Z . P E N G , * J . W . WO N G , E . C . H A N S E N , A . L . A . P U C H L O P E K - D E R M E N I C I , H . J . C L A R K E
Ca t e g o r y
( P F I Z E R WO R L D W I D E R E S E A R C H & D E V E L O P M E N T , G R O T O N , U S A )
Synthesis of Natural
Products and
Potential Drugs
Development of a Concise, Asymmetric Synthesis of a Smoothened Receptor (SMO) Inhibitor: Enzymatic
Transamination of a 4-Piperidone with Dynamic Kinetic Resolution
Org. Lett. 2014, 16, 860–863.
Ke y w o rd s
Synthesis of SMO Inhibitor PF-04449913
PF-04449913
smoothened
receptor antagonist
enzymatic
transamination
OMe
dynamic kinetic
resolution
N
THF–heptane–PhEt
–10 °C, 10 min
Ts
Ts
B (1.0 equiv)
LDA (2.2 equiv)
N
A
O
H3PO4 (2.2 equiv)
H2O, 10 °C, 1 h
N
–10 °C, 10 min
Me
H
N
(S)
N
O
transaminase ATA-036
i-PrNH2⋅HCO2H
NaOH (2.0 equiv)
O
Me
mp 175 °C (dec.)
HCl (4.0 equiv)
H
N
N
THF–H2O, 60 °C
95% (261 mmol scale)
N
Me
N
rac-E
mp 160 °C (dec.)
mp 114 °C
H
N
NH
N
H
H
N
(R)
N
dynamic
kinetic
resolution
N
N
HN
N
H
N
(R)
H
N
(R)
N
Me
(R)-G
N
H
CN
O
CN
O
NH2
O
Me
Ts
N
rac-F
PLP = pyridoxal phosphate
N
LiAlH(Ot-Bu)3 (1.2 equiv)
CuBr (0.05 equiv)
THF, –10 to 0 °C, 30 min
90% (263 mmol scale)
O
(HCl)2⋅H2O
N
sodium borate buffer (pH 10)
DMSO, PLP, 50 °C, 60 h
85% (30 mmol scale)
(S)-G
month
rac-D
O
Me
Me
C
N
of the
N
N
75% from A
(366 mmol scale)
N
mp 85 °C
Me
Ts
N
N
(2R,4R)-I
>99% ee
syn/anti = 1:10
Significance: PF-04449913 is an antagonist of
the smoothened receptor (SMO), a component of
the hedgehog signalling pathway. It is currently
undergoing human trials for the treatment of various blood-related cancers. The key steps in the
synthesis depicted are (1) the addition of a lithiated benzimidazole to the pyridinium salt B and (2)
the asymmetric construction of two stereogenic
centers by an enzymatic transamination accompanied by a dynamic kinetic resolution.
J (1.25 equiv)
imidazole (1.25 equiv)
THF–DMSO–H2O
80% from rac-F
H
N
N
Me
N
SMO Inhibitor
mp 223 °C
Comment: Complete racemization of the single
enantiomer (S)-G occurred in less than eight hours
at 40 °C in a mixture of DMSO and aqueous pH 10
buffer, the medium for the enzymatic transamination. A retro-aza-Michael/aza-Michael mechanism
for the racemization was proposed though no direct evidence of the ring-opened intermediate H
could be adduced. For the discovery synthesis of
PF-04449913, see: M. J. Munchhof et al. ACS
Med. Chem. Lett. 2012, 3, 106.
SYNFACTS Contributors: Philip Kocienski
Synfacts 052014, 10(5), 0449 Published online: 17.04.20141861-19581861-194X
DOI: 10.1055/s-0033-1341076; Reg-No.: K01614SF
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2014 © THIEME STUTTGART • NEW YORK
449
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