NOOH

A

B

CD

E

Synthesis of Morphine Alkaloids

MeN

O

OH

OHHO

MeO

MeOOH

NMe

CO2H

NH2HO

Introduction Cultivation:

Fig 1: Lanced Poppy withraw opium exturding

• Opium is harvested from the immature poppy seed capsule

• Primary areas of cultivation are south east and west asia and latin america

• An average Indian acreage of P. somniferum yields 25-30 kg of opium

MeN

O

OH

OH

10 -15 %

MeN

O

OMe

OH

(-)-codeine(-)-morphine

O

MeO

HN

Me

MeO(-)-thebaine

3-4% 1-2 %

Introduction History of Morphine as a Pharmaceutical

• Laudanum (16th Century):

-Developed by Swiss alchemist Paracelus

-alcoholic tincture of alcohol, opium, and other herbs

-Eased suffering from the plague

• Heroin (1898):

-Developed by Heinrich Dreser at Fredich Bayer and Company

-Diacetyl derivative of morphine

-Marketed to the German people as a cough remedy

• Morphine (Present day)

-One of the most widely used drugs for treatment of severe pain

Introduction Structure

O

HHO

HO

NHMe

12

34

5

67

8

9

1011

12

1314

15 16

NO

OH

A

B

CD

E

Morphine

Key Features: 5 rings, 5contiguous stereocenters,compact array of functionality

Synthesis

• Landmark synthesis was in 1952 by Gates

• Since then at least 18 more total and formal synthesis of Morphine have appeared

• This overview will encompass 6 unique routes

Biosynthesis of Morphine

CO2H

NH2HOL-Tyrosine

NH2HO

CHO

HO

dopamine

HO

NHH

HO

HO

HO

NMeH

MeO

HO

MeO

HO

(S)-reticuline

HO

MeO

MeOOH

NMe

(R)-reticulinePhenolic couplingsalutaridinesalutaridinol

thebaine codeinoneneopinone

(S)-norcoclaurine

O

MeO

MeOO

NMe

O

MeO

MeOO

NMe

HO

MeO

MeOOH

NMe

O

MeO

MeO

NMeHO

MeO

O

NMeH

O

MeO

O

NMeHH

O

HO

HO

NMeHH

morphine

SN2'

??

Gates Synthesis

Retrosynthesis

MeO

NH

O

HO

Morphine

HO

MeO

N

OH

HO

MeO

N

OH14

MeO

MeO

O

NH

OH

MeO

MeO

OH

O

CN

MeO

MeO

O

O

Epimerization[Ox]

[Red]

[Red]

ReductiveAmidation[4 + 2]

NC

Gates Synthesis Forward Synthesis: Diene

OH

HO 1. BzCl2. NaNO23. Pd/C4. FeCl3 O

O

5. SO2

6. (MeO)2SO2

BzO

OMeOMe

BzO

7. KOH8. NaNO29. Pd/C10. FeCl3

OMeOMe

OONC CO2Et1.

NEt32. K3FeCN63. KOH,EtOHOMe

OMe

OO

NC

(56 %)(78 %)

(69 %)

(82 %)

Gates Synthesis Forward Synthesis: Morphine

MeO

MeO

O

O

CN

AcOH/ΔMeO

MeO

OH

O

CN(50 %)

27 atm H2CuO/Cr2O

EtOH150 °C

MeO

MeO

O

NH(50 %)

1. N2H4/KOH2. MeI/NaH3. LAH

MeO

MeO

N

1. H2SO4

2. KOH,(HOCH2CH2)2O3. KOt-Bu/Ph2CO

(76 %)

O

HO

MeO

N

O

H

HH14

HO

MeO

N

OH14

1. (a) Br2 (b) 2,4-DNP2. HCl3. H2/ PtO2

(7 %)(14 %)

Gates Synthesis Forward Synthesis: Morphine

Analysis: Gates Method

• 29 Steps

• Overall Yield: 0.0014%

• Key Disconnections: Diels-Alder & Reductive Amidation

MeO

NH

O

HO

HO

MeO

N

OH

1. (a) Br2 (b) 2,4-DNP2. HCl

MeO

NH

O

O

Br1. LAH (44 %)

2. Pyr-HCl, 220 °C (34%)

MeO

NH

O

HO

1-Bromo-Codeinone Morphine

(8 %)

Rice Synthesis Retrosynthesis

O

HO

N

HO

O

MeO

N

O

HO

MeO

NCHO

Br

O

NCHO

HO

MeO

O

H

Br

NH

HO

MeO

MeO

H

OHOMe

CO2H H2N

OMe

Rice Synthesis Forward Synthesis: Grewe cyclization

CHO

OHOMe

1. a) NaHSO3 b) KCN, H2SO4

2. SnCl2, HCl HOAc OH

OMe

NH2

OMe1.

200 °C2. a) POCl3 b) NaCNBH4

NH

HO

MeO

MeO

H

(67 %)(86 %) 1. Li/NH3

2. PhOCHO, EtOAc

NH

HO

MeO

MeO

H

1. a) MeSO3H b) (CH2OH)2

c) NBSd) HCO2H(aq)

NCHO

HO

MeO

O

H

Br

(85 %)

(90 %)

HO

MeO

NCHO

Br

O

NH4F/HFTfOH(60 %)

CO2H

Rice Synthesis Forward Synthesis: End Game

Analysis: Rice Method

O

HO

N

HO

• 16 steps

• Overall yield 12 %

• Grewe cyclization was key disconnection

• Practical method for conversion of dihydrocodeinone to morphine

HO

MeO

NCHO

Br

O

O

MeO

N

O

1. Br2, AcOH2. CHCl3, NaOH3. H2, Pd(C), CH2O, NaOAc

1. ClCO2Et2. PhSeCl3. NaIO44. NaBH45. BBr3, CHCl3

O

HO

N

HODihydrocodeinone Morphine

(79 %) (42 %)

Evans Synthesis Retrosynthesis

O

OH

NMe

H

HOMeO

OMe

NMe

H

H2C

N Me

OMe

OMe

ClO4H

MeOOMe

NMe

H

O

Gates Intermediate

- [CH2]

N

OMe

OMe

MeBrN

OMe

OMe

Me

BrBr

Evans Synthesis Forward Synthesis: Immonium Perchlorate

N

O

Me

OMeOMe

Li1.

2. TsOH, 110 °CN

OMe

OMe

Me(43 %)

BrBr

1. n-BuLi2.

N

OMe

OMe

Me N

OMe

OMe

MeBr

N Me

3. NaI

OMe

OMeHClO4

N Me

OMe

OMe

ClO4H

MeOH

50 °CN Me

OMe

OMe

ClO4H

60 % overall, 95:5 cis:trans

Kinetic Product

Thermodynamic Product

Evans Synthesis Forward Synthesis:

CH2N2

DCM(95 %) N

OMe

OMe

Me

MeNH

ArNH

ArMe NuH

Nu

DMSO(95 %)

N Me

OMe

OMe

ClO4H H

N

OMe

OMe

CHOMe

H

MeOOMe

NMe

HOH

BF3-Et2OStereochemical Analysis:

?

?

Evans Synthesis Forward Synthesis:

CH2N2

DCM(95 %) N

OMe

OMe

Me

MeNH

ArNH

ArMe NuH

Nu

DMSO(95 %)

N Me

OMe

OMe

ClO4H H

N

OMe

OMe

CHOMe

H

MeOOMe

NMe

HOH

BF3-Et2OStereochemical Analysis:

Evans Synthesis Forward Synthesis: End Game

1. MsCl, TEA2. LiEt3BH3. OsO4, NaIO4

MeOOMe

NMe

HOH

MeOOMe

NMe

H

O

Gates Intermediate

O

OMe

NMe

H

HO

(80 %)

Analysis: Evans Synthesis

• Short sequence to achieve the gates intermediate (10 steps)

• Cleaver and original disconnect

• Major limitation is having to go through gates intermediate

Overman Synthesis Retrosynthesis

MeN

O

OH

OH

(-)-morphine

MeN

OMe

O ON

OMe

DBS

OBn

N

OBn

OMe

DBSI

OMeOBn

OHC

SiMe2Ph

HN DBS

I

RiceEpoxideOpening

HeckCyclization

Mannich

Overman Synthesis Forward Synthesis: amine component

DBS =

OCH3CO2H

1.a) NH3 (l)b.) Li wire

c.) Cld.) HCl aq

O

(27 %)

N BH

O

H PhPh

2.

PhN C P3.4. OsO4/NMO, Acetone

OCONHPh

OO

OO

5. n-BuLi, CuI(Ph3P)2

PhMe2SiLi

SiMe2Ph

R2

O

N OPh

CuR1

R2

CuR1N(III)

Ph

R2

R1

HHSyn FacialOxidativeAddition

ReductiveElimination

(81 %)

6. a) TsOH, NaIO4

b) DBS-NH2, NaCNBH3

SiMe2Ph

HN DBS

catechol borane

,

Stereochemical Analysis:

(90 % ee, 68 %)

(83 %)

?

Overman Synthesis Forward Synthesis: amine component

DBS =

OCH3CO2H

1.a) NH3 (l)b.) Li wire

c.) Cld.) HCl aq

O

(27 %)

N BH

O

H PhPh

2.

PhN C P3.4. OsO4/NMO, Acetone

OCONHPh

OO

OO

5. n-BuLi, CuI(Ph3P)2

PhMe2SiLi

SiMe2Ph

R2

O

N OPh

CuR1

R2

CuR1N(III)

Ph

R2

R1

HHSyn FacialOxidativeAddition

ReductiveElimination

(81 %)

6. a) TsOH, NaIO4

b) DBS-NH2, NaCNBH3

SiMe2Ph

HN DBS

catechol borane

,

Stereochemical Analysis:

(90 % ee, 68 %)

(83 %)

Overman Synthesis Forward Synthesis: aldehyde component

Forward Synthesis: mannich reaction

1. HC(OMe)3, H

2. NaH, ClCH2OMe MOMOOMe

n-BuLi; I2; HCl

BnBr, K2CO3

CHO

HOOMe

CHO

OMeBnO

OMeBnO

CHOMeO OMe

1. CH2SMe2

2. BF3 -THF(78 %)(96 %) (84 %)

I I

N

R2

R1

H

Me3SiN

R2

Me3Si

R1

H

Favored for large R1 Favored for small R1

OMeOBn

OHC

SiMe2Ph

HN DBS

ZnI2EtOH N

DBS

Ar

HPhMe2Si

60 °C

NI

I

OBn

OMe

Vs.

80 %dr > 20:1 DBS

Stereochemical Analysis:

Overman Synthesis Forward Synthesis: Heck Cyclization and End Game

N

OMe

DBS

OBn

N

OMe

DBS

O

HO

N

OBn

OMe

DBS Pd(TFA)2(PPh3)2PMP, 120 °C

(60 %)2. ArCO3H, CSA1. BF3-OEt

1. TPAP/NMO2. H2, Pd/C, CH2O

MeN

OMe

O O

(69 %)

MeN

O

OH

OH

(-)-morphine

1. ClCO2Et2. PhSeCl3. NaIO44. LAH5. BBr3

(36 %)

(60 %)

(1)

I

Overman Synthesis Forward Synthesis: Bis-Heck Cyclizations

1. a) CH2O, Δ b) ClCO2Me2. a) EtSH, BF3 b) TMDSOTf3. CrO3, 3-5-dimethyl pyrazole

NI

OTBDMS

OMe

MeO2C

O

1 PPh3H2C2. TBAF, THF1. N

IOH

OMe

MeO2C

MeO2CN

OMe

OH

PdLn

Pd(TFA)2(PPh3)2PMP, 120 °C

(58 %)

MeO2CN

OMe

O

MeO2C

OMe

O OOsO4NaIO4(70 %)

(47 %)

Overman Synthesis Analysis: Overman Approach

MeN

O

OH

OH

• 1st enantioselective synthesis that did not contain a resolution

• Natural and unnatural morphine available

• 23 steps with an overall yield of 0.56 % (single heck)

• 26 steps with an overall yield of 0.184 % (bis-cyclization)

• Key disconnections were the Heck and Mannich

White Synthesis Retrosynthesis

MeO

OH H NMe

HO

MeO

OH H

ONMe

O

MeO

O

MOMOH H

O

O

O

OHH

HO

MeO

HO

MeO

CO2HO

O

O

MeO

O

MOMOH

H

HN2

HO

MeO

CO2MeHO2C

CHOHO

MeOO

MeO

O

MeO

Rice Beckman C-H

Insertion

RobinsonSEAr

1. Stobbe 2. Hydrogenation

White Synthesis Forward Synthesis:

(CH2CO2Me)21.

2. H2, [RhCl(COD)]2, (-)-MOD-DIOP

HO

MeO

CO2Me

1. P2O5, MeOH2. H2, Pd(OH)2 HO

MeO

CO2HO3. LiOH(aq), THF

1. KH, HCO2Me2. MVK, NEt33. NaOH, THF

1. CH2N2

2. Br2, NaHCO3

O

O

OMeH

HO

MeO Br

O

O

OHH

HO

MeO

Br

O

O

OMe

HO

MeO Br

Br

O

O

OMe

MeO Br

O

HO2CCHOHO

MeO

70 °CDBU

(80 %)

White Synthesis Forward Synthesis:

1. NaBH4

2. H2, Pd/C O

OMe

MeO

O

HOH

H

H

1. CH2(OMe)2

22:1

O

MeO

O

MOMOH

H

HN2

MeO

O

MOMOH H

O

Rh2(OAc)4(50 %)

O

O

OMe

MeO Br

O 3.( COCl)24. CH2N2

MeO

O

MOMOH H NH

AcO

OBs

1. NH2OH-HCl

2. p-BrPhSO2Cl, NaOAc

MeO

O

MOMOH H

ONH

MeO

O

MOMOH H N

H O

11 1

(63 %)

(77 %)

2. LiOH

(50 %)

White Synthesis End Game:

Analysis: White Approach

MeO

O

MOMOH H

ONH

MeO

OH H

ONMe

O

1. NaH/MeI2. HBr, MeCN3. D-Mperiodinane

MeO

OH H NMe

HO

1. PhSeCl/MsOH2. NaIO43. LiAlH44. BBr3

(52 %)(90 %)

• 29 steps

• Overall yield of 1.73 %

• Asymmetry was introduced early via enantioselective hydrogenation

• Key disconnect was the Rhodium (II) catalyzed C-H insertion

MeO

OH H NMe

HO

Parker Synthesis Retrosynthesis:

O

HO

HNMe

HOmorphine

O

MeO

HNMe

O

O

MeO

HHO

NMe O

MeO

HHO

NMe

Ts

Rice [Ox]

O

MeO

HHO

NMe

TsSR

X

RadicalCyclization

MitusunoboOMe

OHBr

PhS

NTs

TBDMSO

HO Me

Parker Synthesis Forward Synthesis:

MeO

NH2 1. Li, NH32. a) TsCl, TEA b) 1N HCl

O

NTs

3. MeI, K2CO3

NTs

TBDMSO

HO1. NaBH4, CeCl32. MCPBA3. Ti(Oi-Pr)44. TBDMSCl

Me Me

(1) racemic(75 %) (63 %)

1. Br2, TEA NTsMeBr

HO

2. catechol borane

Na(Hg) NTsMe

HO

1. MCPBA2. Ti(Oi-Pr)43. TBDMSCl

NTs

TBDMSO

HO Me1

(76 %, 80 % ee)enantiomerically enriched

(90 %)

(52 %)

• Racemic Route:

•Asymmetric Route:

N BMe

O

H PhPh

(S)-B-Me =

Failed routes included direct CBS reduction of 1 (35 % ee) andSharpless kinetic resolution of the allylic alcohol (44 %ee)

Parker Synthesis Forward Synthesis: Mitsunobu Coupling

MeO

HO CHO

MeO

HOBrBr

PO

PhS (OEt)2

n-BuLi

THF SPh(82 %)

OMe

OHBr

PhS

NTs

TBDMSO

HO Me 1. PBu3, DEAD2. 10 % HF SPh

O BrN

Ts

Me

H

HO

MeO

Parker Synthesis Forward Synthesis: Radical Cyclization

SPhO Br

NTs

Me

H

HO

MeO

Bu3SnHAIBN

O

MeO

HHO

NMe

Ts

SPhO

NTs

Me

H

HO

MeO

SPhO

MeO

HHO

NMe

Ts

Bond

Rotation

OH

NMe

Ts

-[ SPh]

O

NMe

Ts

(35 %) (11 %)

Parker Synthesis Forward Synthesis: Radical Cyclization

SPhO Br

NTs

Me

H

HO

MeO

Bu3SnHAIBN

O

MeO

HHO

NMe

Ts

SPhO

NTs

Me

H

HO

MeO

SPhO

MeO

HHO

NMe

Ts

Bond

Rotation

OH

NMe

Ts

-[ SPh]

O

NMe

Ts

(35 %) (11 %)

Draw a mechanism that accountsfor formation of the side product

Parker Synthesis Forward Synthesis: Radical Cyclization

SPhO Br

NTs

Me

H

HO

MeO

Bu3SnHAIBN

O

MeO

HHO

NMe

Ts

SPhO

NTs

Me

H

HO

MeO

SPhO

MeO

HHO

NMe

Ts

Bond

Rotation

OH

NMe

Ts

-[ SPh]

O

NMe

Ts

(35 %) (11 %)

Parker Synthesis End Game

O

MeO

HHO

NMe

Ts

Li/NH3t -BuOH O

MeO

HHO

NMe O

MeO

HHO

NMe DMSO

(COCl)2O

MeO

HN

Me

O(85 %) (83 %)

O

HO

HN

Me

dihydrocodeinone

HO

RiceMethod

morphine

Parker Synthesis Analysis: Parker Method

(+/-) Morphine:

• 22 steps

• Overall yield of 2.07 %

• Radical cyclization was the key disconnect

• First published in August, 1992

(-) Morphine:

• 24 steps

• Overall yield of 1.7 %

• CBS reduction of α-bromoenone was key step

• Published in January, 2006

NTsMeBr

HO

O

MeO

HNMe

HOmorphine

Conclusions Disconnection approaches have evolved with the

methods of synthetic chemistry

Morphine approaches will continue to grow

(Only Rice has come close to synthetically viable route)

Continued need for developing morphine derivativeswhich can attenuate addictive properties

NO

OH

A

B

CD

E

Morphine

Gates (1952): Diels-AlderRice (1980): Grewe CyclizationEvans (1982): Iminium SaltsOverman (1993): Heck chemistryWhite (1997): C-H insertionParker (2006): Radical Cyclization

Racemic

Asymmetric

References

Gates, M.J. J. Am. Chem. Soc. 1953, 75, 4340

Rice, C.; Brossi, A. J. Org. Chem. 1980, 45, 592

Evans, D.A.; Mitch, C.H. Tetrahedron Lett. 1982, 23, 285

Overman, L.E. Pure and Appl. Chem. 1994, 66, 1423

White, J.D. J. Org. Chem. 1999, 64, 7871

Parker, K.A. J. Org. Chem. 2006, 71, 449

Lead References for Syntheses:

Review:Taber, D.F. The Enantioselective Synthesis of Morphine: Strategies andTactics in Organic Synthesis 2004, 5, 353