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Target Directed Synthesis via StReCH Chemistry: Pregabalin (LyricaTM)
Bryan D. Beall, Paul R. Blakemore
Department of Chemistry, Oregon State University
CO2H
H2Npregabalin (LyricaTM)
substrate carbenoidreagent
intermediatemetalate complex
new substrate
Stereospecific Reagent Controlled Homologation (StReCH)
R1 M1
M2 X
R2
M1
R1
M2+
R1 M1
R2
XM2
R3
XM2
R3
R1
R2
M1
R3R1
R2
M1
R3
– M2X1,2-metalate rearrangement
electrophilicsubstitution
R2
X
1
substrate
intermediatemetalate complex
new substrate
carbenoidreagent
Stereospecific Reagent Controlled Homologation (StReCH)
R1 M1
M2 X
R2
M1
R1
M2+
R1 M1
R2
XM2
R3
XM2
R3
R1
R2
M1
R3R1
R2
M1
R3
– M2X1,2-metalate rearrangement
electrophilicsubstitution
R2
X
1
substrate
intermediatemetalate complex
new substrate
carbenoidreagent
Stereospecific Reagent Controlled Homologation (StReCH)
R1 M1
M2 X
R2
M1
R1
M2+
R1 M1
R2
XM2
R3
XM2
R3
R1
R2
M1
R3R1
R2
M1
R3
– M2X1,2-metalate rearrangement
electrophilicsubstitution
R2
X
1
substrate
intermediatemetalate complex
new substrate
Requirement 1configurational and chemical stability of carbenoid during ate-complex formation
carbenoidreagent
Stereospecific Reagent Controlled Homologation (StReCH)
R1 M1
M2 X
R2
M1
R1
M2+
R1 M1
R2
XM2
R3
XM2
R3
R1
R2
M1
R3R1
R2
M1
R3
– M2X1,2-metalate rearrangement
electrophilicsubstitution
R2
X
1
R1 M1
M2 X
R2
M1
R1
M2+
R1 M1
R2
XM2
R3
XM2
R3
R1
R2
M1
R3R1
R2
M1
R3
– M2X1,2-metalate rearrangement
electrophilicsubstitution
R2
X
substrate
intermediatemetalate complex
new substrate
Requirement 2stereospecific formation and break-down of ate-complex
carbenoidreagent
Stereospecific Reagent Controlled Homologation (StReCH)
1
R1 M1
M2 X
R2
M1
R1
M2+
R1 M1
R2
XM2
R3
XM2
R3
R1
R2
M1
R3R1
R2
M1
R3
– M2X1,2-metalate rearrangement
electrophilicsubstitution
R2
X
substrate
intermediatemetalate complex
new substrate
Requirement 3greater stability of ate-complex than carbenoid (to prevent oligomerization)
carbenoidreagent
Stereospecific Reagent Controlled Homologation (StReCH)
1
An Example of a Simple StReCH Reaction
B O
OLi Cl
S Cl
O
t-BuLiPhMe, –78 °C
Ph
Ph
S
O
Ph
+
B O
O
Ph
ClPh
Li+
+ Ph BO
O
Ph
– LiCl
75-85%%ee ≥ 92%
sulfoxide ligand exchange
ate-complex formation
1,2-metalate rearrangement
Blakemore, Burge J. Am. Chem. Soc. 2007, 129, 3068
2
• Discovered by Richard B. Silverman of Northwestern University• First drug approved by the FDA for wide spread pain of
fibromyalgia• Also treats epilepsy and neuropathic pain disorders• Sales of LyricaTM (1.8 billion in 2007)• First Pfizer pharmaceutical drug in a decade to gross over one
billion dollars in a fiscal year
CO2H
H2Npregabalin (LyricaTM)
Pregabalin (LyricaTM)
3
Pregabalin (LyricaTM)
CO2H
H2Npregabalin (LyricaTM)
• Analogue of gamma-aminobutyric acid (GABA)• Binds to the protein subunit of voltage-sensitive calcium
channels, modifying calcium transduction and neurotransmitter release
• Acts as a agonist of GABA receptors• Increases GABA levels by increasing glutamic acid decarboxylase
(GAD) activity• GAD is an enzyme that synthesizes glutamate to GABA in one step
4
NH2 CO2H
GABA pregabalin
Planned Synthetic Approach to Pregabalin
CO2H
H2N
pregabalin
(LyricaTM)B
S
O
Cl
+
t-BuLi, PhMe, –78 °C
THF
–78 °C
NH
(a) O3, H2O2
(b) H2, Pd/C
O
O
BO
OB
O
OLi Cl
(a) BCl3
(b) PhCH2N3Ph
StReCH
methylene insertion amination
ozonolysis /deprotection
5
65%
Synthesis of Chlorosulfoxide
S
O
Cl
S
O
Cl
O2S
ClSH+
K2CO3
acetone, Δ
100%
S
I
I
HO
NHO
t-Bu
(1.5mol%)
VO(acac)2(1mol%)
aq.H2O2,CHCl3,0°C
76%
(%ee=98%)S
OCH2Cl2,rt,4d
N
O
O Cl
K2CO3
75%
13% 9%
Drago, Caggiano, JacksonAngew. Chem., Int. Ed. 2005, 44, 7221
Satoh, Oohara, Ueda, Yamakawa Tetrahedron Lett. 1988, 29, 313
6
Synthesis of Allylboronate
B O
O
MgBr B(OMe)3+ BOMe
OMeOMe
Et2O
–78 °C → rt
+MgBr
HO
HO
+MgBrB O
O
OMe–2xMeOH
H2SO4
49%
Roush, Adam, Walts, Harris, D. J. J. Am. Chem. Soc., 1986, 108, 3422
7
StReCH Reaction Results: Yield Analysis
B
S
O
Cl
+
O
O
t-BuLi, PhMe
–78 °C → rt
BO
O
NaOH+H2O2 H2O+Na+HO–O
B
OOH
OO
Na+OB O
O–NaOH
OH
NaOHH2O
O
O
OMe
4-MeOC6H4COCl
pyridine,rt,61%
%yield
33-48%
16%
t-BuLi
2 eq
1.1 eq
chlorosulf.
2 eq
1 eq
boronate
1 eq
2 eq
8
StReCH Reaction Results: Attempted Ee Analysis
B
S
O
Cl
+
O
O
t-BuLi, PhMe
–78 °C → rt
BO
O
NaOH+H2O2 H2O+Na+HO–O
B
OOH
OO
Na+OB O
O–NaOH
OH
NaOHH2O
O
O
OMe
4-MeOC6H4COCl
pyridine,rt,61%
9
StReCH Reaction Results: Attempted Ee Analysis
no resolution of racemic standard with four standard chiral HPLC columns (Daicel AD, OD, AS, OJ)
•
B
S
O
Cl
+
O
O
t-BuLi, PhMe
–78 °C → rt
BO
O
NaOH+H2O2 H2O+Na+HO–O
B
OOH
OO
Na+OB O
O–NaOH
OH
NaOHH2O
O
O
OMe
4-MeOC6H4COCl
pyridine,rt,61%
9
StReCH Reaction Results: Attempted Ee Analysis
B
S
O
Cl
+
O
O
t-BuLi, PhMe
–78 °C → rt
BO
O
NaOH+H2O2 H2O+Na+HO–O
B
OOH
OO
Na+OB O
O–NaOH
OH
NaOHH2O
O
O
OMe
4-MeOC6H4COCl
pyridine,rt,61%
alternate determination via NMR analysis of Mosher ester derivative in progress
•
OHO
OPh
F3C OMe
DCC
CH2Cl2, rt
OPh
F3C OMe
O
OPh
F3C OMe
9
Methylene Insertion
10
model study
Li Cl
I Cl
n-BuLiTHF, –78 °C
+
B O
OCl
Li+
– LiCl
BO
O
BO
O
BO
O
Ph
n-BuLi, ICH2ClTHF, –78 °C
NaOH, H2O2
(a)
(b)Ph OH
OHPh+
Methylene Insertion
10
model study
Li Cl
I Cl
n-BuLiTHF, –78 °C
+
B O
OCl
Li+
– LiCl
BO
O
BO
O
BO
O
Ph
n-BuLi, ICH2ClTHF, –78 °C
NaOH, H2O2
(a)
(b)Ph OH
OHPh+
73%
≈64%, product was volatile as an alcohol
StReCH and methylene insertion
Summary and Future Work
CO2H
H2N
pregabalin
(LyricaTM)B
S
O
Cl
+
t-BuLi, PhMe, –78 °C
THF
–78 °C
NH
(a) O3, H2O2
(b) H2, Pd/C
O
O
BO
OB
O
OLi Cl
(a) BCl3
(b) PhCH2N3Ph
StReCH
methylene insertion amination
ozonolysis /deprotection
11
Acknowledgements
• HHMI for funding• Paul Blakemore• Chris Emerson• Kevin Ahern
CO2H
H2Npregabalin (LyricaTM)
ArS
Ph
O X+
ArS
Ph
O X
ArS
Ph
O
H
B
X
ArS
Ph
O
X
ArS
Ph
O X
J . Klein Chem. Lett. 1979, 359
Sulfoxide Chlorination: Mechanism
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