19
Osaka University 100 Papers : 10 Selected Papers
ANNUAL REPORT OF OSAKA UNIVERSITY—Academic
Achievement—2007-2008
Enzyme-Like Chemoselective O-Acylation of Aminoalcohols was
Achieved by Tetranuclear Zinc Cluster CatalystOHSHIMA Takashi and
MASHIMA Kazushi(Graduate School of Engineering Science)
Development of chemoselective reactions is one of the most
important and fundamental tasks in organic synthetic chemistry.
Previously, various chemoselective reactions have been reported and
applied to synthesis of medicinal drugs, natural products and so
on. Chemoselective acylation is also developed and various
methodologies have been reported, because acylation reaction
provides ubiquitous functional groups such as esters and amides.1
As the nucleophilicity of the amino group is much greater than that
of the hydroxyl group, the amine can be selectively acylated to
give the corresponding amide, even in the presence of excess amount
of alcohols and/or water (Scheme 1, path a).2 In contrast, the
chemoselective acylation of hydroxyl group in the presence of amino
groups is not a trivial task (path b). Accordingly, the common
strategy for the selective acylation of hydroxyl groups in the
presence of an amino group involves the protection of an amino
group by its conversion into the corresponding amide or carbamate,
fol-lowed by the acylation of the hydroxyl functionality, and final
selective N-deprotection (path c). This multistep process yields
unwanted chemical wastes. In terms of atom-economy and
environmental concerns, the direct O-selective acylation in the
presence of unprotected primary and secondary alkyl amines is
highly desirable; however, to our best knowledge, there are no
examples of such chemoselective reaction using an artificial
catalyst, though only lipase mediates this reaction.3
Recently, we reported that the newly developed
m-oxo-tetra-nuclear zinc cluster Zn4(OCOCF3)6O (1) exhibits unique
cata-lytic activity for the transesterification of various methyl
esters with alcohols under mild conditions4 and the direct
conversion of esters, lactons, and carboxylic acids to oxazolines.5
Since these catalyses involve acylation reaction pathway by a
cooper-ative mechanism of zinc ions similar to that of
metalloenzymes such as aminopeptidase,6 we found the zinc cluster
efficiently catalyzed the O-selective acylation of amino alcohols
in a man-ner similar to that of lipase.7
At first, we investigated selective O-acylation using 1:1
mixture of cyclohexanol (3a) and cyclohexylamine (4a). When the
standard acylation reagents such as acid chloride and acid
anhydride with base were used, the acylation of amine pro-ceeded
exclusively to give the corresponding amide 6aa in quantitative
yield and ester 5aa was not detected (Scheme 2, top). This result
is consistent with normal chemoselectivity. Next, we focused on
zinc cluster 1 catalyzed transesterification8 because it can be
expected that assembled plural zinc ions act highly enhanced
oxophilicity similar to lipase. The zinc cluster 1 efficiently
catalyzed the acylation of not higher nucleophilic
cyclohexylamine (4a) but less reactive cyclohexanol (3a) with
methyl benzoate (2a) as an acylating reagent to achieve the
cor-responding cyclohexyl ester 5aa in 96% yield accompanied by
only trace amount of amide 6aa (Scheme 2, bottom). In contrast to
our catalysis, the reaction using Al(O-i-Pr)3, reported to
cata-lyze the transesterification of aminoesters with low to
moderate selectivity,9 afforded a mixture of ester and amide.
Furthermore, we investigated the substrate generality of the
chemoselective acylation using various combinations of alco-hols 3
and amines 4, and representative results are summarized in Table 1.
The combination of cyclohexyl and n-hexyl substitu-ents showed high
chemoselectiveity of this catalysis (entries 1–4). Because of
higher nucleophilicity of the cyclic secondary amines 4c-e compared
to primary amines, we observed some amide formation, however, the
chemoselectivity of this cataly-sis was still satisfactory level of
result (enties 5–7).
Because of the broad accessibility of methyl esters 2 com-pared
to standard acylation reagents such as acid halides and acid
anhydrides, we applied various methyl esters 2 to the present
catalytic acylation (Table 2). Under the optimized con-ditions,
aromatic esters with electron-donating and electron-withdrawing
substituents (enties 1–6), aliphatic ester (entry 7), and
a,b-unsaturated ester (entry 8) were selectively converted
The following is a comment on the published paper shown on the
preceding page.
Scheme 1 Acylation of Aminoalcohol
Scheme 2 Condition Screening of O-Selective Acylation
20 ANNUAL REPORT OF OSAKA UNIVERSITY—Academic
Achievement—2007-2008
to the corresponding cyclohexyl esters 5 in high yields
accom-panied by only trace amounts of amides 6. Moreover, the
highly acid-sensitive tetrahydropyranyl ether of phenolic alcohol
and tert-butyldimethylsilyl ether remained intact, demonstrating
the high tolerance of sensitive functionalities in the present
reaction conditions (entries, 4, 7).
In the transition state, both esters and alcohols may be
simul-taneously activated by the two adjacent zinc ions in the
cluster 1, leading to a highly selective O-acylation rather than
the usual nucleophilicity-dependent reaction. To the best of our
knowledge, this is the first example of a highly chemoselective
acylation of alcohols, which is far superior to that of primary and
secondary alkyl amines, using an artificial catalyst.
To demonstrate the usefulness and effectiveness of this zinc
catalysis in modern organic synthesis, we performed selective
O-acylation of aminoalcohols 7. When aminoalcohols 7a-c teth-ered
by long alkyl chains were treated, we obtained aminoesters 8 in
good yields (82-90%) (entries 1-3). Even when aminoal-cohols 7d and
7e with highly nucleophilic secondary amino
groups (piperidine unit) were used, the reactions proceeded in
an O-acylation selective manner to give the corresponding
aminoesters 8 in high yields (88% and 92%). Furthermore, the
reaction of trans-4-aminocyclohexanol (7f) provided ami-noester 8af
exclusively (99%).
In summary, we have developed a highly chemoselective
O-acylation in the presence of an unprotected alkyl amine using the
tetranuclear zinc cluster 1 catalyzed transesterification system.
To our best knowledge, this is the first example of a highly
selective acylation of alcohols in the presence of primary and
secondary alkyl amines, using an artificial catalyst. This
methodology is useful as an environmentally-friendly acylation, and
it provides a useful tool for modern organic synthesis, as a
protecting-group free reaction.
References
[1] For general reviews, see: (a) Larock, R. C. Comprehensive
Organic Transformations; Wiley-VCH: New York, 1996. (b)
Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.;
Pergamon Press, New York, 1992; Vol. 6.
[2] For a review of chemoselective esterification, see: Nahmany,
M.; Melman, A. Org. Biomol. Chem. 2004, 2, 1563.
[3] Gardossi, L.; Bianchi, D.; Kibanov, A. M. J. Am. Chem. Soc.
1991, 113, 6328.
[4] Iwasaki, T; Maegawa, Y.; Hayashi, Y.; Ohshima, T; Mashima,
K. J. Org. Chem. 2008, 73, 5147.
[5]Ohshima, T.; Iwasaki, T.; Mashima, K. Chem. Commun. 2006,
2711.
[6] (a) Burley, S. K.; David, P. R.; Taylor, A.; Lipscomb, W. N.
Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 6878. (b) Roderick, S. L.;
Mat-thews, B. W. Biochemistry 1993, 32, 3907. (c) Chevrier, B.;
Schalk, C.; D’orchymont, H.; Rondeau, J. M.; Moras, D.; Tarnus, C.
Struc-ture 1994, 2, 283.
[7] Ohshima, T.; Iwasaki, T.; Maegawa, Y.; Yoshiyama, A.;
Mashima, K. J. Am. Chem. Soc. 2008. 130, 2944; highlighted in
Editors’ Choice of Science, Science 2008, 319, 1163; News and Views
of Nature, Nature 2008, 452, 415.
[8] For reviews of catalytic transesterification, see: (a)
Otera, J. Chem. Rev. 1993, 93, 1449. (b) Hoydonckx, H. E.; De Vos,
D. E.; Chavan, S. A.; Jacobs, P. A. Top. Catal. 2004, 27, 83. (c)
Grasa, G. A.; Singh, R.; Nolan, S. P. Synthesis 2004, 971.
[9] (a) Schultheiss–Reimann, P.; Kunz, H. Angew. Chem. Int. Ed.
1983, 22, 63; (b) Waldmann, H.; Kunz, H. J. Org. Chem. 1988, 53,
4172.
Table 2 Scope and Limitation of Methyl Ester for the Zinc
Cluster Catalyzed Chemoselective Acylation
Table 1 Chemoselective Acylation of Various Alcohols in the
Presence of Alkyl Amine
Table 3 Chemoselective Acylation of Aminoalcohols
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