Catalyst-controlled reversal of chemoselectivity in acylation of 2-aminopentane-1,5-diol derivatives

Article abstract of DOI:10.1039/c2cc32525j

Highly chemo- and regioselective acylation of 2-aminopentane-1,5-diol derivatives has been achieved by organocatalysis. An acyl group can be chemoselectively introduced onto the sterically hindered secondary hydroxy group in the presence of the primary on

Full text of DOI:10.1039/c2cc32525j

View Article Online / Journal Homepage / Table of Contents for this issue
This article is part of the
Organocatalysis
web themed issue
Guest editors: Professors Keiji Maruoka, Hisashi
Yamamoto, Liu-Zhu Gong and Benjamin List
All articles in this issue will be gathered together online at
www.rsc.org/organocatalysis

Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 6981–6983
www.rsc.org/chemcomm
COMMUNICATION
Catalyst-controlled reversal of chemoselectivity in acylation of
2-aminopentane-1,5-diol derivativeswz
Keisuke Yoshida, Takashi Shigeta, Takumi Furuta and Takeo Kawabata*
Received 8th April 2012, Accepted 15th May 2012
DOI: 10.1039/c2cc32525j
Highly chemo- and regioselective acylation of 2-aminopentane-
1,5-diol derivatives has been achieved by organocatalysis. An acyl
group can be chemoselectively introduced onto the sterically
hindered secondary hydroxy group in the presence of the primary
Scheme 1 Hanessian’s example of regioselective acylation based on
one by virtue of the molecular recognition event of the catalyst.
substrate control.
whether the regioselectivity of acylation of N-protected (R)-2-
aminopentane-1,5-diol derivatives could be controlled by the
nature of the catalyst.
Development of nonenzymatic approaches toward regioselective
acylation of polyol derivatives is one of the current synthetic
challenges.1 We have reported organocatalytic regioselective
acylation of carbohydrates2 and chemoselective monoacylation
of linear diols,3 in which substrate recognition by the catalyst
appears to be the origin of the selectivity. Here, we report
regio- and chemoselective acylation of 2-aminopentane-1,5-
diol derivatives by organocatalysis. The selectivity of acylation
was found to be totally catalyst-controlled, independent of the
intrinsic reactivity of the diol substrates.
We first examined N-(2-nitrobenzenesulfonyl) (Ns)-protected
(R)-2-aminopentane-1,5-diol (1) as a substrate for regio-
selective acylation (Table 1). The reasons for the choice of
the Ns group involves versatile chemical transformation of an
NHNs group9 as well as our previous results from geometry-
selective acylation of unsymmetrically substituted 2-alkylidene-
1,3-propanediols.10 Treatment of 1 with acetic anhydride in
The regioselective acylation of polyol derivatives, including
carbohydrates, has been extensively studied using enzymatic
protocols.4 Especially, selective acylation of a primary hydroxy
group in the presence of multiple secondary hydroxy groups of
carbohydrates has been achieved efficiently. On the other
hand, differentiation between the primary hydroxy groups in
polyol substrates has been relatively unexplored, probably due
to the difficulties resulting from the similar intrinsic reactivity
of the primary hydroxy groups. While selective acylation of a
primary hydroxy group in primary diol substrates has been
reported by enzymatic processes,5,6 the corresponding non-
enzymatic process has scarcely been developed.7 Hanessian
and co-workers reported regioselective monoacylation of
(R)-N-protected-2-aminopentane-1,5-diols, in which the
5-pivalates were obtained as the major acylate in 32–50%
yield, which are important building blocks for morphinomi-
metics (Scheme 1).8 The regioselectivity of acylation seemed
to result from the difference in the intrinsic reactivity of the
two hydroxy groups due to steric reasons (substrate-controlled
regioselectivity). Inspired by Hanessian’s results, we investigated
Table 1 Effects of catalysts on chemoselectivity of acylation of 1a
Yield of
Entry Catalyst monoacetates (%) 2 : 3
Yield of
diacetate (%)
1
2
3
4
5
DMAP
38
70
75
88
95
16 : 84
30 : 70
83 : 17
96 : 4
30
12
15
7
4
5
6
7
>99 : o1
3
a
The reactions were run at the substrate concentration of 0.01 M.
Institute for Chemical Research, Kyoto University, Uji,
Kyoto 611-0011, Japan. E-mail: kawabata@scl.kyoto-u.ac.jp;
Fax: +81 774 38 3197; Tel: +81 774 38 3190
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures, characterisation data, copies of 1H NMR and 13C NMR.
See DOI: 10.1039/c2cc32525j
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6981–6983 6981

the presence of 4-dimethylaminopyridine (DMAP) in chloro-
form at ꢀ60 1C gave 5-acetate 2 and 1-acetate 3 in a 16 : 84
ratio in a combined yield of 38% with concomitant formation
of the diacetate in 30% yield (entry 1). This result indicates
that the C(1)–OH is intrinsically more reactive than the
C(5)–OH in substrate 1, and also that the control of over-
acylation is difficult in the DMAP-catalyzed acylation even by
performing the reaction at ꢀ60 1C. Similar regioselectivity
favouring the formation of 3 (2 : 3 = 30 : 70) was observed in
the acylation catalyzed by 4 (entry 2), which was reported to
be an effective catalyst for regioselective acylation of glyco-
pyranoses and chemoselective acylation of linear diols.2,3
Contrary to these results, 5-acetate 2 was obtained as the
major acylate (2 : 3 = 83 : 17) in the acylation catalyzed by 5
(entry 3). High regioselectivity (2 : 3 = 96 : 4) was observed in
the acylation of 1 catalyzed by 6 (entry 4). The monoacetates
were obtained in the increased combined yield of 88%
with diminished formation of the diacetate in 7% yield.
Further selective acylation was achieved by catalyst 7.
Treatment of 1 with acetic anhydride in the presence of
10 mol% of 7 gave 5-acetate 2 as the sole monoacetate in
95% yield with only 3% formation of the diacetate (entry 5).
Thus, regioselectivity of the acylation of 1 promoted by 7
was found to be totally catalyst-dependent. It was also
observed in the acylation reactions in entries 3–5 that the
higher ratio of 5-O-acylation was associated with the
higher ratio of mono/diacylation. These results suggest that
5-O-acylation catalyzed by catalysts 5–7 proceeds in an
accelerated manner.
Table 2 Acylation of the secondary vs. the primary hydroxy groups
catalyzed by 7a
Yield of Yield of
monoacetates sec-OAC : diacetates Recovery
Entry R Substrate (%)
pri-OAC
(%)
(%)
1b
2
3
4
Me 8c
Me 8c
Et 9d
i-Pr 10d
Bu 11c
Bu 11c
90
79
78
81
76
62
1 : 99
98 : 2
98 : 2
98 : 2
98 : 2
46 : 54
3 : 97
4
11
12
10
13
14
3
6
10
12
9
11
21
7
5
6e
7
Bu 5-epi-11 89
Bu 5-epi-11 72
8e
o1 : >99
The reactions were run at the substrate concentration of 0.01 M.
0
28
a
b
c
DMAP (20 mol%) was used as catalyst. The absolute configu-
ration at C(5) was determined by a modified Mosher’s method. See
d
ESI. The absolute configuration at C(5) was tentatively assigned
according to its reactivity toward chemoselective acylation, see text.
e
Catalyst 6 was employed.
secondary and primary hydroxy groups (entry 6). An exclusive
formation of the acylate of the primary hydroxy group among
the monoacylates was observed in the acylation of 5-epi-11
promoted by 6 (entry 8). The results observed in the acylation
reactions in entries 5–8 suggest that chirality of the side chains
of catalysts 6 and 7 is responsible for recognition of the
substrate chirality. The absolute configuration at C(5) of 8
and 11 was determined by a modified Mosher’s method.11,12
The absolute configuration at C(5) of 9 and 10 was tentatively
assigned based on the comparison of their chemoselectivity for
acylation with that of 11 and 5-epi-11. The results in Table 2
indicate that highly chemoselective acylation of 8–11 catalyzed
by 7 (entries 2–5) was assumed to result from recognition of
the distance between the OH group and the NHNs group as
well as chirality at C(5) by catalyst 7. The assumption about
length recognition was supported by the reaction of 2-amino-
butane-1,4-diol derivative 12 (Scheme 2). Treatment of 12 with
the same procedure as that in Table 2 gave 4-acetate 13 and
1-acetate 14 in ca. 1 : 1 ratio. The difference of the only one
methylene unit between 12 and 1 resulted in a dramatic loss of
the regioselectivity in the acylation of 12. This suggests that
catalyst 7 promotes regioselective acylation based on the
recognition of the distance between the functionalities in the
substrates.
The results in Table 1 indicate that 5-O-selective acylation
can be attained in a catalyst-controlled manner, overcoming
the intrinsic higher reactivity of the C(1)–OH of substrate 1,
provided that the regiochemical profile of the DMAP-catalyzed
acylation is the measure of substrate-controlled selectivity
(entry 1). However, the steric environment around the
C(5)–OH in 1 seems to be less hindered compared to that of
the C(1)–OH, which was suggested by Hanessian’s regio-
chemical results observed in the acylation of the related
substrates (Scheme 1). We then examined acylation of the
corresponding derivatives of 1 with a secondary hydroxy
group at C(5), 8–11 (Table 2). The primary hydroxy group
at C(1) of 8 (R = Me) was acylated almost exclusively in
DMAP-catalyzed acylation, indicating the much higher
intrinsic reactivity of the primary C(1)–OH than the secondary
C(5)–OH (entry 1). Contrary to this result, 8 underwent
acylation almost exclusively on the secondary hydroxy group
at C(5) in the presence of catalyst 7 (entry 2). Similarly,
chemoselective acylation at the secondary hydroxy group
was observed in substrate 9 possessing an ethyl substituent
at C(5) (entry 3). Surprisingly, acylation took place almost
exclusively on the sterically hindered secondary hydroxy group
at C(5) of 10 (R = i-Pr) in the presence of catalyst 7 (entry 4).
Acylation of 11 with a butyl substituent at C(5) took
place to give the acylate of the secondary hydroxy group
(sec-OAc : pri-OAc = 98 : 2, entry 5), whereas that of its
C(5)-epimer, 5-epi-11, gave the acylate of the primary hydroxy
group almost exclusively (sec-OAc : pri-OAc = 3 : 97, entry 7).
The acylation of 11 in the presence of 6, the diastereomeric
catalyst of 7, gave ca. 1 : 1 mixture of the acylates of the
Scheme 2 Loss in regioselectivity of acylation of 12 resulting from
one methylene unit difference between 12 and 1 (cf. Table 1, entry 5).
c
6982 Chem. Commun., 2012, 48, 6981–6983
This journal is The Royal Society of Chemistry 2012

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
J. Yoshida, Tetrahedron, 2002, 58, 8669; (c) K. S. Griswold and
S. J. Miller, Tetrahedron, 2003, 59, 8869; (d) E. Kattnig and
M. Albert, Org. Lett., 2004, 6, 945; (e) Y. Demizu, Y. Kubo,
H. Miyoshi, T. Maki, Y. Matsumura, N. Moriyama and
O. Onomura, Org. Lett., 2008, 10, 5075.
2 (a) T. Kawabata, W. Muramatsu, T. Nishio, T. Shibata and
H. Schedel, J. Am. Chem. Soc., 2007, 129, 12890; (b) Y. Ueda,
W. Muramatsu, K. Mishiro, T. Furuta and T. Kawabata, J. Org.
Chem., 2009, 74, 8802.
3 K. Yoshida, T. Furuta and T. Kawabata, Angew. Chem., Int. Ed.,
2011, 50, 4888.
4 For an excellent review, see: D. Kadereit and H. Waldmann, Chem.
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,
44, 3267; (c) T. Hisano, K. Onodera, Y. Toyabe, N. Mase,
H. Yoda and K. Takabe, Tetrahedron Lett., 2005, 46, 6293;
(d) T. Miura, Y. Kawashima, S. Umetsu, D. Kanamori,
N. Tsuyama, Y. Jyo, Y. Murakami and N. Imai, Chem. Lett.,
2007, 814; (e) T. Miura, Y. Kawashima, M. Takahashi,
Y. Murakami and N. Imai, Synth. Commun., 2007, 37, 3105;
(f) T. Miura, K. Okazaki, K. Ogawa, E. Otomo, S. Umetsu,
M. Takahashi, Y. Kawashima, Y. Jyo, N. Koyata, Y. Murakami
and N. Imai, Synthesis, 2008, 2695; (g) T. Miura, S. Umetsu,
D. Kanamori, N. Tsuyama, Y. Jyo, Y. Kawashima, N. Koyata,
Y. Murakami and N. Imai, Tetrahedron, 2008, 64, 9305.
7 For an example of discrimination of prochiral primary diols by
peptide-based catalysts, see: C. A. Lewis, B. R. Sculimbrene, Y. Xu
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.
9 (a) T. Fukuyama, C.-K. Jow and M. Cheung, Tetrahedron Lett.,
1995, 36, 6373–6374; (b) T. Kan and T. Fukuyama, Chem. Commun.,
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.,
Perkin Trans. 1, 1999, 465; (b) T. Kurahashi, T. Mizutani and
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6981–6983 6983