Chemical Neuroscience a course for synthetic chemists

Enzymes in Synaptic Transmission

5

The synapse

The synapse

http://en.wikipedia.org/wiki/Synapse

synaptic vesicle

transporter

vesiculartransporter

deactivating enzyme

Enzymes that inactivate neurotransmitters

acetylcholine esterases (AChE):

monoamine oxidases (MAO):

O

O N HO NAChE

O

OH

H2O+

NH2HO

HO

dopamine

OHO

HO OH

MAO

O2, FADH2

catechol O-methyl transferases (COMT):

NH2HO

HO

noradrenaline

MeO

HO

COMT

SAM

OH OHNH2

Natural products that inhibit AChE

HN

O

NH2

huperzine A

O

OH

NMe

MeO

galanthaminephysostigmine

O

N

Me

NHO

HN

Molecular analysis of physostigmine

O

N

Me

NHO

HN

pyrrolo[2,3-b]indole scaffold

N-methyl carbamate

tricyclic core

benzylic quaternary stereocenter

N,N-aminal

Physostigmine irreversibly blocks AChE via carbamoylation.

The Julian synthesis of physostigmine

The synthesis that established Percy Julian’s reputation. He established the structure of physostigmine with this synthesis and finished before Robert Robinson.

J. Am. Chem. Soc. 1935, 57, 539

EtO

NHAc

Br

COBr

MeI MeI

Br CN

MeCNO

O

N

Me

NHO

HN

O

N

Me

NHO

HN

1,2

3

1) Na, xylene → MeI2) H2SO4, H2O

3) NaOH,

N-methylation,acetate hydrolysis

acylation

4 4) AlCl3 key step: intramolecular Friedel-Crafts alkylation

EtO

NHAc

EtO

NH

EtO

N O

Br

EtO

Br

O

Br

NO

O

N

Me

NHO

HN

5 key step: alkylation to establish the quaternary center

6 6) H2, Pd-C exhaustive hydrogenation of the nitrile

7 7) PhCHO → MeI, H2O monomethylation via N-methyl iminium ion and hydrolysis

5) ClCH2CN, Na

EtO

NO

EtO

NO

MeCN

EtO

NO

Me NH2

EtO

NO

MeHN

8 8) Na, EtOH key step: dissolved metal reduction of the amide

9 9) AlCl3

10 10) MeNCO carbamate formation

(±)-physostigmine

phenol ether cleavage

EtO

NO

MeHN

EtO

N

Me

N

HO

N

Me

N

O

N

Me

NHO

HN

H

H

Percy Julian

Percy Julian became the second black National Academy member (and the first chemist):http://www.pbs.org/wgbh/nova/physics/julian-the-trailblazer.html

The Grieco synthesis of physostigmine

This synthesis hinges on the imino-Diels-Alder reaction developed by Grieco to introduce the pyrrolidine unit of physostigmine while the left-hand portion is synthesized according to Julian.

Tetrahedron. Lett. 1992, 33, 4401

NHAc

MeOO

N

Me

NHO

HN

MeNCOHCHO

O

BrBr

BrNH2

O

N

Me

NHO

HN

3,4 3) Na, xylene → Me2SO44)

amide reduction → methylation,acylation

5 5) AlCl3 Friedel-crafts alkylation

1,2 1) HCHO, NaHCO3 →2) AgOTf

key step: imino-Diels-Alder reaction,aziridinium formation

BrNH2

N OTf

MeO

NHAc

MeO

N

aziridinium triflate

O

BrBr

O

Br

MeO

NO

MeO

NO

6 6) LDA → aziridinium triflate key step: amide enolate alkylation and aziridinium opening

MeO

NH

O

N

7 6) TFA, Et3SiH key step: cycloreversion and iminium ion reduction

MeO

NH

O

HN

8-10 8) LiAlH49) BBr310) MeNCO

reductive ring closure,methyl ether deprotection,carbamoylation

O

N

Me

NHO

HN

physostigmine

This sequence was adapted from Julian.

The Overman synthesis of physostigmine

A short enantioselective synthesis that features one of Overman’s trademark reactions, the Heck reaction to establish quaternary stereocenters.

J. Am. Chem. Soc. 1998,120, 6500

NH

IMeOO

N

Me

NHO

HN MeNH3Cl

MeNCO

OH

O

N

Me

NHO

HN

3 3) Pd(PPh3)4, CO, H2O, Et3N Pd-catalyzed carboxylation

4 4) BOPCl, Et3N, DCC, HOBt key step: amide coupling

1,2 1) Red-Al → I22) TIPSOTf, 2,6-lutidine

hydroalumination → iodination,TIPS protection

OH

Si OTf

TIPSOTf

O O OOAlH H

Na

Red-Al

OTIPSI

OTIPSHOOC

NH

IMeO

N

IMeO O OTIPS

NN

N

OH

HOBt = DCC =N C N

BOPCl = NO

O

PO

NCl

O

O

5 5) Pd2dba3, (S)-BINAP, PMP key step: asymmetric Heck reaction

6,7 6) HCl7) MeNH3Cl, Et3N → LiAlH4

enol ether hydrolysis,reductive amination

8,9 8) BBr39) NaH, MeNCO

methyl ether deprotection,carbamoylation

N

IMeO O OTIPS

MeO

N

Me OTIPS

O

MeO

N

Me

O

N

Me

NHO

HN

(−)-physostigmine

N

PMP = 1,2,2,6,6-pentamethylpiperidine

NH

The Rainier synthesis of physostigmine

A methodology-based ex-chiral-pool synthesis featuring a very different strategy to introduce both the quaternary stereocenter and the pyrroloindole unit.

J. Am. Chem. Soc. 2010,132, 8283

O

N

Me

NHO

HN

NBoc

NHBoc

COOMe

Me3Al

MeNCO

HCHO

O

N

Me

NHO

HN

2 2) KOt-Bu cyclopropane formation

3 3) AlMe3 key step: homo-Michael addition

1 1) NBS key step: bromocyclization via:

The starting material is derived from tryptophane.

NBoc

NBoc

Br

H

COOMe

NBoc

NBoc

Me

H

COOMe

NBoc

NHBoc

COOMeBr

H

NBoc

H

NBoc

COOMe

NBoc

NHBoc

COOMe

O

N

Me

NHO

HN

4,5 4) NaOH

5) EDC, → t-BuSH, hυ

ester hydrolysis,

Barton decarboxylation via:

6,7 6) TMSI7) HCHO, Pd-C, H2

Boc deprotection,reductive amination

8,9 8) NBS9) CuI, NaOMe

electrophilic bromination,Ullmann coupling

NBoc

NBoc

Me

H

COOMe

NBoc

NBoc

Me

H

N SOH

R O

ON

S St-Bu

Rt-BuSH−t-BuS

R H

NN

Me

H

NN

Me

H

MeO

(−)-physostigmine

NN

Me

H

MeO

10, 11 10) BBr311) NaH, MeNCO

methyl ether deprotection,carbamoylation

O

N

Me

NHO

HN

Huperzine A blocks AchE

HN

O

NH2

huperzine A

Molecular analysis of huperzine A

(_)-huperzine A

bicyclo[3.3.1]skeleton

α-tertiary amine (ATA)

α-pyridone

2 stereocenters

ethylidene group

primary amine at bridgehead carbon

1,3-diamine

4 double bonds

NHO

HN O

NH2

H2NHN O

NH2

The Herzon synthesis of huperzine A

A short, modern synthesis that utilizes palladium-catalyzed enolate arylation and silane chemistry to establish the stereocenters of huperzine A.

Chem. Sci. 2011, 2, 2251

Me

OTsCN

N

OMe

Br

Br

Ph3PEtBr

HN O

NH2

4 4) PhMe2SiCuLi →

conjugate addition → alkylation

O

Me

Pulegone is a very cheap and popular chiral pool starting material.

N

OMe

Br

Br

O

Me

SiMe2PhNMeO

Br

Me

O

1-3 1) LHMDS, PhNTf22) O3, Me2S3) Pd(OAc)2, PPh3, Et3N, HCOOH

enol triflation formation,ozonolysisreductive coupling

HN O

NH2

O

Me

SiMe2PhNMeO

Br

NC

6 6) Pd(Pt-Bu3)2, NaOt-Bu key step: Pd-catalyzed enolate arylation

O

Me

SiMe2PhNMeO

Br

5 5) LiHMDS, TsCN α-cyanation

N OMeNCO

PhMe2Si

HN O

NH2

7 7) EtPPh3Br, LiHMDS Wittig olefination

8 8) TfOH → TBAF, H2O2, K2CO3

Fleming-Tamao oxidation

9,10 9)10) H2O,

dehydration with Burgess' reagent,Pt-catalyzed partial cyanide hydrolysis

MeO N

OS NEt3

OH O P

PtP POH

O O

N OMeNCO

PhMe2Si

N OMeNC

PhMe2Si

N OMeNC

HO

N OMeO

NH2

HN O

NH2

11,12 11) PIFA12) TMSI

key step: Hoffmann rearrangement,methyl ether deprotection

(−)-huperzine A

R NH2

O

I OO

O CF3

CF3

O

PIFA

PIFAR N

O

IPh O

O

CF3

H

R N

OIPh

R N

OR N C O

HN O

NH2

N OMeO

NH2

The Shasun Pharma synthesis of huperzine A

Essentially and adaptation of Kozikowski’s third-generation synthesis, this industrial approach features enantioselective palladium catalysis to furnish 275 g batches of huperzine A.

Org. Process Res. Dev. 2012, 16, 635

O

Ph3PEtBr

N3(PhO)2P

O

O

O

COOMeNH3

OAc OAcHN O

NH2

HN O

NH2

O

3,4 3) H3PO44) NaH, (MeO)2CO

ketal hydrolysis,α-acylation

5 5) [C3H5PdCl]2, Taniaphos, TMG,

key step: Pd-catalyzed double Tsuji-Trost allylation

O O

1,2 1) NH3,2) MeI, Ag2CO3

key step: pyridone formation,methoxypyridine formation

COOMe

O

O

N OMe

N OMe

OCOOMe

Fe

PCy2

Taniaphos T002-1

NMe2 PCy2N N

NH

TMG = 1,1,3,3-tetramethyl- guanidine

OAc

OAc

N OMeCOOMe

O

HN O

NH2

6,7 6) TfOH7) EtPPh3Br, LiHMDS

double bond isomerization,Wittig olefination

8 8) PhSH, AIBN, Zn Z-E isomerization under radical conditions

9,10 9) NaOH10) DPPA → MeOH

ester saponification,Curtius rearrangement via:

R OH

O

R O

OP(OPh)2

O

N3

R N3

O

-N2 R N C O

MeOHR

HN

OMe

O

N3(PhO)2P

O

N OMeCOOMe

O

N OMeCOOMe

N OMeCOOMe

N OMeNH

OMe

O

11 11) TMSCl, NaI double deprotection via in situ-generated TMSI

(−)-huperzine A

N OMeNH

OMe

O

HN O

NH2

The Sun synthesis of huperzine A

A chiral-pool synthesis using Buchwald-Hartwig and Heck chemistry to introduce the ATA.

Org. Lett. 2012, 14, 4446

O

Me

EtMgBr

BocNH2

N

OMe

Br

Br

HN O

NH2

3,4 3) Pd2dba3, t-Bu-XPhos, BocNH24) LDA,

key step: Buchwald-Hartwig amination,α-alkylation

5,6 5) NaBH46) Pd(PPh3)4, Et3N

enone reduction,key step: Heck reaction

1,2 1) LDA, Tf2NPh2) O3, PPh3

enol triflate formation with McMurry's reagent,ozonolysis

O

Me

TfO

Me

O

N

OMe

Br

Br

BocHN

Me

ON OMe

Bri-Pri-Pr

i-Pr

Pt-Bu2

t-Bu-XPhos

N OMeNHBoc

HO

The double bond needs to be migrated.

HN O

NH2

HN O

NH2

7 7) TPAP, NMO Ley oxidation

8,9 8) EtMgBr9) SOCl2

Grignard addition,alcohol elimination and Boc deprotection

10 10) HBr double bond migration and deprotection

(−)-huperzine A

N OMeNHBoc

HO

N OMeNHBoc

O

N OMeNH2

HN O

NH2

Formation of the ATA in huperzine A - a comparative analysis

1) (PhO)2P(O)N32) MeOHKozikowski synthesis

The Curtius rearrangement was also used by Shasun Pharma, Fukuyama, Terashima, Langlois, Bai, Yang, Chin and others

(CF3CO2)IPhHerzon synthesisN OMe

ONH2

N OMeH2N

N OMeCOOH

N OMeNH

OMe

O

Formation of the ATA in huperzine A - a comparative analysis

Pd(PPh3)4, Et3N

BocHN

Me

OHN OMe

BrSun synthesis

White synthesis

OH

N OMeH TsOH, H2NCO2Me

NH

N OMeH

EWGH

N OMeNHBoc

HO

N OMeNH2

N OMeNHEWG

H

Galanthamine blocks AchE

O

OH

NMe

MeO

galanthamine

The Sanochemia synthesis of galanthamine

a kilogram scale industrial synthesis of an alkaloid marketed as an anti-Alzheimer drug.

Org. Proc. Res. & Dev. 1999, 3, 425

MeO

MeO

O

H

H

O

OEt

HO

NH2

O

BrMeO

OH

NMe

O N Me

MeO

HO1,2 1) Br2

2) H2SO4

bromination,selective demethylation

3,4 3) tyramine → NaBH44) HCOOEt

reductive amination,formylation

MeO

MeO

O

H

HO

MeO

O

H

Br

HO

NH2

tyramine

HO

MeO

NCHO

Br

OH

5 5) K3[Fe(CN)6] key step: oxidative phenol coupling, probably via:

O NH

O

BrMeO

O

HO NH

O

BrMeO

O

HO NH

O

BrMeO

OFeX2

-H+

-FeX2

Methylated vanillin is a cheap bulk chemical.

6,7 6)7) LiAlH4 → HCl → NaOH

ketal formation,formamide and bromide reduction →ketal deprotection → isolation as free base

8 8) L-Selectride enone reduction

O NH

O

BrMeO

O OHOH

O N Me

MeO

O

(-)-narwedine(± )-Narwedine is converted quantitatively to one enantiomer by addition of (-)-narwedine seed crystals.

O N Me

MeO

HO

galantamine

Nerve gases and chemical warfare

Nerve gases are little effective against prepared opponents and have been mostly used to terrorize civilians.

PO

O

sarin

PO

O

soman

PO

S

PO N

EtO

S8P

O NEtO

VX

binary chemical weapon:

non-lethal precursor

SMe

FMe

FMe

EtOMeP

O

O

tabun

NCN

PS N

EtO

VX

OMe

rearrangement

N

Sarin irreversibly inhibits AChE after “aging”

Me PO

O

O

Cα

O

Cα

NN

H

H

O

O

Cα

Cα

sarin

The 1995 Tokyo subway sarin attack

Ca. 900 mL sarin were deployed, twelve people were killed.

Instant treatment with atropine and pralidoxime

autoinjector from a U.S. Army manual

N

NOH

pralidoxime

(reacts with the organophosphatebefore "aging")

N

O

OH

O

atropine

(muscarinic antagonist)

H

Insecticides that inhibit AChE

NO2

OPS

parathion (E605)

OPO

dichlorvos

Cl

Cl

EtOEtO

MeOMeO

NH

O NO

S

aldicarb

OHN

O

NN

formetanate

O

O

NH

carbaryl

H H

Rasagiline is an irreversible inhibitor of MAO-B

N

N

N

NH

O

O

HO OH

OR

OH

HN

rasagiline

HN

Rasagiline is used to treat Parkinson’s disease.

Tolcapone is an inhibitor of COMT

pdb 4PYL

Tolcapone is used to treat Parkinson’s disease.

O

HO

HO

NO2

tolcapone