A biocatalytic/reductive etherification approach to substituted piperidinyl ethers

Article abstract of DOI:10.1016/j.tet.2014.04.064

A synthetically useful protocol has been developed for the preparation of highly functionalized piperidinyl ethers. Biocatalytic reduction of cyclhexanones 7, 10, and 14 allows for the preparation of both cis- and trans diastereomers with an extremely high degree of stereochemical control. Reductive etherification of the corresponding trimethylsilylethers with 1-(benzyloxycarbonyl)-4-piperidinone 17 in the presence of triethylsilane and catalytic TMSO-Tf provides the desired piperidinyl ethers in good to excellent yields. Finally hygrogenolysis of the nitrogen protecting group leads to piperidinyl ethers in near quantitative yields. Application of the methodology to a range of piperidinyl ethers, including the core scaffolds of diphenylpyraline and ebastine, is also described.

Full text of DOI:10.1016/j.tet.2014.04.064

Tetrahedron xxx (2014) 1e8
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A biocatalytic/reductive etherification approach to substituted
piperidinyl ethers
,
a
a
a
a
Jeffrey T. Kuethe a , Jacob M. Janey , Matthew Truppo , Juan Arredondo , Tao Li ,
*
Kelvin Yong a, Shuwen He b
a Department of Process Chemistry, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
b Department of Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetically useful protocol has been developed for the preparation of highly functionalized piper-
idinyl ethers. Biocatalytic reduction of cyclhexanones 7, 10, and 14 allows for the preparation of both cis-
and trans diastereomers with an extremely high degree of stereochemical control. Reductive ether-
ification of the corresponding trimethylsilylethers with 1-(benzyloxycarbonyl)-4-piperidinone 17 in the
presence of triethylsilane and catalytic TMSO-Tf provides the desired piperidinyl ethers in good to ex-
cellent yields. Finally hygrogenolysis of the nitrogen protecting group leads to piperidinyl ethers in near
quantitative yields. Application of the methodology to a range of piperidinyl ethers, including the core
scaffolds of diphenylpyraline and ebastine, is also described.
Received 6 February 2014
Received in revised form 21 April 2014
Accepted 22 April 2014
Available online xxx
Keywords:
Biocatalysis
Reductive etherification
Piperidinyl ether
Ó 2014 Published by Elsevier Ltd.
1. Introduction
pyridine ring allows for a two-step preparation of compound 1
(Method 1).2 Method 2, which has been less employed, involves
Piperidinyl ethers of subclass 1 have emerged in recent years as
a central pharmacophore in a range of molecules possessing a di-
verse array of biological activity (Scheme 1).1 There are several
methods for the construction of 1 that have been developed, each
offering certain advantages. For example, reaction of 4-
hydroxypyridine with various secondary alcohols under standard
Mitsunobu reaction conditions followed by reduction of the
alkylation of 4-chloropyridine 3 and subsequent reduction of the
pyridine ring.3 The major disadvantage of Methods 1 and 2 is the
necessary reduction of the pyridine ring. Direct hydrogenation of
the pyridine ring often requires forcing conditions including high
pressures of hydrogen and prolonged reaction times. Partial re-
duction of the ring with NaBH4 followed hydrogenation has served
as an alternative approach, but requires an additional synthetic
Scheme 1.
* Corresponding author. E-mail address: Jeffrey_Kuethe@merck.com (J.T. Kuethe).
0040-4020/$ e see front matter Ó 2014 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2014.04.064
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J.T. Kuethe et al. / Tetrahedron xxx (2014) 1e8
step. The third method for the preparation of compound 1 involves
alkylation of 4-hydroxypiperidines with either secondary halides
under basic conditions (SN2)4 or secondary alcohols under acidic
conditions5 when either R1 or R2 is an aromatic group (SN1). Lim-
itations of Method 3 include the potential for elimination of the
secondary halide under both basic and acidic conditions and the
lack of ability to set the stereogenic center under acidic conditions
when R1sR2.
Recently we required gram quantities of piperidinyl ethers 5 and
6 in order to further support an on-going program (Scheme 2).
Initial milligram quantities of these intriguing intermediates were
prepared employing Method 1 as outlined in Scheme 1. The initial
multiple ‘hits’; however there were two KREDs that gave exclu-
sively either the trans or cis diastereomer as determined by gas
chromatography (GC). In all cases, either a co-substrate isopropanol
(IPA) system, or a co-enzyme GDH/glucose system was used to
recycle the NADPH cofactor. For example, reduction of 7 with KRED
MIF-207 in IPA/pH 7 buffer resulted in clean conversion to cyclo-
hexanol 8, which after workup was obtained in 97% isolated yield
and in>99:1 trans/cis diastereoselectivity. On the other hand, re-
duction of ketone 7 with KRED 119 in the presence of GDH (CDX-
901) and -glucose afforded the cis isomer 9 in 98% isolated yield
D
and >99:1 cis/trans diastereoselectivity. The products from these
reductions were of sufficient purity that chromatographic purifi-
cation was not required.
Mitsunobu reaction provided
a 1:1 mixture of cis/trans di-
astereomers due to the fact that the commercially available cyclo-
hexanols employed were also obtained as a mixture of isomers.
Separation of the Mitsunobu products by conventional chroma-
tography was unsuccessful and required purification by supercrit-
ical fluid chromatography (SFC). Finally, hydrogenation of the
pyridine ring system of both compounds 5 and 6 required ex-
tremely long reaction times (up to 5 days) and proceeded in low
yield (<50%) for each of the individual diastereomers. In order to
address these problems, it was envisioned that control of the cis/
trans diastereomers about the cyclohexane ring and elimination of
the challenging pyridine ring reduction would allow for the prep-
aration of diastereomerically pure products 5 and 6. In this paper,
we disclose a highly efficient method for the preparation of dia-
stereomerically pure cyclohexanols followed by reductive ether-
In order to access the diastereomers of piperidinyl ethers 6, the
screening process was repeated with ketone 11. Since this ketone
was not commercially available, it was synthesized in high yield
from phenol 10. Hydrogenation of phenol 10 over Rh/Al2O3 at 45 psi
hydrogen gave alcohols 12 and 13 as a mixture of diastereomers in
99% yield. Oxidation of 6 was accomplished with bleach in AcOH
and furnished ketone 11 in 97% overall yield for the two-steps.
Optimal conditions that were identified for the biocatalytic re-
duction of ketone 11 involved the use of KRED 142, GDH (CDX-901),
and -glucose and provided exclusively trans-cyclohexanol 12 in
D
90% yield and in a 93:7 ratio of trans/cis diastereomers. While it was
believed that further screening and enzyme optimization was
possible to achieve complete diastereoselectivity, these initial
conditions were deemed acceptable for our down-stream chemis-
try, and no additional effort was invested in optimization. Re-
duction of ketone 11 with KRED P3D1 in IPA/pH 7 buffer in the
ification leading to
a general and improved route for the
construction of piperidinyl ethers of type 1.
presence of -glucose afforded cis-cyclohexanol 13 in 97% yield and
D
in >99:1 cis/trans diastereomers. Crude cyclohexanols 12 and 13
were pure enough for use in subsequent chemistry without the
need for chromatography (Scheme 4).
Finally, we were also interested in the reduction of the known
ketone 148 (Scheme 5). Screening the reduction of ketone 14
resulted in a number of enzymes that provided clean conversion to
the cis diastereomer 15. Optimal conditions involved reaction of
ketone 14 with KRED 119 in the presence of GDH (CDX-901) and
glucose and provided 15 in an unoptimized 73% yield and in >99:1
cis/trans selectivity. Access to diastereomer 16 proved difficult and,
despite extensive screening, KRED MIF-20 provided a 90:10 ratio of
diastereomers that was achieved in 90% yield. Although diaster-
eoselectivity improvement of KRED MIF-20 was available via di-
rected evolution, we choose not to pursue this option at this stage
of development.
Scheme 2.
2. Results and discussion
2.1. Biocatalytic reduction of cyclohexanones
Of known enzymatic reductive reactions, the reduction of ke-
tones to chiral alcohols is perhaps the most evolved. These enzymes
are typically known as ketoreductases (KRED) and use NADPH co-
factor, regenerated in situ, as the hydride donor for the reduction.
The evolution of a large number of enzymes with broad substrate
scope has led to the ability of rapid screening of conditions to effect
the desired reduction with a high degree of stereocontrol. With
a wealth of in-house experience,6 we choose to first examine the
diastereoselective reduction of commercially available ketone 7
(Scheme 3). Screening the reduction of ketone 7 resulted in
2.2. Reductive etherification
The reductive etherification of carbonyl compounds and alkox-
ytrimethylsilanes in the presence of triethylsilane is typically pro-
10
moted by Lewis acids, such as Cu(OTf)2,9 FeCl3, TMSO-Tf,11 trityl
perchlorate,12 TMSI,13 and tris(pentafluorophenyl)borane,14 and
Scheme 3.
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J.T. Kuethe et al. / Tetrahedron xxx (2014) 1e8
3
directly in the reductive etherification reaction. Screening the re-
ductive etherification with a number of Lewis acids afforded the
desired product 18 in modest yields (Table 1). In all cases, com-
petitive reduction of ketone 17 to the corresponding piperdinol was
observed as the major by product of these reactions. The best
conditions involved addition of 0.5 equiv of TMSO-Tf to a cold
(ꢁ60 ꢀC) mixture of ketone 17, the silyl ether of cyclohexanol 8
(1 equiv), and Et3SiH (1.1 equiv) in CH2Cl2 followed by warming to
room temperature. Under these conditions, the desired product 18
was obtained in 81% isolated yield after chromatography on silica
gel. It should also be noted that there was no detectable isomeri-
zation about either the CeO bond on the cyclohexyl ring or the
center adjacent to the ester center. Finally, hydrogenolysis of ether
18 with Pd/C in a mixture of EtOH/EtOAc furnished ether 19 in 90%
yield.
Table 1
Lewis acid promoted reductive etherification of 8 and 17
Entry
Lewis acid
Solvent
Temp
Yield of 18
Scheme 4.
1
2
3
4
5
6
Cu(OTf)2
BiBr3
FeCl3
FeCl3
TMSO-Tf
TMSO-Tf
CH2Cl2
MeCN
MeCN
MeNO2
CH2Cl2
CH2Cl2
rt
rt
rt
rt
54%
43%
56%
61%
63%
81%
0
ꢀC to rt
ꢁ60 ꢀC to rt
The sequence outlined in Scheme 6 proved to be general as
highlighted in Table 2. Reductive etherification between ketone 17
and alcohols 9, 12, 13, and 15 allowed for the diastereoselective
synthesis of the desired piperidinyl ethers 21, 23, 25, and 27 in good
to excellent yield for the two-step protocol. Only when cyclobutyl
alcohol 31 was employed did the yield of the reductive ether-
ification product dramatically drop (entry 6). The reductive ether-
ification reaction was not particularly susceptible to steric
constraints about the silyl ether and compounds 41 and 44 (entries
9 and 10) were obtained as single enantiomers/diastereomers in
good yields. While the reductive etherification products generally
required purification by silica gel chromatography to remove im-
purities, such as the reduced starting material 17, the products from
the subsequent hydrogenolysis did not require chromatographic
purification. Finally, the core scaffold of diphenylpyraline and
ebastine, a class of marketed compounds shown to have antiallergic
activity (entry 11, compound 48), was prepared in 66% yield over
the two-steps.19 The advantage of the present methodology in the
preparation of this subclass of piperidinyl ethers is the ability to
start with a single enantiomer of any diarylmethanol derivative of
type 46 allowing straight forward access to chiral piperidinyl
ethers.20
Scheme 5.
Brønsted acids, such as BiBr3.15,16 Although these conditions have
been successfully employed with relatively simple carbonyl com-
pounds and alkoxytrimethylsilanes, application to nitrogen-
containing hetereocycles and more advanced silylethers has been
limited to a few reported examples.17 With a useful method for the
preparation of diastereomerically pure cyclohexanols in hand, we
next set out to examine reductive etherification conditions with
CBz-protected piperidinone 17 (Scheme 6). Generation of the silyl
ether of alcohol 8 involved reaction with TMS-Cl in THF in the
18
presence of NEt3 at 0 ꢀC for 30 min. The resulting ammonium salts
were filtered and the crude silyl ether concentrated and used
Scheme 6.
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J.T. Kuethe et al. / Tetrahedron xxx (2014) 1e8
Reductive etherification product (% yield)
Table 2
Preparation of substituted piperidinyl ethers
Entry
Alcohol
Hydrogenolysis product (% yield)
1
2
3
4
5
6
7
8
9
10
11
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J.T. Kuethe et al. / Tetrahedron xxx (2014) 1e8
5
3. Conclusions
NMR (CDCl3, 100 MHz)
d
14.2, 23.7, 32.0, 41.3, 60.2, 66.8, 175.4.
Anal. Calcd for C9H16O3: C, 62.77; H, 9.36. Found: C, 62.84; H,
9.53.
In conclusion, we have demonstrated a highly efficient and
diastereoselective biocatalytic reduction of cyclohexanones 7, 11,
and 14. Reductive cyclization employing TMSO-Tf and Et3SiH
proved to be an effective method for preparation of a range of
functionalized piperidinyl ethers in good to excellent yields fol-
lowing removal of the CBz-protecting group via hydrogenolysis. In
the case of piperidinyl ethers 5 and 6, the synthetic protocol re-
quired just three synthetic steps and only one chromatographic
purification. From commercially available achiral and chiral alco-
hols, the method allowed for the two-step preparation of the de-
sired piperidinyl ethers.
4.1.3. Preparation of methyl 2-(4-oxocyclohexyl)acetate (11). To
a solution of 100.0 g (602 mmol) of 10 in 1 L of MeOH was added
10.0 g (244 mmol) of Rh/Al2O3. The resulting mixture was degassed
via vacuum/hydrogen purges (3ꢂ) and hydrogenated at 22 ꢀC and
45 psi hydrogen for 20 h. The reaction mixture was filtered through
a pad of Celite and concentrated under reduced pressure to provide
103 g (99%) of the corresponding cyclohexanols 12 and 13 as
a mixture of diastereomers that were used in the next step without
further purification.
To a cooled (w10 ꢀC) solution of 100.3 g (582.0 mmol) of the
above alcohol in 361 mL of AcOH was added drop wise 954 mL of
a 5% solution of NaOCl while maintaining the internal tempera-
ture <25 ꢀC. After the addition was complete, the cooling bath
was removed and the reaction mixture was stirred at room
temperature for 2 h. The reaction mixture was diluted with
500 mL of brine and 1 L of EtOAc and the layers were separated.
The aqueous layer was back extracted with EtOAc (3ꢂ500 mL).
The combined organic extracts were washed with 500 mL of 20%
K2CO3 and then with 500 mL of satd NaHCO3. The organic layer
was dried over MgSO4 and concentrated under reduced pressure
to give 97.0 g (98%) of 11, which was sufficiently pure for use in
the next step.
4. Experimental section
4.1. General
Commercial grade reagents and solvents were used without
further purification. 1H NMR and 13C NMR spectra were measured
with a 400 MHz spectrometer. 1H NMR chemical shifts are
expressed in parts per million (
lane (with the CHCl3 peak at 7.27 used as a standard). 13C NMR
chemical shifts are expressed in parts per million ( ) downfield
from tetramethylsilane (with the central peak of CHCl3 at
77.23 ppm used as a standard). Purifications were carried out by
flash column chromatography on a Teledyne Isco CombiFlash Rf
using a gradient elution of 0e100% EtOAc/hexanes unless other-
wise specified.
d) downfield from tetramethylsi-
d
4.1.4. Preparation of trans methyl 4-hydroxycyclohexylacetate
(12). To a mixture of 5.0 g of KRED 142, 2.2 g of NADP, 402 g of
D-glucose, and 5.0 g of GDH (CDX-901) in 1.8 L of pH 7 phosphate
4.1.1. Preparation of trans ethyl 4-hydroxycyclohexanecarboxylate
(8). To a solution of 1.43 L of water was added 9.70 g (71.2 mmol)
of KH2PO4 and 12.4 g (71.2 mmol) of K2HPO4. To the resulting so-
lution was added 5.71 g of MIF-20 and 1.43 g of NADP to give a pH of
7.0. To the mixture was added 256.8 g (1.51 mol) of ketone 7 in
1.43 L of 2-propanol. The pH of the mixture was controlled at 7.0 by
the addition of 1 M HCl during the course of the reaction, and the
mixture was stirred at 30 ꢀC for 20 h. The reaction mixture was then
extracted with MTBE (1.5 L). The aqueous layer was back extracted
with a 3:1 mixture of MTBE/2-propanol (2ꢂ600 mL). The organic
layer was concentrated under reduced pressure and re-dissolved in
buffer was added drop wise 95.0 g (558 mmol) of ketone 11 over
5 h while maintaining the internal pH at 7 by the addition of 8 N
NaOH. After 4 h, the pH was adjusted to 2 by the addition of
phosphoric acid. To the mixture was added 50 g of Celite and the
slurry was stirred for 20 min and filtered. To the filtrate was added
800 mL of EtOAc and the layers were separated. The aqueous layer
was back extracted with EtOAc (2ꢂ800 mL). The combined organic
extracts were washed with 1 L of water, 200 mL of 5% NaHCO3,
200 mL of 0.5% phosphoric acid, and 200 mL of brine. The solvent
was removed under reduced pressure to provide 93.2 g (97%) of 12
as a colorless oil, which was sufficiently pure for use in the next
1.5
L
of MTBE. The organic layer was washed with brine
reaction: 1H NMR (CDCl3, 400 MHz)
d 1.05 (m, 2H), 1.29 (m, 2H),
(2ꢂ300 mL), dried over MgSO4, and concentrated under reduced
pressure to provide 268 g (97%) of 8 as a colorless solid and in
>99:1 trans/cis diastereoselectivity. 1H NMR (CDCl3, 400 MHz)
1.61 (br s, 1H), 1.70e1.81 (m, 3H), 1.99 (m, 2H), 2.20 (d, 2H,
J¼6.8 Hz), 3.55 (m, 1H), 3.69 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d
30.9, 33.8, 35.1, 41.0, 51.4, 70.4, 173.4. Anal. Calcd for C9H16O3: C,
d
1.19e1.34 (m, 5H), 1.51 (m, 2H), 1.67 (br s, 1H), 2.20 (m, 4H), 2.23
62.77; H, 9.36.
(m, 1H), 4.12 (q, 2H, J¼7.2 Hz); 13C NMR (CDCl3, 100 MHz)
d 14.1,
27.1, 34.4, 42.3, 60.2, 69.6,176.7. Anal. Calcd for C9H16O3: C, 62.77; H,
9.36. Found: C, 62.51; H, 9.12.
4.1.5. Preparation of cis methyl 4-hydroxycyclohexylacetate (13). To
a mixture of 1.80 g of KRED P3D1 and 200 mg of NADP in 140 mL
of 1.0 M pH 7 phosphate buffer was added 10.0 g (58.8 mmol) of
ketone 11 in 60 mL of 2-propanol. The resulting mixture was
stirred at 30 ꢀC for 20 h. The reaction mixture was then diluted
with 60 mL of MTBE and the layers separated. The aqueous layer
was back extracted with 150 mL of a 2:1 mixture of MTBE/2-
propanol (2ꢂ). The organic layer was washed with water
(2ꢂ100 mL) and then brine (100 mL) and dried over Na2SO4.
Concentration of the organic layer afforded 9.8 g (97%) of 13 as
a colorless oil that was sufficiently pure for use in the next
reaction without the need for further purification: 1H NMR (CDCl3,
4.1.2. Preparation of cis ethyl 4-hydroxycyclohexanecarboxylate
(9). To a solution of 1.67 g of KRED 119, 1.67 g of NAPD, and
1.67 g of GDH (CDX-901), and 106 g (588.0 mmol) of D-glucose in
1.5 L of 0.1 M pH 7 phosphate buffer was added 45.6 g
(268 mmol) of ketone 7 in 137 mL of DMSO. The pH of the re-
action mixture was monitored and adjusted as needed with 5 N
NaOH to maintain a constant pH of 7. The reaction mixture was
stirred for 20 h at room temperature. The reaction mixture was
diluted with 200 mL of a 1:1 mixture of EtOH/MTBE and the
layers separated. The aqueous layer was back extracted with
MTBE (3ꢂ500 mL). The combined organic extracts were washed
with brine (2ꢂ250 mL), dried over MgSO4, and concentrated
under reduced pressure to give 45.2 g (98%) of 9 as a colorless
solid and in>99:1 cis/trans diastereoselectivity. 1H NMR (CDCl3,
400 MHz)
d 1.39e1.63 (m, 7H), 1.74 (m, 2H), 1.86 (m, 1H), 2.26
(d, 2H, J¼7.2 Hz), 3.67 (s, 3H), 3.99 (m, 1H); 13C NMR (CDCl3,
100 MHz)
d 26.7, 32.0, 33.4, 40.7, 51.4, 66.2, 173.5. Anal. Calcd for
C9H16O3: C, 62.77; H, 9.36. Found: C, 62.96; H, 9.41.
400 MHz)
d
1.26 (t, 3H, J¼7.2 Hz), 1.49 (br s, 1H), 1.71 (m, 6H), 1.98
4.1.6. Preparation of ethyl 4-hydroxy-1-methylcyclohexane
carboxylate (15). To a solution of 0.17 g of KRED, 0.17 g of NADP,
(m, 2H), 2.39 (m, 1H), 3.90 (m, 1H), 4.14 (q, 2H, J¼7.2 Hz); 13C
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6
J.T. Kuethe et al. / Tetrahedron xxx (2014) 1e8
and 0.17 g of GDH (CDX-901), and 10.8 g (59.7 mmol) of
D
-glucose in
4.3.1. Preparation of cis benzyl-4-(4-(ethoxycarbonyl)cyclohexyl)oxy)
piperidine-1-carboxylate (20). According to general procedure A,
treatment of 0.96 g (5.57 mmol) of alcohol 9 with 0.75 mL
(5.85 mmol) in the presence of 1.17 mL (6.69 mmol) of NEt3 fol-
lowed by reaction with 1.30 g (5.57 mmol) of 17 in the presence of
0.98 mL (6.13 mmol) of triethylsilane and 0.40 mL (2.23 mmol) of
TMS-OTf afforded 1.50 g (69%) of 20 as a colorless oil: 1H NMR
160 mL of a 0.1 M pH 7 phosphate buffer was added 5.00 g
(27.1 mmol) of ketone 14 in 10 mL of DMSO. The pH of the reaction
mixture was monitored and adjusted as needed with 5 N NaOH to
maintain a constant pH of 7. After 1 h, the reaction was diluted with
150 mL of MTBE and the layers were separated. The aqueous layer
was back extracted with 150 mL of MTBE. The combined extracts
were washed with 50 mL of water and then with 50 mL of brine.
The organic layer was dried over MgSO4, filtered and concentrated
under reduced pressure to afford 3.67 g (73%) of 15 as an oil, which
was sufficiently pure for use without further purification: 1H NMR
(CDCl3, 400 MHz)
d
1.26 (t, 3H, J¼7.1 Hz), 1.55 (m, 3H), 1.68 (m, 3H),
1.77 (m, 4H), 1.92 (m, 2H), 2.32 (m, 1H), 3.28 (m, 2H), 3.57 (m, 2H),
3.76 (m, 2H), 4.13 (q, 2H, J¼7.1 Hz), 5.13 (s, 2H), 7.36 (m, 5H); 13C
NMR (CDCl3, 100 MHz)
d 14.2, 24.0, 30.0, 31.6, 41.3, 41.7, 60.1, 67.0,
(CDCl3, 400 MHz)
d
1.15 (s, 3H), 1.16e1.38 (m, 7H), 1.66 (br s, 1H),
70.7, 70.8, 127.8, 127.9, 128.5, 136.9, 155.3, 175.4. Anal. Calcd for
C22H31NO5: C, 67.84; H, 8.02; N, 3.60. Found: C, 68.01; H, 8.22; N,
3.66.
1.84 (m, 2H), 2.22 (m, 2H), 3.59 (m, 1H), 4.15 (q, 2H, J¼7.0 Hz)); 13
C
NMR (CDCl3, 100 MHz)
d
14.1, 25.8, 27.0, 30.6, 32.6, 33.6, 42.6, 60.3,
69.8, 176.9. Anal. Calcd for C10H18O3: C, 64.49; H, 9.74. Found: C,
64.92; H, 9.66.
4.3.2. Preparation
of
cis
ethyl
4-(piperidin-4-yloxy)cyclo-
hexanecarboxylate (21). According to general procedure B, hydro-
genolysis of 1.35 g (3.47 mmol) of 20 provided 0.90 g (99%) of 21 as
4.2. General procedure A: preparation of 4-piperidinyl ethers.
Preparation of trans benzyl-4-(4-(ethoxycarbonyl)cyclohexyl)
oxy)piperidine-1-carboxylate (18)
a colorless solid: 1H NMR (CDCl3, 400 MHz)
d
1.24 (t, 3H, J¼7.1 Hz),
1.53 (m, 2H), 1.70 (m, 4H), 1.88 (m, 4H), 2.09 (m, 2H), 2.33 (m, 1H),
3.19 (m, 2H), 3.33 (m, 2H), 3.58 (m, 1H), 3.24 (m, 1H), 4.12 (q, 2H,
d 14.2, 23.8, 27.8, 29.6, 40.4,
41.6, 60.2, 66.7, 71.0. Anal. Calcd for C14H25NO3: C, 65.85; H, 9.87; N,
5.49. Found: C, 65.89; H, 9.88; N, 5.42.
J¼7.1 Hz); 13C NMR (CDCl3, 100 MHz)
To a solution of 10.0 g (58.1 mmol) of alcohol 8 in 150 mL of
anhydrous THF was added 8.90 mL (63.9 mmoL, 1.1 equiv) of NEt3
and the mixture was cooled in an ice bath to give an internal
temperature of <5 ꢀC. To the solution was added drop wise
7.79 mL (61.0 mmol, 1.05 equiv) of TMS-Cl. The resulting slurry
was stirred at the same temperature for 30 min, diluted with
100 mL of hexane, and filtered to remove the insoluble salts. The
filtrate was concentrated under reduced pressure. The resulting
crude TMS-ether was re-dissolved in 150 mL of CH2Cl2 and
cooled in a dry ice/acetone bath to an internal temperature of
<ꢁ60 ꢀC. To the cooled solution was added sequentially 13.0 g
(58.1 mmol, 1 equiv) of 1-(benzyloxycarbonyl)-4-piperidinone 17,
10.2 mL (63.9 mmol, 1.1 equiv) of triethylsilane, and 5.25 mL
(29.0 mmol, 0.5 equiv) of TMS-OTf. The reaction mixture was
allowed to slowly warm to 0 ꢀC and stirred for 30 min. The re-
action mixture was diluted with 125 mL of EtOAc and 100 mL of
1 M H3PO4 and the layers separated. The organic layer was
washed with 100 mL of brine, dried over MgSO4, and concen-
trated under reduced pressure. The residue was purified by silica
gel chromatography to give 18.3 g (81%) of 18 as a colorless oil: 1H
4.3.3. Preparation of trans benzyl 4-(4-(2-methoxy-2-oxoethyl)cy-
clohexyl)oxy)piperidine-1-carboxylate (22). According to general
procedure A, treatment of 5.15 g (29.9 mmol) of alcohol 12 with
3.82 mL (29.9 mmol) TMS-Cl in the presence of 5.42 mL
(38.9 mmol) of NEt3 followed by reaction with 6.98 g (29.9 mmol)
of 17 in the presence of 5.25 mL (32.9 mmol) of triethylsilane and
2.70 mL (14.98 mmol) of TMS-OTf afforded 8.74 g (75%) of 22 as
a colorless oil: 1H NMR (CDCl3, 400 MHz)
d 1.06 (m, 2H), 1.07
(m, 2H), 1.29 (m, 2H), 1.51 (m, 2H), 1.78 (m, 4H), 1.96 (m, 2H), 2.20
(d, 2H, J¼6.8 Hz), 3.18 (m, 2H), 3.28 (m, 1H), 3.57 (m, 1H), 3.68
(s, 3H), 3.85 (m, 2H), 5.13 (s, 2H), 7.36 (m, 5H); 13C NMR (CDCl3,
100 MHz) d 31.1, 31.9, 32.6, 34.1, 41.1, 41.5, 51.4, 67.0, 71.4, 75.1, 127.9,
127.9, 128.5, 136.9, 155.3, 173.2. Anal. Calcd for C22H31NO5: C, 67.84;
H, 8.02; N, 3.60. Found: C, 68.01; H, 8.31; N, 3.71.
4.3.4. Preparation of trans methyl 2-(4-(piperidin-4-yloxy)cyclo-
hexyl)acetate (23). According to general procedure B, hydro-
genolysis of 3.00 g (7.70 mmol) of 22 gave 1.92 g (98%) of 23 as
NMR (CDCl3, 400 MHz)
(m, 4H), 1.80 (m, 2H), 2.00 (m, 4H), 2.25 (m, 1H), 3.19 (m, 2H),
d
1.26 (t, 3H, J¼7.1 Hz), 1.28 (m, 2H), 1.49
a colorless oil: 1H NMR (CDCl3, 400 MHz)
d 1.06 (m, 2H), 1.29
3.35 (m, 1H), 3.62 (m, 1H), 3.84 (m, 2H), 4.13 (q, 2H, J¼7.2 Hz),
(m, 2H), 1.63e1.83 (m, 8H), 1.93 (m, 4H), 2.06 (m, 2H), 2.21 (d, 2H,
5.14 (s, 2H), 7.35 (m, 5H); 13C NMR (CDCl3, 100 MHz)
d 14.2, 27.2,
J¼6.8 Hz), 3.18e34 (m, 5H), 3.68 (s, 3H), 3.79 (m, 1H); 13C NMR
31.8, 32.0, 41.5, 42.4, 60.2, 67.0, 71.5, 74.3, 127.8, 127.9, 128.5,
136.9, 155.3, 175.6. Anal. Calcd for C22H31NO5: C, 67.84; H, 8.02; N,
3.60. Found: C, 67.54; H, 7.95; N, 3.55.
(CDCl3, 100 MHz)
d 27.9, 30.9, 32.4, 33.9, 40.0, 41.0, 51.4, 66.5, 75.5,
173.2. Anal. Calcd for C14H25NO3: C, 65.85; H, 9.87; N, 5.49. Found:
C, 65.83; H, 9.88; N, 5.51.
4.3. General procedure B: preparation of 4-piperidinyl ethers.
Preparation of trans ethyl 4-(piperidin-4-yloxy)cyclo-
hexanecarboxylate (19)
4.3.5. Preparation of cis benzyl 4-(4-(2-methoxy-2-oxoethyl)cyclo-
hexyl)oxy)piperidine-1-carboxylate (24). According to general pro-
cedure A, treatment of 0.74 g (4.29 mmol) of alcohol 13 with 0.58 mL
(4.50 mmol) TMS-Cl in the presence of 0.90 mL (5.14 mmol) of DIPEA
followed by reaction with 1.00 g (4.29 mmol) of 17 in the presence of
0.74 mL (4.72 mmol) of triethylsilane and 0.31 mL (1.75 mmol) of
TMS-OTfafforded 1.03 g (62%) of 24as a colorless oil: 1H NMR (CDCl3,
To a solution of 1.90 g (4.88 mmol) of 18 in 25 mL of a 1:1
mixture of EtOAc/EtOH was carefully added 150 mg of 10% Pd/C.
The mixture was hydrogenated at 20 psi H2 for 8e20 h or until TLC
indicated that all SM had been consumed. The slurry was filtered
through a pad of cellulose eluting with EtOAc. The solvent was
removed under reduced to provide 1.12 g (90%) of 19 as a colorless
400 MHz)
J¼7.2 Hz), 3.27 (m, 2H), 3.51 (m, 1H), 3.62 (m, 1H), 3.68 (s, 3H), 3.79
(m, 2H), 5.14 (s, 2H), 7.36 (m, 5H); 13C NMR (CDCl3, 100 MHz)
27.2,
d 1.39e1.55 (m, 8H),1.77 (m, 5H),1.83 (m,1H), 2.24 (d, 2H,
d
solid: 1H NMR (CDCl3, 400 MHz)
d
1.26 (t, 3H, J¼7.1 Hz), 1.32
30.0, 31.6, 33.7, 41.0, 41.4, 51.3, 67.0, 70.5, 70.7, 127.8, 127.9, 128.4,
136.9, 155.3, 173.5. Anal. Calcd for C22H31NO5: C, 67.84; H, 8.02; N,
3.60. Found: C, 67.67; H, 7.93; N, 3.48.
(m, 2H), 1.86e2.13 (m, 8H), 2.23 (m, 1H), 3.15 (m, 2H), 3.38 (m, 3H),
3.78 (m, 1H), 4.13 (q, 2H, J¼2H); 13C NMR (CDCl3, 100 MHz)
d 14.2,
27.0, 28.2, 31.8, 40.2, 42.2, 60.3, 67.0, 74.7. Anal. Calcd for
C
14H25NO3: C, 65.85; H, 9.87; N, 5.49. Found: C, 65.76; H, 9.84; N,
4.3.6. Preparation of cis methyl 2-(4-(piperidin-4-yloxy)cyclohexyl)
5.44.
acetate (25). According to general procedure B, hydrogenolysis of
Please cite this article in press as: Kuethe, J. T.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.064

J.T. Kuethe et al. / Tetrahedron xxx (2014) 1e8
7
0.72 g (1.85 mmol) of 24 afforded 0.45 g (95%) of 25 as a colorless
oil: 1H NMR (CDCl3, 400 MHz)
1.28e1.46 (m, 6H), 1.70 (m, 2H),
41.3, 46.2, 61.6, 66.2, 67.1, 73.2, 127.9, 128.0,128.5,155.2,170.9, 171.8.
Anal. Calcd for C23H31NO7: C, 63.73; H, 7.21; N, 3.23. Found: C,
63.69; H, 7.11; N, 3.18.
d
1.82 (m, 3H), 2.06 (m, 2H), 2.17 (d, 2H, J¼7.2 Hz), 3.14 (m, 2H), 3.27
(m, 2H), 3.53 (m, 1H), 3.61 (s, 3H), 3.65 (m, 1H); 13C NMR (CDCl3,
100 MHz)
d
27.1, 27.7, 29.8, 33.7, 39.9, 41.0, 51.3, 66.3, 70.9, 173.4.
4.3.12. Preparation of diethyl 3-(piperidin-4-yloxy)cyclobutane-1,1-
dicarboxylate (33). According to general procedure B, hydro-
genolysis of 0.50 g (1.15 mmol) of 32 afforded 0.34 g (98%) of 33 as
Anal. Calcd for C14H25NO3: C, 65.85; H, 9.87; N, 5.49. Found: C,
65.67; H, 9.81; N, 5.45.
a colorless oil: 1H NMR (CDCl3, 400 MHz)
d 1.23 (m, 6H), 1.43
4.3.7. Preparation of Benzyl 4-((4-(ethoxylcarbonyl)-4-
methylcyclohexyl)oxy)pipereidine-1-carboxylate (26). According to
general procedure A, treatment of 1.12 g (6.00 mmol) of alcohol
15 with 0.81 mL (6.85 mmol) of TMS-Cl in the presence of
1.26 mL (7.20 mmol) of DIPEA followed by reaction with 1.40 g
(6.00 mmol) of 17 in the presence of 1.05 mL (6.60 mmol) of
triethylsilane and 0.43 mL (0.53 mmol) of TMS-OTf afforded
1.57 g (65%) of 26 as a colorless oil: 1H NMR (CDCl3, 400 MHz)
(m, 2H), 1.84 (m, 2H), 2.18 (br m, 2H), 2.47 (m, 2H), 2.55 (m, 2H),
2.77 (m, 2H), 3.06 (m, 2H), 3.34 (m, 1H), 4.18 (m, 5H); 13C NMR
(CDCl3, 100 MHz)
d 14.0, 33.3, 38.7, 39.3, 40.3, 44.3, 61.4, 61.6, 65.9,
74.5, 170.3, 171.5. Anal. Calcd for C15H25NO5: C, 60.18; H, 8.42; N,
4.68. Found: C, 59.99; H, 8.33; N, 4.58.
4.3.13. Preparation of benzyl 4-cyclopentyloxypiperidine-1-
carboxylate (35). According to general procedure A, treatment of
0.39 mL (4.29 mmol) of cyclopentanol 31 with 0.58 mL (4.50 mmol)
of TMS-Cl in the presence of 0.82 mL (4.72 mmol) of diisopropy-
lethylamine followed by reaction with 1.00 g (429 mmol) of 17 in
the presence of 0.75 mL (4.72 mmol) of triethylsilane and 0.31 mL
(1.72 mmol) of TMS-OTf gave 760 mg (58%) of 35 as a colorless oil:
d
1.15 (s, 3H), 1.64 (m, 2H), 1.24 (t, 3H, J¼7.0 Hz), 1.34 (m, 2H), 1.53
(br m, 2H), 1.83 (m, 4H), 2.23 (m, 2H), 3.19 (m, 2H), 3.34 (m, 1H),
3.59 (m, 1H), 3.82 (m, 2H), 4.14 (q, 2H, J¼7.0 Hz), 5.13 (s, 2H), 7.35
(m, 5H); 13C NMR (CDCl3, 100 MHz)
d 14.2, 27.0, 30.2, 31.8, 33.7,
41.9, 42.8, 60.3, 67.0, 71.3, 74.4, 127.8, 127.9, 128.5, 155.3, 176.8.
Anal. Calcd for C23H33NO5: C, 68.46; H, 8.24; N, 3.47. Found: C,
68.29; H, 8.15; N, 3.44.
1H NMR (CDCl3, 400 MHz)
3.19 (m, 2H), 3.49 (m, 1H), 3.84 (m, 2H), 4.03 (m, 1H), 5.13 (s, 2H),
7.33 (m, 5H)); 13C NMR (CDCl3, 100 MHz)
23.5, 31.6, 32.9, 41.6,
67.0, 72.2, 78.4, 127.8, 127.9, 128.5, 136.9, 155.3. Anal. Calcd for
18H25NO3: C, 71.26; H, 8.31; N, 4.62. Found: C, 70.98; H, 8.11; N,
d 1.47e1.64 (m, 6H), 1.67e1.79 (m, 6H),
d
4.3.8. Preparation of ethyl 1-methyl-4-(piperidin-4-yloxy)cyclo-
hexanecarboxylate (27). According to general procedure B, hydro-
genolysis of 0.51 g (1.26 mmol) of 26 gave 0.33 g (97%) of 27 as
C
4.59.
a colorless oil: 1H NMR (CDCl3, 400 MHz)
d 1.15e1.56 (m, 12H), 1.91
(m, 4H), 2.02 (br s,1H), 2.34 (m, 2H), 2.62 (m, 2H), 3.24 (m, 2H), 3.45
4.3.14. Preparation of 4-(cyclopentyloxy)piperidine (36). According
to general procedure B, hydrogenolysis of 1.12 g (3.69 mmol) of 35
furnished 0.62 g (99%) of 36 as a colorless oil: 1H NMR (CDCl3,
(m, 1H), 3.51 (m, 1H), 4,26 (q, 2H, J¼7.0 Hz); 13C NMR (CDCl3,
100 MHz)
d 14.5, 27.4, 30.6, 34.1, 43.1, 44.8, 60.5, 73.0, 4.5, 177.0.
Anal. Calcd for C, 66.88; H,10.10; N, 5.20. Found: C, 67.02; H, 9.95; N,
5.03.
400 MHz)
(m, 3H), 3.05 (m, 2H), 3.33 (m, 1H), 3.98 (m, 1H); 13C NMR (CDCl3,
100 MHz) 23.4, 32.9, 33.4, 44.5, 73.3, 78.1. Anal. Calcd for C10H19NO:
d 01.32e1.56 (m, 6H), 1.67 (m, 4H), 1.85 (m, 2H), 2.57
d
4.3.9. Preparation of benzyl 4-isopropoxypiperidine-1-carboxylate
(29). According to general procedure A, treatment of 0.76 mL
(4.29 mmol) of commercially available isopropoxytrimethylsilane
28 with 1.00 g (4.29 mmol) of 17 in the presence of 0.75 mL
(4.72 mmol) of triethylsilane and 0.31 mL (1.72 mmol) of TMS-OTf
afforded 725 mg (61%) of 29 as a colorless oil: 1H NMR (CDCl3,
C, 70.96; H, 11.31; N, 8.28. Found: C, 71.10; H, 11.36; N, 8.22.
4.3.15. Preparation of benzyl 4-cyclohexyloxypiperidine-1-
carboxylate (38). According to general procedure A, treatment of
0.45 mL (4.29 mmol) of cyclohexanol 37 with 0.58 mL (4.50 mmol)
of TMS-Cl in the presence of 0.82 mL (4.72 mmol) of diisopropy-
lethylamine followed by reaction with 1.00 g (4.29 mmol) of 17 in
the presence of 0.75 mL (4.72 mmol) of triethylsilane and 0.31 mL
(1.72 mmol) of TMS-OTf gave 920 mg (68%) of 38 as a colorless oil:
400 MHz)
3.23 (m, 2H), 3.56 (m, 1H), 3.71 (m, 1H), 3.86 (m, 2H), 5.14 (s, 2H),
7.29e7.37 (m, 5H); 13C NMR (CDCl3, 100 MHz)
22.8, 31.8, 41.5, 67.0,
68.2, 71.3, 127.8, 127.9, 128.5, 136.9, 155.3. Anal. Calcd for
16H23NO3: C, 69.29; H, 8.36; N, 5.05. Found: C, 69.09; H, 8.28; N,
d
1.16 (d, 1H, J¼6.12 Hz), 1.52 (br m, 2H), 1.79 (br m, 2H),
d
1H NMR (CDCl3, 400 MHz)
d 1.17e1.34 (m, 5H), 1.53 (m, 3H),
C
4.97.
1.73e1.88 (m, 6H), 3.17 (m, H), 3.32 (m, 1H), 3.60 (m, 1H), 3.83
(m, 2H), 5.14 (m, 2H), 7.37 (m, 5H); 13C NMR (CDCl3, 100 MHz)
d
24.3, 25.8, 31.9, 33.1, 41.6, 67.0, 71.1, 74.7, 127.8, 127.9, 128.5, 137.0,
4.3.10. Preparation of 4-isopropoxypiperidine (30). According to
general procedure B, hydrogenolysis of 0.64 g (2.31 mmol) of 29
gave 0.33 g (99%) of 30 as a colorless solid: 1H NMR (CDCl3,
155.3. Anal. Calcd for C19H27NO3: C, 71.89; H, 8.57; N, 4.41. Found: C,
71.90; H, 5.60; N, 4.39.
400 MHz)
d
1.14 (d, 6H),1.89 (m, 2H), 2.06 (m, 2H), 3.18 (m, 2H), 3.32
4.3.16. Preparation of 4-(cyclohexyloxy)piperidine (39). According
to general procedure B, hydrogenolysis of 0.90 g (2.84 mmol) of 38
gave 0.52 g (99%) of 3922 as a colorless oil: 1H NMR (CDCl3, 400 MHz)
(m, 2H), 3.67 (sep, J¼6.0 Hz), 3.73 (m, 1H); 13C NMR (CDCl3,
100 MHz)
d 22.6, 27.8, 40.0, 66.4, 69.0. Anal. Calcd for C8H17NO: C,
67.09; H, 11.96; N, 9.78. Found: C, 66.87; H, 12.03; N, 9.81.
d
0.1.23 (m, 5H), 1.49 (m, 1H), 1.68e1.87 (m, 6H), 2.06 (m, 2H), 3.13
(m, 2H), 3.28 (m, 3H), 3.74 (m,1H); 13C NMR (CDCl3,100 MHz)
d
24.0,
4.3.11. Preparation of diethyl 3-((benzyloxy)carbonyl)piperidin-4-yl)
oxy)cyclobutane-1,1-dicarboxylate (32). According to general pro-
cedure A, treatment of 0.927 g (4.29 mmol) of alcohol 3121 with
0.58 mL (4.50 mmol) in the presence of 0.78 mL (5.58 mmol) of
NEt3 followed by reaction with 1.00 g (4.29 mmol) of 17 in the
presence of 0.75 mL (4.72 mmol) of triethylsilane and 0.31 mL
(1.72 mmol) of TMS-OTf afforded 600 mg (32%) of 32 as a colorless
25.6, 27.9, 32.7, 40.0, 66.3, 74.9. Anal. Calcd for C11H21NO: C, 72.08, H,
11.55; N, 7.64. Found: C, 71.90; H, 11.49; N, 7.66.
4.3.17. Preparation of (R)-benzyl 4-(1-phenylethoxy)piperidine-1-
carboxylate (41). According to general procedure A, treatment of
0.57 mL (4.72 mmol) of alcohol 40 with 0.63 mL (4.95 mmol) of
TMS-Cl in the presence of 0.85 mL (6.13 mmol) of NEt3 followed by
reaction with 1.10 g (4.72 mmol) of 17 in the presence of 0.83 mL
(5.19 mmol) of triethylsilane and 0.34 mL (1.90 mmol) of TMS-OTf
afforded 1.14 g (71%) of 41 as a colorless oil: 1H NMR (CDCl3,
oil: 1H NMR (CDCl3, 400 MHz)
d 1.27 (m, 6H), 1.50 (br m, 2H), 1.78
(br m, 2H), 2.48 (m, 2H), 2.81 (m, 2H), 3.18 (m, 2H), 3.49 (m, 1H),
3.82 (m, 2H), 4.10 (m, 1H), 4.22 (m, 4H), 5.12 (s, 2H), 7.32e7.38
(m, 5H); 13C NMR (CDCl3, 100 MHz)
d
14.0, 31.4, 38.6, 39.2, 40.2,
400 MHz)
d
1.44 (d, 3H, J¼6.5 Hz), 1.49e1.67 (m, 3H), 1.85 (m, 1H),
Please cite this article in press as: Kuethe, J. T.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.064

8
J.T. Kuethe et al. / Tetrahedron xxx (2014) 1e8
3.13 (m, 2H), 3.42 (m, 1H), 3.84 (m, 2H), 4.59 (q, 1H, J¼6.5 Hz), 5.14
(s, 2H), 7.36 (m, 10H)); 13C NMR (CDCl3, 100 MHz)
24.8, 30.4, 32.1,
Anal. Calcd for C18H21NO$H2O: C, 75.76; H, 8.12; N, 4.91. Found: C,
76.92; H, 8.18; N, 4.94.
d
41.3, 41.5, 67.0, 71.5, 74.7,126.1,127.4,127.8,127.9,128.4,128.5,137.0,
144.4, 155.3. Anal. Calcd for C21H25NO3: C, 74.31; H, 7.42; N, 4.13.
Found: C, 74.17; H, 7.34; N, 4.01.
References and notes
1. A substructure search in SciFinder revealed >11,000 hits, most of which existed
in the form of patents’.
4.3.18. Preparation of (R)-4-(1-phenylethoxy)piperidine (42).
According to general procedure B, hydrogenolysis of 0.46 g
(1.36 mmol) of 41 gave 0.27 g (98%) of 42 as a colorless oil: 1H NMR
2. For a leading reference, see: (a) Menear, K. A.; Javaid, M. H.; Gomez, S.; Hum-
mersone, M. G.; Lence, C. F.; Martin, N. M. B.; Rudge, D. A.; Roberts, C. A.; Blades,
K. PCT Int. Appl., 2009, WO 2009093032 A1, July 30, 2009. (b) Bailey, J. M.;
Bruton, G.; Huxley, A.; Johnstone, V.; Milner, P. H.; Orlek, B. S.; Stemp, G. Synlett
2009, 1051e1054.
(CDCl3, 400 MHz)
(m, 1H), 1.99 (m, 3H), 2.53 (m, 2H), 3.08 (m, 2H), 3.31 (m, 1H), 4.61
(q, 1H), 7.25e7.37 (m, 5H); 13C NMR (CDCl3, 100 MHz)
24.8, 32.4,
34.0, 44.3, 44.5, 72.7, 74.2, 126.0, 127.2, 128.3, 144.7. Anal. Calcd for
13H19NO: C, 76.06; H, 9.33; N, 6.82. Found: C, 75.98; H, 9.26; H,
d
0.1.41 (d, 3H, J¼6.5 Hz), 1.47 (m, 1H), 1.65
d
3. For a leading reference, see: Jones, R. M.; Buzzard, D. J.; Kim, S. H.; Lehmann, J.
PCT Int. Appl., 2012, WO 2012170702 A1, Dec. 13, 2012.
4. For leading references, see: (a) Buchanan, J. L.; Bregman, H.; Chakka, N.; Di-
mauro, E. F.; Du, B.; Nguyen, H. N.; Zheng, X. M. PCT Int. Appl., 2010,
WO2010022055 A1, Feb. 25, 2010. (b) Cambell, S. F.; Danilewicz, J. C.; Green-
grass, C. W.; Plews, R. M. J. Med. Chem. 1988, 31, 516e520; (c) Bregman, H.;
Berry, L.; Buchanan, J. L.; Chen, A.; Du, B.; Feric, E.; Hierl, M.; Huang, L.; Immke,
O.; Janosky, B.; Johnson, D.; Li, X.; Ligutti, J.; Liu, D.; Malmberg, A.; Matson, D.;
McDermott, J.; Miu, P.; Nguyen, H. N.; Patel, V. F.; Waldon, D.; Wilenkin, B.;
Zheng, X. M.; Zou, A.; McDonough, S. I.; Dimauro, E. F. J. Med. Chem. 2011, 54,
4427e4445.
5. For leading references, see: (a) Weis, R.; Faist, J.; di Vora, V.; Schweiger, K.;
Brandner, B.; Kungl, A. J.; Seebacher, W. Eur. J. Med. Chem. 2008, 43, 872e879;
(b) Lapa, G. B.; Byrd, G. D.; Lapa, A. A.; Budygin, E. A.; Childers, S. R.; Jones, S. R.;
Harp, J. J. Bioorg. Med. Chem. Lett. 2005, 15, 4915e4918; (c) Schickaneder, C.;
McGrath, M.; Schaefer, J.; Schubert, J.; Jacob, V.; Maertens, W. Eur. Pat. Appl.,
2011, EP 2371817 A1, Oct. 5, 2011.
C
6.82.
4.3.19. Preparation of benzyl 4-(((1S, 2S)-2-methylcyclohexyl)oxy)
piperidine-1-carboxylate (44). According to general procedure A,
treatment of 0.53 mL (4.29 mmol) of alcohol 43 with 0.58 mL
(4.50 mmol) of TMS-Cl in the presence of 0.82 mL (4.72 mmol) of
diisopropylethylamine followed by reaction with 1.00
g
(4.29 mmol) of 17 in the presence of 0.75 mL (4.72 mmol) of trie-
thylsilane and 0.31 mL (1.72 mmol) of TMS-OTf gave 935 mg (66%)
of 44 as a colorless oil: 1H NMR (CDCl3, 400 MHz)
d 0.99 (m, 4H),
1.19 (m, 3H), 1.41 (m, 1H), 1.57 (m, 3H), 1.73 (m, 4H), 1.98 (m, 1H),
2.84 (m, 1H), 3.23 (m, 2H), 3.54 (m, 1H), 3.85 (m, 2H), 5.14 (s, 2H),
6. For a recent account describing the chemistry utilized in this section, see:
Moore, J. C.; Savile, C. K.; Pannuri, S.; Kosjek, B.; Janey, J. M. Industrially Relevant
Enzymatic Reductions In Comprehensive Chirality; Carreira, E. M., Yamamoto, H.,
Eds.;Vol. 9; Elsevier: Amsterdam, the Netherlands, 2012; Vol. 9, pp 318e341;
and references cited therein.
7.36 (m, 5H); 13C NMR (CDCl3, 100 MHz)
d 19.1, 25.2, 25.6, 30.9, 32.6,
34.1, 38.6, 41.5, 67.0, 72.1, 81.7, 127.8, 127.9, 128.5, 136.9, 155.3. Anal.
Calcd for C20H29NO3: C, 72.47; H, 8.82; N, 4.23. Found: C, 72.21; H,
8.74; N, 4.18.
7. All enzymes employed in the present manuscript were purchased from
CodexisÒ
.
8. Carmeli, R.; Rozen, S. Tetrahedron Lett. 2006, 47, 763e766.
9. Yang, W.-C.; Lu, X.-A.; Kulkarni, S. S.; Hung, S.-C. Tetrahedron Lett. 2003, 44,
7837e7840.
10. (a) Iwanami, K.; Seo, H.; Tobita, Y.; Oriyama, T. Synthesis 2005, 183e186;
(b) Iwanami, K.; Yano, K.; Oriyama, T. Synthesis 2005, 2669e2672; (c) Iwanami,
K.; Yano, K.; Oriyama, T. Chem. Lett. 2007, 36, 38e39.
11. Hatakeyama, S.; Mori, H.; Kitano, K.; Yamada, H.; Nishizawa, M. Tetrahedron Lett.
1994, 35, 4367e4370.
12. Kato, J.; Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1985, 14, 743e744.
13. (a) Sassaman, M. B.; Kotian, K. D.; Surya Prakash, G. K.; Olah, G. A. J. Org. Chem.
1987, 52, 4314e4319; (b) Hartz, N.; Surya Prakash, G. K.; Olah, G. A. Synlett 1992,
569e572.
4.3.20. Preparation of 4-(((1S,2S)-2-methylcyclohexyl)oxy)piperidine
(45). According to general procedure B, hydrogenolysis of 0.72 g
(2.17 mmol) of 44 afforded 0.42 g (98%) of 45 as a colorless oil: 1H
NMR (CDCl3, 400 MHz)
1.55 (m, 1H), 1.71 (m, 2H), 1.88 (m, 4H), 2.56 (m, 2H), 2.79 (m, 1H),
3.04 (m, 2H), 3.38 (m, 1H); 13C NMR (CDCl3, 100 MHz)
19.0, 25.2,
25.6, 32.8, 33.1, 34.1, 34.8, 44.6, 44.7, 73.8, 81.4. Anal. Calcd for
12H23NO: C, 73.04; H, 11.74; N, 7.10. Found: C, 73.18; H, 11.79; N,
d 0.92 (m, 4H), 1.10 (m, 3H), 1.39 (m, 3H),
d
C
7.14.
14. Chandrasekhar, S.; Chandrashekar, G.; Negendra Babu, B.; Vijeender, K.; Ven-
katram redy, K. Tetrahedron Lett. 2004, 45, 5497e5499.
15. Komatsu, N.; Ishida, J.; Suzuki, H. Tetrahedron Lett. 1997, 38, 7219e7222.
16. For a discussion on how certain other metal salts with weakly coordinating
anions can function as Brøsted acids, see: Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B.
Chem.dEur. J. 2004, 10, 484e493.
4.3.21. Preparation of benzyl 4-(benzhydryloxy)piperidine-1-carbox-
ylate (47). According to general procedure A, treatment of 0.89 g
(4.80 mmol) of alcohol 46 with 0.64 mL (5.04 mmol) of TMS-Cl in
the presence of 0.92 mL (5.28 mmol) of diisopropylethylamine
followed by reaction with 1.12 g (4.80 mmol) of 17 in the presence
of 0.84 mL (5.28 mmol) of triethylsilane and 0.53 mL (2.40 mmol) of
TMS-OTf furnished 1.30 g (67%) of 47 as a colorless solid: 1H NMR
17. (a) Evans, P. A.; Cui, J.; Gharpure, S. J. Org. Lett. 2003, 5, 3883e3885; (b) Kuethe, J.
T.; Marcoux, J.-F.; Wong, A.; Wu, J.; Hillier, M. C.; Dormer, P. G.; Davies, I. W.;
Hughes, D. L. J. Org. Chem. 2006, 71, 7378e7379; (c) Reductive etherification on an
amino acid scaffold has been reported on 50 kg scale, see: Bajwa, J. S.; Jiang, X.;
ꢀ
Slade, J.; Pradad, K.; Repic, Blacklock, T. J. Tetrahedron Lett. 2002, 43, 6709e6713.
18. Diisopropylethylamine was also employed as a base, see Experimental section.
19. For a few leading references on this subclass of compounds, see: (a) Regnier, G. L.;
Guillonneau, C. G.; Duhault, J. L.; Tisserand, F. P.; Saint-Romas, G.; Holstorp, S. M.
Eur. J. Med. Chem. 1987, 22, 243e250; (b) Nishikawa, Y.; Shindo, T.; Ishii, K.; Na-
kamura, H.; Kon, T.; Uno, H. J. Med. Chem. 1989, 32, 583e593; (c) Iwasaki, N.;
Sakaguchi, J.; Ohashi, T.; Takahara, E.; Ogawa, N.; Yasuda, S.; Koshinaka, E.; Kato,
H.; Ito, Y.; Sawanishi, H. Chem. Pharm. Bull.1994, 42, 2276e2284; (d) Zhang, M.-Q.;
Wada, Y.; Sato, F.; Timmerman, H. J. Med. Chem.1995, 38, 2472e2477; (e) Kwon, Y.
E.; Park, J. Y.; No, K. T.; Shin, J. H.; Lee, S. K.; Eun, J. S.; Yang, J. H.; Shin, T. Y.; Kim, D.
K.; Chae, B. S.; Leem, J.-Y.; Kim, K. H. Bioorg. Med. Chem. 2007, 15, 6596e6607.
20. For leading references for the asymmetric synthesis of diarylmethanols, see:
(a) Truppo, M.; Pollard, D.; Devine, P. Org. Lett. 2007, 9, 335e338; (b) Li, H.; Zhu, D.;
Hau, L.; Biehl, E. R. Adv. Synth. Catal. 2009, 351, 583e588 and references cited
therein.
(CDCl3, 400 MHz)
3.65 (m, 1H), 3.83 (m, 2H), 5.15 (s, 2H), 5.54 (s, 1H), 7.25e7.40
(m, 15H)); 13C NMR (CDCl3, 100 MHz)
31.0, 41.23, 67.0, 71.6, 80.4,
d 1.65 (br m, 2H), 1.83 (br m, 2H), 3.29 (m, 2H),
d
127.0, 127.5, 127.8, 128.0, 128.4, 128.5,136.9, 142.6, 155.3. Anal. Calcd
for C26H27NO3: C, 77.78; H, 6.78; N, 3.49. Found: C, 77.69; H, 6.63; H,
3.39.
4.3.22. Preparation of 4-(benzhydryloxy)piperidine (48). According
to general procedure B, hydrogenolysis of 0.80 g (1.99 mmol) of 47
gave 0.53 g (99%) of 48 as a colorless oil: 1H NMR (CDCl3, 400 MHz)
21. Satoh, T.; Kimura, T.; Sasaki, Y.; Nagamoto, S. Synthesis 2012, 2091e2101.
22. The synthesis of the hydrochloride salt has been reported, see: Motoki, K.;
Kawagoe, K.; Nishinaka, S.; Masuda, S.; Sakamoto, A.; Kaneko, S.; Arita, T.;
Yokomizo, A. PCT Int. Appl., 2009, WO2009119537 A1, Oct. 1, 2009.
d
0.1.54 (m, 2H), 1,58 (br s, 1H), 1.94 (m, 2H), 2.56 (m, 2H), 3.14
(m, 2H), 3.53 (m, 1H), 5.57 (s, 1H), 7.24e7.41 (m, 10H); 13C NMR
(CDCl3, 100 MHz) 33.0, 44.3, 73.0, 80.0, 127.1, 127.3, 128.3, 142.9.
d
Please cite this article in press as: Kuethe, J. T.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.064