LETTER 1097 Synlett 1999, No. 07, 1097–1099 ISSN 0936-5214 © Thieme Stuttgart · New York Pd(0)-Mediated Cross Coupling of 2-Iodoestradiol with Organozinc Bromides: A General Route to the Synthesis of 2-Alkynyl, 2-Alkenyl and 2- Alkylestradiol Analogs Arasambattu K. Mohanakrishnan, Mark Cushman * Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, U.S.A. Fax +1 (765) 494-6790; E-mail: cushman@pharmacy.purdue.edu Received 14 May 1999 Abstract: Treatment of 3,17-O-bis(tert-butyldimethylsilyl)-2-io- doestradiol with in situ-generated organozinc bromides in the pres- ence of a catalytic amount of Pd(PPh 3 ) 4 as a Pd(0) source led to efficient displacement reactions. Keywords: estradiol, antitumor compounds, palladium, cross cou- pling, organozinc bromides In order to define the structural parameters associated with the antitublin activity 1 and cytotoxicity 2,3 of 2-meth- oxyestradiol, an array of 2-substituted estradiol analogs were synthesized and evaluated for biological activity. 4,5 Several of them were very potent inhibitors of tubulin po- lymerization acting at the colchicine binding site. In view of the cytotoxic activities of these compounds in human cancer cell cultures, a systematic study was undertaken to synthesize 2-alkynyl, 2-alkenyl, and 2-alkylestradiols. Regioselective lithiation of 3,17-O-bis(methoxymeth- yl)estradiol (1) 6 followed by quenching with I 2 or perfluo- rohexyl iodide 7 gave the 2-iodoestradiol derivative 2 in 78% yield (Scheme 1). Deprotection of the two hydroxyl groups followed by reprotection with TBDMSCl gave compound 3. 8 Scheme 1 The Sonogashira procedure involving the reaction of ter- minal alkynes with aryl halides in the presence of amines and a catalytic amount of Pd(II) complex and CuI (Scheme 2) has been widely used for the synthesis of aryl- alkynes. 9-11 However, the reaction of compound 3 with propyne under the Sonogashira coupling conditions pro- vided only a 12% yield of the required product. 5 Since rel- atively large amounts of 2-propynylestradiol were needed for its preclinical development as an anticancer agent, it was decided to develop a more practical route for its syn- thesis which could possibly be extended to the preparation of related compounds as well. Scheme 2 Scheme 3 Initially, the coupling reaction of compound 3 was at- tempted unsuccessfully under Kumada conditions using commercially available 1-propynylmagnesium bromide. The use of Pd(PPh 3 ) 4 in place of the Ni(II) complex also failed. Finally, the 2-propynylestradiol analog 4 was pre- pared in 82% yield in the presence of tetrakis(triphe- nylphosphine)palladium and in situ-generated 1- propynylzinc bromide. 10 Under these conditions the cou- pling reaction was very facile and the starting material was totally consumed. Encouraged by the remarkable effect of the employment of the organozinc bromide, the coupling reaction was ex- tended further to the synthesis of several alkynyl, alkenyl and alkyl estradiol analogs. As documented in Table 1, the presently employed Negishi coupling procedure 12 pro-