OH O F F R N B N Ph Ph SO2 O2S Tol Tol Br R OH O F F 3 (S,S)-1 * 2 OH O R2 CF3 R1 OH O F F * 4andash;e Et2O Et3 N, CH2Cl2 BuLi 3andash;e ( S, S)-1 R1 R2 OH O TMS CF3 OMOM BrMg 4a indash;iii Enantioselective Claisen rearrangement of difluorovinyl allyl ethers Hisanaka Ito, Azusa Sato, Tetsuo Kobayashi and Takeo Taguchi* Tokyo University of Pharmacy and Life Science, Horinouchi, Hachioji, Tokyo 192-0392, Japan. E-mail: taguchi@ps.toyaku.ac.jp Received (in Cambridge, UK) 29th May 1998, Revised manuscript received 5th October 1998, Accepted 5th October 1998 The enantioselective Claisen rearrangement of difluorovinyl allyl ethers was achieved, for the first time, in moderate to good enantioselectivity using a chiral boron reagent as the Lewis acid.The development of a preparative method for chiral organofluorine compounds is very important in the field of medicinal chemistry.1 The Claisen rearrangement of difluorovinyl allyl ethers is a powerful tool for the synthesis of b-substituted a,adifluorocarbonyl compounds.2 Although enantioselective versions of the Claisen rearrangement have been studied for the construction of chiral molecules,3 there has been no report dealing with the reaction of difluorovinyl allyl ethers.We recently reported the highly enantioselective aromatic Claisen rearrangement of o-allyloxyphenol derivatives mediated by the chiral boron reagent 1.4 The efficiency of this system is based on the s-bond formation of the chiral boron reagent 15 with the phenolic hydroxy group in the substrate and the subsequent coordination of the ethereal oxygen to the boron atom to form a rigid chiral environment in the substrate and to promote the reaction at low temperature.We report herein the application of this system to the enantioselective Claisen rearrangement of difluorovinyl allyl ethers (Scheme 1). The substrate 2 having a phenolic hydroxy group was selected, because of the importance of a binding site to the chiral boron reagent 1 in forming a coordinated cyclic intermediate and promoting the reaction. Compound 4a was prepared from the reaction of 2-methoxymethoxyphenylmagnesium bromide with gaseous trifluoroacetaldehyde generated easily by the reaction of 2 equiv.of trifluoroacetaldehyde ethyl hemiacetal with P2O5 at 100 deg;C, followed by the allylation of the hydroxy group by using 1.2 equiv. of NaH and 1.5 equiv. of (E)- 1-bromo-3-trimethylsilylprop-2-ene and deprotection under acidic conditions (Scheme 2).Other compounds 4bndash;d were also synthesized by the same procedure (32ndash;57 yield). Compound 4 was converted to 2 via elimination of fluoride by treatment with 2.5 equiv. of BunLi at 278 to 0 deg;C in Et2O. After neutral workup, the vinyl ether 2 was treated with 1.5 equiv. of (S,S)-1 in the presence of 1.5 equiv. of Et3N in CH2Cl2 at 278 deg;C and then the mixture was stirred at ambient temperature to give the rearranged product 3. The results are summarized in Table 1.In the chiral boron-mediated Claisen rearrangement, the reaction temperature and enantioselectivity were found to be affected by the configuration of the olefin (E or Z) and the steric bulkiness of the substituent R at the g-position. Thus, in the case of 4a having a TMS substituent, the reaction proceeded at 278 deg;C to give 3a with high asymmetric induction (entry 1), while in the reaction of the substrate derived from 4b having an E primary alkyl substituent, a slightly higher temperature was required, giving rise to the product 3b with moderate selectivity (entry 2).7 With the Z substrate derived from 4c, the direction of asymmetric induction was opposite to that with E substrate 4b (entry 3).The absolute stereochemistry of 3d was determined as shown in Scheme 3. The diastereoselective Claisen rearrangement of 5 Scheme 1 Table 1 The enantioselective Claisen rearrangement of difluorovinyl allyl ethers Entry 4 R1 R2 T/deg;C t/h 3a Yield ()b Ee () 1 4a H TMS 278 3 3a 60 85c 2 4b H Pr 278?220 5 3b 39 41d 3 4c Pr H 278?215 5 3c 55 55d 4 4d Et H 278?215 6 3d 58 43d 5 4e c-Hex H 278?215 3 3e 90 56d a Ref. 6. b Isolated yield based on 4. c Optical purity determined by HPLC using a Chiralcel OD column. d Optical purity was determined by HPLC using a Chiralcel AD column. Scheme 2 Reagents and conditions: i, trifluoroacetaldehyde generated from its hemiacetal with P2O5, THF, 0 deg;C, 92; ii, NaH (1.2 equiv.), (E)- 1-bromo-3-trimethylsilylprop-2-ene, THFndash;DMF, room temp.; iii, 10 HCl, MeOH, reflux, 31 over 2 steps. Chem.Commun., 1998, 2441ndash;2442 2441OH O CF3 O O OH O F F O O OH O F F O O OMs O F F O HO F F OH OH OH O F F i,ii 5 6 7 9 8 3d iii iv v,vii v From 6 aD ndash;24.4 ( c 0.50, CHCl3) From 3d aD ndash;13.2 ( c 1.64, CHCl3) F F O O B N N Ph Ph S O O S O O A OH O F F O O O F F OH O H H H H i,ii NOE 6 10 smoothly proceeded to give 6 as a major isomer (47, 5:1), which has an R configuration at the newly formed chiral center.8 Hydrogenation of the olefin of 6 (79) and the subsequent deprotection of the acetonide group by acid treatment gave compound 8 as an anomeric mixture.After mesylation of the primary and phenolic hydroxy groups of 8, the product was converted to the olefin 9 in 65 yield (four steps). The enantioselective Claisen rearrangement product 3d was also converted to 9 by mesylation. Determination of the absolute stereochemistry of 3d as R configuration could be achieved by comparison of the specific rotation of each compound.The observed enantioselectivity is possibly explained as shown in Fig. 1. The six-membered intermediate is formed by the attachment of the chiral boron reagent 1 to the phenolic hydroxy group, and the subsequent coordination of the ethereal oxygen to the boron atom. In the case of (S,S)-1 and the Z isomer of 2, the Si face of the difluorovinyl ether moiety is shielded by the tolylsulfonyl group (A), thus the allylic moiety approaches preferably from the Re face to avoid steric interaction with A in the chair like transition state. In conclusion, we have demonstrated for the first time enantioselective Claisen rearrangement of difluorovinyl allyl ethers using the chiral boron reagent 1 and the substrate 2 having a phenolic hydroxy group to form an efficient chiral environment.9 This work was partially supported by a Grant-in-Aid (No. 09672163) from the Ministry of Education, Science, Sports and Culture, Japan. Notes and references 1 Biomedicinal Aspects of Fluorine Chemistry, ed.R. Filler and Y. Kobayashi, Elsevier Biomedical Press and Kodansha Ltd, 1982; J. T. Welch, Tetrahedron, 1987, 43, 3123; Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications, ed. R. Filler, Y. Kobayashi and L. M. Yagupolskii, Elsevier, Amsterdam, 1993. 2 W. B. Metcalf, E. T. Jarvi and J. P. Burkhart, Tetrahedron Lett., 1985, 26, 2861; G.-Q.Shi, Z.-Y. Cao and W.-L. Cai, Tetrahedron, 1995, 51, 5011; G.-Q. Shi and W.-L. Cai, J. Org. Chem., 1995, 60, 6289; H. Greuter, R. W. Lang and A. J. Roman, Tetrahedron Lett., 1988, 29, 3291. 3 K. Maruoka, H. Banno and H. Yamamoto, J. Am. Chem. Soc., 1990, 112, 7791; K. Maruoka, H. Banno and H. Yamamoto, Tetrahedron: Asymmetry, 1991, 2, 647; K. Maruoka and H. Yamamoto, Synlett 1991, 793; K. Maruoka, S. Saito and H. Yamamoto, J. Am. Chem. Soc., 1995, 117, 1165; E. J.Corey and D.-H. Lee, J. Am. Chem. Soc., 1991, 113, 4026; E. J. Corey and R. S. Kania, J. Am. Chem. Soc., 1996, 118, 1229; U. Kazmaier and A. Krebs, Angew. Chem., Int. Ed. Engl., 1995, 34, 2012; A. Krebs and U. Kazmaier, Tetrahedron Lett., 1996, 37, 7945. 4 H. Ito, A. Sato and T. Taguchi, Tetrahedron Lett., 1997, 38, 4815. 5 E. J. Corey, R. Imwinkelried, S. Pikul and Y.-B. Xiang, J. Am. Chem. Soc., 1989, 111, 5493. 6 Optical rotation (aD) was measured in CHCl3 at 26 deg;C. 3a: 41.1; 3b: 18.6; 3c: 218.3; 3d: 28.8; 3e: 220.3. 7 In the absence of Lewis acid, the E isomer 2b smoothly rearranged to 3b even at room temperature, possibly due to the presence of the phenolic hydroxy group, to form an intramolecular hydrogen bond between the ethereal oxygen. 8 The relative stereochemistry of compound 6 was determined via conversions to 10 and a NOESY experiment, as shown in Scheme 4. 9 Regarding the removal of the hydroxyphenyl moiety, we examined some conditions, i.e. oxidative degradation of the aromatic ring and cleavage of the carbonndash;carbon bond of the aryl ketone moiety (Baeyerndash;Villiger and Schmidt rearrangement). In these experiments, although the aromatic ring was absent from the 1H NMR analysis of the crude mixture, we were unable to find a clean method for cleavage of the hydroxyphenyl moiety. Communication 8/07157H Scheme 3 Reagents and conditions: i, BunLi, Et2O; ii, toluene, 70 deg;C, 47 over 2 steps (5:1); iii, H2, Pd/C, MeOH, 79; iv, 10 HCl, THF, 60 deg;C; v, MsCl, Et3N, CH2Cl2, vi, NaI, butanone, reflux; vii, Zn, AcOH, H2Ondash;THF, 65 from 7. Fig. 1 Scheme 4 Reagents and conditions: i, 10 HCl, THF, 60 deg;C; ii, toluene, 100deg;C, 63 over 2 steps. 2442 Chem Commun., 1998, 2441ndash;2442
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