Colchicine - David A. Evansevans.rc.fas.harvard.edu/pdf/smnr_1997-1998_Michael_Forrest.pdfA Brief History of Colchicine • Use of the autumn crocus or meadow saffron Colchicum autumnale

Colchicine

An Evans Group Afternoon Seminar

Forrest Michael

MeO

MeO

OMe

OMe

O

NHAc

Active component of the meadow saffron or autumn crocus Colchicum autumnale

Leading ReferencesChemistry and Biological Activity: Brossi "The Alkaloids" v.23, p.1 Brossi "The Alkaloids" v.41, p.125History and Biology: Eigsti "Colchicine in agriculture, medicine, biology, and chemistry"Most Recent Synthesis: Banwell, Pure and Appl. Chem., 1996, 539

A B

C

01-title 4/10/98 9:16 AM

A Brief History of Colchicine

• Use of the autumn crocus or meadow saffron Colchicum autumnale for both medicinal and nefarious purposes has been known since the time of ancient Greece

• The plant is named after the region of Colchis, located along the Eastern tip of the Black sea

• The infamous sorceress Medea may have used it in her black arts, and landowners of the region probably grew it for its toxic properties

• Described in Dioscorides' De materia medica (1st c. AD)-"But being eaten, it killeth by choking like to ye [mushrooms]... But there help them which eat these,...cows milk being drunk"

• A related species (Colchicum parnassicum), which contains a smaller amount of colchicine, was described as such: "The root of this is a remedy for ye toothache...But ye leaves being sodden in wine and smeared on do dissolve Oedemata (swellings) and tumors"

• Also known as "mort a chien" (death to dogs)

• Earliest documented use as medicine was in the treatment of gout as early as 560 AD

• Colchicine was first isolated in pure form in 1820

• First structure proposed by Windaus in 1924 on the basis of degradation studies

• Correct structure proposed by Dewar in 1945

Brossi "The Alkaloids" v.23, p.1Brossi "The Alkaloids" v.41, p.125Eigsti "Colchicine in Agriculture, Medicine, Biology, and Chemistry"Dioscorides "De Materia Medica"

MeO

MeO

OMeO

OMe

Me

NHAc

MeO

MeO

OMe

OMe

O

NHAc

Windaus, 1924Dewar, 1945

02-history 4/10/98 9:37 AM

Biological Activity

Brossi "The Alkaloids" v.23, p.1Brossi "The Alkaloids" v.41, p.125

• In 1889, it was discovered that colchicine caused "a veritable explosion of mitosis". However, it was noticed that a majority of the dividing cells stopped at metaphase

• This useful property has been used to create and study polyploidy in plants

• Colchicine inhibits the formation of the microtubules necessary for chromosome transport during metaphase

• It forms a 1:1 complex with tubulin, which binds to the end of the forming microtubule and inhibits further polymerization

• This binding is slow and essentially irreversible and likely involves changes in conformation of both the protein and colchicine

• It has been calculated that the A/C dihedral angle in bound colchicine is nearly 0°

• Its use in the treatment of gout, familial Mediterranean fever, and certain liver disorders is directly related to its tubulin binding activity

• Although analogs have been tested for anti-cancer activity with some success, the potent toxicity (lethal dose ~10mg) prohibits its use as a drug

• For all analogs, anti-gout activity, tubulin binding affinity, and in vivo toxicity of analogs closely parallel one another

• In addition to its medicinal uses, colchicine is an important substance for biological research

MeO

MeO

OMe

OMe

O

NHAc

Colchicine

03-Bio 4/10/98 9:37 AM

Structure-Activity Relationship

Brossi "The Alkaloids" v.23, p.1Brossi "The Alkaloids" v.41, p.125

MeO

MeO

OMe

OMe

O

NHAc

Demethylation of A-ring results in loss of activity in order of importance 1>2>3. Esterification of the resulting phenols restores activity.

In the 10-position activity decreases in the series SMe>NR2>OMe>OH>>H. An Et substituent in this position is also active

Iso (C-9/10 reversed) compounds have no activity at all

N-acetyl group can be replaced with almost acyl group without loss of activity, N-alkyl versions are slightly less active

Pseudo-equitorial NHAc group gears the biphenyl into the (aS)-atropdiastereomeric form

Only compounds with (aS) axial chirality show activity

Contraction of the tropolone ring to a phenyl ring results in a slight decrease in activity

109

12

37

Activation energy for atropisomerism = 22 kcal/mol

The 2,3-methylenedioxy compound (cornigerine) is as active as colchicine

A B

C

04-SAR 4/10/98 9:37 AM

Biosynthesis of Colchicine

HN

OH

HO

HO

CHO

HO

H2N

OH

HO

CO2H

NH2

H2N

HO

CO2H

Tyrosine Dopamine

Phenylalanine

N

Me

OMe

HO

MeO

OH

MeO

Autumnaline

A

C C

A

A

C

A

C

• Deamination of phenylalanine to cinnamic acid followed by reduction to the saturated aldehyde occurs before oxidation of the aromatic ring

Brossi "The Alkaloids" v.23, p.1Brossi "The Alkaloids" v.41, p.125Herbert Tetrahedron, 1990, 7119

MeO

MeOMeO

OMe

O

NHAcA B

C

05-Biosynth 4/10/98 9:37 AM

Biosynthesis of Colchicine

MeO

MeO

OMe

OMe

O

NHR

NMe

HO

MeO

OMe

MeOOH

NMe

MeO

MeO

OMe

MeOO

Autumnaline O-Methylandrocymbine

Colchicine R = Ac

NMe

MeO

MeO

OMe

MeOO

Cytochrome P-450

Demecolcine R = Me

Brossi "The Alkaloids" v.23, p.1Brossi "The Alkaloids" v.41, p.125Zenk Tetrahedron Lett., 1996, 8161

06-Biosynth2 4/10/98 9:37 AM

Retrosynthetic Analyses of Colchicine-A->AB->ABC*->ABC

Eschenmoser, Boger

MeO

MeO

OHO

MeO

MeO

OHO

O

MeO

MeO

OMeO

MeO

MeOMeO

S

N

MeO

MeO

OMe

CO2Me

MeO

MeO

OMe

S

N

CO2H

CO2H

MeO

MeO

OMeCN

CO2Me

HO2C

O

MeO

MeO

OMeO CO2Me

O

van Tamelen Woodward Martel

MeO

MeO

OMe

OMe

O

NHAc

MeO

MeO

OMe

OMe

O

NHAc

07-Retrosynth 4/10/98 9:36 AM

Eschenmoser Synthesis-Formation of the B ring

A. Eschenmoser Helv. Chim. Acta 1961, 540

HO

HO

OH

MeO

MeO

OH OOMe

MeO

MeO

OHO

1. KIO3, H2O2. Me2SO4, NaOH

1. H2, Pd/C, THF2. LAH, Et2O3. H3PO4

35% 58%

MeO

MeO

OHO

O

4 mol% t-BuOK, Et3NC6H6/t-AmOH, reflux

72%

CO2Me

MeO

MeO

OMeO

O

MeI, K2CO3

93%

MeO

MeOO

O

CO2Me

unknown stereochemistry

1 equiv t-BuOK, Et3NC6H6/t-AmOH, reflux

CO2Me

pyrogallol

1 equivt-BuOK

MeO

MeOMeO

OMe

O

NHAcA B

C

08-Eschenmoser1 4/10/98 9:36 AM

MeO

MeO

OMeO

O

O

Cl

Eschenmoser Synthesis-Elaboration of the C ring (Clint Eastwood)

MeOH/H2SO4CH2N2

MeO

MeO

OMe

CO2Me

CO2Me

Cl

MeO

MeO

OMeO

O

OO O

Cl

∆

One regioisomer

•Reaction of the α-pyrone with methyl propiolate gave a 1:1 mixture of regioisomers•Norcaradiene form preferred when carboxylates are tied back as the anhydride•No trace of other cycloheptatriene isomers resulting from ε-attack observed

90%

MeO

MeO

OMe

CO2Me

CO2Me

t-AmOK, C6H6

90%


68%

MeO

MeO

OMe

CO2H

CO2MeNaOH, MeOH/H2O

87%

MeO

MeOMeO

OMe

O

NHAcA B

C


Eschenmoser Synthesis-Tropolonization (Lee Van Cleef)


MeO

MeO

OMe

CO2H

CO2Me

MeO

MeO

OMe

O

CO2Me

HO

OsO4, pyr, Et2O, rtthen KClO3, NaHCO3, MeOH/H2O, 100°C

38%

•KClO3 not necessary for decarboxylation, but improves the yield somewhat•Significant losses occured during the isolation of the tropolone (spectroscopic yield 54%)

MeO

MeO

OMe

OHO

1. NaOH, H2O, reflux2. SiO2, 270°C

MeO

MeO

OMe

O

NH2

1. TsCl, py, rt2. NH3, EtOH, 90°C

18%

MeO

MeO

OMe

ONH2

MeO

MeOMeO

O

H2N

27%<15%, exact amt. not specified

KOH, MeOH/H2O

82%

Desacetamidocolchiceine

+ +

MeO

MeO

OMe

O

OH

64%

MeO

MeOMeO

OMe

O

NHAcA B

C


Eschenmoser Synthesis-Amination (The Ugly)


• Attempted bromination of the other tropolone isomer gave no desired product• The major product from ammonolysis was elimination (50%)


MeO

MeO

OMe

O

OH

MeO

MeO

OMe

O

OMe

MeO

MeO

OMe

OMe

O

MeO

MeO

OMe

O

NH2

NH2

CH2N2, 70%

1:1

1. NBS, (BzO)2, CCl4, 15%2. NH3, EtOH/H2O, 6%

MeO

MeO

OMe

O

OH

NH2 KOH, EtOH/H2O, 40%

Desacetylcolchiceine

+

MeO

MeOMeO

OMe

O

NHAcA B

C


Resolution, Acetylation, and Methylation

Hardegger Helv. Chim. Acta 1957, 193

• (+)-Desacetylcolchiceine could be isolated from the mother liquor and crystallized to enantiomeric purity

MeO

MeO

OMe

O

OH

NH2

(±)-Desacetylcolchiceine

MeO

MeO

OMe

O

OH

NH2

(–)-Desacetylcolchiceine

MeO

MeO

OMe

O

OH

NHAc

(–)-Colchiceine

1. D-camphorsulfonic acid2. NaOH/H2O, 80%

MeO

MeO

OMe

O

OMe

NHAc

(–)-Isocolchicine

MeO

MeO

OMe

OMe

O

NHAc

(–)-Colchicine

Ac2O, py, 90%

CH2N2

1:1

NaOH, MeOH/H2O

+

12-Resolution 4/10/98 10:31 AM

van Tamelen Synthesis-C-ring Formation

E. E. van Tamelen Tetrahedron 1961, 8

MeO

MeO

OMeO

MeO

MeO

OMeO

CN

t-BuOK, t-BuOH

CN

73%

MeO

MeO

OMeCN

OH

CO2Me

Zn, BrCH2CO2MeC6H6, Et2O reflux

2:1 cis:trans

KOH, MeOH/H2O, 92%

MeO

MeO

OMeO CO2Me

O

MeO

MeO

OMeCO2H

OH

CO2H1. DCC, py2. CH2N2

41%

• Attempted reaction of several other electrophiles with starting ketone failed due to steric hindrance from ortho methoxy group• Diastereomers from the Reformatsky reaction were separated and carried through the sequence separately

From Eschenmoser synthesis

57%

MeO

MeOMeO

OMe

O

NHAcA B

C

13-van Tamelen1 4/10/98 10:30 AM

van Tamelen Synthesis-Acyloin Condensation

MeO

MeO

OMe O

OH

OH

Na, NH3

O

OCO2Me

OMeMeO

MeO OO

CO2Me

OMe

OMe

OMe

trans ester-lactone cis ester-lactone

MeO

MeO

OMe

O

Na, xylenes

• Na in NH3 yielded no recognizeable products• isolated as a 9:1 mixture of diastereomers at C-9• Na in xylenes yielded no recognizeable products


10%

O

O

CO2Me

OMe

MeOMeO

14-van Tamelen2 4/10/98 10:30 AM

van Tamelen Synthesis-Completion

MeO

MeO

OMe O

OH

OH


MeO

MeO

OMe O

OH

O

Cu(OAc)2, MeOH

quant.

MeO

MeO

OMe

O

OH

TsOH, C6H6reflux

MeO

MeO

OMe

O

OH

NBS, CHCl3, reflux

40%

desacetamidocolchiceine

MeO

MeOMeO

OMe

O

NHAcA B

C

15-van Tamelen3 4/10/98 10:30 AM

van Tamelen Synthesis-The Not-Quite-So-Ugly


• Attempted bromination of the other tropolone isomer gave no desired product


MeO

MeO

OMe

O

OH

MeO

MeO

OMe

O

OMe

MeO

MeO

OMe

OMe

O

MeO

MeO

OMe

O

OMe

N3

CH2N2, 70%

1:1

1. NBS, (BzO)2, CCl4, 15%2. NaN3, MeOH, 65%

MeO

MeO

OMe

O

OH

NH2

1. H2, Pd/C2. 1N HCl


+

75%

16-van Tamelen4 4/9/98 11:02 AM

Nakamura Synthesis-B ring closure

Nakamura Chem. Pharm. Bull. 1962, 291

MeO

HO

OHEtO2C

O

MeO

HO

O

O

MsOH

75%

MeO

HO

O

O

1. allylBr, K2CO3, 71%2. DMA, 200°C, 85%

MeO

HO

O

O

CO2HHO2C

1. KOH, MeOH, 80%2. O3, CH2Cl2, 90%3. malonic acid, py, aniline, 44%

MeO

MeO

MeOHO2C

CO2H1. H2, Pd/C, 86%2. 180°C, 99%3. Me2SO4, KOH, 78%

MeO

MeO

OMe

O

1. Ac2O, KOAc, 10% -or-1. CH2N2, MeOH/H2O, quant2. t-BuOK, xylene, 30%

MeO

MeOMeO

OMe

O

NHAcA B

C

17-Nakamura1 4/10/98 10:30 AM

Nakamura Synthesis-Tropolonization

Nakamura Chem. Pharm. Bull. 1962, 291, 299

MeO

MeO

OMe

O

MeO

MeO

OMe

NHAc1. NH2OH, py, EtOH, quant.2. LAH, THF, 10%3. Ac2O, py, quant.

• Yield of LAH reduction before recrystallization was about 40%• Resolution of free amine with tartaric acid or camphorsulfonic acid failed• The major product from the bromination reaction was a bromodiene that could not be converted to the desired triene

MeO

MeO

OMe

NHAcBF3•Et2O

36%

MeO

MeO

OMe

NHAc

NBS, collidine, 40%

MeO

MeO

OMe

NHAc

O

1. PCl52. aq. KOH3. conc. HCl

7%

MeO

MeO

OMe

NHAc

O

OH

1. NH2NH2, EtOH, 7%2. aq. NaOH, 75%

Unknown stereochemistry

colchiceine

18-Nakamura2 4/10/98 10:31 AM

Woodward Synthesis-Isothiazole Formation and Elaboration

Woodward The Harvey Lecture Series 1963, 31

NH2Me

MeO2CS

Cl Cl

N

S

Me

MeO2CN

SMeO2C

Ph3P

Br–

1. NBS, hν, CCl42. Ph3P MeO

MeO

OMe

O

H

S

N

MeO

MeO

MeO

MeO2C

Et3N, Et2O

+

1. NaOMe, MeOH, reflux2. NH2NH2, H2O2, cat. Cu2+

1. LAH2. MnO2

CO2MePh3P

S

N

MeO

MeO

MeO

HO2C

S

N

MeO

MeO

MeO

OHC

1.

2. aq. NaOH3. hν, I2

• "One aspect of our plan to base a synthesis of colchicine upon a simple isothiazole intermediate might well have given us pause. A forceful reminder of the fantastic multiformity of organic chemistry is provided by the fact the although literally millions of different organic molecules were known at the time our plan was laid down, no simple isothiazole of any kind had been prepared!"• The mixture of geometrical isomers originally formed in the olefination was transformed to the all-trans arrangement with hν, I2 procedure

NH2Me

MeO2CS

Cl

MeO

MeOMeO

OMe

O

NHAcA B

C

19-Woodward1 4/10/98 10:30 AM

Woodward Synthesis-B and C-ring Formation


1. 70% aq. HClO4, 60°C2. NH2NH2, H2O2, cat. Cu2+

S

N

MeO

MeO

MeO

HO2C

S

N

MeO

MeO

MeO

HO2C

S

N

MeO

MeO

MeO

HO2C

CO2H

1.

2. CO2

Li

1. Me+

2. NaH, dioxane, 90%

MeO

MeO

MeO

S

N

O

CO2Me

MeO

MeO

MeO

S

N

O

OH

1. aq. HOAc, H2SO4, ∆2. HCO2Et, NaH, THF

S STs Ts

KOAc, i-PrOH, reflux

MeO

MeO

MeO

S

N

O

SS

MeO

MeOMeO

OMe

O

NHAcA B

C

20-Woodward2 4/10/98 10:30 AM

Woodward Synthesis-Tropolonization


MeO

MeO

MeO

S

N

O

SS

MeO

MeO

MeO

S

N

O

OH

aq. HOAc, Hg(OAc)2,cat. HClO4

MeO

MeO

MeO

S

N

OAc

OAc

Ac2O, py

MeO

MeO

MeO

S

N

O

OH

alkali

MeO

MeO

MeO

NHAc

O

OH

1. Raney Ni, aq. NaOH2. NaBH43. Ac2O, py

colchiceine

21-Woodward3 4/10/98 10:48 AM

Martel Synthesis-B-ring Closure

Martel J. Org. Chem. 1965, 1752

MeO

MeO

OMe

Cl CO2EtONa

EtO2C

1. NaI then

2. NaOH, MeOH/H2O, 70%3. CH2N2, quant

MeO

MeO

OMeCO2Me

MeO

MeO

OMe

O

CO2Me

TsOH, C6H6, reflux

80%

• If not rigorously dried by azeotropic removal of water, the acid-catalyzed cyclization did not stop at 1, but cyclized further to give the tricyclic ketone product of Friedel-Crafts type acylation• "The yields given in this series of reaction [sic] [from 1 to 2] are those obtained in the first trials but we have indications suggesting that all the steps can be adjusted to proceed nearly quantitatively."• The conversion of 1 to 2 could also be achieved via an alternate route in 7 steps and 5% overall yield

MeO

MeO

OMeCO2Me

CHO

DMF, POCl3

43%

NCCH2CO2Me, piperidine, AcOH, C6H6, reflux

1. H2, PtO22. KOH, MeOH, H2O, 47%3. 200°C4. CH2N2, CH2Cl2

MeO

MeO

OMe

MeO2CCN

81%

MeO

MeO

MeO

MeO2C MeO2C CN

1

2

MeO

MeOMeO

OMe

O

NHAcA B

C

22-Martel1 4/10/98 10:48 AM

Martel J. Org. Chem. 1965, 1752

MeO

MeO

OMe

MeO2CCN

Martel Synthesis-C-ring Formation

K, toluene, refluxthen BzCl, py, 17%

MeO

MeO

OMe

OBz

CN

1. KOH, MeOH/H2O, 90%2. Na, C6H6, reflux then (BzO)2, rt, 76%

MeO

MeO

OMe

O

OBz

CN

MeO

MeO

OMe

O

OH

aq. NaHCO3, EtOH, 70%

• The final compound has already been converted to desacetamidocolchiceine in 40% yield in the synthesis by van Tamelen

MeO

MeOMeO

OMe

O

NHAcA B

C

23-Martel2 4/10/98 10:48 AM

Boger Synthesis-[3+4] Cycloaddition

MeO

MeO

OMeO

O

• The pyrone used in the cycloaddition is an intermediate on Eschenmoser's route to colchicine• Steric hinderance disfavors the [4+2] cycloaddition at higher temperatures

Boger J. Am. Chem. Soc. 1986, 6713

OO

OOMeO

MeO

OMe

O

O

O

MeOMeO

MeO

O

O

75°C

O

MeOMeO

MeO

O

O

O

75°C[3+4]

6.2 kbar, rt[4+2]

MeO

MeO

OMe

O

∆, hν, LA

88%

73%

210°C, then HOAc, THF/H2O, 60%-or-HOAc, THF/H2O, 100°C, 70%

MeO

MeOMeO

OMe

O

NHAcA B

C

24-Boger1 4/10/98 10:48 AM

Boger Synthesis-Completion

• The hydrazine amination is similar to one performed by Nakamura in his synthesis• The Eschenmoser transposition of 11-hydroxytropone into 9-hydroxytropone is accomplished by tosylation, aminolysis, and hydrolysis

Boger J. Am. Chem. Soc. 1986, 6713

MeO

MeO

OMe

O

MeO

MeO

OMe

NH2

MeO

MeO

OMe

OH2N

NH2NH2, EtOH, rt

54%

46%

+

MeO

MeO

OMe

OHO

MeO

MeO

OMe

O

OH

KOH, EtOH/H2O, 100°C

Eschenmoser, 15%

87% 84%

desacetaminocolchiceine

MeO

MeOMeO

OMe

O

NHAcA B

C

O

25-Boger2 4/10/98 10:48 AM

Retrosynthetic Analyses of Colchicine-A->AC->ABC via Oxidative Phenolic Coupling of Intact Tropolone

MeO

MeO

OMe

OMe

O

NHAc

MeO

MeO

OMe

OH

O

MeO

MeO

OMe

OH

O

MeO

MeO

OMe

CHO

OH

O

O

O

OH

MeO

MeO

OMe

OH

KatoScott, Matsui

26-Retrosynth2 4/10/98 10:48 AM

Scott Synthesis-Set-Up for Phenol Coupling

Scott Tetrahedron 1965, 3605

O

OH

O

OH

O

O

H

MeO

MeO

OMe

∆

4.7 equiv

MeO

MeO

OMe

O O

O

OH

MeO

MeO

OMe

OMe

OMe

OMe

20% based on aldehyde78% based on anhydride(17% based on aldehyde)

HO

HO

OH

O

OH

MeO

MeO

OMe

O

OH

48% HBr, reflux

60%

1. Cu-bronze, 200°C, 70%2. H2, Pd/C, 96%

+

• The starting anhydride is available in 3 steps (7% yield) from the oxidation of pyrogallol

MeO

MeOMeO

OMe

O

NHAcA B

C

27-Scott1 4/10/98 10:48 AM

Scott Synthesis-Phenol Coupling

Scott Tetrahedron 1965, 3605

RO

RO

OH

O

OH

• Attempted cyclizations of the bismethylated compound 2 with MnO2, K3Fe(CN)6, Pd/C, and PbO2, returned recovered starting material

• Compound 1 and the cyclization product were both extremely sensitive to base, decomposing slowly even in pH 7 aqueous solutions

• Most oxidation conditions resulted in decomposition of 1 and the product: air/Na2CO3, air/BaOH, air/NH4OH, PbO2, MnO2, KIO3

• Only K3Fe(CN)6 and FeCl3 did not decompose the starting material and product

• For the oxidation with K3Fe(CN)6, k2/k1 = 1000, and the pyrone could be isolated in 20% yield

• The optimized conditions (FeCl3, 6 N H2SO4, EtOH, CHCl3, 72h) resulted in a 4-5% yield of desired product by UV spectroscopy. Isolation of the product from this reaction could be accomplished by paper chromatography under inert atmosphere (2%)

1: R = H2: R = Me

HO

HO

OH

O

OH

O

O

HO2C

O

OH

k1 k2

oxidant oxidant

28-Scott2 4/9/98 12:43 PM

Matsui Agri. Biol. Chem. 1967, 675Matsui Agri. Biol. Chem. 1968, 995

Matsui Synthesis-B-ring Formation

• The starting material shown was originally synthesized by their own method in 6 steps and 4% overall yield. To illustrate the Pshorr reaction as a phenol coupling method, it was synthesized via the method of Scott (3 steps, 52% yield)• Attempted cyclization of the diazonium chloride synthesized from the aminotropolone with isoamyl nitrite/HCl failed

MeO

MeO

OMe

O

OH

MeO

MeO

OMe

O

OH

MeO

MeO

OMe

O

OHH2N

MeO

MeO

OMe

O

OHN

NAr

1. i-AmONO, H2SO4, dioxane2. Cu

5%

ArN2+Cl–, NaOH, H2O

90% Ar = p-tolyl

H2, Pd/C(yield not given)

MeO

MeOMeO

OMe

O

NHAcA B

C

29-Matsui1 4/10/98 10:48 AM

Kato Bull. Chem. Soc. Jpn. 1974, 1516

Kato Synthesis-Synthesis of the Phenol Coupling Intermediate

• The starting alcohol was synthesized from the cinnamyl ester in two steps and 92% yield• The tropolone was previously cyclized to desacetamidocolchiceine by Matsui

MeO

MeO

OMe

O

OH

MeO

OMe

MeO

OH

1. TsCl, py2. CpNa

MeO

OMe

MeO

MeO

OMe

MeO

O

Cl Cl

O

Cl Cl

42% from alcohol

AcOK, AcOH, H2O, reflux

66%

one regioisomer

MeO

MeOMeO

OMe

O

NHAcA B

C

30-Kato1 4/10/98 11:04 AM

Retrosynthetic Analyses of Colchicine-A--AC'--ABC'--ABC via Cyclopropyl Ring Expansion

MeO

MeO

OMe

OMe

O

NHAc

MeO

MeO

OMe

OMe

O

NHAc

MeOMeO

MeO

OH

OMe

MeO

MeO

MeO

OH

OHMeO

OMe

MeOMeO

MeO

HO

O

CO2R

OMe

O

MeO OMe

MeOMeO

MeO

CO2R

Tobinaga BanwellEvans

MeOMeO

MeO

O

OMe

MeO

MeO

MeO

OH

OOMeMeO

31-Retrosynth3 4/10/98 11:04 AM

Tobinaga Chem. Comm. 1974, 300

Tobinaga Synthesis-Oxidative Phenol Coupling

• The iron reagent used for the oxidative coupling is prepared by adding DMF to a Et2O solution of FeCl3 • Other attempts to cyclopropanate the spirodienone directly failed to give the desired product• The final product has already been transformed to colchicine by Eschenmoser

MeO

MeO

MeO

O

OMe

For R = H:1. [Fe(DMF)2Cl2][FeCl4], 91%2. CH2N2, quant.

-or-For R = Me:Anodic Oxidation, CH3CN,0.95 V, HBF4, 80%

MeOMeO

MeO

O

OMe

1. NaBH42. CH2I2, Zn-Cu3. Jones' reagent

42%

MeO

OMe

MeO

O

OMe

2:1 Ac2O/H2SO4, air

Me2S=CH2

MeO

MeO

MeO

CHO

OMe

MeO

MeO

MeO

OMe

O

Me2S(O)=CH2

Desacetamidoisocolchicine

MeO

MeO

RO

OH

OMe

90%

32-Tobinaga 4/10/98 11:04 AM

Evans J. Am. Chem. Soc. 1978, 4593Evans J. Am. Chem. Soc. 1981, 5813

Evans Synthesis-Synthesis of Phenol Coupling Intermediate

OH

OMe

OMe

1. Me2SO4, aq. KOH, reflux, 90%2. Anodic Oxidation, KOH, MeOH, 4V, 91%

OMe

OMeMeO

MeO OMeOMe

MeO OMe

O

OMeMeO OMe

O

OMeMeO OMe

MeOMeO

MeO

HO

(CO2H)2, THF/H2O

Me2S(O)=CH291%

MeO

MeO

MgBrOMe

THF, rt, 90%

MeO

MeOMeO

OMe

O

NHAcA B

C

72%

33-Evans1 4/10/98 11:04 AM


Evans Synthesis-Cyclization and Rearrangement

OMeMeO OMe

MeOMeO

MeO

HO

O

OMe

OMe

OMeMeO

O

OMeOMe

OMeMeO

OMe

MeO

MeO

OMe

OOMe

O

OMe

OMe

OMe

• Reaction of 1 with TFA for 18 h gave the dihydrotropolone 4 in 68% yield, whereas BF3•OEt2 gave only a 23% yield• All intermediates shown could be isolated by stopping the reaction before it went to completion• Formation of 3A is favored over 3S upon initial cyclization• Treatment of either 3S or 3A with TFA resulted in a mixture of 3S, 3A, and 4• Compound 3S is identical with the compound synthesized by Tobinaga in the course of his synthesis• Treatment of 3S with BF3•OEt2 provided 4 in 40% yield, whereas 3A failed to react under the same conditions• The 3S/3A interconversion is postulated to proceed through a retro-Friedel-Crafts type mechanism• Compound 4 can be converted to desacetamidoisocolchicine by the action of DDQ in 72% yield

1

2

3S

3A

4

H+ onlyH+ or LA

H+ or LA

H+ only

H+ only

H+ or LA

H+ or LA

34-Evans2 4/10/98 11:04 AM

Evans Synthesis-Spirocycles

• MM2 minimized structures

O

OMe

OMeMeO

O

OMe

OMeMeO

3S

3A

OMe OMe

35-Evans4a 4/10/98 11:04 AM


Evans Synthesis-Synthesis of Phenol Coupling Intermediate

OMeMeO OMe

O

OMe

MeOMeO

MeO

HOCO2R

CO2RCO2R

CO2R

OMe

MeO

MeO MeO

MeO

OMe

OMe

MeO

MeO

1. LDA, THF2.

For R = t-Bu:Me2S(O)CH2, 69%

For R = Me:CH2N2, Pd(OAc)2, 98%

3. (CO2H)2, H2O/THF

R = t-Bu: 3:2:1 mixture of diastereomers, 75%R = Me: 1:1 mixture of diastereomers at C-7, 95%

7

H2, Pd/CR = t-Bu: 70%R = Me: quant.

O

MeO

MeOMeO

OMe

O

NHAcA B

C

36-Evans3 4/10/98 11:04 AM



OMe

MeOMeO

MeO

HO

O

OMeOMe

OMeMeO

OMe

MeO

MeO

OMe

O

• Spirocyclization of the 3:2:1 mixture of diastereomers with BF3•OEt2 afforded acid 3A and lactone 3B in 23 and 56% yields respectively• No trace of the syn spiro compounds seen in the previous case was observed• Spontaneous loss of the t-Bu ester occured under the reaction conditions• The acid from 2B is the only one stereoelectronically aligned to open the cyclopropyl ketone• As expected, treatment of 3A-methyl ester with BF3•OEt2 did not result in formation of 4• 3A-methyl ester was converted to the desired product 4 with TFA, but lactone 3B was left unchanged

1

2B

4

1. HC(OMe)2NMe22. TFA

Y

X

OO

O

O H

H

CO2Me

O

OMeOMe

OMeMeO2A

CO2t-Bu

CO2t-Bu

O

OMeOMe

OMeMeO3A

CO2H

56%

23%

3B

X = CO2t-Bu

Y = CO2t-Bu

OMe

OMe

OMe

37-Evans4 4/10/98 11:04 AM



OMe

MeOMeO

MeO

HO

O

OMeOMe

OMeMeO

OMe

MeO

MeO

OMe

O

• Spirocyclization of the 1:1 mixture of diastereomers with BF3•OEt2 afforded a 1:1 mixture of 2A and 2B in 71% yield• No trace of the syn spiro compounds was observed• Equilibration of pure 2A and the 1:1 2A/2B mixture with NaOMe/DMF gave the same 40:60 mixture of 2A and 2B • 4 could be produced in 92% yield by reaction of the ketal precursor to 1 in TFA

1

2B

4

TFA

Y

X

O

CO2Me

O

OMeOMe

OMeMeO2A

CO2Me

CO2Me

X = CO2Me

Y = CO2Me TFA

38-Evans5 4/10/98 11:04 AM


Evans Synthesis-Completion of the Synthesis

OMe

MeO

MeO

OMe

O

• Compound 1 was isolated as a separable 7:3 mixture of the tropolone and its heptafulvene tautomer.• Upon sitting in CDCl3 purified samples of either tautomer were reconverted to the 7:3 mixture.

CO2Me

OMe

MeO

MeO

OMe

O

CO2H1. DDQ, 54%2. NaH, MeOH/H2O, 85%

OMe

MeO

MeO

OMe

O

NHBOC

(PhO)2P(O)N3, Et3N, t-BuOH, reflux, 54%

OMe

MeO

MeO

O

OH

NH2

HCl, H2O, 72%

1


39-Evans6 4/9/98 1:35 PM

Banwell Synthesis-B and C-ring synthesis

• Direct Robinson annulation failed due to insufficient reactivity of the starting ketone• NMR analysis of the crude reaction mixture after enone formation and decarboxylation indicated some demethylation had occured, but methylation of the crude reaction mixture alleviated this problem

Banwell J. Chem. Soc. Perkin Trans 1 1992, 1415

CHOMeO

MeO

OMe

MeO

MeO

OMe

Me

CO2Me

MeO

MeO

OMe OCO2H

1. t-BuOK, t-BuOH, 65°C2. KOH, EtOH/H2O, reflux3. H2, Pd/C

85%

PCl5, C6H6, refluxthen SnCl4+

1. NaOMe, HCO2Et, C6H6, 98%2. MVK, Et3N, 92%

MeO

MeO

OMe

O

MeO

MeO

OMe O

CHO

MeO

1. KOH, EtOH, reflux2. aq. HCl3. Me2SO4, K2CO3, acetone

64%

MeO

MeO

OMe

OOAc

H

Mn(OAc)3, C6H6, reflux

1:1 mixture of diastereomers

MeO

MeOMeO

OMe

O

NHAcA B

C

64%

80%

40-Banwell1 4/10/98 11:10 AM

Banwell Synthesis-Tropolonization

• The initial 3-step sequence to the acetonide was also performed on the other diastereomer in similar yields• Dichlorocarbene addition to the other diastereomer resulted in a low yield of a C-H insertion product due to steric shielding of the olefin• Reversing the order of the Zn reduction and acetal removal steps fails due to the extreme acid sensitivity of the monochlorocyclopropane• This same acid sensitivity may be the cause of the low yield in the Swern oxidation• Base-promoted rearrangement of a dichlorocyclopropyl enone was unsuccessful

Banwell J. Chem. Soc. Perkin Trans 1 1992, 1415

MeO

MeO

OMe

OOAc

H

MeO

MeO

OMe

H

OO

1. NaBH4, CeCl3•7H2O2. KOH, MeOH3. HClO4, acetone

73%

MeO

MeOMeO

H

OO

Cl

Cl H

NaOMe, Cl3CCO2Et, 70%

MeO

MeO

OMe

O

OMe

MeO

MeOMeO

H

HOOH

Cl

H H

1. aq. HCl, MeOH, 95%2. Zn, KOH, EtOH, 74%

MeO

MeOMeO

H

Cl

H HO

OMe

DBU, C6H6, 84% 1. Swern, 31%2. Me2SO4, K2CO3, 69%

Desacetamidoisocolchicine

41-Banwell2 4/9/98 1:35 PM

Banwell Synthesis-New and Improved

• The penultimate product of the sequence was crystallized up to 98% ee and its structure confirmed by X-ray crystallography

Banwell Pure and Appl. Chem. 1996, 539

CHOMeO

MeO

OMe

MeO

MeO

OMe

MeO

MeO

OMe

1. NaOH, MeOH, rt, 96%2. H2, Pd/C, 96%3. NaBH4, THF/MeOH, 96% Pb(OAc)4, 3A MS, 100%

+

1. CBS, 88%, 94%ee2. H2, Pd/C, 99%

MeO

MeO

MeO

1. Tl(NO3)3, MeOH, 83%2. Me2S(O)CH2, 54% at 82% conversion

O

OMe

OBn

OH

MeO OH

MeOOBn

O

MeO

MeO

OMe

MeOOH

OHOH

OOMeMeO

MeO

MeO

OMe

OH

OMeOOAc

1. TFA, 3A MS, THF/C6H6, 42%2. BnBr, K2CO3, MeCN, 88%

MeO

MeOMeO

OMe

O

NHAcA B

C

42-Banwell3 4/10/98 11:10 AM

Banwell Synthesis-New and Improved

• This marks the only synthesis of optically active colchicine that does not involve a resolution• It is also the only synthesis that selectively produces the correct tropolone isomer• The final ee of colchicine produced is only 81%-racemization occured during the Staudinger reduction

Banwell Pure and Appl. Chem. 1996, 539

MeO

MeO

MeO

TFA, CH2Cl2, 48%OH

MeO

MeO

OMe

OMe

O

OH

OOMeMeO

MeO

MeO

OMe

OMe

O

N3

DIAD, Ph3P, Zn(N3)•2py, 30%

1. Ph3P, THF/H2O2. Ac2O, py, 60%

MeO

MeO

OMe

OMe

O

NHAc

colchicine

43-Banwell4 4/9/98 1:35 PM

Summary-The NumbersMeO

MeOOMe

OMe

O

NHAc

Synthesis

Eschenmoser

van Tamelen

Nakamura

Woodward

Martel

Scott

Boger

Matsui

Kato

Tobinaga

Evans

Banwell

(±)-Desacetaminocolchiceine

17 steps, 0.234%

14 steps, 0.0425%

N/A

N/A

15 steps, 0.298%

8 steps, 0.000462%

11 steps, 3.66%

7 steps, 2.36%

8 steps, 1.25%

6 steps, 34.4%

7 steps, 23.6%

17 steps, 0.810%

(±)-Colchicine

24 steps, 0.00243%

21 steps, 0.000442%

22 steps, 0.0000675%

24 steps, ???

22 steps, 0.00310%

15 steps, 0.00000481%

18 steps, 0.038%

14 steps, 0.0245%

15 steps, 0.013%

12 steps, 1.02%

13 steps, 3.03%

14 steps, 1.1% (84% ee)

Starting material

pyrogallol

pyrogallol

monomethylpyrogallol

aminocrotonate

trimethoxyphenylpropylchloride

pyrogallol

pyrogallol

trimethoxyphenylacetaldehyde

trimethoxyphenylpropanol

bis(aryl)propane

3,4-dimethoxyphenol

trimethoxybenzaldehyde

Colchicine

44-summary 4/9/98 11:30 PM

Documents

Colchicine - David A. Evansevans.rc.fas.harvard.edu/pdf/smnr_1997-1998_Michael_Forrest.pdfA Brief History of Colchicine • Use of the autumn crocus or meadow saffron Colchicum autumnale