3114
K. Zhang, F. Schweizer
LETTER
(17) Koep, S.; Gais, H.-J.; Raabe, R. J. Am. Chem. Soc. 2003,
1.48%
NOEa
125, 13243; and references cited therein.
(18) For selected examples of bicyclic proline analogues
incorporated into bioactive peptides, see: (a) Cluzeau, J.;
Lubell, W. D. Biopolym. Pept. Sci. 2005, 80, 98.
BnO
H
CO2Me
O
BnO
MeO2C
O
H
7
H
BnO
BnO
0.17%
NOEa
BnO
BnO
0.73%
NOEa
120 NBn
10 NBn
BnO
(b) Blankley, C. J.; Kaltenbronn, J. S.; DeJohn, D. E.;
Wener, A.; Bennett, L. R.; Bobowski, G.; Krolls, U.;
Johnson, D. R.; Pearlman, W. M.; Hoefle, M. L. J. Med.
Chem. 1987, 30, 992. (c) Dumy, P.; Keller, M.; Ryan, D. E.;
Rohwedder, B.; Wöhr, T.; Mutter, M. J. Am. Chem. Soc.
1997, 119, 918. (d) Li, W.; Moeller, K. D. J. Am. Chem. Soc.
1996, 118, 10106.
BnO
AcO
H
H
H
O
H
CH3
0.78%
NOEa
O
17
19
JH4,H5 = 9.2 Hz
JH5,H6 = 9.4 Hz
JH6,H7 = 9.6 Hz
JH4,H5 = 9.0 Hz
JH5,H6 = 9.4 Hz
JH6,H7 = 9.6 Hz
chair
conformation
(19) For recent reviews on the synthesis and applications of sugar
amino acid hybrids and related materials, see: (a) Dondoni,
A.; Marra, A. Chem. Rev. 2000, 100, 4395. (b) Schweizer,
F. Angew. Chem. Int. Ed. 2002, 41, 230. For recent reviews
on the use of sugar amino acids as peptidomimetics, see:
(c) Gruner, S. W.; Locardi, E.; Lohof, E.; Kessler, H. Chem.
Rev. 2002, 102, 491. (d) Chakraborty, T. K.; Ghosh, S.;
Jayaprakash, J. Curr. Med. Chem. 2002, 9, 421.
Figure 5 Interproton effects (NOE) observed for GlcProHs 17 and
19. The observed NOE between H-2 and H-10 and H-10 and H-7 are
a diagnostic tool to discriminate between C-10 epimers 17 and 19.
a Recorded in C6D6.
In summary, we have developed a novel and short syn-
thetic pathway into spirocyclic polyhydroxylated glucose-
based L-proline analogues. It can be envisaged that deco-
ration of the carbohydrate scaffold provides a tool to
adjust the physical, biological and pharmacological
properties of the proline analogues. We are currently in-
vestigating the prolinemimetic and glycomimetic proper-
ties of the synthesized GlcProHs and glucose–pipecolic
acid hybrid.
(20) Grotenbreg, G. M.; Timmer, M. S. M.; Llamas-Saiz, A. L.;
Verdoes, M.; Van der Marel, G. A.; van Raaij, M. J.;
Overkleeft, H. S.; Overhand, M. J. Am. Chem. Soc. 2004,
126, 3444.
(21) Chakraborty, T. K.; Jayaprakash, S.; Diwan, P. V.; Nagaraj,
R.; Jampani, S. R. B.; Kunwar, A. C. J. Am. Chem. Soc.
1998, 120, 12962.
(22) It has been reported that substitution of D-proline by cis-3-
hydroxy-D-proline (HypC3-OH) in the sequence Boc-Leu-
Pro-Gly-Leu-NHMe resulted in novel pseudo b-turn-like
nine-membered ring structure involving an intramolecular
LeuNH → HypC3-OH hydrogen bond.
References
(23) Prior to this publication, a report on a five-membered
spirocyclic fructose-based proline analogue appeared:
Cipolla, L.; Redaelli, C.; Nicotra, F. Lett. Drug Des. Discov.
2005, 2, 291.
(24) Stott, K.; Stonehouse, J.; Keeler, J.; Hwang, T. L.; Shaka, A.
J. J. Am. Chem. Soc. 1995, 117, 4199.
(25) PCC oxidation of commercially available 2,3,4,6-tetra-O-
benzyl-D-glucopyranose (Toronto Chemicals) in CH2Cl2
provides 1 in 95% yield on a multi-gram scale; see: G
ueyrard, D.; Haddoub, R.; Salem, A.; Bacar, N. S.; Goekjian,
P. G. Synlett 2005, 520.
(26) Analytical data for compounds 17, 19 and 21.
Compound 17: 1H NMR (500 MHz, C6D6, r.t., TMS): d =
1.76 (s, 3 H), 2.20 (dd, H-9a, J = 13.7 Hz, J = 6.2 Hz), 2.38
(dd, H-9b, J = 13.7 Hz, J = 10.3 Hz), 3.00 (s, 3 H), 3.34 (m,
H-10), 3.56–3.70 (m, 5 H, H-5, H-6, H-7, H-8a,b), 3.75 (s,
H-2), 3.83–3.91 (m, H-4, 1 H, J = 9.0 Hz, J = 14.5 Hz), 4.12
(d, 1 H, J = 13.5 Hz), 4.28 (dd, H-11a, J = 10.6 Hz, J = 4.6
Hz), 4.44–4.53 (m, 2 H, H-11b), 4.54–4.58 (d, 2 H, J = 11.0
Hz), 4.60 (d, 1 H, J = 11.2 Hz), 4.80 (d, 2 H, J = 11.2 Hz),
4.83 (d, 1 H, J = 11.2 Hz), 5.17 (d, 1 H, J = 12.4 Hz), 6.98–
7.21 (m, 25 H). 13C NMR (300 MHz, CDCl3, r.t.): d = 20.95,
29.99, 51.54, 60.41, 60.84, 67.20, 69.39, 72.48, 72.77,
73.52, 75.05, 75.52, 76.04, 76.69, 78.66, 86.14, 87.48,
126.01–128.79 (arom. C), 138.03, 138.04, 138.35, 138.91,
139.32, 170.99, 171.96. HRMS: m/z calcd for C49H54NO9
[M + H]+: 800.3793; found: 800.3794.
(1) Kakinoki, S.; Hirano, Y.; Oka, M. Polym. Bull. (Berlin)
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(16) (a) Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J. Am.
Chem. Soc. 1997, 119, 8451. (b) Kuwano, R.; Sato, K.;
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122, 7614. (c) Viswanathan, R.; Prabhakaran, E. N.; Plotkin,
M. A.; Johnston, J. N. J. Am. Chem. Soc. 2003, 125, 163.
Compound 19: 1H NMR (500 MHz, C6D6, r.t., TMS): d =
1.68 (s, 3 H), 2.14 (dd, H-9a, J = 14.2 Hz, J = 1.1 Hz), 2.82
(dd, H-9b, J = 14.2 Hz, J = 9.6 Hz), 3.07 (s, 3 H), 3.57 (dd,
H-6, J = 9.4 Hz, J = 9.3 Hz), 3.63 (dd, H-5, J = 9.4 Hz, J =
9.2 Hz), 3.65–3.72 (m, H-4, H-8a), 3.75 (dd, H-8b, J = 11.1
Hz, J = 1.6 Hz), 3.77–3.81 (m, H-7, H-10), 3.84 (d, 1 H, J =
14.4Hz), 3.92 (s, H-2), 4.11 (d, 1 H, J = 14.2 Hz), 4.28 (dd,
H-11a, J = 10.7 Hz, J = 7.8 Hz), 4.38 (dd, H-11b, J = 10.7
Synlett 2005, No. 20, 3111–3115 © Thieme Stuttgart · New York