Synthesis of the thyroid hormone analog GC-1 via Bi(OTf) 3 -catalyzed benzylation Kassrin Tangdenpaisal a , Somsak Ruchirawat a, b, c , Poonsakdi Ploypradith a, b, c, * a Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Talat Bangken, Laksi, Bangkok 10210, Thailand b Program in Chemical Biology, Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6, Talat Bangken, Laksi, Bangkok 10210, Thailand c Center of Excellence on Environmental Health and Toxicology, Commission on Higher Education (CHE), Ministry of Education, Thailand article info Article history: Received 13 May 2014 Received in revised form 4 July 2014 Accepted 15 July 2014 Available online 19 July 2014 Keywords: Bismuth (III)-catalysis FriedeleCrafts-type benzylation Thyroid hormone analogs Regioselective process Diarylmethane abstract Starting from two commercially available phenol derivatives, the thyroid hormone analog, GC-1, was successfully prepared. The strategy featured a convergent coupling of the two halves via the Lewis/ Brønsted acid-mediated regioselective FriedeleCrafts-type (FC-type) benzylation to furnish the corre- sponding diarylmethane core as the key step. Various transition metal triflates were screened as catalysts for this key step, among which Bi(OTf) 3 was found to be the most effective. Ó 2014 Elsevier Ltd. All rights reserved. 1. Introduction Thyroid hormones, upon binding to their thyroid hormone re- ceptors (TRs), regulate a number of important physiological func- tions in different mammalian tissues, including metabolism of carbohydrates, lipids, and proteins. 1e3 They have been adminis- tered in the replacement therapy to patients with hypothyroidism or as suppressors of the pituitary gland-dependent stimulation of the thyroid gland in patients with thyroid nodules or cancer. 4,5 However, high doses of these hormones may cause adverse side effects, especially those on the heart such as tachycardia, and thus cannot be administered. 6 Among the thyroid hormones, the 3,5,3 0 - triiodo-L-thyronine or T3 (1) is the major active form (Fig. 1). 7 There are two TR subtypes, namely TRa and TRb. Recently, efforts have been directed towards designing ligands, which are selective for the TRb subtype due to fewer side effects on the heart. 8e10 GC-1 (2) and its analogs (3) were designed to be selective halogen-free thyromimetic ligands with high affinity for the TRb. 11e13 GC-1 has been shown to possess a 10-fold selectivity for TRb over TRa and a plasma cholesterol-lowering property without significant tachy- cardia in rats fed with cholesterol. 14 More importantly, in clinical trials, when given to healthy subjects, GC-1 was well tolerated while lowering blood low-density lipoprotein (LDL) cholesterol level up to 41% at the dose of 100 mg given every day over 2 weeks. 15 Thus, GC-1 represents an important template for further de- velopment of selective TRb thyromimetic ligands and efficient synthetic routes are necessary for its preparation. In the previously reported synthetic approaches by Scanlan, the diarylmethane core of 2 was formed by the aryllithium (generated via the lithiume- bromine exchange of 4 and 5) addition to the benzaldehyde de- rivatives 6 and 7 as the key step (Scheme 1). 11e13 While each step in their original and subsequent improved syntheses proceeded in moderate to good yields, a number of drawbacks were evident. Monoalkylation of the phenol group of ring A in the presence of the phenol group of ring B proceeded in low yield and low selectivity (approach a). 11,12 Thus, different protecting groups for the two phenolic moieties on both the A and B rings needed to be in- troduced and removed in separate steps, rendering the synthesis cumbersome (approach b). 13 In addition, for both approaches, the Fig. 1. Natural and synthetic thyroid hormones 1e3. * Corresponding author. Tel.: þ66 2 553 8555; fax: þ66 2 553 8527; e-mail ad- dress: poonsakdi@cri.or.th (P. Ploypradith). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet http://dx.doi.org/10.1016/j.tet.2014.07.063 0040-4020/Ó 2014 Elsevier Ltd. All rights reserved. Tetrahedron 70 (2014) 6789e6795