A novel and concise synthetic access to chiral 2-substituted-4-piperidone

Article abstract of DOI:10.1007/s11426-014-5065-3

A novel and concise synthetic access to enantiopure chiral 2-aryl/alkyl substituted 4-piperidone has been demonstrated. This new route features two key steps: the highly diastereoselective conjugate addition of homochiral lithium amides to trans-β-substituted-α,β-unsaturated methyl esters guaranteed the enantiopurity at 2 position (de >19:1) and the intramolecular attacking of carbanions to methyl esters led to the formation of the piperidone ring. A wide range of substrates, including chiral 2-aryl and 2-alkyl-4-piperidones, were successfully synthesized with modest to high yield. Moreover, some non-chiral 3-substituted-4-piperidones were also synthesized with enhanced ring-formation yield, implicating the versatility of this method in construction of various piperidine rings.

Full text of DOI:10.1007/s11426-014-5065-3

SCIENCE CHINA
Chemistry
• ARTICLES •
doi: 10.1007/s11426-014-5065-3
doi: 10.1007/s11426-014-5065-3
A novel and concise synthetic access to chiral
2-substituted-4-piperidone
CHEN Bai-Ling, WANG Bing* & LIN Guo-Qiang*
Department of Chemistry, Fudan University, Shanghai 200433, China
Received November 30, 2013; accepted December 2, 2013
A novel and concise synthetic access to enantiopure chiral 2-aryl/alkyl substituted 4-piperidone has been demonstrated. This
new route features two key steps: the highly diastereoselective conjugate addition of homochiral lithium amides to
trans-β-substituted-α,β-unsaturated methyl esters guaranteed the enantiopurity at 2 position (de >19:1) and the intramolecular
attacking of carbanions to methyl esters led to the formation of the piperidone ring. A wide range of substrates, including chiral
2-aryl and 2-alkyl-4-piperidones, were successfully synthesized with modest to high yield. Moreover, some non-chiral
3-substituted-4-piperidones were also synthesized with enhanced ring-formation yield, implicating the versatility of this meth-
od in construction of various piperidine rings.
chiral 2-substituted-4-piperidone, homochiral lithium amide, diastereoselective conjugate addition, lithium-iodine ex-
change, intramolecular carbonyl formation
1 Introduction
Piperidine remains as one of the most common and im-
portant structures in natural products and pharmaceutical
active moleculars, implicating its fundamental and important
role in organic synthesis [1–3]. Chiral 2,4-disubstituted pi-
peridines constitute an important category of piperidine
derivatives that appear in many drugs and drug candidates
[4–6]. For example, Selfotel (CGS-19755) is a competitive
NMDA antagonist which exhibits anticonvulsant, anxiolytic,
analgesic and neuroprotective effects [7]. Palinavir is re-
garded as a potent inhibitor of the human immunodeficiency
virus type 1 (HIV-1) and type 2 (HIV-2) proteases and may
be beneficial to the treatment of HIV [8] (Figure 1).
Figure 1 Chemical structures of selfotel and palinavir.
lieved that chiral 2-substituted-4-piperidones would be an
attractive precursor of chiral 2,4-disubstituted piperidine
during the synthetic work. The most frequent method used
in the synthesis of chiral 2-substituted-4-piperidones was
the asymmetric addition of nucleophiles to 2,3-dihydro-4-
pyridones in cooperation with chiral ligands and metal cat-
alysts. In 2004, Hayashi first reported the asymmetric addi-
tion of arylzinc reagents to 2,3-dihydro-4-pyridones in a
rhodium-catalyzed manner and up to 100% yield and 99%
ee value were obtained [9]. After that, various aryl and alkyl
nucleophiles, including arylboron reagents [10–13], ar-
Considering that the carbonyl group lies in the center of
organic synthetic network and can be easily transformed to
various specific functional groups, it is undoubtedly be-
*Corresponding author (email: lingq@sioc.ac.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2014
chem.scichina.com link.springer.com

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Chen BL, et al. Sci China Chem January (2014) Vol.57 No.1
ylsilanes reagents [14, 15], alkylzinc [16, 17] and alkyalu-
minum reagents [18], were successfully introduced, afford-
ing highly enantioenriched chiral 2-aryl/alkyl-4-piperidones.
In 2012, high enantioselective synthesis of chiral 2-alkenyl-
4-piperidones was also realized via asymmetric addition of
alkenyl alanes to 2,3-dihydro-4-pyridones with the aid of
copper catalysts (ee up to 97%) [19]. However, none of
these methods can enable the high enantioselective produc-
tion of chiral 2-aryl and 2-alkyl-4-piperidones simultane-
ously. Another major approach to chiral 2-substituted-
4-piperidones is the Aza Diels-Alder reactions between
imines and Danishefski’s diene [20–24]. Though modest to
high ee value (up to 95%) can be achieved, most reactions
can only give rise to chiral 2-aryl-4-piperidones.
diastereoselective conjugate addition of homochiral lithium
amides to trans-β-substituted-α, β-unsaturated esters proved
to be a powerful tool in establishment of the chirality at 2
position [28]. The retrosynthetic analysis was shown below.
However, we also should note here that the deprotonation at
α-position of ester by lithium reagent and the addition of
lithium reagent to carbonyl group formed in product will
account for the main side reactions and the control of regi-
oselectivity will be challengeable in this novel route
(Scheme 2).
2 Experimental
2.1 General experimental section
In the 1980s, Houpis [25] and Schakel [26] developed a
cyclization method via carbanion generated by lithiumio-
dine exchange attacking ester group intramolecularly at low
temperature, leading to the formation of cyclopentanone and
cyclohexanone with acceptable yield (Scheme 1). Later our
group completed the total synthesis of Allopumiliotoxin
267A using the similar strategy as the key ring-formation
step [27] (Scheme 1). These results prompted us to develop
a similar access to 4-piperidones. On the other hand, careful
literature search revealed that Davis’s pioneering work in
All manipulations were carried out in chemical fume hood.
All reagents were purchased from Sigma-Aldrich, Alfa Al-
ser Chemicals and SCRC unless otherwise noted. Solvents
were distilled under nitrogen from sodium and benzophe-
none (THF, DMF, toluene, diethyl ether) and calcium hy-
1
dride (DCM, Acetonitrile, DMF and DMSO). All H and
13C NMR data were recorded at ambient temperature in
CDCl3 (1H 500 MHz, C 125 MHz) unless indicated other-
wise. Chemical shifts were reported in parts per million as
n
Scheme 1 (a) Formation of cyclopentanone and cyclohexanone via carbanion attacking ester group intramolecularly; (b) Total synthesis of Allopumil-
iotoxin 267A using carbanion attacking ester group as key ring-formation step.
Scheme 2 Retrosynthetic analysis of chiral 2-substituted-4-piperidone based on our hypothesis.

Chen BL, et al. Sci China Chem January (2014) Vol.57 No.1
3
follows: chemical shift, multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet, br = broad), integra-
tion, and coupling constant. Optical rotations were recorded
at 589 nm, and were reported as [α]D (concentration in
grams/100 mL solvent). High-resolution mass spectrum was
performed on SHIMADZU LCMS-IT-TOF machine.
Compound 2c ((3S)-3-[[(1R)-1-phenylethyl]-2-propen-1-
ylamino]-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-butan-
28
oic acid methyl ester): yield 91%. [α]D –18.8 (c 1.40,
1
CHCl3); H NMR (CDCl3) δ 7.35–7.17 (m, 5H), 5.86–5.75
(m, 1H), 5.11 (dd, 1H, J = 17.2, 1.6 Hz), 5.03 (dd, 1H, J =
10.0, 1.6 Hz), 4.05 (q, 1H, J = 6.8 Hz), 3.72–3.65 (m, 1H),
3.60 (s, 3H), 3.59–3.51 (m, 2H), 3.31–3.14 (m, 2H),
2.46–2.23 (m, 2H), 1.39 (d, 3H, J = 6.8 Hz), 0.88 (s, 9H),
0.02 (d, 6H, J = 3.6 Hz); 13C NMR (CDCl3) δ 173.1, 144.8,
138.8, 128.0, 127.4, 126.5, 115.6, 64.3, 57.2, 55.8, 51.3,
49.6, 35.0, 25.8. 19.4, 18.2. –5.6; HR-ESI-MS m/z Calcd for
C22H38NO3Si (M + H+) 392.2621, Found 392.2628.
2.2 Synthesis of (3S)-3-[[(1R)-1-phenylethyl]-2-propen
-1-ylamino]-4-methylpentanoic acid methyl ester (com-
pound 2)
(R)-N-allyl-N-(α-methylbenzyl)amine (240 mg, 1.5 mmol)
was dissolved in THF (10 mL) and cooled to –78oC. n-BuLi
(0.75 mL, 1.6 M in hexane) was slowly dropped into the
reaction system under stirring. After n-BuLi was added,
stirring continued for 45min at –78oC before trans-β-
substituted-α,β-unsaturated methyl ester (1 mmol) dissolved
in THF was added. The reaction was completed after anoth-
er 40 min and quenched with saturated NH4Cl aqueous so-
lution. After the reaction mixture was extracted with diethyl
ether three times, the combined organic phase was washed,
dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by silica gel flash column chro-
matography eluted with EtOAc/hexane.
Compound 2d ((3S)-3-[[(1R)-1-phenylethyl]-2-propen-1-
ylamino]-benzenepropanoic acid methyl ester): yield 90%.
26
1
[α]D –3.6 (c 0.85, CHCl3); H NMR (CDCl3) δ 7.42–7.19
(m, 10H), 5.85–5.74 (m, 1H), 5.15 (dd, 1H, J = 17.6, 1.6
Hz), 5.06 (dd, 1H, J = 10.0, 1.6 Hz), 4.51 (t, 1H, J = 8.8 Hz),
4.05 (q, 1H, J = 6.0 Hz), 3.55 (s, 3H), 3.24–3.11 (m, 2H),
2.93–2.61 (m, 2H), 1.15 (d, 3H, J = 6.0 Hz); 13C NMR
(CDCl3) δ 172.3, 144.7, 141.3, 138.6, 128.2, 127.9, 127.8,
127.3, 127.1, 126.5, 115.8, 58.6, 56.0, 51.4, 49.6, 37.8, 16.3;
HR-ESI-MS m/z Calcd for C21H26NO2 (M + H+) 324.1964,
Found 324.1964.
Compound 2e ((3R)-3-[[(1R)-1-phenylethyl]-2-propen-1-
ylamino]-benzenepentanoic acid methyl ester): yield 94%.
[α]D25 –12.6 (c 0.95, CHCl3); 1H NMR (CDCl3) δ 7.34–7.14
(m, 10H), 5.95–5.84 (m, 1H), 5.22 (dd, 1H, J = 17.2, 1.6
Hz), 5.10 (dd, 1H, J = 10.0, 1.6 Hz), 3.96 (q, 1H, J = 6.8
Hz), 3.56 (s, 3H), 3.40–3.23 (m, 1H), 3.16–3.08 (m, 1H),
2.90–2.80 (m, 1H), 2.56–2.47 (m, 1H), 2.21–2.09 (m, 2H),
1.80–1.69 (m, 1H), 1.66–1.55 (m, 1H), 1.39 (d, 3H, J = 6.8
Hz); 13C NMR (CDCl3) δ 173.1, 144.0, 142.5, 138.9, 128.3,
128.2, 128.0, 127.6, 126.7, 125.6, 115.5, 58.2, 54.5, 51.3,
48.6, 36.6, 35.2, 33.3, 20.2; HR-ESI-MS m/z Calcd for
C23H30NO2 (M + H+) 352.2277, Found 352.2263.
26
Compound 2: yield 75%. [α]D –51.4 (c 1.45, CHCl3);
1H NMR (CDCl3) δ 7.32–7.18 (m, 5H), 5.91–5.80 (m, 1H),
5.20 (dd, 1H, J = 17.6, 1.6 Hz), 5.07 (dd, 1H, J = 10.0, 1.2
Hz), 3.91 (q, 1H, J = 6.8 Hz), 3.58 (s, 3H), 3.22–3.15 (m,
1H), 3.11–3.00 (m, 2H), 2.14–1.98 (m, 2H), 1.73–1.60 (m,
1H), 1.39 (d, 3H, J = 6.8 Hz), 0.98 (d, 3H, J = 6.8 Hz), 0.80,
3H, J = 6.4 Hz); 13C NMR (CDCl3) δ 173.8, 143.7, 139.1,
127.9, 127.8, 126.7, 115.3, 59.6, 58.7, 51.3, 49.6, 34.8, 32.7,
20.9, 20.8, 19.7; HR-ESI-MS m/z Calcd for C18H28NO2 (M
+ H+) 290.2120, Found 290.2120.
Compound 2a ((3R)-3-[[(1R)-1-phenylethyl]-2-propen-
26
Compound 2f ((3S)-3-[[(1R)-1-phenylethyl]-2-propen-1-
ylamino]-4-methylbenzenepropanoic acid methyl ester):
1-ylamino]-butanoic acid methyl ester): yield 85%. [α]D
1
–14.2 (c 1.85, CHCl3); H NMR (CDCl3) δ 7.36–7.20 (m,
27
1
yield 95%. [α]D –0.04 (c 1.35, CHCl3); H NMR (CDCl3)
δ 7.40–7.10 (m, 9H), 5.85–5.73 (m, 1H), 5.14 (dd, 1H, J =
17.2, 1.6 Hz), 5.05 (dd, 1H, J = 10.4, 1.6 Hz), 4.47 (t, 1H, J
= 7.6 Hz), 4.05 (q, 1H, J = 6.8 Hz), 3.55 (s, 3H), 3.23–3.10
(m, 2H), 2.91–2.83 (m, 1H), 2.67–2.60 (m, 1H), 2.34 (s,
3H), 1.15 (d, 3H, J = 6.8 Hz); 13C NMR (CDCl3) δ 172.5,
145.0, 138.9, 138.4, 136.8, 129.1, 128.1, 127.9, 127.6,
126.6, 115.9, 58.6, 56.2, 51.5, 49.8, 38.2, 21.2, 16.6;
HR-ESI-MS m/z Calcd for C22H28NO2 (M + H+) 338.2120,
Found 338.2129.
5H), 5.90–5.77 (m, 1H), 5.14 (dd, 1H, J = 17.1, 1.8 Hz),
5.03 (dd, 1H, J = 10.3, 1.8 Hz), 3.95 (q, 1H, J = 7.2 Hz),
3.56 (s, 3H), 3.47 (q, 1H, J = 7.2 Hz), 3.16 (d, 2H, J = 6.3
Hz), 2.40 (dd, 1H, J = 14.1, 7.2 Hz), 2.17 (dd, 1H, J = 14.4,
7.5 Hz), 1.37 (d, 3H, J = 6.9 Hz), 1.05 (d, 3H, J = 6.6 Hz);
Compound 2b ((3R)-3-[[(1R)-1-phenylethyl]-2-propen-
1-ylamino]-6-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-hexa
26
noic acid methyl ester): yield 100%. [α]D –11.9 (c 1.75,
1
CHCl3) H NMR (CDCl3) δ 7.33–7.18 (m, 5H), 5.90–5.79
(m, 1H), 5.17 (dd, 1H, J = 17.2, 1.2 Hz), 5.05 (dd, 1H, J =
10.0, 1.2 Hz), 3.94 (q, 1H, J = 6.8 Hz), 3.60–3.52 (m, 2H),
3.55 (s, 3H), 3.31–3.19 (m, 2H), 3.12–3.04 (m, 1H),
2.19–2.05 (m, 2H), 1.73–1.63 (m, 1H), 1.57–1.24 (m, 3H),
1.38 (d, 3H, J = 6.8 Hz), 0.89 (s, 9H), 0.04 (s, 6H); 13C
NMR (CDCl3) δ 173.2, 144.3, 139.0, 128.0, 127.6, 126.7,
115.5, 63.1, 58.0, 54.7, 51.3, 48.6, 37.0, 30.3, 29.2, 25.9,
20.2, 18.3, –5.3; HR-ESI-MS m/z Calcd for C24H42NO3Si
(M + H+) 420.2934, Found 420.2945.
2.3 Synthesis of (3S)-3-[[(1R)-1-phenylethyl]-2-hydr-
oxyethylamino]-4-methylpentanoic acid methyl ester
(compound 3)
Compound 2 (1 mmol) was dissolved in t-BuOH/THF/H2O
(4 mL/4 mL/4 mL) followed by addition of catalytic amount
of OsO4 and NMO (3 mmol). The mixture was stirred at

4
Chen BL, et al. Sci China Chem January (2014) Vol.57 No.1
room temperature. Once the reaction was completed evi-
denced by TLC, saturated Na2SO3 and saturated Na2CO3
aqueous solution were both added to quench the reaction.
After stirring at room temperature for another 10 min, the
reaction mixture was extracted with ethyl acetate three
times. The combined organic phase was washed, dried and
concentrated at reduced pressure. The residue was directly
dissolved in THF/H2O (3 mL/3 mL) and NaIO4 (1.2 mmol)
was added at room temperature. When TLC monitoring
showed the reaction was completed, the reaction tempera-
ture was lowered to 0 °C and NaBH4 (2 mmol) was added.
After half an hour, water was added to quench the reaction
at 0 °C. The reaction mixture was extracted with DCM three
times and combined organic phase was washed, dried and
concentrated at reduced pressure. The residue was purified
by silica gel flash column chromatography eluted with
EtOAc/hexane.
143.8, 128.2, 127.6, 126.9, 63.6, 60.0, 57.5, 55.8, 51.6, 47.4,
34.2, 25.8, 18.8, 18.1, –5.5, –5.6; HR-ESI-MS m/z Calcd for
C21H38NO4Si (M + H+) 396.2570, Found 396.2574.
Compound 3d ((3S)-3-[[(1R)-1-phenylethyl]-2-hydrox-
yethylamino]-benzenepropanoic acid methyl ester): yield
26
1
94%. [α]D –13.1 (c 0.86, CHCl3); H NMR (CDCl3) δ
7.40–7.17 (m, 10H), 4.52 (dd, 1H, J = 8.0, 7.2 Hz), 4.08 (t,
1H, J = 6.8 Hz), 3.58 (s, 3H), 3.57–3.37 (m, 2H), 2.99–2.91
(m, 1H), 2.86–2.78 (m, 1H), 2.75–2.55 (m, 3H), 1.11 (d, 3H,
J = 6.8 Hz); 13C NMR (CDCl3) δ 172.7, 144.3, 140.4, 128.5,
128.2, 127.8, 127.5, 127.4, 126.9, 59.8, 58.2, 56.3, 51.7,
47.8, 37.2, 16.5; HR-ESI-MS m/z Calcd for C20H26NO3 (M
+ H+) 328.1913, Found 328.1916.
Compound 3e ((3R)-3-[[(1R)-1-phenylethyl]-2-hydrox-
yethylamino]-benzenepentanoic acid methyl ester): yield
25
1
90%. [α]D –48.9 (c 1.05, CHCl3); H NMR (CDCl3) δ
7.34–7.14 (m, 10H), 3.94 (q, 1H, J = 6.8 Hz), 3.63–3.48 (m,
2H), 3.39 (s, 3H), 3.36–3.20 (m, 2H), 2.82–2.70 (m, 2H),
2.69–2.57 (m, 2H), 2.32–2.16 (m, 2H), 1.91–1.81 (m, 1H),
1.78–1.68 (br, 1H), 1.67–1.56 (m, 1H), 1.32 (d, 3H, J = 6.8
Hz); 13C NMR (CDCl3) δ 173.0, 143.3, 141.4, 128.4, 128.0,
127.8, 126.8, 125.9, 59.7, 57.3, 53.8, 51.5, 47.3, 37.7, 34.6,
33.5, 16.7; HR-ESI-MS m/z Calcd for C22H30NO3 (M + H+)
356.2226, Found 356.2241.
27
Compound 3: yield 95%. [α]D –55.6 (c 1.25, CHCl3);
1H NMR (CDCl3) δ 7.32–7.18 (m, 5H), 3.94 (q, 1H, J = 6.8
Hz), 3.59–3.41 (m, 2H), 3.53 (s, 3H), 3.15–3.08 (m, 1H),
2.95–2.80 (br, 1H), 2.77–2.72 (m, 2H), 2.19–2.01 (m, 2H),
1.85–1.75 (m, 1H), 1.42 (d, 3H, J = 6.8 Hz), 0.98 (d, 3H, J
= 6.8 Hz), 0.83 (d, 3H, J = 6.4 Hz); 13C NMR (CDCl3) δ
174.0, 143.7, 128.3, 128.0, 127.2, 60.1, 59.9, 58.2, 51.6,
48.3, 35.4, 31.9, 21.6, 20.0, 19.6; HR-ESI-MS m/z Calcd for
C17H28NO3 (M + H+) 294.2069, Found 294.2051.
Compound 3f ((3S)-3-[[(1R)-1-phenylethyl]-2-hydroxy-
ethylamino]-4-methylbenzenepropanoic acid methyl ester):
27
1
Compound 3a ((3R)-3-[[(1R)-1-phenylethyl]-2-hydrox-
yield 98%. [α]D –12.2 (c 1.24, CHCl3); H NMR (CDCl3)
δ 7.40–7.13 (m, 9H), 4.49 (t, 1H, J = 7.8 Hz), 4.06 (q, 1H, J
= 6.8 Hz), 3.57 (s, 3H), 3.55–3.48 (m, 1H), 3.43–3.35 (m,
1H), 2.97–2.89 (m, 1H), 2.85–2.77 (m, 1H), 2.74–2.62 (m,
3H), 2.34 (s, 3H), 1.13 (d, 3H, J = 6.8 Hz); 13C NMR
(CDCl3) δ 172.9, 144.6, 137.6, 137.3, 129.3, 128.4, 127.9,
127.6, 127.0, 60.1, 58.2, 56.6, 51.8, 48.0, 37.5, 21.2, 16.8;
HR-ESI-MS m/z Calcd for C21H28NO3 (M + H+) 342.2069,
Found 342.2082.
26
yethylamino]-butanoic acid methyl ester): yield 95%. [α]D
1
–66.4 (c 0.80, CHCl3); H NMR (CDCl3) δ 7.39–7.18 (m,
5H), 3.95 (q, 1H, J = 6.8 Hz), 3.65–3.57 (m, 1H), 3.52–3.40
(m, 2H), 3.38 (s, 9H), 2.82–2.65 (m, 2H), 2.33 (dd, 1H, J =
13.2, 9.2 Hz), 2.11 (dd, 1H, J = 14.0, 4.8 Hz), 1.39 (d, 3H, J
= 6.8 Hz), 1.08 (d, 3H, J = 6.4 Hz); 13C NMR (CDCl3) δ
172.8, 143.9, 128.1, 127.7, 126.7, 59.6, 57.1, 51.5, 49.5,
46.9, 40.7, 17.7, 16.1; HR-ESI-MS m/z Calcd for
C15H24NO3 (M + H+) 266.1756, Found 266.1752.
Compound 3b ((3R)-3-[[(1R)-1-phenylethyl]-2-hydrox-
yethylamino]-6-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-
hexanoic acid methyl ester): yield 73%. [α]D24 –39.6 (c 1.25,
CHCl3); 1H NMR (CDCl3) δ 7.35–7.18 (m, 5H), 3.95 (q, 1H,
J = 6.8 Hz), 3.63–3.54 (m, 3H), 3.54–3.46 (m, 1H), 3.39 (s,
3H), 3.30–3.14 (m, 2H), 2.81–2.71 (m, 2H), 2.21–2.15 (m,
2H), 1.76–1.70 (m, 1H), 1.69–1.44 (m, 3H), 1.40 (d, 3H, J =
6.8 Hz), 1.36–1.23 (m, 1H), 0.89 (s, 9H), 0.04 (s, 6H); 13C
NMR (CDCl3) δ 173.2, 143.7, 128.1, 127.9, 126.9, 62.7,
59.8, 57.2, 54.7, 51.6, 47.4, 38.0, 30.6, 28.7, 25.9, 18.3,
17.0, –5.3; HR-ESI-MS m/z Calcd for C23H42NO4Si (M +
H+) 424.2883, Found 424.2902.
Compound 3c ((3S)-3-[[(1R)-1-phenylethyl]-2-hydroxy-
ethylamino]-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-
butanoic acid methyl ester): yield 91%. [α]D28 –21.7 (c 1.75,
CHCl3); 1H NMR (CDCl3) δ 7.34–7.19 (m, 5H), 4.01 (q, 1H,
J = 6.4 Hz), 3.68–3.40 (m, 5H), 3.51 (s, 3H), 2.86–2.70 (m,
2H), 2.25–2.14 (m, 2H), 1.42 (d, 3H, J = 6.4 Hz), 0.90 (s,
9H), 0.04 (d, 6H, J = 1.6 Hz); 13C NMR (CDCl3) δ 173.1,
2.4 Synthesis of (3S)-3-[[(1R)-1-phenylethyl]-2-iodoe-
thylamino]-4-methylpentanoic acid methyl ester (com-
pound 4)
Compound 3 (1 mmol) along with PPh3 (1.5 mmol) and
imidazole (2 mmol) was dissolved in ether/CH3CN (9 mL/3
mL) under Ar atmosphere. I2 (1.5 mmol) was quickly added
o
to this mixture at 0 C. After stirring for 1 h, the reaction
was quenched with saturated Na2S2O3 aqueous solution and
extracted with ethyl acetate three times. The combined or-
ganic phase was washed, dried and concentrated at reduced
pressure to yield white solid. The white solid was loaded
onto a column filled with silica gel followed by elution with
EtOAc/hexane (1/20). Elution was collected and concen-
trated again at reduced pressure to give desired products.
1
Compound 4: yield 90%. H NMR (CDCl3) δ 7.34–7.19
(m, 5H), 3.87 (q, 1H, J = 6.8 Hz), 3.61 (s, 3H), 3.03–2.80
(m, 5H), 2.35–2.10 (m, 2H), 1.75–1.60 (m, 1H), 1.41 (d, 3H,
J = 6.8 Hz), 0.98 (d, 3H, J = 6.6 Hz), 0.81 (d, 3H, J = 6.6

Chen BL, et al. Sci China Chem January (2014) Vol.57 No.1
5
Hz).
1H), 1.37 (d, 3H, J = 6.8 Hz), 0.89 (d, 3H, J = 6.8 Hz), 0.86
(d, 3H, J = 6.8 Hz); 13C NMR (CDCl3) δ 210.9, 145.0, 128.6,
127.3, 126.8, 63.6, 56.1, 43.1, 39.9, 39.7, 28.7, 19.7, 17.7,
16.3; HR-ESI-MS m/z Calcd for C16H24NO (M + H+)
246.1858, Found 246.1865.
Compound 4a ((3R)-3-[[(1R)-1-phenylethyl]-2-iodoe-
thylamino]-butanoic acid methyl ester): yield 81%. 1H
NMR (CDCl3) δ 7.34–7.19 (m, 5H), 3.86 (q, 1H, J = 6.6
Hz), 3.60 (s, 3H), 3.53–3.39 (m, 1H), 2.99–2.76 (m, 4H),
2.45–2.17 (m, 2H), 1.38 (d, 3H, J = 6.6 Hz), 1.05 (d, 3H, J
= 6.6 Hz).
Compound 5a ((2R)-2-methyl-1-[(1R)-1-phenylethyl]-4-
26
1
piperidone): yield 53%. [α]D +3.5 (c 1.10, CHCl3); H
NMR (CDCl3) δ 7.47–7.22 (m, 5H), 4.00 (q, 1H, J = 6.4
Hz), 3.42–3.32 (m, 1H), 2.79–2.59 (m, 3H), 2.37–2.14 (m,
Compound 4b ((3R)-3-[[(1R)-1-phenylethyl]-2-iodoe-
thylamino]-6-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-hex-
anoic acid methyl ester): yield 89%. H NMR (CDCl3) δ
3H), 1.33 (d, 3H, J = 7.2 Hz), 1.13 (d, 3H, J = 6.0 Hz); 13
C
1
7.34–7.19 (m, 5H), 3.86 (q, 1H, J = 6.6 Hz), 3.59 (s, 3H),
3.64–3.48 (m, 2H), 3.26–3.14 (m, 1H), 3.02–2.82 (m, 4H),
2.28–2.18 (m, 2H), 1.73–1.11 (m, 4H), 1.39 (d, 3H, J = 6.6
Hz), 0.90 (s, 9H), 0.04 (s, 6H).
NMR (CDCl3) δ 210.5, 145.1, 128.3, 127.2, 126.8, 57.6,
52.4, 48.7, 43.8, 41.2, 16.3, 16.2; HR-ESI-MS m/z Calcd for
C14H20NO (M + H+) 218.1545, Found 218.1534.
Compound 5b ((2R)-2-[3-[[(1,1-dimethylethyl)dimeth-
ylsilyl]oxy]propyl]-1-[(1R)-1-phenylethyl]-4-piperidone):
Compound 4c ((3S)-3-[[(1R)-1-phenylethyl]-2-iodoe-
thylamino]-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-but-
24
1
yield 42%. [α]D +14.5 (c 0.82, CHCl3); H NMR (CDCl3)
δ 7.43–7.19 (m, 5H), 4.01 (q, 1H, J = 6.6 Hz), 3.61–3.41 (m,
2H), 3.22–3.13 (m, 1H), 2.99–2.80 (m, 2H), 2.68–2.59 (m,
1H), 2.44–2.32 (m, 1H), 2.26–2.10 (m, 2H), 1.70–1.38 (m,
4H), 1.34 (d, 3H, J = 6.6 Hz), 0.86 (s, 9H), 0.03 (d, 6H, J =
1.8 Hz); 13C NMR (CDCl3) δ 210.3, 145.5, 128.4, 127.2,
127.0, 62.8, 57.8, 56.8, 44.4, 43.4, 40.1, 28.9, 26.6, 25.9,
18.7, 18.2, –5.3; HR-ESI-MS m/z Calcd for C22H38NO2Si
(M + H+) 376.2672, Found 376.2682.
1
anoic acid methyl ester): yield 90%. H NMR (CDCl3) δ
7.33–7.16 (m, 5H), 3.95 (q, 1H, J = 6.9 Hz), 3.60 (s, 3H),
3.67–3.38 (m, 3H), 3.04–2.80 (m, 4H), 2.52–2.23 (m, 2H),
1.37 (d, 3H, J = 6.9 Hz), 0.86 (s, 9H), 0.01 (d, 6H, J = 4.8
Hz).
Compound 4d ((3S)-3-[[(1R)-1-phenylethyl]-2-iodoe-
thylamino]-benzenepropanoic acid methyl ester): yield 88%.
1H NMR (CDCl3) δ 7.38–7.20 (m, 10H), 4.45 (t, 1H, J = 8.1
Hz), 3.94 (t, 1H, J = 6.9 Hz), 3.57 (s, 3H), 3.03–2.62 (m,
6H), 1.26 (d, 3H, J = 6.9 Hz).
Compound 5c ((2S)-2-[[[(1,1-dimethylethyl)dimethylsi-
lyl]oxy]methyl]-1-[(1R)-1-phenylethyl]-4-piperidone): yield
28
1
Compound 4e ((3R)-3-[[(1R)-1-phenylethyl]-2-iodoe-
thylamino]-benzenepentanoic acid methyl ester): yield 91%.
1H NMR (CDCl3) δ 7.37–7.12 (m, 10H), 3.89 (q, 1H, J =
6.6 Hz), 3.60 (s, 3H), 3.41–3.24 (m, 1H), 3.09–2.72 (m, 5H),
2.61–2.47 (m, 1H), 2.26 (d, 2H, J = 6.3 Hz), 1.81–1.58 (m,
2H), 1.40 (d, 3H, J = 6.6 Hz).
67%. [α]D +12.1 (c 1.40, CHCl3); H NMR (CDCl3) δ
7.42–7.20 (m, 5H), 4.10 (q, 1H, J = 6.8 Hz), 3.69 (d, 2H, J
= 4.6 Hz), 3.36–3.30 (m, 1H), 2.95–2.79 (m, 2H), 2.59–2.52
(m, 1H), 2.45–2.38 (m, 1H), 2.37–2.28 (m, 1H), 2.24–2.15
(m, 1H), 1.37 (d, 3H, J = 6.8 Hz), 0.88 (s, 9H), 0.03 (d, 6H,
J = 6.0 Hz); 13C NMR (CDCl3) δ 210.1, 145.5, 128.4, 127.2,
127.0, 64.1, 58.8, 57.7, 44.0, 43.0, 40.5, 26.0, 25.9, 18.3,
17.9; HR-ESI-MS m/z Calcd for C20H34NO2Si (M + H+)
348.2359, Found 348.2360.
Compound 4f ((3S)-3-[[(1R)-1-phenylethyl]-2-iodoe-
thylamino]-4-methylbenzenepropanoic acid methyl ester):
1
yield 91%. H NMR (CDCl3) δ 7.36–7.10 (m, 9H), 4.42 (t,
1H, J = 7.2 Hz), 3.93 (q, 1H, J = 6.9 Hz), 3.57 (s, 3H),
3.02–2.61 (m, 6H), 2.34 (s, 3H), 1.25 (d, 3H, J = 6.9 Hz).
Compound 5d ((2S)-2-phenyl-1-[(1R)-1-phenylethyl]-4-
26
1
piperidone): yield 32%. [α]D +23.9 (c 1.52, CHCl3); H
NMR (CDCl3) δ 7.54–7.22 (m, 10H), 3.97 (q, 1H, J = 6.4
Hz), 3.93 (dd, 1H, J = 10.4, 4.0 Hz), 2.95–2.88 (m, 1H),
2.78–2.69 (m, 1H), 2.66–2.49 (m, 3H), 2.36–2.29 (m, 1H),
1.24 (d, 3H, J = 6.4 Hz); 13C NMR (CDCl3) δ 209.0, 143.8,
142.1, 129.0, 128.1, 127.8, 127.4, 127.3, 126.7, 64.7, 54.8,
50.2, 44.0, 41.9, 9.4; HR-ESI-MS m/z Calcd for C19H22NO
(M + H+) 280.1701, Found 280.1700.
2.5 Synthesis of (2S)-2-isopropyl-1-[(1R)-1-phenylethyl]-
4-piperidone (compound 5)
Compound 4 (1 mmol) was dissolved in dry THF (20 mL)
under Ar atmosphere and cooled to –78°C. n-BuLi (0.63
mL, 1.6 M in hexane) was dropped into the reaction mixture
at same temperature. After 30 min, saturated NaHCO3
aqueous solution was added to quench the reaction. The
mixture was extracted with diethyl ether three times and
combined organic phase was washed, dried and concentrat-
ed at reduced pressure. The residue was purified by silica
gel flash column chromatography eluted with EtOAc/
hexane.
Compound 5e ((2R)-2-(2-phenylethyl)-1-[(1R)-1-phe-
28
nylethyl]-4-piperidone): yield 45%. [α]D +14.1 (c 1.36,
1
CHCl3); H NMR (CDCl3) δ 7.45–7.11 (m, 10H), 4.00 (q,
1H, J = 6.4 Hz), 3.33–3.25 (m, 1H), 3.08–2.99 (m, 1H),
2.96–2.87 (m, 1H), 2.77–2.69 (m, 1H), 2.62 (t, 2H, J = 8.0
Hz), 2.50–2.40 (m, 1H), 2.36–2.28 (m, 1H), 2.22–2.14 (m,
1H), 1.90–1.79 (m, 1H), 1.74–1.61 (m, 1H), 1.33 (d, 3H, J =
6.4 Hz); 13C NMR (CDCl3) δ 210.3, 145.5, 141.8, 128.5,
128.4, 128.3, 127.1, 127.0, 125.9, 58.3, 56.6, 44.1, 43.5,
40.0, 32.1, 32.0, 19.6; HR-ESI-MS m/z Calcd for C21H26NO
(M + H+) 308.2014, Found 308.2046.
26
Compound 5: yield 50%. [α]D +21.3 (c 1.75, CHCl3);
1H NMR (CDCl3) δ 7.47–7.21 (m, 5H), 4.20 (q, 1H, J = 6.8
Hz), 3.05–2.89 (m, 2H), 2.69–2.63 (m, 1H), 2.55–2.47 (m,
1H), 2.40–2.27 (m, 2H), 2.25–2.16 (m, 1H), 1.98–1.86 (m,

6
Chen BL, et al. Sci China Chem January (2014) Vol.57 No.1
Compound 5f ((2S)-2-(4-methylphenyl)-1-[(1R)-1-phenyl-
3 Results and discussion
24
ethyl]-4-piperidone): yield 20%. [α]D +24.3 (c 1.00,
CHCl3); 1H NMR (CDCl3) δ 7.50–7.17 (m, 9H), 3.96 (q, 1H,
J = 6.4 Hz), 3.87 (dd, 1H, J = 10.0, 3.6 Hz), 2.93–2.86 (m,
1H), 2.76–2.68 (m, 1H), 2.62–2.49 (m, 3H), 2.34 (s, 3H),
2.33–2.26 (m, 1H), 1.22 (d, 3H, J = 6.4 Hz); 13C NMR
(CDCl3) δ204.8, 139.5, 134.8, 133.2, 125.3, 123.7, 123.0,
122.9, 122.3, 60.1, 50.3, 46.0, 39.7, 37.6, 16.8, 4.9;
HR-ESI-MS m/z Calcd for C20H24NO (M + H+) 294.1858,
Found 294.1862.
3.1 Novel synthetic access to (2S)-2-isopropyl-1-[(1R)-
1-phenylethyl]-4-piperidone
According to the proposed retrosythetic analysis, we started
our experiment with the highly diastereoselective conjugate
addition of homochiral lithium amides to trans-β-substituted-
α,β-unsaturated esters developed by Davis [28]. Because of
the commercial availability of isobutyraldehyde and (R)-α-
methylbenzylamines, we easily synthesized (R)-N-allyl-N-
(α-methylbenzyl)amine and corresponding trans-β-isopropyl
methyl ester. These two compounds underwent highly dia-
stereoselective conjugate addition, affording compound 2
while the minor diasteroisomeric product can be discarded
through silica gel flash column chromatography. Consecu-
tive dihydroxylation reaction catalyzed by OsO4, oxidation
and cleavage of diol by NaIO4 and reduction of aldehyde by
NaBH4 converts compound 2 to compound 3. After the hy-
droxyl group was replaced by iodine via PPh3/imidazole/I2
reaction system with satisfied yield, compound 4 was in
hand. We first exploited previous condition [25] for the
ring-formation reaction with compound 4 and successfully
obtained the desired product compound 5 with 50% yield
and 81% conversion (Scheme 3). In summary, (2S)-2-iso-
propyl-1-[(1R)-1-phenylethyl]-4-piperidone was synthe-
sized with three steps and 42% overall yield starting from
compound 2. However, the low yield of the ring-formation
reaction compromised the whole efficiency of this novel
2.6
Synthesis of some non-chiral 3-substituted-4-
piperidones
Compound 9, 11 were synthesized according to previous
report [29] and compound 17, 18 were gifts from lab col-
leagues. Compound 6, 7, 8, 10, 12, 16 were synthesized via
above methods. Procedures of synthesis of compound 13,
14, 15 were described in supporting information.
Compound 10 (2-methyl-3-[(2-iodoethyl)(phenylmethyl)
1
amino]-propanoic acid methyl ester): yield 82%. H NMR
(CDCl3) δ 7.37–7.20 (m, 5H), 3.70–3.54 (AB, 2H, JAB
=
13.8 Hz), 3.68 (s, 3H), 3.15–3.00 (m, 2H), 2.88–2.61 (m,
4H), 2.54–2.44 (m, 1H), 1.12 (d, 3H, J = 7.2 Hz).
Compound 6 (3-Methyl-1-(phenylmethyl)-4-piperidone):
1
yield 70%. H NMR (CDCl3) δ 7.40–7.25 (m, 5H), 3.60 (s,
2H), 3.13–3.04 (m, 2H), 2.70–2.54 (m, 2H), 2.46–2.30 (m,
2H), 2.18–2.03 (m, 1H), 0.99 (d, 3H, J = 7.2 Hz); 13C NMR
(CDCl3) δ 211.1, 138.2, 128.9, 128.4, 127.3, 61.8, 60.7,
53.8, 44.3, 40.9, 12.0; HR-ESI-MS m/z Calcd for C13H18NO
(M + H+) 204.1379, Found 204.1367.
Compound 12 (2,2-dimethyl-3-[(2-iodoethyl)(phenyl-
1
methyl)amino]-propanoic acid methyl ester): yield 83%. H
NMR (CDCl3) δ 7.38–7.21 (m, 5H), 3.66 (s, 2H), 3.65 (s,
3H), 3.08–2.78 (m, 4H), 2.77 (s, 2H), 1.17 (s, 6H).
Compound 7 (3,3-dimethyl-1-(phenylmethyl)-4-piperi-
1
done): yield 77%. H NMR (CDCl3) δ 7.45–7.23 (m, 5H),
3.56 (s, 2H), 2.72 (t, 2H, J = 6.0 Hz), 2.51 (t, 2H, J = 6.0
Hz), 2.40 (s, 2H), 1.13 (s, 6H); 13C NMR (CDCl3) δ 214.0,
138.6, 128.6, 128.3, 127.1, 65.5, 62.0, 54.0, 53.4, 45.7, 38.4,
23.6; HR-ESI-MS m/z Calcd for C14H20NO (M + H+)
218.1545, Found 218.1536.
Compound 16 (2-methyl-2-(phenylmethoxy)-3-[(2-iodo
ethyl)(phenylmethyl)amino]-butanoic acid methyl ester):
yield 86%. 1H NMR (CDCl3) δ 7.42–7.18 (m, 10H),
4.60–4.46 (AB, 2H, JAB = 10.8 Hz), 3.88–3.66 (AB, 2H, JAB
= 13.8 Hz), 3.73 (s, 3H), 3.11–2.85 (m, 6H), 1.50 (s, 3H).
Compound 8 (3-methyl-3-(phenylmethoxy)-1-(phenyl-
methyl)-4-piperidone): yield 85%. 1H NMR (CDCl3) δ
7.43–7.24 (m, 10H), 4.59–4.48 (AB, 2H, JAB = 10.8 Hz),
3.66 (s, 2H), 2.94–2.56 (AB, 2H, JAB = 12.0 Hz), 2.83–2.72
(m, 3H), 2.54–2.44 (m, 1H), 1.44 (s, 3H); 13C NMR (CDCl3)
δ 209.9, 138.8, 138.1, 128.8, 128.4, 128.3, 127.4, 127.3,
80.4, 65.9, 63.3, 61.5, 53.5, 39.0, 19.5; HR-ESI-MS m/z
Calcd for C20H24NO2 (M + H+) 310.1807, Found 310.1798.
Scheme 3 Synthesis of compound 5. (a) Allyl bromide, n-BuLi, THF,
–50°C to r.t., 74%; (b) Ph3P=CCO2Me, DCM, r.t., 85%; (c) n-BuLi, THF,
–78°C, 75%; (d) OsO4, THF/H2O, r.t., quant; (e) NaIO4, NaBH4, MeOH,
95%; (f) PPh3, imidazole, I2, ether/CH3CN, 90%; g) n-BuLi, THF, –78°C,
50% (conv 81%). The yield of the ring-formation step was calculated based
on consumed substrate.

Chen BL, et al. Sci China Chem January (2014) Vol.57 No.1
7
route, which urges us to further explore the cyclization con-
dition.
increased to 65%. On the contrary, the conversion ratio de-
creased from 75% to 44% (entry 9, 10, 11). Moreover, em-
ployment of MesLi gave a major side product due to the
prevalence of deprotonation at the α-position of ester (entry
12).
3.2 Optimization of the cyclization condition
With compound 4 in hand, we tested different conditions
for the key ring-formation reaction (Table 1). Solvents al-
ways play decisive roles in organic reactions, so we first
screened several kinds of solvents. When diethyl ether and
hexane were used as solvents, no products was detected and
compound 4 was recovered (entry 2, 4). DME gave trace
product and yield of compound 5 can only be raised up to
17% even 2.5 equiv n-BuLi was added (entry 3). The at-
tempt of using mixed solvent (hexane/THF = 1:1) also
failed (entry 5). These results showed that THF was most
suitable for this ring-formation reaction.
Since ester functions as an electrophilic group in this re-
action which may play a pivotal role in outcome, we next
screened three kinds of esters: methyl ester, ethyl ester and
t-butyl ester (entry 6, 7, 8). We can find that ethyl ester sub-
strate gave little lower yield than methyl ester substrate
while t-Butyl ester substrate failed in this reaction with
complicated results, indicating that methyl ester was better
than the other two counterparts.
We also performed this reaction at lower temperature
(–100°C) according to previous reports[25, 26]. To our dis-
appointment, lower temperature did not show any advantage
because both yield and conversion ratio were similar com-
pared to –78°C (entry 13). From another point of view, liq-
uid nitrogen was more dangerous in manipulation than dry
ice in lab.
After screening of various solvents, reagents, substrates
and temperatures and based on the above observations, we
make sure that this ring-formation reaction should be best
performed in THF at –78°C using 1eq n-BuLi as reagent
and methyl ester as substrate.
3.3 Synthesis of a diversity of chiral 2-aryl/alkyl-4-
piperidones and non-chiral 3-substituted-4-piperidones
Next we prepared a series of trans-β-aryl/alkyl-α,β-
unsaturated methyl esters (Figure 2) and set to synthesize a
diversity of chiral 2-aryl/alkyl-4-piperidone (Scheme 4) as
well as some non-chiral 3-substituted-4-piperidones
(Scheme 5) via this novel route we developed. From the
results below (Table 2), we can see that compounds 4a4f
can be prepared smoothly with good yield after 3 steps
starting from various methyl esters. For the key ring-
formation step, 2-aryl substrates showed lower yield (entry
Schakel [26] and Sakamoto [30] reported t-BuLi and
MesLi were good lithium-iodine exchange reagents as well,
which guided us to test these two lithium reagents. The the-
oretical amount of t-BuLi used in this reaction was 2 equiv.
However, when 2equiv t-BuLi was used, the yield was only
40%. With the decreased amount of t-BuLi used, the yield
Table 1 Screening of conditions for key ring-formation reaction, including substrates, solvents, reagents and temperature
Entry
1
R
Me
Me
Me
Me
Me
Me
Et
Solvent
THF
Reagent
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
t-BuLi
t-BuLi
t-BuLi
MesLi
n-BuLi
Equiv
1.3
1.3
2.5
1.9
1.8
1.3
1.3
1.3
1
Temperature
–78°C
–78°C
–78°C
–78°C
–78°C
–78°C
–78°C
–78°C
–78°C
–78°C
–78°C
–78°C
–100°C
Yield a) % (conv %)
50 (81)
2
DEE
NR
3
DME
17 (90)
4
hexane
hexane/THF (1:1)
THF
NR
5
30 (100)
50 (81)
6
7
THF
40 (83)
8
t-Bu
Me
Me
Me
Me
Me
THF
complex
65 (44)
9
THF
10
11
12
13
THF
1.5
2
50 (50)
THF
40 (75)
side product b)
THF
1.3
1.3
THF
47 (70)
a) The yield was calculated based on consumed substrate. b) The major product was formed due to the prevailing deprotonation followed by SN reaction.

8
Chen BL, et al. Sci China Chem January (2014) Vol.57 No.1
Table 2 Results of this novel synthetic access to chiral 2-aryl/alkyl-4-piperidones and non-chiral 3-substituted-4-piperidones
Entry
Product
2a
Yield (%)
Product
3a
Yield (%)
Product
4a
Yield (%)
Product
Yield a) (%) (conv %)
53 (67)
1
2
3
4
5
6
7
8
9
85
100
91
95
73
91
94
90
98
81
89
90
88
91
91
82
83
82
5a
5b
5c
5d
5e
5f
6
2b
3b
3c
4b
42 (92)
2c
4c
67 (80)
2d
90
3d
3e
4d
32 (87)
2e
94
4e
45 (80)
2f
95
3f
4f
20 (80)
9
10
70 (84)
11
12
7
77 (70)
15
16
8
85 (99)
a) Yield was calculated based on consumed substrates.
thyl, dimethyl and methyl/phenylmethoxy respectively, the
yield of ring-formation reaction can be enhanced to 70%,
77% and 85% (entry 7, 8, 9) due to the more steric effect
and less incidence of deprotonation. This great achievement
clearly demonstrated that side reactions of this ring-
formation reaction could be significantly abolished by in-
creased steric effect adjacent to the ester group and excel-
lent yield could be anticipated.
Figure 2 A variety of trans-β-aryl/alkyl-α,β-unsaturated methyl esters
were prepared.
4 Conclusions
In summary, we reported here a novel, concise and versatile
access to a diversity of chiral 2-aryl/alkyl-4-piperidones that
can be further converted to chiral piperidine structures oc-
curring in many nature products and drug molecules. The
establishment of chirality at 2-position was dependent on
the highly diastereoselective conjugate addition of homo-
chiral lithium amides to trans-β-substituted-α,β-unsaturated
methyl esters. The ring-formation reaction relies on the
competitive intramolecular attack of carbanion to ester. This
method complemented current methods to chiral 2-subs-
tituted-4-piperidone in that it can give chiral 2-aryl and
2-alkyl-4-piperidones simultaneously. Because the severe
side reaction caused by lithium reagents attacking unantici-
pated reactive sites in the substrate, only modest yield were
obtained in the final ring-formation reaction. However, in-
creasing the steric effect adjacent to the ester group led to
satisfied yield of the ring-formation reaction and remarka-
bly enhanced the overall efficiency of this new route,
showing the great potential of its application in the synthe-
sis of chiral piperidine structure in the near future.
Scheme 4 Synthesis of various chiral 2-aryl/alkyl-4-piperidones using
above method.
R1 R2
CO2Me
R1 R2
CO2Me
R1
BnN
R2
BnN
BnN
OH
I
O
R1 = H, R2 = Me
6
10
12
16
9
R1 = Me, R2 = Me
R1 = Me, R2 = OBn
7
8
11
15
Scheme 5 Synthesis of some non-chiral 3-substituted-4-piperidones
using similar method.
We thank CAS Key Laboratory of Synthetic Chemistry of Natural Sub-
stances (2008DP173071) for analysis support. The authors also thank Dr.
Xing-Wen Sun for helpful discussion.
4, 6), possibly attributed to the severe side interaction be-
tween lithium reagent and the bezene ring. Generally
2-alkyl substrates afforded higher yield and compound 4c
gave the highest yield (65%, entry 3). Structure analysis
inspired us that the steric effect at the 2-position may to a
certain extent impede the side reactions. When the
α-position of ester in the substrate was substituted by me-
1
2
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