Synthesis of piperidin-4-ones starting from 2-(2-bromo-1,1-dimethylethyl) azetidines and 2-(2-mesyloxyethyl)azetidines through a ring expansion-oxidation protocol

Article abstract of DOI:10.1016/j.tet.2013.01.045

cis-2-(2-Bromo-1,1-dimethylethyl)azetidines were transformed into novel 5,5-dimethylpiperidin-4-ones through a ring expansion-oxidation protocol upon heating in DMSO in the presence of Ag₂CO₃ or AgBF ₄. In addition, several 5,5-nor-dimethyl analogues of the latter piperidin-4-ones were synthesized in a selective way through a similar ring expansion-oxidation approach involving treatment of cis-2-(2-mesyloxyethyl) azetidines with K₂CO₃ in DMSO. Furthermore, both a diastereoselective and an enantioselective reduction of the carbonyl function in piperidin-4-ones were performed through a chemical and an enzymatic approach, respectively. Whereas the NaBH₄-induced reduction proceeded with cis-diastereoselectivity, alcohol dehydrogenase-mediated reductions resulted in either an S- or R-enantioselectivity.

Full text of DOI:10.1016/j.tet.2013.01.045

Tetrahedron 69 (2013) 2603e2607
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of piperidin-4-ones starting from 2-(2-bromo-1,1-
dimethylethyl)-azetidines and 2-(2-mesyloxyethyl)azetidines
through a ring expansioneoxidation protocol
,
,
a
b
Karen Mollet a y, Matthias D’hooghe a , Leen Broeckx , Barbara Danneels ,
*
Tom Desmet b, Norbert De Kimpe a
a Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent,
,
*
Belgium
b Department of Biochemical and Microbial Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
cis-2-(2-Bromo-1,1-dimethylethyl)azetidines were transformed into novel 5,5-dimethylpiperidin-4-ones
through a ring expansioneoxidation protocol upon heating in DMSO in the presence of Ag2CO3 or AgBF4.
In addition, several 5,5-nor-dimethyl analogues of the latter piperidin-4-ones were synthesized in a se-
lective way through a similar ring expansioneoxidation approach involving treatment of cis-2-(2-
mesyloxyethyl)azetidines with K2CO3 in DMSO. Furthermore, both a diastereoselective and an enan-
tioselective reduction of the carbonyl function in piperidin-4-ones were performed through a chemical
and an enzymatic approach, respectively. Whereas the NaBH4-induced reduction proceeded with cis-
diastereoselectivity, alcohol dehydrogenase-mediated reductions resulted in either an S- or R-
enantioselectivity.
Received 29 November 2012
Received in revised form 8 January 2013
Accepted 15 January 2013
Available online 24 January 2013
Keywords:
b
-Lactams
DMSO
Ring expansioneoxidation
Piperidinones
Azetidines
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
and cis-2-(2-mesyloxyethyl)azetidines to the corresponding piperidin-
4-ones through a ring expansioneoxidation protocol upon heating in
The piperidine ring is a ubiquitous structural feature in many
alkaloid natural products and drug candidates.1 Watson et al. have
asserted that during a recent 10-year period thousands of piperi-
dine compounds have been mentioned in clinical and preclinical
studies.2 Among them, piperidin-4-ones represent an important
class of bioactive heterocycles attracting a progressive interest due
to their observed biological and pharmaceutical properties, such as
antiviral, antitumor,3 analgesic,4 local anesthetic,5 antimicrobial,
bactericidal, fungicidal, herbicidal, insecticidal, antihistaminic,
anti-inflammatory, anticancer, CNS stimulant, and depressant ac-
tivities.6 Furthermore, piperidin-4-ones have been used as eligible
intermediates in the synthesis of a variety of biologically active
compounds, including functionalized piperidines, through further
modification of the carbonyl moiety.7
DMSO in the presence of silver or potassium carbonate or silver tetra-
fluoroborate. An analogous transformation of 2-(bromomethyl)pyr-
rolidines into piperidin-3-ones via bicyclic aziridinium salts has
previously been reported by us,8 although it should be mentioned that
2-(halomethyl)pyrrolidines are known to undergo rearrangements
readily.9 Nonetheless, this type of transformations is peculiar, as DMSO
is known to directly oxidize organic halides to the corresponding car-
bonyl compounds, as demonstrated amply by the Kornblum reaction
and its variants.10
In light of the utilityof piperidin-4-ones as synthetic intermediates,
the stereoselective reduction of the carbonyl functionality in these
structures toward the corresponding 4-hydroxypiperidines is in-
vestigated by means of both a chemical and a biocatalytic approach.
Biologically spoken, the 4-hydroxypiperidine motif is of particular
interest due to its presence in a large number of natural products with
a range of bioactivities including antiarrhythmic, antituberculosis,
antidiarrheal and antischizophrenic activity.11
In the present paper, a new and efficient synthetic methodology
toward functionalized piperidin-4-one scaffolds is developed, i.e., a one-
step ring enlargement of cis-2-(2-bromo-1,1-dimethylethyl)azetidines
2. Results and discussion
* Corresponding authors. Tel.: þ32 9 264 93 94; fax: þ32 9 264 62 21 (M.D.); tel.:
þ32 9 264 59 51; fax: þ32 9 264 62 21 (N.D.); e-mail addresses: matthias.dhooghe@
UGent.be (M. D’hooghe), norbert.dekimpe@UGent.be (N. De Kimpe).
Azetidines comprise a valuable class of small-ring azaheterocyclic
compounds with oftenpronounced biological activities.12 In addition,
y
Aspirant of the Research FoundationdFlanders (FWOdVlaanderen).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.045

2604
K. Mollet et al. / Tetrahedron 69 (2013) 2603e2607
azetidines have proven to be excellent building blocks for the syn-
thesis of a large variety of ring-opened and ring-expanded systems
due to the inherent reactivity of the constrained four-membered
ring.13 In previous work, we have demonstrated the applicability of
2-(2-bromo-1,1-dimethylethyl)azetidines as useful intermediates
toward the diastereoselective preparation of 4-cyano-, 4-azido-, 4-
bromo-, 4-fluoro-, 4-acetoxy- and 4-hydroxypiperidines14,15 and,
more recently, we have studied the reactivity of 2-(2-mesyloxyethyl)
azetidines for the stereoselective synthesis of 4-acetoxy-, 4-hydroxy-,
4-bromo-, and 4-formyloxypiperidines, thus providing an easyaccess
to the 5,5-nor-dimethyl analogues of the former piperidines.16
With the intention to further evaluate the intrinsic reactivity of
these classes of azetidines, cis-2-(2-bromo-1,1-dimethylethyl)aze-
tidines 1aed were treated with 5 equiv of AgBF4 in DMSO at 100 ꢀC
for 18 h,17 unexpectedly affording piperidin-4-ones 4aed in a se-
lective way in good yields and high purity (Scheme 1, Table 1). In
order to assess the importance of AgBF4 in this rearrangement, the
use of other inorganic salts was then evaluated. Surprisingly,
treatment of azetidines 1aed with 5 equiv of K2CO3 in DMSO did
not result in the formation of 5,5-dimethylpiperidin-4-ones 4aed,8
but instead complex reaction mixtures were obtained. On the
other hand, treatment of 1-allyl-3-benzyloxy-2-(2-bromo-1,1-
dimethylethyl)azetidine 1a with 5 equiv of Ag2CO3 in DMSO at
100 ꢀC for 18 h again afforded the corresponding 1-allyl-3-
benzyloxy-5,5-dimethylpiperidin-4-on 4a in 87% yield. Appar-
ently, the presence of a silver ion is crucial for the selective for-
mation of 5,5-dimethylpiperidin-4-ones 4aed. This work
comprises the first report of an azetidine-to-piperidinone ring
expansioneoxidation protocol mediated by a silver salt in DMSO.
1-azoniabicyclo[2.2.0]hexanes such as 2aed in azetidine-to-
piperidine rearrangements has previously been established by us,
supported by computational analyses.14e16 The expelled bromide is
unable to induce ring enlargement toward 4-bromopiperidines due
to complexation with the silver ion. The necessity of the silver
counterion is thus based on trapping of the bromide so that ring
transformation toward brominated piperidines is prevented.14,15 The
intermediate bicyclic azetidinium salts 2aed are subsequently con-
verted into piperidines 3aed upon ring enlargement with dime-
thylsulfoxide, which acts as a nucleophile. Abstraction of the acidic
proton at the oxygenated carbon atom results in the liberation of
dimethylsulfide and the formation of piperidin-4-ones 4aed
(Scheme 1). Although no irrefutable proof for this mechanistic ap-
proach is provided here, the previously described selective trans-
formation of cis-azetidines 1 into different cis-piperidines via
nucleophile-induced ring opening of strained intermediates 2 sup-
ports theproposed mechanisticrationale.14e16 Analternativereaction
pathway involving initial formation of monocyclic carbenium ion
intermediates has been excluded in these previous azetidine-to-
piperidine rearrangements, as nucleophilic addition across these
cyclic carbenium ions cannot account for the observed cis-stereo-
specificity. However, in this case, an alternative reaction pathway
involving monocyclic carbenium ion intermediates cannot be com-
pletely excluded. In addition, formation of the corresponding bicyclic
oxiranium ion intermediates has been excluded as well in these
previous studies, as subsequent nucleophilic ring opening would lead
to mixtures of regioisomers.18
In order to broaden the scope of this synthetic transformation,
our interest was directed toward the ring enlargement of cis-2-(2-
5 equiv
R3 R3
O
R3
R3
Ag2CO3, K2CO3 or AgBF4
R2O
R2O
X
DMSO, 100 °C, 18 h
N
R1
N
R1
1
4
O
S
Me
O
B
S Me
-Me2S
Me
Me
R3
H
R3
H
R2O
R2O
R3
R3
N
N
R1
3
R1
2
Scheme 1.
Table 1
Synthesis of piperidin-4-ones 4
mesyloxyethyl)azetidines 1eeg via
a
similar ring expan-
sioneoxidation mechanism. In that respect, azetidines 1eeg were
stirred in DMSO at 100 ꢀC for 18 h in the presence of 5 equiv of
K2CO3, resulting in full conversion of the starting material toward
the desired piperidin-4-ones 4eeg in good yields (Scheme 1, Table
1), together with minor amounts of unidentified side products
(8e27%). However, when wet DMSO was used, in some cases
a substantial amount (up to 70%) of 4-hydroxypiperidines was
obtained along with piperidin-4-ones 4eeg after heating of azeti-
dines 1eeg in DMSO, which might be the result of an incomplete
oxidation reaction or direct hydrolysis of the strained intermediates
2eeg, probably due to the presence of water in DMSO. Moreover,
the addition of K2CO3 appeared to be essential, as piperidin-4-ones
4eeg were formed in very low yields (5e8%) if the reaction was
performed in the absence of K2CO3. In analogy with the above-
described reaction mechanism, the initially formed bicyclic
Compound
R1
R2
R3
X
Reagent
Yield
4a
4a
4b
4c
4d
4e
4f
Allyl
Allyl
tBu
Bn
Bn
Bn
Ph
Ph
Ph
Bn
Bn
Me
Me
Me
Me
Me
H
Br
Br
Br
Br
Br
OMs
OMs
OMs
AgBF4
Ag2CO3
AgBF4
AgBF4
AgBF4
K2CO3
K2CO3
K2CO3
65%
87%
71%
66%
63%
43%
45%
48%
iPr
cHex
iPr
iPr
H
H
4g
cHex
From a mechanistic point of view, the following rationale can be
suggested. Azetidines 1aed are first transformed into highly reactive
bicyclic azetidinium salts 2aed through intramolecular displacement
of the bromide by the nitrogen lone pair. The intermediacy of

K. Mollet et al. / Tetrahedron 69 (2013) 2603e2607
2605
azetidinium ions 2eeg are ring opened by DMSO at the bridgehead
carbon atom in an SN2-type fashion to yield piperidines 3eeg,
which are subsequently transformed into the corresponding
piperidin-4-ones 4eeg upon proton abstraction. The preferential
formation of piperidin-4-ones 4eeg over 4-mesyloxypiperidines
can be attributed to the relative higher nucleophilicity of DMSO
as compared to the mesylate anion, making inactivation of the
latter by complexation unnecessary. This stands in contrast with
conditions, and this field of research has gained an increased rel-
evance over the past few years, especially concerning the synthesis
of important intermediates for pharmaceuticals and bioactive
compounds.19 Therefore, a biocatalytic approach was explored in
this study as an alternative to the well-established metal-catalyzed
asymmetric reductions known in the literature. As a selected ex-
ample, racemic 3-benzyloxy-1-isopropylpiperidin-4-one 4f was
treated with a commercially available S-specific20 or R-specific21
alcohol dehydrogenase in aqueous MES-buffer [2-(N-morpholino)
ethanesulfonic acid] at 30 ꢀC in the presence of NADH. In contrast to
the chemical reduction process, the merit of this enzymatic ap-
proach comprises the S- and R-enantioselective reduction of the
carbonyl functionality, in each case resulting in the formation of
two diastereoisomers (ratio 1/1, based on 1H NMR, Scheme 3). The
four enantiomers 6, 7, 8, and 9 were obtained in analytically pure
form in 43e49% yield by separation of the latter diastereoisomeric
mixtures through column chromatography on silica gel. In order to
establish their enantiomeric ratio, esterification of hydroxypiper-
idines 6, 7, 8, and 9 was performed utilizing 1 equiv of (1S)-
(ꢁ)-camphanic chloride in CH2Cl2 at room temperature for 15 h in
the presence of 0.1 equiv of DMAP [4-(dimethylamino)pyridine]
and 2 equiv of Et3N, pointing to a diastereoisomeric ratio of 99.4/
0.6, 99.4/0.6, 98.1/1.9, and 97.9/2.1 for piperidines 6, 7, 8, and 9,
respectively (based on GC/MS-analysis). Consequently, an enan-
tiomeric ratio of 99.4/0.6, 99.4/0.6, 98.1/1.9, and 97.9/2.1 could be
assigned to 4-hydroxypiperidines 6, 7, 8, and 9 (Scheme 3). The
absolute configurations were assigned by comparison of the ob-
the necessity of
a silver salt for the selective ring expan-
sioneoxidation of 2-(2-bromoethyl)azetidines 1aed toward
piperidin-4-ones 4aed.
As mentioned before, the 4-hydroxypiperidine moiety com-
prises a privileged scaffold that is encountered in many bioactive
compounds exhibiting antiarrhythmic,11b,c antidepressant, hypo-
tensive,11c and anti-inflammatory activity.11d Furthermore, 4-
hydroxypiperidine-containing compounds are used in the treat-
ment of multiple sclerosis,11e rheumatoid arthritis,11e,f Crohn’s
disease,11f tuberculosis,11g diarrhea,11h and schizophrenia.11i In that
respect, the reduction of piperidin-4-ones 4aeg was contemplated
in the next phase. At first, treatment of piperidin-4-ones 4aeg with
2 molar equiv of NaBH4 in MeOH was performed, affording the
corresponding cis-4-hydroxypiperidines 5aeg14,16 in 73e90% yield
after reflux for 2 h (Scheme 2). It should be noted that this NaBH4-
mediated reduction of racemic piperidin-4-ones 4aeg toward 4-
hydroxypiperidines 5aeg proceeded with complete cis-diaster-
eoselectivity. The relative cis-stereochemistry at positions 3 and 4 is
a direct result of the addition of hydride at the carbonyl moiety,
governed by steric hindrance exerted by the benzyloxy substituent.
20
20
served rotation of piperidines 6 ([
a
]
þ27.7ꢀ, CH2Cl2), 7 ([
a]
D
D
Scheme 2.
S-specific
alcohol
R-specific
OH
OH
O
OH
OH
alcohol
BnO
BnO
R
BnO
BnO
BnO
dehydrogenase
dehydrogenase
S
S
R
R
R
S
S
+
+
MES-buffer
NADH
(CH3)2CHOH
30 °C, 18 h
(quant.)
MES-buffer
NADH
(CH3)2CHOH
30 °C, 18 h
(quant.)
N
N
N
N
N
6 (45%)
er 99.4/0.6
7 (43%)
er 99.4/0.6
6/7 = 1/1
4f
8 (49%)
er 98.1/1.9
8/9 = 1/1
9 (44%)
er 97.9/2.1
Scheme 3.
20
20
In a second approach, an enzyme-mediated enantioselective
reduction of piperidin-4-ones was investigated using alcohol de-
hydrogenases. The reduction of carbonyl compounds by alcohol
dehydrogenases and their cofactors has numerous advantages
compared to classical chemical reactions, such as the high level
of enantioselectivity and the environmentally benign reaction
þ7.6ꢀ, CHCl3), 8 ([
a]
ꢁ7.6ꢀ, CHCl3), and 9 ([
a
]
ꢁ27.7ꢀ, CH2Cl2)
D
D
with optical rotations described in the literature for similar 3,4-
dioxygenated piperidines.22 Based on these findings, both chem-
ical and enzymatic reductions can be used in a complementary way
to effect a diastereoselective or enantioselective synthesis of 4-
hydroxypiperidines from piperidin-4-ones, respectively.

2606
K. Mollet et al. / Tetrahedron 69 (2013) 2603e2607
3. Conclusion
(dꢂd, 1H, J¼11.6, 3.4 Hz), 3.46 (dꢂdꢂd, 1H, J¼10.5, 6.7, 3.4 Hz), 4.23
(dꢂd, 1H, J¼10.5, 6.7 Hz), 4.48 and 4.86 (2ꢂd, 2ꢂ1H, J¼11.6 Hz),
7.27e7.42 (m, 5H); 13C NMR (CDCl3, 75 MHz):
¼21.8, 24.9, 26.6,
In conclusion, functionalized 5,5-dimethylpiperidin-4-ones
were prepared in high yields and purity through
mediated ring expansioneoxidation of the corresponding 2-(2-
bromo-1,1-dimethylethyl)azetidines upon treatment with Ag2CO3
or AgBF4 in DMSO at 100 ꢀC. Furthermore, the synthesis of the 5,5-
nor-dimethyl variants of the latter piperidin-4-ones was accom-
d
a
silver-
45.9, 53.2, 53.5, 59.2, 72.6, 78.3, 127.8, 128.0, 128.4, 138.1, 212.6; IR
(ATR):
n
¼1723 (C]O); MS (ESþ): m/z¼290 (MHþ). Mp¼37.3 ꢀC
(column chromatography (SiO2), petroleum ethereethyl acetate
19:1, Rf¼0.15). Yield 71%, yellow crystals. Anal. Calcd for C18H27NO2:
C 74.70, H 9.40, N 4.84. Found: C 74.74, H 9.51, N 4.79.
plished via
a
similar ring expansioneoxidation of 2-(2-
mesyloxyethyl)azetidines upon treatment with K2CO3 in DMSO.
This is the first report on the full conversion of functionalized
azetidines into piperidin-4-ones. In addition, the synthetic appli-
cability of these novel piperidin-4-ones was demonstrated by
means of a chemical and enzymatic reduction, thus affording
a straightforward entry into the biologically relevant class of
4-hydroxypiperidines. Whereas the NaBH4-induced reduction
4.2.1.3. 1-Isopropyl-5,5-dimethyl-3-phenoxypiperidin-4-one
4c. 1H NMR (CDCl3, 300 MHz):
d
¼1.05 and 1.06 (2ꢂd, 2ꢂ3H,
J¼6.6 Hz), 1.07 and 1.38 (2ꢂs, 2ꢂ3H), 2.37 (d, 1H, J¼11.4 Hz), 2.61
(dꢂd,1H, J¼10.6,10.5 Hz), 2.67 (dꢂd,1H, J¼11.4, 3.3 Hz), 2.96 (septet,
1H, J¼6.6 Hz), 3.41 (dꢂdꢂd, 1H, J¼10.5, 6.7, 3.3 Hz), 5.06 (dꢂd, 1H,
J¼10.6, 6.7 Hz), 6.76e6.89, 6.92e6.98 and 7.22e7.33 (3ꢂm, 5H); 13C
NMR (CDCl3, 75 MHz):
d
¼18.0, 18.7, 21.8, 25.0, 46.3, 54.1, 55.2, 61.0,
is characterized by
a
cis-diastereoselectivity, the alcohol
76.9, 115.4, 121.5, 129.5, 158.0, 209.8; IR (ATR):
n
¼1728 (C]O); MS
dehydrogenase-mediated reductions proceeded with S- or
R-enantioselectivity at the carbonyl functionality.
(ESþ): m/z¼262 (MHþ). Column chromatography (SiO2), petroleum
ethereethyl acetate 24:1, Rf¼0.15. Yield 66%, colorless oil. HRMS
(ESI) calcd for C16H24NO2 262.1807 [MþH]þ, found 262.1811.
4. Experimental part
4.1. General
4.2.1.4. 1-Cyclohexyl-5,5-dimethyl-3-phenoxypiperidin-4-one
4d. 1H NMR (CDCl3, 300 MHz):
d
¼1.06 and 1.38 (2ꢂs, 2ꢂ3H),
1.19e1.30, 1.58e1.68 and 1.73e1.85 (3ꢂm, 10H), 2.44 (d, 1H,
J¼11.1 Hz), 2.44e2.54 (m, 1H), 2.67 (dꢂd, 1H, J¼10.5, 10.3 Hz), 2.71
(dꢂd, 1H, J¼11.1, 3.0 Hz), 3.45 (dꢂdꢂd, 1H, J¼10.3, 6.8, 3.0 Hz), 5.05
(dꢂd, 1H, J¼10.5, 6.8 Hz), 6.77e6.97 and 7.16e7.28 (2ꢂm, 5H); 13C
1H NMR spectra were recorded at 300 MHz (JEOL ECLIPSEþ) with
CDCl3 as solvent and tetramethylsilane as internal standard. 13C NMR
spectra were recorded at 75 MHz (JEOL ECLIPSEþ) with CDCl3 as sol-
vent and tetramethylsilane as internal standard. Mass spectra were
obtained with a mass spectrometer Agilent 1100, 70 eV. IR spectra
were measured with a Spectrum One FT-IR spectrophotometer. Ele-
mental analyses were performed with a Perkin Elmer series II CHNS/O
analyzer 2400. High resolution electron spray (ES) mass spectra were
obtained with an Agilent Technologies 6210 Series Time-of-Flight.
Dichloromethane was distilled over calcium hydride, while diethyl
ether was dried over sodium benzophenone ketyl. Other solvents were
used as received from the supplier. Melting points of crystalline
NMR (ref¼CDCl3, 75 MHz): ¼21.8, 25.0, 25.97 26.03, 26.3, 28.9,
d
29.4, 46.4, 55.7, 61.8, 63.2, 77.1, 115.4, 121.5, 129.5, 158.0, 209.9; IR
(ATR):
n
¼1731 (C]O); MS (ESþ): m/z¼302 (MHþ). Mp¼38.5 ꢀC
(column chromatography (SiO2), petroleum ethereethyl acetate
19:1, Rf¼0.20). Yield 63%, white crystals. Anal. Calcd for C19H27NO2:
C 75.71, H 9.03, N 4.65. Found: C 75.64, H 9.17, N 4.71.
4.2.1.5. 1-Isopropyl-3-phenoxypiperidin-4-one
(CDCl3, 300 MHz):
4e. 1H
NMR
d
¼1.09 (d, 6H, J¼6.5 Hz), 2.52e2.70 and
€
compounds were measured with a Buchi 540 apparatus.
3.06e3.13 (2ꢂm, 4H and 1H), 3.00 (septet, 1H, J¼6.5 Hz), 3.42
(dꢂdꢂd, 1H, J¼10.8, 6.3, 2.9 Hz), 4.83 (dꢂd, 1H, J¼10.3, 6.3 Hz),
6.85e6.91, 6.94e7.00 and 7.23e7.31 (3ꢂm, 2H, 1H and 2H); 13C
4.2. Synthetic procedures
NMR (ref¼CDCl3, 75 MHz): ¼18.4, 18.5, 41.0, 49.0, 53.9, 54.0, 79.2,
d
4.2.1. Synthesis of piperidin-4-ones 4. General procedure: To a solu-
tion of azetidine 114 (10 mmol) in DMSO (40 mL) was added AgBF4,
Ag2CO3 or K2CO3 (50 mmol, 5 equiv). After stirring at 100 ꢀC for
18 h, the reaction mixture was poured into water (40 mL) and
extracted with diethyl ether (3ꢂ50 mL). Afterward, the organic
phase was washed intensively with brine (4ꢂ40 mL). Drying
(MgSO4), filtration of the drying agent, and removal of the solvent
afforded piperidin-4-ones 4, which were further purified by col-
umn chromatography on silica gel.
115.5, 121.6, 129.6, 157.7, 205.6; IR (ATR):
n
¼1733 (C]O); MS (ESþ):
m/z¼234 (MHþ). Column chromatography (SiO2), petroleum
ethereethyl acetate 1:1, Rf¼0.10. Yield 43%, colorless oil. HRMS (ESI)
calcd for C14H20NO2 234.1494 [MþH]þ, found 234.1496.
4.2.1.6. 3-Benzyloxy-1-isopropylpiperidin-4-one 4f. 1H NMR
(CDCl3, 300 MHz):
d
¼1.00 (d, 6H, J¼6.6 Hz), 2.36e2.51 and
2.82e2.98 (2ꢂm, 4H and 2H), 3.19 (dꢂdꢂd, 1H, J¼10.7, 6.3, 2.8 Hz),
4.00 (dꢂd, 1H, J¼10.2, 6.3 Hz), 4.49 and 4.84 (2ꢂd, 2ꢂ1H,
J¼12.1 Hz), 7.21e7.36 (m, 5H); 13C NMR (ref¼CDCl3, 75 MHz):
4.2.1.1. 1-Allyl-3-benzyloxy-5,5-dimethylpiperidin-4-one 4a. 1H
d
¼18.38, 18.42, 40.9, 48.8, 54.0, 54.4, 72.4, 80.1, 127.9, 128.0, 128.5,
NMR (CDCl3, 300 MHz):
d
¼1.05 and 1.27 (2ꢂ s, 2ꢂ3H), 2.11 (d, 1H,
137.9, 208.0; IR (ATR):
n
¼1727 (C]O); MS (ESþ): m/z¼248 (MHþ).
J¼11.6 Hz), 2.29 (dꢂd, 1H, J¼10.9, 10.5 Hz), 2.70 (dꢂd, 1H, J¼11.6,
2.9 Hz), 2.97e3.14 (m, 2H), 3.28 (dꢂdꢂd, 1H, J¼10.5, 6.7, 2.9 Hz),
4.31 (dꢂd,1H, J¼10.9, 6.7 Hz), 4.50 and 4.85 (2ꢂd, 2ꢂ1H, J¼11.8 Hz),
5.15e5.23 (m, 2H), 5.84 (dꢂdꢂt, 1H, J¼16.9, 10.3, 6.5 Hz), 7.24e7.41
Column chromatography (SiO2), petroleum ethereethyl acetate 1:1,
Rf¼0.06. Yield 45%, colorless oil. HRMS (ESI) calcd for C15H22NO2
248.1651 [MþH]þ, found 248.1653.
(m, 5H); 13C NMR (CDCl3, 75 MHz):
d
¼21.8, 25.1, 45.7, 59.5, 60.4,
4.2.1.7. 3-Benzyloxy-1-cyclohexylpiperidin-4-one 4g. 1H NMR
65.5, 72.5, 76.9, 118.0, 127.8, 127.9, 128.4, 134.9, 137.8, 211.7; IR
(CDCl3, 300 MHz):
d
¼1.19e1.31, 1.62e1.66 and 1.78e1.81 (3ꢂm, 5H,
(ATR):
n
¼1723 (C]O); MS (ESþ): m/z¼274 (MHþ). Column chro-
1H and 4H), 2.40e2.64 (m, 5H), 3.03e3.09 (m, 1H), 3.29 (dꢂdꢂd,
1H, J¼11.0, 6.5, 2.8 Hz), 4.03 (dꢂd, 1H, J¼10.2, 6.5 Hz), 4.53 and 4.87
(2ꢂd, 2ꢂ1H, J¼12.1 Hz), 7.27e7.39 (m, 5H); 13C NMR (ref¼CDCl3,
matography (SiO2), petroleum ethereethyl acetate 17:1, Rf¼0.14.
Yield 65%, colorless oil. HRMS (ESI) calcd for C17H24NO2 274.1807
[MþH]þ, found 274.1811.
75 MHz):
d
¼26.0, 26.2, 29.0, 29.1, 41.0, 49.2, 54.9, 62.9, 72.2, 80.2,
127.7, 127.8, 128.4, 138.0, 207.6; IR (ATR):
n
¼1727 (C]O); MS (ESþ):
4.2.1.2. 3-Benzyloxy-1-tert-butyl-5,5-dimethylpiperidin-4-one
m/z¼288 (MHþ). Column chromatography (SiO2), petroleum
ethereethyl acetate 4:1, Rf¼0.04. Yield 48%, colorless oil. HRMS
(ESI) calcd for C18H26NO2 288.1964 [MþH]þ, found 288.1965.
4b. 1H NMR (CDCl3, 300 MHz):
(s, 9H), 2.20 (d, 1H, J¼11.6 Hz), 2.31 (dꢂd, 1H, J¼10.5, 10.5 Hz), 2.79
d
¼1.04 and 1.24 (2ꢂs, 2ꢂ3H), 1.08

K. Mollet et al. / Tetrahedron 69 (2013) 2603e2607
2607
4.2.2. Synthesis of cis-4-hydroxypiperidines 5. General procedure: To
References and notes
an ice-cooled solution of piperidin-4-one 4 (10 mmol) in methanol
(40 mL) was added NaBH4 (20 mmol, 2 equiv) in small portions, and
the mixture was heated under reflux for 2 h. Afterward, water
(40 mL) was added, and the resulting mixture was extracted three
times with 30 mL of CH2Cl2. Drying (MgSO4), filtration of the drying
agent, and removal of the solvent afforded cis-4-hydroxypiperidines
5. The spectral data of cis-4-hydroxypiperidines 5 were judged to be
identical to those reported in the literature.14,16
1. O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435.
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4.2.3. Synthesis of (4S)-3-benzyloxy-4-hydroxy-1-isopropylpiperidines
6
and 7. 3-Benzyloxy-1-isopropylpiperidin-4-one 4f (250 mg,
50 mM), NADH (71 mg, 5 mM), isopropylalcohol (1 mL) and an S-
specific alcohol dehydrogenase20 (100 mg) were dissolved in MES-
buffer (19 mL, 50 mM, pH 6.5). The mixture was incubated over-
night in a thermoshaker (Eppendorf) at 300 rpm and 30 ꢀC, yielding
€
9. (a) Harding, K. E.; Burks, S. R. J. Org. Chem. 1984, 49, 40; (b) Sjoholm, A.;
Hemmerling, M.; Pradeille, N.; Somfai, P. J. Chem. Soc., Perkin Trans. 1 2001, 891.
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Alvarez-Manzaneda, E.; Chahboun, R.; Cabrera, E.; Alvarez, E.; Alvarez-Man-
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D.; Hammadi, M. Synth. Commun. 1995, 25, 3145; (d) Dave, P.; Byun, H. S.; Engel,
R. Synth. Commun. 1986, 16, 1343.
(3S,4S)-3-benzyloxy-4-hydroxy-1-isopropylpiperidine
6
and
(3R,4S)-3-benzyloxy-4-hydroxy-1-isopropylpiperidine 7 in quan-
titative yield (ratio 1/1, based on 1H NMR).
11. (a) O’Hagan, D. Nat. Prod. Rep. 1997, 14, 637; (b) Yamamoto, I.; Itoh, M.; Yama-
saki, F.; Miyazaki, Y.; Ogawa, S. Int. Pat. Appl. 2000, WO 2000061557 A1; (c)
Taylor, C. R., Jr.; Stauffer, H. F., Jr. US Pat. Appl. 1985, US 4508724 A; (d) Ger-
onikaki, A.; Hadjipavlou-Litina, D.; Chatziopoulos, C.; Soloupis, G. Molecules
2003, 8, 472; (e) Hesselgesser, J.; Ng, H. P.; Liang, M.; Zheng, W.; May, K.;
Bauman, J. G.; Monahan, S.; Islam, I.; Wei, G. P.; Ghannam, A.; Taub, D. D.;
Rosser, M.; Snider, R. M.; Morrissey, M. M.; Perez, H. D.; Horuk, R. J. Biol. Chem.
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Lopresti-Morrow, L. L.; McClure, K. F.; Mitchell, P. G.; Natarajan, V.; Noe, M. C.;
Pandit, J.; Reeves, L.; Schulte, G. K.; Snow, S. L.; Sweeney, F. J.; Tan, D. H.; Yu, C. H.
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Hurdle, J. G.; Woolhiser, L. K.; Knudson, S. E.; Lenaerts, A. J.; Slayden, R. A.;
McNeil, M. R.; Lee, R. E. Bioorg. Med. Chem. 2009, 17, 3588; (h) James, K. W.; Lea,
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Meyer, F. P. Clin. Pharmacokinet. 1998, 34, 227.
4.2.3.1. (3S,4S)-3-Benzyloxy-4-hydroxy-1-isopropylpiperidine
6. 1H NMR (CDCl3, 300 MHz):
d¼1.03 (d, 6H, J¼6.1 Hz), 1.59
(dꢂdꢂdꢂd, 1H, J¼17.2, 11.2, 5.9, 3.6 Hz), 1.94e2.05 (m, 2H), 2.20
(dꢂd, 1H, J¼11.2, 10.7 Hz), 2.74e2.85 (m, 2H), 3.11 (d, 1H, J¼11.0 Hz),
3.35e3.49 (m, 2H), 4.56 and 4.70 (2ꢂd, 2ꢂ1H, J¼11.6 Hz), 7.30e7.37
(m, 5H); 13C NMR (ref¼CDCl3, 75 MHz):
¼18.2, 18.4, 31.5, 46.6,
d
50.8, 54.4, 72.0, 73.2, 81.5, 127.9, 128.6, 138.5; IR (ATR):
n
¼3445
20
(OH); MS (ESþ): m/z¼250 (MHþ). [
a]
þ27.7ꢀ (c 1.01, CH2Cl2).
D
ee¼98.8%. Column chromatography (SiO2), petroleum ethereethyl
acetate 1:3, Rf¼0.04. Yield 45%, colorless oil. HRMS (ESI) calcd for
C15H24NO2 250.1807 [MþH]þ, found 250.1812.
12. For selected recent reports on bioactive compounds containing the azetidine
ring, see: (a) Evans, G. B.; Fumeaux, R. H.; Greatrex, B.; Murkin, A. S.; Schramm,
V. L.; Tyler, P. C. J. Med. Chem. 2008, 51, 948; (b) Honcharenko, D.; Barman, J.;
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Bajwa, J.; Liu, H.; Parker, D.; Vivelo, J.; Chen, G. P.; Calienni, J.; Villhauer, E.;
Prasad, K.; Repic, O.; Blacklock, T. J. Org. Process Res. Dev. 2007, 11, 825; (d) Ikee,
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4.2.3.2. (3R,4S)-3-Benzyloxy-4-hydroxy-1-isopropylpiperidine
7. [
a
]
20 þ7.6ꢀ (c 0.95, CHCl3). ee¼98.8%. The spectral data of (3R,4S)-
D
3-benzyloxy-4-hydroxy-1-isopropylpiperidine 7 were judged to be
identical to those for cis-3-benzyloxy-4-hydroxy-1-isopropylpi-
peridine 5.16
4.2.4. Synthesis of (4R)-3-benzyloxy-4-hydroxy-1-isopropylpiperi-
dines 8 and 9. The synthesis of (4R)-3-benzyloxy-4-hydroxy-1-
isopropylpiperidines 8 and 9 was analogous to the synthesis of
(4S)-3-benzyloxy-4-hydroxy-1-isopropylpiperidines 6 and 7 using
an R-specific alcohol dehydrogenase,21 yielding (3S,4R)-3-
benzyloxy-4-hydroxy-1-isopropylpiperidine
benzyloxy-4-hydroxy-1-isopropylpiperidine
yield (ratio 1/1, based on 1H NMR).
8
9
and (3R,4R)-3-
in quantitative
4.2.4.1. (3S,4R)-3-Benzyloxy-4-hydroxy-1-isopropylpiperidine
20
8. Yield (49%) Colorless oil. [
a
]
D
ꢁ7.6ꢀ (c 0.98, CHCl3). ee¼96.2%.
17. (a) Ganem, B. Tetrahedron Lett. 1974, 11, 917; (b) Epstein, W. W.; Ollinger, J. J.
Chem. Soc. D 1970, 1338.
18. (a) Tokuda, O.; Aikawa, T.; Ikemoto, T.; Kurimoto, I. Tetrahedron Lett. 2010, 51,
The spectral data of (3S,4R)-3-benzyloxy-4-hydroxy-1-isopropyl-
piperidine 8 were judged to be identical to those for cis-3-
benzyloxy-4-hydroxy-1-isopropylpiperidine 5.16
ꢀ
ꢀ
2832; (b) Boto, A.; Hernandez, R.; de Leon, Y.; Murguía, J. R.; Rodríguez-Afonso,
A. Tetrahedron Lett. 2004, 45, 6841.
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Curr. Opin. Chem. Biol. 2004, 8, 120.
4.2.4.2. (3R,4R)-3-Benzyloxy-4-hydroxy-1-isopropylpiperidine
20
9. [
a
]
ꢁ27.7ꢀ (c 0.97, CH2Cl2). ee¼95.8%. The spectral data
D
of (3R,4R)-3-benzyloxy-4-hydroxy-1-isopropylpiperidine
9 were
judged to be identical to those for (3S,4S)-3-benzyloxy-4-hydroxy-1-
isopropylpiperidine 6.
20. Evozyme ADH 030 from Evocatal (Germany).
21. Evozyme ADH 200 from Evocatal (Germany).
22. (a) Lim, S. M.; Hill, N.; Myers, A. G. J. Am. Chem. Soc. 2009, 131, 5763; (b) Alanine,
A.; Buettelmann, B.; Heitz Neidhart, M. -P.; Jaeschke, G.; Pinard, E.; Wyler, R. Int.
Pat. Appl. 2001, WO 2001081309 A2; (c) Kubota, D.; Ishikawa, M.; Ishikawa, M.;
Yahata, N.; Murakami, S.; Fujishima, K.; Kitakaze, M.; Ajito, K. Bioorg. Med.
Chem. 2006, 14, 4158; (d) Minato, D.; Arimoto, H.; Nagasue, Y.; Demizu, Y.;
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Acknowledgements
The authors are indebted to Ghent University (GOA/BOF) and
the Research FoundationdFlanders (FWOdVlaanderen) for finan-
cial support.