A novel and stereospecific synthesis of aminocyclitol:N- tosyldihydroconduramine E2

Article abstract of DOI:10.3184/030823410X12628681698796

A stereospecifi c synthesis of N-tosyldihydroconduramine E2, a new aminocyclitol, has been synthesised starting from cyclohexa-1,3-diene. The photooxygenation of cyclohexa-1,3-diene afforded the bicyclic endoperoxide. Reduction of the endoperoxide with th

Full text of DOI:10.3184/030823410X12628681698796

54 RESEARCH PAPER
JANUARY, 54–56
JOURNAL OF CHEMICAL RESEARCH 2010
A novel and stereospecific synthesis of aminocyclitol:
N-tosyldihydroconduramine E2
Latif Kelebeklia,b*, Murat Celikb and Yunus Karab
aDepartment of Chemistry, Ordu University, Ordu, Turkey
bDepartment of Chemistry, Atatürk University, 25240 Erzurum, Turkey
A stereospecific synthesis of N-tosyldihydroconduramine E2, a new aminocyclitol, has been synthesised starting
from cyclohexa-1,3-diene. The photooxygenation of cyclohexa-1,3-diene afforded the bicyclic endoperoxide.
Reduction of the endoperoxide with thiourea and then reaction of the bis-carbamate with p-TsNCO followed by a
palladium-catalysed ionisation/cyclisation reaction, gave a vinyl oxazolidin-2-one. Oxidation of the double bond
in the oxazolidin-2-one with KMnO4 followed by acetylation, gave the oxazolidinone-diacetates. Hydrolysis of the
oxazolidinone ring and removal of the acetate groups gave the desired aminocyclitol, N-tosyldihydroconduramine
E2.
Keywords: N-tosyldihydroconduramine E2, conduramine, aminocyclitol, endoperoxide
Aminocyclitols are mainly structural elements of naturally
occurring some biological active compounds. Aminocycli-
tols such as validamine 1 have gained considerable impor-
tance because of their glycosidase inhibitory properties
and antibacterial properties.1,2 Moreover, aminoglycoside
antibiotics remain important drugs for the treatment of
infections.3 Because aminocyclitols form the aglycons in many
aminoglycoside antibiotics, SAR studies have established
the importance of the aminocyclitol part for antibacterial
activities.4–6
On the other hand, aminocyclitols such as 2, exhibit remark-
ably similar properties as glicosidase inhibitors because of
their similar framework.7 Different approaches and methods
have been used for the synthesis of aminocyclitols.8–12 One of
the promising methods was based on the cycloaddition
approach with a hetero Diels–Alder reaction of nitroso dieno-
philes to 1,3-dienes for synthesis of compounds such as dihy-
droconduramine A2 3.13–17 Nitrosyl cycloaddition provides the
introduction of substituents at the 1,4-position of dienes. Apart
from these methods, Trost et al. designed the synthesis of vinyl
oxazolidin-2-ones via Pd(0) catalysed ionisation reactions.18
Pd(0) catalysed reactions provide selective entry to amino
alcohols of varying regio- and stereoselectivity. The regio-
and stereoselectivity was assured by covalent tethering of
the nitrogen nucleophile to the substrate. The feasibility of
the regio-stereoselective synthesis of vinyl oxazolidin-2-ones
via organopalladium reactions provides the opportunity for
a general and flexible strategy for the synthesis of amino-
cyclitols.19–22 Pandey et al. reported the synthesis of dihydro-
conduramine E1 4 using enantiopure 7-azabicyclo[2.2.1]
heptane-2-ol.23 We report here the synthesis of N-
tosyldihydroconduramine E2 using the Pd(0) catalysed
cyclisation reaction of an allylic cis-diol in the presence of
triisopropyl phosphite.
Results and discussion
The starting material, endoperoxide 5 was synthesised
using tetraphenylporphyrin-sensitised photooxygenation
of cyclohexa-1,3-diene in carbon tetrachloride at room
temperature.24,25 The endoperoxides with thiourea under-
goes stereoselective ring-opening to give allylic cis-diols.
Therefore, endoperoxides are the key-intermediates for
stereoselective synthesis of some cyclitol and their deriva-
tives.26–28 Reduction of the endoperoxide linkage was
performed with thiourea under mild conditions to give diol
6 in 85% yield.24,25 Since only the oxygen–oxygen bond
is cleaved in this reaction, the configuration of the carbon
atoms is preserved.
Pd(0)-catalysed reactions provide the selective entry to
amino alcohols with various regio- and stereoselectivity.
Therefore, for the introduction of the amino alcohol function-
ality, a regio- and stereoselective Pd(0) catalysed reaction of
diol 6 in the presence of TsNCO was employed. The diol 6 was
treated with p-toluenesulfonylisocyanate (p-TsNCO) in THF
to give the corresponding bis-carbamate 7 and then warmed
to 65 °C. The resulting solution was added to a solution of the
catalyst prepared from 5 mol % tris(dibenzylideneacetone)
dipalladium chloroform complex [(dba)3Pd2CHCl3] and 15
mol % triisopropyl phosphite (iPrO)3P at the same tempera-
ture. The mixture was purified by chromatographed on a silica
gel column with hexane/ethylacetate as an eluent to give
oxazolidinone 8 in 51% yield (Scheme 1).29
The oxazolidinone 8 was dihydroxylated with KMnO4
to furnish oxazolidinone-cis-diol 9. During the synthesis of
polyhydroxylated compounds, we often use acetyl chloride
for acetylation of the cis-diols.30–33 For further structural proof
of the product, 9 was converted to oxazolidin-2-one diacetates
10 by acetyl chloride in CH2Cl2 (Scheme 1). The spectral data
confirmed the hydroxylation of double bond and as a sole
* Correspondent. E-mail: lkelebekli@odu.edu.tr

JOURNAL OF CHEMICAL RESEARCH 2010 55
Scheme 1
product. However, the stereochemical course of the hydroxyl-
ation can be syn and anti. Therefore, careful NMR studies did
not reveal the formation of any trace of the other diastereomer.
Indeed, since the syn-face of the molecule 8 is blocked by
the oxazolidin-ring, KMnO approaches the double bond
exclusively from the anti-fa4ce (from less-hindered side) to
give 9.
The structure of oxazolidin-2-one diacetates 10 was eluci-
dated on the basis of 1H and 13C NMR spectroscopic data. The
l
200 MHz H NMR spectrum revealed a quartet at δ 5.33, a
Scheme 2
doublet of doublet at δ 4.94, and a triplet of doublet at δ 4.78,
which was assigned to the acetoxy protons and CH–O (H7a)
in the oxazolidin-2-one ring, respectively. CH–N (H3a) in the
oxazolidin-2-one ring resonate as a double doublet at δ 4.60.
First, while H-4 of 10 is a double doublet (J4,3a = 8.2, J4,5 = 2.9
Hz), H-3a is a double doublet (J3a,4 = 8.2, J3a,7a = 5.9 Hz) and
H-7a is a triplet of doublet (J7a,3a = 5.9, J7,7a = 3.1 Hz). These
observation clearly indicate that H-4 with H-3a have a trans
configuration because of J3a,4 = 8.2 Hz whereas H-3a with
H-7a have a cis configuration because of J7a,3a = 5.9 Hz.
These results indicate that H-3a and H-4 have a trans configu-
ration while H-4 with H-5 and H-3a with H-7a exhibit a cis
configurations with each other.
Oxazolidin-2-one diacetates 10 was hydrolysed with
potassium carbonate in MeOH at room temperature and then
converted to triacetates 11 which include free triacetates
functionalities. Compound 11 was fully characterised by
spectroscopic methods and analytical methods. Especially, a
17-line 13C NMR spectrum of 11 confirms the proposed struc-
ture according to the asymmetry in the molecule. Hence, the
oxazole ring was not only opened in this reaction, but also
acetates groups were hydrolysed. In addition to this, the con-
figuration of all the substituents in ring were determined by
means of NMR spectrum.
efficiently obtained from the singlet oxygen and cyclohexa-
1,3-diene. Thus, we now describe how different stereocon-
trolled aminocyclitols may be synthesised using Pd(0) source
apart from hetero Diels–Alder addition reaction.
Experimental
General
Melting points were determined on a Buchi 539 capillary melting
apparatus and are uncorrected. IR spectra were obtained from KBr
or film on a Mattson 1000 FT-IR spectrophotometer. The 1H and 13
C
NMR spectra were recorded on 200 (50) MHz Varian spectrometer
and are reported in δ units with SiMe as internal standard. TLC was
performed on E. Merck Silica Gel 60 4F plate (0.2 mm). All column
chromatography was performed on s2i5l4ica gel (60 mesh, Merck).
Elemental analyses were carried out on a Carlo Erba 1108 model
CHNS-O analyser.
(1R,4S)-Cyclohex-2-ene-1,4-diol (6): The title compound was
prepared in 85% yield as described in the literature. 24,25
(3aRS,7aSR)-3-Tosyl-3a,6,7,7a-tetrahydro-1,3-benzooxazol-
2(3H)-one (8): To a stirred solution of diol 6 (1.5 g, 13.38 mmol) in
anhydrous THF (20 mL) under nitrogen at room temperature was
added p-toluensulfonyl isocyanate (5.0 g, 3.9 mL, 25.4 mmol) drop-
wise. The reaction was stirred at room temperature for 6 h and then at
65 °C for 60 min. To a flask containing tris(dibenzylideneacetone)dip
alladium chloroform complex (0.38 g, 361 µmol) in anhydrous THF
(20 mL) under nitrogen was added triisopropyl phosphite (0.40 g, 1.94
mmol). The mixture was stirred at room temperature for 30 min until
a clear yellow solution and then the catalyst solution was added to
the reaction flask that at 65 °C. The reaction mixture was stirred at
Removal of the acetate groups with K2CO3 in methanol
obtained N-tosyldihydroconduramine E2 12 in high yield
(Scheme 2).
In summary, N-tosyldihydroconduramine E2 was syn-
thesised from the key intermediate, the diol 6, which was

56 JOURNAL OF CHEMICAL RESEARCH 2010
the same temperature for 24 hours. After removal of the solvent under
reduced pressure (50 °C, 20 mmHg), the mixture was chromato-
graphed on silica gel (60 g) by eluting with 35% ethyl acetate/hexane
to afford the vinyl oxazolidone 8 (1.90 g, 51%). White crystals, m.p.
125 °C (lit29; 122 °C). (recrystallised from ethyl acetate/hexane);
IR (CHCI3, cm−1): 3939, 2950, 2846, 1781, 1600, 1500, 1438, 1365,
1307, 1245, 1207, 1168, 1130, 1091, 1056, 1025, 844, 817, 759, 698,
671, 586; 1H NMR (200 MHz CDCl3 ppm) δ 7.94 (d, A part ofAA’BB’
system, J = 8.3 Hz, 2H, aromatic), 7.34 (d, B part of AA’BB’ system,
J = 8.3 Hz, 2H, aromatic), 6.02 (m, 1H, –CH=CH) 5.94 (m, 1H,
–CH=CH), 4.82 (m, 2H, –CH–O and –CH–N), 2.43 (s, 3H, arom–
CH3), 2.3–2.0 (m, 4H, –CH2–CH2); 13C NMR (50 MHz CDCl ppm) δ
153.9 (C=O), 147.4 (arom–ipso–C), 137.4 (arom–ipso–C)3, 131.7,
130.4 (aromatic), 135.2 (–C=C), 124.2 (–C=C), 75.9 (–C–O), 56.8
(–C–N ), 26.2 (–CH2), 20.7 (–CH2), 23.7 (arom-CH3).
The residue filtered and then the solvent removed under reduced pres-
sure (70 °C, 20 mmHg) to give 2-(4-methylphenylsulfonamido)cyclo
hexane-1,2,4-triol (N-tosyldihydroconduramine E2) 12 (36 mg, 86%).
White crystals, m.p. 184–185 °C (from CH3COCH3); IR (CHCI3,
cm−1): 3383, 3041, 2959, 2511, 1231, 1207, 1171, 1078, 1061, 1028,
1002, 885, 853, 783, 593, 582; 1H NMR (200 MHz CD COCD ppm)
δ 7.80 (d, A part of AA’BB’ system, J = 8.3 Hz, 2H, a3romatic3), 7.36
(d, B part of AA’BB’ system, J = 8.3 Hz, 2H, aromatic), 3.93 (m, 1H,
H4), 3.80 (m, 1H, H1), 3.71 (dd, J = 9.5, 2.9 Hz, 1H, H ), 3.34
(dd, J = 9.4, 3.0 Hz, 1H, H ), 3.30–3.00 (m, 3H, –OH), 2.413(s, 3H,
arom-CH3), 1.80–1.54 (m,2 4H, –CH2–CH ); 13C NMR (50 MHz
CD3COCD ppm) δ 145.4 (arom-ipso-C), 1421.9 (arom-ipso-C), 132.0
(–C=C), 1238.8 (–C=C), 72.7 (–C–O), 71.5 (–C–O), 71.7 (–C–O), 60.3
(–C–N), 28.6 (–CH2), 27.5 (–CH2), 23.2 (arom-CH ). Anal. Calcd for
C H19NO5S: C, 51.81; H, 6.35; N, 4.65; S, 10.64;3 Found: C, 51.73;
H1,36.28; N, 4.81; S, 10.71%.
(3aSR,4RS,5SR,7aSR)-2-Oxo-3-tosyloctahydro-1,3-benzooxazole-
4,5-diyl diacetate (10): To a stirred solution of vinyl oxazolidon 8
(0.60 g, 2.06 mmol) in ethanol (50 mL) was added a solution of
KMnO4 (0.33 g, 2.06 mmol) and MgSO (0.25 g, 1.48 mmol) in water
(30 mL) at –15 °C for 4 h. After the 4addition was completed, the
reaction mixture was stirred for an additional 12 h at 10 °C and then
filtered. The precipitate was washed several times with hot water.
The combined filtrates were concentrated to 15 mL by evaporation.
The aqueous solution was extracted with ethyl acetate (3 × 50 mL)
and the extracts were dried over anhydrous sodium sulfate. After
removal of the solvent, the crude mixture that was dissolved in acetyl
chloride (10 mL) was magnetically stirred at room temperature for
6 h. Removal of the excess of unreacted acetyl chloride under reduced
pressure (50 °C, 20 mmHg) gave 10 (0.16 g, 40%). White crystals,
m.p. 98–100 °C (from CH2Cl2); IR(KBr, cm−1) 3031, 2942, 1785,
1742, 1600, 1538, 1369, 1245, 1168, 1130, 1099, 1022, 763, 667, 578;
1H NMR (200 MHz, CDCl ) δ 7.91 (d, A part of AA’BB’ system,
J = 8.3 Hz, aromatic, 2H), 73.32 (d, B part of AA’BB’ system, J = 8.3
Hz, aromatic, 2H), 5.33 (q, J = 2.9 Hz, 1H, H5), 4.94 (dd, J4,3a = 8.2,
The authors are indebted to TUBITAK (The Scientific and
Technical Research Council of Turkey) for financial support of
this work (Grant No: TBAG-105T162).
Received 31 October 2009; accepted 31 December 2009
Paper 090854 doi: 10.3184/030823410X12628681698796
Published online: 22 January 2010
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1093, 1046, 1027, 950, 923, 819, 731; H NMR (200 MHz, CDCl3)
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(1SR,2RS,3SR,4SR)-3-(4-Methylphenylsulfonamido)cyclohexane-
1,2,4-triol: N-tosyldihydroconduramine E2 (12): To a solution of
triacetate 11 (60 mg, 0.14 mmol) in methanol (15 mL) was added
K2CO3 (110 mg, 0.80 mmol) and stirred at room temperature for 4 h.

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