A practical procedure for the removal of the phenylethanol moiety from phenylglycinol-derived lactams

Article abstract of DOI:10.1016/j.tetasy.2010.09.014

Chiral non-racemic bicyclic lactams derived from phenylglycinol have been appointed as key building blocks for the preparation of enantiopure nitrogen compounds. The removal of the chiral inductor leading to substituted piperidones by using air or oxygen

Full text of DOI:10.1016/j.tetasy.2010.09.014

Tetrahedron: Asymmetry 21 (2010) 2542–2549
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A practical procedure for the removal of the phenylethanol moiety
from phenylglycinol-derived lactams
⇑
Vladislav Semak, Carmen Escolano , Carlos Arróniz, Joan Bosch, Mercedes Amat
Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of Biomedicine (IBUB), University of Barcelona, 08028 Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral non-racemic bicyclic lactams derived from phenylglycinol have been appointed as key building
blocks for the preparation of enantiopure nitrogen compounds. The removal of the chiral inductor leading
to substituted piperidones by using air or oxygen in basic media is presented.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 14 September 2010
Accepted 29 September 2010
Available online 26 October 2010
1. Introduction
kylation reaction involving the introduction of a substituent at
the a-position, or by reductive treatment with Et3SiH in the pres-
Chiral aminoalcohol-derived bicyclic lactams1 are considered as
an outstanding example of organic enantiomeric scaffolds2 for the
enantiocontrolled synthesis of complex molecules. These com-
pounds are easily accessible via cyclocondensation reactions of
racemic or prochiral d-oxo(di)acid derivatives with chiral nonrace-
mic amino alcohols. Amongst them, phenylglycinol-derived oxazo-
lopiperidone lactams (R = Ph) are exceptionally versatile building
blocks for the enantioselective construction of structurally diverse
piperidine-containing natural products and bioactive compounds
(Scheme 1).3
ence of a Lewis acid (TiCl4); and (2) debenzylation by treatment
under dissolving metal conditions (sodium in liquid ammonia)4
or multistep processes.5 This methodology provides versatile
diversely substituted enantiopure piperidones, which are key
intermediates in the construction of nitrogen compounds
(Scheme 2).
Alternatively, removal of the chiral inductor to afford piperidine
derivatives can be performed by the initial reduction (LiAlH4, BH3,
etc.) of the lactam carbonyl followed by debenzylation by
hydrogenolysis.3
R
*
R
*
OH
O
O
N
NH2
+
1.Stereoselective
cyclocondensation
*
R1
R2
COMPLEX
CHIRAL
R1
R2
O
*
*
*
MOLECULES
MeO2C
2.Introduction of
R4
further substituents
R3
Substituted chiral
R3
nonracemic lactams
ENANTIOMERIC
SCAFFOLDS
R1; R2; R3 = H, alkyl, aryl
Scheme 1. General strategy.
Typically, bicyclic lactams with the general structure A are
transformed into enantiopure polysubstituted 2-piperidones by
removing the chiral inductor in two steps: (1) opening of the
Conventional Birch debenzylation reductions6 are performed
with alkali metals in liquid ammonia at ꢀ33 °C. Despite its utility,
this method has several undesirable drawbacks that limit its use,
particularly on a large scale,7 such as the inherent dangers of han-
dling elemental alkali metals and the toxicity of ammonia, and also
the nuisance and hazards of running cryogenic reactions.8 More-
over, in the particular case of phenylglycinol-derived lactams, the
oxazolidine ring, which is accomplished either by an
a-amidoal-
⇑
Corresponding author. Tel.: +34 934 024 540; fax: +34 934 024 539.
E-mail address: cescolano@ub.edu (C. Escolano).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.09.014

V. Semak et al. / Tetrahedron: Asymmetry 21 (2010) 2542–2549
2543
Ph
Ph
*
*
OH
R1
H
N
Cleavage of the
O
R1
O
O
N
O
N
phenylethanol
moiety
*
Opening of the
oxazolidine ring
*
*
R2
R2
R2
A
Enantiopure
polysubstituted 2-piperidones
Scheme 2. Steps to remove the chiral inductor from lactams A.
crude reaction mixture after the aqueous work-up contains phen-
ylethanol, which has to be separated from the final N-unsubstitut-
ed piperidones by column chromatography.
The diastereoselective alkylation of non-substituted oxazolopi-
peridone trans-1 with EtI gave exclusively
a-ethyl substituted
oxazolopiperidone 3,12a and the dialkylation reaction with allylbro-
In 1983, Gigg reported the use of potassium tert-butoxide/DMSO
and O2 for the rapid N-debenzylation of nitrogen-functionalized
glucopyranosides.9 Nearly twenty years later, the same reagents in
the hands of Deaton–Rewolinski allowed the N-debenzylation of
aromatic heterocycles.10 Simultaneously, a novel and efficient oxi-
dation of 1,2-aminoalcohols to dialkylamides with potassium
hydroxide under aerobic conditions was accomplished by Pedrosa.11
Inspired by this previous work, and in an effort to avoid the
drawbacks of using sodium in ammonia or multistep sequences,
we herein report an easy, safe and cost-effective procedure for
the removal of the 2-hydroxy-1-phenylethyl moiety from the phe-
nylglycinol chiral auxiliary in chiral oxazolopiperidone bicyclic lac-
tams. Essentially, it consists of the use of oxygen as an oxidant
under basic conditions.
mide led to bicyclic lactam 4.15
By choosing the appropriate organometallic reagent, the stereo-
controlled formation of a C–C bond at the C-6 position of the pip-
eridone can be ensured.14 The opening of the oxazolidine ring by
Grignard reagents (MeMgBr and PhMgBr) from trans-1 took place
stereoselectively with retention of configuration at the C-8a
stereocentre, to afford the corresponding compounds 5 and 6.14
The reaction of trans-1 with indole in the presence of TiCl4 led to
a 3:1 mixture of 6-(3-indolyl)-2-piperidones 7 and 6-epi-7. The
N-MEM-indole derivative 7a was prepared from 7 by silylation of
the hydroxy group, followed by reaction with MEMCl, and desily-
lation with TBAF (73% overall yield).16
The stereochemical outcome changed when a Lewis acid such
as TiCl4 was used, and introduction of allyltrimethylsilane to
trans-2 and 3 took place with inversion of the configuration at
the C-8a stereocenter to give the respective cis-5,6-disubstituted
piperidone 8 and 3,6-disubstituted piperidone 9.
2. Results and discussion
Finally, reductive cleavage of the C–O bond of the oxazolidine
ring of 4 with Et3SiH–TiCl4 gave compound 10 in 78% yield
(Scheme 4).
2.1. Preparation of N-(2-hydroxy-1-phenylethyl)-2-piperidones
5–10
Enantiopure lactams cis-1 and cis-2 are easily accessible by
cyclocondensation of (S)-phenylglycinol with methyl 5-oxopent-
anoate12 or methyl 4-formylhexanoate,13 respectively, under neu-
tral conditions. Isomerization of cis-1 and cis-2 under acidic
conditions gave access to H-3/H-8a trans lactams trans-112 and
trans-2,4d respectively (Scheme 3).
In order to study the scope of the proposed debenzylation reac-
tion, a variety of diversely substituted N-(2-hydroxy-1-phenyl-
ethyl)-2-piperidones were prepared by diastereoselective enolate
2.2. Debenzylation reaction of lactams 5–10
2.2.1. Reaction conditions
With a variety of diversely substituted N-(2-hydroxy-1-phenyl-
ethyl)-2-piperidones in hand, we first decided to set up new oxida-
tive reaction conditions from the 5,6-cis disubstituted lactam 8
(Table 1).
To start with, we considered the conditions used by Pedrosa in
the oxidation of amino alcohols and amino ketones to dialkyla-
mides and carboxylic acids.11 Treatment of 8 with an excess of
KOH in Et2O at room temperature under aerobic conditions led
to 14 in 65% yield (entry 1), which increased to 80% under an oxy-
gen atmosphere (entry 2). Remarkably, benzoic acid was formed in
these reactions.
In order to fine tune the reaction conditions, we then studied
possible modifications of different factors such as the base, solvent,
atmosphere, and sun lamp/heating. As mentioned earlier, one of
alkylation and/or
experimental conditions previously described by our group.
In previous studies all attempts to carry out -amidoalkylation
a-amidoalkylation procedures, following the
a
reactions from lactams cis-1 or cis-2 have been unsuccessful. In all
cases, only the starting material was recovered, thus confirming
the reluctance of cis H3–H8a phenylglycinol-derived lactams to
undergo
a
-amidoalkylation reactions.14 However, the opening of
the oxazolidine ring in lactams with a trans relationship between
H-3/H-8a has been performed easily. Thus, trans-1 and trans-2 lac-
tams were chosen as starting materials.
Ph
Ph
Ph
(S)
3
H2N
OH
O
O
O
N
O
N
isomerization
b
8a
+
a
MeO2C
CHO
R
8
R
R
R = H, trans-1
R = Et, trans-2
R = H, cis-1
R = Et, cis-2
Scheme 3. Synthesis of the starting lactams. Reagents and conditions: (a) toluene, reflux, 36 h, 86%, cis-1/trans-1 85:15; toluene, reflux, 18 h, 80%, cis-2/trans-2/epi-8-trans-2
63:25:12; (b) TFA–CH2Cl2 64 h, 25 °C, from cis-1, 14:86 cis-1/trans-1; MeOH–HCl 3 M, 25 °C, 25 h, from cis-2, cis-2/trans-2/epi-8-trans-2 28:70:2.

2544
V. Semak et al. / Tetrahedron: Asymmetry 21 (2010) 2542–2549
Ph
Ph
O
O
O
N
O
N
alkylation from trans-1
R1
R2
a
R
trans-1
R = Et, trans-2
R = H,
1
2
3
R = Et, R = H,
R1 = R2 = allyl, 4
b
α-amidoalkylation
b
Ph
Ph
Ph
OH
R3
OH
R3
OH
R3
O
N
O
N
O
N
R1
R2
Et
R3 = Me, 5
R3= allyl, 8
3
R1 = Et, R2 = H, R3 = allyl, 9
6
R = Ph,
1
2
3
10
R = R = allyl, R = H,
R3 = 3-indolyl, 7
c
R3= N-MEM-3-indolyl, 7a
Scheme 4. Synthesis of starting lactams. Reagents and conditions: (a) (i) LiHMDS, ꢀ78 °C, 1 h; (ii) EtI, 2 h, 83%, 3; (b) MeMgBr, Et2O, 0 °C, 8 h, 62%, 5. PhMgBr, 0 °C, 8 h, 72%, 6.
Indole, TiCl4, 25 °C, 30 min, 80%, 3:1, 7: 6-epi-7. AllylSiMe3, TiCl4, CH2Cl2, rt, 23 h, 83%, 8. AllylSiMe3, TiCl4, CH2Cl2, 0 °C, 2 h and rt, 16 h, 91%, 9. Et3SiH, TiCl4, CH2Cl2, rt, 18 h,
78%, 10; (c) (i) tBuMe2SiCl, imidazole, DMF, 35 °C; (ii) KH, ClCH2OCH3, THF, 0 °C, 81%; (iii) Bu4NF, THF, 4 h, rt, 90%, 7a.
2.2.1.2. Solvent. As the use of Et2O or THF under aerobic condi-
tions can result in the formation of dangerous peroxides, other sol-
vents such as toluene and tert-butylmethylether (MTBE) were
tested.18 The use of toluene required increasing the reaction time
to 65 h to complete the conversion of 8 into the final product, with
the yield being lower (49%) (entry 5).
Table 1
Debenzylation conditions of lactam 8
Ph
OH
H
N
O
O
N
In contrast, MTBE, which has a distinct advantage over most
ethers in showing no tendency to form explosive organic perox-
ides, proved to be a good media for the debenzylation reaction (en-
try 6). Changes in the lactam concentration had no influence on the
final yield.
14
8
2.2.1.3. Sun lamp/heat. Based on a previous work suggesting a
radical mechanism in debenzylation reactions by oxidative proce-
dures involving oxygen, we included a sun lamp in the above
experimental process (entries 3–6).19
To determine if the heat provided by the sun lamp was the real
accelerator, the following reactions were carried out at 40 °C in
the dark (entries 7–11). Indeed, the new conditions gave a good
yield (71%) of the pure final product (entry 7). Reduction of the ex-
cess of base to 10 equiv resulted in an 83% yield (entry 8),
although a further reduction to 5 equiv resulted in a lower yield
(entry 9).
a A 250 W sun lamp was used at 25 cm of the reaction flask.
b 27% of 8 was recovered (entry 10), 10% of 8 was recovered (entry 11).
When the reaction was carried out under aerobic conditions,
27% of the starting material was recovered (entry 10). At room
temperature, the debenzylated product 14 was obtained in 68%
yield, with recovery of 10% of the starting material 8 (entry 11).
From the above experiments, the best debenzylation conditions
for lactam 8 were the use of NaOH (10 equiv) in MTBE as the sol-
vent at 40 °C in the presence of oxygen (entry 8).
To compare these new debenzylation conditions with the Birch
procedure, we subjected compound 8 to the Na/liquid NH3 reaction
conditions. The best yield (81%, 14; 7%, 8) was obtained when the
reaction was performed at ꢀ33 °C starting from 1 g of 8. When the
our concerns was to develop a methodology that would tackle the
scale-up problems of other debenzylation methods.
2.2.1.1. Base. The number of equivalents of the base and its solu-
bility were improved by replacing KOH with NaOH and Et2O with
THF, respectively. Thus, when the reaction was carried out using
NaOH as the base in THF under oxygen atmosphere in the presence
of a sun lamp (20 h), the final product 14 was isolated in 60% yield
(entry 3). Halving the NaOH (25 equiv) had no effect on the yield
(entry 4).17

V. Semak et al. / Tetrahedron: Asymmetry 21 (2010) 2542–2549
2545
reaction was scaled up, the starting product 8 (3 g) was consumed
but the formation of 14 was not observed.
2.2.2. Debenzylation of lactams 5–10
With the aim of evaluating the scope of the reaction, the cleav-
age of the 2-hydroxy-1-phenylethyl moiety in different substituted
lactams 5, 6, 7a, 9 and 10 was undertaken (Table 2).
When the 6-methyl substituted lactam 5 was treated under the
standard basic oxidative conditions using THF or MTBE as the sol-
vent, debenzylation occurred in good yield (87%) to give 6-methyl-
2-piperidone 11 (entry 1). Notably, in some runs enamide 17 and
imide 18 were formed in low yield (Scheme 5). These products
are key intermediates to postulate the mechanism of the reaction
(see Section 3).
The experimental conditions involved in the Na/liquid NH3
methodology are somewhat difficult to control. For example, Na
metal is added in small portions to a solution of the lactam in
NH3 until a blue colour persists, but as the surface of Na is rapidly
damaged by the air, the quantities of metal used are variable.
Moreover, the basic conditions can affect some functional
groups.
In contrast, the reagents and conditions involved in the oxygen-
mediated debenzylation reaction are controllable, the consump-
tion of the starting material is easily monitored by TLC and the
reaction can be carried out on a multigram scale.
Similarly, 6-phenyl lactam 6 was transformed into 12 in good
yield (entry 2; 81%). In this case THF was used as a solvent due
Table 2
Cleavage of the 2-hydroxy-1-phenylethyl moiety
Ph
OH
H
O
N
O2
O
N
NaOH (10-25 equiv)
40ºC, 24 h.
ether solvent
R
R
Entry
1
Starting material
Product
Yield (%)
87
Ph
H
O
N
Me
OH
Me
O
O
N
N
11
Ph
5
Ph
H
N
O
OH
Ph
2
3
81
72
12
6
Ph
H
N
O
OH
O
N
N
MEM
N
13
7a
MEM
Ph
Ph
H
N
O
O
OH
O
O
N
N
4
5
85
14
8
H
N
OH
89a
15
9
Ph
H
N
O
OH
O
N
6
88
16
10
a
Epimerization was observed at the C-3 position to furnish a 1:1 mixture of 15 and 3-epi 15.

2546
V. Semak et al. / Tetrahedron: Asymmetry 21 (2010) 2542–2549
O
Ph
Ph
Ph
O
OH
Me
NaOH, O2
H
N
Me
O
Me
+
O
N
O
N
O
N
Me
+
PhCOOH
+
17
11
5
18
O
H
O
-OH
Ph
O
H
- O2,
-H2O
Me
O
N
a
Scheme 5. Postulated mechanism of O2/OHꢀ mediated debenzylation process.
to the low solubility of the starting material in MTBE. Notably, this
transformation involves the chemoselective cleavage of the exocy-
clic N–CHPh bond.
nyl moiety was proven to be an essential structural requirement
for the progress of the reaction.
When the reaction was performed from the 6-N-MEM-indolyl
derivative 7a, the N-unsubstituted lactam 13 was isolated in 72%
yield (entry 3). Debenzylation from the N-unprotected indole
derivative 7 was unsuccessful.
As mentioned above, the reaction of 5,6-cis-disubstituted lac-
tam 8 (3 g) under standard conditions furnished 14 in 85% yield
after 24 h (entry 4).
When 3,6-disubstituted lactam 9 was subjected to the standard
debenzylation conditions, a 1:1 mixture of lactams 15 and 3-epi-15
was obtained (entry 5). The same result was observed when the
reaction was carried out at room temperature. Epimerization of
lactam 15 occurred after treatment with base under an inert atmo-
sphere, indicating the lability of the acidic proton. However, lactam
9 remained unchanged under the same conditions.
4. Conclusion
In conclusion, as an alternative to classical Na/liquid NH3 condi-
tions, we have provided an environmentally friendly, easy to han-
dle, and cost-effective method for cleaving the N-(2-hydroxy-1-
phenyl)ethyl moiety from phenylglycinol-derived oxazolopiperi-
done lactams. Advantageously, air (diluted oxygen) or oxygen,
which are the cheapest oxidants, was used without irradiation or
catalysts. The reaction work-up only requires an acid-base extrac-
tion to eliminate the benzoic acid formed, and the desired deben-
zylated product can be used for synthetic purposes without further
purification. Moreover, a putative mechanism for this transforma-
tion has been proposed based on the isolation of possible interme-
diates in the process.
Finally, the debenzylation of 3,3-diallyl substituted derivative
10 gave 16 in 88% yield (entry 6).
5. Experimental
5.1. General
3. Mechanistic considerations
All non-aqueous reactions were performed under an inert
atmosphere with dry, freshly distilled solvents using standard pro-
cedures. Solvents for the debenzylation reaction (MTBE, Et2O and
PhMe) were used without purification. THF was distilled prior to
use, to avoid possible interaction of BHT (antioxidant stabilizer).
Commonly available hydroxides (NaOH, KOH) were used without
any purification. Drying of organic extracts during the work-up
of reactions was performed over anhydrous Na2SO4 or MgSO4.
Evaporation of solvents was accomplished with a rotatory evapora-
tor. For reactions that need an oxygen atmosphere the flask was
equipped with 1 gallon gas bag (heavy natural rubber, Aldrich
Z186740). In experiments with irradiation, a commercial lamp
(Philips POWERTONE, ML 250 W E40 225–235 V) was installed
ca. 25 cm from the reaction flask. Thin layer chromatography was
done on SiO2 (Silica Gel 60 F254) and the spots were located by
UV or 1% KMnO4 solution. Chromatography refers to flash column
chromatography and was carried out on SiO2 (Silica Gel 60, 230–
400 mesh). Melting points were determined in a capillary tube
and are uncorrected. Unless otherwise indicated, NMR spectra
were recorded in CDCl3 at 300 or 400 MHz (1H) and 75.4 or
100.6 MHz (13C), and chemical shifts are reported in d values
downfield from TMS or relative to residual chloroform (7.26 ,
When the reaction from 8 was conducted in the absence of oxy-
gen or air, or when the base was not included in the experimental
procedure, only the starting material was recovered; this demon-
strates the crucial role that both factors play in the process.
As aforementioned, when the debenzylation of 5 was conducted
in MTBE with 25 equiv of NaOH, enamide 17 was isolated as a by-
product (6% yield)20 and trace amounts of imide 18 were detected.
The structure of 18 was confirmed unequivocally by comparison
with an authentic sample prepared by acylation of N-unsubstitut-
ed lactam 11 with benzoyl chloride.21
It is well known that molecular oxygen can oxidize benzylic
positions22 so in the reaction of 5 an intermediate such as a could
be considered. Extrusion of O2 and H2O from hydroperoxide a
would furnish enamide 17. Further oxidation of enamide 17 would
give imide 18,23 which in turn would undergo hydrolysis under ba-
sic conditions to afford N-unsubstituted lactam 11 and benzoic
acid (Scheme 5).
As an additional test, two different N-substituted lactams were
examined. When either N-benzyl-2-piperidone or N-(2-hydroxy-
ethyl)-2-piperidone was subjected to the NaOH/O2 conditions de-
scribed, only the starting material was recovered. Therefore, in
support of the proposed mechanism, the N-2-hydroxyethyl-1-phe-

V. Semak et al. / Tetrahedron: Asymmetry 21 (2010) 2542–2549
2547
77.0 ppm) as an internal standard. Data are reported in the follow-
ing manner: chemical shift, multiplicity, coupling constant (J) in
hertz (Hz), integrated intensity. Multiplicities are reported using
the following abbreviations: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br s, broad signal.
(0 °C) of 415 (595 mg, 2.0 mmol) in anhydrous CH2Cl2 (7 mL). The
mixture was allowed to warm up to rt, stirred for additional
18 h, and poured into ice. The combined organic layers were
washed with 5% aqueous NaHCO3 solution, dried and concentrated.
The resulting residue was chromatographed (1:4 to 1:1
EtOAc–hexane) to give 10 (470 mg, 78%). IR (NaCl) 3398, 2939,
5.2. (6S)-1-[(1R)-2-Hydroxy-1-phenylethyl]-6-[1-(methoxy-
1611 cmꢀ1 1H NMR (400 MHz, CDCl3, COSY, HETCOR) d 1.59–
;
methyl)indol-3-yl]-piperidin-2-one 7a
1.81 (m, 4H, H-4, H-5), 2.18 (td, J = 13.0, 8.0 Hz, 2H, CH2–CH@),
2.54–2.67 (m, 2H, CH2–CH@), 2.89 (m, 1H, H-6), 3.13 (m, 1H,
H-6), 3.78 (br s, 1H, OH), 4.02 (m, 1H, CH2OH), 4.14 (m, 1H, CH2OH),
5.08–5.09 (m, 4H, @CH2), 5.70–5.88 (m, 2H, CH@), 5.93 (dd, J = 9.0,
5.5 Hz, 1H, CHPh), 7.20–7.35 (m, 5H, ArH); 13C NMR (100.6 MHz,
CDCl3) d 19.9 (C-5), 28.8 (C-4), 43.6 (C-6), 43.8 (CH2–CH@), 43.9
(CH2–CH@), 45.5 (C-3), 58.1 (CHAr), 61.1 (CH2OH), 118.0 (@CH2),
118.1 (@CH2), 127.4 (CHAr), 127.6 (2 ꢁ CHAr), 128.4 (2 ꢁ CHAr),
TBAF (0.6 mL, 0.58 mmol, 1.0 M THF) was added dropwise to a
solution of (6S)-1-[(1R)-(tert-butyldimethylsilyl)oxy-1-phenyl-
ethyl]-6-[1-(methoxymethyl)indol-3-yl]piperidin-2-one16
(190
mg, 0.38 mmol) in THF (1 mL). The mixture was stirred at rt for
4 h. Then EtOAc and 0.5 M HCl solution were added to the reaction
mixture. The organic phase was washed with brine, dried and con-
centrated. The residue was purified by column chromatography
(EtOAc to 99:1 EtOAc–MeOH) to yield 7a (131 mg, 90%). IR (KBr)
134.2 (CH@), 134.4 (CH@), 137.1 (C-i), 175.4 (NCO); ½a D22
¼ þ1:4
ꢂ
(c 1.0, MeOH); MS-EI m/z 299 (M+, 6), 268 (100), 257 (24), 240
(25), 180 (15), 91 (30); HMRS C19H26NO2 (M++1), 300.1958; found,
300.1955. Anal. Calcd for C19H25NO2ꢃ1/2H2O: C, 73.99; H, 8.50; N,
4.54. Found: C, 74.12; H, 8.23; N, 4.30.
3386, 2944, 1621, 1465 cmꢀ1 1H NMR (400 MHz, CDCl3, COSY,
;
HSQC) d 1.67 (m, 1H, H-4), 1.80 (m, 1H, H-4), 2.01 (m, 1H, H-5),
2.11 (m, 1H, H-5), 2.56 (m, 1H, H-3), 2.70 (m, 1H, H-3), 3.27
(s, 3H, OCH3), 3.98 (dap, J = 12.0 Hz, 1H, CH2OH), 4.16 (dt, J = 12.0,
8.2 Hz, 1H, CH2OH), 4.43 (br s, J = 6.8 Hz, 1H, CHPh), 4.83
(t, J = 4.0 Hz, 1H, H-6), 4.88 (br s, 1H, OH), 5.43 (s, 2H, NCH2OMe),
7.10–7.19 (m, 2H, Hind), 7.23–7.34 (m, 6H, Hind), 7.44
(d, J = 7.9 Hz, 1H, H-7ind), 7.50 (d, J = 8.3 Hz, 1H, H-4ind); 13C
NMR (100.6 MHz, CDCl3) d 16.8 (C-4), 29.6 (C-5), 32.9 (C-3), 56.0
(OMe), 56.4 (C-6), 64.9 (CH2OH), 68.2 (CHPh), 77.4 (NCH2OMe),
110.3 (CHind), 115.8 (Cind), 118.6 (CHind), 120.3 (CHind), 122.8
(CHind), 125.6 (CHind), 127.4 (2 ꢁ CHind), 127.5 (CHind), 128.5
5.5. Na/liquid NH3 debenzylation procedure: (5S,6S)-6-allyl-5-
ethylpiperidin-2-one 14
Into a three-necked, round bottomed flask equipped with a
cold-finger condenser charged with dry ice-acetone was con-
densed NH3 (ꢄ150 mL) at ꢀ78 °C. The temperature was allowed
to raise to ꢀ33 °C (reflux of liquid NH3), and a solution of lactam
84d (1 g, 3.48 mL) in THF (5 mL) was added, followed by the addi-
tion of sodium metal in small portions until the dark blue colour
persisted. After the mixture was stirred at -33 °C for 30 min, the
reaction was carefully quenched by the addition of solid NH4Cl un-
til the blue colour disappeared. The mixture was stirred at rt over-
night giving a white solid that was partitioned between water
(50 mL) and CH2Cl2 (100 mL). The aqueous phase was extracted
with CH2Cl2, and the combined organic extracts were dried, filtered
and concentrated. The resulting residue was chromatographed (1:1
to 1:2 hexane–EtOAc) to give 14 as a white solid (470 mg, 81%) and
starting lactam 8 (70 mg, 7%).
(2 ꢁ CHind), 137.1 (Cind), 137.6 (Cind), 172.5 (NCO);
½
a 2D2
ꢂ
¼
þ25:5 (c 2.56, CHCl3); MS-EI m/z 378 (M+, 15), 347 (17), 258 (32),
241 (52), 210 (100), 200 (61), 168 (54), 106 (62); HMRS
C
23H27N2O3 (M++1), 379.2016; found, 379.2020.
5.3. (3R,6R)-6-Allyl-3-ethyl-1-[(1S)-2-hydroxy-1-phenylethyl]-
piperidin-2-one 9
Allyltrimethylsilane (0.83 mL, 5.18 mmol) was added to
a
cooled solution (0 °C) of 312a (635 mg, 2.59 mmol) in CH2Cl2
(10 mL). Then, TiCl4 (9.1 mL of a 1 M solution in CH2Cl2, 9.1 mmol)
was added dropwise in 2 h by a syringe pump. The reaction mix-
ture was warmed up to rt and stirred for an additional 16 h. The
mixture was poured onto ice, and the organic layer was separated,
washed with brine, dried, filtered and concentrated. The residue
was purified by column chromatography (1:1 to 4:1 EtOAc–hex-
ane) to afford 9 (675 mg, 91%). IR (NaCl) 3387, 2952, 2874, 1617,
5.6. (5S,6S)-6-Allyl-5-ethylpiperidin-2-one 14
Table 1, entry 2. Freshly ground KOH (16.6 g, 296 mmol) was
added to a solution of 8 (1.70 g, 5.92 mmol) in Et2O (60 mL). The
round- bottomed flask was equipped with a 1 gallon gas bag of
O2 and stirring was continued for 16 h at rt. The mixture was par-
titioned between H2O and EtOAc. The aqueous phase was extracted
with EtOAc (or CH2Cl2), and the combined organic phases were
dried and concentrated. The resulting residue was purified by flash
column chromatography (1:1 EtOAc–hexane) to yield 14 (790 mg,
; d 0.96
1449 cmꢀ1 1H NMR (400 MHz, CDCl3, COSY, HSQC)
(m, 3H, CH3), 1.64–1.73 (m, 3H, CH2CH3, H-4, H-5), 1.80 (m, 1H,
CH2CH3), 1.87–2.00 (m, 2H, H-4, H-5), 2.20–2.34 (m, 2H, CH2–
CH@), 2.41 (m, 1H, H-3), 3.34 (m, 1H, H-6), 4.03 (dd, J = 12.0,
3.0 Hz, 1H, CH2OH), 4.27 (m, 1H, CH2OH), 4.51 (br s, 1H, OH),
4.63 (dd, J = 7.0, 3.0 Hz, 1H, CHAr), 5.04 (dd, J = 10.5, 1.0 Hz,
@CH2), 5.08 (m, 1H, @CH2), 5.60 (m, 1H, CH@), 7.25–7.35 (m, 5H,
ArH); 13C NMR (100.6 MHz, CDCl3) d 10.8 (CH3CH2), 20.9 (CH2CH3),
25.0 (C-5), 25.5 (C-4), 37.4 (CH2–CH@), 43.1 (C-3), 57.8 (C-6), 64.5
(CH2OH), 66.5 (CHAr), 118.0 (@CH2), 127.4 (2 ꢁ CHAr), 127.5
(CHAr), 128.5 (2 ꢁ CHAr), 134.0 (CH@), 137.2 (C-i), 174.5 (NCO);
80%).
½
a 2D2
ꢂ
¼ ꢀ23:7 (c 2.0, CHCl3); HMRS C10H18NO (M++1),
168.1383; found, 168.1382.4d
Table 1, entry 4. Freshly ground NaOH (2.37 g, 59.2 mmol) was
added to a solution of 8 (680 mg, 2.37 mmol) in THF (30 mL). The
round bottomed flask was equipped with a 1 gallon gas bag of O2
and a sun lamp, and stirring was continued for 24 h. The mixture
was concentrated to dryness. Work up as above gave 14 (261 mg,
66%).
Table 1, entry 8. Freshly ground NaOH (400 mg, 10 mmol) was
added to a solution of 8 (288 mg, 1 mmol) in MTBE (5 mL). The
round bottomed flask was equipped with a 1 gallon gas bag of O2
and the mixture was warmed at 40 °C for 16 h. Work up as above
gave 14 (138 mg, 83%).
½
a 2D2
ꢂ
¼ ꢀ63:1 (c 1.25, CHCl3). HMRS C18H26NO2 (M++1), 288.1958;
found, 288.1958. Anal. Calcd for C18H25NO2ꢃ1/4H2O: C, 74.06; H,
8.80; N, 4.80. Found: C, 74.20; H, 8.88; N, 4.71.
5.4. 3,3-Diallyl-1-[(1S)-2-hydroxy-1-phenylethyl]piperidin-2-
one 10
Table 2, entry 4. The reaction was performed from 8 (3.07 g,
10.67 mmol), NaOH (4.27 g, 106.7 mmol) and MTBE (22 mL) for
24 h. Work up as above gave 14 (1.51 g, 85%).
TiCl4 (8.0 mL of 1.0 M solution in CH2Cl2, 8.0 mmol) and Et3SiH
(0.80 mL, 5.0 mmol) were added dropwise to a cooled solution

2548
V. Semak et al. / Tetrahedron: Asymmetry 21 (2010) 2542–2549
5.7. General procedure for the cleavage of the 2-hydroxy-1-
phenylethyl moiety from lactams 5, 6, 7a, 9 and 10
NMR (400 MHz, CDCl3, COSY, HSQC) d 0.94 (t, J = 7.5 Hz, 3H,
CH2CH3), 1.66–1.80 (m, 3H, H-4, 2 ꢁ H-5), 1.85 (m, 1H, CH2CH3),
2.07–2.30 (m, 3H, H-3, H-5, 2 ꢁ CH2–CH@), 3.37 (m, 1H, H-6),
5.10 (m, 2H, @CH2), 5.13 (m, 2H, @CH2), 5.70 (m, 1H, CH@), 6.11
(br s, 1H, NH); 13C NMR (100.6 MHz, CDCl3) d 11.8 (CH2CH3), 22.8
(C-4), 24.7 (CH2CH3), 25.0 (C-5), 41.1 (CH2–CH@), 41.7 (C-3), 51.7
In a round bottomed flask equipped with a 1 gallon gas bag of
O2, an excess (10–25 equiv) of freshly ground NaOH was added
to a solution of lactam 5, 6, 7a, 9, or 10 (1 equiv) in MTBE (or
THF). The mixture was heated at 40 °C and stirred slowly at this
temperature for 24 h. The solvent was removed, and the residue
was partitioned between H2O and CH2Cl2. The combined organic
phases were dried and concentrated to give the respective com-
pounds 11–16.
(C-6), 118.8 (@CH2), 133.4 (@CH), 175.4 (NCO); ½a D22
¼ þ20:1
ꢂ
(c 0.63, MeOH); HMRS
C
10H18NO (M++1), 168.1383; found,
180.1382. Anal. Calcd for C10H17NOꢃ1/4H2O: C, 69.93; H, 10.27;
N, 8.16. Found: C, 69.80; H, 10.25; N, 7.98. (3S,6R)-6-Allyl-3-
ethyl-2-piperidin-2-one 3-epi-15. IR (NaCl) 3211, 2933, 1656,
1450 cmꢀ1
; d 0.93
1H NMR (400 MHz, CDCl3, COSY, HSQC)
5.7.1. (R)-6-Methylpiperidin-2-one 114a
(m, J = 7.5 Hz, 3H, CH2CH3), 1.39–1.48 (m, 2H, H-4, H-5), 1.56 (m,
1H, CH2CH3), 1.90–1.98 (m, 3H, H-4, H-5, CH2CH3), 2.09 (m, 1H,
CH2–CH@), 2.18 (m, 1H, H-3), 2.32 (m, 1H, CH2–CH@), 3.37 (m,
1H, H-6), 5.14 (m, 1H, @CH2), 5.18 (m, 1H, @CH2), 5.71 (m, 1H,
CH@), 5.78 (br s, 1H, NH); 13C NMR (100.6 MHz, CDCl3) d 11.0
(CH2CH3), 24.1 (CH2CH3), 25.4 (C-4), 28.9 (C-5), 41.5 (CH2–CH@),
42.2 (C-3), 52.3 (C-6), 119.1 (@CH2), 133.3 (@CH), 174.5 (NCO);
Following the general procedure, from lactam
5 (70 mg,
0.30 mmol) and NaOH (600 mg, 15.0 mmol) in THF (15 mL) for
16 h, 48 mg of a 9:1 mixture of 11 and enamide 17 were obtained.24
This crude mixture (48 mg) in Et2O (25 mL) and 5 N aqueous H2SO4
acid (10 mL) was heated at reflux temperature for 1 h. The mixture
was cooled and diluted with water (15 mL). The aqueous phase
was neutralised to pH 7–8 with NaHCO3 and extracted with EtOAc.
The organic extracts were dried and concentrated. The residue was
purified by column chromatography (1:1 hexane–EtOAc to EtOAc)
to yield lactam 114a (30 mg, 87%). An analytical sample of 17 was ob-
tained from the mixture by column chromatography (1:1 hexane–
EtOAc to EtOAc) (R)-6-Methyl-1-(1-phenylvinyl)piperidin-2-one
½
a 2D2
ꢂ
¼ ꢀ5:4 (c 0.7, MeOH); MS-EI m/z 168 (M++1, 1), 126 (100),
98 (9), 83 (69), 55 (29); HMRS C10H18NO (M++1), 168.1383; found,
180.1381.
5.7.4.1. Epimerisation. Freshly ground NaOH (72 mg, 1.79 mmol)
was added under an inert atmosphere to a solution of 15 (30 mg,
0.18 mmol) in MTBE (1 mL) and the mixture was heated at 40 °C
for 24 h. The solvent was evaporated and the residue was parti-
tioned between H2O and CH2Cl2. The combined organic extracts
were washed with aqueous NH4Cl, dried and evaporated to give
a 1:1 mixture of 15 and 3-epi-15 (23 mg, 77%).
17: IR (NaCl) 2936, 1649 cmꢀ1 1H NMR (400 MHz, CDCl3, COSY,
;
HSQC) d 1.19 (d, J = 7.0 Hz, 3H, CH3), 1.67 (m, 1H, H-5), 1.83 (m, 1H,
H-4), 1.95–2.06 (m, 2H, H-4, H-5), 2.56 (m, 2H, H-3), 3.64 (dd,
J = 11.2, 4.9 Hz, 1H, H-6), 5.22 (s, 1H, C@CH2), 5.84 (s, 1H, C@CH2),
7.31–7.38 (m, 5H, ArH); 13C NMR (100.6 MHz, CDCl3) d 18.4 (C-4),
20.6 (CH3), 30.6 (C-5), 32.7 (C-3), 53.6 (C-6), 113.9 (@CH2), 125.7
(2 ꢁ CHAr), 128.4 (CHAr), 128.5 (2 ꢁ CHAr), 136.1 (C-i), 145.3 (C@),
170.2 (NCO). MS-EI m/z 215 (M+, 100), 186 (40), 172 (40), 118 (40),
103 (53), 77 (47), 55 (38).
5.7.5. 3,3-Diallylpiperidin-2-one 16
Following the general procedure, from lactam 10 (150 mg,
0.5 mmol) and NaOH (200 mg, 5.0 mmol) in MTBE (2.5 mL) for
24 h, compound16(80 mg, 88%)was obtainedafter columnchroma-
tography (1:1 EtOAc–hexanes to EtOAc). IR (NaCl) 3214, 3074, 2936,
5.7.2. (S)-6-Phenyl-2-piperidone 12
Following the general procedure, from lactam 6 (200 mg,
0.68 mmol) and NaOH (270 mg, 6.77 mmol) in THF (3.4 mL) for
24 h, compound 1225 (96 mg, 81%) was obtained.26
1657, 1489 cmꢀ1 1H NMR (400 MHz, CDCl3, COSY, HSQC) d 1.66–
;
1.77 (m, 4H, H-4, H-5), 2.15 (dd, J = 13.5, 8.0 Hz, 2H, CH2–CH@),
2.49 (ddd, J = 13.5, 8.0, 1.0 Hz, 2H, CH2–CH@), 3.21 (m, 2H, H-6),
5.02 (m, 2H, @CH2), 5.06 (m, 2H, @CH2), 5.70–5.81 (m, 2H, CH@),
6.59 (br s, 1H, NH); 13C NMR (100.6 MHz, CDCl3) d 19.4 (C-5), 28.8
(C-4), 42.5 (C-6), 42.7 (2 ꢁ CH2–CH@), 44.7 (C-3), 118.0 (2 ꢁ @CH2),
134.2 (2 ꢁ @CH), 176.3 (NCO); HMRS C11H18NO (M++1), 180.1383;
found, 180.1383.
5.7.3. (6S)-6-[1-(Methoxymethyl)indol-3-yl]piperidin-2-one 13
Following the general procedure, from lactam 7a (185 mg,
0.49 mmol) and NaOH (490 mg, 12.2 mmol) in MTBE (2.5 mL) for
24 h, compound 13 (91 mg, 72%) was obtained after column chro-
matography (99:1 to 98:2 CH2Cl2–MeOH). IR (KBr) 3241, 2953,
1662, 1081 cmꢀ1
;
1H NMR (400 MHz, CDCl3, COSY, HSQC) d 1.83
5.8. (R)-1-Benzoyl-6-methylpiperidin-2-one 1821
(m, 1H, H-4), 1.90–2.03 (m, 2H, H-4, H-5), 2.20 (m, 1H, H-5), 2.49
(m, 2H, H-3), 3.25 (s, 3H, OCH3), 4.91 (dd, J = 7.9, 4.6 Hz, 1H,
H-6), 5.41 (d, J = 2.3 Hz, 2H, NCH2OMe), 6.04 (br s, 1H, NH), 7.13
(s, 1H, H-2ind), 7.17 (t, J = 7.5 Hz, H-5ind), 7.28 (t, J = 7.9 Hz, 1H,
H-6ind), 7.48 (d, J = 8.2 Hz, 1H, H-7ind), 7.59 (d, J = 7.9 Hz, 1H,
H-4ind); 13C NMR (100.6 MHz, CDCl3) d 19.6 (C-4), 30.0 (C-5),
31.4 (C-3), 50.6 (C-6), 56.0 (OMe), 77.4 (NCH2OMe), 110.3
(C-7ind), 117.8 (C-3ind), 118.9 (C-4ind), 120.3 (C-5ind), 122.8
(C-6ind), 125.3 (C-2ind), 126.2 (C-3ind), 137.1 (C-7ind), 172.3
6-Methylpiperidone 11 (100 mg, 0.75 mmol) in THF (1 mL) was
added via cannula to a solution of n-BuLi (0.54 mL of a 1.6 M solu-
tion in hexane, 0.86 mmol) in THF (1 mL) at ꢀ78 °C. After stirring at
ꢀ78 °C for 1.5 h, benzoyl chloride (87
lL, 0.75 mmol) was added
dropwise. The mixture was slowly warmed to rt and stirred for
19 h. Then, the yellowish suspension was poured into a saturated
NH4Cl solution (5 mL) and extracted with Et2O. The combined or-
ganic layers were dried and concentrated, and the resulting residue
was chromatographed (9:1 to 1:1 hexane–EtOAc) to afford 18,
which was crystallised from hexane–EtOAc to give a white solid
(NCO). ½a 2D2
ꢂ
¼ ꢀ55:5 (c 0.6, MeOH); MS-EI m/z 258 (M+, 100), 227
(46), 188 (34), 157 (32), 130 (29); HMRS C15H19N2O2 (M++1),
259.1441; found, 259.1443. Anal. Calcd for C15H18N2O2: C, 69.74;
H, 7.02; N, 10.34. Found: C, 69.24; H, 7.04; N, 10.31.
(80 mg, 53%). IR (NaCl) 2953, 1675 cmꢀ1 1H NMR (400 MHz,
;
CDCl3, COSY, HSQC) d 1.81 (m, 1H, H-5), 1.90 (m, 1H, H-4), 2.02–
2.56 (m, 2H, H-4, H-5), 2.52–2.56 (m, 2H, H-3), 4.53 (m, 1H, H-5),
7.36–7.40 (m, 2H, ArH), 7.44 (m, 1H, ArH), 7.54–7.56 (m, 2H,
ArH); 13C NMR (100.6 MHz, CDCl3) d 17.8 (C-4), 20.3 (CH3), 29.4
(C-5), 34.2 (C-3), 51.6 (C-6), 127.8 (2 ꢁ CHAr), 128.2 (2 ꢁ CHAr),
131.6 (CHAr), 136.4 (C-i), 174.0 (NCO), 174.5 (NCO); mp = 74–
76 °C (hexane–EtOAc); HMRS C13H16NO2 (M++1), 218.1176; found,
218.1174.
5.7.4. (3R,6R)-6-Allyl-3-ethylpiperidin-2-one 15
Following the general procedure, from lactam 9 (200 mg,
0.70 mmol) and NaOH (280 mg, 7 mmol) in MBTE (3.5 mL) for
24 h, a 1:1 mixture of 15 and 3-epi-15 (104 mg, 89%) was obtained.
Epimers were separated by column chromatography (4:1 to 1:1
hexane–EtOAc). 15. IR (NaCl) 3204, 2935, 1663, 1459 cmꢀ1 1H
;

V. Semak et al. / Tetrahedron: Asymmetry 21 (2010) 2542–2549
2549
6. For other debenzylation methods for amides, see: TFA: (a) Schlessinger, R. H.;
Bebernitz, G. R.; Lin, P.; Poss, A. Y. J. Am. Chem. Soc. 1985, 107, 1777–1778; (b)
Shimshock, S. J.; Waltermire, R. E.; Deshong, P. J. Am. Chem. Soc. 1991, 113,
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Acknowledgements
We thank Dr. Pavel Mach (Comenius University of Bratislava)
for fruitful discussions. Financial support from the Ministry of Sci-
ence and Innovation, Spain (Project CTQ2009-07021/BQU), and the
AGAUR, Generalitat de Catalunya (Grant 2009-SGR-111) is grate-
fully acknowledged. Thanks are also due to the Ministry of Educa-
tion and Science for fellowships to V.S. and C.A.
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Trost, B. H., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 7, p 10.
23. For examples of the oxidation of enamines with oxygen, see: (a) Huber, J. E.
Tetrahedron Lett. 1968, 9, 3271–3272; (b) Foote, C. S.; Dzakpasu, A. A.; Lin, J. W.-
P. Tetrahedron Lett. 1975, 16, 1247–1250; (c) Wasserman, H. H.; Terao, S.
Tetrahedron Lett. 1975, 16, 1735–1738; (d) Fetter, J.; Lempert, K.; Mølleer, J.
Tetrahedron 1978, 34, 2557–2563; (e) Curtis, N. M.; Gorman, A. A.; Prescott, A.
L. J. Am. Chem. Soc 1988, 110, 7549–7550; (f) Chang, Y.-G.; Kim, K. Synlett 2002,
1423–1426.
24. When reaction was performed in MTBE in the presence of a sun lamp for 44 h,
the yield and ratio of 11 and 17 were coincident with that described in the
Section 5.7.1.
25. Kawe˛cki, R. Tetrahedron 2001, 57, 8385–8390.
26. When reaction was carried out in DMSO instead of THF, lactam 12 was isolated
in 41% yield. The 1H NMR of the crude reaction mixture showed representative
peaks of the corresponding enamide of 12: 5.02 (s, 1H, @CH2) and 5.51 (s, 1H,
@CH2). MS-EI m/z 277 (M++1, 91), 248 (100), 130 (89), 104 (58), 91 (51).