Stereoselective synthesis of spiropiperidines as BACE-1 aspartyl protease inhibitors via late stage N-arylation of a 1,8-diazaspiro[4.5]dec-3-en-2-one pharmacophore

Article abstract of DOI:10.1021/jo400016m

A stereoselective synthesis of spiropiperidine compounds, exemplified by compound 1, was developed, which was based upon the late stage N-arylation of a 1,8-diazaspiro[4.5]dec-3-en-2-one pharmacophore. Previously, compound 1 was prepared in low overall yield from piperidinone 2 via the Strecker reaction. A new route was developed, which employed the stereospecific Corey-Link reaction of an enantiomerically pure trichloromethylcarbinol to give a template compound amenable to late stage N-arylation.

Full text of DOI:10.1021/jo400016m

Article
pubs.acs.org/joc
Stereoselective Synthesis of Spiropiperidines as BACE‑1 Aspartyl
Protease Inhibitors via Late Stage N‑Arylation of a 1,8-
Diazaspiro[4.5]dec-3-en-2-one Pharmacophore
Che-Wah Lee,* Ricardo Lira, Jason Dutra, Kevin Ogilvie, Brian T. O’Neill, Michael Brodney,
Christopher Helal, Joseph Young, Erik Lachapelle, Subas Sakya, and John C. Murray
Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340,
United States
S
* Supporting Information
ABSTRACT: A stereoselective synthesis of spiropiperidine compounds, exemplified by compound 1, was developed, which was
based upon the late stage N-arylation of a 1,8-diazaspiro[4.5]dec-3-en-2-one pharmacophore. Previously, compound 1 was
prepared in low overall yield from piperidinone 2 via the Strecker reaction. A new route was developed, which employed the
stereospecific Corey−Link reaction of an enantiomerically pure trichloromethylcarbinol to give a template compound amenable
to late stage N-arylation.
afford the desired malonamide 4 in modest yield. Subsequent
treatment of 4 with sodium ethoxide in ethanol resulted in
intramolecular cyclization to afford the desired enamine 5 in
essentially quantitative yield. Enamine 5 was then refluxed in
aqueous 6 N HCl to effect both the saponification/
decarboxylation of the ethyl ester and the hydrolysis of the
enamine to the corresponding ketone. Under these strongly
acidic conditions, the Cbz group was cleaved, and therefore the
piperidine nitrogen was reprotected with Cbz-Cl to afford the
desired β-ketoamide 6 in low yield (23%) over two steps.
Reduction of the ketone in 6 with sodium borohydride
provided a mixture of alcohols (7) in essentially quantitative
yield. Subsequent elimination of the hydroxyl group with
thionyl chloride in pyridine followed by removal of the Cbz
protecting group with aqueous acid (6 N HCl/MeOH)
furnished piperidine 9. A final alkylation of 9 with 1-
bromomethyl-3-isopropoxy benzene provided compound 1.
Variation of the N-aryl region of 1 using this route was
cumbersome because of the fact that the aryl moiety is
introduced in the first step as an aniline via the Strecker
reaction in a nonstereoselective fashion. Additionally, although
a large number of anilines are commercially available, many of
the electron deficient ones (e.g., aminopyridines) would not
react well, if at all, under the Strecker conditions. Moreover, the
frequent use of zinc cyanide, the potential need to use chiral
INTRODUCTION
■
Spiropiperidine compounds have found broad utility in a wide
variety of therapeutic programs as chemokine cell surface
receptor antagonists,1 calcium channel blockers,2 and G-protein
coupled receptor ligands3 and have also been identified as
inhibitors for aspartyl protease enzymes such as Renin.4 During
the course of our efforts to identify a novel series of β-site
amyloid precursor protein cleaving enzyme (BACE-1)
inhibitors, compound 1 was identified as a lead compound
with desirable properties.5 One of the strategies for improving
the overall biological profile of the compound involved
maintaining the 1,8-diazaspiro[4.5]dec-3-en-2-one pharmaco-
phore while varying the surrounding substituents. Since
compound 1 contained a fairly lipophilic 3-fluorophenyl
moiety, a systematic investigation was carried out to identify
aryl and heteroaryl replacements that would improve its
physicochemical properties. However, this proved to be a
challenging endeavor as the initial route used to prepare
compound 1 was low yielding and not easily amenable to
variation within the N-aryl region.
The initial route used to prepare compound 1 is shown in
Scheme 1. Treatment of optically active piperidinone 26 with 3-
fluoroaniline and zinc cyanide afforded the desired Strecker
product in 78% yield as a 40:60 mixture of diastereomers 3a
and 3b, respectively.7 The desired diasteromer 3b was
separated from the mixture via chiral HPLC. Acylation of the
secondary amine of 3b was carried out with ethyl malonyl
chloride in the presence of the hindered base 2,6-lutidine to
Received: January 4, 2013
Published: February 25, 2013
© 2013 American Chemical Society
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Scheme 1. Original Synthesis of Compound 1 via the Strecker Route
Scheme 2. Retrosynthetic Approach for a Late Stage N-Arylation Strategy
chromatography after each Strecker condensation, and the
overall length of the sequence (nine steps from piperidinone 2,
2% overall yield in the case of 3-fluoroaniline) were not
conducive to the rapid exploration of the N-aryl region. In
order to facilitate the exploration of this region, we sought an
alternate route that would allow variation of the aryl moiety
much later in the sequence via the metal mediated cross
coupling of an unsubstituted lactam with aryl halides.
related to 1 via the late stage metal mediated N-arylation of
spirolactam 17 with various aryl or heteroaryl halides.
Spirolactam 17 in turn can be accessed from β-ketolactam 15
using standard reduction and elimination procedures. β-
Ketolactam 15 can be prepared from amino-ester 12 via
acylation followed by ketolactam formation, similar to the
sequence of operations previously described in Scheme 1.
In order to access the key amino-ester 12 as a single
diastereomer, we anticipated that C(4) inversion via a modified
Corey−Link reaction using enantiomerically pure trichlorome-
thylcarbinol 10b followed by azide reduction would provide the
desired compound with the correct absolute stereochemistry.8
RESULTS AND DISCUSSION
■
The retrosynthetic approach for this new route is outlined in
Scheme 2. We envisioned access to a variety of compounds
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Scheme 3. Stereoselective Synthesis of Amino-Ester 12 via the Corey−Link Reaction
Scheme 4. Completion of the Synthesis of the Spirolactam Pharmacophore 17
Trichloromethylcarbinol 10b can in turn be prepared via the
base promoted addition of chloroform to optically active
piperidinone 2.9
In the forward sense, the new approach began with the
synthesis of amino-ester 12 (Scheme 3). Treatment of
piperidinone 2 with in situ generated trichloromethyl lithium
at −78 °C provided trichloromethylcarbinols 10a and 10b as a
33:67 mixture of diastereomers, with the bulky trichloromethyl
anion favoring approach from the side opposite the methyl
group. We were pleased to find that the desired major
diastereomer (10b) could be readily separated from the mixture
in 47% yield by crystallization from diethyl ether, thus avoiding
the use of chiral chromatography for purification. The absolute
stereochemistry of 10b was subsequently confirmed via single
crystal X-ray crystallography. Treatment of trichloromethylcar-
binol 10b with sodium azide in the presence of DBU and
methanol resulted in a key C(4) stereocenter inversion and
provided 11 in 88% yield as a single diastereomer. The reaction
is likely to proceed via an in situ generated gem-
dichloroepoxide intermediate followed by regioselective epox-
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ide opening at C(4) with an azide anion.8,10 Gem-
dichloroepoxide intermediates have been reported in the
literature, and have even been isolated in some cases.11
Subsequent reduction of the crude azide-ester 11 with zinc
metal in acetic acid furnished the desired amino-ester 12 in
86% yield. Single crystal X-ray crystallographic analysis of the
mono-HCl salt of 12 verified that complete inversion had taken
place during the previous reaction.
Scheme 5. Copper Mediated N-Arylation of Spirolactam 17
with Aryl Halides
b
Scheme 4 outlines the final elaboration of amino-ester 12 to
the key spirolactam pharmacophore 17. Acylation of the amino
group in 12 with monoethyl malonate using the coupling
reagent EDCI afforded malonamide 13 in essentially
quantitative yield. Subsequent exposure of crude 13 to a 21%
solution of sodium ethoxide in EtOH resulted in a rapid
intramolecular Dieckmann cyclization to afford intermediate
14, again in near quantitative yield. Crude 14 was subsequently
refluxed in aqueous dioxane to effect a one pot hydrolysis−
decarboxylation sequence to afford the desired β-ketoamide 15
in 88% isolated yield. It should be noted that slightly acidic
conditions are essential for the decarboxylation step; when the
reaction was carried out under alkaline conditions (e.g.,
aqueous NaOH or LiOH), decarboxylation did not occur to
any appreciable extent, presumably due to the rapid
deprotonation of the starting material to give an inert, stabilized
enolate anion of 14. It is worth mentioning that this was the
only step in the sequence from 2 to 14 where chromatographic
purification was employed. Subsequent reduction of the ketone
in 15 with NaBH4 afforded the corresponding β-hydroxy amide
16 as a mixture of diastereomers in 88% yield. Finally,
elimination of the resulting alcohol with methanesulfonyl
chloride in the presence of DBU provided the desired
spirolactam template compound 17 in 91% yield. This route
to the spirolactam pharmacophore 17 (Schemes 3 and 4) was
highly scalable, and the material was successfully prepared in
batches of up to 150 g.
The N-arylation of lactams using Goldberg conditions12 is
well precedented in the literature, and the unsubstituted
spirolactam 17 was found to successfully couple with a variety
of aryl and heteroaryl halides in the presence of CuI and N,N′-
dimethylaminoethylene diamine (Scheme 5).
a
b
Ratio of CuI:DMEDA was changed from 1:14 to 1:1. Conditions:
1.0 equiv of 17, 2.0 equiv of Ar−X, 0.5 equiv of CuI, 7.0 equiv of N,N′-
dimethylaminoethylene diamine (DMEDA), 3.0 equiv of Cs2CO3,
dioxane (5 mL/mmol), heated at 90 °C for the indicated times.
It should be noted that a study of the Goldberg reaction by
Buchwald et al.13 has shown that increasing the amount of
diamine ligand relative to copper improves the efficiency of the
coupling, and this was found to be the case in example 22.
When spirolactam 17 was coupled with 3-bromo-5-chloropyr-
idine using 1:1 CuI:DMEDA, the desired product was only
obtained in 14% yield. However, when the ratio of the diamine
ligand to copper was increased to 14:1, the yield of the desired
product increased to 70%. Using these improved conditions, 3-
fluoro-1-iodobenzene was successfully coupled with 17 in 84%
yield to afford 8, which was the same intermediate previously
prepared via the original Strecker route (Scheme 1). The
reaction was similarly successful with a variety of other
heteroaryl iodides and bromides, allowing for the installation
of pyridine, pyrazine, pyrazole, and thiazole moieties (entries
18−22). In the previous route, as shown in Scheme 1, the
preparation of these compounds would require the con-
densation of the corresponding heteroaryl amines with
piperidinone 2 in a Strecker reaction, and it is likely that
these reactions would be difficult to carry out because of the
highly electron deficient nature of the requisite amines.
CONCLUSION
■
A modified Corey−Link route to a series of spiropiperidine
BACE-1 inhibitors (exemplified by 1) was developed, which
offered several advantages when compared to the synthesis of
these compounds via the original Strecker route: the N-aryl
moiety can be installed late in the sequence allowing for rapid
variation, the overall yield and scalability were improved, and
almost all of the intermediates could be purified via
crystallization or an aqueous workup; only one chromato-
graphic purification was necessary in the 8 step sequence from
piperidinone 2 to spirolactam 17. Moreover, the modified route
no longer required the use of zinc cyanide because the Strecker
reaction had been replaced by the Corey−Link reaction for the
construction of the spiroamine center. Also, an early
crystallization to give 10b followed by a series of stereospecific
transformations allowed for the preparation of spirolactam 17
as a single diastereomer, thereby eliminating the potential need
to use chiral HPLC for stereoisomer separation. Finally, a late
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warmed to room temperature, stirred for 45 min, and concentrated to
stage copper mediated Goldberg reaction using spirolactam 17
allowed for the facile installation of a variety of aryl and
heteroaryl moieties, greatly facilitating the exploration of the N-
aryl region of compound 1.
provide 4 as a yellow paste (6.6 g, 100% yield), which was taken into
1
the next transformation without purification: H NMR (400 MHz,
DMSO-d6) δ 7.28−7.34 (m, 2H), 7.21−7.28 (m, 2H), 7.18 (d, J =
7.03 Hz, 2H), 7.10 (td, J = 2.25, 10.35 Hz, 1H), 6.99−7.06 (m, 2H),
4.83 (d, J = 12.50 Hz, 1H), 4.44−4.61 (m, 1H), 4.10 (q, J = 7.03 Hz,
2H), 3.69−3.78 (m, 1H), 3.10−3.27 (m, 3H), 2.45 (td, J = 1.81, 3.81
Hz, 1H), 2.30−2.42 (m, 1H), 1.92−2.04 (m, 3H), 1.16 (t, J = 7.22 Hz,
3H), 0.86 (d, J = 5.86 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ
177.8, 166.9, 165.3, 163.8, 161.3, 154.1, 140.3, 137.4, 130.3, 129.0,
128.3, 128.0, 127.6, 118.5, 115.0, 88.3, 66.4, 63.0, 59.1, 55.6, 45.2, 38.5,
35.6, 33.2, 20.7, 15.1; HRMS and specific rotation data for this
compound could not be obtained due to its poor solubility.
EXPERIMENTAL SECTION
■
General Experimental Methods. All reactions were carried out
under a nitrogen atmosphere with commercially purchased reagents
and anhydrous solvents, unless otherwise noted. Chemical shifts were
recorded in ppm relative to solvent with multiplicities given as s
(singlet), bs (broad singlet), d (doublet), triplet (t), or multiplet (m).
1
Reference H and 13C solvent peaks included CDCl3 (7.27 and 77.0),
Benzyl (5R,7S)-1-(3-fluorophenyl)-7-methyl-2,4-dioxo-1,8-
diazaspiro[4.5]decane-8-carboxylate 6. Compound 5 (8.0 g, 17
mmol) was added in portions to 130 mL of 6 N aqueous hydrochloric
acid, and the resulting yellow suspension was heated at reflux for 28 h.
After cooling to room temperature, the mixture was azeotroped several
times with toluene and dried under a high vacuum for 18 h to provide
a gray-green solid (assumed quantitative yield, 6.3 g). A solution of the
crude intermediate (4.7 g, <15.1 mmol) in a mixture of 40 mL of
tetrahydrofuran and 20 mL of water was cooled to 0 °C and treated
with a solution of sodium hydroxide (4.1 g, 103 mmol) dissolved in 20
mL of water. Benzyl chloroformate (95%, 4.6 mL, 30.8 mmol) was
added, and the resulting solution was stirred at 0 °C for 2 h. Another
portion of benzyl chloroformate (95%, 1.28 mL, 8.6 mmol) was added,
and the reaction mixture was stirred at 0 °C for an additional 2 h. The
reaction mixture was concentrated under reduced pressure, and the
resulting residue was diluted with 50 mL of water and extracted several
times with dichloromethane. The combined organic extracts were
dried over Na2SO4, filtered, and concentrated under reduced pressure.
The crude product was purified by flash chromatography through silica
gel (30−100% ethyl acetate/heptanes). The resulting material (5.8 g)
was identified as the enol benzyl carbonate via mass spectroscopy and
NMR analysis. The bulk of this material (5.0 g) was dissolved in 60
mL of tetrahydrofuran, 200 mL of 1 N aqueous sodium hydroxide was
added, and the mixture was stirred for 5 h. The reaction mixture was
acidified to pH 2 with 1 N aqueous hydrochloric acid and extracted
several times with dichloromethane. The combined organic extracts
were dried over Na2SO4, filtered, and concentrated under reduced
pressure to afford compound 6 as a brown oil (1.55 g, 23%): 1H NMR
(400 MHz, CDCl3) δ 7.41 (dt, J = 6.26, 8.12 Hz, 1H), 7.21−7.36 (m,
5H), 7.14 (dt, J = 2.15, 8.22 Hz, 1H), 6.80−6.96 (m, 2H), 4.89−5.15
(m, 2H), 4.24−4.47 (m, 1H), 4.03 (d, J = 12.91 Hz, 1H), 3.50 (t, J =
12.91 Hz, 1H), 3.50 (m, 1H), 3.36 (d, J = 20.0 Hz, 1H), 3.19 (d, J =
20.0 Hz, 1H), 1.90−2.09 (m, 2H), 1.57−1.76 (m, 2H), 1.14−1.31 (m,
3H); 13C NMR (101 MHz, CDCl3) δ 207.9, 168.0, 164.1, 161.6,
136.4, 130.9, 130.8, 128.5, 128.1, 127.9, 126.3, 126.2, 118.1, 117.9,
116.7, 116.5, 111.9, 67.2, 45.8, 40.0, 35.6, 31.6; HRMS (ESI) m/z
calculated for C23H23FN2O4 [M + H]+ 411.1715, found 411.1717;
DMSO-d6 (2.50 and 39.5), and CD3OD (3.31 and 49.2).
Benzyl (2S,4R)-4-cyano-4-[(3-fluorophenyl)amino]-2-methyl-
piperidine-1-carboxylate 3b. A solution of benzyl (2S)-2-methyl-4-
oxopiperidine-1-carboxylate6 (31 g, 125 mmol) in acetic acid (250
mL) was treated with 3-fluoroaniline (24.1 mL, 250 mmol) followed
by zinc cyanide (36.8 g, 313 mmol). The reaction mixture was stirred
at room temperature for 18 h, after which it was cooled in an ice bath
and slowly basified with aqueous ammonium hydroxide solution. The
resulting mixture was extracted several times with dichloromethane,
and the combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude material was purified
by flash chromatography through silica gel (20−40% ethyl acetate/
heptanes) to afford a mixture of compound 3b and its isomer benzyl
(2S,4S)-4-cyano-4-[(3-fluorophenyl)amino]-2-methylpiperidine-1-car-
boxylate (3a) as an oil (36 g, 78% yield). This material was subjected
to chromatography using a Chiralcel OJ-H column, 5 μm, 30 × 250
mm (Mobile phase: 70/30 CO2/methanol; Flow rate: 120 g/min) to
afford 14.6 g (32%) of 3b as an oil: retention time 3.45−4.46 min; MS
(APCI) m/z 341.1 (M − CN)+; 1H NMR (400 MHz, CDCl3) δ 7.37
(m, 5H), 7.21 (m, 1H), 6.60−6.67 (m, 3H), 5.16 (dd, J = 12.3 Hz,
2H), 4.63 (m, 1H), 4.28 (m, 1H), 3.35 (m, 1H), 2.46 (m, 2H), 1.89
(dd, J = 13.9, 6.6 Hz, 1H), 1.70 (ddd, J = 13.3, 13.3, 4.4 Hz, 1H), 1.49
(d, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 164.7, 162.3,
154.8, 145.1, 136.4, 130.5, 128.6, 128.2, 127.9, 121.4, 112.7, 107.1,
104.2, 67.4, 50.0, 45.9, 39.8, 36.3, 35.8, 17.0; HRMS (ESI) m/z
calculated for C21H22FN3O2 [M + Na]+ 390.1588, found 390.1582;
20
[α]D +21.5 (c 1.05, CH2Cl2).
Benzyl (2S,4R)-4-cyano-4-[(3-ethoxy-3-oxopropanoyl)(3-
fluorophenyl)amino]-2-methylpiperidine-1-carboxylate 4. 2,6-
Dimethylpyridine (4.8 mL, 40.8 mmol) was added to a solution of 3b
(10 g, 27 mmol) in dichloromethane (136 mL). Ethyl 3-chloro-3-
oxopropanoate (4.5 mL, 35.4 mmol) was added dropwise via an
addition funnel, and the reaction mixture was stirred at room
temperature for 4 h. The mixture was diluted with dichloromethane
(30 mL), washed with water (80 mL), saturated aqueous sodium
chloride (80 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure. The crude material was purified by flash
chromatography through silica gel (30% ethyl acetate/heptanes) to
provide compound 4 (6.6 g) as a yellow oil. Mixed fractions were
resubjected to flash chromatography to provide additional 4. Total
yield 8.2 g, 63%: 1H NMR (400 MHz, CDCl3) δ 7.45−7.36 (m, 1H),
7.33−7.22 (m, 5H), 7.20−7.13 (m, 1H), 7.05−6.88 (m, 2H), 5.05 (s,
2H), 4.51 (br s, 1H), 4.20−4.11 (m, 1H), 4.06 (q, J = 7.2 Hz, 3H),
3.39−3.24 (m, 1H), 3.06 (d, J = 2.7 Hz, 2H), 2.82−2.68 (m, 1H),
2.16−2.03 (m, 1H), 1.72 (ddd, J = 2.0, 6.6, 13.7 Hz, 1H), 1.42 (dd, J =
1.4, 7.2 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 171.3, 168.3, 167.3, 166.9, 166.6, 164.3, 161.8, 138.9, 136.5,
131.5, 128.7, 128.3, 128.1, 126.6, 120.3, 118.2, 118.0, 117.8, 117.6,
67.6, 61.8, 54.1, 43.5, 38.2, 32.0, 29.2, 22.8, 14.2; HRMS (ESI) m/z
calculated for C26H28FN3O5 [M + Na]+ 504.1905, found 504.1907;
20
[α]D +32.2° c 10.0, CH2Cl2).
Benzyl (5R,7S)-1-(3-fluorophenyl)-4-hydroxy-7-methyl-2-
oxo-1,8-diazaspiro[4.5]decane-8-carboxylate 7. A solution of
compound 6 (881 mg, 2.15 mmol) in 25 mL of methanol and 5 mL of
tetrahydrofuran at 0 °C was treated portionwise with sodium
borohydride (248 mg, 6.42 mmol), and the resulting yellow solution
was stirred at 0 °C for 2 h. The reaction mixture was quenched with 5
mL of water, the volatile components were removed under reduced
pressure, and the remaining mixture was acidified to pH 3 with 1 N
aqueous hydrochloric acid. The mixture was extracted several times
with EtOAc (3 × 5 mL). The combined organic extracts were dried
over Na2SO4, filtered, and concentrated under reduced pressure. The
crude residue was purified by flash chromatography through silica gel
(100% ethyl acetate) to afford compound 7 as a light brown foam (620
mg, 70%): 1H NMR (400 MHz, CDCl3), mixture of two
diastereomers, δ 7.42−7.20 (m, 6H), 7.44−7.19 (m, 1H), 7.12−7.00
(m, 2H), 6.87−6.72 (m, 2H), 5.02 (br. s., 2H), 4.52−4.27 (m, 2H),
3.03 (t, J = 13.2 Hz, 1H), 2.89 (ddd, J = 5.4, 11.8, 17.4 Hz, 1H), 2.39
(dd, J = 6.3, 17.5 Hz, 1H), 2.26−1.99 (m, 1H), 1.91 (dd, J = 7.4, 14.3
Hz, 1H), 1.79−1.56 (m, 1H), 1.52 (d, J = 14.1 Hz, 1H), 1.43−1.32
20
[α]D +24.1° (c 1.11, CH2Cl2).
8-Benzyl 3-ethyl (5R,7S)-4-amino-1-(3-fluorophenyl)-7-
methyl-2-oxo-1,8-diazaspiro[4.5]dec-3-ene-3,8-dicarboxylate
5. Sodium metal (426 mg, 18.5 mmol, prewashed with heptane) was
added to 12 mL of ethanol and allowed to react completely. This
solution of sodium ethoxide was added to a 0 °C solution of 4 (6.6 g,
14.2 mmol) dissolved in 45 mL of ethanol. The reaction mixture was
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(m, 1H), 1.28−1.08 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 173.6,
164.2, 161.7, 136.7, 130.6, 128.2, 126.0, 118.0, 116.1, 70.1, 69.5, 68.2,
67.5, 46.5, 40.0, 36.4, 29.8; HRMS (ESI) m/z calculated for
C23H25FN2O4 [M + H]+ 413.1871, found 413.1876.
130.5, 130.4, 129.2, 126.7, 125.0, 120.8, 118.3, 118.1, 116.2, 115.8,
115.6, 114.1, 69.7, 67.8, 58.1, 51.3, 44.3, 40.4, 33.7, 22.1, 22.0, 15.3;
HRMS (ESI) m/z calculated for C25H29FN2O2 [M + H]+ 409.2286,
20
found 409.2287; [α]D +18.1° (c 21.0, CH2Cl2).
(5R,7S)-Benzyl 1-(3-fluorophenyl)-7-methyl-2-oxo-1,8-
diazaspiro[4.5]dec-3-ene-8-carboxylate 8. To a solution of
compound 7 (510 mg, 1.24 mmol) in 9 mL of pyridine was added
thionyl chloride (0.27 mL, 3.71 mmol). The resulting mixture was
stirred at room temperature for 1 h, and then at 50 °C for 18 h under a
reflux condenser. The reaction mixture was cooled to room
temperature, concentrated under reduced pressure, diluted with
EtOAc, washed with saturated aqueous NaHCO3 (4 × 10 mL),
brine, dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude material was purified by flash chromatography
through silica gel (20% EtOAc/heptanes to 100% EtOAc) to afford
(2S,4S)-Benzyl 4-hydroxy-2-methyl-4-(trichloromethyl)-
piperidine-1-carboxylate 10b. A solution of 2 in DME (600
mL) was treated at room temperature with MgCl2 (69.3 g, 0.73 mol)
and CHCl3 (58.2 mL, 0.73 mol). The reaction mixture was cooled to
−78 °C and treated over a period of 1 h with a solution of LiHMDS
(1.0 M in THF, 437 mL, 0.44 mol), keeping the internal temperature
below −65 °C. The reaction mixture was stirred at −78 °C for two
hours, after which LC−MS analysis indicated that there was less than
5% starting material remaining. The reaction mixture was warmed to
−20 °C for 1 h and then cautiously quenched with H2O (300 mL).
EtOAc (300 mL) was added, and the resulting mixture was filtered
through a short pad of Celite. The filter cake was washed thoroughly
with EtOAc (300 mL). The layers were separated, and the aqueous
layer was further diluted with water (300 mL) and re-extracted with
EtOAc (600 mL). The combined organic extracts were washed with
brine, dried over MgSO4, filtered, and concentrated under reduced
pressure to afford a dark brown oil (88.5 g). The oil was stirred
vigorously in Et2O (120 mL) for 2 h and filtered. The collected solids
were washed with Et2O (2 × 100 mL) and dried to give alcohol 10b as
1
compound 8 as a light yellow solid (300 mg, 61%): H NMR (400
MHz, CDCl3) δ 7.60 (d, J = 6.2 Hz, 1 H), 7.39 (dt, J = 6.3, 8.2 Hz,
1H), 7.35−7.24 (m, 5H), 7.13−7.06 (m, 1 H), 6.89−6.84 (m, 1 H),
6.81 (dt, J = 2.2, 9.3 Hz, 1H), 6.29 (d, J = 6.2 Hz, 1H), 5.05 (br. s.,
2H), 4.59 (br. s., 1H), 4.20 (br. s., 1H), 3.10 (t, J = 13.4 Hz, 1H), 2.06
(dd, J = 6.6, 13.3 Hz, 1H), 1.88 (t, J = 11.6 Hz, 1H), 1.64 (br. s., 1H),
1.44 (s, 1H), 1.48 (s, 1H), 1.28 (d, J = 7.2 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 170.1, 164.5, 162.0, 151.2, 136.6, 131.0, 130.9, 128.7,
128.3, 128.1, 126.7, 126.6, 126.5, 118.4, 118.1, 116.2, 116.0, 100.0,
76.9, 67.6, 67.5, 46.1, 36.9; HRMS (ESI) m/z calculated for
1
a pale brown solid, (43.6g, 49% yield): H NMR (400 MHz, DMSO-
d6) δ 7.36−7.23 (m, 5 H), 6.15 (s, 1 H), 5.11−4.97 (m, 2 H), 4.44
(quin, J = 7.0 Hz, 1 H), 4.00−3.89 (m, 1 H), 3.22−3.03 (m, 1 H), 2.06
(dt, J = 6.9, 13.8 Hz, 1 H), 1.95−1.75 (m, 3 H), 1.22 (dd, J = 3.7, 7.0
Hz, 3 H); 13C NMR (101 MHz, DMSO-d6) δ 154.9, 154.6, 137.6,
129.1, 128.5, 128.2, 110.8, 100.0, 80.7, 66.9, 46.2, 46.0, 35.3, 34.4, 34.1,
31.4, 31.1, 19.1, 18.4; HRMS (ESI) m/z calculated for C15H18Cl3NO3
[M + Na]+ 388.0244, found 388.0239; [α]D20 +34.7° (c 15.0, CHCl3).
An X-ray quality crystal of 10b was grown from acetonitrile−water
(obtained as white crystals, mp = 147−148 °C); see the Supporting
Information for crystallographic data.
20
C23H23FN2O3 [M + H]+ 395.1765, found 395.1764; [α]D +18.8°
(c 21.0, CHCl3).
(5R,7S)-1-(3-Fluorophenyl)-7-methyl-1,8-diazaspiro[4.5]dec-
3-en-2-one 9. To a solution of compound 8 (17.1 g, 43.4 mmol) in
130 mL of methanol was added 220 mL of 6 N aqueous HCl. The
resulting mixture was heated at 90 °C for 6 h. The reaction mixture
was cooled to room temperature, washed with EtOAc to remove any
unreacted starting material, and made alkaline via the slow addition of
1 N aqueous NaOH. The aqueous phase was washed several times
with EtOAc to extract the product. The combined organic extracts
were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The crude material was purified by flash chromatography
through silica gel (100% DCM to 20% MeOH/DCM) to afford
compound 9 as an off-white foam (10.9 g, 97%): 1H NMR (400 MHz,
CDCl3) δ = 7.41 (dt, J = 6.3, 8.1 Hz, 1H), 7.12 (ddt, J = 0.9, 2.5, 8.3
Hz, 1H), 7.03 (d, J = 6.0 Hz, 1H), 7.01−6.97 (m, 1H), 6.93 (td, J =
2.1, 9.4 Hz, 1H), 6.17 (d, J = 6.0 Hz, 1H), 2.90 (td, J = 4.6, 12.7 Hz,
1H), 2.74 (dqd, J = 3.3, 6.4, 9.8 Hz, 1H), 2.64 (ddd, J = 3.3, 10.9, 12.7
Hz, 1H), 2.05−1.93 (m, 1H), 1.92−1.80 (m, 2H), 1.72 (br. s., 1H),
1.65 (dd, J = 10.0, 14.2 Hz, 1H), 1.04 (d, J = 6.2 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ = 171.1, 164.2, 161.7, 155.6, 139.6, 139.5, 130.5,
130.4, 126.7, 126.6, 124.2, 118.3, 118.1, 115.9, 115.7, 67.1, 63.8, 46.9,
41.4, 33.8, 22.3; HRMS (ESI) m/z calculated for C15H17FN2O [M +
(2S,4R)-1-Benzyl 4-methyl 4-azido-2-methylpiperidine-1,4-
dicarboxylate 11. A suspension of 10b (128.4 g, 0.35 mol) in
methanol (1.0 L) was treated at room temperature with 18-crown-6
ether (9.3 g, 0.04 mol) and sodium azide (68.3 g, 1.05 mol). The
reaction mixture was cooled in an ice bath and treated dropwise over
20 min with DBU (262 mL, 1.75 mol). The dark brown solution was
stirred at room temperature overnight (slight exotherm to 40 °C was
observed upon removal of the ice bath). LC−MS analysis after 20 h
showed consumption of the starting material. The reaction mixture
was concentrated under reduced pressure to remove most of the
methanol, and the residue was partitioned between EtOAc (1.2 L) and
H2O (1.2 L). The aqueous layer was extracted again with EtOAc (1.2
L). The combined organic extracts were washed with water, brine,
dried over MgSO4, and concentrated under reduced pressure to afford
20
1
H]+ 261.1398, found 261.1399; [α]D −30.8° (c 9.5, CH2Cl2).
azide-ester 11 as a brown oil (195.2 g, 84% yield): H NMR (500
(5R,7S)-1-(3-Fluorophenyl)-8-(3-isopropoxybenzyl)-7-meth-
yl-1,8-diazaspiro[4.5]dec-3-en-2-one 1. To a stirred suspension of
compound 9 (200 mg, 0.77 mmol) and potassium carbonate (322 mg,
2.30 mmol) in 4 mL of acetonitrile at 0 °C was added dropwise 1-
bromomethyl-3-isopropoxy benzene (352 mg, 1.54 mmol) over
several minutes. The resulting mixture was slowly warmed to room
temperature and stirred for 18 h. Five milliliters of saturated aqueous
NH4Cl was added to the reaction mixture, followed by 30 mL of
EtOAc. The organic layer was separated, washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The crude
material was purified by flash chromtography through silica gel (25%
EtOAc/heptanes) to afford compound 1 (275 mg, 87%) as a light
MHz, CDCl3) δ 7.40−7.28 (m, 5 H), 5.13 (s, 2 H), 4.52−4.44 (m, 1
H), 4.09−4.03 (m, 1 H), 3.83 (s, 3 H), 3.15 (ddd, J = 3.3, 12.4, 14.3
Hz, 1 H), 2.31−2.22 (m, 2 H), 1.93 (dd, J = 6.0, 13.5 Hz, 1 H), 1.60
(ddd, J = 5.2, 12.4, 13.4 Hz, 1 H), 1.08 (d, J = 7.1 Hz, 3 H); 13C NMR
(126 MHz, CDCl3) δ 171.6, 155.2, 136.8, 128.7, 128.3, 128.1, 67.5,
62.9, 53.1, 46.2, 36.8, 36.7, 32.0, 17.4; HRMS (ESI) m/z calculated for
20
C16H20N4O4 [M + Na]+ 355.1382, found 355.1386; [α]D +4.6° (c
10.2, CH2Cl2).
(2S,4R)-1-Benzyl 4-methyl 4-amino-2-methylpiperidine-1,4-
dicarboxylate 12. A solution of azide-ester 11 (164.4 g, 0.49 mol) in
THF (1.2 L) and glacial acetic acid (1.2 L) was treated with Zn dust
(<10 μm particle size, 161.3 g, 2.5 mol), and the resulting mixture was
heated to 50 °C. LC−MS analysis after 4 h still showed unreacted
starting material. An additional 1.0 equiv of Zn dust was added, and
heating was continued at 50 °C for 10 h. The reaction mixture was
cooled to room temperature. After an additional 6 h, LC−MS analysis
showed the complete consumption of starting material. The reaction
mixture was filtered through Celite, and the filter cake was washed
thoroughly with THF (2 × 200 mL). The filtrate was concentrated
under reduced pressure to remove most of the solvents, and the
residue was partitioned between EtOAc (1.5 L) and saturated aqueous
1
yellow gum: H NMR (400 MHz, CDCl3) δ 7.48−7.37 (m, 2H),
7.21−7.09 (m, 2H), 6.95 (d, J = 7.8 Hz, 1H), 6.89 (td, J = 2.1, 9.4 Hz,
1H), 6.83−6.72 (m, 3H), 6.23 (d, J = 5.9 Hz, 1H), 4.51 (td, J = 6.0,
12.1 Hz, 1H), 3.60 (d, J = 13.7 Hz, 1H), 3.38 (d, J = 13.7 Hz, 1H),
3.06−2.96 (m, 1H), 2.66 (ddd, J = 3.1, 9.7, 12.6 Hz, 1H), 2.46−2.37
(m, 1H), 2.13 (dd, J = 5.1, 13.3 Hz, 1H), 1.98 (ddd, J = 4.1, 9.7, 13.2
Hz, 1H), 1.72 (d, J = 12.9 Hz, 1H), 1.59 (ddd, J = 1.6, 4.7, 13.3 Hz,
1H), 1.31 (d, J = 6.2 Hz, 6H), 1.15 (d, J = 6.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 170.6, 164.2, 161.8, 153.7, 140.5, 137.9, 137.8,
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NaHCO3 (1.2 L). The organic layer was separated and washed again
with 1.2 L saturated aqueous NaHCO3. The original aqueous layer was
treated with solid NaHCO3 (until pH = 8−9 via litmus paper) and
then further extracted with EtOAc (2 × 1 L). The combined organic
extracts were washed with water, brine, dried over MgSO4, and
concentrated under reduced pressure to afford amino-ester 12 as a
brown oil (129.2 g, 86% yield): 1H NMR (400 MHz, CDCl3) δ 7.36−
7.24 (m, 5 H), 5.09 (d, J = 1.4 Hz, 2 H), 4.47−4.37 (m, J = 3.6, 6.8,
6.8, 6.8, 6.8 Hz, 1 H), 4.05−3.96 (m, 1 H), 3.71 (s, 3 H), 3.12 (ddd, J
= 3.0, 12.7, 14.1 Hz, 1 H), 2.21−2.09 (m, 2 H), 1.68 (dd, J = 6.1, 13.5
Hz, 1 H), 1.44−1.35 (m, 1 H), 1.01 (d, J = 7.0 Hz, 3 H); 13C NMR
(101 MHz, DMSO-d6) δ 171.5, 154.9, 137.4, 129.1, 128.5, 67.0, 55.8,
54.0, 45.5, 36.6, 36.3, 30.9, 17.3; HRMS (ESI) m/z calculated for
Hz, 1H), 2.09−2.01 (m, 1 H), 1.86−1.67 (m, 3 H), 1.21 (d, J = 6.6
Hz, 3 H); 13C NMR (101 MHz, CDCl3) δ 209.2, 170.2, 155.3, 136.7,
128.7, 128.3, 128.0, 67.5, 67.3, 45.9, 40.1, 37.9, 36.1, 33.6, 18.9; HRMS
(ESI) m/z calculated for C17H20N2O4 [M + H]+ 317.1496, found
20
317.1494; [α]D +60.8° (c 11.5, CHCl3).
(4R,5R,7S)-Benzyl 4-hydroxy-7-methyl-2-oxo-1,8-
diazaspiro[4.5]decane-8-carboxylate and (4S,5R,7S)-Benzyl 4-
hydroxy-7-methyl-2-oxo-1,8-diazaspiro[4.5]decane-8-carbox-
ylate 16. A solution of 15 (205.5 g, 0.65 mol) in methanol (2.2 L)
was treated portionwise at room temperature with NaBH4 (36.9 g,
0.98 mmol) over 1 h. A slight exotherm was observed, so the reaction
mixture was periodically cooled with an ice bath during the addition to
maintain a temperature of 25 °C. TLC analysis (10% MeOH/EtOAc)
after 45 min showed a small amount of unreacted starting material. An
additional 0.2 equiv of NaBH4 was added. TLC analysis after 90 min
showed complete reaction. The reaction mixture was slowly quenched
with saturated aqueous NH4Cl (600 mL), after which most of the
methanol was removed under reduced pressure. The residue was
diluted with saturated aqueous NH4Cl (600 mL) and EtOAc (2.5 L).
The organic layer was separated, washed with 0.5 N aqueous HCl (1.2
L), brine (1.2 L), dried over MgSO4, and filtered. The filtrate was
concentrated under reduced pressure to afford alcohol 16 as an orange
foam (176.9 g, 86% yield): 1H NMR (400 MHz, CDCl3) (∼3:2
mixture of diastereomers) δ 7.40−7.31 (5H,m), 6.13 (0.4H, s), 6.00
(0.6H, s), 5.18−5.10 (2H, m), 4.48−4.24 (3H, m), 4.11−4.01 (1H,
m), 3.19−3.04 (1H, m), 2.86−2.78 (1H, m), 2.36−2.29 (1.2H, m),
2.29−2.23 (0.8H, m), 1.82−1.56 (3H, m), 1.27 (3H, m); 13C NMR
(100 MHz, CDCl3) δ 136.6, 128.5, 128.1, 127.9, 85.9, 73.0, 71.7, 67.2,
61.4, 46.2, 40.0, 36.2, 35.3, 33.7, 18.5; HRMS (ESI) m/z calculated for
C17H22N2O4 [M + H]+ 319.1657, found 319.1651.
20
C16H22N2O4 [M + H]+ 307.1652, found 307.1651; [α]D +20.3° (c
20.0, CHCl3).
Amino ester 12 (200 mg, 0.653 mmol) was dissolved in ether (1.5
mL) and treated dropwise with 2 M HCl in ether (0.4 mL). The
resulting white precipitate was filtered to afford the mono-HCl salt of
12 (202 mg). An X-ray quality crystal was grown from the salt after
dissolving 53 mg of substrate in 1 mL of acetonitrile (obtained as
white crystals, mp = 170−171 °C); see the Supporting Information for
crystallographic data.
(2S,4R)-1-Benzyl 4-methyl 4-(3-ethoxy-3-oxopropanamido)-
2-methylpiperidine-1,4-dicarboxylate 13. A solution of 12 (250.2
g, 0.82 mol) in CH2Cl2 (1.9 L) was cooled to 0 °C and treated
sequentially with Et3N (296.0 mL, 2.12 mol), monoethyl malonate
(135.0 mL, 1.14 mol), and EDCI·HCl (219.2 g, 1.14 mol). The
reaction mixture was stirred at room temperature overnight. TLC
analysis (100% EtOAc) after 18 h showed complete reaction. The
reaction mixture was concentrated under reduced pressure. The
residue was partitioned between EtOAc (2.2 L) and 0.5 N aqueous
HCl (1.5 L). The organic layer was separated, washed with 0.5 N HCl
(1.5 L), saturated aqueous NaHCO3 (1.5 L), brine (1.5L), dried over
MgSO4, filtered, and concentrated under reduced pressure to afford
(5R,7S)-Benzyl 7-methyl-2-oxo-1,8-diazaspiro[4.5]dec-3-
ene-8-carboxylate 17. A solution of 16 (176.9 g, 0.56 mol) in
CH2Cl2 (4 L) was treated at room temperature with methanesulfonyl
chloride (51.6 mL, 0.67 mol) in one portion and then portionwise
with Et3N (108.4 mL, 0.78 mol). TLC analysis (10% MeOH/EtOAc)
after 1 h showed a small amount of unreacted starting material. An
additional 0.2 equiv of methanesulfonyl chloride and 0.3 equiv of Et3N
were added, and the resulting mixture was stirred for 2 h, after which
TLC analysis showed complete consumption of starting material. The
solution of crude mesylate was then treated portionwise with DBU
(207.7 mL, 1.39 mol) at room temperature. LC−MS analysis after 1 h
showed a small amount of unreacted mesylate. An additional 20 mL of
DBU was added, and TLC analysis after an additional 2 h of stirring
showed complete reaction. The reaction mixture was concentrated
under reduced pressure to remove most of the solvents. The residue
was partitioned between EtOAc (3 L) and 0.5 N aqueous HCl (1.2 L).
The organic layer was separated and washed with saturated aqueous
NaHCO3 (1.2 L), water (1.2 L), brine (1.2 L), dried over MgSO4,
filtered, and concentrated under reduced pressure to afford 17 a light
1
malonamide 13 as an orange oil (322.4 g, 94% yield): H NMR (400
MHz, CDCl3) δ 7.52 (s, 1 H), 7.36−7.25 (m, 5 H), 5.10 (d, J = 1.4
Hz, 2 H), 4.30−4.24 (m, 1 H), 4.14 (q, J = 7.0 Hz, 2 H), 4.01−3.93
(m, 1 H), 3.70 (s, 3 H), 3.30 (ddd, J = 4.7, 11.8, 14.0 Hz, 1 H), 3.20 (s,
2 H), 2.51 (dt, J = 3.1, 14.1 Hz, 1 H), 2.12 (dd, J = 6.3, 13.8 Hz, 1 H),
2.03 (dd, J = 6.1, 13.7 Hz, 1 H), 1.64 (ddd, J = 6.2, 12.0, 14.0 Hz, 1 H),
1.24 (t, J = 7.1 Hz, 3 H), 1.12 (d, J = 6.8 Hz, 3 H); 13C NMR (101
MHz, CDCl3) δ 173.5, 169.7, 164.8, 155.3, 136.9, 128.7, 128.2, 128.0,
67.3, 61.9, 56.0, 52.8, 46.0, 40.8, 37.2, 36.4, 33.3, 17.9, 14.2; HRMS
(ESI) m/z calculated for C21H28N2O7 [M + H]+ 421.1974, found
20
421.1969; [α]D +20.3° (c 20.0, CHCl3).
(5R,7S)-8-Benzyl 3-ethyl 7-methyl-2,4-dioxo-1,8-
diazaspiro[4.5]decane-3,8-dicarboxylate 14. A solution of 13
(319.5 g, 0.76 mol) in EtOH (3.2 L) was treated portionwise at room
temperature with sodium ethoxide (21 wt % in EtOH, 251.2 mL, 0.78
mol), and the resulting mixture was stirred at room temperature. TLC
analysis (100% EtOAc) after 30 min showed complete reaction. The
reaction mixture was concentrated under reduced pressure, and the
resulting residue was partitioned between EtOAc (2.5 L) and 0.5 N
aqueous HCl (1.5 L). The organic layer was separated, washed with
water (1.5 L), brine, dried over MgSO4, and concentrated under
reduced pressure to afford 14 as a brown oil (284.2 g, 96% yield).
NMR showed a mixture of 14 and decarboxylated material 15. The
mixture was advanced to the next step without any further purification.
(5R,7S)-Benzyl 7-methyl-2,4-dioxo-1,8-diazaspiro[4.5]-
decane-8-carboxylate 15. A solution of 14 (288.3 g, 0.74 mol) in
dioxane (2.2 L), acetic acid (0.85 mL, 0.015 mmol), and water (300
mL) was heated at reflux for 1 h. The reaction mixture was cooled to
room temperature and concentrated under reduced pressure. The
residue was purified by flash chromatography through silica gel
(eluting with a sequential gradient of 100% heptanes, 50% EtOAc/
heptanes, 100% EtOAc, and 10% MeOH/EtOAc) to afford 15 as a
1
orange foam (152.2 g, 91% yield): H NMR (400 MHz, CDCl3) δ
7.38−7.27 (m, 5 H), 6.27 (br. s., 1 H), 6.04 (dd, J = 1.7, 6.0 Hz, 1 H),
5.12 (d, J = 3.5 Hz, 2 H), 4.58−4.48 (m, J = 3.2, 6.7, 6.7, 6.7, 6.7 Hz, 1
H), 4.19−4.11 (m, 1 H), 3.13−3.04 (m, 1 H), 1.98 (d, J = 6.4 Hz, 1
H), 2.02 (dd, J = 6.4 Hz, 12.8 Hz, 1 H), 1.88−1.79 (m, 1 H), 1.76−
1.69 (dm, 1 H), 1.61 (dd, J = 1.7, 3.4 Hz, 1 H), 1.25 (d, J = 7.0 Hz, 3
H); 13C NMR (101 MHz, CDCl3) δ 172.6, 155.2, 152.8, 136.8, 128.7,
128.3, 128.1, 126.5, 67.5, 62.6, 46.7, 39.6, 37.3, 34.9, 19.0; HRMS
(ESI) m/z calculated for C17H20N2O3 [M + H]+ 301.1547, found
20
301.1543; [α]D +37.3° (c 17.5, CHCl3).
(5R,7S)-Benzyl 1-(3-fluorophenyl)-7-methyl-2-oxo-1,8-
diazaspiro[4.5]dec-3-ene-8-carboxylate 8. To a 250 mL reaction
vessel was added compound 17 (6.0 g, 20.0 mmol), finely powdered
K3PO4 (14.8 g, 68.3 mmol), 3-fluoro-1-iodobenzene (8.88 g, 40.0
mmol), CuI (2.2 g, 11.4 mmol), and N,N′-dimethylethylenediamine
(17.3 mL, 160 mmol). The reaction vessel was tightly sealed and
heated at 90 °C overnight. The reaction mixture was cooled to room
temperature, diluted with EtOAc and water, and filtered through
Celite. The layers were separated, and the aqueous layer was further
extracted with EtOAc. The combined organic extracts were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The crude
1
viscous amber oil (205.5 g, 88% yield): H NMR (400 MHz, CDCl3)
δ 7.59 (br. s., 1 H), 7.35−7.24 (m, 5 H), 5.15−5.04 (m, 2 H), 4.23
(sxt, J = 6.8 Hz, 1 H), 4.04−3.95 (m, 1 H), 3.65 (s, 3 H), 3.22 (ddd, J
= 4.9, 11.3, 14.3 Hz, 1 H), 3.03 (d, J = 12.0 Hz, 1H), 2.92 (d, J = 12.0
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material was purified by flash chromatography through silica gel (0−
20% EtOAc/heptanes) to afford 8 as a light yellow foam (6.62 g, 84%
yield): 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 6.2 Hz, 1 H), 7.39
(dt, J = 6.3, 8.2 Hz, 1H), 7.35−7.24 (m, 5H), 7.13−7.06 (m, 1 H),
6.89−6.84 (m, 1 H), 6.81 (dt, J = 2.2, 9.3 Hz, 1H), 6.29 (d, J = 6.2 Hz,
1H), 5.05 (br. s., 2H), 4.59 (br. s., 1H), 4.20 (br. s., 1H), 3.10 (t, J =
13.4 Hz, 1H), 2.06 (dd, J = 6.6, 13.3 Hz, 1H), 1.88 (t, J = 11.6 Hz,
1H), 1.64 (br. s., 1H), 1.44 (s, 1H), 1.48 (s, 1H), 1.28 (d, J = 7.2 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 170.1, 164.5, 162.0, 151.2,
136.6, 131.0, 130.9, 128.7, 128.3, 128.1, 126.7, 126.6, 126.5, 118.4,
118.1, 116.2, 116.0, 100.0, 76.9, 67.6, 67.5, 46.1, 36.9; HRMS (ESI)
m/z calculated for C23H23FN2O3 [M + H]+ 395.1765, found 395.1764;
(5R,7S)-Benzyl 1-(5-chloropyridin-3-yl)-7-methyl-2-oxo-1,8-
diazaspiro[4.5]dec-3-ene-8-carboxylate 22. Obtained 288 mg,
70% yield: 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.29 (s, 1H),
7.69 (d, J = 6.2 Hz, 1H), 7.52 (s, 1H), 7.40−7.30 (m, 5H), 6.35 (d, J =
6.0 Hz, 1H), 5.10 (br. s., 2H), 4.67 (br. s., 2H), 4.28 (br. s., 2H), 3.16
(t, J = 12.4 Hz, 2H), 2.03 (dd, J = 6.5, 13.4 Hz, 2H), 1.94−1.66 (m,
4H), 1.55 (d, J = 12.7 Hz, 2H), 1.33 (d, J = 7.2 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 169.8, 151.5, 148.8, 148.4, 138.0, 136.1, 128.4,
128.0, 127.8, 125.8, 81.9, 67.3, 45.7, 38.0, 36.4, 33.5; HRMS (ESI) m/z
calculated for C22H22ClN3O3 [M + H]+ 412.1422, found 412.1420;
20
[α]D +22.5° (c 10.0, CH2Cl2).
20
ASSOCIATED CONTENT
[α]D +18.8° (c 21.0, CHCl3).
■
General Procedure for Cross-Coupling of Spirolactam 17
with Aryl Halides (Goldberg Reaction). To a 20 mL screw capped
vial was added spirolactam 17 (300 mg, 1.0 mmol), finely powdered
Cs2CO3 (985 mg, 3.0 mmol), aryl halide (2.0 mmol), CuI (96 mg, 0.5
mmol), N,N′-dimethylethylenediamine (0.75 mL, 7.0 mmol), and
dioxane (5 mL). The reaction vessel was tightly sealed and heated at
90 °C for the indicated times. The reaction mixture was cooled to
room temperature, diluted with EtOAc and water, and filtered through
Celite. The layers were separated, and the aqueous layer was further
extracted with EtOAc. The combined organic extracts were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The crude
residue was purified by flash chromatography through silica gel
(eluting with EtOAc/heptanes) to afford the product compound.
(5R,7S)-Benzyl 7-methyl-2-oxo-1-(pyridin-3-yl)-1,8-
diazaspiro[4.5]dec-3-ene-8-carboxylate 18. Obtained 277 mg,
S
* Supporting Information
1H and 13C NMR spectra, and single crystal X-ray crystallo-
graphic data (CIF) for compounds 10b and 12. This material is
available free of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
*E-mail: chewah.lee@pfizer.com.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank Brian Samas of Pfizer, Inc., for
providing single crystal X-ray crystallographic data for
compounds 10b and 12 in this paper.
1
72% yield: H NMR (400 MHz, CDCl3) δ 8.31−8.26 (m, 1H), 7.92
(d, J = 8.2 Hz, 1H), 7.64−7.57 (m, 2H), 7.31−7.20 (m, 5H), 7.17 (s,
1H), 6.97 (ddd, J = 0.9, 4.9, 7.3 Hz, 1H), 6.16 (d, J = 6.3 Hz, 1H),
5.12−5.03 (m, 2H), 4.70−4.55 (m, 1H), 4.27−4.10 (m, 1H), 3.08 (br.
s., 3H), 1.46 (br. s., 1H), 1.29 (d, J = 13.7 Hz, 1H), 1.23 (d, J = 7.2 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 169.9, 152.7, 151.3, 147.5,
137.7, 136.7, 128.5, 128.0, 127.8, 125.4, 120.2, 118.6, 69.1, 67.2, 46.1,
37.0; HRMS (ESI) m/z calculated for C22H23N3O3 [M + H]+
REFERENCES
■
(1) Rotstein, D. M.; Gabriel, S. D.; Makra, F.; Filonova, L.; Gleason,
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20
378.1812, found 378.1817; [α]D +15.7° (c 10.1, CHCl3).
(5R,7S)-Benzyl 7-methyl-2-oxo-1-(pyrazin-2-yl)-1,8-
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diazaspiro[4.5]dec-3-ene-8-carboxylate 19. Obtained 259 mg,
1
69% yield: H NMR (400 MHz, CDCl3) δ 8.33−8.18 (m, 1H), 7.92
(d, J = 8.2 Hz, 1H), 7.70−7.44 (m, 2H), 7.37−7.20 (m, 5H), 7.17 (s,
1H), 6.97 (ddd, J = 0.9, 4.9, 7.3 Hz, 1H), 6.16 (d, J = 6.3 Hz, 1H),
5.15−4.97 (m, 2H), 3.08 (br. s., 3H), 1.46 (br. s., 1H), 1.29 (d, J =
13.7 Hz, 1H), 1.23 (d, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3)
δ 169.64, 153.75, 148.29, 141.01, 140.04, 139.59, 136.58, 128.51,
128.09, 127.88, 124.98, 77.32, 77.00, 76.68, 69.16, 67.32, 46.02, 36.84;
HRMS (ESI) m/z calculated for C21H22N4O3 [M + H]+ 379.1765,
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20
A.; Dorn, A.; Fischili, W.; Gruninger, F.; Guller, R.; Hirth, G.; Marki,
̈
̈
̈
found 379.1766; [α]D +7.9° (c 10.7, CH2Cl2).
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(5R,7S)-Benzyl 7-methyl-1-(1-methyl-1H-pyrazol-4-yl)-2-
oxo-1,8-diazaspiro[4.5]dec-3-ene-8-carboxylate 20. Obtained
1
240 mg, 63% yield: H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 6.2
Hz, 1 H), 7.41 (s, 1 H), 7.39−7.26 (m, 5 H), 6.27 (d, J = 6.2 Hz, 1 H),
5.09 (br. s., 2 H), 4.65 (br. s., 1 H), 4.21 (br. s., 1 H), 3.89 (s, 3 H),
3.11 (br. s., 1 H), 2.17 (dd, J = 6.7, 13.6 Hz, 1 H), 1.94 (br. s., 1 H),
1.55 (br. s., 1 H), 1.38 (d, J = 13.3 Hz, 1 H), 1.29 (d, J = 7.2 Hz, 3 H);
13C NMR (100 MHz, CDCl3) δ 169.8, 151.2, 137.3, 136.4, 128.5,
128.3, 128.1, 127.9, 126.1, 67.4, 66.3, 39.5, 36.5; HRMS (ESI) m/z
calculated for C20H21N3O3S [M + H]+ 384.1376, found 384.1380;
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20
[α]D +13.1° (c 20.4, CH2Cl2).
(5R,7S)-Benzyl 7-methyl-2-oxo-1-(thiazol-4-yl)-1,8-
diazaspiro[4.5]dec-3-ene-8-carboxylate 21. Obtained 270 mg,
1
71% yield: H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 2.3 Hz, 1 H),
7.88 (d, J = 2.3 Hz, 1 H), 7.66 (d, J = 6.2 Hz, 1 H), 7.42−7.29 (m, 5
H), 6.27 (d, J = 6.2 Hz, 1 H), 5.26−5.12 (m, 2 H), 4.72 (br. s., 1 H),
4.28 (br. s., 1 H), 3.17 (br. s., 2 H), 3.12−3.01 (m, 1 H), 1.55 (d, J =
12.1 Hz, 1 H), 1.44−1.27 (m, 4 H); 13C NMR (100 MHz, CDCl3) δ
169.0, 151.9, 149.7, 147.4, 136.6, 128.5, 128.0, 127.8, 125.1, 106.2,
99.7, 68.7, 67.2, 46.0, 36.9; HRMS (ESI) m/z calculated for
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20
C21H24N4O3 [M + H]+ 381.1921, found 381.1925; [α]D +16.9° (c
10.3, CH2Cl2).
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