General and efficient synthetic approach to novel tricyclic spiroketones

Article abstract of DOI:10.1016/j.tet.2009.04.094

A general and efficient synthetic approach to tricyclic spiroketones of interest as useful scaffolds in drug discovery was developed. Starting from commercially available benzyl 4-oxo-1-piperidinecarboxylate (5), spirocyclic tetralone 4, spirocyclic indanone 14, and spirocyclic benzocycloheptanone 15 were synthesized via six reaction steps in excellent overall yield.

Full text of DOI:10.1016/j.tet.2009.04.094

Tetrahedron 65 (2009) 5161–5167
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
General and efficient synthetic approach to novel tricyclic spiroketones
*
Guo-Hua Chu , Bertrand Le Bourdonnec, Minghua Gu, Christopher T. Saeui, Roland E. Dolle
Department of Chemistry, Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A general and efficient synthetic approach to tricyclic spiroketones of interest as useful scaffolds in drug
discovery was developed. Starting from commercially available benzyl 4-oxo-1-piperidinecarboxylate
(5), spirocyclic tetralone 4, spirocyclic indanone 14, and spirocyclic benzocycloheptanone 15 were syn-
thesized via six reaction steps in excellent overall yield.
Received 24 November 2008
Received in revised form 8 April 2009
Accepted 29 April 2009
Available online 7 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
hydroxyacetophenone in the presence of pyrrolidine8,9 or
L-pro-
line,10 was used as key intermediate for the synthesis of 1.8 Similarly,
we envisioned to prepare 2 from the corresponding N-protected
spirocyclic tetralone 4 (Fig. 2). However, the synthesis of 4 has never
been reported. Such spirocyclic ketones are also expected to serve as
useful scaffolds for constructing ligands for other biological targets.
Therefore, we sought to develop a general method to prepare this
novel spirocyclic tetralone system. This article describes a general
and efficient synthetic approach to 4, and the related five-mem-
bered ring spirocyclic indanone and the seven-membered ring
spirocyclic benzocycloheptanone.
Privileged structures represent molecular frameworks endowed
with inherent affinity for diverse biological receptors or enzymes.
Since its introduction by Evans and collaborators1 describing 1,4-
benzodiazepine-2-ones, the term privileged structures has
appeared in the literature multiple times and includes structures as
diverse as 1,4-dihydropyridines, benzyl-piperidines, and cyclic
peptides. With the advent of high throughput screening in drug
discovery, there has been significant interest in the incorporation of
structural features (substructures or scaffolds) of privileged struc-
tures in the design of chemical libraries. It has been shown that
biological activity and specificity of compounds based on privileged
structures can be modulated with relatively minor changes in the
nature of the substituents. The spiro(chromane-2,40-piperidine),
shown in Figure 1, is an example of a privileged structure. Indeed
this molecular framework has been used as a core template to
design ligands binding to various molecular targets (Fig. 1).2–8 We
recently reported the discovery of novel delta opioid receptor ag-
onists containing as central template the spiro(chromene-2,40-pi-
peridine) motif. The lead representative in this series (ADL5859)
has been recently advanced to Phase II proof of concept studies for
the management of pain.8
2. Results and discussion
It was speculated that the spirocyclic ring system of 4 could be
constructed via the intramolecular Friedel–Crafts acylation reaction
on an appropriate piperidine-4-acetic acid derivative. Scheme 1
illustrates our initial synthetic approach to the spirocyclic tetralone
4. Condensation of commercially available benzyl 4-oxo-1-piper-
idinecarboxylate (5) with ethyl cyanoacetate in the presence of
acetic acid and ammonium acetate with azeotropic removal of
water formed during the reaction using a Dean–Stark apparatus
gave the unsaturated ester 6 in good yield (88%).11 Compound 6 was
subjected to conjugate addition by reaction with organocuprate
reagents derived from benzylmagnesium chloride (4 equiv) and
copper(I) cyanide (2 equiv) to afford the cyanoester 7 in quantita-
tive yield. Decarboxylation of 7 by treatment with sodium chloride
in dimethylsulfoxide containing a small amount of water at 160 ꢀC
afforded nitrile 8 in nearly quantitative yield. Conversion of the
nitrile functional group in 8 to the corresponding methyl ester by
treatment with methanol, in the presence of concentrated sulfuric
acid, was incomplete even after refluxing for 3 days and during the
reaction the Cbz protecting group was also cleaved. After repro-
tection of the piperidine amino group with Cbz by treatment with
benzyl chloroformate, and subsequent purification by flash
Compound 1, {N,N-diethyl-4-(spiro[chromene-2,40-piperidine]-
4-yl)benzamide}, prototypical molecule in this series, was pre-
viously identified as a potent delta agonist, displaying excellent
selectivity (>1000-fold) for delta over mu and kappa opioid re-
ceptors.8 As part of the lead optimization campaign around this new
series of delta opioid agonists, we investigated the bioisosteric re-
placement of the oxygen atom of the spirocyclic scaffold of 1 with
a methylene moiety (compound 2, Fig. 2). The scaffold 3, prepared
by simply heating
a mixture of N-Boc-4-piperidone and 2-
* Corresponding author. Tel.: þ1 484 595 1083; fax: þ1 484 595 1551.
E-mail address: ghchu@adolor.com (G.-H. Chu).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.094

5162
G.-H. Chu et al. / Tetrahedron 65 (2009) 5161–5167
OH
O
O
MsHN
N
MsHN
O
O
N
N
N
R
O
N
L-691, 1212
antiarrhythmic agent
MK-04993
antiarrhythmic agent
spiro(chromane-2,4'-piperidine)
CN
Me
O
O
O
H
N
MeO
N
S
F
O
O
Me
O
N
N
F
selective 5-HT2A receptor antagonist5
selective α1a-adrenergic receptor antagonist4
R1
O
O
O
R
R
R2
O
N
N
O
NH
dementias alleviating agents6
histamine release inhibitors7
selective delta opioid receptor agonists8
Figure 1. Spiro(chromane-2,40-piperidine) as a privileged structure in drug discovery.
chromatography, methyl ester 9 was obtained in w50% yield with
recovery of w35% of nitrile 8. Ester 9 was then hydrolyzed with
lithium hydroxide to furnish the key intermediate carboxylic acid
10 in nearly quantitative yield. Treatment of acid 10 with oxalyl
chloride gave the acyl chloride, which was reacted with aluminum
chloride to yield, as expected, the intramolecular Friedel–Crafts
acylation product with concomitant loss of the Cbz protecting
group. The resulting piperidine derivative was then treated with
benzyl chloroformate to give the tricyclic spiroketone 4 in excellent
yield (93% from 10).
Thus, starting from commercially available benzyl 4-oxo-1-
piperidinecarboxylate (5), the novel tricyclic spiroketone 4 was
successfully synthesized in nine steps and 40% overall yield. With
a workable synthesis in hand, we turned our attention toward the
development of a more efficient approach for the synthesis of 4.
Treatment of the conjugate addition product 7 with neat concen-
trated sulfuric acid at 90 ꢀC overnight resulted in ester hydrolysis,
decarboxylation, subsequent hydrolysis of the nitrile, and cycliza-
tion of the resulting acid in one pot, leading directly to the desired
spirocyclic tetralone ring system with concomitant cleavage of Cbz
protecting group. Treatment of the resulting crude product with
benzyl chloroformate furnished the pure spirocyclic ketone 4 in
41% yield. This approach constituted a clear improvement over the
previous route, since compound 4 was obtained in only four steps
and 36% overall yield from commercially available 5. However, from
a practical standpoint, the use of a large quantity of concentrated
sulfuric acid during the third reaction step was a potential limita-
tion for large-scale synthesis. Indeed, the large amount of sodium
sulfate produced during the neutralization step (using sodium hy-
droxide) rendered the workup very difficult.
We therefore investigated a third route for the synthesis of the
spirocyclic ketone 4 (Scheme 2). Reaction of benzyl 4-oxo-1-
piperidinecarboxylate (5) with Meldrum’s acid (2,2-dimethyl-1,3-
dioxane-4,6-dione) in pyridine in the presence of a catalytic
amount of piperidine afforded alkylidenemalonate 11 in 82% yield.
Treatment of 11 with benzylmagnesium chloride (2.5 equiv) in the
presence of a catalytic amount of copper(I) iodide (0.036 equiv)
gave the crude conjugate addition product, which was transformed
to the key intermediate 10 in excellent yield (92% for two steps)
simply by heating in a mixture of DMF/water (1:1). Under these
reaction conditions the isopropylidene protecting group was
cleaved leading to the diacid, which was simultaneously decar-
boxylated to provide the resulting carboxylic acid. Thus, the pi-
peridine-4-acetic acid derivative 10 was prepared efficiently in
three steps starting from benzyl 4-oxo-1-piperidinecarboxylate (5)
with 75% overall yield. Carboxylic acid 10 was then converted to
spirocyclic ketone 4 following the same reaction sequence as de-
scribed above in good overall yield (93%).
Thus, starting from the commercially available N-Cbz protected
piperidone 5, the novel spirocyclic tetralone 4 was efficiently
O
O
N
N
O
O
O
O
N
PG
4
N
Boc
N
N
H
1
H
2
3
δ: Ki = 1.8 nM, EC50 = 19 nM
μ: 32% inh @ 10 μM
κ: 29% inh @ 10 μM
Figure 2. Tricyclic spiroketone scaffolds as key building blocks for the selective delta opioid receptor agonists.

G.-H. Chu et al. / Tetrahedron 65 (2009) 5161–5167
5163
O
O
NC
OEt
NCCH2COOEt, NH4OAc,
AcOH, PhCH3, reflux, Dean-Stark
88%
PhCH2MgCl, CuCN, THF
~ 100%
N
Cbz
5
N
Cbz
6
O
CN
MeO
CN
i) MeOH, conc. H2SO4, reflux;
ii) CbzCl, Et3N, DCM, 0 °C
EtO
NaCl, DMSO, H2O, 160 °C
97%
O
52%
N
Cbz
7
N
Cbz
9
N
Cbz
8
i) conc. H2SO4, 90 °C;
ii) CbzCl, Et3N, DCM
41%
O
O
HO
i) (COCl)2, DCM, rt;
ii) AlCl 3, DCM, rt;
iii) CbzCl, Et3N, DCM, 0 °C
93%
N
Cbz
4
N
Cbz
10
Scheme 1. The initial and second approaches to the tricyclic spiroketone 4.
synthesized via six reaction steps with overall yield of 70%. This
synthetic approach is suitable for large-scale synthesis, and also well-
suited for the synthesis of other tricyclic spiroketone scaffolds of
different ring size. For example, by following the same reaction se-
quence and using phenylmagnesium bromide or phenethylmagne-
sium choride in place of the benzylmagnesium chloride in the
conjugate additionreaction(step2), spirocyclicindanone 1412 and the
novel spirocyclic benzocycloheptanone 15 were efficiently synthe-
sized via the intermediate carboxylic acids 12 and 13, respectively, in
good overall yields (78%, 47% for 14, 15, respectively), as reported in
Scheme 2.
by
Suzuki–Miyaura
cross-coupling
with
4-(N,N-diethyl-
aminocarbonyl)phenylboronic acid gave compound 16 in excellent
yield (92%). Removal of the Cbz protective group of 16 by treatment
with iodotrimethylsilane (TMSI) led to the target molecule 2 (93%).
Compound 2 was tested for its affinities toward the cloned human
delta, mu, and kappa opioid receptors as measured by its abilities to
displace [3H]-diprenorphine from its specific binding sites.8 Re-
placement of the spiro[chromene-2,40-piperidine] template of 1
with a 1H-spiro[naphthalene-2,40-piperidine] scaffold was well
tolerated. Indeed, compound 2 displayed high affinity and selec-
tivity toward the delta opioid receptor (Ki¼4.3 nM). In the guano-
Compound 2 was prepared in three steps and high overall yield
from spirocyclic tetralone 4 (Scheme 3).13 Hence, conversion of 4 to
the corresponding enol triflate under standard condition followed
sine 50-O-(3-[35S]thio)triphosphate ([35S]GTP
gS) functional assay, 2
was also identified as a potent agonist at the delta opioid receptor
(EC50¼72 nM).
O
O
O
O
i) PhCH2MgCl or PhMgBr
or PhCH2CH2MgCl, CuI, THF,
-10 °C - 0 °C;
O
(Meldrum's acid)
O
O
O
O
pyridine, piperidine, 45 °C
82%
ii) DMF, H2O, reflux
N
N
Cbz
5
Cbz
11
O
i) (COCl)2, DCM, rt;
ii) AlCl 3, DCM, rt;
iii) CbzCl, Et3N, DCM, 0 °C
O
HO
n
n
N
Cbz
N
Cbz
10: n = 1 (92%)
12: n = 0 (97%)
13: n = 2 (71%)
4: n = 1 (93%)
14: n = 0 (98%)
15: n = 2 (80%)
Scheme 2. General and efficient synthetic approach to tricyclic spiroketones.

5164
G.-H. Chu et al. / Tetrahedron 65 (2009) 5161–5167
O
N
O
N
O
TMSI, DCM, rt
93 %
i) LiHMDS, PhNTf2, THF;
O
ii)
N
N
Cbz
OH
B
N
Cbz
16
N
H
OH
(Ph3P)4Pd, 2.0 N Na2CO3,
LiCl, DME, reflux
4
2
δ: K = 4.3 nM, EC50 = 72 nM
i
92% for 2 steps
μ: 34% inh @ 10 μM
κ: 23% inh @ 10 μM
Scheme 3. Synthesis of highly potent and selective delta opioid receptor agonist 2 from scaffold 4.
3. Conclusion
4.2. 4-(Cyano-ethoxycarbonyl-methylene)-piperidine-1-
carboxylic acid benzyl ester (6)
We have developed three synthetic routes to the novel spiro-
cyclic tetralone 4. Our original approach consisted in a nine-step
reaction sequence and 40% overall yield. The lengthy first-gener-
ation approach was significantly improved in our second route,
which consisted of only four steps in similar overall yield. How-
ever, from the practical standpoint, the use of a large quantity of
concentrated sulfuric acid during the synthesis was a potential
limitation for large-scale synthesis. As a result, we investigated
and successfully developed a third route. Starting from commer-
cially available benzyl 4-oxo-1-piperidinecarboxylate (5), com-
pound 4 was efficiently synthesized in a six-step sequence and
excellent overall yield (70%). This synthetic approach is suitable
for large-scale synthesis, and has been successfully applied to the
synthesis of other tricyclic spiroketone scaffolds. Indeed, the
spirocyclic indanone 14 and spirocyclic benzocycloheptanone 15
were efficiently synthesized in good overall yields (78%, 47% for
14, 15, respectively) by this approach. As an example of the utility
of these novel scaffolds in drug discovery, spirocyclic tetralone 4
was used as the key building block for the synthesis of the novel
delta opioid receptor agonist 2. These novel building blocks could
also have potential utilities for other medicinal chemistry
programs.
To a solution of commercially available benzyl 4-oxo-1-piper-
idinecarboxylate (5) (37.26 g, 160 mmol) in toluene (450 mL) were
added ethyl cyanoacetate (18.8 g, 166 mmol), acetic acid (2 mL),
and ammonium acetate (1.24 g, 16 mmol). The reaction mixture
was refluxed for 2 h with concomitant removal of water formed
during the reaction using a Dean–Stark trap. Additional ethyl cya-
noacetate (10 g, 88.4 mmol), acetic acid (2 mL), and ammonium
acetate (1.24 g, 6 mmol) were added to the reaction mixture and
then refluxed for another 1.5 h and additional amount of ethyl
cyanoacetate (10 g, 88.4 mmol), acetic acid (2 mL), and ammonium
acetate (1.24 g, 6 mmol) was added, and the resulting mixture was
refluxed for another 1 h. The reaction mixture was cooled to room
temperature and washed with saturated aqueous sodium bi-
carbonate (2ꢁ200 mL), and dried (Na2SO4). After evaporation of the
solvent in vacuo, a mixture of hexane (300 mL) and ethyl acetate
(20 mL) was added to the residue, and the mixture was kept at
room temperature overnight. The solid was collected by filtration,
washed with hexane, and dried in vacuo, yielding compound 6
(46 g, 88%) as a light-yellow solid: mp 90–91 ꢀC. 1H NMR (400 MHz,
CDCl3)
d
7.37 (m, 5H), 5.16 (s, 2H), 4.29 (q, J¼7.0 Hz, 2H), 3.69 (t,
J¼6.0 Hz,, 2H), 3.62 (t, J¼6.0 Hz, 2H), 3.15 (t, J¼5.0 Hz, 2H), 2.79 (t,
J¼5.0 Hz, 2H), 1.35 (t, J¼7.0 Hz, 3H); 13C NMR (400 MHz, CDCl3)
d
173.4, 161.4, 154.9, 136.3, 128.6, 128.2, 128.0, 114.9,104.6, 67.6, 62.1,
43.7, 43.3, 35.2, 30.9, 14.0; HRMS m/z calcd for C18H20N2O4Na
(MþNa)þ 351.1315, found 351.1304.
4. Experimental procedures
4.1. General comments
4.3. 4-Benzyl-4-(cyano-ethoxycarbonyl-methylene)-
piperidine-1-carboxylic acid benzyl ester (7)
All chemicals used were reagent grade and used as received. All
the listed new compounds were fully characterized by 1H NMR, 13
C
NMR, and HRMS, and the purity was higher than 95% as assessed by
LC/MS. 1H NMR and 13C NMR spectra were recorded in CDCl3 or
DMSO-d6 on a Bruker 400 MHz spectrometer. They are reported in
To a suspension of copper(I) cyanide (17.3 g, 193.2 mmol) in
anhydrous tetrahydrofuran (400 mL) was added dropwise benzyl-
magnesium chloride (192 mL, 2.0 M in THF, 384 mmol) under ni-
trogen atmosphere at 0 ꢀC. After the reaction mixture was stirred at
room temperature for 2 h, a solution of compound 6 (31.5 g,
96 mmol) in tetrahydrofuran (100 mL) was added dropwise at
ꢂ10 ꢀC. After the addition, the reaction mixture was stirred at room
temperature overnight, and then quenched with saturated aqueous
ammonium chloride (500 mL) and filtered. The filtrate was
extracted with ether (3ꢁ600 mL) and the combined organic ex-
tracts were dried (Na2SO4). Evaporation of the solvent provided the
crude product, which was purified by flash chromatography on
silica gel (hexane–ethyl acetate–methylene chloride, 4:1:1), to give
compound 7 (40 g, w100%) as a colorless oil. 1H NMR (400 MHz,
parts per million on the d scale from TMS. LC/MS was performed on
a Thermo-Finnigan Surveyor HPLC and a Thermo-Finnigan AQA MS
using either positive or negative electrospray ionization. Program
(positive): solvent A, 10 mM ammonium acetate, pH 4.5, 1% aceto-
nitrile; solvent B, acetonitrile; column, Michrom Bioresources
Magic C18 Macro Bullet; detector, PDA
l
¼220–300 nm; gradient,
96% A to 100% B in 3.2 min and hold 100% B for 0.4 min. Program
(negative): solvent A, 1 mM ammonium acetate, pH 4.5, 1% aceto-
nitrile; solvent B, acetonitrile; column, Michrom Bioresources
Magic C18 Macro Bullet; detector, PDA
l
¼220–300 nm; gradient,
96% A to 100% B in 3.2 min and hold 100% B for 0.4 min. HRMS was
performed by the Mass Spectrometry Service Laboratory at the
Department of Chemistry, University of Minnesota. For flash col-
umn chromatography, silica gel (Merck, grade 9385, 230–400
mesh) was used. Melting points are uncorrected.
CDCl3)
d
7.33 (m, 8H), 7.18 (m, 2H), 5.11 (s, 2H), 4.25 (q, J¼7.0 Hz,
2H), 3.74 (m, 2H), 3.63 (s, 1H), 3.54 (m, 2H), 3.05 (d, J¼14.0 Hz, 1H),
2.93 (d, J¼14.0 Hz, 1H), 1.91 (m, 1H), 1.69 (m, 3H), 1.31 (t, J¼7.0 Hz,
3H); 13C NMR (400 MHz, CDCl3)
d 164.9, 155.2, 136.6, 135.2, 130.8,

G.-H. Chu et al. / Tetrahedron 65 (2009) 5161–5167
5165
128.6, 128.5, 128.3, 128.1, 127.9, 127.3, 115.4, 67.3, 62.8, 44.2, 39.9,
4.7. 4-Benzyl-piperidine-1,4-dicarboxylic acid monobenzyl
39.4, 39.3, 31.1, 29.7, 14.0; HRMS m/z calcd for C25H28N2O4Na
ester (10)
(MþNa)þ 443.1941, found 443.1941.
4.7.1. Method A from ester 9
4.4. 4-Benzyl-4-cyanomethyl-piperidine-1-carboxylic acid
benzyl ester (8)
Compound 9 (1.6 g, 4.2 mmol) was dissolved in methanol–tetra-
hydrofuran–water (40 mL/40 mL/40 mL), and the resulting solution
was treated with lithium hydroxide (1.26 g, 30 mmol). The reaction
mixture was stirred at room temperature overnight, concentrated in
vacuo, acidified with 3 N HCl, and extracted with methylene chloride
(3ꢁ50 mL). The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo to yield compound 10 (1.5 g, 97%) as an off-
To a solution of compound 7 (6.0 g, 14.29 mmol) in dime-
thylsulfoxide (50 mL) were added sodium chloride (320 mg,
5.47 mmol) and water (0.6 mL). The reaction mixture was heated at
160 ꢀC under nitrogen atmosphere for 2 h and then cooled to room
temperature. Water (300 mL) was added to the mixture and then
extracted with ether (2ꢁ300 mL). The organic layers were com-
bined and dried (Na2SO4). Evaporation of the solvent provided the
crude product, which was purified by flash chromatography on
silica gel (hexane–ethyl acetate–methylene chloride, 4:1:1) to af-
ford compound 8 (4.8 g, 97%) as a pale-yellow oil. 1H NMR
white solid: mp 137–138 ꢀC.1H NMR (400 MHz, DMSO-d6)
d 12.25 (br
s,1H), 7.33 (m, 7H), 7.21 (m, 3H), 5.06 (s, 2H), 3.61 (br s, 2H), 3.33 (br s,
2H), 2.78 (s, 2H), 2.18 (s, 2H), 1.46 (m, 2H), 1.39 (m, 2H); 13C NMR
(400 MHz, CDCl3) d 177.3, 155.4, 136.9, 136.8, 130.9, 128.5, 128.1, 128.0,
127.9, 126.5, 67.2, 43.3, 39.8, 38.7, 35.5, 34.4; HRMS m/z calcd for
C22H25NO4Na (MþNa)þ 390.1676, found 390.1673.
(400 MHz, CDCl3) d 7.37 (m, 4H), 7.34 (m, 1H), 7.32 (m, 2H), 7.27 (m,
1H), 7.18 (m, 2H), 5.13 (s, 2H), 3.70 (m, 2H), 3.42 (m, 2H), 2.80 (s,
4.7.2. Method B from compound 11
2H), 2.23 (s, 2H), 1.62 (m, 2H), 1.54 (m, 2H); 13C NMR (400 MHz,
To a suspension of CuI (550 mg, 2.88 mmol) in anhydrous tetra-
hydrofuran (600 mL) was added dropwise a 2.0 M solution of ben-
zylmagnesium chloride (100 mL, 200 mmol) in tetrahydrofuran under
nitrogen atmosphere at ꢂ10 ꢀC. After the reaction mixture was stirred
at ꢂ10 ꢀC for 30 min, compound 11 (28.72 g, 80 mmol) was added in
10 portions over 1 h period. After the addition, the reaction mixture
was stirred between ꢂ10 ꢀC and ꢂ0 ꢀC for 3 h, and then quenched
with a mixture of concd NH4OH–satd NH4Cl–H2O (1:2:3, 400 mL). The
mixture was extracted with ethyl acetate, and the combined organic
layers were washed with a mixture of concd NH4OH–satd NH4Cl–H2O
(1:2:3, 3ꢁ200 mL) and brine (3ꢁ200 mL), dried (Na2SO4), and con-
centrated in vacuo. To the residue was added diethyl ether and the
mixture was stirred overnight at room temperature. The product was
collected by filtration, washed with diethyl ether, and dried in vacuo,
yielding the crude conjugate addition product as a yellow powder
(37.8 g), which was used directly for the next step. 1H NMR (400 MHz,
CDCl3)
d 155.2, 136.6, 135.7, 130.4, 128.5, 128.1, 127.9, 127.1, 117.7,
67.3, 43.0, 39.6, 35.5, 34.0, 25.1; HRMS m/z calcd for C22H24N2O2Na
(MþNa)þ 371.1730, found 371.1725.
4.5. 4-Benzyl-piperidine-1,4-dicarboxylic acid 1-benzyl ester
4-methyl ester (9)
To a solution of compound 8 (3.0 g, 8.62 mmol) in methanol
(80 mL) was added concentrated sulfuric acid (16 mL), and the
mixture was heated at reflux under a nitrogen atmosphere for 2
days. The reaction mixture was cooled to 0 ꢀC and basified by slow
addition of 6 N aqueous sodium hydroxide to pHw9 and then
evaporated in vacuo to remove methanol. The mixture was
extracted with methylene chloride (3ꢁ80 mL). Organic layers were
combined, dried (Na2SO4), and concentrated in vacuo. The residue
was dissolved in methylene chloride (80 mL) and cooled to 0 ꢀC. To
this solution was added triethylamine (3.8 mL, 27.3 mmol) followed
by dropwise addition of benzyl chloroformate (2.6 mL, 95%,
17.3 mmol). The reaction mixture was stirred at 0 ꢀC for 1 h and
washed with saturated aqueous NaHCO3 (50 mL). The organic layer
was separated, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel (hex-
ane–ethyl acetate–methylene chloride, 4:1:1) to give compound 9
DMSO-d6)
d
7.32–7.25 (m, 5H), 7.15 (t, J¼7.2 Hz, 2H), 7.07 (t, J¼7.2 Hz,
1H), 7.00 (d, J¼7.2 Hz, 2H), 4.95 (s, 2H), 3.67 (m, 2H), 2.95 (m, 2H), 2.76–
2.72 (m, 2H), 2.73 (s, 2H), 1.44 (s, 6H), 0.80 (m, 2H).
The above crude product was dissolved in a mixture of DMF
(200 mL) and water (200 mL), and the resulting solution heated at
135 ꢀC under nitrogen atmosphere for 2 days, then cooled to room
temperature. To the reaction mixture were added 1 N sodium hy-
droxide (125 mL) and water (500 mL), the resulting mixture was
extracted with diethyl ether, and the aqueous layer was separated,
acidified with 6 N aqueous hydrochloric acid, and extracted with
diethyl ether. The combined organic extracts were washed with
water and brine, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel (hex-
ane–acetone, 1:2) to furnish carboxylic acid 10 (26.9 g, 92% for two
steps) as an off-white solid.
(1.70 g, 52%) as a colorless oil. 1H NMR (400 MHz, CDCl3)
d 7.36 (m,
5H), 7.27 (m, 3H), 7.20 (m, 2H), 5.12 (s, 2H), 3.74 (m, 2H), 3.70 (s,
3H), 3.34 (m, 2H), 2.81 (s, 2H), 2.29 (s, 2H), 1.52 (m, 4H); 13C NMR
(400 MHz, CDCl3)
d 172.2, 155.4, 137.1, 136.9, 130.9, 128.5, 128.1,
128.0, 127.8, 126.4, 67.1, 51.4, 43.4, 39.8, 38.8, 35.5, 34.4; HRMS m/z
calcd for C23H27NO4Na (MþNa)þ 404.1832, found 404.1844.
4.6. Benzyl 4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-
ylidene)piperidine-1-carboxylate (11)
4.8. 2-(1-(Benzyloxycarbonyl)-4-phenylpiperidin-4-yl)acetic
acid (12) and 2-(1-(benzyloxycarbonyl)-4-phenethylpiperidin-
4-yl)acetic acid (13)
To
a mixture of benzyl 4-oxo-1-piperidinecarboxylate (5)
(29.8 g, 127.7 mmol) and Meldrum’s acid (2,2-dimethyl-1,3-di-
oxane-4,6-dione) (18.4 g, 127.7 mmol) was added pyridine
(12.5 mL) followed by 10 drops of piperidine. The mixture was
stirred at 45 ꢀC under nitrogen atmosphere for 1 h and then kept at
room temperature overnight. To the resulting solid was added
methanol, and the solid was collected by filtration, washed with
methanol, dried in vacuo to yield compound 11 (37.65 g, 82%) as
Acids 12 and 13 were prepared in the same manner as method B
for acid 10 as described above except that phenylmagnesium bro-
mide and phenethylmagnesium chloride replaced the benzylmag-
nesium chloride in the conjugate addition reaction, respectively.
Starting from compound 11 (21.54 g, 60 mmol), acid 12 (20.5 g,
97%) was isolated as an off-white solid: mp 137–138 ꢀC. 1H NMR
a white solid: mp 147–148 ꢀC. 1H NMR (400 MHz, CDCl3)
5H), 5.17 (s, 2H), 3.69 (br s, 4H), 3.18 (br s, 4H), 1.74 (s, 6H); 13C NMR
(400 MHz, CDCl3) 176.4, 160.6, 155.0, 136.4, 128.6, 128.2, 128.0,
d
7.37 (m,
(400 MHz, DMSO-d6)
1H), 5.06 (s, 2H), 3.58 (br s, 2H), 3.20 (br s, 2H), 2.57 (s, 2H), 2.11 (m,
2H), 1.94 (m, 2H); 13C NMR (400 MHz, CDCl3)
155.4, 142.6, 136.8,
d
11.79 (br s, 1H), 7.34 (m, 9H), 7.19 (t, J¼7.0 Hz,
d
d
115.7, 104.0, 67.5, 43.3, 33.1, 27.2; HRMS m/z calcd for C19H21NO6Na
(MþNa)þ 382.1261, found 382.1251.
128.7, 128.5, 128.3, 128.0, 127.8, 126.7, 126.6, 67.1, 40.4, 39.2, 34.9;
HRMS m/z calcd for C21H23NO4Na (MþNa)þ 376.1519, found 376.1509.

5166
G.-H. Chu et al. / Tetrahedron 65 (2009) 5161–5167
Starting from compound 11 (21.54 g, 60 mmol), acid 13 (16.2 g,
71%) was isolated as an off-white solid: mp 84–85 ꢀC. 1H NMR
(400 MHz, DMSO-d6)
Starting from acid 12 (2.48 g, 7.03 mmol), spirocyclic indanone
14 (2.3 g, 98%) was isolated as an off-white solid: mp 155–156 ꢀC.
d
12.17 (br s,1H), 7.35 (m, 5H), 7.26 (t, J¼7.0 Hz,
1H NMR (400 MHz, CDCl3)
d
7.75 (d, J¼8.0 Hz, 1H), 7.65 (dt, J¼8.0,
2H), 7.17 (m, 3H), 5.07 (s, 2H), 3.48 (br s, 2H), 3.34 (m, 2H), 2.53 (m,
1.0 Hz, 1H), 7.47 (d, J¼8.0 Hz, 1H), 7.43 (d, J¼8.0 Hz, 1H), 7.39 (m,
2H), 2.37 (s, 2H), 1.65 (m, 2H), 1.57 (m, 2H), 1.45 (m, 2H); 13C NMR
4H), 7.35 (m, 1H), 5.18 (s, 2H), 4.33 (br s, 2H), 2.94 (br s, 2H), 2.65 (s,
(400 MHz, CDCl3)
d
176.8, 155.5, 142.2, 136.8, 128.5, 128.5, 128.3,
2H), 1.98 (m, 2H), 1.53 (m, 2H); 13C NMR (400 MHz, CDCl3)
d 204.3,
128.0, 127.9, 125.9, 67.2, 40.4, 39.7, 39.4, 34.8, 34.6, 29.6; HRMS m/z
calcd for C23H27NO4Na (MþNa)þ 404.1832, found 404.1820.
161.8, 155.3, 136.7, 135.7, 135.2, 128.5, 128.2, 128.1, 128.0, 123.9,
123.8, 67.3, 47.0, 42.0, 41.5, 37.6; HRMS m/z calcd for C21H21NO3Na
(MþNa)þ 358.1414, found 358.1410.
Starting from acid 13 (16.0 g, 42.0 mmol), spirocyclic benzocy-
cloheptanone 15 (12.2 g, 80%) was isolated as an off-white solid:
4.9. Benzyl 4-oxo-3,4-dihydro-1H-spiro[naphthalene-2,40-
piperidine]-10-carboxylate (4)
mp 76–78 ꢀC. 1H NMR (400 MHz, CDCl3)
1H), 7.40 (dd, J¼8.0, 1.0 Hz, 1H), 7.37 (m, 4H), 7.33 (m, 1H), 7.29 (m,
1H), 7.24 (m, 1H), 5.14 (s, 2H), 3.54 (m, 4H), 3.04 (br s, 2H), 2.75 (s,
2H), 1.78 (m, 2H), 1.64 (br s, 2H), 1.50 (br s, 2H); 13C NMR (400 MHz,
d
7.81 (dd, J¼8.0, 1.0 Hz,
4.9.1. Method A from acid 10
To a solution of acid 10 (27 g, 73.6 mmol) in anhydrous methylene
chloride (200 mL) was added oxalyl chloride (39 mL, 447 mmol) in
one portion followed by a few drops of anhydrous dimethylforma-
mide. The reaction mixture was stirred at room temperature for 4 h
and then concentrated in vacuo. The resulting acyl chloride was
dissolved in anhydrous methylene chloride (800 mL) and aluminum
chloride (20 g, 150 mmol) was added in one portion under nitrogen
atmosphere at room temperature. The reaction mixture was stirred
at room temperature overnight and then cooled to 0 ꢀC, quenched by
water (400 mL) followed by addition of concentrated ammonium
hydroxide to make the aqueous layer basic. The organic layer was
separated and the aqueous layer was extracted with methylene
chloride. The combined organic layers were dried (Na2SO4) and
concentrated in vacuo. The residue was then dissolved in methylene
chloride (600 mL) and cooled to 0 ꢀC. To this solution was added
triethylamine (30 mL, 215.6 mmol) followed by dropwise addition of
benzyl chloroformate (22.5 mL, 149.7 mmol). The reaction mixture
was stirred at 0 ꢀC for 1 h and then washed with saturated aqueous
NaHCO3, dried (Na2SO4), and concentrated in vacuo. The residue was
purified by flash chromatography (hexane–ethyl acetate–methylene
chloride, 4:1:1) to yield the tricyclic spirotetralone 4 (23.88 g, 93%) as
CDCl3)
d 201.4, 155.4, 144.7, 138.3, 136.9, 131.8, 130.2, 128.7, 128.5,
128.0, 127.9, 126.4, 67.1, 50.7, 40.0, 38.5, 36.2, 34.2, 30.5; HRMS m/z
calcd for C23H25NO3Na (MþNa)þ 386.1727, found 386.1725.
4.11. Benzyl 4-(4-(diethylcarbamoyl)phenyl)-1H-
spiro[naphthalene-2,40-piperidine]-10-carboxylate (16)
A 1.0 M solution of lithium bis(trimethylsilyl)amide (3.6 mL,
3.6 mmol) was added at ꢂ78 ꢀC under nitrogen atmosphere to
a solution of compound 4 (1.047 g, 3.0 mmol) in anhydrous tetra-
hydrofuran (30 mL). After 45 min, a solution of N-phenyltrifluo-
romethanesulfonimide (1.3 g, 3.6 mmol) in tetrahydrofuran (8 mL)
was added dropwise. The reaction mixture was then warmed to
room temperature and stirred for 2.5 h, quenched by addition of
water (40 mL), and extracted with a mixture of hexane and ether
(1:1, 3ꢁ50 mL). The organic extracts were combined and washed
with water (2ꢁ60 mL), brine (60 mL) and dried (Na2SO4). Evapora-
tion of the solvent gave the crude enol triflate as a yellow oil, which
was used directly for the next step without further purification. 1H
NMR (400 MHz, CDCl3) d 7.35–7.18 (m, 9H), 5.98 (s, 1H), 5.11 (s, 2H),
3.70 (m, 2H), 3.40 (m, 2H), 2.83 (s, 2H), 1.66–1.56 (m, 4H).
a pale-yellow solid: mp 110–111 ꢀC.1H NMR (400 MHz, CDCl3)
d 8.00
(dd, J¼7.0, 1.0 Hz, 1H), 7.51 (dt, J¼8.0, 1.0 Hz, 1H), 7.35–7.30 (m, 6H),
To the solution of above crude enol triflate in 1,2-dimethoxy-
ethane (25 mL) were added 2.0 M aqueous sodium carbonate (5 mL,
10 mmol), lithium chloride (424 mg, 10 mmol), 4-(N,N-diethyl-
aminocarbonyl)phenylboronic acid (796 mg, 3.6 mmol), and tetra-
kis(triphenylphosphine)palladium(0) (104 mg, 0.09 mmol). The
reaction mixturewasrefluxedundernitrogenatmosphere overnight,
cooled to room temperature, diluted with water (30 mL), and
extracted with ether(3ꢁ50 mL). The combinedorganic extracts were
dried (Na2SO4) and concentrated in vacuo. The residue was purified
by flash chromatography on silica gel (hexane–ethyl acetate–meth-
ylene chloride, 2:1:1) to furnish the coupling product 16 as an off-
white foam (1.4 g, 92% for two steps). 1H NMR (400 MHz, CDCl3)
7.25 (d, J¼8.0 Hz, 1H), 5.13 (s, 2H), 3.52 (m, 4H), 2.98 (s, 2H), 2.62 (s,
2H), 1.50 (m, 4H); 13C NMR (400 MHz, CDCl3)
d 197.1, 155.3, 141.0,
136.8, 134.0, 132.0, 129.4, 128.5, 128.0, 127.8, 127.0, 126.8, 67.1, 49.0,
40.4, 39.6, 35.2, 35.0; HRMS m/z calcd for C22H23NO3Na (MþNa)þ
372.1570, found 372.1572.
4.9.2. Method B from cyanoacetate 7
Concentrated sulfuric acid (210 mL) was added slowly to com-
pound 7 (38 g, 90.5 mmol) at 0 ꢀC under nitrogen atmosphere. The
mixture was warmed to room temperature, stirred for 30 min at
room temperature, and then heated at 90 ꢀC overnight. The re-
action mixture was cooled with ice-bath and carefully basified with
6 N aqueous sodium hydroxide to pH¼9–10. The mixture was
extracted with methylene chloride (3ꢁ800 mL), and the organic
layers were combined, dried (Na2SO4), and concentrated in vacuo.
The residue was dissolved in methylene chloride (500 mL) and
treated with benzyl chloroformate (16 mL, 106.5 mmol) and trie-
thylamine (30 mL, 215.6 mmol) followed by purification on silica
gel as described above, furnishing spiroketone 4 (13 g, 41%), which
was identical with the product prepared by method A.
d
7.41–7.32 (m, 9H), 7.19 (m, 2H), 7.13 (m, 1H), 6.99 (d, J¼8.0 Hz, 1H),
6.00 (s, 1H), 5.14 (s, 2H), 3.70 (br s, 2H), 3.57 (br s, 2H), 3.46 (m, 2H),
3.33 (brs, 2H), 2.82(s, 2H),1.64 (brs, 2H),1.53(brs, 2H),1.26(br s, 3H),
1.16 (br s, 3H); 13C NMR (400 MHz, CDCl3)
d 171.1, 155.4, 141.3, 139.0,
136.9,136.4,134.9,134.4,133.9,128.8,128.5,128.0,127.9,127.7,126.6,
126.5, 125.7, 67.0, 43.4, 40.6, 40.2, 39.3, 34.8, 33.4, 14.4, 13.0; HRMS
m/z calcd for C33H36N2O3Na (MþNa)þ 531.2618, found 531.2626.
4.12. N,N-Diethyl-4-(1H-spiro[naphthalene-2,40-piperidine]-
4-yl)benzamide (2)
4.10. Benzyl 3-oxo-2,3-dihydrospiro[indene-1,40-piperidine]-
10-carboxylate (14) and benzyl 5-oxo-5,6,8,9-
tetrahydrospiro[benzo[7]annulene-7,40-piperidine]-10-
carboxylate (15)
Iodotrimethylsilane (0.29 mL, 2 mmol) was added to the solu-
tion of compound 16 (508 mg, 1.0 mmol) in anhydrous methylene
chloride (10 mL) under nitrogen atmosphere. The reaction mixture
was stirred at room temperature for 2 h and quenched with 1 N
hydrochloric acid (30 mL), extracted with ether (2ꢁ60 mL). The
aqueous was basified with 3 N aqueous sodium hydroxide to
pH¼9–10, and extracted with methylene chloride (3ꢁ40 mL). The
Spirocyclic ketones 14 and 15 were prepared from acids 12 and
13, respectively, by using the same reaction conditions of method A
for compound 4 as described above.

G.-H. Chu et al. / Tetrahedron 65 (2009) 5161–5167
5167
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organic extracts were combined, dried (Na2SO4), and concentrated
in vacuo. The residue was dissolved in methylene chloride (3 mL)
and diluted with ether (15 mL). To this solution was added hydro-
gen chloride (1.5 mL, 2.0 M in ether, 3 mmol) and stirred at room
temperature for 30 min. The precipitated solid was collected by
filtration and washed with ether, dried in vacuo to give the target
molecule 2 (380 mg, 93%) as HCl salt and an off-white solid: mp
275 ꢀC dec. 1H NMR (400 MHz, DMSO-d6)
d 9.03 (br s, 1H), 8.93 (br
s, 1H), 7.44 (d, J¼8.0 Hz, 2H), 7.39 (d, J¼8.0 Hz, 2H), 7.32 (dd, J¼8.0,
1.0 Hz, 1H), 7.24 (dt, J¼8.0, 1.0 Hz, 1H), 7.18 (dt, J¼8.0, 1.0 Hz, 1H),
6.94 (dd, J¼8.0, 1.0 Hz, 1H), 6.18 (s, 1H), 3.45 (br s, 2H), 3.21 (m, 6H),
2.83 (s, 2H), 1.69 (m, 4H), 1.12 (m, 6H); 13C NMR (400 MHz, CDCl3)
d
171.0, 140.6, 140.2, 136.6, 133.9, 133.3, 131.8, 128.8, 128.6, 128.2,
8. Le Bourdonnec, B.; Windh, R. T.; Ajello, C. W.; Leister, L. K.; Gu, M.; Chu, G.-H.;
Tuthill, P. A.; Barker, W. M.; Koblish, M.; Wiant, D. D.; Graczyk, T. M.; Belanger,
S.; Cassel, J. A.; Feschenko, M. S.; Brogdon, B. L.; Smith, S. A.; Christ, D. D.;
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Dolle, R. E. J. Med. Chem. 2008, 51, 5893–5896.
126.9, 126.4, 126.0, 43.4, 40.3, 39.3, 32.3, 31.5, 14.3, 12.9; HRMS m/z
calcd for C25H31N2O (MþH)þ 375.2431, found 375.2431.
Supplementary data
9. Kabbe, H. J. Synthesis 1978, 886–887.
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Copies of 1H NMR and 13C NMR spectra of compounds 2, 4, 6–16.
Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2009.04.094.
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References and notes
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