Studies on the hydrogenolysis of benzyl ethers Enric Lla `cer, Pedro Romea * and Fe `lix Urpı ´ * Departament de Quı ´mica Orga ` nica, Universitat de Barcelona, Martı ´ i Franque ´s 1–11, 08028 Barcelona, Catalonia, Spain Received 6 April 2006; accepted 17 May 2006 Available online 16 June 2006 Abstract—Selective hydrogenolysis of benzyl ethers can be achieved by the appropriate choice of the catalyst, solvent, and concen- tration, which facilitates the design of O-benzyl based protecting group strategies for the synthesis of natural products. Ó 2006 Elsevier Ltd. All rights reserved. Benzyl ether is one of the most widely used protecting groups of alcohols since it is easily installed, stable to a broad scope of reaction conditions and readily re- moved in the presence of many common functionalities through hydrogenation, dissolving metal reduction, oxi- dative treatments, or Lewis acid mediated cleavage. 1 Among these methodologies, catalytic hydrogenolysis offers the mildest option for removing benzyl protecting groups because of its technical simplicity and the quanti- tative yields usually achieved without the requirement of further purification of the reaction mixture. In spite of these advantages, studies on the selective hydrogenolysis of benzyl ethers are scarce and, more importantly, there is a lack of information about the experimental condi- tions that permit the removal of true benzyl protecting groups of alcohols when other oxygenated benzylic posi- tions present in the same structure have to remain intact. 2–4 These limitations have traditionally been addressed through the development of more elaborate benzyl-like protecting groups. However, the usefulness of some of these is compromised by a loss of robustness that often introduces additional synthetic difficulties. 5–7 Therefore, it would be worth gaining insight into the experimental conditions required for the selective cleav- age of benzyl protecting group of alcohols in the pres- ence of other ethers placed at a benzylic position. We came across the abovementioned limitations during the preparation of the C9–C21 fragment of debromo- aplysiatoxin and oscillatoxin D. 8 As represented in Scheme 1, we envisaged that protection of C11 and C20 alcohols as benzyl ethers would fulfil the stability requirements expected along the synthesis in such a way that they could be cleanly and simultaneously removed by catalytic hydrogenolysis in a late step. 9 Surprisingly, this approach earlier proved troublesome. Indeed, preliminary trials of hydrogenolysis on the C9–C21 advanced intermediate 1 shown in Scheme 2 in the presence of 10% Pd/C in methanol (1 atm, rt, 0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.05.109 Keywords: Protecting groups; Benzyl ether; Selective hydrogenolysis. * Corresponding authors. Tel.: +34 93 402 12 47/403 91 06; fax: +34 93 339 78 78 (F.U.); e-mail addresses: pedro.romea@ub.edu; felix.urpi@ub.edu OH OMe O O O O OH O OH O 21 15 OH OMe O 9 O O O O O Oscillatoxin D Debromoaplysiatoxin OBn OMe O OBn X Benzyl–protected C9–C21 fragment 21 15 9 9 21 15 Scheme 1. Tetrahedron Letters 47 (2006) 5815–5818