Expedient pathway into optically active 2-oxopiperidines

Article abstract of DOI:10.1002/ejoc.201000587

The piperidine ring system is one of the most common structural subunits and is found in many natural products. Moreover, piperidine alkaloids and derivatives thereof are of great interest for the pharmaceutical industry since they exhibit a wide range of

Full text of DOI:10.1002/ejoc.201000587

FULL PAPER
DOI: 10.1002/ejoc.201000587
Expedient Pathway into Optically Active 2-Oxopiperidines
Sebastiaan (Bas) A. M. W. van den Broek,[a] Peter G. W. Rensen,[a] Floris L. van Delft,[a] and
Floris P. J. T. Rutjes*[a]
Keywords: Nitrogen heterocycles / Alkaloids / Ring-closing metathesis / Amino acids / Dehydroamino acids
The piperidine ring system is one of the most common struc-
tural subunits and is found in many natural products. More-
over, piperidine alkaloids and derivatives thereof are of great
interest for the pharmaceutical industry since they exhibit a
wide range of biological activities. Consequently, short and
valuable routes to highly functionalized building blocks for
this important ring system are of general interest. A ring-
closing metathesis (RCM)-mediated approach based on lin-
ear (substituted) dehydroamino esters was developed to pro-
vide cyclic dehydroamino esters. These structures represent
valuable intermediates en route to highly substituted pipec-
olic acids as well as more elaborate heterocycles.
First examples of the synthesis of nitrogen heterocycles
involving ring-closing metathesis (RCM) of terminal al-
kenes, appeared already in the literature in 1992.[12] Since
then, the development of more reactive ruthenium-based
catalysts[13] tremendously broadened the scope of this reac-
tion, thereby allowing cyclization of highly substituted al-
kenes, including trisubstituted enamides.[14]
Introduction
The 2-oxopiperidine ring structure is encountered in
many biologically active products (e.g., HIV protease inhib-
itors,[1] glycosidase inhibitors,[2] thrombin inhibitors,[3] an-
tagonists of the neurokinin-2 receptor,[4] and fibrinogen re-
ceptor antagonists),[5] but is also a common structural
feature of peptidomimetics.[6,7,8] In addition, functionalized
2-oxopiperidines have served as key building block in the
synthesis of various natural products including piperi-
dines,[9] indolizidines,[10] and quinolizidines[11] (Figure 1).
As a result, the development of new methodology for
enantiopure 2-oxopiperidines remains of general interest for
organic and medicinal chemists.
Among various applications of the metathesis reaction,
ring-closing metathesis (RCM) has emerged as one of the
most powerful tools for construction cyclic com-
pounds.[15,16] Following up on recent research developed in
our own group demonstrating the opportunities of RCM
of a,β-unsaturated dehydroamino esters,[17] we now wish to
report further exploration of this methodology leading to
optically active heterocyclic systems of type 1. Synthesis of
these compounds was anticipated to proceed via initial con-
densation of unsaturated amides with ethyl pyruvate to
yield enamides 2. Subsequently, RCM would provide the 2-
oxopiperidine carboxylic esters 1 (Scheme 1). In addition,
we reasoned that once developed this methodology could
also be applied to more complex systems. For example, con-
densation of functionalized unsaturated amides (R ϶ H)
would provide excellent precursors for 4- and 5-substituted
pipecolic acids, representing key elements in a variety of
natural products.[18] Furthermore, the double bond provides
ample opportunities for introduction of substituents at C5
to further diversify the cyclic structures 1.
Figure 1. Natural products synthesized via 2-oxopiperidines.
Results and Discussion
We envisaged that formation of linear α,β-unsaturated
dehydroamino esters 2 (PG = H) could in principle be car-
ried out in a single transformation via condensation of un-
saturated amides with pyruvate.[19] This requires the unsatu-
rated amides 8, which are readily obtained via acid chloride
formation of the corresponding carboxylic acids with oxalyl
[a] Radboud University Nijmegen,
Institute for Molecules and Materials,
Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
Fax: +31-24-365-3393
E-mail: F.Rutjes@science.ru.nl
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000587.
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Expedient Pathway into Optically Active 2-Oxopiperidines
Scheme 1. Ring-closing metathesis approach to dehydroamino
esters 1.
chloride and subsequent reaction with ammonia.[20] Con-
densation of 8b (n = 1) and 8c (n = 2) with ethyl pyruvate
under Dean–Stark conditions in the presence of p-tolu-
enesulfonic acid (10 mol-%) afforded initial imine formation
followed into the more stable α,β-unsaturated dehy-
droamino esters 9b and c in 82 and 45% yield, respectively
(Scheme 2). Interestingly, condensation of 8a (n = 0) led to
isomerization of the terminal alkene to the corresponding
crotyl amide. Furthermore, the aromatic amide 10 was pre-
pared from a Wittig reaction with 2-formylbenzoic acid[21]
followed by amidation of the carboxylic acid via the afore-
mentioned procedure. Subsequent condensation with ethyl
pyruvate provided 11 in 75% yield. With these three precur-
sors in hand, initial attempts to effect ring closure were un-
dertaken. Reactions involved use of the first generation
Grubbs catalyst (G1) in toluene at 80 °C. However, accord-
ing to mass spectroscopic analysis, no cyclization took place
and only dimerization was observed. Disappointingly, reac-
tions in the presence of the second-generation Grubbs’ cata-
lyst (G2) led to similar results.
Scheme 3. Protection of the dehydroamino esters.
Unfortunately, the dehydroamino ester 12 remained un-
reactive toward RCM upon treatment with G1 and G2
(10 mol-%) and only led to multiple products after extended
reaction times. While the energetically unfavored s-cis con-
formation of the dehydroamino ester is required for cycliza-
tion to proceed, carbamate-protection of the amide proba-
bly renders s-cis/trans isomerization sterically impossible.
Next, N-alkylation was pursued to enhance rotational
freedom. First, 9b was treated with benzyl bromide in the
presence of LHMDS at temperatures ranging from –78 °C
to room temp. However, this attempt led to decomposition
of the starting material. Therefore 9b was treated with
benzyl bromide in the presence of sodium hydride. Al-
though this resulted in the desired compound 13a, the yield
was rather low (34%). Addition of the more reactive p-
methoxybenzyl bromide (PMBBr) on the other hand
yielded 13b in 56%. In addition, portionwise addition of
sodium hydride increased the yield to 83%. Gratifyingly,
subsequent RCM in the presence of G2 (toluene, 80 °C)
proceeded smoothly to give compound 15 in a yield of 71%.
In sharp contrast, cyclization of 13c under similar condi-
tions led to homodimeric species. Finally, PMB-protection
and ring closure of 11 yielded the isoquinoline derivative 16
in 82% yield (Scheme 4).
Scheme 2. Condensation of unsaturated amides with ethyl pyr-
uvate.
The reluctance of the amides to undergo ring closure[22]
could be due to the energetically favored s-trans conforma-
tion of the amide bond. This situation may be altered by
introduction of a protecting group on the nitrogen,[22b,23]
which lowers the s-cis/trans rotation barrier. Attempts to
Cbz-protect the nitrogen in the presence of DMAP resulted
in the recovery of starting material, while deprotonation
with LHMDS followed by addition of CBz-OSu at low tem-
peratures only led to decomposition. Interestingly, reaction
Scheme 4. RCM-mediated synthesis of 2-oxopiperidine and 2-
oxoisoquinazolone carboxylic esters 15 and 16.
Encouraged by these results we decided to investigate the
of the amide with Boc anhydride (CH2Cl2, DMAP, room influence of substituted amides on the condensation reac-
temp.) led to the formation of the desired Boc-protected tion. To this end, methyl-substituted amides 17a and b were
dehydroamino ester 12 in 85% yield (Scheme 3).
prepared from the corresponding commercially available
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F. P. J. T. Rutjes et al.
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carboxylic acids. First, 2-methyl-substituted 17a was con-
densed with ethyl pyruvate (Scheme 5). Subsequent N-alk-
ylation (68%), followed by RCM provided 20a in 71%
yield. Exposed reaction times for cyclization of the sterically
more demanded precursors 19a–b slow down s-cis/trans
isomerization thereby increasing reaction times. Synthesis
of the 3-methyl-substituted derivative 20b gave similar re-
sults.
Scheme 6. Conditions: (a) TBDPSCl, imidazole, DMF, room
temp., 2 h, 85%; (b) R = Et, iPr: RMgBr, PhSCu, THF, –30 °C,
10 min; R = Ph: PhLi, CuI, TMSCl, Et2O, –78 °C, 1 h; (c) TBAF,
THF, 0 °C, 1 h, 76%; (d) PPh3, I2, imidazole, THF, room temp.,
1 h, 74%; (e) Zn, AcOH, MeOH, room temp., 15 min, 86%; (f) i:
oxalyl chloride, CH2Cl2, room temp., 1 h, ii: NH3, THF, room
temp., 2 h, 67%.
In order to prepare hydroxylated derivatives, ribolactonic
acids were considered suitable precursors. Extensive re-
search proved that protection of the alcohols was not
straightforward. While silyl ethers were hydrolyzed during
the condensation reaction, O-alkylation on the other hand
led to multiple products. Gratifyingly, 1-O-methyl--ribofu-
ranoside derivative 28a, readily obtained via literature pro-
cedures,[26] afforded the iodinated precursor for ring open-
ing. Although reduction of 28a with zinc in MeOH pro-
ceeded slowly at 70 °C, resulting in multiple products, ad-
dition of acetic acid in a THF/H2O mixture at room tem-
perature afforded the carboxylic acid 29a in 89% yield. In
the next step, oxidation of the aldehyde into the carboxylic
acid should lead to the carboxylic acid which was then
transformed into the amide precursor for condensation via
described procedures (Scheme 7). Where both Pinnick and
Jones oxidation appeared to be too harsh resulting in de-
composition, treatment with the fairly mild oxidant pyridi-
nium dichromate (PDC) gave the carboxylic acid in 80%
yield. Finally, conversion into the ester and quenching with
ammonia provided 30a. With the synthesis of 30a com-
pleted, the same procedure was applied to the 2-deoxy vari-
ant 30b which proceeded in a similar fashion.
Scheme 5. Conditions: (a) ethyl pyruvate, pTsOH (10 mol-%),
Dean–Stark, PhMe, 110 °C, 2 h; (b) NaH, PMBBr, DMF, room
temp., 1 h; (c) G2 (5 mol-%), PhMe, 80 °C, 2 h.
As mentioned in the introduction, substituted 2- and 3-
oxopiperidines may represent useful intermediates for the
construction of highly functionalized N-heterocyclic build-
ing blocks. While the cyclic dehydroamino esters prepared
so far were racemic, the enantiomerically pure variants
would be more valuable. In order to achieve this, synthesis
of enantiopure allylic amides would be a prerequisite. Lit-
erature examples showing the accessibility of enantiopure
oxygen-substituted pentenoic acids upon zinc-mediated ring
opening of substituted pentoses,[24] prompted us to probe
the generality of this procedure to prepare the aforemen-
tioned allylic amides.
The synthesis of enantiopure amide 27 involved TBDPS-
protection of commercially available furanone 21 yielding
22 in 85% yield, followed by diastereoselective 1,4-addition
using Grignard reagents in the presence of copperthiophen-
olate to give lactones 23a and b (Scheme 6).[25] While reac-
tion with aliphatic Grignard reagents went smoothly, reac-
tion with aromatic ones appeared to be more problematic
leading to multiple products. Treatment of furanone 22 with
phenyllithium in the presence of copper iodide and TMSCl
on the other hand, resulted in a high conversion into lac-
tone 23c. In the next steps, the ethyl-substituted furanone
23a was converted into iodide 25 by deprotection with tet-
rabutylammonium fluoride and iodination with I2/PPh3/
imidazole. Next, Zn-mediated ring opening of iodolactone
25 at elevated temperatures afforded the carboxylic acid 26
in 86% yield. Finally, the carboxylate was readily converted
into amide 27 via acid chloride formation, followed by reac-
tion with ammonia as described previously.
Scheme 7. Conditions: (a) Zn, AcOH, THF/H2O (4:1), 70 °C,
30 min; (b) PDC, DMF, room temp., 16 h; (c) For R = H: a. oxalyl
chloride, CH2Cl2, room temp., 1 h; b. NH3, THF, room temp., 2 h;
for R = OBn: a. TMSCHN2, MeOH, room temp., 15 min; b. 7 
NH3, MeOH, room temp., 48 h.
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Expedient Pathway into Optically Active 2-Oxopiperidines
At this point, having successfully realized the synthesis was iodinated to give a new key intermediate enabling intro-
of the 3-O- and 2,3-O-(di)substituted unsaturated dehy- duction of a variety of substituents via cross-coupling meth-
droamino esters 30a–b, we aimed to synthesize the 2-O-sub- odology. Indeed, when 14 was subjected to NIS at elevated
stituted variant at the α-position. The unnatural amino acid temperatures, the iodinated 37 was isolated, albeit in a yield
-allylglycine (31) was thought to be a suitable precursor. of only 6%. This might be due to electrophilic aromatic
At first, a diazotization reaction introduced the hydroxy substitution onto the PMB group. Gratifyingly, treatment
group with full retention of stereochemistry. Then, O-alk- of 14 at room temperature in the presence of TFA to in-
ylation using benzyl bromide with a large excess of NaH crease the electrophilicity of the iodonium ion, resulted in
provided 32 in a yield of 41% as a single enantiomer. Carb- 37 in a good yield of 78%. Iodide 37 was then subjected to
oxylic acid 32 was successively treated with oxalyl chloride a range of cross-couplings for the formation of C–C bonds
and ammonia to form the amide 33 (Scheme 8). Disap- as depicted in Table 2. Finally, an Ullmann-type addition/
pointingly, HPLC measurements showed complete racemi- elimination protocol led to the successful introduction of
zation. Probably, ammonia acts as a base resulting in ketene aromatic/aliphatic alcohols, aromatic thiols, amides and
formation, thereby leading to the racemic amide 33. To carbamates in moderate to good yields.[27]
avoid racemization, the amide was successfully synthesized
via treatment of the corresponding methyl ester with am-
Table 2. Synthesis of 5-substituted cyclic dehydroamino esters.
monia, which is not prone to ketene formation.
Scheme 8. Conditions: (a) NaNO2, H2O/AcOH (4:1), 70 °C, 3 h;
Entry
R
Method[a]
Product
Yield (%)
(b) BnBr, NaH, DMF, room temp., 2 h (41%, 2 steps); (c)
TMSCHN2, MeOH, room temp., 15 min, then 7  NH3, MeOH,
room temp., 48 h (59%).
1
2
3
4
5
6
7
8
9
Ph
A
A
A
B
C
D
D
D
D
38a
38b
38c
38d
38e
38f
38g
38h
38i
70
78
86
79
74
49
73
75
85
3-FC6H4
PhCH=CH
EtO2CCH=CH
CH2=CH
PhS
BnO
BzHN
With the four unsaturated amides in hand, the stage was
set for condensation with ethyl pyruvate as described above
(Table 1). Indeed, formation of the dehydroamino esters 34
proceeded as anticipated. Next, alkylation of 34 with
PMBBr provided the α,β-unsaturated dehydro-amino esters
ready for RCM. Finally, we were pleased that RCM of both
CbzHN
[a] A: 10 mol-% Pd(OAc)2, PhB(OH)2, Na2CO3, EtOH, 55 °C,
oxygen- and C3-substituted dehydroamino esters 35b and RB(OH)2; B: DIPEA, Pd(OAc)2, 80 °C, ethyl acrylate; C: 5 mol-
% CuI (cat.), 10 mol-% Pd(PPh3)4, CsF, DMF, 45 °C, RSnBu3; D:
35d proceeded smoothly with G2 in toluene at 80 °C. Cycli-
10 mol-% CuI, 10 mol-% 1,10-phenanthroline, PhMe, 110 °C,
RSH/ROH/RCO2NH2.
zation of the 2-O-substituted precursor 35a also proceeded
well in 58% yield. This in sharp contrast to the 2,3-disubsti-
tuted product 35c, which did not lead to any cyclization,
probably due to steric hindrance.
Conclusions
With the synthesis of the functionalized α,β-substituted
cyclic dehydroamino esters completed, we envisioned that
In conclusion, we have developed a short route for the
incorporation of β-substituents onto the heterocycle would synthesis of 2-oxopiperidine carboxylic esters via condensa-
enlarge the diversity of the heterocycle. Thus, the enamide tion of pyruvate with olefinic amides, followed by N-alk-
Table 1. RCM of optically active dehydroamino esters.
Entry
Substrate
X1
X2
Yield (%)
Yield (%)
Yield (%)
1
2
3
4
33
30a
30b
27
H
OBn (S)
H
OBn (R)
H
34a: 59% (R = H)
34b: 38% (R = H)
34c: 73% (R = H)
34d: 57% (R = H)
35a: 52% (R = PMB)
35b: 78% (R = PMB)
35c: 66% (R = PMB)
35d: 77% (R = PMB)
36a: 58% (R = PMB)
36b: 91% (R = PMB)
36c: 0% (R = PMB)
36d: 88% (R = PMB)
OBn
OBn
Et
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4.17 (q, J = 7.2 Hz, 2 H, CH2), 3.82 (s, 3 H, CH3Ar), 2.68–2.77
(m, 2 H, CH2), 2.35–2.43 (m, 2 H, CH2), 1.25 (t, J = 7.0 Hz, 3 H,
CH3) ppm. 13C NMR (CDCl3, 75 MHz): δ = 170.04, 158.32,
133.98, 129.91, 128.77, 120.76, 113.40, 60.83, 54.74, 44.07, 30.55,
19.32, 13.59 ppm. HRMS (ESI) m/z calcd. for C16H19NO4Na [M
+ Na]+: 312.1212, found: 312.1204.
ylation and ring closure to obtain the targeted heterocycles.
Furthermore, both oxygen- and carbon-substituted amides
at the allylic position were readily incorporated via the
newly developed method. Finally, cross-coupling reactions
applied onto iodinated cyclic dehydroamino esters led to
the introduction of both carbon- and hetero-substituents at
C5.
(4S,5S)-4-Ethyl-5-(hydroxymethyl)dihydrofuran-2(3H)-one (24): To
a solution of 23a (81 mg, 0.21 mmol) in THF (1 mL) at 0 °C was
added TBAF (212 µL, 0.21 mmol) and this mixture was stirred for
2 h. The reaction was quenched with aqueous NH4Cl, extracted
with CH2Cl2, dried (MgSO4), concentrated in vacuo and purified
by column chromatography (EtOAc/heptane, 1:1) to afford 24
(17 mg, 56%) as a colorless oil. Rf = 0.23 (EtOAc/heptane, 1:1).
Experimental Section
Ethyl 2-(Pent-4-enoyl)aminoacrylate (9b): To a solution of 8b
(515 mg, 5.2 mmol) in PhMe (50 mL) were added hydroquinone
(57.2 mg, 10 mol-%), pTsOH (98.8 mg, 10 mol-%) and ethyl pyr-
uvate (1.14 mL, 10.4 mmol). The reaction mixture was stirred using
Dean–Stark conditions under slightly reduced pressure. After 3 h
the reaction was cooled to room temperature and filtered through
a plug of neutral Al2O3. The Al2O3 was washed with PhMe
(2ϫ50 mL) and the organic layer was concentrated in vacuo. The
residue was purified by column chromatography (EtOAc/heptane,
1:1) to give ester 9b (594 mg, 3.02 mmol, 82%) as a colorless oil.
[α]2D0 = +12.1 (c 0.09, CH Cl ). FTIR (ATR): ν = 916, 1709, 2930,
˜
2
2
2963 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 4.18–4.16 (m, 1 H,
H4), 3.89 (d, J = 12.6 Hz, 1 H, H5α), 3.63 (dd, J = 4.2, 12.6 Hz, 1
H, H5β), 2.74 (dd, J = 8.5, 17.2 Hz, 1 H, H2α), 2.65 (s, 1 H, OH),
2.31–2.37 (m, 1 H, H3), 2.22 (dd, J = 8.0, 17.2 Hz, 1 H, H2β),
1.38–1.62 (m, 2 H, CH2), 0.94 (t, J = 7.4 Hz, 3 H, CH3) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 176.53, 85.42, 62.80, 37.28, 34.42,
25.80, 11.23 ppm. HRMS (ESI) m/z calcd. for C17H21NO4Na [M
+ Na]+: 167.0684, found: 167.0677.
R = 0.75 (EtOAc/heptane, 1:1). FTIR (ATR): ν = 1187, 1314,
˜
f
1512, 1683, 2980, 3355 cm–1. 1H NMR (CDCl3, 400 MHz): δ =
7.82 (br. s, 1 H, NH), 6.60 (s, 1 H, C=CH2), 5.88 (d, J = 1.5 Hz, 1
H, C=CH2), 5.77–5.88 (m, 1 H, CH=CH2), 5.01–5.11 (m, 2 H,
CH2), 4.29 (q, J = 7.1 Hz, 2 H, CH2), 2.40–2.46 (m, 4 H, 2ϫCH2),
1.34 (t, J = 7.1 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 170.54, 163.61, 136.07, 130.56, 115.29, 107.62, 61.65, 36.24,
28.61, 13.56 ppm. HRMS (ESI) m/z calcd. for C10H15INO4Na [M
+ Na]+: 220.09496, found: 220.09528.
(4S,5S)-4-Ethyl-5-(iodomethyl)dihydrofuran-2(3H)-one (25): Com-
pound 24 (40 mg, 0.28 mmol) and PPh3 (88 mg, 0.34 mmol) were
dissolved in THF (3 mL). This solution was heated to 70 °C and a
solution of imidazole (29 mg, 0.42 mmol), I2 (85 mg, 0.34 mmol) in
CH2Cl2 (2 mL) was added. After stirring for 1 h at room tempera-
ture, the mixture was diluted with CH2Cl2 (15 mL) washed with
10% aqueous Na2S2O3 (15 mL), H2O (20 mL) and brine (15 mL).
The organic layer was dried (Na2SO4), concentrated in vacuo and
purified using column chromatography (EtOAc/heptane, 1:1) to
give furanone 25 (52 mg, 74% yield) as a colorless oil. Rf = 0.81
(EtOAc/heptane, 3:1). [α]2D0 = +36.9 (c 0.0035, CH2Cl2). FTIR
Ethyl 2-[(4-Methoxybenzyl)pent-4-enoylamino]acrylate (13b): To a
solution of 9b (187 mg, 0.88 mmol) in dry DMF (9 mL), were
added at 0 °C NaH (40 mg, 1.1 equiv.) and then PMBBr (190 µL,
1.5 equiv.). The reaction mixture was stirred for 1 h and then an-
other portion of NaH (18 mg, 0.97 mmol) was added. After stirring
for another hour, the reaction was quenched with H2O (10 mL)
and extracted with a mixture of EtOAc/heptane (1:1) (3ϫ25 mL).
The organic layer was dried (MgSO4) and concentrated in vacuo.
The residue was purified by column chromatography (EtOAc/hep-
tane, 1:2) to give 13b (248 mg, 0.73 mmol, 83%) as a colorless oil.
(ATR): ν = 1148, 1170, 1776, 2960 cm–1. 1H NMR (CDCl3,
˜
400 MHz): δ = 4.12 (dd, J = 10.2, 5.2 Hz, 1 H, H4), 3.30–3.42 (m,
2 H, H5), 2.79 (dd, J = 19.8, 11.0 Hz, 1 H, H2α), 2.22–2.30 (m, 1
H, H2β), 1.61–1.69 (m, 1 H, H3), 1.40–1.52 (m, 1 H, CH2), 0.97
(t, J = 7.4 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3, 75 MHz): δ =
174.90, 82.62, 41.87, 34.05, 26.12, 11.12, 6.54 ppm. HRMS (ESI)
m/z calcd. for C17H22NO4 (M – H)–: 127.0759, found: 127.0759.
R = 0.48 (EtOAc/heptane, 1:1). FTIR (ATR): ν = 1175, 1246,
˜
(R)-3-Ethylpent-4-enoic Acid (26): To a solution of 25 (372 mg,
1.75 mmol) in MeOH (20 mL), zinc (307 mg, 5.25 mmol) and 10
drops of acetic acid were added and the mixture was stirred for 2 h
at room temperature. Next, it was filtered through Celite, concen-
trated in vacuo and purified by column chromatography (EtOAc/
heptane, 1:2) to afford carboxylic acid 26 (173 mg, 1.35 mmol,
86%) as a colorless oil. [α]2D0 = +7.8 (c 0.004, CH2Cl2). FTIR
f
1511, 1663, 1723, 2936 cm–1. 1H NMR (CDCl3, 400 MHz): δ =
7.09 (d, J = 8.0 Hz, 2 H, ArH), 6.91 (d, J = 8.2 Hz, 2 H, ArH),
6.33 (s, 1 H, C=CH2), 5.81 (m, 1 H, CH=CH2), 5.29 (s, 1 H,
C=CH2), 4.89–4.96 (m, 2 H, CH=CH2), 4.56 (s, 2 H, CH2Ar), 4.12
(q, J = 7.0 Hz, 2 H, CH2), 3.87 (s, 3 H, CH3Ar), 1.94–2.11 (m, 4 H,
2ϫCH2), 1.27 (t, J = 7.0 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3,
75 MHz): δ = 171.94, 163.33, 158.50, 138.32, 137.55, 129.85,
129.75, 127.29, 114.55, 113.25, 61.28, 54.72, 49.73, 32.72, 32.64,
23.88, 13.09 ppm. HRMS (ESI) m/z calcd. for C19H25INO4Na [M
+ Na]+: 354.1681, found: 354.1694.
(ATR): ν = 916, 1707, 2924, 2962 cm–1. 1H NMR (CDCl3,
˜
400 MHz): δ = 5.58–5.68 (m, 1 H, CH=CH2), 4.97–5.13 (m, 2 H,
CH=CH2), 2.37–2.41 (m, 2 H, CH2), 2.31–2.40 (m, 1 H, CH), 1.41–
1.52 (m, 1 H, CH2), 1.35 (m, 1 H, CH2), 0.88 (t, J = 7.4 Hz, 3 H,
CH3) ppm. 13C NMR (CDCl3, 75 MHz): δ = 177.82, 139.99,
114.90, 41.23, 38.91, 26.76, 10.89 ppm. HRMS (ESI) m/z calcd. for
C17H20NO4 (M – H)–: 127.0759, found: 127.0759.
Ethyl 1-(4-Methoxybenzyl)-6-oxo-1,4,5,6-tetrahydropyridine-2-carb-
oxylate (15): A solution of 13b (170 mg, 0.54 mmol) in dry PhMe
(25 mL) was flushed with nitrogen for 15 min after which the tem-
perature was raised to 80 °C. At 80 °C G2 (23 mg, 5 mol-%) was
added and the reaction was stirred for 1 h. After 1 h the organic
layer was concentrated in vacuo. The residue was purified by col-
umn chromatography (EtOAc/heptane, 1:2) to give 15 (111 mg,
3-Ethylpent-4-enamide (27): To a solution of acid 26 (173 mg,
1.37 mmol) in MeOH (4 mL) a 7  solution of NH3 in MeOH
(3 mL) was added. The mixture was stirred for 4 days at room
temperature, concentrated in vacuo and the residue was purified by
0.38 mmol, 71%) as a brown oil. Rf = 0.34 (EtOAc/heptane, 1:1). column chromatography (EtOAc/heptane, 1:1) to afford amide 27
1
FTIR (ATR): ν = 1249, 1513, 1677, 1720 cm–1. H NMR (CDCl
(110 mg, 67%) as a white solid. Rf = 0.08 (EtOAc/heptane, 1:2).
˜
3,
400 MHz): δ = 7.12 (d, J = 8.0 Hz, 2 H, ArH), 6.85 (d, J = 8.0 Hz,
[α]2D0 = –12.7 (c 0.01, CH Cl ). IR (ATR): ν = 1409, 1631, 1667,
˜
2
2
2 H, ArH), 6.31 (t, J = 2.6 Hz, 1 H, C=CH), 5.06 (s, 2 H, CH2Ar), 3179, 3351 cm–1. H NMR (CD3OD, 400 MHz): δ = 5.63 (ddd, J
1
5910
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5906–5912

Expedient Pathway into Optically Active 2-Oxopiperidines
= 17.2, 10.3, 8.3 Hz, 1 H, CH=CH2) 5.41 (br. s, 2 H, NH2), 5.01– J = 14.9 Hz, 1 H, CH2Ar), 4.12–4.21 (m, 2 H, CH2), 3.77 (s, 3 H,
5.12 (m, 2 H, CH=CH2), 2.35–2.47 (m, 1 H, CH), 2.23 (dq, J =
14.3, 7.1 Hz, 2 H, CH2), 1.42–1.57 (m, 1 H, CH2), 1.26–1.36 (m, 1
CH3Ar), 2.61 (ddd, J = 14.6, 5.0, 1.0 Hz, 1 H, CH2), 2.38–2.48 (m,
1 H, CH), 2.33 (dd, J = 14.6, 10.6 Hz, 1 H, CH2), 1.40–1.46 (m, 2
H, CH2), 0.88 (t, J = 7.4 Hz, 3 H, CH3) ppm. 13C NMR (CD3OD, H, CH2), 1.24 (t, J = 7.1 Hz, 3 H, CH3), 0.93 (t, J = 7.4 Hz, 3 H,
75 MHz): δ = 173.93, 140.58, 115.09, 41.86, 41.02, 26.93, 10.97
ppm. HRMS (ESI) m/z calcd. for C12H15NO [M + H]+: 128.1076,
found: 128.1069.
CH3) ppm. 13C NMR (CDCl3, 75 MHz): δ = 170.00, 158.33,
128.99, 125.36, 113.35, 60.88, 54.73, 44.05, 36.27, 32.62, 25.63,
13.62, 10.71 ppm. HRMS (ESI) m/z calcd. for C18H23NO4Na [M
+ Na]+: 340.1525, found: 340.1523.
(R)-Ethyl 2-(3-Ethylpent-4-enamido)acrylate (34d): To a solution of
amide 27 (52 mg, 0.41 mmol) in PhMe (3 mL), pTsOH (7.9 mg,
0.041 mmol) and ethyl pyruvate (90 µL, 0.82 mmol) were added.
The reaction mixture was stirred under Dean–Stark conditions ap-
plying vacuum for regulation. After 3 h the reaction was cooled to
room temperature and poured over a plug of neutral Al2O3. The
Al2O3 was washed with PhMe (2ϫ25 mL). The organic layer was
concentrated in vacuo to give acrylate 34d (52 mg, 0.23 mmol,
57%). Rf = 0.66 (EtOAc/heptane, 1:1). [α]2D0 = +10.3 (c 0.01,
Ethyl 3-Iodo-1-(4-methoxybenzyl)-6-oxo-1,4,5,6-tetrahydropyridine-
2-carboxylate (37): To a solution of 14 (50 mg, 0.173 mmol) in
CH2Cl2 (2 mL) was added dropwise a mixture of NIS (43 mg,
0.190 mmol) and TFA (13 mL, 0.173 mmol) in CH2Cl2 (2 mL). The
reaction mixture was stirred at room temperature and after 12 h
another equivalent of NIS/TFA mixture was added, after which the
reaction was stirred for three hours. Upon quenching with aqueous
NaHCO3, the layers were separated. The organic layer was washed
with H2O (50 mL) and brine (50 mL), dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy (EtOAc/heptane, 1:2) to give tetrahydropyridine 37 (57 mg,
0.137 mmol, 78%) as a colorless oil. Rf = 0.67 (EtOAc/heptane,
CH Cl ). IR (ATR): ν = 1188, 1316, 1514, 1686, 2950, 3360 cm–1.
˜
2
2
1H NMR (CDCl3, 400 MHz): δ = 7.75 (s, 1 H, NH), 6.60 (s, 1 H,
C=CH2), 5.87 (d, J = 1.4 Hz, 1 H, C=CH2), 5.64 (ddd, J = 17.2,
10.3, 8.3 Hz, 1 H, CH=CH2), 5.01–5.13 (m, 2 H, CH=CH2), 4.29
(q, J = 7.1 Hz, 2 H, CH2), 2.42–2.56 (m, 1 H, CH), 2.39 (dd, J =
5.8, 14.4 Hz, 1 H, CH), 2.29 (dd, J = 14.4, 8.4 Hz, 1 H, CH), 1.32–
1.44 (m, 1 H, CH2), 1.34 (t, J = 7.1 Hz, 3 H, CH3), 1.21–1.39 (m,
1 H, CH2), 0.89 (t, J = 7.4 Hz, 3 H, CH3) ppm. 13C NMR (MeOD,
75 MHz): δ = 170.24, 163.71, 140.16, 130.50, 115.31, 107.86, 61.70,
42.82, 41.83, 26.92, 13.63, 10.97 ppm. HRMS (ESI) m/z calcd. for
C12H19NO3Na [M + Na]+: 248.1363, found: 248.1270.
1:1). FTIR (ATR): ν = 1247, 1681, 1727, 2980 cm–1. 1H NMR
˜
(CDCl3, 400 MHz): δ = 7.09 (d, J = 8.6 Hz, 2 H, ArH), 6.82 (d, J
= 8.7 Hz, 2 H, ArH), 4.75 (s, 2 H, CH2Ar), 4.14 (q, J = 7.2 Hz, 2
H, CH2), 3.78 (s, 3 H, CH3Ar), 2.84 (t, J = 7.6 Hz, 3 H, CH3) ppm.
13C NMR (CDCl3, 75 MHz): δ = 168.4, 162.9, 158.6, 137.1, 128.5,
128.3, 113.4, 74.2, 61.6, 54.8, 46.1, 34.6, 31.7, 13.3 ppm. HRMS
(ESI) m/z calcd. for C16H18INO4Na [M + Na]+: 438.0178, found:
438.0172.
(R)-Ethyl 2-[3-Ethyl-N-(4-methoxybenzyl)pent-4-enamido]acrylate
(35d): To a solution of acrylate 34d (26 mg, 0.116 mmol) in dry
DMF (2 mL) were added at 0 °C NaH (11.4 mg, 0.232 mmol) and
then PMBBr (33.2 µL, 0.232 mmol). The reaction mixture was
stirred for 1 h, quenched with H2O (10 mL) and extracted with a
mixture of EtOAc/heptane (1:1) (3ϫ10 mL). The organic layer was
dried (MgSO4) and concentrated in vacuo. The residue was purified
by column chromatography (EtOAc/heptane, 1:2) to give acrylate
35d (31 mg, 0.090 mmol, 77%) as a colorless oil. Rf = 0.59 (EtOAc/
Ethyl 1-(4-Methoxybenzyl)-6-oxo-3-phenyl-1,4,5,6-tetrahydropyr-
idine-2-carboxylate (38a): To
a
solution of 37 (17.5 mg,
0.042 mmol) in EtOH (1 mL) were added PhB(OH)2 (7.2 mg,
0.063 mmol), Pd(OAc)2 (1 mg, 10 mol-%) and Na2CO3 (8.3 mg,
0.084 mmol). The reaction mixture was stirred at 55 °C for 1 h,
after which H2O (10 mL) was added and the mixture was extracted
with CH2Cl2 (2ϫ10 mL). The organic layer was dried (Na2SO4)
and concentrated in vacuo. The residue was purified by column
chromatography (EtOAc/heptane, 1:2) to give tetrahydropyridine
heptane, 1:1). [α]2D0 = +5.6 (c 0.056, CH Cl ). IR (ATR): ν = 1177,
˜
2
2
1
1248, 1512, 1724 cm–1. H NMR (CDCl3, 400 MHz): δ = 7.17 (d,
J = 8.5 Hz, 2 H, ArH), 6.81 (d, J = 8.4 Hz, 2 H, ArH), 6.32 (s, 1
H, C=CH2), 5.51–5.64 (m, 1 H, CH=CH2), 5.31 (s, 1 H, C=CH2),
4.96–5.08 (m, 2 H, CH=CH2), 4.69 (d, J = 15.2 Hz, 1 H, CH2Ar),
4.57 (d, J = 15.2 Hz, 1 H, CH2Ar), 4.22 (q, J = 7.2 Hz, 2 H, CH2),
3.78 (s, 3 H, CH3Ar), 2.44–2.57 (m, 1 H, CH), 2.21 (d, J = 7.3 Hz,
2 H, CH2), 1.28 (t, J = 7.1 Hz, 3 H, CH3), 0.85 (t, J = 7.4 Hz, 3
H, CH3) ppm. 13C NMR (CDCl3, 75 MHz): δ = 172.31, 171.14,
158.49, 140.78, 138.34, 135.10, 129.90, 127.54, 114.35, 113.22,
61.34, 54.76, 49.72, 41.57, 38.57, 26.73, 13.64, 11.06 ppm. HRMS
(ESI) m/z calcd. for C20H27NO4Na [M + Na]+: 368.1838, found:
368.1838.
38a (10 mg, 0.026 mmol, 70%) as a colorless oil. Rf = 0.42 (EtOAc/
1
heptane, 1:1). FTIR (ATR): ν = 1248, 1678, 2976 cm–1. H NMR
˜
(CDCl3, 400 MHz): δ = 7.21–7.31 (m, 4 H, ArH), 7.11–7.15 (m, 3
H, ArH), 6.81 (d, J = 8.8 Hz, 1 H, ArH), 4.87 (s, 3 H, CH2Ar),
3.79 (q, J = 7.2 Hz, 2 H, CH2), 3.77 (s, 3 H, CH3Ar), 2.67–2.74
(m, 4 H, 2ϫCH2), 0.74 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 169.27, 163.76, 158.40, 138.75, 128.83,
128.76, 128.51, 127.74, 126.95, 126.55, 125.49, 113.377, 60.80,
54.76, 44.82, 30.58, 26.92, 12.72 ppm. HRMS (ESI) m/z calcd. for
C22H23NO4Na [M + Na]+: 388.1525, found: 388.1538.
Supporting Information (see also the footnote on the first page of
1
this article): General experimental and H and 13C NMR spectra
of selected compounds.
(R)-Ethyl 4-Ethyl-1-(4-methoxybenzyl)-6-oxo-1,4,5,6-tetrahydropyr-
idine-2-carboxylate (36d): A solution of acrylate 35d (31 mg,
0.090 mmol) in dry PhMe (2 mL) was flushed with nitrogen for
15 min after which the temperature was raised to 80 °C. At 80 °C
catalyst G2 (8.5 mg, 10 mol-%) was added and the reaction was
stirred for 1 h. Then the organic layer was concentrated in vacuo
and the residue was purified by column chromatography (EtOAc/
heptane, 1:2) to give tetrahydropyridine 36d (26 mg, 0.082 mmol,
91%) as a brown oil. Rf = 0.41 (EtOAc/heptane, 1:1). [α]2D0 = –16.7
Acknowledgments
This research has been financially supported (in part) by the Coun-
cil for Chemical Sciences of The Netherlands Organization for
Scientific Research (NWO-CW). Chiralix B.V. (Nijmegen, The
Netherlands) is kindly acknowledged for generously providing -
allylglycine.
(c 0.02, CH Cl ). FTIR (ATR): ν = 1255, 1507, 1683, 1714,
˜
2
2
2950 cm–1. H NMR (CDCl3, 400 MHz): δ = 7.07 (d, J = 8.8 Hz,
2 H, ArH), 6.79 (d, J = 8.8 Hz, 2 H, ArH), 6.20 (dd, J = 0.8,
4.1 Hz, 1 H, C=CH), 5.22 (d, J = 14.9 Hz, 1 H, CH2Ar), 4.86 (d,
1
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Received: April 27, 2010
Published Online: August 26, 2010
5912
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5906–5912