A new stereoselective approach for N-benzyl amino(hydroxymethyl)cyclopentitols using RCM

Article abstract of DOI:10.1016/j.tetlet.2010.04.011

A new stereoselective approach for the synthesis of N-benzyl amino(hydroxymethyl)cyclopentitols by using stereoselective allylation on lactamine and RCM from d-ribose has been described and the glycosidase inhibitory activities of these amino cyclopentitols have been studied.

Full text of DOI:10.1016/j.tetlet.2010.04.011

Tetrahedron Letters 51 (2010) 3083–3087
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new stereoselective approach for N-benzyl amino(hydroxymethyl)-
cyclopentitols using RCM
b
J. Prasada Rao a, B. Venkateswara Rao a, , J. Lakshmi swarnalatha
*
a Organic Division-III, Indian Institute of Chemical Technology, Hyderabad 500 607, India
b Bio-transformations laboratory, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new stereoselective approach for the synthesis of N-benzyl amino(hydroxymethyl)cyclopentitols by
Received 11 March 2010
Revised 1 April 2010
Accepted 6 April 2010
Available online 10 April 2010
using stereoselective allylation on lactamine and RCM from
dase inhibitory activities of these amino cyclopentitols have been studied.
D-ribose has been described and the glycosi-
Ó 2010 Elsevier Ltd. All rights reserved.
Glycosidases are involved in several metabolic pathways. The
development of inhibitors for glycosidases is an important chal-
lenge toward the treatment of diseases such as diabetes, cancer,
and viral infections.1 Recently aminocyclopentitols have drawn
considerable attention as potent glycosidase inhibitors.2 Aminocy-
clopentitol substructures (Fig. 1) are found in a number of bioactive
natural products such as mannostatin A (1), trehazolin (2), allos-
amidin (3)3 and the carbocyclic nucleosides namely aristeromycin
(4), and neplanocin A (5). The neuraminidase inhibitor BCX 1812
(6) in clinical development to treat influenza is also an aminocyclo-
pentitol.4 In the context of glycosidase inhibition, aminocyclopent-
itols can be considered as structural analogs of monosaccharide
containing basic nitrogen function at the anomeric center. Particu-
larly, the amino group mimics the protonated form of the leaving
report the stereoselective synthesis of novel N-benzyl derivatives
of amino(hydroxylmethyl)cyclopentitols, N-benzyl
a-L-manno
aminocyclopentitol (8a),9 4-deoxy-N-benzyl-
a-L-manno aminocy-
clopentitol (8b), and N-benzyl 6,7-di-epi-trehalamine (8c)10,11
using stereoselective allylation on lactamine and ring-closing
metathesis (RCM)12 as key steps. The retro synthetic analysis of
aminocyclopentitol skeletons (8a–c) is depicted in Scheme 1 which
shows the importance of key intermediate 9 from which a variety
of aminocyclopentitols can be prepared. It was further envisaged
that the presence of 1,3-dioxalane ring in 9 could be helpful in get-
ting better selectivity during further transformations.
In general the success of the RCM strategy depends on the effi-
cient preparation of diene. In our strategy the RCM precursor 10
required for the construction of aminocyclopentene 9 could be pre-
pared from lactamine 11 by allylation, oxidative cleavage of the
double bond followed by condensation with Eschenmoser’s salt
and subsequent reduction.
group oxygen atom in
a or b orientation in the transition state of
glycosidase-catalyzed reaction. Due to interesting biological activ-
ity and fascinating structural features, there has been a remarkable
growth in design, synthesis, and evaluation of new glycosidase
The starting material 5-O-tert-butyl dimethylsilyl-2,3-O-isopro-
inhibitors, such as Merrell-Dow cyclopentylamine (7),5
a
-
a
D
-gluco,
-fuco,
-fuco configured aminocyclopentitols.6 Recent studies by
pylidene-
pared from D
D
-ribofuranose 12, required for our synthesis was pre-
b-D
-gluco,
a-
D
-galacto, b-
D
-galacto,
a-D
-manno, b-
D-manno,
-
L
-ribose using reported procedure (Scheme 2).13
and b-
L
Reaction on 12 with benzylamine gave ribosylamine 13. Treatment
of crude 13 with allylbromide and zinc furnished amino alcohol 14
exclusively as a single isomer. The absolute configuration of the
newly generated stereo center was not confirmed at this stage,
but it was done at the later stages by NOE correlations, which indi-
cated the formation of erythro isomer. Previously there are some
reports on the stereoselective nucleophilic addition on lactamine,
Wilcox and co-workers14 reported that the Grignard addition on
N,N-dibenzyl ribosylamine having 2,3-O-isopropylidene unit gave
threo amino ethers where the nucleophilic addition is taking place
on non-chelated iminium ion. Later Nicotra and co-workers15
reported that the nucleophilic addition on N-benzyl-tri-O-benzyl
glucosamine also gave threo amino ethers. Here the selectivity
Reymond and co-workers revealed that the N-benzyl derivatives
of aminocyclopentitols show an enhanced inhibitory potency.6d,h
Jager and co-workers reported that the presence of hydroxymethyl
functionality in amino cyclopentane skeleton may serve as a gen-
eral framework to generate a new family of glycosidase inhibitors.6f
However, glycosidase inhibition by aminocyclopentitols as a func-
tion of their structural and stereo chemical features still remains
to be fully understood. Hence the synthesis of new analogs can pro-
vide not only better understanding of glycosidase functioning but
also lead to inhibitors with more therapeutic value.
In connection with our ongoing research in the synthesis of gly-
cosidase inhibitors carbasugars7 and azasugars,8 herein we wish to
was due to the chelation between imine and
a-benzyloxy group
whereas in the case of compound 13, allylation gave exclusively
erythro isomer which presumably proceeded via seven-membered
* Corresponding author. Tel./fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B.V. Rao).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.011

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J. P. Rao et al. / Tetrahedron Letters 51 (2010) 3083–3087
HO
OH
SMe
N
HO
HO
NH2
HO
N
HO
HO
NH2
O
N
N
NMe2
N
NHR
N
O
HO
OH
HO
HO
Mannostatin A
( -mannosidase inhibitor)
OH
HO
Trehazolin
(2)
Allosamidin (3)
(chitinase inhibitor)
NH2
(4)
(1)
Artisteromycin
(anti-viral , antitumor & AdoHcy hydrolase)
(α,α–trehalaseinhibitor)
α
OH
N
HO
N
AcHN
NH2
NH2
HO
N
NHMe
N
N
OH
HO
OH
HO
HO
BCX-1812 (
CO2H
6)
(7)
(5)
Merrell-Dow cyclopentylamine
Neplanocin A
(neuraminidase inhibitor)
(α-mannosidaseinhibitor)
(anti-viral & anticancer)
OH
OH
OH
HO
5
4
3
NHBn
HO
NHBn
NHBn
HO
1
2
HO
OH
HO
4-deoxy-N-benzyl-αL-manno
(8b)
OH
HO
OH
N-benzyl-6,7-di-epi
trehalamine
N-benzyl-αL-manno
aminocyclopentitol
(8c)
(8a)
aminocyclopentitol
Figure 1. Some of the natural and unnatural aminocyclopentitols.
OH
NHBn
HO
O
O
O
HO
OH
8a
PO
BnN
O
O
O
OH
NHBn
NBn
NHBn
O
O
O
O
O
HO 8b OH
10
9
11
OH
HO
NHBn
HO
HO
OH
8c
Scheme 1. Retrosynthetic analysis of aminocyclopentitols.
transition state16 or Felkin-Anh model (Fig. 2). In fact the formation
of erythro isomer shows that chelation between imine and isopro-
pylidene group has not taken place due to steric strain.
In order to protect the primary hydroxyl group, compound 16
was treated with sodium hydride to give the cyclic carbamate
17. Global deprotection of bis-silylether in 17 with TBAF gave diol
18. Diol functionality of 18 was converted to olefin using I2/TPP
to give diene 10. The diene 10 was subjected to ring-closing
metathesis using Grubb’s second generation catalyst18 in toluene
under reflux conditions produced the key intermediate amino-
cyclopentene 9 in 75% yield.
The compound 9 was transformed to various aminocyclopenti-
tol derivatives with high stereoselectivity as follows. Hydrobora-
tion of aminocyclopentene 9 with BH3–DMS complex gave
hydroxy product 19. Chemoselective hydrogenation of aminocycl-
opentene 9 using Pd/C afforded 20 and dihydroxylation of 9 with
Having the amino compound 14 in hand we proceeded to the
next stage. Secondary hydroxyl group of compound 14 was pro-
tected as its triethylsilyl ether and then amino functionality was
converted to carbamate with CbzCl to give 15. The next step is
the introduction of 1,1-disubstituted olefin required for RCM.
Oxidative cleavage of terminal double bond in 15 with OsO4/
NaIO4 produced aldehyde which on treatment with Eschenmo-
ser’s salt yielded
was further reduced to alcohol 16 under Luche condition at
ꢀ78 °C, yielding the required olefin without any -elimination.
a
-methylene aldehyde.17 The crude aldehyde
a

J. P. Rao et al. / Tetrahedron Letters 51 (2010) 3083–3087
3085
Cbz
Bn
NHBn
TBSO
TESO
O
TBSO
N
OH
O
TBSO
NHBn
TBSO
OH
ii
iii
i
O
O
O
O
O
O
O
O
O
13
14
12
15
O
O
Cbz
TBSO
TE SO
HO
HO
O
Bn
Bn N
BnN
TBSO
TESO
N
vii
vi
iv
v
OH
O
O
O
O
O
O
18
17
16
OH
NHBn
O
O
HO
HO
NBn
ix
xii
68%
HO
OH
O
O
8a
O
O
19
O
O
O
OH
NHBn
BnN
O
viii
NBn
x
NBn
xii
72%
O
O
O
O
O
O
HO
OH
10
9
8b
20
OH
NHBn
O
O
HO
HO
HO
NBn
HO
xii
xi
65%
HO
OH
O
O
8c
21
Scheme 2. Synthesis of N-benzyl aminocyclopentitols 8a–c. Reagents and conditions: (i) BnNH2, MeOH, reflux, 12 h; (ii) allylbromide, Zn, THF, 0 °C to rt, 4 h, 70% (over two
steps); (iii) (a) TES-Cl, imidazole, DCM, 0 °C, 10 min, 93%; (b) NaH, CbzCl, THF, 0 °C, 1 h, 85%; (iv) (a) OsO4/NaIO4, acetone/water 4:1, 0 °C to rt, 3 h; (b) Et3N, Eschenmoser’s
salt, DCM, 0 °C to rt, 4 h; (c) NaBH4, CeCl3ꢁ7H2O, MeOH, ꢀ78 °C, 30 min, 70% (over three steps); (v) NaH, THF, 0 °C to rt, 2 h, 85%; (vi) TBAF, THF, rt, 5 h, 92%; (vii) TPP, I2,
imidazole, toluene, reflux, 3 h, 83%; (viii) Grubb’s second generation catalyst, toluene, reflux, 18 h, 75%; (ix) BH3ꢁDMS, H2O2, NaOH, THF, ꢀ15 °C to rt, 3 h, 50%; (x) Pd/C, H2,
MeOH, 30 min, 90%; (xi) OsO4, NMO, acetone/water, 4:1, rt, 3 h, 85%; (xii) 6 N HCl, reflux, 12 h.
Nu
M
HO
M
TBSO
Nu
NBn
HO
O
NBn
H
BnN
O
TBSO
H
H
O
OH
O
H
O
O
OTBS
A
B
Figure 2. Seven-membered transition state (A) and Felkin-Anh Model (B).
OsO4 gave dihydroxy compound 21. The stereochemistry of
compounds 19, 20, and 21 was established from 1H-NMR cou-
plings19 and NOE experiments (Fig. 3). Global deprotection of car-
bamate and 2,3-O-isopropylidene group in 19, 20, and 21 were
achieved with 6 N HCl under reflux to give new N-benzyl aminocy-
clopentitols 8a, 8b, and 8c respectively.20

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J. P. Rao et al. / Tetrahedron Letters 51 (2010) 3083–3087
O
O
O
O
O
O
H
O
H
O
HO
NBn
NBn
HO
NBn
HO
H
H
H
H
H
H
H
H
H
O
O
O
O
19
20
21
Figure 3. 2D-NOE correlations.
Table 1
References and notes
Glycosidase inhibitory activity, IC50 values in mM
1. (a) de Melo, E. B.; Gomes, A. S.; Carvalho, I. Tetrahedron 2006, 62, 10277. and
references cited therein; (b) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M.
Chem. Rev. 2002, 102, 515; (c) Asano, N. Glycobiology 2003, 13(10), 93R.
2. Reviews on aminocyclitols and carbasugars: (a) Deglado, A. Eur. J. Org. Chem.
2008, 23, 3893; (b) Arjona, O.; Gomez, A. M.; Lopez, J. C.; Plumet, J. Chem. Rev.
2007, 107, 1919.
Compounds
a-Glucosidase b-Glucosidase a-Galactosidase b-Galactosidase
8a
8b
8c
0.5
0.41
0.21
0.20
NI
0.065
0.098
NI
0.09
1.0
0.79
NI
3. Review on aminocyclopentitols and its biological activity: Berecibar, A.;
Grandjean, C.; Sriwardena, C. Chem. Rev. 1999, 99, 779.
NI: no inhibition at 2 mM concentration.
4. Smith, B. J.; Mckimm-Breshkin, J. L.; McDonald, M.; Fernley, R. T.; Varghese, J.
N.; Colman, P. M. J. Med. Chem. 2002, 45, 2207.
Glycosidase inhibitory study: The glycosidase inhibitory activity
against -glucosidase (yeast), b-glucosidase (almonds), -galacto-
5. Farr, R. A.; Peet, N. P.; Kang, M. S. Tetrahedron Lett. 1990, 31, 7109.
6. Selected references of some of the recent synthesis of aminocyclopentitols and
related compounds: (a) Reddy, Y. S.; Kadigachalam, P.; Doddi, V. R.; Vankar, Y.
D. Tetrahedron Lett. 2009, 50, 5827; (b) Chakraborty, C.; Vyavahare, V. P.;
Puranik, V. G.; Dhavale, D. D. Tetrahedron 2008, 64, 9574; (c) Bojstrup, M.;
Fanefjord, M.; Lundt, I. Org. Biomol. Chem. 2007, 5, 3164; (d) Dickson, L. G.;
Leroy, E.; Reymond, J.-L. Org. Biomol. Chem. 2004, 2, 1217; (e) Soengas, R. G.;
Estevez, J. C.; Estevez, R. J. Org. Lett. 2003, 5, 1423; (f) Kleban, M.; Hilgers, M.;
Greul, J. N.; Kugler, R. D.; Li, J.; Picasso, S.; Vogel, P.; Jager, V. ChemBioChem.
2001, 2, 365; (g) Greul, J. N.; Kleban, M.; Schneider, B.; Picasso, S.; Jager, V.
ChemBioChem. 2001, 2, 368; (h) Blaser, A.; Reymond, J.-L. Helv. Chim. Acta 2001,
84, 2119; (i) Mohal, N.; Mehta, G. Tetrahedron Lett. 2001, 42, 4227; (j) Boss, O.;
Leroy, E.; Blaser, A.; Reymond, J.-L. Org. Lett. 2000, 2, 151; (k) Blaser, A.;
Reymond, J.-L. Org. Lett. 2000, 2, 1733; (l) Blaser, A.; Reymond, J.-L. Synlett 2000,
817.
a
a
sidase (green coffee beans), b-galactosidase (Kluyveromyces lactis)
for compounds 8a–c was studied and the IC50 values are
summarized in Table 1. The residual hydrolytic activities of the
glycosidases were measured spectrometrically of the correspond-
ing chromogenic nitrophenyl glycosides as substrates in aqueous
phosphate buffer at pH 6.8. All the enzymes and substrates were
purchased from Sigma–Aldrich Co., U.S.A.
The assays performed with fixed concentration of the substrate
(1.6 mM) in phosphate buffer and enzyme concentration is 100 ll
(1 mg/ml) in 20 ml of substrate solution. Substrate and compounds
were preincubated for 1 min and the reaction was started by the
addition of the enzyme. The reaction for enzyme activity was fol-
lowed for 5 min at 405 nm.
7. (a) Mishra, G. P.; Ramana, G. V.; Rao, B. V. Chem. Commun. 2008, 29, 3423; (b)
Ramana, G. V.; Rao, B. V. Tetrahedron Lett. 2006, 47, 4441; (c) Ramana, G. V.;
Rao, B. V. Tetrahedron Lett. 2005, 46, 3049; (d) Ramana, G. V.; Rao, B. V.
Tetrahedron Lett. 2003, 44, 5103.
The compounds 8a and 8b have shown better inhibition against
b-galactosidase and the deoxy compound 8b also exhibited good
inhibition against a-glucosidase.
8. (a) Chandrasekhar, B.; Rao, B. V. Tetrahedron: Asymmetry 2009, 20, 1217; (b)
Chandrasekhar, B.; Madhan, A.; Rao, B. V. Tetrahedron 2007, 63, 8746; (c)
Madhan, A.; Rao, B. V. Tetrahedron Lett. 2003, 44, 5641.
9. For the synthesis of enantiomer of N-benzyl aminocyclopentitol 8a see Ref. 6f.
10. Selected references for the synthesis of trehazolamine: (a) Feng, X.; Duesler, E.
N.; Marino, P. S. J. Org. Chem. 2005, 70, 5618; (b) Akiyama, M.; Awamura, T.;
Kimura, K.; Hosomi, Y.; Kobayashi, Y. Tetrahedron Lett. 2004, 45, 7133; (c)
Sugiyama, Y.; Nagasawa, H.; Suzui, H.; Sakuda, S. J. Antibiot. 2002, 55, 263; (d)
Crimmins, T. M.; Tabet, E. A. J. Org. Chem. 2001, 66, 4012; (e) Seepersaud, M.;
Al-Abed, Y. Tetrahedron Lett. 2001, 42, 1471; (f) Clark, M. A.; Goering, B. K.; Li, J.;
Ganem, B. J. Org. Chem. 2000, 65, 4058; (g) de Gracia, I. S.; Bobo, S.; Martin-
Ortega, M. D.; Chiara, J. L. Org. Lett. 1999, 1, 1705; (h) de Gracia, I. S.; Dietrich,
H.; Bobo, S.; Chiara, J. L. J. Org. Chem. 1998, 63, 5883; (i) Boiron, A.; Zillig, P.;
Faber, D.; Giese, B. J. Org. Chem. 1998, 63, 5877; (j) Li, J.; Lang, F.; Ganem, B. J.
Org. Chem. 1998, 63, 3403; (k) Kobayashi, Y. Carbohydr. Res. 1999, 315, 3.
11. Recent structural analogues of trehazolin: (a) Chiara, J. L.; de Gracia, I. S.;
Garcia, A.; Basida, A.; Bobo, S.; Martin-Ortega, M. D. ChemBioChem. 2005, 6,
186; (b) Masson, G.; Philouze, C.; Py, S. Org. Biomol. Chem. 2005, 3, 2067.
12. Plumet, J.; Gomez, A. M.; Lopez, J. C. Mini-Rev. Org. Chem. 2007, 4, 201. and
references cited there in.
In conclusion we have successfully demonstrated a general
strategy for the synthesis of some novel N-benzyl aminocyclopent-
itols. Also we studied their activity against glycosidases. The sali-
ent features of our approach are nucleophilic addition on
lactamine for the introduction of chiral amino group and efficient
preparation of 1,1-disubstituted olefin for the RCM using Esc-
henmoser’s salt. This strategy is also helpful in designing related
skeletons for better activity. Application of this strategy for higher
membered amino carbasugars and azasugars is under progress in
our laboratory.
Acknowledgments
13. Kumar, D. N.; Rao, B. V.; Ramanjaneyulu, G. S. Tetrahedron: Asymmetry 2005, 16,
1611.
14. Nagai, M.; Gaudino, J. J.; Wilcox, C. S. Synthesis 1992, 163.
15. Cipolla, L.; Lay, L.; Nicotra, F.; Pangrazio, C.; Panza, L. Tetrahedron 1995, 51,
4679.
16. Mekki, B.; Singh, G.; Wightman, R. H. Tetrahedron Lett. 1991, 32, 5143.
17. (a) Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew. Chem., Int.
Ed. Engl. 1971, 10, 330; (b) Takano, S.; Inomato, K.; Samizu, K.; Tomita, S.;
Yanase, M.; Suzuki, M.; Iwabuchi, Y.; Sugihara, T.; Ogasawara, K. Chem. Lett.
1989, 1283.
J.P.R. and J.L.S. thank CSIR, New Delhi for research fellowship.
The authors also thank Dr. J. S. Yadav, Dr. A. C. Kunwar, and Dr.
T. K. Chakraborty for their constant support and encouragement.
We specially thank Dr. N. W. Fadnavis for his help in glycosidase
inhibition studies. We also thank DST (SR/S1/OC-14/2007), New
Delhi, for financial assistance.
18. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
19. Compounds 19 and 21 were transformed to their acetate derivatives (21 gave
only mono acetylated product). In their 1H NMR spectrum, protons at OAc
bearing carbons appeared as singlets at d 4.8 and d 4.7, respectively, thus
confirming their orientation as trans to adjacent proton.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.04.011.

J. P. Rao et al. / Tetrahedron Letters 51 (2010) 3083–3087
3087
20. (a) Data of compound 8a: colorless oil
½
a 2D8
ꢂ
ꢀ19.5 (c 1.8, MeOH); 1H
2.46–2.56 (m, 1H), 2.08–2.18 (m, 1H), 1.44–1.53 (m, 1H). 13C NMR
(75 MHz, D2O): 32.72, 37.97, 51.59, 60.27, 62.4, 71.0, 71.38, 129.91,
NMR (400 Mhz, D2O): 7.36 (m, 5H), 4.12 (m, 1H), 4.11 (d, 1H, 13.2 Hz),
3.97 (d, 1H, 13.2 Hz), 3.83 (dd, 1H, 6.6, 8.3 Hz), 3.64–3.74 (m, 4H), 2.11–
2.19 (m, 1H); 13C NMR (75 MHz, D2O): 45.56, 50.99, 57.18, 60.41, 69.66,
76.69, 77.16, 129.93, 130.34, 130.4, 131.1; IR (neat): 3384, 2926, 1641,
130.37, 131.23; IR (neat): 3386, 2924, 2854, 1460, 1120 cmꢀ1
(ESI) for C13H20NO3: calcd: 238.1443, found: 238.1445.
; HRMS
(c) Data of compound 8c: colorless oil ½a D28
ꢂ
ꢀ21.0 (c 0.6, MeOH), 1H NMR
1424, 1027 cmꢀ1
254.1404.
;
HRMS (ESI) for C13H20NO4 calcd: 254.1392, found:
(400 MHz, D2O): 7.38 (m, 5H), 4.08 (br t, 1H, 3.7 Hz), 3.99 (d, 1H,
J = 12.5 Hz) 3.87 (d, 1H, J = 12.5 Hz), 3.77–3.84 (m, 2H), 3.62 (s, 1H), 3.19
(d, 1H, 3.68). 13C NMR (75 MHz, D2O): 51.66, 65.6, 66.4, 68.39, 75.91,
76.23, 77.61, 128.83, 129.49, 129.55, 137.03; IR (neat): 3312, 2926, 1600,
(b) Data of compound 8b: colorless oil
NMR (400 MHz, D2O): 7.46 (m, 5H), 4.35 (d, 1H, J = 12.9 Hz), 4.24 (d, 1H,
J = 12.9 Hz), 4.18 (t, 1H, J = 4.1 Hz), 4.05–4.13 (m, 1H), 3.66–3.73 (m, 3H),
½
a 2D8
ꢂ
ꢀ15.8 (c 0.3, MeOH); 1H
1455 cmꢀ1
, HRMS (ESI) for C13H20NO5: calcd: 270.1341, found: 270.1337.