A Model Route Toward the Synthesis of Conformationally Constrained Polyhydroxylated Dipeptides from Natural Carbohydrates

Abstract

Enantiopure 6,7-diacetoxy-3-t-butoxycarbonylamino-azabicyclo[3.3.0]octan-2-one-8-carboxylic acid 14 (pyrrolizidi­none amino acid) was synthesized in 14 steps and 5.8% overall yield from tri-O-benzyl-d-arabinose 5 through the formyl C-iminosugar 9 as a key intermediate.

integrins - peptidomimetics - pyrrolizidinone amino ­acids - reverse-turn - RGD

References

1a Olson GL. Bolin DR. Bonner MP. Bös M. Cook CM. Fry DC. Graves BJ. Hatada M. Hill DE. Kahn M. Madison VS. Rusiecki VK. Sarabu R. Sepinwall J. Vincent GP. Voss ME. J. Med. Chem.  1993,  36:  3039 

1b Gante J. Angew. Chem., Int. Ed. Engl.  1994,  33:  1699 

2a Peptide Secondary Structure Mimetics In Tetrahedron Symposia-in-Print   Vol. 49:  Kahn M. Elsevier; Amsterdam: 1993.  p.3433-3689  

2b Hanessian S. McNaughton-Smith G. Lombart H.-G. Lubell WD. Tetrahedron  1997,  53:  12789 ; and references cited therein

3a Halab L. Gosselin F. Lubell WD. Biopolymers  2000,  55:  101 

3b Dietrich E. Lubell WD. J. Org. Chem.  2003,  68:  6988 

4a Gillespie P. Cicariello J. Olson GL. Biopolymers  1997,  43:  191 

4b Takeuchi Y. Marshall GR. J. Am. Chem. Soc.  1998,  120:  5363 

4c Belvisi L. Bernardi A. Manzoni L. Potenza D. Scolastico C. Eur. J. Org. Chem.  2000,  2563 

5a Lombart H.-G. Lubell WD. J. Org. Chem.  1994,  59:  6147 

5b Lombart H.-G. Lubell WD. J. Org. Chem.  1996,  61:  9437 

6a Polyak F. Lubell WD. J. Org. Chem.  2001,  66:  1171 

6b Feng Z. Lubell WD. J. Org. Chem.  2001,  66:  1181 

6c Artale E. Banfi G. Belvisi L. Colombo L. Colombo M. Manzoni L. Scolastico C. Tetrahedron  2003,  59:  6241 

7a Hruby VJ. Li G. Haskell-Luevano C. Shenderovich M. Biopolymers  1997,  43:  219 

7b Wang W. Yang J. Ying J. Xiong C. Zhang J. Cai C. Hruby VJ. J. Org. Chem.  2002,  67:  6353 

8a Gosselin F. Lubell WD. J. Org. Chem.  1998,  63:  7463 

8b Angiolini M. Araneo S. Belvisi L. Cesarotti E. Checchia A. Crippa L. Manzoni L. Scolastico C. Eur. J. Org. Chem.  2000,  2571 

8c Gosselin F. Lubell WD. J. Org. Chem.  2000,  65:  2163 

9a Haubner R. Schmitt W. Hölzemann G. Goodman SL. Jonczyk A. Kessler H. J. Am. Chem. Soc.  1996,  118:  7881 

9b Belvisi L. Bernardi A. Checchia A. Manzoni L. Potenza D. Scolastico C. Castorina M. Cupelli A. Giannini G. Carminati P. Pisano C. Org. Lett.  2001,  3:  1001 

9c Marinelli L. Lavecchia A. Gottschalk K.-E. Novellino E. Kessler H. J. Med. Chem.  2003,  46:  4393 

10a Haubner R. Finsinger D. Kessler H. Angew. Chem. Int. Ed.  1997,  36:  1374 

10b Gottschalk K.-E. Kessler H. Angew. Chem. Int. Ed.  2002,  41:  3767 

10c Hynes RO. Nature Med.  2002,  8:  918 

11 Another class of conformationally constrained polyhydroxylated dipeptides has been recently described, see: Tremmel P. Brand J. Knapp V. Geyer A. Eur. J. Org. Chem.  2003,  878 

12 Arap W. Pasqualini R. Ruoslahti E. Science  1998,  279:  377 

Compound 6 was prepared in gram scale quantities by stereoselective addition of 2-lithiothiazole to the nitrone derived from d-arabinose 5 followed by dehydroxylation of the resulting open-chain hydroxylamine and cyclization by intramolecular nitrogen-carbon bond formation via S_N2 process. See:

13a Dondoni A. Perrone D. Tetrahedron Lett.  1999,  40:  9375 

13b Dondoni A. Giovannini P. Perrone D. J. Org. Chem.  2002,  62:  7203 

14

Compound 7. [α]_D = +22.2 (c 1.2, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.74 (d, J = 3.3 Hz, 1 H, Th), 7.32-7.14 (m, 16 H, 3 × Ph, Th), 4.68, 4.50 (2 × d, 2 H, J = 11.7 Hz, PhCH ₂O), 4.58, 4.46 (2 × d, J = 11.7 Hz, 2 H, PhCH ₂O), 4.44 (d, J _2,3 = 4.8 Hz, 1 H, H-2), 4.27 (dd, J _3,4 = 4.5 Hz, 1 H, H-3), 4.16 (dd, J _4,5 = 6.6 Hz, 1 H, H-4), 4.01, 3.82 (2 × d, J = 13.7 Hz, 2 H, PhCH ₂N), 3.63 (dd, J _5,6 = 4.5 Hz, J _6,OH = 6.3 Hz, 2 H, 2 × H-6), 3.34 (dt, 1 H, H-5), 2.65 (t, 1 H, OH). Compound 8. [α]_D = +35.5 (c 0.5, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.68 (d, J = 3.3 Hz, 1 H, Th), 7.38-7.17, 7.00-6.96 (2 × m, 16 H, 3 × Ph, Th), 6.81-6.72 (m, 4 H, MeOPh), 4.69, 4.54 (2 × d, J = 11.8 Hz, 2 H, PhCH ₂O), 4.46 (d, J _2,3 = 2.5 Hz, 1 H, H-2), 4.37, 4.31 (2 × d, J = 11.9 Hz, 2 H, PhCH ₂O), 4.29 (dd, J _3,4 = 2.3 Hz, 1 H, H-3), 4.17 (dd, J _5,6a = 7.1 Hz, J _6a,6b = 9.0 Hz, 1 H, H-6a), 4.12 (dd, J _4,5 = 5.6 Hz, 1 H, H-4), 4.08, 3.99 (2 × d, J = 13.6 Hz, 2 H, PhCH ₂N), 3.92 (dd, J _5,6b = 5.1 Hz, 1 H, H-6b), 3.77 (s, 3 H, Me), 3.67 (ddd, 1 H, H-5). Compound 9. [α]_D = +2.5 (c 0.6, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 9.30 (d, J = 1.3 Hz, 1 H, CHO), 7.40-7.20, 7.16-7.11 (2 × m, 15 H, 3 × Ph), 6.84 (s, 4 H, MeOPh), 4.59, 4.51 (2 × d, J = 11.8 Hz, 2 H, PhCH ₂O), 4.44, 4.28 (2 × d, J = 11.7 Hz, 2 H, PhCH ₂O), 4.29 (dd, J _5,6a = 7.7 Hz, J _6a,6b = 9.3 Hz, 1 H, H-6a), 4.27, 3.76 (2 × d, J = 13.2 Hz, 2 H, PhCH ₂N), 4.11 (dd, J _2,3 = 1.2 Hz, J _3,4 = 1.5 Hz, 1 H, H-3), 4.10 (dd, J _4,5 = 4.3 Hz, 1 H, H-4), 4.09 (dd, J _5,6b = 5.3 Hz, 1 H, H-6b), 3.78 (s, 3 H, Me), 3.68 (ddd, 1 H, H-5), 3.38 (dd, 1 H, H-2). ¹³C NMR (100 MHz, CDCl₃): δ = 204.7 (C-1), 153.9, 153.0, 115.4, 114.6 (MeOPh), 138.8, 137.5, 137.4, 129.1-127.5 (3 × Ph), 84.2 (C-3), 80.0 (C-4), 76.2 (C-2), 71.8 (PhCH₂O), 71.4 (PhCH₂O), 67.2 (C-6), 66.2 (C-5), 60.7 (PhCH₂N), 55.8 (MeO).

15 Dondoni A. Marra A. Scherrmann M.-C. Bertolasi V. Chem.-Eur. J.  2001,  7:  1371 

16 Schmidt U. Lieberknecht A. Wild J. Synthesis  1984,  53 

17

Compound 11. [α]_D = -8.7 (c 0.8, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.34-7.18 (m, 20 H, 4 × Ph), 7.08 (br s, 1 H, NH), 6.81-6.72 (m, 4 H, MeOPh), 6.21 (d, J = 8.2 Hz, 1 H, CH=), 5.09, 5.01 (2 × d, J = 12.3 Hz, 2 H, PhCH ₂OCO), 4.51, 4.46 (2 × d, J = 11.8 Hz, 2 H, PhCH ₂O), 4.45 (s, 2 H, PhCH ₂O), 4.12 (dd, J _5,6a = 7.2 Hz, J _6a,6b = 9.4 Hz, 1 H, H-6a), 4.04 (dd, J _3,4 = 3.0 Hz, J _4,5 = 5.8 Hz, 1 H, H-4), 3.92 (dd,
J _5,6b = 4.7 Hz, 1 H, H-6b), 3.89, 3.80 (2 × d, J = 13.6 Hz,
2 H, PhCH ₂N), 3.89 (dd, J _2,3 = 4.8 Hz, 1 H, H-3), 3.78, 3.71 (2 × s, 6 H, 2 × Me), 3.56 (dd, 1 H, H-2), 3.44 (ddd, 1 H, H-5). Compound 13. [α]_D = -45.3 (c 0.4, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 6.86-6.79 (m, 4 H, MeOPh), 5.50 (dd, J _6,7 = J _7,8 = 7.7 Hz, 1 H, H-7), 5.19 (dd, J _5,6 = 7.3 Hz, 1 H, H-6), 4.94 (br d, J _3,NH = 5.5 Hz, 1 H, NH), 4.75 (dd, J _8,9a = 3.9, J _9a,9b = 10.0 Hz, 1 H, H-9a), 4.44 (dd, J _3,4a = 6.9 Hz, J _3,4b = 12.1 Hz, 1 H, H-3), 4.28 (ddd, J _8,9b = 1.0 Hz, 1 H, H-8), 3.87 (dd, 1 H, H-9b), 3.76 (s, 3 H, Me), 3.64 (dd, J _4a,5 = 5.3 Hz, J _4b,5 = 10.1 Hz, 1 H,, H-5), 2.96 (ddd, J _4a,4b = 11.8 Hz, 1 H, H-4a), 2.10, 2.02 (2 × s, 6 H, 2 × Ac), 1.96 (ddd, 1 H, H-4b), 1.41 (s, 9 H, t-Bu). Compound epi -13. [α]_D = -34.9 (c 0.7, CHCl₃). ¹H NMR (400 MHz, CDCl₃):
δ = 6.85-6.78 (m, 4 H, MeOPh), 5.52 (dd, J _6,7 = 7.8 Hz, J _7,8 = 7.6 Hz, 1 H, H-7), 5.12 (dd, J _5,6 = 7.6 Hz, 1 H, H-6), 5.04 (br s, 1 H, NH), 4.69 (dd, J _8,9a = 4.6 Hz, J _9a,9b = 10.2 Hz, 1 H, H-9a), 4.28 (ddd, J _8,9b = 1.6 Hz, 1 H, H-8), 4.05-3.97 (m, 2 H, H-3, H-5), 3.94 (dd, 1 H, H-9b), 3.75 (s, 3 H, Me), 2.48 (ddd, J _3,4a = 7.6 Hz, J _4a,4b = 13.6, J _4a,5 = 9.5 Hz, 1 H, H-4a), 2.34 (ddd, J _3,4b = 2.2 Hz, J _4b,5 = 6.8 Hz, 1 H, H-4b), 2.10, 1.99 (2 × s, 6 H, 2 Ac), 1.42 (s, 9 H, t-Bu). Compound 14 Methyl Ester. [α]_D =
-63.4 (c 0.3, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 5.61 (dd, J _6,7 = 9.3 Hz, J _7,8 = 8.2 Hz, 1 H, H-7), 5.10 (dd, J _5,6 = 8.4 Hz, 1 H, H-6), 5.08 (br d, J _3,NH = 7.0 Hz, 1 H, NH), 4.58 (d, 1 H, H-8), 4.53 (ddd, J _3,4a = 6.5 Hz, J _3,4b = 12.0 Hz, 1 H, H-3), 3.78 (s, 3 H, Me), 3.69 (ddd, J _4a,5 = 5.4 Hz, J _4b,5 = 9.5 Hz, 1 H, H-5), 3.02 (ddd, J _4a,4b = 12.5 Hz, 1 H, H-4a), 2.16 (ddd, 1 H, H-4b), 2.09, 2.06 (2 × s, 6 H, 2 × Ac), 1.43 (s, 9 H, t-Bu). ¹³C NMR (100 MHz, CDCl₃): δ = 173.4 (Me₃COCO), 173.3 (C-2), 170.4, 169.6 (CH₃ CO), 167.8 (CO₂Me), 80.1 (Me₃ C), 75.7 (C-7), 75.3 (C-6), 57.7 (C-5), 56.5 (C-8), 54.3 (C-3), 52.8 (MeO), 38.8 (C-4), 28.3 (Me ₃C), 20.6 and 20.3 (CH ₃CO).

18 Unnatural hetero-bifunctional ligands bearing the sialyl Lewis oligosaccharide and the RGD peptide sequence have been recently prepared, see: Matsuda M. Nishimura S.-I. Nakajima F. Nishimura T. J. Med. Chem.  2001,  44:  715 

The LDT-mediated binding between the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and its receptor, the α₄β₇ integrins, is responsible for the lymphocytes recruitment to inflamed colon. Cyclic peptidomimetics containing the LDT motif are inhibitors of this recognition process and therefore may lead to a new, organ specific treatment of inflammatory diseases.

19a Gottschling D. Boer J. Schuster A. Holzmann B. Kessler H. Angew. Chem. Int. Ed.  2002,  41:  3007 

19b Gottschling D. Boer J. Marinelli L. Voll G. Haupt M. Schuster A. Holzmann B. Kessler H. ChemBioChem  2002,  575