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Synlett 2009(4): 671-674  
DOI: 10.1055/s-0028-1087808
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© Georg Thieme Verlag Stuttgart ˙ New York

Enantioselective Synthesis of (R)-α-Alkylhomoserines and (R)-α-Alkylhomocysteines via Phase-Transfer Catalytic Alkylation

Taek-Soo Kima, Yeon-Ju Leea, Kyoungyim Leea, Byeong-Seon Jeongb, Hyeung-geun Park*a, Sang-sup Jew*a
a Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul 151-742, Korea
Fax: +82(2)8729129; e-Mail: hgpk@snu.ac.kr;
b Institute for Drug Research and College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Korea
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Publication History

Received 30 September 2008
Publication Date:
16 February 2009 (online)

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Abstract

Efficient enantioselective synthetic methods for (R)-α-alkylhomoserines and (R)-α-alkylhomocysteines have been developed. The phase-transfer catalytic alkylation of 2-phenyl-5,6-di­hydro-4H-1,3-oxazine-4-carboxylic acid tert-butyl ester and 2-phenyl-5,6-dihydro-4H-1,3-thiazine-4-carboxylic acid tert-butyl ester, in the presence of N-2′,3′,4′-trifluorobenzylcinchonidinium bromide, gave the corresponding alkylated products, which could be hydrolyzed to provide (R)-α-alkylhomoserines (up to 97% ee) and (R)-α-alkylhomocysteines (up to 91% ee), respectively.

Key words

phase-transfer catalytic alkylation - enantioselective synthesis - (R)-α-alkylhomoserines - (R)-α-alkylhomocysteines

    References and Notes

  • 1a Ma JS. Chim. Oggi  2003,  21:  65 
    Google Scholar
  • 1b Goodman M. Ro S. In Burger’s Medicinal Chemistry and Drug Discovery   5th ed., Vol. 1:  Wolff ME. John Wiley and Sons; Chichester: 1995.  Chap. 20. p.803-861  
    Google Scholar
  • 2a Barrett GC. Amino Acids, Peptides and Proteins   Vol. 13:  The Chemical Society; London: 1980.  p.1 
    Google Scholar
  • 2b Hunt S. In Chemistry and Biochemistry of the Amino Acids   Barrett GC. Chapman and Hall; London: 1985.  p.55 
    Google Scholar
  • 2c Richardson JS. Biophys. J.  1992,  63:  1186 
    Google Scholar
  • 3a Chhabra SR. Harty C. Hooi DSW. Daykin M. Williams P. Telford G. Pritchard DI. Bycroft BW. J. Med. Chem.  2003,  46:  97 
    Google Scholar
  • 3b Geske GD. O’Neill JC. Blackwell HE. ACS Chem. Biol.  2007,  2:  315 
    Google Scholar
  • 3c Kaufmann GF. Sartorio R. Lee S.-h. Mee JM. Altobell LJ. Kujawa DP. Jeffries E. Clapham B. Meijler MM. Janda KD. J. Am. Chem. Soc.  2006,  128:  2802 
    Google Scholar
  • 3d Geske GD. O’Neill JC. Miller DM. Mattmann ME. Blackwell HE. J. Am. Chem. Soc.  2007,  129:  13613 
    Google Scholar
  • 4a Schollkopf U. Lonsky R. Synthesis  1983,  675 
    Google Scholar
  • 4b Seebach D. Aebi JD. Naef R. Weber T. Helv. Chim. Acta  1985,  68:  144 
    Google Scholar
  • 4c Smith AB. Pastemak A. Yokoyama A. Hirschmann R. Tetrahedron Lett.  1994,  35:  8977 
    Google Scholar
  • 4d Ayoub M. Chassaing G. Loffet A. Lavielle S. Tetrahedron Lett.  1995,  36:  4069 
    Google Scholar
  • 4e Berkowitz DB. McFadden JM. Sloss MK. J. Org. Chem.  2000,  65:  2907 
    Google Scholar
  • 5a Jew S.-s. Lee Y.-J. Lee J. Kang MJ. Jeong B.-S. Lee J.-H. Yoo M.-S. Kim M.-J. Choi S.-h. Ku J.-M. Park H.-g. Angew. Chem. Int. Ed.  2004,  43:  2382 
    Google Scholar
  • 5b Park H.-g. Lee J. Kang MJ. Lee Y.-J. Jeong B.-S. Lee J.-H. Yoo M.-S. Kim M.-J. Choi S.-h. Jew S.-s. Tetrahedron  2004,  60:  4243 
    Google Scholar
  • 5c LeeY j. Lee J. Kim M.-j. Kim T.-S. Park H.-g. Jew S.-s. Org. Lett.  2005,  7:  1557 
    Google Scholar
  • 5d LeeY j. Lee J. Kim M.-j. Jeong B.-S. Lee J.-H. Kim T.-S. Ku J.-M. Park H.-g. Jew S.-s. Org. Lett.  2005,  7:  3207 
    Google Scholar
  • 5e Lee J. Lee Y.-I. Kang MJ. LeeY j. Jeong B.-S. Lee JH. Kim M.-j. Choi J.-y. Ku J.-M. Park H.-g. Jew S.-s. J. Org. Chem.  2005,  70:  4158 
    Google Scholar
  • 5f Kim T.-S. LeeY j. Jeong B.-S. Park H.-g. Jew S.-s. J. Org. Chem.  2006,  71:  8276 
    Google Scholar
  • 6 Mahler SG. Serra GL. Antonow D. Manta E. Tetrahedron Lett.  2001,  42:  8143 
    CrossrefGoogle Scholar
  • 7a Corey EJ. Xu F. Noe MC. J. Am. Chem. Soc.  1997,  119:  12414 
    Google Scholar
  • 7b Park H.-g. Jeong B.-S. Yoo M.-S. Lee J.-H. Park M.-K. Lee Y.-J. Kim M.-J. Jew S.-s. Angew. Chem. Int. Ed.  2002,  41:  3036 
    Google Scholar
  • 7c Jew S.-s. Yoo M.-S. Jeong B.-S. Park H.-g. Org. Lett.  2002,  4:  4245 
    Google Scholar
  • 7d Ooi T. Kameda M. Maruoka K. J. Am. Chem. Soc.  2003,  125:  5139 
    Google Scholar
  • 8 Terashima S. Achiwa K. Yamada S.-i. Chem. Pharm. Bull.  1965,  13:  1399 
    Google Scholar
  • 9 Procopiou PA. Ahmed M. Jeulin S. Perciaccante R. Org. Biomol. Chem.  2003,  1:  2853 
    CrossrefGoogle Scholar
10

Representative Procedure for the Enantioselective Alkylation (Benzylation) of tert -Butyl 2-Phenyl-5,6-dihydro-4 H -1,3-oxazine-4-carboxylate (7)
To a solution of tert-butyl 2-phenyl-5,6-dihydro-4H-1,3-oxazine-4-carboxylate (7, 50 mg, 0.2 mmol) in toluene (1.0 mL) were successively added the chiral PTC 16 (11 mg, 0.02 mmol), solid KOH (54.1 mg, 1.0 mmol), and benzyl bromide (0.1 mL, 1.0 mmol) at 0 ˚C. The reaction mixture was stirred for 1 h at 0 ˚C. After completion of the reaction, the reaction mixture was diluted with EtOAc (20 mL), and the EtOAc solution was washed with brine (2 × 5 mL). The organic solution was then dried over anhyd MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2; hexanes-EtOAc, 50:1) to afford the benzylated product 9d (47 mg, 70% yield) as a pale yellow oil. Because the two enantiomers of 9d were not fully separated by chiral HPLC, the enantioselectivity was determined by the chiral HPLC analysis of the corresponding methyl ester which was prepared from the hydrolysis of 9d followed by methylation using the excess of diazomethane. The enantioselectivity was determined as 97% ee [Chiralcel AD-H column, hexanes-2-PrOH (95:5), flow rate = 1.0 mL/min, 23 ˚C, 254 nm, t R (R, major) = 5.2 min; t R (S, minor) = 6.8 min, 97% ee]. Absolute configu-ration was tentatively determined as R based on the absolute configuration of 9a.