A Versatile Strategy for the Synthesis of N-Acetyl-bacillosamine-Containing Disaccharide Building Blocks Related to Bacterial O-Antigens

Emiliano Bedini; Davide Esposito; Michelangelo Parrilli

doi:10.1055/s-2006-939057

LETTER

A Versatile Strategy for the Synthesis of N-Acetyl-bacillosamine-Containing Disaccharide Building Blocks Related to Bacterial O-Antigens

Emiliano Bedini*, Davide Esposito, Michelangelo Parrilli
Dipartimento di Chimica Organica e Biochimica, Università di Napoli ‘Federico II’, Complesso Universitario Monte Santangelo, Via Cintia 4, 80126 Napoli, Italy
Fax: +39(81)674393; e-Mail: ebedini@unina.it;

Abstract

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Abstract

A N-phenyltrifluoroacetimidate glycosyl donor of bacillosamine, a 2,4-diaminosugar contained in several O-antigens from pathogenic bacteria, was synthesized starting from the known peracetylated d-fucal and was demonstrated to be effective for the high-yield coupling to bacillosamine-containing disaccharides. The stereoselectivity of the glycosylations was from moderate to very good depending on the solvent and glycosyl acceptor. The synthetic path was then slightly modified to obtain a similar glycosyl donor with an axial acetyl group on position 4. This building block could be coupled to give a disaccharide, that after five steps (azido reduction, acetylation, O-deacetylation, mesylation, and azide substitution) afforded a bacillosamine-containing disaccharide with differently protected amino functions, in order to provide access to all the currently known structural features of bacillosamine-containing disaccharides known to date contained in natural polysaccharides.

Key words

carbohydrates - O-antigens - aminosugar - bacillosamine - glycosylation

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References and Notes

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Glycosylation Procedure C: A mixture of acceptor (0.044 mmol) and donor (0.057 mmol) was co-evaporated three times with toluene, the residue was then mixed with freshly powdered AW-300 4 Å molecular sieves and suspended under argon in CH₂Cl₂ (1.0 mL). The mixture was cooled and stirred at 0 °C and a 28 mM solution of TMSOTf in CH₂Cl₂ (50 µL) was added. After completion of the reaction (TLC analysis), the mixture was neutralized by adding a few drops of Et₃N. The mixture was then filtered through a pad of Celite and concentrated to give a residue that was purified by column chromatography. Glycosylation Procedure D: A mixture of acceptor (0.044 mmol) and donor (0.077 mmol) was co-evaporated three times with toluene, the residue was then mixed with freshly powdered AW-300 4 Å molecular sieves and suspended under argon in CH₃CN (1.0 mL). The mixture was cooled and stirred at 0 °C and TMSOTf (1.3 µL, 7.7 µmol) was added and the temperature was allowed to rise gradually to r.t. After completion of the reaction (TLC analysis), the mixture was worked up as for Procedure C.

Compound 8α: [α]_D +109.3 (c 1.2, CH₂Cl₂). ¹H NMR (CDCl₃, 300 MHz): δ = 7.43-7.33 (m, 10 H, ArH), 6.01 (m, 1 H, CH₂CH=CH₂), 5.33 (dd, 1 H, J _vic = 17.7 Hz, J _gem = 1.8 Hz, OCH₂CH=CH _transH), 5.25 (dd, 1 H, J _vic = 10.2 Hz, J _gem = 1.8 Hz, CH₂CH=CH _cisH), 5.02 (d, 1 H, J _1,2 = 3.6 Hz, H-1_B), 4.87 (d, AB, 1 H, J _gem = 10.8 Hz, CHHPh), 4.83 (d, AB, 1 H, J _gem = 10.8 Hz, CHHPh), 4.79 (d, 1 H, J _gem = 11.1 Hz, CHHPh), 4.71 (d, 1 H, J _gem = 1.5 Hz, H-1_A), 4.61 (d, 1 H, J _gem = 11.1 Hz, CHHPh), 4.19 (m, 2 H, CH ₂CH=CH₂), 4.00 (dd, 1 H, J _3,4 = 9.3 Hz, J _3,2 = 3.0 Hz, H-3_A), 3.86 (m, 2 H, H-3_B, H-5_B), 3.76 (dd, 1 H, J _2,3 = 3.0 Hz, J _2,1 = 1.5 Hz, H-2_A), 3.65 (dq, 1 H, J _5,4 = 9.3 Hz, J _5,6 = 6.0 Hz, H-5_A), 3.57 (t, 1 H, J _4,5 = J _4,3 = 9.3 Hz, H-4_A), 3.36 (dd, 1 H, J _2,3 = 10.5 Hz, J _2,1 = 3.6 Hz, H-2_B), 3.33 (s, 3 H, OMe), 3.14 (t, 1 H, J _4,5 = J _4,3 = 9.3 Hz, H-4_B), 1.31 (d, 3 H, J _6,5 = 6.0 Hz, H-6_A), 1.18 (d, 3 H, J _6,5 = 6.0 Hz, H-6_B). ¹³C NMR (CDCl₃, 100 MHz): δ = 138.5, 138.0 (2 C_ipso), 134.7 (CH₂ CH=CH₂), 128.5-127.9 (ArC), 118.1 (OCH₂CH=CH₂), 98.4, 93.5 (C-1_A, C-1_B), 79.6, 78.4, 75.7, 75.3, 74.6, 73.2, 72.1, 68.9, 67.8, 66.6, 63.4 (C-2_A, C-2_B, C-3_A, C-3_B, C-4_A, C-4_B, C-5_A, C-5_B, CH₂Ph, CH₂CH=CH₂), 54.8 (OMe), 18.3, 18.0 (C-6_A, C-6_B). ESI-MS: m/z calcd for C₃₀H₃₈N₆NaO₇ [M + Na]⁺: 617.27; found: 617.10.
Compound 10α: [α]_D +62 (c 0.5, CH₂Cl₂). ¹H NMR (CDCl₃, 400 MHz): δ = 7.97-7.25 (m, 15 H, ArH), 5.96 (m, 1 H, CH₂CH=CH₂), 5.67 (dd, 1 H, J _3,4 = 10.0 Hz, J _3,2 = 3.2 Hz, H-3_A), 5.62 (t, 1 H, J _4,3 = J _4,5 = 10.0 Hz, H-4_A), 5.38 (dd, 1 H, J _vic = 17.2 Hz, J _gem = 1.6 Hz, OCH₂CH=CH _transH), 5.27 (dd, 1 H, J _vic = 10.8 Hz, J _gem = 1.6 Hz, CH₂CH=CH _cisH), 4.99 (d, 1 H, J _1,2 = 1.6 Hz, H-1_A), 4.95 (s, 2 H, CH ₂Ph), 4.88 (d, 1 H, J _1,2 = 3.6 Hz, H-1_B), 4.30 (m, 2 H, H-2_A, CHHCH=CH₂), 4.12 (m, 2 H, H-5_A, CHHCH=CH₂), 3.96 (t, 1 H, J _3,4 = J _3,2 = 9.6 Hz, H-3_B), 3.73 (dq, 1 H, J _5,4 = 9.6 Hz, J _5,6 = 6.4 Hz, H-5_B), 3.20 (dd, 1 H, J _2,3 = 9.6 Hz, J _2,1 = 3.6 Hz, H-2_B), 3.02 (t, 1 H, J _4,3 = J _4,5 = 9.6 Hz, H-4_B), 1.34 (d, 3 H, J _6,5 = 6.3 Hz, H-6_A), 1.34 (d, 3 H, J _6,5 = 6.4 Hz, H-6_B). ¹³C NMR (CDCl₃, 75 MHz): δ = 165.6, 165.5 (2 × COPh), 137.3, 135.0, 133.4, 133.3 (3 × C_ipso, CH₂ CH=CH₂), 129.6-126.3 (ArC), 117.8 (OCH₂CH=CH₂), 97.1, 96.0 (C-1_A, C-1_B), 78.7, 76.2, 75.3, 74.3, 71.3, 71.1, 68.5, 68.4, 67.1, 63.1 (C-2_A, C-2_B, C-3_A, C-3_B, C-4_A, C-4_B, C-5_A, C-5_B, CH₂Ph, CH₂CH=CH₂), 17.5, 17.4 (C-6_A, C-6_B). ESI-MS: m/z calcd for C₃₆H₃₈N₆NaO₉: 721.26 [M + Na]⁺; found: 720.89.
Compound 10β: [α]_D +40 (c 0.5, CH₂Cl₂). ¹H NMR (CDCl₃, 400 MHz): δ = 8.06-7.34 (m, 15 H, ArH), 5.95 (m, 1 H, CH₂CH=CH₂), 5.65 (m, 2 H, H-3_A, H-4_A), 5.37 (dd, 1 H, J _vic = 17.2 Hz, J _gem = 1.6 Hz, OCH₂CH=CH _transH), 5.30 (dd, 1 H, J _vic = 10.4 Hz, J _gem = 1.6 Hz, CH₂CH=CH _cisH), 5.05 (d, 1 H, J _1,2 = 1.6 Hz, H-1_A), 4.85 (d, 1 H, J _gem = 10.8 Hz, CHHPh), 4.73 (d, 1 H, J _gem = 10.8 Hz, CHHPh), 4.69 (br s, 1 H, H-2_A), 4.33-4.22 (3 H, H-1_B, CH ₂CH=CH₂), 4.08 (dq, 1 H, J _5,4 = 9.6 Hz, J _5,6 = 6.0 Hz, H-5_A), 3.51 (t, 1 H, J _3,4 = J _3,2 = 9.6 Hz, H-3_B), 3.08 (m, 3 H, H-2_B, H-4_B, H-5_B), 1.32 (d, 3 H, J _6,5 = 6.0 Hz, H-6_A), 1.27 (d, 3 H, J _6,5 = 6.0 Hz, H-6_B). ¹³C NMR (CDCl₃, 75 MHz): δ = 165.6, 165.4 (2 × COPh), 137.2, 133.5, 133.2, 133.0 (3 × C_ipso, CH₂ CH=CH₂), 129.7-128.4 (ArC), 117.7 (OCH₂CH=CH₂), 103.1, 98.3 (C-1_A, C-1_B), 80.9, 76.5, 75.9, 75.3, 71.7, 70.8, 68.2, 67.3, 66.7, 66.5 (C-2_A, C-2_B, C-3_A, C-3_B, C-4_A, C-4_B, C-5_A, C-5_B, CH₂Ph, CH₂CH=CH₂), 18.4, 17.7 (C-6_A, C-6_B). ESI-MS: m/z calcd for C₃₆H₃₈N₆NaO₉ [M + Na]⁺: 721.26; found: 720.93.
Compound 12α: [α]_D +127 (c 0.5, CH₂Cl₂). ¹H NMR (CDCl₃, 300 MHz): δ = 7.47-7.30 (m, 5 H, ArH), 5.55 (d, 1 H, J _1,2 = 3.3 Hz, H-1_B), 4.86 (app d, 3 H, H-1_A, CH ₂Ph), 4.28 (dd, 1 H, J _3,4 = 7.2 Hz, J _3,2 = 5.7 Hz, H-3_A), 4.11 (d, 1 H, J _2,3 = 5.7 Hz, H-2_A), 3.76-3.61 (m, 3 H, H-3_B, H-5_A, H-5_B), 3.49 (dd, 1 H, J _4,5 = 9.9 Hz, J _4,3 = 7.2 Hz, H-4_A), 3.37 (m, 4 H, H-2_B, OMe), 3.12 (t, 1 H, J _4,3 = J _4,5 = 9.9 Hz, H-4_B), 1.53 (s, 3 H, CH₃), 1.35 (s, 3 H, CH₃), 1.31 (d, 3 H, J _6,5 = 6.0 Hz, H-6_B), 1.28 (d, 3 H, J _6,5 = 6.3 Hz, H-6_A). ¹³C NMR (CDCl₃, 75 MHz): δ = 137.1 (C_ipso), 128.5-128.1 (ArC), 109.5 [C(CH₃)₂], 98.0, 95.6 (C-1_A, C-1_B), 78.3, 78.1, 77.1, 76.1, 75.4, 68.4, 66.9, 63.5, 54.8 (C-2_A, C-2_B, C-3_A, C-3_B, C-4_A, C-4_B, C-5_A, C-5_B, CH₂Ph), 27.9, 26.3 (2 × CH₃), 18.3, 18.1 (C-6_A, C-6_B). ESI-MS: m/z calcd for C₂₃H₃₂N₆NaO₇
[M + Na]⁺: 527.22; found: 526.99.
Compound 12β: [α]_D +20 (c 0.7, CH₂Cl₂). ¹H NMR (CDCl₃, 300 MHz): δ = 7.59-7.22 (m, 5 H, ArH), 4.90-4.79 (m, 3 H, H-1_A, CH ₂Ph), 4.37 (d, 1 H, J _1,2 = 8.1 Hz, H-1_B), 4.22 (dd, 1 H, J _3,4 = 7.2 Hz, J _3,2 = 5.7 Hz, H-3_A), 4.12 (d, 1 H, J _2,3 = 5.7 Hz, H-2_A), 3.72 (dq, 1 H, J _5,4 = 9.9 Hz, J _5,6 = 6.0 Hz, H-5_A), 3.45 (m, 2 H, H-2_B, H-4_A), 3.37 (s, 3 H, OMe), 3.26 (t, 1 H, J _3,4 = J _3,2 = 9.6 Hz, H-3_B), 3.20 (m, 2 H, H-4_B, H-5_B), 1.52 (s, 3 H, CH₃), 1.36 (m, 9 H, H-6_A, H-6_B, CH₃). ¹³C NMR (CDCl₃, 75 MHz): δ = 137.2 (C_ipso), 129.3-128.1 (ArC), 109.4 [C(CH₃)₂], 101.6, 98.0 (C-1_A, C-1_B), 82.2, 81.2, 76.0, 75.5, 71.0, 67.5, 66.8, 64.4, 54.9 (C-2_A, C-2_B, C-3_A, C-3_B, C-4_A, C-4_B, C-5_A, C-5_B, CH₂Ph), 28.1, 26.2 (2 CH₃), 18.3, 17.7 (C-6_A, C-6_B). ESI-MS: m/z calcd for C₂₃H₃₂N₆NaO₇
[M + Na]⁺: 504.23; found: 527.18.
Compound 14β: [α]_D +19 (c 0.7, CH₂Cl₂). ¹H NMR (CDCl₃, 300 MHz): δ = 7.41-7.25 (m, 20 H, ArH), 5.86 (m, 1 H, CH₂CH=CH₂), 5.23 (dd, 1 H, J _vic = 17.7 Hz, J _gem = 1.8 Hz, OCH₂CH=CH _transH), 5.17 (dd, 1 H, J _vic = 10.2 Hz, J _gem = 1.8 Hz, CH₂CH=CH _cisH), 4.91 (d, 1 H, J _1,2 = 1.8 Hz, H-1_A), 4.82-4.65 (m, 6 H, CHHPh), 4.58 (d, 1 H, J _gem = 11.4 Hz, CHHPh), 4.51 (d, 1 H, J _gem = 11.7 Hz, CHHPh), 4.31-4.15 (m, 3 H, H-1_B, H-4_A, CHHCH=CH₂), 3.99-3.77 (m, 6 H, H-2_A, H-3_A, H-5_A, H-6_A, CHHCH=CH₂), 3.23 (t, 1 H, J _2,1 = J _2,3 = 9.3 Hz, H-2_B), 3.06 (t, 1 H, J _3,2 = J _3,4 = 9.3 Hz, H-3_B), 3.02 (t, 1 H, J _4,3 = J _4,5 = 9.3 Hz, H-4_B), 2.89 (dq, 1 H, J _5,4 = 9.3 Hz, J _5,6 = 5.7 Hz, H-5_B), 1.16 (d, 3 H, J _6,5 = 5.7 Hz, H-6_B). ¹³C NMR (CDCl₃, 100 MHz): δ = 139.1, 138.5, 138.4, 137.6 (4 × C_ipso), 133.8 (CH₂ CH=CH₂), 129.7-127.0 (ArC), 117.3 (OCH₂CH=CH₂), 100.9, 97.4 (C-1_A, C-1_B), 81.6, 78.2, 75.5, 75.4, 75.3, 73.4, 72.8, 72.4, 71.5, 70.5, 68.9, 68.0, 67.8, 67.2 (C-2_A, C-2_B, C-3_A, C-3_B, C-4_A, C-4_B, C-5_A, C-5_B, C-6_A, 4 CH₂Ph, CH₂CH=CH₂), 18.3 (C-6_B). ESI-MS: m/z calcd for C₄₃H₄₈N₆NaO₈ [M + Na]⁺: 799.34; found: 799.01.

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Compound 16: [α]_D +48 (c 0.4, CH₂Cl₂). ¹H NMR (CDCl₃, 400 MHz): δ = 7.36-7.26 (m, 10 H, ArH), 6.01 (m, 1 H, CH₂CH=CH₂), 5.33 (dd, 1 H, J _vic = 17.2 Hz, J _gem = 1.5 Hz, OCH₂CH=CH _transH), 5.25 (dd, 1 H, J _vic = 10.3 Hz, J _gem = 1.5 Hz, CH₂CH=CH _cisH), 5.00 (d, 1 H, J _1,2 = 3.3 Hz, H-1_B), 4.81 (d, 1 H, J _gem = 12.6 Hz, CHHPh), 4.77 (d, 1 H, J _gem = 12.6 Hz, CHHPh), 4.75 (d, 1 H, J _gem = 11.3 Hz, CHHPh), 4.70 (m, 2 H, H-1_A, NH), 4.47 (d, 1 H, J _gem = 11.3 Hz, CHHPh), 4.21 (app d, 2 H, CH ₂CH=CH₂), 4.04 (dd, 1 H, J _3,4 = 9.8 Hz, J _3,2 = 3.2 Hz, H-3_A), 3.86-3.71 (m, 3 H, H-2_A, H-4_A, H-5_A), 3.66-3.56 (m, 2 H, H-4_B, H-5_B), 3.44 (t, 1 H, J _3,4 = J _3,2 = 9.8 Hz, H-3_B), 3.37 (m, 4 H, H-2_B, OMe), 1.61 (s, 3 H, NAc), 1.37 (d, 3 H, J _6,5 = 6.2 Hz, H-6_A), 0.97 (d, 3 H, J _6,5 = 6.2 Hz, H-6_B). ¹³C NMR (CDCl₃, 75 MHz): δ = 169.6, 139.5, 137.8, 134.7, 129.7, 125.9 118.2, 98.8, 92.7, 79.3, 76.9, 74.0, 73.3, 73.1, 72.4, 72.2, 67.8, 66.6, 63.1, 54.9, 54.7, 23.3, 17.9, 17.2. ESI-MS: m/z calcd for C₃₂H₄₂N₄NaO₈ [M + Na]⁺: 610.30; found: 633.19.

<A NAME="RG02806ST-33">33</A> Werz DB. Seeberger PH. Chem. Eur. J. 2005, 11: 3194