計畫編號：NSC92-2113-M032-004研究期間：200308~200407研究經費：827,000[[sponsorship]]行政院國家科學委員

施增廉

計畫編號：NSC92-2113-M032-004研究期間：200308~200407研究經費：827,000行政院國家科學委員

Tamkang University Institutional Repository

????????????????  ????   ?? D-quinic acid??????glycosidase?????????   ?????????? ?????NSC92-2113-M-032-004- ?????92?08?01??93?07?31? ????????????     ?????????  ?????????? ???     ?????????  ?????????????     ? ? ? ? 93?8?13?  1??:??????????????? (digestion)????????? (biosynthesis of glycoproteins)?????????? (oligosaccharides)????????????????????? (glycosidase catalyzed reactions)??????? ?????????????? (glycosidase)?????????????????? (? 1)1??????????? (lysis)?????肽????? (glycosidic linkage)????????????? (intermediate oxonium ion)?????????????????????????  OHOHOOHOHO RHOCOENZOCOENZOR'H+ OOHHOHOOH+- OR--(stable) ? 1. ?????? (glycoside)????  ???????????????????????????????????????????????????????????  (glycosidase inhibitors)???????????????? 2??? 3?????????? 4????   ???? ?????? polyhydroxylated piperidines ?????????????????????????????????????????????????????????????? 5???????????? Polyhydroxylated piperidines?????????? (hexoses)??????????????? azasugars? iminosugars5????????????????????? 1????? azasugars ???? (protonated)???????? (mimic) D-glucose??????? (cationic intermediates)?????????????????? (enzymatic glycosidase modification)??? (? 2)1? OHOHOOHOHNHOHOOHOH HH ? 2. ????? oxonium(?)?????? azasugar(?)???????  2????????? (physiological)????????????? azasugar??????????? (active site)??????? (base residues) ?? 6???????????????? (hydroxyl groups)????????????? (hydrophilic region)??(binding)????????????? (amine)????????????? (? 3)7??????????????????????????????????????????????? 7?  -O2CNH2HOHOOHOHBB-O2C+B = base residues  ? 3. ???????????????????????  ???????????????????????? (glycosyl cation)??????????????? (steric)???????????????????????? 6??? azasugars ??????????????????????? glucosidase???? deoxynojirimycin (DNJ)8???-galactosidase??-mannosidase??????? 10?? mannosidase???? deoxymannojirimycin (DMJ)9? glucosidase??????? 10? ? ? ? ? ? ? 1 (1,4,5-trideoxy-1,5-imino-D-lyxohexitol)11 ? ? ? ?-D-glucosidase??-D-glucosidase ??-D-galactosidase ????????????? 11????????????????????????????????????????????????????????????????????????????????????????? D-(-)-quinic acid???????????????????? 12a,13a?????????? 1? 2,3-epi???? 2? 2,3,5-epi???? 3??? 2,5-epi???? 4??????????????????? (? 4)?   3NHOHOHHOHOOHnojirimycinNHOHOHHOOHDNJ DMJNHOHOHHOOHNHOHHOOH1NHOHHOOH2NHOHHOOH3NHOHHOOH4CO2HHOHOOHOHD-(-)-quinic acid325 ? 4. ????? azasugars???? D-(-)-quinic acid??????? 2?3?4  ??? 1?????????? 3-deoxy-D-hexose??????????????酶  (glucose isomerase)11???????????  (? 5)?????D-(-)-quinic acid??? (cis)12a??? (trans)13a??? diols????????????? enone12,13b??? enone? allylic alcohol? 13c,14?????? (amine)15???????????? 16 ?????????????? 17??????immonium ion???????????? pH?? 4??????????? 1??????????????????????????? trihydroxyl piperidines 2?3? 4?  OPOCO2HHOHOOHOHD-(-)-quinic acidPOOPNRPOOPNHRPOOOOPNR OHPOOHNH OHHOOPOHPOOPNRPOOP = different protecting groups*** ? 5. ?? 2,4,5-trihydroxyl piperidine????  4?? azasugar ????????????????  (highly oxygenated cyclohexane derivatives)??? quercitols????????????????????? quercitols???? sylvestre????????????????? 18?  ???????Balci??????? 1,4-cyclohexadiene???? (? 7)????(?)-proto-quercitol21?? Balci??(?)-proto-quercitol??????? CH2Cl2???? TPP (tetraphenylporphyrin)? O2????????? photooxygenation???? endoperoxides???? anti ???????? (LAH)?acetylation (Ac2O/pyridine) ? ? ? ? ? ? ? 38 ? ? ? ? ? dihydroxylation (KMnO4/MgSO4/EtOH/H2O)? acetylation (Ac2O/pyridine)????????NH3/MeOH?? deacetylation?????(?)-proto-quercitols????Balci????? syn? endoperoxide??????????????????? 42????????????????(?)-gala-quercitol21?  OOHOOOOHOO OOHOHOHHO OHOHO2OOOOHOAcOAcAcOO2, TPP, hν3) NH3 / MeOH(±)-proto-quercitolsyn anti1) LAH, or thiourea2) Ac2O / pyridine+anti1) KMnO4, MgSO42) Ac2O / pyridineCH2Cl2, 48 h, rt38OHOHHO OHOHOOOAcOAcAcO3) NH3 / MeOH(±)-gala-quercitol1) LAH, or thiourea2) Ac2O / pyridine1) KMnO4, MgSO42) Ac2O / pyridine42OOHsyn  ? 7. ??(?)-proto-quercitol??(?)-gala-quercitol????  ?????????????????(+)-proto-quercitol???????10???? trihydroxyl piperidines??????????? C4????? 22????????? 38?????? dihydroxylation (KMnO4/MgSO4/EtOH/H2O ?RuCl3·xH2O/NaIO4)21,31b?????(+)-proto-quercitol (? 8)?   5OHOHHO OHOH(+)-proto-quercitolOAcOAcAcO OOOHCO2HHOHOOHOHD-(-)-quinic acid10438  ? 8. (+)-proto-quercitols?????  Trihydroxyl piperidines????? ?? 5??????????????D-(-)-quinic acid?????? benzene????????????? PTSA???? Dean-Stark trap???????????? cyclohexanone???????????? 525????? 82% (????? 98%)???????? 5?? LAH???????? triol??? 612a,26????? 93% (? 10)???????? LAH????????????quench26???????????????????????????????????????????????????????????????????????????????????? 80%??????? Na2SO4?10H2O?????? 27??????????????? 93%?  CO2HHOHOOHOHPTSA, benzeneHOOOOO2.5 eq. LAHOOHOOHHOcyclohexanoneTHF, 0 oC to rtD-(-)-quinic acid82%93%reflux5 6  ? 9. ?? D-(-)-quinic acid????????? 6   ???? 6??MeOH?????NaIO4???? diol??????? hydroxy ketone????? 712a???? 80% (? 11)??????? 7?? CH2Cl2??triethylamine?????? 0 ?????? MsCl?????? 28???????????? enone???? 812b??? 89%???????????????????????? 12b,29 ????????????  (???????p-toluenesulfonyl chloride/pyridine???? 95%)??????????????? (???1-5??????5-6??)?   6OOHOOHHOOOOHO2 eq. NaIO4MeOH80%OOOCH2Cl23 eq. Et3N89%1.2 eq. MsCl0 oC to rt6 7 8  ? 10. ????? 6????? 8  ????? Luche’s reduction (NaBH4/CeCl3·7H2O/MeOH)???????????? 8???? 13c,14?? TLC?? (EtOAc/hexane = 1/1)????????Rf??? 0.4-0.6?????????????Rf??? 0.1?????????? allylic alcohols (? 12)?   OOOOOOHOOOHMeOH,  0 oC+NaBH4CeCl3·8 9 107H2O ? 11. ??? 8?? Luche’s reduction?????? allylic alcohols  ?????? 9? 10??????????????????????????????????????? allylic alcohol ??????????????????????? 36 (? 13)30a???? H1?????????????????? (J1,6a = J5,6a = 9.0 Hz, J1,6e = 4.5 Hz, J5,6e = 4.5 Hz)????? H1??????? pseudoaxial ??? 30a?????????????????????? 9? 10? 1H NMR????????????????????? H1????? pseudoequatorial? pseudoaxial????? 1H NMR?? (?? 5?7)??????????? H1????? H4? H5???????????????H1?  7OOOH1536OOOHH16H6eH6aOOOH37acetylationOOOAcOOOOCH1H4NOE HHH ? 12. ??? 36? 37???????? ??????????????? 3730b????????????????? 37?? acetylation30b??????? H4? H5? 1H NMR?????? 4.32 ppm??? irradiation??????????? NOE difference??????OAc??????? (δ = 1.92)??? (enhancement)????????????????????????????? H1???? pseudoequatorial??? 30b? ?????????????????? 9?? acetylation?????? 28 (? 14)??? 1H NMR??? H1?H4? H5???????????????????? H1? H6??????????J1,6a = 9.2 Hz, J1,6e = 4.8 Hz, J5a,6e = 4.8 Hz????????? NOESY ???? (?? 35)????? H1?H4? H5??????????????????????????????????????? 9? H1?? pseudoaxial?????? 10? H1? pseudoequatorial????????? 9?10 = 56%?41%?  OOOHOOOAc1.2 eq. Ac2O2894 eq. pyridine98%OOOAcH1H6aH6eH5a145 ? 13. ???? 9?? acetylation????? 28???????  ?????????? 9?? mesylation (MsCl/Et3N)???????chloride?? SN2?????? mesylated group??? allylic chloride15a (??? 11)??? 87% (? 15)?????? 11? NaN3/DMF???? 65 ??????azide??? SN2 ???? chloride15b ????? 12??? 85%???? 12 ???dihydroxylation21,31?????? 13????? 68%??? dihydroxylation ?? 8?????????????????????????????????????dihydroxylation???????? cyclohexyl? anti?? 36?  OOClCH2Cl2, 0 oC to rt5 eq. Et3N87%2.2 eq. MsClOOOHOON3OON3OHOHH2O, EtOH85%10 eq. NaN315-crown-5 (cat.)DMF, 65 oC1 eq. MgSO41 eq. KMnO468%9 1112 13  ? 14. ???? 9????? 13  ?????????????????? OsO4/NMO/tert-butanol ????31a?? dihydroxylation?????????? 13??????????????????????????????????? KMnO4/MgSO4 ?????21??????????????????????????????? (??65%-70%)? OON3OHOHMeOH OON3OOOONH OHXNaIO413 1415decomposedab Reagents and conditions: (a) H2 (1 atm), various catalysts, then NaBH3CN/MeOH/AcOH; (b) Pd/C, H2 (3 atm), then NaBH3CN/MeOH. ? 15. ?????? 13????????????  ??????????? 13???? NaIO4/MeOH?? 32 (? 16)??? TLC????? 14??? TLC????? (broad)??? crude? 1H NMR???????? δ = 9-10???????????? aldehyde?????????????????????????? 14?????????????? 15? 9????????Pd (5%-10%)/C?Raney Ni?Pd(OH)2/C? Lindlar’s catalyst????????????????????? 33a-d??? TLC ??? Rf?????????????? NaBH3CN??????????? crude? 1H NMR???????????????????????? (? 2-3 atm)?? 15b????????????????????  OON3OHOHOONHCbzOHOH1) H2, 10% Pd/C2) CbzCl, NaHCO3 (aq),78%NH OHHOOH1) 2 eq. NaIO4, MeOH2) NaBH3CN, AcOH, MeOHH2, 10% Pd/C6N HCl85%76%OONCbz OH132OONHBocOHOH1) 2 eq. NaIO4, MeOH2) NaBH3CN, AcOH, MeOHOONBoc OHLindlar's catalyst, H2, MeOH,Boc2O1620 21NHOHHO OH1234 5XOHNH2OHOH1817HOOONHBocOHOH1) 2 eq. NaIO4, MeOH2) NaBH3CN, AcOH, MeOH80% TFA76%90%191,4-dioxane ? 16. ????????????????? 2  ???????????? 13?????? (Lindlar’s catalyst)?????????????? 33d,33e (? 17)?????? Boc2O?? 33d????? 16???? 90%???? NaIO4/MeOH????? NaBH3CN/MeOH/pH 4?????? 1?????????????????????? 1H NMR???????????????????????????????????? (80% TFA)????????????????????? (????????)?????????????????????????????????????????????????????????????????????????????????(???? MeOH/CH2Cl2/10% NH4OH(aq) = 1/2/0.1-3/1/0.5 ??)???????? 1H NMR ????δ ?1.94-1.16 ?????????  10(methylene)???????????????????????????azasugar????????????????????? 1,11???????????????????? (??? 18)??????????????????????????????? 19? ???????????? 13 ??????? CbzCl ??? 1,33e????? 20???? 78%???????????????????????????? 21???? 76%????? (6N HCl)???? (Pd/C, H2)????? 1??????????? – ??? 2 (?? 85%)???? 2 ????? HMQC?HMBC (?? 18?19)???????????????????????????????? 1H-1H COSY ?????????????????????? H4?????? J4a,5 = 11.8 Hz, J4e,5 = 4.8 Hz??? H5?? axial???????NOESY?? (?? 17)? H5? H2?H3??????????????? H5?H2?H3??????????????? ?????????????????? 10??????? 2???????????????????? 3 (? 18)??????? 10 ?? mesylation15a????????????????????????????? 22??????????? 10?  OOClCH2Cl25 eq. Et3N2.2 eq. MsClOOOHXNHOHHOOH30 oC to rt or heat10 22steps ? 18. ???? 10??????? 3   ?? : ????????????????????????????TetrahedronLett. 2004, 45, 5751-5754 ??????????? 11 

Designs and Syntheses of Glycosidase Inhibitors and Analogues from D-Quinic Acid

http://tkuir.lib.tku.edu.tw:8080/dspace/bitstream/987654321/5561/1/922113M032004.pdf

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