3-位脱氧氨基糖和分枝糖的立体选择性合成研究
摘要
本论文通过研究5-O-苯甲酰基-1，2-O-丙叉基-3-位氧化木糖在合成方法学中的应用，开发出了合成3-位脱氧氨基糖和分枝糖的新方法。在3-位氧化木糖的芳胺亲核加成反应中，得到一系列的3-位脱氧氨基糖。并以硝基甲烷与3-位氧化木糖和2-位氧化葡萄糖苷的立体选择性Henry反应为基础，分别对3-硝甲基-3-位分枝木糖和2-硝甲基-2-位分枝葡萄糖苷进行加氢还原，合成了重要的3-氨甲基-3-位分枝核糖和2-氨甲基-2-位分枝甘露糖苷。取得的主要成果如下：
一、以硝基甲烷与3-位氧化木糖和2-位氧化葡萄糖苷的立体选择性Henry反应为基础，分别对其进行加氢还原，得到了重要的3-氨甲基-3-位分枝核糖12、13和2-氨甲基-2-位分枝甘露糖苷14。该反应为饱和脂肪族尤其是不稳定糖环上硝基的还原提供了一种新的方法，更为合成分枝糖和杂环化合物开辟了新的途径。所合成的化合物均经红外光谱、核磁共振谱及氢氢和碳氢二维谱图鉴定。
摘要
二、利用Schiff碱双键所处的手性环境，对其进行了立体专一性的NaBH4还原，合
成了一系列3一芳胺一3一位脱氧氨基糖。并通过氨基糖5一位轻基的氯化，为合成氮杂糖类
化合物提供了一条新的路径。该方法以资源丰富的D一木糖为原料，选择性高，较之已
有报道的合成方法更为经济有效，所合成的氨基糖类衍生物由于氨基取代基富于变化，
而可用于糖昔酶抑制剂的筛选。该系列化合物结构均经红外光谱、核磁共振谱和质谱鉴
定。其中有两个氨基糖衍生物的绝对构型经X一射线单晶衍射证实。
R二H .OCHs，F，CI，Br
(1)，(2)，(3)
R二H，OCH3，F.Cl，Br
R==H，H，H，Bz，H
(4)，(5).(6)，(7).(8)
R二F
(9)
综上所述，本研究开发了3一位氧化木糖在立体选择性合成氨基糖类衍生物、分枝糖
类衍生物及杂环化合物合成中的新用途。共合成出
物结构均经红外光谱、核磁共振波谱及质谱鉴定，
型经X一射线单晶衍射证实。
12种新型的糖类衍生物，所有化合
其中有两个氨基糖和分枝糖的绝对构
In this thesis, use for 5-O-benzoyl-l,2-O-isopropylidene-a-D-erythro-3-pentosulofuranose in synthetic methodology was discussed. Through studying on the nucleophilic addition of anilines to 5-O-benzoyl-l,2-O-isopropylidene-a-D-erythro-3-pentosulofuranose, some new ammo sugar analogues were obtained. Furthermore, 3-methylnitro ribofuranose and methyl 2-nitromethyl-2-deoxy a-D-mannopyranoside, which are important branched sugars, were prepared with highly stereoselectivity through Henry reaction. The main results obtained are as follows.
1. 3-methylnitro ribofuranoside and 2-methylnitro mannopyranoside were stereo-selective by Henry reaction, which were reduced to C-branched chain amino sugars in almost pure and comparable yield. This reaction provides an efficient method for reduction of aliphatic nitro compounds, especially the nitro group in unstable sugar ring. A new approach is developed to synthesis branched-chain sugar and azasugar. All of the compounds were characterized by IR, NMR, MS, HMBC and HMQC spectra.
2. The stereospecific reduction of C=N double bond has been also studied. When the compounds were reduced by sodium borohydride, five of 3-deoxy-3-arylamino sugars were achieved. And the chloridization of 5-OH in 3-deoxy -3- arylamino sugar led to the important synthon of azasugar. The configuration of the product was elucidated by the X-ray diffraction analysis. This reaction provides a new way to synthesis amino sugar derivatives which are the candidate of glucosidase inhibitor. In consideration of that the substrate we used was the most abundant D-xylose, this synthesis was more convenient to the others reported. All of the compounds were characterized by IR, NMR and MS spectra.
In summary, in this study a new method was developed for synthesis of amino sugars, branched-chain sugars and heterocycle compounds from 3-pentosulofuranose and 2 - keto a -D - glucopyranoside. Twelve new compounds were prepared in the work, and the structures were all characterized by IR, 'H-NMR, 13C-NMR and MS spectra.
一、以硝基甲烷与3-位氧化木糖和2-位氧化葡萄糖苷的立体选择性Henry反应为基础，分别对其进行加氢还原，得到了重要的3-氨甲基-3-位分枝核糖12、13和2-氨甲基-2-位分枝甘露糖苷14。该反应为饱和脂肪族尤其是不稳定糖环上硝基的还原提供了一种新的方法，更为合成分枝糖和杂环化合物开辟了新的途径。所合成的化合物均经红外光谱、核磁共振谱及氢氢和碳氢二维谱图鉴定。
摘要
二、利用Schiff碱双键所处的手性环境，对其进行了立体专一性的NaBH4还原，合
成了一系列3一芳胺一3一位脱氧氨基糖。并通过氨基糖5一位轻基的氯化，为合成氮杂糖类
化合物提供了一条新的路径。该方法以资源丰富的D一木糖为原料，选择性高，较之已
有报道的合成方法更为经济有效，所合成的氨基糖类衍生物由于氨基取代基富于变化，
而可用于糖昔酶抑制剂的筛选。该系列化合物结构均经红外光谱、核磁共振谱和质谱鉴
定。其中有两个氨基糖衍生物的绝对构型经X一射线单晶衍射证实。
R二H .OCHs，F，CI，Br
(1)，(2)，(3)
R二H，OCH3，F.Cl，Br
R==H，H，H，Bz，H
(4)，(5).(6)，(7).(8)
R二F
(9)
综上所述，本研究开发了3一位氧化木糖在立体选择性合成氨基糖类衍生物、分枝糖
类衍生物及杂环化合物合成中的新用途。共合成出
物结构均经红外光谱、核磁共振波谱及质谱鉴定，
型经X一射线单晶衍射证实。
12种新型的糖类衍生物，所有化合
其中有两个氨基糖和分枝糖的绝对构
In this thesis, use for 5-O-benzoyl-l,2-O-isopropylidene-a-D-erythro-3-pentosulofuranose in synthetic methodology was discussed. Through studying on the nucleophilic addition of anilines to 5-O-benzoyl-l,2-O-isopropylidene-a-D-erythro-3-pentosulofuranose, some new ammo sugar analogues were obtained. Furthermore, 3-methylnitro ribofuranose and methyl 2-nitromethyl-2-deoxy a-D-mannopyranoside, which are important branched sugars, were prepared with highly stereoselectivity through Henry reaction. The main results obtained are as follows.
1. 3-methylnitro ribofuranoside and 2-methylnitro mannopyranoside were stereo-selective by Henry reaction, which were reduced to C-branched chain amino sugars in almost pure and comparable yield. This reaction provides an efficient method for reduction of aliphatic nitro compounds, especially the nitro group in unstable sugar ring. A new approach is developed to synthesis branched-chain sugar and azasugar. All of the compounds were characterized by IR, NMR, MS, HMBC and HMQC spectra.
2. The stereospecific reduction of C=N double bond has been also studied. When the compounds were reduced by sodium borohydride, five of 3-deoxy-3-arylamino sugars were achieved. And the chloridization of 5-OH in 3-deoxy -3- arylamino sugar led to the important synthon of azasugar. The configuration of the product was elucidated by the X-ray diffraction analysis. This reaction provides a new way to synthesis amino sugar derivatives which are the candidate of glucosidase inhibitor. In consideration of that the substrate we used was the most abundant D-xylose, this synthesis was more convenient to the others reported. All of the compounds were characterized by IR, NMR and MS spectra.
In summary, in this study a new method was developed for synthesis of amino sugars, branched-chain sugars and heterocycle compounds from 3-pentosulofuranose and 2 - keto a -D - glucopyranoside. Twelve new compounds were prepared in the work, and the structures were all characterized by IR, 'H-NMR, 13C-NMR and MS spectra.
引文
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2) Sharon,N, Scientific American,1998,243,90
3) a. Varki,A.,Glycobiology,1993,3,97 b. Boons,G.J., Carbohydrate Chemistry, Blackie Academic Professional,London, 1998 c. Schmidt,R.R. A ngew. Chem. Int. ed. Engl., 1986,25,212
4) Cintas,P., Tetrahedron,1991,47,6079
5) Kunz,H., Pure Appl.Chem.,1995,67,1627
6) Hultin,P.G..;Earle,M.A.;Sudharshan,M., Tetrahedron,1997,53,14823
7) Ko K.-Y.; Kunz,H., Tetrahedron lett,1997,38,407
8) Follrnann,M.;Kunz,H., Synlett,1998,989
9) Weymann,M.;Schultz-kukula,M.;Kuna,H., Tetrahedron Lett.,1998,39,7835
10) Baer, E.;Fisher,H.O.L., J.Am. Chem.Soc.,1948,70,609
11) Jung,M.E. ;Shaw, T.J., J.Am. Chem. Soc., 1980,102,6304
12) Emons,C.H.H.;Kuster B.F.M.;Vekemans,J.A.J.M.;Sheldon,R.A., Tetrahedron Asymmetry, 1991,2,359
13) Carlsen,P.H.J.;Misund,K.;Roe.J., Acta Chem.Scand.,1995,49,297
14) Bock,K.;Lundt,I.;Pederson,C., A eta Chem. Scand.,1983,B37,341
15) Hollingsworth,R.I., Biotech.Ann. Rev.,1996,2,281
16) Hollingsworth,R.I., 1994,U.S.Patent 5,292,939
17) Osterveld,A.;Beldman G.;Schols,H.A., Carbohydr.Res.,1996,288,143
18) Cheng,Q.;Oritani.T.;Hassner, A., Synth. Commun.,2000,30,293
19) Mulzer, J.;Kermanchahi,A.K.;Buschmann,J.;Luger, P, Liebigs Ann. Chem.,1994,531
20) Qu,F.C.;Hong.J.H.;Du,J.F.;Newton,M.G.;Chu,C.K., Tetrahedron, 1999,55,9073
21) Goekjian,P.G. ;Wu,G.Z. ;Chen,S. ;Zhou,L.X. ;Jirouawk.M.R. ;Gillig,J.R. ;Ballas,L. M.;Dixon,J.T., J. Org. Chem.,1999,64,4238
22) Srisiri,W.;Lamparski,H.G.;Obrien,D.F., J. Org. Chem.,1996,61,5911
23) Wang,Y.F.;Li,J.C.;Wu,Y.L., Acta Chom.Sinica,1993,51,409
24) Pirrung,M.V.;Lee,Y.R., J.Am. Chem. Soc.,1995, 117,4814
25) Pearson,W.H.;Lovering,F.E., J. am. Chem.Soc.,1995,117,12336
26) Wei,C.C. ;Debernado, S. ;Tengi,J.P. ;Borgese,J. ;Weigele,M., J. Org. Chem., 1985,50,3462
27) Ruiz,M.;Ojea,V.;Quintela,J.M., Synlett,1999,204
28) Kang, S.H.;Kim,G.T., Tetrahedron Lett.,1995,36,5049
29) Shieh,H.M. ;Presteich,G. D., Tetrahedron Lett., 1982,23,4643
30) Wu,G.Z.;Chen,X.;Wong,Y.S.;Wu,G.;Wong,Y.;Chen,C.;Ding,Z., J. Org. Chem.,1999, 64,3714
31) Wang,G.J.,Hollingsworth,R.I., Tetrahedron Asymmetry,1999,10,1895
32) Scott,J.W.;Hollingsworth,R.I.,Tetrahedron Asymmetry,1999,10,1895
33) Hanessian, S., Total Synthetic of Natural Products. The chiron approach, Pergamon Press, Oxford,1986
34) Vasella,A.,in modern Synthetic Methods,R.E.D.Scheffold,Ed,Otto Salle Verlad,Frankfurt, 1980,2,173
35) Ferrier, R.J. ;Middleton,S.,Chem. Rev., 1993,93,2779
36) Berecibar, A.;Grandjean.C.;Siriwardena, A.,Chem.Rev.,1999,99,779
37) Deraadt,A. ;Ekhart.C.W. ;Ebner, M. ;Stutz,A.E.,Top. Curr. Chem.,1997,187,157
38) Platt,F.M. ;Butters,T.D.,Trends Glycosic. Glycotechnol.,1995,7,495
39) Ermolenko,M.S.;Pipelier, M.,Tetrahedron Lett.,1997,34,5975
40) Paquette.L.A.;Shin,T.L.;Zeng,Q.;Hofferberth,J.E.,Tetrahedron Lett.,1999,40,3519
41) Desire,J.;Prandi,J., Tetrahedron Lett.,1997,38,6189
42) Grove,J.J.C.;Holzapfel.C.W.;Williams.D.B.G..,Tetrahedron Lett.,1998,39,2857
43) Bennett,S.M.;Biboutou,R.K.;Salari,B.S.F.,Tetrahedron Lett.,1998,39,7075
44) Wood,A.J. ;Holt,D.J.;Dominguez.M.C.;Jenkins,P.R.,J. Org. Chem,1998,63,8522
45) Bar,N.C.;Poy, A.;Achari.B.;Mandal,S.B.,J. Org. Chem.,1997,62,8948
46) Kuhn.C.;Florent,J.C.,Tetrahedron Lett.,1998,39,4247
47) Marco-Contelles,J.;Gallego,P.;Rodriguez-Fenandez,M. ;Khiar, N.;Destabel,C.; Bernabe,M. ;Martinez-Grau,A. ;Chiara,J.L.,J. Org. Chem.,1997,62,7397
48) Golovchenko, V.V.; Ovodova, R.G.;Shashkov, A.S.;Ovodov, Y.S.Phytochemistry, 2002, 60, 89
49) Guo,S.G..;Kene,L.,Phytochemistry,2000,54,615
50) Sum Y. F. ;Koike, K. ;Guo,D. ;S atou,T. ;ILiu,J. S. ;Zheng,J. H. ;Nikaido,T., Tetrahedron, 2001,57,
6721
51) Rezanka,T. ;Guschina,I.A.,Phytochemistry, 2000,54,635
52) Williams,N.R.;Wander, J.D.,in the Crbohydrates Chemistry and Biochemistry, W.pigmaan and D. Horton, Academic Press,New York,2nd edu,1980,17
53) Adinolfi,M. ;Corsaro.M.M. ;Castro.C. ;Lanzetta,R.;Parrilli,M.,Carbohydr Res., 1995,274, 223
54) Adinolfi,M.; Corsaro.M.M.;Castro.C.;Lanzetta,R.;Parrilli,M.,Carbohydr.Res.,1996,284, 119
55) Danishefssky, S .J. ;Maring.C.J.,J. Am. Chem. Soc., 1959,111,2193
56) Charette.A.B. ;Cote,B.,J.Am. Soc.,1995,117,12721
57) Kang,J.;Lim,G.J.;Yoon,S.K.;Kin,M.Y.,J. Org.Chem.,1995,60,564
58) Nutt,R.F.;Dickinson,M.J.;Holly, F.W.;Walton,E.,J. Org. Chem.,1968,33,1789
59) Flaherty, B.;Nahar, S.;Overend,W.G.;Williams,N.R.,J. C.S.Perkinl,1973,632
60) Lu,Y.L.;Just,G., Tetrahedron, 2001,57,1677
61) Filichev, V.V.;Brandt,M. ;Pedersen,E.B., Carbohydr. Res.,2001,333,115
62) 梅尺纯夫，有机合成化学协会志，1996，24：85
63) Okruszek,A.,J.Med. Chem.,1979,22,882-885
64) Tsuda, Y.;Okuno,Y.;Iwaki,M.;Kanemitsu,K., Chem.Pharm.Bull.,1989,37,2673
65) Postel,D.;Nhien,A.N.V. ;Pillon,M. ;Villa,P. ;Ronco,G., Tetrahedron Lett., 2000,41,6403
66) Botta,O.;Moyroud,E.;Lobato,C. ;Strazewski,P.,Tetrahedron,1998,54,13529
2) Sharon,N, Scientific American,1998,243,90
3) a. Varki,A.,Glycobiology,1993,3,97 b. Boons,G.J., Carbohydrate Chemistry, Blackie Academic Professional,London, 1998 c. Schmidt,R.R. A ngew. Chem. Int. ed. Engl., 1986,25,212
4) Cintas,P., Tetrahedron,1991,47,6079
5) Kunz,H., Pure Appl.Chem.,1995,67,1627
6) Hultin,P.G..;Earle,M.A.;Sudharshan,M., Tetrahedron,1997,53,14823
7) Ko K.-Y.; Kunz,H., Tetrahedron lett,1997,38,407
8) Follrnann,M.;Kunz,H., Synlett,1998,989
9) Weymann,M.;Schultz-kukula,M.;Kuna,H., Tetrahedron Lett.,1998,39,7835
10) Baer, E.;Fisher,H.O.L., J.Am. Chem.Soc.,1948,70,609
11) Jung,M.E. ;Shaw, T.J., J.Am. Chem. Soc., 1980,102,6304
12) Emons,C.H.H.;Kuster B.F.M.;Vekemans,J.A.J.M.;Sheldon,R.A., Tetrahedron Asymmetry, 1991,2,359
13) Carlsen,P.H.J.;Misund,K.;Roe.J., Acta Chem.Scand.,1995,49,297
14) Bock,K.;Lundt,I.;Pederson,C., A eta Chem. Scand.,1983,B37,341
15) Hollingsworth,R.I., Biotech.Ann. Rev.,1996,2,281
16) Hollingsworth,R.I., 1994,U.S.Patent 5,292,939
17) Osterveld,A.;Beldman G.;Schols,H.A., Carbohydr.Res.,1996,288,143
18) Cheng,Q.;Oritani.T.;Hassner, A., Synth. Commun.,2000,30,293
19) Mulzer, J.;Kermanchahi,A.K.;Buschmann,J.;Luger, P, Liebigs Ann. Chem.,1994,531
20) Qu,F.C.;Hong.J.H.;Du,J.F.;Newton,M.G.;Chu,C.K., Tetrahedron, 1999,55,9073
21) Goekjian,P.G. ;Wu,G.Z. ;Chen,S. ;Zhou,L.X. ;Jirouawk.M.R. ;Gillig,J.R. ;Ballas,L. M.;Dixon,J.T., J. Org. Chem.,1999,64,4238
22) Srisiri,W.;Lamparski,H.G.;Obrien,D.F., J. Org. Chem.,1996,61,5911
23) Wang,Y.F.;Li,J.C.;Wu,Y.L., Acta Chom.Sinica,1993,51,409
24) Pirrung,M.V.;Lee,Y.R., J.Am. Chem. Soc.,1995, 117,4814
25) Pearson,W.H.;Lovering,F.E., J. am. Chem.Soc.,1995,117,12336
26) Wei,C.C. ;Debernado, S. ;Tengi,J.P. ;Borgese,J. ;Weigele,M., J. Org. Chem., 1985,50,3462
27) Ruiz,M.;Ojea,V.;Quintela,J.M., Synlett,1999,204
28) Kang, S.H.;Kim,G.T., Tetrahedron Lett.,1995,36,5049
29) Shieh,H.M. ;Presteich,G. D., Tetrahedron Lett., 1982,23,4643
30) Wu,G.Z.;Chen,X.;Wong,Y.S.;Wu,G.;Wong,Y.;Chen,C.;Ding,Z., J. Org. Chem.,1999, 64,3714
31) Wang,G.J.,Hollingsworth,R.I., Tetrahedron Asymmetry,1999,10,1895
32) Scott,J.W.;Hollingsworth,R.I.,Tetrahedron Asymmetry,1999,10,1895
33) Hanessian, S., Total Synthetic of Natural Products. The chiron approach, Pergamon Press, Oxford,1986
34) Vasella,A.,in modern Synthetic Methods,R.E.D.Scheffold,Ed,Otto Salle Verlad,Frankfurt, 1980,2,173
35) Ferrier, R.J. ;Middleton,S.,Chem. Rev., 1993,93,2779
36) Berecibar, A.;Grandjean.C.;Siriwardena, A.,Chem.Rev.,1999,99,779
37) Deraadt,A. ;Ekhart.C.W. ;Ebner, M. ;Stutz,A.E.,Top. Curr. Chem.,1997,187,157
38) Platt,F.M. ;Butters,T.D.,Trends Glycosic. Glycotechnol.,1995,7,495
39) Ermolenko,M.S.;Pipelier, M.,Tetrahedron Lett.,1997,34,5975
40) Paquette.L.A.;Shin,T.L.;Zeng,Q.;Hofferberth,J.E.,Tetrahedron Lett.,1999,40,3519
41) Desire,J.;Prandi,J., Tetrahedron Lett.,1997,38,6189
42) Grove,J.J.C.;Holzapfel.C.W.;Williams.D.B.G..,Tetrahedron Lett.,1998,39,2857
43) Bennett,S.M.;Biboutou,R.K.;Salari,B.S.F.,Tetrahedron Lett.,1998,39,7075
44) Wood,A.J. ;Holt,D.J.;Dominguez.M.C.;Jenkins,P.R.,J. Org. Chem,1998,63,8522
45) Bar,N.C.;Poy, A.;Achari.B.;Mandal,S.B.,J. Org. Chem.,1997,62,8948
46) Kuhn.C.;Florent,J.C.,Tetrahedron Lett.,1998,39,4247
47) Marco-Contelles,J.;Gallego,P.;Rodriguez-Fenandez,M. ;Khiar, N.;Destabel,C.; Bernabe,M. ;Martinez-Grau,A. ;Chiara,J.L.,J. Org. Chem.,1997,62,7397
48) Golovchenko, V.V.; Ovodova, R.G.;Shashkov, A.S.;Ovodov, Y.S.Phytochemistry, 2002, 60, 89
49) Guo,S.G..;Kene,L.,Phytochemistry,2000,54,615
50) Sum Y. F. ;Koike, K. ;Guo,D. ;S atou,T. ;ILiu,J. S. ;Zheng,J. H. ;Nikaido,T., Tetrahedron, 2001,57,
6721
51) Rezanka,T. ;Guschina,I.A.,Phytochemistry, 2000,54,635
52) Williams,N.R.;Wander, J.D.,in the Crbohydrates Chemistry and Biochemistry, W.pigmaan and D. Horton, Academic Press,New York,2nd edu,1980,17
53) Adinolfi,M. ;Corsaro.M.M. ;Castro.C. ;Lanzetta,R.;Parrilli,M.,Carbohydr Res., 1995,274, 223
54) Adinolfi,M.; Corsaro.M.M.;Castro.C.;Lanzetta,R.;Parrilli,M.,Carbohydr.Res.,1996,284, 119
55) Danishefssky, S .J. ;Maring.C.J.,J. Am. Chem. Soc., 1959,111,2193
56) Charette.A.B. ;Cote,B.,J.Am. Soc.,1995,117,12721
57) Kang,J.;Lim,G.J.;Yoon,S.K.;Kin,M.Y.,J. Org.Chem.,1995,60,564
58) Nutt,R.F.;Dickinson,M.J.;Holly, F.W.;Walton,E.,J. Org. Chem.,1968,33,1789
59) Flaherty, B.;Nahar, S.;Overend,W.G.;Williams,N.R.,J. C.S.Perkinl,1973,632
60) Lu,Y.L.;Just,G., Tetrahedron, 2001,57,1677
61) Filichev, V.V.;Brandt,M. ;Pedersen,E.B., Carbohydr. Res.,2001,333,115
62) 梅尺纯夫，有机合成化学协会志，1996，24：85
63) Okruszek,A.,J.Med. Chem.,1979,22,882-885
64) Tsuda, Y.;Okuno,Y.;Iwaki,M.;Kanemitsu,K., Chem.Pharm.Bull.,1989,37,2673
65) Postel,D.;Nhien,A.N.V. ;Pillon,M. ;Villa,P. ;Ronco,G., Tetrahedron Lett., 2000,41,6403
66) Botta,O.;Moyroud,E.;Lobato,C. ;Strazewski,P.,Tetrahedron,1998,54,13529