4832
K. Yoshida et al. / Tetrahedron Letters 51 (2010) 4830–4832
Table 2
Supplementary data
Regioselective acylation of 2 with various acid anhydridea
Supplementary data associated with this article can be found, in
References and notes
1. Abel, U.; Koch, C.; Speitling, M.; Hansske, F. G. Curr. Opin. Chem. Biol. 2002, 6,
453–458.
2. For recent examples of regioselective acylation of biologically active molecules,
see: (a) Lewis, C. A.; Miller, S. J. Angew. Chem., Int. Ed. 2006, 45, 5616–5619; (b)
Lewis, C. A.; Longcore, K. E.; Miller, S. J.; Wender, P. A. J. Nat. Prod. 2009, 72,
1864–1869.
3. For pioneering examples for organocatalytic regioselective acylation of
carbohydrates, see: (a) Kurahashi, T.; Mizutani, T.; Yoshida, J. J. Chem. Soc.,
Perkin Trans. 1 1999, 465–473; (b) Kurahashi, T.; Mizutani, T.; Yoshida, J.
Tetrahedron 2002, 58, 8669–8677; (c) Griswold, K. S.; Miller, S. J. Tetrahedron
2003, 59, 8869–8875; (d) Kattnig, E.; Albert, M. Org. Lett. 2004, 6, 945–948; (e)
Moitessier, N.; Englebienne, P.; Chapleur, Y. Tetrahedron 2005, 61, 6839–6853.
4. Highly regioselective benzoylation of monosaccahrides has been reported, see:
Demizu, Y.; Kubo, Y.; Miyoshi, H.; Maki, T.; Matsumura, Y.; Moriyama, N.;
Onomura, O. Org. Lett. 2008, 10, 5075–5077.
5. (a) Kawabata, T.; Muramatsu, W.; Nishio, T.; Shibata, T.; Schedel, H. J. Am. Chem.
Soc. 2007, 129, 12890–12895; (b) Kawabata, T.; Furuta, T. Chem. Lett. 2009, 38,
640–647; (c) Ueda, Y.; Muramatsu, W.; Mishiro, K.; Furuta, T.; Kawabata, T. J.
Org. Chem. 2009, 74, 8802–8805; (d) Muramatsu, W.; Mishiro, K.; Ueda, Y.;
Furuta, T.; Kawabata, T. Eur. J. Org. Chem. 2010, 74, 827–831.
6. Acylated carbohydrates have been examined toward the development of
vaccines, see: (a) Guiard, J.; Collmann, A.; Gilleron, M.; Mori, L.; De Libero, G.;
Prandi, J.; Puzo, G. Angew. Chem., Int. Ed. 2008, 47, 9734–9738; (b) Pozsgay, V.;
Kubler-Kielb, J. Carbohydr. Res. 2007, 342, 621–626; (c) Kulkarni, S. S.; Gervay-
Hague, J. Org. Lett. 2008, 10, 4739–4742.
7. For the synthesis and biological evaluation of digitoxin and the derivatives, see:
Zhou, M.; O’Doherty, G. Curr. Top. Med. Chem. 2008, 8, 114–125.
8. It has been reported that acylation of digitoxin with acetic anhydride in
pyridine gave the 4000-acetate and the 3000,4000-diacetate in 31% and 21% yield,
respectively, see: Satoh, D.; Morita, J. Chem. Pharm. Bull. 1969, 17, 1456–1461.
Entry
R
Regioselectivityb
Yieldc (%) Recovery (%)
4000-O:3000-O:300-O:30-O
1
2
3
4
5
6
7
C11H23
>99:0:0:0
>99:0:0:0
>99:0:0:0
92
90
96
90
94
93
90
7
8
2
7
4
5
6
C
C
15H31
21H43
CH2@CH–(CH2)2 >99:0:0:0
2-Thiophene
3-Furyl
>99:0:0:0
>99:0:0:0
>99:0:0:0
(E)-Ph-CH@CH
a
b
c
Reactions were carried out with a substrate concentration of 0.02 M.
% Regioselectivity among four monoacylates.
Formation of 3000-O-, 4000-O-diacylate was negligible in each run.
yield (76% recovery), respectively. These results also suggest that
the 3000,4000-diacetate was formed via acylation of the 4000-acylate.
We finally examined whether selective formation of the 4000-O-
acylate could be the result from the migration of the 3000-O-acylate.
Treatment of the 3000-acetate14 of digitoxin under the conditions
identical to those for entry 5 in Table 1 except for the absence of
acetic anhydride gave quantitative recovery of the 3000-acetate
without any trace of formation of the 4000-acetate. This clearly indi-
cates that the exclusive formation of the 4000-O-acylates is the result
from the kinetic control by catalyst 1.
9. Typical procedure of regioselective acylation of digitoxin (Table 1, entry 5):
*
Introduction of various acyl groups into C(4000)–OH of 2 was
examined (Table 2). Regioselective lipidation of 2 was achieved
with anhydrides derived from long-chain saturated fatty acids such
as lauric (dodecanoic), palmitic (hexadecanoic), and behenic (doc-
osanoic) acid, giving the corresponding 4000-O-manoacylate as the
sole product in 92%, 90%, and 96% yield, respectively, in the pres-
ence of 1 (entries 1–3). An acyl group derived from an unsaturated
fatty acid was introduced exclusively at C(4000)–OH (entry 4). Het-
eroaromatic carbonyl groups such as thiophene carbonyl and furan
carbonyl groups were also introduced at C(4000)–OH exclusively in
94% and 93% yield, respectively (entries 5 and 6). Similarly, a cin-
namoyl group was introduced at C(4000)–OH exclusively in 90%
yield (entry 7). While 2–8% recovery of 2 was observed, the forma-
tion of the diacylate was negligible in the each run of acylation of 2
promoted by 1.
Digitoxin (30 mg, 0.039 mmol), catalyst 1 (3.3 mg, 3.9
lmol, 10 mol %) and
2,4,6-collidine (7.7
(2.0 mL). After stirring for 10 min at 20 °C, acetic anhydride (4.1
l
L, 0.059 mmol, 1.5 equiv) were dissolved in CHCl3
L,
l
0.043 mmol, 1.1 equiv) was added to the mixture. The mixture was stirred
for 24 h at 20 °C. The reaction was quenched with 1N aq HCl and extracted with
AcOEt. The organic layer was washed with brine, dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by SiO2 column
chromatography (ethyl acetate/hexane = 3:1) to give pure 4000-O-acethyl
digitoxin (31 mg, 98%). Mp 219–223 °C. [a]
D +19 (c 0.1, CHCl3). 1H NMR
(CDCl3, 400 MHz) d 5.87 (s, 1H), 4.99 (d, J = 17.4 Hz, 1H), 4.95–4.85 (m, 3H),
4.80 (d, J = 17.4 Hz, 1H), 4.60 (dd, J = 9.8, 2.5 Hz, 1H), 4.24–4.22 (m, 3H), 4.10–
3.90 (m, 2H), 3.90–3.70 (m, 2H), 3.24 (dd, J = 10.0, 3.2 Hz, 1H), 3.22 (dd, J = 10.0,
3.2 Hz, 1H), 3.06 (s, 1H), 2.91 (s, 1H), 2.78 (bt, 1H), 2.20–1.30 (m, 29H), 2.12 (s,
3H), 1.22 (d, J = 6.0 Hz, 6H), 1.18 (d, J = 6.0 Hz, 3H), 0.92 (s, 3H), 0.87 (s, 3H). 13
C
NMR (CDCl3, 100 MHz) d 174.6, 169.7, 117.6, 98.3, 98.1, 95.3, 85.6, 82.5, 82.3,
77.2, 74.5, 73.4, 72.5, 68.2, 68.0, 67.2, 66.4, 66.2, 50.9, 49.6, 41.8, 40.0, 37.4,
37.1, 36.6, 36.2, 35.7, 35.1, 33.1, 30.1, 29.7, 26.8, 26.6, 26.5, 23.6, 21.4, 21.1,
21.09, 21.00, 18.1, 17.9, 15.7. IR (KBr) 3484, 2935, 1780, 1742, 1622, 1450,
1405 cmꢀ1. MS m/z (FAB) m/z (rel intensity) 829 (MNa+, 10), 252 (35). HRMS
(FAB) calcd for
C43H66O14Na: 829.4350, found: 829.4347. Analysis of the
In summary, we have developed a method for organocatalytic
regioselective acylation of digitoxin. This method provides the
4000-O-manoacylate as the sole product without the concomitant
formation of diacylates. The extremely high regioselectivity was
assumed to be the result from the combined effects of the high
intrinsic reactivity of C(4000)–OH of digitoxin and catalyst-promoted
regioselective acylation.
product was further performed with H–H COSY, HMQC, HMBC (see
Supplementary data).
10. Catalyst 1 is commercially available from Wako Pure Chemical Industries, Ltd.
11. In the regioselective acylation of octyl b-D-glucopyranoside by catalyst 1, it was
found that the higher ratio of the C(4)-O-acylation was associated with the
higher ratio of mono-/diacylation, indicating that the acylation at C(4)–OH
would proceed in an accelerative manner, see: Refs. 5a and b.
12. The conformation of digitoxose and digitoxin in solution has been studied in
detail, see: (a) Coxon, B. J. Carbohydr. Chem. 1984, 3, 525–543; (b) Drakenberg,
T.; Brodelius, P.; McIntyre, D. D.; Vogel, H. J. Can. J. Chem. 1990, 68, 272–277.
13. This could be ascribed to be the difference in the acidities of axial and
equatorial alcohols. It has been reported that axial alcohols have higher acidity
than the equatorial alcohols in substituted cyclohexanols, see: Majumdar, T. K.;
Clairet, F.; Tabet, J.-C.; Cooks, R. G. J. Am. Chem. Soc. 1992, 114, 2897–2903.
Acknowledgment
This work was supported by Grant-in-aid for Scientific Research
(A) from Ministry of Education, Culture, Sports, Science and
Technology.
14. The 3000-O-acetate of digitoxin was prepared by hydrolysis of the 3000,4000
diacetate with K2CO3 in MeOH at ꢀ20 °C.
-