K. M. Whitten et al. / Tetrahedron Letters 53 (2012) 5753–5755
5755
Lipases have found wide use as biocatalysts for many chemical
transformations. Many lipases have been studied for their use in
amide formation,17,18 such as, amidation of benzyl esters,19 synthe-
sis of acetamides in the presence of ionic liquids,20 and acylation of
amines with acids.21 Most of these methods utilize either carbox-
ylic acids or vinyl esters of carboxylic acids as reactants and the
reactions require relatively high temperatures. In the kinetic reso-
lution of amines, Nechab et al. reported that the reaction condi-
tions required 80 °C and 3–10 h to acylate chiral amines with
Candida antarctica (CAL) and ethyl acetate.22 The aminolysis of
linoleyl ethyl ester with ethanolamine, catalyzed by CAL, in a sol-
vent free system produced the linoleylethanolamide only in 24%
yield in 20 h including the presence of the unwanted o-acylation
product.23 While these examples show the use of lipases for the
amidation of esters, there is limited reported work on the use of
lipases as a direct method for the synthesis of biologically active
NAEs with regard to functional group sensitivity common in the
synthesis of modified fatty acid moieties. We have thus focused
our efforts on the synthesis of biologically active NAEs with immo-
bilized CAL from methyl esters and various amines. Development
in this area will ameliorate the synthesis of multistep tail-modified
N-acylethanolamines as well as other biologically important fatty
acid amide analogs.
In summary, we have demonstrated that CAL can be useful for
achieving direct formation of amides from various amines and
esters containing skipped polyenes, allyl alcohol, allyl azide,
alkyne, and aryl moieties. The method described in this report, is
simple, efficient, and environmentally friendly and does not re-
quire any protection of other susceptible functional groups. This
transacylation reaction provides excellent yields and is selective.
It may find general utility in the synthesis of amides from the cor-
responding esters without requiring prior hydrolysis of the esters,
as it can be difficult to synthesize amides directly from esters un-
der mild conditions. The method should prove to be useful in the
synthesis of drug intermediates and biologically important natural
products.
Acknowledgment
One of the authors (S.K.V.) acknowledges the financial support
for this research from NIDA (R03 DA029184-02).
References and notes
1. Coulon, D.; Faure, L.; Salmon, M.; Wattelet, V.; Bessoule, J.-J. Plant Sci. 2012, 184,
129–140.
2. Ezzili, C.; Otrubova, K.; Boger, D. L. Bioorg. Med. Chem. Lett. 2010, 20, 5959–
5968.
3. Ueda, N.; Tsuboi, K.; Uyama, T. BBA—Mol. Cell Biol. L. 1801, 2010, 1274–1285.
4. Abadji, V.; Lin, S.; Taha, G.; Griffin, G.; Stevenson, L. A.; Pertwee, R. G.;
Makriyannis, A. J. Med. Chem. 1994, 37, 1889–1893.
5. Goutopoulos, A.; Fan, P.; Khanolkar, A. D.; Xie, X.-Q.; Lin, S.; Makriyannis, A.
Bioorg. Med. Chem. 2001, 9, 1673–1684.
6. Bezuglov, V.; Bobrov, M.; Gretskaya, N.; Gonchar, A.; Zinchenko, G.; Melck, D.;
Bisogno, T.; Di Marzo, V.; Kuklev, D.; Rossi, J.-C.; Vidal, J.-P.; Durand, T. Bioorg.
Med. Chem. Lett. 2001, 11, 447–449.
To optimize reaction conditions, we chose methyl arachidonate
and cyclopropylamine as reactants and hexane as a solvent. When
carried out at room temperature in the presence of immobilized
CAL, the reaction proceeded smoothly, but very slow as it required
24 h for completion. When heated to 45 °C, reaction completion
was observed in a much improved 3 h. For amines not sufficiently
soluble in n-hexane, the reaction proceeded equally well in a 1:1
hexanes–diisopropyl ether mixture (Scheme 1). The results are
outlined in Table 1.
7. El Fangour, S.; Balas, L.; Rossi, J.-C.; Fedenyuk, A.; Gretskaya, N.; Bobrov, M.;
Bezuglov, V.; Hillard, C. J.; Durand, T. Bioorg. Med. Chem. Lett. 2003, 13, 1977–
1980.
Esters and amines were chosen based on their biological
importance. Thus methyl arachidonate was treated with
cyclopropyl amine, ethanolamine, and (R)-2-aminopropanol to pro-
vide arachidonoylcyclopropylamide (ACPA), anandamide, and R-
methanandamide, respectively, in excellent yields. Unprotected
ethanolamine was directly used in the preparation of various
ethanolamides (2, 3, 4, and 10). When performed with a substituted
fatty acid carrying a terminal hydroxyl group (4) the reaction
proceeded smoothly to provide the desired amide. There was no
observable transesterification product in any reactions where
hydroxyl groups were present either in the amine or the fatty acid
moieties. To investigate general applicability of the method, we
chose various esters and amines and showed that reactions pro-
ceeded within 24 h in good yield. Variation in yield was mainly
dependent on the amine used. Primary amines, including benzylic
amines, underwent amidation smoothly and in excellent yields after
24 h. Conversely, cyclohexylamine exhibited slower reactivity with
decreased yield under the present conditions. Longer reaction times
and increased temperature did not improve the yield significantly.
Esters of non-fatty acids (9, 10, and 11) underwent amidation with
amines in excellent yields and in all the cases the reaction time ap-
peared to be more dependent on the amine used.
8. Urbani, P.; Cavallo, P.; Cascio, M. G.; Buonerba, M.; De Martino, G.; Di Marzo, V.;
Saturnino, C. Bioorg. Med. Chem. Lett. 2006, 16, 138–141.
9. Li, C.; Xu, W.; Vadivel, S. K.; Fan, P.; Makriyannis, A. J. Med. Chem. 2005, 48,
6423–6429.
10. Yao, F.; Li, C.; Vadivel, S. K.; Bowman, A. L.; Makriyannis, A. Bioorg. Med. Chem.
Lett. 2008, 18, 5912–5915.
11. Bundesmann, M. W.; Coffey, S. B.; Wright, S. W. Tetrahedron Lett. 2010, 51,
3879–3882.
12. Hoegberg, T.; Stroem, P.; Ebner, M.; Raemsby, S. J. Org. Chem. 1987, 52, 2033–
2036.
13. Gnanaprakasam, B.; Milstein, D. J. Am. Chem. Soc. 2011, 133, 1682–1685.
14. Han, C.; Lee, J. P.; Lobkovsky, E.; Porco, J. A. J. Am. Chem. Soc. 2005, 127, 10039–
10044.
15. Ishihara, K.; Kuroki, Y.; Hanaki, N.; Ohara, S.; Yamamoto, H. J. Am. Chem. Soc.
1996, 118, 1569–1570.
16. Nuijens, T.; Cusan, C.; Kruijtzer, J. A. W.; Rijkers, D. T. S.; Liskamp, R. M. J.;
Quaedflieg, P. J. L. M. J. Org. Chem. 2009, 74, 5145–5150.
17. Gotor, V. Bioorg. Med. Chem. 1999, 7, 2189–2197.
18. Bistline, R.; Bilyk, A.; Feairheller, S. J. Am. Oil Chem. Soc. 1991, 68, 95–98.
19. Adamczyk, M.; Grote, J. Tetrahedron Lett. 1996, 37, 7913–7916.
20. Dhake, K. P.; Qureshi, Z. S.; Singhal, R. S.; Bhanage, B. M. Tetrahedron Lett. 2009,
50, 2811–2814.
21. Tufvesson, P.; Annerling, A.; Hatti-Kaul, R.; Adlercreutz, D. Biotechnol. Bioeng.
2007, 97, 447–453.
22. Nechab, M.; Azzi, N.; Vanthuyne, N.; Bertrand, M.; Gastaldi, S.; Gil, G. J. Org.
Chem. 2007, 72, 6918–6923.
23. Couturier, L.; Taupin, D.; Yvergnaux, F. J. Mol. Catal. B: Enzym. 2009, 56, 29–
33.