Planned and unplanned halogenations in route to selected oroidin alkaloids Shaohui Wang, Anja S. Dilley, y Karine G. Poullennec z and Daniel Romo * Department of Chemistry, Texas A&M University, PO Box 30012, College Station, TX 77843-3012, USA Received 12 December 2005; revised 1 January 2006; accepted 5 January 2006 Available online 19 May 2006 Abstract—Highly diastereoselective, substrate-controlled, halogenation/ring contraction sequences delivered the naturally occurring chlo- rinated and unnatural brominated and iodinated axinellamine core structure. An unexpected azide displacement of the chlorinated cyclopen- tane, which proceeded with retention of stereochemistry, suggested a modification of the Scheuer/Kinnel proposal that may account for the related natural product massadine. Two unsuccessful routes to access the stereochemistry proposed for palau’amine were S N 2 displacement of the bromo- and iodocyclopentane with excess chloride anion and an intramolecular directed chlorination pathway. Finally, an unexpected chlorination during our phakellstatin synthesis proceeded with retention of stereochemistry during tosylation possibly resulting from neigh- boring group participation. Ó 2006 Elsevier Ltd. All rights reserved. 1. Introduction More than 3800 halogenated organic compounds, primarily bearing chlorine or bromine, have been isolated from natural sources including bacteria, fungi, plants, marine organisms, insects, and higher organisms including humans. 1 The struc- tural diversity and large but still increasing number of halo- genated organics found in nature is truly astounding. As a primary reservoir for chlorine on earth, oceans have an aver- age chlorine concentration of 19.4 g L 1 and containw 26 Zg (zettagram¼10 21 g) Cl in total. 2 More than 1000 halogen- containing natural products have been isolated from marine organisms and not unexpectedly, this accounts for a large por- tion of the naturally occurring halogenated natural products. 1 Among these, oroidin family of marine alkaloids was isolated from various species of marine sponges. 3 Our interest in this class of alkaloids has led to stereoselective approaches 4 to various members including the phakellins (e.g., 2) and pha- kellstatins, 5 and palau’amines (3) 6 and the axinellamines (4)(Fig. 1). 7 This family of marine alkaloids has garnered much interest from a number of synthetic groups. 8 One of the most challenging aspects of these compounds is the highly substituted cyclopentane core structure, which includes a chlo- rine bearing stereocenter. This paper describes both planned and unplanned halogenations in our synthetic studies toward several members of the oroidin-derived marine alkaloids. 1.1. Unified strategy toward axinellamine and palau’amine Considering the structural similarities of the axinellamines and palau’amines, the two alkaloids were envisioned to arise from a common core structure, which differ in the relative stereochemistry of the chlorine and aminomethylene bearing stereocenters. Imidazolone annulation onto the common Cl NHR 3 R 3 HN N HN NH HN NH OH H HN RO Cl NHR 3 R 3 HN N HN NH HN NH OH H HN RO H N N N O Cl NH 2 HN H 2 N HO H N N H 2 N H Palau'amine 3a R 1 , R 2 = H Bromopalau'amine 3b R 1 = H, R 2 = Br Dibromopalau'amine 3c R 1 , R 2 = Br Axinellamine A 4a R = H Axinellamine B 4b R = Me R 1 R 2 N N O H N N H 2 N R 1 R 2 Phakellin 2a R 1 , R 2 = H Bromophakellin 2b R 1 = H, R 2 = Br Dibromophakellin 2c R 1 , R 2 = Br N NH H 2 N H N Axinellamine C (4c, R = H) Axinellamine D (4d, R = Me) Oroidin (1) O HN Br Br R 3 = 4, 5-dibromopyrrolo-2-carboxamide Figure 1. Oroidin-derived marine alkaloids. Keywords: Oroidin alkaloids; Stereoselective chlorination; Bromination; Iodination. * Corresponding author. Tel.: +1 979 845 9571; fax: +1 979 862 4880; e-mail: romo@mail.chem.tamu.edu y Present address: Wyeth Research, CN-8000, Princeton, NJ 08543, USA. z Present address: Vernalis, Reading, Berkshire, RG1 6QR, UK. 0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2006.01.115 Tetrahedron 62 (2006) 7155–7161