Synthesis of 13-Aryl Derivatives of the Sesquiterpene Lactone Argolide and their Analgesic Activity
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SYNTHESIS OF 13-ARYL DERIVATIVES OF THE SESQUITERPENE LACTONE ARGOLIDE AND THEIR ANALGESIC ACTIVITY
A. E. Esenbaeva,1* E. E. Shulcts,2 Yu. V. Gatilov,2 M. M. Shakirov,2 S. S. Patrushev,2 G. A. Atazhanova,1 A. B. Kenesheva,1 and S. M. Adekenov1
UDC 547.913.3;547.539;548.737
13-Aryl-substituted derivatives of the germacranolide argolide were synthesized by a Heck reaction with arylhalides. The structure of (E)-13-(4-methoxyphenyl)-3-oxogermacra-1(10),11(13)-dien-6D,12-olide was proved by an x-ray crystal structure analysis. Analgesic activity was found in the acetic-acid writhing test for the 13-arylgermacranolides. Keywords: sesquiterpene lactones, argolide, Heck reaction, x-ray crystal structure analysis, analgesic activity. The germacrane sesquiterpene lactone argolide (1) was isolated for the first time from the aerial part of Artemisia glabella Kar. et Kir. [1]. Later, it was isolated from Stevia grisebachiana (1 was called 4-epitansanin) [2], Ajania fruticulosa [3], Artemisia albida [4], and also from A. filatovii and A. radicans that are endemic to the Republic of Kazakhstan [5]. Two research groups performed independently in 1991 x-ray crystal structure analyses (XSA) of argolide 1 [2, 6]. Argolide was chemically modified to prepare 13-amino-, 1,10-epoxy-, and 1-hydroxy-derivatives [7]. Herein we report the synthesis of argolide derivatives containing an aromatic substituent on C-13 and results from an analysis of the analgesic activity of several synthesized compounds in the acetic-acid writhing test. Reaction of 1 with 4-iodoanisole (2a) catalyzed by Pd(OAc)2–tris(o-tolyl)phosphine in DMF in the presence of Et3N as the base formed under the published conditions [8] 13-(4-methoxyphenyl)-3-oxogermacra-1(10),11(13)-dien-6,12-olide (3a) in trace quantities. Column chromatography isolated (~90%) starting argolide 1. Increasing the reaction time of 1with the aryliodides (2a and 2b) to 30 h increased the conversion of 1 to 35 and 33%, respectively (according to PMR data for the reaction mixture). I 1 3
9
10
R1
5
7
13
O O
15
+
O
R2
12 11
1
R3
i - iii
O
R2
O
R3 2a - e
3a - e
R1
O
Br CH3 iii
+
O
O
O
2f 3f
O O
4
O
2a,3a: R1 = R2 = H, R3 = OCH3; 2b,3b: R1 = R3 = H, R2 = CF3; 2c,3c: R1 = R2 = H, R3 = F 2d,3d: R1 = R2 = H, R3 = Cl; 2e,3e: R1 = SCH3, R2 = R3 = H i. Pd(OAc)2, (o-Tol)3P, Et3N, DMF, 120qC, 12 h; ii. Pd(OAc)2, (o-Tol)3P, Et3N, DMF, 120–130qC, TBAB, 10–36 h; iii. Pd(OAc)2, (o-Tol)3P, Cs2CO3, DMF, 120–130qC, 32–36 h.
Scheme 1 1) Phytochemistry Corp., 100009, Republic of Kazakhstan, Karaganda, Ul. Gazalieva, 4, fax: 8 (7212) 43 31 27, e-mail: [email protected]; 2) N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, 630090, Novosibirsk, Prosp. Lavrentceva, 9, fax: +7 (383) 330 97 52, e-mail: [email protected]. Translated from Khimiya Prirodnykh Soedinenii, No. 5, September–October, 2013, pp. 752–757. Original article submitted July 19, 2013. 0009-3130/13/4905-0875
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Springer Science+Business Media New York
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