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DOI: 10.1055/s-2005-865226
Synthesis of the Phosphono Analogue of the Dimeric Subunit of Neisseria meningitidis Type A Capsular Polysaccharide
Publikationsverlauf
Publikationsdatum:
14. April 2005 (online)
Abstract
The development of a glycoconjugate vaccine against N. meningitidis type A bacterium is greatly hampered by the chemical lability of the phosphodiester bridges joining the N-acetyl mannosamine repeating units of its capsular polysaccharide. We describe the first synthesis of the phosphonodisaccharide α-d-ManpNAc-[1→CH2-P(O)(O-)→6]-β-d-ManpNAc-(1→O) (CH2)3NH2 as a stable analogue of the corresponding phosphate-bridged disaccharide. The key phosphonoester linkage is obtained by condensation of monosaccharide building blocks under Mitsunobu conditions. Moreover, the protected precursor of the target compound is suitably designed to allow further elongation and synthesis of higher oligomers.
Key words
carbohydrates - Mitsunobu reaction - phosphonates - protecting groups - glycoconjugate vaccines
- 1
Jones C. Carbohydrates in Europe 1998, 21: 10 -
2a
Lindberg AA. Vaccine 1999, 17: S28 -
2b
Morley SL.Pollard AJ. Vaccine 2002, 20: 666 -
3a
Gold R.Lepow ML.Goldschneider I.Gotschlich EC. J. Infect. Dis. 1977, 136: S31 -
3b
Reingold AL.Broome CV.Hightower AW.Ajello GW.Bolan GA.Adamsbaum C.Jones EE.Phillips C.Tiendrebeogo H.Yada A. Lancet 1985, 2: 114 -
4a
Pozsgay V. In Advances in Carbohydrate Chemistry and Biochemistry Vol. 56:Tipson RS.Horton D. Academic Press; New York: 2000. p.153 -
4b
Ravenscroft N.Jones C. Curr. Opin. Drug Discovery Dev. 2000, 3: 222 -
5a
Bishop CT.Jennings HJ. In The Polysaccharides Vol. 16:Aspinall GO. Academic Press; New York: 1982. p.292 -
5b
Jennings HJ. In Advances in Carbohydrate Chemistry and Biochemistry Vol. 41:Tipson RS.Horton D. Academic Press; New York: 1983. p.155 -
5c
Arndt B.Porro M. In Immunobiology of Proteins and Peptides VIAtassi MZ. Plenum Press; New York: 1991. p.129 -
6a
Schneerson R.Barrera O.Sutton A.Robbins JB. J. Exp. Med. 1980, 152: 361 -
6b
Robbins JB.Schneerson R.Anderson P.Smith DH. J. Am. Med. Assoc. 1996, 276: 1181 -
7a
Pozsgay V. J. Org. Chem. 1998, 63: 5983 -
7b
Pozsgay V.Chu C.Pannell L.Wolfe J.Robbins JB.Schneerson R. Proc. Natl. Acad. Sci. U.S.A. 1999, 96: 5194 - 8
Verez-Bencomo V.Fernandez-Santana V.Hardy E.Toledo ME.Rodriguez MC.Heynngnezz L.Rodriguez A.Baly A.Herrera L.Izquierdo M.Villar A.Valdés Y.Cosme K.Deler ML.Montane M.Garcia E.Ramos A.Aguilar A.Medina E.Toraño G.Sosa I.Hernandez I.Martinez R.Muzachio A.Carmenates A.Costa L.Cardoso F.Campa C.Diaz M.Roy R. Science 2004, 305: 522 -
9a
Bundle DR.Smith ICP.Jennings HJ. J. Biol. Chem. 1974, 249: 83 -
9b
Lemercinier X.Jones C. Biologicals 2000, 28: 175 - 10
Costantino P,Berti F,Norelli F, andBartoloni A. inventors; Int. Appl. WO 03/080678 A1. ; Chem. Abstr. 2003, 139, 275732 - Reviews:
-
11a
Engel R. Chem. Rev. 1977, 77: 349 -
11b
Nicotra F. In Carbohydrate MimicsChapleur Y. Wiley-VCH; Weinheim: 1998. p.67 -
11c
Compain P.Martin OR. Bioorg. Med. Chem. 2001, 9: 3077 - See also:
-
11d
Vargas LA.Miao LX.Rosenthal AF. Biochim. Biophys. Acta 1984, 796: 123 -
11e
Blackburn GM.Thatcher GR.Taylor GE.Prescott M.McLennan AG. Nucleic Acids Res. 1987, 15: 6991 -
11f
Biller SA.Forster C.Gordon EM.Harrity T.Scott WA.Ciosek CP. J. Med. Chem. 1988, 31: 1869 -
11g
Bartlett PA.Hanson JE.Giannousis PP. J. Org. Chem. 1990, 55: 6268 -
11h
Morgan BP.Scholtz JM.Ballinger MD.Zipkin ID.Bartlett PA. J. Am. Chem. Soc. 1991, 113: 297 -
11i
Orsini F.Di Teodoro E. Tetrahedron: Asymmetry 2002, 13: 1307 -
11l
Wen X.Hultin PG. Tetrahedron Lett. 2004, 45: 1773 -
12a
Cipolla L.Lay L.Nicotra F.Panza L.Russo G. J. Chem. Soc., Chem. Commun. 1995, 1993 -
12b
Casero F.Cipolla L.Lay L.Nicotra F.Panza L.Russo G. J. Org. Chem. 1996, 61: 3428 - 13
Draghetti V.Poletti L.Prosperi D.Lay L. J. Carbohydr. Chem. 2001, 20: 813 -
14a
Babirad SA.Wang Y.Kishi Y. J. Org. Chem. 1987, 52: 1370 -
14b
Kobertz WR.Bertozzi CR.Bednarski MD. Tetrahedron Lett. 1992, 33: 737 -
14c
Bertozzi CR.Bednarski MD. Tetrahedron Lett. 1992, 33: 3109 - 16
Staudinger H.Meyer J. Helv. Chim. Acta 1919, 2: 635 - 17
Garegg PJ.Samuelsson B. J. Chem. Soc., Perkin Trans. 1 1980, 2866 - 18
Wang MF.Crilley MML.Golding BT.McInally T.Robinson DH.Tinker A. J. Chem. Soc., Chem. Commun. 1991, 667 - 20
Müller B.Martin TJ.Schaub C.Schmidt RR. Tetrahedron Lett. 1998, 39: 509 - 21
Yang G.Ding X.Kong F. Tetrahedron Lett. 1997, 38: 6725 - 22
Malachowski WP.Coward JK. J. Org. Chem. 1994, 59: 7616 -
23a
Norbeck DW.Kramer JB.Lartey PA. J. Org. Chem. 1987, 52: 2174 -
23b
Campbell DA. J. Org. Chem. 1992, 57: 6331 -
23c
Malachowski WP.Coward JK. J. Org. Chem. 1994, 59: 7625 -
23d
Pungente MD.Weiler L. Org. Lett. 2001, 3: 643 -
23e
Borodkin VS.Milne FC.Ferguson MAJ.Nikolaev AV. Tetrahedron Lett. 2002, 43: 7821
References
All new compounds gave satisfactory analytical and spectroscopic data.
19Spectroscopic and analytical data of compound 11: [α]D 25 +20.7 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.37-7.19 (m, 15 H, Ph), 5.87 (d, 1 H, J = 9.3 Hz, NH), 4.65, 4.56 (each d, each 1 H, J gem = 11.7 Hz, CH 2 Ph), 4.55, 4.51 (each d, each 1 H, J gem = 11.9 Hz, CH 2 Ph), 4.46, 4.41 (each d, each 1 H, J gem = 11.5 Hz, CH 2 Ph), 4.36 (dt, 1 H, J 2,1 = 3.5 Hz = J 2,3, H-2), 4.16 (m, 1 H, H-1), 4.00 (dd, 1 H, J 5,6a = 5.1 = J 5,4, J 5,6b = 9.7 Hz, H-5), 3.82 (dd, 1 H, J 6a,6b = 10.0, H-6a), 3.78-3.69 (m, 3 H, H-3, H-4, H-6b), 3.74 (d, 3 H, J Me,P = 11.3 Hz, OMe), 3.71 (d, 3 H, J Me,P = 11.3 Hz, OMe), 2.13 (dt, 1 H, J 7a,1 = 9.3 Hz, J 7a,7b = 15.7 Hz = J 7a,P, H-7a), 2.04 (dt, 1 H, J 7b,1 = 4.0 Hz, J 7b,P = 15.7 Hz, H-7b), 1.87 (s, 3 H, COCH 3). 13C NMR (100.6 MHz, CDCl3): δ = 170.37 (CO), 138.39, 138.27, 137.74 (C ipso), 129.19-128.15 (Ph), 76.49 (C-3), 74.06 (C-5), 73.81, 73.35, 72.31 (3 CH 2 Ph), 72.31 (C-4), 68.79 (C-1), 68.69 (C-6), 53.26 (d, J OMe,P = 5.9 Hz, OMe), 52.60 (d, J OMe,P = 5.9 Hz, OMe), 45.28 (d, J 2,P = 14.8 Hz, C-2), 28.06 (d, J 7,P = 142.0 Hz, C-7), 23.71 (COCH3). 31P NMR (162 MHz, CDCl3): δ = 32.48. HRMS (MALDI): m/z calcd for C32H40NO8PNa: 620.2389 [M + Na+]; found: 620.2386; m/z calcd for C32H40NO8PK: 636.2129 [M + K+]; found: 636.2132.
24A fraction containing a single phosphorous diastereoisomer of 16 was isolated during column chromatography and fully characterized: [α]D 25 +8.1 (c 0.25, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 8.25 (br s, 1 H, NH), 7.46-7.25 (m, 25 H, Ph), 5.76 (br d, 1 H, NH), 5.28 (br s, 1 H, NH), 5.11 (s, 2 H, CH 2 Ph Z), 4.95, 4.60 (each d, each 1 H, J gem = 10.7 Hz, CH 2 Ph), 4.89 (1 H, overlapping signal, H-2), 4.89, 4.51 (each d, each 1 H, J gem = 10.9 Hz, CH 2 Ph), 4.66, 4.59 (each d, each 1 H, J gem = 11.8 Hz, CH 2 Ph), 4.49, 4.42 (each d, each 1 H, J gem = 11.9 Hz, CH 2 Ph), 4.45 (br s, 1 H, H-1), 4.37-4.29 (m, 2 H, H-2′, H-6a), 4.22 (br dd, 1 H, J 6a,6b = 12.0 Hz, H-6b), 4.14 (m, 1 H, H-1′), 4.04 (dd, 1 H, J 3 ′ ,4 ′ = 9.7 Hz, J 3 ′ ,2 ′ = 5.4 Hz, H-3′), 3.92-3.77 (m, 6 H, H-4, H-7a, H-4′, H-5′, H-6′a, H-6′), 3.75 (d, 3 H, J Me,P = 10.9 Hz, OMe), 3.69 (dd, 1 H, J 3,4 = 8.3 Hz, J 3,2 = 3.7 Hz, H-3), 3.58 (m, 1 H, H-7b), 3.38 (br d, 1 H, J 5,4 = 9.5 Hz, H-5), 3.27 (m, 2 H, H-9a, H-9b), 2.23-2.06 (m, 2 H, H-7′a, H-7′b), 1.84 (br s, 6 H, COCH 3 ), 1.78 (m, 2 H, H-8a, H-8b). 13C NMR (125.7 MHz, CDCl3): δ = 171.62 (CO), 169.82 (CO), 156.52 (CO Z), 138.21 (2 × C), 137.92, 137.61, 137.11 (C ipso), 128.73-127.80 (Ph), 99.57 (C-1), 79.88 (C-3), 75.92, 73.01, 71.81 (C-4, C-4′, C-5′), 75.24, 73.35, 72.80, 71.06 (4 CH2Ph), 74.51 (C-5), 73.75 (C-3′), 68.24 (C-1′), 68.21 (C-6′), 67.49 (C-7), 66.79 (d, J 6,P = 38.5 Hz, C-6), 66.54 (CH2Ph Z), 53.87 (d, J OMe,P = 6.8 Hz, OMe), 49.94 (C-2), 48.68 (d, J 2 ′ ,P = 12.8, C-2′), 38.46 (C-9), 30.81 (C-7′), 29.64 (C-8), 23.98 (COCH3), 23.31 (COCH3). 31P NMR (202.5 MHz, CDCl3): δ = 29.71. HRMS (ESI): m/z calcd for C57H70N3O15PNa: 1090.4436 [M + Na+]; found: 1090.4410.
25Spectroscopic and analytical data of compound 17: [α]D 25 -40.5 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.78 (br s, 1 H, NH), 7.34-7.20 (m, 30 H, Ph), 5.92 (d, 1 H, J = 8.9 Hz, NH), 5.14 (s, 2 H, CH 2 Ph Z), 4.98, 4.62 (each d, each 1 H, J gem = 10.8 Hz, CH 2 Ph), 4.98, 4.52 (each d, each 1 H, J gem = 10.8 Hz, CH 2 Ph), 4.80 (br dd, 1 H, H-2), 4.74, 4.50 (each d, each 1 H, J gem = 11.3 Hz, CH 2 Ph), 4.63-4.52 (m, 3 H, H-1, H-2′, H-6a), 4.54, 4.47 (each d, each 1 H, J gem = 11.4 Hz, CH 2 Ph), 4.42, 4.32 (each d, each 1 H, J gem = 12.1 Hz, CH 2 Ph), 4.26 (m, 1 H, H-1′), 4.18 (br dd, 1 H, J 6a,6b = 11.4 Hz, H-6b), 3.98-3.87 (m, 3 H, H-4, H-5′, H-7a), 3.81-3.79 (m, 3 H, H-3′, H-4′, H-6′a), 3.73 (dd, 1 H, J 6 ′ b,6 ′ a = 9.7 Hz, J 6 ′ b,5 = 2.9 Hz, H-6′b), 3.68 (dd, 1 H, J 3,2 = 3.5 Hz, J 3,4 = 9.4 Hz, H-3), 3.53 (br s, 1 H, H-7b), 3.39 (d, 1 H, J 5,4 = 9.5 Hz, H-5), 3,34 (m, 1 H, H-9a), 3.10 (m, 1 H, H-9b), 2.27 (dt, 1 H, J 7 ′ a,1 ′ = 10.2 Hz, J 7 ′ a,7 ′ b = 16.8 Hz = J 7 ′ a,P, H-7′a), 2.07 (1 H, overlapping signal, H-7′b), 2.07 (s, 3 H, COCH 3 ), 1.85 (s, 3 H, COCH 3 ), 1.73 (m, 2 H, H-8a, H-8b). 13C NMR (100.6 MHz, CDCl3): δ = 171.79 (CO), 169.88 (CO), 159.46 (CO Z), 138.34 (2 × C), 138.11, 138.02, 137.87 (2, C ipso), 128.58-127.66 (Ph), 97.27 (C-1), 80.12 (C-3), 76.82 (C-3′), 75.38, 73.86, 73.30, 71.37, 70.74 (5 CH2Ph), 73.86 (C-5), 73.10 (C-4′), 72.74 (C-4, C-5′), 71.05 (C-1′), 68.40 (C-6′), 67.62 (CH2Ph Z), 65.13 (d, J 6,P = 37.8 Hz, C-6), 62.09 (C-7), 49.47 (C-2), 48.90 (d, J 2 ′ ,P = 15.3, C-2′), 37.40 (C-9), 28.76 (d, J 7 ′ ,P = 147.6 Hz, C-7′), 27.21 (C-8), 23.42 (COCH3), 22.94 (COCH3). 31P NMR (202.5 MHz, CDCl3): δ = 24.83. HRMS (MALDI): m/z calcd for C63H73N3O15PNa: 1166.4677 [M + H+]; found: 1167.4669; m/z calcd for C63H73N3O15PNa2: 1188.4575 [M + H + Na+]; found: 1189.4552.
26Spectroscopic and analytical data of compound 1: [α]D 25 -17.8 (c 1.0, H2O). 1H NMR (400 MHz, D2O): δ = 4.94 (d, 1 H, J 1,2 = 1.7 Hz, H-1), 4.69 (1 H, overlapped by HDO signal, H-2), 4.51 (br dd, 1 H, H-2′), 4.38-4.23 (m, 3 H, H-1′, H-6a, H-6b), 4.17-4.08 (m, 2 H, H-3′, H-7a), 4.02-3.93 (m, 4 H, H-3, H-7b, H-6′a, H-6′b), 3.81-3.73 (m, 3 H, H-4, H-4′, H-5′), 3.66 (m, 1 H, H-5), 3.26 (br t, 2 H, J = 7.5 Hz, H-9a, H-9b), 2.40-2.27 (m, 2 H, H-7′a, H-7′), 2.22 (s, 3 H, COCH 3 ), 2.20 (s, 3 H, COCH 3 ), 2.11 (m, 2 H, H-8a, H-8b). 13C NMR (100.6 MHz, D2O): δ = 175.73 (CO), 174.60 (CO), 99.73 (C-1), 75.63 (C-5), 74.44, 67.70, 66.90 (C-4, C-4′, C-5′), 72.84 (C-1′), 71.86 (C-3), 69.57 (C-3′), 67.97 (C-7), 63.38 (C-6), 60.77 (C-6′), 53.27 (C-2), 53.05 (d, J 2 ′ ,P = 9.7 Hz, C-2′), 38.02 (C-9), 27.80 (d, J 7 ′ ,P = 134.6 Hz, C-7′), 26.85 (C-8), 22.31 (2 COCH3). 31P NMR (162 MHz, D2O): δ = 22.95. HRMS (ESI): m/z calcd for C20H38N3O13PNa: 582.2034 [M + H+]; found: 582.2035; m/z calcd for C20H37N3O13PNa2: 604.1853 [M + Na+]; found: 604.1857.