Stereoselective synthesis of cis,cis-configured vicinal triamines

Article abstract of DOI:10.1002/ejoc.201402685

The first stereoselective synthesis of a cis,cis-configured vicinal triamine was achieved, starting from N-cyclohexenylpyrrolidone (10). The reaction sequence consists of the stereoselective construction of the trans-configured 1,3-diamide 14, trans-to-ci

Full text of DOI:10.1002/ejoc.201402685

FULL PAPER
DOI: 10.1002/ejoc.201402685
Stereoselective Synthesis of cis,cis-Configured Vicinal Triamines
[a]
[b]
[a,c]
Adrian Schulte, Susumu Saito, and Bernhard Wünsch*
Keywords: Stereoconvergent synthesis / Medicinal chemistry / Drug design / Nitrogen heterocycles / Tautomerism / Imines /
Reduction
The first stereoselective synthesis of a cis,cis-configured
vicinal triamine was achieved, starting from N-cyclohexenyl-
pyrrolidone (10). The reaction sequence consists of the
stereoselective construction of the trans-configured 1,3-di-
amide 14, trans-to-cis isomerization via enols or enamines,
and subsequent highly stereoselective reduction of the inter-
mediate imine 17D to the amine 18A. The postulated reaction
pathway explains the observed stereoconvergence and is
supported by calculation of the heats of formation of its inter-
mediates at the PM3 level. LiAlH reduction of 18A yielded
4
the tetracyclic aminal 19, which was converted into the pyr-
rolidinylquinoxaline 7, which showed low to moderate affin-
1
ity towards κ and σ receptors.
Introduction
Vicinal triamines on alicyclic systems are found in
various types of compounds including sugars, amino acids,
natural products, and pharmacologically active agents. The
[
1,2]
structural motif is prominent within triaminoglucose 1
and tetraaminoglucose,[ as well as in galactose and pyro-
glutamate derivatives. These amino sugars and amino acid
derivatives exhibit antibacterial activity.[ A great effort has
been invested in the stereoselective synthesis of naphthyridi-
3]
[4]
5]
[
6]
nomycins 2, which contain a 1,2,3-triamine fragment and
[
7]
display high antibacterial and anticancer activities. The
saxitoxins 3 are vicinal triamines that block voltage-gated
sodium channels and have been discussed in the context of
pain control. A considerable effort has been devoted to
the stereoselective synthesis of agelastatins 4, which exhi-
[
8]
[9]
[
10]
bit strong antitumor and GSK-3β-inhibiting activities.
Alicyclic vicinal triamines have also been found in the very
potent neuraminidase inhibitors 5[ and κ agonists 6
Figure 1).
The aim of this work was to produce 7, the cis,cis-config-
11]
[12]
(
ured analogue of the κ agonist 6. The modified relative con-
figuration of the center of chirality in the 4a-position
should give insight into the relationship between the relative
Figure 1. Examples of vicinal triamines with biological activity.
[
a] Westfälische Wilhelms-Universität Münster, Institut für
Pharmazeutische und Medizinische Chemie,
Corrensstr. 48, 48149 Münster, Germany
E-mail: wuensch@uni-muenster.de
configuration of the cyclohexane-1,2,3-triamine framework
and the κ receptor affinity. This entailed the development of
a strategy to provide cis,cis-configured cyclohexane-1,2,3-
triamines stereoselectively and, moreover, a method for the
transformation of these triamines into the target di-
chlorophenylacetamide 7 (Figure 2).
http://www.uni-muenster.de/Chemie.pz/forschen/ag/wuensch/
index.html
[
[
b] Graduate School of Science and Institute for Advanced
Research, Nagoya University,
Chikusa, Nagoya 464-8602, Japan
c] Cells-in-Motion Cluster of Excellence (EXC 1003 – CiM),
University of Münster,
The stereoselective synthesis of alicyclic vicinal triamines
is to date restricted to the construction of trans,trans- and
cis,trans-configured derivatives, such as 1,2,3-triaminocyclo-
4
8149 Münster, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402685.
[
13]
[14]
[15]
propanes,
-cyclobutanes,
and -cycloheptanes.
Eur. J. Org. Chem. 2014, 5749–5756
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5749

A. Schulte, S. Saito, B. Wünsch
FULL PAPER
advantages associated with a trans-configured leaving group
in the 2-position locked into an equatorial orientation by
large substituents in the 1- and 3-positions, we reasoned
that the third amino moiety between the two amide groups
should be installed by reductive amination. Oxidation of
the alcohol in I would produce planar ketones of type II.
Tautomeric equilibration could enable isomerization to the
thermodynamically most favored cis-configured diamides,
Figure 2. Production of cis,cis-configured aminoquinoxaline 7 from thus producing stereoconvergence. Deprotection would give
trans,trans-configured κ agonist 6.
intermediate primary amines that would undergo formation
of imines of type III, in which the cis configuration would
be favored due to 1,3-allylic strain. Finally, the imines III
would be reduced diastereoselectively under kinetic control
to provide cis,cis-configured amidoquinoxalines of type IV
Various methods have been established for cyclopentane-
1
,2,3-triamines, which are found as precursors of the age-
[
9]
lastatines 4. One method uses a syn-selective, intramolec-
(Scheme 1).
ular aziridination of an allylamine derivative catalyzed by
[16a]
the Du Bois catalyst [Rh esp ].
The same method was
2
2
also applied to prepare the analogous cyclohexane deriva-
[
16b]
tives.
However, terminal opening of the aziridine ring Results and Discussion
led to decomposition, whereas nucleophilic attack at the 2-
To carry out this plan, pyrrolidin-2-one (8) was depro-
tonated with NaH and allylated with 3-bromocyclohex-1-
ene (9) to give the alkene 10 in 80% yield. The alkene 10
had previously been prepared by acylation and alkylation
of cyclohex-2-en-1-amine with 4-chlorobutyryl chloride.[
The alkene 10 reacted diastereoselectively with m-chloro-
perbenzoic acid (mCPBA) in a Prileshaev reaction to afford
the cis-configured epoxide 11 exclusively, in 74% yield. A
comparable result was obtained in the epoxidation of N-
position exclusively produced trans,trans-configured cyclo-
hexane-1,2,3-triamines.[
17]
A cis,trans-configured cyclohex-
ane derivative was obtained on use of cis-3-bromo-1,2-ep-
oxycyclohexane as a starting material. The authors also re-
ported that neighboring-group participation of vicinal
21]
3
amino groups prevented inversion of sp -centered electro-
philes and promoted formation of cis,trans- instead of
cis,cis-configured triamines.[18] No conversion was observed
when 1,2-diamido-3-bromides bearing the leaving group
conformationally locked in an equatorial orientation were
(
cyclohex-2-en-1-yl)-2-nitrobenzenesulfonamides,
which
[
22]
[
19]
2
gave exclusively cis-configured products.
The observed
combined with strong nucleophiles such as sodium azide.
diastereoselectivity can be explained by a Bartlett-type
The synthesis of the triamine 6 was enabled by use of sp -
centered electrophiles under thermodynamic control, thus
leading to the stereoselective formation of trans,trans-con-
[
23]
mechanism, which involves H-bond interactions between
the peroxy acid and H-bond acceptor substituents on the
cyclohexene ring. Mono-Boc-protected ethylenediamine
[
20,12]
figured triamines.
[
24]
(
12) was combined with the epoxide 11 to yield the amine
Therefore, a synthetic route using 1,3-diamides I as de-
activated diamines was envisaged. To circumvent the dis-
13 through regioselective ring-opening. The amine 13 was
converted into the benzamide 14 with benzoyl chloride un-
der Schotten–Baumann conditions in 68% yield
(Scheme 2).
The relative configuration of the alcohol 14 was deter-
mined by analysis of the coupling constants of the methyne
protons, which are J(1-H/2-H) = 9.9 Hz and J(2-H/3-H) =
4.2 Hz. These values indicate a diaxial and an equatorial/
axial orientation of the respective protons and overall
trans,cis configuration. This result was confirmed by a
differential NOE experiment in which the intensity of the
signal at δ = 3.75 ppm (2-H) was increased upon saturation
of the signal at δ = 4.52 ppm (3-H).
The alcohol 14 did not react under Swern oxidation con-
[
25]
ditions.
However, oxidation with PCC immobilized on
[
26]
neutral alumina provided the ketone 15 in 64% yield and
as a 9:1 mixture of isomers according to LC/MS analysis.
The determination of the relative configuration of the
major isomer was, however, inhibited by signal broadening,
probably caused by slow rotation of the amide N–C=O
bond. The Boc group was subsequently removed with tri-
fluoroacetic acid, giving the intermediate primary amine 16.
Monitoring of the transformation by LC/MS showed com-
Scheme 1. Concept for the stereoselective synthesis of cis,cis-config-
ured amidoquinoxalines of type IV. Only one enantiomer of the
racemic mixture is shown.
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Eur. J. Org. Chem. 2014, 5749–5756

Stereoselective Synthesis of cis,cis-Configured Vicinal Triamines
energy of structurally related compounds, thus minimizing
the known discrepancies between calculated and experimen-
[
28]
tally determined values (Figure 3).
Scheme 2. Synthesis of the alcohol 14. Reagents and reaction con-
ditions: (a) (i) NaH, THF, room temp., 3 h, (ii) 9, DMSO, room
temp., 19 h; (b) mCPBA, CH
room temp., 1 d; (d) BzCl, NaOH (1 m, aq.), CH
8 h. For the racemic mixtures only one enantiomer is shown in
2
Cl
2
, room temp., 2 d; (c) 12, H
2
O,
2
Cl , room temp.,
2
1
each case.
plete conversion after 3 h at ambient temperature, resulting
in the imine or enamine species 17. After removal of the
solvent, the intermediate imine/enamine 17 was reduced.
Interestingly, use of l-Selectride (Li[sec-Bu BH]) did not re-
3
sult in any conversion of 17, but NaBH reduced the octa-
4
hydroquinoxaline derivative 17 to afford the diastereomeric
decahydroquinoxalines 18A and 18B in 63% yield and in a
1
ratio of 93:7 according to HPLC and H NMR analysis
(Scheme 3).
Figure 3. Relative heats of formation (Hf,rel) of the diastereomers
and tautomers of 16·TFA (blue) and 17·TFA (green), calculated at
the PM3 level and displayed with the aid of Chem3D, together with
the resulting Boltzmann distributions at 0 °C.
The results show that the cis-configured diamido ketone
1
6D·TFA is more stable than the trans-configured dia-
–1
stereomer 16A·TFA by 13.8 kJmol . Although the acti-
vation energy for tautomerization strongly depends on the
[
29]
solvent,
isomerization of 16A to 16D occurs via the enol tautomer
6C rather than via the enol tautomer 16B, which is ener-
the results calculated in vacuo suggest that the
1
–1
getically less stable by 9.1 kJmol . The thermodynamic
equilibrium of 16A to 16D lies at 436:1 in favor of 16D with
the assumption of a Boltzmann distribution at 0 °C.
Subsequent ring-closure yielded the iminium or enam-
monium salts 17·TFA and a stoichiometric amount of water
–1
with an exothermic reaction enthalpy of –6.41 kJmol .
The 4a,8a-dehydro enammonium tautomer 17B is more
stable than its 4a,5-dehydro isomer 17C by 23.9 kJmol .
, room temp., This observation is in good agreement with the preference
Scheme 3. Oxidation of the alcohol 14 and intramolecular re-
ductive amination to the amines 18A and 18B. Reagents and reac-
–1
tion conditions: (a) PCC/Al
d; (b) TFA, mol. sieves (4 Å), CH
c) NaBH , THF, 0 °C, 11 h. For the racemic mixtures only one
enantiomer is shown in each case.
2
O
3
(25%-w/w), CH
2
Cl
2
2
2
2
Cl , room temp., 3 h;
seen in octalins for the double bond in the 4a,8a- over the
(
4
–1 [30]
4
,4a-position by 16.3 kJmol .
The cis-configured imin-
ium salt 17D is more stable than the trans-configured dia-
–1
The heats of formation of the intermediates in the intra- stereomer 17A by 6.9 kJmol , corresponding to a Boltz-
molecular reductive amination pathway were calculated to mann distribution of 146:7 (17D/17A) at 0 °C. Because the
clarify the trans-to-cis isomerization of the ketones 15 and iminium salts 17D and 17A have the same configurations
1
6 and/or the imine 17. The semiempirical parametrized of the 1,3-propylenediamine fragment as the amines 18A
[
27]
model 3 (PM3)
was applied to determine differences in and 18B, respectively, it is assumed that the predominance
Eur. J. Org. Chem. 2014, 5749–5756
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5751

A. Schulte, S. Saito, B. Wünsch
FULL PAPER
of 17D in the tautomeric equilibria led to the preferred for- rated and the intensities of the signals of the vicinal protons
mation of 18A by selective backside reduction of the imine were increased. The results unequivocally confirmed the
1
7D. The ratio of 93:7 (18A/18B) is in good accordance cis,cis configuration of the vicinal triamine fragment in 7,
with the calculated ratio of the diastereomeric iminium salts 18A, 19, and 20.
7D and 17A (146:7), and this supports the discussed path- The affinities of 7 towards the κ, δ, σ , and σ receptors
way. It is known that TFA and NaBH form trifluoro- were determined by competition experiments with the ra-
1
1
2
4
acetoxyborohydride species in THF,[
probable reducing agents in this reaction. The enammo- cine, and [ H]-DTG, respectively. Membrane preparations
31,32]
so these are the dioligands [ H]-U-69,593, [ H]-DPDPE, [ H]-(+)-pentazo-
3
3
3
3
nium salt 17B is more stable than the iminium salt 17D by from guinea pig brain (κ, σ receptors), rat brain (δ recep-
1
–
1
1
2.2 kJmol ; however, initially formed enammonium spe- tor), and rat livers (σ receptor) were used as receptor mate-
2
cies are known to undergo H-shift towards the iminium rials.
[
33]
tautomer.
The acetamide 7 showed a κ receptor affinity of 1.2 μm.
Reduction of the diamide 18 with LiAlH provided a Additionally, a σ receptor affinity of 0.5 μm was deter-
4
1
mixture of the tetracyclic aminal 19 and the triamine 20 in mined, but interactions with σ and δ receptors could not
2
a ratio of 2:3 as determined by LC/MS. The mixture was be observed. The decreased κ affinity in comparison with
separated after acetylation of 20 under Schotten–Baumann the κ affinity of the trans,trans-configured stereoisomer 6
[
34]
conditions with 3,4-dichlorophenylacetyl chloride (21),
(K = 9.4 nm) is consistent with the results found for U-
i
to provide the acetamide 7 and the aminal 19 in 24% and 50,488 and its cis-configured diastereomer: the trans config-
5
9% yields, respectively. The aminal 19 was reduced with uration corresponded with high κ affinity, whereas the cis-
[
35]
NaBH in the presence of TFA to give the triamine 20 in configured diastereomer preferred the σ receptor.
4
1
28% yield. Acetylation of 20 with the chloride 21 gave the
identical amide 7 in 64% yield (Scheme 4).
Conclusions
The stereoselective construction of vicinal triamines was
made possible by use of 2-hydroxy-1,3-diamides as precur-
sors. The synthesis strategy made use of the hydrogen bor-
rowing concept, which was split into its components oxi-
dation, imine formation, and reduction. Steric shielding of
the leaving group in the central position was overcome by
oxidation of the alcohol 14 with PCC. Deprotection pro-
vided the primary amine 16, which underwent intramolecu-
lar imine formation directly. Calculations on the intermedi-
ate ketone and imine forms 16 and 17, respectively, showed
that tautomeric equilibria were responsible for the stereo-
Scheme 4. Synthesis of the κ agonist 7. Reagents and reaction con-
ditions: (a) LiAlH , THF, reflux, 11 h; (b) TFA, NaBH , CH Cl /
4 4 2 2
DMSO (2:1), 0 °C, 2 h, 28%; (c) 2-(3,4-dichlorophenyl)acetyl chlor- convergent formation of 1,3-cis-configured α,αЈ-diamido-
ide (21), NaOH (1 m, aq.), CH
2 2
Cl , room temp., 14 h. Only one
enantiomer of each racemic mixture is shown.
imines, which were stereoselectively reduced with NaBH to
give the cis,cis-configured perhydroquinoxaline 18A. Di-
4
amide reduction and acylation transformed the quinoxaline
1
The signal broadening observed in the H NMR spec-
18 into the cis,cis-configured dichlorophenylacetamide 7.
trum of 7 was prominent within a temperature range from
30 to 100 °C. Therefore, differential NOE experiments
The low κ receptor affinity of 7 showed that the relative
trans,trans configuration of 6 is crucial for high κ affinity.
–
failed to provide information on relative configuration.
The relative configuration of the tetracyclic aminal 19,
however, was clearly determined from the coupling con-
stants of the methyne protons. The proton 11a-H produces
a triplet (J = 5.1 Hz), which indicates a cis,cis configuration
of the substituents on the cyclohexane ring. Furthermore,
saturation of the signal at δ = 4.25 ppm (10a-H) in a
However, the moderate σ affinity of 7 confirmed the obser-
1
vation that changing of the configuration in potent κ ago-
nists leads to σ ligands.
1
Experimental Section
differential NOE spectrum led to an increased intensity of General Information: All commercially available reagents were used
without further purification. CH
2 2
Cl and THF were dried by distil-
the signal at δ = 1.98 ppm (11a-H); this is attributed to a
cis configuration of these protons in the imidazolidine ring.
Moreover, the relative configuration of the triamine 20
was determined from the coupling of the methyne protons
lation over CaH and sodium, respectively. DMSO was dried with
2
molecular sieves (4 Å). All reactions were carried out under nitro-
gen. The reactions were monitored by thin layer chromatography
(
tlc) with silica gel-coated aluminum plates (Merck 60 F254) and
4
3
a-H, 5-H, and 8a-H on the cyclohexane ring with J =
.0 Hz, resulting in a triplet for the signal of the 4a-H and
visualized with KMnO or cerium molybdate stain (Hanessian’s
4
stain), yields refer to chromatographically purified or distilled com-
pounds. Flash column chromatography (fc) was carried out with
indicating a cis,cis configuration of the vicinal triamine.
This assignment was confirmed by two differential NOE silica gel (400–630 μm mesh) at medium pressure (1.5 bar). Paren-
spectra in which the signals of 4a-H and 8a-H were satu- theses include diameter (d) of the column, stationary phase length
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Eur. J. Org. Chem. 2014, 5749–5756

Stereoselective Synthesis of cis,cis-Configured Vicinal Triamines
(
l), fraction size (V), eluent, and R
f
value. All new compounds gave
was concentrated by distillation. After cooling to ambient tempera-
ture, the mixture was filtered (glass frit, no. 3) and the residue was
1
13
satisfactory spectroscopic analyses (IR, H NMR, C NMR,
HRMS). NMR spectra were recorded with a 400 MHz or a washed with cyclohexene. Excess cyclohexene was removed by dis-
1
6
4
00 MHz spectrometer. H NMR spectra were recorded at
tillation under ambient pressure. Distillation under reduced pres-
sure afforded the desired bromide 9 as a colorless oil, b.p. (7 mbar)
90 °C, yield 12.6 g (70%). Spectroscopic data are identical to the
00 MHz or 600 MHz and are reported in parts per million (δ)
relative to TMS calculated from the residual solvent signals. Data
for H NMR spectra are as follows: chemical shift δ (ppm), multi-
1
[37]
reported data.
plicity (s = singlet, br = broad, d = doublet, t = triplet, q = quartet,
1
-[(1RS)-Cyclohex-2-enyl]-pyrrolidin-2-one (10):[21] NaH (60%-w/w
dd = doublet of doublets, m = multiplet), coupling constant J [Hz],
13
suspension in mineral oil, 6.46 g, 161 mmol, 4.0 equiv.) was sus-
pended in abs. THF (200 mL). Pyrrolidin-2-one (8, 15.5 mL,
and relative integration. C NMR spectra were recorded at
00 MHz or 150 MHz and are reported in parts per million (δ)
1
201 mmol, 5.0 equiv.) was added dropwise and the mixture was
relative to TMS calculated from the residual solvent signal. High-
resolution mass spectra (HRMS) were obtained with a TOF-Q in-
strument. Infrared (IR) spectra were recorded with an FTIR spec-
trometer by the attenuated total reflection (ATR) technique or by
transmission through NaCl plates and are reported as wave num-
stirred for 3 h until no more evolution of gas was observed. It was
then concentrated under reduced pressure and the residue was sus-
pended in dry DMSO (100 mL). 3-Bromocyclohex-1-ene (9, 6.50 g,
4
0.4 mmol, 1.0 equiv.) was added dropwise and the resulting mix-
ture was stirred for 19 h and then diluted with H O (100 mL) and
extracted with ethyl acetate (5ϫ 50 mL). The combined organic
layers were washed with brine, dried (Na SO ), and concentrated
under reduced pressure. The residue was purified by fc [d = 8 cm,
–1
2
bers υ (cm ). Melting points were measured in capillary tubes
sealed on one side and are uncorrected.
2
4
1
-[(4aRS,8SR,8aSR)-4-Benzyl-8-(pyrrolidin-1-yl)perhydroquinox-
alin-1-yl]-2-(3,4-dichlorophenyl)ethan-1-one (7): The amine 20
25 mg, 84 μmol, 1.0 equiv.) was dissolved in CH Cl (2 mL). 3,4-
l
1
=
15 cm,
V
=
100 mL, cyclohexane/ethyl acetate
(
2
2
:0Ǟ7:1Ǟ3:1Ǟ7:3, R
f
= 0.83 (tlc, ethyl acetate/methanol 1:1, de-
Dichlorophenylacetic acid (26 mg, 120 μmol, 1.4 equiv.) was added.
After 1 h, aqueous NaOH (2 m, 7 μL, 0.1 mmol, 1.7 equiv.) was
added. The mixture was stirred for 48 h and washed with a mixture
of aqueous NaOH (2 m, 2 mL) and brine (5 mL). The aqueous
4
tection: KMnO )] to afford the olefin 10 as a colorless oil, yield
1
5.36 g (80%). H NMR (400 MHz, CDCl
3
): δ = 1.48–1.58 (m, 1 H,
6-CH2,cycl), 1.58–1.71 (m, 1 H, 5-CH2,cycl), 1.71–1.84 (m, 2 H, 5-
CH2,cycl, 6-CH2,cycl), 1.88–2.03 (m, 4 H, 4-CH2,cycl, 4-CH2,py), 2.38
t, J = 8.1 Hz, 2 H, 3-CH2,py), 3.31 (t, J = 7.0 Hz, 2 H, 5-CH2,py),
.72 (ddd, J = 11.4, 5.5, 2.7 Hz, 1 H, 1-CHcycl), 5.43–5.35 [dtdd,
2 2
layer was extracted with CH Cl (2ϫ 4 mL). The combined organic
(
layers were dried (Na SO ) and concentrated under reduced pres-
2
4
4
sure. The residue was purified by fc [d = 2 cm, l = 5 cm, V = 20 mL,
cyclohexane/ethyl acetate 1:0Ǟ1:1Ǟethyl acetate/methanol
3
4
3
J(H/H) = 10.2, 2.3, J = 2.3, 2.0, J(H/N) = 1.1 Hz, 1 H, 2-CHcycl],
3
4
4
5
3
4
.88 [dtdd, J = 10.2, 3.4, J(H/H) = 2.4, J(H/N) = 0.9 Hz, 1 H,
1
:0Ǟ19:1Ǟ7:1, R
tion: KMnO )] to afford the acetamide 7 (WMS-36–01) as a brown
oil, yield 26 mg (64%). LC/MS (ESI ): 1.18 min (100%, 486
f
= 0.25 (tlc, ethyl acetate/methanol 1:1, detec-
13
1
-CHcycl] ppm. C{ H} NMR (100 MHz, CDCl
3
): δ = 18.3 (C-
4
py), 21.2 (C-5cycl), 24.6 (C-4cycl), 26.6 (C-6cycl), 31.6 (C-3py), 43.5
+
(
2
(
C-5py), 47.5 (C-1cycl), 127.4 (C-2cycl), 131.5 (C-3cycl), 174.8 (C-
py) ppm. FT-IR (ATR): ν˜ = 2940 (m, C–H), 2862 (m, C–H), 1678
35
+
35 37
{
C
27
+
H34 Cl
2
N
3
O [M + H] }, 488 {C27
H
34 Cl ClN
O [M + H] }). Purity (HPLC): 96.1%, t
): δ = 1.40 (dt, J = 13.4,
3
O [M +
37
+
H] }, 490 [C27
=
H34 Cl
2
N
3
R
–1
s, C=O), 1420 (m, C=C) cm . HRMS (APCI): m/z calcd. for
1
16.39 min. H NMR (600 MHz, CDCl
3
16NO [M + H]+ 166.1232; found 166.1248.
10
C H
5
1
.0 Hz, 1 H, 6-CH2,eq,bicycl), 1.43–1.51 (m, 1 H, 5-CH2,bicycl), 1.61–
.82 (m, 6 H, 6-CH2,ax,bicycl, 7-CH2,bicycl, 3-CH2,py, 4-CH2,py), 1.87
1
-[(1RS,2RS,6SR)-7-Oxabicyclo[4.1.0]heptan-2-yl]pyrrolidin-2-one
(11): The olefin 10 (1.34 g, 8.10 mmol, 1.0 equiv.) was dissolved in
CH Cl (100 mL) and 3-chloroperbenzoic acid (77 %, 2.72 g,
2.1 mmol, 1.5 equiv.) was added. The mixture was stirred for 2 d
and was then washed with a saturated aqueous solution of
NaHSO (10 mL) and a saturated aqueous solution of K CO
(10 mL), dried (Na SO ), and concentrated under reduced pressure.
2
3
(td, J = 11.5, J = 11.5, 3.7 Hz, 1 H, 2-CH2,ax,bicycl), 2.09–2.13 (m,
1
4
2
3
8
2
H, 7-CH
2
), 2.14–2.22 (m, 1 H, 5-CH2,bicycl), 2.43–2.49 (m, 1 H,
2
2
1
a-CHbicycl), 2.62–2.67 (m, 1 H, 2-CH2,eq,bicycl), 2.75–2.88 (m, 2 H,
-CH2,py, 5-CH2,py), 2.94 [d, J = 12.7 Hz, 1 H, (Ar2)-CH
.29 (m, 2 H, 2-CH2,py, 5-CH2,py), 3.34–3.48 (m, 2 H, 3-CH2,bicycl
2
2
], 3.13–
,
3
2
3
2
-CHbicycl), 3.60 (d, J = 15.4 Hz, 1 H, CH
H, CH
2
-C=O), 3.68–3.78 (m,
2
4
The residue was purified by fc [d = 8 cm, l = 12 cm, V = 100 mL,
cyclohexane/ethyl acetate 1:0Ǟ7:1Ǟ13:7Ǟ1:3, R = 0.13 (tlc, cy-
2
-C=O, 3-CH2,bicycl), 4.06–4.10 (m, 1 H, 8a-CHbicycl), 4.09
2
3
4
[d, J = 13.3 Hz, 1 H, (Ar2)-CH
2
], 7.06 (dd, J = 8.2, J = 1.5 Hz,
f
4
clohexane/ethyl acetate 1:1, detection: KMnO )] to afford the epox-
1
H, 6-CHar1), 7.23–7.27 (m, 3 H, 2-CHar1, 3-CHar2, 5-CHar2), 7.29
1
3
4
ide 11 as a colorless oil, yield 1.09 g (74%). H NMR (600 MHz,
CDCl ): δ = 1.33–1.40 (m, 2 H, 3-CH2,bicycl, 4-CH2,bicycl), 1.54 (tdd,
(t, J = 5.0 Hz, 1 H, 4-CHar2), 7.31 (dd, J = 7.2, J = 1.1 Hz, 2 H,
2
-CHar2, 6-CHar2), 7.35 (d, J = 8.2 Hz, 1 H, 5-CHar1) ppm.
3
2
3
13
1
J = 12.9, J = 12.9, 11.0, 2.1 Hz, 1 H, 3-CH2,bicycl), 1.57–1.61 (m,
C{ H} NMR (150 MHz, CDCl
C-4py), 23.9 (C-7bicycl), 25.5 (C-5bicycl), 40.1 (CH
bicycl), 50.8 (C-2bicycl), 52.0 (C-2py, C-5py), 53.6 (C-8abicycl), 58.1
C-8bicycl, (Ar2)-CH ], 59.1 (C-4abicycl), 127.3 (C-4ar2), 128.5 (C-3ar2
C-5ar2), 128.6 (C-6ar1), 129.1 (C-2ar2, C-6ar2), 130.5 (C-5ar1), 131.1
C-2ar1), 131.4 (C-4ar1), 132.5 (C-3ar1), 135.6 (C-1ar1), 138.4 (C-
ar2), 149.6 (C=O) ppm. FT-IR (ATR): ν˜ = 2947 (s, C–H), 2796 (s,
3
): δ = 18.0 (C-6bicycl), 23.6 (C-3py
,
1
1
H, 4-CH2,bicycl), 1.70–1.76 (m, 1 H, 5-CH2,bicycl), 1.90 (dddd, J =
1.7, 6.9, 4.8, 2.1 Hz, 1 H, 5-CH2,bicycl), 1.96–2.07 (m, 2 H, 4-
2
-C=O), 45.2 (C-
3
[
CH2,py), 2.34–2.43 (m, 2 H, 3-CH2,py), 3.09 (dd, J = 1.8, 1.4 Hz, 1
H, 1-CHbicycl), 3.18 (td, J = 4.8, 1.4 Hz, 1 H, 6-CHbicycl), 3.40–3.45
2
,
(
1
m, 1 H, 5-CH2,py), 3.54–3.58 (m, 1 H, 5-CH2,py), 4.46 (ddd, J =
1.0, 6.2, 1.8 Hz, 1 H, 2-CHbicycl) ppm. C{ H} NMR (150 MHz,
(
1
1
3
1
–1
3 py
CDCl ): δ = 18.4 (C-4 ), 21.0 (C-4bicycl), 22.1 (C-3bicycl), 23.0 (C-
5bicycl), 31.3 (C-3 ), 44.6 (C-5 ), 49.0 (C-2bicycl), 52.6 (C-6bicycl),
py py
C–H), 1631 (s, C=O), 732 (C=Car,oop) cm . HRMS (APCI): m/z
calcd. for C27
calcd. for C27
calcd. for C27
3
5
+
H
H
H
34 Cl
2
37
N
3
O [M + H] 486.2079; found 486.2081,
3
5
+
py
54.4 (C-1bicycl), 175.1 (C-2 ) ppm. FT-IR (NaCl): ν˜ = 3472 (br. s,
34 Cl ClN
3
O [M + H] 488.2049; found 488.2081,
O [M + H] 490.2020; found 490.2073.
–
1
3
7
+
O–H), 2934 (s, C–H), 2877 (s, C–H), 1686 (s, C=O) cm . HRMS
34 Cl
2
N
3
+
H15NO
2
Na [M + Na]+ 204.1000; found
(
2
ESI ): m/z calcd. for C10
04.1058.
3
1
9
-Bromocyclohex-1-ene (9):[36] N-Bromosuccinimide (20.0 g,
12 mmol, 1.0 equiv.) was suspended in cyclohexene (90 mL,
64 mmol, 8.6 equiv.) and AIBN (250 mg) was added. The vigor-
tert-Butyl N-(2-Aminoethyl)carbamate (12):[24] A solution of di-tert-
ously stirred suspension was heated to reflux for 2 h. The mixture
butyl dicarbonate (16 mL, 70 mmol, 1.0 equiv.) in CH
2
Cl
2
Eur. J. Org. Chem. 2014, 5749–5756
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
5753

A. Schulte, S. Saito, B. Wünsch
FULL PAPER
+
(
500 mL) was added dropwise at 0 °C over a period of 1 h to a
solution of ethylenediamine (29 mL, 427 mmol, 6.1 equiv.) in
CH Cl (140 mL). The resulting mixture was stirred for 12 h with
slow warming to ambient temperature and concentrated under re-
duced pressure. The residue was dissolved in aqueous NaHCO
17.30 min; 13.7%, t
344 {C1 9
{C20
R
= 17.07 min. LC/MS (ESI ): 0.78 min (100%,
+
H
2 6
N
3
O
3
[M + H – CH
[M + H – CH =C(CH
+ H] }, 466 {C24 NaO [M + Na] }). Three sets of signals
2
=C(CH
3
)
2
CO
H N O [M
34 3 5
2
] }, 388
+
2
2
H
26
N
3
O
5
2
3
)
2
] }, 444 {C24
+
+
H
33
N
3
5
1
1
3
( H NMR intensity ratio A1/A2/B = 6:3:1) are seen in the H NMR
spectrum, originating from two diastereomers (A, B) and rotational
isomers observed for the major diastereomer (A1, A2). Rotational
isomerism of the minor diastereomer is not observed. Rotational
(20% w/w, 150 mL) and extracted with CH
2
Cl
2
(3ϫ 150 mL). The
) and concentrated un-
combined organic layers were dried (Na SO
der reduced pressure to afford the amine 12 as a colorless oil, yield
2
4
1
3
1
1 g (98 %). Spectroscopic data are identical to the reported
isomerism is not seen in the C NMR spectrum due to low signal
[
24]
1
data.
intensity. H NMR (600 MHz, CDCl
C(CH ], 1.44 [s, 0.3ϫ9 H, 0.1ϫ9 H, C(CH
H, 5-CH2,cycl), 1.93–2.20 (m, 5 H, 4-CH2,cycl, 5-CH2,cycl, 4-CH2,py),
.22–2.32 (m, 1 H, 6-CH2,cycl), 2.35–2.55 (m, 3 H, 6-CH2,cycl, 3-
CH2,py), 2.92–3.05 (m, 0.6ϫ1 H, CH -NH), 3.12–3.32 (m, 0.6ϫ1
H, 0.4ϫ3 H, CH -NH, CH -CH -NH), 3.32–3.47 (m, 0.6ϫ1 H, 1
H, CH -CH -NH, 5-CH2,py), 3.47–3.63 (m, 0.6ϫ1 H, 1 H, CH
CH -NH, 5-CH2,py), 3.84–3.95 (m, 0.4 ϫ 1 H, CH -CH -NH),
.95–4.07 (m, 0.6ϫ1 H, 0.1ϫ1 H, 1-CHcycl), 4.30–4.38 (m, 0.3ϫ1
H, 1-CHcycl), 4.42–4.51 (m, 0.3 ϫ1 H, 3-CHcycl), 4.64–4.68 (m,
3
): δ = 1.39 [s, 0.6 ϫ 9 H,
3
)
3
3 3
)
], 1.77–1.89 (m, 1
tert-Butyl N-(2-{N-[(1RS,2RS,3RS)-2-Hydroxy-3-(2-oxopyrrolidin-
-yl)cyclohexyl]benzamido}ethyl)carbamate (14): A solution of the
amine 12 (332 mg, 2.07 mmol, 1.5 equiv.) in H O (5 mL) was added
dropwise to a solution of the epoxide 11 (250 mg, 1.38 mmol,
.0 equiv.) in H O (5 mL). The resulting mixture was stirred at am-
1
2
2
2
2
2
2
1
2
2
2
2
-
bient temperature for 1 d and then concentrated under reduced
pressure. The residue was dissolved in toluene and concentrated
under reduced pressure. This process was repeated. The residue was
2
2
2
3
dissolved in CH
1
2
2
Cl
.2 equiv.) and, after 30 min, aqueous NaOH (1 m, 2.30 mL,
.30 mmol, 1.7 equiv.) were carefully added to the stirred solution.
2
(3 mL). Benzoyl chloride (0.18 mL, 1.6 mmol,
0
0
.1ϫ1 H, 3-CHcycl), 4.69–4.82 (m, 0.6ϫ1 H, 3-CHcycl), 5.19 (br. s,
.3ϫ1 H, NH), 5.30 (br. s, 0.1ϫ1 H, NH), 5.34 (br. s, 0.6ϫ1 H,
1
3
1
NH), 7.32–7.50 (m, 5 H, CHar) ppm. C{ H} NMR (150 MHz,
CDCl ): δ = 18.3 (C-4py, both), 22.5 (C-5cycl, both), 28.1 (C-4cycl
both), 28.6 [C(CH , both], 29.5 (C-6cycl, both), 30.9 (C-3py, both),
9.1 (CH -NH, both), 44.2 (CH -CH -NH, both), 51.0 (C-5py
both), 59.3 (C-3cycl, both), 63.8 (C-1cycl, both), 79.5 [C(CH
both], 126.2 (C-2ar, C-6ar, minor), 126.9 (C-2ar, C-6ar, major), 128.5
C-3ar, C-5ar, minor), 128.7 (C-3ar, C-5ar, major), 129.1 (C-4ar
minor), 129.7 (C-4ar, major), 130.2 (C-1ar, both), 162.8 (O-C=O,
both), 171.8 (Ph-C=O, both), 176.3 (C-2py, both), 200.2 (C-2cycl
Stirring was continued for 18 h. The layers were separated and the
aqueous layer was extracted with CH Cl (3ϫ 5 mL). The com-
bined organic layers were dried (Na SO ) and concentrated under
reduced pressure. The residue was purified by fc [d = 3 cm, l =
0 cm, V = 20 mL, cyclohexane/ethyl acetate 1:0 Ǟ 7:3 Ǟ 0:1 Ǟ
ethyl acetate/methanol 7:1, R = 0.84 (tlc, ethyl acetate/methanol
:1, detection: KMnO )] to afford the alcohol 14 as a colorless
solid, m.p. 63–66 °C, yield 419 mg (68%). LC/MS (ESI ): 1.12 min
3
,
2
2
3 3
)
2
4
3
2
2
2
,
3 3
) ,
1
f
(
,
1
4
+
+
,
(
{
100%, 346 {C19
[M + H – CH
H] }, 468 {C24 NaO
): δ = 1.28–1.36 (m, 1 H, 5-CH2,cycl), 1.44 [s, 9 H, C(CH
H
28
N
3
O
3
[M + H – CH
2
=C(CH
3
)
2
CO
2
] }, 390
[M
[M + Na] }). H NMR (600 MHz,
],
+
both) ppm. FT-IR (ATR): ν˜ = 2970 (s, N–H), 2932 (s, C–H), 2878
C
20
H
28
N
3
O
5
2 3 2 36 3 5
=C(CH ) ] }, 446 {C24H N O
+
+
1
(m, C–H), 1705 (s, 2–C=O), 1674 (s, Car,q–C=O), 1624 (s,
+
CDCl
H
35
N
3
5
–
1
2 34 3 5
CH C=O) cm . HRMS (APCI): m/z calcd. for C24H N O [M +
3
3
)
3
+
H] 444.2498; found 444.2499.
1
1
.58–1.78 (m, 6 H, 4-CH2,cycl, 5-CH2,cycl, 6-CH2,cycl, 4-CH2,py),
.78–1.88 (m, 1 H, 4-CH2,py), 2.30 (t, J = 7.7 Hz, 2 H, 3-CH2,py),
1
2
-[(4aRS,5RS,8aSR)-1-Benzoyldecahydroquinoxalin-5-yl]pyrrolidin-
-one (18A) and 1-[(4aRS,5SR,8aSR)-1-Benzoyldecahydroquinox-
2
3
2
2
.74 (dt, J = 6.3, J = 6.1 Hz, 1 H, 5-CH2,py), 3.19 (dt, J = 6.3,
3
J = 5.1 Hz, 1 H, 5-CH2,py), 3.39–3.48 (m, 3 H, CH
2 2
-CH -NH,
alin-5-yl]pyrrolidin-2-one (18B): The ketone 15 (88 mg, 0.198 mmol,
.0 equiv.) was dissolved in dry CH Cl (4 mL). TFA (1.0 mL) was
CH
2
-NH), 3.51–3.58 (m, 1 H, CH -CH -NH), 3.72 (dt, J = 11.1,
2
2
1
2
2
9.9 Hz, 1 H, 1-CHcycl), 3.75 (dd, J = 9.9, 4.2 Hz, 1 H, 2-CHcycl),
4.52 (td, J = 4.2, 2.1 Hz, 1 H, 3-CHcycl), 5.55 (br. s, 1 H, NH),
7.34–7.37 (m, 3 H, 3-CHar, 4-CHar, 5-CHar), 7.41–7.45 (m, 2 H, 2-
added. The mixture was stirred at ambient temperature for 3 h and
concentrated under reduced pressure. The residue was dissolved in
abs. THF (25 mL) and cooled to 0 °C. Sodium borohydride
CHar, 6-CHar) ppm. No signal for the OH proton is seen in the
(
8.0 mg, 0.21 mmol, 1.05 equiv.) was added. The resulting mixture
1
3
1
spectrum. C{ H} NMR (150 MHz, CDCl
3
): δ = 18.4 (C-4py),
], 29.5 (C-6cycl), 30.5 (C-
-NH), 48.0 (C-5py), 53.1 (C-
cycl), 59.1 (C-1cycl), 73.1 (C-2cycl), 79.3 [C(CH ], 127.3 (C-2ar, C-
ar), 128.2 (C-3ar, C-5ar), 128.9 (C-4ar), 137.7 (C-1ar), 156.7 (O-
was allowed to warm slowly to ambient temperature while being
stirred for 11 h. The mixture was concentrated under reduced pres-
2
3
3
6
1.2 (C-5cycl), 26.6 (C-4cycl), 28.6 [C(CH
py), 39.9 (CH -NH), 41.0 (CH -CH
3 3
)
2
2
2
sure, immobilized on SiO
l = 5 cm, V = 20 mL, cyclohexane/ethyl acetate 1:0Ǟ1:1Ǟ0:1Ǟ
ethyl acetate/methanol 7:1Ǟ7:3, R = 0.28 (tlc, ethyl acetate/meth-
anol 1:1, detection: KMnO )] to afford a mixture of the dia-
stereomers 18A and 18B (dr = 93:7) as a colorless solid, m.p. 65–
2
(200 mg), and purified by fc [d = 2 cm,
3 3
)
f
C=O), 173.7 (Ph-C=O), 178.8 (C-2py) ppm. FT-IR (ATR): ν˜ = 3329
br. s, O–H, N–H), 2974 (s, C–H), 2936 (s, C–H), 2870 (m, C–H),
705 [s, O(C=O)NH], 1655 (s, Ph–C=O), 1620 (s, CH C=O), 702
m, C=Car,oop) cm . HRMS (APCI): m/z calcd. for C19
4
(
1
(
2
1
6
7 °C, yield 31 mg (63%). Two sets of signals ( H NMR intensity
–
1
28 3 3
H N O
ratio = 9:1) are observed, originating from two diastereomers. LC/
+
[M + H -CH
2
=C(CH
3
)
2
CO
2
]
346.2131; found 346.2168.
+
+
MS (ESI ): 0.75 min (B, 7%, 328 {C19
H
26
N
3
O
H
2
[M + H] }, 346
NaO [M +
O] }), 0.86 min (A,
+
tert-Butyl N-(2-{N-[2-Oxo-3-(2-oxopyrrolidin-1-yl)cyclohexyl]benz-
amido}ethyl)carbamate (15): The alcohol 14 (1.80 g, 4.040 mmol,
{C19
H
28
N
3
O
3
[M + H + H
NaO
[M + H] }, 346 {C19
NaO [M + Na + H
2
O] }, 350 {C19
25
+
N
3
2
+
Na] }, 368 {C19
H
27
N
3
3
[M + Na + H
2
+
1
.0 equiv.) was dissolved in dry CH
rochromate adsorbed on neutral alumina (25 %-w/w, 5.57 g, H + H
.46 mmol, 1.6 equiv.) was added and the resulting mixture was (600 MHz, CD
2
Cl
2
(180 mL). Pyridinium chlo-
93 %, 328 {C19
H
26
N
3
O
2
H
28
+
N
3
1
O
3
[M +
+
2
O] }, 368 {C19
H
27
N
3
3
2
O] }). H NMR
OD): δ = 1.51–1.96 (m, 6 H, 6-CH2,bicycl, 7-
6
3
stirred at ambient temperature for 2 d, filtered, and concentrated
under reduced pressure. The residue was purified by fc [d = 5 cm,
l = 10 cm, V = 100 mL, cyclohexane/ethyl acetate 1:0Ǟ0:1Ǟethyl
CH2,bicycl, 8-CH2,bicycl), 2.09–2.19 (m, 2 H, 4-CH2,py), 2.32–2.53 (m,
2 H, 3-CH2,py), 3.13–3.25 [m, 0.9ϫ2 H, 3-CH2,bicycl(A)], 3.34–3.41
[m, 0.9ϫ1 H, 0.1ϫ2 H, 5-CH2,py(A), 5-CH2,py(B)], 3.43–3.56 [m,
0.9 ϫ 1 H, 1 H, 5-CH2,py(A), 2-CH2,bicycl], 3.57–3.66 [m, 1 H,
0.1ϫ1 H, 2-CH2,bicycl, 3-CH2,bicycl(B)], 3.70–3.82 [m, 0.1ϫ2 H, 3-
CH2,bicycl(B), 8a-CHbicycl(B)], 3.92–3.95 [m, 0.9 ϫ 1 H, 4a-
acetate/methanol 19:1, R
f
= 0.16 (tlc, ethyl acetate, detection:
Hanessian’s stain)] to afford the ketone 15 as a colorless solid, m.p.
5
5
0–52 °C, yield 1.15 g (64 %). Purity (HPLC): 80.3 %, t
754
R
=
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5749–5756

Stereoselective Synthesis of cis,cis-Configured Vicinal Triamines
CHbicycl(A)], 4.01–4.07 [m, 0.9ϫ1 H, 8a-CHbicycl(A)], 4.13 [dd, J =
1
CH
CDCl
10), 44.6 (C-2), 46.7 (C-8), 48.8 (C-1), 56.0 (C-3a), 58.0 (Ph-CH
2
), 2.34 (1-CH2,ax), 3.01 (11a-H). 13C{ H} NMR (100 MHz,
): δ = 17.5 (C-4), 21.5 (C-5), 23.1 (C-6), 24.7 (C-9), 28.2 (C-
),
1
0
0
1.2, 3.6 Hz, 0.1ϫ1 H, 4a-CHbicycl(B)], 4.18 [td, J = 11.2, 5.6 Hz,
.1 ϫ 1 H, 5-CHbicycl(B)], 4.66 (br. s, 1 H, NH), 4.90–4.99 [m,
3
2
1
3
1
.9ϫ1 H, 5-CHbicycl(A)], 7.42–7.56 (m, 5 H, CHar) ppm. C{ H} 60.8 (C-6a), 63.2 (C-11a), 86.9 (C-10a), 127.4 (C-4ar), 128.6 (C-2ar
OD): δ = 18.5 (C-4py, minor, B), 18.8 (C-4py C-3ar, C-5ar, C-6ar), 130.5 (C-1ar) ppm. FT-IR (ATR): ν˜ = 2940 (s,
major, A), 23.2 (C-7bicycl, minor, B), 23.3 (C-7bicycl, major, A), 23.4
,
NMR (150 MHz, CD
3
,
C–H), 740 (C=Car,oop). HRMS (APCI): m/z calcd. for C19
H
28
N
3
(
(
C-8bicycl, both), 23.6 (C-6bicycl, both), 32.0 (C-3py, minor, B), 32.1
C-3py, major, A), 40.9 (C-3bicycl, major, A), 41.4 (C-3bicycl, minor,
[M + H]+ 298.2283; found 298.2271.
B), 45.2 (C-5py, minor, B), 45.3 (C-5py, major, A), 48.2 (C-2bicycl
both), 49.0 (C-5bicycl, major, A), 53.1 (C-5bicycl, minor, B), 54.5 (C-
bicycl, minor, B), 54.9 (C-8abicycl, major, A), 57.5 (C-4abicycl
minor, B), 57.7 (C-4abicycl, major, A), 128.0 (C-2ar, C-6ar, major, A),
,
(4aRS,5RS,8aSR)-1-Benzyl-5-(pyrrolidin-1-yl)decahydroquinoxaline
(20): The aminal 19 (100 mg, 0.336 mmol, 1.0 equiv.) was dissolved
8
a
,
in CH
2
Cl
2
(5 mL) and DMSO (2.5 mL). At 0 °C, TFA (26 μL,
(15 mg, 0.40 mmol, 1.2 equiv.)
0.34 mmol, 1.0 equiv.) and NaBH
4
1
4
28.2 (C-2ar, C-6ar, minor, B), 129.9 (C-3ar, C-5ar, both), 131.6 (C-
ar, major, A), 131.8 (C-4ar, minor, B), 135.8 (C-1ar, both), 163.0
were added. The mixture was stirred for 12 h while being allowed
to warm slowly to ambient temperature. It was washed with a mix-
ture of aqueous NaOH (2 m, 2 mL) and brine (4 mL) and extracted
(
Ph-C=O, minor, B), 163.2 (Ph-C=O, major, A), 179.4 (C-2py,
both) ppm. FT-IR (ATR): ν˜ = 2959 (s, N–H), 2800 (s, C–H), 1627 twice with a mixture of aqueous HCl (2 m, 1.5 mL) and brine
–
1
(
br. s, C=O), 729 (s, C=Car,oop) cm . HRMS (APCI): m/z calcd. (2 mL). The combined acidic aqueous layers were adjusted to
+
for C19
H
26
N
3
O
2
[M + H] 328.2025; found 328.2036.
pH Ͼ 12 with aqueous NaOH (2 m, 3.5 mL) and extracted with
CH Cl (4ϫ 10 mL). The combined organic layers were dried
3aRS,6aSR,10aSR,11aRS)-3-Benzylperhydropyrrolo[1Ј,2Ј:1,2]imid- (Na SO ) and concentrated under reduced pressure. The residue
2
2
(
2
4
azo[3,4,5-de]quinoxaline (19): The ketone 15 (1.05 g, 2.37 mmol,
.0 equiv.) was dissolved in dry CH Cl (41 mL). TFA (10.2 mL)
and molecular sieves (4 Å, 200 mg) were added. The mixture was
stirred at ambient temperature for 3 h, decanted, and concentrated
under reduced pressure. The residue was dissolved in abs. THF
was purified by fc [d = 2 cm, l = 3 cm, V = 20 mL, cyclohexane/
ethyl acetate 1:0Ǟ7:1Ǟethyl acetate/methanol
1:0Ǟ7:1Ǟ7:3Ǟ1:1, R = 0.00 (tlc, methanol, detection: KMnO )]
1
2
2
f
4
to afford the decahydroquinoxaline 20 as a colorless oil, yield
+
28 mg (28%). LC/MS (ESI ): 0.60 min (100%, 300 {C H N [M
1
9
1
30
3
+
(
60 mL) and cooled to 0 °C. NaBH
4
(131 mg, 3.46 mmol,
R
+ H] }). Purity (HPLC): 74.5%, t = 5.14 min. H NMR
(400 MHz, CDCl ): δ = = 1.09 (qt, J = 13.3, J = 13.3, 4.0 Hz, 1
3
H, 7-CH2,ax,bicycl), 1.49 (ddd, J = 12.4, J = 7.6, 4.0 Hz, 1 H, 6-
CH2,eq,bicycl), 1.59–1.69 (m, 2 H, 8-CH2,bicycl), 1.75–1.86 (m, 5 H,
7-CH2,eq,bicycl, 3-CH2,py, 4-CH2,py), 1.98 (dtd, J = 13.3, J = 12.4,
2
3
1.46 equiv.) was added. The resulting mixture was allowed to warm
2
3
slowly to ambient temperature while being stirred for 11 h. Lithium
aluminum hydride (677 mg, 17.8 mmol, 7.5 equiv.) was added, and
the resulting mixture was heated under reflux for 24 h. After the
3
2
3
system had cooled to ambient temperature, H
fully added. The mixture was filtered and concentrated under re-
duced pressure. The residue was suspended in CH Cl (20 mL), fil-
2
O (20 mL) was care-
J = 12.4, 3.9 Hz, 1 H, 6-CH2
(m, 1 H, 8a-CHbicycl), 2.43 (ddd, J = 11.3, J = 3.2, 1.8 Hz, 1 H,
), 2.04 (s, 1 H, NH), 2.06–2.12
,ax,bicycl
2
3
2
2
3-CH2,eq,bicycl), 2.57–2.69 (m,
6
H, 2-CH
2,py
, 5-CH2,py, 3-
2
3
tered, and concentrated under reduced pressure to give a crude
mixture of the triamine 20 and the aminal 19 (yield 294 mg, 42%).
CH2,ax,bicycl, 5-CHbicycl), 2.83 (td, J = 11.3, J = 11.3, 3.4 Hz, 1
2
3
H, 2-CH2,ax,bicycl), 3.00 (ddd, J = 11.3, J = 3.1, 1.8 Hz, 1 H, 2-
2
3
1
3
,4-Dichlorophenylacetyl chloride (21, 689 mg, 3.08 mmol,
.3 equiv.) was added. After 1 h, aqueous NaOH (1 m, 3.56 mL,
.56 mmol, 1.5 equiv.) was added and the resulting mixture was
CH2,eq,bicycl), 3.17 (t, J = 3.0 Hz, 1 H, 4a-CHbicycl), 3.56 (d, J =
13.5 Hz, 1 H, Ph-CH ), 3.70 (d, J = 13.5 Hz, 1 H, Ph-CH ), 7.21
2
2
3
4
(tt, J = 7.1, J = 1.5 Hz, 1 H, 4-CH ), 7.36–7.27 (m, 4 H, 2-CH ,
ar
ar
stirred at ambient temperature for 14 h. The layers were separated
and the aqueous layer was diluted with brine (5 mL) and extracted
ar ar ar 3
3-CH , 5-CH , 6-CH ) ppm. NOE (400 MHz, CDCl ): irradia-
tion at δ = 2.04–2.14 (8a-CHbicycl) ppm, increase in signal intensity
at δ = 1.59–1.69 (8-CH2,bicycl), 2.57–2.69 (3-CH2,ax,bicycl, 5-CHbicycl),
3.17 (4a-CHbicycl); irradiation at δ = 3.15–3.20 (4a-CHbicycl), in-
crease in signal intensity at δ = 2.06–2.12 (8a-CHbicycl), 2.57–2.69
with CH
with a mixture of aqueous NaOH (1 m, 5 mL) and brine (5 mL),
dried (Na SO ) and concentrated under reduced pressure. The resi-
2 2
Cl (10 mL). The combined organic layers were washed
2
4
1
3
1
due was purified by fc [d = 3 cm, l = 10 cm, V = 20 mL, cyclohex-
ane/ethyl acetate 1:0 Ǟ 1:1 Ǟ 0:1 Ǟ ethyl acetate/methanol
(2-CH2,py, 5-CH2,py, 5-CHbicycl), 2.83 (2-CH2,ax,bicycl). C{ H}
NMR (100 MHz, CDCl ): δ = 16.4 (C-6bicycl), 23.1 (C-7bicycl), 23.3
3
1
9:1Ǟ7:1Ǟ7:3, R
f
(19) = 0.01 (tlc, ethyl acetate/methanol 1:1, de-
(C-3 , C-4 ), 26.1 (C-8bicycl), 46.6 (C-3bicycl), 46.7 (C-2bicycl), 51.9
py
py
tection: KMnO
4
)] to afford the acetamide 7, yield 48 mg (4%), and (C-2 , C-5 ), 57.8 (C-4a), 59.0 (Ph-CH ), 59.3 (C-5), 67.0 (C-8a),
py py 2
the triamine 19, yield 172 mg (24%) as a colorless solid; m.p. could
ar ar ar ar ar
126.9 (C-4 ), 128.3 (C-3 , C-5 ), 128.9 (C-2 , C-6 ), 139.5 (1-
not be determined due to decomposition before melting. LC/MS
C ) ppm. FT-IR (ATR): ν = 2940 (s, N–H), 2799 (s, C–H), 729
ar
˜
+
+
1
–1
(
(
ESI ): 0.75 min (100%, 298 {C19
400 MHz, CDCl ): δ = 1.09 (ddt, J = 18.4, 13.7, 3.1 Hz, 1 H, 5-
), 1.54–1.68 (m, 2 H, 4-CH ),
), 1.86–1.93 (m, 1 H, 5-CH2,eq), 1.94–2.01 2-(3,4-Dichlorophenyl)acetyl Chloride (21):[34] 2-(3,4-Dichloro-
H
28
N
3
[M + H] }). H NMR
(C=C
ar,oop 19 30 3
) cm . HRMS (APCI): m/z calcd. for C H N [M +
H] 300.2440; found 300.2456.
+
3
CH2,ax), 1.41–1.53 (m, 1 H, 6-CH
.72–1.80 (m, 1 H, 6-CH
m, 3 H, 9-CH , 10-CH
J = 10.3, J = 11.1, 3.2 Hz, 1 H, 1-CH2,ax), 2.57 (ddd, J = 11.8,
J = 3.2, 2.5 Hz, 1 H, 2-CH2,eq), 2.71 (ddd, J = 11.8, J = 11.1,
.5 Hz, 1 H, 2-CH2,ax), 2.80 (dt, J = 10.3, J = 2.5 Hz, 1 H, 1-
2
2
1
2
(
2
2
), 2.01–2.10 (m, 1 H, 9-CH
2
), 2.34 (ddd,
phenyl)acetic acid (10.3 g, 50.0 mmol, 1.0 equiv.) was suspended in
2
3
2
abs. Et O (100 mL). At 0 °C, oxalyl chloride (5.1 mL, 60 mmol,
2
3
2
3
1.2 equiv.) and DMF (0.5 mL) were carefully added. The resulting
mixture was stirred for 14 h. It was then concentrated under re-
2
3
2
CH2,eq), 2.95 (dt, J = 11.2, 5.1 Hz, 1 H, 3a-CH), 3.01 (t, J = 5.1 Hz, duced pressure. The acid chloride 21 was isolated by distillation
2
1
H, 11a-CH), 3.17–3.34 (m, 2 H, 8-CH
2
), 3.64 (d, J = 13.6 Hz, 1
), 3.74 (d, J = 13.6 Hz, 1 H, Ph-CH ), 3.89–3.98 (m, 1 yield 9.22 g (83%). Spectroscopic data are identical to the reported
H, 6a-CH), 4.25 (dd, J = 5.0, 3.5 Hz, 1 H, 10a-CH), 7.29–7.32 data.[
m, 4 H, 2-CHar, 3-CHar, 5-CHar, 6-CHar), 7.37–7.45 (m, 1 H, 4-
CHar) ppm. NOE (400 MHz, CDCl ): irradiation at δ = 4.22–4.28
10a-CH) ppm, increase in signal intensity at δ = 1.94–2.01 (10-
under reduced pressure as a pale yellow oil, b.p.0.012 mbar = 98 °C,
2
H, Ph-CH
2
2
34]
(
3
Supporting Information (see footnote on the first page of this arti-
cle): Methods and results of theoretical calculations, chromatog-
(
Eur. J. Org. Chem. 2014, 5749–5756
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5755

A. Schulte, S. Saito, B. Wünsch
FULL PAPER
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Published Online: August 1, 2014
5756
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5749–5756