Group Meeting
1/12/2005
Shikimic acid
Narendra Ambhaikar
Biosynthetic pathway
OPO3H2
OH
CO2H
OH
O
phosphoenolpyruvic
acid
OH
CO2H
OH
OH
OH
OH
OH
OPO3H2
O
H2O3PO
glucose
HO
HO CO2H
OH
O
3-deoxy-D-arabinoheptulosonic acid phosphate
H
OH
OH
D-erythrose 4-phosphate
(E4P)
OH
(-)-shikimic acid
CO2H
HO CO2H
OH
OH
-Shikimic acid is a hydroaromatic intermediate in the common pathway of aromatic
amino acid biosynthesis.
O
CO2H
-Relative and absolute stereochemistry realized only in 1930s through the works of
Fischer, Freudenberg and Karrer.
-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.
HO
3-dehydroquinic acid
CO2H
OH
H2O3PO
OH
HO
OH
(-)-shikimic acid
shikimate 3-phosphate
HO
O
H
N
OBz
O
H
N
H2N
CO2Me
zeylenone
HO
dragmacidin F (Stoltz)
OH
OH
OH
pericosine B
(Usami)
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.
N
H
O
oseltamivir phosphate
O
N
H
HO
MeO
Br
N
H
HN
BzO
OH
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.
(-)-quinic acid
Some molecules synthesized
from (-)-quinic acid
CO2Et
AcHN
OH
OH
Some molecules synthesized
from (-)-shikimic acid
HO
CO2H
HO
OH
NH2.H3PO4
-There is great potential for the design and synthesis of enzyme inhibitors which may
selectively block specific enzyme-catalysed transformations along this pathway.
OH
OH
3-dehydroshikimic acid
-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.
-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.
O
OH
OH
CO2H
OMe
HO
1α,dihydroxy-19-norprevitamin D3
NH MeO
O
HO
OH
(-)-MK7607
OH
OH
H
OH
OH
HO
N
N
H H
OH
OH
H
MeO2C
mycosporin-gly
HO
(White)
OH
OH
(+)-proto-quercitol
(Shih)
OR
OMe
(-)-reserpine
(Hanessian)
Group Meeting
1/12/2005
Shikimic acid
Narendra Ambhaikar
SYNTHESIS OF SHIKIMIC ACID
CO2Me
CO2Me
- Several syntheses have been reported. The following discussion will cover some of them.
Br
+
Br
OAc
OAc
OAc
CO2H
hydroquinone
85-90 oC
HO
OsO4, Et2O
Py, CH2N2
OAc
O
HO
HO
KOH, MeOH-H2O
OAc
i) Ac2O, Py
ii) (-)-quinine, MeOH
iii) KOH, MeOH-H2O
HO
HO
OH
O
O
OAc
2-acetoxyfuran
O
O
O
H2O, rt, 3 d
(66%)
OAc
i) MeOH, HCl
ii) Ac2O (57%)
AcO
O
OAc
AcO
OAc
HO
SiMe3
OAc
i) AcOH, H2O2 then
H2O (85%)
CO2Me
i) HCl, MeOH
ii) Ac2O, Py
O iii) DBU, THF
AcO
AcO
65%
71%
O
(±)-shikimic acid
3% overall yield
OAc O
O
OAc O
hydroquinone
TMS monomethyl
ether (cat.),
xylenes (77%)
O
SiMe2Ph
O
TMS
HO
OsO4, NMO
(96%)
O
O
TMS
HO
CO2H
O
DBU, THF
(94%)
OH
NBS, CCl4
OAc
TMS
n-Bu4NF
(98%)
HO
OH
TMS
SiMe2Ph
OAc O
HO
O
HO
SiMe2Ph
HO
CO2Me
OAc
OAc
OH
OH
OAc
AcO
Koreeda's 2nd generation synthesis employing Fleming oxidation
+
HO
ii) Ac2O, Py (80%)
ii) MeOH, c. H2SO4
(97%)
OAc
CO2Me i) LiOH, THF-H2O
(±)-shikimic acid
29% overall yield
OAc
CO2H
i) soft glass powder
sealed tube, vac
256 - 258 oC (92%)
ii) saponification (75%)
OAc
CO2Me
CO2Me
OAc
Grewe (1964)
toluene, 130 -140 oC
(85%)
HO
p-TsOH
PhH (98%)
ii) Ac2O, Py
KBr , AcOOH
AcOH, NaOAC
(81%)
CO2H i) hydroquinone
OAc
CO2Me
O
O
ketoacid
AcO
HO
O
HO
O
CO2Me
+
OsO4, NMO
H2O (96%)
HO
O
i) NaBH4
ii) Ac2O
xylenes
(72%)
HO
SiMe3
MCPBA
(91%)
CO2H
O
OsO4, H2O2 HO
(54%)
HO
OAc
+
OAc
CO2Me
OAc
O
O
OH
OAc
CO2Me
SiMe3
Smissman (1968)
+
7%
Koreeda (1982)
OAc
OH
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.
O
1%
Grewe, R.; Hinrichs, I. Chem. Ber. 1964, 97, 443.
(−)-shikimic acid
15% overall yield
PhH, heat
(67%)
OAc
(±)-shikimic acid
11% overall yield
OAc
OAc
O
5%
OAc
OAc
CO2H
H2O, AcOH
O
+
OAc
OH
O
OAc
CO2Me
+
OAc
OAc
20%
CO2Me
OH
CO2Me
HO
HCl
acetone
CO2H
O
OAc
CO2Me
OH
OAc
CO2Me
OAc
MgO, 290 oC
OAc HO
CO2H
OAc
CO2H
+
HO
KOH, MeOH,H2O
Raphael (1960) and Smissman (1959) - identical routes
OAc
CO2Me
+
OAc ii) MeOH, HCl
OAc
Synthesis of shikimic acid via Diels Alder reaction
CO2Me
i) AgOAc, AcOH
H2 O
Koreeda, M.; Ciufolini, M. A. J. Am. Chem. Soc. 1982, 104, 2308.
Koreeda, M.; Teng, K.; Murata, T. Tetrahedron Lett. 1990, 31, 5997.
HO
OH
OH
(±)-shikimic acid
55% overall yield
Narendra Ambhaikar
Group Meeting
1/12/2005
Shikimic acid
From benzene (Birch, 1988)
APPLICATIONS OF (-)-SHIKIMIC ACID IN SYNTHESIS
(-)-zeylenone
CO2H
CO2- Ph
CO2H
Ph NH2
Me H
i) Me2SO4, KOH
M
ii) Fe(CO)5, n-Bu2O
iii) c. H2SO4
Me
Me
H
BzO
i) aq. HCl, EtOH
ii) CH2N2, Et2O
CO2Me
Ph3PF6
hexane
CH2Cl2
(73%)
M
M
+
OBz
O
HO
H
+M
- a polyoxygenated cyclohexene showing antiviral, anticancer and antibiotic activities isolated
from Uvaria grandiflora
mixture subjected to resolution
CO2Me
HO
NH3+
CHCl3-acetone
NH3+
M
CO2- Ph
Me
H
M
racemic complex
CO2- Ph
NH3
+
CO2Me
NaHCO3, H2O
MeCN (95%)
PF6-
Enantioselective synthesis of zeylenone from (-)-shikimic acid
M
OH
100%
CSA, MeOH
CO2Me
i) TBDMSCl
i-Pr2NEt (98%)
ii) Me3NO (84%)
CO2Me
OsO4 (67%)
OTBDMS
(MeCO)2
CH(OMe)3
CSA (93%)
TBAF (85%)
HO
OTBDMS
HO
OH
OH
HO
(−)-methyl shikimate
OH
TBDMSO
CO2Me
OAc
PdCl2(PPh3)2 (cat.)
HCO2NH4, MeCN (79%)
CO2Me
O
O
Ph2O, 280 oC
O
O CH2OBz
O CH2OBz
TBAF
PhCO2H
(94%)
Ph3P, Im
I2 (87%)
TBDMSO
OH
O CH2OBz
CO2Me
TBDMSO
O
HO
BzO
OH
OH
Yoshida, N.; Ogasawara, K. Org. Lett. 2000, 2, 1461.
BzCl, DMAP
Py (99%)
cyclohexene
SeO2, THF
(40%)
O
O CH2OBz
O TFA/H2O (9:1)
HO
HO CH2OBz
O
(85%)
BzO
i) K2CO3, MeOH (72%)
ii) KOH, THF
OBF3
O
TFA/H2O (1:1)
(79%)
OMe
OMe
O
OH
CO2Me
O
O
O
O CH2OBz
O
CO2Me
Ph
TBDMSO
O
BF3.OEt2
BzO
O
BzO
exo-epoxide
O
O CH2OBz
i) OsO4, NMO (94%)
ii) Me2C(OMe)2, TsOH
(99%)
OMe
OMe
30% H2O2
Triton B (75%)
O
CO2Me
CO2Me
i) NaBH4 NaOHMeOH(79%)
ii) BzCl, BuNCl,NaOH
toluene (59%)
OMe
OMe
83%
O
CO2Me
HO
O
O
O
OMe
OMe
10%
i) DIBAL-H (92%)
ii) BzCl, DMAP
Py (97%)
TBDMSO
O
CH2OBz
Palladium mediated elimination reaction (Ogasawara, 2000)
HO
TBDMSCl
Im, DMAP
(97%)
O
OMe
(-)-methyl shikimate
Birch, A. J.; Kelly, L. F.; Weerasuria, D. V.; J. Org. Chem. 1988, 53, 278.
i) TBSCl, Im, DMF
ii) AcCl, TEA, DMAP
(81%)
iii) TBAF, THF (80%)
HO
O
MeO
M = Fe(CO)3, provides lateral control for enantiospecifically installing the hydroxy group
CO2Me
OH
CO2 Me
+
O
OH
OH
OH
CO2 Me
CO2 Me
CO2 Me
CO2Me
BzO
HO
OH
OH
(−)-shikimic acid
BzO
(+)-zeylenone:CD spectra
indicated (+)-antipode of the
natural product
Liu, A.; Liu, Z. Z.; Zou, Z. M.; Chen, S. Z.; Xu, L. Z.; Yang, S. L. Tetrahedron, 2004, 60, 3689.
Narendra Ambhaikar
Group Meeting
1/12/2005
Shikimic acid
Chiral syntheses of (-)-shikimic acid
From carbohydrates
O
OH
HO
O
acetone
c. H2SO4
(cat.)
O
OH
HO
O
HO
OBn
i) BnCl, NaH, DMF
HO
ii) c. HCl, MeOH, H2O
O
CO2Me
CO2Me
SO2Cl2, Py
-70 oC (78%)
OR
BzCl, Py (85%)
HO
OH
O
HO
CO2Me
HO
NaIO4, H2O, rt
O
O
OH
BzO
NaOMe
MeOH
OBz
BzO
POCl3, Py (75%)
OBz
OH
CO2Me
OBz
HO
OH
(-)-methyl quinate
O
OH
OBz
(-)-methyl shikimate
OH
D-mannose
O
O
OHC
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.
OBn
F CO2CSO
NaBH4, EtOH
O
O
OBn
HO
O
3
(CF3SO2)2O
Py, CH2Cl2, -30 oC
100%
O
O
O
O
lyxo-alcohol
(66% from D-mannose)
O
(MeO)2OP
NaH
(MeO)2OPCH2CO2t-Bu
DMF, 15-crown-5 (81%)
t-BuO2C
O
HO
CO2t-Bu
OBn
i) Pd-C (10%),
MeOH, H2
O ii) NaH, THF (73%,
two steps)
CO2H
HO
aq. TFA (100%)
OH
O
HO
butan-2,3-dione
(MeO)3CH, CSA HO
MeOH, D (79%)
OH
OH
O
OH
O
O
MeO
(-)-quinic acid
OH
CO2Me
HO
CO2H
CO2Me
HO
OMe
TBSOTf
Et3N (97%)
O
TBSO
O
Me
MeO
Me
butane diacetal
OMe
Me
Me
(-)-shikimic acid
10 steps, 39% overall yield
CO2Me
CO2Me
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%)
From (-)-quinic acid
CO2H
CO2NH2
HO
CN
OH
OH
(-)-quinic acid
OAc
O
O
OAc
O
O
OH
O
HO
TBSO
O
O
MeO
Me
A:B 30:1
OMe
Me
Me
B
TFA, H2O
rt
HO
OH
OH
(-)-methyl shikimate
Box, J. M.; Harwood, L. M.; Humphreys, J. L.; Morris, G. A.; Redon, P. M.; Whitehead, R. C. Synlett
2002, 2, 358.
aq. H2SO4
reflux
O
+
OMe
Me
A
CO2H
CO2H
aq. NaOH
reflux 2.5 h
p-TsCl, Py
37 oC, 7 days
HO
O
MeO
- 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
O
OH
OH
(-)-shikimic acid
Dangschat, G.; Fischer, H. O. L. Naturwissenschaften 1938, 26, 562. Dangschat, G.; Fischer, H. O. L.
Biochim. Biophys. Acta 1950, 4, 199.
Group Meeting
1/12/2005
Shikimic acid
Narendra Ambhaikar
Synthesis of (-)-MK7607 and other carbasugars
1α,dihydroxy-19-norprevitamin D3
OH
OH
OH
OAc
OH
HO
HO
H
OMOM
CO2H
HO
CO2Me
OTBS
HO
CH2OH
OH
S
CO2Me
Name reaction TBSO
O
CO2Me
HO CO2Me
OH
CsOAc, DMF
(81%)
OsO4, NMO
O
HO
+
OH
O
O
O
O
OTBS
Name reaction
OTf
O
O
i) Zn, Ph3P, CBr4
Py (93%)
ii) n-BuLi (80%)
TBSO
Tf2O, DMAP, Py
CH2Cl2 (98%)
OH
O
CHO
MnO2 (82%)
CO2Me
OTBS
O
OPh
OTBS
pentaacetate of carba-βD-altropyranose
CO2Me
OH
TBSO
OH
TBSO
gabosine K
i) CSA, MeOH (96%)
ii) CSA, Me2C(OMe)2 (95%)
CH2OH
i) PhOC(S)Cl, DMAP (93%)
ii) DIBAL-H (86%)
TBSO
n-Bu3SnH
AIBN (cat.)
(63%)
OAc
OAc
CO2H
OH
(-)-shikimic acid
AcO
OH
vinyl triflate
i) MeOH, HCl (cat.)
(98%)
ii) TBSCl, TEA
DMAP (82%)
OH
OH
OAc
- 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
H
OTf
known compound derived from
vitamin D2
HO
(-)-MK7607
OMOM
O
OH
OH
- an analogue of the hormone 1α,25-dihydroxyvitamin D3
LDA, THF, -78 oC
PhNTf2 (89%)
OH
OAc
O
A(38%)
OTBS
B (35%)
enyne
vinyl triflate
+
enyne
(Ph3P)2PdCl2
TEA, DMF, 75 oC
85%
80%
TBSO
OH
i) H2, Lindlar's catalyst
quinoline
ii) TBAF, THF
OTBS
OH
A
O
Me2C(OMe)2, CSA
(98%)
O
O
O
OH
O
DIBALH
(99%)
O
O
O
TFA-H2O
(92%)
HO
OH
OH
(-)-MK7607
HO
1α,dihydroxy-19-norprevitamin D3
17% overall yield, 11 steps
Sarandeses, L. A.; Mascerenas, J. L.; Castedo, L.; Mourino, A. Tetrehedron Lett. 1992, 33, 5445.
OH
OH
CO2Me
OH
Song, C.; Jiang, S.; Singh, G. Synlett 2001, 12, 1983.
Roche-Basel Route to oseltamivir phosphate (azide free synthesis)
Kilogram scale synthesis of Oseltamivir phosphate (Tamiflu)
O
Group Meeting
1/12/2005
Shikimic acid
Narendra Ambhaikar
CO2Et
O
AcHN
CO2H
AcHN
NH2.H3PO4
O
NH2
GS-4104
CO2Et
GS-4071
O
i) MgBr2.OEt2 (0.2 equiv.)
t-BuOMe/MeCN 9:1
55 oC, 16h
ii) (NH4)2SO4/H2O
+
NH2
-it is a prodrug of the potent and selective competitive inhibitor (GS-4071) of influenza A and B
neuraminidase
O
CO2Et i) Pd/C, EtOH
HO
H2N(CH2)2OH
reflux
ii) H2SO4/H2O
HN
97%
O
CO2Et
HO
77%
NH2
-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
CO2Et
i) EtOH, SOCl2
ii) 3-pentanone, TsOH
iii) MsCl, Et3N
HO
OH
CO2Et TMSOTf
O
CO2Et
O
O
80%
OMs
(-)-shikimic acid
major product
CO2Et
CO2Et
O
NaN3, NH4Cl
aq. EtOH (86%)
+
HO
O
CO2Et
O
HN
i) Pd/C, EtOH
H2NCH2CH2OH
reflux
ii) H3PO4, EtOH
O
CO2Et
83%
OH
i) NaN3, NH4Cl
DMF (44%)
ii) Ac2O
HN
CO2Et
O
i) Ra-Ni, H2
EtOH
ii) 85% H3PO4
AcHN
aziridine (74% purity)
N3
B
A:B 10:1
(71-75%)
O
CO2Et
AcHN
NH2.H3PO4
Oseltamivir phosphate in
35-38% overall yield from
the epoxide
N3
N3
A
O
H2N
80%
70%
Me3P
(97%)
O
Ac2O, AcOH, MsOH
t-BuOMe, 15 h, 20 oC
HO
63-75%
OMs
O
CO2Et
BH3.Me2S
OH
KHCO3, aq. EtOH
96%
O
CO2Et
AcHN
NH2
21% overall yield in 10 steps from (-)-shikimic acid
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.
Karpf, M.; Trussardi, R. J. Org. Chem. 2001, 66, 2044.
CO2Et
AcHN
HN
Narendra Ambhaikar
Shikimic acid
Industrial synthesis of oseltimivir phosphate (50-250 kg)
HO
CO2H
HO
i) EtOH, SOCl2
reflux
ii) evaporation
HO
CO2Et
HO
OH
97%
OH
i) MsCl (1.3 eq)
ii) Et3N (2.0 eq)
EtOAc, 0-5 oC
iii) filtration
iv) evaporation
v) cryst. MeOH
89%
i) Et3SiH (1.3 eq)
TiCl4 (1.1 eq)
CH2Cl2, -34 oC, 2-6 h
ii) poured on H2O
extr.NaHCO3
CO2Et
O
O
i) pentanone (15 eq)
CF3SO3H (0.045 eq)
ii)extraction
iii) evaporation
CO2Et
O
+
HO
OH
CO2Et
O
O
98%
OMs
O
95%
(-)-shikimic acid
OMs
HO
O
CO2Et
HO
+
HO
2-4%
regioisomers 32:1
i) NaHCO3 (1.6 eq)
EtOH/H2O, 60 oC, 1.5 h
ii) extr. n-hexane
iii) cryst n-hexane
CO2Et
OMs
OMs
OMs
CO2Et
O
i) Me2C(OMe)2 (2.0eq)
TsOH (0.01 eq)
EtOAc,
ii) evaporation
CO2Et
O
O
O
80% from pentylidnene ketal,
63-65% from (-)-shikimic acid in
6 steps
assay HPLC > 98%
Federspiel, M. et al. Org. Proc. Res. Dev. 1999, 3, 266.
CO2Et
AcHN
NH2.H3PO4
Group Meeting
1/12/2005