ambhaikar jan 05

Group Meeting1/12/2005Narendra Ambhaikar Shikimic acid

CO2H

OHHOOH

(-)-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.

CO2H

OHHOOH

NHO

HO

H

NH

N

O

HN

BrHN

HN

H2N

dragmacidin F (Stoltz)

NH

N

OMe

H

HMeO2C OR

MeOH

(-)-reserpine (Hanessian)

NHOMe

O

HO OH

CO2H

mycosporin-gly(White)

OH

OHHO

OH

OH(+)-proto-quercitol

(Shih)

OHOH

HO

MeOCO2Me

pericosine B(Usami)

OHHOOH

OH

OH(-)-MK7607

CO2EtO

NH2.H3PO4

AcHN

oseltamivir phosphate

OHO

HO

BzO

OBz

zeylenone

HO

OHOH

1α,dihydroxy-19-norprevitamin D3

Some molecules synthesized from (-)-shikimic acid

Some molecules synthesized from (-)-quinic acid

O

OHOH

OHOH

OH

glucose

CO2H

OPO3H2

phosphoenolpyruvic acid

H2O3POH

OOH

OHD-erythrose 4-phosphate

(E4P)

OOH

OHOH

OPO3H2

HO CO2H

3-deoxy-D-arabino-heptulosonic acid phosphate

OH

OHO OH

HO CO2HOH

OHO OH

CO2H

3-dehydroshikimic acid 3-dehydroquinic acid

OHHOOH

CO2HHOCO2H

OHH2O3POOH

(-)-shikimic acid shikimate 3-phosphate (-)-quinic acid

Biosynthetic pathway

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.

Reviewsii) 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.


OAc

OAc

CO2H

OAcCO2H

OAc

OAcCO2Me

OAc

hydroquinone85-90 oC

HO

HO

OsO4, Et2O Py, CH2N2

OAcCO2Me

OAc

O

OHCl

acetone

OAc

O

O

CO2MeMgO, 290 oC

H2O, AcOH

KOH, MeOH-H2OOAc

HO

HO

CO2H i) Ac2O, Pyii) (-)-quinine, MeOHiii) KOH, MeOH-H2O

(−)-shikimic acid15% overall yield

Raphael (1960) and Smissman (1959) - identical routes

Smissman (1968)

O

OAc

O

O

O

+

+ O

O

O

O

OAc

O

O

O

O

OAc

HO

HO

PhH, heat(67%)

OsO4, H2O2(54%)

H2O, rt, 3 d(66%)

OAc

HO

HO

CO2H

O

i) NaBH4ii) Ac2O

OAc

AcO

OOAc

O

OAc

AcO

AcO

CO2Me

OAc

i) MeOH, HClii) Ac2O (57%)

i) soft glass powdersealed tube, vac256 - 258 oC (92%)ii) saponification (75%)

OHHO

CO2H

OH

(±)-shikimic acid3% overall yield

NBS, CCl4

CO2Me

OAcOAcBr

CO2Me

OAcOAc

Br+

CO2Me

OAcOAcHO

CO2Me

OAcOAcHO

i) AgOAc, AcOHH2O

ii) MeOH, HCl

+ +

CO2Me

OAcOAc

OHCO2Me

OAcOAc

OH

+

20% 5% 1% 7%KOH, MeOH,H2O

Koreeda (1982)

OAc

SiMe3

CO2Me+ xylenes

(72%)

OAcCO2Me

SiMe3

OsO4, NMOH2O (96%)

OAcCO2Me

SiMe3

HO

HO

OAcCO2MeHO

p-TsOHPhH (98%)

OAcCO2MeHO

O

MCPBA(91%) i) LiOH, THF-H2O

ii) Ac2O, Py

65%

OAcAcO

AcOO

O

OAcAcO

CO2Me

OAc

i) HCl, MeOHii) Ac2O, Pyiii) DBU, THF

71%

OAc

SiMe2Ph

Koreeda's 2nd generation synthesis employing Fleming oxidation

O

OTMS

+

hydroquinonemonomethyl ether (cat.),

xylenes (77%)

OAc

SiMe2Ph

O

OTMS

OsO4, NMO (96%)

OAc

SiMe2Ph

O

OTMSHO

HO

KBr , AcOOHAcOH, NaOAC(81%)

OAc

OH

O

OTMSHO

HO

DBU, THF(94%)

OH

O

OTMSHO

HOn-Bu4NF

(98%)

CO2H

OHHOOH

SYNTHESIS OF SHIKIMIC ACID

- Several syntheses have been reported. The following discussion will cover some of them.

Synthesis of shikimic acid via Diels Alder reaction

(±)-shikimic acid 11% 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.

Grewe, R.; Hinrichs, I. Chem. Ber. 1964, 97, 443.

CO2H

+

i) hydroquinonetoluene, 130 -140 oC(85%)

ii) MeOH, c. H2SO4(97%)

CO2Me CO2Mei) AcOH, H2O2 thenH2O (85%)

ii) Ac2O, Py (80%)

OAcOAc

Grewe (1964)

Koreeda, M.; Ciufolini, M. A. J. Am. Chem. Soc. 1982, 104, 2308.Koreeda, M.; Teng, K.; Murata, T. Tetrahedron Lett. 1990, 31, 5997.

2-acetoxyfuran ketoacid


OHHO

CO2H

OH

OHHO

CO2H

OH


Group Meeting1/12/2005

Narendra Ambhaikar Shikimic acid

From benzene (Birch, 1988)

CO2H CO2H

M

CO2-

MPh NH2Me H

Ph NH3+

Me H

CO2-

M

Ph NH3+

Me H+

i) Me2SO4, KOH

ii) Fe(CO)5, n-Bu2Oiii) c. H2SO4 CHCl3-acetone

CO2-

M

Ph NH3+

Me H

mixture subjected to resolution

i) aq. HCl, EtOHii) CH2N2, Et2O

100%

CO2Me

M

CO2Me

+ PF6-

Ph3PF6hexane CH2Cl2(73%)

NaHCO3, H2O MeCN (95%)

CO2Me

MOH

i) TBDMSCli-Pr2NEt (98%)ii) Me3NO (84%)

CO2Me

OTBDMS

OsO4 (67%)

CO2Me

OTBDMSOH

HO

CO2Me

OHOH

HO

TBAF (85%)

M = Fe(CO)3, provides lateral control for enantiospecifically installing the hydroxy group

OH

HO

CO2MeOAc

HO

CO2Me

O

CO2Me

O

CO2Me

O

BzO

CO2Me

O BzO O

CO2Me

CO2Me

OO

Ph

OBF3BzO

CO2Me

OHOH

(−)-shikimic acid

i) TBSCl, Im, DMFii) AcCl, TEA, DMAP (81%)iii) TBAF, THF (80%)

PdCl2(PPh3)2 (cat.)HCO2NH4, MeCN (79%)

30% H2O2Triton B (75%)

i) NaBH4 NaOH-MeOH(79%)ii) BzCl, BuNCl,NaOH toluene (59%)

Ph2O, 280 oC BF3.OEt2

exo-epoxide

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

Palladium mediated elimination reaction (Ogasawara, 2000)

Yoshida, N.; Ogasawara, K. Org. Lett. 2000, 2, 1461.

Birch, A. J.; Kelly, L. F.; Weerasuria, D. V.; J. Org. Chem. 1988, 53, 278.

(−)-methyl shikimate

CO2Me

OHOH

HO

APPLICATIONS OF (-)-SHIKIMIC ACID IN SYNTHESIS

Enantioselective synthesis of zeylenone from (-)-shikimic acid

(-)-zeylenone

OHO

HO

BzO

OBz

CO2 Me

HOOH

OH

(MeCO)2CH(OMe)3

CSA (93%)

CO2 Me

OO

OH

MeOOMe

CO2 Me

HOO

O+

OMeOMe

CSA, MeOH

TBDMSClIm, DMAP

(97%)

CO2 Me

TBDMSOO

O

OMeOMe

i) DIBAL-H (92%)ii) BzCl, DMAPPy (97%)

CH2OBz

TBDMSOO

O

OMeOMe

CH2OBz

TBDMSOO

O

OMeOMe

i) OsO4, NMO (94%)ii) Me2C(OMe)2, TsOH(99%) TFA/H2O (1:1)

(79%)

OO

CH2OBz

TBDMSOOH

OH

OO

TBAF PhCO2H

(94%)

Ph3P, ImI2 (87%)

CH2OBz

TBDMSO

OO

CH2OBz

HO

OO

BzCl, DMAPPy (99%)

CH2OBz

BzO

OO

SeO2, THF(40%)

CH2OBz

BzO

OO O

CH2OBz

BzO

HOHO O

TFA/H2O (9:1)(85%)

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

natural product

cyclohexene

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

Liu, A.; Liu, Z. Z.; Zou, Z. M.; Chen, S. Z.; Xu, L. Z.; Yang, S. L. Tetrahedron, 2004, 60, 3689.

racemic complex

(-)-methyl shikimate 10% 83%

M



OHHO

CO2Me

OH

Chiral syntheses of (-)-shikimic 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

CO2HHO

HOOH

OH

(-)-quinic acid

CO2NH2HO

OAc

p-TsCl, Py37 oC, 7 days

OAc

CN

OH

CO2H

aq. NaOHreflux 2.5 h

OO

OO

OO

aq. H2SO4 reflux

OH

CO2H

HOOH

(-)-shikimic acid

Dangschat, G.; Fischer, H. O. L. Naturwissenschaften 1938, 26, 562. Dangschat, G.; Fischer, H. O. L. Biochim. Biophys. Acta 1950, 4, 199.

CO2MeHO

HOOH

OH

BzCl, Py (85%)

CO2MeHO

BzOOBz

OBz BzOOBz

OBz

SO2Cl2, Py-70 oC (78%)

OR

POCl3, Py (75%)

NaOMeMeOH

OH

CO2Me

HOOH

(-)-methyl shikimate(-)-methyl quinate

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.

CO2MeHO

HOO

O

MeMe

OMe

MeO

butan-2,3-dione(MeO)3CH, CSAMeOH, D (79%)

(-)-quinic acid

CO2MeHO

TBSOO

O

MeMe

OMe

MeO

TBSOTfEt3N (97%)

Martin's sulfuraneCH2Cl2, rt (83%)

TBSOO

O

MeMe

OMe

MeO

TBSOO

O

MeMe

OMe

MeO

CO2Me CO2Me

+

A BA:B 30:1

TFA, H2Ort

Box, J. M.; Harwood, L. M.; Humphreys, J. L.; Morris, G. A.; Redon, P. M.; Whitehead, R. C. Synlett 2002, 2, 358.

OHO

HO

OH

OH

OH

acetonec. H2SO4

(cat.)

O

O O

O

OOH

i) BnCl, NaH, DMFii) c. HCl, MeOH, H2O

O

O O

HO

HOOBn

NaIO4, H2O, rt

O

O O

OHC OBnO

O O

OBnHO

NaBH4, EtOH

lyxo-alcohol(66% from D-mannose)

O

O O

OBnF3CO2CSO(CF3SO2)2O

Py, CH2Cl2, -30 oC100%

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

O

O O

OBn(MeO)2OP

t-BuO2Ci) Pd-C (10%), MeOH, H2ii) NaH, THF (73%, two steps)

CO2t-Bu

OHOO

aq. TFA (100%)

(-)-shikimic acid10 steps, 39% overall yield

D-mannose

(-)-methyl shikimate

OHHO

CO2H

OH

From carbohydrates

Fleet, G. W. J.; Shing, T. K. M.; Warr, S. M. J. Chem. Soc. Perkin Trans. I, 1984, 905.

From (-)-quinic acid

CO2HHO

HOOH

OH

butane diacetal

CO2Me


HO

OHOH

1α,dihydroxy-19-norprevitamin D3

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

Sarandeses, L. A.; Mascerenas, J. L.; Castedo, L.; Mourino, A. Tetrehedron Lett. 1992, 33, 5445.

OH

OMOMLDA, THF, -78 oCPhNTf2 (89%)

OTfH

OMOM

vinyl triflate

HOOH

OH

CO2Hi) MeOH, HCl (cat.)(98%)ii) TBSCl, TEADMAP (82%)

TBSOOH

OTBS

CO2Me

TBSOO

OTBS

CH2OH

i) PhOC(S)Cl, DMAP (93%) ii) DIBAL-H (86%)

OPh

S

n-Bu3SnHAIBN (cat.)

(63%)

TBSO OTBS

CH2OH

MnO2 (82%)

TBSO OTBS

CHOi) Zn, Ph3P, CBr4Py (93%)ii) n-BuLi (80%)

TBSO OTBSName reaction

(-)-shikimic acid

Name reactionenyne

vinyl triflate

+

enyne

(Ph3P)2PdCl2TEA, DMF, 75 oC

OH

TBSO OTBS

85%

i) H2, Lindlar's catalystquinolineii) TBAF, THF

80%

1α,dihydroxy-19-norprevitamin D317% overall yield, 11 steps

known compound derived fromvitamin D2

Synthesis of (-)-MK7607 and other carbasugars

Song, C.; Jiang, S.; Singh, G. Synlett 2001, 12, 1983.

OHHOOH

OH

OH

(-)-MK7607

OHHOOH

OAc

OH

OAcAcOOAc

OAc

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

gabosine K pentaacetate of carba-β-D-altropyranose

OH

CO2H

HOOH

OH

CO2Me

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

OO

Tf2O, DMAP, PyCH2Cl2 (98%)

OTf

CO2Me

OO

CsOAc, DMF(81%)

CO2Me

OO

OH

CO2Me

OO

OHCO2Me

OO

HOHO

+OsO4, NMO

A(38%) B (35%)

AMe2C(OMe)2, CSA

(98%)

CO2Me

OO

O

ODIBALH(99%)

OO

O

O

OH

TFA-H2O(92%)

(-)-MK7607HO

OHOH OHHOOH

OH

OH


OHHO

CO2Et

OH

(-)-shikimic acid

Kilogram scale synthesis of Oseltamivir phosphate (Tamiflu)

-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.

CO2EtO

NH2.H3PO4

AcHN

CO2HO

NH2

AcHN

GS-4104 GS-4071

i) EtOH, SOCl2ii) 3-pentanone, TsOHiii) MsCl, Et3N

80%

CO2EtO

O

OMs

TMSOTfBH3.Me2S

63-75%

CO2EtO

OMsHO

major product

KHCO3, aq. EtOH96%

CO2EtO

O

NaN3, NH4Claq. EtOH (86%)

CO2EtO

N3

HO

CO2EtO

OHN3

+

A BA:B 10:1

Me3P(97%)

CO2EtO

HNaziridine (74% purity)

CO2EtO

N3

AcHN

i) NaN3, NH4ClDMF (44%)ii) Ac2O

CO2EtO

NH2

AcHN

i) Ra-Ni, H2EtOHii) 85% H3PO4

(71-75%)

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.

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

O

O

CO2Et

NH2

i) MgBr2.OEt2 (0.2 equiv.)t-BuOMe/MeCN 9:155 oC, 16hii) (NH4)2SO4/H2O

O CO2Et

HOHN+

i) Pd/C, EtOHH2N(CH2)2OHrefluxii) H2SO4/H2O

77%97%

O CO2Et

HONH2

i) PhCHO, tBuOMe, -H2Oii) MsCl, Et3Niii) allyl amine, 112 oC, 15 hiv) HCl/H2O

80%

O CO2Et

H2NHN

Ac2O, AcOH, MsOHt-BuOMe, 15 h, 20 oC

83%

O CO2Et

AcHNHN

O CO2Et

AcHNNH2.H3PO4

i) Pd/C, EtOHH2NCH2CH2OHrefluxii) H3PO4, EtOH

70%

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

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

Oseltamivir phosphate in 35-38% overall yield from

the epoxide



CO2HHO

HOOH

(-)-shikimic acid

i) EtOH, SOCl2refluxii) evaporation

CO2EtHO

HOOH

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

97%95%

CO2Et

OH

O

O

CO2Et

OMs

O

O

i) MsCl (1.3 eq)ii) Et3N (2.0 eq)EtOAc, 0-5 oCiii) filtrationiv) evaporationv) cryst. MeOH

89%

i) pentanone (15 eq)CF3SO3H (0.045 eq)ii)extractioniii) evaporation

98%

CO2Et

OMs

O

O

i) Et3SiH (1.3 eq)TiCl4 (1.1 eq)CH2Cl2, -34 oC, 2-6 hii) poured on H2Oextr.NaHCO3

CO2Et

OMs

O

HO

CO2Et

OMs

HO

O

regioisomers 32:1

+

CO2Et

OMs

HO

HO+

2-4%

i) NaHCO3 (1.6 eq)EtOH/H2O, 60 oC, 1.5 hii) extr. n-hexaneiii) cryst n-hexane

CO2EtO

O

80% from pentylidnene ketal,63-65% from (-)-shikimic acid in

6 stepsassay HPLC > 98%

Industrial synthesis of oseltimivir phosphate (50-250 kg)

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

O CO2Et

AcHNNH2.H3PO4

ambhaikar jan 05

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