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

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<A NAME="RG26703ST-11">11</A> 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 

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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:

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<A NAME="RG26703ST-14">14</A>

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).

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<A NAME="RG26703ST-16">16</A> Schmidt U. Lieberknecht A. Wild J. Synthesis  1984,  53 

<A NAME="RG26703ST-17">17</A>

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).

<A NAME="RG26703ST-18">18</A> 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.

<A NAME="RG26703ST-19A">19a</A> Gottschling D. Boer J. Schuster A. Holzmann B. Kessler H. Angew. Chem. Int. Ed.  2002,  41:  3007 

<A NAME="RG26703ST-19B">19b</A> Gottschling D. Boer J. Marinelli L. Voll G. Haupt M. Schuster A. Holzmann B. Kessler H. ChemBioChem  2002,  575