![]() The indene skeleton 13 favors the regioisomer 18 over 17 with a 4.4:1.0 ratio and 70% overall yield after 75 min. Oxidation of the phenol 12 results in a 1.0:2.3 ratio of 15:16 in a 63% overall yield after 90 min. Reactions were conducted in deuterated dimethylformamide (0.1 M, 0 ☌) and monitored with 1H NMR using a methylene chloride standard. Our results for IBX oxidation of the three skeletons 12– 14 are summarized in Scheme 3. Some Literature Examples of Regioselective Electrophillic Aromatic Substitutions 17 An abbreviated excerpt from these studies is shown in Scheme 2 for 2,3-dimethyl phenol 12, 2,3-dihydro-1 H-inden-5-ol 13, and 5,6,7,8-tetrahydro-naphthalen-2-ol 14. Among the most comprehensive and enlightening investigations are studies examining the regiochemistry for bromination 16 and amino-methylation. ![]() As expected, trends in regioselective substitution have been known for some time. We began by evaluating literature examples of other electrophillic aromatic substitution reactions. 15 Because of our intended strategy for the synthesis of 1, we paused to consider the cause of these potentially problematic findings. 14 Given our considerable experience using this reagent for o-quinone formation, we were surprised by a recent article reporting low yields and poor selectivity when IBX was applied to the 2,3-dimethylphenol 12 and a tetralin system similar to 14 shown in Scheme 2. 11 We expect that it should enable improved synthetic access to a variety of biologically active catechols, such as those that inhibit protein tyrosine phosphatase 1B, 12 decrease anxiety, 13 and serve as a 5-HT 2C receptor agonists. 10 In addition, our method found application in several syntheses. These included the development of a benzoic acid stabilized and supposedly nonexplosive IBX reagent, 9 as well as the use of Dess-Martin periodane. Our disclosure of this transformation was followed by several publications from others. 8 Unlike the Fremy’s salt procedure, our IBX procedure proves successful in oxidizing phenols to o-quinones even in the absence of a para substituent. Some time ago, we revealed the first convenient method for regioselective formation of an o-quinone such as 7 from a phenol such as 8 and established the first step of this mechanism to be an intramolecular electrophilic aromatic substitution. Herein, we report the successful conclusion of the initial phase of our plan, a racemic synthesis of brazilin ( 1) using o-iodoxybenzoic acid (IBX) for o-quinone formation followed by tautomerization and a desymmetrizing cyclization. ![]() Therefore, we devised a strategy that would enable an asymmetric preparation of 1 by desymmetrization. 7 These properties are fairly common among anticancer agents. Beyond this redox chemistry, our interest in devising a general synthesis for this family emerged after reading a report on the ability of brazilin ( 1) to serve as a micromolar telomerase inhibitor 6 and to nick DNA. The origins of their pink color resides in the ability of these catechol products to oxidize to their o-quinone and tautomeric p-quinone methide counterparts. 5 These ethanolic tinctures were formally used in medicines, but have since found application in the production of dyes and inks. 4 Compounds 1– 5 ( Figure 1) are all found in the alcoholic extracts of trees collectively referred to as Brazil wood located in the equator regions. 3 Recent efforts culminated in the first enantioselective synthesis of a member of this family, a tris-methylated derivative of 1. 2 Brazilide A ( 5) has been proposed as the newest constituent of this natural product family. The structurally related natural products (+)-brazilin ( 1) and (−)-haematoxylin ( 2) 1 and their reduced counterparts (+)-brazilane ( 3) and haematoxylane ( 4) have been known for some time. ![]()
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