The synthetic challenges of

accessing design space

Nick Summerhill
Pfizer Global Research & Development
Sandwich, UK
nick.summerhill@pfizer.com
SCI exploring Chemical Space
23rd March 2011

Outline of Talk
Introduction
Accessingchemicalspacebyevolvingexisting
methodology.
methodology
Expandingchemicalspacebyinnovativesynthesisof
p
g
p
y
y
idealmedicinalchemistryfragments

Conclusion
l

Chemical space the numbers

ca6001000drugable targets
2500 therapeutically relevant genes
2500therapeuticallyrelevantgenes

1063 possiblestablestructureswithlessthan30non
possible stable structures with less than 30 non
hydrogenatoms(C,N,O,P,S,F,ClandBr),witha
molecularweightoflessthan500dalton
1020-24 possiblestructuresfromcurrentlyknown
possible structures from currently known
syntheticmethods.
winningthelottery10
winning
the lottery 107 to1chance
to 1 chance
1017 numberofsecondssincetheBigBang
(15 billion years)
(15billionyears)
Nature Drug Disc. Rev. (2002), 1 (9), 727-730

Nature Drug Disc. Rev. (2003), 2,38-51

Chemical Space A synthetic chemists

definition!
Whatourmoleculesreallylooklike:
OH
CO2Me

HO

NH2

H
H

OH

N
H

CO2H

Steroids 2008,
Steroids,
2008 274

H
N

H
N
O

HO

J Med Chem,
Chem 2007,
2007 6095

HO

BMCL 2008,
BMCL,
2008 1280
O

NH

H
N

HN

N
N

OEt

Cl

NC
N N
N

N
N

OPRD, 2000, 17

Tet Lett, 2005, 5005

Tet Lett, 2009, 389

MeO

CN
HN

HN

N
N

NH2

H O
N
O

Synlett, 2008, 2421

H
N

N
O

O
Cl

O
N
H

N
N
H

OH OH

Org Lett, 2006, 1725

OPRD, 2008, 575

Accessing chemical space

(I)
Methodology
gy evolution

1) Suzuki Coupling
ImprovingthemethodologyofaNobelprizewinner??
OurbreadandbutterforSP2SP2couplingsinthepharma
p g
p
industry:
y
OH
B
R

OH

R'

Pd(PPh3)4, aq Na2CO3

R'
Toluene/EtOH 100oC

Yethowmucharewebiasing/restrictingourchemicalspacebystarting
withboronic
ith b
i acids?
id ?
CommerciallyavailableinScifinder:
OH
B
R

OH

CO2H
R

5094

Itsmorethanjustthenumbers.

250701

Carboxylic Acid Vs. Boronic Acid: Chemical

Space Comparison
Green = Available
Red = Non Available

MeO

Phenyl Aromatic Space

Heterocyclic Ar Space

CO2H

CO2H

N
N

OH

OH
MeO

OH

Carboxylic acids open up more heterocyclic design space!

OH

Expanded space..
Goossen decarboxylative couplingprotocolenablescarboxylicacidtobe
usedasstartingmaterial
7.5mol% Cu2O, 15mol% phen
2mol% PdBr2, 3mol% TolBINAP

CO2K
R'

NMP, 190 C/150W, 10min

TfO

R'
R
48 examples, 40-99% yield
o-, m-, p-substituted acids

Chem. Eur. J . 2009, 15, 9336-9349

Severalexamplesofheterocyclicacids

CO2K

N
O

Cl

+
TfO

Cl

5mol% Ag2CO3, 9mol% PPh3

20mol% 2,6-lutidine
NMP, 130 C/150W, 10min

87%

N
O

Chem. Eur. J . 2010, 16, 3906-3909

2) Aromatic trifluoromethylation
CF3 grouplovedbymedicinalchemistsbutitsintroductionusedtobeaholy
grailforsynthesis.
Typicallyinvolvedchlorideexchangewithfluorideunderharshconditions
Cl

F F

Cl

HF and/or SbF5

Cl

Swarts reaction

Bull. Soc. Chim. Belg. 1892, 24, 309

Fantasticprogressmadeinacademiaoverthelast3years:
y
pp
Amii 2008.FirstaromatichalidetoCF3 catalyticincopper:
CuX (10mol%)
ligand (10mol%)

CF3-SiEt3

R
KF (2 eq.)
NMP/DMF 1/1
60oC, 24h

CF3
EtO2C

CF3
Cl

89%

CF3

63%
Chem. Comm. 2009, 14, 1909-1911

95%

CF3

Aromatic trifluoromethylation
Buchwald2010:Trifluoromethylation
Buchwald 2010: Trifluoromethylation ofarylchlorides!
of aryl chlorides!
CF3

Pd2(dba)3 (6mol%)
Brettphos (9mol%)

Cl

CF3-SiEt3

KF (2 eq.)
dioxane 130oC
20h

CF3
R

CF3

BnO

NC

Bn

72%

Science. 2010, 328, 1679-1681

88%

80%

CF3

Xiao2011:excellentrangeof5and6memberedheteroaromatic substrates
N
Ar-I

CF3

CF3

Cu (3 Eq.)

Ar-CF3

DMF 60oC
10h

CF3 OTf

Ph3C

95%

Cl

98%
CF3

Angew. Chem. Int. Ed. 2011, 50, 1896-1900

91%

Buchwald2011:Oxidativetrifluoromethylation ofboronic acidsatr.t.!

MeO2C

OH
B
R

OH

Cu(OAc)2 (1 eq.)
phenanthroline (1.1eq)
CF3-SiMe
SiMe3

CsF (2 eq.), O2 (1atm)

DCE or iPr-CN, 4A MS
r.t. 1-4h

CF3

CF3
R

J. Org. Chem. 2011, 76, 1174-1176

CF3

68%

Cl
O

61%
CF3

58%

N
Boc

An in house example
Sulfonamide isanothergrouplovedindrugdesignbutsubstituentscopeisgenerally
limitedtocommercialavailability(orsynthesisability)ofsulfonylchlorides:
O

R1
R

R2
O

Cl

R1
HN
R2

O
sulfonyl
f
chloride

Commonmethodstosynthesisesulphonyl
Common methods to synthesise sulphonyl chlorides:
O

1) n-BuLi
Het/Ar

Het/Ar

X
2) SO2(g)

Cl

Het/Ar

3) SO2Cl2
ClSO3H

Het/Ar

Het/Ar SH
or

SR

Het/Ar

An in house example
Sulfonamide isanothergrouplovedindrugdesignbutsubstituentscopeisgenerally
limitedtocommercialavailability(orsynthesisability)ofsulfonylchlorides:
O

R1
R

R2
O

Cl

R1
HN
R2

O
sulfonyl
lf
l
chloride

Commonmethodstosynthesisesulphonyl chlorides:
O

1) n-BuLi
Het/Ar

Het/Ar

X
2) SO2(g)

Cl

Het/Ar SH
or
Het/Ar

Het/Ar

SR

3) SO2Cl2
ClSO3H

Het/Ar

XRegiochemistry drivenbysubstituents.
XRequireselectronrichrings.
X Lo FG tolerance stronglyacidic.
XLowFGtolerance
strongl acidic

An in house example
Sulfonamide isanothergrouplovedindrugdesignbutsubstituentscopeisgenerally
limitedtocommercialavailability(orsynthesisability)ofsulfonylchlorides:
O

R1
R

R2
O

Cl

R1
HN
R2

O
sulfonyl
f
chloride

Commonmethodstosynthesisesulphonyl chlorides:
O

1) n-BuLi
Het/Ar

Het/Ar

X
2) SO2(g)

Cl

Het/Ar

3) SO2Cl2
ClSO3H

Het/Ar

XOrganometallics airsensitive,difficult
tohandle,lowFGtolerance.
XSO2 gas hazardous.

Het/Ar SH
or

SR

Het/Ar

An in house example
Sulfonamide isanothergrouplovedindrugdesignbutsubstituentscopeisgenerally
limitedtocommercialavailability(orsynthesisability)ofsulfonylchlorides:
O

R1
R

R2
O

Cl

R1
HN
R2

O
sulfonyl
lf
l
chloride

Commonmethodstosynthesisesulphonyl
Common methods to synthesise sulphonyl chlorides:
O

1) n-BuLi
Het/Ar

Het/Ar

X
2) SO2(g)

Cl

Het/Ar SH
or
Het/Ar

Het/Ar

SR

3) SO2Cl2
ClSO3H

X Requires strongly acidic conditions

XRequiresstronglyacidicconditions.
Het/Ar

XLackofgeneral/mildmethodsforconverting
Het/ArXtoHet/ArSH(orR).

 Aryl/heteroaryl halidedefinitelyabetterstartingpointthansulphonyl chlorideto

maximisechemicalspaceaccessedbysulfonamide synthesis.Commerciallyavailablein
Scifinder:
I

SO2Cl
R

6503

108253

Oxidationofthioacetatestosulfonylchlorideswellestablished
y
O

NCS
Ar

Ar

2M HCl-MeCN
10oC

Cl

Synthesis. 2006, 1896-1900

buttheirformationfromarylhalidesnotwellprecedented.
Howeverformationofthiobenzoates fromaryliodidesis wellprecedented.
O
Ar

HS

CuII (10 mol%)

C
l%)
1,10-phen (20 mol%)
Ph

i-Pr2NEt (2 eq.)
toluene
reflux,, 16 hrs

Ar

Ph

>95% conversion (HPLC)

Itoh, T. et. al., Tet. Lett., 2006, 6595

Sohowaboutoxidationofthiobenzoates tosulphonyl chlorides???

Optimisation Studies
Chlorinatingagent

Additives

pH

Result

TCCA(1eq)1

BnMe3NCl(3eq),H2O

2to0

90%

TCCA(1eq)

BnMe3NCl(3eq),H2O,NEt3(1eq)

911

Noreaction

TCCA(1eq)

BnMe3NCl(3eq),H2O,Na2CO3(1eq)

6to5

87%

TCCA(1eq)

BnMe3NCl(3eq),H2O,K2CO3(1eq)

~4

100%*

TCCA(1eq)

BnMe3NCl(3eq),H2O,NaOAc(1eq)

~1

100%*

HOCl(~3eq)

None

12

Littlereaction

HOCl(~3eq)

NaOAc(2eq)

Littlereaction

*CrudeYield

Bonk, J. et. al., Syn. Comm., 2007, 2039

O

TCCA (1.2
(1 2 eq))
Cl

BnMe3NCl (3.4 eq)

O
Ph
Ar/Het S

1N Na2CO 3 (1 eq)
acetonitrile
0oC, 20 mins

O
Ar/Het S Cl
O

N
N

Cl
O

Cl
TCCA

Tet. Lett 2011, 52, 820-823

Developedbufferedconditionstocarryoutrequiredoxidationandalsoallow
tolerationofacidlabilegroups improvedfunctionalgroupcompatibility:

One-pot oxidation/sulfonamide formation

Asecondequivalentofbaseaddedatthestartallowssulfonamidestobeformed
A second equivalent of base added at the start allows sulfonamides to be formed
inonepot,uponadditionofappropriateamine.GoodforunstableSO2Cl!
TCCA (1.2 eq)
BnMe3NCl (3.4 eq)

O
Ar/Het S

acetonitrile
0 0C, 20 mins

MeO

O
N

Tr

S
O
84%

S
N

N
N

O
59%

O
BocHN

S
O
45%

Tet. Lett 2011,

52, 820-823

85%

O
N

31%

87%

R2

R1

NHBoc
O
N

S N

no base needed

74%

O
BocHN

Ar/Het

70%

81%

amine (1.2eq)

O
Ph

O
Ar/Het S Cl
O

1N Na2CO 3 (2 eq)

Ph

N
N

O
S

O
0%

Overall2stepprotocol:aryl/heteroaryl halidetosulfonamide chemicalspaceexpansion!

A
Accessing
i
chemical
h
i l space
( )
(II)
Ideal medicinal chemistry
fragments

Maraviroc
F
F

H
N

N
N

CCR5inhibitorforHIV
DiscoveredinSandwich

Difluorocyclohexane carboxylicacid asimplemoleculebut

F
F
_O

OH
clogP = 1.77

OH
clogP = 0.86

Improvedmetabolicprofileandreducedlipophilicity
DrasticallyreducedhERG liabilityduetodipoleofgemdifluoro
Biorg. Med. Chem. Lett. 2006, 16, 4633-4637

Synthesis
O

DAST

+
0 oC
O

Tet. Lett. (2005), 5005

/ DCM

85% (1:1)

OEt

OEt

OEt

Fluorinationofketonegaveaninseparablemixtureofdifluoro andvinylfluoride..
F

F
OH

OsO4 (cat) / NMO

NaOH

Acetone / water
O

OEt

74%

OEt

Water
THF
O

OEt

OEt

65%

Separatedifluoroesterbysilicachromatography
Straightforwardchemistrybutaccessesanicefragmentwithbetter
physicochemical properties
physicochemicalproperties
Othersagree!
Scifinder hits:

F
F
O
OH

Before
B f
M
Maraviroc
i
Since Maraviroc

2
74

OH

Further reducing lipophilicity

F

F
_O

OH

O
HO
clogP = 0.09

OH

clogP = 1.77

clogP = 0.86

Existingdifluorocyclobutane synthesisimpractical toxicreagents/solvents

Improvedsynthesis:
RuCl3, NaIO4

CN

Et2NSF3

CN

F
NaOH

F
CO2H

CN

Synlett, (2005), 657

Scifinder hits:

F
F
OH
O

y
Before Synlett
Since Synlett

2
34

Synthetic innovation drives chemical space

expansion
Hinderedethertarget

N
F3C

CO2Me

N
F3C

OH

Br

Ancientliteratureholdsthekey:
NaOH

Ar OH

+
O

CHCl3

O
Cl

Ar O
Cl

CO2H

Bargellini reaction (1906)

Reactiongeneratesdichlorocarbene,whichaddsacrossketone
Nowcomestheinnovation;whatelsecanweuseinthisreaction??

CO2Me

Different nucleophiles and ketones?

OriginalBargellini reactionusedphenolsonly.

N
F3 C

OH

F3C

CO2H

45%

O
Boc
N

Boc
N

56%
Br

OH
O

NaOH, CHCl3
THF

Br

CO2H
Boc
B
N

Boc
N
SH

CO2H

71%

O
Boc
N

Boc
N

99%

NH2
MeO

N
H
MeO

CO2H

Perfect medchem fragments.

Boc
N

Boc
N

N
Br

NH2

46%

N
Br

N
H

CO2H
Boc
N

Boc
N
N
NH2
O

NH2

72%

N
N
H

NaOH, CHCl3
THF

CO2H
Boc
N

Boc
N

N N
O

N
H

N N

NH
N
O

4pointsofsyntheticdiversity!!

35%

Boc
N

Boc
N
N

CO2H

56%
N

CO2H

Compare and contrast.

Boc
N

CO2H

SciFinder Hits

>>10,000

Boc
N
N

CO2H

pKa (-2)

4.1

2.1

cLogP
g ((-1.6))

2.9

1.3

TPSA (+18)

67

85

MWt (-10)
( 10)

305

295

Dipole

Availability

Aldrich

Now 4 suppliers!

Improved synthesis of a Carfentanil

intermediate
Originalsynthesis

N
O

Strecker,CH3I,3day
amide formation
amideformation

CO2Me

Boc
N

Boc
N

Boc
N
O

HN

CO2H

CO2Me

N
O
N

ii.Aniline,NaOH,CHCl
Aniline NaOH CHCl3,THF,70%,
THF 70%
ii.Propionic anhydride,Et3Niii.
MeOH

Tet.Lett.2009,2497

CO2Me

Carfentanil

Another great fragment

R1
N

HowmanyhitsinSciFinderforthissubstructure?
<10 makesitnoveldesignspace

SO2NR2

Polar,bifunctional,unusualvectors,pKa
Polar bifunctional unusual vectors pKa

Boc
N
SO 2 Cl

Thiswouldbetheperfectintermediate
This would be the perfect intermediate buthasnever
but has never
beenreported!
Generallysulfonylchloridesynthesisrequiresharsh
conditions.Newsyntheticmethodologysolvestheproblem.
BOC
N

AcSH

BOC
N

Base

OMs

Cl2, EtOH
NaOAc buffer

SAc

BOC
N
SO2Cl

Innovation from the literature

Oxetanes
O t
verymuchinvogueinmedicinalchemistryrecently
hi
i
di i l h i t
tl

Asmetabolicblockinggroups

orascarbonylisosteres

SeminalpaperfromCarreira synthesisedsomeveryusefulspirocyclic oxetanes:

O
N

R
N

R
N

R
O

Angew. Chem. Int. Ed. 2008, 47, 4512-4515

Oxetane diversity
GreatpaperfromMerck
Aminooxetanes modulatedpKa,possibleamideisostere?
O

H2N

H3C S
H3C

Ti(OEt)4, THF
60oC, 5h, (45%)

O
+

CH2

DMSO, r.t.
DMSO
t
2h, (83%)

i)PhSH, Et3N
MeOH, tol

ii) HCl, MeOH

i)

Ph

H2N

S
O

Org. Lett. 2010, 12, 1116-1119

H
N
N

Cs2CO3
DMF

ii) HCl,
HCl M
MeOH
OH

ii) HCl, MeOH

Versatile
Intermediates!

i) ArMgBr, CuI
THF

H2N

H2N

N
O

Conclusions
Innovativesynthesisisthecornerstoneofchemicalspaceexplorationand
expansion
Newtakesonubiquitousreactionsutilisingmorecommonlyavailable
N
k
bi i
i
ili i
l
il bl
substratestoincreasesubstituentscopeareclearlydesirable.
Populationofchemicalspacewithsmallexpressionsofpolarityand
Population of chemical space with small expressions of polarity and
lipophilicity containing1or2pointsofdiversity,ishighlydesirablebut.
O

O
N
OH

F
O

Notifitsa9steproute.
Ph
Cl
NH3, MeOH

PMPOH
Cl

Cl KOtBu
(41%)

NH

H2N

Ph

Ph

Et3N.3HF

O
130 C
(77%)
OMe

Ph

Ph

(71%)

Ph
N

NBS
(69%)

Br
F

OMe
OMe

OMe

NaCNBH3, AcOH
(74%)
O

RuCl3, NaIO4

N
OH

(47%)

1. H2, Pd/C

N
F

Ph

Ph

OH

2. Boc2O (62%)

N
F

3. CAN, -10 C (74%)

OMe

JOC, 2009, 74, 2250-2253

Conclusions
Innovativesynthesisisthecornerstoneofchemicalspaceexplorationand
expansion
Newtakesonubiquitousreactionsutilisingmorecommonlyavailable
N
k
bi i
i
ili i
l
il bl
substratestoincreasesubstituentscopeareclearlydesirable.
Populationofchemicalspacewithsmallexpressionsofpolarityand
Population of chemical space with small expressions of polarity and
lipophilicity containing1or2pointsofdiversity,ishighlydesirablebut.
O

O
N
OH

F
O

Mustbeaccessibleinarelativelysmallnumberofsteps
SyntheticInnovationcancomefromanywhere.Communicationand
collaborationbetweenthepharmaceuticalindustryandacademiaiskey.
ll b
i b
h h
i li d
d
d i i k

Acknowledgements
DafyddOwen
D
f dd O
DavidBlakemore
DannyHo
LilyChan
KenButcher
Pete Wilson
PeteWilson
MattSelby
JonathanFray
Andrew Cronin
AndrewCronin
NunzioSciammetta
AllothersyntheticchemistsatSandwich

Backups

Goossen Mech

CombinationofadecarboxylationwithaPdcatalyzedcrosscoupling
CO2

[Cu]
R'

R'
X

L2Pd
X
O
[Cu]+

R
L2Pd

Pd0-precursor

R'
O

R'

O
R

[Cu]+ X

L2Pd
R

o Inprinciple,onlyacatalyticamountofcopperisrequired
o Ligandexchangebetweenpotassiumcarboxylateandcopperhalide
closesasecondcatalyticcycle
l
d
l i
l

( )

Originofvinylfluoride

F
O

OEt

S F
F

F O

S F
F
H

OEt

OEt

ThiobenzoateOxidationmechanism
O

O-

O
+

Ph

Ph

..

Cl

Cl

Cl

Ph

Cl

Cl

: Cl
Ph

..S

Cl

OH

-HCl
HCl

S
OH

Cl

Cl

-HCl
HCl

S
Cl

Cl

-HCl
HCl

Cl

OH

OH
H
H

S
HO

-HCl

O
Cl

..

R1
O
Ar/Het

S
O

O
Cl

Ph

Cl

..

HN
R2
Cl

O
Ar/Het

S
O

R1

R1
Ph

Cl
H

:O
H

O
S

Cl

:O

Cl

R2
R2

 It is believed that Cl2 is generated in-situ, so Cl2 is the actual oxidant.

O
Cl

O
N

+
O

N
Cl
TCCA

Practicalobservation:
NeedtopremixTCCAandR4NCl.

Cl
O

3 BnMe3NCl

3 Cl2

3 BnMe3N+
O

N
N

Solutiongoesgreenuponmixing.