Synlett 2003(10): 1411-1414
DOI: 10.1055/s-2003-40820
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Facile Two-Step Synthesis of Novel Ring-A Double Substituted Tryptophan Building Blocks for Combinatorial Chemistry

Sofia Gorohovskya, Simcha Meira, Vladimir Shkouleva, Gerardo Bykb, Garry Gellerman*a
a Compugen Ltd., Chemistry Division, 11 Ha’Amal St., P.O.Box 3066, Ashkelon 78785, Israel
b Laboratory of Peptidomimetics and Genetic Chemistry, Department of Chemistry, Bar Ilan University, 52900-Ramat Gan, Israel
e-Mail: garyg@compugen.co.il.;
Further Information

Publication History

Received 31 March 2003
Publication Date:
24 July 2003 (online)

Abstract

A fast synthesis of ring-A disubstituted Fmoc and Boc protected l-tryptophan analogs was achieved starting from the appropriate 2,4- or 2,3-disubstituted phenylhydrazines and optically active N,N-diprotected l-glutamic acid γ-aldehydes, utilizing a Fischer-indole synthesis as a key step. Unlike most of the previously reported methods, that required the multistep stereoselective generation of a chiral carbon, this fast methodology is useful for generating optically active ring-A disubstituted protected tryptophans starting from a simple and common chiral precursor. These building blocks have a wide application scope in peptide and combinatorial chemistry fields.

    References

  • 1 Kobayashi J. Ishibashi M. Chem. Rev.  1993,  93:  1753 
  • 2 Braekman JC. Daloze D. Moussiaux B. J. Nat. Prod.  1987,  50:  99 
  • 3 Safdy ME. Kurchasova E. Schut RN. Vidro H. Hong E. J. Med. Chem.  1982,  25:  723 
  • 4 Wright CW. Allen D. Cai Y. Phillipson JD. Said IM. Kirby GC. Warhurst DC. Phytother. Res.  1992,  6:  121 
  • 5 Cook JM. LeQuesne PW. Phytochemistry  1971,  10:  437 
  • 6 Yamazaki M. Suzuki K. Fijimoto H. Akijama T. Sankawa U. Iitaka Y. Chem. Pharm. Bull.  1980,  28:  861 
  • 7 Botting N. Chem. Soc. Rev.  1995,  24:  401 
  • 8 Berk SC. Rohrer SP. Degrado SJ. Birzin ET. Mosley RT. Hutchins SM. Pasternak A. Schaeffer JM. Underwood DJ. Chapman KT. J. Comb. Chem.  1999,  1:  388 
  • 9 Liu R. Zhang P. Gan T. Cook JM. J. Org. Chem.  1997,  62:  7447 
  • 10 Ma C. Liu X. Li X. Flippen-Anderson J. Yu S. Cook JM. J. Org. Chem.  2001,  66:  4525 
  • 11 Allen MS. Hamaker LK. La Loggia AJ. Cook JM. Synth. Commun.  1992,  22:  2077 
  • 12 Zhang P. Cook JM. Synth. Commun.  1995,  25:  3883 
  • 13 Zhang P. Liu R. Cook JM. Tetrahedron Lett.  1995,  36:  9133 
  • 14 Schöllkopf U. Lonsky R. Lehr P. Liebigs Ann. Chem.  1985,  413 
  • 15 Masumi F. Takeuchi H. Kondo S. Suzuki K. Yamada S. Chem. Pharm. Bull.  1982,  30:  3831 
  • 16 Irie K. Ishida A. Nakamura T. Ohishi T. Chem. Pharm. Bull.  1984,  32:  2126 
  • 17 Schirlin D. Gerhart F. Hornsperger JM. Haman M. Wagner J. Jung MJ. J. Med. Chem.  1988,  31:  30 
  • 18 Bold G. Steiner H. Moesch L. Walliser B. Helv. Chim. Acta  1990,  73:  405 
  • 19 Kokotos G. Padron JM. Martin T. Gibbons WA. Martin VS. J. Org. Chem.  1998,  63:  3741 
  • 20 Constantinou-Kokotou V. Magrioti V. Markidis T. Kokotos G. J. Peptide Res.  2001,  58:  325 
  • 22 Gellerman G. Elgavi A. Salitra Y. Kramer M. J. Peptide Res.  2001,  57:  277 
  • 24a

    Commercially available 2,4-dimethylphenylhydrazine hydrochloride(5a) and 2,3-dimethylphenylhydrazine hydrochloride(5c) were purchased from Aldrich.

  • 24b Bare TM, Chapdelaine MJ, Davenport TW, Empfield JR, James R, Garcia-Davenport LE, Jackson PF, McKinney JA, McLaren CD, and Sparks RB. inventors; PCT Int. Appl., CODEN: PIXXD2 WO  9615127.  2-Methyl-4-methoxyphenylhydrazine hydrochloride(5b) was synthesized according to the procedure from: 1996
  • 24c 5-Ethyl-biphenyl-2-yl-hydrazine(5d) was prepared according to the procedure from: Katritzky A. Wang Z. J. Heterocycl. Chem.  1988,  25:  671 
  • 24d 5-Ethyl-biphenyl-2-ylamine was prepared according to procedure from: Bumagin NA. Luzikova EV. J. Organomet. Chem.  1997,  532:  271 
21

17 g (49.13 mmol) of 2 were dissolved in 300 mL of CH2Cl2. 53.60 g (245.65 mmol) of (Boc)2O, 147 mL (1.1 mol) of Et3N and 0.6 g (4.91 mmol) of DMAP were added under Ar atmosphere. The reaction mixture was stirred under Ar atmosphere for 3 days. The CH2Cl2 solution was washed with 0.35 M KHSO4 (3 × 50 mL) and water (3 × 50 mL). The solvent was evaporated under reduced pressure. The product 3 was purified by MPLC on RP18 to give 15.35 g (72%). 1H NMR (CDCl3) (δ ppm): 4.82 (m, 1 H), 3.66 (s, 3 H), 3.16 (s, 3 H), 2.47 (m, 3 H), 2.14 (m, 1 H), 1.50 (s, 9 H), 1.47 (s, 9 H), 1.45 (s, 9 H). MS (m/z): 447 (MH+).

23

5.11 g (13.2 mmol) of 4 and 2.28 g (13.2 mmol) of 2,4-dimethylphenyl hydrazine hydrochloride 5a were refluxed in 100 mL of iso-propanol for 5 h. The reaction mixture was cooled to r.t. and the solvent was evaporated under vacuum to give 4.5 g of crude mixture. Yields (according to HPLC): 26.9% of mono-Boc product 6 and 50.5% of di-Boc product 7. The mixture of 6 and 7 was dissolved in 40 mL dichloromethane. 100 µL of tri-iso-propyl silane and 40 mL of trifluoroacetic acid were added at 0 °C. The reaction mixture was stirred for 30 min at 0 °C and for 3 h at r.t. The solvent was evaporated and the residue was dissolved in 40 mL ACN/H2O (2:1) and DIEA (to pH = 9). Fmoc-OSu (3.14 g) was then added and the final mixture was stirred overnight at r.t. The reaction mixture was acidified with 5% HCl. Acetonitrile was evaporated and the product was extracted with EtOAc (3 × 30 mL). The organic phase was washed with NaHCO3 (3 × 30 mL), water and dried over MgSO4. The pure product was isolated after elution from a self-packed column RP-MPLC (LiChroprep RP-18, 40-63 µL Merck) using acetonitrile and water (0.1% of TFA), 2.7 g (46%).

25

Selected data for compounds 8a and 8d. 8a: 1H NMR (d 6-DMSO) (δ ppm): 12.65 (br s, COOH), 10.66 (br s, NH), 7.87 (d, 2 H, J = 7.5 Hz), 7.66 (d, 2 H, J = 7.2 Hz), 7.62 (s, NH), 7.38-7.42 (m, 2 H), 7.26-7.33 (m, 2 H), 7.14 (s, 1 H), 7.12 (d, 1 H, J = 1.8 Hz), 6.70 (s, 1 H), 4.18-4.21 (m, 4 H), 3.12-3.18 (m, 1 H), 2.96-3.01 (m, 1 H), 2.38 (s, 3 H), 2.33 (s, 3 H). HRMS (m/z): 455.1964 (MH+, calculated 455.1971 for C28H27N2O4). 8d: 1H NMR (d 6-DMSO) (δ ppm): 12.75 (br s, COOH), 10.65 (br s, NH), 7.87 (d, 2 H, J = 7.5 Hz), 7.60-7.75 (m, 5 H), 7.51 (t, 2 H, J = 7.5Hz), 7.37-7.40 (m, 4 H), 7.20-7.34 (m, 2 H), 7.17 (d, 1 H), 6.98 (d, 1 H, J = 1.2 Hz), 4.15-4.28 (m, 4 H), 3.19-3.25 (m, 1 H), 3.00-3.15 (m, 1 H), 2.72 (q, 2 H, J = 7.5 Hz), 1.28 (t, 3 H, J = 7.5Hz). HRMS
(m/z): 531.2281 (MH+, calculated 531.2284 for C34H31N2O4).

26

Selected data for compound 19: 1H NMR (d 6-DMSO) (δ ppm): 12.50 (br s, COOH), 10.66 (br s, NH), 7.10 (s, 1 H), 7.07 (d, NH), 6.92 (d, 1 H, J = 7.8 Hz), 6.69 (s, 1 H), 4.09-4.18 (m, 1 H), 3.04-3.11 (m, 1 H), 2.87-2.95 (m, 1 H), 2.36 (s, 3 H), 2.34 (s, 3 H), 1.33 (s, 9 H). HRMS (m/z): 333.1831 (MH+, calculated 333.1814 for C18H25N2O4).