Asymmetric synthesis of vabicaserin via oxidative multicomponent annulation and asymmetric hydrogenation of a 3,4-substituted quinolinium salt

Article abstract of DOI:10.1021/ol401029k

An efficient, asymmetric synthesis of the 5-HT_2C agonist vabicaserin in four chemical steps and 54% overall yield from commercially available benzodiazepine was achieved. The synthesis was highlighted by a novel oxidative, multicomponent reaction to affect the quinolinium ring assembly in one step followed by an unprecedented asymmetric hydrogenation of a 3,4-substituted quinolinium salt.

Full text of DOI:10.1021/ol401029k

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Asymmetric Synthesis of Vabicaserin
via Oxidative Multicomponent Annulation
and Asymmetric Hydrogenation of a
3,4-Substituted Quinolinium Salt
Vladimir Dragan,*,†,§ J. Christopher McWilliams,*,† Ross Miller,*,†, Karen Sutherland,†
John L. Dillon,‡ and Michael K. O’Brien†
Pharmaceutical Sciences, Pfizer, Inc., Eastern Point Road, Groton, Connecticut 06340,
United States, and Global Supply, Pfizer, Inc., 100 U.S. 206, Peapack,
New Jersey 07970, United States
vdragan777@gmail.com; chris.mcwilliams@pfizer.com; rmiller@jstar-research.com
Received April 13, 2013
ABSTRACT
An efficient, asymmetric synthesis of the 5-HT2C agonist vabicaserin in four chemical steps and 54% overall yield from commercially available
benzodiazepine was achieved. The synthesis was highlighted by a novel oxidative, multicomponent reaction to affect the quinolinium ring
assembly in one step followed by an unprecedented asymmetric hydrogenation of a 3,4-substituted quinolinium salt.
Vabicaserin (SCA-136, 1) is a potent and selective
5-HT2C receptor full agonist (Ki = 3 nM; EC50 = 8 nM),
demonstrating efficacy in several animal models predictive
of antipsychotic activity.1 Vabicaserin advanced through
phase 2 clinical trials as a potential treatment for schizo-
phrenia, exhibiting positive trends across several PANSS
measures.2 An efficient and scalable synthesis of 1, con-
taining an unusual cyclopentadiazepinoquinoline ring sys-
tem with two syn-oriented chiral centers, posed several
challenges. In this paper, we describe a four-step, enantio-
selective synthesis of 1 that was enabled by the discovery of
an oxidative, multicomponent reaction yielding two car-
bonꢀcarbon and two carbonꢀnitrogen bonds of the pen-
tacylic core structure, and an unprecedented asymmetric
hydrogenation of a 1,3,4,8-tetrasubstituted quinolinium
salt.
Early pharmaceutical development supplies were pro-
videdbythepreviously disclosedracemicsyntheticrouteto
SCA-136 (Scheme 1).3 A Povarov reaction between benzo-
diazepine (2), cyclopentene, and formaldeyde provided race-
mic 1, which was resolved by classical diastereoselective salt
resolution. While the synthesis was short, the overall yield for
the route was only 23%. Toward a more efficient route to 1,
several asymmetric approaches were pursued. One of the
more promising routes consisted of reaction of chiral allylsi-
lane 3 with the in situ generated iminium ion I, which gave a
highly diastereoselective Povarov product. However, subse-
quent cleavage of the carbonꢀsilicon bond proved to be
difficult.4 Installation of chirality via asymmetric hydrogena-
tion of a fully assembled pentacyclic core was an attractive
route to 1, and several permutations of this approach were
† Pharmaceutical Sciences, Pfizer, Inc.
‡ Global Supply, Pfizer, Inc.
§ Stepan Co., 100 W Hunter Ave, Maywood, NJ 07026.
J-Star Research, South Plainfield, NJ 07080.
(1) (a) Dunlop, J.; Watts, S. W.; Barrett, J. E.; Coupet, J.; Harrison, B.;
Mazandarani, H.; Nawoschik, S.; Pangalos, M. N.; Ramamoorthy, S.;
Schechter, L.; Smith, D.; Stack, G.; Zhang, J.; Zhang, G.; Rosenzweig-
Lipson, S. J. Pharm. Exp. Tech. 2011, 337, 673. (b) Rosenzweig-Lipson,
S.; Dunlop, J.; Marquis, K. L. Drug News Perspect. 2005, 9, 565–71.
(2) PANSS: Positive and Negative Syndrome Scale used to measure
symptom severity of patients with schizophrenia.
(3) (a) Megati, S.; Bhansali, S.; Dehnhardt, C.; Deshmukh, S.; Fung,
P.; Macewan, M.; Tinder, R. J. Chiral Synthesis of Diazepinoquinolines
PCT WO 2009/039362; 26 March 2009. (b) Dehnhardt, C. M.; Espinal, Y.;
Venkatesan, A. M. Syn. Comm. 2008, 796. (c) Dehnhardt, C.; Megati, S.;
Sun, J. Process for Preparing Quinoline Compounds and Products
Obtained Therefrom PCT WO 2006/052768; 18 May 2006.
(4) Akiyama, T.; Suzuki, M.; Kagoshima, H. Heterocycles 2000, 52, 529.
r
10.1021/ol401029k
XXXX American Chemical Society

evaluated. The unsaturated amide 4and the unfunctionalized
alkene 5 were found to be either unreactive or nonselective
under a variety of reduction conditions. The asymmetric
hydrogenation of tetrasubstituted quinolinium salts of type
II was unprecedented. However, the potential of assembling
the quinolinium salt in a single step coupled to an enantio-
selective hydrogenation made this route a very attractive
target for study.
NADH-type redox process, producing equal quantities of
8a and 9.9,10 Several oxidants were tested for their potential
to compete with III, but most gave only modest improve-
ments in overall conversion. A previous report indicated
catalytic iodine alonecould effectthistransformation, with
air as a stoichiometric oxidant.8c Applying this protocol to
7 led predominantly to iodination of the aromatic ring,
with no product formation.11 To redirect oxidation, we
considered deactivation of the aromatic ring by protona-
tion withacid prior tothe addition of iodine. To that effect,
the addition of HI prior to iodine not only led to inhibition
of ring iodination, observing only trace amounts of 9, the
modified conditions also affected conversion of 7 to 8b at
substantially lower temperature (30°C). Consequently, the
quinolinium salt 8b was accessed in 89% isolated yield
using this new, one-pot annulation/elimination/oxidation
MCR sequence.12
Scheme 1. Retrosynthetic Routes to Vabicaserin (1)
The enantioselective reduction of highly substituted
heterocycles, such as quinolines or pyridines, remains an
elusive target in an active field of research. While there are
a variety of methods described for highly selective asym-
metric reduction of 2-substituted quinolines, there are only
two reports describing substrates with substitution at
the 3-position and no reports with substitution at the 4-
or 8-positions.13 Further, while many of the prescribed
protocols invoke N-activation, there are no examples of
N-alkylquinolinium salts as substrates for asymmetric
hydrogenation. Consequently, we were not surprised to
find that applying the current state of the art reaction
conditions to highly substituted 8, or model substrates
thereof, resulted in little or no enantioselectivity. The most
promising lead came from the use of the phosphoramidite-
iridium catalyst system described by de Vries and Feringa,
in which we observed low reactivity and modest enantios-
electivity (Figure 1, Table 1, entries 2ꢀ4).13h Analogous to
the findings of de Vries and Feringa, a mixed ligand system
Assembly of a quinolinium salt II directly from a derivative
of readily available benzodiazepine 65 was initially envisioned
to occur through an economical multicomponent reaction
(MCR) with components at the targeted oxidation state.6
However, all attempts to produce structures of type II with
benzodiazepine derivatives in the absence of oxidants were
unsuccessful.7 We then considered a more complex, oxidative
MCR sequence, which required annulation, elimination, and
oxidation all occurring in the same pot.8
The substrate selected for the oxidative MCR study,
N-tosylbenzodiazepine 7, was obtained in 95% yield from
6 by treatment with p-TsCl and NaHCO3 in EtOAc
(Scheme 2). We were encouraged when the oxidative
MCR conditions developed by Kozlov were examined.8d
Accordingly, treating 7 with paraformaldehyde, cyclopen-
tanone, and triflic acid in n-butanol at 100 °C yielded the
desired quinolinium triflate 8a. However, an equal amount
of the N-methyl derivative 9 was also formed. We propose
the formation of 9 occurs through hydride transfer from
dihydroquinoline intermediateIVtoiminium ion III via an
(9) Meyers, A. I.; Stout, D. M. Chem. Rev. 1982, 82, 223.
(10) When the reaction was run using paraformaldehdye-d2, 9 was
formed with incorporation of three deuterium atoms (94% of theoretical)
and 8a with one deuterium atom, consistent with single deuterium transfer
from the intermediate hydroquinoline IV to the iminium ion III. For a related
example of an imine acting as an oxidant, see ref 8b.
(11) Iodination was not noted in ref 8c, although the authors indicate the
reaction was limited in scope to a single substrate, 2-aminonaphthalene.
(12) In this unoptimized process, an excess of cyclopentanone and
paraformaldedyde was used to drive the reaction to completion.
(5) Bergman, J.; Brynolf, A. Tetrahedron Lett. 1989, 30, 2979 and
references therein.
ꢀ
(6) For MCR reviews, see: (a) Toure, B. B.; Hall, D. G. Chem. Rev. 2009,
ꢀ
(13) For a recent review article, see: (a) Maj, A. M.; Suisse, I.; Meliet,
109, 4439. (b) Kumaravel, K.; Vasuki, G. Curr. Org. Chem. 2009,13, 1820. (c)
Martin, S. F.; Sunderhaus, J. D. Chem.;Eur. J. 2009, 15, 1300. (d) Ganem,
B. Acc. Chem. Res. 2009, 42, 463. (e) Zhu, J., Bienayame, H., Eds.
C.; Hardoin, C.; Agbossou-Neidercorn, F. Tetrahedron Lett. 2012, 53,
4747. (b) Wang, D.-S.; Chen, Q.-A.; Lu, S.-M.; Zhou, Y.-G. Chem. Rev.
2012, 112, 2557. Representative examples: (c) Wang, T.-L.; Zhuo, L. G.;
Li, Z.-W.; Chen, F.; Ding, Z.-Y.; He, Y.-M.; Fan, Q.-H.; Xiang, J.-F.;
Yu, Z.-X.; Chan, A. S. C. J. Am. Chem. Soc. 2011, 133, 9878. (d)
Dobereiner, G. E.; Nova, A.; Schley, N. D.; Hazari, N.; Miller, S.;
Eisenstein, O.; Crabtree, R. H. J. Am. Chem. Soc. 2011, 133, 7547. (e)
Tang, W.-J.; Tan, J.; Xu, L.-J.; Lam, K.-H.; Fan, Q.-H.; Chan Adv.
Synth. Catal. 2010, 352, 1055. (f) Wang, D.-S.; Zhou, Y.-G. Tetrahedron
Lett. 2010, 51, 3014. (g) Wang, C.; Li, C.; Wu, X.; Pettman, A.; Xiao, J.
ꢀ
Multicomponent Reactions; Wiley-VCH: Weinheim, 2005. Recemt examples
ꢀ
of MCR, see: (f) Bienayame, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.;Eur.
J. 2000, 6, 3321. (g) Hutt, J. T.; Aron, D. Org. Lett. 2011, 13, 5256.
(7) Combinations of cyclopentanone with formate derivatives, such
as the Vilsmeier reagent or DMF dimethyl acetal, did not yield product.
Cyclopentanone-2-carboxaldehyde also did not yield the desired pro-
duct under a variety of conditions examined.
ꢁ ꢀ
(8) For recent examples of oxidative MCR, see: (a) Adib, M.;
Sheikhi, E.; Bijanzadeh, H. R. Synlett 2012, 23, 85. (b) Shindoh, N.;
Tokuyama, H.; Takemoto, Y.; Takasu, K. J. Org. Chem. 2008, 73, 7451.
(c) Wang, X-S; Li, Q.; Yao, C-S; T, S.-J. Eur. J. Org. Chem. 2008, 3513.
(d) Kozlov, N. G.; Gusak, K. N. Russ. J. Org. Chem 2008, 44, 830. For
Angew. Chem., Int. Ed. 2009, 48, 6524. (h) Mrsic, N.; Lefort, L.; Boogers,
J. A. F.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. Adv. Synth.
Catal. 2008, 350, 1081. (i) Lu, S.-M.; Bolm, C. Adv. Synth. Catal. 2008,
350, 1101. (j) Lu, S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Angew.
Chem., Int. Ed. 2006, 45, 2260. (k) Rueping, M.; Antonchick, A. P.;
Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683. (l) Wang, W.-B.;
Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G. J. Am. Chem. Soc.
2003, 125, 10536. Example of quinoline N-oxide: (m) Gou, F.-R.; Li, W.;
Zhang, X.; Liang, Y.-M. Adv. Synth. Catal. 2010, 352, 2441.
ꢀ
oxidation of Povarov products, see: (e) Vicente-Garcıa, E.; Ramon, R.;
´
Preciado, S.; Lavilla, R. Multicomponent reaction access to complex
quinolines via oxidation of the Povarov adducts. Beilsein J. Org. Chem.
[Online] 2011, 7, 980, DOI:10.3762/bjoc.7.110 (accessed May 11, 2012).
B
Org. Lett., Vol. XX, No. XX, XXXX

Optimization of the achiral phosphine loading yielded
a key observation; increasing the concentration of the
achiral phosphine led to an increase in reactivity (Table 2,
entries 1ꢀ4). We postulated that the role of the excess
phosphine maybetoact asabaseinadditiontoservingasa
ligand for iridium. Apparent confirmation of this conclusion
is evidenced by the analogous effect of added base at low
phosphine charge (Table 2, entries 5ꢀ7), yielding high con-
version without significant loss in enantioselectivity. With the
addition of 2,6-di-tert-butylpyridine (2,6-DtBP), catalyst
loading could be reduced to e0.5 mol %, making this the
first practical method for the enantioselective hydrogenation
of highly substituted N-alkylquinolinium salts.14
Scheme 2. Multicomponent Reaction Annulation/Oxidation
Table 2. Impact of Achiral Phosphine Loading and Bases on
Conversion and Enantioselectivitya
provided the best results with regard to enantioseletivity.
In contrast to the decreased enantioselectivity observed by
de Vries, the addition of iodide salts had a positive effect on
enantioselectivity with this substrate (Table 1, entries
5ꢀ6). Although promising, the catalyst loading was too
high to be a practical synthetic method, and further opti-
mization based upon these leads was pursued.
entry
(t-Bu)3P (mol %)
additive (equiv)
conv (%)
er
1
2
1
40
80
100
3
none
none
22
50
85
78
81
75
99
96
90:10
87:13
85:15
83:17
89:11
89:11
89:11
89:11
3
none
4
none
5
DBU (1.3)
KO-t-Bu (1.3)
2,6-DtBP (2)b
2,6-DtBP (4)b
6
3
7
8c
3
1.5
a 5 mol % of n-Bu4I for entries 1ꢀ4; 1.3 equiv of LiI for entries 5ꢀ8.
b 2,6-di-tert-butylpyridine. c 0.5mol%of[Ir(COD)Cl]2, 1 mol % of Morphos.
The initial asymmetric hydrogenation was performed
using the triflate salt 8a. The iodide 8b acquired by the
oxidative MCR conditions provided similar results. How-
ever, we found that added chloride increased enantio-
selecivity (Table 3). This is consistent with recent reports
implicating the involvement of mixed halide catalysts.15
This procedure now provided conditions to achieve up
to 94% of the desired enantiomer in the asymmetric
Figure 1. Structures of Monophos ligands.
Table 1. Representative Examples of the Initial Catalyst Screena
Table 3. Impact of LiCl on Enantioselective Hydrogenation of 8ba
entry
ligand 1
ligand 2
additive
conv (%)
er
1
Josiphosb
none
Pip-HCl
Pip-HCl
Pip-HCl
Pip-HCl
nBu4I
99
28
57
99
39
35
50:50
75:25
70:30
76:24
91:09
90:10
2
(S)-PipPhos
(S)-MorPhos
(S)-MorPhos
(S)-MorPhos
(S)-MorPhos
(o-Tol)3P
(o-Tol)3P
(t-Bu)3P
(o-Tol)3P
(t-Bu)3P
entry
mol % Ir
additive
equiv
conv (%)
er
3
4
1
2
3
0.5
none
LiCl
LiCl
N/A
3
99
99
99
90:10
93:07
94:06
5c
6c
0.5
nBu4I
0.75
3
a 2:1:5:1 ratio of ligand 1/ligand 2/additive/[Ir(COD)Cl]2. b 0.5 equiv
relative to Ir. c 0.10 equiv of [Ir(COD)Cl]2
a 2:3:1 ratio of (S)-Morphos/(t-Bu)3P/[Ir(COD)Cl]2, 2.5 equiv of
2,6-DtBP.
Org. Lett., Vol. XX, No. XX, XXXX
C

hydrogenation of a tetrasubstituted quinolinium salt.
Crystalline 11 was isolated from the hydrogenation mix-
ture in 82% yield.
The final conversion of 11 to 1 consisted of deprotection
with HCl in acetic acid, yielding vabicaserin 1 in 92% yield
and 92% ee after crystallization (eq 1). An additional
recrystallization from EtOH/MTBE provided the target
compound in 86% yield and 99.9þ% ee.
steps and 54% overall yield from commercially available
benzodiazepine, a >2 fold increase compared to the
resolution approach to 1. The short synthesis was enabled
by the discovery of two new reaction processes: an oxida-
tive, multicomponent reaction to affect the quinolinium
ring assembly in one step, and an unprecedented asym-
metric hydrogenation of a highly substituted quinolinium
salt. Notably, this work provides the first example of an
enantioselective reduction of a quinoline heterocycle with
substitution at the 4 position.
Acknowledgment. We thank Thomas Storz (Pfizer,
Inc.) for providing samples of the unsaturated amide 4.
We thank Joel Hawkins, Javier Magano, and Sebastien
Monfette (Pfizer, Inc.) for helpful comments in the pre-
paration of the manuscript.
In summary, we have developed an efficient, asymmetric
synthesis of the 5-HT2c agonist vabicaserin in four chemical
(14) The role of added base is under investigation and may be critical
to enabling enamine T iminium ion equilibria (we have detected
partially reduced intermediates that accumulate in the absence of added
base) or to remove hydrogen from an unreactive iridium complex.
(15) Wang, D.-W.; Wang, X.-B.; Wang, D.-S.; Lu, S.-W.; Zhou,
Y. G.; Li, Y.-X. J. Org. Chem. 2009, 74, 2780. For an example of mixed
halide acceleration in rhodium transfer hydrogenation, see: Wu, J.;
Wang, C.; Tang, W.; Pettman, A.; Xiao, J. Chem.;Eur. J. 2012, 18,
9525.
Supporting Information Available. Copies of 1H NMR
and 13NMR, as well as experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX