Asymmetric Synthesis of 2,3,4-Trisubstituted Piperidines

Article abstract of DOI:10.1055/s-0036-1588299

Two different organocatalytic approaches for the asymmetric synthesis of 2,3,4-trisubstituted piperidines were developed. Both approaches were based on an aza-Michael addition followed by cyclization and gave products in high enantiomeric excess.

Full text of DOI:10.1055/s-0036-1588299

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–K
paper
A
K. Kriis et al.
Paper
Synthesis
Asymmetric Synthesis of 2,3,4-Trisubstituted Piperidines
O
Kadri Kriis
Triin Melnik
Kristiina Lips
Ilona Juhanson
Sandra Kaabel
Ivar Järving
Ar
COOEt
6 examples
yield 34–89%, ee up to 92%
aminocatalysis
O
R'
Ar
A
B
*
*
*
RHN
OEt
Ar
N
R
7 examples
yield 68–98%, ee up to 98%
NO2
Tõnis Kanger*
R = Bn or OBn
R' = CHO or NO2
H-bond catalysis
Department of Chemistry, Tallinn University of
Technology, Akadeemia tee 15, 12618 Tallinn,
Estonia
tonis.kanger@ttu.ee
Received: 28.06.2016
OH
Accepted after revision: 01.08.2016
Published online: 02.09.2016
DOI: 10.1055/s-0036-1588299; Art ID: ss-2016-t0463-op
OMe
H
N
Br
O
O
O2N
Abstract Two different organocatalytic approaches for the asymmet-
ric synthesis of 2,3,4-trisubstituted piperidines were developed. Both
approaches were based on an aza-Michael addition followed by cycliza-
tion and gave products in high enantiomeric excess.
N
HO
OMe
OH
OH
N
Key words organocatalysis, asymmetric catalysis, trisubstituted
piperidines, aza-Michael addition, cyclization
N
N
MeO
Piperidine is a very important scaffold in medicinal
chemistry1 being the third most prevalent ring system in
small molecule drugs.2 The biological activity of the piperi-
dine ring containing compounds may vary from high toxici-
ty to useful pharmaceutical functions. Properties of their
derivatives depend on the substituents as well as on the
substitution pattern. Several pharmaceutical agents, such
as farnesyltransferase inhibitors,3 natural compounds,4,5 or
biologically active tetrahydroquinolines6–8 contain 2,3,4-
trisubstituted piperidine core (Figure 1).
The synthesis of substituted piperidines has been thor-
oughly studied.9 There are several examples of the enantio-
selective catalytic synthesis of fully10,11 or densely substi-
tuted piperidines.12–14 The asymmetric synthesis of 2,3,4-
trisubstituted piperidines is not as well described. Indanol
or amino acid auxiliary based approaches have been used
for an aza-Diels–Alder reaction.15,16 In 2015, Rovis disclosed
a Zn-catalyzed formal [4+2] cycloaddition leading to the
above-mentioned substitution pattern of the piperidine
ring.17 From the synthetic point of view, cascade or domino
reactions where several chemical bonds are formed consec-
utively in one step are the most preferred due to their effi-
ciency.18,19 One of the most useful technologies for cascade
cyclization reactions is the Michael addition-mediated ring
O
Figure 1 Bioactive compounds containing 2,3,4-trisubstituted piperi-
dine cores
closure (MIRC).20,21 To conduct the cascade reaction, multi-
functional starting compounds are needed. By choosing a
properly substituted Michael donor and acceptor a variety
of cyclic products can be obtained. Planning the first step of
the cascade as an aza-Michael reaction provides a platform
for the synthesis of heterocycles.22 Aminocrotonates (4-am-
inobut-2-enoates) contain both nucleophilic amino groups
and electrophilic conjugated double bonds. We have previ-
ously shown the effectiveness of aminocrotonates in the
one-step construction of the pyrrolidine ring by enantiose-
lective organocatalytic cascade23 or diastereoselective mul-
ticomponent reactions.24–26 Lengthening the chain of the
crotonate by one methylene group affords a starting mate-
rial for the synthesis of piperidines. A different substitution
pattern of the first Michael acceptor reacting with a multi-
functional Michael donor, such as a 5-aminopentenoate 1,
allows the formation of products of diversity oriented syn-
thesis.27 Herein we describe two new organocatalytic cas-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

B
K. Kriis et al.
Paper
Synthesis
cades for the asymmetric synthesis of 2,3,4-trisubstituted
piperidines, starting from N-protected 5-aminopentenoates
1 (Scheme 1).
Table 1 Screening of the Conditions for the Aminocatalytic Approach
catalyst
(20 mol%)
additive
COOEt
O
O
O
(20 mol%)
H
r.t.
Ph
H
BnHN
OEt
O
Ph
N
2a
4a
1a
Bn
Ph
2
COOEt
Entry Catalyst Additive
Solvent
Time Yield ee
(d)
O
aminocatalysis
Ph
A
B
R'
(%)a
(%)b
*
*
*
RHN
OEt
NO2
1
2
I
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
4
6
3
2
2
3
1
2
2
2
39
47
56
36
53
63
77
71
47
25
43
61
75
51
78
76
86
84
rac
rac
Ph
N
R
1a R = Bn
3
I
PhCO2H
1b R = OBn
1c R = Boc
1d R = Ts
1e R = Ns
H-bond catalysis
4, R' = CHO
5 and 6, R' = NO2
3
I
4-NO2C6H4CO2H
4
I
3,5-(NO2)2C6H3CO2H
4-NO2C6H4OH
4-NO2C6H4OH
4-NO2C6H4OH
4-NO2C6H4OH
4-NO2C6H4OH
4-NO2C6H4OH
Scheme 1 Organocatalytic routes to 2,3,4-trisubstituted piperidines
5
I
6
I
7
I
toluene
toluene
toluene
toluene
Depending on the structure of the first Michael acceptor
different activation modes can be used. α,β-Unsaturated
carbonyl compounds 2 can be activated via the formation of
iminium ions in aminocatalysis (Scheme 1, A), and unsatu-
rated nitro compounds 3 via H-bonding catalysis (Scheme
1, B). In both cases the first step of the cascade is an aza-
Michael addition followed by the second intramolecular
conjugated addition. Three stereogenic centers are generat-
ed in the course of the reaction. The main goal of our strate-
gy to be addressed is obtaining a single enantiomerically
pure stereoisomer. Highly stereodefined reactions have to
be used for that task.
An aminocatalytic aza-Michael addition is always a
challenge because of the possible competing reactions of
the amino catalyst and aza-nucleophile.28 The reaction be-
tween ethyl (E)-5-(benzylamino)pent-2-enoate (1a) and
cinnamaldehyde (2a) was chosen as a model (Table 1). It
was found that in the absence of additives the reaction was
very slow affording only 8% of conversion during 24 hours
at room temperature in dichloromethane. To achieve the
asymmetric synthesis of trisubstituted piperidines: i) the
reactivity has to be increased considerably by using the ap-
propriate catalyst; and, ii) the catalyst has to provide high
enantio- and diastereoselectivity. The screening for optimal
conditions and the most efficient catalyst was performed in
the presence of various additives in different solvents (Table
1). Diarylprolinol silyl ethers29 are the most widely used
aminoacatalysts and they were our first choice (Figure 2).
8
II
III
IV
9
10
a Isolated yield of a single diastereoisomer.
b Determined by chiral HPLC.
The catalysis in the presence of trimethylsilylprolinol I
was inefficient (Table 1, entry 1). Acidic additives increased
the rate and also enantioselectivity of the reaction (entries
2–5). However, the reaction time remained unreasonably
long. Significant enhancement of the rate and selectivity
was observed by changing the solvent from dichlorometh-
ane to toluene (entry 7). Other prolinol derivatives II, III
and MacMillan’s catalyst IV had detrimental effects on the
reaction (entries 8–10). In all cases, the reaction was highly
diastereoselective and only one stereoisomer was detected.
The relative configuration of the diastereoisomer 4a was
determined by vicinal coupling constants (Figure 3, 4a
trans,trans-isomer). On the basis of the Karplus equation, it
is known that the coupling constants of a six-membered
ring are about 9–12 Hz for trans-orientated protons, but
cis-coupling constants may be as low as 3 Hz.30 The spin-
spin coupling constants of the proton at the C3 position of
the major diastereomer 4a are 10 Hz and 11 Hz. Conse-
quently, the protons at C2, C3, and C4 positions are axial,
and substituents at those positions are in trans,trans con-
figuration.
J
H2–H3 = 10 Hz
O
Ph
Ph
Ph
Ph
Ar
N
JH3–H4 = 11 Hz
tBu
N
N
COOEt
N
Ar
OTMS
Ar = 3,5-(CF3)2PC6H3
H
H
O
H
O
N
H
H
H
OTMS
OTBMS
COOEt
Ph
4
H
Ph
3
2
N
I
II
III
IV
H
Bn
Ph
N
Figure 2 Aminocatalysts screened
4a, trans,trans-isomer
Bn
Figure 3 Relative configuration of the diastereoisomer 4a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

C
K. Kriis et al.
Paper
Synthesis
Having established the optimal conditions (20 mol% of
catalyst I and 4-nitrophenol in toluene at r.t.) the scope of
the reaction was explored (Table 2).
Table 2 Scope of the Aminocatalytic Reactiona
catalyst I
(20 mol%)
4-NO2C6H4OH
(20 mol%)
COOEt
O
R
O
O
H
toluene, r.t.
R
H
BnHN
OEt
N
2a–g
4a–g
1a
Bn
Entry
Product 4, R
4a: Ph
Time (d) Conv. (%)b Yield (%)c ee (%)d
Figure 4 X-ray crystal structure of compound 4f
1
2
3
4
5
6
7
1
1
1
1
2
3
85
97
99
72
24
98e
–
77
75
89
55
34
63
–
86
86
92
68
85
88
–
4b: 4-BrC6H4
4c: 4-NO2C6H4
4d: 2-NO2C6H4
4e: 4-MeOC6H4
4f: thiophen-2-yl
4g: Et
lyst (Scheme 2). Si-attack of the nucleophile affords product
with S-configuration at the second position of the piperi-
dine ring. The stereochemistry of the enamine-activated
second Michael addition is determined by the thermody-
namic factor affording the product with the most stable
trans,trans-configuration where all substituents are in
equatorial position.
a Reaction conditions: 1 equiv of 2a and 1.1 equiv of 1a were used.
b Conversion was determined by NMR analysis of the crude mixture after
1 d.
c Isolated yield.
RH
O
COOEt
O
d Determined by chiral HPLC.
e Conversion was determined by NMR analysis after 3 d.
– RH
H
Ph
Ph
Several aromatic or heteroaromatic unsaturated alde-
hydes 2 were used as Michael acceptors. All reactions with
different aldehydes were diastereoselective, predominantly
affording the single diastereoisomer 4 in a trans,trans con-
figuration. The electron-withdrawing nitro group and elec-
tron-donating methoxy group were well tolerated and did
not change the enantioselectivity significantly. However,
the methoxy group and thiophenyl substituent retarded the
reaction (Table 2, entries 5 and 6). The reaction with ali-
phatic aldehyde 4g gave a mixture of products. No reactions
were observed when tert-butoxycarbonyl, tosyl, or 2-nitro-
benzenesulfonyl protected aminopentenoate derivatives
1c–e were used. The more nucleophilic compound 1b af-
forded NOBn protected piperidine 4h (Scheme 1, 4h: R =
OBn) in good yield and with very high enantioselectivity
(ee 98%).
The absolute configuration of the product was estab-
lished by single-crystal X-ray diffraction for compound 4f
(Figure 4, see Supporting Information for details). The con-
figuration of other compounds in the series was assigned by
analogy.
Based on the obtained results, the following explanation
is proposed. The first Michael addition of amine 1 is the ste-
reodefining step of the cascade. In the preferred transition
state, the Re-face of the acceptor is shielded by the sterically
demanding substituent at the pyrrolidine ring of the cata-
N
Ph
N
Ph
OTMS
Bn
O
Ph
CHO
EtOOC
R
COOEt
HN
Bn
OEt
Ph
N
Bn
Ph
R =
Ph
N
N
Ph
OTMS
Bn
Scheme 2 Proposed mechanism of the aminocatalytic formation of
substituted piperidines
Urea and thiourea derivatives have been intensively in-
vestigated in the area of molecular recognition due to their
strong hydrogen-bonding activity.31 It is generally accepted
that chiral bifunctional thioureas with both hydrogen do-
nor and acceptor moieties are very efficient in organocata-
lytic reactions. The activation of the nucleophile and elec-
trophile affects both the reactivity and enantioselectivi-
ty.32,33 We decided to investigate the potential of various
chiral thioureas as organocatalysts in the aza-Michael/Michael
cascade process leading to the same substitution pattern of
the piperidine ring as in the aminocatalytic reaction.
The initial model reaction was performed using trans-β-
nitrostyrene (3a) and ethyl (E)-5-(benzylamino)pent-2-
enoate (1a) in the presence of a Takemoto catalyst V in tolu-
ene at room temperature (Table 3, entry 1 and Figure 5).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

D
K. Kriis et al.
Paper
Synthesis
The reaction was completed within five hours and afforded
almost 1:1 mixture of diastereoisomers 5a and 6a in high
yield and high enantioselectivity.
alyst loading, the yield of product was even increased (10 or
5 mol%, Table 3, entries 6 and 7). When the catalyst loading
was further reduced from 5 to 2 mol%, the enantioselectivi-
ty was slightly decreased (entry 8). Therefore, the optimal
conditions were found to be the use of 5 mol% of catalyst
VIII in toluene at room temperature.
N
N
H
H
H
H
N
N
N
CF3
N
CF3
Unfortunately, the obtained diastereoisomers were in-
separable by column chromatography. The diastereoiso-
mers 5a and 6a differed in relative configuration of the car-
boxymethylene substituent. In the isomer 5a, the car-
boxymethylene and nitro groups are in trans-configuration
O
S
S
CF3
V
CF3
VI
N
N
N
H
H
H
H
N
N
N
N
CF3
(J3,4 = 11.2 Hz) and in isomer 6a in cis-configuration (J3,4
=
O
S
S
4.9 Hz). The nitro and phenyl groups are always in the
trans-configuration (J2,3 = 9.7 Hz for 5a and J2,3 = 10.3 Hz for
6a).
CF3
N
N
VII
VIII
With optimal conditions in hand, the substrate scope
was briefly investigated by reacting differently substituted
nitroalkenes 3a–g with aminopentenoate 1a. In all cases,
good yields and high enantioselectivities were obtained
(Table 4, entries 1–7).
N
H
H
N
N
S
N
IX
Table 4 Scope of Asymmetric Cascade Aza-Michael/Michael Addition
Figure 5 Chiral thioureas screened
for Piperidinesa
Table 3 Screening for the Catalysta
O
COOEt
COOEt
O2N
BnHN
OEt
catalyst VIII
(5 mol%)
O
1a
COOEt
COOEt
O2N
R
BnHN
OEt
+
catalyst
(20 mol%)
O2N
Ph
O2N
Ph
1a
3a
toluene
r.t., 5 h
NO2
R
N
N
R
6a–g
+
5a–g
3a–g
toluene
r.t.
NO2
Bn
Bn
N
Bn
Ph
N
Bn
6a
5a
Entry
R
Yield (%)b
drc
ee 5/6 (%)d
Entry
Catalyst
Time (h) Yield (%)b drc
ee 5a/6a (%)d
1
2
3
4
5
6
7
a: Ph
95
89
98
79
73
85
68
1.4:1
97/97
97/98
85/91
89/94
n.d.
b: 4-MeOC6H4
c: 4-CF3OC6H4
d: 4-ClC6H4
1.2:1
1.3:1
1.3:1
1.3:1
1:1
1
2
3
4
5
6
7
8
V
5
5
9
5
9
5
5
5
91
81
80
83
65
88
95
95
1.1:1
1.1:1
3.8:1
1.3:1
1.1:1
1.4:1
1.4:1
1.3:1
85/91
–93/–94
–86/–80
97/98
VI
VII
VIII
IX
e: 3-MeC6H4
f: 4-NO2C6H4
g: thiophen-2-yl
88/93
96/96
82/80
1.3:1
VIII (10 mol%)
VIII (5 mol%)
VIII (2 mol%)
97/98
a Reaction conditions: 1 equiv of 3, 1.1 equiv of 1a in toluene were used.
b Isolated yield of the mixture of two diastereoisomers.
c Determined by NMR analysis of the crude mixture.
97/97
93/95
d Determined by chiral HPLC; n.d.: not determined.
a Reaction conditions: 1 equiv of 3a, 1.1 equiv of 1a in toluene were used.
b Isolated yield of the mixture of two diastereoisomers.
c Determined by NMR analysis of the crude mixture.
d Determined by chiral HPLC.
The results show that the electronic effect of the sub-
stituents at the aromatic rings has little influence on the
cascade process. Heteroaryl nitroolefin 3g also gave the de-
sired products 5g and 6g in slightly lower yield but with
high enantioselectivity (Table 4, entry 7). Similar to the pre-
viously described aminocatalytic method of the synthesis
of substituted piperidines, only N-benzyl and N-benzyloxy
derivatives (1a and 1b, respectively) of the aza-Michael do-
nor were reactive. A mixture of NOBn-protected piperidine
diastereoisomers 5h and 6h (Scheme 1,R = OBn) was ob-
tained in thiourea VIII catalyzed reaction with nitrostyrene
Cinchona alkaloid based thioureas VI–VIII gave princi-
pally similar results: low diastereoselectivity and high to
very high enantioselectivity (Table 3, entries 2–5). Among
the catalysts examined thiourea VIII proved to be superior
to the others. The highest enantioselectivity of both diaste-
reoisomers was obtained by sacrificing the diastereoselec-
tivity. Next, the effect of catalyst loading on the yield and
selectivity of the cascade reaction was investigated. Excel-
lent enantioselectivity was maintained with a reduced cat-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

E
K. Kriis et al.
Paper
Synthesis
3a under optimal conditions in low diastereoselectivity but
in high yield and enantioselectivity (dr 2:1, 86%, ee
97/85%).
We tried to solve the problem of the separation of dia-
stereoisomers by the reduction of the nitro group to the
amino group (Scheme 3).
Ethyl 2-[(2S,3S,4S)-1-Benzyl-3-formyl-2-phenylpiperidin-4-yl]ace-
tate (4a); Typical Procedure
A mixture of α,β-unsaturated aldehyde 2a (0.2 mmol), catalyst I (13.0
mg, 0.04 mmol, 20 mol%) and co-catalyst 4-nitrophenol (5.6 mg, 0.04
mmol, 20 mol%) in toluene (1 mL) was stirred at r.t. for 5 min. Then 5-
aminopentenoate 1a (51 mg, 0.22 mmol) was added in one portion.
After stirring for 24 h, the reaction mixture was concentrated and di-
rectly purified by silica gel column chromatography (PE/EtOAc, 20:1
to 5:1) to afford the product 4a as a single diastereoisomer (64 mg,
77%); pale yellow oil; [α]D20 –22 (c 1.3, CHCl3).
O
COOEt
COOEt
Raney Ni
H2
COOEt
O2N
H2N
Ph
HN
O2N
Ph
+
HPLC: Chiralcel AD-H, n-hexane/i-PrOH (90:10), flow rate 1.0
mL/min, detection at λ = 230 nm; major enantiomer tR = 8.8 min, mi-
nor enantiomer tR = 11.1 min; 86% ee.
+
N
R
Ph
N
R
Ph
N
R
N
R
5a,h
6a,h
7a,h
8a,h
a: R = Bn
h: R = OBn
IR (film): 3062, 3029, 2924, 2799, 2724, 1730, 1602, 1494, 1453,
1376, 1307, 1239, 1216, 1162, 1096, 1057, 1030, 916, 844, 763, 702
7a: 27%
7h: 34%
cm–1
.
Scheme 3 Reduction of nitro group
1H NMR (400 MHz, CDCl3): δ = 9.34 (d, J = 3.9 Hz, 1 H, CHO), 7.45–7.38
(m, 2 H, Ar), 7.38–7.29 (m, 2 H, Ar), 7.30–7.21 (m, 3 H, Ar), 7.24–7.17
(m, 3 H, Ar), 4.09 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.71 (d, J = 13.4 Hz, 1 H,
NCH2Ph), 3.38 (d, J = 10.1 Hz, 1 H, H-2), 2.98 (dt, J = 11.8, 3.5 Hz, 1 H,
H-6), 2.79 (d, J = 13.4 Hz, 1 H, NCH2Ph), 2.59 (ddd, J = 11.2, 10.1, 4.0
Hz, 1 H, H-3), 2.36 (dd, J = 15.1, 4.5 Hz, 1 H, CH2CO), 2.25–2.36 (dddd,
J = 15.9, 11.9, 7.8, 3.8 Hz, 1 H, H-4), 2.14 (dd, J = 15.1, 8.0 Hz, 1 H,
CH2CO), 2.08 (td, J = 12.1, 2.6 Hz, 1 H, H-6), 1.83 (dq, J = 12.9, 2.8 Hz, 1
H, H-5), 1.46 (qd, J = 12.5, 3.9 Hz, 1 H, H-5), 1.23 (t, J = 7.1 Hz, 3 H,
OCH2CH3).
13C NMR (101 MHz, CDCl3): δ = 203.3, 172.0, 140.6, 139.0, 129.0,
128.6, 128.2, 128.1, 126.8, 68.7, 62.0, 60.5, 58.4, 51.9, 38.6, 33.4, 30.7,
14.2.
HRMS (ESI): m/z [M + H]+ calcd for (C23H27NO3H)+: 366.2064; found:
366.2055.
The mixture of piperidines 5a and 6a was used as a
model substrate because of the high enantiomeric excess of
both diastereomers. The trans,trans-isomer 5a was convert-
ed into amine 7a while the trans,cis-isomer 6a afforded lac-
tam 8a in reduction with Raney nickel during one hour. Col-
umn chromatography afforded amine 7a as a single com-
pound together with the fraction of the mixture of amine
7a and lactam 8a. Corresponding NOBn-protected piperi-
dines 5h and 6h afforded products 7h and 8h in a similar
way. Longer reaction time (20 h) led also to the reduction of
the protection group at the nitrogen atom.
In conclusion, we have developed two different synthet-
ic routes to enantiomerically enriched 2,3,4-trisubstituted
piperidines. Both methods are based on organocatalytic
aza-Michael–Michael cascade reactions. The activation of
the first Michael acceptor via aminocatalysis or H-bond ca-
talysis is a trigger for the following cascade. The results re-
ported here highlight the synthetic utility of the asymmet-
ric organocatalysis in the synthesis of heterocycles.
Ethyl 2-[(2S,3S,4S)-1-Benzyl-2-(4-bromophenyl)-3-formylpiperi-
din-4-yl]acetate (4b)
The title compound 4b was obtained as a single diastereoisomer ac-
20
cording to the typical procedure (67 mg, 75%); pale yellow oil; [α]D
–14 (c 1.82, CHCl3).
HPLC: Chiralcel AD-H, n-hexane/i-PrOH (90:10), flow rate 1.0
mL/min, detection at λ = 230 nm; major enantiomer tR = 9.5 min, mi-
nor enantiomer tR = 13.3 min; 86% ee.
1
Full assignment of H and 13C chemical shifts is based on the 1D and
IR (film): 3028, 2934, 2800, 2723, 1730, 1590, 1492, 1453, 1406,
1376, 1295, 1240, 1216, 1163, 1070, 1029, 1010, 968, 847, 820, 747,
2D FT NMR spectra measured on a Bruker Avance 400 MHz instru-
ment. Internal standard TMS (δ = 0.00) or residual solvent signal
[CDCl3; δ = 7.26 (1H NMR), 77.16 (13C NMR)] were used as internal
standards. Standard abbreviations were used to report the 1H NMR
peaks. IR spectra were recorded with a Bruker Tensor 27 FTIR spec-
trophotometer. High-resolution mass spectra were recorded on an
Agilent Technologies 6540 UHD Accurate-Mass Q-TOF LC/MS spec-
trometer by using AJ-ESI ionization. Optical rotations were obtained
with an Anton Paar GWB Polarimeter MCP500. Chiral HPLC was per-
formed using Chiralpak AD-H (250 × 4.6 mm) and Chiralcel OD-H
(250 × 4.6 mm). Precoated silica gel (Merck 60 F254) plates were used
for TLC analyses. Silica gel was used for column chromatography. The
measured melting points are uncorrected. Commercial reagents were
used as received. The solvents were freshly distilled using standard
methods (CH2Cl2 over P2O5, toluene over Na).
699, 677 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.46 (d, J = 4.0 Hz, 1 H, CHO), 7.57 (d,
J = 8.6 Hz, 2 H, 4-BrC6H4, 3′,5′-H), 7.42–7.33 (m, 5 H, C6H5), 7.33–7.28
(m, 2 H, 4-BrC6H4, 2′,6′-H), 4.19 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.76 (d,
J = 13.4 Hz, 1 H, NCH2Ph), 3.47 (d, J = 10.1 Hz, 1 H, H-2), 3.08 (dt, J =
11.8, 3.4 Hz, 1 H, H-6), 2.90 (d, J = 13.4 Hz, 1 H, NCH2Ph), 2.63 (ddd, J =
11.1, 10.2, 4.0 Hz, 1 H, H-3), 2.45 (dd, J = 15.1, 4.4 Hz, 1 H, CH2CO),
2.37 (dddd, J = 15.7, 11.7, 7.7, 3.8 Hz, 1 H, H-4), 2.24 (dd, J = 15.1, 7.8
Hz, 1 H, CH2CO), 2.17 (td, J = 12.0, 2.5 Hz, 1 H, H-6), 1.92 (ddd, J = 13.1,
6.4, 2.8 Hz, 1 H, H-5), 1.55 (qd, J = 12.6, 3.9 Hz, 1 H, H-5), 1.32 (t, J = 7.1
Hz, 3 H, OCH2CH3).
13C NMR (101 MHz, CDCl3): δ = 200.7, 169.7, 137.7, 136.4, 130.0,
127.6, 126.4, 126.0, 124.8, 119.7, 65.7, 59.8, 58.4, 56.2, 49.7, 36.3,
31.3, 28.4, 12.0.
HRMS (ESI): m/z [M + H]+ calcd for (C23H26BrNO3H)+: 444.1169;
found: 444.1170.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

F
K. Kriis et al.
Paper
Synthesis
Ethyl 2-[(2S,3S,4S)-1-Benzyl-3-formyl-2-(4-nitrophenyl)piperidin-
4-yl]acetate (4c)
HPLC: Chiralcel AD-H, n-hexane/i-PrOH (90:10), flow rate 1.0
mL/min, detection at λ = 230 nm: major enantiomer tR = 10.8 min, mi-
nor enantiomer tR = 14.0 min; 85% ee.
The title compound 4c was obtained as a single diastereoisomer ac-
20
cording to the typical procedure (73 mg, 89%); pale yellow oil; [α]D
IR (film): 2936, 2798, 1728, 1611, 1584, 1512, 1453, 1375, 1303,
1248, 1172, 1111, 1032, 829, 744, 670 cm–1
.
+3.4 (c 1.07, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 9.33 (d, J = 4.0 Hz, 1 H, CHO), 7.31 (d,
J = 8.2 Hz, 2 H, 4-MeOC6H4, 2′,6′-H), 7.24–7.19 (m, 5 H, C6H5), 6.87 (d,
J = 8.8 Hz, 2 H, 4-MeOC6H4, 3′,5′-H), 4.09 (q, J = 7.1 Hz, 2 H, OCH2CH3),
3.78 (s, 3 H, CH3O), 3.73 (d, J = 13.4 Hz, 1 H, NCH2Ph), 3.33 (d, J = 10.1
Hz, 1 H, H-2), 2.97 (dt, J = 11.8, 3.4 Hz, 1 H, H-6), 2.77 (d, J = 13.4 Hz, 1
H, NCH2Ph), 2.55 (ddd, J = 11.1, 10.2, 4.0 Hz, 1 H, H-3), 2.36 (dd, J =
15.2, 4.4 Hz, 1 H, CH2CO), 2.27 (tdd, J = 11.8, 7.8, 4.0 Hz, 1 H, H-4), 2.13
(dd, J = 15.2, 8.1 Hz, 1 H, CH2CO), 2.07 (dt, J = 12.3, 2.5 Hz, 1 H, H-6),
1.82 (ddt, J = 13.1, 6.4, 2.7 Hz, 1 H, H-5), 1.44 (qd, J = 12.5, 3.9 Hz, 1 H,
H-5), 1.22 (t, J = 7.1 Hz, 3 H, OCH2CH3).
13C NMR (101 MHz, CDCl3): δ = 203.4, 172.0, 159.3, 139.1, 132.5,
129.2, 128.6, 128.1, 126.8, 114.4, 68.0, 62.1, 60.5, 58.2, 55.2, 52.0,
38.6, 33.5, 30.7, 14.2.
HRMS (ESI): m/z [M + H]+ calcd for (C24H29NO4H)+: 396.2169; found:
396.2161.
HPLC: Chiralcel AD-H, n-hexane/i-PrOH (90:10), flow rate 1.0
mL/min, detection at λ = 230 nm: major enantiomer tR = 10.8 min, mi-
nor enantiomer tR = 14.0 min; 92% ee.
IR (film): 3430, 3029, 2937, 2805, 1728, 1605, 1522, 1494, 1453,
1375, 1348, 1312, 1290, 1241, 1217, 1172, 1106, 1058, 1029, 857,
756, 701 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.41 (d, J = 4.0 Hz, 1 H, CHO), 8.21 (d,
J = 8.9 Hz, 2 H, 4-NO2C6H4, 3′,5′-H), 7.62 (d, J = 8.5 Hz, 2 H, 4-NO2C6H4,
2′,6′-H), 7.31–7.14 (m, 5 H, C6H5), 4.10 (q, J = 7.1 Hz, 2 H, OCH2CH3),
3.58 (d, J = 13.5 Hz, 1 H, NCH2Ph), 3.57 (d, J = 10.0 Hz, 1 H, H-2), 3.02
(dt, J = 11.8, 3.3 Hz, 1 H, H-6), 2.88 (d, J = 13.4 Hz, 1 H, NCH2Ph), 2.57
(ddd, J = 10.9, 10.3, 4.0 Hz, 1 H, H-3), 2.36 (dd, J = 14.9, 4.5 Hz, 1 H,
CH2CO), 2.29 (tdd, J = 10.9, 7.5, 3.4 Hz, 1H, H-4), 2.19 (dd, J = 15.0, 7.4
Hz, 1 H, CH2CO), 2.14 (dt, J = 12.2, 2.7 Hz, 1 H, H-6), 1.86 (dq, J = 13.0,
2.8 Hz, 1 H, H-5), 1.50 (qd, J = 12.6, 3.8 Hz, 1 H, H-5), 1.23 (t, J = 7.1 Hz,
3 H, OCH2CH3).
13C NMR (101 MHz, CDCl3): δ = 202.3, 171.7, 148.7, 147.7, 138.0,
129.1, 128.5, 128.33, 127.2, 124.3, 67.6, 62.0, 60.6, 58.8, 51.7, 38.4,
33.7, 30.5, 14.2.
HRMS (ESI): m/z [M + H]+ calcd for (C23H26N2O5H)+: 444.1914; found:
444.1913.
Ethyl 2-{(2S,3S,4S)-1-Benzyl-3-formyl-2-[4-(thiophen-2-yl)phe-
nyl]piperidin-4-yl}acetate (4f)
The title compound 4f was obtained as a single diastereoisomer ac-
cording to the typical procedure (47 mg, 63%); off-white solid; mp
70–72 °C; [α]D20 –20 (c 0.48, CHCl3).
HPLC: Chiralcel AD-H, n-hexane/i-PrOH (95:5), flow rate 1.0 mL/min,
detection at λ = 230 nm: major enantiomer tR = 10.7 min, minor enan-
tiomer tR = 16.5 min; 88% ee.
Ethyl 2-[(2S,3S,4S)-1-Benzyl-3-formyl-2-(2-nitrophenyl)piperidin-
4-yl]acetate (4d)
The title compound 4d was obtained as a single diastereoisomer ac-
cording to the typical procedure (45 mg, 55%); pale yellow oil; [α]D
IR (KBr): 2936, 2800, 1728, 1494, 1453, 1371, 1303, 1237, 1206, 1075,
20
1029, 854, 745, 700 cm–1
.
+3.9 (c 0.34, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 9.42 (d, J = 3.9 Hz, 1 H, CHO), 7.31–7.26
(m, 5 H, C6H5 + thiophenyl 3′-H), 7.24–7.19 (m, 1 H, C6H5), 6.97 (dd, J =
3.4, 1.2 Hz, 1 H, thiophenyl 5′-H), 6.89 (dd, J = 5.1, 3.4 Hz, 1 H, thio-
phenyl 4′-H), 4.10 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.91 (d, J = 13.3 Hz, 1
H, NCH2Ph), 3.77 (d, J = 10.2 Hz, 1 H, H-2), 2.97 (dt, J = 11.9, 3.4 Hz, 1
H, H-6), 2.85 (d, J = 13.3 Hz, 1 H, NCH2Ph), 2.60 (ddd, J = 11.2, 10.2, 3.9
Hz, 1 H, H-3), 2.38 (dd, J = 15.3, 4.4 Hz, 1 H, CH2CO), 2.27 (tdt, J = 11.8,
8.1, 4.0 Hz, 1 H, H-4), 2.14 (dd, J = 15.3, 8.1 Hz, 1 H, CH2CO), 2.08 (ddd,
J = 12.2, 2.6 Hz, 1 H, H-6), 1.81 (dq, J = 13.0, 3.1 Hz, 1 H, H-5), 1.44 (qd,
J = 12.5, 3.9 Hz, 1 H, H-5), 1.23 (t, J = 7.1 Hz, 3 H, OCH2CH3).
13C NMR (101 MHz, CDCl3): δ = 202.6, 171.9, 144.9, 138.7, 128.8,
128.2, 126.9, 126.3, 126.2, 126.1, 63.5, 62.6, 60.5, 58.2, 51.9, 38.4,
33.5, 30.5, 14.2.
HRMS (ESI): m/z [M + H]+ calcd for (C21H25NO3SH)+: 372.1628; found:
372.1601.
HPLC: Chiralcel AD-H, n-hexane/i-PrOH (90:10), flow rate 1.0
mL/min, detection at λ = 230 nm: major enantiomer tR = 13.7 min, mi-
nor enantiomer tR = 17.25 min; 68% ee.
IR (film): 2933, 2807, 1728, 1606, 1578, 1529, 1495, 1453, 1355,
1216, 1172, 1095, 1029, 856, 786, 752, 700, 684 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.49 (d, J = 4.4 Hz, 1 H, CHO), 7.97 (d,
J = 7.9 Hz, 1 H, 2-NO2C6H4, 3′-H), 7.71 (d, J = 8.1 Hz, 1 H, 2-NO2C6H4, 6′-
H), 7.67–7.62 (m, 2 H, 2-NO2C6H4 4′-H + C6H5), 7.45–7.35 (m, 1 H, 2-
NO2C6H4, 5′-H), 7.29–7.14 (m, 4 H, C6H5), 4.11 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 4.13–4.08 (m, 1 H, H-2), 3.55 (d, J = 13.4 Hz, 1 H, NCH2Ph),
2.99 (dt, J = 12.0, 3.5 Hz, 1 H, H-6), 2.93 (d, J = 13.5 Hz, 1 H, NCH2Ph),
2.62–2.51 (m, 1 H, H-3), 2.41–2.30 (m, 2 H, CH2CO, H-4), 2.17–2.16
(m, 1 H, CH2CO), 2.14 (ddd, J = 12.3, 2.6 Hz, 1 H, H-6), 1.85 (dq, J = 13.1,
2.8 Hz, 1 H, H-5), 1.48 (qd, J = 12.6, 3.8 Hz, 1 H, H-5), 1.23 (t, J = 7.1 Hz,
3 H, OCH2CH3).
13C NMR (101 MHz, CDCl3): δ = 202.1, 171.6, 150.7, 138.5, 135.2,
133.3, 129.9, 128.8, 128.4, 128.3, 127.1, 123.8, 62.8, 61.3, 60.6, 58.8,
51.9, 38.5, 33.4, 30.5, 14.2.
HRMS (ESI): m/z [M + H]+ calcd for (C23H26N2O5H)+: 411.1914; found:
411.1883.
Ethyl 2-[(2S,3S,4S)-1-Benzyloxy-3-formyl-2-phenylpiperidin-4-
yl]acetate (4h)
The title compound 4h was obtained as a single diastereoisomer ac-
cording to the typical procedure (65 mg, 80%); pale yellow solid; mp
74–76 °C; [α]D20 –43 (c 1.24, CHCl3).
HPLC: Chiralcel AD-H, n-hexane/i-PrOH (95:5), flow rate 1.0 mL/min,
detection at λ = 230 nm: major enantiomer tR = 11.7 min, minor enan-
tiomer tR = 10.4 min; 98% ee.
Ethyl 2-[(2S,3S,4S)-1-Benzyl-3-formyl-2-(4-methoxyphenyl)piper-
idin-4-yl]acetate (4e)
The title compound 4e was obtained as a single diastereoisomer ac-
cording to the typical procedure (25 mg, 34%); pale yellow oil; [α]D
IR (KBr): 3032, 2925, 2853, 1731, 1594, 1496, 1455, 1375, 1338, 1218,
20
1172, 1096, 1030, 914, 861, 755, 700 cm–1
.
–24 (c 0.51, CHCl3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

G
K. Kriis et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 9.29 (d, J = 3.7 Hz, 1 H, CHO), 7.44 (d,
J = 6.7 Hz, 2 H, C6H5), 7.40–7.31 (m, 3 H, C6H5), 7.21 (m, 3 H, CH2C6H5),
6.81 (m, 2 H, CH2C6H5), 4.39 (d, J = 10.0 Hz, 1 H, OCH2Ph), 4.12 (q, J =
7.2 Hz, 2 H, OCH2CH3), 4.08 (d, J = 10.2 Hz, 1 H, OCH2Ph), 3.67 (d, J =
10.9 Hz, 1 H, H-2), 3.47 (dt, J = 10.7, 3.4 Hz, 1 H, H-6), 2.79–2.67 (m, 2
H, H-3, H-6), 2.40 (dd, J = 15.4, 4.2 Hz, 1 H, CH2CO), 2.34–2.21 (m, 1 H,
H-4), 2.15 (dd, J = 15.4, 8.2 Hz, 1 H, CH2CO), 2.04–1.98 (m, 1 H, H-5),
1.63 (qd, J = 12.8, 3.3 Hz, 1 H, H-5), 1.25 (t, J = 7.1 Hz, 3 H, OCH2CH3).
Ethyl 2-[(2R*,3S*,4S*)-1-Benzyl-2-(4-methoxyphenyl)-3-nitro-
piperidin-4-yl]acetate (5b) and Ethyl 2-[(2R*,3S*,4R*)-1-Benzyl-2-
(4-methoxyphenyl)-3-nitropiperidin-4-yl]acetate (6b)
The title compounds 5b and 6b were obtained according to the gener-
al procedure as a diastereomeric mixture (46 mg, 89%, 1.2:1 dr); pale
yellow oil.
HPLC: Chiralcel AD-H, n-hexane/i-PrOH/EtOH (94:4:2), flow rate 1.0
mL/min, detection at λ = 230 nm): for 5b major enantiomer tR = 23.4
min, minor enantiomer tR = 15.2 min; 97% ee; and for 6b major enan-
tiomer tR = 17.8 min, minor enantiomer tR = 12.7 min; 98% ee.
13C NMR (101 MHz, CDCl3): δ = 201.4, 171.8, 138.9, 136.5, 128.8,
128.7, 128.5, 128.2, 128.1, 127.8, 75.3, 71.3, 60.6, 60.3, 55.8, 38.0,
32.6, 30.5, 14.2.
HRMS (ESI): m/z [M + H]+ calcd for (C23H27NO4H)+: 382.2013; found:
5b
382.2013.
1H NMR (400 MHz, CDCl3): δ = 7.33 (d, J = 8.0 Hz, 2 H, 4-MeOC6H4,
2′,6′-H), 7.29–7.23 (m, 2 H, C6H5), 7.23–7.15 (m, 3 H, C6H5), 6.87 (d, J =
8.9 Hz, 2 H, 4-MeOC6H4, 3′,5′-H), 4.52 (dd, J = 11.3, 9.6 Hz, 1 H, H-3),
4.12 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.77 (s, 3 H, CH3O), 3.72 (d, J = 13.4
Hz, 1 H, NCH2Ph), 3.62 (d, J = 9.6 Hz, 1 H, H-2), 2.97 (dt, J = 11.9, 3.4
Hz, 1 H, H-6), 2.88 (d, J = 13.5 Hz, 1 H, NCH2Ph), 2.64–2.54 (m, 1 H, H-
4), 2.36 (dd, J = 16.0, 3.6 Hz, 1 H, CH2CO), 2.22 (dd, J = 16.0, 9.1 Hz, 1 H,
CH2CO), 2.17 (td, J = 12.2, 2.6 Hz, 1 H, H-6), 1.97–1.90 (m, 1 H, H-5),
1.49 (qd, J = 12.6, 4.1 Hz, 1 H, H-5), 1.23 (t, J = 7.2 Hz, 3 H, OCH2CH3).
Piperidines 5 and 6; General Procedure
A mixture of nitroalkene 3 (0.14 mmol) and catalyst VIII (4.0 mg,
0.007 mmol, 5 mol%) in toluene (0.7 mL) was stirred at r.t. for 5 min.
Then 5-aminopentenoate 1a (37 mg, 0.16 mmol) was added in one
portion. After stirring for 5 h, the reaction mixture was concentrated
and directly purified by silica gel column chromatography (PE–EtOAc,
20:1 to 5:1) to afford a diastereomeric mixture of products 5 and 6.
13C NMR (101 MHz, CDCl3): δ = 170.7, 159.8, 138.5, 129.6, 129.3,
128.5, 128.2, 127.0, 114.4, 95.5, 70.3, 60.7, 58.4, 55.2, 51.4, 37.8, 37.0,
29.0, 14.2.
Ethyl 2-[(2R*,3S*,4S*)-1-Benzyl-3-nitro-2-phenylpiperidin-4-
yl]acetate (5a) and Ethyl 2-[(2R*,3S*,4R*)-1-Benzyl-3-nitro-2-
phenylpiperidin-4-yl]acetate (6a)
The title compounds 5a and 6a were obtained according to the gener-
al procedure as a diastereomeric mixture (50 mg, 95%, 1.4:1 dr); pale
yellow oil.
6b
1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 8.4 Hz, 2 H, 4-MeOC6H4,
2′,6′-H), 7.29–7.23 (m, 2 H, CH2C6H5), 7.23–7.15 (m, 3 H, CH2C6H5),
6.86 (d, J = 8.9 Hz, 2 H, 4-MeOC6H4, 3′,5′-H), 4.92 (dd, J = 10.4, 4.9 Hz, 1
H, H-3), 4.12 (q, J = 7.2 Hz, 2 H, OCH2CH3), 3.80 (d, J = 10.4 Hz, 1 H, H-
2), 3.76 (s, 3 H, CH3O), 3.68 (d, J = 13.3 Hz, 1 H, NCH2Ph), 3.15–3.07 (m,
1 H, H-4), 2.91 (d, J = 13.4 Hz, 1 H, NCH2Ph), 2.76 (dt, J = 12.4, 3.7 Hz, 1
H, H-6), 2.65 (d, J = 7.2 Hz, 2 H, CH2CO), 2.28 (td, J = 12.7, 2.6 Hz, 1 H,
H-6), 2.01–1.95 (m, 1 H, H-5), 1.74 (dq, J = 14.1, 2.8 Hz, 1 H, H-5), 1.24
(t, J = 7.1 Hz, 3 H, OCH2CH3).
HPLC: Chiralcel AD-H, n-hexane/i-PrOH/EtOH (95:2.5:2.5), flow rate
1.0 mL/min, detection at λ = 230 nm: for 5a major enantiomer tR
=
17.1 min, minor enantiomer tR = 9.4 min; 97% ee; and for 6a major
enantiomer tR = 11.6 min, minor enantiomer tR = 10.8 min; 97% ee.
5a
1H NMR (400 MHz, CDCl3): δ = 7.50–7.16 (m, 10 H, 2 × C6H5), 4.55 (dd,
J = 11.2, 9.7 Hz, 1 H, H-3), 4.12 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.70 (d, J =
13.6 Hz, 1 H, NCH2Ph), 3.67 (d, J = 9.5 Hz, 1 H, H-2), 2.98 (ddd, J = 11.9,
3.9, 3.0 Hz, 1 H, H-6), 2.90 (d, J = 13.5 Hz, 1 H, NCH2Ph), 2.66–2.55 (m,
1 H, H-4), 2.36 (dd, J = 16.0, 3.6 Hz, 1 H, CH2CO), 2.23 (dd, J = 16.1, 9.1
Hz, 1 H, CH2CO), 2.18 (td, J = 12.2, 2.6 Hz, 1 H, H-6), 1.94 (ddd, J = 13.5,
6.8, 2.8 Hz, 1 H, H-5), 1.51 (dtd, J = 13.4, 12.4, 4.0 Hz, 1 H, H-5), 1.23 (t,
J = 7.1 Hz, 3 H, OCH2CH3).
13C NMR (101 MHz, CDCl3): δ = 171.2, 159.6, 138.6, 129.9, 129.8,
128.5, 128.2, 127.0, 114.4, 92.1, 64.1, 60.8, 58.5, 55.2, 46.0, 33.2, 32.1,
28.4, 14.2.
HRMS (ESI): m/z [M + H]+ for 5b and 6b (diastereomeric mixture)
calcd for (C23H28N2O5H)+: 413.2071; found: 413.2077.
Ethyl 2-[(2R*,3S*,4S*)-1-Benzyl-3-nitro-2-(4-triflouromethoxy-
phenyl)piperidin-4-yl]acetate (5c) and Ethyl 2-[(2R*,3S*,4R*)-1-
Benzyl-3-nitro-2-(4-triflouromethoxyphenyl)piperidin-4-yl]ace-
tate (6c)
13C NMR (101 MHz, CDCl3): δ = 170.7, 138.4, 137.8, 129.0, 128.5,
128.2, 95.4, 70.9, 60.7, 58.6, 51.3, 37.8, 36.9, 29.0, 14.1.
6a
The title compounds 5c and 6c were obtained according to the gener-
al procedure as a diastereomeric mixture (58 mg, 98%, 1.3:1 dr); pale
yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.50–7.16 (m, 10 H, 2 × C6H5), 4.96 (dd,
J = 10.3, 4.9 Hz, 1 H, H-3), 4.12 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.86 (d, J =
10.3 Hz, 1 H, H-2), 3.65 (d, J = 13.4 Hz, 1 H, NCH2Ph), 3.12 (dtt, J = 9.9,
4.7, 2.3 Hz, 1 H, H-4), 2.93 (d, J = 13.4 Hz, 1 H, NCH2Ph), 2.77 (ddd, J =
12.4, 4.1, 3.1 Hz, 1 H, H-6), 2.66 (d, J = 7.3 Hz, 2 H, CH2CO), 2.28 (td, J =
12.7, 2.7 Hz, 1 H, H-6), 2.02–1.97 (m, 1 H, H-5), 1.76 (dq, J = 14.2, 2.9
Hz, 1 H, H-5), 1.24 (t, J = 7.1 Hz, 3 H, OCH2CH3).
HPLC: Chiralcel AD-H, n-hexane/i-PrOH/EtOH (95:2.5:2.5), flow rate
1.0 mL/min, detection at λ = 230 nm): for 5c major enantiomer tR
=
20.5 min, minor enantiomer tR = 8.2 min; 85% ee; and for 6c major
enantiomer tR = 9.9 min, minor enantiomer tR = 7.3 min; 91% ee.
13C NMR (101 MHz, CDCl3): δ = 171.2, 138.5, 138.2, 128.8, 128.5,
5c
1H NMR (400 MHz, CDCl3): δ = 7.46 (d, J = 8.1 Hz, 2 H, 4-CF3OC6H4,
2′,6′-H), 7.31–7.23 (m, 3 H, C6H5), 7.23–7.14 (m, 4 H, C6H5 + 4-
CF3OC6H4, 3′,5′-H), 4.52 (dd, J = 11.2, 9.7 Hz, 1 H, H-3), 4.12 (q, J = 7.1
Hz, 2 H, OCH2CH3), 3.71 (d, J = 9.6 Hz, 1 H, H-2), 3.66 (d, J = 13.6 Hz, 1
H, NCH2Ph), 3.00 (ddd, J = 11.9, 3.8, 3.0 Hz, 1 H, H-6), 2.93 (d, J = 13.5
127.0, 92.0, 64.8, 60.8, 58.6, 45.9, 33.1, 32.1, 28.3, 14.1.
HRMS (ESI): m/z [M + H]+ for 5a and 6a (diastereomeric mixture)
calcd for (C22H26N2O4H)+: 383.1968; found: 383.1968.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

H
K. Kriis et al.
Paper
Synthesis
Hz, 1 H, NCH2Ph), 2.64–2.54 (m, 1 H, H-4), 2.37 (dd, J = 16.1, 3.6 Hz, 1
H, CH2CO), 2.24 (dd, J = 16.2, 9.0 Hz, 1H, CH2CO), 2.24–2.17 (m, 1 H, H-
6), 1.99–1.92 (m, 1 H, H-5), 1.53 (qd, J = 12.5, 4.0 Hz, 1 H, H-5), 1.24 (t,
J = 7.1 Hz, 3 H, OCH2CH3).
13C NMR (101 MHz, CDCl3): δ = 170.6, 149.4 (br), 138.0, 136.4, 129.6
(br), 128.5, 128.4, 127.2, 121.3 (br), 120.4 (q, J = 257.7 Hz), 95.2, 70.1,
60.8, 58.7, 51.4, 37.7, 36.8, 28.9, 14.2.
13C NMR (101 MHz, CDCl3): δ = 171.0, 137.7, 135.6, 134.5, 130.1,
129.1, 128.5, 128.4, 127.3, 91.7, 64.0, 60.9, 58.6, 45.9, 33.1, 32.0, 28.1,
14.2.
HRMS (ESI): m/z [M + H]+ for 5d and 6d (diastereomeric mixture):
calcd for (C22H25ClN2O4H)+: 417.1576; found: 417.1574.
Ethyl 2-[(2R*,3S*,4S*)-1-Benzyl-2-(3-methylphenyl)-3-nitropiperi-
din-4-yl]acetate (5e) and Ethyl 2-[(2R*,3S*,4R*)-1-Benzyl-2-(3-
methylphenyl)-3-nitropiperidin-4-yl]acetate (6e)
6c
1H NMR (400 MHz, CDCl3): δ = 7.53 (d, J = 8.5 Hz, 2 H, 4-CF3OC6H4,
2′,6′-H), 7.33–7.20 (m, 3 H, C6H5), 7.22–7.15 (m, 4 H, C6H5 + 4-
CF3OC6H4, 3′,5′-H), 4.90 (dd, J = 10.3, 4.9 Hz, 1 H, H-3), 4.12 (q, J = 7.1
Hz, 2 H, OCH2CH3), 3.90 (d, J = 10.3 Hz, 1 H, H-2), 3.62 (d, J = 13.3 Hz, 1
H, NCH2Ph), 3.17–3.08 (m, 1 H, H-4), 2.96 (d, J = 13.5 Hz, 1 H, NCH2Ph),
2.79 (ddd, J = 12.4, 4.2, 3.1 Hz, 1 H, H-6), 2.65–2.62 (m, 2 H, CH2CO),
2.29 (td, J = 12.7, 2.7 Hz, 1 H, H-6), 2.03–1.97 (m, 1 H, H-5), 1.78 (dq,
J = 14.2, 2.8 Hz, 1 H, H-5), 1.24 (t, J = 7.1 Hz, 3 H, OCH2CH3).
The title compounds 5e and 6e were obtained according to the gener-
al procedure as a diastereomeric mixture (39 mg, 73%, 1.3:1 dr); pale
yellow oil.
5e
1H NMR (400 MHz, CDCl3): δ = 7.31–7.15 (m, 5 H, Ar), 7.12–7.05 (m, 4
H, Ar), 4.55 (dd, J = 11.3, 9.6 Hz, 1 H, H-3), 4.12 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 3.70 (d, J = 13.5 Hz, 1 H, NCH2Ph), 3.63 (d, J = 9.6 Hz, 1 H, H-
2), 2.97 (dt, J = 11.9, 3.4 Hz, 1 H, H-6), 2.89 (d, J = 13.5 Hz, 1 H,
NCH2Ph), 2.65–2.54 (m, 1 H, H-4), 2.36 (dd, J = 16.0, 3.6 Hz, 1 H,
CH2CO), 2.33 (s, 3 H, ArCH3), 2.23 (dd, J = 16.0, 9.2 Hz, 1 H, CH2CO),
2.17 (ddd, J = 12.2, 2.6 Hz, 1 H, H-6), 1.98–1.90 (m, 1 H, H-5), 1.50 (qd,
J = 12.6, 3.9 Hz, 1 H, H-5), 1.23 (t, J = 7.2 Hz, 3 H, OCH2CH3).
13C NMR (101 MHz, CDCl3): δ = 171.0, 149.2 (br), 138.0, 136.9, 130.2
(br), 128.5, 128.4, 127.2, 121.1 (br), 120.4 (q, J = 257.7 Hz), 91.9, 64.0,
60.9, 58.7, 45.9, 33.1, 32.0, 28.2, 14.2.
HRMS (ESI): m/z [M + H]+ for 5c and 6c (diastereomeric mixture)
calcd for (C23H25F3N2O5H)+: 467.1788; found: 467.1789.
13C NMR (101 MHz, CDCl3): δ = 170.7, 138.6, 138.5, 137.7, 129.6,
128.9, 128.8, 128.5, 128.2, 127.0, 125.2, 95.3, 70.9, 60.7, 58.6, 51.4,
37.77, 37.0, 29.0, 21.5, 14.2.
Ethyl 2-[(2R*,3S*,4S*)-1-Benzyl-2-(4-chlorophenyl)-3-nitropiperi-
din-4-yl]acetate (5d) and Ethyl 2-[(2R*,3S*,4R*)-1-Benzyl-2-(4-
chlorophenyl)-3-nitropiperidin-4-yl]acetate (6d)
6e
The title compounds 5d and 6d were obtained according to the gener-
al procedure as a diastereomeric mixture (44 mg, 79%, 1.3:1 dr); pale
yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.31–7.15 (m, 5 H, Ar), 7.12–7.05 (m, 4
H, Ar), 4.97 (dd, J = 10.3, 4.9 Hz, 1 H, H-3), 4.12 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 3.81 (d, J = 10.3 Hz, 1 H, H-2), 3.66 (d, J = 13.4 Hz, 1 H,
NCH2Ph), 3.17–3.06 (m, 1 H, H-4), 2.92 (d, J = 13.3 Hz, 1 H, NCH2Ph),
2.76 (dt, J = 12.3, 3.7 Hz, 1 H, H-6), 2.65 (d, J = 7.3 Hz, 2 H, CH2CO), 2.33
(s, 3 H, ArCH3), 2.28 (ddd, J = 12.7, 2.8 Hz, 1 H, H-6), 2.02–1.96 (m, 1 H,
H-5), 1.75 (dq, J = 14.1, 2.8 Hz, 1 H, H-5), 1.24 (t, J = 7.1 Hz, 3 H,
OCH2CH3).
HPLC: Chiralcel AD-H, n-hexane/i-PrOH/EtOH (95:2:4), flow rate 1.0
mL/min, detection at λ = 230 nm: for 5d major enantiomer tR = 18.5
min, minor enantiomer tR = 12.0 min; 89% ee; and for 6d major enan-
tiomer tR = 14.0 min, minor enantiomer tR = 10.4 min; 94% ee.
5d
13C NMR (101 MHz, CDCl3): δ = 171.2, 138.6, 138.3, 138.0, 129.5,
129.4, 128.6, 128.5, 128.2, 127.0, 125.8, 91.9, 64.8, 60.8, 58.6, 45.9,
33.1, 32.1, 28.3, 21.4, 14.2.
1H NMR (400 MHz, CDCl3): δ = 7.42–7.30 (m, 3 H, C6H5 + 4-ClC6H4,
3′,5′-H), 7.30–7.21 (m, 4 H, C6H5), 7.21–7.14 (m, 2 H, 4-ClC6H4, 2′,6′-
H), 4.56 (dd, J = 11.1, 9.9 Hz, 1 H, H-3), 4.12 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 3.70 (d, J = 9.8 Hz, 1 H, H-2), 3.69 (d, J = 13.3 Hz, 1 H,
NCH2Ph), 3.03 (dt, J = 12.0, 3.3 Hz, 1 H, H-6), 2.96 (d, J = 13.5 Hz, 1 H,
NCH2Ph), 2.63–2.54 (m, 1 H, H-4), 2.37 (dd, J = 16.1, 3.6 Hz, 1 H,
CH2CO), 2.24 (dd, J = 16.2, 8.9 Hz, 1 H, CH2CO), 2.23 (td, J = 12.3, 2.6
Hz, 1 H, H-6), 2.00–1.93 (m, 1 H, H-5), 1.55 (qd, J = 12.5, 4.1 Hz, 1 H,
H-5), 1.23 (t, J = 7.2 Hz, 3 H, OCH2CH3).
HRMS (ESI): m/z [M + H]+ for 5e and 6e (diastereomeric mixture) cal-
cd for (C23H28N2O4H)+: 397.2122; found: 397.2130.
Ethyl 2-[(2R*,3S*,4S*)-1-Benzyl-3-nitro-2-(4-nitrophenyl)piperi-
din-4-yl]acetate (5f) and Ethyl 2-[(2R*,3S*,4R*)-1-Benzyl-3-nitro-
2-(4-nitrophenyl)piperidin-4-yl]acetate (6f)
13C NMR (101 MHz, CDCl3): δ = 170.6, 137.4, 135.9, 134.8, 129.6,
129.4, 128.6, 128.4, 127.4, 94.9, 77.3, 70.1, 60.8, 58.5, 51.4, 37.6, 36.8,
28.7, 14.2.
The title compounds 5f and 6f were obtained according to the general
procedure as a diastereomeric mixture (50 mg, 85%, 1.1:1 dr); pale
yellow oil.
HPLC: Chiralcel AD-H, n-hexane/i-PrOH/EtOH (88:7:5), flow rate 1.0
mL/min, detection at λ = 230 nm: for 5f major enantiomer tR = 26.0
min, minor enantiomer tR = 24.2 min; 88% ee; and for 6f major enan-
tiomer tR = 28.7 min, minor enantiomer tR = 20.4 min; 93% ee.
6d
1H NMR (400 MHz, CDCl3): δ = 7.45 (d, J = 8.1 Hz, 2H, 4-ClC6H4, 3′,5′-
H), 7.39–7.30 (m, 1 H, Ar), 7.30–7.21 (m, 4 H, Ar), 7.21–7.14 (m, 2 H,
Ar), 4.93 (dd, J = 10.4, 4.9 Hz, 1 H, H-3), 4.12 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 3.87 (d, J = 10.4 Hz, 1 H, H-2), 3.65 (d, J = 13.4 Hz, 1 H,
NCH2Ph), 3.19–3.08 (m, 1 H, H-4), 2.97 (d, J = 13.4 Hz, 1 H, NCH2Ph),
2.80 (dt, J = 12.4, 3.6 Hz, 1 H, H-6), 2.64–2.61 (m, 2 H, CH2CO), 2.31
(ddd, J = 12.7, 2.7 Hz, 1 H, H-6), 2.05–1.97 (m, 1 H, H-5), 1.77 (dq, J =
14.3, 2.8 Hz, 1 H, H-5), 1.24 (t, J = 7.1 Hz, 3 H, OCH2CH3).
5f
1H NMR (400 MHz, CDCl3): δ = 8.22 (d, J = 9.0 Hz, 2 H, 4-NO2C6H4,
3′,5′-H), 7.64 (d, J = 8.1 Hz, 2 H, 4-NO2C6H4, 2′,6′-H), 7.31–7.22 (m, 3 H,
C6H5), 7.20–7.12 (m, 2 H, C6H5), 4.56 (dd, J = 11.3, 9.6 Hz, 1 H, H-3),
4.13 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.83 (d, J = 9.6 Hz, 1 H, H-2), 3.58 (d,
J = 13.6 Hz, 1 H, NCH2Ph), 3.03 (ddd, J = 12.0, 4.0, 2.9 Hz, 1 H, H-6),
3.02 (d, J = 13.4 Hz, 1 H, NCH2Ph), 2.66–2.56 (m, 1 H, H-4), 2.38 (dd, J =
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

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K. Kriis et al.
Paper
Synthesis
16.2, 3.7 Hz, 1 H, CH2CO), 2.25 (dd, J = 16.3, 8.6 Hz, 1 H, CH2CO), 2.23
(dd, J = 12.3, 2.7 Hz, 1 H, H-6), 2.01–1.95 (m, 1 H, H-5), 1.57 (qd, J =
12.6, 4.0 Hz, 1 H, H-5), 1.24 (t, J = 7.1 Hz, 3 H, OCH2CH3).
13C NMR (101 MHz, CDCl3): δ = 171.2, 141.0, 138.2, 128.5, 128.4,
128.3, 127.2, 126.5, 126.1, 91.5, 60.8, 60.6, 58.7, 45.8, 33.3, 32.5, 27.5,
14.1.
13C NMR (101 MHz, CDCl3): δ = 170.5, 148.2, 145.4, 137.4, 129.2,
128.4, 128.4, 127.4, 124.3, 94.9, 70.1, 60.9, 58.9, 51.3, 37.6, 36.6, 28.8,
14.1.
HRMS (ESI): m/z [M + H]+ for 5g and 6g (diastereomeric mixture)
calcd for (C20H24N2O4SH)+: 389.1530; found. 389.1530.
Ethyl 2-[(2R*,3S*,4S*)-1-Benzyloxy-3-nitro-2-phenylpiperidin-4-
yl]acetate (5h) and Ethyl 2-[(2R*,3S*,4R*)-1-Benzyloxy-3-nitro-2-
phenylpiperidin-4-yl]acetate (6h)
6f
1H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 8.9 Hz, 2 H, 4-NO2C6H4,
3′,5′-H), 7.71 (d, J = 8.4 Hz, 2 H, 4-NO2C6H4, 2′,6′-H), 7.31–7.22 (m, 3 H,
C6H5), 7.20–7.12 (m, 2 H, C6H5), 4.92 (dd, J = 10.3, 4.9 Hz, 1 H, H-3),
4.13 (q, J = 7.2 Hz, 2 H, OCH2CH3), 4.03 (d, J = 10.3 Hz, 1 H, H-2), 3.54
(d, J = 13.6 Hz, 1 H, NCH2Ph), 3.20–3.12 (m, 1 H, H-4), 2.98 (d, J = 13.5
Hz, 1 H, NCH2Ph), 2.82 (ddd, J = 12.4, 4.2, 3.0 Hz, 1 H, H-6), 2.64 (dd, J =
8.2, 6.4 Hz, 2 H, CH2CO), 2.31 (dd, J = 12.7, 2.8 Hz, 1 H, H-6), 2.04–1.98
(m, 1 H, H-5), 1.81 (dq, J = 14.3, 2.9 Hz, 1 H, H-5), 1.23 (t, J = 7.1 Hz, 3
H, OCH2CH3).
The title compounds 5h and 6h were obtained according to the gen-
eral procedure as a diastereomeric mixture (64 mg, 91%, 2:1 dr); pale
yellow oil.
HPLC: Chiralcel AD-H, n-hexane/i-PrOH/EtOH (95:3:2), flow rate 1.0
mL/min, detection at λ = 230 nm: for 5h major enantiomer tR = 13.0
min, minor enantiomer tR = 8.2 min; 97% ee; and for 6h major enan-
tiomer tR = 9.6 min, minor enantiomer tR = 10.5 min; 85% ee.
13C NMR (101 MHz, CDCl3): δ = 170.9, 148.0, 146.0, 137.5, 129.8,
128.4, 128.4, 127.4, 124.0, 91.6, 64.1, 61.0, 59.0, 45.8, 33.1, 31.9, 28.1,
14.1.
5h
1H NMR (400 MHz, CDCl3): δ = 7.59–7.41 (m, 2 H, C6H5), 7.41–7.28 (m,
3 H, C6H5), 7.23–7.13 (m, 3 H, CH2C6H5), 6.95–6.70 (m, 2 H, CH2C6H5),
5.16–4.84 (m, 1H, H-3 ), 4.37–4.25 (m, 1 H, OCH2Ph), 4.20–4.07 (m, 3
H, OCH2CH3, H-2), 4.03 (d, J = 10.0 Hz, 1 H, OCH2Ph), 3.26 (dt, J = 11.6,
3.4 Hz, 1 H, H-6), 3.16–3.00 (m, 1 H, H-4), 2.98–2.82 (m, 1 H, H-6),
2.70–2.50 (m, 2 H, CH2CO), 2.17–1.82 (m, 2 H, H-5), 1.24 (td, J = 7.1
Hz, 3 H, OCH2CH3).
13C NMR (101 MHz, CDCl3): δ = 171.0, 136.7 (br), 136.2, 128.8, 128.5,
128.4, 128.3, 128.2, 128.0, 89.2 (br), 75.6, 67.6 (br), 60.9, 50.2 (br),
32.6 (br), 31.9, 26.9 (br), 14.1.
HRMS (ESI): m/z [M + H]+ for 5f and 6f (diastereomeric mixture) calcd
for (C22H25N3O6H)+: 428.1816; found: 428.1814.
Ethyl 2-[(2R*,3S*,4S*)-1-Benzyl-3-nitro-2-thiophenylpiperidin-4-
yl]acetate (5g) and Ethyl 2-[(2R*,3S*,4R*)-1-Benzyl-3-nitro-2-thio-
phenylpiperidin-4-yl]acetate (6g)
The title compounds 5g and 6g were obtained according to the gener-
al procedure as a diastereomeric mixture (38 mg, 68%, 1.3:1 dr); pale
yellow oil.
6h
HPLC: Chiralcel AD-H, n-hexane/i-PrOH/EtOH (88:5:7), flow rate 1.0
mL/min, detection at λ = 230 nm: for 5g major enantiomer tR = 12.3
min, minor enantiomer tR = 8.1 min, 96% ee; and for 6g major enan-
tiomer tR = 10.7 min, minor enantiomer tR = 8.8 min; 96% ee.
1H NMR (400 MHz, CDCl3): δ = 7.59–7.41 (m, 2 H, C6H5), 7.41–7.28 (m,
3H, C6H5), 7.23–7.13 (m, 3 H, CH2C6H5), 6.95–6.70 (m, 2 H, CH2C6H5),
4.64 (t, J = 10.5 Hz, 1 H, H-3), 4.40 (d, J = 10.0 Hz, 1 H, OCH2Ph), 4.20–
4.07 (m, 3 H, OCH2CH3, OCH2Ph), 3.96 (d, J = 10.2 Hz, 1 H, H-2), 3.54–
3.35 (m, 1 H, H-6), 2.83–2.73 (m, 1 H, H-6), 2.62–2.52 (m, 2 H, H-4),
2.39 (dd, J = 16.2, 3.5 Hz, 1 H, CH2CO), 2.24 (dd, J = 16.0, 8.9 Hz, 1 H,
CH2CO), 2.14–2.06 (m, 1 H, H-5), 1.68–1.60 (m, 1 H, H-5), 1.24 (td, J =
7.1 Hz, 3 H, OCH2CH3).
5g
1H NMR (400 MHz, CDCl3): δ = 7.32 (d, J = 5.2 Hz, 1 H, thiophenyl 3′-
H), 7.30–7.28 (m, 2 H, C6H5), 7.29–7.18 (m, 3 H, C6H5), 6.99 (dd, J = 3.5,
1.2 Hz, 1 H, thiophenyl 5′-H), 6.90 (dd, J = 5.1, 3.4 Hz, 1 H, thiophenyl
4′-H), 4.55 (dd, J = 11.4, 9.5 Hz, 1 H, H-3), 4.12 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 4.06 (d, J = 9.5 Hz, 1 H, H-2), 3.92 (d, J = 13.5 Hz, 1 H,
NCH2Ph), 3.00–2.93 (m, 1 H, H-6), 2.97 (d, J = 13.3 Hz, 1 H, NCH2Ph),
2.68–2.53 (m, 1 H, H-4), 2.36 (dd, J = 16.1, 3.6 Hz, 1 H, CH2CO), 2.23
(dd, J = 16.1, 9.2 Hz, 1 H, CH2CO), 2.18 (td, J = 12.3, 2.7 Hz, 1 H, H-6),
1.96–1.90 (m, 1 H, H-5), 1.48 (qd, J = 12.6, 4.0 Hz, 1 H, H-5), 1.23 (t, J =
7.1 Hz, 3 H, OCH2CH3).
13C NMR (101 MHz, CDCl3): δ = 170.5, 136.7, 136.2, 128.7, 128.5,
128.4, 128.3, 128.2, 128.0, 92.8, 75.6, 73.5, 60.9, 55.4, 37.1, 36.4, 27.8,
14.1.
HRMS (ESI): m/z [M + H]+ for 5h and 6h (diastereomeric mixture)
calcd for (C22H26N2O5H)+: 399.1914; found: 399.1917.
Reduction of Piperidines 5 and 6; General Procedure
13C NMR (101 MHz, CDCl3): δ = 170.6, 141.5, 138.2, 128.6, 128.3,
127.9, 127.1, 126.7, 126.5, 96.2, 66.2, 60.8, 58.6, 51.3, 37.7, 36.9, 28.8,
14.1.
A mixture of piperidines 5 and 6 (0.2 mmol) and a suitable amount (a
spatula) of Raney Ni in MeOH (4 mL) was stirred under an atmo-
sphere of H2. After stirring for 1 h, the reaction mixture was purged
with N2 and filtered through Celite. The filtrate was dried (anhyd
Na2SO4) and concentrated in vacuo. The crude product was purified
by silica gel column chromatography (CH2Cl2–EtOAc, 2:1) to afford
amine 7 and lactam 8 (in a mixture with amine 7).
6g
1H NMR (400 MHz, CDCl3): δ = 7.30–7.28 (m, 3 H, thiophenyl 3′-H +
C6H5), 7.29–7.18 (m, 3 H, C6H5), 7.04 (dd, J = 3.6, 1.2 Hz, 1 H, thiophe-
nyl 5′-H), 6.93 (dd, J = 5.2, 3.5 Hz, 1 H, thiophenyl 4′-H), 4.93 (dd, J =
8.3, 4.5 Hz, 1 H, H-3), 4.44 (d, J = 8.3 Hz, 1 H, H-2), 4.12 (q, J = 7.2 Hz, 2
H, OCH2CH3), 3.81 (d, J = 13.5 Hz, 1 H, NCH2Ph), 3.15 (d, J = 13.4 Hz, 1
H, NCH2Ph), 3.06 (ddd, J = 8.1, 6.3, 4.7 Hz, 1 H, H-4), 2.82 (dt, J = 12.6,
4.6 Hz, 1 H, H-6), 2.62 (dd, J = 7.2, 4.4 Hz, 2 H, CH2CO), 2.43–2.36 (m, 1
H, H-5), 1.86 (dt, J = 6.8, 4.8 Hz, 1 H, H-5), 1.24 (t, J = 7.1 Hz, 3 H,
OCH2CH3).
Ethyl 2-[(2R*,3S*,4S*)-3-Amino-1-benzyl-2-phenylpiperidin-4-
yl]acetate (7a)
The title compound 7a was obtained according to the general proce-
dure (20 mg, 27%); pale yellow oil; [α]D20 +21 (c 0.31, MeOH).
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K. Kriis et al.
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Synthesis
HPLC: Chiralcel OD-H, n-hexane/i-PrOH (95:5), flow rate 1.0 mL/min,
detection at λ = 230 nm: for major enantiomer tR = 7.4 min, minor en-
antiomer tR = 6.9 min; 95% ee.
(3aR*,7R*,7aS*)-6-Benzyloxy-7-phenyloctahydro-2H-pyrrolo[2,3-
c]pyridin-2-one (8h)
The title compound 8h was obtained according to the general proce-
dure as a 1:0.2 mixture with amine 7h (33 mg).
IR (film): 3379, 3028, 2917, 2794, 1731, 1602, 1494, 1453, 1369,
1169, 1029, 762, 702 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.50–7.41 (m, 2 H, C6H5), 7.44–7.29 (m,
3 H, C6H5), 7.23–7.11 (m, 3 H, CH2C6H5), 6.90–6.74 (m, 2 H, CH2C6H5),
5.47 (s, 1 H, NH), 4.46 (d, J = 10.0 Hz, 1 H, OCH2Ph), 4.24 (d, J = 10.0 Hz,
1 H, OCH2Ph), 3.79–3.69 (m, 1 H, H-3), 3.37–3.33 (m, 1 H, H-6), 3.33
(d, J = 9.7 Hz, 1 H, H-2), 2.78 (ddd, J = 13.8, 11.2, 3.0 Hz, 1 H, H-6),
2.74–2.67 (m, 1 H, H-4), 2.46 (dd, J = 16.6, 12.7 Hz, 1 H, CH2CO), 2.22
(dd, J = 16.6, 8.4 Hz, 1 H, CH2CO), 2.20–2.07 (m, 1 H, H-5), 1.92–1.83
(m, 1 H, H-5).
1H NMR (400 MHz, CDCl3): δ = 7.44 (br s, 2 H, C6H5), 7.35 (td, J = 7.2,
1.2 Hz, 2 H, C6H5), 7.29–7.15 (m, 6 H, Ar), 4.11 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 3.63 (d, J = 13.5 Hz, 1 H, NCH2Ph), 2.92 (dt, J = 11.6, 3.4 Hz,
1 H, H-6), 2.80 (d, J = 13.7 Hz, 1 H, NCH2Ph), 2.80 (d, J = 8.7 Hz, 1 H, H-
2), 2.75 (dd, J = 15.2, 5.3 Hz, 1 H, CH2CO), 2.49 (dd, J = 10.3, 8.9 Hz, 1 H,
H-3), 2.16 (dd, J = 15.2, 7.4 Hz, 1 H, CH2CO), 2.04 (td, J = 12.1, 2.5 Hz, 1
H, H-6), 1.85–1.76 (m, 1 H, H-4), 1.76–1.70 (m, 1 H, H-5), 1.47 (qd, J =
12.5, 3.9 Hz, 1 H, H-5), 1.23 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 177.5, 139.3, 136.7, 129.0, 128.9,
128.7, 128.3, 128.2, 128.0, 75.4, 75.2, 60.5 (br), 51.7 (br), 32.9, 32.6,
24.5 (br).
13C NMR (101 MHz, CDCl3): δ = 173.5, 142.0, 139.5, 128.7 (2 C), 128.6,
128.0, 127.7, 126.6, 77.7, 60.2, 59.9, 59.7, 52.2, 40.5, 39.0, 30.8, 14.2.
HRMS (ESI): m/z [M + H]+ calcd for (C20H22N2O2H)+ : 323.1754; found:
HRMS (ESI): m/z [M + H]+ calcd for (C22H28N2O2H)+: 353.2224; found:
323.1757.
353.2224.
(3aR*,7R*,7aS*)-6-Benzyl-7-phenyloctahydro-2H-pyrrolo[2,3-
c]pyridin-2-one (8a)
Acknowledgment
The title compound 8a was obtained according to the general proce-
dure as a 1.4:1 mixture with amine 7a (31 mg).
The authors thank the Estonian Ministry of Education and Research
(Grant No. IUT 19-32) and Centre of Excellence in Molecular Cell Engi-
neering 2014-2020.4.01.15-0013 for financial support.
1H NMR (400 MHz, CDCl3): δ = 7.47–7.41 (m, 2 H, C6H5), 7.39–7.32 (m,
2 H, C6H5), 7.32–7.15 (m, 6 H, Ar), 3.70 (d, J = 13.7 Hz, 1 H, NCH2Ph),
3.55 (ddd, J = 8.7, 7.0, 1.3 Hz, 1 H, H-3), 3.03 (d, J = 9.1 Hz, 1 H, H-2),
2.87–2.71 (m, 3 H, NCH2Ph, H-6, H-4), 2.55–2.45 (m, 1 H, CH2CO), 2.20
(dd, J = 16.5, 8.5 Hz, 1 H, CH2CO), 2.17–2.12 (m, 1 H, H-6), 2.04–1.97
(m, 1 H, H-5), 1.76–1.68 (m, 1 H, H-5).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588299.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
13C NMR (101 MHz, CDCl3): δ = 177.5, 140.8, 139.1, 129.1, 128.5,
128.3, 128.2, 128.1, 126.8, 72.7, 60.5, 58.7, 47.6, 33.6, 32.6, 25.2.
HRMS (ESI): m/z [M + H]+ calcd for (C20H22N2OH)+: 307.1805; found:
307.1806.
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