Enantioselective, protecting group-free synthesis of 1S-ethyl-4-substituted quinolizidines

Article abstract of DOI:10.1039/c2ob25392e

A practical enantioselective protecting group-free four-step route to the key quinolizidinone 6 from phenylglycinol-derived bicyclic lactam 1 is reported. The Grignard addition reaction to 6 takes place stereoselectively to give 1-ethyl-4-substituted quinolizidines 4-epi-207I and 7-9. Following a similar synthetic sequence, 9a-epi-6 is also accessed. However, the addition of Grignard reagents to 9a-epi-6 proceeds in a non-stereoselective manner. In order to gain insight into the different stereochemical outcome in the two series, theoretical calculations on the iminium salts A and B have been performed. The study concludes that the addition of the hydride, which is the step that determines the configuration of the final products, occurs in a stereoelectronic controlled manner. The theoretical study is in agreement with the experimental results.

Full text of DOI:10.1039/c2ob25392e

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 6866
www.rsc.org/obc
PAPER
Enantioselective, protecting group-free synthesis of 1S-ethyl-4-substituted
quinolizidines†
Mercedes Amat,*a Vladislav Semak,a Carmen Escolano,*a Elies Molinsb and Joan Boscha
Received 23rd February 2012, Accepted 30th March 2012
DOI: 10.1039/c2ob25392e
A practical enantioselective protecting group-free four-step route to the key quinolizidinone 6 from
phenylglycinol-derived bicyclic lactam 1 is reported. The Grignard addition reaction to 6 takes place
stereoselectively to give 1-ethyl-4-substituted quinolizidines 4-epi-207I and 7–9. Following a similar
synthetic sequence, 9a-epi-6 is also accessed. However, the addition of Grignard reagents to 9a-epi-6
proceeds in a non-stereoselective manner. In order to gain insight into the different stereochemical
outcome in the two series, theoretical calculations on the iminium salts A and B have been performed.
The study concludes that the addition of the hydride, which is the step that determines the configuration
of the final products, occurs in a stereoelectronic controlled manner. The theoretical study is in agreement
with the experimental results.
There are currently about 20 compounds assigned to this par-
Introduction
ticular structural family of amphibian alkaloids4 including seven
The extracts from the skin of certain poisonous frogs and toads
contain alkaloids showing promising biomedical activities. So
far, none of these alkaloids has been reported from any other
natural source. Most of them contain as a common structural
feature an azabicyclic “izidine” nucleus, e.g. disubstituted pyrro-
lizidines, di- and trisubstituted indolizidines, or disubstituted
quinolizidines.1
1-ethylquinolizidine representatives (Fig. 1). Among them, six
show a 1,4-trans relative configuration while alkaloid (−)-207I
is unique, with substituents being 1,4-cis.
The relative stereochemistry of natural quinolizidine (−)-207I
was determined in 1997 by Momose’s group by comparison of
the GC-MS and GC-FIT spectra of the 1-epi-207I isomer syn-
thesized by them and the natural alkaloid.5 In 2003, Toyooka
and co-workers published the first enantioselective synthesis of
(+)-207I, the enantiomer of the alkaloid, thus determining the
absolute stereochemistry of the natural product.6 More recently,
the same research team reported the synthesis of 233A, 235U
and 251AA alkaloids.7 Although pioneering, these syntheses
suffer from the drawback of requiring a considerable number of
synthetic steps, leading to a low yield of the final product, partly
due to the use of protecting groups. Therefore, a general and
Among them, 1,4-disubstituted quinolizidines2 are a relatively
new class of alkaloids that have been isolated in minute quan-
tities. Their structures have been partially elucidated based on
the GC-MS and GC-FTIR spectra, the latter showing significant
Bohlmann bands3 indicating that the hydrogens at positions 4
and 9a are cis. The relative configuration at position 1 is only
tentative and the absolute configuration of the stereocenters is
unknown. As total synthesis is required for structural proof, it
would be highly desirable to develop general asymmetric metho-
dologies to easily access these biologically interesting
compounds.
aLaboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of
Biomedicine (IBUB), University of Barcelona, 08028 Barcelona, Spain.
E-mail: cescolano@ub.edu, amat@ub.edu; Fax: +34-93-402-4539
bInstitut de Ciència de Materials de Barcelona (CSIC), Campus UAB,
08193 Cerdanyola, Spain
†Electronic supplementary information (ESI) available: Additional
experimental information. Copies of 1H and 13C NMR spectra of new
products. Cartesian coordinates and total energies for compounds 9,
4-epi-9 and iminium salts A and B. CCDC 861638. For ESI and crys-
tallographic data in CIF or other electronic format see DOI:
10.1039/c2ob25392e
Fig. 1 1-Ethyl-4-substituted quinolizidines.
6866 | Org. Biomol. Chem., 2012, 10, 6866–6875
This journal is © The Royal Society of Chemistry 2012

View Article Online
efficient procedure providing access to different 1,4-disubstituted
quinolizidine alkaloids would be of interest.
and its C6 epimer, 6-epi-2. The absolute stereochemistry of 2
was unambiguously confirmed by X-ray crystallographic analy-
sis (Fig. 2). The configuration of the 5 and 6 stereocenters
remains in the final product since both of them are configuration-
ally stable in the subsequent synthetic transformations
(Scheme 2).
Interestingly from the biological point of view, 1-epi-207I
selectively blocks α7 nicotinic receptors (IC50 = 0.6 μM).8 In
contrast, alkaloids 233A, 235U and 251AA block the responses
mediated by α7 and α4β2 nicotinic receptors without any selec-
tivity observed between both subtypes. Comparing the latter
compounds with 1-epi-207I led the authors to conclude that the
α7 subtype selectivity of 1,4-disubstituted quinolizidines is
remarkably dependent on the structure of the C4 side chain.
Increasing the length of the 4-moiety beyond three carbons
appears to markedly reduce potency and selectivity at the α7
receptor.
In this paper we disclose a general protocol for the enantio-
selective construction of these biologically attractive structural
motifs using chiral bicyclic lactams as enantiomeric scaffolds.9
Taking into account the aforementioned biological studies, we
planned to attach a 1 to 3 carbon chain at the C4 position of the
azabicyclic nucleus.
Preparation of azabicyclic compound 6
To construct the second six-membered ring from 2, removal of
the 2-phenylethanol moiety and installation of a second allyl
moiety was required. To this end, treatment of 2 with Na/liquid
NH3 afforded 3 in 81% yield. Transformation of 3 into the di-
olefinic compound 4 was accomplished by deprotonation with
NaH followed by alkylation with allyl bromide. More con-
veniently, we developed a one-pot two-step process from 2 to 4
Results and discussion
Retrosynthetic analysis
Our retrosynthetic analysis is briefly outlined in Scheme 1. We
envisioned that the alkyl group at C-4 could be installed by a
stereoselective addition of an organometallic reagent to the car-
bonyl amide group of a 1-ethyl quinolizidine derivative. This
bicyclic lactam was surmised to be constructed by a ring-closing
metathesis reaction of a monocyclic diallylated derivative. In
turn, the required trisubstituted 2-piperidone would be obtained
by alkylation of (5S,6S)-6-allyl-5-ethyl-2-piperidone, whose
enantiomer had been previously synthesized by our group by an
α-amidoalkylation reaction10 of the enantiomer of the chiral
bicyclic lactam 1.11
Fig. 2 X-Ray structure of (5S,6S)-6-allyl-5-ethyl-1-[(1S)-2-hydroxy-1-
phenylethyl]-2-piperidone (2). Molecules are linked along the a-axis of
the crystal through the hydrogen bond O8–H8⋯O2i (d(O⋯O) =
1
2.722(3) Å, angle(O–H⋯O) = 171.2°, i = [x − 112, − y, z]) forming
2
zigzag motifs.
Preparation of (5S,6S)-6-allyl-5-ethyl-2-piperidone (2)
As previously reported by our group in the enantiomeric series,
the TiCl4-promoted addition of allyltrimethylsilane to 1 occurs
stereoselectively, with inversion of the configuration at C8a to
afford a 9 : 1 mixture of cis-6-allyl-5-ethyl disubstituted lactam 2
Scheme 2 Reagents and conditions: (i) allyltrimethylsilane (2.0
equiv), TiCl4 (4.0 equiv), CH2Cl2, 0 °C to rt, 16 h, 2 (77%) and 6-epi-2
(7%); (ii) Na (metal), NH3 (l), 30 min, −33 °C, 81%; (iii) NaH (2.0
equiv), allyl bromide (1.1 equiv), THF, 0 °C to rt, 24 h, 75%; (iv) (a)
NaOH (10 equiv), O2 (1 atm), MTBE, 40 °C, 24 h; (b) allyl bromide
(1.25 equiv), rt, 19 h, 69% overall; (v) second-generation Grubbs cat.
(2.5 mol%), CH2Cl2, rt, 8 h, 87%; (vi) H2 (1 atm), 10% Pd/C, MeOH,
rt, 18 h, 87%.
Scheme 1 Retrosynthetic analysis.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6866–6875 | 6867

View Article Online
involving removal of the 2-phenylethanol moiety and
alkylation in the same vessel in basic media by sequential
treatment with O2 and allyl bromide (69% overall yield).12
With all the carbon atoms installed in compound 4 a ring-closing
metathesis reaction could be performed and the required six-
membered piperidine ring accessed.
A second-generation
ruthenium Grubbs catalyst mediated this reaction from 4 to
generate 5 (87%) under mild conditions.13 Chemoselective
reduction of
5
employing catalytic hydrogenation was
Scheme 4 Reagents and conditions: (i) (a) CeCl3 (2.0 equiv), 2-methyl-
allylmagnesium chloride (8.0 equiv), propylmagnesium bromide (4.0
equiv) or methylmagnesium bromide (4.0 equiv), THF, rt, 18 h; (b)
NaBH4 (1.25 equiv), MeOH, AcOH, −78 °C, 30 min, 56%, 7; 64% 8;
69%, 9.
accomplished to give 6, which is a valuable synthetic intermedi-
ate for the formation of the targeted diversely 4-substituted
1-ethylquinolizidines.
Table 1 Significant 13C NMR data for bicyclic amines
Addition of Grignard reagents to azabicyclic compound 6
Carbon
(−)-207Ia
4-epi-207I
7
8
9
With bicyclic lactam 6 in hand, the stage was set to execute the
installation of an alkyl substituent at carbon 4. To this end, a
one-pot procedure, involving the reaction of 6 with Grignard
reagents followed by dehydration to the corresponding iminium
salts and reduction to the final products, was studied.
In order to access alkaloid (−)-207I we first considered the
addition of allylmagnesium bromide. Interestingly, while there
are several reports dealing with the addition of organometallic
reagents to the 2-quinolizidinone nucleus,14 to the best of our
knowledge, the addition of an allylmetallic reagent is unprece-
dented.15 Only after much experimentation did we find that the
reaction indeed occurs using an excess of Grignard reagent
(4 equiv) in the presence of anhydrous CeCl3.16
Being aware that the reduction step would be responsible
for the stereochemistry of the final product, different reducing
agents were evaluated. While reduction with NaBH3CN or
NaBH(AcO)3 gave inseparable mixtures of (−)-207I and its
C4-epimer, 4-epi-207I, (34 : 66 and 23 : 77, respectively),
NaBH4 and DIBAL-H furnished 4-epi-207I with a high degree
of diastereoselectivity (3 : 97 and 4 : 96, respectively)
(Scheme 3).17
1
4
9a
6
40.6
64.2
66.7
53.1
41.9
50.9
61.1
50.1
41.8
49.7
61.1
50.3
42.1
51.2
61.2
50.2
41.8
46.7
60.8
50.1
a δ values from ref. 6.
Table 2 Significant 1H NMR data for bicyclic amines
Carbon
(−)-207Ia
4-epi-207I
7
8
9
1
4
9a
6eq
6ax
1.55
1.88
1.96
3.33
1.54
1.53
3.00
2.93
3.34
2.71
1.54
3.03
2.94
3.32
2.69
1.52
2.88
2.93
3.30
2.66
1.58
2.98
2.92
3.27
2.67
a δ values from ref. 6.
Structural elucidation of the final bicyclic amines
In order to access C4 analogues of the alkaloid (−)-207I, the
addition of different Grignard reagents was studied. In all cases,
the alkyl chain introduced was limited to a length of up to three
carbon atoms, taking into account previous biological studies.7,8
To this end, an excess of (2-methylallyl)magnesium bromide
was added to 6, followed by treatment with NaBH4 to give 7 and
4-epi-7 (96 : 4) in 56% yield. Following similar experimental
conditions, a propyl and a methyl chain were also introduced to
stereoselectively furnish 8 and 9 in 64 and 69% yield, respect-
ively (Scheme 4).
The absolute configuration of the C4 stereogenic center in
(−)-207I and 4-epi-207I was assigned by correlation of the
NMR data of these two compounds with those reported for the
previously synthesized enantiomer, (+)-207I.6
It is worthy of note that in 4-epi-207I the peaks corresponding
to C-6 and C-9a are about 5 and 3 ppm more shielded, respect-
ively, than in (−)-207I (Table 1). This shielding probably reflects
the γ-gauche effect due to an axial disposition of the allyl substi-
1
tuent in 4-epi-207I. Comparison of the 13C NMR and H NMR
(Table 2) of compounds 7–9 with that of 4-epi-207I led to the
depicted configuration being assigned to the C-4 stereocenter of
these new products (Scheme 4).18
In fact, full geometry optimization of 9 and its hypothetical
C4 epimer (4-epi-9), performed with the B3LYP density func-
tional method using the 6-31G(d) basis set, revealed that while
both compounds were in a chair–chair conformation, only 9 dis-
played its 4-methyl group in an axial manner (Fig. 3), while the
methyl group in 4-epi-9 was in an equatorial disposition (Fig. 4).
Thus, theoretical calculations are in concordance with the
13C-NMR observations.
Scheme 3 Reagents and conditions: (i) (a) CeCl3 (4.0 equiv), allyl-
magnesium bromide (4.0 equiv), THF, rt, 18 h; (b) NaBH4 (1.25 equiv),
MeOH, AcOH, −78 °C, 30 min, 58%, d.r. = 97 : 3.
6868 | Org. Biomol. Chem., 2012, 10, 6866–6875
This journal is © The Royal Society of Chemistry 2012

View Article Online
Scheme 5 Reagents and conditions: (i) (a) NaOH (10 equiv), O2 (1
atm.), MTBE, 40 °C, 24 h; (b) allyl bromide (1.25 equiv), rt, 19 h, 56%
overall; (ii) second-generation Grubbs cat. (3 mol %), CH2Cl2, rt, 6 h,
90%; (iii) H2 (1 atm.), 10% Pd/C, MeOH, rt, 16 h, 98%.
Fig. 3 The most stable conformation of compound 9 (γ-gauche effects
are indicated).
Scheme 6 Reagents and conditions: (i) (a) CeCl3 (2.0 equiv), allyl-
magnesium bromide or methylmagnesium bromide (4.0 equiv), THF, rt,
18 h; (b) NaBH4 (1.25 equiv), MeOH, AcOH, −78 °C, 30 min, 10 and
9a-epi-207I (54%); 11 and 4-epi-11 (48%).
Fig. 4 The most stable conformation of hypothetical compound
4-epi-9.
Synthesis of 9a-epi derivatives of 4-substituted
2-ethylquinolizidines
Scheme 7 Intermediate iminium salts.
With compounds 6-epi-2 in hand (Scheme 2), we decided to go
a step further and apply the developed procedure to prepare
9a-epi-6 to study the stereochemical outcome of the Grignard
addition reactions in compounds with a C9a R configuration.
Thus, the introduction of an allyl group on the piperidone nitro-
gen of 6-epi-2 gave compound 6-epi-4 in 56% yield. Subsequent
treatment with Grubbs second-generation catalyst furnished
9a-epi-5, which was hydrogenated to give 9a-epi-6 with yields
comparable to those obtained in the previous series (Scheme 5).
The addition reaction of allylmagnesium bromide in the pres-
ence of anhydrous CeCl3 to 9a-epi-6, followed by NaBH4
reduction, occurs in a non-stereoselective manner to give a
1 : 1 mixture of 10 and 9a-epi-207I. Similar results were
observed in the reaction of 9a-epi-6 with methylmagnesium
bromide, yielding an equimolecular mixture of the two possible
products (Scheme 6). These results are in striking contrast with
the stereochemical behaviour of the additions previously studied
in 6, which occurred with very high stereoselectivity.
stability of different conformers of the iminium ion intermediates
when
a methyl substituent is attached were considered
(Scheme 7). Indeed, exploration of the different conformational
states for the iminium salts A and B, at the B3LYP/6-31 (G)
level, gave two main possible conformations, depending on the
disposition adopted by the ethyl substituent. Starting from A, the
non-substituted six-membered ring of the quinolizidine adopts a
chair conformation in both iminium forms. As expected, the sub-
stituted ring adopts a half-chair conformation with the C3, C4, N
and C9a atoms in the same plane, with the ethyl group either in
an equatorial, AI, or axial disposition, AII (Fig. 5 and 6), AI
being more stable by 3.1 kcal mol−1. This fact could be ascribed
to a 1,3-diaxial destabilizing interaction in AII between the axial
ethyl substituent and the axial hydrogens at positions 3 and
9. On the basis of these findings, the stereochemical outcome of
the addition reaction can be explained considering an axial
attack of the hydride, under stereoelectronic control,20 at the
electrophilic carbon of the lowest-energy iminium ion intermedi-
ate, AI. This directed nucleophile attack dictates an S configur-
ation in the newly created stereocenter, as depicted in Fig. 5.
In a similar fashion, in the two possible conformations of the
iminium salt B, the non-substituted ring adopts a chair confor-
mation, whereas the substituted ring shows a half-chair confor-
mation with the C3, C4, N and C9a atoms in the same plane.
However, in the iminium salt B both possible conformations, BI,
with the ethyl group in an equatorial disposition, and BII, with
the ethyl group in an axial disposition, are energetically similar
The structural assignation of these quinolizidines was done by
comparison with the spectroscopic data of compound 10 whose
enantiomer had been previously described in the literature.5,19
Theoretical considerations of the stereochemical outcome in the
introduction of the C-4 substituent
As previously mentioned, the stereochemistry of the organo-
metallic addition reaction is determined by the attack of the
hydride to the iminium salt. In order to gain insight into the
stereochemistry of the final products, studies on the relative
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6866–6875 | 6869

View Article Online
Conclusions
In conclusion, we have developed a straightforward enantioselec-
tive synthesis of potentially biologically interesting 1-ethyl-4-
substituted quinolizidines without using protecting groups. The
stereochemistry of the stereocenters is defined by the use of (S)-
phenylglycinol as the source of chirality and by two stereocon-
trolled reactions, an α-amidoalkylation and an organometallic
addition. Compounds in the 9a-epi series have been efficiently
obtained following the synthetic sequence developed in the orig-
inal series. However, the final organometallic addition reaction
proved to be not stereoselective. In order to rationalize the differ-
ent stereochemical outcome in the Grignard addition reactions in
the two series, theoretical calculations on the iminium salts were
performed indicating that the addition of the hydride occurs in a
stereoelectronic controlled fashion.
Fig. 5 Two views of the most stable conformation of the iminium salt
intermediate AI and indication of the hydride stereocontrolled addition.
Experimental section
General methods
NMR spectra were recorded in CDCl3 at 300 or 400 MHz (1H)
and 75.4 or 100.6 MHz (13C), and chemical shifts are reported
in δ values downfield from TMS or relative to residual chloro-
form (7.26 ppm, 77.0 ppm) as an internal standard. Data are
reported in the following manner: chemical shift, multiplicity,
coupling constant (J) in hertz (Hz), integrated intensity. Multipli-
cities are reported using the following abbreviations: s, singlet;
d, doublet; dd, doublet of doublets; t, triplet; m, multiplet; br s,
broad signal, app, apparent. Evaporation of solvents was accom-
plished with a rotatory evaporator. Melting points were deter-
mined in a capillary tube and are uncorrected. Thin-layer
chromatography was done on SiO2 (silica gel 60 F254), and the
spots were located by UV, 1% aqueous KMnO4 or iodoplatinate
(for tertiary amines). Chromatography refers to flash column
chromatography and was carried out on SiO2 (silica gel 60, SDS,
230–400 mesh) or Al2O3 (Aluminium oxide 90 active basic,
Merck). Mass spectra were recorded on a LTQ spectrometer
using electrospray (ES+) ionization techniques.
Fig. 6 Two views of the most stable conformation of the iminium salt
intermediate AII. 1,3-Diaxial destabilizing interactions are indicated.
Fig. 7 Two views of the most stable conformation of the iminium salt
intermediate BI and indication of the hydride stereocontrolled addition.
(5S,6S)-6-Allyl-5-ethyl-1-[(1S)-2-hydroxy-1-phenylethyl]-2-
piperidone, (2). TiCl4 (20 mL, 182.12 mmol) was slowly added
to a cooled (0 °C) solution of 1 (11.17 g, 45.53 mmol) in anhy-
drous CH2Cl2 (90 mL) and the mixture was stirred for 15 min.
Allyltrimethylsilane (14.5 mL, 91.06 mmol) was added in 3 por-
tions and the resulting mixture was warmed at rt and stirred for
16 h. The mixture was poured onto ice and the aqueous layer
was extracted with CH2Cl2. The combined organic extracts were
dried, filtered and concentrated to give a 90 : 10 (1H NMR)
mixture of 2 and 6-epi-2, which was purified by column chrom-
atography (Biotage Si 40M 2197-1, CH2Cl2–MeOH 99.5 : 0.5 to
97 : 3) to yield 2 (10.02 g, 77%) and C6-epi-2 (0.87 g, 7%). 2:10
m.p. 75.0–76.0 °C (cyclohexane/pentane); [α]2D2 = +21.3 (c 0.45,
CHCl3). Anal. Calcd for C18H25NO2: C, 75.22; H, 8.77; N,
4.87. Found: C, 75.29; H, 8.68; N, 4.94%.
Fig. 8 Two views of the most stable conformation of the iminium salt
intermediate BII and indication of the hydride stereocontrolled addition.
1,3-Diaxial destabilizing interaction is indicated.
(ΔE < 1 kcal mol−1) (Fig. 7 and 8). The smaller energy gap
between both conformations may be indicative of a relative
stabilization of the conformation BII in comparison with AII
because only one 1,3-diaxial destabilizing interaction (ax-Et/
ax-H3) is found in the former. Consequently, as both conformations
are of similar energies, the stereoelectronic controlled addition of
the hydride upon the iminium salt can occur on both BI and BII,
yielding compounds 11 and 4-epi-11 in nearly equal amounts.
(5S,6R)-6-Allyl-5-ethyl-1-[(1S)-2-hydroxy-1-phenylethyl]-2-
piperidone, (6-epi-2). IR (NaCl) 3383, 2958, 1624 (s, NCO),
1
1452 cm−1; H NMR (400 MHz, CDCl3) δ 0.62 (t, J = 8.2 Hz,
3H, CH2CH3), 1.01 (m, 1H, CH2CH3), 1.17 (m, 1H, CH2CH3),
6870 | Org. Biomol. Chem., 2012, 10, 6866–6875
This journal is © The Royal Society of Chemistry 2012

View Article Online
1.51 (m, 1H, H-4), 1.61 (m, 1H, H-5), 1.99 (m, 1H, H-4), 2.28
(m, 1H, CH2CHv), 2.41–2.46 (m, 3H, H-3, CH2CHv), 3.06
(dm, J = 10.5 Hz, 1H, H-6), 3.96 (br s, 1H, OH), 4.16 (m, 1H,
H-2′), 4.24 (m, 1H, H-2′), 5.01 (d, J = 4.5 Hz, 1H, CHvCH2),
5.05 (m, 1H, CHvCH2), 5.41 (dd, J = 8.1, 5.1 Hz, 1H, H-1′),
5.57 (m, 1H, CHvCH2), 7.26–7.37 (m, 5H, H–Ar); 13C NMR
(100.6 MHz) δ 11.3 (CH2CH3), 22.2 (C-4), 24.3 (CH2CH3),
28.5 (C-3), 35.4 (C-5), 39.3 (CH2CHv), 59.1 (C-6), 62.7
(C-1′), 63.6 (C-2′), 117.7 (CHvCH2), 127.8 (CHAr),128.3
(2CHAr), 128.5 (2CHAr), 134.0 (CHvCH2), 136.9 (CAr),
172.4 (NCO); [α]D22 −19.6 (c 1.0, CHCl3); HRMS C18H26NO2
[M + H]+ 288.1958; found, 288.1958.
was continued for an additional 19 h at rt. The solvent was
removed, the residue was partitioned between H2O and CH2Cl2,
and the aqueous layer was extracted with CH2Cl2. The organic
extracts were washed with saturated NH4Cl solution, dried and
concentrated to give a residue, which was purified by column
chromatography (hexane–EtOAc 4 : 1) to yield 4 (994 mg, 69%)
1
as a yellow oil. IR (NaCl film) 2932, 1642 (s, NCO) cm−1; H
NMR (300 MHz, COSY, HSQC) δ 0.93 (t, J = 7.4 Hz, 3H
CH2CH3), 1.31–1.42 (m, 2H, –CH2CH3), 1.58–1.83 (m, 3H,
H-4 and H-5), 2.23 (m, 1H, H-1′), 2.36–2.49 (m, 3H, H-3 and
H-1′), 3.35 (m, 1H, H-1′′), 3.40 (m, 1H, H-6), 4.71 (dddd, J =
15.3, 4.2, 1.5, 1.5 Hz, 1H, H-1′′), 5.04–5.16 (m, 4H, H-3′,
H-3′′), 5.69–5.90 (m, 2H, H-2′, H-2′′); 13C NMR (100.6 MHz) δ
11.8 (CH2CH3), 22.6 (CH2CH3), 25.4 (C-4), 30.6 (C-3), 34.1
(C-1′), 40.6 (C-5), 49.0 (C-1′′), 58.7 (C-6), 116.9 (vCH2),
117.4 (vCH2), 133.2 (CHvCH2), 135.7 (CHvCH2), 170.0
(CON); [α]2D2 = –95.56 (c 1.0, MeOH); HRMS C13H22NO [M +
H]+ 208.1696; found, 208.1696. Anal. Calcd for C13H21NO·1/4
H2O: C, 73.72; H, 10.23; N, 6.61. Found: C, 73.96; H, 10.18; N,
6.18%. Note: Trace amounts of (5S,6S)-6-allyl-1-[(S)-2-(allyl-
oxy)-1-phenylethyl)]-5-ethylpiperidin-2-one were also isolated.
(5S,6S)-6-Allyl-5-ethyl-2-piperidone, (3). Into a three-necked,
round-bottomed flask equipped with a cold-finger condenser
charged with dry ice–acetone was condensed NH3 (ca. 150 mL)
at −78 °C. The temperature was allowed to rise to −33 °C and a
solution of alcohol 2 (1.00 g, 3.48 mmol) in THF (5 mL) was
added, followed by the addition of sodium metal in small por-
tions until the blue colour persisted. After the mixture was
stirred at −33 °C for 30 min, the reaction was carefully quenched
by the addition of solid NH4Cl until the blue colour disappeared.
The mixture was stirred at rt overnight, the residue was parti-
tioned between H2O and CH2Cl2, and the aqueous layer was
extracted with CH2Cl2. The combined organic extracts were
dried, filtered and concentrated. The resulting residue was chro-
matographed (SiO2, hexane–EtOAc 1 : 1 to 1 : 2) to give 3 as a
white solid (0.47 g, 81%) and 2 (0.07 g, 7%). IR (NaCl) 3208,
IR (NaCl) 2961, 1641 (s, NCO), 1452 cm−1 1H NMR
;
(400 MHz, CDCl3, HSQC, COSY) δ 0.88 (t, J = 7.4 Hz, 3H,
CH2CH3), 1.24–1.37 (m, 2H, CH2CH3), 1.60 (m, 1H, H-4),
1.73–1.87 (m, 2H, H-4, H-5), 1.96 (dddt, J = 14.6, 7.2, 4.5,
1.3 Hz, 1H, CH2CHv), 2.21 (m, 1H, CH2CHv), 2.45–2.54 (m,
2H, H-3), 3.46 (m, 1H, H-6), 4.01 (ddt, J = 7.0, 5.5, 1.4 Hz, 2H,
OCH2CHv), 4.08 (dd, J = 6.1, 1.6 Hz, 2H, H-2′), 4.83 (m, 1H,
1
2959, 1664 (s, NCO) cm−1; H NMR (300 MHz, COSY) δ 0.96
C6-CH2CHvCH2), 4.87 (app t,
J
=
1.4 Hz, 1H,
(t, J = 7.4, 3H, (CH2CH3), 1.52–1.24 (m, 2H, CH2CH3),
1.70–1.86 (m, 3H, H-4, H-5), 2.02–2.12 (m, 1H, CH2CHv),
2.21–2.40 (m, 3H, CH2CHv, H-3), 3.39–3.50 (m, 1H, H-6),
5.16 (d, J = 7.6, 1H, CHvCH2), 5.20 (d, J = 0.7, 1H,
CHvCH2), 5.65–5.82 (m, 1H, CHvCH2), 5.83 (br s, 1H, NH);
13C NMR (75.4 MHz) δ 11.6 (CH2CH3) 20.7 and 22.7 (C-4/
CH2CH3), 29.1 (C-3), 36.3 (CH2CHv), 37.3 (C-5), 54.8 (C-6),
C6CH2CHvCH2), 5.16 (m, app dq, J = 10.4, 1.3 Hz, 1H,
OCH2CHvCH2), 5.23–5.28 (m, 2H, H-1′, OCH2CHvCH2),
5.48 (m, 1H, CH2CHv), 5.89 (ddt, J = 17.2, 10.4, 5.5 Hz, 1H,
OCH2CHvCH2), 7.24–7.36 (m, 5H, H–Ar); 13C NMR
(100.6 MHz) δ 11.9 (CH2CH3), 22.2 (C-4), 25.7 (CH2CH3),
30.6 (C-3), 34.8 (CH2CHv), 41.3 (C-5), 58.8 (C-6), 60.1
(C-1′), 70.6 (C-2′), 71.9 (OCH2CHvCH2), 116.5 (CHvCH2),
116.8 (OCH2CHvCH2), 127.6 (CHAr), 128.4 (4CHAr), 134.6
(CH2CHv), 135.6 (C6CH2CHvCH2), 138.4 (CAr), 171.0
(NCO); HRMS C21H30NO2 [M + H]+ 328.2271; found,
328.2270.
119.1 (CHvCH2), 134.0 (CHvCH2), 172.0 (NCO); [α]D22
=
−66.32 (c 1.03, MeOH); HRMS C10H18NO [M + H]+ 168.1383;
found, 168.1382.
(5S,6S)-1,6-Diallyl-5-ethyl-2-piperidone, (4). Method A. A solu-
tion of 3 (656 mg, 3.93 mmol) in THF (20 mL) was added via
cannula to NaH (320 mg, 7.85 mmol, 60% dispersion in mineral
oil). After 15 min, the reaction mixture was cooled (0 °C) and
allyl bromide (380 μL, 4.32 mmol) was added with a syringe
pump over 60 min. Then, the mixture was warmed up at rt and
stirred for 24 h. The reaction mixture was cooled (0 °C),
quenched by the addition of water (10 mL), and extracted with
EtOAc. The combined organic extracts were dried and concen-
trated to give a residue, which was chromatographed (hexane–
EtOAc 4 : 1) to furnish 4 (613 mg, 75%) as a yellow oil.
Method B. In a round-bottomed flask equipped with a 1 gallon
gas bag of O2, an excess of freshly ground NaOH (2.78 g,
69.6 mmol) was added to a solution of 2 (2.00 g, 6.96 mmol) in
MTBE (20 mL). The mixture was heated at 40 °C and stirred
slowly at this temperature for 24 h. The progress of reaction was
monitored by TLC and, when 2 was consumed, the gas bag was
disconnected and the reaction mixture was cooled to rt. Allyl
bromide (0.75 mL, 8.70 mmol) was slowly added and stirring
(1S,9aS)-1-Ethyl-4-oxo-1,2,3,6,9,9a-hexahydro-4H-quinolizine,
(5). Ruthenium catalyst (Grubbs 2nd generation, 245 mg,
0.29 mmol) was added to a solution of 4 (2.40 g, 11.58 mmol)
in CH2Cl2 (300 mL) and the solution was stirred at rt for 8 h.
The mixture was concentrated and the resulting residue was
purified by column chromatography (Al2O3, hexane–EtOAc 3 : 1
to 3 : 2) to afford 5 (1.80 g, 87%), which was unstable. IR
(NaCl) 2960, 2932, 1662 (s, NCO), 1634 cm−1 1H NMR
;
(300 MHz, CDCl3, COSY, HSQC) δ 0.96 (t, 3H, J = 7.4 Hz,
–CH2CH3), 1.36 (m, 2H, –CH2CH3), 1.50–1.75 (m, 3H, 2 × H2
and H-1), 1.80–2.22 (m, 2H, H-9), 2.30–2.55 (m, 2H, H-3), 3.39
(app d, J = 18.0 Hz, 1H, H-6), 3.58 (td, J = 11.6, 4.5 Hz, 1H,
H-9a), 4.95 (app d, J = 18.0 Hz, 1H, H-6), 5.68 (m, 1H, H-7),
5.73 (m, 1H, H-8); 13C NMR (75.4 MHz, CDCl3) δ 11.8
(CH2CH3), 22.1 (C-2), 24.3 (CH2CH3), 26.3 (C-9), 32.3 (C-3),
38.3 (C-1), 43.1 (C-6), 55.9 (C-9a), 124.8 and 125.0 (C-7/C-8),
168.8 (NCO); [α]2D2 = –44.3 (c = 1.20, MeOH); HRMS
C11H18NO [M + H]+ 180.1383; found, 180.1379.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6866–6875 | 6871

View Article Online
(1S,9aS)-1-Ethyl-4-oxo-1,2,3,6,7,8,9,9a-octahydro-4H-quinoli-
zine, (6). 10% Pd/C (60 mg) was added to a solution of 5
(1.20 g, 6.69 mmol) in MeOH (20 mL) and the mixture was
stirred under hydrogen atmosphere for 18 h. Then, the crude
mixture was filtered through Celite® and the solvent was evapor-
ated to afford a residue, which was purified by bulb-to-bulb dis-
tillation (6 Torr, 160–170 °C) to obtain 6 (1.05 g, 87%) as a
colourless liquid. IR (NaCl) 2934, 2863, 1642 (s, NCO),
(1S,9aR)-1-Ethyl-4-oxo-1,2,3,6,7,8,9,9a-octahydro-4H-quinoli-
zine, (9a-epi-6). Following the procedure for the preparation of
6, from lactam 6-epi-5 (315 mg, 1.76 mmol), 10% Pd/C (32 mg)
and MeOH (9.0 mL), compound 9a-epi-6 (310 mg, 98%) was
obtained as a colourless liquid after bulb-to-bulb distillation (6
Torr, 160–170 °C). IR (NaCl) 2933, 1643 (s, NCO), 1463 cm−1
;
1H NMR (400 MHz, CDCl3, COSY, HSQC) δ 0.95 (t, 3H, J =
7.4 Hz, CH3CH2–), 1.14–1.47 (m, 6H, CH2CH3), H-1, H-2,
H-8, H-9), 1.55–1.68 (m, 2H, CH2CH3, H-9), 1.83–1.97 (m, 3H,
H-2, H-7, H-8), 2.23 (m, 1H, H-3), 2.35 (td, 1H, J = 12.8, 2.9
Hz, H-6), 2.44 (dt, 1H, J = 17.3, 4.4 Hz, H-3), 2.89 (ddd, 1H,
J = 11.3, 6.9, 2.4 Hz, H-9a), 4.81 (ddt, 1H, J = 12.8, 4.0,
2.9 Hz, H-6); 13C NMR (100.6 MH) δ 11.3 (CH2CH3), 23.5
(C-2*), 24.7 (C-8*), 25.3 (CH2CH3), 25.4 (C-9*), 31.4 (C-3),
33.0 (C-7), 41.4 (C-1), 42.9 (C-6), 61.9 (C-9a), 169.0 (NCO);
[α]2D2 = −27.5 (c 1.0, CHCl3); HRMS calcd for C11H20NO
[M + H]+ 182.1539; found, 182.1538. Anal. Calcd for
C11H19NO·1/4 H2O: C, 71.12; H, 10.58; N, 7.54. Found: C,
71.36; H, 10.49; N, 6.94%.
1
1466 cm−1; H NMR (400 MHz, CDCl3, COSY, HSQC) δ 0.87
(t, 3H, J = 7.4 Hz, CH2CH3), 1.16–1.64 (m, 9H, CH2CH3, H-2,
H-7, H-8, H-9), 1.78 (m, 1H, H-1), 1.87 (m, H7), 2.27 (m, 1H,
H-3), 2.30–2.41 (m, 2H, H-3, H-6), 3.24 (dd, 1H, J = 11.8, 5.1
Hz, H-9a), 4.65 (ddd, 1H, J = 12.8, 3.9, 1.9 Hz, H-6); 13C NMR
(100.6 MHz) δ 11.7 (CH2CH3), 22.9 (C-8), 24.1 (CH2CH3),
25.1 (C-7), 25.7 (C-2), 26.2 (C-9), 32.3 (C-3), 38.7 (C-1), 44.6
(C-6), 60.6 (C-9a), 168.6 (NCO); [α]2D2 = –49.1 (c 2.0, CHCl3);
MS-EI m/z 181 M+ (37), 125 (51), 97 (100), 83 (43), 55 (30);
HRMS C11H20NO [M + H]+, 182.1539; found, 182.1541. Anal.
Calcd for C11H19NO·1/3 H2O: C, 70.57; H, 10.58; N, 7.48.
Found: C, 70.23; H, 10.14; N, 7.32%.
General procedure for the addition of organometal reagents
(5S,6R)-1,6-Diallyl-5-ethyl-2-piperidone, (6-epi-4). Following
the procedure for the preparation of 4 (method B), from lactam
6-epi-2 (2.10 g, 7.27 mmol), NaOH (2.91 g, 72.7 mmol),
MTBE (25 mL), and allyl bromide (0.79 mL, 9.09 mmol), com-
pound 6-epi-4 (0.84 g, 56%) was obtained after column chrom-
atography (hexane–EtOAc 4 : 1). IR (NaCl) 2932, 1642 (s,
21
Anhydrous CeCl3 (2.0 equiv) was added to a solution of 6 (1
equiv) in anhydrous THF. The resulting suspension was vigor-
ously stirred at rt for 1 h. Grignard reagent was added dropwise
(4.0–8.0 equiv) over 30 min and the mixture was stirred for
additional 18 h. MeOH was added to quench the reaction and
the mixture was cooled at −78 °C. NaBH4 (1.25 equiv) and
AcOH (0.3 mL) were added and the mixture was stirred at
−78 °C for 30 min. The mixture was concentrated and the
residue was partitioned between Et2O and 1 N HCl solution.
Then, the acidic aqueous phase was washed with Et2O and
basified with 4 N NaOH solution (pH = 12–14). The resulting
suspension was centrifuged (800g for 30 min at rt) and the
supernatant was extracted with CH2Cl2.22 The combined organic
extracts were dried, filtered, concentrated and analysed by
GC-MS. The crude product was purified by flash chromato-
graphy (Al2O3).
1
NCO) cm−1; H NMR (400 MHz, COSY, HSQC) δ 0.91 (t, J =
7.4 Hz, 3H, CH2CH3), 1.32–1.43 (m, 2H, CH2CH3), 1.58 (m,
1H, H-4), 1.69 (m, 1H, H-5), 1.98 (m, 1H, H-4), 2.22–2.51 (m,
4H, 2 × H-3 and 2 × H-1′), 3.20 (dt, J = 9.3, 3.3 Hz, 1H, H-6),
3.37 (dd, J = 15.0, 7.7 Hz, 1H, H-1′′), 4.67 (ddt, J = 15.0, 4.7,
1.6 Hz, 1H, H-1′′), 5.07–5.21 (m, 4H, H-3′ and H-3′′),
5.62–5.82 (m, 2H, H-2′ and H-2′′); 13C NMR (100.6 MHz) δ
11.3 (CH2CH3), 20.3 (C-4), 24.1 (–CH2CH3), 27.9 (C-3), 35.4
(C-5), 37.3 (C-1′), 47.5 (C-1′′), 59.3 (C-6), 117.3 (C-3′ or C-3′′),
117.8 (C-3′ or C-3′′), 133.2 (C-2′′ or C-2′), 135.9 (C-2′′ or C-2′),
169.6 (CON); [α]2D2 = +44.1 (c 1.0, CHCl3); HRMS calcd for
C13H22NO [M + H]+, 208.1696; found, 208.1695. Anal. Calcd
for C13H21NO·1/5 H2O: C, 74.07; H, 10.23; N, 6.64. Found: C,
74.07; H, 10.40; N, 6.42%.
(1S,4R,9aS)-4-Allyl-1-ethylquinolizidine, (4-epi-207I), (1S,4S,-
9aS)-4-allyl-1-ethylquinolizidine, (−)-207I and (1S,9aS)-4,4-
diallyl-1-ethylquinolizidine. Following the general procedure,
from lactam 6 (300 mg, 1.66 mmol), CeCl3 (1.63 g, 6.62 mmol),
allylmagnesium bromide (7.0 mL, 7.0 mmol, 1.0 M solution in
Et2O), THF (7 mL), and NaBH4 (78 mg, 2.7 mmol), a 97 : 3 dia-
stereomeric mixture of 4-epi-207I and (−)-207I (GC-MS) was
obtained. Traces of diallylated quinolizidine were also detected.
4-epi-207I (198 mg, 58%) was obtained after column chromato-
graphy (Al2O3, hexanes–EtOAc 95 : 5 to 85 : 15). 4-epi-207I. IR
(NaCl) 2957, 2928, 2856, 1456, 908 cm−1; 1H NMR (400 MHz,
CDCl3, COSY, HSQC) δ 0.87 (t, 3H, J = 7.4 Hz, CH3),
1.13–1.74 (m, 12H, CH2CH3, H-1, H-2, H-3, H-7, H-8, H-9),
1.88 (m, app dd, 1H, J = 12.7, 2.5 Hz, H-7), 2.14 (m, 1H,
CH2CHv), 2.37 (m, 1H, CH2CHv), 2.71 (td, 1H, J = 13.6, 2.5
Hz, H-6ax.), 2.93 (m, 1H, H-9a), 3.00 (m, 1H, H-4), 3.34 (app d
1H, J = 13.6 Hz, H-6eq.), 4.98–5.10 (m, 2H, –CHvCH2), 5.83
(dddd, J = 16.8, 10.2, 7.7, 6.6 Hz, 1H, CHvCH2); 13C NMR
(75.4 MHz) δ 11.8 (CH3), 18.0 (CH2), 19.3 (CH2), 25.2 (CH2),
25.7 (C-7), 29.7 (CH2), 31.3 (CH2), 36.9 (CH2CHv), 41.9
(1S,9aR)-1-Ethyl-4-oxo-1,2,3,6,9,9a-hexahydro-4H-quinolizine,
(9a-epi-5). Following the procedure for the preparation of 5,
from lactam 6-epi-4 (0.62 g, 2.99 mmol) and 2nd generation
Grubbs catalyst (76 mg, 0.09 mmol, 0.03 equiv) in CH2Cl2
(100 mL), compound 9a-epi-5 (0.48 g, 90%) was obtained after
column chromatography (Al2O3, hexane–EtOAc 1 : 1 to 0 : 1).
9a-epi-5 was unstable. 1H NMR (400 MHz, CDCl3, COSY,
HSQC) δ 0.96 (t, 3H, J = 7.3 Hz, CH2CH3), 1.36 (m, 1H,
CH2CH3), 1.45–1.55 (m, 2H, H-1, H-2), 1.60 (m, 1H, CH2CH3),
1.92 (m, 1H, H-2), 2.11 (m, 1H, H-9), 2.26 (m, 1H, H-9), 2.32
(m, 1H, H-3), 2.45 (m, 1H, H-3), 3.21 (ddd, J = 9.9, 5.8, 3.8 Hz,
1H, H-9a), 3.40 (app d, J = 18.5 Hz, 1H, H-6), 4.83 (app d, J =
18.5 Hz, 1H, H-6), 5.68 (m, 1H, H-7), 5.77 (m, 1H, H-8); 13C
NMR (100.6 MHz, CDCl3) δ 11.3 (CH2CH3), 22.9 (C-2), 25.1
(CH2CH3), 30.7 (C-3), 32.5 (C-9), 40.4 (C-1), 42.5 (C-6), 57.7
(C-9a), 124.1 and 124.3 (C-7/C-8), 169.5 (NCO); HRMS calcd
for C11H18NO [M + H]+, 180.1383; found, 180.1380.
6872 | Org. Biomol. Chem., 2012, 10, 6866–6875
This journal is © The Royal Society of Chemistry 2012

View Article Online
(C-1), 50.1 (C-6), 50.9 (C-4), 61.1 (C-9a), 116.5 (CHvCH2),
135.7 (CHvCH2); [α]D22 = +14.4 (c 0.5, CH2Cl2); MS-EI m/z
206 (1), 167 (14), 166 (100), 110 (12), 55 (3); HRMS calcd for
C14H26N [M + H]+ 208.2060; found, 208.2061. (−)-207I. 13C
NMR spectra of (−)-207I (from a mixture of 4-epi-207I and
(−)-207I) was coincident with that described previously in the
literature;6 MS-EI m/z 206 M+ (1), 167 (12), 166 (100), 136 (4),
110 (8), 55 (3).
2.88 (m, 1H, H-4), 2.93 (app d, 1H, J = 14.1, H-9a), 3.30 (app
d, 1H, J = 13.5, H-6eq.); 13C NMR (100.6 MHz) δ 11.8
(CH2CH3), 14.7 (CH2CH2CH3), 18.5 (CH2), 18.5 (CH2), 19.3
(CH2), 25.3 (CH2), 25.8 (C-7), 25.9 (CH2), 29.7 (CH2), 31.3
(CH2), 34.6 (CH2), 42.0 (C-1), 50.0 (C-6), 50.8 (C-4), 61.1
(C-9a); MS-EI m/z 209 M+ (2), 167 (13), 166 (100), 110 (7), 84
(4); [α]2D2 = +22.2 (c 1.0, CHCl3); HRMS calcd for C14H27N
[M + H]+ 210.2216; found, 210.2218. 4-epi-8. MS-EI m/z
209 (2), 167 (21), 166 (100), 138 (6), 110 (12), 84 (5), 55 (6).
(1S,9aS)-4,4-Diallyl-1-ethylquinolizidine. 1H NMR (300 MHz,
CDCl3, COSY) δ 0.89 (t, 3H, J = 7.4 Hz, CH2CH3), 1.12–1.94
(m, 13H, CH2CH3, H-1, H-2, H-3, H-7, H-8, H-9), 2.24 (app d,
4H, J = 7.4 Hz, CH2CHv), 2.54 (m, 1H, H-9a), 2.61 (app t,
1H, J = 11.4 Hz, H-6ax.), 3.12 (app d, 1H, J = 11.4 Hz, H-6eq.),
5.03–5.19 (m, 4H, CH2CHvCH2), 5.86 (m, 2H,
CH2CHvCH2); 13C NMR (75.4 MHz) δ 12.0 (CH2CH3), 22.7
(CH2), 25.1 (CH2), 26.5 (CH2), 28.7 (CH2), 36.9 (CH2), 43.6 (2
× CH2CHv), 44.1 (CH2), 45.5 (C-1), 47.5 (C-6), 59.1 (C-9a),
73.5 (C-4), 118.3 (2 × CHvCH2), 134.0 (2 × CHvCH2);
MS-EI m/z 224 (34), 110 (3), 85 (6), 84 (100), 69 (5), 56 (6), 55
(6); HRMS calcd for C14H32NO [M + H2O]+ 266.2478; found,
266.2478.
(1S,4S,9aS)-1-Ethyl-4-methylquinolizidine, (9). Following the
general procedure, from lactam 6 (90 mg, 0.50 mmol), CeCl3
(250 mg, 1.0 mmol), methylmagnesium bromide (0.7 mL,
2.0 mmol, 3.0 M solution in Et2O), THF (2.5 mL) and NaBH4
(25 mg, 0.63 mmol), only one diastereomer (9) was detected by
GC-MS. Pure 9 (62 mg, 69%) was obtained after filtration
thought a pad of Al2O3 (hexane–EtOAc 95 : 5). IR (NaCl) 2958,
2935, 2877, 1665, 1463 cm−1 1H NMR (400 MHz, CDCl3,
;
COSY, HSQC) δ 0.82 (t, J = 7.4 Hz, 3H, CH2CH3), 1.02 (d, J =
6.2 Hz, 3H, CH3C4), 1.07–1.31 (m, 6H, CH3CH2, H-3, H-8,
H-9), 1.36–1.66 (m, 6H, H-1, H-2, H-7, H-8, H-9), 1.83 (app d,
J = 12.7 Hz, 1H, H-7), 2.67 (td, J = 13.7, 2.7 Hz, 1H, H-6ax.),
2.92 (app d, J = 12.6 Hz, 1H, H-9a), 2.98 (m, 1H, H-4), 3.27
(app d, J = 13.7 Hz, 1H, H-6eq.); 13C NMR (100.6 MHz,
CDCl3) δ 11.7 (CH2CH3), 17.8 (CH2), 18.8 (CH2), 19.3
(CH3C4), 25.2 (CH2), 25.4 (CH2), 25.8 (CH2), 34.8 (CH2), 41.8
(C-1), 46.7 (C-4), 50.1 (C-6), 60.8 (C-9a); MS-EI m/z 181 M+
(10), 167 (13), 166 (100), 152 (13), 110 (11), 83 (17); [α]2D2 = –
23.8 (c 1.0, CHCl3); HRMS calcd for C12H24N [M + H]+
182.1903; found, 182.1907.
(1S,4R,9aS)-1-Ethyl-4-(2-methylallyl)quinolizidine, (7). Fol-
lowing the general procedure, from lactam
6 (50 mg,
0.28 mmol), CeCl3 (140 mg, 0.55 mmol), 2-methylallylmagne-
sium chloride (3 mL, 2.20 mmol, 0.7 M solution in THF), THF
(1.5 mL), and NaBH4 (14 mg, 0.35 mmol), a 96 : 4 diastereo-
meric mixture of 7 and 4-epi-7 (GC-MS) was obtained. Pure 7
(34 mg, 56%) was obtained after column chromatography
(Al2O3, hexane–EtOAc 90 : 10 to 75 : 25). 7. IR (NaCl) 2956,
2926, 2855, 1734, 1460, 1377 cm−1
;
1H NMR (400 MHz,
(1S,4R,9aR)-4-Allyl-1-ethylquinolizidine, (10) and (1S,4S,9aR)-
4-allyl-1-ethylquinolizidine, (9a-epi-207I). Following the general
procedure, from lactam 9a-epi-6 (124 mg, 0.6840 mmol), CeCl3
(340 mg, 1.37 mmol), allylmagnesium bromide (2.75 mL,
2.75 mmol, 1.0 M solution in Et2O), THF (3.0 mL) and NaBH4
(33 mg, 0.86 mmol), a 1 : 1 diastereomeric mixture of 10 and
9a-epi-207I (GC-MS) was obtained (75 mg, 54%). Compound
9a-epi-207I was isolated by column chromatography (Al2O3,
hexane–EtOAc 95 : 5). 10:5 MS-EI m/z 206 (1), 167 (42), 166
(100), 110 (54), 84 (20), 67 (23), 55 (42), 54 (20). 9a-epi-207I.
CDCl3, COSY, HSQC) δ 0.87 (t, 3H, J = 7.4 Hz, CH2CH3),
1.10–1.70 (m, 12H, CH2CH3, H-1, H-2, H-3, H-7, H-8, H-9),
1.73 (s, 3H, CCH3), 1.81–1.90 (m, 2H, H-7, CH2C), 2.52 (dd,
1H, J = 13.0, 3.7 Hz, CH2C), 2.69 (td, 1H, J = 13.6, 2.6 Hz,
H-6ax.), 2.94 (app d, 1H, J = 12.7 Hz, H-9a), 3.03 (m, 1H, H-4),
3.32 (app d, J = 13.6 Hz, H-6eq.), 4.71 (br s, 1H,vCH2), 4.77
(br s, 1H,vCH2); 13C NMR (100.6 MHz) δ 11.9 (CH2CH3),
19.7 (CH2), 22.7 (CCH3), 24.8 (CH2), 25.4 (CH2), 25.6 (C-7),
29.7 (CH2), 30.3 (CH2), 40.7 (CH2C), 41.8 (C-1), 49.7 (C-4),
50.3 (C-6), 61.1 (C-9a), 112.5 (vCH2), 143.7 (CH2C); MS-EI
m/z 220 (1), 167 (13), 166 (100), 110 (10), 55 (3); HRMS calcd
for C15H27N [M + H]+, 222.2216; found, 222.2219. 4-epi-7:
MS-EI m/z 221 (13), 220 (12), 206 (10), 192 (18), 167 (12), 166
(100), 164 (16), 136 (11), 110 (14), 84 (35), 83 (11), 82 (15),
67 (10), 55 (10).
IR (neat) 2958, 2928, 2856, 1450, 1119 cm−1 1H NMR
;
(400 MHz, CDCl3, TMS, NOE, COSY, HSQC) δ = 0.86 (t, 3H,
J = 7.3 Hz, CH2), 1.13–1.74 (m, 13H, CH2CH3, H-1, H-2, H-3,
H-7, H-8, H-9), 2.04 (td, 1H, J = 9.6, 3.0 Hz, 1H, H-9a), 2.17
(m, 1H, CH2CHv), 2.42 (m, 1H, CH2CHv), 2.50 (td, 1H, J =
11.3, 3.7 Hz, H-6ax.), 2.66 (m, app dt, 1H, J = 11.3, 4.4 Hz,
H-6eq.), 2.81 (m, 1H, H-4), 4.97–5.06 (m, 2H, CHvCH2), 5.71
(dddd, J = 17.0, 10.1, 8.4, 6.1 Hz, 1H, CH2CHv); 13C NMR
(100.6 MHz) δ 10.8 (CH2CH3), 23.4 (CH2), 24.9 (CH2), 25.0
(CH2), 26.1 (C-7), 27.3 (CH2), 27.4 (CH2CHv), 31.1 (CH2),
43.2 (C-1), 52.9 (C-6), 58.4 (C-4), 59.8 (C-9a), 115.8 (vCH2),
137.5 (–CH2CHv); [α]2D2 = +57.5 (c 0.75, CHCl3); MS-EI m/z
206 M (1), 167 (27), 166 (100), 110 (55), 84 (17), 67 (21), 55
(37), 54 (20). HRMS calcd for C14H26N [M + H]+, 208.2060;
found, 208.2058.
(1S,4S,9aS)-1-Ethyl-4-propylquinolizidine, (8). Following the
general procedure, from lactam 6 (90 mg, 0.50 mmol), CeCl3
(250 mg, 1.0 mmol), propylmagnesium bromide (1.0 mL,
2.0 mmol, 2.0 M solution in Et2O), THF (2.5 mL) and NaBH4
(25 mg, 0.63 mmol), a 99 : 1 diastereomeric mixture of 8 and
4-epi-8 (GC-MS) was obtained. Pure amine 8 (67 mg, 64%) was
isolated after column chromatography (Al2O3, hexane–EtOAc
95 : 5 to 80 : 20). 8. IR (NaCl) 2958, 2928, 2858, 1461,
1276 cm−1; 1H NMR: (400 MHz, CDCl3, COSY, HSQC) δ 0.86
(t, 3H, J = 7.4 Hz, CH3CH2), 0.91 (t, 3H, J = 7.1 Hz,
CH3CH2CH2C4), 1.10–1.30 (m, 10H), 1.36–1.75 (m, 6H), 1.87
(app d, 1H, J = 14.6, H-7), 2.66 (td, 1H, J = 13.5, 2.7, H-6ax.),
(1S,4S,9aR)-1-Ethyl-4-methylquinolizidine, (11) and (1S,4R,9aR)-
1-ethyl-4-methylquinolizidine, (4-epi-11). Following the general
procedure, from lactam 9a-epi-6 (90 mg, 0.50 mmol), CeCl3
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6866–6875 | 6873

View Article Online
5 (a) N. Toyooka, K. Tanaka, T. Momose, J. W. Daly and H. M. Garraffo,
Tetrahedron, 1997, 53, 9553–9574; (b) For the racemic synthesis of
alkaloid 207I, see: P. Michel and A. Rassat, Chem. Commun., 1999,
2281–2282; (c) For a very recent racemic synthesis of alkaloid 207I and
1-epi-207I, see: C. Tsukano, A. Oimura, I. Enkhtaivan and Y. Takemoto,
Org. Lett., 2012, 14, 1902–1905.
6 N. Toyooka and H. Nemoto, Tetrahedron Lett., 2003, 44, 569–570.
7 N. Toyooka, S. Kobayashi, D. Zhou, H. Tsuneki, T. Wada, H. Sakai,
H. Nemoto, T. Sasaoka, H. M. Garraffo, T. F. Spande and J. W. Daly,
Bioorg. Med. Chem. Lett., 2007, 17, 5872–5875.
8 H. Tsuneki, Y. You, N. Toyooka, S. Kagawa, S. Kobayashi, T. Sasaoka,
H. Nemoto, I. Kimura and J. A. Dani, Mol. Pharmacol., 2004, 66, 1061–
1069.
9 (a) T. C. Coombs, M. D. Lee, IV, H. Wong, M. Armstrong, B. Cheng,
W. Chen, A. F. Moretto and L. S. Liebeskind, J. Org. Chem., 2008, 73,
882–888; (b) H. Wong, E. C. Garnier-Amblard and L. S. Liebeskind,
J. Am. Chem. Soc., 2011, 133, 7517–7527.
(250 mg, 1.0 mmol), methylmagnesium bromide (0.70 mL,
2.0 mmol, 3.0 M solution in Et2O), THF (3.0 mL) and NaBH4
(25 mg, 0.63 mmol), a 1 : 1 diastereomeric mixture of 11 and
4-epi-11 (GC-MS) was obtained (46 mg, 48%). The amines
proved to be unstable under chromatography conditions. 11*.
MS-EI: m/z 181 M+ (34), 180 (29), 166 (100), 152 (46),
138 (35), 124 (47), 110 (48), 96 (49), 83 (90), 67 (30), 55 (74).
C4-epi-11*. MS-EI m/z 181 M+ (29), 180 (30), 166 (100),
152 (47), 138 (37), 124 (46), 110 (42), 96 (50), 83 (88), 67 (32),
55 (78). Dimethylated product was detected in the GC-MS
MS-EI m/z 195 M (17), 181 (16), 180 (100), 124 (20), 110 (20),
84 (43), 83 (43), 82 (21), 56 (23), 55 (37).
10 M. Amat, C. Escolano, A. Gómez-Esqué, O. Lozano, N. Llor, R. Griera,
E. Molins and J. Bosch, Tetrahedron: Asymmetry, 2006, 17, 1581–1588.
11 M. Amat, N. Llor, J. Hidalgo and J. Bosch, Tetrahedron: Asymmetry,
1997, 8, 2237–2240.
12 V. Semak, C. Escolano, C. Arróniz, J. Bosch and M. Amat, Tetrahedron:
Asymmetry, 2010, 21, 2542–2549.
Theoretical calculations
Initial geometries were obtained using the PCMODEL
program.23 Further geometry optimizations were carried out
using the Gaussian 03 suite of programs on an Compaq HPC320
computer,24 at the Hartree–Fock (HF) level,25 and at the Becke’s
three-parameter hybrid functional with the Lee, Yang and Parr
correlation functional (B3LYP) level,26 using the 6-31G(d) basis
set.27 Analytical energy second derivatives were calculated at all
optimized structures to confirm that these were minima.
13 For some representative examples in the formation of the second ring of
the quinolizidine skeleton by RCM, see: (a) N. Diedrichs and
B. Westermann, Synlett, 1999, 1127–1129; (b) C. A. Tarling,
A. B. Holmes, R. E. Markwell and N. D. Pearson, J. Chem. Soc., Perkin
Trans. 1, 1999, 1695–1701; (c) S. S. Kinderman, R. Gelder, J. H. Van
Maarseveen, H. E. Schoemaker, H. Hiemstra and F. P. J. T. Rutjes, J. Am.
Chem. Soc., 2004, 126, 4100–4101; (d) M. Katoh, H. Mizutani and
T. Honda, Tetrahedron Lett., 2005, 46, 5161–5163; (e) T. L. Suyama and
W. H. Gerwick, Org. Lett., 2006, 8, 4541–4543; (f) G. Cheng, X. Wang,
D. Su, H. Liu, F. Liu and Y. Hu, J. Org. Chem., 2010, 75, 1911–1916;
(g) For a review on the RCM as key reaction to access to piperidine alka-
loids, see: F.-X. Felpin and J. Lebreton, Eur. J. Org. Chem., 2003, 68,
3693–3712.
14 For some representative examples in the addition of organometal reagents
to the 2-quinolizidinone nucleus, see: (a) D. L. Comins, X. Zheng and
R. R. Goehring, Org. Lett., 2002, 4, 1611–1613; (b) V. Gracias, Y. Zeng,
P. Desai and J. Aube, Org. Lett., 2003, 5, 4999–5001; (c) B. B. Snider
and J. G. Grabowski, J. Org. Chem., 2007, 72, 1039–1042; (d) See ref.
13f (e) S.-S. P. Chou, Y.-Ch. Chung, P.-A. Chen, S.-L. Chiang and
Ch.-J. Wu, J. Org. Chem., 2011, 76, 692–695.
Acknowledgements
Financial support from the Ministerio de Ciencia e Innovación
(MICINN), Spain (Projects CTQ2009-12520-C03-03 and
CTQ2009-07021/BQU), and the Agència de Gestió d’Ajuts Uni-
versitaris i de Recerca (AGAUR), Generalitat de Catalunya
(Grants 2009SGR-203 and 2009-SGR-1111) is gratefully
acknowledged. Thanks are also due to the MICINN (Spain) for a
fellowship to V. S. We are indebted to Dr Pilar Franco for her
helpful discussions and experimental efforts to separate (−)-207I
and 4-epi-207I by HPLC chromatography. We are deeply grate-
ful to Dr Santiago Vázquez for his invaluable advice and help in
carrying out molecular calculations.
15 A single report on the addition of allyl Grignard derivatives to
an N-methyl protected δ-valerolactam, furnishing 2,2-disubstituted
piperidine and 2-substituted piperidine derivatives, was found:
R. Lukeš and M. Černý, Collect. Czech. Chem. Commun., 1959, 24,
3596–3600.
16 Noteworthy, larger excess of the Grignard reagent led to considerable
amounts of the diallylated derivative.
17 All ratios were determined by GC-MS chromatography.
18 T. A. Crabb, R. F. Newton and D. Jackson, Chem. Rev., 1971, 71, 109–
126. For comments on mass spectrometry and IR Bohlmann bands of
new compounds, see ESI†
19 For comments on NOE experiments of compound 9-epi-207I, see ESI.†
20 (a) P. Deslongchamps, Stereoelectronic Effects in Organic Chemistry, Per-
gamon Press, Oxford, UK, 1983, pp. 101–162, Ch. 4; (b) R. V. Stevens,
Acc. Chem. Res., 1984, 17, 289–296 and references therein.
21 (a) V. Dimitrov, K. Kostova and M. Genov, Tetrahedron Lett., 1996, 37,
6787–6790; (b) D. A. Conlon, D. Kumke, Ch. Moeder, M. Hardiman,
G. Hutson and L. Sailer, Adv. Synth. Catal., 2004, 346, 1307–1315.
22 Purification protocol inspired by: (a) W. Wysocka and A. K. Przybyl,
Sci. Legum., 1994, 1, 37–50; (b) T. Aniszewski, Alkaloids Secrets of Life,
Elsevier, Amsterdam, 2007, pp 235.
23 PCMODEL, Version 8.00.1 for Windows, Serena Software.
24 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, Jr., J. A. Montgomery, T. Vreven, K. N. Kudin,
J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone,
B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson,
H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa,
M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li,
J. E. Knox, H. P. Hratchian, J. B. Cross, C. Adamo, J. Jaramillo,
R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi,
C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth,
P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich,
Notes and references
1 (a) J. W. Daly and T. F. Spande, in Alkaloids: Chemical and Biological
Perspectives, ed. S. W. Pelletier, Wiley, New York, 1986, vol. 4, pp.
1–274; (b) J. W. Daly, H. M. Garraffo and R. F. Spande. in The Alkaloids,
ed. G. A. Cordell, Academic Press, San Diego, 1993, vol. 43, pp.
185–288; (c) J. Daly, in The Alkaloids, ed. G. A. Cordell, Academic
Press, New York, 1997, vol. 50. For a review on the indolizidine and qui-
nolizidine alkaloids, see: (d) J. P. Michael, Nat. Prod. Rep., 2008, 25,
139–165, and other reviews in these series.
2 1,4-Disubstituted quinolizidines occur in the dendrobatid frogs of the
genera Dendrobates, Minyobates, and Epipedobates (ref. 1b), in Martel-
line frogs of genus Mantella: H. M. Garrafo, J. Caceres, J. W. Daly,
T. F. Spande, N. R. Andriamahavaravo and M. Andriantsiferana, J. Nat.
Prod., 1993, 56, 1016–1038, and in bufonid toads of the genus Melano-
phryniscus: H. M. Garraffo, T. F. Spande, J. W. Daly, F. Baldessari and
E. G. Gros, J. Nat. Prod., 1993, 56, 357–373. For the racemic synthesis
of 1,4-disubstituted quinolizidines found in poison frog skins, see:
P. Michel, A. Rassat, J. W. Daly and T. F. Spande, J. Org. Chem., 2000,
65, 8908–8918.
3 H. M. Garraffo, L. D. Simon, J. W. Daly, T. F. Spande and T. H. Jones,
Tetrahedron, 1994, 50, 11329–11338.
4 J. W. Daly, T. F. Spande and H. M. Garraffo, J. Nat. Prod., 2005, 68,
1556–1575.
6874 | Org. Biomol. Chem., 2012, 10, 6866–6875
This journal is © The Royal Society of Chemistry 2012

View Article Online
A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck,
K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul,
S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko,
P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-
Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill,
B. Johnson, W. Chen, M. W. Wong, C. Gonzalez and J. A. Pople,
Theoretical calculations were carried out using GAUSSIAN 03, (Revision
B.01), Gaussian, Inc., Pittsburgh PA, 2003.
25 P. Echenique and J. L. Alonso, Mol. Phys., 2007, 105, 3057–3098.
26 (a) A. D. Becke, J. Chem. Phys., 1993, 98, 5648–5652; (b) C. Lee,
W. Yang and R. G. Parr, Phys. Rev. B, 1988, 37, 785–789.
27 P. A. Hariharan and J. A. Pople, Theor. Chim. Acta, 1973, 28, 213–222.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6866–6875 | 6875