Intramolecular ketonitrone-olefin cycloaddition reaction: direct and stereocontrolled synthesis of nitrogenated quaternary centered aminocyclopentitols as galactosidase inhibitors

Article abstract of DOI:10.1016/j.tetlet.2009.07.157

Synthesis of nitrogenated quaternary centered polyhydroxylated aminocyclopentanes by implementation of ketonitrone-olefin cycloaddition reaction as a key step has been accomplished in a stereocontrolled manner. The target molecules were found to be modera

Full text of DOI:10.1016/j.tetlet.2009.07.157

Tetrahedron Letters 50 (2009) 5827–5830
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Tetrahedron Letters
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Intramolecular ketonitrone-olefin cycloaddition reaction: direct
and stereocontrolled synthesis of nitrogenated quaternary centered
aminocyclopentitols as galactosidase inhibitors
*
Y. Suman Reddy, P. Kadigachalam, Venkata Ramana Doddi, Yashwant D. Vankar
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208 016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of nitrogenated quaternary centered polyhydroxylated aminocyclopentanes by implementa-
tion of ketonitrone-olefin cycloaddition reaction as a key step has been accomplished in a stereocon-
trolled manner. The target molecules were found to be moderate but selective inhibitors of
galactosidases.
Received 8 July 2009
Revised 29 July 2009
Accepted 31 July 2009
Available online 9 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Ketonitrone
Cycloaddition
Aminocyclopentitol
Glycosidase inhibitors
Synthesis of novel heterocyclic ring systems and polyhydroxy-
lated carbocycles from sugars by using intramolecular nitrone-al-
kene cycloaddition (INAC) reaction1 has gained importance in
recent times. The derived cycloadducts bearing an amino function-
ality emanating due to INAC reactions can serve as excellent pre-
cursors for the synthesis of carbamino sugars, some natural
products, and their analogs.2 In INAC reactions, ketonitrone-olefin
cycloaddition reaction is particularly useful for the synthesis of
nitrogenated quaternary centered molecules.3,4 Inspite of its syn-
thetic potential it has received little attention,4 as compared to
reactions of nitrones derived from aldehydes.1a,5
Over the last few years, synthesis of glycosidase inhibitors has
become one of the promising areas of research in organic chemis-
try.6 Because of their crucial role in biological events, glycosidase
inhibitors are used in the treatment and study of a wide range of
diseases such as diabetes,7 viral infections,8 and cancer.9 Amongst
glycosidase inhibitors, aminocyclopentitols are an important class
of compounds and their chemistry is of significance in medicinal
chemistry as well as natural products chemistry.10 Aminocyclo-
pentitols are structurally similar to sugars and therefore they are
also called as aminocarbasugars.11 These contain three hydroxy
groups along with one free or substituted amino group.12 The core
structure of aminocyclopentitol system is present in a growing
number of natural products. For example, an important group of
naturally occurring glycosidase inhibitors (Fig. 1) bearing aminocy-
clopentitol moiety includes mannosidase inhibitor mannostatin A
1, the carbocyclic nucleosides viz. aristeromycin 2, neplanocin A
3, and analogs such as epi-50-nor-aristeromycin 4 and the selective
trehalase inhibitor trehazolin 5. Another important aminocyclo-
pentitol BCX-1812 6 is a neuraminidase inhibitor and it is in clin-
ical development to treat influenza.13 Besides these, many other
polyhydroxylated five- and six-membered and bicyclic aza hetero-
cycles and their analogs are potent glycosidase inhibitors.14a Be-
cause of their remarkable structural features and ability to act as
carbohydrate mimics,14b there has been an explosive growth in de-
sign, synthesis and biological evaluation of new glycosidase
inhibitors.15
In conjunction with our interest toward the synthesis of natural
and unnatural azasugars, carbasugars, and hybrid sugars as glyco-
sidase inhibitors16 and in view of the potential of the intramolecu-
lar ketonitrone-olefin cycloaddition reaction, we hereby report on
the synthesis of nitrogenated quaternary centered polyhydroxylat-
ed aminocyclopentanes (aminocyclopentitols) from commercially
available tetra-O-benzyl-D-glucopyranose. Retrosynthetic analysis
for our approach is shown in Scheme 1 which indicates the imple-
mentation of intramolecular ketonitrone-olefin cycloaddition reac-
tion as a key step.
Our synthesis of the target aminocyclopentitol system began
with the Wittig methylenation of commercially available tetra-O-
benzyl-D-glucopyranose 7 (Scheme 2) by Martin’s modified proce-
dure17 to give the corresponding heptenitol 8 in high yield. This
secondary alcohol was subjected to oxidation by pyridinium chlo-
rochromate (PCC) which produced the ketone 9.
* Corresponding author. Tel.: +91 512 2597169; fax: +91 512 259 0007.
E-mail address: vankar@iitk.ac.in (Y.D. Vankar).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.157

5828
Y. Suman Reddy et al. / Tetrahedron Letters 50 (2009) 5827–5830
NH2
N
NH2
N
N
HO
N
HO
NH2
SMe
N
N
HO
HO
N
N
HO
HO OH
HO OH
Aristeromycin
Mannostatin A
Neplanocin A
1
2
3
NH2
N
OH
OH
NHAc
N
HO
Me
Me
NH2
NH2
N
N
OH
OH
N
HO
HO
O
N
HO
HO
O
HO OH
OH
CO2H
epi-5'-nor-Aristeromicin
Trehazolin
BCX-1812
5
4
6
Figure 1. Structures of some biologically important aminocyclopentitols.
HO
HO
O
OH
BnO
O
OBn
BnO
BnO
OBn
NH2
BnO
Bn
HO
OBn
N
O
OBn OBn
OBn
OBn OBn
OH
OH
Scheme 1. The retrosynthetic analysis of aminocyclopentitols.
OH OBn
O
OH
O
OBn
BnO
R2
a
BnO
b
BnO
OBn
R1
R1 OBn
R2
R1
OBn
R2
OBn
9: R1 = OBn, R2 = H, 89%
16: R1 = H, R2 = OBn, 80%
8: R1 = OBn, R2 = H, 80%
15: R1 = H, R2 = OBn, 84%
7: R1 = OBn, R2 = H
14: R1 = H, R2 = OBn
Scheme 2. Reagents and conditions: (a) Ph3P+CH3 Brꢀ (3 equiv), n-BuLi (6 equiv), toluene, rt, 48 h; (b) PCC (1.8 equiv), molecular sieves 3 Å, CH2Cl2, 1 h.
Intramolecular ketonitrone-olefin cycloaddition reaction on ke-
groups at C-1 and C-3 are a-oriented, and the acetoxy groups at
tone 9 upon treatment with N-benzylhydroxylamine in methylene
chloride in the presence of dry pyridine readily led to the forma-
tion of bis-isoxazolidine 11 in 78% yield via intermediate 10
(Scheme 3). In order to obtain the target aminocyclopentitol sys-
tem, global deprotection was carried out by catalytic hydrogena-
tion in 5% TFA/EtOH with 6 bars of H2 for 3 days, which resulted
in cleavage of the N–O bond and removal of all the benzyl protect-
ing groups. The product 12 was isolated in 91% yield by passing
over a column of Dowex 50 resin. This compound was character-
ized as its acetate 13 which was obtained in 68% yield upon
acetylation of 12 using Ac2O/pyridine. The structure and stereo-
chemical outcome of the aminocyclopentitol was deduced from
COSY, NOE, and other spectral data18 of its peracetylated derivative
13. In an NOE experiment, irradiation of the signal for H-5 led to
the enhancement (Fig. 2) of the signal for H-2, H-7, and H-70 and
there was no enhancement of the signals for N–H and H-3. This
suggested that H-2, H-5, carbon side chain containing H-7 and H-
70 are in cis relationship. Therefore it was concluded that the two
carbon side chains are trans to each other whereas the acetoxy
C-2 and NHAc are b-oriented. These NOE observations confirm
the absolute stereochemistry of newly generated chiral centers as
4R and 5S, respectively.
Further investigations on the intramolecular ketonitrone-olefin
cycloaddition were undertaken using ketone 16, which was pre-
pared from
D-galactose using the same synthetic sequence and
reaction conditions as shown in Scheme 3 for the conversion of 9
to 13.
The stereochemical outcome of compound 18, obtained from
16, was confirmed from the COSY and NOE (Fig. 2) spectral data
of the corresponding peracetylated derivative 19. In an NOE exper-
iment the irradiation of the signal for H-5 led to the enhancement
of the signal for H-7 and H-70 and there was no enhancement of
the signals for H-3 and H-2. This indicated that H-5, H-7, and H-
70 are in cis relationship. Thus, it was concluded that the two car-
bon side chains are trans to each other, whereas the acetoxy
groups at C-2 and C-3 are b-oriented. This confirmed the absolute
stereochemistry of the newly generated chiral centers as 4S and
5R, respectively.

Y. Suman Reddy et al. / Tetrahedron Letters 50 (2009) 5827–5830
5829
HO
BnO
BnO
Bn
OBn
BnO
BnO
HO
HO
BnNHOH
NH2
OH
N
9
H2/Pd/C
Ac2O
Bn
N
O
O
CH2Cl2
pyridine
78%
Pyridine, 10h
68%
OBn OBn
5% TFA/ EtOH
3 days, 91%
reflux, 72h
BnO
OH
12
10
11
AcO
AcO
AcO
AcO
AcO
HO
BnO
Bn
HO
HO
BnO
BnO
NHAc
OAc
NH2
OH
NHAc
OAc
N
AcO
O
OAc
OH
18 (87%)
OAc
19 (
BnO
17
13
64%)
(84%)
Scheme 3. The stereocontrolled synthesis of aminocyclopentitols.
7'
stereochemical outcome proved by NOE experiments of the final
acetate derivatives 13 and 19.
Enzyme inhibition studies: The inhibitory activity of aminocyclo-
pentitols 12 and 18 were tested against five commercially available
glycosidases. Thus, aminocyclopentitol 12 was active only against
b-galactosidase (bovine liver) (IC50 = 0.4 mM), while aminocyclo-
7'
AcO
AcO
H
H
H7
H7
AcO
H
AcO
3
NHAc
4
NHAc
6
4
5
3
2
6
2
5
AcO
AcO
1
H
1
H
OAc
OAc
13
H
H
OAc
AcO
pentitol 18 was active against
a-galactosidase (coffee beans)
(IC50 = 0.2 mM); otherwise compounds were inactive up to 3 mM.
19
Although these compounds are not as strongly active as mannost-
atin A, an
hazolin,
a
a
-mannosidase inhibitor19 with IC50 = 160 nm, and tre-
trehalase inhibitor20 with IC50 = 27 nm, they are
Figure 2. The NOE analysis of compounds 13 and 19.
specific galactosidase inhibitors. It is expected that further struc-
tural modifications may lead to improved inhibitions.
The obtained stereochemistry of these molecules can be ex-
plained by the following transition state analysis. During the con-
In conclusion, we have developed a direct and efficient route to
the synthesis of nitrogenated quaternary centered polyhydroxylat-
ed aminocyclopentanes (aminocyclopentitols) with full stereo-
chemical control by using intramolecular ketonitrone-olefin
cycloaddition as a key step. To the best of our knowledge, these
are the first examples of aminocyclopentitols bearing an amino
group at the quaternary center that act as galactosidase inhibitors.
Compounds 12 and 18 showed specific inhibition toward b-galac-
version of
D-glucose-derived ketone into the corresponding
cycloadduct, the transition state A in which nitrone and olefin
could orient in exo manner and then the formation of the 5-mem-
bered ring occur in such a way that –H and the –CH2OBn group are
cis to each other at the ring junction (Scheme 4). In D-galactose-de-
rived case, a closely related transition state C is favored, in
which –CH2OBn and the C-6 OBn group avoid repulsive interac-
tions present in transition state B as was evident by the inspection
of molecular models. These transition state analyses support the
tosidase and
a
-galactosidase, respectively.
#
Bn
OBn
6a
BnO
1
6
7
Bn
BnO
N
6
4
BnO
1
N
4
BnO
O
5
BnO
O
2
3a
11
3
2
7
BnO
H
BnO
Transition state A
#
#
BnO
Bn
BnO
OBn
6a
BnO
6
7
1
BnO
6
1
Bn
1
7
H
BnO
BnO
BnO
Bn
N
O
6
5
N
4
O
N
2
3a
5
BnO
O
2
4
3
4
2
3a
7
BnO
3
BnO
H
BnO
17
Transition state B
Transition state C
Scheme 4. Proposed transition states of intramolecular ketonitrone-olefin cycloaddition reaction

5830
Y. Suman Reddy et al. / Tetrahedron Letters 50 (2009) 5827–5830
10. Antonio, D. Eur. J. Org. Chem. 2008, 3893–3906.
Acknowledgments
11. Arjona, O.; Gomez, A. M.; Lopez, J. C.; Plumet, J. Chem. Rev. 2007, 107, 1919–
2036.
We thank the Department of Science and Technology, New Del-
hi, for financial support to one of us (Y.D.V.) in the form of Raman-
na Fellowship (Grant No. SR/S1/RFOC-04/2006). Y.S.R. thanks CSIR,
New Delhi, for a senior research fellowship.
12. For recommendations on the nomenclature of cyclitols, see: http://
www.chem.qmul.ac.uk/iupac/cyclitol.
13. Smith, B. J.; McKimm-Breshkin, J. L.; McDonald, M.; Fernley, R. T.; Varghese, J.
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10302; (b) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. Rev. 2002,
102, 515–553.
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Supplementary data
16. (a) Kumar, A.; Rawal, G. K.; Vankar, Y. D. Tetrahedron 2008, 64, 2379–2390; (b)
Ramana, D. V.; Vankar, Y. D. Eur. J. Org. Chem. 2007, 33, 5583–5589; (c) Reddy,
B. G.; Vankar, Y. D. Angew. Chem., Int. Ed. 2005, 44, 2001–2004; (d) Jayakanthan,
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18. Experimental data of selected compounds: (3aS,4S,5R,6R,6aR)-1-benzyl-4,5,6-
tris(benzyloxy)-6a-(benzyloxymethyl)hexahydro-1H-cyclopenta[c]isoxazole
(11): To a stirred solution of the requisite ketone 9 (536 mg, 1 mmol) in
methylene chloride (9 mL), benzylhydroxylamine (369 mg, 3 mmol) and
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.157.
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pyridine (242 lL, 3 mmol) were added. The reaction mixture was heated to
reflux for 72 h. On cooling, the reaction mixture was poured into water and
extracted with dichloromethane (3 ꢁ 8 mL). Usual work-up thereafter gave a
crude product whose purification gave bis-isoxazolidine 11 (517 mg) as a
colorless thick liquid. Yield: 78%. Rf: 0.40 (hexane:ethyl acetate, 9:1), ½a D28
ꢂ
+25
(c 0.85, CH2Cl2). IR (neat) mmax: 3086, 3062, 3029, 2865, 1604, 1495, 1453, 1361,
1308, 1207, 1092, 1027, 909, 807, 734, 697, 602 cmꢀ1 1H NMR (400 MHz,
.
CDCl3): d 7.34–7.21 (m, 25H, Ar–H), 4.93 (d, 1H, J = 11.7 Hz, O–CH2Ph), 4.88 (d,
1H, J = 11.4 Hz, O–CH2Ph), 4.75 (d, 1H, J = 11.4 Hz, O–CH2Ph), 4.73 (d, 1H,
J = 11.7 Hz, O–CH2Ph), 4.64–4.52 (m, 4H, O–CH2Ph), 4.30 (overlapping dd, 1H,
J = 8.8 Hz, H-5), 4.13 (d, 1H, J = 9.2 Hz, H-6), 3.94 (d, 1H, J = 14.8 Hz, N–CH2Ph),
3.83 (d, 2H, J = 10.2 Hz, H-7, H-3), 3.68 (dd, 2H, J = 15.1, 8.8 Hz, H-4, N–CH2Ph),
3.57 (d, 1H, J = 10.2 Hz, H-70), 3.50 (d, 1H, J = 8.8 Hz, H-30), 3.03–3.01 (m, 1H, H-
3a). 13C NMR (100 MHz, CDCl3): d 138.7–138.1 (m), 128.4–126.9 (m), 87.39,
86.03, 80.33, 73. 190, 73.62, 72.94, 72.58, 71.81, 71.25, 69.34, 54.49, 52.26.
ESMS: m/z 664.303 [M+Na]+. Anal. Calcd for C42H43NO5: C, 78.60; H, 6.75; N,
2.18; O, 12.46. Found: C, 78.62; H, 6.69; N, 2.23.
(1S,2R,3S,4R,5S)-4-Amino-4,5-bis(hydroxymethyl) cyclopentane-1,2,3-triol (12):
Compound 11 (332 mg, 0.5 mmol) was dissolved in 5% of TFA/EtOH (8 mL),
10% Pd/C (249 mg) was added and this mixture was hydrogenated under 6 bars
H2 for 3 days at room temperature. The catalyst was filtered off through celite
and the filtrate was concentrated in vacuo. Passing over a column of Dowex 50
resin gave 12 (87 mg) as a thick liquid. Yield: 91% Rf = 0.45 (MeOH/EtOAc, 3:7).
½ ꢂ
a 2D8 +4.7 (c 1.0, MeOH). 1H NMR (400 MHz, D2O): d 3.57 (m, 3H), 3.46–3.44 (m,
2H), 3.38 (m, 2H), 1.73 (s, 1H). 13C NMR (100 MHz, CDCl3): d 73.06, 71.56,
71.19, 69.51, 60.51, 54.99, 48.85.
(1S,2R,3R,4R,5S)-4-Acetamido-4,5-bis(acetoxymethyl)
cyclopentane-1,2,3-triyl
triacetate (13): Compound 12 (40 mg, 0.2 mmol) was subjected to acetylation
with excess of pyridine and Ac2O (1:1, 2 mL) at room temperature for 10 h.
Usual work-up and purification by column chromatography gave 13 (63 mg) as
a colorless oil. Yield: 68% Rf = 0.5 (hexane/EtOAc, 1:1). ½a D28
ꢀ20 (c 1.0, CH2Cl2).
ꢂ
IR (neat) mmax: 3358, 2924, 2853, 1744, 1678, 1537, 1463, 1367, 1231, 1030,
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896, 722 cmꢀ1 1H NMR (400 MHz, CDCl3):
. d 6.62 (s, N–H), 5.55 (d, 1H,
J = 8.0 Hz, H-3), 5.44 (dd, 1H, J = 8.0, 6.0 Hz, H-2), 5.34 (t, 1H, J = 6.0 Hz, H-1),
4.44 (t, 2H, J = 12.0 Hz, H-7, H-70), 4.28 (dd, 1H, J = 12.0, 11.5 Hz, H-6), 4.20 (dd,
1H, J = 12, 11.5 Hz, H-60), 2.61–2.58 (m, 1H, H-5), 2.12–2.09 (m, 15H), 1.96 (s,
3H). 13C NMR (100 MHz, CDCl3): d 171.89, 170.81, 170.36, 170.27, 170.13,
79.69, 75.69, 63.90, 62.74, 62.54, 47.51, 23.67, 21.05–20.85 (m). ESMS: m/z
468.148 [M+Na]+. Anal. Calcd for C19H27NO11: C, 51.23; H, 6.11; N, 3.14 O,
39.51. Found: C, 51.20; H, 6.05; N, 3.19.
19. Tropea, J. E.; Kaushal, G. P.; Pastuszak, I.; Mitchell, M.; Aoyagi, T.; Molyneux, R.
J.; Elbein, A. D. Biochemistry 1990, 29, 10062–10069.
20. Ando, O.; Nakajima, M.; Kifune, M.; Fang, H.; Tanzawa, K. Biochim. Biophys. Acta
1995, 1244, 295–302.