1430
H. Tanaka et al.
LETTER
(18) Spectral data; 1H NMR (300 MHz, CDCl3): = 9.71–9.58 (1
H, br s), 9.56 (1 H, s), 7.22 (1 H, t, J = 8.1 Hz), 7.16 (2 H, d,
J = 8.4 Hz), 6.84 (2 H, d, J = 8.4 Hz), 6.39 (2 H, d, J = 8.1
Hz), 3.79 (3 H, s), 3.43 (2 H, t, J = 8.1 Hz), 2.98 (2 H, t, J =
8.1 Hz); MS (ESI): 273 [M + H+].
References
(1) (a) Sencei, P. In Solid-Phase Synthesis and Combinatorial
Technology; Wiley-Interscience: New York, 2000.
(b) Dorwald, F. Z. Organic Synthesis on Solid Phase; Willy-
VCH: New York, 2000, .
(19) Zenkoh, T.; Tanaka, H.; Setoi, H.; Takahashi, T. Synlett
2002, 867.
(2) (a) Matsuda, A.; Doi, T.; Tanaka, H.; Takahashi, T. Synlett
2001, 1101. (b) Ohno, H.; Kawamura, K.; Otake, A.;
Nagase, H.; Tanaka, H.; Takahashi, T. Synlett 2002, 93.
(3) Zhu, Z.; Mckittrick, B. Tetrahedron Lett. 1998, 39, 7479.
(4) (a) Review: McKee, F. W.; Hawkins, W. B. Physiol. Rev.
1945, 25, 255. (b) Alvarado, F.; Crane, R. K. Physiol. Rev.
1964, 93, 116. (c) Toggenburger, G.; Kessler, M.; Semenza,
G. Physiol. Rev. 1982, 688, 557.
(20) General procedure for the solid-phase synthesis of phlorizin
derivatives exemplified with the synthesis of 27: The resin
21 (2 30 mg, 0.17 mmol/g) was loaded into IRORITM
MicroKans. To a solution of benzaldehyde (35 L) in EtOH
(1.75 mL) and 50% KOH aq (0.35 mL) were added the
MicroKans at ambient temperature. After being shaken for
17 hours at the same temperature, the reaction mixture was
drained to isolate the Kans. The Kans were sequentially
washed with DMF (4 3 mL), 5% AcOH–THF (2 3 mL),
(5) ArgoGelTM-Wang-Cl resin was purchased from Argonaut
Technologies, San Carlos, CA.
(6) (a) O’Donnell, M. J.; Zhou, C.; Scott, W. L. J. Am. Chem.
Soc. 1996, 118, 6070. (b) O’Donnell, M. J.; Delgado, F.;
Hostettler, C.; Schwesinger, R. Tetrahedron Lett. 1998, 39,
8775. (c) O’Donnell, M. J.; Drew, M. D.; Pottorf, R. S.;
Scott, W. L. J. Comb. Chem. 2000, 2, 172.
(7) Hollinshead, S. P. Tetrahedron Lett. 1996, 37, 9157.
(8) Yield (%) was calculated based on weight of isolated
products and based on the initial loading of resin. Purity was
determined by LC-MS analysis employing UV detection at
254 nm.
(9) Column: Mightysil RP-18 GP (ODS) 3 m, 4.6 mmI. D. 50
mm; mobile phase: 20 mM AcONH4: MeOH = 70:30 (0
min.)–10: 90 (4–8 min.); UV: 254 nm.
(10) (a) Paquette, L. A.; Annis, G. D. J. Am. Chem. Soc. 1983,
105, 7358. (b) Rosen, T.; Heathcock, C. H. J. Am. Chem.
Soc. 1985, 107, 3731. (c) Hecker, S. J.; Heathcock, C. H. J.
Am. Chem. Soc. 1986, 108, 4586.
THF–H2O (2:1, 2 3 mL), THF (4 3 mL), MeOH (4
mL), and CH2Cl2 (4 3 mL) and dried in vacuo to give
immobilized enone 22a in two Kans. Two MicroKans were
exposed to a solution of (Ph3P)3RhCl (72 mg) and Et3SiH
(125 L) in benzene (2.0 mL). After being shaken at ambient
temperature for 16 hours, the mixture was drained.
3
Remaining two Kans were washed sequentially with benz-
ene (3 mL), DMF (4 3 mL), 5% AcOH–THF (4 3 mL),
THF (4 3 mL), MeOH (4 3 mL), and CH2Cl2 (4 3 mL)
and dried to give ketone 23a. To a solution of p-TsOH
(42 mg) in CH2Cl2–MeOH (5: , 2.1 mL) were added the
MicroKans at ambient temperature and the mixture was
shaken for 20 hours. The reaction mixture was drained to
isolate the Kans. The Kans were sequentially washed with
MeOH (4 3 mL), dioxane (4 3 mL), DMF (4 3 mL), and
CH2Cl2 (4 3 mL) and then dried in vacuo to afford
immobilized phenol 24a in two Kans. The MicroKans were
exposed to a solution of glucosyl bromide 25 (168 mg) in
1,2-dichloroethane (2.8 mL). To the mixture were suc-
cessively added 5% NaOH aq (1.4 mL) and benzyl tri-n-
butylammonium chloride (14.6 mg). After being shaken at
ambient temperature for 15.5 hours, the mixture was
drained. Remaining two Kans were washed sequentially
with CH2Cl2 (3 mL), DMF (4 3 mL), THF–H2O (2:1,
(11) Spectral data; 19: 1H NMR (270 MHz, CDCl3): =12.30 (1
H, s), 7.71 (1 H, d, J = 7.9 Hz), 7.44 (1 H, t, J = 7.9 Hz),
7.37–7.14 (5 H, m), 6.97 (1 H, d, J = 7.9 Hz), 6.85 (1 H, t,
J = 7.9 Hz), 3.30 (2 H, t, J = 8.3 Hz), 3.05 (2 H, t, J = 8.3 Hz);
13C NMR (67.8 MHz, CDCl3): = 205.3, 162.4, 140.7,
136.3, 129.8, 126.3, 119.2, 118.9, 118.5, 77.5, 77.0, 76.5,
39.9, 29.9; MS (ESI): 227 [M + H+].
(12) (a) Arens, B.; Dauvarte, M.; Arens, A. Zh. Org. Khim. 1969,
5, 534. (b) Dhawan, D.; Grover, S. K. Synth. Commun. 1992,
22, 2405. (c) Elmorsy, S. S.; El-Ah, A.-A. S.; Soliman, H.;
Amer, F. A. Tetrahedron Lett. 1996, 37, 2297.
(d) Makrandi, J. K.; Kumari, V. Synth. Commun. 1990, 20,
1885.
(13) Miles, C. O.; Main, L.; Nicholson, B. K. Aust. J. Chem.
1989, 42, 1103.
(14) The loading amount of ketone was determined by acidic
cleavage after removal of THP group, followed by mass
recovery and HPLC analysis.
2
3 mL), 5% AcOH–THF (2 3 mL), THF (4 3 mL),
MeOH (4 3 mL), and CH2Cl2 (4 3 mL) and dried to give
protected glycoside 26. To a solution of Cs2CO3 (74 mg) in
THF–MeOH (1:1, 2.0 mL) were added the MicroKans at
ambient temperature. After being shaken for 18 hours at the
same temperature, the reaction mixture was drained to
isolate the Kans. The Kans were sequentially washed
with THF–MeOH (1:1, 4 3 mL), DMF (4 3 mL), THF–
water (2:1, 2 3 mL), 5% AcOH–THF (2 3 mL), THF
(4 3 mL), MeOH (4 3 mL), and CH2Cl2 (4 3 mL). The
resin in the two MicroKans was cleaved with 10% TFA–
CH2Cl2 (5.0 mL) for 30 minutes. The resulting solution was
diluted with CH2Cl2 (5 mL) and toluene (2 mL). The
MicroKans were removed from the solution by means of
tweezers. The acidic solution was concentrated to afford 27
(3.6 mg, 8.90 mol, 87% yield with 79% purity). Spectrum
data of 27: 1H NMR (300 MHz, DMSO-d6): = 10.97 (1 H,
s), 7.30–7.13 (6 H, m), 6.67 (1 H, d, J = 8.8 Hz), 6.55 (1 H,
d, J = 8.1 Hz), 5.26 (1 H, d, J = 4.8 Hz), 5.13 (1 H, d, J = 5.1
Hz), 5.06 (1 H, d, J = 5.9 Hz), 4.91 (1 H, d, J = 7.3 Hz), 4.59
(1 H, t, J = 5.5 Hz), 3.74–3.65 (2 H, m), 3.52–3.10 (6 H, m),
(15) Yield (%) was calculated based on weight of isolated
products and based on the loading amount of 2 , 6 -
dihydroxyacetophenone. Purity was determined by LC-MS
analysis employing UV detection at 254 nm..
(16) Spectral data; 1H NMR (270 MHz, CDCl3): = 9.50–9.28 (2
H, brs), 7.37–7.17 (8 H, m), 3.47 (2 H, t, J = 7.9 Hz), 3.04 (2
H, t, J = 7.9 Hz); MS (ESI): 243 [M + H+].
(17) Poonia, N. S.; Chhabra, K.; Kumar, C.; Bhagwat, V. W. J.
Org. Chem. 1977, 42, 3311.
+
2.90 (2 H, t, J = 7.5 Hz); MS (ESI): 422 [M + NH4 ].
(21) (a) Nicolaou, K. C.; Xiao, X. Y.; Parandoosh, Z.; Senyei, A.;
Nova, M. P. Angew. Chem., Int. Ed. Engl. 1995, 34, 2289.
(b) IRORI, P. O. Box 502778, San Diego, CA 92150-2778,
Synlett 2002, No. 9, 1427–1430 ISSN 0936-5214 © Thieme Stuttgart · New York