charcoal (0.03 g, 20% w/w) was added followed by slow addition of HCl (0.1 mL).
Hydrogen gas was bubbled slowly in to the reaction mixture continuously while stirring
at room temperature for 44 h. The reaction mixture was filtered through bed of Celite pad
and the filtrate was concentrated under vacuum. After neutralization by the addition of
aqueous ammonium hydroxide solution (~1 mL), the resulting solution was directly
loaded on to a silica gel column and purified using a mixture of acetonitrile and aqueous
ammonium hydroxide solution (3:1) to get 26 (0.04 g, 80%) as colorless viscous liquid.
28
D
TLC: R 0.24 (CH CN /NH OH, 3:2); [α]
̶ 40.22 (c 0.44, H O); IR (neat) ν 3491,
2 max
f
3
4
ꢀ1 1
3
083, 2925, 1529, 1409, 1099, 1073 cm . H NMR (300 MHz, D O) δ 3.84 (bm, 2H),
2
3
.67 (dd, J = 10.5, 1.8 Hz, 1H), 3.56 (dd, J = 9.9, 2.1 Hz, 1H), 3.46 (t, J = 9.9 Hz, 1H),
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5
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1
2
.94 (t, J = 10.5 Hz, 1H); H NMR (300 MHz, MeOD) δ 3.99 (bm, 2H), 3.86 (d, J = 10.5
1
3
Hz, 1H), 3.75ꢀ3.66 (m, 2H), 3.12 (t, J = 10.2 Hz, 1H); C NMR (75 MHz, D O) δ 71.49
2
+
(
d), 71.40 (d), 70.5 (d), 70.1 (d), 68.2 (d), 54.4 (d); HRMS (ESI): [M + H] calcd for
0
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4
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C H NO : 180.0866; found: 180.0867.
6
14
5
(1R,2S,3s,4R,5S,6s)ꢀ6ꢀAminoꢀ1,2,3,4,5ꢀpentahydroxycyclohexane
(27).
Compound 25 (0.2 g, 0.37 mmol) was dissolved in ethanol (4 mL). 10% Palladium on
charcoal (0.04 g, 20% w/w) was added followed by slow addition of HCl (0.1 mL).
Hydrogen gas was bubbled slowly in to the reaction mixture continuously while stirring
at room temperature for 46 h. The reaction mixture was filtered through a bed of Celite
pad and the filtrate was concentrated under vacuum. After neutralization by the addition
of aqueous ammonium hydroxide solution (1 mL), the resulting solution was directly
loaded on to a silica gel column and purified using a mixture of acetonitrile and aqueous
ammonium hydroxide solution (10:2) to get 27 (0.05 g, 75%) as a colorless viscous
3
D
0
liquid. TLC: R 0.22 (CH CN/NH OH, 3:2); [α] +0.00 (c 0.57, H O); IR (neat) ν
f
3
4
2
max
ꢀ1
1
3
072, 2925, 1530, 1095, 1062 cm . H NMR (300 MHz, D O) δ 3.98 (t, 2.7 Hz, 1H),
2
1
3
3.64 (m, 2H) 3.47 (m, 2H), 2.80 (t, J = 10.5 Hz, 1H); C NMR (75 MHz, D O) δ 71.8
2
+
(
d), 71.7 (d), 69.4 (d), 56.3 (d); HRMS (ESI): [M + H] calcd for C H NO : 180.0866;
6
14
5
found: 180.0865.
(1R,2S,3r,4S,5S,6s)ꢀ6ꢀ(N-Acetyl)aminoꢀ1,2,3,4,5ꢀpentahydroxycyclohexane
(
28). Polyhydroxyaminocyclitol 26 (0.03 g, 0.167 mmol) was dissolved in water (0.2
mL). Triethyl amine (0.0188 g, 0.184 mmol) in MeOH (0.1 mL) was added dropwise
followed by acetic anhydride (0.01845 g, 0.184 mmol) dissolved in MeOH (0.1 mL).
Reaction mixture was stirred at room temperature for 30 min, after which it was directly
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loaded on to a silica gel column and the product was eluted with a mixture of acetonitrile
and aqueous ammonium hydroxide solution (3:1) to get 28 (0.031 g, 85%) as a colorless
2
0
viscous liquid. TLC: R 0.26 (CH CN /NH OH, 3:2); [α]
D
̶ 49.05 (c 0.316, MeOH); IR
f
3
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
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54
55
56
57
58
59
60
ꢀ1 1
(
neat) νmax 3268, 1629, 1568, 1441, 1378, 1322, 1071, 1015, 666 cm . H NMR (300
MHz, MeOD) δ 4.06ꢀ3.99 (m, 1H), 3.95ꢀ3.93 (m, 2H), 3.77ꢀ3.73 (m, 2H), 3.61ꢀ3.54 (m,
1
3
1
H), 2.02 (s, 3H); C NMR (75 MHz, MeOD) δ 174.7 (s); 73.5 (d); 73.3 (d); 72.9 (d);
10d,32
+
7
2.7 (d); 71.2 (d), 55.4 (d), 22.9 (q);
HRMS (ESI): [M + Na] calcd for
C H NNaO : 244.0791; found: 244.0783.
8
15
6
(
1R,2S,3s,4R,5S,6s)ꢀ6ꢀ(N-Acetyl)aminoꢀ1,2,3,4,5ꢀpentahydroxycyclohexane
(
29). Polyhydroxyaminocyclitol 27 (0.015 g, 0.083 mmol) was dissolved in water (0.15
mL). Triethyl amine (0.0094 g, 0.092 mmol) dissolved in MeOH (0.1 mL) was added
dropwise followed by acetic anhydride (0.00923 g, 0.092 mmol) dissolved in MeOH (0.1
mL). Reaction mixture was then stirred at room temperature for 30 min after which it was
directly loaded on to a silica gel column and the product was eluted with a mixture of
acetonitrile and aqueous ammonium hydroxide solution (3:2) to get 29 (0.015 g, 81%) as
2
0
a colorless viscous liquid. TLC: R 0.30 (CH CN/NH OH, 3:2); [α] +0.00 (c 0.212,
f
3
4
D
ꢀ1 1
H O); IR (neat) ν 3272, 1629, 1570, 1442, 1378, 1323, 1073, 1016, 666, 605 cm . H
2
max
1
3
NMR (300 MHz, D O) δ 3.92 (bs, 1H), 3.54ꢀ3.38 (m, 5H), 1.88 (s, 3H); C NMR (75
2
1
0d,32
MHz, D O) δ 176.0 (s); 73.2 (d); 73.1 (d); 71.9 (d); 56.9 (d); 23.4 (q);
HRMS (ESI):
2
+
[
M + Na] calcd for C H NNaO : 244.0791; found: 244.0787.
8
15
6
(
3R,4R,5R,6S)ꢀ6ꢀ(NꢀBenzylꢀNꢀpꢀtoluenesulfonyl)aminoꢀ3,4,5ꢀtrisꢀbenzyloxyꢀ
1
,7ꢀoctaꢀdiene (8). To a solution of methyltriphenylphosphonium bromide (2.05 g, 5.74
mmol) in dry THF (20 mL), nꢀbutyllithium (3.41 mL of 1.6 M solution in hexane, 5.46
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