Access to 2,6-Disubstituted 4-Oxopiperidines Using a 6-Endo-trig Cyclization: Stereoselective Synthesis of Spruce Alkaloid and (+)-241D

Article abstract of DOI:10.1021/acs.joc.7b02799

A synthetic route to cis-2-methyl-4-oxo-6-alkylpiperidines has been developed using a 6-endo-trig cyclization of (E)-enones. The base-mediated intramolecular cyclization was found to be general for both alkyl- and aryl-substituted enones, providing the corresponding 4-oxopiperidines in high yields (80-89%). Stereoselective reduction of the 2,6-cis-disubstituted 4-oxopiperidines then gave the 2,4,6-cis,cis-trisubstituted 4-hydroxypiperidines in high diastereoselectivity. The general nature of this approach was demonstrated with the synthesis of the natural products, spruce alkaloid and (+)-241D.

Full text of DOI:10.1021/acs.joc.7b02799

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Note
Access to 2,6-Disubstituted 4-Oxopiperidines Using a 6-endo-trig
Cyclization: Stereoselective Synthesis of Spruce Alkaloid and (+)-241D
Alexander H. Harkiss, and Andrew Sutherland
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02799 • Publication Date (Web): 08 Dec 2017
Downloaded from http://pubs.acs.org on December 9, 2017
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The Journal of Organic Chemistry
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Access to 2,6ꢀDisubstituted 4ꢀOxopiperidines using a 6ꢀ
endoꢀtrig Cyclization: Stereoselective Synthesis of
Spruce Alkaloid and (+)ꢀ241D
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Alexander H. Harkiss and Andrew Sutherland*
WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow,
Glasgow G12 8QQ, United Kingdom.
Andrew.Sutherland@glasgow.ac.uk
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
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Abstract: A synthetic route to cisꢀ2ꢀmethylꢀ4ꢀoxoꢀ6ꢀalkylpiperidines has been developed using a 6ꢀ
endoꢀtrig cyclization of Eꢀenones. The baseꢀmediated intramolecular cyclization was found to be
general for both alkyl and aryl substituted enones, providing the corresponding 4ꢀoxopiperidines in high
yields (80–89%). Stereoselective reduction of the 2,6ꢀcisꢀdisubstituted 4ꢀoxopiperidines then gave the
2
,4,6ꢀcis,cisꢀtrisubstituted 4ꢀhydroxypiperidines in high diastereoselectivity. The general nature of this
approach was demonstrated with the synthesis of the natural products, spruce alkaloid and (+)ꢀ241D.
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The Journal of Organic Chemistry
The piperidine ring system is found as a key structural element in a vast array of natural products and
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pharmaceutically active compounds. Among the various structural classes, 2,6ꢀcisꢀdialkylpiperidines
have been isolated from plants, insects and amphibians and have demonstrated a wide range of
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biological activities. These include cis,cisꢀ2ꢀmethylꢀ4ꢀhydroxyꢀ6ꢀalkylpiperidines such as spruce
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alkaloid (1), isolated from the Colorado blue spruce, Picea pungens (Figure 1). Interestingly, the
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absolute configuration of spruce alkaloid (1) is not known. The structure was determined from GCꢀMS
data, a racemic synthesis and analogy to similar 2,6ꢀdisubstituted piperidines from conifers, which
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generally possess the same absolute configuration at the C2ꢀmethyl center. Other examples of this class
of alkaloid include (+)ꢀ241D (2), isolated from the skin of the Panamanian poison frog Dendrobates
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speciosus. (+)ꢀ241D (2) and the corresponding 4ꢀpiperidone 3 are potent inhibitors of binding of
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[
H]perhydrohistrionicotoxin to nicotinic acetylcholine receptor ion channels.
Figure 1. Structures of biologically active cisꢀ2,6ꢀdisubstituted piperidines.
As a result of significant biological activity and the common cis,cisꢀ2ꢀmethylꢀ4ꢀhydroxyꢀ6ꢀ
alkylpiperidine framework, there have been significant interest in developing approaches for the
synthesis of these alkaloids. In particular, many strategies have been reported for the asymmetric
5
synthesis of (+)ꢀ241D (2). These include a highly efficient, sixꢀstep approach reported by Ma and Sun
involving the condensation of ethyl acetoacetate with a βꢀamino ester, followed by hydrolytic
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decarboxylation and high pressure hydrogenation (Scheme 1a). This gave (+)ꢀ241D (2) in 46% overall
yield. In contrast, only one asymmetric synthesis has been reported for the proposed structure of spruce
7
alkaloid (1). Helmchen and coꢀworkers used an iridiumꢀcatalyzed allylic cyclization, in combination
with the matched pairing of a chiral allylic carbonate and a chiral phosphoramidite ligand as the key
transformation in a fourteenꢀstep synthesis of spruce alkaloid (1) (Scheme 1b). This approach was also
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used for the preparation of other 2,6ꢀcisꢀdialkylpiperidine alkaloids such as (+)ꢀprosophylline and (+)ꢀ
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41D.
In recent years, we have reported stereoselective methods for the synthesis of highly substituted
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,9
pipecolic acid analogues using a 6ꢀendoꢀtrig cyclization of enoneꢀderived αꢀamino acids. We found
that formation of a particular cyclization conformer using substrate control generated either 2,6ꢀtransꢀ or
2,6ꢀcisꢀ6ꢀsubstituted 4ꢀoxopipecolic acids. We were interested in investigating a similar approach for
the synthesis of cisꢀ2ꢀmethylꢀ4ꢀoxoꢀ6ꢀalkylpiperidines (Scheme 1c). Herein, we now report the use of a
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ꢀendoꢀtrig cyclization of amineꢀsubstituted enones for the preparation of a series of 2ꢀmethylꢀ4ꢀ
hydroxyꢀ6ꢀalkylpiperidines and the application of this approach for the eightꢀstep synthesis of spruce
alkaloid and (+)ꢀ241D.
Scheme 1. Methods for the Synthesis of cis,cis-2-Methyl-4-hydroxy-6-alkylpiperidines
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The Journal of Organic Chemistry
A series of amineꢀsubstituted enones were prepared in five steps from commercially available NꢀBocꢀ
ꢀaspartic acid 4ꢀmethyl ester (4) (Scheme 2). The αꢀcarboxylic acid of 4 was reduced in a twoꢀstage
process involving activation with Nꢀhydroxysuccinimide (NHS) and DCC, followed by reduction of the
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resulting succinimide ester with sodium borohydride. Direct conversion of alcohol 5 to iodide 6 was
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achieved using triphenylphosphine, imidazole and iodine under Tanner’s modified conditions. Basic
hydrodehalogenation under mild conditions allowed the highly efficient synthesis of βꢀhomoalanine
derivative 7. It should be noted that Hünig’s base is required during the hydrodehalogenation to
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neutralize the hydrogen iodide formed and prevent poisoning of the Pd/C catalyst. Reaction of 7 with
the lithium anion of dimethyl methylphosphonate (2.5 equivalents) completed the fourꢀstep synthesis of
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βꢀketophosphonate ester 8 in 72% overall yield. It should be noted that this simple and robust fourꢀ
step synthesis was easily scalable for the efficient multigram synthesis of βꢀketophosphonate ester 8.
HornerꢀWadsworthꢀEmmons (HWE) reaction of 8 with various alkyl and aryl aldehydes gave the
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corresponding Eꢀenones 9a–9h as the sole products in 63–97% yield.
a
Scheme 2. Synthesis of E-Enones 9
a
Isolated yields are shown.
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Enones 9 were then converted to 2,6ꢀdisubstituted 4ꢀoxopiperidines 10 and 11 by acidic removal of
the Bocꢀprotecting group, followed by cyclization of the resulting amine by treatment with DIPEA
(
Table 1). In our previous study involving 6ꢀendoꢀtrig cyclization of αꢀamino acid derived enones, the
use of this twoꢀstep approach gave the corresponding 2,6ꢀcisꢀ6ꢀsubstituted 4ꢀoxopipecolic acids as the
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major products, although with modest diastereoselectivity. As expected of enones 9, with a smaller
methyl group to impart facial selectivity during the conjugate addition, the 2,6ꢀcisꢀ and 2,6ꢀtransꢀ6ꢀ
1
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substituted 4ꢀoxopiperidines were formed in essentially a 1:1 ratio.
However, these structurally more
simple substrates were found to undergo the twoꢀstage deprotection and cyclization in a highly efficient
and general manner, forming the two diastereomers in highly consistent yields (80–89%), irrespective of
the enone sideꢀchain. Furthermore, 4ꢀoxopiperidines 10 and 11 were easily separated by column
chromatography, allowing the isolation of the 2,6ꢀcisꢀdiastereomer in 41–46% yields over two steps.
a
Table 1.
6-Endo-Trig Cyclization of E-Enones 9
entry
R
overall yield (%) 10 (%) 11 (%)
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nꢀPr (9a)
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nꢀnonyl (9b)
CH CH Ph (9c)
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2
Ph (9d)
pꢀMeOPh (9e)
2ꢀNaphth (9f)
pꢀNO Ph (9g)
2
3ꢀPy (9h)
a
Isolated yields are shown.
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The Journal of Organic Chemistry
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To complete the synthesis of spruce alkaloid (1) and (+)ꢀ241D (2) required the stereoselective
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reduction of the 2,6ꢀcisꢀ4ꢀoxopiperidines. We briefly surveyed various reducing agents [e.g. Lꢀ
selectride, NaBH CN and NaBH(OAc) ] and found that sodium borohydride was fast, selective and
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5d,17
high yielding (Scheme 3).
In all cases, this gave a diastereoselective ratio of 9:1 with the major
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cis,cisꢀ4ꢀhydroxypiperidines isolated in 68–91% yields. This completed the total synthesis of spruce
alkaloid (1) and (+)ꢀ241D (2) in eight steps and in 26% and 21% overall yield, respectively, as well as
various novel cis,cisꢀ2ꢀmethylꢀ4ꢀhydroxyꢀ6ꢀarylpiperidines (12c–12f). The relative stereochemistry of
all novel compounds generated from the 6ꢀendoꢀtrig cyclization and the stereoselective reduction was
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confirmed using NOE experiments.
a
Scheme 3. Stereoselective Reduction of 4-Piperidones 10
a
Isolated yields of cis,cisꢀ4ꢀhydroxypiperidines are shown.
In summary, a short and efficient synthesis of a series of amino substituted Eꢀenones was developed
from an
L
ꢀaspartic acid analogue using hydrodehalogenation and HWE reactions as the key steps. These
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compounds were investigated as substrates for a baseꢀmediated 6ꢀendoꢀtrig cyclization. The twoꢀstage
deprotectionꢀcyclization process was highly efficient and tolerant of both aliphatic and aryl side chains.
Stereoselective reduction of the resulting 2,6ꢀcisꢀ4ꢀoxopiperidines completed a new approach for the
preparation of the natural products, spruce alkaloid and (+)ꢀ241D, as well as the synthesis of a series of
novel cis,cisꢀ2ꢀmethylꢀ4ꢀhydroxyꢀ6ꢀarylpiperidines.
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EXPERIMENTAL SECTION
All reagents and starting materials were obtained from commercial sources and used as received. All
dry solvents were purified using a solvent purification system. All reactions were performed in ovenꢀ
dried glassware under an atmosphere of argon unless otherwise stated. Brine refers to a saturated
solution of sodium chloride. Flash column chromatography was performed using silica gel 60 (40–63
ꢀm). Aluminiumꢀbacked plates preꢀcoated with silica gel 60F254 were used for thin layer
1
chromatography and were visualized with a UV lamp or by staining with potassium permanganate. H
NMR spectra were recorded on a NMR spectrometer at either 400 or 500 MHz and data are reported as
follows: chemical shift in ppm relative to tetramethylsilane or the solvent as the internal standard
(CDCl , δ 7.26 ppm or CD OD, δ 3.31 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q =
3
3
13
quartet, m = multiplet or overlap of nonequivalent resonances, integration). C NMR spectra were
recorded on a NMR spectrometer at either 101 or 126 MHz and data are reported as follows: chemical
shift in ppm relative to tetramethylsilane or the solvent as internal standard (CDCl , δ 77.0 ppm or
3
CD OD, δ 49.0 ppm), multiplicity with respect to hydrogen (deduced from DEPT experiments, C, CH,
3
–1
CH or CH ). IR spectra were recorded on a FTIR spectrometer; wavenumbers are indicated in cm .
2
3
Mass spectra were recorded using electrospray techniques. HRMS spectra were recorded using a dualꢀ
focusing magnetic analyzer mass spectrometer. Melting points are uncorrected. Optical rotations were
determined as solutions irradiating with the sodium D line (λ = 589 nm) using a polarimeter. [α] values
D
−
1
2
−1
are given in units 10 deg cm g .
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The Journal of Organic Chemistry
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Methyl (3S)-3-(tert-butoxycarbonylamino)-4-hydroxybutanoate (5). To a solution of NꢀBocꢀLꢀ
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aspartic acid 4ꢀmethyl ester (4) (8.27 g, 33.5 mmol) in ethyl acetate (200 mL) at 0 °C was added Nꢀ
hydroxysuccinimide (4.24 g, 36.9 mmol). N,N'ꢀDicyclohexylcarbodiimide (7.05 g, 34.2 mmol) in ethyl
acetate (20 mL) was then added dropwise. The reaction mixture was allowed to warm to room
temperature and stirred for 16 h. Once the reaction was complete, the reaction mixture was filtered
through Celite. The filtrate was washed with saturated sodium carbonate solution (100 mL), brine (100
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mL), dried (MgSO ) and concentrated in vacuo. The resulting residue was then dissolved in
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tetrahydrofuran (20 mL) and added dropwise to a solution of sodium borohydride (2.03 g, 53.6 mmol)
in a mixture of tetrahydrofuran and water (7.5:1, 85 mL). The reaction mixture was stirred for 0.1 h
before quenching with saturated aqueous ammonium chloride (5 mL). The reaction mixture was
extracted with dichloromethane (3 × 50 mL). The organic fractions were combined, washed with brine
(
100 mL), dried (MgSO ), filtered and concentrated in vacuo. Purification by flash column
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chromatography on silica gel, eluting with 30% ethyl acetate in dichloromethane gave methyl (3S)ꢀ3ꢀ
tertꢀbutoxycarbonylamino)ꢀ4ꢀhydroxybutanoate (5) as a colorless oil (7.03 g, 90%). R 0.22 (40% ethyl
(
f
26
19
23
D
1
acetate in dichloromethane); [α]D +5.6 (c 1.0, CHCl ), lit. [α] +6.3 (c 0.5, CHCl ); H NMR (400
3
3
MHz, CDCl ) δ 1.42 (s, 9H), 2.62 (d, J = 6.1 Hz, 2H), 2.82 (br s, 1H), 3.65–3.73 (m, 5H), 3.92–4.04 (m,
3
1
3
1
H), 5.25 (br s, 1H); C NMR (126 MHz, CDCl ) δ 28.4 (3 × CH ), 35.8 (CH ), 49.4 (CH), 51.9 (CH ),
3 3 2 3
+
6
4.3 (CH ), 79.8 (C), 155.9 (C), 172.3 (C); MS (ESI) m/z 256 (MNa , 100).
2
10
Methyl (3S)-3-(tert-butoxycarbonylamino)-4-iodobutanoate (6). To a suspension of imidazole
(4.11 g, 60.4 mmol) and triphenylphosphine (11.9 g, 45.3 mmol) in a mixture of diethyl ether and
dichloromethane (2:1, 100 mL) at 0 °C was added iodine (11.5 g, 45.3 mmol) in three portions over 0.5
h. After stirring for a further 0.2 h, a solution of methyl (3S)ꢀ3ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀ
hydroxybutanoate (5) (7.03 g, 30.2 mmol) in a mixture of diethyl ether and dichloromethane (2:1, 50
mL) was added and the resulting mixture was stirred for 3 h at room temperature. The reaction mixture
was filtered through Celite and the filtrate was concentrated in vacuo. Purification by flash column
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chromatography on silica gel, eluting with 30% diethyl ether in petroleum ether (40–60) gave methyl
3S)ꢀ3ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀiodobutanoate (6) (9.33 g, 90%) as a colorless oil. Spectroscopic
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
1
0
33
D
data were consistent with the literature. R 0.27 (20% ethyl acetate in petroleum ether); [α] +7.3 (c
f
1
1
1
.0, CHCl ); H NMR (400 MHz, CDCl ) δ 1.40 (s, 9H), 2.60 (dd, J = 16.4, 6.1 Hz, 1H), 2.70 (dd, J =
3 3
13
6.4, 5.6 Hz, 1H), 3.28–3.45 (m, 2H), 3.66 (s, 3H), 3.81–3.95 (m, 1H), 5.11 (d, J = 7.2 Hz, 1H); C
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (101 MHz, CDCl ) δ 11.1 (CH ), 28.3 (3 × CH ), 38.5 (CH ), 47.7 (CH), 51.9 (CH ), 80.0 (C)
3
2
3
2
3
+
1
54.7 (C), 171.1 (C); MS (ESI) m/z 366 (MNa , 100).
2
0
Methyl (3R)-3-(tert-butoxycarbonylamino)butanoate (7). A solution of methyl (3S)ꢀ3ꢀ(tertꢀ
butoxycarbonylamino)ꢀ4ꢀiodobutanoate (6) (9.33 g, 27.2 mmol), N,Nꢀdiisopropylethylamine (7.11 mL,
4
0.8 mmol) and 10% Pd/C (2.89 g, 2.72 mmol) in methanol (50 mL) were purged with hydrogen for 0.5
h. The reaction mixture was stirred under an atmosphere of hydrogen for 18 h at room temperature. The
mixture was then filtered through Celite and the filtrate was concentrated in vacuo. The resulting residue
was dissolved in dichloromethane (100 mL) and washed with a saturated solution of sodium hydrogen
carbonate (50 mL), 1 M hydrochloric acid (50 mL), brine (50 mL), dried over MgSO , filtered and
4
concentrated in vacuo to give methyl (3R)ꢀ3ꢀ(tertꢀbutoxycarbonylamino)butanoate (7) as a colorless oil
2
0
(
5.87 g, 99%). Spectroscopic data were consistent with the literature. R 0.17 (20% ethyl acetate in
f
2
6
1
petroleum ether); [α]D +21.5 (c 1.0, CHCl ); H NMR (500 MHz, CDCl ) δ 1.20 (d, J = 6.8 Hz, 3H),
3
3
1
.43 (s, 9H), 2.47 (dd, J = 15.5, 6.0 Hz, 1H), 2.52 (dd, J = 15.5, 5.4 Hz, 1H), 3.68 (s, 3H), 4.03 (br s,
13
1
H), 4.91 (br s, 1H); C NMR (126 MHz, CDCl ) δ 20.6 (CH ), 28.5 (3 × CH ), 40.8 (CH ), 43.6 (CH),
3
3
3
2
+
51.8 (CH ), 79.4 (C), 155.2 (C), 172.1 (C); MS (ESI) m/z 240 (MNa , 100).
3
(4R)-4-(tert-Butoxycarbonylamino)-1-(dimethyloxyphosphoryl)pentan-2-one
methylphosphonate (3.74 mL, 34.5 mmol) was dissolved in tetrahydrofuran (100 mL) and cooled to −78
C under an argon atmosphere. nꢀButyl lithium (2.5 M, in hexane, 13.8 mL, 34.5 mmol) was added
(8).
Dimethyl
°
dropwise and the mixture was stirred for 0.3 h. A solution of methyl (3R)ꢀ3ꢀ(tertꢀ
butoxycarbonylamino)butanoate (7) (3.00 g, 13.8 mmol) in tetrahydrofuran (20 mL) was added
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The Journal of Organic Chemistry
dropwise. The resulting mixture was then stirred at −78 °C for 0.5 h and allowed to warm to 0 °C over a
period of 1 h. The reaction was quenched with a saturated aqueous solution of ammonium chloride (4
mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were combined, washed
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
with brine (100 mL), dried (MgSO ), filtered and concentrated in vacuo. Purification by flash column
4
chromatography on silica gel, eluting with 40% ethyl acetate in dichloromethane gave (4R)ꢀ4ꢀ(tertꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
butoxycarbonylamino)ꢀ1ꢀ(dimethyloxyphosphoryl)pentanꢀ2ꢀone (8) (3.84 g, 90%) as a colorless oil. Rf
−
1
31
1
0
.19 (100% ethyl acetate); IR (neat) 3316, 2976, 1704, 1700, 1248 cm ; [α] +38.3 (c 1.0, CHCl ); H
D 3
NMR (400 MHz, CDCl ) δ 1.17 (d, J = 6.7 Hz, 3H), 1.39 (s, 9H), 2.71 (dd, J = 16.9, 5.9 Hz, 1H), 2.80
3
(dd, J = 16.9, 5.9 Hz, 1H), 3.03 (dd, J = 22.6, 13.6 Hz, 1H), 3.12 (dd, J = 22.6, 13.6 Hz, 1H), 3.74 (d, J
1
3
= 0.8 Hz, 3H), 3.77 (d, J = 0.8 Hz, 3H), 3.93–4.09 (m, 1H), 4.92 (br s, 1H); C NMR (101 MHz,
CDCl ) δ 20.6 (CH ), 28.4 (3 × CH ), 41.9 (d, J = 127.5 Hz, CH ), 43.3 (CH), 50.2 (CH ), 53.1 (d, J
3
3
3
CꢀP
2
2
Cꢀ
=
6.5 Hz, CH ), 53.2 (d, JCꢀOꢀP = 6.5 Hz, CH ), 79.3 (C), 155.2 (C), 200.6 (C); MS (ESI) m/z 332
3 3
OꢀP
+
+
(MNa , 100); HRMS (ESI) calcd for C H NNaO P (MNa ), 332.1233, found 332.1225.
1
2
24
6
(2R,5E)-2-(tert-Butoxycarbonylamino)-4-oxonona-5-ene (9a). (4R)ꢀ4ꢀ(tertꢀButoxycarbonylamino)ꢀ1ꢀ
(dimethyloxyphosphoryl)pentanꢀ2ꢀone (8) (0.421 g, 1.36 mmol) was dissolved in anhydrous acetonitrile
(14 mL) and potassium carbonate (0.225 g, 1.63 mmol) was added. The mixture was stirred at room
temperature for 0.5 h followed by addition of butyraldehyde (0.250 mL, 2.72 mmol). The temperature
was increased to 50 °C and the mixture stirred for 72 h. The solution was then concentrated in vacuo,
redissolved in ethyl acetate (20 mL), washed with water (2 × 15 mL) and then brine (15 mL). The
organic layer was dried (MgSO ) and concentrated in vacuo. Purification using a plug of silica gel,
4
eluting with 20% ethyl acetate in petroleum ether (40–60) gave (2R,5E)ꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ
4
ꢀoxononaꢀ5ꢀene (9a) as a clear colorless oil (0.337 g, 97%). R 0.24 (20% ethyl acetate/petroleum
f
−
1
26
D
1
ether); IR (neat) 3350, 2968, 1689, 1516, 1365 cm ; [α] +9.3 (c 1.0, CHCl ); H NMR (500 MHz,
3
CDCl ) δ 0.94 (t, J = 7.3 Hz, 3H), 1.20 (d, J = 6.9 Hz, 3H), 1.43 (s, 9H), 1.46–1.55 (m, 2H), 2.20 (qd, J
3
=
6.9, 1.5 Hz, 2H), 2.64 (dd, J = 15.9, 6.5 Hz, 1H), 2.86 (dd, J = 15.9, 4.5 Hz, 1H), 3.98–4.09 (m, 1H),
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13
5
.02 (br s, 1H), 6.09 (dt, J = 15.9, 1.5 Hz, 1H), 6.86 (dt, J = 15.9, 6.9 Hz, 1H); C NMR (126 MHz,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CDCl ) δ 13.7 (CH ), 20.5 (CH ), 21.3 (CH ), 28.4 (3 × CH ), 34.5 (CH ), 43.7 (CH), 45.7 (CH ), 79.1
3
3
3
2
3
2
2
+
(C), 130.8 (CH), 148.2 (CH), 155.2 (C), 199.2 (C); MS (ESI) m/z 278 (MNa , 100); HRMS (ESI) calcd
+
for C H NNaO (MNa ), 278.1727, found 278.1725.
1
4
25
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(2R,5E)-2-(tert-Butoxycarbonylamino)-4-oxopentadec-5-ene (9b). The reaction was carried out
according to the procedure for the synthesis of 9a using (4R)ꢀ4ꢀ(tertꢀbutoxycarbonylamino)ꢀ1ꢀ
(dimethyloxyphosphoryl)pentanꢀ2ꢀone (8) (0.405 g, 1.31 mmol) and decanal (0.500 mL, 2.62 mmol) for
9
6 h. Purification by flash column chromatography on silica gel, eluting with 30% diethyl ether in
petroleum ether (40–60) gave (2R,5E)ꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀoxopentadecꢀ5ꢀene (9b) (0.345
g, 78%) as a colorless oil. R 0.25 (30% diethyl ether in petroleum ether); IR (neat) 3327, 2958, 1693,
f
−
1
25
1
1
365 cm ; [α] +4.2 (c 1.0, CHCl ); H NMR (400 MHz, CDCl ) δ 0.88 (t, J = 6.3 Hz, 3H), 1.20 (d, J
D 3 3
=
6.7 Hz, 3H), 1.23–1.34 (m, 12H), 1.39–1.50 (m, 11H), 2.20 (q, J = 7.0 Hz, 2H), 2.63 (dd, J = 15.7, 6.6
Hz, 1H), 2.85 (dd, J = 15.7, 4.5 Hz, 1H), 3.96–4.08 (m, 1H), 4.95 (br s, 1H), 6.08 (d, J = 15.6 Hz, 1H),
13
6.85 (dt, J = 15.6, 7.0 Hz, 1H); C NMR (126 MHz, CDCl ) δ 14.1 (CH ), 20.5 (CH ), 22.7 (CH ), 28.1
3
3
3
2
(CH ), 28.4 (3 × CH ), 29.2 (CH ), 29.3 (CH ), 29.4 (CH ), 29.5 (CH ), 31.9 (CH ), 32.5 (CH ), 43.7
2 3 2 2 2 2 2 2
+
(
CH), 45.7 (CH ), 79.2 (C), 130.6 (CH), 148.5 (CH), 155.2 (C), 199.2 (C); MS (ESI) m/z 362 (MNa ,
2
+
100); HRMS (ESI) calcd for C H NNaO (MNa ), 362.2666, found 362.2649.
2
0
37
3
(2R,5E)-8-Phenyl-2-(tert-butoxycarbonylamino)-4-oxooct-5-ene (9c). The reaction was carried out
according to the procedure for the synthesis of 9a using (4R)ꢀ4ꢀ(tertꢀbutoxycarbonylamino)ꢀ1ꢀ
(dimethyloxyphosphoryl)pentanꢀ2ꢀone (8) (0.349 g, 1.13 mmol) and hydrocinnamaldehyde (0.300 mL,
2.26 mmol) for 48 h. Purification by flash column chromatography on silica gel, eluting with 20% ethyl
acetate in petroleum ether (40–60) gave (2R,5E)ꢀ8ꢀphenylꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀoxooctꢀ5ꢀ
ene (9c) (0.288 g, 80%) as a pale yellow oil. R 0.19 (20% ethyl acetate in petroleum ether); IR (neat)
f
−1
23
D
1
3353, 2976, 1692, 1496, 1247, 1221, 1054 cm ; [α]
+4.1 (c 1.0, CHCl ); H NMR (400 MHz,
3
CDCl ) δ 1.17 (d, J = 6.7 Hz, 3H), 1.43 (s, 9H), 2.53 (q, J = 6.8 Hz, 2H), 2.60 (dd, J = 15.7, 7.8 Hz,
3
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1
H), 2.77 (t, J = 6.8 Hz, 2H), 2.84 (dd, J = 15.7, 4.5 Hz, 1H), 3.95–4.08 (m, 1H), 4.99 (br s, 1H), 6.09
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
(d, J = 15.9 Hz, 1H), 6.87 (dt, J = 15.9, 6.8 Hz, 1H), 7.14–7.23 (m, 3H), 7.25–7.32 (m, 2H); C NMR
(101 MHz, CDCl ) δ 20.5 (CH ), 28.4 (3 × CH ), 34.2 (CH ), 34.3 (CH ), 43.7 (CH), 45.8 (CH ), 79.1
3
3
3
2
2
2
(C), 126.2 (CH), 128.3 (2 × CH), 128.5 (2 × CH), 131.0 (CH), 140.6 (C), 146.9 (CH), 155.1 (C), 198.9
+
+
(C); MS (ESI) m/z 340 (MNa , 100); HRMS (ESI) calcd for C H NNaO (MNa ), 340.1883, found
19 27 3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
40.1868.
(2R,5E)-6-Phenyl-2-(tert-butoxycarbonylamino)-4-oxohex-5-ene (9d). The reaction was carried out
according to the procedure for the synthesis of 9a using (4R)ꢀ4ꢀ(tertꢀbutoxycarbonylamino)ꢀ1ꢀ
(dimethyloxyphosphoryl)pentanꢀ2ꢀone (8) (0.251 g, 0.810 mmol) and benzaldehyde (0.160 mL, 1.62
mmol) for 48 h. Purification by flash column chromatography on silica gel, eluting with 20% ethyl
acetate in petroleum ether (40–60) gave (2R,5E)ꢀ6ꢀphenylꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀoxohexꢀ5ꢀ
ene (9d) (0.227 g, 97%) as a white solid. Mp 59–62 °C; R 0.18 (20% ethyl acetate in petroleum ether);
f
−
1
23
D
1
IR (neat) 3345, 2976, 1687, 1655, 1608, 1495 cm ; [α] +10.0 (c 1.0, CHCl ); H NMR (400 MHz,
3
CDCl ) δ 1.25 (d, J = 6.8 Hz, 3H), 1.43 (s, 9H), 2.77 (dd, J = 15.8, 6.8 Hz, 1H), 3.00 (dd, J = 15.8, 4.6
3
Hz, 1H), 4.05–4.18 (m, 1H), 5.04 (br s, 1H), 6.73 (d, J = 16.2 Hz, 1H), 7.36–7.41 (m, 3H), 7.52–7.54
1
3
(m, 2H), 7.56 (d, J = 16.2 Hz, 1H); C NMR (101 MHz, CDCl ) δ 20.6 (CH ), 28.4 (3 × CH ), 43.8
3 3 3
(CH), 46.6 (CH ), 79.2 (C), 126.4 (CH), 128.4 (2 × CH), 129.0 (2 × CH), 130.6 (CH), 134.4 (C), 143.2
2
+
(CH), 155.2 (C), 198.9 (C); MS (ESI) m/z 312 (MNa , 100); HRMS (ESI) calcd for C H NNaO
1
7
23
3
+
(MNa ), 312.1570, found 312.1558.
(2R,5E)-6-(4’-Methoxyphenyl)-2-(tert-butoxycarbonylamino)-4-oxohex-5-ene (9e). The reaction was
carried out according to the procedure for the synthesis of 9a using (4R)ꢀ4ꢀ(tertꢀbutoxycarbonylamino)ꢀ
ꢀ(dimethyloxyphosphoryl)pentanꢀ2ꢀone (8) (0.241 g, 0.781 mmol) and anisaldehyde (0.190 mL, 1.56
1
mmol) for 96 h. Purification by flash column chromatography on silica gel, eluting with 20% ethyl
acetate in petroleum ether (40–60) gave (2R,5E)ꢀ6ꢀ(4’ꢀmethoxyphenyl)ꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ
4
ꢀoxohexꢀ5ꢀene (9e) (0.186 g, 75%) as a white solid. Mp 102–105 °C; R 0.10 (20% ethyl acetate in
f
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−
1
23
D
1
petroleum ether); IR (neat) 3375, 2980, 1682, 1600, 1511 cm ; [α] +50.1 (c 1.0, CHCl ); H NMR
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
400 MHz, CDCl ) δ 1.24 (d, J = 6.8 Hz, 3H), 1.43 (s, 9H), 2.74 (dd, J = 15.7, 6.8 Hz, 1H), 2.97 (dd, J =
3
15.7, 4.5 Hz, 1H), 3.84 (s, 3H), 4.04–4.16 (m, 1H), 5.03 (br s, 1H), 6.62 (d, J = 16.1 Hz, 1H), 6.91 (d, J
1
3
=
8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 16.1 Hz, 1H); C NMR (101 MHz, CDCl ) δ 20.6
3
(CH ), 28.4 (3 × CH ), 43.9 (CH), 46.4 (CH ), 55.4 (CH ), 79.2 (C), 114.4 (2 × CH), 124.2 (CH), 127.0
3 3 2 3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
(C), 130.1 (2 × CH), 143.1 (CH), 155.2 (C), 161.7 (C), 198.8 (C); MS (ESI) m/z 342 (MNa , 100);
+
HRMS (ESI) calcd for C H NNaO (MNa ), 342.1676, found 342.1661.
1
8
25
4
(2R,5E)-6-(Naphthalen-2’-yl)-2-(tert-butoxycarbonylamino)-4-oxohex-5-ene (9f). The reaction was
carried out according to the procedure for the synthesis of 9a using (4R)ꢀ4ꢀ(tertꢀbutoxycarbonylamino)ꢀ
1
1
ꢀ(dimethyloxyphosphoryl)pentanꢀ2ꢀone (8) (0.262 g, 0.849 mmol) and 2ꢀnaphthaldehyde (0.265 g,
.70 mmol) for 48 h. Purification by flash column chromatography on silica gel, eluting with 30% ethyl
acetate in petroleum ether (40–60) gave (2R,5E)ꢀ6ꢀ(naphthalenꢀ2’ꢀyl)ꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀ
oxohexꢀ5ꢀene (9f) (0.231 g, 80%) as a white solid. Mp 103–106 °C; R 0.35 (30% ethyl acetate in
f
−
1
23
D
1
petroleum ether); IR (neat) 3358, 2972, 1683, 1518, 1364 cm ; [α] +30.4 (c 1.0, CHCl ); H NMR
3
(400 MHz, CDCl ) δ 1.27 (d, J = 6.7 Hz, 3H), 1.44 (s, 9H), 2.81 (dd, J = 15.9, 6.7 Hz, 1H), 3.04 (dd, J =
3
1
5.9, 4.4 Hz, 1H), 4.07–4.21 (m, 1H), 5.00 (br s, 1H), 6.85 (d, J = 16.1 Hz, 1H), 7.48–7.56 (m, 2H),
13
7.68 (dd, J = 8.6, 1.2 Hz, 1H), 7.75 (d, J = 16.1 Hz, 1H), 7.81–7.90 (m, 3H), 7.97 (br s, 1H); C NMR
(101 MHz, CDCl ) δ 20.6 (CH ), 28.4 (3 × CH ), 43.9 (CH), 46.7 (CH ), 79.2 (C), 123.5 (CH), 126.4
3 3 3 2
(CH), 126.8 (CH), 127.4 (CH), 127.8 (CH), 128.6 (CH), 128.7 (CH), 130.5 (CH), 131.9 (C), 133.3 (C),
+
1
34.4 (C), 143.2 (CH), 155.2 (C), 198.8 (C); MS (ESI) m/z 362 (MNa , 100); HRMS (ESI) calcd for
+
C H NNaO (MNa ), 362.1727, found 362.1710.
21
25
3
(2R,5E)-6-(4’-Nitrophenyl)-2-(tert-butoxycarbonylamino)-4-oxohex-5-ene (9g). The reaction was
carried out according to the procedure for the synthesis of 9a using (4R)ꢀ4ꢀ(tertꢀbutoxycarbonylamino)ꢀ
1ꢀ(dimethyloxyphosphoryl)pentanꢀ2ꢀone (8) (0.209 g, 0.676 mmol) and 4ꢀnitrobenzaldehyde (0.204 g,
1
.35 mmol) for 6 h. Purification by flash column chromatography on silica gel, eluting with 30% ethyl
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The Journal of Organic Chemistry
acetate in petroleum ether (40–60) gave (2R,5E)ꢀ6ꢀ(4’ꢀnitrophenyl)ꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
oxohexꢀ5ꢀene (9g) (0.143 g, 63%) as a pale yellow solid. Mp 122–126 °C; R 0.19 (30% ethyl acetate in
f
−
1
26
D
1
petroleum ether); IR (neat) 3365, 2980, 1683, 1612, 1514 cm ; [α] +14.7 (c 1.0, CHCl ); H NMR
3
(
400 MHz, CDCl ) δ 1.27 (d, J = 6.7 Hz, 3H), 1.43 (s, 9H), 2.80 (dd, J = 15.8, 6.7 Hz, 1H), 3.06 (dd, J =
3
1
5.8, 4.2 Hz, 1H), 4.07–4.20 (m, 1H), 4.94 (br s, 1H), 6.86 (d, J = 16.2 Hz, 1H), 7.63 (d, J = 16.2 Hz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
H), 7.72 (d, J = 8.8 Hz, 2H), 8.26 (d, J = 8.8 Hz, 2H); C NMR (101 MHz, CDCl ) δ 20.6 (CH ), 28.4
3
3
(
3 × CH ), 43.8 (CH), 47.4 (CH ), 79.4 (C), 124.2 (2 × CH), 128.9 (2 × CH), 129.6 (CH), 140.0 (CH),
3 2
+
1
40.7 (C), 148.6 (C), 155.2 (C), 198.2 (C); MS (ESI) m/z 357 (MNa , 100); HRMS (ESI) calcd for
+
C H N NaO (MNa ), 357.1421, found 357.1405.
17 22
2
5
(
2R,5E)-6-(Pyridin-3’-yl)-2-(tert-butoxycarbonylamino)-4-oxohex-5-ene (9h). The reaction was
carried out according to the procedure for the synthesis of 9a using (4R)ꢀ4ꢀ(tertꢀbutoxycarbonylamino)ꢀ
ꢀ(dimethyloxyphosphoryl)pentanꢀ2ꢀone (8) (0.212 g, 0.687 mmol) and 3ꢀpyridinecarboxaldehyde
0.130 mL, 1.37 mmol) for 24 h. Purification by flash column chromatography on silica gel, eluting
with 40% ethyl acetate in dichloromethane gave (2R,5E)ꢀ6ꢀ(pyridinꢀ3’ꢀyl)ꢀ2ꢀ(tertꢀ
butoxycarbonylamino)ꢀ4ꢀoxohexꢀ5ꢀene (9h) (0.130 g, 65%) as an offꢀwhite solid. Mp 93–96 °C; R 0.1
1
(
f
−
1
26
D
(
40% ethyl acetate in dichloromethane); IR (neat) 3362, 2970, 1678, 1519, 1365 cm ; [α]
+6.0 (c
1
1.0, CHCl ); H NMR (400 MHz, CDCl ) δ 1.26 (d, J = 6.8 Hz, 3H), 1.43 (s, 9H), 2.78 (dd, J = 15.8,
3
3
6
1
1
7
.8 Hz, 1H), 3.03 (dd, J = 15.8, 4.6 Hz, 1H), 4.06–4.19 (m, 1H), 5.03 (br s, 1H), 6.81 (d, J = 16.3 Hz,
H), 7.35 (dd, J = 7.9, 4.1 Hz, 1H), 7.59 (d, J = 16.3 Hz, 1H), 7.85–7.91 (m, 1H), 8.62 (d, J = 4.1 Hz,
1
3
H), 8.77 (br s, 1H); C NMR (101 MHz, CDCl ) δ 20.6 (CH ), 28.4 (3 × CH ), 43.8 (CH), 47.1 (CH ),
3
3
3
2
9.3 (C), 123.8 (CH), 128.0 (CH), 130.3 (C), 134.4 (CH), 139.3 (CH), 150.1 (CH), 151.2 (CH), 155.2
+
+
(
C), 198.3 (C); MS (ESI) m/z 313 (MNa , 100); HRMS (ESI) calcd for C H N NaO (MNa ),
16 22 2 3
3
13.1523, found 313.1513.
(2R,6S)-2-Methyl-6-propylpiperidin-4-one (10a) and (2R,6R)-2-methyl-6-propylpiperidin-4-one
(11a). (2R,5E)ꢀ2ꢀ(tertꢀButoxycarbonylamino)ꢀ4ꢀoxononaꢀ5ꢀene (9a) (0.298 g, 1.17 mmol) was
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Page 16 of 29
dissolved in dichloromethane (12 mL) and trifluoroacetic acid (0.890 mL, 11.7 mmol) was added
dropwise. The mixture was stirred for 1.5 h at room temperature. The mixture was then concentrated in
vacuo and the crude residue was redissolved in methanol (12 mL) and cooled to 0 °C. N,Nꢀ
Diisopropylethylamine (0.300 mL, 1.75 mmol) was added dropwise and the mixture was allowed to
warm to room temperature and left to stir for 2 h. The mixture was then diluted with ethyl acetate (15
mL) and washed with a saturated aqueous solution of sodium hydrogen carbonate (10 mL) and brine (10
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mL). The organic layer was dried over MgSO and concentrated in vacuo. Purification by flash column
4
chromatography on silica gel (soaked with 1% triethylamine/dichloromethane), with a gradient elution
from 40% ethyl acetate/10% dichloromethane/1% triethylamine in petroleum ether (40–60) to 40%
ethyl acetate/30% dichloromethane/1% triethylamine in petroleum ether (40–60) gave (2R,6S)ꢀ2ꢀ
methylꢀ6ꢀpropylpiperidinꢀ4ꢀone (10a) (0.0780 g, 43%) as a dark orange oil. Further elution yielded
(2R,6R)ꢀ2ꢀmethylꢀ6ꢀpropylpiperidinꢀ4ꢀone (11a) (0.0760 g, 42%) as a dark orange oil. Data for (2R,6S)ꢀ
2ꢀmethylꢀ6ꢀpropylpiperidinꢀ4ꢀone (10a): R 0.47 (40% ethyl acetate/30% dichloromethane/1%
f
−
1
26
D
1
triethylamine in petroleum ether); IR (neat) 3302, 2962, 1658, 1527 cm ; [α] +9.8 (c 0.2, CHCl ); H
3
NMR (400 MHz, CDCl ) δ 0.93 (t, J = 7.2 Hz, 3H), 1.21 (d, J = 6.2 Hz, 3H), 1.29–1.68 (m, 5H), 1.99–
3
2
.12 (m, 2H), 2.30–2.39 (m, 2H), 2.85 (tdd, J = 9.1, 6.2, 2.9 Hz, 1H), 2.96 (dqd, J = 12.4, 6.2, 2.9 Hz,
1
3
1
H); C NMR (101 MHz, CDCl ) δ 14.1 (CH ), 18.9 (CH ), 22.7 (CH ), 39.2 (CH ), 48.2 (CH ), 50.2
3
3
2
3
2
2
+
(
CH ), 52.1 (CH), 56.3 (CH), 209.6 (C); MS (ESI) m/z 156 (MH , 100); HRMS (ESI) calcd for
2
+
C H NO (MH ), 156.1383, found 156.1377. Data for (2R,6R)ꢀ2ꢀmethylꢀ6ꢀpropylpiperidinꢀ4ꢀone (11a):
9
18
R 0.23 (40% ethyl acetate/30% dichloromethane/1% triethylamine in petroleum ether); IR (neat) 3271,
f
−1
26
1
2
954, 1720, 1535 cm ; [α] −7.9 (c 0.1, CHCl ); H NMR (400 MHz, CDCl ) δ 0.92 (t, J = 7.1 Hz,
D 3 3
3
H), 1.16 (d, J = 6.5 Hz, 3H), 1.23–1.52 (m, 4H), 1.61 (br s, 1H), 2.14 (dddd, J = 13.6, 11.6, 6.0, 1.6
1
3
Hz, 2H), 2.47 (dddd, J = 15.6, 14.0, 5.2, 1.6 Hz, 2H), 3.27–3.36 (m, 1H), 3.39–3.49 (m, 1H); C NMR
(
101 MHz, CDCl ) δ 13.9 (CH ), 19.3 (CH ), 21.6 (CH ), 36.9 (CH ), 47.8 (CH and CH), 49.6 (CH ),
3
3
2
3
2
2
2
+
+
5
1
2.3 (CH), 210.0 (C); MS (ESI) m/z 156 (MH , 100); HRMS (ESI) calcd for C H NO (MH ),
9
18
56.1383, found 156.1378.
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The Journal of Organic Chemistry
5
d
(
2R,6S)-2-Methyl-6-nonylpiperidin-4-one (10b) and (2R,6R)-2-methyl-6-nonylpiperidin-4-one
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
11b). The reaction was carried out according to the procedure for the synthesis of 10a and 11a using
(2R,5E)ꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀoxopentadecꢀ5ꢀene (9b) (0.30 g, 0.89 mmol). Purification by
flash column chromatography on silica gel, (soaked with 1% triethylamine/petroleum ether) eluting with
2
0% ethyl acetate/1% triethylamine in petroleum ether (40–60) gave (2R,6S)ꢀ2ꢀmethylꢀ6ꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
nonylpiperidinꢀ4ꢀone (10b) (0.095 g, 45%) as an orange oil. Further elution yielded (2R,6R)ꢀ2ꢀmethylꢀ
6
ꢀnonylpiperidinꢀ4ꢀone (11b) (0.093 g, 44%) as an orange oil. Data for (2R,6S)ꢀ2ꢀmethylꢀ6ꢀ
26
D
nonylpiperidinꢀ4ꢀone (10b): R 0.22 (20% ethyl acetate/1% triethylamine in petroleum ether); [α]
f
5
d
22
1
−
2.4 (c 1.0, CHCl ), lit. [α] −1.5 (c 1.0, CHCl ); H NMR (400 MHz, CDCl ) δ 0.88 (t, J = 6.2 Hz,
3 D 3 3
3H), 1.21 (d, J = 5.8 Hz, 3H), 1.23–1.61 (m, 17H), 1.99–2.12 (m, 2H), 2.24–2.45 (m, 2H), 2.77–2.89
13
(m, 1H), 2.90–3.04 (m, 1H); C NMR (101 MHz, CDCl ) δ 14.1 (CH ), 22.7 (CH and CH ), 25.7
3
3
3
2
(CH ), 29.3 (CH ), 29.5 (2 × CH ), 29.6 (CH ), 31.9 (CH ), 37.1 (CH ), 48.2 (CH ), 50.2 (CH ), 52.1
2
2
2
2
2
2
2
2
+
(CH), 56.6 (CH), 209.6 (C); MS (ESI) m/z 240 (MH , 100). Data for (2R,6R)ꢀ2ꢀmethylꢀ6ꢀ
nonylpiperidinꢀ4ꢀone (11b): R 0.07 (20% ethyl acetate/1% triethylamine in petroleum ether); IR (neat)
f
−1
26
1
3
300, 2958, 1710, 1458 cm ; [α] −3.5 (c 1.0, CHCl ); H NMR (400 MHz, CDCl ) δ 0.88 (t, J = 6.3
D 3 3
Hz, 3H), 1.16 (d, J = 6.4 Hz, 3H), 1.20–1.54 (m, 17H), 2.09–2.20 (m, 2H), 2.42–2.54 (m, 2H), 3.24–
1
3
3
.34 (m, 1H), 3.39–3.49 (m, 1H); C NMR (101 MHz, CDCl ) δ 14.1 (CH ), 21.7 (CH ), 22.7 (CH ),
3 3 3 2
2
6.1 (CH ), 29.3 (CH ), 29.5 (CH ), 29.5 (CH ), 29.6 (CH ), 31.9 (CH ), 34.8 (CH ), 47.8 (CH), 47.8
2
2
2
2
2
2
2
+
(CH ), 49.6 (CH ), 52.7 (CH), 210.0 (C); MS (ESI) m/z 240 (MH , 100); HRMS (ESI) calcd for
2 2
+
C H NO (MH ), 240.2322, found 240.2316.
15
30
(2R,6S)-2-Methyl-6-(2’-phenylethyl)piperidin-4-one
(10c)
and
(2R,6R)-2-methyl-6-(2’-
phenylethyl)piperidin-4-one (11c). The reaction was carried out according to the procedure for the
synthesis of 10a and 11a using (2R,5E)ꢀ8ꢀphenylꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀoxooctꢀ5ꢀene (9c)
(0.133 g, 0.420 mmol). Purification by flash column chromatography on silica gel (soaked with 1%
triethylamine/petroleum ether), with a gradient elution from 60% ethyl acetate/1% triethylamine in
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petroleum ether (40–60) to 90% ethyl acetate/1% triethylamine in petroleum ether (40–60) gave
2R,6S)ꢀ2ꢀmethylꢀ6ꢀ(2’ꢀphenylethyl)piperidinꢀ4ꢀone (10c) (0.0380 g, 42%) as a brown oil. Further
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
elution yielded (2R,6R)ꢀ2ꢀmethylꢀ6ꢀ(2’ꢀphenylethyl)piperidinꢀ4ꢀone (11c) (0.0360 g, 40%) as a brown
oil. Data for (2R,6S)ꢀ2ꢀmethylꢀ6ꢀ(2’ꢀphenylethyl)piperidinꢀ4ꢀone (10c): R 0.32 (60% ethyl acetate/1%
f
−1
26
1
triethylamine in petroleum ether); IR (neat) 3300, 2960, 1714, 1454 cm ; [α]D +2.2 (c 1.0, CHCl ); H
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (500 MHz, CDCl ) δ 1.20 (d, J = 6.2 Hz, 3H), 1.67 (br s, 1H), 1.75–1.91 (m, 2H), 2.04–2.14 (m,
3
2
H), 2.34 (dt, J = 15.0, 5.0 Hz, 1H), 2.41 (dt, J = 15.0, 5.0 Hz, 1H), 2.70 (t, J = 8.0 Hz, 2H), 2.84–2.98
13
(
m, 2H), 7.15–7.32 (m, 5H); C NMR (126 MHz, CDCl ) δ 22.6 (CH ), 32.2 (CH ), 38.6 (CH ), 48.1
3
3
2
2
(
CH ), 50.2 (CH ), 52.0 (CH), 56.1 (CH), 126.1 (CH), 128.3 (2 × CH), 128.5 (2 × CH), 141.4 (C), 209.2
2
2
+
+
(C); MS (ESI) m/z 218 (MH , 100); HRMS (ESI) calcd for C H NO (MH ), 218.1539, found
1
4
20
2
18.1540. Data for (2R,6R)ꢀ2ꢀmethylꢀ6ꢀ(2’ꢀphenylethyl)piperidinꢀ4ꢀone (11c): R 0.11 (60% ethyl
f
−
1
26
D
acetate/1% triethylamine in petroleum ether); IR (neat) 3300, 2926, 1708, 1454 cm ; [α] +6.0 (c 1.0,
1
CHCl ); H NMR (500 MHz, CDCl ) δ 1.14 (d, J = 6.5 Hz, 3H), 1.68–1.86 (m, 3H), 2.13 (ddd, J = 13.8,
3
3
7
.3, 1.4 Hz, 1H), 2.21 (ddd, J = 13.8, 6.0, 1.4 Hz, 1H), 2.47 (ddd, J = 13.8, 4.6, 1.4 Hz, 1H), 2.52 (ddd, J
13.8, 5.1, 1.4 Hz, 1H), 2.61–2.73 (m, 2H), 3.31–3.38 (m, 1H), 3.40–3.48 (m, 1H), 7.15–7.31 (m, 5H);
=
1
3
C NMR (126 MHz, CDCl ) δ 21.6 (CH ), 32.5 (CH ), 36.2 (CH ), 47.8 (CH ), 47.8 (CH), 49.7 (CH ),
3
3
2
2
2
2
+
5
2.3 (CH), 126.0 (CH), 128.3 (2 × CH), 128.5 (2 × CH), 141.4 (C), 209.6 (C); MS (ESI) m/z 218 (MH ,
+
1
00); HRMS (ESI) calcd for C H NO (MH ), 218.1539, found 218.1537.
1
4
20
1
6b
(
(
(
2R,6R)-2-Methyl-6-phenylpiperidin-4-one (10d) and (2R,6S)-2-methyl-6-phenylpiperidin-4-one
11d). The reaction was carried out according to the procedure for the synthesis of 10a and 11a using
2R,5E)ꢀ6ꢀphenylꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀoxohexꢀ5ꢀene (9d) (0.105 g, 0.365 mmol),
dichloromethane (4 mL) and trifluoroacetic acid (0.279 mL, 3.65 mmol). Purification by flash column
chromatography on silica gel (soaked with 1% triethylamine/petroleum ether), with a gradient elution
from 30% ethyl acetate/1% triethylamine in petroleum ether (40–60) to 60% ethyl acetate/1%
triethylamine in petroleum ether (40–60) gave (2R,6R)ꢀ2ꢀmethylꢀ6ꢀphenylpiperidinꢀ4ꢀone (10d) (0.0290
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The Journal of Organic Chemistry
g, 42%) as an orange solid. Further elution yielded (2R,6S)ꢀ2ꢀmethylꢀ6ꢀphenylpiperidinꢀ4ꢀone (11d)
0.0280 g, 40%) as an orange solid. Data for (2R,6R)ꢀ2ꢀmethylꢀ6ꢀphenylpiperidinꢀ4ꢀone (10d): Mp 58–
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
2
6
61 °C; R 0.30 (30% ethyl acetate/1% triethylamine in petroleum ether); [α]D +69.4 (c 0.9, CHCl3),
f
16b
20
1
lit. [α]D +72.2 (c 0.9, CHCl ); H NMR (400 MHz, CDCl ) δ 1.26 (d, J = 6.1 Hz, 3H), 1.80 (br s,
3
3
1
1
H), 2.23 (dd, J = 14.0, 11.9 Hz, 1H), 2.41 (dd, J = 14.0, 2.7 Hz, 1H), 2.47–2.53 (m, 2H), 3.12 (dqd, J =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1.9, 6.1, 2.7 Hz, 1H), 3.96 (dt, J = 11.9, 8.0 Hz, 1H), 7.27–7.43 (m, 5H); C NMR (101 MHz, CDCl )
3
δ 22.7 (CH ), 49.8 (CH ), 50.0 (CH ), 52.4 (CH), 61.1 (CH), 126.5 (2 × CH), 127.9 (CH), 128.8 (2 ×
3
2
2
+
CH), 142.7 (C), 208.9 (C); MS (ESI) m/z 190 (MH , 100). Data for (2R,6S)ꢀ2ꢀmethylꢀ6ꢀ
phenylpiperidinꢀ4ꢀone (11d): Mp 65–69 °C; R 0.06 (30% ethyl acetate/1% triethylamine in petroleum
f
−
1
26
D
1
ether); IR (neat) 3309, 2962, 1712, 1450 cm ; [α] +8.2 (c 0.2, CHCl ); H NMR (400 MHz, CDCl )
3
3
δ 1.19 (d, J = 6.4 Hz, 3H), 1.82 (br s, 1H), 2.23 (ddd, J = 14.2, 6.4, 1.1 Hz, 1H), 2.59–2.73 (m, 3H),
1
3
3
.41–3.51 (m, 1H), 4.48 (t, J = 8.0 Hz, 1H), 7.25–7.41 (m, 5H); C NMR (101 MHz, CDCl ) δ 21.2
3
(CH ), 47.8 (CH), 47.8 (CH ), 48.9 (CH ), 55.6 (CH), 126.9 (2 × CH), 127.6 (CH), 128.7 (2 × CH),
3
2
2
+
+
1
1
42.7 (C), 209.5 (C); MS (ESI) m/z 190 (MH , 100); HRMS (ESI) calcd for C H NO (MH ),
12 16
90.1226, found 190.1226.
(2R,6R)-2-Methyl-6-(4’-methoxyphenyl)piperidin-4-one
(10e)
and
(2R,6S)-2-methyl-6-(4’-
methoxyphenyl)piperidin-4-one (11e). The reaction was carried out according to the procedure for the
synthesis of 10a and 11a using (2R,5E)ꢀ6ꢀ(4’ꢀmethoxyphenyl)ꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀoxohexꢀ
5
1
ꢀene (9e) (0.18 g, 0.56 mmol). Purification by flash column chromatography on silica gel (soaked with
% triethylamine/petroleum ether), with a gradient elution from 40% ethyl acetate/1% triethylamine in
petroleum ether (40–60) to 80% ethyl acetate/1% triethylamine in petroleum ether (40–60) gave
2R,6R)ꢀ2ꢀmethylꢀ6ꢀ(4’ꢀmethoxyphenyl)piperidinꢀ4ꢀone (10e) (0.056 g, 46%) as an orange solid.
(
Further elution yielded (2R,6S)ꢀ2ꢀmethylꢀ6ꢀ(4’ꢀmethoxyphenyl)piperidinꢀ4ꢀone (11e) (0.045 g, 37%) as
a red solid. Data for (2R,6R)ꢀ2ꢀmethylꢀ6ꢀ(4’ꢀmethoxyphenyl)piperidinꢀ4ꢀone (10e): Mp 83–85 °C; Rf
−1
0
.22 (40% ethyl acetate/1% triethylamine in petroleum ether); IR (neat) 3300, 2966, 1708, 1510 cm ;
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6
1
[
α]D +65.3 (c 1.0, CHCl ); H NMR (500 MHz, CDCl ) δ 1.25 (d, J = 6.2 Hz, 3H), 1.79 (br s, 1H),
3 3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
.21 (dd, J = 14.0, 11.9 Hz, 1H), 2.39 (dd, J = 14.0, 2.6 Hz, 1H), 2.44–2.51 (m, 2H), 3.10 (dqd, J = 11.9,
13
6.2, 2.6 Hz, 1H), 3.80 (s, 3H), 3.90 (dd, J = 8.6, 6.2 Hz, 1H), 6.87–6.91 (m, 2H), 7.30–7.34 (m, 2H); C
NMR (126 MHz, CDCl ) δ 22.6 (CH ), 49.8 (CH ), 50.1 (CH ), 52.3 (CH), 55.3 (CH ), 60.5 (CH),
3
3
2
2
3
+
1
14.1 (2 × CH), 127.7 (2 × CH), 134.9 (C), 159.2 (C), 209.0 (C); MS (ESI) m/z 220 (MH , 100); HRMS
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
(ESI) calcd for C H NO (MH ), 220.1332, found 220.1327. Data for (2R,6S)ꢀ2ꢀmethylꢀ6ꢀ(4’ꢀ
13 18
2
methoxyphenyl)piperidinꢀ4ꢀone (11e): Mp 78–80 °C; R 0.070 (40% ethyl acetate/1% triethylamine in
f
−1
26
1
petroleum ether); IR (neat) 3300, 2823, 1705, 1512 cm ; [α]D +34.7 (c 0.2, CHCl ); H NMR (400
3
MHz, CDCl ) δ 1.18 (d, J = 6.5 Hz, 3H), 1.76 (br s, 1H), 2.22 (ddd, J = 14.2, 6.5, 1.1 Hz, 1H), 2.58–
3
2.70 (m, 3H), 3.39–3.48 (m, 1H), 3.80 (s, 3H), 4.44 (t, J = 6.5 Hz, 1H), 6.85–6.90 (m, 2H), 7.23–7.29
13
(m, 2H); C NMR (101 MHz, CDCl ) δ 21.2 (CH ), 47.7 (CH), 48.0 (CH ), 48.9 (CH ), 55.1 (CH ),
3
3
2
2
3
+
5
5.3 (CH), 114.0 (2 × CH), 128.0 (2 × CH), 134.8 (C), 158.9 (C), 209.7 (C); MS (ESI) m/z 220 (MH ,
+
100); HRMS (ESI) calcd for C H NO (MH ), 220.1332, found 220.1331.
1
3
18
2
(2R,6R)-2-Methyl-6-(naphthalen-2’-yl)piperidin-4-one (10f) and (2R,6S)-2-methyl-6-(naphthalen-
2
’-yl)piperidin-4-one (11f). The reaction was carried out according to the procedure for the synthesis of
0a and 11a using (2R,5E)ꢀ6ꢀ(naphthalenꢀ2’ꢀyl)ꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀoxohexꢀ5ꢀene (9f)
1
(0.13 g, 0.39 mmol). Purification by flash column chromatography on silica gel (soaked with 1%
triethylamine/petroleum ether), with a gradient elution from 40% ethyl acetate/1% triethylamine in
petroleum ether (40–60) to 1% triethylamine in ethyl acetate gave (2R,6R)ꢀ2ꢀmethylꢀ6ꢀ(naphthalenꢀ2’ꢀ
yl)piperidinꢀ4ꢀone (10f) (0.041 g, 44%) as an orange oil. Further elution yielded (2R,6S)ꢀ2ꢀmethylꢀ6ꢀ
(naphthalenꢀ2’ꢀyl)piperidinꢀ4ꢀone (11f) (0.039 g, 42%) as an orange oil. Data for (2R,6R)ꢀ2ꢀmethylꢀ6ꢀ
(naphthalenꢀ2’ꢀyl)piperidinꢀ4ꢀone (10f): R 0.39 (40% ethyl acetate/1% triethylamine in petroleum
f
−
1
26
D
1
ether); IR (neat) 3311, 2970, 1714, 1373 cm ; [α] +65.9 (c 1.0, CHCl ); H NMR (500 MHz, CDCl )
3
3
δ 1.29 (d, J = 6.2 Hz, 3H), 1.91 (br s, 1H), 2.27 (dd, J = 14.0, 11.9 Hz, 1H), 2.44 (dd, J = 14.0, 2.7 Hz,
1
H), 2.57 (d, J = 8.0 Hz, 2H), 3.17 (dqd, J = 11.9, 6.2, 2.7 Hz, 1H), 4.08–4.15 (m, 1H), 7.45–7.51 (m,
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3
2
H), 7.52 (dd, J = 8.6, 1.5 Hz, 1H), 7.80–7.86 (m, 4H); C NMR (126 MHz, CDCl ) δ 22.7 (CH ), 49.8
3 3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
CH ), 49.9 (CH ), 52.4 (CH), 61.1 (CH), 124.7 (CH), 125.1 (CH), 126.0 (CH), 126.3 (CH), 127.7
2 2
+
(CH), 127.9 (CH), 128.5 (CH), 133.1 (C), 133.4 (C), 140.0 (C), 208.7 (C); MS (ESI) m/z 240 (MH ,
+
1
00); HRMS (ESI) calcd for C H NO (MH ), 240.1383, found 240.1379. Data for (2R,6S)ꢀ2ꢀmethylꢀ
1
6
18
6
ꢀ(naphthalenꢀ2’ꢀyl)piperidinꢀ4ꢀone (11f): R 0.10 (40% ethyl acetate/1% triethylamine in petroleum
f
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
−
1
26
D
1
ether); IR (neat) 3315, 2964, 1708, 1506, 1305 cm ; [α] −58.7 (c 1.0, CHCl ); H NMR (500 MHz,
3
CDCl ) δ 1.20 (d, J = 6.6 Hz, 3H), 1.86 (br s, 1H), 2.26 (ddd, J = 14.2, 6.6, 1.4 Hz, 1H), 2.65 (ddd, J =
3
1
3
4.2, 4.9, 1.4 Hz, 1H), 2.74 (ddd, J = 14.4, 5.3, 1.4 Hz, 1H), 2.81 (ddd, J = 14.4, 6.9, 1.4 Hz, 1H), 3.41–
13
.49 (m, 1H), 4.65 (dd, J = 6.9, 5.3 Hz, 1H), 7.45–7.51 (m, 3H), 7.75 (br s, 1H), 7.79–7.86 (m, 3H); C
NMR (101 MHz, CDCl ) δ 21.1 (CH ), 47.4 (CH ), 47.8 (CH), 48.8 (CH ), 55.7 (CH), 125.1 (CH),
3
3
2
2
1
25.6 (CH), 126.1 (CH), 126.4 (CH), 127.6 (CH), 128.0 (CH), 128.6 (CH), 132.8 (C), 133.2 (C), 139.5
+
+
(C), 208.6 (C); MS (ESI) m/z 240 (MH , 100); HRMS (ESI) calcd for C H NO (MH ), 240.1383,
16
18
found 240.1386.
(2R,6R)-2-Methyl-6-(4’-nitrophenyl)piperidin-4-one
(10g)
and
(2R,6S)-2-methyl-6-(4’-
nitrophenyl)piperidin-4-one (11g). The reaction was carried out according to the procedure for the
synthesis of 10a and 11a using (2R,5E)ꢀ6ꢀ(4’ꢀnitrophenyl)ꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀoxohexꢀ5ꢀ
ene (9g) (0.103 g, 0.309 mmol). Purification by flash column chromatography on silica gel (soaked with
1
% triethylamine/petroleum ether), eluting with 40% ethyl acetate/1% triethylamine in petroleum ether
(40–60) gave (2R,6R)ꢀ2ꢀmethylꢀ6ꢀ(4’ꢀnitrophenyl)piperidinꢀ4ꢀone (10g) (0.0310 g, 43%) as a red solid.
Further elution yielded (2R,6S)ꢀ2ꢀmethylꢀ6ꢀ(4’ꢀnitrophenyl)piperidinꢀ4ꢀone (11g) (0.0300 g, 41%) as a
brown solid. Data for (2R,6R)ꢀ2ꢀmethylꢀ6ꢀ(4’ꢀnitrophenyl)piperidinꢀ4ꢀone (10g): Mp 117–120 °C; Rf
0
.21 (40% ethyl acetate/1% triethylamine in petroleum ether); IR (neat) 3321, 2968, 1705, 1510, 1346
−
1
26
D
1
cm ; [α] +62.4 (c 1.0, CHCl ); H NMR (500 MHz, CDCl ) δ 1.29 (d, J = 6.1 Hz, 3H), 1.86 (br s,
3
3
1H), 2.25 (ddd, J = 14.0, 12.0, 0.8 Hz, 1H), 2.37–2.54 (m, 3H), 3.15 (dqd, J = 12.0, 6.1, 2.9 Hz, 1H),
13
4
.09 (dd, J = 11.8, 3.2 Hz, 1H), 7.58–7.64 (m, 2H), 8.19–8.26 (m, 2H); C NMR (126 MHz, CDCl ) δ
3
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2.6 (CH ), 49.6 (CH ), 49.7 (CH ), 52.2 (CH), 60.3 (CH), 124.1 (2 × CH), 127.4 (2 × CH), 147.5 (C),
3 2 2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
+
1
49.9 (C), 207.4 (C); MS (ESI) m/z 235 (MH , 100); HRMS (ESI) calcd for C H N O (MH ),
1
2
15
2
3
235.1077, found 235.1073. Data for (2R,6S)ꢀ2ꢀmethylꢀ6ꢀ(4’ꢀnitrophenyl)piperidinꢀ4ꢀone (11g): Mp 88–
9
1
1
5
1 °C; R 0.07 (40% ethyl acetate/1% triethylamine in petroleum ether); IR (neat) 3300, 2962, 1707,
f
−1
26
D
1
508, 1344 cm ; [α] +11.1 (c 0.2, CHCl ); H NMR (500 MHz, CDCl ) δ 1.22 (d, J = 6.6 Hz, 3H),
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
.82 (br s, 1H), 2.26 (ddd, J = 14.0, 6.1, 1.0 Hz, 1H), 2.61–2.72 (m, 3H), 3.42–3.50 (m, 1H), 4.59 (t, J =
1
3
.0 Hz, 1H), 7.55–7.60 (m, 2H), 8.18–8.23 (m, 2H); C NMR (126 MHz, CDCl ) δ 21.1 (CH ), 47.7
3
3
(CH ), 48.2 (CH), 48.9 (CH ), 55.2 (CH), 123.9 (2 × CH), 127.8 (2 × CH), 147.3 (C), 150.0 (C), 208.3
2 2
+
+
(C); MS (ESI) m/z 235 (MH , 100); HRMS (ESI) calcd for C H N O (MH ), 235.1077, found
12 15 2 3
235.1075.
(
2R,6R)-2-Methyl-6-(pyridin-3’-yl)piperidin-4-one (10h) and (2R,6S)-2-methyl-6-(pyridin-3’-
yl)piperidin-4-one (11h). The reaction was carried out according to the procedure for the synthesis of
0a and 11a using (2R,5E)ꢀ6ꢀ(pyridinꢀ3’ꢀyl)ꢀ2ꢀ(tertꢀbutoxycarbonylamino)ꢀ4ꢀoxohexꢀ5ꢀene (9h) (0.096
1
g, 0.33 mmol). Purification by flash column chromatography on silica gel (soaked with 1%
triethylamine/dichloromethane), eluting with 2% methanol/50% dichloromethane/1% triethylamine in
petroleum ether (40–60) gave (2R,6R)ꢀ2ꢀmethylꢀ6ꢀ(pyridinꢀ3’ꢀyl)piperidinꢀ4ꢀone (10h) (0.026 g, 41%)
as an orange oil. Further elution yielded (2R,6S)ꢀ2ꢀmethylꢀ6ꢀ(pyridinꢀ3’ꢀyl)piperidinꢀ4ꢀone (11h) (0.025
g, 39%) as an orange oil. Data for (2R,6R)ꢀ2ꢀmethylꢀ6ꢀ(pyridinꢀ3’ꢀyl)piperidinꢀ4ꢀone (10h): R 0.22 (2%
f
methanol/50% dichloromethane/1% triethylamine in petroleum ether); IR (neat) 3285, 2965, 1709, 1426
−
1
26
D
1
cm ; [α] +70.5 (c 1.0, CHCl ); H NMR (500 MHz, CDCl ) δ 1.27 (d, J = 6.1 Hz, 3H), 1.85 (br s,
3
3
1
H), 2.23 (dd, J 14.0, 10.6 Hz, 1H), 2.40–2.54 (m, 3H), 3.14 (dqd, J = 12.2, 6.1, 2.9 Hz, 1H), 4.01 (dd, J
10.6, 4.4 Hz, 1H), 7.31 (dd, J = 7.9, 4.8 Hz, 1H), 7.77 (dt, J = 7.9, 1.9 Hz, 1H), 8.56 (dd, J = 4.8, 1.9
=
1
3
Hz, 1H), 8.64 (br d, J = 1.9 Hz, 1H); C NMR (126 MHz, CDCl ) δ 22.6 (CH ), 49.6 (CH ), 49.6
3
3
2
(CH ), 52.4 (CH), 58.6 (CH), 123.7 (CH), 134.2 (CH), 138.0 (C), 148.5 (CH), 149.5 (CH), 207.9 (C);
2
+
+
MS (ESI) m/z 191 (MH , 100); HRMS (ESI) calcd for C H N O (MH ), 191.1179, found 191.1181.
1
1
15
2
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Data for (2R,6S)ꢀ2ꢀmethylꢀ6ꢀ(pyridinꢀ3’ꢀyl)piperidinꢀ4ꢀone (11h): R 0.11 (2% methanol/50%
f
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
−1
26
D
dichloromethane/1% triethylamine in petroleum ether); IR (neat) 3263, 2962, 1705, 1419 cm ; [α]
1
+38.9 (c 0.2, CHCl ); H NMR (400 MHz, CDCl ) δ 1.22 (d, J = 6.4 Hz, 3H), 1.69 (br s, 1H), 2.26 (dd,
3
3
J = 14.1, 6.4 Hz, 1H), 2.62–2.70 (m, 3H), 3.42–3.52 (m, 1H), 4.54 (t, J = 6.2 Hz, 1H), 7.28 (dd, J 7.9,
13
4
.8 Hz, 1H), 7.70 (dt, J = 7.9, 1.8 Hz, 1H), 8.54 (dd, J = 4.8, 1.8 Hz, 1H), 8.64 (d, J = 1.8 Hz, 1H); C
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (101 MHz, CDCl ) δ 21.0 (CH ), 47.5 (CH ), 48.1 (CH), 48.8 (CH ), 53.6 (CH), 123.5 (CH),
3
3
2
2
+
1
34.4 (CH), 137.8 (C), 148.9 (CH), 149.1 (CH), 208.4 (C); MS (ESI) m/z 191 (MH , 100); HRMS (ESI)
+
calcd for C H N O (MH ), 191.1179, found 191.1178.
1
1
15
2
7a
(
2R,4S,6S)-2-Methyl-6-propylpiperidin-4-ol (1). (2R,6S)ꢀ2ꢀMethylꢀ6ꢀpropylpiperidinꢀ4ꢀone (10a)
(0.094 g, 0.061 mmol) was dissolved in anhydrous methanol (2 mL) and cooled to −15 °C. Sodium
borohydride (0.0046 g, 0.12 mmol) was added and the solution was stirred rapidly for 0.25 h. Brine (1
mL) was added to quench the reaction and the mixture was diluted with ethyl acetate (10 mL). The
organic layer was washed with brine (5 mL), dried over MgSO and concentrated in vacuo. Purification
4
by flash column chromatography on silica gel, eluting with 30% methanol/1% triethylamine in ethyl
acetate gave (2R,4S,6S)ꢀ2ꢀmethylꢀ6ꢀpropylpiperidinꢀ4ꢀol (1) (0.080 g, 87%) as an offꢀwhite solid. Mp
2
D
6
7a
7
4–76 °C; R 0.25 (30% methanol/1% triethylamine in ethyl acetate); [α]
+9.0 (c 0.7, MeOH), lit.
f
2
0
1
[α]D +8.8 (c 0.4, MeOH); H NMR (400 MHz, CDCl ) δ 0.91 (t, J = 7.1 Hz, 3H), 0.98 (q, J = 11.8 Hz,
3
1
H), 1.03 (q, J = 11.8 Hz, 1H), 1.12 (d, J = 6.3 Hz, 3H), 1.29–1.46 (m, 4H), 1.86 (br s, 2H), 1.91–2.01
13
(
m, 2H), 2.52–2.61 (m, 1H), 2.69 (dqd, J = 11.8, 6.3, 2.4 Hz, 1H), 3.65 (tt, J = 11.8, 4.5 Hz, 1H); C
NMR (101 MHz, CDCl ) δ 14.2 (CH ), 19.2 (CH ), 22.4 (CH ), 38.9 (CH ), 41.6 (CH ), 43.9 (CH ),
3
3
2
3
2
2
2
+
5
0.2 (CH), 54.6 (CH), 69.3 (CH); MS (ESI) m/z 158 (MH , 100).
5
a
(
2R,4S,6S)-2-Methyl-6-nonylpiperidin-4-ol (2). The reaction was carried out according to the
procedure for the synthesis of 1 using (2R,6S)ꢀ2ꢀmethylꢀ6ꢀnonylpiperidinꢀ4ꢀone (10b) (0.028 g, 0.12
mmol). Purification by flash column chromatography on silica gel, eluting with 10% methanol/1%
triethylamine in ethyl acetate gave (2R,4S,6S)ꢀ2ꢀmethylꢀ6ꢀnonylpiperidinꢀ4ꢀol (2) (0.023 g, 84%) as an
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6
offꢀwhite solid. Mp 86–88 °C; R 0.16 (10% methanol/1% triethylamine in ethyl acetate); [α]D +7.9 (c
f
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
a
25
1
1
.0, MeOH), lit. [α] +7.0 (c 1.0, MeOH); H NMR (500 MHz, CDCl ) δ 0.88 (t, J = 7.0 Hz, 3H),
D 3
0.93–1.06 (m, 2H), 1.12 (d, J = 6.3 Hz, 3H), 1.20–1.48 (m, 16H), 1.63 (br s, 2H), 0.97 (q, J = 11.8 Hz,
1
1
H), 1.02 (q, J = 11.8 Hz, 1H), 2.50–2.58 (m, 1H), 2.68 (dqd, J = 11.8, 6.3, 2.4 Hz, 1H), 3.65 (tt, J =
13
1.8, 4.6 Hz, 1H); C NMR (126 MHz, CDCl ) δ 14.1 (CH ), 22.5 (CH ), 22.7 (CH ), 26.1 (CH ), 29.3
3
3
3
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
CH ), 29.6 (CH ), 29.6 (CH ), 29.8 (CH ), 31.9 (CH ), 36.8 (CH ), 41.8 (CH ), 43.9 (CH ), 50.2 (CH),
2 2 2 2 2 2 2 2
+
5
4.9 (CH), 69.4 (CH); MS (ESI) m/z 242 (MH , 100).
2
1
(
2R,4S,6S)-2-Methyl-6-(2’-phenylethyl)piperidin-4-ol (12a). The reaction was carried out according
to the procedure for the synthesis of 1 using (2R,6S)ꢀ2ꢀmethylꢀ6ꢀ(2’ꢀphenylethyl)piperidinꢀ4ꢀone (10c)
0.014 g, 0.063 mmol). Purification by flash column chromatography on silica gel, eluting with 1%
(
methanol/1% triethylamine in dichloromethane gave (2R,4S,6S)ꢀ2ꢀmethylꢀ6ꢀ(2’ꢀphenylethyl)piperidinꢀ
21
4
ꢀol (12a) (0.011 g, 80%) as an offꢀwhite solid. Spectroscopic data was consistent with the literature.
2
6
Mp 98–102 °C; R 0.19 (1% methanol/1% triethylamine in dichloromethane); [α]D +7.0 (c 0.6,
f
1
CHCl ); H NMR (400 MHz, CDCl ) δ 1.02 (q, J = 11.7 Hz, 1H), 1.04 (q, J = 11.7 Hz, 1H), 1.12 (d, J =
3
3
6
1
.3 Hz, 3H), 1.47 (br s, 2H), 1.67–1.83 (m, 2H), 1.95 (ddt, J = 11.7, 4.5, 2.2 Hz, 1H), 2.03 (ddt, J =
1.7, 4.5, 2.2 Hz, 1H), 2.56–2.72 (m, 4H), 3.66 (tt, J = 11.7, 4.5 Hz, 1H), 7.16–7.21 (m, 3H), 7.25–7.31
13
(m, 2H); C NMR (101 MHz, CDCl ) δ 22.5 (CH ), 32.4 (CH ), 38.5 (CH ), 41.7 (CH ), 43.9 (CH ),
3
3
2
2
2
2
5
2
0.1 (CH), 54.4 (CH), 69.3 (CH), 125.9 (CH), 128.3 (2 × CH), 128.4 (2 × CH), 142.0 (C); MS (ESI) m/z
+
20 (MH , 100).
2
2
(
2R,4S,6R)-2-Methyl-6-phenylpiperidin-4-ol (12b). The reaction was carried out according to the
procedure for the synthesis of 1 using (2R,6R)ꢀ2ꢀmethylꢀ6ꢀphenylpiperidinꢀ4ꢀone (10d) (0.015 g, 0.077
mmol). Purification by flash column chromatography on silica gel, eluting with 1% methanol/1%
triethylamine in dichloromethane gave (2R,4S,6R)ꢀ2ꢀmethylꢀ6ꢀphenylpiperidinꢀ4ꢀol (12b) (0.013 g,
91%) as an off white solid. Mp 92–94 °C; R 0.19 (1% methanol/1% triethylamine in dichloromethane);
f
2
6
22
20
D
1
[
α]D +27.6 (c 1.0, CHCl ), lit. [α] +29.0 (c 0.5, CHCl ); H NMR (400 MHz, CDCl ) δ 1.10–1.21
3
3
3
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(
m, 4H), 1.45 (q, J = 11.8 Hz, 1H), 1.58 (br s, 2H), 2.00 (ddt, J = 11.8, 4.6, 2.4 Hz, 1H), 2.10 (ddt, J =
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1.8, 4.6, 2.4 Hz, 1H), 2.86 (dqd, J = 11.8, 6.3, 2.4 Hz, 1H), 3.69 (dd, J = 11.8, 2.4 Hz, 1H), 3.81 (tt, J =
1
3
11.8, 4.6 Hz, 1H), 7.23–7.41 (m, 5H); C NMR (101 MHz, CDCl ) δ 22.5 (CH ), 43.4 (CH ), 43.4
3
3
2
(CH ), 50.7 (CH), 59.8 (CH), 69.8 (CH), 126.8 (2 × CH), 127.3 (CH), 128.5 (2 × CH), 144.0 (C); MS
2
+
(ESI) m/z 192 (MH , 100).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(2R,4S,6R)-2-Methyl-6-(4’-methoxyphenyl)piperidin-4-ol (12c). The reaction was carried out
according to the procedure for the synthesis of
1
using (2R,6R)ꢀ2ꢀmethylꢀ6ꢀ(4’ꢀ
methoxyphenyl)piperidinꢀ4ꢀone (10e) (0.0170 g, 0.0780 mmol). Purification by flash column
chromatography on silica gel, eluting with 70% ethyl acetate/1% triethylamine in dichloromethane gave
(2R,4S,6R)ꢀ2ꢀmethylꢀ6ꢀ(4’ꢀmethoxyphenyl)piperidinꢀ4ꢀol (12c) (0.015 g, 85%) as a white solid. Mp 85–
9
1
1
0 °C; R 0.11 (70% ethyl acetate/1% triethylamine in dichloromethane); IR (neat) 3340, 2933, 1514,
f
−1
26
D
1
303 cm ; [α] +21.3 (c 1.0, CHCl ); H NMR (500 MHz, CDCl ) δ 1.09–1.19 (m, 4H), 1.43 (q, J =
3
3
2.0 Hz, 1H), 1.61 (br s, 2H), 1.99 (ddt, J = 12.0, 4.4, 2.3 Hz, 1H), 2.07 (ddt, J = 12.0, 4.4, 2.3 Hz, 1H),
2.84 (dqd, J = 12.0, 6.2, 2.3 Hz, 1H), 3.64 (dd, J = 12.0, 2.3 Hz, 1H), 3.75–3.83 (m, 4H), 6.83–6.89 (m,
13
2
H), 7.27–7.32 (m, 2H); C NMR (126 MHz, CDCl ) δ 22.5 (CH ), 43.4 (2 × CH ), 50.7 (CH), 55.3
3
3
2
(CH ), 59.1 (CH), 69.8 (CH), 113.8 (2 × CH), 127.8 (2 × CH), 136.3 (C), 158.8 (C); MS (ESI) m/z 222
3
+
+
(MH , 95); HRMS (ESI) calcd for C H NO (MH ), 222.1489, found 222.1487.
1
3
20
2
(2R,4S,6R)-2-Methyl-6-(naphthalen-2’-yl)piperidin-4-ol (12d). The reaction was carried out
according to the procedure for the synthesis of 1 using (2R,6R)ꢀ2ꢀmethylꢀ6ꢀ(naphthalenꢀ2’ꢀyl)piperidinꢀ
4
ꢀone (10f) (0.036 g, 0.15 mmol). Purification by flash column chromatography on silica gel, eluting
with 80% ethyl acetate/1% triethylamine in dichloromethane gave (2R,4S,6R)ꢀ2ꢀmethylꢀ6ꢀ(naphthalenꢀ
’ꢀyl)piperidinꢀ4ꢀol (12d) (0.032 g, 88%) as a white solid. Mp 157–160 °C; R 0.21 (80% ethyl
2
f
−
1
26
D
acetate/1% triethylamine in dichloromethane); IR (neat) 3284, 2926, 1599, 1371 cm ; [α]
+6.9 (c
1
1.0, CHCl ); H NMR (400 MHz, CDCl ) δ 1.12–1.26 (m, 4H), 1.53 (q, J = 12.2 Hz, 1H), 1.68 (br s,
3
3
2
H), 2.03 (ddt, J = 12.2, 4.5, 2.3 Hz, 1H), 2.18 (ddt, J = 12.2, 4.5, 2.3 Hz, 1H), 2.90 (dqd, J = 12.2, 6.3,
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1
3
2
.3 Hz, 1H), 3.80–3.90 (m, 2H), 7.41–7.53 (m, 3H), 7.77–7.86 (m, 4H); C NMR (101 MHz, CDCl ) δ
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2.5 (CH ), 43.5 (CH ), 43.5 (CH ), 50.8 (CH), 59.8 (CH), 69.8 (CH), 125.0 (CH), 125.3 (CH), 125.6
3
2
2
(CH), 126.0 (CH), 127.6 (CH), 127.9 (CH), 128.1 (CH), 132.9 (C), 133.5 (C), 141.5 (C); MS (ESI) m/z
+
+
2
42 (MH , 100); HRMS (ESI) calcd for C H NO (MH ), 242.1539, found 242.1538.
16 20
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(2R,4S,6R)-2-Methyl-6-(4’-nitrophenyl)piperidin-4-ol (12e). The reaction was carried out according
to the procedure for the synthesis of 1 using (2R,6R)ꢀ2ꢀmethylꢀ6ꢀ(4’ꢀnitrophenyl)piperidinꢀ4ꢀone (10g)
(0.019 g, 0.082 mmol). Purification by flash column chromatography on silica gel, eluting with 70%
ethyl acetate/1% triethylamine in petroleum ether (40–60) gave (2R,4S,6R)ꢀ2ꢀmethylꢀ6ꢀ(4’ꢀ
nitrophenyl)piperidinꢀ4ꢀol (12e) (0.015 g, 75%) as a yellow oil. R 0.12 (70% ethyl acetate/1%
f
−1
26
D
triethylamine in petroleum ether); IR (neat) 3298, 2935, 1516, 1344 cm ; [α]
+20.0 (c 0.9, CHCl3);
1
H NMR (500 MHz, CDCl ) δ 1.12–1.22 (m, 4H), 1.37 (q, J = 12.3 Hz, 1H), 1.58 (br s, 2H), 2.03 (ddt, J
3
=
12.3, 4.5, 2.4 Hz, 1H), 2.10 (ddt, J = 12.3, 4.5, 2.4 Hz, 1H), 2.89 (dqd, J = 12.3, 6.2, 2.4 Hz, 1H),
13
3
.79–3.88 (m, 2H), 7.54–7.58 (m, 2H), 8.16–8.21 (m, 2H); C NMR (126 MHz, CDCl ) δ 22.5 (CH ),
3 3
43.1 (CH ), 43.5 (CH ), 50.5 (CH), 59.2 (CH), 69.4 (CH), 123.8 (2 × CH), 127.6 (2 × CH), 147.2 (C),
2
2
+
+
1
2
51.6 (C); MS (ESI) m/z 237 (MH , 100); HRMS (ESI) calcd for C H N O (MH ), 237.1234, found
12 17 2 3
37.1239.
(
2R,4S,6R)-2-Methyl-6-(pyridin-3’-yl)piperidin-4-ol (12f). The reaction was carried out according to
the procedure for the synthesis of 1 using (2R,6R)ꢀ2ꢀmethylꢀ6ꢀ(pyridinꢀ3’ꢀyl)piperidinꢀ4ꢀone (10h)
0.018 g, 0.092 mmol). Purification by flash column chromatography on silica gel, eluting with 5%
(
methanol/1% triethylamine in dichloromethane gave (2R,4S,6R)ꢀ2ꢀmethylꢀ6ꢀ(pyridinꢀ3’ꢀyl)piperidinꢀ4ꢀ
ol (12f) (0.012 g, 68%) as a pale yellow oil. R 0.23 (5% methanol/1% triethylamine in
f
−
1
26
D
1
dichloromethane); IR (neat) 3254, 2933, 1425, 1305 cm ; [α] +17.7 (c 0.8, CHCl ); H NMR (400
3
MHz, CDCl ) δ 1.10–1.23 (m, 4H), 1.44 (q, J = 12.2 Hz, 1H), 1.87 (br s, 2H), 2.02 (ddt, J = 12.2, 4.5,
3
2.3 Hz, 1H), 2.09 (ddt, J = 12.2, 4.5, 2.3 Hz, 1H), 2.88 (dqd, J = 12.2, 6.2, 2.3 Hz, 1H), 3.74 (dd, J =
1
2.2, 2.3 Hz, 1H), 3.82 (tt, J = 12.2, 4.5 Hz, 1H), 7.26 (dd, J = 7.9, 4.8 Hz, 1H), 7.74 (dt, J = 7.9, 1.8
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1
3
Hz, 1H), 8.50 (dd, J = 4.8, 1.8 Hz, 1H), 8.58 (d, J = 1.8 Hz, 1H); C NMR (101 MHz, CDCl ) δ 22.5
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
CH ), 43.2 (2 × CH ), 50.7 (CH), 57.3 (CH), 69.4 (CH), 123.6 (CH), 134.4 (CH), 139.4 (C), 148.7
3 2
+
+
(CH), 148.8 (CH); MS (ESI) m/z 193 (MH , 100); HRMS (ESI) calcd for C H N O (MH ), 193.1335,
11
17
2
found 193.1339.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
13
SUPPORTING INFORMATION. NOE data of all novel cyclic compounds and, H and C NMR
spectra for all compounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
ACKNOWLEDGEMENT. Financial support from the EPSRC (studentship to A.H.H.,
EP/K503058/1) and the University of Glasgow is gratefully acknowledged.
REFERENCES:
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U.K., 1996, Vol. 10. (b) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139.
(2) Tawara, J. N.; Lorenz, P.; Stermitz, F. R. J. Nat. Prod. 1999, 62, 321.
(
3) (a) Daly, J. W.; Myers, C. W.; Whittaker, N. Toxicon 1987, 25, 1023. (b) Edwards, M. W.; Daly,
J. W.; Myers, C. W. J. Nat. Prod. 1988, 51, 1188.
(4) Edwards, M. W.; Garraffo, H. M.; Daly, J. W. Synthesis 1994, 1167.
(5) For recent examples, see: (a) Gouault, N.; Le Roch, M.; de Campos Pinto, G.; David, M. Org.
Biomol. Chem. 2012, 10, 5541. (b) Saha, N.; Chattopadhyay, S. K. J. Org. Chem. 2012, 77, 11056.
(c) AbrunhosaꢀThomas, I.; Plas, A.; Vogrig, A.; Kandepedu, N.; Chalard, P.; Troin, Y. J. Org.
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Chem. 2013, 78, 2511. (d) Vu, V. H.; Louafi, F.; Girard, N.; Marion, R.; Roisnel, T.; Dorcet, V.;
Hurvois, J.ꢀP. J. Org. Chem. 2014, 79, 3358.
1
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
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4
5
5
5
5
5
5
5
5
5
5
6
(
6) Ma, D.; Sun, H. Org. Lett. 2000, 2, 2503.
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Gnamm, C.; Brödner, K.; Krauter, C. M.; Helmchen, G. Chem. Eur. J. 2009, 15, 10514.
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7
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9
0
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2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
(
8) Fowler, L. S.; Thomas, L. H.; Ellis, D.; Sutherland, A. Chem. Commun. 2011, 47, 6569.
(
9) Daly, M.; Cant, A. A.; Fowler, L. S.; Simpson, G. L.; Senn, H. M.; Sutherland, A. J. Org. Chem.
2
012, 77, 10001.
(10) Dexter, C. S.; Jackson, R. F. W.; Elliott, J. J. Org. Chem. 1999, 64, 7579.
(11) Hjelmgaard, T.; Tanner, D. Org. Biomol. Chem. 2006, 4, 1796.
(
12) (a) Ku, Y.ꢀY.; Pu, Y.ꢀM.; Grieme, T.; Sharma, P.; Bhatia, A. V.; Cowart, M. Tetrahedron 2006,
2, 4584. (b) Mandal, P. K.; Birtwistle, J. S.; McMurray, J. S. J. Org. Chem. 2014, 79, 8422.
6
(
13) (a) Corey, E. J.; Kwiatkowski, G. T. J. Am. Chem. Soc. 1966, 88, 5654. (b) Begley, M. J.;
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(14) Fowler, L. S.; Ellis, D.; Sutherland, A. Org. Biomol. Chem. 2009, 7, 4309.
(
15) To investigate whether the basic conditions of the 6ꢀendoꢀtrig cyclization were causing
conversion of the 2,6ꢀcisꢀisomers to the more stable 2,6ꢀtransꢀisomers during these reactions,
isolated 10a was reꢀsubjected to the same basic conditions for 24 h. However, 10a was found to be
configurationally stable during this experiment, thus showing that the two diastereomers are
formed during the cyclization and not via equilibration of the cisꢀ2,6ꢀproduct.
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(
16) The preparation of 2,6ꢀcisꢀoxopiperidine 10b was recently reported using a similar 6ꢀendoꢀtrig
cyclisation. In this case, the use of triethylamine gave 2,6ꢀcisꢀoxopiperidine 10b in 84% yield.
See: Reddy, A. A.; Reddy, P. O.; Prasad, K. R. J. Org. Chem. 2016, 81, 11363.
1
2
3
4
5
6
7
8
9
(17) (a) Ciblat, S.; Calinaud, P.; Canet, J.ꢀL.; Troin, Y. J. Chem. Soc. Perkin Trans. 1 2000, 353. (b)
Davis, F. A.; Chao, B.; Rao, A. Org. Lett. 2001, 3, 3169.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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0
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2
3
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5
6
7
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9
0
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2
3
4
5
6
7
8
9
0
(
18) For NOE enhancements of all novel compounds from the 6ꢀendoꢀtrig cyclization and the
stereoselective reduction, see supporting information.
(19) Markidis, T.; Kokotos, G. J. Org. Chem. 2001, 66, 1919.
(20) Hansen, K. B.; Rosner, T.; Kubryk, M.; Dormer, P. G.; Armstrong, J. D. Org. Lett. 2005, 7,
4
935.
(21) Yang, Y. RSC Adv. 2015, 5, 18894.
(22) Davis, F. A.; Rao, A.; Carroll, P. J. Org. Lett. 2003, 5, 3855.
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