Chemo and diastereoselective conjugate addition of Grignard reagents on parthenin, a bioactive natural sesquiterpene lactone q Jajula Kashanna, Paramesh Jangili, Rathod Aravind Kumar, Bethapudirr Rama Rao ⇑ Cell Tech Laboratory–NPL, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India article info Article history: Received 12 October 2012 Revised 10 December 2012 Accepted 12 December 2012 Available online 19 December 2012 Keywords: Parthenin analogues Grignard reagents Mono nucleophilic addition Chiral products Diastereoselectivity abstract The conjugate addition on a natural bioactive pseudoguaianolide sesquiterpene lactone parthenin with various Grignard reagents leads to 13-C alkylated products chemo and diastereoselectively in fair overall yields. Compared with other Grignard reagents vinyl and smaller straight chain alkyl Grignard reagents gave better yields. Ó 2013 Elsevier Ltd. All rights reserved. Organometallic reagents provide one of the most important syn- thetic routes to construct C–C bond in organic chemistry. 1–3 These reagents undergo addition reaction with a range of active amides, esters, thioesters, anhydrides, 4 acid chlorides 5 and a,b-unsaturated carbonyl derivatives. 6 The conjugate addition (1,4 addition) of organocopper reagents and copper(I) mediated Grignard reagents to a,b-unsaturated carbonyl derivatives is another fundamental operation in the construction of carbon–carbon bonds. 7 These addi- tion reactions give enantioselective and regioselective products in the presence of chiral ligands. 8 Parthenin (Fig. 1) is a pseudoguaiano- lide sesquiterpene lactone which occurs in an exotic noxious proliferating weed Parthenium hysterophorus Linn (Compositae). The molecule has a central seven-membered saturated carbocyclic ring (B) which was fused to two essentially planar five membered rings-one is a carbocyclic cyclopentenone ring and the other is a heterocyclic a-methylene c-lactone moiety (C). The compound possesses significant anticancer, 9 antibacte- rial, 10 antifungal, 11 antimalarial, 12 anti-HCV, 13 allelopathic proper- ties, 14 herbicides, antifeedant, insecticides, nematicides 15 and amoebicides. 16 In continuation of our work on chemical transformation of par- thenin herein, we report a chemo and diastereoselective conjugate addition of Grignard reagents with exocyclic double bond of par- thenin (Scheme 1), which could efficiently proceed with Cu(I)I as catalyst and (R)-BINOL as ligand. Cu(I)I and (R)-BINOL mediated Grignard reactions of parthenin with vinyl magnesium bromide in dry toluene at À78 °C afforded the formation of b-oriented product, which was isolated by column chro- matography and characterized as 3a on the basis of its spectral data. Compound 3a was obtained as a viscous material. Its molecular formula was determined to be C 17 H 22 O 4 from elemental analysis, and MS showed a peak at m/z 313[M+Na]. The structure of 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.12.043 q Part 2 in the series ‘Synthetic studies on natural products’. ⇑ Corresponding author. Tel./fax: +91 40 27160387. E-mail address: bethapudirr@rediffmail.com (B.R. Rao). O O O HO A B C 1 2 3 4 5 6 7 8 9 10 12 11 13 14 15 Figure 1. O O O HO + RMgX O O O HO R 1 2 3a Cu(I)I, (R)-BINOL dry Toluene -78 o C, 4-6 h 61-84 % Scheme 1. Tetrahedron Letters 54 (2013) 1634–1637 Contents lists available at SciVerse ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet