Studies into the Diels–Alder reactions of 5-trimethylsilylthebaine Weibin Chen, a Gary D. Strahan, a Damon A. Parrish, b Jeffrey R. Deschamps b and Andrew Coop a, * a Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Room 637, Baltimore, MD 21201, USA b Laboratory for the Structure of Matter, Naval Research Laboratory, Washington, DC 20375, USA Received 13 August 2004; revised 1 November 2004; accepted 2 November 2004 Available online 21 November 2004 Abstract—The introduction of a 5-trimethylsilyl group on the least hindered face of the diene thebaine was anticipated to favor attack by dienophiles from the alternate face, but only gave rise to a rearrangement product when treated with 3-butene-2-one at 110 °C. Reaction with the more reactive benzoquinone at lower temperature gave rise to a very slow reaction from the same face as the silyl group, indicating that a trimethylsilyl group does not sufficiently hinder this face to achieve reaction at the other face. Ó 2004 Elsevier Ltd. All rights reserved. 1. Introduction The opium alkaloid thebaine (1) readily undergoes Diels–Alder reactions with various dienophiles to give the adducts such as thevinone (2). 1,2 Further manipula- tion of these adducts leads to an extremely potent class of opioid analgesics termed the orvinols, which continue to receive extensive attention. 3–5 The diene system of thebaine could potentially be attacked from both faces, yet reactions with dienophiles always occur from the same face as the nitrogen bridge (upper face) due to the nitrogen bridge causing the lower face to be hindered through concealment inside a concave system. 3 At- tempts to entice Diels–Alder reactions to occur at the lower face have concentrated on introducing substitu- ents into the 5-position of thebaine, thereby providing additional steric hindrance on the upper face. Maat showed that the introduction of a 5b-methyl substitu- ent 6,7 caused some attack from the lower face, and that the corresponding orvinols possessed lower opioid activ- ity than the traditional orvinols. 3 Although these studies provide compelling evidence that the orvinols derived from adducts at the lower face possess little activity, the influence of the 5-methyl group cannot be ignored as 5-methyl groups are known to significantly affect the pharmacology of opioids. 3 Our recent studies into Diels–Alder reactions of 5b-butyl thebaine gave exclu- sive attack from the upper face, contrasting with the re- sults of Maat. 8 We considered that the introduction of a sterically demanding removable substituent into the 5b- position would be more likely to direct Diels–Alder reactions to occur from the lower face. The 5b group could be subsequently removed to give the desired 5- unsubstituted adducts, and allow a thorough investiga- tion of the effect of the stereochemistry of the bridge on the pharmacology of this important class of narcotic analgesics Figure 1. 2. Results and discussion We recently reported the preparation and Lewis acid- catalyzed rearrangement reactions of 5-trimethylsilyl- thebaine (3), 9 and considered that 3 possesses the potential to act as an analog of thebaine with severe steric hindrance to the upper face of the diene. Treat- ment of 3 with 3-butene-2-one in refluxing toluene gave rise to a single product in 63% yield, which possessed the 0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2004.11.010 Keywords: Diels–Alder; Rearrangement; NMR analysis. * Corresponding author. Tel.: +1 4107062029; fax: +1 4107065017; e-mail: acoop@rx.umaryland.edu MeO OMe NMe O 1 MeO OMe NMe O 2 O 5 Figure 1. Structures of thebaine (1) and thevinone (2). Tetrahedron Letters 46 (2005) 131–133 Tetrahedron Letters