Shikimic acid Group Meeting Narendra Ambhaikar 1/12/2005 Biosynthetic pathway OPO3H2 HO CO H OH 2 OH OH CO2H O O phosphoenolpyruvic OH OH acid CO2H OH OH OH OH O OPO3H2 H2O3PO 3-deoxy-D-arabino- glucose H heptulosonic acid phosphate HO OH OH OH D-erythrose 4-phosphate (E4P) (-)-shikimic acid CO2H HO CO2H OH OH -Shikimic acid is a hydroaromatic intermediate in the common pathway of aromatic O OH O OH amino acid biosynthesis. OH OH 3-dehydroshikimic acid -First isolated in 1885 by Eykman from the fruit of Illicium religiosum. Found to exist 3-dehydroquinic acid widely in leaves of fruit of many plants and also in microorganisms, but in limited CO H CO H quantities. 2 2 HO CO2H -Relative and absolute stereochemistry realized only in 1930s through the works of Fischer, Freudenberg and Karrer. HO OH H2O3PO OH HO OH OH OH OH -It is mainly involved in the biosynthetic shikimate pathway operative in plants and (-)-shikimic acid shikimate 3-phosphate (-)-quinic acid microorganisms and discovered by Davis, Sprinson and Gibson. Three amino acids (L-phenylalanine, L-tyrosine and L-tryptophan) are synthesized along the pathway. Some molecules synthesized Some molecules synthesized from (-)-shikimic acid from (-)-quinic acid H -Available commercially (from Aldrich $58.00 per gram). Limited availability from HO OBz N H plants has led to the discovery of other synthetic and biosynthetic means to obtain HO O H N N 2 N Br shikimic acid. Recently reported to be derived from microbial fermentation of glucose O CO2Et using recombinant E. coli. Used as starting material for the synthesis of drug HN H BzO O AcHN CO2Me N molecules and natural products. H zeylenone MeO HO NH2.H3PO4 O N -There is great potential for the design and synthesis of enzyme inhibitors which may oseltamivir phosphate H selectively block specific enzyme-catalysed transformations along this pathway. HO OH dragmacidin F (Stoltz) OH OH OH pericosine B (Usami) CO2H OMe HO N References on recombinant microbial catalysis: 1) Draths, K. M.; Knop, D. R.; Frost, J. W. J. O NH MeO N Am. Chem. Soc.1999, 121, 1603. 2) Knop, D. R.; Draths, K. M.; Chandran, S. S.; Barker, J. 1α,dihydroxy-19-norprevitamin D3 H H H L.; von Daeniken, R.; Weber, W.; Frost, J. W. J. Am. Chem. Soc. 2001, 123, 10173. OH OH Leuenberger, H. G. W.; Matzinger, P. K.; Wirz, B. Chimia 1999, 53, 536. OH H HO OH OH MeO2C OR Reviews mycosporin-gly ii) Bohm, B. A. Chem. Rev. 1965, 65, 435. (-)-MK7607 (White) HO OH OMe ii)Campbell, M. M.; Sainsbury, M.; Searle, P. A.. Synthesis 1993, 179. HO OH OH (-)-reserpine iii) Jiang, S.; Singh, G. Tetrahedron 1998, 54, 4697. OH (+)-proto-quercitol (Hanessian) (Shih) Shikimic acid Group Meeting Narendra Ambhaikar 1/12/2005 SYNTHESIS OF SHIKIMIC ACID CO2Me CO2Me CO2Me CO2Me CO2Me CO2Me - Several syntheses have been reported. The following discussion will cover some of them. Br i) AgOAc, AcOH OH OH + H2O + + + Br OAc OAc ii) MeOH, HCl HO OAc HO OAc OAc OAc Synthesis of shikimic acid via Diels Alder reaction OAc OAc OAc OAc OAc OAc KOH, MeOH,H2O Raphael (1960) and Smissman (1959) - identical routes 20% 5% 1% 7% CO2H OAc OAc OAc OAc CO2H HO CO2Me O CO2Me CO2H hydroquinone OsO , Et O HO OH + 85-90 oC 4 2 HCl Py, CH2N2 HO acetone O OH OAc OAc OAc OAc (±)-shikimic acid 11% overall yield CO2H Grewe, R.; Hinrichs, I. Chem. Ber. 1964, 97, 443. o O CO2Me HO CO2H MgO, 290 C i) Ac2O, Py H2O, AcOH ii) (-)-quinine, MeOH iii) KOH, MeOH-H2O Koreeda (1982) O KOH, MeOH-H2O HO HO OH OAc OAc OH OAc OAc OAc OAc (−)-shikimic acid CO Me CO2Me HO CO2Me 2 HO CO Me 15% overall yield xylenes OsO , NMO 2 + (72%) 4 p-TsOH H2O (96%) McCrindle, R.; Overton, K. H.; Raphael, R. A. J. Chem. Soc. 1960, 1560. HO PhH (98%) Smissman, E. E.; Suh, J. T.; Oxman, M.; Deniels, R. J. Am. Chem. Soc. 1959, 81, 2909. SiMe3 SiMe3 SiMe3 OAc OAc CO2Me Smissman (1968) MCPBA i) HCl, MeOH HO CO2Me i) LiOH, THF-H2O AcO (91%) ii) Ac2O, Py CO2H ii) Ac2O, Py O O O O iii) DBU, THF PhH, heat OsO4, H2O2 HO H O, rt, 3 d HO AcO (54%) 2 65% AcO OAc + (67%) O O O O (66%) O O 71% O O OAc HO HO O (±)-shikimic acid OAc O OAc O OAc O OAc 29% overall yield 2-acetoxyfuran ketoacid Koreeda's 2nd generation synthesis employing Fleming oxidation O CO Me CO H OAc OAc O OAc O 2 i) soft glass powder 2 O hydroquinone i) NaBH i) MeOH, HCl TMS HO TMS 4 AcO AcO sealed tube, vac TMS monomethyl O O ii) Ac2O ii) Ac2O (57%) o ether (cat.), 256 - 258 C (92%) + O OsO , NMO xylenes (77%) 4 O ii) saponification (75%) (96%) OAc AcO OAc HO OH HO OAc OAc OH SiMe2Ph SiMe2Ph SiMe2Ph (±)-shikimic acid 3% overall yield OAc O O CO2H KBr , AcOOH HO TMS HO TMS AcOH, NaOAC O DBU, THF O Grewe (1964) (81%) (94%) n-Bu4NF HO HO (98%) HO OH CO2H i) hydroquinone CO2Me CO2Me toluene, 130 -140 oC i) AcOH, H2O2 then OH OH OH H O (85%) + (85%) 2 NBS, CCl4 ii) Ac O, Py (80%) (±)-shikimic acid 2 Koreeda, M.; Ciufolini, M. A. J. Am. Chem. Soc. 1982, 104, 2308. 55% overall yield ii) MeOH, c. H2SO4 OAc (97%) Koreeda, M.; Teng, K.; Murata, T. Tetrahedron Lett. 1990, 31, 5997. OAc Narendra Ambhaikar Shikimic acid Group Meeting 1/12/2005 From benzene (Birch, 1988) APPLICATIONS OF (-)-SHIKIMIC ACID IN SYNTHESIS (-)-zeylenone HO OBz CO H CO H - + - + 2 2 CO2 Ph NH3 CO2 Ph NH3 HO O Ph NH2 i) Me2SO4, KOH Me H Me H M Me H M +M BzO ii) Fe(CO)5, n-Bu2O iii) c. H2SO4 CHCl3-acetone - a polyoxygenated cyclohexene showing antiviral, anticancer and antibiotic activities isolated racemic complex mixture subjected to resolution from Uvaria grandiflora - + CO2 Ph NH3 CO2Me CO2Me CO2Me Ph3PF6 Me H i) aq. HCl, EtOH hexane NaHCO3, H2O Enantioselective synthesis of zeylenone from (-)-shikimic acid M M M + - ii) CH2N2, Et2O CH2Cl2 PF6 MeCN (95%) M (73%) OH 100% CSA, MeOH CO2 Me CO2 Me CO2Me CO2Me CO2Me CO2 Me CO2 Me i) TBDMSCl (MeCO)2 i-Pr2NEt (98%) TBDMSCl ii) Me NO (84%) OsO4 (67%) TBAF (85%) CH(OMe)3 + 3 CSA (93%) Im, DMAP O OH HO O (97%) OTBDMS HO OTBDMS HO OH HO OH TBDMSO O O O OH OH OH MeO O OMe (−)-methyl shikimate OMe OMe (-)-methyl shikimate OMe 10% 83% OMe M = Fe(CO)3, provides lateral control for enantiospecifically installing the hydroxy group CH OBz Birch, A. J.; Kelly, L. F.; Weerasuria, D. V.; J. Org. Chem. 1988, 53, 278. 2 O CH2OBz i) DIBAL-H (92%) i) OsO4, NMO (94%) O ii) BzCl, DMAP ii) Me2C(OMe)2, TsOH Py (97%) (99%) TFA/H O (1:1) Palladium mediated elimination reaction (Ogasawara, 2000) TBDMSO O 2 TBDMSO O (79%) CO2Me CO2Me CO2Me O OH OAc O i) TBSCl, Im, DMF OMe OMe OMe ii) AcCl, TEA, DMAP PdCl (PPh ) (cat.) 2 3 2 30% H2O2 OMe (81%) HCO2NH4, MeCN (79%) Triton B (75%) iii) TBAF, THF (80%) O O CH OBz O CH2OBz HO HO O CH2OBz 2 O O O CO2Me CO2Me CO2Me TBAF Ph3P, Im i) NaBH NaOH- I (87%) PhCO2H 4 2 (94%) BzCl, DMAP MeOH(79%) Ph O, 280 oC TBDMSO OH TBDMSO HO Py (99%) ii) BzCl, BuNCl,NaOH 2 BF3.OEt2 O toluene (59%) O BzO OH O cyclohexene O BzO HO CH2OBz exo-epoxide CH OBz CH OBz CO Me O 2 O 2 O 2 CO Me SeO2, THF HO 2 O (40%) O O TFA/H2O (9:1) CO2Me (85%) i) K2CO3, MeOH (72%) BzO ii) KOH, THF BzO BzO OBF O 3 HO OH (+)-zeylenone:CD spectra O BzO OH indicated (+)-antipode of the OH natural product OH Ph (−)-shikimic acid Yoshida, N.; Ogasawara, K. Org. Lett. 2000, 2, 1461. Liu, A.; Liu, Z. Z.; Zou, Z. M.; Chen, S. Z.; Xu, L. Z.; Yang, S. L. Tetrahedron, 2004, 60, 3689. Narendra Ambhaikar Shikimic acid Group Meeting 1/12/2005 Chiral syntheses of (-)-shikimic acid From carbohydrates CO2Me CO2Me CO2Me CO2Me HO HO SO2Cl2, Py -70 oC (78%) NaOMe O BzCl, Py (85%) OR MeOH OH O HO OH O BzO OBz BzO OBz HO OH HO acetone O OBn HO OH POCl , Py (75%) O c. H SO i) BnCl, NaH, DMF HO 3 2 4 OH OBz OBz OH (cat.) ii) c. HCl, MeOH, H2O NaIO4, H2O, rt OH OO HO OO (-)-methyl quinate (-)-methyl shikimate OH D-mannose O Cleophax, J.; Mercier, D.; Gero, S. D. Angew. Chem. Int. Ed. Engl. 1971, 10, 652. OBn O OBn O Cleophax, J.; Leboul, J.; Mercier, D.; Gaudemer, A.; Gero, S. D. Bull. Soc. Chim. Fr. 1973, 2992. OHC OBn HO F3CO2CSO (CF3SO2)2O o NaBH4, EtOH Py, CH2Cl2, -30 C OO 100% OO OO CO2Me lyxo-alcohol HO HO CO2Me (66% from D-mannose) HO CO2H CO t-Bu O OBn 2 CO2H butan-2,3-dione TBSOTf (MeO)2OP (MeO) CH, CSA HO O Et3N (97%) NaH i) Pd-C (10%), 3 TBSO O MeOH, D (79%) OMe (MeO)2OPCH2CO2t-Bu MeOH, H2 HO OH OMe t-BuO2C aq. TFA (100%) O O DMF, 15-crown-5 (81%) OOii) NaH, THF (73%, OH Me two steps) MeO Me O OH HO OH MeO (-)-quinic acid Me Me O OH butane diacetal (-)-shikimic acid 10 steps, 39% overall yield CO2Me CO2Me CO Me Fleet, G.