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Narendra Ambhaikar

Shikimic acid
Biosynthetic pathway
OH O CO2H OH OH OH OH H2O3PO OH OPO3H2 CO2H

Group Meeting 1/12/2005


HO CO2H OH O OH OH OPO3H2

phosphoenolpyruvic acid
OH O H

glucose
HO OH OH

3-deoxy-D-arabinoheptulosonic acid phosphate

D-erythrose 4-phosphate (E4P)


CO2H OH HO CO2H OH O 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

(-)-shikimic acid Some molecules synthesized from (-)-shikimic acid


HO HO O AcHN NH2.H3PO4 CO2Et BzO OBz O

shikimate 3-phosphate

(-)-quinic acid

Some molecules synthesized from (-)-quinic acid


H N H2N HN CO2Me MeO HO OH OH HO O OH N H H N H N H O

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

CO2H NH MeO OH N H H OH OH OH H MeO2C OMe OR N H

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

Group Meeting 1/12/2005


CO2Me CO2Me CO2Me OH CO2Me OH OAc OAc

- 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

OAc ii) MeOH, HCl

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%

CO2H OAc OAc CO2Me


HCl acetone

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

i) Ac2O, Py ii) (-)-quinine, MeOH iii) KOH, MeOH-H2O

HO OH

OH

Koreeda (1982)
OAc CO2Me OAc CO2Me
xylenes (72%) OsO4, NMO H2O (96%)

OAc HO HO SiMe3 OAc CO2Me


p-TsOH PhH (98%)

()-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

CO2Me i) LiOH, THF-H2O


ii) Ac2O, Py 65%

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%)

i) NaBH4 ii) Ac2O

AcO O OAc OAc

i) MeOH, HCl ii) Ac2O (57%)

AcO AcO OAc OAc

HO HO SiMe2Ph

+
HO OH OH SiMe2Ph

TMS

()-shikimic acid 3% overall yield

SiMe2Ph OAc O O O TMS


DBU, THF (94%)

CO2H O TMS
n-Bu4NF (98%)

Grewe (1964)
CO2H i) hydroquinone
toluene, 130 -140 oC (85%) ii) MeOH, c. H2SO4 (97%)

KBr , AcOOH AcOH, NaOAC (81%)

HO HO OH

HO HO OH

CO2Me

i) AcOH, H2O2 then H2O (85%)

CO2Me
NBS, CCl4

HO OH

OH

ii) Ac2O, Py (80%)

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.

()-shikimic acid 55% overall yield

Narendra Ambhaikar
From benzene (Birch, 1988)

Shikimic acid
APPLICATIONS OF (-)-SHIKIMIC ACID IN SYNTHESIS (-)-zeylenone
HO HO BzO OBz O

Group Meeting 1/12/2005

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%

mixture subjected to resolution


CO2Me
Ph3PF6 hexane CH2Cl2 (73%)

- a polyoxygenated cyclohexene showing antiviral, anticancer and antibiotic activities isolated from Uvaria grandiflora

CO2Me M M

CO2Me
NaHCO3, H2O MeCN (95%)

PF6-

M OH

Enantioselective synthesis of zeylenone from (-)-shikimic acid

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

Palladium mediated elimination reaction (Ogasawara, 2000)


CO2Me OH
i) TBSCl, Im, DMF ii) AcCl, TEA, DMAP (81%) iii) TBAF, THF (80%)

TBDMSO O

i) OsO4, NMO (94%) ii) Me2C(OMe)2, TsOH (99%)

O TBDMSO O O OMe OMe


TFA/H2O (1:1) (79%)

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 OBF3 O Ph BzO OH


i) K2CO3, MeOH (72%) ii) KOH, THF

CO2Me

O BzO

SeO2, THF (40%)

HO BzO

HO CH2OBz O

O BzO

OH

HO OH

OH

()-shikimic acid

(+)-zeylenone:CD spectra indicated (+)-antipode of the natural product

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


HO OH HO HO OH O OH
acetone c. H2SO4 (cat.)

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

i) BnCl, NaH, DMF HO ii) c. HCl, MeOH, H2O

(-)-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.

lyxo-alcohol (66% from D-mannose)


(MeO)2OP
NaH (MeO)2OPCH2CO2t-Bu DMF, 15-crown-5 (81%)

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

(-)-shikimic acid 10 steps, 39% overall yield


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

Group Meeting 1/12/2005


Synthesis of (-)-MK7607 and other carbasugars
OH OH HO OH OH HO OH OAc OH OH AcO OAc OAc OAc OAc

1,dihydroxy-19-norprevitamin D3

OH

OH

HO

- an analogue of the hormone 1,25-dihydroxyvitamin D3

(-)-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

known compound derived from vitamin D2


CO2H

vinyl triflate
CO2H
i) CSA, MeOH (96%) ii) CSA, Me2C(OMe)2 (95%)

CO2Me
Tf2O, DMAP, Py CH2Cl2 (98%)

CO2Me

i) MeOH, HCl (cat.) (98%) ii) TBSCl, TEA DMAP (82%)

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%)

vinyl triflate + enyne


(Ph3P)2PdCl2 TEA, DMF, 75 oC 85% i) H2, Lindlar's catalyst quinoline ii) TBAF, THF 80%

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

Group Meeting 1/12/2005

Kilogram scale synthesis of Oseltamivir phosphate (Tamiflu)

Roche-Basel Route to oseltamivir phosphate (azide free synthesis)

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

CO2Et i) Pd/C, EtOH


H2N(CH2)2OH reflux ii) H2SO4/H2O 77%

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

CO2Et O O OMs CO2Et TMSOTf


BH3.Me2S 63-75%

O HO OMs

CO2Et

80%

HO OH

OH

80%

(-)-shikimic acid

major product

i) Pd/C, EtOH H2NCH2CH2OH reflux ii) H3PO4, EtOH 70%

O AcHN

CO2Et

KHCO3, aq. EtOH 96%

CO2Et

O HO N3

CO2Et

O N3 OH

CO2Et

NaN3, NH4Cl aq. EtOH (86%)


O

NH2.H3PO4

+ A

A:B 10:1
O AcHN

Oseltamivir phosphate in 35-38% overall yield from the epoxide

Me3P (97%)

CO2Et

i) NaN3, NH4Cl DMF (44%) ii) Ac2O

O AcHN N3

CO2Et

i) Ra-Ni, H2 EtOH ii) 85% H3PO4 (71-75%)

CO2Et

HN

aziridine (74% purity) 21% overall yield in 10 steps from (-)-shikimic acid

NH2

Karpf, M.; Trussardi, R. J. Org. Chem. 2001, 66, 2044.

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

Group Meeting 1/12/2005

Industrial synthesis of oseltimivir phosphate (50-250 kg)


HO HO OH
97%

CO2H
i) EtOH, SOCl2 reflux ii) evaporation

HO HO OH

CO2Et

i) Me2C(OMe)2 (2.0eq) TsOH (0.01 eq) EtOAc, ii) evaporation 95%

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

Federspiel, M. et al. Org. Proc. Res. Dev. 1999, 3, 266.