Enantioselective syntheses of the alkaloids cis -195A (pumiliotoxin C) and trans -195A based on multiple applications of asymmetric catalysis

Article abstract of DOI:10.1021/jo202241b

Short enantio- and diastereoselective syntheses of the decahydroquinoline alkaloids cis- (pumiliotoxin C) and trans-195A are presented. Key steps are an enantioselective iridium-catalyzed allylic amination, a Suzuki-Miyaura coupling, a catalyst-controlled

Full text of DOI:10.1021/jo202241b

Note
pubs.acs.org/joc
Enantioselective Syntheses of the Alkaloids cis-195A (Pumiliotoxin C)
and trans-195A Based on Multiple Applications of Asymmetric
Catalysis
Martin Gartner, Jianping Qu, and Gunter Helmchen*
̈
̈
Organisch-Chemisches Institut der Ruprecht-Karls-Universitat Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg,
̈
Germany
S
* Supporting Information
ABSTRACT: Short enantio- and diastereoselective syntheses of the decahydroquinoline
alkaloids cis- (pumiliotoxin C) and trans-195A are presented. Key steps are an
enantioselective iridium-catalyzed allylic amination, a Suzuki−Miyaura coupling, a
catalyst-controlled copper-catalyzed 1,4-addition, and a reductive amination.
Scheme 1. Retrosynthetic Analysis for cis-195A
ecahydroquinolines are found in skin secretions of
dendrobatid poison-dart frogs and in other amphibian
D
skins.1 These relatively nontoxic alkaloids have been found to
interact with ion channels2 and are noncompetitive blockers of
nicotinic acetylcholine receptors.3 Because of their interesting
biological activity and poor availability, stereoselective
syntheses of decahydroquinoline alkaloids have attracted
considerable attention. Since the isolation of the most
prominent representative cis-195A (formerly designated
pumiliotoxin C, Figure 1) from skin secretions of Dendrobates
developments in the field would allow chiral catalyst-controlled
installation of a methyl group at C3, although 2-substituted
enones have rarely been used as substrates. The configuration
at the center C2 α to the carbonyl group was expected to be
regulated by thermodynamic control. Finally, the reductive
amination was expected to be mainly controlled by the center
C2.8b
Figure 1. Structures of (+)-cis-195A·HCl (1·HCl) (pumiliotoxin C
hydrochloride)10 and (−)-trans-195A·HCl (2·HCl).
pumilio in 19694 and the determination of the absolute
configuration in 1977,5 about 50 alkaloids of this structural
class have been identified.1 The diastereomer trans-195A
(Figure 1) was isolated in trace amounts from Epipedobates
bassleri in 1999,6 and the absolute configuration was
determined by Blechert et al. in 2005 via an enantioselective
synthesis.7 While many stereoselective syntheses of cis-195A
have been reported,8 routes based on asymmetric catalysis are
rare.9 In view of this observation, we are pleased to present the
shortest (5 steps) synthesis so far, making use of two chiral
catalyst-controlled steps.
Our strategy is described as retrosynthesis in Scheme 1. An
enantioselective Ir-catalyzed allylic substitution was expected to
yield the allylic carbamate with at least 95% ee. For the control
of the configuration of the stereogenic centers C4a and C5 of
the target, Cu-catalyzed conjugate addition at C3 of the
cyclohexenone was planned. It was hoped that recent
The Ir-catalyzed allylic substitution is a reliable method for
the synthesis of chiral allylamines starting from easily available
monosubstituted allyl carbonates. A variety of C-, N-, O-, and
S-nucleophiles can be applied with high degrees of regio- and
enantioselectivity.11 The reaction is particularly well suited for
cyclizations.12
The allylic amination of carbonate 3 with NH(CHO)Cbz13
as pronucleophile was carried out under salt-free conditions14
(Scheme 2, Table 1). Chiral cyclometalated Ir-catalysts15 were
generated in situ from [Ir(cod)Cl]2 (cod = 1,5-cyclooctadiene),
a phosphoramidite ligand,16 and TBD (TBD = 1,5,7-
triazabicyclo[4.4.0]dec-5-ene) as base. The reaction proceeded
Received: November 8, 2011
Published: December 16, 2011
© 2011 American Chemical Society
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Note
Scheme 2. Iridium-Catalyzed Allylic Amination
Scheme 3. Suzuki−Miyaura Coupling, Cu-Catalyzed 1,4-
Addition, and Reductive Amination
Table 1. Results According to Scheme 2
a
c
d
catalyst
time
(h)
yield
(%)
ee
b
entry
1
L*
(mol %)
4/5
(%)
e
(R,R,aR)-
L1
4
1
87:13
91
94
as anticipated (see above). The mixture was subjected to
reductive amination to give the target compounds 1 (formed
from 8a) and 2 (formed from 8b), which were separable by
chiral GC as well as preparative chromatography; at this stage
the ee could also be determined. 1 and 2 were obtained in 77%
yield in a 2:1 ratio (Table 2, entry 1). Low selectivity was
2
3
(S,S,aS)-L2
(S,S,aS)-L3
4
4
1
0.5
1
92:8
90:10
92:8
83
96
85
97
96
f
e
4
(R,R,aR)-
L2
1.5
96
f
5
(S,S,aS)-L3
1
3
89:11
95
94
a
4 mol % of catalyst was prepared from [Ir(cod)Cl]2 (2 mol %), L* (4
b
mol %), and TBD (8 mol %). Determined by 1H NMR of the crude
c
d
Table 2. Results from Reactions According to Scheme 3
product. Combined yield of regioisomers 4 and 5. Determined by
HPLC. The enantiomer ent-4 was obtained. The reaction was carried
out at 50 °C.
e
f
c
yield of yield (%),
ee 1/2
(%)
a
b
entry
1
conditions
8
(%) ratio 1/2
(1) CuCN, MeMgBr, Et2O, −30
°C, (2) aq NH3
75
77, 2:1
97/96
with high regio- and enantioselectivity, allowing a reduction of
catalyst loading to 1 mol % (Table 1, entries 4 and 5) without
significant loss of enantiomeric excess. Typically, highest
selectivities were obtained with Alexakis’ ligand L2.
d
2
(1) CuTC, (R,R,aS)-L1, AlMe3,
85
80, 5:1
>99/80
Et2O, −30 °C, (2) CH3OH/
NH4Cl
e
d
3
(1) CuTC, (R,R,aS)-L1, AlMe3,
72
49
65
83, <1:99
92, 2:1
−/99
98/88
89/98
Et2O, −30 °C, (2) CH3OH/
Substitution product 4 was obtained in 85% yield after
chromatographic purification. The formyl group was cleaved
with KOH to give carbamate 6 in excellent yield (Scheme 2).17
Hydroboration of 6 was carried out with an excess of 9-BBN at
50 °C in order to ensure complete conversion.13 Subsequent
Suzuki−Miyaura coupling18 with 2-iodocyclohex-2-en-1-one19
was carried out with Pd(dppf)Cl2/Ph3As20 (dppf = 1,1′-
bis(diphenylphosphino)ferrocene) as catalyst and Cs2CO3 as
base (Scheme 3). Removal of 9-BBN-derived impurities
required careful chromatographic purification of enone 7.
The Cu-catalyzed conjugate addition of a methylmetal
compound to enone 7 (Scheme 3) generates two new chirality
centers, and therefore, four diastereoisomeric products are
possible. However, the addition to the enone initially yields an
enolate with one new chirality center; the subsequent
protonation under thermodynamically controlled conditions is
expected to favor the trans- over the cis-disubstituted
cyclohexanone.21 Thus, mainly the diastereomers 8a and 8b
are expected as products.
First, substrate control of the reaction was examined.
Addition of an achiral cuprate to enone 7 followed by
protonation with NH4Cl yielded a mixture of trans-cyclo-
hexanones 8a and 8b, which could not be separated. 2,3-cis-
Isomers of these compounds could not be isolated; NMR
spectra of the trans-isomers contained signals of maximally 10%
impurities, which might have been due to cis-isomers. We
assume that the protonation of intermediary enolates is
thermodynamically controlled under the workup conditions
NH4Cl
d
4
5
(1) CuTC, (R,R)-L4, AlMe3,
Et2O, −30 °C, (2) CH3OH/
NH4Cl
d
(1) CuTC, (S,S)-L4, AlMe3,
82, 1:8
Et2O, −30 °C, (2) CH3OH/
NH4Cl
a
b
Combined yield of 8a and 8b. Combined yield of 1 and 2; the ratio
c
d
1/2 was determined by GC−MS. Determined by chiral GC. TC =
thiophene-2-carboxylate. The enantiomer ent-7 was used; thus, ent-8b
e
and ent-2 were obtained.
expected here, as the chirality center in 7 is far away from the
enone moiety. Optical rotations of the products were
measured; 1: [α]20 −2.2 (c 1.34, MeOH), 1·HCl: [α]20
D
D
+12.9 (c 0.36, MeOH), 2: [α]20 −31.6 (c 0.91, MeOH),
D
2·HCl: [α]20 −26.0 (c 0.61, MeOH). Within the range of
D
precision, these values agree with those reported.7b,8b The
relative configuration of 1 was confirmed by comparison of 13C
NMR data with those reported by Daly et al.22 The 13C NMR
data of 2·HCl matched those reported by Habermehl et al.8b
Next, chiral copper catalysts were probed. Trimethylalumi-
num was used as metal organyl under conditions developed by
Alexakis.23 The addition promoted by L1 proceeded smoothly
to give a 5:1 mixture of 8a and 8b in 85% yield (Table 2, entry
2). 2,3-cis-Isomers of 8a and 8b might have been formed as side
products but could not be isolated. The alkaloids 1 and 2 were
prepared by reductive amination;24 separation by column
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Note
removed in vacuo, and the residue was purified by flash
chromatography gave 1 in 67% and 2 in 13% yield. Because of
double asymmetric induction, the enantiomeric excess of 1 was
increased to >99% ee.
chromatography (PE/EtOAc 10:1) to yield 6 (900 mg, 98%) as
colorless needles (mp 61−62 °C (EtOAc/PE)): [α]20 +8.7 (c 0.63,
D
CHCl3), lit.17c for ent-6 [α]26 −10.1 (c 0.79, CHCl3); 1H NMR
D
For the synthesis of ent-2, the substrate ent-7 was prepared
from ent-4 in the way described above, and the addition and
subsequent reductive amination were run as with 7.
Remarkably, only the product ent-2 was obtained in 72%
yield. Thus, a ratio ent-8a/ent-8b of 1:99 was achieved in the
conjugate addition step (Table 2, entry 3). In the reductive
amination, the center C2 of the hydroquinoline intermediate
constitutes the control element for the configuration at C8a.
Phosphoramidite ligands have been found to react with
AlMe3 to form aminophosphine ligands, which are the active
species in the cuprate addition reaction.25 In order to avoid this
complication, the cuprate addition reaction was also carried out
with simplephos ligands L4 (Table 2, entries 4 and 5).26 With
respect to reactivity and diastereoselectivity, the results with
these were inferior to those obtained with the phosphoramidite
ligand L1.
In conclusion, we have developed a 5-step enantioselective
route yielding the decahydroquinoline alkaloids cis- (pum-
iliotoxin C) and trans-195A, each in total yields of 28%.27 Every
bond-forming step is controlled by catalysis. The route
comprises an asymmetric Ir-catalyzed allylic amination, a Pd-
catalyzed Suzuki−Miyaura coupling, a Cu-catalyzed conjugate
addition, and a Pd-catalyzed reductive amination. Because of
double asymmetric induction, enantiomeric excesses of the final
products were very high (≥99%).
(CDCl3, 300 MHz) δ 0.92 (3 H, t, J = 7.2 Hz), 1.29−1.55 (4 H, m),
4.11−4.24 (1 H, m), 4.55−4.75 (1 H, br s), 5.06−5.12 (3 H, m), 5.16
(1 H, d, J = 17.3 Hz), 5.75 (1 H, ddd, J = 16.9, 10.4, 5.8 Hz), 7.29−
7.40 (5 H, m); 13C NMR (CDCl3, 75 MHz) δ 14.0 (CH3), 19.0
(CH2), 37.4 (CH2), 53.3 (CH), 66.8 (CH2), 114.7 (CH2), 128.2
(CH), 128.7 (CH), 136.7 (Cq), 138.9 (CH), 156.0 (Cq); HR-MS (ESI
+) calcd for C14H19NNaO2 [M + Na]+ 256.13080, found 256.13094.
Benzyl {(1R)-1-[2-(6-Oxocyclohex-1-en-1-yl)ethyl]butyl}-
carbamate (7). 2-Iodocyclohex-2-en-1-one was prepared according
to ref 19 and purified by column chromatography immediately before
use. Under an atmosphere of argon, a solution of 6 (450 mg, 1.92
mmol) and 9-BBN (470 mg, 3.85 mmol) in dry THF (4 mL) was
heated at 50 °C. Complete conversion was reached after 3.5 h [TLC:
Rf(6) = 0.44, Rf(7) = 0.25, PE/EtOAc 3:1]. After cooling to rt, the
solution was added to a suspension of Pd(dppf)Cl2 (70 mg, 96 μmol),
Ph3As (59 mg, 0.19 mmol), Cs2CO3 (1.16 g, 3.56 mmol), 2-
iodocyclohex-2-en-1-one (472 mg, 2.11 mmol), and degassed DMF/
H2O 15:1 (6 mL). The suspension was stirred at rt for 16 h. Then,
water (5 mL) was added, and the solution was extracted with Et2O (3
× 50 mL). The combined organic layers were dried over MgSO4 and
concentrated in vacuo. Purification by flash chromatography (PE/Et2O
3:1) yielded 7 (370 mg, 58%) as pale orange amorphous solid: [α]20
D
+1.3 (c 1.04, MeOH); 1H NMR (CDCl3, 300 MHz) δ 0.89 (3 H, t, J =
6.8 Hz), 1.25−1.52 (5 H, m), 1.53−1.66 (1 H, m), 1.88−2.00 (2 H,
m), 2.06−2.19 (1 H, m), 2.20−2.35 (3 H, m), 2.36−2.43 (2 H, m),
3.48−3.68 (1 H, m), 4.66 (1 H, d, J = 8.9 Hz), 5.03−5.17 (2 H, m),
6.72 (1 H, t, J = 3.5 Hz), 7.26−7.38 (5 H, m); 13C NMR (CDCl3, 75
MHz) δ 14.1 (CH3), 19.1 (CH2), 23.2 (CH2), 26.1 (CH2), 26.5
(CH2), 34.1 (CH2), 37.7 (CH2), 38.6 (CH2), 50.9 (CH), 66.5 (CH2),
128.1 (CH), 128.6 (CH), 136.9 (Cq), 139.2 (Cq), 146.0 (CH), 156.2
(Cq), 199.6 (Cq); HR-MS (ESI+) calcd for C20H28NO3 [M + H]+
330.20637, found 330.20661.
EXPERIMENTAL SECTION
■
Benzyl Formyl[(1R)-propylprop-2-en-1-yl]carbamate (4) and
Benzyl Formyl[(2E)-hex-2-en-1-yl]carbamate (5). Success with
the following procedure requires dry TBD (dried in a desiccator over
KOH). Under an atmosphere of argon, a solution of [Ir(cod)Cl]2
(14.0 mg, 20.8 μmol), dry TBD (11.5 mg, 82.6 μmol), and (S,S,aS)-L3
(22.8 mg, 40.1 μmol) in dry THF (1.5 mL) was stirred at rt for 20
min. Carbonate 3 (158 mg, 999 μmol) and (HCO)NH(Cbz)13 (206.3
mg, 1.151 mmol) were added, and the solution was stirred at rt.
Complete conversion was reached after 1 h [TLC: Rf(3) = 0.57, Rf(4)
= 0.52, Rf(5) = 0.40, PE/EtOAc 10:1]. The solvent was removed in
Benzyl ((1R)-1-{2-[(1″R,2″S)-2-Methyl-6-oxocyclohexyl]-
ethyl}butyl)carbamate (8a) and Benzyl ((1R)-1-{2-[(1″S, 2″R)-
2-Methyl-6-oxocyclohexyl]ethyl}butyl)carbamate (8b). Sub-
strate-Controlled 1,4-Addition According to Table 2, Entry 1.
Under an atmosphere of argon, methylmagnesium bromide (3 M in
Et2O, 0.63 mL, 1.9 mmol) was added dropwise to a suspension of
CuCN (70 mg, 0.78 mmol) in dry Et2O (10 mL) at −40 °C. The
suspension was allowed to warm to −20 °C and stirred for 3.5 h. It
was then cooled to −30 °C, and a solution of 7 (129 mg, 392 μmol) in
dry Et2O (5 mL) was added dropwise. Complete conversion was
reached after 20 h at −30 °C [TLC: Rf(7) = 0.25, Rf(8) = 0.36, PE/
EtOAc 3:1]. Saturated aqueous NH3 (5 mL) and aqueous NH4Cl (5
mL) were added, and the solution was extracted with Et2O (3 × 20
mL). The combined organic layers were dried over MgSO4 and
concentrated in vacuo. Purification by flash chromatography on silica
(PE/EtOAc 5:1) yielded a mixture of 8a and 8b (102 mg, 75%) as
colorless needles; separation by chromatography was not accom-
plished. The ratio 8a/8b 2:1 is deduced from the ratio of 1 and 2
(GC−MS) obtained after reductive amination.
1
vacuo, and the ratio 4/5 = 90:10 was determined by H NMR of the
crude product. Flash chromatography (PE/EtOAc 20:1) yielded pure
4 (223 mg, 85%) and 5 (27 mg, 10%) as colorless oils.
4: [α]20 +6.8 (c 0.73, in CHCl3); HPLC (Chiralpak AD-H, n-
D
hexane/iPrOH 99.5:0.5, flow 0.5 mL min−1, λ 210 nm) tR((−)-(S)-4)
22.0 min, tR((+)-(R)-4) 22.7 min; 1H NMR (CDCl3, 300 MHz) δ 0.87
(3 H, t, J = 7.3 Hz), 1.13−1.33 (2 H, m), 1.68−1.94 (2 H, m), 4.94 (1
H, td, J = 7.3, 7.7 Hz), 5.08−5.20 (2 H, m), 5.25 (1 H, d, J = 12.2 Hz),
5.30 (1 H, d, J = 12.2 Hz), 6.06 (1 H, ddd, J = 7.2, 10.2, 17.3 Hz),
7.30−7.42 (5 H, m), 9.26 (1 H, s); 13C NMR (CDCl3, 75 MHz) δ
13.7 (CH3), 19.5 (CH2), 33.8 (CH2), 54.9 (CH), 68.7 (CH2), 117.4
(CH2), 128.4 (CH), 128.73 (CH), 128.79 (CH), 134.7 (Cq), 136.5
(CH), 153.8 (Cq), 162.9 (CH); HR-MS (FAB+) calcd for C15H19NO3
[M]+ 261.1365, found 261.1362.
Mixture of 8a and 8b: 1H NMR (CDCl3, 300 MHz) δ 0.90 (3 H, t, J
= 5.9 Hz), 1.02 (3 H, d, J = 6.4 Hz), 1.16−1.72 (11 H, m), 1.77−1.90
(1 H, m), 1.92−2.06 (2 H, m), 2.17−2.40 (2 H, m), 3.50−3.66 (1 H,
m), 4.61−4.86 (1 H, m), 5.03−5.19 (2 H, m), 7.24−7.42 (5 H, m);
13C NMR (CDCl3, 75 MHz) δ 14.1 (CH3), 19.00 (CH2), 19.08
(CH2), 20.6 (CH3), 22.9 (CH2), 25.7 (CH2), 25.9 (CH2), 32.4 (CH2),
32.8 (CH2), 33.5 (CH2), 33.6 (CH2), 37.7 (CH2), 38.0 (CH2), 38.2
(CH), 38.8 (CH), 41.7 (CH2), 41.9 (CH2), 51.3 (CH), 51.7 (CH),
56.9 (CH), 57.1 (CH), 66.4 (CH2), 128.00 (CH), 128.02 (CH), 128.5
(CH), 136.9 (Cq), 156.3 (Cq), 213.1 (Cq), 213.2 (Cq); HR-MS (ESI+)
calcd for C21H31KNO3 [M + K]+ 384.19355, found 384.19392.
Reagent-Controlled 1,4-Addition According to Table 2, Entry 2.
Under an atmosphere of argon, a solution of CuTC (1.3 mg, 6.8
μmol) and (R,R,aS)-L1 (6.7 mg, 12 μmol) in dry Et2O (1 mL) was
stirred for 30 min at rt. The solution was cooled to −30 °C, and AlMe3
5: 1H NMR (CDCl3, 300 MHz) δ 0.85 (3 H, t, J = 7.4 Hz), 1.34 (2
H, qt, J = 6.8, 7.4 Hz), 1.95 (2 H, td, J = 6.8, 6.6 Hz), 4.18 (2 H, dd, J
= 6.2, 0.9 Hz), 5.29 (2 H, s), 5.39 (1 H, dtt, J = 15.3, 6.3, 1.3 Hz), 5.63
(1 H, dtt, J = 14.8, 6.9, 1.1 Hz), 7.34−7.40 (5 H, m), 9.23 (1 H, s); 13C
NMR (CDCl3, 75 MHz) δ 13.7 (CH3), 22.1 (CH2), 34.2 (CH2), 42.5
(CH2), 68.8 (CH2), 123.5 (CH), 128.5 (CH), 128.83 (CH), 128.89
(CH), 134.8 (Cq), 135.2 (CH), 154.0 (Cq), 162.5 (CH); HR-MS
(FAB+) calcd for C15H20NO3 [M + H]+ 262.1443, found 262.1431.
Benzyl [(1R)-1-Propylprop-2-en-1-yl]carbamate (6). KOH (46
mg, 0.82 mmol) was added to a solution of 4 (1.025 g, 3.922 mmol) in
methanol (25 mL) at rt. Complete conversion was reached after 13 h
[TLC: Rf(4) = 0.52, Rf(6) = 0.34, PE/EtOAc 10:1]. The solvent was
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Note
(2 M in hexane, 0.31 mL, 0.62 mmol) and 7 (102.9 mg, 312.3 μmol)
were added successively. Complete conversion was reached after 19 h
at −30 °C. MeOH (0.1 mL) and aqueous NH4Cl (3 mL) were added,
and the solution was allowed to warm to rt. The aqueous layer was
separated and extracted with Et2O (2 × 20 mL). The combined
organic layers were dried over MgSO4 and concentrated in vacuo.
Flash chromatography (PE/EtOAc 5:1) yielded a mixture of 8a and 8b
(91.5 mg, 85%) as colorless needles; separation by chromatography
was not accomplished. The ratio 8a/8b >5:1 is deduced from the ratio
of 1 and 2 (GC−MS) obtained after reductive amination.
Benzyl ((1S)-1-{2-[(1″R, 2″S)-2-Methyl-6-oxocyclohexyl]-
ethyl}butyl)carbamate (ent-8b). Reagent-Controlled 1,4-Addi-
tion According to Table 2, Entry 3. Under an atmosphere of argon, a
solution of CuTC (1.4 mg, 7.2 μmol) and (R,R,aS)-L1 (7.8 mg, 14
μmol) in dry Et2O (0.5 mL) was stirred for 30 min at rt and was then
cooled to −30 °C. AlMe3 (2 M in hexane, 0.4 mL, 0.8 mmol) and a
solution of ent-7 (100 mg, 304 μmol) in dry Et2O (1 mL) were added
successively. Complete conversion was reached after 19 h at −30 °C.
MeOH (1 mL) and aqueous NH4Cl (2 mL) were added, and the
mixture was allowed to warm to rt. The aqueous layer was separated
and extracted with Et2O (2 × 20 mL). The combined organic layers
were dried over MgSO4 and concentrated in vacuo. Flash
chromatography (PE/EtOAc 5:1) yielded ent-8b (75 mg, 72%) as
colorless needles (mp 86−88 °C (EtOAc/PE)). The product was
diastereomerically and enantiomerically pure according to the
determination after reductive amination.
(1 H, qd, J = 12.4, 3.6 Hz), 1.04−1.13 (2 H, m), 1.21−1.39 (6 H, m),
1.59−1.67 (2 H, m), 1.68−1.74 (2 H, m), 1.97 (1 H, dq, J = 12.6, 3.2
Hz), 2.17 (1 H, ddd, J = 10.5, 10.1, 3.6 Hz), 2.46−2.53 (1 H, m); 13C
NMR (CDCl3, 75 MHz) δ 14.4 (CH3), 19.31 (CH3), 19.34 (CH2),28
24.9 (CH2), 29.2 (CH2), 33.2 (CH2), 34.1 (CH2), 35.8 (CH2), 36.3
(CH), 39.6 (CH2), 48.7 (CH), 56.7 (CH), 61.5 (CH); HR-MS (ESI
+) calcd for C13H26N [M + H]+ 196.20598, found 196.20615.
2·HCl: [α]20 −26.0 (c 0.61, MeOH), lit.8b [α]20 −27.3 (c 0.6,
D
D
MeOH); 13C NMR (CDCl3, 75 MHz) δ 13.9 (CH3), 18.89 (CH3),
18.90 (CH2), 24.2 (CH2), 27.3 (CH2), 28.1 (CH2), 30.0 (CH2), 34.3
(CH2), 35.1 (CH2), 36.6 (CH), 44.6 (CH), 58.3 (CH), 61.8 (CH).
(2R,4aR,5S,8aS)-5-Methyl-3-propyldecahydroquinoline (1)
and (2R,4aS,5R,8aS)-5-Methyl-3-propyldecahydroquinoline
(2). In this experiment, a mixture of 8a/8b prepared via reagent
control (Table 2, entry 2) was used. A suspension of 8a/8b (119.4 mg,
345.6 μmol, 8a/8b >5:1), Pd(OH)2/C (22.7 mg), and Rh/C (5.9 mg)
in MeOH (5 mL) was vigorously stirred under an atmosphere of
hydrogen (30 bar). Complete conversion was reached after 18 h at rt.
Insoluble material was removed by filtration through a pad of silica,
and the solution was concentrated in vacuo. The ratio 1/2 >5:1 was
determined by GC−MS. Purification by flash chromatography (PE/
NEt3 95:5) yielded 1 (45 mg, 67%) and 2 (8.9 mg, 13%) as colorless
oils.
(2S,4aR,5S,8aR)-5-Methyl-3-propyldecahydroquinoline (ent-
2). In this experiment, ent-8b prepared via reagent control (Table 2,
entry 3) was used. A suspension of ent-8b (50 mg, 145 μmol),
Pd(OH)2/C (10 mg), and Rh/C (2.9 mg) in MeOH (4 mL) was
vigorously stirred under an atmosphere of hydrogen (30 bar).
Complete conversion was reached after 16 h at rt. Insoluble material
was removed by filtration through a pad of silica, and the solution was
concentrated in vacuo to yield ent-2 (23.5 mg, 83%) as colorless oil.
ent-2: [α]20 +32.4 (c 1.1, MeOH). ent-2·HCl: [α]20 +25.2 (c 0.43,
ent-8b: [α]20D +3.3 (c 0.43, MeOH); 1H NMR (CDCl3, 300 MHz)
δ 0.89 (3 H, t, J = 6.7 Hz), 1.02 (3 H, d, J = 6.4 Hz), 1.24−1.72 (11 H,
m), 1.78−1.88 (1 H, m), 1.92−2.06 (2 H, m), 2.20−2.40 (2 H, m),
3.50−3.66 (1 H, m), 4.69 (1 H, d, J = 8.8 Hz), 5.04−5.17 (2 H, m),
7.25−7.40 (5 H, m); 13C NMR (CDCl3, 75 MHz) δ 14.1 (CH3), 19.1
(CH2), 20.6 (CH3), 22.9 (CH2), 25.9 (CH2), 32.8 (CH2), 33.7 (CH2),
38.1 (CH2), 38.8 (CH), 41.9 (CH2), 51.4 (CH), 57.0 (CH), 66.5
(CH2), 128.06 (CH), 128.08 (CH), 128.6 (CH), 137.0 (Cq), 156.4
(Cq), 213.3 (Cq).
D
D
MeOH).
ASSOCIATED CONTENT
■
(2R,4aR,5S,8aS)-5-Methyl-3-propyldecahydroquinoline (1)
and (2R,4aS,5R,8aS)-5-Methyl-3-propyldecahydroquinoline
(2). In this experiment, a mixture of 8a/8b prepared via substrate
control (Table 2, entry 1) was used. A suspension of 8a/8b (136 mg,
394 μmol, 8a/8b 2:1), Pd(OH)2/C (27.0 mg), and Rh/C (6.8 mg) in
MeOH (4 mL) was vigorously stirred under an atmosphere of
hydrogen (30 bar). Complete conversion was reached after 17 h at rt
[TLC: Rf(8) = 0.36, Rf(1,2) = 0.00, PE/EtOAc 3:1]. Insoluble material
was removed by filtration through a pad of silica, and the solution was
concentrated in vacuo. The ratio 1/2 2:1 was determined by GC−MS.
Purification by flash chromatography (PE/NEt3 95:5, Rf(1) = 0.61,
Rf(2) = 0.47) yielded 1 (40.5 mg, 53%) and 2 (18.3 mg, 24%) as
colorless oils. Crystalline hydrochlorides were obtained in quantitative
yield by treatment with HCl (5% in MeOH) followed by evaporation.
S
* Supporting Information
Determination of regio-, enantio-, and diastereoselectivities and
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: g.helmchen@oci.uni-heidelberg.de.
ACKNOWLEDGMENTS
■
We thank Andreas Farwick, Daniel Hack, Nicole Bauer, and
Olena Tverskoy for experimental assistance, Prof. Dr. K. Ditrich
(BASF AG) for enantiomerically pure 1-arylethylamines, and
Prof. Dr. A. Alexakis, Geneva, for generous gifts of CuTC and
phosphoramidite ligands.
1: [α]20 −2.2 (c 1.34, MeOH); GC (Chrompack β-CD, 130 °C
D
isothermal) tR((+)-(2S,4aS,5R,8aR)-1) 13.1 min, tR((−)-
1
(2R,4aR,5S,8aS)-1) 14.4 min; H NMR (CDCl3, 500 MHz) δ 0.83
(3 H, d, J = 6.6 Hz), 0.90 (3 H, t, J = 7.0 Hz), 0.94−1.03 (1 H, m),
1.05−1.14 (2 H, m), 1.22−1.49 (9 H, m), 1.50−1.71 (4 H, m), 1.77−
1.90 (1 H, m), 1.90−1.99 (1 H, m), 2.53 (1 H, dtd, J = 11.4, 5.8, 2.7
Hz), 2.84 (1 H, q, J = 2.8 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.5
(CH3), 19.3 (CH2), 20.1 (CH3), 21.4 (CH2), 27.2 (CH2), 27.54
(CH), 27.55 (CH2), 33.6 (CH2), 36.1 (CH2), 39.9 (CH2), 42.8 (CH),
56.1 (CH), 57.9 (CH); HR-MS (ESI+) calcd for C13H26N [M + H]+
196.20598, found 196.20600.
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1190
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