Stereoselective Total Synthsis of (±)‐Urechitol A

Abstract

Urechitol A (1) was isolated from the methanolic root extract of Pentalinon andrieuxii by Peaea-Rodríguez and co-workers in 2009.[1] P. andrieuxii is a plant used commonly in Yucatecan traditional medicine for the treatment of cutaneous eruptions derived from leishmaniasis, an infectious disease caused by protozoan parasites of the Leishmania genus. The relative stereochemistry of 1 has been elucidated unambiguously by X-ray crystallographic analysis (Scheme 1). This compound has a novel and very unique structure, incorporating a highly functionalized cycloheptane ring with two oxygen bridges. Although urechitol A itself exhibited no biological activity, its unique tetracyclic structure prompted us to investigate its synthesis.Our synthetic strategy toward 1 is shown in Scheme 1. We decided to form the six-membered hemiacetal at a late stage in the synthesis from A. For the construction of the sevenmembered ring with the oxygen bridge (the so-called dioxa analogue of noradamantane [2] ), [4+3] cycloaddition between a furan and a silyloxyallyl cation with a p-donating alkoxy substituent was thought to be a straightforward approach. [2, 3] As there are two tetrahydrofuran rings in A, two types of cycloaddition are possible: C + D (route a) and G + F (route b). In both cycloadducts (B and E, respectively), the oxygen functionalities and double bonds were expected to be located in the required positions for further transformations leading to urechitol A. However, a preliminary investigation indicated that the cycloaddition between C (R 2 = allyl) and D (R 1 = CO 2 Me) afforded a product with both undesired regioand stereochemistry. Therefore, route b was adopted for the synthesis of urechitol A, as described below.Our synthesis started from the key [4+3] cycloaddition reaction between known compounds 2[4] and 3 [3b] ; the product (4) was obtained as a sole regio-and stereoisomer in a moderate yield (Scheme 2). For the reaction, TiCl 4[3a] was used as a Lewis acid instead of the more generally used TMSOTf, [3b] and the reaction was carried out at a relatively lower concentration (0.1m) relative to that of the standard reaction conditions (1m) [3b] to avoid the generation of unidentified by-products. The allylic alcohol was then oxidized into the unstable epoxy alcohol 5 under Sharpless conditions [5] in the presence of NaHCO 3 as a basic additive, which prevented the decomposition of the product during the Scheme 1. Synthetic strategies for urechitol A (1). TMS = trimethylsilyl. Scheme 2. a) TiCl 4 , EtNO 2 , NaHCO 3 , À78 8C, 46 %; b) [VO(acac) 2 ], TBHP, NaHCO 3 , CH 2 Cl 2 , RT, 47 %; c) TsOH·H 2 O, MeOH, 40 8C, 67 % of 6 and 28 % of 7; d) TBSCl, imidazole, DMF, RT, 74 %; e) TPAP, NMO, M.S. 4 , CH 2 Cl 2 , RT, quant. Bn = benzyl, TES = triethylsilyl, Et = ethyl, acac = acetylacetonate, TBHP = tert-butylhydroperoxide, Ts = para-toluenesulfonyl, Me = methyl, TBS = tert-butyldimethylsilyl, DMF = N,N-dimethylformamide, TPAP = tetra-n-propylammonium perruthenate, NMO = 4-methylmorpholine N-oxide, M.S. = molecular ...