Straightforward access to enantioenriched 2-allylpiperidine: Application to the synthesis of alkaloids

Article abstract of DOI:10.1021/jo202211u

An efficient stereocontrolled preparation of (2R,R_S)-2-allyl-(N- tert-butylsulfinyl)piperidine and its enantiomer is detailed. The sequence requires only two synthetic operations with one-column chromatography and is readily scaled up. The versatility of these chiral building blocks was exemplified by the total or formal synthesis of some natural and unnatural alkaloids.

Full text of DOI:10.1021/jo202211u

Note
pubs.acs.org/joc
Straightforward Access to Enantioenriched 2-Allylpiperidine:
Application to the Synthesis of Alkaloids
Irene Bosque, Jose C. Gonzalez-Gomez,* Francisco Foubelo,* and Miguel Yus
́
́
́
Departamento de Química Organ
99, 03080 Alicante, Spain
́
ica, Facultad de Ciencias and Instituto de Síntesis Organ
́
ica (ISO), Universidad de Alicante, Apdo.
S
* Supporting Information
ABSTRACT: An efficient stereocontrolled preparation of
(2R,RS)-2-allyl-(N-tert-butylsulfinyl)piperidine and its enan-
tiomer is detailed. The sequence requires only two synthetic
operations with one-column chromatography and is readily
scaled up. The versatility of these chiral building blocks was
exemplified by the total or formal synthesis of some natural
and unnatural alkaloids.
2-Substituted piperidines are widespread subunits in natural
alkaloids1 and pharmaceuticals.2 Among them, chiral 2-
allylpiperidines constitute prominent examples that have been
extensively used as building blocks for the synthesis of
biologically active natural products.3−5 Notably, the natural
alkaloids structurally related to 2-allylpiperidine have different
biosynthetic origins, and the stereocenter adjacent to the
nitrogen atom can show different configurations (R/S).6 The
exceptional versatility of these small molecules is obviously
related to the wide range of synthetical manipulations that can
be done in the allyl moiety, as well as in the amino group.
Consequently, their synthesis has garnered much attention
using diverse approaches (Scheme 1). The most common
metalation and reaction with allyl chloride.9,10 These methods,
though elegant and efficient, suffer from some drawbacks
including limitations in the maximal yield attainable in classical
or kinetic resolutions, long reaction sequences, and the use of
expensive or dangerous starting materials that are restricted
from use on a large scale. Another practical approach that has
recently afforded enantioenriched 2 allylpiperidine in gram-
scale is the use of Betti base as chiral auxiliary (e).11 Despite
important progresses, new general, efficient, and scalable
methods to access both enantiomers of 2-allylpiperidine are
still highly desirable to expand the synthetic utility of these
versatile building blocks.
The ready availability of both enantiomers of tert-
butanesulfinamide in large-scale processes,12 the easy depro-
tection of the amine under acidic conditions, and practical
procedures for recycling the chiral auxiliary13 have contributed
to its widespread use in many practical asymmetric synthesis of
amines.14 Recently, an efficient asymmetric synthesis of 2-
substituted pyrrolidines by addition of Grignard reagents to γ-
chloro-N-tert-butanesulfinyl aldimines followed by base-medi-
ated cyclization was reported.15 We reasoned that the indium-
mediated α-aminoallylation of 5-bromopentanal with (RS)- or
(SS)-tert-butanesulfinamide could be implemented in a similar
approach to enantioenriched 2-allylpiperidine derivatives
(Scheme 1).16
Scheme 1. Prior Syntheses of Enantioenriched 2-
Allylpiperidine
As outlined in Scheme 2, indium-mediated one-pot α-
aminoallylation of 5-bromo-pentanal17 with (RS)-tert-butane-
sulfinamide (1) and allylbromide took place smoothly. It is
worthy to point out that using this one-pot protocol, we did not
observe any reaction product of tert-butanesulfinamide or allyl
indium reagent at C-5 of 5-bromopentanal, or elimination
products, and the desired compound 2 was obtained with high
asymmetric strategies to access these molecules are (a)
resolution of racemic piperidine-2-ethanol with enantiopure
camphorsulfonic acid;7 (b) enzymatic resolution of racemic
piperidine-2-ethanol;8 (c) Sharpless asymmetric dihydroxyla-
tion (AD) of 5-hexenyl azide;3 and (d) dynamic resolution of
enantioenriched N-Boc-2-lithio-piperidine, followed by trans-
1
chemo- and diasteroselectivity (94:6 dr by H NMR). After
filtration of crude 2 through Celite, its cyclization was
Received: October 27, 2011
Published: November 27, 2011
© 2011 American Chemical Society
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Note
Scheme 2. Preparation of (R)-2-Allylpiperidine (3b) from (RS)-tert-Butanesulfinamide (1)
attempted with different bases and conditions (like Et3N/
MeCN 80 °C or KOH/THF-H2O 80 °C), obtaining the best
results with KHMDS in THF at 0 °C (at 23 °C, other
byproducts were observed). Notably, only two synthetic
operations were needed to efficiently prepare pure compound
3a (90% yield from 1) in 4 g scale within a few hours.
Moreover, ent-3a was prepared from ent-1 using the same
pathway with similar efficiency. Importantly, the sulfinyl group
was readily cleaved under mild acidic conditions to provide
enantioenriched (R)-2-allylpiperidine hydrochloride 3b in
excellent yield.
results were obtained when the N-Boc-protected compound
(R)-3c was submitted to Wacker oxidation conditions, which
after conventional acidic deprotection, afforded unnatural (R)-
(−)-pelletierine (9) in good overall yield (Scheme 4).
Scheme 4. Synthesis of (−)-Pelletierine and Formal
Synthesis of (+)-Lasubine II and (+)-Allosedridine
As depicted in Scheme 3, hydrogenation of 3b afforded (S)-
(+)-coniine hydrochloride (4), the major alkaloid extracted
Scheme 3. Synthesis of (+)-Coniine and Formal Synthesis of
(−)-Cermizine C from 3b
Importantly, stereoselective reduction of (R)-N-Boc-pelletierine
(8) has been recently reported to obtain natural (+)-allose-
dridine,23 as well as a two-step transformation of (S)-
(+)-pelletierine into (−)-lasubine II.11
As previously reported for racemic 5-epi-cermizine C,19 the
Knoevenagel condensation of the ammonium acetate salt of
(R)-pelletierine (9) with Meldrum’s acid took place with
concomitant lactam formation, followed by decarboxylation and
kinetic protonation to provide the unconjugated lactam (R)-10
in good yield (Scheme 5). Hydrogenation of (R)-10 at 4 atm of
from poison hemlock and responsible for its toxicity, which
confirms the absolute configuration of the stereogenic center
introduced in the α-aminoallylation step. Treatment of
compound (R)-3b with acryloyl chloride under basic
conditions, followed by ring-closing metathesis with Hovey-
da−Grubbs catalyst, allowed the efficient preparation of
unsaturated lactam (R)-6 (Scheme 3), the enantiomer of a
key intermediate in the synthesis of lycopodium alkaloids.18
The stereoselective conjugate addition of Me2CuLi to the
convex face of compound (R)-6 was performed with good
selectivity to afford lactam 7, following a protocol described by
Snider in the first total synthesis of senepodine-G and
cermizine-C.19 This method represents a formal synthesis of
the enantiomers of the above-mentioned quinolizidine
alkaloids.20,21
Pelletierine has been recognized to play an important role in
the biosynthesis of a number of alkaloids, and consequently this
molecule is potentially a key intermediate in the biomimetic
synthesis of natural alkaloids.22 However, the application of
pelletierine in synthesis is limited, probably because its
asymmetric preparation in the required amounts to be used
as building block is not straightforward. Wacker oxidation of N-
sulfinyl-protected compound 3a under different reaction
conditions gave always a complex mixture of products. Better
Scheme 5. Synthesis of 5-epi-(+)-Cermizine C
H2 occurred mainly on the convex face, affording the desired
lactam 11 in excellent yield and good selectivity (13:1 dr).
Addition of MeMgBr to compound 11 was followed by in situ
stereoselective reduction of the iminium-intermediate to afford
5-epi-cermizine C in good overall yield, which was further
transformed to its trifluoroacetate salt (12). It is worth pointing
out that protonation of 5-epi-cermizine C should render a
stereogenic nitrogen via equilibration through the most stable
trans-quinolizidine conformation of the free amine.24 Impor-
tantly, since 2-allyl piperidines 3a and ent-3a are available using
the present methodology, formally all four diasteroisomers of
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°C under Ar and then quenched with saturated NH4Cl solution. The
aqueous phase was extracted with EtOAc (3 times), and the combined
extracts were washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by column
chromatography (75:25 hexane/EtOAc) to provide the product as a
senepodine G and the corresponding cermizine C diaster-
oisomers could be prepared following the pathways described
in Schemes 3 and 5.
In conclusion, we have developed a highly efficient two-step
process for the synthesis of enantioenriched 2-allylpiperidine 3a
in 4 g scale. Because of its operational ease, we believe this
method provides a useful complement to existing methods for
the preparation of both enantiomers of 3a. The usefulness of 3a
as a building block was illustrated by the total synthesis of
alkaloids such as (+)-coniine, (−)-pelletierine, and 5-epi-
(+)-cermizine C as well as in the formal synthesis of
(−)-cermizine C, (+)-allosedridine, and (+)-lasubine II.
Extension of this work is currently underway in our laboratory.
20
pale-yellow oil (3.608 g, 15.76 mmol, 90% from 1): [α]D +20.7 (c
1.0, CHCl3); Rf 0.30 (7:3 hexane/EtOAc); IR ν 3075, 2939, 1639,
1
1074, 986, 906 cm−1; H NMR (300 MHz, CDCl3) δ 5.84−5.70 (m,
1H), 5.15−5.04 (m, 2H), 3.46−3.28 (m, 1H), 3.20−3.11 (m, 1H),
2.99−2.90 (m, 1H), 2.59−2.43 (m, 2H), 1.72−1.49 (m, 6H), 1.17 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 135.5 (CH), 117.4 (CH2), 58.3
(C), 56.4 (CH), 40.8 (CH2), 34.4 (CH2), 28.1 (CH2), 25.8 (CH2),
23.2 (CH3), 19.5 (CH2); LRMS (EI) m/z (%) 229 (M+, 0.1), 173
(28), 132 (100), 83 (11), 57 (17), 55 (20); HRMS (EI) calcd for
C12H23NOS 229.1500, found 229.1507.
(2S,SS)-2-Allyl-(N-tert-butylsulfinyl)piperidine (ent-3a). It was
prepared from (SS)-N-tert-butanesulfinamide (ent-1, 0.52 mmol),
following the same procedure described above for compound 3a (90
mg, 0.40 mmol, 77% from ent-1). Physical and spectroscopic data were
found to be same than for (2R,RS)-3a, except for the optical rotation:
EXPERIMENTAL SECTION
■
General Remarks. (RS)-tert-Butanesulfinamide and its enan-
tiomer were a gift of Medalchemy (>99% ee by chiral HPLC on a
Chiracel AS column, 90:10 n-hexane/i-PrOH, 1.2 mL/min, λ = 222
nm). TLC was performed on silica gel 60 F254 using aluminum plates
and visualized with phosphomolybdic acid (PMA) stain. Flash
chromatography was carried out on handpacked columns of silica
gel 60 (230−400 mesh). Melting points are uncorrected. Optical
rotations were measured using a polarimeter with a thermally jacketted
5 cm cell at approximately 20 °C, and concentrations (c) are given in
g/100 mL. Infrared analyses were performed with a spectropho-
tometer equipped with an ATR component; wavenumbers are given in
cm−1. Mass spectra (EI) were obtained at 70 eV, and fragment ions in
m/z with relative intensities (%) are in parentheses. HRMS analyses
20
[α]D −22.0 (c 1.1, CHCl3).
(R)-2-Allylpiperidine Hydrochloride (3b). A solution of HCl in
dioxane (6.8 mL, 4 M) was added dropwise to a solution of 3a (1.557
g, 6.80 mmol) in dry MeOH (40 mL) at 0 °C under Ar. The reaction
mixture was allowed to reach 23 °C while being stirred for 2 h. The
solvent was removed in vacuo, and the resulting solid was triturated
with Et2O (2 × 5 mL). The Et2O was removed, and the solid was dried
under reduced pressure to give a white crystalline solid (1.040 g, 95%):
mp 159−161 °C (i-PrOH/EtOAc) [lit.3 175−178 °C]; [α]D20 +2.4 (c
0.8, EtOH) [lit.3 [α]D25 +2.1 (c 1.3, EtOH)]. 1H NMR, 13C NMR, and
IR data were in agreement with previously reported values.3
1
were also carried out in the electron impact mode (EI) at 70 eV. H
NMR spectra were recorded at 300 or 400 MHz for H NMR and 75
1
(S)-Coniine Hydrochloride (4). To a solution of 3b (154 mg,
0.95 mmol) in dry MeOH (20 mL) was added 10% Pd/C (50 mg). A
balloon of H2 gas was fitted to the equipment, and the reaction
mixture was stirred under H2 for 20 h at 23 °C. The reaction mixture
was filtered through a short pad of Celite and washed successively with
Et2O and a 4 M solution of HCl in dioxane. The residue was
concentrated in vacuo, and the solid obtained was triturated with Et2O
(2 × 1 mL) and recrystallized from 3:1 EtOAc/EtOH (2 mL) to afford
a white solid (120 mg, 78%): mp 226−230 °C [lit.3 216−218 °C];
or 100 MHz for 13C NMR, using CDCl3 as the solvent and TMS as
internal standard (0.00 ppm). The data is reported as s = singlet, d =
doublet, t = triplet, m = multiplet or unresolved, br s = broad signal,
coupling constant(s) in Hz, integration. 13C NMR spectra were
recorded with 1H-decoupling at 100 MHz and referenced to CDCl3 at
77.16 ppm. DEPT-135 experiments were performed to assign CH,
CH2, and CH3.
(4R,RS)-N-(tert-Butylsulfinyl)-8-bromooct-1-en-4-amine (2).
To a dry flask was added (RS)-N-tert-butanesulfinamide (1, 2.109 g,
17.40 mmol) followed by indium powder (2.485 g, 21.80 mmol), and
the mixture was evacuated and put under Ar. Then, a solution of 5-
bromopentanal (3.141 g, 19.15 mmol) in dry THF (34.9 mL) and
Ti(OEt)4 (7.8 mL, 34.80 mmol) were added successively, and the
reaction mixture was stirred under Ar for 1 h at 23 °C. At this time,
allyl bromide (2.3 mL, 26.10 mmol) was added to the mixture, and it
was heated to 60 °C for 5 h. The mixture was allowed to reach room
temperature and was carefully added over a stirring mixture of 4:1
EtOAc/brine (200 mL). The resulting white suspension was filtered
through a short pad of Celite and washed with EtOAc, and the
organics were concentrated in vacuo. The resulting suspension was
diluted in 4:1 EtOAc/hexane (200 mL) and filtered again through
Celite. Organics were concentrated to afford the expected compound
[α]D +7.2 (c 1.0, EtOH) [lit.3 [α]D +5.2 (c 0.35, EtOH)]. H
NMR,13C NMR, and IR data were in agreement with previously
reported values.25
20
25
1
(R)-tert-Butyl 2-Allylpiperidine-1-carboxylate (3c). To a sol-
ution of 3b (614 mg, 3.80 mmol) in CH2Cl2 (40 mL) at 0 °C was
added aqueous NaOH solution (40 mL, 2 M) followed by Boc2O (997
mg, 4.56 mmol). The reaction mixture was left stirring for 16 h while
the temperature reached 23 °C. The mixture was extracted with
CH2Cl2 (3 times), washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The product was obtained as a
colorless oil (905 mg contaminated with 12 mol % of Boc2O according
to GC, resulted in 93% estimated yield) and was used in the next step.
A sample of compound 3c was purified by column chromatography
20
(98:2 hexane/EtOAc) for characterization: [α]D +46.5 (c 1.0,
CHCl3) {lit.9 for er 78:22 [α]D +39.7 (c 1.2, CHCl3)}; Rf 0.60
23
1
2 (5.050 g, 94%, 94:6 dr according H NMR) as a yellow oil, pure
1
(9:1 hexane/EtOAc). H NMR, 13C NMR, IR, and MS data were in
enough to be used in the next step. To provide the spectroscopy data,
a sample of compound 2 was purified by column chromatography (7:3
hexane/EtOAc): Rf 0.15 (7:3 hexane/EtOAc); H NMR (400 MHz,
agreement with previously reported values.9 CSP-GC [20% β-
cyclodextrin-permethylated capillary column 30 m × 0.25 mm i.d.,
hydrogen carrier at 12 psi; temperature at 80 °C over 60 min, then a
ramp of 10 °C/min.] analysis showed 93:7 er (see chromatograms in
the Supporting Information).
1
CDCl3) δ 5.85−5.71 (m, 1H), 5.16 (dd, J = 14.0, 1.5 Hz, 2H), 3.41 (t,
J = 6.6 Hz, 2H), 3.32 (dt, J = 11.3, 5.8 Hz, 1H), 3.23 (d, J = 6.1 Hz,
1H), 2.42 (dt, J = 13.0, 5.9 Hz, 1H), 2.33 (dt, J = 13.8, 6.8 Hz, 1H),
1.92−1.80 (m, 2H), 1.62−1.46 (m, 4H), 1.21 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 134.1 (CH), 119.3 (CH2), 56.0 (C), 54.7 (CH), 40.5
(CH2), 34.1 (CH2), 33.8 (CH2), 32.6 (CH2), 24.1 (CH2), 22.8
(CH3); LRMS (EI) m/z (%) 237 (M+ − C4H8, 19), 235 (M+ − C4H8,
20), 213 (67), 211 (67), 156 (100).
(2R,RS)-2-Allyl-(N-tert-butylsulfinyl)piperidine (3a). A titrated
solution of KHMDS in THF (33 mL, 0.79 M, 26.10 mmol) was added
via syringe to a cold solution (0 °C) of crude 2 (5.050 g, 16.30 mmol)
in dry THF (36.5 mL). The reaction mixture was stirred for 2 h at 0
(S)-N-tert-Butyl 2-Allylpiperidine-1-carboxylate (ent-3c). It
was prepared from ent-3b (0.30 mmol), following the same procedure
described above for compound 3c. Physical and spectroscopic data
were found to be same as for (R)-3c, except for the optical rotation:
[α]D −41.7 (c 1.0, CHCl3) {lit.3 [α]D −39.96 (c 1.23, CHCl3)}.
CSP-GC analysis was performed as indicated for 3c, showing 93:7 er
(see the Supporting Information).
20
25
(R)-N-Acryloyl-2-allylpiperidine (5). A mixture of 3b (230 mg,
1.42 mmol) in a 10% solution of NaOH (1.4 mL) was cooled to 0 °C,
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Note
and a solution of acryloyl chloride (290 μL, 3.56 mmol) in CH2Cl2
(3.6 mL) was then added dropwise. The solution was allowed to reach
room temperature and was stirred for 20 h. The reaction mixture was
concentrated under reduced pressure, and the residue was purified by
flash column chromatography (7:3 hexane/EtOAc) to provide the
column chromatography (9:1 hexane/EtOAc) to provide the product
20
as a yellow oil (292 mg, 67%): [α]D −8.7 (c 0.90, CHCl3); Rf 0.50
1
(EtOAc). H NMR, 13C NMR, IR, and MS data were in agreement
with previously reported values for rac-10.19
(2S,9aR)-2-Methyl-1,6,7,8,9,9a-hexahydro-(4H)-quinolizin-4-
one (11). PtO2 (9 mg, 0.04 mmol) was added to a solution of 10
(282 mg, 1.71 mmol) in EtOH (8.5 mL). The resulting suspension
was shaken under H2 atmosphere (4 atm) for 6 h at 23 °C. The
reaction mixture was diluted in EtOAc (3 mL) and the catalyst was
removed by filtration through Celite. The resulting solution was
concentrated under reduced pressure to give the product as a colorless
20
product as a pale-yellow oil (208 mg, 82%): [α]D +62.4 (c 0.7,
CHCl3) {lit.11 for ent-5 [α]D −70.6 (c 0.42, CHCl3)}; Rf 0.15 (6:4
20
hexane/EtOAc). 1H NMR, 13C NMR, IR, and MS data were in
agreement with previously reported values for ent-5.11
(R)-1,6,7,8,9,9a-Hexahydro-(4H)-quinolizin-4-one (6). To a
solution of 5 (222 mg, 1.24 mmol) in dry CH2Cl2 (10 mL) was
added the Hoveyda−Grubbs catalyst (23 mg, 0.04 mmol) at room
temperature. The reaction mixture was put under Ar and heated to 40
°C with stirring. After 30 min, the reaction mixture was cooled to
room temperature and concentrated under reduced pressure. The
residue was purified by column chromatography (6:4 hexane/EtOAc)
20
oil (274 mg, 96%, 13:1 dr by 1H NMR): [α]D −33.2 (c 1.00,
1
CHCl3); Rf 0.24 (1:1 hexane/EtOAc). H NMR, 13C NMR, IR, and
MS data were in agreement with previously reported values for rac-
11.19
(+)-5-epi-Cermizine C-TFA Salt (12). To a stirring solution of 11
(151 mg, 0.90 mmol) in dry THF (9 mL) was added dropwise a
solution of MeMgBr in THF (3.8 mL, 0.95 M, 3.61 mmol). The
mixture was heated to 60 °C for 3 h and then allowed to cool to 0 °C.
NaBH3CN (340 mg, 5.40 mmol) and glacial acetic acid (450 μL, 7.86
mmol) were successively added, and the mixture was stirred for 30 min
at 0 °C followed by another 30 min at 23 °C. The reaction mixture
was diluted with 5% aqueous solution of Na2CO3 (20 mL), verifying
pH 10, and extracted with EtOAc (3 × 40 mL). The combined extracts
were dried over MgSO4, concentrated under reduced pressure, and
purified by column chromatography (90:9:1 CHCl3/MeOH/
NH4OH). The obtained oil was dissolved in MeOH (2 mL) and
treated with TFA (0.50 mL). The solution was concentrated under
reduced pressure, and the latter process was repeated to afford 180 mg
(66%) of the TFA salt as a yellow oil: [α]D20 +5.0 (c 0.53, MeOH); Rf
0.32 (90:9:1 CHCl3/MeOH/NH4OH); IR ν 2962, 1666, 1781, 1451,
20
to provide the product as a pale-yellow oil (150 mg, 80%): [α]D
−39.0 (c 0.64, CHCl3), {lit.11 for ent-6 [α]D20 +45.7 (c 0.42, CHCl3)};
Rf 0.17 (6:4 hexane/EtOAc). H NMR, 13C NMR, IR, and MS data
1
were in agreement with previously reported values for ent-6.11
(2R,9aR)-2-Methyloctahydro-(4H)-quinolizin-4-one (7). A
solution of MeLi in Et2O (2.4 mL, 1.2 M, 2.80 mmol) was added
dropwise to a suspension of CuI (273 mg, 1.44 mmol) in dry THF
(9.1 mL) at 0 °C. The resulting solution was stirred for 30 min and
then cooled to −78 °C. BF3·OEt2 was added dropwise, and the
resulting solution was stirred for 5 min at −78 °C. A solution of 6 (106
mg, 0.70 mmol) in dry THF (4.2 mL) was carefully added to the
stirring mixture, and the resulting solution was slowly allowed to reach
room temperature (30 min). Saturated NH4Cl solution (20 mL) was
then added, and the aqueous layer was extracted with EtOAc (3 × 20
mL). The combined organic layers was dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (98:2 to 95:5 CH2Cl2/MeOH) to give the
1
1142, 797 cm−1; H NMR (300 MHz, MeOD) δ 3.79 (br d, J = 12.5
Hz, 1H), 3.23−3.12 (m, 1H), 3.06 (br t, J = 11.5 Hz, 1H), 2.73 (br t, J
= 12.9 Hz, 1H), 2.04−1.90 (m, 3H), 1.90−1.62 (m, 4H), 1.62−1.48
(m, 2H), 1.37 (d, J = 6.4 Hz, 3H), 1.33−1.12 (m, 2H), 0.98 (d, J = 6.4
Hz, 3H); 13C NMR (75 MHz, MeOD) δ 65.6 (CH), 62.5 (CH), 52.0
(CH2), 41.8 (CH2), 40.5 (CH2), 32.3 (CH2), 30.1 (CH), 24.9 (CH2),
23.2 (CH2), 21.4 (CH3), 18.0 (CH3).
A sample of compound 12 was dissolved in EtOAc, washed with 2
M NaOH (3 times), and dried over MgSO4. After being concentrated
under reduced pressure, the free amine was submitted to 1H NMR, IR,
and MS analysis, obtaining a data in agreement with previously
reported values for free amine rac-12.19
20
product as a yellow oil (90 mg, 78%): [α]D +21.0 (c 0.36, CHCl3)
{lit.19 for ent-7 [α]D −21 (c 1.0, CHCl3)}; Rf 0.36 (9:1 CH2Cl2/
23
1
MeOH); H NMR, 13C NMR, IR, and MS data were in agreement
with previously reported values for ent-7.19
(R)-N-tert-Butoxycarbonylpelletierine (8). A mixture of 3c
(905 mg with 88% purity, 3.42 mmol), PdCl2 (60 mg, 0.34 mmol),
and Cu(OAc)2 (126 mg, 0.68 mmol) in 7:1 DMF/H2O (27 mL) was
stirred for 24 h under O2 (1 atm) at 50 °C. The reaction was quenched
with 1 M solution of KHSO4 (27 mL) and extracted with CH2Cl2 (3 ×
15 mL). The combined organic layers were successively washed with
saturated NaHCO3 solution (15 mL) and H2O (3 × 20 mL), dried
over MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography (9:1 hexane/EtOAc) to
provide the product as a colorless oil (577 mg, 70%): [α]D20 +10.5 (c
0.95, CHCl3) {lit.23 [α]D25 +8.2 (c 2.0, CHCl3)}; Rf 0.18 (9:1 hexane/
EtOAc). 1H NMR, 13C NMR, IR, and MS data were in agreement with
previously reported values.23
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for compounds 2−12 and
chromatograms of CSP-GC for 3c and ent-3c. This material is
available free of charge via the Internet at http://pubs.acs.org.
(R)-Pelletierine Hydrochloride (9). A solution of HCl in dioxane
(2.5 mL, 4 M) was added dropwise to a solution of 8 (870 mg, 3.61
mmol) in dry CH2Cl2 (36 mL) at 0 °C, and the reaction mixture was
stirred at 23 °C for 2 h under Ar. After removal of the solvent under
vacuum, the resulting solid was triturated with Et2O (2 × 3 mL) to
afford a pale brown amorphous solid (600 mg, 94%): [α]D20 −12.0 (c
0.60, EtOH) {lit.26 [α]D25 −18.0 (c 0.5, EtOH)}. 1H NMR, 13C NMR,
IR, and MS data were in agreement with previously reported values.26
(R)-2-Methyl-3,6,8,9,9a-hexahydro-(4H)-quinolizin-4-one
(10). Meldrum’s acid (478 mg, 3.32 mmol) and acetic acid (156 μL,
2.70 mmol) were successively added to a stirring solution of (R)-
pelleterine (9)27 (380 mg, 2.65 mmol) in EtOH (2.7 mL) at room
temperature. The resulting solution was heated to 60 °C and stirred
for 24 h. The solution was allowed to reach room temperature, and
more Meldrum’s acid (388 mg, 2.69 mmol) was added. The solution
was heated to 60 °C and stirred for another 24 h. The reaction mixture
was allowed to reach room temperature and concentrated under
reduced pressure. The residue was diluted in EtOAc (18 mL), washed
with a saturated solution of Na2CO3, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: josecarlos.gonzalez@ua.es; foubelo@ua.es.
ACKNOWLEDGMENTS
■
We thank the Spanish Ministerio de Ciencia e Innovacion
́
(Grant No. CTQ2007-65218, Consolider Ingenio 2010-CSD-
2007-00006 and CTQ2011-24165), the Generalitat Valenciana
(Grant No. PROMETEO/2009/039 and FEDER) and the
University of Alicante for generous and continuous financial
support.
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