Sugar-amino acid cyclic conjugates as novel conformationally constrained hydroxyethylamine transition-state isosteres

Article abstract of DOI:10.1016/j.tetlet.2012.04.086

Hydroxyethylamine (HEA) isosteres have previously been shown to display a multitude of biomedical applications. In fact, the first protease inhibitor, saquinavir is an HEA based peptidomimetic. Herein we describe an easy-to-operate synthetic route to a series of carbohydrate-based conformationally constrained hydroxyethylamine (HEA) isosteres featuring amino acid side chains, starting from d-glucose. This class of novel sugar-amino acid-tethered conformationally restricted HEA systems may have bearing in practical application, particularly in the development of conformationally restricted protease inhibitors.

Full text of DOI:10.1016/j.tetlet.2012.04.086

Tetrahedron Letters 53 (2012) 3361–3363
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Sugar–amino acid cyclic conjugates as novel conformationally constrained
hydroxyethylamine transition-state isosteres
⇑
Arup Roy, Gangadhar J. Sanjayan
Division of Organic Chemistry, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Hydroxyethylamine (HEA) isosteres have previously been shown to display a multitude of biomedical
applications. In fact, the first protease inhibitor, saquinavir is an HEA based peptidomimetic. Herein
we describe an easy-to-operate synthetic route to a series of carbohydrate-based conformationally con-
Received 27 March 2012
Revised 18 April 2012
Accepted 19 April 2012
Available online 26 April 2012
strained hydroxyethylamine (HEA) isosteres featuring amino acid side chains, starting from D-glucose.
This class of novel sugar–amino acid-tethered conformationally restricted HEA systems may have bearing
in practical application, particularly in the development of conformationally restricted protease
inhibitors.
Keywords:
Hydroxyethylamine isosteres
Conformationally constrained
Ó 2012 Elsevier Ltd. All rights reserved.
D-Glucose
Protease inhibitor
Reductive amination
Recent years have witnessed the design and development of a
number of protease inhibitor—systems which mimic the transi-
tion-state of the protease’s actual substrate.1 Protease inhibitors
can be obtained by the isosteric replacement of the scissile peptide
bond.2 One of the most important transition-state isosteres devel-
oped so far is the hydroxyethylamine motif (HEA, Fig. 1).3 Ever
since the successful development of the first protease inhibitor
based on transition-state simulation principle, the amount of
attention given to this class of compounds has increased mani-
folds.4 The HEA isosteres have already been proven to be promising
candidates for various curative programs—in conditions varying
from contagious malaria to the deadly AIDS and many others.5 Suc-
cess of using this moiety as a peptide bond replacement can be
readily understood by the number of HEA-based drugs which have
been available in the market that includes saquinavir, indinavir,
nelfinavir and amprenavir which are the FDA approved protease
inhibitors (PIs). Several other therapeutically significant HEA iso-
sters are known for their potential for treating cancer, Alzheimer0s
disease and nosocomial infections.3a,4,6
the side chain lengths and composition and introducing conforma-
tional constraints on the backbone, which would often enhance the
binding affinity of the ligands (Fig. 2).9
A carbohydrate-based starting material was chosen herein ow-
ing to the enormous scope of its functionalization and ready avail-
H2N
O
H
H
N
H
N
N
OH
HN
S
O
HN
O
O
OH
HN
O
N
HO
O
Scissile Bond
Nelfinavir
NH
O
Saquinavir
P1
H
N
O
O
NH
In continuation of our ongoing programmes directed toward the
development of novel HEA isosteres,7 and robust peptide second-
ary structure scaffolds,8 herein we describe a general synthetic
route, starting from the readily available D-glucose, to access car-
bohydrate-based conformationally constrained hydroxyethyl-
amine (HEA) isosteres featuring amino acid side chains.
HN
O
P1'
OH
O
HO
O
N
S
OH
O
N
O
N
N
HN
As per the literature precedents, the structural modulations of
HEA isosteres can be achieved by amino acid variations, changing
H2N
Amprenavir
Indinavir
⇑
Corresponding author. Tel.: +91 020 2590 2082; fax: +91 020 2590 2629.
E-mail address: gj.sanjayan@ncl.res.in (G.J. Sanjayan).
Figure 1. Selected FDA approved protease inhibitors (PIs) wherein the scissile
peptide bond has been modified with an HEA moiety.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.086

3362
A. Roy, G. J. Sanjayan / Tetrahedron Letters 53 (2012) 3361–3363
benzyl groups were removed using 20% Pd(OH)2 in methanol at
O
OH
150 psi under hydrogen atmosphere for 16 h to furnish the macro-
H
N
R
R
cyclic HEA isosteres 9a–c.14
O
HO
HO
NH
It is noteworthy that at some stage during the formation of the
10-membered macrocyclic ring from the amino acid coupled fura-
nose precursor, a water molecule got associated with the molecule,
as clearly evident from their spectral data (vide infra), which is a
common feature in carbohydrates and their analogs bearing multi-
ple hydroxyl groups.15
OH
OH
OH
R
Figure 2. Design strategy to form conformationally constrained carbohydrate
derived macrocyclic HEA isosteres featuring amino acid side chain.
baility,10 as well as the ease of tuning of the ring size of these con-
strained HEA isosteres. The design strategy illustrated herein is a
straightforward one which makes use of established synthetic pro-
tocols. The main challenge of our synthetic strategy was the forma-
tion of the 10-membered macrocycle which was finally achieved
through a two-step 1,2 acetonide deprotection cum reductive ami-
nation process. The constrained HEA isosteres were synthesized in
In summary, this work has provided an elegant synthetic route
to access amino-acid-tethered carbohydrate conjugates, which
may eventually find potential application in the development of
conformationally restricted HEA isosteres. The synthetic strategy
reported herein is a convenient and straightforward one starting
from the readily available D-glucose. The generality of this syn-
thetic strategy has been demonstrated by the introduction of three
different amino acid residues into the carbohydrate cyclic frame
work.
an overall thirteen steps starting from
To synthesize the carbohydrate-based conformationally con-
strained HEA isosteres 9a–c, we began with -glucose which was
D-glucose (Scheme 1).
D
transformed into the tosyl analog 5 in four steps, following the
known protocols reported in the literature.11 The tosyl protected
furanose sugar 5 furnished the azide displaced product 6 in excel-
lent yield upon heating it at 50 °C in DMF containing NaN3.12 Ben-
zyl protection of the two secondary hydroxyl groups was carried
out by reacting with benzyl bromide in THF, having NaH as the
base and TBAI as a phase transfer catalyst affording the di-benzyl
ether 7. The furanose 7 was then subjected to selective azide
reduction using triphenylphosphine/water followed by coupling
with different BOC-protected amino acids to furnish 8a–c in very
good yields.13 The 1,2 acetonide protected furanose sugar bearing
amino acid side chains were then subjected to a two-step TFA-as-
sisted acetonide cleavage followed by reductive amination in the
presence of NaBH3CN. The crude secondary amine was then
protected using BOC anhydride in water as a solvent. Finally the
Acknowledgments
AR thanks the CSIR, New Delhi, for a senior research fellowship.
This work was funded partly by the International Foundation for
Science (IFS, Sweden) and the Department of Science and Technol-
ogy (New Delhi). We also thank NCL-IGIB (New Delhi) for financial
support.
Supplementary data
Supplementary data (general experimental procedures, 1H, 13C,
DEPT-135 NMR spectra and ESI mass spectra of all new
compounds) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.086.
O
O
OH
O
O
O
O
O
OH
i
ii
iii
HO
HO
O
O
O
OH
O
O
D-Glucose OH
2
1
3
N3
HO
TsO
HO
O
O
O
v
O
iv
vi
O
O
O
HO
HO
R
O
O
O
HO
O
5
6
4
O
NHBoc
O
R
HN
H
N
N3
BnO
NBoc
O
BnO
viii, ix, x
HO
OH
vii
O
O
O
BnO
BnO
OH
9a-c
O
O
OH
7
8a-c
8a, R=iPr (75%)
9a, R=iPr (48%)
9b, R=iBu (45%)
9c, R=Me (47%)
8b, R=iBu (78%)
8c, R=Me (80%)
Scheme 1. Reagents and conditions: (i) H3PO4, ZnCl2, acetone, reflux, 36 h, 43%; (ii) PDC, DCM, Ac2O, 2 h, 95%; (iii) NaBH4, EtOH, 2 h, 70%; (iv) (a) 80% aq AcOH, 8 h, 92%, (b)
Bu2SnO, CHCl3, TsCl, 5 h, 86%; (v) NaN3, DMF, 0 °C, 10 h, 94%; (vi) NaH, BnBr, TBAI, THF, 2.5 h, 68%; (vii) (a) TPP, THF–H2O, rt, 3 h, (b) HBTU, DIPEA, BOC-amino acids, CH3CN,
10 h; (viii) (a) 80% aq TFA, 30 h, (b) NaBH3CN, AcOH, 40 h; (ix) BOC2O, H2O, 12 h; (x) H2, Pd(OH)2, MeOH, 150 psi, 16 h.

A. Roy, G. J. Sanjayan / Tetrahedron Letters 53 (2012) 3361–3363
3363
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solution of 1,2-O-isopropylidene-3,5-di-O-benzyl-6-azido-a-D-allofuranose 7
(1.2 g, 2.82 mmol, 1 equiv) in 4:1 (v/v) THF:H2O mixture (15 ml) and was
stirred for 3 h. THF was then completely evaporated and the residue was
extracted with ethyl acetate, dried over anhy. Na2SO4 and was concentrated
under reduced pressure. The residue containing the crude amine (1.22 g,
3.05 mmol, 1 equiv) was dissolved in acetonitrile containing Boc LValine
(0.729 g, 3.36 mmol, 1.1 equiv). To the resulting mixture at 0 °C, HBTU (1.5 g,
3.97 mmol, 1.3 equiv) was added followed by the addition of DIPEA (1.04 mL,
6.11 mmol, 2 equiv) and the mixture was allowed to stir at room temperature for
10 h. The reaction mixture was then taken into ethyl acetate, sequentially
washed with aq NaHCO3 and KHSO4, dried over anhy. Na2SO4, concentrated
under reduced pressure and was finally purified by column chromatography to
furnish a white solid. Yield 1.35 g (75%); mp: 73–75 °C; ½a D28
ꢀ
: 333.3 (c = 0.6,
CHCl3); IR (CHCl3)
m
cmꢁ1): 3436, 3018, 2299, 1666, 1369, 1215, 756; 1H NMR
(200 MHz, CDCl3): d = 7.35–7.28 (m, 10H), 6.24 (br s, 1H), 5.71–5.69 (d,
J = 3.66 Hz, 1H), 4.96–4.92 (d, J = 8.59 Hz, 1H), 4.81–4.54 (m, 5H), 4.24–4.19
(m, 1H), 3.99–3.92 (m, 1H), 3.82–3.75 (m, 2H), 3.68–3.55 (m, 1H), 3.29-3.22 (m,
1H), 2.07–2.00 (m,1H), 1.80 (s, 1H), 1.58 (s, 3H), 1.44 (s, 9H), 1.36 (s, 3H), 0.89–
0.85 (d, J = 6.82 Hz, 3H), 0.79–0.76 (d, J = 6.82 Hz, 3H); 13C NMR (50 MHz, CDCl3):
d 171.3, 155.5, 138.2, 137.1, 128.4, 128.3, 128.0, 127.8, 127.6, 112.9, 103.9, 79.7,
77.2, 77.1, 75.9, 72.9, 71.9, 59.7, 39.2, 30.7, 28.2, 26.7, 26.5, 19.0, 17.3; ESI-MS:
599.2980 (M+H)+, 621.2883 (M+Na)+, 637.2506 (M+K)+; Elemental Anal. Calcd
for C33H46N2O8: C, 66.20; H, 7.74; N, 4.68. Found: C, 66.32; H, 7.82; N, 4.48.
14. (6R,7R,8R,9S)-tert-Butyl-6,7,8,9-tetrahydroxy-2-isopropyl-3-oxo-1,4-diazecane-1-
carboxylate monohydrate (9a):
Representative procedure: Valine coupled furanose sugar 8a (0.34 g, 0.56 mmol,
1 equiv) was taken in a 25 mL two-neck round bottomed flask containing 6 mL
aq trifluoro acetic acid (80%) and the reaction mixture was stirred for 30 h at rt
The residue (0.4 g, 0.73 mmol, 1 equiv) obtained after evaporation of TFA at
reduced pressure was then taken into methanol and NaBH3CN (0.13 g,
2.1 mmol) was added followed by the addition of AcOH (0.04 mL, 0.73 mmol,
1 equiv) at 0 °C. The reaction mixture was then allowed to come to rt and was
further stirred for 40 h. Methanol was then evaporated under reduced pressure
and the aq layer was washed with ethyl acetate, followed by neutralization
with saturated NaHCO3. The neutralized aq layer thus obtained was
subsequently extracted with dichloromethane. The organic layer was
concentrated and the crude product obtained was carried forward for the
next reaction without further purification. To the crude free amine (0.13 g,
0.30 mmol, 1 equiv), BOC anhydride (0.33 g, 1.5 mmol, 5 equiv) was added
followed by water (3 mL) and the resulting mixture was stirred for 12 h, when
7. Kale, S. S.; Chavan, S. T.; Sabharwal, S. G.; Puranik, V. G.; Sanjayan, G. J. Org.
Biomol. Chem. 2011, 9, 7300.
8. (a) Prabhakaran, P.; Kale, S. S.; Puranik, V. G.; Rajamohanan, P. R.; Chetina, O.;
Howard, J. A. K.; Hofmann, H.-J.; Sanjayan, G. J. J. Am. Chem. Soc. 2008, 130,
17743; (b) Roy, A.; Prabhakaran, P.; Baruah, P. K.; Sanjayan, G. J. Chem. Commun.
2011, 47, 11593; (c) Ramesh, V. V. E.; Priya, G.; Rajamohanan, P. R.; Hofmann,
H.-J.; Sanjayan, G. J. Tetrahedron 2012, 53, 1936; (d) Prabhakaran, P.; Priya, G.;
Sanjayan, G. J. Angew. Chem., Int. Ed. 2012. http://dx.doi.org/10.1002/
anie.201107521.
a
sticky material settled down, which was taken into DCM, washed
sequentially with aq KHSO4 and NaHCO3, dried over Na2SO4, and
concentrated under reduced pressure to obtain residue whose benzyl
a
9. (a) Dolle, R. E.; Prasad, C. V. C.; Prouty, C. P.; Salvino, J. M.; Awad, M. M. A.;
Schmidt, S. J.; Hoyer, D.; Ross, T. M.; Graybill, T. L.; Speier, G. J.; Uhl, J.; Miller, B.
E.; Helaszek, C. T.; Ator, M. A. J. Med. Chem. 1997, 40, 1941; (b) Olson J. Med.
Chem. 1993, 36, 3039; (c) Guarna, A.; Guidi, A.; Machetti, F.; Menchi, G.;
Occhiato, E. G.; Scarpi, D.; Sisi, S.; Trabocchi, A. J. Org. Chem. 1999, 64, 7347; (d)
Scholz, D.; Hecht, P.; Schmidt, H.; Billich, A. Monatsh. Chem. 1999, 130, 1283; (e)
Robl, J. A.; Cimarusti, M. P.; Simpkins, L. M.; Brown, B.; Ryono, D. E.; Bird, J. E.;
Asaad, M. M.; Schaeffer, T. R.; Trippodo, N. C. J. Med. Chem. 1996, 39, 494; (f)
Marsault, E.; Peterson, M. L. J. Med. Chem. 2011, 54, 1961; (g) Kim, Y.-K.; Arai, M.
A.; Arai, T.; Lamenzo, J. O.; Dean, E. F.; Patterson, N.; Clemons, P. A.; Schreiber, S.
L. J. Am. Chem. Soc. 2004, 126, 14740.
10. (a) Jockusch, R. A.; Talbot, F. O.; Rogers, P. S.; Simone, M. I.; Fleet, G. W. J.;
Simons, J. P. J. Am. Chem. Soc. 2006, 128, 16771; (b) Risseeuw, M. D. P.;
Overhand, M.; Fleet, G. W. J.; Simone, M. I Tetrahedron: Asymmetry 2007, 18,
2001; (c) Yu, C. Y.; Asano, N.; Ikeda, K.; Wang, M. X.; Butters, T. D.; Wormald, M.
R.; Dwek, R. A.; Winters, A. L.; Nash, R. J.; Fleet, G. W. J. Chem. Commun. 2004,
groups were subjected to hydrogenolysis using 20% Pd(OH)2 in methanol at
150 psi under hydrogen atmosphere for 16 h to furnish 9a, which was then
purified using preparative TLC to furnish the pure product as an off white fluffy
solid. Yield over three steps (48%); mp: 82–85 °C; ½a D28
ꢀ : ꢁ7.07° (c = 5.09,
CHCl3); IR (Nujol)
m
(cmꢁ1): 3323, 2922, 2359, 1633, 1454, 1163, 727; 1H NMR
(500 MHz, CD3OD): d = 3.94–3.93 (m, 2H), 3.89 (br s, 1H), 3.85–3.79 (m, 2H),
3.72–3.70 (m, 2H), 3.61–3.58 (m, 1H), 3.45–3.42 (m, 1H), 3.37 (br s, 1H), 2.14–
2.10 (m, 1H), 1.51 (s, 9H), 1.02–1.01 (d, J = 6.60 Hz, 3H), 0.99–0.98 (d,
J = 6.88 Hz, 3H); 13C NMR (125 MHz, CD3OD): d 175.2, 158.1, 80.7, 74.8, 74.4,
74.3, 72.6, 64.3, 61.8, 43.2, 31.9, 28.8, 19.8, 18.4; ESI-MS: 381.2047 (M+H)+,
403.1407 (M+Na)+; Elemental Anal. Calcd for C16H32N2O8: C, 50.51, H, 8.48, N,
7.36. Found: C, 50.35; H, 8.40; N, 7.60.
15. Booth, K. V.; Jenkinson, S. F.; Watkin, D. J.; Fleet, G. W. J. Acta Cryst. 2007, E63,
o3592.