Metal Template Assisted Proximal Arrangement of a Nucleophile and an Electrophile: Site-Selective Acylation of α-Hydroxyamides in Polyols

Article abstract of DOI:10.1021/acs.orglett.8b01288

Site-selective acylation of α-hydroxyl groups in amides has been achieved in the presence of other primary hydroxyl groups with intrinsic high reactivity. In this methodology, a relatively stable pyridine aldoxime ester was exploited as an acyl donor to suppress undesired acylation. The catalytic activation of a pyridine aldoxime ester with a Lewis acid produced a cationic complex, which preferentially attracted the Lewis basic α-hydroxyamide via a template effect, to thus facilitate o-acylation.

Full text of DOI:10.1021/acs.orglett.8b01288

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Metal Template Assisted Proximal Arrangement of a Nucleophile and
an Electrophile: Site-Selective Acylation of α‑Hydroxyamides in
Polyols
Yasuhiro Nishikawa,* Kohei Takemoto, Kana Matsuda, Risa Tanaka, Akira Arashima, Kanako Ito,
Yuki Kamezawa, Yuna Hori, and Osamu Hara*
Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, Aichi 468-8503, Japan
*
S Supporting Information
ABSTRACT: Site-selective acylation of α-hydroxyl groups in
amides has been achieved in the presence of other primary
hydroxyl groups with intrinsic high reactivity. In this method-
ology, a relatively stable pyridine aldoxime ester was exploited as
an acyl donor to suppress undesired acylation. The catalytic
activation of a pyridine aldoxime ester with a Lewis acid
produced a cationic complex, which preferentially attracted the
Lewis basic α-hydroxyamide via a template effect, to thus
facilitate o-acylation.
he multiple hydroxyl groups present in carbohydrates
function as hydrogen-bonding donors and acceptors and
The method utilizes metal templates formed by α-hydrox-
yamides and pyridine aldoxime esters.
T
offer noncovalent hydrogen-bonding interactions with other
While investigating the dual Brønsted acid catalyst A, which
utilizes a cationic heterocycle as an electron-withdrawing group
(EWG) for the activation of the adjacent phosphoramide
proton, we envisioned that pyridine 2-aldoxime ester (2) could
be an effective acylating agent for site-selective reactions of α-
1
molecules, leading to dynamic biological phenomena. In this
context, the site-selective modification of carbohydrates such as
the acylation of hydroxyl groups has the potential to reveal the
detailed mechanisms of the corresponding biological actions
and also harness these actions for therapeutics by changing the
8
hydroxycarbonyl compounds (Scheme 1). In the complex
2
original properties of the hydroxyl groups. Among the various
formed between 2 and the Lewis acid MX, the cationic
nonenzymatic polyol acylation methods studied so far, most of
the examples involve the acylation of a specific primary or
secondary alcohol functionality in the presence of other
secondary alcohol groups, which remain unaffected in this
Scheme 1. Working Hypothesis for Site-Selective Acylation
3
,4
transformation.
On the other hand, the differentiation
between the primary alcohol functions in polyols has scarcely
been explored, apart from the monoacylation of symmetric
5
,6
primary diols, where the range of substrates investigated was
7
quite limited. This is probably a result of their intrinsically high
reactivity and conformational flexibility, which allowed the
nonselective reactions to proceed even under controlled
reaction conditions and led to undesired multiple acylation.
In their pioneering work on the site-selective acylation of
primary alcohols, Kawabata and co-workers succeeded in the
intramolecular differentiation of primary alcohol functions in 2-
nosylaminopentane-1,5-diol derivatives with chiral 4-(N,N-
7b
dimethylamino)pyridine catalysts. Although extensive re-
search has been performed, the existing methods still suffer
from a narrow range of applicable polyol substrates, and there is
a dearth of carboxylic acid derivatives that can serve as acyl
donors. Overall, there are just a few classes of reliable
methodologies for the site-selective acylation of primary
alcohols. Herein, we propose a new site-selective method for
the acylation of α-hydroxyamides possessing other primary
alcohols, such as seen in a variety of N-glycolyl amino sugars.
Received: April 23, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01288
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
pyridinium moiety conjugated with the imine should activate
the connected ester via an inductive effect. The oxime ester 2
itself was expected to be sufficiently less reactive to suppress the
led to diminished yields, implying that the presence of the
Lewis acid is crucial in this reaction (entries 4 and 5). In turn,
the regioisomers iso-2a and iso-2a′, having 3-pyridyl and 4-
pyridyl moieties on the oxime ester, respectively, showed
poorer selectivity than 2a (entries 6 and 7). No conversion
took place when the phenyl derivative 2aPh was employed
(entry 8). These results proved that it was the strong
coordination between the cationic Lewis acid and the pyridine
2-aldoxime moiety in 2a (attributable to its bidentate nature)
that was leading to this favorable template in this site-selective
acylation. To our delight, several polar solvents could be used
in this system with comparable results, affording a variety of
solvent options to dissolve the relatively polar polyol
compounds (entries 9−11). A small amount of water was
tolerant in this system with slightly less site-selectivity (entry
uncatalyzed reactions because of the acidity of the leaving
9
pyridine oxime (pK 10). In addition, we hypothesized that
a
this pyridine oxime−metal complex would coordinate to
alcohol 1 with the Lewis basic site in preference to alcohol
1
′, which did not possess a Lewis basic site, because of the
bidentate nature of 1. The resulting metal complex could then
induce facile acylation of the coordinating alcohol (1), which
would be arranged in a proximal position to the pyridine oxime
5c,10,11
ester through a template effect.
To verify our working hypothesis, we evaluated several Lewis
acids during the acylation of ester 2a and diol 1a, which bears
both a primary α-hydroxyl group in an amide and another
primary alcohol that functions remotely from the amide (Table
1
2). When 2 equiv of the acylating reagent 2a was used, the
1
). Among the metal salts examined, Zn(OTf) exhibited the
2
amount of the byproduct 3aAB increased, rather than that of
monoacylate 3aA (entry 13). To evaluate the possibility of
thermodynamic amplification of 3aA via the transfer reaction of
3aB during acylation, the reaction was quenched after a short
time. This produced monoacylate 3aA as the sole product in
low yield (entry 14). In addition, no acyl transfer was observed
when 3aB was used under the standard conditions in the
absence of 2a, implying that 3aA is not a thermodynamic
product, but instead, a kinetic product. Interestingly, acylation
with the corresponding acyl chloride instead of 2a under
otherwise identical standard conditions afforded 3aB preferen-
tially (entry 15). Conventional conditions using the corre-
sponding acyl chloride in the presence of pyridine produced
best catalytic performance to achieve the selective acylation of
the α-hydroxyl group in 1a in good yield and with excellent site
selectivity (entries 1−3). Decreasing the amount of Zn(OTf)2
a
Table 1. Optimization Studies
3aB as the major product in an unselective reaction, suggesting
that the selective acylation of α-hydroxyamide 1a under the
new standard conditions was achieved in a catalyst-controlled
manner (entries 1, 9, and 16).
Having achieved site-selective acylation of 1a, we tested the
applicability of our method to various diols and triols 1b−l
(
Table 2). α-Hydroxyamides with different lengths of alkyl
chains could be acylated to give monoacylated products 3aA−
cA in high yields and with excellent site-selectivities. An N-alkyl
group on an amide, or alkyl substituents on the carbon adjacent
to the nitrogen, had no deleterious effect on the reactivity and
site selectivity (products 3dA−fA). Triol 1g with its phenolic
hydroxyl group could also be reacted and gave monoacylate
b
yield (%)
entry
variation from standard conditions
3aA 3aAB 3aB
1
2
3
4
5
6
7
8
9
none
ZnTFA instead of Zn(OTf)
82
55
35
71
1
2
2
0
2
3gA in a high yield, alongside 5% of the diester 3gAB as a result
2
2
Cu(OTf) instead of Zn(OTf)
0
0
of overreaction at the phenol moiety. The acylation of β-
hydroxyester in 1h could also be successfully avoided under
these reaction conditions, and the monoacylated product 3hA
was obtained selectively. Subsequently, we examined the
selective acylation of a sterically hindered secondary alcohol
in the presence of a primary alcohol. The acylation of the
lactamide derivative 1i under conventional conditions resulted
in the selective acylation of the primary alcohol, consistent with
the much higher intrinsic reactivity of the primary alcohol.
Surprisingly, our method enabled the selective acylation of the
secondary alcohol in 1i to produce 3iA in 89% yield,
accompanied by 10% of diacylate 3iAB. In substrates where
there was a competitive primary alcohol functionality in an α-
hydroxyamide distant from the amide function, higher
selectivities were observed. Thus, in the acylation of 1j and
1k, even when a bulky ethyl group was attached at the α-
position of the amide, the products 3jA and 3kA were obtained.
Unfortunately, no acylation occurred for both the tertiary and
2
2
Zn(OTf) (10 mol %)
2
0
2
without Zn(OTf)2
iso-2a instead of 2a
iso-2a′ instead of 2a
2aPh instead of 2a
DME as the solvent
0
0
40
33
0
29
2
7
2
0
0
77
71
50
80
70
35
1
5
0
10
11
12
13
14
15
16
CH CN as the solvent
5
0
3
DMF as the solvent
0
0
H O (1 equiv) as the additive
6
0
2
2a (2 equiv)
6
0
3 h for the reaction time
acyl chloride instead of 2a
0
0
9
33
32
c
conventional conditions: acyl chloride (1 equiv),
pyridine (1.5 equiv)
3
23
a
Standard reaction conditions: A mixture of 1a (0.2 mmol), 2a (0.24
mmol), and Zn(OTf) (0.04 mmol) in 10% N,N-dimethylformamide/
,2-dimethoxyethane (DMF/DME) was stirred at 30 °C for 18 h.
2
1
b
1
c
12
Determined by H NMR analysis. DME as the solvent.
primary alcohol groups in 1l (product 3lA).
B
DOI: 10.1021/acs.orglett.8b01288
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Substrate Range of α-Hydroxyamides in Site-
Selective Acylation
Table 3. Substrate Range of Pyridine Aldoxime Esters in
Site-Selective Acylation
a
a
a
Standard reaction conditions: A mixture of 1 (0.2 mmol), 2a (0.24
mmol), and Zn(OTf) (0.04 mmol) in 10% DMF/DME was stirred at
2
a
Standard reaction conditions: A mixture of 1a (0.2 mmol), 2 (0.24
3
0 °C for 16−20 h. Yields are for the isolated product. Single
1
mmol), and Zn(OTf) (0.04 mmol) in 10% DMF/DME was stirred at
3
regioisomers with less than 5% of byproducts were observed in H
NMR of the crude products in all cases. Reaction temperature = 15
2
regioisomers with less than 5% of byproducts were observed in H
0 °C for 16−20 h. Yields are given for the isolated product. Single
1
NMR of the crude products unless otherwise noted.
b
N,N-Dimethylglycolamide esters have the potential to be
biolabile prodrugs of carboxylic acid agents, owing to their
similar structure to acetylcholine, which can be rapidly
hydrolyzed by the choline esterases in human plasma. In
this context, the selective esterification of carboxylic acids with
glycolamides is extremely desirable, and a range of acyl donors
applicable for this system were examined (Table 3). In addition
to a 3-phenylpropanoyl group, benzoyl and acetyl groups could
also be introduced selectively to the α-hydroxyl group in amide
°C.
ester 2l and its regioselective reaction with 1a, almost no
racemization occurred, producing dipeptide ester 14aA in a
regioselective manner (98% ee).
Glycolamide structures, an example of α-hydroxyamides, are
abundant in various bioactive glycosides (Figure 1). For
13
14
1
a, and these processes were accompanied by the formation of
less than 5% of byproducts (product 4aA and 5aA). Although
acylation performed with a bulky acyl donor such as a pivaloyl
ester was feasible, the product (6aA) was obtained in a
relatively low yield. Both the terminal C−C double bond and
the nucleophilic double bond within the unprotected indole
moiety in acyl donors were compatible with Lewis acid
activation to afford the monoacyl products 7aA and 8aA,
respectively. Furthermore, we succeeded in the highly
regioselective introduction of amino acid derivatives to diol
Figure 1. Example of the α-glycolamide structure in glycoconjugates.
1
a in good yields (products 9aA to 13aA). In these results, it is
example, N-glycolylneuraminic acid (Neu5Gc), one of the sialic
acids present at the nonreducing terminals of many
glycoconjugates on the surfaces of mammalian cells, is
recognized as an epitope in the human immune system, while
N-acetylneuraminic acid (Neu5Ac) causes no immune
reaction. Subtle changes in the carbohydrates, even as little
as the presence of a single hydroxyl group, can cause a drastic
change in the biological properties. This property makes
glycolamides an attractive target for modification.
noteworthy that a free primary hydroxyl group in the acyl
donor 2j remained intact during the acylation of the α-hydroxy
group in amide 1a (product 12aA). Acylation using the
phenylglycine derivative 2k, in which the α-proton is prone to
dissociation, took place with no racemization (product 13aA).
Next, we examined a challenging site-selective acylation
involving the introduction of a dipeptide. This transformation
is difficult to achieve because the C-terminus of a peptide is
liable to undergo racemization through the formation of an
oxazolone during the activation of the terminal carboxylic acid.
Surprisingly, during the course of the preparation of the oxime
15
Therefore, we prepared N-glycolylamino sugars having
multiple hydroxyl groups to demonstrate the site-selective
acylation of carbohydrates (Scheme 2). Standard conditions
C
DOI: 10.1021/acs.orglett.8b01288
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Site-Selective Acylation of N-Glycolyl Amino
ORCID
Sugars
Yasuhiro Nishikawa: 0000-0003-1606-7288
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Y.N. thanks Meijo University for financial support.
REFERENCES
■
(
1) (a) Boltje, T. J.; Buskas, T.; Boons, G.-J. Nat. Chem. 2009, 1, 611.
b) Seeberger, P. H.; Werz, D. B. Nature 2007, 446, 1046. (c) Doores,
(
K. J.; Gamblin, D. P.; Davis, B. G. Chem. - Eur. J. 2006, 12, 656.
2) For recent reviews, see: (a) Lawandi, J.; Rocheleau, S.; Moitessier,
N. Tetrahedron 2016, 72, 6283. (b) Taylor, M. S. Acc. Chem. Res. 2015,
8, 295.
3) For examples of site-selective acylation of primary alcohols, see:
a) Ren, B.; Rahm, M.; Zhang, X.; Zhou, Y.; Dong, H. J. Org. Chem.
(
4
(
(
2
014, 79, 8134. (b) Zhou, Y.; Rahm, M.; Wu, B.; Zhang, X.; Ren, B.;
with a slight change of solvents enabled the acylation of the α-
glycolyl moiety in N-glycolylglucosamine 1m over the other
Dong, H. J. Org. Chem. 2013, 78, 11618. (c) Kattnig, E.; Albert, M.
Org. Lett. 2004, 6, 945. (d) Martinelli, M. J.; Vaidyanathan, R.; Pawlak,
J. M.; Nayyar, N. K.; Dhokte, U. P.; Doecke, C. W.; Zollars, L. M. H.;
Moher, E. D.; Khau, V. V.; Kosmrlj, B. J. Am. Chem. Soc. 2002, 124,
̌
3578. (e) Iwasaki, F.; Maki, T.; Onomura, O.; Nakashima, W.;
Matsumura, Y. J. Org. Chem. 2000, 65, 996.
(4) For recent examples of site-selective acylation of secondary
alcohols, see: (a) Yanagi, M.; Imayoshi, A.; Ueda, Y.; Furuta, T.;
Kawabata, T. Org. Lett. 2017, 19, 3099. (b) Xiao, G.; Cintron-Rosado,
G. A.; Glazier, D. A.; Xi, B.-M.; Liu, C.; Liu, P.; Tang, W. J. Am. Chem.
Soc. 2017, 139, 4346. (c) Cramer, D. L.; Bera, S.; Studer, A. Chem. -
Eur. J. 2016, 22, 7403. (d) Peng, P.; Linseis, M.; Winter, R. F.;
Schmidt, R. R. J. Am. Chem. Soc. 2016, 138, 6002. (e) Huber, F.;
Kirsch, S. F. Chem. - Eur. J. 2016, 22, 5914. (f) Chen, I.-H.; Kou, K. G.
M.; Le, D. N.; Rathbun, C. M.; Dong, V. M. Chem. - Eur. J. 2014, 20,
5013. (g) Allen, C. L.; Miller, S. J. Org. Lett. 2013, 15, 6178. (h) Sun,
X.; Lee, H.; Lee, S.; Tan, K. L. Nat. Chem. 2013, 5, 790. (i) Lee, D.;
three hydroxyl groups, including a primary alcohol (Scheme
1
2
a). Comparison of the H NMR spectra of the crude product
in our protocol with that obtained in a conventional reaction
showed that the glycolamide ester 3mA was the sole product in
the site-selective acylation, and products arising from multiple
acylation and unselective reactions were not observed (see the
Supporting Information for details). Likewise, site-selective
acylation of the N-glycolylneuraminic acid derivative 1v was
examined by using it as a model for the acylation of sialic acids
(Scheme 2b). Regardless of the presence of four hydroxyl
groups and one carboxylic acid in addition to the target α-
hydroxyl group, the acylation of the highly polar substrate 1v
proceeded at 40 °C in a regioselective manner (35% isolated
yield, 92% based on recovered starting material 1v). As 1v was
poorly soluble in 10% DMF/DME, the amount of DMF was
increased to 50% in this case. However, 3vA was obtained in a
relatively low yield, as mentioned above, probably because
DMF had a deleterious effect on the acylation reaction (Table
Taylor, M. S. J. Am. Chem. Soc. 2011, 133, 3724. (j) Sanchez-Rosello,
M.; Puchlopek, A. L. A.; Morgan, A. J.; Miller, S. J. J. Org. Chem. 2008,
3, 1774. (k) Kawabata, T.; Muramatsu, W.; Nishio, T.; Shibata, T.;
Schedel, H. J. Am. Chem. Soc. 2007, 129, 12890.
5) For monoacylation of 1,n-linear diols, see: (a) Imayoshi, A.;
́
7
(
1
, entry 11).
Yamanaka, M.; Sato, M.; Yoshida, K.; Furuta, T.; Ueda, Y.; Kawabata,
T. Adv. Synth. Catal. 2016, 358, 1337. (b) Hikawa, H.; Hamada, M.;
Yokoyama, Y.; Azumaya, I. RSC Adv. 2014, 4, 23131. (c) Yoshida, K.;
Furuta, T.; Kawabata, T. Angew. Chem., Int. Ed. 2011, 50, 4888.
(6) For recent examples of desymmetrization of 1,3-diols, see: (a) Li,
B.-S.; Wang, Y.; Proctor, R. S. J.; Jin, Z.; Chi, Y. R. Chem. Commun.
2016, 52, 8313. (b) Sakakura, A.; Umemura, S.; Ishihara, K. Adv. Synth.
Catal. 2011, 353, 1938. (c) Lee, J. Y.; You, Y. S.; Kang, S. H. J. Am.
Chem. Soc. 2011, 133, 1772.
In conclusion, we have developed a method for the site-
selective acylation of α-hydroxyl groups in amides in the
presence of the other primary and secondary hydroxyl groups.
Examination of the scope of this protocol revealed that a variety
of α-hydroxyamides as well as acyl donors could be employed
including stereochemically labile amino acid derivatives. Future
work in our laboratory will involve investigations of site-
selective reactions using the strategy in this study for different
classes of substrates.
(
7) (a) Yamanaka, M.; Yoshida, U.; Sato, M.; Shigeta, T.; Yoshida, K.;
Furuta, T.; Kawabata, T. J. Org. Chem. 2015, 80, 3075. (b) Yoshida, K.;
Shigeta, T.; Furuta, T.; Kawabata, T. Chem. Commun. 2012, 48, 6981.
(
Kitamura, C.; Hara, O. Org. Lett. 2016, 18, 2004.
(9) Pyridine oxime derivatives have been studied in the acylation and
ASSOCIATED CONTENT
Supporting Information
■
8) Nishikawa, Y.; Nakano, S.; Tahira, Y.; Terazawa, K.; Yamazaki, K.;
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01288.
the hydrolysis of the resulting ester as a model of esterases and
́ ́
peptidases; see: (a) Gomez-Tagle, P.; Lugo-Gonzalez, J. C.;
Yatsimirsky, A. K. Chem. Commun. 2013, 49, 7717. (b) Hampl, F.;
Liska, F.; Mancin, F.; Tecilla, P.; Tonellato, U. Langmuir 1999, 15,
Complementary results, experimental procedures, and
spectroscopic data of all new compounds (PDF)
4
05. (c) Breslow, R.; Chipman, D. J. Am. Chem. Soc. 1965, 87, 4195.
(10) Related strategies were exploited in the monoacylation of 1,2-
diols, see: (a) Cameron, L. L.; Wang, S. C.; Kluger, R. J. Am. Chem.
Soc. 2004, 126, 10721. (b) Clarke, P. A.; Arnold, P. L.; Smith, M. A.;
Natrajan, L. S.; Wilson, C.; Chan, C. Chem. Commun. 2003, 2588.
(11) (a) Nishii, Y.; Hirai, T.; Fernandez, S.; Knochel, P.; Mashima, K.
Eur. J. Org. Chem. 2017, 2017, 5010. (b) Kita, Y.; Nishii, Y.; Higuchi,
AUTHOR INFORMATION
Corresponding Authors
■
*
*
E-mail: yasuhiro@meijo-u.ac.jp.
E-mail: oshara@meijo-u.ac.jp.
D
DOI: 10.1021/acs.orglett.8b01288
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Organic Letters
Letter
T.; Mashima, K. Angew. Chem., Int. Ed. 2012, 51, 5723. (c) Tan, K. L.
ACS Catal. 2011, 1, 877.
(
12) Toward further evaluation of the specific reactivity to α-
hydroxyamides in this system, intermolecular competition experiments
were conducted between an α-hydroxyamide and the other alcohols
for acylation with 2a. See the Supporting Information for details.
(
13) (a) Beaulieu, P. L.; De Marte, J.; Garneau, M.; Luo, L.;
Stammers, T.; Telang, C.; Wernic, D.; Kukolj, G.; Duan, J. Bioorg. Med.
Chem. Lett. 2015, 25, 210. (b) Nielsenw, N. M.; Bundgaard, H. J.
Pharm. Sci. 1988, 77, 285.
(
14) N-Glycolylmuramic acid is found in peptideglycan in some
bacteria including Mycobacterium tuberculosis, which exhibits unique
properties; see: (a) Wang, Q.; Matsuo, Y.; Pradipta, A. R.; Inohara, N.;
Fujimoto, Y.; Fukase, K. Org. Biomol. Chem. 2016, 14, 1013.
(
b) Melnyk, J. E.; Mohanan, V.; Schaefer, A. K.; Hou, C.-W.;
Grimes, C. L. J. Am. Chem. Soc. 2015, 137, 6987. (c) Raymond, J. B.;
Mahapatra, S.; Crick, D. C.; Pavelka, M. S. J. Biol. Chem. 2005, 280,
3
(
26.
̈
15) (a) Samraj, A. N.; Pearce, O. M. T.; Laubli, H.; Crittenden, A.
N.; Bergfeld, A. K.; Banda, K.; Gregg, C. J.; Bingman, A. E.; Secrest, P.;
Diaz, S. L.; Varki, N. M.; Varki, A. Proc. Natl. Acad. Sci. U. S. A. 2015,
1
12, 542. (b) Ghaderi, D.; Taylor, R. E.; Padler-Karavani, V.; Diaz, S.;
Varki, A. Nat. Biotechnol. 2010, 28, 863.
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