Synthesis of Novel Bicyclic Ketals of Galacturonic Acid as Potential Glycosidase Inhibitors

Michael Rommel; Alexander Ernst; Klaus Harms; Ulrich Koert

doi:10.1055/s-2006-939693

LETTER

Synthesis of Novel Bicyclic Ketals of Galacturonic Acid as Potential Glycosidase Inhibitors

Michael Rommel^a, Alexander Ernst^b, Klaus Harms^a, Ulrich Koert*^a
^a Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse, 35032 Marburg, Germany
Fax: +49(6421)2825677; e-Mail: koert@chemie.uni-marburg.de;
^b Schering AG, Medicinal Chemistry IV, Müllerstr. 178, 13342 Berlin, Germany

Abstract

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Abstract

A synthesis of novel bicyclic ketals of galacturonic acid is described. The key cyclisation step was realised under acidic anhydrous conditions in very good yield. X-ray crystal structure analysis determined the correct regio- and stereochemistry.

Key words

galactose - glycosidase inhibitors - bicyclic acetal/ketal - lactol Wittig reaction - δ-amino acids

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References

References and Notes

1

Current address: Polyphor AG, Gewerbestr. 14, 4123 Allschwil (BL), Switzerland.

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19

Preparation of (2 R ,3 S ,4 R ,5 S )-4,5-Di- O -benzyl-1,3- O -benzylidenehept-6-ene-1,2,3,4,5-pentaol.
A suspension of 4.79 g (13.4 mmol, 4.0 equiv) methyltri-phenylphosphonium bromide (purchased and stored in vacuo over P₂O₅) in 70 mL dry THF was cooled to -30 °C and 7.9 mL of a solution of n-BuLi in hexane (1.6 M, 12.7 mmol, 3.8 equiv) were added dropwise with a syringe. The reaction mixture turned to a clear yellow solution within 20 min. At the same temperature a solution of 1.50 g (3.35 mmol, 1.0 equiv) lactol 5 in 30 mL dry THF was added dropwise with a syringe. The syringe was washed with 2 × 2 mL THF. The reaction mixture was stirred for 24 h while the temperature gradually came to r.t. The resulting orange suspension was quenched with 100 mL H₂O and the layers were seperated. The aqueous layer was neutralised with 100 mL sat. NH₄Cl and extracted with 3 × 80 mL MTBE. The combined organic layers were washed with 2 × 50 mL sat. NH₄Cl, 50 mL H₂O and 50 mL brine, dried over MgSO₄ and the solvents were evaporated. The remaining sticky yellow oil was purified by flash column chromatography (100 g silica, 3:1 → 2:1 pentane-MTBE) giving 1.35 g (90%) of the corresponding alkene. The colourless oil solidified on standing at r.t. R _f = 0.19
(n-hexane-MTBE, 3:1); mp 76 °C; [α]_D ²⁰ +51.8 (c 3.29, CHCl₃). IR (KBr): 578 (w), 598 (w), 698 (vs), 749 (s), 811 (w), 844 (w), 886 (w), 926 (m), 951 (w), 1028 (s), 1089 (vs), 1216 (s), 1308 (m), 1340 (m), 1396 (s), 1454 (s), 1496 (m), 2866 (m), 3031 (m), 3064 (m), 3472 (br m). ¹H NMR (400 MHz, CDCl₃): δ = 2.86 (d, 1 H, J = 10.7 Hz, OH), 3.76 (dd, 1 H, J = 2.4, 8.7 Hz, 4-H), 3.84 (br d, 1 H, J = 10.1 Hz, 2-H), 4.05 (dd, 1 H, J = 1.1, 11.8 Hz, 5-H), 4.08 (dd, 1 H, J = 2.2, 6.8 Hz, 1-H^a), 4.19 (dd, 1 H, J = 1.0, 8.7 Hz, 3-H), 4.24 (dd, 1 H, J = 2.0, 11.9 Hz, 1-H^b), 4.34 (d, 1 H, J = 12.1 Hz, PhCH ₂), 4.69 (d, 1 H, J = 12.1 Hz, PhCH ₂), 4.70 (d, 1 H, J = 10.9 Hz, PhCH ₂), 4.78 (d, 1 H, J = 10.9 Hz, PhCH ₂), 5.27-5.38 (m, 2 H, 7-H₂), 5.40 (s, 1 H, PhCH), 5.96 (ddd, 1 H, J = 7.5, 10.2, 17.5 Hz, 6-H), 7.12-7.40 (m, 15 H, H_arom). ¹³C NMR (100 MHz, CDCl₃): δ = 63.4 (C-6), 70.6 (PhCH₂), 72.8 (C-7), 75.6 (PhCH₂), 77.8 (C-5), 78.3 (C-3), 79.9 (C-4), 101.2 (PhCH), 118.6 (C-1), 126.0 (2 C), 127.7, 127.9, 128.2 (2 C), 128.3 (2 C), 2 × 128.4 (4 C), 128.6 (2 C), 129.0 (CH_arom), 136.1 (C-2), 137.9, 138.3, 138.5 (C_{q arom}). HRMS (ESI): m/z calcd for C₂₈H₃₀NaO₅ [M + Na⁺]: 469.1985; found: 469.1978.

20 van Heeswijk WAR. Goedhart JB. Vliegenthart JFG. Carbohydr. Res. 1977, 58: 337

21

Preparation of (1 S ,3 R ,4 S ,5 S ,6 R )-1-Azidomethyl-3-( tert -butyldiphenylsilyloxymethyl)-5,6-dibenzyloxy-2,7-dioxabicyclo[2.2.1]heptane (9).
Powdered molecular sieves (2.30 g, 4 Å) were dried by heating in vacuo. Subsequently, 45 mL dry CH₂Cl₂ and 2.30 g (3.19 mmol) of ketone 8 were added. After the starting material had dissolved, 45 mL TFA were added in one portion at r.t. resulting in a yellow reaction mixture. TLC indicated complete conversion of the starting material within 25 min. The suspension was cooled to 0 °C, 20 mL dry toluene were added and the solvents were evaporated at the same temperature. The remaining solid was coevaporated twice with 10 mL dry toluene to remove traces of TFA. The pale pink crude product was purified by flash column chromatography (200 g silica, 7:1 pentane-MTBE) to yield 1.80 g (89%) of the bicyclic ketal 9 as colourless oil. R _f = 0.36 (n-hexane-MTBE, 3:1); [α]_D ²⁰ -1.1 (c 4.89, CHCl₃). IR (film): 607 (m), 700 (s), 739 (m), 823 (m), 998 (w), 1113 (s), 1283 (w), 1361 (w), 1428 (m), 1472 (w), 2104 (s), 2857 (m), 2930 (m), 3069 (w). ¹H NMR (500 MHz, CDCl₃): δ = 1.06 [s, 9 H, C(CH₃)₃], 3.40 (d, 1 H, J = 13.7 Hz, CH ^aH^bN₃), 3.55 (d, 1 H, J = 13.7 Hz, CH^a H ^bN₃), 3.57 (d, 1 H, J = 9.4 Hz, CH ^aH^bOR), 3.61-3.66 (m, 2 H, CH^a H ^bOR, 6-H), 3.80 (dd, 1 H, J = 9.2, 4.6 Hz, 3-H), 3.82 (t, 1 H, J = 1.5 Hz, 5-H), 4.45 (d, 1 H, J = 11.9 Hz, PhCH ₂), 4.53 (d, 1 H, J = 11.7 Hz, PhCH ₂), 4.55 (d, 1 H, J = 12.4 Hz, PhCH ₂), 4.58 (d, 1 H, J = 12.4 Hz, PhCH ₂), 4.74 (d, 1 H, J = 1.6 Hz, 4-H), 7.28-7.45 (m, 16 H, H_arom), 7.59-7.65 (m, 4 H, H_arom). ¹³C NMR (125 MHz, CDCl₃): δ = 19.4 [C(CH₃)₃], 27.0 [C(CH₃)₃], 48.7 (CH₂N₃), 63.1 (CH₂OR), 71.4, 73.1 (PhCH₂), 77.2 (C-3), 81.1 (C-4), 83.6 (C-6), 87.4 (C-5), 106.9 (C-1), 127.9 (2C), 2 × 128.0 (4 C), 128.2, 128.3 (3 C), 2 × 128.7 (4 C), 130.0 (2 C, CH_arom), 133.3, 133.4 (C_{q arom}), 135.6 (4 C, CH_arom), 137.4, 137.5 (C_{q arom}). HRMS (ESI): m/z calcd for C₃₇H₄₁N₃NaO₅Si [M + Na⁺]: 658.2708; found: 658.2701.

22a De Mico A. Margarita R. Parlanti L. Vescovi A. Piancatelli G. J. Org. Chem. 1997, 62: 6974

22b Vescovi A. Knoll A. Koert U. Org. Biomol. Chem. 2003, 1: 2983

23

Preparation of (1 R ,3 S ,4 R ,5 R ,6 R )-1-Aminomethyl-5,6-dihydroxy-2,7-dioxabicyclo[2.2.1]heptane-3-carboxylic Acid (1).
The amount of 120 mg (0.292 mmol, 1.0 equiv) of the azide 10 was dissolved under argon in 25 mL EtOAc-MeOH 2:1 (v/v, HPLC grade). Then, 819 mg (0.584 mmol, 2.0 equiv) Pd(OH)₂/C (wet, 20% Pd on dry basis, Degussa type E101 NE/W) were added, and the flask was evacuated five times with subsequent hydrogen insertion. Complete conversion was achieved within 90 min. The reaction mixture was filtered through a short column of Celite^® and it was washed with 5 × 5 mL MeOH. Evaporation to dryness gave 60 mg (quant.) of the title compound 1 as white foam in pure form. In order to get a powder for better handling, the foam was dissolved in 1 mL MeOH and precipitated by slow addition of 4 mL EtOAc. The suspension was centrifuged and the supernatant was decanted. The resulting white solid was washed with 4 mL Et₂O and dried in vacuo. R _f = 0.26
(n-BuOH-H₂O-HOAc 2:1:1); mp 140 °C (dec.); [α]_D ²⁰ +45.1 (c 0.35, H₂O). IR (KBr): 696 (w), 824 (w), 958 (m), 1035 (w), 1072 (m), 1170 (w), 1307 (w), 1429 (m), 1510 (w), 1602 (s), 2925 (m), 3401 (br vs). ¹H NMR (500 MHz, DMSO): δ = 3.19 (d, 1 H, J = 13.9 Hz, CH ^aH^bNH₂), 3.24 (d, 1 H, J = 13.7 Hz, CH^a H ^bNH₂), 3.60 (s, 1 H, 5-H), 3.71 (d, 1 H, J = 1.6 Hz, 6-H), 3.96 (s, 1 H, 3-H), 4.42 (s, 1 H, 4-H). ¹³C NMR (100 MHz, DMSO): δ = 36.6 (CH₂NH₂), 73.9 (C-3), 77.0 (C-6), 82.3 (C-5), 86.5 (C-4), 106.5 (C-1), 171.3 (COOH). HRMS (ESI): m/z calcd for C₇H₁₂NO₆ [M + H⁺]: 206.0659; found: 206.0660.

24

The crystal data of 1 has been deposited in the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 295618. Crystal Data: C₇H₁₁NO₆, M = 205.17, monoclinic, P2₁, a = 4.9367 (6) Å, b = 13.0534 (19) Å, c = 7.0289 (8) Å, α = 90°, β = 91.297 (13)°, γ = 90°, V = 452.83 (10) Å³, Z = 2, D _calcd = 1.505 g/cm³, 4497 collected reflections, 1760 independent (R _int = 0.0347), R1 = 0.0274, wR2 = 0.0703 (all data).