Oxidation DOI: 10.1002/ange.201003503 Enantiodifferentiating endo-Selective Oxylactonization of ortho-Alk-1-enylbenzoate with a Lactate-Derived Aryl-l 3 -Iodane** Morifumi Fujita,* Yasushi Yoshida, Kazuyuki Miyata, Akihiro Wakisaka, and Takashi Sugimura Ongoing efforts have been dedicated to the development of reaction processes controlled by chiral hypervalent iodine reagents with high enantioselectivity. [1–12] The oxidation of sulfides into sulfoxides, [2] the a-oxygenation of ketones, [3, 4] the dioxygenation of alkenes, [4, 5, 12] and the dearomatization of phenols [6–8, 9b] have been reported, and most of these reactions resulted in an encouraging level of enantioselectivity. Kita and co-workers reported dearomatizing spirolactonization of naphthols (78–86 % ee) using a spirocyclic iodine(III) reagent. [6] Ishihara and co-workers recently reported that higher enantioselectivities were obtained for the spirolacto- nization by using a chiral iodine compound derived from lactic acid. [8] Our studies with optically active hypervalent iodine compounds have been focused on mechanisms of the reaction concerned [11] as well as synthetic applications. [12] Asymmetric oxidation of 4-acyloxybut-1-ene into 3-acyloxytetrahydro- furan (up to 64 % ee) was achieved by using chiral hypervalent iodine(III) reagents, 1 and 2, which have a lactate moiety as a chiral source. [12] During the course of these studies for the asymmetric oxidative cyclization of alkenes, we found that oxidation of ortho-alk-1-enylbenzoate with the hypervalent iodine reagent regio- and diastereoselectively gave 3-alkyl-4- oxyisochroman-1-one in a practically useful degree of enan- tiomeric purity (90—98 % ee) ; the isochromanone framework is a biologically relevant building block of natural prod- ucts. [13, 14] Herein, we report the synthetic utility of such enantiodifferentiating endo-selective oxylactonizations. The series of optically active hypervalent iodine (III) reagents 1–6 employed in this report is shown in Scheme 1. On the basis of reagents 1 and 2 reported previously, [12] the structures of the iodine reagents were tuned for improved enantioselectivity. The X-ray crystallographic structures of 1– 4 showed a typical T-shape orientation around the iodine center, where the two acetoxy ligands occupied apical positions (see the Supporting Information). 2-Ethenylbenzoic acid (7a) was subjected to the reaction conditions with the optically active hypervalent iodine(III) reagent. The reaction was carried out in the presence of para- toluenesulfonic acid (TsOH) to activate the iodine reagent, and the tosylate also worked as a nucleophile to give lactones 8a and 9a (Table 1). The reaction proceeded regioselectively to give the d-lactone product 8a as the major product. The reaction with 6 gave a higher ee value of 8a with high regioselectitvity (Table 1, entry 5). It is remarkable that the oxylactonization proceeds with endo selectivity [15, 16] in addition to the high enantioselectivity. For elucidation of the mechanism of the endo selectivity and its synthetic applications, we varied the nucleophile and the substrate in the oxylactonization. When boron trifluoride diethyl etherate was employed as an activator in the presence Scheme 1. Optically active hypervalent iodine(III) reagents. Table 1: Tosyloxylactonization of 2-ethenylbenzoic acid. [a] Entry Ar*I(OAc) 2 Yield [%] ee [%] [b] (8a/9a) (S)-8a 9a 1 1 66 (93:7) 75 18(R) 2 2 69 (96:4) 90 42(R) 3 4 70 (96:4) 76 22(S) 4 5 74 (86:14) 60 28(S) 5 [c] 6 65 (95:5) 97 26(S) [a] Reaction conditions are given in the Supporting Information. The acetoxylactonization product 10a was detected in less than 10 % yield. [b] The ee values were determined by HPLC analysis on a chiral stationary phase. [c] In order to estimate a change in ee value of the product owing to the crystallization for isolation, the crude mixture was analyzed before crystallization. The ee value of 8a in the crude mixture was 97 % and agreed with that in the isolated product. [*] Prof.Dr. M. Fujita, Y. Yoshida, K. Miyata, Prof.Dr. T. Sugimura Graduate School of Material Science, University of Hyogo Kohto, Kamigori, Hyogo 678-1297 (Japan) Fax: (+ 81) 791-58-0115 E-mail: fuji@sci.u-hyogo.ac.jp Dr. A. Wakisaka National Institute of Advanced Industrial Science and Technology Onogawa, Tsukuba, Ibaraki 305-8569 (Japan) [**] We are very grateful to Dr. Hiroki Akutsu and Prof. Shin’ichi Nakatsuji (Hyogo) for X-ray crystallographic analyses and to Prof. Tadashi Okuyama (Hyogo) for reading this manuscript. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201003503. Zuschriften 7222  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. 2010, 122, 7222 –7225