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Shikimic acid
Biosynthetic pathway
OH O CO2H OH OH OH OH H2O3PO OH OPO3H2 CO2H
phosphoenolpyruvic acid
OH O H
glucose
HO OH OH
(-)-shikimic acid
-Shikimic acid is a hydroaromatic intermediate in the common pathway of aromatic amino acid biosynthesis. -First isolated in 1885 by Eykman from the fruit of Illicium religiosum. Found to exist widely in leaves of fruit of many plants and also in microorganisms, but in limited quantities. -Relative and absolute stereochemistry realized only in 1930s through the works of Fischer, Freudenberg and Karrer. -It is mainly involved in the biosynthetic shikimate pathway operative in plants and microorganisms and discovered by Davis, Sprinson and Gibson. Three amino acids (L-phenylalanine, L-tyrosine and L-tryptophan) are synthesized along the pathway. -Available commercially (from Aldrich $58.00 per gram). Limited availability from plants has led to the discovery of other synthetic and biosynthetic means to obtain shikimic acid. Recently reported to be derived from microbial fermentation of glucose using recombinant E. coli. Used as starting material for the synthesis of drug molecules and natural products. -There is great potential for the design and synthesis of enzyme inhibitors which may selectively block specific enzyme-catalysed transformations along this pathway.
HO OH
O OH
OH
3-dehydroshikimic acid
CO2H CO2H
3-dehydroquinic acid
HO CO2H
OH
H2O3PO OH
OH
HO OH
OH
shikimate 3-phosphate
(-)-quinic acid
Br
zeylenone
oseltamivir phosphate
OH
dragmacidin F (Stoltz)
pericosine B (Usami) References on recombinant microbial catalysis: 1) Draths, K. M.; Knop, D. R.; Frost, J. W. J. Am. Chem. Soc.1999, 121, 1603. 2) Knop, D. R.; Draths, K. M.; Chandran, S. S.; Barker, J. L.; von Daeniken, R.; Weber, W.; Frost, J. W. J. Am. Chem. Soc. 2001, 123, 10173. Leuenberger, H. G. W.; Matzinger, P. K.; Wirz, B. Chimia 1999, 53, 536. Reviews ii) Bohm, B. A. Chem. Rev. 1965, 65, 435. ii)Campbell, M. M.; Sainsbury, M.; Searle, P. A.. Synthesis 1993, 179. iii) Jiang, S.; Singh, G. Tetrahedron 1998, 54, 4697.
HO OMe O
1,dihydroxy-19-norprevitamin D3
OH OH
HO
OH
(-)-MK7607
HO OH OH
mycosporin-gly HO (White)
(+)-proto-quercitol (Shih)
(-)-reserpine (Hanessian)
Narendra Ambhaikar
SYNTHESIS OF SHIKIMIC ACID
Shikimic acid
CO2Me CO2Me Br
i) AgOAc, AcOH H2 O
- Several syntheses have been reported. The following discussion will cover some of them. +
Br OAc OAc OAc
+
HO OAc OAc HO OAc
+
OAc OAc
+
OAc
Synthesis of shikimic acid via Diels Alder reaction Raphael (1960) and Smissman (1959) - identical routes
OAc OAc CO2H
hydroquinone 85-90 oC
KOH, MeOH,H2O
20%
5%
1%
7%
CO2H
OsO4, Et2O Py, CH2N2
HO HO OAc
O O OAc
CO2Me HO OH OH
+
OAc
OAc
()-shikimic acid 11% overall yield Grewe, R.; Hinrichs, I. Chem. Ber. 1964, 97, 443.
CO2H
MgO, 290 C
o
O O OAc
CO2Me
H2O, AcOH KOH, MeOH-H2O
HO HO OAc
CO2H
HO OH
OH
Koreeda (1982)
OAc CO2Me OAc CO2Me
xylenes (72%) OsO4, NMO H2O (96%)
()-shikimic acid 15% overall yield McCrindle, R.; Overton, K. H.; Raphael, R. A. J. Chem. Soc. 1960, 1560. Smissman, E. E.; Suh, J. T.; Oxman, M.; Deniels, R. J. Am. Chem. Soc. 1959, 81, 2909. Smissman (1968)
O O O
PhH, heat (67%)
OAc HO CO2Me
+
SiMe3
SiMe3 OAc
CO2Me
i) HCl, MeOH ii) Ac2O, Py O iii) DBU, THF
O
OsO4, H2O2 HO (54%)
CO2H
H2O, rt, 3 d (66%)
MCPBA (91%)
HO
AcO AcO O
HO O HO O OAc
O O
O OAc
O O
O OAc
O O
71%
AcO OAc
OAc
HO
2-acetoxyfuran
OAc
()-shikimic acid 29% overall yield Koreeda's 2nd generation synthesis employing Fleming oxidation
OAc O O TMS OAc O
hydroquinone monomethyl ether (cat.), xylenes (77%)
ketoacid
O CO2Me
i) soft glass powder sealed tube, vac 256 - 258 oC (92%) ii) saponification (75%)
CO2H
OAc O O TMS
OsO4, NMO (96%)
HO HO SiMe2Ph
+
HO OH OH SiMe2Ph
TMS
CO2H O TMS
n-Bu4NF (98%)
Grewe (1964)
CO2H i) hydroquinone
toluene, 130 -140 oC (85%) ii) MeOH, c. H2SO4 (97%)
HO HO OH
HO HO OH
CO2Me
CO2Me
NBS, CCl4
HO OH
OH
OAc OAc
Koreeda, M.; Ciufolini, M. A. J. Am. Chem. Soc. 1982, 104, 2308. Koreeda, M.; Teng, K.; Murata, T. Tetrahedron Lett. 1990, 31, 5997.
Narendra Ambhaikar
From benzene (Birch, 1988)
Shikimic acid
APPLICATIONS OF (-)-SHIKIMIC ACID IN SYNTHESIS (-)-zeylenone
HO HO BzO OBz O
CO2H
i) Me2SO4, KOH ii) Fe(CO)5, n-Bu2O iii) c. H2SO4
CO2H M Ph NH2 Me H
CHCl3-acetone
CO2- Ph Me M
NH3+ H
CO2- Ph Me
NH3+ H
+ M
racemic complex
CO2- Ph Me M NH3+ H
i) aq. HCl, EtOH ii) CH2N2, Et2O 100%
- a polyoxygenated cyclohexene showing antiviral, anticancer and antibiotic activities isolated from Uvaria grandiflora
CO2Me M M
CO2Me
NaHCO3, H2O MeCN (95%)
PF6-
M OH
CSA, MeOH
CO2Me
i) TBDMSCl i-Pr2NEt (98%) ii) Me3NO (84%) OsO4 (67%)
CO2Me
TBAF (85%)
CO2Me
CO2 Me
(MeCO)2 CH(OMe)3 CSA (93%)
CO2 Me
CO2 Me
CO2 Me
TBDMSCl Im, DMAP (97%)
+
O O OMe OH HO O OMe OMe O
OTBDMS
HO OH
OTBDMS
HO OH
OH
HO OH
OH MeO
TBDMSO O
O OMe OMe
()-methyl shikimate M = Fe(CO)3, provides lateral control for enantiospecifically installing the hydroxy group Birch, A. J.; Kelly, L. F.; Weerasuria, D. V.; J. Org. Chem. 1988, 53, 278.
(-)-methyl shikimate
CH2OBz
i) DIBAL-H (92%) ii) BzCl, DMAP Py (97%)
10%
83%
O CH2OBz
TBDMSO O
CO2Me OAc
PdCl2(PPh3)2 (cat.) HCO2NH4, MeCN (79%)
CO2Me
30% H2O2 Triton B (75%)
OMe OMe
HO CO2Me
HO CO2Me
i) NaBH4 NaOHMeOH(79%) ii) BzCl, BuNCl,NaOH toluene (59%) Ph2O, 280 C
o
O CO2Me
BF3.OEt2
O CH2OBz O
Ph3P, Im I2 (87%)
O CH2OBz O
TBAF PhCO2H (94%)
O CH2OBz O HO
BzCl, DMAP Py (99%)
TBDMSO OH
OH
TBDMSO
O BzO
BzO
O O CH2OBz
cyclohexene
O CH2OBz O TFA/H2O (9:1)
(85%)
exo-epoxide
CO2Me
CO2Me
O BzO
HO BzO
HO CH2OBz O
O BzO
OH
HO OH
OH
()-shikimic acid
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
CO2Me
BzCl, Py (85%)
HO
CO2Me
CO2Me
SO2Cl2, Py -70 oC (78%) OR NaOMe MeOH
CO2Me
O O O O O OH
HO O OBn
NaIO4, H2O, rt
HO OH
OH
BzO OBz
OBz
POCl3, Py (75%)
BzO OBz
OBz
HO OH
OH
(-)-methyl quinate
(-)-methyl shikimate
D-mannose
O OHC O OBn HO
NaBH4, EtOH
OBn
(CF3SO2)2O Py, CH2Cl2, -30 oC 100%
O F3CO2CSO O O
OBn
Cleophax, J.; Mercier, D.; Gero, S. D. Angew. Chem. Int. Ed. Engl. 1971, 10, 652. Cleophax, J.; Leboul, J.; Mercier, D.; Gaudemer, A.; Gero, S. D. Bull. Soc. Chim. Fr. 1973, 2992.
HO CO2t-Bu
aq. TFA (100%)
CO2H
butan-2,3-dione (MeO)3CH, CSA HO MeOH, D (79%)
HO
CO2Me
HO
TBSOTf Et3N (97%)
CO2Me
OBn
i) Pd-C (10%), MeOH, H2 O ii) NaH, THF (73%, two steps)
CO2H HO OH OH OH OH
O O MeO Me
OMe Me
TBSO O MeO Me
t-BuO2C
OMe Me
O O
OH
HO
(-)-quinic acid
butane diacetal
CO2Me
Fleet, G. W. J.; Shing, T. K. M.; Warr, S. M. J. Chem. Soc. Perkin Trans. I, 1984, 905.
Martin's sulfurane TBSO CH2Cl2, rt (83%)
CO2Me O O MeO Me
+
OMe Me
TBSO O MeO Me
OMe Me
TFA, H2O rt
HO OH
OH
From (-)-quinic acid - several synthesis of (-)-shikimic acid from (-)-quinic acid have been published - (-)quinic acid is found in Cinchona bark and more readily available (available from Aldrich $110.50 / 100g) than (-)-shikimic acid
HO CO2H HO CO2NH2
p-TsCl, Py 37 oC, 7 days
A:B 30:1
(-)-methyl shikimate
CN
aq. NaOH reflux 2.5 h
CO2H
aq. H2SO4 reflux
CO2H
Box, J. M.; Harwood, L. M.; Humphreys, J. L.; Morris, G. A.; Redon, P. M.; Whitehead, R. C. Synlett 2002, 2, 358.
HO OH
OH
O O
OAc
O O
OAc
O O
OH
HO OH
OH
(-)-quinic acid
(-)-shikimic acid
Dangschat, G.; Fischer, H. O. L. Naturwissenschaften 1938, 26, 562. Dangschat, G.; Fischer, H. O. L. Biochim. Biophys. Acta 1950, 4, 199.
Narendra Ambhaikar
Shikimic acid
1,dihydroxy-19-norprevitamin D3
OH
OH
HO
(-)-MK7607
gabosine K
pentaacetate of carba-D-altropyranose
OMOM
LDA, THF, -78 oC PhNTf2 (89%)
OMOM
H OTf
- carbasuguars or pseudosugars lack the acetal function which is characteristic of common monosaccharades - known to display a range of biological activities, particular as glycosidase inhibitors
vinyl triflate
CO2H
i) CSA, MeOH (96%) ii) CSA, Me2C(OMe)2 (95%)
CO2Me
Tf2O, DMAP, Py CH2Cl2 (98%)
CO2Me
CO2Me
i) PhOC(S)Cl, DMAP (93%) ii) DIBAL-H (86%)
CH2OH
HO OH
OH
O O
OH
O O
OTf
HO OH
OH
TBSO OH
OTBS
TBSO O
OTBS S OPh
CsOAc, DMF (81%)
CO2Me
OsO4, NMO
CO2Me OH HO
HO CO2Me
(-)-shikimic acid
n-Bu3SnH AIBN (cat.) (63%)
CH2OH
MnO2 (82%)
CHO
i) Zn, Ph3P, CBr4 Py (93%) ii) n-BuLi (80%)
+
O OH O O O
O O
TBSO
Name reaction
OTBS
TBSO
OTBS
Name reaction TBSO
OTBS
A(38%)
OH O O O O
B (35%)
OH OH
TFA-H2O (92%)
enyne
OH CO2Me
Me2C(OMe)2, CSA (98%)
O O O O
DIBALH (99%)
OH
OH
HO OH
OH
HO
(-)-MK7607
TBSO
OTBS
1,dihydroxy-19-norprevitamin D3 17% overall yield, 11 steps Song, C.; Jiang, S.; Singh, G. Synlett 2001, 12, 1983.
Sarandeses, L. A.; Mascerenas, J. L.; Castedo, L.; Mourino, A. Tetrehedron Lett. 1992, 33, 5445.
Narendra Ambhaikar
Shikimic acid
O AcHN
CO2Et
O AcHN
CO2H
NH2.H3PO4
NH2
CO2Et
GS-4104
GS-4071
O
i) MgBr2.OEt2 (0.2 equiv.) t-BuOMe/MeCN 9:1 55 oC, 16h ii) (NH4)2SO4/H2O 97%
O HO HN
O HO NH2
CO2Et
+ -it is a prodrug of the potent and selective competitive inhibitor (GS-4071) of influenza A and B neuraminidase -research and development by Gilead Sciences Inc. and F. Hoffmann-La Roche Ltd.
i) PhCHO, tBuOMe, -H2O ii) MsCl, Et3N iii) allyl amine, 112 oC, 15 h iv) HCl/H2O i) EtOH, SOCl2 ii) 3-pentanone, TsOH iii) MsCl, Et3N
NH2
O H2N HN
CO2Et
Ac2O, AcOH, MsOH t-BuOMe, 15 h, 20 oC 83%
O AcHN HN
CO2Et
O HO OMs
CO2Et
80%
HO OH
OH
80%
(-)-shikimic acid
major product
O AcHN
CO2Et
CO2Et
O HO N3
CO2Et
O N3 OH
CO2Et
NH2.H3PO4
+ A
A:B 10:1
O AcHN
Me3P (97%)
CO2Et
O AcHN N3
CO2Et
CO2Et
HN
aziridine (74% purity) 21% overall yield in 10 steps from (-)-shikimic acid
NH2
1. Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C. Y.; Laver, G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119, 681. 2. Rohloff, J. C.; Kent, K. M.; Postich, M. J.; Becker, M. W.; Chapman, H. H.; Kelly, D. E.; Lew, W.; Louie, M.S.; McGee, L. R.; Prisbe, E. J.; Shultze, L. M.; Yu, R. H.; Zhang, L. J. Org. Chem. 1998, 63, 4545.
Narendra Ambhaikar
Shikimic acid
CO2H
i) EtOH, SOCl2 reflux ii) evaporation
HO HO OH
CO2Et
O O OH
CO2Et
(-)-shikimic acid
i) MsCl (1.3 eq) ii) Et3N (2.0 eq) EtOAc, 0-5 oC iii) filtration iv) evaporation v) cryst. MeOH 89%
O O OMs
CO2Et
i) pentanone (15 eq) CF3SO3H (0.045 eq) ii)extraction iii) evaporation 98%
O O OMs
CO2Et
i) Et3SiH (1.3 eq) TiCl4 (1.1 eq) CH2Cl2, -34 oC, 2-6 h ii) poured on H2O extr.NaHCO3
O HO OMs
CO2Et
HO O OMs
CO2Et
HO HO OMs
CO2Et
regioisomers 32:1
i) NaHCO3 (1.6 eq) EtOH/H2O, 60 oC, 1.5 h ii) extr. n-hexane iii) cryst n-hexane
2-4%
CO2Et O O CO2Et
80% from pentylidnene ketal, 63-65% from (-)-shikimic acid in 6 steps assay HPLC > 98%
AcHN NH2.H3PO4