Conformation of gem-disubstituted alkylarylpiperidines and their implication in design and synthesis of a conformationally-rigidified NK 1 antagonist

Article abstract of DOI:10.1016/j.tetlet.2013.08.131

Piperidines are ubiquitous in pharmaceuticals and bioactive natural products. Understanding the structural and functional properties of piperidines plays a key role in drug design and development. This Letter reported studies of conformation of a set of g

Full text of DOI:10.1016/j.tetlet.2013.08.131

Accepted Manuscript
Conformation of gem-disubstituted alkylarylpiperidines and their implication
in design and synthesis of a conformationally-rigidified NK antagonist
1
Dong Xiao, Cheng Wang, Hon-Chung Tsui, Anandan Palani, Robert Aslanian,
Alexei V. Buevich
PII:
S0040-4039(13)01529-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.131
TETL 43494
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
29 July 2013
28 August 2013
30 August 2013
Please cite this article as: Xiao, D., Wang, C., Tsui, H-C., Palani, A., Aslanian, R., Buevich, A.V., Conformation
of gem-disubstituted alkylarylpiperidines and their implication in design and synthesis of a conformationally-
rigidified NK antagonist, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.08.131
1
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Abstract
Piperidines are ubiquitous in pharmaceuticals and bioactive natural products. Understanding the structural and
functional properties of piperidines plays key role in drug design and development. This paper reported
studies of conformation of a set of gem-disubstituted methylphenylpiperidines in the context of discovery of
NK1 antagonists. The findings led to re-design and an efficient synthesis of a potent NK1 antagonist with
excellent in vivo activity and rodent and monkey pharmacokinetic profiles.
Key Words
Piperidine conformation
NMR study on conformation
Piperidine synthesis
Diastereoselective synthesis
NK1 antagonists

Graphic Abstract:

Conformation of gem-disubstituted alkylarylpiperidines and their implication in design and synthesis of
a conformationally-rigidified NK1 antagonist
Dong Xiao,* Cheng Wang, Hon-Chung Tsui, Anandan Palani, Robert Aslanian and Alexei V. Buevich*
Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033
dong.xiao@merck.com; alexei.buevich@merck.com
Piperidines are important motifs in pharmaceuticals and bioactive natural products.1 Understanding the
structural and functional properties of piperidines naturally plays key role in drug design and development.2
Synthesis of piperidines also attracted much attention and several reviews3 have been published on that
subject. In this paper, we would like to report our study of conformation of a set of gem-disubstituted
methylphenylpiperidines in the context of discovery of neurokinin 1 (NK1) antagonists.4 Our findings led to
re-design and an efficient synthesis of a potent NK1 antagonist with excellent in vivo activity and rodent and
monkey pharmacokinetic profile.
Neurokinin 1 (NK1) receptor belongs to the family of G-protein coupled receptors (GPCRs). This receptor
mediates the action of substance P and other tachykinins in both the central and peripheral nervous systems.
Therefore, NK1 receptor antagonists may have therapeutic values in treating emesis, anxiety, depression,
inflammation and pain.4 In 2003, US Food and Drug Administration (FDA) approved Merck’s Emend® for
the treatment of chemotherapy-induced nausea and vomiting (CINV).5 This demonstrated the clinic utility of
NK1 antagonists and further stimulated discovery research in this area. Recently we reported5 our discovery of
a non-racemic NK1 antagonist 1 based on an earlier literature lead 2.6 Shortly after establishment of 1 as our
program lead for in-depth medicinal study, we also accomplished two complimentary stereoselective
asymmetric syntheses7 of 1. Armed with these chemistries, we undertook an SAR investigation of 1 to
improve its overall biological profiles. Our efforts resulted in the discovery of a series potent, orally active
NK1 antagonists8 represented by compound 3a (Figure 1).
Figure 1. Representative NK1 antagonists.
RHN
CF
CF
CF
3
3
3
NH
Ph
O
NH
Ph
O
NH
Ph
O
CF
CF
CF
3
3
3
2
3a:
3b
1
During the process of this investigation, particularly in efforts to address development issues of 3a (vide
infra), we became interested by the conformation effect of these 2, 2-disubstituted piperidines. It was reported
that compound 2 existed in a single chair conformation in which the phenyl group took an axial position.9
This result was somewhat intriguing and prompted some questions. Considering the well-established 1,1-
methylphenylcyclohexane case, the phenyl showed only moderate preference of occupying axial position with
a ratio of 72:28.10 For the strong axial phenyl preference of compound 2, did the large alkylether group play a
role or if the piperidine nitrogen contributed to it? Our desire to answer these fundamentally important
questions, coupled with long-standing interests in the properties of piperidines, motivated our studies of the
conformational equilibriums of 2,2-methylphenylpiperidine (4) along with 3,3- (5) and 4,4-methylphenyl (6)
piperidines. As in case of 1,1-methyl-phenylcyclohexane, conformational equilibriums of 4-6 are described by
two chair forms with axial (A) and equatorial (B) orientations of phenyl group (Figure 2):
Figure 2. Conformational equilibriums in compounds 4-6.

Conformational equilibriums of 4-6 were studied by NMR spectroscopy.11 Conformational analysis was
performed based on vicinal proton-proton J-couplings. At room temperature the exchange between A and B
conformations is fast and therefore experimentally measured J-couplings are seen as average values described
by the following equation (Equation 1):
J
exp = pAJA + pBJB,
(1)
where Jexp is experimentally observed J-coupling, JA and JB are corresponding J-couplings in conformations
A and B, and pA and pB are probabilities of conformations A and B. Since probabilities are normalized (pA +
pB =1), only one of them needs to be determine.
The JA and JB-couplings was calculated quantum-mechanically using density functional theory (DFT) method
at the B3LYP/6-311+G(d,p) level. That method showed excellent accuracy in predicting homo- and
heteronuclear J-couplings,12 as well as NMR chemical shifts.13
Among different J-couplings that can be measured in pepridines 4-6, the most relevant for conformational
analysis are trans-3JHH. The wide range of trans-3JHH from 2-3 Hz between diequatorial protons to 10-12 Hz
between diaxial protons makes them a sensitive parameter to small changes in conformational equilibrium,
particularly when equilibrium constants are close to unity. With JA and JB couplings calculated by DFT, the
pA:pB ratio can be estimated from a single experimentally measured J-coupling by solving equation 1. To
ensure a higher accuracy of estimated conformational probabilities we have used two trans-3JHH for each of
the studied piperidines. In this case a least-squares minimization approach was applied to find conformational
probabilities producing the best fit of both trans-3J-couplings (Jcalc) to their corresponding experimental values
(Jexp) simultaneously. Results of conformational analysis of 4-6 are summarized in Table 1.
Table 1. Conformational analysis of piperidines 4-6.
Ph
H
H
1
2
HN
Me
H
H
Ph
2
1
HN
H '
H '
1
2
H '
H '
Me
2
1
6A
JH1’,H2
3.4
12.7
6.4
6B
JH1,H2’
12.7
2.7
9.9
9.70
JH5,H6’
2.4
12.8
4.1
JH5’,H6
12.6
2.6
10.7
10.84
JH5,H6’
2.4
12.5
7.5
JH5’,H6
12.5
2.4
7.2
7.30
JA, Hz
JB, Hz
Jexp, Hz
J
calc, Hza
4.23
7.60
6.19
RMSDb
pA:pB
0.17
82:18
0.10
48.5:51.5
0.21
70:30
a Jcalc were calculated as pAJA+pBJB
b Root-mean-square deviations (RMSD) were calculated as (Σ(Jcalc-Jexp)2/2)1/2.

As seen by a very small root-mean-square deviations (RMSD) of J-coupling fittings (0.10 – 0.21 Hz), the
DFT method used to predict J-couplings for individual conformations was well justified.
The combined experimental and calculated results were quite interesting. First of all, the conformer ratio of
phenyl ax:eq for 4,4-substituted piperidine was 70:30. This ratio was in good agreement with the
corresponding cyclohexane case of 72:28. As in 4,4-substituted piperidine system the nitrogen atom was not
in a position that could influence the conformation of 4 position, this result was indeed highly anticipated.
This also further validated our NMR-based method used in this study. Similarly, the 3,3-substitution can be
viewed to have less 1,3-diaxial interaction with axial methyl group,14 resulting in little difference between the
methyl and phenyl substituents. This was reflected by near equal distribution of axial and equatorial phenyl
group in a ratio of 48.5:51.5. A similar phenomenon had been observed in the 1,3-dioxane system.14
Intriguing and relevant to NK1 antagonists, the 2,2-piperidine pattern produced a more preferred
conformation, with an ax:eq ratio of 82:18. In addition, when the NK1 antagonist 1 was subjected to the same
NMR analysis, the ax:eq ratio of 88:12 was observed. This result corroborated the fact that for 2,2-
disubstituted NK1 antagonists, the preferred conformation is the axial phenyl. It is an inherent preference of
2,2-methylphenylpiperidines, the bulky bis-trifluoromethylbenzyl ether side chain contributed marginally to
this phenomenon.
The result of NMR study confirmed the preference of phenyl group in axial position in compound 1 and 2,
which shed a light of addressing the program issue of lead 3a. At the time, it was found that 3a was
metabolized in vivo to yield 3b. This diamine metabolite showed undesirable long half-life in rat brain.8
Literature precedents indicated that dibasic amine drugs tend to attach to lipid bilayer and were likely to
induce phospholipidosis.15 To circumvent the problem, it was envisioned that the acetyl group could be
cyclized to various positions on the piperidine ring to generate bicyclic lactam structures.16 Among a number
of potential targets, the fused analog 7, which would maintain desired axial phenyl conformation, emerged as
a high priority target (Figure 3).
Figure 3. Evolution of design strategy based on NMR study.
The synthesis of 7 was based on reproduction of chirality approach17 using commercial oxazolidinone
template 8.18 Alkylation with alkyl bromide 9 (ref. 19) afforded the desired quaternary chiral center in 10. The
ester was reduced to the corresponding hydroxyl oxazolidine 11. Subsequent Wittig reaction provided
required carbon framework of piperidine. After saturation of alkene double bond with hydrogenation, an acid-
promoted cyclization on acetal 12 yielded enamide 13. The nucleophilic enamide was treated with NO2BF4 to
install the nitro functionality20 and set the stage for the ensuing Michael reaction. The nitroalkene 14 reacted
with lithium enolate of EtOAc to afford key nitroester 15 and 16 as a pair of diastereomer in 2:1 ratio
separable with 0-80% EtOAc in hexanes (v:v) on silica gel column. Final approach towards target 7 was
completed by reduction of nitro group using hydrogenation with Ni(Ra) with concomitant removal of Cbz
group. The crude mixture was treated with K2CO3 in refluxing MeOH to afford the final product 7. The
diastereomer 17 was also obtained in the same fashion (Scheme 1).
Scheme 1. Synthesis of compound 7.

O
Ph
Ph
CbzN
Ph
CbzN
Ph
CF
3
O
CbzHN
Ph
O
O
O
Ph
O
Br
O
CbzN
Ph
1) H , PtO
2
OH
O
2
CF
3
Br-Ph P
3
O
O
LiBH , 0 oC
4
O
O
9
o
KHMDS
2) HCl, 80
C
O
o
-78 C-RT
84%, 2 steps
8
o
C
CF
3
CF
3
LDA, -78
70%, 2 steps
CF
3
68%
10
11
F C
3
F C
3
12
F C
3
O
O
CO Et
2
CO Et
2
NO
2
CbzN
Ph
CbzN
Ph
NH
NH
NO
NO
2
2
NH
CbzN
CbzN
Ph
NH
EtOAc
1) Pd/C, Ni(Ra)
Ph
NO BF
2
Ph
Ph
4
LHMDS
O
O
o
o
C
2) MeOH, 60
K CO
C
O
O
O
O
-78
65%
2
3
75%, (2:1)
CF
3
CF
3
70%, 2 steps
CF
3
CF
3
CF
3
CF
3
13
F C
3
F C
3
14
15
F C
3
F C
3
F C
3
16
F C
3
7
17
Ki (NK ) = 0.23 nM Ki (NK ) = 4.0 nM
1 1
The analog 7 indeed proved to be a potent NK1 antagonist whereas diastereomer 17 showed significant 17 fold
loss of NK1 potency based on their dissociation constants (Ki).8 Additional data of analog 7, also known as L-
004060882, was obtained. In a pharmacodynamic model, the gerbil foot thumping (GFT) assay,8 L-
004060882 showed 100% inhibition at 4 h and 6 h with 1 mpk per oral dosing. It showed excellent
pharmacokinetic profiles in rodents and monkeys.21
The attractive preliminary profiles of L-004060882 demanded a better synthesis in order to generate multi-
gram quantity for additional investigations. We decided to concentrate on improving the yield and selectivity
in key Michael addition step. Initially, we thought that the selectivity can be delivered by using chiral
nucleophiles, therefore, several chiral enolates were screened (Scheme 2). For example, neither enantiomer of
the lithium enolates of acetyloxazolidinone 20 or 2121 was reactive enough towards the nitroalkene 14. The
more reactive enolates of chiral cyclohexanolacetate22 provided good yield of products. It was interesting to
confirm that selectivity was indeed predominantly controlled by the chirality of enolates. The (1S, 2R)
cyclohexnolacetate 22 afforded mostly 19, while the (1R, 2S) isomer 23 provided an excellent selectivity of
14.7:1 favoring 18, reflecting a match and mismatch case. The resulting nitroester 18, however, could not be
converted to the final product. After nitro group reduction, the lactam cyclization failed even under forcing
conditions, likely due to extreme steric hindrance of cyclohexylester. We were, therefore, forced to investigate
other routes. Literature search revealed that silylketeneacetal could add to nitroalkene efficiently23 when
promoted by Lewis acids, such as MAD (Figure 5).24 This extremely hindered Lewis acid has been shown to
convey excellent selectivity25 in a number of synthetic transformations. When substrate 14 was treated with 2
eq. of MAD followed by addition of silylketeneacetal at -78 °C, a very clean reaction occurred and the desired
product was obtained in greater than 20:1 selectivity and 90% yield. This excellent selectivity was a result of
spatial preference of MAD-nitro adduct, which took equatorial position, forcing the nucleophilic addition
from axial direction (Figure 4). With the improved Michael addition step adopted, the overall synthesis of L-
004060882 was achieved in 10 steps and 16% overall yield starting from 8. In the end, greater than ten grams
of this potent NK1 antagonist was synthesized, which greatly facilitated its characterization (Scheme 2).
Scheme 2. Optimization of the key Michael addition step.

CO R*
2
CO R*
2
NO
2
CbzN
Ph
NO
NO
2
2
CbzN
Ph
CbzN
Ph
conditions
O
O
O
CF
3
CF
CF
3
3
F C
3
14
F C
3
F C
3
18
19
O
O
O
O
AcO
AcO
OTBS
OMe
(S)
(R)
(R)
(S)
N
O
N
O
Ph
Ph
Reaction
Conditions
@ -78 oC
(S)
(R)
20
21
22
23
24
Ph
Ph
MAD
90%
LHMDS
65%
LHMDS
68%
LHMDS
NR
LHMDS
NR
yield:
ratio (
:
18 19
):
1:5
14.7:1
>20:1
ND
ND
* R in ractions with 22 and 23 were corresponding chiral alcohols, while with 24 a methyl group.
Fiugure 4. MAD and postulated transition state of Michael addition reaction.
To finally confirm the proposed conformation, NMR study was conducted on compound 7. As shown in
Figure 5, in the energy optimized conformation by MMX force filed (PCModel software), which was
consistent with experimental long-range NOE’s, the phenyl group indeed occupied an axial position (Figure
5).
Figure 5: Energy optimized conformation and long-range NOE’s (red arrows) of 7.
To summarize our research, we investigated the conformational preference of gem-disubstituted methyl-
phenyl piperidines. It was revealed that only in 2,2-methylphenylpiperidine system that the phenyl group has a
strong preference in occupying axial position. This information was used to design a constrained bicyclic

piperidine NK1 antagonist L-004060882. A practical stereoselective synthesis was achieved to deliver the
designed NK1 antagonist, which proved to be very potent and devoid of later stage metabolic complications.
Acknowledgement: We would like to thank Dr. Ruth Duffy for NK1 binding assay, Dr. Goeff Varty for GFT
assay, Dr. Walter Korfmacher for DMPK studies and Dr. John J. Piwinski for support of this program.
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Graphic Abstract: