T. Mochizuki et al. / Tetrahedron Letters 51 (2010) 977–979
979
OBn
O
OBn
O
OBn
O
OMe
O
AcO
O
O
O
AcO
AcO
O
O
AcO
c
d
BnO
BnO
b
a
BnO
OMe
6
O
O
O
O
O
O
9a: X = H
9b: X = F
7
8
O
N
AcO
OAc
AcO
X
OBn
O
OBn
O
OBn
R2O
R2O
OR1
OTBS
AcO
AcO
O
AcO
O
BnO
BnO
AcO
O
e
O
g
i
BnO
O
N
O
N
3a and 3b
O
O
R2O
X
AcO
X
N
AcO
X
13a: X = H, R2 = H
13b: X = F, R2 = H
11a: X = H, R1 = H
11b: X = F, R1 = H
10a: X = H
10b: X = F
h
f
14a: X = H, R2 =
O
P
O
12a: X = H, R1 = TBS
12b: X = F, R1 = TBS
14b: X = F, R2
=
O
Scheme 2. Reagents and conditions: (a) (1) TBAF, THF, rt; (2) CH2@CHCH2Br, Ca(OH)2, CaO, DMF, rt, 97%; (b) (1) 90% aq TFA, rt; (2) Ac2O, DMAP, Et3 N, MeCN, rt, 77%; (c)
indoline, AcOH, EtOH, reflux; (d) MnO2, toluene, rt, 69% (10a) from 8, 77% (10b) from 8; (e) (PPh3)3RhCl, toluene/EtOH, reflux, 68% (11a), 72% (11b); (f) TBSCl, DMAP, pyridine,
rt, 64% (12a), 79% (12b); (g) NaOMe, MeOH, rt, quant (13a), quant (13b); (h) XEPA, tetrazole, CH2Cl2, ꢁ40 °C to rt, then m-CPBA, ꢁ40 °C, 97% (14a), 71% (14b); (i) (1) TBAF,
THF, rt; (2) Pd(OH)2, cyclohexene, MeOH, reflux, 97% (3a), 97% (3b).
2. Total synthesis of adenophostin A: (a) Hotoda, H.; Takahashi, M.; Tanzawa, K.;
Takahashi, S.; Kaneko, M. Tetrahedron Lett. 1995, 36, 5037–5040; (b) van
Straten, N. C. R.; van der Marel, G. A.; van Boom, J. H. Tetrahedron 1997, 53,
6509–6522; (c) Marwood, R. D.; Correa, V.; Taylor, C. W.; Potter, B. V. L.
Tetrahedron: Asymmetry 2000, 11, 397–403.
3. Synthesis of adenophostin A analogs see: (a) de Kort, M.; Regenbogen, A. D.;
Overkleeft, H. S.; Challis, J.; Iwata, Y.; Miyamoto, S.; van der Marel, G. A.; van
Boom, J. Tetrahedron 2000, 56, 5915–5928. and references therein; (b) Chretien,
F.; Moitessier, N.; Roussel, F.; Mauger, J. P.; Chapleur, Y. Curr. Org. Chem. 2000, 4,
513–534; (c) Roussel, F.; Moitessier, N.; Hilly, M.; Chrétien, F.; Mauger, J.-P.;
Chapleur, Y. Bioorg. Med. Chem. 2002, 10, 759–768; (d) Rosenberg, H. J.; Riley, A.
M.; Laude, A. J.; Taylor, C. W.; Potter, B. V. L. J. Med. Chem. 2003, 46, 4860–4871;
(e) Rossi, A. M.; Riley, A. M.; Tovey, S. C.; Rahman, T.; Dellis, O.; Taylor, E. J.;
Veresov, V. G.; Potter, B. V.; Taylor, C. W. Nat. Chem. Biol. 2009, 5, 631–639. and
references therein.
4. (a) Shuto, S.; Tatani, K.; Ueno, Y.; Matsuda, A. J. Org. Chem. 1998, 63, 8815–
8824; (b) Abe, H.; Shuto, S.; Matsuda, A. J. Org. Chem. 2000, 65, 4315–4325; (c)
Shuto, S.; Yahiro, Y.; Ichikawa, S.; Matsuda, A. J. Org. Chem. 2000, 65, 5547–
5557; (d) Mochizuki, T.; Kondo, Y.; Abe, H.; Taylor, C. W.; Potter, B. L. V.;
Matsuda, A.; Shuto, S. Org. Lett. 2006, 8, 1455–1458; (e) Terauchi, M.; Abe, H.;
Tovey, S. C.; Dedos, S. G.; Taylor, C. W.; Paul, M.; Trusselle, M.; Potter, B. V. L.;
Matsuda, A.; Shuto, S. J. Med. Chem. 2006, 49, 1900–1909; (f) Mochizuki, T.;
Kondo, Y.; Abe, H.; Tovey, S. C.; Dedos, S. G.; Taylor, C. W.; Paul, M.; Potter, B. V.
L.; Matsuda, A.; Shuto, S. J. Med. Chem. 2006, 49, 5750–5758. and references
therein.
5. (a) Berridge, M. J. Nature (London) 1993, 361, 315–325; (b) Joseph, S. K. Cell.
Figure 3. Binding affinities of adenophostin A (2) and its indole derivatives 3a and
3b for LIBRAvI and LIBRAvII. Effects of compounds on the emission ratio (480/
535 nm) of LIBRAvI and LIBRAvII are expressed as % of maximal response. The
Signalling 1996, 8, 1–7.
6. (a) Mecozzi, S.; West, A. P.; Dougherty, D. A. J. Am. Chem. Soc. 1996, 118, 2307–
2308; (b) Yorita, H.; Otomo, K.; Hiramatsu, H.; Toyama, A.; Miura, T.; Takeuchi,
H. J. Am. Chem. Soc. 1996, 118, 2307–2308; (c) Inoue, Y.; Sugio, S.; Andzelm, J.;
Makamura, N. J. Phys. Chem. A 1998, 102, 646–648.
maximal response was determined by the application of 30
each experiment.
lM IP3 at the end of
*
7. The preoptimized geometries by HF/3-21G were taken to be the input
*
geometries for final optimization by B3LYP/6-31G . Single point energies and
all electronic properties were calculated by B3LYP/6-31G*.
8. Preliminary experiments suggested that in the glycosidation of a-disaccharide
selectivity may be manipulated by changing the substituent at the
indole 4-position in indole derivatives of adenophostin A.
In conclusion, the indole derivatives 3a and 3b designed as a no-
vel IP3 receptor ligands were successfully synthesized from the key
disaccharide unit 6. While binding affinities of 3a and 3b for IP3R1
and IP3R2 are weaker than adenophostin A, the 4-fluoroindole
derivative 3b was shown to be an IP3R1-selective ligand. Therefore,
3a may be an effective lead for developing subtype-selective IP3
receptor ligands, which can be useful biological tools.
donors at the 1b-position of the ribose moiety with indoline as an acceptor, a
bulky protecting group, such as TBS group, at the 5-primary hydroxyl of the
donor might prevent the glycosidation to proceed.
9. Preobrazheskaya, M. N.; Vigdorchik, M. M.; Suvorov Tetrahedron 1967, 23,
4653–4660.
10. The anomeric b-configuration was confirmed from an NOE correlation between
H-2 of the indole moiety and H-20 of the ribose moiety.
11. When deprotection of the 50-O-allyl group was examined after the introduction
of the o-xylene phosphate units at the 20, 300, and 400-hydroxyls, it was
unsuccessful.
12. Watanabe, Y.; Komoda, Y.; Ebisuya, K.; Ozaki, S. Tetrahedron Lett. 1990, 31,
255–256.
13. Nezu, A.; Tanimura, A.; Morita, T.; Shitara, A.; Tojyo, Y. Biochim. Biophys. Acta
Gen. Subj. 2006, 1760, 1274–1280.
References and notes
1. (a) Takahashi, M.; Kagasaki, T.; Hosoya, T.; Takahashi, S. J. Antibiot. 1993, 46,
1643–1647; (b) Takahashi, M.; Tanzawa, K.; Takahashi, S. J. Biol. Chem. 1994,
269, 369–372; (c) Hirota, J.; Michikawa, T.; Miyawaki, A.; Takahashi, M.;
Tanzawa, K.; Okura, I.; Furuichi, T.; Mikoshiba, K. FEBS Lett. 1995, 368, 248–252.
14. Zhang, L.; Huang, W.; Tanimura, A.; Morita, T.; Harihar, S.; De Wald, D. B.;
Prestwich, G. D. Chem. Med. Chem. 2007, 2, 1281–1289.
15. Tanimura, A.; Morita, T.; Nezu, A.; Shitara, A.; Hashimoto, N.; Tojyo, Y. J. Biol.
Chem. 2009, 284, 8910–8917.