Table 3 Effects of solvents, temperature, and nitrogen-protecting groups on chemoselectivity of acylation of 2-aminopentane-1,5-diol derivativesa
Entry
R
Substrate
Solvent
Temperature (1C)
Yield of monoacetates (%)
5-OAc : 1-OAc
Yield of diacetate (%)
1
2
3
4
5
6
7
8
9
Ns
Ns
Ns
Ns
Ns
Ns
Boc
Cbz
Ts
1
1
1
1
1
1
15
16
17
CHCl3
CHCl3
CHCl3
CHCl3
THF
20
0
81
85
90
95
47
35
80
49
84
81 : 19
96 : 4
99 : 1
>99 : o1
24 : 76
48 : 52
16 : 84
31 : 69
52 : 48
10
8
6
ꢀ20
ꢀ60
ꢀ60
ꢀ60
ꢀ60
ꢀ60
ꢀ60
3
16
10
B0
15
8
DMF
CHCl3
CHCl3
CHCl3
a
The reactions were run at the substrate concentration of 0.01 M.
In order to gain mechanistic insights into the observed
chemoselectivity in the acylation of 1 catalyzed by 7, effects
of solvents, temperature, and substrate structure were investi-
gated (Table 3). The selectivity for 5-O-acylation of 1 in
the presence of 7 increases along with the decrease in the
temperature (entries 1–4) and the decrease of the solvent
polarity (entries 4–6). This observation indicates that the
driving force for the 5-O-acylation may involve the hydrogen
bonding interaction between substrate 1 and catalyst 7. The
Ns-protecting group of the nitrogen was found to be critical
for the 5-O-acylation of 2-aminopentane-1,5-diol derivatives.
Reactions of N-Boc and N-Cbz analogues, 15 and 16, respec-
tively, gave the 1-O-acetate as the major acylate (entries 7 and 8)
by the similar treatment to that for N-Ns derivative 1. The
N-Ts derivative 17 underwent regio-random acylation by the
similar treatment as above (entry 9). These results suggest that
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Rev., 2001, 101, 3367.
5 For enzymatic differentiation of unsymmetrical 1,5-diols,
see: C. Oger, Z. Marton, Y. Brinkmann, V. Bultel-Ponce,
´
T. Durand, M. Graber and J.-M. Galano, J. Org. Chem., 2010,
75, 1892.
6 For enzymatic differentiation of unsymmetrically substituted
2-alkylidene-1,3-propanediols, see: (a) T. Schirmeister and
H.-H. Otto, J. Org. Chem., 1993, 58, 4819; (b) K. Takabe,
N. Mase, T. Hisano and H. Yoda, Tetrahedron Lett., 2003,
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M. Takahashi, Y. Kawashima, Y. Jyo, N. Koyata, Y. Murakami
and N. Imai, Synthesis, 2008, 2695; (g) T. Miura, S. Umetsu,
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7 For an example of discrimination of prochiral primary diols by
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and S. J. Miller, Org. Lett., 2005, 7, 3021.
the more acidic hydrogen of the NHNs group in 1 serves as a
ꢀ
hydrogen bond donor suitable for the interaction with catalyst 7.
Obviously, further investigations including spectroscopic
analyses of the catalyst–substrate interaction are to be carried
out for clarifying the mechanism of the regio- and chemo-
selective acylation promoted by catalyst 7.
In conclusion, we have developed highly chemo- and regio-
selective acylation of 2-aminopentane-1,5-diol derivatives
promoted by organocatalysts. Catalyst 7 appears to be able
to recognize the distance between the functionalities and
chirality of the substrates, and promote catalyst-controlled
regio- and chemoselective acylation efficiently. By virtue of the
molecular recognition event of the catalyst, an acyl group
can be chemoselectively introduced onto the sterically much
hindered secondary hydroxy group in the presence of the
primary one.
8 S. Hanessian, S. Parthasarathy and M. Mauduit, J. Org. Chem.,
2003, 46, 34.
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2004, 353.
10 A Ns-protective group was found to be effective for geometry-
selectivity in the acylation of unsymmetrically substituted
2-alkylidene-1,3-propanediols, see: T. Furuta and T. Kawabata,
Science of Synthesis, Asymmetric Organocatalysis 1, Lewis Base
and Acid Catalysts, ed. B. List, George Thieme Verlag KG,
Stuttgart, New York, 2012, p. 529.
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas ‘‘Advanced Molecular
Transformations by Organocatalysts’’ from The Ministry of
Education, Culture, Sports, Science and Technology, Japan.
11 Compounds 8–11 were prepared by addition of Grignard reagents
to the corresponding 5-al derivatives, see ESIz.
Notes and references
12 T. Kusumi, I. Ohtani, Y. Inouye and H. Kakisawa, Tetrahedron
Lett., 1988, 29, 4731.
1 (a) T. Kurahashi, T. Mizutani and J. Yoshida, J. Chem. Soc.,
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6981–6983 6983