Cycloalkene Carbonitriles in Rhodium-Catalyzed 1,4-Addition and Formal Synthesis of Vabicaserin

Article abstract of DOI:10.1021/acs.orglett.5b01849

Cycloalkenes with exocyclic acceptor substituents still remain challenging substrates for enantioselective rhodium-catalyzed 1,4-addition. Cycloalkene carbonitriles and carboxylates have been investigated, and a highly diastereo- and enantioselective prot

Full text of DOI:10.1021/acs.orglett.5b01849

Letter
pubs.acs.org/OrgLett
Cycloalkene Carbonitriles in Rhodium-Catalyzed 1,4-Addition and
Formal Synthesis of Vabicaserin
Wojciech J. Dziechciejewski, Regina Weber, Oliver Sowada, and Mike M. K. Boysen*
Leibniz University of Hannover, Institute of Organic Chemistry, Schneiderberg 1B, D-30167 Hannover, Germany
S
* Supporting Information
ABSTRACT: Cycloalkenes with exocyclic acceptor substituents still remain
challenging substrates for enantioselective rhodium-catalyzed 1,4-addition. Cyclo-
alkene carbonitriles and carboxylates have been investigated, and a highly diastereo-
and enantioselective protocol for 1,4-addition to cyclopentene and cycloheptene
carbonitrile has been developed. This new asymmetric transformation was
subsequently applied in the asymmetric formal synthesis of the drug candidate
Vabicaserin.
ince the first report by Hayashi and Miyaura in 1998,1
Scheme 1. Examples for Enantioselective 1,4-Additions to
Cycloalkenes with Exocyclic Acceptor Substituents
Sasymmetric rhodium(I)-catalyzed 1,4-addition has evolved
into an attractive method for C−C bond formation under
concomitant setup of one new stereocenter. The reaction scope
comprises cyclic or acyclic enones and enoates as electrophiles
and aryl- or alkenylboronic acids as nucleophiles, yielding
products in excellent enantioselectivity.2 Apart from these,
there still remain interesting nucleo- and electrophiles, which
have received little attention or are known as taxing.
In the course of our work on challenging substrates for 1,4-
additions, we have recently performed an extensive study on
heteroaryl boronates as nucleophiles.3 In this letter we are
presenting the highly stereoselective 1,4-addition to cycloalkene
For our investigation, we selected cycloalkene carbonitriles
carbonitriles as electrophiles and its application in an efficient
asymmetric formal synthesis of the antipsychotic drug
candidate Vabicaserin.
and carboxylates 4. To the best of our knowledge, electrophiles
4 are unprecedented in enantioselective 1,4-addition; only the
substrate-controlled reaction of a chiral cyclopentene carbo-
nitrile has been reported.10 Even examples employing acyclic
α,β-unsaturated nitriles are few and restricted to highly
activated substrates carrying two nitriles or one nitrile and
one ester group at the α-position.11,12
Nowadays, chiral dienes are the ligands of choice for
rhodium-catalyzed 1,4-additions.13 For our study, we selected
(S,S)-Ph-bod (5) developed by Hayashi’s group,14 a ligand
giving excellent results for a wide range of substrates. First,
cyclohexene carbonitrile 4a and cyclohexene carboxylate 4b
were reacted with phenylboronic acid 2a (Table 1). Very
surprisingly, both electrophiles failed to yield any of the
expected products (entries 1 and 2). In contrast, cyclopentene
carbonitrile 4c smoothly underwent 1,4-addition with 2a with
good diastereoselectivity in favor of cis-6ca, which was isolated
in 90% ee (entry 3). Interestingly, the minor diastereomer
trans-6ca was formed in significantly lower enantioselectivity
(72% ee). These results are in striking contrast to the ones
reported for nitrocycloalkenes (cf. Scheme 1), where excellent
Cycloalkenes with exocyclic acceptor substituents are
attractive substrates for 1,4-additions, as they yield products
with two new contiguous stereocenters. Nevertheless, these
electrophiles have rarely been explored, probably due to the
reduced reactivity of their trisubstituted double bond4 and
diastereoselectivity issues. While the stereocenter at the β-
position is set up by the addition of the chiral arylrhodium
species, the stereocenter at the α-position generated by
diastereoselective protonation of the transient rhodium
enolate.5 Most reports on this substrate class concern
nitrocycloalkenes: In the first study by Hayashi, nitro-
cyclohexene 1a mainly yielded cis-3aa, while nitrocycloheptene
1c gave predominantly trans-3ca; both products were isolated
in high enantiomeric excess.6 Nitrocyclopentene 1b, on the
other hand, gave only 73% ee and very low diastereoselectivity
in favor of trans-3ba.6 (Scheme 1). Later, 1,4-additions to a
nitrocyclohexene with an allylic acetate residue7 and to
dihydronitronaphthalenes8 were reported. The only enantiose-
lective example not involving a nitro group as an acceptor
substituent was published with pyrroline carboxylate 1d,
yielding exclusively trans-3da in high ee.9
Received: June 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01849
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Letter
Table 1. Asymmetric 1,4-Addition of Arylboronic Acids to Cycloalkene Carbonitriles and Carboxylates
electrophile 4
boronic acid 2
1,4-adduct 6
a
b
c
d
entry
n
Z
Ar1
yield [%]
cis/trans
ee cis [%]
ee trans [%]
1
2
4a
4b
4c
4c
4c
4c
4c
4d
4d
4e
4e
4e
4e
2
2
1
1
1
1
1
1
1
3
3
3
3
CN
2a
2a
2a
2a
2b
2c
2d
2a
2b
2a
2b
2c
2d
Ph
Ph
Ph
Ph
6aa
6ba
6ca
6ca
6cb
6cc
6cd
6da
6db
6ea
6eb
6ec
6ed
no reaction
−
−
−
−
−
−
CO2Me
CN
no reaction
e
3
75
86
76
70
94
88
67
73
75
71
75:25
86:14
74:26
82:18
89:11
32:68
48:52
64:36
71:29
65:35
57:43
90
95
95
96
97
91
98
82
94
88
72
32
59
66
29
54
94
73
92
49
80
f
4
CN
5
6
7
8
9
CN
o-MeO-C6H4
CN
p-MeO-C6H4
p-F3C-C6H4
Ph
CN
CO2Me
CO2Me
CN
o-MeO-C6H4
Ph
e
10
e
11
CN
o-MeO-C6H4
p-MeO-C6H4
e
12
CN
e
13
CN
p-F3C-C6H4
71
88
a
b
c
d
e
Isolated yield after chromatography. Determined by 1H NMR. Determined by chiral GC. Determined by chiral HPLC. With 1.0 equiv of KOH.
f
With 0.5 equiv of PMP.
Scheme 2. Basic Epimerization of cis-6ca and Preparation of
para-Bromobenzamide 7
Scheme 3. Retrosynthetic Approach to Vabicaserin
modest, the major products 6cb-6cd were formed in 95−97%
ee (entries 5−7).
Next, we studied the reaction of cyclopentene carboxylate 4d
with boronic acid 2a. This also yielded the expected products,
but this time with moderate diastereoselectivity in favor of
trans-6da. Unfortunately, the trans-compound was formed in
only low ee, while 91% ee was observed for the minor product
cis-6da (entry 8). With ortho-methoxyphenylboronic acid 2b, a
near 1:1 mixture of cis- and trans-6db was isolated, but this
time, the ee was high for both diastereomers, with 98 and 92%
ee respectively (entry 9). As diastereoselectivities with ester 4d
were generally lower than with nitrile analogue 4c, we did not
perform any further experiments with 4d. While the reaction
with cyclohexene carbonitrile 4a had been unsuccessful (entry
1), the higher homologue cycloheptene carbonitrile 4e proved
to be a suitable substrate (entries 10−13). In most cases,
however, the diastereoselectivity was only low but again in favor
of the cis-configured products, which were obtained in higher
Figure 1. X-ray crystal structure of para-bromobenzamide 7.
ee and a high dr of 87:13 in favor of the cis-product was
observed for cyclohexene-derived electrophile 1a, while the
cyclopentene congener 1b gave poor dr and ee.6 Both, the
diastereo- and enantioselectivity of the 1,4-addition with
carbonitrile 4c could be further improved (cis/trans 86:14;
95% ee for cis-6ca) by switching the base from KOH to
1,2,2,6,6-pentamethylpiperidine (PMP)15 (entry 4). Subse-
quently, we explored nitrile 4c in 1,4-additions with arylboronic
acids 2b−2d carrying electron-donating methoxy groups or an
electron-withdrawing trifluoromethyl residue. As in the case
with 2a, the reactions proceeded with high cis-selectivity and
while the ee for the minor trans-diastereomers was again only
B
DOI: 10.1021/acs.orglett.5b01849
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Letter
Scheme 4. Formal Synthesis of (+)-Vabicaserin (8) from 1,4-Addition Product cis-6ca
enantioselectivity than the trans-diastereomers (entries 10, 12
and 13). The best result for electrophile 4e was obtained with
boronic acid 2b, yielding the diastereomeric addition products
6eb both in >90% ee and a cis/trans ratio of 71:29 (entry 11).
These findings are also in contrast to the results reported by
Hayashi, who observed a distinctly trans-selective reaction for
nitrocycloheptene6 (cf. Scheme 1).
of 1,2-disubstituted cyclopentenes23 and quinolinium salts,24
respectively.
For a stereoselective synthesis of Vabicaserin (8), we
envisioned the retrosynthetic approach in Scheme 3.
Tetracyclic 8 can be prepared from 9 by known methods.
The tricyclic core structure 9 can be accessed via pathway A
using cyclopentane carbonitriles cis-6ce−cg as key intermedi-
ates, which may be prepared by 1,4-addition of phenylboronic
acids 2e−g carrying an ortho-halogen or hydroxy group to
carbonitrile 4c. But even though ortho-modified substrate 2b
had produced the desired adduct, the reaction with 2e−g only
led to complex mixtures or decomposition of the boronic acids,
rendering this approach unsuccessful.
Since introduction of an ortho-functionalized phenyl residue
by 1,4-addition had failed, we set up alternative retrosynthetic
pathway B (Scheme 3). In this approach, 9 is prepared from
ortho-iodo amide 10, which may be accessed by a late-stage
halogenation: Barluenga25 and Chen26 reported the direct
ortho-iodination of β- and γ-aryl alkylamides with TFA or 2-
picolinyl residues. This reaction gives fair to high ortho/para
ratios, but the scope is so far restricted to acyclic substrates.
The precursor for iodide 10 should be available from cis-6ca,
the major 1,4-addition product of 4c with phenylboronic acid
2a, via reduction and amidation.
The new synthetic approach is summarized in Scheme 4.
First, we repeated the 1,4-addition of phenylboronic acid 2a to
nitrile 4c with 1.00 g (10.74 mmol) of the electrophile.27 This
produced an excellent combined yield of cis- and trans-6ca
(1.63 g, 9.51 mmol) which were isolated in a ratio of 87:13.
From this mixture, 1.06 g (6.20 mmol) of cis-6ca (58% yield)
was isolated in 96% ee and subsequently transformed into TFA
amide 11 by reduction18 and amidation.25 Iodination of 11 was
performed using Chen’s protocol with NIS26 rather than
IPy2BF4 as reported by Barluenga.25 In our first attempt at 0
°C, we observed an ortho,para-diiodinated compound as the
major product, but decreasing the temperature to −20 °C led
to the desired iodide 10a, which was isolated in excellent yield
and an ortho/para ratio of 86:14. With 10a in hand, the stage
was set for the cyclization to 9. Ullmann C−N coupling under
conditions previously described by Chen26 yielded the N-TFA
substituted product 12 along with an impure fraction of amine
9. Removal of the TFA group from 12 yielded pure tricyclic
amine 9 in 96% ee. This compound can be transformed into
the (+)-enantiomer of Vabicaserin via a known route in three
steps.22b
At this stage, it is difficult to give a satisfactory explanation
for the rather large variation of the cis/trans diastereoselectiv-
ities observed for electrophiles 4c−e and the failure of the
reaction for 4a,b (cf. Table 1). In the literature, 2-phenyl
cyclohexane nitronate16 and the enol derived from 1-phenyl-2-
benzoylcyclohexane17 have been reported to predominantly
yield cis-configured products upon protonation under kinetic
conditions. Preferential formation of cis-configured products
from 4c may therefore be rationalized by a kinetically
controlled protonation of a transient nitrile enolate. In order
to exclude the possibility of an epimerization of cis-6ca during
the reaction, we subjected a pure sample to the reaction
conditions (0.5 equiv of KOH, dioxane/H2O 6:1, 60 °C) in the
absence and presence of the rhodium catalyst, and in both
cases, cis-6ca was recovered unchanged. We are currently
conducting further studies to elucidate possible reasons for the
varying cis/trans diastereoselectivities observed for 4c−e.
With the 1,4-addition of boronic acids to cyclopentene
carbonitrile described in Table 1, we have successfully
established a new, highly diastereoselective and enantioselective
approach to chiral 1,2-cis-disubstituted cyclopentanes. Even
though the trans-products are isolated as minor diastereomers
in only modest ee, it should be noted that they can be obtained
in high ee from the major cis-products. Epimerization of
enantioenriched cis-6ca with sodium methoxide in methanol
led to the thermodynamically more stable diastereomer trans-
6ca in good yield and high dr without erosion of the
enantiomeric excess (Scheme 2).
In order to elucidate the absolute configuration of the
addition products from Table 1, cis-6ca was converted into
para-bromobenzamide 7, via hydride reduction18 and amida-
tion19 (Scheme 2). X-ray crystal structure analysis of 7
unequivocally established the absolute configuration of cis-6ca
as (1S,2R)20 (Figure 1).
To demonstrate the synthetic value of the new 1,4-addition
to cyclopentene carbonitrile, we decided to employ this method
in the formal synthesis of the drug candidate Vabicaserin.
Developed by Wyeth as a selective agonist of the 5-
hydroxytryptamine 2 C receptor, (−)-Vabicaserin (SCA-136)
is under evaluation for its antipsychotic properties.21 Syntheses
of enantioenriched Vabicaserin have been reported previously,
using chiral resolution22 or asymmetric hydrogenation reactions
In summary, we have described new enantioselective 1,4-
addition reactions with cycloalkenes carrying exocyclic acceptor
substituents. Cyclopentene carbonitrile yielded cis-configured
products in high dr and excellent ee. This new transformation
was successfully applied as a key step in the formal synthesis of
C
DOI: 10.1021/acs.orglett.5b01849
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Organic Letters
Letter
(14) Otomaru, Y.; Okamoto, K.; Shintani, R.; Hayashi, T. J. Org.
Chem. 2005, 70, 2503.
(15) PMP in Pd-catalyzed carboiodination: Petrone, D. A.; Yoon, H.;
Weinstabl, H.; Lautens, M. Angew. Chem., Int. Ed. 2014, 53, 7908.
(16) Bordwell, F. G.; Yee, K. C. J. Am. Chem. Soc. 1970, 92, 5939.
(17) (a) Zimmerman, H. E. J. Org. Chem. 1955, 20, 549.
Vabicaserin. Further studies on the factors governing cis/trans
ratios of the new 1,4-addition reaction and its failure for
cyclohexene-derived electrophiles are underway in our
laboratories.
ASSOCIATED CONTENT
* Supporting Information
■
(b) Zimmerman, H. E.; Wang, P. J. Org. Chem. 2003, 68, 9226.
S
́
(18) Lorenzo, J.; Delgado, A.; Montana, A. M.; Mesas, J. M.; Alegre,
M.-T.; del Carmen Rodríguez, M.; Aviles
2014, 83, 374.
̃
́
, F.-X. Eur. J. Med. Chem.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01849.
(19) Rovis, T.; Dirocco, D.; Guiles, J. WO 2012/9372 A2, 2012.
(20) CCDC 1408648. The absolute configurations of the other 1,4-
addition products was assigned by analogy to that of para-
bromobenzamide 7.
Full experimental details, characterization data, copies of
spectra and chromatograms (PDF)
(21) 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. Pharmacol. Exp. Ther. 2011, 337, 673.
(22) (a) Megati, S.; Bhansali, S.; Dehnhardt, C.; Deshmukh, S.; Fung,
P.; MacEwan, M.; Tinder, R. J. WO 2009/039362A2, 2009.
(b) Neelamegam, R.; Hellenbrand, T.; Schroeder, F. A.; Wang, C.;
Hooker, J. M. J. Med. Chem. 2014, 57, 1488.
CIF file for compound 7 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mike.boysen@oci.uni-hannover.de.
Notes
(23) Feigelson, G. B. US 2007/0088022 A1, 2007.
(24) Dragan, V.; McWilliams, J. C.; Miller, R.; Sutherland, K.; Dillon,
The authors declare no competing financial interest.
J. L.; O’Brien, M. K. Org. Lett. 2013, 15, 2942.
ACKNOWLEDGMENTS
■
́
(25) Barluenga, J.; Alvarez-Guitier
J. M. Angew. Chem., Int. Ed. 2007, 46, 1281.
́ ́
rez, J. M.; Ballesteros, A.; Gonzalez,
Dedicated to Prof. Dr. Ekkehard Winterfeldt, deceased October
11th 2014. Financial support by the DFG (BO 1938/5-1) and a
Heisenberg Fellowship for M.M.K.B. (BO 1938/4-1) is
(26) Nack, W. A.; He, G.; Zhang, S.-Y.; Lu, C.; Chen, G. Org. Lett.
2013, 15, 3440.
gratefully acknowledged. We thank Dr. Gerald Drager, Institute
of Organic Chemistry, Leibniz University of Hannover, for the
̈
(27) For experimental details see Supporting Information.
X-ray crystallographic analysis of para-bromobenzamide 7.
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DOI: 10.1021/acs.orglett.5b01849
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