COMMUNICATIONS
the solution at RT under nitrogen. After stirring for 1 min, AgSbF6
(0.02 mmol in ClCH2CH2Cl) was added to the mixture. The reaction was
completed within 5 min. The reaction mixture was directly subjected to
column chromatography, from which (þ)-4a (24.9 mg, 87%, over
99% ee)[20] was obtained. The ee value was determined by HPLC with an
OJ-H column (hexane:isopropanol ¼ 95:5, 1 mLminÀ1, 254 nm). [a]D25 ¼ þ
3.52 (c ¼ 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d ¼ 7.28 7.16 (m, 5H),
5.85 (dt, J ¼ 2.2, 5.9 Hz, 1H), 5.58 5.53 (m, 1H), 5.08 5.02 (m, 2H), 4.80
4.77 (m, 2H), 4.61 (s, 2H), 4.48 (d, J ¼ 14.6 Hz, 1H), 4.35 (d, J ¼ 14.6 Hz,
1H), 3.32 ppm (s, 3H); 13C NMR (90 MHz, CDCl3) d ¼ 167.72, 137.76,
136.57, 134.50, 129.13, 128.65, 128.07, 118.00, 96.84, 95.57, 64.04, 54.54, 50.22,
47.15, 42.17 ppm; MS m/z: 288.1 [Mþþ1]; HRMS (APCI) calcd for
C17H22NO3 [Mþþ1)]: 288.1600; found: 288.1603.
high reactivity (100% conversion within 5 min) but poor enantiose-
lectivity (6.5% ee) was observed.
[15] a) M. Blouin, R. Frenette, J. Org. Chem. 2001, 66, 9043 9045, and
references therein; b) M. C. Croudace, N. E. Schore, J. Org. Chem.
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[16] L. Abraham, R. Czerwonka, M. Hiersemann, Angew. Chem. 2001,
113, 4835 4837; Angew. Chem. Int. Ed. 2001, 40, 4700 4703, and
references therein.
[17] B. M. Trost, J.-P. Surivet, Angew. Chem. 2001, 113, 1516 1519; Angew.
Chem. Int. Ed. 2001, 40, 1468 1471, and references therein.
[18] Bn-substituted substrates failed to yield the desired 1,4-diene prod-
ucts, while the starting materials were completely consumed.
[19] J. Tsuji, Transition Metal Reagents and Catalysts: Innovations in
Organic Synthesis, Wiley, Chichester, 2000, pp. 10 14 and pp. 238
280.
Received: July 11, 2002
Revised: September 19, 2002 [Z19714]
[20] Using freshly prepared 3a and freshly distilled solvent was important
to achieve 99% ee.
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Mechanistic Studies of HPP Epoxidase:
Configuration of the Substrate Governs Its
Enzymatic Fate**
Zongbao Zhao, Pinghua Liu, Kazuo Murakami,
Tomohisa Kuzuyama, Haruo Seto, and Hung-
wen Liu*
[5] F. Khuong-Huu, X. Monseur, G. Ratle, G. Lukacs, R. Goutarel,
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d) B. M. Trost, M. J. Krische, Synlett 1998, 1; e) B. M. Trost, Chem.
Eur. J. 1998, 4, 2405.
Non-heme iron-dependent enzymes are an important class
of catalysts involved in many biological transformations of
medical, pharmaceutical, and environmental significance.
Although considerable progress has been made in our under-
standing of their catalyses, characterization of the metal
centers and the modes of dioxygen activation remain a
challenge because of the great structural and mechanistic
diversity found among these enzymes.[1] Recently, HPP
epoxidase,[2] an enzyme in the biosyntheticpathway of the
antibiotic fosfomycin, was recognized as a new member of this
enzyme family.[3] This epoxidase performs the final trans-
formation in the fosfomycin biosynthesis by converting (S)-2-
hydroxypropylphosphonicacid (HPP, ( S)-1) to (1R,2S)-epoxy-
[7] a) B. M. Trost, M. Lautens, C. Chan, D. J. Jebaratnam, T. Mueller, J.
Am. Chem. Soc. 1991, 113, 636 644, and references therein; b) B. M.
Trost, Y. Li, J. Am. Chem. Soc. 1996, 118, 6625 6633; c) B. M. Trost,
M. J. Krische, J. Am. Chem. Soc. 1999, 121, 6131 6141; d) B. M. Trost,
J. R. Corte, M. S. Gudiksen, Angew. Chem. 1999, 111, 3945 3947;
Angew. Chem. Int. Ed. 1999, 38, 3662 3664; e) B. M. Trost, J. R. Corte
Angew. Chem. 1999, 111, 3947 3949; Angew. Chem. Int. Ed. 1999, 38,
3664 3666; f) C. Fernandez-Rivas, M. Mendez, A. M. Echavarren, J.
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S. L. Buchwald, J. Am. Chem. Soc. 1999, 121, 1976 1977; h) Y.
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3560; i) B. M. Trost, C. D. Haffner, D. J. Jebaratnam, M. J. Krische,
A. P. Thomas, J. Am. Chem. Soc. 1999, 121, 6183 6192.
[8] Tetrahydrofuran: a) M. Hatano, M. Terada, K. Mikami, Angew. Chem.
2001, 113, 255 259; Angew. Chem. Int. Ed. 2001, 40, 249 253;
pyrrolidine: b) A. Goeke, M. Sawamura, R. Kuwano, Y. Ito, Angew.
Chem. 1996, 108, 686; Angew. Chem. Int. Ed. Engl. 1996, 35, 662.
[9] B. M. Trost, C. Pedregal, J. Am. Chem. Soc. 1992, 114, 7292 7294.
[10] X. Xie, X. Lu, Y. Liu, W. Xu, J. Org. Chem. 2001, 66, 6545 6550.
[11] a) P. Cao, B. Wang, X. Zhang, J. Am. Chem. Soc. 2000, 122, 6490
6491; b) P. Cao, X. Zhang, Angew. Chem. 2000, 112, 4270 4272;
Angew. Chem. Int. Ed. 2000, 39, 4104 4106.
propylphosphonicaidc
(
2), also known as fosfomycin
[*] Prof. Dr. H.-w. Liu, Dr. Z. Zhao,+ Dr. P. Liu,+ Dr. K. Murakami
Division of Medicinal Chemistry
College of Pharmacy and
Department of Chemistry and Biochemistry
University of Texas
Austin, TX 78712 (USA)
Fax : (þ 1)512-471-2746
[12] Some other preliminary results for preparing lactones, and tetrahy-
drofurans will be published.
E-mail: h.w.liu@mail.utexas.edu
Prof. Dr. T. Kuzuyama
Institute of Molecular and Cellular Biosciences
University of Tokyo
[13] a) From the NMR spectra, there is clear evidence that all of these
protected enyne amides are trans/cis-mixtures while the unprotected
enyne amides are single isomers: b) W. E. Stewart III, T. H. Siddall,
Chem. Rev. 1970, 70, 517; c) L. A. LaPlanche, M. T. Rogers, J. Am.
Chem. Soc. 1963, 85, 3728.
[14] a) The reactions of the substrates that contained E olefins were totally
different. The reaction of (E)-1c was examined; 20% conversion and
6% ee were obtained under the same conditions; b) the different
reactivity of Z and E substrates may be explained by the stronger
coordination of Z substrates to RhI. F. R. Hartley, The Chemistry of
Platinum and Palladium: with Particular Reference to Complexes of
the Elements, Applied Science Publication Ltd, London, 1973, p. 377;
c) a terminal alkynyl-ene substrate was also examined in this reaction;
Bunkyo-ku, Tokyo 113-0032 (Japan)
Prof. Dr. H. Seto
Faculty of Applied Bio-Science
Tokyo University of Agriculture
Setagaya-ku, Tokyo 156-8502 (Japan)
[+] Contributed equally to the work.
[**] We thank Ms. Bettina H˘j for her assistance on the chemical synthesis
of 12, and Amano Pharmaceutical Co. Ltd. for a gift of lipase PS from
Pseudomonas cepacia. This work was supported in part by a National
Institutes of Health Grant (GM40541).
Angew. Chem. Int. Ed. 2002, 41, No. 23
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