Synthesis of 2,6-disubstituted piperidine-bearing α-amino acid side-chains

Article abstract of DOI:10.1002/ejoc.200300148

A straightforward synthesis of 2,6-disubstituted piperidines bearing α-amino acid side-chains was developed. Synthesis was based on a Horner-Wadsworth-Emmons condensation of a β-ketophosphonate derived from an α-amino acid residue with a β-homologated ald

Full text of DOI:10.1002/ejoc.200300148

FULL PAPER
Synthesis of 2,6-Disubstituted Piperidine-Bearing α-Amino Acid Side-Chains
Damien Boeglin,[a] Annie Heitz,[b] Jean Martinez,[a] and Jean-Alain Fehrentz*[a]
Keywords: Nitrogen heterocycles / Reductive aminations / Peptidomimetics
A straightforward synthesis of 2,6-disubstituted piperidines
bearing α-amino acid side-chains was developed. Synthesis
was based on a Horner−Wadsworth−Emmons condensation
ine moieties. Introduction of a new conformational restriction
in the obtained molecules allowed total assignment of the
stereocenters by NMR experiments. This assignment allowed
us to propose a mechanistic pathway during the cyclization
process, explaining the loss of exocyclic carbon-center con-
figuration.
of
a β-ketophosphonate derived from an α-amino acid
residue with a β-homologated aldehyde of an N-protected
amino acid residue. The generated α-β unsaturated ketones
were then reduced, deprotected, and cyclized in a hydro-
genation/hydrogenolysis one-pot procedure to yield piperid-
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
Peptides are usually reported as being poor drug candi-
dates. They do not cross biological barriers well and are
subject to enzymatic degradation. For these reasons, great
efforts have been made in peptide-based drug design
towards the development of a wide range of non-peptidic
structural modifications (pseudopeptides, peptidomimetics,
conformational-mimetics).[1] On the other hand, small cyc-
lic organic molecules, to which essential pharmacophoric
groups can be appended in a suitable way, are frequently
used as nonpeptidic scaffolds to stabilize or to probe a
putative bioactive conformation.[2] Functionalized hetero-
cyclic compounds such as piperazine,[3] piperidine,[4] or ke-
topiperazine[5] are very good tools to achieve this challenge
and are often found in natural and synthetic bioactive li-
gands, making them interesting synthetic targets.
We have demonstrated that, in the case of a peptide am-
ide, the amide moiety was not always essential for binding
of hormones to their receptors.[6,7] In this case, molecule B
(Figure 1) could be used as starting material for rigidified
molecules. Cyclization through a dimethylene or trimethy-
lene bridge between the carbonyl group of residue i and the
α-carbon of residue iϩ1 of the C-terminal dipeptide would
respectively lead to pyrrolidine (molecule D) or piperidine
(molecule C) moieties which could be interesting tools to
probe side-chain orientations in the active conformation.
Figure 1. C-terminus-constrained pseudo-peptides
Our current interest in such chemical templates, onto which
relevant groups can be appended, led us to describe the
preparation of various 2,6-disubstituted piperidine-based
scaffolds bearing α-amino acid side-chains.[8] This cyclic
platform was designed by introduction of a trimethylene
bridge generated through a HornerϪWadsworthϪEmmons
condensation of an amino acid β-ketophosphonate deriva-
tive with an aldehyde of an N-protected β-amino acid resi-
due (Scheme 1). This synthetic pathway allowed the intro-
duction of a wide variety of side chains. Furthermore, these
heterocycles present two amino functional groups for ad-
ditional structural diversification and can be useful as plat-
[a]
´
Laboratoire des Amino Acides, Peptides et Proteines (LAPP),
´
UMR 5810 CNRS-UM1-UM2, Faculte de Pharmacie,
15 Avenue Charles Flahault, BP 14491, 34093 Montpellier
´
Cedex 5, France
Fax: (internat.) ϩ33-(0)4-67548654
E-mail: fehrentz@colombes.pharma.univ-montp1.fr
Center de Biochimie Structurale, UMR 5048 CNRS-UM1,
UMR 554 INSERM-UM1, Faculte de Pharmacie,
[b]
´
Scheme 1. Synthetic pathway for 2,6-substituted piperidine
synthesis
´
34093 Montpellier Cedex 5, France
Eur. J. Org. Chem. 2003, 3139Ϫ3146
DOI: 10.1002/ejoc.200300148
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3139

D. Boeglin, A. Heitz, J. Martinez, J.-A. Fehrentz
FULL PAPER
forms for the design of biologically active peptidomimetics
or non-peptide small molecule ligands (Figure 2).
Aldehydes 5aϪd (Scheme 3) were prepared in three steps
from commercial Z-α-amino acids. These latter were first
converted into their corresponding α-diazo ketones via the
mixed anhydride method (isobutyl chloroformate, IBCF, in
the presence of one equivalent of base, then diazomethane
excess). The latter upon treatment with free N,O-dimeth-
ylhydroxylamine, excess of Et3N and a catalytic amount of
silver benzoate in THF yielded Weinreb amides (Z-N-pro-
tected-β-amino dimethylhydroxamates) 4aϪd.[10]
Z-N-protected-β-amino dimethylhydroxamates 4aϪd
were treated with LiAlH4 (1.1 equivalent)[11] in THF at 0
°C to yield aldehydes 5aϪd which were treated without
purification with 2 (0.9 equivalent) in an HWE reaction
(Scheme 4). Olefination proceeded slowly using anhydrous
potassium carbonate in CH3CN at room temperature with-
out decomposition of the aldehyde moiety and gave the ex-
pected unsaturated ketones 6aϪd with up to 70% yield after
chromatography. The reaction was accelerated using cesium
carbonate in CH3CN and went to completion in less than
four hours with similar yields. Olefins 6aϪd were of E-con-
figuration as indicated by the large (15.5Ϫ15.9 Hz) vicinal
coupling constant for the vinyl protons.
Figure 2. 2,6-Substituted piperidine template
Results and Discussion
The chosen synthetic pathway for 2,6-disubstituted
piperidine derivatives involved two key steps:
a
HornerϪWadsworthϪEmmons (HWE) reaction between
two amino acid derivatives 2 and 5 followed by an intramol-
ecular reductive amination (Scheme 1). As an example, a -
Trp α-amino acid residue was selected as the single precur-
sor of 2 but this procedure could be extended to other am-
ino acid residues. β-Ketophosphonate (R)-2 was synthesized
in two steps from commercial Boc--Trp-OH. Boc--Trp-
OH was first converted into the Weinreb amide 1 by using
BOP[9] as coupling reagent. It was then reacted with a six-
fold excess of lithium dimethyl methylphosphonate anion at
Ϫ78 °C to give enantiopure β-ketophosphonate (R)-2 in
good yield (Scheme 2).
Scheme 4. HornerϪWadsworthϪEmmons condensation
Compounds 6aϪd were hydrogenated overnight at room
temperature and 150 psi pressure, using Pd-C as catalyst.
In these conditions, removal of the Z protecting group,
saturation of the double bond, and reductive amination
took place in a one-pot reaction (Scheme 5) and proceeded
very cleanly (no side-product could be detected during the
formation of the piperidine ring). Boc removal in acidic
conditions yielded 7aϪd. This synthetic pathway, HWE
condensation followed by cyclization and reductive amin-
ation, was described for generation of pipecolic acid deriva-
tives.[12] Starting from enantiomerically pure compound 6,
we expected to obtain a single diastereomer with a cis con-
figuration on the piperidine ring as already described[13] for
other piperidine derivatives. Examination of LC-MS of the
obtained piperidine compounds revealed the presence of
two diastereomers in a ratio of about 60:40 which could
be separated after removal of the Boc protecting group by
acidolysis (Table 1). Their separations were performed by
reversed-phase preparative HPLC and all compounds were
characterized and studied by mass spectrometry and 1H
and 13C NMR spectroscopy, with the exception of 7b, for
which only one pure diastereomer was obtained.
Scheme 2. Synthesis of β-ketophosphonates
Scheme 3. Preparation of the aldehyde moiety
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Eur. J. Org. Chem. 2003, 3139Ϫ3146

2,6-Disubstituted Piperidine-Bearing α-Amino Acid Side-Chains
FULL PAPER
these two protons are in a cis disposition towards the piperi-
dine ring. As C6Ј epimerization has never been observed
during such a ring-closure procedure,[12,13,15,16] we assumed
that configuration of the starting amino acid derivative 5
was conserved. This allowed us to ascertain the configura-
tion of asymmetric carbons C2Ј and C6Ј. Unfortunately, it
was not possible to determine the configuration of the third
asymmetric carbon C1 by NOE experimental analysis. To
ascertain its absolute configuration, both diastereomers of
7d were separately converted into their respective hexa-
hydroimidazo[1,5-a]pyridin-3-one derivatives (1R)- and
(1S)-8d. Attempts to form cyclic urea with triphosgene as
described[2] yielded the expected compound in poor yield
and with several side-products. This conversion was then
performed using p-nitrophenylchloroformate in dilute solu-
tion. The p-nitrophenylcarbamate formation was followed
by TLC. After its completion, a catalytic amount of DMAP
was added to start cyclization. It was achieved overnight
and led to cleaner compounds.
Scheme 5. Piperidine ring formation
Table 1. Results for the preparation of compounds 6 and 7
Entry
3
Yield 6 Yield 7 HPLC tR (min)[a] (%) (1S)-7/
(%)
(%)
of (1S)-7/(1R)-7
(1R)-7
a
b
c
-Phe 63
L -Ala 68
L -Val 65
L -Leu 51
L -Leu 37
66
59
71
71
69
8.92:9.13
6.88:6.80
7.45:7.33
40:60[a]
34:66[b]
39:61[c]
42:58[a]
57:43[a]
d
12.10:12.43
12.10:12.43
dЈ[d]
[a]
Determined by RP-HPLC, linear gradient 100% A to 50:50%
(A/B) in 15 min, A: 0.1% TFA in water/B: 0.1% TFA in CH3CN.
[b] Determined by RP-HPLC, isocratic run 85:15% (A/B). [c] Deter-
[d]
mined by RP-HPLC, isocratic run 84:16% (A/B). Starting from
(S)-2.
Configuration Assignment
Compounds 7aϪd contained three asymmetric carbons.
Two of them came from the starting amino acid residues
and the third one was formed during the cyclization step.
The enantiomeric purity of ketophosphonate (R)-2 was
confirmed by optical rotation measurements which were in
agreement with the literature.[14] Furthermore, its enantiom-
Scheme 6. Configuration assignment
The observed NOE effects and the coupling constants in
eric purity was also ascertained by chiral column HPLC the 1H NMR spectra of compounds 8d allowed the un-
analysis of both R and S synthetic ketophosphonates 2, equivocal assignment of the absolute configuration at C1 in
which showed an ee Ն 98%. In this reaction care must be each epimer (Scheme 6). Indeed, in the major compound, a
taken to keep a low temperature during addition of Weinreb NOE effect could be observed between H8a and H5 and the
amide 1 to lithium dimethyl methylphosphonate to prevent 3J(H8a-H1) coupling constant was 6.7 Hz indicating a cis
epimerization. The best conditions for this reaction were disposition between H1, H5, and H8a and a configuration
the use of n-butyllithium (nBuLi) as base and THF as sol- (1R,8-aS,5R) for this isomer. In the minor compound, a
3
vent. For compounds 5aϪd, the ArndtϪEistert homol- NOE effect between H8a and H5 and the J(H8a-H1) coup-
ogation is known to proceed with retention of configuration ling constant of 3.4 Hz indicated a trans disposition be-
and the generated aldehyde could not racemize by enoliz- tween H1 and H8a and a configuration (1S,8-aS,5R) for this
ation as the aldehyde function was in the β-position of the isomer. Furthermore, in this minor isomer, two extra NOE
asymmetric carbon. Furthermore these aldehydes were pre- effects were observed between H1 and the two H8 protons
pared just before use. Starting from pure (R)-2 and 5aϪd confirming the trans disposition between H1 and H8a. These
compounds, the olefins 6aϪd were obtained enantiomer- results clearly demonstrated that the hydrogenation pro-
ically pure. Hydrogenolysis/hydrogenation and reductive ceeded via a syn addition which is always imposed by the
amination steps were then performed. Two diastereomers R2 group orientation. These results confirmed the epimeriz-
were obtained and separated as described earlier. NOE ef- ation at C1 which could be explained by the equilibrium
fects observed between H2Ј and H6Ј (see Scheme 5 for num- between the A imine and B or BЈ enamines (Scheme 7).
bering) in the two diastereomers clearly demonstrated that Such an enamineϪimine equilibrium has already been de-
Eur. J. Org. Chem. 2003, 3139Ϫ3146
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D. Boeglin, A. Heitz, J. Martinez, J.-A. Fehrentz
FULL PAPER
scribed for cyclic structures.[16] All these data allowed attri- These piperidine derivatives bearing α-amino acid side-
bution of the (1R,2ЈS,6ЈR) configuration to the major dia- chains should find general interest in the conformational
stereoisomer of 7d and the (1S,2ЈS,6ЈR) configuration to analysis of bioactive peptido-mimetics and should be use-
the minor diastereoisomer of 7d. By analogy, as in all com- ful templates.
pounds 7aϪd the C1 carbon is bearing the same substituent
On the other hand, Michael 1,4-additions to the α-β un-
and the R2 groups are of the same nature, the same configu- saturated δ-amino ketones could also provide additional di-
rations were assigned to the major and minor compounds versity on the heterocyclic derivatives. This present
7aϪd. All ratios (1R)/(1S)-7aϪd were found to be around methodology is actually used in our laboratory for pyrro-
60:40% indicating: (i) the minor influence of the R2 group lidine derivative synthesis starting from N-protected α-
in epimerization at C1; (ii) that the formation of the aminoaldehydes instead of N-protected β-aminoaldehydes
enamine form must be slow compared to hydrogenation of (Figure 1, compound D).
the imine form, excluding a 50:50% ratio.
Experimental Section
General Remarks: All reagents were of commercial quality. Solvents
were dried and purified by standard methods. Analytical TLC was
performed on aluminum sheets coated with a 0.2-mm layer of silica
gel 60 F254. Silica gel 60 (40Ϫ63 µm) was used for flash chromatog-
raphy. 1H, 13C, and 31P NMR spectra were recorded in [D6]DMSO
at 400, 100, and 100 MHz respectively at 300 K. H3PO4 was used
as external reference for 31P NMR spectra. Chemical shifts were
reported as δ values (ppm) indirectly referenced to the solvent sig-
nal. 1H NMR assignments were made by means of homonuclear
H-H correlations (COSY) when needed and 13C NMR assignments
made by means of heteronuclear H-C correlations (HMQC and
HMBC when needed). Mass spectra were recorded on a Platform
II (Micromass, Manchester, UK) quadrupole mass spectrometer
operating at an ionization potential of 30 eV by positive ES fitted
with an electrospray interface and coupled with an Alliance Waters
LC. HR-Mass spectra were recorded on a JEOL SX 102 spec-
trometer (FAB positive mode) using NBA (3-nitrobenzylic acid) or
Scheme 7. Proposed stereochemical course of the hydrogenation/
GT (glycerol-thioglycerol) as the matrix. RP-HPLC analysis were
performed on a RPC18 SymmetryShieldTM (4.6 ϫ 50 mm, 3.5 µm)
from Waters with a flow rate of 1 mL/min and using a tunable UV
detector set at 214 nm. Solutions of 0.1% TFA in H2O (solvent A)
and of 0.1% TFA in CH3CN (solvent B) were used as mobile
phases. Preparative RP-HPLC was performed on C18 Delta-PakTM
cyclization step
Olefin 6dЈ (2S,4E,7S) [diastereoisomer of 6d (2R,4E,7S)]
was synthesized from β-ketophosphonate (S)-2 and β-ami-
noaldehyde 5d and submitted to the hydrogenation/cycliza-
tion step. After removal of the Boc protecting group, two
diastereoisomers (1R)-/(1S)-7dЈ were obtained. They
showed identical physico-chemical data to (1R)- and (1S)-
7d and the (1R)/(1S) ratio was the opposite to the compo-
nent obtained previously starting from -Trp residue. This
result validated the proposed equilibrium imine/enamine
during the hydrogenation/cyclization step leading to epi-
merization at C1 and the fact that formation of the enamine
form is slower than hydrogenation of the imine form.
˚
(40 ϫ 100 mm, 15 µm, 100 A) from Waters with a flow rate of
50 mL/min and using a tunable UV detector set at 214 nm. Solvents
A and B were used as mobile phases. Optical rotations were meas-
ured at 589 nm on a PerkinϪElmer 341 polarimeter. Chiral HPLC
analyses were performed on a Chiralcel OJ column at 30 °C with
a flow rate of 1 mL/min, detection at 214 nm and using a 80:20
(v/v) solution of hexane/2-propanol as mobile phase.
(3R)-3-(tert-Butyloxycarbonylamino)-1-(dimethoxyphosphoryl)-4-(3-
indolyl)butan-2-one [(R)-2]: MePO(OMe)2 (5.57 g, 44.9 mmol) was
dissolved in THF (30 mL), cooled to Ϫ78 °C, and then treated
with nBuLi (1.6  in hexane, 25.7 mL, 41.1 mmol), maintaining the
temperature below Ϫ70 °C. The reaction mixture was stirred for
10 min before adding dropwise a precooled solution of Boc--Trp-
N(CH3)O(CH3) (2.6 g) dissolved in THF (10 mL). The reaction
mixture was stirred at Ϫ70 °C for 30 min before the reaction was
quenched with saturated NH4Cl. The resulting mixture was ex-
tracted with EtOAc and the organic layer washed with brine, dried
with sodium sulfate, and concentrated in vacuo. The residue was
purified by flash chromatography (elution EtOAc) to yield the title
compound as a colorless oil (2.31 g, 75%). Rf ϭ 0.30 (EtOAc); tR
17.450 min (chiral HPLC). [α]2D0 ϭ ϩ26.3 (c ϭ 1.2, MeOH). 1H
NMR: δ ϭ 1.31 (s, 9 H), 2.90 (dd, J ϭ 14.7, J ϭ 9.3 Hz, 1 H), 3.20
(dd, J ϭ 14.8, J ϭ 4.6 Hz, 1 H), 3.40 (d, J ϭ 21.3 Hz, 2 H), 3.63
Conclusion
We have developed a methodology for synthesizing pip-
eridines incorporating two amino acid side-chains. The
cyclization step was performed by reductive amination of
δ-amino-ketones 6 concurrently with deprotection of the
amine moiety and reduction of the double bond. During
ring closure, epimerization occurred at the C1 center. We
proposed an equilibrium between imine and enamine forms
that led to the partial loss of C1 stereo-integrity. NMR
analysis of bicyclic constrained derivatives 8d allowed attri-
bution of the absolute configuration of both diastereomers. (d, J ϭ 11.2 Hz, 6 H), 4.30 (m, 1 H), 6.95 (t, J ϭ 7.2 Hz, 1 H),
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2,6-Disubstituted Piperidine-Bearing α-Amino Acid Side-Chains
FULL PAPER
7.05 (t, J ϭ 7.2 Hz, 1 H), 7.11 (br. s, 1 H), 7.16 (d, J ϭ 8.0 Hz, 1 H, 7-H indole), 7.53 (d, J ϭ 7.8 Hz, 1 H, 4-H indole), 10.80 (s, 1
H), 7.30 (d, J ϭ 7.9 Hz, 1 H), 7.55 (d, J ϭ 7.6 Hz, 1 H), 10.82 (br. H, NH indole) ppm. 13C NMR: δ ϭ 20.4 (C8), 25.8 (C1), 28.1
s, 1 H). 13C NMR: δ ϭ 25.9 (s), 28.96 (s,), 37.3 (d, JC,P ϭ 129.5 Hz), (CH3, Boc), 38.9 (C6), 45.8 (C7), 58.6 (C2), 65.1 (CH2,Z), 78.1 (C,
53.4 (d, JC,P ϭ 5.9 Hz), 53.4 (d, JC,P ϭ 6.3 Hz), 61.8 (d, JC,P
ϭ
Boc), 109.9 (C3 indole), 111.3 (C7 indole), 118.2 (C4 and C5 in-
3.5 Hz), 80.0 (s), 110.7 (s), 112.2 (s), 2 ϫ 119.2 (s), 121.8 (s), 124.6 dole), 120.8 (C6 indole), 123.6 (C2 indole), 127.1 (C3a indole),
(s), 128.1 (s), 137.0 (s), 156.2 (s), 202.4 (d, JC,P ϭ 6.3 Hz) ppm. 31P 127.5 (C ar), 127.6 (2C ar, Z), 128.2 (2C ar, Z), 128.4 (C4), 136.0
NMR: δ ϭ 24.5 ppm. MS (ES): m/z ϭ 311.0 [M ϩ H Ϫ 100]ϩ, (C7a indole), 137.1 (C ar), 144.2 (C5), 155.2 and 155.4 [-NH-C(O)-
355.1 [M ϩ H Ϫ 56]ϩ, 411.1 [M ϩ H]ϩ, 433.1 [M ϩ Na]ϩ, 821.2
[2 M ϩ H]ϩ, 843.1 [2 M ϩ Na]ϩ.
O-, Z and Boc], 197.9 (C3) ppm. MS (ES): m/z ϭ 528.3 [M ϩ
Na]ϩ, 506.1 [M ϩ H]ϩ, 450.3 [M ϩ H Ϫ 56]ϩ, 406.1 [M ϩ H
Ϫ 100]ϩ.
(3S)-3-(tert-Butyloxycarbonylamino)-1-(dimethoxyphosphoryl)-4-(3-
indolyl)butan-2-one [(S)-2]: tR 22.250 min (chiral HPLC). [α]D20
Ϫ24.6 (c ϭ 0.9, MeOH).
ϭ
(2R,4E,7R)-2-(tert-Butyloxycarbonylamino)-7-(benzyloxycarbonyl-
amino)-1-(3-indolyl)-8-methylnon-4-en-3-one (6c): Rf
ϭ
0.34
1
(EtOAc/hexane, 3:7). [α]2D1 ϭ Ϫ22.2 (c ϭ 0.80, MeOH). H NMR:
δ ϭ 0.84 (d, J ϭ 6.4 Hz, 3 H, 9-H), 0.86 (d, J ϭ 6.4 Hz, 3 H, 9-
H), 1.33 (s, 9 H, Boc), 1.67 (m, 1 H, 8-H), 2.28 (m, 1 H, 6-H), 2.39
(dd, J ϭ 14.0, J ϭ 6.7 Hz, 1 H, 6-H), 2.87 (dd, J ϭ 14.6, J ϭ
9.2 Hz, 1 H, 1-H), 3.10 (dd, J ϭ 14.6, J ϭ 4.6 Hz, 1 H, 1-H), 3.45
(m, 1 H, 7-H), 4.45 (m, 1 H, 2-H), 4.96 [d, J ϭ 12.5 Hz, 1 H, -CH2-
(Z)], 5.02 [d, J ϭ 12.5 Hz, 1 H, -CH2-(Z)], 6.43 (d, J ϭ 15.7 Hz, 1
H, 4-H), 6.85 (m, 1 H, 5-H), 6.98 (t, J ϭ 7.8 Hz, 1 H, 5-H indole),
7.00 (m, 1 H, NH urethane Boc), 7.06 (t, J ϭ 7.8 Hz, 1 H, 6-H
indole), 7.11 (s, 1 H, 2-H indole), 7.23 (d, J ϭ 9.3 Hz, 1 H, NH
urethane Z), 7.33 (d, J ϭ 7.8 Hz, 1 H, 7-H indole), 7.26Ϫ7.37 (m,
5H ar), 7.54 (d, J ϭ 7.8 Hz, 1 H, 4-H indole), 10.80 (s, 1 H, NH
indole) ppm. 13C NMR: δ ϭ 18.0 (C9), 19.0 (C9), 25.8 (C1), 28.1
(CH3, Boc), 31.6 (C8), 34.5 (C6), 55.2 (C7), 58.8 (C2), 65.0
(CH2,Z), 78.1 (C, Boc), 109.9 (C3 indole), 111.3 (C7 indole), 118.2
(C4 and C5 indole), 120.8 (C6 indole), 123.6 (C2 indole), 127.2
(C3a indole), 127.4 (2 C ar, Z), 127.6 [1 C ar (Z)], 128.1 (C4), 128.2
(2 C ar, Z), 136.0 (C7a indole), 137.2 (C ar), 144.9 (C5), 155.2 and
156.0 [-NH-C(O)-O- (Z and Boc)], 197.8 (C3) ppm. MS (ES):
m/z ϭ 556.3 [M ϩ Na]ϩ, 534.2 [M ϩ H]ϩ, 478.1 [M ϩ H Ϫ 56]ϩ,
434.0 [M ϩ H Ϫ 100]ϩ.
General Procedure for the Synthesis of Aminoalkyl-α,β-unsaturated
Ketones 6a؊d: AlLiH4 (1.54 mmol) was added to a stirred solution
of 4aϪd (1.46 mmol) in anhydrous THF (10 mL) placed in an ice
bath. After 10 min, excess hydride was quenched by addition of a
1  KHSO4 aqueous solution and the expected aldehydes 5aϪd
were extracted with EtOAc. The organic layers were washed with
1  KHSO4 and brine, dried with Na2SO4, and concentrated under
reduced pressure. 5aϪd were used in the next step without further
purification. 5aϪd and β-ketophosphonate 2 (1.19 mmol) were dis-
solved in acetonitrile (5 mL) then K2CO3 (1.82 mmol) was added
to the reaction mixture which was stirred at room temperature for
16 h. The reaction mixture was diluted with EtOAc and quenched
by addition of a 1  KHSO4 solution. The organic layers were
washed with 1  KHSO4 solution, brine, dried with sodium sulfate,
and concentrated in vacuo. The residue was purified by flash chro-
matography on a silica-gel column to yield title compounds 6aϪd
as colorless oils. Structures of compounds 6aϪd were checked by
NMR and mass spectroscopy; yields are reported in Table 1.
(2R,4E,7R)-2-(tert-Butyloxycarbonylamino)-7-(benzyloxycarbonyl-
amino)-1-(3-indolyl)-8-phenyloct-4-en-3-one (6a): Rf ϭ 0.42 (EtOAc/
hexane, 3:7). [α]2D1 ϭ Ϫ23.1 (c ϭ 0.91, MeOH). 1H NMR: δ ϭ 1.31
(s, 9 H, Boc), 2.39 (m, 2 H, 6-H), 2.71 (m, 2 H, 8-H), 2.88 (dd, J ϭ
14.8, J ϭ 9.2 Hz, 1 H, 1-H), 3.10 (dd, J ϭ 14.8, J ϭ 4.6 Hz, 1 H,
1-H), 3.84 (m, 1 H, 7-H), 4.46 (m, 1 H, 2-H), 4.91 [d, J ϭ 12.2 Hz,
1 H, -CH2-(Z)], 4.98 [d, J ϭ 12.2 Hz, 1 H, -CH2-(Z)], 6.41 (d, J ϭ
15.7 Hz, 1 H, 4-H), 6.88 (m, 1 H, 5-H), 6.96 (t, J ϭ 7.8 Hz, 1 H,
5-H indole), 7.03 (d, J ϭ 9.0 Hz, 1 H, NH urethane Boc), 7.05 (t,
J ϭ 7.8 Hz, 1 H, 6-H indole), 7.11 (s, 1 H, 2-H indole), 7.15Ϫ7.30
(m, 10 H ar), 7.32 (d, J ϭ 7.8 Hz, 1 H, 7-H indole), 7.37 (d, J ϭ
8.5 Hz, 1 H, NH urethane Z), 7.53 (d, J ϭ 7.8 Hz, 1 H, 4-H indole),
10.80 (s, 1 H, NH indole) ppm. 13C NMR: δ ϭ 25.8 (C1), 28.1
(CH3, Boc), 37.2 (C6), 39.9 (C8), 51.5 (C7), 58.8 (C2), 64.9
(CH2,Z), 78.1 (C, Boc), 109.9 (C3 indole), 111.3 (C7 indole), 118.2
(C4 and C5 indole), 120.8 (C6 indole), 123.6 (C2 indole), 126.0 (C
ar), 127.2 (C3a indole), 127.3 (2 C ar), 127.5 (C ar), 128.1 (2 C ar),
128.2 (2 C ar), 128.4 (C4), 129.1 (2 C ar), 136.0 (C7a indole), 137.1
(C ar), 138.6 (C ar), 144.1 (C5), 155.2 and 155.5 [-NH-C(O)-O- (Z
and Boc)], 197.8 (C3) ppm. MS (ES): m/z ϭ 582.4 [M ϩ H]ϩ; 526.2
[M ϩ H Ϫ 56]ϩ, 482.3 [M ϩ H Ϫ 100]ϩ.
(2R,4E,7S)-2-(tert-Butyloxycarbonylamino)-7-(benzyloxycarbonyl-
amino)-1-(3-indolyl)-9-methyldec-4-en-3-one (6d): Rf
ϭ
0.43
1
(EtOAc/hexane, 3:7). [α]2D1 ϭ Ϫ32.2 (c ϭ 1.0, MeOH). H NMR:
δ ϭ 0.86 (d, J ϭ 6.4 Hz, 6 H, 10-H), 1.17 (m, 1 H, 8-H), 1.33 (s, 9
H, Boc), 1.37 (m, 1 H, 8-H), 1.61 (m, 1 H, 9-H), 2.33 (m, 2 H, 6-
H), 2.88 (dd, J ϭ 14.8, J ϭ 9.0 Hz, 1 H, 1-H), 3.11 (dd, J ϭ 14.8,
J ϭ 4.7 Hz, 1 H, 1-H), 3.69 (m, 1 H, 7-H), 4.45 (m, 1 H, 2-H), 4.99
[m, 2 H, -CH2-(Z)], 6.41 (d, 1 H, 15.6 Hz, 4-H), 6.85 (m, 1 H, 5-
H), 6.98 (t, 1 H, 7.8 Hz, 5-H indole), 7.02 (d, J ϭ 8 Hz, 1 H, NH
urethane Boc), 7.06 (t, J ϭ 7.8 Hz, 1 H, 6-H indole), 7.12 (s, 1 H,
2-H indole), 7.22 (d, J ϭ 8.8 Hz, 1 H, NH urethane Z), 7.34 (d,
J ϭ 7.8 Hz, 1 H, 7-H indole), 7.26Ϫ7.37 (m, 5 H ar), 7.53 (d, 1 H,
7.8 Hz, 4-H indole), 10.80 (s, 1 H, NH indole) ppm. 13C NMR:
δ ϭ 21.7 (C10), 23.0 (C10), 24.2 (C9), 25.8 (C1), 28.1 (CH3, Boc),
38.3 (C6), 43.3 (C8), 48.0 (C7), 58.7 (C2), 65.0 (CH2,Z), 78.1 (C,
Boc), 109.9 (C3 indole), 111.3 (C7 indole), 118.2 (C4 and C5 in-
dole), 120.8 (C6 indole), 123.6 (C2 indole), 127.2 (C3a indole),
127.5 (2C ar, Z), 127.6 (C ar, Z), 128.2 (C4), 128.2 (2 C ar), 136.0
(C7a indole), 137.2 (C ar), 144.4 (C5), 155.2 and 155.7 [ϪNH-
C(O)-O-(Z and Boc)], 197.8 (C3) ppm. MS (ES): m/z ϭ 548.3 [M
ϩ H]ϩ, 492.3 [M ϩ H Ϫ 56]ϩ, 448.1 [M ϩ H Ϫ 100]ϩ.
(2R,4E,7S)-2-(tert-Butyloxycarbonylamino)-7-(benzyloxycarbonyl-
amino)-1-(3-indolyl)oct-4-en-3-one (6b): Rf ϭ 0.11 (EtOAc/hexane,
1
3:7). [α]2D1 ϭ Ϫ23.3 (c ϭ 1.0, MeOH). H NMR: δ ϭ 1.05 (d, J ϭ
(2S,4E,7S)-2-(tert-Butyloxycarbonylamino)-7-(benzyloxycarbonyl-
6.4 Hz, 3 H, 8-H), 1.33 (s, 9 H, Boc), 2.33 (m, 2 H, 6-H), 2.89 (dd, amino)-1-(3-indolyl)-9-methyldec-4-en-3-one (6dЈ): Rf
J ϭ 14.8, J ϭ 9.2 Hz, 1 H, 1-H), 3.10 (dd, J ϭ 14.8, J ϭ 4.7 Hz, (EtOAc/hexane, 3:7). [α]2D1 ϭ Ϫ3.9 (c ϭ 1.00,MeOH). 1H NMR:
1 H, 1-H), 3.66 (m, 1 H, 7-H), 4.45 (m, 1 H, 2-H), 5.00 [m, 2 H, - δ ϭ 0.86 (d, J ϭ 6.4 Hz, 6 H, 10-H), 1.17 (m, 1 H, 8-H), 1.33 (s, 9
CH2-(Z)], 6.39 (d, J ϭ 15.7 Hz, 1 H, 4-H), 6.82 (m, 1 H, 5-H), 6.97 H, Boc), 1.37 (m, 1 H, 8-H), 1.61 (m, 1 H, 9-H), 2.33 (m, 2 H, 6-
ϭ
0.40
(t, J ϭ 7.8 Hz, 1 H, 5-H indole), 7.04 (m, 1 H, NH urethane Boc),
7.07 (t, J ϭ 7.8 Hz, 1 H, 6-H indole); 7.11 (s, 1 H, 2-H indole),
H), 2.87 (dd, J ϭ 14.8, J ϭ 9.0 Hz, 1 H, 1-H), 3.09 (dd, J ϭ 14.8,
J ϭ 4.7 Hz, 1 H, 1-H), 3.69 (m, 1 H, 7-H), 4.45 (m, 1 H, 2-H),
7.26Ϫ7.37 (m, 5H ar), 7.29 (m, 1 H, NH urethane Z), 7.33 (m, 1 4.99 [m, 2 H, -CH2-(Z)], 6.38 (d, 1 H, 15.6 Hz, 4-H), 6.85 (m, 1 H,
Eur. J. Org. Chem. 2003, 3139Ϫ3146
www.eurjoc.org  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3143

D. Boeglin, A. Heitz, J. Martinez, J.-A. Fehrentz
5-H), 6.98 (t, 1 H, 7.8 Hz, 5-H indole), 7.02 (d, J ϭ 8 Hz, 1 H, NH (t, J ϭ 7.8 Hz, 1 H, 6-H indole), 7.28 (s, 1 H, 2-H indole),
FULL PAPER
urethane Boc), 7.06 (t, J ϭ 7.8 Hz, 1 H, 6-H indole), 7.12 (s, 1 H,
2-H indole), 7.22 (d, J ϭ 8.8 Hz, 1 H, NH urethane Z), 7.34 (d,
J ϭ 7.8 Hz, 1 H, 7-H indole), 7.26Ϫ7.37 (m, 5H ar), 7.53 (d, 1 H,
7.28Ϫ7.40 (m, 5H ar), 7.42 (d, J ϭ 7.8 Hz, 1 H, 7-H indole), 7.70
(d, J ϭ 7.8 Hz, 1 H, 4-H indole), 8.16 (br. s, 2 H, primary amine),
8.87 (br. s, 1 H, secondary amine), 9.41 (br. s, 1 H, secondary am-
7.8 Hz, 4-H indole), 10.80 (s, 1 H, NH indole) ppm. 13C NMR: ine), 11.07 (s, 1 H, NH indole) ppm. 13C NMR: δ ϭ 21.6 (C3Ј,
δ ϭ 21.7 (C10), 23.0 (C10), 24.2 (C9), 25.8 (C1), 28.1 (CH3, Boc),
38.3 (C6), 43.3 (C8), 48.0 (C7), 58.7 (C2), 65.0 (CH2, Z), 78.1 (C,
Boc), 109.9 (C3 indole), 111.3 (C7 indole), 118.2 (C4 and C5 in-
dole), 120.8 (C6 indole), 123.6 (C2 indole), 127.2 (C3a indole),
C4Ј), 23.5 (C2), 26.8 (C5Ј), 38.8 (-CH2-Ph), 51.6 (C1), 58.4 (C2Ј),
59.3 (C6Ј), 107.0 (C3 indole), 111.6 (C7 indole), 118.3 (C4 indole),
118.4 (C5 indole), 121.3 (C6 indole), 124.8 (C2 indole), 126.6 (C3a
indole), 126.9 (C ar), 128.6 (2C ar), 129.3 (2C ar), 136.0 (C ar),
127.5 (2 C ar, Z), 127.6 (C ar, Z), 128.2 (C4), 128.2 (2 C ar), 136.0 136.5 (C7a indole) ppm. MS (ES): m/z ϭ 334.4 [M ϩ H]ϩ. HRMS
(C7a indole), 137.2 (C ar), 144.4 (C5), 155.2 and 155.7 [-NH-C(O)-
O- (Z and Boc)], 197.8 (C3) ppm. MS (ES): m/z ϭ 548.4 [M ϩ
H]ϩ, 492.2 [M ϩ H Ϫ 56]ϩ, 448.0 [M ϩ H Ϫ 100]ϩ.
calcd. for C22H27N3 [MHϩ] 334.2283, found 334.2293.
(1R,2S,6R)-1-[6-Benzylpiperidin-2-yl]-2-(1H-indol-3-yl)ethylamine,
1
TFA Salt [(1R)-7a]: H NMR: δ ϭ 1.38 (m, 1 H, 5Ј-H), 1.42 (m, 1
General Procedure for the Synthesis of 2,6-Disubstituted Piperidine
7a؊d: Compounds 6aϪd (0.40 mmol) were dissolved in a 0.1%
AcOH/ethanol solution (25 mL). Solutions were placed in a Parr
apparatus and a catalytic amount of 10% Pd/C was added. The
Parr apparatus was purged several times and then filled with H2 at
150 psi pressure. After 12 h, the reaction mixtures were filtered
through celite and the filtrates evaporated under reduced pressure.
Residues were treated with a 2  HCl EtOAc/MeOH solution
(10 mL) for 1 h for Boc deprotection. The reaction mixtures were
H, 4Ј-H), 1.55 (m, 1 H, 3Ј-H), 1.60 (m, 1 H, 5Ј-H), 1.85 (m, 1 H,
4Ј-H), 2.10 (m, 1 H, 3Ј-H), 2.67 (dd, J ϭ 12.7, J ϭ 10.4 Hz, 1 H, -
CH2-Ph), 3.07 (dd, J ϭ 12.7, J ϭ 3.5 Hz, 1 H, -CH2-Ph), 3.10 (d,
J ϭ 7.5 Hz, 2 H, 2-H), 3.36 (m, 1 H, 6Ј-H), 3.39 (m, 1 H, 2Ј-H),
3.83 (m, 1 H, 1-H), 7.04 (t, J ϭ 7.8 Hz, 1 H, 5-H indole), 7.13 (t,
J ϭ 7.8 Hz, 1 H, 6-H indole), 7.21 (d, J ϭ 7.6 Hz, 2 H, ar), 7.27
(m, 1 H, ar), 7.32 (s, 1 H, 2-H indole), 7.33 (t, J ϭ 7.6 Hz, 2 H,
ar), 7.41 (d, J ϭ 7.8 Hz, 1 H, 7-H indole), 7.63 (d, J ϭ 7.8 Hz, 1
H, 4-H indole), 8.28 (br. s, 2 H, primary amine), 8.48 (br. s, 1 H,
evaporated and the residues were purified by RP-HPLC and then secondary amine), 8.98 (br. s, 1 H, secondary amine), 11.08 (s, 1
lyophilized to yield 7aϪd as their trifluoroacetate salts (white
foam). The significant analytical and spectroscopic data of these
compounds are summarized in Table 2; yields are reported in
Table 1.
H, NH indole) ppm. 13C NMR: δ ϭ 21.3 (C3Ј, C4Ј), 25.8 (C2),
26.8 (C5Ј), 38.9 (-CH2-Ph), 52.5 (C1), 57.4 (C2Ј), 58.4 (C6Ј), 107.2
(C3 indole), 111.6 (C7 indole), 118.1 (C4 indole), 118.6 (C5 indole),
121.3 (C6 indole), 124.8 (C2, indole), 126.8 (C3a indole), 126.9 (C
ar), 128.5 (2C ar), 129.2 (2C ar), 135.7 (C ar), 136.4 (C7a indole)
ppm. MS (ES): m/z ϭ 334.5 [M ϩ H]ϩ. HRMS calcd. for C22H27N3
[MHϩ] 334.2283, found 334.2293.
1
Table 2. Selected H and 13C NMR chemical shift (δ) of 7-piperi-
dine derivatives
(1R,2S,6S)-2-(1H-Indol-3-yl)-1-[6-methylpiperidin-2-yl]ethylamine,
TFA Salt [(1R)-7b]: 1H NMR: δ ϭ 1.22 (d, J ϭ 6.4 Hz, 3 H, -CH3),
1.39 (m, 1 H, 5Ј-H), 1.49 (m, 1 H, 4Ј-H), 1.52 (m, 1 H, 3Ј-H), 1.81
(m, 1 H, 5Ј-H), 1.89 (m, 1 H, 4Ј-H), 2.09 (m, 1 H, 3Ј-H), 3.09 (m,
2 H, 2-H), 3.17 (m, 1 H, 6Ј-H), 3.33 (m, 1 H, 2Ј-H), 3.77 (m, 1 H,
1-H), 7.03 (t, J ϭ 7.9 Hz, 1 H, 5-H indole), 7.12 (t, J ϭ 7.9 Hz, 1
H, 6-H, indole), 7.31 (s, 1 H, 2-H indole), 7.40 (d, J ϭ 7.9 Hz, 1
H, 7-H indole), 7.61 (d, J ϭ 7.9 Hz, 1 H, 4-H indole), 8.32 (br. s,
3 H, amine), 8.87 (br. s, 1 H, secondary amine), 11.08 (s, 1 H, NH
indole) ppm. 13C NMR: δ ϭ 18.8 (-CH3), 21.2 (C3Ј), 21.7 (C4Ј),
25.8 (C2), 29.5 (C5Ј), 52.6 (C1), 53.8 (C6Ј), 57.1 (C2Ј), 107.3 (C3
indole), 111.6 (C7 indole), 118.1 (C4 indole), 118.5 (C5 indole),
121.3 (C6 indole), 124.7 (C2, indole), 126.7 (C3a indole), 136.4
(C7a indole) ppm. MS (ES): m/z ϭ 258.3 [M ϩ H]ϩ. HRMS calcd.
for C16H23N3 [MHϩ] 258.1970, found 258.1951.
(1R)-7aϪd
1H NMR
(δ)
(1S)-7aϪd
1H NMR
(δ)
13C NMR
(δ)
13C NMR
(δ)
a
2Ј-H 3.39
C2Ј 57.4
2Ј-H 3.56
C2Ј 58.4
3Ј-H 1.55/2.10 C3Ј 21.3
4Ј-H 1.42/1.85 C4Ј 21.3
5Ј-H 1.38/1.60 C5Ј 26.8
3Ј-H 1.65/2.02 C3Ј 21.6
4Ј-H 1.42/1.89 C4Ј 21.6
5Ј-H 1.49/1.65 C5Ј 26.8
6Ј-H 3.36
b[a] 2Ј-H 3.33
C6Ј 58.4
C2Ј 57.1
6Ј-H 3.42
C6Ј 59.3
3Ј-H 1.52/2.09 C3Ј 21.2
4Ј-H 1.49/1.89 C4Ј 21.7
5Ј-H 1.39/1.81 C5Ј 29.5
6Ј-H 3.17
2Ј-H 3.39
C6Ј 53.8
C2Ј 58.3
c
2Ј-H 3.51
C2Ј 59.5
3Ј-H 1.57/2.11 C3Ј 21.0
4Ј-H 1.50/1.95 C4Ј 21.7
5Ј-H 1.36/1.80 C5Ј 23.1
3Ј-H 1.69/2.07 C3Ј 22.9
4Ј-H 1.49/1.96 C4Ј 22.0
5Ј-H 1.45/1.86 C5Ј 23.3
(1R,2S,6R)-2-(1H-Indol-3-yl)-1-[6-isopropylpiperidin-2-yl]ethyl-
1
6Ј-H 2.98
2Ј-H 3.37
C6Ј 63.1
C2Ј 57.2
6Ј-H 2.99
2Ј-H 3.54
C6Ј 64.1
C2Ј 58.4
amine, TFA Salt (First Eluted) [(1R)-7c)]: H NMR: δ ϭ 0.92 [d,
d
J ϭ 6.2 Hz, 3 H, -CH(CH3)2], 0.94 [d, J ϭ 6.2 Hz, 3 H, -
CH(CH3)2], 1.36 (m, 1 H, 5Ј-H), 1.50 (m, 1 H, 4Ј-H), 1.57 (m, 1
H, 3Ј-H), 1.80 (m, 1 H, 5Ј-H), 1.88 [m, 1 H, -CH(CH3)2], 1.95 (m,
1 H, 4Ј-H), 2.11 (m, 1 H, 3Ј-H), 2.98 (m, 1 H, 6Ј-H), 3.05 (dd, J ϭ
15.1, J ϭ 8.1 Hz, 1 H, 2-H), 3.11 (dd, J ϭ 15.1, J ϭ 7.5 Hz, 1 H,
2-H), 3.39 (m, 1 H, 2Ј-H), 3.90 (m, 1 H, 1-H), 7.04 (t, J ϭ 7.8 Hz,
1 H, 5-H indole), 7.12 (t, J ϭ 7.8 Hz, 1 H, 6-H, indole), 7.30 (s, 1
3Ј-H 1.53/2.10 C3Ј 21.3
4Ј-H 1.55/1.90 C4Ј 21.4
5Ј-H 1.28/1.89 C5Ј 27.6
3Ј-H 1.63/2.03 C3Ј 22.2
4Ј-H 1.54/1.94 C4Ј 21.8
5Ј-H 1.40/1.94 C5Ј 27.7
6Ј-H 3.14
C6Ј 55.9
6Ј-H 3.19
C6Ј 56.9
[a]
Only the R isomer was obtained pure for NMR analysis.
(1S,2S,6R)-1-[6-Benzylpiperidin-2-yl]-2-(1H-indol-3-yl)- H, 2-H indole), 7.40 (d, J ϭ 7.8 Hz, 1 H, 7-H indole), 7.61 (d, J ϭ
1
ethylamine, TFA Salt (First Eluted) [(1S)-7a]: H NMR: δ ϭ 1.42
7.8 Hz, 1 H, 4-H indole), 7.78 (br. s, 1 H, secondary amine), 8.28
(m, 1 H, 4Ј-H), 1.49 (m, 1 H, 5Ј-H), 1.65 (m, 2 H, 3Ј-H, 5Ј-H), 1.89 (br. s, 2 H, primary amine), 8.45 (br. s, 1 H, secondary amine),
(m, 1 H, 4Ј-H), 2.02 (m, 1 H, 3Ј-H), 2.78 (dd, J ϭ 12.8, J ϭ
10.7 Hz, 1 H, -CH2-Ph), 2.91 (dd, J ϭ 14.8, J ϭ 11.8 Hz, 1 H, 2-
H), 3.22 (dd, J ϭ 12.8, J ϭ 2.3 Hz, 1 H, -CH2-Ph), 3.36 (dd, J ϭ
11.08 (s, 1 H, NH indole) ppm. 13C NMR: δ ϭ 16.7 [-CH(CH3)2],
18.7 [-CH(CH3)2], 21.0 (C3Ј), 21.7 (C4Ј), 23.1 (C5Ј), 26.0 (C2), 30.3
[-CH(CH3)2], 52.3 (C1), 58.3 (C2Ј), 63.1 (C6Ј), 107.3 (C3 indole),
14.8, J ϭ 2.0 Hz, 1 H, 2-H), 3.42 (m, 1 H, 6Ј-H), 3.56 (m, 1 H, 2Ј- 111.6 (C7 indole), 118.1 (C4 indole), 118.5 (C5 indole), 121.3 (C6
H), 3.77 (m, 1 H, 1-H), 7.05 (t, 1 H,, J ϭ 7.8 Hz, 5-H indole), 7.14 indole), 124.8 (C2, indole), 126.8 (C3a indole), 136.4 (C7a indole)
3144
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3139Ϫ3146

2,6-Disubstituted Piperidine-Bearing α-Amino Acid Side-Chains
FULL PAPER
ppm. MS (ES): m/z ϭ 286.5 [M ϩ H]ϩ. HRMS calcd. for C18H27N3 47 µmol) in CH2Cl2. (4.5 mL) After 1 h, a catalytic amount of 4-
[MHϩ] 286.2283, found 286.2296.
(dimethylamino)pyridine was added and the reaction mixture was
stirred overnight at room temperature. A 1  KHSO4 aqueous solu-
tion (10 mL) and CH2Cl2 (10 mL) were added to the reaction mix-
ture, the organic layer was separated and washed with a saturated
solution of NaHCO3 and brine, dried with Na2SO4, and concen-
trated. The obtained residue was directly purified by RP-HPLC
and then lyophilized to yield (1S)-8d as a white foam. (1R)-8d was
obtained in a similar manner starting from (1R)-7d. For selected
NMR data see Table 3.
(1S,2S,6R)-2-(1H-Indol-3-yl)-1-[6-isopropylpiperidin-2-yl]ethyl-
amine, TFA Salt [(1S)-7c]: 1H NMR: δ ϭ 0.98 [d, J ϭ 6.2 Hz, 3
H, -CH(CH3)2], 1.02 [d, J ϭ 6.2 Hz, 3 H, -CH(CH3)2], 1.45 (m, 1
H, 5Ј-H), 1.49 (m, 1 H, 4Ј-H), 1.69 (m, 1 H, 3Ј-H), 1.86 (m, 1 H,
5Ј-H), 1.96 (m, 1 H, 4Ј-H), 1.99 [m, 1 H, -CH(CH3)2], 2.07 (m, 1
H, 3Ј-H), 2.90 (dd, J ϭ 15.3, J ϭ 11.6 Hz, 1 H, 2-H), 2.99 (m, 1
H, 6Ј-H), 3.35 (dd, J ϭ 15.3, J ϭ 2.6 Hz, 1 H, 2-H), 3.51 (m, 1 H,
2Ј-H), 3.86 (m, 1 H, 1-H), 7.03 (t, J ϭ 7.8 Hz, 1 H, 5-H indole),
7.13 (t, J ϭ 7.8 Hz, 1 H, 6-H indole), 7.28 (s, 1 H, 2-H indole),
7.41 (d, J ϭ 7.8 Hz, 1 H, 7-H indole), 7.66 (d, J ϭ 7.8 Hz, 1 H, 4-
H indole), 8.13 (br. s, 2 H, primary amine), 8.30 (br. s, 1 H, second-
ary amine), 8.43 (br. s, 1 H, secondary amine), 11.09 (s, 1 H, NH
indole) ppm. 13C NMR: δ ϭ 17.1 [-CH(CH3)2], 19.2 [-CH(CH3)2],
22.0 (C4Ј), 22.9 (C3Ј), 23.3 (C5Ј), 24.0 (C2), 30.3 [-CH(CH3)2], 51.7
(C1), 59.5 (C2Ј), 64.1 (C6Ј), 107.1 (C3 indole), 111.6 (C7 indole),
118.4 (C4 indole, C5 indole), 121.3 (C6 indole), 124.8 (C2, indole),
126.7 (C3a indole), 136.5 (C7a indole) ppm. MS (ES): m/z ϭ 286.0
[M ϩ H]ϩ. HRMS calcd. for C18H27N3 [MHϩ] 286.2283, found
286.2296.
Table 3. Selected NMR spectroscopic data of compounds 8d
(1R)-8d
1H NMR
(1S)-8d
1H NMR
13C NMR
13C NMR
(δ)
(δ)
(δ)
(δ)
1-H
2-H
5-H
3.95
6.10
2.95
C1
C3 160.7
C5
52.8
1-H
2-H
5-H
3.28
6.27
2.88
C1
C3 159.8
C5
55.7
55.2
31.0
23.6
22.9
54.8
31.3
23.6
29.3
6-H/6Ј-H 1.13/1.50 C6
7-H/7Ј-H 1.35/1.80 C7
8-H/8Ј-H 1.48
8a-H 3.30
6-H/6Ј-H 1.09/1.51 C6
7-H/7Ј-H 1.31/1.68 C7
8-H/8Ј-H 1.24/1.32 C8
C8
C8a 60.3
(1S,2S,6R)-2-(1H-Indol-3-yl)-1-[6-isobutylpiperidin-2-yl]ethylamine,
TFA Salt (First Eluted) [(1S)-7d]: 1H NMR: δ ϭ 0.91 [d, J ϭ
6.6 Hz, 3 H, -CH2-CH(CH3)2], 0.94 [d, J ϭ 6.6 Hz, 3 H, -CH2-
CH(CH3)2], 1.40 (m, 1 H, 5Ј-H), 1.53 [m, 2 H, -CH2-CH(CH3)2],
1.54 (m, 1 H, 4Ј-H), 1.63 (m, 1 H, 3Ј-H), 1.77 [m, 1 H, -CH2-
CH(CH3)2], 1.94 (m, 2 H, 4Ј-H, 5Ј-H), 2.03 (m, 1 H, 3Ј-H), 2.88
(dd, J ϭ 14.8, J ϭ 11.6 Hz, 1 H, 2-H), 3.19 (m, 1 H, 6Ј-H), 3.32
(dd, J ϭ 14.8, J ϭ 2.3 Hz, 1 H, 2-H), 3.54 (m, 1 H, 2Ј-H), 3.76 (m,
1 H, 1-H), 7.03 (t, J ϭ 7.8 Hz, 1 H, 5-H indole), 7.13 (t, J ϭ 7.8 Hz,
1 H, 6-H indole), 7.27 (s, 1 H, 2-H indole), 7.41 (d, J ϭ 7.8 Hz, 1
H, 7-H indole), 7.68 (d, J ϭ 7.8 Hz, 1 H, 4-H indole), 8.15 (br. s,
2 H, primary amine), 8.63 (br. s, 1 H, secondary amine), 8.97 (br.
s, 1 H, secondary amine), 11.06 (s, 1 H, NH indole) ppm. 13C
NMR: δ ϭ 21.5 [-CH2-CH(CH3)2], 21.8 (C4Ј), 22.2 (C3Ј), 23.2 [-
CH2-CH(CH3)2], 23.4 (C2), 23.5 [-CH2-CH(CH3)2], 27.7 (C5Ј),
42.0 [-CH2-CH(CH3)2], 51.5 (C1), 56.9 (C6Ј), 58.4 (C2Ј), 107.0 (C3
indole), 111.6 (C7 indole), 118.4 (C4 indole, C5 indole), 121.3 (C6
indole), 124.8 (C2, indole), 126.6 (C3a indole), 136.5 (C7a indole)
ppm. MS (ES): m/z ϭ 300.4 [M ϩ H]ϩ. HRMS calcd. for C19H29N3
[MHϩ] 300.2440, found 300.2445.
8a-H
3.07
C8a 61.9
(1S,8aS,5R)-1-(1H-Indol-3-ylmethyl)-5-isobutylhexahydroimidazo-
[1,5-a]pyridin-3-one [(1S)-8d]: White foam (6.8 mg, 44%); Rf ϭ 0.26
(EtOAc/hexane, 1:1). 1H NMR: δ ϭ 0.83 [d, J ϭ 6.6 Hz, 3 H, -
CH2-CH(CH3)2], 0.86 [d, J ϭ 6.6 Hz, 3 H, -CH2-CH(CH3)2], 1.09
(m, 1 H, 6-H), 1.20 [m, 1 H, -CH2-CH(CH3)2], 1.24 (m, 1 H, 8-H),
1.31 (m, 1 H, 7-H), 1.32 (m, 1 H, 8-H), 1.51 (m, 1 H, 6-H), 1.68
(m, 1 H, 7-H), 1.70 [m, 1 H, -CH2-CH(CH3)2], 2.40 [m, 1 H, -CH2-
CH(CH3)2], 2.81 (m, 2 H, 1Ј-H), 2.88 (m, 1 H, 5-H), 3.07 (m, 1 H,
8a-H), 3.28 (m, 1 H, 1-H), 6.27 (s, 1 H, 2-H), 6.97 (t, J ϭ 7.9 Hz,
1 H, 5-H indole), 7.06 (t, J ϭ 7.9 Hz, 1 H, 6-H indole), 7.18 (s, 1
H, 2-H indole), 7.33 (d, J ϭ 7.9 Hz, 1 H, 7-H indole), 7.50 (d, J ϭ
7.9 Hz, 1 H, 4-H indole), 10.84 (s, 1 H, NH indole) ppm. 13C
NMR:
δ ϭ 22.5 [-CH2-CH(CH3)2], 22.6 [-CH2-CH(CH3)2],
23.6(C7), 24.5 [-CH2-CH(CH3)2], 29.3 (C8), 29.6 (C1Ј), 31.3 (C6),
40.9 [-CH2-CH(CH3)2], 54.8 (C5), 55.7 (C1), 61.9 (C8a), 110.0 (C3
indole), 111.3 (C7 indole), 118.0 (C4 indole), 118.2 (C5 indole),
120.8 (C6 indole), 123.2 (C2 indole), 127.5 (C3a indole), 136.1 (C7a
indole), 159.8 (C3) ppm. MS (ES): m/z ϭ 326.1 [M ϩ H]ϩ, 367.1
[M ϩ H ϩ CH3CN]ϩ, 651.4 [2 M ϩ H]ϩ. HRMS calcd. for
C20H28ON3 [MHϩ] 326.2232, found 326.2241.
(1R,2S,6R)-2-(1H-Indol-3-yl)-1-[6-isobutylpiperidin-2-yl]ethyl-
amine, TFA salt [(1R)-7d]: 1H NMR: δ ϭ 0.84 [d, J ϭ 6.4 Hz, 3
H, -CH2-CH(CH3)2], 0.89 [d, J ϭ 6.4 Hz, 3 H, -CH2-CH(CH3)2],
1.28 (m, 1 H, 5Ј-H), 1.39 [m, 2 H, -CH2-CH(CH3)2], 1.53 (m, 1 H,
3Ј-H), 1.55 (m, 1 H, 4Ј-H), 1.69 [m, 1 H, -CH2-CH(CH3)2], 1.89
(m, 1 H, 5Ј-H), 1.90 (m, 1 H, 4Ј-H), 2.10 (m, 1 H, 3Ј-H), 3.08 (m,
2 H, 2-H), 3.14 (m, 1 H, 6Ј-H), 3.37 (m, 1 H, 2Ј-H), 3.80 (m, 1 H,
1-H), 7.03 (t, J ϭ 7.8 Hz, 1 H, 5-H indole), 7.13 (t, J ϭ 7.8 Hz, 1
H, 6-H indole), 7.31 (s, 1 H, 2-H indole), 7.40 (d, J ϭ 7.8 Hz, 1 H,
7-H indole), 7.61 (d, J ϭ 7.8 Hz, 1 H, 4-H indole), 8.22 (br. s, 3 H,
amine), 8.54 (br. s, 1 H, secondary amine), 11.07 (s, 1 H, NH in-
dole) ppm. 13C NMR: δ ϭ 21.3 (C3Ј), 21.4 [C4Ј, -CH2-CH(CH3)2],
23.1 [-CH2-CH(CH3)2], 23.4 [-CH2-CH(CH3)2], 25.8 (C2), 27.6
(C5Ј), 42.1 [-CH2-CH(CH3)2], 52.4 (C1), 55.9 (C6Ј), 57.2 (C2Ј),
107.2 (C3 indole), 111.6 (C7 indole), 118.1 (C4 indole), 118.5 (C5
indole), 121.3 (C6 indole), 124.7 (C2, indole), 126.7 (C3a indole),
136.4 (C7a indole) ppm. MS (ES): m/z ϭ 300.0 [M ϩ H]ϩ. HRMS
calcd. for C19H29N3 [MHϩ] 300.2440, found 300.2445.
(1R,5aS,5R)-1-(1H-Indol-3-ylmethyl)-5-isobutylhexahydroimidazo-
[1,5-a]pyridin-3-one [(1R)-8d]: White foam (8.4 mg, 51%); Rf ϭ 0.26
(EtOAc/hexane, 1:1). 1H NMR: δ ϭ 0.83 [d, 3 H, -CH2-CH(CH3)2],
0.86 [d, 3 H, -CH2-CH(CH3)2], 1.13 (m, 1 H, 6-H), 1.24 [m, 1 H, -
CH2-CH(CH3)2], 1.35 (m, 1 H, 7-H), 1.48 (m, 2 H, 8-H), 1.50 (m,
1 H, 6-H), 1.73 [m, 1 H, -CH2-CH(CH3)2], 1.80 (m, 1 H, 7-H), 2.38
[m, 1 H, -CH2-CH(CH3)2], 2.78 (dd, J ϭ 14.8, J ϭ 6.3 Hz, 1 H,
1Ј-H), 2.85 (dd, J ϭ 14.8, J ϭ 8.8 Hz, 1 H, 1Ј-H), 2.95 (m, 1 H, 5-
H), 3.30 (m, 1 H, 8a-H), 3.95 (m, 1 H, 1-H), 6.10 (s, 1 H, 2-H),
6.95 (t, J ϭ 8.1 Hz, 1 H, 5-H indole), 7.06 (t, J ϭ 8.1 Hz, 1 H, 6-
H indole), 7.21 (s, 1 H, 2-H indole), 7.33 (d, J ϭ 8.1 Hz, 1 H, 7-H
indole), 7.51 (d, J ϭ 8.1 Hz, 1 H, 4-H indole), 10.84 (s, 1 H, NH
indole) ppm. 13C NMR: δ ϭ 22.3 [-CH2-CH(CH3)2], 22.7 [-CH2-
CH(CH3)2], 22.9 (C8), 23.6(C7), 24.4 [-CH2-CH(CH3)2], 24.6 (C1Ј),
31.0 (C6), 41.4 [-CH2-CH(CH3)2], 52.8 (C1), 55.2 (C5), 60.3 (C8a),
110.3 (C3 indole), 111.3 (C7 indole), 118.1 (C4 indole), 118.2 (C5
indole), 120.9 (C6 indole), 122.8 (C2, indole), 127.1 (C3a indole),
Procedure for the Conversion of (1R)- and (1S)-7d into (1R)- and
(1S)-8d: NMM (42 µL) and p-nitrophenylchloroformate (9.5 mg,
47 µmol) were added at 0 °C to a solution of (1S)-7d (14.2 mg, 136.1 (C7a indole), 160.7 (C3) ppm. MS (ES): m/z ϭ 326.2 [M ϩ
Eur. J. Org. Chem. 2003, 3139Ϫ3146
www.eurjoc.org  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3145

D. Boeglin, A. Heitz, J. Martinez, J.-A. Fehrentz
FULL PAPER
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3146
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3139Ϫ3146